PMID- 21233529 TI - Simultaneous identification of duplications and lateral gene transfers. AB - The incongruency between a gene tree and a corresponding species tree can be attributed to evolutionary events such as gene duplication and gene loss. This paper describes a combinatorial model where so-called DTL-scenarios are used to explain the differences between a gene tree and a corresponding species tree taking into account gene duplications, gene losses, and lateral gene transfers (also known as horizontal gene transfers). The reasonable biological constraint that a lateral gene transfer may only occur between contemporary species leads to the notion of acyclic DTL-scenarios. Parsimony methods are introduced by defining appropriate optimization problems. We show that finding most parsimonious acyclic DTL-scenarios is NP-hard. However, by dropping the condition of acyclicity, the problem becomes tractable, and we provide a dynamic programming algorithm as well as a fixed-parameter tractable algorithm for finding most parsimonious DTL scenarios. PMID- 21233530 TI - Visual exploration across biomedical databases. AB - Though biomedical research often draws on knowledge from a wide variety of fields, few visualization methods for biomedical data incorporate meaningful cross-database exploration. A new approach is offered for visualizing and exploring a query-based subset of multiple heterogeneous biomedical databases. Databases are modeled as an entity-relation graph containing nodes (database records) and links (relationships between records). Users specify a keyword search string to retrieve an initial set of nodes, and then explore intra- and interdatabase links. Results are visualized with user-defined semantic substrates to take advantage of the rich set of attributes usually present in biomedical data. Comments from domain experts indicate that this visualization method is potentially advantageous for biomedical knowledge exploration. PMID- 21233531 TI - Graph comparison by log-odds score matrices with application to protein topology analysis. AB - A TOPS diagram is a simplified description of the topology of a protein using a graph where nodes are alpha-helices and beta-strands, and edges correspond to chirality relations and parallel or antiparallel bonds between strands. We present a matching algorithm between two TOPS diagrams where the likelihood of a match is measured according to previously known matches between complete 3D structures. This totally new 3D training is recorded on transition matrices that count the likelihood that a given TOPS feature, or combination thereof, is replaced by another feature on homologs. The new algorithm outperforms existing ones on a benchmark database. Some biologically significant examples are discussed as well. The method can be used whenever frequencies of edge relationship matches are known, as it is the case for several biopolymer structures. PMID- 21233532 TI - Important advances in the field of anti-dengue virus research. AB - There are currently no licensed antivirals available for the treatment of dengue virus (DENV), which causes significant morbidity and mortality throughout tropical areas of the world and is now encroaching on the southern United States. Recent improvements in existing animal models and cell culture systems have been very important in elucidating the mechanisms of DENV pathogenesis in humans, including the identification of potential viral and host proteins that might be targeted for the treatment of DENV infection. The AG129 mouse model is a major advance in the development of antiviral and vaccine candidates for clinical use. It allows for testing of potential therapeutics in a relevant system that exhibits some aspects of disease that are similar to those observed in humans. This review focuses on recent developments in the AG129 mouse model and discusses compounds that have been found to be active in available cell and animal model systems within the past year. PMID- 21233533 TI - Therapeutic targeting of HCV internal ribosomal entry site RNA. AB - HCV infection is a significant human disease, leading to liver cirrhosis and cancer, and killing >10,000 people in the US annually. Translation of the viral RNA genome is initiated by ribosomal binding to a highly structured RNA element, the internal ribosomal entry site (IRES), which presents a novel target for therapeutic intervention. We will first discuss studies of oligonucleotide therapeutics targeting various regions of the 340-nucleotide IRES, many of which have effectively blocked IRES function in vitro and are active against virus replication in cell culture. Although low nanomolar potencies have been obtained for DNA- and RNA-based molecules, stability and drug delivery challenges remain to be addressed for these particular HCV compounds. Several classes of small molecule inhibitors have been identified from screening protocols or designed from established RNA therapeutic scaffolds. In particular, small molecule IRES inhibitors based on a benzimidazole scaffold bind specifically to the IRES, and inhibit viral replication in cell culture at micromolar concentrations with low toxicity. The structure of the RNA target in complex with a representative member of these small molecule inhibitors demonstrates that a large RNA conformational change occurs upon inhibitor binding. The RNA complex shows how the inhibitor alters the global RNA structure and provides a framework for structure-based drug design of novel HCV therapeutics. PMID- 21233534 TI - Phenylboronic-acid-based carbohydrate binders as antiviral therapeutics: bisphenylboronic acids. AB - BACKGROUND: carbohydrate-binding agents are considered as potential therapeutic agents for the inhibition of highly glycosylated enveloped viruses such as HIV type-1. Phenylboronic acids are well-known to bind the cis-diol functionality of carbohydrate structures, thereby identifying themselves as potential lead structures. METHODS: bisphenylboronic acids connected via a functionalized linker at variable length (1-13 atoms) bearing the binding boronic acid functionality at the three possible ring geometries relative to the linker have been investigated as probes for selective and non-selective saccharide sensors. Herein, we describe the compilation of a 'linker-diverse' compound library of bisphenylboronic acids and the determination of the structure-activity relationship versus a variety of enveloped viruses. Molecular modelling of the gp120 glycans of simian immunodeficiency virus was undertaken to ascertain a theoretical minimum length of the linker unit. RESULTS: the compounds demonstrated no pronounced antiviral activity. The general low toxicity of the boronic acids became evident in this study, thereby justifying further studies. CONCLUSIONS: a higher concentration of phenylboronate functional groups per molecule, resulting in multivalency, might be necessary to bind with sufficient potency to HIV type-1 gp120 and to elicit an antiviral action. PMID- 21233535 TI - Synthesis and an antiviral activity evaluation of nucleoside 5'-O-(N-acyl) phosphoramidates. AB - BACKGROUND: pyrimidine nucleoside analogues represent an established class of clinically useful antiviral agents. Once inside the cell, they are activated by a series of intracellular phosphorylation steps to produce 5'-triphosphate derivatives. In many cases, nucleoside analogues are poor substrates for the cellular kinases needed for their activation. It is clear that intracellular introduction of nucleoside analogues as phosphorylated metabolites (so called pronucleotides) could circumvent difficulties associated with the use of non phosphorylated nucleoside analogues. METHODS: among the current diverse pronucleotide approaches, nucleoside phosphoramidate derivatives appear to be an interesting class of potential antiviral agents because of the known relatively low stability of the P-N bond in cellular media. On the basis of oxathiaphospholane chemistry, a series of novel conjugates of 5'-O-phosphorylated zidovudine (AZT) and stavudine (d4T) with amino acids carboxamidates were obtained. The synthesis was performed using N-(2-thiono-1,3,2-oxathiaphospholane) derivatives of amino acids carboxamides as precursors. RESULTS: all synthesized compounds were studied against DNA and RNA viruses. Specific antiviral activities were only detected against HIV type-1 and HIV type-2 in MT-4 cell cultures at compound concentrations that were equally active or slightly inferior to the activity of their parent drugs (2- to 20-fold for the AZT prodrugs and 6- to 40 fold for the d4T prodrugs). The compounds were also evaluated for their anti-HIV activity in CEM and in CEM thymidine-kinase-deficient (CEM/TK(-)) cell cultures. CONCLUSIONS: loss of compound antiviral potency in the CEM/TK(-) cells suggested an eventual conversion of the test compounds to the free nucleosides prior to further phosphorylation to the active 5'-triphosphate metabolite. PMID- 21233536 TI - High-resolution electron microscopy study of mesoporous dichalcogenides and their hydrogen storage properties. AB - In this work, we report a detailed investigation on the surface topology of ordered mesoporous WS(2) nanoarrays nanocast from the silica SBA-15 template. Using a high-resolution scanning electron microscopy (HRSEM) technique, we acquire distinguishably clear images of the WS(2) surface. A large number of small nanorods are found to be evenly distributed among the nanowire arrays, supporting their ordered mesostructures. Based on these observations, tunnel-like connecting pores are proposed to have a similar distribution in the mother mesoporous silica SBA-15 template. Interestingly, we observe the atomic crystal lattices of the layered WS(2) on the HRSEM image. To the best of our knowledge, this is the first time that atomic crystal lattices have been directly observed using a SEM technique. In addition, both materials show good adsorption desorption capabilities with hydrogen, and the maximum amount of hydrogen that can be taken up is 0.34 wt% for mesoporous WS(2) and 0.52 wt% for mesoporous MoS(2) at a pressure of 10 bar, indicating that both are potential hydrogen storage materials. PMID- 21233537 TI - The synthesis of newly modified CdTe quantum dots and their application for improvement of latent fingerprint detection. AB - Motivated by the urgent demand for the detection of latent fingerprints using fluorescence-based nanotechnology, this work was devoted to developing a simple synthetic approach to obtain positively charged CdTe QDs with enhanced fluorescence and affinity for the improvement of latent fingerprint detection. Through this synthetic method, the positively charged CdTe-COONH(3)NH(3)(+) QDs were successfully achieved by using hydrazine hydrate as both the surface stabilizer and pH adjuster during the preparation process. In comparison to the negatively charged CdTe-COO(-) QDs prepared by using sodium hydroxide as the pH adjuster, the CdTe-COONH(3)NH(3)(+) QDs showed enhanced fluorescence. The effectiveness of CdTe-COO(-) and CdTe-COONH(3)NH(3)(+) QDs for detection of latent fingerprints present on a large variety of smooth objects was systematically and comparatively studied. The results indicate that the detection of latent fingerprints by using CdTe-COONH(3)NH(3)(+) QDs as fluorescent labeling marks was greatly enhanced, and more characteristic finger ridge details were detected and identified due to their enhanced affinity with latent fingerprints, in comparison to the detection by using CdTe-COO(-) QDs as fluorescent labeling marks. The CdTe-COONH(3)NH(3)(+) QDs show superior detection capability than the CdTe-COO(-) QDs, which greatly improves the applicability of CdTe QDs for practical application in latent fingerprint detection. PMID- 21233538 TI - Correlation between the performance and microstructure of Ti/Al/Ti/Au Ohmic contacts to p-type silicon nanowires. AB - Understanding the electrical and microstructural aspects of contact formation at nanoscale is essential for the realization of low-resistance metallization suitable for the next generation of nanowire based devices. In this study, we present detailed electrical and microstructural characteristics of Ti/Al/Ti/Au metal contacts to p-type Si nanowires (SiNWs) annealed at various temperatures. Focused ion beam cross-sectioning techniques and scanning transmission electron microscopy (STEM) were used to determine the microstructure of the source/drain metal contacts of working SiNW field-effect transistors (FETs) annealed for 30 s in the 450-850 degrees C temperature range in inert atmosphere. Formation of titanium silicides is observed at the metal/semiconductor interface after the 750 degrees C anneal. Extensive Si out-diffusion from the nanowire after the 750 degrees C anneal led to Kirkendall void formation. Annealing at 850 degrees C led to almost complete out-diffusion of Si from the nanowire core. Devices with 550 degrees C annealed contacts had linear electrical characteristics; whereas the devices annealed at 750 degrees C had the best characteristics in terms of linearity, symmetric behavior, and yield. Devices annealed at 850 degrees C had poor yield, which can be directly attributed to the microstructure of the contact region observed in STEM. PMID- 21233539 TI - Growth of doped silicon nanowires by pulsed laser deposition and their analysis by electron beam induced current imaging. AB - Doped silicon nanowires (NWs) were epitaxially grown on silicon substrates by pulsed laser deposition following a vapour-liquid-solid process, in which dopants together with silicon atoms were introduced into the gas phase by laser ablation of lightly and highly doped silicon target material. p-n or p(++)-p junctions located at the NW-silicon substrate interfaces were thus realized. To detect these junctions and visualize them the electron beam induced current technique and two-point probe current-voltage measurements were used, based on nanoprobing individual silicon NWs in a scanning electron microscope. Successful silicon NW doping by pulsed laser deposition of doped target material could experimentally be demonstrated. This doping strategy compared to the commonly used doping from the gas phase during chemical vapour deposition is evaluated essentially with a view to potentially overcoming the limitations of chemical vapour deposition doping, which shows doping inhomogeneities between the top and bottom of the NW as well as between the core and shell of NWs and structural lattice defects, especially when high doping levels are envisaged. The pulsed laser deposition doping technique yields homogeneously doped NWs and the doping level can be controlled by the choice of the target material. As a further benefit, this doping procedure does not require the use of poisonous gases and may be applied to grow not only silicon NWs but also other kinds of doped semiconductor NWs, e.g. group III nitrides or arsenides. PMID- 21233540 TI - The synthesis and photoluminescence properties of selenium-treated porous silicon nanowire arrays. AB - Here we prepared vertical and single crystalline porous silicon nanowire (SiNW) arrays using the silver-assisted electroless etching method. The selenization was carried out by annealing the samples in vacuum with selenium atmosphere. The selenization treatment at 700 degrees C is useful for investigating the photoluminescence (PL) properties of porous SiNWs, with an enhancement of 30 times observed. The observed PL peaks blue-shift to 650 nm and the decomposition of the spectrum reveals that three PL bands with different origins are obtained. It is proved that selenization treatment could remove the Si-H bonds on the surface and form Si-Se bonds, which could increase the absorbance of the SiNWs and also enhance the stability of the PL intensity. These Se-treated porous SiNWs may be useful as nanoscale optoelectronic devices. PMID- 21233541 TI - Near-field thermal transport in a nanotip under laser irradiation. AB - We report on a systematic study of highly enhanced optical field and its induced thermal transport in nanotips under laser irradiation. The effects on electric field distribution caused by curvature radius, tip aspect ratio, and polarization angle of the incident laser are studied. Our Poynting vectors' study clearly shows that when a laser interacts with a metal tip, it is bent around the tip and concentrated under the apex, where extremely high field enhancement appears. This phenomenon is more like a liquid flow being forced/squeezed to go through a narrow channel. As the tip-substrate distance increases, the peak field enhancement decreases exponentially. A shift of field peak position away from the tip axis is observed. For the incident light, only its component along the tip axis direction has a contribution to the electric field enhancement under the tip apex. The optimum tip apex radius for field enhancement is about 9 nm when the half taper angle is 10 degrees . For a tip with a fixed radius of 30 nm, field enhancement increases with the half taper angle when it is less than 25 degrees . The thermal transport inside the nanoscale tungsten tips due to absorption of incident laser light is explored using the finite element method. A small fraction of light penetrates into the tip. As the polarization angle or apex radius increases, the peak apex temperature decreases. The peak apex temperature goes down as the half taper angle increases, even though the mean laser intensity inside the tip increases, revealing a very strong effect of the taper angle on thermal transport. PMID- 21233542 TI - Imprinting nanoporous alumina patterns into the magneto-transport of oxide superconductors. AB - We used oxygen ion irradiation to transfer the nanoscale pattern of a porous alumina mask into high-T(C) superconducting thin films. This causes a nanoscale spatial modulation of superconductivity and strongly affects the magneto transport below T(C), which shows a series of periodic oscillations reminiscent of the Little-Parks effect in superconducting wire networks. This irradiation technique could be extended to other oxide materials in order to induce ordered nanoscale phase segregation. PMID- 21233543 TI - Magnetic properties of Cd(1 - x)Mn(x)Te/C nanocrystals. AB - Mn doped CdTe nanocrystals coated by carbon (Cd(1 - x)Mn(x)Te/C) were synthesized by a one-step, kinetically controlled solid state reaction under autogenic pressure at elevated temperatures. Electron microscopic analysis confirmed that the 40-52 nm Cd(1 - x)Mn(x)Te core was encapsulated by a 6-9 nm carbon shell. The efficient doping by Mn(2+) in the zinc blende Cd(1 - x)Mn(x)Te lattice, up to an atomic ratio of Mn/Cd of 0.031, was confirmed from electron paramagnetic resonance (EPR) experiments. In the case of higher doping, it is likely that manganese is partially expelled to the nanocrystal surface. All the doped samples exhibit ferromagnetism at room temperature. The lowest doped sample has the highest magnetic moment (1.91 +/- 0.02 u(B)/Mn). The more concentrated samples exhibit weaker ferromagnetic interactions, probably due to an incomplete coupling between carriers in the host CdTe semiconductor and dopant spins. PMID- 21233544 TI - High conductivity transparent carbon nanotube films deposited from superacid. AB - Carbon nanotubes (CNTs) were deposited from a chlorosulfonic superacid solution onto PET substrates by a filtration/transfer method. The sheet resistance and transmission (at 550 nm) of the films were 60 Omega/sq and 90.9% respectively, which corresponds to a DC conductivity of 12,825 S cm(-1) and a DC/optical conductivity ratio of 64.1. This is the highest DC conductivity reported for CNT thin films to date, and attributed to both the high quality of the CNT material and the exfoliation/doping by the superacid. This work demonstrates that CNT transparent films have not reached the conductivity limit; continued improvements will enable these films to be used as the transparent electrode for applications in solid state lighting, LCD displays, touch panels, and photovoltaics. PMID- 21233545 TI - The synthesis and characterization of poly(gamma-glutamic acid)-coated magnetite nanoparticles and their effects on antibacterial activity and cytotoxicity. AB - Magnetite nanoparticles (MNPs) modified with sodium and calcium salts of poly(gamma-glutamic acid) (NaPGA and CaPGA) were synthesized by the coprecipitation method, followed by characterization and evaluation of their antibacterial and cytotoxic effects. Superparamagnetic MNPs are particularly attractive for magnetic driving as well as bacterial biofilm and cell targeting in in vivo applications. Characterization of synthesized MNPs by the Fourier transform infrared spectra and magnetization curves confirmed the PGA coating on MNPs. The mean diameter of NaPGA- and CaPGA-coated MNPs as determined by transmission electron microscopy was 11.8 and 14 nm, respectively, while the x ray diffraction pattern revealed the as-synthesized MNPs to be pure magnetite. Based on agar dilution assay, both NaPGA- and CaPGA-coated MNPs showed a lower minimum inhibitory concentration in Salmonella enteritidis SE 01 than the commercial antibiotics linezolid and cefaclor, but the former was effective against Escherichia coli ATCC 8739 and Staphylococcus aureus ATCC 10832, whereas the latter was effective against Escherichia coli O157:H7 TWC 01. An in vitro cytotoxicity study in human skin fibroblast cells as measured by MTT assay implied the as-synthesized MNPs to be nontoxic. This outcome demonstrated that both gamma-PGA-modified MNPs are cytocompatible and possess antibacterial activity in vitro, and thereby should be useful in in vivo studies for biomedical applications. PMID- 21233546 TI - Coupled effects of ion beam chemistry and morphology on directed self-assembly of epitaxial semiconductor nanostructures. AB - We study the coupled effects of ion beam chemistry and morphology on the assembly of templated epitaxial nanostructures. Using a focused ion beam (FIB) system equipped with a mass-selecting filter, we pattern Si substrates with local ion doses of Si, Ge and Ga to control subsequent Ge(x)Si(1 - x) epitaxial nanostructure assembly. This capability to employ different templating species allows us to study how different incorporated ion species in the near surface region affect the ability to localize nucleation during subsequent epitaxial growth. Our results indicate that FIB-directed self-assembly is a complex process, dependent on dose-induced morphology in addition to ion-specific chemical effects. PMID- 21233547 TI - Structural and optical properties of InGaN/GaN nanowire heterostructures grown by PA-MBE. AB - The structural and optical properties of InGaN/GaN nanowire heterostructures grown by plasma-assisted molecular beam epitaxy have been studied using a combination of transmission electron microscopy, electron tomography and photoluminescence spectroscopy. It is found that, depending on In content, the strain relaxation of InGaN may be elastic or plastic. Elastic relaxation results in a pronounced radial In content gradient. Plastic relaxation is associated with the formation of misfit dislocations at the InGaN/GaN interface or with cracks in the InGaN nanowire section. In all cases, a GaN shell was formed around the InGaN core, which is assigned to differences in In and Ga diffusion mean free paths. PMID- 21233548 TI - Electronic transport properties of carbon nanotoroids. AB - We investigate the electronic transport properties of carbon nanotori covalently connected to external electrodes made up of carbon nanotubes of various chiralities. The study is based on computing ballistic transport characteristics within the framework of Green's function theory using a simple pi-orbital tight binding model. The calculations focus on the effect of the relative angle made by the electrodes as they are placed at different positions along the nanoring. The conductance behavior is found to depend on the details of the atomic structure of the torus but also on the positions of the electrodes. Our findings are rationalized using an elementary quantum mechanical interference model, which reproduces well the main features of the numerical data. PMID- 21233549 TI - Force gradient sensitive detection in lift-mode Kelvin probe force microscopy. AB - We demonstrate frequency modulation Kelvin probe force microscopy operated in lift-mode under ambient conditions. Frequency modulation detection is sensitive to force gradients rather than forces as in the commonly used amplitude modulation technique. As a result there is less influence from electric fields originating from the tip's cone and cantilever, and the recorded surface potential does not suffer from the large lateral averaging observed in amplitude modulated Kelvin probe force microscopy. The frequency modulation technique further shows a reduced dependence on the lift-height and the frequency shift can be used to map the second order derivative of the tip-sample capacitance which gives high resolution material contrast of dielectric sample properties. The sequential nature of the lift-mode technique overcomes various problems of single scan techniques, where crosstalk between the Kelvin probe and topography feedbacks often impair the correct interpretation of the recorded data in terms of quantitative electric surface potentials. PMID- 21233550 TI - Emission properties of hydrothermal Yb(3+), Er(3+) and Yb(3+), Tm(3+)-codoped Lu2O3 nanorods: upconversion, cathodoluminescence and assessment of waveguide behavior. AB - Yb(3+) and Ln(3+) (Ln(3+) = Er(3+) or Tm(3+)) codoped Lu(2)O(3) nanorods with cubic Ia3 symmetry have been prepared by low temperature hydrothermal procedures, and their luminescence properties and waveguide behavior analyzed by means of scanning near-field optical microscopy (SNOM). Room temperature upconversion (UC) under excitation at 980 nm and cathodoluminescence (CL) spectra were studied as a function of the Yb(+) concentration in the prepared nanorods. UC spectra revealed the strong development of Er(3+) (4)F(9/2) -> (4)I(15/2) (red) and Tm(3+) (1)G(4) -> (3)H(6) (blue) bands, which became the pre-eminent and even unique emissions for corresponding nanorods with the higher Yb(3+) concentration. Favored by the presence of large phonons in current nanorods, UC mechanisms that privilege the population of (4)F(9/2) and (1)G(4) emitting levels through phonon-assisted energy transfer and non-radiative relaxations account for these observed UC luminescence features. CL spectra show much more moderate development of the intensity ratio between the Er(3+) (4)F(9/2) -> (4)I(15/2) (red) and (2)H(11/2), (4)S(3/2) -> (4)I(15/2) (green) emissions with the increase in the Yb(3+) content, while for Yb(3+), Tm(3+)-codoped Lu(2)O(3) nanorods the dominant CL emission is Tm(3+) (1)D(2) -> (3)F(4) (deep-blue). Uniform light emission along Yb(3+), Er(3+)-codoped Lu(2)O(3) rods has been observed by using SNOM photoluminescence images; however, the rods seem to be too thin for propagation of light. PMID- 21233551 TI - The synthesis and fluorescence quenching properties of well soluble hybrid graphene material covalently functionalized with indolizine. AB - Chemically functionalized graphene-indolizine functionalized graphene (IMG) sheets, which can be well dispersed in different organic solvents over four months without obvious aggregation, are obtained through a 1,3-dipolar cycloaddition to graphene with pyridinium ylide. The properties of IMG sheets are investigated using a thorough set of measurements including UV-visible spectroscopy, Fourier transform infrared spectroscopy (FT-IR), thermogravimetric analysis (TGA), Raman spectroscopy, x-ray photoelectron spectroscopy (XPS), photoluminescence spectroscopy (PL), transmission electron microscopy (TEM), atomic force microscopy (AFM) and cyclic voltammetry (CV), and a tagging technique has exhibited the distribution of functional groups on the graphene surface. The IMG sheets show very strong quenching by a factor of ~ 93.4% to that of indolizine, which is attributed to the fluorescence resonance energy transfer (FRET) from indolizine molecules to few-layer graphene sheets. The CV method also proved the catalytic properties of IMG sheets in some redox systems. PMID- 21233552 TI - Single molecule magnets on a gold surface: in situ electrospray deposition, x-ray absorption and photoemission. AB - Single molecule magnets based on the dodecamanganese (III, IV) cluster with two different types of ligand (acetate and benzoate) have been studied on the Au(111) surface. Due to the non-volatile and fragile nature of the molecules, we have used ultra-high vacuum electrospray deposition to produce a series of surface coverages from a fraction of a monolayer to multilayer films in both cases. Synchrotron radiation based electron spectroscopy has been used to study the adsorption of the molecules on the Au(111) surface and the effect that this has on the oxidation states of the manganese atoms in the core. In both cases, reduction of the core is observed due to the interaction with the surface, to essentially the same extent despite substantial differences in the size and nature of the ligand shell. PMID- 21233553 TI - Rapid and precise coulometric determination and separation of redox inert ions based on electrolysis for ion transfer at the aqueous|organic solution interface. AB - Flow systems for precise and accurate coulometric determinations of ions that were developed on the basis of electrolytic ion transfer at the aqueous|organic solution (W|O) interface are reviewed. The electrolysis cell in the system is composed of a porous poly(tetrafluoroethylene) tube (1.0 mm inner diameter), a metal wire (0.8 mm diameter) inserted into the tube, O into which the tube is immersed, a reference electrode in O and a platinum wire counter electrode in O. The electrolysis is carried out by forcing W containing a species of interest to flow through the narrow gap between the tube and the metal wire. The coulometric determination can be performed with an efficiency of more than 99% and a precision of better than 0.2% based on the ion transfer under an optimum condition, even if the ion is redox inert such as Na(+), K(+), Mg(2+), Ca(2+), ClO(4)(-), picrate or alkylsulfonates. The system can be applied to selective electrolytic solvent extraction of ions. PMID- 21233554 TI - Optimization of peptide density on microarray surface for quantitative phosphoproteomics. AB - Procedures to determine the density of peptides immobilized on a glass surface for the quantitative detection of phosphorylated peptides for phosphoproteomic applications of peptide microarrays are described. Two kinds of representative fluorescent probe molecules, anti-phosphotyrosine antibody (AB) and phos-tag (PT), were examined to compare their ability for the quantitative detection of phosphorylated peptides. PT is a metal complex with a binding specificity to phosphorylated amino acids, and is much smaller in size than AB. Thus, PT is quantitatively bound to the phosphorylated peptides, even at a high immobilization density without steric hindrance, making them highly suited for future microarrays requiring smaller sized peptide spots for much higher throughput. PMID- 21233555 TI - Galactose-functionalized magnetic iron-oxide nanoparticles for enrichment and detection of ricin toxin. AB - To generate a new specific recognition module for the enrichment and detection of ricin, galactose-functionalized silanized magnetic iron-oxide nanoparticles (Gal SiMNPs) were assembled by amino-silanized MNPs (amino-SiMNPs) and a galactose linker. Amino-SiMNPs were produced by a coprecipitation method, and were coated with double layers of silica and aminosilane by hydrolysis of tetraethoxysilane and 3-aminopropyltriethoxysilane, respectively. A galactose with an amido-acid linker was synthesized by four steps of chemical modification from O-acetyl protected galactose. The diameters of Gal-SiMNPs were characterized as being 60 +/- 20 nm. The average amount of galactose-loading and ricin-binding on Gal SiMNPs was 30 +/- 2 ug galactose and 29 +/- 2 ug ricin toxin on the surface of 1 mg of Gal-SiMNPs, respectively. Furthermore, a rapid, simple and efficient colorimetric assay was established for the detection of ricin based on the Gal SiMNPs, and the limits of detection (LODs) of 2 and 4 ng/mL for ricin in physiological buffer and serum were obtained, respectively. PMID- 21233556 TI - Preconcentration method of antimony using modified thiol cotton fiber for isotopic analyses of antimony in natural samples. AB - It is very important to investigate antimony geochemical behavior in order to identify its source, or reveal contamination processes, since antimony and its compounds are considered to be pollutants of high priority by the Environmental Protection Agency of the United States (USEPA). However, the concentration of antimony in most geological samples is very low, and its stable isotope mass difference is only 1.6%. An antimony preconcentration method for isotope analysis using modified Thiol Cotton Fiber has been developed. Using this new method, the recovery of antimony was 99.5 +/- 3.6% (n = 3) and blank values were <0.1 ng. The standard error of the epsilon(123)Sb isotope ratios in the proposed method is only 0.4epsilon, much smaller than those of the previous method. The proposed method is therefore effective in the preconcentration and separation of antimony for antimony isotope analysis. PMID- 21233557 TI - Isotope ratio analysis of lead in blood and environmental samples by multi collector inductively coupled plasma mass spectrometry. AB - It is widely recognized that lead (Pb) affects children's cognitive function, even at relatively low blood lead levels (<10 ug dL(-1)). The determination of the source of Pb in children is essential for effective risk management. The use of multi-collector ICPMS (MC-ICPMS) for isotope ratio measurements of Pb in environmental and biological samples was examined for this purpose. MC-ICPMS with an instrumental mass fractionation correction by Tl allowed accurate isotope ratio measurements of the Pb isotopic reference material NIST SRM 981. However, the presence of matrix elements (Al, Ca, Fe and Na) at more than 10 mg kg(-1) in the sample solution significantly deteriorated the accuracy. The separation of Pb from the matrix is necessary for accurate measurements of the isotope ratio of Pb in environmental and biological samples. Bromide-complexation, followed by anion exchange was found to be satisfactory in terms of the recovery of Pb (90 to 104%) and the efficiency of matrix separation. The procedure was applied to a preliminary source analysis of Pb in the blood of Japanese children, and a significant contribution of indoor dust was demonstrated. PMID- 21233558 TI - Kinetic investigation of the autocatalytic reaction between potassium permanganate and hydrogen peroxide with soft-modeling methods. AB - The complex autocatalytic reaction between potassium permanganate (KMnO(4)) and hydrogen peroxide (H(2)O(2)) was studied by online UV-Vis spectra methods. The kinetic profiles of the absorptive components, including KMnO(4) and two intermediates, were obtained by resolving the spectra-kinetic matrix with iterative target transformation factor analysis (ITTFA). But for the product Mn(II), which is not absorptive in the monitoring wavelength range, this was not applicable. Therefore, local mass balance region (LMBR) technique was proposed to get all of the scaled profiles, especially the non-absorptive components. Influences of various reaction conditions, such as concentrations of H(2)O(2) and sulfuric acid (H(2)SO(4)) and reaction temperatures, were also investigated. Contrary to most other reactions, when initial concentrations of hydrogen peroxide ([H(2)O(2)](0)) are largely excessive ([H(2)O(2)](0)/[KMnO(4)](0) >40), higher [H(2)O(2)](0) will decrease the degradation rate, while the higher temperature makes the reaction go much slower. PMID- 21233559 TI - Simultaneous derivatization and extraction of primary short-chain aliphatic amines using an ultrasonic-mixed water-ionic liquid two-phase system for liquid chromatography. AB - Here, we report on a procedure in which ultrasonic waves were used to mix a water ionic liquid two-phase system to simultaneously derivatize amines with dansyl chloride and extract, and the resulting dansyl amines into an ionic liquid (IL) at room temperature within 15 min. The ILs used were room-temperature ionic liquids (RTILs), such as 1-alkyl-3-methylimidazolium hexafluorophosphate ([C(n)MIM][PF(6)], n = 4, 6, 8), which are insoluble in water, and can extract more than 88% of the total dansyl amines (Dns-amines) present in aqueous solution. The Dns-amines formed were separated by chromatography in 20 uL of RTIL in a mobile-phase gradient of acetonitrile-water flowing through an Agilent Zorbax SB-C18 column. The eluents were analyzed at 333 nm using a UV detector. The optimal analytical conditions were achieved by using the following: RTILs with a 4-carbon alkyl chain; a 7-mL water sample and 1 mL each of 5 mM dansyl chloride in acetone and 20 mM sodium tetraborate buffer for use with a fixed volume (1 mL) of IL; buffer pH of 10.4; duration of 15 min; and an acetonitrile water ratio of 50:50 from zero time to 3 min, 80:20 from 4 to 10 min, and 50:50 from 11 to 16 min. In comparison to the single-phase hot-water (70 degrees C) derivatization process reported earlier, the simultaneous process developed here showed a higher derivatization efficiency at the tested concentration. The linear range of analysis (0.14-7.14 mg/L) was determined, and the correlation coefficient (R) ranged from 0.9878 to 0.9980. Furthermore, the estimated percentage of recovery from amine-spiked river-water samples ranged from 76 to 108%. The method presented here is simple and fast, and does not involve the use of volatile organic extractants. PMID- 21233560 TI - Determination of phenoxyacetic acids and chlorophenols in aqueous samples by dynamic liquid-liquid-liquid microextraction with ion-pair liquid chromatography. AB - Dynamic liquid-liquid-liquid microextraction coupled with ion-pair liquid chromatography (IP-LC) and photodiode array detection was developed and used for the extraction and analysis of chlorinated phenoxyacetic acids (CPAs) and chlorophenols (CPs) from water samples. An organic extraction solvent mixture was chosen to simultaneously and effectively extract both CPAs and CPs from aqueous samples. The method detection limit (MDL) ranged from 0.06 to 0.45 ug L(-1) with good reproducibility. The relative standard deviations were in the range of 2.6 6.5% at lower spiked concentrations and 3.0-4.6% at higher concentrations. Good linearity of analytes was achieved in the range of 0.5-500 ug L(-1). The acceptable relative recoveries (82.9-112.4%) for environmental waters revealed the presence of negligible matrix effects in the case of real samples. The applicability of this newly developed method was illustrated by determinations of CPAs and CPs in environmental water samples. PMID- 21233561 TI - Pharmacokinetics of propranolol hydrochlorid in human urine by capillary electrophoresis coupled with electrochemiluminescence. AB - A novel method for the determination of propranolol hydrochlorid (PRO) in human urine was developed using capillary electrophoresis coupled with electrochemiluminescence detection (CE-ECL). The parameters that affected the separation and detection were optimized. Under the optimal conditions, the linear range for PRO was from 0.003 to 2 ug/mL (r(2) = 0.9993), and the detection limit was 1.3 ng/mL (S/N = 3). The method was successfully applied to the study of the pharmacokinetics of PRO in human urine. The relative standard deviations of ECL intensity and migration time were 2.6 and 2.1%, respectively (1.0 ug/mL PRO, n = 6). The recovery was between 96.71 and 97.30%. The peak excretion rate in urine was observed during the 0.5-1 h after oral administration of a 10-mg PRO tablet and the urinary excretion ratio of PRO was 13.6% within 12 h. The method was simple, rapid, economical and sensitive, and may improve the detection of PRO as a doping agent in sports. PMID- 21233562 TI - Electrochemical sensing of anions and heparin by an alkyl-chain ferrocene cationic surfactant. AB - Alkyl-chain ferrocene cationic surfactants (ACFcCS) can form ion-pair complexes with anions, and are then adsorbed at hydrophobic electrode surfaces or extracted to organic layers. The amount of adsorbed ACFcCS-anion complex is dependent on the anion concentration in a solution, and the anion concentration can be determined from the current intensity of the oxidation wave of the ferrocene part of ACFcCS. In this work, we studied the adsorption behavior of (ferrocenylmethyl)dodecyldimethyl ammonium ion (FcMDDMA) on a carbon-paste electrode, which accompanies the ion-pair formation with an inorganic anion, an organic anion, or heparin molecule. A concentration analysis of a heparin sodium injection sample was carried out using adsorption voltammetry, and the amperometric titration used FcMDDMA as the end-point indicator. PMID- 21233563 TI - Electrochemical sensing of acyclovir at a gold electrode modified with 2 mercaptobenzothiazole-[5,10,15,20-tetrakis-(3-methoxy-4 hydroxyphenyl)porphyrinato]copper(II). AB - The electrooxidation of acyclovir (ACV) was studied using a gold electrode (GE) modified with a self-assembled monolayer of 2-mercaptobenzothiazol (MBZ) and [5,10,15,20-tetrakis(3-methoxy-4-hydroxyphenyl)porphyrinato]copper(II) (TMHPP Cu(II)) by square wave voltammetry (SWV). The self-assembled films are stable and showed blocking characteristics towards the faradaic processes such as gold surface oxidation and under potential deposition of copper. The optimized conditions obtained for the MBZ/TMHPP Cu(II)-modified GE were 0.1 M phosphate buffer solution (pH 7.0), square wave frequency of 15 Hz and square wave amplitude of 25 mV. Under these optimum conditions, the resultant peak current increases linearly with the concentration of ACV in the range of 1.0 * 10(-3) to 1.0 * 10(-8) M with a detection limit of 1.0 * 10(-8) M. The MBZ/TMHPP Cu(II) modified GE showed good stability and selectivity and it can be used to quantify ACV in pharmaceutical formulations and urine samples. PMID- 21233564 TI - Simultaneous determination of amoxicillin and diclofenac in pharmaceutical formulations using UV spectral data and the PLS chemometric method. AB - A new method for the simultaneous determination of amoxicillin trihydrate (AMT) and sodium diclofenac (DIC) in pharmaceutical formulations is proposed. The resolution of binary mixtures of these drugs has been accomplished by using partial least squares (PLS) regression analysis. The model was obtained from UV spectral data and validated by internal cross-validation; it was used to find the concentration of analytes in some commercial samples. The method was applied in the concentration ranges of 0-120.0 mg L(-1) for AMT and 0-16.0 mg L(-1) for DIC, allowing a rapid, accurate and precise simultaneous estimation of the concentration of both analytes of interest in the presence of small amounts of different, unmodelled, absorbing excipients, in spite of their important spectral overlapping. The accuracy, precision and figures of merit (FOM) for AMT and DIC were calculated. This new method proved to be useful for a fast and simultaneous determination of AMT and DIC in pharmaceutical formulations. PMID- 21233565 TI - Interaction between alizarin and human serum albumin by fluorescence spectroscopy. AB - The binding properties on alizarin to human serum albumin (HSA) have been studied for the first time using fluorescence spectroscopy in combination with UV-visible absorbance spectroscopy. The results showed that alizarin strongly quenched the intrinsic fluorescence of HSA through a static quenching procedure, and non radiation energy transfer occurred within the molecules. The number of binding sites was 1, and the efficiency of Forster energy transfer provided a distance of 1.83 nm between tryptophan and alizarin binding site. DeltaH(theta), DeltaS(theta) and DeltaG(theta) were obtained based on the quenching constants and thermodynamic theory (DeltaH(theta) < 0, DeltaS(theta) > 0 and DeltaG(theta) < 0). These results indicated that hydrophobic and electrostatic interactions are the main binding forces in the alizarin-HSA system. In addition, the results obtained from synchronous fluorescence spectra and three-dimensional fluorescence spectra showed that the binding of alizarin with HSA could induce conformational changes in HSA. PMID- 21233566 TI - Ultra-trace determination of lead(II) in water using electrothermal atomic absorption spectrometry after preconcentration by solid-phase extraction to a small piece of cellulose acetate type membrane filter. AB - A simple and inexpensive preconcentration technique has been developed for the ultra-trace determination of lead(II) using electrothermal atomic absorption spectrometry (ETAAS). The lead(II) complex with dicyclohexano-18-crown 6-ether (DC18C6) was extracted to a small piece of cellulose acetate-type membrane filter (2 * 5 mm) merely by vigorously eccentric stirring for 120 min under the coexistence of sodium dodecyl sulfate (SDS) at around pH 7. The extraction medium was inserted into a graphite cuvette for the determination of lead(II) by ETAAS. A linear relation was obtained for the range of 0.1-5.0 ng in 10 ml of lead(II) standard solution (r = 0.998). The detection limit was found to be 0.03 ng of lead(II) in 10 ml (0.003 ug l(-1)) of water sample. The proposed method was applied to the ultra-trace determination of lead(II) in river water, underground water, tap water, and snow fall samples. PMID- 21233567 TI - Inhibition of electrochemical fouling against biomolecules on a diamond-like carbon electrode. AB - An anti-fouling ability of diamond-like carbon (DLC) electrodes to biological macromolecules has been investigated from a decrease in the electrochemical redox current of Fe(CN)(6)(4-/3-), used as a redox marker. A DLC electrode and a glassy carbon (GC) electrode were immersed in a solution containing bovine serum albumin (BSA) or DNA. The GCs treated with biological macromolecules gave rise to a significant decrease in the currents, while there was no signal decreases from the treated DLCs. The signals from the DLCs remain essentially unchanged for at least 24 h at a 10 mg/mL concentration level of BSA. PMID- 21233568 TI - Alternative plugs flow liquid chromatography (APFLC)/EI-MS system using a T shaped flow path. AB - The vapor condensation method can be used for forming an alternative flow of liquid masses using a single solvent for alternative plugs flow liquid chromatography (APFLC), described in our previous paper. APFLC is more effective when adopting a T-shaped flow path and aqueous-organic solvents with a liquid-to gas volume ratio (bulk fraction; beta) ranging between 0.0006 and 0.004 in an open tubular GC capillary column at below 70 degrees C. High-density plugs flow by a T-shaped flow path leads to extremely high resolution. Alternative plugs flow is formed when the liquid contact angle to the solid phase is above 75 degrees . An aqueous mixture of the usual HPLC solvent can be readily used for APFLC. An EI-mass spectrum is obtained that is comparable with that in the NIST library, except for the DMF mixture medium. Due to low-pressure loss properties in the column, the system does not require a high-pressure liquid pump. Solid hydrocarbon resin with a contact angle to water of between 75 degrees and 79 degrees , such as polystyrene and olefinic polymers, is anticipated to be applicable to APFLC and hydro-membrane gas chromatography (HMGC) by a consideration of their surface tensions. PMID- 21233569 TI - In-gel staining of proteins in native poly acryl amide gel electrophoresis using tetrakis(4-sulfonato phenyl)porphyrin. AB - Protein identification in polyacrylamide gel electrophoresis (PAGE) requires post electrophoretic steps like fixing, staining and destaining of the gel, which are time-consuming and cumbersome. We have developed a method for direct visualization of protein bands in PAGE using tetrakis(4-sulfonato phenyl)porphyrin (TPPS) as a dye without the need for any post electrophoretic steps, where separation and recovery of enzymes become much easier for further analysis. Activity staining was done to prove that the biochemical activity of the enzymes was preserved after electrophoresis. PMID- 21233570 TI - Fluorescent derivatization of xanthurenic acid and nicotinic acid with horseradish peroxidase in the presence of excess hydrogen peroxide. AB - The fluorescent derivatization of tryptophan metabolites (xanthurenic acid, nicotinic acid, picolinic acid, and 3-hydroxyanthranilic acid) by the catalytic activity of horseradish peroxidase (HRP) was investigated in the presence of excess H(2)O(2). Non-fluorescent xanthurenic acid (XA) and nicotinic acid (NA) were converted into a fluorescent compound with maximum excitation and emission wavelengths at 325 and 425 nm, and 318 and 380 nm, respectively. This fluorescent derivatization was developed for the fluorometric determination of trace amounts of XA and NA. The calibration curves were linear from 1.0 to 10.0 nmol XA and from 5.0 to 20.0 nmol NA in a 1.0-mL sample solution. The UV spectra of the reaction solutions suggested that compound III as an intermediate of HRP played an essential role in this fluorescent derivatization with HRP. PMID- 21233571 TI - Interaction between Al3+ and acrylic acid and polyacrylic acid in acidic aqueous solution: a model experiment for the behavior of Al3+ in acidified soil solution. AB - From the viewpoint of the phytotoxicity and mobility of Al(3+) released from soil minerals due to soil acidification, the interaction between Al(3+) and acrylic acid (AA) and polyacrylic acid (PAA) as a model compound of fulvic acid was investigated. The interaction was examined at pH 3 so as to avoid the hydrolysis of Al(3+). The interaction between Al(3+) and AA was weak. However, the interaction between Al(3+) and PAA was strong and depended on the initial (COOH in PAA)/Al molar ratio (R(P)) of the solution. For the range of 1/R(P), the interaction between Al(3+) and PAA can be divided into three categories: (1) 1:1 Al-PAA-complex (an Al(3+) combines to a carboxyl group), (2) intermolecular Al PAA-complex (an Al(3+) combines to more than 2 carboxyl groups of other Al-PAA complexes) in addition to the 1:1 Al-PAA-complex and (3) precipitation of intermolecular complexes. In conclusion, R(P) is an important factor affecting the behavior of Al(3+) in acidic soil solution. PMID- 21233573 TI - Limitations and problems of assessment of mechanical dyssynchrony in determining cardiac resynchronization therapy indication. Is assessment of mechanical dyssynchrony necessary in determining CRT indication? (Con). AB - Contraction delay of the lateral left ventricular free wall can be improved by biventricular pacing. Cardiac resynchronization therapy (CRT) is based on the principle of resynchronizing un-uniformed contraction of the ventricle. Prolongation of the QRS duration on an electrocardiogram served as an indirect marker to identify mechanical dyssynchrony. One of the greatest problems is approximately 30% of the patients who met the criteria do not respond for CRT. One possible explanation for the lack of response for CRT could be the absence of sufficient dyssynchrony to allow the therapy to have any impact. Direct assessments of mechanical dyssynchrony might better select responder patients for CRT. However, RethinQ study demonstrated that patients with heart failure and narrow QRS intervals might not benefit from CRT, even with dyssynchrony. Moreover, the results of the PROSPECT study suggest given the modest sensitivity and specificity in the multicenter setting, despite training and central analysis, no single echocardiographic measurement of dyssynchrony could be recommended to improve patient selection for CRT beyond current guidelines. At present, assessment of mechanical dyssynchrony is not necessary in determining CRT indication. Current indication including QRS width is recommended as selection criteria to identify patients suitable for CRT. PMID- 21233574 TI - Mechanical dyssynchrony is not everything of substrate but is essential for cardiac resynchronization therapy. Is assessment of mechanical dyssynchrony necessary in determining CRT indication? (Pro). AB - Cardiac resynchronization therapy (CRT) improves heart failure symptoms, cardiac function and long-term prognosis. As a result, it has been established as a treatment for refractory heart failure by using a specialized pacemaker to restore coordinated ventricular contractions with pacing. Despite being an invasive treatment, however, the above effects are not observed in 30-45% of patients selected based on the standard criteria that includes New York Heart Association class III or IV heart failure, left ventricular ejection fraction <=35%, and QRS duration >=120 or 130ms. From the fact that quantifiable resynchronization was associated with hemodynamic and clinical improvements, it should follow that mechanical dyssynchrony is a critical substrate for the benefits from CRT. The PROSPECT study unexpectedly demonstrated limitations of echocardiographic parameters using M-mode, pulsed-wave Doppler, and tissue Doppler imaging for accurately and reproducibly predicting response to CRT. However, advances in speckle tracking strain and real-time 3-D echocardiography have furthered the development of more sophisticated indices of dyssynchrony. Stress echocardiography might be useful for the detection of latent mechanical dyssynchrony in failing hearts. Because the substrate for CRT efficacy is multifactorial, a discriminant score that includes various clinical parameters and echocardiographic indices of mechanical dyssynchrony is needed to improve patient selection for CRT. PMID- 21233575 TI - Vascular function tests. -For whom and why?-. PMID- 21233576 TI - Mechanism of mitral regurgitation in the acute phase of inferior wall myocardial infarction: reduced closing force as a consequence of left ventricular systolic dysfunction in the presence of tethering as a determinant of mitral regurgitation. AB - BACKGROUND: To delineate the mechanism of mitral regurgitation (MR) in the acute phase of inferior wall myocardial infarction (MI). METHODS AND RESULTS: In 97 patients (age 59 +/- 12 years) with acute inferior wall MI, the severity of MR, left ventricular (LV) geometric changes and function within 1.7 +/- 1.3 days after MI by echocardiography was retrospectively evaluated. Infarct size was measured within 3.9 +/- 1.7 days by cardiac magnetic resonance. Mild MR was present in 16 (16.5%) and moderate MR in 12 (12.4%) of 97 patients. There were no significant differences in mitral annular area, sphericity and distances between papillary muscle tips and the contralateral mitral annulus. However, patients with moderate MR had significantly larger LV end-systolic volume, tenting area and infarct size. There was a graded relationship between the severity of MR and LV ejection fraction. In a multivariable regression analysis, LV ejection fraction and tenting area were found to be independent predictors of the severity of MR (r(2)=0.180, P=0.001). CONCLUSIONS: MR was associated with LV systolic dysfunction, increase in end-systolic LV volume and tethering of mitral leaflet, suggesting reduced closing force as a consequence of LV systolic dysfunction in the presence of leaflet tethering would play a more pivotal role in the development of MR. PMID- 21233577 TI - Clinical significance of framingham risk score, flow-mediated dilation and pulse wave velocity in patients with stable angina. AB - BACKGROUND: To evaluate the age-adjusted Framingham risk score (AFRS), flow mediated dilation (FMD) and brachial-ankle pulse wave velocity (baPWV) for the prediction of the coronary heart disease (CHD) in patients with stable angina. METHODS AND RESULTS: In 138 consecutive patients with stable angina, the interrelationship and predictive power of CHD were compared between the study parameters. In total, 71 patients demonstrated CHD after scheduled coronary angiography. The AFRS showed significant correlation with FMD (r = -0.43, P < 0.01) and baPWV (r = 0.41, P < 0.01). Based on AFRS, FMD, baPWV and other risk factors of CHD, multivariate analysis showed that AFRS and FMD (odds ratio (OR) 20.098, 95% confidence interval (CI) 4.773-84.627, P < 0.01, and OR 0.865, 95%CI 0.752-0.995, P < 0.05, respectively) were independent predictors of CHD. The area under the receiver operating characteristic (ROC) curves for detecting CHD, AFRS, inverse FMD (iFMD) and baPWV were 0.863, 0.726 and 0.694, respectively (all P < 0.01). However, there was no difference of the area under the ROC curves between AFRS alone and combined complex parameters (AFRS plus iFMD, AFRS plus baPWV, and AFRS plus iFMD plus baPWV) for detecting CHD. CONCLUSIONS: AFRS was a better predictor of CHD than either FMD or baPWV in patients with stable angina. This means that conventional risk factors for cardiovascular disease do not affect uniformly for atherosclerosis in coronary and peripheral arteries. PMID- 21233578 TI - Atropine sulfate for patients with out-of-hospital cardiac arrest due to asystole and pulseless electrical activity. AB - BACKGROUND: The 2005 guidelines for cardiopulmonary resuscitation (CPR) have recommended that administration of atropine can be considered for non-shockable rhythm, but there are insufficient data in humans. METHODS AND RESULTS: The effects of atropine were assessed in 7,448 adults with non-shockable rhythm from the SOS-KANTO study. The primary endpoint was a 30-day favorable neurological outcome after cardiac arrest. In the 6,419 adults with asystole, the epinephrine with atropine group (n=1,378) had a significantly higher return of spontaneous circulation (ROSC) rate than the epinephrine alone group (n=5,048) with an adjusted odds ratio of 1.6 (95% confidence interval (CI) 1.4-1.7, P<0.0001), but the 2 groups had similar 30-day favorable neurological outcome with an adjusted odds ratio of 0.6 (95%CI 0.2-1.7; P=0.37). In the 1,029 adults with pulseless electrical activity (PEA), the 2 groups had similar rates of ROSC and 30-day favorable neurological outcome, and the epinephrine with atropine group had a significantly lower 30-day survival rate than the epinephrine alone group with an adjusted odds ratio of 0.4 (95%CI 0.2-0.9, P=0.016). CONCLUSIONS: Administration of atropine had no long-term neurological benefit in adults with out-of-hospital cardiac arrest due to non-shockable rhythm. Atropine is not useful for adults with PEA. PMID- 21233580 TI - Importance of multi-disciplinary approach in diabetic patients undergoing coronary revascularization. PMID- 21233581 TI - [Age-related pharmacological actions of Kampo medicine: effectiveness for elderly individuals]. PMID- 21233582 TI - [Clinical effects of Kampo medicine related to the quality of crude drugs]. PMID- 21233583 TI - [Kampo medicine daikenchuto--Its Exodus from the complementary and alternative medicines]. PMID- 21233584 TI - [Analysis of the Rikkunshito efficacy on patients with functional dyspepsia]. PMID- 21233585 TI - [Cause of retinitis pigmentosa and new therapeutics under development]. PMID- 21233586 TI - [Translational research of cancer vaccine]. PMID- 21233587 TI - [Pharmacological and clinical profiles of panitumumab injection (Vectibix(r))]. PMID- 21233588 TI - [Pharmacological and clinical profile of alogliptin benzoate (NESINA(r))]. PMID- 21233589 TI - Associations of lower-body fat mass with favorable profile of lipoproteins and adipokines in healthy, slim women in early adulthood. AB - AIM: We determined the association of lower-body fat mass (LFM) and trunk fat mass (TFM) with cardiometabolic risk factors and adipokines in young, healthy, slim women. METHODS: A total of 481 college female students underwent the following: regional body fat distribution as assessed by dual energy X-ray absorptiometry (DXA), a 75g oral glucose tolerance test (OGTT) and fasting blood sampling for measurement of lipids, lipoproteins, apolipoproteins (apo), liver enzymes and adipokines. RESULTS: After adjusting for TFM, LFM was positively associated with HDL cholesterol, adiponectin, pre-heparin lipoprotein lipase and insulin sensitivity, as estimated by the Matsuda index, whereas it was negatively related to triglycerides, apo B, apo B/A1 ratio, small dense LDL, FFA, glucose and insulin at 2h during OGTT, area under the curve of insulin response during OGTT and the white blood cell count. Participants were divided into 9 groups according to tertiles of TFM and LFM. In the middle tertile of TFM, HDL cholesterol and adiponectin increased and triglycerides, apoB/A1 ratio and plasminogen-activator inhibitor-1 decreased from the low to high LFM tertiles. Gamma-glutamyltransferase levels in middle and high LFM tertiles were lower than in the lower LFM tertile. CONCLUSION: For a given level of trunk fat mass, a higher lower-body fat mass is associated with an advantageous profile of not only blood lipoproteins but also serum adipokines, even in healthy, slim women in early adulthood. PMID- 21233590 TI - Plasma NOx concentrations in glucose intolerance and type 2 diabetes. A case control study in a Vietnamese population. AB - AIM: The Vietnamese develop type 2 diabetes (T2D) and metabolic syndrome (MS) at a lower BMI than other ethnicities. Thus, biomarkers that identify subjects at an increased risk of T2D independently of obesity are being sought. Recent studies show that circulating NO metabolites (NOx) are increased in T2D. We investigated whether plasma NOx levels predict insulin resistance and glucose intolerance before the development of T2D, independently of obesity. METHODS: The current study was derived from a population-based study in HCMC, Vietnam, which was designed to investigate the prevalence of MS and T2D in a population aged 30-69 years. Four hundred and twenty-two subjects were recruited from the study and were stratified into 4 age- and gender-matched groups according to a glucose tolerance test {normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and T2D}. RESULTS: Plasma NOx concentrations were significantly increased in T2D but not in IFG or IGT compared with NGT. Multiregression analysis showed that plasma NOx levels were inversely correlated with BMI in T2D whereas no association was found between plasma NOx levels and BMI in non-diabetic subjects. Moreover, there was no correlation between plasma NOx levels and homeostasis model assessment-insulin resistance (HOMA-IR) in both diabetic and non-diabetic subjects. CONCLUSION: Plasma NOx levels did not predict glucose intolerance or insulin resistance before the development of T2D and the increase in plasma NOx levels in T2D was not caused by adiposity. Thus, plasma NOx is not a useful marker for the prediction of high-risk subjects for T2D among Vietnamese. PMID- 21233591 TI - Serum concentrations of DDT and DDE among malaria control workers in the Amazon region. AB - BACKGROUND: In Brazil, DDT was used to control malaria-transmitting mosquitoes from 1945 to 1997. Owing to concerns about the potential adverse health consequences of long-term exposures to DDT, workers of the National Foundation of Health (FNS) who had taken part in malaria control operations in the Amazon region were monitored for blood levels of DDT as well as for their health status between 1997 and 2001. OBJECTIVES: To evaluate blood levels of DDT/DDE and elimination half-life (t(1/2)) of pp'-DDE in malaria control personnel. METHODS: Levels of DDT and pp'-DDE were measured in the blood serum of 119 public health workers (32-67 yr old, 117 males) from Para state-Brazil. Serum levels of DDT/DDE were determined by gas chromatography with electron capture detection. RESULTS: Blood serum levels of -Sigma-DDT and pp'-DDE (mean +/- SD) were as follows (ug/l): February 1997 (N=110), 231.5 +/- 366.4 (156.9 +/- 236.8 as pp'-DDE); February 1998 (N=116), 126.4 +/- 86.6 (83.0 +/- 54.6 as pp'-DDE); May 2001 (N=117), 50.4 +/- 53.3 (39.4 +/- 37.6 as pp'-DDE). The half-life (mean +/- SD) of pp'-DDE was 29.5 +/- 22.7 mo. CONCLUSIONS: Concentrations of Sigma-DDT/ pp'-DDE in the blood serum of malaria control workers were much higher than levels found in the general population in Brazil and elsewhere. The half-life of pp'-DDE (29.5 mo) estimated for this group of occupationally exposed male adults was shorter than t(1/2) values previously reported for environmentally exposed subjects. PMID- 21233592 TI - Two- and 13-week inhalation toxicities of indium-tin oxide and indium oxide in rats. AB - OBJECTIVES: Two- and 13-week inhalation toxicities of indium-tin oxide (ITO) and indium oxide (IO) were characterized for risk assessments of workers exposed to ITO. METHODS: F344 rats of both sexes were exposed by inhalation to ITO or IO aerosol for 6 h/day, 5 day/wk for 2 wk at 0, 0.1, 1, 10 or 100 mg/m(3) or 13 wk at 0, 0.1 or 1 mg/m(3). An aerosol generator and inhalation exposure system was constructed. RESULTS: Blood and lung contents of indium were elevated in a dose related manner in the ITO- and IO-exposed rats. ITO and IO particles were deposited in the lung, mediastinal lymph node and nasal-associated lymphoid tissue. Exposures to ITO and IO induced alveolar proteinosis, infiltrations of alveolar macrophages and inflammatory cells and alveolar epithelial hyperplasia in addition to increased lung weight. ITO affected the lung more severely than IO did. Fibrosis of alveolar wall developed and some of these lesions worsened at the end of the 26-week post-exposure period. CONCLUSIONS: Persistent pulmonary lesions including alveolar proteinosis and macrophage infiltration occurred after 2- and 13-week inhalation exposures of rats to ITO and IO. Fibrosis of alveolar wall developed later. These lesions occurred after ITO exposure at the same concentration as the current occupational exposure limit in the USA and at blood indium levels below the biological exposure index in Japan for indium. PMID- 21233593 TI - Evaluation of acute oxidative stress induced by NiO nanoparticles in vivo and in vitro. AB - OBJECTIVES: Nickel oxide (NiO) is an important industrial material, and it is also a harmful agent. The toxicity of NiO is size-related: nanoparticles are more toxic than fine-particles. The toxic mechanism induced by NiO nanoparticles remains unexplained, and the relationship between in vitro and in vivo NiO toxicity results is unclear. In the present study, we focused on the oxidative stress caused by NiO nanoparticles by examining and comparing in vitro and in vivo acute responses induced by NiO nanoparticles. METHODS: Cellular responses induced by black NiO nanoparticles with a primary particle size of 20 nm, were examined in human lung carcinoma A549 cells. In vivo responses were examined by instillation of NiO nanoparticles into rat trachea. Bronchoalveolar lavage fluid (BALF) was collected after intratracheal instillation at different time points, and concentrations of lipid peroxide heme oxygenase-1 (HO-1), surfactant protein D (SP-D) and lactate dehydrogenase (LDH) in BALF were measured. RESULTS: The levels of intracellular reactive oxygen species and lipid peroxidation in A549 cells increased with increasing exposure to NiO nanoparticles, and increases in gene expressions of HO-1 and SP-D were observed in A549 cells. The lipid peroxide level in BALF significantly increased after 24 h instillation but decreased three days later. LDH leakage was also observed three days later. CONCLUSIONS: NiO nanoparticles induce oxidative stress-related lung injury. In vivo and in vitro oxidative stress was induced resulting in activation of antioxidant systems. Based on these responses, we conclude that the results of the in vivo and in vitro studies tend to correspond. PMID- 21233594 TI - Full genome sequence and virulence analyses of the recent equine isolate of Japanese encephalitis virus. AB - In the past 25 years, there has been only one case of Japanese encephalitis in horses in Japan. We determined the full genome sequence of the Japanese encephalitis virus (JEV) strain JEV/eq/Tottori/2003 isolated from an afflicted horse and also analyzed its virulence in mice. The sequence analysis showed that the genome of JEV/eq/Tottori/2003 is similar to that of genotype I, a dominant genotype of JEV presently circulating in Japan. Its neurovirulence, but not neuroinvasiveness, was still as high as it was for genotype III, thus indicating the necessity for continuation of a vaccination program of horses against JEV. PMID- 21233595 TI - Pregnancy rate and conception date in a wild population of Japanese monkeys. AB - This study is the first to determine the conception dates of specific individuals and estimate the pregnancy rate of a wild population in Japanese monkeys. The conception dates estimated from the embryonic ages of 37 fetuses were distributed over 128 days between September 17 and January 23, with a mean conception date of November 19 (SD=29.2 days). A comparison of the mean conception dates among age groups showed a significantly delayed conception in the subadult animals (aged 4 to 5 years; December 5, n=8) than in the adult animals (aged 6 or more years; November 15, n=29; P<0.03). The mean pregnancy rate among animals aged 4 years or more in this local population was estimated to be 48.5% (32/66). PMID- 21233596 TI - Magnetic resonance imaging assessment of pituitary posterior lobe displacement in dogs with pituitary-dependent hyperadrenocorticism. AB - The displacement and signal intensity (SI) of the pituitary posterior lobe were evaluated on T1 weighted magnetic resonance (MR) images in 28 dogs with pituitary dependent hyperadrenocorticism (PDH). Compared with normal dogs, the posterior lobe was displaced dorsally in the pituitary of the PDH dogs. Correlation between the pituitary height/brain area (P/B) ratio and the displacement of the posterior lobe in the PDH dogs suggests that dorsal displacement of the posterior lobe increases in accordance with enlargement of the pituitary. As to the SI of the posterior lobe, the PDH dogs showed significantly lower SI in comparison to the normal dogs. Taken together, these results suggest that assessment of the displacement and SI of the posterior lobe of the pituitary on T1-weighted MR images is useful for the diagnosis of pituitary adenoma. In pituitary microadenoma that presents no apparent tumorigenesis on MRI, evaluation of these values may be useful for diagnosis and selection of an appropriate therapy. PMID- 21233597 TI - Allometric scaling of orbifloxacin disposition in nine mammal species: a retrospective analysis. AB - The objective of this study was to analyze the relationship between pharmacokinetic parameters and body weight (W) for orbifloxacin using reported pharmacokinetic data. The parameters of interest: clearance (Cl), volume of distribution at steady state (Vss) and elimination half-life were correlated across nine mammal species, including cattle, dog, rat, rabbit, goat, camel, horse, cat and sheep as a function of W using the conventional allometric equation Y = aW(b), where Y is the pharmacokinetic parameter, W is the body weight, a is the allometric coefficient (intercept) and b is the exponent that describes the relationship between the pharmacokinetic parameter and W. Our estimates (Cl=4.40 W(1.03); Vss=1.10W(1.05)) indicated that the increase in these parameters with W approximates a linear power relationship with slopes being very close to one. Overall, the results of this study indicated that it is possible to use allometry to predict pharmacokinetic variables of orbifloxacin based on W of mammal species. PMID- 21233598 TI - Vibrio parahaemolyticus, enterotoxigenic Escherichia coli, enterohemorrhagic Escherichia coli and Vibrio cholerae. AB - This review highlighted the following: (i) pathogenic mechanism of the thermostable direct hemolysin produced by Vibrio parahaemolyticus, especially on its cardiotoxicity, (ii) heat-labile and heat-stable enterotoxins produced by enterotoxigenic Escherichia coli, especially structure-activity relationship of heat-stable enterotoxin, (iii) RNA N-glycosidase activity of Vero toxins (VT1 and VT2) produced by enterohemorrhagic Escherichia coli O157:H7, (iv) discovery of Vibrio cholerae O139, (v) isolation of new variant of Vibrio cholerae O1 El Tor that carries classical ctxB, and production of high concentration of cholera toxin by these strains, and (vi) conversion of viable but nonculturable (VBNC) Vibrio cholerae to culturable state by co-culture with eukaryotic cells. PMID- 21233600 TI - Aneuploidy in cancer: sudden or sequential? PMID- 21233599 TI - Multifactorial intervention in Type 2 diabetes: the promise of incretin-based therapies. AB - Type 2 diabetes mellitus is increasing in prevalence at alarming rates. Concurrent with its expanding prevalence is the increase in the related risk of morbidity and mortality. Because diabetic patients are prone to cardiovascular disease, treatment strategies should address the cardiovascular risk factors, including blood pressure, lipids, and body weight, in addition to the glycemic aspects of the disease. Newer agents, such as glucagon-like peptide-1 (GLP-1) analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors, have varying degrees of evidence to support their effects on body weight, blood pressure, and lipid levels, beyond glycated hemoglobin reduction. While GLP-1 agonists produce a weight loss, the DPP-4 inhibitors, conversely, appear to have a weight-neutral effect. Substantial evidence demonstrates that both medications produce modest reductions in systolic blood pressure and, in some cases, diastolic blood pressure, and reduce several markers of cardiovascular risk, including C-reactive protein. Moreover, GLP-1 influences endothelial function. The effect of the incretin hormones on serum lipids are either neutral or beneficial, with small, non-significant decreases in LDL cholesterol, increases in HDL cholesterol, and occasionally significant decreases in fasting triglyceride levels. Also, they have positive effects on hepatic steatosis. Although GLP-1 agonists and DPP-4 inhibitors are at present not appropriate for primary treatment of cardiovascular risks factors, the reduction of these parameters is evidently beneficial. PMID- 21233601 TI - Human Cdc14A becomes a cell cycle gene in controlling Cdk1 activity at the G2/M transition. AB - Cdc14 belongs to a dual-specificity phosphatase family highly conserved through evolution that preferentially reverses CDK (Cyclin dependent kinases) -dependent phosphorylation events. In the yeast Saccharomyces cerevisiae, Cdc14 is an essential regulator of late mitotic events and exit from mitosis by counteracting CDK activity at the end of mitosis. However, many studies have shown that Cdc14 is dispensable for exiting mitosis in all other model systems analyzed. In fission yeast, the Cdc14 homologue Flp1/Clp1 regulates the stability of the mitotic inducer Cdc25 at the end of mitosis to ensure Cdk1 inactivation before cytokinesis. We have recently reported that human Cdc14A, the Cdc14 isoform located at the centrosomes during interphase, down-regulates Cdc25 activity at the G2/M transition to prevent premature activation of Cdk1-Cyclin B1 complexes and untimely entry into mitosis. Here we speculate about new molecular mechanisms for Cdc14A and discuss the current evidence suggesting that Cdc14 phosphatase plays a role in cell cycle control in higher eukaryotes. PMID- 21233602 TI - Uncovering the role of Snapin in regulating autophagy-lysosomal function. AB - The autophagy-lysosomal system is the major degradation pathway essential for the maintenance and survival of neurons. This process requires efficient late endocytic transport from distal processes to the soma, in which lysosomes are predominantly localized. However, it is not clear how late endocytic transport has an impact upon neuronal autophagy-lysosomal function. We recently revealed that Snapin acts as a dynein motor adaptor and coordinates retrograde transport and late endosomal-lysosomal trafficking, thus maintaining efficient autophagy lysosomal function in neurons. Snapin(-/-) neurons display impaired retrograde transport and clustering of late endosomes along neuronal processes, aberrant accumulation of immature lysosomes, and impaired clearance of autolysosomes. Snapin deficiency leads to reduced neuron viability, neurodegeneration, and developmental defects in the central nervous system. Reintroducing the snapin transgene rescues these phenotypes by enhancing the delivery of endosomal cargos to lysosomes and by facilitating autophagy-lysosomal function. Our study suggests that Snapin is a candidate molecular target for autophagy-lysosomal regulation. PMID- 21233603 TI - Functional performance and quality of life in patients with squamous esophageal carcinoma receiving surgery or chemoradiation: results from a randomized trial. AB - OBJECTIVE: The aim of this study was to compare the 2-year functional performance and quality of life in patients with operable squamous cell carcinoma of the esophagus, who have received either surgery or definitive chemoradiation (CRT). SUMMARY BACKGROUND DATA: The functional outcomes and quality of life in patients receiving esophagectomy or definitive CRT is uncertain. METHODS: Data were extracted from the database of a prospective randomized controlled trial that included patients with resectable mid or lower thoracic esophageal cancers. The patients were randomized to either standard esophagectomy or definitive CRT. Quality of life assessments were performed using the EORTC QLQ-C30 and QLQ-OES24 modules. Other functional assessments included pulmonary and eating functions. RESULTS: From July 2000 to December 2004, a total of 81 patients were enrolled into the study. No significant longitudinal changes were detected in the global health status in both groups upon available follow-up. Surgery was associated with worsened physical functioning and fatigue symptoms up to 6 months after treatment (P < 0.001 and P = 0.021, respectively) and these scales improved at 2 years. In terms of pulmonary function, dyspnoic and coughing symptoms were significantly worsened 3 months after surgery (P = 0.024 and P = 0.036, respectively) whereas symptoms in the CRT group progressively deteriorated over time. Concerning the eating function, both groups had improvements in dysphagia but there were frequent need for endoscopic intervention. This study has been registered with clinicaltrials.gov and the clinicaltrials.gov ID number is NCT01032967. CONCLUSION: Neither surgery nor definitive CRT significantly impaired the global health status of patients. Surgery was associated with a short-term negative impact in some aspects of health related quality of life assessments but these changes became insignificant 2 years after treatment. However, CRT was associated with progressive deteriorations in pulmonary function in the longer term. PMID- 21233604 TI - Defining a "successful" esophagectomy. PMID- 21233605 TI - Long-term outcome of laparoscopic nissen fundoplication compared with laparoscopic thal fundoplication in children: a prospective, randomized study. AB - BACKGROUND: Laparoscopic fundoplication is increasingly performed in pediatric surgery. Many types of fundoplication are performed, each has advantages and disadvantages. To date there has been no prospective randomized study to determine the optimal laparoscopic technique in children. The aim of the study was to compare the long-term outcomes and control of symptoms after laparoscopic Nissen fundoplication with laparoscopic Thal fundoplication in children. METHODS: Between July 1998 and April 2007, 175 patients were recruited to this prospective, randomized study. Patients were assessed before the operation and after defined intervals starting at 3 months after surgery. The "absolute" outcome measure for fundoplication failure was recurrence of symptoms that merited a redofundoplication or insertion of a transgastric jejunostomy. "Relative" outcome measures were recurrence of symptoms necessitating reintroduction of antireflux medication (ie, "intention to treat") and postoperative complications (eg, postoperative dysphagia). The median follow-up time was 30 months (range, 1-109). This study has been registered with clinicaltrials.gov (NCT01027975). RESULTS: Long-term results were available in 167 patients of which 85 underwent a Nissen and 82 a Thal fundoplication. Four patients in the Nissen group (4.7%) and 12 in the Thal group (14.6%) required a redofundoplication. One child in each group developed recurrence of symptoms and had a transgastric jejunostomy performed. The "absolute" failure rate was significant lower in the Nissen group (n = 5; 5.9%) compared with the Thal group (n = 13; 15.9%) (P = 0.038). The vast majority of these patients (17 of 18) had underlying neurological disorders. The "relative" failure rate (ie, "intention to treat") was similar in both groups. Nearly one-quarter of patients developed postoperative dysphagia similarly distributed between both groups. However, severe dysphagia requiring endoscopy +/- dilatation was significantly higher in the Nissen group (n = 10, 11.8%) compared with the Thal group (n = 2; 2.4%) (P = 0.020). One of 31 deaths (0.6%) in this series occurred after surgery, but was not directly related to the fundoplication technique. CONCLUSIONS: In the long term a laparoscopic Nissen fundoplication had a significantly lower recurrence rate than a Thal fundoplication, particularly in patients with underlying neurological disorders. There was no significant difference between the 2 types of fundoplication in normal children. There was no significant difference between the need for restarting antireflux medication between both groups because of recurrence of moderate symptoms. The incidence of postoperative dysphagia was similar in the 2 groups, however, significantly more patients in the Nissen group required intervention for severe dysphagia. Overall the perioperative death rate was low even in high-risk patients. PMID- 21233606 TI - Validation of perioperative steroids administration in liver resection: a randomized controlled trial. AB - OBJECTIVE: We performed a randomized controlled trial to investigate the clinical benefits of perioperative treatment with steroids in patients undergoing liver resection. BACKGROUND: Perioperative steroids are considered to reduce surgical stress, but evidence supporting proposed clinical benefits is largely anecdotal. PATIENTS AND METHODS: The 210 patients scheduled to undergo liver resection were randomly assigned to a steroids group (n = 105) or a control group (n = 105). The steroids group received 500 mg hydrocortisone immediately before hepatic-pedicle clamping, followed by 300 mg hydrocortisone on postoperative day (POD) 1, 200 mg on POD 2, and 100 mg on POD 3. Serum levels of total bilirubin, aminotransferases coagulation factors, and inflammatory-related cytokines, and the clinical course were compared between the 2 groups. The primary end point was the postoperative bilirubin level. RESULTS: All 210 patients underwent radical liver resection with no operative mortality. The median bilirubin level on POD 2 was significantly lower in the steroids group [0.71 mg/dL (0.33-2.17)] than in the control group [1.03 mg/dl (0.39-3.57); P = 0.01]. The postoperative time courses of the bilirubin level (P = 0.01), the interleukin-6 level (P = 0.01) and the C-reactive protein level (P = 0.01) were significantly lower whereas the the prothrombin level (P = 0.01) and interleukin-10 level (P = 0.01) were significantly higher in the steroids group. There was no difference between the groups in the proportion of patients with complications (40% vs 43%; P = 0.66) or the length of the hospital stay (14 days vs 13 days; P = 0.68). CONCLUSIONS: Perioperative treatment with steroids has a positive impact on the liver function of patients who undergo liver resection, without increasing the risk of complications. PMID- 21233607 TI - Fluorodeoxyglucose positron emission tomography for evaluating early response during neoadjuvant chemoradiotherapy in patients with potentially curable esophageal cancer. AB - BACKGROUND: Neoadjuvant chemoradiotherapy before surgery can improve survival in patients with potentially curable esophageal cancer, but not all patients respond. Fluorodeoxyglucose positron emission tomography (FDG-PET) has been proposed to identify nonresponders early during neoadjuvant chemoradiotherapy. The aim of the present study was to determine whether FDG-PET could differentiate between responding and nonresponding esophageal tumors early in the course of neoadjuvant chemoradiotherapy. METHODS: This clinical trial comprised serial FDG PET before and 14 days after start of chemoradiotherapy in patients with potentially curable esophageal carcinoma. Histopathologic responders were defined as patients with no or less than 10% viable tumor cells (Mandard score on resection specimen). PET response was measured using the standardized uptake value (SUV). Receiver operating characteristic analysis was used to evaluate the ability of SUV in distinguishing between histopathologic responders and nonresponders. RESULTS: In 100 included patients, 64 were histopathologic responders. The median SUV decrease 14 days after the start of therapy was 30.9% for histopathologic responders and 1.7% for nonresponders (P = 0.001). In receiver operating characteristic analysis, the area under the curve was 0.71 (95% CI = 0.60-0.82). Using a 0% SUV decrease cutoff value, PET correctly identified 58 of 64 responders (sensitivity 91%) and 18 of 36 nonresponders (specificity 50%). The corresponding positive and negative predictive values were 76% and 75%, respectively. CONCLUSIONS: SUV decrease 14 days after the start of chemoradiotherapy was significantly associated with histopathologic tumor response, but its accuracy in detecting nonresponders was too low to justify the clinical use of FDG-PET for early discontinuation of neoadjuvant chemoradiotherapy in patients with potentially curable esophageal cancer. PMID- 21233608 TI - A characterization of factors determining postoperative ileus after laparoscopic colectomy enables the generation of a novel predictive score. AB - BACKGROUND/OBJECTIVE: Postoperative ileus (POI) after colorectal surgery is associated with prolonged hospital stay and increased costs. The aim of this study is to investigate pre-, intra-, and postoperative risk factors associated with the development of POI in patients undergoing laparoscopic partial colectomy. METHODS: Patients operated between 2004 and 2008 were retrospectively identified from a prospectively maintained database, and clinical, metabolic, and pharmacologic data were obtained. Postoperative ileus was defined as the absence of bowel function for 5 or more days or the need for reinsertion of a nasogastric tube after starting oral diet in the absence of mechanical obstruction. Associations between likelihood of POI and study variables were assessed univariably by using chi tests, Fisher exact tests, and logistic regression models. A scoring system for prediction of POI was constructed by using a multivariable logistic regression model based on forward stepwise selection of preoperative factors. RESULTS: A total of 413 patients (mean age, 58 years; 53.5% women) were included, and 42 (10.2%) of them developed POI. Preoperative albumin, postoperative deep-vein thrombosis, and electrolyte levels were associated with POI. Age, previous abdominal surgery, and chronic preoperative use of narcotics were independently correlated with POI on multivariate analysis, which allowed the creation of a predictive score. Patients with a score of 2 or higher had an 18.3% risk of POI (P < 0.001). CONCLUSION: Postoperative ileus after laparoscopic partial colectomy is associated with specific preoperative and postoperative factors. The likelihood of POI can be predicted by using a preoperative scoring system. Addressing the postoperative factors may be expected to reduce the incidence of this common complication in high-risk patients. PMID- 21233609 TI - Endoscopic treatment of biliary fistulas after complex liver resection. AB - OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of endoscopic treatment for biliary fistulas after complex liver resection. BACKGROUND: The role of endoscopy in the treatment of fistulas of the common bile duct is well documented. On the contrary, results of endoscopic procedures for fistulas arising from peripheral bile ducts after liver resections are poorly studied, although more complex hepatectomies are increasingly performed. We analyzed retrospectively the results of these procedures in our experience. PATIENTS: Twenty-six patients aged 10 to 74 years were included. Fistulas arose after extended right hepatectomy, n = 14; extended left hepatectomy, n = 2; segmentectomy, n = 7; and split-liver transplantation, n = 3. All patients underwent radiologic or surgical external drainage before endoscopic retrograde cholangiopancreatography (ERCP). Mean bile outflow before endoscopy was 493.1 +/- 386.1 mL/24 h (median, 400; range, 100-2000 mL). The mean time from surgery to diagnosis was 29.4 +/- 45.5 days. RESULTS: The ERCP was performed after a median of 13 days after the diagnosis of biliary fistula. A sphincterotomy was required in 96.1% of patients. A 5F to 10F polyethylene stent bypassing the leaking bile duct was implanted in 21 (80.7%) of 26 patients. Fistulas were dried up completely in 25 (96.1%) of 26 patients. The mean time from initial ERCP to running dry of the leaks was 17.5 +/- 12.4 days. Procedure-related morbidity was 0%. There was no mortality. CONCLUSION: Biliary fistulas arising from intrahepatic ducts after complex liver resections are more difficult to treat than distal fistulas arising from the common bile duct. However, despite a longer time for cure and the need for repeated ERCP, endoscopic therapy appears efficient and does not induce additional morbidity. PMID- 21233610 TI - Gene expression signature of the gross morphology in hepatocellular carcinoma. AB - OBJECTIVE: To evaluate the gene expression signature of hepatocellular carcinoma (HCC) in relation to the gross morphology. BACKGROUND: Eggel's nodular type of HCC is morphologically subclassified into the single nodular (SN) type, the single nodular type with extranodular growth (SNEG), and the confluent multinodular (CM) type, but their biomolecular differences remain unclear. METHODS: The clinicopathological characteristics and genome-wide gene expressions were analyzed in 275 patients with nodular-type HCC (124 SN-type, 91 SNEG-type, and 60 CM-type) who received curative hepatectomy. RESULTS: Significantly poor prognosis was recognized in CM types in overall survival (P = 0.0020) and recurrence-free survival (P = 0.0066). Analysis of the genome-wide expression patterns revealed significant difference of CM-type HCC from either SN- or SNEG type HCC. In particular, a stem cell marker EpCAM was dominantly expressed in CM type HCC. Immunohistochemical studies confirmed the specific expression of EpCAM in HCC cancer cells of CM type. In multivariate analysis, the gross morphology of CM type was significantly associated with EpCAM expression (P = 0.0092), alpha fetoprotein (P = 0.0424), "lens culinaris agglutinin-reactive fraction of alpha fetoprotein" level (P = 0.0288), and the portal vein invasion (P = 0.0150). Furthermore, EpCAM was predictive for poor prognosis in overall and recurrence free survivals of patients with CM-type HCC (P = 0.0082 and P = 0.0043, respectively). CONCLUSION: Our studies suggest that the distinct signature of gene expression is closely related to morphological progression in HCC. Especially, EpCAM might play a critical role in the aggressiveness of CM-type HCC. PMID- 21233611 TI - The effects of serum calcium and parathyroid hormone changes on psychological and cognitive function in patients undergoing parathyroidectomy for primary hyperparathyroidism. AB - OBJECTIVE: This study had 2 aims: (1) to assess the timing and magnitude of psychological and neurocognitive changes before and after parathyroidectomy and (2) to examine correlations between changes in serum biomarkers and psychological symptoms and neurocognitive performance. BACKGROUND: Psychological and neurocognitive changes are common in patients with primary hyperparathyroidism (pHPT), but the associations of serum biomarkers and these changes have not been established. METHODS: This prospective cohort study carried out at a large tertiary care referral center from 2004 to 2008 screened all adult patients with the biochemical diagnosis of pHPT who underwent first-time parathyroidectomy. Laboratory results, psychological symptom reports, and results of neurocognitive testing using validated instruments were obtained preoperatively and at 1, 3, and 6 months postoperatively. Outcomes measures included serum calcium, intact parathyroid hormone (iPTH), and thyroid stimulating hormone; psychological symptom inventories (Beck Depression Inventory-II, Brief Symptom Inventory-18, and Spielberger State-Trait Anxiety Inventory); and neurocognitive test scores (Rey Auditory Verbal Learning Test and Groton Maze Learning Test). RESULTS: Two hundred twelve patients were enrolled; mean age was 60 years; 78% were female and had low comorbidity; 78% had parathyroidectomy under ambulatory, minimally invasive techniques; cure rate was 99%. Improvements in psychological and neurocognitive measures were observed at all postoperative follow-up visits. The most pronounced improvements were noted in depressive and anxiety symptoms, and visuospatial and verbal memory. Examination of change scores revealed that postoperative reduction in iPTH was associated with a decrease in state anxiety, which was also associated with improvement in visuospatial working memory. CONCLUSIONS: Reduction in mood and anxiety symptoms is associated with reductions in both iPTH and spatial working memory in patients with pHPT who undergo successful parathyroidectomy. PMID- 21233612 TI - The effect of an organized trauma system on mortality in major trauma involving serious head injury: a comparison of the United kingdom and victoria, australia. AB - OBJECTIVE: To compare outcomes following major trauma involving serious head injury managed in an inclusive trauma system (Victoria, Australia) and a setting where rationalization of trauma services is absent (England/Wales). BACKGROUND: The introduction of regionalized trauma systems has the potential to reduce preventable deaths, but their uptake has been slow around the world. Improved understanding of the benefits and limitations of different systems of trauma care requires comparison across systems. METHODS: Mortality outcomes following major trauma involving serious head injury managed in the 2 settings were compared using multivariate logistic regression. Data pertaining to the period July 2001 to June 2006 (inclusive) were extracted from the Trauma Audit and Research Network (TARN) in the United Kingdom and the Victorian State Trauma Registry (VSTR) in Australia. RESULTS: A total of 4064 (VSTR) and 6024 (TARN) cases were provided for analysis. The odds of death for TARN cases were significantly higher than those for VSTR cases [odds ratio = 2.15, 95% confidence interval = 1.95 2.37]. After adjusting for age, gender, cause of injury, head injury severity, Glasgow Coma Scale score, and Injury Severity Score, TARN cases remained at elevated odds of death (3.22; 95% confidence interval = 2.84-3.65) compared with VSTR cases. CONCLUSIONS: Management of the severely injured patient with an associated head injury in England and Wales, where an organized trauma system is absent, was associated with increased risk-adjusted mortality compared with management of these patients in the inclusive trauma system of Victoria, Australia. This study provides further evidence to support efforts to implement such systems. PMID- 21233613 TI - External benchmarking of trauma center performance: have we forgotten our elders? AB - OBJECTIVE: The elderly injured have been identified as a population with unique needs compared with nonelderly trauma patients. We sought to determine whether trauma center (TC) performance is consistent across age groups and to assess whether aggregate evaluations of TC performance capture quality of care among the elderly. BACKGROUND: The recently launched Trauma Quality Improvement Program utilizes external benchmarking of TC outcomes to identify centers with above average performance, with the goal of disseminating best practices. If variation exists in TC performance across age groups, such variation might significantly impact on the success of external benchmarking programs in improving quality of care. METHODS: Study data were derived from the National Trauma Databank (2007), limited to level I and II centers and adults with moderate to severe injuries (injury severity score > 9). Separate logistic regression models were constructed to produce TC risk-adjusted mortality for both the young and the elderly (age > 65 years). Observed-to-expected mortality ratios were used to identify centers with above or below average performance overall, among the young and among the elderly. RESULTS: We identified 87,754 patients across 132 facilities; 25% were elderly. After adjustment for case mix, 9 centers were identified as above average performers in the elderly population. Only 2 of these centers were also above-average performers among young patients. Overall, concordance for center performance across age strata evidenced poor agreement (kappa, 0.23). In addition, aggregate assessment of center performance did not reliably identify high-performing centers for elderly patients. CONCLUSIONS: The use of outcome based benchmarking harbors significant potential for trauma quality improvement. Evaluations of aggregate TC performance may not adequately reflect the care provided to the elderly injured. Elderly trauma patients may warrant special attention in the context of ongoing quality improvement programs. PMID- 21233614 TI - Risk factors for liver failure and mortality after hepatectomy associated with portal vein resection. AB - OBJECTIVE: To report the postoperative outcome of hepatectomy associated with portal vein resection (PVR) and to identify risk factors of clinical value for predicting postoperative liver failure and mortality. SUMMARY BACKGROUND DATA: Resection of the portal vein during hepatectomy allows an increase in the number of patients who may benefit from a potentially curative operation that is, however, technically difficult and may increase postoperative morbidity and mortality. Few data are available about risk factors for liver failure and mortality after such extensive operations. METHODS: Between July 1996 and July 2008, a total of 1348 patients were operated on for liver disease in our institution. Among them, 55 patients underwent liver resection associated with PVR. Medical records of these patients were prospectively collected and retrospectively analyzed. RESULTS: Overall mortality for this selected group of patients was 7.2%. Irreversible liver failure was the main cause of death. Overall morbidity was 58.1%. A total of 94% of the patients (n = 52) underwent a major (>= 3 segments) or an extended > 4 segments) right or left hepatectomy. Univariate analysis showed that male gender (P = 0.004), extended liver resection (P = 0.028), and, particularly, extended right hepatectomy (P = 0.015) were significantly associated with an increased risk of postoperative liver failure. Male gender was the single independent risk factor for liver failure. Moreover, the presence of liver steatosis (P = 0.014), an extended right hepatectomy procedure (P = 0.047), and postoperative liver failure (P = 0.046) were significantly associated with an increased rate of postoperative mortality. CONCLUSION: The present study confirmed that major or extended hepatic resection with PVR can be performed with acceptable overall morbidity and mortality rates. Preoperative selection of the patients should take in consideration the gender and the extent of hepatic resection to avoid irreversible postoperative liver failure. Extended right hepatectomy with PVR should be carefully considered in patients with liver steatosis due to the high risk of postoperative mortality. PMID- 21233615 TI - Effects of the balance in activity of RhoA and Rac1 on the shock-induced biphasic change of vascular reactivity in rats. AB - OBJECTIVE: To investigate the effects of the balance in activity of RhoA and Rac1 on the shock-induced biphasic change in vascular reactivity and the related mechanism. BACKGROUND: Vascular reactivity after hemorrhagic shock shows a biphasic change. RhoA and Rac1 are the main members of a family of Rho GTPases; whether and how they participate in the regulation of the biphasic change in vascular reactivity after shock is not known. METHODS: The relationship of the balance of the activity RhoA and Rac1 with the changes in vascular reactivity after hemorrhagic shock, the effects of artificially changing the balance of RhoA and Rac1 activity on vascular reactivity, and the roles of Rho kinase and p21 activated kinase (PAK) in RhoA/Rac1 regulation of vascular reactivity were observed in isolated superior mesenteric arteries (SMAs) from hemorrhagic shocked rats and hypoxia-treated vascular smooth muscle cells (VSMCs). RESULTS: The reactivity of SMAs and VSMCs to norepinephrine after shock or hypoxia was positively correlated with changes in the RhoA and Rac1 activity ratio. Artificially changing the balance in activity of RhoA and Rac1 significantly changed the shock-induced biphasic response of vascular reactivity. Specific antagonist of Rho kinase and PAK (Y-27632 and PAK-18) respectively abolished the effect of activation of RhoA and Rac1. Activation of RhoA significantly increased the activity of Rho kinase and inhibited the activity of Rac1 in SMAs. Rac1 activation significantly increased the activity of PAK and decreased the activity of RhoA. CONCLUSIONS: The balance in the activity of RhoA and Rac1 participated in the biphasic vascular reactivity seen after hemorrhagic shock. RhoA and Rac1 regulation of the vascular reactivity after shock are closely related to Rho kinase and the PAK pathway. RhoA regulates vascular reactivity mainly through activation of Rho kinase and inhibition of Rac1. Rac1 regulates vascular reactivity mainly through inhibition of RhoA and activation of PAK. These findings have potential significance for the treatment of vascular hyporesponsiveness. PMID- 21233616 TI - A multicenter prospective study of surgical audit systems. AB - OBJECTIVE: This study was undertaken to evaluate a modified form of Estimation of Physiologic Ability and Surgical Stress (E-PASS) for surgical audit comparing with other existing models. BACKGROUND: Although several scoring systems have been devised for surgical audit, no nation-wide survey has been performed yet. METHODS: We modified our previous E-PASS surgical audit system by computing the weights of 41 procedures, using data from 4925 patients who underwent elective digestive surgery, designated it as mE-PASS. Subsequently, a prospective cohort study was conducted in 43 national hospitals in Japan from April 1, 2005, to April 8, 2007. Variables for the E-PASS and American Society of Anesthesiologists (ASA) status-based model were collected for 5272 surgically treated patients. Of the 5272 patients, we also collected data for the Portsmouth modification of Physiologic and Operative Severity Score for the enUmeration of Mortality and morbidity (P-POSSUM) in 3128 patients. The area under the receiver operative characteristic curve (AUC) was used to evaluate discrimination performance to detect in-hospital mortality. The ratio of observed to estimated in-hospital mortality rates (OE ratio) was defined as a measure of quality. RESULTS: The numbers of variables required were 10 for E-PASS, 7 for mE-PASS, 20 for P-POSSUM, and 4 for the ASA status-based model. The AUC (95% confidence interval) values were 0.86 (0.79-0.93) for E-PASS, 0.86 (0.79-0.92) for mE-PASS, 0.81 (0.75-0.88) for P-POSSUM, and 0.73 (0.63-0.83) for the ASA status-based model. The OE ratios for mE-PASS among large-volume hospitals significantly correlated with those for E-PASS (R = 0.93, N = 9, P = 0.00026), P-POSSUM (R = 0.96, N = 6, P = 0.0021), and ASA status-based model (R = 0.83, N = 9, P = 0.0051). CONCLUSION: Because of its features of easy use, accuracy, and generalizability, mE-PASS is a candidate for a nation-wide survey. PMID- 21233617 TI - Bone marrow-derived mesenchymal stem cells transplantation accelerates tissue expansion by promoting skin regeneration during expansion. AB - OBJECTIVE: To evaluate the effect of bone marrow-derived mesenchymal stem cells (BM-MSCs) transplantation on tissue expansion. BACKGROUND: Tissue expansion provides a better solution to large defect reconstruction with perfectly matched skin and without deformity at the donor site. How to promote tissue expansion and reduce complications has been a focus in this field. BM-MSCs have been found to exhibit tissue regeneration-promoting ability, but their effect on skin growth during tissue expansion has remained unclear. METHODS: BM-MSCs transplantation was performed on a rat tissue expansion model. Inflation volume, expansion time, and area were examined to determine the effect on tissue expansion. Factors related to skin regeneration were examined to evaluate BM-MSCs' role in skin regeneration during expansion. The mechanism was explored by in vivo and in vitro experiments. RESULTS: Higher inflation volume, larger expansion area, and shorter expansion time could be achieved by BM-MSCs transplantation (all P < 0.05). The skin regeneration during expansion was enhanced by BM-MSCs treatment, as evidenced by a thicker epidermis and further evidenced by increased cell proliferation, collagen synthesis, and angiogenesis. Cell tracking showed that the transplanted BM-MSCs appeared in skin structures, suggesting a direct contribution to skin regeneration. The paracrine secretion effect of BM-MSCs was also examined. The roles of epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) were studied, and EGF was found to play an important role in the skin regeneration-promoting effect of BM-MSCs. CONCLUSIONS: This study shows that BM-MSCs transplantation can shorten the tissue expansion process by enhancing skin regeneration. PMID- 21233620 TI - Lowering LDL-cholesterol through diet: potential role in the statin era. AB - PURPOSE OF REVIEW: A healthy diet should be rich in vegetables and fruits, whole grain, high-fiber foods, and fish and should contain a small amount of saturated and trans fats. In addition to these recommendations, some food ingredients such as plant sterol/stanol soy protein and isoflavones may help reduce cholesterol levels. Increased dietary fiber intakes are associated with significantly lower prevalence of cardiovascular disease and lower LDL-cholesterol concentration of about 5-10%. Beyond LDL-cholesterol lowering effects, other benefits have been observed on hypertension, diabetes mellitus. In this review, we summarize the different dietary approaches proven to be associated with LDL-cholesterol decrease. Nutritional interventions that do not exert significant LDL-cholesterol decrease have not been included in this review. RECENT FINDINGS: On top of a 'classical' step 1 and step 2 diet, the cornerstone of dietary recommendations, recent findings confirm the deleterious effects of trans fatty acid or the beneficial effects of sterols/stanols and nuts. SUMMARY: Dietary recommendations may have an impressive impact on cardiovascular events because they can be implemented early in life and because the sum of the effect on LDL-cholesterol is far from being negligible: step 1 diet (-10%), dietary fibers (-5 to -10%), plant sterols/stanols (-10%), nut consumption (-8%), and soy protein (-3 to -10%). PMID- 21233621 TI - Current world literature. PMID- 21233622 TI - Recent advances in understanding the role and use of marine omega3 polyunsaturated fatty acids in cardiovascular protection. PMID- 21233623 TI - The ABC transporters and the thickening cholesterol plot. PMID- 21233624 TI - Atherosclerosis: cell biology and lipoproteins. PMID- 21233625 TI - Evidence for use of fibrates in diabetic dyslipidemia: are we looking hard enough? PMID- 21233627 TI - Current world literature. PMID- 21233629 TI - Current world literature. PMID- 21233630 TI - Effects of HIV-1 gp120 and protease inhibitors on apoptotic susceptibility of CD34+ hematopoietic progenitor cells. PMID- 21233631 TI - Integrase and fusion inhibitors transmitted drug resistance in naive patients with recent diagnosis of HIV-1 infection. PMID- 21233632 TI - Expression of the mRNA levels for MDR1, MRP1, MRP4, and MRP5 in HIV antiretroviral naive patients: follow-up at 48 weeks after the beginning of therapy. PMID- 21233633 TI - Hyperinflation of quoted co-authors in observational and clinical studies, intercohort and pooled analyses, in the field of HIV disease. An increasing worrying phenomenon for its clinical consequences and the degeneration of the role of authorship. PMID- 21233634 TI - Rapid oral HIV screening: expectations revisited. PMID- 21233635 TI - Is testing for glucose-6-phosphate dehydrogenase deficiency before starting sulfa useful in HIV-infected male patients originating from sub-Saharan Africa? PMID- 21233636 TI - Maternal and infant outcomes with concurrent treatment of tuberculosis and HIV infection in pregnant women. PMID- 21233637 TI - Similar short-term efficacy of antiretroviral therapy in patients infected with HIV B and non-B subtype strains in france. PMID- 21233638 TI - Impact of HIV-1 group O genetic diversity on genotypic resistance interpretation by algorithms designed for HIV-1 group M. AB - BACKGROUND: HIV-1 group O (HIV-O) is characterized by a high genetic divergence from HIV-1 group M viruses. Little is known about the therapeutic impact of this diversity. The aim of this study was to assess in a large series of samples (1) the genotypic impact of natural polymorphism of the HIV-O reverse transcriptase and protease genes; and (2) the predictive value of resistance interpretation algorithms developed for HIV-1 group M when used for highly mutated HIV-O viruses. METHODS: Sixty-eight antiretroviral-naive and 9 highly antiretroviral experienced HIV-O-infected patients were included. The viruses were sequenced and resistance-associated mutations were identified using 3 different algorithms (Agence Nationale de Recherches sur le SIDA et les hepatites virales, Rega, Stanford). RESULTS: All HIV-O samples naturally exhibited the A98G and V179E resistance mutations in the reverse transcriptase region; 54% of samples presented the Y181C mutation, conferring resistance to nonnucleoside reverse transcriptase inhibitors. Twelve minor resistance mutations, present in more than 75% of the protease sequences, led to the different algorithms giving discrepant results for nelfinavir and saquinavir susceptibility. A marked virological response was observed in 8 of the 9 antiretroviral-experienced patients, despite the prediction of limited activity of the combination for 5 to 8 patients according to the algorithm used. CONCLUSIONS: The high level of natural polymorphism in HIV-O genes, and the important discrepancies between genotypic resistance interpretation and the virological response, emphasize the need for resistance algorithm rules better adapted to HIV-O. PMID- 21233639 TI - Estimated HIV incidence among high-risk heterosexuals in New York City, 2007. AB - Estimates of HIV incidence rates among high-risk heterosexuals (HRH) in the United States have been limited to heterosexual subgroups like prison inmates and commercial sex workers. In this analysis, we estimate incidence with detuned assay testing among a group of HRH defined through a multidimensional sampling strategy and recruited through respondent-driven sampling. Incidence was 3.31% per year (95% confidence interval = 1.43 to 6.47) overall and 2.59% per year (95% confidence interval = 0.84 to 6.06) among participants with no lifetime history of drug injection or male-to-male sex. This study design is suggested as an efficient method for recruiting HRH for cohort studies and behavioral interventions. PMID- 21233640 TI - Pharmacological activity of novel 2-hydroxyacetophenone isatin derivatives on cardiac and vascular smooth muscles in rats. AB - Isatin (1H-indole-2,3 dione) is an endogenous compound with biological activities. Many of its derivatives have pharmacological effects, including inhibition of cyclic guanosine monophosphate levels in cardiac tissue; sedative hypnotic profiles; anticonvulsant, analgesic, antithermic, and anti-inflammatory activities; and anxiolytic, antimicrobial, and proapoptotic effects. Carbamates derived from isatin have a vasorelaxant profile. This study investigated the activity of 2 novel 2-hydroxyacetophenone derivatives of isatin (named MB101 and MB130) on the contractility of rat aorta and papillary muscles. Both compounds induced a concentration-dependent relaxation (5-100 MUM) in the endothelium intact aorta that was abolished by N-nitro-L-arginine methyl ester. Atropine, a muscarinic receptor antagonist, significantly prevented vasodilatation of 100 MUM MB101. In contrast, atropine caused no significant alteration in MB130-induced vasorelaxation. Naloxone, a nonselective opioid receptor antagonist, completely prevented the relaxing effect of MB101 and MB130 at all concentrations. In papillary muscles, only MB130 induced a significant depression, and this contractile response was not altered by propranolol and atropine. Both the compounds reduced systolic and diastolic pressures in a dose-dependent manner in anesthetized rats. The 2-hydroxyacetophenones produced direct effects on vascular tonus through either muscarinic or opioid pathways. MB130 produced cardiac depression by opioid receptors and bradykinin because pretreatment HOE140 or with naloxone, an antagonist of type-2, bradykinin were able to partially block the decrease in twitch amplitude in papillary muscles induced by MB130. These findings provide information for designing new strategies for the treatment of cardiovascular disorders. PMID- 21233661 TI - Colostomy irrigation and peristomal skin complications. PMID- 21233641 TI - Effects of selective cyclooxygenase-2 and nonselective cyclooxygenase inhibition on myocardial function and perfusion. AB - Nonselective nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 (COX-2) inhibitors are purported to increase adverse cardiovascular events. We hypothesized that COX-2 inhibitors would alter myocardial blood flow, microvascular reactivity, oxidative stress, and prostaglandin levels. Adult Yorkshire swine were divided into 3 groups: no drug (control, n = 7), a nonselective COX inhibitor (naproxen 400 mg daily, NAP, n = 7), or a selective COX-2 inhibitor (celecoxib 200 mg daily, CBX, n = 7). After 7 weeks, physiologic measurements were taken and tissue harvested. Animals in the CBX group demonstrated significantly higher blood pressure and rate-pressure product. The NAP and CBX groups demonstrated an increased microvascular contraction response to serotonin. The NAP group showed increased myocardial levels of thromboxane and lower levels of prostacyclin. Levels of protein oxidative stress were increased in the CBX group. Myocardial apoptosis was lowest in the NAP group. Immunoblotting demonstrated decreased vascular endothelial growth factor and phosphorylated endothelial nitric oxide synthase expression in the NAP and CBX groups. Myocardial tumor necrosis factor-alpha was increased in both treated groups. Immunostaining for thromboxane A2 synthase and receptor demonstrated expression within the vascular smooth muscle and no observable differences between groups. Nonselective and selective COX inhibition does not alter myocardial perfusion but results in altered myocardial and vascular physiology that may have implications regarding cardiovascular risk. PMID- 21233662 TI - Statistical hypothesis testing: motivation and methods for the comparison of means between 2 patient samples. PMID- 21233663 TI - Assessment and management of children with abdominal wall defects. PMID- 21233664 TI - Hospital-acquired pressure ulcer prevalence--evaluating low-air-loss beds. AB - PURPOSE: Higher-category pressure redistribution mattresses are considered a critical component of a pressure ulcer prevention program, but few studies have quantified the impact of specific preventive measures on the incidence or prevalence of hospital-acquired pressure ulcers (HAPUs). Therefore, this study was undertaken to determine the impact of low-air-loss beds on HAPU prevalence. METHODS: This prospective, comparative cohort study monitored the prevalence of HAPU at our hospital and compared rates of matched medical-surgical units with and without low-air-loss beds. Units without low-air-loss beds used a variety of alternative pressure redistribution devices for patients deemed at risk for pressure ulceration. The prevalence of HAPU was operationally defined as the number of patients with HAPUs divided by numbers of patients observed. RESULTS: The prevalence of HAPU over 3 quarters in 2008 ranged from 1.0% to 3.3% (overall rate 2.4%). Eighty-three percent of patients with HAPUs were cared for on low-air loss beds. Of 12 patients with 16 HAPUs during this time, 75% were aged 70 years or older and 25% were managed in critical care units. Over half of patients who developed HAPUs had been hospitalized for 20 days or more. Half of the patients with HAPUs were scored as no-low risk on the Braden Scale.On the paired medical surgical units, no statistically significant differences were found when patients with low-air-loss beds were compared to standard hospital mattresses supplemented by a variety of pressure redistribution devices. Seven of 11 HAPUs (63%) occurred in patients placed on low-air-loss beds. CONCLUSIONS: The prevalence of HAPU in patients placed on low-air-loss beds was no different from patients placed on standard hospital mattresses supplemented by a variety of pressure redistribution devices. Further research is needed to determine the impact of specific strategies on prevention of HAPU. PMID- 21233665 TI - The certification examination. PMID- 21233666 TI - Successful treatment of venous stasis ulcers with combination compression therapy and pulsed radio frequency energy in a patient scheduled for amputation. AB - BACKGROUND: Venous ulcers are a frequent complication of chronic venous insufficiency. Compression therapy remains the mainstay of conservative treatment, as many patients are not candidates for surgical intervention. CASE: A 78-year-old man was referred to our Preservation-Amputation Care and Treatment for management of 3 venous stasis ulcers on the front of the left lower leg. Multiple comorbid conditions and his generally poor health rendered him a poor candidate for surgical reperfusion In addition, his right leg was amputated approximately 3 years before, and he was nonweight bearing on the remaining left leg. In order to heal these venous stasis ulcers and preserve his limb, Mr A underwent treatment with a combination of compression therapy and pulsed radio frequency energy. CONCLUSION: Compression therapy plus pulsed radio frequency energy led to healing of his venous leg ulcers and avoided amputation of the affected limb. This treatment is currently being evaluated in other patients with chronic venous insufficiency and ulceration. PMID- 21233668 TI - Overview and recent advances in neuropathology. PMID- 21233669 TI - Overview and recent advances in neuropathology. Part 1: Central nervous system tumours. AB - This review highlights the recent changes to the World Health Organization (WHO) 4th edition of the classification of central nervous system tumours. The mixed glial and neuronal tumour group continues to expand to encompass three new subtypes of glioneuronal tumours. The main diagnostic points differentiating these tumours are covered. Also covered is an update on issues relating to grading of astrocytic, oligodendroglial and pineal tumours and the recent molecular subtypes observed in medulloblastomas. The theme of molecular genetics is continued in the following section where the four subtypes in the molecular subclassification of glioblastoma; classical, mesenchymal, proneural and neural are outlined. The genetic profile of these subtypes is highlighted as is their varying biological responses to adjuvant therapies. The relationship between chromosome 1p and 19q deletions and treatment responsive oligodendrogliomas is discussed, as are the newer advances relating to silencing of the MGMT gene in astrocytomas and mutations in the IDH-1 gene in both astrocytomas and oligodendrogliomas. The final section in this article provides an update on the concept of glioma stem cells. PMID- 21233670 TI - Overview and recent advances in neuropathology. Part 2: Neurodegeneration. AB - The sections in the following review cover six main neurodegenerative diseases. The first article on Alzheimer's disease (AD) outlines the major evidence available to date that links Abeta-amyloid peptide as a proximal cause of AD. The article also highlights how an initial finding of the protein content of the amyloid plaque seen in the brains of patients with AD has led to many very significant findings in the neuroscience field. The next section outlines the many and recent advances that have occurred in the field of frontotemporal lobar degeneration (FTLD), including the most recent finding related to the fused sarcoma gene (FUS) and the newest nomenclature whereby the FTLD is subtyped according to the presence of specific proteins seen at a microscopic level. The section on Lewy bodies outlines the latest advances in the relationship between the anatomical distribution of Lewy bodies and disease phenotype. The following section includes an overview of current known genetic links with familial causes of motor neuron disease (MND) and an update on the areas being researched into the causes of sporadic MND. The presence of TDP-43 within inclusions and its new diagnostic role in MND are discussed. The final article on prion diseases gives an overview of human prion diseases, including the phenotypic spectrum, epidemiology and diagnostic investigations relevant to disease. PMID- 21233671 TI - What's new in non-small cell lung cancer for pathologists: the importance of accurate subtyping, EGFR mutations and ALK rearrangements. AB - In the past, the only critical point of distinction in the pathological diagnosis of lung cancer was between small cell and non-small cell lung cancer (NSCLC). The emergence of new targeted therapies and clinical trials demonstrating differing efficacy and toxicity of treatments according to specific histological subtypes of NSCLC, has resulted in an increasing need for improvements in pathological diagnosis. Accurate distinction between adenocarcinoma and squamous cell carcinoma is now critical as histological subtyping has the potential to influence clinical decision making and impact on patient outcome. While morphological criteria remain the most important feature to distinguish NSCLC subtypes, use of mucin and immunohistochemical stains (TTF-1, p63 and CK5/6) can be of assistance in difficult small biopsy cases. With the emergence of selective kinase inhibitors targeting epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), there is a corresponding need to identify the subset of NSCLCs harbouring specific genetic mutations associated with sensitivity to these agents, almost all of which are found in adenocarcinomas. In this review, the importance of accurately subtyping NSCLC is discussed, along with a suggested approach for distinguishing histological subtypes in small biopsy specimens. The significance of EGFR and ALK mutations in NSCLC and the impact of these genotypes on pathology and clinical practice are also reviewed. PMID- 21233672 TI - Molecular assays in breast cancer pathology. AB - Recent advances in understanding the molecular pathology of breast cancer offer significant potential to identify patients who may benefit from adjuvant therapies. To date, few of these advances are utilised in a routine setting. We review molecular assays that are currently in use or are in the advanced stages of development, which may be used as predictive or prognostic biomarkers in breast cancer.The only widely used breast cancer molecular assay is in situ hybridisation (ISH) for human epidermal growth factor receptor 2 (HER2) gene amplification and we highlight key issues with the interpretation of this assay, with particular attention to the difficulties of the equivocal category. New molecular assays such as ISH for the topoisomerase II alpha (TOP2A) gene and for the aberrations in the copy number of the centromeric region of chromosome 17 are readily performed in a standard histopathology laboratory, but to date there are insufficient data to support their routine use. We also review the current data on two commercially available multigene expression assays, Oncotype DX and MammaPrint and discuss their potential use. Overall, while new molecular assays have significant potential to improve patient selection for therapy, well performed histopathology with reliable interpretation of standard hormone and HER2 assays provides the most important predictive and prognostic information in early breast cancer. PMID- 21233673 TI - Validation of tissue microarray technology in malignant pleural mesothelioma. AB - AIMS: Tissue microarray (TMA) technology has been utilised for assessment of cancers including malignant pleural mesothelioma (MPM). Given the intralesional heterogeneity of MPM, it is questionable if TMAs can adequately represent MPMs. We here investigate the validity of TMAs for MPM. METHODS: TMAs were constructed from at least five cores for each of 80 archival tumours processed by two centres between 1994 and 2009. The percentage of cases correctly subtyped on TMAs compared with whole sections, in relation to the number of cores analysed, was calculated. Immunohistochemical labelling for calretinin and D2-40 was performed on TMAs and whole sections. To evaluate the validity of quantitative immunohistochemistry, percentages of positive cells were recorded and two-way analysis of variance (ANOVA) performed. RESULTS: Five cores were assessable for 91% of patients. Four cores were sufficient to reach concordance with the whole section result in 98% of cases for calretinin and 99% for D2-40. The correlation of the quantitative scores between the whole section and TMA cores was statistically significant (D2-40, rho = 0.84, p < 2.2e-16; calretinin, rho = 0.65, p = 7.9e-11). Neither the origin nor age of the blocks affected the results. CONCLUSION: If a minimum of four cores is used, TMA is an appropriate method for immunohistochemistry in MPM. PMID- 21233674 TI - Loss of E-cadherin independently predicts the lymph node status in colorectal cancer. AB - BACKGROUND: The identification of biomarkers that improve risk stratification in patients with colorectal cancer (CRC) is still a challenge. The objective of our study was to identify independent protein markers as predictors of lymph node (N) stage in CRC. METHODS: Tumour specimens from 221 CRC patients were mounted onto a multiple-punch tissue microarray and evaluated for 21 tumour related factors and one host related factor involved in CRC carcinogenesis, namely beta-catenin, E cadherin, EGFR, pERK, RHAMM, pAKT, pSMAD2, p21, p16, Bcl-2, Ki-67, APAF-1, MST1, RKIP, VEGF, EphB2, MMP7, Laminin5gamma2, MUC1, CDX2, caspase-3 as well as intra tumoural and stromal CD8+ tumour infiltrating lymphocytes (iTILs and sTILs). RESULTS: Node positive cancers showed significant losses for p21 (p = 0.026), Bcl 2 (p = 0.027), APAF-1 (p = 0.033), EphB2 (p = 0.006), E-cadherin (p < 0.001), RKIP (p = 0.019), CD8+ iTILs and sTILs (p < 0.001 and p = 0.008, respectively) and cytoplasmic MST1 (p = 0.014). Based on the area under the receiver operating characteristic curve (AUC) EphB2, E-cadherin, iTILs and sTILs were identified as potential predictors of N stage (AUC values >0.6), but only loss of E-cadherin was an independent predictor in multivariate analysis. CONCLUSIONS: E-cadherin appears to be a strong predictor of N stage in CRC and should be considered in pre-operative and post-operative management of colon and rectal cancer patients. PMID- 21233675 TI - Prostate tumour volume is an independent predictor of early biochemical recurrence in a high risk radical prostatectomy subgroup. AB - AIMS: To assess if accurately determined tumour volume variables could serve as independent predictors of early biochemical recurrence in high risk prostate cancer patients who underwent radical prostatectomy. METHODS: Tumour volume variables were calculated by digital planimetry in 269 prostatectomy specimens of patients with high risk prostate cancer. The associations to biochemical progression of tumour volume and clinicopathological variables, including age, pre-operative prostate specific antigen (PSA) levels, final Gleason score, pathological T stage, and surgical margins, were examined using univariate and multivariate Cox proportional hazards analyses. RESULTS: Median tumour volume was 3.7 ml [interquartile range (IQR) 2.1-6.1 mL] and median follow-up time was 12 months (IQR 6-24 months). Biochemical recurrence occurred in 64 men (24%) during this period, with a median time to recurrence of 7.5 months (IQR 3.0-15.5 months). On univariate analysis all of the tumour volume variables were strongly correlated with the clinicopathological variables, as well as biochemical recurrence (p < 0.001). On multivariate analysis, we found that tumour volume variables served as independent predictors of PSA progression whilst other routinely reported pathological variables did not. CONCLUSION: Accurately assessing tumour volume in the high risk setting may aid in identifying patients at greatest risk of developing early biochemical recurrence and most in need of adjuvant therapy. PMID- 21233676 TI - Claudin expression is dysregulated in prostate adenocarcinomas but does not correlate with main clinicopathological parameters. AB - AIMS: Claudins, a large family of essential tight junction (TJ) proteins, are abnormally regulated in human carcinomas. The aim of this study was to determine the expression of claudins 1, 2, 3, 4, 5, 7, and 11 in prostate samples from Brazilian patients and correlate it with the clinicopathological features of prostate cancer. METHODS: Using a tissue microarray (TMA) of specimens of prostate adenocarcinoma and benign prostatic hyperplasia (BPH) we analysed the expression of claudins 1, 2, 3, 4, 5, 7, and 11 by immunohistochemistry. RESULTS: Claudin 4 was down-regulated and claudins 2, 3, and 5 were overexpressed in prostate adenocarcinomas compared with BPH samples. Expression of claudins 1 and 7 was similar in tumours and BPH samples. Claudin 11 was absent from all prostate samples. Overexpression of claudin 3 was associated with perineural invasion (p = 0.014) and tended to occur in advanced stages of the disease (p = 0.064). Increased expression of claudin 5 was marginally associated with perineural invasion (p = 0.060). CONCLUSIONS: Our results suggest that alterations in claudin expression occur in prostate cancer cells, although we have not found an association with the main clinicopathological parameters. PMID- 21233677 TI - Accuracy of on-bench biopsies in the evaluation of the histological subtype, grade, and necrosis of renal tumours. AB - AIMS: Few data are available on the diagnostic accuracy of kidney tumour biopsy. METHODS: We sought to evaluate morphological diagnostic accuracy--such as histotype, Fuhrman grading, and necrosis--on a series of renal biopsies and matched whole tumours. RESULTS: Among 56 renal tumours, the benign instances consisted of six oncocytomas (10.7%), one angiomyolipoma (AML; 1.8%), and one metanephric adenoma (1.8%). Malignant tumours consisted of clear cell renal cell carcinoma (RCC) in 37 cases (66.1%), papillary RCC in six cases (10.7%), chromophobe RCC in three cases (5.4%), and unclassified RCC in one case (1.8%). Core biopsies were conclusive in 53 cases (94.6%), identifying six (10.7%) benign and 47 (83.9%) RCCs. The accuracy in identifying histological subtype was 92%, and the concordance between core biopsies and surgical specimens was nearly perfect (kappa = 0.858; p < 0.001). With regard to nuclear grade, the concordance index was only moderate (kappa = 0.253) and the concordance between core biopsies and surgical specimens was fair (kappa = 0.20; p = 0.11), such as for necrosis. CONCLUSIONS: We concluded that the accuracy in identifying histological subtype is high. Tumours with oncocytic features are the most problematic for diagnosis. Results for nuclear grades and coagulative tumour necrosis are less convincing. PMID- 21233678 TI - Clinicopathological features of hepatitis C virus disease after living donor liver transplantation: relationship with in situ hybridisation data. AB - AIMS: Recurrent hepatitis is a significant complication after liver transplantation for hepatitis C virus (HCV) disease. To evaluate responsiveness to treatment of HCV disease after liver transplantation, in situ hybridisation (ISH) was employed. METHODS: Sense and anti-sense probes for HCV were synthesised, and ISH studies were performed on 19 liver biopsy specimens from 19 recipients who had undergone living donor liver transplantation for HCV disease. ISH positive cells and total hepatocytes were counted, and the percentage of positive cells was calculated. Other clinical findings were compared retrospectively with the ISH results. RESULTS: The subjects were divided into three groups: recurrent HCV hepatitis (RHC, n = 11), acute cellular rejection (ACR, n = 5), and recurrent HCV hepatitis with ACR (MIX, n = 3). The percentage of ISH positive cells was almost the same degree (10-20%) in the three groups. The RHC group was subdivided into two sets of patients in whom serum HCV titres decreased (group D, n = 7) or did not decrease (group ND, n = 3) after 1 month of IFN therapy. The percentage of ISH positive cells in group D was significantly lower than that in group ND (p < 0.05) CONCLUSIONS: ISH for the recipients with HCV may be useful for predicting the response to interferon therapy. PMID- 21233679 TI - Primary giant-cell-rich osteosarcoma of the urinary bladder: usefulness of osteocalcin and osteonectin immunohistochemical staining and literature review. PMID- 21233680 TI - Urinary bladder melanosis: case report of a rare mucosal lesion. PMID- 21233681 TI - Hepatocellular carcinomas can develop in simple fatty livers in the setting of oxidative stress. PMID- 21233682 TI - Benign prostatic glands as a tissue component of testicular teratoma: an uncommon histological finding. PMID- 21233683 TI - Mutational analysis of the extracellular domain of ERBB4 gene in common carcinomas. PMID- 21233684 TI - Metachronous malignant composite phaeochromocytoma and pancreatic mucinous cystadenoma in a patient with neurofibromatosis type 1. PMID- 21233685 TI - Chondroblastoma with adamantinoma differentiation of the calcaneus. PMID- 21233686 TI - Composite haemangioendothelioma: report of four cases with emphasis on atypical clinical presentation. PMID- 21233687 TI - Acute myeloid leukaemia with variant t(8;21)(q22;q22) as a result of cryptic ins(8;21). PMID- 21233688 TI - Apparent elevated creatinine after ingestion of nitromethane: interference with the Jaffe reaction. AB - We assessed a 2-year 4-month-old boy found to have a persistently elevated serum creatinine (peak 926 MUmol/L) as measured by the Jaffe reaction after ingesting an unknown quantity of fuel for a model car, which commonly contains nitromethane. The patient was otherwise clinically well and the remaining investigations were unremarkable. When creatinine concentrations were measured with specific enzymatic testing on these same blood samples, all values were within normal limits. Nitromethane has been shown to interfere with the determination of serum creatinine through the Jaffe reaction. Because many ingestions present only rarely, it is not possible for the emergency department clinician to be aware of all toxin factors affecting patient management. This case illustrates the importance of analysis of laboratory results in the context of the patient's clinical status. PMID- 21233690 TI - Excretion of the principal urinary metabolites of phenytoin and absolute oral bioavailability determined by use of a stable isotope in patients with epilepsy. AB - BACKGROUND: The anticonvulsant properties of phenytoin (PHT) were discovered in 1938. Since then, it has been one of the most widely used antiepileptic drugs. It is slowly absorbed, extensively plasma protein-bound, exhibits a nonlinear, concentration-dependent pharmacokinetic profile, and has a narrow therapeutic range. METHODS: We determined PHT bioavailability during steady-state therapy by 1) measurement of the two principal deconjugated PHT urinary metabolites, 5-(4 hydroxyphenyl)-5-phenylhydantoin (p-HPPH) and 5-(3,4-dihydroxy-1,5-cyclohexadien 1-yl)-5-phenylhydantoin (DHD); and 2) direct determination of absolute bioavailability after simultaneous administration of an oral formulation and parenteral stable-labeled PHT (SL-PHT). Urinary metabolites were quantified by an isocratic HPLC-NI-APCI-MS method. The urinary dose recovery was calculated by dividing the molar recovery of the major PHT urinary metabolites by the molar dose received. RESULTS: Urinary metabolite recovery was surprisingly low, 35.4% +/- 15.7% in younger patients (age 21-49 years old) and 32.9% +/- 15.0% in patients aged 65 to 93 years. Absolute bioavailability was 86.4% +/- 19.4% and 92.5% +/- 25.2%, respectively. A weak, but significant, Spearman rank correlation was observed between urinary metabolite recovery and oral bioavailability (P = 0.00924, R = 0.166). CONCLUSION: This weak correlation may be the result of variability in urinary versus biliary-fecal excretion of p-HPPH glucuronide. This study demonstrates that daily PHT oral absorption exhibits wide interpatient variability, which may account for fluctuations in PHT concentration over time. PMID- 21233689 TI - Influence of body weight on achieving indinavir concentrations within its therapeutic window in HIV-infected Thai patients receiving indinavir boosted with ritonavir. AB - Indinavir boosted with ritonavir (IDV/r) dosing with 400/100 mg, twice daily, is preferred in Thai adults, but this dose can lead to concentrations close to the boundaries of its therapeutic window. The objectives of this analysis were to validate a population pharmacokinetic model to describe IDV/r concentrations in HIV-infected Thai patients and to investigate the impact of patient characteristics on achieving adequate IDV concentrations. IDV/r concentration data from 513 plasma samples were available. Population means and variances of pharmacokinetic parameters were estimated using a nonlinear mixed effects regression model (NONMEM Version VI). Monte Carlo simulations were performed to estimate the probability of achieving IDV concentrations within its therapeutic window. IDV/r pharmacokinetics were best described by a one-compartment model coupled with a single transit compartment absorption model. Body weight influenced indinavir apparent oral clearance and volume of distribution and allometric scaling significantly reduced the interindividual variability. Final population estimates (interindividual variability in percentage) of indinavir apparent oral clearance and volume of distribution were 21.3 L/h/70 kg (30%) and 90.7 L/70 kg (22%), respectively. Based on model simulations, the probability of achieving an IDV trough concentration greater than 0.1 mg/L was greater than 99% for 600/100 mg and greater than 98% for 400/100 mg, twice daily, in patients weighing 40 to 80 kg. However, the probability of achieving IDV concentrations associated with an increased risk of drug toxicity (greater than 10.0 mg/L) increased from 1% to 10% with 600/100 mg compared with less than 1% with 400/100 mg when body weight decreased from 80 to 40 kg. The validated model developed predicts that 400/100 mg of IDV/r, twice daily, provides indinavir concentrations within the recommended therapeutic window for the majority of patients. The risk of toxic drug concentrations increases rapidly with IDV/r dose of 600/100 mg for patients less than 50 kg and therapeutic drug monitoring of IDV concentrations would help to reduce the risk of IDV-induced nephrotoxicity. PMID- 21233691 TI - Developing an assay for ceftazidime: is it worth the effort? PMID- 21233692 TI - Anaphylactic reaction to different gonadotropin-releasing hormone agonists for the treatment of endometriosis. AB - Anaphylactic reactions to gonadotropin-releasing hormone (GnRH) agonists are exceedingly rare, but if they occur, they can be life threatening. This case describes a 33-year-old patient with endometriosis who developed an acute allergic reaction on leuprolide (Lucrin) administration. Although skin tests with the replacement goserelin (Zoladex) were negative, usage of this medication resulted in a similar allergic reaction. This is the first case report that shows that, in case of a proven allergy to one GnRH agonist, a switch to another GnRH agonist should not be made even if allergy tests are negative for this medication. PMID- 21233693 TI - Clinical improvement in psoriasis with treatment of associated hyperlipidemia. AB - Psoriasis is associated with an increased risk of cardiovascular disease, a principal cause of which is atherosclerosis caused by hyperlipidemia. However, it is not known whether treatment of hyperlipidemia in patients with psoriasis lead to clinical improvement in psoriasis condition. In this study, the authors summarize the existing literature relevant to this inquiry. They also describe the potential pathways believed to link psoriasis with atherosclerosis and the role of hyperlipidemia therapy in this setting. A few studies indicated clinical improvement in psoriasis with treatment of associated hyperlipidemia. Some studies showed that a low-fat diet improved psoriasis. Others indicated a decreased risk of psoriasis associated with intake of cholesterol-lowering drugs such as "statins." Treatment with statins increased lactate dehydrogenase level and diminished Psoriasis Area and Severity Index score, ie, reduced cutaneous lesion in psoriasis. Beneficial effects of statin therapy on psoriasis included downregulation of lymphocyte function-associated antigen-1, inhibition of leukocyte endothelial adhesion, extravasation and natural killer cell activity, inhibition of proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin 1 and 6, lowering of C-reactive protein, promotion of a T(H)1 to T(H)2 cells and inhibition of T(H)1 cytokine receptors on T cells, leading to inhibition of activation of lymphocytes and infiltration into the inflammation sites. Taken together, current literature indicates clinical improvement in psoriasis condition with treatment of associated hyperlipidemia, particularly with statins of which the mechanisms could be attributed to immunomodulatory and anti-inflammatory effects. PMID- 21233694 TI - Impact of contact sensitization in chronic spontaneous urticaria. AB - INTRODUCTION: Patch testing is performed to diagnose allergic contact dermatitis to avoid exposure to the revealed contact allergens. Nevertheless, patch testing is not routinely performed in the evaluation of patients with chronic idiopathic (spontaneous) urticaria (CIU). The objective of this study was to determine the frequency of sensitization to patch test allergens in severe CIU and assess a role of the allergen avoidance in CIU remission. METHODS: The cases of patients with severe CIU were retrospectively studied. The patients were patch tested using T.R.U.E. TEST. Three groups were studied: CIU with positive patch test group; CIU with negative patch test group and control group, which included the cases of not patch-tested patients with CIU. The groups were followed up monthly to assess changes in Chronic Urticaria Severity Score (CUSS) after allergen avoidance. RESULTS: Forty-three subjects with severe CIU were patch tested. Nickel sulphate was positive in 4 (9.3%) cases, potassium dichromate in 2 (4.7%) cases, cobalt, balsam of Peru, paraphenylene diamine, fragrance mix and epoxy resin were positive in 1 (2.3%) case. Their baseline CUSS (5.4 +/- 0.5) improved significantly after 1 month of allergen avoidance (3.2 +/- 1.1; P < 0.001); but similar improvement of CUSS (5.3 +/- 0.5) was seen in 34 patients with CIU with negative patch test (3.2 +/- 1.3; P < 0.001) and in 49 patients with CIU of control group (5.2 +/- 0.4 to 3.4 +/- 1.3; P < 0 < 0.001) after 1 month. CONCLUSIONS: There is no relationship between avoidance of contact allergens and the course of CIU. PMID- 21233695 TI - Influence of predictive modeling in implementing optimal heart failure therapy. AB - INTRODUCTION: A gap remains between evidence-based guidelines in the treatment of heart failure (HF) and current pharmacologic and device therapy. The Seattle Heart Failure Model (SHFM) is an accurate predictive tool that allows the clinician to quantitatively assess the influence of pharmacologic and device therapy on HF. The authors hypothesized that graphically demonstrating the improvement in survival using such a tool may well modify physician practice behavior. METHODS: The authors examined 50 randomly selected patients from 10 primary care physicians having HF with a left ventricular ejection fraction <40%. Twenty-one data elements were entered into the SHFM to create a survival estimate before and after implementation of interventions known to be beneficial, both pharmacologic (addition of angiotensin-converting enzyme/angiotensin receptor blocker, statin, beta-blocker and aldosterone blocker) and device based (consideration for automatic implantable cardioverter-defibrillator, biventricular pacer and biventricular implantable cardioverter-defibrillator). The influence of therapeutic change was presented in a focused clinical session with the primary care physician. RESULTS: The mean age of the population examined was 73 +/- 10 years with New York Heart Association class 2.2 +/- 0.5 symptoms. In the 50 patients examined, the authors altered device or medical therapy in 82%. This included advancement of medical therapy in 50%, consideration for device referral in 10% or both (medical therapy and device referral) in 22%. This augmentation of therapy resulted in an increase in estimated mean life expectancy from 8.8 to 10.9 years (P < 0.001). CONCLUSION: Use of the SHFM significantly impacted intensification of HF therapy in this ambulatory HF population. PMID- 21233696 TI - Scleroderma: the need for extreme remedies. AB - Scleroderma is a multisystem disorder of unknown etiology, which presents major challenges for clinical management. Although it is usually classified as an autoimmune disorder, theories of pathogenesis also must consider the major contributions of vascular abnormalities and noninflammatory connective tissue accumulation to the disease manifestations. Premature mortality remains significant despite institution of earlier and more intense approaches to therapy. Advances in control of renal crisis including avoidance of glucocorticoids and early use of angiotensin system blockade have resulted in decreased prevalence of renal failure since this topic was reviewed in these grand rounds more than 25 years ago. Pulmonary complications including interstitial fibrosis and pulmonary hypertension are now major contributors to morbidity and mortality. Recent studies of interventions to suppress immune activity suggest that the fibrotic burden might be reduced by such an approach, raising the possibility that some organ damage might be halted or even reversed. PMID- 21233697 TI - Use of Integra in complex pediatric wounds. AB - The usefulness of Integra is well described in the adult reconstructive and burn literature. There is limited documentation of its utility in the pediatric plastic surgery population. We presented 8 cases referred to us for flap coverage that were treated using Integra. These cases describe difficult wounds resulting from trauma, and congenital abnormalities. The charts of all 8 cases were retrospectively reviewed. There were 5 females and 3 newborns. The average age at coverage with Integra was 4.6 years (range, 1 day-16 years). There were 4 traumatic wounds, 2 cases of cutis aplasia, 1 myelomeningocele, and 1 case of congenitally absent cranium. The average time to coverage was 8 days, and all trauma patients underwent at least 2 prior washout procedures. The average area covered was 43 cm (range, 6-100 cm). At a mean follow-up of 14.25 months (range, 9-20 months), 7 patients' wounds had healed without need for further flap coverage. Only 1 patient required a skin graft over the Integra bed. There was 1 infection resulting in total dermal matrix loss and need for local flap reconstruction. One patient developed severe hypertrophic scarring requiring surgical revision. Integra is a reliable option in pediatric reconstruction, which may save a child the morbidity of a more extensive procedure. PMID- 21233698 TI - Tissue expander breast reconstruction using prehydrated human acellular dermis. AB - INTRODUCTION: Human acellular dermal matrices help facilitate immediate tissue expander-implant breast reconstruction by providing support to the inferolateral pole, improving control of implant position, and enhancing early volume expansion. Although several freeze-dried human acellular dermal products have demonstrated reasonable safety and efficacy in immediate tissue expander-implant breast reconstruction, no dedicated studies have evaluated clinical outcomes of prehydrated human acellular dermal matrix (PHADM) in breast reconstruction. METHODS: The outcomes of 121 consecutive tissue expander reconstructions performed by the senior author using PHADM were evaluated. RESULTS: Mean intraoperative tissue expander fill volume was 256.6 +/- 133 mL, 60% of final expander volume. Patients required an average of 3.2 additional expansions prior to tissue expander-to-implant exchange. Mean follow-up period after reconstruction was 44 +/- 26.5 weeks. Complications occurred in 20 (16.5%) breasts, including 9 (7.4%) soft-tissue infections, 8 (6.6%) partial mastectomy flap necroses, and 2 (1.7%) seromas. Eleven (9.1%) breasts ultimately required explantation. Patients receiving radiation demonstrated a strong trend toward greater complications (30.8% vs. 13.7%, P = 0.0749). CONCLUSIONS: The outcomes and complication rates of PHADM tissue expander breast reconstruction are comparable to those reported with freeze-dried human acellular dermis. PMID- 21233699 TI - Microdeformation of three-dimensional cultured fibroblasts induces gene expression and morphological changes. AB - BACKGROUND: Vacuum-assisted closure induces microdeformations of the wound surface and accelerates healing of complex wounds; however, a thorough understanding of the biology of cellular mechanotransduction is lacking. We hypothesized that fibroblast shape and function can be altered in an in vitro vacuum-assisted closure device. METHODS: A 3-dimensional fibrin matrix with cultured murine fibroblasts and an intervening polyurethane foam was exposed to 125 mm Hg suction and compared with similar wells without suction. We measured fibroblast proliferation and morphology using fluorescence microscopy and gene expression change using real-time reverse-transcriptase polymerase chain reaction at 24, 48, and 72 hours. RESULTS: Wells exposed to suction induced significant proliferation of fibroblasts and morphologic changes visible by larger, rounder, and notable dendrite-like branching and process extensions. Type 1 collagen alpha 1 (COL1A1), fibroblast growth factor 2 (FGF2, bFGF), and transforming growth factor beta 1 (TGFbeta1) were all up-regulated after 48 hours of exposure to suction. Smooth muscle actin alpha 2 (Acta2, alpha-SMA) was up-regulated after 72 hours. CONCLUSIONS: Microdeformations produced by the combination of polyurethane foam and suction are associated with increased fibroblast proliferation and up regulation of gene expressions in fibroblasts. PMID- 21233700 TI - Changes in the blood flow and prevention of vasospasm of the femoral artery by topical application of lidocaine in rats. AB - Free-tissue transfer with anastomosis has become an important microsurgical technique. Sometimes vasospasm occurs after anastomosis. We examined the changes in blood flow and the effect on the treatment of vasospasm of the femoral artery of rats. The rat models of vasospasm were generated by topical application of epinephrine. We topically applied 2% lidocaine as a single dose (0.2 mL) and a continuous infusion (1.0 mL/h). Our results suggest that although the effect lasts for a short period, a single application of 2% lidocaine has a rapid effect and is effective for treating a sudden manifestation of vasospasm. In contrast, continuous topical application may be more effective for maintaining the blood flow and preventing vasospasm. Therefore we believe that persistent vasospasm should first be treated with several topical applications of lidocaine; if this helps improve the condition, continuous topical application can be subsequently used as a preventive measure. PMID- 21233701 TI - Primary cutaneous malignancies in sub-Saharan Africa. AB - Cutaneous malignancies are the most common malignancies in Whites; traditionally considered rare among Blacks, their occurrence in sub-Saharan Africa is yet to be fully characterized.Data on specimens submitted between 1992 and April 2008 on all histologically proven primary cutaneous malignancies were collected from the Pathology Department, including patient age, sex, anatomic site of malignancy, and histologic diagnosis. There were 1900 patients with primary cutaneous malignancies, aged between 8 months and 110 years, with a mean age of 49 years. There were 14 different types of malignancies found, with squamous cell carcinoma representing 45% of the total. A number of the rarer types have not been reported previously, from this region.Cutaneous malignancies in Africa present a number of management challenges including the following: difficulties in early diagnosis in the dark skin, late presentation, access to treatment, and the ability to pay for the appropriate treatment. The current human immunodeficiency virus/acquired immune deficiency syndrome scourge on the continent may lead a significant increase in cutaneous malignancies, posing even bigger challenges. PMID- 21233702 TI - Clinical applications of the pedicled anterolateral thigh flap in complex abdominal-pelvic reconstruction. AB - BACKGROUND: The free anterolateral thigh (ALT) flap has become a reconstructive workhorse with great versatility throughout the body. However, the utility of the pedicled ALT flap is less described for complex defects. A skin paddle with reliable blood circulation and wide range of reach, low donor site morbidity along with the avoidance of many of the complications plaguing free flaps, are just some of the several benefits offered by the pedicled ALT flap. We investigated specific clinical examples within our ALT flap database where the pedicled ALT flap was used for coverage of complex wounds and highlight its advantages. METHODS: We conducted a retrospective chart review on those patients in whom a pedicled ALT flap was used for complex wound reconstruction over a 7 year period between July 2002 and October 2009 at The R Adams Cowley Shock Trauma Center performed by a single surgeon. RESULTS: : Four patients underwent a pedicled ALT flap as part of their reconstruction. Flaps ranged in size from 75 to 648 cm, and all but one were cutaneous in nature with the other one being fasciocutaneous. The flaps averaged 2 perforators (range, 1-3) and the donor sites were all closed primarily except for one. CONCLUSIONS: When faced with a complex defect in the abdominal-pelvic region, we propose that the pedicled ALT flap has several advantages to other types of tissue coverage and is an excellent option for the reconstructive surgeon. PMID- 21233703 TI - Congenital leukemia cutis presenting as multiple violaceous lesions in a newborn. AB - We present a case of congenital leukemia cutis that was the presenting sign of systemic acute myeloid leukemia. The initial diagnosis was benign hemangiomatosis because ultrasound of the liver was negative for visceral involvement. However, biopsy showed monocytic cells and led to a further workup which involved a bone marrow biopsy, giving the final diagnosis of acute myeloid leukemia with leukemia cutis. Even with a thorough knowledge of the differential diagnosis of such presenting lesions, a diagnostic biopsy is often needed for a final histologic diagnosis, to proceed with the proper course of treatment. We review congenital leukemia cutis and the differential diagnosis for violaceous lesions in the newborn that may be encountered by the pediatric plastic surgeon. PMID- 21233704 TI - The prefabricated gracilis muscle flap with full-thickness skin graft and delay for urethral channel reconstruction. AB - BACKGROUND: Reconstruction of complex urethral defects should provide lasting coverage, a patent tube for voiding, and a natural appearing contour with minimal morbidity to the donor and recipient sites. Many reports have emerged in the literature regarding complex urethral reconstruction through a variety of methods including anterolateral thigh flaps, radial artery forearm free flap, and other simple skin and mucosal flaps. Recently, Ozkan and Ozkan reported using a prefabricated anterolateral thigh flap for reconstruction of a traumatic urethral defect (Ozkan and Ozkan, J Plast Reconstr Aesthet Surg. 2009;62:380-384). In this report, we describe our experience with the use of a prefabricated gracilis muscle flap in a female-to-male transsexual with a complex proximal urethral stricture and distal fistula. We believe this is the first report of a prefabricated gracilis myocutaneous muscle flap being used for a long segment urethral stricture and distal fistula. We believe that this procedure offers a unique solution to a difficult problem with decreased morbidity and cosmetic advantages over other methods requiring microvascular anastomoses. PMID- 21233705 TI - Perfusion of the deep inferior epigastric perforator flap measured by laser Doppler imager. AB - BACKGROUND: During surgery, circulation changes in the deep inferior epigastric perforator free flap (DIEP). Although blood flow is an important parameter for surgical outcome, little research has been performed on this topic, especially during the process of transplantation. This study examined the pattern of perfusion of DIEP flaps over time. METHODS: In all, 16 flaps were studied in 14 DIEP patients. Flap perfusion was measured with the laser Doppler imager at 4 different time points-before, during, and after surgery. RESULTS: Both central and peripheral perfusion did not alter after dissection, when blood supply became restricted to the abdominal vascular pedicle. After transplantation, blood flow was higher in the central part of the flap compared with the peripheral border. Central flow increased after transplantation, compared with measurements before and during surgery. Peripheral flow, however, decreased after transplantation. CONCLUSIONS: Surprisingly, flap perfusion did not alter after dissection. It only changed after flap transplantation, when central blood flow increased and peripheral flow decreased. PMID- 21233706 TI - Murine orthotopic model for the assessment of chemoradiotherapeutic interventions in rectal cancer. AB - A murine orthotopic model for the study of colon cancer has been described earlier. However, for the study of rectal cancer, three issues remain: (i) the relative sensitivity of the implanted tumors to ionizing radiation (IR); (ii) the location of the tumor for the delivery of external beam IR; and (iii) the assessment of a given modality over time before necropsy. In this protocol, we have modified an orthotopic model for colon cancer described earlier for the specific assessment of chemoradiation in rectal cancer by (i) cecal transplantation of tumors with a known response to IR; (ii) securing the tumor to the lateral abdominal wall with a permanent suture for the administration of IR; and (iii) transfection of cells with luciferase before tumor implantation for the assessment of the chemoradiotherapeutic interventions over time by bioluminescence imaging before the end on the study. This technique allows targeted delivery of IR in an intraperitoneal tumor. Imaging throughout the course of the treatment is possible such that the timing of chemoradiation can be determined and permits comparison between groups before the end of the treatment. This model represents a modified technique that allows the assessment of chemoradiotherapeutic interventions in rectal cancer. PMID- 21233707 TI - Tailoring treatment of rectal adenocarcinoma: immunohistochemistry for predictive biomarkers. AB - Over the past couple of decades, multimodality treatment for the management of resectable rectal cancer has substantially improved the outcome of affected patients. However, the broad and unpredictable response to tumor of patients with rectal cancer treated with preoperative chemoradiotherapeutic interventions shows that our understanding of the molecular events leading to radioresistance in patients affected with this malignancy remains sparse. Multiple attempts by individual molecular markers in gene array and tissue microarray studies have emerged with the goal of identifying predictors of a response to chemoradiation in patients with rectal cancer. In this report, we discuss the status of the markers currently available in an attempt to tailor specific targeted therapies for rectal cancer in the neoadjuvant setting. PMID- 21233708 TI - Effect of microtubule-targeting drugs on cell-cell and cell-matrix junctions in tumor epithelial cells. AB - In this study, we investigated the effects of microtubule-targeting drugs, which either destabilize (the Vinca alkaloid vincristine) or stabilize (the taxane derivative docetaxel) microtubules, on the cell-cell and cell-matrix adhesive junctions of Caco-2 tumor epithelial cells, using fluorescence imaging and functional assays. We found that, in sub-confluent (but not confluent) cells, vincristine (but not docetaxel) affected cell-cell junction morphology. Furthermore, docetaxel (but not vincristine) attenuated the formation of the peri junctional actomyosin ring and enhanced the internalization of junctional adhesion molecule-A. However, these effects of vincristine and docetaxel did not translate into appreciable functional changes during the opening and resealing of the cell-cell junctions. We also found that vincristine caused enlargement of focal adhesions (the major cell-matrix junctions) without affecting cell adhesion onto the matrix. Thus, we conclude that the microtubule-targeting drugs interfere to variable degrees with the morphology and/or function of the cell-cell and cell matrix adhesive junctions. In addition, the results highlight the importance of considering the cellular context and dynamics (e.g. cell confluence and junction opening, respectively), when determining the final effects of microtubule manipulation on cell adhesiveness. PMID- 21233709 TI - Superior sternal cleft, supraumbilical midline raphe and haemangiomas in a baby girl with an ostium secundum ASD. PMID- 21233710 TI - Red cell distribution width as a novel prognostic marker in patients undergoing primary angioplasty for acute myocardial infarction. AB - OBJECTIVES: Red cell distribution width (RDW), a measure of red blood cell size heterogeneity, was evaluated in patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Higher RDW is associated with mortality in patients with symptomatic cardiovascular disease, heart failure, and also in the general population. We hypothesized that admission RDW would be predictive of adverse outcomes in patients after primary PCI. METHODS: Two thousand five hundred and six consecutive STEMI patients (mean age 56.6+/-11.8 years; 2075 males, 431 females) undergoing primary PCI were retrospectively enrolled into this study. Admission RDW was measured as part of the automated complete blood count. Patients were grouped as elevated or nonelevated RDW using the upper limit of normal value of 14.8% and were followed for in-hospital and long-term outcomes for a mean period of 1.8+/-1.3 years (median 21 months). RESULTS: A higher in-hospital mortality rate was observed among patients with elevated admission RDW (mean 16.1+/-1.6%) compared with those with nonelevated RDW (mean 13.4+/-0.8%) (7.6 vs. 3.6%, P<0.001). The long-term cardiovascular prognosis was worse for patients with elevated admission RDW (Kaplan-Meier, log-rank P<0.001). We used Cox proportional hazard models to examine the association between RDW and adverse clinical outcomes. After discharge, there were 129 deaths during follow-up. A significant association was noted between elevated admission RDW level and the adjusted risk of cardiovascular mortality (hazard ratio: 1.831, 95% confidence interval: 1.034 3.24, P=0.03). In addition, elevated admission RDW was also an independent predictor of cardiovascular mortality in the nonanemic subpopulation of patients (hazard ratio: 2.703, 95% confidence interval: 1.208-6.048, P=0.016). CONCLUSION: A high admission RDW level in patients with STEMI undergoing primary PCI was associated with increased risk for in-hospital and long-term cardiovascular mortality. PMID- 21233711 TI - Cognitive load during speech perception in noise: the influence of age, hearing loss, and cognition on the pupil response. AB - OBJECTIVES: The aim of the present study was to evaluate the influence of age, hearing loss, and cognitive ability on the cognitive processing load during listening to speech presented in noise. Cognitive load was assessed by means of pupillometry (i.e., examination of pupil dilation), supplemented with subjective ratings. DESIGN: Two groups of subjects participated: 38 middle-aged participants (mean age = 55 yrs) with normal hearing and 36 middle-aged participants (mean age = 61 yrs) with hearing loss. Using three Speech Reception Threshold (SRT) in stationary noise tests, we estimated the speech-to-noise ratios (SNRs) required for the correct repetition of 50%, 71%, or 84% of the sentences (SRT50%, SRT71%, and SRT84%, respectively). We examined the pupil response during listening: the peak amplitude, the peak latency, the mean dilation, and the pupil response duration. For each condition, participants rated the experienced listening effort and estimated their performance level. Participants also performed the Text Reception Threshold (TRT) test, a test of processing speed, and a word vocabulary test. Data were compared with previously published data from young participants with normal hearing. RESULTS: Hearing loss was related to relatively poor SRTs, and higher speech intelligibility was associated with lower effort and higher performance ratings. For listeners with normal hearing, increasing age was associated with poorer TRTs and slower processing speed but with larger word vocabulary. A multivariate repeated-measures analysis of variance indicated main effects of group and SNR and an interaction effect between these factors on the pupil response. The peak latency was relatively short and the mean dilation was relatively small at low intelligibility levels for the middle-aged groups, whereas the reverse was observed for high intelligibility levels. The decrease in the pupil response as a function of increasing SNR was relatively small for the listeners with hearing loss. Spearman correlation coefficients indicated that the cognitive load was larger in listeners with better TRT performances as reflected by a longer peak latency (normal-hearing participants, SRT50% condition) and a larger peak amplitude and longer response duration (hearing-impaired participants, SRT50% and SRT84% conditions). Also, a larger word vocabulary was related to longer response duration in the SRT84% condition for the participants with normal hearing. CONCLUSIONS: The pupil response systematically increased with decreasing speech intelligibility. Ageing and hearing loss were related to less release from effort when increasing the intelligibility of speech in noise. In difficult listening conditions, these factors may induce cognitive overload relatively early or they may be associated with relatively shallow speech processing. More research is needed to elucidate the underlying mechanisms explaining these results. Better TRTs and larger word vocabulary were related to higher mental processing load across speech intelligibility levels. This indicates that utilizing linguistic ability to improve speech perception is associated with increased listening load. PMID- 21233712 TI - Development of auditory processing in 6- to 11-yr-old children. AB - OBJECTIVES: The aim of this study is to provide developmental standards on a variety of temporal, spectral, and binaural psychoacoustic (auditory processing [AP]) tests in typically developing children, including immediate and delayed retest reliability, and comparisons between single listener performance on different tests. This study also informs choices on the selection of tests for clinical evaluation of hearing and listening (e.g., for auditory processing disorder). DESIGN: This is a laboratory-based study of AP threshold and variability of 75 children, aged 6 to 11 yrs, and 21 young adults with normal audiometry recruited from local schools and colleges. Data were gathered in clinic-like conditions, without training and across two sessions. Eleven individual (e.g., simultaneous masking and backward masking [BM], amplitude modulation [AM], and frequency modulation [FM] detection) and three derived (temporal integration, frequency resolution, masking level difference) measure tests were embedded within a suite of computer games, each employing a three interval, three-alternative (odd-one-out) forced choice response paradigm and a staircase adaptive method. RESULTS: AP measures generally showed lower thresholds and reduced variance with increasing age. At 6 to 7 yrs, performance was markedly poorer than in the older groups; 35% of the children could not do the test of frequency discrimination (FD). However, on all the tasks, some children in the same group performed at near-adult levels. The distribution of performance between individuals varied widely across tasks, with clustered performance on tests of tone detection (with or without a simultaneous masker) and AM detection, and scattered performance on BM, FM detection, and FD. Threshold maturity was achieved at different rates across tests and by 10 to 11 yrs of age on all tests except FD. Masking level difference (MLD) performance did not change with age. Retest reliability was mostly high within test sessions but, again, was poorer for some of the younger children. Between test sessions separated by one to several weeks, reliability varied from poor (for FM detection) to high (for long tone detection in quiet, BM, and FD). Correlations between thresholds on different tests were generally low. CONCLUSIONS: Data suggest that the perception of different auditory stimuli occurs and develops using rather independent mechanisms, even for tasks that are closely related in procedure. While individual children can perform reliably on several distinct tasks, differences between individuals on the same tasks can be large. Because some of the youngest children perform reliably across time, at or near adult levels, immaturity between 6 and 11 yrs of age, as reflected in group statistics, reflects poor performance of some individual children rather than obligate, age-related deficits in AP. While several of the tests used were found to have potential clinical applicability, because of their reliability and ability to distinguish between individuals, it is currently unclear how performance on such tests relates to everyday listening skills. PMID- 21233713 TI - Evaluating bias from birth-cohort effects in the age-based cox proportional hazards model. AB - The nested case-control design is frequently used to evaluate exposures and health outcomes within the confines of a cohort study. When incidence-density sampling is used to identify controls, the resulting data can be analyzed using conditional logistic regression (equivalent to stratified Cox proportional hazards regression). In these studies, exposure lagging is often used to account for disease latency. In light of recent criticism of incidence-density sampling, we used simulated occupational cohorts to evaluate age-based incidence-density sampling for lagged exposures in the presence of birth-cohort effects and associations among time-related variables. Effect estimates were unbiased when adjusted for birth cohort; however, unadjusted effect estimates were biased, particularly when age at hire and year of hire were correlated. When the analysis included an adjustment for birth cohort, the inclusion of lagged-out cases and controls (assigned a lagged exposure of zero) did not introduce bias. PMID- 21233714 TI - The effect of age on transmission of 2009 pandemic influenza A (H1N1) in a camp and associated households. AB - BACKGROUND: A major portion of influenza disease burden during the 2009 pandemic was observed among young people. METHODS: We examined the effect of age on the transmission of influenza-like illness associated with the 2009 pandemic influenza A (H1N1) virus (pH1N1) for an April-May 2009 outbreak among youth-camp participants and household contacts in Washington State. RESULTS: An influenza like illness attack rate of 51% was found among 96 camp participants. We observed a cabin secondary attack rate of 42% (95% confidence interval = 21%-66%) and a camp local reproductive number of 2.7 (1.7-4.1) for influenza-like illness among children (less than 18 years old). Among the 136 contacts in the 41 households with an influenza-like illness index case who attended the camp, the influenza like illness secondary attack rate was 11% for children (5%-21%) and 4% for adults (2%-8%). The odds ratio for influenza-like illness among children versus adults was 3.1 (1.3-7.3). CONCLUSIONS: The strong age effect, combined with the low number of susceptible children per household (1.2), plausibly explains the lower-than-expected household secondary attack rate for influenza-like illness, illustrating the importance of other venues where children congregate for sustaining community transmission. Quantifying the effects of age on pH1N1 transmission is important for informing effective intervention strategies. PMID- 21233715 TI - Plasma citrulline levels in paediatric patients with celiac disease and the effect of a gluten-free diet. AB - OBJECTIVE: Citrulline is a nonprotein amino acid synthesized in the small intestine. The aim of this study is to explore plasma citrulline levels in children with celiac disease (CD) and monitor the time-related changes of these levels after initiation of a gluten-free diet (GFD). METHODS: Fasting-plasma citrulline levels were determined by high-performance liquid chromatography in (i) 23 patients with CD before the institution of GFD, (ii) 20 patients with CD under treatment for more than 2 years responsive to a GFD, (iii) 10 children with gastrointestinal symptoms and normal small bowel biopsy, and (iv) 20 healthy controls. In group A, citrulline levels were also measured after 1, 3, 6, and 12 months on a GFD. RESULTS: Mean plasma citrulline levels were lower in untreated patients with CD (24.5+/-4.9) than in patients on a GFD (31.2+/-6.7 MUmol/l, P<0.001), patients with gastrointestinal symptoms and normal intestinal mucosa (30.3+/-4.7 MUmol/l, P<0.01), and healthy controls (32.4+/-7.5 MUmol/l, P<0.001). In untreated patients with CD,an inverse correlation was observed between citrulline concentrations and the severity of villous atrophy (r=-0.67, P<0.01). After 1 month on a GFD, patients had significantly higher levels than before diet (P<0.05) and after 3 months on diet, levels were similar to those observed in the healthy controls. CONCLUSIONS: Plasma citrulline levels are lower in celiacs reflecting small bowel involvement in this disease. After a short period on GFD, citrulline levels increased rapidly, indicating that citrulline is a sensitive marker of the positive effect of GFD on intestinal repair. PMID- 21233716 TI - Idursulfase treatment of Hunter syndrome in children younger than 6 years: results from the Hunter Outcome Survey. AB - PURPOSE: To use the Hunter Outcome Survey, an international database, to assess the safety and effectiveness of enzyme replacement therapy with idursulfase in patients with Hunter syndrome who started treatment before 6 years of age. METHODS: The study population included all patients enrolled in the Hunter Outcome Survey who started idursulfase infusions (0.5 mg/kg every other week) before 6 years of age and who had at least one follow-up examination recorded. RESULTS: The study population included 124 patients, younger than 6 years, who had a mean age at start of idursulfase of 3.6 +/- 1.6 years (mean +/- SD). The mean duration of treatment was 22.9 +/- 14.6 months. A total of 69 infusion related reactions occurred in 33 (26.6%) patients, including three serious infusion-related reactions occurring in a single patient. After at least 6 months of idursulfase, urine glycosaminoglycan levels decreased from 592 +/- 188 to 218 +/- 115 MUg/mg creatinine (P < 0.0001, n = 34). Liver size, estimated by palpation, was also significantly decreased (P = 0.005, n = 23). Similar safety and effectiveness results were seen in patients who were aged 6 years or older when initiating idursulfase. CONCLUSION: No new safety concerns were identified in patients younger than 6 years, and clinical benefit was suggested by the reduction in liver size. PMID- 21233717 TI - Prospective validation of quantitative fluorescent polymerase chain reaction for rapid detection of common aneuploidies. AB - PURPOSE: To prospectively validate a quantitative fluorescent polymerase chain reaction (PCR) assay as a method of rapid prenatal aneuploidy detection for chromosomes 13, 18, 21, X, and Y. METHODS: A commercial quantitative fluorescent PCR kit was validated on 200 known, blinded, prenatal DNA specimens. The kit was then validated prospectively on 1069 amniotic fluid specimens, and the results were compared with the karyotype results and the results of interphase fluorescence in situ hybridization testing, when performed in the course of standard care. Turnaround time was monitored in a subset of the prospective specimens. RESULTS: The analytical sensitivity and specificity of testing in the validation specimens were 98.9% and 100%, respectively. There were no false positives and a single false negative, a mosaic sex chromosome aneuploidy interpreted as normal. In the prospective study, the analytical sensitivity and specificity were 98% and 100%, respectively. No false positives and a single false negative, again a sex chromosome mosaic, were detected. Overall, 72.5% of all chromosomal anomalies and 87.7% of clinically significant chromosome anomalies were detected by quantitative fluorescent PCR. The average and median turnaround times were 30.5 and 25.1 hours, respectively. CONCLUSIONS: Quantitative fluorescent PCR is a robust and accurate method of rapid prenatal aneuploidy detection. PMID- 21233719 TI - Large-scale population screening for spinal muscular atrophy: clinical implications. AB - PURPOSE: To determine the frequency of SMN1 deletion carriers in the Israeli population and to assess the feasibility of population screening for spinal muscular atrophy. METHODS: A total of 6394 individuals without family history of spinal muscular atrophy underwent genetic screening by multiplex ligation dependent probe amplification, designed to detect SMN1 exon 7 and exon 8 copy number. RESULTS: One hundred fifty-nine individuals carried an SMN1 heterozygous exon 7 deletion, yielding a carrier frequency of 1:40. About 10.8% of individuals were found to carry two or more SMN1 exon 7 copies on the same chromosome (cis configuration). This implies that some deletion carriers may not be detected by multiplex ligation-dependent probe amplification or similar quantitative methods. The acceptance of spinal muscular atrophy screening among women undergoing testing for fragile X syndrome and cystic fibrosis reached 93%. CONCLUSIONS: Currently used molecular techniques cannot detect about 5% of spinal muscular atrophy carriers with a cis configuration or individuals with SMN1 sequence mutations and de novo deletions. Thus, it is estimated that the spinal muscular atrophy carrier detection rate is about 90%. Given the severity of spinal muscular atrophy, the relatively high carrier frequency, and the estimated detection rate, we conclude that population-based screening for spinal muscular atrophy is feasible and acceptable. PMID- 21233718 TI - Novel MLH1 duplication identified in Colombian families with Lynch syndrome. AB - PURPOSE: Lynch syndrome accounts for 2-4% of all colorectal cancer, and is mainly caused by germline mutations in the DNA mismatch repair genes. Our aim was to characterize the genetic mutation responsible for Lynch syndrome in an extensive Colombian family and to study its prevalence in Antioquia. METHODS: A Lynch syndrome family fulfilling Amsterdam criteria II was studied by immunohistochemistry and by multiplex ligation-dependent probe amplification (MLPA). Results were confirmed by additional independent MLPA, Southern blotting, and sequencing. RESULTS: Index case tumor immunohistochemistry results were MLH1 , MSH2+, MSH6+, and PMS2-. MLPA analysis detected a duplication of exons 12 and 13 of MLH1. This mutation was confirmed and characterized precisely to span 4219 base pairs. Duplication screening in this family led to the identification of six additional carriers and 13 noncarriers. We also screened 123 early-onset independent colorectal cancer cases from the same area and identified an additional unrelated carrier. CONCLUSION: A novel duplication of exons 12 and 13 of the MLH1 gene was detected in two independent Lynch syndrome families from Colombia. A putative founder effect and prescreening Lynch syndrome Antioquia families for this specific mutation before thorough mismatch repair mutational screening could be suggested. PMID- 21233720 TI - Horizon scanning for new genomic tests. AB - PURPOSE: The development of health-related genomic tests is decentralized and dynamic, involving government, academic, and commercial entities. Consequently, it is not easy to determine which tests are in development, currently available, or discontinued. We developed and assessed the usefulness of a systematic approach to identifying new genomic tests on the Internet. METHODS: We devised targeted queries of Web pages, newspaper articles, and blogs (Google Alerts) to identify new genomic tests. We finalized search and review procedures during a pilot phase that ended in March 2010. Queries continue to run daily and are compiled weekly; selected data are indexed in an online database, the Genomic Applications in Practice and Prevention Finder. RESULTS: After the pilot phase, our scan detected approximately two to three new genomic tests per week. Nearly two thirds of all tests (122/188, 65%) were related to cancer; only 6% were related to hereditary disorders. Although 88 (47%) of the tests, including 2 marketed directly to consumers, were commercially available, only 12 (6%) claimed United States Food and Drug Administration licensure. CONCLUSION: Systematic surveillance of the Internet provides information about genomic tests that can be used in combination with other resources to evaluate genomic tests. The Genomic Applications in Practice and Prevention Finder makes this information accessible to a wide group of stakeholders. PMID- 21233721 TI - Genetic risk estimation in the Coriell Personalized Medicine Collaborative. AB - PURPOSE: Recent genome wide-association studies have identified hundreds of single nucleotide polymorphisms associated with common complex diseases. With the momentum of these discoveries comes a need to communicate this information to individuals. METHODS: The Coriell Personalized Medicine Collaborative is an observational research study designed to evaluate the utility of personalized genomic information in health care. Participants provide saliva samples for genotyping and complete extensive on-line medical history, family history, and lifestyle questionnaires. Only results for diseases deemed potentially actionable by an independent advisory board are reported. RESULTS: We present our methodology for developing personalized reports containing risks for both genetic and nongenetic factors. Risk estimates are given as relative risk, derived or reported from representative peer-reviewed publications. Estimates of disease prevalence are also provided. Presenting risk as relative risk allows for consistent reporting across multiple diseases and across genetic and nongenetic factors. Using this approach eliminates the need for assumptions regarding population lifetime risk estimates. Publications used for risk reporting are selected based on the strength of the design and study quality. CONCLUSION: Coriell Personalized Medicine Collaborative risk reports demonstrate an approach to communicating risk of complex disease via the web that encompasses risks due to genetic variants along with risks caused by family history and lifestyle factors. PMID- 21233722 TI - Direct-to-consumer genetic testing: an assessment of genetic counselors' knowledge and beliefs. AB - PURPOSE: Direct-to-consumer genetic testing is a new means of obtaining genetic testing outside of a traditional clinical setting. This study assesses genetic counselors' experience, knowledge, and beliefs regarding direct-to-consumer genetic testing for tests that would currently be offered in genetics clinics. METHODS: Members of the National Society of Genetic Counselors completed a web administered survey in February 2008. RESULTS: Response rate was 36%; the final data analysis included 312 respondents. Eighty-three percent of respondents had two or fewer inquiries about direct-to-consumer genetic testing, and 14% had received requests for test interpretation or discussion. Respondents believed that genetic counselors have a professional obligation to be knowledgeable about direct-to-consumer genetic testing (55%) and interpret results (48%). Fifty-one percent of respondents thought genetic testing should be limited to a clinical setting; 56% agreed direct-to-consumer genetic testing is acceptable if genetic counseling is provided. More than 70% of respondents would definitely or possibly consider direct-to-consumer testing for patients who (1) have concerns about genetic discrimination, (2) want anonymous testing, or (3) have geographic constraints. CONCLUSIONS: Results indicate that genetic counselors have limited patient experiences with direct-to-consumer genetic testing and are cautiously considering if and under what circumstances this approach should be used. PMID- 21233723 TI - Surgical management of acute infectious purpura fulminans. AB - Purpura fulminans is a syndrome characterized by hemorrhagic infarction of the skin and underlying soft tissue as a result of disseminated intravascular coagulation and intravascular thrombosis. In this study, the authors report their experience with surgical intervention for acute infectious purpura fulminans (AIPF). A retrospective chart review was performed including all patients diagnosed with AIPF from January 1, 2006, to December 31, 2008, and treated at an academic medical center. Primary endpoints of interest were overall survival rate and the need for and level of eventual amputation. Improvement in limb perfusion was included as a secondary endpoint. Nine patients were diagnosed with AIPF at the authors' institution during a 3-year period, and seven of these diagnoses were made within 12 months. Overall mortality was 44% (5/9). Amputation was required in 80% of survivors (4/5). All patients explored within 24 hours of diagnosis had evidence for compartment syndrome with visible bulging muscle on fascial release. AIPF is a devastating disease with significant mortality and morbidity primarily related to the loss of multiple limbs. This study suggests that early diagnosis and surgical intervention in the form of compartment release and sympathectomy should be performed concurrently with the initial treatment of sepsis to minimize amputations in surviving patients. PMID- 21233725 TI - Car seat heaters as a potential burn hazard: a clarification. PMID- 21233726 TI - Stridor occurring after postburn neck contracture release caused by bilateral vocal cord palsy. PMID- 21233727 TI - Burn caused by cupping therapy. PMID- 21233728 TI - Development of a combined radiation and burn injury model. AB - Combined radiation and burn injuries are likely to occur after nuclear events, such as a meltdown accident at a nuclear energy plant or a nuclear attack. Little is known about the mechanisms by which combined injuries result in higher mortality than by either insult alone, and few animal models exist for combined radiation and burn injury. Herein, the authors developed a murine model of radiation and scald burn injury. Mice were given a single dose of 0, 2, 4, 5, 6, or 9 Gray (Gy) alone, followed by a 15% TBSA scald burn. All mice receiving <=4 Gy of radiation with burn survived combined injury. Higher doses of radiation (5, 6, and 9 Gy) followed by scald injury had a dose-dependent increase in mortality (34, 67, and 100%, respectively). Five Gy was determined to be the ideal dose to use in conjunction with burn injury for this model. There was a decrease in circulating white blood cells in burn, irradiated, and combined injury (5 Gy and burn) mice by 48 hours postinjury compared with sham (49.7, 11.6, and 57.3%, respectively). Circulating interleukin-6 and tumor necrosis factor-alpha were increased in combined injury at 48 hours postinjury compared with all other treatment groups. Prolonged overproduction of proinflammatory cytokines could contribute to subsequent organ damage. Decreased leukocytes might exacerbate immune impairment and susceptibility to infections. Future studies will determine whether there are long lasting consequences of this early proinflammatory response and extended decrease in leukocytes. PMID- 21233729 TI - Health professionals' and consumers' opinion: what is considered important when rating burn scars from photographs? AB - With advances in wound care technology, there is a trend toward patients undertaking specialist burns treatment in an outpatient capacity. Photographic scar evaluation is a part of this trend in some health services because it permits scar assessment by different health professionals, both within and across outpatient services, to assess the impact of scar management strategies. The aim of this study was to explore the parameters considered integral to scar assessment when completing photographic scar evaluation. First, opinions were sought from 38 burn health professionals in 2 tertiary pediatric hospitals who participated in focus groups where in-person and in-photograph scar rating were completed using three burn scar rating scales (modified Vancouver scar scale, Manchester scar scale, and patient and observer scar assessment scale) presented with a standard format and instructions. Second, 36 occupational therapists and physiotherapists from Australia and New Zealand completed questionnaires. Third, 10 healthcare consumers from 1 tertiary pediatric hospital participated in face to-face or telephone interviews. Parameters believed to be assessed using photographic evaluation of burns scarring were vascularity, surface area, color, contour, height, and overall opinion. However, surface area was considered questionable as an indicator of scar maturity. These parameters mostly differ from those considered important in a burn scar outcome measure when rating scars in-person: height/thickness, vascularity, color, pliability, joint function, and patient/client opinion. A categorical scale with visual descriptors, as well as specific strategies to improve photographic technique, may go some way to addressing the perceived difficulty in rating these parameters using burn scar photographs. PMID- 21233730 TI - Severe burn injuries caused by bioethanol-design fireplaces-an overview on recreational fire threats. AB - Commercially available bioethanol-fueled fireplaces have become increasingly popular additions for interior home decoration in Europe and more recently in the United States. These fireplaces are advertised as smokeless, ecologically friendly, and do not require professional installation, formal gas lines, or venting. Although manufacturers and businesses promote their safety, recent presentations of injuries have alerted the authors to the relevant danger bioethanol fireplaces can pose for the incautious user. Are bioethanol fireplaces going to become the future threat in domestic burn accidents beside common barbeque burns? A Medline literature search on barbeque and domestic fireplace accidents was performed to compare and stratify the injury patterns reported and to identify a risk profile for contemporary bioethanol-fueled fireplaces. To exemplify, two representative clinical cases of severe burn accidents caused by bioethanol-fueled fireplaces, both treated in the burn unit of the authors, are being presented. Design fireplaces are being recognized as an increasing source of fuel and fire-related danger in the home. This risk may be underestimated by the uninformed customer, resulting in severe burn injuries. Because bioethanol fueled fireplaces have become more commonplace, they may overtake barbecue related injury as the most common domestic burn injury. PMID- 21233731 TI - The changing pattern of pediatric burns. AB - After scalds, flame burns have been considered the next most common mode of burn injury in childhood. Recent experience in the authors' unit suggested that contact burns were becoming more frequent. The authors sought to determine the contemporary frequency of different burn modalities in children presenting to a burns unit. A retrospective review of 3621 children treated in the burns unit, both ambulatory and inpatient, at the authors' institution between January 2003 and December 2007 was performed. Patients were identified using the Burns Unit database. Data collected included age, gender, burn etiology and site, TBSA, and whether operative surgery was required. Of the 3515 patients eligible for inclusion, scalds accounted for 55.9%, contact 30.5%, and flame 7.9% of all burns. Contact burns were shown to be consistently more frequent than flame burns for every year of the study (z = 17.30, P < .001). No seasonal variation was demonstrated amongst contact burns, reflecting the variety of mechanisms involved. The data suggest a change in the historical pattern of pediatric burns previously reported in the literature. These findings have implications for public health awareness and burns prevention campaigns. PMID- 21233732 TI - Clinical experience with the screw extraction set for broken screw. AB - Titanium plate systems are used frequently for bone fractures and postosteotomy fixation in craniomaxillofacial surgery. However, sometimes the head of the screw for plate fixation is deformed or the screw breaks in the bone. Screw removal can be difficult in these cases. In this study, we examined the utility of the Screw Extraction Set (Synthes Inc) in facilitating the removal of screws broken in craniomaxillofacial bones. In the past, we often encountered screw head sockets that had become deformed. In the removal of such a screw, the extraction screw tip did not engage well with the deformed screw head socket because the extraction screw tip was angled obtusely. Thus, its removal was difficult, and this method was clearly problematic. Using the Screw Extraction Set, the removal method for a screw broken in the bone was relatively easy. In particular, it was very convenient in removing broken screws in the mandibular angle and ramus, where surgery is difficult under direct vision. This system was thought to be useful for craniofacial surgeons if proper patient selection is performed. PMID- 21233733 TI - Whole cranial vault expansion by continual occipital and fronto-orbital distraction in syndromic craniosynostosis. AB - BACKGROUND: In cases of surgery for syndromic craniosynostosis with posterior flattering, it is not possible to achieve sufficient expansion of the skull through fronto-orbital advancement alone. Although it is necessary to expand the occipital region, the surgery is risky and highly invasive. We applied the distraction osteogenesis technique for skull expansion and performed occipital expansion and fronto-orbital advancement in succession. METHODS: Three patients with syndromic craniosynostosis (2 with Crouzon syndrome, 1 with Pfeiffer syndrome) were treated in Juntendo University Hospital between 2002 and 2007. Using the distraction osteogenesis technique, we performed occipital advancement followed immediately by fronto-orbital advancement for 2 cases of Crouzon syndrome and performed fronto-orbital advancement followed by occipital advancement for a case of Pfeiffer syndrome. RESULTS: In all of the cases, we were able to perform bone extension of 25 mm or more and achieve sufficient skull expansion for both of the frontal and occipital regions. Within 1 year after the surgery, in all of the cases, favorable osteogenesis was observed in the distraction gap, and there were no bone defects. DISCUSSION: By using the distraction osteogenesis technique, the difficult procedure of occipital advancement can be performed relatively safely. In addition, as active expansion of the cranium is possible after the surgery, sufficient expansion of the cranium can be successfully performed to a degree that cannot be achieved through conventional methods. New bone is formed in the distraction gap, and there are no bone defects. The present method is extremely useful for skull formation in cases of syndromic craniosynostosis with posterior flattering. PMID- 21233734 TI - Surgical treatment of metopic synostosis. AB - Metopic synostosis is characterized by keel-shaped forehead (trigonocephaly), prominent midline ridge of the forehead, bitemporal narrowing, bilateral retrusion of supraorbits, egg-shaped orbits, low nasal dorsum, and reduced volume of the anterior cranial fossa. The mainstay treatment is early surgical intervention before the age of 12 months, which usually consists of bifrontal craniotomy with bilateral recontouring, lateral advancement, and lateral displacement of the superior orbital rims. Here, we have developed a new simplified technique for surgical treatment of trigonocephaly. A total of 60 cases of trigonocephaly were operated on between January 1995 and January 2010 by the first author. Surgical outcomes were evaluated 6 months after surgery using postoperative photographs and clinical examination notes, and scaling was made using the Whitaker classification. The evaluation showed that 85% of them were in class I, 11.6% were in class II, and 3.3% were in class III. No case was in class IV. Only the last 10 cases received the new surgical technique, and all were in class I. Complication rate was 38.3% for all cases and was only 20% for the last 10 cases, that is, the new technique group. Revision rate for trigonocephaly surgery was 13.3%, and the most common reason was hardware removal. None of the patients from the new technique group underwent revision surgery. We believe that our new technique is fast and easy, can provide sufficient bone graft, and is more useful for older patients (>1 y). Early postoperative results have been promising. PMID- 21233735 TI - Plates removal in orthognathic surgery and facial fractures: when and why. AB - BACKGROUND: There is agreement that symptomatic plates should be removed, but there is no consensus among maxillofacial surgeons on the need for routine removal of asymptomatic plates. Only by evaluating long follow-up studies conducted with large-volume data that guidelines about when to remove and why remove plates used for internal rigid fixation can be traced. MATERIALS AND METHODS: This study was conducted as a retrospective study. Clinical findings of all the patients presented at the department of maxillofacial surgery of 2 Italian hospitals, in whom miniplates were inserted between January 2004 and December 2007, were included: a follow-up of these patients was conducted until August 2009. RESULTS: The region most involved with plates' insertion was the upper maxilla (49.8%), followed by mandibular body (38.1%), angle (7.9%), condyle (2.4%), and symphysis (1.8%). The region most involved in plates' removal was the maxilla in 9%, followed by mandibular body in the 7.5%. All plates inserted in angle regions were removed. Plates placed in the condylar area did not need any plate removal. CONCLUSIONS: From this study, there is no evidence to support the advice for routine removal of titanium miniplates from the maxillofacial skeleton, although when using plates in the mandibular angle region, it would be necessary to inform the patient about the very high probability of a second operation necessary for the plates' removal. PMID- 21233736 TI - Complications of hydroxyapatite bone cement in secondary pediatric craniofacial reconstruction. AB - Hydroxyapatite cement has become a popular alternative to bone grafts in reconstructing the calvarium. Although animal studies have shown promising results with use of hydroxyapatite, human clinical studies have shown mixed results including significant rates of infection. This is a retrospective chart review during a 7-year period (1997-2003) of 20 patients who underwent secondary forehead cranioplasty with hydroxyapatite cement (Norian Craniofacial Reconstruction System). Basic demographics including age, sex, and diagnosis were identified. Characteristics of the defects were recorded including size, location, and depth (full versus partial thickness). The volume of hydroxyapatite and any adjunctive procedures were identified. The postoperative course was analyzed for length of follow-up and the presence of infections.Twenty patients were identified in which Norian had been used and 3 patients were lost to follow up. Secondary forehead asymmetry was the most common presentation. The mean volume of hydroxyapatite used was 24.4 mL. All patients had initially acceptable aesthetic results. Of the 17 patients, 10 (59%) ultimately had infectious complications. Infection occurred on a mean of 17.3 months after surgery (range, 4 mo to 4 y), and the mean amount of hydroxyapatite used was 32.5 mL (infections) versus 14.3 mL (no infections). Of the 10 patients with complications, 9 required surgical debridement and subsequent delayed reconstruction. Although hydroxyapatite cement can yield excellent aesthetic results, its use in secondary reconstruction has yielded unacceptably high infection rates leading to discontinuation of its use in this patient population. PMID- 21233737 TI - Correction of congenital transverse cleft of the earlobe. AB - Congenital cleft earlobe is classified into longitudinal, transverse, triple, and defective types. The transverse type is rare. We report an 11-year-old girl with a transverse cleft of the earlobe that was corrected with a dermofat graft and a de-epithelialized tongue flap. The anterior (superior) and posterior (inferior) lobes of the transverse cleft were divided. Dermofat tissue from the ipsilateral retroauricular area was grafted between the lobes, and an anterior de epithelialized (tongue) flap was inset in addition. Dermofat graft and de epithelialized flap were applied effectively to a soft tissue defect in a congenital cleft of the earlobe. The shape and contour of the earlobe were then acceptable. Congenital transverse cleft of the earlobe can be corrected by supplementing a soft tissue defect with a dermofat graft and a de-epithelialized flap. PMID- 21233738 TI - Transternocleidomastoid vertical muscle approach in the extirpation of the lateral cervical cysts: video-assisted technique. AB - Congenital tumors as branchiogenic cysts and hygromas are most likely to occur in the middle and superior third of the lateral area of the neck. They are found beneath the sternocleidomastoid (SCM); domus can lie just beneath anterior, middle, and posterior aspect of the muscle, depending on the development of the tumor. When tumor is placed on the anterior edge of SCM, an anterior approach is used; if it develops on the posterior border, a posterior way is indicated. In both cases, muscular fibers must be displaced forward or behind, permitting safe and easy exposition and resection. This article describes a new video-assisted approach for benign cystic tumors projecting in the middle of the SCM. Cyst exposure and resection are performed by passing through the muscle body vertically. PMID- 21233739 TI - Vomer-palatal flap, reconstruction of the palatal defect after maxillectomy. AB - Rotational palatal flaps are frequently used to repair defects after partial or total maxillectomy procedures. However, their use is determined by the availability of sound tissues for defect closure. In an attempt to increase the amount of tissues available, we developed a vomer-palatal flap to include a part of vomer mucoperiosteum. The technique proved efficiency in a series of patients treated at Seoul National University Dental Hospital. PMID- 21233741 TI - Superficial cervical artery island flap for large soft-tissue reconstruction of occipital and parotid region after tumor resection. AB - The application of microvascular free flaps is the most widespread method currently used for the reconstruction of extensive defects after resection of head and neck tumor. But not all patients are suitable for a free-flap reconstruction. The pectoralis major flap and trapezius musculocutaneous flap are the most used pedicled flap in large head and neck reconstruction. However, muscle is not always necessary, even for complicated wounds. In addition, there is the possibility of some functional loss when a musculocutaneous flap is used. In this report, we present favorable outcome of 2 cases with the use of superficial cervical artery island flap for occipital and parotid region large soft-tissue reconstruction after tumor resection. We think that superficial cervical artery island flap is a reliable and convenient flap suitable for repairing large-size defects of the scalp, neck, and face, which obviates the need for a microvascular reconstruction. PMID- 21233740 TI - Combined bone and soft-tissue augmentation surgery in temporo-orbital contour reconstruction. AB - Temporal hollowing due to temporal muscle atrophy after standard skull base surgery is common. Various techniques have been previously described to correct the disfiguring defect. Most often reconstruction is performed using freehand molded polymethylmethacrylate cement. This method and material are insufficient in terms of aesthetic results and implant characteristics. We herein propose reconstruction of such defects with a polyetheretherketone (PEEK)-based patient specific implant (PSI) including soft-tissue augmentation to preserve normal facial topography. We describe a patient who presented with a large temporo orbital hemangioma that had been repaired with polymethylmethacrylate 25 years earlier. Because of a toxic skin atrophy fistula, followed by infection and meningitis, this initial implant had to be removed. The large, disfiguring temporo-orbital defect was reconstructed with a PEEK-based PSI. The lateral orbital wall and the temporal muscle atrophy were augmented with computer-aided design and surface modeling techniques. The operative procedure to implant and adopt the reconstructed PEEK-based PSI was simple, and an excellent cosmetic outcome was achieved. The postoperative clinical course was uneventful over a 5 year follow-up period. Polyetheretherketone-based combined bony and soft contour remodeling is a feasible and effective method for cranioplasty including combined bone and soft-tissue reconstruction of temporo-orbital defects. Manual reconstruction of this cosmetically delicate area carries an exceptional risk of disfiguring results. Augmentation surgery in this anatomic location needs accurate PSIs to achieve satisfactory cosmetic results. The cosmetic outcome achieved in this case is superior compared with previously reported techniques. PMID- 21233742 TI - Reconstruction of coup de sabre deformity (linear localized scleroderma) by using galeal frontalis muscle flap and demineralized bone matrix combination. AB - In this clinical report, we are presenting the combination of demineralized bone matrix combined with bilateral galea frontalis flaps. Based on our 6-month results, this seems to be a reasonable combination to accomplish long-lasting restoration of forehead defects related to en coup de sabre linear localized scleroderma. PMID- 21233743 TI - Tracheostomy in maxillofacial surgery: a simple and safe technique for residents in training. AB - BACKGROUND: Tracheostomy is a frequently performed surgical procedure and may be required under emergency, semiurgent, or elective conditions. In maxillofacial surgery, it is indicated in congenital, inflammatory, oncologic, or traumatic respiratory obstruction and prolonged intubation. This article presents a simplified tracheostomy procedure based on anatomic markers that gives the best compromise between minimum invasiveness and safety. PATIENTS AND METHODS: A retrospective study analyzed the clinical aspects, treatment methods, and clinical course of 198 patients who underwent tracheostomies performed by residents in training under the supervision of surgeons between October 2002 and December 2007 at the Maxillofacial Surgery Department of Carlo Poma Hospital, Mantova, and the Maxillofacial Unit, Head and Neck Department, University of Modena and Reggio Emilia, Italy. Tracheostomies were performed in 127 patients (64.14%) with neoplastic diseases (tumors of the tongue base, tonsils, and oral and pharyngeal regions) and in 71 patients with trauma (35.86%). The patients were followed up for 3 to 65 months. RESULTS: Acceptable clinical healing and outcomes were obtained in all patients. Intraoperative complications occurred in 35 patients (17.7%): bleeding in 32 patients (16.2%) and pretracheal or paratracheal tube placement in 3 patients (1.51%). Postoperative complications after tracheostomy closure included tracheostomy dehiscence in 5 patients (2.52%) and subcutaneous emphysema in 26 patients (13.12%). Tracheostomy dehiscence occurred in 3 patients with neoplasia (1.51%) and in 2 patients with trauma (1.01%). No symptomatic tracheal stenosis developed. CONCLUSIONS: The standardized surgical technique presented here reduces the associated surgical risk when the correct anatomic markers are used and important structures are recognized and handled correctly. PMID- 21233744 TI - Retrograde fiberoptic technique to avoid tracheostomy in a patient with a tracheocutaneous fistula and Treacher Collins syndrome. AB - Children with Treacher Collins syndrome have multiple craniofacial abnormalities that can cause difficulty ventilating and intubating under general anesthesia. We describe a unique technique to secure an endotracheal tube via a retrograde technique using patent tracheocutaneous fistula and fiberoptic bronchoscopy. In this setting, the presence of a tracheocutaneous fistula spared tracheostomy in this patient. PMID- 21233745 TI - Utilization of a modified bite guard for preventing traumatic macroglossia. AB - This clinical report describes the treatment of a patient having traumatic macroglossia due to schwannoma in the craniocervical region. Enlarged tongue or macroglossia may compromise vital functions of the patient. To avoid a chronic tongue bite trauma, a bite guard that was inspired from a habit breaker was fabricated. Tongue injury has significantly healed with the use of this appliance, and the patient was able to masticate without biting on his tongue. PMID- 21233746 TI - Horizontal flip pedicled genioplasty for correction of asymmetric chin in adult unilateral temperomandibular joint ankylosis. AB - It has been the desire and a great challenge to clinicians treating maxillofacial deformities to bring about symmetry in asymmetric faces. As one understands, it is very difficult to reproduce nature, that is, the normal side out of abnormal side, and it is easier to manage bilateral symmetrical deformities. Temporomandibular joint (TMJ) ankylosis, when it occurs in early childhood, will have devastating effects on the future growth and development of the jaws and teeth with obvious facial deformity including the chin, which worsens with advancing age and the time elapsed between the onset of ankylosis and the treatment instituted. We have been treating these chin deformities in adult unilateral TMJ ankylosis cases for over more than a decade with horizontal flip pedicled genioplasty, which has a mathematical basis of turning a scalene triangle to an isosceles triangle and thereby achieving symmetry. Fixation of the genial segment in an overriding position not only adds to the length of mandible but also overcomes the obstructive sleep apnea many times associated with TMJ ankylosis. We have successfully treated 15 patients using horizontal flip pedicled genioplasty during last 14 years. This instantaneous corrective and unique technique requiring minimal patient compliance is put forward with refinements developed during a period of years. PMID- 21233747 TI - Hemangioma causing deformational plagiocephaly. AB - Hemangioma is the most common tumor of infancy, occurring mostly in the head and neck region. Intervention during the proliferating phase is indicated if the lesion poses a threat to life or function. Posterior head and neck hemangioma causing deformational plagiocephaly is a further indication for intervention. PMID- 21233748 TI - Relapse in fronto-orbital advancement: a pilot study. AB - Our unit policy in fronto-orbital advancement (FOA) and remodeling has been initial overcorrection to improve the ultimate aesthetic outcome of surgery. To assess relapse of anteroposterior (AP) correction in patients with cranial synostosis undergoing FOA and remodeling, a retrospective pilot study identified patients from the unit database. Serial AP calvarial measurements were used to record surgical and postsurgical changes. Patients showing a change in measurements toward preoperative values were considered to have relapsed. Associated factors were recorded, and statistical analysis was carried out using SPSS.Thirty-one patients (female n = 10, male n = 21) with a median age at surgery of 17 months and a mean weight of 11 kg were included in the study. The mean hospital stay was 7 days. The mean advancement was 13 (SD, 4) mm, and relapse occurred in 65% (20/31). Mean AP relapse at 5 months was 6.2 mm. No patient required subsequent FOA. No significant correlation was found between relapse and age, weight, hospital stay, and syndromic status. Anteroposterior relapse of the fronto-orbital segment occurred in two thirds (65%) of our cohort at 5 months. A prospective study is now under way to analyze this further. The results of this pilot study suggest that strategies to minimize or to compensate for relapse may enhance the ultimate surgical result. PMID- 21233749 TI - Treatment of midline cleft of the mandible-A 2-stage approach. AB - Midline clefts of the lower lip and mandible are rare congenital anomalies. They may present as complete or incomplete in nature along with associated bifid tongue and ankyloglossia. Some may present with cleft of lower lip, cleft of mandible, fissured tongue, absent hyoid bone, cleft of manubrium sterni, or an extremely rare anomaly known as Tessier cleft no. 30. We present this unique case of midline cleft of the lower lip (incomplete) and mandible (complete) with initial soft-tissue surgery for the lower lip. The hard-tissue surgery for this case is deferred at a later date, and the reasons are discussed. PMID- 21233750 TI - Refinement of the correction of orbital hypertelorism. AB - The objective of this article was to explore the effect of paraorbital soft tissue expansion before orbital osteotomies and medial translocation by combined intracranial-extracranial approach. Tissue expansion was implanted in the zygomatic and temporal region 3 weeks before traditional operation in 2 cases of severe orbital hypertelorism. The measurements of interorbital and intercanthal distance were studied preoperatively and postoperatively by three-dimensional computed tomography. The interorbital distance of the 2 patients decreased from 4.4 and 3.2 cm to 2.0 and 1.4 cm, respectively. The intercanthal distance decreased from 6.7 and 4.8 cm to 5.0 and 3.8 cm, respectively. The paraorbital soft-tissue-expansion technique may be an effective technique for the stability of the corrected orbital framework and the prevention of reoccurrence in severe cases of orbital hypertelorism. PMID- 21233751 TI - A rare association of tension pneumocephalus and a large frontoethmoidal osteoma: imaging features and surgical treatment. AB - Osteomas are the most common benign paranasal sinus tumors and are often found in the frontal and ethmoidal sinus. Intracranial complications such as pneumocephalus have occasionally been reported in association with osteomas. We describe a 33-year-old man with a large frontoethmoidal osteoma complicated by tension pneumocephalus and neurological disturbances, and we discuss the clinical and imaging resolutions after surgical management. We emphasize the imaging features and neuroendoscopic approach to avoid life-threatening conditions. PMID- 21233752 TI - Intraoperative transfusion-related acute lung injury in a child during calvarial vault remodeling. AB - Transfusion-related acute lung injury (TRALI) is currently recognized by the US Food and Drug Administration as the number one cause of mortality related to blood transfusion. Although various pathophysiologic mechanisms have been proposed, it is thought to be related to the presence of anti-HLA antibodies or bioactive lipid components in the donor blood product, which results in activation of recipient leukocytes and the resultant pulmonary damage from the release of bioactive substances including cytokines. As TRALI manifests as acute lung injury with signs and symptoms consistent with acute respiratory distress syndrome, it is frequently underdiagnosed, as the acute lung injury may be attributed to other factors. Transfusion-related acute lung injury is an important clinical entity for anesthesia providers to recognize and diagnose accurately, as many transfusions occur in the surgical patient. We present a case report of a pediatric patient who developed intraoperative TRALI during calvarial vault remodeling to treat craniosynostosis. The history, pathophysiology, and treatment of TRALI are discussed. Potential preventive measures are reviewed. PMID- 21233753 TI - Surgical correction of a median cleft of the mandible. AB - We report a rare case of a boy with median clefts of the lower lip and mandible. In addition, there was a fibrous band extending from the symphysis of the mandible to the suprasternal notch. We repaired the mandibular cleft using autologous iliac bone grafts. The separated mandibular bones were reconnected by rigid fixation with titanium miniplates. Z-plasty with cervical skin was also performed. The fibrous band extending from the mandibular symphysis to the suprasternal notch was dissected. The suprasternal notch end of the band was cut off, and a fibrous soft-tissue pedicled superior flap was formed. The flap was turned over and transferred to the mental region subcutaneously to correct the microgenia. The appearance of this child was greatly improved by this procedure. PMID- 21233754 TI - Coronal synostosis syndrome (Muenke syndrome): the value of genetic testing versus clinical diagnosis. AB - BACKGROUND: Muenke syndrome is a fibroblast growth factor receptor 3 (FGFR-3) associated coronal craniosynostosis syndrome, which was first described in 1997. CASE: We report an infant girl who was born to a 29-year-old primapara at 38 weeks' gestation. When evaluated at 3 days old, physical examination revealed a high forehead with frontal bossing, upturned nose, arched palate, shallow midface structures, and heavily ridged coronal sutures bilaterally. Clinically, the infant seemed to be neurologically normal. Skull radiographs and computed tomography confirmed the presence of bilateral coronal synostosis, with patency of all other sutures. Family history was remarkable, in that the infant's father, paternal grandmother, and a paternal cousin demonstrated subtle craniofacial features, which had not been previously identified. Mutation analysis of FGFR-3 revealed a missense mutation in exon 6, c.749 C>G, with a resultant amino acid change from proline to arginine at codon 250 (P250R), in keeping with Muenke syndrome (Am J Hum Genet 1997;60:555-564). The mutation was subsequently identified in her father, suggesting variable expression in this family, as he had only mild midfacial flattening. At 9 months of age, our patient underwent anterior cranial expansion, correction of orbital hypertelorism, intracranial orbital osteotomies, and advancement of the frontal bandeau. She tolerated the procedure well and has done well postoperatively. CONCLUSIONS: We report the case of an infant with Muenke syndrome, with evidence of variable expressivity within the paternal family. The pertinent literature, in which only 2 prior Canadian cases were identified, is reviewed. PMID- 21233755 TI - Meningoencephalocele and other dural disruptions: complications of Le Fort III midfacial osteotomies and distraction. AB - OBJECTIVE: Complications of Le Fort III midfacial advancement include cerebrospinal fluid (CSF) rhinorrhea, meningitis, and ocular and cerebral injury. This report reviews our experience with Le Fort III distraction, highlighting complications of dural disruption, and correlates occurrences with the anatomy of the cranial base and prior cranial procedures. METHODS: This was a retrospective chart review of all patients who had Le Fort III subcranial osteotomies and midfacial advancement with distraction. Complications related to dural disruption were documented. The anatomy of the anterior cranial fossa was assessed with preoperative computed tomographic (CT) scans and compared with age- and sex matched normal control scans, with particular attention paid to the anterior cranial fossa and fovea ethmoidalis (FE). On reconstructed midline sagittal images, the anterior cranial fossa was characterized as normal, sagging, or slanting. On reconstructed coronal images, immediately posterior to the plane of the lacrimal sac, each FE was characterized as normal, flattened, or depressed, relative to the adjacent cribriform plates. RESULTS: Thirty-one patients have had Le Fort III midfacial advancement with distraction at Children's Hospital Boston since 1995. Two patients underwent a second Le Fort III distraction. Two patients (6.5%) had postoperative CSF rhinorrhea, 2 had CSF leak at a pin site, and 1 patient had a late complication of meningoencephalocele. Twenty-six patients had 27 available preoperative three-dimensional reformatted CT scans. Seven of these had a normal sagittal anterior cranial fossa and normal coronal FE morphology. One of these 7 patients had a second CT at an older age showing development of bilateral FE flattening. Eleven patients had a sagging midline anterior cranial fossa including both patients who developed CSF rhinorrhea. Of these 11 patients, all had unilateral or bilateral flattening or depression of the FE, and 5 had abnormal slanting of the anterior cranial fossa. Eight patients had normal sagittal morphology, but bilateral or unilateral depression of the FE, including the patient who developed a meningoencephalocele. All patients with CSF leak had previously had a fronto-orbital advancement (FOA). Three of 4 patients with CSF leak did not have prior ventriculoperitoneal shunt placement. The patient with postoperative meningoencephalocele had prior FOA and shunt. CONCLUSIONS: We studied the abnormal position of the sagging or slanted anterior cranial base and depressed FE in patients with syndromic coronal synostosis. These findings may explain the risk for dural tear during osteotomies at the nasofrontal suture and superior-medial orbital wall. Attention to the morphology of the anterior cranial base, as seen on sagittal and coronal CT images, aids in preventing these complications. Patients who have a shunt are at lower risk for CSF leak; however, patients who have had an FOA are at higher risk. PMID- 21233756 TI - Calcified subgaleal hematoma with secondary cranial deformity in a patient with Kasabach-Merritt phenomenon. AB - We present here the case of a 25-month-old boy who, in conjunction with his preexisting Kasabach-Merritt phenomenon (KMP), developed a massive calcified subgaleal hematoma (SGH) with secondary cranial deformity. Kasabach-Merritt phenomenon is a rare condition that involves a secondary consumptive coagulopathy in the setting of congenital hemangiomatous lesions. The vascular lesions of KMP are often large, singular, and cutaneous, but may also be diffuse, and involve internal structures. Subgaleal hematomas are a rare condition, most frequently observed in neonates as a complication of instrument-assisted delivery. There have been few cases reported beyond the perinatal period, but those that are present within the literature have typically resulted from some instance of minor trauma to the scalp. Most cases resolve spontaneously and without complication. However, our patient's SGH developed into a large, organized, and calcified lesion, likely with some contribution from his hematologic deficit. In addition, this subgaleal lesion resulted in a cranial deformity, ultimately requiring surgical evacuation and reconstruction. We believe the case presented here represents the first report of an SGH in the setting of KMP. PMID- 21233757 TI - Efficacy and safety of early cranioplasty, at least within 1 month. AB - INTRODUCTION: Patients may experience problems, including severe adhesion during skull restoration procedures performed after decompressive craniectomy. Cranioplasty is currently the only solution for these adverse outcomes, although there is no established consensus on optimal surgical timing. Here, we study the efficacy and safety of early cranioplasty performed within 1 month after first surgical decompression. METHODS: In this study, we retrospectively enrolled 30 patients during a 30-month period. Serial brain computed tomographic scans were obtained to demonstrate relief of brain swelling. During the operative procedure, the efficacy of early cranioplasty was assessed by measuring elapsed operating time, dissection time, and blood loss. Fifteen patients were selected for the control group, all of whom had undergone cranioplasty performed more than 3 months after first decompression. RESULTS: All primary causes for craniectomy were traumatic in enrolled patients. The mean interval for cranioplasty was 28.6 days after first operation. When compared with the control group, the mean time for dissection was much shorter (15.3 min, P < 0.0001) and estimated blood loss was much smaller (336.67 mL, P < 0.0001) in the early cranioplasty group. No patients experienced surgery-related complications during the 6-month follow-up period. CONCLUSIONS: Early cranioplasty provides satisfactory securing dissection plane during operative procedures compared with later cranioplasty, without causing additional complications including infection, subdural hygroma, and brain parenchymal damage, in selected cases. PMID- 21233758 TI - Orbit and maxilla augmentation of oblique facial clefts using mandibular outer cortex. AB - BACKGROUND: This study focused on using the mandibular outer cortex for orbital and maxillary augmentation of oblique facial clefts. METHODS: Eight oblique facial clefts were reconstructed with the mandibular outer cortex from April 2000 to April 2008. RESULTS: No visible scars and few complications were observed at the donor site. Postoperative follow-up for 6 months to 3 years demonstrated that all of the patients had good aesthetic facial appearances. CONCLUSIONS: The mandibular outer cortex can be used for orbital and maxillary augmentation of oblique facial clefts. PMID- 21233759 TI - Complications of calvarial bone harvesting for maxillofacial reconstructions. AB - BACKGROUND: For almost a century, autologous bone grafts are the criterion standard for facial skeleton rehabilitations. Progressively, because of its various advantages, calvarial bone imposed as one of the most adapted for craniomaxillofacial reconstructions. Also, calvarial harvesting remains a controversial technique because of its potential complications described in the literature. The aim of this study was to report the precocious and late complications encountered in our practice and to compare them with the previous data of the literature. METHODS: We decided to realize a retrospective study over 10 years and 511 cases of calvarial bone harvesting performed in our maxillofacial department. RESULTS: Our results are very clear, reporting some annoying consequences and long-term aesthetic reattempts, but any serious complication. DISCUSSION: According to our experience and previous data of the literature, we described some technical refinements that could improve our technique and reduce its potentials complications. Nevertheless, we think that nowadays calvarial harvesting is the criterion standard for maxillofacial bone grafts, and the complications described in the literature are negligible for experienced operators. PMID- 21233760 TI - Investigation on the structure of nasal cavity and its airflow field in Crouzon syndrome. AB - OBJECTIVE: Setup computational fluid dynamics (CFD) model of the nasal cavity in patients with Crouzon syndrome analyze inspiratory airflow hydrokinetics of its nasal cavity. After changing the morphosis structure of the nasal cavity by operation, compare the preoperative and postoperative alteration of the airflow field of the nasal cavity and evaluate the effect of operation on the physiological function of nasal ventilation. METHODS: Eleven patients with Crouzon syndrome were underwent spiral computed tomographic laminar scanning to obtain DICOM data and establish the CFD model. The field features of the nasal cavity with inspiratory static state phase were simulated and analyzed by the Fluent software. The changed data on preoperative and postoperative flow field in the nasal cavity in 5 of 11 patients were compared and analyzed. RESULTS: The nasal cavity of a patient with Crouzon syndrome reflected the structural features of relatively short and high-vaulted anteroposterior diameter. The nasal valve was the narrowest region in the nasal cavity and was the key region of producing obvious pressure drop. The inspiratory static state phase reflected comparatively high local airflow rate (approximately 2.469 m/s) and sheer force of the nasal wall. With the distance increasing from the anterior naris, the pressure inside the nasal cavity was decreased gradually. The pressure drop in the nasal cavity before the front end of the concha nasalis inferior (approximately 2 cm from anterior naris) accounted for most of the pressure of the whole nasal cavity (69% 88% of the overall pressure in nasal cavity and 79.24% on average). Osteotomy advancement and distraction osteogenesis increased the anteroposterior diameter of the nasal cavity and the changed nasal resistance. CONCLUSIONS: By analyzing the structure of the nasal cavity of patients with Crouzon syndrome and the CFD numerical simulation of patients after the procedure, airflow distribution in patients' nasal cavity and the effect of the surgery on the structure of the nasal cavity and airflow field were realized. Nasal valve played a pivotal role in the airflow field distribution of the nasal cavity. Operation changed the nasal resistance, improved the ventilation of nasal cavity, but did not affect the airflow field distribution of nasal cavity. PMID- 21233761 TI - Normally shaped heads with no sutures, normally shaped heads with abnormal sutures, and abnormally shaped heads with normal sutures. AB - We present a series of children whose head shapes and suture status do not make sense. There were 3 patients with complete absence of sutures and normal head shapes. One patient was evaluated for microcephaly at 6 years of age. In the second, the absence of sutures was discovered on workup for headaches at 8 years of age. The third underwent x-ray imaging for parasagittal bony nodules at 1 month of age. The head circumferences fell at the 4th, 25th, and 50th percentiles, respectively. The 2 older children were in normal classes, and the youngest was meeting milestones appropriately. We encountered 3 patients with fusion of the sagittal suture and normal head shapes. One had a flattened occiput, the second patient was thought to be brachycephalic, and the third was macrocephalic. Head circumferences were at the fourth, 50th, and 75th percentiles. The patient with head circumference at the fourth percentile had fetal alcohol syndrome and speech delay. The other 2 were developing normally with follow-up of 14 months. Finally, 3 patients underwent surgery for characteristic craniosynostotic head shapes and were found to have patent sutures at surgery. One patient had classic unilateral coronal synostosis and a patent suture on the side of the defect. The second patient had Crouzon syndrome with characteristic head shape, but open coronal sutures. The third patient had the appearance of bicoronal synostosis, with a patent suture on one side. They have had good results from their craniofacial reconstructions at 24, 12, and 6 months' follow-up. CONCLUSIONS: We have no explanation for these interesting findings. PMID- 21233762 TI - Intraoral multistage mandibular angle ostectomy: 10 years' experience in mandibular contouring in Asians. AB - In Asia, a round face rather is more acceptable than a square face. Intraoral mandibular angle ostectomy is a common aesthetic procedure for correcting a prominent mandibular angle. However, an operation of sheer straight-lined prominent mandibular angle resection would sometimes create extramandibular angles or palpable bone steps in the margin of mandibular body and produce unnatural lower one-third facial appearance, especially for a square and disproportional mandibular angle even extending to the middle mandibular body. This article describes the method of multistage mandibular angle ostectomy to produce a natural lower one-third facial contour. This method mainly focused on the posterior area of mandibular ostectomy by intraoral approach, although it has modifications. Mandibular contouring is realized first through bone cutting from antegonial notch posteriorly upperward, reaching to the middle ramus of the mandible near the earlobe; second ostectomy followed along mandible lower part is to get rid of extramandibular angle according to the preoperative design; sometimes necessarily, third ostectomy creates a smooth mandibular contour. From January 2000 to January 2010, 379 patients were operated on, and satisfactory results were achieved. Thus, this procedure could avoid excessive bone cutting, extramandibular angles, unnatural appearance, and palpable bone steps. PMID- 21233763 TI - Use of continuation or maintenance electroconvulsive therapy in adolescents with severe treatment-resistant depression. AB - Retrospective data are presented for 6 adolescents ranging in age from 14 to 17 years, who were diagnosed with severe treatment-resistant major depression (TRD). Subjects were treated with one or more index courses of electroconvulsive therapy (ECT) followed by continuation ECT (C-ECT, up to 6 months of ECT) or maintenance ECT (M-ECT; ECT beyond 6 months) when necessary. Electroconvulsive therapy was continued until remission or until minimal residual symptoms were evident. Pharmacotherapy and psychotherapy were reintroduced during C-ECT or M-ECT. Premorbid functioning was achieved by 5 of 6 cases. Cognitive deficits were not evident. In fact, comparison of pre-ECT and post-ECT neuropsychological functioning revealed a trend toward improved auditory and verbal memory on most of the results. We concluded that C-ECT and M-ECT are useful and safe treatment strategies for selected adolescents with severe treatment-resistant depression, and symptom remission may be achieved without experiencing cognitive impairment. PMID- 21233764 TI - Effect of closing facilities on electroconvulsive therapy use in Glasgow. AB - OBJECTIVES: : To assess the effect of closure of electroconvulsive therapy (ECT) centers on ECT use. Electroconvulsive therapy remains a recommended and effective treatment for mental disorders. Declining rates of ECT use in the United Kingdom have been observed over the last 20 years with anecdotal observations that use has declined as the result of centralization of provision. In Glasgow, there have been site closures in the north with no such rationing taking place in the south. METHODS: : A naturalistic retrospective survey of the number of ECT courses commenced each year in Glasgow, with a comparison made between the north and the south of the city. Data were available from 1996 to 2008. RESULTS: : Our analysis showed no change in the mean number of ECT courses commenced in southern Glasgow (period 1, 42.25; period 2, 41.83; period 3, 31; F = 1.369; P = 0.298). There was a significant reduction in the mean number of ECT treatments commenced in northern Glasgow (period 1, 91.25; period 2, 51; period 3, 33.33; F = 10.06; P = 0.04). CONCLUSIONS: : In northern Glasgow, where there have been 2 site closures since 1996, ECT use has declined. This trend was not replicated in the south of the city. This would suggest that the closure of ECT centers does reduce the use of ECT. However, there may be a number of confounding variables that could not be factored into the analysis because of lack of available data. PMID- 21233765 TI - The use of topical lidocaine to reduce pain during repetitive transcranial magnetic stimulation for the treatment of depression. AB - Repetitive transcranial magnetic stimulation (rTMS) is a form of neurostimulation therapy that was recently approved by the Food and Drug Administration for the treatment of depression. Repetitive transcranial magnetic stimulation is considered noninvasive and relatively safe; however, there have been reports of scalp pain during and at the site of stimulation. This case report documents the use of topical lidocaine to reduce scalp pain during rTMS administration. All patients had a diagnosis of major depressive disorder according to research diagnostic criteria and were washed off antidepressant medications before treatment. Patients were given active rTMS treatment during a masked, open-label, or long-term follow-up treatment schedule. Treatment was delivered to the left dorsolateral prefrontal cortex at 120% of the patient's observed motor threshold. Ten patients received 3000 magnetic pulses per session with an on time of 4 seconds and an off time of 26 seconds. Patients who reported pain during stimulation were given topical lidocaine HCl 2%, which was applied 20 minutes before treatment. Patients reported mixed outcomes of using topical lidocaine to reduce scalp pain during stimulation. Half of the patients reported no significant reduction in pain, whereas the other half indicated a noticeable decrease during rTMS. As a case report, our study has limited results. Given the recent approval of rTMS for the treatment of depression, additional studies are warranted to determine optimal methods of reducing scalp pain. PMID- 21233766 TI - Use of modified electroconvulsive therapy in a case of polymyositis presenting with delusion of nihilism of proxy (Odysseus syndrome). AB - We present a case of psychotic depression with polymyositis presenting with the distinct phenomenon of nihilism by proxy, which was treated with electroconvulsive therapy (ECT). A female patient with polymyositis was initially treated with pharmacotherapy. After initial response, there was deterioration in her mental state and hence, after careful consideration, neurological, and anaesthetic consultations, modified ECT was given with close monitoring. The mental state of the patient improved with a course of ECT, which proceeded without any complications. Her depressive symptoms including the delusion of nihilism by proxy responded to ECT. To the best of our knowledge, the use of ECT has not been reported in a case of polymyositis before, and this case shows that modified ECT can be given successfully in patients with polymyositis. PMID- 21233767 TI - Successful electroconvulsive therapy in a drug-refractory depressed patient with idiopathic intracranial hypertension. AB - The condition of a 42-year-old woman with drug-refractory major depression, severe headache, and progressive visual impairment was diagnosed as idiopathic intracranial hypertension (IICH). Idiopathic intracranial hypertension is a relative contraindication to electroconvulsive therapy (ECT), chiefly due to the theoretical risk of brain herniation. Although the diagnosis of IICH was unequivocal, the patient's headache was interpreted as being unassociated with IICH. Nine ECT sessions were performed, and both depression and headache improved dramatically. People with IICH are at an increased risk of depression and report more physical complains, including headache. Cases of IICH may be considered for ECT if depression is drug-refractory. In this case, cerebrospinal fluid open pressure should be closely monitored. PMID- 21233768 TI - Relationship of the protein Z intron F G79A and IL6 C634G gene polymorphisms with the risk of recurrent pregnancy loss in Egyptian women. AB - PURPOSE: To investigate the relationship between recurrent pregnancy loss and single nucleotide polymorphisms in the protein Z (PZ) intron F G79A and the promoter region of the IL6 C634G genes in Egyptian women. PROCEDURES: Single nucleotide polymorphisms in the PZ intron F G79A gene and the promoter region of the IL6 C634G gene were studied in 70 Egyptian women; 40 patients and 30 healthy and parous volunteers using the polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: Regarding the PZ intron F G79A polymorphism; a higher prevalence of the A allele in the controls (53.3%) compared with the cases (22.5%) was found, and the difference proved to be statistically significant (P = 0.008). As for the IL6 C634G polymorphism, the frequency of the G allele was higher in the controls (100%) than in the cases (95%), but the difference did not prove to be statistically significant (P = 0.503). A statistically significant difference between the prevalence of the IL6 C634G (95%) and the PZ intron F G79A (22.5%) was detected (P <= 0.001). CONCLUSION: A statistically significant difference of the frequency of the A allele of the PZ intron F G79A polymorphism was found with a higher prevalence of the A allele among the controls compared with the patients, suggesting a lower risk of recurrent pregnancy loss among the studied patients, but the IL6 C634G polymorphism did not prove to have an equivalent effect. PMID- 21233769 TI - Condition concern: an innovative response system for enhancing hospitalized patient care and safety. AB - Patient safety is rapidly becoming everyone's responsibility. Bedside clinicians, physicians, and ancillary and administrative staff are well aware of their roles in patient safety, but patients and their families are becoming increasingly knowledgeable about potential safety issues related to hospitalization. This article describes how a Midwestern regional health care system enhances safety for its hospitalized patients through a program called "Condition Concern," designed to provide patients and their families/friends with a quick, convenient method for reporting unattended care concerns. The program's structure is described along with postimplementation findings to date. PMID- 21233770 TI - Effects of official Taekwondo competitions on all-out performances of elite athletes. AB - This study investigated physiological and performance aspects of 15 (4 women and 11 men) elite Taekwondo athletes (24.0 +/- 5.7 years) during their National Championship. The load of the competition was evaluated by means of heart rate (HR) and blood lactate (La). Pre and postmatch countermovement jump (CMJ), and handgrip performances were compared (p < 0.05). The match imposed a high load (HR > 85% of individual HRmax = 92 +/- 12%; La = 6.7 +/- 2.5 mmol.L-1) on athletes. After the match, better (p < 0.0001) CMJ (men: 43.9 +/- 5.2 cm; women: 30.8 +/- 2.3 cm) and worst (p = 0.006) handgrip performances (men: 459 +/- 87 N; women: 337 +/- 70 N) were found with respect to prematch ones (CMJ: men = 40.8 +/- 4.9 cm, women = 28.2 +/- 2.5 cm; handgrip: men = 486 +/- 88 N, women: 337 +/- 70 N). Results indicate that the intermittent activity of the Taekwondo competition elicits a high neuromuscular activation of the lower limbs. Instead, the decreases in grip strength could be because of the repeated concussions on the upper limbs used to protect from the opponent's kicks and punches directed toward the scoring area of the torso. Practically, these results urge coaches to structure training sessions that enable athletes to maintain their upper limb strength during their match. PMID- 21233771 TI - MEF2A binding to the Glut4 promoter occurs via an AMPKalpha2-dependent mechanism. AB - PURPOSE: The role of AMP-activated protein kinase alpha2 (AMPKalpha2) in regulating MEF2A nucleus translocation, nuclear histone deacetylase 5 (HDAC5) association with MEF2, HDAC5 nuclear export, MEF2A binding to the Glut4 promoter, and GLUT4 expression was investigated. METHODS: This was investigated in muscles from AMPKalpha2 overexpression (OE) mice, AMPKalpha2 knockout (KO) mice, and corresponding wild-type (WT) mice that had undertaken a 28-d program of treadmill training by: 1) AMPKalpha-Thr172 phosphorylation by Western blot, 2) total and nuclear MEF2A by Western blot, 3) nuclear HDAC5 association with MEF2 by coimmunoprecipitation, 4) total and nuclear HDAC5 by Western blot, 5) bound MEF2A at the Glut4 MEF2 cis-element by chromatin immunoprecipitation, and 6) GLUT4 expression by real-time polymerase chain reaction and Western blot. RESULTS: OE or KO of AMPKalpha2 isoform heightened or attenuated the training-induced increase in nuclear MEF2A content, Glut4 promoter-bound MEF2A. However, OE or KO of the AMPKalpha2 isoform did not have any effect on the content of nuclear HDAC5 association with MEF2 after 28 d of exercise training, although 35% lower nuclear HDAC5 protein content was found in alpha2-OE training muscles. Lastly, OE of the alpha2-isoform was associated with 120% and 155% higher GLUT4 protein and mRNA in training muscles. However, the training-induced increases of GLUT4 protein and mRNA contents were normal in alpha2-KO muscles despite the reduced AMPK signaling. CONCLUSIONS: Exercise training increases the nuclear MEF2A content and binding of MEF2A to their binding sites on the Glut4 gene by an AMPKalpha2 dependent mechanism, but intracellular signaling molecules other than AMPKalpha2 are important in regulating training-induced HDAC5 nuclear export. Furthermore, although AMPKalpha2 mediates the training-induced increase in Glut4 promoter bound MEF2A, the present data do not support an essential role of AMPKalpha2 in regulating training-induced GLUT4 expression in skeletal muscle. PMID- 21233772 TI - Effect of resistance training on physical disability in chronic heart failure. AB - PURPOSE: Patients with chronic heart failure (CHF) report difficulty performing activities of daily living. To our knowledge, however, no study has directly measured performance in activities of daily living in these patients to systematically assess their level of physical disability. Moreover, the contribution of skeletal muscle weakness to physical disability in CHF remains unclear. Thus, we measured performance in activities of daily living in CHF patients and controls, its relationship to aerobic capacity and muscle strength, and the effect of resistance exercise training to improve muscle strength and physical disability. METHODS: Patients and controls were assessed for performance in activities of daily living, self-reported physical function, peak aerobic capacity, body composition, and muscle strength before and after an 18-wk resistance training program. To remove the confounding effects of several disease related factors (muscle disuse, hospitalization, acute illness), we recruited controls with similar activity levels as CHF patients and tested patients >6 months after any disease exacerbation/hospitalization. RESULTS: Performance in activities of daily living was 30% lower (P < 0.05) in CHF patients versus controls and was related to both reduced aerobic capacity (P < 0.001) and muscle strength (P < 0.01). Moreover, resistance training improved (P < 0.05 to P < 0.001) physical function and muscle strength in patients and controls similarly, without altering aerobic capacity. CONCLUSIONS: CHF patients are characterized by marked physical disability compared with age- and physical activity-matched controls, which is related to reduced aerobic capacity and muscle strength. CHF patients respond to resistance training with normal strength/functional adaptations. Our results support muscle weakness as a determinant of physical disability in CHF and show that interventions that increase muscle strength (resistance training) reduce physical disability. PMID- 21233773 TI - Are calcineurin genes associated with athletic status? A function, replication study. AB - PURPOSE: Polymorphisms in calcineurin genes are candidates to explain individual variations in endurance sports performance owing to the pivotal role that the calcineurin signaling pathway plays in the regulation of important cardiac and skeletal muscle phenotypes. METHODS: We compared genotypic/allelic frequencies in 55 single nucleotide polymorphisms (SNP) of the five genes (PPP3CA, PPP3CB, PPP3CC, PPP3R1, and PPP3R2) encoding the calcineurin protein subunits between 123 elite runners (cases, n = 61 women) and 125 healthy nonathletes (controls, n = 56 women) from the same ethnic background (Han Chinese) and used the dual-luciferase reporter assay to analyze the functional significance of the associated SNP. RESULTS: The C allele of the PPP3CA rs3804358 polymorphism was overrepresented in athletes (17%) compared with controls (8%) (P = 0.003), whereas the T allele of the PPP3CB rs3763679 polymorphism was underrepresented in athletes (23%) compared with controls (37%) (P = 0.001). The luciferase reporter constructs containing C allele of the rs3804358 and rs3763679 polymorphisms produced significantly greater luciferase activity than that of the G or T alleles, respectively. However, the results on the two aforementioned polymorphisms were not corroborated in a Caucasian (Spanish) cohort of male elite endurance athletes (n = 100) and nonathletic male controls (n = 175). CONCLUSIONS: Although there are large differences between ethnicities and more research is needed, our findings suggest that intronic polymorphisms of the calcineurin genes have functional significance and show evidence of association with elite endurance performance in the northern Han Chinese population. PMID- 21233774 TI - Tear fluid osmolarity as a potential marker of hydration status. AB - It has been suggested that tear fluid is isotonic with plasma, and plasma osmolality (P(osm)) is an accepted, albeit invasive, hydration marker. Our aim was to determine whether tear fluid osmolarity (T(osm)) assessed using a new, portable, noninvasive, rapid collection and measurement device tracks hydration. PURPOSE: This study aimed to compare changes in T(osm) and another widely used noninvasive marker, urine specific gravity (USG), with changes in P(osm) during hypertonic-hypovolemia. METHODS: In a randomized order, 14 healthy volunteers exercised in the heat on one occasion with fluid restriction (FR) until 1%, 2%, and 3% body mass loss (BML) and with overnight fluid restriction until 08:00 h the following day, and on another occasion with fluid intake (FI). Volunteers were rehydrated between 08:00 and 11:00 h. T(osm) was assessed using the TearLab osmolarity system. RESULTS: P(osm) and USG increased with progressive dehydration on FR (P < 0.001). T(osm) increased significantly on FR from 293 +/- 9 to 305 +/- 13 mOsm.L(-1) at 3% BML and remained elevated overnight (304 +/- 14 mOsm.L(-1); P < 0.001). P(osm) and T(osm) decreased during exercise on FI and returned to preexercise values the following morning. Rehydration restored P(osm), USG, and T(osm) to within preexercise values. The mean correlation between T(osm) and P(osm) was r = 0.93 and that between USG and P(osm) was r = 0.72. CONCLUSIONS: T(osm) increased with dehydration and tracked alterations in P(osm) with comparable utility to USG. Measuring T(osm) using the TearLab osmolarity system may offer sports medicine practitioners, clinicians, and research investigators a practical and rapid hydration assessment technique. PMID- 21233775 TI - Influence of contouring and hardness of foot orthoses on ratings of perceived comfort. AB - PURPOSE: Comfort is a vital component of orthosis therapy. The purpose of this study was to examine what features of orthoses (design or hardness) influence the perception of comfort by using previously established footwear comfort measures: 100-mm visual analog scale (VAS) and ranking scale. METHODS: Twenty subjects were consecutively allocated to two experiments consisting of five sessions of repeated measures. Comfort measures were taken from four prefabricated orthosis in each session using the VAS (experiment 1) and ranking scale (experiment 2). Subjects in experiment 1 were also asked to rate each orthosis relative to their shoe using a criterion scale. Measures were taken in both walking and jogging. RESULTS: A soft-flat orthosis was found to be significantly more comfortable than all contoured orthoses, including one of the same hardness using both the VAS and ranking scale. Using the VAS, differences between the soft-flat and contoured orthoses were also found to be clinically meaningful for dimensions of overall comfort and arch cushioning (>10.2 mm). Perceived comfort of orthoses significantly differed between walking and jogging on the VAS but was not clinically meaningful. Comparisons between the VAS and criterion scale detected a VAS difference of 11.34 mm between orthoses judged as comfortable as my shoe and slightly more comfortable than my shoe. There was a VAS difference of 17.49 mm between orthoses judged as comfortable as my shoe and slightly less comfortable than my shoe. CONCLUSIONS: Healthy subjects prioritize contouring over hardness when judging the comfort of orthoses. Clinically meaningful changes were required to change or enhance the comfort of orthoses standardized in material type and fabrication. PMID- 21233776 TI - Montmorency cherry juice reduces muscle damage caused by intensive strength exercise. AB - PURPOSE: Montmorency cherries contain high levels of polyphenolic compounds including flavonoids and anthocyanins possessing antioxidant and anti inflammatory effects. We investigated whether the effects of intensive unilateral leg exercise on oxidative damage and muscle function were attenuated by consumption of a Montmorency cherry juice concentrate using a crossover experimental design. METHODS: Ten well-trained male overnight-fasted athletes completed two trials of 10 sets of 10 single-leg knee extensions at 80% one repetition maximum. Trials were separated by 2 wk, and alternate legs were used in each trial. Participants consumed each supplement (CherryActive(r) (CA) or isoenergetic fruit concentrate (FC)) for 7 d before and 48 h after exercise. Knee extension maximum voluntary contractions (MVC) were performed before, immediately after, and 24 and 48 h after the damaging exercise. Venous blood samples were collected at each time point, and serum was analyzed for creatine kinase (CK) activity, nitrotyrosine, high-sensitivity C-reactive protein, total antioxidant capacity, and protein carbonyls (PC). Two-way repeated-measures ANOVA were used for statistical analysis of the data. RESULTS: MVC force recovery was significantly faster (24 h: CA 90.9% +/- 4.2% of initial MVC vs FC 84.9% +/- 3.4% of initial MVC; 48 h: CA 92.9% +/- 3.3% of initial MVC vs FC 88.5% +/- 2.9% of initial MVC (mean +/- SEM); P < 0.05) after CA than FC consumption. Only serum CK and PC increased significantly from baseline, peaking 24 h after exercise (P < 0.001). The exercise-induced increase in CK activity was not different between trials. However, both the percentage (24 h after: CA 23.8% +/- 2.9% vs FC 82.7% +/- 11.7%; P = 0.013) and absolute (24 h after: CA 0.31 +/- 0.03 nmol.mg(-1) protein vs FC 0.60 +/- 0.08 nmol.mg(-1) protein; P = 0.079) increase in PC was lower in CA than FC trials. CONCLUSIONS: Montmorency cherry juice consumption improved the recovery of isometric muscle strength after intensive exercise perhaps owing to the attenuation of the oxidative damage induced by the damaging exercise. PMID- 21233777 TI - Validation of wearable monitors for assessing sedentary behavior. AB - PURPOSE: A primary barrier to elucidating the association between sedentary behavior (SB) and health outcomes is the lack of valid monitors to assess SB in a free-living environment. The purpose of this study was to examine the validity of commercially available monitors to assess SB. METHODS: Twenty overweight (mean +/ SD: body mass index = 33.7 +/- 5.7 kg.m(-2)) inactive, office workers age 46.5 +/- 10.7 yr were directly observed for two 6-h periods while wearing an activPAL (AP) and an ActiGraph GT3X (AG). During the second observation, participants were instructed to reduce sitting time. We assessed the validity of the commonly used cut point of 100 counts per minute (AG100) and several additional AG cut points for defining SB. We used direct observation (DO) using focal sampling with duration coding to record either sedentary (sitting/lying) or nonsedentary behavior. The accuracy and precision of the monitors and the sensitivity of the monitors to detect reductions in sitting time were assessed using mixed-model repeated-measures analyses. RESULTS: On average, the AP and the AG100 underestimated sitting time by 2.8% and 4.9%, respectively. The correlation between the AP and DO was R2 = 0.94, and the AG100 and DO sedentary minutes was R2 = 0.39. Only the AP was able to detect reductions in sitting time. The AG 150 counts-per-minute threshold demonstrated the lowest bias (1.8%) of the AG cut points. CONCLUSIONS: The AP was more precise and more sensitive to reductions in sitting time than the AG, and thus, studies designed to assess SB should consider using the AP. When the AG monitor is used, 150 counts per minute may be the most appropriate cut point to define SB. PMID- 21233778 TI - HEALTHY intervention: fitness, physical activity, and metabolic syndrome results. AB - PURPOSE: This study aimed to assess the effect of the HEALTHY intervention on the metabolic syndrome (Met-S), fitness, and physical activity levels of US middle school students. METHODS: Cluster randomized controlled trial conducted in 42 (21 intervention) US middle schools. Participants were recruited at the start of sixth grade (2006) when baseline assessments were made, with post-assessments made 2.5 yr later at the end of eighth grade (2009). The HEALTHY intervention had four components: 1) improved school food environment, 2) physical activity and eating educational sessions, 3) social marketing, and 4) revised physical education curriculum. Met-S risk factors, 20-m shuttle run (fitness), and self reported moderate to vigorous physical activity (MVPA) were assessed at each time point. Ethnicity and gender were self-reported. Obesity status (normal weight, overweight, or obese) was also assessed. RESULTS: At baseline, 5% of the participants were classified with Met-S, with two-thirds of the males and one third of the females recording below average baseline fitness levels. Control group participants reported 96 min of MVPA at baseline with 103 min reported by the intervention group. There were no statistically significant (P < 0.05) differences in Met-S, fitness, or MVPA levels at the end of the study after adjustment for baseline values and confounders. There were no differences in any ethnic, obesity, or ethnic * obesity subgroups for either gender. CONCLUSIONS: The HEALTHY intervention had no effect on the Met-S, fitness, or physical activity levels. Approaches that focus on how to change physical activity, fitness, and Met-S using nonschool or perhaps in addition to school based components need to be developed. PMID- 21233779 TI - Neuromuscular activity of the peroneal muscle after foot orthoses therapy in runners. AB - PURPOSE: Foot orthoses are a standard option to treat overuse injury. Biomechanical data providing mechanisms of foot orthoses' effectiveness are sparse. Stability of the ankle joint complex might be a key factor. The purpose was therefore to analyze neuromuscular activity of the musculus peroneus longus in runners with overuse injury symptoms treated with foot orthoses. METHODS: A total of 99 male and female runners with overuse injury symptoms randomized in a control group (CO) and an orthoses group (OR) were analyzed on a treadmill at 3.3 m.s(-1) before and after an 8-wk foot orthoses intervention. Muscular activity of the musculus peroneus longus was measured and quantified in the time domain (initial onset of activation (T(ini)), time of maximal activity (T(max)), total time of activation (T(tot))) and amplitude domain (amplitude in preactivation (A(pre)), weight acceptance (A(wa)), push-off (A(po))). RESULTS: Peroneal activity in the time domain did not differ initially between CO and OR, and no effect was observed after therapy (T(ini): CO = -0.88 +/- 0.09, OR = -0.88 +/- 0.08/T(max): CO = 0.14 +/- 0.06, OR = 0.15 +/- 0.06/T(tot): CO = 0.40 +/- 0.09, OR = 0.41 +/- 0.09; P > 0.05). In preactivation (A(pre)), muscle activity was higher in OR after intervention (CO = 0.97 +/- 0.32, 95% confidence interval = 0.90-1.05; OR = 1.18 +/- 0.43, 95% confidence interval = 1.08-1.28; P = 0.003). There was no group or intervention effect during stance (A(wa): CO = 2.33 +/- 0.66, OR = 2.33 +/- 0.74/A(po): CO = 0.80 +/- 0.41, OR = 0.88 +/- 0.40; P > 0.05). CONCLUSIONS: Enhanced muscle activation of the musculus peroneus longus in preactivation suggests an altered preprogrammed activity, which might lead to better ankle stability providing a possible mode of action for foot orthoses therapy. PMID- 21233780 TI - Time course of electromagnetic activity associated with detection of rare events. AB - The neural origins of the cortical response to rare sensory events remain poorly understood. Using simultaneous event-related potentials and magnetic resonance imaging, we investigated the anatomical profile of regional activity at various processing stages during performance of auditory and visual variants of an oddball paradigm. The earliest rarity-detection response was found in sensory specific cortices, rapidly spreading to tertiary association areas, mesial temporal and frontal cortices by 150-200 ms. P3m-related activity was not found in sensory-specific cortices. On the basis of the anatomic distribution of P3m related activity, this component is likely to reflect more generalized cognitive abilities hosted by association cortical regions. PMID- 21233782 TI - Epidemiology and risk factors for Clostridium difficile infection in children. AB - BACKGROUND: Pediatric Clostridium difficile infection (CDI)-related hospitalizations are increasing. We sought to describe the epidemiology of pediatric CDI at a quaternary care hospital. METHODS: Nested case-control study within a cohort of children <18 years tested for C. difficile between January and August 2008. The study included patients who were >= 1 year with a positive test and diarrhea; those without diarrhea (ie, presumed colonization) were excluded. Two unmatched controls per case were randomly selected from patients >= 1 year with a negative test. Potential predictors of CDI included age, gender, comorbidities, prior hospitalization, receipt of C. difficile-active antibiotics in the prior 24 hours, and recent (<= 4 weeks) exposure to antibiotics or acid blocking medications. Multivariate logistic regression models were created to identify independent predictors of CDI. RESULTS: Of 1891 tests performed, 263 (14%) were positive in 181 children. Ninety-five patients >= 1 year with CDI were compared with 238 controls. In multivariate analyses, predictors of CDI included solid organ transplant (odds ratio [OR], 8.09; 95% confidence interval [CI], 2.10 31.12), lack of prior hospitalization (OR, 8.43; 95% CI, 4.39-16.20), presence of gastrostomy or jejunostomy (G or J) tube (OR, 3.32; 95% CI 1.71-6.42), and receipt of fluoroquinolones (OR, 17.04; 95% CI, 5.86-49.54) or nonquinolone antibiotics (OR, 2.23; 95% CI, 1.18-4.20) in the past 4 weeks. Receipt of C. difficile-active antibiotics within 24 hours before testing was associated with a lower odds of CDI (OR, 0.22; 95% CI, 0.09-0.58). CONCLUSIONS: Recent antibiotic exposure and certain comorbid conditions (solid organ transplant, presence of a gastrostomy or jejunostomy tube) were associated with CDI. Diagnostic testing has less utility in patients being treated with C. difficile-active antibiotics. PMID- 21233781 TI - The contribution of genes to cortical thickness and volume. AB - We analyzed brain MRI data from 372 young adult twins to identify cortical regions in which gray matter thickness and volume are influenced by genetics. This was achieved using an A/C/E structural equation model that divides the variance of these traits, at each point on the cortex, into additive genetic (A), shared (C), and unique environmental (E) components. A strong genetic influence was found in frontal and parietal regions. In addition, we correlated cortical thickness with full-scale intelligence quotient for comparison with the A/C/E maps, and several regions where cortical structure was correlated with intelligence quotient are under genetic control. These cortical measures may be useful phenotypes to narrow the search for quantitative trait loci influencing brain structure. PMID- 21233783 TI - COMT (Val(158/108)Met) genotype moderates the impact of antipsychotic medication on verbal IQ in twins with schizophrenia. AB - OBJECTIVES: In this study, we aimed to assess the moderating effects of the catechol-O-methyl transferase (COMT) (Val(158/108)Met) genotype on antipsychotic medication-induced changes in the cognitive performance of patients with chronic schizophrenia. METHODS: The sample consisted of 85 monozygotic and 53 dizygotic twin pairs, of varying concordance for schizophrenia, and healthy control twins. Cognitive ability was measured using the Wechsler Adult Intelligence Scale-third edition. We used structural equation modelling to estimate main and interaction effects of the COMT status and antipsychotic medication dose on verbal intelligence quotient (VIQ) and performance intelligence quotient scores. RESULTS: There was no evidence of a main or interaction effect of the COMT status or chlorpromazine equivalent dose on the performance intelligence quotient. There were no main effects of COMT or chlorpromazine equivalent dose on VIQ; however, there was evidence of a statistically significant interaction (P<0.01) between the COMT and chlorpromazine equivalents on VIQ. The VIQ performance of val/val individuals was significantly lower with increasing antipsychotic medication dose, up to 12 intelligence quotient points lower than met carriers treated with medication. In the absence of medication, the three genotypes did not significantly differ, whereas at the highest doses (1500), the val/val homozygotes and Met carriers differed by more than one standard deviation. CONCLUSION: Our results show that the verbal abilities of val homozygotes of the COMT gene are cognitively impaired by higher doses of antipsychotic medication. This association is reversed in Met carriers. These data are consistent with an earlier study that found evidence of moderating effects of antipsychotic medication on N-back and verbal fluency tasks. PMID- 21233784 TI - Genetic and functional studies of a missense variant in a glutamate transporter, SLC1A3, in Tourette syndrome. AB - OBJECTIVE: Abnormalities in neurotransmission within the cortico-striatal-thalamo cortical circuitry are implicated in the pathogenesis of Tourette syndrome. Glutamate is a major excitatory neurotransmitter and an important member in the cortico-striatal-thalamo-cortical circuitry. To explore the role of glutamatergic neurotransmission in genetic susceptibility of Tourette syndrome, we carried out the genetic and functional characterization of sequence variants in SLC1A3 gene, which encodes the main glutamate transporter in astrocytes in individuals with well-characterized Tourette syndrome (n=256) and normal controls (n=224). METHODS: Exon-containing regions of SLC1A3 gene were screened using capillary electrophoresis-single strand conformation polymorphism followed by direct sequencing. Sequence variants were genotyped by restriction enzyme digestion and studied using glutamate uptake assay and membrane protein pull-down for transporter function. RESULTS: A missense variant involving a highly conserved residue, E219D, was identified in 11 heterozygous individuals with Tourette syndrome and four in the controls. The allele frequency for E219D was 2.4 folds higher in the Tourette syndrome (0.022) compared with the control cohort (0.009) although the difference did not reach statistical significance in the current cohorts (P=0.09). A H-glutamate-uptake assay showed that E219D conveys a significant increase (1.66 fold) in the SLC1A3-mediated glutamate uptake in HEK293 cells. A biotin-mediated membrane pull-down analysis showed a similar increase (1.5 fold) of mutant SLC1A3 protein in the membrane fraction of transfected HEK293 cells compared with that in the wild type controls. CONCLUSION: These results indicate that E219D is a functional SLC1A3 variant that is presented in a small number of individuals with Tourette syndrome. Further studies on possible changes in glutamate transport in the pathogenesis of Tourette syndrome are warranted. PMID- 21233785 TI - Aging changes of vitreomacular interface. AB - PURPOSE: The posterior precortical vitreous pocket (the pocket) is a premacular liquefied lacuna, the physiologic presence of which was reported in autopsy eyes. We describe the morphologic features of the pocket in normal individuals. METHODS: We performed spectral-domain optical coherence tomography in 102 eyes of 51 normal subjects of various ages in a sitting position. RESULTS: The pocket was identified as an optically lucent space anterior to the posterior fundus in 85 of 102 eyes (83.3%) in the age-group. The vitreous cortex was extremely thin at the central fovea, and it gradually thickened along with age in the perifoveal area. A shallow perifoveal posterior vitreous detachment developed in 16 of 32 eyes (50%) of subjects aged >51 years. The lamellar structure of the vitreous cortex was seen in 7 of the 32 eyes (22%) of subjects aged >51 years. CONCLUSION: Spectral-domain optical coherence tomography confirmed the presence of the pocket in all ages. Thickened vitreous cortex and perifoveal posterior vitreous detachment were physiologic findings in older individuals. The lamellar structure of the vitreous cortex may be related to the vitreoschisis. PMID- 21233786 TI - Preoperative inner segment/outer segment junction in spectral-domain optical coherence tomography as a prognostic factor in epiretinal membrane surgery. AB - PURPOSE: To evaluate the macular structure on spectral-domain optical coherence tomographic (SD-OCT) images to predict the outcome of surgery for idiopathic epiretinal membrane. METHODS: Forty-five eyes of 45 consecutive patients with idiopathic epiretinal membrane who had a preoperative visual acuity of <= 20/32 and were scheduled to undergo a transconjunctival 25-gauge vitrectomy were involved in this prospective cohort study. The best-corrected visual acuity (BCVA) and SD-OCT images of the fovea were examined before the surgery and at 3, 6, and 12 months after the surgery. Associations between the visual acuity parameters and the preoperative SD-OCT features, including the morphology of the photoreceptor inner segment/outer segment junction, macular thickness, presence/absence of retinal cysts, and presence/absence of a macular pseudohole, were investigated as predictors of the outcome of the surgery. The main outcome measures were the association between the macular microstructure on preoperative SD-OCT images and the visual acuity parameters, such as the BCVA, at 12 months after the surgery (postoperative BCVA) and the difference between the preoperative visual acuity and the postoperative BCVA. RESULTS: A total of 45 patients were enrolled in this study. The postoperative visual acuity was significantly better for the eyes with an intact inner segment/outer segment junction on the preoperative SD-OCT images than for those with an irregular or a disrupted inner segment/outer segment junction on the images (P < 0.001). Better preoperative visual acuity was associated with better visual acuity at 12 months and a lesser degree of improvement in the visual acuity (P < 0.001, respectively). CONCLUSION: The presence of an intact inner segment/outer segment junction on the preoperative SD-OCT images was found to be an important predictor of better visual recovery and better postoperative BCVA after epiretinal membrane surgery. PMID- 21233788 TI - The vitreous trap: a simple, surgeon-controlled technique for obtaining undiluted vitreous and subretinal specimens during pars plana vitrectomy. PMID- 21233789 TI - Evaluation of an IgM/IgG sensitive enzyme immunoassay and the utility of index values for the screening of syphilis infection in a high-risk population. AB - BACKGROUND: Increasing interest in the use of enzyme immunoassays (EIA) for syphilis screening has generated a considerable need for data on the performance of such tests. METHODS: We compared the performance of 1 EIA, the TREP-SURE EIA to that of the Venereal Disease Research Laboratory (VDRL) and Treponema pallidum particle agglutination assay (TPPA) in the detection of infection with Treponema pallidum. In total, 674 specimens were tested by VDRL and EIA (356 VDRL nonreactive and 318 VDRL-reactive). All specimens that were found to be reactive by either the VDRL or EIA were subsequently analyzed by TPPA. RESULTS: We found that the TREP-SURE EIA was marginally less sensitive than the VDRL test for screening, but was significantly more specific. All EIA-TPPA discordant specimens were analyzed by multiple tests, including Immunoglobulin M- and G-specific Western blots and an IgM-specific EIA. Signal-to-cutoff ratios (index values) generated by the TREP-SURE EIA were also investigated. It was found that these values may be instructive regarding the interpretation of test results, as they were found to correlate strongly with the probability of positivity on a TPPA assay. Specimens that reacted positively on the EIA with very high index values were found overwhelmingly to be reactive by TPPA, perhaps obviating the need for the testing of most EIA positive specimens with a secondary treponemal test. CONCLUSIONS: An IgM/IgG sensitive EIA would be an effective alternative to VDRL for syphilis screening. Using the EIA index values may provide additional, helpful information to the diagnostic process. PMID- 21233790 TI - Can experiential-didactic training improve clinical STD practices? AB - BACKGROUND: High rates of sexually transmitted diseases (STDs) present an ongoing costly public health challenge. One approach to reduce STD transmission is to increase the number of clinicians adopting the Centers for Disease Control and Prevention's STD Treatment Guidelines. This evaluation assesses the effectiveness of a 3-day experiential and didactic training to translate recommendations into practice by increasing clinician knowledge and skills and helping participants anticipate and overcome barriers to implementation. METHODS: Between 2001 and 2004, 110 direct care clinicians from 10 states participated in one of 27 standardized 3-day interactive trainings offered by the Denver STD/human immunodeficiency virus (HIV) Prevention Training Center. STD/HIV knowledge and clinical skills were measured before, immediately after, and 6 months after training. Practice patterns were assessed before training and after 6 months. Structural barriers to implementation were identified 6 months post-training. RESULTS: Trainees demonstrated significant post-training gains in mean knowledge scores immediately post-training (P < 0.001) and 6 months post-training (P = 0.002). After 6 months, self-reported mean skill levels remained significantly improved compared to precourse (P < 0.05) for each of 27 skills including STD risk assessment, clinical examination, diagnosis, and treatment. Self-reported improvement in practice patterns was significant for 23 of 35 practices (P < 0.05) 6 months post-training. Participants indicated that inadequate time (52.9%), facilities/equipment (51.5%), and staffing (47.1%) interfered with implementation of recommended practices. CONCLUSIONS: Experiential-didactic STD/HIV training can modestly improve knowledge, clinical skills, and implementation of STD recommended practices 6 months after training. Further research is needed to identify the impact of improved clinical practices on STD/HIV transmission. PMID- 21233791 TI - The role of Medicaid managed care interventions in Chlamydia screening by physicians. AB - BACKGROUND: Chlamydia trachomatis (CT) guidelines call for annual screening of all sexually active young females. In previous studies, Medicaid health maintenance organizations (HMOs) did not consistently recommend CT and other sexually transmitted disease guidelines, but physicians with HMO practices were more likely to comply with guidelines than those without HMO practices. This study examines the relationship between HMO interventions and physician adherence to annual (CT) screening guidelines for sexually active young (ages 15-25) females. METHODS: Medicaid HMOs (N = 17) of California were surveyed regarding their interventions to increase physician adherence with national CT screening guidelines in 2002. Primary care physicians (N = 941) who contracted with these HMOs were also surveyed on their frequency (always/usually) of CT screening. Data were analyzed using logistic regression models. RESULTS: HMO-reported recommendations for CT screening and other interventions were associated with significantly higher odds of frequent CT screening by contracted physicians in unadjusted models. HMO recommendations to screen young females increased the odds of frequent CT screening, but other interventions were no longer significantly associated after controlling for physician characteristics. Physicians also had higher odds of reporting frequent CT screening if they had received training in the past, had received feedback from their contracted HMOs, or reported having access to national CT screening guidelines. Physician gender, specialty, years of clinical experience, and other factors were also significantly associated with the odds of frequency of CT screening. DISCUSSION: Improving physician adherence with CT screening guidelines requires a refinement of current approaches with targeted interventions that are tailored to the characteristics of physicians. In addition, interventions are more likely to be effective if provided in formats that are perceived and acknowledged by physicians. PMID- 21233792 TI - Acetylcholine and chronic vasculopathy in rat renal allografts. AB - BACKGROUND: Chronic allograft vasculopathy (CAV) is an important aspect of chronic allograft injury, which limits the long-term success of renal transplantation. The pathogenesis of CAV is ill defined, and no effective therapies exist. Acute rejection episodes are a major risk factor for CAV. Recently, we demonstrated that leukocytes, which strongly accumulate in allograft blood vessels during fatal acute rejection, produce acetylcholine (ACh), which has the potential to provoke CAV. Herein, we test the hypothesis that ACh is also produced by leukocytes during the development of CAV. METHODS: Kidneys were transplanted in the Fischer 344 to Lewis rat strain combination, an established experimental model for CAV. Isografts were performed in Lewis rats. The capacity of intravascular graft leukocytes to synthesize ACh was investigated during reversible acute rejection on day 9 posttransplantation and during the process of vascular remodeling on day 42. Furthermore, allograft recipients were treated with rivastigmine, which blocks enzymatic degradation of ACh. RESULTS: The protein expression of the high-affinity choline transporter-1 and choline acetyltransferase was increased in leukocytes from allografts on day 9 and 42 posttransplantation. In addition, leukocytes accumulating in the lumina of allograft blood vessels were by far more numerous compared with isografts. In line with our hypothesis, ACh itself was detected by high-pressure liquid chromatography in graft leukocytes but not in leukocytes from untreated kidneys. Treatment with rivastigmine drastically exacerbated CAV compared with placebo. CONCLUSION: We suggest that endogenous ACh contributes to the pathogenesis of CAV and may be a promising target for novel therapies preventing CAV. PMID- 21233793 TI - Antimicrobial activity of diterpenes from Viguiera arenaria against endodontic bacteria. AB - Six pimarane-type diterpenes isolated from Viguiera arenaria Baker and two semi synthetic derivatives were evaluated in vitro against a panel of representative microorganisms responsible for dental root canal infections. The microdilution method was used for the determination of the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Porphyromonas gingivalis, Prevotella nigrescens, Prevotella intermedia, Prevotella buccae, Fusobacterium nucleatum, Bacteroides fragilis, Actinomyces naeslundii, Actinomyces viscosus, Peptostreptococcus micros, Enterococcus faecalis and Aggregatibacter actinomycetemcomitans. The compounds ent-pimara-8(14),15-dien-19 oic acid, its sodium salt and ent-8(14),15-pimaradien-3beta-ol were the most active, displaying MIC values ranging from 1 to 10 MUg mL-1. The results also allow us to conclude that minor structural differences among these diterpenes significantly influence their antimicrobial activity, bringing new perspectives to the discovery of new chemicals for use as a complement to instrumental endodontic procedures. PMID- 21233794 TI - Historical evidence for the origin of teaching hospital, medical school and the rise of academic medicine. AB - Historical progression and the development of current teaching hospitals, medical schools and biomedical research originated from the people of many civilizations and cultures. Greeks, Indians, Syriacs, Persians and Jews, assembled first in Gondi-Shapur during the Sasanian empire in Persia, and later in Baghdad during the Golden Age of Islam, ushering the birth of current academic medicine. PMID- 21233795 TI - Vitamin A and E status in very low birth weight infants. AB - OBJECTIVE: To determine vitamin A and vitamin E status in very low birth weight (VLBW) infants at the time of birth (TB), at the time of full feeding (TFF) and at term postmenstrual age (TT). STUDY DESIGN: An observational study was conducted in VLBW infants. Plasma retinol and alpha-tocopherol levels were measured at TB, TFF and TT. Multivitamin supplementation was given to all infants to meet the daily requirement. RESULT: A total of 35 infants were enrolled. The median (interquartile range) of gestational age and birth weight was 30 (28 to 32) weeks and 1157 g (982 to 1406 g). The median of vitamin A and vitamin E intakes from TFF to TT was 832 and 5.5 IU kg(-1) day(-1), respectively. Vitamin A deficiency occurred in 67.7% at birth, 51.6% at TFF and 82.1% at TT. Vitamin E deficiency occurred in 77.4% at birth, 16.1% at TFF and 35.7% at TT. Small-for gestational age was the only risk factor for vitamin A deficiency. Lower amount of breast milk consumption was associated with higher incidence of vitamin E deficiency. No differences in vitamin A- or vitamin E-related morbidities between infants with and without vitamin deficiencies were found. CONCLUSION: High prevalence of vitamin A and vitamin E deficiency was found in VLBW infants starting from birth to term postmenstrual age. Therefore, a higher dose of vitamin supplementation is required. PMID- 21233796 TI - Hyperglycemia, insulin and slower growth velocity may increase the risk of retinopathy of prematurity. AB - OBJECTIVE: Strategies to reduce Retinopathy of Prematurity (ROP) have focused primarily on respiratory management. Hyperglycemia (HG) and insulin use, risk factors for adult diabetic retinopathy, as well as growth rates may be modifiable variables useful to reduce ROP. STUDY DESIGN: This was a retrospective chart review of all infants born at <30 weeks gestation from 2003 to 2007 who survived to discharge in our neonatal intensive care unit (NICU). All whole-blood glucose values (BG in mg dl(-1)) done in the first 29 days of life were collected for analysis. RESULT: BGs were done at least every 3 to 6 h for the first 48 to 96 h of life, then every 6 to 24 h thereafter, as long as infants remained on hyperalimentation. Hyperglycemia was defined as mild (BG 151 to 180), moderate (181 to 210) or severe (>210). Insulin use (given if BG>180 to 210) was also noted for each simultaneous BG. ROP was classified as none, mild (stage 1 to 2) or severe (stage 3 to 4). Growth velocity (g kg(-1) per day), length and head circumference were also analyzed. In all, 372 infants mean (s.d.) gestational age 27.6 (1.4) weeks, mean (s.d.) birth weight 994 (242)g had 18,649 BGs analyzed. 103 (28%) of the infants had mild ROP and 29 (8%) had severe ROP. 137 (37%) of the infants received at least 1 day of exogenous insulin (median days 9, range 1 to 26). Higher cumulative mean BG, more episodes of HG, and more insulin exposure were associated with an increased incidence and severity of ROP. Ordinal logistic regression identified lower gestational age, male gender, fetal growth restriction, slower NICU growth velocity, and higher BG as predictors for severity of ROP. However, insulin use was a stronger predictor than BG, and replaced it in the risk model. CONCLUSION: After adjusting for important risk factors, HG and especially insulin use in premature infants may increase the risk of ROP. In addition, slower NICU growth velocity, but not rates of head or length growth, was predictive of ROP. PMID- 21233797 TI - Oseltamivir treatment and prophylaxis in a neonatal intensive care unit during a 2009 H1N1 influenza outbreak. AB - OBJECTIVE: To evaluate safety of oseltamivir in neonates with significant comorbidities in a level-III neonatal intensive care unit during an outbreak of 2009 H1N1 influenza. STUDY DESIGN: We performed a retrospective chart review of neonates who received oseltamivir for treatment and prophylaxis of influenza during the outbreak. RESULT: A total of 11 neonates received twice daily dosing and 21 neonates received once daily dosing (12 to 25 mg per dose) for treatment and prophylaxis of influenza, respectively. Age ranged from 2 days to 11.4 months (mean, 2.1 months). Corrected gestational age and weight at initiation of oseltamivir ranged from 32 to 86 weeks (mean, 41 weeks) and 775 to 8635 g (mean, 3074 g), respectively. All had complex underlying conditions. Oseltamivir was well tolerated. Neurologic adverse effects or mortality attributable to oseltamivir were not identified. Mild rash and gastrointestinal signs in four infants resolved without oseltamivir discontinuation. Three showed a transient rise in transaminases; all returned to baseline after completing therapy. CONCLUSION: Oseltamivir appears to be well tolerated in preterm and term neonates and infants with complex underlying conditions. More studies are needed to determine optimal dosing for treatment and prophylaxis in this vulnerable age group. PMID- 21233798 TI - Reversal of experimental renovascular hypertension restores coronary microvascular function and architecture. AB - BACKGROUND: Hypertension (HTN) may lead to left ventricular hypertrophy and vascular dysfunction, which are independent factors for adverse cardiovascular outcomes. We hypothesized that decreased blood pressure by percutaneous transluminal renal angioplasty (PTRA) would improve the function and architecture of coronary microvessels, in association with decreased inflammation and fibrosis. METHODS: Three groups of pigs were studied: normal, HTN, and HTN+PTRA. After 6 weeks of renovascular HTN, induced by placing a local-irritant coil in the renal artery, pigs underwent PTRA or sham. Four weeks later multidetector computed tomography (CT) was used to assess systolic, diastolic, and microvascular function, and responses to adenosine. Microvascular architecture, oxygen sensors, inflammation, and fibrosis were then explored in cardiac tissue. RESULTS: PTRA successfully decreased blood pressure and left ventricular hypertrophy. Basal fractional vascular volume (FVV) was similar among the groups, but its response to adenosine was significantly attenuated in HTN, whereas microvascular permeability (MP) and response to adenosine were greater than normal. Both were restored by PTRA. These were accompanied by increased myocardial expression of hypoxia-inducible factor (HIF)-1alpha, inflammation, and microvascular remodeling, including increased density of epicardial microvessels (20-200 um), as well as cardiac diastolic dysfunction, all of which improved by reversal of HTN. However, PTRA only partially decreased myocardial fibrosis. CONCLUSIONS: Reversal of early renovascular HTN improved coronary microvascular function and architecture and reversed myocardial hypertrophy and diastolic dysfunction, in association with decreased levels of myocardial ischemia and inflammation markers, underscoring the benefits of blood pressure normalization for preservation of cardiovascular function and structure. PMID- 21233799 TI - Association of age with timing and amplitude of reflected pressure waves during exercise in men. AB - BACKGROUND: Increased elastic conduit artery stiffness with aging is associated with early wave reflection and increased wasted left ventricular pressure energy (LVE(W)). The effects of aging on central hemodynamics during exercise have not been well characterized. This study sought to investigate changes in central hemodynamics during cycle exercise in young, middle-aged, and older men. METHODS: Central blood pressure and wave reflection characteristics were measured noninvasively using radial artery applanation tonometry at rest and during cycling exercise (45, 55, and 65% of predicted maximum heart rate (HR(max))) in 14 young (24 +/- 1 years), 16 middle-aged (49 +/- 2 years) and 13 older (73 +/- 2 years) men. RESULTS: Repeated measures analysis of variance revealed significant group-by-time interactions for heart rate, central diastolic blood pressure (DBP), central pulse pressure (PP), PP amplification (PPA), central aortic pressure augmentation (AP), aortic augmentation index (AI(X)), and LVE(W). Magnitude of change from baseline was significantly different in the older group compared to young and middle-aged groups in response to exercise at 65% of predicted HR(max) for AP (+3 +/- 1 mm Hg vs. -7 +/- 1, P < 0.001 and -3 +/- 1 mm Hg, P < 0.001) and LVE(W) (+724 +/- 215 dynes s/cm(2).min vs. -494 +/- 199, P < 0.001 and -315 +/- 192, P < 0.001). CONCLUSIONS: This study suggests that changes in the timing and amplitude of reflected pressure waves during exercise alter the hemodynamic response to exercise with aging. In response to exercise, AP and LVE(W) increased in older subjects while young and middle-aged subjects exhibited a decline in AP and no change in LVE(W). PMID- 21233800 TI - Moderate waist circumference and hypertension prevalence: the REGARDS Study. AB - BACKGROUND: High waist circumference (WC) (women: >88 cm; men: >102 cm) increases cardiovascular risk. Less is known about moderate WC (women: 80-88 cm; men: 94 102 cm). Therefore, we examined the association between moderate WC and hypertension prevalence, independent of body mass index (BMI). METHODS: Among 24,247 eligible adults 45-84 years old, when recruited from January 2003 to October 2007 in the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort, we examined hypertension prevalence (systolic blood pressure (BP) >=140 mm Hg, or diastolic BP >=90 mm Hg, or self reported antihypertensive medication use) by WC before and after stratification by BMI (normal: 18.5-24.9; overweight: 25-29.9; obese class I: 30-34.9). Logistic regression adjusted associations between WC, BMI, and hypertension prevalence for age, race, sex, region, income, education, cigarette smoking, glomerular filtration rate, alcohol use, and physical activity. RESULTS: Overall, hypertension prevalence was 44% among those with low WC (n = 8,068), 55% with moderate WC (n = 6,488), and 66% with high WC (n = 9,691). After full adjustment, moderate WC was independently associated with hypertension prevalence among persons with normal BMI, (adjusted odds ratio (aOR), 1.49; 95% confidence interval (CI), 1.31-1.70), overweight BMI (aOR, 1.80; 95% CI, 1.64-1.98), and obese class I BMI (aOR, 2.28; 95%CI, 1.96-2.65) (referent: low WC-normal BMI). The moderate WC-hypertension association was observed in blacks and whites and in men and women. CONCLUSION: Moderate WC is associated with hypertension prevalence independent of BMI and several hypertension risk factors in middle-aged and older adults. PMID- 21233801 TI - Plasma volume and arterial stiffness in the cardiac alterations associated with long-term high sodium feeding in rats. AB - BACKGROUND: Rats fed an early and long-term high-salt diet (HS, NaCl 8%) developed significant cardiovascular hypertrophy without major changes in blood pressure. The mechanism of this cardiac hypertrophy has not been yet elucidated. METHODS: In the present work, we assessed the influence of volume overload and arterial stiffness on the structural and functional cardiac changes induced by a high salt feeding from weaning to 5 months of age in Sprague-Dawley rats. RESULTS: Cardiac hypertrophy in HS rats was associated with clear augmentation in the size of left ventricular (LV) cardiomyocyte as compared with rats fed regular diet (NS). Echocardiography revealed a marked increase in relative wall thickness. Of note, no alteration of global and regional systolic and diastolic function was detected in HS rats. High sodium consumption was associated with a slight increase in aortic mean and pulse pressure (PP) without effect on pulse wave velocity (PWV) and elastic modulus. Plasma volume and central venous pressure were higher in HS than NS rats. Whereas plasma endothelin level was twofold higher in HS than in NS rats, LV endothelin level was similar in both groups. Treatment by the endothelin receptors blocker bosentan had no detectable effect on the changes induced by HS diet. CONCLUSIONS: High sodium intake was associated with concentric cardiac hypertrophy without change of systolic and diastolic function. Aortic rigidity was not a determinant of cardiac hypertrophy. Beside a likely direct effect of sodium on cardiovascular system the slight increase in arterial pressure and plasma volume play a role. PMID- 21233804 TI - Accurate measurement of body weight and food intake in environmentally enriched male Wistar rats. AB - Laboratory animals are crucial in the study of energy homeostasis. In particular, rats are used to study alterations in food intake and body weight. To accurately record food intake or energy expenditure it is necessary to house rats individually, which can be stressful for social animals. Environmental enrichment may reduce stress and improve welfare in laboratory rodents. However, the effect of environmental enrichment on food intake and thus experimental outcome is unknown. We aimed to determine the effect of environmental enrichment on food intake, body weight, behavior and fecal and plasma stress hormones in male Wistar rats. Singly housed 5-7-week-old male rats were given either no environmental enrichment, chew sticks, a plastic tube of 67 mm internal diameter, or both chew sticks and a tube. No differences in body weight or food intake were seen over a 7-day period. Importantly, the refeeding response following a 24-h fast was unaffected by environmental enrichment. Rearing, a behavior often associated with stress, was significantly reduced in all enriched groups compared to controls. There was a significant increase in fecal immunoglobulin A (IgA) in animals housed with both forms of enrichment compared to controls at the termination of the study, suggesting enrichment reduces hypothalamo-pituitary-adrenal (HPA) axis activity in singly housed rats. In summary, environmental enrichment does not influence body weight and food intake in singly housed male Wistar rats and may therefore be used to refine the living conditions of animals used in the study of energy homeostasis without compromising experimental outcome. PMID- 21233802 TI - Copy number variations at the Prader-Willi syndrome region on chromosome 15 and associations with obesity in whites. AB - Obesity is a serious health problem with strong genetic determination. Copy number variation (CNV) is a common type of genomic variant associated with some complex human diseases. However, it is not clear how CNVs contribute to the etiology of obesity. In this study, we examined 1,000 unrelated US whites to search for CNVs that may predispose to obesity. We focused our analyses on the Prader-Willi syndrome (PWS) critical region (chromosome 15q11-q13), because the PWS region is a hotspot for CNV generation and obesity is one of the major clinical manifestations for chromosome abnormalities at this region. We constructed a map containing 39 CNVs at the PWS critical region with CNV occurrence rates higher than 1%. Among them, three CNVs were significantly associated with body fat mass (P < 0.05), with a higher copy number (CN) associated with an increase of 5.08-9.77 kg in body fat mass. These three CNVs are close to two known PWS genes, NDN (necdin homolog) and C15orf2 (chromosome 15 open reading frame 2), and partially overlap with another obesity gene PWRN1 (Prader-Willi region nonprotein-coding RNA 1). Interestingly, our recently published whole genome association scan study using the same sample by examining single-nucleotide polymorphisms (SNPs) did not find any significant associations at these CNV regions, suggesting the importance of examining both CNVs and SNPs for better understanding of genetic basis of obesity. Further studies are warranted to validate these CNVs and their importance to obesity. PMID- 21233803 TI - Impact of patient-doctor race concordance on rates of weight-related counseling in visits by black and white obese individuals. AB - The objective of this study was to assess the impact of patient-provider race concordance on weight-related counseling among visits by obese patients. We hypothesized that race concordance would be positively associated with weight related counseling. We used clinical encounter data obtained from the 2005-2007 National Ambulatory Medical Care Surveys (NAMCS). The sample size included 2,231 visits of black and white obese individuals (ages 20 and older) to their black and white physicians from the specialties of general/family practice and general internal medicine. Three outcome measures of weight-related counseling were explored: weight reduction, diet/nutrition, and exercise. Logistic regression was used to model the outcome variables of interest. Wald tests were used to statistically compare whether physicians of each race provided counseling at different rates for obese patients of different races. We did not observe a positive association between patient-physician race concordance and weight related counseling. We found that visits by black obese patients to white doctors had a lower odds of exercise counseling as compared to visits by white obese patients to white doctors (odds ratio (OR) = 0.54; 95% confidence interval (CI): 0.31, 0.95), and visits by black obese patients to black physicians had lower odds of receiving weight-reduction counseling than visits among white obese patients seeing black physicians (OR = 0.34; 95% CI: 0.13, 0.90). Black obese patients receive less exercise counseling than white obese patients in visits to white physicians and may be less likely than white obese patients to receive weight-reduction counseling in visits to black physicians. PMID- 21233805 TI - Projected progression of the prevalence of obesity in Australia. AB - Several country-specific and global projections of the future obesity prevalence have been conducted. However, these projections are obtained by extrapolating past prevalence of obesity or distributions of body weight. More accurate would be to base estimates on the most recent measures of weight change. Using measures of overweight and obesity incidence from a national, longitudinal study, we estimated the future obesity prevalence in Australian adults. Participants were adults aged >=25 years in 2000 participating in the Australian Diabetes, Obesity, and Lifestyle (AusDiab) study (baseline 2000, follow-up 2005). In this population, approximately one-fifth of those with normal weight or overweight progressed to a higher weight category within 5 years. Between 2000 and 2025, the adult prevalence of normal weight was estimated to decrease from 40.6 to 28.1% and the prevalence of obesity to increase from 20.5 to 33.9%. By the time, those people aged 25-29 in 2000 reach 60-64 years, 22.1% will be normal weight, and 42.4% will be obese. On average, normal-weight females aged 25-29 years in 2000 will live another 56.2 years: 26.6 years with normal weight, 15.6 years with overweight, and 14.0 years with obesity. Normal-weight males aged 25-29 years in 2000 will live another 51.5 years: 21.6 years with normal weight, 21.1 years with overweight, and 8.8 years with obesity. If the rates of weight gain observed in the first 5 years of this decade are maintained, our findings suggest that normal weight adults will constitute less than a third of the population by 2025, and the obesity prevalence will have increased by 65%. PMID- 21233806 TI - Efficacy of a school-based childhood obesity intervention program in a rural southern community: TEAM Mississippi Project. AB - A healthy lifestyle school-based obesity intervention was evaluated in a rural southern community where the rate of obesity ranks as the highest. School-age children (N = 450) ranging from 6 to 10 years of age (Mage = 8.34) participated in monthly physical activity and nutritional events during a 9-month academic year. The children's nutritional knowledge, number of different physical activities, fitness level, dietary habits, waist circumference, BMI percentile, and percentage body fat were measured pre- and postintervention. Changes on these measures were compared to students in a school employing the school system's standard health curriculum. Regression analyses with residualized change scores revealed that the intervention school showed statistically significant improvement in percentage body fat, physical activity, performance on fitness tests, and dietary habits compared to the control school. There was no evidence of differences in outcomes based on gender or ethnicity/race. With rates of obesity and overweight reaching 50% in southern rural communities, intervening early in development may offer the best outcome because of the difficulties with changing lifestyle behaviors later in adulthood. A population-based approach is recommended over a targeted approach to cultivate a culture of healthy lifestyle behaviors when children are developing their health-care habits. Evidence suggests that both boys and girls, and African-American and white children can benefit equally from such interventions. PMID- 21233808 TI - New specific equation to estimate resting energy expenditure in severely obese patients. AB - Calculating the estimated resting energy expenditure (REE) in severely obese patients is useful, but there is controversy concerning the effectiveness of available prediction equations (PE) using body weight (BW). We evaluated the efficacy of REE equations against indirect calorimetry (IC) in severely obese subjects and aimed to develop a new equation based on body composition compartments. One hundred and twenty severely obese patients had their REE measured (MREE) by IC and compared to the most commonly used PE (Harris-Benedict (HB), Ireton-Jones, Owen, and Mifflin St. Jeor). In a random sample (n = 60), a new REE equation based on fat-free mass (FFM) was developed and validated. All PE studied failed to estimate REE in severe obesity (low concordance correlation coefficient (CCC) and limits of agreement of nearly 50% of the sample +/-10% of MREE). The HB equation using actual BW exhibited good results for all samples when compared to IC (2,117 +/- 518 kcal/day by HB vs. 2,139 +/- 423 kcal/day by MREE, P > 0.01); these results were blunted when patients were separated by gender (2,771 vs. 2,586 kcal/day, P < 0.001 in males and 1,825 vs. 1,939 kcal/day, P < 0.001 in females). A new resting energy expenditure equation prediction was developed using FFM, Horie-Waitzberg, & Gonzalez, expressed as 560.43 + (5.39 * BW) + (14.14 * FFM). The new resting energy expenditure equation prediction, which uses FFM and BW, demonstrates higher accuracy, precision, CCC, and limits of agreement than the standard PE in patients when compared to MREE (2,129 +/- 45 kcal/day vs. 2,139 +/- 423 kcal/day, respectively, P = 0.1).The new equation developed to estimate REE, which takes into account both FFM and BW, provides better results than currently available equations. PMID- 21233807 TI - RGS6 variants are associated with dietary fat intake in Hispanics: the IRAS Family Study. AB - Recently, a genome-wide association scan was completed in the IRAS (Insulin Resistance Atherosclerosis Study) Family Study (IRASFS) Hispanic-American cohort. Multiple single-nucleotide polymorphisms (SNPs) in the G-protein signaling 6 (RGS6) gene were found to be associated with adiposity phenotypes. RGS6 has shown downstream antagonistic interplay with opioid receptors, targets of fatty/sugary food agonists. The possibility that RGS6 promotes tolerance and tachyphylaxis among the opioid receptor is a plausible pathway for overconsuming fat/sugar laden food. Therefore, we hypothesized that RGS6 variants are associated with intake of fatty/sugary foods. In 932 Hispanics from San Antonio and San Luis Valley, CO, the following dietary intake variables were assessed using the Block Brief 2000 food frequency questionnaire: total calories, total fat, % calories from fat, % calories from saturated fat, protein, % calories from protein, carbohydrates, % calories from carbohydrates, and daily frequency of servings of fats/oils/sweets. We tested for association between 23 SNPs in RGS6 and dietary intake using a variance components measured genotype approach. All models were adjusted for gender, recruitment site, admixture, BMI, and age. Using an additive genetic model, rs1402064 was associated with higher intake of fats/oils/sweets, total calories, total fat and saturated fat (P = 0.0007, 0.026, 0.023, and 0.024). SNPs rs847330 and rs847354 were associated with higher intake of fats/oils/sweets (P = 0.002 and 0.018), total fat (P = 0.040 and 0.048) and saturated fat (P = 0.044 and 0.041). Finally, rs769148 was associated with higher intake of fats/oils/sweets (P = 0.002). RGS6 is a new candidate gene for adiposity traits that may be associated with a behavioral tendency toward fat laden food intake. PMID- 21233809 TI - Body size phenotypes and inflammation in the Women's Health Initiative Observational Study. AB - Individuals with "metabolically benign" obesity (obesity unaccompanied by hypertension, dyslipidemia, and diabetes) are not at elevated 10-year risk of cardiovascular disease (CVD) compared to normal weight individuals. It remains unclear whether these obese individuals or normal weight individuals with clustering of cardiometabolic factors display heightened immune activity. Therefore, we characterized levels of acute-phase reactants (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), white blood cell (WBC) count), adhesion molecules (E-selectin, vascular cell adhesion molecule-1), and coagulation products (fibrinogen, plasminogen activator inhibitor-1 (PAI-1)) among four body size phenotypes (normal weight with 0/1 vs. >=2 metabolic syndrome components/diabetes and overweight/obesity with 0/1 vs. >=2 metabolic syndrome components/diabetes) in cross-sectional analyses of 1,889 postmenopausal women from the Women's Health Initiative Observational Study (WHI OS) nested case-control stroke study. Higher levels of all three inflammatory marker categories were found among women with overweight/obesity or >=2 metabolic syndrome components or diabetes. Compared to normal weight women with 0 or 1 metabolic syndrome components, normal weight women with >=2 metabolic syndrome components or diabetes were more likely to have >=3 inflammatory markers in the top quartile (multivariate odds ratio (OR) 2.0, 95% confidence interval (CI): 1.3 3.0), as were overweight/obese women with 0 or 1 metabolic syndrome components (OR 2.3; 95% CI: 1.5-3.5). Overweight/obese women with >=2 metabolic syndrome components or diabetes had the highest OR (OR 4.2; 95% CI: 2.9-5.9). Despite findings that metabolically benign obese individuals are not at increased 10-year risk of CVD compared to normal weight individuals, the current results suggest that overweight/obese women without clustering of cardiometabolic risk factors still possess abnormal levels of inflammatory markers. PMID- 21233811 TI - Multilocus analyses of seven candidate genes suggest interacting pathways for obesity-related traits in Brazilian populations. AB - We investigated whether variants in major candidate genes for food intake and body weight regulation contribute to obesity-related traits under a multilocus perspective. We studied 375 Brazilian subjects from partially isolated African derived populations (quilombos). Seven variants displaying conflicting results in previous reports and supposedly implicated in the susceptibility of obesity related phenotypes were investigated: beta2-adrenergic receptor (ADRB2) (Arg16Gly), insulin induced gene 2 (INSIG2) (rs7566605), leptin (LEP) (A19G), LEP receptor (LEPR) (Gln223Arg), perilipin (PLIN) (6209T > C), peroxisome proliferator-activated receptor-gamma (PPARG) (Pro12Ala), and resistin (RETN) ( 420 C > G). Regression models as well as generalized multifactor dimensionality reduction (GMDR) were employed to test the contribution of individual effects and higher-order interactions to BMI and waist-hip ratio (WHR) variation and risk of overweight/obesity. The best multilocus association signal identified in the quilombos was further examined in an independent sample of 334 Brazilian subjects of European ancestry. In quilombos, only the PPARG polymorphism displayed significant individual effects (WHR variation, P = 0.028). No association was observed either with the risk of overweight/obesity (BMI >= 25 kg/m2), risk of obesity alone (BMI >= 30 kg/m2) or BMI variation. However, GMDR analyses revealed an interaction between the LEPR and ADRB2 polymorphisms (P = 0.009) as well as a third-order effect involving the latter two variants plus INSIG2 (P = 0.034) with overweight/obesity. Assessment of the LEPR-ADRB2 interaction in the second sample indicated a marginally significant association (P = 0.0724), which was further verified to be limited to men (P = 0.0118). Together, our findings suggest evidence for a two-locus interaction between the LEPR Gln223Arg and ADRB2 Arg16Gly variants in the risk of overweight/obesity, and highlight further the importance of multilocus effects in the genetic component of obesity. PMID- 21233810 TI - The effect of pioglitazone and resistance training on body composition in older men and women undergoing hypocaloric weight loss. AB - Age-related increases in ectopic fat accumulation are associated with greater risk for metabolic and cardiovascular diseases, and physical disability. Reducing skeletal muscle fat and preserving lean tissue are associated with improved physical function in older adults. PPARgamma-agonist treatment decreases abdominal visceral adipose tissue (VAT) and resistance training preserves lean tissue, but their effect on ectopic fat depots in nondiabetic overweight adults is unclear. We examined the influence of pioglitazone and resistance training on body composition in older (65-79 years) nondiabetic overweight/obese men (n = 48, BMI = 32.3 +/- 3.8 kg/m(2)) and women (n = 40, BMI = 33.3 +/- 4.9 kg/m(2)) during weight loss. All participants underwent a 16-week hypocaloric weight-loss program and were randomized to receive pioglitazone (30 mg/day) or no pioglitazone with or without resistance training, following a 2 * 2 factorial design. Regional body composition was measured at baseline and follow-up using computed tomography (CT). Lean mass was measured using dual X-ray absorptiometry. Men lost 6.6% and women lost 6.5% of initial body mass. The percent of fat loss varied across individual compartments. Men who were given pioglitazone lost more visceral abdominal fat than men who were not given pioglitazone (-1,160 vs. -647 cm(3), P = 0.007). Women who were given pioglitazone lost less thigh subcutaneous fat ( 104 vs. -298 cm(3), P = 0.002). Pioglitazone did not affect any other outcomes. Resistance training diminished thigh muscle loss in men and women (resistance training vs. no resistance training men: -43 vs. -88 cm(3), P = 0.005; women: -34 vs. -59 cm(3), P = 0.04). In overweight/obese older men undergoing weight loss, pioglitazone increased visceral fat loss and resistance training reduced skeletal muscle loss. Additional studies are needed to clarify the observed gender differences and evaluate how these changes in body composition influence functional status. PMID- 21233812 TI - ADRB2 and LEPR gene polymorphisms: synergistic effects on the risk of obesity in Japanese. AB - The objective of the present study was to validate a recently reported synergistic effect between variants located in the leptin receptor (LEPR) gene and in the beta-2 adrenergic receptor (ADRB2) gene on the risk of overweight/obesity. We studied a middle-aged/elderly sample of 4,193 nondiabetic Japanese subjects stratified according gender (1,911 women and 2,282 men). The LEPR Gln223Arg (rs1137101) variant as well as both ADRB2 Arg16Gly (rs1042713) and Gln27Glu (rs1042714) polymorphisms were analyzed. The primary outcome was the risk of overweight/obesity defined as BMI >=25 kg/m(2), whereas secondary outcomes included the risk of a BMI >=27 kg/m(2) and BMI as a continuous variable. None of the studied polymorphisms showed statistically significant individual effects, regardless of the group or phenotype studied. Haplotype analysis also did not disclose any associations of ADRB2 polymorphisms with BMI. However, dimensionality reduction-based models confirmed significant interactions among the investigated variants for BMI as a continuous variable as well as for the risk of obesity defined as BMI >=27 kg/m(2). All disclosed interactions were found in men only. Our results provide external validation for a male specific ADRB2-LEPR interaction effect on the risk of overweight/obesity, but indicate that effect sizes associated with these interactions may be smaller in the population studied. PMID- 21233813 TI - Postprandial endothelial function, inflammation, and oxidative stress in obese children and adolescents. AB - Most studies in adults suggest that acute glucose consumption induces a transient impairment in endothelial function. We hypothesized that obese youth would demonstrate reduced endothelial function and increased inflammation and oxidative stress following acute glucose ingestion and that transient elevations in plasma glucose would correlate with endothelial dysfunction, inflammation, and oxidative stress. Thirty-four obese (BMI >= 95th percentile) children and adolescents (age 12.4 +/- 2.6 years; BMI = 37.9 +/- 6.7 kg/m2; 50% females) underwent measurement of endothelial function (reactive hyperemic index (RHI)), glucose, insulin, C reactive protein (CRP), interleukin-6 (IL-6), circulating oxidized low-density lipoprotein (oxLDL), and myeloperoxidase (MPO) in a fasting state and at 1- and 2 h following glucose ingestion. Repeated measures ANOVA with Tukey post-tests and Pearson correlations were performed. Glucose and insulin levels significantly increased at 1- and 2-h (all P values < 0.001). Compared to baseline, there were no statistically significant differences in 1- and 2-h RHI, CRP, IL-6, and oxLDL. However, MPO significantly decreased at the 1- (P < 0.05) and 2-h (P < 0.001) time points. At the 1-h time point, glucose level was significantly inversely correlated with RHI (r = -0.40, P < 0.05) and at the 2-h time point, glucose level was positively correlated with MPO (r = 0.40, P < 0.05). An acute oral glucose load does not reduce endothelial function or increase levels of inflammation or oxidative stress in obese youth. However, associations of postprandial hyperglycemia with endothelial function and oxidative stress may have implications for individuals with impaired glucose tolerance or frank type 2 diabetes. PMID- 21233814 TI - The 100-calorie semi-solution: sub-packaging most reduces intake among the heaviest. AB - This study addresses two questions about sub-packaging: (i) Do 100-calorie packages reduce the calorie intake of overweight individuals differently than normal-weight individuals? (ii) Do they enable individuals to accurately track intake? Thirty-seven undergraduates were randomly given either four 100-calorie packages of crackers or one 400-calorie package of crackers to eat while watching television. The average participant ate 25.2% (75.1 calories) less when given four 100-calorie packages of crackers than when given one 400-calorie package (P = 0.006). In addition, much of this influence was driven by overweight participants whose intake decreased by 54.1%. However, all of the participants underestimated their consumption by 60% or more, indicating that sub-packaging does not appear to increase one's accuracy in estimating how much is consumed. Smaller sized sub-packaging most greatly benefits those who are overweight, yet it does so without making people more aware of how much they have eaten. PMID- 21233815 TI - Discovery of basement membrane zone ultrastructural entities by electron microscopy. PMID- 21233816 TI - Role of the basement membrane zone in skin development. PMID- 21233817 TI - BMZ Destruction and Remodeling: Understanding Proteases and the Basement Membrane. PMID- 21233818 TI - Discovery of basement membrane components. PMID- 21233819 TI - Discovery of Specialized Basement Membrane Zone Proteins and their Alterations in Epidermolysis Bullosa. PMID- 21233820 TI - Cloning of genes for basement membrane proteins and discovery of mutations in epidermolysis bullosa. PMID- 21233821 TI - Development of animal models to study basement membranes. PMID- 21233822 TI - Introduction to the milestones in autoimmune bullous diseases. PMID- 21233824 TI - Clinical and molecular characterization of autoimmune bullous diseases. PMID- 21233823 TI - Autoimmune bullous diseases: historical perspectives. PMID- 21233825 TI - Pathophysiology of autoimmune bullous diseases. PMID- 21233826 TI - Duplicating autoimmune bullous diseases by passively transferring autoantibodies into animals. PMID- 21233827 TI - The Relationship between Autoimmune Bullous Disease and Systemic Disorders. PMID- 21233828 TI - Epidemiology and immunogenetics of autoimmune bullous diseases. PMID- 21233829 TI - EZH2 Y641 mutations in follicular lymphoma. PMID- 21233830 TI - Nuclear expression of MATK is a novel marker of type II enteropathy-associated T cell lymphoma. PMID- 21233831 TI - The isotype of the BCR as a surrogate for the GCB and ABC molecular subtypes in diffuse large B-cell lymphoma. AB - Gene expression profiling has identified two major molecular subtypes of diffuse large B-cell lymphoma (DLBCL) that are histologically indistinguishable but differ in cure rates. Here, we investigated whether the isotype of the B-cell receptor (BCR) expressed by the tumoral cells correlated with the molecular subtype and survival. Gene expression analysis clustered the 53 patients included in this study into three subgroups, 17 germinal center B-cell-like (GCB) cases, 26 activated B-cell-like (ABC) cases and 10 intermediate cases. The molecular subtype was correlated with the isotype, as 15/17 GCB cases expressed a secondary isotype (immunoglobulin (Ig)G or IgA), whereas 24/26 ABC cases expressed a primary isotype (IgM or IgD) (P<0.0001). There was a trend toward a worse outcome for patients with an ABC DLBCL and a shorter overall survival for patients with IgM+ tumor (P=0.21 and 0.014, respectively). Finally, fluorescence in situ hybridization (FISH) analysis revealed a striking asymmetric pattern, as the IGHM gene is conserved only on the productive IGH allele in most IgM+ tumors. Taken together, these data indicate that the isotype of the BCR is a reliable indicator for the GCB and ABC subtypes in DLBCL, and suggest that the conservation of an IgM is required for ABC DLBCL lymphomagenesis to occur. PMID- 21233832 TI - Melphalan and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: a meta-analysis. AB - Trials comparing efficacy of melphalan prednisone (MP) with MP plus thalidomide in transplant ineligible, elderly patients with multiple myeloma have provided conflicting evidence. Although there is agreement regarding improved response rates (RRs) and higher toxicity with the addition of thalidomide to MP, the impact on progression free survival (PFS) and overall survival (OS) is less clear. We performed a meta-analysis comparing efficacy of melphalan, prednisone and thalidomide (MPT) and MP by pooling results on RR, PFS and OS reported in all the identified randomized controlled trials (RCTs) under a random effects model. Overall, six prospective RCTs, with data extractable from five published trials (n=1571) [corrected] were identified. The pooled odds ratio of responding to therapy with MPT vs MP was 3.39 (P<0.001, 95% CI: 2.24-5.12). The pooled hazard ratios for PFS and OS were and 0.68 (P<0.001; 95% CI: 0.55-0.82) and 0.80 (P=0.07; 95% CI: 0.63-1.02), respectively, in favor of MPT. The odds ratios for high grade peripheral neuropathy and deep venous thrombosis were 6.6 and 2.4, respectively, in favour of MP. There was significant heterogeneity among the RCTs. Our meta-analysis demonstrates that in previously untreated, transplant ineligible, elderly myeloma patients, the addition of T to MP results in significantly improved RR and PFS with a trend towards improvement in OS compared with MP alone, but at a cost of significantly greater toxicity. PMID- 21233833 TI - Higher number of stem cells in the bone marrow of circulating low Igf-1 level Laron dwarf mice--novel view on Igf-1, stem cells and aging. PMID- 21233834 TI - The heterodimerization domains of MLL-FYRN and FYRC--are potential target structures in t(4;11) leukemia. AB - The chromosomal translocation t(4;11)(q21;q23) is a frequent genetic aberration of the mixed lineage leukemia (MLL) gene, predominantly associated with high-risk acute lymphoblastic leukemia (ALL) in pediatric patients. Previous studies demonstrated that mice transplanted with hematopoietic cells expressing the AF4 MLL fusion protein develop proB ALL. The AF4-MLL oncoprotein becomes activated by Taspase1-mediated hydrolysis, which subsequently leads to a heterodimer of the cleavage products AF4-MLL.N and MLL.C. This protein-protein interaction is due to the FYRN and FYRC interaction domains present in both protein fragments. Heterodimerization subsequently induces high-molecular-weight protein complex formation that is protected against SIAH1/2-mediated polyubiquitinylation. Here, we attempted to selectively block this initial heterodimerization step, aiming to prevent the oncogenic activation of the AF4-MLL multiprotein complex. The minimal interaction interface was experimentally defined first in a bacterial two-hybrid system, and then in mammalian cells by using a biosensor assay. Expression of the FYRC domain, or smaller portions thereof, resulted in the inhibition of heterodimer formation, and blocked AF4-MLL multiprotein complex formation with subsequent destruction of the AF4-MLL oncoprotein. Thus, it is in principle possible to specifically target the AF4-MLL protein. This knowledge can now be exploited to design inhibitory decoys in order to destroy the AF4-MLL oncoprotein. PMID- 21233835 TI - Differential expression of the BCR gene in sequential stages of murine hematopoietic hierarchy. PMID- 21233836 TI - An accumulation of cytogenetic and molecular genetic events characterizes the progression from MDS to secondary AML: an analysis of 38 paired samples analyzed by cytogenetics, molecular mutation analysis and SNP microarray profiling. PMID- 21233837 TI - Characterization of NPM1-mutated AML with a history of myelodysplastic syndromes or myeloproliferative neoplasms. AB - The role of the nucleophosmin (NPM1) mutations in de novo acute myeloid leukemia (AML) is well analyzed, but the impact in secondary AML (s-AML) following myelodysplastic syndromes (MDS) or transformed myeloproliferative neoplasms (MPNs) remains unclear. We investigated 350 patients-283 s-AML after MDS and 67 transformed MPNs-for NPM1mut. NPM1mut was detected in 43/350 patients (12.3%) at diagnosis of s-AML (transformed MDS: 37/283; 13.1%; transformed MPNs: 6/67; 9.0%). Cytogenetic alterations were present in 12/40 cases (30.0%) with available karyotypes. Additional molecular mutations were found in 23/43 NPM1mut s-AML after MDS (53.5%) and in transformed MPN in 18/37 (48.6%): FLT3-ITD: 14/37 (37.8%); FLT3-TKD: 3/28 (10.7%); NRASmut: 4/37 (10.8%), RUNX1mut: 1/16 (6.3%). In NPM1mut-transformed MPNs, five out of six cases showed 1-2 additional molecular mutations (2 * KITD816V, ETV6-PDGFRB, 2 * JAK2V617F, 2 * FLT3-ITD). Backtracking of nine of these cases by quantitative real time PCR showed the NPM1mut already at diagnosis of MDS/MPN, at variable levels and up to 14 months before diagnosis of AML, and at transformation often being preceded or accompanied by other genetic alterations. Thus, NPM1 mutations are involved in the transformation from MDS to AML or MPN to blast phase in single cases, which should be further confirmed in larger studies. PMID- 21233839 TI - CLL-like B-lymphocytes are systematically present at very low numbers in peripheral blood of healthy adults. PMID- 21233838 TI - A unique three-dimensional SCID-polymeric scaffold (SCID-synth-hu) model for in vivo expansion of human primary multiple myeloma cells. PMID- 21233840 TI - PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect. AB - Protein phosphatase 2A (PP2A) is a human tumor suppressor that inhibits cellular transformation by regulating the activity of several signaling proteins critical for malignant cell behavior. PP2A has been described as a potential therapeutic target in chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia and B-cell chronic lymphocytic leukemia. Here, we show that PP2A inactivation is a recurrent event in acute myeloid leukemia (AML), and that restoration of PP2A phosphatase activity by treatment with forskolin in AML cells blocks proliferation, induces caspase-dependent apoptosis and affects AKT and ERK1/2 activity. Moreover, treatment with forskolin had an additive effect with Idarubicin and Ara-c, drugs used in standard induction therapy in AML patients. Analysis at protein level of the PP2A activation status in a series of patients with AML at diagnosis showed PP2A hyperphosphorylation in 78% of cases (29/37). In addition, we found that either deregulated expression of the endogenous PP2A inhibitors SET or CIP2A, overexpression of SETBP1, or downregulation of some PP2A subunits, might be contributing to PP2A inhibition in AML. In conclusion, our results show that PP2A inhibition is a common event in AML cells and that PP2A activators, such as forskolin or FTY720, could represent potential novel therapeutic targets in AML. PMID- 21233841 TI - IDH1 and IDH2 mutations are rare in pediatric myeloid malignancies. PMID- 21233842 TI - The EEL-1 ubiquitin ligase promotes DNA damage-induced germ cell apoptosis in C. elegans. AB - E3 ubiquitin ligases target a growing number of pro- and anti-apoptotic proteins, including tumour suppressor p53, caspases, and the Bcl-2 family. The core apoptosis pathway is well conserved between mammals and Caenorhabditis elegans, but the extent to which ubiquitin ligases regulate apoptotic cell death is not known. To investigate the role of E3 ligases in apoptosis, we inhibited 108 of the 165 predicted E3 ubiquitin ligase genes by RNA interference and quantified apoptosis in the C. elegans germline after genotoxic stress. From this screen, we identified the homologous to E6-associated protein C terminus-domain E3 ligase EEL-1 as a positive regulator of apoptosis. Intriguingly, the human homologue of EEL-1, Huwe1/ARF-BP1/Mule/HectH9, has been reported to possess both pro- and anti apoptotic functions through its ability to stimulate Mcl-1 and p53 degradation, respectively. Here, we demonstrate that eel-1 is required to promote DNA damage induced germ cell apoptosis, but does not have a role in physiological germ cell apoptosis or developmental apoptosis in somatic tissue. Furthermore, eel-1 acts in parallel to the p53-like gene cep-1 and intersects the core apoptosis pathway upstream of the Bcl-2/Mcl-1 orthologue ced-9. Although ee1-1 mutants exhibit hypersensitivity to genotoxic stress they do not appear to be defective in DNA repair, suggesting a distinct role for EEL-1 in promoting damage-induced apoptosis in the germline. PMID- 21233843 TI - TAK1 regulates SCF expression to modulate PKBalpha activity that protects keratinocytes from ROS-induced apoptosis. AB - Dysregulated reactive oxygen species (ROS) generation contributes to many human pathologies, including cancer and diabetes. During normal wound repair, inflammation-induced ROS production must be tightly controlled, but the mechanisms reining their generation remain unclear. Herein, we show that transforming growth factor beta-activated kinase 1 (TAK1) directly regulates stem cell factor (SCF) expression, which activates the protein kinase B (PKB)alpha pro survival pathway in a cell-autonomous manner to protect keratinocytes from ROS mediated cell death. TAK1 is a pivotal inflammatory mediator whose expression was transiently elevated during wound healing, paralleling the ROS production profile. TAK1 deficiency in keratinocytes led to increased apoptosis in response to anoikis and TNF-alpha treatment and was associated with elevated ROS level as analyzed by FACS. Using organotypic skin co-culture and comparative growth factor array analysis, we revealed a cell-autonomous mechanism that involved the SCF/c Kit/PKBalpha signaling cascade. Ectopic expression of TAK1 or treatment with exogenous recombinant SCF restored the increased ROS production and apoptotic cell death in TAK1-deficient keratinocytes. Conversely, normal keratinocytes treated with various inhibitors targeting the SCF/c-Kit/PKBalpha pathway exhibited increased ROS production and TNF-alpha- or anoikis-induced apoptosis. Our study reveals a novel anti-apoptotic role for SCF in keratinocytes and identifies TAK1 as a novel player uniting inflammation and ROS regulation in skin redox biology. PMID- 21233844 TI - Stimulation of the midkine/ALK axis renders glioma cells resistant to cannabinoid antitumoral action. AB - Identifying the molecular mechanisms responsible for the resistance of gliomas to anticancer treatments is an issue of great therapeutic interest. Delta(9) Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoids inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, by analyzing the gene expression profile of a large series of human glioma cells with different sensitivity to cannabinoid action, we have identified a subset of genes specifically associated to THC resistance. One of these genes, namely that encoding the growth factor midkine (Mdk), is directly involved in the resistance of glioma cells to cannabinoid treatment. We also show that Mdk mediates its protective effect via the anaplastic lymphoma kinase (ALK) receptor and that Mdk signaling through ALK interferes with cannabinoid-induced autophagic cell death. Furthermore, in vivo Mdk silencing or ALK pharmacological inhibition sensitizes cannabinod-resistant tumors to THC antitumoral action. Altogether, our findings identify Mdk as a pivotal factor involved in the resistance of glioma cells to THC pro-autophagic and antitumoral action, and suggest that selective targeting of the Mdk/ALK axis could help to improve the efficacy of antitumoral therapies for gliomas. PMID- 21233845 TI - MicroRNA miR-885-5p targets CDK2 and MCM5, activates p53 and inhibits proliferation and survival. AB - Several microRNA (miRNA) loci are found within genomic regions frequently deleted in primary neuroblastoma, including miR-885-5p at 3p25.3. In this study, we demonstrate that miR-885-5p is downregulated on loss of 3p25.3 region in neuroblastoma. Experimentally enforced miR-885-5p expression in neuroblastoma cell lines inhibits proliferation triggering cell cycle arrest, senescence and/or apoptosis. miR-885-5p leads to the accumulation of p53 protein and activates the p53 pathway, resulting in upregulation of p53 targets. Enforced miR-885-5p expression consistently leads to downregulation of cyclin-dependent kinase (CDK2) and mini-chromosome maintenance protein (MCM5). Both genes are targeted by miR 885-5p via predicted binding sites within the 3'-untranslated regions (UTRs) of CDK2 and MCM5. Transcript profiling after miR-885-5p introduction in neuroblastoma cells reveals alterations in expression of multiple genes, including several p53 target genes and a number of factors involved in p53 pathway activity. Taken together, these data provide evidence that miR-885-5p has a tumor suppressive role in neuroblastoma interfering with cell cycle progression and cell survival. PMID- 21233846 TI - Involvement of BH4 domain of bcl-2 in the regulation of HIF-1-mediated VEGF expression in hypoxic tumor cells. AB - In addition to act as an antiapoptotic protein, B-cell lymphoma (bcl)-2 can also promote tumor angiogenesis. In this context, we have previously demonstrated that under hypoxia bcl-2 promotes hypoxia-inducible factor-1 (HIF-1)-mediated vascular endothelial growth factor (VEGF) expression in melanoma and breast carcinoma. Here, we report on the role of the BH4 domain in bcl-2 functions, by showing that removal of or mutations at the BH4 domain abrogate the ability of bcl-2 to induce VEGF protein expression and transcriptional activity under hypoxia in human melanoma cells. We have also extended this observation to other human tumor histotypes, such as colon, ovarian and lung carcinomas. The involvement of BH4 on HIF-1alpha protein expression, stability, ubiquitination and HIF-1 transcriptional activity was also demonstrated in melanoma experimental model. Moreover, we validated the role of the BH4 domain of bcl-2 in the regulation of HIF-1/VEGF axis, demonstrating that BH4 peptide is sufficient to increase HIF 1alpha protein half-life impairing HIF-1alpha protein ubiquitination, and to enhance VEGF secretion in melanoma cells exposed to hypoxia. Finally, we found that the mechanism by which bcl-2 regulates HIF-1-mediated VEGF expression does not require BH1 and BH2 domains, and it is independent of antiapoptotic and prosurvival function of bcl-2. PMID- 21233847 TI - Mortalin-p53 interaction in cancer cells is stress dependent and constitutes a selective target for cancer therapy. AB - Stress protein mortalin is a multifunctional protein and is highly expressed in cancers. It has been shown to interact with tumor suppressor protein-p53 (both wild and mutant types) and inactivates its transcriptional activation and apoptotic functions in cancer cells. In the present study, we found that, unlike most of the cancer cells, HepG2 hepatoma lacked mortalin-p53 interaction. We demonstrate that the mortalin-p53 interaction exists in cancer cells that are either physiologically stressed (frequently associated with p53 mutations) or treated with stress-inducing chemicals. Targeting mortalin-p53 interaction with either mortalin small hairpin RNA or a chemical or peptide inhibitor could induce p53-mediated tumor cell-specific apoptosis in hepatocellular carcinoma; p53-null hepatoma or normal hepatocytes remain unaffected. PMID- 21233848 TI - Differential regulation of the proapoptotic multidomain protein Bak by p53 and p73 at the promoter level. AB - During apoptosis Bcl-2 proteins control permeabilization of the mitochondrial outer membrane leading to the release of cytochrome c. Essential gatekeepers for cytochrome c release are the proapoptotic multidomain proteins, Bax, and Bak. The expression of Bax is upregulated upon cellular stress by the tumor suppressor p53. Despite the high functional homology of Bax and Bak, little is known about how the bak gene is regulated. To investigate its transcriptional regulation in further detail, we have analyzed a region spanning 8200 bp upstream of the bak start codon (within exon 2) for transcription factor-binding sites, and identified three p53 consensus sites (BS1-3). Reporter gene assays in combination with site-directed mutagenesis revealed that only one putative p53-binding site (BS3) is necessary and sufficient for induction of reporter gene expression by p53. Consistently, p53 induces expression of endogenous Bak. At the mRNA level, induction of Bak expression is weaker than induction of Puma and p21. Interestingly, Bak expression can also be induced by p73 that binds however to each of the three p53-binding sites within the bak promoter region. Our data suggest that expression of Bak can be induced by both, p53 and p73 utilizing different binding sites within the bak promoter. PMID- 21233849 TI - Evolution of multisubunit RNA polymerases in the three domains of life. AB - RNA polymerases (RNAPs) carry out transcription in all living organisms. All multisubunit RNAPs are derived from a common ancestor, a fact that becomes apparent from their amino acid sequence, subunit composition, structure, function and molecular mechanisms. Despite the similarity of these complexes, the organisms that depend on them are extremely diverse, ranging from microorganisms to humans. Recent findings about the molecular and functional architecture of RNAPs has given us intriguing insights into their evolution and how their activities are harnessed by homologous and analogous basal factors during the transcription cycle. We provide an overview of the evolutionary conservation of and differences between the multisubunit polymerases in the three domains of life, and introduce the 'elongation first' hypothesis for the evolution of transcriptional regulation. PMID- 21233850 TI - Microbial seed banks: the ecological and evolutionary implications of dormancy. AB - Dormancy is a bet-hedging strategy used by a wide range of taxa, including microorganisms. It refers to an organism's ability to enter a reversible state of low metabolic activity when faced with unfavourable environmental conditions. Dormant microorganisms generate a seed bank, which comprises individuals that are capable of being resuscitated following environmental change. In this Review, we highlight mechanisms that have evolved in microorganisms to allow them to successfully enter and exit a dormant state, and discuss the implications of microbial seed banks for evolutionary dynamics, population persistence, maintenance of biodiversity, and the stability of ecosystem processes. PMID- 21233851 TI - Health biotechnology innovation on a global stage. AB - With increasing globalization, infectious diseases are spreading faster than ever before, creating an urgent need for international collaboration. The rise of emerging economies has changed the traditional collaborative landscape and provided opportunities for more diverse models of collaboration involving developing countries, including North-South, South-South and North-South-South partnerships. Here, we discuss how developing countries can partner with other nations to address their shared health problems and to promote innovation. We look specifically at what drives collaborations and at the challenges that exist for them, and we propose actions that can strengthen these partnerships. PMID- 21233854 TI - Sustainability, capitalism and evolution. Nature conservation is not a matter of maintaining human development and welfare in a healthy environment. PMID- 21233853 TI - Metabolism, migration and memory in cytotoxic T cells. AB - The transcriptional and metabolic programmes that control CD8(+) T cells are regulated by a diverse network of serine/threonine kinases. The view has been that the kinases AKT and mammalian target of rapamycin (mTOR) control T cell metabolism. Here, we challenge this paradigm and discuss an alternative role for these kinases in CD8(+) T cells, namely to control cell migration. Another emerging concept is that AMP-activated protein kinase (AMPK) family members control T cell metabolism and determine the effector versus memory fate of CD8(+) T cells. We speculate that one link between metabolism and immunological memory is provided by kinases that originally evolved to control T cell metabolism and have subsequently acquired the ability to control the expression of key transcription factors that regulate CD8(+) T cell effector function and migratory capacity. PMID- 21233855 TI - Engineering a waste management enzyme to overcome cancer resistance to apoptosis: adding DNase1 to the anti-cancer toolbox. AB - Cancer treatment is often complicated by resistance to conventional anti-cancer treatment and to more recently developed immunotherapy and gene therapy. These therapeutic modalities aim at activating death pathways within cancer cells. Attempts to activate the apoptotic death pathway, by overexpressing proapoptotic signals, are compromised by cancer defense mechanisms, which disrupt the apoptotic-signaling cascade downstream of the overexpressed component. Here, we describe a therapeutic option of triggering apoptosis without activating the apoptotic-signaling cascade or using the native apoptosis executioner nuclease. We have engineered Deoxyribonuclease-1 (DNase1), a waste-management enzyme, by deleting its signal peptide, adding a nuclear localization signal, and mutating its actin-binding site. Apoptosis studies and colony-forming assay for assessing cell viability were conducted in apoptosis-resistant Mel-Juso human melanoma cells. The modified DNase1 reduced cell viability by 77% relative to controls. It also induced typical microscopic features of cellular apoptosis, such as Terminal Transferase dUTP Nick-End Labeling-positive cells and DNA fragmentation. Quantification of apoptosis by Laser scanning cytometry demonstrated high-killing efficiency of 70-100%. The results suggest that this modified DNase1 can efficiently eliminate apoptosis-resistant cancer cells through apoptosis. Coupled to different tissue-specific gene expression elements, this recombinant DNase1 may serve as a platform for eliminating a variety of cancer types. PMID- 21233856 TI - Effects of RNA interference targeting four different genes on the growth and proliferation of nasopharyngeal carcinoma CNE-2Z cells. AB - To explore the effects of RNA interference targeting four different genes (VEGF, C-myc, Survivin, hTERT) on the growth and proliferation of nasopharyngeal carcinoma (NPC) CNE-2Z cells. Fluorescein-labeled short-hairpin (sh)RNA plasmids together and separately targeting VEGF, C-myc, Survivin and hTERT were built and respectively called plasmid-shVEGF-shC-myc-shSurvivin-shhTERT, plasmid-shVEGF, plasmid-shC-myc, plasmid-shSurvivin, plasmid-shhTERT. These plasmids were respectively transfected into human NPC CNE-2Z cells and xenograft tumors in nude mice. The expression of plasmids in NPC CNE-2Z cells and xenograft tumors was observed. Cell proliferation was detected with MTT assay. The mRNA and protein expression were determined by real-time PCR and western blot, respectively. The effects of plasmids on the biological behavior of CNE-2Z cells were observed with transwell invision chamber models. Apoptosis was determined with flow cytometer. The inhibitory effect of plasmids on xenograft tumors was observed in nude mice. The plasmid containing four different shRNAs could significantly inhibit CNE-2Z cell proliferation and decrease invasion ability in vitro compared with plasmids with each single shRNA (P<0.05). The plasmid containing four different shRNAs could simultaneously downregulate VEGF, C-myc, surviving, hTERT mRNA and protein expression in the CNE-2Z cells. The multiple gene shRNA could more significantly induce cell apoptosis than each single shRNA, respectively (P<0.05). The combinative silencing of these four genes had a better inhibitory effect on xenograft tumors than the silencing of each single shRNA (P<0.05). RNA interference targeting multiple genes can effectively inhibit NPC proliferation and induce apoptosis, which provides an experiment basis for NPC gene therapy. PMID- 21233852 TI - Type 2 diabetes as an inflammatory disease. AB - Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease. PMID- 21233857 TI - An Ad5[E1-, E2b-]-HER2/neu vector induces immune responses and inhibits HER2/neu expressing tumor progression in Ad5 immune mice. AB - Immunotherapy is a promising approach for the treatment of cancers. Modified adenovirus 5 (Ad5) vectors have been used as a platform to deliver genes encoding tumor associated antigens (TAA). A major obstacle to Ad5 vector immunotherapy has been the induction of vector immunity following administration or the presence of pre-existing Ad5 immunity, which results in vector mitigation. It has been reported by us that the Ad5[E1-, E2b-] platform with unique deletions in the E1, E2b and E3 regions can induce potent cell mediated immunity (CMI) against delivered transgene products in the presence of pre-existing Ad5 immunity. Here we report the use of an Ad5[E1-, E2b-] vector platform expressing the TAA HER2/neu as a breast cancer immunotherapeutic agent. Ad5[E1-, E2b-]-HER2/neu induced potent CMI against HER2/neu in Ad5 naive and Ad5 immune mice. Humoral responses were also induced and antibodies could lyse HER2/neu expressing tumor cells in the presence of complement in vitro. Ad5[E1-, E2b-]-HER2/neu prevented establishment of HER2/neu-expressing tumors and significantly inhibited progression of established tumors in Ad5 naive and Ad5 immune murine models. These data demonstrate that in vivo delivery of Ad5[E1-, E2b-]-HER2/neu can induce anti-TAA immunity and inhibit progression of HER2/neu expressing cancers. PMID- 21233858 TI - Telomerase inhibition strategies by siRNAs against either hTR or hTERT in oral squamous cell carcinoma. AB - Human telomerase RNA (hTR) and human telomerase reverse transcriptase (hTERT) are considered effective molecular targets for current anticancer therapy. In this study, we investigated the therapeutic effects of targeting hTR and hTERT individually or in combination by recombinant adenovirus-delivered small interfering RNA (siRNA) in oral squamous cell carcinoma (OSCC) Tca8113. Further, we screened the optimal strategy for RNA interference. Our results show that these different recombinant adenoviruses specifically reduced the levels of hTR mRNA, hTERT mRNA, hTERT protein and telomerase activity in Tca8113 cells. Moreover, they successfully inhibited xenograft tumor growth in nude mice. The potency of their antitumor activities was ranked as follows: anti-hTR >anti hTR+anti-hTERT >anti-hTERT. Therefore, we demonstrated that the siRNA-expressing recombinant adenoviruses were an effective anticancer tool for treatment of OSCC. Furthermore, the anticancer effect of solely targeting hTR was more direct and efficient, compared with the effect of targeting hTR and hTERT in combination, or hTERT exclusively. The mechanism of this anticancer effect in OSCC was not only related to the inhibition of cell proliferation and the induction of cell apoptosis, but might also involve the inhibition of tumor angiogenesis. PMID- 21233859 TI - Pre-clinical toxicity assessment of tumor-targeted interleukin-12 low-intensity electrogenetherapy. AB - This study's goal was to assess the safety of tumor-targeted interleukin-12 (ttIL 12) when administered by electrogenetherapy in C3H/HeJ mice by identifying an initial safe dose for human dose escalation schemes, toxicity target organs, markers of toxicity, and toxicity reversibility. Tumor-free mice receiving two doses of 0.45% NaCl, 1 MUg ttIL-12 DNA in 0.45% NaCl or 5 MUg ttIL-12 DNA in 0.45% NaCl, 10 days apart combined with low-intensity electroporation were compared with non-treatment controls over time. All mice had blood cell counts, serum chemistry profiles, plasma interleukin-12 and IFNgamma determinations, necropsy and multi-organ histopathology. Mild treatment-associated changes included electroporation-associated muscle changes that resolved by 30 days; decreased total white blood cell counts and infectious disease in the 5 MUg ttIL 12 group, but not in the 1 MUg group, and liver changes in ttIL-12 groups that correlated with alanine transaminase levels and resolved by 30 days. Dystrophic cardiac calcification seen in older, 5 MUg ttIL-12-treated mice was the only serious toxicity. Based on these results and the lack of any effect on wound healing when combined with surgery, low-intensity electrogenetherapy with ttIL-12 appears to be safe and well tolerated. PMID- 21233860 TI - [Non-mydiatric retinography for the detection of diabetic retinopathy. An example of adaptation to the setting]. PMID- 21233861 TI - [Teaching coping strategies to parents of children suffering from cancer using a short film]. AB - This paper studies the usefulness of a short film in teaching strategies for parents of children with cancer to cope with the situation. The short film is based on an analysis of the transcripts from eight sessions of a self-help group. The short film has been evaluated by psychologists working for each of the parent groups belonging to the Federation of parents of children with cancer. Furthermore, the film has been exhibited in group sessions that took place in the Valencia and Alicante branches of ASPANION (Association of Parents with Oncologic Children in the Valencia Region). About 70% of the experts have declared that the film is a valuable resource for teaching useful strategies to parents. The film also improves the group sessions since it addresses a number of issues that had not been addressed before, and it stimulates the participation of, and communication between, parents during the session. PMID- 21233862 TI - [Prevalence of diabetic retinopathy using non-mydriatic retinography]. AB - OBJECTIVES: To establish the prevalence of diabetic retinopathy (RD) diagnosed after non-mydriatic retinography and to evaluate its utility as a screening test in the area of San Sebastian. METHODS: A prospective study including 2,444 diabetic patients sent by their primary attention doctors and/or their endocrinologists. All patients underwent non-mydriatic retinography in the central 45 degrees; visual acuity was explored, as well as IOP through non contact tonometry. The retinographies and information obtained were sent to our hospital and were revised by an ophthalmologist from the Retina Department. RESULTS: Fifteen point zero two (15.02%) of the patients suffered from diabetes and were under dietary treatment, 62.55% suffered from non-insulin-dependant diabetes, and 22.43% suffered from insulin-dependant diabetes. The prevalence of diabetic retinopathy was 9.36%; 5.27% mild non-proliferative diabetic retinopathy (DR); 2.21% moderate-non-proliferative DR; 1.67 % severe non-proliferative DR; and 0.05% proliferative-diabetic retinopathy. Eight point two two (8.22%) of the sample studied was diagnosed with ocular hypertension. CONCLUSIONS: We observed a low prevalence of DR in our sample. Use of non-mydriatic retinopathy in telemedicine plays an important role in the early diagnosis of diabetic retinopathy and it can be applied to other ophthalmic diseases. PMID- 21233863 TI - [Parent-doctor relations in oncology: a qualitative approach]. AB - We want to learn how parents of children with cancer perceive their relationship with hospital staff, especially with doctors. We used group-based qualitative methodology. The sample is composed of 14 mothers/fathers whose children contracted the disease more than two years previously. All parents want information that is both intelligible and detailed. The word cancer has a strong social stigma and is avoided when giving information to parents and to children. Communication between doctors and parents can lead to situations of tension during diagnosis and relapses. Parents trust the professionalism of doctors. Parents also want doctors to be competent and to have human qualities. The preparation of reports by physicians is the task most criticized by parents. PMID- 21233865 TI - [Current management of venous malformations]. AB - Venous malformations represent 2/3rds of all vascular malformations and are frequently much more complex than they appear to be. Patients with large venous malformations require a deep analytical and radiological study, as well as specific treatment to control any possible localised intravascular coagulation. If the lesions are extensive, especially in the lower member, a study should be made to detect the presence of an underlying osteoporosis with the idea of preventing pathological fractures. Equally, a check must be made for arthropathy, and an early prophylactic synovectomy must be considered when the radiological extension makes this advisable, with the idea of avoiding irreversible damage to the joints with the passage of time. Currently, microfoam scleropathy is favoured as the treatment of choice for low-flow vascular malformations. In the not too distant future, the use of selective antiangiogenic medicines, besides low molecular-weight heparins, will serve to control and treat malformations. PMID- 21233866 TI - [Follow-up of two patients with mesangial IgA glomerulonephritis exposed to cadmium and organic solvents]. AB - For several years we carried out a follow-up of two patients with IgA mesangial glomerulonephritis with antecedents of exposure to toxic substances (cadmium and organic solvents). The first case involved a 47 year old male who was diagnosed with mesangial IgA glomerulonephritis eight years ago; he had been working for twelve years as a solderer. He had used metal bars containing 25% cadmium as part of the soldering material. Very high levels of cadmium were detected in his blood and urine. The second case involved a 50 year male who was exposed to a wide number of organic dissolvents for 23 years. Three years ago he was diagnosed with a proliferative diffuse mesangial glomerulonephritis with IgA deposits; in spite of that, the patient continued working until one year ago, when was found to have a chronic stage 3 renal disease secondary to IgA nephropathy. Patients diagnosed with mesangial IgA glomerulonephritis should be kept apart from exposure to nephrotoxic substances. PMID- 21233867 TI - [Coordinating efforts in complex clinical cases: added value of palliative care at a university teaching hospital]. AB - Palliative care is generally understood on caring for terminal patients in chronic settings but more recently these units are developing also in acute care settings or university hospitals as consultants teams. We report the case of a complex patient with rectal adenocarcinoma and four problems of difficult approach: uncontrolled neuropathic pain despite opioids treatment, systemic infection, depression with intense demoralisation and open surgery wound. We show the measures adopted and how an excellent inter-departmental collaboration under the co-ordination of palliative medicine consultant team helped to resolve the untenable situation. PMID- 21233864 TI - [The 2009 H1N1 flu pandemic in Navarre, Spain]. AB - BACKGROUND: To describe flu activity during the 2009-2010 pandemic in Navarre and compare it to previous seasons. METHODS: An analysis was made of all flu cases reported in primary care and all the virological confirmations made in patients in primary care and in hospitals of Navarre between week 21 of 2009 and week 20 of 2010. RESULTS: Influenza A (H1N1) Virus 2009 was detected in Navarre between week 23 of 2009 and week 2 of 2010, a period when 39 medically diagnosed cases of flu syndrome per 1,000 inhabitants were registered. The epidemic threshold was surpassed in two periods, with a peak in July and a greater one in November. The greatest incidence was reached in children aged between 5 and 14 years (121 per thousand), followed by the group of under fives. There were 224 hospitalisations (36 per 100,000 inhabitants) with confirmation of Influenza A (H1N1) Virus 2009, 8% of whom required admission to intensive care units and there were four deaths (0.6 per 100,000 inhabitants). The rate of hospitalisation was greater amongst children under five (163 per 100,000 inhabitants), while the probability of referral to intensive care increased with age. CONCLUSION: In spite of not having a specific vaccine available until the season was very well advanced, Influenza A (H1N1)Virus 2009 produced a flu wave with similar levels to those of other seasons and its repercussion in hospitalisations and serious cases was moderate. PMID- 21233868 TI - [Visual hallucinations and unusual pain related to hypomagnesemia in an advanced cancer patient]. AB - Hypomagnesemia has been related to high accumulated doses of cisplatin, and its clinical presence is characterized by neuromuscular and cardiovascular alterations. We present the case of an advanced cancer patient who had received successive lines of chemotherapy and who was receiving opioid treatment for cancer pain. During his hospital stay, he experienced visual hallucinations and very intense, unexplained pain in one shoulder. Symptoms reverted with the normalization of his plasma magnesium levels, which were low. We consider that plasma magnesium levels should be monitored in oncology patients with neurological or psychiatric symptoms or with unusual pain. PMID- 21233869 TI - [Partial jejunal volvulus due to a mesenteric cystic lymphangioma]. AB - Mesenteric cysts are unusual benign tumours that include lymphangioma. Their clinical presentation is variable and acute symptoms can be produced due to complications. This tumour appears especially in childhood, and its prognosis after surgical removal is excellent. We present the case of a 15 year old female patient with symptoms of postprandial abdominal pain and palpation of smooth mass in hypogastrium. Radiological studies showed a big polilobular mass of cystic substance that included a portion of jejune with incomplete volvulus. The treatment was the removal of the cyst and a jejunal portion and the pathological diagnosis was mesenteric cyst lymphangioma. The patient is asymptomatic more than three years after the intervention. PMID- 21233870 TI - [Rare complication in a patient with giant cell arteritis]. AB - Giant cell arteritis (temporal arteritis) is a chronic vasculitis that usually affects older people. Although this is a systemic disease, it most often affects the cranial arteries. The most frequent complication of this disorder is visual loss. We report the case of a patient who suffered several rare complications, including tongue necrosis, as a result of being diagnosed with giant cell arteritis following the start of treatment. PMID- 21233871 TI - [Clubfoot in Uganda]. PMID- 21233872 TI - [Medical art]. PMID- 21233873 TI - [Children and burns]. PMID- 21233875 TI - Immunological thrombo-cytopenia in children. PMID- 21233877 TI - [Misleading about HPV testing]. PMID- 21233878 TI - [Misleading about ADHD]. PMID- 21233879 TI - [New guidelines for investigation and treatment of hepatitis C]. PMID- 21233880 TI - Should patients have obligations? PMID- 21233881 TI - [Declining prevalence of proliferative retinopathy in patients with type 1 diabetes]. AB - BACKGROUND: It is likely that improved treatment of diabetes during the last decades has led to a declining prevalence of retinopathy. We have assessed whether this is the case for patients with type I diabetes. MATERIAL AND METHODS: Medical records were retrospectively reviewed for all patients who were diagnosed with type 1 diabetes in the periods 1960-1975 (early group) and 1985-1990 (late group) at the diabetes clinic in St. Olavs Hospital (Trondheim). Information on the prevalence of retinopathy ten and 15 years after diabetes onset was obtained from hospital records and private ophthalmologists in Trondheim. RESULTS: 125 patients were identified in the early group and 147 patients in the late group. The prevalence of proliferative retinopathy was higher in the early group than in the late group, both after ten years (4% vs. 0%, p = 0.04) and 15 years (13% vs. 5%, p = 0.04) of diabetes. The prevalence of background retinopathy was not significantly different between the two groups after ten (12% vs. 14%, p = 0.70) or 15 years (29% vs. 24%, p = 0.36) of diabetes. INTERPRETATION: Our results indicate that the prevalence of proliferative retinopathy is decreasing in patients with type 1 diabetes in Norway. Explanations may be improved follow-up and treatment of diabetes and diabetic retinopathy. PMID- 21233882 TI - [Burn injuries in children]. AB - BACKGROUND: Burn injuries in children may cause permanent harm. This study reports data on incidence, injury mechanisms and products that cause burn injuries (in the period 01.01.07-31.12.07) and compares findings with those from previous studies (in 1989 and 1998). MATERIAL AND METHODS: Semi-structured questionnaires were filled in by patients or next-of-kin and health workers at Bergen Accident and Emergency Department, casualty centres in three municipalities in western Norway (Fana, Asane and Loddefjord) and at the National Burns Centre, Haukeland University Hospital. Missing data were retrieved retrospectively from medical records. RESULTS: We recorded 142 children with burn injuries; 35% were boys under two years of age. The annual incidence was the same as earlier; 6.6 per 1,000 under five years and 3.1 per 1,000 children under 15 years living in the community of Bergen. Contact injuries and scalds were most common and were caused by contact with ovens, stoves and hot food or liquids. Most children (93%) had less severe burns; 6% (9) were hospitalized (four of them had a non-western background). Almost 95% were given first aid by cooling. INTERPRETATION: Children under two years, especially boys, are most at risk of burn injuries. Ovens were the cause more often now than before. The incidence has been the same the last 20 years and is the same as that in Trondheim ten years ago. The fact that the small city, Harstad, (northern Norway) attained substantially less injuries after the introduction of preventive actions indicates that such actions are needed to reduce the number of burn injuries among children. PMID- 21233883 TI - [Lennox-Gastaut syndrome--course and treatment]. AB - BACKGROUND: Lennox-Gastaut syndrome (LGS) is a severe epileptic encephalopathy, which starts in childhood with various seizure types. The children develop cognitive impairment and a typical EEG pattern. The aim of this article is to describe the clinical presentation of LGS, with particular emphasis on the course in adulthood. MATERIAL AND METHODS: The article is based on literature (up to November 2009) identified through a non-systematic search in PubMed and our own clinical experience. RESULTS: There are cases with unknown etiology and symptomatic cases with a wide spectrum of etiologies. While children with LGS have a high frequency of generalized seizures, seizure activity tends to decrease somewhat in adulthood and the seizures may become more focal. The prognosis is usually poor. The adult patient with LGS is clearly affected by global encephalopathy and is typically characterized by bluntness, apathy, progressive cognitive failure and motoric deficits. Valproate has been the first-line treatment for many years, but newer antiepileptic drugs; such as lamotrigine, topiramate and rufinamide, have shown efficacy as add-on therapy. Overtreatment with antiepileptic drugs is common. INTERPRETATION: For optimal treatment, a specialist should follow LGS patients at all ages. New treatment options with milder side effects may improve the quality of life for these patients. PMID- 21233885 TI - [Tumor diagnosis]. PMID- 21233884 TI - [Nurses and social care workers in emergency teams in Norway]. AB - BACKGROUND: The Norwegian counties Troms and Finnmark are dominated by large areas with widespread habitation and rather long response times for ambulances and doctors. We wished to investigate the extent to which the municipal preparedness in these counties use employees from the municipal nursing and social care services and if these are part of local emergency teams. MATERIAL AND METHODS: In the autumn of 2008, we sent a questionnaire to the district medical officers and the leaders for municipal nursing and social care services in all 44 municipalities in Troms and Finnmark. The answers were analyzed manually. RESULTS: 41 municipalities responded. In 34 of these the municipal nurses and social care workers practice emergency medicine procedures. The content in these training sessions is much more comprehensive than that in a typical first aid course. In three of four municipalities ambulance personnel do not participate in this training. In 31 municipalities the inhabitants contact nurses and social care workers directly if they are acutely ill. In only 10 of the municipalities the nurses and social care workers are organized in local teams including a doctor and an ambulance. INTERPRETATION: In the districts, nursing and social care services are a resource in an emergency medicine context. The potential within these professions can be exploited better and be an important supplement in emergencies. In emergencies, cooperation across disciplines requires a clear organizational and economical structure, local basis and leadership. PMID- 21233886 TI - Local treatment of acne. PMID- 21233887 TI - [A young man with mononucleosis and swelling of the right eye]. AB - Treatment of acute infections in the upper airways comprises a significant part of direct healthcare expenditure and is a challenge for healthcare professionals. In Norway, 11,495 hospitalized days were recorded for acute infections (influenza and pneumonia excluded) in the upper airways in 2008. Acute bacterial rhinosinusitis (ABRS) is defined as inflammation of the nose and the paranasal sinuses characterized by both 1): symptoms of nasal blockage/obstruction/congestion or nasal discharge, and/or facial pain/pressure and 2): endoscopic signs of mucopurulent discharge from middle meatus and/or CT changes within the osteomeatal complex/sinuses. After 12 weeks of symptoms the definition changes to chronic rhinosinusitis. With antibiotic treatment of complicated ABRS we see fewer severe complications, but they still occur. Due to anatomical proximity of the orbit and intracranial structures a localized spread of the infection is especially unfortunate and potentially dangerous. We present a case report (with pan sinusitis and grave local complications) from the ear, nose and throat department in St. Olav's University Hospital in Trondheim, Norway. PMID- 21233888 TI - [My and your specialty]. PMID- 21233889 TI - The Norwegian Register for Cardiac Surgery and specialist environments. PMID- 21233892 TI - Suggested guidelines for the family medicine case report. PMID- 21233893 TI - Sick or sinner? Comment. PMID- 21233894 TI - AIDS and the Family Physician: Survey of Practices in AIDS Counselling and HIV Antibody Testing. AB - In January and February of 1988, a questionnaire was sent to family physicians affiliated with family practice teaching departments in Toronto to determine whether there was any consensus among family physicians as to which patients they counselled about AIDS and to whom they recommended antibody testing for HIV. Ninety-seven out of 126 questionnaires were answered, for a response rate of 77.0%. More than 90% of the physicians reported discussing AIDS and its prevention with patients in high-risk groups, sexual partners of such patients, and those with multiple sexual contacts. More than 90% recommended HIV antibody testing for patients in high-risk groups who requested it. For discussing AIDS with all sexually active patients, however, there was much less consensus in the reported physician practices. PMID- 21233895 TI - Family practice nurses and the telephone. AB - All nurses from four family medical centres in London, Ontario, affiliated with the University of Western Ontario's Department of Family Medicine, participated in a study to 1) determine the types, number, and management of patient problems presented over the telephone; 2) determine the time provided to patients over the telephone; and 3) determine the reactions of nurses to problems presented over the telephone. The authors developed a data sheet to record specific information about all telephone calls (total 2125) with which each participant was involved for two one-week periods one month apart. Most calls took place on Mondays, occurred during the afternoon, were initiated by the caller, and were, on average, three minutes or less in length. Prescription renewal, reassurance and support, and health teaching were the ranked order of management handled primarily by the nurse alone. PMID- 21233896 TI - HSOs, HMOs, and CHOs: The Continuing History of Capitation-Funded Health Care. AB - Ontario Health service organizations (HSOs) provide physician services funded by monthly payments per enrollee and one-third the cost of hospital days saved. They reduce hospitalization rates, but are providing less multidisciplinary care than expected. American health maintenance organizations (HMOs) provide both physicians' services and hospital care. They reduce hospitalizations, and their physicians manage greater patient loads, while patients receive equivalent ambulatory care. Comprehensive health organizations (CHOs) in Ontario provide almost all health services for their current per capita cost. Greater cost effectiveness is expected through greater use of management, deinstitutionalization, auxiliary personnel, and health promotion. Proponents of organized medicine have strong reservations about the expected results. The ethics of providing incentives (i.e., capitation) to underservice patients should also be considered. PMID- 21233897 TI - Geriatric house calls: relic of the past or challenge of the future? AB - Historically, house calls played an important role in mainstream medical practice, but since the early part of the 20th century, medical care has been increasingly focused on the acute care hospital. This focus appears to have contributed to increasing physician frustration, patient alienation, and a growing public dissatisfaction with service. The geriatric population, and in particular the frail elderly, are a unique and growing proportion of the general population, and they are also the major consumers of health care resources. Patient-oriented and professional factors point to a need for physicians to return to making more house calls. Active participation by primary care physicians in developing standards and conducting research in this area of practice is necessary. PMID- 21233898 TI - Achieving continuity of care in family medicine training. AB - While the value of continuity of medical care can be debated, colleges of family medicine and residency training programs continue to support the concept. Although teaching hospitals are a poor environment for continuity of care, faculty have a responsibility to ensure that it is taught and, just as importantly, practised in the training centres. PMID- 21233899 TI - The automated medical office. AB - With shock and surprise many physicians learned in the 1980s that they must change the way they do business. Competition for patients, increasing government regulation, and the rapidly escalating risk of litigation forces physicians to seek modern remedies in office management. The author describes a medical clinic that strives to be paperless using electronic innovation to solve the problems of medical practice management. A computer software program to automate information management in a clinic shows that practical thinking linked to advanced technology can greatly improve office efficiency. PMID- 21233900 TI - [Not Available]. AB - For the most part, doctors working in Quebec's local community service centres (or CLSCs) receive a fixed amount for their services. This type of remuneration is often associated with employee status. In the case of the CLSC doctors, however, their status is determined by the nature of their relationship with the centre's administration. It is evident from the conditions under which they practise that the CLSC doctors are not employees. Their autonomy is determined by the mission, orientation, and operation of the centre in a way that is similar to that of doctors paid on a fee-for-services basis in the province's hospital centres. PMID- 21233901 TI - 386 computer: a solution to 'computer lag' in medical practice. AB - Physicians have been quick to utilize computers in the business aspects of medical practice. The movement of computers into clinical medicine, however, especially in office practice, has been much slower. The main reason for this "computer lag" is suggested to be the inability of most computer systems to handle the numerous tasks often occurring concurrently in a medical practice. The 386 computer, with multitasking capabilities, can manage this type of information flow and could allow the entry of computers into daily office medical practice. PMID- 21233902 TI - The role of family physicians in organ donation. PMID- 21233903 TI - Surgical patients need their family doctors. AB - The author addresses the reasons family doctors should be involved in the treatment of their patients who are hospitalized. The author was hospitalized while her family doctor was on holidays. The physician's locum did not see her presence as necessary because the patient already had two surgeons in attendance. The author missed the presence of her family doctor, so she discussed the situation with the nurses and other patients. Her observations led to the writing of this article. PMID- 21233904 TI - Common diagnoses: comment. PMID- 21233905 TI - Education on emergency medicine. PMID- 21233906 TI - Primary eye care. PMID- 21233907 TI - Profile of rural physicians in alberta. AB - A questionnaire was mailed to 564 rural Alberta physicians to determine the demographic profile of practising rural physicians, to identify factors that attracted and retained physicians in rural practice, and to identify the skills that newly trained general practitioners require for rural practice. Rural-based physicians were relatively young (50% below the age of 38 years) and predominantly male (86%). Approximately 73% were general practitioners without certification by the College of Family Physicians of Canada, and 19% were family physicians with certification. Compared with the Canadian-trained physicians (56%), foreign-trained rural physicians (44%) tended to be older, to have been longer than 10 years in rural practice, and to have had more than four years of postgraduate training. The major reasons for contemplating leaving rural practice were retirement, career advancement or limited challenge, and heavy work-load. PMID- 21233908 TI - Post-partum Misery: A Family Physician's Perspective. AB - A chart audit of 106 women after delivery was undertaken consecutively to discover the extent and type of problems they encountered during the first six months after childbirth. In 34% of the charts, no complaints were noted. The most common problems were non-obstetrical infections, fatigue, and back pain, while hemorrhoids, dyspareunia, and depression were noted less often. PMID- 21233909 TI - Powassan encephalitis in new brunswick. AB - A case Powassan encephalitis was diagnosed in a 76-year-old man who had viral encephalitis. The patient had been staying at a cottage in Upper Rexton, north of Moncton, New Brunswick. No history of tick bite was elicited. Seven months after onset, the patient is much improved in his cognitive and physical functioning, but has minor memory impairment. This is the 11th case of Powassan encephalitis to be recognized in Canada and the first from New Brunswick. PMID- 21233910 TI - Information for travellers' physicians. AB - Physicians can obtain advice about international travel for their patients from many different sources of information. The authors review some of the most common sources based on their experience at the International Travellers' Clinic operated by the New Brunswick Department of Health and Community Services in Fredericton. They identify readily available handbooks and periodicals and compare two computer software programs. PMID- 21233911 TI - Before departure: advising tropical travellers. AB - Advising travellers to tropical and subtropical countries before their departure requires physician use of regularly updated information sources. The author outlines an approach to risk assessment and presents an overview of important issues and some information sources. PMID- 21233912 TI - Altitude-related illness: advice to travellers. AB - Altitude-related medical problems have received much attention in the recent medical literature. Family physicians must be knowledgeable about these problems so that they can give appropriate advice to travellers. The author, a practising family physician, discusses issues arising from both the modest cabin altitudes experienced in modern-day air travel and the greater altitudes experienced by skiers and trekkers, pilots and mountaineers, and lowland adventurers of all sorts. He reviews the process of acclimatization to altitude and the four principal forms of altitude illness. PMID- 21233913 TI - Travellers' diarrhea. AB - Travellers' diarrhea is reported to affect one-third of those journeying to the tropics. The incidence varies with the destination and risks taken by travellers. Most people are affected by the third day of travel by usually short-lived symptoms. Interest in prevention and treatment reflects the size of the problem and not the severity of the syndrome. Prevention is best achieved by dietary precautions. Prophylactic drugs should be reserved for those likely to suffer most severely or who have the greatest need to avoid symptoms. Treatment should usually be limited to fluid replacement and non-antimicrobial drugs unless circumstances are exceptional. PMID- 21233914 TI - 'Imported' sexually transmitted diseases. AB - A sexual history should be routinely obtained from all travellers. Those whose symptoms indicate a sexually transmitted disease may need to be investigated for unusual infections. Resistant strains of gonorrhea are becoming a major concern. Chancroid should be considered in the differential diagnosis of genital ulcer disease. The possiblility of human immunodeficiency virus infection should be discussed with all these patients. PMID- 21233915 TI - International approaches to otitis media. PMID- 21233916 TI - Professional autonomy in medicine comment. PMID- 21233917 TI - Discharged against medical advice: causes and consequences. AB - Patients discharged against medical advice in a rural general hospital in Alberta were studied retrospectively. The rate of discharge against medical advice (AMA) was 1.4% and was found to be comparable to the rates for other rural and urban general hospitals in central Alberta. Fifty consecutive discharges AMA were compared with 50 randomly selected adult discharges by physician during the same period. Demographic, diagnostic, and therapeutic variables were compared, and the fate of patients discharged AMA after departure was studied. A diagnosis of substance abuse or psychiatric illness discriminated significantly between the groups and accounted for apparent differences in the demographic variables. Those discharged AMA stayed for a shorter time in hospital and were noncompliant while there. PMID- 21233918 TI - Pilot survey of nursing home patients, using index of personal care activities of daily living. AB - The author describes a simple eight-item personal care index of activities of daily living (ADL) to aid in assessing the needs of patients requiring placement in a long-term care institution. Using the index, an analysis of patients in a nursing home was undertaken, comparing regular care patients with patients designated as heavy care. The results of the survey, including the ADL index and demographic and diagnostic data, are described. PMID- 21233919 TI - [Not Available]. AB - A patient's personal experience of an illness is as important as the illness itself. A patient-centred approach focuses on the patient's views and feelings concerning his health problem or illness, i.e., his beliefs, fears, his expectations, and the impact that the problem or illness is having on his life. A review of the literature by a group of researchers at the University of Western Ontario suggests that this approach results in improved patient satisfaction, observance and results. This approach can be used on a daily basis in almost all clinical situations. The results of a study on strategies used by clinicians with experience in family medicine to detect the "functional" patient are also presented. PMID- 21233920 TI - Family physicians' roles in the psychosocial well-being of refugees and immigrants. AB - Although many immigrants and refugees quickly blend into our society, many others face continuing problems as they try to learn a new language, find employment, and make friends in this new, and often perplexing, culture. The family physician can be an important contact person and source of help to these patients if he or she knows something about their special problems and needs. A large percentage of refugee and immigrant interactions with the medical profession are for other than strictly medical problems. The key to working with refugees seems to be in abandoning the "medical model" and developing an awareness of the person as an individual, learning details about his or her background, current stresses, and social supports, and in developing trust over time. PMID- 21233921 TI - Normal newborns: special problems during the first three days of life. AB - Most newborns are admitted and managed in level 1 nurseries. Hypoglycemia, polycythemia, and jitteriness are three common clinical problems of these newborns, for which the family physician may request pediatric consultation. The authors discuss the definition, incidence, etiologies, clinical features, and the current diagnostic and treatment approach of these problems. PMID- 21233922 TI - Breast-feeding among Mothers of Low Birth Weight Infants. AB - The physical and emotional condition of the mother delivering a premature or low birth weight infant may be quite different than that of the mother of a healthy term infant when initiating breast-feeding. Despite this difference, incidence and duration of lactation among mothers of pre-term or low birth weight infants was found to be quite good compared with that of mothers of term infants. Considerable problems, however, are encountered by premature or low birth weight infants when breast-feeding, including delayed first suckling, poor or no suction, need for daily supplemental bottle feeding, and culminating sometimes in weaning off breast milk before discharge. Optimal milk production has been associated with five or more milk expressions daily and with pumping durations of 100 minutes or more daily and initiation of pumping early in the first post partum days. PMID- 21233923 TI - Problem-Solving Formula for Failure to Thrive in Breast-fed Infants. AB - Failure to thrive and insufficient milk are common reasons given for terminating breast-feeding early. Mothers often doubt their natural ability to successfully suckle a young infant. This perceived inadequacy may be reinforced by health professionals who advise supplemental formula feeds to ensure rapid weight gain before an accurate diagnosis has been made. The growth of healthy infants depends on maternal milk production, milk transfer at the breasts, and the quantity and quality of milk intake by the baby. Problems with any one of these areas can present as failure to thrive. The author focuses on a diagnostic approach to failure to thrive in a breast-fed infant and outlines ways to assess maternal lactation ability, milk production, milk transfer, and milk intake. The diagnosis of failure to thrive is often simple and follows sound physiological and anatomical principles. PMID- 21233924 TI - Role of the world health organization in the promotion of breast-feeding. AB - In response to the global decline in breast-feeding initiation and duration rates, the World Health Organization has produced several documents to assist governments and health professionals to reverse the trend. The WHO International Code of Marketing of Breast-Milk Substitutes addresses the detrimental influence of promotional methods by the infant formula industry. The recent WHO/UNICEF statement Protecting, Promoting and Supporting Breast-feeding has been prepared to increase the awareness of the critical role that health services play in promoting breast-feeding. To implement these statements, health professionals must be convinced of the unequalled superiority of breast milk. Examples of benefits of breast-feeding and risks of artificial feeding are given. PMID- 21233925 TI - Immunizations in pediatrics: an update. AB - A Vaccine Evaluation Center has been established in Canada to evaluate vaccines from the developmental stage through to post-marketing surveillance. Special populations need special treatment, particularly day care attendees, children infected with HIV, immunocompromised patients, children who have had a splenectomy, premature infants, the hospitalized child, the traveller, health care workers, and pregnant women. Real and imaginary adverse reactions, their management, and their presentation are discussed. The use of acetaminophen prophylaxis to minimize the most common adverse reactions to diphtheria-pertussis tetanus-polio immunization is recommended. The most remarkable of the new developments in modern vaccines is the recombinant hepatitis B vaccine. PMID- 21233926 TI - Evaluation of Fever in a child aged three months to 24 months. AB - Fever in the young infant may be especially challenging to the attending physician, particularly when no focus for the infection can be found on physical examination. Can the physician's clinical judgement be trusted? What constitutes a fever? How was the temperature measured? Can the fever harm the child? Does the child have a benign viremia or does the fever indicate a more serious underlying bacterial illness? Does a blood culture, a spinal tap, or a complete blood count need to be done? Should antibiotics or just antipyretics be prescribed? Should antipyretics be used in all febrile children; if so, in what dose? These questions have been considered at one time or another by all physicians taking care of children. Only with a comprehensive, scientific, and practical approach can the febrile infant be optimally managed. PMID- 21233927 TI - Diaper dermatitis: differential diagnosis and management. AB - Diaper dermatitis is one of the most common dermatoses occurring in infancy. It is an irritant dermatitis, in which a variety of factors act in concert to produce inflammation of the diapered skin. The differential diagnosis includes many common and some uncommon conditions. Successful treatment requires detailed instructions to caregivers regarding simple hygienic procedures and diapering practices. PMID- 21233928 TI - 'Doctor, my son walks funny': a guide for the perplexed. AB - The primary care physician plays a critical role in reassuring parents about their child's orthopedic development in the lower extremity. Paramount to this reassurance is the ability to understand the normal and natural history of lower extremity development. Family physicians should be able to diagnose and treat metatarsus varus, internal and external tibial torsion, femoral anteversion and femoral retroversion, bow legs, knock knees, and flat feet. The chief complaint often turns out to be only a variation of normal physiological growth and development. PMID- 21233929 TI - Helping Families Manage Eating Difficulties in the Toddler and Pre-schooler. AB - Parents of toddlers and pre-schoolers often report "eating difficulties" to their family doctors. Most problems arise from a combination of the normal psychological development of children, their changing nutritional needs, and parental responses to these changes. During well child and episodic visits, family doctors can assess these issues by taking a careful nutritional history, charting growth and development, and exploring the role of the family in defining and coping with the problem. Management includes prevention through anticipatory guidance and general information, treating problems with specific suggestions, and ongoing support. PMID- 21233930 TI - Attention-deficit hyperactivity disorder. AB - The attention-deficit hyperactivity disorder is a common chronic disorder of childhood. No precise definition or approach to treatment is universally accepted; however, an extensive literature exists on which to base a rational approach to management. Symptomatic treatment with stimulant medication in selected patients is effective and safe, but not curative. Successful outcome depends on multimodality therapy, involving parents, teachers, and other professionals. Associated conditions, including learning disorders and emotional disturbance, must be identified and dealt with. PMID- 21233931 TI - Urinary tract infection in children: diagnosis and treatment. AB - The history and the physical examination are important and rewarding in the assessment of urinary tract infection in children. Urinary tract infection is usually an ascending infection; periurethral colonization is fundamental to its pathogenesis. It is important to treat predisposing factors, such as poor personal hygiene, diarrhea, and diaper rash. Parents should be specifically instructed on the proper procedures for introital and foreskin cleansing. To minimize the risk of urinary tract infection, children should be encouraged to void frequently and instructed not to hold their urine. Antibiotics should be chosen after taking into account the susceptibilities of the common bacterial pathogens and antibiotics received by the child. Consideration of the symptoms and signs of urinary tract infection is important to develop an appropriate treatment plan. PMID- 21233932 TI - Fibromyalgia: Does it Exist? AB - Fibromyalgia is a widely accepted clinical syndrome that is encountered frequently in general practice. It occurs in all age groups and is characterized by widespread rheumatism with specific tender areas, which are semi-quantifiable and are remarkable, not only for their constant presence, but also for their constant absence in areas that are typically not involved. Treatment consists of reassurance, aerobic exercise, and avoidance of prolonged medical leave. Tricyclic medications in doses subtherapeutic for depression can help, but anti inflammatory drugs alone have been disappointing. PMID- 21233933 TI - Welcome home. PMID- 21233935 TI - Third-year training positions in family medicine. PMID- 21233934 TI - Medical etiquette. PMID- 21233936 TI - Professionalism: Ethics vs etiquette. PMID- 21233937 TI - Evaluating A Graduate Studies Program: A survey of former participants. AB - To evaluate the outcome of the program for graduate studies in family medicine at the University of Western Ontario, all 45 participants in the program were surveyed. Thirty-six percent of respondents held full-time academic appointments and 42% part-time academic positions. Eighty-four percent indicated a moderate to major effect on their career as a teacher; 67% indicated a moderate to major change in research skills; 42% indicated such a change in administrative skills. Ninety-one percent said they had achieved all or most of their objective in taking the program. PMID- 21233938 TI - Family Orientation in Family Medicine Training: A survey of Canadian programs. AB - Teaching about the family has become an important part of the family medicine curriculum. The family orientation index, a 39-item questionnaire, was designed to evaluate the family orientation of services and care provided as well as the teaching and research. The questionnaire was distributed to 55 program directors at 16 Canadian universities. The response rate was 84%. The results indicate that the family orientation of services is less than optimal. PMID- 21233939 TI - Education in Sports Medicine: A resident perspective. AB - The relative frequency with which family medicine residents managed several sports-related problems, their level of comfort with each of the conditions, and the sources of information they planned to use to improve their knowledge or skills were studied. Pearson correlation analysis revealed that residents reported greater comfort with conditions they saw most often. Reading was the preferred information source regardless of the clinical problem. The choice of information source did not differ by the frequency with which the condition was seen by the resident. PMID- 21233940 TI - Riding Fletcher's Trolley: The unlikely renaissance of the generalist in modern medicine. AB - We are witness to a major change in the direction and focus of medical education and practice. After a period of fascination with increasingly specialized and technologically driven medical practice, we are moving to a more balanced view in which generalists are likely to play a greater role. We must recognize the trends in society that parallel this view and respond to the changing expectations of our patients. Training systems must reflect our understanding of this new era. PMID- 21233942 TI - Future Trends in Family Medicine: Reaching family medicine's goals in a changing world. AB - Family medicine has changed greatly within the past 50 years in response to demographic changes in Canada's population, and social and technical changes. Recent family medicine graduates are now looking to several alternative forms of practice rather than solo country practices; our educational systems should address these changes and prepare our students to meet the challenges of today's family practice. PMID- 21233941 TI - Computers in Primary Care Teaching: New software can help train residents to diagnose and treat illness. AB - Physicians have used computers for years. Although the most popular applications are billing and scheduling software, physicians are increasingly turning to the computer as a tool for medical education. Computers can teach core topics to residents in family medicine and help assess their clinical competence, can help the program director monitor the quality of the educational experience for residents, and can help physicians improve the quality of patient care. Teachers in family medicine can play a role in apprising residents of these developments. PMID- 21233943 TI - Training Physicians for the Next Decade: A new physician predicts the future. AB - Growing evidence for the impact of social and economic determinants on the health of Canadians and on current mobidity and mortality trends indicates that graduating family medicine residents lack necessary skills. Current teaching practices and clinical rotations are providing neither the context nor the critical tools that primary care providers in the 1990s will require to make a positive and lasting impact on health and disease prevention. PMID- 21233944 TI - The Science of In-Training Evaluation: Facilitating learning with qualitative research. AB - In-training evaluation requires a rigorous approach and high academic standards. Qualitative research principles can be applied to meet student, preceptor, and program needs; methods that enhance trust are helpful. Ideally the student and preceptors should collaborate to explore the student's strengths and weaknesses. While student and preceptor may not agree, the qualitative process clarifies reasons for differences of opinion. A properly performed in-training evaluation not only documents skills attained and learning needs, but also will facilitate learning during the rotation. PMID- 21233945 TI - Family Medicine in Rural Communities: The McGill experience. AB - Recruitment of physicians for rural communities is a continuing problem in Canada. Medical schools can be involved through preferential admission policies. Departments of family medicine across the country are including on-site training in rural communities and are seeking to improve their rural program curriculum. The McGill rural program is described from its origins to its present state. A rural coordinator oversees 12 sites at which both residents and students are trained. One site at Shawville, Que, is described from a rural physician's point of view. PMID- 21233946 TI - The Rural Physician as Preceptor: How rural physicians can supervise residents in a rural practice. AB - Rural family practice offers a wealth of potential clinical teaching material for family practice residents. In order to exploit this potential, the Department of Family Practice at the University of British Columbia has developed a community based program in which second-year residents in family practice spend the year in rural communities under the supervision of a family physician preceptor. This paper describes some of the problems and satisfactions facing the rural physician who is interested in becoming a preceptor and offers practical guidelines on how a resident can be incorporated into the practice. PMID- 21233947 TI - Defining The Other Solitude: Urban family practice training. AB - The changing content of urban-based family practice needs to be redefined so that appropriate family medicine training programs can be planned to meet the primary care health needs of Canada's urban-based population. Although the core content of family practice is common to both rural and urban areas, each requires specific skills and attitudes dictated by differences in patient characteristics, disease incidence, physician expectations, and professional contexts. A challenge for the future is the development of both rural-based and urban-based streams of family medicine training that will unite rather than divide the profesiion. PMID- 21233948 TI - New Frontiers in Geriatric Education: Integrated hospital and community rotation. AB - The author describes a 1-month rotation in geriatric medicine for family practice residents. Residents work at a geriatric center with day patients, residents in a home for the aged, and acute and chronic-care hospital patients, under the supervision of geriatricians, family physicians, and specialists. They then work in the office of a family physician or in an outpatient miniclinic within a senior citizen housing complex. All residents reported increased comfort with elderly patients, and many have chosen to include geriatrics in their practices. PMID- 21233949 TI - Quebec's Compulsory 2-Year Training Program: Effects on family medicine teaching. AB - The Government of Quebec promulgated regulations in June 1987 that precipitately expanded the number of family medicine residencies in Quebec while effectively abolishing the rotating internship. The authors describe the context in which the expansion took place, the problems posed for the four Quebec programs, the solutions attempted, the outcomes envisaged, and some remaining difficulties. PMID- 21233950 TI - The Impact of Expansion: One family medicine department's experience with mandatory 2-year residency programs. AB - Postgraduate training for family physicians has become increasingly centred on 2 year residency programs. The expansion of family medicine residency programs in Quebec raises challenges: to uphold program standards, to recruit and develop new teachers, to recognize and respect the needs of students, to balance program objectives with service requirements for house staff, and to adapt to change within family medicine centers and their affiliated hospitals. PMID- 21233951 TI - Effective Presentations: How you can get your message to your audience. AB - Where the purpose of presentations is to inform, effective delivery is important to ensure that audiences receive the educational message. We offer six suggestions: introduce the topic in an interesting way; speak loudly enough; do not read; involve the audience actively; respect the attention span of the audience; and limit the amount of content. We conclude that the skills of live public presentation can be learned, but that the art of presentation is innate. PMID- 21233952 TI - CFPC's Certification Examination: An overview. AB - The certification examination of the College of Family Physicians of Canada is designed to assess the extent to which the College's educational objectives have been achieved. Since the first examination in 1969, more than 7000 physicians have received their certification. The authors describe the basic elements of this test and the process through which the Committee on Examinations designs and sets the examination. The authors comment on the role of the certification process in the education of family physicians in Canada. PMID- 21233954 TI - Easily Missed Fractures in Children: How you can recognize hidden fractures. PMID- 21233953 TI - How to write an Effective Curriculum Vitae: Making the most of your asstes. PMID- 21233955 TI - Role of the family physician in treatment of cancer. PMID- 21233956 TI - Medifacts tapes and advertising. PMID- 21233957 TI - Alert for eosinophilia-myalgia syndrome. PMID- 21233958 TI - Intravenous fluids and the hospitalized dying: a medical last rite? AB - The authors examined charts for evidence of the use of intravenous fluids in all patients who died from malignant disease occurring in a tertiary care teaching hospital during a one-year period. Of 106 patients who were identified, 86 received intravenous fluids within their last 30 days of life, and 73 died with an intravenous line running.Intravenous fluid use appeared to be independent of age, sex, language, presence of family members, primary tumour site, presence of metastases, duration of illness, and presence of a "no cardiopulmonary resuscitation" order. Total lengths of stay and survival time after obtaining "do not resuscitate" orders were longer in those who died without intravenous fluids. More than two-thirds of patients with cancer who died in hospital did so with an intravenous line. PMID- 21233959 TI - Pharmacological treatment of depression in the elderly. AB - The author systematically reviewed the literature on primary clinical trials of pharmacological treatments of depression in elderly. Studies published between 1978 and 1988 were critically assessed and summarized. She considers the findings of selected studies and discusses conflicts in research findings and possible reasons for differences. The clinical implications of these findings and suggestions for further research are outlined. PMID- 21233960 TI - Prospective care of elderly patients in family practice part 1: health maintenance for the elderly. AB - The author examines Canadian demographic data that underline the urgency of planning future services for the elderly. "Health" of the elderly is defined as not simply the absence of infirmity, but rather the ability to function and maintain quality of life. The components of a health maintenance plan are discussed, as well as some of the practical and political issues that must be dealt with for such a program to be fully effective. PMID- 21233962 TI - Observations from since daisy creek. PMID- 21233961 TI - Aminophylline infusion in acute severe asthma: where do we go from here? AB - The authors critically appraised the literature according to study design, patient characteristics, and the outcome measures used. Well-designed studies suggest that aminophylline is not an appropriate first-line medication for acute asthma. The literature does not clearly indicate whether aminophylline is an appropriate second-line medication. A telephone survey of full-time emergency physicians, conducted to determine current practice, suggests that full-time emergency physicians add aminophylline to their treatment protocol more often than not (60.9%) when patients have not improved after two salbutamol nebulizer treatments. PMID- 21233963 TI - Changing epidemiology of cancer. AB - At current rates, approximately one in three Canadians will develop cancer, and one in four will die from it. For each sex, three cancer sites account for more than 50% of all new diagnoses and cancer deaths, these being lung, prostate, and colorectum in men and breast, colorectum, and lung in women. Although the total numbers of new cases and cancer deaths have risen, the overall cancer incidence and mortality rates have increased only slightly. The ranking of specific sites have changed, however; most notably, lung cancer has moved from the fifth to the second most common site of cancer death in women since 1970. The authors review trends in cancer incidence and mortality in Canada. Changes in lifestyle and behaviour could reduce cancer incidence and mortality. PMID- 21233964 TI - Fecal occult blood screening for colorectal cancer. AB - Fecal occult blood testing with guaiac gum is a simple, safe, and cheap method for screening for colorectal cancer. In the office setting, compliance is good. Asymptomatic colorectal cancers are detected at a more favourable pathologic stage than those detected in symptomatic patients. Because of the low positive predictive value of the test, many persons testing positive undergo unnecessary bowel examinations. As yet, randomized controlled studies have not shown that fecal occult blood screening reduces mortality from colorectal cancer. At present, screening with this test is left to the judgement of the individual physician. PMID- 21233965 TI - Epidemiology of smoking-related malignancies. AB - It is well known that tobacco use is the major single cause of cancer mortality. Cigarette smokers have increased risk for cancer of the lung, bladder, oral cavity and pharynx, pancreas, kidney, larynx, and esophagus. Although smoking is the primary risk factor for several of the malignancies, each tumour site has other known or suspected risk factors. The author describes the smoking association for each tumour site and reviews other risk factors for these smoking related malignancies. PMID- 21233966 TI - Early cervical neoplasia: treatment methods. AB - Cervical cancer screening programs have been one of the most important developments in women's health care during the past 50 years. Sound knowledge of the principles and techniques for taking Papanicolaou smears, interpreting results, and investigating abnormalities detected are essential skills for individuals providing primary health care to women. The author briefly reviews the current investigatory methods and the common treatments for cervical intraepithelial neoplasia and early invasive cancer of the cervix. PMID- 21233967 TI - Advances in diagnosis and management of prostate cancer. AB - Carcinoma of the prostate accounts for 17% of malignancies in men. Great strides have been made in the understanding of the biology and natural history of this disease. It is clear that earlier diagnosis of the clinical carcinoma will improve overall disease-specific survival rates. The author reviews the diagnostic techniques and advances in management of localized and metastatic disease. PMID- 21233968 TI - Prognosis of common cancers. AB - Four cancers in each sex account for nearly 60% of all cases. Lung cancer therapy is stymied by a lack of effective agents, but can be prevented by a smoking cessation program. Breast cancer is far too prevalent, but has the best response rate to drugs and the best palliation of any of these tumours. Prostate cancer, once androgen deprivation has failed, is untreatable. Colorectal cancer therapy after years of inactivity is now exciting, while pancreas cancer remains almost untreatable. All Canadian patients should be encouraged to participate in clinical trials when appropriate. PMID- 21233969 TI - Lung cancer in the 1990s. AB - The author reviews the investigation and staging of patients with lung cancer. Surgical, radiotherapy, and chemotherapy roles in management of non-small cell lung cancer and small cell lung cancer are discussed. The author concludes with practical guidelines for screening and prevention by family physicians. PMID- 21233970 TI - Constipation: a frequent iatrogenic complication in cancer patients receiving narcotics. AB - Many patients who are receiving opiates develop a problem with constipation. Constipation can be prevented in most patients who are receiving narcotics by judicious and routine use of laxatives contributing to the comfort of the patients. In general the responsibility for bowel management is delegated to the nursing staff, but joint responsibility between the nursing and medical staff is recommended. The author defines constipation, highlights its incidence, and gives a short overview of its numerous causes, including the effects of narcotics on the gut. He suggests a protocol for bowel management, lists the different types of laxatives, and discusses rectal measures, such as suppositories, enemas, and manual disimpaction. A stepladder approach, which has proven to be effective and simple, is outlined. PMID- 21233971 TI - Diet and cancer. AB - Most of the common cancers in Canada have been associated in some way with diet. More than half of all newly diagnosed cancers and cancer-related deaths are limited to three sites in each sex: lung, prostate, and colorectum in men and breast, colorectum, and lung in women. The earliest and strongest epidemiologic evidence associating diet and cancer has come from descriptive correlation studies. The findings of subsequent, more powerful, analytic studies have been inconsistent. The author reviews the importance of diet for common cancers in Canada and considers the methodologic limitations of various study designs. PMID- 21233972 TI - Comforts of home: home care of the terminally ill. AB - When a terminal illness is diagnosed, it is appropriate for the family physician to take a primary role in future management. Care goals change from being disease focused and cure-directed to being person-focused and comfort-targeted. The patient and family comprise the unit of care. Care of the terminally ill in the home requires good planning, teamwork, excellent symptom management, and a commitment by the family physician to be available or provide alternate coverage. Death in the home should be an option for the patient and family whenever feasible. Caring for patients until death and supporting their families and friends are rewarding and positive parts of family practice. PMID- 21233973 TI - The many faces of lupus. AB - Systemic lupus erythematosus is a multisystem disorder that presents itself in several different ways. Arthritis, dermatitis, nephritis, and pleuropericarditis are the most common features initially. Various hematologic and neuropsychiatric manifestations are also seen during the course of the disease. Anti-nuclear antibodies are the hallmark of lupus but are nonspecific and detectable in many other disorders. Once the diagnosis is established, the severity of the disease needs to be determined, in particular the extent of major organ involvement. The level of disease activity should be repeatedly estimated using clinical and laboratory parameters. Therapeutic decisions are based on disease severity and activity. Aggressive suppression of major organ inflammation and reduction of long-term toxicity are the main goals of therapy. PMID- 21233974 TI - Psychosocial aspects of rheumatic diseases. AB - Chronic diseases have major effects on all aspects of a person's life. The physician should be aware of the psychosocial issues and responses commonly occurring during the course of chronic rheumatic disease. Management strategies are designed to help the patient and family cope successfully with the effects of the disease. Children with arthritis and their families present special problems in attaining their full potentials as they grow up. Compliance with treatment can be improved by education. A team approach involving physicians, allied health professionals, the patient, and the family is desirable for an optimal outcome. PMID- 21233976 TI - Moments that Make It All Worthwhile. PMID- 21233975 TI - Is british general practice dead? PMID- 21233977 TI - Episiotomy in low-risk deliveries: physician factors. AB - From 376 randomly selected nulliparous women who delivered at the Grace Hospital in 1986, we selected 133 low-risk women and performed a retrospective chart review to ascertain the episiotomy rate for physicians by sex, years since graduation, and specialty status. There was a statistically significant difference between the rate for specialists (65%) and general practitioners (38%). A non-significant difference was found between male physicians (41%) and female physicians (56%) and between physicians who had graduated within 15 years (42%) and those who graduated more than 15 years ago (52%). Subgroup analysis of the general practitioner data revealed different patterns for male and female physicians according to their graduation cohort. PMID- 21233978 TI - Maternal concerns: what are they? AB - If one strives to provide care for the mother as a person adjusting to a major life change, then one needs to know more about the particular concerns of mothers of newborns. Open-ended interviews with mothers of newborns provided a list of basic concerns, which was then used to create a self-administered check-list. Eighty-four mothers of newborns revealed that their top three concerns were "feeling exhausted," "amount of time as a couple," and "body weight." These concerns were similar for many subgroups of mothers except when the babies were older than 10 weeks of age. Paradoxically, physicians and nurses providing post partum care are not seen as sources of help for any of the 10 most frequent concerns reported by the mothers. PMID- 21233979 TI - Short course in psychiatric emergencies and crisis intervention. AB - Faculty of the Discipline of Family Medicine at Memorial University of Newfoundland saw a need to improve the teaching to residents in the management of psychiatric emergencies and in crisis intervention. A short course, entitled "Psychiatric Emergencies and Crisis Intervention" (PEACI), was developed around the common psychiatric emergencies that family physicians encounter. The elements of this course included a pre-test and post-test, selected reading for independent study, lectures and seminars, simulated patient encounters, debriefing sessions, and evaluation. Most of the residents rated the course as "very good" or "excellent" and wished to repeat the course in a year's time. PMID- 21233980 TI - Professional autonomy in medicine. PMID- 21233981 TI - Prospective care of elderly patients in family practice part 2: is screening worthwhile? AB - In 1980-1981, the elderly accounted for 48% of patient days in general hospitals in Canada and 72% of those using long-term care facilities. This use is disproportionately generated by those 85 years of age and older and by patients in areas where beds are more readily available and community support services relatively absent. The author critically reviews the literature and describes the efficacy and efficiency of screening and case-finding programs for the elderly. The best evidence from four randomized trials indicates that screening and case finding is effective in reducing disability, promoting independence, and improving morale and functional capacity, while reducing the use of hospital beds. PMID- 21233982 TI - Neonatal Cardio-pulmonary Arrest: Emergency Catheterization of Umbilical Vein. AB - In an emergency, the physician responsible for neonatal care must be skilled in umbilical catheterization. Several drugs can be given through an endotracheal tube, but some require intravenous administration. The umbilical vein is a better route of administration than peripheral veins because it is easily located and can be entered readily. It allows immediate access to the central circulation, enhancing drug distribution. The authors outline the procedure in a step-by-step description. This pictorial article can be used as a handy reference by physicians needing to administer fluids and drugs during cardio-pulmonary arrest in neonates. PMID- 21233983 TI - Intrapartum hemorrhage. AB - Intrapartum hemorrhage complicates about 5% of all deliveries. Cases can be classified according to the time bleeding begins: before or after delivery of the infant. The author outlines the causes, clinical presentation, and methods of management. PMID- 21233984 TI - Monoamine oxidase inhibitors: clinical review. AB - Monoamine oxidase inhibitors (MAOIs) are effective antidepressant agents. They are increasingly and effectively used in a number of other psychiatric and non psychiatric medical syndromes. Their potential for serious toxicity (i.e., hypertensive reaction) is far less than original reports suggest, and newer reversible substrate-specific MAOIs may offer even less toxicity. The author reviews the pharmacology, mechanism of action, clinical indications, and dosing strategies of MAOIs. The common MAOI side-effects (hypotension, weight gain, sexual dysfunction, insomnia, daytime sedation, myoclonus, and hypertensive episodes) are described and management techniques suggested. Recent clinical developments involving MAOIs are outlined. PMID- 21233985 TI - Stuttering: current status of theory and therapy. AB - When people become concerned about stuttering, either their own or their child's, they typically seek help from their family physician or pediatrician. Characteristics and effects of stuttering can help the physician determine whether the child's speech patterns are within normal range or could be early warning signs of stuttering. Referral to a speech-language pathologist should be considered when any of the following are noted: excessive part-word repetitions or sound prolongations; signs of tension, such as lip tremors, facial grimaces, or breath holding associated with speech; indications of embarrassment or apprehension; and a tendency to withdraw from speech opportunities. The authors briefly review theories on the causes of stuttering, describe current therapy, and identify some specialized treatment centres. PMID- 21233986 TI - Seasonal affective disorder. AB - Seasonal affective disorder (SAD) is a recently described mood disorder characterized by recurrent winter depressive episodes and summer remissions. The symptoms of SAD include DSM III-R criteria for recurrent major depression, but atypical depressive symptoms predominate with hypersomnia, hyperphagia and carbohydrate craving, and anergia. Seasonal affective disorder is effectively treated by exposure to bright light (phototherapy or light therapy), a novel antidepressant treatment. The authors review the syndrome of SAD, hypotheses about its pathophysiology, and the use of phototherapy to treat the disorder. PMID- 21233987 TI - Diagnosis and management of acute knee ligament injuries. AB - Knee ligament injuries are a common problem, especially in the athletic age group. The most common knee ligament injury is the so-called isolated anterior cruciate ligament tear. This is also the injury most likely to be missed. Isolated collateral ligament tears are generally managed non-operatively, but combined collateral and cruciate tears should be surgically repaired. "Isolated" anterior cruciate tears are generally repaired in the younger active athlete but are managed by hamstring exercises in the older individual. Isolated posterior cruciate ligament tears are managed non-operatively unless a bony avulsion is present. PMID- 21233988 TI - Chronic back pain: assessing the patient at risk. AB - Pain in the lower back is a growing and costly problem. A simple, effective diagnosis can usually be provided by the family physician, based on a clinical history, especially regarding the circumstances surrounding an injury, and physical examination. Work-related risk factors implicated in the cause of the disorder are also important. Spinal X-ray examinations are of little value in diagnosis during the acute stage of low back pain. Chronic cases can be avoided by appropriate early treatment: a short period of analgesia and rest, followed by education about the back, a graduated exercise program, and if the clinical condition is stable or improving, early return to a modified level of work, even in the presence of symptoms. PMID- 21233989 TI - Functional somatic symptoms: family practice perspective. AB - Functional symptoms are a common and at times irritating part of family practice. The expedient way of dealing with these patients is to investigate, prescribe, and reassure that nothing serious is wrong. This reassurance may not be convincing to the patient whose symptom persists. The author reviews the main issues in this field and describes a subset of patients who seem to have identification as the basis for their functional symptom. When cases are of short term, this subset can be handled by the family physician who is aware of the logic behind the functional symptoms in certain cases. An understanding of functional symptoms and a belief in their logic are important dimensions of comprehensive care in family practice. PMID- 21233990 TI - Multiple sleep pathologies presenting as depression. AB - Successful management of patients with sleep disorders requires attention to the clinical history, particularly the sleep history, knowledge of the causes of insomnia and hypersomnia, and familiarity with a variety of therapeutic interventions. To illustrate these principles, the authors describe a 68-year-old woman who had a history of clinical depression but who, on further investigation, was found to suffer from three sleep disorders: narcolepsy, periodic leg movements during sleep, and rapid eye movement sleep behaviour disorder. Treatment of these sleep disorders caused a complete amelioration of the mood symptoms and a significant improvement in psychosocial functioning and well being. PMID- 21233991 TI - Changing ideas in intrapartum care. PMID- 21233992 TI - Diapers: what do parents choose and why? AB - Self-administered questionnaires about diaper choices and the reasons for such choices were completed by 600 parents of children younger than two years of age attending a hospital walk-in clinic or the private office of one of four pediatricians. Only 2.7% of the parents used cloth alone; another 15% used both cloth and disposable diapers; a further 18% reported having used cloth at some time. Convenience and rash prevention were reasons for choosing disposable diapers. Those who used only cloth washed at home cited cost and rash prevention. Those who used cloth diapers from a service cited convenience and rash prevention. Only 10% of parents received advice about diapers from their physicians, but 70% said they would follow such advice. Primary care providers can point out to parents that disposable diapers are more costly and present environmental concerns. PMID- 21233993 TI - Physician-Patient Interaction: A Reliable and Valid Check-list of Quality. AB - A 21-item check-list is presented that evaluates the quality of the medical interview, focusing on politeness, respect, and communication. Twenty-eight interviews conducted by family medicine residents were videotaped. Using the check-list, four teachers as well as the resident evaluated each interview. Reliability and content validity were demonstrated. This list is easy to use and may enhance the learning of interviewing skills by giving objective feedback to the resident. PMID- 21233994 TI - Babes in the woods: teaching the use of the vacuum extractor. AB - Many family physicians in North America have been trained to use forceps when instrumental deliveries are needed; few have been trained to use the vacuum extractor. Vacuum extraction was introduced to family physicians in a geographically isolated hospital. A retrospective chart audit of all instrumental deliveries was done, comparing the four years before the vacuum extractor was introduced with the subsequent four years. Vacuum extraction quickly became the most common form of instrumental delivery and was associated with a lower maternal complication rate than the use of forceps. Fetal complications were infrequent in both groups. A questionnaire was administered to all family physicians practising obstetrics at the hospital after the introduction of the vacuum extractor. Those exposed to the vacuum extractor were enthusiastic about it. PMID- 21233996 TI - Critical appraisal of medical literature: second update. AB - This skill-testing exercise was created for the purpose of updating the teaching package, Critical Appraisal Package: Therapy, published by the College of Family Physicians of Canada in 1986. This exercise follows the same format as the original package: presentation of a clinical scenario, an article, a worksheet, and methodology notes. The article being evaluated concerns the effectiveness of antihistamine decongestants in the prevention of acute otitis media in children with colds. PMID- 21233995 TI - Influence of perinatal asphyxia on neurologic outcome: consequences for family practice accoucheurs. AB - Inappropriate concern with perinatal asphyxia, based on false notions about causes, may be behind the decision of some family physicians to avoid obstetrics. Asphyxia can cause motor or mental deficits, but only if the insult was severe and prolonged (when there will be evidence of hypoxia in systems other than the CNS). Even abnormal CNS signs do not necessarily reflect clinically important neurologic damage. Intrapartum care has much less impact on neonatal outcome than previously believed, and most bad outcomes have their origins in events occuring long before the onset of labour and outside the detection capabilities of current technology. Nevertheless, family physicians require resuscitation skills because vigorous, effective management of even very hypoxic neonates can improve and normalize outcome. PMID- 21233997 TI - An antihistamine decongestant in the prevention of acute otitis media in children with colds. AB - Most clinical drug trials relating to acute otitis media have evaluated medications in terms of treatment. In this randomized double-blind, cross-over study, the effectiveness of an antihistamine decongestant in the prevention of AOM was investigated, rather than the treatment. The medication/placebo was started at the onset of a cold and continued throughout its duration. No treatment effect was evident in the results obtained with 308 children who completed the eight-month study. However, the results indicated a strong relationship between colds and AOM, and a trend toward higher occurrence of AOM in children under four years of age. PMID- 21233998 TI - [Not Available]. AB - With the increasing expenditure on health care programs for seniors, there is an urgent need to evaluate such programs. The Measurement Iterative Loop is a tool that can provide both health administrators and health researchers with a method of evaluation of existing programs and identification of gaps in knowledge, and forms a rational basis for health-care policy decisions. In this article, the Loop is applied to one common problem of the elderly: dementia. PMID- 21233999 TI - [Not Available]. AB - General practice and out-patient emergency records for a five-year period were reviewed for injuries and illnesses that occurred during the week of deer rifle hunting on Manitoulin Island. Of 65 hunters who were identified, most had lacerations secondary to knife injuries. There were two deaths (one shooting and one in a motor vehicle accident), and 19 persons required hospitalization. More than half of these serious accidents occurred on the weekends immediately preceding or following the hunting season. Incidence of injury or illness requiring medical attention was calculated to be 0.23% per hunter each week of the deer season. Spot checks for alcohol and improved hunter safety courses might prevent many of these injuries and illnesses. PMID- 21234000 TI - Benzodiazepines: dependence and a therapeutic approach to gradual withdrawal. AB - The extensive use of benzodiazepines in the treatment of anxiety and insomnia has led clinicians to wonder about the dependence potential of these drugs. It is estimated that, in Canada, the United States, and western Europe, between 10% and 20% of the population take tranquilizers or hypnotics (mainly benzodiazepines). Of these, 70% are 50 years of age or older; 15% have been taking these drugs for more than 12 months. One researcher reported that 50% of patients who received a prescription for benzodiazepines renewed it without consulting their physician. In this article, the authors briefly review the concept of dependence, the risk factors, and the clinical signs of a benzodiazepine withdrawal syndrome. They then develop a rational therapeutic approach to make it easier to discontinue these drugs. PMID- 21234001 TI - Managing diabetes mellitus in children and adolescents: some guidelines for family physicians. AB - Insulin-dependent diabetes mellitus is a relatively common condition affecting children and adolescents. Successful management from the time of diagnosis can help prevent chronic complications of diabetes. This article reviews initial and follow-up management of diabetes in children. Guidelines for management during the remission phase, exercise, hypoglycemia, and illness, and the problems of recurrent ketoacidosis management in adolescence are discussed. The keys to successful management of diabetes mellitus in children and adolescents are patient and family education, continued support and encouragement, and early detection of and counselling for the dysfunctional family. PMID- 21234002 TI - The diabetic foot. AB - The diabetic foot presents a complex interplay of neuropathic, macrovascular, and microvascular disease on an abnormal metabolic background, complicated by an increased susceptibility to mechanical, thermal, and chemical injury and decreased healing ability. The abnormalities of diabetes, once present, are not curable. But most severe foot abnormalities in the diabetic are due to neglect of injury and are mostly preventable. The physician must ensure that the diabetic patient learns the principles of good foot care. If time for teaching is limited, this task must be delegated to a podiatrist or a diabetes nurse educator in a diabetes day centre. It is the physician's responsibility to confirm foot care by personal inspection of the feet of all diabetic patients at every visit. PMID- 21234003 TI - Thyroid tests: guide for primary care physicians. AB - Recent advances in thyroid testing have simplified the approach to the screening and diagnosis of thyroid disorders. The metabolic state is best determined by the serum free thyroxine and a sensitive assay for serum thyroid-stimulating hormone. The presence and nature of a goitre is assessed by clinical examination and, in the case of nodular thyroid disease, this examination can be supplemented by pertechnetate isotope scanning, ultrasonography, or fine needle aspiration biopsy. In most patients, these tests will identify the presence of and provide a guide to the diagnosis of thyroid disease. There is little need for radioactive iodine studies for diagnostic purposes. PMID- 21234004 TI - Evaluation of the child with short stature. AB - The author reviews the various causes of short stature in childhood. The different patterns of growth seen with each of these conditions are emphasized, as an understanding of these patterns is essential to diagnosis. Short stature is a frequent finding in childhood, with endocrine causes being relatively rare. PMID- 21234005 TI - Congenital hypothyroidism and goitre in childhood. AB - The problems of congenital hypothyroidism and goitre are relatively common in childhood. The investigation and treatment of these disorders requires a knowledge of their various causes, appropriate investigation, and referral for specialist consultation as necessary, as well as involvement of the family physician in the monitoring of effectiveness of and compliance with treatment. Many of these disorders have life-long implications for the individual affected. PMID- 21234006 TI - Treating the treatment: toxicity of cancer chemotherapy. AB - Many cancer chemotherapeutic agents can produce toxicity, even at the usual therapeutic doses. Family physicians are often called upon to treat symptoms of these toxicities and to advise patients about them. This brief discussion may help family physicians to anticipate some of the problems, to avoid some, and to manage others more effectively. PMID- 21234007 TI - Long-Term Follow up of Cancer Patients. AB - The long-term follow up of cancer patients should be based on the natural history of the disease and its known recurrence rates, patterns, and timing. Information from follow-up trials should be used in the context of diagnostic capabilities and practice setting. The increased involvement of family practitioners in the follow up of cancer patients is desirable, and some recommendations for follow-up procedures are presented. PMID- 21234008 TI - Coping with humour. PMID- 21234009 TI - Cholesterol: controversy and confusion. PMID- 21234010 TI - Primary Eye Care: Are We Giving it Away? PMID- 21234011 TI - Unique perspective of family practice. PMID- 21234012 TI - Flexible sigmoidoscopy: comment. PMID- 21234013 TI - Physician information package available. PMID- 21234014 TI - Testing immigrant physicians. PMID- 21234015 TI - Disposable infuser. PMID- 21234016 TI - Barriers to prevention: physician perceptions of ideal versus actual practices in reducing cardiovascular risk. AB - We conducted a study to explore physician perceptions of factors that facilitate or inhibit the integration of preventive activities into primary care, particularly regarding the reduction of cardiovascular risk. Fifty randomly selected family physicians practising in the Maritimes were interviewed. Physicians described both ideal and actual practice in relation to reducing high blood pressure, reducing elevated serum cholesterol, and helping patients quit smoking. Perceived barriers related to 1) knowledge, attitudes, and perceptions (e.g., lack of counselling skills, lack of belief in the efficacy of the activities); 2) conditions in which the activities occur (e.g., lack of available and accessible referral, lack of time); and 3) reactions of others to the activities (e.g., lack of patient compliance). PMID- 21234017 TI - Knowledge and Attitudes of Physicians about Lipids. AB - A sample of 323 physicians from Edmonton, Alberta, was surveyed to evaluate their attitudes and knowledge level concerning heart disease and lipids. Of the sample, 117 physicians returned the questionnaire. When asked to choose significant risk factors of cardiovascular disease, 69% of the physicians indicated hypertension; 85% indicated smoking; and 87% indicated elevated serum cholesterol. Concerning the minimal low-density lipoprotein level that warrants treatment, 82% of the general practitioners and 50% of the specialists indicated that 4.2 mmol/L was the minimal level. This is in contrast to the level of 3.4 mmol/L for low-density lipoprotein recommended by the Canadian Consensus Conference on Cholesterol as the level at which treatment should be initiated. PMID- 21234018 TI - Dietary guidelines for prevention of cancer: are they justified? AB - Although dietary guidelines for reduction of cancer risk have been issued and well publicized, there is still controversy within the scientific community about whether such guidelines are appropriate. Given that the scientific evidence of a causal role for diet in carcinogenesis is suggestive but not conclusive, is it more responsible to promulgate guidelines that might be ineffective or to delay communicating findings to the public until all the evidence is in-a process that could take decades? Because the public is already familiar with guidelines intended to minimize the risk of cancer, how should they be promoted by health professionals given the strength of the evidence on which they are based? PMID- 21234019 TI - Cholesterol screening: introducing new technology from the ontario task force on the use and provision of medical services. AB - The Ontario Task Force on the Use and Provision of Medical Services has recognized an opportunity in the confusion resulting from discrepancies in the recommendations between the Canadian Task Force on the Periodic Health Examination and the Canadian Consensus Conference on Cholesterol. The Task Force has attempted to clarify some of the issues on dietary cholesterol and elevated serum levels for the practising physician and to assess the formulation and dissemination of guidelines on how to use new technology. The Toronto Working Group on Cholesterol was commissioned by the Task Force to conduct a critical review of the current evidence and to delineate the defensible parameters for clinical policy in this field. The voluntary guidelines produced from this process were then disseminated to physicians in Ontario. PMID- 21234021 TI - Office Ophthalmology: What is Urgent? AB - The author describes eye problems in general practice, from problems appearing in neonates to those in the elderly. Refractive problems are most common. Visually threatening eye disease that requires urgent treatment or referral is important, despite its rarity. Early detection and treatment of amblyopia is important in children. In diabetic retinopathy, a potentially blinding disease, maculopathy and proliferative retinopathy require immediate referral. Chronic simple glaucoma and cataracts cause gradual loss of vision in the older adult. Sudden loss of vision can be caused by optic neuritis, which is occasionally the first sign of multiple sclerosis. Retinal artery and retinal vein thrombosis are more common in older individuals with vascular disease. One of the most common causes of gradual visual loss in the elderly is senile macular degeneration. PMID- 21234020 TI - Bicycle helmet use in Ottawa. AB - A survey of cyclists was conducted in Ottawa in September 1988 to determine the use of protective helmets. The survey observed 1963 cyclists, of whom 211 (10.7%) wore helmets. The highest level of helmet use was found among older, commuting cyclists (17.9%), followed by recreational cyclists (14.3%). Overall helmet use among students was found to be very low (1.9%), and differed significantly (p < 0.0001) from the other two groups, which consisted almost entirely of adults. When the student population was subdivided, helmet use was found to be 3% among university and college students, 1.9% among high school students, and 0.8% among elementary school students. The authors conclude that children and young adults are the least likely groups to wear helmets while cycling. The five to 19 age group, however, suffer the most cycling injuries, particularly head injuries. PMID- 21234022 TI - Amblyopia and strabismus. AB - Strabismus and amblyopia, two of the most common problems in children's vision, can be prevented only by early recognition, diagnosis, and treatment. Strabismus, a misalignment of the eyes that causes one eye to deviate from its normal position, is the most common cause of amblyopia. Amblyopia is impaired vision in one eye caused by disuse. The author describes diagnostic tests, common causes, and frequently used treatment for both conditions. PMID- 21234023 TI - Abnormalities of the optic fundus. AB - Common abnormalities of the optic fundus are illustrated in this article. The authors provide brief clinical descriptions and discuss a test used to screen for a shallow anterior chamber of the eye before dilating the pupil. PMID- 21234024 TI - Management and diagnosis of glaucoma for the family physician. AB - Glaucoma, from whatever cause, is a relatively common affliction, characterized by a progressive unremitting course. The optic neuropathy frequently is asymptomatic. The goal of treatment is to halt progression because a cure is unavailable for many patients. A significant number of patients will have a visual deficit that will qualify them for blind registration. Early detection is therefore important. The family physician is in a unique position to oversee the processes of detection and management. PMID- 21234025 TI - Clinical assessment, diagnosis, and management of the cornea. AB - The cornea should be examined carefully during any ocular examination. Certain simple procedures can aid diagnosis and help the physician choose easy therapy to prevent changes in the patient's vision that can result in blindness. The use of good lighting and magnification is mandatory for better diagnosis. Corneal epithelial defects can be better defined with fluorescein staining. PMID- 21234026 TI - Modern concepts of tonsillectomy. AB - Tonsillectomy and adenoidectomy is still the most commonly performed surgical procedure in North America. The indications for surgery are constantly debated and seem to vary subjectively. The merits of performing a tonsillectomy for what is an essentially benign condition must be taken in perspective and require a more scientific approach. It is important to understand the pathophysiology of Waldeyer's ring and the changes brought about by recurring infections in the region. Treatment protocols vary, as do physician attitudes. Many tonsillectomies are still performed by surgeons other than otolaryngologists: for example, by family physicians and general surgeons. The authors discuss the indications and the scientific basic for tonsillectomy. PMID- 21234027 TI - Chronic sinusitis. AB - Paranasal sinuses, which communicate with the nasal passages through the sinus ostia, are essentially sterile structures, sterility being maintained by a healthy epithelium with normal actively beating cilia. Irritants, including viruses and bacteria, are trapped in mucus and cilia to allow the clearance of sinuses through the natural ostia into the nasal cavity. Interference with this normal physiological function results in inflammation and infection within the sinus cavities. All of the sinuses are subjected to the same environmental as well as physiological stimuli; thus it is uncommon for a single sinus to be infected and for the others to remain entirely normal. Allergic and non-allergic vasomotor rhinitis should be differentiated from chronic bacterial rhinosinusitis. The understanding of these diseases cannot be separated from the physiological function of the sinus mucosa. PMID- 21234028 TI - Epistaxis. AB - Good equipment, readily available, and organized management are essential for successful control of epistaxis without exacerbating the patient's trauma. Epistaxis most commonly results from localized causes but can reflect systemic disease. The author describes practical management of epistaxis, particularly for acute problems in the emergency room. PMID- 21234029 TI - Profile of your geriatric patient. AB - The family doctor cares for many geriatric patients. Many of these patients enter the family practice for the first time, having either recently moved to the area or to a nearby long-term care facility. Obtaining a meaningful patient profile is essential to the physicians' care, allowing future medical decisions to be made in the best interest of that person. Patients' beliefs motivate their functioning in a system. Any system has its own history, structure, and function. PMID- 21234030 TI - After-hours Care: Where is your Family Doctor? PMID- 21234031 TI - Exercise after myocardial infarction: comment. PMID- 21234032 TI - Neonatal resuscitation: comment. PMID- 21234033 TI - Midwifery in ontario. PMID- 21234035 TI - Ecologic implications of beef consumption. PMID- 21234034 TI - Resident training in northern communities. PMID- 21234036 TI - Nerves and nostalgia: expression of loss among greek immigrants in montreal. AB - The authors interviewed first-generation Greek immigrant women in Montreal about nonspecific somatic symptoms. The concept of nevra (nerves), which was central to these discussions, was used to link environmental and psychosocial variables with distress and painful physical states. The authors discuss the cultural construction of female identity in Greece and analyze the negative effect of immigration on self-esteem, often manifested as attacks of nevra. Metaphorical concepts, such as nevra, can be used to improve physician understanding and to facilitate communication with, and enhance care of, immigrant patients. PMID- 21234037 TI - Perceived learning needs of family physicians in british columbia. AB - To determine family physicians' preferences for time, location, instructional format, and topics, the Division of Continuing Medical Education at the University of British Columbia conducted a survey, in which 1200 questionnaires were mailed to a stratified, proportional random sample of the 3270 general practitioners in the province, the stratifications being urban or rural and decade of graduation. A return rate of 61% yielded 648 usable questionnaires, which exceeds the sample required for analysis with no stratifications. Most popular days for involvement in continuing medical education were Fridays and Saturdays in the months of February, March, October, and November. Common skin disorders and hypertension headed the list of most relevant topics for the whole group and for the urban stratification. Hypertension was superseded by eye emergencies in the rural stratification. PMID- 21234038 TI - [Not Available]. AB - Various authors have suggested the possibility of a link between biological age and sexual activity. Zelnick (1981) described the relationship between sexual activity and age at menarche. To determine the relationship between biological age and age at first sexual intercourse, we presented a questionnaire to 450 students attending a comprehensive secondary school in Montreal. Age at menarche and age at first conscious ejaculation were used to measure biological age. A partial correlation was made between biological age and age at first sexual intercourse by controlling for chronological age. The results were r = 0.24 (p <0.029) for female students and r = 0.21 (p <0.08) for male students. The value of the correlation was weak but significant where the female students were concerned. For the male students, the value of the correlation could not be determined due to the insufficient number of respondents. Biological age would appear to be an indicator of the age at which sexual activity first occurs. This indicator could be used by clinicians directly, and to develop a more general model for determining the age at which sexual activity first occurs. PMID- 21234039 TI - Hysteria and conversion in the ojibway patient: cross-cultural psychiatry for the family physician. AB - Case examples of hysterical coma and paralysis in two Ojibway patients are used to introduce a discussion of conversion symptoms. Somatoform disorders are described using the criteria of the Diagnostic and Statistical Manual of Mental Disorders, third edition; these are then applied to hysteria in the Native American patient. The authors discuss the cultural context of conversion symptoms in this population and describe guidelines for the provision of culturally sensitive therapy by the family physician. PMID- 21234040 TI - Is the canadian health care system suffering from abuse? A commentary. AB - The authors suggest that more attention must be paid to acting on information about the effectiveness of diagnostic and therapeutic procedures, their cost effectiveness, and their net benefit to Canadians. Canadian health professionals and policy-makers must translate information on ineffective procedures, poor use of effective procedures, and the relative cost of services delivered in different settings by different personnel into changes in use levels and patterns. Another challenge, which involves the general public as well, is to achieve an informed social consensus about the level of health care spending and its distribution across types of services. Education of Canadians, including health professionals, is needed so that they can contribute responsibly and effectively to this change. PMID- 21234041 TI - Neonatal screening part 2: neonatal screening in Canada. AB - Neonatal screening is a widely accepted, cost-effective method for early detection of various inborn errors of metabolism. This series of three articles examines different aspects of neonatal screening. In the first article, the author discussed general principles of screening and its function in the spectrum of diagnostic techniques for genetic disease. In this, the second article, the author reviews the history and current practices of neonatal screening in Canada. The individual diseases for which screening is used and particular points of interest for each of these diseases are briefly described. The author also outlines the benefits of screening and treatment. In the final article of this series, the author will examine controversial topics that represent the possible future of screening. PMID- 21234042 TI - What should a family physician know about neurology? AB - Ten per cent of patients visiting their family physician have a neurological complaint, and 1% to 2% eventually are diagnosed as having a definite neurological problem. Although most neurological problems can be managed effectively by the family physician, many physicians have trouble conducting a neurological examination confidently, interpreting the results of their findings, or deciding what tests should be done. The author outlines what the family practitioner should know about the field, including certain basic concepts about the nervous system, the appropriate attitude toward neurological problems and patients, characteristics of an efficient, high-yield neurological screening examination, and emergency management of common and treatable neurological conditions. PMID- 21234043 TI - Differential diagnosis of non-parkinsonian tremors. AB - Tremors present to the practitioner a problem that can be solved clinically. Attention to the circumstances under which the tremors occur permits their classification as resting, postural, and intentional types. Each type has a specific locus in the nervous system. The cause can be established by a careful history. Many tremors respond to treatment. PMID- 21234044 TI - Diagnosis of seizure disorders. AB - The author addresses the diagnosis of seizure disorders by discussing clinical features of the different types of seizures, including generalized tonic-clonic, absence, myoclonic, partial complex seizures, and non-epileptic or "pseudoseizures." She also discusses the use of appropriate laboratory tests, electroencephalography, computed tomography, magnetic resonance imaging, and positron emission tomographic scanning. The rationale of and approach to treatment of these conditions with some of the common anticonvulsant drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, and primidone) is provided. PMID- 21234045 TI - Peripheral neuropathy: approach to numbness. AB - Peripheral neuropathy can cause numbness and many other distressing symptoms. Diagnosing the cause of neuropathy can prove to be a frustrating exercise for both the physician and the patient. After a few common diagnostic considerations are excluded, a physician can become discouraged by the long list of uncommon disorders that could produce peripheral neuropathy. The author presents an approach to diagnosing peripheral neuropathy and examines the limitations inherent in evaluating this problem. PMID- 21234046 TI - Nerve conduction studies and electromyography. AB - Nerve conduction studies and electromyography can aid in the diagnosis of peripheral nervous system disease. The author reviews various techniques used during electromyography and nerve conduction studies. He reviews briefly peripheral nerve and muscle neuroanatomy and neurophysiology. The author defines terms used in nerve conduction studies and electromyography and relates terminology to the underlying pathophysiology and histopathology. He also reviews briefly typical nerve conduction and electromyographic findings in various diseases. PMID- 21234047 TI - Perceptual and cognitive impairments and driving. AB - Perceptual and cognitive disorders that frequently accompany stroke and head injury influence an individual's ability to drive a motor vehicle. Canadian physicians are legally responsible for identifying patients who are potentially unsafe to drive and, if they fail to do so, may be held liable in a civil action suit. The authors review the guidelines for physicians evaluating a patient's fitness to drive after brain injury. They also examine the actions a physician should take when a patient with perceptual and cognitive problems wants to drive. Ultimately, by taking these actions, physicians will help to prevent driving accidents. PMID- 21234048 TI - Headaches in Children: Is it Always Migraine? AB - Headache can occur in children. There are several causes, but the most common cause of recurrent severe headaches is migraine. There are several types of migraine, some of which are associated with neurologic deficits (so-called complicated migraine). Investigations, such as electroencephalography and computed tomography, might be necessary to exclude other disorders, but are unnecessary in most cases. PMID- 21234049 TI - Family practice and social work: who really cares? AB - Fragmentation of services in rural practice can create many frustrations for physicians, often demanding extra time, skills, and energy. Can collaboration between the family physician and a community-based social worker reduce stresses in a rural practice? The authors discuss cases that illustrate how physicians and social workers can work together in a semi-rural socially deprived area. The effect of collaboration in this medical practice has been to reduce the time spent contacting resources, to broaden the physician's skills and knowledge to include social and economic needs in the assessment of patient health, and to increase interest in political action and self-help initiatives within the community. PMID- 21234050 TI - Prognosis of cutaneous polyarteritis nodosa. AB - A 17-year-old girl had cutaneous polyarteritis nodosa (CPN) of four years' duration. She had no clinical or laboratory evidence of associated systemic disease but was concerned about whether the CPN would remain cutaneous. Her case is reviewed in the context of previously reported cases. The authors include photographs and a microphotograph of the lesions that could help to alert clinicians to the possibility of this disease in their patients. PMID- 21234051 TI - Ulcerative colitis: an overview. AB - Idiopathic ulcerative colitis primarily affects young adults. Colonic symptoms are the most annoying. In severe colitis, systemic and extraintestinal inflammatory manifestations can be disabling. Proximal extension of colitis is demonstrated by double-contrast barium enema and total colonoscopy. Bacterial and parasitic colitis must be excluded by appropriate microbiological studies. Colonoscopy is recommended to screen for high-grade dysplasia or neoplasia in cases of chronic diffuse colitis (after seven years). Severe colitis can benefit from hospitalization, parenteral nutritional support, and high doses of corticosteroids that are progressively tapered. Mild or moderate cases or severe cases in remission respond well to rest, low-irritant diets, mild symptomatic medication, oral sulfasalazine, or more recent 5-acetylsalicylic derivatives. Long-term maintenance with reduced dosages will control more than 80% of cases. PMID- 21234052 TI - Why rheumatology? PMID- 21234053 TI - Spring cleaning. PMID- 21234054 TI - Medifacts tapes and general practice. PMID- 21234055 TI - Fudging the diagnosis: comment. PMID- 21234056 TI - Treating attention deficit disorder. PMID- 21234057 TI - Meeting the crisis: academic family physicians. PMID- 21234058 TI - Controlling pain: comment. PMID- 21234059 TI - Subcutaneous infusion of analgesics: comment. PMID- 21234060 TI - Assessment of family physicians' knowledge of social and community services. AB - A survey of 255 family physicians and general practitioners in the Hamilton Wentworth area, revealed that knowledge of social services and community treatment programs was often poor: 65% of 122 respondents did not know about one or more points of access to social services information, and 26% reported that they knew of appropriate social services for less than half of 13 psychosocial problems commonly encountered in family practice. Although 43% indicated that they preferred to treat patients themselves, 47% agreed that lack of information precluded referral, and 75% agreed that opportunities to increase their knowledge of community services would be helpful. PMID- 21234061 TI - Breast rejection: a little-appreciated cause of lactation failure. AB - Breast rejection is a common cause of breast-feeding failure. We describe 51 mother-infant pairs who visited the Hospital for Sick Children breast-feeding clinic because the baby refused to take the breast. Management was successful in 21 (40%), partially successful in 11 cases (22%), and unsuccessful in 16 (31%). (Three mothers were lost to follow up.) We believe that the early introduction of bottles results in the baby's developing an ineffective suckle, which then causes frustration when the baby tries to breast-feed. Good management of breast-feeding in the newborn period involves avoiding bottles and teaching the mother proper positioning and latching, as well as signs that indicate whether her baby is getting adequate milk. A method of giving supplemental fluids without direct bottle-feeding is described. PMID- 21234062 TI - [Not Available]. AB - Research is just one part of an academic physician's activities, which also include teaching, patient care, and administration. Research productivity, however, is still expected for academic advancement and to enhance family medicine as an academic discipline. The five units of Laval University's Department of Family Medicine were surveyed to determine the effect of family physicians trained in research on the number and type of publications produced by all of their teachers between 1982 and 1987. A total of 55 articles were published. Forty-eight per cent of the teachers had participated in the generation of at least one publication during the study period. The presence of family physicians trained in research proved to be the most significant factor influencing the number and type of articles published in each unit. PMID- 21234064 TI - Neonatal screening part 3: controversial issues. AB - This series of three articles examines different aspects of neonatal screening. In the first article, the author discussed general principles, including criteria for test selection, sensitivity and specificity of tests, cost-benefit analyses, laboratory factors in screening, and the role of neonatal screening in the spectrum of diagnostic techniques for genetic disease. The second article described the status of screening in Canada, the diseases for which screening is now applied, and the benefits of screening and treatment. In this, the final article of this series, the author describes the controversial topics that represent the possible future of screening. He examines four diseases (cystic fibrosis, hypercholesterolemia, sickle cell disease, and muscular dystrophy) for which we can screen, but currently do not screen in Canada. PMID- 21234063 TI - Prescribing by canadian general practitioners: review of the english language literature. AB - General practitioners write the vast majority of the 190 million prescriptions issued annually in Canada. The author reviewed the English language literature to determine the general characteristics of that prescribing, the appropriateness of prescribing, and factors that influence prescribing. On average, GPs write one prescription for every two office visits. Each prescription is for 1.2 to 1.4 items. Most of any GP's prescriptions are for a group of fewer than 30 different medications. Factors that influence prescribing include generic prescribing and knowledge of drug contents, provincial drug programs, physician and patient characteristics, type of practice, source of information about drugs, and rapidity of adoption of new drugs. The author offers suggestions for improving prescribing. PMID- 21234065 TI - [Not Available]. AB - Rheumatoid arthritis is the most common chronic inflammatory joint disease. To overcome joint inflammation and eventually induce disease remission, the physician must often use drugs that are more and more toxic. Indications, method of administration, and common adverse effects of non-steroidal anti-inflammatory drugs, local steroid injections, second-line agents, and steroids are reviewed. The author briefly discusses a new therapeutic concept and emphasizes the importance of patient education and early referral to an interdisciplinary rehabilitation team. PMID- 21234066 TI - Immunogenetic markers in rheumatic diseases. AB - Certain genetic markers in the major histocompatibility complex have been associated with increased risk of developing ankylosing spondylitis, rheumatoid arthritis, and systemic lupus erythematosus. These markers, however, do not appear in all patients with these diseases, suggesting that other gene products or environmental factors may play a role in disease expression. Current investigations using monoclonal antibody and peptide mapping techniques suggest that many gene products share similar protein sequences with known disease susceptibility genetic markers. PMID- 21234068 TI - Vasculitis: classification and management. AB - Vasculitis, which is pathologically an inflammatory or necrotic state of blood vessels, consists of a diverse group of disesases. The clinical manifestations of vasculitis vary greatly in severity. The simplified classification described in this article is geared toward recognizing the degree of severity of the vasculitic process so that appropriate management can be initiated expeditiously. Emphasis is placed on the vasculitides likely to be encountered in general practice. PMID- 21234067 TI - Psychologic, social, emotional, and practical problems of patients with arthritis. AB - Family physicians will have increasing numbers of patients with arthritis in their practices during the 1990s. Medical management is often complicated by subclinical psychologic, social, and emotional problems, and other problems of everyday living that affect the care of these people. The author reviews some typical patients with arthritis and offers practical suggestions about non medical treatments that can assist them. PMID- 21234069 TI - Rehabilitating the patient with arthritis: team approach. AB - Canadian family physicians must revolutionize their approach to the treatment of patients with arthritis. The consequences of the disease are so diverse that it demands a total approach by a team of specially trained professionals. By learning what the rehabilitation team offers, the physician can create treatment strategies and help improve the patient's quality of life. PMID- 21234070 TI - Rheumatic disease, the family physician, and the consultants: when to hold them and when to fold them. AB - The principles of when to refer in rheumatologic disorders vary little from the general pattern, but some disease-specific advice is helpful. Follow the age-old tenets of referring if diagnosis is uncertain, if treatment advice is needed, or if you are unable to meet the many needs of patients with chronic illnesses. It is often valuable to ask why the patient wants a referral. Education, referral to allied health professionals, and assessing how well you are supporting the patient are all important. It is also essential to maintain contact with both patient and consultant if referral is necessary. PMID- 21234071 TI - Advances in pediatric rheumatology. AB - Rheumatic diseases among children are being recognized with increasing frequency. The emergence of rheumatology as a pediatric subspecialty has been associated with a more comprehensive and co-ordinated approach to patient assessment and care. More clearly focused pediatric rheumatology research has contributed to improved disease classification, to the development of more sophisticated diagnostic tests, and to more judicious use of pharmacologic therapy. A heightened awareness among physicians of rheumatic diseases in children has been an important factor contributing to earlier diagnosis and improved care. PMID- 21234072 TI - Update on osteoarthritis. AB - Osteoarthritis is the most common type of arthritis affecting humans. Its clinical features are well recognized, and its diagnosis is easily established. The etiopathogenesis of the disease is still poorly understood. The definition and classification of osteoarthritis have only recently been set up by the American Rheumatism Association and the National Institutes of Health-sponsored workshop. Management should be four-fold: educational, physiatric, medical, and surgical. The management goal should be individualized and be aimed at symptomatic relief and restoration of function. PMID- 21234073 TI - Post-menopausal Osteoporosis: Can it Be Prevented? AB - The prevention of post-menopausal osteoporosis is a challenge for primary care physicians. Recently available technology to determine bone density can help determine whether intervention other than dietary calcium recommendations and an exercise program is appropriate. Estrogen replacement therapy can be used for post-menopausal women who have no contra-indications. The use of concomitant progestational agents in a cyclic fashion or with a low-dose continuous regimen reduces the risk of endometrial malignancy. In the future new investigational agents that modulate bone turnover could be recommended. PMID- 21234074 TI - Approach to the patient with polyarthritis. AB - When a patient has joint pain, the most important decision for the physician is to distinguish between an inflammatory or non-inflammatory process. The most common inflammatory polyarthritides include rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, and less likely, chronic tophaceous gout. Investigations usually help only to confirm a diagnosis already suspected. Generally, few symptoms are pathognomonic of a particular diagnosis. Follow up over several months to a year and anti-inflammatory medications, when indicated, are the mainstay of early management. PMID- 21234075 TI - Reconstructive surgery of the lower extremity. AB - Non-operative treatments for degenerative arthritis, such as physiotherapy, anti inflammatory medication, and occupational therapy, can help reduce the impact of the disease on the joint and hence on the mobility of the patient. Once the joint has become so diseased that non-operative modalities are inadequate, it is the task of the orthopedic surgeon to evaluate these individuals and determine which ones would benefit from a reconstructive procedure. The author explores the indications for arthrotomies, resection arthroplasties, arthrodeses, osteotomies, and total joint replacements. Total joint arthroplasty has revolutionized the treatment of degenerative arthritis of the lower extremity, although it is not a panacea for arthritis in the lower extremity. PMID- 21234077 TI - The changing relationship of physicians and nurses: Perspective from Vancouver. PMID- 21234076 TI - Help wanted-apply within. PMID- 21234078 TI - Community hospital integrated computer systems: Using computers in clinical teaching. PMID- 21234079 TI - Improving Feedback for Medical Students in a Family Medicine Clerkship: Evaluating medical student performance using frequent feedback. AB - To evaluate whether feedback to medical students could be improved by asking teachers to complete a student performance rating form during a family practice clerkship, the authors had students and teachers fill out a questionnaire. Teachers in the intervention group reported observing students more frequently. Students' perceptions of feedback frequency correlated strongly with their ratings of feedback quality. PMID- 21234080 TI - Female and Male Physicians: Different Practice Profiles: Will increasing numbers of female GPs affect practice patterns of the future? AB - In a descriptive study using provincial billing profiles, women physicians were found to perform fewer services, see fewer patients, and earn less. Their practices included relatively more female patients and were less likely to include emergency room duty, assists at technical or surgical procedures, visits outside the office, obstetrical care, or after-hours services. Women provided more psychotherapy and counseling, ordered more laboratory tests, and generated higher laboratory costs than the men. PMID- 21234081 TI - [Not Available]. AB - Psychological distress was measured in Quebec immigrants and native Quebeckers using the Psychiatric Symptom Index. The percentage of elevated scores did not differ significantly between the two groups, although immigrant men and women 65 and over had higher scores, and immigrant women between 25 and 64 suffered more psychological stress than immigrant men. PMID- 21234082 TI - Topical Acyclovir for Recurrent Herpes Labialis in Primary Care: Critical appraisal. AB - I reviewed the literature on the treatment of recurrent herpes labialis with topical acyclovir ointment to determine the effectiveness of this treatment for family practice patients. This article discusses the generalizability of the results to family practice. I concluded that the evidence supporting this therapy is weak and that it cannot, in the light of current knowledge, be strongly recommended. PMID- 21234083 TI - The Doctor's, the Druggist's, and the Detail Rep's Dance: Who leads, who follows? AB - The author reviews some of the literature about interventions designed to influence physicians' prescribing patterns, particularly how the pharmacist and drug industry alter prescribing by primary care physicians. Many of the usual interventions are probably ineffective; a personal relationship with the physician is necessary to modify prescribing behavior consistently. PMID- 21234084 TI - Adverse Drug Reactions: Review of the Canadian literature. AB - A combined manual and computer search of the literature on the Canadian experience with adverse drug reactions (ADRs) to prescribed drugs yielded a total of 23 articles. The risk of developing an ADR, factors influencing that risk, the incidence of ADRs, ADRs as a cause of hospitalization, case fatality ratios, whether ADRs increase hospitalization time, and the drugs that are most commonly implicated in ADRs were analyzed. PMID- 21234085 TI - Polypharmacy in the Elderly: Drug reactions and interaction in the aged. AB - The elderly tolerate smaller doses of most drugs, largely because changes in body fat content, water content, and muscle mass often lead to higher blood levels than in a young person of the same weight. Moreover, diminished renal blood flow and creatinine clearance decrease excretion of agents cleared by the kidney. This leads to an increased number of drug reactions and interactions and consequent hospital admissions. PMID- 21234086 TI - Migraine Prophylaxis: A pharmacologic approach. AB - While the pathophysiology of recurrent migraine remains elusive, effective treatment for the prevention of attacks is available. Pharmacologic agents are useful adjuncts to a therapeutic approach that includes abundant patient education, rigorous follow up by the treating physician, and a commitment by both patient and physician to work out an individualized solution over time. PMID- 21234087 TI - Remedies for Common Cold Symptoms: Making sense of myriad drugs. AB - Individuals suffering from intolerable symptoms of the common cold can now be advised of safe and effective products for symptomatic relief. This article describes and discusses four categories of drugs used to treat the common cold. To simplify the product selection process for family physicians, suggestions are included for possible ingredients for treatments of specific cold symptoms. PMID- 21234088 TI - The Treatment of PVCs and Prevention of Sudden Cardiac Death: New findings from the CAST study. AB - Premature ventricular complexes (PVCs) have traditionally been suppressed using antiarrhythmic drugs. Recent studies have failed to show that reducing the number of PVCs can prevent sudden death; moreover, treatment with some antiarrhythmic agents can increase the risk. There is a close link between the severity of ischemic heart disease and sudden death. PMID- 21234089 TI - Matching the Drug to the Patient: The rational use of antiarthritic drugs. AB - Antirheumatic drugs now available are often effective in helping control the more serious rheumatic disorders, but are not curative. All have potentially serious side effects and need to be used with caution in the presence of recognized risk factors. Treatment should be individualized for the diagnosis and severity of the underlying disease, which must be of sufficient magnitude to justify the risk of potential adverse reactions from the prescribed medication. PMID- 21234090 TI - Non-steroidal Anti-inflammatory Drugs: Monitoring to help prevent serious adverse effects. AB - Gastrointestinal, renal, hepatic, and hematological adverse effects are all associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs). Some patients are particularly at risk for such problems. Preventive measures and recommendations for managing and monitoring high-risk patients are presented. Patients receiving long-term NSAID therapy should be carefully monitored. PMID- 21234091 TI - Antidiarrheal Agents: More to the Apple Sauce Than You Might Think: Treating infectious diarrheas. AB - Recent advances have now made it possible to target specific therapy for infectious diarrheas for individual microbes that are well established as diarrheal pathogens. Improvements in non-specific therapy have particularly addressed hydration, electrolyte balance, and nutritional intake. As our understanding of the infectious diarrheas continues to progress, we can anticipate further improvement. PMID- 21234092 TI - ADPKD: Prototype of Cardiorenal Syndrome Type 4. AB - The cardiorenal syndrome type 4 (Chronic Renocardiac Syndrome) is characterized by a condition of primary chronic kidney disease (CKD) that leads to an impairment of the cardiac function, ventricular hypertrophy, diastolic dysfunction, and/or increased risk of adverse cardiovascular events. Clinically, it is very difficult to distinguish between CRS type 2 (Chronic Cardiorenal Syndrome) and CRS type 4 (Chronic Renocardiac Syndrome) because often it is not clear whether the primary cause of the syndrome depends on the heart or the kidney. Autosomal dominant polycystic kidney disease (ADPKD), a genetic disease that causes CKD, could be viewed as an ideal prototype of CRS type 4 because it is certain that the primary cause of cardiorenal syndrome is the kidney disease. In this paper, we will briefly review the epidemiology of ADPKD, conventional and novel biomarkers which may be useful in following the disease process, and prevention and treatment strategies. PMID- 21234093 TI - Interim FDG-PET Scan in Hodgkin's Lymphoma: Hopes and Caveats. AB - FDG-PET has recently emerged as an important tool for the management of Hodgkins lymphoma. Although its use for initial staging and response evaluation at the end of treatment is well established, the place of interim PET for response assessment and subsequent treatment tailoring is still quite controversial. The use of interim PET after a few cycles of chemotherapy may allow treatment reduction for good responders, leading to lesser treatment toxicities as well as early treatment adaptation for bad responders with a potential higher chance for cure. Interpretation of interim PET is a rapidly moving field. Actually, visual interpretation is preferred over quantitative interpretation in this situation. The notion of minimal residual uptake emerged for faint persisting FDG uptake, but has evolved during the recent years. Guidelines using mediastinum and liver as references have been proposed at the expert meeting in Deauville 2009. Actually, several trials are ongoing both for localised and advanced disease to evaluate the FDG-PET potential for early treatment monitoring and tailoring. Until the results of these prospective randomized trials become available, treatment changes according to the interim PET results should remain inappropriate and limited to well-conducted clinical trials. PMID- 21234094 TI - Extranodal natural-killer/t-cell lymphoma, nasal type. AB - The World Health Organization (WHO) classification recognizes 2 main categories of natural killer (NK) cell-derived neoplasms, namely, extranodal NK/T-cell lymphoma, nasal type, and aggressive NK-cell leukaemia. Extranodal nasal NK/T cell lymphoma is more frequent in the Far East and Latin America. Histopathological and immunophenotypical hallmarks include angiocentricity, angiodestruction, expression of cytoplasmic CD3 epsilon (epsilon), CD56, and cytotoxic molecules and evidence of Epstein-Barr virus (EBV) infection. Early stage disease, in particular for localized lesion in the nasal region, is treated with chemotherapy and involved-field radiotherapy. On the other hand, multiagent chemotherapy is the mainstay of treatment for advanced or disseminated disease. L asparaginase-containing regimens have shown promise in treating this condition. The role of autologous hematopoietic stem cell transplantation is yet to be clearly defined. Allogeneic hematopoietic stem cell transplantation, with the putative graft-versus-lymphoma effect, offers a potentially curative option in patients with advanced disease. PMID- 21234095 TI - Cellular senescence as a target in cancer control. AB - Somatic cells show a spontaneous decline in growth rate in continuous culture. This is not related to elapsed time but to an increasing number of population doublings, eventually terminating in a quiescent but viable state termed replicative senescence. These cells are commonly multinucleated and do not respond to mitogens or apoptotic stimuli. Cells displaying characteristics of senescent cells can also be observed in response to other stimuli, such as oncogenic stress, DNA damage, or cytotoxic drugs and have been reported to be found in vivo. Most tumors show unlimited replicative potential, leading to the hypothesis that cellular senescence is a natural antitumor program. Recent findings suggest that cellular senescence is a natural mechanism to prevent undesired oncogenic stress in somatic cells that has been lost in malignant tumors. Given that the ultimate goal of cancer research is to find the definitive cure for as many tumor types as possible, exploration of cellular senescence to drive towards antitumor therapies may decisively influence the outcome of new drugs. In the present paper, we will review the potential of cellular senescence to be used as target for anticancer therapy. PMID- 21234097 TI - Guillain-barre syndrome after thrombolysis with streptokinase. AB - Guillain-Barre syndrome (GBS) is an eponym for a heterogeneous group of immune mediated peripheral neuropathies. We describe a case of GBS in a patient who recieved intravenous streptokinase therapy for acute anterior myocardial infarction. Clinical symptoms are thought to result from streptokinase-antibody complex mediated damage to the local blood-nerve barrier. Patient was treated with 5-days course of intravenous gammaglobulin and his outcome was good. PMID- 21234098 TI - Association between Depression and C-Reactive Protein. AB - Objective. Depression has been associated with increased cardiovascular disease risk, and a depression-related elevation of high sensitivity C-reactive protein (hs-CRP) has been proposed as a possible mechanism. The objective of this paper is to examine association between depression and high sensitivity C-reactive protein (hs-CRP). Methods. Subjects consisted of 508 healthy adults (mean age 48.5 years; 49% women, 88% white) residing in central Massachusetts. Data were collected at baseline and at quarterly intervals over a one-year period per individual. Multivariable linear mixed models were used to assess the association for the entire sample and by gender. Results. The mean Beck Depression Inventory score was 5.8 (standard deviation (SD) 5.4; median 4.3), and average serum hs-CRP was 1.8 mg/L (SD 1.7; median 1.2). Results from the multivariable linear mixed models show that individuals with higher depression scores have higher levels of hs-CRP. Analyses by gender show persistence of an independent association among women, but not among men. Body mass index (BMI = weight(kg)/height(m)(2)) appears to be a partial mediator of this relationship. Conclusion. Depression score was correlated to hs-CRP levels in women. Further studies are required to elucidate the biological mechanisms underlying these associations and their implications. PMID- 21234099 TI - The Effect of Race, Sex, and Insurance Status on Time-to-Listing Decisions for Liver Transplantation. AB - Fair allocation of organs to candidates listed for transplantation is fundamental to organ-donation policies. Processes leading to listing decisions are neither regulated nor understood. We explored whether patient characteristics affected timeliness of listing using population-based data on 144,507 adults hospitalized with liver-related disease in Pennsylvania. We linked hospitalizations to other secondary data and found 3,071 listed for transplants, 1,537 received transplants, and 57,020 died. Among candidates, 61% (n = 1,879) and 85.5% (n = 2,626) were listed within 1 and 3 years of diagnosis; 26.7% (n = 1,130) and 95% (n = 1,468) of recipients were transplanted within 1 and 3 years of listing. Using competing-risks models, we found few overall differences by sex, but both black patients and those insured by Medicare and Medicaid (combined) waited longer before being listed. Patients with combined Medicare and Medicaid insurance, as well as those with Medicaid alone, were also more likely to die without ever being listed. Once listed, the time to transplant was slightly longer for women, but it did not differ by race/ethnicity or insurance. The early time period from diagnosis to listing for liver transplantation reveals unwanted variation related to demographics that jeopardizes overall fairness of organ allocation and needs to be further explored. PMID- 21234096 TI - Deciphering squamous cell carcinoma using multidimensional genomic approaches. AB - Squamous cell carcinomas (SqCCs) arise in a wide range of tissues including skin, lung, and oral mucosa. Although all SqCCs are epithelial in origin and share common nomenclature, these cancers differ greatly with respect to incidence, prognosis, and treatment. Current knowledge of genetic similarities and differences between SqCCs is insufficient to describe the biology of these cancers, which arise from diverse tissue origins. In this paper we provide a general overview of whole genome approaches for gene and pathway discovery and highlight the advancement of integrative genomics as a state-of-the-art technology in the study of SqCC genetics. PMID- 21234100 TI - Dyssynchrony Assessment with Tissue Doppler Imaging and Regional Volumetric Analysis by 3D Echocardiography Do Not Predict Long-Term Response to Cardiac Resynchronization Therapy. AB - Background. Currently there are no reliable predictors of response to cardiac resynchronization therapy (CRT) before implantation. We compared pre-CRT left ventricular (LV) dyssynchrony by tissue Doppler imaging (TDI) and regional volumetric analysis by 3-dimensional transthoracic echocardiography (3DTTE) in predicting response to CRT. Methods. Thirty-eight patients (79% nonischemic cardiomyopathy) with symptomatic heart failure who underwent CRT were enrolled. Clinical and echocardiographic responses were defined as improvement in one NYHA class and reduction in LV end-systolic volume by >=15% respectively. Functional status was assessed by Minnesota Living with Heart Failure questionnaire and 6 minute walk distance. Results. In 33 patients, after CRT for 7.86 +/- 2.27 months, there were 24 (73%) clinical and 19 (58%) echocardiographic responders. Functional parameters, LV dimensions, volumes and synchrony by TDI and 3DTTE improved significantly in responders. There was no difference in the number of responders and nonresponders when cut-off values for dyssynchrony by different measurements validated in other trials were applied. Area under receiver operating-characteristic curve ranged from 0.4 to 0.6. Conclusion. CRT improves clinical and echocardiographic parameters in patients with systolic heart failure. The dyssynchrony measurements by TDI and 3DTTE are not comparable and are unable to predict response to CRT. PMID- 21234101 TI - Pulmonary valve infective endocarditis in an adult patient with severe congenital pulmonary stenosis and ostium secundum atrial septal defect. AB - A hypertensive 76-year-old man with severe pulmonary valve stenosis (PVS) and recent initiation of haemodialysis was referred with fever, chills, and asthenia. One month prior, he had been admitted with similar symptoms. Transthoracic echocardiography (TTE) had shown a PVS and no valve vegetations were observed. Following discharge, he was readmitted with fever and blood cultures positive for Staphylococcus haemolyticus. A new TTE revealed two pulmonary valve vegetations and a previously undetected ostium secundum-type atrial septal defect (ASD), confirmed by transesophageal echocardiography. The clinical course was uneventful with intravenous antibiotic treatment and the patient was safely discharged. This is a case of pulmonary valve infective endocarditis (IE). The incidence of right sided IE is on the rise due to the increased number of patients using central venous lines, pacing, haemodialysis and other intravascular devices. Pulmonary valve IE is extremely rare, especially in structurally normal hearts. The case reported here, presents a combination of predisposing factors, such as severe congenital PVS, the presence of a central venous catheter, and haemodialysis. The fact that it was an older patient with severe congenital PVS and associated with a previously undiagnosed ASD, is also an unusual feature of this case, making it even more interesting. PMID- 21234103 TI - Use of nebulized amphotericin B in the treatment of allergic bronchopulmonary aspergillosis in cystic fibrosis. AB - Background. Systemic steroids and adjunctive antifungal therapy are the cornerstone in treating allergic bronchopulmonary aspergillosis (ABPA) in the context of CF. Aim. Evaluate the use of inhaled amphotericin B (iAMB) as antifungal agent in this context. Methods. Report of 7 CF patients with recurrent or difficult to treat ABPA and failure to taper systemic corticosteroids treated with AMB deoxycholate (AMB-d) (Fungizone 25 mg 3* a week) or AMB lipid complex (ABLC) (Abelcet 50 mg twice weekly). Successful therapy was defined as steroid withdrawal without ABPA relapse within 12 months. Results. Therapy was successful in 6 of 7 patients treated with iAMB. In 5/6, lung function improved. The patient with treatment failure has concomitant MAC lung infection. Conclusion. Inhaled AMB may be an alternative to commonly used adjunctive antifungal therapy in the treatment of ABPA. More data are needed on safety and efficacy. PMID- 21234102 TI - New proteins found interacting with brain metallothionein-3 are linked to secretion. AB - Metallothionein 3 (MT-3), also known as growth inhibitory factor (GIF), exhibits a neuroinhibitory activity. Our lab and others have previously shown that this biological activity involves interacting protein partners in the brain. However, nothing specific is yet known about which of these interactions is responsible for the GIF activity. In this paper, we are reporting upon new proteins found interacting with MT-3 as determined through immunoaffinity chromatography and mass spectrometry. These new partner proteins-Exo84p, 14-3-3 Zeta, alpha and beta Enolase, Aldolase C, Malate dehydrogenase, ATP synthase, and Pyruvate kinase along with those previously identified have now been classified into three functional groups: transport and signaling, chaperoning and scaffolding, and glycolytic metabolism. When viewed together, these interactions support a proposed model for the regulation of the GIF activity of MT-3. PMID- 21234104 TI - Long-term changes in physical activity following a one-year home-based physical activity counseling program in older adults with multiple morbidities. AB - This study assessed the sustained effect of a physical activity (PA) counseling intervention on PA one year after intervention, predictors of sustained PA participation, and three classes of post-intervention PA trajectories (improvers, maintainers, and decliners) in 238 older Veterans. Declines in minutes of PA from 12 to 24 months were observed for both the treatment and control arms of the study. PA at 12 months was the strongest predictor of post-intervention changes in PA. To our surprise, those who took up the intervention and increased PA levels the most, had significant declines in post-intervention PA. Analysis of the three post-intervention PA trajectories demonstrated that the maintenance group actually reflected a group of nonresponders to the intervention who had more comorbidities, lower self-efficacy, and worse physical function than the improvers or decliners. Results suggest that behavioral counseling/support must be ongoing to promote maintenance. Strategies to promote PA appropriately to subgroups of individuals are needed. PMID- 21234105 TI - Regulation of Immune Responses and Autoimmune Encephalomyelitis by PPARs. AB - PPARs are members of the steroid hormone nuclear receptor superfamily and play an important role in regulating inflammation as well as lipid metabolism. The PPAR subfamily has been defined as PPARalpha, PPARbeta/delta, and PPARgamma, each with different ligands, target genes, and biological roles. PPARs regulate the expression of target inflammatory genes through mechanisms involving both transactivation and transrepression. The anti-inflammatory properties of PPAR agonists have led to the investigation of PPAR functions in regulating autoimmune encephalomyelitis. This paper will summarize some of the general mechanisms by which PPARs regulate inflammatory gene expression and focus on the recent advances of PPAR regulation of autoimmune encephalomyelitis. PMID- 21234106 TI - Online intelligent controllers for an enzyme recovery plant: design methodology and performance. AB - This paper focuses on the development of intelligent controllers for use in a process of enzyme recovery from pineapple rind. The proteolytic enzyme bromelain (EC 3.4.22.4) is precipitated with alcohol at low temperature in a fed-batch jacketed tank. Temperature control is crucial to avoid irreversible protein denaturation. Fuzzy or neural controllers offer a way of implementing solutions that cover dynamic and nonlinear processes. The design methodology and a comparative study on the performance of fuzzy-PI, neurofuzzy, and neural network intelligent controllers are presented. To tune the fuzzy PI Mamdani controller, various universes of discourse, rule bases, and membership function support sets were tested. A neurofuzzy inference system (ANFIS), based on Takagi-Sugeno rules, and a model predictive controller, based on neural modeling, were developed and tested as well. Using a Fieldbus network architecture, a coolant variable speed pump was driven by the controllers. The experimental results show the effectiveness of fuzzy controllers in comparison to the neural predictive control. The fuzzy PI controller exhibited a reduced error parameter (ITAE), lower power consumption, and better recovery of enzyme activity. PMID- 21234107 TI - Depressive symptoms and deliberate self-harm in a community sample of adolescents: a prospective study. AB - The associations between depressive symptoms and deliberate self-harm were studied by means of a 2-wave longitudinal design in a community sample of 1052 young adolescents, with longitudinal data for 83.6% of the sample. Evidence was found for a bidirectional relationship in girls, with depressive symptoms being a risk factor for increased self-harm one year later and self-harm a risk factor for increased depressive symptoms. Cluster analysis of profiles of depressive symptoms led to the identification of two clusters with clear depressive profiles (one severe, the other mild/moderate) which were both characterized by an overrepresentation of girls and elevated levels of self-harm. Clusters with more circumscribed problems were also identified; of these, significantly increased levels of self-harm were found in a cluster characterized by negative self-image and in a cluster characterized by dysphoric relations to parents. It is suggested that self-harm serves more to regulate negative self-related feelings than sadness. PMID- 21234108 TI - Enhanced healing of diabetic wounds by topical administration of adipose tissue derived stromal cells overexpressing stromal-derived factor-1: biodistribution and engraftment analysis by bioluminescent imaging. AB - Chronic ulcers represent a major health problem in diabetic patients resulting in pain and discomfort. Conventional therapy does not guarantee adequate wound repair. In diabetes, impaired healing is partly due to poor endothelial progenitor cells mobilisation and homing, with altered levels of the chemokine stromal-derived factor-1 (SDF-1) at the wound site. Adipose tissue-associated stromal cells (AT-SCs) can provide an accessible source of progenitor cells secreting proangiogenic factors and differentiating into endothelial-like cells. We demonstrated that topical administration of AT-SCs genetically modified ex vivo to overexpress SDF-1, promotes wound healing into diabetic mice. In particular, by in vivo bioluminescent imaging analysis, we monitored biodistribution and survival after transplantation of luciferase-expressing cells. In conclusion, this study indicates the therapeutic potential of AT-SCs administration in wound healing, through cell differentiation, enhanced cellular recruitment at the wound site, and paracrine effects associated with local growth factors production. PMID- 21234110 TI - Do patients wish to 'listen in' when doctors dictate letters to colleagues? AB - OBJECTIVES: To evaluate the effects on clinical outcome of dictating correspondence in front of patients and sending them copies of letters. DESIGN: Observational study of the practices of two consultants, one of whom (RDS) routinely dictated letters in front of his patients and almost always sent them a copy while the other (AM) did neither. Questionnaires were completed anonymously by patients at the end of their consultation. SETTING: Neurology department of a teaching hospital. PARTICIPANTS: Patients attending neurology outpatient clinics. RESULTS: Seventy-two percent and 62% of the two consultants' patients were audited, and the demographic features of the two groups were similar. Eighty-six percent and 25% of RDS's and AM's patients, respectively, said that they wished to be present during dictation (p < 0.001). Within AM's group, those who had had some experience of the practice (with other consultants) were more likely to express a desire to be present during dictation (p = 0.023). Ninety-two percent and 77% of RDS's and AM's patients, respectively, felt that having a copy of their letter would be 'very useful' or 'useful' (p < 0.001). The perceived usefulness of receiving a copy letter and the desire to be present during dictation were associated for the total group and for RDS's patients. The two groups of patients were asked to express their degree of understanding at the end of the consultation, and 81% and 93% of RDS's and AM's patients, respectively, thought that their understanding was 'excellent' or 'good'. No trends emerged with regard to patients' preferences (to be present or absent during dictation and to receive or not receive a copy of their letter) and their level of understanding. CONCLUSIONS: Patients appear to like being present when their letters are dictated, and appreciate receiving copies of these, but their overall understanding is seemingly independent of these variables. The success of the clinical consultation is probably influenced by numerous factors, and the elevation of patients' presence during dictation of correspondence and receipt of copy letters above all others seems unjustified. PMID- 21234109 TI - Treatment of disseminated mycobacterial infection with high-dose IFN-gamma in a patient with IL-12Rbeta1 deficiency. AB - IFN-gamma has been used in the treatment of IL-12Rbeta1 deficiency patients with disseminated BCG infection (BCGosis), but the optimal dose to reach efficacy is not clear. We used IFN-gamma in the treatment of a 2.7-year-old patient with IL 12Rbeta1 deficiency and refractory BCG-osis. IFNgamma was started at a dose of 50 MUg/m2 3 times per week. The dose was upgraded to 100 mcg/m2 after 3 months, then to 200 mcg/m2 6 months afterwards. Serum mycobactericidal activity and lymphocytes number and function were evaluated throughout the study. There was no clinical response to IFN-gamma with 50 or 100 MUg/m2 doses. However, there was some response to the 200 MUg/m2 dose with no additional adverse effects. The serum mycobactericidal activity was not significantly different during the whole treatment period. Lymphocytes proliferation in response to PHA was significantly higher after 3 months of using the highest dose as compared to the lowest dose. The tuberculin skin test reaction remained persistently negative. We conclude that in a patient with IL-12Rbeta1 deficiency, IFN-gamma at a dose of 200 MUg/m2, but not at lower dosages, was found to have a noticeable clinical effect with no additional adverse effects. PMID- 21234111 TI - Rectal cancer presenting with erythema ab igne. PMID- 21234112 TI - Liposarcoma of the spermatic cord: a diagnostic dilemma. PMID- 21234113 TI - Emergent Caesarean section in parturient with congenital complete atrioventricular block. PMID- 21234114 TI - A cupric pregnancy - thirteenth time lucky. PMID- 21234115 TI - Impact of visual art in patient waiting rooms: survey of patients attending a transplant clinic in Dumfries. AB - BACKGROUND: The clinic waiting area in Dumfries received the highest score among nine units offering transplant follow-up (p < 0.001 for differences between units) in the recent Quality Improvement Scotland Renal Transplant Survey. DESIGN: The purpose of the present study was to determine which aspects of the Dumfries waiting area patients considered important to their outpatient experience. METHODS: We posted a questionnaire to all 44 renal transplant patients attending the Dumfries Renal Unit in October 2009 in which we asked patients to rate seven aspects of their clinic environment on a scale from 1 (not at all important) to 5 (very important). These were, in random order, comfy chairs, magazines and puzzle books, paintings on the wall, a 42-inch plasma screen TV, views from the windows, potted plants and computers with Internet access. RESULTS: Thirty-nine (89%) patients responded. The most highly rated feature of our clinic waiting room was the comfy chairs with an average score of 4.4. This was followed by the magazines and puzzle books (3.6), the plasma screen TV (3.6) and the paintings on the walls (3.4). The views from the windows (3.1), the computer (3.0) and the potted plants (2.9) were less highly rated. Respondents expressed a preference for landscapes/nature scenes (84%) and paintings of animals/birds (84%). Fewer wished to look at abstract paintings (27%) or portraits (24%). CONCLUSION: The QIS transplant survey has shown large differences in the quality of the environment of the transplant follow-up clinics in Scotland. Our survey of renal transplant patients attending the Dumfries Renal Unit suggests that the paintings we chose to display in our clinic waiting room contributed positively to their outpatient experience. PMID- 21234116 TI - Pituitary apoplexy: two very different presentations with one unifying diagnosis. PMID- 21234117 TI - An interesting rash: leucocytoclastic vasculitis with type 2 cryoglobulinaemia. PMID- 21234118 TI - An unusual case of triorchidism. PMID- 21234119 TI - A case of Lyme neuroborreliosis with bilateral recurrent laryngeal nerve palsy. PMID- 21234120 TI - Decrypting the labyrinth of inflammatory cell signaling pathways: Editorial to the meeting "Inflammation 2010". PMID- 21234122 TI - Selective regulation of nuclear orphan receptors 4A by adenosine receptor subtypes in human mast cells. AB - Nuclear orphan receptors 4A (NR4A) are early responsive genes that belong to the superfamily of hormone receptors and comprise NR4A1, NR4A2 and NR4A3. They have been associated to transcriptional activation of multiple genes involved in inflammation, apoptosis and cell cycle control. Here, we establish a link between NR4As and adenosine, a paradoxical inflammatory molecule that can contribute to persistence of inflammation or mediate inflammatory shutdown. Transcriptomics screening of the human mast cell-line HMC-1 revealed a sharp induction of transcriptionally active NR4A2 and NR4A3 by the adenosine analogue NECA. The concomitant treatment of NECA and the adenosine receptor A(2A) (A(2A)AR) selective antagonist SCH-58261 exaggerated this effect, suggesting that upregulation of these factors in mast cells is mediated by other AR subtypes (A(2B) and A(3)) and that A(2A)AR activation counteracts NR4A2 and NR4A3 induction. In agreement with this, A(2A)AR-silencing amplified NR4A induction by NECA. Interestingly, a similar A(2A)AR modulatory effect was observed on ERK1/2 phosphorylation because A(2A)AR blockage exacerbated NECA-mediated phosphorylation of ERK1/2. In addition, PKC or MEK1/2 inhibition prevented ERK1/2 phosphorylation and antagonized AR-mediated induction of NR4A2 and NR4A3, suggesting the involvement of these kinases in AR to NR4A signaling. Finally, we observed that selective A(2A)AR activation with CGS-21680 blocked PMA-induced ERK1/2 phosphorylation and modulated the overexpression of functional nuclear orphan receptors 4A. Taken together, these results establish a novel PKC/ERK/nuclear orphan receptors 4A axis for adenosinergic signaling in mast cells, which can be modulated by A(2A)AR activation, not only in the context of adenosine but of other mast cell activating stimuli as well. PMID- 21234121 TI - Steroid signaling activation and intracellular localization of sex steroid receptors. AB - In addition to stimulating gene transcription, sex steroids trigger rapid, non genomic responses in the extra-nuclear compartment of target cells. These events take place within seconds or minutes after hormone administration and do not require transcriptional activity of sex steroid receptors. Depending on cell systems, activation of extra-nuclear signaling pathways by sex steroids fosters cell cycle progression, prevents apoptosis, leads to epigenetic modifications and increases cell migration through cytoskeleton changes. These findings have raised the question of intracellular localization of sex steroid receptors mediating these responses. During the past years, increasing evidence has shown that classical sex steroid receptors localized in the extra-nuclear compartment or close to membranes of target cells induce these events. The emerging picture is that a process of bidirectional control between signaling activation and sex steroid receptor localization regulates the outcome of hormonal responses in target cells. This mechanism ensures cell cycle progression in estradiol-treated breast cancer cells, and its derangement might occur in progression of human proliferative diseases. These findings will be reviewed here together with unexpected examples of the relationship between sex steroid receptor localization, signaling activation and biological responses in target cells. We apologize to scientists whose reports are not mentioned or extensively discussed owing to space limitations. PMID- 21234123 TI - TSP-1 in lung fibrosis. AB - Lung fibrosis is often treated with corticosteroids to reduce the inflammatory response, however, no effective treatment options exist for the underlying disease. An important player in the fibrotic cascade is the cytokine, transforming growth factor beta (TGFbeta). TGFbeta is converted from an inactive procytokine complex to active TGFbeta by enzymes such as thrombospondin-1 (TSP 1). It is therefore presumed that TSP-1 deficient mice would fare better to bleomycin-induced pulmonary fibrosis because TGFbeta would not be efficiently converted to the active form. Interestingly, a recent article by Ezzie and colleagues shows that TSP-1 deficiency does not protect mice from systemic bleomycin challenge. Indeed, they find the opposite, as TSP-1-null mice appear to exhibit greater lung fibrosis than wild type mice, although similar TGFbeta signaling was observed in the lungs of both mouse strains. PMID- 21234124 TI - Commentary on a recent article-"A prostacyclin analogue, Iloprost, protects from bleomycin-induced fibrosis in mice" Zhu Y et al. Respir Res. 2010 Mar 20;11(1):34. AB - Data from our laboratory show that in vitro fibroblasts are exquisitely responsive to prostacyclin and the prostacyclin derivative Iloprost, which block their activation by TGFbeta. A recent article by Zhu Y et al confirm these effects in vivo showing that Iloprost, given as a single intraperitoneal injection, blocks lung fibrosis in the bleomycin model of lung injury and fibrosis. These results are important because at present no effective clinical treatments are available to treat idiopathic lung fibrosis, which progresses and leads to respiratory failure. Limiting factors for the clinical use of prostacyclin derivatives as anti-fibrotics are failure to achieve therapeutic levels in the involved fibrotic tissues, and dose limiting side effects due to vasodilatation and binding to the IP receptor on vascular cells. Possible approaches include fibroblast directed gene therapies or amelioration of the vascular side effects. PMID- 21234126 TI - Targeting the jagged/notch pathway: a new treatment for fibrosis? AB - There is no treatment for fibrotic disease. TGFbeta is known to promote fibrogenesis in vivo and in vitro, however, development of anti-fibrotic strategies targeting the TGFbeta axis is problematic owing to the pleitropic nature of TGFbeta action. Two recent papers (Kavian et al. 2010; Nyhan et al. 2010) suggest that the jagged/Notch pathway may selectively mediate fibrogenic properties of TGFbeta and thus may represent a novel therapeutic approach to fibrosis for scleroderma and kidney fibrosis; these papers are the subject of this commentary. PMID- 21234125 TI - Mastering a mediator: blockade of CCN-2 shows early promise in human diabetic kidney disease. AB - In diabetes complications, CCN-2 (known originally as CTGF) has been implicated in diabetic nephropathy both as a marker and a mediator of disease. This commentary addresses CCN-2 in diabetic nephropathy, in the context of the recent publication of the first human study to inhibit CCN-2 bioactivity in diabetic kidney disease. PMID- 21234127 TI - CCN6 (WISP3): a new anti-cancer therapy? AB - The CCN family of matricellular proteins are dysregulated in cancers, and may strategies targeting them may represent novel approaches to treating these diseases. A recent study from Huang and colleagues (Cancer Res. 70: 3340-50, 2010) suggests that CCN6 (WISP3) is downregulated in aggressive breast cancers, and this phenomenon may result in the promotion of tumor survival. CCN6 may represent a novel therapeutic approach to breast cancer. PMID- 21234128 TI - B cell block: is rituximab a new possible treatment for systemic sclerosis? AB - There is no treatment for fibrotic diseases, including the autoimmune disease systemic sclerosis (sclerderma, SSc). Although broad spectrum immune suppressants have little to no effect on the fibrosis in SSc, agents targeting specific proinflammatory agents are currently being considered as possible therapeutic approaches to combating SSc. B cells are lymphocytes that proliferate and secrete antibody molecules which drive the autoimmune response. CD20 is a B cell marker; the agent rituximab is an antibody against CD20. In a recent report by Bosello and colleagues (Arthritis Res. Ther. 12(2): R54, 2010), rituximab was tolerated in SSc patients and appeared to result in an improvement of the skin score and of clinical symptoms of SSc. This report is one of a series of recent studies suggesting that rituximab may be a possible treatment for SSc. This commentary summarizes these observations. PMID- 21234129 TI - Invasive fatal rhino-orbito-cerebral mucormycosis in diabetic ketoacidosis. PMID- 21234130 TI - Exacerbation of inflammatory bowel disease with isotretinoin. PMID- 21234131 TI - Wegener's granulomatosis in primary care. PMID- 21234132 TI - Extramedullary plasmacytoma of the tongue base. PMID- 21234133 TI - Postpartum caecal perforation due to endometriosis. PMID- 21234134 TI - Effect of age on subjective complaints and objective severity of carpal tunnel syndrome: prospective study. AB - OBJECTIVES: Older patients with carpal tunnel syndrome who are resistant to conservative treatment often have a less than satisfactory outcome after surgery. We therefore investigated whether the age of the patient affects the subjective complaints or the objective severity of the nerve entrapment prior to surgery in patients younger than 40 years compared with those above 70 years of age. DESIGN: Prospective study. SETTING: NHS specialist neurophysiology department. PARTICIPANTS: One hundred and six splint-resistant patients scored their subjective complaints and scores were then compared with the neurophysiology results. MAIN OUTCOME MEASURES: Nerve conduction speeds and subjective visual analogue score of pain, sensation and motor function. RESULTS: Conduction speeds were significantly more affected in patients over 70 years of age than in those under 40 years. Older patients scored their subjective complaints lower than younger patients. CONCLUSIONS: Older patients' subjective complaints misrepresent the severity of the nerve entrapment. Clinicians should have a lower threshold for objective investigation of patients older than 70 years of age to minimize development of irreversible nerve damage. PMID- 21234135 TI - Primary retroperitoneal seminoma: an unusual cause of testicular pain. PMID- 21234136 TI - Yet another journal .... PMID- 21234137 TI - Barrett's oesophagus: Is there a need for laparoscopic anti-reflux surgery? PMID- 21234138 TI - Anaesthetic implications of paediatric thoracoscopy. AB - Anaesthetic care during thoracic surgical procedures in children combines components of the knowledge bases of paediatric anaesthesia with those of thoracic anaesthesia. This article highlights the principles of anaesthesia during thoracoscopic surgery in children including preoperative evaluation, anaesthetic induction techniques, maintenance anaesthesia and options for postoperative analgesia. In addition, given the need to provide optimal surgical visualization during the procedure, one lung ventilation may be required. Techniques to provide one lung ventilation in the paediatric patient and the principles of anaesthesia care during one lung ventilation are discussed. PMID- 21234139 TI - Laparoscopic versus open appendicectomy: An Indian perspective. AB - BACKGROUND: Laparoscopic appendicectomy though widely practiced has not gained universal approval. Laparoscopic appendicectomy in India is relatively new and the literature is scant. This study was aimed to compare laparoscopic with open appendicectomy and ascertain the therapeutic benefit, if any, in the overall management of acute appendicitis. MATERIALS AND METHODS: The study group consisted of two hundred and seventy nine patients suffering from acute appendicitis. One hundred patients underwent laparoscopic appendicectomy (LA) and one hundred seventy nine patients underwent open appendecectomy (OA). Comparison was based on length of hospital stay, operating time, postoperative morbidity, duration of convalescence and operative cost in terms of their medians. The Mann Whitney statistics (T) were calculated and because of large samples, the normal deviate test (Z) was used. RESULTS: Of the hundred patients, six patients (6%) had the procedure converted to open surgery. The rate of infections and overall complications (LA: 15%, OA: 31.8%, P < 0.001) were significantly lower in patients undergoing LA. The median length of stay was significantly shorter after LA (3 days after LA, 5 days after OA, P < 0.0001) than after OA. The operating time was shorter {OA: 25 min (median), LA: 28 min (median), 0.01< P < 0.05} in patients undergoing open appendicectomy compared to laparoscopic appendicectomy. CONCLUSION: Hospital stay for LA is significantly shorter and the one-time operative charges appear to be almost the same. LA is also associated with increased clinical comfort in terms of fewer wound infections, faster recovery, earlier return to work and improved cosmesis. PMID- 21234140 TI - Does laparoscopic Nissen fundoplication prevent the progression of Barrett's oesophagus? Is the length of Barrett's a factor? AB - INTRODUCTION: Recent studies have suggested that both laparoscopic and open anti reflux surgery may produce regression of Barrett's mucosa. MATERIAL AND METHODS;: We reviewed 21 patients (13M: 8F, mean age 46.7+/-3.18 years) with documented Gastroesophageal Reflux Disease (GERD) and Non-dysplastic Barrett's esophagus (15 patients ?3 cm segment, 6 patients < 3 cm segment) on long term proton pump inhibitor therapy who underwent laparoscopic Nissen fundoplication (LNF) between 1993 and 2000. All patients had undergone pre and yearly postoperative upper GI endoscopy with 4 quadrant biopsies every 2 cm. All patients also underwent pre- and 6 months postoperative 24-hr pH study, esophageal manometry, SF36, and GERD symptom score. The mean duration of GERD symptoms was 8.4+/-1.54 years pre operative. The mean follow-up after surgery was 39+/-6.32 months. RESULTS: Postoperatively, there was significant improvement in reflux symptom score (37.5 +/- 3.98 points versus 8.7 +/- 2.46 points, P = 0.0001), % acid reflux in 24 hr (26.5 +/- 3.91% versus 2.1 +/- 0.84%, P< 0.0001) and an increase in lower esophageal sphincter pressure (3.71 +/- 1.08 mmHg versus 12.29 +/- 1.34 mmHg, P = 0.0053). Complete or partial regression of Barrett's mucosa occurred in 9 patients. All patients with complete regression had <4 cm segment of Barrett's. Progression or cancer transformation was not observed in any of the patients. CONCLUSION: LNF in patients with Barrett's oesophagus results in significant control of GERD symptoms. LNF can prevent progression of Barrett's oesophagus and in patients with Barrett's <4 cm may lead to complete regression. PMID- 21234141 TI - A study evaluating the safety of laparoscopic radical operation for colorectal cancer. AB - AIM: This study aimed to assess the safety and feasibility of laparoscopic curative resection for colorectal cancer through the clinical practice and basic research. MATERIAL AND METHODS: From September 2001 to September 2002, 47 patients with colorectal cancer were treated using laparoscopic approach, compared with 113 patients underwent traditional operation. The length of intestinal segment excised, size of tumour, clearance of lymph nodes, local recurrence and distant metastasis rate during the period of follow-up in both groups were compared. The other part of the study involved the detection of exfoliated tumour cells in the peritoneal washing before and after surgery; flushing of the instruments was performed in both groups and the results compared. For the laparoscopic cases, the filtrated liquid of CO(2) pneumoperitoneum was also checked for tumour cells. RESULTS: No significant differences existed in tumour size, operative site and manner between the two groups. The exfoliated tumour cell was not detected in the CO(2) filtrated liquid. Between both groups there was no difference in the incidence of exfoliated tumour cells in peritoneal washing before and after surgery as well as in the fluid used for flushing the instruments. The total number of lymph nodes harvested was 13.71+/-9.57 for the laparoscopic group and 12.10+/-9.74 for the traditional procedure. Similar length of colon was excised in both groups; this was (19.38+/-7.47) cm in the laparoscopic and (18.60+/-8.40) cm in the traditional groups. The distal margins of resection for rectal cancer were (4.19+/-2.52) cm and (4.16+/-2.00) cm respectively. The local recurrence rate was 2.13% (1/47) and 1.77% (2/113) with the distant metastasis rate 6.38% (3/47) and 6.19% (7/113) respectively. Both the statistics were comparable between the laparoscopic and traditional surgery for the colorectal cancer. CONCLUSION: Laparoscopic curative resection for colorectal cancer can be performed safely and effectively. In the treatment of colorectal malignancy, laparoscopic resection can achieve similar radicalilty as compared to the traditional laparotomy. PMID- 21234142 TI - Management of post cholecystectomy Mirizzi's syndrome. AB - Various strategies have been proposed for the management of retained calculi within the biliary tree following cholecystectomy. We present a unique case of a cystic duct remnant calculus causing Mirizzi syndrome, only the fourth such case of its kind. An open procedure was planned, however the calculus was eventually extracted endoscopically. The pathophysiology and management of Mirizzi syndrome and retained calculi within the cystic duct remnant are discussed along with the merits of a minimally invasive approach. PMID- 21234143 TI - Two-stage laparoscopic resection of colon cancer and metastatic liver tumour. AB - We report herein the case of 70-year-old woman in whom colon cancer and a synchronous metastatic liver tumour were successfully resected laparoscopically. The tumours were treated in two stages. Both postoperative courses were uneventful, and there has been no recurrence during the 8 months since the second procedure. PMID- 21234144 TI - Gastric diverticulum - 'Double pylorus appearance'. PMID- 21234145 TI - Laparoscopic colostomy takedown offers advantages over traditional surgery. PMID- 21234146 TI - Laparoscopic approach for Hartmann reversal procedures. PMID- 21234147 TI - Laparoscopic surgery for colorectal cancers: Current status. AB - Laparoscopy was introduced more than 15 years ago into clinical practice. However, its role in colorectal surgery was not well established for want of better skills and technology. This coupled with high incidences of port site recurrences, prevented laparoscopic surgery from being incorporated into mainstream colorectal cancer surgery. A recent increase in the number of reports, retrospective analyses, randomized trials and multicentric trials has now provided sufficient data to support the role of laparoscopy in colorectal cancer surgery. We, thus, present a review of the published data on the feasibility, safety, short - and long-term outcomes following laparoscopic surgery for colorectal cancers. While the data available strongly favors the use of laparoscopic surgery in colonic cancer, larger well powered studies are required to prove or disprove its role in rectal cancer. PMID- 21234148 TI - Laparoscopic reversal of Hartmann procedure. AB - BACKGROUND: The Hartmann procedure is a standard life-saving operation for acute left colonic complications. It is usually performed as a temporary procedure with the intent to reverse it later on. This reversal is associated with considerable morbidity and mortality by open method. The laparoscopic reestablishment of intestinal continuity after Hartmann procedure has shown better results in terms of decrease in morbidity and mortality. MATERIALS AND METHODS: The laparoscopic technique was used consecutively in 12 patients for the reversal of Hartmann procedure in the last 3 years. The adhesiolysis and mobilization of the colon was done under laparoscopic guidance. The colostomy was mobilized and returned to abdominal cavity after tying the anvil in the proximal end. An end-to-end intracorporeal anastomosis was performed between the proximal colon and the rectum using the circular stapler. RESULTS: Mean age of the patients was 40 years and the mean time of restoration of intestinal continuity was 130 days. Two patients were converted to open. The mean time of operation was 90 min. There were no postoperative complications and mortality. The mean hospital stay was 5 days. CONCLUSION: Laparoscopic reversal of Hartmann is technically safe and feasible. PMID- 21234149 TI - Teaching impact in pediatric minimal access surgery: Personal perspective from "Fellow". AB - The global objective of this paper is to review from the "Fellow" perspective, the current status of pediatric minimal access surgery (MAS) in terms of teaching feasibility, safety and impact on standard practice paradigms. In the pediatric general surgery field, surgeons are dealing with a wide range of pathology that includes thoracic, abdominal, urological and gynecological procedures. The learning curve is slow because of a relatively small volume of patients. However, gradually but steadily, a significant proportion of the procedures traditionally performed, with major open exposures at present, are preferentially performed by minimal access. Currently, minimal access surgery training is incorporated into adult general surgery residency/fellowship programs and teaching techniques of pediatric MAS are available only as seldom international workshops. Pediatric surgery fellowship programs with incorporated guidelines for MAS training are just recently feasible in select centers, mostly as "self" established programs. In many other pediatric surgery centers, teaching the "glamour" of MAS is quite dependent on a program director's vision. Integration of MAS training into the secondary residency/fellowship curriculum of pediatric surgeons is the inevitable goal. MAS- minded education and research through adequate training will pay dividends and "manufacture" competent, contemporary trainees. National Pediatric Surgery Associations should be responsible for setting criteria that consider the MAS for accreditation with maintaining the international standards of these teaching programs. PMID- 21234150 TI - Laparoscopic management of acute appendicitis in situs inversus. AB - Situs inversus is often detected incidentally in adults during imaging for a acute surgical emergency. We present a case of acute appendicitis in an adult who was previously unaware about his situs anomaly. A laparoscopic approach is helpful to deal with this condition. A 40 year old man was admitted with history of acute left lower abdominal pain, with uncontrolled diabetic keto-acidosis. Clinically, he was diagnosed as acute diverticulitis with localized peritonitis. Subsequent imaging studies and laparoscopy confirmed the diagnosis of situs inversus and acute left- sided appendicitis.He successfully underwent laparoscopic appendectomy. His postoperative recovery was uneventful. Although technically more challenging because of the reverse laparoscopic view of the anatomy, the laparoscopic diagnosis and management of acute appendicitis is indicated in situs inversus. PMID- 21234151 TI - Massive intestinal infarction following retroperitoneoscopic right lumbar sympathectomy. AB - The adverse physiological effects of pneumo and retro-peritoneum are relatively well known. However, the clinical implications of compromised mesenteric circulation through several mechanical and physiological mechanisms are not as well recognized. We describe a fatal case of intestinal infarction following an elective retroperitoneoscopic right sympathectomy. The patient was a 88-year-old man who died 30 hours after an uneventful anesthesia and right endoscopic lumbar sympathectomy. An emergency explorative laparotomy revealed a massive intestinal infarction due to thrombosis of the superior mesenteric artery. We reviewed the literature on laparoscopic procedures and mesenteric ischemia. To our knowledge, this is the first reported case of intestinal infarction following retro pneumoperitoneum. We conclude that the presence of a severe multidistrectual? arteriopathy may represent a major risk factor in retroperitoneoscopic procedures. PMID- 21234152 TI - Laparoscopic treatment of heterotopic pancreas in the prepyloric region. AB - Heterotopic pancreas is a rare condition and its diagnosis is often difficult. Traditionally the condition is treated by open surgery. We report two young women with symptomatic heterotopic pancreas located in the prepyloric region. In the first patient, upper gastrointestinal endoscopy identified a round sessile lesion with a central umbilication of the mucosa without bleeding and in the second endoscopy showed a lesion with intraluminal protrusion. In both cases, a diagnostic laparoscopy identified masses amenable to laparoscopic excision. Intraoperative histology confirmed ectopic pancreatic tissue in both. In the treatment of heterotopic pancreas, laparoscopic excision provides a feasible, safe and effective treatment option. PMID- 21234153 TI - Quest for the best procedure in minimal access thoracic surgery: Optimization of what? PMID- 21234154 TI - Mental health and industry: Dynamics and perspectives. PMID- 21234155 TI - Understanding delusions. AB - Delusion has always been a central topic for psychiatric research with regard to etiology, pathogenesis, diagnosis, treatment, and forensic relevance. The various theories and explanations for delusion formation are reviewed. The etiology, classification and management of delusions are briefly discussed. Recent advances in the field are reviewed. PMID- 21234156 TI - Impact of doctor-patient communication on preoperative anxiety: Study at industrial township, Pimpri, Pune. AB - BACKGROUND: Anxiety may not be recognized by physicians though they affect a large number of patients awaiting surgery as reported in some studies. Good doctor-patient communication may have an impact on preoperative anxiety. AIM: To find out the incidence of anxiety in patients awaiting surgery and its association with good doctor-patient communication. MATERIALS AND METHODS: The study was undertaken in a medical college hospital situated in an industrial township, for the duration of two months. It was a cross-sectional study. The study included 79 patients admitted to various surgical wards of a teaching hospital. Data was collected on a pretested questionnaire, which included a set of questions on various aspects of doctor-patient communication. The level of anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS). Statistical analysis was carried out using the WHO/CDC package EPI INFO 2002. Though preoperative anxiety was collected on an ordinal scale, later during analysis, it was collapsed to give a categorical scale. Aspects of doctor-patient communication associated with preoperative anxiety were explored by Chi square tests. RESULTS: Out of the total 79 patients, 26.5% reported definite anxiety levels. Good doctor-patient communication was found to be inversely associated with anxiety levels in the preoperative period. CONCLUSIONS: Preoperative anxiety is a common phenomenon among indoor surgical patients. A lot can be done to alleviate this anxiety by improving doctor-patient communication. PMID- 21234157 TI - Knowledge and practices of general practitioners regarding psychiatric problems. AB - BACKGROUND: Mental health problems account for 12% of global disease burden and non-psychiatrist medical practitioners deal with a large proportion of this burden. This study was planned to assess the knowledge, attitude and treatment practices of non-psychiatrist medical practitioners regarding mental health problems. MATERIALS AND METHODS: One hundred Allopathic and 25 each of Homeopathic and Ayurvedic medical practitioners were interviewed and assessed using a semi-structured performa. RESULTS: Majority (95%) of them were aware regarding etiology, increasing incidence and treatment facilities available for mental health problems. Treatment modalities include counseling and medication but 69.9% of them had not received any formal training in administering them. CONCLUSIONS: 98.5% practitioners providing mental health services at the primary level feel the need to be properly trained and oriented in the management of these patients to improve quality of healthcare. PMID- 21234158 TI - The short-form revised Eysenck personality questionnaire: A Hindi edition (EPQRS H). AB - BACKGROUND: There is a growing consensus about the validity of human personality traits as important dispositions toward feelings and behaviors (Matthews, Deary, & Whiteman, 2003). MATERIALS AND METHODS: Here we examine the reliability of the Hindi translation of the Eysenck Personality Questionnaire-Revised Short Form (EPQR-S; Eysenck, Eysenck, & Barrett, 1985), which consists of 48 items that assess neuroticism, extraversion, psychoticism, and lying. The questionnaire was first translated into Hindi and then back translated. Subsequently, it was administered to 202 students (78 men and 124 women) from Banaras Hindu University. The internal consistency of the scale was evaluated. RESULTS: The findings provide satisfactory psychometric properties of the extraversion, neuroticism and lie scales. The psychoticism scale, however, was found to be less satisfactory. CONCLUSION: It can be proposed that due to satisfactory internal consistency scores, the EPQRS-H is a reliable scale for the measurement of various personality traits. PMID- 21234159 TI - Parent-child relationship in children of alcoholic and non-alcoholic parents. AB - AIM: Overall aim of the study was to see parent-child relationship in children of alcoholic and non-alcoholic parents. MATERIALS AND METHODS: The sample consisted of 30 alcoholic and 30 non-alcoholic parents and their children taken from Kanke Block of Ranchi district. The sample was selected on the basis of inclusion and exclusion criteria. Socio-demographic data sheet and Parent Child Relationship Scale (Rao, 1978) were administered to the children. RESULTS: In a child's perception of father in various domains of parent-child relationship, significant difference at P < 0.01 was found in the domain of symbolic punishment, rejecting, objective punishment, demanding, indifferent, symbolic reward in loving and neglecting, and in child's perception of the mother. Significant difference at P < 0.01 was found in the domain of symbolic punishment, rejecting, object punishment, indifferent and in neglecting. CONCLUSION: The result showed that the children of alcoholic parents tended to have more symbolic punishment, rejecting, objective punishment, demanding, indifferent, symbolic reward loving and in neglecting than children of non alcoholic parents. PMID- 21234160 TI - Coping behaviour of female teachers: Demographic determinants. AB - BACKGROUND: The study investigates the role of certain demographic variables in determining stress-coping behavior of female teachers. MATERIALS AND METHODS: The sample consists of 150 female teachers selected by stratified sampling method from various schools of Bhopal. Stress-coping behavior was measured with the help of a subscale of 'The Occupational Stress Indicator' (Wendy Lord, 1993) consisting of 28 items encompassing six dimensions of coping strategies i.e. Logics, Involvement, Social Support, Task Strategies, Time Management and Home and Work Relations. The scores of the subjects were compared in terms of marital status, age, and level of teaching with the help of 't' test and 'F' test was used for comparing experience. RESULTS: Marital status, age, and experience were found to be significant determinants of stress-coping, whereas the sores did not differ significantly on the basis of level of teaching. CONCLUSION: Married teachers in the age range of 40-60 years, with higher experience can cope better with the job stress than their counterparts. PMID- 21234161 TI - Insight and its relationship with stigma in psychiatric patients. AB - BACKGROUND: The literature on insight has paid insufficient attention to the social experiences that are associated with receiving and endorsing a diagnosis of mental illness. The psychological and behavioral commitments associated with insight extend beyond agreeing with a diagnosis and accepting treatment to include taking on the identity of an individual diagnosed with mental illness. This study sought to examine the relationship between insight and stigma in psychiatric patients. MATERIALS AND METHODS: Cross-sectional assessment of insight and stigma was done using the system adopted by Kaplan and Sadock in their comprehensive textbook of psychiatry and Felt Stigma Scale in 100 psychiatric patients (40 patients suffering from Bipolar affective disorder, 30 Schizophrenics, 20 Substance dependents and 10 with Obsessive Compulsive disorder). RESULTS: It was found that the level of stigma felt by patients with insight was significantly higher than that felt by patients without insight. CONCLUSION: Though there is a certain extent of stigma present in patients without insight, as is expected, the level of stigma increases as the patients develop insight. PMID- 21234162 TI - Study of prevalence of depression in adolescent students of a public school. AB - BACKGROUND: Three to nine per cent of teenagers meet the criteria for depression at any one time, and at the end of adolescence, as many as 20% of teenagers report a lifetime prevalence of depression. Usual care by primary care physicians fails to recognize 30-50% of depressed patients. MATERIALS AND METHODS: Cross sectional one-time observational study using simple screening instruments for detecting early symptoms of depression in adolescents. Two psychological instruments were used: GHQ-12 and BDI. Also socio-demographic data (e.g. academic performance, marital harmony of parents, bullying in school, etc) was collected in a separate semi-structured performa. Statistical analysis was done with Fisher's Exact Test using SPSS17. RESULTS: 15.2% of school-going adolescents were found to be having evidence of distress (GHQ-12 score e14); 18.4% were depressed (BDI score e12); 5.6% students were detected to have positive scores on both the instruments. Certain factors like parental fights, beating at home and inability to cope up with studies were found to be significantly (P < 0.05) associated with higher GHQ-12 scores, indicating evidence of distress. Economic difficulty, physical punishment at school, teasing at school and parental fights were significantly (P < 0.05) associated with higher BDI scores, indicating depression. CONCLUSION: The study highlights the common but ignored problem of depression in adolescence. We recommend that teachers and parents be made aware of this problem with the help of school counselors so that the depressed adolescent can be identified and helped rather than suffer silently. PMID- 21234163 TI - An experience of community mental health program in rural areas of Jharkhand. AB - BACKGROUND: In the present era, mental disability is a major public health problem in the society. Many of the mental disabilities are correctable if detected early. OBJECTIVES: To assess the prevalence and pattern of mental disability. MATERIALS AND METHODS: Community-based cross-sectional study. Patients of all age groups in the age range of 0-60 years were randomly selected from 10 blocks of 2 districts, viz., Ranchi and Hazaribagh. Thirty villages from each block were taken for the study. The study was conducted by making house-to house visits, interviewing and examining all the individuals in the families selected using pre-tested questionnaire. STATISTICAL ANALYSIS: It was done by the proportions. RESULTS AND CONCLUSION: The prevalence of mental disability was found higher among males (67.9%) than among females (32.1%). The prevalence rate was higher among the productive groups and among individuals with low socioeconomic status. There is scope of community-based rehabilitation of the mentally disabled. PMID- 21234164 TI - Loneliness, depression and sociability in old age. AB - BACKGROUND: The elderly population is large in general and growing due to advancement of health care education. These people are faced with numerous physical, psychological and social role changes that challenge their sense of self and capacity to live happily. Many people experience loneliness and depression in old age, either as a result of living alone or due to lack of close family ties and reduced connections with their culture of origin, which results in an inability to actively participate in the community activities. With advancing age, it is inevitable that people lose connection with their friendship networks and that they find it more difficult to initiate new friendships and to belong to new networks. The present study was conducted to investigate the relationships among depression, loneliness and sociability in elderly people. MATERIALS AND METHODS: This study was carried out on 55 elderly people (both men and women). The tools used were Beck Depression Inventory, UCLA Loneliness Scale and Sociability Scale by Eysenck. RESULTS: Results revealed a significant relationship between depression and loneliness. CONCLUSION: Most of the elderly people were found to be average in the dimension of sociability and preferred remaining engaged in social interactions. The implications of the study are discussed in the article. PMID- 21234165 TI - Social development of children with mental retardation. AB - BACKGROUND: Social development of children with mental retardation has implications for prognosis. The present study evaluated whether the social maturity scale alone can reflect on the social maturity, intellectual level and consequent adjustment in family and society of children with mental retardation. MATERIALS AND METHODS: Thirty-five mentally retarded children were administered Vineland Social Maturity Scale and Stanford Binet Intelligence Scale. RESULTS: It was found that there was significant relationship between the measures of social maturity scale and the IQ of the subjects. Further it was found that with increasing severity of retardation, social development also decreases and age does not have any effect on social development. CONCLUSION: Social quotient increases from profound to mild level of retardation. PMID- 21234166 TI - Cognitive behavioral therapy in the treatment of social phobia. AB - Cognitive behavior therapy is probably the most well-known and the most practiced form of modern psychotherapy and has been integrated into highly structured package for the treatment of patients suffering from social phobia. The present case study is an attempt to provide therapeutic intervention program to a 27-year old, unmarried Christian man suffering from social phobia. The patient was treated by using cognitive behavioral techniques. After 17 sessions of therapeutic intervention program, significant improvement was found. He was under follow-up for a period of 6 months and recovered to the premorbid level of functioning. PMID- 21234167 TI - Probability, clinical decision making and hypothesis testing. AB - Few clinicians grasp the true concept of probability expressed in the 'P value.' For most, a statistically significant P value is the end of the search for truth. In fact, the opposite is the case. The present paper attempts to put the P value in proper perspective by explaining different types of probabilities, their role in clinical decision making, medical research and hypothesis testing. PMID- 21234168 TI - Event-related potential: An overview. AB - Electroencephalography (EEG) provides an excellent medium to understand neurobiological dysregulation, with the potential to evaluate neurotransmission. Time-locked EEG activity or event-related potential (ERP) helps capture neural activity related to both sensory and cognitive processes. In this article, we attempt to present an overview of the different waveforms of ERP and the major findings in various psychiatric conditions. PMID- 21234169 TI - From the Editor's desk. PMID- 21234170 TI - Nobel prize for scientist Professor Robert G Edwards. PMID- 21234171 TI - Fertility and age. AB - The changing social scenario together with economic growth and an increase in job opportunities has to a great extent reduced gender inequality and has resulted in more and more older women seeking help from infertility clinics. Fertility and aging have always been closely linked and the age of the female partner remains the single most important factor in predicting success with treatment. Although tests for the ovarian reserve are an important informative tool and are helpful in selecting treatment options, they are poor predictors of the outcome. PMID- 21234172 TI - Relationship between seminal plasma zinc and semen quality in a subfertile population. AB - RATIONALE: Current knowledge on the relationship between seminal zinc levels and different parameters of human semen is inconsistent. OBJECTIVES: To assess the relationship between seminal plasma zinc and semen quality using two markers; zinc concentration (Zn-C) and total zinc per ejaculate (Zn-T). DESIGN: The study was carried out as a cross-sectional study. SUBJECTS AND METHODS: Semen parameters of 152 healthy men undergoing evaluation for subfertility were assessed. Seminal plasma zinc levels were determined using flame atomic absorption spectrometry. Zn-C, expressed as MUg/mL, was multiplied by ejaculated volume to calculate Zn-T. Mann Whitney U test and Chi-square test were used to compare the zinc levels between different seminal groups when appropriate. Correlations were observed with Pearson's correlation of coefficient. Analysis was carried out using SPSS 10.0 for windows software. RESULTS: Zn-C was low in 23 (15%) samples, while in 32 (21%) of the samples Zn-T was abnormal. The number of subnormal samples was high in the low-zinc groups compared with the normal-zinc groups, 15 vs. 8 (P > 0.05) for Zn-C and 28 vs. 4 (P < 0.001) for Zn-T. Zn-C was significantly high in the asthenozoospermics compared with the normal motile group; 138.11 MUg/mL (83.92) vs. 110.69 11 MUg/mL (54.59) (P < 0.05). Zn-T was significantly low in samples with hyperviscosity compared with samples with normal viscosity; 220.06 MUg (144.09) vs. 336.34 MUg (236.33) (P < 0.05). Conversely, Zn-T was high in samples with low viability compared with those with normal viability; 437.67 MUg (283.88) vs. 305.15 MUg (221.19) (P < 0.05). Weak correlations were found between Zn and some semen parameters. However, the correlation was negative between pH and Zn-C (r = -0.193, P < 0.05) as well as Zn T (r = -0.280, P < 0.01). On the other hand, correlations were positive between Zn-T and sperm count (r = 0.211, P < 0.05). CONCLUSION: Count, motility, viability, pH and viscosity are affected by variations of seminal plasma zinc. Seminal plasma Zn-T is the better marker for assessing the relationship between zinc and semen quality. PMID- 21234173 TI - Predictive factors for pregnancy after intrauterine insemination: A prospective study of factors affecting outcome. AB - OBJECTIVE: To determine the predictive factors for pregnancy after controlled ovarian hyperstimulation (COH)/intrauterine insemination (IUI). DESIGN: Prospective observational study. SETTING: University-level tertiary care center. PATIENTS AND METHODS: 366 patients undergoing 480 stimulated IUI cycles between November 2007 and December 2008. INTERVENTIONS: Ovarian stimulation with gonadotrophins was initiated and a single IUI was performed 36 h after triggering ovulation. MAIN OUTCOME MEASURES: The primary outcome measures were clinical pregnancy and live birth rates. Predictive factors evaluated were female age, duration of infertility, indication for IUI, number of preovulatory follicles, luteinizing hormone level on day of trigger and postwash total motile fraction (TMF). RESULTS: The overall clinical pregnancy rate and live birth rate were 8.75% and 5.83%, respectively. Among the predictive factors evaluated, the duration of infertility (5.36 vs. 6.71 years, P = 0.032) and the TMF (between 10 and 20 million, P = 0.002) significantly influenced the clinical pregnancy rate. CONCLUSION: Our results indicate that COH/IUI is not an effective option in couples with infertility due to a male factor. Prolonged duration of infertility is also associated with decreased success, and should be considered when planning treatment. PMID- 21234174 TI - Effect of body mass index on in vitro fertilization outcomes in women. AB - BACKGROUND: Obesity has become a major health problem across the world. In women, it is known to cause anovulation, subfecundity, increased risk of fetal anomalies and miscarriage rates. However, in women going for assisted reproduction the effects of obesity on egg quality, embryo quality, clinical pregnancy, live birth rates are controversial. OBJECTIVES: To assess the effect of women's body mass index (BMI) on the reproductive outcome of non donor In vitro fertilization (IVF)/Intracytoplasmic sperm injection (ICSI). The effects of BMI on their gonadotrophin levels (day 2 LH, FSH), gonadotrophin dose required for ovarian stimulation, endometrial thickness and oocyte/embryo quality were looked at, after correcting for age and poor ovarian reserve. MATERIALS AND METHODS: Retrospective study of medical records of 308 women undergoing non donor IVF cycles in a University affiliated teaching hospital. They were classified into three groups: normal weight (BMI<25 kg/m(2)), overweight (BMI>25 <30 kg/m(2)) and obese (BMI>30 kg/m(2)). All women underwent controlled ovarian hyper stimulation using long agonist protocol. RESULTS: There were 88 (28.6%) in the normal weight group, 147 (47.7%) in the overweight and 73 (23.7%) in the obese group. All three groups were comparable with respect to age, duration of infertility, female and male causes of infertility. The three groups were similar with respect to day 2 LH/FSH levels, endometrial thickness and gonadotrophin requirements, oocyte quality, fertilization, cleavage rates, number of good quality embryos and clinical pregnancy rates. CONCLUSION: Increase in body mass index in women does not appear to have an adverse effect on IVF outcome. However, preconceptual counselling for obese women is a must as weight reduction helps in reducing pregnancy-related complications. PMID- 21234175 TI - Effect of metformin therapy on 2-h post-glucose insulin levels in patients of polycystic ovarian syndrome. AB - AIMS: To evaluate if 2-h post glucose insulin level is an effective tool to monitor insulin resistance in response to metformin therapy, in infertile women with polycystic ovarian syndrome (PCOS). SETTINGS AND DESIGN: This prospective observational study was carried out in a tertiary care infertility clinic. MATERIALS AND METHODS: 40 women with PCOS were categorized as having insulin resistance if fasting or 2-h post glucose insulin levels were >25 or >41MUU/ml respectively. Post glucose insulin was compared before and after six months of metformin therapy along with other clinical, hormonal and metabolic parameters by using McNemar and the Student's t-test. RESULTS: Fasting insulin was elevated in 4 (10%) and post-load insulin in 34 (85%) patients; after metformin therapy respective values were 2 (5%) and 16 (40%). Metformin therapy reduced post glucose insulin levels (P<0.001), improved the regularity of periods (P<0.001) and resulted in reduction of LH levels (P<0.001), total testosterone (P<0.001) and mean Body mass index (BMI) (P=0.047). Metformin therapy did not alter waist hip ratio and fasting insulin levels. CONCLUSION: 2-h post glucose insulin level is an effective tool to monitor insulin resistance in PCOS patients and improves significantly after metformin therapy, similar to improvements observed in clinical, hormonal and metabolic parameters. PMID- 21234176 TI - Reproductive outcome of septate uterus following hysteroscopic septum resection. AB - OBJECTIVE: To evaluate the reproductive outcome following hysteroscopic septum resection in patients with primary and secondary (recurrent pregnancy loss [RPL] and bad obstetric history [BOH]) infertility. STUDY DESIGN: Retrospective study. MATERIALS AND METHODS: Hysteroscopic septum resection was performed on 26 patients with a history of either recurrent pregnancy loss, BOH or infertility. The septum resection was performed using a bipolar versapoint system. Reproductive performance of these patients after septum resection was analyzed. The main outcome measures were clinical pregnancy and live birth rates. RESULTS: Hysteroscopic septum resection was performed on seven patients with the history of secondary infertility. Post operatively, the pregnancy rate was 86% (n=6), and the live birth rate was 67% (n=4). After septum resection in 19 primary infertile patients, 6 (32%) patients conceived which resulted in live birth rates of 67% (n=4). CONCLUSION: Hysteroscopic septum resection using bipolar versapoint system is an effective and safe approach for the removal of septum. Hysteroscopic septum resection in women with septate uterus significantly improves the live birth rates and future fertility is not impaired. PMID- 21234177 TI - Potential protein post-translational modification in ERp57: A phenotype marker for male fertility. AB - BACKGROUND: In protein expression, post-translational modification is an important process. It is also an important process in human reproductive science. ERp57 is a molecule that is mentioned for post-translational modification. ERp57 is a component of human sperm acrosome proteins. However, the data on post translational modifications of ERp57 is limited. AIM: The aim of this work is to assess potential protein post-translational modifications in ERp57 protein. SETTINGS AND DESIGN: A descriptive computational bioinformatics study. MATERIALS AND METHODS: In this work, potential protein post-translational modifications in ERp57 protein were assessed via a standard bioinformatics technique. STATISTICAL ANALYSIS USED: Bioinformatics analysis. RESULTS: There are three post translational modifications within ERp57 from bioinformatics analysis. CONCLUSION: This new knowledge can be useful for better realization on molecular process of male infertility. PMID- 21234178 TI - Effect of duration of fluoride exposure on the reproductive system in male rabbits. AB - BACKGROUND AND OBJECTIVES: Fluorosis has become an endemic problem worldwide. Fluoride has its effect on various organs, including the reproductive system, although there are controversial reports over it. Thus, the present study was designed to study the effect of sodium fluoride (NaF) exposure for different durations. MATERIALS AND METHODS: 30 healthy rabbits were divided into three equal groups. Group I was fed on a standard diet for 30 days, Group II was fed on sodium fluoride (20 mg/kg body weight) for 30 days and Group III was fed on sodium fluoride (20 mg/kg body weight) for 60 days. Sperm count, motility, progressive motility and weight of testis and epididymis were measured and compared with the control group. RESULTS: We observed that in the group exposed to NaF for 30 days (Group II), there was a significant decrease in all the parameters except the testicular weight and in the group on exposure of 60 days (Group III), there was a significant decrease in all the parameters when compared with the control group (Group I). On applying the Tukey post-hoc test between Groups II and III, we observed that there was a significant decrease in the sperm count while the other parameters showed a non-significant decrease. Testicular histology was confirmatory for the above findings. CONCLUSION: The present study demonstrates that fluoride hampers the reproductive functions of male rabbits and is proportional to the duration of fluoride exposure. PMID- 21234179 TI - Maturation arrest of human oocytes at germinal vesicle stage. AB - Maturation arrest of human oocytes may occur at various stages of the cell cycle. A total failure of human oocytes to complete meiosis is rarely observed during assisted conception cycles. We describe here a case of infertile couples for whom all oocytes repeatedly failed to mature at germinal vesicle (GV) stage during in vitro fertilization/Intra cytoplasmic sperm injection (IVF/ICSI). The patient underwent controlled ovarian stimulation followed by oocyte retrieval and IVF/ICSI. The oocytes were stripped off cumulus cells prior to the ICSI procedure and their maturity status was defined. The oocyte maturation was repeatedly arrested at the GV. Oocyte maturation arrest may be the cause of infertility in this couple. The recognition of oocyte maturation arrest as a specific medical condition may contribute to the characterization of the currently known as "oocyte factor." The cellular and genetic mechanisms causing oocyte maturation arrest should be the subject for further investigation. PMID- 21234180 TI - A case of unilateral dysmenorrhea. AB - Unilateral dysmenorrhea in an adolescent may be associated with uterine malformation. Relevant investigations in suspected cases and timely intervention can prevent future complications in such cases. Here, we present a case of unicornuate uterus with rudimentary horn in an adolescent complaining of unilateral dysmenorrhea. PMID- 21234181 TI - High-dose hook effect in prolactin macroadenomas: A diagnostic concern. PMID- 21234182 TI - Hyperprolactinemia with normal serum prolactin: "Hook effect" a concern in laboratory medicine aspect. PMID- 21234183 TI - Predictive value of human chorionic gonadotrophin in the outcome of early pregnancy achieved by assisted reproductive technology: A summative assessment. PMID- 21234184 TI - Management of polyorchidism: Surgery or conservative management? PMID- 21234185 TI - Recent advances in physiological priming of spermatozoa. PMID- 21234186 TI - Evidence-based medicine: How evident is it ? PMID- 21234188 TI - Myocardial dysfunction in malnourished children. AB - BACKGROUND: Malnourished children suffer several alterations in body composition that could produce cardiac abnormalities. AIM: The aim of the present study was to detect the frequency of myocardial damage in malnourished children as shown by echocardiography and cardiac troponin T (cTnT) level. METHODS: Forty-five malnourished infants and young children (mean+/-SD of age was 11.24 +/-7.88 months) were matched with 25 apparently healthy controls (mean+/-SD of age was 10.78+/-6.29 months). Blood sample was taken for complete blood picture, liver and kidney function tests, serum sodium, potassium, calcium levels and cTnT. All the malnourished children were subjected to echocardiographic evaluation. RESULTS: Malnourished children showed a significantly lower left ventricular (LV) mass than the control group. The LV systolic functions were significantly impaired in patients with severe malnutrition. The cTnT level was higher than the upper reference limits in 11 (24.44%) of the studied malnourished children and all of them had a severe degree of malnutrition. The cTnT level was significantly higher in patients with anemia, sepsis and electrolyte abnormalities and it correlated negatively with LV ejection fraction (EF). Six of the studied children with high cTnT levels (54.5%) died within 21 days of treatment while only one case (2.9%) with normal level of cTnT died within the same period. CONCLUSIONS: LV mass is reduced in malnourished children. Children with severe malnutrition have a significant decrease in LV systolic functions. Elevated cTnT levels in malnourished children has both diagnostic and prognostic significance for cardiomyocyte damage. PMID- 21234187 TI - Sudden cardiac death in children and adolescents (excluding Sudden Infant Death Syndrome). AB - Sudden death in the young is rare. About 25% of cases occur during sports. Most young people with sudden cardiac death (SCD) have underlying heart disease, with hypertrophic cardiomyopathy and coronary artery anomalies being commonest in most series. Arrhythmogenic right ventricular dysplasia and long QT syndrome are the most common primary arrhythmic causes of SCD. It is estimated that early cardiopulmonary resuscitation and widespread availability of automatic external defibrillators could prevent about a quarter of pediatric sudden deaths. PMID- 21234189 TI - Isolated absence of right pulmonary artery. AB - BACKGROUND: Absence of right pulmonary artery (RPA) is a rare congenital abnormality with variable presentation. The diagnosis is often missed in infants OBJECTIVE: The aim of this study was to describe infantile presentation of isolated absence of RPA along with a brief review of the literature. METHODS: The details of five patients diagnosed with isolated absence of RPA from April 2007 to October 2009 were reviewed retrospectively RESULTS: Five patients were identified with this anomaly. The median age of presentation was 86 days (range, 40-120 days) and the median weight was 3.65 kg (range, 3.1-5.5 kg). All patients presented with breathing difficulty and had severe pulmonary hypertension (PHT) along with absent RPA on echocardiography. A multidetector computed tomographic scan was performed to confirm the diagnosis in four cases. Three patients had major aortopulmonary collateral and the hilar RPA was not well developed in all. A correct diagnosis was made before referral in one patient only. Differential vascularity in chest X-ray, a useful clue, was seen in four of five cases. Surgical correction was not considered in view of the small hilar pulmonary artery. The patients were all managed medically with diuretics and Sildenafil. CONCLUSION: Isolated absence of RPA is a rare congenital abnormality with varied presentation. Infantile presentation is marked with congestive cardiac failure and PHT. Specific diagnostic clue includes differential vascularity on the chest X-ray. PMID- 21234190 TI - Recurrence rate of different techniques for repair of coarctation of aorta: A 10 years experience. AB - BACKGROUND AND AIM: The main goal of this study was to assess the frequency of recurrent coarctation after repair using different surgical methods. METHODS: Surgical results of repairs for coarctation of aorta (Co-A) in 188 patients under the age 14 years who were treated in Rajaee Heart Center, Tehran, Iran, were evaluated retrospectively. The most common methods included patch-graft aortoplasty (59%), resection with end-to-end anastomosis (20.7%) and subclavian flap aortoplasty (SCFA) (16.5%). The remaining patients underwent bypass tube graft and excision with placement of a tube graft. Seventy eight percent had discrete stenosis while 22% had long segment narrowing. The patients were followed for 81.6+/-32.8 months. RESULTS: The overall mortality rate was 2.6%. The highest incidence rate of recoarctation was found in the patch-graft aortoplasty group (12.7%) and the lowest was found in SCFA (3.2%). The incidence of recoarctation in long-segment lesions was significantly higher than that in the discrete ones (30% vs. 4%, P<0.001). In patients <1 year, the incidence of recoarctation was lower than that in the other age groups. CONCLUSION: The patch graft aortoplasty technique had the highest incidence of recoarctation and SCFA had the lowest rate. Long-segment Co-A had a higher chance of recoarctation. In contrast to some previous reports, the incidence of recoarctation was not higher in the age below 1 year. PMID- 21234192 TI - Staged repair of pulmonary atresia, ventricular septal defect, and major systemic to pulmonary artery collaterals. PMID- 21234191 TI - Management of ventricular septal defect with pulmonary atresia and major aorto pulmonary collateral arteries: Challenges and controversies. PMID- 21234193 TI - Techniques for transcatheter recanalization of completely occluded vessels and pathways in patients with congenital heart disease. AB - Occlusions of major vessels in patients with congenital heart disease may occur due to a variety of factors. These occlusions are often felt to be best addressed surgically; however, we and others have been successful in recanalizing most of these vessels in the catheterization laboratory. Most of these patients will require multiple procedures in the catheterization laboratory to ensure vessel patency and to facilitate vessel growth. Physicians performing the procedure should have a thorough understanding of the anatomic considerations for the intended procedure and have access to a variety of devices and equipment to optimize the result of the procedure. In this article, we review some of the technical aspects that are vital for the success of the procedure. PMID- 21234194 TI - Management of perioperative low cardiac output state without extracorporeal life support: What is feasible? AB - A transient and reversible reduction in cardiac output-low cardiac output state (LCOS) often occurs following surgery for congenital heart disease. Inappropriately managed LCOS is a risk factor for increased morbidity and death. LCOS may occasionally be progressive and refractory needing a period of "myocardial rest" with extracorporeal life support (ECLS). ECLS is currently considered a routine tool available for rapid deployment in most industrialized countries. Accumulated experience and refinements in technology have led to improving survivals - discharge survivals of 35%-50%, with almost 100% survival in select groups on elective left ventricular assist device. Thus, there is an increasing trend to initiate ECLS "early or electively in the operating room" in high-risk patients. India has a huge potential need for ECLS given the large number of infants presenting late with preexisting ventricular dysfunction or in circulatory collapse. ECLS is an expensive and resource consuming treatment modality and is not a viable therapeutic option in our country. The purpose of this paper is to reiterate an anticipatory, proactive approach to LCOS: (1) methods for early detection of evolving LCOS and (2) timely initiation of individualized therapy. This paper also explores what is feasible with the refinement of "simple, conventional, inexpensive strategies" for the management of LCOS. Therapy for LCOS should be multimodal based on the type of circulation and physiology. Our approach to LCOS includes: (1) intraoperative strategies, (2) aggressive afterload reduction, (3) lusitropy, (4) exclusion of structural defects, (5) harnessing cardiopulmonary interactions, and (6) addressing metabolic and endocrine abnormalities. We have achieved a discharge survival rate of greater than 97% with these simple methods. PMID- 21234195 TI - Right atrial myxoma with glandular differentiation: A rare entity in pediatric age group. AB - Cardiac myxomas (CMs) account for nearly half of the primary cardiac tumors in the elderly. They arise from sub-endocardial "reserve" or lepidic" cells, which may show divergent differentiation. We describe a CM with glandular differentiation in the right atrium of a 10-year-old child who presented with respiratory distress on exertion, of 2 months duration. On echocardiography, two large interconnected masses measuring 34*30 mm and 20*17 mm were seen to arise from the free wall of the right atrium. Cut surface of the excised mass was myxoid with areas of calcification. On microscopy, there were typical features of a myxoma with prominent glandular differentiation and characteristic immunophenotype. The case is being reported due to its rarity in pediatric age group as well as its glandular differentiation, which must be recognized as a spectrum of histomorphologic diversity and must not be mistaken for a metastatic adenocarcinoma. PMID- 21234196 TI - The window ductus: Circulatory arrest as an option for surgical repair. AB - The window ductus represents a very rare anatomical anomaly. Only a few cases of successful surgical repair have been reported. We present a 12 year old boy in whom window ductus was diagnosed and successfully operated. The operation included closure of the large (2.5 cm*0.5 cm) connection between the main pulmonary artery and the aortic arch using cardiopulmonary bypass and hypothermia with circulatory arrest. PMID- 21234197 TI - Ectopia cordis with endocardial cushion defect: Prenatal ultrasonographic diagnosis with autopsy correlation. AB - The prenatal ultrasonographic diagnosis of ectopia cordis associated with a complex intra-cardiac defect (common atrium, common atrioventricular valve with single ventricle) is illustrated in a 32-week gestation fetus. The fetus showed associated features of amniotic band disruption sequence. The cardiac autopsy findings correlated with the antenatal diagnosis. The association of ectopia cordis with amniotic band disruption is rare and infrequently reported in literature. PMID- 21234198 TI - Imaging features of double aortic arch shown by multidetector computed tomography angiography. AB - We present a three-dimensional reconstructed image of vascular ring in a 2.5 month-old patient, which was obtained using multidetector computed tomography (MDCT). MDCT angiography made an accurate diagnosis of this life-threatening, but correctable, anomaly in an infant with a stridor, repeated respiratory infections and episodes of apnea. PMID- 21234199 TI - A case of symptomatic double coronary artery-pulmonary artery fistulae. AB - A 57-year-old lady presenting with angina was found to have multiple coronary arterio venous fistulae (CAVF) arising from both left and the right coronary arteries and draining into the pulmonary artery. She underwent successful surgical closure of these CAVF. PMID- 21234200 TI - Candida tropicalis endocarditis: Treatment in a resource-poor setting. AB - Fungal endocarditis (FE) is rare in children and does not usually occur in structurally normal hearts. The commonest causative agent is Candida albicans. We report a 5-year-old female child presenting with high-grade fever and cardiac failure. Anemia, leukocytosis and high CRP were found, but bacterial blood culture was sterile. There was no response to antimicrobial agents. Two dimensional echocardiography revealed a large heterogeneous mass attached to the right ventricle and tricuspid valve. Provisional diagnosis of FE was made, which was confirmed by growth of Candida tropicalis in blood culture. Liposomal amphotericin B was started, followed by radical curative surgery including excision of the entire vegetation with total tricuspid valve excision. Histopathology and culture of the resected vegetation confirmed the diagnosis. The patient was given antifungal therapy for a total of 7 weeks, including 2 weeks of post-operative treatment, following which she was afebrile. PMID- 21234201 TI - Transcatheter closure of ruptured right-coronary aortic sinus fistula to right ventricle. AB - A 22-year-old man was referred for evaluation of exertional fatigue. On examination, there were no overt signs of congestive heart failure. Transthoracic and transesophageal echocardiography revealed rupture of the right coronary aortic sinus of Valsalva into the right ventricle. It was successfully closed with a 12 * 10 Amplatzer duct occluder. PMID- 21234202 TI - Constriction of juxta-ductal aorta and rapid progression of obstruction in a newborn. AB - A 13-day-old baby girl presenting with features of congestive cardiac failure was found to have coarctation of the aorta (CoA) and patent ductus arteriosus (PDA) by echocardiography. Doppler spectral display revealed moderate CoA. Echocardiogram, 12 hours later, showed severe juxtaductal aortic coarctation with spontaneous closure of PDA. This case emphasises the need to keep a close watch on the progress of CoA in the neonatal period, even if the duct has narrowed to a small size thus demonstrating the role of constriction of juxtaductal aorta in pathogenesis of coaractation. Closure of even asmall PDA can cause acute progression CoA in the presence of posterior shelf. PMID- 21234203 TI - Severe pulmonary hypertension in a young patient with end-stage renal disease on chronic hemodialysis. AB - Severe pulmonary hypertension in a teenager with end-stage renal disease on chronic hemodialysis via arteriovenous access is reported. Clinical presentation included persistent volume overload and pericardial effusion. Serial hemodynamic data obtained at cardiac catheterization confirmed the diagnosis. In addition, detailed biochemical and imaging data (echo- Doppler, computed tomography of chest, computed tomographic pulmonary angiography, VQ lung scan, etc.) were obtained to find out the mechanism. The exact cause of pulmonary hypertension remains unclear, and a multi- factorial mechanism is postulated. This rare case is presented to highlight the role of aggressive dialysis, pericardiocentesis, and use of sildenafil and bosentan in the management. PMID- 21234204 TI - Anatomically corrected malposition of great arteries. AB - Anatomically corrected malposition of great arteries (ACMGA) is a rare form of congenital heart disease in which the great arteries arise above the anatomically correct ventricles but have abnormal spatial relationship. We report the case of a 26-year-old female with ACMGA and tunnel type of subaortic obstruction. The abnormal relationship and segmental arrangement necessitates systematic approach in evaluation for proper diagnosis and surgical repair. This unusual case is reported for its rarity and to highlight the need for awareness to differentiate it from other more common conditions. PMID- 21234205 TI - Off-pump coronary bypass grafting for kawasaki disease. AB - A 6-year-old girl, a known case of Kawasaki disease, presented with acute thrombotic occlusion of right coronary artery (RCA) with symptoms of acute angina and myocardial dysfunction. She underwent beating heart off-pump coronary artery bypass graft (CABG) surgery with right internal mammary artery (RIMA) grafted to distal RCA. Follow-up computed tomography angiogram revealed well-flowing RIMA with no obstruction or kink. This case highlights the importance of CABG as a safe and life-saving procedure in expert hands, even for children in emergent conditions. PMID- 21234206 TI - Transcatheter occlusion of multiple pulmonary arterio venous malformations. AB - Pulmonary arterio venous malformations are one of the rare vascular anomalies. Usually single large pulmonary arteriovenous fistula (PAVF) can be closed through transcatheter route but multiple PAVF require surgical lobectomy. We describe a case of an 8-year-old boy with multiple PAVF, who underwent successful transcatheter closure with multiple coils. PMID- 21234207 TI - Twin heart with a fused atria and separate ventricles in conjoined twins. AB - One of the most interesting congenital malformations is that of conjoined twins. We report echocardiographic features of twin heart in dicephalus, tribrachius, dispinous, thoracoomphalopagus twin. It showed two hearts fused at atrial level. Right-sided heart had single atrial chamber with a single ventricle. A single great vessel, aorta, originated from it. Left-sided heart was well developed with two atria and two ventricles. There was a small mid muscular ventricular septal defect and a small patent ductus arteriosus. Great arteries had normal origins. PMID- 21234208 TI - Beyond quantum physics. PMID- 21234209 TI - Measures of spiritual and transpersonal constructs for use in yoga research. AB - This article presents information on standardized paper-and-pencil measures of spiritual and transpersonal constructs that hold promise for use in yoga research. Nine instruments are discussed at length including the Assessment Schedule for Altered States of Consciousness, Ego Grasping Orientation, Expressions of Spirituality Inventory, Hindu Religious Coping Scale, Measures of Hindu Pathways, Self-Expansiveness Level Form, Spiritual Orientation Inventory, Spiritual Transcendence Scale, and the Vedic Personality Inventory. As well, a listing of an additional 14 measures, along with primary citations, is provided. In conclusion, the authors proffer recommendations for the use of psychometric tests and provide a general proposal for programmatic research. PMID- 21234210 TI - A randomized control trial of the effect of yoga on Gunas (personality) and Self esteem in normal healthy volunteers. AB - BACKGROUND/AIMS: To study the efficacy of yoga on Gunas (personality) and self esteem in normal adults through a randomized comparative study. MATERIALS AND METHODS: Of the 1228 persons who attended motivational lectures, 226 subjects aged 18-71 years, of both sexes, who satisfied the inclusion and exclusion criteria, and who consented to participate in the study were randomly allocated into two groups. The Yoga (Y) group practised an integrated yoga module that included asanas, pranayama, meditation, notional correction, and devotional sessions. The comparison group practised mild to moderate physical exercises (PE). Both groups had supervised practices for one hour daily, six days a week, for eight weeks. Guna (personality) was assessed before and after eight weeks using the self-administered "The 'Gita" Inventory of Personality" (GIN) to assess Sattva, Rajas, and Tamas. Self esteem in terms of competency (COM), global self esteem (GSE), moral and self esteem (MSE), social esteem (SET), family self esteem (FSE), body and physical appearance (BPA), and the lie scale (LIS) were assessed using the self esteem questionnaire (SEQ). RESULTS: The baseline scores for all domains for both the groups did not differ significantly (P > 0.05 independent samples t-test). There were significant pre-post improvements in all domains in both groups (P < 0.001 paired t-test). The number of persons who showed improvement in Sattva and decrease in Tamas was significant in the Y but not in the PE group (McNemar test). The effect size for self esteem in the Y group is greater than for the PE group in three out of seven domains. CONCLUSIONS: This randomized controlled study has shown the influence of Yoga on Gunas and self esteem in comparison to physical exercise. PMID- 21234211 TI - The effect of various breathing exercises (pranayama) in patients with bronchial asthma of mild to moderate severity. AB - BACKGROUND/AIM: The incidence of bronchial asthma is on increase. Chemotherapy is helpful during early course of the disease, but later on morbidity and mortality increases. The efficacy of yoga therapy though appreciated is yet to be defined and modified. AIM: To study the effect of breathing exercises (pranayama) in patients with bronchial asthma of mild to moderate severity. MATERIALS AND METHODS: Fifty cases of bronchial asthma (Forced Expiratory Volume in one second (FEV1) > 70%) were studied for 12 weeks. Patients were allocated to two groups: group A and group B (control group). Patients in group A were treated with breathing exercises (deep breathing,Brahmari, and Omkara, etc.) for 20 minutes twice daily for a period of 12 weeks. Patients were trained to perform Omkara at high pitch (forceful) with prolonged exhalation as compared to normal Omkara. Group B was treated with meditation for 20 minutes twice daily for a period of 12 weeks. Subjective assessment, FEV1%, and Peak Expiratory Flow Rate (PEFR) were done in each case initially and after 12 weeks. RESULTS: After 12 weeks, group A subjects had significant improvement in symptoms, FEV1, and PEFR as compared to group B subjects. CONCLUSION: Breathing exercises (pranayama), mainly expiratory exercises, improved lung function subjectively and objectively and should be regular part of therapy. PMID- 21234212 TI - Can physical activity maintain normal grades of body mass index and body fat percentage? AB - BACKGROUND/AIMS: A cross-sectional study was undertaken on 767 urban male volunteers performing physical activity and 469 age and socioeconomic status matched controls not doing any physical activity from the city limits of North India. MATERIALS AND METHODS: Height and weight were recorded for each participant to determine their Body Mass Index (BMI). Body fat percentage and weight was measured using a body fat monitor. RESULTS: Fifty three percent of the physical activity performers showed normal BMI compared to 49% nonphysical activity performers. Overweight was observed in 43.3% physical activity performers compared to 44.7% nonphysical activity performers. Fifty two percent of physical activity performers had normal body fat percent compared to 48.5% nonphysical activity performers. Low body fat percent was observed in 23.4% physical activity performers compared to 2.7% nonphysical activity performers. High body fat percent was observed in 48.7% nonphysical activity performers compared to 45.8% physical activity performers. CONCLUSIONS: Overall, the study suggested that physical activity alone cannot maintain BMI and body fat percent, but it can reduce the risk of overweight and high body fat percent in the population. PMID- 21234213 TI - Effect of yoga relaxation techniques on performance of digit-letter substitution task by teenagers. AB - BACKGROUND/AIMS: Memory and selective attention are important skills for academic and professional performance. Techniques to improve these skills are not taught either in education or company training courses. Any system which can systematically improve these skills will be of value in schools, universities, and workplaces. AIMS: To investigate possible improvements in memory and selective attention, as measured by the Digit-Letter Substitution Task (DLST), due to practice of Cyclic Meditation (CM), a yoga relaxation technique, as compared to Supine Rest (SR). MATERIALS AND METHODS: Subjects consisted of 253 school students, 156 boys, 97 girls, in the age range 13-16 years, who were attending a 10-day yoga training course during summer vacation. The selected subjects had English as their medium of instruction in school and they acted as their own controls. They were allocated to two groups, and tested on the DLST, immediately before and after 22.5 minutes practice of CM on one day, and immediately before and after an equal period of SR on the other day. The first group performed CM on day 9 and SR on day 10. For the second group, the order was reversed. RESULTS: Within each group pre-post test differences were significant for both the relaxation techniques. The magnitude of net score improvement was greater after SR (7.85%) compared to CM (3.95%). Significance levels were P < 0.4 * 10(-9)for SR and P < 0.1 * 10(-3) for CM. The number of wrong attempts also increased significantly on both interventions, even after removing two outlier data points on day 1 in the SR group. CONCLUSIONS: Both CM and SR lead to improvement in performance on the DLST. However, these relaxation techniques lead to more wrong cancellation errors. PMID- 21234214 TI - Effect of yogic education system and modern education system on sustained attention. AB - BACKGROUND/AIM: Sustained attention is a vital function mediated by the right frontoparietal cortex. The Six Letter Cancellation Task (SLCT) measures sustained attention. Development of sustained attention in a yoga-based education system compared to a modern one is the theme of the present study. AIM: To compare the effectiveness of the Modern Education System (MES) and the Gurukula Education System (GES) in developing sustained attention. MATERIALS AND METHODS: Forty nine boys (11-13 years) were selected from two residential schools, one MES and the other GES, providing similar ambiance and daily routines. The boys were matched for age and socioeconomic status. The GES educational program is based around integrated yoga modules while the MES provides a conventional modern education program. Sustained attention was assessed using the SLCT at the start and end of an academic year. RESULTS: Within groups, the pre-post test differences were significant for both groups. However, the between groups result showed improvement in the GES group compared to the MES group at a P < 0.001 significance level. CONCLUSIONS: The study suggests that both MES and GES improve sustained attention in school boys, but GES is more effective. PMID- 21234215 TI - Effect of yoga on academic performance in relation to stress. AB - BACKGROUND: Academic performance is concerned with the quantity and quality of learning attained in a subject or group of subjects after a long period of instruction. Excessive stress hampers students' performance. Improvement in academic performance and alertness has been reported in several yogic studies. AIMS AND OBJECTIVES: The main objective of the study was to assess the effect of yoga on academic performance in relation to stress. MATERIALS AND METHODS: The study started with 800 adolescent students; 159 high-stress students and 142 low stress students were selected on the basis of scores obtained through Stress Battery. Experimental group and control group were given pre test in three subjects, i.e., Mathematics, Science, and Social Studies. A yoga module consisting of yoga asanas, pranayama, meditation, and a value orientation program was administered on experimental group for 7 weeks. The experimental and control groups were post-tested for their performance on the three subjects mentioned above. RESULTS: The results show that the students, who practiced yoga performed better in academics. The study further shows that low-stress students performed better than high-stress students, meaning thereby that stress affects the students' performance. PMID- 21234216 TI - Ocular surface tumors. PMID- 21234218 TI - Combined scleral buckling and phacoemulsification. AB - AIMS: To analyze the outcome of combined scleral buckling and phacoemulsification for primary rhegmatogenous retinal detachment and visually significant cataract. SETTINGS AND DESIGN: Retrospective, interventional case series. MATERIALS AND METHODS: Retrospective review of patients with primary rhegmatogenous detachment with or without proliferative vitreoretinopathy (PVR) changes and visually significant cataract who underwent combined scleral buckling and phacoemulsification with or without intraocular lens (IOL) implantation between 1991 and 2006. Of the ten eyes, all underwent phacoemulsification and five eyes had posterior chamber Intraocular lens (PC IOL) implantation. All eyes underwent scleral buckling with solid silicone explant combined with #240 encircling band. Subretinal fluid (SRF) drainage was done in five eyes RESULTS: Four eyes improved to better than 6/12 at a mean follow-up of 9 months. Anatomical success was achieved in all eyes (100%). CONCLUSION: Combined scleral buckling and phacoemulsification is a safe and effective procedure that spares the patient the burden of repeated surgeries. It may be considered as a treatment option in selected cases of rhegmatogenous retinal detachment with significant cataract with/without early PVR. PMID- 21234217 TI - Ocular surface tumors. AB - Tumors of the conjunctiva and cornea comprise a large and varied spectrum of conditions. These tumors are grouped into two major categories of congenital and acquired lesions. The acquired lesions are further subdivided based on origin of the mass into surface epithelial, mucoepidermoid, melanocytic, vascular, fibrous, neural, histiocytic, myxoid, myogenic, lipomatous, lymphoid, leukemic, metastatic and secondary tumors. Ocular surface tumors include a variety of neoplasms originating from squamous epithelium, melanocytic tumors and lymphocytic resident cells of the conjunctival stroma. In this review, we highlight clinical features of these lesions, important diagnostic and investigative tools and standard care of management. PMID- 21234219 TI - Evaluation of resources for contact lens practice in private contact lens clinics of Muscat, Oman. AB - BACKGROUND: The integration of the contact lens (CL) practice with the VISION 2020 initiative is important. We assessed the facilities at the private CL clinics of Muscat. Accordingly, we suggested the appropriate eye care for CL wearers in Oman. STUDY DESIGN: This was a descriptive study. MATERIALS AND METHODS: This study was conducted between May and July 2006. A team of optometrists and health inspectors visited clinics and collected information about the infrastructure, available human resources, and materials used in the CL practice. We used a pre-tested close-ended questionnaire to collect responses of the practitioners and observations of the field staff. STATISTICAL METHOD: Univariate parametric type of analysis. RESULTS: The team visited 67 CL clinics and interviewed 75 CL practitioners. Proper hand washing facility was available at 61 clinics. Thirty-nine practitioners had >10 years of experience in dispensing contact lenses. Only 13 clinics had a bio-microscope. None of the clinics had legal documents signed by both providers and end users of the contact lens. CONCLUSIONS: Contact lens has received less attention in areas outside the developed world. The CL practice in the private sectors of Oman needs to be strengthened. Minimum standards, standard operating procedures for CL practice, and its periodic supervision would be useful. PMID- 21234220 TI - Treatment of primary pterygium: Role of limbal stem cells and conjunctival autograft transplantation. AB - PURPOSE: The limbus and its stem cells are very important in the pathogenesis of pterygium. In this study, the efficacy of limbal stem cells and conjunctival autograft transplantation for the treatment of primary pterygium will be assessed. DESIGN: Prospective noncomparative cohort study. MATERIALS AND METHODS: Forty-two eyes of 42 patients with grade I-III primary pterygium were included in the study. Pterygium excision was performed followed by superotemporal limbal stem cells and conjunctival autograft transplantation in all cases. Recurrence of pterygium and complications within a mean follow-up period of 18.26 months (10-28 months) was studied. RESULTS: Recurrence of pterygium occurred in two eyes (2/42; 4.75%). No significant complications were noted. Apart from re-operation in the two recurrent cases, no further surgical interventions were needed in any case. CONCLUSIONS: Limbal stem cells and conjunctival autograft transplantation is a safe and effective technique for the treatment of different grades of pterygium. It is very useful in preventing pterygium recurrence, which is a major problem in pterygium surgery. PMID- 21234221 TI - Long-term variability in short-wavelength automated perimetry compared to standard perimetry in glaucoma patients and normal subjects. AB - AIMS: To compare long-term variability (LTV) in short-wavelength automated perimetry (SWAP) with that of standard white-on-white (W-W) perimetry, in primary open angle glaucoma (POAG) patients and normal subjects and to determine its clinical significance. PATIENTS AND METHODS: The sample comprised 30 patients of stable POAG (group 1) and 20 age-matched normal controls (group2) who performed both SWAP and W-W perimetry thrice at monthly intervals. Long-term variability at each location in the visual field was calculated as the standard deviation of three threshold decibel values taken from the three visual fields performed. Mean LTV was then calculated for the entire field for each subgroup and compared. RESULTS: Mean LTV in SWAP and W-W perimetry in glaucoma patients was 3.01 +/- 0.74 dB and 2.73 +/- 1.07dB respectively. In normal subjects mean LTV of SWAP and W-W perimetry was 2.69 +/- 0.91 db and 1.97 +/- 1.34 dB respectively. Intra group analysis revealed that mean LTV of SWAP was greater compared to W-W perimetry in normal subjects and glaucoma patients. In the latter, the difference did not reach statistical significance. Inter group analysis showed that mean LTV in both SWAP and W-W perimetry was greater in glaucoma patients than in normal subjects. Factors other than POAG that could influence LTV, including progression of cataract and change in pupil size due to use of pilocarpine were excluded. Mean examination time for SWAP per sitting was 7.65% longer than that for W-W perimetry. CONCLUSIONS: Higher mean LTV of SWAP as compared to W-W perimetry needs to be taken into consideration when evaluating serial visual fields for change. Use of rapid threshold algorithms e.g. SITA (Swedish interactive test algorithm) SWAP should be encouraged as these will reduce the patient fatigue and increase the reliability of the test. PMID- 21234223 TI - Cyanoacrylate-induced pseudo-tarsorrhaphy of the eye. AB - Cyanoacrylate, also known as superglue, is a polymer which forms a strong bond at room temperature with a variety of materials including metal, glass, plastic, rubber, skin, mucous membranes and other epithelial tissues as well. We hereby present a 22-year-old female who had an accidental instillation of the glue in her eye, with an uneventful outcome. PMID- 21234222 TI - Collagen cross-linking with riboflavin and ultraviolet-A light in keratoconus: One-year results. AB - BACKGROUND: The aim of this study is to evaluate the safety and effectiveness of riboflavin-ultraviolet type A (UV-A) light rays induced cross-linking of corneal collagen in improving visual acuity and in stabilizing the progression of keratoconic eyes. The method of corneal cross-linking using riboflavin and UV-A light is technically simple and less invasive than all other therapies proposed for keratoconus. It is the only treatment that treats not only the refractive effects of the condition but the underlying pathophysiology. MATERIALS AND METHODS: In this prospective, nonrandomized clinical study, 20 eyes of 19 patients with keratoconus were treated by combined riboflavin UV-A collagen cross linking. The eyes were saturated with riboflavin solution and were subjected for 30 min under UV-A light with a dose parameter of 3 mW/cm(2). Safety and effectiveness of the treatment was assessed by measuring the uncorrected visual acuity, best corrected visual acuity, manifest cylinder/sphere, keratometry, pachymetry, posterior and anterior elevations from Pentacam and corneal aberrations at 6 months and 1 year post-treatment. RESULTS: Comparative analysis of the pre-operative and 1 year post-operative evaluation showed a mean gain of 4.15 lines of UCVA (P= 0.001) and 1.65 lines of BCVA (P= 0.002). The reduction in the average keratometry reading was 1.36 D (P= 0.0004) and 1.4 D (P= 0.001) at the apex. Manifest refraction sphere showed a mean reduction of 1.26 D (P= 0.033) and 1.25 D (0.0003) for manifest cylinder. Topo-aberrometric analysis showed improvement in corneal symmetry. CONCLUSION: Cross-linking was safe and an effective therapeutical option for progressive keratoconus. PMID- 21234224 TI - Orbital myiasis in a case of invasive basal cell carcinoma. PMID- 21234225 TI - Albinism: Images in ophthalmology. PMID- 21234226 TI - White dot in the eye. PMID- 21234227 TI - Tele-ophthalmology. PMID- 21234228 TI - Phosphagen kinases of parasites: unexplored chemotherapeutic targets. AB - Due to the possible emergence of resistance and safety concerns on certain treatments, development of new drugs against parasites is essential for the effective control and subsequent eradication of parasitic infections. Several drug targets have been identified which are either genes or proteins essential for the parasite survival and distinct from the hosts. These include the phosphagen kinases (PKs) which are enzymes that play a key role in maintenance of homeostasis in cells exhibiting high or variable rates of energy turnover by catalizing the reversible transfer of a phosphate between ATP and naturally occurring guanidine compounds. PKs have been identified in a number of important human and animal parasites and were also shown to be significant in survival and adaptation to stress conditions. The potential of parasite PKs as novel chemotherapeutic targets remains to be explored. PMID- 21234229 TI - Involvement of Src family tyrosine kinase in apoptosis of human neutrophils induced by protozoan parasite Entamoeba histolytica. AB - Tyrosine kinases are one of the most important regulators for intracellular signal transduction related to inflammatory responses. However, there are no reports describing the effects of tyrosine kinases on neutrophil apoptosis induced by Entamoeba histolytica. In this study, isolated human neutrophils from peripheral blood were incubated with live trophozoites in the presence or absence of tyrosine kinase inhibitors. Entamoeba-induced receptor shedding of CD16 and PS externalization in neutrophils were inhibited by pre-incubation of neutrophils with the broad-spectrum tyrosine kinase inhibitor genistein or the Src family kinase inhibitor PP2. Entamoeba-induced ROS production was also inhibited by genistein or PP2. Moreover, genistein and PP2 blocked the phosphorylation of ERK and p38 MAPK in neutrophils induced by E. histolytica. These results suggest that Src tyrosine kinases may participate in the signaling event for ROS-dependent activation of MAPKs during neutrophil apoptosis induced by E. histolytica. PMID- 21234230 TI - Transcriptional activity of Plasmodium subtilisin-like protease 2 (Pf-Sub2) 5'untranslated regions and its interaction with hepatocyte growth factor. AB - The onset, severity, and ultimate outcome of malaria infection are influenced by parasite-expressed virulence factors and individual host responses to these determinants. In both humans and mice, liver injury is involved after parasite entry, which persists until the erythrocyte stage after infection with the fatal strain Plasmodium falciparum (Pf). Hepatocyte growth factor (HGF) has strong anti apoptotic effects in various kinds of cells, and also has diverse metabolic functions. In this work, Pf-subtilisin-like protease 2 (Pf-Sub2) 5'untranslated region (UTR) was analyzed and its transcriptional activity was estimated by luciferase expression. Fourteen TATA boxes were observed but only one Oct-1 and c Myb were done. In addition, host HGF interaction with Pf-Sub2 was evaluated by co transfection of HGF- and Pf-Sub2-cloned vector. Interestingly, -1,422/+12 UTR exhibited the strongest luciferase activity but -329 to +12 UTR did not exhibit luciferase activity. Moreover, as compared with the control of unexpressed HGF, the HGF protein suppressed luciferase expression driven by the 5'untranslated region of the Pf-Sub2 promoter. Taken together, it is suggested that HGF controls and interacts with the promoter region of the Pf-Sub2 gene. PMID- 21234231 TI - Multiplex PCR detection of waterborne intestinal protozoa: microsporidia, Cyclospora, and Cryptosporidium. AB - Recently, emerging waterborne protozoa, such as microsporidia, Cyclospora, and Cryptosporidium, have become a challenge to human health worldwide. Rapid, simple, and economical detection methods for these major waterborne protozoa in environmental and clinical samples are necessary to control infection and improve public health. In the present study, we developed a multiplex PCR test that is able to detect all these 3 major waterborne protozoa at the same time. Detection limits of the multiplex PCR method ranged from 10(1) to 10(2) oocysts or spores. The primers for microsporidia or Cryptosporidium used in this study can detect both Enterocytozoon bieneusi and Encephalitozoon intestinalis, or both Cryptosporidium hominis and Cryptosporidium parvum, respectively. Restriction enzyme digestion of PCR products with BsaBI or BsiEI makes it possible to distinguish the 2 species of microsporidia or Cryptosporidium, respectively. This simple, rapid, and cost-effective multiplex PCR method will be useful for detecting outbreaks or sporadic cases of waterborne protozoa infections. PMID- 21234232 TI - Molecular markers for identification of Stellantchasmus falcatus and a phylogenic study using the HAT-RAPD method. AB - Stellantchasmus falcatus is a minute intestinal fluke in the family Heterophyidae. Metacercariae, the infective stage, were reported in a marine fish, mullet Liza subviridis, and a fresh water fish, Dermogenus pusillus, in Thailand. Adults were found in chicks, rats, cats, and humans. Morphological studies were done for comparing Stellantchasmus sp. worms found in 2 different fish hosts; their shapes and organ arrangements were very similar except for the prepharynx length. Therefore, the present study aimed to compare their DNA fingerprints using the HAT-RAPD method for both types of Stellantchasmus and several other related species. Ten arbitrarily selected primers (OPA-04, OPA-09, OPN-02, OPN-03, OPN-09, OPN-12, OPP-11, OPR-15, OPX-13, and OPAD-01) were used. It was found that OPA-09, OPN-03, and OPAD-01 were able to generate S. falcatus specific fragments in mullets which consisted of 200, 760, and 280 bp, respectively. In addition, the results of morphologic, DNA fingerprinting, and phylogenetic analyses strongly suggest that the fresh water and marine specimens of Stellantchamus may be different species. PMID- 21234233 TI - A case of sparganosis in the leg. AB - The life-span of the sparganum in humans is not exactly known, but it may survive longer than 5 years in some patients. We experienced a case infected with a sparganum that is presumed to have lived for 20 years in a patient's leg. The patient was a 60-year-old woman, and she was admitted to a hospital due to ankle pain that was aggravated on dorsiflexion. She had noticed a mass on her knee some 20 years ago, but she received no medical management for it. The mass moved into the ankle joint 3 months before the current admission, and then the aforementioned symptoms appeared. A living sparganum was recovered by surgery, and the calcified tract near the knee was proved to be the pathway along which the larva had passed. PMID- 21234234 TI - A case of Amblyomma testudinarium tick bite in a Korean woman. AB - A case of tick bite was found in the inguinal region of a 74-year-old Korean woman. She was attacked by the tick while working in her vegetable garden in the vicinity of mountain located in Suncheon City, the southern coastal area of the Korean Peninsula. On admission she complained of mild discomfort and itching around the bite area. The causative tick was 23 mm long and had slender pedipalps. The scutum was quite ornate and had eyes at the edge. The genital aperture was located anterior to the level of the coxa II. The spiracular plate was comma-shaped and the anus was surrounded posteriorly by the anal groove. The coxa I had subequal 2 spurs; the external one slightly larger. The spur of coxa IV was slightly longer than those of coxae II and III. The tarsus IV had 2 distinct subapical ventral spurs. It was identified as the fully engorged adult female of Amblyomma testudinarium. This is the first human case of Amblyomma bite in Korea. PMID- 21234235 TI - Molecular cloning of Plasmodium vivax calcium-dependent protein kinase 4. AB - A family of calcium-dependent protein kinases (CDPKs) is a unique enzyme which plays crucial roles in intracellular calcium signaling in plants, algae, and protozoa. CDPKs of malaria parasites are known to be key regulators for stage specific cellular responses to calcium, a widespread secondary messenger that controls the progression of the parasite. In our study, we identified a gene encoding Plasmodium vivax CDPK4 (PvCDPK4) and characterized its molecular property and cellular localization. PvCDPK4 was a typical CDPK which had well conserved N-terminal kinase domain and C-terminal calmodulin-like structure with 4 EF hand motifs for calcium-binding. The recombinant protein of EF hand domain of PvCDPK4 was expressed in E. coli and a 34 kDa product was obtained. Immunofluorescence assay by confocal laser microscopy revealed that the protein was expressed at the mature schizont of P. vivax. The expression of PvCDPK4-EF in schizont suggests that it may participate in the proliferation or egress process in the life cycle of this parasite. PMID- 21234236 TI - Suppression of CD4 T-Cells in the spleen of mice infected with Toxoplasma gondii KI-1 tachyzoites. AB - Toxoplasma gondii KI-1, a recent new isolate from Korea, shows similar pathogenicity and infectivity to mice compared to the virulent RH strain. To understand characteristics of host immunity, including immune enhancement or suppression, we investigated proliferative responses and phenotypes of spleen cells. In addition, kinetics of IFN-gamma, a Th1 cytokine, was examined in BALB/c mice up to day 6 post-infection (PI). Intraperitoneal injection of mice with 10(3) KI-1 tachyzoites induced significant decreases (P < 0.05) in proliferative responses of spleen cells. This occurred at days 2-6 PI even when concanavalin A (con A) was added and when stimulated with KI-1 antigen, suggesting suppression of the immunity. CD4(+) T-cells decreased markedly at day 2 PI (P < 0.05), whereas CD8(+) T-cells, NK cells, and macrophages did not show significant changes, except a slight, but significant, increase of CD8(+) T-cells at day 6 PI. The capacity of splenocytes to produce IFN-gamma by con A stimulation dropped significantly at days 2-6 PI. These results demonstrate that intraperitoneal injection of KI-1 tachyzoites can induce immunosuppression during the early stage of infection, as revealed by the decrease of CD4(+) T-cells and IFN-gamma. PMID- 21234237 TI - Experimental Toxocara cati infection in gerbils and rats. AB - Mongolian gerbils and Wistar rats were inoculated orally with 240 and 2,500 Toxocara cati embryonated eggs, respectively, to evaluate the larval recovery in different tissues and organs, such as the liver, lungs, heart, kidney, and skeletal muscles after 5, 30, 49, 70, and 92 days post-infection (PI). Larval recovery rates were 1.7-30.0% in Mongolian gerbils on days 5-92 PI and 0.2-3.8% in rats on the same days. These results indicate that Mongolian gerbils and Wistar rats are suitable experimental paratenic hosts for the study of neurological toxocariasis as well as visceral toxocariasis. PMID- 21234238 TI - Discovery of Maritrema jebuensis n. sp. (Digenea: Microphallidae) from the Asian Shore Crab, Hemigrapsus sanguineus, in Korea. AB - Maritrema spp. (Digenea: Microphallidae) are parasites of birds, but have not been found in the Republic of Korea. In this study, metacercariae of Maritrema sp. were discovered in the Asian shore crab, Hemigrapsus sanguineus, caught in the mud-flats of Jebu-do, Hwasung-gun, Gyeonggi-do, and the adult flukes were confirmed by experimental infection into mice. Based on the symmetric ribbon-like vitellarium, adult flukes of Maritrema sp. were identified, but did not belong to previously described species in terms of the following morphologic characteristics: ceca reaching to the lateral wall at the anterior border of the ovary; ventral sucker larger than oral sucker; a prominent metraterm; and vitellarium forming a complete ring. Hence, we named this microphallid M. jebuensis n. sp. after the island where the second intermediate hosts were collected. From this study, it has been shown that Maritrema sp. is distributed in Korea and transmitted by the Asian shore crab, H. sanguineus. PMID- 21234239 TI - Prevalence of the intestinal flukes Haplorchis taichui and H. yokogawai in a mountainous area of Phongsaly Province, Lao PDR. AB - Phongsaly Province, located in the northernmost area of Lao PDR, was previously suggested to be endemic for the liver fluke Opisthorchis viverrini infection. To confirm, or rule out, this suggestion, the Phonxay village in the Khoua District, Phongsaly Province, was selected for a survey. Ten volunteers (8 men and 2 women aged 31-57 years) who consumed raw freshwater fish and had gastrointestinal troubles were treated with a single dose of praziquantel (40 mg/kg) and pyrantel pamoate (10 mg/kg) and purged with magnesium sulfate to recover any worm parasites. Eight of the 10 volunteers expelled 1 or more species of trematodes, nematodes, or cestodes (worm positive rate; 80%). The worms were morphologically identified as H. taichui (861 worms from 8 people), H. yokogawai (59 from 6 people), Phaneropsolus bonnei (1 from 1 person), Trichostrongylus sp. (2 from 2 people), Ascaris lumbricoides (2 from 1 person), Enterobius vermicularis (11 from 3 people), and Taenia saginata (1 strobila with scolex from 1 person). The results indicate that the mountainous area of Phongsaly Province, Lao PDR, is not endemic for the liver fluke but endemic for intestinal flukes, in particular, Haplorchis taichui and H. yokogawai. PMID- 21234240 TI - Prevalence of Haplorchis taichui in field-collected snails: a molecular approach. AB - The prevalence of the cercarial stage of an intestinal trematode, Haplorchis taichui, in thiarid snails (Gastropoda: Thiaridae) was investigated using light microscope and species-specific PCR procedures. A total of 988 snails were collected from Mae Taeng district, Chiang Mai province, northern Thailand, which comprised of 3 species; Melanoides tuberculata, Tarebia granifera, and Thiara scabra. The overall prevalence of pleurolophocercous cercariae was 21.7% as determined by the morphology. For genetic detection of H. taichui infection in snails, 2 primers Hapt_F (5'-GGCCAACGCAATCGTCATCC-3') and Hapt_R (5' GCGTCGGGTTTCAGACATGG-3'), were used. The genomic DNA of H. taichui, which was used as a positive control, gave an amplification of the 256 bp fragment. The overall prevalence of H. taichui from specific PCR was 9.7%. The proportion of H. taichui among the pleurolophocercous cercariae in this study was 44.9%. PMID- 21234241 TI - Intestinal parasite infections in pigs and beef cattle in rural areas of Chungcheongnam-do, Korea. AB - The present study was performed to investigate the infection status of intestinal parasites in pigs and beef cattle in rural areas of Chungcheongnam-do, Korea. From November 2009 to April 2010, a total of 241 fecal samples of pigs and beef cattle (136 and 105, respectively) were examined by direct smear and centrifugal sedimentation methods. The overall positive rates of intestinal parasites among pigs and beef cattle were 73.5% and 4.8%, respectively, and the double-infection rate was 10.3% in pigs. Of 136 specimens from pigs, Balantidium coli, Ascaris suum, and Entamoeba spp. infections were found in 88 (64.7%), 24 (17.6%), and 5 cases (3.7%), respectively. Of 105 beef cattle, Entamoeba spp. infections were detected in 5 cases (4.8%). From these results, it is shown that pigs raised on rural farms in Chungcheongnam-do had a high B. coli infection rate and a moderate A. suum infection rate. These results demonstrate that environmentally resistant cysts or eggs could be widespread on the farms examined, and thus an effective hygienic management system is needed to prevent them from serving as the source of infection for human beings. PMID- 21234242 TI - Population dynamics of five anopheles species of the Hyrcanus group in northern Gyeonggi-do, Korea. AB - To investigate the population densities of potential malaria vectors, Anopheles species were collected by light traps in malaria endemic areas, Paju and Gimpo, Gyeonggi-do of Korea. Five Anopheles Hyrcanus sibling species (An. sinensis, An. pullus, An. lesteri, An. kleini, and An. belenrae) were identified by PCR. The predominant species, An. pullus was collected during the late spring and mid summer, while higher population consists of An. sinensis were collected from late summer to early autumn. These 2 species accounted for 92.1% of all Anopheles mosquitoes collected, while the other 3 species accounted for 7.9%. Taking into account of these population densities, late seasonal prevalence, and long-term incubation period (9-13 months) of the Korean Plasmodium vivax strain, An. sinensis s.s is thought to play an important role in the transmission of vivax malaria in the study areas. PMID- 21234243 TI - Inference of kinetic parameters of delayed stochastic models of gene expression using a markov chain approximation. AB - We propose a Markov chain approximation of the delayed stochastic simulation algorithm to infer properties of the mechanisms in prokaryote transcription from the dynamics of RNA levels. We model transcription using the delayed stochastic modelling strategy and realistic parameter values for rate of transcription initiation and RNA degradation. From the model, we generate time series of RNA levels at the single molecule level, from which we use the method to infer the duration of the promoter open complex formation. This is found to be possible even when adding external Gaussian noise to the RNA levels. PMID- 21234244 TI - Current evidence on the use of antifilarial agents in the management of bancroftian filariasis. AB - Many trials have explored the efficacy of individual drugs and drug combinations to treat bancroftian filariasis. This narrative review summarizes the current evidence for drug management of bancroftian filariasis. Diethylcarbamazine (DEC) remains the prime antifilarial agent with a well-established microfilaricidal and some macrofilaricidal effects. Ivermectin (IVM) is highly microfilaricidal but minimally macrofilaricidal. The role of albendazole (ALB) in treatment regimens is not well established though the drug has a microfilaricidal effect. The combination of DEC+ALB has a better long-term impact than IVM+ALB. Recent trials have shown that doxycycline therapy against Wolbachia, an endosymbiotic bacterium of the parasite, is capable of reducing microfilaria rates and adult worm activity. Followup studies on mass drug administration (MDA) are yet to show a complete interruption of transmission, though the infection rates are reduced to a very low level. PMID- 21234245 TI - Pesticide Use and Self-Reported Symptoms of Acute Pesticide Poisoning among Aquatic Farmers in Phnom Penh, Cambodia. AB - Organophosphates and carbamates (OPs/CMs) are known for their acetylcholinesterase inhibiting character. A cross-sectional study of pesticide handling practices and self-perceived symptoms of acute pesticide poisoning was conducted using questionnaire-based interviews with 89 pesticide sprayers in Boeung Cheung Ek (BCE) Lake, Phnom Penh, Cambodia. The study showed that 50% of the pesticides used belonged to WHO class I + II and personal protection among the farmers were inadequate. A majority of the farmers (88%) had experienced symptoms of acute pesticide poisoning, and this was significantly associated with the number of hours spent spraying with OPs/CMs (OR = 1.14, CI 95%: 1.02-1.28). The higher educated farmers reduced their risk of poisoning by 55% for each extra personal protective measure they adapted (OR = 0.45, CI 95%: 0.22-0.91). These findings suggest that improving safe pesticide management practices among the farmers and enforcing the effective banning of the most toxic pesticides will considerably reduce the number of acute pesticide poisoning episodes. PMID- 21234246 TI - Xenotransplantation of embryonic pig kidney or pancreas to replace the function of mature organs. AB - Lack of donor availability limits the number of human donor organs. The need for host immunosuppression complicates transplantation procedures. Ultrastructurally precise kidneys differentiate in situ following xenotransplantation in mesentery of embryonic pig renal primordia. The developing organ attracts its blood supply from the host, obviating humoral rejection. Engraftment of pig renal primordia transplanted directly into rats requires host immune suppression. However, insulin-producing cells originating from embryonic pig pancreas obtained very early following initiation of organogenesis [embryonic day 28 (E28)] engraft long term in nonimmune-suppressed diabetic rats or rhesus macaques. Engraftment of morphologically similar cells originating from adult porcine islets of Langerhans (islets) occurs in rats previously transplanted with E28 pig pancreatic primordia. Here, we review recent findings germane to xenotransplantation of pig renal or pancreatic primordia as a novel organ replacement strategy. PMID- 21234247 TI - Sclerosing angiomatoid nodular transformation of the spleen masquerading as a sarcoma metastasis. AB - We report a case of sclerosing angiomatoid nodular transformation (SANT) of the spleen presenting as an incidental splenic mass in a patient with a history of retroperitoneal spindle cell sarcoma. Imaging studies and preoperative fine needle biopsy failed to differentiate this lesion from other vascular splenic lesions or a metastatic focus of a prior sarcoma. The patient was treated with splenectomy, which has proved both diagnostic and therapeutic in this and other cases of SANT. Although histology can lead to the diagnosis of vascular tumor, immunohistochemistry is the only way to confirm the diagnosis of SANT. The etiology of SANT is unknown. SANT of the spleen is a benign lesion that does not recur after splenectomy. PMID- 21234248 TI - Perivascular epithelioid cell neoplasm of the uterine cervix: an unusual tumor in an unusual location. AB - A 46-year-old woman presented for a second opinion regarding a 3-4 cm mass of the uterine cervix. A prior biopsy had been interpreted as a malignant melanoma of the cervix, resulting in a radical hysterectomy with bilateral salpingooophorectomy. This was to be followed by external beam irradiation and immunotherapy; however, given the rarity of this diagnosis, the patient sought a second opinion at our institution. Further review of the pathological material from the hysterectomy revealed a morphologically benign perivascular epithelioid cell neoplasm rather than a malignant melanoma. Close monitoring of the patient was recommended; she is currently diseasefree more than three years after her initial presentation. PMID- 21234249 TI - Prostatic stromal tumor with fatal outcome in a young man: histopathological and immunohistochemical case presentation. AB - Stromal tumors of the prostate are rare and only a few cases have been described in the literature, including exceptional cases of stromal tumors with unknown malignant potential (STUMP) and a fatal outcome in young patients. Morphologically distinguishing a STUMP from a stromal sarcoma of the prostate (PSS) is still a challenge. We describe the histopathological and immunohistochemical findings in a 34-year-old man with a malignant specialized cell stromal tumor of the prostate that was diagnosed initially as STUMP, and he developed lung metastases within a few months. The patient attended our hospital because of lower urinary tract symptoms, after having excreted tissue through the urethra a few months before. Ultrasonography and urethrocystoscopy examinations showed a mass arising from the verumontanum, and a transurethral resection (TUR) revealed a highgrade spindle cell sarcoma reminiscent of a phyllode tumor of the breast. The tumor cells were immunoreactive for vimentin, progesterone receptor and, focally, CD34. The preliminary histological findings were subsequently confirmed after radical prostatectomy. The patient developed bilateral lung metastases and died 25 months after the initial diagnosis. Although rare in young patients, the challenging differential diagnosis of STUMP and PSS means that a prostate STUMP diagnosis made on the basis of biopsy or TUR specimens also requires urethrocystoscopic monitoring for the early detection of any progression to PSS. Radical prostatectomy should also be carefully considered. PMID- 21234250 TI - An unusual site of metastasis from gastrointestinal stromal tumor. AB - Gastrointestinal stromal tumors are mesenchymal tumors of the gastrointestinal tract. They commonly metastasize within the abdominal cavity, particularly to the liver. Less commonly, metastases can be found in the lung or bone. This report describes the first two cases of metastasis to the left ventricle in patients with advanced gastrointestinal stromal tumor. PMID- 21234251 TI - Localized nasal cavity, sinus, and massive bilateral orbital involvement by human T cell leukemia virus 1 adult T cell lymphoma, with epidermal hypertrophy due to mite infestation. AB - HTLV1 adult T cell lymphoma occurs tends to be widely disseminated and aggressive, with only brief responses to chemotherapy. Aside from cervical adenopathy, involvement of head and neck structures is uncommon and orbital involvement rare.We report a case of nasal cavity HTLV lymphoma with massive bilateral orbital involvement and proptosis, resulting in complete left and partial right eye amaurosis. No other sites of disease were found. Response to chemotherapy was rapid and complete, with almost complete restoration of vision and oculo-motor function; the patient has remained in remission for one year. An associated problem was striking bilateral hypertrophic, hyperkeratotic eyelid and breast lesions due to mite infestation. PMID- 21234252 TI - Two cases of retrobulbar meningioma excised by skull base approaches. AB - We present two cases of orbital meningioma which were totally excised by a neurosurgical and craniomaxillofacial team using skull base approaches. PMID- 21234253 TI - A case of nephrotic syndrome associated with hydatiform mole. AB - The present case study is on a 16-year-old woman who was suffering from nephrotic syndrome after recovery from complete type of hydatiform mole. She was admitted in hospital because of proteinurea and hematuria. Then she was showing a generalized edema compatible with neprhotic syndrome. In her past medical history she had a suction curettage for hydatiform mole. After she received 4 courses chemotherapy, she completely recovered and betahCG has fallen from 12127 IU/L to under 10 IU/mL. Then she showed generalized edema, proteinurea and hematuria compatible with nephritic syndrome. After six courses chemotherapy the symptoms of nephrotic syndrome and invasive mole diminished, she released from hospital and scheduled for follow-up. PMID- 21234254 TI - A case of pancreatic acinar cell carcinoma metastatic to skin. AB - We report a rare case of pancreatic acinar cell carcinoma with widespread metastases in a 68-year-old woman who presented with subcutaneous nodules as the initial symptom. Computed tomography showed a pancreatic mass with hepatic tumors and enlarged lymph nodes besides ring-enhanced subcutaneous nodules. Magnetic resonance diffusionweighted imaging detected the presence of lesions in other organs. Histological analysis of a colonic polypoid lesion revealed carcinoma with endocrine and acinar differentiation compatible with pancreatic origin. Regrettably, she died of a cerebral infarction without any treatment, and autopsy findings confirmed our diagnosis. PMID- 21234255 TI - Ocular manifestations and pathology of adult T-cell leukemia/lymphoma associated with human T-lymphotropic virus type 1. AB - The human T-cell lymphotropic virus type 1 (HTLV-1), endemic in defined geographical areas around the world, is recognized as the etiologic agent of adult T-cell leukemia/lymphoma (ATL), or HTLV-1. ATL is a rare adult onset T-cell malignancy that is characterized by the presence of ATL flower cells with T-cell markers, HTLV-1 antibodies in the serum, and monoclonal integration of HTLV-1 provirus in affected cells. Ocular manifestations associated with HTLV-1 virus infection have been reported and include HTLV-1 uveitis and keratoconjunctivitis sicca, but reports of ocular involvement in ATL are exceedingly rare. This article describes the ocular manifestations and pathology of ATL. We also report for the first time a case of a 34-year-old male with systemic ATL and prominent atypical lymphoid cell infiltration in the choroid. To our knowledge, this is the first report defining prominent choroidal involvement as a distinct ocular manifestation of ATL. ATL may masquerade as a variety of other conditions, and molecular techniques involving microdissection and PCR have proven to be critical diagnostic tools. International collaboration will be needed to better understand the presentation and diagnosis of this rare malignancy. PMID- 21234256 TI - Solitary fibrous tumor. AB - Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm which may be found everywhere in the body. It is now distinguished into two forms, pleural and extrapleural, which morphologically resemble each other. Abdominal localizations are quite rare, with 10 cases only reported in bladder; rarely they can be source of paraneoplastic syndromes (i.e., hypoglycemia secondary to insulin-like growth factor). In April 2006 a 74-year-old white male presented with chills, diaphoresis and acute abdominal pain with hematuria. At admission in emergency he underwent an abdominal Xray (no pathological findings) and an ultrasound examination of the kidneys and urinary tract, which revealed a pelvic hyperechogenic neoformation measuring approximately 10*8*7 cm, compressing the bladder. Blood chemistry at admission revealed only a mild neutrophilic leucocytosis (WBC 16600, N 80%, L 11%), elevated fibrinogen and ESR, and hypoglycemia (38 mg/dL). Macro scopic hematuria was evident, while urinocolture was negative. Contrast enhanced CT scan of the abdomen and pelvic region revealed a large round neoformation dislocating the bladder, with an evident contrast enhanced periphery and a central necrotic area. Continuous infusion of glucose 5% solution was necessary in order to maintain blood glucose levels above 50 mg/dL. The patient underwent complete surgical resection of an ovoidal mass coated by adipose tissue, with well delimited margins; histological findings were consistent with solitary fibrous tumor (SFT). Hypoglycemia resolved completely with removal of the growth. In this case report we describe a SFT growing in the bladder, a quite rare localization, which presented a unique hypoglycemia. In contrast to the majority of cases reported in the literature, the behavior of this SFT was not aggressive, and, since the patient is still alive, surgical resection was considered conclusive. PMID- 21234257 TI - Multiple urinary bladder masses from metastatic prostate adenocarcinoma. AB - We present an unusual case of metastatic prostate adenocarcinoma that manifested with multiple exophytic intravesical masses, mimicking a multifocal primary bladder tumor. Biopsy with immunohistochemical analysis confirmed metastatic prostate adenocarcinoma. The patient was treated palliatively with external beam radiotherapy to prevent possible symptoms from local tumor progression. This case illustrates that when a patient with known prostate cancer presents with multifocal bladder tumors, the possibility of metastatic prostate cancer should be considered. PMID- 21234258 TI - Familial adenomatous polyposis with synchronous invasive colonic carcinomas and metastatic jejunal adenocarcinoma in a Nigerian male. AB - Familial adenomatous polyposis is rare. Three cases were previously reported in Nigeria. An intriguing feature of this case is an ulcerated jejunal carcinoma which was metastatic rather than synchronous carcinoma. This patient presented with partial large bowel obstruction and the pathological analysis revealed 4 invasive adenocarcinomas, 3 in the colon and 1 in the jejunum (Dukes stage D). Palliative pancolectomy and jejunal tumour resection with chemotherapy was offered to him. He died eight months after surgery from disease progression. The challenges of managing a hereditary cancer syndrome in a resource poor country are highlighted. PMID- 21234259 TI - Chorangioma placentae. AB - Chorangioma of the placenta is a rare tumor with a frequency of about 1%, which usually presents as a solitary nodule or, less frequently, as multiple nodules. It is found on the fetal surface of the placenta or in placental parenchyma. Most chorangiomas are small and possess no clinical significance. On the contrary, clinically significant chorangiomas, greater then 5 cm or multiple, may be associated with pregnancy complications. The case presented is one of the uncommon presentations of chorangioma, in which its presence and size were not related to a pregnancy disorders or developmental anomalies of the fetus. PMID- 21234261 TI - State of the art in intravesical therapy for lower urinary tract symptoms. AB - Intravesical therapy is the routine first-line treatment for effectively delaying or preventing the recurrence of bladder cancer. This route of drug administration has also shown tremendous promise in the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS) and potentially overactive bladder to justify investments for further improvements. This review takes a bird's eye view into the current status of intravesical therapy, with emphasis on liposomal nanoparticles, in diseases associated with lower urinary tract symptoms (LUTS). Ongoing efforts to advance the field of intravesical drug delivery include development of sustained-release drug implants and efforts to improve delivery of biotechnological products including large protein acting as neurotoxins and small interfering RNAs. PMID- 21234262 TI - Chronic spontaneous nephrocutaneous fistula associated with renal replacement lipomatosis. AB - Chronic spontaneous nephrocutaneous fistula is a rare renal disease. Renal replacement lipomatosis (RRL) is the result of the atrophy and destruction of renal parenchyma with massive increases in the amount of fat in the sinus and perirenal space. The 2 conditions can be associated because they may have the same etiology. Indeed, urolithiasis is the most common cause of these diseases. We report a case of chronic nephrocutaneous fistula associated with RRL due to both urolithiasis and renal tuberculosis. PMID- 21234263 TI - Spontaneous rupture of a renal artery aneurysm presenting as gross hematuria. AB - Renal artery aneurysms (RAAs) are localized dilations of the renal artery and/or its branches. They are being found with increasing frequency as a result of unrelated abdominal imaging or on workup for hypertension. They are rarely symptomatic; however, they can be a cause of life-threatening hematuria. Discussed is the case of a previously healthy 46-year-old man presenting with flank pain and gross hematuria. It is imperative for the practicing urologist to be aware of the appropriate evaluation and management of RAAs. PMID- 21234264 TI - Neuroendocrine tumor of the bladder. AB - Small cell carcinoma (SCC) of the bladder is a rare and aggressive tumor associated with a poor prognosis. It often presents at a later stage than urothelial carcinoma of the bladder, and comprises less than 1% of bladder malignancies. A number of treatment algorithms have been used to treat bladder SCC, including cystectomy, partial cystectomy, radiotherapy, chemoradiotherapy, chemotherapy alone, and neoadjuvant/adjuvant chemotherapy. Presented is a case of SCC of the bladder, and the epidemiology, prognosis, and current treatment algorithms for patients with bladder SCC are reviewed. PMID- 21234265 TI - Publications From the International Children's Continence Society. PMID- 21234260 TI - Metabolic syndrome and urologic diseases. AB - Metabolic syndrome (MetS) is a complex entity consisting of multiple interrelated factors including insulin resistance, central adiposity, dyslipidemia, endothelial dysfunction and atherosclerotic disease, low-grade inflammation, and in males, low testosterone levels. MetS has been linked to a number of urologic diseases including nephrolithiasis, benign prostatic hyperplasia and lower urinary tract symptoms, erectile dysfunction, male infertility, female incontinence, and prostate cancer. This article reviews the relationships between MetS and these entities. Urologists need to be cognizant of the impact that MetS has on urologic diseases as well as on overall patient health. PMID- 21234266 TI - PCA3 Urinary Biomarker for Prostate Cancer. PMID- 21234268 TI - MALDI-TOF MS combined with magnetic beads for detecting serum protein biomarkers and establishment of boosting decision tree model for diagnosis of colorectal cancer. AB - The aim of present study is to study the serum protein fingerprint of patients with colorectal cancer (CRC) and to screen protein molecules that are closely related to colorectal cancer during the onset and progression of the disease with Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Serum samples from 144 patients with CRC and 120 healthy volunteers were adopted in present study. Weak cation exchange (WCX) magnetic beads and PBSII-C protein chips reader (Ciphergen Biosystems Ins.) were used. The protein fingerprint expression of all the Serum samples and the resulted profiles between cancer and normal groups were analyzed with Biomarker Wizard system. Several proteomic peaks were detected and four potential biomarkers with different expression profiles were identified with their relative molecular weights of 2870.7 Da, 3084 Da, 9180.5 Da, and 13748.8 Da, respectively. Among the four proteins, two proteins with m/z 2870.7 and 3084 were down-regulated, and the other two with m/z 9180.5 and 13748.8 were up-regulated in serum samples from CRC patients. The present diagnostic model could distinguish CRC from healthy controls with the sensitivity of 92.85% and the specificity of 91.25%. Blind test data indicated a sensitivity of 86.95% and a specificity of 85%. The result suggested that MALDI technology could be used to screen critical proteins with differential expression in the serum of CRC patients. These differentially regulated proteins were considered as potential biomarkers for the patients with CRC in the serum and of the potential value for further investigation. PMID- 21234269 TI - Ozone therapy and hyperbaric oxygen treatment in lung injury in septic rats. AB - Various therapeutic protocols were used for the management of sepsis including hyperbaric oxygen (HBO) therapy. It has been shown that ozone therapy (OT) reduced inflammation in several entities and exhibits some similarity with HBO in regard to mechanisms of action. We designed a study to evaluate the efficacy of OT in an experimental rat model of sepsis to compare with HBO. Male Wistar rats were divided into sham, sepsis+cefepime, sepsis+cefepime+HBO, and sepsis+cefepime+OT groups. Sepsis was induced by an intraperitoneal injection of Escherichia coli; HBO was administered twice daily; OT was set as intraperitoneal injections once a day. The treatments were continued for 5 days after the induction of sepsis. At the end of experiment, the lung tissues and blood samples were harvested for biochemical and histological analysis. Myeloperoxidase activities and oxidative stress parameters, and serum proinflammatory cytokine levels, IL-1beta and TNF-alpha, were found to be ameliorated by the adjuvant use of HBO and OT in the lung tissue when compared with the antibiotherapy only group. Histologic evaluation of the lung tissue samples confirmed the biochemical outcome. Our data presented that both HBO and OT reduced inflammation and injury in the septic rats' lungs; a greater benefit was obtained for OT. The current study demonstrated that the administration of OT as well as HBO as adjuvant therapy may support antibiotherapy in protecting the lung against septic injury. HBO and OT reduced tissue oxidative stress, regulated the systemic inflammatory response, and abated cellular infiltration to the lung demonstrated by findings of MPO activity and histopathologic examination. These findings indicated that OT tended to be more effective than HBO, in particular regarding serum IL-1beta, lung GSH-Px and histologic outcome. PMID- 21234270 TI - Helicobacter pylori induces mitochondrial DNA mutation and reactive oxygen species level in AGS cells. AB - To investigate the role of ROS in the helicobacter pylori (Hp) induced mtDNA mutations, AGS cells were treated by extracts of Hp11638 or Hp11638M. The ROS levels, cytochrome C reductions, and intracellular ATP levels were measured. The coding region and the D-Loop region were amplified and sequenced. Results showed the ROS levels, cytochrome C reduction and mtDNA mutations were markedly increased and cell viability decreased after treatment with both Hp extracts, and 616 mutations were detected in D-Loop region and 3 heteroplasmic point mutations in the Cytb gene. No mutations were found in the coding region. The mutation rates of mtDNA D-Loop region were positively correlated with the ROS levels and negatively to the ATP levels. PMID- 21234271 TI - Two-year outcome of Turkish patients treated with Zotarolimus versus Paclitaxel eluting stents in an unselected population with coronary artery disease in the real world: a prospective non-randomized registry in southern Turkey. AB - BACKGROUND: Our purpose was to investigate the clinical outcomes of Zotarolimus- and Paclitaxel-eluting stents in Turkish patients with coronary artery disease (CAD). In general, the outcome of drug-eluting stent (DES) placement has a proven efficacy in randomized trials. However, the difference in efficacy between the Zotarolimus and Paclitaxel-eluting stents in unselected Turkish patients is controversial. Therefore, we investigated the clinical outcomes of these two drug eluting stents in the real-world. METHODS: We created a registry and prospectively analyzed data on a consecutive series of all patients who presented to our institution with symptomatic coronary artery disease between February 2005 and March 2007 and who were treated with the zotarolimus- or the paclitaxel eluting stent. The follow-up period was approximately two years. The primary end point was major cardiac events, and the secondary end-point was definite stent thrombosis. Informed consent was obtained from all subjects, and the study protocol was approved by the local ethical committee. RESULTS: In total, 217 patients were treated with either the zotarolimus-eluting stent (n = 116) or the paclitaxel-eluting stent (n = 101). The lesions in the 2 arms of the study were treated similarly by conventional technique. At 24-month follow-up the paclitaxel eluting stent group showed significantly higher non-Q wave myocardial infarction (2.6% vs 5.9%, p: 0.02), Q wave myocardial infarction (1.7% vs 5.9%, p: 0.049), coronary artery binding graft surgery (2.6% vs 6.9%, p: 0.002), and late stent thrombosis (1.7% vs 3.9%, p: 0.046). CONCLUSIONS: Zotarolimus-eluting stents demonstrated better clinical outcomes than Paclitaxel-eluting stents in a daily routine practice of coronary intervention in an unselected Turkish population. PMID- 21234272 TI - Intravenous transplantation of allogeneic bone marrow mesenchymal stem cells and its directional migration to the necrotic femoral head. AB - In this study, we investigated the feasibility and safety of intravenous transplantation of allogeneic bone marrow mesenchymal stem cells (MSCs) for femoral head repair, and observed the migration and distribution of MSCs in hosts. MSCs were labeled with green fluorescent protein (GFP) in vitro and injected into nude mice via vena caudalis, and the distribution of MSCs was dynamically monitored at 0, 6, 24, 48, 72 and 96 h after transplantation. Two weeks after the establishment of a rabbit model of femoral head necrosis, GFP labeled MSCs were injected into these rabbits via ear vein, immunological rejection and graft versus host disease were observed and necrotic and normal femoral heads, bone marrows, lungs, and livers were harvested at 2, 4 and 6 w after transplantation. The sections of these tissues were observed under fluorescent microscope. More than 70 % MSCs were successfully labeled with GFP at 72 h after labeling. MSCs were uniformly distributed in multiple organs and tissues including brain, lungs, heart, kidneys, intestine and bilateral hip joints of nude mice. In rabbits, at 6 w after intravenous transplantation, GFP labeled MSCs were noted in the lungs, liver, bone marrow and normal and necrotic femoral heads of rabbits, and the number of MSCs in bone marrow was higher than that in the, femoral head, liver and lungs. Furthermore, the number of MSCs peaked at 6 w after transplantation. Moreover, no immunological rejection and graft versus host disease were found after transplantation in rabbits. Our results revealed intravenously implanted MSCs could migrate into the femoral head of hosts, and especially migrate directionally and survive in the necrotic femoral heads. Thus, it is feasible and safe to treat femoral head necrosis by intravenous transplantation of allogeneic MSCs. PMID- 21234273 TI - Bronchial anthracofibrosis case with endobronchial tuberculosis. AB - We reported a case with bronchial anthracofibrosis and endobronchial tuberculosis. Our case demonstrated this possible correlation between anthracofibrosis and endobronchial tuberculosis. We showed this correlation visually and microbiologically. PMID- 21234274 TI - AN ARRAY OF MONOLITHIC FBAR-CMOS OSCILLATORS FOR MASS-SENSING APPLICATIONS. AB - We present a monolithic, solidly-mounted CMOS-FBAR oscillator array for mass sensing applications. Thin-film bulk acoustic resonators (FBAR) are an effective platform for sensitive biological and chemical detection, where their high operating frequencies make them many times more sensitive than a quartz crystal microbalance. By monolithic integration with CMOS drive circuitry, we aim to overcome the spatial limitations of externally-coupled resonators to build dense sensor arrays without specialized fabrication techniques. The sensors in this work are constructed in a 6 * 4 array atop a 0.18MUm CMOS active substrate, and mass sensitivity comparable to off-chip FBAR sensors is demonstrated. PMID- 21234276 TI - Understanding Drug Use Over the Life Course: Past, Present, and Future. AB - Over the past 20 years, much exciting addiction research has been conducted. Extensive knowledge has been gathered about comorbid issues, particularly mental health disorders, HIV, and criminal justice involvement. Health services addiction research has become increasingly sophisticated, shifting its focus from patients to consider also services, organizations, and financing structures. Furthermore, through several long-term follow-up studies, empirical evidence convincingly demonstrates that drug dependence is not an acute disorder, and is best understood through a life course perspective with an emphasis on chronicity This article highlights three major directions for future addiction research: developing strategies for chronic care (including longitudinal intervention studies), furthering cross-system linkage and coordination, and utilizing innovative methods (e.g., growth curve modeling, longitudinal mixed methods research) to strengthen the evidence base for the life course perspective on drug addiction. PMID- 21234275 TI - State-of-the-art measurements in human body composition: A moving frontier of clinical importance. AB - The measurement of human body composition allows for the estimation of body tissues, organs, and their distributions in living persons without inflicting harm. From a nutritional perspective, the interest in body composition has increased multi-fold with the global increase in the prevalence of obesity and its complications. The latter has driven in part the need for improved measurement methods with greater sensitivity and precision. There is no single gold standard for body-composition measurements in-vivo. All methods incorporate assumptions that do not apply in all individuals and the more accurate models are derived by using a combination of measurements, thereby reducing the importance of each assumption. This review will discuss why the measurement of body composition or human phenotyping is important; discuss new areas where the measurement of body composition (human phenotyping) is recognized as having important application; and will summarize recent advances made in new methodology. Reference will also be made to areas we cannot yet measure due to the lack of appropriate measurement methodologies, most especially measurements methods that provide information on kinetic states (not just static state) and metabolic function. PMID- 21234277 TI - Evidence for T-helper 2 shift and association with illness parameters in chronic fatigue syndrome (CFS). AB - Few immunological markers have been consistently reported in CFS. However, a shift to a T-helper 2 (Th2) type immune response has been hypothesized for individuals with CFS. The current study investigated whether individuals with CFS who exhibited a stronger shift towards a Th2 type of immune response would also exhibit more severe symptoms, poorer neurocognitive functioning, and poorer physical and psychosocial functioning. The current investigation measured the percentage of Th1-like and Th2-like memory cells using cell surface flow cytometry in 114 individuals with CFS. The associations between the ratio of Th1 and Th2 memory cells and various illness parameters measures were then examined, including symptom severity, psychiatric functioning, neurocognitive functioning, salivary cortisol levels, and chronic pain status. Results indicated that individuals who exhibited a more extreme shift towards a Th2 immune response also exhibited poorer sleep and high levels of basal salivary cortisol. The implications of these findings are discussed. PMID- 21234278 TI - Information Extraction as Link Prediction: Using Curated Citation Networks to Improve Gene Detection. AB - In this paper we explore the usefulness of various types of publication-related metadata, such as citation networks and curated databases, for the task of identifying genes in academic biomedical publications. Specifically, we examine whether knowing something about which genes an author has previously written about, combined with information about previous coauthors and citations, can help us predict which new genes the author is likely to write about in the future. Framed in this way, the problem becomes one of predicting links between authors and genes in the publication network. We show that this solely social-network based link prediction technique outperforms various baselines, including those relying only on non-social biological information. PMID- 21234279 TI - Correlation of diffusion tensor imaging with executive function measures after early childhood traumatic brain injury. AB - OBJECTIVE: Examine relationships of diffusion tensor imaging (DTI) fractional anisotropy (FA) to executive function (EF) and attention measures following early childhood (3-7 years) traumatic brain injury (TBI). DESIGN: Exploratory correlation and comparison study. SETTING: Children's hospital outpatient facilities. PARTICIPANTS: 9 children with a history of TBI (age = 7.89 +/- 1.00 years; Glasgow Coma Scale (GCS) = 10.11 +/- 4.68) were compared to 12 children with OI (age = 7.51 +/- 0.95). All children were at least 12 months post injury at time of evaluation. MAIN OUTCOME MEASURES: FA in various regions of interest (ROI), EF and attention measures. RESULTS: FA values primarily in the frontal white matter tracks correlated with EF measures. Separate tasks of inhibition and switching correlated significantly with FA in bilateral frontal lobes. Tasks combining both inhibition and switching correlated significantly with FA values in the left frontal lobe. Tasks of attention negatively correlated with FA values in the right frontal white matter and the superior longitudinal fasciculus. CONCLUSIONS: Associations between late measurement of FA and EF measures following early childhood TBI suggest that persistent white matter changes, especially in the frontal white matter, may provide an index of EF deficits. PMID- 21234280 TI - Ciliary Body and Ciliary Epithelium. PMID- 21234281 TI - Tailoring Cognitive-Behavioral Therapy to Treat Anxiety Comorbid with Advanced Cancer. AB - Patients with advanced cancer often experience debilitating anxiety symptoms that interfere with quality of life and relate to worse medical outcomes. Although cognitive behavioral therapy (CBT) is an empirically-validated, first-line treatment for anxiety disorders, clinical trials of CBT for anxiety typically exclude patients with medical comorbidities in general, and those with terminal illnesses, such as advanced cancer, in particular. Moreover, CBT has generally targeted unrealistic fears and worries in otherwise healthy individuals with clinically significant anxiety symptoms. Consequently, traditional CBT does not sufficiently address the cognitive components of anxiety in patients with cancer, especially negative thought patterns that are rational but nonetheless intrusive and distressing, such as concerns about pain, disability and death, as well as management of multiple stressors, changes in functional status and burdensome medical treatments. In this paper, we describe a treatment approach for tailoring CBT to the needs of this population. Three case examples of patients diagnosed with terminal lung cancer are presented to demonstrate the treatment methods along with outcome measures for anxiety and quality of life. PMID- 21234282 TI - Statistical Modelling of Brain Morphological Measures Within Family Pedigrees. AB - Large, family-based imaging studies can provide a better understanding of the interactions of environmental and genetic influences on brain structure and function. The interpretation of imaging data from large family studies, however, has been hindered by the paucity of well-developed statistical tools for that permit the analysis of complex imaging data together with behavioral and clinical data. In this paper, we propose to use two methods for these analyses. First, a variance components model along with score statistics is used to test linear hypotheses of unknown parameters, such as the associations of brain measures (e.g., cortical and subcortical surfaces) with their potential genetic determinants. Second, we develop a test procedure based on a resampling method to assess simultaneously the statistical significance of linear hypotheses across the entire brain. The value of these methods lies in their computational simplicity and in their applicability to a wide range of imaging data. Simulation studies show that our test procedure can accurately control the family-wise error rate. We apply our methods to the detection of statistical significance of gender by-age interactions and of the effects of genetic variation on the thickness of the cerebral cortex in a family study of major depressive disorder. PMID- 21234283 TI - Self-Regulation and School Readiness. AB - RESEARCH FINDINGS: In this article, we review research on the relations of self regulation and its dispositional substrate, effortful control, to variables involved in school success. First, we present a conceptual model in which the relation between self-regulation/effortful control and academic performance is mediated by low maladjustment and high-quality relationships with peers and teachers, as well as school engagement. Then we review research indicating that effortful control and related skills are indeed related to maladjustment, social skills, relationships with teachers and peers, school engagement, as well as academic performance. PRACTICE OR POLICY: Initial findings are consistent with the view that self-regulatory capacities involved in effortful control are associated with the aforementioned variables; only limited evidence of mediated relations is currently available. PMID- 21234284 TI - Glutaminase: a hot spot for regulation of cancer cell metabolism? AB - Cancer cells re-program their metabolic machinery in order to satisfy their bioenergetic and biosynthetic requirements. A critical aspect of the re programming of cancer cell metabolism involves changes in the glycolytic pathway (referred to as the "Warburg effect"). As an outcome of these changes, much of the pyruvate generated via the glycolytic pathway is converted to lactic acid, rather than being used to produce acetyl-CoA and ultimately, the citrate which enters the citric acid cycle. In order to compensate for these changes and to help maintain a functioning citric acid cycle, cancer cells often rely on elevated glutamine metabolism. Recently, we have found that this is achieved through a marked elevation of glutaminase activity in cancer cells. Here we further consider these findings and the possible mechanisms by which this important metabolic activity is regulated. PMID- 21234286 TI - The Distracting Effects of a Ringing Cell Phone: An Investigation of the Laboratory and the Classroom Setting. AB - The detrimental effects of a ringing phone on cognitive performance were investigated in four experiments. In Experiments 1 and 2, the effects of different types of sounds (a standard cell phone ring, irrelevant tones and an instrumental song commonly encountered by participants) on performance were examined. In Experiment 1, slower responses were observed in all auditory groups relative to a silence condition, but participants in the ring and song conditions recovered more slowly. In Experiment 2, participants who were warned about the potential for distraction recovered more quickly, suggesting a benefit of this prior knowledge. This investigation continued in a college classroom setting (Experiments 3a and 3b); students were exposed to a ringing cell phone during the lecture. Performance on a surprise quiz revealed low accuracy rates on material presented while the phone was ringing. These findings offer insight into top-down cognitive processes that moderate involuntary orienting responses associated with a common stimulus encountered in the environment. PMID- 21234285 TI - Human Umbilical Cord Blood Cells Have Trophic Effects on Young and Aging Hippocampal Neurons in Vitro. AB - In experimental models of central nervous system (CNS) aging, injury and disease, administering human umbilical cord blood (HUCB) cells induce recovery, most likely by interacting with multiple cellular processes. The aim of this study was to examine whether the HUCB cells produce trophic factors that may enhance survival and maturation of hippocampal neurons in an in vitro test system. We co cultured the mononuclear fraction of HUCB cells with hippocampal neurons isolated from either young (7-months of age) or aging (21 month of age) rat brain for 14, 21, 28, 35 and 42 days in vitro (DIV), respectively. Immunocytochemistry was then employed to identify neurons (MAP2(+)) and glial cells (GFAP(+)) as well as arborization of neurites. The average number of MAP2(+) hippocampal neurons cells in both young and aging neuronal-HUCB co-cultures was significantly higher than in the control cultures (hippocampal mono-cultures). These MAP2(+) neurons in co culture were richly arborized, especially in 21 and 28 DIV co-cultures, and expressed functional enzymes (Synaptophysin, tyrosine hydryoxlase (TH)), gamma amino butyric acid receptor (GABAAr) and glutamate transporter (EAAC1). The majority of hippocampal neurons in both co-culture systems grew very well and survived for up to 42 DIV with an increment of immature neurons which were positive for Nestin and TuJ1. Using a multiplex protein array, a number of secreted proteins that could have trophic effects on the neurons were identified. PMID- 21234287 TI - Determination of Trace Amounts of Lead Using the Flotation-spectrophotometric method. AB - The present study describes a simple and highly selective method for separation, preconcentration and spectrophotometric determination of extremely low concentrations of lead. It is based on flotation of a complex of Pb(2+) ions and Alizarin yellow between aqueous and n-hexane interface at pH = 6. The proposed procedure is also applied for determination of lead in both tap water and prepared sea water samples. Beer's Law was obeyed over the concentration range of 3.86 * 10(-8) To 8.20 * 10(-7) molL(-1) (8-170 ngmL(-1)) with an apparent molar absorptivity of 1.33 * 10(6) molL(-1) cm(-1) for a 100 mL aliquot of the water sample. The detection limit (n = 10) was 8.7 * 10(-9) molL(-1) (1.0 ngmL(-1)) and the Relative standard deviation (R.S.D), (n = 10) for 7.2 * 10(-7) molL(-1) (150 ngmL(-1)) of Pb (II) was 4.36%. A notable advantage of the method is that the determination of Pb (II) is free from the interference of almost all cations and ions found in the environment and waste water samples. The determination of Pb (II) in tap and synthetic seawater samples was also carried out by the present method. The results were satisfactorily comparable so that the applicability of the proposed method was confirmed to the real samples. PMID- 21234288 TI - Effects of a breast-health herbal formula supplement on estrogen metabolism in pre- and post-menopausal women not taking hormonal contraceptives or supplements: a randomized controlled trial. AB - INTRODUCTION: Both indole-3-carbinol and dietary lignans have beneficial effects on estrogen metabolism and breast cancer risk. There is no published literature on the effects of a combination product. This study was designed to investigate the impact of a combination product on estrogen metabolism. The major trial objective was to determine whether a breast health supplement containing indole-3 carbinol and hydroxymatairesinol lignan would alter estrogen metabolism to favour C-2 hydroxylation and reduce C-16 hydroxylation. Higher concentrations of C-2 metabolites and lower concentrations of C-16 metabolites may reduce breast cancer risk and risk for other hormonally-related cancers. METHODS: Forty-seven pre menopausal and forty-nine post-menopausal women were recruited for this study, and were divided by random allocation into treatment and placebo group. The treatment supplement contained HMR lignan, indole-3-carbinol, calcium glucarate, milk thistle, Schisandra chinesis and stinging nettle, and each woman consumed either treatment or placebo for 28 days. At day 0 and day 28, blood samples were analysed for serum enterolactone concentrations, and first morning random urine samples were assessed for estrogen metabolites. Repeated measures ANOVA statistical testing was performed. RESULTS: In pre-menopausal women, treatment supplementation resulted in a significant increase (P < 0.05) in urinary 2-OHE concentrations and in the 2:16alpha-OHE ratio. In post-menopausal women, treatment supplementation resulted in a significant increase in urinary 2-OHE concentrations. In pre- and post-menopausal women combined, treatment supplementation produced a significant increase in urinary 2-OHE concentration and a trend (P = 0.074) toward an increased 2:16alpha-OHE ratio. There were no significant increases in serum enterolactone concentrations in the treatment or placebo groups. CONCLUSIONS: Supplementation with a mixture of indole-3-carbinol and HMR lignan in women significantly increased estrogen C-2 hydroxylation. This may constitute a mechanism for the reduction of breast cancer risk as well as risk for other estrogen-related cancers. Further studies with higher numbers of subjects are indicated. PMID- 21234289 TI - Phytohemagglutinin-induced mitotic index in blood lymphocytes: a potential biomarker for breast cancer risk. AB - BACKGROUND: Cell proliferation is associated with the pathogenesis of cancer because it provides opportunities for accumulating genetic mutations. However, biomarkers of cell proliferation in response to environmental stimuli have not been adequately explored for breast cancer risk. METHODS: In a case-control study of 200 breast cancer patients and 360 healthy controls, we investigated the association between phytohemagglutinin (PHA)-induced mitotic index in blood lymphocyte and breast cancer risk. RESULTS: Having high mitotic index (>3.19%) was associated with an increased risk of breast cancer, with adjusted odds ratios (95% confidence interval) of 1.54 (1.03-2.30) and 2.03 (1.18-3.57) for all women and post-menopausal women, respectively. Mitotic index was correlated with some reproductive factors and body mass index in controls. CONCLUSIONS: Our data suggest increased PHA-induced mitotic index in blood lymphocytes is associated with an increased breast cancer risk and that this association may be modulated by reproductive and other hormones. PMID- 21234290 TI - Establishment of prognostic models for astrocytic and oligodendroglial brain tumors with standardized quantification of marker gene expression and clinical variables. AB - BACKGROUND: Prognosis models established using multiple molecular markers in cancer along with clinical variables should enable prediction of natural disease progression and residual risk faced by patients. In this study, multivariate Cox proportional hazards analyses were done based on overall survival (OS) of 100 glioblastoma multiformes (GBMs, 92 events), 49 anaplastic astrocytomas (AAs, 33 events), 45 gliomas with oligodendroglial features, including anaplastic oligodendroglioma (AO, 13 events) and oligodendraglioma (O, 9 events). The modeling included two clinical variables (patient age and recurrence at the time of sample collection) and the expression variables of 13 genes selected based on their proven biological and/or prognosis functions in gliomas (ABCG2, BMI1, MELK, MSI1, PROM1, CDK4, EGFR, MMP2, VEGFA, PAX6, PTEN, RPS9, and IGFBP2). Gene expression data was a log-transformed ratio of marker and reference (ACTB) mRNA levels quantified using absolute real-time qRT-PCR. RESULTS: Age is positively associated with overall grade (4 for GBM, 3 for AA, 2_1 for AO_O), but lacks significant prognostic value in each grade. Recurrence is an unfavorable prognostic factor for AA, but lacks significant prognostic values for GBM and AO_O. Univariate models revealed opposing prognostic effects of ABCG2, MELK, BMI1, PROM1, IGFBP2, PAX6, RPS9, and MSI1 expressions for astrocytic (GBM and AA) and oligodendroglial tumors (AO_O). Multivariate models revealed independent prognostic values for the expressions of MSI1 (unfavorable) in GBM, CDK4 (unfavorable) and MMP2 (favorable) in AA, while IGFBP2 and MELK (unfavorable) in AO_O. With all 13 genes and 2 clinical variables, the model R(2) was 14.2% (P = 0.358) for GBM, 45.2% (P = 0.029) for AA, and 62.2% (P = 0.008) for AO_O. CONCLUSION: The study signifies the challenge in establishing a significant prognosis model for GBM. Our success in establishing prognosis models for AA and AO_O was largely based on identification of a set of genes with independent prognostic values and application of standardized gene expression quantification to allow formation of a large cohort in analysis. PMID- 21234291 TI - Tocilizumab: a review of its safety and efficacy in rheumatoid arthritis. AB - Recent years have seen many exciting developments in the treatment of rheumatoid arthritis. Tocilizumab (TCZ) is a monoclonal antibody which inhibits the interleukin-6 receptor. After initial studies in Japan, it has been extensively studied in five multicentre clinical trials. This report summarises the key efficacy and toxicity findings from the major clinical trials. TCZ works quickly and effectively in rheumatoid arthritis either as monotherapy or in combination with other agents in early disease, DMARD inadequate responders, seronegative disease and after anti-TNF failure. The toxicity profile is manageable but includes infections (most notably skin and soft tissue), increases in serum cholesterol, transient decreases in neutrophil count and abnormal liver function tests (especially in combination with methotrexate). In summary, there is sufficient evidence to make TCZ a first line biologic therapy for rheumatoid arthritis especially for those who are unable to take methotrexate or who fail anti-TNF therapy. PMID- 21234292 TI - Characteristics and prognostic importance of myocardial fibrosis in patients with dilated cardiomyopathy assessed by contrast-enhanced cardiac magnetic resonance imaging. AB - INTRODUCTION: Dilated cardiomyopathy (DCM) is associated with significant morbidity and mortality. Contrast-enhanced cardiac MRI (CE-CMR) can detect potentially prognostic myocardial fibrosis in DCM. We investigated the role of CE CMR in New Zealand patients with DCM, both Maori and non-Maori, including the characteristics and prognostic importance of fibrosis. METHODS: One hundred and three patients (mean age 58 +/- 13, 78 male) referred for CMR assessment of DCM were followed for 660 +/- 346 days. Major adverse cardiac events (MACE) were defined as death, infarction, ventricular arrhythmias or rehospitalisation. CE CMR used cines for functional analysis, and delayed enhancement to assess fibrosis. RESULTS: Myocardial fibrosis was present in 30% of patients, the majority of which was mid-myocardial (63%). Volumetric parameters were similar in patients with or without fibrosis. At 2 years patients with fibrosis had an increased rate of MACE (HR = 0.77, 95% CI 0.3-2.0). Patients with full thickness or subendocardial fibrosis had the highest MACE, even in the absence of CAD). More Maori had fibrosis on CE-CMR (40% vs. 28% for non-Maori), and the majority (75%) was mid-myocardial. Maori and non-Maori had similar outcomes (25% vs. 24% with events during follow-up). CONCLUSIONS: DCM patients frequently have myocardial fibrosis detected on CE-CMR, the majority of which is mid-myocardial. Fibrosis is associated with worse outcome in the medium term. The information obtained using CE-CMR in DCM may be of incremental clinical benefit. PMID- 21234293 TI - The pro-BNP Serum Level and Echocardiographic Tissue Doppler Abnormalities in Patients with Beta Thalassemia Major. AB - BACKGROUND: Doppler echocardiographic studies of the left ventricle (LV) function in patients with beta-Thalassemia Major (beta-TM) had shown different patterns of systolic and diastolic dysfunctions associated with abnormal serum brain natriuretic peptide (BNP). AIM: This cross-sectional study was designed to study the LV systolic and diastolic functions and correlate that with serum level of N terminal pro brain natriuretic hormone (NT- pro BNP) in patients with beta-TM using Pulsed Doppler (PD) and Tissue Doppler (TD) echocardiography. METHODS: The study was conducted on patients with beta-TM (n = 38, age 15.7 +/- 8.9 years) and compared with an age-matched controls (n = 38, age 15.9 +/- 8.9 years). In all participants, PD and TD echocardiography were performed and blood samples were withdrawn for measuring the serum level of NT-pro BNP, ferritin, and alanine transaminase. RESULTS: Patients with beta-TM compared with controls, have thicker LV septal wall index (0.65 +/- 0.26 vs. 0.44 +/- 0.21 cm, P < 0.001), posterior wall index (0.65 +/- 0.23 vs. 0.43 +/- 0.21 cm, P < 0.01), and larger LVEDD index (4.35 +/- 0.69 vs.3.88 +/- 0.153 mm, P < 0.001). In addition, beta-TM patients have higher transmitral E wave velocity (E) (70.818 +/- 10.139 vs. 57.532 +/- 10.139, p = 0.027) and E/A ratio (1.54 +/- 0.17 vs. 1.23 +/- 0.19, P < 0.01) and shorter deceleration time (DT) (160.13 +/- 13.3 vs. 170.50 +/- 19.20 m sec, P < 0.01). Furthermore, the ratio of transmitral E wave velocity to the tissue Doppler E wave at the basal septal mitral annulus (E/Em(-)) was significantly higher in beta-TM group (19.6 +/- 2.81 vs. 13.868 +/- 1.41, P < 0.05). The tissue doppler systolic wave (Sm) velocity and the early diastolic wave (Em) were significantly lower in beta-TM group compared to controls (Sm: 4.82 +/- 1.2 vs. 6.22 +/- 2.1 mm/sec, P < 0.05; Em: 3.51 +/- 2.7 vs. 4.12 +/- 2.5 mm/sec P < 0.05, respectively). The tricuspid valve velocity was significantly higher in beta-TM patients compared with controls (2.993 +/- 0.569 vs. 1.93 +/- 0.471 m/sec, respectively, P < 0.01). The mean serum NT pro-BNP in beta-TM was significantly higher compared with controls (37.6 +/- 14.73 vs. 5.5 +/- 5.4pg/ml, P < 0.05). The left ventricle ejection fraction (EF%) and fractional shortening (FS%) were not significantly different between both groups. CONCLUSION: We conclude that patients with beta-TM had a significantly higher serum level of NT-pro BNP that is positively correlated with the E/Em ratio on tissue Doppler. Furthermore, we confirm our previous findings that patients with beta-TM exhibit LV diastolic pattern on echocardiogram suggestive of restrictive type with well preserved left ventricle systolic function. PMID- 21234294 TI - Comparison of the response of the right ventricle with endovascular occlusion and surgical closure in adults with atrial septal defect one year after intervention. AB - BACKGROUND: Use of the Amplatzer septal occluder (ASO) for the closure of secundum atrial septal defect (ASD) has recently become the procedure of choice, while earlier the only treatment for ASD was surgical closure. This study compares the right ventricular indices of the ASO group with the surgical closure group one year after intervention in adults. METHODS: From January 2008 to February 2010, 38 patients with isolated atrial septal defect of the secundum type one year after surgical (n = 20, age = 27 +/- 4 years, 13 females, 7 males) or Amplatzer septal occluder closure (n = 18, age = 25 +/- 4 years, 12 females, 6 males) were studied. At the same time, thirty-one age-matched normal subjects (age = 26 +/- 6 years, 23 females, 9 males) were included as the control group. Strain and strain rate of the right ventricle were measured. RESULTS: The mean values of strain of the midportion were -26% +/- 11.7%, -8.9% +/- 4.2%, and 24.5% +/- 7.4% (P < 0.001). Strain rates of the midportion were -2.19 +/- 0.6 s(-1), 1.2 +/- 0.4 s(-1), -1.9 +/- 0.6 s(-1) (P < 0.001) in ASO, surgery, and control groups, respectively. CONCLUSION: This study showed that the right ventricle might show better performance in the ASO than the surgery group in adults with ASD in midterm follow-up. PMID- 21234295 TI - Renal cell carcinoma: focus on safety and efficacy of temsirolimus. AB - Metastatic renal cell carcinoma has harboured a poor prognosis for decades with immunotherapy being the only available therapy with high toxicity and modest effect. Dependance of renal cell carcinoma oncogenesis on the mTOR pathway has led to clinical development of temsirolimus in this setting. This sirolimus derivative has shown clinical efficacy in monotherapy for poor-risk renal cell carcinoma leading to an overall survival of 10.8 months in the pivotal phase III trial of this agent. Its specific adverse events consist of metabolic dysregulation (hyperlipemia, hyperglycemia), mucositis, rash and pneumonitis which can be severe and need careful monitoring and management. In this review, we will discuss of the clinical development of this molecule, its efficacy, its safety profile and future perspectives. PMID- 21234296 TI - Efficacy and tolerability after unusually low doses of dasatinib in chronic myeloid leukemia patients intolerant to standard-dose dasatinib therapy. AB - We report our experience in 4 patients with chronic myeloid leukemia (CML) who had discontinued imatinib as a result of adverse events and had switched to dasatinib. The chronic phase (n 2) and accelerated phase (n 2) CML patients received dasatinib at starting dose of 100 and 140 mg once daily, respectively. Reappearance of hematological toxicity was observed in 3 patients and pancreatitis in one patient. Treatment was given at a lower dose and patients were followed. The median follow-up was 13 months and the median dose of dasatinib until achievement of complete cytogenetic remission (CCyR) was 60 mg daily (range = 20 to 120 mg). All four patients had achieved CCyR at a median of 4 months (range = 3 to 5 months) and among them, three had also achieved major molecular remission. We conclude that low-dose dasatinib therapy in intolerant patients appears safe and efficacious and may be tried before drug discontinuation. PMID- 21234297 TI - Early Detection of t(8;21) Chromosomal Translocations During Treatment of PML RARA Positive Acute Promyelocytic Leukemia: A Case Study. AB - Here we describe a female patient who developed acute promyelocytic leukemia (APL) characterized by t(l5;17) translocation at diagnosis. The patient began treatment with all-trans retinoic acid (ATRA) + chemotherapy. During follow up, the patient was found to be negative for the t(15;17) transcript after 3 months of therapy which remained undetectable, thereafter. However, the emergence of a small clone with a t(8;21) abnormality was observed in the bone marrow and peripheral blood (PB) cells between 3 and 18 months following treatment initiation. The abnormal translocation observed in PB cells obtained at 3 months was detected after the second cycle of consolidation therapy and reappeared at 15 months during maintenance treatment, a period without ATRA. Although based on a single case, we conclude that genetic screening of multiple translocations in AML patients should be requested to allow early identification of other emerging clones during therapy that may manifest clinically following treatment. PMID- 21234298 TI - The impact of 9/11 on the association of ambient air pollution with daily respiratory hospital admissions in a Canada-US border city, Windsor, Ontario. AB - The 11 September 2001 (9/11) terrorist attacks in the United States resulted in long lines of trucks at the border crossing in Windsor, Ontario. Public concern about the potential impact of these trucks spewing toxic pollutants into the air drew attention to the need to investigate the impact of 9/11 on the daily levels of air pollutants and respiratory hospitalization. In this study, significant increases in respiratory admissions were found one month and 6 months post-9/11. Mean daily respiratory admission was also significantly higher than the same period one year earlier and one year later. SO(2) and CO concentration levels were found to be generally higher after 9/11 than one year before and immediately before. Relative risk estimates of respiratory hospitalization after 9/11 showed that SO(2) (RR = 1.15 for two-day, RR = 1.18 for three-day, and RR = 1.21 for five-day averages), NO(2) (RR = 1.10 for current day), and COH (RR = 1.09 for current day, RR = 1.10 for two-day average) had the most significant effects after 9/11. These results suggest the need for more stringent regulatory efforts in air quality in the region in response to the changing transportation dynamics at this Canada-US border crossing. PMID- 21234299 TI - Computational Analysis of Molecular Interaction Networks Underlying Change of HIV 1 Resistance to Selected Reverse Transcriptase Inhibitors. AB - MOTIVATION: Despite more than two decades of research, HIV resistance to drugs remains a serious obstacle in developing efficient AIDS treatments. Several computational methods have been developed to predict resistance level from the sequence of viral proteins such as reverse transcriptase (RT) or protease. These methods, while powerful and accurate, give very little insight into the molecular interactions that underly acquisition of drug resistance/hypersusceptibility. Here, we attempt at filling this gap by using our Monte Carlo feature selection and interdependency discovery method (MCFS-ID) to elucidate molecular interaction networks that characterize viral strains with altered drug resistance levels. RESULTS: We analyzed a number of HIV-1 RT sequences annotated with drug resistance level using the MCFS-ID method. This let us expound interdependency networks that characterize change of drug resistance to six selected RT inhibitors: Abacavir, Lamivudine, Stavudine, Zidovudine, Tenofovir and Nevirapine. The networks consider interdependencies at the level of physicochemical properties of mutating amino acids, eg,: polarity. We mapped each network on the 3D structure of RT in attempt to understand the molecular meaning of interacting pairs. The discovered interactions describe several known drug resistance mechanisms and, importantly, some previously unidentified ones. Our approach can be easily applied to a whole range of problems from the domain of protein engineering. AVAILABILITY: A portable Java implementation of our MCFS-ID method is freely available for academic users and can be obtained at: http://www.ipipan.eu/staff/m.draminski/software.htm. PMID- 21234300 TI - Effects of an Indolocarbazole-Derived CDK4 Inhibitor on Breast Cancer Cells. AB - INTRODUCTION: Cyclin D1 (D1) binds to cyclin-dependent kinases (CDK) 4 or 6 to form a holoenzyme that phosphorylates the Rb protein to promote cell cycle progression from G1 to S phase. Therefore, targeting CDK4/6 may be a good strategy for chemotherapy of cancer. We performed a proof-of-principle study to determine the effect of Naphtho [2, 1-alpha] pyrrolo [3, 4-c] carbazole-5, 7 (6H, 12H)-dione (NPCD), a novel CDK4 inhibitor, on breast cancer cell lines. METHODS: NPCD was synthesized and purified to over 99% purity verified by HPLC. MCF7, MB231, MCF15, T47D and GI101Ap human breast cancer cells were analyzed for the efficacy of NPCD with MTT and clonogenic assays, with FACS and staining for ethidium bromide and acridine orange for cell death and cell cycle profile. Western blot, reverse transcription and PCR were used for studies of gene expression, and co-immunoprecipitation for protein-complex formation. RESULTS: MTT assay showed that NPCD caused growth arrest and apoptosis of MCF7, MDA-MB231, T47D, MCF15 and GI101Ap cells with an IC50 ranging between 3 to 8 uM given as a single dose. The growth arrest persisted for many days after cessation of the treatment, as shown in a clonogenic assay. NPCD could induce or reduce the D1 and CDK4 protein levels, depending on the cell line, but this effect was not correlated with its efficacy. Phosphorylation of D1 at Thr286 was decreased but it unexpectedly did not correlate with the change in D1 level in the cell lines studied. Phosphorylation of the Rb protein was decreased as expected whereas the p27kip1 protein level was decreased unexpectedly. Protein levels of p21cip1, CDK2 and cyclin E were also decreased in some, but not all, of the cell lines, whereas the mRNA levels of D1, CDK4, cyclin E, CDK2, p27kip1 and p21cip1 were increased in different cell lines. CONCLUSIONS: NPCD can cause long-lasting growth arrest and cell death of breast cancer cell lines at an IC50 of 3-8 uM. Decreased phosphorylation of Rb by D1-CDK4/6 and decreased p27kip1 protein level may be part of the underlying mechanism. PMID- 21234301 TI - Smoking and prognostic factors in an observational setting in patients with advanced non-small cell lung carcinoma. AB - BACKGROUND: This prospective observational study estimated the effect of prognostic factors, particularly continued smoking during therapy, on survival in advanced non-small cell lung cancer (NSCLC) patients receiving gemcitabine platinum. Further, prognostic factors were used to build a survival model to improve prognosis prediction in naturalistic clinical settings. METHODS: Eligibility criteria included: Stage IIIB/IV NSCLC, no prior chemotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. A Cox regression model was constructed and validated by randomizing patients into two datasets (Construction [C]:Validation [V]; 3:1 ratio). Country, disease stage, hypercalcemia, "N" factor, weight reduction, performance status, and superior vena cava obstruction were pre-defined variables forced into the model. Continued smoking was tested with adjustment for these variables. RESULTS: One thousand two hundred and fourteen patients (C=891 and V=323) were enrolled. The final predictive model, established in the Construction dataset, identified four significant (p<=0.05) and independent predictors of survival, which were disease stage, performance status, gemcitabine-platinum regimen, and T-stage. Smoking during therapy was not significantly associated with survival (Hazard Ratio [95% CI]: 0.955 [0.572, 1.596], p=0.8618; versus never smokers). CONCLUSIONS: Although continued smoking during therapy was not significantly associated with shorter survival, the model developed in this study forms an evidence-based approach to assessing prognosis in advanced stage NSCLC. PMID- 21234302 TI - Thiamin (vitamin B1) biosynthesis and regulation: a rich source of antimicrobial drug targets? AB - Drug resistance of pathogens has necessitated the identification of novel targets for antibiotics. Thiamin (vitamin B1) is an essential cofactor for all organisms in its active form thiamin diphosphate (ThDP). Therefore, its metabolic pathways might be one largely untapped source of antibiotics targets. This review describes bacterial thiamin biosynthetic, salvage, and transport pathways. Essential thiamin synthetic enzymes such as Dxs and ThiE are proposed as promising drug targets. The regulation mechanism of thiamin biosynthesis by ThDP riboswitch is also discussed. As drug targets of existing antimicrobial compound pyrithiamin, the ThDP riboswitch might serves as alternative targets for more antibiotics. PMID- 21234303 TI - Intratumoral expression of IL-17 and its prognostic role in gastric adenocarcinoma patients. AB - In this study, we characterized the intratumoral expression of IL-17 and CD8(+) TILs in gastric adenocarcinoma patients after resection and determined the correlation between the survival probability of gastric adenocarcinoma patients and the expression of IL-17 in tumor. Expression of IL-17 and CD8 was assessed by immunohistochemistry, and the prognostic effects of intratumoral IL-17 expression and CD8(+) TILs were evaluated by Cox regression and Kaplan-Meier analysis. Immunohistochemical detection revealed the presence of IL-17 and CD8(+) cells in gastric adenocarcinoma tissue samples (90.6%, 174 out of 192 patients and 96.9%, 186 out of 192 patients, respectively). We have also found that intratumoral IL 17 expression was significantly correlated with age (p=0.004) and that the number of CD8(+)TILs was significantly correlated with UICC staging (p=0.012) and the depth of tumor invasion (p=0.022). The five-year overall survival probability among patients intratumorally expressing higher levels of IL-17 was significantly better than those expressing lower levels of IL-17 (p=0.036). Multivariate Cox proportional hazard analyses revealed that intratumoral IL-17 expression (HR: 0.521; 95% CI: 0.329-0.823; p=0.005) was an independent factor affecting the five year overall survival probability. We conclude that low levels of intratumoral IL 17 expression may indicate poor prognosis in gastric adenocarcinoma patients. PMID- 21234304 TI - Dual antiplatelet therapy in secondary prevention of ischemic stroke: a ghost from the past or a new frontier? AB - With majority of ischemic strokes attributable to atherothrombosis and many being predictable after transient ischemic attacks (TIA), the role of early secondary prevention with antiplatelet agents is under renewed investigation. Prior major clinical trials of various secondary stroke prevention regimens pointed to a greater efficacy of dual antiplatelet agents if initiated early from symptom onset. This paper examines data and rationale behind dual antiplatelet regimens across the completed clinical trials. The safety of dual antiplatelets approach is of concern, but it could be outweighed, at least in early management, by a greater reduction in recurrence of ischemic events since this risk is "front loaded" after minor stroke or TIA. Aspirin monotherapy, though considered standard of care, is compared to aspirin-extended release dipiridamole and its combination with clopidogrel in early-phase completed and efficacy-phase ongoing clinical trials. PMID- 21234305 TI - Correlation of copper interaction, copper-driven aggregation, and copper-driven h(2)o(2) formation with abeta40 conformation. AB - The neurotoxicity of Abeta is associated with the formation of free radical by interacting with redox active metals such as Cu(2+). However, the relationship between ion-interaction, ion-driven free radical formation, and Abeta conformation remains to be further elucidated. In the present study, we investigated the correlation of Cu(2+) interaction and Cu(2+)-driven free radical formation with Abeta40 conformation. The Cu(2+)-binding affinity for Abeta40 in random coiled form is 3-fold higher than that in stable helical form. Unexpectedly but interestingly, we demonstrate in the first time that the stable helical form of Abeta40 can induce the formation of H(2)O(2) by interacting with Cu(2+). On the other hand, the H(2)O(2) generation is repressed at Abeta/Cu(2+) molar ratio >=1 when Abeta40 adopts random coiled structure. Taken together, our result demonstrates that Abeta40 adopted a helical structure that may play a key factor for the formation of free radical with Cu(2+) ions. PMID- 21234306 TI - Alzheimer's disease: a pathogenetic autoimmune disorder caused by herpes simplex in a gene-dependent manner. AB - Herpes simplex is implicated in Alzheimer's disease and viral infection produces Alzheimer's disease like pathology in mice. The virus expresses proteins containing short contiguous amino acid stretches (5-9aa "vatches" = viralmatches) homologous to APOE4, clusterin, PICALM, and complement receptor 1, and to over 100 other gene products relevant to Alzheimer's disease, which are also homologous to proteins expressed by other pathogens implicated in Alzheimer's disease. Such homology, reiterated at the DNA level, suggests that gene association studies have been tracking infection, as well as identifying key genes, demonstrating a role for pathogens as causative agents. Vatches may interfere with the function of their human counterparts, acting as dummy ligands, decoy receptors, or via interactome interference. They are often immunogenic, and antibodies generated in response to infection may target their human counterparts, producing protein knockdown, or generating autoimmune responses that may kill the neurones in which the human homologue resides, a scenario supported by immune activation in Alzheimer's disease. These data may classify Alzheimer's disease as an autoimmune disorder created by pathogen mimicry of key Alzheimer's disease-related proteins. It may well be prevented by vaccination and regular pathogen detection and elimination, and perhaps stemmed by immunosuppression or antibody adsorption-related therapies. PMID- 21234307 TI - Impact of HPV in Oropharyngeal Cancer. AB - The incidence of oropharyngeal cancers has increased in the western world and Human Papilloma Virus (HPV) has been recognised as a risk factor in the last decades. During the same period the prevalence of HPV in oropharyngeal tumours has increased and HPV has been suggested responsible for the increase. The HPV positive tumours are today recognized as a distinct subset of head and neck cancers with its own clinopathological and risk profile and have a significantly improved prognosis regardless of treatment strategy. This review summarizes current knowledge regarding human papillomavirus biology, oncogenic mechanisms, risk factors, and impact of treatment. PMID- 21234308 TI - Gene Expression Signatures of Peripheral Blood Mononuclear Cells during the Early Post-Transplant Period in Patients Developing Cardiac Allograft Vasculopathy. AB - Background. Cardiac allograft vasculopathy (CAV) is a major cause of graft loss and death after heart transplantation. Currently, no diagnostic methods are available during the early post-transplant period to accurately identify patients at risk of CAV. We hypothesized that PBMC gene expression profiles (GEP) can identify patients at risk of CAV. Methods. We retrospectively analyzed a limited set of whole-genome PBMC microarrays from 10 post-transplant patients who did (n = 3) or did not (n = 7) develop advanced grade CAV during their long-term follow up. We used significance analysis of microarrays to identify differentially expressed genes and High-Throughput GoMiner to assess gene ontology (GO) categories. We corroborated our findings by retrospective analysis of PBMC real time PCR data from 33 patients. Results. Over 300 genes were differentially expressed (FDR < 5%), and 18 GO-categories including "macrophage activation", "Interleukin-6 pathway", "NF-KappaB cascade", and "response to virus" were enriched by these genes (FDR < 5%). Out of 8 transcripts available for RT-PCR analysis, we confirmed 6 transcripts (75.0%) including FPRL1, S100A9, CXCL10, PRO1073, and MMP9 (P < .05). Conclusion. Our pilot data suggest that GEP of PBMC may become a valuable tool in the evaluation of patients at risk of CAV. Larger prospectively designed studies are needed to corroborate our hypothesis. PMID- 21234309 TI - Heart-kidney interaction: epidemiology of cardiorenal syndromes. AB - Cardiac and kidney diseases are common, increasingly encountered, and often coexist. Recently, the Acute Dialysis Quality Initiative (ADQI) Working Group convened a consensus conference to develop a classification scheme for the CRS and for five discrete subtypes. These CRS subtypes likely share pathophysiologic mechanisms, however, also have distinguishing clinical features, in terms of precipitating events, risk identification, natural history, and outcomes. Knowledge of the epidemiology of heart-kidney interaction stratified by the proposed CRS subtypes is increasingly important for understanding the overall burden of disease for each CRS subtype, along with associated morbidity, mortality, and health resource utilization. Likewise, an understanding of the epidemiology of CRS is necessary for characterizing whether there exists important knowledge gaps and to aid in the design of clinical studies. This paper will provide a summary of the epidemiology of the cardiorenal syndrome and its subtypes. PMID- 21234310 TI - Relationship between Fibroblast Growth Factor-23 and Mineral Metabolism in Chronic Kidney Disease. AB - Fibroblast growth factor- (FGF-)23 is a recently discovered regulator of calcium phosphate metabolism. FGF-23 appears to decrease in synthesis and accelerated degradation of 1,25(OH)(2)D. Together with its cofactor Klotho, FGF-23 maintains serum phosphate levels within the normal range by increasing renal phosphate excretion. In chronic kidney disease (CKD), FGF-23 levels rise in parallel with the decline in renal function long before a significant increase in serum phosphate concentration occurs. Both Klotho and FGF-23, linked by a receptor mechanism, affect vitamin D synthesis and parathyroid hormone (PTH) secretion. Previous studies have shown a close association between reduced FGF-23 or Klotho activities and vascular calcification. The possible association of FGF-23 and left ventricular hypertrophy or vascular dysfunction has been proposed. Finally, prospective studies have shown that high serum FGF-23 concentrations predict more rapid disease progression in CKD patients who were not on dialysis and increased mortality in patients on maintenance hemodialysis. FGF-23 may therefore prove to be an important therapeutic target for the management of CKD. PMID- 21234311 TI - The utility of repeat endoscopic ultrasound-guided fine needle aspiration for suspected pancreatic cancer. AB - Background. The utility of repeat EUS in patients with suspicion for pancreatic cancer after non-diagnostic EUS-FNA study is not well established. Aim. Determine the accuracy of repeat EUS-FNA in patients with suspected pancreatic cancer and prior non-diagnostic EUS-FNA. Methods. Retrospective cohort study. Results. From 2002 to 2008 in our institution 28 patients underwent repeat EUS-FNA for suspected pancreatic cancer. Initial EUS showed a pancreatic mass in 24 (85.71%), no mass in 3 (10.71%) and possible mass in 1 (3.58%). FNA was performed and was negative for malignancy in all patients. Repeat EUS showed pancreatic mass in 27 patients (96.42%) and no mass in 1 (3.58%). FNA was performed in all patients and cytology was positive for malignancy in 6 (21.43%). Out of the 28 patients, 17 (60.71%) were eventually confirmed to have cancer. Overall repeat EUS-FNA correctly determined the true final status in 17 out of 28 patients providing sensitivity for the diagnosis of cancer of 35% (95% CI 14%-62%), specificity 100% (95% CI 72%-100%), and overall accuracy of 61%, (95% CI 28%-72%). Conclusion. Repeat EUS-FNA provides reasonable accuracy and may be worthwhile in patients with suspected pancreatic cancer who had had prior negative EUS-FNA. PMID- 21234312 TI - Treatment challenges in pediatric stroke patients. AB - Aim. In this study we presented our experience of 18 years on the etiology, risk factors, prophylactic and acute treatment, the effect of treatment to recurrence rate of patients with stroke. Methods. The population included 108 patients who had been treated for stroke at Pediatric Neurology Department of Ankara University with the diagnosis of arterial ischemic stroke and sinovenous thrombosis between January 1992 and August 2010. Forty-one girls (38%) and 67 boys (62%) with mean symptom age 3.1 +/- 4.04 years, (0-18 years old) were followed up with a mean period of 4.9 +/- 3.78 years (0-17 years). Results. 30 patients had no risk factors, 34 patients had only one risk factor and 44 patients had multiple risk factors. Recurrence was seen in three patients. There was no any statistical correlation between the recurrence of stroke and the existence of risk factors (P = .961). Seventeen patients received prophylactic treatment; 2 of them without any risk factors, 3 had one risk factor, 12 patients, who constituted the majority of our patients, had multiple risk factors (P = .024). Conclusion. With this study we showed that the right prophylaxis for right patients reduces the rate of recurrence. PMID- 21234313 TI - The efficacy of dandelion root extract in inducing apoptosis in drug-resistant human melanoma cells. AB - Notoriously chemoresistant melanoma has become the most prevalent form of cancer for the 25-29 North American age demographic. Standard treatment after early detection involves surgical excision (recurrence is possible), and metastatic melanoma is refractory to immuno-, radio-, and most harmful chemotherapies. Various natural compounds have shown efficacy in killing different cancers, albeit not always specifically. In this study, we show that dandelion root extract (DRE) specifically and effectively induces apoptosis in human melanoma cells without inducing toxicity in noncancerous cells. Characteristic apoptotic morphology of nuclear condensation and phosphatidylserine flipping to the outer leaflet of the plasma membrane of A375 human melanoma cells was observed within 48 hours. DRE-induced apoptosis activates caspase-8 in A375 cells early on, demonstrating employment of an extrinsic apoptotic pathway to kill A375 cells. Reactive Oxygen Species (ROS) generated from DRE-treated isolated mitochondria indicates that natural compounds in DRE can also directly target mitochondria. Interestingly, the relatively resistant G361 human melanoma cell line responded to DRE when combined with the metabolism interfering antitype II diabetic drug metformin. Therefore, treatment with this common, yet potent extract of natural compounds has proven novel in specifically inducing apoptosis in chemoresistant melanoma, without toxicity to healthy cells. PMID- 21234314 TI - Age-dependent variation in hormonal concentration and biochemical constituents in blood plasma of Indian native fowl. AB - This experiment was to investigate the age-related changes in hormonal concentration and biochemical constituents of blood plasma in Indian native desi fowl. One hundred and sixty two (54 from each breed, i.e., Kadaknath (KN), Aseel peela (AP), and White leghorn (WLH)) day-old female chicks were randomly divided into nine groups each of 18 chicks (3 groups * 3 replicates). WLH was taken in this study to compare the characteristics of Indian native desi fowl. The highest level of estrogen hormone in WLH and desi fowl in blood plasma was occurred at 18 and 24 wks of age, respectively. Whereas, the peak of progesterone hormone in WLH hens noticed around 24 wks, in case of desi fowls, it was at 30 wks of age. Irrespective of the breed, the hormonal profile of Triiodothyronine (T3) and Thyroxine (T4) in blood plasma was found highest around 6 to 12 wks of age. Activities of acid phosphatase (ACP) increased with the reduction of alkaline phosphate (ALP) activities at different time intervals. Irrespective of the breed, transaminases (glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT)) activities of blood plasma increased linearly with the advancement of the age. From this study, it may be concluded that sexual maturity of the Indian native desi fowl occurred nearly 6 wk later (24 wk) than WLH. PMID- 21234315 TI - SALSA : SAving Lives Staying Active to Promote Physical Activity and Healthy Eating. AB - Physical inactivity, poor dietary habits, and obesity are vexing problems among minorities. SAving Lives, Staying Active (SALSA) was an 8-week randomized controlled crossover design, pilot study to promote regular physical activity (PA) and fruit and vegetable (FV) consumption as a means to preventing weight gain among women of color. Participants completed measures of demographics, PA, and dietary habits. Women (N = 50; M = 42 years) who participated were overweight (MBMI = 29.7 kg/m(2); Mbody fat = 38.5%) and reported low levels of leisure time PA (M = 10.7 MET-min/wk) and FV consumption (M = 4.2 servings/day). All were randomized to a four-week (1) semiweekly Latin dance group or (2) internet-based dietary education group. All participants reported a significant increase in weekly leisure time PA from baseline (M = 10.7 MET-min/wk) to follow up (M = 34.0 MET-min/wk, P < .001), and FV consumption increased over time by group (P = .02). Data suggest that Latin dance interventions to improve PA and web-based interventions to improve dietary habits show promise for improving health among women of color. PMID- 21234316 TI - Fatal fulminant hepatic failure in a diabetic with primary dengue. AB - We report a 49-year-old diabetic with dengue hemorrhagic fever who developed fulminant hepatitis, severe coagulopathy, shock, and refractory metabolic acidosis and died on the eighth day of illness. This is the only second report of an adult with fatal fulminant hepatic failure due to dengue, and the first case arising from a primary dengue infection. PMID- 21234317 TI - Reclassification of ICD-9 Codes into Meaningful Categories for Oncology Survivorship Research. AB - Background. The International Classification of Disease, ninth revision (ICD-9) is designed to code disease into categories which are placed into administrative databases. These databases have been used for epidemiological studies. However, the categories used in the ICD9-codes are not always the most effective for evaluating specific diseases or their outcomes, such as the outcomes of cancer treatment. Therefore a re-classification of the ICD-9 codes into new categories specific to cancer outcomes is needed. Methods. An expert panel comprised of two physicians created broad categories that would be most useful to researchers investigating outcomes and morbidities associated with the treatment of cancer. A Senior Data Coordinator with expertise in ICD-9 coding, then joined this panel and each code was re-classified into the new categories. Results. Consensus was achieved for the categories to go from the 17 categories in ICD-9 to 39 categories. The ICD-9 Codes were placed into new categories, and subcategories were also created for more specific outcomes. The results of this re classification is available in tabular form. Conclusions. ICD-9 codes were re classified by group consensus into categories that are designed for oncology survivorship research. The novel re-classification system can be used by those involved in cancer survivorship research. PMID- 21234318 TI - Risk factors for radiographic tibiofemoral knee osteoarthritis: the wuchuan osteoarthritis study. AB - Objective. To investigate the risk factors of radiographic tibiafemoral knee osteoarthritis (OA). Methods. A population-based cross-sectional survey was conducted in Wuchuan County. A questionnaire and bilateral weight-bearing posterior-anterior semi-flexed knee radiographs were completed and read for Kellgren and Lawrence (K/L) grade and joint space narrowing (JSN; 0-3 scale) in each compartment. An logistic regression analysis was performed for radiographic tibiafemoral, lateral compartment, and medial compartment knee OA, respectively. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated. Results. Age, sex, and knee injury were strongly associated with tibiafemoral, lateral and medial compartment knee OA. BMI also had a dose-response relationship with them. Physical activity level, and physical activity exposure at work, not significantly though, were associated with an elevated risk for this three kinds of knee OA. Conclusions. Physical activity exposure increased the risk of knee OA. It was likely to be the heavier physical activity in Wuchuan osteoarthritis study that counteracted the BMI gap compared with the Beijing and the Framingham OA study. We verified that Chinese had a more valgus alignment of the knee compared with Caucasian population, and this provide a possible explanation why Chinese have a higher prevalence of lateral compartment OA. PMID- 21234319 TI - Role of meconium and hypoxia in meconium aspiration-induced lung injury in neonatal rabbits. AB - BACKGROUND: We previously showed that meconium causes lung cell death by apoptosis and inflammatory cytokine expression. Whether this is due to meconium exposure itself, or meconium related hypoxia remains unclear. OBJECTIVES: To elucidate the effects of meconium, saline, milk, hypoxia and hyperoxia induced lung injury. DESIGN/METHODS: We studied 5 groups of rabbit pups: (I) normal saline; (II) Milk; (III) 10% solution of meconium; (IV) only to 15 minutes of hypoxia (10% O(2)), and (V) 5 minutes of hypoxia (95% O(2)). After exposure lung lavage cells were used for apoptotic cell count and cytokine expression. In vitro response of human A 549 epithelial cells to meconium-and milk exposure was also studied. RESULTS: There was no difference in cell death between saline and milk groups. However, meconium caused a significant cell loss compared to saline and milk-Inflammatory cytokines increased significantly in meconium group compared to saline or milk group. Although hypoxic and hyperoxic lungs showed increased inflammatory reaction compared to saline-treated lungs, this injury was not significant compared to meconium group. Studies with A549 cells also showed similar results. CONCLUSIONS: We conclude that lung cell injury in meconium aspiration is mainly from meconium itself. PMID- 21234320 TI - Antiobesogenic and Antiatherosclerotic Properties of Caralluma fimbriata Extract. AB - There is evidence that the principles present in the widely consumed Indian food plant C. fimbriata extract (CFE) suppress appetite, and provide antiobesogenic and metabolic benefits. The Diet-Induced Obesity (DIO) rat model was used to investigate CFE's anorexigenic effects. Rats were randomly divided into three groups: (i) untreated control (C), (ii) control for cafeteria diet (CA), and (iii) cafeteria diet fed + CFE treated. Rats in the test group received cafeteria diet and CFE from day one onwards. CFE was administered by gavage at three doses (25, 50, 100 mg/Kg BW per day) for 90 days. The antiobesogenic effects of CFE were evaluated by monitoring changes in feed intake, body weight, serum lipid and hormonal (leptin) profiles, fat pads, and liver weight. Antiatherosclerotic effects were measured by histology. CFE induced significant and dose-dependent inhibition of food intake, with dose-related prevention of gains in body weight, liver weight, and fat pad mass. Alterations in serum lipid profiles associated with weight gain were similarly inhibited, as were the typical increases in serum leptin levels. These data substantiate CFE's reported anorexigenic effects. CFE treatment also conferred protection against atherogenesis. We conclude that CFE possesses antiobesogenic and antiatherosclerotic properties. PMID- 21234321 TI - Association of inflammatory and oxidative stress markers with metabolic syndrome in asian indians in India. AB - Metabolic syndrome (MetS) is a primary risk factor for cardiovascular disease and is associated with a proinflammatory state. Here, we assessed the contribution of inflammatory and oxidative stress markers towards prediction of MetS. A total of 2316 individuals were recruited in Phase I of the Indian Atherosclerosis Research Study (IARS). Modified ATPIII guidelines were used for classification of subjects with MetS. Among the inflammatory and oxidative stress markers studied, levels of hsCRP (P < .0001), Neopterin (P = .036), and oxLDL (P < .0001) were significantly higher among subjects with MetS. Among the markers we tested, oxLDL stood out as a robust predictor of MetS in the IARS population (OR 4.956 95% CI 2.504-9.810; P < .0001) followed by hsCRP (OR 1.324 95% CI 1.070-1.638; P = .010). In conclusion, oxLDL is a candidate predictor for MetS in the Asian Indian population. PMID- 21234322 TI - Nanoporosity of alumina surfaces induces different patterns of activation in adhering monocytes/macrophages. AB - The present study shows that alumina nanotopography affects monocyte/macrophage behavior. Human mononuclear cells cultured on alumina membranes with pore diameters of 20 and 200 nm were evaluated in terms of cell adhesion, viability, morphology, and release of proinflammatory cytokines. After 24 hours, cell adhesion was assessed by means of light microscopy and cell viability by measuring LDH release. The inflammatory response was evaluated by quantifying interleukin-1beta and tumour necrosis factor-alpha. Finally, scanning electron microscopy was used to study cell morphology. Results showed pronounced differences in cell number, morphology, and cytokine release depending on the nanoporosity. Few but highly activated cells were found on the 200 nm porous alumina, while relatively larger number of cells were found on the 20 nm porous surface. However, despite their larger number, the cells adhering on the 20 nm surface exhibited reduced pro-inflammatory activity. The data of this paper implies that nanotopography could be exploited for controlling the inflammatory response to implants. PMID- 21234323 TI - Determinants of catch-up growth in international adoptees from eastern europe. AB - Children raised in orphanages frequently experience growth suppression due to multiple risk factors. Placing such children in more nurturing environments through adoption leads to significant catch-up growth (CUG), the determinants of which are not entirely understood. The goal of this study was to perform an auxological evaluation and examine the degree and correlates of CUG in international adoptees. Children adopted from Eastern Europe, (n = 148, 71 males), 7 to 59 months of age, were recruited within 3 weeks of their arrival to the US. At baseline, mean height SDS was -1.2 +/- 1.1 and 22% were <-2 SDS for height. IGF-1 and/or IGFBP-3 levels <-2 SDS were present in 32%. CUG, defined as a gain of >+0.5 in height SDS, was seen in 62% of adoptees at 6 months after adoption; 7% of children remained <-2 SDS for height (two had growth hormone deficiency). Growth factors improved in the majority of children. Younger age, greater degree of initial growth failure, and higher caloric intake were significantly associated with improved linear growth in multiple regression models. In summary, most adoptees demonstrate excellent CUG within six months after adoption. If growth failure persists after 6 months of appropriate caloric intake, nutrition-independent causes should be considered. PMID- 21234324 TI - Antenatal Corticosteroids and Postnatal Fluid Restriction Produce Differential Effects on AQP3 Expression, Water Handling, and Barrier Function in Perinatal Rat Epidermis. AB - Loss of water through the immature skin can lead to hypothermia and dehydration in preterm infants. The water and glycerol channel aquaglyceroporin-3 (AQP3) is abundant in fetal epidermis and might influence epidermal water handling and transepidermal water flux around birth. To investigate the role of AQP3 in immature skin, we measured in vivo transepidermal water transport and AQP3 expression in rat pups exposed to clinically relevant fluid homeostasis perturbations. Preterm (E18) rat pups were studied after antenatal corticosteroid exposure (ANS), and neonatal (P1) rat pups after an 18 h fast. Transepidermal water loss (TEWL) and skin hydration were determined, AQP3 mRNA was quantified by RT-PCR, and in-situ hybridization and immunocytochemistry were applied to map AQP3 expression. ANS resulted in an improved skin barrier (lower TEWL and skin hydration), while AQP3 mRNA and protein increased. Fasting led to loss of barrier integrity along with an increase in skin hydration. These alterations were not paralleled by any changes in AQP3. To conclude, antenatal corticosteroids and early postnatal fluid restriction produce differential effects on skin barrier function and epidermal AQP3 expression in the rat. In perinatal rats, AQP3 does not directly determine net water transport through the skin. PMID- 21234325 TI - Histopathological variants of cutaneous squamous cell carcinoma: a review. AB - Nonmelanoma skin cancer (NMSC) is the most common form of cancer in the Caucasian population, with squamous cell carcinoma (SCC) accounting for the majority of NMSC-related metastases and death. While most SCC lesions are indolent tumors with low malignant potential, a wide diversity of SCC subtypes exist, several of which are associated with markedly more aggressive behaviors. Distinguishing these high-risk variants from their counterparts is possible through microscopic analysis, since each subtype possesses unique histopathological features. Early identification of high-risk lesions can allow for more rapid therapeutic intervention, reducing the likelihood of metastasis and death. The authors review specific histopathological features and associated clinical outcomes of the primary subdivisions of SCC. PMID- 21234326 TI - Behavioral and psychological factors associated with 12-month weight change in a physical activity trial. AB - Examining behavioral and psychological factors relating to weight stability over a 1-year period is of public health importance. We conducted a physical activity (PA) intervention trial for women (N = 247; mean age = 47.5 +/- 10.7; mean BMI = 28.6 +/- 5.3) in which participants were assigned to one of three groups (two PA and one contact-control). By Month 12, participants achieved 140.4 +/- 14.82 min of PA/week, with no group differences. Weight status change from baseline to Month 12 was categorized: no change (N = 154; 62.4%); increase (N = 34; 13.8%); decrease (N = 59; 23.9%). Discriminant function analyses indentified two statistically significant dimensions associated with weight change. Dimension 1 was positively weighted by mood (0.73) and self-efficacy (0.79); dimension 2 was positively weighted to change in physical activity (0.58) and fat consumption (0.55). Results provide further evidence for the importance of behavior in long term weight maintenance, particularly physical activity and dietary fat. These findings also provide evidence for the importance of addressing psychosocial variables, in particular depressed mood and self-efficacy. PMID- 21234327 TI - Benefits of massage-myofascial release therapy on pain, anxiety, quality of sleep, depression, and quality of life in patients with fibromyalgia. AB - Fibromyalgia is a chronic syndrome characterized by generalized pain, joint rigidity, intense fatigue, sleep alterations, headache, spastic colon, craniomandibular dysfunction, anxiety, and depression. The purpose of the present study was to determine whether massage-myofascial release therapy can improve pain, anxiety, quality of sleep, depression, and quality of life in patients with fibromyalgia. A randomized controlled clinical trial was performed. Seventy-four fibromyalgia patients were randomly assigned to experimental (massage-myofascial release therapy) and placebo (sham treatment with disconnected magnotherapy device) groups. The intervention period was 20 weeks. Pain, anxiety, quality of sleep, depression, and quality of life were determined at baseline, after the last treatment session, and at 1 month and 6 months. Immediately after treatment and at 1 month, anxiety levels, quality of sleep, pain, and quality of life were improved in the experimental group over the placebo group. However, at 6 months postintervention, there were only significant differences in the quality of sleep index. Myofascial release techniques improved pain and quality of life in patients with fibromyalgia. PMID- 21234328 TI - Antiapoptotic and Antioxidant Properties of Orthosiphon stamineus Benth (Cat's Whiskers): Intervention in the Bcl-2-Mediated Apoptotic Pathway. AB - Antiapoptotic and antioxidant activities of aqueous-methanolic extract (CAME) of Orthosiphonstamineus Benth(OS), and its hexane (HF), chloroform (CF), n-butanol (NBF), ethyl acetate (EAF) and water (WF) fractions were investigated. Antioxidant properties were evaluated using the assays of Folin-Ciocalteu, aluminiumtrichloride, beta-carotene bleaching and DPPH. The role of OS against hydrogen peroxide induced apoptosis on MDA-M231 epithelial cells was examined using MTT assay, phase contrast microscope, colorimetric assay of caspase-3, western blot and quantitative real-time PCR. Results showed that EAF showed the highest total phenolic content followed by CAME, NBF, WF, CF and HF, respectively. Flavonoid content was in the order of the CF > EAF > HF > CAME > NBF > WF. The IC(50) values on DPPH assay for different extract/fractions were 126.2 +/- 23, 31.25 +/- 1.2, 15.25 +/- 2.3, 13.56 +/- 1.9, 23.0 +/- 3.2, and 16.66 +/- 1.5 MUg/ml for HF, CF, EAF, NBF, WF and CAME, respectively. OSreduced the oxidation of beta-carotene by hydroperoxides. Cell death was dose-dependently inhibited by pretreatment with OS. Caspase-3 and distinct morphological features suggest the anti-apoptotic activities of OS. This plant not only increased the expression of Bcl-2, but also decreased Bax expression, and ultimately reduced H(2)O(2)-induced apoptosis. The current results showed that phenolics may provide health and nutritional benefits. PMID- 21234329 TI - Approaching biomarkers of membranous nephropathy from a murine model to human disease. AB - BACKGROUND: Membranous glomerulonephropathy (MN) is the most prevalent cause of nephrotic syndrome in adult humans. However, the specific biomarkers of MN have not been fully elucidated. We examined the alterations in gene expression associated with the development of MN. METHODS: Murine MN was induced by cationic bovine serum albumin (cBSA). After full-blown MN, cDNA microarray analysis was performed to identify gene expression changes, and highly expressed genes were evaluated as markers both in mice and human kidney samples. RESULTS: MN mice revealed clinical proteinuria and the characteristic diffuse thickening of the glomerular basement membrane. There were 175 genes with significantly different expressions in the MN kidneys compared with the normal kidneys. Four genes, metallothionein-1 (Mt1), cathepsin D (CtsD), lymphocyte 6 antigen complex (Ly6), and laminin receptor-1 (Lamr1), were chosen and quantified. Mt1 was detected mainly in tubules, Lamr1 was highly expressed in glomeruli, and CtsD was detected both in tubules and glomeruli. The high expressions of Lamr1 and CtsD were also confirmed in human kidney biopsies. CONCLUSION: The murine MN model resembled the clinical and pathological features of human MN and may provide a tool for investigating MN. Applying cDNA microarray analysis may help to identify biomarkers for human MN. PMID- 21234330 TI - Presenilin-2 mutation causes early amyloid accumulation and memory impairment in a transgenic mouse model of Alzheimer's disease. AB - In order to clarify the pathophysiological role of presenilin-2 (PS2) carrying the Volga German Kindred mutation (N141I) in a conventional mouse model of Alzheimer's disease (AD) expressing amyloid precursor protein (APP) with the Swedish mutation (Tg2576 line), we generated a double transgenic mouse (PS2Tg2576) by crossbreeding the PS2 mutant with Tg2576 mice. Here, we demonstrate that the PS2 mutation induced the early deposition of amyloid beta protein (Abeta) at 2-3 months of age and progressive accumulation at 4-5 months of age in the brains of the mutant mice. The PS2 mutation also accelerated learning and memory impairment associated with Abeta accumulation at 4-5 months of age in Tg2576 mice. These results suggest that the PS2 mutation causes early cerebral amyloid accumulation and memory dysfunction. PS2Tg2576 mice are a suitable mouse model for studying amyloid-lowering therapies. PMID- 21234331 TI - Histone acetyltransferases as regulators of nonhistone proteins: the role of interferon regulatory factor acetylation on gene transcription. AB - When studying transcription factors, it is necessary to investigate posttranslational modifications. Histone acetyltransferases (HATs) are typical of the modification enzymes involved in chromatin regulation. HATs acetylate the transcription factors (nonhistone proteins) as well as histones. Interferon regulatory factors (IRFs) are transcription factors that bind to the interferon regulatory element (IRF-E) and are involved in regulating cell growth, differentiation, and the immune and hematopoietic systems. During the process of binding to a specific DNA element, IRFs also bind to coactivators such as HATs and become modified. This review looks at how IRFs associate with HATs, p300, and PCAF, and thereby contribute to transcriptional activation. PMID- 21234332 TI - DNA damage and base excision repair in mitochondria and their role in aging. AB - During the last decades, our knowledge about the processes involved in the aging process has exponentially increased. However, further investigation will be still required to globally understand the complexity of aging. Aging is a multifactorial phenomenon characterized by increased susceptibility to cellular loss and functional decline, where mitochondrial DNA mutations and mitochondrial DNA damage response are thought to play important roles. Due to the proximity of mitochondrial DNA to the main sites of mitochondrial-free radical generation, oxidative stress is a major source of mitochondrial DNA mutations. Mitochondrial DNA repair mechanisms, in particular the base excision repair pathway, constitute an important mechanism for maintenance of mitochondrial DNA integrity. The results reviewed here support that mitochondrial DNA damage plays an important role in aging. PMID- 21234333 TI - A Bayesian Approach for Identifying miRNA Targets by Combining Sequence Prediction and Expression Profiling. AB - MicroRNAs (miRNAs) are single-stranded non-coding RNAs shown to plays important regulatory roles in a wide range of biological processes and diseases. The functions and regulatory mechanisms of most of miRNAs are still poorly understood in part because of the difficulty in identifying the miRNA regulatory targets. To this end, computational methods have evolved as important tools for genome-wide target screening. Although considerable work in the past few years has produced many target prediction algorithms, most of them are solely based on sequence, and their accuracy is still poor. In contrast, gene expression profiling from miRNA over-expression experiments can provide additional information about miRNA targets. This paper presents a Bayesian approach to integrate sequence level prediction result with expression profiling to improve the performance of miRNA target identification. The test on proteomic and IP pull-down data demonstrated better performance of the proposed approach. PMID- 21234335 TI - Human sperm bioassay for reprotoxicity testing in embryo culture media: some practical considerations in reducing the assay time. AB - Human sperm assay (HSA) is a preferred in house quality control and proficiency test (PT) practiced in fertility laboratories. HSA is performed over varying durations, apparently without following set criteria. To better understand the assay time required for reprotoxicity testing in embryo culture media, we compared American-Association-of-Bioanalysts-(AAB-) administered HSA data to our own assay performed using PT samples obtained from AAB. Participating laboratories were required to culture sperm for 48 hours to determine media acceptability. Conclusions drawn from 48- and 24-hour observations were the same, suggesting that HSA could identify reprotoxic media in less time than required by AAB. Our assay revealed that changes in motility grade in adulterated media are significantly different from those in control media. Furthermore, grade changes can be identified earlier than differences in motility loss between samples. Analyzing motility and motility quality together provides a method for establishing an optimal time for HSA. PMID- 21234334 TI - Mesenchymal Progenitor Cells and Their Orthopedic Applications: Forging a Path towards Clinical Trials. AB - Mesenchymal progenitor cells (MPCs) are nonhematopoietic multipotent cells capable of differentiating into mesenchymal and nonmesenchymal lineages. While they can be isolated from various tissues, MPCs isolated from the bone marrow are best characterized. These cells represent a subset of bone marrow stromal cells (BMSCs) which, in addition to their differentiation potential, are critical in supporting proliferation and differentiation of hematopoietic cells. They are of clinical interest because they can be easily isolated from bone marrow aspirates and expanded in vitro with minimal donor site morbidity. The BMSCs are also capable of altering disease pathophysiology by secreting modulating factors in a paracrine manner. Thus, engineering such cells to maximize therapeutic potential has been the focus of cell/gene therapy to date. Here, we discuss the path towards the development of clinical trials utilizing BMSCs for orthopaedic applications. Specifically, we will review the use of BMSCs in repairing critical sized defects, fracture nonunions, cartilage and tendon injuries, as well as in metabolic bone diseases and osteonecrosis. A review of www.ClinicalTrials.gov of the United States National Institute of Health was performed, and ongoing clinical trials will be discussed in addition to the sentinel preclinical studies that paved the way for human investigations. PMID- 21234338 TI - Effect of bleaching on color change and surface topography of composite restorations. AB - This study was conducted to determine the effect of 15% carbamide peroxide bleaching agent on color change and surface topography of different composite veneering materials (Filtek Z350 (3M ESPE), Esthet X (Dentsply India), and Admira (Voco, Germany). Methods. 30 samples were fabricated for evaluation of color change using CIELAB color system and Gonioreflectometer (GK 311/M, ZEISS). 45 disc-shaped specimens were made for evaluation of surface topography after bleaching (Nupro White Gold; Dentsply) using SEM. Statistical analysis. One way ANOVA and Multiple comparison tests were used to analyze the data. Statistical significance was declared if the P value was .05 or less. Results and conclusion. All the specimens showed significant discoloration (DeltaE > 3.3) after their immersion in solutions representing food and beverages. The total color change after bleaching as compared to baseline color was significant in Filtek Z350 (P = .000) and Esthet X (P = .002), while it was insignificant for Admira (P = .18). Esthet X showed maximum surface roughness followed by Admira and Filtek Z350. Bleaching was effective in reducing the discoloration to a clinically acceptable value in all the three groups (DeltaE < 3.3). PMID- 21234337 TI - Assortativity and the Probability of Epidemic Extinction: A Case Study of Pandemic Influenza A (H1N1-2009). AB - Unlike local transmission of pandemic influenza A (H1N1-2009), which was frequently driven by school children, most cases identified in long-distance intranational and international travelers have been adults. The present study examines the relationship between the probability of temporary extinction and the age-dependent next-generation matrix, focusing on the impact of assortativity. Preferred mixing captures as a good approximation the assortativity of a heterogeneously mixing population. We show that the contribution of a nonmaintenance host (i.e., a host type which cannot sustain transmission on its own) to the risk of a major epidemic is greatly diminished as mixing patterns become more assortative, and in such a scenario, a higher proportion of non maintenance hosts among index cases elevates the probability of extinction. Despite the presence of various other epidemiological factors that undoubtedly influenced the delay between first importations and the subsequent epidemic, these results suggest that the dominance of adults among imported cases represents one of the possible factors explaining the delays in geographic spread observed during the recent pandemic. PMID- 21234339 TI - Increased daytime sleepiness in patients with childhood craniopharyngioma and hypothalamic tumor involvement: review of the literature and perspectives. AB - Childhood craniopharyngiomas are rare embryogenic malformations of the sellar region, presumably derived from Rathke cleft epithelium. The overall survival rates after neurosurgical intervention and/or irradiation are high (92%). However, the quality of survival is frequently impaired due to endocrine deficiencies, sleep disturbances, daytime sleepiness, and severe obesity caused by hypothalamic lesions. Based on self-assessment using nutritional diaries, caloric intake was similar in patients and BMI-matched controls. Analyses of physical activity by accelerometric measurements showed a markedly lower level of physical activity. Significant daytime sleepiness and disturbances of circadian rhythms have been demonstrated in obese childhood craniopharyngioma patients. Daytime sleepiness and obesity in these patients were both correlated with low nocturnal and early morning melatonin levels. Polysomnographic studies in patients with severe daytime sleepiness revealed sleeping patterns typical for secondary narcolepsy. Reports on a beneficial effect of treatment with central stimulating agents supported the hypothesis that secondary narcolepsy should be considered as a rare cause for severe daytime sleepiness in patients with childhood craniopharyngioma. PMID- 21234336 TI - Formation and repair of tobacco carcinogen-derived bulky DNA adducts. AB - DNA adducts play a central role in chemical carcinogenesis. The analysis of formation and repair of smoking-related DNA adducts remains particularly challenging as both smokers and nonsmokers exposed to smoke are repetitively under attack from complex mixtures of carcinogens such as polycyclic aromatic hydrocarbons and N-nitrosamines. The bulky DNA adducts, which usually have complex structure, are particularly important because of their biological relevance. Several known cellular DNA repair pathways have been known to operate in human cells on specific types of bulky DNA adducts, for example, nucleotide excision repair, base excision repair, and direct reversal involving O(6) alkylguanine DNA alkyltransferase or AlkB homologs. Understanding the mechanisms of adduct formation and repair processes is critical for the assessment of cancer risk resulting from exposure to cigarette smoke, and ultimately for developing strategies of cancer prevention. This paper highlights the recent progress made in the areas concerning formation and repair of bulky DNA adducts in the context of tobacco carcinogen-associated genotoxic and carcinogenic effects. PMID- 21234340 TI - T cell-tumor interaction directs the development of immunotherapies in head and neck cancer. AB - The competent immune system controls disease effectively due to induction, function, and regulation of effector lymphocytes. Immunosurveillance is exerted mostly by cytotoxic T-lymphocytes (CTLs) while specific immune suppression is associated with tumor malignancy and progression. In squamous cell carcinoma of the head and neck, the presence, activity, but also suppression of tumor-specific CTL have been demonstrated. Functional CTL may exert a selection pressure on the tumor cells that consecutively escape by a combination of molecular and cellular evasion mechanisms. Certain of these mechanisms target antitumor effector cells directly or indirectly by affecting cells that regulate CTL function. This results in the dysfunction or apoptosis of lymphocytes and dysregulated lymphocyte homeostasis. Another important tumor-escape mechanism is to avoid recognition by dysregulation of antigen processing and presentation. Thus, both induction of functional CTL and susceptibility of the tumor and its microenvironment to become T cell targets should be considered in CTL-based immunotherapy. PMID- 21234342 TI - Stroke in young in India. AB - Stroke in young has special significance in developing countries. This is so because some etiologies like cardioembolic infections are more common than in developed countries, and the affection of economically productive group adds further to the overall disease burden. The paper discusses the burden of stroke in young and its implications in a developing country like India along with an approach to identifying different causes that are known to occur in this age group. PMID- 21234343 TI - Ocular involvement and blindness secondary to linear IgA dermatosis. AB - A 43-year-old man with linear immunoglobulin A (IgA) dermatosis associated with gluten intolerance presented with progressive vision loss, pain and photosensitivity in both eyes. His visual acuity was light perception (LP) in both eyes. A physical examination revealed bullous, papular lesions with erythematous borders in periocular tissues, limbs, and thorax. Slit-lamp examination showed conjunctival hyperemia, fibrosis, corneal opacification, and vascularization with epithelial defects. Immunofluorescent skin and corneal surface biopsy studies showed linear IgA deposits. The patient was treated with keratolimbal allogenic transplantation and cryopreserved amniotic membrane in the right eye. Regardless of the treatment he persisted with torpid evolution developing retinal and choroidal detachments. After these events he was started on intravenous immune globulin (IVIG) and showed very slight improvement in ocular surface. These types of blistering diseases are rare in the eye. Even when adequate local treatment is given, systemic treatment is mandatory and ocular prognosis can be unsatisfactory. PMID- 21234344 TI - Construction, characterization, and preliminary BAC-end sequence analysis of a bacterial artificial chromosome library of the tea plant (Camellia sinensis). AB - We describe the construction and characterization of a publicly available BAC library for the tea plant, Camellia sinensis. Using modified methods, the library was constructed with the aim of developing public molecular resources to advance tea plant genomics research. The library consists of a total of 401,280 clones with an average insert size of 135 kb, providing an approximate coverage of 13.5 haploid genome equivalents. No empty vector clones were observed in a random sampling of 576 BAC clones. Further analysis of 182 BAC-end sequences from randomly selected clones revealed a GC content of 40.35% and low chloroplast and mitochondrial contamination. Repetitive sequence analyses indicated that LTR retrotransposons were the most predominant sequence class (86.93%-87.24%), followed by DNA retrotransposons (11.16%-11.69%). Additionally, we found 25 simple sequence repeats (SSRs) that could potentially be used as genetic markers. PMID- 21234341 TI - Pathogenesis, immunology, and diagnosis of latent Mycobacterium tuberculosis infection. AB - Phagocytosis of tubercle bacilli by antigen-presenting cells in human lung alveoli initiates a complex infection process by Mycobacterium tuberculosis and a potentially protective immune response by the host. M. tuberculosis has devoted a large part of its genome towards functions that allow it to successfully establish latent or progressive infection in the majority of infected individuals. The failure of immune-mediated clearance is due to multiple strategies adopted by M. tuberculosis that blunt the microbicidal mechanisms of infected immune cells and formation of distinct granulomatous lesions that differ in their ability to support or suppress the persistence of viable M. tuberculosis. In this paper, current understanding of various immune processes that lead to the establishment of latent M. tuberculosis infection, bacterial spreading, persistence, reactivation, and waning or elimination of latent infection as well as new diagnostic approaches being used for identification of latently infected individuals for possible control of tuberculosis epidemic are described. PMID- 21234345 TI - The genome sequence of Methanohalophilus mahii SLP(T) reveals differences in the energy metabolism among members of the Methanosarcinaceae inhabiting freshwater and saline environments. AB - Methanohalophilus mahii is the type species of the genus Methanohalophilus, which currently comprises three distinct species with validly published names. Mhp. mahii represents moderately halophilic methanogenic archaea with a strictly methylotrophic metabolism. The type strain SLP(T) was isolated from hypersaline sediments collected from the southern arm of Great Salt Lake, Utah. Here we describe the features of this organism, together with the complete genome sequence and annotation. The 2,012,424 bp genome is a single replicon with 2032 protein-coding and 63 RNA genes and part of the Genomic Encyclopedia of Bacteria and Archaea project. A comparison of the reconstructed energy metabolism in the halophilic species Mhp. mahii with other representatives of the Methanosarcinaceae reveals some interesting differences to freshwater species. PMID- 21234347 TI - The Role of Polyphenols, beta-Carotene, and Lycopene in the Antioxidative Action of the Extracts of Dried, Edible Mushrooms. AB - One of the nutritional benefits of mushrooms is the presence of bioactive secondary metabolites which have been reported to exert various beneficial effects in vivo. Therefore, we selected thirteen frequently consumed species of Polish mushrooms and determined the concentration of polyphenols, flavonoids, beta-carotene, and lycopene in aqueous and methanolic extracts of dried fruiting bodies as well as their reducing power and ability to scavenge ABTS cation radical. We found that the concentration of antioxidants is different in different species and in various parts of the fruiting body of mushrooms. We observed a strong correlation (r > 0.9) between the concentration of total phenolics and reducing power/scavenging effects in both aqueous and methanolic extracts, while this correlation was moderate for flavonoids. Beta-carotene did not contribute discernibly to the antioxidative properties of the extracts, while lycopene had a significant contribution to the scavenging activity of methanolic mushroom extracts. PMID- 21234346 TI - An update on the genetics of usher syndrome. AB - Usher syndrome (USH) is an autosomal recessive disease characterized by hearing loss, retinitis pigmentosa (RP), and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous and is the most common cause underlying deafness and blindness of genetic origin. Clinically, USH is divided into three types. Usher type I (USH1) is the most severe form and is characterized by severe to profound congenital deafness, vestibular areflexia, and prepubertal onset of progressive RP. Type II (USH2) displays moderate to severe hearing loss, absence of vestibular dysfunction, and later onset of retinal degeneration. Type III (USH3) shows progressive postlingual hearing loss, variable onset of RP, and variable vestibular response. To date, five USH1 genes have been identified: MYO7A (USH1B), CDH23 (USH1D), PCDH15 (USH1F), USH1C(USH1C), and USH1G(USH1G). Three genes are involved in USH2, namely, USH2A (USH2A), GPR98 (USH2C), and DFNB31 (USH2D). USH3 is rare except in certain populations, and the gene responsible for this type is USH3A. PMID- 21234348 TI - Impairment of methotrexate transport is common in osteosarcoma tumor samples. AB - Osteosarcoma does not respond well to conventional dose methotrexate but does respond to high-dose methotrexate. Previous work has indicated that this resistance may be due to impaired transport of methotrexate across the cell membrane. In this study, the PT430 competitive displacement assay was adapted to evaluate methotrexate transport in 69 high-grade osteosarcoma tumor samples. All samples studied were shown to have relatively impaired methotrexate transport by PT430 assay. Ninety-nine percent of the samples had less than 20% PT430 displacement by methotrexate. Eighty-eight percent exhibited displacement by methotrexate at less than 50% of the displacement by trimetrexate. The high frequency of impaired transport suggests the presence of decreased functionality of the reduced folate carrier protein. The overwhelming presence of impaired transport may explain why methotrexate needs to be given in high doses to be effective in osteosarcoma therapy and suggests that reduced folate carrier independent antifolates should be explored. PMID- 21234349 TI - Boric Acid Disturbs Cell Wall Synthesis in Saccharomyces cerevisiae. AB - Boric acid (BA) has broad antimicrobial activity that makes it a popular treatment for yeast vaginitis in complementary and alternative medicine. In the model yeast S. cerevisiae, BA disturbs the cytoskeleton at the bud neck and impairs the assembly of the septation apparatus. BA treatment causes cells to form irregular septa and leads to the synthesis of irregular cell wall protuberances that extend far into the cytoplasm. The thick, chitin-rich septa that are formed during BA exposure prevent separation of cells after abscission and cause the formation of cell chains and clumps. As a response to the BA insult, cells signal cell wall stress through the Slt2p pathway and increase chitin synthesis, presumably to repair cell wall damage. PMID- 21234350 TI - Elevated adiponectin serum levels in women with systemic autoimmune diseases. AB - Adipose tissue produces a wide range of proteins that may influence the immune system. In this study, we assessed the serum levels of leptin, adiponectin, and ghrelin, in association with the measurements of body composition, in 15 female patients with various autoimmune diseases (systemic lupus erythematosus, primary Sjogren's syndrome, sarcoidosis, mixed connective tissue disease, vasculitis, CREST syndrome, and polymyositis) and in 15 healthy female controls. There were no statistically significant differences between the patients and controls with regard to serum leptin, serum ghrelin, global fat mass, adiposity, and fat mass in the android or gynoid regions, whereas serum adiponectin levels were higher in patients than controls (16.3 +/- 1.6 MUg/mL versus 9.7 +/- 0.6 MUg/mL; P = .01). As adiponectin is known to exhibit potent anti-inflammatory properties, a high adiponectinemia in patients with systemic autoimmune disease may mitigate the inflammatory response. However, the precise consequences of these elevated serum adiponectin levels on the metabolic syndrome development and atherosclerotic cardiovascular risk in this patient population still needs to be determined. PMID- 21234351 TI - Role of nutrition in the management of hepatic encephalopathy in end-stage liver failure. AB - Malnutrition is common in patients with end-stage liver failure and hepatic encephalopathy, and is considered a significant prognostic factor affecting quality of life, outcome, and survival. The liver plays a crucial role in the regulation of nutrition by trafficking the metabolism of nutrients, their distribution and appropriate use by the body. Nutritional consequences with the potential to cause nervous system dysfunction occur in liver failure, and many factors contribute to malnutrition in hepatic failure. Among them are inadequate dietary intake, malabsorption, increased protein losses, hypermetabolism, insulin resistance, gastrointestinal bleeding, ascites, inflammation/infection, and hyponatremia. Patients at risk of malnutrition are relatively difficult to identify since liver disease may interfere with biomarkers of malnutrition. The supplementation of the diet with amino acids, antioxidants, vitamins as well as probiotics in addition to meeting energy and protein requirements may improve nutritional status, liver function, and hepatic encephalopathy in patients with end-stage liver failure. PMID- 21234352 TI - Prognostic and diagnostic value of spontaneous tumor-related antibodies. AB - There is an urgent need for earlier diagnosis of malignancies and more stringent monitoring of relapses after antitumor therapy. In addition, new prognostic markers are needed for risk stratification and design of individualized cancer therapies. New diagnostic and prognostic parameters should overcome the impairments of current standards in a cost-effective manner. Serological approaches measuring spontaneous antibody responses against tumor-associated antigens could be of use as diagnostic and prognostic markers and could also be employed to evaluate response to therapy in cancer patients. Autoantibodies have been suggested to be of frequent and specific occurrence in patients with malignancies and to correlate with clinical parameters. Screening the relevant literature on this topic, we suggest that the analysis of single antibody specificities is unlikely to provide sufficient diagnostic and prognostic accuracy. The combined analysis of autoantibodies targeting different antigens, however, may reach high sensitivity and specificity. In addition, screening cancer patients for autoantibodies might identify subgroups with high relapse risk and a worse prognosis. Larger prospective trials should be initiated to identify sets of tumor-associated autoantibodies suited for the use in diagnostic algorithms for cancer detection and followup. PMID- 21234353 TI - Focus on adoptive T cell transfer trials in melanoma. AB - Adoptive Cell Transfer (ACT) of Tumor-Infiltrating Lymphocytes (TIL) in combination with lymphodepletion has proven to be an effective treatment for metastatic melanoma patients, with an objective response rate in 50%-70% of the patients. It is based on the ex vivo expansion and activation of tumor-specific T lymphocytes extracted from the tumor and their administration back to the patient. Various TIL-ACT trials, which differ in their TIL generation procedures and patient preconditioning, have been reported. In the latest clinical studies, genetically engineered peripheral T cells were utilized instead of TIL. Further improvement of adoptive T cell transfer depends on new investigations which seek higher TIL quality, increased durable response rates, and aim to treat more patients. Simplifying this therapy may encourage cancer centers worldwide to adopt this promising technology. This paper focuses on the latest progress regarding adoptive T cell transfer, comparing the currently available protocols and discussing their advantages, disadvantages, and implication in the future. PMID- 21234354 TI - Theoretical modeling techniques and their impact on tumor immunology. AB - Currently, cancer is one of the leading causes of death in industrial nations. While conventional cancer treatment usually results in the patient suffering from severe side effects, immunotherapy is a promising alternative. Nevertheless, some questions remain unanswered with regard to using immunotherapy to treat cancer hindering it from being widely established. To help rectify this deficit in knowledge, experimental data, accumulated from a huge number of different studies, can be integrated into theoretical models of the tumor-immune system interaction. Many complex mechanisms in immunology and oncology cannot be measured in experiments, but can be analyzed by mathematical simulations. Using theoretical modeling techniques, general principles of tumor-immune system interactions can be explored and clinical treatment schedules optimized to lower both tumor burden and side effects. In this paper, we aim to explain the main mathematical and computational modeling techniques used in tumor immunology to experimental researchers and clinicians. In addition, we review relevant published work and provide an overview of its impact to the field. PMID- 21234356 TI - Transforming Growth Factor-beta1 as a Common Target Molecule for Development of Cardiovascular Diseases, Renal Insufficiency and Metabolic Syndrome. AB - Transforming growth factor-beta1 (TGF-beta1) is a polypeptide member of the transforming growth factor beta superfamily of cytokines. It is a secreted protein that performs many cellular functions including control of cell growth, cell proliferation, cell differentiation and apoptosis. In the cardiovascular system, TGF-beta1 plays pivotal roles in the pathogenesis of hypertension, restenosis after percutaneous coronary intervention, atherosclerosis, cardiac hypertrophy and heart failure. In addition, TGF-beta1 has been shown to be increased in adipose tissue of obese subjects with insulin resistance. Furthermore, TGF-beta1 is a potent initiator of proliferation of renal mesangial cells leading to chronic kidney disease. Some currently available agents can manipulate TGF-beta1 expression leading to amelioration of cardiovascular diseases. Thus, an understanding of interactions between chronic kidney disease and metabolic syndrome and the development of cardiovascular diseases is an important issue, and attention should be given to TGF-beta1 as a crucial factor for regulation and modulation of those pathological conditions. PMID- 21234357 TI - Peripheral T-cell lymphoma: review and updates of current management strategies. AB - The classification of T-cell and natural-killer- (NK-) cell lymphomas has been updated in the 4th edition of the World Health Organization (WHO) classification of tumors of the haematopoietic and lymphoid tissue published in 2008. Based on recent epidemiological studies, NK-cell lymphomas occur almost exclusively in Asia and South America, although T-cell lymphomas appear to occur in the East as commonly as in the West. Due to the low prevalence of this disease, diagnosis and optimal treatment of patients have not been studied prospectively in large randomized trials. Nevertheless, there has been development in the understanding of T-cell lymphomas and how they should be managed; FDG-PET emerges as an increasingly important tool in diagnosis, gene-expression signatures may aid with prognostication in the future, and novel therapies are currently being studied to improve outcomes in T-cell lymphomas. More work, however, needs to be done, and international collaboration will be pertinent to deriving meaningful results from future clinical studies. PMID- 21234359 TI - Long-term followup of dermal substitution with acellular dermal implant in burns and postburn scar corrections. AB - Full-thickness burn and other types of deep skin loss will result in scar formation. For at least partial replacement of the lost dermal layer, there are several options to use biotechnologically derived extracellular matrix components or tissue scaffolds of cadaver skin origin. In a survey, we have collected data on 18 pts who have previously received acellular dermal implant Alloderm. The age of these patients at the injury varied between 16 months and 84 years. The average area of the implants was 185 cm(2). Among those, 15 implant sites of 14 patients were assessed at an average of 50 months after surgery. The scar function was assessed by using the modified Vancouver Scar Scale. We have found that the overall scar quality and function was significantly better over the implanted areas than over the surrounding skin. Also these areas received a better score for scar height and pliability. Our findings suggest that acellular dermal implants are especially useful tools in the treatment of full-thickness burns as well as postburn scar contractures. PMID- 21234358 TI - Induction of granulysin and perforin cytolytic mediator expression in 10-week-old infants vaccinated with BCG at birth. AB - BACKGROUND: While vaccination at birth with Mycobacterium bovis Bacilli Calmette Guerin (BCG) protects against severe childhood tuberculosis, there is no consensus as to which components of the BCG-induced immune response mediate this protection. However, granulysin and perforin, found in the granules of cytotoxic T lymphocytes and Natural Killer (NK) cells, can kill intracellular mycobacteria and are implicated in protection against Mycobacterium tuberculosis. METHODS: We compared the cellular expression of granulysin and perforin cytolytic molecules in cord blood and peripheral blood from 10-week-old infants vaccinated at birth with either Japanese or Danish BCG, administered either intradermally or percutaneously. RESULTS: In cord blood, only CD56+ NK cells expressed granulysin and perforin constitutively. These cytolytic mediators were upregulated in CD4+ and CD8+ cord blood cells by ex vivo stimulation with BCG but not with PPD. Following BCG vaccination of neonates, both BCG and PPD induced increased expression of granulysin and perforin by CD4+ and CD8+ T cells. There was no difference in expression of cytolytic molecules according to vaccination route or strain. CONCLUSIONS: Constitutive expression of perforin and granulysin by cord blood NK-cells likely provides innate immunity, while BCG vaccination-induced expression of these cytolytic mediators may contribute towards protection of the neonate against tuberculosis. PMID- 21234360 TI - Age- and sex-specific in-hospital mortality after myocardial infarction in routine clinical practice. AB - Background. Literature regarding the influence of age/sex on mortality trends for acute myocardial infarction (AMI) hospitalizations is limited to hospitals participating in voluntary AMI registries. Objective. Evaluate the impact of age and sex on in-hospital AMI mortality using a nationally representative hospital sample. Methods. Secondary data analysis using AMI hospitalizations identified from the Nationwide-Inpatient-Sample (NIS). Descriptive and Cox proportional hazards analysis explored mortality trends by age and sex from 1997-2006 while adjusting for the influence of, demographics, co-morbidity, length of hospital stay and hospital characteristics. Results. From 1997-2006, in-hospital AMI mortality rates decreased across time in all subgroups (P < .001), except for males aged <55 years. The greatest decline was observed in females aged <55 years, compared to similarly aged males, mortality outcomes were poorer in 1997 1998 (RR 1.47, 95% CI = 1.30-1.66), when compared with 2005-2006 (RR 1.03, 95% CI = 0.90-1.18), adjusted P value for trend demonstrated a statistically significant decline in the relative AMI mortality risk for females when compared with males (<0.001). Conclusion. Over the last decade, in-hospital AMI mortality rates declined for every age/sex group except males <55 years. While AMI female male mortality disparity has narrowed, some room for improvement remains. PMID- 21234361 TI - Sentinel node biopsy for breast cancer patients: issues for discussion and our practice. AB - Sentinel node biopsy has been established for several years now as a standard procedure of breast cancer surgery, but there are several variations of the indications and the technique used. This paper provides information regarding several issues of debate for its application as are the selection criteria, the application to patients with multifocal/multicentric breast cancer or DCIS, postneoadjuvant chemotherapy, the necessary number of nodes to be biopsied, the need for lymphoscintigraphy, the technique for frozen section, the factors that may predict nonsentinel nodes (NSNs) involvement, the value of micrometastasis and isolated tumour cells, the internal mammary chain sentinel nodes, and finally the axillary recurrence after SLNB. Our view for these issues is included together with our experience of 430 SLNBs. PMID- 21234363 TI - Surmounting chemotherapy and radioresistance in chondrosarcoma: molecular mechanisms and therapeutic targets. AB - Chondrosarcoma, a primary malignancy of bone, has eluded successful treatment with modern chemotherapeutic and radiation regimens. To date, surgical resection of these tumors remains the only curative treatment offered to patients with this diagnosis. Understanding and exploring the nature of chemotherapy and radiation resistance in chondrosarcoma could lead to new molecular targets and more directed therapy for these notoriously difficult-to-treat tumors. Here we review the most current hypotheses regarding the molecular mechanisms mediating chemotherapy and radiation resistance and the future direction of chondrosarcoma therapy research. PMID- 21234364 TI - High Rate of Obesity-Associated Hypertension among Primary Schoolchildren in Sudan. AB - Cardiovascular disease (CVD) frequently has roots in childhood, including following childhood-onset hypertension. Incidence of CVD has increased in developing countries in East Africa during recent urbanization. Effects of these shifts on childhood hypertension are unclear. Our objectives were to (1) Determine the prevalence of hypertension among primary schoolchildren in Khartoum, Sudan; (2) Determine whether hypertension in this setting is associated with obesity. We performed a cross sectional study of 6-12y children from two schools randomly selected in Khartoum, Sudan. Height, weight, BMI, BP and family history of hypertension were assessed. Age-, height- and gender-specific BP curves were used to determine pre-hypertension (90-95%) and hypertension (>95%). Of 304 children, 45 (14.8%) were overweight; 32 (10.5%) were obese; 15 (4.9%) were pre-hypertensive and 15 (4.9%) were hypertensive. Obesity but not family history of hypertension was associated with current hypertension. In multiple logistic regression, adjusting for family history, children who were obese had a relative-risk of 14.7 (CI 2.45-88.2) for systolic hypertension compared to normal weight children. We conclude that overweight and obesity are highly prevalent among primary schoolchildren in urban Sudan and are strongly associated with hypertension. That obesity-associated cardiovascular sequelae exist in the developing world at young ages may be a harbinger of future CVD in sub-Saharan Africa. PMID- 21234365 TI - Lead, manganese, and methylmercury as risk factors for neurobehavioral impairment in advanced age. AB - Contamination of the environment by metals is recognized as a threat to health. One of their targets is the brain, and the adverse functional effects they induce are reflected by neurobehavioral assessments. Lead, manganese, and methylmercury are the metal contaminants linked most comprehensively to such disorders. Because many of these adverse effects can appear later in life, clues to the role of metals as risk factors for neurodegenerative disorders should be sought in the exposure histories of aging populations. A review of the available literature offers evidence that all three metals can produce, in advanced age, manifestations of neurobehavioral dysfunction associated with neurodegenerative disease. Among the critical unresolved questions is timing; that is, during which periods of the lifespan, including early development, do environmental exposures lay the foundations for their ultimate effects? PMID- 21234366 TI - Effect of ochratoxin a on body weight, feed intake and feed conversion in broiler chicken. AB - The effect of ochratoxin A (OA) on the body weight, feed intake, and feed conversion was investigated in broiler chicken fed dietary levels of OA at 0, 1, and 2 ppm for 28 days from hatch. Feeding OA significantly reduced the growth rate of broiler chicken. The reduction was observed from the first week onwards in OA-treated groups. Feed consumption and feed conversion also showed a diminishing trend from the first week of feeding toxin. Its implication on the performance of broiler chicken is discussed. PMID- 21234362 TI - Inflammatory mechanisms of neurodegeneration in toxin-based models of Parkinson's disease. AB - Parkinson's disease (PD) has been associated with exposure to a variety of environmental agents, including pesticides, heavy metals, and organic pollutants; and inflammatory processes appear to constitute a common mechanistic link among these insults. Indeed, toxin exposure has been repeatedly demonstrated to induce the release of oxidative and inflammatory factors from immunocompetent microglia, leading to damage and death of midbrain dopamine (DA) neurons. In particular, proinflammatory cytokines such as tumor necrosis factor-alpha and interferon gamma, which are produced locally within the brain by microglia, have been implicated in the loss of DA neurons in toxin-based models of PD; and mounting evidence suggests a contributory role of the inflammatory enzyme, cyclooxygenase 2. Likewise, immune-activating bacterial and viral agents were reported to have neurodegenerative effects themselves and to augment the deleterious impact of chemical toxins upon DA neurons. The present paper will focus upon the evidence linking microglia and their inflammatory processes to the death of DA neurons following toxin exposure. Particular attention will be devoted to the possibility that environmental toxins can activate microglia, resulting in these cells adopting a "sensitized" state that favors the production of proinflammatory cytokines and damaging oxidative radicals. PMID- 21234367 TI - Performance and emission characteristics of diesel engine fueled with ethanol diesel blends in different altitude regions. AB - In order to investigate the effects ethanol-diesel blends and altitude on the performance and emissions of diesel engine, the comparative experiments were carried out on the bench of turbo-charged diesel engine fueled with pure diesel (as prototype) and ethanol-diesel blends (E10, E15, E20 and E30) under different atmospheric pressures (81 kPa, 90 kPa and 100 kPa). The experimental results indicate that the equivalent brake-specific fuel consumption (BSFC) of ethanol diesel blends are better than that of diesel under different atmospheric pressures and that the equivalent BSFC gets great improvement with the rise of atmospheric pressure when the atmospheric pressure is lower than 90 kPa. At 81 kPa, both HC and CO emissions rise greatly with the increasing engine speeds and loads and addition of ethanol, while at 90 kPa and 100 kPa their effects on HC and CO emissions are slightest. The changes of atmospheric pressure and mix proportion of ethanol have no obvious effect on NO(x) emissions. Smoke emissions decrease obviously with the increasing percentage of ethanol in blends, especially atmospheric pressure below 90 kPa. PMID- 21234370 TI - Investigation into the Prevalence of Cryptosporidium Infection in Calves among Small-Holder Dairy and Traditional Herds in Tanzania. AB - A cross-sectional study was conducted to determine prevalence and risk factors of cryptosporidiosis in bovine from two contrasting production system in and around Tanga municipality between May 2003 and January 2004. The study populations comprised 117 calves aged <=3 months, randomly selected from 44 smallholders dairy and traditional managed herds, respectively. Individual calf and herd-level information was collected using a structured questionnaire and feacal samples were screened for Cryptosporidium spp oocysts using the modified Ziehl-Neelsen method. Overall, 35% of the calves in the study were shedding Cryptosporidium spp oocysts, with at least one positive calf detected in 54.5% of herds. Independent risk factors for cryptosporidiosis were: age >=1 to <=2 months and level of cleanness of calf house floor categorized as dirty (P < .05). Similarly an increases risk of Cryptosporidium spp infection was found in calves from smallholder dairy units compared to traditional herds (P < .05). The finding highlights that Cryptosporidium spp is prevalent among calves in the area under study. The high prevalence of cryptosporidiosis detected in this study suggests that it may have a significant impact on livestock industry and that the close interaction between cattle and human may play a role in zoonotic transmission to humans. PMID- 21234369 TI - Iron and mechanisms of neurotoxicity. AB - The accumulation of transition metals (e.g., copper, zinc, and iron) and the dysregulation of their metabolism are a hallmark in the pathogenesis of several neurodegenerative diseases. This paper will be focused on the mechanism of neurotoxicity mediated by iron. This metal progressively accumulates in the brain both during normal aging and neurodegenerative processes. High iron concentrations in the brain have been consistently observed in Alzheimer's (AD) and Parkinson's (PD) diseases. In this connection, metalloneurobiology has become extremely important in establishing the role of iron in the onset and progression of neurodegenerative diseases. Neurons have developed several protective mechanisms against oxidative stress, among them, the activation of cellular signaling pathways. The final response will depend on the identity, intensity, and persistence of the oxidative insult. The characterization of the mechanisms mediating the effects of iron-induced increase in neuronal dysfunction and death is central to understanding the pathology of a number of neurodegenerative disorders. PMID- 21234368 TI - Toxin-induced and genetic animal models of Parkinson's disease. AB - Parkinson's disease (PD) is a common progressive neurodegenerative disorder. The major pathological hallmarks of PD are the selective loss of nigrostriatal dopaminergic neurons and the presence of intraneuronal aggregates termed Lewy bodies (LBs), but the pathophysiological mechanisms are not fully understood. Epidemiologically, environmental neurotoxins such as pesticides are promising candidates for causative factors of PD. Oxidative stress and mitochondrial dysfunction induced by these toxins could contribute to the progression of PD. While most cases of PD are sporadic, specific mutations in genes that cause familial forms of PD have led to provide new insights into its pathogenesis. This paper focuses on animal models of both toxin-induced and genetically determined PD that have provided significant insight for understanding this disease. We also discuss the validity, benefits, and limitations of representative models. PMID- 21234371 TI - Identification of four potential epigenetic modulators from the NCI structural diversity library using a cell-based assay. AB - Epigenetic pathways help control the expression of genes. In cancer and other diseases, aberrant silencing or overexpression of genes, such as those that control cell growth, can greatly contribute to pathogenesis. Access to these genes by the transcriptional machinery is largely mediated by chemical modifications of DNA or histones, which are controlled by epigenetic enzymes, making these enzymes attractive targets for drug discovery. Here we describe the characterization of a locus derepression assay, a fluorescence-based mammalian cellular system which was used to screen the NCI structural diversity library for novel epigenetic modulators using an automated imaging platform. Four structurally unique compounds were uncovered that, when further investigated, showed distinct activities. These compounds block the viability of lung cancer and melanoma cells, prevent cell cycle progression, and/or inhibit histone deacetylase activity, altering levels of cellular histone acetylation. PMID- 21234372 TI - Ceramide and Related-Sphingolipid Levels Are Not Altered in Disease-Associated Brain Regions of APP and APP/PS1 Mouse Models of Alzheimer's Disease: Relationship with the Lack of Neurodegeneration? AB - There is evidence linking sphingolipid abnormalities, APP processing, and neuronal death in Alzheimer's disease (AD). We previously reported a strong elevation of ceramide levels in the brain of the APP(SL)/PS1Ki mouse model of AD, preceding the neuronal death. To extend these findings, we analyzed ceramide and related-sphingolipid contents in brain from two other mouse models (i.e., APP(SL) and APP(SL)/PS1(M146L)) in which the time-course of pathology is closer to that seen in most currently available models. Conversely to our previous work, ceramides did not accumulate in disease-associated brain regions (cortex and hippocampus) from both models. However, the APP(SL)/PS1Ki model is unique for its drastic neuronal loss coinciding with strong accumulation of neurotoxic Abeta isoforms, not observed in other animal models of AD. Since there are neither neuronal loss nor toxic Abeta species accumulation in APP(SL) mice, we hypothesized that it might explain the lack of ceramide accumulation, at least in this model. PMID- 21234373 TI - Increased mRNA Levels of TCF7L2 and MYC of the Wnt Pathway in Tg-ArcSwe Mice and Alzheimer's Disease Brain. AB - Several components in the Wnt pathway, including beta-catenin and glycogen synthase kinase 3 beta, have been implied in AD pathogenesis. Here, mRNA brain levels from five-month-old tg-ArcSwe and nontransgenic mice were compared using Affymetrix microarray analysis. With surprisingly small overall changes, Wnt signaling was the most affected pathway with altered expression of nine genes in tg-ArcSwe mice. When analyzing mRNA levels of these genes in human brain, transcription factor 7-like 2 (TCF7L2) and v-myc myelocytomatosis viral oncogene homolog (MYC), were increased in Alzheimer's disease (AD) (P < .05). Furthermore, no clear differences in TCF7L2 and MYC mRNA were found in brains with frontotemporal lobar degeneration, suggesting that altered regulation of these Wnt-related genes could be specific to AD. Finally, mRNA levels of three neurogenesis markers were analyzed. Increased mRNA levels of dihydropyrimidinase like 3 were observed in AD brain, suggesting that altered Wnt pathway regulation may signify synaptic rearrangement or neurogenesis. PMID- 21234374 TI - New and emerging therapies for osteoporosis. PMID- 21234375 TI - Evaluation of x-inactivation status and cytogenetic stability of human dermal fibroblasts after long-term culture. AB - Human primary fibroblasts are a popular type of somatic cells for the production of induced pluripotent stem (iPS) cells. Here we characterized biological properties of primary fibroblasts in terms of cell-growth rate, cytogenetic stability, and the number of inactive X chromosomes during long-term passaging. We produced eight lines of female human dermal fibroblasts (HDFs) and found normal karyotype and expected pattern of X chromosome inactivation (XCI) at low passages (Passage P1-5). However, four out of the eight HDF lines at high passage numbers (>= P10) exhibited duplicated hallmarks of inactive X chromosome including two punctuate signals of histone H3 lysine 27 trimethylation (H3K27me3) and X inactive-specific transcript (XIST) RNA signals in approximately 8.5-18.5% of the cells. Our data suggest that the copy number of inactive X chromosomes in a subset of female HDF is increased by a two-fold. Consistently, DNA fluorescent in situ hybridization (FISH) identified 3-4 copies of X chromosomes in one nucleus in this subset of cells with two inactive Xs. We conclude that female HDF cultures exhibit a higher risk of genetic anomalies such as carrying an increased number of X chromosomes including both active and inactive X chromosomes at a high passage (>= P10). PMID- 21234376 TI - E22Delta Mutation in Amyloid beta-Protein Promotes beta-Sheet Transformation, Radical Production, and Synaptotoxicity, But Not Neurotoxicity. AB - Oligomers of 40- or 42-mer amyloid beta-protein (Abeta40, Abeta42) cause cognitive decline and synaptic dysfunction in Alzheimer's disease. We proposed the importance of a turn at Glu22 and Asp23 of Abeta42 to induce its neurotoxicity through the formation of radicals. Recently, a novel deletion mutant at Glu22 (E22Delta) of Abeta42 was reported to accelerate oligomerization and synaptotoxicity. To investigate this mechanism, the effects of the E22Delta mutation in Abeta42 and Abeta40 on the transformation of beta-sheets, radical production, and neurotoxicity were examined. Both mutants promoted beta-sheet transformation and the formation of radicals, while their neurotoxicity was negative. In contrast, E22P-Abeta42 with a turn at Glu22 and Asp23 exhibited potent neurotoxicity along with the ability to form radicals and potent synaptotoxicity. These data suggest that conformational change in E22Delta-Abeta is similar to that in E22P-Abeta42 but not the same, since E22Delta-Abeta42 exhibited no cytotoxicity, unlike E22P-Abeta42 and wild-type Abeta42. PMID- 21234377 TI - Proteins with RNA chaperone activity: a world of diverse proteins with a common task-impediment of RNA misfolding. AB - Proteins with RNA chaperone activity are ubiquitous proteins that play important roles in cellular mechanisms. They prevent RNA from misfolding by loosening misfolded structures without ATP consumption. RNA chaperone activity is studied in vitro and in vivo using oligonucleotide- or ribozyme-based assays. Due to their functional as well as structural diversity, a common chaperoning mechanism or universal motif has not yet been identified. A growing database of proteins with RNA chaperone activity has been established based on evaluation of chaperone activity via the described assays. Although the exact mechanism is not yet understood, it is more and more believed that disordered regions within proteins play an important role. This possible mechanism and which proteins were found to possess RNA chaperone activity are discussed here. PMID- 21234378 TI - Developmental profiles of mucosal immunity in pre-school children. AB - This study investigated the effect of attending pre-school on mucosal immunity. Children 3.5 to 5 years of age who attended pre-school were observed for a 10 month period. Demographic information was collected on previous childcare experiences, the home environment and clinical information relating to the child and the family. A daily illness log was kept for each child. A multivariate longitudinal analysis of the relation between immunoglobulins in saliva and age, gender, childcare experience, pre-school exposure, number of siblings, environmental tobacco smoke (ETS), atopy and hospitalisation was conducted. There was a positive association of higher IgA levels with the winter season and with children being older than 4 years (P < .001), having attended childcare prior to commencing pre-school (P < .05), and having been exposed to ETS at home (P < .05). Lower IgA levels were associated with being atopic (P < .05). Higher IgG levels were associated with exposure to ETS (P < .001), while lower levels were associated to having atopy. Higher IgM levels were associated with previous childcare experience (P < .01) whilst having been hospitalised was associated with having low salivary IgM levels (P < .01). Lagged analyses demonstrated that immunological parameters were affected by the number of respiratory infections in the preceding 2 months. PMID- 21234379 TI - An Open-Label, Noncomparative, Multicenter Study to Evaluate Efficacy and Safety of NASHA/Dx Gel as a Bulking Agent for the Treatment of Fecal Incontinence. AB - Fecal incontinence (FI) is the involuntary loss of rectal contents through the anal canal. Reports of its prevalence vary from 1-21%. Studies, have demonstrated a positive effect on FI symptoms with injectable bulking agents. This study evaluated the safety and efficacy of NASHA/Dx gel in the treatment of FI. One hundred fifteen eligible patients suffering from FI received 4 injections of 1 mL NASHA/Dx gel. Primary efficacy was based on data from 86 patients that completed the study. This study demonstrated a >=50% reduction from baseline in the number of FI episodes in 57.1% of patients at 6 months, and 64.0% at 12 months. Significant improvements (P < .001) were also noted in total number of both solid and loose FI episodes, FI free days, CCFIS, and FIQL scores in all 4 domains. The majority of the treatment related AEs (94.9%) were mild or moderate intensity, and (98.7%) of AEs resolved spontaneously, or following treatment, without sequelae. Results of this study indicate NASHA/Dx gel was efficacious in the treatment of FI. Treatment effect was significant both in reduction of number of FI episodes and disease specific quality of life at 6 months and lasted up to 12 months after treatment. PMID- 21234381 TI - Dental laboratory production of prosthetic restorations in a population in sofia, bulgaria: a descriptive study. AB - Objective. To describe prosthodontic production related to mutilated dentitions in Sofia, Bulgaria. Methods. Prosthodontic production from 5 dental laboratories was recorded during a 14-day period. Production was related to dentitions as noted from casts. Dentitions were classified as edentulous, interrupted/reduced, slightly interrupted, shortened, and complete. The representativeness of the laboratory sample was verified trough comparison with a Sofia population sample using proportions of crowned or replaced teeth per dental region. Results. The total production consisted of 243 crowns, 16 post and cores, 82 fixed dental prostheses, and 41 removable dentures. Proportions of crowned teeth were significantly different between the samples; proportions of replaced teeth were not. Of the 58 incomplete dentitions analyzed, 19 were restored to the level of completeness, 15 resulted in slightly interrupted, and 24 in shortened dentitions. Conclusions. Predominantly fixed restorations were provided to restore mutilated dentitions to a functional level and not necessarily to complete dentitions. PMID- 21234380 TI - Timing of antiretroviral therapy for HIV in the setting of TB treatment. AB - The convergent human immunodeficiency virus (HIV) and tuberculosis (TB) pandemics continue to collectively exact significant morbidity and mortality worldwide. Highly active antiretroviral therapy (HAART) has been a critical component in combating the scourge of these two conditions as both a preemptive and therapeutic modality. However, concomitant administration of antiretroviral and antituberculous therapies poses significant challenges, including cumulative drug toxicities, drug-drug interactions, high pill burden, and the immune reconstitution inflammatory syndrome (IRIS), thus complicating the management of coinfected individuals. This paper will review data from recent studies regarding the optimal timing of HAART initiation relative to TB treatment, with the ultimate goal of improving coinfection-related morbidity and mortality while mitigating toxicity resulting from concurrent treatment of both infections. PMID- 21234382 TI - PET Response-Guided Treatment of Hodgkin's Lymphoma: A Review of the Evidence and Active Clinical Trials. AB - Risk-adaptive therapy for Hodgkin's lymphoma focuses on treatment modifications based on assessment of response. [(18)F]Fluoro-deoxyglucose positron emission tomography (PET) performed during or after completion of chemotherapy is a strong prognostic factor for eventual treatment outcome. Conceptually, this strategy seeks to increase efficacy and minimize toxicity through the appropriate selection of patients for either therapy escalation (high-risk, PET positive) or de-escalation (low-risk, PET negative). Preliminary evidence with tailoring both chemotherapy (drug selection, number of cycles, and dose) and radiotherapy (omission or inclusion) is varied; however, numerous clinical trials seeking to validate this approach are ongoing. This paper summarizes the available evidence and active protocols involving PET response-adapted therapy for adult (early and advanced stages) Hodgkin's lymphoma. PMID- 21234383 TI - Stem Cells Grown in Osteogenic Medium on PLGA, PLGA/HA, and Titanium Scaffolds for Surgical Applications. AB - Pluripotent adipose tissue-derived stem cells (hASCs) can differentiate into various mesodermal cell types such as osteoblasts, chondroblasts, and myoblasts. We isolated hASCs from subcutaneous adipose tissue during orthopaedic surgery and induced the osteogenic differentiation for 28 days on three different synthetic scaffolds such as polylactide-co-glycolide (PLGA), polylactide-co glycolide/hydroxyapatite (PLGA/HA), and trabecular titanium scaffolds (Ti6Al4V). Pore size can influence certain criteria such as cell attachment, infiltration, and vascularization. The aim of this study was to investigate the performance of PLGA and PLGA/HA scaffolds with a higher porosity, ranging between 75% and 84%, with respect to Ti scaffolds but with smaller pore size, seeded with hASCs to develop a model that could be used in the treatment of bone defects and fractures. Osteogenesis was assessed by ELISA quantitation of extracellular matrix protein expression, von Kossa staining, X-ray microanalysis, and scanning electron microscopy. The higher amount of protein matrix on the Ti scaffold with respect to PLGA and PLGA/HA leads to the conclusion that not only the type of material but the structure significantly affects cell proliferation. PMID- 21234385 TI - Safety Evaluation of Yukmijihwang-tang: Assessment of Acute and Subchronic Toxicity in Rats. AB - Yukmijihwang-tang (YMJ; Liu wei di huang tang (China), Rokumigan (Japan)) has been used in the treatment of diseases including renal disorder, cognitive vitality, and diabetes mellitus. However, there is very little information regarding the toxicity of YMJ to give an assurance of safety for clinical treatment. To provide safety information for YMJ, we evaluated its acute and sub chronic toxicity in rats. The single-dose toxicity of YMJ was examined using Sprague-Dawley rats. Rats were treated with YMJ extract orally at 0, 500, 1000, or 2000 mg/kg body weight. After a single administration, clinical signs were observed every day for two weeks, and body weights were measured five times, including an initial measurement on day 1 (the day of administration). In the sub chronic oral toxicity study, YMJ was administered to rats at 0, 500, 1000, or 2000 mg/kg/day for 13 weeks. Mortalities, clinical signs, body weight changes, food and water consumption, ophthalmologic findings, urinalysis, hematological and biochemical parameters, gross findings, organ weights, and histological examination were monitored during the study period. We found no mortality and no abnormalities in clinical signs, body weights, and necropsy findings for any of the animals in the acute and sub-chronic studies following oral administration in the rat at up to 2000 mg/kg/day YMJ. YMJ may not have any single-dose toxicity; the LD(50) of YMJ was over 2000 mg/kg, and it is safe for rats. The no-observed adverse-effect-level (NOAEL) was considered to be 2000 mg/kg/day. PMID- 21234384 TI - Towards a systems approach in the genetic analysis of archaea: Accelerating mutant construction and phenotypic analysis in Haloferax volcanii. AB - With the availability of a genome sequence and increasingly sophisticated genetic tools, Haloferax volcanii is becoming a model for both Archaea and halophiles. In order for H. volcanii to reach a status equivalent to Escherichia coli, Bacillus subtilis, or Saccharomyces cerevisiae, a gene knockout collection needs to be constructed in order to identify the archaeal essential gene set and enable systematic phenotype screens. A streamlined gene-deletion protocol adapted for potential automation was implemented and used to generate 22 H. volcanii deletion strains and identify several potentially essential genes. These gene deletion mutants, generated in this and previous studies, were then analyzed in a high throughput fashion to measure growth rates in different media and temperature conditions. We conclude that these high-throughput methods are suitable for a rapid investigation of an H. volcanii mutant library and suggest that they should form the basis of a larger genome-wide experiment. PMID- 21234386 TI - The role of chemokine receptor CXCR4 in the biologic behavior of human soft tissue sarcoma. AB - The molecular basis of sarcoma remains poorly understood. However, recent studies have begun to uncover some of the molecular pathways involved in sarcomagenesis. The chemokine receptor CXCR4 has been implicated in sarcoma development and has been found to be a prognostic marker for poor clinical outcome. There is growing evidence that overexpression of CXCR4 plays a significant role in development of metastatic disease, especially in directing tumor cells towards the preferential sites of metastases in sarcoma, lung and bone. Although further investigation is necessary to validate these pathways, there is potential for clinical application, particularly in the use of pharmacologic inhibitors of CXCR4 as means of preventing sarcoma metastasis. PMID- 21234387 TI - Feeding regulates the expression of pancreatic genes in gastric mucosa. AB - The ineffective short-term control of feeding behavior compromises energy homeostasis and can lead to obesity. The gastrointestinal tract secretes several regulatory peptides. However, little is known about the stomach peptide contribution to the acute regulation of intake. In an attempt to identify new gastric signals, the serial analysis of gene expression (SAGE) method was used for the transcription profiling of stomach mucosa in 7 groups of mice: fasting and sacrificed 30 minutes, 1 hour, 3 hours after a low-fat (LF) or high-fat (HF) ad libitum meal. In total, 35 genes were differentially modulated by LF and HF meals compared to fasting, including 15 mRNAs coding for digestive enzymes/secretory proteins, and 10 novel transcripts. Although the basic expression profile did not undergo substantial variations, both LF and HF meals influenced the transcription. This study represents the first global analysis of stomach transcriptome as induced by different nutritional stimuli. Further studies including the characterization of novel genes may help to identify new targets for the therapy and prevention of obesity. PMID- 21234388 TI - The modulation of adaptive immune responses by bacterial zwitterionic polysaccharides. AB - The detection of pathogen-derived molecules as foreign particles by adaptive immune cells triggers T and B lymphocytes to mount protective cellular and humoral responses, respectively. Recent immunological advances elucidated that proteins and some lipids are the principle biological molecules that induce protective T cell responses during microbial infections. Polysaccharides are important components of microbial pathogens and many vaccines. However, research concerning the activation of the adaptive immune system by polysaccharides gained interest only recently. Traditionally, polysaccharides were considered to be T cell-independent antigens that did not directly activate T cells or induce protective immune responses. Here, we review several recent advances in "carbohydrate immunobiology". A group of bacterial polysaccharides that are known as "zwitterionic polysaccharides (ZPSs)" were recently identified as potent immune modulators. The immunomodulatory effect of ZPSs required antigen processing and presentation by antigen presenting cells, the activation of CD4 T cells and subpopulations of CD8 T cells and the modulation of host cytokine responses. In this review, we also discuss the potential use of these unique immunomodulatory ZPSs in new vaccination strategies against chronic inflammatory conditions, autoimmunity, infectious diseases, allergies and asthmatic conditions. PMID- 21234389 TI - Mortality in extremely low-birth-weight neonates in mexico city (1985-2009). AB - Objective. To analyze 25 years of mortality of extremely low-birth-weight (ELBW) neonates (<=1000 g) in a private hospital in Mexico City and to establish the current viability limit for ELBW neonates. Methods. We designed a prospective observational study of all ELBW neonates born between 1985 and 2009. Neonatal mortality, early neonatal mortality, and the 120-day mortality rate were analyzed in 5-year intervals by two categories of birth weight (501-750 g and 751-1000 g). Results. Among the 50,823 total births, 158 were ELBW (3.1 per 10(3)). Neonatal mortality (death <=28 days) decreased for the 501-750 g neonates from 88.9% (1985 1989) to 55.6% (2005-1999) (P = .008) and for 751-1000 g neonates also decreased from 50% to 5.3% (P = .002). The 120-day mortality for neonates over 500 g diminished: 501-750 g neonates, 88.9% to 61.1% (P = .02) and for 751-1000 g neonates, 62.5% to 15.8% (P = .002). The highest viability limit was established in neonates who weighed >=650 g and were >=26 weeks in gestational age. Conclusions. The survival of ELBW neonates has improved in Mexico particularly in private hospitals, and it was more evident over the years 2004-2009. These data suggest that it is possible to increase the ELBW neonates survive in developing counties. PMID- 21234390 TI - IGF-I and IGF Binding Protein-3 Generation Tests and Response to Growth Hormone in Children with Silver-Russell Syndrome. AB - Objectives. To evaluate, in children with Silver-Russell Syndrome, the response to the IGF-I and IGFBP-3 generation test and compare results to the growth response after 6 months of rhGH. Methods. Eight children (6 males), with a mean age of 5.71 +/- 2.48 years and height SDS of -3.88 +/- 1.28 received rhGH for 6 months. IGF-I and IGFBP-3 were analyzed before and after 4 doses of rhGH. Results. The mean growth velocity (GV) before treatment was 5.28 +/- 1.9 cm/year. GV increased after rhGH in five children to a mean GV of 10.3 +/- 3.64 cm/year. Six children had normal basal IGF-I levels and two low levels. After 4 doses of rhGH, the IGF-I levels were normal in seven. There was no correlation between the growth response and the IGF-I generation test. Conclusions. Children with SRS have normal IGF-I generation test. There is no correlation between the generation test and the growth velocity after 6 months of rhGH. PMID- 21234391 TI - Insight into glutamate excitotoxicity from synaptic zinc homeostasis. AB - Zinc is released from glutamatergic (zincergic) neuron terminals in the hippocampus, followed by the increase in Zn(2+) concentration in the intracellular (cytosol) compartment, as well as that in the extracellular compartment. The increase in Zn(2+) concentration in the intracellular compartment during synaptic excitation is mainly due to Zn(2+) influx through calcium-permeable channels and serves as Zn(2+) signaling as well as the case in the extracellular compartment. Synaptic Zn(2+) homeostasis is important for glutamate signaling and altered under numerous pathological processes such as Alzheimer's disease. Synaptic Zn(2+) homeostasis might be altered in old age, and this alteration might be involved in the pathogenesis and progression of Alzheimer's disease; Zinc may play as a key-mediating factor in the pathophysiology of Alzheimer's disease. This paper summarizes the role of Zn(2+) signaling in glutamate excitotoxicity, which is involved in Alzheimer's disease, to understand the significance of synaptic Zn(2+) homeostasis in the pathophysiology of Alzheimer's disease. PMID- 21234392 TI - Fourteen-year long-term results after gastric banding. AB - Background. Gastric banding (GB) is a common bariatric procedure that is performed worldwide. Weight loss can be substantial after this procedure, but it is not sufficient in a significant portion of patients. Long-term rates for associated complications increase with every year of follow up, and only a few long-term studies have been published that examine these rates. We present our results after 14 years of postoperative follow up. Methods. Two hundred patients were operated upon form 01.02.1995 to 31.01.2009. Data collection was performed prospectively. In retrospective analysis, we analyzed weight loss, short- and long-term complications, amelioration of comorbidities and long-term outcome. Results. The mean postoperative follow up time was 94.4 months (range 2-144). The follow up rate was 83.5%. The incidence of postoperative complications for slippage was 2.5%, for pouch dilatation was 9.5%, for band migration was 5.5% and 12.0% for overall band removal. After 14 years, the reoperation rate was 30.5% with a reoperation rate of 2.2% for every year of follow up. Excess weight loss was 40.2% after 1 year, 46.3% after 2 years, 45.9% after 3 years, 41.9% after five years, 33.3% after 8 years, 30.8% after 10 years, 33.3% after 12 years and 15.6% after 14 years of follow up. Conclusion. The complication and reoperation rate after GB is high. Nevertheless, GB is still a therapeutic option in morbid obese patients, but the criteria for patient selection should be carefully evaluated. PMID- 21234393 TI - Changes in glucose and glutamine lymphocyte metabolisms induced by type I interferon alpha. AB - In lymphocytes (LY), the well-documented antiproliferative effects of IFN-alpha are associated with inhibition of protein synthesis, decreased amino acid incorporation, and cell cycle arrest. However, the effects of this cytokine on the metabolism of glucose and glutamine in these cells have not been well investigated. Thus, mesenteric and spleen LY of male Wistar rats were cultured in the presence or absence of IFN-alpha, and the changes on glucose and glutamine metabolisms were investigated. The reduced proliferation of mesenteric LY was accompanied by a reduction in glucose total consumption (35%), aerobic glucose metabolism (55%), maximal activity of glucose-6-phosphate dehydrogenase (49%), citrate synthase activity (34%), total glutamine consumption (30%), aerobic glutamine consumption (20.3%) and glutaminase activity (56%). In LY isolated from spleen, IFNalpha also reduced the proliferation and impaired metabolism. These data demonstrate that in LY, the antiproliferative effects of IFNalpha are associated with a reduction in glucose and glutamine metabolisms. PMID- 21234395 TI - Comparative quality of laparoscopic and open cholecystectomy in the elderly using propensity score matching analysis. AB - The safety of laparoscopic cholecystectomy (LC) in patients >=65 years of age requires further investigation of postoperative outcomes before it becomes more widely accepted as a safe technique. The advantages of using LC versus open cholecystectomy (OC) in elderly patients were analyzed using propensity score matching. The demographics, cholecystitis severity, comorbidities, complications, and admission and discharge Barthel Index (BI) scores of patients with benign gallbladder diseases were analyzed. Outcomes were analyzed by age, length of stay (LOS), total charges (TCs), BI improvement, and postoperative complications. OC, which was indicated in severe disease cases, increased hospital resource use and caused more complications than LC, but did not improve BI. Advanced age and OC resulted in greater LOS and TCs and was the best indicator of BI deterioration. Whenever possible, surgeons should use LC in elderly patients to minimize postoperative complications and allow them to regain a good quality of life. PMID- 21234394 TI - Candida albicans and C. tropicalis Isolates from the Expired Breathes of Captive Dolphins and Their Environments in an Aquarium. AB - Genotypes of Candida spp. isolated from exhalation of 20 dolphins, 11 water samples from captive pools, and 24 oral cavities of staff members in an aquarium using a combination of multiple drug resistance 1 gene (MDR1) and the internal transcribed spacer (ITS) 1 5.8s-ITS 2 regions of ribosomal RNA gene (ITS rDNA) sequences were studied. The holding ratios of the dolphins, captive pools, and staff members were 70, 90, and 29%, respectively. Isolated pathogenic yeast species common to the dolphins and environments were Candida albicans and C. tropicalis. Identical genotypes in both Candida spp. based on the combination of MDR1 and ITSrDNA were found in some dolphins, between a dolphin and a staff, among dolphins and environments, and among environments. The results indicated the diffusion and exchange of pathogenic yeasts at the aquarium among dolphins and environments. The isolates at the aquarium showed higher rates of resistance to azole antifungals compared to reference isolates. PMID- 21234396 TI - Birth weight in type 1 diabetic pregnancy. AB - Our aim was to investigate whether birth weight in mothers with diabetes mellitus type 1 is higher as compared to nondiabetic controls. Methods. A retrospective study was performed using an existing database covering the region of Flanders, Belgium. Data included the presence of diabetes type 1, hypertension, parity, maternal age, the use artificial reproductive technology, fetal- neonatal death, congenital anomalies, admission to a neonatal intensive care unit, and delivery by Caesarean section or vaginally. Results. In the period studied, 354 women with diabetes type 1 gave birth and were compared with 177.471 controls. Women with type 1 diabetes more often had a maternal age of over 35 years (16.7% versus 12.0%, P = .008, OR 1.46; 95% CI 1.09-1.95). They more frequently suffered hypertension in pregnancy (19.5% versus 4.7%, P < .0001, OR 4.91; 95% CI 3.73 6.44). Perinatal death was significantly higher in the diabetes mellitus group (3.05% versus 0.73%, P < .0001, OR 4.28; 95% CI 2.22-8.01). Caesarean section was performed almost 5 times as frequently in the diabetes versus the control group (OR 4.57; 95% CI 3.70-5.65). Birth weight was significantly higher in diabetic pregnant women from 33 until 38 weeks included, but those reaching 39 weeks and later were not different with control groups. Conclusion. In Belgium, diabetic pregnancy still carries a high risk for fetal and maternal complications; in general birth weight is significantly higher but for those reaching term there is no significant difference in birth weight. PMID- 21234397 TI - DNA damage, mutagenesis, and DNA repair. PMID- 21234398 TI - Immunomodulation of Autoimmune Arthritis by Herbal CAM. AB - Rheumatoid arthritis (RA) is a debilitating autoimmune disease of global prevalence. The disease is characterized by synovial inflammation leading to cartilage and bone damage. Most of the conventional drugs used for the treatment of RA have severe adverse reactions and are quite expensive. Over the years, increasing proportion of patients with RA and other immune disorders are resorting to complementary and alternative medicine (CAM) for their health needs. Natural plant products comprise one of the most popular CAM for inflammatory and immune disorders. These herbal CAM belong to diverse traditional systems of medicine, including traditional Chinese medicine, Kampo, and Ayurvedic medicine. In this paper, we have outlined the major immunological pathways involved in the induction and regulation of autoimmune arthritis and described various herbal CAM that can effectively modulate these immune pathways. Most of the information about the mechanisms of action of herbal products in the experimental models of RA is relevant to arthritis patients as well. The study of immunological pathways coupled with the emerging application of genomics and proteomics in CAM research is likely to provide novel insights into the mechanisms of action of different CAM modalities. PMID- 21234401 TI - Ceruloplasmin/Transferrin ratio changes in Alzheimer's disease. AB - The link between iron and Alzheimer's disease (AD) has been mainly investigated with a focus on the local accumulation of this metal in specific areas of the brain that are critical for AD. In the present study, we have instead looked at systemic variations of markers of iron metabolism. We measured serum levels of iron, ceruloplasmin, and transferrin and calculated the transferrin saturation and the ceruloplasmin to transferrin ratio (Cp/Tf). Cp/Tf and transferrin saturation increased in AD patients. Cp/Tf ratios also correlated positively with peroxide levels and negatively with serum iron concentrations. Elevated values of ceruloplasmin, peroxides, and Cp/Tf inversely correlated with MMSE scores. Isolated medial temporal lobe atrophy positively correlated with Cp/Tf and negatively with serum iron. All these findings indicate that the local iron accumulation found in brain areas critical for AD should be viewed in the frame of iron systemic alterations. PMID- 21234400 TI - Beyond histone and deacetylase: an overview of cytoplasmic histone deacetylases and their nonhistone substrates. AB - Acetylation of lysines is a prominent form of modification in mammalian proteins. Deacetylation of proteins is catalyzed by histone deacetylases, traditionally named after their role in histone deacetylation, transcriptional modulation, and epigenetic regulation. Despite the link between histone deacetylases and chromatin structure, some of the histone deacetylases reside in various compartments in the cytoplasm. Here, we review how these cytoplasmic histone deacetylases are regulated, the identification of nonhistone substrates, and the functional implications of their nondeacetylase enzymatic activities. PMID- 21234403 TI - Pediatric pain management and sedation. PMID- 21234399 TI - Organic nitrates and nitrate resistance in diabetes: the role of vascular dysfunction and oxidative stress with emphasis on antioxidant properties of pentaerithrityl tetranitrate. AB - Organic nitrates represent a class of drugs which are clinically used for treatment of ischemic symptoms of angina as well as for congestive heart failure based on the idea to overcome the impaired NO bioavailability by "NO" replacement therapy. The present paper is focused on parallels between diabetes mellitus and nitrate tolerance, and aims to discuss the mechanisms underlying nitrate resistance in the setting of diabetes. Since oxidative stress was identified as an important factor in the development of tolerance to organic nitrates, but also represents a hallmark of diabetic complications, this may represent a common principle for both disorders where therapeutic intervention should start. This paper examines the evidence supporting the hypothesis that pentaerithrityl tetranitrate may represent a nitrate for treatment of ischemia in diabetic patients. This evidence is based on the considerations of parallels between diabetes mellitus and nitrate tolerance as well as on preliminary data from experimental diabetes studies. PMID- 21234402 TI - Benefits from treatment and control of patients with resistant hypertension. AB - Resistant hypertension is commonly found in everyday clinical practice. However, the risks of resistant hypertension, as well as the benefits of treatment and control of blood pressure in patients with resistant hypertension remain vaguely clarified. Data from small clinical studies and observational cohorts suggest that patients with resistant hypertension are at increased cardiovascular risk, while control of blood pressure offers substantial benefits. It has to be noted however that data from appropriate large randomized studies are missing, and resistant hypertension remains remarkably understudied. Resistant hypertension has attracted significant scientific interest lately, as new therapeutic modalities become available. The interventional management of resistant hypertension either by carotid baroreceptor stimulation or renal sympathetic denervation is currently under investigation with promising preliminary results. This review presents available evidence regarding the benefits of treatment and control of blood pressure in patients with resistant hypertension and offers a critical evaluation of existing data in this field. PMID- 21234404 TI - QT Measurement and Heart Rate Correction during Hypoglycemia: Is There a Bias? AB - Introduction. Several studies show that hypoglycemia causes QT interval prolongation. The aim of this study was to investigate the effect of QT measurement methodology, heart rate correction, and insulin types during hypoglycemia. Methods. Ten adult subjects with type 1 diabetes had hypoglycemia induced by intravenous injection of two insulin types in a cross-over design. QT measurements were done using the slope-intersect (SI) and manual annotation (MA) methods. Heart rate correction was done using Bazett's (QTcB) and Fridericia's (QTcF) formulas. Results. The SI method showed significant prolongation at hypoglycemia for QTcB (42(6) ms; P < .001) and QTcF (35(6) ms; P < .001). The MA method showed prolongation at hypoglycemia for QTcB (7(2) ms, P < .05) but not QTcF. No difference in ECG variables between the types of insulin was observed. Discussion. The method for measuring the QT interval has a significant impact on the prolongation of QT during hypoglycemia. Heart rate correction may also influence the QT during hypoglycemia while the type of insulin is insignificant. Prolongation of QTc in this study did not reach pathologic values suggesting that QTc prolongation cannot fully explain the dead-in-bed syndrome. PMID- 21234406 TI - Polyploidization facilitates biotechnological in vitro techniques in the genus Cucumis. AB - Prezygotic interspecific crossability barrier in the genus Cucumis is related to the ploidy level of the species (cucumber (C. sativus), x = 7; muskmelon (C. melo) and wild Cucumis species, x = 12). Polyploidization of maternal plants helps hybridization among other Cucumis species by overcoming prezygotic genetic barriers. The main objective of this paper is to compare the results of several methods supporting interspecific crosses in cucumber without and with polyploidization (comparison between diploid (2x) and mixoploid (2x/4x) cucumber maternal plants). Mixoploid plants were obtained after in vivo and in vitro polyploidization by colchicine and oryzalin. Ploidy level was estimated by flow cytometry. Embryo rescue, in vitro pollination, and isolation of mesophyll protoplast were tested and compared. Positive effect of polyploidization was observed during all experiments presented by higher regeneration capacity of cultivated mixoploid cucumber embryos, ovules, and protoplasts. Nevertheless, the hybrid character of putative hybrid accessions obtained after cross in vivo and in vitro pollination was not confirmed. PMID- 21234408 TI - Multispeciality approach in the management of patient with hereditary gingival fibromatosis: 1-year followup: a case report. AB - Background. Hereditary gingival fibromatosis is a fibrotic enlargement of the gingiva. It may exist as an isolated abnormality or as part of multisystem syndrome. This paper reports a case of 16-year-old male with generalized severe gingival overgrowth, involving the maxillary and mandibular arches and covering almost all teeth. Methods. Periodontal management of gingival enlargement included gingivectomy in both arches except in the lower right molar region where flap surgery was done under general anesthesia. After a 2-month followup period, orthodontic treatment was started with fixed appliances. Monthly periodontal checkups and maintainance (scaling and polishing) were scheduled to control the gingival inflammation. Results. Reevaluation of the patient of surgical treatment after two months did not show any recurrence of condition; however, minimal overgrowth was noted 1 month after the beginning of orthodontic treatment which was treated nonsurgically. Conclusions. Although the risk of recurrence is high with this condition, surgical treatment with correction of malocclusion and regular followup can provide excellent outcome as seen in this case. PMID- 21234405 TI - Local bone marrow Renin-Angiotensin system and atherosclerosis. AB - Local hematopoietic bone marrow (BM) renin-angiotensin system (RAS) affects the growth, production, proliferation differentiation, and function of hematopoietic cells. Angiotensin II (Ang II), the dominant effector peptide of the RAS, regulates cellular growth in a wide variety of tissues in pathobiological states. RAS, especially Ang II and Ang II type 1 receptor (AT1R), has considerable proinflammatory and proatherogenic effects on the vessel wall, causing progression of atherosclerosis. Recent investigations, by analyzing several BM chimeric mice whose BM cells were positive or negative for AT1R, disclosed that AT1R in BM cells participates in the pathogenesis of atherosclerosis. Therefore, AT1R blocking not only in vascular cells but also in the BM could be an important therapeutic approach to prevent atherosclerosis. The aim of this paper is to review the function of local BM RAS in the pathogenesis of atherosclerosis. PMID- 21234409 TI - Intracytoplasmic crystalline inclusions in the hepatocytes of an antelope. AB - This case report describes intracytoplasmic crystalline inclusions in the hepatocytes of a 13-year-old female Thomson's gazelle. Histologically, multifocal to coalescing areas of many hepatocytes contained large cytoplasmic vacuoles filled with pale eosinophilic homogeneous material and rare fine basophilic granules. Von Kossa staining showed the presence of calcium within cytoplasm, mainly in the inclusions, of hepatocytes. Transmission electron microscopy, scanning electron microscopy, energy dispersive X-rays analyses, and infrared spectroscopy on the liver showed the hepatocellular material consistent with protein and carbohydrate with secondary accumulation of calcium and phosphorus. It was concluded that crystalline inclusions may have been derived due to failure of normal physiological hepatocellular clearance associated with a severe chronic disease. To the authors' knowledge this is the first reported case of hepatocellular crystalline inclusions in an antelope. PMID- 21234407 TI - Potential Applications of Immobilized beta-Galactosidase in Food Processing Industries. AB - The enzyme beta-galactosidase can be obtained from a wide variety of sources such as microorganisms, plants, and animals. The use of beta-galactosidase for the hydrolysis of lactose in milk and whey is one of the promising enzymatic applications in food and dairy processing industries. The enzyme can be used in either soluble or immobilized forms but the soluble enzyme can be used only for batch processes and the immobilized form has the advantage of being used in batch wise as well as in continuous operation. Immobilization has been found to be convenient method to make enzyme thermostable and to prevent the loss of enzyme activity. This review has been focused on the different types of techniques used for the immobilization of beta-galactosidase and its potential applications in food industry. PMID- 21234410 TI - Propylthiouracil-induced acute liver failure: role of liver transplantation. AB - Propylthiouracil- (PTU-) induced hepatotoxicity is rare but potentially lethal with a spectrum of liver injury ranging from asymptomatic elevation of transaminases to fulminant hepatic failure and death. We describe two cases of acute hepatic failure due to PTU that required liver transplantation. Differences in the clinical presentation, histological characteristics, and posttransplant management are described as well as alternative therapeutic options. Frequent monitoring for PTU-induced hepatic dysfunction is strongly advised because timely discontinuation of this drug and implementation of noninvasive therapeutic interventions may prevent progression to liver failure or even death. PMID- 21234412 TI - Multiple Papillomatosis of Breast and Patient's Choice of Treatment. AB - Papillary lesions of breast represent a range of lesions. Intraductal papilloma and its association with nipple discharge are well known. However, multiple papillomatosis has quite distinct characteristics and decision making can be somewhat challenging. We report a case of multiple papillomatosis in association with ductal carcinoma in situ (DCIS). Patient opted for ipsilateral mastectomy and prophylactic mastectomy of contralateral breast. Her decision of having prophylactic mastectomy was vindicated by presence of incidental DCIS in the contralateral breast. To our knowledge, this is the first reported case of multiple papillomatosis with DCIS of breast, along with incidental synchronous papillomatosis of contralateral breast with DCIS. The case illustrates few distinct features of multiple papillomatosis of breast and exemplifies how a patient's choice is so paramount in decision making process. Patients should be fully informed of the treatment options of the condition, and their wishes should be fully taken into account while making the final decision. PMID- 21234413 TI - A missense mutation in canine CLN6 in an Australian shepherd with neuronal ceroid lipofuscinosis. AB - The childhood neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases that are progressive and ultimately fatal. An Australian Shepherd that exhibited a progressive neurological disorder with signs similar to human NCL was evaluated. The cerebral cortex, cerebellum, and retina were found to contain massive accumulations of autofluorescent inclusions characteristic of the NCLs. Nucleotide sequence analysis of DNA from the affected dog identified a T to C variant (c.829T>C) in exon 7 of CLN6. Mutations in the human ortholog underlie a late-infantile form of NCL in humans. The T-to-C transition results in a tryptophan to arginine amino acid change in the predicted protein sequence. Tryptophans occur at homologous positions in the CLN6 proteins from all 13 other vertebrates evaluated. The c.829T>C transition is a strong candidate for the causative mutation in this NCL-affected dog. Dogs with this mutation could serve as a model for the analogous human disorder. PMID- 21234411 TI - Mitochondrial dysfunction in Parkinson's disease: pathogenesis and neuroprotection. AB - Mitochondria are vitally important organelles involved in an array of functions. The most notable is their prominent role in energy metabolism, where they generate over 90% of our cellular energy in the form of ATP through oxidative phosphorylation. Mitochondria are involved in various other processes including the regulation of calcium homeostasis and stress response. Mitochondrial complex I impairment and subsequent oxidative stress have been identified as modulators of cell death in experimental models of Parkinson's disease (PD). Identification of specific genes which are involved in the rare familial forms of PD has further augmented the understanding and elevated the role mitochondrial dysfunction is thought to have in disease pathogenesis. This paper provides a review of the role mitochondria may play in idiopathic PD through the study of experimental models and how genetic mutations influence mitochondrial activity. Recent attempts at providing neuroprotection by targeting mitochondria are described and their progress assessed. PMID- 21234414 TI - Creating a long-term diabetic rabbit model. AB - This study was to create a long-term rabbit model of diabetes mellitus for medical studies of up to one year or longer and to evaluate the effects of chronic hyperglycemia on damage of major organs. A single dose of alloxan monohydrate (100 mg/kg) was given intravenously to 20 young New Zealand White rabbits. Another 12 age-matched normal rabbits were used as controls. Hyperglycemia developed within 48 hours after treatment with alloxan. Insulin was given daily after diabetes developed. All animals gained some body weight, but the gain was much less than the age-matched nondiabetic rabbits. Hyperlipidemia, higher blood urea nitrogen and creatinine were found in the diabetic animals. Histologically, the pancreas showed marked beta cell damage. The kidneys showed significantly thickened afferent glomerular arterioles with narrowed lumens along with glomerular atrophy. Lipid accumulation in the cytoplasm of hepatocytes appeared as vacuoles. Full-thickness skin wound healing was delayed. In summary, with careful management, alloxan-induced diabetic rabbits can be maintained for one year or longer in reasonably good health for diabetic studies. PMID- 21234415 TI - Preparative separation and enrichment of syringopicroside from Folium syringae leaves with macroporous resins. AB - Syringopicroside is the major constituent in Folium syringae leaves with known pharmacological activities. In this study, a simple method for preparative separation of syringopicroside from F. syringae leaves with macroporous resins was developed. Adsorption characteristics of syringopicroside on six types of macroporous resins, including ADS-8, ADS-17, D141, NKA-9, HPD450, and HPD600, have been compared, among which D141 resin showed the best adsorption and desorption capacities for syringopicroside. Adsorption isotherms were used to D141 resin at different temperatures and fitted well to Langmuir and Freundlich equations. Dynamic adsorption and desorption tests were performed on D141 resin packed column to optimize the separation process of syringopicroside. After one run with D141 resin, the content of syringopicroside was increased 24-fold from 2.32% to 55.74% with a recovery yield of 92.16%. The chromatographic process optimized in this work avoids toxic organic solvent and, thus, is a promising basis for large-scale preparation of syringopicroside. PMID- 21234416 TI - Resistant hypertension workup and approach to treatment. AB - Resistant hypertension is defined as blood pressure above the patient's goal despite the use of 3 or more antihypertensive agents from different classes at optimal doses, one of which should ideally be a diuretic. Evaluation of patients with resistive hypertension should first confirm that they have true resistant hypertension by ruling out or correcting factors associated with pseudoresistance such as white coat hypertension, suboptimal blood pressure measurement technique, poor adherence to prescribed medication, suboptimal dosing of antihypertensive agents or inappropriate combinations, the white coat effect, and clinical inertia. Management includes lifestyle and dietary modification, elimination of medications contributing to resistance, and evaluation of potential secondary causes of hypertension. Pharmacological treatment should be tailored to the patient's profile and focus on the causative pathway of resistance. Patients with uncontrolled hypertension despite receiving an optimal therapy are candidates for newer interventional therapies such as carotid baroreceptor stimulation and renal denervation. PMID- 21234418 TI - Metabolic syndrome and outcomes after renal intervention. AB - Metabolic syndrome significantly increases the risk for cardiovascular disease and chronic kidney disease. The increased risk for cardiovascular diseases can partly be caused by a prothrombotic state that exists because of abdominal obesity. Multiple observational studies have consistently shown that increased body mass index as well as insulin resistance and increased fasting insulin levels is associated with chronic kidney disease, even after adjustment for related disorders. Metabolic syndrome appears to be a risk factor for chronic kidney disease, likely due to the combination of dysglycemia and high blood pressure. Metabolic syndrome is associated with markedly reduced renal clinical benefit and increased progression to hemodialysis following endovascular intervention for atherosclerotic renal artery stenosis. Metabolic syndrome is associated with inferior early outcomes for dialysis access procedures. PMID- 21234417 TI - Lipid Rafts: Linking Alzheimer's Amyloid-beta Production, Aggregation, and Toxicity at Neuronal Membranes. AB - Lipid rafts are membrane microdomains, enriched in cholesterol and sphingolipids, into which specific subsets of proteins and lipids partition, creating cell signalling platforms that are vital for neuronal functions. Lipid rafts play at least three crucial roles in Alzheimer's Disease (AD), namely, in promoting the generation of the amyloid-beta (Abeta) peptide, facilitating its aggregation upon neuronal membranes to form toxic oligomers and hosting specific neuronal receptors through which the AD-related neurotoxicity and memory impairments of the Abeta oligomers are transduced. Recent evidence suggests that Abeta oligomers may exert their deleterious effects through binding to, and causing the aberrant clustering of, lipid raft proteins including the cellular prion protein and glutamate receptors. The formation of these pathogenic lipid raft-based platforms may be critical for the toxic signalling mechanisms that underlie synaptic dysfunction and neuropathology in AD. PMID- 21234419 TI - Chronological Reorganization of Microtubules, Actin Microfilaments, and Chromatin during the First Cell Cycle in Swamp Buffalo (Bubalus bubalis) Embryos. AB - This paper aimed to study the dynamics of early embryonic development, in terms of redistribution of cytoskeleton (microtubules, actin microfilaments) and chromatin configurations during the first cell cycle in swamp buffalo embryos. Oocytes were matured and fertilized in vitro, and they were fixed at various time points after IVF. At 6 h after IVF, 44.4% matured oocytes were penetrated by spermatozoa. Partial ZP digestion, however, did not improve fertilization rate compared to control (P > .05). At 12 h after IVF, the fertilized oocytes progressed to the second meiotic division and formed the female pronucleus simultaneously with the paternal chromatin continued to decondense. A sperm aster was observed radiating from the base of the decondensing sperm head. At 18 h after IVF, most presumptive zygotes had reached the pronuclear stage. The sperm aster was concurrently enlarged to assist the migration and apposition of pronuclei. Cell cleavage was facilitated by microfilaments and firstly observed by 30 h after IVF. In conclusion, the cytoskeleton actively involves with the process of fertilization and cleavage in swamp buffalo oocytes. The centrosomal material is paternally inherited. Fertilization failure is predominantly caused by poor sperm penetration. However, partial digestion of ZP did not improve fertilization rate. PMID- 21234420 TI - Pseudosarcomatous proliferation of cx43- and kit-expressing interstitial cell in the urinary bladder. AB - The authors report a case showing proliferation of KIT- and connexin 43 expressing mesenchymal cells of the urinary bladder. A 75-year-old woman had an ulcerated endophytic mass (size, approximately 2 * 2 cm) in the left posterolateral wall. She underwent transurethral resection and subsequent partial cystectomy. The suburothelial mass extended to the muscularis propria. The histopathological analysis revealed spindle-shaped mesenchymal cells that were loosely arranged with myxoid stroma and showed a focal compact fascicular arrangement. In the immunohistochemical analysis, these spindle cells were stained with specific antibodies to KIT and connexin 43. The patient is currently free of disease at 5 years after operation. The proliferating spindle cells in the present case might represent a phenotype of interstitial cells of the lamina propria. PMID- 21234421 TI - Fenofibrate treatment enhances antioxidant status and attenuates endothelial dysfunction in streptozotocin-induced diabetic rats. AB - Diabetic endothelial dysfunction is accompanied by increased oxidative stress and upregulated proinflammatory and inflammatory mediators in the vasculature. Activation of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) results in antioxidant and anti-inflammatory effects. This study was designed to investigate the effect of fenofibrate, a PPAR-alpha activator, on the endothelial dysfunction, oxidative stress, and inflammation in streptozotocin diabetic rats. Diabetic rats received fenofibrate (150 mg kg(-1) day(-1)) for 4 weeks. Fenofibrate treatment restored the impaired endothelium-dependent relaxation and increased basal nitric oxide availability in diabetic aorta, enhanced erythrocyte/liver superoxide dismutase and catalase levels, ameliorated the abnormal serum/aortic thiobarbituric acid reactive substances, and prevented the increased aortic myeloperoxidase without a significant change in serum total cholesterol and triglyceride levels. It did not affect the decreased total homocysteine level and the increased tumor necrosis factor-alpha level in the serum of diabetic rats. Fenofibrate-induced prevention of the endothelial function seems to be related to its potential antioxidant and antiinflammatory activity. PMID- 21234422 TI - The selection and use of sorghum (Sorghum propinquum) bacterial artificial chromosomes as cytogenetic FISH probes for maize (Zea mays L.). AB - The integration of genetic and physical maps of maize is progressing rapidly, but the cytogenetic maps lag behind, with the exception of the pachytene fluorescence in situ hybridization (FISH) maps of maize chromosome 9. We sought to produce integrated FISH maps of other maize chromosomes using Core Bin Marker loci. Because these 1 Kb restriction fragment length polymorphism (RFLP) probes are below the FISH detection limit, we used BACs from sorghum, a small-genome relative of maize, as surrogate clones for FISH mapping. We sequenced 151 maize RFLP probes and compared in silico BAC selection methods to that of library filter hybridization and found the latter to be the best. BAC library screening, clone verification, and single-clone selection criteria are presented along with an example of transgenomic BAC FISH mapping. This strategy has been used to facilitate the integration of RFLP and FISH maps in other large-genome species. PMID- 21234423 TI - Saddle pulmonary embolism in a cancer patient with thrombocytopenia: a treatment dilemma. AB - The association between cancer and venous thromboembolism (VTE) is well established. Saddle pulmonary embolism is not uncommon in hospitalized cancer patients and confers a higher mortality. We report a case of saddle pulmonary embolism in a cancer patient with thrombocytopenia, discuss the bleeding risks, complexity of managing such patients and review current guidelines. PMID- 21234424 TI - Analysis of differences between physiological and pathological tremor of human fingers. AB - The study tried to reveal the differences between physiological and pathological tremor appearing during maintenance of isometric force in healthy individual and parkinsonian patients with tremor. Six-level wavelet expansion was used presenting the tremor as a sum of smoothed (slow) component and high-frequency detailed components of 6 expansion levels. The differences in the high-frequency components were assessed by calculating the energetic parameters in the power spectrum of these components. These parameters make it possible not only to reliably distinguish the energetic spectra of the detail components of the physiological and pathological tremor, but also to correlate changes in patient state caused by drug treatment of parkinsonian trembling with the decrease in these parameters. PMID- 21234425 TI - Transcutaneus photophoresis of metal ions using emitters of band spectrum of chemical elements. AB - Local exposure to light with hollow cathode lamp radiating band spectrum typical of manganese, copper, potassium, sodium, calcium, and magnesium enhances migration of these elements from the solution applied to the skin to the blood in rats. This effect is most pronounced at low initial blood level of manganese. Its serum concentration increased 17-fold after application of manganese salts and exposure to hollow cathode lamp radiating manganese spectrum. PMID- 21234426 TI - Adaptation to short-term stress exposures prevents poststress dysfunction of calcium-activated potassium channels in coronary vessels. AB - Adaptation to short-term stress exposures prevents immobilization stress-induced decrease in functional activity of BK(Ca)channels in smooth muscle cells of coronary vessels developing against the background of NO overproduction and increase in the relative content of oxidized glutathione (change in redox state of the glutathione system). The protective antistress mechanisms of adaptation probably include prevention of NO overproduction by inducible NO synthase and maintenance of dependent glutathione redox state functional activity of BK(Ca)channels in smooth muscle cells of coronary vessels. PMID- 21234427 TI - Effects of electrical stimulation of respiratory center in the event of termination of its natural rhythmic activity. AB - The possibility of restoration of the natural rhythmic activity of the respiratory system by transcutaneous electrical stimulation of the respiratory center after termination of spontaneous respiratory movements caused by narcosis was shown in experiments on mongrel cats of both sexes under nembutal anesthesia. Natural rhythmic activity of respiratory center was stopped by additional administration of sodium thiopental. The proposed method of electrical stimulation of the respiratory center allows maintaining the rhythmic respiratory movements and their recovery after narcotic apnea up to complete recovery of spontaneous respiration. PMID- 21234428 TI - Effects of euphylline on breathing pattern and chemosensitivity of the respiratory system after activation of GABAb-receptors. AB - We studied changes in breathing pattern in nembutal-anaesthetized mongrel rats after administration of euphylline against the background of preliminary treatment with lithium hydroxybutyrate. Two types of external respiration responses to euphylline were observed; they depended on the initial blood pressure in systemic circulation and on its drop after euphylline administration. Thus, the reaction of the respiratory system to adenosine receptors blockade against the background of hydroxybutyrate pretreatment was associated with not only the effect of euphylline, but also the state of brain hemodynamics. The effects of euphylline on chemosensitive contour of the respiratory system regulation were also investigated. It was found that euphylline did not abolish desensitization of respiratory system to hypercapnia, but smoothed the response to hypoxia under conditions of GABA(b)-receptor activation. PMID- 21234429 TI - Early and delayed effects of hypoxia during the infantile period on behavioral and hormonal reactions of rats. AB - We studied the early and delayed effects of hypoxia during the infantile period on the behavioral reactions and corticosterone concentration in male rats. The elevation of corticosterone concentration, decrease in the immobility time (forced swimming test), and increase in the nociceptive response (formalin test) were observed in 7-day-old rats immediately after hypoxia. Adult animals exposed to hypoxia at the age of 7 days exhibited elevated basal corticosterone level and lengthened immobility time. Hypoxia had the same effect on plasma corticosterone concentration in 7-day-old and adult rats. Changes in corticosterone concentration after forced swimming were shown to differ in hypoxic animals and non-hypoxic specimens. Studying the dynamics of age-related variations in the test parameters will contribute to the understanding of pathogenetic mechanisms and development of new methods for pharmacological correction of postnatal changes in CNS after hypoxia during early ontogeny. PMID- 21234430 TI - Experimental models for culturing of eye tissues of Pleurodeles waltl for evaluation of specific effects of sclera bioregulator in ultra-low doses. AB - Experiments on stationary culture of posterior eye and roll-bottle culture of the whole eye from adult water lizards Pleurodeles waltl showed that sclera bioregulator produces a stabilizing effects on adhesion interactions between the sclera, choroid, and pigment epithelium and on the maintenance of viability of sclera fibroblasts and pigment epithelium cells. PMID- 21234431 TI - Effect of selenium-containing products on antioxidant enzyme activity in the kidneys, liver, and blood of guinea pigs. AB - The antioxidant system of some tissues in guinea pigs with no selenium deficiency was studied after treatment with selenium-containing products. Activity of a selenium-containing enzyme glutathione peroxidase was significantly reduced in the kidneys and blood. The kidneys were characterized by low activity of glutathione reductase and high activity of SOD. These features illustrate the development of oxidative stress in the kidneys. PMID- 21234432 TI - Role of hemopoietic precursors of various classes in the effect of granulocyte colony-stimulating factor on hemopoiesis during cytostatic-induced myelosuppression. AB - Experiments were performed on the model of cyclophosphamide-induced myelosuppression. We showed that regeneration of the granulocytic hemopoietic stem is related to activation of multipotent, granulocyte-erythroid-macrophage megakaryocyte, and granulocyte-macrophage precursors. The division and maturation of granulocyte colony-forming cells and significant decrease in the number of these cells in the bone were suppressed under these conditions. The granulocytopoiesis-stimulating effect of granulocyte CSF during myelosuppression was associated with an increase in functional activity of multipotent and granulocyte-erythroid-macrophage-megakaryocyte precursors (primarily of differentiation). In the period of regeneration, this effect was attributed to activity of granulocyte precursors. PMID- 21234433 TI - Neuroprotective effects of immobilized granulocyte colony-stimulating factor and hyaluronidase. AB - Neuroprotective activity of immobilized granulocyte CSF (nanotechnology with electron-beam synthesis) and hyaluronidase was studied on the model of posthypoxic encephalopathy. Oral administration of immobilized granulocyte CSF had no effect on manifestations of posthypoxic psychoneurological disorders in animals. Combined treatment with immobilized granulocyte CSF and hyaluronidase prevented impairment of orientation and exploratory behavior and development of amnesia in mice with hypoxic injury. PMID- 21234434 TI - Number of stromal precursors in mouse bone marrow and expression of cytokine genes in primary cultures of mouse bone marrow cells during various periods after immunization with S. typhimurium antigens. AB - Administration of S. typhimurium microbial mass to mice was followed by a significant increase (by 3-4 times) in the efficiency of cloning and number of stromal precursors in the femoral bone marrow. These parameters were maximum on days 1-3, but returned to normal by the 8th-15th day after immunization. As differentiated from intact animals, the expression of genes for proinflammatory cytokines IL-1beta (day 1 after immunization), IL-6 (days 1-3), TNF-alpha (days 1, 3, and 6), and IFN-alpha (days 1-3) was detected in bone marrow cultures from immunized mice. The expression of genes for IFN-gamma, IL-18, and IFN-alpha was decreased on days 1, 3, and 6 after immunization of animals, respectively. Gene expression for the anti-inflammatory cytokine IL-4 was observed on day 6 after immunization. Therefore, this system was not characterized by a decrease in the immune response of stromal cells. The stromal component of hemopoietic and lymphoid organs has the vector of influences in response to bacterial antigens. This vector is directed to the stimulation and progression, but not to the suppression of immune reactions. Our results indicate that resident stromal cells play a role in the immune response of the body. PMID- 21234435 TI - Congenital immune defense of the hair. AB - Studies of two recent decades provided ample data on antibacterial peptides protecting animal and human epithelium of different types; however, no reports about the presence of these compounds in hair keratinocytes appeared up to the present time. Peptides were extracted from specimens of normal intact hair with citric acid solution in 50% ethanol. Antibacterial activity of the resultant extracts was evaluated on Candida albicans test culture by staining and microscopy, by evaluation of growth inhibition zones, and by inoculations. Direct contact with the extract destroyed the greater part of Candida albicans cells up to complete destruction of membranes. Application of the extract to dishes with agar with Candida albicans led in the formation of apparent zones of growth inhibition. The percentage of killed cells increased with prolongation of incubation with the extract. Electrophoresis of hair extract showed bands characteristic of antibacterial peptides RNase, psoriasin, and beta-defensins. Removal of the peptides from the extract by filtration through membrane filter led to loss of its activity. The results indicate that human hair keratinocytes possess congenital antibacterial immunity. PMID- 21234436 TI - Clustogenesis level in children with gastroduodenal diseases. AB - The mean count of cells with chromosome aberrations increased in a 72-h culture of peripheral blood lymphocytes of children with Helicobacter pylori-associated gastroduodenal diseases. After eradication therapy, intensification of clastogenesis was observed in the majority of children. Addition of vetoron to the treatment protocols reduced manifestations of clastogenesis. PMID- 21234437 TI - Analysis of associations between 5-HTT, 5-HTR2A, and GABRA6 gene polymorphisms and health-associated personality traits. AB - The development of personality traits united by the notion of conscientiousness, should promote, along with reduction of anxiety, the physical and mental health. In order to detect the sources of conscientiousness and neuroticism formation, we evaluated associations between polymorphic markers of 5-HTT, 5-HTR2A, and GABRA6 genes and relevant scores of TCI questionnaire in a group of 369 volunteers. Associations of markers VNTR and LPR of 5-HTT gene and marker T1521C of GABRA6 gene with "self-directedness" and the effects of 5-HTR2A gene marker T102C and its interactions with the GABRA6 gene on the "harm avoidance" were detected. PMID- 21234438 TI - Lipid peroxidation in erythrocyte membranes of women with benign and malignant neoplasms of the endometrium. AB - The content of primary and secondary products of membrane peroxidation, total cholesterol concentration, and relative microviscosity of erythrocyte membranes were measured in women with endometrial cancer and uterine leiomyoma. The content of conjugated dienes in erythrocytes was highest in female patients with malignant tumors of the endometrium. The relative microviscosity of erythrocyte membranes in patients with uterine leiomyoma and endometrial cancer was elevated in the zone of lipid--lipid and protein--lipid contacts. PMID- 21234439 TI - Impact of position of light mesh endoprosthesis with anisotropic structure for the efficiency of anterior abdominal wall reconstruction. AB - Mechanical testing of light mesh endoprosthesis Ultrapro for stretching and bending resistance showed strong anisotropy of the material along and across the loop columns. Ultrapro endoprosthesis was placed parallel and perpendicularly to the midline during plastic repair of a hernial defect in rats. Six months after surgery, the development of hernias and violation of endoprosthesis structure were observed in the group with longitudinal orientation of the endoprosthesis. Transverse orientation of the endoprosthesis led to fortification of the defect site. However, the meshes were in some cases misshapen and formed folds across the loop columns, because of insufficient bending rigidity and elasticity of the material. PMID- 21234440 TI - Evaluation of genotoxicity and reproductive toxicity of silicon nanocrystals. AB - Silicon crystal 2-5 nm nanoparticles in the form of 1-5-MU granules in water suspension were injected intraperitoneally in a single dose to male F(1)(CBA*C57Bl/6) mice or to outbred albino rats on days 1, 7, and 14 of gestation. Silicon crystal nanoparticles in doses of 5, 25, and 50 mg/kg exhibited no cytogenetic activity in mouse bone marrow cells after 24-h exposure and in doses of 5 and 25 mg/kg after 7 and 14-day exposure. A 24-h exposure to silicon nanoparticles in a dose of 5 mg/kg significantly increased DNA damage (detected by DNA comet assay) in bone marrow cells. In a dose of 50 mg/kg they considerably increased DNA damage in bone marrow and brain cells after exposure of the same duration. Silicon nanoparticles in doses of 5 and 50 mg/kg caused no genotoxic effects in the same cells after 3-h and in a dose of 5 mg/kg after 7 day exposure. Silicon crystal nanoparticles in a dose of 50 mg/kg caused death of 60-80% mice after exposure <24 h. Injected in a dose of 50 mg/kg on days 1, 7, and 14 of gestation, silicon crystal nanoparticles reduced body weight gain in pregnant rats and newborn rats at different stages of the experiment, but had no effect on other parameters of physical development of rat progeny and caused no teratogenic effects. PMID- 21234441 TI - The use of nanosized cortisol-polymer complex for analysis of mechanisms of regulation of functional activity of skin fibroblast. AB - Cortisol in concentrations within the therapeutic range inhibits calcium response of fibroblast to angiotensin II. In physiological concentrations, cortisol potentiates the effects of angiotensin II via modulation of membrane mineralocorticoid receptors. The inhibitory effects of glucocorticoids on cell proliferation and collagen synthesis are manifestations of its genomic effects mediated by intracellular receptors. The use of glucocorticoid preparation based on nanosized polymer structure made it possible to distinguish between the genomic and nongenomic mechanisms of regulation of activity of target-cells. PMID- 21234442 TI - Dynamics of growth and nonspecific resistance of productive animals under biogeochemical conditions of the Sura and Trans-Sura regions in Chuvashia. AB - Complex evaluation of the effects of biogenic compounds Permamic, Combiolax, DAFS 25, Selenopyrane, and Trepel on pigs and young boars with consideration for the biogeochemical characteristics of the Sura and Trans-Sura regions in Chuvashia demonstrated their pronounced neuroimmunoendocrine effect. PMID- 21234443 TI - Angiogenesis after transplantation of auto- and allogenic cells. AB - Neoangiogenesis after transplantation of auto- and allogenic mononuclears and multipotent stromal cells from the bone marrow was studied on the model of inflammatory angiogenesis. Transplanted auto- and allogenic cells stimulate the formation of new blood vessels in the granulation tissue, this manifesting in an increase in the quantity and volume density of blood vessels. The most pronounced angiogenesis was observed after transplantation of allogenic mononuclears and multipotent stromal cells. It was associated with intense inflammatory infiltration, with less numerous and mature collagen fibers in the granulation tissue. Injection of allogenic cells led to stimulation and chronization of inflammation, infiltration with inflammatory and poorly differentiated cells, and more pronounced and lasting angiogenesis. However, neither auto-, nor allogenic transplanted labeled cells were detected in the walls of new blood vessels. Hence, it seems that bone marrow mononuclears and multipotent stromal cells stimulated angiogenesis mainly at the expense of production of angiogenic factors, and after transplantation of allogenic cells also by stimulating the inflammation. PMID- 21234444 TI - Experimental cytomorphological studies of the reaction of mononuclear phagocyte system in granulomatosis of mixed (silicotic and tuberculous) etiology. AB - Silicon dioxide in combination with Mycobacterium tuberculosis in BCG vaccine is characterized by a significantly higher granuloma-inducing activity than BCG or silicon dioxide alone. Cell "dissociation" from granulomas is not characteristic of granulomas induced by silicon dioxide or its combination with BCG (in contrast to BCG-induced granulomas). A steady increase in the counts and size, particularly on days 120-180, mainly at the expense of fibroblast accumulation and subtotal fibrosis, are intrinsic to these granulomas. Monocyte retention in the bone marrow is characteristic starting from day 56 until day 180 after injection of both granulomatous factors alone or in combination, particularly so in BCG granulomatosis. PMID- 21234445 TI - Morphofunctional analysis of experimental model of esophageal achalasia in rats. AB - We carried out a detailed analysis of rat model of esophageal achalasia previously developed by us. Manifest morphological and functional disorders were observed in experimental achalasia: hyperplasia of the squamous epithelium, reduced number of nerve fibers, excessive growth of fibrous connective tissue in the esophageal wall, high contractile activity of the lower esophageal sphincter, and reduced motility of the longitudinal muscle layer. Changes in rat esophagus observed in experimental achalasia largely correlate with those in esophageal achalasia in humans. Hence, our experimental model can be used for the development of new methods of disease treatment. PMID- 21234446 TI - Histo- and cytoarchitectonics of the hippocampus in young rats injected with propofol and mexidol. AB - Light microscopic examination of the hippocampus was carried out in young rats (intact and injected with propofol and mexidol according to different protocols). Propofol had a negative effect on hippocampal neurons causing an almost 2-fold increase in the count of modified cells in comparison with the normal level. Mexidol effectively corrected these shifts. PMID- 21234447 TI - Posttraumatic activity of signal pathways of nuclear factor kappaB in mature sensory neurons. AB - The aim of this study was to clear out whether injury to the peripheral nerve leads to activation of nuclear factor kappaB in mature spinal ganglia. Analysis of matrix RNA of nuclear factor kappaB-dependent genes (monocyte chemoattractant protein MCP-1 and inhibitor of nuclear factor kappaB IkappaBalpha) showed different levels of expression of these genes in the spinal ganglia in vivo after axotomy and in vitro after TNF-alpha stimulation. On the other hand, DNA-binding activity of nuclear factor kappaB increased in the spinal ganglia 6 h after axotomy and after 10-min incubation of sensory neuron culture with TNF-alpha. These data attest to possible involvement of nuclear factor kappaB in the posttraumatic regulation of gene transcription in spinal ganglion cells. PMID- 21234448 TI - Experimental model of combined pain and depression status in rats. AB - Combined pain and depression status in rats was created by inducing experimental depressive syndrome (by subchronic injection of MPTP proneurotoxin) in animals with manifest and developing neurogenic pain syndrome induced by preliminary crossing of the sciatic nerve in the hind limb. The neurogenic pain syndrome augmented by some parameters the depressive symptoms and provoked manifestation of signs of depressive behavior in animals treated with saline. PMID- 21234449 TI - Detection of inflammatory processes during various diseases by the method of flow cytofluorometry. AB - Oxidative (respiratory) burst is an important manifestation of inflammation. Precise quantitative assessment of this reaction by flow cytometry made it possible to record and evaluate the severity of the inflammatory processes in a wide spectrum of diseases including diphtheria, hepatitis, pneumonia, bronchial asthma, arthritis, vasculitis, postoperative complications, tuberculosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and myocardial infarction. This approach can be employed as a highly sensitive method of detection of inflammatory reactions and monitoring of their course in various pathological processes. PMID- 21234450 TI - Models of reactions of human heart as nonlinear dynamic system to cosmic and geophysical factors. AB - The paper analyzes theoretical models of the adaptive modes of generation and stability of human heart as a nonlinear point source. The analysis encompasses only ECG time-domain dynamics. To solve the general problem of the study of the adaptive changes of the cardiosignal under the action of external periodic force and parametric noise, a new dynamic model is proposed, which incorporates two control physical parameters: power of signal generation and coefficient of diffuse signal scattering. For the entire set of parameters, the examined modeled nonlinear system demonstrated a number of various performance modes ranging from steady-state periodic and quasi-periodic states to chaos. The model showed that variations in cosmic, geophysical, and weather conditions in the frequency range of 0.1-0.9 Hz produce the greatest biotropic influence. PMID- 21234451 TI - Standardization of biochemical profile of mesenchymal cell materials by probing the level of dehydrogenase activity. AB - It is demonstrated that the output optical signal of MTT test is directly proportional to the number of viable cells in the primary culture of mesenchymal cells (skin fibroblasts and mesenchymal stem cells from the bone marrow, placenta, and umbilical cord). The slope of the best curve in coordinates "cell number - optical signal" reflecting specific productivity of MTT-formazan characterizes mean dehydrogenase activity of cells and their physiological activity. It was found that in vitro dehydrogenase activity of primary cultures of mesenchymal cells increased during the first 3-5 passages and then tended to decrease. The variant of MTT method presented here can be used for standardization of cell materials. PMID- 21234452 TI - Experimental evaluation of rat cord blood as a source of stem cells stimulating regeneration of the bone tissue. AB - We studied subpopulation structure of rat cord blood and its effects on regeneration of the bone tissue. In cord blood leukocytes, cell fractions with phenotypes CD45+/CD90-, CD45-/CD90+, CD34+/CD45+ were determined. The cells adhered to plastic during culturing and had a fibroblast-like morphology. Transplantation of rat cord blood cells into modeled femoral bone defects stimulated regeneration of the bone tissue and led to recovery of its anatomical integrity, which was confirmed by X-ray examination and histological analysis. No complete recovery of the bone structure was observed in controls (without cell implantation). PMID- 21234453 TI - Regeneration of skull bones in adult rabbits after implantation of commercial osteoinductive materials and transplantation of a tissue-engineering construct. AB - We performed a comparative study of reparative osteogenesis in rabbits with experimental critical defects of the parietal bones after implantation of commercial osteoinductive materials "Biomatrix", "Osteomatrix", "BioOss" in combination with platelet-rich plasma and transplantation of a tissue-engineering construct on the basis of autogenic multipotent stromal cells from the adipose tissue predifferentiated in osteogenic direction. It was found that experimental reparative osteogenesis is insufficiently stimulated by implantation materials and full-thickness trepanation holes were not completely closed. After transplantation of the studied tissue-engineering construct, the defect was filled with full-length bone regenerate (in the center of the regenerate and from the maternal bone) in contrast to control and reference groups, where the bone tissue was formed only on the side of the maternal bone. On day 120 after transplantation of the tissue-engineering construct, the percent of newly-formed bone tissue in the regenerate was 24% (the total percent of bone tissue in the regenerate was 39%), which attested to active incomplete regenerative process in contrast to control and reference groups. Thus, the study demonstrated effective regeneration of the critical defects of the parietal bones in rabbits 120 days after transplantation of the tissue-engineering construct in contrast to commercial osteoplastic materials for directed bone regeneration. PMID- 21234454 TI - In vitro effect of Knotolan, a new lignan from Abies sibirica, on the growth of hormone-dependent breast cancer cells. AB - Here we present antiestrogenic effects of Knotolan, a new dietary lignan from Abies sibirica raw material. Knotolan abolished growth-stimulating effects of 17beta-estradiol on hormone-dependent MCF-7 cells. PMID- 21234455 TI - Morphological and molecular analysis of angiogenesis after intramyocardial transplantation of autologous bone marrow mononuclear cells. AB - We studied the peculiarities of angiogenesis in the postinfarction period after transmyocardial laser revascularization and intramyocardial implantation of mononuclear bone marrow cells into the pericicatrical zone of the left ventricular myocardium in dogs. Morphological manifestation of angiogenesis in the myocardium after application of laser and cell technologies are angiomatosis, formation of large thin-wall vessels and sinusoids. The angiogenic effect of implanted mononuclear bone marrow cells is determined by high content (43-47%) of CD31+ cells in both adherent and nonadherent fractions. More pronounced angiogenic potential of nonadherent cells is determined by intensive expression of cytokine VEGF-B and D mRNA essential for arterial vessels growth. Immunohistochemical studies showed that about 90% cells of the nonadherent fraction are endothelial precursors expressing endothelial cell markers isolectin B4 and VEGF-R2. It was found that the use of adherent mononuclear bone marrow cells during the postinfarction period induces ossification of the epicardium and subepicardial myocardium layer, formation of cartilage plates, and focal calcification. Implantation of nonadherent mononuclear bone marrow cells into transmyocardial laser channels did not induce ectopic ossification of the myocardium. PMID- 21234456 TI - Peculiarities of proliferation and differentiation of cambial and daughter cells of epidermal-dermal morphofunctional zone in normal epithelium and in cancer. AB - The cambial and daughter cells of normal epithelium function in the morphofunctional zone consisting of two subunits with 12 cambial cells in each. Daughter cells are differentiated in an electrical field created by 12 pairs of maternal and daughter cells, products of division of cambial cells located in the same subunit. The differentiation requires relaxation of the cortex of daughter cells via expression of SH3 domain of Src kinase by dermal daughter cells, which leads to a decrease in activity of RhoA in epidermal cells, their stretching, and activation of SH2 domain of Src responsible for differentiation. Reduction of the number of cambial cells to 6 and, consequently, weakening of electrical field produced by them to a threshold value corresponding to very weak stretching of daughter epithelial cells results in a decrease in SH2 domain expression in these cells and its kinase contribution in Src. This leads to an increase in RhoA relative to Src, enhances cell contraction, impairs formation of stress fibrils and focal contacts, reduces cell flattening, and increases cell mobility. The decrease in the number of microtubules, intermediate filaments, and stress fibrils changes the major cell axis direction, which, in turn, sharply reduces nucleus stretching and leads to impaired chromosome looping out near the centromeres and telomeres; the cells acquires signs of an epitheliocyte and a fibroblast, protein transcription is impaired, and daughter cells are transformed into malignant cell. PMID- 21234457 TI - The use of autologous peripheral blood stem cells as a hemopoietic support during polychemotherapy of children with soft tissue sarcomas. AB - Intensification of cycle polychemotherapy in disseminated tumors considerably improves the efficiency of complex treatment. Reinfusion of peripheral blood stem cells as a factor of replacement treatment during hemopoietic suppression or disorders is now becoming more and more promising. PMID- 21234458 TI - Delayed results of transplantation of fetal neurogenic tissue in patients with consequences of spinal cord trauma. AB - We analyzed delayed effects of transplantation of nervous and hemopoietic fetal cells to patients with consequences of spinal trauma. A decrease in neurological deficit associated with pronounced improvement of functional independence was observed in 48.9% cases. The best results were observed in patients receiving cell transplantation within the first 2 years after trauma and in younger individuals. The pattern of morphological changes in the spinal cord at site of injury, severity of damage, and the method of transplantation had no appreciable effects on its delayed results. PMID- 21234459 TI - Effect of preliminary load of macrophages with silicium dioxide on phagocytosis of BCG strain micobacteria by macrophages and antimicrobial activity. AB - We studied the effect of preliminary loading of peritoneal macrophages with silicium dioxide on in vitro viability, phagocytosis of BCG strain mycobacteria, and the capability to destroy the phagocytosed mycobacterium tuberculosis. It was shown that preliminary loading of macrophages with silicium dioxide did not reduce their viability and stimulated phagocytosis of BCG strain mycobacteria, but reduced their antibacterial activity. PMID- 21234460 TI - Morphofunctional characteristics of fetoplacental barrier of placental villi during pregnancy complicated by herpes-virus infection. AB - Analysis of placenta homogenate from pregnant women having an episode of herpes virus infection during the third trimester revealed suppression of Bcl-2 protein activity and increase in caspase 3 concentration. Activity of Bcl-2 protein decreases with increasing the titer of antibodies to herpes virus. Increased caspase-3 activity increases the risk of DNA damage in syncytiotrophoblast nuclei. PMID- 21234461 TI - Compaction principle and approaches to biopolymer structure deciphering. AB - On the basis of a principle of maximum compaction of biopolymer structure in a limited space derived from the concept about the existence of three different types of dimers in the studied structure, we propose a hypothesis according to which side groups in macromolecules (nitrogenous bases in nucleic acids or R groups in proteins) are specifically distributed in different points depending on geometrical shape of dimer bending in the biopolymer chain backbone. The latter provides the possibility of complete deciphering of biopolymer structure. PMID- 21234463 TI - A novel synthesis of (di)-benzazocinones via an endocyclic N-acyliminium ion cyclisation. AB - The triflic acid-mediated endocyclic N-acyliminium ion cyclisation provides a facile synthesis of (di)-benzazocinones. On reduction of the 10-phenyl derivative, an unusually non-polar tertiary alkylamine was obtained. PMID- 21234462 TI - Molecular mechanisms of the effect of interleukin-2 on apoptosis of blood lymphocytes. AB - The effects of recombinant IL-2 on apoptosis of lymphocytes of healthy donors were studied in in vitro experiments. It was shown that the inductive and inhibitory effects of IL-2 on apoptotic process depend on the dose of the cytokine and cell microenvironmental conditions. Culturing of lymphocytes with recombinant IL-2 increases the percent of cells with reduced transmembrane potential, reduces the content of intracellular proteins Bcl-2, Bcl-X(L) and i Bax, and increases the level of Bad. The proapoptotic effect of this cytokine is realized with participation of nuclear transcription factor NF-kappaB and transcription factor P53. PMID- 21234464 TI - A BODIPY-based fluorescent chemodosimeter for Cu(II) driven by an oxidative dehydrogenation mechanism. AB - A boradiazaindacene (BODIPY) derivative containing a simple NO bidentate ligand shows a Cu(2+)-selective fluorescence in aqueous media. This is promoted via a coordination of Cu(2+) followed by oxidative dehydrogenation of an amine moiety, leading to a formation of a fluorescent Cu(+)-Schiff base complex. PMID- 21234465 TI - The inherent structural instability: concentration-dependent transformation of pyrogallarene to pyrogallarene lactones. AB - Pyrogallarene shows concentration-dependent instability in dilute solutions resulting in elimination of two ketene molecules and formation of pyrogallarene lactones. This unexpected phenomenon, which is not observed with resorcinarenes, highlights the significance of the four hydroxyl groups at 2-position for the molecular characteristics of pyrogallarenes. PMID- 21234466 TI - Conversions between metal-ligand multiple bond (MLMB) types: carbonyl olefination and other applications. AB - In this Perspective, methods for the direct conversion of one type of metal ligand multiple bond (MLMB) to another are discussed. Of particular interest, because of their potential utility in organic synthesis, are examples of direct conversion of N- and O-based MLMB to alkylidenes and alkylidynes. Recent efforts in this area from our laboratory with some background are detailed. The research from our group involves metallacycles prepared directly from an imido ligand where a metal-carbon bond can have alkylidene-like or alkyl-like properties and reactivity depending on the ancillary ligands. PMID- 21234467 TI - Fabrication of CuO-ZnO nanowires on a stainless steel mesh for highly efficient photocatalytic applications. AB - We report the photocatalytic activity of flower-like CuO-ZnO heterostructured nanowires (NWs) fabricated on a stainless steel mesh. The mesh provided an extensive surface area and facilitated efficient mass transfer. The composed NWs exhibited excellent photocatalytic activity and showed additional enhanced properties due to multilayered, dual light source effects during the photodecomposition of a non-biodegradable azo dye. PMID- 21234468 TI - High performance "ionic liquid" chromatography. AB - We firstly developed high performance liquid chromatography methods with "ionic liquids" as eluents (HPILC) and successfully demonstrated the analysis of various biopolymers including scarcely soluble highly polymerized cellulose by means of HPILC with highly polar ionic liquid. PMID- 21234469 TI - Catalytic C-H amination: the stereoselectivity issue. AB - Catalytic C-H amination has recently emerged as a unique tool for the synthesis of amines. This tutorial review highlights the existing protocols catalyzed by metal complexes (rhodium, copper, ruthenium, manganese and palladium) allowing diastereo- and enantioselective C-H amination. Substrate-, catalyst- and reagent controlled methodologies are detailed. They involve either catalytic nitrene C-H insertion or C-H activation. PMID- 21234470 TI - Tailored TiO2 layers for the photocatalytic ozonation of cumylphenol, a refractory pollutant exerting hormonal activity. AB - Photocatalytic ozonation by Al-supported TiO(2) films is successfully applied to the mineralization of 4-cumylphenol, a recalcitrant endocrine disrupting compound. A possible reaction mechanism implying the intermediate formation of bisphenols is proposed on the grounds of HPLC-MS and FTIR analyses. PMID- 21234471 TI - A post-labeling strategy based on dye-induced peeling of the aptamer off single walled carbon nanotubes for electrochemical aptasensing. AB - A simple and efficient post-labeling strategy based on dye-induced peeling of the aptamer molecules off single-walled carbon nanotubes was developed for electrochemical aptasensing of thrombin with a detection limit down to 3 pM. PMID- 21234472 TI - Photocatalytic methane decomposition over vertically aligned transparent TiO2 nanotube arrays. AB - We report here on a study of vertically aligned TiO(2) nanotube arrays grown by the one-step anodic oxidation technique and their photocatalytic performance for methane decomposition. Quantitative activity data as a function of film thickness is obtained. PMID- 21234473 TI - Modification of transmembrane and GPI-anchored proteins on living cells by efficient protein trans-splicing using the Npu DnaE intein. AB - The naturally split Npu DnaE intein can be used for ligation of an exogenous polypeptide to membrane proteins on living cells. No reducing agents or other factors are required. The approach is rapid and virtually traceless, because the intein removes itself during the reaction. PMID- 21234474 TI - Stereoselective construction of a 5-aza-spiro[2,4]heptane motif via catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides and ethyl cyclopropylidene acetate. AB - A direct and facile synthesis of highly functional 5-aza-spiro[2,4]heptanes, a valuable structural motif for drug discovery, is developed via catalytic asymmetric 1,3-dipolar cycloaddition of cyclopropylidene acetate and azomethine ylides for the first time. PMID- 21234475 TI - Highly diastereo- and enantio-selective epoxidation of secondary allylic alcohols catalyzed by styrene monooxygenase. AB - Enantiomerically enriched glycidol derivatives with contiguous stereogenic centers were obtained in a highly diastereo- and enantio-selective epoxidation catalyzed with the styrene monooxygenase StyAB2. PMID- 21234476 TI - Highly selective detection of phosphate in very complicated matrixes with an off on fluorescent probe of europium-adjusted carbon dots. AB - A simple method for phosphate (Pi) detection is established by developing an off on fluorescence probe of europium-adjusted carbon dots (CDs), which has been successfully applied to the detection of Pi in very complicated matrixes such as artificial wetlands system. PMID- 21234477 TI - Ellipsoidal hollow nanostructures assembled from anatase TiO2 nanosheets as a magnetically separable photocatalyst. AB - A simple approach was proposed to synthesize three types of ellipsoidal hollow nanostructures whose shells are assembled from anatase TiO(2) nanosheets (NSs) with exposed (001) facets. Among them, ellipsoid Fe(3)O(4)@TiO(2)-NS nanorattles can be readily generated as a magnetically separable photocatalyst with enhanced activity through in situ reduction of the alpha-Fe(2)O(3) core. PMID- 21234478 TI - Microfluidic synthesis of Janus particles by UV-directed phase separation. AB - A synthetic methodology based on microfluidics has been developed to fabricate monodisperse polymer Janus particles by UV-directed phase separation. PMID- 21234479 TI - In situ molecular detection of ischemic cells by enhanced protein direct electron transfer on a unique horseradish peroxidase-Au nanoparticles-polyaniline nanowires biofilm. AB - To overcome shortcomings of the ex situ approaches, in situ detection using H(2)O(2) molecules to diagnose ischemia through enhanced protein direct electron transfer on a unique horseradish peroxidase-Au nanoparticles-polyaniline nanowires biofilm is demonstrated and it is discovered that the extracellular H(2)O(2) molecule released per ischemic cell is 2.7-times of that of a normal cell. PMID- 21234480 TI - Synthesis of bimagnetic ionic liquid and application for selective aerobic oxidation of aromatic alcohols under mild conditions. AB - The first bimagnetic ionic liquid based on Fe and TEMPO with cooperative functionalities not only exhibited strong paramagnetic behaviour at room temperature under an applied magnetic field of 5000 Oe but also proved to be an effective catalyst for selective aerobic oxidation of aromatic alcohols under mild and clean conditions. PMID- 21234481 TI - Construction of a molecular beacon based on two-photon excited fluorescence resonance energy transfer with quantum dot as donor. AB - A new molecular beacon (MB) driven by two-photon excitation (TPE) using quantum dots as energy donor is constructed, which provides reduced direct excitation of acceptor and is free of interferences from autofluorescence or scattering light in a complicated biological matrix. PMID- 21234482 TI - Formation of a porous cerium oxide membrane by anodization. AB - A two-step synthetic process is reported to fabricate porous ceria membranes by anodization of cerium metal foils with subsequent calcination. "Ribbon-like" structures were found to form the backbones of these porous frameworks. The hydrophobic nature of these membranes was revealed by water contact angle measurements. PMID- 21234483 TI - Palladium catalyzed bicyclization of 1,8-diiodonaphthalene and tertiary propargylic alcohols to phenalenones and their applications as fluorescent chemosensor for fluoride ions. AB - Phenalenone derivatives were efficiently constructed from 1,8-diiodonaphthalene and tertiary propynols via a one-pot domino reaction which eventually included Pd catalyzed Sonogoshira coupling, Pd-catalyzed allylic oxidation and Pd-catalyzed C(sp(2))-H activation. Moreover, the synthesized phenalenone derivative presented a practical application as a fluorescent chemosensor for fluoride anion with high sensitivity and selectivity. PMID- 21234484 TI - A water-soluble C60-porphyrin compound for highly efficient DNA photocleavage. AB - A water-soluble covalently linked C(60)-porphyrin compound-C(60)Por is reported to show enhanced DNA-cleaving activity. The highly enhanced DNA-cleaving activity is expected to be ascribed to the high water-solubility and affinity of C(60)Por to DNA, as well as to the accessibility to the charge-separated states C(60)(-) Por(+) formed under radiation. PMID- 21234485 TI - An iodine-free electrolyte based on ionic liquid polymers for all-solid-state dye sensitized solar cells. AB - An ionic liquid polymer, poly (1-alkyl-3-(acryloyloxy)hexylimidazolium iodide), was employed as an iodine-free electrolyte in all-solid-state dye-sensitized solar cells with an overall conversion efficiency of 5.29% under AM 1.5 simulated solar light (100 mW cm(-2)) illumination. PMID- 21234486 TI - Low temperature CVD growth of PbS films on plastic substrates. AB - The low temperature growth of crystalline PbS films has been achieved on plastic substrates by CVD using a xanthate. The possible mechanism involved in this low temperature deposition has been probed by density functional theory calculations. PMID- 21234487 TI - Formation of chiral mesostructured porphyrin-silica hybrids. AB - Formation of a chiral mesostructured porphyrin-silica hybrid with cylindrical helical stacking of anionic porphyrins was achieved by the aid of cationic organosilane. The enantiopurity of the hybrid was dramatically enhanced by a small amount of (R)-1,1'-bi-2-naphthol or its enantiomer. PMID- 21234488 TI - Ionic liquid-assisted synthesis of thorned gold plates comprising three-branched nanotip arrays. AB - Hierarchically structured, thorned gold plates comprising regular, three-branched nanotip arrays were synthesized by a facile, one-pot reduction process in mixed solvents of the ionic liquid [BMIM][PF(6)] and formamide without additives. PMID- 21234489 TI - Fluorescence-enhanced nucleic acid detection: using coordination polymer colloids as a sensing platform. AB - Coordination polymer colloids have been used as an effective fluorescent sensing platform for multiplexing nucleic acid detection capable of distinguishing complementary and mismatched target sequences for the first time. PMID- 21234490 TI - Kinetic subtleties of nitroxide mediated polymerization. AB - Due to the academic and industrial interest of Nitroxide Mediated Polymerization (NMP), a lot of investigations have focused on the kinetics of this process. During the last decade, although the simplified kinetic scheme--equilibrium reactions between dormant species (alkoxyamine) and active species (alkyl radicals and nitroxides), propagation reaction of the macro-alkyl radical, and termination reactions--was suitable to predict the main trends at the macromolecular level, it has become obvious that it was not sufficient to describe all the kinetic effects involved in the NMP process. Indeed, like the conventional radical polymerization, NMP should be described as a 3 stage process including initiation, propagation, and self- and cross-termination. These two types of radical polymerization differ by the occurrence during NMP of an activation/deactivation process involving the dormant species in both the initiation and propagation stages. Evidence is provided of the importance of the rate of homolysis of the initiator (alkoxyamines) and of the rate of the first alkyl radical addition onto the monomer for the success of NMP. Thus, the fundamental kinetics of the main reactions involved in NMP as well as side reactions are also discussed in this tutorial review. PMID- 21234491 TI - Metamaterials: a new frontier of science and technology. AB - Metamaterials, artificial composite structures with exotic material properties, have emerged as a new frontier of science involving physics, material science, engineering and chemistry. This critical review focuses on the fundamentals, recent progresses and future directions in the research of electromagnetic metamaterials. An introduction to metamaterials followed by a detailed elaboration on how to design unprecedented electromagnetic properties of metamaterials is presented. A number of intriguing phenomena and applications associated with metamaterials are discussed, including negative refraction, sub diffraction-limited imaging, strong optical activities in chiral metamaterials, interaction of meta-atoms and transformation optics. Finally, we offer an outlook on future directions of metamaterials research including but not limited to three dimensional optical metamaterials, nonlinear metamaterials and "quantum" perspectives of metamaterials (142 references). PMID- 21234492 TI - The de novo engineering of pyrrolysyl-tRNA synthetase for genetic incorporation of L-phenylalanine and its derivatives. AB - Using evolved pyrrolysyl-tRNA synthetase-tRNA(CUA)(Pyl) pairs, L-phenylalanine, p iodo-L-phenylalanine and p-bromo-L-phenylalanine have been genetically incorporated into proteins at amber mutation sites in E. coli. PMID- 21234493 TI - Characterization of the adaptive response and growth upon hyperosmotic shock in Saccharomyces cerevisiae. AB - Molecular and physiological details of osmoadaptation in yeast Saccharomyces cerevisiae are well characterized. It is well known that a cell, upon osmotic shock, delays its growth, produces a compatible solute like glycerol in yeast to maintain the osmotic equilibrium. Many genes are regulated by the hyperosmolarity glycerol (HOG) singling pathway, some of which in turn control the carbon flux in the glycolytic pathway for glycerol synthesis and reduced growth. The whole process of survival of cells under hyperosmotic stress is controlled at multiple levels in signaling and metabolic pathways. To better understand the multi-level regulations in yeast to osmotic shock, a mathematical model is formulated which integrates the growth and the osmoadaptation process. The model included the HOG pathway which consists of Sho1 and Sln1 signaling branches, gene regulation, metabolism and cell growth on glucose and ethanol. Experiments were performed to characterize the effect of various concentrations of salt on the wild-type and mutant strains. The model was able to successfully predict the experimental observations for both the wild-type and mutant strains. Further, the model was used to analyze the effects of various regulatory mechanisms prevalent in the signaling and metabolic pathways which are essential in achieving optimum growth in a saline medium. The analysis demonstrated the relevance of the combined effects of regulation at several points in the signaling and metabolic pathways including activation of GPD1 and GPD2, inhibition of PYK and PDC1, closure of the Fps1 channel, volume effect on the glucose uptake rate, downregulation of ethanol synthesis and upregulation of ALD6 for acetate synthesis. The analysis demonstrated that these combined effects orchestrated the phenomena of adaptation to osmotic stress in yeast. PMID- 21234494 TI - Molecular computing with plant cell phenotype serving as quality controlled output. AB - The ability of autonomous biomolecular computing devices to interact directly with biological systems and even with living organisms without any interface represents their main advantage over the electronic computers. This study shows that the expression of fluorescent proteins in live plant cells can be utilized as a highly accurate visual output of DNA-based computing. Each of the two possible outputs of a 2-symbol 2-state finite automaton was represented here by either green or cyan fluorescence in eukaryotic cells. The automata were programmed by the choice of several molecules from a library of 8 transition molecules, each containing a recognition site for a type II endonuclease. Two enzymes, endonuclease and a DNA ligase, as well as ATP, represented the hardware. Each input molecule, in the form of a dsDNA, included a string of symbols, 6 bp each, and a 6 bp terminator. The two detection molecules were also dsDNA, each containing a 4-base sticky end, complementary to the appropriately restricted terminator and a gene encoding for a different fluorescent protein. Computation was carried out by mixing all components in a homogeneous solution, leading to autonomous processing of the input molecule via repetitive cycles of digestion, hybridization, and ligation. The output processing procedure involved the creation of a circular dsDNA that contained the gene of either green fluorescent protein or cyan fluorescent protein. Insertion of these plasmids into onion cells by particle bombardment resulted in either green fluorescent or cyan fluorescent live cells as phenotypical output signals. The plasmid formation was an important step because it served as a quality control gate that transformed a rather noisy output into a clean signal. This process of noise elimination allowed for clean and flawless outputs with high fidelity and zero noise. PMID- 21234495 TI - Indenyl-functionalised triethylborane adduct of N-heterocyclic carbene: stepwise coordination of indenyl and NHC ligands toward molybdenum fragment. AB - Indenyl-functionalised BEt(3)-adduct NHCs were prepared by the reaction of imidazolium pro-ligands with LiBEt(3)H. This compound was converted into the indenyl-coordinate molybdenum complex dangling the NHC.BEt(3) moiety as a substituent. The stepwise coordination of NHC afforded a chelate-type mononuclear complex as well as a bimetallic complex. PMID- 21234496 TI - Size-selective sampling of particulates using a physiologic sampling pump. AB - Recent laboratory research indicates physiologic sampling of gas and vapor may provide more representative estimates of personal exposures than traditional methods. Modifications to the physiologic sampling pump (PSP) used in that research are described which extend its usefulness to size-selective sampling of particulates. PSPs used in previous research varied motor speed to keep sampling proportional to the subject's inhalation. This caused airflow and particle velocities through the collection device to continually change making those pumps unsuitable for sampling particulates. The modified implementation of the PSP pulls a constant airflow into and through a cyclone, then uses valves to either direct the airflow through, or divert the airflow around, the sampling filter. By using physiologic inputs to regulate the fraction of each second that air flows through the sampling filter, samples may be collected in proportion to inhalation rate. To evaluate the performance of a functional prototype 5 different sizes of monodisperse aerosols of ammonium fluorescein were generated by a vibrating orifice aerosol generator and introduced into a calm air chamber. To simulate different inhalation rates the valves of the PSP were energized using 9 different duty cycles. Efficiency curves are presented and compared to a standard respirable convention by bias mapping. The performance of the modified cyclone used in the PSP sampling head compared favorably with a commercially available cyclone of the same model, operating at a constant airflow (+/- 10% over almost all the size distributions of concern). The new method makes physiologic sampling of the respirable fraction of particulates feasible. PMID- 21234497 TI - Catalysis by metal-organic frameworks: fundamentals and opportunities. AB - Crystalline porous materials are extremely important for developing catalytic systems with high scientific and industrial impact. Metal-organic frameworks (MOFs) show unique potential that still has to be fully exploited. This perspective summarizes the properties of MOFs with the aim to understand what are possible approaches to catalysis with these materials. We categorize three classes of MOF catalysts: (1) those with active site on the framework, (2) those with encapsulated active species, and (3) those with active sites attached through post-synthetic modification. We identify the tunable porosity, the ability to fine tune the structure of the active site and its environment, the presence of multiple active sites, and the opportunity to synthesize structures in which key-lock bonding of substrates occurs as the characteristics that distinguish MOFs from other materials. We experience a unique opportunity to imagine and design heterogeneous catalysts, which might catalyze reactions previously thought impossible. PMID- 21234498 TI - Operation of micro and molecular machines: a new concept with its origins in interface science. AB - A landmark accomplishment of nanotechnology would be successful fabrication of ultrasmall machines that can work like tweezers, motors, or even computing devices. Now we must consider how operation of micro- and molecular machines might be implemented for a wide range of applications. If these machines function only under limited conditions and/or require specialized apparatus then they are useless for practical applications. Therefore, it is important to carefully consider the access of functionality of the molecular or nanoscale systems by conventional stimuli at the macroscopic level. In this perspective, we will outline the position of micro- and molecular machines in current science and technology. Most of these machines are operated by light irradiation, application of electrical or magnetic fields, chemical reactions, and thermal fluctuations, which cannot always be applied in remote machine operation. We also propose strategies for molecular machine operation using the most conventional of stimuli, that of macroscopic mechanical force, achieved through mechanical operation of molecular machines located at an air-water interface. The crucial roles of the characteristics of an interfacial environment, i.e. connection between macroscopic dimension and nanoscopic function, and contact of media with different dielectric natures, are also described. PMID- 21234499 TI - Adsorptive behavior of CO2, CH4 and their mixtures in carbon nanospace: a molecular simulation study. AB - Using molecular simulation, four types of nanoporous carbons are examined as adsorbents for the separation of CO(2)/CH(4) mixtures at ambient temperature and pressures up to 10 MPa. First, the adsorption selectivity of CO(2) is investigated in carbon slit pores and single-walled carbon nanotube bundles in order to find the optimal pore dimensions for CO(2) separation. Then, the adsorptive properties of the optimized slit pore and nanotube bundle are compared with two realistic nanoporous carbon models: a carbon replica of zeolite Y and an amorphous carbon. For the four carbon models, adsorption isotherms and isosteric heats of adsorption are presented for both pure components and mixtures. Special attention is given to the calculation of excess isotherms and isosteric heats, which are necessary to assess the performance of model nanoporous materials in the context of experimental measurements. From these results, we discuss the impact that variables such as pore size, pore morphology, pressure and mixture composition have on the performance of nanoporous carbons for CO(2) separation. PMID- 21234500 TI - Picosecond X-ray absorption measurements of the ligand substitution dynamics of Fe(CO)5 in ethanol. AB - Ultrafast X-ray absorption near edge spectroscopy has been carried out for photo excited iron pentacarbonyl in ethanol with 2 picosecond resolution. A temporal resolution limited dissociation process was observed, followed by the formation of the mono-substituted complex Fe(CO)(4)EtOH within a few tens of picoseconds. The measurements have been carried out with a newly developed X-ray absorption instrument at station 7 ID-C of the Advanced Photon Source. The results show that single picosecond temporal resolution can be achieved at a synchrotron beam line. PMID- 21234501 TI - Auger recombination dynamics in hybrid silica-coated CdTe nanocrystals. AB - CdTe quantum dots coated with a silica layer containing CdS-like clusters exhibit intense photoluminescence and a spectral red-shift. Biexciton Auger recombination of these particles is examined by transient absorption spectroscopy. A lengthening of the Auger recombination lifetime by a factor of ~3.5 in the presence of the CdS-like clusters is observed and may contribute to the good PL properties of these nanostructures. PMID- 21234502 TI - Magnetic field induced aggregation of nanoparticles for sensitive molecular detection. AB - A molecular detection method utilizing the magnetically induced aggregation of silver nanoparticle (NP)-embedded silica NPs for SERS activation is described. Here, silver embedded magnetic NPs (Ag-M-dots) composed of a magnetic core and silica shells, on whose surface silver NPs were formed, were used. Because the magnetic field induced aggregated Ag-M-dots exhibit a strong SERS signal compared to the dispersed Ag-M-dots, the system allows for the detection of adsorbed Raman label compound even at the 100 fM level. Adenine was tested as a model biocompound and its Raman spectrum could be observed at concentrations as low as 1 pM. The experimental results were supported by the theoretical calculations. PMID- 21234503 TI - Tautomers of cytosine and their excited electronic states: a matrix isolation spectroscopic and quantum chemical study. AB - We have measured the IR and UV spectra of cytosine in a low-temperature argon matrix. An attempt was made to determine the tautomeric ratios existing in the matrix, making use of the matrix-isolation IR spectrum and computed IR intensities of the tautomers in a least squares fitting procedure. The mole fractions are about 0.22 for oxo(-amino) form, 0.26 and 0.44 for the two rotamers, respectively, of the hydroxy(-amino) form and 0.08 for the (oxo-)imino tautomer. These ratios were then used to simulate the matrix-isolation UV spectrum as a composite of the individual spectra, the latter calculated ab initio at high levels of electron correlation theory. The agreement between simulated and experimental UV spectra seems satisfactory. This indicates that, in contrast to the solid state and solution spectra described up to now by the oxo( amino) form alone, the reproduction of the matrix-isolation UV spectrum needs at least the hydroxy(-amino) and oxo(-amino) forms, and probably also the (oxo )imino form. PMID- 21234504 TI - Sol-gel nanocasting synthesis of patterned hierarchical LaFeO3 fibers with enhanced catalytic CO oxidation activity. AB - Hierarchical LaFeO3 fibers were prepared by a sol-gel nanocasting method using a cotton cloth as the template. The resulting LaFeO3 fibers inherited the initial network morphology of the template very well and showed enhanced catalytic CO oxidation activity and satisfactory stability compared to the counterpart particles prepared by the conventional sol-gel method. PMID- 21234505 TI - New integrated elemental and molecular strategies as a diagnostic tool for the quality of water soluble quantum dots and their bioconjugates. AB - Herein, we demonstrate that both qualitative molecular and quantitative elemental data obtained from size exclusion chromatography coupled online for the first time to both molecular fluorescence and elemental mass spectrometry, respectively, turned out to be critical to evaluate the quality of coatings of quantum dots. Moreover, such an instrumental approach also allowed us to study quantitatively the appropriated bioconjugation of quantum dots to antibodies, a critical step for QDs future use in quantitative fluorescence immunoassays. PMID- 21234506 TI - Breast on-a-chip: mimicry of the channeling system of the breast for development of theranostics. AB - Improved detection and therapy of breast neoplasia might benefit from nanodevices traveling inside mammary ducts. However, the decreasing size of branched mammary ducts prevents access to remote areas of the ductal system using a pressure driven fluid-based approach. Magnetic field guidance of superparamagnetic submicron particles (SMPs) in a stationary fluid might provide a possible alternative but it is critical to first reproduce the breast ductal system to assess the use of such devices for future therapeutic & diagnostic ("theranostic") purposes. Here we describe the engineering of a portion of a breast ductal system using polydimethylsiloxane (PDMS) microfluidic channels with a total volume of 0.09 MUl. A magnet was used to move superparamagnetic/fluorescent SMPs through a static fluid inside the microchannels. Non-neoplastic mammary epithelial S1 cells developed basoapical polarity as a flat monolayer on the PDMS surface when cultured in the presence of laminin 111, and incubation with SMPs did not result in detectable toxicity. Cells could not withstand the fluid pressure if microinjected directly in completed channels. Whereas, they readily covered laminin 111-coated PDMS surfaces when cultured in U-shaped "hemichannels" before completing the channels. This breast-on-chip model represents a critical step towards the mimicry of the tree-like ductal system of the breast for further testing and targeting of SMPs. PMID- 21234507 TI - Effects of glucocorticoids on growth and bone mineralization. AB - OBJECTIVE: To review the various mechanisms of glucocorticoid action and the ability of these agents to induce osteoporosis and growth deficits. SOURCES: A review of the scientific literature was conducted on the basis of a MEDLINE search using the keywords and descriptors "glucocorticoids," "bone mineralization," "growth," and "side effects" and limited to articles published in the last decade. The references cited by these articles were used to identify relevant older publications, with an emphasis on landmark studies essential to an understanding of the topic. SUMMARY OF THE FINDINGS: Emphasis was placed on the actions of glucocorticoids on the hormones and cytokines that modulate linear growth. The end effects of glucocorticoids on the skeletal system are the result of systemic effects on bone metabolism and of direct actions on bone cells, which alter bone cell counts and predispose to bone loss. The mechanisms underlying catch-up growth and bone mass recovery after discontinuation of glucocorticoid treatment are discussed, followed by a review of diagnostic methods available for assessment of bone metabolism and mineralization and of measures for prevention and management of glucocorticoid-induced bone changes. CONCLUSION: Patient monitoring on a case-by-case basis plays an essential role in detection and, potentially, reversal of the damage associated with chronic glucocorticoid therapy. PMID- 21234508 TI - Low prevalence of middle ear disease in cystic fibrosis patients. AB - OBJECTIVE: To assess the prevalence of middle ear alterations in cystic fibrosis (CF) patients. METHODS: In this descriptive study, 120 CF patients aged 5 months to 18 years were assessed by clinical history, otoscopy, and tympanometry. Data on P. aeruginosa colonization and parenteral and/or inhaled aminoglycoside use were also collected from medical charts. RESULTS: Clinical history revealed absence of previous otitis media in 57% of patients. Tympanic membranes were normal in 94% of patients who underwent otoscopic evaluation; chronic otitis media was suggested in about 1% of the cases, otitis media with effusion (OME) in 2%, and Eustachian tube dysfunction in 3%. As for tympanometry, 91% of patients who underwent the exam showed normal results, OME was suggested in 2% of the cases, and Eustachian tube dysfunction in 7%. CONCLUSION: There was a low prevalence rate of middle ear alterations in our series of CF patients. The use of aminoglycosides and colonization by P. aeruginosa did not influence the prevalence of middle ear alterations. Our results suggest that a detailed clinical history and a routine otoscopy evaluation may confirm or rule out most middle ear alterations in CF patients. PMID- 21234510 TI - Validation of the comprehensive ICF Core Sets for patients receiving rehabilitation interventions in the acute care setting. AB - OBJECTIVE: To examine the relevance and completeness of the comprehensive International Classification of Functioning, Disability and Health (ICF) Core Sets for patients with rehabilitation needs in acute hospital care. DESIGN: Multi centre cohort study. PATIENTS: A total of 391 patients (50.1% female, mean age 63.4 years) from 4 university hospitals in Austria, Germany and Switzerland and one Austrian general hospital. METHODS: Data on functioning were collected using the respective comprehensive acute ICF Core Sets. Data were extracted from patients' medical record sheets and interviews with health professionals and patients. RESULTS: Most of the categories of the comprehensive ICF Core Sets describing impairments, limitations or restrictions occurred in a considerable proportion of the study population. The most outstanding limitations and restrictions of the patients were problems with sleep and blood vessel functions, walking and moving and self-care. Thirty-eight aspects of functioning not previously covered by the comprehensive ICF Core Sets were ranked as relevant. CONCLUSION: Categories of the comprehensive ICF Core Sets for the acute hospital situation were confirmed. Some additional categories not covered by the Set in its present version emerged from the interviews, and should be considered for inclusion in a finalized version. PMID- 21234511 TI - Validation of the comprehensive ICF Core Sets for patients in early post-acute rehabilitation facilities. AB - OBJECTIVES: To examine the relevance and completeness of the comprehensive International Classification of Functioning, Disability and Health (ICF) Core Sets for patients in post-acute rehabilitation facilities. DESIGN: Multi-centre cohort study. PATIENTS: A total of 165 patients (46% female; mean age 67.5 years) from post-acute rehabilitation facilities in 2 Austrian and 7 German hospitals. METHODS: Data on functioning were collected using the respective comprehensive post-acute ICF Core Sets. Data was extracted from patients' medical record sheets and interviews with health professionals and patients. RESULTS: Most of the categories of the comprehensive ICF Core Sets describing impairments, limitations or restrictions occurred in a considerable proportion of the study population. The most outstanding limitations and restrictions of the patients were problems with sleep and blood vessel functions, walking and moving and self-care. Twenty six aspects of functioning not previously covered by the comprehensive ICF Core Sets were ranked as relevant. CONCLUSION: Most categories of the comprehensive ICF Core Set for patients in post-acute rehabilitation facilities were confirmed. No significant gaps in the established set could be identified. PMID- 21234512 TI - Brief ICF Core Sets for the acute hospital. AB - OBJECTIVE: To identify candidate categories for brief International Classification of Functioning, Disability and Health (ICF) Core Sets for the reporting and measurement of functioning in patients in the acute hospital. DESIGN: Prospective multi-centre cohort study. PATIENTS: Patients receiving rehabilitation interventions for musculoskeletal, neurological or cardiopulmonary injury or disease in acute hospitals. METHODS: Functioning and contextual factors were coded using the ICF. The criterion for selecting candidate categories for the brief ICF Core Sets was based on their ability to discriminate between patients with high or low functioning status. Discrimination was assessed using multivariable regression models, the independent variables being all of the ICF categories of the respective comprehensive ICF Core Set. Analogue ratings of overall functioning as reported by patients and health professionals were used as dependent variables. RESULTS: A total of 391 patients were included in the study (91 neurological, 109 cardiopulmonary, 191 musculoskeletal), mean age 63.4 years, 50.1% female. Selection yielded 33 cate-gories for neurological, 31 for cardiopulmonary, and 30 for musculoskeletal. CONCLUSION: The present selection of categories can be considered an initial proposal, serving to identify the ICF cate-gories most relevant for the practical assessment and monitoring of functioning in patients with acute neurological, cardiopulmonary, and musculoskeletal conditions. PMID- 21234513 TI - ICF Core Sets for early post-acute rehabilitation facilities. AB - OBJECTIVE: To identify candidate categories for International Classification of Functioning, Disability and Health (ICF) Core Sets for the reporting and measurement of functioning in patients in early post-acute rehabilitation facilities. DESIGN: Prospective multi-centre cohort study. PATIENTS: Patients receiving rehabilitation interventions for musculoskeletal, neurological or cardiopulmonary injury or disease in early post-acute rehabilitation facilities. METHODS: Functioning was coded using the ICF. The criterion for selecting candidate categories for the ICF Core Sets was based on their ability to discriminate between patients with high or low functioning status. Discrimination was assessed using multivariable regression models, the independent variables being all of the ICF categories of the respective comprehensive ICF Core Set. Analogue ratings of overall functioning as reported by patients and health professionals were used as dependent variables. RESULTS: A total of 165 patients were included in the study (67 neurological, 37 cardiopulmonary, 61 musculoskeletal), mean age 67.5 years, 46.1% female. Selection yielded 38 cate gories for neurological, 32 for cardiopulmonary, and 31 for musculoskeletal. CONCLUSION: The present selection of categories can be considered an initial proposal, serving to identify the issues most relevant for the assessment and monitoring of functioning in patients undergoing early post-acute rehabilitation for neurological, cardiopulmonary, and musculoskeletal conditions. PMID- 21234514 TI - Goals of patients with rehabilitation needs in acute hospitals: goal achivement is an indicator for improved functioning. AB - OBJECTIVE: To identify goals of patients with rehabilitation needs in the acute hospital setting using the International Classification of Functioning, Disability and Health (ICF), to examine association of goal achievement with improvement in overall functioning, and to examine whether ICF Core Sets for the acute hospital cover patients goals. DESIGN: Multi-centre cohort study. PATIENTS: A total of 397 patients (50% female, mean age 63 years) from 5 hospitals in Austria, Switzerland and Germany. METHODS: A semi-structured questionnaire was used to assess patient goals and goal achievement. Overall functioning from the patients' and health professionals' perspective was assessed on a numerical rating scale. Improvement in functioning was calculated using a residualized gain score. Association between goal achievement and improvement in overall functioning was assessed with logistic regression. RESULTS: A total of 397 patients reported achievement of at least 1 goal. Eighty-eight percent of the goals were translated into categories of the ICF. Logistic regression analyses revealed significant association between goal achievement and overall functioning. CONCLUSION: The ICF might be useful to identify and structure patient's goals in acute hospital care. The association between goal achievement and improved functioning underlines that it is essential to involve the patient in the process of planning rehabilitation interventions in acute hospitals. PMID- 21234515 TI - The ICF forms a useful framework for classifying individual patient goals in post acute rehabilitation. AB - OBJECTIVE: Timely goal setting in close collaboration with the patient is essential to successful rehabilitation. We therefore sought to identify goals of patients in early post-acute rehabilitation as predictors of improved functioning. DESIGN: We conducted a prospective multi-centre cohort study in 5 early post-acute rehabilitation facilities. PATIENTS: Patients with musculoskeletal, cardiopulmonary and neurological conditions were recruited between May 2005 and August 2008. METHODS: A semi-structured questionnaire was used to identify patient goals and to assess improvement in overall functioning. Patients' goals were coded according to the International Classification of Functioning, Disability and Health (ICF). By means of a mixed effects model we examined the association between goal attainment and improved functioning. RESULTS: A total of 116 patients gave 546 statements, of which 426 were linked to 74 ICF categories, which were assigned to the existing comprehensive post-acute ICF Core Sets. Improvements in walking, recreation and leisure, pain, and transfer were the most frequently reported goals. In multivariable analysis patients' goal attainment was not a predictor for improved overall functioning. CONCLUSION: The ICF can be used to identify and structure patients' goals. Patients' perspective should be considered in the rehabilitation process. PMID- 21234516 TI - Patient goals in post-acute geriatric rehabilitation--goal attainment is an indicator for improved functioning. AB - OBJECTIVE: To identify goals of older patients in geriatric rehabilitation and to measure their improvement in overall functioning. DESIGN: A prospective multi centre cohort study. METHODS: A semi-structured questionnaire was used to identify patient goals and to assess improvement in overall functioning from patients' and health professionals' perspectives. Patients' goals were linked to the International Classification of Functioning, Disability and Health (ICF). Using a residualized change score, we identified patients who improved more than statistically expected. RESULTS: A total of 209 patients gave 476 statements. Of these, 346 (72.7%) statements were linked to 58 different ICF categories. More than 90% of the ICF categories were part of the comprehensive geriatric ICF Core Set. "Walking", "getting rid of pain", "autonomy" and "returning home" were the most frequently reported goals. Multivariable analysis identified shorter length of inpatient stay and goal attainment to be significant predictors for an improvement in overall functioning from the patients' perspective. CONCLUSION: The ICF can be used to identify and structure patients' goals in geriatric rehabilitation. The association between goal attainment and improved overall functioning underlines the necessity of considering the patients' perspective in the rehabilitation process. PMID- 21234517 TI - Assessment of functioning in the acute hospital: operationalisation and reliability testing of ICF categories relevant for physical therapists interventions. AB - OBJECTIVE: To operationalize items based on categories of the International Classification of Functioning, Disability and Health (ICF) relevant to patient problems that are addressed by physiotherapeutic interventions in the acute hospital, and to test the reliability of these items when applied by physiotherapists. METHODS: A selection of 124 ICF categories was operation-alized in a formal decision-making and consensus process. The reliability of the newly operationalized item list was tested with a cross-sectional study with repeated measurements. RESULTS: The item writing process resulted in 94 dichotomous and 30 polytomous items. Data were collected in a convenience sample of 28 patients with neurological, musculoske-letal, cardiopulmonary, or internal organ conditions, requiring physical therapy in an acute hospital. Fifty-six percent of the polytomous and 68% of the dichotomous items had a raw agreement of 0.7 or above, whereas 36% of all polytomous and 34% of all dichotomous items had a kappa coefficient of 0.7 and above. CONCLUSION: The study supports that the ICF is adaptable to professional and setting-specific needs of physiotherapists. Further research towards the development of reliable instruments for physiotherapists based on the ICF seems justified. : PMID- 21234518 TI - The ICF as a way to specify goals and to assess the outcome of physiotherapeutic interventions in the acute hospital. AB - OBJECTIVE: The aim of this study was to demonstrate the use of the International Classification of Functioning, Disability and Health (ICF) to measure the effect of physiotherapy treatment. DESIGN: A prospective cohort study with an additional case report. PATIENTS: Individuals were eligible for the study if they were patients at the University Hospital of Zurich and had received physiotherapeutic interventions during their inpatient stay. METHODS: Patient's functioning was assessed by physiotherapists at initiation of physiotherapeutic treatment and at discharge using ICF Core Sets. RESULTS: A total of 425 patients were analysed, mean age 60 years, 42% female. The median of treatment days varied between 4 (intensive care unit) and 19 (low back pain). The majority of patients had improved or stable results; improvement was most prominent in the surgical and internal medicine group. The ICF category d450 "Walking" appears in 4 out of 6 ICF Core Sets, being only infrequently treated in intensive care unit and low back pain CONCLUSION: Analysis showed that the ICF can be used to record precise information on patients' functioning in the acute hospital. Typical impairments and restrictions, intervention goals and trajectories of functioning could be documented. The qualifiers used in our clinical example were sensitive to change. Definitions of qualifiers, however, should be the subject of further research. PMID- 21234519 TI - microRNA-155 regulates angiotensin II type 1 receptor expression in umbilical vein endothelial cells from severely pre-eclamptic pregnant women. AB - Angiotensin II is critical in pre-eclampsia pathogenesis. In addition, microRNA 155 regulates angiotensin II type 1 receptor expression. We have explored the function of microRNA-155 in pre-eclamptic pregnant women. Human umbilical vein endothelial cells were isolated and cultured from healthy puerperant women and pre-eclampsia patients. The cells were transfected with a mature microRNA-155 plasmid. The effect of microRNA-155 was assessed by Northern blotting, in situ hybridization, quantitative real-time PCR, immunofluorescent staining and Western blotting. In addition, activation of extracellular signal-regulated kinase 1/2 was assessed by co-immunoprecipitation and Western blotting. Severely pre eclamptic pregnant women expressed less mature miR-155 compared to healthy pregnant women. In addition, angiotensin II type 1 receptor expression decreased substantially in healthy cells and miR-155-transfected cells compared to miR-155 mutant-transfected cells and cells from pre-eclamptic patients. Mature miR-155 reduced angiotensin II-induced extracellular signal-regulated kinase 1/2 activation. In conclusion, endogenous mature miR-155 expression may be an important contributor to the pathogenesis of severe pre-eclampsia. PMID- 21234520 TI - High-level expression of podoplanin in benign and malignant soft tissue tumors: immunohistochemical and quantitative real-time RT-PCR analysis. AB - Podoplanin is a 38 kDa mucin-type transmembrane glycoprotein that was first identified in rat glomerular epithelial cells (podocytes). It is expressed in normal lymphatic endothelium, but is absent from vascular endothelial cells. D2 40 is a commercially available mouse monoclonal antibody which binds to an epitope on human podoplanin. D2-40 immunoreactivity is therefore highly sensitive and specific for lymphatic endothelium. Recent investigations have shown widespread applications of immunohistochemical staining with D2-40 in evaluating podoplanin expression as an immunohistochemical marker for diagnosis and prognosis in various tumors. To determine whether the podoplanin (D2-40) antibody may be useful for the diagnosis of soft tissue tumors, 125 cases, including 4 kinds of benign tumors, 15 kinds of malignant tumors and 3 kinds of tumor-like lesions were immunostained using the D2-40 antibody. Total RNA was extracted from frozen tumor tissue obtained from 41 corresponding soft tissue tumor patients and 12 kinds of soft tissue tumor cell lines. Quantitative real-time PCR reactions were performed. Immunohistochemical and quantitative real-time RT-PCR analyses demonstrated the expression of the podoplanin protein and mRNA in the majority of benign and malignant soft tissue tumors and tumor-like lesions examined, with the exception of alveolar soft part sarcoma, embryonal and alveolar rhabdomyosarcoma, extraskeletal Ewing's sarcoma/peripheral primitive neuro-ectodermal tumor and lipoma, which were completely negative for podoplanin. Since it is widely and highly expressed in nearly all kinds of soft tissue tumors, especially in spindle cell sarcoma, myxoid type soft tissue tumors and soft tissue tumors of the nervous system, podoplanin is considered to have little value in the differential diagnosis of soft tissue tumors. PMID- 21234521 TI - Differential gene expression during colon-to-lung metastasis. AB - Primary tumors in certain metastatic cases have potential dissemination mechanisms. However, they often lack the potential to colonize distant microenvironments, and consequently the disseminated cancer cells enter into a state of latency which can last for years. In order to investigate the metastatic colonization potential at the gene expression level, we compared such primary tumors with their matching, actively proliferating metastatic tumors. Six pairs of colon-to-lung metachronous tumor samples were examined for the expression levels of 84 well-known metastatic genes using the quantitative RT-PCR-based PCR Array technology. The unsupervised hierarchical clustering of all 12 samples together, resulted in the formation of one closely related cluster by the primary tumors, but highly diversified ones by the metastatic tumors. A pair-wise comparison of the matching primary-metastatic tumors showed that different groups of genes were activated in the lung metastases. Therefore we charted specific genes involved in the genetic diversification processes. A number of these genes showed similar differential expression (DeltaCt) patterns in all the patients. These were the cancer cell-, the microenvironment- and the stem cell-specific gene groups. In conclusion, the results suggest that the primary colorectal cancer cells are diversified as regards colonization of the lung, which could explain why the effective therapies for primary colorectal cancers are often not appropriate for controling the growth of pulmonary metastases. PMID- 21234522 TI - Feasibility study of high-temperature thermoseed inductive hyperthermia in melanoma treatment. AB - Current treatment modalities for melanoma do not offer satisfactory efficacy. We have developed a new, minimally invasive hyperthermia technology based on radio frequency hyperthermia. Herein, we investigated the feasibility of using a nickel copper thermoseed for inductive hyperthermia at a relatively high temperature (46 55 C). In vitro, the thermoseed showed good thermal effects and effective killing of B16/F10 melanoma cells. Temperatures of 53.1 +/- 0.5 C were achieved for a single thermoseed and 56.5 +/- 0.5 C for two in parallel (spacing 5 mm). No B16/F10 melanoma cells survived with heating time longer than 20 min in the parallel thermoseed group. Magnetic fields or thermoseeds alone did not affect the survival rate of B16/F10 cells (P>0.05). In vivo, B16/F10 melanoma cells were subcutaneously injected into the right axilla of C57BL/6 mice. After the tumors grew to ~11-13 mm, two thermoseeds (spacing 5 mm) were implanted into the tumors and the mice were subjected to an alternating magnetic field (100-250 kHz, 15 kA/m) to induce hyperthermia. The temperature at the center of the tumor reached 46 C at 5 min and plateaued at 50 C. Thermoseed treatment produced large necrotic areas, inhibited tumor growth in 60% (6 of 10) of animals and prolonged survival time (P<0.05). Thus, with further optimization and testing, high-temperature thermoseed inductive hyperthermia may have therapeutic potential for melanoma. PMID- 21234523 TI - Suppressor of cytokine signaling 1 interacts with oncogenic lymphocyte-specific protein tyrosine kinase. AB - Lymphocyte-specific protein tyrosine kinase (Lck) plays a key role in T cell signal transduction and is tightly regulated by phosphorylation and dephosphorylation. Lck can function as an oncoprotein when overexpressed or constantly activated by mutations. Our previous studies showed that Lck-induced cellular transformation could be suppressed by enforced expression of suppressor of cytokine signaling 1 (SOCS1), a SOCS family member involved in the negative feedback control of cytokine signaling. We observed attenuated Lck kinase activity in SOCS1-expressing cells, suggesting an important role of SOCS in regulating Lck functions. It remains largely unknown whether and how SOCS proteins interact with the oncogenic Lck kinase. Here, we report that among four SOCS family proteins, SOCS1, SOCS2, SOCS3 and CIS (cytokine-inducible SH2 domain containing protein), SOCS1 has the highest affinity in binding to the oncogenic Lck kinase. We identified the positive regulatory phosphotyrosine 394 residue in the kinase domain as the key interacting determinant in Lck. Additionally, the Lck kinase domain alone is sufficient to bind SOCS1. While the SH2 domain in SOCS1 is important in its association with the oncogenic Lck kinase, other functional domains may also contribute to overall binding affinity. These findings provide important mechanistic insights into the role of SOCS proteins as tumor suppressors in cells transformed by oncogenic protein tyrosine kinases. PMID- 21234524 TI - The microtubule inhibiting agent epothilone B antagonizes glioma cell motility associated with reorganization of the actin-binding protein alpha-actinin 4. AB - Invasion of normal brain tissue by brain tumor cells is a major contributing factor to the recurrence and resistance of clinically diagnosed glioblastomas to therapy (surgery, chemotherapy, radiation). Here, we have assessed the efficacy of the microtubule inhibiting agent epothilone B on glioblastoma cell motility, a prerequisite cellular program of invasive glioblastomas. Using cell migration assays and immunofluorescence techniques we demonstrated that epothilone B abrogated glioblastoma cell motility as a consequence of alpha-actinin 4 redistristrubiton and the breakdown of cellular structures (leading edge, stress fibers) it is associated with during cell migration. Evaluation of the microtubule actin cross linking factor in glioblastoma cells also revealed epothilone B invoked changes in this cytoskeleton cross linking protein, resembling alpha-actinin 4 changes in response to epothilone B. We have demonstrated in this study that epothilone B antagonizes glioblastoma cell motility due to the disruption of cytoskeleton binding proteins that aide in preserving the structural organization of the cytoskeleton filamentous network. Furthermore, we provide preclincial evidence that epothilone B effects on glioblastomas are not limited to the impairment of dividing tumors cells but that it also targets migratory and invasive glioblastoma cells, suggesting that this agent has potential clinical benefit due to its ability to target divergent cellular programs in the glioblastoma tumor mass. PMID- 21234525 TI - Patient- and treatment-related risk factors for nausea and emesis during concurrent chemoradiotherapy. AB - PURPOSE: To evaluate the prevalence of acute nausea and emesis during concurrent chemoradiotherapy (CRT) with emphasis on the influence of patient- and treatment related risk factors and prophylactic antiemetic medication. PATIENTS AND METHODS: A total of 335 patients treated with different intravenous standard chemoradiotherapy protocols in the inpatient setting were included in this retrospective study. Acute nausea and emesis, scored according to the CTC (version 3.0) criteria, were evaluated during 821 chemotherapy cycles. Side effects were correlated with patient-, tumor-, and treatment-related parameters. RESULTS: Overall, at least one episode of acute nausea occurred in 48% of the patients and at least one episode of vomiting occurred in 25% of patients. The emetogenic level of the applied chemotherapy protocol was the most significant risk factor for developing nausea and emesis (p < 0.0001). The site of irradiation - namely the thorax (p = 0.0110) and head and neck (p = 0.0415) - was also confirmed as a risk factor. Patient-related parameters, e.g., female gender (p = 0.0003), young age (< 40 years; p = 0.0029), weight loss > 5% (p = 0.0004), and the presence of a percutaneous endoscopic gastrostomy (PEG; p = 0.0071), were associated with higher rates of nausea and emesis, while a history of alcohol abuse showed a protective effect (p = 0.0553). In high emetogenic chemotherapy protocols, prophylaxis with 5-HT3 antagonist plus dexamethasone was superior to 5 HT3 antagonist alone (p = 0.0383). CONCLUSION: Future studies should evaluate more effective prophylaxis protocols in CRT in order to reduce the high rates of nausea and emesis. PMID- 21234526 TI - Feasibility, toxicity, and efficacy of short induction chemotherapy of docetaxel plus cisplatin or carboplatin (TP) followed by concurrent chemoradio-therapy for organ preservation in advanced cancer of the hypopharynx, larynx, and base of tongue. Early results. AB - PURPOSE: Concurrent chemoradiotherapy (CRT) is standard treatment for advanced head and neck cancer. Whether short induction chemotherapy (ICT) provides additional benefit or, in particular, predictive benefit for the response to chemoradiotherapy is an open question. The present study aimed to assess the feasibility, toxicity, and efficacy of induction with docetaxel and platinum salt (TP) and subsequent CRT. PATIENTS AND METHODS: A total of 25 patients with functionally inoperable cancer of the base of the tongue, hypopharynx, or larynx received 1 cycle of docetaxel (75 mg/m2, day 1) combined with either cisplatin (30 mg/m2, days 1-3; n = 23) or carboplatin (AUC 1.5 days 1-3; n = 2). Responders (n = 22, >30% tumor reduction, graded by endoscopy) and 1 non-responder received CRT (target dose: 69-72 Gy) with cisplatin/paclitaxel, carboplatin/paclitaxel, or cisplatin/docetaxel. RESULTS: All patients completed ICT with acceptable toxicity (leukocytopenia grade 4: 8%). The remission rate of the primary tumor was 88% (22/25 patients). There was no need to delay CRT due to toxicity in any case. Each patient received the full radiation dose. Of the patients, 56% received >80% of the chemotherapy. The acute toxicity of CRT was moderate, no grade 4 toxicities occurred, while grade 3 toxicities included the following: infection (39%), dermatitis (13%), leukocytopenia (30%), and thrombocytopenia (4%). The local control rate was 84.6% +/- 8.5% and the survival rate was 89.6% +/- 7.2% at 12 months. Organ preservation was possible in 22/23 (95%) cases. CONCLUSION: Short induction with a TP regimen and subsequent CRT with a taxan is feasible and associated with an encouraging local control rate. PMID- 21234527 TI - Comparison of stereotactic brachytherapy (125 iodine seeds) with stereotactic radiosurgery (LINAC) for the treatment of singular cerebral metastases. AB - PURPOSE: To compare stereotactic brachytherapy (SBT) with stereotactic radiosurgery (SRS) for treating singular cerebral metastases, regarding feasibility, complications, cerebral disease control, and survival. PATIENTS AND METHODS: For this retrospective, single-center study, all patients treated for newly diagnosed, untreated singular cerebral metastasis with SBT using (125)iodine seeds (cumulative tumor surface dose 50 Gy, applied for 42 days) were compared with patients receiving LINAC-based SRS for the same indication. Survival and actuarial local and distant disease control were evaluated using univariate Kaplan-Meier estimates and Cox regression. Results were compared using Student's t test and the chi2 test. RESULTS: A total of 142 patients treated with SRS were compared with 77 patients undergoing SBT. No significant differences were observed between epidemiological and disease-related features (p > 0.05), except a lower KPS (p < 0.007) and a larger tumor volume (p < 0.001) in the SBT group. Neither median survival (LINAC-SRS vs. SBT = 8.1 vs. 8.0 months, respectively) nor actuarial local/distant cerebral disease control after 12 months showed significant differences (93.6% vs. 96.7% / 42.4% vs. 46.4%). There was no treatment-related mortality and no permanent grade 3 or 4 CNS toxicity (RTOG/EORTC CNS toxicity criteria). CONCLUSION: For the treatment of singular cerebral metastasis, SBT represents a safe, minimally invasive, and effective local treatment option with results comparable to SRS regarding survival and cerebral disease control. Its advantage is that it allows histological (re )evaluation and treatment within one stereotactic procedure and, compared to microneurosurgery, is almost unrestricted regarding tumor localization. Furthermore, larger metastases can be treated than with SRS. SBT, therefore, represents an alternative local treatment in selected cases. PMID- 21234529 TI - IMRT reirradiation with concurrent cetuximab immunotherapy in recurrent head and neck cancer. AB - PURPOSE: In this retrospective investigation, the outcome and toxicity after reirradiation with concurrent cetuximab immunotherapy of recurrent head and neck cancer (HNC) in patients who had contraindications to platinum-based chemotherapy were analyzed. MATERIALS AND METHODS: Ten patients with locally advanced recurrent HNC were retrospectively evaluated. In 9 cases, histology was squamous cell carcinoma, in one case adenoid cystic carcinoma. External beam radiotherapy was part of the initial treatment in all cases. Reirradiation was carried out using step-and-shoot intensity-modulated radiotherapy (IMRT) with a median dose of 50.4 Gy. Cetuximab was applied as loading dose (400 mg/m(2)) 1 week prior to reirradiation and then weekly concurrently with radiotherapy (250 mg/m(2)). RESULTS: The median overall survival time after initiation of reirradiation was 7 months; the 1-year overall survival (OS) rate was 40%. Local failure was found in 3 patients, resulting in a 1-year local control (LC) rate of 61%. The 1-year locoregional control (LRC) rate was 44%, while the 1-year distant metastasis-free survival (DMFS) was 75%. Acute hematological toxicity was not observed in the group. Severe acute toxicity included one fatal infield arterial bleeding and one flap necrosis. Severe late toxicities were noted in 2 patients: fibrosis of the temporomandibular joint in 1 patient and stenosis of the cervical esophagus in another. CONCLUSIONS: IMRT reirradiation with concurrent cetuximab immunotherapy in recurrent HNC is feasible with acceptable acute toxicity. Further investigations are necessary to determine the clinical role of this therapy concept. PMID- 21234528 TI - Comparison of the micronucleus and chromosome aberration techniques for the documentation of cytogenetic damage in radiochemotherapy-treated patients with rectal cancer. AB - PURPOSE: The goal of the interdisciplinary Clinical Research Unit KFO179 (Biological Basis of Individual Tumor Response in Patients with Rectal Cancer) is to develop an individual Response and Toxicity Score for patients with locally advanced rectal cancer treated with neoadjuvant radiochemotherapy. The aim of the present study was to find a reliable and sensitive method with easy scoring criteria and high numbers of cell counts in a short period of time in order to analyze DNA damage in peripheral blood lymphocytes. Thus, the cytokinesis-block micronucleus (CBMN) assay and the chromosome aberration technique (CAT) were tested. MATERIALS AND METHODS: Peripheral blood lymphocytes obtained from 22 patients with rectal cancer before (0 Gy), during (21.6 Gy), and after (50.4 Gy) radiochemotherapy were stimulated in vitro by phytohemagglutinin (PHA); the cultures were then processed for the CBMN assay and the CAT to compare the two methods. RESULTS: A significant increase of chromosomal damage was observed in the course of radiochemotherapy parallel to increasing radiation doses, but independent of the chemotherapy applied. The equivalence of both methods was shown by Westlake's equivalence test. CONCLUSION: The results show that the CBMN assay and the CAT are equivalent. For further investigations, we prefer the CBMN assay, because it is simpler through easy scoring criteria, allows high numbers of cell counts in less time, is reliable, sensitive, and has higher statistical power. In the future, we plan to integrate cytogenetic damage during radiochemotherapy into the planned Response and Toxicity Score within our interdisciplinary Clinical Research Unit. PMID- 21234530 TI - Outcome after re-irradiation of head and neck cancer patients. AB - PURPOSE: To retrospectively report the outcome of head and neck cancer patients following re-irradiation. PATIENTS AND METHODS: A total of 51 patients with recurrent or second primary head and neck cancer received re-irradiation at Leuven University Hospital. Survival and locoregional control were calculated. Doses to organs at risk were retrieved from dose-volume histograms. Radiation related toxicities were reported. RESULTS: The 2-year actuarial overall survival rate was 30%. On univariate analysis, surgery before re-irradiation and high radiation dose were associated with superior survival. Grade 3 acute and grade 3 or more late toxicity occurred in respectively 29.4% and 35.3% of the patients. CONCLUSION: Re-irradiation in head and neck cancer patients is feasible with acceptable late toxicity, although the survival remains poor. PMID- 21234531 TI - Celecoxib enhances radiation response of secondary bone tumors of a human non small cell lung cancer via antiangiogenesis in vivo. AB - PURPOSE: Cyclooxygenase-2 (COX-2) inhibitors mediate a systemic antitumor activity via antiangiogenesis and seem to enhance the response of primary tumors to radiation. Radiosensitizing effects of COX-2 inhibition have not been reported for bone metastases. Therefore, the aim of this study was the investigation of the radiosensitizing effects of the selective COX-2 inhibitor celecoxib in secondary bone tumors of a non-small cell lung carcinoma in vivo. MATERIALS AND METHODS: Human A549 lung carcinomas were implanted into a cranial window preparation in male SCID mice (n = 24). Animals were treated with either celecoxib or radiation (7 Gy single photon dose) alone or a combination of celecoxib and radiation, respectively. Untreated animals served as controls. The impact of radiation and COX-2 inhibition on angiogenesis, microcirculation, and tumor growth was analyzed over 28 days by means of intravital microscopy and histological methods. RESULTS: Monotherapies with radiation as well as celecoxib had significant antitumor effects compared to untreated controls. Both therapies reduced tumor growth and vascularization to a similar extent. The simultaneous administration of celecoxib and radiation further enhanced the antitumor and antiangiogenic effects of single-beam radiation. With the combined treatment approach, tumor vascularization and tumor size were decreased by 57% and 51%, respectively, as compared to monotherapy with radiation. CONCLUSION: The combined application of radiation therapy and COX-2 inhibition showed synergistic effects concerning the inhibition of tumor growth and tumor angiogenesis. Therefore, the combination of radiation with COX-2 inhibitor therapy represents a promising approach to improve the therapeutic efficacy of radiotherapy of bone metastases. PMID- 21234532 TI - [Interventional bronchoscopy in lung cancer]. AB - Stenosis of central airways or hemoptysis are classical indications for interventional bronchoscopy in lung cancer. In the case of endoluminal tumor growth cryo-, laser- or brachytherapy are widely used. In the case of airway stenosis due to compression by extraluminal tumor masses balloon-dilatation and/or stenting and - with delayed effect - brachytherapy are first-choice therapies. Carcinoma in situ and early stage tumors can be treated curatively with brachytherapy or photodynamic therapy. Recently introduced bronchoscopic techniques like electro-magnetic navigation may result in new curative options for peripheral lung tumors. PMID- 21234534 TI - Three job-related stress models and depression: a population-based study. AB - OBJECTIVES: To estimate the current prevalence of major depression in a sample of working population, and to examine the associations between job strain, effort reward imbalance and family-work conflicts and major depression. METHODS: A sample of employees who were between the ages of 25 and 65 years and who were working in Alberta at the time of survey was recruited using the method of random digit dialing (n = 4,302). Data about job stress, effort-reward imbalance and work-family conflicts and depression were collected via telephone. Depression was assessed by the Patient Health Questionnaire (PHQ-9) for depression. RESULTS: The 2-week prevalence of major depression based on the DSM algorithm was 3.2%. The prevalence of severe depression was 0.8%. Job strain, effort-reward imbalance and work-family conflicts were strongly associated with continuous depression score. Effort-reward imbalance was significantly associated with depression scores in women, but not in men. Effort-reward imbalance was significantly associated with depression scores in participants with job strain ratio >1, but not in those with a lower job strain ratio. The association between work to family conflict and depression score was stronger in participants with a job strain ratio greater than one than in those whose job strain ratio was one or less. CONCLUSIONS: The three job-related stress models are widely used in occupational health research. They are equally important in predicting depression and interact with each other. Improving work environment based on these models holds potentials to reduce the synergetic effects, therefore, improving employees' mental health. PMID- 21234535 TI - Health risk associated to dietary intake of mercury in selected coastal areas of Mexico. AB - A hazard quotient (HQ) was evaluated for Mexican population considering Hg levels and consumption rates. Fish and shrimp were caught in selected coastal areas. HQ's ranged from 0.004 to 0.01 in shrimp; from 0.004 to 1.04 in fish from NW Mexico; and from 0.02 to 0.19 in fish from the Gulf of Mexico. Highest HQ in fish were found in carnivorous fish Caranx caninus (HQ = 0.71) and Sphyrna lewini (HQ = 1.04) from NW Mexico. A more accurate study should be made considering organic Hg, contribution of Hg from other sources, and consumption rates according to age, sex and economic status. PMID- 21234536 TI - Fate of fipronil in cotton and soil under tropical climatic conditions. AB - Field study was carried out to investigate fate of fipronil (Regent 0.3G) in cotton and soil applied at the time of sowing of cotton crop (Variety: H-1117)@56 (T1) and 112 g a.i.ha-1 (T2) during kharif season (summer season, from April to November) 2006-07. The residues of fipronil in both the doses dissipated almost completely with in 90 days. Kinetic studies revealed that dissipation of fipronil followed first order kinetics with half-life period of 23.35 days in single dose and 24.31 days in double dose. At the time of harvest, residues in soil, cotton lint and seed were below the quantifiable limit of 0.01 mg kg-1. PMID- 21234537 TI - Intra-articular variations of the long head of the biceps tendon. AB - PURPOSE: The long head of the biceps tendon (LHBT) generally runs free through its course in the glenohumeral joint. It can rarely be seen as attached to the joint capsule or the rotator cuff in different patterns. Although these variations are usually considered harmless in the literature, they may occur in conjunction with the labral pathologies. This study was designed to determine their prevalence and investigate their relationship with intra-articular pathologies encountered during arthroscopy. METHODS: Out of a patient population of 671 arthroscopies performed in one center, the data regarding the LHBT variations and labral pathologies were collected retrospectively. RESULTS: Fifty patients (7.4%) of this total population were included as possible LHBT variants. Categorized into seven groups ranging from the simple vinculum, cord, and pulley types to the synovial tunnel types partially or totally fused to the capsule and to more complex types adherent to the capsule or the rotator cuff, their association with the labral pathologies was analyzed. The labral pathology prevalence was significantly higher in this group of 50 patients with LHBT variants compared to the total population (32 vs. 13%; P < 0.001). In the pulley type variant group, the labral pathologies were also encountered at a significantly higher rate than the total population (62.5%; P = 0.026). CONCLUSION: The prevalence of embryological variations of the biceps tendon may be higher than common presumptions, and a particular type of these variants displays an increased association with labral pathologies. PMID- 21234533 TI - MicroRNAs (miRNAs) in cancer invasion and metastasis: therapeutic approaches based on metastasis-related miRNAs. AB - The management of tumor cell invasion and metastasis is instrumental in cancer therapy, since metastases are the prime reason for cancer patient mortality. Various cellular mechanisms and underlying molecular pathways relevant for metastasis have been identified so far, providing a basis for antimetastatic drugs. MicroRNAs (miRNAs) are highly conserved, small noncoding RNA molecules that have been shown to regulate various cellular processes by interfering with protein expression through posttranscriptional repression or mRNA degradation. More importantly, beyond their roles in physiological processes, many miRNAs are aberrantly expressed in various pathologies including cancer and regulate tumor- and metastasis-associated genes. Their pivotal role in metastasis has emerged only recently. After an introduction into the mechanisms of miRNA action, this review article describes the roles of miRNAs in cancer invasion and metastasis. Various miRNAs are discussed with regard to their upstream regulators, downstream target genes, and pro-/antimetastatic effects. A table provides a comprehensive overview of miRNAs that are misregulated/relevant in metastasis and the current knowledge regarding their underlying molecular effects. Furthermore, therapeutic approaches based on miRNAs, either as drugs or as therapeutic targets, are described prior to the discussion of the delivery of miRNA-based therapeutics as novel strategy in antimetastatic treatment. PMID- 21234538 TI - The variability of surgical practice during total knee arthroplasty: results of a national survey amongst Belgian knee surgeons. AB - PURPOSE: Implant registries have been effective in detecting poorly performing implants and surgical strategies. They learn us however little about many variables that may be equally important to the final result. Today, no standards of care exist for performing total knee arthroplasties (TKA), and little is known about the variability that exists amongst surgeons performing this procedure. METHODS: A questionnaire with 39 aspects regarding standard surgical routine during TKA was sent to all 112 members of the Belgian Knee Society. Surgeons were stratified according to surgical experience and surgical volume. RESULTS: An important number of routines were performed as standard by the majority (>70%) of surgeons. Surgeons however significantly differed in the following aspects of the procedure: radiographic evaluation, use of minimally invasive surgery (MIS), preferred landmark for femoral component rotation, method of closure and activities allowed postoperatively. Both surgical experience and surgical volume had a significant effect, but their influence on strategies was different. Less experienced surgeons used the posterior condylar line as their reference for femoral component rotation significantly more frequent than more-experienced surgeons and were more aggressive towards postoperative sports activities compared to more-experienced surgeons. High-volume surgeons used significantly more frequent MIS and low-volume surgeons preferred a more extensive postoperative radiographic evaluation. CONCLUSIONS: Data of this study show that an important number of routines are performed similarly by the majority of surgeons, and that minor but significant differences exist between high-volume versus low-volume surgeons, and between experienced versus less-experienced surgeons. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 21234539 TI - Patellar resurfacing in total knee arthroplasty for osteoarthritis: a meta analysis. AB - PURPOSE: Whether to resurface the patella during a primary total knee arthroplasty remains a controversial issue. The aim of this study was to determine the advantages and disadvantages of patellar resurfacing during total knee arthroplasty for osteoarthritis through an evaluation of the current literature. METHODS: A meta-analysis of randomized controlled trials comparing patellar resurfacing with nonresurfacing during total knee arthroplasties was performed. The focus of this analysis was on outcomes of reoperation, anterior knee pain and knee scores. RESULTS: Ten trials assessing 1,003 knees were eligible. The absolute risk of reoperation was reduced by 4% (95% confidence interval, 1-7%) in the patellar resurfacing arm (between-study heterogeneity, P = 0.06, I (2) = 45%), implying that one would have to resurface 25 patellae (95% confidence interval, 14-100 patellae) in order to prevent one reoperation. Only seven trials provided adequate data of anterior knee pain for a quantitative synthesis. On the basis of those seven trials, there was no difference between the two groups in terms of anterior knee pain. Anterior knee pain after total knee arthroplasty could have multiple etiologies such as surgical factors and nonresurfaced patella is not the sole cause of this problem. CONCLUSION: The available evidence indicates that patellar resurfacing reduce the risk of reoperation after total knee arthroplasty for osteoarthritis. Not resurfacing the patella might be considered a reasonable option, but patients must accept the increased risk of reoperation for which the quantitative evidence-based synthesis is mild. Based on the evidence provided by this study and those previously published ones, the authors do not now resurface the patella as a matter of routine for patients having a primary total knee arthroplasty for osteoarthritis. PMID- 21234540 TI - Anteroposterior stability after posterior cruciate-retaining total knee arthroplasty. AB - PURPOSE: A functional posterior cruciate ligament (PCL) is important for the knee stability after PCL-retaining total knee arthroplasty (TKA). The objectives of this study were to determine the anteroposterior (AP) displacement of the knee after a mobile- or fixed-bearing PCL-retaining TKA operated with a ligament balancing technique and the correlation of AP stability with the clinical outcome. METHODS: The AP displacement of 160 TKAs in 143 patients was measured pre- and intra-operatively, and the results were compared to the AP displacement measured 4 years post-surgery. RESULTS: The change in AP displacement from intra operative measurement to follow-up at the 25 degrees measuring point was -1.2 mm; at 90 degrees , it was -0.2 mm. Mobile bearings showed significantly greater AP displacement than fixed bearings. Older patients, male patients and patients receiving a fixed prosthesis had lower post-operative laxity compared with the overall population. CONCLUSIONS: The small change in AP displacement indicates that the PCL remains functional over time. In our study, we could not find any correlation between knee AP stability and clinical outcome, including passive flexion, Knee Society Score or Visual Analogue Scale of pain and satisfaction. PMID- 21234541 TI - Mid-term outcomes of computer-assisted total knee arthroplasty. AB - PURPOSE: The aim of this study is to investigate the clinical results of total knee arthroplasty (TKA) using a navigation system after a minimum of 5 years. METHOD: Thirty cases of posterior-stabilized, TKA-implanted using a computed tomography-free navigation system were compared with 30 cases having matched TKA of the same type implanted via a classical, manual technique. At mid term, a minimum of 5 years after surgery, Knee Society scores (KSSs), Knee Society Functional scores (KSFSs), range of motion (ROM), and radiographic results of 27 patients in each group were assessed and reported in this study. RESULTS: The accuracy of the implantations in relation to the coronal mechanical axis in the navigation group was superior to that of the manual group (P < 0.01). The femoral rotational profile revealed the prosthesis in the navigation group that was implanted with significantly less internal rotation than the manual group. Mid term 5-year clinical results, including ROMs and KSSs, were significantly better in the navigation group (P < 0.01). KSFSs were equally good in both the groups. CONCLUSION: Better alignment and similarity of good clinical results at mid-term follow up may provide patients who receive navigation TKA with long-term endurance of their implants. Further studies on longer-term outcomes and functional improvements are required to validate these possibilities. PMID- 21234542 TI - The influence of graft choice on isokinetic muscle strength 4-24 months after anterior cruciate ligament reconstruction. AB - PURPOSE: Regaining adequate strength of the quadriceps and hamstrings after anterior cruciate ligament (ACL) reconstruction is important for maximizing functional performance. However, the outcome of muscle strength after either BPTB or hamstrings autograft is unclear given the plethora of published studies that report post-operative muscle strength. The purpose of this study was to systematically compare the muscle strength of patients who have undergone ACL reconstruction using either Bone Patellar Tendon Bone (BPTB) or Hamstrings (HST) autograft. METHODS: The databases of MEDLINE, Cinahal and EMBASE were systematically searched for articles that report muscle strength outcome following ACL reconstruction. The quality of the studies was evaluated and a meta analysis of the muscle strength outcomes was conducted on reported data. RESULTS: Fourteen studies were included in this systematic review: eight Randomized Control Studies (RCT) and six non-Randomized Control Studies (non-RCT). A meta analysis was performed involving eight of the included studies (4 RCTs & 3 non RCTs). At 60 degrees /s and 180 degrees /s, patients with BPTB graft showed a greater deficit in extensor muscle strength and lower deficit in flexor muscle strength compared with patients with HST. CONCLUSION: This systematic review of Level III evidence showed that isokinetic muscle strength deficits following ACL reconstruction are associated with the location of the donor site. These deficits appear to be unresolved up to 2 years after ACL reconstruction. LEVEL OF EVIDENCE: III. PMID- 21234543 TI - The treatment of chondral and osteochondral defects of the knee with autologous matrix-induced chondrogenesis (AMIC): method description and recent developments. AB - PURPOSE: Articular resurfacing by treatment of chondral defects may include chondral abrasion, autologous chondrocyte Implantation (ACI), matrix-induced chondrocyte transplantation (MACT) or osteochondral autologous transplantation (OATS). This technical note describes the method of autologous matrix-induced chondrogenesis (AMIC), a one-step procedure combining subchondral microfracture with the fixation of a collagen I/III membrane with fibrin glue or sutures. METHODS: This is a technical note on the AMIC procedure and its further development. RESULTS AND CONCLUSION: This method is applied primarily in chondral or osteochondral lesions of the knee. Indications and contraindications are provided; the technique is described. The further development of AMIC is described with an increased focus on the subchondral zone and the complex of cartilage and bone, the osteochondral unit, which receives increased attention in cartilage research. LEVEL OF EVIDENCE: IV. PMID- 21234544 TI - Operative versus non-operative management of patellar dislocation. A meta analysis. AB - PURPOSE: Conservative management of patellar dislocation can result in recurrent instability in up to 60% of patients. Surgery is therefore advocated in an attempt to reduce the incidence of recurrent dislocation and instability. The purpose of this study was to compare the clinical outcomes of operative to non operative treatment strategies for patients following patellar dislocation. METHODS: A systematic review of published and unpublished literature was undertaken. Following data extraction, a meta-analysis was conducted to compare the two treatment strategies. The methodological quality of the literature was assessed using the PEDro critical appraisal tool. RESULTS: Eleven studies were included, five randomised controlled trials (RCTs) and six non-RCTs. These assessed 403 patients managed conservatively, compared to 344 managed surgically. The findings of this study indicate that operative management of patellar dislocation is associated with a significantly higher risk of patellofemoral joint osteoarthritis (P=0.04), but a significantly lower risk of subsequent patellar dislocation compared to non-surgical management (P<0.01). CONCLUSIONS: The meta-analysis indicates that there may be a difference in the incidence of patellofemoral joint osteoarthritis and rate of subsequent dislocation. However, this finding should currently be interpreted with great caution due to the demonstration of statistically significant publication bias, issues related to the methodological quality of the evidence base, and due to the variety of different surgical interventions currently presented within the literature. LEVEL OF EVIDENCE: III. PMID- 21234546 TI - Surgical treatment of mixed urinary incontinence: effect of anterior colpoplasty. AB - INTRODUCTION AND HYPOTHESIS: The aims of this study are to study the surgical outcomes in patients with stress-predominant mixed urinary incontinence (MUI) treated with tension-free vaginal tape, and to evaluate the effect of concomitant anterior colpoplasty. METHODS: A total of 134 women with MUI clinical and urodynamic were assessed at 6 months and annually (maximum 9 years) after surgery. RESULTS: As a whole, a complete healing of 49-51% at 3 years is observed, which hence could result in a tax drop of 36.8% at 5-9 years. Nevertheless, the rate of healing or improvement (subjective) is 73.7% at long term (5-9 years). There were no significant differences between the two techniques used: TVT vs TVT-Obturator. On the other hand, we have found significant differences between association of anterior colpoplasty and not (complete healing rate 34.6% vs 64.6%, p = 0.014), at 2 years of monitoring. CONCLUSIONS: MUI with cystocele presents better surgical results for two components of incontinence, with its physiopathogenic implications. PMID- 21234545 TI - A prospective randomized study of ACL-reconstructions using bone-patellar tendon bone grafts fixed with bioabsorbable or metal interference screws. AB - INTRODUCTION: Bioabsorbable screws are, at the expense of metal screws, increasingly used as fixation device in ACL-reconstructions. The possible advantages with bioabsorbable screws are better postoperative MRI evaluations and easier revision surgery. PURPOSE: The aim of this study was to compare the clinical outcome after ACL-reconstructions with BPTB-grafts fixed with metal interference screws or bioabsorbable screws 7 years postoperatively. The resorption of the bioabsorbable screws was also analyzed. METHODS: Between 2000 and 2001, 41 patients with ACL deficient knees were randomized for the use of BPTB-graft fixed with either metal interference screws or bioabsorbable poly-L: lactic acid screws. This is a 7-year follow-up with clinical examinations of both groups and, MRI of the patients with bioabsorbable screws. RESULTS: The clinical and functional results were satisfactory in both groups. There were no significant differences between the groups in any parameter measured, except for better Pivot shift results in the bioscrew group (P = 0.04). The MRI evaluation showed degradation of the bioscrews. A residual screw tract which appeared threaded was seen in the tibia in 11 of the 16 patients. There was no sign of bony ingrowth in the previous screw site in the tibia in any of the patients. CONCLUSION: The potential advantages of using PLLA-screws compared to metal screws are not sufficient to warrant the routine use of PLLA-screws in ACL reconstructions. LEVEL OF EVIDENCE: I. PMID- 21234547 TI - Posterior intravaginal slingplasty: efficacy and complications in a continuous series of 118 cases. AB - INTRODUCTION AND HYPOTHESIS: Posterior intravaginal slingplasty (PIVS) is a minimally invasive procedure that aims to suspend vaginal vault. Our study evaluated efficacy and complications of PIVS at long-term follow-up. METHODS: One hundred eighteen consecutive women underwent PIVS operation for Pelvic Organ Prolapse Quantification stage 3 or 4 vaginal cuff prolapse (VCP; 25 patients) or utero-vaginal prolapse (UVP; 93 patients). Apical vaginal wall at stage 0 or 1 was considered as cured. RESULTS: Follow-up mean duration was 58.6 months (range, 24-84 months). The success rate of PIVS was 96.6%. Some 8.5% mesh erosion (20% in patients with VCP and 5.4% with UVP), 2.5% vaginal-perineal fistula, and 3.4% paravaginal hematoma occurred. Neither erosion nor fistulas occurred with monofilament polypropylene mesh. CONCLUSION: PIVS seems a safe and effective procedure for VCP and UVP. Vaginal erosion was mainly observed in patients with VCP treated with multifilament polypropylene mesh. PMID- 21234548 TI - Bone mineral density enhances use of clinical risk factors in predicting ten-year risk of osteoporotic fractures in Chinese men: the Hong Kong Osteoporosis Study. AB - This prospective study aimed to determine the risk factors and the 10-year probability of osteoporotic fracture in Southern Chinese men. The findings show substantial population differences in fracture incidence and risk prediction compared to the FRAX(TM) model, and the addition of BMD information to clinical risk factor assessment improved fracture risk prediction in Chinese men. INTRODUCTION: Clinical risk factors with or without bone mineral density (BMD) measurements are increasingly recognized as reliable predictors of fracture risk. Prospective data on fracture incidence in Asian men remain sparse. This prospective study aimed to determine the risk factors and the 10-year absolute fracture risk in Southern Chinese men. METHODS: This is a part of the Hong Kong Osteoporosis Study. One thousand eight hundred ten (1,810) community-dwelling, treatment-naive men aged 50 years or above were evaluated. Baseline demographic characteristics, clinical risk factors and BMD were recorded. Ten-year risk of osteoporotic fracture was calculated using Cox proportional hazards models. RESULTS: The mean age of subjects was 68.0 +/- 10.3 years. After a mean follow-up period of 3.5+/-2.9 years (range 1 to 14 years), 37 incident low-trauma fractures were recorded. The incidence for all osteoporotic fractures and hip fractures was 635/100,000 and 123/100,000 person-years, respectively. The most significant predictors of osteoporotic fracture were history of fall (RR 14.5), femoral neck BMD T-score < -2.5 (RR 13.8) and history of fracture (RR 4.4). Each SD reduction in BMD was associated with a 1.8 to 2.6-fold increase in fracture risk. Subjects with seven clinical risk factors and BMD T-score of -1 had an absolute 10-year risk of osteoporotic fracture of 8.9%, but this increased to 22.7% if they also had a femoral neck BMD T-score of -2.5. CONCLUSIONS: These findings show substantial population differences in fracture incidence and risk prediction. The addition of BMD information to clinical risk factor assessment improved fracture risk prediction in Chinese men. PMID- 21234549 TI - Dose-dependent binding of AZD3783 to brain 5-HT1B receptors in non-human primates and human subjects: a positron emission tomography study with [11C]AZ10419369. AB - RATIONALE: The serotonin 5-HT(1B) receptor is a potential target for the pharmacologic treatment of depression. Positron emission tomography (PET) determination of 5-HT(1B) receptor occupancy with drug candidates targeting this receptor in non-human primate and human subjects may facilitate translation of research from animal models and guide dose selection for clinical studies. AZD3783 is a recently developed, orally bioavailable 5-HT(1B) receptor antagonist with potential antidepressant properties. OBJECTIVES: To determine the relationship between plasma concentration of AZD3783 and occupancy at primate brain 5-HT(1B) receptors using PET and the radioligand [(11)C]AZ10419369. METHODS: PET studies with [(11)C]AZ10419369 were performed in three non-human primates at baseline and after intravenous injection of AZD3783. Subsequently, PET measurements were undertaken in six human subjects at baseline and after administration of different single oral doses of AZD3783 (1-40 mg). RESULTS: After administration in non-human primates and human subjects, AZD3783 reduced regional [(11)C]AZ10419369 binding in a dose-dependent and saturable manner. The AZD3783 plasma concentration required for 50% receptor occupancy (K (i,plasma)) for monkeys was 25 and 27 nmol/L in occipital cortex and striatum, respectively. Corresponding estimates for human occipital cortex and ventral striatum were 24 and 18 nmol/L, respectively. CONCLUSIONS: The potential antidepressant AZD3783 binds in a saturable manner to brain 5-HT(1B) receptors with a similar in vivo affinity for human and monkey receptors. [(11)C]AZ10419369 can be successfully used to determine occupancy at brain 5-HT(1B) receptors in vivo and constitutes a useful tool for dose selection in clinical studies with 5-HT(1B) receptor compounds. PMID- 21234550 TI - Effect of social stress during acute nicotine abstinence. AB - RATIONALE: Relapse to smoking is often precipitated by stress, yet little is known about the effects of nicotine withdrawal on responses to acute stress, or whether nicotine replacement reverses withdrawal-induced changes in stress response. OBJECTIVES: The aim of the present study is to use an effective social stressor, the Trier Social Stress Test (TSST), to study subjective, cardiovascular and hormonal responses to stress during withdrawal, and examine whether nicotine replacement moderates responses to stress during withdrawal. METHODS: Forty-nine current regular smokers were randomly assigned to smoke as normal (SM), 12-h abstention with placebo patch (PL), or 12-h abstention with nicotine patch (NIC). They participated in a single session using the TSST, during which subjective affect, heart rate (HR), mean arterial blood pressure (MAP) and salivary cortisol were measured. RESULTS: The TSST produced expected increases in subjective negative affect, HR, MAP, and cortisol. Groups did not differ in subjective or cardiovascular responses, but the PL group exhibited larger stress-induced increase in cortisol than the other groups. CONCLUSIONS: The increased cortisol response might indicate a greater hormonal stress response during nicotine withdrawal. Alternatively, considering that cortisol also provides negative feedback to the stress system, and blunted cortisol responses are predictive of smoking relapse, the lower cortisol responses in the NIC and SM groups might indicate chronic dysregulation of the stress system. In this case, restoration of cortisol response by nicotine treatment to the lower levels seen during regular smoking may actually represent an undesired side effect of nicotine replacement. PMID- 21234551 TI - Using nanoelectrospray ion mobility spectrometry (GEMMA) to determine the size and relative molecular mass of proteins and protein assemblies: a comparison with MALLS and QELS. AB - The determination of protein assembly size and relative molecular mass is currently of great importance in biochemical analysis. In particular, the technique of nanoelectrospray (nES) with a gas-phase electrophoretic mobility molecular analyzer (GEMMA) has received increased attention for such measurements. However, in order for the GEMMA technique to gain broader acceptance in protein analysis, it must be further evaluated and compared with other established bioanalytical techniques. In the present study, nES-GEMMA was evaluated for the analysis of a set of protein and protein complexes involved in the Sec and the bacterial type III secretion pathway of enteropathogenic Escherichia coli bacteria. The same set of proteins, isolated and purified using standard biochemical protocols, were also analyzed using multi-angle laser light scattering (MALLS) and quasi-elastic light scattering (QELS), following size exclusion chromatography. This allowed for direct comparisons between the three techniques. It was found that nES-GEMMA, in comparison to the more established MALLS and QELS techniques, offers several complementary advantages. It requires considerably less amount of material, i.e., nanogram vs. milligram amounts, and time per sample analysis, i.e., few minutes vs. tens of minutes. Whereas the determined size and relative molecular mass are similar between the compared methods, the electrophoretic diameters determined using nES-GEMMA seem to be systematically smaller compared to the hydrodynamic diameter derived by QELS. Some of the GEMMA technique disadvantages include its narrow dynamic range, limited by the fact that at elevated protein concentrations there is increased potential for the occurrence of nES-induced oligomers. Thus, it is preferred to analyze dilute protein solutions because non-specific oligomers are less likely to occur whereas biospecific oligomers remain detected. To further understand the formation of nES-oligomers, the effect of buffer concentration on their formation was evaluated. Also, nES-GEMMA is not compatible with all the buffers commonly used with MALLS and QELS. Overall, however, the nES-GEMMA technique shows promise as a high-throughput proteomics/protein structure tool. PMID- 21234552 TI - 10th European Workshop on Laser Ablation. PMID- 21234553 TI - Ciprofloxacin-induced theophylline toxicity: a population-based study. AB - PURPOSE: Ciprofloxacin can inhibit the cytochrome P450-mediated metabolism of theophylline, but the clinical relevance of this drug interaction is uncertain. We studied the risk of theophylline toxicity associated with the co-prescription of ciprofloxacin and theophylline. METHODS: This was a population-based, nested case-control study of a cohort of Ontario residents aged 66 years of age or older treated with theophylline between April 1, 1992 and March 31, 2009. Within this group, case patients were those hospitalized with theophylline toxicity. For each case, 50 age- and sex-matched control patients were identified from the same cohort. The odds ratio (OR) for the association between hospitalization for theophylline toxicity and receipt of ciprofloxacin in the 14 days preceding hospitalization was determined. RESULTS: Among the 77,251 elderly patients receiving therapy with theophylline, 180 eligible case patients hospitalized for theophylline toxicity and 9000 matched controls were identified. Following multivariable adjustment, a nearly twofold increase in the risk of theophylline toxicity following the receipt of ciprofloxacin was observed [adjusted OR 1.86, 95% confidence interval (CI) 1.18-2.93]. In contrast, there was no increased risk of theophylline toxicity within a group of patients receiving neutral comparator antibiotics (levofloxacin, trimethoprim-sulfamethoxazole or cefuroxime) (adjusted OR 0.78; 95% CI 0.38-1.62). CONCLUSION: Treatment with ciprofloxacin is associated with a significant increase in the risk of theophylline toxicity. When clinically appropriate, alternate antibiotics should be considered for elderly patients receiving theophylline. PMID- 21234554 TI - Cooperation of phosphates and carboxylates controls calcium oxalate crystallization in ultrafiltered urine. AB - Osteopontin (OPN) is one of a group of proteins found in urine that are believed to limit the formation of kidney stones. In the present study, we investigate the roles of phosphate and carboxylate groups in the OPN-mediated modulation of calcium oxalate (CaOx), the principal mineral phase found in kidney stones. To this end, crystallization was induced by addition of CaOx solution to ultrafiltered human urine containing either human kidney OPN (kOPN; 7 consecutive carboxylates, 8 phosphates) or synthesized peptides corresponding to residues 65 80 (pSHDHMDDDDDDDDDGD; pOPAR) or 220-235 (pSHEpSTEQSDAIDpSAEK; P3) of rat bone OPN. Sequence 65-80 was also synthesized without the phosphate group (OPAR). Effects on calcium oxalate monohydrate (COM) and dihydrate (COD) formation were studied by scanning electron microscopy. We found that controls form large, partly intergrown COM platelets; COD was never observed. Adding any of the polyelectrolytes was sufficient to prevent intergrowth of COM platelets entirely, inhibiting formation of these platelets strongly, and inducing formation of the COD phase. Strongest effects on COM formation were found for pOPAR and OPAR followed by kOPN and then P3, showing that acidity and hydrophilicity are crucial in polyelectrolyte-affected COM crystallization. At higher concentrations, OPAR also inhibited COD formation, while P3, kOPN and, in particular, pOPAR promoted COD, a difference explainable by the variations of carboxylate and phosphate groups present in the molecules. Thus, we conclude that carboxylate groups play a primary role in inhibiting COM formation, but phosphate and carboxylate groups are both important in initiating and promoting COD formation. PMID- 21234555 TI - A comparative assessment of the clinical efficacy of intranasal desmopressin spray and diclofenac in the treatment of renal colic. AB - The aim of this study was to assess the efficacy of desmopressin nasal spray compared with diclofenac given intramuscularly in patients with acute renal colic caused by urolithiasis. The study included 72 patients randomized into three different groups: group A received desmopressin (40 mg, nasal spray), group B diclofenac (75 mg) intramuscularly and group C, both desmopressin and diclofenac. Pain was assessed using a visual analogue scale at baseline, 10, 30 min and 1 h after administering the treatments. Rescue analgesia was given at 30 min if needed. On admission, the pain level was the same in all three groups (group A 85; and group B and C 90 each). At 10 min the pain decreased minimally in all the groups but more in group B and C (group A 80 and group B and C 70 each). At 30 min pain scores were 75, 37.5 and 40 for group A, B and C, respectively, indicating that there was no significant pain relief in desmopressin group. Rescue analgesic had to be given to all patients in group A and two patients in group B and three patients in group C. Pain relief in the desmopressin only group was significantly less at 1 h even after rescue analgesia (pain scores of 27.5, 15 and 20 for group A, B and C respectively). Intranasal desmopressin is not an effective analgesic in renal colic: exerts mild analgesic effect over a period of 30 min. It does not potentiate the effect of diclofenac. PMID- 21234558 TI - Quantitative prediction of the arrhythmogenic effects of de novo hERG mutations in computational models of human ventricular tissues. AB - Mutations to hERG which result in changes to the rapid delayed rectifier current I(Kr) can cause long and short QT syndromes and are associated with an increased risk of cardiac arrhythmias. Experimental recordings of I(Kr) reveal the effects of mutations at the channel level, but how these changes translate to the cell and tissue levels remains unclear. We used computational models of human ventricular myocytes and tissues to predict and quantify the effects that de novo hERG mutations would have on cell and tissue electrophysiology. Mutations that decreased I(Kr) maximum conductance resulted in an increased cell and tissue action potential duration (APD) and a long QT interval on the electrocardiogram (ECG), whereas those that caused a positive shift in the inactivation curve resulted in a decreased APD and a short QT. Tissue vulnerability to re-entrant arrhythmias was correlated with transmural dispersion of repolarisation, and any change to this vulnerability could be inferred from the ECG QT interval or T wave peak-to-end time. Faster I(Kr) activation kinetics caused cell APD alternans to appear over a wider range of pacing rates and with a larger magnitude, and spatial heterogeneity in these cellular alternans resulted in discordant alternans at the tissue level. Thus, from channel kinetic data, we can predict the tissue-level electrophysiological effects of any hERG mutations and identify how the mutation would manifest clinically, as either a long or short QT syndrome with or without an increased risk of alternans and re-entrant arrhythmias. PMID- 21234559 TI - A kinked antimicrobial peptide from Bombina maxima. I. Three-dimensional structure determined by NMR in membrane-mimicking environments. AB - Maximin-4 is a 27-residue cationic antimicrobial peptide exhibiting selectivity for bacterial cells. As part of the innate defense system in the Chinese red belly toad, its mode of action is thought to be ion channel or pore formation and dissipation of the electrochemical gradient across the pathogenic cell membrane. Here we present the high-resolution structure of maximin-4 in two different membrane mimetics, sodium dodecyl sulfate micelles and 50% methanol, as determined by (1)H solution NMR spectroscopy. In both environments, the peptide chain adopts a helix-break-helix conformation following a highly disordered N terminal segment. Despite the similarities in the overall topology of the two structures, major differences are observed in terms of the interactions stabilizing the kink region and the arrangement of the four lysine residues. This has a marked influence on the shape and charge distribution of the molecule and may have implications for the bacterial selectivity of the peptide. The solution NMR results are complemented by CD spectroscopy and solid-state NMR experiments in lipid bilayers, both confirming the predominantly helical conformation of the peptide. As a first step in elucidating the membrane interactions of maximin-4, our study contributes to a better understanding of the mode of action of antimicrobial peptides and the factors governing their selectivity. PMID- 21234560 TI - Influence of the MHC genotype on the progression of experimental SIV infection in the Mauritian cynomolgus macaque. AB - Experimental infection of Mauritian cynomolgus macaques by simian immunodeficiency virus is a representative model of HIV infection, currently in favour for evaluating the efficacy of new preventive or curative treatments. Extensive studies of major histocompatibility complex (MHC) polymorphism by microsatellites revealed seven haplotypes (H1-H7). We present statistical evidence of the influence of MHC polymorphism on the set-point plasma viral load (PVL). Our analysis was based on the study of 45 Mauritian cynomolgus macaques inoculated by intravenous or intrarectal injection of a 50 AID50 dose of the SIVmac251 virus. The animals received no treatment before or after the inoculation. MHC polymorphism was investigated by means of 20 microsatellites distributed across the MHC and by DRB genotyping using the DGGE sequencing method. Statistical analysis with UNPHASED: software revealed that two markers located in the class IB region significantly influenced the Log PVL and that three class IB haplotypes were significantly associated with lower (H2 or H6) or higher (H4) set-point Log PVL values. Although the impact of MHC on Log PVL was found to be low (around one Log10), it is important to dispose of animals paired for their MHC genotypes, each animal tested for a given treatment and its untreated control, to minimize the influence of the MHC and clearly reveal the effect of the treatment. PMID- 21234561 TI - Comments on Kailu et al.: Chronic perilunate dislocations treated with open reduction and internal fixation: results of medium term follow-up. PMID- 21234562 TI - Cementless acetabular revision: past, present, and future. Revision total hip arthroplasty: the acetabular side using cementless implants. AB - BACKGROUND: Acetabular revision is probably the most difficult aspect of hip reconstructive surgery. Although the majority of acetabular revisions can be performed using an uncemented hemispherical acetabular device with ancillary fixation, patients with severe acetabular deficiencies and poor bone quality require more complex alternatives for revision. The limitations of traditional cementless acetabular implants has promoted the development of improved methods of fixation and revision techniques. Highly porous metals have been introduced for clinical use in arthroplasty surgery over the last decade. Their higher porosity and surface friction are ideal for acetabular revision, optimising biological fixation. The use of trabecular metal cups in acetabular revision has yielded excellent clinical results. PURPOSE: This review focuses on the use of cementless implants for acetabular revision. The use of trabecular metal cups, augments, jumbo cups, oblong cups, cages, and structural grafting are also discussed. PMID- 21234563 TI - Results of hip resurfacing. AB - BACKGROUND: The renewed popularity of resurfacing hip arthroplasty in the last 10 years has generated a remarkable quantity of scientific contributions based on mid- and short-term follow-up. More than one paper has reported a consistent early revision rate as a consequence of biological or biomechanical failure. Two major complications are commonly described with resurfacing implants: avascular necrosis and femoral-neck fracture. A close relationship between these two events has been suggested, but not firmly demonstrated, whereas cementing technique seems to be better understood as potential cause of failure. METHODS: We performed an in vitro study in which four different resurfacing implants were evaluated with a simulated femoral head, two types of cement, (low and high viscosity) and two cementing techniques: direct (cement apposition directly on the femoral head) and indirect (cement poured into the femoral component). RESULTS: High-viscosity cement showed homogeneous distribution over the entire femoral head. Low-viscosity cement showed a massive polar concentration with insufficient, if not absent, distribution in the equatorial zone. CONCLUSION: Polar cement concentration could be a risk factor for early implant failure due to two effects on the femoral head: biological (excessive local exothermic reaction could cause osteocyte necrosis) and biomechanical (which could lead to uneven load distribution on the femoral head). PMID- 21234565 TI - Adaptive capacity and social-environmental change: theoretical and operational modeling of smallholder coffee systems response in Mesoamerican Pacific Rim. AB - Communities who rely directly on the natural environment for their survival typically have developed risk management strategies to enable them to avoid dangerous thresholds of change to their livelihoods. Development policy appropriate for natural resource-based communities requires an understanding of the primary drivers of social-ecological change, the ways in which affected households autonomously respond to such drivers, and the appropriate avenues for intervention to reduce vulnerability. Coffee has been, and still remains, one of the most important commodities of the Mesoamerican region, and hundreds of thousands of smallholder households in the region are dependent in some way on the coffee industry for their livelihood stability. We used the Analytical Network Process to synthesize expert knowledge on the primary drivers of livelihood change in the region as well as the most common household strategies and associated capacities necessary for effective response. The assessment identified both gradual systemic processes as well as specific environmental and market shocks as significant drivers of livelihood change across the region. Agronomic adjustments and new forms of social organization were among the more significant responses of farmers to these changes. The assessment indicates that public interventions in support of adaptation should focus on enhancing farmers' access to market and technical information and finance, as well as on increasing the viability of farmers' organizations and cooperatives. PMID- 21234564 TI - Metal-on-metal: history, state of the art (2010). AB - The history of metal-on-metal bearing began with K. Mc Kee. Several "episodes" have marked the history of metal-on-metal articulations, and each has contributed to a better understanding of this type of tribology. But to date the indications for this bearing are debated and are subject to reservations because of the existence of permanently elevated levels of circulating metal ions. It therefore appears that the monitoring of our patients, the documentation of our revisions and the collaboration with our industry partners as well as communicating with our biology and pathology colleagues is necessary to help us solve these problems. PMID- 21234566 TI - Bone marrow mesenchymal stem cells reduce the antitumor activity of cytokine induced killer/natural killer cells in K562 NOD/SCID mice. AB - Adoptive cellular immunotherapy is an important treatment to eliminate residual tumor cells after hematopoietic stem-cell transplantation. Bone marrow mesenchymal stem cells (MSC) have previously been shown to exert immunoregulation functions, including inhibition of proliferation and killing activities of T cells and natural killer (NK) cells in vitro and reduction of the graft-versus host disease. MSC can survive in vivo for a long period of time, the influence of MSC on the antitumor activity of subsequently infused immune killer cells is not clear. The aim of this study was to investigate the influences of MSC infused via different paths and at different times on the antitumor activities of cytokine induced killer (CIK)/NK cells derived from umbilical cord blood in K562 NOD/SCID mice. The potential interaction mechanisms of MSC and CIK/NK cells infused through different paths using different intervals in vivo were subsequently explored. The results show that the antitumor activities of CIK/NK cells was inhibited by MSC when injected via the same path (tail vein), and the suppressive effect of MSC on CIK/NK cells were less pronounced when they were injected separately through different paths. There were no effects of MSC on the antitumor activities of CIK/NK cells if the MSC and CIK/NK cells were injected with a 48-h interval. Moreover, the suppressive effect continuous, even if MSC were infused 48 h earlier than CIK/NK cells. It suggests that pre-injected MSC can reduce the antitumor activities of CIK/NK cells in vivo. The probable mechanisms are that MSC and CIK/NK cells might have a greater opportunity to meet and interact if they are injected simultaneously via the same path. The suppression of MSC on CIK/NK cells in vivo mainly takes place in the reticuloendothelial system, including the lung and the liver. PMID- 21234567 TI - Alkylating chemotherapeutic agents cyclophosphamide and melphalan cause functional injury to human bone marrow-derived mesenchymal stem cells. AB - The adverse effects of melphalan and cyclophosphamide on hematopoietic stem cells are well-known; however, the effects on the mesenchymal stem cells (MSCs) residing in the bone marrow are less well characterised. Examining the effects of chemotherapeutic agents on patient MSCs in vivo is difficult due to variability in patients and differences in the drug combinations used, both of which could have implications on MSC function. As drugs are not commonly used as single agents during high-dose chemotherapy (HDC) regimens, there is a lack of data comparing the short- or long-term effects these drugs have on patients post treatment. To help address these problems, the effects of the alkylating chemotherapeutic agents cyclophosphamide and melphalan on human bone marrow MSCs were evaluated in vitro. Within this study, the exposure of MSCs to the chemotherapeutic agents cyclophosphamide or melphalan had strong negative effects on MSC expansion and CD44 expression. In addition, changes were seen in the ability of MSCs to support hematopoietic cell migration and repopulation. These observations therefore highlight potential disadvantages in the use of autologous MSCs in chemotherapeutically pre-treated patients for future therapeutic strategies. Furthermore, this study suggests that if the damage caused by chemotherapeutic agents to marrow MSCs is substantial, it would be logical to use cultured allogeneic MSCs therapeutically to assist or repair the marrow microenvironment after HDC. PMID- 21234568 TI - A theoretical analysis of filament length fluctuations in actin and other polymers. AB - Control of the structure and dynamics of the actin cytoskeleton is essential for cell motility and for maintaining the structural integrity of cells. Central to understanding the control of these features is an understanding of the dynamics of actin filaments, first as isolated filaments, then as integrated networks, and finally as networks containing higher-order structures such as bundles, stress fibers and acto-myosin complexes. It is known experimentally that single filaments can exhibit large fluctuations, but a detailed understanding of the transient dynamics involved is still lacking. Here we first study stochastic models of a general system involving two-monomer types that can be analyzed completely, and then we report stochastic simulations on the complete actin model with three monomer types. We systematically examine the transient behavior of filament length dynamics so as to gain a better understanding of the time scales involved in reaching a steady state. We predict the lifetime of a cap of one monomer type and obtain the mean and variance of the survival time of a cap at the filament end, which together determine the filament length fluctuations. PMID- 21234569 TI - A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone. AB - Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide (NO) have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which may reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways, (ii) the concentrations in the tracheo-bronchial lining fluid, (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, the model illuminates the discrepancies between observed and theoretically predicted blood-breath ratios of acetone during resting conditions, i.e., in steady state. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases and thus is expected to have general relevance for a wider range of blood-borne inert gases. The chief intention of the present modeling study is to provide mechanistic relationships for further investigating the exhalation kinetics of acetone and other water-soluble species. This quantitative approach is a first step towards new guidelines for breath gas analyses of volatile organic compounds, similar to those for nitric oxide. PMID- 21234570 TI - Modeling the adaptive immune response in HBV infection. AB - The aim of this work is to investigate a new mathematical model that describes the interactions between Hepatitis B virus (HBV), liver cells (hepatocytes), and the adaptive immune response. The qualitative analysis of this as cytotoxic T lymphocytes (CTL) cells and the antibodies. These outcomes are (1) a disease free steady state, which its local stability is characterized as usual by R (0) < 1, (2) and the existence of four endemic steady states when R (0) > 1. The local stability of these steady states depends on functions of R (0). Our study shows that although we give conditions of stability of these steady states, not all conditions are feasible. This rules out the local stability of two steady states. The conditions of stability of the two other steady states (which represent the complete failure of the adaptive immunity and the persistence of the disease) are formulated based on the domination of CTL cells response or the antibody response. PMID- 21234571 TI - Global analysis of a stoichiometric producer-grazer model with Holling type functional responses. AB - Cells, the basic units of organisms, consist of multiple essential elements such as carbon, nitrogen, and phosphorus. The scarcity of any of these elements can strongly restrict cellular and organismal growth. During recent years, ecological models incorporating multiple elements have been rapidly developed in many studies, which form a new research field of mathematical and theoretical biology. Among these models, the one proposed by Loladze et al. (Bull Math Biol 62:1137 1162, 2000) is prominent and has been highly cited. However, the global analysis of this nonsmooth model has never been done. The aim of this paper is to provide the complete global analysis for the model with Holling type I functional response and perform a bifurcation analysis for the model with Holling type II functional response. PMID- 21234573 TI - Editorial for anniversary issue of European Radiology. AB - This special anniversary issue of European Radiology illustrates the wide range of topics which this journal now covers and charts some of the key recent advances in radiology over the last two decades. It includes several review articles in which each author considers some recent groundbreaking papers published in this journal and relates them to developments within their area of interest. PMID- 21234572 TI - [Pleomorphic high-grade soft tissue sarcomas: is the subclassification up to date?]. AB - The conceptual evolution in the classification of pleomorphic high-grade sarcomas is a paradigm of how the integrative morphological, immunohistochemical and molecular genetic analysis has contributed to a clinical, prognostic and therapy oriented characterization of this complex group of tumors. The clinical and prognostic relevance of a refined subtyping of pleomorphic high-grade sarcomas, which until recently was considered a mere academic exercise, is now undisputed. It is imperative to unequivocally differentiate sarcomas from non-sarcomatous, clearly defined malignancies to start adequate therapy. Furthermore, pleomorphic sarcomas which are particularly aggressive and prone to poor prognosis, have to be separated from sarcomas which, in contrast to the pleomorphic phenotype, are characterized by a less aggressive behavior. Also, morphologically pleomorphic but benign mesenchymal tumors must be recognized. Finally, it is important to promote the promising, array-based identification of diagnostic, prognostic and clinically relevant gene signatures on larger collections of pathomorphologically and clinically precisely defined subtypes of pleomorphic high-grade sarcomas. PMID- 21234574 TI - Trends in head and neck radiology. AB - Trends in clinical research of head and neck radiology are well described within four articles published in the European Radiology in the last 2 years. One constant top issue is to gain more, better or new morphological information by so called "conventional" methods (CT, MRI) with thin-sliced imaging including special reconstructions. The addition of functional or metabolic methods (e.g. diffusion-weighted MRI, dynamic contrast-enhanced MRI, positron emission tomography) to anatomical imaging is a further general trend in oncological radiology over the last few years and has been invaluable in head and neck radiology. PMID- 21234575 TI - Radiation-induced tumors in children irradiated for brain tumor: a longitudinal study. AB - BACKGROUND: Radiation-induced tumors (RIT) are increasingly recognized as delayed complications of brain irradiation during childhood. However, the true incidence is not established, their biology is poorly understood, and few guidelines exist regarding the long-term follow-up of irradiated children. METHODS: We studied retrospectively patients irradiated for brain tumor under 18 years and followed in our institution since 1970. RIT were defined as new masses, different from the original tumor, occurring after delay in irradiated areas, and not related to phacomatosis. RESULTS: Among 552 irradiated patients, 42 (7.6%) developed one or more RIT, 26 months to 29 years after irradiation (mean 12.8 years). The cumulated incidence was 2.0% at 5 years and 8.9% at 10 years. Of the patients, 73.8% were adult at the time of diagnosis of RIT, and 75% were diagnosed within 18.1 years after irradiation. We identified 60 cavernomas, 26 meningiomas, 2 malignant gliomas, 1 meningosarcoma, and 6 thyroid tumors. Compared with meningiomas, cavernomas appeared earlier, in children irradiated at an older age, and with a male predominance. Although RIT were correlated with higher irradiation doses, 80.9% of these occurred at some distance from the maximum irradiation field. Twenty-five lesions were operated in 20 patients; three patients died because of progression of the RIT. CONCLUSION: A significant number of patients undergoing irradiation for brain tumor during childhood develop a RIT, often during adulthood. Our data suggest that radiation-induced cavernomas result from angiogenetic processes rather than true tumorigenesis. Protracted follow-up with MRI is warranted in children irradiated for brain tumor. PMID- 21234577 TI - Women in neurosurgery: a challenge to change history--Brazil, Sao Paulo. PMID- 21234576 TI - Incidence of hydrocephalus and the need to ventriculoperitoneal shunting in premature infants with intraventricular hemorrhage: risk factors and outcome. AB - OBJECTIVE: To investigate the associated risk factors for ventriculoperitoneal (VP) shunting in infantile hydrocephalus following intraventricular hemorrhage (IVH) in premature infants. METHODS: A historical cohort study was conducted, consisting of 97 premature infants in whom the diagnosis of IVH was previously made by cranial ultrasound and were referred to pediatric neurosurgery clinic and/or neonatal intensive care unit of Children's Hospital Medical Center in Tehran, Iran, from April 2004 to March 2009. Among the patients, those who were followed up for at least 6 months after the diagnosis of IVH were included in the study, and data regarding signs and symptoms of increased intracranial pressure, cranial ultrasound, non-surgical treatment (CSF drainage and/or acetazolamide), and shunt requirement were extracted. Patients who required VP shunting were followed up for at least 6 months thereafter considering shunt infection. RESULTS: All the patients were followed up for at least 1 year, except for three who died at the ages of 6 (two of them) and 7 months. Thirty five percent (35%) of patients required VP shunting, in all of whom IVH was of grade 3 or 4. The need for VP shunting in these patients was predicted only by the severity of IVH. Non-surgical treatments for IVH had no statistically significant effect on shunt requirement. Moreover, 11 of 31 patients with shunt developed shunt infection, which was significantly associated with repeated cerebrospinal fluid (CSF) drainage. CONCLUSION: It is suggested that children with IVH, especially of higher grades, should be followed up meticulously (by signs, symptoms, and periodic cranial ultrasounds). Non-surgical treatments are considered for patients requiring VP shunting who are not good candidates for immediate surgical intervention. The only predictor for surgical intervention was the grade of IVH. PMID- 21234578 TI - A retrospective clinicopathological analysis of appendiceal tumors from 3,744 appendectomies: a single-institution study. AB - PURPOSE: This study was conducted to describe the clinicopathological characteristics of appendiceal tumors and to evaluate their appropriate management. METHODS: Between September 2000 and September 2005, 28 appendiceal tumors were identified by a retrospective review of 3,744 appendectomies. RESULTS: Twenty-eight patients were found to have appendiceal tumors (incidence, 0.7%).The largest single group of tumors were benign mucinous cystadenomas (50%); carcinoids (32.1%) were next, and they were followed by malignant tumors (17.9%). Four out of five patients who had malignant appendiceal tumors presented with periappendiceal abscess. None of the patients was correctly diagnosed preoperatively. One-stage curative resection was possible in more than 76% of the patients, and the rate of making the correct preoperative diagnosis was 35%. CONCLUSION: Most appendiceal tumors presented with appendicitis and periappendiceal abscess. Appendiceal tumors should be included in the differential diagnosis when an unexpected appendiceal mass is encountered during appendectomy. PMID- 21234579 TI - Treatment of postoperative ileus with choline citrate--results of a prospective, randomised, placebo-controlled, double-blind multicentre trial. AB - OBJECTIVES: This was a prospective, randomised, placebo-controlled, double-blind multicentre trial to analyse the efficacy of choline citrate in patients with postoperative ileus (POI) after elective colorectal surgery. METHODS: From October 2005 until June 2008, 122 patients with POI were randomised to receive choline citrate or placebo. One hundred twenty patients were evaluable for tolerability and 107 patients were evaluable for efficacy. The treatment group, 47% (50/107), received 300.2 mg choline citrate intravenously, while the placebo group, 53% (57/107), received sodium chloride. Injections were performed every 12 h until defecation. RESULTS: Demographic data analysis did not show clinically differences between both groups. Operative procedures included 40% (43/107) hemicolectomy, 38% (41/107) sigmoid resection and 22% (23/107) other colorectal resections. Defecation occurred after an average of 91.8 +/- 26.6 h postoperatively in the treatment group, vs. 96.7 +/- 35.2 h in the placebo group (p = 0.805). After laparoscopy, defecation occurred after 78.7 +/- 25.3 h, vs. 99.2 +/- 31.6 h after laparotomy (p = 0.001). Serious adverse effects occurred in 2% (1/60) in the treatment group, vs. 3% (2/60) in the placebo group. None of the events have been assessed as related to the study medication. CONCLUSION: An efficacy of choline citrate in the treatment of POI after elective colorectal surgery could not be verified. The problem of POI requiring drug treatment seems to be less frequent than suggested by the literature. With technical advances in surgery, especially laparoscopic and fast track surgery, the frequency of POI will further decrease in the future. PMID- 21234580 TI - Visualization of multiple catheters in left atrial ablation procedures. Comparison of two different 3D mapping systems. AB - BACKGROUND: Visualization of intracardiac catheters placed in predefined anatomic locations is a cornerstone for successful atrial fibrillation (AF) ablation. The 3D mapping system Carto3TM (Biosense Webster, Diamond Bar, CA, USA) released in 2009 provides the possibility to visualize more than one intracardiac catheter at a time. The aim of the study was to evaluate the feasibility and safety of the system, to show the learning curve, and to compare it to the established Ensite NavXTM system regarding procedural handling parameters. METHODS: A total of 100 patients were enrolled in the study. The Carto3TM system was used by a team of four specialized operators in 50 patients (mean age 62+/-9 years, paroxysmal AF n=28, persistent AF n=17, left atrial flutter n=5). Patients were consecutively enrolled and matched (regarding type of ablated arrhythmias, ablation strategy, left atrial size, age, and gender) with patients ablated during the same time period with the EnSite NavXTM system. In patients with paroxysmal AF, ostial pulmonary vein isolation (PVI) was performed. Patients with persistent AF underwent PVI plus additional ablation of complex fractionated atrial electrograms (CFAE) and patients with left atrial flutter were treated with specific lines. RESULTS: In 50 case-control pairs, all procedures were performed as planned without complications in both groups except one cardiac tamponade in 1 patient in the Ensite NavXTM control group. The learning curve using the Carto3TM system was fast regarding x-ray time and procedural duration and reached the level of the EnSite NavXTM system after 15 and 25 patients, respectively. CONCLUSION: The Carto3TM system with its feature of visualizing several catheters is feasible and safe compared to an established system, e.g., Ensite NavXTM. The learning curve is steep regarding reduction of x-ray time and procedural duration. PMID- 21234581 TI - Sildenafil (Viagra) ameliorates clinical symptoms and neuropathology in a mouse model of multiple sclerosis. AB - Cyclic GMP (cGMP)-mediated pathways regulate inflammatory responses in immune and CNS cells. Recently, cGMP phosphodiesterase inhibitors such as sildenafil, commonly used to treat sexual dysfunction in humans including multiple sclerosis (MS) patients, have been reported to be neuroprotective in animal models of stroke, Alzheimer's disease, and focal brain lesion. In this work, we have examined if sildenafil ameliorates myelin oligodendrocyte glycoprotein peptide (MOG35-55)-induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We show for the first time that treatment with sildenafil after disease onset markedly reduces the clinical signs of EAE by preventing axonal loss and promoting remyelination. Furthermore, sildenafil decreases CD3+ leukocyte infiltration and microglial/macrophage activation in the spinal cord, while increasing forkhead box transcription factor 3-expressing T regulatory cells (Foxp3 Tregs). However, sildenafil treatment did not significantly affect MOG35 55-stimulated proliferation or release of Th1/Th2 cytokines in splenocytes but decreased ICAM-1 in spinal cord infiltrated cells. The presence of reactive astrocytes forming scar-like structures around infiltrates was enhanced by sildenafil suggesting a possible mechanism for restriction of leukocyte spread into healthy parenchyma. These results highlight novel actions of sildenafil that may contribute to its beneficial effects in EAE and suggest that treatment with this widely used and well-tolerated drug may be a useful therapeutic intervention to ameliorate MS neuropathology. PMID- 21234582 TI - Immunohistochemical expression of fibronectin and C5b-9 in the myocardium in cases of fatal ethanol intoxication. AB - Data from the literature indicate that the pulmonary pressure rises in cases of ethanol intake. We have recently proposed a method for the detection of prevalent right ventricular damage in cases of fatal pulmonary thromboembolism and pulmonary fat embolism. In the present study, we compared the expression of the antibodies against fibronectin and C5b-9 in 19 cases of lethal alcohol intoxications (study group: 5 females, 14 males, mean age 46 years, mean blood ethanol concentration 3.50/00, min. 2.110/00, max. 5.310/00) to a group of 26 cases of fatal pulmonary thromboembolism (PE; group 2: 16 females, 10 males, mean age 56 years). Moreover, a group of 15 cases of hanging (group 3: 5 females, 10 males, mean age 50 years) as well as a group of 18 cases of myocardial infarction (group 4: 5 females, 13 males, mean age 61 years) were investigated as examples of typical cardiac damage due to global hypoxia during agony and ischemic damage, respectively. The results of this study show that fresh cardiac damage can be detected at both ventricles in cases of fatal ethanol intoxication with the antibody against fibronectin. The damage is prevalently localised at the right ventricle (RV), as already observed in cases of acute pulmonary hypertension determining right heart failure. The degree of damage at the RV in cases of ethanol intoxications is lower than the one observed in cases of fatal PE. PMID- 21234583 TI - Age and gender-dependent bone density changes of the human skull disclosed by high-resolution flat-panel computed tomography. AB - INTRODUCTION: The objective of this article was to estimate the age at death in forensic or anthropologic applications based on human skull investigation. Sex dependent differences were analyzed. METHODS: Digital, high-resolution, flat panel-based volumetric computed tomography (eXplore Locus Ultra scanner) images (165,920) of 244 European human skulls-163 males, 81 females-were analyzed according to their radiological bone density, based on Hounsfield units (H) that are directly related to the x-ray attenuation of the scanned material. Data were collected by the Department of Forensic Medicine at the University Hospital Giessen and Marburg during 2007 and 2008. Correlation analysis was used for data description. RESULTS: Human skull density estimates are widely scattered as a function of age for both sexes. Male skull bone density remains constant during lifetime, whereas female skull bone density decays slowly from approximately 20 years onwards. CONCLUSIONS: Bone density decay only theoretically provides a new method to determine age at death for adult females. Due to the scattering of the data, an accuracy of approximately +/-18 years is found at a confidence interval of 75%, which is, unfortunately, of limited practical interest. We found new sex differences of bone density decay in the skull that are potentially of relevance for the general understanding of bone degradation processes. PMID- 21234584 TI - Mehdi-ODM; a modified digital monitoring of the occlusion therapy for amblyopia. PMID- 21234585 TI - Comparative evaluation of anatomical and functional outcomes using brilliant blue G versus triamcinolone assisted ILM peeling in macular hole surgery in Indian population. AB - PURPOSE: To compare anatomical and functional outcomes using brilliant blue G (BBG) vs triamcinolone acetonide (TA)-assisted ILM peeling in macular hole surgery (MHS). STUDY DESIGN: Simple, comparative, retrospective, non-randomised, interventional single-centre study. METHODS: Ninety-four eyes of 94 patients with idiopathic macular holes (>= stage 2) who underwent MHS at our centre were included. Patients with failed macular holes, post-traumatic macular holes, history of previous vitreoretinal surgery, high myopia (6 dioptres or more) or any other macular pathology potentially limiting visual acuity, such as diabetic retinopathy or age-related macular degeneration, were excluded. An OCT evaluation of hole status was followed by pars plana vitrectomy for each of these eyes. Those who underwent TA-assisted ILM peeling were considered as group 1 and those with BBG-assisted ILM peeling were considered as group 2. Primary outcome measures included anatomical hole closure and functional success in terms of change in visual acuity of >=2 LogMAR lines. Various preoperative factors were also evaluated. RESULTS: Anatomical hole closure was achieved in 85 eyes (90.43%) and visual gain in 78 eyes (82.9%). Mean postoperative follow-up duration was 16.14 +/- 1.95 months. No significant difference was found in anatomical and functional success between the two groups. Group 1 had a significantly higher incidence of postoperative glaucoma. Duration of symptoms of <12 months (p = 0.004) and preoperative visual acuity <=1.0 LogMAR were related to anatomical success. However, greater visual gain was found in patients with chronic holes (>=12 months) (p = 0.046) and poor preoperative visual acuity (>1.0 LogMAR) (p = 0.001). CONCLUSION: BBG-assisted ILM peeling offers an effective alternative to triamcinolone, with the added advantage of marked enhancement of vitreoretinal interface contrast with comparable hole closure rates and visual outcomes. PMID- 21234586 TI - c-Jun N-terminal kinase is involved in the regulation of proliferation and apoptosis by integrin-linked kinase in human retinoblastoma cells. AB - PURPOSE: To determine the presence of integrin-linked kinase (ILK) in tissue samples of retinoblastoma patients, and to explore the function of ILK in human Y79 retinoblastoma cells. METHODS: The expression of ILK was studied in samples of retinoblastoma patients by immunohistochemistry. In vitro, specific small interfering RNA (siRNA) targeting ILK was transfected into Y79 retinoblastoma cells using liposome. Silencing of ILK expression was measured by reverse transcription-polymerase chain reaction (RT-PCR), real-time PCR and Western blotting assays. Then the regulation of cell proliferation and apoptosis was assessed by Cell Counting Kit-8(CCK-8), Annexin V-FITC/ propidium iodide (PI) immunofluorescence, and flow cytometry assays. Furthermore, the involvement of c Jun N-terminal kinase signal pathway was tested by JNK signal transduction inhibitor assay. RESULTS: Positive staining for ILK was detected in 15 of the 17 retinoblastoma tissue samples. Specific siRNA targeting ILK significantly silenced ILK expression in Y79 retinoblastoma cells, as confirmed by RT-PCR, real time PCR and Western blotting assays (P < 0.01). This was accompanied by decreased cell proliferation (P < 0.05) and enhanced apoptosis (P < 0.01). The phosphorylation status of JNK and c-Jun was constitutively activated by ILK siRNA (P < 0.01), and JNK inhibitor simultaneously reversed the effects on cell proliferation and apoptosis induced by ILK siRNA. CONCLUSION: Our results demonstrated that ILK promoted proliferation and suppressed apoptosis via repressing phosphorylations of the JNK signal pathway in human retinoblastoma cells. This might provide a potential therapeutic target in the treatment of this deadly disease. PMID- 21234587 TI - Intraocular pressure fluctuations in professional brass and woodwind musicians during common playing conditions. AB - BACKGROUND: We investigated the effects on intraocular pressure (IOP) and blood pressure (BP) of playing brass and woodwind instruments by monitoring IOP and BP in a representative group of professional musicians under a variety of common playing conditions. METHODS: IOP and BP measurements were recorded from 37 brass and 15 woodwind instrument players, before and after playing tones of low, middle and high frequency. We also measured IOP and BP before and during playing common exercises of 10 minutes duration, as well as after playing a sustained high pitched tone, to test for changes in IOP under conditions of maximum effort. RESULTS: Playing tones on brass and woodwind instruments causes a temporary elevation in IOP and BP, depending on the tone frequency: brass instrument players showed a significant elevation after playing high and middle frequency tones (p < 0.0001) whereas woodwind instrument players showed a significant increase only for high frequencies (e.g., oboe, 17 +/- 2.9 mm Hg to 21 +/- 4.4 mm Hg; p = 0.017). Playing a typical exercise of 10 minutes temporarily increased IOP in both groups of musicians. Finally, playing a sustained tone of high pitch caused a significant elevation in IOP in brass instrument players only (16.6 +/- 3.5 mm Hg to 23.3 +/- 8.9 mm Hg; p < 0.0001). CONCLUSIONS: The temporary and sometimes dramatic elevations and fluctuations in IOP observed in this study, coupled with daily exposure to instrument play, puts professional wind instrument players at increased risk of developing glaucoma. Consequently, these musicians should be monitored for signs of glaucoma, especially those with co-existing risk factors. PMID- 21234590 TI - Orbital venous hemangioma. PMID- 21234589 TI - Solitary neurofibroma without neurofibromatosis in the superior tarsal plate simulating a chalazion. PMID- 21234588 TI - Myopic choroidal neovascularization treated by intravitreal bevacizumab: comparison of two different initial doses. AB - BACKGROUND: Myopic maculopathy is the leading cause of subfoveal choroidal neovascularization (CNV) in patients under 50 years of age. New antiangiogenic drugs are being used off-label with varied therapeutic schedules to treat CNV. The aim of this study is to report the anatomical and visual outcomes of myopic choroidal neovascularization (CNV) treated by two different schedules with intravitreal bevacizumab. METHODS: Prospective, comparative, consecutive, non randomized, multicentric, interventional pilot study. Two groups of highly myopic patients with subfoveal and juxtafoveal CNV were treated by monthly intravitreal injections with 1.25 mg bevacizumab. Group 1 comprised 19 eyes treated by three consecutive monthly intravitreal injections. Group 2 comprised 20 eyes treated by one single intravitreal injection. Patients were evaluated for best-corrected visual acuity (BCVA) and optical coherence tomography (OCT) at baseline and then monthly. Fluorescein angiography was performed at baseline and when CNV activity was suspected. Further intravitreal injections were performed if CNV activity was detected. RESULTS: Both groups were matched for age, spherical equivalent, LogMAR BCVA, and central foveal thickness (CFT) as determined by OCT at baseline and number of eyes with previous PDT treatment. The average number of letters gained was 6.3 in group 1 vs 7.2 in group 2 (p = 0.001 and 0.09 respectively, Student's t-test for paired data). Changes in OCT were not significant for either group by the end of follow-up. The mean number injections performed was 3.2 in group 1 vs 1.7 in group 2 (p = 0.00, Mann-Whitney test). Four recurrences (four eyes) occurred in group 1 vs 15 (seven eyes) in group 2 (p = 0.001; Fisher's exact test). CONCLUSIONS: Both schedules achieved similar results improving BCVA, though the second group required a lower number of injections, showing a higher rate of recurrences during the first year. PMID- 21234591 TI - Unilateral recurrent acute idiopathic maculopathy. AB - BACKGROUND: To report a patient with repeated recurrence of unilateral acute idiopathic maculopathy (UAIM) at the same site of the eye. METHODS: A 27-year-old female with UAIM in the left eye was followed up and examined by fundus photography and optical coherence tomography (OCT). RESULTS: The clinical features of the maculopathy at first presentation were compatible with UAIM. The maculopathy recurred twice at the same site of the eye during the 20-month follow up. After three episodes of the disease, best corrected visual acuity decreased from 20/20 to 20/33, and discontinuity of IS/OS in the macular area was observed by OCT. CONCLUSIONS: We report a patient with UAIM occurring three times at the same site of the eye. To our knowledge, the feature of recurrence of UAIM has not been reported. PMID- 21234592 TI - The effect of a carbohydrate beverage on the physiological responses during prolonged load carriage. AB - Effects of a carbohydrate beverage on the physiological responses to load carriage were examined. Ten fit male participants (age: 28 +/- 9 years, body mass: 81.5 +/- 10.5 kg, VO(2max): 55.0 +/- 5.5 mL kg(-1) min(-1)) completed two test conditions in random order, walking on a treadmill (6.5 km h(-1)) for 120 min, carrying a 25-kg backpack. At 0 and 60 min of exercise participants consumed 250 mL of a placebo (flavoured water) (PLA) or 6.4% carbohydrate (CHO) beverage. There were no differences in VO(2,) respiratory exchange ratio (RER), heart rate or EMG activity of m. rectus femoris, m. vastus lateralis, m. semitendinosus and m. biceps femoris between conditions at minute 5 of exercise. The increase in VO(2) between minutes 5 and 120 was less during CHO than PLA (8 +/- 5 vs. 14 +/- 6%, P = 0.036). RER decreased during PLA, from 0.96 +/- 0.05 at minute 5 to 0.87 +/- 0.04 at minute 120 (P < 0.001), but not during CHO (P = 0.056). Heart rate increased between minutes 5 and 120 during PLA (16 +/- 10%, P < 0.001) and CHO (12 +/- 6%, P < 0.001), with no difference between conditions (P = 0.251). EMG peak RMS did not change between minutes 7 and 107 during PLA or CHO for the leg muscles. However, individual responses in EMG were highly variable (i.e. both increases and decreases in RMS). It was concluded that carbohydrate intake during load carriage reduced the VO(2) drift, which could be partially attributed to higher carbohydrate oxidation rates. Despite muscle fatigue/damage previously being identified as a cause of VO(2) drift, it appears that carbohydrate had no effect on neuromuscular responses during load carriage. PMID- 21234593 TI - Venous occlusion plethysmography versus Doppler ultrasound in the assessment of leg blood flow during calf exercise. AB - This study explored the accuracy with which venous occlusion plethysmography (VOP) assesses the hyperaemic response during calf exercise. Using Doppler ultrasound (DU) as a criterion standard technique, we tested the hypotheses that leg blood flow during contraction is not greater than at rest and that VOP provides similar estimates of the hyperaemic response between contractions as DU. Eleven subjects performed several bouts of calf exercise across a wide range of forces (50-400 N ? 6-45%MVC). Each bout consisted of 2 min of intermittent contractions preceded and immediately followed by sustained (40 s) contractions. DU estimates of leg blood flow during the sustained contractions were never significantly greater (P > 0.05) than those measured at rest. Paired (DU and VOP) estimates of leg blood flow (n = 488) were obtained between intermittent contractions and ranged between ~50-900 ml min(-1). There was a strong correlation between these DU and VOP estimates (Pearson r = 0.91; P < 0.05). Ordinary least products regression analysis, with VOP as the y variable, showed a relatively small proportional bias (slope = 0.942; CI = 0.938-0.946) and fixed bias (y intercept = -13.3 ml min(-1); CI = -14.4 to -12.2 ml min(-1)) between the two measurement techniques. Since these small biases can be explained by the slight differences in vascular regions which the two techniques assess, these data suggest that VOP can accurately assess the hyperaemic response to exercise. PMID- 21234594 TI - Post-exercise protein synthesis rates are only marginally higher in type I compared with type II muscle fibres following resistance-type exercise. AB - We examined the effect of an acute bout of resistance exercise on fractional muscle protein synthesis rates in human type I and type II muscle fibres. After a standardised breakfast (31 +/- 1 kJ kg(-1) body weight, consisting of 52 Energy% (En%) carbohydrate, 34 En% protein and 14 En% fat), 9 untrained men completed a lower-limb resistance exercise bout (8 sets of 10 repetitions leg press and leg extension at 70% 1RM). A primed, continuous infusion of L: -[ring (13)C(6)]phenylalanine was combined with muscle biopsies collected from both legs immediately after exercise and after 6 h of post-exercise recovery. Single muscle fibres were dissected from freeze-dried biopsies and stained for ATPase activity with pre-incubation at a pH of 4.3. Type I and II fibres were separated under a light microscope and analysed for protein-bound L: -[ring-(13)C(6)]phenylalanine labelling. Baseline (post-exercise) L: -[ring-(13)C(6)]phenylalanine muscle tissue labelling, expressed as (?(13)C/(12)C), averaged -32.09 +/- 0.28, -32.53 +/- 0.10 and -32.02 +/- 0.16 in the type I and II muscle fibres and mixed muscle, respectively (P = 0.14). During post-exercise recovery, muscle protein synthesis rates were marginally (8 +/- 2%) higher in the type I than type II muscle fibres, at 0.100 +/- 0.005 versus 0.094 +/- 0.005%/h, respectively (P < 0.05), whereby rates of mixed muscle protein were 0.091 +/- 0.005%/h. Muscle protein synthesis rates following resistance-type exercise are only marginally higher in type I compared with type II muscle fibres. PMID- 21234595 TI - Reliability and accuracy of segmental bioelectrical impedance analysis for assessing muscle and fat mass in older Europeans: a comparison with dual-energy X ray absorptiometry. AB - Segmental determination of muscle and fat mass (MM, FM) attains growing importance for judging effects of training and malnutrition in older people. This study evaluated the reliability and accuracy of segmental bioelectrical impedance analysis (sBIA) for use in older people. In 72 (40 men, 32 women) healthy elderly (mean age 69.0 +/- 4.8 years), the MM and FM of right and left arm (RA, LA), right and left leg (RL, LL), and trunk were determined by sBIA (BC-418-MA, Tanita) and dual-energy X-ray absorptiometry (DXA) as a reference method. The sBIA provided in both sexes reliable values for limb and truncal MM and FM, except for MM of RL in women. The accuracy of sBIA displayed sex-specific bias. For MM, accurate values were noted for men's trunk and women's limbs (except LA). By contrast, MM was significantly underestimated in men's limbs by 6-18% and overestimated in women's LA (13%) and trunk (14%). Estimates of FM were accurate for men's arms as well as women's legs and trunk. However, FM was significantly overestimated in men's legs (34-37%) and trunk (60%), but underestimated in women's arms (27-35%). The proportional deviations of sBIA estimates from DXA values for limbs and trunk were significantly related to the respective MM or FM. The sBIA tends to underestimate MM in men and to overestimate in women. The reverse occurs for FM. The actual equations of the Tanita device may not completely represent the European older population and should be partly revised. PMID- 21234596 TI - Functional characterization of nonsynonymous single nucleotide polymorphisms in the electrogenic Na+-HCO3- cotransporter NBCe1A. AB - The electrogenic Na(+)-HCO(3)(-) cotransporter NBCe1 encoded by SLC4A4 plays essential roles in the regulation of intracellular/extracellular pH. Homozygous mutations in NBCe1 cause proximal renal tubular acidosis associated with ocular abnormalities. In the present study, we tried to perform functional characterization of the four nonsynonymous single nucleotide polymorphisms (SNPs), E122G, S356Y, K558R, and N640I in NBCe1A. Functional analysis in Xenopus oocytes revealed that while the K558R variant had a significantly reduced transport activity corresponding to 47% of the wild-type activity, the remaining variants E122G, S356Y, and N640I did not change the NBCe1A activity. Apparent Na(+) affinity of K558R was not different from that of wild-type NBCe1A. Immunohistological analyses in HEK293 cells and MDCK cells indicated that none of these SNPs changed the trafficking behaviors of NBCe1A. Functional analysis in HEK293 cells also revealed that only the K558R variant had a reduced transport activity, corresponding to 41-47% of the wild-type activity. From these results, we conclude that among four SNPs, only the K558R variant, which is predicted to lie in transmembrane segment 5, significantly reduces the NBCe1A activity without changing the trafficking behavior or the apparent extracellular Na(+) affinity. PMID- 21234597 TI - CO2-dependent opening of an inwardly rectifying K+ channel. AB - CO(2) chemosensing is a vital function for the maintenance of life that helps to control acid-base balance. Most studies have reported that CO(2) is measured via its proxy, pH. Here we report an inwardly rectifying channel, in outside-out excised patches from HeLa cells that was sensitive to modest changes in PCO(2) under conditions of constant extracellular pH. As PCO(2) increased, the open probability of the channel increased. The single-channel currents had a conductance of 6.7 pS and a reversal potential of -70 mV, which lay between the K(+) and Cl(-) equilibrium potentials. This reversal potential was shifted by +61 mV following a tenfold increase in extracellular [K(+)] but was insensitive to variations of extracellular [Cl(-)]. The single-channel conductance increased with extracellular [K(+)]. We propose that this channel is a member of the Kir family. In addition to this K(+) channel, we found that many of the excised patches also contained a conductance carried via a Cl(-)-selective channel. This CO(2)-sensitive Kir channel may hyperpolarize excitable cells and provides a potential mechanism for CO(2)-dependent inhibition during hypercapnia. PMID- 21234598 TI - Nicotiana tabacum overexpressing gamma-ECS exhibits biotic stress tolerance likely through NPR1-dependent salicylic acid-mediated pathway. AB - The elaborate networks and the crosstalk of established signaling molecules like salicylic acid (SA), jasmonic acid (JA), ethylene (ET), abscisic acid (ABA), reactive oxygen species (ROS) and glutathione (GSH) play key role in plant defense response. To obtain further insight into the mechanism through which GSH is involved in this crosstalk to mitigate biotic stress, transgenic Nicotiana tabacum overexpressing Lycopersicon esculentum gamma-glutamylcysteine synthetase (LeECS) gene (NtGB lines) were generated with enhanced level of GSH in comparison with wild-type plants exhibiting resistance to pathogenesis as well. The expression levels of non-expressor of pathogenesis-related genes 1 (NPR1) dependent genes like pathogenesis-related gene 1 (NtPR1), mitogen-activated protein kinase kinase (NtMAPKK), glutamine synthetase (NtGLS) were significantly enhanced along with NtNPR1. However, the expression levels of NPR1-independent genes like NtPR2, NtPR5 and short-chain dehydrogenase/reductase family protein (NtSDRLP) were either insignificant or were downregulated. Additionally, increase in expression of thioredoxin (NtTRXh), S-nitrosoglutathione reductase 1 (NtGSNOR1) and suppression of isochorismate synthase 1 (NtICS1) was noted. Comprehensive analysis of GSH-fed tobacco BY2 cell line in a time-dependent manner reciprocated the in planta results. Better tolerance of NtGB lines against biotrophic Pseudomonas syringae pv. tabaci was noted as compared to necrotrophic Alternaria alternata. Through two-dimensional gel electrophoresis (2-DE) and image analysis, 48 differentially expressed spots were identified and through identification as well as functional categorization, ten proteins were found to be SA-related. Collectively, our results suggest GSH to be a member in cross communication with other signaling molecules in mitigating biotic stress likely through NPR1-dependent SA-mediated pathway. PMID- 21234599 TI - Changes in gravity rapidly alter the magnitude and direction of a cellular calcium current. AB - In single-celled spores of the fern Ceratopteris richardii, gravity directs polarity of development and induces a directional, trans-cellular calcium (Ca(2+)) current. To clarify how gravity polarizes this electrophysiological process, we measured the kinetics of the cellular response to changes in the gravity vector, which we initially estimated using the self-referencing calcium microsensor. In order to generate more precise and detailed data, we developed a silicon microfabricated sensor array which facilitated a lab-on-a-chip approach to simultaneously measure calcium currents from multiple cells in real time. These experiments revealed that the direction of the gravity-dependent polar calcium current is reversed in less than 25 s when the cells are inverted, and that changes in the magnitude of the calcium current parallel rapidly changing g forces during parabolic flight on the NASA C-9 aircraft. The data also revealed a hysteresis in the response of cells in the transition from 2g to micro-g in comparison to cells in the micro-g to 2-g transition, a result consistent with a role for mechanosensitive ion channels in the gravity response. The calcium current is suppressed by either nifedipine (calcium-channel blocker) or eosin yellow (plasma membrane calcium pump inhibitor). Nifedipine disrupts gravity directed cell polarity, but not spore germination. These results indicate that gravity perception in single plant cells may be mediated by mechanosensitive calcium channels, an idea consistent with some previously proposed models of plant gravity perception. PMID- 21234601 TI - Revision of the species complex Amidostomum acutum (Lundahl, 1848) (Nematoda: Amidostomatidae). AB - Most available literature indicates that the most dominant nematode in Anatinae is a cosmopolitan species Amidostomum acutum (Lundahl, 1848). However, studies on wild duck helminthofauna in northwestern Poland suggest that these birds are attacked by not one but three different parasite species, previously described as a single species. Hence the aim of this study was the redescription of the species complex Amidostomum acutum, conducted on a representative sample of parasites and their hosts. The study material consisted of 6,430 nematode individuals, isolated from the digestive tracts of 1,005 wild ducks, representing 17 species. Unsupervised classification was performed using a Kohonen artificial neural network. The analysis confirmed the division of nematodes into three groups corresponding to three species, both for males and females. Taking into account the qualitative characteristics of the parasites, one can 100% accurately identify these species. The three groups of parasites were also significantly different in their ecology, manifested in their distinct host specificity. PMID- 21234600 TI - Neurological complications of pandemic influenza A H1N1 2009 infection: European case series and review. AB - Neurological manifestations and outcomes of children with the 2009 H1N1 virus infection have been reported in three American series and from smaller cohorts and case reports worldwide. Of the 83 children admitted between April 2009 and March 2010 with H1N1 virus infection to a tertiary children's hospital in a European setting, five children aged between 2 and 10 years had neurological symptoms. Four patients had seizures and encephalopathy at presentation. One patient presented with ataxia; one developed neuropsychiatric manifestations, and two developed movement disorders during the disease course. Early neuroimaging showed evidence of acute necrotising encephalopathy (ANE) in one case and non specific white matter changes in another. Initial neuroimaging was normal for the other three, but interval MRI showed increased signal in bilateral periventricular distribution in one and significant cerebral volume loss in the other. Clinical outcomes varied: two recovered fully while three had residual seizures and/or significant cognitive deficits. Conclusion An analysis of our patients along with all reported cases reveal that seizures and encephalopathy were common neurological presentations associated with pandemic 2009 H1N1 influenza virus infection in children requiring hospital admission. Neuroimaging suggestive of ANE, basal ganglia involvement and volume loss appears to be associated with worse neurological outcome. PMID- 21234602 TI - Recent transposition activity of Xenopus T2 family miniature inverted-repeat transposable elements. AB - To investigate the recent transposition activity of T2 family miniature inverted repeat transposable elements (MITEs) in Xenopus tropicalis (Western clawed frog), we analyzed the intraspecific polymorphisms associated with MITE insertion in X. tropicalis for three subfamilies of the T2 family (T2-A1, T2-C, and T2-E). A high frequency of MITE-insertion polymorphisms was observed at the T2-A1 (50%) and T2 C insertion loci (60%), but none were noted at the T2-E insertion locus (0%). Analyses of the collected data indicated that members of the T2-A1 and T2-C subfamilies may be currently active in the host species. Identification of these active transpositions will help us in understanding the mechanisms underlying the long-term survival (over several tens of millions of years) of the T2-A1 and T2-C subfamilies. PMID- 21234603 TI - Cellular morphology and markers of cartilage and bone in the marine teleost Sparus auratus. AB - Modifications have been characterised in terms of cellular organisation and the extracellular matrix (ECM) during bone ontogeny in the sea bream (Sparus auratus). During endochondral development, the agglomeration of matrix-secreting cells gives rise to chondrones; these chondrones frequently contain proliferating cell-nuclear-antigen-positive cells, which subsequently become large collagen-II positive cells with the characteristics of chondrocytes. Moreover, the matrix:cell ratio within the perichondrium increases, accompanied by a modification in ECM composition. Mineralisation of cartilage ECM is marked by a rapid fall in cell number, the switching off of collagen II transcription and the switching on of collagen X transcription, followed by collagen I transcription and bone mineralisation. The formation of dermal structures initiated upon the condensation of mesenchyme cells defines the future location of the dermal bone. Subsequent cellular differentiation gives rise to cells on the bone surface; these cells are positive for collagen I and osteonectin transcripts. The fish skeleton, with the exception of vertebrae, tends to comprise flattened bones that are covered by a monolayer of cells, the periosteum. A third type of tissue, present in gills, consists of chondrocyte-like cells embedded in a mineralised matrix resembling chondroid bone in mammals. The results suggest that the cellular organisation and ontogeny of endochondral and dermal bone in the sea bream are similar to those described in other vertebrates. PMID- 21234604 TI - Phenotypic and genetic differences in a perennial herb across a natural gradient of CO2 concentration. AB - The atmospheric CO(2) concentration [CO(2)] has been increasing markedly since the industrial revolution and is predicted to reach 500-1,000 MUmol mol(-1) by the end of this century. Although the short-term and acclimatory responses to elevated [CO(2)] have been well studied, much less is understood about evolutionary responses to high [CO(2)]. We studied phenotypic and genetic differences in Plantago asiatica populations around a natural CO(2) spring, where [CO(2)] has been consistently high over an evolutionary time scale. Our common garden experiment revealed that plants transferred from habitats with higher [CO(2)] had higher relative growth rates, greater leaf to root ratios, lower photosynthetic rates, and lower stomatal conductance. The habitat-dependent differences were partly heritable because a similar trend of leaf to root ratio was found among their offsprings. Genetic analyses indicated that selfing or biparental inbreeding might promote local adaptation in areas with high [CO(2)] despite substantial gene flow across the [CO(2)] gradient. These results indicate that phenotypic and genetic differences have occurred between high and normal [CO(2)] populations. PMID- 21234605 TI - Surgery needs better support from EU. PMID- 21234606 TI - Vitamin E for preventing chemotherapy-induced peripheral neuropathy. PMID- 21234607 TI - Pneumatosis intestinalis in children with acute lymphoblastic leukemia and acute myeloid leukemia. AB - PURPOSE: To describe symptoms, diagnostic features, treatments, and outcomes of pneumatosis intestinalis (PI) in pediatric patients being treated for acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). METHODS: This retrospective chart review included 514 patients <= 18 years of age diagnosed with ALL or AML between January 1999 and December 2007. PI episodes were identified by radiology report reviews. RESULTS: Twenty patients with ALL and four patients with AML presented 31 PI episodes. The median time between diagnoses of leukemia and PI was 1.0 month (interquartile range 0.8-6.4 months). Plain radiographs diagnosed all PI episodes. Computerized tomography (CT) and ultrasound were performed in 6 and 13 episodes, respectively. All CT and three ultrasounds demonstrated PI. Thirty episodes occurred exclusively in the colon, most commonly in the ascending (n = 26) and transverse (n = 18) segments. Treatment included complete bowel rest in 27 (87.1%) and intravenous broad spectrum antibiotics in 29 (93.5%). One case required colectomy. Two episodes were untreated. There were no fatalities associated with PI. CONCLUSIONS: PI is uncommon in children with ALL or AML. Ultrasound is less sensitive than plain radiographs for diagnosis. PI occurred almost exclusively in the colon. With conservative management, most patients had excellent outcome. PMID- 21234608 TI - Baseline depression predicts malnutrition in head and neck cancer patients undergoing radiotherapy. AB - PURPOSE: Poor nutritional status is common and associated with mortality and morbidity in patients with head and neck cancer (HNC). While there are several established clinical risk factors for poor nutritional status during HNC radiotherapy, the complete aetiology is not known. The association of malnutrition with psychological factors has been recognised in other chronic illnesses but has not been studied in HNC patients who have higher levels of malnutrition and psychological disorder than many other patient populations. METHOD: Patients with HNC were assessed at three time points: week 1 of radiotherapy treatment (T1, n = 72), end of radiotherapy treatment (T2, n = 64) and 4 weeks post-radiotherapy treatment (T3, n = 58). Nutritional outcome was measured using the Patient-Generated Subjective Global Assessment, and psychological factors measured were depression, anxiety and adjustment style. RESULTS: Linear mixed models indicated that a model containing the variables time, tumour site and baseline depression best explained malnutrition at T2 and T3 (-2 restricted log likelihood = 695.42). The clinical risk factors: cancer stage, number of radiotherapy fractionations, a PEG feeding tube, availability of a care giver and dietitian's informal clinical assessment did not predict later nutritional status. CONCLUSIONS: Depression is a modifiable risk factor for malnutrition among HNC patients undergoing radiation therapy, offering the potential to ameliorate malnutrition in this group. While the nature of any causal relationship between depression and malnutrition in HNC is yet to be understood, the utility of a short depression screen in predicting malnutrition has been demonstrated and could be adopted in clinical practice. PMID- 21234609 TI - Adherence to ESMO clinical recommendations for prophylaxis of chemotherapy induced nausea and vomiting. AB - BACKGROUND: We assessed adherence to the European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) at our institution. PATIENTS AND METHODS: The charts of 299 patients starting a new chemotherapy between November 2008 and April 2009 were reviewed. Baseline characteristics and prophylaxis of CINV during the first cycle were recorded, and adherence to ESMO recommendations was determined. Chi-square tests and logistic regression were used to test for predictors of adherence. RESULTS: Prophylaxis of acute CINV was not adherent in 39% of the patients: 39 of 54 patients with low emetogenic chemotherapy had a serotonin antagonist, and 24 of 100 with moderately emetogenic therapy had a neurokinin antagonist. Nevertheless, 71% of the patients treated with highly emetogenic therapy received the guideline-specified prescription. Prophylaxis of delayed CINV was not adherent in 89% of the patients: 101 of 125 patients with highly or moderately emetogenic single-day chemotherapy received a serotonin antagonist. Male gender (odds ratio (OR) 0.484, 95% confidence interval (CI) 0.291-0.806; P = 0.005) and hematologic neoplasia (OR 2.151, 95% CI 1.19-3.887; P = 0.011) were independent predictors of non adherence. Age (OR 0.981, 95% CI 0.964-0.998; P = 0.029) and inpatient treatment (OR 0.457, 95% CI 0.25-0.836; P = 0.011) indicated a lower risk of non-adherence. CONCLUSION: Contrary to older studies reporting frequent omissions of corticosteroids, the current study demonstrated significant overuse of serotonin antagonists for prophylaxis of delayed CINV. PMID- 21234610 TI - Sinisan, a traditional Chinese medicine, attenuates experimental chronic pancreatitis induced by trinitrobenzene sulfonic acid in rats. AB - BACKGROUND/PURPOSE: Sinisan, a traditional Chinese medicine, is effective for the treatment of gastrointestinal disorders. In this study, we investigated the potential protective role of Sinisan against chronic pancreatitis (CP) in rats. METHODS: CP was induced in rats by intrapancreatic injection of trinitrobenzene sulfonic acid (TNBS). Rats were randomly divided into a sham group, a TNBS induced CP group and a Sinisan-treated group. Serum amylase and histological score were used to evaluate the severity of disease. The levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), cyclooxygenase-2 (COX-2), interleukin-10 (IL-10) and alpha-smooth muscle actin (alpha-SMA) were also measured in the three groups. Mechanical allodynia was measured with von Frey filaments. In addition, the protein levels of nerve growth factor (NGF) were measured in pancreatic tissues. RESULTS: Administration of Sinisan significantly decreased the severity of CP. In the Sinisan-treated group, serum amylase, TNF alpha, IL-1beta, COX-2 and alpha-SMA levels were lower and the level of IL-10 was upregulated compared with the TNBS-induced CP group. Furthermore, treatment with Sinisan significantly, though not completely, attenuated the allodynia. Simultaneously NGF expression was also significantly downregulated in the Sinisan treated group compared with the TNBS-induced CP group. CONCLUSIONS: Sinisan could be an effective treatment modality for CP via its anti-inflammatory, anti fibrotic and analgesic properties. It may be a promising drug candidate for the treatment of patients with CP. PMID- 21234611 TI - The clinicopathological significance of heat shock protein 70 and glutamine synthetase expression in hepatocellular carcinoma. AB - BACKGROUND/PURPOSE: Heat shock protein 70 (HSP70) and glutamine synthetase (GS) have been proposed to be promising markers for the differentiation of malignant and benign hepatocellular lesions. The aim of this study was to investigate the clinicopathological significance of the expression of HSP70 and GS in surgically resected hepatocellular carcinoma (HCC). METHODS: The authors collected 412 HCC samples and 120 non-neoplastic hepatic tissue samples and performed an immunohistochemical study. RESULTS: HSP70 staining was observed in 282 of 392 HCC samples (71.9%), and GS immunoreactivity was observed in 212 of 395 HCC cases (53.7%). Of the several clinicopathological parameters examined, microscopic vascular invasion, a large tumor size, and a high Edmonson-Steiner grade were found to be correlated with positive staining for HSP70 (P = 0.032, 0.002, and 0.012, respectively). Survival analysis showed a correlation between HSP70 expression and disease-free survival. GS was not found to be related to clinicopathological parameters. CONCLUSIONS: The findings of the present study suggest that HSP70 be viewed as a predictor of prognosis as well as a useful diagnostic marker for HCC. PMID- 21234612 TI - Immunohistochemical study of hepatocyte, cholangiocyte and stem cell markers of hepatocellular carcinoma. AB - BACKGROUND/PURPOSE: Hepatocellular carcinomas (HCCs) commonly originate from pre malignant lesions consisting of mature hepatocytes. However, recent studies have suggested that some HCCs emerge from hepatic stem/progenitor cells because stem/progenitor cell markers and cholangiocyte markers are found in these HCCs. At the same time, the expression of stem/progenitor cell markers and cholangiocyte markers may also indicate de-differentiation and transdifferentiation of ordinary HCC cells. This study was performed to help clarify the uncertainty surrounding these HCCs. METHODS: Sixty-eight surgically resected HCC lesions no larger than 5 cm were studied immunohistochemically using a hepatocyte marker (Hepatocyte), 2 cholangiocyte markers (cytokeratins CK7 and CK19), a marker for mucin (Muc1), and a hepatic stem/progenitor cell marker (C kit). RESULTS: Hepatocyte, CK7, CK19, Muc1 and C-kit were positively stained in 68 cases (100%), 51 cases (75.0%), 15 cases (22.1%), 8 cases (11.8%) and 8 cases (11.8%), respectively. In those cases positive for CK7, CK19, Muc1 and C-kit, the positively stained cells formed small foci within a large area of negatively stained cells. Small-sized positive cells suggesting hepatic/stem cell origin were found rarely. CONCLUSIONS: The positivity of cholangiocyte markers, the stem/progenitor cell marker and mucin production were thought to be due to transdifferentiation of HCC cells rather than malignant transformation of stem/progenitor cells. PMID- 21234614 TI - Metabolic syndrome and vascular risk: a 9-year follow-up among the aged in Finland. AB - The aim was to analyze the relationship between metabolic syndrome (MetS) and vascular risk among the aged. A prospective population-based study, with a 9-year follow-up. All subjects of the municipality of Lieto in Finland aged >=64 in 1998 99 participated (n = 1183). Hazard ratios (HRs) for fatal or non-fatal coronary (CHD), cerebrovascular (CV), or all vascular events predicted by MetS (defined by International Diabetes Federation) were estimated. During the 9-year follow-up, a total of 348 vascular events occurred, including 208 CHD and 150 CV events. After multivariable adjustment, CHD events (1.70, 1.07-2.71, P = .026) and vascular events (1.57, 1.07-2.30, P = .021) were more common in men with MetS compared to men without it. Evaluating MetS components individually, low HDL-cholesterol among women predicted a higher occurrence of CV (2.44, 1.46-4.09, P < .001) and all vascular (1.78, 1.26-2.53, P = .001) events. Elevated blood pressure among men was related to fewer CHD events (0.46, 0.25-0.83, P = .010). Our findings suggest that MetS does predict vascular events in late life among men. In older women, only low HDL-cholesterol was associated with vascular risk. Slightly or moderately elevated blood pressure values do not predict vascular events in this age group. PMID- 21234613 TI - Relationships between serum adiponectin and soluble TNF-alpha receptors and glucose and lipid oxidation in lean and obese subjects. AB - Insulin resistance might be associated with an impaired ability of insulin to stimulate glucose oxidation and inhibit lipid oxidation. Insulin action is also inversely associated with TNF-alpha system and positively related to adiponectin. The aim of the present study was to analyze the associations between serum adiponectin, soluble TNF-alpha receptors concentrations and the whole-body insulin sensitivity, lipid and glucose oxidation, non-oxidative glucose metabolism (NOGM) and metabolic flexibility in lean and obese subjects. We examined 53 subjects: 25 lean (BMI < 25 kg * m(-2)) and 28 with overweight or obesity (BMI > 25 kg * m(-2)) with normal glucose tolerance. Hyperinsulinemic euglycemic clamp and indirect calorimetry were performed. An increase in respiratory exchange ratio in response to insulin was used as a measure of metabolic flexibility. Obese subjects had lower insulin sensitivity, adiponectin and higher sTNFR1 (all P < 0.001) and sTNFR2 (P = 0.001). Insulin sensitivity was positively related to adiponectin (r = 0.49, P < 0.001) and negatively related to sTNFR1 (r = -0.40, P = 0.004) and sTNFR2 (r = -0.52, P < 0.001). Adiponectin was related to the rate of glucose (r = 0.47, P < 0.001) and lipid (r = -0.40, P = 0.003) oxidation during the clamp, NOGM (r = 0.41, P = 0.002) and metabolic flexibility (r = 0.36, P = 0.007). Serum sTNFR1 and sTNFR2 were associated with the rate of glucose (r = -0.45, P = 0.001; r = -0.51, P < 0.001, respectively) and lipid (r = 0.52, P < 0.001; r = 0.46, P = 0.001, respectively) oxidation during hyperinsulinemia, NOGM (r = -0.31, P = 0.02; r = -0.43, P = 0.002, respectively) and metabolic flexibility (r = -0.47 and r = -0.51, respectively, both P < 0.001) in an opposite manner than adiponectin. Our data suggest that soluble TNF-alpha receptors and adiponectin have multiple effects on glucose and lipid metabolism in obesity. PMID- 21234615 TI - Giant, thrombosed, sellar-suprasellar internal carotid artery aneurysm with persistent, primitive trigeminal artery causing hypopituitarism. AB - A rare case of a giant, thrombosed, sellar-suprasellar paraclinoid internal carotid artery (ICA) aneurysm with persistent primitive trigeminal artery (PPTA) causing hypopituitarism that manifested as hypogonadism, hypothyroidism, and hypocortisolism is reported. There were no visual/neurological deficits, diabetes insipidus, or episodes of subarachnoid hemorrhage. The alteration in the flow dynamics of the circle of Willis due to the presence of PPTA may have been responsible for both the genesis of the giant aneurysm as well as for the induction of thrombogenesis within its lumen. As the digital subtraction angiogram showed complete thrombosis within the aneurysm and hormonal replacement therapy was effective in ensuring complete normalization of symptoms, the patient was unwilling to undergo surgical clipping of the aneurysm and removal of the suprasellar clot in an attempt to restore pituitary functions. Hypopituitarism recurred when the patient stopped her hormonal supplementation therapy after 7 years, and she again became symptom-free on restarting the therapy. To the best of the authors' knowledge, this represents the first reported case in the literature of hypopituitarism consequent to a giant, thrombosed, sellar suprasellar ICA aneurysm with an associated PPTA on the side of the aneurysm. PMID- 21234616 TI - Giant intracavernous carotid aneurysm with intraorbital extension: an unusual cause of unilateral proptosis. PMID- 21234617 TI - Outcome of severe arteriovenous malformation-related intracranial hemorrhage: the importance of cisternal subarachnoid hemorrhage and early seizures. AB - BACKGROUND: Although arteriovenous malformations (AVM)-related intracranial hemorrhage (ICH) is infrequently devastating, there is a subgroup of patients that present comatose requiring immediate surgical treatment. We sought to determine the outcome and prognostic factors in those patients with severe AVM ICH. METHODS: Between 2003 and 2009, medical records of 16 consecutive patients presented with severe AVM-ICH were retrospectively reviewed. Outcome was determined using 30-day survival and Glasgow outcome scale and modified Rankin scale scores at last follow-up. RESULTS: There were seven males and nine females with a mean age of 32 years (range 6-66). All had Glasgow coma score 8 or less and most exhibited motor posturing and/or dilated pupils. Fifteen patients had intraprenchymal, ten had intraventricular, and four had subarachnoid hemorrhage (SAH). Twelve patients underwent hematoma evacuation with concomitant decompressive craniectomy in 11 and external ventricular drainage (EVD) in six. EVD was the only treatment offered to four patients. AVM excision was not routinely attempted in the acute phase. Three patients died from extensive bihemispheric infarction and refractory intracranial pressure. All 13 survivors improved neurologically and 12 had an acceptable functional outcome (modified Rankin scale <= 4) after a mean follow-up of 10 months (range 1-49). Among all clinical, radiological, and operative variables, only cisternal SAH (P = 0.007) and early seizures (P = 0.018) were significantly associated with death. CONCLUSION: Despite their poor initial clinical condition, most survivors of severe AVM-ICH achieve an acceptable functional outcome. Therefore, patients with severe AVM-ICH, particularly those without aneurysmal-like SAH, should be managed aggressively given their remarkable potential for neurological recovery. PMID- 21234618 TI - Intraoperative MRI detects a pattern of remnants? PMID- 21234619 TI - Typical 3-D localization of tumor remnants of WHO grade II hemispheric gliomas- lessons learned from the use of intraoperative high-field MRI control. AB - BACKGROUND: Complete resection of grade II gliomas might prolong survival but is not always possible. The goal of the study was to evaluate the location of unexpected grade II gliomas remnants after assumed complete removal with intraoperative (iop) MRI and to assess the reason for their non-detection. METHODS: Intraoperative MR images of 35 patients with hemispheric grade II gliomas, acquired after assumed complete removal of preoperatively segmented tumor/tumor part, were studied for existence of unexpected tumor remnants. Remnants location was classified in relation to tumor cavity in axial and vertical planes. The relation of remnants to retractor position and to surgeons' visual axis, and the role of neuronavigational accuracy and brain shift, was assessed. RESULTS: Unexpected remnants were found in 16 patients (46%). In 29.2%, the reason was loss of neuronavigational accuracy. In 21%, remnants were in that part of the resection cavity, where the retractor had been placed initially. In 17%, they were deeply located and hidden by the retractor. In 13%, remnants were hidden by the overlapping brain; and in 21%, the reason was not obvious. In 75% of all temporomesial tumors, remnants were posterolateral to the resection cavity. Remnants detection with iopMRI and update of neuronavigational data allowed further removal in 14 of 16 cases. In two cases, remnant location precluded their removal. CONCLUSIONS: Distribution of tumor remnants of grade II gliomas tends to follow some patterns. Targeted attention to the areas of possible remnants could increase the radicality of surgery, even if intraoperative imaging is not performed. PMID- 21234620 TI - Gene expression profiling of meningiomas: current status after a decade of microarray-based transcriptomic studies. AB - PURPOSE: This article provides a review of the transcriptomic expression profiling studies that have been performed on meningiomas so far. We discuss some future prospects and challenges ahead in the field of gene expression profiling. METHODS: We performed a systematic search in the PubMed and EMBASE databases in May 2010 using the following search terms alone or in combination: "meningioma", "microarray analysis", "oligonucleotide array sequence analysis", or "gene expression profiling". Only original research articles in English that had used RNA hybridized to high-resolution microarray chips to generate gene expression profiles were included. RESULTS: We identified 13 articles matching the inclusion criteria. All studies had been performed during the last decade. CONCLUSIONS: The main results of the studies can be grouped in three categories: (1) several groups have identified meningioma-specific genes and genes associated with the three WHO grades, and the main histological subtypes of grade I meningiomas; (2) one publication has shown that the general transcription profile of samples of all WHO grades differs in vivo and in vitro; (3) one report provides evidence that microarray technology can be used in an automated fashion to classify tumors. Due to lack of consensus on how microarray data are presented, possible general trends found across the studies are difficult to extract. This could obstruct the discovery of important genes and pathways universally involved in meningioma biology. PMID- 21234621 TI - Ultrasound bone mass in patients undergoing chronic therapy with oral anticoagulants. AB - The purpose of this study was to assess the effects of chronic oral anticoagulant (OAC) treatment on bone mass using quantitative ultrasound (QUS) techniques. A total of 120 patients (47 women and 73 men) undergoing treatment with OAC and 57 healthy subjects (27 women and 30 men) participated in this study. Bone status was assessed using QUS devices that measure the amplitude-dependent speed of sound (Ad-SoS) in phalanges and the broadband ultrasound attenuation (BUA) in the calcaneus. Men undergoing OAC treatment had lower Ad-SoS, Z-score, T-score, and BUA values (all p < 0.005) and higher levels of undercarboxylated osteocalcin (u OC) and tartrate-resistant acid phosphatase (TRAP) (both p < 0.0001) than controls. Women receiving OAC treatment had lower BUA values (p < 0.005) and total osteocalcin (OC) levels (p < 0.0001) and higher levels of u-OC and TRAP (both p < 0.0001) than controls. There was a statistically significant negative correlation between u-OC levels and Ad-SoS values in both men (r = -0.432, p = 0.0328) and women (r = -0.332, p = 0.0269) undergoing OAC treatment. In conclusion, patients undergoing OAC treatment had a loss of trabecular and cortical bone mass, possibly due to a decrease in the gamma-carboxylation of osteocalcin resulting from the vitamin K antagonism of these drugs. PMID- 21234623 TI - Toward a strategic plan for pulp healing: from repair to regeneration. PMID- 21234622 TI - Antibacterial properties and human gingival fibroblast cell compatibility of TiO2/Ag compound coatings and ZnO films on titanium-based material. AB - Titanium (Ti)-based materials are widely used in biomedical implant components and are applied successfully in various types of bone-anchored reconstructions. However, in dental implants the Ti materials contact not only bone but also gingival tissues, and are partially exposed to the oral cavity that includes bacteria. This study used titania and silver (TiO(2)/Ag) compound coatings and zinc oxide (ZnO) films to enhance the antibacterial activity of the Ti-based implant. The hydrophobicity of each sample was examined by measuring the contact angle. Streptococcus mutans and human gingival fibroblast (HGF) was cultured on the coated samples, and the antibacterial effects and cell compatibility were determined using a Syto9 fluorescence staining and MTT methods. For the TiO(2)/Ag samples, depositing Ag on the plate at a higher power (which increased the proportion of Ag) increased the contact angle and the hydrophobicity. The bacterial count was lowest for the 50 W TiO(2)/Ag sample, which contained 5.9% Ag. The contact angles of the ZnO samples did not show the same tendency. The antibacterial effect was higher on ZnO-coated samples since bacterial count was threefold lower on ZnO samples as compared to control samples (Ti plate). From the MTT assay test, the mean optical density values for TiO(2)/Ag-coated samples after 72 h of HGF adhesion were similar to the value obtained from the uncoated Ti. However, biocompatibility was lower on ZnO films than in control samples. Conclusively, the antibacterial activity was higher but the cell compatibility was lower on ZnO films than on TiO(2)/Ag coatings. PMID- 21234624 TI - Curing efficiency of modern LED units. AB - Recent reports claim that modern light-emitting diode (LED) curing units improve curing efficiency by increasing the units' irradiance. In this context also, short polymerisation times up to 5 s are proposed. The aim of this study was to examine whether there are differences in the curing efficiency of modern LED curing units by assessing their effect on two different composite materials and by varying the irradiation time. A nano- and a micro-hybrid resin-based composite (RBC) were polymerised for 5, 10 and 20 s with three commercial and a Prototype LED unit (EliparTM S10). Cylindrical specimens (6 mm in depth, 4 mm in diameter) were prepared in three increments, each 2-mm thick, and were consecutively cured. Degree of cure was measured for 20 min in real time at the bottom of the samples, starting with the photoinitiation. The micro-mechanical properties (modulus of elasticity, E and Vickers hardness, HV) were measured as a function of depth, in 100-MUm steps, on the above described samples stored in distilled water for 24 h at 37 degrees C. Data were analysed with multivariate ANOVA followed by Tukey's test, t test and partial eta-squared statistics. In descending order of the strength of their effect, the type of RBC, depth, polymerisation time and curing unit were significant factors affecting the micro-mechanical parameters (p < 0.05). The degree of cure at 6-mm depth was less but significantly influenced by the curing unit and curing time and was independent from the type of RBC. A 5-s irradiation time is not recommended for these units. Whereas a 5-s irradiation is acceptable at the sample's surface, a minimum of 20 s of irradiation is necessary for an adequate polymerisation 2 mm beyond the surface. PMID- 21234625 TI - Early intervention for at risk children: 3-year follow-up. AB - Childhood behavioral and emotional symptoms are linked with distress and dysfunction that may persist into adulthood. Effective and practical early prevention could make a significant contribution to the well-being of individuals and the functioning of communities. School-based targeted interventions are relatively easy and inexpensive to deliver and have been shown to reduce symptoms in the short term. The current study evaluates the 2- and 3-year outcome of targeted school-based drama group therapy (DGT) as compared to teaching maths and English. It shows a rapid decline in teacher-observed behavioral symptoms following DGT. By a year post intervention, symptom rates following both interventions converged and remained low throughout follow-up. Drama group therapy is rapidly effective in reducing symptoms. However, the findings also suggest that despite differing content, school-based small-group interventions are likely to share some effective components. PMID- 21234627 TI - Seasonal variations in serum levels of 25-hydroxyvitamin D in patients with systemic sclerosis. PMID- 21234626 TI - Comparison of PermacolTM and StratticeTM for the repair of abdominal wall defects. AB - BACKGROUND: Incisional hernias repaired with mesh can be expected have a lower recurrence rate than with primary repair. Biologic implants have replaced synthetic meshes in certain complex settings. We compared two porcine-dermis derived implants--cross-linked PermacolTM biologic implant and non-cross linked Strattice-firmTM tissue matrix--in a ventral hernia animal model. Our hypothesis is that cross-linked biologic implants are remodeled differently and thus behave differently than non-cross-linked biologic implants. METHODS: Eighty-nine, female Sprague-Dawley rats had a 3 * 3 cm full-thickness segment of the abdominal wall excised. A 3 * 3 cm biologic mesh, either PermacolTM or StratticeTM, was secured and the skin was closed. At 1-, 3-, 6- and 12-month time intervals, rats in each group were sacrificed and the mesh was excised. The number of adhesions, surface area, mesh thickness and tensile strength were determined, and immunohistochemical analysis performed. RESULTS: PermacolTM biologic implant maintained thickness while StratticeTM thickness decreased significantly starting at 3 months. Adhesion area and tenacity were not significantly different between PermacolTM and StratticeTM at all time points. The tensile strength of the PermacolTM biologic implant was greater than that of StratticeTM at 3, 6 and 12 months. Migration of host cells and neo-vascularization was observed in both implant groups. CONCLUSIONS: Cross-linked materials may prove more durable in the remodeling process as suggested by the increased thinning and weakening observed in non-cross-linked biomesh. PMID- 21234628 TI - The presence of anti-citrullinated protein antibodies (ACPA) does not affect the clinical response to adalimumab in a group of RA patients with the tumor necrosis factor (TNF) alpha-308 G/G promoter polymorphism. AB - The introduction of antitumor necrosis factor (TNF) agents has improved the outcome for many patients with rheumatoid arthritis (RA). To date, the only replicated genetic predictor of anti-TNF response is the -308 G > A single nucleotide polymorphism in the TNF promoter region. The presence of the -308 TNF G/G genotype appears to be a marker of good response to anti-TNF treatment. Anti citrullinated protein antibodies (ACPA) have been linked with erosive disease, and have been established as the single most reliable prognostic factor in clinical practice. To test the hypothesis that the ACPA status may affect the 308 G/G patients rate of response to TNF blockade, we prospectively investigated a group of 52 RA patients with the -308 G/G genotype who were ACPA (+) or ACPA ( ). All patients were treated with adalimumab, and the clinical response was studied using the Disease Activity Score in 28 joints (DAS28) at 24 weeks of treatment. Over 85% of patients were DAS28 responders in both groups. No significant differences were found between patients from both groups, according to the DAS28 criteria of response at week 24 (p = 0.79). In conclusion, our findings suggest that the ACPA status does not affect the clinical response to anti-TNF therapy in -308 TNF G/G patients. PMID- 21234629 TI - Health-related quality of life in patients with chronic fatigue syndrome: group cognitive behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial with 1 year of follow-up. AB - Chronic fatigue syndrome (CFS) produces physical and neurocognitive disability that significantly affects health-related quality of life (HRQL). Multidisciplinary treatment combining graded exercise therapy (GET) cognitive behavioural therapy (CBT) and pharmacological treatment has shown only short-term improvements. To compare the effects on HRQL of (1) multidisciplinary treatment combining CBT, GET, and pharmacological treatment, and (2) usual treatment (exercise counselling and pharmacological treatment) at 12 months of follow-up. Prospective, randomized controlled trial with a follow-up of 12 months after the end of treatment. Patients consecutively diagnosed with CFS (Fukuda criteria) were randomly assigned to intervention (n = 60) or usual treatment (n = 60) groups. HRQL was assessed at baseline and 12 months by the Medical Outcomes Study Short-Form questionnaire (SF-36). Secondary outcomes included functional capacity for activities of daily living measured by the Stanford Health Assessment Questionnaire (HAQ) and comorbidities. At baseline, the two groups were similar, except for lower SF-36 emotional role scores in the intervention group. At 12 months, the intervention did not improve HRQL scores, with worse SF-36 physical function and bodily pain scores in the intervention group. Multidisciplinary treatment was not superior to usual treatment at 12 months in terms of HRQL. The possible benefits of GET as part of multidisciplinary treatment for CFS should be assessed on an individual patient basis. PMID- 21234630 TI - Prevalence of IgA class antibodies to cyclic citrullinated peptide (anti-CCP) in patients with primary Sjogren's syndrome, and its association to clinical manifestations. AB - This study aims to determine the prevalence and clinical significance of anti-CCP isotype IgA in a population of patients with primary Sjogren's syndrome (pSS). Sixty-two patients diagnosed according to the USA-European classification criteria for pSS were examined two to four times during a 60.4-month follow-up, and clinical and laboratory data were registered prospectively. Antibodies against cyclic citrullinated peptides (anti-CCP) isotype IgG and IgA were determined in serum samples by an immunofluorescence ELiATM system. Healthy individuals and patients with rheumatoid arthritis (RA) with matching sex and age served as controls. The serum level of anti-CCP IgA was higher in pSS patients than healthy individuals (2.37 versus 1.37 EU/ml; p < 0.0001), and lower than matching patients with RA (2.37 versus 6.51 EU/ml; p < 0.0001). Using a cutoff for anti-CCP IgA at 4.12 EU/ml, 8.1 % pSS patients had a positive test compared to 26.7% of patients with RA. Positive test for anti-CCP IgG was demonstrated in 4.8% pSS patients. There were no significant differences between demographic and serological variables in pSS patients with positive versus negative anti-CCP IgA. There was significantly more pSS patients with cutaneous vasculitis in the anti CCP IgA-positive population, however (40.0% versus 3.5%; p = 0.030), and there was a nonsignificant trend of lower unstimulated whole saliva collection (USWC) in the anti-CCP IgA-positive patients. There were no correlations between arthritis and anti-CCP IgG and IgA. This is the first study on the prevalence of anti-CCP isotype IgA in patients with pSS, demonstrating that anti-CCP isotype IgA is moderately increased in patients with pSS but lower than the prevalence in patients with RA. The presence of IgA and IgG anti-CCP isotypes were not associated with arthritis or other clinical manifestations in pSS patients. We demonstrated an association of anti-CCP IgA to cutaneous vasculitis. PMID- 21234631 TI - Cardiac tamponade and large pericardial effusions in systemic sclerosis: a report of four cases and a review of the literature. AB - Cardiac tamponade in systemic sclerosis is rare. We report four cases of SSc with hemodynamically significant pericardial effusions associated with pulmonary arterial hypertension, three of whom died, two following pericardiocentesis. Of 26 SSc cases reported in the literature with large pericardial effusions, seven were associated with PAH. Including our series, the mortality rate is 55%.The potential contributory role of PAH in the development of pericardial effusion and the management implications are explored. In SSc patients with hemodynamically significant pericardial effusions and severe pulmonary hypertension, initial stabilization of pulmonary artery pressure and right heart function with vasoactive therapy and then cautious pericardial drainage should be considered. PMID- 21234632 TI - Sonographically guided hydrodissection and corticosteroid injection for scleroderma hand. AB - Scleroderma is associated with intractable hand pain from vasospasm, digital ischemia, tenosynovitis, and nerve entrapment. This study investigated the effect of hydrodissection of the carpal tunnel followed by corticosteroid injection for the painful scleroderma hand. Twenty-six consecutive subjects [12 with painful scleroderma hand and 14 with rheumatoid arthritis and carpal tunnel syndrome (RA/CTS)] underwent sonographically observed carpal tunnel hydrodissection with 3 ml of 1% lidocaine administered with a 25-gauge 1-in. needle on a 3-ml RPD mechanical syringe (reciprocating procedure device). After hydrodissection, a syringe exchange was performed, and 80 mg of triamcinolone acetonide was injected. Baseline pain, procedural pain, pain at outcome, responders, therapeutic duration, and reinjection interval were determined. Hydrodissection and injection with corticosteroid significantly reduced pain scores by 67% in scleroderma (p < 0.001) and by 47% in RA/CT (p < 0.001). Scleroderma and RA/CTS were similar in outcome measures: injection pain (p = 0.47), pain scores at outcome (p = 0.13), responders (scleroderma, 83.3%; RA/CTS, 57.1%, p = 0.15), pain at 6 months (p = 0.15), and therapeutic duration (p = 0.07). Scleroderma patients responded better in time to next injection (scleroderma, 8.5 +/- 3.0 months; RA/CTS, 5.2 +/- 3.1 months, p = 0.03). Reduced Raynaud's attacks and healing of digital ulcers occurred in 83% of subjects. There were no complications. Hydrodissection with lidocaine followed by injection of triamcinolone reduces pain and vasomotor changes in the scleroderma hand. The mechanism may be a combination of hydrodissection-mediated mechanical freeing of entrapped arteries, nerves, and tendinous structures and corticosteroid-induced reduction of inflammatory vasospasm. PMID- 21234633 TI - Time to revise the paradigm of hantavirus syndromes? Hantavirus pulmonary syndrome caused by European hantavirus. AB - Hantaviruses have previously been recognised to cause two separate syndromes: hemorrhagic fever with renal syndrome in Eurasia, and hantavirus pulmonary syndrome (HPS) in the Americas. However, increasing evidence suggests that this dichotomy is no longer fruitful when recognising human hantavirus disease and understanding the pathogenesis. Herein are presented three cases of severe European Puumala hantavirus infection that meet the HPS case definition. The clinical and pathological findings were similar to those found in American hantavirus patients. Consequently, hantavirus infection should be considered as a cause of acute respiratory distress in all endemic areas worldwide. PMID- 21234634 TI - Effect of acid and laser etching on shear bond strength of conventional and resin modified glass-ionomer cements to composite resin. AB - Success in sandwich technique procedures can be achieved through an acceptable bond between the materials. The aim of this study was to compare the effect of 35% phosphoric acid and Er,Cr:YSGG laser on shear bond strength of conventional glass-ionomer cement (GIC) and resin-modified glass-ionomer cement (RMGIC) to composite resin in sandwich technique. Sixty-six specimens were prepared from each type of glass-ionomer cements and divided into three treatment groups as follows: without pretreatment, acid etching by 35% phosphoric acid for 15 s, and 1-W Er,Cr:YSGG laser treatment for 15 s with a 600-MUm-diameter tip aligned perpendicular to the target area at a distance of 1 mm from the surface. Energy density of laser irradiation was 17.7 J/cm(2). Two specimens in each group were prepared for evaluation under a scanning electron microscope (SEM) after surface treatment and the remainder underwent bonding procedure with a bonding agent and composite resin. Then the shear bond strength was measured at a crosshead speed of 0.5 mm/min. Two-factor analysis of variance and post-hoc Tukey test showed that the cement type, surface treatment method, and the interaction of these two factors significantly affect the shear bond strength between glass-ionomer cements and composite resin (p < 0.05). Surface treatment with phosphoric acid or Er,Cr:YSGG laser increased the shear bond strength of GIC to composite resin; however, in RMGIC only laser etching resulted in significantly higher bond strength. These findings were supported by SEM results. The fracture mode was evaluated under a stereomicroscope at *20. PMID- 21234635 TI - Myocardial infarction after blunt chest trauma: usefulness of cardiac ECG-gated CT and MRI for positive and aetiologic diagnosis. AB - Myocardial infarction after blunt chest trauma has been reported in only few cases, and mechanisms of this complication have rarely been described. We report two cases of coronary artery lesions, one parietal hematoma of right coronary artery and one dissection of the left main coronary artery, which resulted in acute myocardial infarction following a blunt chest trauma. In these two cases, cardiac CT and MRI were useful to noninvasively explore these lesions. PMID- 21234636 TI - Oral premalignant lesions: from the pathological viewpoint. AB - Under the widely used World Health Organization (WHO) classification for the pathological diagnosis of oral premalignant lesions, dysplasia, which is graded as mild, moderate or severe, and carcinoma in situ (CIS), which is a non-invasive carcinoma, are classified as precursor lesions of oral squamous cell carcinoma. Since the first edition (Wahi et al. International histological classification of tumours no. 4, WHO, Geneva, 1971), the criterion for CIS--that all epithelial layers are replaced by atypical cells--has remained unchanged. However, this dysplasia-carcinoma sequence theory was introduced from the viewpoint of pathological changes in the uterine cervix: in contrast, almost all premalignant lesions and CIS of the oral mucosa show superficial maturation and differentiation. Based on this recognition, the squamous intraepithelial neoplasia (SIN) classification and Ljubljana classification were included in WHO's latest edition published in 2005. Although the WHO classification is commonly used in Japan, recent developments in oral oncology have promoted modifications of the classification used in this country. In 2005, the Working Group of the Japan Society for Oral Tumours advocated iodine staining and proposed a modified SIN system, and in 2007, the Working Committee of the Japanese Society for Oral Pathology (JSOP) reported a new CIS (JSOP) definition that included differentiated-type CIS. In 2010, based on these studies, a new entity--oral intraepithelial neoplasia (OIN)--was included in the first edition of General Rules for Clinical and Pathological Studies on Oral Cancer. In this review, we focus on the OIN/CIS (JSOP) new classification of premalignant lesions in oral mucosa, which further advances the concept of SIN. PMID- 21234637 TI - Can vacuum-assisted closure and instillation therapy (VAC-Instill therapy) play a role in the treatment of the infected open abdomen? AB - Severe superimposed infection during open abdomen treatment with development of intra-abdominal sepsis is a challenging complication associated with high mortality rates. We report our experience with VAC-Instill therapy (KCI, San Antonio, USA) used for treatment of an infected open abdomen following pancreatic surgery. A literature search revealed no analogous case reports using VAC-Instill therapy for treatment of an infected laparostomy. The encouraging result of the case presented seems to indicate that VAC-Instill therapy could be used as adjunctive treatment in the management of the infected open abdomen when traditional therapy fails to control the infection. PMID- 21234638 TI - Traditional laparoscopic colorectal resections can be performed effectively using a three-port technique. PMID- 21234639 TI - The umbilicus as a site for defunctioning ileostomies. PMID- 21234640 TI - Understanding paternal genome demethylation through live-cell imaging and siRNA. AB - Identification of a DNA demethylase responsible for zygotic paternal DNA demethylation has been one of the most challenging goals in the field of epigenetics. Several candidate molecules have been proposed, but their involvement in the demethylation remains controversial, partly due to the difficulty of preparing a sufficient quantity of materials for biochemical analysis. In this review, we utilize a recently developed method for live-cell imaging of mouse zygotes combined with RNA interference (RNAi) to search for factors that affect zygotic paternal DNA demethylation. The combined use of various fluorescent probes and RNAi is a useful approach for the study of not only DNA demethylation but also the spatiotemporal dynamics of histone depositions in zygotes, although it is not appropriate for large-scale screening or knockdown of genes that are abundantly expressed before fertilization. This new technique enables us to understand the epigenetic hierarchy during cellular response and differentiation in preimplantation embryos. PMID- 21234641 TI - Changes in imatinib plasma trough level during long-term treatment of patients with advanced gastrointestinal stromal tumors: correlation between changes in covariates and imatinib exposure. AB - A pharmacokinetic study in patients with gastrointestinal stromal tumors (GIST) suggested that imatinib plasma concentration may decrease following long-term exposure. We assessed changes in imatinib plasma trough levels (C(min)) during long-term treatment. Follow-up (FU) imatinib C(min) was measured in 65 patients who received the same dose of imatinib for at least 9 months after previous (initial) tests. After exclusion of 7 patients who had been treated with imatinib for over 2 years at the time of initial testing, 58 patients were included in this analysis. The median intervals from initiation of imatinib to initial testing and from initial to FU testing were 5.5 months (range, 0.5-24.0 months) and 13.0 months (range, 9.6-17.9 months), respectively. Mean inter- and intra subject variability values were 47.7% and 20.9%, respectively, at initial measurements, and 45.2% and 19.4%, respectively, at FU. Mean FU imatinib C(min) (1,370 +/- 661 ng/mL) was significantly higher than mean initial C(min) (1,171 +/ 573 ng/mL; p = 0.003). Compared with initial C(min), FU C(min) was decreased in 22 patients and increased in 36, with median changes of 13% and 32%, respectively. Multivariate analysis showed a significant correlation between the ratio of FU to initial imatinib C(min) and that of albumin (r = -0.39, p = 0.003). During long-term treatment, imatinib C(min) did not decrease significantly but remained stable or increased in most patients. Changes in imatinib C(min) were associated with changes in albumin concentration. Monitoring of imatinib C(min) only for concerns about time-dependent increases in imatinib clearance is not necessary. PMID- 21234642 TI - Meningeal carcinomatosis in breast cancer: prognostic factors and outcome. AB - Meningeal carcinomatosis (MC) occurs in up to 5% of breast cancer patients. Few studies have evaluated prognostic markers in breast cancer patients with MC. Our aim was to describe the treatment of breast cancer patients with MC, and identify prognostic factors related to survival. Sixty breast cancer patients that had a diagnosis of MC between January 2003 and December 2009 were included. The median age was 46 years (range 27-76). Most patients had invasive ductal carcinoma (78.3%) and high histological/nuclear grade (61.7/53.3%). Estrogen and progesterone receptors were positive in 51.7 and 43.3% of patients, respectively, and 15% were HER-2-positive. Symptoms at presentation were headache, cranial nerve dysfunction, seizures, and intracranial hypertension signals. Diagnosis was made by CSF cytology in 66.7% of cases and by MRI in 71.7%. Intrathecal (IT) chemotherapy was used in 68.3% of patients, and 21.6% received a new systemic treatment (chemo- or hormone therapy). Median survival was 3.3 months (range 0.03 90.4). There was no survival difference according to age, nuclear grade, hormonal and HER-2 status, CSF features, sites of metastasis, systemic and IT chemotherapy, or radiotherapy. However, histological grade and performance status had a significant impact on survival in the multivariate analysis. Only four papers have addressed prognostic factors in breast cancer patients with MC in the last two decades. The results of those reports are discussed here. High histological grade and poor performance status seem to impact survival of breast cancer patients with MC. Prospective studies are necessary to clarify the role of IT and systemic treatment in the treatment of those patients. PMID- 21234643 TI - Morphine facilitates doxorubicin penetration in the central nervous system: a new prospect for therapy of brain tumors. PMID- 21234644 TI - Random coil chemical shift for intrinsically disordered proteins: effects of temperature and pH. AB - Secondary chemical shift analysis is the main NMR method for detection of transiently formed secondary structure in intrinsically disordered proteins. The quality of the secondary chemical shifts is dependent on an appropriate choice of random coil chemical shifts. We report random coil chemical shifts and sequence correction factors determined for a GGXGG peptide series following the approach of Schwarzinger et al. (J Am Chem Soc 123(13):2970-2978, 2001). The chemical shifts are determined at neutral pH in order to match the conditions of most studies of intrinsically disordered proteins. Temperature has a non-negligible effect on the (13)C random coil chemical shifts, so temperature coefficients are reported for the random coil chemical shifts to allow extrapolation to other temperatures. The pH dependence of the histidine random coil chemical shifts is investigated in a titration series, which allows the accurate random coil chemical shifts to be obtained at any pH. By correcting the random coil chemical shifts for the effects of temperature and pH, systematic biases of the secondary chemical shifts are minimized, which will improve the reliability of detection of transient secondary structure in disordered proteins. PMID- 21234645 TI - Hyper-homocysteinemia: a novel risk factor or a powerful marker for cardiovascular diseases? Pathogenetic and therapeutical uncertainties. AB - Increased homocysteine levels can be responsible for arterial ischemic events, such as MI, stroke or peripheral vascular disease. Homocysteine is metabolized by two pathways: re-methylation and trans-sulfuration. Both involve folic acid, and vitamins B(6-12.) Several studies assumed that the folates and vitamins B supplementation or dietary source to normalize plasma homocysteine. But, even if tends to normalize homocysteine levels, lowering homocysteine by B-group vitamins and/or folates does not reduce cardiovascular risk. In fact, recent reports confirmed that hyper-homocysteinemia is not directly responsible for cardiovascular disease, but is merely present in individuals suffering for acute and/or chronic cardiovascular events, as a collateral finding. Reduced methylation potential (MP) [due to decreased S-adenosyl-methionine (AdoMet)/S adenosyl-homocysteine (AdoHcy) ratio] induced by the elevated plasma homocysteine levels seems to be the true responsible for cardiovascular diseases (CVD). The pathogenic mechanisms responsible for CVD appear to be dependent of DNA hypomethylation inducing an inhibition of cyclin A transcription and a reduction of endothelial cells growth. But, other human studies performed in a wide range are requested. PMID- 21234646 TI - Effect of chromosome arrangements on mate recognition system leading to behavioral isolation in Drosophila ananassae. AB - The mechanisms of speciation that appear in the early stages of reproductive isolation has been of recent interest to evolutionary biologists. Experiments were conducted to study behavioral isolation between karyotypically different homozygous strains derived from natural populations of Drosophila ananassae. Three mass cultures stocks established from flies collected from natural populations were employed and homozygous stocks (ST/ST and AL/AL) were made through selection for homozygosity. By employing male-choice technique, mating success was scored by direct observation in the Elens-Wattiaux mating chamber. There is preference for homogamic matings in all the three populations and the differences between homogamic and heterogamic matings are statistically significant in two populations (Lucknow and Varanasi). These findings provide evidence that there is incipient sexual isolation between karyotypically different strains of D. ananassae derived from natural populations which shows that chromosome arrangements may affect the mate recognition system in D. ananassae. PMID- 21234647 TI - Quaternary phylogeography: the roots of hybrid zones. AB - The older history of hybrid zones is explored through consideration of recent advances in climatology, paleontology and phylogeography in the Late Cenozoic, particularly the Quaternary Period with its major climatic cycles. The fossil record shows that these ice ages and their nested millennial oscillations caused substantial changes in species distributions and with genetic evidence allows deduction of refugia and colonization routes in arctic, temperate, desert and tropical regions. The age of divergence between hybridizing lineages varies from the Late Pleistocene to the Late Miocene, implying much range change and varying selection on sister lineages. Hybridizing lineages in the Tropical and Temperate regions range in age from young to old, but those studied in the Arctic are no more than a few ice ages old and their refugial roots are not clear. Mid to low latitude regions often show parapatric patchworks of lineages and multiple refugia stable through many climatic oscillations. Particular hybrid zones may have formed more than once; while some expansions were not the same, producing reticulation and introgression in previous glacial cycles. Hybrid-zone roots are complex and deep, and considerations of their complexity can reveal evolutionary pathways of species. They are indeed windows on evolution. PMID- 21234648 TI - Bacterial Pu(V) reduction in the absence and presence of Fe(III)-NTA: modeling and experimental approach. AB - Plutonium (Pu), a key contaminant at sites associated with the manufacture of nuclear weapons and with nuclear-energy wastes, can be precipitated to "immobilized" plutonium phases in systems that promote bioreduction. Ferric iron (Fe(3+)) is often present in contaminated sites, and its bioreduction to ferrous iron (Fe(2+)) may be involved in the reduction of Pu to forms that precipitate. Alternately, Pu can be reduced directly by the bacteria. Besides Fe, contaminated sites often contain strong complexing ligands, such as nitrilotriacetic acid (NTA). We used biogeochemical modeling to interpret the experimental fate of Pu in the absence and presence of ferric iron (Fe(3+)) and NTA under anaerobic conditions. In all cases, Shewanella alga BrY (S. alga) reduced Pu(V)(PuO(2) (+)) to Pu(III), and experimental evidence indicates that Pu(III) precipitated as PuPO(4(am).) In the absence of Fe(3+) and NTA, reduction of PuO(2) (+) was directly biotic, but modeling simulations support that PuO(2) (+) reduction in the presence of Fe(3+) and NTA was due to an abiotic stepwise reduction of PuO(2) (+) to Pu(4+), followed by reduction of Pu(4+) to Pu(3+), both through biogenically produced Fe(2+). This means that PuO(2) (+) reduction was slowed by first having Fe(3+) reduced to Fe(2+). Modeling results also show that the degree of PuPO(4(am)) precipitation depends on the NTA concentration. While precipitation out-competes complexation when NTA is present at the same or lower concentration than Pu, excess NTA can prevent precipitation of PuPO(4(am)). PMID- 21234649 TI - Production of thermotolerant and alkalotolerant cellulolytic enzymes by isolated Nocardiopsis sp. KNU. AB - A novel cellulolytic bacterium was isolated from the forest soil of KNU University campus. Through 16S rRNA sequence matching and morphological observation it was identified as Nocardiopsis sp. KNU. This strain can utilize a broad range of cellulosic substrates including: carboxymethyl cellulose (CMC), avicel, xylan, cellobiose, filter paper and rice straw by producing a large amount of thermoalkalotolerant endoglucanase, exoglucanase, xylanase and glucoamylase. Optimal culture conditions (Dubos medium, 37 degrees C, pH 6.5 and static condition) for the maximal production of the cellulolytic enzymes were determined. The activity of cellulolytic and hemicelluloytic enzymes produced by this strain was mainly present extracellularly and the enzyme production was dependent on the cellulosic substrates used for the growth. Effect of physicochemical conditions and metal additives on the cellulolytic enzymes production were systematically investigated. The cellulases produced by Nocardiopsis sp. KNU have an optimal temperature of 40 degrees C and pH of 5.0. These cellulases also have high thermotolerance as evidenced by retaining 55-70% activity at 80 degrees C and pH of 5.0 and alkalotolerance by retaining >55% of the activity at pH 10 and 40 degrees C after 1 h. The efficiency of fermentative conversion of the hydrolyzed rice straw by Saccharomyces cerevisiae (KCTC-7296) resulted in 64% of theoretical ethanol yield. PMID- 21234650 TI - Phe27Cys polymorphism of the human delta opioid receptor predisposes cells to compromised calcium signaling. AB - A quarter of the human population with European background carries at least one allele of the OPRD1 gene that encodes the delta opioid receptor with cysteine at the amino acid position 27 (hdeltaOR(Cys27)) instead of the evolutionary conserved phenylalanine (hdeltaOR(Phe27)). The two variants have indistinguishable pharmacological properties but, importantly, hdeltaOR(Cys27) differs from hdeltaOR(Phe27) in having low maturation efficiency, lower stability at the cell surface and pronounced intracellular location. Both variants were previously shown to interact with the Sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) 2b in the early phase of their biosynthesis. We analyzed by pulse-chase assays, whether cellular signaling can affect hdeltaOR(Cys27) maturation. Neither activation of the receptor by a deltaOR-specific agonist Leu-enkephalin, induction of intracellular calcium (Ca2+) release by ATP nor the direct stimulation of SERCA 2b by protein kinase C activation affected receptor maturation in HEK-293 cells. No signaling-mediated regulation of receptor maturation could therefore be demonstrated. Instead, we found by using single cell Ca2+ measurements that over-expression of hdeltaOR(Cys27), but not hdeltaOR(Phe27), compromised ATP-induced intracellular Ca2+-signaling. Furthermore, hdeltaOR(Cys27) precursors showed slower dissociation from SERCA2b and hdeltaOR(Cys27) expression caused down-regulation of the homocysteine inducible endoplasmic reticulum-resident ubiquitin domain-like member 1 protein (HERP). We suggest that aging individuals with at least one hdeltaOR(Cys27) encoding allele might have lowered threshold for Ca2+ dysregulation in neurons expressing hdeltaOR. PMID- 21234651 TI - Lipocalin 2 deficiency inhibits cell proliferation, autophagy, and mitochondrial biogenesis in mouse embryonic cells. AB - Lipocalin 2 (LCN2) has been recently implicated as a critical player in multiple cancer tumorigeneses. However, the molecular mechanisms for its tumorigenic role are poorly understood. Herein, we investigated the effects of LCN2 on cell proliferation, autophagy, and mitochondrial biogenesis in MEF cells. We observed that LCN2 deficiency significantly inhibited cell proliferation and autophagy in MEF cells. Furthermore, mitochondrial DNA content, mRNA expression levels of mitochondrial-encoded gene cytochrome oxidase 2 and PGC-1alpha were all markedly reduced in LCN2-/- MEF cells. Additionally, when compared with wild-type MEF cells, LCN2-/- MEF cells expressed significantly higher levels of IRS-1, and displayed more potent TNFalpha-stimulated NF-kappaB activation. These findings demonstrate that LCN2 is a critical regulator of cell proliferation, autophagy, and mitochondrial biogenesis. PMID- 21234652 TI - Modulation of Na+/Mg2+ exchanger stoichiometry ratio by Cl- ions in basolateral rat liver plasma membrane vesicles. AB - The Na+/Mg2+ exchanger represents the main Mg2+ extrusion mechanism operating in mammalian cells including hepatocytes. We have previously reported that this exchanger, located in the basolateral domain of the hepatocyte, promotes the extrusion of intravesicular trapped Mg2+ for extravesicular Na+ with ratio 1. This electrogenic exchange is supported by the accumulation of tetraphenyl phosphonium within the vesicles at the time when Mg2+ efflux occurs. In this present study, the role of extra- and intra-vesicular Cl- on the Na+/Mg2+ exchange ratio was investigated. The results reported here suggest that Cl- ions are not required for the Na+ to Mg2+ exchange to occur, but the stoichiometry ratio of the exchanger switches from electrogenic (1Na(in)+ :1Mg(out)2+) in the presence of intravesicular Cl- to electroneutral (2Na(in)+ :1 Mg(out)2+) in their absence. In basolateral liver plasma membrane vesicles loaded with MgCl2 labeled with 36Cl-, a small but significant Cl- efflux (~30 nmol Cl-/mg protein/1 min) is observed following addition of NaCl or Na-isethionate to the extravesicular medium. Both Cl- and Mg2+ effluxes are inhibited by imipramine but not by amiloride, DIDS, niflumic acid, bumetanide, or furosemide. In vesicles loaded with Mg-gluconate and stimulated by Na-isethionate, an electroneutral Mg2+ extrusion is observed. Taken together, these results suggest that the Na+/Mg2+ exchanger can operate irrespective of the absence or the presence of Cl- in the extracellular or intracellular environment. Changes in trans-cellular Cl- content, however, can affect the modus operandi of the Na+/Mg2+ exchanger, and consequently impact "cellular" Na+ and Mg2+ homeostasis as well as the hepatocyte membrane potential. PMID- 21234653 TI - Anti-tumor effects of dihydroartemisinin on human osteosarcoma. AB - Dihydroartemisinin (DHA) exhibits antitumor activity against a wide spectrum of cancer cells. However, whether DHA has anti-tumor effect on human osteosarcoma cells remains unknown. This study aims to investigate the anti-tumor activity of DHA and the underlying mechanisms in human osteosarcoma cell lines with different p53 mutation statuses. Four human osteosarcoma cell lines were treated with different concentrations of DHA. Then, cell proliferation was determined by the CCK-8 viability assay; apoptosis and cell cycle progression were evaluated by flow cytometry; protein expression was analyzed by western blot assay; and NF-kB activity was examined by luciferase assay. The results demonstrated that DHA treatment could inhibit the proliferation of four osteosarcoma cell lines in a dose-dependent manner. P53 wild-type osteosarcoma cells were more sensitive to DHA. Moreover, the percentage of apoptotic cell and cell arrest in G2/M phase was increased upon DHA treatment in a dose-dependent manner. Mechanistically, DHA activated caspase-3, caspase-8, and caspase-9; upregulated the expression of Bax, FAS, and cyclin D1; downregulated the expression of Bcl-2, Cdc25B, and cyclin B1; and inhibited the activity of NF-kB. In conclusion, DHA has significant anticancer effects against human osteosarcoma cells, which include induction of apoptosis and cell cycle arrest. The p53 gene may play a certain role in the DHA induced human osteosarcoma apoptosis and cell cycle arrest. DHA is a novel anti osteosarcoma drug candidate that merits further study. PMID- 21234654 TI - Angiotensin II type 1 receptor gene polymorphism and telomere shortening in essential hypertension. AB - Several genetic studies were carried out among hypertensive patients to assess allelic association at the 1166 position of the 3' untranslated region of angiotensin II type 1 receptor gene. In addition, attempts have also been made to find out whether telomere length attrition is associated with hypertension. The main aim of this study was to examine the association of A1166C polymorphism of angiotensin II type 1 receptor and telomere length with essential hypertension in Egyptian people. Angiotensin II type 1 genotyping and relative telomere length were investigated by PCR in 40 patients of essential hypertension and 15 healthy controls. The homozygous AA1166 allele frequency was 92.8% among the studied subjects. There was no intergroup variation in A allele frequency in normotensive group. The frequency of homozygous A allele was significantly higher in hypertensive than normotensive subjects (97.5 and 80%, respectively) with higher frequencies in male patients. The average telomere length ratio was significantly shorter in hypertensive than in normal subjects (1.08 +/- 0.3 and 1.54 +/- 0.18, respectively). No correlation was observed between telomere length ratio and body mass index. This study suggests that the homozygous A1166 allele of angiotensin II type 1 and short telomeres may be predisposing factors for essential hypertension in Egyptians and may be involved in the pathogenesis of the disease. Further strategies for treating high-risk patients could result in prevention or delay of end organ damage. PMID- 21234655 TI - The synthetic triterpenoid CDDO-Imidazolide suppresses experimental liver metastasis. AB - Survival following diagnosis of liver metastasis remains poor and improved treatment strategies to combat liver metastases are needed. Synthetic triterpenoids, including 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28 oyl]imidazole (CDDO-Imidazolide or CDDO-Im), have been shown to inhibit primary tumor growth and lung metastasis in experimental models. Oral administration of CDDO-Im results in relatively high liver concentrations, suggesting that CDDO-Im may provide an approach to treatment of liver metastases. Here we assessed the effect of CDDO-Im on liver metastasis, using B16F1 (mouse melanoma) and HT-29 (human colon carcinoma) cells. In vitro, nanomolar concentrations of CDDO-Im arrested proliferation or induced cell death in both cell lines. In vivo, cells were injected via a surgically exposed mesenteric vein to target cells to the liver of mice. Mice were then treated with CDDO-Im (800 mg/kg diet) or vehicle control. Livers were removed at endpoint and metastatic burden was quantified by standard histology. In addition, a novel whole liver magnetic resonance imaging (MRI) technique was used to assess the effect of CDDO-Im on growing metastases as well as on non-dividing, solitary cancer cells present in the same livers. CDDO Im treatment significantly decreased liver metastasis burden in both HT-29 (n = 8 treated, 10 control) and B16F1 (n = 15 treated, 16 control) injected mice (>60%, P < 0.05), but did not reduce the numbers of solitary B16F1 cancer cells (hypo intensity) in the same livers (P = 0.9). This study demonstrates that CDDO-Im may be useful for the treatment metastatic liver disease as it successfully inhibits growth of actively proliferating liver metastases. PMID- 21234656 TI - IFN-gamma is essential for the inhibition of B16BL6 melanoma lung metastasis in chronic alcohol drinking mice. AB - We previously found that chronic alcohol consumption (20% w/v in drinking water) that models the level consumed by human alcoholics, when administered to female C57BL/6 mice inhibits B16BL6 melanoma metastasis to the lung; however, the mechanism is not known. Chronic alcohol consumption increases IFN-gamma producing NK, NKT, CD4(+), and CD8(+) T cells. To examine the impact of IFN-gamma on metastasis, we inoculated B16BL6 melanoma cells i.v. into control and chronic alcohol drinking IFN-gamma knockout (KO) mice. Knockout of the ifn-gamma gene abrogated the anti-metastatic effects associated with alcohol consumption. We examined metastasis in common gamma-chain (gammaC) KO mice, which are deficient in NK, NKT and CD8(+) T cells, and in Valpha14Jalpha281(-/-) KO mice, which are deficient in invariant NKT (iNKT) cells, in order to assess the importance of specific IFN-gamma producing cell types to this effect. We found that the antimetastatic effect of alcohol was still present in gammaC KO mice and also in gammaC KO mice depleted of Gr-1(+) cells. Knockout of iNKT cells reduced the degree but not the antimetastatic effect associated with alcohol. These results indicate that the antimetastatic effect induced by chronic alcohol consumption is IFN-gamma dependent and that multiple IFN-gamma producing cell types contribute to this effect. PMID- 21234658 TI - Assessment of pharmacologic area under the curve when baselines are variable. AB - PURPOSE: The area under the curve (AUC) is commonly used to assess the extent of exposure of a drug. The same concept can be applied to generally assess pharmacodynamic responses and the deviation of a signal from its baseline value. When the initial condition for the response of interest is not zero, there is uncertainty in the true value of the baseline measurement. This necessitates the consideration of the AUC relative to baseline to account for this inherent uncertainty and variability in baseline measurements. METHODS: An algorithm to calculate the AUC with respect to a variable baseline is developed by comparing the AUC of the response curve with the AUC of the baseline while taking into account uncertainty in both measurements. Furthermore, positive and negative components of AUC (above and below baseline) are calculated separately to allow for the identification of biphasic responses. RESULTS: This algorithm is applied to gene expression data to illustrate its ability to capture transcriptional responses to a drug that deviate from baseline and to synthetic data to quantitatively test its performance. CONCLUSIONS: The variable nature of the baseline is an important aspect to consider when calculating the AUC. PMID- 21234657 TI - Nano-fibrous tissue engineering scaffolds capable of growth factor delivery. AB - Tissue engineering aims at constructing biological substitutes to repair damaged tissues. Three-dimensional (3D) porous scaffolds are commonly utilized to define the 3D geometry of tissue engineering constructs and provide adequate pore space and surface to support cell attachment, migration, proliferation, differentiation and neo tissue genesis. Biomimetic 3D scaffolds provide synthetic microenvironments that mimic the natural regeneration microenvironments and promote tissue regeneration process. While nano-fibrous (NF) scaffolds are constructed to mimic the architecture of NF extracellular matrix, controlled release growth factors are incorporated to modulate the regeneration process. The present article summarizes current advances in methods to fabricate NF polymer scaffolds and the technologies to incorporate controlled growth factor delivery systems into 3D scaffolds, followed by examples of accelerated regeneration when the scaffolds with growth factor releasing capacity are applied in animal models. PMID- 21234659 TI - Effects of surfactants on lipase structure, activity, and inhibition. AB - Lipase inhibitors are the main anti-obesity drugs prescribed these days, but the complexity of their mechanism of action is making it difficult to develop new molecules for this purpose. The efficacy of these drugs is known to depend closely on the physico-chemistry of the lipid-water interfaces involved and on the unconventional behavior of the lipases which are their target enzymes. The lipolysis reaction which occurs at an oil-water interface involves complex equilibria between adsorption-desorption processes, conformational changes and catalytic mechanisms. In this context, surfactants can induce significant changes in the partitioning of the enzyme and the inhibitor between the water phase and lipid-water interfaces. Surfactants can be found at the oil-water interface where they compete with lipases for adsorption, but also in solution in the form of micellar aggregates and monomers that may interact with hydrophobic parts of lipases in solution. These various interactions, combined with the emulsification and dispersion of insoluble substrates and inhibitors, can either promote or decrease the activity and the inhibition of lipases. Here, we review some examples of the various effects of surfactants on lipase structure, activity and inhibition, which show how complex the various equilibria involved in the lipolysis reaction tend to be. PMID- 21234660 TI - Prevalence and correlates of gambling problems among a nationally representative sample of Brazilian adolescents. AB - The objectives of the study are: (a) to provide the first prevalence estimates of pathological gambling among Brazilian adolescents using an age-specific instrument in a nationally representative sample; (b) to investigate the extent to which adolescents participate in gambling activities in a developing country; and (c) to correlate different levels of gambling behavior with demographic variables. Multistage cluster sampling selected 3,007 individuals over 14 years of age from Brazilian household population. A total of 661 participants were between 14 and 17 years old. The Lie/Bet Questionnaire and the DSM-IV-MR-J were used for assessing problem and pathological gambling. 2.8% scored positive on the screening questionnaire, while 1.6% were classified as problem and pathological gamblers. Factors associated with problem and pathological gambling were male sex, not currently studying and considering religion as not important. Less than 4 months elapsed between the age of regular gambling involvement and the first gambling problem. Prevalence rates were quite similar from recent studies which used nationally representative samples. The association of problem and pathological gambling with male sex, school drop-out and low religiosity supports the Problem Behavior Theory. The fast progression to problem gambling adds evidence that adolescents may be more vulnerable to the effects of gambling. PMID- 21234661 TI - Mechanisms of ceftazidime and ciprofloxacin transport through porins in multidrug resistance developed by extended-spectrum beta-lactamase E.coli strains. AB - Resistance towards antibiotics stands out today as a major issue in the clinical act of treatment of bacterial-generated infections. This process was characterized in proteoliposomes reconstituted from an E.coli strain isolated from invasive infections (blood culture) occurred in patients with a cardio vascular device admitted for surgery. Fluorescence spectroscopy and patch-clamp technique have been used. Two types of antibiotics have been targeted: ceftazidime and ciprofloxacin. Antibiotics addition in proteoliposomes suspension undergoes a quenching in tryptophan residues from outer membrane porins structure, probably due to the formation of a transient non-fluorescent porin antibiotic complex. Patch-clamp recordings revealed strong ion current blockages for both antibiotics, reflecting antibiotic-channel interactions but with varying strength of interaction. The present study puts forward the mechanism of multidrug-resistance in extended-spectrum beta-lactamase E.coli strains, as being caused by alterations of the antibiotics transport across the porins of the outer bacterial membrane. PMID- 21234662 TI - Photophysical properties of rare earth (Eu3+, Sm3+, Tb3+) complex covalently immobilized in hybrid Si-O-B xerogels. AB - The molecular linkage (phenSi) from functionalized 5-amino-1,10-phenanthroline (PhenNH(2)) by 3-(triethoxysilyl)-propyl isocyanate (TESPIC) is to construct the rare earth (Sm(3+), Eu(3+), Tb(3+)) center covalently immobilized in the hybrid xerogels of Si-O-B through the cohydrolysis and copolycondensation process between different alkoxide precursors of them (tetraethoxysilane (TEOS), tri-n butylborate (TBB)). NMR, FTIR and ultraviolet absorption are measured to confirm the obtained materials. X-ray diffraction patterns revealed the hybrid materials are amorphous. Scanning electronic microscopy images show the stripe microstructure without phase separation phenomenon in the obtained hybrid materials. The covalently bonded Si-O-B hybrid xerogel presents the similar photoluminescent behavior to the pure Si-O-Si hybrid xerogels, which indicates that Si-O-B hybrid xerogel is a suitable system for the luminescence of RE(3+). PMID- 21234663 TI - Molecular cloning and expression of Aven gene in chicken. AB - Aven was originally identified as a protein that regulates apoptosis by binding to apoptotic regulators, Bcl-xL and Apaf-1. Recently was found that Aven protein is a potent activator of ATM, critical for its DNA damage-induced activation. An Aven cDNA clone was isolated from chicken (Gallus gallus) after screening of a cerebellum cDNA library. The full-length cDNA is 1,430 nt in size, encoding for a polypeptide of 352 amino acid residues. The predicted amino acid sequence of the chicken Aven is 69, 46, 45 and 37% identical to those of zebra finch, human, xenopus and zebrafish orthologs, respectively. Expression analysis reveals that the chicken Aven gene is expressed in the adult brain, heart, intestine, kidney, lung, stomach and spleen, as well as in the whole embryos of 4- and 6-days old. Phylogenetic analysis of the Aven ortholog proteins from various organisms clusters the chicken Aven in the same group with other bird Avens. PMID- 21234664 TI - Externally-resident daughters, social capital, and support for the elderly in rural Tibet. AB - This paper focuses on assistance that externally-resident daughters provide for their aging parents in rural Tibet, China, to challenge the notion that rapid modernization invariably threatens family-based care systems for the elderly. The authors discuss social and economic changes associated with modernization that have created new opportunities for parents to send daughters out of their natal households in ways that can benefit them in old age. By investing in a daughter's education so she can secure salaried employment, or by helping a daughter establish a small business so she can earn an independent livelihood, the authors demonstrate how some externally-resident daughters represent a novel form of social capital that parents can draw on for social support. Daughters with income and freedom from extended family obligations are now providing elderly parents with (1) leverage against co-resident children who do not treat them well, (2) temporary places of refuge from ill-treatment at home, (3) caretaking services and financial support when they require hospitalization, and (4) financial resources independent of their household which they can use to pursue age appropriate activities like pilgrimage. The authors conclude that this new form of social capital vested in externally-resident daughters is having a positive impact on the lives of the elderly in rural Tibet. PMID- 21234665 TI - Letter to the editor: molecular genotyping of Dengue Virus Types 2 and 4 from the Guatemalan and Honduran Epidemics of 2007 using the envelope glycoprotein gene. AB - Eight serum specimens collected from dengue patients in Guatemala and Honduras during the Central American epidemic of 2007 were analyzed. Virus identification and serotyping performed by a nested RT-PCR assay revealed two DENV-1 isolates from Guatemala, four DENV-2 isolates, two each from Guatemala and Honduras, and two DENV-4 isolates from Honduras. Viral genotyping determined by phylogenetic analysis of the complete envelope gene sequences demonstrated that the DENV-2 isolates from Guatemala and Honduras fell into the American/Asian Genotype III, and were most closely related to DENV-2/NI/BID-V2683-1999 isolated from a dengue case in Nicaragua in 1999; and the DENV-4 F07-076 isolate from Honduras belonged to genotype II, and was most closely related to DENV-4/US/BID-V1093/1998 isolated from Puerto Rico in 1998. Our results suggest that the 2007 dengue outbreaks in Guatemala and Honduras were most likely caused by the re-emergence of earlier, indigenous DENV strains rather than by newly introduced strains and there were at least three serotypes of DENV co-circulating during the 2007 Central American epidemics. PMID- 21234666 TI - Patterns of substance use among a large urban cohort of HIV-infected men who have sex with men in primary care. AB - The present study sought to identify characteristics of HIV-infected MSM that are associated with the use of specific substances and substance abuse in general. Participants were 503 HIV-infected MSM who were receiving primary care. A self assessment and medical records were used to obtain information about past 3-month alcohol and drug use and abuse, and demographics, HIV-disease stage and treatment, sexual risk, and mental health. Associations of these four domains with substance use and abuse outcomes were examined using hierarchical block stepwise multivariable logistic regression. Substance use and abuse in the sample was high. Transmission risk behavior was significantly associated with over half of the outcomes. The associations of demographic and HIV-disease stage and treatment variables varied by substance, and mental health problems contributed differentially to almost every outcome. These findings should be considered for designing, implementing, and evaluating substance use programming for HIV infected MSM. PMID- 21234667 TI - Considerations of viscosity in the preliminaries to mammalian fertilisation. AB - Migration of spermatozoa in the female genital tract will be strongly influenced by the viscosity of the fluids encountered, yet little systematic analysis has been given to such a consideration. This essay reviews the series of milieux confronting a fertilising sperm during its progression to the oviduct ampulla. Two groups are discussed, first those in which ejaculation is into the vagina, second those in which semen enters the uterus during a protracted mating. Viscous glycoprotein secretions that accumulate in the oviduct isthmus of both groups before ovulation are highlighted, as is the environment generated in the ampulla by the post-ovulatory suspension of oocyte(s), cumulus cells and spermatozoa; follicular and peritoneal fluids may also be present. The viscosity of all female tract fluids responds to cyclical variations in temperature, and these exist within the oviduct near the time of ovulation. Gradations in viscosity influence the pattern and strength of sperm flagellar activity and the rate of forward movement. Measurements of sperm motility are currently made in a physiological medium of constant viscosity and temperature, thereby overlooking changes in the female genital tract. A more sophisticated approach might reveal an adequate fertilising potential in a proportion of putatively poor semen samples. PMID- 21234668 TI - Pressure induced nucleus DNA fragmentation. AB - PURPOSE: The present study was designed to investigate the impact of pressure on nuclear DNA integrity in viable cells of mouse blastocysts. METHODS: The blastocysts of hybrid F1 females [(C57Bl/10 J * CBA-H);N = 15] aged 2-3 months were exposed into the pressure impulse lasting ~0.021 s and characterized by a positive pressure peak of ~76 mmHg. The nuclear DNA fragmentation index of mouse blastocysts was assessed by TUNEL assay within 60 s after exposure to pressure impulse. RESULTS: The mean nuclear DNA fragmentation index was significantly higher in the experimental group (83%) than in the control group (19.7%); p < 0.001. CONCLUSION(S): A low magnitude pressure impulse can induce nuclear DNA fragmentation in mouse blastocysts. The compression and decompression forces appearing during pressure fluctuations are responsible for the observed DNA shearing. PMID- 21234669 TI - Simulating linkage disequilibrium structures in a human population for SNP association studies. AB - Existing simulation methods usually simulate linkage disequilibrium (LD) structures starting with an initial population that is randomly generated according to specified allele frequencies. These at random based methods might be unstable because the LD level of the initial population is generally extremely low. This study presents a new algorithm, SIMLD, to simulate genome populations with real LD structures. SIMLD begins from an initial population with possibly the highest LD level, and then the LD decays to fit the desired level through processes of mating and recombination over generations. SIMLD can produce case control samples according to various disease models. Using empirical SNP marker information from three populations of HapMap data, we implement the proposed algorithm and demonstrate a set of experimental results. PMID- 21234671 TI - High-resolution mass spectrometric analysis of the secretome from mouse lung endothelial progenitor cells. AB - Recently, we isolated and characterized resident endothelial progenitor cells from the lungs of adult mice. These cells have a high proliferation potential, are not transformed and can differentiate into blood- and lymph-vascular endothelial cells under in vitro and in vivo conditions. Here we studied the secretome of these cells by nanoflow liquid chromatographic mass spectrometry (LC MS). For analysis, 3-day conditioned serum-free media were used. We found 133 proteins belonging to the categories of membrane-bound or secreted proteins. Thereby, several of the membrane-bound proteins also existed as released variants. Thirty-five proteins from this group are well known as endothelial cell or angiogenesis-related proteins. The MS analysis of the secretome was supplemented and confirmed by fluorescence activated cell sorting analyses, ELISA measurements and immunocytological studies of selected proteins. The secretome data presented in this study provides a platform for the in-depth analysis of endothelial progenitor cells and characterizes potential cellular markers and signaling components in hem- and lymphangiogenesis. PMID- 21234670 TI - Cohesin proteins load sequentially during prophase I in tomato primary microsporocytes. AB - Proteins of the cohesin complex are essential for sister chromatid cohesion and proper chromosome segregation during both mitosis and meiosis. Cohesin proteins are also components of axial elements/lateral elements (AE/LEs) of synaptonemal complexes (SCs) during meiosis, and cohesins are thought to play an important role in meiotic chromosome morphogenesis and recombination. Here, we have examined the cytological behavior of four cohesin proteins (SMC1, SMC3, SCC3, and REC8/SYN1) during early prophase I in tomato microsporocytes using immunolabeling. All four cohesins are discontinuously distributed along the length of AE/LEs from leptotene through early diplotene. Based on current models for the cohesin complex, the four cohesin proteins should be present at the same time and place in equivalent amounts. However, we observed that cohesins often do not colocalize at the same AE/LE positions, and cohesins differ in when they load onto and dissociate from AE/LEs of early prophase I chromosomes. Cohesin labeling of LEs from pachytene nuclei is similar through euchromatin, pericentric heterochromatin, and kinetochores but is distinctly reduced through the nucleolar organizer region of chromosome 2. These results indicate that the four cohesin proteins may form different complexes and/or perform additional functions during meiosis in plants, which are distinct from their essential function in sister chromatid cohesion. PMID- 21234672 TI - Effect of adding gefitinib to neoadjuvant chemotherapy in estrogen receptor negative early breast cancer in a randomized phase II trial. AB - Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has shown both anti-proliferative and anti-tumoral activity in breast cancer. This study was designed to determine the effect of adding gefitinib to neoadjuvant epirubicin and cyclophosphamide (EC) on tumor response rates. Women with unilateral, primary operable, estrogen receptor negative invasive breast cancer >= 2 cm were eligible for inclusion. Randomized patients were to receive four cycles of neoadjuvant EC plus 12 weeks of either gefitinib (250 mg daily) or placebo. Primary endpoint was pathologic complete response (pCR), and secondary endpoints were complete response (CR) and overall objective response (OR). 181 patients were randomized. A pCR was observed in 17% (12/71) of patients treated with gefitinib and in 12% (9/73) of patients treated with placebo (4.57% difference, 95% CI -7.19 to 6.33; P = 0.44). CR was observed in 10% of patients in both the gefitinib (7/71) and the placebo group (7/73) (0.27% difference, 95% CI -9.6 to 10.2; P = 0.96). There was no significant difference in OR (5.96%; 95% CI -9.9 to 21.9; P = 0.45) between the two groups. Post hoc subgroup analysis showed a significant difference in pCR between triple negative breast cancer (TNBC) and non-TNBC tumors (P = 0.03). More patients in the gefitinib arm had hematological toxicity (P = 0.15) and discontinued treatment (9/94 vs. 2/86) because of adverse events (AE). Tumor response rates were similar in the two groups. A significantly higher pCR rate was observed post hoc in TNBC versus non TNBC independent of treatment. More patients in the gefitinib group discontinued treatment because of AE. PMID- 21234673 TI - beta-Adrenergic receptors (beta-AR) regulate VEGF and IL-6 production by divergent pathways in high beta-AR-expressing breast cancer cell lines. AB - Activation of beta-adrenergic receptors (beta-AR) drives proangiogenic factor production in several types of cancers. To examine beta-AR regulation of breast cancer pathogenesis, beta-AR density, signaling capacity, and functional responses to beta-AR stimulation were studied in four human breast adenocarcinoma cell lines. beta-AR density ranged from very low in MCF7 and MB-361 to very high in MB-231 and in a brain-seeking variant of MB-231, MB-231BR. Consistent with beta-AR density, beta-AR activation elevated cAMP in MCF7 and MB-361 much less than in MB-231 and MB-231BR. Functionally, beta-AR stimulation did not markedly alter vascular endothelial growth factor (VEGF) production by MCF7 or MB-361. In the two high beta-AR-expressing cell lines MB-231 and MB-231BR, beta-AR-induced cAMP and VEGF production differed considerably, despite similar beta-AR density. The beta(2)-AR-selective agonist terbutaline and the endogenous neurotransmitter norepinephrine decreased VEGF production by MB-231, but increased VEGF production by MB-231BR. Moreover, beta(2)-AR activation increased IL-6 production by both MB 231 and MB-231BR. These functional alterations were driven by elevated cAMP, as direct activation of adenylate cyclase by forskolin elicited similar alterations in VEGF and IL-6 production. The protein kinase A antagonist KT5720 prevented beta-AR-induced alterations in MB-231 and MB-231BR VEGF production, but not IL-6 production. Conclusions beta-AR expression and signaling is heterogeneous in human breast cancer cell lines. In cells with high beta-AR density, beta-AR stimulation regulates VEGF production through the classical beta-AR-cAMP-PKA pathway, but this pathway can elicit directionally opposite outcomes. Furthermore, in the same cells, beta-AR activate a cAMP-dependent, PKA independent pathway to increase IL-6 production. The complexity of breast cancer cell beta-AR expression and functional responses must be taken into account when considering beta-AR as a therapeutic target for breast cancer treatment. PMID- 21234674 TI - Further studies based on better design are needed to explore the association of NPAS2 gene polymorphisms with breast cancer. PMID- 21234675 TI - Antibodies to myelin P0 and ceramide perpetuate neuropathy in long standing treated leprosy patients. AB - Anti neural antibodies are known to play a role in the immunopathogenesis of nerve damage in leprosy and HIV/AIDS. Myelin Protein zero (P0) and ceramide are two nerve components which maintain the integrity of the peripheral nerve. The present study was undertaken to identify antibodies to myelin P0 and ceramide in the sera of treated leprosy patients, HIV positive individuals and healthy subjects using enzyme linked immunosorbant assay (ELISA). The results revealed that treated leprosy patients continue to have significantly elevated myelin P0 and ceramide antibody levels as compared to healthy subjects (P < 0.05). The elevated antibody response to myelin P0 and ceramide in leprosy patients indicate a low grade autoimmune activity that perpetuates nerve damage in treated leprosy. There was no significant difference in the myelin P0 and ceramide antibody levels between HIV positive and healthy subjects (P > 0.05) suggesting that these antibodies do not play a role in early HIV infection. PMID- 21234677 TI - High prevalence of F4+ and F18+ Escherichia coli in Cuban piggeries as determined by serological survey. AB - Little information is available on the prevalence of swine enteropathogens in Cuba where diarrheic diseases are responsible for 31% and 37% of the total mortality during the neonatal and postweaning periods. F4+ and F18+ enterotoxigenic Escherichia coli and F18+ verotoxigenic E. coli induce diarrhea and edematous disease in pigs, but their distribution has never been thoroughly studied in the Cuban swine population. Therefore, the present study estimated the prevalence of F4- and F18-specific antibodies in sera of 1,044 6-month-old gilts distributed in 34 piggeries spread over the Cuban territory. For the data analysis, which included the optical density of individual samples tested by ELISA, random-effects models and a mixture model in R (package "mixAK"; Komarek, Computational Statistics and Data Analysis 53:3932-3947, 2009) were fitted. Low, moderate, and high levels of F4-specific antibodies were found in 67.6%, 26.8%, and 5.6% of the gilts, while 66.4% and 33.6% of gilts showed low and high levels of F18-specific antibodies. Hereby, we show that F4+ and F18+ E. coli are highly prevalent as potential enteropathogens in Cuban piggeries. PMID- 21234678 TI - Assessment of milk ring test and some serological tests in the detection of Brucella melitensis in Syrian female sheep. AB - Brucella melitensis infection prevalence among Syrian female sheep, to evaluate a number of serological tests and to discuss some epidemiological aspects of brucellosis, was studied. A total of 2,580 unvaccinated Syrian female sheep sera samples were tested for B. melitensis antibodies detection using four serological methods: the Rose Bengal test (RBT), the serum agglutination test (SAT), the complement fixation test (CFT) and an indirect enzyme-linked immunosorbent assay (iELISA). In addition, 2,375 milk samples were collected, then milk ring test (MRT) and bacterial isolation test were employed to evaluate the natural organism shedding. The samples were considered positive in 66%, 64%, and 60% when we employed the RBT, SAT, and iELISA tests, respectively. Whereas, the CFT test revealed the smallest number of positive samples. By using the MRT, the total prevalence of brucellosis was nearly 38% of samples. A large variation was observed concerning the studied areas, ranging from 24% in Tartous to 44% in both Damascus and Damascus rural areas. Brucella was isolated from only 677 samples out of the 2,375 female sheep milk samples. PMID- 21234676 TI - The physiological function of store-operated calcium entry. AB - Store-operated Ca(2+) entry is a process whereby the depletion of intracellular Ca(2+) stores signals the opening of plasma membrane Ca(2+) channels. It has long been thought that the main function of store-operated Ca(2+) entry was the replenishment of intracellular Ca(2+) stores following their discharge during intracellular Ca(2+) signaling. Recent results, however, suggest that the primary function of these channels may be to provide direct Ca(2+) signals to recipients localized to spatially restricted areas close to the sites of Ca(2+) entry in order to initiate specific signaling pathways. PMID- 21234679 TI - Lessons learned from a fatal case of mercury intoxication. AB - CONTEXT: While many cases of metallic mercury poisoning have been reported, cases of metallic mercury poisoning from multiple exposure routes are rare. CASE PRESENTATION: We report the case of a 36-year-old Latin American male who presented with rash, sore throat, fever, chills, cough, and diarrhea after chronic mercury vapor exposure and likely intravenous injection. Despite chelation treatment with meso-2,3-dimercaptosuccinic acid (DMSA) and 2,3 dimercaptopropanesulfonic acid (DMPS), the patient's clinical course was complicated by renal failure and he passed away after 18 days. DISCUSSION: The most striking aspect of this case is that despite use of chelators, a dramatic increase in blood mercury level occurred. We discuss the rationale for combined use of chelators with hemodialysis and other treatments such as plasma exchange in the setting of acute mercury poisoning. This case also illustrated the potentially serious side effects of the chelation drug DMSA, and we discuss the potential relevance of dosing frequency to the occurrence rates of such side effects. RELEVANCE TO CLINICAL PRACTICE: Despite the tragic outcome, on review of case literature, we believe this case provides valuable lessons concerning the use of DMSA and DMPS to treat mercury toxicity, particularly with regard to the combined use of chelation agents and hemodialysis. PMID- 21234680 TI - Brucella glomerulonephritis and prosthetic valve endocarditis: a case report. AB - Although brucellosis is an endemic disease in Mediterranean countries, there are few reported cases of Brucella endocarditis and glomerulonephritis. We report a case of Brucella prosthetic mitral valve endocarditis and glomerulonephritis that could be managed by using only antibiotic therapy, including rifampicin, doxycycline and ceftriaxone, without a surgical procedure. PMID- 21234681 TI - Description of a novel actinobacterium Kocuria assamensis sp. nov., isolated from a water sample collected from the river Brahmaputra, Assam, India. AB - A Gram-positive, pale yellow pigmented actinobacterium, strain S9-65(T) was isolated from a water sample collected from the river Brahmaputra, Assam, India and subjected to a polyphasic taxonomic study. The physiological and biochemical properties, major fatty acids (anteiso-C15:0 and anteiso-C17:0), estimated DNA G+C content (69.2 mol %) and 16S rRNA gene sequence analysis showed that strain S9-65(T) belonged to the genus Kocuria. Strain S9-65(T) exhibited highest 16S rRNA gene sequence similarity with Kocuria palustris (99.1%); however, the DNA DNA relatedness value between strain S9-65(T) and K. palustris was 20.6%. On the basis of differential phenotypic characteristics and genotypic distinctiveness, strain S9-65(T) should be classified as representative of a novel species Kocuria, for which the name Kocuria assamensis is proposed. The type strain is S9 65(T) (=MTCC 10622(T) = DSM 23999(T)). PMID- 21234682 TI - The relationship between consumer insight and provider-consumer agreement regarding consumer's quality of life. AB - This study examined the relationship between insight and mental health consumers and providers agreement regarding consumers rated quality of life (QoL). Seventy mental health consumers and their 23 care providers filled-out parallel questionnaires designed to measure consumer QoL. Consumers' insight was also assessed. For most QoL domains, agreement between consumers and providers was higher for persons with high insight. For the Psychological well being dimension a negative correlation was uncovered for persons with low insight indicating disagreement between consumer and provider. These findings are discussed within the context of the literature on insight and agreement between consumer and provider as related to the therapeutic alliance. PMID- 21234683 TI - Neighborhood environment and internalizing problems in African American children. AB - This study examines gender differences in the association between environment and internalizing problems in a sample of predominately African American schoolchildren. Internalizing problems was assessed using the Youth Self Report. Violence and alcohol and other drug (AOD) exposure subscales were created using observational assessments of neighborhood blocks. Logistic regression models were used to assess the relationship between neighborhood environment and internalizing problems. For each AOD item present on the block the odds of internalizing problems among girls increased by 17% (OR = 1.17, CI: 1.01, 1.35, P = 0.039). The relationship was not significant among boys. Violence exposure did not predict internalizing problems in boys or girls. These preliminary findings suggest that primary school-aged girls' emotional well-being is more negatively impacted by deleterious environments. Future investigations will examine the relationship between deleterious neighborhood environments and internalizing problems as the children age into adolescence. PMID- 21234684 TI - Evaluation of the Mental Healthiness Aging Initiative: community program to promote awareness about mental health and aging issues. AB - The objective of this study is to evaluate the Mental Healthiness Aging Initiative, designed to promote community awareness and knowledge about mental health and aging issues. This study occurred during 2007-2009 in 67 of 120 counties in Kentucky. A rural region (11 counties) received the intervention, consisting of focus groups, Extension Agent training, and television-based social marketing campaign. Partial-intervention counties (29 counties) received only the television-based social marketing campaign. The control counties (27 counties) received no intervention activities. Results indicated that the intervention counties agreed more with being able to assist elder adults with a potential mental illness. Also, the intervention counties understood the risk of consuming alcohol and medications better, but had a poorer recognition of drinking problems in elder adults. These findings need to be considered within study limitations, such as measurement error, degree of intervention exposure, and regional differences across intervention groups. The study demonstrates that community interventions on mental health awareness and knowledge are feasible within majority rural regions, with Extension Agents being gatekeepers, for promoting positive messages about mental health and aging issues. PMID- 21234685 TI - Crecemos juntos: understanding and alleviating parental stress among lowcountry migrant workers. AB - The focus of this study was to determine challenges and needs faced by families of migrant farm workers served by Rural Mission Migrant Head Start in the South Carolina Lowcountry. Data on common problems was collected via surveys, and results were analyzed. The Crecemos Juntos (We Grow Together) program was developed with the support of a Helping Hands Grant from the American Psychiatric Foundation, which funds service initiatives by medical students. A multimedia library of materials was compiled, addressing frequently encountered issues in mental health and child development. A presentation on effective positive disciplinary techniques was provided to parents. PMID- 21234686 TI - Isolated Russell body duodenitis. PMID- 21234687 TI - Time trends of mortality from gastric cancer in Europe. AB - BACKGROUND: The time trends of gastric and duodenal ulcer disease are shaped by a birth-cohort phenomenon. AIMS: The aim of this study was to assess the extent by which a birth-cohort phenomenon also affected the long-term time trends of gastric cancer among different European countries. METHODS: Mortality data from France, Germany, Netherlands, Scotland, Spain, and Sweden of the past 56-85 years were analyzed. The age-specific death rates were plotted against the period of death as period-age contours and against the period of birth as cohort-age contours. RESULTS: The long-term time trends of gastric cancer mortality were found to have risen among generations born during the 18th century until the mid 19th century and then to have declined in all subsequent generations. The rise and fall of gastric cancer preceded similar birth-cohort patterns of gastric and duodenal ulcer by about 10-30 years. With the exception of gastric cancer in Germany, similar birth-cohort phenomena were found in all countries, as well as in men and women. CONCLUSIONS: The time trends of mortality from gastric cancer and peptic are shaped by birth-cohort patterns that have affected all countries of Europe. It remains an enigma why mortality associated with gastric cancer and peptic ulcer suddenly started to rise within a short time period during the 19th century. PMID- 21234688 TI - Screening prevalence and incidence of colorectal cancer among American Indian/Alaskan natives in the Indian Health Service. AB - BACKGROUND: Studies on colorectal cancer (CRC) screening and incidence among American Indian/Alaska Natives (AI/AN) are few. AIMS: Our aim was to determine CRC screening prevalence and to calculate CRC incidence among AI/AN receiving care within the Indian Health Service (IHS). METHODS: A retrospective cohort study of AI/AN who utilized IHS from 1996 to 2004. AI/AN who were average-risk for CRC and received primary care within IHS were identified by searching the IHS Resource Patient Management System for selected ICD-9/CPT codes (n = 142,051). CRC screening prevalence was calculated and predictors of screening were determined for this group. CRC incidence rates were ascertained for the entire AI/AN population ages 50-80 who received IHS medical care between 1996 and 2004 (n = 283,717). RESULTS: CRC screening was performed in 4.0% of average-risk AI/AN. CRC screening was more common among women than men (RR = 1.6, 95% CI 1.4 1.7) and among AI/AN living in the Alaska region compared to the Pacific Coast region (RR = 2.5, 95% CI 2.2-2.8) while patients living in the Northern Plains (RR = 0.4, 95% CI 0.3-0.4) were less likely to have been screened. CRC screening was less common among patients with a greater number of primary care visits. The age-adjusted CRC incidence among AI/AN ages 50-80 was 227 cancers per 100,000 person-years. CONCLUSIONS: CRC was common among AI/AN receiving medical care within IHS. However, CRC screening prevalence was far lower than has been reported for the U.S. population. PMID- 21234690 TI - Microfluidic cell culture chip with multiplexed medium delivery and efficient cell/scaffold loading mechanisms for high-throughput perfusion 3-dimensional cell culture-based assays. AB - This study reports a microfluidic cell culture chip consisting of 48 microbioreactors for high-throughput perfusion 3-dimensional (3-D) cell culture based assays. Its advantages include the capability for multiplexed and backflow free medium delivery, and both efficient and high-throughput micro-scale, 3-D cell culture construct loading. In this work, the microfluidic cell culture chip is fabricated using two major processes, specifically, a computer-numerical controlled (CNC) mold machining process and a polydimethylsiloxane (PDMS) replication process. The chip is composed of micropumps, microbioreactors, connecting microchannels and a cell/agarose scaffold loading mechanism. The performance of the new pneumatic micropumps and the cell/agarose scaffold loading mechanism has been experimentally evaluated. The experimental results show that this proposed multiplexed medium-pumping design is able to provide a uniform pumping rate ranging from 1.5 to 298.3 MUl hr(-1) without any fluid backflow and the resultant medium contamination. In addition, the simple cell/agarose loading method has been proven to be able to load the 3-D cell culture construct uniformly and efficiently in all 48 microbioreactors investigated. Furthermore, a micro-scale, perfusion, 3-D cell culture-based assay has been successfully demonstrated using this proposed cell culture chip. The experimental results are also compared to a similar evaluation using a conventional static 3-D cell culture with a larger scale culture. It is concluded that the choice of a cell culture format can influence assay results. As a whole, because of the inherent advantages of a miniaturized perfusion 3-D cell culture assay, the cell culture chip not only can provide a stable, well-defined and more biologically-meaningful culture environment, but it also features a low consumption of research resources. Moreover, due to the integrated medium pumping mechanism and the simple cell/agarose loading method, this chip is economical and time efficient. All of these traits are particularly useful for high-precision and high throughput 3-D cell culture-based assays. PMID- 21234689 TI - Osteoblast interactions within a biomimetic apatite microenvironment. AB - Numerous reports have shown that accelerated apatites can mediate osteoblastic differentiation in vitro and bone formation in vivo. However, how cells interact within the apatite microenvironment remains largely unclear, despite the vast literature available today. In response, this study evaluates the in vitro interactions of a well-characterized osteoblast cell line (MC3T3-E1) with the apatite microenvironment. Specifically, cell attachment, spreading, and viability were evaluated in the presence and absence of serum proteins. Proteins were found to be critical in the mediation of cell-apatite interactions, as adherence of MC3T3-E1 cells to apatite surfaces without protein coatings resulted in significant levels of cell death within 24 h in serum-free media. In the absence of protein-apatite interaction, cell viability could be "rescued" upon treatment of MC3T3-E1 cells with inhibitors to phosphate (PO(4) (3-)) transport, suggesting that PO(4) (3-) uptake may play a role in viability. In contrast, rescue was not observed upon treatment with calcium (Ca(2+)) channel inhibitors. Interestingly, a rapid "pull-down" of extracellular Ca(2+) and PO(4) (3-) ions onto the apatite surface could be measured upon the incubation of apatites with alpha-MEM, suggesting that cells may be subject to changing levels of Ca(2+) and PO(4) (3-) within their microenvironment. Therefore, the biomimetic apatite surface may significantly alter the microenvironment of adherent osteoblasts and, as such, be capable of affecting both cell survival and differentiation. PMID- 21234691 TI - Pycnodysostosis with extreme sleep apnea: a possible alternative to tracheotomy. AB - PURPOSE: Pycnodysostosis (OMIM:265800) is an autosomal recessive genetic disorder due to a mutation in the cathepsin K gene, which causes a decrease of the bone turnover and a deterioration of the bone structure. Our aim was to describe a 5 year-old patient affected by pycnodysostosis, associated with an extremely severe obstructive sleep apnea syndrome, who was treated effectively with a combination of upper airway surgery and positive pressure ventilation. METHODS: A 5 year-old child affected by pycnodysostosis was referred to us for failure to thrive, facial dysmorphisms and respiratory disorders, and who developed an extremely severe sleep apnea syndrome. RESULTS: Polysomnography showed extremely severe OSAS (AHI = 81.6 events/hour). The child was treated successfully with a combination of adenotonsillectomy, uvulo-palato-pharingo plasty (UPPP), followed by positive pressure ventilation. Polysomnographic recordings confirmed the striking reduction of obstructive respiratory events during sleep (from 81.6 to 12.3 events/hour). Lateral skull Rx and cephalometric measures showed that the Posterior Airway Space (PAS) increased from 3 to 19 mm. The decision to perform UPPP in association with adeno-tonsillectomy was motivated by the presence of palatal obstruction, caused by hypertrophic and prolapsed soft tissue. CONCLUSIONS: Our observations suggest that a conservative surgical treatment, consisting of adenotonsillectomy plus UPPP, may increases the patency of the upper airway, both at palatal and pharyngeal level. The combination of adenotonsillectomy plus UPPP, followed by CPAP ventilation, may avoid tracheotomy in very severe OSAS patients. PMID- 21234693 TI - Chemical studies on the roots of Uvaria welwitschii. AB - A chemical investigation of the chloroform extract of the roots of Uvaria welwitschii (Annonaceae), an African traditional medicine taken for stomach ache, led to the isolation of eight new compounds, named welwitschins A-H (1-8), together with five known compounds (9-13). The structural elucidation by spectroscopic studies of the compounds isolated is described. All new compounds were flavonoids having a 2-hydroxy-3,4,6-trimethoxyphenyl moiety in the A-ring, and unsubstituted phenyl in the B-ring. Four of them (1-4) were monomeric flavonoids while the others (5-8) were dimeric flavonoids. The cytotoxicity of the isolated compounds against human promyelocytic leukemia HL-60 cells was investigated. PMID- 21234692 TI - Novel image-novel location object recognition task sensitive to age-related cognitive decline in nondemented elderly. AB - Traditional tests used in the clinic to identify dementia, such as the mini mental state examination (MMSE), are useful to identify severe cognitive impairments but might be less sensitive to detect more subtle age-related cognitive changes. Previously, the novel image-novel location (NINL) object recognition test was shown to be sensitive to detect effects of apolipoprotein E4, a risk factor for developing age-related cognitive decline and Alzheimer's disease, in nondemented elderly. In the present longitudinal study, performance on the MMSE and the NINL tests were compared over a 4-year period. Individual NINL scores over this period were highly correlated. In addition, while MMSE scores did not change over the 4-year period, NINL scores did. In a final testing session of a subset of the participants, NINL scores correlated with logical memory and word recall lists, cognitive tasks used to detect dementia in the clinic, as well as clinical dementia rating scales. These results support that the NINL might be a valuable tool to assess age-related cognitive decline. PMID- 21234694 TI - Hunger and food insecurity in Nairobi's slums: an assessment using IRT models. AB - Although linked to poverty as conditions reflecting inadequate access to resources to obtain food, issues such as hunger and food insecurity have seldom been recognized as important in urban settings. Overall, little is known about the prevalence and magnitude of hunger and food insecurity in most cities. Yet, in sub-Saharan Africa where the majority of urban dwellers live on less than one dollar a day, it is obvious that a large proportion of the urban population must be satisfied with just one meal a day. This paper suggests using the one- and two parameter item response theory models to infer a reliable and valid measure of hunger and food insecurity relevant to low-income urban settings, drawing evidence from the Nairobi Urban Health and Demographic Surveillance System. The reliability and accuracy of the items are tested using both the Mokken scale analysis and the Cronbach test. The validity of the inferred household food insecurity measure is assessed by examining how it is associated with households' economic status. Results show that food insecurity is pervasive amongst slum dwellers in Nairobi. Only one household in five is food-secure, and nearly half of all households are categorized as "food-insecure with both adult and child hunger." Moreover, in line with what is known about household allocation of resources, evidence indicates that parents often forego food in order to prioritize their children. PMID- 21234695 TI - Social network characteristics and HIV sexual risk behavior among urban African American women. AB - HIV/AIDS has emerged as a significant health threat for African American women with well-documented disparities. The purpose of this study was to assess the association between social network characteristics and high-risk sexual behaviors among a sample of urban African American women at risk of heterosexually acquired HIV/STIs. We performed a cross-sectional study of baseline data collected from the CHAT study, a randomized HIV-prevention trial targeting urban HIV-at-risk women in Baltimore, MD. Our primary outcomes were risky sexual behaviors defined as either (a) two or more sexual partners or (b) having a risky sex partner within the past 90 days. Bivariable and multivariable logistic regression examining the associations between individual and social network factors and our two outcomes of interest were conducted. The study population included 513 sexually active African American women with a mean age of 41.1 years. High levels of unemployment (89.5%), depressive symptoms (60.0%), and drug use (68.8%) were present among this high-risk urban cohort. Controlling for individual factors including participant drug use, age, and depression, having two or more sex partners within the past 90 days was associated with having a larger personal network (OR = 1.11; 95% CI, 1.06 and 1.17); more network members who pitched in to help (OR = 1.22; 95% CI, 1.04 and 1.44), provided financial support (OR = 1.33; 95% CI, 1.11 and 1.60), or used heroin or cocaine (OR = 1.26; 95% CI, 1.14 and 1.40). Having a risky sexual partner within the past 90 days was associated with having a larger social network (OR = 1.06; 95% CI, 1.00 and 1.12) and having more social networks who used heroin or cocaine (OR = 1.30; 95% CI, 1.14 and 1.49).In summary, social network characteristics are associated with HIV sexual risk behaviors among African American urban women. Social-network-based interventions that promote norms pertaining to HIV risk reduction and provide social support are needed for African American women at risk of heterosexually acquired HIV/STIs. PMID- 21234696 TI - Low levels of the omega-3 index are associated with sudden cardiac arrest and remain stable in survivors in the subacute phase. AB - In previous studies, low blood levels of n-3 fatty acids (FA) have been associated with increased risk of cardiac death, and the omega-3 index (red blood cell (RBC) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) expressed as weight percentage of total FA) has recently been proposed as a new risk factor for death from coronary artery disease, especially following sudden cardiac arrest (SCA). As blood samples often haven been harvested after the event, the aim of our study was to evaluate the stability of RBC fatty acids following SCA. The total FA profile, including the omega-3 index, was measured three times during the first 48 h in 25 survivors of out-of-hospital cardiac arrest (OHCA), in 15 patients with a myocardial infarction (MI) without SCA and in 5 healthy subjects. We could not demonstrate significant changes in the FA measurements in any of the groups, this also applied to the omega-6/omega-3 ratio and the arachidonic acid (AA)/EPA ratio. Furthermore, we compared the omega-3 index in 14 OHCA-patients suffering their first MI with that of 185 first-time MI-patients without SCA; mean values being 4.59% and 6.48%, respectively (p = 0.002). In a multivariate logistic regression analysis, a 1% increase of the omega-3 index was associated with a 58% (95% CI: 0.25-0.76%) reduction in risk of ventricular fibrillation (VF). In conclusion, the omega-3 index remained stable after an event of SCA and predicted the risk of VF. PMID- 21234697 TI - Living post treatment: definitions of those with history and no history of cancer. AB - INTRODUCTION: Breast cancer is the leading cause of cancer, and the second leading cause of cancer death in women. Due to advances in medicine, the 10 year survival rate is 80%, resulting in a large and growing number of breast cancer survivors. Definitions of cancer survivorship from a number of professional organizations and researchers vary, but the research is scant on the meaning of cancer survivorship to people with and without a prior cancer history. METHODS: Two studies were conducted (1) to compare individuals with and without a prior personal cancer diagnosis in terms of those who identified as survivors vs. those who did not identify as survivors and (2) to explore explanations of those with and without a prior personal cancer for the term cancer survivor. In Study 1, individuals were surveyed at cancer-themed community health fairs. In Study 2, women were surveyed at a breast oncology clinic. RESULTS: In Study 1 comparing those with and without a prior cancer diagnosis, prior cancer history was the best predictor of survivorship identity, and only three individuals without a prior cancer history included family and friends as survivors. In Study 2 of those with a personal history, longer time since diagnosis, type of cancer (ductal), and comparative risk (higher) were associated with survivor identity. CONCLUSION: Completion of treatment was seen as a 'rite of passage', and thus, may be seen as a shift from the patient identity, which may have negative connotations, to the positive identity of survivor. IMPLICATIONS: Definitions of survivorship vary considerably, and caution should be used when applying the term to those who have no prior personal cancer diagnosis and to those who have had a more recent cancer diagnosis with a more severe disease course. PMID- 21234698 TI - Revisional surgery for failed vertical-banded gastroplasty. AB - Vertical-banded gastroplasty (VBG) was once a common bariatric procedure. It has fallen out of favor due to the emergence of the adjustable gastric band and late complications including band erosion and stenosis. Options for revision include conversion to a Roux-en-Y gastric bypass (RYGB) or VBG reversal via gastrogastrostomy. Patients undergoing revision of a previous VBG were identified. VBG reversal was performed laparoscopically. Conversion to RYGB was performed by both laparotomy and laparoscopy. Perioperative outcomes and long term weight loss were evaluated. A total of 34 patients with a previous open VBG underwent revision over a nearly 8-year period (January 2003 to September 2010). Conversion to RYGB was performed in 25 (four laparoscopically) and VBG reversal in nine patients. Mean age for all patients was 56.3 years (range 36-70), and VBG had been performed 23 years previously (range 16-30). Patients to undergo VBG reversal were more likely to be male and less likely to be morbidly obese at the time of revision. Operative time and length of stay were shorter for laparoscopic procedures. Complication rates did not differ based on technique or procedure. Patients with a previous VBG may present with complications and obesity decades after the primary procedure. Revisional surgery can be accomplished laparoscopically. Following VBG reversal, most patients gain weight and many become morbidly obese again. Conversion to RYGB is associated with weight loss and resolution of morbid obesity in most patients. When feasible, laparoscopic conversion to RYGB may offer the best outcomes. PMID- 21234699 TI - Vitamin D deficiency before bariatric surgery: should supplement intake be routinely prescribed? AB - BACKGROUND: Before bariatric surgery, we demonstrate a 96% rate of vitamin D deficiency in morbidly obese French patients: should supplement intake be routinely prescribed? We conducted a prospective observational study to demonstrate the prevalence of vitamin D deficiency in morbidly obese patients awaiting bariatric surgery. METHODS: Clinical and biological data were collected on 50 successive patients. RESULTS: Data showed vitamin D deficiency in 96% (25 OH vitamin D = 31 +/- 13 nmol/l), with a cut-point of 50 nmol/l. Secondary hyperparathyroidism was found in 44% of patients with hypovitaminosis D (parathyroid hormone (PTH), 59 +/- 24 pg/ml). Impaired PTH level concerned 89% of this group, considering the cut-point at 30 pg/ml. No significant correlation appeared between vitamin D and calcium or phosphate levels. CONCLUSIONS: Before surgery, we demonstrated a higher incidence of vitamin D deficiency in morbidly obese French patients as compared to the general population. The incidence was also higher than previous American studies. Screening for hypovitaminosis D may routinely be considered in morbid obesity. Long-term observation is, however, needed to assess the advantages and potential side effects of systematic vitamin D supplements. PMID- 21234700 TI - Antidepressant drug therapy does not affect weight loss one year after gastric bypass surgery. AB - BACKGROUND: Preliminary data suggest that patients with actively treated depression should expect the same outcomes after surgery. The objective of this study was to compare weight loss 12 months after gastric bypass surgery in patients taking antidepressants before surgery (AD) versus those who were not (non-AD). METHODS: IRB approval was obtained. All patients gave informed consent prior to participating in the study. Medication and weight loss histories were retrospectively reviewed in adult patients who were followed at 12 months post surgery. RESULTS: 145 of 364 patients were taking antidepressants at baseline. There was no significant difference in weight loss between the AD and non-AD groups at 12 months (p > 0.05). CONCLUSIONS: Taking antidepressant medication prior to gastric bypass surgery did not affect weight loss outcomes at 12 months. PMID- 21234701 TI - Study of the alkyl chain length on laccase stability and enzymatic kinetic with imidazolium ionic liquids. AB - The activity and stability of laccase and their kinetic mechanisms in water soluble ionic liquids (ILs): 1-butyl-3-methyl imidazolium chloride [C(4)mim][Cl], 1-octyl-3-methyl imidazolium chloride [C(8)mim][Cl], and 1-decyl-3-methyl imidazolium chloride [C(10)mim][Cl] were investigated. The results show that an IL concentration up to 10% is satisfactory for initial laccase activity at pH 9.0. The laccase stability was well maintained in [C(4)mim][Cl] IL when compared to the control. The inactivation of laccase increases with the length of the alkyl chain in the IL: [C(10)mim][Cl] > [C(8)mim][Cl] > [C(4)mim][Cl]. The kinetic studies in the presence of ABTS as substrate allowed calculating the Michaelis-Menten parameters. Among the ILs, [C(4)mim][Cl] was the suitable choice attending to laccase activity and stability. Alkyl chains in the ions of ILs have a deactivating effect on laccase, which increases strongly with the length of the alkyl chain. PMID- 21234702 TI - Optimization of alpha-Terpineol production by the biotransformation of R-(+) limonene and (-)-beta-pinene. AB - The main objective of this work is to present the optimization of the biotransformation of R-(+)-limonene and (-)-beta-pinene aiming at the production of alpha-terpineol by strains of fungal and yeasts previously isolated by our research group using the methodology of experimental design. New optimized experimental data on alpha-terpineol production by the biotransformation of R-(+) limonene and (-)-beta-pinene using newly isolated microorganisms are reported in this work. Conversion of about 1,700 mg/L was achieved when R-(+)-limonene was used as substrate and the newly isolated strain 05.01.35 as microorganism at the central point of the experimental design, corresponding to a substrate concentration of 1.75%, mass of inoculum of 2 g, and substrate to ethanol volume ratio of 1:1. The same experimental condition led to higher conversions when (-) beta-pinene was used as substrates and the strains coded as 04.05.08 and 01.04.03 as microorganism. Here, conversions of about 770 mg/L were achieved. PMID- 21234704 TI - Effects of Pluronic F68 on Manganese peroxidase production by pelletized Phanerochaete chrysosporium. AB - In this study, a new process was developed for manganese peroxidase (MnP) production by Phanerochaete chrysosporium under an agitated and aerated cultivation condition. It was found that change of the inoculum from spore suspension to pellets resulted in enhanced MnP production of 200 U/L in rotated shake flasks. Several additives, including Pluronic F68, Tween 80, and PEG8000, significantly increased the enzyme production. With an optimal concentration in 125 mL flasks, Pluronic F68 increased MnP productivity by 180%. Moreover, successful enzyme production was achieved in a 5-L fermentor at an agitation speed of 300 rpm with the addition of 0.1% Pluronic F68. PMID- 21234705 TI - Values of using QTc and N-terminal fragment of B-type natriuretic peptide as markers for early detection of acute antipsychotic drugs-induced cardiotoxicity. AB - We aimed at studying the acute cardiotoxicity of the most commonly used antipsychotics in Egypt using QTc interval and NT-proBNP as markers for the early detection of such cases. Eighty-two admitted patients, at El-Minia PCC (period from 1-7-2005 to 30-6-2010), were classified into 3 groups: I: acute thioridazine overdose (n = 28), II: acute pimozide overdose (n = 23), and III: acute clozapine overdose (n = 31). Patients were investigated for NT-proBNP level and QTc on admission (day 0) and after 24 h (day 1). All the studied drugs had the ability to induce cardiotoxicity in the form of hypotension and dysrhythmias. Thioridazine and pimozide had potentially serious cardiotoxic effects than clozapine. NT-proBNP levels were elevated significantly in all groups on days 0 and 1 when compared with the reference value and a significant decrease in the same parameter on day 1 when compared with that of day 0 within the same group. QTc showed a significant prolongation in all studied groups on days 0 and 1, and there was a significant shortening of QTc on day 1 when compared with that of day 0 within the same group. A significant positive correlation of NT-proBNP level elevation with QTc prolongation was reported in all groups on days 0 and 1. Serious dysrhythmias were associated with QTc prolongation greater than 500 ms. And it was concluded that NT-proBNP, in adjunction with QTc measurement, may be a valuable and sensitive laboratory biomarker to predict cardiotoxicity of antipsychotic overdose. Larger multicenter studies are still needed to verify this possible relationship. PMID- 21234706 TI - Grape seed extract alleviates high-fat diet-induced obesity and heart dysfunction by preventing cardiac siderosis. AB - Obesity is a tremendous public health problem, characterized by ectopic accumulation of fat into non-adipose tissues, leading to oxidative stress and chronic inflammation, in which the heart is the most severely affected organ. We used an experimental model of high-fat-diet (HFD)-induced obesity to analyze the link between oxidative stress and heart dysfunction. We also studied the cardioprotective effect of a grape seed and skin extract (GSE). Exposure of rats to HFD during 45 days induced heart hypertrophy, inflammation as assessed by plasma CRP elevation and contractile dysfunction as revealed after ischemia/reperfusion of Langendorff-perfused hearts. HFD also induced cardiac steatosis and lipotoxicity, which are linked to an oxidative stress status, worsened by increased siderosis and resulting in Ca(2+) overload. Importantly, GSE alleviated all the deleterious effects of HFD treatment. These studies suggest that GSE is a safe anti-obesity and cardioprotective agent that should also find potential applications in other inflammatory damaging conditions as stroke. PMID- 21234707 TI - Inmunohistochemical profile of solid cell nest of thyroid gland. AB - It is widely held that solid cell nests (SCN) of the thyroid are ultimobranchial body remnants. SCNs are composed of main cells and C cells. It has been suggested that main cells might be pluripotent cells contributing to the histogenesis of C cells and follicular cells, as well as to the formation of certain thyroid tumors. The present study sought to analyze the immunohistochemical profile of SCN and to investigate the potential stem cell role of SCN main cells. Tissue sections from ten cases of nodular hyperplasia (non-tumor goiter) with SCNs were retrieved from the files of the Hospital Infanta Luisa (Seville, Spain). Parathormone (PTH), calcitonin (CT), thyroglobulin (TG), thyroid transcription factor (TTF-1), galectin 3 (GAL3), cytokeratin 19 (CK 19), p63, bcl-2, OCT4, and SALL4 expression were evaluated by immunohistochemistry. Patient clinical data were collected, and tissue sections were stained with hematoxylin-eosin for histological examination. Most cells stained negative for PTH, CT, TG, and TTF-1. Some cells staining positive for TTF-1 and CT required discussion. However, bcl 2, p63, GAL3, and CK 19 protein expression was detected in main cells. OCT4 protein expression was detected in only two cases, and SALL4 expression in none. Positive staining for bcl-2 and p63, and negative staining for PTH, CT, and TG in SCN main cells are both consistent with the widely accepted minimalist definition of stem cells, thus supporting the hypothesis that they may play a stem cell role in the thyroid gland, although further research will be required into stem cell markers. Furthermore, p63 and GAL-3 staining provides a much more sensitive means of detecting SCNs than staining for carcinoembryonic antigen, calcitonin, or other markers; this may help to distinguish SCNs from their mimics. PMID- 21234709 TI - Cost-effectiveness of gemcitabine + cisplatin vs. gemcitabine monotherapy in advanced biliary tract cancer. AB - OBJECTIVES: The ABC-02 trial demonstrated a statistically significant survival benefit associated with the addition of cisplatin to gemcitabine in the palliative treatment of advanced biliary tract cancer (BTC). Based on the ABC-02 findings, this analysis seeks to evaluate the cost-utility of adding cisplatin to standard gemcitabine therapy from a U.S. societal perspective. METHODS: A decision-analytic model was developed to estimate direct medical costs, patient time costs, and quality-adjusted life-years (QALYs) for two treatment strategies: (1) gemcitabine + cisplatin, (2) gemcitabine monotherapy. Model parameters were derived from the pivotal trial of gemcitabine + cisplatin in advanced BTC, published literature, and government sources. The model included trial-based adverse events and costs related to drug treatment, routine follow-up, adverse events, and post-progression care. The model results were examined using one-way and probabilistic sensitivity analyses (PSA). RESULTS: Total QALYs for the gemcitabine + cisplatin and gemcitabine monotherapy strategies were 0.751 and 0.561, respectively. Total costs were $44,885 and $33,653 respectively. Relative to gemcitabine monotherapy, gemcitabine + cisplatin had an incremental cost effectiveness ratio (ICER) of $59,480 per QALY gained. One-way sensitivity analyses found results to be sensitive to progression-free survival, overall survival, pre and post-progression health state utility values, and the cost of post-progression care. In the PSA, gemcitabine monotherapy had the highest probability of being cost-effective until a willingness-to-pay of $60,000, after which the gemcitabine + cisplatin strategy had the highest probability. CONCLUSION: The results of this analysis suggest that in advanced BTC, the cisplatin + gemcitabine regimen is a cost-effective treatment alternative to gemcitabine monotherapy by currently accepted standards of willingness to pay. PMID- 21234708 TI - A case of corticotroph carcinoma that caused multiple cranial nerve palsies, destructive petrosal bone invasion, and liver metastasis. AB - A 52-year-old woman experienced sudden onset of double vision due to a right abducens nerve palsy and was diagnosed as having a pituitary macroadenoma that invaded into the right cavernous sinus. Otherwise, she was asymptomatic despite marked elevation of ACTH (293 pg/ml) and cortisol (24.6 MUg/dl) levels. The patient underwent transsphenoidal surgery followed by gamma-knife radiosurgery (GKR), which healed the diplopia and ameliorated the hypercortisolemia. The excised tumor was diffusely stained for ACTH with a high (15%) Ki-67 labeling index. Early tumor recurrence occurred twice thereafter, producing right lower cranial nerve palsies with petrosal bone destruction at 8 months and an ipsilateral oculomotor nerve palsy at 12 months after GKR; all palsies resolved completely with the second and third GKRs. Hypercortisolemia worsened rapidly soon after the third GKR, and the patient developed marked weight gain, hypokalemia, and hypertension. Multiple liver lesions were incidentally detected with computer tomography and identified as metastatic pituitary tumor on immunohistochemistry. An ACTH-producing adenoma should be followed carefully for early recurrence and/or metastatic spread when the tumor is an invasive macroadenoma with a high proliferation marker level. The unique aggressive behavior and high potential for malignant transformation of this case are discussed. PMID- 21234710 TI - The strategies used for treatment of experimental autoimmune neuritis (EAN): a beneficial effect of glatiramer acetate administered intraperitoneally. AB - Glatiramer acetate (GA) significantly ameliorates multiple sclerosis and was initially discovered through its effects on the animal model experimental autoimmune encephalomyelitis (EAE). Guillain-Barre syndrome (GBS) is a relatively common demyelinating disease of peripheral nerves for which there is a parallel animal model, experimental autoimmune neuritis (EAN). We review the treatments found useful in EAN with special emphasis on the need for quick onset of action and the relevance of treatments used for EAE and multiple sclerosis. We evaluated the effect of GA administered by a novel intraperitoneal route in EAN. GA significantly ameliorated the severity of disease in rats (F = 6.3, p = 0.01 by analysis of variance (ANOVA)) and course of disease (F = 4.9, p = 0.02 by repeated-measures ANOVA with a day x treatment interaction term). Neurophysiology data supported the trend for the beneficial effect of GA. Myelin-induced immune cell proliferation was significantly modulated by GA (p < 0.025). This report describes a novel route of administration of GA and a rapid beneficial effect of GA in EAN. GA may be useful in human diseases, such as GBS, where the intravenous route may offer a rapid onset of drug action. PMID- 21234711 TI - Cutting edge: the etiology of autoimmune thyroid diseases. AB - Significant progress has been made in our understanding of the mechanisms leading to autoimmune thyroid diseases (AITD). For the first time, we are beginning to unravel these mechanisms at the molecular level. AITD, including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common autoimmune diseases affecting the thyroid. They have a complex etiology that involves genetic and environmental influences. Seven genes have been shown to contribute to the etiology of AITD. The first AITD gene discovered, HLA-DR3, is associated with both GD and HT. More recently, this association was dissected at the molecular level when it was shown that substitution of the neutral amino acids Ala or Gln with arginine at position beta 74 in the HLA-DR peptide binding pocket is the specific sequence change causing AITD. Non-MHC genes that confer susceptibility to AITD can be classified into two groups: (1) immune-regulatory genes (e.g., CD40, CTLA-4, and PTPN22); (2) thyroid-specific genes-thyroglobulin and TSH receptor genes. These genes interact with environmental factors, such as infection, likely through epigenetic mechanisms to trigger disease. In this review, we summarize the latest findings on disease susceptibility and modulation by environmental factors. PMID- 21234712 TI - Immunology, autoimmunity, and autoantibodies in Parkinson's disease. AB - Recent revelations of immune alterations in Parkinson's disease have led to the convergence that an autoimmune mechanism may play a role in the etiopathogenesis of this neurodegenerative disease. In the current study, 77 Parkinson's disease patients and 77 matched healthy controls were analyzed for the presence of seven autoantibodies previously found to be associated with central nervous system manifestations namely: antineuronal-cells, anti-brain lysate, anti-dsDNA, anti phosphatidylserine, anti-cardiolipin, anti-serotonin, and anti-melanocytes antibodies. Patients underwent systematic assessments of demographics, clinical, and biochemical manifestations. Three autoantibodies were found to be more prevalent among Parkinson's disease patients (antineuronal cells10.3% vs. 1.3%, p = 0.017; anti-brain lysate 9.1% vs. 1.3%, p = 0.032; anti-dsDNA 10.3% vs. 2.6%, p = 0.049). Clinical manifestations of Parkinson's disease, particularly dyskinesia and depression, were found to be associated with the presence of these autoantibodies. PMID- 21234713 TI - Uric acid in the early risk stratification of ST-elevation myocardial infarction. AB - Controversy still exists about uric acid as a potential prognostic risk factor for outcomes in patients with acute myocardial infarction. We prospectively assessed, in 856 patients with ST-elevation myocardial infarction (STMI) consecutively admitted to our Intensive Cardiac Care Unit after primary percutaneous coronary intervention (PCI) whether uric acid (UA) levels are associated with in-hospital mortality and complications. Killip classes III-IV were more frequent in the 3 degrees UA tertile that was associated with the highest values of peak Tn I (p = 0.005), NT-proBNP (p < 0.001), and fibrinogen (p = 0.036). Uric acid was associated with mortality (crude OR: 1.24; 95% CI 1.03 1.51; p = 0.025), but, when adjusted for Tn I and renal failure (as inferred by eGFR <60 ml/min/1.73 m(2)), uric acid lost its statistical significance, while Tn I (100 pg/ml step OR: 1.002; 95% CI 1.000-1.003; p = 0.007) and renal failure (OR 9.16; 95% CI 3.60-23.32; p < 0.001) were independent predictors for in-ICCU mortality. Uric acid remained as independent predictor for in-ICCU complications (1 mg/dl step OR: 1.11; 95% CI 1.01-1.21; p = 0.030) together with admission glycemia (1 g/dl step OR: 1.50; 95% CI 1.19-1.91; p < 0.001) and renal failure (OR: 1.46; 95% CI 0.99-2.16; p < 0.001). In STEMI patients submitted to PCI, increased uric acid levels identify a subgroup more prone to in-ICCU complications, probably because hyperuricemia stems from several complex mechanisms ranging from pre-existing risk factors to the degree of myocardial ischemia (as indicated by Killip class, ejection fraction) and to the acute metabolic response (as inferred by glucose levels). Hyperuricemia is not independently associated with early mortality when adjusted for renal function and the degree of myocardial damage. PMID- 21234715 TI - Indigenous communities and the forensic autopsy. PMID- 21234714 TI - Significance of microsatellite instability (MSI) for colorectal cancer following adjuvant therapy with doxifluridine. PMID- 21234716 TI - Evaluation of growth, puberty and endocrine dysfunctions in relation to iron overload in multi transfused Indian thalassemia patients. AB - OBJECTIVE: To determine the prevalence of growth abnormality and endocrine dysfunction in a group of multi transfused thalassemic children and to correlate these with their body iron stores. METHODS: This cross sectional study included 35 Thalassemia Major patients, aged 13 to 24 years. Growth and puberty were assessed clinically and the laboratory values of various hormone levels were stratified with their age and sexual maturity. RESULTS: 57.14% patients were short, 60% had not attained puberty, and 87.5% of the girls had primary amenorrhea. 14.29% had low FSH and 2.86% low LH levels. 89.47% of the boys had low free testosterone and 43.75% of the girls had low estradiol levels. While 20% had high TSH levels, 40% had high PTH levels, of which 92.8% had low levels of Vitamin D. Low levels of IGF-1 were noted in 51.43%. CONCLUSIONS: In this study analysis, short stature and hypogonadism were frequent findings. These results support the need for vigilant clinical evaluation of growth and puberty, as well as appropriate hormonal evaluation in poly transfused thalassemic children in order to detect and treat endocrine dysfunction early. The authors also recommend aggressive and adequate chelation from early life so that permanent damage to the endocrine glands can be prevented. PMID- 21234717 TI - Knocking out angiotensin II in the heart. AB - Despite ongoing medical advances, cardiovascular disease continues to be a leading health concern. The renin-angiotensin system (RAS) plays an important role in regulating cardiovascular function, and is, therefore, the subject of extensive study. Several drugs currently used to treat hypertension and heart failure are designed to target angiotensin II synthesis and function, but thus far, none have been able to completely block the effects of RAS signaling. This review discusses current and emerging approaches towards inhibiting cardiac RAS function in order to further improve cardiovascular disease outcomes. PMID- 21234718 TI - The sleep manifestations of frontal lobe epilepsy. AB - Frontal lobe seizures have a tendency to occur from sleep, and in some cases occur exclusively (or almost exclusively) from sleep; these individuals are said to have nocturnal frontal lobe epilepsy (NFLE). NFLE can be difficult to distinguish clinically from various other sleep disorders, particularly parasomnias, which also present with paroxysmal motor activity in sleep. Here, the manifestations of frontal lobe epilepsy are reviewed in detail, with particular reference to the influence of sleep and the characteristics of NFLE. Key aspects of differential diagnosis are also considered, and the underlying mechanisms involved in NFLE discussed. PMID- 21234719 TI - Advances in MRI assessment of gliomas and response to anti-VEGF therapy. AB - Bevacizumab is thought to normalize tumor vasculature and restore the blood-brain barrier, decreasing enhancement and peritumoral edema. Conventional measurements of tumor response rely upon dimensions of enhancing tumor. After bevacizumab treatment, glioblastomas are more prone to progress as nonenhancing tumor. The RANO (Response Assessment in Neuro-Oncology) criteria for glioma response use fluid-attenuated inversion recovery (FLAIR)/T2 hyperintensity as a surrogate for nonenhancing tumor; however, nonenhancing tumor can be difficult to differentiate from other causes of FLAIR/T2 hyperintensity (e.g., radiation-induced gliosis). Due to these difficulties, recent efforts have been directed toward identifying new biomarkers that either predict treatment response or accurately measure response of both enhancing and nonenhancing tumor shortly after treatment initiation. This will allow for earlier treatment decisions, saving patients from the adverse effects of ineffective therapies while allowing them to try alternative therapies sooner. An active area of research is the use of physiologic imaging, which can potentially detect treatment effects before changes in tumor size are evident. PMID- 21234721 TI - Second primary tumors in patients with head and neck cancer. AB - This is a review on second primary tumors in patients with head and neck cancer. These patients have a high risk of developing other cancers simultaneously or subsequently. The incidence of multiple primary tumors in this population can be as high as 27%. Recurrences are the most common cause of treatment failure within the first 2 years of follow-up. After the third year the diagnosis of a second primary tumor becomes the most important cause of morbimortality in head and neck cancer patients, especially in those treated for cancers early diagnosed. Most second primary tumors occur in the upper aerodigestive tract (40%-59%), lung (31% 37.5%), and esophagus (9%-44%). Patients who develop second primary tumor have a significant reduction of survival expectancy. PMID- 21234720 TI - Optimal therapy in hypertensive subjects with diabetes mellitus. AB - Diabetes and its micro- and macrovascular complications represent a worldwide epidemic that will place an enormous financial burden on poorer countries in the years to come. In patients with diabetes and hypertension, the main determinant of the cardiovascular and renal benefits of antihypertensive drugs is the blood pressure (BP) level achieved under treatment. Quite recently, the paradigm of a BP target < 130/80 mm Hg in these patients has been questioned by a number of trials, including data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) blood pressure-lowering arm and from the diabetic cohort of International Verapamil SR-Trandolapril Study (INVEST). At the same time, even if the key role of BP control is unquestionable, a growing number of published trials suggest that different antihypertensive combinations may offer specific cardio-, vasculo-, and renoprotective advantages that go beyond BP reduction per se. The present review focuses on the most recent and important literature that explored the "optimal" antihypertensive therapy in patients with type 2 diabetes and concomitant hypertension, and it discusses in detail the various areas of uncertainty, including the specific renoprotective effects of renin-angiotensin system blocking agents and the long-term effects of angiotensin-converting enzyme/angiotensin receptor blocker combinations on the progression of diabetic nephropathy. PMID- 21234722 TI - Preoperative stent placement versus prompt surgery for cancer of the head of the pancreas. PMID- 21234723 TI - Hepatic falciform ligament Tc-99m-macroaggregated albumin activity on SPECT/CT prior to Yttrium-90 microsphere radioembolization: prophylactic measures to prevent non-target microsphere localization via patent hepatic falciform arteries. AB - Yttrium-90 (Y-90) selective internal radiation therapy (SIRT) is increasingly used to treat inoperable hepatocellular carcinoma. We describe two patients where hepatic falciform ligament Technetium-99m-macroaggregated albumin (Tc-99m-MAA) activity was identified on single photon emission computed tomography with integrated low-dose CT (SPECT/CT) scan during pre-therapy planning, and the steps taken to prevent radiation dermatitis. The first patient underwent prophylactic coil embolization of the patent hepatic falciform artery; the second patient underwent super-selective infusion of Y-90 resin microspheres to avoid the patent hepatic falciform artery. The incidence of falciform ligament Tc-99m-MAA activity detected on SPECT/CT at our institution is 10%. Tc-99m-MAA SPECT/CT scan provides valuable diagnostic information for treatment planning prior to Y-90 SIRT. PMID- 21234724 TI - The usefulness of fully three-dimensional OSEM algorithm on lymph node metastases from lung cancer with 18F-FDG PET/CT. AB - OBJECTIVE: This work assessed the usefulness of fully three-dimensional ordered subset expectation maximization (3D-OSEM) algorithm for lymph node (LN) metastases from lung cancer. 3D-OSEM images were evaluated by comparing them with those reconstructed by conventional algorithms, such as conventional OSEM algorithm (2D-OSEM) for 2D acquisition and Fourier rebinning plus conventional OSEM algorithm (FORE + OSEM) for 3D acquisition. MATERIALS AND METHODS: In a phantom study, the contrast ratio, the image noise and the signal-to-noise ratio (SNR) were calculated, and the detectability and the image quality of these images were visually evaluated. In a clinical study, 14 patients suffering from lung cancer with LN metastases were evaluated. The image quality and the malignancy, and the detectability were visually evaluated. RESULTS: The contrast ratio was significantly improved using 3D-OSEM as compared with FORE + OSEM, and it was similar to 2D-OSEM. The image noise and SNR in 3D-OSEM images were significantly improved compared with those by other algorithms (p < 0.001). In the visual assessment, the image quality was significantly improved in 3D-OSEM images compared with those by 2D-OSEM and FORE + OSEM (p < 0.001, p = 0.001, respectively). In the clinical study, the image quality and the detectability of LN metastases were improved in 3D-OSEM images compared with those by FORE + OSEM (p < 0.001, p = 0.006, respectively), and image quality and detectability were similar to those of 2D-OSEM images. CONCLUSIONS: 3D-OSEM algorithm successfully improved the diagnostic accuracy of LN metastases in 3D-PET tests. PMID- 21234725 TI - Clinical significance of CT density-based, non-uniform photon attenuation correction of deep-inspiratory breath-hold perfusion SPECT. AB - PURPOSE: The effect of computed tomography (CT) density-based, non-uniform photon attenuation correction (AC) on lung perfusion distribution and the clinical significance were evaluated. MATERIALS AND METHODS: 40 patients with pulmonary emphysema, 32 with pulmonary thromboembolism, 25 with lung cancer and 8 normal controls underwent deep-inspiratory breath-hold (DIBrH) Tc-99m-MAA perfusion SPECT, using a dual-head SPECT system and a respiratory tracking device. Scatter corrected DIBrH SPECT was automatically co-registered with DIBrH CT. AC of DIBrH SPECT was performed using an attenuation coefficient map of a variable-effective linear coefficient calculated from CT pixel density of the co-registered DIBrH CT. The effect of AC on pulmonary perfusion was evaluated by comparison with uncorrected SPECT. RESULTS: After AC, lung perfusion in normal lungs was increased predominantly at deep lungs near the mediastinum and vertebrae and at the upper-middle lungs, with systematic increases of radioactivity (145 +/- 28%) and significant enhancement of physiological gravitational ventral-dorsal gradient (P < 0.01). Throughout the lung diseases, AC significantly enhanced perfusion defect clarity and heterogeneity (P < 0.001), without noticeable artifacts. The correlation between perfusion heterogeneity and the lung diffusing capacity for carbon monoxide was significantly improved in patients with emphysema (P < 0.005). CONCLUSION: CT density-based, non-uniform AC of DIBrH perfusion SPECT provides better assessment of physiologic or impaired perfusion distributions in normal and lung diseases. PMID- 21234726 TI - A case of diffuse-type primary hepatic lymphoma mimicking diffuse hepatocellular carcinoma. AB - Primary hepatic lymphoma (PHL) is a very rare disease, especially in the diffuse type. We report a case of a middle-aged man with hepatitis C virus infection who developed diffuse-type PHL mimicking diffuse hepatocellular carcinoma (HCC). Contrast-enhanced computed tomography (CT) and magnetic resonance imaging showed diffusely infiltrated hypovascular lesions throughout the liver, but no intrahepatic portal venous thrombus was observed. Diffusion-weighted imaging and (18)F-FDG positron emission tomography/CT, respectively, showed a very low apparent diffusion coefficient value and high FDG uptake. These findings were more suggestive of diffuse-type PHL than diffuse HCC. Liver biopsy examination confirmed a diagnosis of diffuse large B-cell lymphoma. Systemic staging revealed no evidence of nodal or bone marrow involvement, so PHL was diagnosed. The patient was treated with chemotherapy and achieved complete remission. We suggest that a combination of image modalities may enable differentiation of diffuse-type PHL from diffuse HCC. PMID- 21234727 TI - Differential uptake of 18F-FDG in patients with synchronous lung cancers. AB - (18)F-fluoro-2-deoxy-D: -glucose positron emission tomography ((18)F-FDG PET/CT) has developed into the standard of care for investigating patients with non-small cell lung cancer (NSCLC) to determine the optimal treatment. However, although the majority of patients with NSCLC do have intense uptake of tracer, false negatives do occur and should be considered. We report cases of patients that have synchronous NSCLCs. In both cases, there was intense uptake of FDG in one tumour type, with very low grade uptake in the separate tumour. Histology confirmed separate lung malignancies, demonstrating that differential FDG uptake may not always be inflammatory and should be considered to have a separate malignant aetiology. PMID- 21234728 TI - Laparoscopic and image-guided radiofrequency ablation of renal tumors: patient selection and outcomes. AB - Multiple modalities exist for the management of small renal tumors, including active surveillance, extirpation (radical nephrectomy and partial nephrectomy), and ablative therapies. Radiofrequency ablation (RFA) is an alternative to extirpative surgery for renal tumors. This article presents the current literature on RFA for renal tumors. We reviewed 28 RFA series in the English literature from 2003 to 2010 to assess patient selection, biopsy, renal outcomes, and oncologic outcomes. PMID- 21234729 TI - The role of uric acid as an endogenous danger signal in immunity and inflammation. AB - Gout is an ancient disease that still plagues us. Its pathogenic culprit, uric acid crystal deposition in tissues, is a strong inflammatory stimulant. In recent years, the mechanisms through which uric acid crystals promote inflammation have been a subject of increasing interest among rheumatologists and immunologists. Uric acid has been identified as an endogenous adjuvant that drives immune responses in the absence of microbial stimulation. Because uric acid is a ubiquitous metabolite that is produced in high quantities upon cellular injury, the ramifications of its effects may be considerable in health and in disease. Uric acid crystals also have been shown to trigger interleukin-1beta-mediated inflammation via activation of the NOD-like receptor protein (NLRP)3 inflammasome, a multimolecular complex whose activation appears to be central to many pathological inflammatory conditions. In this article, we review the possible mechanisms of uric acid-mediated inflammation and offer some historical perspectives on what has been learned about the complex effects of a relatively simple substance. PMID- 21234730 TI - The immune system, the skin, and childhood rheumatic disease. AB - As the body's largest organ and first line of defense against the environment, the skin plays a vital role in host immune defense. In addition to its function as a physical barrier, the skin contains an active immune surveillance network and can mount highly specific responses to eliminate invading organisms. In this review, we discuss the functions of adhesion molecules in regulating the recruitment of distinct cell populations to skin in both healthy and disease states, and the interaction between innate and adaptive immune mechanisms active in the skin. We also review how these systems underlie the pathogenesis of skin manifestations of pediatric rheumatologic diseases. PMID- 21234731 TI - Human cannabinoid 1 GPCR C-terminal domain interacts with bilayer phospholipids to modulate the structure of its membrane environment. AB - G protein-coupled receptors (GPCRs) play critical physiological and therapeutic roles. The human cannabinoid 1 GPCR (hCB1) is a prime pharmacotherapeutic target for addiction and cardiometabolic disease. Our prior biophysical studies on the structural biology of a synthetic peptide representing the functionally significant hCB1 transmembrane helix 7 (TMH7) and its cytoplasmic extension, helix 8 (H8), [hCB1(TMH7/H8)] demonstrated that the helices are oriented virtually perpendicular to each other in membrane-mimetic environments. We identified several hCB1(TMH7/H8) structure-function determinants, including multiple electrostatic amino-acid interactions and a proline kink involving the highly conserved NPXXY motif. In phospholipid bicelles, TMH7 structure, orientation, and topology relative to H8 are dynamically modulated by the surrounding membrane phospholipid bilayer. These data provide a contextual basis for the present solid-state NMR study to investigate whether intermolecular interactions between hCB1(TMH7/H8) and its phospholipid environment may affect membrane-bilayer structure. For this purpose, we measured (1)H-(13)C heteronuclear dipolar couplings for the choline, glycerol, and acyl-chain regions of dimyristoylphosphocholine in a magnetically aligned hCB1(TMH7/H8) bicelle sample. The results identify discrete regional interactions between hCB1(TMH7/H8) and membrane lipid molecules that increase phospholipid motion and decrease phospholipid order, indicating that the peptide's partial traversal of the bilayer alters membrane structure. These data offer new insight into hCB1(TMH7/H8) properties and support the concept that the membrane bilayer itself may serve as a mechanochemical mediator of hCB1/GPCR signal transduction. Since interaction with its membrane environment has been implicated in hCB1 function and its modulation by small-molecule therapeutics, our work should help inform hCB1 pharmacology and the design of hCB1-targeted drugs. PMID- 21234732 TI - The effect of SYT-SSX and extracellular signal-regulated kinase (ERK) on cell proliferation in synovial sarcoma. AB - The character of Synovial sarcoma is the chromosomal translocation t(X; 18)(p11.2;q11.2), which results in the fusion of the SYT gene with a SSX gene. There is little study that could fully elucidate the mechanism of pathogenesis of this fusion transcript. This study is designed to gain more insight into the function of this fusion gene. We evaluated the whole genome expression in SYO-1 cells inhibited as a result of specific small interfering RNA for SYT-SSX. Cell proliferation and apoptosis were analyzed by flow cytometer and MTT. The proteins correlated with proliferation were also detected using western blot. TUNEL and Immunohistochemical stain assessment were also carried out on TMA of SS tissues. The mRNA level reduced over 90% caused by SYT-SSX specific siRNA. Five pathways were employed, that ERK1/2 pathway was differential significantly (p = 0.043218). Meanwhile, down-regulation of SYT-SSX fusion gene expression would inhibit the proliferation of SS cell and the survival rate decreased (34.1%), while apoptotic rate increased (10.92%). After transfected with SYT-SSX-specific siRNA it caused a block in G1/G0 phase (31.99%) of SYO-1 cells compared with control cells. The protein level of ERK1/2, p-ERK, and cyclin D1 altered in same trend with expression of SYT-SSX. In TMA stain assessment, SYT-SSX positive group with high ki-67 LI expressed more cyclin D1and CDK4 than the SYT-SSX negative group. High ki-67 LI was detected in cases with p-ERK expression. Meanwhile, cyclin D1 and CDK4 were shown to be more expressed in tumor cells with p-ERK expression. Our results suggest that the fusion gene SYT-SSX should be considered to play important role on SS cell growth via ERK pathway. This study may be valuable for understanding the pathogenic role and molecular mechanism of the fusion gene SYT SSX in synovial sarcoma through the proposed genome-wide approach. Furthermore, the research would open up the possibility of using SYT-SSX and ERK as a therapeutic target. PMID- 21234733 TI - Phospho-STAT5 expression is associated with poor prognosis of human colonic adenocarcinoma. AB - The signal transducer and activator of transcription-5 (STAT5) protein has been shown to play an important role in tumor progression through stimulating cell proliferation and preventing apoptosis. STAT5 activation has been observed in a variety of human tumors and cancer cell lines. However, it is not clear how activated STAT5 is expressed in colon cancer. In this study, we aimed to investigate phospho-STAT5 (activated form of STAT5) expression and its relationship with the clinicopathological factors and overall survival of patients with colonic adenocarcinoma. A total of 121 histological samples were selected for this study. Immunohistochemistry was used to detect the expression of phospho-STAT5. Analysis of the immunohistochemical staining was based on the proportion of stained cells in the field: positive, >15% stained cells, and negative, <15% stained cells. Survival times were analyzed using the Kaplan-Meier method, and the differences between groups were assessed with the log-rank test. A multivariate Cox regression model was used for prognostic power analysis. Expression of phospho-STAT5 was observed in the cytoplasms of colonic adenocarcinoma cells. Univariate analysis showed that phospho-STAT5 immunoreactivity was correlated with the depth of tumor invasion (P-value = 0.009), tumor-node-metastasis (TNM) stage (P-value = 0.048) and shorter overall survival times (P-value = 0.026). Lymph node metastasis, distant metastasis and TNM stage were associated with shorter overall survival times (P-value range from 0.003- < 0.001). Multivariate analysis showed that only distant metastasis was an independent predictor of overall survival time (P-value = 0.016). Our findings first demonstrate that phospho-STAT5 is frequently present and active in colonic adenocarcinoma and related to poor prognosis. PMID- 21234734 TI - Involvement of brain ketone bodies and the noradrenergic pathway in diabetic hyperphagia in rats. AB - Uncontrolled type 1 diabetes leads to hyperphagia and severe ketosis. This study was conducted to test the hypothesis that ketone bodies act on the hindbrain as a starvation signal to induce diabetic hyperphagia. Injection of an inhibitor of monocarboxylate transporter 1, a ketone body transporter, into the fourth ventricle normalized the increase in food intake in streptozotocin (STZ)-induced diabetic rats. Blockade of catecholamine synthesis in the hypothalamic paraventricular nucleus (PVN) also restored food intake to normal levels in diabetic animals. On the other hand, hindbrain injection of the ketone body induced feeding, hyperglycemia, and fatty acid mobilization via increased sympathetic activity and also norepinephrine release in the PVN. This result provides evidence that hyperphagia in STZ-induced type 1 diabetes is signaled by a ketone body sensed in the hindbrain, and mediated by noradrenergic inputs to the PVN. PMID- 21234735 TI - Health-promoting and health-risk behaviors: theory-driven analyses of multiple health behavior change in three international samples. AB - BACKGROUND: Co-occurrence of different behaviors was investigated using the theoretical underpinnings of the Transtheoretical Model, the Theory of Triadic Influence and the concept of Transfer. PURPOSE: To investigate relationships between different health behaviors' stages of change, how behaviors group, and whether study participants cluster in terms of their behaviors. METHOD: Relationships across stages for different behaviors were assessed in three studies with N = 3,519, 965, and 310 individuals from the USA and Germany by telephone and internet surveys using correlational analyses, factor analyses, and cluster analyses. RESULTS: Consistently stronger correlations were found between nutrition and physical activity (r = 0.16-0.26, p < 0.01) than between non smoking and nutrition (r = 0.08-0.16, p < 0.03), or non-smoking and physical activity (r = 0.01-0.21). Principal component analyses of investigated behaviors indicated two factors: a "health-promoting" factor and a "health-risk" factor. Three distinct behavioral patterns were found in the cluster analyses. CONCLUSION: Our results support the assumption that individuals who are in a higher stage for one behavior are more likely to be in a higher stage for another behavior as well. If the aim is to improve a healthy lifestyle, success in one behavior can be used to facilitate changes in other behaviors--especially if the two behaviors are both health-promoting or health-risky. Moreover, interventions should be targeted towards the different behavioral patterns rather than to single behaviors. This might be achieved by addressing transfer between behaviors. PMID- 21234738 TI - Method for selection of femoral component in total knee arthroplasty (tka). AB - A method is proposed enabling a surgeon to preoperatively determine the preeminent type and size of prosthesis, from those available, to be used in a particular patient undergoing knee replacement surgery. Parameters of healthy knee geometry were estimated by employing an unsupervised neural network. These estimated parameters were then applied in a chi(2) goodness of fit (GoF) test to determine which femoral prosthesis type and size delivers the most appropriate fit. This approach was used to determine the most suitable match of three implants for 34 different cases. Implant C performed the best and was the optimal fit in 59% of the cases, Implant A was the best fit in 38% of the cases and Implant B the best fit in 3% of the cases. This method shows promise in aiding a surgeon to select the optimal prosthesis type and size from an array of different conventional total knee replacements. PMID- 21234739 TI - [Recruitment for multicenter surgical studies in Germany]. PMID- 21234736 TI - The effect of docosahexaenoic Acid on visual evoked potentials in a mouse model of Parkinson's disease: the role of cyclooxygenase-2 and nuclear factor kappa-B. AB - This study aimed to investigate the effect of docosahexaenoic acid (DHA) on visual evoked potentials (VEPs) in a mice model of Parkinson's disease (PD). Mice model was created by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and DHA was given by gavage. Cyclooxygenase-2 (COX-2), caspase-3 activities, nuclear factor kappa-B (NF-kappaB) and prostaglandin E2 (PGE2) levels were determined in substantia nigra (SN) and retina. Cyclooxygenase-2 intensities were also determined immunohistochemically. The tyrosine hydroxylase (TH) immunolabelling was significantly decreased in MPTP group compared to control. Docosahexaenoic acid decreased dopaminergic neuron death in MPTP + DHA group when compared to MPTP group. Mice treated with MPTP showed motor deficits as compared to control. Significant improvement was observed in MPTP + DHA group when compared to MPTP group. Treatment with MPTP significantly increased the activity of COX-2 and total COX in SN when compared to the control group. Docosahexaenoic acid caused a significant decrease in total COX and COX-2 activity in SN of mice given MPTP. Cyclooxygenase-2 showed strong immunostaining in MPTP group when compared to other groups in SN. Levels of PGE2 increased in MPTP group when compared to control in SN. Docosahexaenoic acid treatment in MPTP group reduced PGE2 in SN. Nuclear factor kappa-B levels were found to be decreased in SN of MPTP group. The mean latencies of P1, N1, P2, N2, P3, N3, P4, N4, and P5 VEP components were significantly prolonged in MPTP group when compared to control. In MPTP + DHA group, the mean latencies of all components except P5 returned to control values. Current data shows that DHA treatment improves prolonged VEPs latencies and locomotor activity. PMID- 21234740 TI - [Carpal instability]. AB - Carpal instability can be understood as a disturbed anatomical alignment between bones articulating in the carpus. This disturbed balance occurs either only dynamically (with movement) under the effect of physiological force or even statically at rest. The most common cause of carpal instability is wrist trauma with rupture of the stabilizing ligaments and adaptive misalignment following fractures of the radius or carpus. Carpal collapse plays a special role in this mechanism due to non-healed fracture of the scaphoid bone. In addition degenerative inflammatory alterations, such as chondrocalcinosis or gout, more rarely aseptic bone necrosis of the lunate or scaphoid bones or misalignment due to deposition (Madelung deformity) can lead to wrist instability. Under increased pressure the misaligned joint surfaces lead to bone arrosion with secondary arthritis of the wrist. In order to arrest or slow down this irreversible process, diagnosis must occur as early as possible. Many surgical methods have been thought out to regain stability ranging from direct reconstruction of the damaged ligaments, through ligament replacement to partial stiffening of the wrist joint. PMID- 21234741 TI - Understanding and predicting viscous, elastic, plastic flows. AB - Foams, gels, emulsions, polymer solutions, pastes and even cell assemblies display both liquid and solid mechanical properties. On a local scale, such "soft glassy" systems are disordered assemblies of deformable rearranging units, the complexity of which gives rise to their striking flow behaviour. On a global scale, experiments show that their mechanical behaviour depends on the orientation of their elastic deformation with respect to the flow direction, thus requiring a description by tensorial equations for continuous materials. However, due to their strong non-linearities, the numerous candidate models have not yet been solved in a general multi-dimensional geometry to provide stringent tests of their validity. We compute the first solutions of a continuous model for a discriminant benchmark, namely the flow around an obstacle. We compare it with experiments of a foam flow and find an excellent agreement with the spatial distribution of all important features: we accurately predict the experimental fields of velocity, elastic deformation, and plastic deformation rate in terms of magnitude, direction, and anisotropy. We analyse the role of each parameter, and demonstrate that the yield strain is the main dimensionless parameter required to characterize the materials. We evidence the dominant effect of elasticity, which explains why the stress does not depend simply on the shear rate. Our results demonstrate that the behaviour of soft glassy materials cannot be reduced to an intermediate between that of a solid and that of a liquid: the viscous, the elastic and the plastic contributions to the flow, as well as their couplings, must be treated simultaneously. Our approach opens the way to the realistic multi dimensional prediction of complex flows encountered in geophysical, industrial and biological applications, and to the understanding of the link between structure and rheology of soft glassy systems. PMID- 21234742 TI - High throughput analysis of grape genetic diversity as a tool for germplasm collection management. AB - Using 20 SSR markers well scattered across the 19 grape chromosomes, we analyzed 4,370 accessions of the INRA grape repository at Vassal, mostly cultivars of Vitis vinifera subsp. sativa (3,727), but also accessions of V. vinifera subsp. sylvestris (80), interspecific hybrids (364), and rootstocks (199). The analysis revealed 2,836 SSR single profiles: 2,323 sativa cultivars, 72 wild individuals (sylvestris), 306 interspecific hybrids, and 135 rootstocks, corresponding to 2,739 different cultivars in all. A total of 524 alleles were detected, with a mean of 26.20 alleles per locus. For the 2,323 cultivars of V. vinifera, 338 alleles were detected with a mean of 16.9 alleles per locus. The mean genetic diversity (GDI) was 0.797 and the level of heterozygosity was 0.76, with broad variation from 0.20 to 1. Interspecific hybrids and rootstocks were more heterozygous and more diverse (GDI = 0.839 and 0.865, respectively) than V. vinifera cultivars (GDI = 0.769), Vitis vinifera subsp. sylvestris being the least divergent with GDI = 0.708. Principal coordinates analysis distinguished the four groups. Slight clonal polymorphism was detected. The limit between clonal variation and cultivar polymorphism was set at four allelic differences out of 40. SSR markers were useful as a complementary tool to traditional ampelography for cultivar identification. Finally, a set of nine SSR markers was defined that was sufficient to distinguish 99.8% of the analyzed accessions. This set is suitable for routine characterization and will be valuable for germplasm management. PMID- 21234743 TI - Glucose tolerance, insulin sensitivity and insulin release in European non diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B. AB - AIMS/HYPOTHESIS: The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry. METHODS: Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay. RESULTS: The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (-35.09 [95% CI 14.68-55.52], p = 0.0008 for CC+CT vs TT; and -29.45 [95% CI 9.51-49.38], p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 [95% CI 1.20-1.95] for the meta-analysis of the three samples). CONCLUSIONS/INTERPRETATION: Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function. PMID- 21234744 TI - Leptin downregulates expression of the gene encoding glucagon in alphaTC1-9 cells and mouse islets. AB - AIMS/HYPOTHESIS: Leptin, released by adipocytes, can modulate glucose homeostasis through direct actions on pancreatic alpha and beta cells. Although this hormone rapidly regulates alpha cell exocytosis, its long-term effects on glucagon gene expression are currently unknown. METHODS: We analysed glucagon mRNA levels and protein content in alphaTC1-9 cells and isolated mouse islets cultured with leptin, as well as in islets from mice treated in vivo with leptin. We also studied the involvement of the signal transducers and activators of transcription (STAT) pathway by western blot, immunofluorescence and interference RNA. RESULTS: Leptin incubation (0.0625-18.75 nmol/l) for 24 h inhibited glucagon gene expression in alphaTC1-9 cells. This inhibitory effect was also observed in isolated mouse islets cultured with leptin, as well as in islets from mice treated with leptin for 5 days. In contrast, no changes were detected in islets from db/db mice, which lack leptin receptors. Leptin treatment also reduced the glucagon protein content in alphaTC1-9 cells and mouse islets. Moreover, leptin induced phosphorylation of STAT3 and its translocation to the nucleus, which was confirmed by western blot analysis in alphaTC1-9 cells and by immunofluorescence in isolated alpha cells. Interestingly, the effect of leptin on glucagon mRNA levels was significantly reduced by Stat3 knockdown. In contrast, pharmacological inhibition of the phosphoinositide 3-kinase pathway did not affect leptin actions. CONCLUSIONS/INTERPRETATION: Our results demonstrate that leptin can regulate glucagon gene expression in alpha cells via a STAT3 pathway, and are important for understanding the role of leptin in glucose homeostasis. PMID- 21234745 TI - Acute right heart decompensation in a multiple trauma patient with chronic pulmonary hypertension. PMID- 21234746 TI - Improving the quality of training programs in intensive care: a view from the ESICM. PMID- 21234747 TI - Significant differences exist between the type strain of a newly described bacterial species and a non-type strain included in the original or other scientific publications. PMID- 21234748 TI - A large inversion in the linear chromosome of Streptomyces griseus caused by replicative transposition of a new Tn3 family transposon. AB - We have comprehensively analyzed the linear chromosomes of Streptomyces griseus mutants constructed and kept in our laboratory. During this study, macrorestriction analysis of AseI and DraI fragments of mutant 402-2 suggested a large chromosomal inversion. The junctions of chromosomal inversion were cloned and sequenced and compared with the corresponding target sequences in the parent strain 2247. Consequently, a transposon-involved mechanism was revealed. Namely, a transposon originally located at the left target site was replicatively transposed to the right target site in an inverted direction, which generated a second copy and at the same time caused a 2.5-Mb chromosomal inversion. The involved transposon named TnSGR was grouped into a new subfamily of the resolvase encoding Tn3 family transposons based on its gene organization. At the end, terminal diversity of S. griseus chromosomes is discussed by comparing the sequences of strains 2247 and IFO13350. PMID- 21234749 TI - Azospirillum brasilense siderophores with antifungal activity against Colletotrichum acutatum. AB - Anthracnose, caused by the fungus Colletotrichum acutatum is one of the most important diseases in strawberry crop. Due to environmental pollution and resistance produced by chemical fungicides, nowadays biological control is considered a good alternative for crop protection. Among biocontrol agents, there are plant growth-promoting bacteria, such as members of the genus Azospirillum. In this work, we demonstrate that under iron limiting conditions different strains of A. brasilense produce siderophores, exhibiting different yields and rates of production according to their origin. Chemical assays revealed that strains REC2 and REC3 secrete catechol type siderophores, including salicylic acid, detected by thin layer chromatography coupled with fluorescence spectroscopy and gas chromatography-mass spectrometry analysis. Siderophores produced by them showed in vitro antifungal activity against C. acutatum M11. Furthermore, this latter coincided with results obtained from phytopathological tests performed in planta, where a reduction of anthracnose symptoms on strawberry plants previously inoculated with A. brasilense was observed. These outcomes suggest that some strains of A. brasilense could act as biocontrol agent preventing anthracnose disease in strawberry. PMID- 21234750 TI - In silico prediction of horizontal gene transfer in Streptococcus thermophilus. AB - A combination of gene loss and acquisition through horizontal gene transfer (HGT) is thought to drive Streptococcus thermophilus adaptation to its niche, i.e. milk. In this study, we describe an in silico analysis combining a stochastic data mining method, analysis of homologous gene distribution and the identification of features frequently associated with horizontally transferred genes to assess the proportion of the S. thermophilus genome that could originate from HGT. Our mining approach pointed out that about 17.7% of S. thermophilus genes (362 CDSs of 1,915) showed a composition bias; these genes were called 'atypical'. For 22% of them, their functional annotation strongly support their acquisition through HGT and consisted mainly in genes encoding mobile genetic recombinases, exopolysaccharide (EPS) biosynthesis enzymes or resistance mechanisms to bacteriophages. The distribution of the atypical genes in the Firmicutes phylum as well as in S. thermophilus species was sporadic and supported the HGT prediction for more than a half (52%, 189). Among them, 46 were found specific to S. thermophilus. Finally, by combining our method, gene annotation and sequence specific features, new genome islands were suggested in the S. thermophilus genome. PMID- 21234751 TI - Predicting direction detection thresholds for arbitrary translational acceleration profiles in the horizontal plane. AB - In previous research, direction detection thresholds have been measured and successfully modeled by exposing participants to sinusoidal acceleration profiles of different durations. In this paper, we present measurements that reveal differences in thresholds depending not only on the duration of the profile, but also on the actual time course of the acceleration. The measurements are further explained by a model based on a transfer function, which is able to predict direction detection thresholds for all types of acceleration profiles. In order to quantify a participant's ability to detect the direction of motion in the horizontal plane, a four-alternative forced-choice task was implemented. Three types of acceleration profiles (sinusoidal, trapezoidal and triangular) were tested for three different durations (1.5, 2.36 and 5.86 s). To the best of our knowledge, this is the first study which varies both quantities (profile and duration) in a systematic way within a single experiment. The lowest thresholds were found for trapezoidal profiles and the highest for triangular profiles. Simulations for frequencies lower than the ones actually measured predict a change from this behavior: Sinusoidal profiles are predicted to yield the highest thresholds at low frequencies. This qualitative prediction is only possible with a model that is able to predict thresholds for different types of acceleration profiles. Our modeling approach represents an important advancement, because it allows for a more general and accurate description of perceptual thresholds for simple and complex translational motions. PMID- 21234752 TI - Male killing and incomplete inheritance of a novel spiroplasma in the moth Ostrinia zaguliaevi. AB - Bacteria of the genus Spiroplasma are widely found in plants and arthropods. Some of the maternally transmitted Spiroplasma endosymbionts in arthropods are known to kill young male hosts (male killing). Here, we describe a new case of Spiroplasma-induced male killing in a moth, Ostrinia zaguliaevi. The all-female trait caused by Spiroplasma was maternally inherited for more than 11 generations but was spontaneously lost in several lineages. Antibiotic treatment eliminated the Spiroplasma infection and restored the 1:1 sex ratio. The survival rates and presence/absence of the W chromosome in the embryonic and larval stages of O. zaguliaevi showed that males were selectively killed, exclusively during late embryogenesis in all-female broods. Based on phylogenetic analyses of 16S rRNA, dnaA and rpoB gene sequences, the causative bacteria were identified as Spiroplasma belonging to the tick symbiont Spiroplasma ixodetis clade. Electron microscopy confirmed bacterial structures in the follicle cells and follicular sheath of adult females. Although many congeneric Ostrinia moths harbor another sex ratio-distorting bacterium (Wolbachia), only O. zaguliaevi harbors Spiroplasma. PMID- 21234753 TI - Plumage bacterial assemblages in a breeding wild passerine: relationships with ecological factors and body condition. AB - Microorganisms have been shown to play an important role in shaping the life histories of animals, and it has recently been suggested that feather-degrading bacteria influence the trade-off between parental effort and self-preening behavior in birds. We studied a wild breeding population of great tits (Parus major) to explore habitat-, seasonal-, and sex-related variation in feather degrading and free-living bacteria inhabiting the birds' yellow ventral feathers and to investigate associations with body condition. The density and species richness of bacterial assemblages was studied using flow cytometry and ribosomal intergenic spacer analysis. The density of studied bacteria declined between the nest-building period and the first brood. The number of bacterial phylotypes per bird was higher in coniferous habitat, while bacterial densities were higher in deciduous habitat. Free-living bacterial density was positively correlated with female mass; conversely, there was a negative correlation between attached bacterial density and female mass during the period of peak reproductive effort. Bacterial species richness was sex dependent, with more diverse bacterial assemblages present on males than females. Thus, this study revealed that bacterial assemblages on the feathers of breeding birds are affected both by life history and ecological factors and are related to body condition. PMID- 21234754 TI - Continuous ethanol production from wheat straw hydrolysate by recombinant ethanologenic Escherichia coli strain FBR5. AB - Continuous production of ethanol from alkaline peroxide pretreated and enzymatically saccharified wheat straw hydrolysate by ethanologenic recombinant Escherichia coli strain FBR5 was investigated under various conditions at controlled pH 6.5 and 35 degrees C. The strain FBR5 was chosen because of its ability to ferment both hexose and pentose sugars under semi-anaerobic conditions without using antibiotics. The average ethanol produced from the available sugars (21.9-47.8 g/L) ranged from 8.8 to 17.3 g/L (0.28-0.45 g/g available sugars, 0.31 0.48 g/g sugar consumed) with ethanol productivity of 0.27-0.78 g l(-1)h(-1) in a set of 14 continuous culture (CC) runs (16-105 days). During these CC runs, no loss of ethanol productivity was observed. This is the first report on the continuous production of ethanol by the recombinant bacterium from a lignocellulosic hydrolysate. PMID- 21234755 TI - Vancomycin-resistance transferability from VanA enterococci to Staphylococcus aureus. AB - In last decade methicillin-resistant Staphylococcus aureus with high level of vancomycin-resistance (VRSA) have been reported and generally the patients with VRSA infection were also infected with a vancomycin-resistant Enterococcus (VRE). Considering that the high level of vancomycin-resistance in VRSA isolates seems to involve the horizontal transfer of Tn1546 transposon containing vanA gene from coinfecting VRE strains, the authors have studied the "in vitro" conjugative transfer of this resistance from VanA enterococci to S. aureus. Out of 25 matings performed combining five vancomycin-resistant enterococci as donors (three Enterococcus faecalis and two Enterococcus faecium), and five S. aureus as recipients, all clinical isolates, two have been successful using E. faecalis as donor. The transfer of vancomycin-resistance was confirmed by vanA gene amplification in both transconjugants and the resistance was expressed at lower levels (MIC 32 MUg/ml) in comparison with the respective VRE donors (MIC > 128 MUg/ml). The vancomycin-resistance of trasconjugants was maintained even after subsequent overnight passages on MSA plates containing subinhibitory levels of vancomycin. This study shows that the vanA gene transfer can be achieved through techniques "in vitro" without the use of laboratory animals employed, in the only similar experiment previously carried out by other authors, as substrate for the trasconjugant growth. Moreover, in that previous experiment, contrary to this study, the vancomycin resistant S. aureus trasconjugants were selected on erythromycin agar and not by direct vancomycin agar selection. PMID- 21234757 TI - Molecular characterization of thyroid hormone-inhibited atrial L-type calcium channel expression: implication for atrial fibrillation in hyperthyroidism. AB - Atrial fibrillation (AF) is a common complication in hyperthyroidism. Earlier studies demonstrate that thyroid hormone decreases L-type calcium channel (LCC) current expression with resultant shortening of action potential duration (APD), providing a substrate for AF. The aim of this study was to investigate the potential mechanism underlying the regulatory effect of thyroid hormone on LCC. In a hyperthyroid rat model, thyroid hormone (triiodothyronine [T3]) administration down-regulated atrial LCC expression. In vitro, treatment of murine atrial myocytes (HL-1) with T3 decreased the expression of LCC and its current, resulting in abbreviation of APD. Furthermore, T3 inhibited the activation of cyclic AMP response element (CRE)-binding protein (CREB), including phosphorylation at Ser133 and its nuclear translocation. Transient transfection studies in HL-1 cells indicated that T3 reduced LCC promoter activity. Deletion and mutation analysis of the LCC promoter region along with chromatin immunoprecipitation using anti-CREB antibody showed that CRE was essential for T3 mediated LCC gene expression. Transfection of dominant-negative CREB (mutated Ser133) and mutant thyroid hormone receptor (TR, mutated Cys51) abolished the T3 dependent effects, suggesting an association between both transcriptional factors. Co-immunoprecipitation documented an increased binding of TR with CREB after T3 treatment. The transcriptional cross-talk 3 between TR and CREB bound to CRE mediates T3-inhibited CREB activity and LCC expression. Thyroid hormone induced TR binding of CREB inhibits CREB activity and LCC current expression, which may contribute to AF. These findings provide an important mechanistic insight into hyperthyroidism-induced AF. PMID- 21234756 TI - The occurrence of mtDNA heteroplasmy in multiple cetacean species. AB - In population genetics and phylogenetic studies, mitochondrial DNA (mtDNA) is commonly used for examining differences both between and within groups of individuals. For these studies, correct interpretation of every nucleotide position is crucial but can be complicated by the presence of ambiguous bases resulting from heteroplasmy. Particularly for non-model taxa, the presence of heteroplasmy in mtDNA is rarely reported, therefore, it is unclear how commonly it occurs and how it can affect phylogenetic relationships among taxa and the overall understanding of evolutionary processes. We examined the occurrence of both site and length heteroplasmy within the mtDNA of ten marine mammal species, for most of which mtDNA heteroplasmy has never been reported. After sequencing a portion of the mtDNA control region for 5,062 individuals, we found heteroplasmy in at least 2% of individuals from seven species, including Stenella frontalis where 58.9% were heteroplasmic. We verified the presence of true heteroplasmy, ruling out artifacts from amplification and sequencing methods and the presence of nuclear copies of mitochondrial genes. We found no evidence that mtDNA heteroplasmy influenced phylogenetic relationships, however, its occurrence does have the potential to increase the genetic diversity for all species in which it is found. This study stresses the importance of both detecting and reporting the occurrence of heteroplasmy in wild populations in order to enhance the knowledge of both the introduction and the persistence of mutant mitochondrial haplotypes in the evolutionary process. PMID- 21234758 TI - Meta-analysis: the comparison of clinical results between vaginal and laparoscopic myomectomy. AB - PURPOSE: To evaluate the clinical results of vaginal myomectomy and laparoscopic myomectomy (LM). METHODS: The database of PubMed, EMBASE, Web of Science, ProQuest, Cochrane library and China Biological Medicine Database (CBM), Chinese National Knowledge Infrastructure (CNKI), Wanfang (Chinese) and VIP (Chinese) were searched using the keywords "laparoscopic", "laparoscopically", "vaginal", "trasvaginal", "myomectomy", "randomized", "randomised" and "randomly" to identify randomized controlled trails which compared vaginal myomectomy and LM. Studies are also searched by hand. No language restrictions were made. RESULTS: Four trials were studied and the analysis was performed using Review Manager Version 5 and R software Version 2.11.1. The results had shown that vaginal myomectomy was associated with less operation time significantly, but reduced blood loss, hospital stay and gas recovery and more minor complications without significant difference. CONCLUSIONS: This meta-analysis was not powerful to form an accurate conclusion because of less number, low quality of included studies and no data on major complications and long-term outcomes such as recurrence and pregnancy. Hence, more studies and data should be awaited and involved for further evaluation. PMID- 21234759 TI - The accuracy of the preoperative diagnosis in women undergoing emergent gynecological laparoscopy for acute abdominal pain. AB - OBJECTIVES: To analyze the accuracy of the working diagnosis in emergent laparoscopies and identify variables associated with an accurate or faulty preoperative diagnosis. METHODS: A retrospective cohort study including 217 consecutive women who underwent emergent laparoscopy for acute abdominal pain in 2000-2007. Each case was designated a preoperative-postoperative diagnostic match or mismatch by file review. The agreement between the clinical and preoperative ultrasound findings was analyzed according to the circumstances of imaging tests (Doppler-ultrasound examination performed by a specialist or ultrasound performed by the on-call physician without Doppler examination). RESULTS: On multivariate logistic stepwise regression analysis, the significant independent variables for prediction of preoperative-postoperative diagnostic match (n = 63, 29%) were pregnant state, preoperative clinical-ultrasound match, and duration of symptoms. The circumstances of imaging tests were not a significant predictor for accurate preoperative diagnosis. CONCLUSIONS: In this retrospective analysis, Doppler ultrasound examination performed by a specialist was not associated with higher accuracy of the preoperative diagnosis in women undergoing emergent laparoscopy for acute abdominal pain. These data should be further validated in future prospective cohorts. Doppler-ultrasound examination performed by a specialist does not add to the accuracy of the preoperative diagnosis in women undergoing emergent gynecological laparoscopy for acute abdominal pain. PMID- 21234760 TI - Gastric cancer: surgery in 2011. AB - BACKGROUND: Treatment of gastric cancer is more and more becoming an individualized decision. The choice of the optimal approach is based on prognostic factors, on the anatomic site of the tumor, and on expectations about the response to neoadjuvant treatment. Early gastric cancer that is limited to the mucosal layer is the domain of endoscopic resections. As soon as the submucosal layer is invaded, surgical strategies with adequate lymphadenectomy become necessary. DISCUSSION: In many East Asian Centers and some other centers in the world, these tumors are resected by a laparoscopic approach. With a high experience, this can be done with excellent quality and outcome. In locally advanced gastric cancer, multimodal treatment can improve survival in comparison to surgery alone. However, the strategies differ significantly around the world. While adjuvant chemoradiotherapy is standard in the USA, in Europe, perioperative chemotherapy is the first choice, and in Japan, adjuvant chemotherapy is recommended. In Europe, three randomized phase III studies on the value of preoperative chemotherapy have been performed. Two of them have shown that perioperative chemotherapy does significantly improve the survival of patients with adenocarcinoma of the stomach and of the esophagogastric junction. The one including only preoperative chemotherapy failed to show a survival benefit for the combined treatment arm but showed excellent outcomes in both the surgery alone and the preoperative chemotherapy arms. Based on these studies, patients with stage II or stage III disease are now treated with perioperative chemotherapy. Additionally, it is generally accepted for more than 10 years now that responding patients have a significantly improved prognosis compared to nonresponding patients. The percentage of responding patients varies depending on the applied regimen between 20% and 45%. Therefore, early response evaluation or response prediction is an utmost important field of research. Proximal tumors are treated with a transhiatal extended gastrectomy, tumors in the middle third with a total gastrectomy, and distal tumors with a subtotal gastrectomy, if possible. Modified D2 lymphadenectomy avoiding splenectomy is now accepted as the standard procedure, providing improved prognosis for certain subgroups of patients. Individualized resection and lymphadenectomy techniques for early tumor stages and response-based neoadjuvant concepts for locally advanced tumors are the challenge for the future. PMID- 21234762 TI - Sudden death of an immunocompetent young adult caused by novel (swine origin) influenza A/H1N1-associated myocarditis. AB - The main cause of death from novel (swine origin) influenza A/H1N1 infection is acute respiratory distress syndrome. Most fatal cases are immunocompromised patients or patients with a severe underlying disease. Here, we report a fatal case of acute interstitial myocarditis associated with novel influenza A/H1N1 infection in an immunocompetent young woman. A previously healthy 18-year-old woman experienced malaise, diarrhea, and fever for several days prior to a sudden collapse at home. Autopsy revealed a predominantly lymphocytic myocarditis in the absence of a significant respiratory tract infection. Infection with novel (swine origin) influenza A/H1N1 was confirmed by PCR analysis of blood as well as myocardial tissue. Influenza-caused diarrhea with consecutive hypokalemia potentially contributed to the fatal outcome of the myocarditis, characterized by ventricular fibrillation. In conclusion, sudden death by myocarditis may be a rare complication of novel influenza A/H1N1 infection in otherwise healthy individuals, even in the absence of significant respiratory tract infection. PMID- 21234761 TI - Association between polymorphisms in the XRCC1 and GST genes, and CpG island methylation status in colonic mucosa in ulcerative colitis. AB - CpG island hypermethylation (CIHM) is frequently observed in the colonic mucosa in ulcerative colitis (UC) and is deeply involved in UC-associated colorectal carcinogenesis. We evaluated the influence of common polymorphisms related to DNA repair or xenobiotic pathway (XRCC1, GSTP1, GSTT1, and GSTM1) on the individual susceptibility to CIHM status in the non-neoplastic rectal mucosa in UC patients. XRCC1 Arg399Gln and Arg194Trp, GSTP1 Ile104Val, and GSTT1, GSTM1 null polymorphisms were genotyped in 84 UC patients without neoplastic lesions, in relation to CIHM in the rectal mucosa of three candidate CpG loci (p14, p16, and CDH1) assessed by methylation-specific polymerase chain reaction. XRCC1 codon 399 Arg/Gln genotype (odds ratio (OR) = 0.31, 95%CI = 0.12-0.81, p = 0.017) and 399 Gln carrier (GlnGln+Arg/Gln: OR = 0.30, 95%CI = 0.12-0.76, p = 0.01) were significantly associated with reduced susceptibility to CIHM of the CDH1 promoter. GSTP1 Val carrier (Ile Val+Val/Val) also held a significantly lower susceptibility to CIHM of the p16 promoter (OR = 0.26, 95%CI = 0.08-0.86, p = 0.028). In contrast, GSTT1 present genotype (OR = 3.16, 95%CI = 1.27-7.89, p = 0.01) was significantly associated with increased susceptibility to CIHM of the same gene. XRCC1 codon 399 Gln/Gln genotype was significantly associated with lower mean number of CIHM when compared to the Arg/Arg genotype (1.53 +/- 1.01 vs. 0.63 +/- 1.06, p = 0.024). In addition, the GSTP1 Ile/Val carrier (Ile/Val+Val/Val) was also significantly associated with lower mean number of CIHM (1.43 +/- 1.03 vs. 0.84 +/- 1.07, p = 0.03). XRCC1 Arg399Gln and GSTP1 Ile104Val polymorphisms may influence the CIHM status in the rectal mucosa of UC patients and may be substantially involved in UC-associated carcinogenesis. PMID- 21234763 TI - Downregulation of the hedgehog receptor PTCH1 in colorectal serrated adenocarcinomas is not caused by PTCH1 mutations. AB - Colorectal serrated adenocarcinoma forms about 15-20% of colorectal carcinomas. We have previously shown that downregulation of PTCH1 is distinctive for this type of colorectal cancer. In several other tumor types, somatic inactivating PTCH1 mutations have been shown to lead to aberrant Hedgehog signaling, but in colorectal cancer the role of PTCH1 mutations has not been thoroughly studied. Here, we have analyzed the mutation status of PTCH1 in a series of 33 colorectal serrated adenocarcinomas by sequencing all 23 coding exons. We detected 11 previously known SNPs and eight new alterations. The latter included five synonymous changes and two previously unknown missense variations, somatic M319V, and germline V1231A. V1231A was also present in population controls and likely represents polymorphism. The somatic M319V variant does not appear to be an attractive candidate for a disease-associated mutation because in silico analyses did not support the pathogenic nature of the change. A somatic, intronic 1-bp deletion was detected in a short poly(T) stretch in two microsatellite unstable tumors. None of the three changes had predicted effect on splicing when analyzed in silico. Our results did not reveal any clearly deleterious inactivating PTCH1 mutations in our collection of colorectal serrated adenocarcinomas. This suggests that other mechanisms are involved in the observed downregulation of the PTCH1 gene. These might include, e.g., constantly active MAPK signaling by KRAS or BRAF mutations or silencing of PTCH1 by hypermethylation, and further studies are needed to reveal these mechanisms. PMID- 21234764 TI - Transcriptional control of the human glucocorticoid receptor: identification and analysis of alternative promoter regions. AB - Glucocorticoid receptor levels are thought to be controlled by multiple alternative first exons. Seven of these exons are located in an upstream CpG island. In this study, we investigated the promoter activity of the intronic regions between these exons, and their susceptibility to CpG methylation and sequence variability. The seven promoters were cloned into luciferase reporter genes, and their activity measured in ten cell lines. CpG islands of 221 donors were genotyped and the effects of these SNPs were investigated in a reporter gene assay. We showed that each of the first exons was independently controlled by a unique promoter located directly upstream. Promoter activities were cell type specific, and varied considerably between cell types. Irrespective of the cell type, in vitro methylation effectively silenced all reporter constructs. Eleven SNPs were observed within the CpG island of 221 donors, and a new promoter specific haplotype was revealed. Four of the minor alleles reduced the reporter gene activity, with cell type specific effects. This complexity within the CpG island helps to explain the variable, tissue-specific transcriptional control of the GR, and provides insight into the mechanisms underlying tissue specific deregulation of GR levels. PMID- 21234765 TI - Genomic and genealogical investigation of the French Canadian founder population structure. AB - Characterizing the genetic structure of worldwide populations is important for understanding human history and is essential to the design and analysis of genetic epidemiological studies. In this study, we examined genetic structure and distant relatedness and their effect on the extent of linkage disequilibrium (LD) and homozygosity in the founder population of Quebec (Canada). In the French Canadian founder population, such analysis can be performed using both genomic and genealogical data. We investigated genetic differences, extent of LD, and homozygosity in 140 individuals from seven sub-populations of Quebec characterized by different demographic histories reflecting complex founder events. Genetic findings from genome-wide single nucleotide polymorphism data were correlated with genealogical information on each of these sub-populations. Our genomic data showed significant population structure and relatedness present in the contemporary Quebec population, also reflected in LD and homozygosity levels. Our extended genealogical data corroborated these findings and indicated that this structure is consistent with the settlement patterns involving several founder events. This provides an independent and complementary validation of genomic-based studies of population structure. Combined genomic and genealogical data in the Quebec founder population provide insights into the effects of the interplay of two important sources of bias in genetic epidemiological studies, unrecognized genetic structure and cryptic relatedness. PMID- 21234766 TI - Biofilm coupled with UV irradiation for phenol degradation and change of its community structure. AB - The extensive use of phenol compounds and the inability to remove these compounds during wastewater treatment have resulted in the widespread occurrence of phenols in the natural environment. Phenols have been linked to serious risks to human and environmental health. Hence, the need to develop technologies that can effectively remove phenols from wastewater and source waters is a pressing challenge. In this study, light ceramic particles were immersed in activated sludge acclimated to degrade phenol, and microorganisms were allowed to attach to the particles surface to form biofilm. Then the ceramic particles with biofilm were moved into the photolytic circulating-bed biofilm reactor made of quartz glass, which was used for the degradation of phenol by three protocols: photolysis with UV light alone (P), biodegradation alone (B), and the two mechanisms operating simultaneously (photobiodegradation, P&B). The experimental results indicated that phenol removal rate was quickest by B experiment. However, P&B experiment gave more complete mineralization of phenol than that by other protocols. During P&B experiment, the microorganisms grown on porous ceramic carrier still kept the bioactivity degrading phenol, even under UV light irradiation. However, the dominant members of the bacterial community changed dramatically after the intimately coupled photobiodegradation, according to molecular biological analysis to the biofilm. Whereas Beijerinckia sp. was the dominant strain in the inoculum, it was replaced by Thauera sp. MZ1T that played a main role on degrading phenol during P&B experiment. PMID- 21234767 TI - Adequacy of control of preoperative hypertension can affect landiolol-induced hemodynamic changes in elderly patients during emergence from anesthesia. AB - We examined the dose-related effects of landiolol on hemodynamics during emergence from anesthesia of elderly patients with uncontrolled hypertension. Thirty-three normotensive, 34 controlled hypertensive, and 31 uncontrolled hypertensive elderly patients were divided into three groups: control (saline infusion), 0.125 landiolol group, and 0.25 landiolol group. Landiolol or saline infusion was administered at 0.125 (0.125 landiolol group) or 0.25 (0.25 landiolol group) mg/kg/min for 1 min and thereafter decreased to 0.04 or 0.08 mg/kg/min, respectively, until extubation, under regular heart rate and blood pressure monitoring. In normotensive patients, the 0.125 mg/kg/min landiolol infusion was suitable for stabilization of systolic blood pressure and heart rate during tracheal extubation. Controlled hypertensive patients required a 0.25 mg/kg/min landiolol infusion for stabilization of systolic blood pressure and heart rate during tracheal extubation. In uncontrolled hypertensive patients the 0.25 mg/kg/min landiolol infusion could stabilize heart rate, but not systolic blood pressure. In conclusion, the adequacy of preoperative hypertensive control could affect landiolol infusion-induced hemodynamic stability during emergence of elderly patients from anesthesia. PMID- 21234768 TI - Pandemic H1N1 influenza virus causes a stronger inflammatory response than seasonal H1N1 influenza virus in ferrets. AB - A 2009 H1N1 influenza virus pandemic, which had its origin in swine, caused severe illness and mortality in humans. Inflammatory responses may be responsible for pathogenesis caused by infection with influenza viruses. To better understand the pathogenic mechanism, clinical signs and inflammatory responses in ferrets infected with the pandemic H1N1 were compared with those caused by seasonal H1N1 influenza virus. Ferrets infected with the 2009 pandemic H1N1 virus displayed higher body temperatures, greater reduction in body weight, and higher viral titers in the tracheae and lungs. Levels of inflammatory cytokines, including interleukin-6, interferon-alpha, and tumor necrosis factor-alpha, were higher in the lungs of ferrets infected with the 2009 pandemic H1N1. The data support the idea that increased pathogenesis caused by the 2009 pandemic H1N1 influenza virus may have been partially mediated by a higher induction of pro-inflammatory cytokines in the lungs of affected humans or animals. PMID- 21234769 TI - Molecular characterization of rotavirus diarrhea among children in South Korea: detection of an unusual G11 strain. AB - Among 312 rotavirus-positive samples collected from eight hospitals across South Korea during 2008 and 2009, the most prevalent circulating G genotype was G1 (35.9%), followed by G3 (24.7%), G2 (17.0%), G4 (7.7%), and G9 (2.6%). Notably, one unusual G11 lineage III strain-the first hypoendemic infection case in the world-was found. Of the P genotypes, P[8] (43.9%) was the most common, followed by P[6] (29.5%), P[4] (9.3%) and P[9] (0.6%). Determining G- and P-type combinations showed that G1P[8] was the most prevalent (20.5%), followed by G2P[6] (12.8%) and G3P[8] (12.8%). These findings provide new information concerning the current prevalence and spread of the rare G11 rotavirus. PMID- 21234770 TI - A human papillomavirus 8 E7 protein produced in plants is able to trigger the mouse immune system and delay the development of skin lesions. AB - We investigated the potential of Nicotiana benthamiana to express the E7 protein of human papillomavirus 8 (HPV-8), a paradigm genotype among cutaneous HPVs. The protein, modified in its putative pRb-binding domain (E7(QGD)), was transiently expressed in leaves following infiltration with agrobacteria carrying either a binary vector combined with silencing suppressor constructs or replicating tobacco mosaic virus (TMV)-based vectors with different targeting signals. HPV-8 E7(QGD) yields ranged from 250 ng to 4.6 mg per gram of fresh leaf tissue. The highest yields were obtained with TMV-based vectors targeting the antigen to the apoplast. HPV8-CER (H2(q)) mice transformed with the complete early region of HPV 8 showed a delay in the onset of skin papillomatous lesions and produced E7 specific immunoglobulins G when inoculated subcutaneously with leaf extracts expressing E7(QGD). Furthermore, we demonstrated that the plant-made HPV-8 E7(QGD) induced a specific cytotoxic response in C57BL/6 (H2(b)) mice. PMID- 21234771 TI - The bindosome is a structural component of the Sulfolobus solfataricus cell envelope. AB - Sugar binding proteins of the thermoacidophile Sulfolobus solfataricus function together with ABC transporters in the uptake of sugars. They are synthesized as precursors with a class III signal peptide that are normally found in archaeal flagellins and bacterial type IV pilins. The functional expression of sugar binding proteins at the cell surface is dependent on the bindosome assembly system (Bas) that is homologous to bacterial type IV pilin assembly systems. The Bas system consists of an assembly ATPase, BasE; a membrane anchoring protein, BasF; and three small class III signal peptide containing proteins BasABC. Expression of BasEF in a S. solfataricus DeltabasEF strain restored the uptake of glucose, while an ATPase mutant of BasE was unable to complement. BasEF was detergent-extracted from S. solfataricus membranes as a stable protein complex. Solute binding proteins can be extracted from the cell surface as two high molecular mass complexes of 600 and 400 kDa, wherein the largest complex also contains the main S-layer protein SlaA. Electron microscopic analysis of the cell surface of the wild-type and DeltabasEF strain indicates that the absence of the BasEF complex causes an alteration in cell morphology and the corrugation of the S-layer pattern that is reversed by complementation with the BasEF complex. These results suggest an interaction between the S-layer and the sugar binding proteins that contribute to cell shape. PMID- 21234772 TI - Hypofractionated stereotactic radiotherapy for oligometastases in the brain: a single-institution experience. AB - The treatment of brain metastases is changing. Many different radiotherapy options are now available and under clinical evaluation. As part of this effort, we retrospectively evaluated the efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) in patients with up to three brain metastases. Sixty-five patients with 81 lesions were treated with hypofractionated radiotherapy. Median dose was 24 Gy in three fractions. Median follow-up was 24.6 months. Actuarial tumour control was 75 and 45% at 9 months and 24 months after treatment, respectively. Median survival time was 7.5 months, and 32% of the patients died from brain tumour progression. Actuarial overall survival was 75% at 3 months and 25% at 12 months. Recursive partitioning analysis class was the only significant prognostic factor. Neoadjuvant whole-brain radiotherapy (in 29 patients) had no impact on survival or local control. Neurological status improved in 42 patients (65%). Adverse events were rare and usually mild. This experience suggests HSRT should be considered as an alternative approach in the treatment of one to three metastatic lesions in selected patients. PMID- 21234773 TI - A case of complex arteriovenous malformation with skull destruction presented in sixth decade of life. AB - Intracranial AVMs are typically diagnosed before the patient has reached the age of 40 years, and a few cases have been reported of AVM with skull destruction. We described a rare case of a complex cerebral AVM with skull destruction, presented de novo in 52-year-old woman with epileptic seizures. Neuroimaging investigations revealed complex AVM in right hemisphere as well as extracranially, with signs of skull destructions, likely caused by significant involvement of feeders from external carotid artery. Neurosurgery treatment was not recommended due to morphological characteristics and drainage patterns of the AVM. EEG investigation showed discrete specific activity in correspondent area and pharmacology treatment for seizures was initiated. One year after the initial presentation patient had survived rebleeding episode witch left permanent neurology deficit. This patient considered as a rare case of complex AVM with skull destruction, presented de novo in sixth decade of life. PMID- 21234774 TI - Acute transient inflammatory leukoencephalopathy in HIV. AB - HIV-related acute inflammatory leukoencephalopathy of undetermined origin (AIL) is characterized by abrupt onset of symptoms generally associated with focal brain lesions and inflammatory CSF findings. A previously asymptomatic 31-year old HIV+ woman presented with acute cognitive difficulties, right hemiparesis and dysphasia. Brain MRI showed a large contrast-enhancing lesion in the left frontal lobe; brain biopsy revealed an inflammatory process. No etiological agent was found in blood, CSF or brain tissue. The patient was given systemic steroids and gammaglobulins and put on HAART. Clinical conditions progressively and completely recovered. Further brain MRI showed the shrinkage of the lesion with no contrast enhancement. Our case could be classified as AIL in HIV resembling ADEM pattern and highlights the importance of taking into consideration. ADEM in the diagnostic process of HIV-related leukoencephalopathy even if the typical features are lacking, as immunodeficiency could modify both presentation and disease course. PMID- 21234775 TI - Natalizumab therapy of multiple sclerosis: recommendations of the Multiple Sclerosis Study Group--Italian Neurological Society. AB - Three years after the introduction of natalizumab (NA) therapy for the second line treatment of relapsing-remitting multiple sclerosis (MS), Italian MS centers critically reviewed the scientific literature and their own clinical experience. Natalizumab was shown to be highly efficacious in the treatment of MS. However, the risk of progressive multifocal leukoencephalopathy was confirmed and defined better. This article summarizes the MS-SIN Study Group recommendations on the use of NA in MS, with particular reference to the appropriate selection and monitoring of patients as well as to the management of adverse events. PMID- 21234776 TI - Medulloblastoma and gliomatosis cerebri: rare brain tumors in multiple sclerosis patients. AB - The simultaneous appearance of both multiple sclerosis (MS) and central nervous system (CNS) tumors is relatively uncommon. Whether the co-existence of two diseases is due to chance alone or the result of a causal relationship is still a matter of debate. There is also controversy about the effect of long-term exposure of MS patients to immunomodulatory drugs on the incidence of cancer. This paper reports two cases of rare CNS tumors (i.e., medulloblastoma and gliomatosis cerebri) in adult MS patients. Our cases emphasize that when uncommon neurological features appear in patients with MS, brain magnetic resonance imaging (MRI) ought to be done and brain biopsy should be considered to exclude a concomitant CNS disorder. These procedures are essential for the differential diagnosis and early treatment. PMID- 21234777 TI - Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss diagnosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with rarer neurological presentation. When this occurs, diagnosis may be delayed. This report aims to call attention to clinical, laboratory, and radiological features that should prompt the correct diagnosis. A 13-year-old girl presented with progressive increase in intracranial pressure and ataxia. MRI showed a diffuse tumor-like swelling of the cerebellum with tonsillar herniation and patchy white matter post-contrast enhancement. Regression of swelling with steroids ruled out glioma and medulloblastoma, and brain lymphoma was considered. Diagnosis of HLH was reached 2 months after onset when uncontrolled fever and severe elevation of liver enzymes occurred. Two bone marrow biopsies were needed to demonstrate hemophagocytosis. Familial HLH was confirmed by perforin gene mutations. Bone marrow transplantation was performed. The early diagnosis of HLH may be life saving. Awareness of the disease is necessary to investigate its characteristic findings, thus avoiding a delay in diagnosis. PMID- 21234778 TI - Reversible posterior leukoencephalopathy syndrome in a patient with thrombotic thrombocytopenic purpura. AB - Thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder characterised by fever, microangiopathic haemolytic anaemia, renal insufficiency, and thrombocytopenia. Neurological involvement, a prominent component of TTP, is characterised by a variety of brain lesions which include reversible cerebral oedema or magnetic resonance imaging (MRI) features of reversible posterior leukoencephalopathy syndrome (RPLS). TTP is frequently associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13.Here, we report a case of TTP with severe acute encephalopathy. Posterior leukoencephalopathy and brainstem oedema with triventricular hydrocephalus were observed on MRI. The low activity of ADAMTS13 was not observed and ADAMTS-13 antibodies were absent. Neurological symptoms and patient's condition were completely resolved by plasma exchange therapy in addition to high dose of methylprednisolone. PMID- 21234779 TI - An unusual growth of an intraventricular meningioma: a case report. AB - Intraventricular meningiomas are rare often histologically benign tumors arising most always from the trigonal region of the lateral ventricle. We report the first described case of a rapidly growing histologically benign intraventricular meningioma in a 68-year-old woman whose magnetic resonance imaging (MRI) executed 1 year before surgical operation was negative for intracranial mass lesion. PMID- 21234780 TI - Aseptic meningitis after transsphenoidal management of Rathke's cleft cyst: case report and review of the literature. AB - Aseptic meningitis after transsphenoidal surgery (TSS) for treatment of Rathke's cleft cyst (RCC) is a rare complication caused by the leakage of the cyst contents within the subarachnoid space. We present a case of aseptic meningitis occurring after TSS for a RCC. During surgery, the cyst wall was subtotally removed, and intraoperative cerebrospinal fluid (CSF) leakage was observed. The patient developed meningeal signs and symptoms on the first postoperative day. CSF examinations were highly suggestive of aseptic meningitis. Histological examination confirmed a granulomatous inflammatory reaction of the RCC wall. Preexisting inflammation, subtotal cyst wall resection, intraoperative erosion of the diaphragma sellae and placement of a lumbar drain may be risk factors for the development of aseptic meningitis. PMID- 21234781 TI - A study of six point mutation analysis of LRRK2 gene in Chinese mainland patients with Parkinson's disease. PMID- 21234782 TI - Selective underexpression of Kv3.2 and Kv3.4 channels in the cortex of rats exposed to ethanol during early postnatal life. AB - The expression of voltage-gated potassium channels belonging to the Kv3 family has been studied in the sensori-motor cortex of rats exposed to alcohol inhalation during the first postnatal week (P2-P6). The study was carried out using comparative RT-PCR. At P9, a significant reduction of the expression of Kv3.2 and Kv3.4 subunits occurred in alcohol-treated animals, as compared with controls. The expression of the Kv3.4a splicing variant, which is thought to be critically involved in the high-frequency firing of some cortical interneurons, was also correspondingly reduced. The downregulation of Kv3.2 and Kv3.4a subunits represented a long-lasting effect of alcohol exposure, since it was also observed in P24 animals. The expression of both Kv3.1 and Kv3.3 channels appeared to be not significantly affected by alcohol exposure. An increased susceptibility to apoptotic neuronal death after early postnatal exposure to ethanol was confirmed by the lower bcl-2/bax ratio observed in alcohol-treated animals. Although Kv3.4 subunits are thought to trigger apoptosis, the lack of upregulation in our model argues against their involvement in the mechanism leading to alcohol-induced apoptosis. The possible consequences of the selective downregulation of Kv3 subunits on the cortical function, as well as their relevance for the genesis of fetal alcohol effects, are discussed. PMID- 21234783 TI - Proteins involved in biotic and abiotic stress responses as the most significant biomarkers in the ripening of Pinot Noir skins. AB - We propose an integrated approach, obtained by the combination of multivariate statistics and proteomics, useful to isolate candidate biomarkers for the evaluation of grape ripening. We carried out a comparative 2-DE analysis of grape skins collected in three moments of ripening and analyzed the spot volume dataset through the application of principal component analysis followed by forward stepwise-linear discriminant analysis. This technique allowed to discriminate veraison, quite mature and mature samples, and to sort the matched spots according to their significance. We identified 36 spots showing high discriminating coefficients through liquid chromatography - electrospray ionization - tandem mass spectrometry (LC-ESI-MS/MS). Most of them were involved in biotic and abiotic stress responses indicating these enzymes as good candidate markers of berry ripening. These evidences hint at a likely developmental role of these proteins, in addition to their reported activity in stress events. Restricting the same statistical analysis to the samples belonging to the two last stages, it was indicated that this approach can clearly distinguish these close and similar phases of berry development. Taken all together, these results bear out that the employment of the combination of 2-DE and multivariate statistics is a reliable tool in the identification of new protein markers for describing the ripening phases and to assess the overall quality of the fruit. PMID- 21234784 TI - The association of plasma prorenin level with an oxidative stress marker, 8-OHdG, in nondiabetic hemodialysis patients. AB - BACKGROUND: Circulating prorenin contributes to the pathogenesis of tissue damage leading to cardiovascular disease (CVD) in hypertension and diabetic mellitus (DM) by activating the tissue renin-angiotensin-aldosterone (RAS) system; however, little is known about its roles in hemodialysis (HD) patients. METHODS: We evaluated plasma prorenin level and prorenin receptor [(P)RR] expression in peripheral blood mononuclear cells (PBMCs) in 49 nondiabetic HD (non-DM-HD) patients. Then we investigated the association between plasma prorenin level or (P)RR expression level in PBMCs and CVD-predictive biomarkers. RESULTS: The plasma prorenin level increased in non-DM-HD patients [147.1 +/- 118.9 pg/ml (standard value <100 pg/ml)]. The (P)RR mRNA expression level in PBMCs also increased 1.41 +/- 0.39-fold in non-DM-HD patients compared with that in healthy control subjects (p < 0.001). Although plasma prorenin level did not correlate with plasma BNP level and plasma high-sensitivity C-reactive protein level, it significantly correlated with plasma 8-hydroxydeoxyguanosine (8-OHdG) level (r = 0.535, p < 0.001). The plasma prorenin level did not correlate with plasma renin activity (PRA), plasma angiotensin I (AT I) level, plasma angiotensin II (AT II) level and plasma aldosterone (Ald) level. PRA, plasma AT I level, plasma AT II level and plasma Ald level did not correlate with the level of any CVD predictive biomarker. (P)RR expression level in PBMCs did not correlate with the level of any CVD predictive biomarker. CONCLUSIONS: The plasma prorenin level and (P)RR expression level in PBMCs increased, and the plasma prorenin level was associated with plasma 8-OHdG level independent of circulating RAS in non-DM-HD patients. PMID- 21234785 TI - Management of anemia in chronic kidney disease patients: baseline findings from Chronic Kidney Disease Japan Cohort Study. AB - BACKGROUND: Anemia is a factor that affects the outcome of patients with chronic kidney disease (CKD); however, there are only a few reports on the management of anemia in Japanese patients with CKD who are not on dialysis. METHODS: We investigated the prevalence, related factors and management of anemia in CKD stage 3-5 patients in Japan based on the baseline data obtained from a prospective cohort study (Chronic Kidney Disease Japan Cohort). Anemia was defined as having a hemoglobin (Hb) level of <11 g/dL or receiving erythropoiesis stimulating agent (ESA) therapy. RESULTS: The result indicated that 946 out of 2,930 patients had anemia. Of these 946 patients, 385 were receiving ESA treatment for anemia and had an Hb level of 10.28 +/- 1.19 g/dL (mean +/- SD). The percentage of these patients with an Hb level above the target of 11 g/dL proposed for treatment by the Japanese guidelines, and above the maintenance level of 10 g/dL approved for ESA therapy in Japan, was only 30.1 and 61.6%, respectively. In contrast, the percentage of patients receiving no ESA therapy was 67.6 and 55.7%, respectively, among those with an Hb level of <11 and <10 g/dL. CONCLUSIONS: These data suggested that prevalence of anemia was high in Japanese patients with CKD stage 3-5, that the percentage of patients receiving ESA was low among those who required ESA, and that a large number of patients receiving ESA failed to maintain the recommended level of Hb. PMID- 21234786 TI - Inferring an organism-specific optimal threshold for predicting protein coding regions in eukaryotes based on a bootstrapping algorithm. AB - The accuracy of prediction methods based on power spectrum analysis depends on the threshold that is used to discriminate between protein coding and non-coding sequences in the genomes of eukaryotes. Because the structure of genes vary among different eukaryotes, it is difficult to determine the best prediction threshold for a eukaryote relying only on prior biological knowledge. To improve the accuracy of prediction methods based on power spectral analysis, we developed a novel method based on a bootstrap algorithm to infer organism-specific optimal thresholds for eukaryotes. As prior information, our method requires the input of only a few annotated protein coding regions from the organism being studied. Our results show that using the calculated optimal thresholds for our test datasets, the average prediction accuracy of our method is 81%, an increase of 19% over that obtained using the same empirical threshold P=4 for all datasets. The proposed method is simple and convenient and easily applied to infer optimal thresholds that can be used to predict coding regions in the genomes of most organisms. PMID- 21234787 TI - Cloning and sequence analysis of a novel xylanase gene, Auxyn10A, from Aspergillus usamii. AB - A full-length cDNA sequence, encoding a novel endo-1,4-beta-D: -xylanase (AuXyn10A) of Aspergillus usamii, was obtained by using rapid amplification of cDNA ends (RACE) methods and cloned into the pUCm-T vector, followed by DNA sequencing. The cDNA gene, designated as Auxyn10A, is 1,235 bp in length harboring 5'- and 3'-non-encoding regions, as well as an ORF of 984 bp that encodes a 19-aa signal peptide, a 6-aa propeptide and a 302-aa mature peptide with a calculated MW of 32,756 Da. The AuXyn10A displays high similarity to the xylanases of Aspergillus niger, Aspergillus kawachii and Aspergillus niger, members of the glycoside hydrolase family 10. Its three-dimensional structure was predicted using http://swiss-model.expasy.org/on-line programs based on the crystal structure of Penicillium simplicissimum xylanase (1B30_A) from the family 10. The complete DNA gene was cloned from the genomic DNA of A. usamii using conventional PCR and hairpin structure-mediated PCR techniques. The DNA gene is 2,255 bp in length, containing a 510 bp of 5'-flanking promoter region and a 1,745 bp of downstream fragment that consists of ten exons and nine short introns ranging from 52 to 62 bp. PMID- 21234788 TI - Different physiological responses influenced by salinity in genetically related Dunaliella salina isolates. AB - An isolate of Dunaliella salina (DUNS-1) and other two isolates (DUNS-2 and DUNS 3), collected from coastal lagoons with 14 and 30% (w/v) of NaCl, respectively, were analyzed under different saline conditions. Glycerol (380 mg l(-1)) and carotene (5.9 mg l(-1)) contents for DUNS-2 were 0.3 and 10 times higher than DUNS-3, even though both isolates were collected from the same lagoon and share a similar ribosomal DNA sequence. PMID- 21234789 TI - A mutant L-asparaginase II signal peptide improves the secretion of recombinant cyclodextrin glucanotransferase and the viability of Escherichia coli. AB - L-Asparaginase II signal peptide was used for the secretion of recombinant cyclodextrin glucanotransferase (CGTase) into the periplasmic space of E. coli. Despite its predominant localisation in the periplasm, CGTase activity was also detected in the extracellular medium, followed by cell lysis. Five mutant signal peptides were constructed to improve the periplasmic levels of CGTase. N1R3 is a mutated signal peptide with the number of positively charged amino acid residues in the n-region increased to a net charge of +5. This mutant peptide produced a 1.7-fold enhancement of CGTase activity in the periplasm and significantly decreased cell lysis to 7.8% of the wild-type level. The formation of intracellular inclusion bodies was also reduced when this mutated signal peptide was used as judged by SDS-PAGE. Therefore, these results provide evidence of a cost-effective means of expression of recombinant proteins in E. coli. PMID- 21234790 TI - Functional analysis of the grapevine paralogs of the SMG7 NMD factor using a heterolog VIGS-based gene depletion-complementation system. AB - Nonsense-mediated mRNA decay (NMD) is a eukaryotic quality control system that identifies and eliminates transcripts having a premature translation termination codon (PTC). NMD is also involved in the control of several wild-type mRNAs. The NMD core machinery consists of three highly conserved NMD factors (UPF1, UPF2 and UPF3) and at least one less conserved 14-3-3-like domain containing protein (SMG7). A PTC is identified by UPF factors, and then SMG7 triggers rapid transcript decay. UPF factors are generally encoded by a single gene, whereas SMG7 has duplicated several times during evolution. Recently it was reported that the plant SMG7 is autoregulated through NMD and that SMG7 has two relatively divergent paralogs in dicots, SMG7 and SMG7L. In mammals all three SMG7 related genes (SMG5, SMG6 and SMG7) are essential in NMD, so we hypothesized that in plants the SMG7 and SMG7L duplicates may also play distinct roles in NMD. To test this possibility, we have analyzed the evolution and the function of plant SMG7 homologs. We show that SMG7L is not required for plant NMD. Interestingly, we found that the grapevine and poplar genomes contain two quite divergent SMG7 paralogs which may have derived from an ancient duplication event. Using heterolog depletion/complementation assays we demonstrate that both grapevine SMG7 copies retained the complete NMD activity and both of them are under NMD control, whilst SMG7L has lost NMD activity and NMD control. PMID- 21234791 TI - Pulsed laser deposition of hydroxyapatite on titanium substrate with titania interlayer. AB - Pulsed laser deposition (PLD) has been used to deposit hydroxyapatite (HA) ceramic over titanium substrate with an interlayer of titania. PLD has been identified as a potential candidate for bioceramic coatings over metallic substrates to be used as orthopedic and dental implants because of better process control and preservation of phase identity of the coating component. However, direct deposition of hydroxyapatite on titanium at elevated temperature results in the formation of natural oxide layer along with some perovskites like calcium titanate at the interface. This leads to easy debonding of ceramic layer from the metal and thereby affecting the adhesion strength. In the present study, adherent and stable HA coating over Ti6Al4V was achieved with the help of an interlayer of titania. The interlayer was made to a submicron level and HA was deposited consecutively to a thickness of around one micron by exposing to laser ablation at a substrate temperature of 400 degrees C. The deposited phase was identified to be phase pure HA by X-ray diffraction, scanning electron microscopy, energy dispersive X-ray analysis, and inductively coupled plasma spectrometry. The mechanical behavior of coating evaluated by scratch test indicates that the adhesion strength of HA coating was improved with the presence of titania interlayer. PMID- 21234792 TI - Chinese Acupuncture Expert System (CAES)-a useful tool to practice and learn medical acupuncture. AB - This paper describes the development of a Chinese Acupuncture Expert System (CAES) that will assist the learning and practice of medical acupuncture. This was the development of a Chinese Acupuncture Expert System which incorporated eight functional modules. These modules were 1) Add Patient Record subsystem; 2) Diagnosis subsystem ; 3) Acupuncture Prescription subsystem ; 4) Needle Insertion Position Animation subsystem ; 5) Acupuncture Points Usage Statistic subsystem ; 6) History Query subsystem; 7) Acupuncture Points Query subsystem and 8) Diagnosis Remarks and Diagnosis Record Save subsystem. Two databases were built Patient Record database and Diagnosis (Acupuncture) Knowledge database. All the Traditional Chinese Medicine (TCM) knowledge and acupuncture treatment prescriptions were extracted from officially used TCM textbooks and received guidance and expert advice from two acupuncturists working in this project. A Chinese Acupuncture Expert System (CAES) was built, which after the input from users of any Chinese disease symptoms and signs, it can provide a list of related TCM syndrome diagnoses based on the patients' disease symptoms and signs, and at the same time it can offer advice of the appropriate Chinese acupuncture treatment to the users. CAES also provided text descriptions and acupuncture animations showing the acupoint locations and the direction and depth of the needle insertion technique. Therefore users can easily learn acupuncture and practice it. This new acupuncture expert system will hopefully provide an easy way for users to learn and practice Chinese Acupuncture and establish its usefulness after it was fully evaluated. PMID- 21234793 TI - Testing an empowerment intervention to help parents make homes smoke-free: a randomized controlled trial. AB - The objective of this randomized controlled trial was to test if parents' participation in an intervention based on an empowerment ideology and participatory experiences decreased the number of cigarettes smoked in homes. Sixty families were randomized to the intervention (n = 30) or control (n = 30) group. The intervention included three weekly group sessions followed by three weekly follow-up telephone calls over six consecutive weeks. During group sessions, parents shared experiences about environmental tobacco smoke, identified personal strengths and resources, and developed action plans. Data were collected in interviewer-administered questionnaires at baseline and 6 months follow-up. Ninety-three percent of the sample consisted of mothers, 77% of whom smoked during pregnancy. Forty-two percent of the total sample reported a household income of <$15,000. The median number of cigarettes smoked in the home daily decreased from 18 to 4 in the total sample however no statistically significant difference was detected between groups at 6 months follow-up. Participation in the study, independent of group, may have resulted in parents decreasing the number of cigarettes smoked in the home. Valuable lessons were learned about recruiting and working with this group of parents, all of whom faced the challenges of tobacco and almost half of whom lived in poverty. PMID- 21234795 TI - Leader neurons in leaky integrate and fire neural network simulations. AB - In this paper, we highlight the topological properties of leader neurons whose existence is an experimental fact. Several experimental studies show the existence of leader neurons in population bursts of activity in 2D living neural networks (Eytan and Marom, J Neurosci 26(33):8465-8476, 2006; Eckmann et al., New J Phys 10(015011), 2008). A leader neuron is defined as a neuron which fires at the beginning of a burst (respectively network spike) more often than we expect by chance considering its mean firing rate. This means that leader neurons have some burst triggering power beyond a chance-level statistical effect. In this study, we characterize these leader neuron properties. This naturally leads us to simulate neural 2D networks. To build our simulations, we choose the leaky integrate and fire (lIF) neuron model (Gerstner and Kistler 2002; Cessac, J Math Biol 56(3):311-345, 2008), which allows fast simulations (Izhikevich, IEEE Trans Neural Netw 15(5):1063-1070, 2004; Gerstner and Naud, Science 326:379-380, 2009). The dynamics of our lIF model has got stable leader neurons in the burst population that we simulate. These leader neurons are excitatory neurons and have a low membrane potential firing threshold. Except for these two first properties, the conditions required for a neuron to be a leader neuron are difficult to identify and seem to depend on several parameters involved in the simulations themselves. However, a detailed linear analysis shows a trend of the properties required for a neuron to be a leader neuron. Our main finding is: A leader neuron sends signals to many excitatory neurons as well as to few inhibitory neurons and a leader neuron receives only signals from few other excitatory neurons. Our linear analysis exhibits five essential properties of leader neurons each with different relative importance. This means that considering a given neural network with a fixed mean number of connections per neuron, our analysis gives us a way of predicting which neuron is a good leader neuron and which is not. Our prediction formula correctly assesses leadership for at least ninety percent of neurons. PMID- 21234794 TI - Interactions of persistent sodium and calcium-activated nonspecific cationic currents yield dynamically distinct bursting regimes in a model of respiratory neurons. AB - The preBotzinger complex (preBotC) is a heterogeneous neuronal network within the mammalian brainstem that has been experimentally found to generate robust, synchronous bursts that drive the inspiratory phase of the respiratory rhythm. The persistent sodium (NaP) current is observed in every preBotC neuron, and significant modeling effort has characterized its contribution to square-wave bursting in the preBotC. Recent experimental work demonstrated that neurons within the preBotC are endowed with a calcium-activated nonspecific cationic (CAN) current that is activated by a signaling cascade initiated by glutamate. In a preBotC model, the CAN current was shown to promote robust bursts that experience depolarization block (DB bursts). We consider a self-coupled model neuron, which we represent as a single compartment based on our experimental finding of electrotonic compactness, under variation of g (NaP), the conductance of the NaP current, and g (CAN), the conductance of the CAN current. Varying these two conductances yields a spectrum of activity patterns, including quiescence, tonic activity, square-wave bursting, DB bursting, and a novel mixture of square-wave and DB bursts, which match well with activity that we observe in experimental preparations. We elucidate the mechanisms underlying these dynamics, as well as the transitions between these regimes and the occurrence of bistability, by applying the mathematical tools of bifurcation analysis and slow-fast decomposition. Based on the prevalence of NaP and CAN currents, we expect that the generalizable framework for modeling their interactions that we present may be relevant to the rhythmicity of other brain areas beyond the preBotC as well. PMID- 21234796 TI - Natural disaster and risk of psychiatric disorders in Puerto Rican children. AB - We examined the persistence of psychiatric disorders at approximately 18 and 30 months after a hurricane among a random sample of the child and adolescent population (4-17 years) of Puerto Rico. Data were obtained from caretaker-child dyads (N = 1,886) through in person interviews with primary caretakers (all children) and youth (11-17 years) using the Diagnostic Interview Schedule for Children IV in Spanish. Logistic regressions, controlling for sociodemographic variables, were used to study the relation between disaster exposure and internalizing, externalizing, or any disorder. Children's disaster-related distress manifested as internalizing disorders, rather than as externalizing disorders at 18 months post-disaster. At 30 months, there was no longer a significant difference in rates of disorder between hurricane-exposed and non exposed youth. Results were similar across age ranges. Rates of specific internalizing disorders between exposed and unexposed children are provided. Research and clinical implications are discussed. PMID- 21234797 TI - Modulation of LPA receptor expression in the human brain following neurotrauma. AB - Lysophosphatidic acid (LPA) is involved in physiological and pathological states, including in neural development and inflammation. We assessed the expression pattern of the LPA receptors 1-3 and of LPA-producing enzyme autotaxin in post mortem human brain tissue, both in normal individuals and in individuals who died following traumatic brain injury. We found that LPA receptors and autotaxin are weakly expressed in the normal control adult brain. Quantitative PCR for the LPA receptors and autotaxin mRNA showed an increase of LPAR(2) and a decrease of autotaxin mRNA expression in the cortex following brain injury. Immunohistochemical analysis showed that LPAR(1) colocalized with astrocytes and that LPAR(2) is present on the ependymal cells lining the lateral ventricle in the brain samples from individuals who died following severe head injury. This work shows for the first time that key components of the LPA pathway are modulated following TBI in humans. PMID- 21234798 TI - SMN deficiency reduces cellular ability to form stress granules, sensitizing cells to stress. AB - Spinal Muscular Atrophy (SMA) is a neurodegenerative disease that is caused by deletion of the SMN (Survival of Motor Neuron) gene. The SMN protein is essential for cell survival and co-localized with TIA-1/R and G3BP, two characteristic markers of stress granules (SGs). To further study the SMN function in stress granules and in response to stress, we generated stable cell lines with SMN knockdown. Our data indicate that suppression of SMN drastically reduces cellular ability to form stress granules in response to stress treatment. In addition, we show that SMN deficiency sensitizes cells to sodium arsenite and H(2)O(2), two well-known stress inducers, leading to cell death at a much lower concentration of inducers in SMN knockdown cells than in control cells. Interestingly, the cell death is correlated with formation of stress granules, suggesting that involvement of SMN in formation of stress granules may play an important role in cell survival. Furthermore, rescue of SGs formation by overexpression of G3BP can reverse the defective formation of stress granules and results in partial abrogation of cell death against SMN deficiency. We deduce that modulation of stress response may be useful for potential SMN treatment. PMID- 21234799 TI - No observable relationship between the 12 genes of nervous system and reasoning skill in a young Chinese Han population. AB - Reasoning skill is an advanced cognitive ability which is needed for drawing inferences from given information. It is well known that the ability depends on the neural network of the frontal and parietal brain regions. In this study, we hypothesized that some genes involved in neurotransmitter systems were related to reasoning skill. To confirm this hypothesis, we examined the effects of 13 genes (BDNF, NRSF, COMT, DBH, DRD(2), DRD(3), DAT(1), MAOA, GRM(1), GRIN2B, TPH(2), 5 HT(2A), and 5-HT(6)) in neurotransmitter systems on the non-verbal reasoning and verbal reasoning skills. The results indicated there were on significant effects of the 17 functional variants of these genes on the performance of non-verbal reasoning and verbal analogical reasoning skills (chi(2) > 3.84, df = 1, P > 0.05). This study suggests that some of the functional variations in BDNF, COMT, DBH, DRD(2), DRD(3), MAOA, 5-HT(2A), 5-HT(6), GRM(1), and GRIN2B have no observable effects on the certain reasoning skills in a young healthy Chinese Han population. PMID- 21234800 TI - Application of continuous flow and alternative energy devices for 5 hydroxymethylfurfural production. AB - Dehydration of fructose and glucose in dipolar, aprotic solvents leads to formation of 5-hydroxymethylfurfural. Conditions for continuous flow reactions using a cartridge-based reactor system and a stop-flow microwave reactor were established showing very good product yields and selectivity without the limitation of a batch process such as upscaling and precise temperature monitoring and control. A maximum product HPLC yield of 90.3% under cartridge based heating and 85.6% under microwave heating could be achieved using mild and quick reaction conditions. Formation of levulinic acid as a by-product could not be detected under the optimized reaction conditions. PMID- 21234801 TI - Radiation hormesis and radioadaptive response in Drosophila melanogaster flies with different genetic backgrounds: the role of cellular stress-resistance mechanisms. AB - The purpose of this work is to investigate the role of cellular stress-resistance mechanisms in the low-dose irradiation effects on Drosophila melanogaster lifespan. In males and females with the wild type Canton-S genotype the chronic low dose irradiation (40 cGy) induced the hormetic effect and radiation adaptive response to acute irradiation (30 Gy). The hormesis and radioadaptive responses were observed in flies with mutations in autophagy genes (atg7, atg8a) but absent in flies with mutations in FOXO, ATM, ATR, and p53 homologues. The hormetic effect was revealed in Sirt2 mutant males but not in females. On the contrary, the females but not males of JNK/+ mutant strain showed adaptive response. The obtained results demonstrate the essential role of FOXO, SIRT1, JNK, ATM, ATR, and p53 genes in hormesis and radiation adaptive response of the whole organism. PMID- 21234802 TI - Biogerontology in Turkey: a brief report. AB - In this brief report, aging in biogerontology science perspective has been discussed based on the Turkish literature review with major key recommendations for future studies. Biogerontology in Turkey has focused on general retardation of the aging process giving priority to caloric restriction and oxidative stress mechanisms. The most popular investigation area for the scientists has been the oxidant and anti-oxidant systems in different tissues. However, the Turkish biogerontology science needs more manpower, economical and infrastructural and other resources for the promising studies in the future. PMID- 21234808 TI - The performance of nature reserves in capturing the biological diversity on Hainan Island, China. AB - PURPOSE: The performance of nature reserves depends on the degree to which they represent a region's full biodiversity. Here, we conducted a study on Hainan Island, China, to assess how well Hainan's biodiversity features were captured by existing nature reserves. We also explored the driving forces behind the current protection pattern so as to provide guidelines for improving the island's conservation system. METHODS: We integrated the information on nature reserves, ecological variables, and human activities into a spatial database, then assessed the performance of nature reserves in representing natural variation, vegetation types, and species, and examined the impacts of human activities and land ownership on the current protection pattern. RESULTS: About 8.4% of Hainan Island was protected by nature reserves; the coverage was geographically biased toward its central mountainous areas with higher elevation, rugged terrain, and fertile soils. We found that 60% of the environmental units and 39.4% of the natural vegetation types had more than 10% of their area protected, respectively. Lowlands tended to have higher animal species richness, and the protection for endangered species was less efficient. Nature reserve coverage was negatively correlated with amount of converted habitats, human population density, and road density, and 82.4% of the total reserved area was allocated on state-owned land. CONCLUSIONS: Nature reserve coverage was not enough to capture lowlands biodiversity features. The current protection pattern was significantly driven by several major conservation targets, human development, planning methods, and land ownership. To improve its conservation system, Hainan should enhance protection in the north and northeast plains and coastal regions, implement systematic planning approaches to define clear visions for guiding future conservation actions, and develop flexible management and funding mechanisms toward sustainable use of natural resources. PMID- 21234807 TI - Diagnosis and treatment of osteopenia. AB - Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5. There are many causes for osteopenia including calcium and vitamin D deficiency and inactivity. Genetics plays an important role in a person's bone mineral density and often Caucasian women with a thin body habitus who are premenopausal are found to have osteopenia. Correction of calcium and vitamin D deficiency and walking 3 to 5 miles a week can often improve bone density in the hip and spine. There are a variety of pharmaceutical agents that have been recommended for the treatment of osteopenia and osteoporosis including hormone replacement therapy, selective estrogen receptor modulator therapy, anti-resorptive therapy. In addition patients with osteoporosis who have failed anti-resorptive therapy can have a significant improvement in their bone density with anabolic therapy. PMID- 21234809 TI - Tuning of CD40-CD154 interactions in human B-lymphocyte activation: a broad array of in vitro models for a complex in vivo situation. AB - Naive and memory B-lymphocyte populations can be activated through the binding of CD154 to CD40, a receptor that is constitutively expressed on the surface of these cells. Models based on the in vitro stimulation of human B lymphocytes through CD40 have greatly contributed to our understanding of the human immune response in healthy individuals and patients suffering from immune disorders. The nature of the engineered CD40 ligands is as diverse as the in vitro models used in studies of CD40-activated B lymphocytes. Monoclonal anti-CD40 antibodies, recombinant CD154 proteins, soluble CD154(+) membranes as well as CD154(+) cell lines have turned out to be very useful tools, and are still in use today. As for any receptor-ligand interaction, parameters such as duration and strength of contact, timing, affinity, and receptor density are major determinants of CD40 binding by CD154 or anti-CD40. Furthermore, variation in the intensity of CD40 stimulation has been shown to influence proliferation, differentiation and immunoglobulin secretion of human hybridomas, B-cell lines, tonsil and blood B lymphocytes. The objective of this review is to present an overview of the great diversity of CD40 agonists used in in vitro models of B-lymphocyte activation, with a particular emphasis on variations in the resulting strength of CD40 signaling generated by these models. A better understanding of these models could open up new avenues for the rational use of human B lymphocytes as antigen presenting cells in cellular therapies. PMID- 21234810 TI - Antiviral signaling through retinoic acid-inducible gene-I-like receptors. AB - The innate immune system is essential for the first line of host defense against micropathogens. In virus-infected cells, exposed viral nucleotides are sensed by pattern recognition receptors (PRRs), resulting in the induction of type I interferon. Retinoic acid-inducible gene-I-like receptors (RLRs) are a member of PRRs and are known to be crucial molecules in innate immune responses. Upon viral recognition, RLRs recruit their specific adaptor molecules, leading to the activation of antiviral signaling molecules including interferon regulatory factor-3 and nuclear factor-kappaB. Mitochondrial antiviral signaling (MAVS) protein is also known as one of the adaptor molecules responsible for antiviral signaling triggered by RLRs. Recent reports have identified numerous intracellular molecules involved in the antiviral responses mediated by RLRs/MAVS. Several viral proteins interfere with the RLR/MAVS signaling, allowing the virus to evade the host defense. In this review, we comprehensively update RLR-dependent antiviral signaling with special reference to the RLRs/MAVS mediated responses. PMID- 21234811 TI - Dual peripheral actions of immune cells in neuropathic pain. AB - Ability to perceive physiological pain is essential in protecting the individual from tissue destruction. In contrast, pathological chronic pain is an expression of maladaptive alterations outlasting its biological usefulness. In such conditions even eating, speaking or wearing clothes might be painful, as in neuropathic pain. Such pain is caused by diseases or injuries affecting nerves (e.g. diabetes, trigeminal neuralgia or amputation). Neuropathic pain is not an exclusive neuronal phenomenon but also involves immune responses. Damaged peripheral nerves are infiltrated by mast cells, granulocytes, macrophages and T lymphocytes. It is widely emphasized that these cells, via secretion of inflammatory mediators (e.g. proinflammatory cytokines, chemokines), contribute to the generation of neuropathic pain. However, leukocytes are also a source of analgesic mediators such as anti-inflammatory cytokines and opioid peptides. Recent findings indicate that immune cell-derived opioid peptides can interact with opioid receptors in the injured nerves and ameliorate neuropathic pain. Targeting opioid-containing immune cells might represent a new disease-modifying approach based on the use of beneficial effects of neuro-inflammation in painful neuropathies. This review analyzes both detrimental and advantageous actions of leukocytes at peripheral nerves in neuropathic pain. PMID- 21234812 TI - Legal and ethical aspects of ghostwriting in medicine. AB - Ghostwriting in medicine represents a highly significant problem in both legal and ethical terms, and particularly in recent years owing to a sudden increase in the practice. The main goal in this paper is to present the legal and ethical rules connected with the ghostwriting phenomenon. The problem is presented in the context of international, European and Polish law. From a legal perspective the issues bound up with ghostwriting are those of the notion and authorship of a work, authors' rights (both moral rights and copyright), the content of these rights and their nature, as well as the question of the transfer of such rights. From the point of view of ethics there arises a need for reflection on honesty, accuracy and credibility as defined both generally and scientifically. PMID- 21234813 TI - Trace elements in the hair of hemodialysis patients. AB - Trace element disturbance is often observed in hemodialysis patients. While trace element concentrations have been reported in blood samples from hemodialysis patients, they have not been well investigated in scalp hair. In the present study, 22 trace elemental concentrations were measured by inductively coupled plasma-atomic emission spectrometry in the scalp hair of 80 male hemodialysis patients and compared with those of 100 healthy male subjects. In hemodialysis patients, the concentrations of beryllium, arsenic, magnesium, chromium, manganese, iron, selenium, molybdenum, iodine, vanadium, and cobalt were significantly higher than those in healthy subjects, while lead, mercury, copper, germanium, and bromine were significantly lower than those in the former group. No significant differences were observed for lithium, aluminum, cadmium, zinc, boron, or nickel. There were significant positive correlations between the duration of hemodialysis and the magnesium and manganese concentrations. There was a significant negative correlation between cadmium concentration and the duration of hemodialysis. There were significant positive correlations between dialysis efficacy (Kt/V) and magnesium, manganese, zinc, and selenium concentrations. In conclusion, trace element concentrations of the scalp hair are different between hemodialysis patients and healthy subjects. Essential trace elements, such as magnesium, manganese, zinc, and selenium, may be affected by the duration of hemodialysis and Kt/V. PMID- 21234814 TI - Cancer-related PRUNE2 protein is associated with nucleotides and is highly expressed in mature nerve tissues. AB - Human PRUNE is thought to enhance the metastasis of tumor cells. We found that a hypothetical paralog of PRUNE, PRUNE2, binds to 8-oxo-GTP, an oxidized form of GTP. Hypothetical PRUNE2 gene consists of C9orf65 and BMCC1/BNIPXL, both of which are malignant tumor-associated genes. We isolated PRUNE2 complementary DNA and revealed that the protein is composed of 3,062 residues. C9orf65 and BMCC1/BNIPXL encode the N-terminal part (259 residues) and C-terminal part (2,729 residues) of PRUNE2, respectively. We demonstrated the endogenous full-length PRUNE2 protein (338 kDa) by Western blot and mass spectrometry. PRUNE2 bound to 8-oxo-GTP as well as GTP. The expression levels of human PRUNE2 and mouse Prune2 messenger RNA (mRNA) were highest in the dorsal root ganglia (DRG) and, to a lesser extent, in other nerve tissues. DRG neurons express higher levels of PRUNE2 in their soma compared with adjacent cells. In addition, their expression levels in the adult nerve tissues were higher than those in fetal or neonatal nerve tissues. The present study indicates that C9orf65 and BMCC1/BNIPXL are transcribed as PRUNE2 mRNA, which is translated to a large PRUNE2 protein. The nerve tissue-specific and post-development expression of PRUNE2/Prune2 suggests that PRUNE2 may contribute to the maintenance of mature nervous systems. PMID- 21234815 TI - Ageing, neuronal connectivity and brain disorders: an unsolved ripple effect. AB - Cognitive decline associated with ageing and age-related disorders emerges as one of the greatest health challenges in the next decades. To date, the molecular mechanisms underlying the onset of neuronal physiological changes in the central nervous system remain unclear. Functional MRI and PET studies have indicated the decline in working memory performance in older adults. Similarly, age-related disorders, such as Alzheimer's disease, are associated with changes in the prefontral cortex and related neural circuitry, which underlines the decline of integrative function between different brain regions. This is mainly attributed to the loss of synaptic connectivity, which is a feature commonly observed in neurodegenerative disorders. In humans, the morphological and functional changes in neurons, such as reduction of spine numbers and synaptic dysfunction, precede the first signs of cognitive decline and likely contribute to pathology progression. Thus, a new scenario emerges in which apparently unrelated diseases present common features, such as the remodelling of neuronal circuitries promoted by ageing. For many years, ageing was considered a process of slow deterioration triggered by accidental environmental factors. Conversely, it is now evident that ageing is a biological process tightly controlled by evolutionary highly conserved signalling pathways. Importantly, genetic mutations that enhance longevity significantly delay the loss of synaptic connectivity and, therefore, the onset of age-related brain disorders. Accordingly, tweaking ageing might be an attractive approach to prevent cognitive decline caused by age-related synaptic dysfunction. PMID- 21234816 TI - Signaling pathways in reactive astrocytes, a genetic perspective. AB - Reactive astrocytes are associated with a vast array of central nervous system (CNS) pathologies. The activation of astrocytes is characterized by changes in their molecular and morphological features, and depending on the type of damage can also be accompanied by inflammatory responses, neuronal damage, and in severe cases, scar formation. Although reactive astrogliosis is the normal physiological response essential for containing damage, it can also have detrimental effects on neuronal survival and axon regeneration, particularly in neurodegenerative diseases. It is believed that progressive changes in astrocytes as they become reactive are finely regulated by complex intercellular and intracellular signaling mechanisms. However, these have yet to be sorted out. Much has been learned from gain-of-function approaches in vivo and culture paradigms, but in most cases, loss-of-function genetic studies, which are a critical complementary approach, have been lacking. Understanding which signaling pathways are required to control different aspects of astrogliosis will be necessary for designing therapeutic strategies to improve their beneficial effects and limit their detrimental ones in CNS pathologies. In this article, we review recent advances in the mechanisms underlying the regulation of aspects of astrogliosis, with the main focus on the signaling pathways that have been studied using loss-of function genetic mouse models. PMID- 21234817 TI - Microvascular angina: assessment of coronary blood flow, flow reserve, and metabolism. AB - Microvascular angina (MVA) is an often overlooked cause of significant chest pain. Decreased myocardial perfusion secondary to dysregulated blood flow in the microvasculature can occur in the presence or absence of obstructive epicardial coronary artery disease. The corresponding myocardial ischemia and angina is now a well-established diagnosis, made by detection of decreased coronary flow reserve (CFR). Although low CFR and MVA are associated with poor prognosis, there is initial evidence for reversibility of this abnormal vascular regulation with aggressive medical therapy and control of associated risk factors. Current assessment of MVA is carried out predominantly during cardiac catheterization; however, noninvasive techniques to assess CFR are being developed, including PET, MRI, and CT modalities. Quantitative tracer techniques or imaging of metabolic disturbances reflecting ischemia will likely enhance diagnostic approaches for such patients as well as allow more frequent monitoring of response to therapy. PMID- 21234818 TI - Fad diets in the treatment of diabetes. AB - Use of the term "fad diet" reflects the contentious nature of the debate in the treatment of diabetes and generally targets diets based on carbohydrate restriction, the major challenge to traditional dietary therapy. Although standard low-fat diets more accurately conform to the idea of a practice supported by social pressure rather than scientific data, it is suggested that we might want to give up altogether unscientific terms like "fad" and "healthy." Far from faddish, diets based on carbohydrate restriction have been the historical treatment for diabetes and are still supported by basic biochemistry, and it is argued that they should be considered the "default" diet, the one to try first, in diseases of carbohydrate intolerance or insulin resistance. The barrier to acceptance of low-carbohydrate diets in the past has been concern about saturated fat, which might be substituted for the carbohydrate that is removed. However, recent re-analysis of much old data shows that replacing carbohydrate with saturated fat is, if anything, beneficial. The dialectic of impact of continued hemoglobin A(1c) versus effect of dietary saturated fat in the risk of cardiovascular disease is resolved in direction of glycemic control. Putting biased language behind us and facing the impact of recent results that point to the value of low-carbohydrate diets would offer patients the maximum number of options. PMID- 21234819 TI - Quality of life in patients with chronic rhinosinusitis. AB - Health-related quality of life (HRQoL) is a domain of quality-of-life assessment that is influenced by the individual's perception of his or her health status. Measurement of HRQoL can enable physicians to understand how an illness interferes with a patient's day-to-day life, improve patient-physician communication, and optimize clinical outcomes. Chronic rhinosinusitis (CRS) is one of the most common chronic diseases, affecting 14-16% of the adult US population. In addition to significant health care costs, CRS has been shown to substantially reduce HRQoL. In this review article, we discuss the definition and interpretation of HRQoL data and describe several validated rhinosinusitis HRQoL instruments. Additionally, we review how CRS functions to lower HRQoL and the effect of medical and surgical intervention on improving HRQoL status. By understanding the relationship between CRS and associated chronic conditions, clinicians can target their evaluation to problems that will maximize clinical success. PMID- 21234820 TI - Excellent outcomes of children with CML treated with imatinib mesylate compared to that in pre-imatinib era. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) and tyrosine kinase inhibitor have revolutionized the treatment of patients with chronic myeloid leukemia (CML). In this study, the clinical impact of HSCT and imatinib mesylate (IM) was retrospectively analyzed in 28 children with CML treated in our institutes from 1984 to 2008. Twelve patients were given oral IM. At 36 months after initiation of IM therapy, the complete cytogenetic response rate was 90.9%, and the major molecular response rate was 36.4%. Sixteen children received allogeneic HSCT without administration of IM. The stage of disease at transplantation was: first chronic phase (n = 10), second chronic phase (n = 2), accelerated phase (n = 2), and blastic crisis (n = 2). The progression rate was significantly lower in patients treated with IM than in those treated without IM (0 vs. 28.6%, p = 0.006). In summary, the survival outcomes of pediatric patients with CML were dramatically improved by treatment with IM compared to HSCT. PMID- 21234821 TI - Circulating myeloid dendritic cells are increased in individuals with severe aplastic anemia. AB - The objectives of the study were to investigate the number of myeloid dendritic cells (mDC) and plasmacytoid dendritic cells (pDC) present in peripheral blood mononuclear cells (PBMC) from severe aplastic anemia (SAA) patients before and after intensive immunosuppressive therapy (IST) and to assess the expression of co-stimulatory molecules (CD80, CD86, and CD40) expressed by dendritic cells (DC) from SAA patients. The quantities of mDC and pDC and ratios of mDC to pDC in PBMC were measured in 38 SAA patients at active phase, 19 patients at recovery phase, and 17 normal controls. The surface expression of CD80, CD86, and CD40 on DCs and B lymphocytes was analyzed in 16 SAA patients and 15 normal controls. The percentages of mDC and the ratio of mDC:pDC of SAA patients at active phase increased compared to that of healthy controls [0.65% (range 0.10-2.19%) vs. 0.40% (range 0.11-1.54%), 2.64% (range 1.07-4.33%) vs. 1.56% (range 0.89-2.27), respectively (P < 0.05)]. The percentages of mDCs in recovered SAA patients decreased to 0.43% (range 0.06-0.80), and the ratio of mDC:pDC decreased to 1.78% (range 0.49-3.07). The percentages of mDC and pDC in 10 SAA patients were 0.87% (range 0.10-1.85) and 0.35% (range 0.05-0.65) before IST, which decreased to 0.24% (range 0.06-0.52) and 0.14% (range 0.01-0.28) after IST (P < 0.05). The percentages of CD86 expression on DC of SAA patients increased compared to that of healthy controls [29.84% (range 20.28-39.40) vs. 11.97% (range 0.02-24.15), respectively (P < 0.05)]. The number of mDCs increased in SAA patients, which was associated with stage of disease. The increased number of mDCs and the high expression of costimulatory molecules (CD86) on these DCs may contribute to abnormal activation of T lymphocytes in these patients and subsequent immune system-mediated bone marrow failure. PMID- 21234822 TI - Post-tonsillectomy pulmonary complication in a patient with tonsillar myeloid sarcoma. AB - Myeloid sarcoma in a patient with myelodysplastic syndrome (MDS) manifesting as a non-healing tonsillar ulcer is an extremely rare occurrence. We report the case of a 57-year-old male smoker with a non-healing tonsillar ulcer who underwent tonsillectomy to rule out tonsillar carcinoma after failed antibiotic therapy. On postoperative day 2, he presented with a temperature of 40 degrees C and white blood cell count of 34700/MUL. Antibiotic therapy was begun; however, he died 1 day later due to pulmonary infection and septic shock. Though extremely rare, tonsillar involvement of MDS should be considered in the differential diagnosis of a non-healing tonsillar lesion. When definitive diagnosis requires a tissue sample, punch biopsy may be preferable to tonsillectomy in a patient who may be immunocompromised, and appropriate prophylactic antibiotics should be administered. PMID- 21234823 TI - Purification and characterization of novel alpha-amylase from Bacillus subtilis KIBGE HAS. AB - Purification of extracellular alpha-amylase from Bacillus subtilis KIBGE HAS was carried out by ultrafiltration, ammonium sulfate precipitation and gel filtration chromatography. The enzyme was purified to homogeneity with 96.3-fold purification with specific activity of 13011 U/mg. The molecular weight of purified alpha-amylase was found to be 56,000 Da by SDS-PAGE. Characteristics of extracellular alpha-amylase showed that the enzyme had a Km and V (max) value of 2.68 mg/ml and 1773 U/ml, respectively. The optimum activity was observed at pH 7.5 in 0.1 M phosphate buffer at 50 degrees C. The amino acid composition of the enzyme showed that the enzyme is rich in neutral/non polar amino acids and less in acidic/polar and basic amino acids. The N-terminal protein sequence of 10 residues was found to be as Ser-Ser-Asn-Lys-Leu-Thr-Thr-Ser-Trp-Gly (S-S-N-K-L-T T-S-W-G). Furthermore, the protein was not N-terminally blocked. The sequence of alpha-amylase from B. subtilis KIBGE HAS was a novel sequence and showed no homology to other reported alpha-amylases from Bacillus strain. PMID- 21234824 TI - Complexities of particulate matter measurement in parenteral formulations of small-molecule amphiphilic drugs. AB - Reconstituted parenteral solutions of three surface-active anti-infective small molecule drugs and solutions of sodium dodecyl sulfate (SDS, a model surfactant) were studied to quantify the impact of sample preparation and handling on particle counts. Turbidimetry and light obscuration profiles were recorded as a function of agitation and shearing with and without the introduction of foam into the solutions. SDS solutions at concentrations above the critical micelle concentration (CMC) show significantly greater sensitivity to shear and foam presence than SDS solution below the CMC: Values of >10 MUm particles increased 8 fold over control (an unsheared sample) in the micellar solution vs. 4 fold particle count increase over control at a sub-micellar concentration. An even more significant increase in the ratio of particle count in sheared/unsheared solution is seen for >25 MUm unit counts, due to the increased interference of foam with the measurement. Two commercial products, injection formulations of teicoplanin and cefotaxime sodium, as well as an investigational compound 1, showed an increase in scattering as a function of foam production. The impact of foaming was significant, resulting in an increase of turbidity and light obscuration measurements in all solutions. The results illustrate some of the challenges that are inherent to optically clear, homogeneous pharmaceutical injections containing compounds which have a tendency toward self-association and surfactant-like behavior. PMID- 21234825 TI - Acute vertebral body fracture visualized on SPECT MPI study. PMID- 21234826 TI - Soft tissue attenuation patterns in stress myocardial perfusion SPECT images: a comparison between supine and upright acquisition systems. AB - BACKGROUND: Soft tissue attenuation patterns and their interaction with body habitus and gender in Single Photon Emission Computed Tomography (SPECT) myocardial perfusion imaging (MPI) of upright patient-position acquisition systems are not well described. METHODS: In a retrospective cross-sectional study, we compared the prevalence and patterns of soft tissue attenuation in two groups of normal SPECT-MPI studies acquired by supine (n = 263) vs upright (n = 212) acquisition systems. RESULTS: Attenuation patterns observed in the study population were: anterior (22.3%), inferior (51.6%) and lateral (18.1%). Anterior attenuation was significantly less in those imaged upright (6.1% vs 35.4%), P < .001; particularly among women (9.5% vs 50.7%), P < .001. Inferior attenuation was more common among women imaged upright (49.5% vs 13.5%), P < .001; but was not affected by imaging position among men. Lateral attenuation was more prevalent in the upright group (24.1% vs 13.3%), P = .002; and had a strong association with female gender (P < .001) and BMI >= 30 (P < .001). CONCLUSIONS: Upright SPECT-MPI acquisition is associated with a unique attenuation pattern which is vastly different than the supine position. Female gender strongly impacted this attenuation pattern, particularly obese women. Our study is the first to describe, in details, the attenuation patterns with upright imaging and is critical for the accurate interpretation of SPECT-MPI acquired with upright systems. PMID- 21234830 TI - Pharmacoeconomics of intravenous immunoglobulin in various neurological disorders. PMID- 21234827 TI - Evaluation of left ventricular function using cardiac magnetic resonance imaging. PMID- 21234831 TI - Confused, frustrated, and broke. AB - Texas physicians are troubled as 2011 begins. Evidence of their concerns is found in the latest TMA survey of Texas physicians, medical students, residents, and interns. The survey shows the biggest challenges for Texas physicians are declining reimbursement, rising practice costs, and economic viability. Physicians are also confronted by increased scrutiny from insurers who want to rate them on their "cost efficiency" and a confusing federal overhaul of the health care system that may fundamentally change the way they practice medicine. It's enough to make many of them rethink their career choices. PMID- 21234832 TI - Got $25 billion? AB - The Texas Medical Association has an ambitious agenda for the 82nd Texas Legislature, which convenes Jan. 11. Not only does TMA hope to defend Medicaid and the Children's Health Insurance Program from deep cuts, but it also plans to push for additional state funding for residency training and a statewide ban on smoking in public places and to fight off attempts by midlevel practitioners to expand their scope of practice beyond their training. PMID- 21234828 TI - PTEN gene silencing prevents HIV-1 gp120(IIIB)-induced degeneration of striatal neurons. AB - To assess the role of the phosphatase and tensin homologue on chromosome 10 (PTEN) in mediating envelope glycoprotein 120 (gp120)-induced neurotoxicity in the striatum, PTEN was silenced using short interfering RNA (siRNA) vectors. PTEN activity directs multiple downstream pathways implicated in gp120-induced neuronal injury and death. PTEN is a negative regulator of Akt (protein kinase B) phosphorylation, but has also been shown to directly activate extrasynaptic NMDA receptors and dephosphorylate focal adhesion kinase. Rodent striatal neurons were nucleofected with green fluorescent protein (GFP)-expressing siRNA constructs to silence PTEN (PTENsi-GFP) or with negative-control (NCsi-GFP) vectors, and exposed to HIV-1 gp120(IIIB) using rigorously controlled, cell culture conditions including computerized time-lapse microscopy to track the fate of individual neurons following gp120 exposure. Immunofluorescence labeling showed that subpopulations of striatal neurons possess CXCR4 and CCR5 co-receptor immunoreactivity and that gp120(IIIB) was intrinsically neurotoxic to isolated striatal neurons. Importantly, PTENsi-GFP, but not control NCsi-GFP, constructs markedly decreased PTEN mRNA and protein levels and significantly attenuated gp120-induced death. These findings implicate PTEN as a critical factor in mediating the direct neurotoxic effects of HIV-1 gp120, and suggest that effectors downstream of PTEN such as Akt or other targets are potentially affected. The selective abatement of PTEN activity in neurons may represent a potential therapeutic strategy for the CNS complications of HIV-1. PMID- 21234833 TI - Consider the source. AB - Six Grapevine physicians find themselves embroiled in a lawsuit with Texas Attorney General Greg Abbott for selling patients birth control devices the U.S. Food and Drug Administration has not approved for distribution in this country. The clinic, along with other medical practices in several states, is under fire for using a Canadian Mirena intrauterine device. PMID- 21234834 TI - A healthy bottom line. AB - Narrowing the gap between caring for patients and receiving payment is vital to the financial stability of a medical practice. Thus, physicians are consulting experts and turning to technology to improve their billing and collections process and reduce the time staff members spend chasing overdue accounts. TMA Practice Consulting offers a billing and collections assessment, during which a consultant reviews a practice's billing and collections procedures, staffing efficiency, workflow, and front office processes, and also analyzes the accounts receivable. PMID- 21234836 TI - Peroral esophageal segmentectomy and anastomosis with single transthoracic trocar: a step forward in thoracic NOTES. AB - BACKGROUND AND STUDY AIMS: A transesophageal natural orifice transluminal endoscopic surgery (NOTES) approach has been proposed for thoracic and mediastinal access. Similarly to transgastric surgery, serious limitations remain related to creating an esophagotomy and its safe closure. A hybrid approach in thoracic NOTES could work as an intermediate step before pure transesophageal NOTES. We assessed the benefit of hybrid thoracic NOTES for peroral segmental esophagectomy and subsequent complete esophageal anastomosis with a single transthoracic port. METHODS: Two protocols were used to attempt esophago esophageal anastomosis: ex vivo using a phantom model (n = 5), and in vivo after esophageal mobilization, and segmental esophagectomy achieved using either a gastroscope (flexible) (n = 5) or thoracoscope (rigid) instruments (n = 5). A forward-viewing double-channel endoscope and a transthoracic operative thoracoscope with a working channel were coordinated in order to create a complete single-layer, end-to-end esophageal anastomosis ex vivo as well as in vivo. Feasibility and anastomosis quality were evaluated by inside and outside assessment of: patency, the incorporation of mucosa in all stitches, and a leak test. RESULTS: Anastomosis was achieved in all ex vivo experiments and thoracoscopically-led in vivo procedures. All anastomoses were patent, allowing distal passage of the endoscope, with mucosa incorporation. In in vivo experiments, a leak was detected in three animals and corrected with additional stitching. CONCLUSIONS: Peroral esophageal anastomosis with a single transthoracic trocar is feasible, which may represent a step forward in thoracic NOTES. PMID- 21234837 TI - Reflux and Barrett's disease. PMID- 21234838 TI - Upper gastrointestinal tumors. PMID- 21234839 TI - Gastrointestinal bleeding. PMID- 21234840 TI - Biliary endoscopic retrograde cholangiopancreatography. PMID- 21234841 TI - Pancreatic endoscopic retrograde cholangiopancreatography. PMID- 21234842 TI - Endoscopic ultrasound. PMID- 21234843 TI - Safety notes: how to avoid infections in natural orifice transluminal endoscopic surgery. PMID- 21234844 TI - Sedation and preparation. PMID- 21234845 TI - Use of a plastic endoprosthesis to successfully treat esophageal perforation following radiofrequency ablation of Barrett's esophagus. PMID- 21234846 TI - How to improve biopsy sampling of bile duct strictures: use small- or large-cup biopsy forceps or imagine another kind of forceps! PMID- 21234850 TI - ["15 questions on". Interview by Anne Brunner]. PMID- 21234851 TI - Presence of hyperemic islets in human donor-pancreata results in reduced islet isolation yield. AB - When studying histological characteristics of human donor-pancreata, a remarkably high number of hyperemic islets (HIs) were encountered. The abnormalities in these HIs ranged from single/multiple dilated vessels to hemorrhages extending into the exocrine tissue. We aimed to determine the relevance of the presence of HIs in human donor-pancreata for isolation outcome and to identify donor and procurement factors associated with the occurrence of HIs. The presence of HIs was scored semi-quantitatively (HI-, HI+) in 102 human donor-pancreata. Islet isolation was performed in 40 cases. Donor and procurement factors were retrospectively analyzed in 94 donors. HIs were found in 54.6% of all donor pancreata. However, only 4.5% of all islets in the affected pancreata was hyperemic. The affected pancreata contained slightly more endocrine tissue, but produced significantly lower yields. When corrected for other factors known to influence isolation outcome, the presence of HIs and endocrine content were the only factors significantly influencing isolation outcome. Prolonged ICU stay and pre-procurement hypertension were associated with the presence of HIs. This study is a first indication that the presence of HIs in human donor-pancreata are associated with reduced isolation outcomes and suggest an impact of the procurement procedure and pre-procurement hemodynamic status of the donor on the islet quality. It is tempting to speculate that this contributes to the generally experienced difficulties in obtaining sufficient amounts of human islets. PMID- 21234852 TI - Short-term glucocorticoid intake and metabolic responses during long-lasting exercise. AB - The aim of the study was to evaluate the effects of short-term glucocorticoid treatment on plasma amino acids, free fatty acids, blood glucose, and several hormones in healthy volunteers performing long-lasting exercise. 9 young female subjects exercised 2 h at 50-55% VO2 max twice, once after placebo (Pla) ingestion and once after prednisone (Cor, 50 mg/day/7 days) ingestion, according to a double-blind and randomized protocol. Blood samples were tat rest and during exercise for measurement of amino acids, free fatty acids, blood glucose, adrenocorticotrophic hormone (ACTH), growth hormone, dehydroepiandrosterone (DHEA), insulin, and glucagon. Both ACTH and DHEA values were significantly decreased by Cor vs. Pla (p < 0.01) throughout exercise, and Cor intake also induced lower growth hormone concentrations vs. Pla (p < 0.05) from 60 min to the end of exercise. No significant difference in glucagon, insulin or free fatty acid values was found between the treatments. Branched-chain amino acids and other essential amino acids were significantly higher after Cor vs. Pla from 60 min to the end of exercise (p < 0.05), whereas blood glucose was significantly higher from 90 min to the end of exercise (p < 0.05). We conclude that short-term glucocorticoid intake induces marked hormonal and metabolic changes during long lasting exercise. Proteolysis can increase with glucocorticoid during this type of exercise and the related higher plasma amino acid concentrations may contribute as energy substrates. Further studies will be necessary to explore and accurately quantify the mechanisms of proteolysis and glyconeogenesis induced by short-term glucocorticoid intake during this type of exercise. PMID- 21234853 TI - Insulin resistance variability in women with anovulatory and ovulatory polycystic ovary syndrome, and normal controls. AB - Women with polycystic ovary syndrome (PCOS) were found to have a higher biological variability in insulin resistance (IR) compared to controls, but it is unknown whether this variability in IR differs between PCOS who are anovulatory compared to those who have an ovulatory cycle. The primary aim of this study was to compare and contrast the variability of IR in women with ovulatory and anovulatory PCOS, in comparison to normal subjects. 53 Caucasian women with PCOS and 22 normal ovulating women were recruited. Fasting blood was collected each day on 10 consecutive occasions at 3-4 day intervals for analysis of insulin, glucose, progesterone, and testosterone. Analysis of progesterone levels showed 22 of 53 women with PCOS to have had an ovulatory cycle. Insulin resistance was calculated by HOMA method. Women with anovulatory PCOS had higher mean and variability of IR compared to those having an ovulatory cycle, and both were significantly higher than controls (mean +/- SEM; HOMA-IR 4.14 +/- 0.14 vs. 3.65 +/- 0.15 vs. 2.21 +/- 0.16, respectively) after adjustment or BMI. The mean BMI for individual PCOS patients correlated with mean HOMA-IR (p=0.009). Insulin resistance in women with anovulatory PCOS is both higher and more variable than in ovulatory PCOS. Since anovulatory PCOS therefore mimics the IR features of type 2 diabetes more closely, anovulation may be particularly associated with a higher cardiovascular risk compared to PCOS patients who ovulate. PMID- 21234854 TI - Risk of perforation during dilation for esophageal strictures after endoscopic resection in patients with early squamous cell carcinoma. AB - BACKGROUND AND STUDY AIMS: Growing evidence suggests that esophageal stricture frequently develops after endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) in early esophageal cancer patients, with an incidence proportional to the greater extent of mucosal defects resulting from improved EMR/ESD techniques. There seems to be a potential risk of perforation during bougienage in such patients. PATIENTS AND METHODS: 648 stricture dilations for 78 lesions in 76 patients were consecutively included. The outcomes after combined use of Maloney and Savary wire-guided bougienage for esophageal strictures after EMR/ESD were analyzed in a single-institute retrospective case series study. The perforation rate was determined and risk factors for perforation were identified. RESULTS: Patients underwent a median of 5.0 dilation procedures performed over a median 3.0 months for post-EMR/ESD strictures. Initial dilation was done a median 14 days following endoscopic resection. Perforations developed in seven patients (7/648 dilation procedures, 1.1%), all in the lower esophagus, and bleeding occurred in one patient (0.1% dilations). Two independent risk factors for development of perforation during dilation therapy for post-EMR/ESD stricture were identified: multiple dilations (odds ratio [OR] 1.2; P=0.012), and lower site of stricture (OR 12.8; P=0.043). Dysphagia was ameliorated by the dilations, and no patient required surgery. CONCLUSIONS: A specific emerging risk of perforation in dilation therapy for post EMR/ESD strictures was identified. Carefully planned treatment is necessary in patients with severe post-EMR/ESD strictures especially strictures requiring multiple dilations or located in the lower esophagus. PMID- 21234855 TI - Endorectal ultrasound in rectal carcinoma--do the literature results really correspond to the realities of routine clinical care? AB - BACKGROUND AND STUDY AIMS: This multicenter, prospective, country-wide quality assurance study at more than 300 hospitals in Germany was designed to characterize and analyze the diagnostic accuracy of rectal endoscopic ultrasound (EUS) in the routine clinical staging of rectal carcinoma (depth of tumor infiltration). PATIENTS AND METHODS: Patients were surveyed between 1 January 2000 and 31 December 2008. Those who received neoadjuvant therapy after EUS were excluded. The correspondence between the EUS assessment of tumor depth (uT) and that determined by histology (pT) was calculated, and the influence of hospital volume upon the sensitivity, specificity, and positive and negative predictive values was investigated. RESULTS: At 384 hospitals providing care at all levels, 29 206 patients were included; of the 27 458 treated by surgical resection, EUS was performed for 12 235 (44.6 %). Of these, 7096 did not receive neoadjuvant radiochemotherapy, allowing a uT-pT comparison. The uT-pT correspondence was 64.7 % (95 % confidence interval [CI] 63.6 % - 65.8 %); the frequency of understaging was 18 % (95 %CI 17.1 % - 18.9 %) and that of overstaging was 17.3 % (95 %CI 16.4 % - 18.2 %). The kappa coefficient was greatest in the category T1 (kappa = 0.591). For T3 tumors kappa was 0.468. The poorest correspondence was found for T2 and T4 tumors (kappa = 0.367 and 0.321, respectively). A breakdown by hospital volume showed that the uT-pT correspondence was 63.2 % (95 %CI 61.5 % - 64.9 %) for hospitals undertaking <= 10 EUS/year, 64.6 % (95 %CI 62.9 % - 66.2 %) for doing 11 - 30 EUS/year, and 73.1 % (95 %CI 69.4 % - 76.5 %) for those hospitals performing > 30 EUS/year. CONCLUSIONS: In clinical routine, the diagnostic accuracy of transrectal ultrasound in staging rectal carcinoma does not attain the very good results reported in the literature. Only in the hands of diagnosticians with a large case volume of rectal carcinoma patients can EUS lead to therapy-relevant decisions. PMID- 21234856 TI - Minimally invasive treatment of esophageal perforation using a multidisciplinary treatment algorithm: a case series. PMID- 21234857 TI - Serum retinol and beta-carotene levels and risk factors for cardiovascular disease in morbid obesity. AB - OBJECTIVE: to evaluate retinol and beta-carotene serum levels and their relationship with risk factors for cardiovascular disease in individuals with morbid obesity, resident in Rio de Janeiro. METHODOLOGY: blood serum concentrations of retinol and beta-carotene of 189 morbidly obese individuals were assessed. The metabolic syndrome was identified according to the criteria of the National Cholesterol Education Program (NCEP) and World Health Organization (WHO). Lipid profile, insulin resistance, basal insulin, glycemia, blood pressure, and anthropometry and their correlation with retinol and beta-carotene serum levels were evaluated. RESULTS: metabolic syndrome diagnosis was observed in 49.0% of the sample. Within this percentage the levels of beta-carotene were significantly lower when body mass index increased. Serum retinol didn't show this behavior. Serum retinol inadequacy in patients with metabolic syndrome (61.3%), according to WHO criterion, was higher (15.8%) than when the whole sample was considered (12.7%). When metabolic syndrome was diagnosed by NCEP criterion, beta-carotene inadequacy was higher (42.8%) when compared to the total sample (37.5%). There was a significant difference between average beta-carotene values of patients with and without metabolic syndrome (p=0.048) according to the classification of the NCEP. Lower values were found in patients with metabolic syndrome. CONCLUSION: considering the vitamin A contribution in antioxidant protection, especially when risk factors for cardiovascular disease are present, it is suggested that great attention be given to morbidly obese. This could aid in prevention and treatment of cardiovascular disease, which affects a significant part of the population. PMID- 21234858 TI - Pyridoxine improves platelet nitric oxide synthase dysfunction induced by advanced glycation end products in vitro. AB - Advanced glycation end products (AGEs) increase platelet aggregation and suppress vascular nitric oxide (NO) synthase (NOS) activity, and these effects may contribute to the atherothrombotic disease seen in diabetes. The aims of this study were to determine in vitro whether pyridoxine can abrogate the impairment in platelet NOS activity caused by AGEs, and to determine the mechanism by which it does this. Platelet aggregation was measured by Born aggregometry. Intraplatelet cyclic guanosine-3',5'-monophosphate (cGMP, an index of bioactive NO) was measured by radioimmunoassay. Serine-1177-specific phosphorylation of NOS type 3 (NOS-3) and phosphorylation of protein kinase Akt were determined in platelets by Western blotting. Phosphatidylinositol 3-kinase (PI3K) activity in platelets was ascertained by homogeneous time-resolved fluorescence (HTRF) assay. We found that AGE-modified albumin (AGEs) 200 mg/L increased platelet aggregability and decreased intraplatelet cGMP; these effects were largely attenuated by pyridoxine. Western blotting studies revealed that AGEs decreased NOS-3 phosphorylation on serine-1177, increased NOS-3 O-glycosylation, and decreased serine phosphorylation of protein kinase Akt; all of these changes were abrogated by pyridoxine. Direct measurement of PI3K activity in platelets demonstrated that all of the above effects could be attributed to a suppression by AGEs of PI3K activity, which was prevented by co-incubation with pyridoxine. We conclude that pyridoxine is effective in ameliorating the dysfunction of platelet NO signaling in response to AGEs, through improving PI3K activity, and hence downstream Akt phosphorylation and in turn serine-1177 phosphorylation of NOS-3. PMID- 21234859 TI - Effects of vitamin E on plasma lipid status and oxidative stress in Chinese women with metabolic syndrome. AB - Following the change of dietary structure and living style, metabolic syndrome (MetS) has become increasingly common in China, especially in women, who have abnormal plasma lipid profiles with increased levels of oxidative stress. Vitamin E (VitE) is a powerful chain-breaking antioxidant, which may be a protective factor against oxidative stress-related diseases. This study investigated the effects of three different dosages of tocopherol supplementation (100 IU /day, 200 IU /day, 300 IU /day) for 4 months in Chinese women with MetS. The plasma VitE concentrations increased significantly after the 4 months of supplementation (p < 0.01). The protective decreases in plasma total cholesterol were significant in 200 IU/day and 300 IU/day VitE groups (p < 0.05), but decreases in high density lipoprotein cholesterol were also significant in all the supplementation groups (p < 0.05). Plasma triglycerides were unaltered (p > 0.05). The indicators of oxidative stress decreased substantially in all of the VitE supplementation groups: malondialdehyde (MDA) was reduced by nearly 50 percent (all groups, p < 0.001), erythrocyte hemolysis was decreased by nearly 40 percent (all groups, p < 0.05); among which the 300IU/day VitE group showed the most significant effect. However, the activity of superoxide dismutase (SOD) decreased after the trial (p < 0.001). VitE provided marked benefits in reducing oxidative stress levels and improving lipid status in women with MetS. Although no dose-effect relationship was observed, 300 IU VitE per day showed the optimal effect. Research is needed to identify potential protective mechanisms or utilization of vitamin E during MetS. PMID- 21234860 TI - The impact of vitamin A supplementation on the immune system of vitamin A deficient children. AB - BACKGROUND & AIMS: To investigate the effect of vitamin A supplementation on parameters of the immune system of vitamin A-deficient children. METHODS: The study was carried out in four phases: 1) determination of serum retinol in 631 children from 36 to 83 months of age; 2) assessment of immunological markers [immunoglobulins and complement fractions, immunophenotyping of T and B lymphocytes, and natural killer (NK) cells], blood count, and serum ferritin of 52 vitamin A-deficient children (serum retinol < 0.70 micromol/L); 3) supplementation of the 52 deficient children with 200,000 IU of vitamin A; 4) determination of serum retinol and the immunological parameters 2 months after vitamin A supplementation. RESULTS: before vitamin A supplementation, 24.0 % of the children were anemic and 4.3 %had reduced ferritin concentrations. There was no significant difference between mean values of retinol according to the presence/absence of anemia. The mean values of the humoral and cellular immunological parameters did not show a statistically significant difference before and after supplementation with vitamin A. Children with concomitant hypovitaminosis A and anemia presented a significant increase in absolute CD4 and CD8 T-cell counts after vitamin A supplementation (p < 0.05). CONCLUSION: vitamin A had an effect on the recruitment of T and B lymphocytes to the circulation of children with hypovitaminosis A and anemia. PMID- 21234861 TI - The effects of vitamin C administration, acute food deprivation, and acute food intake on vitamin C levels in different brain areas of guinea pigs. AB - Vitamin C is crucial for the brain. We aimed to investigate the effects of vitamin C administration following 24 hours of acute food deprivation and 24 hours of acute food intake on changes in vitamin C levels in different brain areas of guinea pigs. Vitamin C was administered as a single intraperitoneal dose (500 mg kg(-1) body weight) both before acute food deprivation and before acute food intake. At the end of our study, we measured the vitamin C levels in cerebral cortex lobes, brain stem structures, hypophysis, hypothalamus, cerebellum, hippocampus, and amygdala. Vitamin C levels in the frontal and parietal lobes were found to be significantly higher in animals pretreated with vitamin C prior to 24 hours of food deprivation (p < 0.05). Temporal lobe vitamin C level was significantly lower in animals that were subjected to 24 hours of acute food intake following 24 hours of food deprivation (p < 0.05). Increased vitamin C levels were observed in the occipital lobe of all animals that received vitamin C administration (p < 0.05). Vitamin C levels in the brain stem structures such as mesencephalon and pons were significantly decreased in animals pretreated with vitamin C before normal feeding (p < 0.05). Vitamin C level in the hypothalamus was significantly increased after 24 hours of food deprivation (p < 0.05). In conclusion, different areas of the brain may differ in terms of vitamin C content during nutritional changes with or without vitamin C pretreatment, such as 24 hours of food deprivation or 24 hours of food intake following 24 hours of food deprivation. These differences may be attributed to several functions of vitamin C which may occur under these circumstances. PMID- 21234862 TI - Relationship between dietary intake and dental caries in preschool children. AB - This study assessed the relationship between intake of nutrients and dental caries in preschool children. One hundred and eighty-two children aged three to six years were recruited from nine day care centers in central Taiwan. These children had an oral health examination, and their parents or guardians answered a questionnaire. Each child's intake of nutrients was estimated using the 24-hour dietary recall and food frequency questionnaire data. Logistic regression analysis was applied to assess the associations between dental caries and intake of each nutrient or food group, with adjustment for potential confounders. The prevalence of dental caries was 73 % and increased with age. Not being a first born and having more between-meal snacks were associated with increased caries risk. After controlling for other important factors, vitamin A intake was significantly associated with fewer dental caries (deft, decayed, indicated for extraction, and filled primary teeth: >= 4 vs. < 4), with an odds ratio of 0.97 (95 % confidence interval: 0.94 - 0.99) for an 100-MUg increase in vitamin A intake. There was no significant association between dental caries and energy, macronutrient intake, and Ca/P ratio, respectively. Vegetable intake was also significantly associated with lower dental caries score. PMID- 21234863 TI - The -11377C > G adiponectin gene polymorphism alters the adiponectin concentration and the susceptibility to type 2 diabetes in Thais. AB - The aims of this study were first to detect the levels of adiponectin, insulin, albumin, glucose, alanine aminotransferase (ALT), lipids, homeostasis model assessment for insulin resistance (HOMA-IR), and anthropometric variables in type 2 diabetes mellitus (T2DM) as well as healthy control groups, and to determine whether two adiponectin gene polymorphisms, at the position -11377C > G as well as +45T > G, are associated with serum levels of adiponectin and other variables; then to search for the association between these two single nucleotide polymorphisms (SNPs) of the adiponectin gene and T2DM. We investigated 93 T2DM patients and 90 healthy volunteers. Compared with the healthy control group, the T2DM group had significantly lower adiponectin levels. Waist circumference, total cholesterol, ALT, glucose, insulin, and HOMA-IR scores were significantly higher in the T2DM group than in the control group. The polymorphism of the adiponectin gene at position -11377C > G among type 2 diabetes subjects showed that the adiponectin concentration was significantly lower in CG/GG genotypes (6.2 MUg/mL) than the CC genotype (7.8 MUg/mL), whereas SNP +45T > G was not associated with adiponectin levels. Adiponectin gene polymorphisms at position -11377C > G and +45T > G were significantly more frequent in type 2 diabetes patients than in the control group (p = 0.022; p = 0.045, respectively). However, multivariate logistic regression analysis showed that the strong impact on T2DM was found for 11377C > G gene polymorphism (p = 0.023) and waist circumference (p < 0.001). Therefore, the single nucleotide polymorphism of -11377C > G in adiponectin promoter region has impact on the lower adiponectin concentrations, and may influence susceptibility to T2DM in Thais. PMID- 21234864 TI - [Correlation between pathologic features and perfusion CT of renal cancer: a feasibility study]. AB - OBJECTIVES: The computerized tomography with perfusion technique (pCT) has proved to have some potentialities in the oncologic field as a possible tool to identify neoangiogenesis in vivo. The purpose of the present job is to test the correlations existing between perfusion data and pathologic features in the evaluation of vascularization in kidney cancer. METHODS: 6 patients with clinical diagnosis of renal tumor awaiting surgical treatment underwent preoperatively pCT scans. Axial images encompassing the greatest diameter of the cancer were compared with the respective histological sections. RESULTS: A correlation between tumor histological subtype and perfusion index was observed and shown. Moreover, clear cell RCC of different Fuhrman grades showed statistically significant differences in perfusion values (T test). Specifically, high perfusion indexes were associated with high density of microvessels with abnormal architecture at the microscopic evaluation of tumor specimen. Conversely, lower perfusion index were detected in tumors with lower microvascular density. CONCLUSIONS: pCT scans can provide significant data on tumor angiogenesis and, eventually, suggest tumor histological subtype. The possibility of identifying preoperatively tumor histotype can be of particular relevance in patients with small renal tumors, suitable for minimally-invasive surgery or active surveillance program. PMID- 21234865 TI - [Continuing evolution of statistical tests in medical research]. AB - The role of statistics in medical research starts at the planning stage of a clinical trial or laboratory experiment to establish the design and size of an experiment that will ensure a good prospect of detecting effects of clinical or scientific interest. Statistics is again used during data analysis (sample data) to make inferences valid in a wider population. In simple situations, computation of simple quantities such as P-values, confidence intervals, standard deviations, standard errors or application of some standard parametric or nonparametric tests may suffice. Moreover, despite the wide use of statistics in medical research, simple notions are sometimes misunderstood or misinterpreted by medical research workers, who have only a limited knowledge of statistics. This article, written for non-statisticians, is to explain what are the most common statistical tests used today in the field of medical research, tracing the evolution of statistical tests over time, in particular the introduction of nonparametric methods and, more recently, the NonParametric Combination (NPC) methodology. At the same time, this work seeks to identify some of the errors associated with their use, that often lead to an incorrect assessment and interpretation of results of medical research. PMID- 21234866 TI - [Prevention of topic toxicity of BCG with single-dose prulifloxacin. Preliminary results of a randomized pilot study]. AB - INTRODUCTION: Toxicity is a major problem for patients undergoing intravesical therapy with Bacillus Calmette-Guerin (BCG) for the conservative management of intermediate or high-risk non-muscle invasive bladder cancer (NMI-BC). A prospective pilot trial was designed to evaluate the adoption of a single dose of prulifloxacin to prevent the toxicity of BCG. Treatment tolerability and its possible influence on BCG efficacy have been analyzed. MATERIALS AND METHODS: The study was designed to evaluate the action of prulifloxacin in patients with intermediate or high-risk NMI-BC, undergoing 6-week induction cycle of BCG. Main exclusion criteria were previous intravesical therapy, urinary infection and any other factor that could influence tolerability to BCG intravesical immunotherapy. The patients were randomized to receive BCG alone versus BCG plus prulifloxacin. BCG toxicity and local tolerability were evaluated by self-administered EORTC QLQ BLS24 questionnaire, and BCG adverse events (AEs) were classified according a four-class classification. The toxicity and tolerability evaluations were performed at baseline, one week after every instillation and one week and one month after the last instillation. Cystoscopy and cytology were performed 3 monthly. Recurrence and progression were recorded. RESULTS: The study included 43 patients receiving 258 instillations of BCG. The patients were randomized to receive BCG alone (Arm A: 132 instillations in 22 patients) versus BCG plus prulifloxacin given as a single oral dose (600 mg) 6 hours after the instillation. An advantage in favor of prulifloxacin prophylaxis emerged, according to EORTC QLQ-BLS24, in overall incidence of nocturnal micturitions (56% vs 28.6%; p=0.001), insomnia (40% vs 14.3%; p=0.002), urgency (70% vs 42.6%; p=0.05), incontinence (44% vs 12.7%; p=0.01) and bothersome events due to intravesical therapy (84% vs 63.5%; p=0.02). Systemic class IIB and III adverse events occurred in only 14.2% and 3.5% of the patients, respectively. No class IV AE was detected. Due to the low incidence no statistically significant difference was evident between the two arms (p=0.6). Three patients of Arm B and 1 patient of Arm A interrupted the treatment, after the 3rd - 4th instillation. Anti tuberculosis therapy war required for 3 months in only one patient. Three and 2 instillations were postponed for one-(two) week(s) in Arm B and Arm A, respectively. Prulifloxacin, generally well tolerated, was withdrawn in one patient due to skin allergic reaction. Recurrence rate at a mean follow-up of 12 months did not significantly differ between the two arms. CONCLUSIONS: Prulifloxacin decreases the incidence of local symptoms and improves the compliance to BCG intravesical therapy. Due to the low number of events, no evidence emerges in our study about its capability of preventing severe systemic toxicity, although it has proved effective in reducing local symptoms. PMID- 21234867 TI - [Real-time elastography in the diagnosis of prostate cancer: personal experience]. AB - INTRODUCTION: Prostate cancer is the most common cancer in men. In the future, a significant further increase in the incidence of prostate cancer is expected. The indication to perform a prostate biopsy is digital rectal examination suspicious for prostate cancer, total prostate specific antigen (PSA) value, free PSA/total PSA ratio, PSA density and PSA velocity, and an evidence of hypoechoic area at transrectal ultrasound scan. Unfortunately the specificity and sensibility are still poor. The aim of this retrospective study is to evaluate the specificity and sensibility of real time elastography versus ultrasound transrectal B-mode scan. METHODS: We retrospectively evaluated 108 pts. having undergone TRUS-guided transrectal prostate biopsy (10 samples). The indication for biopsy is: digital rectal examination, total prostate specific antigen (PSA) value, PSA ratio, PSA density and PSA velocity suspicious for prostate cancer, and/or an evidence of hypoechoic area at transrectal ultrasound scan, and/or hard area at real-time elastography. The mean age of patients is 66.8 years, mean PSA 6.5 ng/mL, and mean ratio 16.5%. We compared the histopathological findings of needle prostate biopsies with the results of transrectal ultrasound and transrectal real-time elastography. RESULTS: 32/108 (29.6%) pts. were positive for prostate cancer (mean Gleason score 7.08), mean PSA 14 ng/mL and mean ratio 9.5%. Transrectal ultrasound scan shows a sensibility of 69% and specificity of 68%. Transrectal ultrasound scan shows a VPP of 51.4%. Transrectal ultrasound scan shows a VPN of 80.9%. Real-time elastography shows a sensibility of 56% and specificity of 85.7%. Real-time elastography shows a VPP of 60.1%. Real-time elastography shows a VPN of 83%. CONCLUSIONS: Elastography has a significantly higher specificity for the detection of prostate cancer than the conventionally used examinations including DRE and TRUS. It is a useful real-time diagnostic method because it is not invasive, and simultaneous evaluation is possible while performing TRUS. PMID- 21234868 TI - Level of gold in normal and pathological semen. AB - The study included the estimation of gold in seminal plasma and spermatozoa of 36 semen samples of normal and different pathological conditions. The method employed for analysis was atomic absorption spectrophotometry. The metal was seen in seminal plasma and spermatozoa of all normal samples. PMID- 21234869 TI - Can Hyperbaric Oxygen Therapy (HOT) have a place in the treatment of some urological diseases. AB - HOT (Hyperbaric Oxygen Therapy) is used in urological diseases: Scrotal/perineal fasciitis and Radiation-induced cystitis (and proctopathy); in urgency and frequency syndrome and with chronic pelvic pain the use of HOT is still experimental. The basic principle of HOT is to increase oxygen dissolved in the blood when it is administered at high pressure. O2 is then distributed to the tissues through the pressure gradient; tissue hyper-oxygenation has anti inflammatory and pain-killing effects, it increases bacterial permeability to antibiotics, strengthens neo-angiogenesis, reinforces lymphocytes and macrophages function, augments testosterone secretion (in males), and finally enhances wound healing process. We treated with HOT (integrating other treatments) 17 cases of necrotizing fasciitis, 13 radiation-induced cystitis and 4 cases of urgency and frequency syndrome. We always had good results, with a good cleansing of the dissected areas in Fournier's gangrene; in the cases of radiation-induced cystitis we had an improvement in the symptoms and hematuria, and finally in cases of urgency and frequency syndrome we had a transient reduction of symptomatology and pain. Our experiences and the specific literature on this subject suggest that HOT, sometimes associated with other medical and surgical therapies, can be an effective tool to treat urological diseases; in some cases its efficacy was well demonstrated (Fournier's gangrene and Radiation-induced cystitis), in others (urgency-frequency syndrome and chronic pelvic pain) it is a promising technique which definitely needs further research. PMID- 21234870 TI - [Fibromyxoid sarcoma of the kidney. A case report]. AB - Low grade fibromyxoid sarcoma is an uncommon soft tissue tumor. We present the case of a 83-year-old female who developed large mass in the right kidney. A nephrectomy was performed. The tumor measured 18,5x17,5x11,5 cm and on pathology evaluation was diagnosed as low grade fibromyxoid sarcoma. Currently, the patient is doing well without evidence of local recurrence and distant metastasis. Low grade fibromyxoid sarcoma of the Kidney is a very rare tumor. The metastasizing potential is high. Sometimes long interval between tumor presentation and metastasis is observed. The treatment of choice is surgery. The role of radiotherapy and chemotherapy is uncertain. PMID- 21234871 TI - [Single session cystolitholapaxy and PCNL for encrusted DJ stent with large associated stone burden]. AB - INTRODUCTION: Ureteral stent use is commonplace in urology to prevent or relieve ureteral obstruction. If ureteral stents are neglected, they can cause severe morbidity due to migration, occlusion, encrustation, breakage, stone formation, and even death, due to life-threatening urosepsis or complications related to operative intervention. Extracorporeal shockwave lithotripsy, ureterorenoscopy, electrohydraulic lithotripsy, laser lithotripsy, and percutaneous nephrolitholapaxy (PCNL) have been reported for forgotten ureteral stent management, but currently there are no guidelines for this challenging situation and only few algorithms have been introduced by some studies. METHODS: We present a case of a man presenting with an encrusted left double J (DJ) stent, inserted two years before, and bulky radiolucent lithiasis at both ends of the stent. The patient was studied with intravenous pyelogram and non contrast-enhanced computed tomography, and then treated with cystolithotripsy and PCNL in a single session. RESULTS: Complete clearance of the stones was obtained and the DJ stent was removed without breaking from the percutaneous access. CONCLUSIONS: Neglected stents still represent a challenge in urology: while endourology remains the best option for treatment, the management of ureteral stents should be based on follow up and prevention, using for example a computerized warning and stent retrieval software system. PMID- 21234872 TI - [Morris syndrome: description of a case characterized by partial androgen insensitivity]. AB - The Morris syndrome is a X-linked recessive condition due to a complete or partial insensitivity to androgens, resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. This failure of virilization can be either complete or partial depending on the amount of residual androgen receptor function. The phenotype of individuals with partial androgen insensitivity syndrome may range from mildly virilized female external genitalia to mildly undervirilized male external genitalia. We describe a case of Partial Androgen Insensitivity Syndrome in a 21-year-old patient with a 46, XY karyotype, bilateral inguinal masses, clitoral enlargement and partial posterior labial fusion. Surgical care consisted of bilateral orchiectomy and plastic surgery of external genitalia. The patient underwent estrogen replacement therapy. PMID- 21234873 TI - [History and stone stories (from Frere Jacques to lithotripsy)]. PMID- 21234876 TI - Strategies for genotyping. AB - The identification of genomic loci linked to or associated with human disease has been greatly facilitated by the evolution of genotyping strategies and techniques. The success of these strategies continues to be based upon clear clinical assessment, accurate sample handling, and careful data management, but also increasingly upon experimental design. Technological advances in the field of genotyping have permitted increasingly complex and large population studies to be performed. An understanding of publicly available genetic variation databases, including an awareness of the limitations of these data, and an appreciation of the strategic approaches that should be used to exploit this information will provide tremendous insight for researchers are aiming to utilize this accessible technology. As genome-wide association studies (GWAS) and Next Generation (NextGen) sequencing become the mainstays of genetic analyses, it is important that their technical strengths and limitations, as well as their impact on study design, be understood before use in a linkage or genetic association study. PMID- 21234875 TI - Quality control procedures for genome-wide association studies. AB - Genome-wide association studies (GWAS) are being conducted at an unprecedented rate in population-based cohorts and have increased our understanding of the pathophysiology of complex disease. Regardless of context, the practical utility of this information will ultimately depend upon the quality of the original data. Quality control (QC) procedures for GWAS are computationally intensive, operationally challenging, and constantly evolving. Here we enumerate some of the challenges in QC of GWAS data and describe the approaches that the electronic MEdical Records and Genomics (eMERGE) network is using for quality assurance in GWAS data, thereby minimizing potential bias and error in GWAS results. We discuss common issues associated with QC of GWAS data, including data file formats, software packages for data manipulation and analysis, sex chromosome anomalies, sample identity, sample relatedness, population substructure, batch effects, and marker quality. We propose best practices and discuss areas of ongoing and future research. PMID- 21234877 TI - Analysis of mitochondrial DNA point mutation heteroplasmy by ARMS quantitative PCR. AB - Mitochondrial disorders are a group of complex and heterogeneous diseases that may be caused by molecular defects in both the nuclear and mitochondrial genomes. Pathogenic mitochondrial DNA (mtDNA) mutations are usually present in the heteroplasmic form. The degree of mtDNA mutation heteroplasmy (mutation load) varies among different tissues. Manifestation of clinical phenotypes depends on the mutation load in affected tissues. Thus, it is important to quantify the degree of mutation heteroplasmy in various tissues. This unit outlines the design of allele refractory mutation system (ARMS)-based quantitative PCR (qPCR) analysis of three common mtDNA point mutations. This is a cost-effective and sensitive single-step method to simultaneously detect and quantify heteroplasmic mtDNA point mutations. It requires as little as 0.1 ng of total genomic DNA per reaction and can be used to quantify mutation heteroplasmy in various noninvasively obtained tissues such as hair follicles, buccal swab, and urine sediment. Detailed protocols for ARMS primer design and qPCR set up, validation procedures, and cautions in the interpretation of results, as well as advantages and limitations are discussed. ARMS qPCR is an important tool for addressing some of the diagnostic challenges of mitochondrial disease. PMID- 21234878 TI - Real-time quantitative PCR analysis of mitochondrial DNA content. AB - Mitochondrial disorders are a group of complex and heterogeneous diseases that may be caused by molecular defects in the nuclear or mitochondrial genome. The biosynthesis and integrity of the small 16.6-kb mitochondrial genome require a group of nuclear encoded genes. The mitochondrial DNA (mtDNA) depletion syndromes (MDDSs) are autosomal recessive disorders caused by molecular defects in nuclear genes, and characterized by a reduction in mtDNA content. To date, mutations in at least nine genes (POLG, DGUOK, TK2, TYMP, MPV17, SUCLA2, SUCLG1, RRM2B, and C10orf2) have been reported to cause various forms of MDDSs. In the clinical setting, a simple method to determine mtDNA depletion would be useful prior to undertaking gene sequence analysis. This unit outlines the real-time quantitative polymerase chain reaction (qPCR) analysis of mtDNA content in tissues. MtDNA content varies among different tissues and at different ages in the same individual. Detailed protocols for the selection of nuclear genes for normalization, PCR set up, validation procedures, tissue and age matched controls, and sensitivity and specificity in various tissues, as well as interpretation of results are discussed. PMID- 21234898 TI - A phenotype-based genetic association study reveals the contribution of neuregulin1 gene variants to age of onset and positive symptom severity in schizophrenia. AB - By pure endpoint diagnosis of the disease, the risk of developing schizophrenia has been repeatedly associated with specific variants of the neuregulin1 (NRG1) gene. However, the role of NRG1 in the etiology of schizophrenia has remained unclear. Since Nrg1 serves vital functions in early brain development of mice, we hypothesized that human NRG1 alleles codetermine developmentally influenced readouts of the disease: age of onset and positive symptom severity. We analyzed 1,071 comprehensively phenotyped schizophrenic/schizoaffective patients, diagnosed according to DSM-IV-TR, from the GRAS (Gottingen Research Association for Schizophrenia) Data Collection for genetic variability in the Icelandic region of risk in the NRG1 gene. For the case-control analysis part of the study, we included 1,056 healthy individuals with comparable ethnicity. The phenotype based genetic association study (PGAS) was performed on the GRAS sample. Instead of a risk constellation, we detected that several haplotypic variants of NRG1 were, unexpectedly, less frequent in the schizophrenic than in the control sample (mean OR=0.78, range between 0.68 and 0.85). In the PGAS we found that these "protective" NRG1 variants are specifically underrepresented in subgroups of schizophrenic subjects with early age of onset and high positive symptom load. The GRAS Data Collection as a prerequisite for PGAS has enabled us to associate protective NRG1 genotypes with later onset and milder course of schizophrenia. PMID- 21234916 TI - The Impella Recover 2.5 and TandemHeart ventricular assist devices are safe and associated with equivalent clinical outcomes in patients undergoing high-risk percutaneous coronary intervention. AB - OBJECTIVES: To compare the practical use, safety, and clinical outcomes associated with the TandemHeart (TH) versus Impella Recover 2.5 (IR2.5) devices when used for circulatory support during high-risk percutaneous coronary intervention (PCI). BACKGROUND: Small studies and registries suggest safety and efficacy for the TH and IR2.5 percutaneous-left ventricular assist devices (P LVADs). However, these P-LVADs differ markedly in their insertion, operation, and manner of circulatory augmentation. To date, no study has compared these devices. METHODS: We identified 68 patients (49 males, 19 females; age 71.1 +/- 12.1 years) from our single-center database that underwent "high-risk" PCI with P-LVAD support from April 2005 to June 2010 (32 with TH, 36 with IR2.5). Relevant data were extracted for analysis. RESULTS: Baseline demographics were similar, including low LVEF (overall mean 31.0 +/- 13.7%) and elevated STS mortality risk score (4.2 +/- 3.7%). Angiographic characteristics were also similar, with a mean of 2.4 +/- 1.0 lesions treated per patient, and 29% undergoing left main PCI. PCI success rates were 99% in both groups, with similar in-hospital outcomes and a combined 7% major vascular access site complication rate. A single episode of left atrial perforation occurred during TH use. No patient required emergent CABG and no in-hospital deaths occurred. The 30-day MACE rate (death, myocardial infarction, target lesion revascularization) was 5.8%. There were no differences between the IR2.5 and TH groups with respect to short- or long-term clinical outcomes. CONCLUSIONS: The IR2.5 and TH assist devices are safe, equally effective, and associated with acceptable short- and long-term clinical outcomes in patients undergoing "high-risk" PCI. PMID- 21234917 TI - Successful subxyphoid hybrid approach for placement of a Melody percutaneous pulmonary valve. AB - A variety of complex congenital heart defects in the pediatric population involve placement of a right ventricle to pulmonary artery conduit as part of surgical repair. With the advent of percutaneous pulmonary valve implantation (PPVI), patients may avoid the risks of serial surgical reinterventions as the PPVI acts to prolong the life of a previously placed conduit. As the experience with PPVI is growing, new challenges arise from complicated anatomy and severe conduit stenosis. We present a case of a 16-year-old male who underwent successful pulmonary valve placement with a Melody valve via a subxyphoid hybrid approach after an unsuccessful attempt at percutaneous placement. PMID- 21234920 TI - Aspiration coronary thrombectomy for acute myocardial infarction increases myocardial salvage: single center randomized study. AB - OBJECTIVES: The aim of the study was to assess if aspiration thrombectomy in high risk patients with STEMI and angiographic evidence of thrombus may improve myocardial salvage. BACKGROUND: It is unclear if thrombus aspiration before percutaneous intervention (PCI) improves myocardial salvage. METHODS: The trial was a prospective randomized study. The inclusion criteria were: first STEMI within 12 hr from symptoms onset, culprit lesion in left anterior descending or right coronary artery, culprit artery TIMI flow <= 2 and angiographic evidence of thrombus. The primary endpoint was myocardial salvage index (MSI) as assessed by (99m) Tc-sestamibi SPECT imaging. RESULTS: We randomized 137 patients (98 male, mean age 64.1 +/- 12.5 years) either to aspiration thrombectomy followed by standard PCI with stent implantation (n = 67) or to standard primary PCI (n = 70). Index perfusion defect was similar in both study groups: 34.2% +/- 13.1% in thrombectomy group versus 37.1% +/- 12.0% in primary PCI group (P = 0.2). MSI was larger in aspiration thrombectomy group than in control patients [25.4% (IQR 13.5 44) vs. 18.5% (IQR 7.7-30.3) respectively, P = 0.02]. The final infarct size was smaller in patients treated with aspiration thrombectomy (23.1% +/- 13.3% vs. 28.9% +/- 10.2% in the control group, P = 0.002). CONCLUSIONS: Aspiration thrombectomy improves myocardial salvage in high risk STEMI patients with angiographic evidence of thrombus. PMID- 21234921 TI - Acute myocardial infarction caused by multivessel coronary spasm due to calcium channel blocker withdrawal. AB - Calcium channel blockers are a commonly used class of medications for the management of hypertension, angina, and superventricular tachyarrhythmias. Abrupt withdrawal of these agents can precipitate coronary vasospasm, which may result in myocardial infarction. We present the case of a 47-year-old woman who sustained an acute myocardial infarction mediated by multivessel coronary vasospasm secondary to verapamil withdrawal and the associated interventional management. PMID- 21234922 TI - Balloon aortic valvuloplasty for congenital aortic stenosis using the femoral and the carotid artery approach: a 16-year experience from a single center. AB - OBJECTIVES: The aim of this article is to report a 16-year experience with percutaneous balloon aortic valvuloplasty (BAVP) in newborns and young infants up to 3 months of age in a tertiary care cardiac reference center in a developing country and to determine its value in postponing open heart surgery. BACKGROUND: Congenital aortic stenosis (AS) is a potentially life threatening disorder. BAVP and surgical procedures have similar short and medium-term efficacy. METHODS: Thirty-one consecutive newborns and young infants with critical AS underwent BAVP in our department from 1991 to 2007. Mean patient age at time of the procedure was 22 days (range 2-92 days) and mean weight was 3,310 g (1,840-4,400 g). RESULTS: There was a significant reduction in mean Doppler-derived peak gradient across the aortic valve immediately after the procedure (75.1 +/- 22 versus 32.2 +/- 13.02, P < 0.001), and this finding was maintained throughout follow-up. Since 2003, when the carotid approach became routine practice, no major vascular complications were observed. Mean time of follow-up was 81 months (5 days-196 months) with only two deaths (7.4%). Only 24% patients required surgical reintervention on the aortic valve during follow-up. Survival free from aortic valve surgery was 80% at 24 months, 66% at 63 months, and 50% at 80 months. CONCLUSION: Percutaneous intervention for relief of critical aortic stenosis in newborns in a tertiary center of a developing country is safe and has excellent short and long-term results comparable to other centers throughout the world. PMID- 21234923 TI - Limitations of closing percutaneous transthoracic ventricular access ports using a commercial collagen vascular closure device. AB - INTRODUCTION: Closed-chest access and closure of direct cardiac punctures may enable a range of therapeutic procedures. We evaluate the safety and feasibility of closing percutaneous direct ventricular access sites using a commercial collagen-based femoral artery closure device. METHODS: Yorkshire swine underwent percutaneous transthoracic left ventricular access (n = 13). The access port was closed using a commercial collagen-based vascular closure device (Angio-Seal, St. Jude Medical) with or without prior separation of the pericardial layers by instillation of fluid into the pericardial space ("permissive pericardial tamponade"). After initial nonsurvival feasibility experiments (n = 6); animals underwent 1-week (n = 3) or 6-week follow-up (n = 4). RESULTS: In naive animals, the collagen plug tended to deploy outside the parietal pericardium, where it failed to accomplish hemostasis. "Permissive pericardial tamponade" was created under MRI, and accomplished early hemostasis by allowing the collagen sponge to seat on the epicardial surface inside the pericardium. After successful closure, six of seven animals accumulated a large pericardial effusion 5 +/- 1 days after closure. Despite percutaneous drainage during 6-week follow-up, the large pericardial effusion recurred in half, and was lethal in one. CONCLUSIONS: A commercial collagen-based vascular closure device may achieve temporary but not durable hemostasis when closing a direct left ventricular puncture port, but only after intentional pericardial separation. These insights may contribute to development of a superior device solution. Elective clinical application of this device to close apical access ports should be avoided. PMID- 21234924 TI - Impact of diabetes mellitus status on coronary pathoanatomy and interventional treatment: insights from the Euro heart survey PCI registry. AB - OBJECTIVES: The present analysis was performed to evaluate the impact of diabetes mellitus (DM) status on the severity of coronary artery disease (CAD) and current approaches in interventional treatment. BACKGROUND: Little is known about the effect of DM treated with diet, oral agents, or insulin on lesion characteristics and anatomical pattern of CAD and their interventional treatment. METHODS AND RESULTS: Patients (n = 46,779) of the contemporary Euro Heart Survey PCI registry with known DM status were included in this analysis. Nondiabetics (n = 35,280, 75.4%) were compared with diabetics treated with diet (n = 1,533, 3.3%), oral agents (n = 7,222, 15.4%), and insulin (n = 2,744, 5.8%). Diabetic patients were older, suffered more frequently from comorbidities and presented more often with cardiogenic shock. The number of severely stenosed (>= 70%) segments incrementally increased from nondiabetics to insulin-requiring diabetics. The location of lesions did not differ between patients with and without DM. The ratio stenosed/treated segments progressively rose among the four patient cohorts. The severity of DM negatively correlated with the extent of complete revascularization. After adjustment for confounding variables no significant differences in hospital mortality could be observed between patients without DM and diabetics treated with diet, but a significantly higher rate of death was seen in diabetic patients with oral medication and insulin therapy. CONCLUSIONS: Although CAD was more severe in patients with DM the percentage of treated segments with >= 70% stenosis was lower. Adjusted hospital mortality was increased among diabetics treated with oral medication or insulin, but not among those treated with diet. PMID- 21234926 TI - The use of a guide catheter extension system as an aid during transradial percutaneous coronary intervention of coronary artery bypass grafts. AB - AIMS: Prior coronary artery bypass graft (CABG) surgery is one of the main predictors of failure of transradial PCI. Frequently this is due to difficulty in graft cannulation and/or poor backup support. In addition to Proxis'sTM embolic protection role, the ProxisTM, HeartrailTM, and GuideLinerTM guide catheter extension devices have all been shown to facilitate coronary intervention by increasing backup support and aiding stent delivery. We describe our institution's experiences using these devices to aid transradial graft intervention. METHODS: Between October 2007 and March 2010, the utility and safety of these devices were assessed in consecutive transradial graft intervention procedures. ProxisTM cases used for proximal protection alone were excluded. Deep intubation was defined as an intubation depth of >=2 cm. RESULTS: Guide catheter extensions were used in 33 of 41 transradial graft interventions identified. ProxisTM was used for proximal protection alone in 3 cases, leaving 30 cases as the study group (HeartrailTM n = 18, GuideLinerTM n = 3, ProxisTM n = 9). In all study cases procedural success with final TIMI-3 flow was achieved. Guide catheter extensions were used to aid during graft cannulation (n = 11), to improve backup support via deep intubation (n = 26) and as an adjunctive aspiration device (n = 11). Filter-based distal embolic protection devices were used in 11/21 HeartrailTM and GuideLinerTM cases. Deep intubation depths ranged from 30 to 138 mm (mean 61 mm) with no complications related to deep intubation seen. CONCLUSIONS: The use of guide catheter extension systems facilitated transradial graft intervention via several mechanisms including aid to graft cannulation, increasing backup support, and as an adjunctive aspiration device. PMID- 21234927 TI - Catheter closure of atrial septal defect in anatomically corrected malposition with left juxtaposition of the atrial appendages using intracardiac echocardiography. AB - Anatomically corrected malposition is characterized by abnormally related great vessels and atrioventricular and ventriculoarterial concordance. It is often associated with juxtaposition of the atrial appendages where the plane of the atrial septum is abnormally oriented. We describe the device closure of an atrial septal defect in a patient with such a lesion under intracardiac echocardiography guidance. PMID- 21234973 TI - Monochorionic diamniotic twin gestations discordant for markedly enlarged nuchal translucency. AB - OBJECTIVE: To assess karyotypes and outcomes of monochorionic diamniotic (MCDA) twin pregnancies discordant for markedly enlarged nuchal translucency (NT) in the first trimester. METHOD: Brigham and Women's Hospital's ultrasound database was queried to identify all MCDA gestations in which one twin had NT >= 3.5 mm and the co-twin had normal NT. Cytogenetic results, ultrasound findings, and pregnancy outcomes were reviewed. RESULTS: Of 162 MCDA twin pairs, 11 were discordant for NT >= 3.5. Chromosomal abnormalities were present in three cases: one twin pair was concordant for trisomy 18; one pair discordant for mosaic trisomy 2; and one pair discordant for confined placental mosaicism (CPM) (high frequency tetraploidy). Adverse outcomes for twins with euploid or unknown karyotypes included twin reverse arterial perfusion (TRAP) sequence, growth discordance, and esophageal atresia with tracheoesophageal fistula. CONCLUSION: Postfertilization nondisjunction leading to mosaicism in one fetus, discordant phenotypes yet concordant karyotypes, and discordance for CPM were documented phenomena, supporting karyotyping of both twins. In this case series, discordant NT was a marker for chromosome abnormalities, as well as for complications specific to monochorionic gestations, including TRAP sequence, amniotic fluid discordance, and structural anomalies. Nonetheless, normal fetal anatomy and karyotype were the most common outcomes. PMID- 21234977 TI - Peptide-based materials: from nanostructures to applications. PMID- 21234978 TI - Bioinspired peptide nanotubes: deposition technology, basic physics and nanotechnology applications. AB - Synthetic peptide monomers can self-assemble into PNM such as nanotubes, nanospheres, hydrogels, etc. which represent a novel class of nanomaterials. Molecular recognition processes lead to the formation of supramolecular PNM ensembles containing crystalline building blocks. Such low-dimensional highly ordered regions create a new physical situation and provide unique physical properties based on electron-hole QC phenomena. In the case of asymmetrical crystalline structure, basic physical phenomena such as linear electro-optic, piezoelectric, and nonlinear optical effects, described by tensors of the odd rank, should be explored. Some of the PNM crystalline structures permit the existence of spontaneous electrical polarization and observation of ferroelectricity. The PNM crystalline arrangement creates highly porous nanotubes when various residues are packed into structural network with specific wettability and electrochemical properties. We report in this review on a wide research of PNM intrinsic physical properties, their electronic and optical properties related to QC effect, unique SHG, piezoelectricity and ferroelectric spontaneous polarization observed in PNT due to their asymmetric structure. We also describe PNM wettability phenomenon based on their nanoporous structure and its influence on electrochemical properties in PNM. The new bottom-up large scale technology of PNT physical vapor deposition and patterning combined with found physical effects at nanoscale, developed by us, opens the avenue for emerging nanotechnology applications of PNM in novel fields of nanophotonics, nanopiezotronics and energy storage devices. PMID- 21234979 TI - A new family of peptide-nucleic acid nanostructures with potent transfection activities. AB - A family of His-rich peptides has been shown to complex DNA and efficiently deliver these nucleic acids into eukaryotic cells. Therefore, these nanoscale complexes have potential applications in gene therapy. Here, we review a number of spectroscopic and biophysical investigations aimed at characterizing the supramolecular interactions of the peptides with the nucleic acids and when overcoming the membrane barriers of the cell. Furthermore, solid-state NMR distance measurements for the first time reveal close interatomic distances between the amino acid side chains and the DNA phosphates within the transfection complex. A recent study indicates that the peptides are also potent transfectants of siRNAs and they could thereby be of potential interest for gene silencing therapies using these compounds. Copyright (c) 2010 European Peptide Society and John Wiley & Sons, Ltd. PMID- 21234980 TI - Rational design of peptide nanotubes for varying diameters and lengths. AB - Amphiphilic helical peptides (Sar)(m) -b-(L-Leu-Aib)(n) (m = 22-25; n = 7, 8, 10) with a hydrophobic block as a right-handed helix were synthesized and their mixtures with (Sar)(25) -b-(D-Leu-Aib)(6) containing the hydrophobic block as a left-handed helix were examined in their molecular assembly formation. The single component (Sar)(25) -b-(D-Leu-Aib)(6) forms peptide nanotubes of 70 nm diameter and 200 nm length. The two-component mixtures of (Sar)(25) -b-(D-Leu-Aib)(6) with (Sar)(24) -b-(L-Leu-Aib)(7) , (Sar)(22) -b-(L-Leu-Aib)(8) , and (Sar)(25) -b-(L Leu-Aib)(10) yield peptide nanotubes of varying dimensions with 200 nm diameter and 400 nm length, 70 nm diameter and several micrometer length (maximum 30 um), and 70 nm diameter and 100-600 nm length, respectively. The right-handed and the left-handed helix were thus found to be molecularly mixed due to the stereo complex formation and to generate nanotubes of different sizes. When the mismatch of the hydrophobic helical length between the two components was of four residues, the longest nanotube was generated. Correspondingly, the hydrophobic helical segments have to interdigitate with an anti-parallel orientation at the hydrophobic core region of the nanotube. PMID- 21234981 TI - De novo design of orthogonal peptide pairs forming parallel coiled-coil heterodimers. AB - We used the principles governing the selectivity and stability of coiled-coil segments to design and experimentally test a set of four pairs of parallel coiled coil-forming peptides composed of four heptad repeats. The design was based on maximizing the difference in stability between desired pairs and the most stable unwanted combinations using N-terminal helix initiator residues, favorable combinations of the electrostatic and hydrophobic interaction motifs and negative design motif based on burial of asparagine residues. Experimental analysis of all 36 pair combinations among the eight peptides was performed by circular dichroism (CD). On the basis of CD spectra, each peptide formed a high level of alpha helical structure exclusively in combination with its designed peptide partner which demonstrates the orthogonality of the designed peptide pair set. PMID- 21234982 TI - Self-assembly of amphiphilic beta-sheet peptide tapes based on aliphatic side chains. AB - Amphiphilic beta-sheet nanotapes based on the self-assembly of 9mer and 7mer de novo designed beta-strand peptides were studied in the dilute regime. The hydrophobic face of the tapes consisted predominantly of aliphatic (leucine) side chains, while the hydrophilic tape face contained polar side chains (glutamine, arginine and glutamic acid). Both peptides underwent a transition from a monomeric random coil to a self-assembled beta-sheet tape upon increase of peptide concentration in aqueous solutions. P(9) -6 exhibited lower critical concentration (c*) for self-assembly and thus higher propensity for self-assembly in water, compared to the shorter P(7) -6. At neutral pH where there was little net charge per peptide, self-assembly was favoured compared to low pH in which there was a net + 1 charge per peptide; the net charge decreased overall intermolecular attraction, manifested as an increase in c* for self-assembly in low compared to neutral pH aqueous solutions. Propensity for self-assembly and beta-sheet formation was found to be greatly enhanced in a polar organic solvent (methanol) compared to water. These studies combined with future more extensive comparative studies between amphiphilic tapes based on aliphatic amino acid residues and amphiphilic tapes based on aromatic residues will throw more light on the relative importance of hydrophobic versus aromatic interactions for the stabilisation of peptide assemblies. Systematic studies of this kind may also allow us to throw light on the fundamental principles that drive peptide self assembly and beta-sheet formation; they may also lead to a set of refined criteria for the effective design of peptides with prescribed combination of properties appropriate for specific applications. PMID- 21234983 TI - Impact on the replacement of Phe by Trp in a short fragment of Abeta amyloid peptide on the formation of fibrils. AB - Abeta(16-22) (Ac-KLVFFAE-NH(2) ) is one of the shortest amyloid fibril-forming sequences identified in beta-amyloid peptide. At neutral pH, the peptide forms fibrils in the concentration range of 0.2-2.0 mM after >= 10 days of incubation. Structures of the fibrils proposed based on solid-state NMR and MD simulations studies suggest antiparallel arrangement of beta-strands and aromatic interactions between the Phe residues. In an effort to examine the role of aromatic interactions between two Phe residues in Abeta(16-22) , we have studied the self-assembly of Abeta(16-22) (AbetaFF) and two of its variants, Ac-KLVFWAE NH(2) (AbetaFW) and Ac-KLVWFAE-NH(2) (AbetaWF). The peptides were dissolved in methanol (MeOH) at a concentration of 1 mM and in water (AbetaFW and AbetaWF, 1 mM; AbetaFF, 330 uM). Peptide solutions (100 uM) were prepared in 50 mM sodium phosphate buffer at pH 7 by diluting from MeOH and water stock solutions. AbetaFW forms amyloid-like fibrils immediately from MeOH, as indicated by atomic force microscopy. Dilution of AbetaFW into phosphate buffer from stock solution prepared in MeOH results in fibrils, but with different morphology and dimensions. The secondary structure potentiated by MeOH seems to be important for the self-assembly of AbetaFW, as fibrils are not formed from water where the peptide is unordered. On the other hand, AbetaFF and AbetaWF do not form amyloid fibrils rapidly from any of the solvents used for dissolution. However, drying of AbetaWF from MeOH on mica surface gives rod-like and fibrous structures. Our study indicates that positioning of the aromatic residues F and W has an important role to play in promoting self-assembly of the Abeta(16-22) peptides. PMID- 21234984 TI - Photocurrent generation through peptide-based self-assembled monolayers on a gold surface: antenna and junction effects. AB - The photocurrent generation properties of mono- and bi-component peptide-based self-assembled monolayers (SAMs) immobilized on a gold surface were studied by electrochemical and spectroscopic techniques. The peptides investigated comprised almost exclusively C-tetrasubstituted -amino acids. These non-coded residues, because of their unique conformational properties, forced the peptide backbone to attain a helical conformation, as confirmed by X-ray crystal structure and CD determinations in solution. The peptide helical structure promoted the formation of a stable SAM on the gold surface, characterized by an electric macrodipole directed from the C(delta-) to the N(delta+) terminus, that remarkably affected the electron transfer (ET) process through the peptide chain. The peptides investigated were derivatized with chromophores strongly absorbing in the UV region to enhance the efficiency of the photocurrent generation (antenna effect). The influence of the nature of the peptide-gold interface on the ET process (junction effect) was analyzed by comparing the photocurrent generation process in peptide SAMs immobilized on a gold surface through AuS linkages with that in a bi-component SAM embedding a photoactive peptide into the linked palisade formed by disulfide-functionalized peptides. PMID- 21234985 TI - Atomistic modeling of peptides bound to a chemically active surface: conformational implications. AB - This work presents a computational strategy to model flexible molecules tethered to a metallic rigid surface. The method is based on a previously developed procedure for inert surfaces, in which peptide-surface interactions were not considered. This procedure is able to generate uncorrelated relaxed microstructures at the atomistic level of systems containing relatively high densities of peptides tethered to the surface. The reliability of the strategy has been tested by simulating CREKA (Cys-Arg-Glu-Lys-Ala), a short linear pentapeptide that recognizes clotted plasma proteins and selectively homes to tumors, covalently tethered to a gold surface, results being compared with those obtained when the surface was represented as inert. The results indicate that the whole conformational profile of CREKA presents some correlation with the chemical activity of the surface, even though the bioactive conformation was found as the most favored in all cases. Specifically, simulations reflect that consideration of the peptide-surface interactions affect the geometrical orientation of the side chains, whereas the main chain conformation does not undergo significant modifications. PMID- 21234986 TI - Phages recognizing the Indium Nitride semiconductor surface via their peptides. AB - Considerable advances in materials science are expected via the use of selected or designed peptides to recognize material, control their growth, or to assemble them into elaborate novel devices. Identifying specific peptides for a number of technologically useful materials has been the challenge of many research groups in recent years. This can be accomplished by using affinity-based bio-panning methods such as phage display technologies. In this work, a combinatorial library including billions of clones of genetically engineered M13 bacteriophage was used to select peptides that could recognize improved indium nitride (InN) semiconductor (SC) material. Several rounds of biopanning were necessary to select the phage with the higher affinity from the low variant library. The DNA of this specific phage was extracted and sequenced to set up the related specific adherent peptide. Atomic force microscopy (AFM) is used to demonstrate the real affinity of a selected phage for the InN surface. Due to the possibility of its functionalization with biomolecules and its important physical properties, InN is a promising candidate for developing affinity-based optical and electrical biosensors and/or for biomimetic applications. PMID- 21234987 TI - Synthesis and self-assembly of a neoglycopeptide: morphological studies and ultrasound-mediated DNA encapsulation. AB - Self-assembly in peptides and proteins is an often encountered concept, where constituent building blocks are recruited and stabilized, via carefully orchestrated hydrophobic interactions, hydrogen bonding and other non-covalent interactions, to eventually reveal an array of supramolecular aggregates, with defined structural features. This study presents synthesis and self-assembly of a mannosylated peptide in aqueous medium. Turbidimetric assay with Concanavalin A (Con A), a mannose binding protein, was conducted to confirm the presence of hydrophilic mannose group on the exterior surface of self-assembled structures. DNA encapsulation in these soft structures was achieved by ultrasonication of soft spherical structures in the presence of plasmid DNA. PMID- 21234988 TI - Nanoparticles containing octreotide peptides and gadolinium complexes for MRI applications. AB - New mixed nanoparticles were obtained by self-aggregation of two amphiplic monomers. The first monomer (C18)(2) L5-Oct contains two C18 hydrophobic moieties bound to the N-terminus of the cyclic peptide octreotide, and spaced from the bioactive peptide by five units of dioxoethylene linkers. The second monomer, (C18)(2) DTPAGlu, (C18)(2) DTPA or (C18)(2) DOTA, and the corresponding Gd(III) complexes, contains two C18 hydrophobic moieties bound through a lysine residue to different polyamino-polycarboxy ligands: DTPAGlu, DTPA or DOTA. Mixed aggregates have been obtained and structurally characterized by small angle neutron scattering (SANS) techniques and for their relaxometric behavior. According to a decrease of negative charges in the surfactant head-group, a total or a partial micelle-to-vesicle transition is observed by passing from (C18)(2) DTPAGlu to (C18)(2) DOTA. The thicknesses of the bilayers are substantially constant, around 50 A, in the analyzed systems. Moreover, the mixed aggregates, in which a small amount of amphiphilic octreotide monomer (C18)(2) L5-Oct (10% mol/mol) was inserted, do not differ significantly from the respective self assembled systems. Fluorescence emission of tryptophan residue at 340 nm indicates low mobility of water molecules at the peptide surface. The proton relaxivity of mixed aggregates based on (C18)(2) DTPAGlu(Gd), (C18)(2) DTPA(Gd) and (C18)(2) DOTA(Gd) resulted to be 17.6, 15.2 and 10.0 mM(-1) s(-1) (at 20 MHz and 298K), respectively. The decrease in the relaxivity values can be ascribed to the increase in tau(M) (81, 205 and 750 ns). The presence of amphiphilic octreotide monomer exposed on mixed aggregate surface gives the entire nanoparticles a potential binding selectivity toward somatostatin sstr2 receptor subtype, and these systems could act as MRI target-specific contrast agent. PMID- 21234989 TI - Binding analysis of peptides that recognize preferentially cis-azobenzene groups of synthetic polymers. AB - Peptides identified by the PD method against a film surface composed of azobenzene-containing synthetic polymers were characterized by QCM measurements. Among the four peptides analyzed, the c16 peptide with the sequence Trp-His-Thr Leu-Pro-Asn-Ala showed the highest binding affinity to the films rich in cis azobenzene groups. SPR served to determine the association/dissociation constants of the c16 peptide against the trans- and cis-azobenzene groups. The binding constants were estimated to be 1.3 * 10(5) and 1.4 * 10(6) /M, respectively, indicating a high specificity of the c16 peptide for cis-azobenzene conformer. Then mutants of the c16 peptide were synthesized and characterized to gain information on the structural requirements for the cis-form specificity. An Ala scan clearly revealed that all the amino acid residues of the c16 peptide were essential for the specificity. More importantly, the results with peptides of inverted sequence and containing Gly insertions confirmed that the specificity is strictly derived from the primary sequence of the c16 peptide. PMID- 21234990 TI - Walking speed and peak plantar pressure distribution during barefoot walking in persons with diabetes. AB - BACKGROUND: The impact of walking speed has not been evaluated as a feasible outcome measure associated with peak plantar pressure (PPP) distribution, which may result in tissue damage in persons with diabetic foot complications. The objective of this pilot study was to determine the walking speed and PPP distribution during barefoot walking in persons with diabetes. METHODS: Nine individuals with diabetes and nine age-gender matched individuals without diabetes participated in this study. Each individual was marked at 10 anatomical landmarks for vibration and tactile pressure sensation tests to determine the severity of sensory deficits on the plantar surface of the dominant limb foot. A steady state walking speed, PPP, the fore and rear foot (F/R) PPP ratio and gait variables were measured during barefoot walking. RESULTS: Persons with diabetes had a significantly slower walking speed than the age-gender matched group resulting in a significant reduction of PPP at the F/R foot during barefoot walking (p < 0.05). There was no significant difference in F/R foot PPP ratio in the diabetic group compared with the age-gender matched group during barefoot walking (p > 0.05). There was a significant difference between the diabetic and non-diabetic groups for cadence, step time, toe out angle and the anterior posterior excursion (APE) for centre of force (p < 0.05). CONCLUSION: Walking speed may be a potential indicator for persons with diabetes to identify PPP distribution during barefoot walking in a diabetic foot. However, the diabetic group demonstrated a more cautious walking pattern than the age-gender matched group by decreasing cadence, step length and APE, and increasing step time and toe in/out angle. People with diabetes may reduce the risk of foot ulcerations as long as they are able to prevent severe foot deformities such as callus, hammer toe or charcot foot. PMID- 21234993 TI - The sealed osteons of cortical diaphyseal bone. Early observations revisited with scanning electron microscopy. AB - The frequency, structure, mode of formation and significance of sealed osteons remain unsettled. Sealed osteons have been reported as an unusual finding in the cortical bone of experimental animals: we extended the observation to human cortical bone studied with SEM. Tibial bone specimens from three patients who sustained a traumatic below-the-knee amputation were used in the study. The observed total mean density of osteons was 19.25/mm(2) and the percentage of sealed and partially sealed osteons was 4.2% and 1.7% respectively. The material sealing the central canal showed an X-ray microanalysis spectrum with the same Ca/P ratio as the peripheral lamellae and a lower carbon signal. The morphology suggested a reactivation of bone apposition triggered by exclusion of the occluded canal from blood flow rather than a physiological evolution of the closing process of secondary osteons. This presupposes collapse and degeneration of the central vessel before the osteoblasts resting on the inner surface of the canal could start to lay down new bone matrix. This explanation is consistent with a dynamic model of intracortical blood flow. PMID- 21234992 TI - Volumetric reconstruction of the mouse meibomian gland using high-resolution nonlinear optical imaging. AB - Recent studies suggest that mouse meibomian glands (MG) undergo age-related atrophy that mimics changes seen in age-related human MG dysfunction (MGD). To better understand the structural/functional changes that occur during aging, this study developed an imaging approach to generate quantifiable volumetric reconstructions of the mouse MG and measure total gland, cell, and lipid volume. Mouse eyelids were fixed in 4% paraformaldehyde, embedded in LR White resin and serially sectioned. Sections were then scanned using a 20* objective and a series of tiled images (1.35 * 1.35 * 0.5 mm) with a pixel size of 0.44 microm lateral and 2 microm axial were collected using a Zeiss 510 Meta LSM and a femtosecond laser to simultaneously detect second harmonic generated (SHG) and two-photon excited fluorescence (TPEF) signals from the tissue sections. The SHG signal from collagen was used to outline and generate an MG mask to create surface renderings of the total gland and extract relevant MG TPEF signals that were later separated into the cellular and lipid compartments. Using this technique, three-dimensional reconstructions of the mouse MG were obtained and the total, cell, and lipid volume of the MG measured. Volumetric reconstructions of mouse MG showed loss of acini in old mice that were not detected by routine histology. Furthermore, older mouse MG had reduced total gland volume that is primarily associated with loss of the lipid volume. These findings suggest that mice MG undergo "dropout" of acini, similar to that which occurs in human age-related MGD. PMID- 21234994 TI - Foramen magnum ontogeny in Homo sapiens: a functional matrix perspective. AB - Historically, the foramen magnum (FM) has been an integral component of studies on skull ontogeny and evolutionary transformations of cranial form. Although this foramen has been considered a single entity, we hypothesize that it comprises two functional matrices, a ventral matrix and a dorsal matrix. In general, the ventral matrix is related to locomotor functions, whereas the dorsal matrix is related to neurological functions and fluid flow dynamics. To test our hypothesis, we used a large ontogenetic sample of modern human crania (seventh fetal month to adult) to (1) delineate bony size and shape ontogeny for both the foramen and its dorsal and ventral units; (2) delineate the role of synchondroses in the observed growth patterns and rates; and (3) explore the relationship between FM and cranial size, shape, and growth. Detailed growth patterns and rates are established for the bony FM and its ventral and dorsal skeletal units. These data are supplemented by literature and observational data on embryonic and fetal FM ontogeny, soft tissue relationships, anomalous/pathological extremes of size, and craniocervical anatomy and locomotor functions. The hypothesis that the FM is composed of a ventral and a dorsal functional matrix is supported by observed ontogenetic differences between ventral and dorsal skeletal units, as well as by the soft tissue anatomy of these matrices. Further documentation of these matrices has the potential to significantly enhance our understanding of the ontogenetic and evolutionary transformations of skull base morphology. PMID- 21234995 TI - Geometric morphometric analysis of tibial shape and presentation among Catarrhine taxa. AB - The proximal component of the talo-crural joint, the tibia, was compared, using geometric morphometrics, in 240 specimens from 10 extant taxa to identify differences in shape and the factors influencing them. The specimens were laser scanned, digitally reconstructed, and landmarked. Regression analysis was used to evaluate tibial shape, and significant amounts of shape variation among taxa were due to body mass, tibial size, superfamily, and substrate preference in the whole tibia, as well as, separate analysis of the distal tibial articular facets, and the medial malleolar facet. The most important factor for whole tibial shape was tibial robusticity, which closely correlated with body mass. However, substrate preference was also a significant factor in tibial shape and independent from body mass. Substrate preference was also the most important factor defining distal articular morphology. Principal components analysis and pairwise permutation tests were used to compare differences in morphology among taxa. Nearly all were significantly different in overall tibial shape, and distal morphology. Shape and presentational morphology associated with body mass, tibial size, superfamily, and substrate preference were identified, along with the similarities and differences among individual taxa. These were visualized by TPS deformation of an exemplar surface. Relationships among these factors were assessed with their dot-product. Results demonstrated that size significantly influenced proximal presentation, while substrate preference influenced articular morphology. PMID- 21234996 TI - The occurrence and morphology of a lateral metatarsal splint bone in moose (Alces alces). AB - Moose (Alces alces) appear to be different from most other cervids in that a well developed metatarsal splint bone is present. It is found apposed to the plantolateral portion of the cannon bone in over 70 % of adults. It averages 3.3 mm in width and extends about 22% of the total length of the metatarsal. It may be derived through calcification of connective tissue or by elongation of the vestigial metatarsal V. PMID- 21234997 TI - The atrioventricular region of the teleost heart. A distinct heart segment. AB - This article reports the morphological characteristics of the atrioventricular (AV) region of the teleost heart. A total of 29 teleost species belonging to 19 families and 10 orders were analyzed. The study includes hearts with entirely trabeculated ventricles and hearts possessing a ventricular compacta. In all cases, the AV region is formed by a ring of compact myocardium surrounded by a connective tissue ring. The myocardium contains vessels in most species having entirely trabeculated ventricles, and in all species possessing a compacta. The ring of connective tissue is rich in collagen and elastin, partially isolating the AV muscle from the surrounding musculature. Continuity between the AV muscle and the atrial and ventricular musculature is always observed. The AV muscle supports the AV valves, which are formed by two leaflets, lack papillary muscles, show a collagenous fibrosa on the atrial side, and present a variable number of cells and a variable amount of extracellular material. Ventricular trabeculae attach to the AV muscle. These trabeculae may help to bear the stress generated by ventricular contraction and may constitute a preferential pathway for the conduction of electrical impulses. In all teleosts studied, the AV region can be recognized as a distinct morphological segment interposed between the atrium and the ventricle. The morphological characteristics of the AV segment appear to be species specific. PMID- 21234998 TI - Varying assay geometry to emulate connective tissue planes in an in vitro model of acupuncture needling. AB - During traditional acupuncture, fine needles are inserted subcutaneously and rotated, which causes loose fascial tissue to wind around the needle. This coupling is stronger at acupuncture points, which tend to fall above intermuscular fascial planes, than control points, which lay above skeletal muscle. These different anatomical constraints may affect the mechanical coupling. Fascia at acupuncture points is bounded on two sides by skeletal muscle, but at control points is essentially unbounded. These differences were approximated in simple in vitro models. To emulate the narrower boundary within the intermuscular plane, type I collagen was cast in circular gels of different radii. To model the channel-like nature of these planes, collagen was cast in elliptical gels with major and minor axes matching the large and small circular gels, respectively, and in planar gels constrained on two sides. Acupuncture needles were inserted into the gels and rotated via a computer-controlled motor while capturing the evolution of fiber alignment under cross-polarization. Small circular gels aligned faster, but failed earlier than large circular gels. Rotation in elliptical and planar gels generated more alignment-per-revolution than circular gels. Planar gels were particularly resistant to failure. Fiber alignment in circular gels was isotropic, but was stronger in the direction of the minor axis in elliptical and planar gels. In fibroblast-populated gels, cells followed the alignment of the collagen fibers, and also became denser in regions of stronger alignment. These results suggest that the anatomy at acupuncture points provides unique boundaries that accentuate the mechanical response to needle manipulation. PMID- 21234999 TI - Restorative regeneration of digital tips in the African clawed frog (Xenopus laevis daudin). AB - Localized, specialized structures are carried on the tips of digits of many amniote and certain non-amniote tetrapods. The pes of some members of Pipidae represents a rare example among tetrapods of differential expression of digital tip form (clawed vs. non-clawed digits). As a step towards understanding how such localized forms are generated and maintained, we conducted a series of amputation experiments and observed, through the process of regeneration, the potential for reconstitution, at the tissue and organ level, of the different digit tip morphologies. Results of this study reveal that immediately following metamorphosis specialized digit tip structures are regenerated with a high degree of structural and spatial accuracy by a process that essentially replicates normal development in recently metamorphosed Xenopus laevis froglets. Furthermore, this regenerative capacity is maintained in juveniles 4 months beyond metamorphosis, and also in adults of 1 year or more in age, indicating that metamorphosis-specific conditions do not exclusively facilitate regeneration of digit tips. In addition, regenerative capacity is maintained through repeated bouts of amputation and regeneration, indicating deep-seated digit identity and retention of the distinct digit tip developmental programs within the digits. Together, these data suggest that the developmental programing responsible for the formation of the discrete digital tip morphologies is located regionally within each digit, and that it is retained through time. Our results suggest that Xenopus can serve as a model organism for exploring the molecular underpinnings of digit tip formation because regeneration leads to morphologically identical structures to those of the original digit tips. PMID- 21235000 TI - Cochlear labyrinth volume in euarchontoglirans: implications for the evolution of hearing in primates. AB - Using high resolution X-ray computed tomography data we examined the relationship between cochlear labyrinth volume and body mass in extant, non-primate euarchontoglirans, and in two fossils, to allow for comparison with the results of Kirk and Gosselin-Ildari (2009). Modern primates have significantly higher cochlear labyrinth volumes relative to body mass than other euarchontoglirans, which may be related to a downward shift in the highest and lowest audible frequencies over the course of primate evolution, and to the relative increase in brain size observed in Euprimates. PMID- 21235001 TI - Differential expression of metallothionein in gastrointestinal stromal tumors and gastric carcinomas. AB - Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that account for about 2% of gastric tumors. Metallothioneins (MTs) are multifunctional proteins associated with carcinogenesis and known to be coded by 10 functional MT genes. This study evaluated MT mRNA and protein expression in GISTs and compared the expression levels with gastric carcinomas. An immunohistochemical study of MT protein expression was performed in 15 GISTs (specifically located in the stomach) and 38 early stage gastric carcinomas. The percentage of cells stained and intensity of staining were determined. MT-2A mRNA expression was investigated in 6 GISTs and 6 early stage gastric carcinoma patients. All GISTs displayed positive nuclear immunostaining, with most GISTs having predominantly mildly stained nuclei (93.3%). On the other hand, 37 out of 38 gastric carcinoma cases were positively stained for nuclear MT with 24 cases (63.2%) exhibiting predominantly mild nuclear staining, 7 cases (18.4%) moderate nuclear staining, and 6 cases (15.8%) strong nuclear staining. Nuclear MT expression was found to be significantly lower in GIST samples when compared with gastric carcinoma tissues based on the percentage stained and immunoreactive score. We then established that the MT-2A gene transcript was the most abundant MT isoform in MKN28 gastric cancer cells and analyzed its expression in GIST and gastric carcinoma tissues. We found that GISTs had significantly lower MT-2A mRNA levels than gastric carcinoma tissues. Lower MT-2A gene expression and nuclear MT protein expression in GISTs when compared with gastric carcinomas may reflect their different underlying biology and divergent histogenesis. PMID- 21235002 TI - "Anatomical" view of the protein composition and protein characteristics for Gloydius shedaoensis snake venom via proteomics approach. AB - The bioactive protein components from snake venom complexes have been utilized for studies of enzymology, structural biology, and pharmacology. The Gloydius shedaoensis snake (GSS) is the only snake species found exclusively at the Chinese Shedao (snake) Island in Dalian. To investigate the protein components of Chinese GSS venom (GSSV), we initialized a proteomic assay for GSSV by the combination of sodium dodecyl sulfate-polyacrylamide gel electrophoresis with high-performance liquid chromatography (HPLC)-nanoelectrospray ionization tandem mass spectrometry (nESI-MS/MS). Thirty gel bands visualized by Coomassie blue staining were excised and digested by trypsin. The tryptic-digested peptides were separated by HPLC and subsequently sequenced by nESI-MS/MS. Twenty-four types of proteins were identified by searching the mass spectrometry data against NCBInr database through TurboSequest Bioworks. The most abundant proteins are phospholipase A(2) , metalloproteinase, L-amino acid oxidase (LAAO), serine protease/thrombin-like enzyme. Except for 20 types of known snake venom proteins, the homolog peptides of hypothetical protein PFLC2230, LOC495267 protein, DEAD/DEAH box helicase-like, and pancreatic trypsin 1 from other organisms are matched for GSSV protein components. Mass spectrometric data also indicated that (i) dimerization happens to PLA(2) s as monomer and dimer of PLA(2) s coexist in GSSV and (ii) truncation or hydrolysis might happen to LAAOs as three molecular weight-ranged LAAO species are present in GSSV. The results provide an "anatomical" view of the protein composition and important information for protein characteristics of GSSV. PMID- 21235003 TI - Expression of utrophin at dystrophin-deficient neuromuscular synapses of mdx mice: a study of protected and affected muscles. AB - In mdx mice, intrinsic laryngeal muscles are spared and sternomastoid muscles are affected, showing cycles of muscle regeneration. We observed that utrophin and acetylcholine receptors are fragmented only in affected muscles, providing further evidence that changes in the overall distribution of molecules at dystrophic neuromuscular junctions may be correlated with muscle regeneration. PMID- 21235004 TI - Effects of fibrillar Abeta(1-40) on the viability of primary cultures of cholinergic neurons and the expression of insulin signaling-related proteins. AB - To investigate the effects of fibrillar Abeta(1-40) on the morphology and viability of cholinergic neurons and the involvement of the insulin-signaling pathway, we established primary cultures of rat basal forebrain cholinergic neurons and observed their responses to treatment with fibrillar Abeta(1-40) at different concentrations for different durations. Cell morphology was examined under microscope after immunofluorescence staining for neurofilament protein, cell vitality accessed by the Methyl thiazolyl tetrazolium assay, and expressions of a panel of insulin signaling-related proteins was detected by Western blot analysis. We show here that, at low concentrations of 0.1-1.0 micromol/L, fibrillar Abeta(1-40) had little effects on the cells; however, at higher concentrations of 2-10 MUmicromol/L, it caused pathological changes, decreased the cell viability, and reduced the expression of insulin receptor, insulin receptor substrate-I, Protein Kinase B, and B cell lymphoma/leukemia-2 in a dose- and time-dependent manner. These results demonstrate that fibrillar Abeta(1-40) not only decreases the viability of cholinergic neuron but also down regulates the expression of important proteins in the insulin signal transduction pathway. We speculate that fibrillar Abeta(1-40) may contribute to the pathogenesis of Alzheimer's through disrupting the insulin signaling pathway, therefore decreasing neuronal activity and eventually leading to the apoptosis and cell loss. PMID- 21235005 TI - Locations of the motor endplate band and motoneurons innervating the sternomastoid muscle in the rat. AB - Sternocleidomastoid (SCM) is a long muscle with two bellies, sternomastoid (SM) and cleidomastoid (CM) in the lateral side of the neck. It has been widely used as muscle and myocutaneous flap for reconstruction of oral cavity and facial defects and as a candidate for reinnervation studies. Therefore, exact neuroanatomy of the SCM is critical for guiding reinnervation procedures. In this study, SM in rats were investigated to document banding pattern of motor endplates (MEPs) using whole-mount acetylcholinesterase (AChE) staining and to determine locations of the motoneurons innervating the muscle using retrograde horseradish peroxidase (HRP) tracing technique. The results showed that the MEPs in the SM and CM were organized into a single band which was located in the middle portion of the muscle. After HRP injections into the MEP band of the SM, ipsilaterally labeled motoneurons were identified in the caudal medulla oblongata (MO), C1, and C2. The SM motoneurons were found to form a single column in lower MO and dorsomedial (DM) nucleus in C1. In contrast, the labeled SM motoneurons in C2 formed either one (DM nucleus), two [DM and ventrolateral (VL) nuclei], or three [DM, VL, and ventromedial (VM)] columns. These findings are important not only for understanding the neural control of the muscle but also for evaluating the success rate of a given reinnervation procedure when the SM is chosen as a target muscle. PMID- 21235006 TI - Lectins as a tool for detecting neural stem/progenitor cells in the adult mouse brain. AB - Glycoconjugates are biopolymers that are broadly distributed in the central nervous system, including the cell surface of neural stem cells or neural precursor cells (NSCs/NPCs). Glycoconjugates can be recognized by carbohydrate binding proteins, lectins. Two lectins, Phaseolus vulgaris lectin agglutinin E form (PHA-E4) and wheat germ agglutinin (WGA) have been reported to be useful in isolating NSCs/NPCs by fluorescence-activated cell sorting (FACS) or immunopanning methods. In this study, we analyzed the lectin-binding properties of NSCs/NPCs in two neurogenic regions of the adult mouse brain to determine whether PHA-E4 and WGA exhibit specific binding patterns on sections and whether there are other lectins presenting the binding pattern similar to those of PHA-E4 and WGA in lectin histochemistry. Among nine types of lectins, peanut agglutinin was localized to the white matter and four lectins bound to cells within the subventricular zone (SVZ) of the lateral ventricle. Lectin histochemistry combined with immunohistochemistry demonstrated that one lectin, Ricinus communis agglutinin, specifically detected type A neuronal precursors and that the remaining three lectins, Agaricus bisporus agglutinin (ABA), PHA-E4, and WGA, recognized type B NSCs and type C transient amplifying cells in the SVZ. These three lectins also recognized type 1 quiescent neural progenitors and type 2a amplifying neural progenitors in the subgranular layer of the dentate gyrus. Lectin histochemistry of the neurosphere culture also yielded similar results. These observations suggest that, in addition to PHA-E4 and WGA, ABA lectin may also be applicable in FACS or immunopanning for the isolation of NSCs/NPCs. PMID- 21235007 TI - Allometric and metameric shape variation in Pan mandibular molars: a digital morphometric analysis. AB - The predominance of molar teeth in fossil hominin assemblages makes the patterning of molar shape variation a topic of bioanthropological interest. Extant models are the principal basis for understanding dental variation in the fossil record. As the sister taxon to the hominin clade, Pan is one such model and the only widely accepted extant hominid model for both interspecific and intraspecific variation. To explore the contributions of allometric scaling and meristic variation to molar variation in Pan, we applied geometric shape analysis to 3D landmarks collected from virtual replicas of chimpanzee and bonobo mandibular molars. Multivariate statistical analysis and 3D visualization of metameric and allometric shape vectors were used to characterize shape differences and test the hypothesis that species of Pan share patterns of metameric variation and molar shape allometry. Procrustes-based shape variables were found to effectively characterize crown shape, sorting molars into species and tooth-row positions with >= 95% accuracy. Chimpanzees and bonobos share a common pattern of M(1) -M(2) metameric variation, which is defined by differences in the relative position of the metaconid, size of the hypoconulid, curvature of the buccal wall, and proportions of the basins and foveae. Allometric scaling of molar shape is homogeneous for M(1) and M(2) within species, but bonobo and chimpanzee allometric vectors are significantly different. Nevertheless, the common allometric shape trend explains most molar-shape differences between P. paniscus and P. troglodytes. When allometric effects are factored out, chimpanzee and bonobo molars are not morphometrically distinguishable. Implications for hominid taxonomy and dietary reconstruction are discussed. PMID- 21235008 TI - Nandrolone decanoate and physical effort: histological and morphometrical assessment in adult rat uterus. AB - In the past decades, the therapeutic use of anabolic androgenic steroids (AAS) has been overshadowed by illicit abuse of these drugs by athletes and non athletes. Since that AAS can affect the reproductive tract, resulting in reproduction and fertilization damages, the purpose of this study was to investigate the nandrolone decanoate (ND) effects, associated or not with physical effort, on the uterine histomorphometric parameters. Female Wistar rats, sedentary or not, were exposed to treatment with ND by intraperitoneal injection (5 mg/kg/day, once a week) during four consecutive weeks. Control animals, sedentary or not, received vehicle alone (propylene glycol) in the same manner. The physical activity was forced swimming (20 min/day). During the experiment, all animals were monitored by daily vaginal smears. After 30 days of treatment, the females were sacrificed and their uteri collected and examined under light microscopy techniques. The ND-treated females showed estrus acyclicity and decreased thickness of both the epithelium and endometrial stroma. A reduction in the number and size of blood vessels was also found in ND-treated rats submitted to physical effort when compared to ND sedentary rats. ND-treated rats, regardless of exercise, exhibited stromal fibrosis and reduced gland ducts that displayed high mitotic activity. A remarkable widespread presence of leukocytes occurred in rats receiving ND and submitted to exercise. These results suggest that ND associated or not with physical effort causes histomorphometric changes to the rat uterus. PMID- 21235009 TI - Apoptosis in the uterotubal junction and oviductal isthmus during the estrous cycle of the bitch. AB - Apoptotic cells were evaluated in the lamina epithelialis (LE) and lamina propria (LP) of the canine uterotubal junction and oviductal isthmus by means of the TUNEL assay and Caspase-3 detection regarding cyclic changes. Oviducts of bitches in anestrus, early and late follicular phase, 2 and 4 days after ovulation, mid luteal phase, and endometrial reparation were available. The rate of apoptosis was generally low (min = 0; max = 33 apoptotic cells in 500 cells). Regardless of the stage of the estrous cycle, the number of apoptotic cells was significantly higher in the LE compared to the LP (P < 0.05). In anoestrus, early and late follicular phase as well as during endometrial reparation, the number of apoptotic cells was on a constantly low level. A significant increase was found 4 days after ovulation by caspase-3 detection coinciding with early luteal development and in mid-luteal phase. The results demonstrate that the number of apoptotic cells changes depending on the stage of the ovarian cycle. The coincidence of the increase in the number of apoptotic cells and the time of achievement of oocyte competence, which is known to occur in the bitch 3-4 days after ovulation, suggests a causal relationship between the postovulatory maturation stage of oocytes and the rate of apoptosis in the caudal oviduct. Furthermore, a specific relevance of apoptosis may exist in the process of fertilization regarding sperm storage and detachment of spermatozoa bound to the epithelium of the caudal oviduct, which has been identified as a functional sperm reservoir in other species. PMID- 21235010 TI - Cloacal morphology in Bolitoglossa nicefori (Caudata: Plethodontidae): Variation during the reproductive cycle. AB - Male and female plethodontid salamanders have specialized cloacal glands associated with the reproductive activity. The reproductive cycle in Bolitoglossa nicefori is characterized by males that are potentially reproductive throughout the year, and females that are reproductive only for a few months. To determine whether morphological and histochemical variation occur in cloacal structures related to reproductive activity, the cloacal region of male and female specimens of B. nicefori was studied in different stages of their annual reproductive cycle using light microscopy and compared with features reported in other plethodontid salamanders. The main anatomy and histology of the male and female cloacal regions of B. nicefori are similar to those of other salamanders; however, in comparison to other Bolitoglossa previously studied, B. nicefori has a relatively larger cloacal tube and a tubular rather than acinar spermatheca. As a common trait, the spermatheca has a common tube that diverges into two tubules, before branching into spermathecal tubules, horizontally arranged on frontal planes. The secretions of the spermathecal glands differed between reproductive and nonreproductive adult females. This secretory product consists of prevailing neutral carbohydrates that were related to the increase in ovarian follicular size during the breeding season. Sperm was found only in the spermatheca of reproductive periovulatory females, suggesting that the reproductive cycle involves a no long-term storage of sperm. Although males can produce sperm throughout the year, spermatophores, namely specialized structures involved in sperm transport, were found in their cloaca only during the breeding season. In these males, some of the cloaca-associated glands were seen to undergo change their secretory activity and their secretory products were related to spermatophore formation. PMID- 21235011 TI - Identification of N-acetylgalactosamine in carbohydrates of Xenopus laevis testis. AB - Identification of glycans in amphibian testis has shown the existence of N acetylgalactosamine (GalNAc)-containing carbohydrates. Labeling of the sperm acrosome with GalNAc-binding lectins has allowed the identification of GalNAc containing glycans in this organelle. Futhermore, this specific labeling of the acrosome has allowed the study of acrosomal biogenesis by lectin histochemistry. However, the testis of Xenopus laevis has never been analyzed by lectin histochemistry to locate GalNAc-containing glycoconjugates. The aim of this work was to elucidate the expression of GalNAc in glycoconjugates of Xenopus testis using five specific lectins. The results showed that most of the lectins labeled the interstitium with variable intensity. However, labeling of the different spermatogenetic germ cell types showed different labeling patterns. Some lectins produced weak or very weak staining in germ cells, for example, horse gram Dolichos biflorus agglutinin, which labeled most of the germ cell types, and lima bean Phaseolus lunatus agglutinin, which weakly labeled only spermatogonia, but did not stain other germ cells. By contrast, Maclura pomifera lectin (MPL) moderately labeled all germ cell types, except mature sperm. Labeling with other lectins was seen only at later stages, suggesting variations involved in the spermatogenetic development. Thus, snail Helix pomatia agglutinin labeled spermatids, but neither spermatogonia nor spermatocytes, while soybean Glycine max agglutinin (SBA) labeled from preleptotene spermatocytes to later stages. The periphery of the acrosome was labeled with MPL and SBA, but no specific labeling of the acrosomal content was seen with any lectin. Thus, the GalNAc-binding lectins that have been used as acrosomal markers in some amphibians cannot be used in Xenopus testis, suggesting that acrosomal glycoconjugates in amphibians are species specific. PMID- 21235020 TI - [Online programs for patients with anxiety. Please log in for therapy! (interview by Waldtraud Paukstadt)]. PMID- 21235021 TI - [Adverse effects of radiation therapy. Skin and mucous membrane "under fire"]. PMID- 21235022 TI - The utility of proteomics in gynecologic cancers. AB - PURPOSE OF REVIEW: For more than a decade, proteomic techniques have been used to unravel the nature and function of human proteins. In 2002 it came to the attention of clinicians that this technique could be used to discover new biomarkers. However, the first reports were hampered by technical and methodological flaws. Since these first reports, proteomics has matured and the technical abilities have grown enormously. An in-depth analysis of fluid or tissue specimens is now possible. We reviewed recent literature to see whether proteomics has changed our clinical practice in the diagnosis and treatment of gynecological cancers. RECENT FINDINGS: In ovarian cancer a great effort has been put into discovering new diagnostic and screening markers. Several proteins have been put forward as possible candidates to fulfill this task. However, none of the proteins turned out to be better than CA125 alone. In endometrial cancer many of the presumed tumor markers are not specific for endometrial cancer but are more tumor markers for cancer in general. The same problem was noticed in cervical cancer. Papers are now focusing more on therapy response and carcinogenesis. SUMMARY: To date, proteomic studies have not been able to change our clinical practice in gynecological oncology. PMID- 21235024 TI - Abstracts of the World Stroke Congress 2010. October 13-16, 2010. Seoul, Republic of Korea. PMID- 21235025 TI - Abstracts of the Fourth European Nursing Congress - Older Persons: the Future of Care. October 4-7 2010. Rotterdam, The Netherlands. PMID- 21235027 TI - Abstracts of the European College of Veterinary Surgeons 19th Annual Scientific Meeting, July 1-3, 2010, Helsinki, Finland and the 2010 American College of Veterinary Surgeons Veterinary Symposium, October 21-23, 2010, Seattle, Washington, USA. PMID- 21235023 TI - Update on sentinel lymph node evaluation in gynecologic malignancies. AB - PURPOSE OF REVIEW: Sentinel lymph node (SLN) dissections have been shown to be sensitive for the evaluation of nodal basins for metastatic disease and are associated with decreased short-term and long-term morbidity when compared with complete lymph node dissection. There has been increasing interest in the use of SLN technology in gynecologic cancers. This review assesses the current evidence based literature for the use of SLN dissections in gynecologic malignancies. RECENT FINDINGS: Recent literature continues to support the safety and feasibility of SLN biopsy for early stage vulvar cancer with negative predictive value approaching 100% and low false negative rates. Alternatively, for endometrial cancer most studies have reported low false-negative rates, with variable sensitivities and have reported low detection rates of the sentinel node. Studies examining the utility of SLN biopsy in early-stage cervical cancer remain promising with detection rates, sensitivities, and false-negative rates greater than 90% for stage 1B1 tumors. SUMMARY: SLN dissections have been shown to be effective and safe in certain, select vulvar cancer patients and can be considered an alternative surgical approach for these patients. For endometrial and cervical cancer, SLN dissection continues to have encouraging results and however needs further investigation. PMID- 21235028 TI - The importance of diversity in veterinary medicine. PMID- 21235029 TI - Thoughts on staying relevant in food animal care. PMID- 21235030 TI - Reaching out to undeserved populations. Highlights from programs to improve cancer disparities. PMID- 21235032 TI - Human organ and tissue transplantation. Resolution WHA 63.22 of the Sixty-Third World Health Assembly. PMID- 21235031 TI - Incorporating fertility preservation into the care of young oncology patients. AB - As the number of cancer survivors continues to increase, oncologists are faced with the challenge of providing cancer therapy to patients who may 1 day want to have children. Yet, gonadotoxic cancer treatments can compromise future fertility, either temporarily or permanently. There are established means of preserving fertility before cancer treatment; specifically, sperm cryopreservation for men and in vitro fertilization and embryo cryopreservation for women. Several innovative techniques are being actively investigated, including oocyte and ovarian follicle cryopreservation, ovarian tissue transplantation, and in vitro follicle maturation, which may expand the number of fertility preservation choices for young cancer patients. Fertility preservation may also require some modification of cancer therapy; thus, patients' wishes regarding future fertility and available fertility preservation alternatives should be discussed before initiation of therapy. This commentary provides an overview of the range of fertility preservation options currently available and under development, using case-based discussions to illustrate ways in which fertility preservation can be incorporated into oncology care. Cases involving breast cancer, testicular cancer, and rectal cancer are described to illustrate fertility issues experienced by male and female patients, as well as to provide examples of strategies for modifying surgical, medical, and radiation therapy to spare fertility. Current guidelines in oncology and reproductive medicine are also reviewed to underscore the importance of communicating fertility preservation options to young patients with cancer. PMID- 21235033 TI - Zoledronic acid use in cancer patients: more than just supportive care? AB - Bone is the most common site for metastasis from solid tumors, and the majority of patients will develop bone metastases during the natural course of their disease. Bisphosphonates are an effective treatment for preventing skeletal related events in patients with bone metastases and may preserve functional independence and quality of life. Although several bisphosphonates have been investigated in patients with solid tumors, only zoledronic acid (ZOL) is approved by the US Food and Drug Administration and the European Medicines Agency for preventing skeletal-related events in patients across a broad range of solid tumors. In addition, bisphosphonates, notably ZOL, prevent cancer treatment induced bone loss in breast and prostate cancer patients who are receiving endocrine therapy. It also has been demonstrated that ZOL directly and indirectly inhibits cancer cell growth in vitro and growth and tumorigenesis in animal model systems. These properties may produce clinically meaningful benefits. In recent clinical studies in patients with cancer, ZOL improved overall and prolonged disease-free survival. Ongoing clinical trials in patients with solid tumors will provide further insight into the potential of ZOL to prevent distant metastases and improve survival. PMID- 21235034 TI - WHO Guiding Principles on Human Cell, Tissue and Organ Transplantation. AB - In May 2010, the Sixty-third World Health Assembly Resolution WHA63.22 endorsed the WHO Guiding Principles, updated in the light of changes in practices and attitudes regarding organ and tissue transplantation. The Guiding Principles are intended to provide an orderly, ethical and acceptable framework for the procurement and transplantation of human cells, tissues and organs for therapeutic purposes. Each jurisdiction will determine the means of implementing these WHO Guiding Principles.They preserve the essential points of the 1991 version while incorporating new provisions in response to current trends in transplantation, particularly the protection of the living donor, and the increasing use of human cells and tissues. The Guiding Principles stress the necessity of documentation and transparency, both for quality management purposes and to justify the confidence of patients, clinicians and the community at large in donation and transplantation services. PMID- 21235035 TI - Letter to the editor. Cultural competence: a necessity for the 21st century. PMID- 21235036 TI - A guide to developing a culturally competent organization. AB - The journey to organizational cultural competence for a health care organization, educational setting, freestanding clinic, or long-term-care organization is a process that requires the collaborative efforts from people at all levels in every department as well as external consumers such as public policy officials, students, and community leaders. Broadly speaking, four main but overlapping areas must be considered in institute activities and strategies to accomplish a comprehensive culturally competent organization. These four areas are (a) administration and governance, (b) orientation and education, (c) language, and (d) staff competencies. This article presents key content areas and activities to consider on the journey to cultural competence. Tables with suggested departmental responsibilities for implementation are included. In some cases, the journey may best be facilitated by a consultant who is well versed in cultural competence and organizational dynamics. PMID- 21235037 TI - Social energy exchange theory for postpartum depression. AB - Postpartum depression (PPD), a significant health problem affecting about 19.4% of postpartum women worldwide, may result in long-term cognitive and behavior problems in children, spousal depression, widespread family dysfunction, and chronic and increasingly severe maternal depression. Although current theoretical frameworks provide a rich context for studying PPD,none provides a framework that specifically addresses the dynamic relationship of the inner personal experience with the social and cultural context of PPD. The authors propose the social energy exchange theory for postpartum depression to understand how PPD impedes this dynamic relationship and suggest it as a theoretical framework for the study of interventions that would target intra- and interpersonal disturbance within the social and cultural context. PMID- 21235038 TI - Letter to the editor: Concomitant fungal and bacterial atlanto-axial osteomyelitis: a case report. PMID- 21235040 TI - Willingness to try acupuncture again: reports from patients on their treatment reactions in a low back pain trial. AB - BACKGROUND: Reactions to treatment are common following acupuncture. Understanding how these reactions are interpreted by patients is largely unexplored. OBJECTIVE: To examine patients ratings of the severity and bothersomeness of a range of common treatment reactions, and to assess their impact on willingness to try acupuncture again. METHODS: Self-reported ratings of the frequency, severity and bothersomeness of treatment reactions from 133 patients in the acupuncture arm of a pragmatic randomised controlled trial of acupuncture for chronic back pain are described and analysed. RESULTS: A total of 133 acupuncture patients reported at3 months reactions that they had experienced at anytime during a course of up to 10 acupuncture treatment sessions. They received a total of 1150 treatments, an average of 8.6 sessions per patient. All patients reported treatment reactions, most commonly relaxation (84%,n = 112), which was significantly associated with willingness to try acupuncture again, (chi2 = 7.860,df = 1, p = 0.005). Only 16% (n=21) were unwilling to experience a specific treatment reaction again, and 9%(n = 12) were unwilling to try acupuncture again. The most bothersome reaction was a temporary worsening of symptoms (29%, n=38), though this was not associated with an unwillingness to try acupuncture again (chi2 = 0.382, df = 1, p>0.536). Those unwilling to try acupuncture again reported significantly less reduction in their pain at 3 months (mean (SE) SF-36 bodily pain score at 3 months 30.453 (3.598) vs 19.30(1.128); p=0.003). CONCLUSION: Among this group of patients seeking help for low back pain, the experience of treatment reactions was universal. There was no evidence that the bothersomeness of treatment reactions was associated with patient's willingness to try acupuncture again. The benefit of pain reduction over the course of treatment appeared to outweigh self-rated bothersome reactions to treatment. PMID- 21235039 TI - Clinical outcomes for patients with soft tissue sarcoma of the hand. AB - BACKGROUND: In an earlier report from the current study center regarding surgical treatment for patients with soft tissue sarcoma (STS) of the hand, it was concluded that repeat resection or amputation improves outcomes. Since then, the authors have aggressively sought to achieve negative resection margins, using standard or modified amputations when needed, and performing repeat resections to negative surgical margins when they were not achieved at the time of initial surgery. The current review was conducted to determine whether this approach resulted in better outcomes. METHODS: A retrospective review of 53 patients with STS of the hand who were treated between 1996 and 2005 was performed. Recurrence free survival (RFS) and functional outcome of hand-preserving procedures were assessed according to the Musculoskeletal Tumor Society (MSTS) system. RESULTS: The median RFS was not reached at the time of last follow-up. Of 53 patients, 6 (11%) had positive microscopic resection margins. Three patients underwent repeat resection to negative surgical margins, whereas another 3 patients did not. All 3 patients with positive microscopic surgical margins that were not re-excised developed local disease recurrence; 2 patients also developed distant metastases. Two of the 50 patients with negative resection margins developed distant metastases. All 5 patients who developed local and/or distant disease recurrence had deep tumors. The median MSTS score was 29 (interquartile range, 27-30). Patients who underwent more extensive resections, such as double ray amputations, had lower MSTS scores. CONCLUSIONS: Suboptimal biopsies and positive resection margins are associated with local and distant disease recurrence in patients with STS. The results of the current study suggest that aggressive surgical treatment can result in better clinical outcomes, and underscore that care must be taken when planning biopsies of hand tumors. PMID- 21235041 TI - The comprehensive spending review on mental health problems. PMID- 21235043 TI - The comprehensive spending review a lot of bad news. PMID- 21235044 TI - Fight for your rights. PMID- 21235045 TI - Sail away. PMID- 21235046 TI - Out of the margins. PMID- 21235049 TI - Smaller budgets will have bigger impacts for social care. PMID- 21235050 TI - Women with borderline personality disorder in prison. PMID- 21235051 TI - Doctor's orders. PMID- 21235052 TI - Perspectives. Volunteering is a great way to aid recovery. PMID- 21235053 TI - Modernisation, personalisation and cuts. PMID- 21235054 TI - Viewpoint. Alzheimer's drugs debate. PMID- 21235055 TI - The personal touch. PMID- 21235056 TI - Making drama out of a crisis. PMID- 21235057 TI - On the record: Robyn Steward. Interview by Alita Howe. PMID- 21235058 TI - [Mast cell and substance P are involved in the process of acupoint sensitization induced by acute gastric mucosal injury]. AB - OBJECTIVE: To observe changes of mast cells (MCs) number and morphology, and substance P (SP) expression in Evans blue (EB) extravasated region around acupoint "Pishu" (BL 20) and "Weishu" (BL 21) after acute gastric mucosal injury (AGMI) so as to investigate the mechanism underlying visceral problems-induced acupoint activation. METHODS: Thirty adult Wistar rats were randomly divided into normal control (n = 15) and AGMI groups (n = 15). AGMI model was duplicated by perfusing the rats with 0.5 mol/L HCl (1 mL/100 g) after fasting for 20 h. Five hours after AGMI, the rats were treated by tail-intravenous injection of EB dye (5 mg/100 g, 50 mg/mL in normal saline) for inducing dye-plasma extravasation in the skin around BL 20, BL 21 regions, etc. at the back. The rats of the normal control group were treated with tail-intravenous injection of 0.9% NaCl. The skin and subcutaneous tissues (2 mmx 2 mm) of extravasated EB dye points (BL 20 or BL 21 region) and those 2 mm lateral to the extravasated EB dye points in the model group and the corresponding points in the normal control group were sampled (followed by fixing them in 4% paraformaldehyde), sectioned and stained by toluidine blue (for labeling MCs). The expression of SP in the extravasated EB dye skin and subcutaneous tissues was detected by immunohistochemistry (n = 5) and western blot (n = 5) respectively. The number of MCs in these samples was counted and the degranulation rate of MCs calculated. RESULTS: The total number of MCs and the number of degranulated MCs were significantly more in the EB extravasation points (corresponding to BL 20/BL 21 area) of AGMI group than those in the control spots of AGMI group and than those in the normal control group (P < 0.05, P < 0.001). The degranulation rate of MCs was significantly higher in the EB extravasation points of AGMI group than those in the control spots of AGMI group and in the normal control group (P < 0.01). In comparison with normal control group, the SP expression level was increased consideraly in the control spots of AGMI group and AGMI group (P < 0.01). CONCLUSION: After AGMI, the numbers of MCs and the degranulated MCs, and the SP expression level in BL 20/BL 21 area were increased significantly, suggesting an involvement of MCs and SP in the process of AGMI-induced activation of acupoints. PMID- 21235059 TI - [Effect of electroacupuncture on hippocampal apoptosis and JNK signal pathway in chronic stress depression rats]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) on hippocampal apoptosis and c-Jun N-terminal kinase (JNK) signal pathway in chronic stress depression rats so as to study its mechanism underlying acupuncture-induced improvement of depression. METHODS: Sixty-five SD rats were randomly divided into control, control + EA, model, EA and Prozac groups, with 13 rats in each. Open field test was used to detect the rats' behavior changes. The apoptotic rate of the hippocampal cells was detected by Annexin V fluorescein isothiocyanate (FITC)/ Propidium iodide (PI) (Annexin V-FITC/PI) double-staining, and the expression of hippocampal JNK protein detected by Western blot. RESULTS: After repeated stress stimulation (21 days), the crossing numbers (1.8 +/- 0.2) and rearing times (0.5 +/- 0.01) in the model group were apparently lower than those (48.1 +/- 18.3, 14.2 +/- 2.4) in the control group and those (47.2 +/- 15.8, 13.5 +/- 2.6) in the control + EA group (P < 0.05). Compared with the model group, the crossing numbers and rearing times (40.2 +/- 10.1, 10.3 +/- 2.2) during 3 min in the EA group and those (39.8 +/- 12.4, 10.6 +/- 3.2) in the Prozac group were increased considerably (P < 0.05). The hippocampal apoptotic rate was significantly higher in the model group (67 +/- 10) than in the control (53 +/- 13) and control + EA groups (52 +/- 10, P < 0.05). In comparison with the model group, the apoptotic rate (29 +/- 9) of the EA group and that (51 +/- 13) of the Prozac group were significantly lower (P < 0.05). Compared with the control group, the phosphorylated JNK (p-JNK) level was considerably higher in the model group (P < 0.05); while compared with the model group, the p-JNK level was significantly lower in the EA and Pozac groups (P < 0.05). No apparent differences were found between the EA and and Prozac groups in the aforementioned indexes (P > 0.05). CONCLUSION: EA can reduce hippocampal apoptotic rate and down regulate hippocampal p-JNK level in depression rats, which is responsible for its effect in improving depression-induced decreased movement. PMID- 21235060 TI - [Effects of electroacupuncture of different acupoints on changes of blood pressure and autonomic nerve system after colorectal distension in rats]. AB - OBJECTIVE: To observe the influence of electroacupuncture (EA) of different acupoints on changes of mean arterial pressure (MAP), heart rate (HR) and heart rate variability (HRV) in colorectal distension (CRD) rats, so as to analyze the specificity of actions of acupoints in relieving visceral pain and regulating activities of the autonomic nerve system. METHODS: Forty-five Wistar rats were randomized into control, Zusanli (ST 36), non-acupoint, Neiguan (PC 6) and Taichong (LR 3) groups (n = 9/group). Under anesthesia, CRD was given to the rats by using an aerostat for 5 min. EA (2 Hz/15 Hz, 2 mA) was applied to bilateral ST 36, non-acupoint (1.0 cm lateral to ST 36), PC 6 and LR 3 for 15 min, respectively. Electrocardiogram of the cervico-chest lead was recorded by using a bioelectric amplifier, and MAP recorded by using a pressure transducer and an amplifier. Low frequency and high frequency of HRV were analyzed by Chart 5.0. RESULTS: Following CRD, the HR, MAP, LF and LF/HF levels increased significantly in all the 5 groups (P < 0.05), while HF had no apparent changes (P > 0.05). Compared with the control group, 5 min and 15 min after EA ,and 10 min after ceasing EA, MAP values of ST 36 and PC 6 groups were decreased obviously (P < 0.05). The HR values of ST 36 and PC 6 groups at 15 min after EA and 10 min after ceasing EA were decreased markedly in comparison with those of each of the other groups during CRD (P < 0.05). The LF levels of both ST 36 and PC 6 groups at 5 min after EA, and those of ST 36, PC 6 and LR 3 at 15 min after EA were significantly lower than those of control group (P < 0.05). LF/HF levels of ST 36 and PC 6 at 10 min after ceasing EA were obviously lower than those of control group (P < 0.05). No significant differences were found among ST 36, non acupoint, PC 6 and LR 3 groups in HR, LF and LF/HF (P > 0.05). CONCLUSION: EA of ST 36 and PC 6 can suppress CRD-induced increase of MAP, HR and LF/HF, suggesting beneficial effects of EA in relieving visceral pain and mediating autonomic nerve system. The aforementioned effects of EA of LR 3 and non-acupoint are not obvious. PMID- 21235061 TI - [Effects of electroacupuncture of "Sanyinjiao" (SP 6) on contents of MDA and beta EP, and expression of HSP 70 in the uterus in rats with dysmenorrhea]. AB - OBJECTIVE: To investigate the effect of electroacupuncture (EA) of "Sanyinjiao" (SP 6) on the uterus in dysmenorrhea rats so as to study its underlying analgesic mechanism. METHODS: A total of 48 SD rats during diestrus were randomized into normal saline (control) group, model group and acupuncture group according to a random number table, with 16 rats in each group. Dysmenorrhea model was established by subcutaneous injection of Estradiol benzoate (0.5 mg/d on the 1st and 10th day, and 0.2 mg/d from day 2 to day 9, once daily for 10 days) and oxytocin (2 U/rat, once on day 10). Malondialdehyde (MDA) and beta-endorphin (beta-EP) contents in the uterus were detected by radioimmunoassay, and the heat shock protein 70 (HSP 70) immunoactivity of the uterus was detected by immunohistochemistry. RESULTS: In comparison with the control group, MDA content in the uterus was increased significantly in the model group (P < 0.01), while the beta-EP level and the immunoactivity of HSP 70 immune-reaction (IR) positive products in the uterus decrease significantly (P < 0.01) and moderately, respectively in the model group. In comparison with the model group, uterine MDA content in the EA group was decreased significantly (P < 0.01), while uterine beta-EP level increased considerably (P < 0.01) and HSP 70 expression was upregulated to a certain degree. CONCLUSION: EA of "Sanyinjiao" (SP 6) can reduce MDA content and upregulate beta-EP level of the uterus in rats with dysmenorrhea, which may contribute to its analgesic effect in relieving dysmenorrhea by clearing away oxygen free radicals and raising analgesic substance in the uterus. PMID- 21235062 TI - [Effect of electroacupuncture on proliferation and differentiation of neural stem cells in the subependymal zone of the cerebral lateral ventricle in rats with hyperlipemia and cerebral ischemia]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) on the expression of vimentin and beta-Tubulin (Tju-1) in the dorsolateral extension and the lateral wall of the lateral ventricle (both of which belong to the subependymal ventricular zone, SVZ) on the ischemic side of the brain in rats with hyperlipemia (HL) plus cerebral ischemia (CI) so as to study its underlying mechanism in relievting HL, CI and combined HL and CI by regulating the proliferation and differentiation of neural stem cells. METHODS: Seventy two male SD rats were randomized into control, HL, HL + EA, CI, CI + manual acupuncture (MA), HL + CI, HL + CI + EA I and HL + CI + EA II groups, with 9 cases in each. HL model was established by feeding the animals with high fat forage for 6 weeks and CI model was duplicated by occlusion of the unilateral middle cerebral artery induced by regional application of FeCl3. For rats of HL+ EA group, EA (15 Hz, 1 3 mA) was applied to bilateral "Sanyinjiao" (SP 6) and "Fenglong" (ST 40) for 20 min, once daily for 17 days. For rats of CI+ MA group, "Baihui" (GV 20) and "Shuigou" (GV 26) were punctured and stimulated manually for 1 min (the former with the needle retained for 20 min), once daily for 7 days. For rats of HL+ CI + EA I group, bilateral "Sanyinjiao" (SP 6) and "Fenglong"(ST 40) were stimulated electrically after needle-insertion, once daily for 10 days, followed by duplicating CI model and performing MA stimulation of GV 20 and GV 26 respectively, once daily for 7 days. For rats of HL + CI + EA II groups, EA was applied to bilateral SP 6 and ST 40, and simultaneous MA stimulation of GV 20 and GV 26, once daily for 7 days after HL + CI. The expression of vimentin and Tuj-1 in the dorsolateral extension and the lateral wall of the cerebral lateral ventricle on the ischemic side was detected by immunohistochemistry. RESULTS: Compared with the control group, the expression levels of both vimentin and Tuj-1 in the dorsolateral extension and the lateral wall of the lateral ventricle of the brain on the ischemic side were increased significantly in the CI and HL + CI groups (P < 0.01), while compared with the CI group, the expression of vimentin and Tuj-1 in the CI + MA group were increased further significantly (P < 0.01). In comparison with the HL + CI group, the expression of vimentin and Tuj-1 in the HL + CI + EA I and HL + CI + EA II groups were also upregulated considerably (P < 0.01). Comparison between the HL + CI + EA I and HL + CI + EA II groups showed that the expression levels of vimentin and Tuj-1 were significantly lower in the latter group than in the former group (P < 0.01). No significant diffrences were found between the HL and control groups, and between the HL and HL+ EA groups in the expression of vimentin and Tuj-1 (P > 0.05). CONCLUSION: Acupuncture and Acupuncture + EA can further significantly upregulate the expression levels of vimentin and Tuj-1 in both the dorsolateral extension and the lateral wall of the cerebral lateral ventricle on the ischemic side in rats with CI and CI + HL, which may contribute to their effects in improving CI and HL+CI by suppressing the reduction of proliferation and differentiation of neural stem cell in the SVZ of the ischemic brain induced by CI and HL+ CI. PMID- 21235063 TI - [Effect of acupotomy lysis on hypothalamic POMC mRNA and PPE mRNA expression in rats with 3rd lumbar vertebrae transverse process syndrome]. AB - OBJECTIVE: To observe the effect of acupotomy lysis (AL) on hypothalamic proopiomelanocortin (POMO) mRNA and preproenkephalin (PPE) mRNA expression in rats with the third lumbar vertebrae transverse process syndrome (TLVTPS) so as to study its underlying mechanism in relieving symptoms of lumbar muscle strain. METHODS: Twenty-four SD rats were randomly divided into normal control group, model group, AL group and electroacupunture (EA) group. The TLVTPS model was established by inserting a piece of gelatin sponge into the posterior of the left 3rd lumbar vertebrae transverse process. AL and EA were applied to the left "Shenshu"(BL 23) and "Yaoyangguan" (GV 3) respectively. The POMC mRNA and PPE mRNA expression levels in the hypothalamus were detected by in situ hybridization. RESULTS: In comparison with the normal group, the integrated optical density (IOD) values of hypothalamic POMC mRNA and PPE mRNA positive cells in the model group were increased significantly (P < 0.01); while compared with the model group, those of POMC mRNA and PPE mRNA positive cells in both left and right hypothalamus were increased further considerably in both AL and EA groups (P < 0.01). No significant differences were found between AL and EA groups in POMC mRNA and PPE mRNA expression levels (P > 0.05). CONCLUSION: AL and EA therapies can increase the expression of POMC mRNA and PPE mRNA in hypothalamus in rats with TLVTPS, which may contribute to its effect in relieving pain in the treatment of lumbar muscle strain. PMID- 21235064 TI - [Influence of acupuncture on the motor ability in training-induced fatigue mice]. AB - OBJECTIVE: To observe the influence of acupuncture on the motor ability of training-induced fatigue mice so as to explore its mechanism underlying acupuncture-induced improvement of physical training fatigue. METHODS: Sixty Kunming mice were divided into normal control, training model and acupuncture groups, with 20 mice in each. The training-fatigue model was established by forcing the mouse to swim in a water tank for 30 min/d in the 1st week, 60 min/d in the 2nd week, 90 min/d in the 3rd week and 120 min/d in the 4th and 5th weeks. "Guanyuan" (CV 4), and bilateral "Zusanli" (ST 36) and "Shenshu" (BL 23) were punctured with filiform needles, and with the needle twirled for about 30 s and retained for 5 min. Thetreatment was conducted once daily for 2 weeks. The duration of exhaustion training was recorded. Serum lactic acid (LA), lactate dehydrogenase (LDH) and creatine kinase (CK) contents were detected by LA oxidase method, immune-suppressive assay and enzyme-linked immunoassay, respectively. RESULTS: Compared with the training-fatigue (model) group, the duration of the exhausted swimming of the acupuncture group was obviously longer (P < 0.05). In comparison with the control group, serum LA, LDH and CK contents were increased considerably in the model and acupuncture groups (P < 0.05, P < 0.01), while compared with the model group, serum LDH level of acupuncture group was increased significantly (P < 0.05), and serum CK level of acupuncture group decreased obviously (P < 0.05). No significant difference was found between the model and acupuncture groups in serum LA content (P > 0.05). CONCLUSION: Acupuncture can effectively improve the motor ability of the training-fatigue mice, which may be closely relevant to its effects in upregulating LDH activity and reducing serum CK. PMID- 21235065 TI - [Effects of electroacupuncture of "source-" plus "collateral-" acupoints on the cardiac function and myocardial enzymes in acute myocardial ischemia rabbits]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) of "Source-" + "Collateral-" acupoints ["Shenmen" (HT 7) + "Zhizheng"(SI 7)] and single acupoints "Neiguan"(PC 6) and HT 7 on cardiac function and myocardial enzymes in acute myocardial ischemia (AMI) rabbits. METHODS: Sixty Chinchilla rabbits were randomized into normal control, model, Shenmen (HT 7), Neiguan (PC 6), HT 7 + SI 7 groups, with 8 rabbits in each. AMI model was duplicated by occlusion of the anterior descending branch of left coronary artery under anesthesia. EA (2 Hz,1 mA) was applied to acupoints HT 7, PC 6,and HT 7 + SI 7 for 10 min. The maximum ascending rate (+ dp/dt max) and maximum descending rate (-dp/dt max) of the left ventricular pressure (LVP) were recorded by using PowerLab System. Serum lactate dehydrogenase (LDH) and creatine kinase MB (CK-MB) contents were detected with chromatometry. RESULTS: Serum LDH and OK-MB contents increased significantly in model group than in normal control group (P < 0.01). Compared with model group, serum LDH and CK-MB contents decreased remarkably in PC 6, HT 7 and HT 7 + SI 7 groups (P < 0.01, P < 0.05), and the effects of HT 7 + SI 7 group were significantly superior to those of PC 6 and HT 7 groups in lowering serum LDH and CK-MB levels (P < 0.01, P < 0.05). Compared with the normal control group, + dp/dt max lowered significantly and -dp/dt max increased markedly in the model group (P < 0.01), while compared with the model group, + dp/dt max increased obviously and -dp/dt max decreased significantly in the three EA groups (P < 0.01, P < 0.05). The effects of HT 7 + SI 7 group were markedly superior to those of HT 7 and PC 6 in raising + dp/dt max and lowering -dp/dt max (P < 0.05, P < 0.01), and those effects of PC 6 group were evidently better than those of HT 7 group (P < 0.05, P < 0.01). CONCLUSION: EA of "Source-" + "Collateral-" aoupoints (HT 7 + SI 7), HT 7 and PC 6 has a positive effect in improving changes of cardiac function and in lowering serum LDH and CK-MB contents in AMI rabbits, and the effect of EA of HT 7 + SI 7 is superior to that of EA of single acupoint. PMID- 21235066 TI - [Effects of electroacupuncture of different acupoint groups on sevoflurane anesthesia in patients undergoing resection of supratentorial tumors]. AB - OBJECTIVE: To observe the effect of electroacupuncture (EA) of different acupoint groups on the sevoflurane anesthetic requirement for resection of supratentorial tumors and the speed of post-operation recovery. METHODS: A total of 120 cases of supratentorial tumor resection patients were randomly and equally allocated into general anesthesia (GA) group, EA-proximal acupoints group (EA-PA group) and EA distant acupoints group (EA-DA group). The supratentorial tumor patients were anesthetized with sevoflurane for surgery. Proximal acupoints used were Fengchi (GB 20), Tianzhu (BL 10), Cuanzhu (BL 2) and Yuyao (EX-HN 4) that the former 2 acupoints and the latter 2 acupoints were for penetrative needling; and distant acupoints used were Hegu (LI 4), Waiguan (TE 5), Jinmen (BL 63), Taichong (LR 3), Zusanli (ST 36) and Qiuxu (GB 40) on the craniotomy side, and stimulated with EA (2 Hz/100 Hz, a tolerable electric stimulating strength), beginning from the anesthesia induction till the end of surgical operation. All patients were anesthetized by inhalation of propofol (2 mg/kg), sufentanil (0.3 microg/kg) and vecuronium bromide (0.1 mg/kg) and maintained with sevoflurane. The end-tidal sevoflurane concentration, minimum alveolar concentration (MAC), bispectral index (BIS), and the speed of recovery were recorded. RESULTS: In comparison with the GA group, the end-tidal concentrations during anesthesia maintenance at the time points of post skull drilling, dura incising, intracranial operation in EA-PA group, the time-points of post skull drilling, skull opening, dura incising, and intracranial operation in EA-DA group, and the MAC of sevoflurane at the time points of skull drilling in EA-DA group, and skull opening, dura incising, intracranial operation and dura suturing in both EA-PA and EA-DA groups were significantly lower (P < 0.05, P < 0.01). Compared to the GA group, the BIS values of EA-DA group at the time-points of skull drilling and opening, and dura incising were significantly higher (P < 0.05), while during the recovery stage of anesthesia, in comparison with the GA group, the autonomous respiration recovery time, tracheo-tube removing time, eye-opening time, voluntary motion recovery time, orientation force recovery time, and operating room-departure time of both EA-PA and EA-DA groups were significantly shorter (P < 0.05, P < 0.01). No significant differences were found between the EA-PA and EA-DA groups in the aforementioned indexes (P > 0.05). CONCLUSION: EA of both proximal and distant acupoints can reduce the expired concentration and MAC of sevoflurane during anesthesia maintenance, and accelerate the recovery after cease of anesthesia in supratentorial tumor resection patients. PMID- 21235067 TI - [Effect of electroacupuncture of Tianshu (ST 25) on the rational symptoms of functional constipation patients and evaluation on its efficacy satisfaction: a single-center, prospective, practical and randomized control trial]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) of Tianshu (ST 25) and medication on the subjective symptoms and the satisfactory degree of functional constipation (FO) patients, and to evaluate the efficacy of different depth-needling. METHODS: Single-blind, randomized and parallel-controlled methods were adopted in the present study and a total of 95 FC patients were randomly divided into medication group (Lactulose, 20-30 mL/d, n = 24), deep needling (DN, about 45 mm beneath the skin) of ST 25 group (n = 48), and shallow needling (SN, about 5 mm beneath the skin) of ST 25 group (n = 23). The treatment was given once daily (except weekends) for 4 weeks. The actual number of patients whose defecation frequency was up to 4 times per week, the integrative score of defecation symptoms (defecation exertion degree, abdominal pain, etc.), and the patients' satisfaction degree after the treatment were recorded and evaluated. RESULTS: One, 2, 3 and 4 weeks after the treatment, of the 48, 23 and 24 cases in DN, SN and medication groups, the numbers of FC patients whose defecation was up to 4 times per week were 31 (64.58%), 32 (66.67%), 34 (70.83%) and 37 (77.08%), 9 (39.13%), 16 (69.57%), 15 (65.22%) and 14 (60.87%), and 8 (33.33%), 7 (29.17%), 5 (20.83%) and 4 (16.67%), respectively. The effects of DN and SN groups were significantly superior to those of medication group in increasing the number of FC patients whose defecation was up to 4 times per week, improving constipation symptom integrative score (defecation exertion degree, survival desire for defecation, abdominal distension, etc.) and patients' satisfaction degree (P < 0.05). Comparison between DN and SN groups showed that the effects of the former group in accelerating the improvement of survival desire for defecation, patients' satisfaction degree were markedly superior to those of the latter group (P < 0.05). CONCLUSION: Deep needling-EA of ST 25 has a positive effect in improving functional constipation, being faster in the onset of action and stable efficacy in comparison with shallow needling. PMID- 21235068 TI - [Clinical observation on the therapeutic effect of electroacupuncture combined with cupping on post-stroke fatigue]. AB - OBJECTIVE: To observe the therapeutic effect of electroacupuncture (EA) combined with cupping at the lumbo-back on post-stroke fatigue. METHODS: A total of 128 cases of post-stroke fatigue patients were randomly divided into EA + cupping group and medication group, with 64 cases in each group. EA (20 Hz, 2 mA) was applied to Baihui (GV 20), Yintang (EX-HN 3), Shuigou (GV 26), Hegu (LI 4), Zusanli (ST 36), Sanyinjiao (SP 6), and Taichong (LR 3) for 30 min, once daily for 30 times, and cupping was applied at the patient's lumbo-back region once every two days, and continuously for 5 weeks. Patients of medication group were ordered to take compound aminobutyric acid vitamin E capsule (20 mg, t. i.d, po), magnesium gluconate solution (10 mL, t. i. d, po), sertraline hydrochloridetablet (50 mg, qd, po) for 5 weeks. The Stroke Specific Quality of Life Scale (SS-QOL) was used to evaluate the patients' energy state. RESULTS: After the treatment, the energy scores of SS-QOL of both EA + cupping and medication groups were increased significantly in comparison with the pre-treatment in each group (P < 0.05), and that of the EA+ cupping group was significantly higher than the score of the medication group (P < 0.05). Of the two 64 cases in EA + cupping group and medication group, 42 and 23 were recovered basically, 13 and 13 experienced marked improvement, 7 and 18 were effective, 2 and 10 failed in the treatment, with the effective rates being 96.87% and 84.37% respectively. The effective rate of EA + cupping group was obviously higher than that of medication group (P < 0.01). CONCLUSION: EA+ cupping at the lumbo-back can effectively relieve fatigue of post-stroke patients, and its therapeutic effect is superior to medication. PMID- 21235069 TI - [Single-acupoint electroacupuncture based on traditional acupuncture becomes true]. AB - [ In current clinical acupuncture practice, many exiting problems including changes in the treated region, simultaneous covering two meridians of the two stimulating electrodes (acupuncture needles), inability to realize the reinforcing-reducing functions of the traditional acupuncture, etc. during application of electroacupuncture (EA) could be found, which may affect the therapeutic results or lead to failure in playing EA's functions. For this reason, the authors of the present paper put forward a concept of "single acupoint EA". Base on the design of "double electrodes of two acupuncture needles" of the conventional EA therapeutic apparatus, a "single acupoint EA therapy" was put forward and a single acupoint EA electronic apparatus (stimulating needle electrode) was manufactured. It not only realizes single acupoint stimulation, but also corresponds to the features of traditional EA therapy, avoiding some problems in currently-used EA therapy. It may be helpful to raising clinical therapeutic effect. PMID- 21235070 TI - [Research and identification of the concept and terminology of "tender-point"and "Ashi-point"]. AB - It is generally acknowledged that "tender-point is taken as the acupoint" (tender point) and "Ashi-point" belong to the same one concept. Through a series of research and analysis, it was found that these two nomenclatures contain both identical and different points in connotation, and reflect different experience in the treatment of abundant clinical conditions. "Tender-point" is involved in the general experience, for which the affected site is punctured directly by using an acupuncture needle or stimulated by using a moxa-stick or moxa-cone. "Ashi-point" is referred to the regional reactive site, i.e., the sensitive point for acupuncture and moxibustion, which is involved in the specific experience for taking the reactive point of clinical problems as the therapeutic site. The so called "Tianying-point" and "Buding-point" in classical books on acu-moxibustion as Qian-jin Fang (Prescriptions Worth a Thousand Gold for Emergencies), Yulong Ge (Lyrics of Jade Dragon), etc., are the same to "Tender-point" but different to "Ashi-point". Currently, explanations and clinical application about "Tender point" have been generalized and mixed up with "Ashi-point". The author of the present paper makes an analysis on their causes. PMID- 21235071 TI - [Discussion on the location of acupoints of the spleen meridian of foot-Taiyin in the abdominal region]. AB - The four acupoints Fushe (SP 13), Fujie (SP 14), Daheng (SP 15) and Fuai (SP 16) (except SP 12 ) of the Spleen Meridian of Foot-Taiyin in the abdomen are all 4 cun lateral to the abdominal midline. The origin of "4-cun" distance and the related explanations have not been found in any books including textbooks and related Chinese national standards about acupuncture and moxibustion. In the graphical representations, these 4 acupoints are directly below the nipple, because the nipple is 4 cun from the chest midline. The authors of the present paper don't think that is right, because in locating the acupoint, the nearest body surface anatomical landmarks should be used first as the basis. The abdomen and the chest are two anatomic sites after all, locating the abdominal acupoints with the chest surface landmarks often results in larger deviation, because many people's bodies are not so symmetrical and standard, and the adult abdominal fat difference is very big. Therefore, it is highly recommended that the abdominal acupoints are located by using the abdominal anatomical landmarks, for example, the outer edge of rectus abdominis, the outer edge of abdomen ,etc. PMID- 21235072 TI - [Graded-disease-spectrum of the nervous system of acu-moxibustion therapy was determined based on its clinical efficacy and by fuzzy comprehensive estimation technique]. AB - OBJECTIVE: To determine the graded-disease-spectrum of the nervous system of acu moxibustion treatment based on its clinical efficacy. METHODS: We carried out a cross-sectional academic sample investigation on the graded-disease-spectrum of acu-moxibustion by collecting and analyzing data from the self-administered questionnaires which were completed by professional persons who have high-ranking professional titles (associate chief physicians and chief physicians) and are majoring in acupuncture and moxibustion. Then, the collected experts' opinions were analyzed by fuzzy comprehensive estimation technique and statistical processing. RESULTS: A total of 58 medical conditions involving 4 grades and 126 subtypes were included and analyzed. The Grade I contains 14 subtypes as Bell's palsy (in the acute stage and convalescence stage), primary sciatic neuralgia, migraine (mild type and moderate type), etc. which can be relieved by using acu moxibustion therapy only. The Grade II contains 53 subtypes, such as transient cerebral ischemic attack, acute cerebrovascular disease (in the convalescence stage and sequelae stage), chronic Bell's palsy (sequelae), Hunt's facial palsy, etc. which can be relieved by using acu-moxibustion as the main therapy. The Grade III contains 22 subtypes, such as acute stage of ischemic cerebrovascular disease (with coma and without coma), acute stage of hemorrhagic ischemic cerebrovascular disease (with coma and without coma), etc. which may be relieved to a certain degree by using acu-moxibustion as the supplementary or main therapy. The Grade IV contains 37 subtypes, such as Wohlfart-Kugelberg-Welander disease, myasthenia gravis (type III and type IV), myasthenia gravis of medicinal herbs resource, chorea major, etc. whose clinical effects are not known if treated with acu-moxibustion. CONCLUSION: Acu-moxibustion therapy has apparent advantages in the treatment of different clinical conditions of the nervous system. PMID- 21235073 TI - CME examination. PMID- 21235074 TI - [In a certain corporation: politicizing social relations in black brotherhoods in Brazilian slave society, 1700-1850]. PMID- 21235075 TI - [Sociability and affective relations between the classes in the popular world]. PMID- 21235077 TI - Radiation. PMID- 21235078 TI - [City, marriage cycles, and ethnicity: immigrants of German and Lutheran origin and their descendants in Curitiba, 1866-1939]. PMID- 21235079 TI - Keeping up with technology. PMID- 21235080 TI - Management connections: Checklist offers improved efficiency for MIS cases. PMID- 21235081 TI - [Woman and African heritage: an essay]. PMID- 21235082 TI - [The background of national myth in the ethnic genocide in Kosovo.]. PMID- 21235083 TI - [A Finnish essay on capital punishment, 1939-45]. PMID- 21235084 TI - [From the fragrance of the nursery to the stench of the trenches: Virginia Woolf and the critique of bourgeois power]. PMID- 21235085 TI - [Antiquated water: development of Finland's water supply system, 1850-1994.]. PMID- 21235086 TI - [The legacy of intolerance: the Enlightenment and racism.]. PMID- 21235087 TI - [Drainage systems: pollution control in Finland, 1945-70.]. PMID- 21235088 TI - [The evasion of Anglo-American gentlemen: John Locke's exclusion of slaves from human rights.]. PMID- 21235089 TI - [Current organ topics: chemotherapy of breast cancer]. PMID- 21235090 TI - [Anti-HER2 therapy for breast cancer--an added increasing therapeutic option]. PMID- 21235091 TI - [PARP inhibitors to treat triple negative breast cancer]. PMID- 21235092 TI - [Progress in gene signatures--significant clinical introduction]. PMID- 21235093 TI - [Benefits of pharmacists' assessment of outpatients undergoing chemotherapy]. PMID- 21235094 TI - [Survey of breast cancer patients on chemotherapy of generic drugs]. PMID- 21235095 TI - [Another type of tuberculosis: endobronchial tuberculosis]. PMID- 21235096 TI - Studies on the chemical constituents from the stem and leaves of Tagetes erecta. AB - OBJECTIVE: To investigate the chemical constituents of the stem and leaves of Tagetes erecta. METHODS: The materials extracted with ethanol were first purified with D101 resin and then separated by repeated silica gel column chromatography as well as recrystallization to get single compounds. The chemical structures of the compounds were elucidated on the basis of physicochemical properties, spectroscopic analysis and comparing with standard sample and literatures. RESULTS: Six compounds were identified as 4'-methoxy-eupatolitin-3-O-glucoside (I), kaempferitrin (II), rutin (III), beta-sitosterol (IV), daucosterol (V) and gallic acid (VI). CONCLUSION: Compounds I, II, III are isolated from the plant for the first time; the compounds IV, V, VI are isolated from the stem and leaves of the plant for the first time. PMID- 21235097 TI - The Blue Journal: a collaborative effort. PMID- 21235098 TI - Oxygenation state and twilight vision at 2438 m. AB - INTRODUCTION: Under twilight viewing conditions, hypoxia, equivalent to breathing air at 3048 m (10,000 ft), compromises low contrast acuity, dynamic contrast sensitivity, and chromatic sensitivity. Selected past experiments have been repeated under milder hypoxia, equivalent to altitude exposure below 2438 m (8000 ft), to further define the influence of oxygenation state on mesopic vision. METHODS: To assess photopic and mesopic visual function, 12 subjects each undertook three experiments using the Contrast Acuity Assessment test, the Frequency Doubling Perimeter, and the Color Assessment and Diagnosis (CAD) test. Experiments were conducted near sea level breathing 15.2% oxygen (balance nitrogen) and 100% oxygen, representing mild hypobaric hypoxia at 2438 m (8000 ft) and the benefit of supplementary oxygen, respectively. RESULTS: Oxygenation state was a statistically significant determinant of visual performance on all three visual parameters at mesopic, but not photopic, luminance. Mesopic sensitivity was greater with supplementary oxygen, but the magnitude of each hypoxic decrement was slight. Hypoxia elevated mesopic contrast acuity thresholds by approximately 4%; decreased mesopic dynamic contrast sensitivity by approximately 2 dB; and extended mean color ellipse axis length by approximately one CAD unit at mesopic luminance (that is, hypoxia decreased chromatic sensitivity). CONCLUSIONS: The results indicate that twilight vision may be susceptible to conditions of altered oxygenation at upper-to-mid mesopic luminance with relevance to contemporary night flying, including using night vision devices. Supplementary oxygen should be considered when optimal visual performance is mission-critical during flight above 2438 m (8000 ft) in dim light. PMID- 21235100 TI - Quadriceps muscle use in the flywheel and barbell squat. AB - BACKGROUND: Resistance exercise has been proposed as an aid to counteract quadriceps muscle atrophy in astronauts during extended missions in orbit. While space authorities have advocated the squat exercise should be prescribed, no exercise system suitable for in-flight use has been validated with regard to quadriceps muscle use. We compared muscle involvement in the terrestrial "gold standard" squat using free weights and a nongravity dependent flywheel resistance exercise device designed for use in space. METHODS: The subjects were 10 strength trained men who performed 5 sets of 10 repetitions using the barbell squat (BS; 10 repetition maximum) or flywheel squat (FS; each repetition maximal), respectively. Functional magnetic resonance imaging (MRI) and surface electromyography (EMG) techniques assessed quadriceps muscle use. Exercise induced contrast shift of MR images was measured by means of transverse relaxation time (T2). EMG root mean square (RMS) was measured during concentric (CON) and eccentric (ECC) actions and normalized to EMG RMS determined during maximal voluntary contraction. RESULTS: The quadriceps muscle group showed greater exercise-induced T2 increase following FS compared with BS. Among individual muscles, the rectus femoris displayed greater T2 increase with FS (+24 +/- 14%) than BS (+8 +/- 4%). Normalized quadriceps EMG showed no difference across exercise modes. DISCUSSION: Collectively, the results of this study suggest that quadriceps muscle use in the squat is comparable, if not greater, with flywheel compared with free weight resistance exercise. Data appear to provide support for use of flywheel squat resistance exercise as a countermeasures adjunct during spaceflight. PMID- 21235099 TI - Effects of promethazine and midodrine on orthostatic tolerance. AB - INTRODUCTION: Astronauts experience both orthostatic hypotension and space motion sickness during re-entry. Midodrine, an alpha1-adrenergic agonist, is used to treat orthostatic hypotension. Promethazine, a histamine H1-receptor antagonist, is prescribed for space motion sickness. Many astronauts need both midodrine and promethazine. This study evaluated the interactive effects of midodrine and promethazine on hemodynamic responses to upright tilt. METHODS: Subjects (5 men; 3 women) were studied four times: control (no drug); midodrine only; promethazine only; or midodrine plus promethazine. Hemodynamic parameters, plasma norepinephrine, renin activity, and aldosterone were measured supine and upright. RESULTS: Rates of presyncope were 38% with no drug; 0% with midodrine alone; 100% with promethazine alone; and 63% with both drugs. Supine to upright decreases in systolic pressure were greater with promethazine alone than control (P < 0.01); midodrine (P < 0.05) or both drugs (P < 0.05). Supine to upright increases in plasma norepinephrine, renin activity, and aldosterone all were significantly reduced with promethazine alone compared to control (P < 0.05, P < 0.05, P < 0.05) and midodrine alone (P < 0.05, P < 0.01, P < 0.01). Cardiac output fell more with promethazine alone than with no drug (P < 0.05) or with midodrine plus promethazine (P < 0.05). DISCUSSION: Promethazine significantly increased the incidence of orthostatic hypotension in subjects, even when combined with midodrine. Inhibition of sympathetic responses, likely via enhancement of the inhibitive effects of GABA, by promethazine may underlie the increased orthostatic hypotension. Promethazine also appears to inhibit responses of the renin angiotensisn system during orthostatic challenge. PMID- 21235101 TI - Anxiety and psychomotor performance in divers on the surface and underwater at 40 m. AB - INTRODUCTION: Performance impairments attributed to the effects of nitrogen narcosis have been reported to be significantly larger in studies conducted underwater compared to in hyperbaric chambers. One suggestion is that the larger impairment results from higher levels of anxiety in the underwater environment. The current study aimed to investigate the impact of anxiety and narcosis, in isolation and in combination, on a measure of psychomotor performance. METHODS: The effects of self-reported anxiety (anxious vs. not anxious) and depth (surface vs. underwater) on performance on the digit letter substitution test (DLST) were measured in 125 divers. RESULTS: Change from baseline scores indicated that divers performed significantly worse on the DLST underwater (mean = 3.35; SD = 4.2) compared to the surface (mean = 0.45-0.73; SD = 4.0-4.2). This decrement was increased when divers reported they were also anxious (mean = 7.11; SD = 6.1). There was no difference on DLST performance at the surface between divers reporting they were anxious and those reporting they were not anxious. DISCUSSION: The greater decrement in performance at depth in divers reporting anxiety compared to those not reporting anxiety and the lack of this effect on the surface suggested that anxiety may magnify performance deficits presumed to be caused by narcosis. PMID- 21235102 TI - Cognitive demands and the relationship between age and workload in apron control. AB - INTRODUCTION: Apron controllers (ACs) determine the taxiways for aircraft entering the apron area until they reach their parking positions and vice versa. The aims of this study were to identify age-sensitive job requirements of apron control (Study 1), and to investigate the relationship between age of ACs and their workload (Study 2). METHODS: Study 1: There were 14 experienced ACs who assessed the job requirements of apron control with the Fleishman-Job Analyses Survey. Additionally, during one shift, the number of parallel processed traffic data sets (indicating memory-load) and the number of delivered radio messages (indicating processing speed requirements) were assessed. Study 2: There were 30 ACs (age: 23-51 yr) who volunteered for trials during late shifts at an international airport. ACs assessed their subjective workload (NASA-Task Load Index) at four times during the shift and carried out an attention test (d2) before and after the shift. Moreover, their heart rate was assessed during the shift and in a reference period. RESULTS: Study 1: Results indicate that apron control requires especially high levels of memory-load and processing speed. Study 2: Hierarchical regression analyses revealed a u-shaped relationship between age and subjective workload (beta = 0.59) as well as heart rate (beta = 0.33). Up to the age of about 35-37 yr, workload and heart rate decreased with age, but afterwards the relationship became positive. There was no association between chronological age and attention performance. DISCUSSION: There is a need for age adequate job design in apron control that should especially aim at the reduction of memory-load and processing speed. PMID- 21235103 TI - Automated Neuropsychological Assessment Metrics: repeated assessment with two military samples. AB - INTRODUCTION: U.S. military troops deploying to war zones are currently administered the Automated Neuropsychological Assessment Metrics (ANAM4) Traumatic Brain Injury (TBI) Battery to establish individual neurocognitive performance baselines. In part, the utility of the ANAM4 TBI Battery baseline measurement depends on test-retest reliability of this instrument. The purpose of this report was to evaluate performance following multiple administrations of the ANAM4 TBI Battery: does performance in a repeated measures paradigm constitute a stable, interpretable indication of baseline neurocognitive ability? METHODS: The data presented here are from the ANAM4 TBI Battery administered four times to a group of U.S. Marines in Study 1 and eight times to a group of New Zealand Defence Force personnel in Study 2. RESULTS: The results show practice effect in five of six performance subtests in both Study 1 and Study 2. DISCUSSION: Results are consistent with expectations that multiple test sessions are required to reach stable performance on some computerized tasks. These results have implications for taking ANAM4 TBI Battery practice effects into account in test administration and in data interpretation. PMID- 21235104 TI - A no-decompression air dive and ultrasound lung comets. AB - INTRODUCTION: Increased accumulation of extravascular lung water after repetitive deep trimix dives was recently reported. This effect was evident 40 min post dive, but in subsequent studies most signs of this lung congestion were not evident 2-3 h post-dive, indicating no major negative effects on respiratory gas exchange following deep dives. Whether this response is unique for trimix dives or also occurs in more frequent air dives is presently unknown. METHODS: A single no-decompression field dive to 33 m with 20 min bottom time was performed by 12 male divers. Multiple ultrasound lung comets (ULC), bubble grade (BG), and single breath lung diffusing capacity (DLCO) measurements were made before and up to 120 min after the dive. RESULTS: Median BG was rather high with maximal values observed at 40 min post-dive [median 4 (4-4)]. Arterialization of bubbles from the venous side was observed only in one diver lasting up to 60 min post-dive. Despite high BG, no DCS symptoms were noted. DLCO and ULC were unchanged after the dive at any time point (DLCO(corr) was 33.6 +/- 1.9 ml x min(-1) mmHg(-1) pre dive, 32.7 +/- 3.8 ml x min(-1) x mmHg(-1) at 60 min post-dive, and 33.2 +/- 5.3 ml x min(-1) x mmHg(-1) at 120 min post-dive; ULC count was 4.1 +/- 1.9 pre-dive, 4.9 +/- 3.3 at 20 min post-dive, and 3.3 +/- 1.9 at 60 min post-dive. DISCUSSION: These preliminary findings show no evidence of increased accumulation of extravascular lung water in male divers after a single no-decompression air dive at the limits of accepted Norwegian diving tables. PMID- 21235105 TI - Evaluation of a Human Factors Analysis and Classification System as used by simulated mishap boards. AB - BACKGROUND: The reliability of the Department of Defense Human Factors Analysis and Classification System (DOD-HFACS) has been examined when used by individuals working alone to classify the causes of summary, or partial, information about a mishap. However, following an actual mishap a team of investigators would work together to gather and analyze a large amount of information before identifying the causal factors and coding them with DOD-HFACS. METHOD: There were 204 military Aviation Safety Officer students who were divided into 30 groups. Each group was provided with evidence collected from one of two military aviation mishaps. DOD-HFACS was used to classify the mishap causal factors. RESULTS: Averaged across the two mishaps, acceptable levels of reliability were only achieved for 56.9% of nanocodes. There were high levels of agreement regarding the factors that did not contribute to the incident (a mean agreement of 50% or greater between groups for 91.0% of unselected nanocodes); the level of agreement on the factors that did cause the incident as classified using DOD-HFACS were low (a mean agreement of 50% or greater between the groups for 14.6% of selected nanocodes). DISCUSSION: Despite using teams to carry out the classification, the findings from this study are consistent with other studies of DOD-HFACS reliability with individuals. It is suggested that in addition to simplifying DOD HFACS itself, consideration should be given to involving a human factors/organizational psychologist in mishap investigations to ensure the human factors issues are identified and classified in a consistent and reliable manner. PMID- 21235106 TI - Thyroid status of Space Shuttle crewmembers: effects of iodine removal. AB - INTRODUCTION: Iodine is often used for water purification and has been used throughout the U.S. space program. Because of concern about potential effects on crewmembers' thyroid function, in 1997 a system was implemented on board the Space Shuttles to remove iodine from water before it was consumed. We report here thyroid hormone data from crews flying before and after this system was implemented. METHODS: Blood samples were collected and analyzed for thyroid hormone content during routine medical exams before and after Space Shuttle missions. Data are reported for 224 male and 49 female astronauts (about two thirds of them before implementation of iodine removal). RESULTS: Serum concentrations of total thyroxine (T4) and the free T4 index were elevated in men after flight and triiodothyronine (T3) was lower after flight, regardless of iodine removal status. T4 was higher, even before flight, in the group of men who flew after iodine removal was implemented. Conversely, T3 was lower in men who flew during that period. Before iodine removal was implemented, thyroid stimulating hormone (TSH) was elevated in male and tended to be elevated in female astronauts, with average increases of 27% and 19% after flight, respectively. After iodine removal was implemented, postflight TSH was not significantly different from preflight values. DISCUSSION: These data provide evidence that crewmembers' increase in serum TSH on landing day after early Shuttle flights resulted from their consumption of iodinated water during spaceflight, because the same increase was not observed after implementation of the iodine removal system. PMID- 21235107 TI - Exit strategies and safety concerns for machinery occupants following ice failure and submersion. AB - BACKGROUND: Of all drownings, 5 to 11% occur in submerged vehicles. Winter road workers are at high risk for vehicle submersion because they drive heavy vehicles over ice. METHODS: A crane was used for repeated occupied and unoccupied submersions of a 5-ton truck/snow plow (N = 25) and a 1-ton truck/snow plow (N = 23); some data were compared to those from our previous study on passenger vehicles (Aviat Space Environ Med 2010; 81:779-84). RESULTS: The 1-ton truck sank faster than an intact car, while the 5-ton truck sank within 4 s. Four subjects could escape through the windows, doors, or roof hatch when the 1-ton truck was on the surface or submerged. Hatch exit took 2-3 times longer than windows/doors. Because the 5-ton truck sank so quickly, there was no opportunity to escape while on the surface. With windows open, exit through the window, door, or roof hatch could only occur after the cab was full of water. With windows closed, rapid pressure buildup imploded the windshield. Bulk and buoyancy of thermoprotective flotation clothing did not impede exit in any scenario. One to three 200-L sealed containers mounted to the front of the 1-ton truck increased the Floating Phase by approximately 20-40 s each. CONCLUSIONS: Results suggest that a heavy vehicle will sink before surface exit is possible. Occupants would, therefore, be forced to breath-hold and make an underwater exit through a window, door, or roof hatch. Front-mounted external flotation devices on a light truck increased floating time and the possibility of exit while still on the surface. PMID- 21235108 TI - Pressurized flight immediately after splenic infarction in two patients with the sickle cell trait. AB - Splenic infarction in individuals harboring the sickle cell trait can occur in the setting of exposure to low oxygen tension at high altitudes. While this is a concern in unpressurized aircraft flight, it has not been well documented in pressurized flight. What has not been addressed is whether this relative safety of pressurized flight extends to the postinfarction period and whether or not pressurized flight in the immediate post-infarction period, especially air evacuation, would change the patient's outcome. We present two cases of splenic infarction suffered during climbing Mt. Fuji (12,388 ft, 3776 m) in patients harboring the sickle cell trait. Both patients were initially assessed and misdiagnosed by a local hospital. They then voluntarily took a 2-h, 30-min pressurized commercial flight [cruising altitude 40,000 ft (12,192 m), minimal cabin pressure: 0.73 atmospheric pressure] within 48 h of their initial presentation. Shortly after their arrival in their final destination they underwent a full workup, including a contrast enhanced CT scan, and were found to have the above-mentioned diagnosis. In both cases, supportive care was sufficient; both patients recovered without sequelae and did not deviate from what would be considered the standard, expected natural history of splenic infarction in patients with the sickle cell trait. It would seem from this anecdotal experience that pressurized commercial flights undertaken in the immediate post-splenic infarction period by individuals with the sickle cell trait may not change either the disease course or the patient's outcome and might be safe. PMID- 21235109 TI - Return to flight with multiple sclerosis: aeromedical considerations. AB - Multiple sclerosis (MS) is the most frequent demyelinating disease of the central nervous system, with versatile manifestations--relapsing-remitting or progressive -and an unpredictable course, with prognoses ranging from minimal neurological impairment to severely disabled. Disease modifying agents can minimize relapse rate and slow disease progression. Yet most patients suffer relapses and progression despite use of these agents. Several of the manifestations of MS may cause overall decrease in the performance of the aviator. These include cognitive impairment, fatigue, and depression. Episodes of spasms, dysarthria, ataxia, parasthesias, diplopia, and hemiplegia, as well as drug side effects may also affect flight. Seizures and episodes of vertigo may occur suddenly and result in in-flight incapacitation. We present our experience with two aviators with definite MS and a navigator with probable MS. The various manifestations of MS are specifically addressed with an emphasis on the aeromedical implications. PMID- 21235110 TI - Comment on "Vestibular evoked myogenic potentials and saccular plasticity in divers". PMID- 21235111 TI - Implications of "technology horizons". PMID- 21235112 TI - You're the flight surgeon: testicular cancer. PMID- 21235113 TI - This month in aerospace medicine history. PMID- 21235114 TI - Risk factors for colorectal polyps: findings from a Greek case-control study. AB - There is a body of evidence showing that several lifestyle and dietary factors are associated with colorectal polyps' formation; however, the magnitude of this association in diverse populations remains unclear. The aim of this study was to investigate this association in a Greek sample. MATERIAL AND METHOD: The study comprised of 52 subjects with histologically confirmed advanced colorectal polyps and 52 healthy controls. Data concerning lifestyle and dietary factors were collected using a validated questionnaire. Logistic regression analysis was used to estimate odds ratios and 95% confidence intervals after adjustment for potential confounders. RESULTS: Physical activity level (95% CI 0.032-0.953, P = 0.044) and consumption of yoghurt (95% CI 0.969-0.996, P = 0.024), cheese (95% CI 0.932-0.996, P = 0.030), fish (95% CI 0.782-0.964, P = 0.008), vegetables (95% CI 0.965-0.998, P = 0.029), and garlic (95% CI 0.005-0.671, P = 0.022) were inversely associated with colorectal polyps. Increasing age (95% CI 1.005-1.231, P = 0.039) and central obesity (95% CI 1.001-1.019, P = 0.025) were strongly associated with their presence. CONCLUSION: Our study indicates that a cluster of modifiable risk factors have significant impact on colorectal polyps' occurrence in Greek population. PMID- 21235115 TI - Colonoscopic screening of asymptomatic first-degree relatives of colorectal cancer patients. AB - AIM: First-degree relatives of colorectal cancer (CRC) patients are at increased risk for developing colorectal neoplasm, and current guidelines recommend screening colonoscopy in such individuals. The aim of this study was to evaluate the use of colonoscopy as the screening test in asymptomatic first-degree relatives of CRC patients. MATERIAL AND METHOD: Colonoscopy was performed in 102 asymptomatic individuals who had at least one first-degree relatives with CRC. Subjects included in the screening program were aged between 36 and 72 years, and majority came from two counties (Suceava, Iasi) located in north-eastern Romania. RESULTS: Thirty colorectal lesions were found in 17 individuals: two (6.6%) had adenocarcinomas, and remaining 15 patients had 28 polypoid lesions: 14 (46.6%) adenomas, 5 (16.6%) tubulovillous adenomas, 3 (10%) adenomas with high grade dysplasia and 6 (20%) had hyperplasic polyps. CONCLUSION: Colonoscopy is a useful, feasible and safety initial screening tool for first-degree relatives of patients with CRC. PMID- 21235116 TI - Differentiation of patients with chronic lombosciatica due to disc hernia using gait analysis techniques. AB - Nowadays gait analysis represent a modern technique used as a useful tool in the assessment of patients with locomotors disease. AIM: To make a differentiation of patients with chronic sciatica due to disc hernia using gait analysis techniques. MATERIAL AND METHOD: Study was prospective, with consecutive selection of subjects according to eligibility criteria, using a control group. The number of subjects was 47: 28 patients and 19 healthy subjects. The patients were characterized clinically, imagistically and biomechanically. The biomechanically evaluation was made with VICON MX optical motion capture system. Our data of interest were: temporo-spatial and kinematic parameters. These data were factorial analyzed with a principal component extraction technique, resulting 10 variables, which characterized the system variability in 94.67%. Next step was represented by a hierarchical cluster analysis for sub-group identification. RESULTS: We have differentiated two clusters. The two clusters were individualized regarding the temporo-spatial parameters (opposite foot contact, step width) as well as the kinematic parameters (maximum upward rotation in stance of pelvis, maximum adduction of the hip in stance, maximum abduction of the hip in swing, maximum plantar flexion angle in swing, total sagittal plane excursion of the ankle). CONCLUSIONS: The two clusters can be defined as following: cluster 1: reduced stance phase and mainly distal problems (of the ankle); cluster 2: normal stance phase duration, severely low step width and mainly proximal problems (pelvic belt). PMID- 21235117 TI - Obstructive sleep apnea patients voice analysis. AB - It is generally considered that obstructive sleep apnea may associate larynx abnormalities--either anatomic or functional in nature; considering the vocal tract as a series of uniform loss cylindrical pipes the idea of non-invasively exploring this by means of spectral analysis emerged. The aim of our study is to evaluate potential changes in acoustic features of voice in sleep apnea patients as compared to matched controls in order to develop a potential screening test. MATERIAL AND METHOD: Sleep apnea subjects and controls were asked to produce sustained vowels such as "a" and "i" which were recorded and analyzed. Some parameters were estimated--average of fundamental frequency, peak amplitude variation and compared and others are still to be developed. PMID- 21235118 TI - New original in vitro method to assess cholinesterase reactivity in organophosphate poisoning. AB - Assessment of organophosphate poisoning could benefit from a safe, non-expensive, easy to perform, quick (< 1 hour) test, which evaluates the level of cholinesterase activity "in vitro" regarding to the capability of oximes to reactivate OF-blocked cholinesterase. In the proposed protocol, 0.5 mL of sample serum is incubated, prior to the evaluation of level of cholinesterase activity, with 5 microL of a Toxogonin dilution (0.125 mg) for 30 minutes at 37 degrees C. For the standardization of the newly proposed protocol, several important issues were documented in the present article. The new original method of assessing cholinesterase reactivability will consist in an advantage for the diagnosis, prognostic evaluation and therapeutic orientation in OF intoxication. PMID- 21235119 TI - Elastography, progression factor in liver ultrasound. AB - Elastography is a method which, using ultrasound, obtains images and measurements of tissue elasticity when applying a force on it. As an imaging method it was developed to quantify objectively the pathological changes related to the presence of an abnormal tissue, compared to the surrounding tissues, giving information about the elasticity/stiffness of the examined tissue, the degree of fibrosis, the degree of stiffness compared to tumor free tissue. The tissue analysis can be done through a compression technology "eSie touch elasticity imaging" (with applications for the surface elastography) or ARFI technology- "acoustic radiation force imaging" (the diffusion impulse of the acoustic force). The ARFI method allows valid, accurate and flexible evaluation of liver stiffness and it is correlates with the fibrosis stage. The liver elastosonography, through new technologies available, has reached the level of the fibro-elastoscanner and magnetic resonance imaging. The ultrasound elastography application quickly advances, starting with the researches in this field. At present, it has analised the most various fields of application, from the breast, prostate, thyroid, pancreas imaging to the study of abdominal lymphnodes and peripheral vessels, gastrointestinal stromal tumors, primary and secondary liver tumors, the evaluation of uterine cervix, from cardiology to gastroenterology and urology, both in adults and in pediatrics. PMID- 21235120 TI - Early recurrence in favorable stage II breast cancer--which approach is the best? AB - AIM: Changing the sequence of therapeutic options in stage II breast cancer: first, a core biopsy, followed by the evaluation of the tumoral markers, adaptation of the chemotherapy scheme and finally, surgical approach. Thus would be possible to improve the hope of life in some stage II breast cancer patients, in whom survival is poorer than in some stage III patients. MATERIAL AND METHOD: 144 patients in stage II breast cancer were included in this study, over a period of 5 years (2000-2004). In all these patients the first therapeutic option was surgery (radically modified mastectomy type Madden), followed by systemic chemotherapy-FAC or FEC, 6 cycles, and finally Tamoxifen. RESULTS: 34 out of them developed metastases in a period between 6 and 72 months, most of them in the first 26 months; 25 out of these 34 didn't have metastases in the axillary lymph nodes, and in 18 patients estrogen--and progesterone--receptors were highly positive. HER 2 neu was negative or low expressed in patients with metastases. CD 34 wasn't evaluate in the whole group. CONCLUSIONS: Early onset of metastases in the studied patients, in whom tumoral aggressiveness markers were not obvious, impose the evaluation of the angiogenesis markers and, when positive, chemotherapy as the first therapeutic option. PMID- 21235121 TI - Corelations between the ENT modifications and BMI in patients with sleep breathing disorders. AB - AIM: To show if between the BMI index of weight and the oro and hypopharingeal modifications we can establish a link for the same value of the index of AHI hypoapnea. MATERIAL AND METHOD: At the patients with sleep breathing pathology of an obstructive type we conducted nasal, oro- and hypopharingeal endoscopic examinations, measurements and calculation of the weight index, followed by the polygraphic evaluation of the sleep, the establishment of the degree of sleep obstructive apnea; we used a form of ENT examination. The classification of patients according to the value of the apnea index of AHI hypoapnea in 3 groups: AHI < 10, 10 < AHI < 50, and AHI > 50. According to the value of the BMI weight index we analyze 3 groups of patients: BMI < 27, 27 < BMI < 40, BMI > 40. RESULTS: For AHI < 10, habitual snoring we can notice that normal amygdales appear in an increased percent for BMI < 27 or BMI > 40 and AHI < 10 the increased webbing is specific for 27 < BMI < 40. For AHI > 50 the occurring oropharingeal modifications are: normal amygdales, long and broad uvula and webbing spanning between 5-10 mm. CONCLUSION: Oropharingeal modifications and the index of BMI weight are essential elements, taken individually in the preoperatory evaluation of patients with syndrome of obstructive sleep apnea. PMID- 21235122 TI - Serum lipoprotein (a) levels in patients with arterial hypertension. AB - Lp(a) is capable of deleteriously altering the balance between the procoagulant and anticoagulant, proinflammatory and anti-inflammatory, and vasorelaxing and vasoconstricting properties of the endothelium. MATERIAL AND METHOD: The purpose of this study was to investigate the serum concentration of Lp(a) and the main parameters of lipid profile in three groups of subjects: a control group that included 16 healthy subjects, 20 patients with arterial hypertension and dyslipidemia and 20 patients with arterial hypertension without dyslipidemia. Using B-mode ultrasonography, we evaluated carotid intima-media thickness (IMT) and flow mediated vasodilation (FMD) on brachial artery. RESULTS: We found significant higher Lp(a) concentrations in hypertensive patients with dislipidemia (70 +/- 55.95 mg/dL, p < 0.001) and in hypertensive patients without dislipidemia (69 +/- 52.33 mg/dL, p < 0.001), comparative with the control group (19 +/- 14.64 mg/dL). In hypertensive patients with dislipidemia we found a strong negative correlation between Lp(a) and carotid IMT (R2 = -0.75, p < 0.001) and a moderate negative correlation between Lp(a) and FMD (R2 = -0.38, p < 0.001). Lp(a) level wasn't correlated with the main parameters of lipid profile. CONCLUSIONS: These results indicated that serum Lp(a) values could play an important role in essential hypertension pathogenesis and could be considered as an individual risk factor in hypertensive patients. PMID- 21235123 TI - Ghrelin and Ang 1-7 have cumulative vasodilatory effects on pulmonary vessels. AB - Ghrelin is an orexigenic hormone that has been shown to have vasodilator effects. Angiotensin 1-7 (Ang 1-7) is a bioactive component of the renin-angiotensin system and may play an important role in the regulation of cardiovascular homeostasis. AIM: The aim of this study was to investigate the interaction between ghrelin and a better known vasodilatator, Ang 1-7. MATERIAL AND METHOD: The dose-dependent relaxing effects of ghrelin were assessed on pulmonary artery rings of male Wistar rats with intact endothelium in the absence or the presence of Ang 1-7. Ang 1-7 was added in the organ bath with 5 minutes before N(G)-nitro L-arginine methyl ester (L-NAME, 1 micro/M) and indomethacin administration in the presence of cumulative doses of ghrelin. RESULTS: Our results showed that Ang 1-7 could improve and restore vasorelaxant effects of ghrelin on rat pulmonary rings with intact endothelium. CONCLUSION: Vasodilatatory actions of ghrelin are potentiated by Ang 1-7 and mediated by local synthesis of prostaglandins and nitric oxide. PMID- 21235124 TI - In vitro evaluation of ketoprofen controlled release from various formulations. AB - The aim of this study is to investigate the potential utility of some hydrogels, based on chitosan, chitosan modified with phthalic anhydride and 75/25 poly(N isopropyl acrylamide)/alginate, for preparing drug release systems containing ketoprofen, as model drug. MATERIAL AND METHOD: The in vitro release profiles and swelling studies were done in ethanol medium, where the studied drug presents high solubility, at 25 degrees C (room temperature). The ketoprofen release was observed by monitoring the absorbance at max = 254 nm as a function of time. RESULTS: The experimental results indicated that the smallest amount of drug was released from chitosan matrices, appreciatively 31%. CONCLUSIONS: The composition of hydrogels had an important effect on ketoprofen release. PMID- 21235125 TI - Grapefruit juice--drug interactions: importance for pharmacotherapy. AB - In spite of known health benefits of grapefruit juice, its consumption in combination with drugs requires caution. The drugs most susceptible to pharmacokinetic interactions with clinical significance are those with narrow therapeutic index and low bioavailability due to important first-pass metabolism. Most vulnerable populations are elderly, cirrhotics, subjects with genetic polymorphisms and individuals taking other CYP3A4 inhibitors. The major drug classes that have been reported to present interactions with grapefruit juice are antiallergics, antibiotics, antimalaria drugs, anxiolytics, calcium channel blockers, HIV protease inhibitors, HMG-CoA reductase inhibitors; the degree of pharmacokinetic interaction varies among the compounds of the same class. PMID- 21235126 TI - Measurement of total antioxidant activity with chlorpromazine radical cation. AB - In the present study there is described a simple and sensitive method for the evaluation of antioxidant activity in chlorpromazine-Fe (III) system using ascorbic acid as standard. MATERIAL AND METHOD: Chlorpromazine [2-chloro-N-(3 dimethyl-aminopropyl)-phenothiazine] is oxidized in acidic media by Fe (III) with the formation of a stable radical cation characterized by an intense visible absorbtion band (lambda = 540 nm). The optimum parameters for the stability of the radical cation have been studied: molar ratio chlorpromazine-Fe (III), pH, solvents. Spectrophotometric methods have been used in these studies. RESULTS: The chlorpromazine radical cation is stable in the acidic media (pH = 3) at a molar ratio chlorpromazine: Fe (III) of 2: 1. Ascorbic acid reduces these radicals and induces a decrease of absorbance. Percent inhibition was calculated and plotted as a function of the concentration of standard antioxidant solutions. The results show that percent inhibition varies in a linear manner with the ascorbic acid concentration. Percent inhibition is higher when the antioxidant solution is added after generation of radical cation. CONCLUSIONS: It has been developed a method for evaluating antioxidant activity in the chlorpromazine: Fe (III) system using ascorbic acid as a standard. The method is fast, simple and sensitive; it can be applied for the detection and evaluation of the antioxidant activity of simple or complex systems. PMID- 21235127 TI - Evaluation of some pharmaceutical formulations of lisinopril through dissolution testing. AB - AIM: Lisinopril is a drug of the angiotensin converting enzyme (ACE) inhibitor class that is primarily used in treatment of hypertension, congestive heart failure, heart attacks and also in preventing renal and retinal complications of diabetes. We compared the dissolution profiles of Lisinopril 20 mg tablets (Antibiotice S.A. lasi) and Zestril 20 mg tablets (Astra Zeneca). MATERIAL AND METHOD: Because lisinopril is a third class active substance, we performed dissolution tests in standard media at three pH values: 1.2, 4.5 and 6.8 using the paddle apparatus at 75 rpm. RESULTS: Both pharmaceutical formulations present a dissolution percentage more than 85% (Q) of the labeled amount. CONCLUSION: Both pharmaceutical formulations present similar dissolution profile. Key words: PMID- 21235128 TI - Community pharmacy--ideal location to screen and monitor hypertensive patients. AB - The goals of this study were (a) to create a patient electronic database by filling in the specially designed Patient Data Sheets (PDS) after interviewing hypertensive patients and (b) to evaluate pharmacists' opportunities for intervention in order to improve hypertensive patients' outcomes. MATERIAL AND METHOD: Pharmacists from two Romanian chain community pharmacies interviewed all hypertensive patients that entered the pharmacies during the study period (November-December 2008) and selected 106 subjects using several selection criteria. Pharmacists recorded in specially designed Patient Data Sheet relevant information such as: demographic data, additional diagnostics (if any), lifestyle behaviors and therapeutic data. The records were then transferred into an electronic database and interpreted by the research team. RESULTS: Hypertension (HT) as a single disease was present in only 7 patients (6.6%), most of them being diagnosed with multiple illnesses (such as HT and cardiovascular disease (CVD) in 25 patients, HT and dyslipidemia (DL) in 20 patients). More than half of the subjects (61.3%) declared they have adopted at least one lifestyle modification component and almost 80% of the patients use two, three or more antihypertensive agents in their medication. CONCLUSIONS: The high incidence of complications among our hypertensive subjects justifies implementing blood pressure monitoring programs in community pharmacies and requires pharmacists' intervention for a better management of hypertension. PMID- 21235129 TI - An alternative method for the removal of the ocular artifact from the EEG signal. AB - The aim of this paper is to develop a technique of rejection or minimization of ocular artifacts from the electroencephalographic (EEG) recordings. MATERIAL AND METHOD: The method presented is based on mathematical morphology. The algorithm and the individual structuring element are presented along with the particularities concerning the parameters that characterize the structuring element. RESULTS: The obtained results are shown in a comprehensive form by means of an illustrating example that evidences the efficiency of the method. CONCLUSIONS: The proposed method simplyfies the task of removing the ocular artifacts by means of nonlinear filtering and introduces a new structural element for the job. The results are validated by means of Fourier analysis and this clearly shows its effectiveness. PMID- 21235130 TI - Differential equations with small parameter with applications in radioimmunotherapy. AB - The Akzo Nobel research laboratories formulated this problem in their study of the penetration of radio-labeled antibodies into a tissue that has been infected by a tumor. This study was carried out for diagnostic as well as therapeutic purposes. The treatment of malignant diseases, after its primary treatment by surgery, is either by external beam radiotherapy, which is effective but local, or by chemotherapy, which is effective but not selective. The radiotherapy labelled antibody has to be able to penetrate the whole of the tumour, whereas for imaging only uptake on the surface of the tumour is needed. Factors such as dose, rate delivered, tumor size, and radiosensitivity play a major role in determining therapeutic response, while target-to-nontarget ratios and, particularly, circulating radioactivity to the bone marrow determine the major dose-limiting toxicities. In this article, we introduced a system of differential equations with small parameter with applications in radioimmunotherapy. The problem consists of two partial differential equations. Both the equation of this system includes small parameter epsilon. We introduce the mathematical technique known as boundary function method for singular perturbation system. In this system, the small parameter is an asymptotic variable, different from the independent variable. We write solution of this system in a small parameter, and investigation of asymptotic solution for system. Using the program Matlab and numerical method Runge-Kutta, I did various simulations for different values of biological parameters presented in the model studied. PMID- 21235132 TI - Cold atmospheric plasma jet effects on V79-4 cells. AB - The effects of cold plasmas are due to charged particles, reactive oxygen species (ROS), reactive nitrogen species (RNS), UV photons, and intense electric field. In order to obtain a more efficient action on mammalian cells (useful for cancer therapy), we used in our studies chemically activated cold plasma (He and O2 gas mixture). V79-4 cells were exposed to plasma jet for different time periods (30, 60, 90, 120 and 150s), using different combinations of helium and oxygen inputs (He:2.5l/min + 02:12.5ml/min; He:2.51/min + O2:25ml/min; He:2.51/min + O2:37.5 ml/min). Using MTT test we demonstrated that plasma jet induced cell viability decrease in all cases. The effect of chemically activated cold plasma--apoptosis or necrosis--depends on gas mixture and treatment period. Taking into account that ROS density in cell microenvironment is related to O2 percent in the gas mixture and treatment period, we can presume that cell death is due to ROS produced in plasma jet. PMID- 21235131 TI - The effects of some Curdlan derivatives on Dectin-1 expression and cytokine production in human peripheral blood mononuclear cells. AB - The cells of immune system such as monocytes and macrophages are in first line defence against dangerous signals. In the present paper the recognition of Dectin 1 receptors and the modulation of Interleukin-10 (IL-10) and Tumor Necrosis Factor-alpha (TNF-alpha) cytokine production by Curdlan and Curdlan derivatives in peripheral blood mononuclear cells (PBMCs) were studied. The effect of Curdlan or Curdlan derivatives on the expression of Dectin 1 receptors in PBMCs was revealed by flow-cytometry and the levels of IL-10 and TNFalpha were measured by ELISA kit in supernatants of PBMCs cultured in presence or absence of Curdlan, Curdlan derivatives and LPS. Our results suggested that Curdlan and Curdlan derivatives were able to increase the expression of Dectin-1 receptors on monocyte cells. The combined treatment of Curdlan/Curdlan derivatives and Pam3Cys produced an increase of CD14+ cells possessing Dectin-1 receptors. We demonstrated that Curdlan (at 20 microg unique dose) up-regulated TNF-alpha production and down-regulated IL-10 production in PBMCs. Conversely, Palm CM/SP Curdlan (20 microg unique dose) was able to down-regulate TNF-alpha production and to up-regulate IL-10 production in PBMCs. For instance, Palm CM/SP-Curdlan determined a 5 times decrease of TNF-alpha production than Curdlan. Regarding the effect of Palm CM/SP-Curdlan on IL-10 production in PBMCs, we noticed that the level of IL-10 was about 4 times greater than Curdlan activity. We observed that a combined treatment of Curdlan/Curdlan derivatives and LPS induced about 5 times decrease in TNF-alpha production in PBMCs. IL-10 production induced by Palm CM/SP Curdlan and LPS was about 6 times greater than the combined effect of Curdlan and LPS. The treatment of PBMCs with SP-Curdlan alone affected neither TNF-alpha production nor IL-10 production. Our results are in accordance with other studies demonstrating that Dectin-1 and TLR2/TLR6 signaling combine to enhance the responses triggered by each receptor and the signaling pathway induced by Dectin 1 could mediate the production of pro-inflammatory cytokines. PMID- 21235133 TI - Comparative study of RT23 and IC-65 tuberculins tested on children with tuberculosis. AB - This study, conducted in 2009, proposed to evaluate and compare the biological potency of two different tuberculins, RT23 (Statens Serum Institute, Copenhagen) and IC-65 (Cantacuzino Institute, Bucharest) when administered to 89 children with confirmed tuberculosis, admitted to Paediatric Department of Pneumophtysiology Institute, Bucharest. Mean age of subjects was 10.4 years [SD (standard deviation) = 5.2 years; variance = 27.2], and sex distribution in the group was: 55.1% girls and 44.9% boys. Tuberculin skin tests were performed using Mantoux method simultaneously with the two tuberculins in the same concentration, 2TU (tuberculin units)/0.1 ml. RT23 skin test reactions ranged from 8 mm to 18 mm (mean = 12.8 mm, SD = 2.1 mm, variance = 4.4; median = 12.0), and IC-65 reactions ranged from 8 mm to 18 mm (mean = 13.1 mm; SD = 2.1 mm; variance = 4.3; median = 13.0). The mean difference in paired reaction sizes for the two reagents was 0.04 mm and was not statistically different from zero (P value = 0.3). The difference in reaction sizes was = 2 mm in 70.8% and = 5 mm in 7.9% patients. With a cutoff of 10 mm to define a positive reaction, the results were highly correlated with a sensitivity of 98.9% for RT23 and 97.8% for IC-65. No statistically significant difference was established for the efficacy of the two commercially available PPD TST reagents, both tuberculins appearing to have equivalent potency. PMID- 21235134 TI - Regulatory T cells and TH1/TH2 cytokines as immunodiagnosis keys in systemic autoimmune diseases. AB - We assessed Helper T-cell involvement and possibilities to quantify the cell based immune response in systemic autoimmune diseases (SAID) in 14 systemic lupus erythematosus (SLE) and 7 rheumatoid arthritis (RA) patients. The goals of investigation were T-CD4+/T-CD8+ ratio, regulatory T cells (Treg) status and TH1/TH2 serum cytokine profiles (IFN-gamma and IL-2, respectively IL-4 and IL-6). SLE group proved significant decreased average Treg value as compared to RA group and controls and showed significant low Treg incidence (86% patients). The distribution of high T-CD4+/T-CD8+ ratio registered no significant distinction among LES and RA groups. SAID patients presented low serum IFN-gamma (86% RA, 60% SLE), high IL-2 (57% RA) and high IL-6 (53% LES), but no significant IL-4 modification. We conclude that Treg percentage remains the only cellular criterion for SAID immune evaluation. In the same time, different secretion mechanisms seem to be involved in SAID, i.e. TH2 in SLE and TH1 in RA. PMID- 21235135 TI - Phenotypic and molecular methods used for identification of oral streptococci and related microorganisms. AB - The oral cavity contains the greatest biodiversity, over 70 species being isolated from mouth mucosa, saliva, denture surfaces and/or dental-plaque. The oral streptococci, representing over 80% of the mouth micro flora, are able to synthesize glucosyl-transferases, enzymes involved in glucans production. Glucans are involved in production of an extracellular slime layer promoting adhesion and formation of a dental plaque biofilm. The 43 isolates studied obtained from partially and/or totally edentulous, were identified by VITEK system using gram positive identification cards. Species-specific regions within the genes coding for glucosyl-transferases (gtf genes) were targeted for PCR identification of isolates. Sequencing of 16S rRNA was used as gold standard for strain confirmation. VITEK system identified a number of 11 strains as S. mitis/oralis, 12 strains as S. anginosus/gordonii, 12 strains as S. sanguinis/parasanguinis, 3 strains as S. salivarius, 3 strains as S. plurianimalium, 1 strain as S. cristatus and 1 strain as S. alactolyticus, respectively. The PCR system targeting gtf genes was able to identify S. oralis, S. salivarius and S. gordonii strains. Sequence of 16S rRNA discriminated among streptococci species and revealed 16 strains of Leuconostoc mesenteroides. Many studies are needed in order to select the most reliable phenotypic and genotypic methods in order to improve the identification algorithm for oral streptococci used by clinical laboratories. Their accurate identification is mandatory for better understanding their role in human infections. PMID- 21235136 TI - Antimicrobial activity of some new of 2-(4-ethyl-phenoximethyl) benzoic acid thioureides against planktonic cells. AB - The aim of the present study was to evaluate the antimicrobial activity of new 2 (4-ethyl-phenoxymethyl) benzoic acid thioureides. The synthesis of the new compounds was done in three steps starting with the synthesis of 2-(4-ethyl phenoxymethyl) benzoic acid. In the second stage, the 2-(4-ethyl-phenoxymethyl) benzoyl chloride was prepared and the new thioureides were synthesized in the third step by the reaction of 2-(4-ethyl-phenoxymethyl) benzoyl isothiocyanate with various primary aromatic amines. The original compounds were screened for their in vitro antimicrobial activity against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa) as well as to fungal strains (Candida albicans, Aspergillus niger), using both reference and clinical, multidrug resistant strains. The qualitative screening of the susceptibility spectra of various microbial strains versus these compounds was performed by three adaptated diffusion methods: (1) impregnation of the filter paper disks with the respective substance solutions, (2) distribution of the tested solutions into agar wells and (3) spotting of the respective solutions on the solid medium previously inoculated with the microbial suspensions. The quantitative assay of the antimicrobial activity was performed by broth microdilution method in 96-well microplates in order to establish the minimal inhibitory concentration (MIC). The tested compounds exhibited specific antimicrobial activity with MICs ranging from 3.9 microg/mL to 250 microg/mL. PMID- 21235137 TI - Architecture and physiology of microbial biofilms. AB - The microbial biofilm, composed by a single or multiple species, is defined as a sessile community of microbial cells irreversibly attached to a substratum or an interface and also among them, embedded in a matrix of extracellular polymeric substances as their own products, exhibiting a modified phenotype concerning the rate of growth and gene transcription. The biofilm is considered a primitive form of cellular differentiation, with primitive circulatory system, homeostasis and "integrality", similar to eukaryotic tissues in their intercellular cooperation. A microbial biofilm is considered to be the most successful and competitive expression of the prokaryotic genome--biofilm cells being metabolically more efficient and well protected, exhibiting resistance to different stress factors, including host defence mechanisms and antibiotics. The ability of the bacterial cells to behave as a community is the result of a complex intra- and inter cellular communication based on a signaling system regulated by quorum-sensing and response (QS), mechanism ubiquitous in bacteria, and implicated in the regulation of very different and complex physiological processes, depending on cellular density. The language used for this intercellular communication is based on small, self-generated signal molecules known as bacterial pheromones with different chemical structures (N-homoserine lactones and derivatives in Gram negative, and octapeptides, amino acids respectively in Gram-positive bacteria). The signal molecules level required for a specific response is very low in comparison with those of intracellular hormones. The aim of this review is to present the development, architecture and physiology of microbial biofilms. PMID- 21235138 TI - Protect yourself from rejections: ICD-9-CM coding update. PMID- 21235139 TI - Fast-track sales of primary care practices. PMID- 21235140 TI - Preparing for change: HIPAA Version 5010 and ICD-10. PMID- 21235141 TI - Healthcare crisis in 2012: fact or fiction? PMID- 21235142 TI - With time comes performance. PMID- 21235143 TI - Strut your organizationaI governance savvy. PMID- 21235145 TI - Reduce conflict: clarify board duties. PMID- 21235144 TI - How to improve your practice's approach to information governance. PMID- 21235146 TI - Medical philanthropy creates global community. PMID- 21235147 TI - Integrate or disintegrate: integrated delivery systems, a re-emerging trend. PMID- 21235148 TI - Making a difference in the delivery of healthcare. PMID- 21235149 TI - Hospital reaps rewards from RVU incentive-based program. PMID- 21235150 TI - Feeding a need. PMID- 21235151 TI - Advanced treatment of dyeing wastewater towards reuse by the combined Fenton oxidation and membrane bioreactor process. AB - The performance of combined Fenton oxidation and membrane bioreactor (MBR) process for the advanced treatment of an effluent from an integrated dyeing wastewater treatment plant was evaluated. The experimental results revealed that under the optimum Fenton oxidation conditions (initial pH 5, H2O2 dosage 17 mmol/L, and Fe2+ 1.7 mmol/L) the average total organic carbon (TOC) and color removal ratios were 39.3% and 69.5% after 35 min of reaction, respectively. Results from Zahn-Wallens Test also represented that Fenton process was effective to enhance the biodegradability of the test wastewater. As for the further purification of MBR process, TOC removal capacity was examined at different hydraulic retention times (HRT) of 10, 18 and 25 hr. Under the optimum HRT of 18 hr, the average TOC concentration and color of the final MBR effluent were 16.8 mg/L and 2 dilution time, respectively. The sludge yield coefficient was 0.13 g MLSS/g TOC and TOC degradation rate was 0.078 kg TOC/(m3 x day). The final effluent of MBR can meet the reuse criteria of urban recycling water - water quality standard for miscellaneous water consumption GBT18920-2002. PMID- 21235152 TI - Effect of phosphorus fluctuation caused by river water dilution in eutrophic lake on competition between blue-green alga Microcystis aeruginosa and diatom Cyclotella sp. AB - Tega-numa (Lake Tega) is one of the eutrophic lakes in Japan. For the improvement of water quality in Lake Tega, the North-chiba Water Conveyance Channel was constructed in 2000, which transfer water from Tone River into the lake. After 2000, the dominant species of diatoms, mainly Cyclotella sp., have been replacing blue-green algae, mainly Microcystis aeruginosa in Lake Tega. This transition of dominant species would be due to the dilution, but the detail mechanism has not been understood yet. This study examined the relationship between phosphorus fluctuation caused by river water dilution to Lake Tega and dominance of algal species, M. aeruginosa or Cyclotella sp. based on the single-species and the mixed-species culture experiments. The single-species culture experiment showed that the half-saturation constant and uptake rate of phosphorus were one order lower and seven times higher for M. aeruginosa than those for Cyclotella sp. These findings implied that M. aeruginosa would possess a potential for the growth and survival over Cyclotella sp. in the phosphorus limited condition. The superiority of M. aeruginosa was reflected in the outcome of the mixed-species culture experiment, i.e., dominance of M. aeruginosa, even phosphorus concentration was lowered to 0.01 mg-P/L. Therefore, it could be concluded that the decrease in phosphorus concentration due to the river water dilution to Lake Tega would be interpreted as a minor factor for the transition of dominant species from M. aeruginosa to Cyclotella sp. PMID- 21235153 TI - Impact of different benthic animals on phosphorus dynamics across the sediment water interface. AB - As a diagenetic progress, bioturbation influences solute exchange across the sediment-water interface (SWI). Different benthic animals have various mechanical activities in sediment, thereby they may have different effects on solute exchange across the SWI. This laboratory study examined the impacts of different benthic animals on phosphorus dynamics across the SWI. Tubificid worms and Chironomidae larvae were introduced as model organisms which, based on their mechanical activities, belong to upward-conveyors and gallery-diffusers, respectively. The microcosm simulation study was carried out with a continuous flow culture system, and all sediment, water, and worms and larvae specimens were sampled from Taihu Lake, China. To compare their bioturbation effects, the same biomass (17.1 g wet weight (ww)/m2) was adopted for worms and larvae. Worms altered no oxygen penetration depth in sediment, while larvae increased the O2 penetration depth, compared to the control treatment. Their emergence also enhanced sediment O2 uptake. The oxidation of ferrous iron in pore water produced ferric iron oxyhydroxides that adsorbed soluble reactive phosphorus (SRP) from the overlying water and pore water. Larvae built obviously oxidized tubes with about 2 mm diameter and the maximum length of 6 cm in sediment, and significantly decreased ferrous iron and SRP in the pore water compared to the control and worms treatments. Worms constructed no visually-oxidized galleries in the sediment in contrast to larvae, and they did not significantly alter SRP in the pore water relative to the control treatment. The adsorption of ferric iron oxyhydroxides to SRP caused by worms and larvae inhibited SRP release from sediment. Comparatively, worms inhibited more SRP release than larvae based on the same biomass, as they successively renewed the ferric iron oxyhydroxides rich oxidation layer through their deposition. PMID- 21235154 TI - Effect of high-strength ammonia nitrogen acclimation on sludge activity in sequencing batch reactor. AB - The effect of high-strength ammonia nitrogen acclimation on sludge activity in sequencing batch reactor (SBR) was investigated. Two batch experiments, RUN1 and RUN2, were conducted with the influent ammonia nitrogen concentrations 60 and 500 mg/L, respectively. The sludges inoculated from RUN1 and RUN2 were used to treat a series of influent with ammonia nitrogen concentrations of 59, 232, 368, 604 and 1152 mg/L. It is found that the activated sludge acclimated to higher ammonia nitrogen concentrations revealed higher COD and NH4(+)-N removal efficiencies, and slower DHA decrease. The results confirmed that the activities of the bacteria in activated sludge in SBR were inhibited by high-strength ammonia nitrogen, whereas the activated sludge acclimated to high-strength ammonia nitrogen showed substantial resistance to inhibition by influents containing high levels of ammonia nitrogen. PMID- 21235155 TI - Characteristics and model studies for fluoride and arsenic adsorption on goethite. AB - Fluoride and arsenic are major anionic elements of concern in drinking water treatment. The effects of contact time, pH, surface loading and ionic strength on adsorption of fluoride and As(V) were investigated using batch methods. Adsorption of fluoride and As(V) onto goethite obeyed a pseudo second-order rate law. Through experimental data and adsorption kinetic analysis, the affinity of As(V) onto goethite was stronger than fluoride. Fluoride and As(V) uptake by goethite all decreased with pH increasing at the same surface loading; however, ionic strength had slight influence on their adsorption. A surface sites-species model was used to quantify the adsorption of fluoride and As(V) onto goethite as function of pH and surface loading. This model can satisfactorily predict their adsorption characteristics with several adsorption constants. PMID- 21235156 TI - Comparative characterization of two natural humic acids in the Pearl River Basin, China and their environmental implications. AB - Two humic acids (HAs) were isolated from contaminated river sediments present under comparative conditions in the Pearl River Basin, China. YFHA (the HA extracted at an open pyrite mining area in Yunfu) exhibited a lower absorption intensity for certain bands in the Fourier transform infrared spectra, a lower E4/E6 value (the UV absorbances at 465 nm (E4) and 665 nm (E6)), a lower apparent molecular weight, a lower polarity and a lower oxygen functionality in comparison with GZHA (the HA isolated at an urban living area in Guangzhou). All these differences indicated a higher degree of humification of YFHA than GZHA. Overall, the enrichment patterns of permanent heavy metals in the studied HAs were similar to those in corresponding sediments. In particular, YFHA exhibited high enrichment of trace element Tl, a characteristic concomitant from the mining of the pyrite minerals. The adsorption isotherms of two HAs for goethite and pyrolusite, two representative geological materials, conformed to the Langmuir equation. Based on the qualitative relationships between the Langmuir constants of the adsorption isotherms and the chemical characteristics of HAs, the main mechanism of HA adsorption on these materials was suggested to be hydrophobic interaction. This study highlighted the promising use of HA as a peculiar bio indicator of uncommon trace metal contaminations. The HA adsorption mechanism on representative geological materials further provided a theoretical basis for the study on the unusual metal behavior in complex environmental settings. PMID- 21235157 TI - Uncertainties in stormwater runoff data collection from a small urban catchment, Southeast China. AB - Monitoring data are often used to identify stormwater runoff characteristics and in stormwater runoff modelling without consideration of their inherent uncertainties. Integrated with discrete sample analysis and error propagation analysis, this study attempted to quantify the uncertainties of discrete chemical oxygen demand (COD), total suspended solids (TSS) concentration, stormwater flowrate, stormwater event volumes, COD event mean concentration (EMC), and COD event loads in terms of flow measurement, sample collection, storage and laboratory analysis. The results showed that the uncertainties due to sample collection, storage and laboratory analysis of COD from stormwater runoff are 13.99%, 19.48% and 12.28%. Meanwhile, flow measurement uncertainty was 12.82%, and the sample collection uncertainty of TSS from stormwater runoff was 31.63%. Based on the law of propagation of uncertainties, the uncertainties regarding event flow volume, COD EMC and COD event loads were quantified as 7.03%, 10.26% and 18.47%. PMID- 21235158 TI - Nutrient concentration variations during Oenanthe javanica growth and decay in the ecological floating bed system. AB - The ecological floating bed system is a natural alternative to technical methods of wastewater treatment and involves complex processes induced by plants or microorganisms in the wastewater. This study aimed to identify nutrient concentration variations during Oenanthe javanica (Blume) DC growth and decay in the ecological floating bed system. Results showed that the third-order polynomial equation was suitable to describe pollutant concentration changes, showing that the effect of O. javanica ecological floating bed system on polluted water could be divided into the purification phase and decay phase. During the purification phase, nutrient concentrations rapidly decreased because O. javanica influenced water microbial communities and water physical parameters (i.e., dissolved oxygen, pH, and temperature), and had a direct uptake of nutrients. However, during the decay phase, nitrogen and phosphorus concentrations in the plant tissues decreased, and these lost nutrients ultimately transferred to water and led to water quality deterioration. Results also showed that the uptake and storage of O. javanica in nutrients were temporary and the plant served only as media of the nutrients removed from the water. Under these circumstances, harvesting was an appropriate intervention to improve the treatment efficiency of O. javanica ecological floating bed system. PMID- 21235159 TI - Distribution of chironomidae (Insecta: Diptera) in polluted rivers of the Juru River Basin, Penang, Malaysia. AB - The influence of physical and chemical parameters on the abundance and diversity of chironomids was studied in six rivers with moderate to highly polluted water in the Juru River Basin. The rivers: Ceruk Tok Kun (CTKR) as reference site, and polluted rivers of Pasir (PR), Juru (JR), Permatang Rawa (PRR), Ara (AR) and Kilang Ubi (KUR) were sampled over a period of five months (November 2007-March 2008). Nine chirnomid species: Chironimus kiiensis, C. javanus, Polypedilum trigonus, Microchironomus sp., Dicrotendipes sp., Tanytarsus formosanus, Clinotanypus sp., Tanypus punctipennis and Fittkauimyia sp. were identified. Assessment of their relationships with several environmental parameters was performed using the canonical correspondence analysis (CCA). Tanytarsus formosanus was the most dominant in the relatively clean CTKR and moderately polluted JR with mean densities of 19.66 and 25.32 m(-2), respectively while C. kiiensis was abundant in more polluted rivers. Tanytarsus formosanus, Dicrotendipes sp. and Microchironomus sp. were grouped under moderate to high water temperature, total organic matter (TOM), total suspended solids (TSS), velocity, pH, phosphates and sulphates. However, Tanypus punctipennis, Fittkauimyia sp., and Clinotanypus sp. were associated with high contents of river sediment such as TOM, Zn and Mn and water ammonium-N and nitrate-N and they were associated with higher dissolved oxygen (DO) content in the water. Chironomus kiiensis, C. javanus and P. trigonus showed positive relationships with TOM, ammonium-N and nitrate-N as well as trace metals of Zn, Cu and Mn. These three species could be considered as tolerant species since they have the ability to survive in extreme environmental conditions with low DO and high concentrations of pollutants. Based on the water parameter scores in all rivers, the highest diversity of chironomid larvae was reported in CTKR. With higher concentrations of organic and/or inorganic pollutants as reported in PPR, KUR and AR, the chironomid larval diversity decreased, and the abundance of tolerant species, mainly Chironomus spp., increased. PMID- 21235160 TI - Characterization of dissolved organic matter in urban sewage using excitation emission matrix fluorescence spectroscopy and parallel factor analysis. AB - Wastewater dissolved organic matter (DOM) from different processing stages of a sewage treatment plant in Xiamen was characterized using fluorescence and absorption spectroscopy. Parallel factor analysis modeling of excitation-emission matrix spectra revealed five fluorescent components occurring in sewage DOM: one protein-like (C1), three humic-like (C2, C4 and C5) and one xenobiotic-like (C3) components. During the aerated grit chamber and primary sedimentation tank stage, there was only a slight decrease in fluorescence intensity and the absorption coefficient at 350 nm (a350). During the second aeration stage, high concentration of protein-like and short-wavelength-excited humic-like components were significantly degraded accompanied by significant loss of DOC (80%) and a350 (30%), indicating that C1 and C2 were the dominant constituents of sewage DOM. As a result, long-wavelength-excited C4 and C5 became the dominant humic-like components and the DOM molecular size inferred from the variation of spectral slope S (300-650 nm) and specific absorption (a280/DOC) increased. Combination use of F(max) of C1 and the ratio of C1/C5, or a350 may provide a quantitative indication for the relative amount of raw or treated sewage in aquatic environment. PMID- 21235161 TI - Nonylphenol in bivalves and sediments in the northeast coast of China. AB - To understand nonylphenol (NP) contamination in the northeast coastal environment in China, NP was determined in 19 sediment and 20 bivalve samples collected during November 2005. NP was identified in all sediment samples in the range of 8.8 to 1.0 x 10(3) ng/g dw (dry weight), with an average of 0.12 x 10(3) ng/g dw. Most of the bivalve samples (oysters and mussels) contained detectable amounts of NP that ranged from ND (not detected) to 7.6 x 10(3) ng/g dw, with an average value of 0.79 x 10(3) ng/g dw. These results indicated that NP is ubiquitous in sediments and bivalves from the northeast coast of China, and are even present in bivalves sold as seafood. Serious contamination with NP was recorded off the coast of Bohai Strait and in semi-enclosed coastal environment such as Jiaozhou Bay and Liaodong Bay. Possible environmental and human health implications were understood in this study. PMID- 21235162 TI - Effects of pH and particle size on kinetics of nitrobenzene reduction by zero valent iron. AB - Nitrobenzene has been considered as a significant groundwater contaminant due to its wide usage in explosives, insecticides, herbicides, pharmaceuticals and dyes. Nitrobenzene is of environmental concern because of its toxicity. In the presence of zero-valent iron (ZVI), reduction of the nitro group is the dominant transformation process for nitrobenzene. A series of experiments were carried out to investigate the kinetics of nitrobenzene reduction by ZVI and the effects of pH and ZVI particle size on nitrobenzene removal in groundwater. The results indicated that nitrobenzene could be reduced to aniline by ZVI; the reduction of nitrobenzene by ZVI followed a pseudo first-order kinetics; the observed nitrobenzene reduction rate constant (k(obs)) was 0.0006 min(-1) and the half life of nitrobenzene (t1/2) was 115.5 min; the mass balance achieved 87.5% for nitrobenzene reduction by the 1 mm ZVI particle and the final removal efficiency was 80.98%. In addition, the pH and ZVI particle size were found to exhibit significant influences on the nitrobenzene reduction. The observed nitrobenzene reduction rate constant linearly decreased with increase pH and the data fitted on polynomial regression equation for the observed nitrobenzene reduction rate constant and ZVI particle size. Therefore, use of ZVI based permeable reactive barrier technology to remedy nitrobenzene contaminated groundwater was feasible. PMID- 21235163 TI - Carbonaceous particles in the atmosphere and precipitation of the Nam Co region, central Tibet. AB - A continuous air and precipitation sampling for carbonaceous particles was conducted in a field observatory beside Nam Co, Central Tibetan Plateau during July of 2006 through January of 2007. Organic carbon (OC) was the dominant composition of the carbonaceous particles both in the atmosphere (1660 ng/m3) and precipitation (476 ng/g) in this area, while the average elemental carbon (BC) concentrations in the atmosphere and precipitation were only 82 ng/m3 and 8 ng/g, respectively. Very high OC/BC ratio suggested local secondary organic carbon could be a dominant contribution to OC over the Nam Co region, while BC could be mainly originated from Southern Asia, as indicated by trajectory analysis and aerosol optical depth. Comparison between the BC concentrations measured in Lhasa, those at "Nepal Climate Observatory at Pyramid (NCO-P)" site on the southern slope of the Himalayas, and Nam Co suggested BC in the Nam Co region reflected a background with weak anthropogenic disturbances and the emissions from Lhasa might have little impact on the atmospheric environment here, while the pollutants from the Indo-Gangetic Basin of Southern Asia could be transported to the Nam Co region by both the summer monsoon and the westerly. PMID- 21235164 TI - Characterization of personal exposure concentration of fine particles for adults and children exposed to high ambient concentrations in Beijing, China. AB - In China, the health risk from overexposure to particles is becoming an important public health concern. To investigate daily exposure characteristics to PM2.5 with high ambient concentration in urban area, a personal exposure study was conducted for school children, and office workers in Beijing, China. For all participants (N = 114), the mean personal 24-hr exposure concentration was 102.5, 14.7, 0.093, 0.528, 0.934, 0.174 and 0.703 microg/m3 for PM2.5, black carbon, Mn, Al, Ca, Pb, and Fe. Children's exposure concentrations of PM2.5 were 4-5 times higher than those in related studies. The ambient concentration of PM2.5 (128.5 microg/m3) was significantly higher than the personal exposure concentration (P < 0.05), and exceed the reference concentration (25 microg/m3) of WHO air quality guideline. Good correlation relationships and significant differences were identified between ambient concentration and personal exposure concentration. The relationships indicate that the ambient concentration is the main factor influencing personal exposure concentration, but is not a good indicator of personal exposure concentration. Outdoor activities (commute mode, exposure to heating, workday or weekend travel) influenced personal exposure concentrations significantly, but the magnitude of the influence from indoor activities (exposure to cooking) was masked by the high ambient concentrations. PMID- 21235165 TI - Response of runoff and soil loss to reforestation and rainfall type in red soil region of southern China. AB - To evaluate the long-term effects of reforestation types on soil erosion on degraded land, vegetation and soil properties under conventional sloping farmland (CSF) and three different reforestation types including a Pinus massoniana secondary forest (PSF), an Eucommia ulmoides artificial economic forest (EEF) and a natural succession type forest (NST), were investigated at runoff plot scale over a six-year period in a red soil region of southern China. One hundred and thirty erosive rainfall events generating runoff in plots were grouped into four rainfall types by means of K-mean clustering method. Erosive rainfall type I is the dominant rainfall type. The amount of runoff and the soil loss under erosive rainfall type III were the most, followed by rain-fall type II, IV and I. Compared with CSF treatment, reforestation treatments decreased the average annual runoff depth and the soil loss by 25.5%-61.8% and 93.9%-96.2% during the study period respectively. Meanwhile, runoff depth at PSF and EEF treatments was significantly lower than that in NST treatment, but no significant difference existed in soil erosion modulus among the three reforestation treatments. This is mainly due to the improved vegetation properties (i.e., vegetation coverage, biomass of above- and below-ground and litter-fall mass) and soil properties (i.e., bulk density, total porosity, infiltration rate and organic carbon content) in the three reforestation treatments compared to CSF treatment. The PSF and EEF are recommended as the preferred reforestation types to control runoff and soil erosion in the red soil region of southern China, with the NST potentially being used as an important supplement. PMID- 21235166 TI - Photodegradation of new herbicide HW-02 in organic solvents. AB - HW-02 is a new organophosphates herbicide which is discovered and developed in China. The kinetics and mechanism of HW-02 photodegradation in the organic solvents were studied at 25 degrees C under the irradiation of ultraviolet light. The results showed that photochemical reaction of HW-02 in organic solvents such as n-hexane, methanol, dimethyl benzene and acetone under UV light could be well described by the first kinetic equation, and the photodegradation efficiency decreased with a order of n-hexane > methanol > xylene > acetone. The photodegradation efficiency constant of HW-02 in n-hexane, methanol, xylene and acetone were 4.951 x 10(-2), 3.253 x 10(-2), 2.377 x 10(-2) and 1.628 x 10-2 min( 1), and the corresponding half-lives were 13.99, 21.20, 29.15 and 42.56 min, respectively. By separation and identification of photoproducts using GC-MS, it could be concluded that HW-02 was photolyzed through ester cleavage, photo dechlorination and photoisomerization of the molecule itself. PMID- 21235167 TI - Response of bacteria in the deep-sea sediments and the Antarctic soils to carbohydrates: effects on ectoenzyme activity and bacterial community. AB - The response of bacteria to various carbohydrates in the deep-sea sediments and the Antarctic soils was investigated using cellulose, chitin, and olive oil. It was found that the carbohydrates significantly increased the corresponding specific ectoenzyme activity (beta-glucosidase, beta-N-acetylglucosaminidase, lipase) in the samples from deep-sea sediments. In the case of Antarctic soil samples, the cellulose or olive oil amendments had minor or no effect on beta glucosidase or lipase activity, except the chitin which stimulated beta-N acetylglucosaminidase production. The responses of the bacteria in the deep-sea sediment sample WP02-3 and the Antarctic soil sample CC-TY2 towards the chitin amendment were further analyzed. Chitin amendments were shown to stimulate the ectoenzyme activity in all the tested sediments and the soils. The bacterial response before and after the carbohydrates amendments were compared by denaturing gradient gel electrophoresis and quantitative competitive polymerase chain reaction. Significant changes were found in the structure and density of the bacterial community in the deep sea sediments as compared to the Antarctic soil sample, where the effects were relatively lower. There was no change in the bacterial population in both studied samples in response to carbohydrates amendments. These data indicate that the bacterial communities in the oligotrophic deep-sea sediments are more dynamic than that in the Antarctic soils as they respond to the nutrient sources efficiently by regulation of ectoenzyme activity and/or changing community structure. PMID- 21235168 TI - Ecophysiological responses of winter wheat seedling to aerosol wet deposition of Xi'an area, China. AB - Aerosol leads to 30% reduction in solar radiation reaching the earth's surface, and a similar reduction in crops yield for both wheat and rice. To determine the effect of aerosol wet deposition on crops, aerosol samples were collected in September, 2006 at Xi'an urban suburb (34 degrees 44'N, 109 degrees 49'E), and wheat seedlings were treated with aerosol of different concentrations in laboratory conditions. Changes in physiological and biochemical parameters of wheat seedlings were measured. In comparison with the control, the activities of superoxide dismudase (SOD) and catalase (CAT) and the concentration malondialdehyde (MDA) and oxidized glutathione (GSSG) of wheat seedlings increased progressively with increasing concentrations of added aerosol, while the opposite trend was seen for the activities of nitric oxide synthase (NOS), the concentrations of glutathione (GSH) and nitric oxide (NO), and the ratio of GSH/GSSG. When the seedlings were treated with the aerosol of 1 and 2 mg/L, the coleoptile elongation, shoot elongation and biomass accumulation were increased, the effect at treatment of 2 mg/L was most significant. However, aerosol treatments with rates of 3 and 4 mg/L resulted in a decrease in coleoptile elongation, shoot elongation and biomass accumulation in seedlings, and significant effect was for the treatment of 4 mg/L. Hence, lower concentrations of aerosol wet deposition were in favor of crops growth, but its higher concentrations could result in deleterious effects for crops and decreased crops growth. PMID- 21235169 TI - Heavy metals in rice and garden vegetables and their potential health risks to inhabitants in the vicinity of an industrial zone in Jiangsu, China. AB - Contamination of soil and agricultural products by heavy metals resulting from rapid industrial development has caused major concern. In this study, we investigated heavy metal (Cu, Zn, Pb, Cr, Hg and Cd) concentrations in rice and garden vegetables, as well as in cultivated soils, in a rural-industrial developed region in southern Jiangsu, China, and estimated the potential health risks of metals to the inhabitants via consumption of locally produced rice and garden vegetables. A questionnaire-based survey on dietary consumption rates of foodstuffs showed that rice and vegetables accounted for 64% of total foodstuffs consumed, and over 60% of rice and vegetables were grown in the local region. Average concentrations of Cr, Cu, Zn, Cd, Hg and Pb were 0.75, 2.64, 12.00, 0.014, 0.006 and 0.054 mg/kg dw (dry weight) in rice and were 0.67, 1.18, 4.34, 0.011, 0.002 and 0.058 mg/kg fw (fresh weight) in garden vegetables, respectively. These values were all below the maximum allowable concentration in food in China except for Cr in vegetables. Leafy vegetables had higher metal concentrations than solanaceae vegetables. Average daily intake of Cr, Cu, Zn, Cd, Hg and Pb through the consumption of rice and garden vegetables were 5.66, 16.90, 74.21, 0.10, 0.04 and 0.43 microg/(kg x day), respectively. Although Hazard Quotient values of individual metals were all lower than 1, when all six metal intakes via self-planted rice and garden vegetables were combined, the Hazard Index value was close to 1. Potential health risks from exposure to heavy metals in self-planted rice and garden vegetables need more attention. PMID- 21235170 TI - Efficient microwave-assisted photocatalytic degradation of endocrine disruptor dimethyl phthalate over composite catalyst ZrO(x)/ZnO. AB - A highly active ZrO(x)/ZnO catalyst for microwave-assisted photocatalytic (MW/PC) degradation of endocrine disruptor dimethyl phthalate (DMP) has been prepared via cetyltrimethylammonium assisted hydrothermal method. The ZrO(x)/ZnO was characterized by XPS, XRD, UV-Vis, BET and SEM techniques. The XPS result showed that Zr oxides with different valences (+2, +3, +4) co-existed in ZrO(x)/ZnO. By using the ZrO(x)/ZnO (0.1 g), the TOC removal efficiency of DMP (100 mL of 50 mg/L) was 88% after 30 min reaction, which was about 15% higher than P25 TiO2. It was found that the removal process of DMP by MW/PC followed pseudo first-order kinetics in all cases, and ZrO(x)/ZnO significantly accelerated the degradation of DMP. The degradation half-life time of DMP was shortened 45% compared with P25 TiO2. A possible catalytic mechanism was proposed based on microwave response and interfacial charge transfer. ZrO(x)/ZnO could be reused for six times without obvious decrease in catalytic activity. The study offers new insights into designing highly efficient catalysts for MW/PC process and is applicable for MW/PC environmental remediation. PMID- 21235171 TI - Perchlorate removal using granular activated carbon supported iron compounds: synthesis, characterization and reactivity. AB - Synthesis and use of the iron compounds supported on granular activated carbon (ICs/GAC) have shown significant environmental implications for perchlorate (ClO4 ) removal. ICs/GAC was synthesized via hydrolyzing FeSO4 x 7H2O on GAC, reduced by NaBH4 solution in polyethylene glycol 6000 and ethanol solution, dried in vacuum condition and exposed to air. Synthesized ICs/GAC was characterized using transmission electron micrograph (TEM), Brunauer-Emmett-Teller, X-ray photoelectron spectroscopy (XPS). ICs/GAC was determined to be containing a large amount of FeOHSO4, Fe2O3 and a small amount of zero-valent iron (ZVI) nanoparticles according to TEM and XPS measurements. Batch static kinetic tests showed that 97% of ClO4- was removed within 10 hr at 90 degrees C and 86% of ClO4 was removed within 12 hr at 25 degrees C, at ICs/GAC dosage of 20 g/L. The experimental results also showed that FeOHSO4 and Fe2O3 nanoparticles have the function of perchlorate adsorption and play important roles in ClO4- removal. The activation energy (E(a)) was determined to be 9.56 kJ/mol. PMID- 21235172 TI - Metal chlorides loaded on activated carbon to capture elemental mercury. AB - Activated carbon (AC) was considered to be an effective sorbent to control mercury in combustion systems. However, its capture capacity was low and it required a high carbon-to-mercury mass ratio. AC loaded with catalyst showed a high elemental mercury (Hg0) capture capacity due to large surface area of AC and high oxidization ability of catalyst. In this study, several metal chlorides and metal oxides were used to promote the sorption capacity of AC. As a result, metal chlorides were better than metal oxides loaded on AC to remove gaseous mercury. X ray diffractometer (XRD), thermogravimetric analyzer (TGA) and specific surface area by Brunauer-Emmett-Teller method (BET) analysis showed the main mechanisms: first, AC had an enormous surface area for loading enough MClx; second, Cl and MxOy were generated during pyrogenation of MClx; finally, there were lots of active elements such as Cl and MxOy which could react with elemental mercury and convert it to mercury oxide and mercury chloride. The HgO and HgCl2 might be released from AC's porous structure by thermo regeneration. A catalytic chemisorption mechanism predominates the sorption process of elemental mercury. As Co and Mn were valence variable metal elements, their catalytic effect on Hg0 oxidization may accelerate both oxidation and halogenation of Hg0. The sorbents loaded with metal chlorides possessed a synergistic function of catalytic effect of valence variable metal and chlorine oxidation. PMID- 21235173 TI - Extraction of 17beta-estradiol in water using non-imprinted polymer submicron particles in membrane filters. AB - 17beta-Estradiol (E2) is an endocrine disrupting chemical of harm to both animals and human beings at a low concentration level (ng/L). It cannot be completely removed by wastewater treatments, and is often detected in both environment and drinking waters. The purpose of this feasibility study, towards environmental engineering in the field of water analysis and treatment, was to remove E2 by extraction using non-imprinted polymer (NIP) submicron particles. Experimental results showed that 0.5 mg/L of E2 could be completely extracted by adding 10 mg of NIP particles directly into 10 mL of water. However, the extraction efficiency decreased to 64% for 100 mL of water, prefilling the NIP particles inside a membrane filter showed a potential for water treatment of a large volume, requiring no effort to distribute the particles uniformly in the water. High extraction efficiency (80 +/- 10)% for E2 was achieved for 100 mL of water. A total mass of 0.29 mg E2 was extracted from 1000 mL of water containing 0.8 mg/L E2 (by using only 10 mg of NIP particles). Both efficiency and mass capacity can be increased, by scaling up the amount of NIP particles, towards environmental engineering applications. PMID- 21235174 TI - Fish transplantation and stress-related biomarkers as useful tools for assessing water quality. AB - The active biomonitoring (ABM) approach was investigated using species of indigenous (from a pristine site) and transplanted (to a polluted area) fish Carassius auratus as an indicator organism of water/sediment pollution in Taihu Lake, a highly urbanized and industrialized area. The biotransformation enzymes 7 ethoxyresorufin-O-deethylase (EROD), reduced glutathione (GSH) content, catalase activities (CAT) and lipoperoxidation (as MDA) in liver were determined as stress related biomarkers during the field exposure period. At the same time, the contents of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs) and heavy metals in the surface sediments of biomonitoring sites were also determined. The results indicate that the in situ exposed organisms were stressed. The marked increases of EROD, GSH, CAT and MDA in transplanted animals, suggested their potential application as biomarkers in pollution monitoring. Integrated biomarker response (IBR) was used to evaluate an integrated impact of toxicants from different polluted sites. PMID- 21235175 TI - Seasonal variability in CDOM absorption and fluorescence properties in the Barataria Basin, Louisiana, USA. AB - Absorption and fluorescence properties of chromophoric dissolved organic matter (CDOM) along a 124 km transect in the Barataria Basin, a large estuary located in Louisiana, USA, were investigated during high and low flow periods of the Mississippi River in the spring and winter of 2008-2009. Mean CDOM absorption at 355 nm from the marine to the freshwater end member stations ranged from (3.25 +/ 0.56) to (20.76 +/- 2.43) m(-1) for the three month high flow period whereas it varied from (1.48 +/- 1.08) to (25.45 +/- 7.03) m(-1) for the same stations during low flow period. Corresponding salinity values at these stations indicated the influence of river and shelf exchanges in the lower basin and precipitation and runoff in the upper basin. An inverse relationship of CDOM absorbance and fluorescence with salinity observed in the basin could be a useful indicator of salinity. CDOM fluorescence also varied over a large range showing an approximately 8 to 12-fold increase between the marine and freshwater end members for the two flow seasons. Excitation-emission matrix spectral plots indicated the presence of various fluorescence components with highest being the A-peak, lowest the T-peak, and the C and M-peaks showing similar trends along the transect. During low flow season the A/C ratio were well correlated with station locations indicating increased terrestrial influence towards the upper basin. CDOM absorption and fluorescence at 355 nm were highly correlated and independent of CDOM sources suggesting that fluorescence could be used to characterize CDOM in the basin. PMID- 21235176 TI - Phytoplankton community from Lake Taihu, China, has dissimilar responses to inorganic and organic nutrients. AB - To evaluate the response of phytoplankton from Lake Taihu to different types of nutrients, the phytoplankton responses were measured after adding inorganic nitrogen (N) and phosphorus (P) or decomposed algal scum (Microcystis spp.) into the lake water. Both types of nutrients promoted an increase in phytoplankton biomass as determined by chlorophyll a and algal wet weight. The addition of decomposed algal scum resulted in a significantly greater phytoplankton response than the addition of inorganic N and P alone. The dissolved inorganic N and P in the inorganic nutrient treatment were found not limit phytoplankton growth. The higher algal biomass obtained in the treatment with decomposed algal scum indicated the importance of other organic nutrients besides N and P such as trace elements, as well as the importance of the form of N since the levels of ammonia nitrogen (NH4(+)-N) from the decomposed algal treatment were actually higher than that of the inorganic N and P addition. Microcystis spp. (Cyanobacteria), Scenedesmus spp. (Chlorophyta) and Synechocystis spp. (Cyanobacteria) were the dominant taxa in the control, inorganic N and P treatment, and the decomposed algal scum treatment, respectively. Microcystis never bloomed in response to both types of nutrient additions indicating that the bloom propagation is not solely related to nutrient additions, but may be related to the absence of selective grazing from zooplankton. PMID- 21235177 TI - Impacts of algal blooms removal by chitosan-modified soils on zooplankton community in Taihu Lake, China. AB - It is important to assess the effect on zooplankton when perform the environmental protection or restoration technology, especially removing algal blooms, because algae were the major primary producer in algal lakes. The influence on zooplankton community after half a year of algal blooms removed by chitosan-modified soils in Taihu Lake was assessed and the rationality of carrying out the process semiannually was evaluated in the present study. Morphological composition and genetic diversity of zooplankton community were investigated by microscope checkup and polymerase chain reaction-denatured gradient gel electrophoresis (PCR-DGGE). A total of 44 zooplankton taxa (23 protozoa, 17 rotifers, 3 copepoda and 1 cladocera) were detected by microscope checkup, and a total of 91 bands (28 bands amplified by primers F1427-GC and R1616, 63 bands amplified by primers Fung-GC and NS1) were detected by PCR-DGGE. The results of cluster analysis or detrended correspondence analysis indicated that there was no considerable difference in morphological composition of zooplankton and DGGE profiles between experimental and control sites, and DGGE profiles could represent the biologic diversity. The study showed that zooplankton community could recover original condition after half year of algal blooms removed by chitosan-modified soils and it was acceptable to apply this process semiannually. In addition, the results revealed that PCR-DGGE could be applied to investigate the impacts of the environmental protection or restoration engineering on zooplankton community diversity. PMID- 21235178 TI - Determination of N-nitrosodimethylamine in drinking water by UPLC-MS/MS. AB - The method for detecting N-nitrosodimethylamine (NDMA) in drinking water using ultra performance liquid chromatography (UPLC) coupled with tandem mass spectrometry (MS/MS) was improved by optimizing the clean-up procedure to remove the matrix interference in pretreatment process, and was then applied to a survey of NDMA in both raw and finished water samples from five water treatment plants in South China. The NDMA concentrations ranged from 4.7 to 15.1 ng/L in raw water samples, and from 4.68 to 46.9 ng/L in finished water. The NDMA concentration in raw water was found to be related with nitrite concentration, and during the treatment, the NDMA concentration increased following ozonation but decreased after subsequent activated carbon treatment. PMID- 21235179 TI - Adsorption behavior of ammonium by a bioadsorbent--Boston ivy leaf powder. AB - The adsorption behaviors of ammonium ions from aqueous solution by a novel bioadsorbent, the Boston ivy (Parthenocissus tricuspidata) leaf powder (BPTL) were investigated. The SEM images and FT-IR spectra were used to characterize BPTL. The mathematical models were used to analyze the adsorption kinetics and isotherms. The optimum pH range for ammonium adsorption by BPTL was found to be 5 10. The adsorption reached equilibrium at 14 hr, and the kinetic data were well fitted by the Logistic model. The intraparticle diffusion was the main rate controlling step of the adsorption process. The high temperature was favorable to the ammonium adsorption by BPTL, indicating that the adsorption was endothermic. The adsorption equilibrium fitted well to both the Langmuir model and Freundlich model, and the maximum monolayer adsorption capacities calculated from Langmuir model were 3.37, 5.28 and 6.59 mg N/g at 15, 25 and 35 degrees C, respectively, which were comparable to those by reported minerals. Both the separation factor (RL) from the Langmuir model and Freundlich exponent (n) suggested that the ammonium adsorption by BPTL was favorable. Therefore, the Boston ivy leaf powder could be considered a novel bioadsorbent for ammonium removal from aqueous solution. PMID- 21235180 TI - Characteristics of phosphorus fractionated from the sediment resuspension in abrupt expansion flow experiments. AB - Phosphorous (P) fraction characteristics in sediment resuspension were investigated under adequately hydrodynamic conditions. Four forms of P in overlying water, including dissolved inorganic P, dissolved total P, total P, and particulate P, and six fractions of P in suspended particulate matter (SPM), including loosely sorbed P (NH4Cl-P), redox-sensitive P (BD-P), aluminum-bound P (Al-P), organic P (NaOH-nrP), calcium-bound P (Ca-P) and residual P (Res-P), were quantified, respectively. Different hydrodynamic conditions resulted in different P form changes. Four states could be ascribed: (1) P desorption by sediment and SPM, and P adsorption by overlying water; (2) P desorption by SPM, and P adsorption by overlying water; (3) P adsorption by SPM, and P desorption by overlying water; and (4) P equilibrium between SPM and overlying water. The contents of P in overlying water acquired peak values in the middle position of the vertical P distribution due to the combined actions of SPM and sediment. P fractions in SPM were in the following order: BD-P > NaOH-nrp > Ca-P > Al-P > Res P > NH4Cl-P. BD-P in SPM frequently exchanged with P forms in overlying water. Resuspension was favorable to forming Ca-P in SPM. PMID- 21235181 TI - Enhanced ozonation of dichloroacetic acid in aqueous solution using nanometer ZnO powders. AB - Nanometer zinc oxide (ZnO) powders were used as a catalyst to enhance the ozonation for the degradation of dichloroacetic acid (DCAA) in aqueous solution. The batch experiments were carried out to investigate the effects of key factors such as catalyst dosage, ozone dosage, solution pH and tert-butyl alcohol (t BuOH) on the degradation efficiency of DCAA. Density functional theory (DFT) was adopted to explore the mechanism of generating hydroxyl radical (*OH) on the ZnO surface. The results showed that adsorption and ozonation processes were not effective for DCAA removal, and the addition of ZnO catalyst improved the degradation efficiency of DCAA during ozonation, which caused an increase of 22.8% for DCAA decomposition compared to the case of ozonation alone after 25 min. Under the same experimental conditions, the DCAA decomposition was enhanced by increasing catalyst dosage from 100 to 500 mg/L and ozone dosage from 0.83 to 3.2 mg/L. The catalytic ozonation process is more pronounced than the ozonation process alone at pH 3.93, 6.88, and 10. With increasing the concentration of t BuOH from 10 to 200 mg/L, the degradation of DCAA was significantly inhibited in the process of catalytic ozonation, indicating that ZnO catalytic ozonation followed *OH reaction mechanism. Based on the experimental results and DFT analysis, it is deduced that the generation of *OH on the ZnO surface is ascribed to the adsorption of molecule ozone followed by the interaction of adsorbed ozone with active sites of the catalyst surface. It is also concluded that ZnO may be an effective catalyst for DCAA removal, which could promote the formation of *OH derived from the catalytic decomposition of ozone. PMID- 21235182 TI - Numerical simulation of a horizontal sedimentation tank considering sludge recirculation. AB - Most research conducted on the concentration distribution of sediment in the sedimentation tank does not consider the role of the suction dredge. To analyze concentration distribution more accurately, a suspended sediment transportation model was constructed and the velocity field in the sedimentation tank was determined based on the influence of the suction dredge. An application model was then used to analyze the concentration distribution in the sedimentation tank when the suction dredge was fixed, with results showing that distribution was in accordance with theoretical analysis. The simulated value of the outlet concentration was similar to the experimental value, and the trends of the isoconcentration distribution curves, as well as the vertical distribution curves of the five monitoring sections acquired through simulations, were almost the same as curves acquired through experimentation. The differences between the simulated values and the experimental values were significant. PMID- 21235183 TI - Experimental evaluation of eco-friendly flocculants prepared from date palm rachis. AB - Sodium carboxymethylcellulose (CMCNa) is an anionic water soluble polyelectrolyte widely used in many industrial sectors including food, textiles, papers, adhesives, paints, pharmaceuticals, cosmetics and mineral processing. CMCNa was produced by chemical modification of cellulose, and represents many advantages: natural, renewable, non-toxic and biodegradable. In this study, different kinds of CMCNa, prepared from an agricultural waste date palm rachis, were tested as eco-friendly flocculants for drinking water treatment and their performances as flocculants in turbidity removal enhancement were assessed. The prepared materials were characterized by the degree of substitution (DS) and polymerisation (DP). The study of the effect of some experimental parameters on the coagulation-flocculation performance, using the prepared materials combined with aluminium sulphate (as coagulant), showed that the best conditions for turbidity treatment were given for pH 8, coagulant dose 20 mg/L, flocculant concentration of 100 mg/L and stirring velocity (during the flocculation step) of 30 r/min. Under the optimum conditions, the turbidity removal using CMCNa, prepared from raw material, was about 95%. A comparison study between the flocculation performance of a commercial anionic flocculant (A100PWG: polyacrylamide) and that of the prepared CMCNa showed that the performance of the waste-based flocculant with a DS of 1.17 and a DP of 480 was 10% better than that achieved by the commercial one. PMID- 21235184 TI - Using electrotopological state indices to model the depuration rates of polychlorinated biphenyls in mussels of Elliptio complanata. AB - A quantitative structure-activity relationship (QSAR) model on depuration rate constants (k(d)) of polychlorinated biphenyls (PCBs) in freshwater mussel Elliptio complanata was successfully constructed using electrotopological state indices (ESI) and partial least squares (PLS) regression. The cross validated Q2(cum) and the correlation coefficient R for the model were determined to be 0.845 and 0.954, respectively. The satisfactory Q2(cum) and R values indicated significantly high robustness and good predictive ability for the model. The model was tested and found acceptable for the prediction of logk(d) (the logarithm of the depuration rate constants) by validation set. According to the model, an increase in the values of S(aasC), S5', S4, S5 and S4, led to increased logk(d), and a decrease in the values of N(Cl), S2' and S6 also resulted in increased logkd. Among these descriptors, N(Cl), S(aasC), S5', S4 and S5 made significant contributions to the value of logk(d). These significant descriptors showed that the depuration of PCBs in Elliptio complanata may be mainly attributed to an equilibrium partitioning process among compartments with different lipid contents, while the reactivity of PCBs with enzymes or other molecules may play a subordinate role. PMID- 21235185 TI - Distributions and sources of n-alkanes in PM2.5 at urban, industrial and coastal sites in Tianjin, China. AB - Aliphatic hydrocarbons (n-alkanes) associated with fine particulate matter were determined in the ambient air of urban, industrial and coastal areas in Tianjin, China, where intensive coal burning for industrial and domestic purpose takes place. n-Alkane homologues from C12 to C35 were quantifiable in all samples with C20-C31 being the most abundant species. Average concentrations of the total n alkanes were 148.7, 250.1 and 842.0 ng/m3 in July, April and January, respectively. Seasonal variations were mainly attributed to ambient temperature changes and coal combustion for residential heating. Among the three studied areas, the highest levels of n-alkanes were observed in the industrial complex in winter and spring, but in summer the coastal alkane concentration moved up to the highest. A mono-modal distribution for n-alkanes was observed in spring and summer with odd carbon number predominance and a maximum centered at C27-C31, suggesting the release of plant wax into the atmosphere. The bimodal distribution with maxima at C22 and C26 observed in winter indicated a substantial influence of fossil fuel sources. All the CPIs (CPI1, CPI2, CPI3) values, varying between 0.64 and 1.97, indicated the influence of anthropogenic emissions on fine organic aerosols. The estimated contributions of plant wax to total n-alkanes were on average of 12.9%, 19.1% and 26.1% for winter, spring and summer, respectively. PMID- 21235186 TI - Capture of carbon dioxide by amine-impregnated as-synthesized MCM-41. AB - The novel carbon dioxide (CO2) adsorbents with a high capture efficiency were prepared through impregnating the as-synthesized MCM-41 with three kinds of amines, namely diethylenetriamine (DETA), triethylenetetramine (TETA) and 2-amino 2-methyl-1-propanol (AMP). The resultant samples were characterized by small angle X-ray diffraction and low temperature N2 adsorption. The synthesis way not only saves the energy or extractor to remove the template but also is environmentally friendly due to the absence of the potential pollutants such as toluene. CO2 capture was investigated in a dynamic packed column. The sample impregnated by TETA showed the highest adsorption capacity, approximately 2.22 mmol/g at 60 degrees C due to its highest amino-groups content among the three amines. The CO2 adsorption behavior was also investigated with the deactivation model, which showed an excellent prediction for the breakthrough curves. PMID- 21235187 TI - Methane emissions during storage of different treatments from cattle manure in Tianjin. AB - Many studies on methane emissions from animal manure have revealed that animal manure is a major source of methane emissions to the atmosphere that can have negative consequences for people, animals and environment. In general, the release of methane can be influenced by the type of feed taken by animals, temperature, manure characteristics and so on. This study aimed at quantifying and comparing methane release from dairy manure with different piling treatments. Four treatments were designed including manure piling height 30, 45, 60 cm and adding 6 cm manure every day until the piling height was 60 cm. Static chamber method and gas chromatography were adopted to measure the methane emissions from April to June in 2009. Methane emission rates of all four manure treatments were low in the first week and then increased sharply until reaching the peak values. Subsequently, all the methane emission rates decreased and fluctuated within the steady range till the end of the experiment. Wilcoxon nonparametric tests analysis indicated that methane emission rate was greatly influenced by manure piling height and manner. There were no significant relationships between methane emission rates and the temperatures of ambience and heap. However, regression analysis showed that the quadratic equations were found between emission rates of all treatments and the gas temperature in the barrels. PMID- 21235188 TI - Experimental study of photooxidation products of ethylbenzene. AB - Smog chamber experiments were performed to investigate the composition of products formed from photooxidation of aromatic hydrocarbon ethylbenzene. Vacuum ultraviolet photoionization mass spectrometer and aerosol time-of-flight mass spectrometer were used to measure the products in the gas and particle phases in real-time. Experimental results demonstrated that ethylphenol, methylglyoxal, phenol, benzaldehyde, and 2-ethylfurane were the predominant photooxidation products in both the gas and particle phases. However, there were some differences between detected gas phase products and those of particle phase, for example, 2-ethylfurane, ethylglyoxylic acid, nitroethylbenzene, 3,4-dioxopentanal and ethyl-nitrophenol were only existing in the particle-phase. The possible reaction mechanisms leading to these products were also discussed and proposed. PMID- 21235189 TI - Screening and degrading characteristics and community structure of a high molecular weight polycyclic aromatic hydrocarbon-degrading bacterial consortium from contaminated soil. AB - Inoculation with efficient microbes had been proved to be the most important way for the bioremediation of polluted environments. For the treatment of abandoned site of Beijing Coking Chemical Plant contaminated with high level of high molecular-weight polycyclic aromatic hydrocarbons (HMW-PAHs), a bacterial consortium capable of degrading HMW-PAHs, designated 1-18-1, was enriched and screened from HMW-PAHs contaminated soil. Its degrading ability was analyzed by high performance liquid chromatography (HPLC), and the community structure was investigated by construction and analyses of the 16S rRNA gene clone libraries (A, B and F) at different transfers. The results indicated that 1-18-1 was able to utilize pyrene, fluoranthene and benzo[a]pyrene as sole carbon and energy source for growth. The degradation rate of pyrene and fluoranthene reached 82.8% and 96.2% after incubation for 8 days at 30 degrees C, respectively; while the degradation rate of benzo[a]pyrene was only 65.1% after incubation for 28 days at 30 degrees C. Totally, 108, 100 and 100 valid clones were randomly selected and sequenced from the libraries A, B, and F. Phylogenetic analyses showed that all the clones could be divided into 5 groups, Bacteroidetes, alpha-Proteobacteria, Actinobacteria, beta-Proteobacteria and gamma-Proteobacteria. Sequence similarity analyses showed total 39 operational taxonomic units (OTUs) in the libraries. The predominant bacterial groups were alpha-Proteobacteria (19 OTUs, 48.7%), gamma Proteobacteria (9 OTUs, 23.1%) and beta-Proteobacteria (8 OTUs, 20.5%). During the transfer process, the proportions of alpha-Proteobacteria and beta Proteobacteria increased greatly (from 47% to 93%), while gamma-Proteobacteria decreased from 32% (library A) to 6% (library F); and Bacteroidetes group disappeared in libraries B and F. PMID- 21235190 TI - Interaction mechanisms of organic contaminants with burned straw ash charcoal. AB - Black carbons (e.g., charcoal) have a great impact on the transport of organic contaminants in soil and water because of its strong affinity and ubiquity in the environment. To further elucidate their interaction mechanism, sorption of polar (p-nitrotoluene, m-dinitrobenzene and nitrobenzene) and nonpolar (naphthalene) aromatic contaminants to burned straw ash charcoal under different de-ashed treatments were investigated. The sorption isotherms fitted well with Freundlich equation, and the Freundlich N values were all around 0.31-0.38, being independent of the sorbate properties and sorbent types. After sequential removal of ashes by acid treatments (HCl and HCl-HF), both adsorption and partition were enhanced due to the enrichment of charcoal component. The separated contribution of adsorption and partition to total sorption were quantified. The effective carbon content in ash charcoal functioned as adsorption sites, partition phases, and hybrid regions with adsorption and partition were conceptualized and calculated. The hybrid regions increased obviously after de-ashed treatment. The linear relationships of Freundlich N values with the charring-temperature of charcoal or biochar (the charred byproduct in biomass pyrolysis) were observed based on the current study and the cited publications which included 15 different temperatures (100-850 degrees C), 10 kinds of precursors of charcoal/biochar, and 10 organic sorbates. PMID- 21235191 TI - Fungal contamination of stored automobile-fuels in a tropical environment. AB - Because of the lack of reports, the base levels of microbial contamination on stored fuels are unknown in tropical regions and it is unclear whether these levels have some influence on fuel quality parameters. Therefore, fungal quality in automobile fuels stored across Costa Rican territory was evaluated during two years according to the standard ASTM D6974-04. For a total of 96 samples, counts and identification of molds and yeasts were performed on regular gas, premium gas and diesel taken from the bottom and superior part of the container tanks. The highest contamination was found on the bottom of the tanks, where an aqueous phase was usually identified, showing populations over the ones present in the hydrocarbon itself (up to 10(8) CFU/L). Diesel was the most contaminated fuel (up to 10(7) CFU/L); however, an alteration on the physicochemical parameters was not observed in any kind of fuel. Seventy-five mold strains were isolated, Penicillium sp. being the most common genus (45.8% of the samples), and ten yeast strains, from the genera Candida sp. and Rhodotorula sp. Four of the yeasts were able to grow on diesel as the sole carbon source, at concentrations ranging from 0.5% to 25%. Increasing the frequency of tank cleaning, adding antimicrobial agents and monitoring microbial populations are recommended strategies to improve microbial quality of stored fuels. PMID- 21235192 TI - Effects of phosphorus and nitrogen limitation on PHA production in activated sludge. AB - The effects of phosphorus and nitrogen limitation on polyhydroxyalkanoate (PHA) production and accumulation by activated sludge biomass with acetate as a carbon source were investigated. Pre-selected influent carbon-phosphorus (C:P, W/W) of 100, 160, 250, 500 and 750, and carbon-nitrogen (C:N, W/W) of 20, 60, 100, 125 and 180 were applied in the phosphorus limitation experiments and the nitrogen limitation experiments, respectively. The maximum PHA accumulation up to 59% of the cell dry weight with a PHA productivity of 1.61 mg PHA/mg COD consumed was observed at the C:N 125 in the nitrogen limitation experiment. This value was much higher than that obtained in previous studies with a normal substrate feeding. The study showed that activated sludge biomass would produce more polyhydroxybutyrate than polyhydroxyvalerate under the stress of nutrient limitation, especially under phosphorus limitation conditions. The experimental result also indicated that both phosphorus and nitrogen limitation may cause sludge bulking. PMID- 21235193 TI - Pentachlorophenol degradation by Pseudomonas stutzeri CL7 in the secondary sludge of pulp and paper mill. AB - A pentachlorophenol (PCP) mineralizing bacterium was isolated from the secondary sludge of pulp and paper mill and identified as Pseudomonas stutzeri strain CL7. This isolate used PCP as its sole source of carbon and energy and was capable of degrading this compound as indicated by stoichiometric release of chloride and biomass formation. P. stutzeri (CL7) was able to mineralize a high concentration of PCP (600 mg/L) than any previously reported Pseudomonad with PCP as sole carbon source. As the concentration of PCP increased from 50 to 600 mg/L, the reduction in the cell growth was observed and the PCP degradation was more than 90% in all studied concentrations. This isolate was able to remove 66.8% of PCP from the secondary sludge of pulp and paper mill when supplemented with 100 mg/L of PCP and grown for two weeks. This study showed that the removal efficiency of PCP by CL7 was found to be very effective and can be used in PCP remediation of pulp paper mill waste in the environment. PMID- 21235194 TI - Assessing the estrogenic potency in a Portuguese wastewater treatment plant using an integrated approach. AB - The estrogenic potency of a wastewater treatment plant (WWTP) was evaluated using chemical and biological analyses, which showed that after the station treatment processes some of the selected endocrine disruptor compounds (EDCs) were still present in the treated effluent (e.g., bisphenol A, alkylphenols, estrone). Thus, the most common endocrine EDCs were identified and quantified and the overall estrogenicity of the treated effluent assessed by integrating the results. Male goldfish (Carassius auratus) were used as biological indicators in a 28-day experiment. Vitellogenin (Vtg), gonadosomatic and hepatosomatic indices, steroids (17beta-estradiol and 11-ketotestosterone) and histopathology were biomarkers used in fish to evaluate WWTP treated effluent estrogenicity, in combination with instrumental analyses. The results showed a significant increase (P < 0.01) in plasma and liver Vtg, which were significantly correlated (r = 0.66; P < 0.01). The gonadosmatic index was significantly (P < 0.01) reduced in exposed fish. The steroid analyses revealed significant elevations in 17beta-estradiol and depressed 11-ketotestosterone concentrations. The histological examinations show changes in exposed fish gonads, such as regressed testes and in some cases (43% to 75%) the development of ovo-testis in fish exposed to 50% and 100% treated effluent. PMID- 21235195 TI - Catalytic performance of Fe3O4-CoO/Al2O3 catalyst in ozonation of 2-(2,4 dichlorophenoxy)propionic acid, nitrobenzene and oxalic acid in water. AB - Fe3O4-CoO/Al2O3 catalyst was prepared by incipient wetness impregnation using Fe(NO3)3 x 9H2O and Co(NO3)2 x 6H2O as the precursors, and its catalytic performance was investigated in ozonation of 2-(2,4-dichlorophenoxy)propionic acid (2,4-DP), nitrobenzene and oxalic acid. The experimental results indicated that Fe3O4-CoO/Al2O3 catalyst enabled an interesting improvement of ozonation efficiency during the degradation of each organic pollutant, and the Fe3O4 CoO/Al2O3 catalytic ozonation system followed a radical-type mechanism. The kinetics of ozonation alone and Fe3O4-CoO/Al2O3 catalytic ozonation of three organic pollutants in aqueous solution were discussed under the mere consideration of direct ozone reaction and OH radical reaction to well investigate its performance. In the catalytic ozonation of 2,4-DP, the apparent reaction rate constants (k) were determined to be 1.456 x 10(-2) min(-1) for ozonation alone and 4.740 x 10(-2) min(-1) for O3/Fe3O4-CoO/Al203. And O3/Fe3O4 CoO/Al2O3 had a larger R(ct) (6.614 x 10(-9)) calculated by the relative method than O3 did (1.800 x 10(-9)), showing O3/Fe3O4-CoO/Al2O3 generated more hydroxyl radical. Similar results were also obtained in the catalytic ozonation of nitrobenzene and oxalic acid. The above results demonstrated that the catalytic performance of Fe3O4-CoO/Al2O3 in ozonation of studied organic substance was universal to a certain degree. PMID- 21235196 TI - Removal of elemental mercury by iodine-modified rice husk ash sorbents. AB - Iodine-modified calcium-based rice husk ash sorbents (I2/CaO/RHA) were synthesized and characterized by X-ray diffraction, X-ray fluorescence, and N2 isotherm adsorption/desorption. Adsorption experiments of vapor-phase elemental mercury (Hg0) were performed in a laboratory-scale fixed-bed reactor. I2/CaO/RHA performances on Hg0 adsorption were compared with those of modified Ca-based fly ash sorbents (I2/CaO/FA) and modified fly ash sorbents (I2/FA). Effects of oxidant loading, supports, pore size distribution, iodine impregnation modes, and temperature were investigated as well to understand the mechanism in capturing Hg0. The modified sorbents exhibited reasonable efficiency for Hg0 removal under simulated flue gas. The surface area, pore size distribution, and iodine impregnation modes of the sorbents did not produce a strong effect on Hg0 capture efficiency, while fair correlation was observed between Hg0 uptake capacity and iodine concentration. Therefore, the content of I2 impregnated on the sorbents was identified as the most important factor influencing the capacity of these sorbents for Hg0 uptake. Increasing temperature in the range of 80-140 degrees C caused a rise in Hg0 removal. A reaction mechanism that may explain the experimental results was presumed based on the characterizations and adsorption study. PMID- 21235197 TI - Effect of temperature and oxygen on the formation of chlorobenzene as the indicator of PCDD/Fs. AB - Sampling and analysis of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) are both time-consuming and expensive. In principle, real-time monitoring of chlorobenzene (CBz) as an indicator for PCDD/Fs could be useful to control and optimize incinerator operating conditions. To test this strategy, CBz was analyzed together with PCDD/Fs in flue gas samples collected from a hospital waste incinerator. Moreover, lab experiments were conducted to investigate the effect of temperature and oxygen on CBz formation from fly ash from the same incinerator. The experimental results demonstrate that chlorobenzene (in particular PeCBz) correlate well with PCDD/Fs, in line with previous research. The optimum temperature of CBz formation is in a range of 350 to 400 degrees C and CBz yield increases significantly with oxygen, in line with PCDD/Fs formation. This study is useful for confirming the de novo mechanism and defining correlations between CBz and PCDD/Fs. PMID- 21235198 TI - Characterization of mechanochemical treated fly ash from a medical waste incinerator. AB - The mechanochemical treatment of fly ash generated from a medical waste incinerator was subjected to grinding for 2 hr at 400 r/min in a planetary ball mill. The treated fly ash was characterized by a suite of analytical methods including High Resolution Gas Chromatograph/High Resolution Mass Spectrometer, Mastersizer 2000 Particle Size Analyzer, QUADRASORB SI Surface Area Analyzer, Scanning Electron Microscopy and X-ray diffraction. Results showed that abatement efficiency of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDDs/Fs) in terms of total concentration averagely amount to 76% which was relatively higher than that of I-TEQ concentration averagely amount to 56%; the most concentration of toxic congeners as well as isomers of PCDDs/Fs decreased after mechanochemical treatment. The treated fly ash was characterized by a more homogeneous distribution of concaves as well as the significant decreasing in overall particle size and great enlargement in surface area. The major crystallization phases or intensities were considerably changed by mechanochemical treatment, of which a new phase containing chlorine formed may be a possible factor suggesting chlorination reaction occurring on the crystalline surface. PMID- 21235199 TI - An implementation assessment of China's Environmental Information Disclosure Decree. AB - China's 2007 Open Government Information Regulations is widely considered as a milestone in the country's information policy history and is praised as a "sunshine program". The Environmental Information Disclosure Decree was the first to operationalize these general regulations into a sectoral information disclosure system on environment. This study assessed the implementation of the environmental information disclosure system about six months after the Decree took effect on May 1, 2008. Through reviewing the websites of all 31 provincial Environmental Protection Bureaus and the Ministry of Environmental Protection, conducting an experiment with actual information disclosure request, and through interviews with all provincial Environmental Protection Bureaus, this article concluded that the implementation of the environmental information disclosure system still falls short. Future improvements should focus on further publicity of the regulations and decree to enhance public participation, the establishment of an independent evaluation and supervision system for information disclosure, the exchange of experiences and best practices among provincial Environmental Protection Bureaus, and on strengthening the legal status of environmental information disclosure. PMID- 21235200 TI - Alcohol screening and brief interventions for college freshmen. AB - This study examined the effectiveness of the Brief Alcohol Screening and Intervention for College Students using theory-driven harm reduction brief motivational interviewing (BMI) for decreasing high-risk drinking and negative consequences. Three surveys were administered to 102 volunteer freshmen college students at baseline and 3 months postintervention. The BMI intervention was administered at baseline and 2 weeks later. Descriptive statistics and summary graphs were used to determine longitudinal changes in drinking quantity, frequency, and negative outcomes. Number of drinks, hours of drinking, and negative consequences decreased, indicating a significant decrease in alcohol consumption and negative consequences. This study contributes valuable implications for the design of theory-driven harm reduction, evidence-based interventions for high-risk drinking among freshmen college students. PMID- 21235201 TI - Hunting for protein markers of hypoxia by combining plasma membrane enrichment with a new approach to membrane protein analysis. AB - Nontransient hypoxia is strongly associated with malignant lesions, resulting in aggressive behavior and resistance to treatment. We present an analysis of mRNA and protein expression changes in neuroblastoma cell lines occurring upon the transition from normoxia to hypoxia. The correlation between mRNA and protein level changes was poor, although some known hypoxia-driven genes and proteins correlated well. We present previously undescribed membrane proteins expressed under hypoxic conditions that are candidates for evaluation as biomarkers. PMID- 21235202 TI - Fetal exposure to chlordane and permethrin mixtures in relation to inflammatory cytokines and birth outcomes. AB - We sought to characterize the relationships between cord serum concentrations of chlordane and permethrin pesticides, inflammatory cytokines, gestational age, and size at birth. Umbilical cord serum levels of trans-nonachlor, oxychlordane, cis- and trans-permethrin, piperonyl butoxide, and cytokines (TNF-alpha, IFN-gamma, IL 1beta, IL-2, IL-6, IL-8, IL-10, IL-12p70, GMCSF) were quantified in 300 newborns at the Johns Hopkins Hospital in Baltimore, MD (2004-2005). Principal component analyses were used to quantitate chlordane and permethrin mixtures and to identify independent cytokine components. Five cytokine components described 87% of the variance in cord serum cytokine levels; these (and predominant loadings) were as follows: (1) all 9 cytokines; (2) acute phase (IL-1beta, IL-6); (3) anti inflammatory (IL-10); (4) TNF-alpha; and (5) IL-1beta. Of these, the TNF-alpha component was significantly associated with a 2-day decrease in gestational age. Chlordane was associated with lower levels of the pro-inflammatory IL-1beta [beta: -0.11 (-0.20, -0.02)]. Permethrin was negatively associated with the anti inflammatory cytokine IL-10 [beta: -0.14 (-0.22, -0.05)]. Neither pesticides nor cytokines were significantly associated with birthweight, length, or head circumference, and pesticides were not associated with gestational age. Our findings suggest that chlordane and permethrin concentrations in cord blood may be associated with levels of inflammatory cytokines in the fetus. PMID- 21235203 TI - Fate of sucralose through environmental and water treatment processes and impact on plant indicator species. AB - The degradation and partitioning of sucralose during exposure to a variety of environmental and advanced treatment processes (ATP) and the effect of sucralose on indicator plant species were systematically assessed. Bench scale experiments were used to reproduce conditions from environmental processes (microbial degradation, hydrolysis, soil sorption) and ATPs (chlorination, ozonation, sorption to activated carbon, and UV radiation). Degradation only occurred to a limited extent during hydrolysis, ozonation, and microbial processes indicating that breakdown of sucralose will likely be slow and incomplete leading to accumulation in surface waters. Further, the persistence of sucralose was compared to suggested human tracer compounds, caffeine and acesulfame-K. In comparison sucralose exhibits similar or enhanced characteristics pertaining to persistence, prevalence, and facile detection and can therefore be considered an ideal tracer for anthropogenic activity. Ecological effects of sucralose were assessed by measuring sucrose uptake inhibition in plant cotelydons and aquatic plant growth impairment. Sucralose did not inhibit plant cotelydon sucrose uptake, nor did it effect frond number, wet weight, or growth rate in aquatic plant, Lemna gibba. Though sucralose does not appear toxic to plant growth, the peristent qualities of sucralose may lead to chronic low-dose exposure with largely unknown consequences for human and environmental health. PMID- 21235206 TI - Molecular weight distributions and linkages in lignocellulosic materials derivatized from ionic liquid media. AB - A novel and reproducible method is described for accurately determining the molecular weight distribution by size exclusion chromatography (SEC) of whole lignocellulosic materials. This approach offers the opportunity to compare the molecular weight distributions of intact milled woods and its component fractions, lignins and holocelluloses, all from the same source, thus highlighting the potential of the technique and the contributions of the individual components to the chromatogram. The method is based on the dissolution of the ball-milled samples in the ionic liquid 1-allyl-3-methylimidazolium chloride ([amim]Cl). Under these homogeneous ionic liquid media, a derivatization reaction was performed with benzoyl chloride in the presence of pyridine. The thoroughly benzoylated wood with its associated carbohydrate and lignin components was found to be completely soluble in the THF SEC eluent with marked UV detector sensitivity. This methodology, when applied to the individually isolated holocellulose and lignin (enzymatic mild acidolysis lignin; EMAL) materials from Norway spruce ( Eucalyptus grandis ) wood and corn stover, offered a better understanding as to the possible ways the lignin and the carbohydrates may interact within these three different species. Finally, the applicability of the methodology is shown for a series of pure cellulosic samples under intense mechanical defibration conditions, offering a visualization of the molecular weight distribution changes induced during the production of nanofibrillated cellulose. PMID- 21235207 TI - Quantitative analysis of steroidal glycosides in different organs of Easter lily (Lilium longiflorum Thunb.) by LC-MS/MS. AB - The bulbs of the Easter lily ( Lilium longiflorum Thunb.) are regularly consumed in Asia as both food and medicine, and the beautiful white flowers are appreciated worldwide as an attractive ornamental. The Easter lily is a rich source of steroidal glycosides, a group of compounds that may be responsible for some of the traditional medicinal uses of lilies. Since the appearance of recent reports on the role steroidal glycosides in animal and human health, there is increasing interest in the concentration of these natural products in plant derived foods. A LC-MS/MS method performed in multiple reaction monitoring (MRM) mode was used for the quantitative analysis of two steroidal glycoalkaloids and three furostanol saponins, in the different organs of L. longiflorum. The highest concentrations of the total five steroidal glycosides were 12.02 +/- 0.36, 10.09 +/- 0.23, and 9.36 +/- 0.27 mg/g dry weight in flower buds, lower stems, and leaves, respectively. The highest concentrations of the two steroidal glycoalkaloids were 8.49 +/- 0.3, 6.91 +/- 0.22, and 5.83 +/- 0.15 mg/g dry weight in flower buds, leaves, and bulbs, respectively. In contrast, the highest concentrations of the three furostanol saponins were 4.87 +/- 0.13, 4.37 +/- 0.07, and 3.53 +/- 0.06 mg/g dry weight in lower stems, fleshy roots, and flower buds, respectively. The steroidal glycoalkaloids were detected in higher concentrations as compared to the furostanol saponins in all of the plant organs except the roots. The ratio of the steroidal glycoalkaloids to furostanol saponins was higher in the plant organs exposed to light and decreased in proportion from the aboveground organs to the underground organs. Additionally, histological staining of bulb scales revealed differential furostanol accumulation in the basal plate, bulb scale epidermal cells, and vascular bundles, with little or no staining in the mesophyll of the bulb scale. An understanding of the distribution of steroidal glycosides in the different organs of L. longiflorum is the first step in developing insight into the role these compounds play in plant biology and chemical ecology and aids in the development of extraction and purification methodologies for food, health, and industrial applications. In the present study, (22R,25R)-spirosol-5-en-3beta-yl O-alpha-l rhamnopyranosyl-(1->2)-beta-d-glucopyranosyl-(1->4)-beta-d-glucopyranoside, (22R,25R)-spirosol-5-en-3beta-yl O-alpha-l-rhamnopyranosyl-(1->2)-[6-O-acetyl beta-d-glucopyranosyl-(1->4)]-beta-d-glucopyranoside, (25R)-26-O-(beta-d glucopyranosyl)furost-5-ene-3beta,22alpha,26-triol 3-O-alpha-l-rhamnopyranosyl-(1 >2)-beta-d-glucopyranosyl-(1->4)-beta-d-glucopyranoside, (25R)-26-O-(beta-d glucopyranosyl)furost-5-ene-3beta,22alpha,26-triol 3-O-alpha-l-rhamnopyranosyl-(1 >2)-alpha-l-arabinopyranosyl-(1->3)-beta-d-glucopyranoside, and (25R)-26-O-(beta d-glucopyranosyl)furost-5-ene-3beta,22alpha,26-triol 3-O-alpha-l-rhamnopyranosyl (1->2)-alpha-l-xylopyranosyl-(1->3)-beta-d-glucopyranoside were quantified in the different organs of L. longiflorum for the first time. PMID- 21235208 TI - Influence of growing season on phenolic compounds and antioxidant properties of grape berries from vines grown in subtropical climate. AB - The influence of growing season (winter vs summer) on the synthesis and accumulation of phenolic compounds and antioxidant properties was studied in five grape cultivars for three consecutive years. Four phenolic compound parameters (total phenols, flavonoids, flavan-3-ols, and anthocyanins) and three antioxidant property parameters [2,2-diphenyl-1-picrylhydrazyl radical scavenging, 2,2 azinobis(3-ethylbenzothiazolinesulfonic acid) radical scavenging, and ferric reducing antioxidant power] were investigated. Results showed that both phenolic compounds and antioxidant properties in the seed and skin of winter berries were significantly (p < 0.05) higher than those of summer berries for all of the cultivars investigated. The anthocyanin profiles of berry skins appeared to be extremely consistent in different years for the same crop, whereas they varied greatly between the two crops within the same year (winter vs summer). Winter berries contained richer glucosides of delphinidin, cyanidin, peonidin, and malvidin than summer berries. These seasonal variations of phenolic compounds and antioxidant properties on grape berries were largely contributed by climatic factors such as temperature, solar radiation, rainfall, and hydrothermic coefficient between different growing seasons. PMID- 21235209 TI - pH-induced shift in hemoglobin spectra: a spectrophotometeric comparison of atlantic cod ( Gadus morhua ) and mammalian hemoglobin. AB - Due to a pH-sensitive effect in many fish hemoglobins (Hb), analytical errors may occur when mammalian Hb is used as a standard in quantitative spectrophotometric multicomponent analysis of fish blood. The aim of this work was to examine differences in the optical spectra of mammalian (human) and fish (farmed Atlantic cod) Hb subjected to pH 7.4 and 6.5. The absorption spectra of the common derivatives, deoxy- (HHb), oxy- (OHb), carboxy- (COHb), and methemoglobin (metHb), were determined in the spectral range of 450-700 nm. The metHb spectra of fish differed considerably from the corresponding human Hb spectra, whereas only minor differences in OHb, HHb, and COHb were found. Cod Hb was significantly (P < 0.05) influenced by a drop in pH compared to mammalian Hb. This resulted in deoxygenation of the Hb and increased autoxidation. For human Hb, a pH independent isosbestic point in the spectra of OHb, HHb, and metHb at 523 nm was found. This isosbestic point was not found in the absorption spectra of cod Hb. In conclusion, spectra of cod metHb and human metHb behave differently. This must thus be taken into account in spectrophotometric multicomponent analysis. Ideally, Hb in muscle or blood should be determined by comparison to a standard made from the same species. PMID- 21235210 TI - Synthetic routes to N-heterocyclic carbene precursors. PMID- 21235212 TI - Synthesis and optical properties of hybrid and alloy plasmonic nanoparticles. PMID- 21235211 TI - p38gamma activation triggers dynamical changes in allosteric docking sites. AB - Mitogen-activated protein kinases (MAPKs) are serine-threonine kinases that participate in signal transduction pathways. p38 MAPKs have four isoforms (p38alpha, p38beta, p38gamma, and p38delta) which are involved in multiple cellular functions such as proliferation, differentiation, survival, and migration. MAPK kinases phosphorylate p38s in the dual-phosphorylation motif, Thr Gly-Tyr, located in their activation loop, which induces a conformational change that increases ATP binding affinity and catalytic activity. Several works have proposed that MAPK dynamics is a key factor in determining their function. However, we still do not understand the dynamical changes that lead to MAPK activation. In this work we have used molecular dynamics techniques to study the dynamical changes associated with p38gamma activation, the only fully active MAPK crystallized so far. We performed MD simulations of p38gamma in three different states, fully active with ATP, active without ATP, and inactive. We found that the dynamical fluctuations of the docking sites, important for protein-protein interactions, are regulated allosterically by changes in the active site. Interestingly, in the phosphorylated and ATP-bound states the whole protein dynamics lead to concerted motions of whole protein domains in contrast to the inactive state. The binding/unbinding of ATP participates in the reorientation of the two domains and in the regulation of protein plasticity. Our study shows that beyond the conformational changes associated with MAPK activation their correlated dynamics are highly regulated by phosphorylation and ATP binding. This means that MAPK plasticity may have a role in their catalytic activity, specificity, and protein-protein interactions and, therefore, in the outcome of the signaling network. PMID- 21235213 TI - Homogeneous ice nucleation from aqueous inorganic/organic particles representative of biomass burning: water activity, freezing temperatures, nucleation rates. AB - Homogeneous ice nucleation plays an important role in the formation of cirrus clouds with subsequent effects on the global radiative budget. Here we report on homogeneous ice nucleation temperatures and corresponding nucleation rate coefficients of aqueous droplets serving as surrogates of biomass burning aerosol. Micrometer-sized (NH(4))(2)SO(4)/levoglucosan droplets with mass ratios of 10:1, 1:1, 1:5, and 1:10 and aqueous multicomponent organic droplets with and without (NH(4))(2)SO(4) under typical tropospheric temperatures and relative humidities are investigated experimentally using a droplet conditioning and ice nucleation apparatus coupled to an optical microscope with image analysis. Homogeneous freezing was determined as a function of temperature and water activity, a(w), which was set at droplet preparation conditions. The ice nucleation data indicate that minor addition of (NH(4))(2)SO(4) to the aqueous organic droplets renders the temperature dependency of water activity negligible in contrast to the case of aqueous organic solution droplets. The mean homogeneous ice nucleation rate coefficient derived from 8 different aqueous droplet compositions with average diameters of ~60 MUm for temperatures as low as 195 K and a(w) of 0.82-1 is 2.18 * 10(6) cm(-3) s(-1). The experimentally derived freezing temperatures and homogeneous ice nucleation rate coefficients are in agreement with predictions of the water activity-based homogeneous ice nucleation theory when taking predictive uncertainties into account. However, the presented ice nucleation data indicate that the water activity-based homogeneous ice nucleation theory overpredicts the freezing temperatures by up to 3 K and corresponding ice nucleation rate coefficients by up to ~2 orders of magnitude. A shift of 0.01 in a(w), which is well within the uncertainty of typical field and laboratory relative humidity measurements, brings experimental and predicted freezing temperatures and homogeneous ice nucleation rate coefficients into agreement. The experimentally derived ice nucleation data are applied to constrain the water activity-based homogeneous ice nucleation theory to smaller than +/-1 order of magnitude compared to the predictive uncertainty of larger than +/-6 orders of magnitude. The atmospheric implications of these findings are discussed. PMID- 21235214 TI - Experimental and modeling studies of the pressure and temperature dependences of the kinetics and the OH yields in the acetyl + O2 reaction. AB - The acetyl + O(2) reaction has been studied by observing the time dependence of OH by laser-induced fluorescence (LIF) and by electronic structure/master equation analysis. The experimental OH time profiles were analyzed to obtain the kinetics of the acetyl + O(2) reaction and the relative OH yields over the temperature range of 213-500 K in helium at pressures in the range of 5-600 Torr. More limited measurements were made in N(2) and for CD(3)CO + O(2). The relative OH yields were converted into absolute yields by assuming that the OH yield at zero pressure is unity. Electronic structure calculations of the stationary points of the potential energy surface were used with a master equation analysis to fit the experimental data in He using the high-pressure limiting rate coefficient for the reaction, k(infinity)(T), and the energy transfer parameter, (DeltaE(d)), as variable parameters. The best-fit parameters obtained are k(infinity) = 6.2 * 10(-12) cm(-3) molecule(-1) s(-1), independent of temperature over the experimental range, and (DeltaE(d))(He) = 160(T/298 K) cm(-1). The fits in N(2), using the same k(infinity)(T), gave (DeltaE(d))(N(2)) = 270(T/298 K) cm( 1). The rate coefficients for formation of OH and CH(3)C(O)O(2) are provided in parametrized form, based on modified Troe expressions, from the best-fit master equation calculations, over the pressure and temperature ranges of 1 <= p/Torr <= 1.5 * 10(5) and 200 <= T/K <= 1000 for He and N(2) as the bath gas. The minor channels, leading to HO(2) + CH(2)CO and CH(2)C(O)OOH, generally have yields <1% over this range. PMID- 21235216 TI - The label-free unambiguous detection and symbolic display of single nucleotide polymorphisms on DNA origami. AB - Single nucleotide polymorphisms (SNPs) are the most common genetic variation in the human genome. Kinetic methods based on branch migration have proved successful for detecting SNPs because a mispair inhibits the progress of branch migration in the direction of the mispair. We have combined the effectiveness of kinetic methods with atomic force microscopy of DNA origami patterns to produce a direct visual readout of the target nucleotide contained in the probe sequence. The origami contains graphical representations of the four nucleotide alphabetic characters, A, T, G and C, and the symbol containing the test nucleotide identity vanishes in the presence of the probe. The system also works with pairs of probes, corresponding to heterozygous diploid genomes. PMID- 21235217 TI - Carijodienone from the octocoral Carijoa multiflora. A spiropregnane-based steroid. AB - Two new steroids (1 and 2) and the known pregna-1,4,20-trien-3-one (3) have been isolated from the Pacific octocoral Carijoa multiflora. Compound 1 possesses a novel spiropregnane-based steroidal skeleton. The photochemical transformation of 3 into 1 allowed the assignment of the absolute configuration at C-10 of 1. The antibacterial activities of compounds 1 and 3 were evaluated against a panel of bacterial strains. PMID- 21235218 TI - Synthesis of platinum dendrites and nanowires via directed electrochemical nanowire assembly. AB - Directed electrochemical nanowire assembly is a promising high growth rate technique for synthesizing electrically connected nanowires and dendrites at desired locations. Here we demonstrate the directed growth and morphological control of edge-supported platinum nanostructures by applying an alternating electric field across a chloroplatinic acid solution. The dendrite structure is characterized with respect to the driving frequency, amplitude, offset, and salt concentration and is well-explained by classical models. Control over the tip diameter, side branch spacing, and amplitude is demonstrated, opening the door to novel device architectures for sensing and catalytic applications. PMID- 21235219 TI - Chronic exposure to arsenic causes increased cell survival, DNA damage, and increased expression of mitochondrial transcription factor A (mtTFA) in human prostate epithelial cells. AB - Arsenic is a known carcinogen, and its exposure is associated with cancers in multiple target organs including the prostate. Whether arsenic causes cancer by increased cell proliferation or cell survival is not clear. Additionally, mitochondria have been shown to play important roles in arsenic-induced DNA damage and carcinogenesis. However, the mechanism of mitochondrial involvement in arsenic-induced cancer is not clear. Therefore, the objectives of this study were to investigate the effect of arsenic on cell proliferation/survival and genotoxicity, and to determine the effect of arsenic on the expression of mitochondrial transcription factor A (mtTFA) in human prostate epithelial cells, RWPE-1. Results of this study revealed that chronic exposure to arsenic causes increased cell survival. Arsenic also induced nuclear DNA damage and mutations in mitochondrial DNA. Expressions of DNA repair genes ERCC6, XPC, OGG1, and reactive oxygen species (ROS) scavenger MnSOD was also altered in arsenic-exposed cells. Arsenic concentration-dependent increased expression of mtTFA and its regulator NRF-1 was observed in arsenic-exposed cells, suggesting that arsenic regulates mitochondrial activity through an NRF-1-dependent pathway. In summary, this study suggests that chronic exposure to arsenic causes DNA damage and increased cell survival that may ultimately result in neoplastic transformation of human prostate epithelial cells. Additionally, this study also provides evidence that arsenic controls mitochondrial function by regulating mtTFA expression. PMID- 21235220 TI - Antifungal lipopeptides from Bacillus amyloliquefaciens strain BO7. AB - Three new lipopeptides (1-3) were isolated from the organic extract of Bacillus amyloliquefaciens strain (BO7). These compounds represented the major constituents (>60%) of the total cell lipids extractable with CHCl(3)/MeOH (2:1). Elucidation of their chemical structure was carried out by spectroscopic analyses, including 1D and 2D NMR spectroscopy, mass spectrometry (MS), and secondary ion mass spectrometry (MS/MS), along with chemical degradation. The compounds are members of the surfactins family and are based on the heptapeptide Glu-Leu-Leu-Ala-Asp-Leu-Leu, N-acylated to the N-terminal by an (R)-3-hydroxy fatty acid with linear alkyl chains from 16:0 to 18:0 (1-3, respectively). An ester bond between the 3-hydroxyl group of the fatty acid and the carboxylic group of the C-terminal amino acid closes a 13-membered lactone ring. The bacterial lipopeptides, particularly compound 3, displayed strong and dose dependent antifungal activity against the plant pathogenic fungus Fusarium oxysporum. PMID- 21235221 TI - Oxidative stress, DNA damage, and inflammation induced by ambient air and wood smoke particulate matter in human A549 and THP-1 cell lines. AB - Combustion of biomass and wood for residential heating and/or cooking contributes substantially to both ambient air and indoor levels of particulate matter (PM). Toxicological characterization of ambient air PM, especially related to traffic, is well advanced, whereas the toxicology of wood smoke PM (WSPM) is poorly assessed. We assessed a wide spectrum of toxicity end points in human A549 lung epithelial and THP-1 monocytic cell lines comparing WSPM from high or low oxygen combustion and ambient PM collected in a village with many operating wood stoves and from a rural background area. In both cell types, all extensively characterized PM samples (1.25-100 MUg/mL) induced dose-dependent formation of reactive oxygen species and DNA damage in terms of strand breaks and formamidopyrimidine DNA glycosylase sites assessed by the comet assay with WSPM being most potent. The WSPM contained more polycyclic aromatic hydrocarbons (PAH), less soluble metals, and expectedly also had a smaller particle size than PM collected from ambient air. All four types of PM combined increased the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine dose-dependently in A549 cells, whereas there was no change in the levels of etheno-adducts or bulky DNA adducts. Furthermore, mRNA expression of the proinflammatory genes monocyte chemoattractant protein-1, interleukin-8, and tumor necrosis factor-alpha as well as the oxidative stress gene heme oxygenase-1 was upregulated in the THP-1 cells especially by WSPM and ambient PM sampled from the wood stove area. Expression of oxoguanine glycosylase 1, lymphocyte function-associated antigen-1, and interleukin-6 did not change. We conclude that WSPM has small particle size, high level of PAH, low level of water-soluble metals, and produces high levels of free radicals, DNA damage as well as inflammatory and oxidative stress response gene expression in cultured human cells. PMID- 21235222 TI - Photoionization-induced water migration in the amide group of trans-acetanilide (H2O)1 in the gas phase. AB - IR-dip spectra of trans-acetanilide-water 1:1 cluster, AA-(H(2)O)(1), have been measured for the S(0) and D(0) state in the gas phase. Two structural isomers, where a water molecule binds to the NH group or the CO group of AA, AA(NH) (H(2)O)(1) and AA(CO)-(H(2)O)(1), are identified in the S(0) state. One-color resonance-enhanced two-photon ionization, (1 + 1) RE2PI, of AA(NH)-(H(2)O)(1) via the S(1)-S(0) origin generates [AA(NH)-(H(2)O)(1)](+) in the D(0) state, however, photoionization of [AA(CO)-(H(2)O)(1)] does not produce [AA(CO)-(H(2)O)(1)](+), leading to [AA(NH)-(H(2)O)(1)](+). This observation explicitly indicates that the water molecule in [AA-(H(2)O)(1)](+) migrates from the CO group to the NH group in the D(0) state. The reorganization of the charge distribution from the neutral to the D(0) state of AA induces the repulsive force between the water molecule and the CO group of AA(+), which is the trigger of the water migration in [AA (H(2)O)(1)](+). PMID- 21235223 TI - Hydrazine-sensitive thiol protecting group for peptide and protein chemistry. AB - In the search for a new Cys side-chain protecting group that is compatible to the solid-phase peptide synthesis yet can be removed under mild conditions, the Hqm and Hgm groups that are readily deprotected by using aqueous hydrazine have been developed. The utility of these groups for peptide and protein chemistry is tested by the total synthesis of a peptide antibiotic trifolitoxin and the human neutrophil defensin hNP2. PMID- 21235224 TI - Expeditious chemical synthesis of ubiquitinated peptides employing orthogonal protection and native chemical ligation. AB - Ubiquitination-the attachment of ubiquitin to a protein target-is involved in a wide range of cellular processes in eukaryotes. This dynamic posttranslational modification utilizes three enzymes to link, through an isopeptide bond, the C terminal Gly of ubiquitin to the lysine side chain from a protein target. Progress in the field aiming at deciphering the role of ubiquitination in biological processes has been very dependent on the discovery of the enzymatic machinery, which is known to be very specific to each protein target. Chemical approaches offer a complementary route to the biochemical methods to construct these conjugates in vitro in order to assist in unraveling the role of ubiquitination on protein function. Herein is presented a novel method for the rapid synthesis of ubiquitinated peptides employing solid-phase peptide to generate the critical isopeptide linkage. Using these tools, several ubiquitinated peptides derived from known ubiquitinated proteins were prepared. Among them is the ubiquitinated C-terminal fragment of H2B, which can be used in the synthesis of monoubiquitinated H2B. For the first time, we systematically assessed the effect of the length of the ubiquitinated peptides on the UCH-L3 activity and found that peptides of up to ~20 residues are preferred substrates. PMID- 21235225 TI - Polymer shelled microparticles for a targeted doxorubicin delivery in cancer therapy. AB - Targeting is a main feature supporting any controlled drug delivery modality. Recently we developed poly(vinyl alcohol), PVA, based microbubbles as a potential new ultrasound contrast agent featuring an efficient ultrasound backscattering and a good shelf stability. The chemical versatility of the polymeric surface of this device offers a vast variety of coupling modalities useful for coating and specific targeting. We have designed a conjugation strategy on PVA shelled microbubbles to enable the localization and the drug delivery on tumor cells by modifying the surface of this polymeric ultrasound contrast agent (UCA) with oxidized hyaluronic acid (HAox). After the conversion of the microbubbles into microcapsules, the kinetics of the release of doxorubicin, a well-known antitumor drug, from uncoated and HAox-coated PVA microbubbles and microcapsules was investigated. Cytocompatibility and bioadhesive properties of the HA-modified microparticles were then tested on the HT-29 tumor cell line. Cytotoxicity to HT 29 tumor cells of microcapsules after loading with doxorubicin was studied, evidencing the efficacy of the HAox coating for the delivery of the drug to cells. These features are a prerequisite for a theranostic, that is, diagnostic and therapeutic, use of polymer-based UCAs. PMID- 21235226 TI - Orderly microaggregates of G-/C-rich oligonucleotides associated with spermine. AB - Spermine-induced orderly assembling properties of G-/C-rich oligonucleotides are investigated in dilute and crowding conditions. The first time we report that the parallel G-quadruplexes is preferential to condense into anisotropic microaggregates in the presence of spermine, whereas the hybrid-type and the antiparallel G-quadruplexes have no significant interactions with spermine; and spermine can induce the condensation of i-motif C-rich oligonucleotides other than the random coiled C-rich strands. Moreover, the condensation of C-rich oligonucleotides can be reversibly regulated by pH and temperature. G-/C-rich oligonucleotides exhibit the cholesteric liquid crystalline phase at low strand concentration in the presence of spermine under crowding conditions. The results illuminate that the parallel G-quadruplex and i-motifs are probably necessity conformations for G-/C-rich oligonucleotides that involved in the regulation of chromosome organization in living cells. PMID- 21235227 TI - Temperature behavior of the AlH3 polymorph by in situ investigation using high resolution Raman scattering. AB - A Raman investigation of the AlH(3) polymorph has been carried out at a low temperature (20 K) under helium atmosphere (2 bar). The pristine material was composed of three polymorphs, namely, the alpha, beta, and gamma phases. The beta phase has been removed by warming the sample to 70 degrees C, while further heating at 100 degrees C was used to remove the gamma phase. This allowed us to evidence, on a purely experimental basis, the characteristic Raman spectrum for each phase. Raman spectra, for the three phases, have been also calculated using density functional theory, and the results have been compared to the present experimental data, allowing for a univocal assignment, to each phase, of its characteristic spectral features. PMID- 21235229 TI - Effect of pH on H2O2 production in the radiolysis of water. AB - The yields of hydrogen peroxide have been measured in the radiolysis of aqueous solutions of acrylamide, bromide, nitrate, and air in the pH range of 1-13. Hydrogen peroxide is the main stable oxidizing species formed in the radiolysis of water, and its long-term yield is found to be very sensitive to the system used in the measurements. Experiments with gamma-irradiation combined with model calculations show that the primary yields of hydrogen peroxide are nearly independent of pH in the range of 2-12. Slightly higher primary yields are suggested at very low pH in particular when O(2) is present, while the yields seem to decrease at very high pH. Irradiations were performed with 5 MeV H ions, 5 MeV He ions, and 10 MeV C ions to evaluate the intratrack and homogeneous kinetic contributions to H(2)O(2) formation with different ions. Many of the trends in hydrogen peroxide yields with pH observed with gamma-irradiations are observed with irradiation by the heavy ions. The lower yields of radicals in the homogeneous phase with the heavier ions tend to minimize the effects of radicals on the hydrogen peroxide yields at long times. PMID- 21235228 TI - Identification of a chemical that inhibits the mycobacterial UvrABC complex in nucleotide excision repair. AB - Bacterial DNA can be damaged by reactive nitrogen and oxygen intermediates (RNI and ROI) generated by host immunity, as well as by antibiotics that trigger bacterial production of ROI. Thus a pathogen's ability to repair its DNA may be important for persistent infection. A prominent role for nucleotide excision repair (NER) in disease caused by Mycobacterium tuberculosis (Mtb) was suggested by attenuation of uvrB-deficient Mtb in mice. However, it was unknown if Mtb's Uvr proteins could execute NER. Here we report that recombinant UvrA, UvrB, and UvrC from Mtb collectively bound and cleaved plasmid DNA exposed to ultraviolet (UV) irradiation or peroxynitrite. We used the DNA incision assay to test the mechanism of action of compounds identified in a high-throughput screen for their ability to delay recovery of M. smegmatis from UV irradiation. 2-(5-Amino-1,3,4 thiadiazol-2-ylbenzo[f]chromen-3-one) (ATBC) but not several closely related compounds inhibited cleavage of damaged DNA by UvrA, UvrB, and UvrC without intercalating in DNA and impaired recovery of M. smegmatis from UV irradiation. ATBC did not affect bacterial growth in the absence of UV exposure, nor did it exacerbate the growth defect of UV-irradiated mycobacteria that lacked uvrB. Thus, ATBC appears to be a cell-penetrant, selective inhibitor of mycobacterial NER. Chemical inhibitors of NER may facilitate studies of the role of NER in prokaryotic pathobiology. PMID- 21235231 TI - Quantification of VX vapor in ambient air by liquid chromatography isotope dilution tandem mass spectrometric analysis of glass bead filled sampling tubes. AB - An analysis method has been developed for determining low parts-per-quadrillion by volume (ppqv) concentrations of nerve agent VX vapor actively sampled from ambient air. The method utilizes glass bead filled depot area air monitoring system (DAAMS) sampling tubes with isopropyl alcohol extraction and isotope dilution using liquid chromatography coupled with a triple-quadrupole mass spectrometer (LC/MS/MS) with positive ion electrospray ionization for quantitation. The dynamic range was from one-tenth of the worker population limit (WPL) to the short-term exposure limit (STEL) for a 24 L air sample taken over a 1 h period. The precision and accuracy of the method were evaluated using liquid spiked tubes, and the collection characteristics of the DAAMS tubes were assessed by collecting trace level vapor generated in a 1000 L continuous flow chamber. The method described here has significant improvements over currently employed thermal desorption techniques that utilize a silver fluoride pad during sampling to convert VX to a higher volatility G-analogue for gas chromatographic analysis. The benefits of this method are the ability to directly analyze VX with improved selectivity and sensitivity, the injection of a fraction of the extract, quantitation using an isotopically labeled internal standard, and a short instrument cycle time. PMID- 21235230 TI - Evidence that epoxide-opening cascades promoted by water are stepwise and become faster and more selective after the first cyclization. AB - A detailed kinetic study of the endo-selective epoxide-opening cascade reaction of a diepoxy alcohol in neutral water was undertaken using (1)H NMR spectroscopy. The observation of monoepoxide intermediates resulting from initial endo and exo cyclization indicated that the cascade proceeds via a stepwise mechanism rather than through a concerted one. Independent synthesis and cyclization of these monoepoxide intermediates demonstrated that they are chemically and kinetically competent intermediates in the cascade. Analysis of each step of the reaction revealed that both the rate and regioselectivity of cyclization improve as the cascade reaction proceeds. In the second step, cyclization of an epoxy alcohol substrate templated by a fused diad of two tetrahydropyran rings proceeds with exceptionally high regioselectivity (endo:exo = 19:1), the highest we have measured in the opening of a simple trans-disubstituted epoxide. The origins of these observations are discussed. PMID- 21235232 TI - Spatial correlations of density and structural fluctuations in liquid water: a comparative simulation study. AB - We use large-scale classical simulations employing different force fields to study spatial correlations between local density and structural order for water in the liquid temperature range. All force fields investigated reproduce the main features of the experimental SAXS structure factor S(q), including the minimum at small q, and the recent TIP4P/2005 parametrization yields almost quantitative agreement. As local structural order parameters we consider the tetrahedrality and the number of hydrogen bonds and calculate all pure and mixed spatial two point correlation functions. Except for the density-density correlation function, there are only weak features present in all other correlation functions, showing that the tendency to form structural clusters is much weaker than the well-known tendency of water to form density clusters (i.e., spatially correlated regions where the density deviates from the mean). In particular, there are only small spatial correlations between local density and structural fluctuations, suggesting that features in density-density correlations (such as measured by the structure factor) are not straightforwardly related to spatial correlations of structure in liquid water. PMID- 21235233 TI - Venturi easy ambient sonic-spray ionization. AB - The development and illustrative applications of an ambient ionization technique termed Venturi easy ambient sonic-spray ionization (V-EASI) is described. Its dual mode of operation with Venturi self-pumping makes V-EASI applicable to the direct mass spectrometric analysis of both liquid (V(L)-EASI) and solid (V(S) EASI) samples. V-EASI is simple and easy to assemble, operating solely via the assistance of a sonic stream of nitrogen or air. The sonic gas stream causes two beneficial and integrated effects: (a) the self-pumping of solutions via the Venturi effect and (b) sonic-spray ionization (SSI) of analytes either in solution or resting on solid surfaces. In its liquid mode, V(L)-EASI is applicable to analytes in solution, forming negatively and/or positively charged intact molecular species in a soft fashion with little or no fragmentation. In its solid mode, V(S)-EASI relies on Venturi self-pumping of a proper SSI solvent solution in combination with SSI to form a stream of bipolar charged droplets that bombard the sample surface, causing desorption and ionization of the analyte molecules. As for its precursor technique (EASI), V-EASI generates bipolar droplets with considerably lower average charging, which increases selectivity for ionization with high signal-to-noise ratios and clean spectra dominated by single molecular species with minimal solvent ions. V-EASI also operates in a voltage-, heat-, and radiation-free fashion and is therefore free of thermal, electrical, or discharge interferences. PMID- 21235234 TI - Sorption to dissolved humic acid and its impacts on the toxicity of imidazolium based ionic liquids. AB - Two typical ionic liquids (ILs), 1-butyl-3-methylimidazolium chloride ([C4MIM]Cl) and 1-octyl-3-methylimidazolium chloride ([C8MIM]Cl), are demonstrated to associate strongly with dissolved organic matter (DOM) with distribution coefficients (KDOC) in the range of 10(4.2) to 10(4.6) for Aldrich humic acid (used as model DOM). With the increase of humic acid concentration to 11 MUg/mL DOC (dissolved organic carbon), the free fraction (ratio of freely dissolved to total concentration) of [C4MIM]Cl and [C8MIM]Cl reduced to about 0.85 and 0.79, respectively. This reduction of freely dissolved concentration gave rise to remarkable reduction of bioavailability and toxicity of the two ILs. MTT assay with HepG2 cell lines showed that the EC50 values were 459 MUmol/L for [C4MIM]Cl and 12 MUmol/L for [C8MIM]Cl, respectively, and the cell viability increased about 50% in the presence of trace amount of humic acid (1 MUg/mL DOC). The SOS/umu test indicated mutagenicity for [C4MIM]Cl at levels above 664 MUmol/L, and the genotoxicity was diminished with the addition of trace humic acid (0.00000374-0.374 MUg/mL DOC). The studied ILs showed acute toxicity toward model fish medaka with a 96 h median lethal concentration (LC50) of 2254 MUmol/L for [C4MIM]Cl and 366 MUmol/L for [C8MIM]Cl. The addition of humic acid (5.49 MUg/mL DOC for [C8MIM]Cl, 1.37 MUg/mL DOC for [C4MIM]Cl) to IL solutions reduced the death rate of medaka to a minimum value of ~25% of that at zero DOC. Our results suggest that DOM may play an important role in determining the environmental fate and toxicity of imidazolium-based ILs, and its effects should be taken into account in assessing the environmental risk of ILs. PMID- 21235235 TI - Effects of olefin group and its position on the kinetics for intramolecular H shift and HO2 elimination of alkenyl peroxy radicals. AB - Two classes of unimolecular reactions of peroxy radicals are key to autoignition, namely, intramolecular H-atom shift (which promotes autoignition) and concerted HO(2) elimination (which inhibits autoignition). Olefin groups are prominent functional groups in biodiesel fuels. This paper explores the effects of the presence of an olefin group and its position on the kinetics of unimolecular reactions of peroxy radicals. CBS-QB3 calculations were carried out for 10 selected alkyl- and alkenylperoxy radicals. Transition-state theory was used to determine the temperature dependence of the high-pressure limiting rate constants, and Rice-Ramsperger-Kassel-Marcus/master equation simulations were performed to determine the pressure dependence of selected rate constants. Tunneling effects were computed using the asymmetric Eckart potential. The contribution of internal rotors to partition functions were included by using the hindered-rotor treatment. PMID- 21235236 TI - Mutational analysis of catecholamine binding in tyrosine hydroxylase. AB - Tyrosine hydroxylase (TH) performs the first and rate-limiting step in the synthesis of catecholamines, which feed back to regulate the enzyme by irreversibly binding to a high-affinity site and inhibiting TH activity. Phosphorylation of Ser40 relieves this inhibition by allowing dissociation of catecholamine. We have recently documented the existence of a low-affinity catecholamine binding which is dissociable, is not abolished by phosphorylation, and inhibits TH by competing with the essential cofactor, tetrahydrobiopterin. Here, we have substituted a number of active site residues to determine the structural nature of the low- and high-affinity sites. E332D and Y371F increased the IC(50) of dopamine for the low-affinity site 10-fold and 7 0-fold, respectively, in phosphorylated TH, indicating dramatic reductions in affinity. Only 2-4-fold increases in IC(50) were measured in the nonphosphorylated forms of E332D and Y371F and also in L294A and F300Y. This suggests that while the magnitude of low-affinity site inhibition in wild-type TH remains the same upon TH phosphorylation as previously shown, the active site structure changes to place greater importance on E332 and Y371. Changes to high affinity binding were also measured, including a loss of competition with tetrahydrobiopterin for E332D, A297L, and Y371F and a decreased ability to inhibit catalysis (V(max)) for A297L and Y371F. The common roles of E332 and Y371 indicate that the low- and high-affinity catecholamine binding sites are colocalized in the active site, but due to simultaneous binding, may exist in separate monomers of the TH tetramer. PMID- 21235237 TI - Structural and functional studies indicate that the EPEC effector, EspG, directly binds p21-activated kinase. AB - Bacterial pathogens secrete effectors into their hosts that subvert host defenses and redirect host processes. EspG is a type three secretion effector with a disputed function that is found in enteropathogenic Escherichia coli. Here we show that EspG is structurally similar to VirA, a Shigella virulence factor; EspG has a large, conserved pocket on its surface; EspG binds directly to the amino terminal inhibitory domain of human p21-activated kinase (PAK); and mutations to conserved residues in the surface pocket disrupt the interaction with PAK. PMID- 21235238 TI - Tyrosine sulfation influences the chemokine binding selectivity of peptides derived from chemokine receptor CCR3. AB - The interactions of chemokines with their G protein-coupled receptors play critical roles in the control of leukocyte trafficking in normal homeostasis and in inflammatory responses. Tyrosine sulfation is a common post-translational modification in the amino-terminal regions of chemokine receptors. However, tyrosine sulfation of chemokine receptors is commonly incomplete or heterogeneous. To investigate the possibility that differential sulfation of two adjacent tyrosine residues could bias the responses of chemokine receptor CCR3 to different chemokines, we have studied the binding of three chemokines (eotaxin 1/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26) to an N-terminal CCR3-derived peptide in each of its four possible sulfation states. Whereas the nonsulfated peptide binds to the three chemokines with approximately equal affinity, sulfation of Tyr-16 gives rise to 9-16-fold selectivity for eotaxin-1 over the other two chemokines. Subsequent sulfation of Tyr-17 contributes additively to the affinity for eotaxin-1 and eotaxin-2 but cooperatively to the affinity for eotaxin-3. The doubly sulfated peptide selectively binds to both eotaxin-1 and eotaxin-3 approximately 10-fold more tightly than to eotaxin-2. Nuclear magnetic resonance chemical shift mapping indicates that these variations in affinity probably result from only subtle differences in the chemokine surfaces interacting with these receptor peptides. These data support the proposal that variations in sulfation states or levels may regulate the responsiveness of chemokine receptors to their cognate chemokines. PMID- 21235240 TI - 3-Thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (S1) based molecules as potent, dual inhibitors of B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1): structure-based design and structure-activity relationship studies. AB - We recently described the discovery of a dual inhibitor of Bcl-2 and Mcl-1, 3 thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1). Here we report a structure-guided design in combination with structure-activity relationship studies to exploit the difference in the p2 binding pocket of Bcl-2 and Mcl-1, from which a novel dual inhibitor 3-(4-aminophenylthio)-8-oxo-8H acenaphtho[1,2-b]pyrrole-9-carbonitrile (6h) was obtained, which showed significant enhanced IC(50) value against Mcl-1 (5 nM), greater Mcl-1/Bak disruption potential, and accordingly a 10-fold increased cytotoxicity over 3. PMID- 21235239 TI - Solution structure of 4'-phosphopantetheine - GmACP3 from Geobacter metallireducens: a specialized acyl carrier protein with atypical structural features and a putative role in lipopolysaccharide biosynthesis. AB - GmACP3 from Geobacter metallireducens is a specialized acyl carrier protein (ACP) whose gene, gmet_2339, is located near genes encoding many proteins involved in lipopolysaccharide (LPS) biosynthesis, indicating a likely function for GmACP3 in LPS production. By overexpression in Escherichia coli, about 50% holo-GmACP3 and 50% apo-GmACP3 were obtained. Apo-GmACP3 exhibited slow precipitation and non monomeric behavior by (15)N NMR relaxation measurements. Addition of 4' phosphopantetheine (4'-PP) via enzymatic conversion by E. coli holo-ACP synthase resulted in stable >95% holo-GmACP3 that was characterized as monomeric by (15)N relaxation measurements and had no indication of conformational exchange. We have determined a high-resolution solution structure of holo-GmACP3 by standard NMR methods, including refinement with two sets of NH residual dipolar couplings, allowing for a detailed structural analysis of the interactions between 4'-PP and GmACP3. Whereas the overall four helix bundle topology is similar to previously solved ACP structures, this structure has unique characteristics, including an ordered 4'-PP conformation that places the thiol at the entrance to a central hydrophobic cavity near a conserved hydrogen-bonded Trp-His pair. These residues are part of a conserved WDSLxH/N motif found in GmACP3 and its orthologs. The helix locations and the large hydrophobic cavity are more similar to medium- and long-chain acyl-ACPs than to other apo- and holo-ACP structures. Taken together, structural characterization along with bioinformatic analysis of nearby genes suggests that GmACP3 is involved in lipid A acylation, possibly by atypical long chain hydroxy fatty acids, and potentially is involved in synthesis of secondary metabolites. PMID- 21235241 TI - ATP-binding site of bacterial enzymes as a target for antibacterial drug design. PMID- 21235242 TI - Extract of lotus leaf ( Nelumbo nucifera ) and its active constituent catechin with insulin secretagogue activity. AB - The effect of lotus leaf ( Nelumbo nucifera Gaertn.) on diabetes is unclear. We hypothesized that lotus leaf can regulate insulin secretion and blood glucose levels. The in vitro and in vivo effects of lotus leaf methanolic extract (NNE) on insulin secretion and hyperglycemia were investigated. NNE increased insulin secretion from beta cells (HIT-T15) and human islets. NNE enhanced the intracellular calcium levels in beta cells. NNE could also enhance phosphorylation of extracellular signal-regulated protein kinases (ERK)1/2 and protein kinase C (PKC), which could be reversed by a PKC inhibitor. The in vivo studies showed that NNE possesses the ability to regulate blood glucose levels in fasted normal mice and high-fat-diet-induced diabetic mice. Furthermore, the in vitro and in vivo effects of the active constituents of NNE, quercetin, and catechin, on glucose-induced insulin secretion and blood glucose regulation were evaluated. Quercetin did not affect insulin secretion, but catechin significantly and dose-dependently enhanced insulin secretion. Orally administered catechin significantly reversed the glucose intolerance in high-fat-diet-induced diabetic mice. These findings suggest that NNE and its active constituent catechin are useful in the control of hyperglycemia in non-insulin-dependent diabetes mellitus through their action as insulin secretagogues. PMID- 21235244 TI - Identification of isopeptide bonds in heat-treated wheat gluten peptides. AB - Results in this paper confirm heat-induced isopeptide bond formation in wheat gluten. Heating (24 h, 130 degrees C) of wheat gluten [moisture content 7.4%] decreased its extractability in sodium dodecyl sulfate containing buffer (pH 6.8), even after reduction of disulfide (SS) bonds. Thus, both SS bonds and non SS bonds were responsible for the extractability loss. Cross-links of the lysinoalanine and lanthionine type were not present in the heated samples, but heat treatment reduced levels of available amino groups. Heating of purified and alkylated high molecular weight glutenin subunits (HMW-GS) under similar conditions also resulted in extractability loss, demonstrating that cross-linking did not solely depend on the availability of cysteine or cystine. These observations indicated that heat treatment had induced isopeptide bond formation, resulting in larger and unextractable molecules. Heating HMW-GS lysine- and glutamine-containing peptides induced the formation of isopeptide bonds, thereby supporting the above hypothesis. The level of isopeptide bond formation increased with heating time. PMID- 21235243 TI - Synthesis and pharmacological activities of 6-glycine substituted 14 phenylpropoxymorphinans, a novel class of opioids with high opioid receptor affinities and antinociceptive potencies. AB - The synthesis and the effect of a combination of 6-glycine and 14-phenylpropoxy substitutions in N-methyl- and N-cycloproplymethylmorphinans on biological activities are described. Binding studies revealed that all new 14 phenylpropoxymorphinans (11-18) displayed high affinity to opioid receptors. Replacement of the 14-methoxy group with a phenylpropoxy group led to an enhancement in affinity to all three opioid receptor types, with most pronounced increases in delta and kappa activities, hence resulting in a loss of MU receptor selectivity. All compounds (11-18) showed potent and long-lasting antinociceptive effects in the tail-flick test in rats after subcutaneous administration. For the N-methyl derivatives 13 and 14, analgesic potencies were in the range of their 14 methoxy analogues 9 and 10, respectively. Even derivatives 15-18 with an N cyclopropylmethyl substituent acted as potent antinociceptive agents, being several fold more potent than morphine. Subcutaneous administration of compounds 13 and 14 produced significant and prolonged antinociceptive effects mediated through peripheral opioid mechanisms in carrageenan-induced inflammatory hyperalgesia in rats. PMID- 21235245 TI - Rapid synthesis of 1,3,5-substituted 1,2,4-triazoles from carboxylic acids, amidines, and hydrazines. AB - A general method for the synthesis of 1,3,5-trisubstituted 1,2,4-triazoles has been developed from reaction of carboxylic acids, primary amidines, and monosubstituted hydrazines. This highly regioselective and one-pot process provides rapid access to highly diverse triazoles. PMID- 21235246 TI - Synthesis of novel angular spirocyclic azetidines. AB - The syntheses of a variety of novel angular azaspiro[3.3]heptanes are reported. gem-Difluoro and gem-dimethyl variants of the angular 1,6-diazaspiro[3.3]heptane module were prepared in high yields using efficient sequences. Additionally, a practical one-pot synthesis of 5-oxo-2-azaspiro[3.3]heptanes and subsequent conversions into functionalized derivatives are described. The methods reported are amenable to the synthesis of these building blocks for drug discovery as members of a library or individually on a preparative scale. PMID- 21235248 TI - Dielectric studies of the mobility in pentitols. AB - Broad-band dielectric relaxation measurements were performed for the four pentitols isomers, xylitol, adonitol, L-arabitol and D-arabitol. The comparison of the dynamical properties of these compounds shows similarities between the secondary relaxation processes but also important differences for the temperature dependence of the primary process characterized by the steepness index. These differences enable us to distinguish two groups of compounds that correspond to two kinds of molecular conformation. We show that the formation of more or less extended networks of hydrogen bonds, which reflects the more or less non Arrhenius variation of the primary relaxation, can be related to the differences of conformation of the studied isomers. PMID- 21235247 TI - Increased in vivo glucose recovery via nitric oxide release. AB - The in vivo glucose recovery of subcutaneously implanted nitric oxide (NO) releasing microdialysis probes was evaluated in a rat model using saturated NO solutions to steadily release NO. Such methodology resulted in a constant NO flux of 162 pmol cm(-2) s(-1) from the probe membrane over 8 h of perfusion daily. The in vivo effects of enhanced localized NO were evaluated by monitoring glucose recovery over a 14 day period, with histological analysis thereafter. A difference in glucose recovery was observed starting at 7 days for probes releasing NO relative to controls. Histological analysis at 14 days revealed lessened inflammatory cell density at the probe surface and decreased capsule thickness. Collectively, the results suggest that intermittent sustained NO release from implant surfaces may improve glucose diffusion for subcutaneously implanted sensors by mitigating the foreign body reaction. PMID- 21235249 TI - Vinyl diazophosphonates as precursors to quaternary substituted indolines and cyclopentenes. AB - Vinyl diazophosphonates can be stereoselectively synthesized and, depending upon their substitution pattern, undergo intramolecular C-H insertion reactions or sulfonium ylide rearrangements when exposed to Rh(2)(OAc)(4). PMID- 21235250 TI - Organocatalytic enantioselective Friedel-crafts reactions of 1-naphthols with aldimines. AB - An organocatalytic enantioselective Friedel-Crafts reaction of 1-naphthols with aldimines has been developed. The method affords a direct access to chiral aminoarylnaphthols in good yields and with good to high enantioselectivities. PMID- 21235252 TI - The power of solvent in altering the course of photorearrangements. AB - A clean bifurcation between two important photochemical reactions through competition of a triplet state Type II H-abstraction reaction with a photo Favorskii rearrangement for (o/p)-hydroxy-o-methylphenacyl esters that depends on the water content of the solvent has been established. The switch from the anhydrous Type II pathway that yields indanones to the aqueous-dependent pathway producing benzofuranones occurs abruptly at low water concentrations (~8%). The surprisingly clean yields suggest that such reactions are synthetically promising. PMID- 21235251 TI - Protein-based block copolymers. AB - Advances in genetic engineering have led to the synthesis of protein-based block copolymers with control of chemistry and molecular weight, resulting in unique physical and biological properties. The benefits from incorporating peptide blocks into copolymer designs arise from the fundamental properties of proteins to adopt ordered conformations and to undergo self-assembly, providing control over structure formation at various length scales when compared to conventional block copolymers. This review covers the synthesis, structure, assembly, properties, and applications of protein-based block copolymers. PMID- 21235254 TI - Density functional theory study on the mechanism of Rh-catalyzed decarboxylative conjugate addition: diffusion- and ligand-controlled selectivity toward hydrolysis or beta-hydride elimination. AB - The mechanism of Rh-catalyzed decarboxylative conjugate addition has been investigated with Density Functional Theory (DFT). Calculations indicate that the selectivity toward hydrolysis or beta-hydride elimination of the investigated reaction is a compromise between diffusion control and kinetic control. Ligand control can be adjusted by modifying the intermolecular interaction between the Rh(I) enolate intermediate and water. PMID- 21235253 TI - Highly enantioselective Mannich reactions with alpha-aryl silyl ketene acetals and imines. AB - Mannich reactions with chiral silicon Lewis acid activated acylhydrazones and alpha-aryl silyl ketene acetals and alpha-aryl,alpha-alkyl silyl ketene imines proceed efficiently and with good to excellent levels of both diastereoselectivity and enantioselectivity. The reactions provide access to alpha-aryl,beta-hydrazido esters and alpha-aryl,alpha-alkyl,beta-hydrazido nitriles, which are valuable analogs of beta-amino acids. PMID- 21235255 TI - Evaluating glutamate and aspartate binding mechanisms to rutile (alpha-TiO2) via ATR-FTIR spectroscopy and quantum chemical calculations. AB - Attenuated total reflectance (ATR) Fourier transform infrared (FTIR) spectroscopy and quantum chemical calculations were used to elucidate the influence of solution chemistry (pH, amino acid concentration) on the binding mechanisms of glutamic and aspartic acid to rutile (alpha-TiO(2)). The amino acids, glutamate and aspartate, contain carboxyl and amine groups whose dissociation over a pH range results in changes of molecular charge and reactivity, including reactions with mineral surfaces. At pH 3, a decrease of IR bands corresponding to protonated carboxyl groups is observed upon reaction with TiO(2) and indicates involvement of distal carboxyl groups during sorption. In addition, decreased IR bands arising from carboxyl bonds at 1400 cm(-1), concomitant to shifts to higher wavenumbers for nu(as)(gamma-COO(-)) and nu(as)(alpha-COO(-)) (particularly at low glutamate concentrations), are indicative of inner-sphere coordination of both carboxyl groups and therefore suggest a "lying down" surface species. IR spectra of aspartate reacted with rutile are similar to those of solution-phase samples, without peak shifts indicative of covalent bonding, and outer-sphere coordination is predicted. Quantum chemical calculations were carried out to assist in elucidating molecular mechanisms for glutamate binding to rutile and are in reasonable agreement with experimental data. The combined use of ATR-FTIR data and quantum calculations suggests three potential surface configurations, which include (1) bridging-bidentate where glutamate is "lying down" and binding occurs through inner-sphere coordination of both alpha- and gamma-carboxyl groups; (2) chelating-monodentate in which glutamate binds through inner-sphere coordination with the gamma-carboxyl group in a "standing up" configuration (with or without protonation of the alpha-carboxyl); and (3) another bridging-bidentate configuration where glutamate is binding to rutile via inner-sphere coordination of the alpha-carboxyl group and outer-sphere coordination with the gamma-carboxyl ("lying down"). PMID- 21235256 TI - Are electrophilicity and electrofugality related concepts? A density functional theory study. AB - It is proposed that the electrofugality of a fragment within a molecule is determined by its group nucleophilicity. The variation of electrofugality should be tightly related to the electron releasing ability of the substituent attached to the electrofuge moiety. This contribution closes the set of relationships between philicity and fugality quantities: while nucleofugality appears related to the group electrophilicity of the leaving group, electrofugality is related to the group nucleophilicity of the permanent group. PMID- 21235257 TI - 3-Sulfanylhexanol precursor biogenesis in grapevine cells: the stimulating effect of Botrytis cinerea. AB - Volatile thiols, compounds that contribute strongly to the varietal aroma, are present in much higher concentrations in sweet wines than in dry wines. This positive effect, due to the presence of Botrytis cinerea on the berries, in fact results from a strong enrichment of cysteine S-conjugate precursors in botrytized berries. In the present study, a convenient model was investigated to reproduce and therefore study this phenomenon. A Vitis vinifera cell culture was used as a simple model, and we focused on S-3-(hexan-1-ol)-l-cysteine (P-3SH), the cysteinylated precursor of 3-sulfanylhexanol. We demonstrated that grapevine cells were able to produce P-3SH and that the presence of B. cinerea considerably increased the precursor level (up to 1000-fold). This positive result was determined to be due to metabolites secreted by the fungus. These molecules were temperature sensitive, unstable over time, and their production was activated in the presence of grapevine cells. Moreover, part of the pathway leading to P-3SH was deciphered: it was directly derived from the cleavage of S-3-(hexan-1-ol)-l glutathione, which itself was generated after a conjugation of glutathione on (E) 2-hexenal. PMID- 21235258 TI - Portable microcoil NMR detection coupled to capillary electrophoresis. AB - High-efficiency separation techniques, such as capillary electrophoresis (CE), coupled to a nondestructive nuclear magnetic resonance (NMR) spectrometer offer the ability to separate, chemically identify, and provide structural information on analytes in small sample volumes. Previous CE-NMR coupled systems utilized laboratory-scale NMR magnets and spectrometers, which require very long separation capillaries. New technological developments in electronics have reduced the size of the NMR system, and small 1-2 T permanent magnets provide the possibilities of a truly portable NMR. The microcoils used in portable and laboratory-scale NMR may offer the advantage of improved mass sensitivity because the limit of detection (LOD) is proportional to the coil diameter. In this work, CE is coupled with a portable, briefcase-sized NMR system that incorporates a microcoil probe and a 1.8 T permanent magnet to measure (19)F NMR spectra. Separations of fluorinated molecules are demonstrated with stopped- and continuous-flow NMR detection. The results demonstrate that coupling CE to a portable NMR instrument is feasible and can provide a low-cost method to obtain structural information on microliter samples. An LOD of 31.8 nmol for perfluorotributylamine with a resolution of 4 ppm has been achieved with this system. PMID- 21235260 TI - Synthesis of 2,5-disubstituted 3-iodofurans via palladium-catalyzed coupling and iodocyclization of terminal alkynes. AB - 2,5-Disubstituted 3-iodofurans are readily prepared under very mild reaction conditions by the palladium/copper-catalyzed cross-coupling of (Z)-beta-bromoenol acetates and terminal alkynes, followed by iodocyclization. The useful intermediates conjugated enyne acetates are obtained in high yields in the transformation. Aryl- and alkyl-substituted alkynes undergo iodocyclization in good yields. The resulting iodine-containing furans can be readily elaborated to 2,3,5-trisubstituted furans. PMID- 21235259 TI - Room temperature aryl trifluoromethylation via copper-mediated oxidative cross coupling. AB - A method for the room temperature copper-mediated trifluoromethylation of aryl and heteroaryl boronic acids has been developed. This protocol is amenable to normal benchtop setup and reactions typically require only 1-4 h. Proceeding under mild conditions, the method tolerates a range of functional groups, allowing access to a variety of trifluoromethylarenes. PMID- 21235261 TI - Ph2N-susbtituted ethylene-bridged p-phenylene oligomers: synthesis and photophysical and redox properties. AB - For a series of p-phenylene-based oligomers terminated with two triphenylamines, their absorption, photoluminescence, and band gaps show a pattern of extensive pi conjugation with increasing array size. Oligomers with large central arrays have greater quantum yields than their small analogues. Cyclic voltammetric (CV) measurements indicated two-step oxidations of the two diphenylamino groups for compounds 1-5 and one-step oxidations for the two amines of large oligomers 6 and 7. PMID- 21235262 TI - Total synthesis of microcin B17 via a fragment condensation approach. AB - The total synthesis of the 43 amino acid antibacterial peptide Microcin B17 (MccB17) is described. The natural product was synthesized via a convergent approach from a heterocycle-derived peptide and peptide thioester fragments prepared via Fmoc-strategy solid phase peptide synthesis (SPPS). Final assembly was achieved in an efficient manner using two Ag(I)-assisted peptide ligation reactions to afford MccB17 in excellent overall yield. PMID- 21235263 TI - Phosphine-catalyzed cascade [3 + 2] cyclization-allylic alkylation, [2 + 2 + 1] annulation, and [3 + 2] cyclization reactions between allylic carbonates and enones. AB - The phosphine-catalyzed annulations between Morita-Baylis-Hillman adduct carbonates and enones are reported. Under the catalysis of PBu(3) (20 mol %), cascade [3 + 2] cyclization-allylic alkylation, [2 + 2 + 1] annulation, and [3 + 2] cyclization reactions chemoselectively occur depending on the substituent variation of both the carbonate and enone. These reactions provide efficient syntheses of highly functionalized cyclopentenes and cyclopentanes. PMID- 21235264 TI - Synthesis of CF3-substituted sulfoximines from sulfonimidoyl fluorides. AB - N-Protected trifluoromethyl-substituted sulfoximines have been prepared by treatment of sulfonimidoyl fluorides with a combination of the Ruppert-Prakash reagent (TMSCF(3)) and tetrabutyl ammonium fluoride (TBAF). The starting materials were accessed following two synthetic routes, and for each reaction sequence the substrate scope was evaluated. Accordingly, a wide variety of aryl substituted products were obtained in moderate to good yield. PMID- 21235265 TI - Magnetically driven agitation in a tube mixer affords clog-resistant fast mixing independent of linear velocity. AB - An economical and simple flow mixer based on magnetically driven agitation in a tube (MDAT) is reported. Mixing via MDAT compared favorably to both Tee and multilaminar mixers at low flow and was successfully used to screen and optimize two challenging organometallic reactions at low temperature without clogging or the need for high dilution. PMID- 21235266 TI - Diastereo- and enantioselective synthesis of oxazine and oxazolidine derivatives with a chiral quaternary carbon center under multifunctional catalysis. AB - An easy one-pot, multistep cascade reaction which could afford a series of substituted benzo[d]pyrido[2,1-b]oxazolidine and [1,3]oxazine derivatives in a highly enantio- (up to 98% ee) and diastereoselective (4:1 to >20:1 dr) manner with generally good to excellent yields (up to 99%) has been developed. This well designed strategy could be applied to a wide scope of substrates under mild conditions with simple operations. PMID- 21235267 TI - Palladium-catalyzed addition of alkynes to cyclopropenes: an entry to stereodefined alkynylcyclopropanes. AB - The Herrmann-Beller (H-B) phosphapalladacycle catalyzed the addition of terminal alkynes to unsymmetrical gem-disubstituted cyclopropenes to give alkynylcyclopropanes as single diastereomers in good to excellent yields. The stereofacial discrimination at the approach of the bulky alkynylpalladium species is believed responsible for the diastereoselectivity control of the addition reaction. PMID- 21235268 TI - Photochemical synthesis of bismuth selenide nanocrystals in an aqueous micellar solution. AB - The photolytic decomposition of triphenylbismuth and di-tert-butyl diselenide under aqueous micellar conditions yields 5-nm bismuth selenide nanocrystals of the BiSe stoichiometry. This is the first example of the bismuth-rich BiSe phase being prepared in a well-dispersed colloidal nanocrystal form. PMID- 21235269 TI - Arsenic in a speleothem from Central China: stadial-interstadial variations and implications. AB - In a pilot study, arsenic in a stalagmite (SJ3) collected from Central China was measured, and its association with past climate and environment was explored. Most of the SJ3 arsenic concentrations ranged from 120 to 320 ppb with the highest concentrations associated with relatively warm and humid climatic phases and lowest concentrations with cold and dry phases. The SJ3 arsenic record was very similar to the manganese record of SJ3. Variations of arsenic in SJ3 might be controlled by metal oxides of iron, manganese, and aluminum in karst groundwater at the study site, which in turn were closely related with changes in past climate and environment. A considerable proportion of arsenic was in excess over manganese in SJ3, which might be related with incorporation of arsenic into the calcite lattice during the formation of SJ3. It was speculated that more arsenic was released due to stronger weathering of the surface soils and sequestrated by metal oxides in karst groundwater under warm-humid climatic phases than under cold-dry phases. This suggested that climate shift might alter arsenic balance in sedimentary areas and aquifer systems and potentially exert significant influence on global arsenic contamination. PMID- 21235270 TI - Effect of inclining strain on the crystal lattice along an extended series of lanthanide hydroxysulfates Ln(OH)SO4 (Ln = Pr-Yb, except Pm). AB - A series of trivalent lanthanide hydroxysulfates, Ln(OH)SO(4), (Ln = Pr through Yb, except radioactive Pm) has been synthesized via hydrothermal methods from Ln(2)(SO(4))(3).8H(2)O by reaction with aqueous NaOH at 170 degrees C in Teflon lined Parr steel autoclaves, and were characterized by single crystal X-ray diffraction and FT-IR spectroscopy. Two types of arrangements were found in the solid state. The lighter (Ln = Pr-Nd, Sm-Gd) and heavier lanthanide(III) hydroxysulfates (Tb-Yb) are each isostructural. Both structure types exhibit the monoclinic space group P2(1)/n, but the unit cell content is doubled with two crystallographically distinct LnO(8) polyhedra for the heavier lanthanide compounds. The lighter complexes maintain the coordination number 9, forming a three-dimensional extended lattice. The heavier counterparts exhibit the coordination number 8, and arrange as infinite columns of two crystallographically different LnO(8) polyhedra, while extending along the "c" axis. These columns of LnO(8) polyhedra are surrounded and separated by six columns of sulfate ions, also elongating in the "c" direction. The rigid sulfate entities seem to obstruct the closing in of the lighter LnO(9) polyhedra, and show an inclining degree of torsion into the "ac" layers. The crystal lattice of the lighter 4f complexes can sufficiently withstand the tension buildup, caused by the decreasing Ln(3+) radius, up to Gd(OH)SO(4). The energy profile of this structural arrangement then seems to exceed levels at which this structure type is favorable. The lattice arrangement of the heavier Ln-analogues seems to offer a lower energy profile. This appears to be the preferred arrangement for the heavier lanthanide hydroxysulfates, whose crystal lattice exhibits more flexibility, as the coordination sphere of these analogues is less crowded. The IR absorbance frequencies of the hydroxide ligands correlate as a function of the Ln(3+) ionic radius. This corresponds well with the X-ray single crystal analysis data. PMID- 21235272 TI - Proteomic approaches to identifying carbonylated proteins in brain tissue. AB - Oxidative stress plays a critical role in the pathogenesis of a number of diseases. The carbonyl end products of protein oxidation are among the most commonly measured markers of oxidation in biological samples. Protein carbonyl functional groups may be derivatized with 2,4-dinitrophenylhydrazine (DNPH) to render a stable 2,4-dinitrophenylhydrazone-protein (DNP-protein) and the carbonyl contents of individual proteins then determined by two-dimensional electrophoresis followed by immunoblotting using specific anti-DNP antibodies. Unfortunately, derivatization of proteins with DNPH could affect their mass spectrometry (MS) identification. This problem can be overcome using nontreated samples for protein identification. Nevertheless, derivatization could also affect their mobility, which might be solved by performing the derivatization step after the initial electrophoresis. Here, we compare two-dimensional redox proteome maps of mouse cerebellum acquired by performing the DNPH derivatization step before or after electrophoresis and detect differences in protein patterns. When the same approach is used for protein detection and identification, both methods were found to be useful to identify carbonylated proteins. However, whereas pre-DNPH derivatized proteins were successfully analyzed, high background staining complicated the analysis when the DNPH reaction was performed after transblotting. Comparative data on protein identification using both methods are provided. PMID- 21235273 TI - Effect of ultrasound on the growth of probiotics and bioconversion of isoflavones in prebiotic-supplemented soymilk. AB - The objective of the present study was to evaluate the effects of ultrasound on the growth of probiotics and bioconversion of isoflavones in prebiotic-soymilk. Previous studies have shown that ultrasound elevated microbial enzymatic activity and growth by altering cellular membranes. The growth of probiotics was significantly decreased (P < 0.05) immediately after ultrasound treatment, attributed to membrane permeabilization, cell lysis, and membrane lipid peroxidation upon ultrasound treatment. The ultrasound treatment also caused alteration at the acyl chain, polar head, and interface region of the probiotic membrane phospholipid bilayers. The cells treated with ultrasound showed recovery from injury with subsequent increase in growth upon fermentation in soymilk (P < 0.05). Ultrasound treatment at 100 W for 2 and 3 min also enhanced (P < 0.05) the intracellular and extracellular beta-glucosidase activity of probiotics, leading to increased (P < 0.05) bioconversion of glucosides to aglycones in the prebiotic soymilk. Our present study illustrated that ultrasound treatment could produce bioactive synbiotic-soymilk with increased concentrations of bioactive aglycones. PMID- 21235271 TI - Transition metal-catalyzed decarboxylative allylation and benzylation reactions. PMID- 21235274 TI - Organochlorine pesticide residues in strawberries from integrated pest management and organic farming. AB - A rapid, specific, and sensitive method based on the Quick Easy Cheap Effective Rugged and Safe (QuEChERS) method and a cleanup using dispersive solid-phase extraction with MgSO(4), PSA, and C18 sorbents has been developed for the routine analysis of 14 pesticides in strawberries. The analyses were performed by three different analytical methodologies: gas chromatography (GC) with electron capture detection (ECD), mass spectrometry (MS), and tandem mass spectrometry (MS/MS). The recoveries for all the pesticides studied were from 46 to 128%, with relative standard deviation of <15% in the concentration range of 0.005-0.250 mg/kg. The limit of detection (LOD) for all compounds met maximum residue limits (MRL) accepted in Portugal for organochlorine pesticides (OCP). A survey study of strawberries produced in Portugal in the years 2009-2010 obtained from organic farming (OF) and integrated pest management (IPM) was developed. Lindane and beta endosulfan were detected above the MRL in OF and IPM. Other OCP (aldrin, o,p'-DDT and their metabolites, and methoxychlor) were found below the MRL. The OCP residues detected decreased from 2009 to 2010. The QuEChERS method was successfully applied to the analysis of strawberry samples. PMID- 21235275 TI - Analysis of 2D CS spectra for systems with non-gaussian dynamics. AB - We investigate how accurate different methods of the spectral line shape analysis work in two-dimensional correlation spectroscopy (2D CS) for systems with non gaussian dynamics. A direct link is established between the frequency dependent correlation functions and a number of line shape metrics. Two model systems are constructed mimicking a typical molecular system with conventional gaussian and non-gaussian spectral dynamics. The frequency dependent correlation function and several line shape parameters extracted from the 2D CS spectra at different waiting times reveal dissimilar dynamics in different frequency domains in the non-gaussian case and similar dynamics in all domains in the gaussian case. The extracted frequency dependent correlation times agree well with the local dynamics in the underlying model for all analysis methods. We also find an extension of the existing line shape analysis methods that allows the extraction of the third-order correlation function. PMID- 21235276 TI - Genetic targeting of a voltage-sensitive dye by enzymatic activation of phosphonooxymethyl-ammonium derivative. AB - Optical recording of action potentials in individual neurons requires cell selective targeting with a fluorescent, voltage-sensitive probe. We report on a new labeling system that takes advantage of recent developments in prodrug-based chemistry and allows for the targeting of a lipophilic dye into the plasma membrane of genetically specified cells. With the introduction of two phosphonooxymethylammonium zwitterions into the hydrocarbon chains of an amphiphilic, voltage-sensitive hemicyanine dye, a precursor dye was formed that is water-soluble to an extent that it can no longer bind into cell membranes and hence prevents unspecific staining. Glycosylphosphatidylinositol anchored placental alkaline phosphatase expressed in HEK293 cells converted the precursor dye to a homologue of the widely used dye di-4-ANEPPS and gave rise to excellent levels of plasma membrane localized staining. The voltage sensitivity of the enzymatically activated dye was tested and shown to be similar to sensitivity reported for di-4-ANEPPS. PMID- 21235277 TI - Modulating the redox potential of the stable electron acceptor, Q(B), in mutagenized photosystem II reaction centers. AB - One of the unique features of electron transfer processes in photosystem II (PSII) reaction centers (RC) is the exclusive transfer of electrons down only one of the two parallel cofactor branches. In contrast to the RC core polypeptides (psaA and psaB) of photosystem I (PSI), where electron transfer occurs down both parallel redox-active cofactor branches, there is greater protein-cofactor asymmetry between the PSII RC core polypeptides (D1 and D2). We have focused on the identification of protein-cofactor relationships that determine the branch along which primary charge separation occurs (P(680)(+)/pheophytin(-)(Pheo)). We have previously shown that mutagenesis of the strong hydrogen-bonding residue, D1 E130, to less polar residues (D1-E130Q,H,L) shifted the midpoint potential of the Pheo(D1)/Pheo(D1)(-) couple to more negative values, reducing the quantum yield of primary charge separation. We did not observe, however, electron transfer down the inactive branch in D1-E130 mutants. The protein residue corresponding to D1 E130 on the inactive branch is D2-Q129 which presumably has a reduced hydrogen bonding interaction with Pheo(D2) relative to the D1-E130 residue with Pheo(D1). Analysis of the recent 2.9 A cyanobacterial PSII crystal structure indicated, however, that the D2-Q129 residue was too distant from the Pheo(D2) headgroup to serve as a possible hydrogen bond donor and directly impact its midpoint potential as well as potentially determine the directionality of electron transfer. Our objective was to characterize the function of this highly conserved inactive branch residue by replacing it with a nonconservative leucine or a conservative histidine residue. Measurements of Chl fluorescence decay kinetics and thermoluminescence studies indicate that the mutagenesis of D2-Q129 decreases the redox gap between Q(A) and Q(B) due to a lowering of the redox potential of Q(B). The resulting increased yield of S(2)Q(B)(-) charge recombination in the D2 Q129 mutants leads to an increased susceptibility to photoinhibitory light presumably due to (3)P(680)-mediated oxidative damage. The results indicate that the D2-Q129 residue plays a critical role in stabilizing the charge-separated state in PSII and further documents the structural and functional asymmetry between the two cofactor branches in PSII. PMID- 21235278 TI - Butyrate-induced apoptosis in HCT116 colorectal cancer cells includes induction of a cell stress response. AB - Short chain fatty acids (SCFA), principally butyrate, propionate, and acetate, are produced in the gut through the fermentation of dietary fiber by the colonic microbiotica. Butyrate in particular is the preferred energy source for the cells in the colonic mucosa and has been demonstrated to induce apoptosis in colorectal cancer cell lines. We have used proteomics, specifically 2D-DIGE and mass spectrometry, to identify proteins involved in butyrate-induced apoptosis in HCT116 cells and also to identify proteins involved in the development of butyrate insensitivity in its derivative, the HCT116-BR cells. The HCT116-BR cell line was characterized as being less responsive to the apoptotic effects of butyrate in comparison to its parent cell line. Our analysis has revealed that butyrate likely induces a cellular stress response in HCT116 cells characterized by p38 MAPK activation and an endoplasmic reticulum (ER) stress response, resulting in caspase 3/7 activation and cell death. Adaptive cellular responses to stress-induced apoptosis in HCT116-BR cells may be responsible for the development of resistance to apoptosis in this cell line. We also report for the first time additional cellular processes altered by butyrate, such as heme biosynthesis and dysregulated expression of nuclear lamina proteins, which may be involved in the apoptotic response observed in these cell lines. PMID- 21235279 TI - Cycloaddition reactions of allenylphosphonates and related allenes with dialkyl acetylenedicarboxylates, 1,3-diphenylisobenzofuran, and anthracene. AB - Cycloaddition reactions of allenylphosphonates [(RO)(2)P(O)[(R(1))C?C?CR(2)(2)] with dialkyl acetylenedicarboxylates, 1,3-diphenylisobenzofuran, and anthracene have been investigated and compared with those of allenoates [(EtO(2)C)RC?C?CH(2)] and allenylphosphine oxides [Ph(2)P(O)(R(1))C?C?CR(2)(2)] in selected cases. Allenylphosphonates (RO)(2)P(O)(Ar)C?C?CH(2) with an alpha aryl group preferentially undergo [4 + 2] cycloaddition with DMAD/DEAD under thermal activation, but in addition to the expected 1:1 (allene: DMAD) product, the reaction also leads to 1:2 as well as 2:1 products that were not reported before. When an extra vinyl group is present at the gamma-carbon of allenylphosphonate [e.g., (OCH(2)CMe(2)CH(2)O)P(O)(Ph)C?C?CH(C?CHMe)], [4 + 2] cycloaddition takes place utilizing either the vinylic or the aryl end, but additionally a novel cyclization wherein complete opening of the [beta,gamma] carbon-carbon double bond of the allene is realized. In contrast to these, the reaction of allenylphosphonate (OCH(2)CMe(2)CH(2)O)P(O)(H)C?C?CMe(2) possessing a terminal ?CMe(2) group with DMAD occurs by both [2 + 2] cycloaddition and ene reaction. While the reaction of ?CH(2) terminal allenylphosphonates as well as allenylphosphine oxides with 1,3-diphenylisobenzofuran afforded preferentially endo-[4 + 2] cycloaddition products via [alpha,beta] attack, the analogous allenoates [(EtO(2)C)RC?C?CH(2)] underwent exo-[4 + 2] cyclization. Under similar conditions, allenylphosphonates with a terminal ?CR(2) group gave only [beta,gamma]-cycloaddition products. An unusual ring-opening of a [4 + 2] cycloaddition product followed by ring-closing via [4 + 4] cycloaddition, as revealed by (31)P NMR spectroscopy, is reported. Anthracene reacted in a manner similar to 1,3-diphenylisobenzofuran, albeit with lower reactivity. Key products, including a set of exo- and endo- [4 + 2] cycloaddition products, have been characterized by single crystal X-ray crystallography. PMID- 21235280 TI - When ethnology informs clinical medicine: non-Bantu peoples without apparent sickle cell disease in the Mbulu area of Northern Tanzania. PMID- 21235281 TI - Parental attitudes towards childhood immunizations in Eastern Uganda. PMID- 21235282 TI - Effect of functional groups on antioxidant properties of substituted selenoethers. AB - Selenoethers attached to functional groups through propyl chain viz., bis(3 carboxypropyl)selenide (SeBA), bis(3-hydroxypropyl)selenide (SePOH) and bis(3 aminopropyl)selenide dihydrochloride (SePAm), have been examined for their ability to inhibit peroxyl radical mediated DNA damage, peroxyl radical scavenging ability and glutathione peroxidase (GPx) like activity. The DNA damage was monitored by gel electrophoresis, bimolecular rate constants for scavenging of model peroxyl radical were determined by pulse radiolysis and the GPx activity was followed by their ability to reduce hydrogen peroxide in the presence of glutathione utilizing NADPH decay and HPLC analysis. Among these compounds, SeBA showed maximum DNA protecting activity and it was also the most efficient in scavenging peroxyl radicals with the highest GPx mimicking activity. Quantum chemical calculations confirmed that SeBA with the highest energy level of HOMO (highest occupied molecular orbital) is the easiest to undergo oxidation and therefore exhibits better radical scavenging, GPx mimicking and DNA protecting activity than SePOH or SePAm. PMID- 21235283 TI - Mechanistic enhancement of the intestinal absorption of drugs containing the polar guanidino functionality. AB - INTRODUCTION: Guanidino-containing compounds are well-known for their important biological roles in vivo. In a rational drug design process, the guanidino group is frequently adopted to mimic the arginine residue of the endogenous substrate and secure the affinity of the drug to the target. However, due to their inherent polarity and positive charge in the gastrointestinal tract, it is difficult for guanidino-containing compounds to be orally absorbed by passive diffusion. Hence, guanidino-containing compounds are frequently associated with low oral bioavailability. AREAS COVERED: In this review, we present the barriers and challenges toward the oral absorption of guanidino-containing compounds, provide an overview of the research that has been done so far in the area, and summarize recent advances and future directions in the mechanistic enhancement of the intestinal absorption of drugs containing the polar guanidino functionality. For instance, application of several different prodrug approaches, a novel recently developed ion-pairing strategy and the utilization of advanced formulations are discussed. EXPERT OPINION: While additional research is required to allow efficient and facile solutions to low oral bioavailability of guanidino containing compounds, novel and exciting strategies have been developed in recent years. Although challenging, the development of a potent guanidino-containing compound into an orally administered drug is becoming an achievable target. PMID- 21235284 TI - Pharmacological management of autoimmune hepatitis. AB - INTRODUCTION: Without prompt immunosuppressive treatment, autoimmune hepatitis is a devastating, albeit rare, liver disease. It affects both adults and children, being particularly aggressive in the latter. Eighty per cent of patients respond satisfactorily to treatment; the other 20% progress to end-stage liver disease and require transplantation. AREAS COVERED: This review emphasizes the importance of a timely diagnosis of autoimmune hepatitis and provides a practical guide for its treatment. The authors summarize the treatment options available for autoimmune hepatitis and stress that most patients respond successfully to standard treatment with prednisolone and azathioprine, two well-tried and inexpensive drugs. The authors also review the options for difficult-to-treat patients (non-responders and frequent relapsers), for whom newer immunosuppressive agents--usually employed as anti-rejection drugs--have been tried with variable success. EXPERT OPINION: Autoimmune hepatitis is exquisitely responsive to immunosuppression but treatment must be started as soon as possible to achieve full remission and halt progression of liver disease. New strategies aiming at treating the unresponsive patients and at specifically curbing the liver autoimmune attack, without provoking unwanted systemic side effects, are being investigated and may be available within the next 5 years. PMID- 21235285 TI - The effects of oxidation products of arachidonic acid and n3 fatty acids on vascular and platelet function. AB - 15-F2(t)-isoprostane (15-F2(t)-IsoP), an oxidation product of arachidonic acid (AA), affects vascular and platelet function; however, the bioactivity of other fatty acids oxidation products is unknown. This paper studied rat aortic vascular reactivity and human platelet aggregation in response to 14 oxidation products of AA, eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and alpha-linolenic acid (ALA) compared with 15-F2(t)-IsoP. It also compared the F2(t)-IsoPs profile in human platelets. EPA-derived 15-F3(t)-IsoP constricted rat aorta less than 15 F2(t)-IsoP, but none of the other oxidation products affected vascular reactivity. Only 15-F2(t)-IsoP (10-4 M) directly affected platelet aggregation. 15-F3(t)-IsoP, ent-16-F1-phytoprostane (from ALA) and isofurans A and B (from AA) inhibited reversible aggregation to U46619. Unlike plasma, the platelet profile of F2-IsoP showed that 8-F(2t)-IsoP were higher than 15-F2(t)-IsoP. Unlike 15 F2(t)-IsoP, the test compounds derived from fatty acids oxidation did not affect vascular or platelet function. Elevated platelet 8-F2(t)-IsoP could limit 15 F2(t)-IsoP-induced aggregation under conditions of oxidant stress. PMID- 21235286 TI - Piceatannol is more effective than resveratrol in restoring endothelial cell dimethylarginine dimethylaminohydrolase expression and activity after high glucose oxidative stress. AB - Glucose-induced oxidative stress is involved in endothelial dysfunction. Dimethylarginine dimethylaminohydrolase (DDAH) and arginase are regulators of the endothelial NO synthase (eNOS). This study aimed to compare the effect of two polyphenolic antioxidants, resveratrol and piceatannol, on DDAH and arginase pathways in bovine aortic endothelial cells under 25 mM glucose for 24 h. DDAH activity and expression were decreased in these cells as compared to control cells, whereas arginase activity was unchanged. DDAH inhibition led to intracellular accumulation of asymmetric dimethylarginine (ADMA), a natural inhibitor of eNOS. Under these conditions, cell pre-treatment with resveratrol (0.1-10 MUM) restored basal DDAH activity and ADMA level with a dose-dependent effect. Piceatannol acted as resveratrol on DDAH pathway but at 10-fold lower concentrations. Resveratrol and piceatannol restored DDAH activity even in the presence of splitomicin, a specific inhibitor of Sirtuin 1. These results suggest potential therapeutic intervention targeting resveratrol or piceatannol administration to improve endothelial dysfunction. PMID- 21235288 TI - Frequency of Candida species in Papanicolaou smears taken from Sudanese oral hormonal contraceptives users. AB - The aim of our study was to compare the numbers of Candida detected in Pap smears from Sudanese users of oral contraceptives (OCs) with non-users of OCs. The frequency of Candida observed in Pap smears was assessed among 158 Sudanese women of whom 108 were OCs users, subsequently termed cases, and the remaining 50 who were not OCs users, subsequently termed controls. Of the 158 smears, Candida were observed in 28 (17%) of the study subjects of whom 27 (25%) were OCs users compared to 1 (2%) among non-OCs users. We concluded that OCs may increase the number of Candida present, which suggests that OCs users may be more prone to infection by cervico-vaginal Candida compared to non-OCs users. The exact role of OCs use as a risk factor for candidiasis requires further assessment using a larger sample size and more precise mycological techniques. PMID- 21235289 TI - Report on the 2nd Workshop on Fluorescence Chemosensors and Bioimaging, Dalian, China: one participant's view. AB - I was invited to this Workshop, because I have published papers on the mechanisms of action of small molecule fluorescent probes used with living cells. The Workshop provided an opportunity to interact with some significant figures in the chemosensor and bioimaging field from across the planet; to spend time with a large, friendly and active group of local investigators and their graduate students; and to take a brief look at a vibrant modern city. Many scientific connections were made and collaborations planned for the Biological Stain Commission and for my own future work. PMID- 21235290 TI - The Malachowski-Wright-Giemsa stain: a many-splendored thing. PMID- 21235291 TI - The color purple: from royalty to laboratory, with apologies to Malachowski. AB - The components of the blood stain, eosin and methylene blue, were introduced by Baeyer and Caro, respectively. Methylene blue was used primarily for detecting Mycobacterium tuberculosis until Ehrlich in 1880 mixed methylene blue with acid fuchsin to produce what he termed a "neutral stain," which allowed differentiation of blood cells. Eight years later, Checin ski changed the acidic component of the dye to eosin. Plehn subsequently altered the proportions of eosin and methylene blue to produce a greater range of red and blue hues. In 1891, Malachowski and Romanowsky independently developed stains composed of eosin and "ripened" methylene blue that not only differentiated blood cells, but also demonstrated the nuclei of malarial parasites. A number of "ripening" or "polychroming" techniques were investigated by different groups, but the aqueous dye solutions produced were unstable and precipitated rapidly. Subsequently, methanol was introduced as a solvent for the dye precipitate and techniques were developed that utilized the fixative properties of the methanolic solution prior to aqueous dilution for staining. This avoided the troublesome process of heat fixation of blood films. Giemsa further improved these techniques by using more controlled methods of methylene blue demethylation. In addition, he used measured amounts of known dyes and increased dye stability by adding glycerol to the methanol solvent. With the outbreak of World War I, it became difficult to obtain German dyes outside of Germany; during the World War II, it became impossible. In their effort to improve the inferior American versions of Giemsa's stain, Lillie, Roe, and Wilcox discovered that the best staining results were obtained using pure methylene blue, one of its breakdown products (azure B) and eosin. These three substituents remain the major components of the stain to this day. PMID- 21235292 TI - How Romanowsky stains work and why they remain valuable - including a proposed universal Romanowsky staining mechanism and a rational troubleshooting scheme. AB - An introduction to the nomenclature and concept of "Romanowsky stains" is followed by a brief account of the dyes involved and especially the crucial role of azure B and of the impurity of most commercial dye lots. Technical features of standardized and traditional Romanowsky stains are outlined, e.g., number and ratio of the acidic and basic dyes used, solvent effects, staining times, and fixation effects. The peculiar advantages of Romanowsky staining are noted, namely, the polychromasia achieved in a technically simple manner with the potential for stain intensification of "the color purple." Accounts are provided of a variety of physicochemically relevant topics, namely, acidic and basic dyeing, peculiarities of acidic and basic dye mixtures, consequences of differential staining rates of different cell and tissue components and of different dyes, the chemical significance of "the color purple," the substrate selectivity for purple color formation and its intensification in situ due to a template effect, effects of resin embedding and prior fixation. Based on these physicochemical phenomena, mechanisms for the various Romanowsky staining applications are outlined including for blood, marrow and cytological smears; G bands of chromosomes; microorganisms and other single-cell entities; and paraffin and resin tissue sections. The common factors involved in these specific mechanisms are pulled together to generate a "universal" generic mechanism for these stains. Certain generic problems of Romanowsky stains are discussed including the instability of solutions of acidic dye-basic dye mixtures, the inherent heterogeneity of polychrome methylene blue, and the resulting problems of standardization. Finally, a rational trouble-shooting scheme is appended. PMID- 21235294 TI - Multiple strategies must be pursued in the development of cellular therapies. PMID- 21235293 TI - Efficiency of cellular delivery of antisense peptide nucleic acid by electroporation depends on charge and electroporation geometry. AB - Electroporation is potentially a very powerful technique for both in vitro cellular and in vivo drug delivery, particularly relating to oligonucleotides and their analogs for genetic therapy. Using a sensitive and quantitative HeLa cell luciferase RNA interference mRNA splice correction assay with a functional luciferase readout, we demonstrate that parameters such as peptide nucleic acid (PNA) charge and the method of electroporation have dramatic influence on the efficiency of productive delivery. In a suspended cell electroporation system (cuvettes), a positively charged PNA (+8) was most efficiently transferred, whereas charge neutral PNA was more effective in a microtiter plate electrotransfer system for monolayer cells. Surprisingly, a negatively charged ( 23) PNA did not show appreciable activity in either system. Findings from the functional assay were corroborated by pulse parameter variations, polymerase chain reaction, and confocal microscopy. In conclusion, we have found that the charge of PNA and electroporation system combination greatly influences the transfer efficiency, thereby illustrating the complexity of the electroporation mechanism. PMID- 21235295 TI - Stem and progenitor cells in liver regeneration and repair. AB - Mammalian liver has a unique capacity to regenerate following resection or injury, and recovery of liver mass is mainly through proliferation of remaining adult hepatocytes. However, in pathologic conditions, especially during acute liver failure (ALF) and advanced stages of chronic liver disease (CLD), regeneration eventually fails and orthothopic liver transplantation (OLT) represents the only curative approach. The clinical scenario of a world-wide increasing incidence of end-stage CLD and an associated lack of organ availability has led several laboratories to explore the feasibility and efficiency of experimental alternatives to OLT involving cellular therapy. This review presents experimental and clinical studies performed in the last 10-15 years where adult and embryonic hepatocytes, hepatic stem/progenitor cells and extrahepatic stem cells have been used as transplantable cell sources. PMID- 21235296 TI - Enhancement of wound healing by secretory factors of endothelial precursor cells derived from human embryonic stem cells. AB - BACKGROUND AIMS: Stem cells have been shown to have a therapeutic effect in several ischemic animal models, including hindlimb ischemia and chronic wound. We examined the wound-healing effect of secretory factors released by human embryonic stem cell (hESC)-derived endothelial precursor cells (EPC) in cutaneous excisional wound models. METHODS: hESC-EPC were sorted by CD133/KDR, and endothelial characteristics were confirmed by reverse transcription (RT) polymerase chain reaction (PCR), Matrigel assay and ac-LDL uptake. Conditioned medium (CM) of hESC-EPC was prepared, and concentrated hESC-EPC CM was applied in a mouse excisional wound model. RESULTS: hESC-EPC CM accelerated wound healing and increased the tensile strength of wounds after topical treatment and subcutaneous injection. In addition, hESC-EPC CM treatment caused more rapid re formation of granulation tissue and re-epithelialization of wounds compared with control vehicle medium and CB-EPC CM-treated wounds. In vitro, hESC-EPC CM significantly improved the proliferation and migration of dermal fibroblasts and epidermal keratinocytes. hESC-EPC CM also increased the extracellular matrix synthesis of fibroblasts. Analysis of hESC-EPC CM with a multiplex cytokine array system indicated that hESC-EPC secreted distinctively different cytokines and chemokines, such as epidermal growth factor (EGF), fibroblast growth factor (bFGF), fractalkine, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, IL-8, platelet-derived growth factor-AA (PDGF-AA) and vascular endothelial growth factor (VEGF), which are well known to be important in normal angiogenesis and wound healing. CONCLUSIONS: This study has demonstrated the wound-healing effect of hESC-EPC CM and characterized the spectrum of cytokines released by hESC-EPC that are functionally involved in the wound-healing process. These results suggest that secretory factors released from stem cells could be an important mediator of stem cell therapy in ischemic tissue diseases. PMID- 21235297 TI - Transcriptional profiling of CD133(+) cells in coronary artery disease and effects of exercise on gene expression. AB - BACKGROUND AIMS: Bone marrow (BM)-derived progenitor cells are under investigation for cardiovascular repair but may be altered by disease. Our aim was to identify differences in gene expression in CD133(+) cells of patients with coronary artery disease (CAD) and healthy controls, and determine whether exercise modifies gene expression. METHODS: CD133(+) cells were flow-sorted from 10 CAD patients and four controls, and total RNA was isolated for microarray based gene expression profiling. Genes that were found to be differentially regulated in patients were analyzed further to investigate whether exercise had any normalizing effect on CD133(+) cells in CAD patients following 3 months of an exercise program. RESULTS: Improvement in effort tolerance and increases in the number of CD133(+) cells were observed in CAD patients after 3 months of exercise. Gene expression analysis of the CD133(+) cells identified 82 differentially expressed genes (2-fold cut-off, 25% false-discovery rate and % present calls) in patients compared with controls, of which 59 were found to be up-regulated and 23 down-regulated. These genes were found to be involved in carbohydrate metabolism, cell cycle, cellular development and signaling, and molecular transport. Following completion of the exercise program, gene expression patterns resembled those of controls in seven of 10 patients. CONCLUSIONS: Alterations in gene expression of BM-derived CD133(+) progenitor cells were found in CAD patients, which in part may be normalized by exercise. PMID- 21235298 TI - Posterior approach for thoracolumbar corpectomies with expandable cage placement and circumferential arthrodesis: a multicenter case series of 67 patients. AB - OBJECT: The purpose of this multicenter trial was to investigate the outcome and durability of a single-stage thoracolumbar corpectomy using expandable cages via a posterior approach. METHODS: The authors conducted a retrospective chart review of 67 consecutive patients who underwent single-stage thoracolumbar corpectomies with circumferential reconstruction for pathological, traumatic, and osteomyelitic pathologies. Circumferential reconstruction was accomplished using expandable cages along with posterior instrumentation and fusion. Correction of the sagittal deformity, the American Spinal Injury Association score, and complications were recorded. RESULTS: Single-stage thoracolumbar corpectomies resulted in an average sagittal deformity correction of 6.2 degrees at a mean follow-period of 20.5 months. At the last follow-up, a fusion rate of 68% was observed for traumatic and osteomyelitic fractures. Approximately one-half of the patients remained neurologically stable. Improvement in neurological function occurred in 23 patients (38%), whereas 7 patients (11%) suffered from a decrease in lower-extremity motor function. The deterioration in neurological function was due to progression of metastatic disease in 5 patients. Five constructs (7%) failed-3 of which had been placed for traumatic fractures, 1 for a pathological fracture, and 1 for an osteomyelitic fracture. Other complications included epidural hematomas in 3 patients and pleural effusions in 2. CONCLUSIONS: Single stage posterior corpectomy and circumferential reconstruction were performed at multiple centers with a consistent outcome over a wide range of pathologies. Correction of the sagittal deformity was sustained, and the neurological outcome was good in the majority of patients; however, 18% of acute traumatic fractures required revision of the construct. PMID- 21235299 TI - Functional and clinical outcomes following surgical treatment in patients with cervical spondylotic myelopathy: a prospective study of 81 cases. AB - OBJECT: Cervical spondylotic myelopathy (CSM) is the most common cause of spinal dysfunction in the elderly. Operative management is beneficial for most patients with moderate/severe myelopathy. This study examines the potential confounding effects of age, sex, duration of symptoms, and comorbidities on the functional outcomes and postoperative complications in patients who underwent cervical decompressive surgery. METHODS: We included consecutive patients who underwent surgery from December 2005 to October 2007. Functional outcomes were assessed using the Nurick grading system and the modified Japanese Orthopaedic Association and Berg Balance scales. Comorbidity indices included the Charlson Comorbidity Index and the number of ICD-9 codes. RESULTS: There were 57 men and 24 women with a mean age of 57 years (range 32-88 years). The mean duration of symptoms was 25.2 months (range 1-120 months). There was a significant functional recovery from baseline to 6 months after surgery (p < 0.01). Postoperative complications occurred in 18.5% of cases. Although the occurrence of complications was not significantly associated with sex (p = 0.188), number of ICD-9 codes (p = 0.113), duration of symptoms (p = 0.309), surgical approach (p = 0.248), or number of spine levels treated (p = 0.454), logistic regression analysis showed that patients who developed complications were significantly older than patients who had no complications (p = 0.018). Only older age (p < 0.002) and greater number of ICD-9 codes (p < 0.01) were significantly associated with poorer functional recovery after surgical treatment. However, none of the studied factors were significantly associated with clinically relevant functional recovery after surgical treatment for CSM (p > 0.05). CONCLUSIONS: Our results indicate that surgery for CSM is associated with significant functional recovery, which appears to reach a plateau at 6 months after surgery. Age is a potential predictor of complications after decompressive surgery for CSM. Whereas older patients with a greater number of preexisting medical comorbidities had less favorable functional outcomes after surgery for CSM in the multivariate regression analysis, none of the studied factors were associated with clinically relevant functional recovery after surgery in the logistic regression analysis. Therefore, age-matched protocols based on preexisting medical comorbidities may reduce the risk for postoperative complications and improve functional outcomes after surgical treatment for CSM. PMID- 21235300 TI - Lumbar spinal stenosis in elderly patients: is a unilateral microsurgical approach sufficient for decompression? AB - OBJECT: For the treatment of lumbar spinal stenosis, less invasive procedures, which preserve maximal bony and ligamentous structures, have been recommended to reduce associated morbidity. The authors examined the outcome after decompression of spinal stenosis in the elderly by comparing 3 different surgical approaches. Their focus was whether a unilateral microsurgical decompression provided sufficient outcomes in the elderly population. METHODS: The authors investigated 108 elderly patients (age >= 60 years) with lumbar spinal stenosis (mean age 71 years [range 60-93 years]) who underwent surgery between 2004 and June 2006 at the authors' institution. Three different modes of decompression were analyzed in this study: a unilateral partial hemilaminectomy, a hemilaminectomy, and a laminectomy. The outcome was assessed 12 months postoperatively using the Quebec Back Pain Disability Scale and the Hannover Functional Back Pain Questionnaire. RESULTS: The authors performed a unilateral partial hemilaminectomy in 53 patients (49%). Patients who underwent unilateral partial hemilaminectomies achieved favorable results of at least 80% as assessed using the Quebec Back Pain Disability Scale and Hannover Functional Back Pain Questionnaire. Hemilaminectomies were performed in 45 patients (41.7%), and laminectomies were performed in 10 patients (9.3%). However, there was no statistically significant difference between the various techniques regarding the postoperative results (p < 0.05). CONCLUSIONS: Laminectomies did not show any advantage when compared with unilateral transmedian approaches. A unilateral partial hemilaminectomy combined with a transmedian decompression sufficiently treated the stenosis. This method seemed advantageous in minimizing the procedure and associated morbidity in this elderly population. Further investigations with long-term results (> 5 years) are still necessary. PMID- 21235301 TI - Economic impact of comorbidities in spine surgery. AB - OBJECT: Comorbidities in patients undergoing spine surgery may reasonably be factors that increase health care costs. To verify this hypothesis, the authors conducted the following study. METHODS: Major comorbidities and age-adjusted Charlson Comorbidity Index scores were retrospectively analyzed for 816 patients who underwent spine surgery at the authors' institutions between 2005 and 2008, and treatment costs (hospital charges) were assessed with the help of statistical software. The sample was collected by a nonmedical staff (hired at the beginning of 2006). Patients underwent one of the three most common types of spine surgery: lumbar microdiscectomy (20.5%), anterior cervical decompression and fusion (ACDF; 60.3%), or lumbar decompression and fusion (LDF; 19.2%). Patients were nearly equally divided by sex (53% were female and 47% male), and 78% were Caucasian versus 21% who were African American; the rest were of mixed or unidentified race. The average age was 54 years, with an SD of +/- 14 years. RESULTS: There were significant differences in the prevalence of major comorbidities between male and female and between severely obese and nonseverely obese patients. The impact of comorbidities on the cost of spine surgery was more prominent in older patients, and an additive effect from some comorbidities was recorded in various types of spine surgery. For instance, in the ACDF group, female patients with both severe obesity and diabetes mellitus (DM) had significantly higher hospital charges than those with only one or neither of these conditions ($34,943 for both severe obesity and DM vs $25,633 for severe obesity only; $25,826 for DM only; and $25,153 for those with neither condition [p < 0.05]). In the LDF group, female patients with both DM and a history of depression had significantly higher hospital charges than those with only one or neither of these conditions ($65,782 for both DM and depression vs $53,504 for DM only; $55,990 for depression only; and $52,249 for those with neither condition [p < 0.05]). A significant difference was also found in hospital cost ($16,472 [p < 0.01]; 32% increase over baseline) in the LDF group between patients with the lowest and highest scores on the Charlson Index. CONCLUSIONS: Comorbidities additively increase hospital costs for patients who undergo spine surgery, and should be considered in payment arrangements. PMID- 21235302 TI - Surgical management of cervical spine manifestations of neurofibromatosis Type 1: long-term clinical and radiological follow-up in 22 cases. AB - OBJECT: Patients with neurofibromatosis Type 1 (NF-1) at the cervical spine present significant surgical challenges due to neural compression, multiplicity of tumors, and complex spinal deformities. Iatrogenic instability following resection of tumors is underappreciated in the literature. The focus of this study was to understand the indications for stabilization in this specific group of patients. METHODS: The authors performed a retrospective review of 20 cases involving NF-1 patients with symptomatic cervical spine neurofibromas who underwent surgical decompression and tumor resection, with or without instrumentation, between 1991 and 2008. They also included 2 additional cases involving patients treated before 1991. Imaging findings and data pertaining to clinical presentation, intraoperative management, and postoperative assessment were compiled to clarify the indications for stabilization. An ordinal pain scale based on patient self-assessment was used. Neurological function was evaluated using American Spinal Injury Association Impairment Scale scores. RESULTS: The patient group comprised 13 men and 9 women. Their median age at presentation was 42.5 years; their median age at initial diagnosis of NF-1 was 30 years (range 8 74 years). The median duration of follow-up (since presentation) was 7 years (range 1-32 years). Progressive myelopathy was the main presenting symptom. Spinal cord compression was identified in 13 patients on presentation. Complete removal of the symptomatic tumors was performed in 11 patients. Ten patients underwent instrumented fusion during their first surgery. Six of these 10 required a second surgery-with fixation in 4 cases and without in 2. Of the 12 patients who did not receive instrumented fusion in their first surgery, 8 required a second surgery-with fixation in 5 cases and without in 3. Neurological deterioration due to progressive deformity was the indication for the second surgery in 3 of the 5 patients who required instrumented fusion only in their second surgery; the other 2 patients presented with neurological deterioration secondary to tumor progression. Four patients needed a third operation and instrumented fusion: 3 for deformity-related deficit and 1 for tumor progression. Based on the latest follow-up, 21 patients were stable clinically and radiologically, and 1 patient had died. CONCLUSIONS: This specific group of patients represents a significant surgical challenge. In this retrospective analysis, emphasis is placed on early stabilization of the cervical spine to prevent late deformity as part of the comprehensive management of patients with NF-1. PMID- 21235303 TI - Surgery for lumbar stenosis. PMID- 21235304 TI - Factors affecting lateral mass screw placement at C-7. AB - OBJECT: The C-7 lateral mass has been considered difficult to fit with instrumentation because of its unique anatomy. Of the methods that exist for placing lateral mass screws, none particularly accommodates this anatomical variation. The authors have related 12 distinct morphological measures of the C-7 lateral mass to the ability to place a lateral mass screw using the Magerl, Roy Camille, and a modified Roy-Camille method. METHODS: Using CT scans, the authors performed virtual screw placement of lateral mass screws at the C-7 level in 25 male and 25 female patients. Complications recorded included foraminal and articular process violations, inability to achieve bony purchase, and inability to place a screw longer than 6 mm. Violations were monitored in the coronal, axial, and sagittal planes. The Roy-Camille technique was applied starting directly in the middle of the lateral mass, as defined by Pait's quadrants, with an axial angle of 15 degrees lateral and a sagittal angle of 90 degrees . The Magerl technique was performed by starting in the inferior portion of the top right square of Pait's quadrants and angling 25 degrees laterally in the axial plane with a 45 degrees cephalad angle in the sagittal plane. In a modified method, the starting point is similar to the Magerl technique in the top right square of Pait's quadrant and then angling 15 degrees laterally in the axial plane. In the sagittal plane, a 90 degrees angle is taken perpendicular to the dorsal portion of the lateral mass, as in the traditional Roy-Camille technique. RESULTS: Of all the morphological methods analyzed, only a combined measure of intrusion of the T-1 facet and the overall length of the C-7 lateral mass was statistically associated with screw placement, and only in the Roy-Camille technique. Use of the Magerl technique allowed screw placement in 28 patients; use of the Roy-Camille technique allowed placement in 24 patients; and use of the modified technique allowed placement in 46 patients. No screw placement by any method was possible in 4 patients. CONCLUSIONS: There is only one distinct anatomical ratio that was shown to affect lateral mass screw placement at C-7. This ratio incorporates the overall length of the lateral mass and the amount of space occupied by the T-1 facet at C-7. Based on this virtual study, a modified Roy-Camille technique that utilizes a higher starting point may decrease the complication rate at C-7 by avoiding placement of the lateral mass screw into the T1 facet. PMID- 21235305 TI - Biomechanical analysis of cervicothoracic junction osteotomy in cadaveric model of ankylosing spondylitis: effect of rod material and diameter. AB - OBJECT: Ankylosing spondylitis (AS) is a genetic condition that frequently results in spinal sagittal plane deformity of thoracolumbar or cervicothoracic junctions. Generally, a combination of osteotomy and spinal fixation is used to treat severe cases. Although surgical techniques for traumatic injury across the cervicothoracic junction have been well characterized in clinical and biomechanical literature, the specific model of instrumented opening wedge osteotomy in autofused AS has not been studied biomechanically. This study characterizes the structural stability of various posterior fixation techniques across the cervicothoracic junction in spines with AS, specifically considering the effects of posterior rod diameter and material type. METHODS: For each of 10 fresh-frozen human spines (3 male, 7 female; mean age 60 +/- 10 years; C3-T6), an opening wedge osteotomy was performed at C7-T1. Lateral mass screws were inserted bilaterally from C-4 to C-6 and pedicle screws from T-1 to T-3. For each specimen, 3.2-mm titanium (Ti), 3.5-mm Ti, and 3.5-mm cobalt chromium (CoCr) posterior spinal fusion rods were tested. To simulate the anterior autofusion and long lever arms characteristic of AS, anterior cervical plates were placed from C 4 to C-7 and T-1 to T-3 using fixed angle screws. Nondestructive flexion extension, lateral bending, and axial rotation tests were conducted to 3.0 Nm in each anatomical direction; 3D motion tracking was used to monitor primary range of motion across the osteotomy (C7-T1). Biomechanical tests used a repeat measures test design. The order of testing for each rod type was randomized across specimens. RESULTS: Constructs instrumented with 3.5-mm Ti and 3.5-mm CoCr rods were significantly stiffer in flexion-extension than those with the 3.2-mm Ti rod (25.2% +/- 16.4% and 48.1% +/- 15.3% greater than 3.2-mm Ti, respectively, p < 0.05). For axial rotation, the 3.5-mm Ti and 3.5-mm CoCr constructs also exhibited a significant increase in rigidity compared with the 3.2-mm Ti construct (36.1% +/- 12.2% and 52.0% +/- 20.0%, respectively, p < 0.05). There were no significant differences in rigidity seen between the 3 types of rods in lateral bending (p > 0.05). The 3.5-mm CoCr rod constructs showed significantly higher rigidity in flexion-extension than the 3.5-mm Ti rod constructs (33.1% +/- 15.5%, p < 0.05). There was a trend for 3.5-mm CoCr to have greater rigidity in axial rotation (36.2% +/- 18.6%), but this difference was not statistically significant (p > 0.05). CONCLUSIONS: The results of this study suggest that 3.5 mm CoCr rods are optimal for achieving the most rigid construct in opening wedge osteotomy in the cervicothoracic region of an AS model. Rod diameter and material properties should be considered in construct strategy. Some surgeons have advocated anterior plating in patients with AS after osteotomy for additional stability and bone graft surface. Although this effect was not examined in this study, additional posterior stability achieved with CoCr may decrease the need for additional anterior procedures. PMID- 21235307 TI - Performance of the FibroTest cannot be accurately estimated in nine paediatric patients with advanced fibrosis. PMID- 21235308 TI - Theta-gamma dysrhythmia and auditory phantom perception. AB - Tinnitus is considered an auditory phantom percept analogous to phantom pain. Thalamocortical dysrhythmia has been proposed as a possible pathophysiological mechanism for both tinnitus and pain. Thalamocortical dysrhythmia refers to a persistent pathological resting state theta-gamma coupling that is spatially localized at an area where normally alpha oscillations predominate. Auditory cortex stimulation via implanted electrodes has been developed to treat tinnitus, targeting an area of activation on functional MR imaging elicited by tinnitus matched sound presentation. The authors describe a case in which clinical improvement was correlated with changes in intracranial recordings. Maximal tinnitus suppression was obtained by current delivery exactly at the blood oxygen level-dependent activation hotspot, which colocalizes with increased gamma and theta activity, in contrast to the other electrode poles, which demonstrated a normal alpha peak. These spectral changes normalized when stimulation induced tinnitus suppression, both on electrode and source-localized electroencephalography recordings. These data suggest that thetagamma coupling as proposed by the thalamocortical dysrhythmia model might be causally related to a conscious auditory phantom percept. PMID- 21235309 TI - Persistent fetal intracranial arteries: a comprehensive review of anatomical and clinical significance. AB - As fetal intracranial vessels may persist into adulthood, knowledge of their anatomy and potential clinical and surgical complications should be borne in mind by the surgeon. A comprehensive review of these vessels, however, is not easily identified in the literature. Therefore, the present analysis was undertaken so that such information is available to the clinician and morphologist. PMID- 21235306 TI - Molecular epidemiology of HIV type 1 in Singapore and identification of novel CRF01_AE/B recombinant forms. AB - To investigate HIV-1 molecular epidemiology in Singapore, we sequenced portions of three regions of the HIV-1 genome (protease HXB2: 2163 to 2620, gp120 HXB2: 6904 to 7628, and gp41 HXB2: 7817 to 8264) from 212 plasma samples collected between February 2008 and August 2009. From these samples, 109 (51.4%) generated interpretable data in all regions. Sixty-one (56.0%) were identified as CRF01_AE, 26 (23.9%) as subtype B and 14 (12.8%) as possible novel recombinant forms. The main novel recombinant pattern, detected in 13 sequences, had subtype B in protease and gp41 and CRF01_AE in gp120. There was intermixing of subtypes within transmission risk groups. However, 85% of subjects infected with the novel recombinant forms self-identified as men who have sex with men or bisexuals compared with only 41% of individuals infected with CRF01_AE and 62% infected with subtype B (p = 0.001). PMID- 21235310 TI - Shunt surgery in patients with hydrocephalus and white matter changes. AB - OBJECT: Patients with idiopathic normal pressure hydrocephalus (iNPH) often present with impaired gait and cognition together with ventricular enlargement and normal intracranial pressure. Many have vascular risk factors as well as periventricular and deep white matter changes on MR imaging. Abnormal CSF dynamics, that is, high resistance to outflow or improvement after CSF drainage, indicate good effects of shunt surgery. The authors examined whether the worst case iNPH patients with extensive vascular white matter disease and normal CSF dynamics would benefit from shunt surgery. These patients also fulfilled the criteria for Binswanger disease. Therefore, a randomized controlled double-blind study was performed. METHODS: Fourteen consecutive patients fulfilling the above criteria were randomized to receive either open or closed shunts. At 3 months after surgery, the patients with initially ligated shunts had their shunts opened. Clinical evaluation consisting of 7 quantitative psychometric and 6 continuous gait tests was performed preoperatively and 3 and 6 months after surgery. RESULTS: Patients randomized to receive open shunts had improved motor (30% increase) and psychometric (23% increase) scores 3 months after shunt placement. There were no significant changes between the 3- and 6-month follow-up in these same patients. Conversely, those with initially ligated shunts were unchanged during the first 3-month period, although they improved in both motor (28%) and cognitive (18%) functions following removal of the ligature. CONCLUSIONS: Patients with enlarged ventricles, hydrocephalic symptoms, and extensive vascular white matter changes benefit from shunt surgery. PMID- 21235311 TI - A method to map the visual cortex during an awake craniotomy. AB - Much has been reported regarding the technique of performing an awake craniotomy with cortical mapping for the functional cortex responsible for sensorimotor activity and language. However, documentation for mapping the visual cortex during an awake craniotomy with a description of its technical details is rare. The authors report the case of a patient who underwent an awake craniotomy with mapping of the visual cortex to remove a glioma situated in the left medial occipital lobe. The techniques that made such a mapping procedure possible are discussed. PMID- 21235312 TI - Right hemisphere language. PMID- 21235313 TI - Impact of temozolomide chemotherapy on seizure frequency in patients with low grade gliomas. AB - OBJECT: Seizures occur in approximately 80% of patients with low-grade gliomas (LGGs). The majority of patients are treated with anticonvulsant monotherapy; however, many patients require multidrug therapy, or their seizures are refractory to antiepileptic drugs altogether. The oral alkylating agent temozolomide has emerged as a potential initial treatment option for LGG. A few reports suggest an association between temozolomide and reduced seizure frequency in patients with intractable epilepsy. METHODS: Using their clinical database, the authors identified adult patients whose LGGs were treated using temozolomide as the initial antineoplastic therapy at the University of Virginia Health System. As a control group, the authors assessed patients whose LGGs were under observation. All patients had seizure disorders that were treated with anticonvulsants. Seizure frequency in patients with intractable epilepsy was analyzed before and after treatment with temozolomide. Age at diagnosis, sex, antiepileptic drugs, pathological subtype, surgical treatment, and follow-up until progression were also assessed. Interval seizure frequency was meticulously analyzed at each neurooncology clinic visit. A meaningful difference in seizures was defined as a reduction in seizure frequency of greater than 50% per month. RESULTS: Thirty-nine patients were identified in the temozolomide cohort and 30 patients in the control cohort. The median age at diagnosis was 46 years for the former cohort and 41.5 years for the latter. The median length of follow-up was 39 months for the temozolomide group and 37 months for the control group. There was a significant difference in reduced seizure frequency between patients receiving temozolomide (59%) and those who did not receive temozolomide (13%, p < 0.001). Seven patients (18%) in the temozolomide group displayed this improvement independent of antiepileptic drug adjustment compared with no patient in the control group (p < 0.001). CONCLUSIONS: The authors' data suggest that a subset of patients with LGGs experience improvement in seizure frequency during treatment with temozolomide independent of antiepileptic drug adjustment. This decrease in seizure frequency appears independent of the natural history of seizures in patients whose tumors are under observation. Consequently, seizures in patients with LGGs may be better controlled with the combination of AEDs and temozolomide. PMID- 21235314 TI - Homotopic organization of essential language sites in right and bilateral cerebral hemispheric dominance. AB - OBJECT: Language dominance in the right hemisphere is rare. Therefore, the organization of essential language sites in the dominant right hemisphere is unclear, especially compared with cases involving the more prevalent left dominant hemisphere. METHODS: The authors reviewed the medical records of 15 patients who underwent awake craniotomy for tumor or epilepsy surgery and speech mapping of right hemisphere perisylvian language areas at the University of California, San Francisco. All patients were determined to have either complete right-sided or bilateral language dominance by preoperative Wada testing. RESULTS: All patients but one were left-handed. Of more than 331 total stimulation sites, 27 total sites were identified as essential for language function (14 sites for speech arrest/anarthria; 12 for anomia; and 1 for alexia). While significant interindividual variability was observed, the general pattern of language organization was similar to classic descriptions of frontal language production and posterior temporal language integration for the left hemisphere. Speech arrest sites were clustered in the ventral precentral gyrus and pars opercularis. Anomia sites were more widely distributed, but were focused in the posterior superior and middle temporal gyri as well as the inferior parietal gyrus. One alexia site was found over the superior temporal gyrus. Face sensory and motor cortical sites were also identified along the ventral sensorimotor strip. The prevalence and specificity of essential language sites were greater in unilateral right hemisphere-dominant patients, compared with those with bilateral dominance by Wada testing. CONCLUSIONS: The authors' results suggest that the organization of language in right hemisphere dominance mirrors that of left hemisphere dominance. Awake speech mapping is a safe and reliable surgical adjunct in these rare clinical cases and should be done in the setting of right hemisphere dominance to avoid preventable postoperative aphasia. PMID- 21235315 TI - Cortical ependymoma: an unusual epileptogenic lesion. AB - OBJECT: Supratentorial cortical ependymomas (CE) are rare, with 7 cases reported. The lesions, typically occurring in the superficial cortex in young adults and associated with a history of seizures, are not fully characterized. Furthermore, their relationship with the recently described angiocentric glioma (AG) is still being debated. This study was undertaken to summarize the authors' experience with CEs. METHODS: Between 1997 and 2009, 202 cases of ependymoma were surgically treated at the Mayo Clinic, 49 of which were supratentorial. Among these, 9 CE cases were retrospectively identified. Clinical, imaging, and pathological features of each case were reviewed. RESULTS: Tumors arose from the frontal (5 cases), parietal (3), and occipital (1) lobes. No tumor occurred in the temporal lobe, despite its reported association with seizures. The mean age at presentation was 27 +/- 19 years (+/- SD) and age at resection was 36 +/- 16 years. The mean size of the lesion was 16 +/- 14 cm(3). Seizures were the presenting symptom in 78%. Cross-sectional imaging in 8 cases was characterized by a heterogeneous mass with multiple cystlike areas and enhancement of the soft tissue component. Gross-total resection was achieved in 8 of 9 tumors. Pathologically, 6 were low-grade (WHO Grade II) and 3 were anaplastic (WHO Grade III) ependymomas. All tumors exhibited the focal presence of perivascular pseudorosettes, but only 1 (11%) exhibited the focal presence of a true rosette. A bipolar spindle cell component resembling AG was present in 3 (33%) and "Schwannian-like" nodules in 2 (22%). Subpial aggregation and peripheral infiltration were present in 4 cases (44%). With a mean postsurgery follow-up of 62 +/- 38 months, only 2 lesions recurred locally after imaging-confirmed gross total resection, both being Grade III. In 5 (71%) of 7 patients presenting with seizures an Engel Class I outcome was achieved. CONCLUSIONS: Cortical ependymomas represent a rare type of ependymoma occurring superficially in the cortex. Morphologically, these tumors are protean, varying from classic to epithelioid, clear cell, and tanycytic. Some also exhibited features typical of AG. Most tumors were low grade and cured with resection. Anaplastic tumors occur and may recur locally despite provision of radiation therapy. Cortical ependymomas frequently, but not always, present with seizures, but despite their high association with epilepsy, none occurred in the temporal lobe in any of the authors' 9 patients. Overall, CEs appear to have a relatively favorable prognosis compared with other supratentorial ependymomas. PMID- 21235316 TI - Safe entry point. PMID- 21235317 TI - The neurosurgical anatomy of the sphenoid sinus and sellar floor in endoscopic transsphenoidal surgery. AB - OBJECT: A considerable degree of variability exists in the anatomy of the sphenoid sinus, sella turcica, and surrounding skull base structures. The authors aimed to characterize neuroimaging and intraoperative variations in the sagittal and coronal surgical anatomy of healthy controls and patients with sellar lesions. METHODS: Magnetic resonance imaging studies obtained in 100 healthy adults and 78 patients with sellar lesions were reviewed. The following measurements were made on midline sagittal images: sellar face, sellar prominence, sellar angle, tuberculum sellae angle, sellar-clival angle, length of planum sphenoidale, and length of clivus. The septal configuration of the sphenoid sinus was classified as either simple or complex, according to the number of septa, their symmetry, and their morphological features. The following measurements were made on coronal images: maximum width of the sphenoid sinus and sellar face, and the distance between the parasellar and midclivus internal carotid arteries. Neuroimaging results were correlated with intraoperative findings during endoscopic transsphenoidal surgery. RESULTS: Three sellar floor morphologies were defined in normal adults: prominent (sellar angle of < 90 degrees ) in 25%, curved (sellar angle 90-150 degrees ) in 63%, flat (sellar angle > 150 degrees ) in 11%, and no floor (conchal sphenoid) in 1%. In healthy adults, the following mean measurements were obtained: sellar face, 13.4 mm; sellar prominence, 3.0 mm; sellar angle, 112 degrees ; angle of tuberculum sellae, 112 degrees ; and sellar-clival angle, 117 degrees . Compared with healthy adults, patients with sellar lesions were more likely to have prominent sellar types (43% vs 25%, p = 0.01), a more acute sellar angle (102 degrees vs 112 degrees , p = 0.03), a more prominent sellar floor (3.8 vs 3.0 mm, p < 0.005), and more acute tuberculum (105 degrees vs 112 degrees , p < 0.01) and sellar-clival (105 degrees vs 117 degrees , p < 0.003) angles. A flat sellar floor was more difficult to identify intraoperatively and more likely to require the use of a chisel or drill to expose (75% vs 25%, p = 0.01). A simple sphenoid sinus configuration (no septa, 1 vertical septum, or 2 symmetric vertical septa) was noted in 71% of studies, and the other 29% showed a complex configuration (2 or more asymmetrical septa, 3 or more septa of any kind, or the presence of a horizontal septum). Intraoperative correlation was more challenging in cases with complex sinus anatomy; the most reliable intraoperative midline markers were the vomer, superior sphenoid rostrum, and bilateral parasellar and clival carotid protuberances. CONCLUSIONS: Preoperative assessment of neuroimaging studies is critical for characterizing the morphological characteristics of the sphenoid sinus, sellar floor, tuberculum sellae, and clivus. The flat sellar type identified in 11% of people) or a complex sphenoid sinus configuration (in 29% of people) may make intraoperative correlation substantially more challenging. An understanding of the regional anatomy and its variability can improve the safety and accuracy of transsphenoidal and extended endoscopic skull base approaches. PMID- 21235318 TI - Transcranial magnetic stimulation and extradural electrodes implanted on secondary auditory cortex for tinnitus suppression. AB - OBJECT: Tinnitus is a prevalent symptom, with clinical, pathophysiological, and treatment features analogous to pain. Noninvasive transcranial magnetic stimulation (TMS) and intracranial auditory cortex stimulation (ACS) via implanted electrodes into the primary or overlying the secondary auditory cortex have been developed to treat severe cases of intractable tinnitus. METHODS: A series of 43 patients who benefited transiently from 2 separate placebo controlled TMS sessions underwent implantation of auditory cortex electrodes. Targeting was based on blood oxygen level-dependent activation evoked by tinnitus matched sound, using functional MR imaging-guided neuronavigation. RESULTS: Thirty-seven percent of the patients responded to ACS with tonic stimulation. Of the 63% who were nonresponders, half benefited from burst stimulation. In total, 33% remained unaffected by the ACS. The average tinnitus reduction was 53% for the entire group. Burst stimulation was capable of suppressing tinnitus in more patients and was better than tonic stimulation, especially for noise-like tinnitus. For pure tone tinnitus, there were no differences between the 2 stimulation designs. The average pure tone tinnitus improvement was 71% versus 37% for noise-like tinnitus and 29% for a combination of both pure tone and noise like tinnitus. Transcranial magnetic stimulation did not predict response to ACS, but in ACS responders, a correlation (r = 0.38) between the amount of TMS and ACS existed. A patient's sex, age, or tinnitus duration did not influence treatment outcome. CONCLUSIONS: Intracranial ACS might become a valuable treatment option for severe intractable tinnitus. Better understanding of the pathophysiological mechanisms of tinnitus, predictive functional imaging tests, new stimulation designs, and other stimulation targets are needed to improve ACS results. PMID- 21235319 TI - Black grain mycetoma caused by Leptosphaeria tompkinsii. AB - Leptosphaeria tompkinsii is a dematiaceous fungus which is rarely reported as an agent of black-grain mycetoma. We present a case involving a mycetoma of the hand of a former farmer from Mali, West Africa, who has been a resident in France for 27 years. The patient was successfully treated with surgery and the use of oral itraconazole for 6 months. Species identification was based on sexual reproductive structures observed on potato-carrot agar media and the use of internal transcribed spacer sequencing. PMID- 21235320 TI - Prenatal psychiatry. PMID- 21235321 TI - In this issue: sensing immune danger through unfolded protein response plus pathogen recognition receptors; and immune modulation for cancer and HIV-1 disease. PMID- 21235322 TI - Control of NF-kappaB and inflammation by the unfolded protein response. AB - Under inflammatory situations, endoplasmic reticulum (ER) stress occurs at local sites and modulates inflammatory processes. NF-kappaB is a key regulator for immune and inflammatory responses, and its activity is influenced by ER stress positively or negatively. Recent investigation suggested that ER stress induces activation of NF-kappaB in the early phase, whereas in the later phase, consequent unfolded protein response (UPR) inhibits NF-kappaB. This review summarizes current knowledge on potential mechanisms underlying the biphasic, bidirectional regulation of NF-kappaB by the UPR and possible roles for ER stress in the regulation of inflammation. PMID- 21235323 TI - Pathogen recognition by the innate immune system. AB - Microbial infection initiates complex interactions between the pathogen and the host. Pathogens express several signature molecules, known as pathogen-associated molecular patterns (PAMPs), which are essential for survival and pathogenicity. PAMPs are sensed by evolutionarily conserved, germline-encoded host sensors known as pathogen recognition receptors (PRRs). Recognition of PAMPs by PRRs rapidly triggers an array of anti-microbial immune responses through the induction of various inflammatory cytokines, chemokines and type I interferons. These responses also initiate the development of pathogen-specific, long-lasting adaptive immunity through B and T lymphocytes. Several families of PRRs, including Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), NOD-like receptors (NLRs), and DNA receptors (cytosolic sensors for DNA), are known to play a crucial role in host defense. In this review, we comprehensively review the recent progress in the field of PAMP recognition by PRRs and the signaling pathways activated by PRRs. PMID- 21235324 TI - Soluble MHC I and soluble MIC molecules: potential therapeutic targets for cancer. AB - It has become clear that soluble MHC I (sMHC I) and soluble MIC (sMIC), which are highly elevated in sera of cancer patients, can be viewed to be tolerogenic, and that metalloproteinases are involved in their generation process. In this review, an overview is provided of the recent progress made in the sMHC I and sMIC fields, with emphasis on their structure, formation, and function, and the key questions that still await answers are addressed. Understanding better their formation mechanism, it will become more feasible to modulate the immune responses in cancer patients by targeting molecules involved in their generation process. PMID- 21235325 TI - Multiscale biomimetic topography for the alignment of neonatal and embryonic stem cell-derived heart cells. AB - Nano- and microscale topographical cues play critical roles in the induction and maintenance of various cellular functions, including morphology, adhesion, gene regulation, and communication. Recent studies indicate that structure and function at the heart tissue level is exquisitely sensitive to mechanical cues at the nano-scale as well as at the microscale level. Although fabrication methods exist for generating topographical features for cell culture, current techniques, especially those with nanoscale resolution, are typically complex, prohibitively expensive, and not accessible to most biology laboratories. Here, we present a tunable culture platform comprised of biomimetic wrinkles that simulate the heart's complex anisotropic and multiscale architecture for facile and robust cardiac cell alignment. We demonstrate the cellular and subcellular alignment of both neonatal mouse cardiomyocytes as well as those derived from human embryonic stem cells. By mimicking the fibrillar network of the extracellular matrix, this system enables monitoring of protein localization in real time and therefore the high-resolution study of phenotypic and physiologic responses to in-vivo like topographical cues. PMID- 21235326 TI - NANOG has a role in mesenchymal stem cells' immunomodulatory effect. AB - It is well known that terminally differentiated cells derived from mesenchymal stem cells (MSCs) will lose the immunomodulation capacity. NANOG is known to be a core transcription factor in the maintenance of stem cell specific features or stemness. To evaluate whether NANOG was involved in the immunomodulation effects of MSCs, MSCs' immunomodulation capacity on lymphocyte activation and proliferation before or after endogenous NANOG interference was investigated. We found that MSCs' inhibitory effects on lymphocyte activation and proliferation was significantly weakened after NANOG knockdown. In addition, NANOG RNAi and chromatin immunoprecipitation experiments showed that NANOG suppressed the expression and secretion of DKK-1, transforming growth factor-beta1 (TGF-beta1), TGF-beta2, and TGF-beta3, which are all important factors mediating MSCs' immunomodulation capacity. Based on these data, we propose that NANOG plays an important role in maintaining the immunomodulation functions of MSCs by regulating the expression and secretion of TGF-beta1, TGF-beta2, TGF-beta3, and DKK-1. PMID- 21235327 TI - PTC124-mediated translational readthrough of a nonsense mutation causing Usher syndrome type 1C. AB - We investigated the therapeutic potential of the premature termination codon (PTC) readthrough-inducing drug PTC124 in treating the retinal phenotype of Usher syndrome, caused by a nonsense mutation in the USH1C gene. Applications in cell culture, organotypic retina cultures, and mice in vivo revealed significant readthrough and the recovery of protein function. In comparison with other readthrough drugs, namely the clinically approved readthrough-inducing aminoglycoside gentamicin, PTC124 exhibits significant better retinal biocompatibility. Its high readthrough efficiency in combination with excellent biocompatibility makes PTC124 a promising therapeutic agent for PTCs in USH1C, as well as other ocular and nonocular genetic diseases. PMID- 21235328 TI - Functional characterization and expression profiling of human induced pluripotent stem cell- and embryonic stem cell-derived endothelial cells. AB - With regard to human induced pluripotent stem cells (hiPSCs), in which adult cells are reprogrammed into embryonic-like cells using defined factors, their functional and transcriptional expression pattern during endothelial differentiation has yet to be characterized. In this study, hiPSCs and human embryonic stem cells (hESCs) were differentiated using the embryoid body method, and CD31(+) cells were sorted. Fluorescence activated cell sorting analysis of hiPSC-derived endothelial cells (hiPSC-ECs) and hESC-derived endothelial cells (hESC-ECs) demonstrated similar endothelial gene expression patterns. We showed functional vascular formation by hiPSC-ECs in a mouse Matrigel plug model. We compared the gene profiles of hiPSCs, hESCs, hiPSC-ECs, hESC-ECs, and human umbilical vein endothelial cells (HUVECs) using whole genome microarray. Our analysis demonstrates that gene expression variation of hiPSC-ECs and hESC-ECs contributes significantly to biological differences between hiPSC-ECs and hESC ECs as well as to the "distances" among hiPSCs, hESCs, hiPSC-ECs, hESC-ECs, and HUVECs. We further conclude that hiPSCs can differentiate into functional endothelial cells, but with limited expansion potential compared with hESC-ECs; thus, extensive studies should be performed to explore the cause and extent of such differences before clinical application of hiPSC-ECs can begin. PMID- 21235329 TI - Selective vulnerability of non-myelinated axons to stretch injury in an in vitro co-culture system. AB - Diffuse axonal injury (DAI) is an evolving axonopathy commonly characterized clinically as widespread damage to the white matter tracts. In recent electrophysiological studies, researchers have proposed that myelinated and unmyelinated axons differ in their vulnerability and functional recovery following DAI. In this study we present for the first time an in vitro stretch injury approach that utilizes a novel myelinating co-culture system to determine the differential response between myelinated and non-myelinated axon bundles to injury. In implementing this technique we demonstrate that myelinated axon bundles are less vulnerable to stretch injury compared to caliber-matched non myelinated bundles. Interestingly, moderate axonal strain did not induce demyelination, but instead caused an increase in the proportion of degenerated myelin basic protein over time. Additionally, there were no significant differences in the expression of axonal swellings, which is indicative of disrupted axonal transport. In summary, we present an ideal in vitro model that permits further mechanistic investigations into the role of myelin and oligodendrocyte-neuron interactions in response to DAI. PMID- 21235331 TI - Salivary interleukin-1beta levels in patients with chronic periodontitis before and after periodontal phase I therapy and healthy controls: a case-control study. AB - BACKGROUND: The role of interleukin (IL)-1beta in periodontal disease pathogenesis is well researched. This study aimed to assess and compare the salivary IL-1beta levels in patients with chronic periodontitis before and after periodontal phase I therapy and periodontally healthy controls. Further, relationships between IL-1beta levels and various clinical parameters were explored. METHODS: Twenty-eight patients with moderate-to-severe generalized chronic periodontitis and 24 age-, race-, and ethnicity-matched controls participated in this study. Saliva samples were obtained from all patients. The clinical parameters recorded were clinical attachment loss (AL), probing depth, bleeding on probing, periodontal index, and gingival index. Clinical evaluation and sample collection were repeated 1 month after periodontal phase I therapy in patients with periodontitis. IL-1beta levels were assessed using enzyme-linked immunosorbent assay. RESULTS: Mean IL-1beta levels in patients with periodontitis at baseline (1,312.75 pg/mL) were significantly higher (P <0.0001; eight-fold) than in controls (161.51 pg/mL). Although treatment in patients with periodontitis resulted in significant reduction in IL-1beta levels (mean: 674.34 pg/mL; P = 0.001), they remained significantly higher (P <0.0001; four-fold) than control levels. There were significant correlations between IL-1beta levels and all clinical parameters (P <0.01) except percentage sites with clinical AL >2 mm (P >0.05). CONCLUSIONS: The data indicate that IL-1beta levels are raised in the saliva of patients with chronic periodontitis, which are reduced after phase I therapy, suggesting a close association between salivary IL-1beta and periodontitis. Additional longitudinal studies are needed to validate salivary IL 1beta as a marker for periodontal disease. PMID- 21235330 TI - Comparison of gingival crevicular fluid sampling methods in patients with severe chronic periodontitis. AB - BACKGROUND: The analysis of samplings from periodontal pockets is important in the diagnosis and therapy of periodontitis. In this study, three different sampling techniques were compared to determine whether one method yielded samples suitable for the reproducible and simultaneous determination of bacterial load, cytokines, neutrophil elastase, and arginine-specific gingipains (Rgps). Rgps are an important virulence factor of Porphyromonas gingivalis, the exact concentration of which in gingival crevicular fluid (GCF) has not been quantified. METHODS: GCF was sampled from four sites per patient (one sample per quadrant using two samples per method) in 36 patients with chronic periodontitis. One week later, the procedure was repeated with alternative methods. Variables determined were loads of Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) and P. gingivalis, levels of interleukin-6 and -8, activity of neutrophil elastase, and level of Rgps. RESULTS: The detected cytokine levels were higher using paper strips compared to paper points. Bacteria were found in similar loads from paper strips and paper points. Rgps were only detectable in high quantities by washing the periodontal pocket. The level of Rgps correlated with the load of P. gingivalis. CONCLUSIONS: The use of paper strips was suitable for the simultaneous determination of microbial and immunologic parameters. Obtaining GCF by washing can be useful for special purposes. The gingipain concentration in periodontal pockets was directly determined to be <=1.5 MUM. This value indicated that most of the substrates of these proteases by in vitro assays identified until now can be easily degraded in P. gingivalis-infected sites. PMID- 21235332 TI - Recombinant human bone morphogenetic protein-2 for peri-implant bone regeneration: a case report. AB - BACKGROUND: Currently, clinicians have a limited treatment arsenal in the repair of peri-implant defects. The aim of the present report is to present the clinical results of treating a dental implant using recombinant human bone morphogenetic protein (rhBMP)-2 in an elderly patient. METHODS: A 75-year-old man presented for routine dental prophylaxis. Clinical and radiographic examination revealed significant loss of attachment and bone loss around an implant replacing the maxillary left first molar. The patient did not report any symptoms, and the implant showed no signs of mobility. Because of the severity of the defect, regenerative treatment using a combination of rhBMP-2 and freeze-dried bone allograft was used. RESULTS: The patient was followed for 80 weeks postoperatively. By 28 weeks, significant probing depth reduction and radiographic bone fill was observed, and the original implant crown was replaced. From 28 weeks postoperatively to 80 weeks, no significant clinical or radiographic changes were observed. CONCLUSIONS: rhBMP-2 represents a potential therapeutic modality for severe peri-implant hard tissue loss. Future studies should examine parameters, such as surgical technique, to maximize the rhBMP-2 driven regenerative outcomes. PMID- 21235333 TI - Systemic antimicrobials adjunctive to a repeated mechanical and antiseptic therapy for aggressive periodontitis: a 6-month randomized controlled trial. AB - BACKGROUND: The purpose of this study is to compare the additional benefit of systemic antimicrobials versus placebos to a repeated mechanical instrumentation combined with comprehensive local chemical plaque control for the periodontal treatment of generalized aggressive periodontitis (GAgP). METHODS: This was a 6 month randomized, double-masked, placebo-controlled clinical trial. All GAgP patients received full-mouth disinfection followed by staged scaling and root planing without (placebo group; n = 17) or with (test group; n = 18) systemic antimicrobials (500 mg amoxicillin [AMX] + 250 mg metronidazole [MET]; three times a day for 10 days). Clinical parameters were measured at baseline and 3 and 6 months post-therapy. Significant differences between groups at baseline were sought by using the Mann-Whitney U test, whereas comparisons over time were examined by using a general linear model repeated measures procedure. RESULTS: Both groups demonstrated similar improvements in most parameters over time. The test group presented a greater mean probing depth (PD) reduction and clinical attachment level (CAL) gain at sites with initially moderate PD at 6 months (P <0.03). No differences were seen between groups regarding mean reductions and mean gains, respectively, for PD and CAL initially >=7 mm. The test group presented a higher percentage of sites that improved >=2 mm and ended up with PD <=4 mm or a lower percentage of sites that worsened >=2 mm and remained with PD >4 mm at 3 months (P <0.01). No differences were noticed between groups for these parameters at 6 months. CONCLUSION: AMX + MET brought additional clinical effects to the repeated mechanical and antiseptic treatment of GAgP in a very short time (3 months), which tended to fade away over time (6 months). PMID- 21235334 TI - The use of etoricoxib and celecoxib for pain prevention after periodontal surgery: a double-masked, parallel-group, placebo-controlled, randomized clinical trial. AB - BACKGROUND: Postoperative pain is an adverse effect of periodontal surgeries and may therefore be prevented or minimized. This study was conducted to evaluate the clinical efficacy of two selective cyclooxygenase-2 inhibitors, celecoxib and etoricoxib, on pain prevention after periodontal surgery. METHODS: For this double-masked, parallel-group, placebo-controlled, and randomized clinical trial, 56 open-flap debridement surgeries were performed. The groups received three different protocols 1 hour before surgery: 1) 200 mg celecoxib (and another 200 mg 12 hours after the first dose); 2) 120 mg etoricoxib; or 3) placebo. Pain intensity and discomfort were assessed up to 2 days after surgery using the visual analog scale and the four-point verbal rating scale, respectively. Patients were instructed to take 750 mg acetaminophen as a rescue medication if necessary. RESULTS: Pain intensity levels in the etoricoxib group were lower than in the placebo group at the 2-, 3-, 4-, 5-, 6-, and 7-hour periods after surgery (Kruskal-Wallis test; P <0.05). There was no statistically significant difference between celecoxib and etoricoxib. Discomfort in the celecoxib group was significantly lower than in the placebo group only at the 3-hour period (P = 0.03). Rescue medication intake was significantly less frequent in the etoricoxib group than in the placebo and celecoxib groups (analysis of variance; P = 0.009). CONCLUSION: It was concluded that a single etoricoxib dose is not superior to two split doses of celecoxib when used for pain prevention after open-flap debridement surgery. PMID- 21235335 TI - Assessment of local hemodynamics in periodontal inflammation using optical spectroscopy. AB - BACKGROUND: Among the newly emerging diagnostic approaches for periodontitis, optical spectroscopy is a promising complementary diagnostic tool. The objective of this study is to verify the reproducibility of this method at a geographically distinct location (Suzhou, China) to a broader patient population using similar instrumentation to that in a previous report. METHODS: Using a portable optical near-infrared spectrometer, optical spectra were obtained, processed, and evaluated from healthy (n = 62), gingivitis (n = 98), and periodontitis (n = 47) sites from a total of 51 patients. A modified Beer-Lambert unmixing model that incorporates a non-parametric scattering loss function was used to determine the relative contribution of oxyhemoglobin and deoxyhemoglobin to the overall spectrum. The balance between tissue oxygen delivery and oxygen use in periodontal tissues was then assessed. RESULTS: Tissue oxygenation decreased significantly from healthy sites to sites with gingivitis (P <0.01) and between gingivitis and periodontitis (P = 0.015). This is largely caused by a significant increase in deoxyhemoglobin between normal and gingivitis (P <0.01) and a concomitant decrease in oxyhemoglobin between gingivitis and periodontitis (P = 0.02). CONCLUSION: This study supports previous findings that tissue oxygenation as measured by optical spectroscopy is significantly decreased in periodontitis and that optical spectroscopy can simultaneously determine multiple inflammatory indices related to periodontal disease directly in gingival tissues in vivo. PMID- 21235336 TI - De novo bone formation after the sinus lift procedure. AB - BACKGROUND: The primary objective of this study is to use histomorphometric techniques to evaluate the concept that the new bone formed in the maxillary sinus lift procedure emanates from the endosteum of the sinus floor. In addition, the effect of the residual crest vertical dimension on the graft outcome and assessment of osteoclast numbers as an indirect measure of a connection between the crest and graft compartment are reported. METHODS: After grafting the maxillary sinus with irradiated allogenic bone, 37 intact, vertical bone cores with a 2.7 mm diameter were trephined at right angles to the alveolar crest. Quantitative measures were derived from a histomorphometric analysis of new bone and residual graft particles at contiguous zones along the long axis of the cores. Mean and median data were analyzed for associations with the distance from the sinus floor, dimensions of the residual crest, and other descriptive variables. A parallel series of tartrate resistant acid phosphatase-stained sections were evaluated for osteoclast counts. RESULTS: Mean new bone formation ranged from 24.3% to 30.2%. A statistically significant gradient of graft particle area combined with this uniform distribution of new bone resulted in a false impression of less consolidation with the distance from the floor. There was no significant relationship between the distance from the sinus floor or dimension of the residual crest and the graft result. Mean osteoclast counts revealed a statistically significant difference (P <0.001) between the residual crest and the graft compartment with increased counts in the graft. CONCLUSIONS: Histologically, the process of new bone formation resembled a combination of de novo appositional and intramembraneous ossification. The findings suggested a passive role for the graft material and implicated the ingrowth of vascular and perivascular tissues as the most logical source of osteogenic capacity. PMID- 21235337 TI - A 5-year prospective multicenter clinical trial of non-submerged dental implants with a titanium plasma-sprayed surface in 200 patients. AB - BACKGROUND: Endosseous dental implants are a popular treatment to replace missing teeth. Although many advances have occurred and affected the macrogeometry and surface characteristics of dental implants, among other aspects, it is important to document how the implants perform in patients over time. Such evaluations are helpful not only to document the clinical survival of the implants but also patient satisfaction over an extended period. METHODS: A formal prospective multicenter human clinical was performed at five centers involving 200 patients and 626 implants. Specific inclusion and exclusion criteria were used and detailed data collected at specified times using case report forms. An independent study monitor reviewed all study data before entry into the study database. Two implant designs were used in two different clinical indications. A non-submerged titanium plasma-sprayed (TPS) hollow cylindrical implant with a smooth transgingival collar was evaluated in the maxillary anterior sextant and a non-submerged TPS solid screw implant with similar collar in the mandible. RESULTS: Over the course of the 5-year clinical trial, there was one early failure occurring before definitive prosthesis delivery. Three late failures were documented, one occurring at each of the 6, 12, and 18 months postoperative visits. Life table analysis at 5 years revealed a 99.4% survival rate and a 92.5% success rate. Patient satisfaction was rated as good to excellent for 96.1% of implants in regards to esthetics after 5 years; 98.8% for appearance; and 99.4% for prosthesis comfort, ability to chew and taste, fit, and general satisfaction. No serious adverse events were reported. CONCLUSIONS: Implant success and survival was over 92% and 99%, respectively, in a formal 5-year prospective multicenter clinical trial involving 200 patients and 626 non-submerged TPS implants. These implants included hollow cylinder implants in the anterior maxilla and solid screw implants placed in the mandible. These findings document the predictability and patient satisfaction of tooth replacement using a non submerged surgical technique involving a tissue-level, rough surfaced endosseous dental implant. PMID- 21235339 TI - Readiness to change and training expectations prior to a training workshop for substance abuse clinicians. AB - Understanding clinicians' readiness to change their clinical practice, as well as their training expectations prior to a clinical workshop, may be helpful for improving technology transfer in the substance user treatment field. This study aimed to explore both these areas prior to a workshop designed to offer a new clinical intervention for their practice. Fifty-four clinicians volunteered to participate in a Behavioral Couples Therapy (BCT) workshop. Using negative binomial regression models, significant associations were found between clinicians' readiness to change and training expectations. Participants were found to be highly motivated to learn new technologies and highly endorsed notions of adopting elements of BCT into their practice. There was greater caution with regard to committing to adopt the full protocol. Exploring some of the obstacles in adopting new treatment approaches by even the most motivated of clinicians could be a fruitful area for future research. PMID- 21235340 TI - Switching from methadone to diamorphine: 2-year results of the german heroin assisted treatment trial. AB - BACKGROUND: Several international clinical studies have found diamorphine treatment for opioid-dependent patients to show significantly better effects compared with methadone maintenance treatment. AIMS: This analysis of the German trial of heroin-assisted treatment investigates the effects on patients' health and drug use after switching from 12-month methadone to 12-month diamorphine treatment under similar study conditions. METHODS: For a period of 24 months, the state of health was explored using the Opiate Treatment Index (OTI) health scale and the Symptom Checklist-90-R (SCL-90-R), while drug use and social situation by an extended version of the European Addiction Severity Index (EuropASI) every 6 months. Changes in these criteria were tested for significance by repeated measures analyses. Of the 434 patients, who started the 2nd year of study treatment, 90 were methadone-diamorphine switchers, and 344 received diamorphine for 2 years. RESULTS: In the 2nd year, the methadone-diamorphine switchers succeed in catching up with the diamorphine patients. After switching to diamorphine, significant improvements in health and use of street heroin and cocaine were achieved during 1 year of diamorphine treatment. CONCLUSIONS: The results of the course of methadone-diamorphine switchers are a methodologically independent contribution toward confirming the positive effects of diamorphine treatment for difficult-to-treat opioid-dependent patients. This study supports the hypothesis that changing from optimized methadone treatment under the conditions of the clinical trial to diamorphine treatment is associated with improvements in health and drug use behavior. The study's limitations are noted. PMID- 21235341 TI - Essential elements of treatment: a comparative study between European and American therapeutic communities for addiction. AB - The purpose of this study was to investigate whether European and American therapeutic communities (TCs) for addiction, both traditional and modified, share a common perspective on what is essential in treatment using the Survey of Essential Elements Questionnaire (SEEQ). The European sample (N = 19) was gathered in 2009. For the American sample (N = 19), we used previously published research data. Despite comparable perspectives, European traditional TCs (N = 11) scored significantly higher than their American predecessors (N = 11) on four SEEQ domains. Cluster differences were more pronounced in Europe than in America. PMID- 21235343 TI - SAF-A has a role in transcriptional regulation of Oct4 in ES cells through promoter binding. AB - Methodologies to reprogram somatic cells into patient-specific pluripotent cells, which could potentially be used in personalized drug discovery and cell replacement therapies, are currently under development. Oct4 activation is essential for successful reprogramming and pluripotency of embryonic stem (ES) cells, albeit molecular details of Oct4 activation are not completely understood. Here we report that endogenous SAF-A is involved in regulation of Oct4 expression, binds the Oct4 proximal promoter in ES cells, and dissociates from the promoter upon early differentiation induced by LIF withdrawal. Depletion of SAF-A decreases Oct4 expression even in the presence of LIF, and results in an increase of the mesodermal marker Brachyury. The overexpression of wild-type human SAF-A rescues the mouse knock-down phenotype and results in increased Oct4 level. We also demonstrate that endogenous SAF-A interacts with the C-terminal domain (CTD) of endogenous RNA polymerase II and that the interaction is independent of CTD phosphorylation and mRNA. Moreover, we show that SAF-A exist in complexes with transcription factors Sox2 and Oct4 as well as STAT3 in ES cells. The number of endogenous SAF-A:Oct4 and SAF-A:Sox2 complexes decreases upon LIF depletion. These discoveries allow us to propose a model for activation of Oct4 transcription. PMID- 21235344 TI - Diploid oocyte formation and tetraploid embryo development induced by cytochalasin B in bovine. AB - Tetraploid embryos are a useful model for postimplantation development of polyploidy cells, and tetraploid cells are an advantage in studies for chimeras yielding offspring completely derived from embryo stem cells or induced pluripotent cells. This study was designed to investigate the effects of cytochalasin B (CB) on bovine oocyte meiosis, and to induce the formation of diploid oocytes and tetraploid embryos. The results showed that: (1) incubation of oocytes in CB at >=2.0 MUg/mL concentrations for 24 h significantly decreased oocyte maturation and the matured oocytes' haploid composition. Over 50% of the CB-treated oocytes did not expel PB1 (non-PB1), and most of the non-PB1 oocytes contained 2n (60) chromosomes. (2) Pretreatment of oocytes with CB at concentrations of 7.5 and 15 MUg/mL for 10 h significantly decreased oocyte maturation. Posttreatment of oocytes with CB resulted in most of the oocytes containing 2n chromosomes. (3) The parthenogenetic blastocysts (25-28%) derived from the non-PB1 oocytes of posttreatment group was significantly higher than that from pretreatment, whole period treatment, and the control oocytes (12-16%). (4) Cytogenetic analysis of the embryos derived from CB-treated non-PB1 oocytes resulted in 74% of the one-cell stage embryos being 4n = 120 chromosomes, 82% of two-cell stage embryos contained 4n chromosomes in each blastomere, and 75% of the blastocysts were tetraploidy (4n = 120). (6) The stopped uncleaved one-cell embryos showed an amazing phenomenon of over 15% of them containing extra chromosomes, which suggested multiple DNA duplication occurred within 40 h after activation. In conclusion, CB inhibits PB1 extrusion, disfigures spindle structure, decreases oocyte maturation, and results in formation of diploid (2n or 4c) oocytes. The diploid oocytes resulted in a higher development of tetraploid embryos, which would be a unique approach for the production of tetraploid embryos in bovine. PMID- 21235345 TI - The chemistry of nitroxyl-releasing compounds. AB - Nitroxyl (HNO) demonstrates a diverse and unique biological profile compared to nitric oxide, a redox-related compound. Although numerous studies support the use of HNO as a therapeutic agent, the inherent chemical reactivity of HNO requires the use of donor molecules. Two general chemical strategies currently exist for HNO generation from nitrogen-containing molecules: (i) the disproportionation of hydroxylamine derivatives containing good leaving groups attached to the nitrogen atom and (ii) the decomposition of nitroso compounds (X-N=O, where X represents a good leaving group). This review summarizes the synthesis and structure, the HNO releasing mechanisms, kinetics and by-product formation, and alternative reactions of six major groups of HNO donors: Angeli's salt, Piloty's acid and its derivatives, cyanamide, diazenium diolate-derived compounds, acyl nitroso compounds, and acyloxy nitroso compounds. A large body of work exists defining these six groups of HNO donors and the overall chemistry of each donor requires consideration in light of its ability to produce HNO. The increasing interest in HNO biology and the potential of HNO-based therapeutics presents exciting opportunities to further develop HNO donors as both research tools and potential treatments. PMID- 21235347 TI - Nitroxyl in the central nervous system. AB - Nitroxyl (HNO) is the one-electron-reduced and protonated congener of nitric oxide (NO). Compared to NO, it is far more reactive with thiol groups either in proteins or in small antioxidant molecules either converting those into sulfinamides or inducing disulfide bond formation. HNO might mediate cytoprotective changes of protein function through thiol modifications. However, HNO is a strong oxidant that in vitro reacts with glutathione to form glutathione disulfide and glutathione sulfinamide. The resulting oxidative stress might aggravate tissue damage in inflammatory diseases. In this review, we will summarize the current knowledge of how exogenous HNO affects the central nervous system, especially nerve cells and glia in health and disease. Unlike most other organs, the brain is separated from the circulation by the blood-brain barrier, which limits access of many pharmacological compounds. Given that, we will review what is known about the ability of currently used HNO donors to cross the blood brain barrier. Moreover, considering that the physiology and composition of the brain has unique properties, for example, expression of brain-specific enzymes like neuronal NO synthase, its high iron content, and increased energy metabolism, we will discuss possible sources of endogenous HNO in the brain. PMID- 21235348 TI - HNO signaling mechanisms. AB - Due to recent discoveries of important and novel biological activity, nitroxyl (HNO) has become a molecule of significant interest. Although it has been used in the past as a treatment for alcoholism, it is currently being touted as a treatment for heart failure. It is becoming increasingly clear that many of the biological actions of HNO can be attributed to its ability to react with specific thiol- and, possibly, heme-proteins. Herein is discussed the chemistry of HNO with likely biological targets. A particular focus is given to targets associated with the pharmacological utility of HNO as a cardiovascular agent and for the treatment of alcoholism. PMID- 21235346 TI - The specificity of nitroxyl chemistry is unique among nitrogen oxides in biological systems. AB - The importance of nitric oxide in mammalian physiology has been known for nearly 30 years. Similar attention for other nitrogen oxides such as nitroxyl (HNO) has been more recent. While there has been speculation as to the biosynthesis of HNO, its pharmacological benefits have been demonstrated in several pathophysiological settings such as cardiovascular disorders, cancer, and alcoholism. The chemical biology of HNO has been identified as related to, but unique from, that of its redox congener nitric oxide. A summary of these findings as well as a discussion of possible endogenous sources of HNO is presented in this review. PMID- 21235350 TI - 2010 Workshop: Mucosal immunity in the male and female reproductive tract and prevention of HIV transmission. PMID- 21235349 TI - Playing with cardiac "redox switches": the "HNO way" to modulate cardiac function. AB - The nitric oxide (NO(*)) sibling, nitroxyl or nitrosyl hydride (HNO), is emerging as a molecule whose pharmacological properties include providing functional support to failing hearts. HNO also preconditions myocardial tissue, protecting it against ischemia-reperfusion injury while exerting vascular antiproliferative actions. In this review, HNO's peculiar cardiovascular assets are discussed in light of its unique chemistry that distinguish HNO from NO(*) as well as from reactive oxygen and nitrogen species such as the hydroxyl radical and peroxynitrite. Included here is a discussion of the possible routes of HNO formation in the myocardium and its chemical targets in the heart. HNO has been shown to have positive inotropic/lusitropic effects under normal and congestive heart failure conditions in animal models. The mechanistic intricacies of the beneficial cardiac effects of HNO are examined in cellular models. In contrast to beta-receptor/cyclic adenosine monophosphate/protein kinase A-dependent enhancers of myocardial performance, HNO uses its "thiophylic" nature as a vehicle to interact with redox switches such as cysteines, which are located in key components of the cardiac electromechanical machinery ruling myocardial function. Here, we will briefly review new features of HNO's cardiovascular effects that when combined with its positive inotropic/lusitropic action may render HNO donors an attractive addition to the current therapeutic armamentarium for treating patients with acutely decompensated congestive heart failure. PMID- 21235351 TI - Absence of tumor suppressor tumor protein 53-induced nuclear protein 1 (TP53INP1) sensitizes mouse thymocytes and embryonic fibroblasts to redox-driven apoptosis. AB - The p53-transcriptional target TP53INP1 is a potent stress-response protein promoting p53 activity. We previously showed that ectopic overexpression of TP53INP1 facilitates cell cycle arrest as well as cell death. Here we report a study investigating cell death in mice deficient for TP53INP1. Surprisingly, we found enhanced stress-induced apoptosis in TP53INP1-deficient cells. This observation is underpinned in different cell types in vivo (thymocytes) and in vitro (thymocytes and MEFs), following different types of injury inducing either p53-dependent or -independent cell death. Nevertheless, absence of TP53INP1 is unable to overcome impaired cell death of p53-deficient thymocytes. Stress induced ROS production is enhanced in the absence of TP53INP1, and antioxidant NAC complementation abolishes increased sensitivity to apoptosis of TP53INP1 deficient cells. Furthermore, antioxidant defenses are defective in TP53INP1 deficient mice in correlation with ROS dysregulation. Finally, we show that autophagy is reduced in TP53INP1-deficient cells both at the basal level and upon stress. Altogether, these data show that impaired ROS regulation in TP53INP1 deficient cells is responsible for their sensitivity to induced apoptosis. In addition, they suggest that this sensitivity could rely on a defect of autophagy. Therefore, these data emphasize the role of TP53INP1 in protection against cell injury. PMID- 21235353 TI - Occludin protein family: oxidative stress and reducing conditions. AB - The occludin-like proteins belong to a family of tetraspan transmembrane proteins carrying a marvel domain. The intrinsic function of the occludin family is not yet clear. Occludin is a unique marker of any tight junction and is found in polarized endothelial and epithelial tissue barriers, at least in the adult vertebrate organism. Occludin is able to oligomerize and to form tight junction strands by homologous and heterologous interactions, but has no direct tightening function. Its oligomerization is affected by pro- and antioxidative agents or processes. Phosphorylation of occludin has been described at multiple sites and is proposed to play a regulatory role in tight junction assembly and maintenance and, hence, to influence tissue barrier characteristics. Redox-dependent signal transduction mechanisms are among the pathways modulating occludin phosphorylation and function. This review discusses the novel concept that occludin plays a key role in the redox regulation of tight junctions, which has a major impact in pathologies related to oxidative stress and corresponding pharmacologic interventions. PMID- 21235354 TI - Protein carbamylation renders high-density lipoprotein dysfunctional. AB - Carbamylation of proteins through reactive cyanate has been demonstrated to predict an increased cardiovascular risk. Cyanate is formed in vivo by breakdown of urea and at sites of inflammation by the phagocyte protein myeloperoxidase. Because myeloperoxidase (MPO) associates with high-density lipoprotein (HDL) in human atherosclerotic intima, we examined in the present study whether cyanate specifically targets HDL. Mass spectrometry analysis revealed that protein carbamylation is a major posttranslational modification of HDL. The carbamyllysine content of lesion-derived HDL was more than 20-fold higher in comparison with 3-chlorotyrosine levels, a specific oxidation product of MPO. Notably, the carbamyllysine content of lesion-derived HDL was five- to eightfold higher when compared with lesion-derived low-density lipoprotein (LDL) or total lesion protein and increased with lesion severity. The carbamyllysine content of HDL, but not of LDL, correlated with levels of 3-chlorotyrosine, suggesting that MPO mediated carbamylation in the vessel wall. Remarkably, one carbamyllysine residue per HDL-associated apolipoprotein A-I was sufficient to induce cholesterol accumulation and lipid-droplet formation in macrophages through a pathway requiring the HDL-receptor scavenger receptor class B, type I. The present results raise the possibility that HDL carbamylation contributes to foam cell formation in atherosclerotic lesions. PMID- 21235355 TI - Astrocytic redox remodeling by amyloid beta peptide. AB - Astrocytes are critical for neuronal redox homeostasis providing them with cysteine needed for glutathione synthesis. In this study, we demonstrate that the astrocytic redox response signature provoked by amyloid beta (Abeta) is distinct from that of a general oxidant (tertiary-butylhydroperoxide [t-BuOOH]). Acute Abeta treatment increased cystathionine beta-synthase (CBS) levels and enhanced transsulfuration flux in contrast to repeated Abeta exposure, which decreased CBS and catalase protein levels. Although t-BuOOH also increased transsulfuration flux, CBS levels were unaffected. The net effect of Abeta treatment was an oxidative shift in the intracellular glutathione/glutathione disulfide redox potential in contrast to a reductive shift in response to peroxide. In the extracellular compartment, Abeta, but not t-BuOOH, enhanced cystine uptake and cysteine accumulation, and resulted in remodeling of the extracellular cysteine/cystine redox potential in the reductive direction. The redox changes elicited by Abeta but not peroxide were associated with enhanced DNA synthesis. CBS activity and protein levels tended to be lower in cerebellum from patients with Alzheimer's disease than in age-matched controls. Our study suggests that the alterations in astrocytic redox status could compromise the neuroprotective potential of astrocytes and may be a potential new target for therapeutic intervention in Alzheimer's disease. PMID- 21235356 TI - Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. AB - Cancer-associated fibroblasts (CAFs) are key determinants in the malignant progression of cancer, supporting tumorigenesis and metastasis. CAFs also mediate epithelial mesenchymal transition (EMT) of tumor cells and their achievement of stem cell traits. We demonstrate that CAFs induce EMT and stemness through a proinflammatory signature, which exploits reactive oxygen species to drive a migratory and aggressive phenotype of prostate carcinoma cells. CAFs exert their propelling role for EMT in strict dependence on cycloxygenase-2 (COX-2), nuclear factor-kappaB, and hypoxia-inducible factor-1. CAF-secreted metalloproteases elicit in carcinoma cells a Rac1b/COX-2-mediated release of reactive oxygen species, which is mandatory for EMT, stemness, and dissemination of metastatic cells. Tumor growth is abolished, and metastasis formation is severely impaired by RNA interfering-mediated targeting of the proinflammatory signature, thereby supporting the therapeutic targeting of the circuitry COX-2/nuclear factor-kappaB /hypoxia-inducible factor-1 as a valuable antimetastatic tool affecting cancer cell malignancy. PMID- 21235352 TI - S-glutathionylation: from molecular mechanisms to health outcomes. AB - Redox homeostasis governs a number of critical cellular processes. In turn, imbalances in pathways that control oxidative and reductive conditions have been linked to a number of human disease pathologies, particularly those associated with aging. Reduced glutathione is the most prevalent biological thiol and plays a crucial role in maintaining a reduced intracellular environment. Exposure to reactive oxygen or nitrogen species is causatively linked to the disease pathologies associated with redox imbalance. In particular, reactive oxygen species can differentially oxidize certain cysteine residues in target proteins and the reversible process of S-glutathionylation may mitigate or mediate the damage. This post-translational modification adds a tripeptide and a net negative charge that can lead to distinct structural and functional changes in the target protein. Because it is reversible, S-glutathionylation has the potential to act as a biological switch and to be integral in a number of critical oxidative signaling events. The present review provides a comprehensive account of how the S-glutathionylation cycle influences protein structure/function and cellular regulatory events, and how these may impact on human diseases. By understanding the components of this cycle, there should be opportunities to intervene in stress- and aging-related pathologies, perhaps through prevention and diagnostic and therapeutic platforms. PMID- 21235357 TI - Current advances in DNA repair: regulation of enzymes and pathways involved in maintaining genomic stability. AB - Novel discoveries in the DNA repair field have lead to continuous and rapid advancement of our understanding of not only DNA repair but also DNA replication and recombination. Research in the field transcends numerous areas of biology, biochemistry, physiology, and medicine, making significant connections across these broad areas of study. From early studies conducted in bacterial systems to current analyses in eukaryotic systems and human disease, the innovative research into the mechanisms of repair machines and the consequences of ineffective DNA repair has impacted a wide scientific community. This Forum contains a select mix of primary research articles in addition to a number of timely reviews covering a subset of DNA repair pathways where recent advances and novel discoveries are improving our understanding of DNA repair, its regulation, and implications to human disease. PMID- 21235358 TI - The peroxide dilemma: opposing and mediating insulin action. AB - Recent compelling data show that reactive oxygen species (ROS) not only are a harmful by-product of aerobic metabolism, but also are used as signaling molecules to regulate various cellular processes. In mammalian cells, ROS are produced transiently in response to many extracellular stimuli, including insulin, and specific inhibition of the ROS suppresses insulin-dependent signaling. Initially, this finding rationalized the concept of ROS acting as insulin mimetics. However, it is becoming evident that ROS are also causal to diabetes, a metabolic disorder characterized by insufficiency of secretion of, or receptor insensitivity to, endogenous insulin. This notion underlines a dual role for ROS in insulin signaling as both deleterious and beneficiary. Moreover, it strongly suggests that a delicate redox balance is required for insulin signaling to remain "healthy" for an organism. PMID- 21235359 TI - Advanced diagnostics in renal mass using optical coherence tomography: a preliminary report. AB - OBJECTIVE: To avoid unnecessary surgical treatment of small renal masses (<= 4 cm), a more accurate diagnostic method would be desirable since radiological differentiation between malignant and benign is difficult and nondiagnostic biopsies account from 9% to 37%. Optical coherence tomography (OCT) measures backscattered light versus depth, with an attenuation coefficient (MU(t)) that may vary among different histological types. We hypothesize that quantitative measurements of MU(t) using OCT can differentiate between normal renal parenchyma and renal cell carcinoma (RCC). MATERIALS AND METHODS: Both normal and tumor renal tissues (RCC) were harvested after partial or radical nephrectomy. Analysis of MU(t) was based on difference of (1) MU(t) between normal and tumor tissue across all patients and (2) MU(t) between normal and tumor tissue within individual patients. RESULTS: Tissue samples of 18 patients were measured, of which 4 were excluded (urothelial carcinoma, oncocytoma, and benign lesion without normal tissue available). Of the remaining 14 patients, 8 contributed with both normal and RCC tissue and 6 with only normal or RCC tissue. Independent observation showed a significant difference between the median MU(t) of normal renal tissue (4.95 mm-1) and the median MU(t) of RCC (8.86 mm-1). No statistically significant difference was found when comparing the difference in MU(t) between normal renal parenchyma and RCC within individual patients. CONCLUSION: There is a significant difference in MU(t) between normal and RCC tissue across all patients. These results overpower the lack of significant difference within individuals, encouraging further research and suggesting a possible role for OCT in the diagnostic work-up of renal masses. PMID- 21235362 TI - The effects of human activity on animal species. PMID- 21235363 TI - Elements of and factors important in veterinary hospice. PMID- 21235364 TI - What is your diagnosis? Disk herniation in the tail of a dog. PMID- 21235365 TI - What is your diagnosis? Palatal cyst. PMID- 21235366 TI - Theriogenology question of the month. Trauma-induced paraphimosis. PMID- 21235367 TI - Pathology in practice. Renal lymphoma. PMID- 21235368 TI - Pathology in practice. Cutaneous mycobacteriosis. PMID- 21235369 TI - Cortisol and aldosterone response to various doses of cosyntropin in healthy cats. AB - OBJECTIVE: To determine the lowest dose of cosyntropin on a per body weight basis that would produce maximal cortisol and aldosterone secretion and the ideal timing of blood sample collection after ACTH stimulation in healthy cats. DESIGN: Randomized crossover trial. ANIMALS: 7 adult sexually intact male purpose-bred cats. PROCEDURES: Each cat received saline (0.9% NaCl) solution (control) and 5 doses (125 MUg/cat and 10, 5, 2.5, and 1 MUg/kg [4.54, 2.27, 1.14, and 0.45 MUg/lb]) of cosyntropin IV with a 2-week washout period between treatments. Blood samples were obtained before (baseline) and at 15, 30, 45, 60, 75, and 90 minutes after administration of saline solution or cosyntropin. RESULTS: Serum cortisol and aldosterone concentration increased significantly, compared with baseline values, after administration of all cosyntropin doses. Lower doses of cosyntropin resulted in an adrenocortical response equivalent to the traditional dose of 125 MUg/cat. The lowest doses of cosyntropin that stimulated a maximal cortisol and aldosterone response were 5 and 2.5 MUg/kg, respectively. Lower doses of cosyntropin resulted in a shorter interval between IV administration of cosyntropin and peak serum cortisol and aldosterone concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: Low-dose ACTH stimulation testing with IV administration of cosyntropin at 5 MUg/kg followed by blood sample collection at 60 to 75 minutes resulted in concurrent peak serum cortisol and aldosterone concentrations that were equivalent to those achieved following administration of cosyntropin at 125 MUg/cat, the standard dose currently used. PMID- 21235371 TI - Assessment of exposure to Leptospira serovars in veterinary staff and dog owners in contact with infected dogs. AB - OBJECTIVE: To assess patterns of seroreactivity to Leptospira serovars in veterinary professional staff and dog owners exposed to dogs with acute leptospirosis and to contrast these patterns in people with those observed in dogs. DESIGN: Cross-sectional study. SAMPLE POPULATION: Human subjects consisted of 91 people (50 veterinarians, 19 technical staff, 9 administrative personnel, and 13 dog owners) exposed to dogs with leptospirosis. Canine subjects consisted of 52 dogs with naturally occurring leptospirosis admitted to the University of Bern Vetsuisse Faculty Small Animal Clinic in 2007 and 2008. PROCEDURES: People were tested for seroreactivity to regionally prevalent Leptospira serovars by use of a complement fixation test. A questionnaire designed to identify risk factors associated with seropositivity was used to collect demographic information from each study participant. Dogs were tested for seroreactivity to Leptospira serovars by use of a microscopic agglutination test. RESULTS: On the basis of microscopic agglutination test results, infected dogs were seropositive for antibodies against Leptospira serovars as follows (in descending order): Bratislava (43/52 [83%]), Australis (43/52 [83%]), Grippotyphosa (18/52 [35%]), Pomona (12/52 [23%]), Autumnalis (6/52 [12%]), Icterohemorrhagiae (4/52 [8%]), Tarassovi (2/52 [4%]), and Canicola (1/52 [2%]). All 91 people were seronegative for antibodies against Leptospira serovars. Therefore, statistical evaluation of risk factors and comparison of patterns of seroreactivity to Leptospira serovars between human and canine subjects were limited to theoretical risks. CONCLUSIONS AND CLINICAL RELEVANCE: Seroreactivity to Leptospira serovars among veterinary staff adhering to standard hygiene protocols and pet owners exposed to dogs with acute leptospirosis was uncommon. PMID- 21235372 TI - Comparison of surgical variables and short-term postoperative complications in healthy dogs undergoing ovariohysterectomy or ovariectomy. AB - OBJECTIVE: To determine whether ovariohysterectomy (OVH) required more time to complete and was associated with more short-term postoperative complications than ovariectomy (OVE) in dogs. DESIGN: Randomized prospective clinical trial. ANIMALS: 40 healthy, sexually intact female dogs. PROCEDURES: OVH (in 20 dogs) or OVE (20 dogs) was performed by use of standardized anesthetic and surgical protocols. Physical characteristics of the dogs, surgical variables, pain scores derived from behavior-based composite pain scales, and surgical wound characteristics were analyzed. RESULTS: Body weight, age, body condition score, and distance between the sternal manubrium and the pubic rim were comparable among dogs that underwent either surgical procedure. Body weight was positively correlated with the total duration of the procedure and with time required for closure of the surgical wound. No effect of body condition score was determined for any variable. Skin and fascia incision lengths relative to the distance from the sternal manubrium to pubic rim were significantly greater in dogs that underwent OVH, compared with those of dogs that underwent OVE, but total surgical time was not different for the 2 procedures. No other significant differences were detected between the 2 groups. CONCLUSIONS AND CLINICAL RELEVANCE: Significant differences in total surgical time, pain scores, and wound scores were not observed between dogs that underwent OVH and dogs that underwent OVE via standardized protocols. PMID- 21235373 TI - Predictors of outcome in dogs treated with adjuvant carboplatin for appendicular osteosarcoma: 65 cases (1996-2006). AB - OBJECTIVE: To determine outcomes and prognostic factors for those outcomes in dogs with appendicular osteosarcoma treated with curative-intent surgery and adjuvant carboplatin. DESIGN: Retrospective case series. ANIMALS: 65 client-owned dogs with appendicular osteosarcoma and no evidence of gross metastatic disease at the time of diagnosis. PROCEDURES: Medical records of dogs that underwent limb amputation or distal ulnectomy and adjuvant carboplatin treatment for appendicular osteosarcoma were reviewed. Adverse effects of chemotherapy and findings regarding preoperative biopsy specimens and postoperative diagnostic imaging were recorded. Signalment, clinical history, and chemotherapy variables were evaluated for associations with outcome. Histologic grade and other variables were evaluated for association with outcome for 38 tumors that were retrospectively graded. RESULTS: The median disease-free interval was 137 days (95% confidence interval [CI], 112 to 177 days). Median survival time was 277 days (95% CI, 203 to 355 days). The 1-, 2-, and 3-year survival rates were 36%, 22%, and 19%, respectively. None of the chemotherapy variables were associated with outcome. Preoperative proteinuria was the only clinical variable associated with poor outcome. Histologic features of tumors associated with a poor outcome were intravascular invasion, mitotic index > 5 in 3 microscopic hpfs, and grade III classification. CONCLUSIONS AND CLINICAL RELEVANCE: Carboplatin administration was well tolerated and resulted in a disease-free interval and median survival time similar to those of other published protocols. PMID- 21235374 TI - Clinical progression of X-linked muscular dystrophy in two German Shorthaired Pointers. AB - CASE DESCRIPTION: 2 full-sibling male German Shorthaired Pointer (GSHP) puppies (dogs 1 and 2) with X-linked muscular dystrophy and deletion of the dystrophin gene (gene symbol, DMD) each had poor growth, skeletal muscle atrophy, pelvic limb weakness, episodic collapse, and episodes of coughing. CLINICAL FINDINGS: Initial examination revealed stunted growth, brachygnathism, trismus, and diffuse neuromuscular signs in each puppy; clinical signs were more severe in dog 2 than in dog 1. Immunohistochemical analysis revealed a lack of dystrophin protein in both dogs. During the next 3 years, each dog developed hyperinflation of the lungs, hypertrophy of the cervical musculature, and hypertrophy of the lateral head of the triceps brachii muscle. TREATMENT AND OUTCOME: Monitoring and supportive care were provided at follow-up visits during an approximately 7-year period. No other specific treatment was provided. Neuromuscular signs in both dogs remained stable after 3 years of age, with dog 2 consistently more severely affected than dog 1. The dogs had multiple episodes of aspiration pneumonia; dogs 1 and 2 were euthanatized at 84 and 93 months of age, respectively. CLINICAL RELEVANCE: The clinical course of disease in these dogs was monitored for a longer period than has been monitored in previous reports of dystrophin-deficient dogs. The clinical progression of muscular dystrophy in the 2 GSHPs was compared with that for other breeds and species with dystrophin-deficient conditions, and the potential basis for the phenotypic variation observed between these littermates, along with potential therapeutic ramifications for dogs and humans, was evaluated. PMID- 21235375 TI - Retroperitoneal pyogranulomatous and fibrosing inflammation secondary to fungal infections in two dogs. AB - CASE DESCRIPTIONS: A 4-year-old spayed female Golden Retriever (dog 1) was examined because of acute edema and erythema in the left hind limb and an inguinal mass, and a 5-year-old female Jack Russell Terrier (dog 2) was examined because of a recurring retro-peritoneal mass. CLINICAL FINDINGS: Dog 1 had an edematous, hyperemic left hind limb with a fixed inguinal mass. Monocytic neutrophilic leukocytosis and hypoalbuminemia were detected. Diagnostic imaging revealed abnormal tissue surrounding the larger vessels and ureters and complete occlusion of the left limb veins. Surgery resulted in incomplete removal of the mass. Histologic examination revealed fibrosing pyogranulomatous inflammation. Results of a Histoplasma antigen test were positive, and reanalysis of the tissues revealed yeast cells indicative of Histoplasma capsulatum. Dog 2 had incomplete removal of a retroperitoneal mass. Histologic examination revealed fibrosing pyogranulomatous inflammation. The mass recurred 8 months later in dog 2; exploratory abdominal surgery at that time resulted in substantial hemorrhage from the adhered caudal aorta. Histologic examination of tissue sections from the second surgery revealed yeast cells consistent with Blastomyces dermatitidis. TREATMENT AND OUTCOME: Both dogs had temporary improvement after surgery. Full clinical resolution required treatment for fungal disease. Dog 1 was treated with itraconazole, then fluconazole (total treatment time, 23 weeks). Dog 2 was treated with fluconazole for 36 weeks. CLINICAL RELEVANCE: Retroperitoneal pyogranulomatous fibrosis caused by fungal infections has not been reported in veterinary medicine. There was substantial morbidity, but the prognosis can be good when this abnormality is recognized and antifungal medications are administered. PMID- 21235377 TI - Why do health professionals refer individual patients to specialist day hospice care? AB - BACKGROUND: There are no nationally agreed criteria for admission to specialist palliative day care (SPDC). Previous work has called for future research to qualitatively examine why health and social professionals make referrals to day care. Therefore the current study aims to address this question using semistructured interviews to gain first hand accounts of referrers' reasons for making referrals to SPDC. DESIGN AND METHOD: The reasons for referral to SPDC of eight professionals were explored using semistructured interviews. An exploratory methodology (interpretative phenomenological analysis [IPA]) was used to analyze the data to allow for an in-depth investigation. RESULTS: Six main themes were apparent with regard to referring a patient to SPDC: physical, social and psychological well-being, continuity of care, introduction to the hospice environment, and caregiver respite. CONCLUSIONS: This study provides an insight into reasons for referral to SPDC. Referrers value the multiprofessional team, the holistic approach to care as useful to managing difficult, complex, and persistent problems in patients wishing to be cared for in the community. Additional benefits include a helpful introduction to hospice services and much needed regular respite for caregivers. Future research into patient and professional perceptions of the process of referral to SPDC could be useful. Expansion of the current study could contribute to the development of a standardized referral tool to be used in conjunction with referrers' clinical judgment. PMID- 21235376 TI - Evaluation of the analgesic effects of oral and subcutaneous tramadol administration in red-eared slider turtles. AB - OBJECTIVE: To determine the dose- and time-dependent changes in analgesia and respiration caused by tramadol administration in red-eared slider turtles (Trachemys scripta). DESIGN: Crossover study. ANIMALS: 30 adult male and female red-eared slider turtles. PROCEDURES: 11 turtles received tramadol at various doses (1, 5, 10, or 25 mg/kg [0.45, 2.27, 4.54, or 11.36 mg/lb], PO; 10 or 25 mg/kg, SC) or a control treatment administered similarly. Degree of analgesia was assessed through measurement of hind limb thermal withdrawal latencies (TWDLs) at 0, 3, 6, 12, 24, 48, 72, and 96 hours after tramadol administration. Nineteen other freely swimming turtles received tramadol PO (5, 10, or 25 mg/kg), and ventilation (V(E)), breath frequency, tidal volume (V(T)), and expiratory breath duration were measured. RESULTS: The highest tramadol doses (10 and 25 mg/kg, PO) yielded greater mean TWDLs 6 to 96 hours after administration than the control treatment did, whereas tramadol administered at 5 mg/kg, PO, yielded greater mean TWDLs at 12 and 24 hours. The lowest tramadol dose (1 mg/kg, PO) failed to result in analgesia. Tramadol administered SC resulted in lower TWDLs, slower onset, and shorter duration of action, compared with PO administration. Tramadol at 10 and 25 mg/kg, PO, reduced the V(E) at 12 hours by 51% and 67%, respectively, and at 24 through 72 hours by 55% to 62% and 61 % to 70%, respectively. However, tramadol at 5 mg/kg, PO, had no effect on the V(E). CONCLUSIONS AND CLINICAL RELEVANCE: Tramadol administered PO at 5 to 10 mg/kg provided thermal analgesia with less respiratory depression than that reported for morphine in red-eared slider turtles. PMID- 21235379 TI - Robot-assisted partial nephrectomy: early unclamping technique. AB - Robot-assisted partial nephrectomy (RAPN) is emerging as a viable minimally invasive surgical technique for small renal tumors. The warm ischemia time (WIT) during laparoscopic partial nephrectomy has been reduced using an early unclamping (EU) technique. We present our technique of EU technique in RAPN. From November 2009 to June 2010, 12 consecutive RAPNs were performed by a single surgeon (A.W.) using EU technique. The median operative time was 227 minutes (176 315); median WIT, 16 minutes (11-25). Median estimated blood loss was 150 mL (50 500) and length of stay 2 days. There were no intraoperative or postoperative complications. RAPN using EU technique is a safe and feasible option in experienced hands, allowing for a shorter WIT without increasing blood loss. This approach requires a highly skilled bedside assistant who is imminently familiar with the robotic system and advanced laparoscopic techniques. PMID- 21235378 TI - Neutrophil elastase inhibitors. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) constitutes a worldwide health problem. There is currently an urgent and unmet need for the development of small molecule therapeutics capable of blocking and/or reversing the progression of the disorder. Recent studies have greatly illuminated our understanding of the multiple pathogenic processes associated with COPD. Of paramount importance is the key role played by proteases, oxidative stress, apoptosis and inflammation. Insights gained from these studies have made possible the exploration of new therapeutic approaches. AREAS COVERED: An overview of major developments in COPD research with emphasis on low-molecular mass neutrophil elastase inhibitors is described in this review. EXPERT OPINION: Great strides have been made toward our understanding of the biochemical and cellular events associated with COPD. However, our knowledge regarding the inter relationships among the multiple pathogenic mechanisms and their mediators involved is still limited. The problem is further compounded by the unavailability of suitable validated biomarkers for assessing the efficacy of potential therapeutic interventions. The complexity of COPD suggests that effective therapeutic interventions may require the administration of more than one agent such as a human neutrophil elastase or MMP-12 inhibitor with an anti inflammatory agent such as a PDE4 inhibitor or a dual function agent capable of disrupting the cycle of proteolysis, apoptosis, inflammation and oxidative stress. PMID- 21235380 TI - Unusual scalp crusted scabies in an adult T-cell leukemia/lymphoma patient. PMID- 21235381 TI - Effects of Ramadan fasting on biochemical and hematological parameters and cytokines in healthy and obese individuals. AB - BACKGROUND: The typical nutritional plan in Ramadan may have beneficial influences on the inflammatory state, as well as on metabolic and anthropometric parameters. We aimed to investigate the effects of Ramadan fasting on biochemical and hematological parameters and cytokines in healthy and obese individuals. METHODS: This study was performed during the Ramadan holy month (September and October 2007). The study group consisted of 10 obese males and the control group consisted of 10 males with a normal body mass index (BMI), who were admitted to the Family Medicine Outpatient Clinic of Dicle University Medical Faculty in Diyarbakir, Turkey, and who indicated that they were going to fast throughout the entire month of Ramadan. Individuals with any acute or chronic disease or medication during the study were excluded. Height, weight, BMI, and waist and hip circumferences were measured. High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), urea, creatinine, insulin, total protein, albumin, C-reactive protein (CRP), lactic dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and cytokine levels were evaluated. RESULTS: The average age of the participants was 27.4 +/- 5.2 years. Of the study group, 7 fulfilled the criteria of metabolic syndrome. Significant weight reduction, significant decrease in BMI, and significant decrease of homeostasis model assessment of insulin resistance (HOMA IR) and fasting blood glucose (FBG) were observed in study group; weight and BMI reduction were insignificant and no significant change was observed in FBG levels, but a significant increase was observed in HOMA-IR in the control group. Post-Ramadan systolic and diastolic blood pressure values, serum white blood cells (WBC) count, interleukin-2 (IL-2), IL-8, tumor necrosis factor-alpha (TNF alpha, TG, and ALT levels were significantly lower in both groups compared to pre Ramadan values. CONCLUSION: Ramadan fasting has beneficial influences on the inflammatory state, as well as metabolic and anthropometric parameters. PMID- 21235382 TI - Laparoscopic transperitoneal pyeloplasty. AB - Laparoscopic pyeloplasty is a first-line option for the management of ureteropelvic junction obstruction. It has a greater success rate than endopyelotomy and is associated with a shorter and less intense convalescence than open surgical pyeloplasty. The technique is well established and reproducible, although the procedure is more difficult in certain situations, such as after a previous pyeloplasty. Because laparoscopic suturing is needed, it is considered an advanced laparoscopic procedure. Suturing devices can facilitate suturing, but they are not optimal for all repairs. This article and the accompanying video summarize the preoperative, intraoperative, and postoperative considerations for laparoscopic pyeloplasty. PMID- 21235383 TI - Issues arising during the treatment of Jehovah's Witnesses by in vitro fertilisation. AB - Four Jehovah's Witness couples were treated between 2000 and 2009 using in vitro fertilization or intracytoplasmic sperm injection. A review of the issues encountered during their treatment, and the options chosen, was made in an attempt to provide effective treatment without compromising the moral views of the individuals concerned. Considerations specific to the Jehovah's Witness faith were identified that required departure from the standard operating procedures used in the clinic, and the development of modified protocols prior to treatment is recommended to minimize the stress and anxiety of patients and staff alike. Issues raised included the collection of semen by masturbation, the use of donor gametes, the number of oocytes inseminated, the discard of poor quality embryos conventionally thought unsuitable for transfer or embryo cryopreservation. A common request was the avoidance of blood products as a culture medium supplement. The use of recombinant human albumin circumvented this, although a recent shift by the Watchtower Bible and Tract Society of Pennsylvania in the interpretation of the Bible opens the possibility of using blood fractions if not whole blood, and so the use of standard culture medium containing human serum albumin is now acceptable to some Jehovah's Witnesses. PMID- 21235384 TI - Intravenous fluconazole for bilateral endogenous Candida endophthalmitis. AB - PURPOSE: To report a case of bilateral endogenous candida endophthalmitis treated with intravenous fluconazole. METHOD: A 54-year-old man with poorly controlled diabetes presented with blurring of vision in both eyes, associated with eye pain for the past 2 months. Ocular examination revealed vision RE 4/60 ph 6/24, left eye (LE) 3/60. Anterior chamber examination showed 2+ anterior chamber cells in the LE. A streak of hypopyon was also noted in the LE. Both fundi showed presence of vitritis and white opacities. Proliferative diabetic retinopathy was present bilaterally. A diagnosis of bilateral endogenous endophthalmitis was made. RESULT: The patient was empirically treated with intravitreal vancomycin/ceftazidime on 3 consecutive days pending culture and sensitivity result. Blood and urine samples were negative for organisms. Vitreous samples were taken at the first intravitreal. The culture and sensitivity report of the vitreous sample was positive for candida albicans, which was sensitive to fluconazole. The patient was commenced on intravenous fluconazole 400 mg daily. The patient underwent core vitrectomy in the LE. Fluconazole was continued for 4 weeks, and he showed dramatic improvement with vision 6/12 in both eyes (OU) and endophthalmitis completely resolved. CONCLUSION: There should be high index of suspicion of fungal endophthalmitis in patients with immune-compromised state even with no known septic foci. PMID- 21235385 TI - Gene regulatory and clinical effects of interferon beta in patients with metastatic melanoma: a phase II trial. AB - Interferon (IFN)-beta in preclinical studies, compared to IFN-alpha2, bound with higher affinity to its receptor, induced to higher levels of IFN-stimulated gene products, induced more apoptosis in melanoma cells, and had antitumor effects against melanoma. A maximally tolerated dose of 12 * 10(6) international units/m(2) after 2 weeks subcutaneously daily with dose escalation to 18 * 10(6) international units/m(2) was thus used in a phase II trial of IFN-beta1a in cutaneous metastatic melanoma (n = 17) and uveal melanoma (n = 4). It resulted in expected but reversible drug-related severe (grade 3) adverse events in 13/21 patients; anorexia and fatigue were mostly of mild or moderate severity and infrequently needed dose reduction. Although a single patient had a sustained regression, overall IFN-beta1a did not have clinical benefit (response rate <10%; median progression-free survival 1.8 months). Effective and potent induction in peripheral blood cells and into serum of products of IFN-stimulated genes such as the pro-apoptotic cytokine, TRAIL, and the immunomodulatory and anti-angiogenic chemokines, CXCL10 and CCL8, confirmed gene regulatory actions. To probe further anti-angiogenic mechanisms, both VEGF-A and CXCL-5 were assessed; compared to before treatment, both proteins decreased. Continued improvements in understanding of antitumor mechanisms will enhance usefulness of IFNs for nodal or distant metastases from melanoma. PMID- 21235386 TI - Increasing resistance in multiresistant methicillin-resistant Staphylococcus aureus clones isolated from a Chinese hospital over a 5-year period. AB - BACKGROUND: The aim was to study the changes in the antimicrobial resistance of methicillin-resistant Staphylococcus aureus (MRSA) clones over a 5-year period (from 2000 to 2005) at a representative hospital in Beijing, China. METHODS: A total of 100 randomly selected MRSA strains were analyzed using antimicrobial susceptibility testing, pulsed-field gel electrophoresis, spa typing, multilocus sequence typing, SCCmec typing, and PCR for the Panton-Valentine leukocidin virulence factor. RESULTS: Resistance to rifampin greatly increased from 32% (16/50) to 68% (34/50). High-level mupirocin-resistant isolates were found only in 2005, when four were identified. Intermediate susceptibly to quinupristin dalfopristin increased from 22% (11/50) to 52% (26/50) between 2000 and 2005. The main antimicrobial resistance profiles changed from TC-GM-CI-EM-CM in 2000 to TC GM-CI-EM-CM-RI in 2005. The main pulsed-field gel electrophoresis type changed from types C, L, and E in 2000 to types J, F, and N, respectively, in 2005. ST239 MRSA-III was the most predominant clone in 2000 and 2005, whereas ST5-MRSA-II was found only in 2005. CONCLUSIONS: There were increasing levels of antimicrobial resistance and epidemiological changes in the hospital-associated MRSA strains isolated in this facility between 2000 and 2005. PMID- 21235387 TI - The influence of substance use, social sexual environment, psychosocial factors, and partner characteristics on high-risk sexual behavior among young Black and Latino men who have sex with men living with HIV: A qualitative study. AB - Understanding the sexual risk behaviors of youths living with HIV/AIDS is critical to secondary prevention of HIV. As part of a larger qualitative study of youths living with HIV, in-depth interviews were conducted with 27 African American and Latino, HIV-infected young men who have sex with men, aged 16-24 years, living in New York City. The study explored the role of substance use, the social-sexual-environmental, and psychological contexts in which sexual risk behaviors occurred. Since learning of their HIV infection, the majority of participants had reduced their risky sexual behaviors; however, a subset (26%) of participants continued to have unprotected sex, in most cases with multiple partners. Substance use, the social environmental context of the sexual encounter, the psychological impact of HIV on sexual behavior, and partner characteristics were associated with high-risk sexual behaviors in this group. Among high-risk participants, factors associated with risky sexual behaviors clustered, with 57% reporting two or more factors. More intensive interventions are needed for this subset of youths living with HIV, including assessment and treatment for substance use and mental health issues, strategies for stress reduction, and partner interventions. PMID- 21235388 TI - Distinct expression of interleukin-1alpha, interleukin-1beta, and interleukin-1 receptor antagonist in testicular tissues and cells from human biopsies with normal and abnormal histology. AB - Cytokines are paracrine/autocrine growth factors known to affect testicular cell functions. The cellular origin and expression levels of interleukin-1 (IL-1) in human normal and pathological testicular biopsies are not yet clear. In the present study, we have investigated the levels and cellular origin of IL-1 family members [IL-1alpha, IL-beta, and IL-1 receptor antagonist (IL-1ra)] in human testicular normal and abnormal biopsies with incomplete maturation arrest (IMA) or Sertoli only syndrome (SOS), using real-time polymerase chain reaction and immunohistochemical staining analysis. Our results show that the levels of IL 1alpha were higher in Leydig/interstitial cells of biopsies with IMA and SOS compared with normal. The levels of IL-1alpha in Sertoli cells of normal biopsies were higher than IMA and SOS. The mRNA levels of IL-1alpha were similar in all biopsies. IL-1beta levels were higher in Leydig/interstitial cells of normal biopsies compared with Sertoli and germ cells. The levels of IL-1beta were similar in testicular cells of all biopsies. However, the mRNA levels of IL-1beta were significantly lower in SOS and IMA biopsies compared with normal. IL-1ra was expressed only in Leydig/interstitial cells, and their expression in normal biopsies was higher than in biopsies with IMA and SOS. The mRNA levels of IL-1ra were similar in all biopsies. Thus, it is possible to suggest the involvement of IL-1 system in the regulation of spermatogenesis and male infertility. PMID- 21235390 TI - Why do different EQA schemes have apparently different limits of acceptability? PMID- 21235389 TI - Characterization of Salmonella enterica isolates from turkeys in commercial processing plants for resistance to antibiotics, disinfectants, and a growth promoter. AB - Salmonella enterica isolates from turkeys in two commercial processing plants (1 and 2) were characterized for susceptibility to antibiotics, disinfectants, and the organoarsenical growth promoter, 4-hydroxy-3-nitrophenylarsonic acid (3 NHPAA, roxarsone), and it's metabolites, NaAsO(2) (As(III)) and Na(2)HAsO(4) * 7H(2)O (As(V)). The 130 Salmonella serovars tested demonstrated a low incidence of resistance to the antibiotics gentamicin (GEN), kanamycin (KAN), sulfamethoxazole (SMX), streptomycin (STR), and tetracycline (TET). Isolates resistant to antibiotics were most often multidrug resistant. Serovars Hadar and Typhimurium were resistant to KAN, STR, and TET and GEN, SMX, and STR, respectively. All isolated Salmonella serovars were resistant to the disinfectant chlorhexidine with minimum inhibitory concentrations (MICs; 1-8 MUg/mL), and they were susceptible to triclosan and benzalkonium chloride. The didecyldimethylammonium chloride component was the most active ammonium chloride tested. No cross-resistance was observed between antibiotics and disinfectants. The MICs for 3-NHPAA (4096 MUg/mL) were consistent between processing Plant 1 and Plant 2, but MICs for the 3-NHPAA metabolites (As(III) and As(V)) were higher in Plant 1 than in Plant 2. In Plant 1, 76% of the isolates had MICs >256 MUg/mL for As(III) and 92% of the isolates had MICs >1024 MUg/mL for As(V). In Plant 2, all of the isolates had MICs <=256 MUg/mL for As(III) and 90% of the isolates had MICs <=1024 MUg/mL for As(V). Only 4 Salmonella serovars were isolated from Plant 1, but 10 serovars were isolated from Plant 2. S. enterica serovar Derby from Plant 1 was highly resistant to As(III) and As(V) with MICs >1024 and >8192 MUg/mL, respectively, suggesting previous exposure to high arsenic metabolite concentrations. These levels may have been high enough to kill other Salmonella serovars, thus possibly explaining the lack of serovar diversity observed in Plant 1. The application of a growth promoter may affect the serovar diversity in treated birds. PMID- 21235391 TI - De novo acquisition of resistance to three antibiotics by Escherichia coli. AB - The acquisition of resistance to amoxicillin, tetracycline, and enrofloxacin by Escherichia coli MG 1655 was examined by exposing growing cells to constant or stepwise increasing concentrations of these compounds. The minimal inhibitory concentration (MIC) of E. coli for amoxicillin increased from 4-8 to 32 MUg/ml after growth in the presence of 1.25 or 2.5 MUg/ml. By stepwise increasing the exposure, an MIC of 512 MUg/ml was reached. This high MIC was maintained after removal of the antibiotics, whereas the lesser increase after exposure to low levels was reversed, indicating that the high MIC was due to a genetic change, but the lower one to phenotypic adaptation only. The MIC for tetracycline increased from 2 MUg/ml to maximally 32 MUg/ml. The MIC decreased to control levels in the absence of tetracycline, so no genetic changes seem to have occurred. The MIC for enrofloxacin increased from 0.25 MUg/ml to maximally 512 MUg/ml depending on the concentration during growth. These data mostly support the "radical-based" theory that bactericidal antibiotics induce a common mechanism that contributes to cell killing. Our findings indicate that exposure to low levels of antibiotics causes an increase in MIC above the concentration that the cells were exposed to. The implication is that exposure to low levels of antibiotics should be prevented as much as possible, because this causes resistance far more than high concentrations that inhibit growth or kill the cell and thus prevent acquisition of resistance. PMID- 21235392 TI - Role of angiotensin II type 1 receptor in angiotensin II-induced cytokine production in macrophages. AB - This study was aimed to investigate the regulatory effects of angiotensin II (Ang II) on the expression of Ang II type 1 (AT1) receptor and to characterize the mechanism underlying AT1 receptor promotion of inflammatory cytokines and reactive oxygen species (ROS). The RAW 264.7 cells were stimulated with various concentrations of Ang II for different times. The mRNA and protein expressions of AT1 receptor in the cells were determined by reverse transcriptase-polymerase chain reaction and Western blot analysis, respectively. The macrophages secretion of proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta (IL 1beta), IL-6, and anti-inflammatory cytokine IL-10 and generation of ROS (by flow cytometry) were also examined. Nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) activities were determined by electrophoretic mobility shift assay. Ang II resulted in an upregulation of AT1 receptor expression in dose- and time-dependent manners in macrophages. Ang II not only induced the production of tumor necrosis factor-alpha, IL-1beta, IL-6, and IL-10 but also increased the release of ROS. Further, both NF-kappaB and AP-1 were activated after stimulation with Ang II. However, these events were all abolished by preincubation with ZD7155, a selective competitive antagonist for the AT1 receptor. These results suggest that the AT1 receptor plays an important role in Ang II-induced cytokines production and ROS release via NF-kappaB and AP-1 pathways in macrophages. PMID- 21235393 TI - Improving anal cancer screening in an ambulatory HIV clinic: experience from a quality improvement initiative. AB - Evidence suggests that persons living with HIV (PLWH) are at increased risk for anal cancer. Early detection of anal cancer is an important prevention measure, but screening rates have been low. This report describes the experience of a quality improvement initiative to increase anal cancer screening at an HIV specialty clinic. Chart reviews were conducted for three time periods: baseline year, prior to program discussion; transition year, during planning; and implementation year, during program availability. Odds ratios using Fisher's exact test showed that the odds of receiving anal cancer screening increased significantly in the transition year, odds ratio (OR) = 2.859, 95% confidence interval (CI): [1.798; 4.546], Fisher's z = 4.40, p < 0.0001, and in the implementation year, OR = 7.446, 95% CI: [4.783; 11.588], Fisher's z > 8.2, p < 0.0001. Patients and clinicians reported high levels of satisfaction with the program. Referring clinicians were also more likely to discuss anal cancer screening. PMID- 21235394 TI - Application of Bayesian techniques to model the burden of human salmonellosis attributable to U.S. food commodities at the point of processing: adaptation of a Danish model. AB - Mathematical models that estimate the proportion of foodborne illnesses attributable to food commodities at specific points in the food chain may be useful to risk managers and policy makers to formulate public health goals, prioritize interventions, and document the effectiveness of mitigations aimed at reducing illness. Using human surveillance data on laboratory-confirmed Salmonella infections from the Centers for Disease Control and Prevention and Salmonella testing data from U.S. Department of Agriculture Food Safety and Inspection Service's regulatory programs, we developed a point-of-processing foodborne illness attribution model by adapting the Hald Salmonella Bayesian source attribution model. Key model outputs include estimates of the relative proportions of domestically acquired sporadic human Salmonella infections resulting from contamination of raw meat, poultry, and egg products processed in the United States from 1998 through 2003. The current model estimates the relative contribution of chicken (48%), ground beef (28%), turkey (17%), egg products (6%), intact beef (1%), and pork (<1%) across 109 Salmonella serotypes found in food commodities at point of processing. While interpretation of the attribution estimates is constrained by data inputs, the adapted model shows promise and may serve as a basis for a common approach to attribution of human salmonellosis and food safety decision-making in more than one country. PMID- 21235395 TI - Biometric measurements inside the model eye using a two wavelengths Fourier domain low coherence interferometer. AB - We present a setup to measure biometric data of the eye using Fourier domain interferometry. The measuring depth of a Fourier domain system is basically limited owing to the spectral resolution. Combining two spectral domain interferometers with different wavelength ranges creates two measurement sections and allows for a simultaneous biometric measurement in terms of corneal thickness, anterior chamber depth, and axial length. The necessary offset between both sections in the combined setup was calibrated with a known reference object. The setup was tested by measuring a self-constructed model eye. All biometric data of the model eye can be detected simultaneously. This system has a precision of 13 MUm (standard deviation) and a trueness of 46 MUm. The signal-to-noise ratio was 98 dB for the anterior part and 76 dB for the posterior part. In contrast to time domain interferometry, this setup does not need any mechanically moving parts. Owing to the short time frame of the biometric measurement, potential eye movements should have no influence on the result. In addition to the fast measurement, this setup provides the possibility to adjust the laser power of both sections independently. This could help in the case of dense cataract. PMID- 21235396 TI - Prevalence and characterization of extended-spectrum beta-lactamases-producing Salmonella enterica isolates in Saragossa, Spain (2001-2008). AB - We analyzed the prevalence of resistance to extended-spectrum cephalosporins (ESCs) among clinical strains of Salmonella enterica collected by the Laboratory of Clinical Microbiology in the University Clinical Hospital Lozano Blesa in the region of Aragon (Spain), for which very few epidemiological information exists. A total of 2,092 strains of S. enterica were identified in stool samples from patients with gastroenteritis. Five isolates showed an extended-spectrum beta lactamase (ESBL) phenotype: four isolates of S. enterica serotype Virchow harbored the ESBL-encoding bla(CTX-M-9) gene and an isolate of serotype Enteritidis carried a bla(CTX-M-1) gene, which, to the best of our knowledge, is described here for the first time in this serotype of S. enterica. The five ESC resistant isolates were also resistant to spectinomycin, streptomycin, kanamycin, sulfonamides, tetracycline, and trimethoprim as well as to nalidixic acid. The ESBL isolate of serotype Enteritidis, however, remained susceptible to kanamycin and nalidixic acid. A class 1 integron of 1.5 kb was detected for the four serotype Virchow isolates with the gene cassette dfrA16-aadA2. The bla(CTX-M-9) gene was carried by an ~300-kb IncHI2 conjugative plasmid in the case of the S. enterica serotype Virchow isolates. The bla(CTX-M-1) gene was carried by an ~100 kb IncI1-N conjugative plasmid for the serotype Enteritidis ESC-resistant isolate. All the four ESC-resistant strains of S. enterica serotype Virchow clustered together in a XbaI pulsed-field gel electrophoresis, which also revealed a strong similarity between them and some pulsotypes of S. enterica serotype Virchow from France. PMID- 21235397 TI - ULK1, mammalian target of rapamycin, and mitochondria: linking nutrient availability and autophagy. AB - A fundamental function of autophagy conserved from yeast to mammals is mobilization of macromolecules during times of limited nutrient availability, permitting organisms to survive under starvation conditions. In yeast, autophagy is initiated following nitrogen or carbon deprivation, and autophagy mutants die rapidly under these conditions. Similarly, in mammals, autophagy is upregulated in most organs following initiation of starvation, and is critical for survival in the perinatal period following abrupt termination of the placental nutrient supply. The nutrient-sensing kinase, mammalian target of rapamycin, coordinates cellular proliferation and growth with nutrient availability, at least in part by regulating protein synthesis and autophagy-mediated degradation. This review focusses on the regulation of autophagy by Tor, a mammalian target of rapamycin, and Ulk1, a mammalian homolog of Atg1, in response to changes in nutrient availability. Given the importance of mitochondria in maintaining bioenergetic homestasis, and potentially as a source of membrane for autophagosomes during starvation, possible roles for mitochondria in this process are also discussed. PMID- 21235398 TI - Connexin43 hemichannels contribute to cadmium-induced oxidative stress and cell injury. AB - We investigated the potential involvement of connexin hemichannels in cadmium ions (Cd(2+))-elicited cell injury. Transfection of LLC-PK1 cells with a wild type connexin43 (Cx43) sensitized them to Cd(2+)-elicited cell injury. The cell susceptibility to Cd(2+) was increased by depletion of glutathione (GSH) with DL buthionine-[S,R]-sulfoximine, and decreased by N-acetyl-cysteine or glutathione reduced ethyl ester. Fibroblasts derived from Cx43 wild-type (Cx43+/+) and knockout (Cx43-/-) fetal littermates displayed different susceptibility to Cd(2+). Cd(2+) induced a higher concentration of reactive oxygen species, a stronger activation c-Jun N-terminal kinase, and significantly more severe cell injury in Cx43+/+ fibroblasts, as compared with Cx43-/- fibroblasts. Cd(2+) caused a reduction in intracellular GSH, whereas it elevated extracellular GSH. This effect of Cd(2+) was more dramatic in Cx43+/+ than Cx43-/- fibroblasts. Treatment of Cx43+/+ fibroblasts with Cd(2+) caused a Cx43 hemichannel-dependent influx of Lucifer Yellow and efflux of ATP. Collectively, our study demonstrates that Cx43 sensitizes cells to Cd(2+)-initiated cytotoxicity, possibly through hemichannel-mediated effects on intracellular oxidative status. PMID- 21235399 TI - Functional and genetic survey of all known single-nucleotide polymorphisms within the human deoxyribonuclease I gene in wide-ranging ethnic groups. AB - The single-nucleotide polymorphisms (SNPs) in the human DNase I gene (DNASE1) might be involved in susceptibility to some common diseases; however, only limited population data are available. Further, the effects of these SNPs on in vivo DNase I activity remain unknown. The genotype and haplotype of all the SNPs in DNASE1 were determined in 3 ethnic groups including 14 populations using newly developed methods. Together with our previous data on the nonsynonymous SNPs, two major haplotypes based on the five exonic SNPs were identified; genetic diversity in the Asian population was low. Among 10 SNPs, other than exonic SNPs in the gene, only 3 were polymorphic among all the populations. Haplotype distribution, based on all the polymorphic SNPs, was clarified to be generally varied in an ethnic-dependent manner. Thus, the genetic aspects of DNASE1 with regard to all the SNPs in wide-ranging ethnic groups could be first demonstrated. Further, there was no correlation of all the polymorphic SNPs other than nonsynonymous ones with serum DNase I activity levels. Polymorphic SNPs other than the exonic SNPs might not be directly related to common diseases through alterations in in vivo levels of the activity. PMID- 21235401 TI - Biphasic electrical targeting plays a significant role in schwann cell activation. AB - Electrical stimulation (ES) is a promising technique for axonal regeneration of peripheral nerve injuries. However, long-term, continuous ES in the form of biphasic electric current (BEC) to stimulate axonal regeneration has rarely been attempted and the effects of BEC on Schwann cells are unknown. We hypothesized that long-term, continuous ES would trigger the activation of Schwann cells, and we therefore investigated the effect of BEC on the functional differentiation of primary human mesenchymal stromal cells (hMSCs) into Schwann cells, as well as the activity of primary Schwann cells. Differentiation of hMSCs into Schwann cells was determined by coculture with rat pheochromocytoma cells (PC12 cell line). We also investigated the in vivo effects of long-term ES (4 weeks) on axonal outgrowth of a severed sciatic nerve with a 7-mm gap after retraction of the nerve ends in rats by implanting an electronic device to serve as a neural conduit. PC12 cells cocultured with hMSCs electrically stimulated during culture in Schwann cell differentiation medium (Group I) had longer neurites and a greater percentage of PC12 cells were neurite-sprouting than when cocultured with hMSCs cultured in growth medium (control group) or unstimulated hMSCs in the same culture conditions as used for Group I (Group II). Group I cells showed significant upregulation of Schwann cell-related neurotrophic factors such as nerve growth factor and glial-derived neurotrophic factor compared to Group II cells at both the mRNA and protein levels. Primary Schwann cells responded to continuous BEC with increased proliferation and the induction of nerve growth factor and glial-derived neurotrophic factor, similar to Group I cells, and in addition, induction of brain-derived neurotrophic factor was observed. Immunohistochemical investigation of sciatic nerve regenerates revealed that BEC increased axonal outgrowth significantly. These results demonstrate that BEC enhanced the functional activity of Schwann cells via the induction of neurotrophic factor release and guide-increased axonal outgrowth in vivo. The effectiveness of long-term ES highlights the feasibility of a BEC-based therapeutic device to accelerate nerve regeneration of severed peripheral nerve injuries with a gap. PMID- 21235400 TI - NO-released zinc supports the simultaneous binding of Raf-1 and PKCgamma cysteine rich domains to HINT1 protein at the mu-opioid receptor. AB - In the brain, the mu-opioid receptor (MOR) activates neural nitric oxide synthase (nNOS) through the PI3K/Akt pathway. The resulting nitric oxide (NO) enhances the function of the glutamate N-methyl-d-aspartate receptor (NMDAR)/calcium and calmodulin-dependent serine/threonine kinase (CaMKII), which subsequently diminishes MOR signaling strength. Because the ERK1/2 cascade is implicated in opioid tolerance, we analyzed the role of morphine-generated NO in this negative regulation. We found that NO-released endogenous zinc ions recruit the Ras/Raf 1/ERK1/2 cassette to histidine triad nucleotide-binding protein 1 (HINT1). A-Raf and B-Raf showed little or no MOR association. The zinc ions bridge the Raf-1 cysteine-rich domain (CRD) with HINT1 at the MOR C-terminus. Morphine also recruits PKCgamma via NO/zinc to the MOR-HINT1 complex. Both Raf-1 and PKCgamma CRDs bind simultaneously to HINT1, enabling PKCgamma to enhance Raf-1 function to intensify MEK/ERK1/2 activation. Thus, through attached HINT1, the MOR facilitates the cross-talk of two NO- and zinc-regulated signal-transduction pathways, PKC/Src and Raf-1/ERK1/2, implicated in the negative control of morphine effects. This study reveals new aspects of ERK1/2 regulation by the MOR without requiring the transactivation of a receptor tyrosine kinase. PMID- 21235403 TI - Baseline predictors of ninety percent or higher antiretroviral therapy adherence in a diverse urban sample: the role of patient autonomy and fatalistic religious beliefs. AB - The role of patient autonomy and influence of religious/spiritual beliefs on antiretroviral therapy (ART) adherence is to date not fully understood. This study assessed baseline predictors of high ART adherence (>=90%) measured by electronic drug monitors (EDM) at 12 and 24 weeks after enrollment in a randomized controlled trial testing behavioral interventions to improve ART adherence. Baseline data were collected with audio computer-assisted self interviews (ACASI) surveys among a diverse urban sample of HIV-infected participants (n = 204) recruited from community clinics in a large midwestern city. Baseline variables included a range of established ART adherence predictors as well as several less frequently studied variables related to patient autonomy and religious/spiritual beliefs. Statistically significant (p < 0.05) variables identified in univariate analyses were included in subsequent multivariate analyses predicting higher than 90% adherence at 12 and 24 weeks. Several baseline predictors retained statistical significance in multivariate analysis at 24 weeks. Baseline levels of autonomous support from friends and family, motivation to adhere, and having an active coping style were all positively associated with adherence, while the belief that God is in control of one's health was negatively associated with adherence. Results indicate that effective interventions should include a focus on promoting patients' autonomous regulation and religious/spiritual beliefs regarding ART adherence. PMID- 21235402 TI - Surveillance of HIV type 1 recent infection and molecular epidemiology among different risk behaviors between 2007 and 2009 after the HIV type 1 CRF07_BC outbreak in Taiwan. AB - The objective of this study was to analyze recent infections and the molecular epidemiology of human immunodeficiency virus type 1 (HIV-1) among different risk groups since the outbreak of circulating recombinant form CRF07_BC among intravenous drug users (IDUs) in 2004 in Taiwan. Phylogenetic analysis was performed using the env and pol fragment sequences amplified from these specimens. The BED IgG capture incidence EIA (BED-CEIA assay) was used to determine recent infections. Among the 683 HIV-1-positive individuals enrolled between 2007 and 2009, 394 (57.7%) were subtype B, 260 (38.1%) were CRF07_BC, 26 (3.8%) were CRF01_AE, two (0.3%) were CRF08_BC, and one (0.1%) was CRF06_cpx. While the percentage of CRF07_BC decreased (58.5-17.9%, p < 0.001) from 2007 to 2009, the percentage of subtype B increased (37.6% to 74.9%, p < 0.001). A concordant decrease in the proportion of recent infections to new infections among IDUs (63.6% to 9.8%, p < 0.001), accompanied with an increase of the proportion of recent infections in MSM (men having sex with men) (22.4-67.1%, p = 0.77) and heterosexual groups (13.1- 23.2%, p = 0.852), was observed. The decrease in CRF07_BC infections and the reduction in the proportion of recent infections among IDUs reflected the success of harm reduction strategies initiated by the government in 2005. PMID- 21235405 TI - The economic burden of advanced Parkinson's disease: an analysis of a UK patient dataset. AB - BACKGROUND: To evaluate the cost burden of patients with advanced Parkinson's disease (PD) according to the waking hours per day spent in OFF state. An analysis of resource use comprising medical services, professional care and informal care data from an observational, cross-sectional study was conducted. METHODS: A total of 60 physicians comprising 40 neurologists and 20 geriatricians across the UK participating in the Adelphi PD Disease Specific Programme took part. There were 302 PD patients at H&Y stages 3-5. Patients were characterised according to the percentage of time per day spent in OFF state (<25%, 26-50%, 51 75%, >75%). RESULTS: Average 12-monthly total costs increased according to the time spent in OFF state from L25,630 in patients spending less than 25% of their waking hours in OFF to L62,147 for patients spending more than 75% of their time in OFF. Overall, 7% of costs were attributed to direct medical care, while 93% were split between direct non-medical professional care (50%) and indirect informal care (43%). LIMITATIONS: Low patient numbers in the more advanced disease stages of PD led to very little or no data to directly inform some of the severe health states of the analysis. Data gaps were filled in with data derived from a regression analysis which may affect the robustness of the analysis. CONCLUSION: This study illustrates the increasing costs of advancing PD, in particular related to the time spent in OFF state, and identifies that the foremost cost burden is associated with the care needs of the patient rather than medical services. PMID- 21235404 TI - First report of plasmid-mediated quinolone resistance qnrA1 gene in Klebsiella pneumoniae isolate of animal origin. AB - One QnrA1-producing Klebsiella pneumoniae isolate GDKA1 from chicken was detected. The qnrA1 gene on plasmid pGDKA1 was located in a genetic environment similar to that in In36 on plasmid pHSH1 and could be cotransferred to Escherichia coli J53 Az(R) with other resistances by a conjugation experiment. Upstream of the qnrA1 gene, there was a class I integron with the dfrA27 and aadA2 cassettes. Similar genetic environments of qnrA1 in Enterobacteriaceae isolates from both human and animal origin might, to some extent, demonstrate similar mechanisms of qnrA distribution. The presence of qnrA1 in health animal commensal bacteria should be worthy of note. This is the first report of qnrA1 in K. pneumoniae and dfrA27 in an Enterobacteriaceae isolate of animal origin. PMID- 21235406 TI - Observation of pain control in patients with bisphosphonate-induced osteonecrosis using low level laser therapy: preliminary results. AB - BACKGROUND: Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is an adverse side effect associated with bisphosphonate (BP) therapy, especially when parenteral BP administration is used. Patients affected by BRONJ present wide areas of exposed necrotic bone, particularly after surgical oral procedures. The main symptom is pain that is poorly controlled by common analgesic drugs. Recently, many studies have pointed to the beneficial effect of low-level laser therapy (LLLT) in pain reduction for many pathological conditions. The purpose of this study is to investigate whether LLLT could be helpful in managing BRONJ by reducing the problems associated with this condition and the use of analgesic drugs. METHODS: Twelve patients affected by BRONJ were monitored at the Complex Operative Unit of Oral Pathology. Among these patients, only seven referred to pain in necrotic areas and were recruited for LLLT. Laser applications were performed with a double diode laser simultaneously emitting at two different wavelengths (lambda = 650 nm and lambda = 904-910 nm, spot size = 8 mm). All of the patients were irradiated with a fluence of 0.053 J/cm(2) for 15 min five times over a period of 2 weeks, in a non-contact mode, ~1 mm from the pathologic area. The patient's maximum and minimum pain was recorded using a numeric rating scale (NRS) evaluation before and after the treatment. Statistical analysis was performed using the Kruskal-Wallis test. RESULTS: Six patients showed significant pain reduction, and only one patient indicated a worsening of the symptoms, which was probably related to a reinfection of the BRONJ site, which occurred during the study. A statistically significant difference (p < 0.05) was found between the NRS rates before and after the protocol. CONCLUSIONS: This pilot study suggests that LLLT may be a valid technique to support the treatment of BRONJ related pain, even though the low number of cases in this study does not permit any conclusive consideration. PMID- 21235408 TI - Poor differential adherence of ritonavir tablets used as protease inhibitor booster. PMID- 21235407 TI - Molecular characterization of Campylobacter lanienae strains isolated from food producing animals. AB - During 2008 and 2009, within the framework of the Hungarian monitoring program of antibiotic resistance of zoonotic agents from food-producing animals, a significant number (43 strains) of Campylobacter lanienae were detected for the first time in Hungary. The isolates were genotyped using partial 16S rRNA gene sequencing and pulsed-field gel electrophoresis using three different restriction enzymes. The antimicrobial resistance of the isolates was determined by microtiter broth dilution. C. lanienae isolation was successful only from swine but not from other animal species. According to phylogenetic analysis, clustering of the isolates shows the same extensive genetic diversity as other Campylobacter species. Sequence analysis of the partial 16S rRNA gene showed that additional variations exist in variable regions Vc2 and Vc6. SmaI restriction enzyme proved to be the most efficient for pulsed-field gel electrophoresis analysis of C. lanienae. A significant tetracycline resistance (60.9%) and the presence of erythromycin-, enrofloxacin-, and multiresistant C. lanienae strains were found. Although the pathogenic potential of C. lanienae in humans is currently unknown, this study demonstrates that C. lanieanae is common in pigs in the country, provides further details on the genotypic and phenotypic properties of C. lanienae, and offers a genotyping method for use in source tracing. PMID- 21235409 TI - The connection between agr and SCCmec elements of Staphylococcus aureus strains and their response to photodynamic inactivation. AB - OBJECTIVE: The aim of this work was to analyze the presence of specific types of agr and SCCmec in Staphylococcus aureus strains and to determine the correlation between these types of genes and the response of S. aureus strains to photodynamic inactivation. BACKGROUND: S. aureus is an important human pathogen that is still one of the most common etiological factors of nosocomial infections. The genetic factor connected with high pathogenicity of S. aureus strains is the agr locus, which encodes a molecule responsible for activation of virulence genes. The characteristic feature of strains resistant to methicillin (MRSA) is the presence of the gene determining the resistance to beta-lactam antibiotics. This gene is a part of a mobile genetic element known as Staphylococcal Chromosome Cassette mec (SCCmec). Polymorphic differences in the agr locus and SCCmec cassette enable classification of strains into different groups. MATERIALS AND METHODS: We cultured and incubated each strain with defined dose of photosensitizer (protoporphyrin diarginate). Next, strains were irradiated with a red light at a dose of 12 J/cm(2). After an 18-h incubation, the Colony Forming Units were counted and the results were analyzed statistically. Furthermore, the genetic profile of the studied strains was determined with the use of the Multiplex PCR reaction both for agr and SCCmec elements. RESULTS: The results agreed with previous data, confirming that the response to photodynamic inactivation varies among different S. aureus strains. We also found a connection between some of the agr and SCCmec groups and the response of analyzed S. aureus strains to photoinactivation. CONCLUSION: Unfortunately, those relations are not specific enough to determine a diagnostically important pattern, which could enable predictions of strain response to PDI. Nevertheless, we can conclude that the connection between the response of S. aureus strains to photoinactivation and the strain specific agr/SCCmec pattern could be observed. PMID- 21235410 TI - Differences in grip forces among various robotic instruments and da Vinci surgical platforms. AB - INTRODUCTION: The da Vinci surgical platform is becoming increasingly available and utilized. Due to the lack of haptic feedback, visual cues are necessary to estimate grip forces and tissue tensions during surgery. We directly measured the grip forces of robotic EndoWrist instruments using the three available da Vinci robotic surgical platforms. METHODS: Robotic instruments were tested in the da Vinci S, Si, and Standard systems. A load cell was placed in a housing unit that allowed for measurement of the grip forces applied by the tip of each robotic instrument. Each instrument was tested six times, and all data were analyzed using Student's t-tests or analysis of variance when appropriate. RESULTS: Slight differences in grip force were seen when the instrument was tested through 2 degrees of freedom at the tip (p = 0.02, analysis of variance) and when comparing a new instrument to an older instrument (p = 0.001 at the neutral position). There was no statistical difference in grip force between the left and right robotic arms. There was a broad range of grip forces between the various robotic instruments. The lowest grip force was registered in the double fenestrated grasper (2.26 +/- 0.15 N), whereas the highest was seen in the Hem-o-lok clip applier (39.92 +/- 0.89 N). In comparison to the S and Si, the Standard platform appeared to have significantly higher grip forces. CONCLUSION: Different grip forces were observed among the various robotic instruments commonly used during urologic surgery and between the Standard and the S and Si platforms. PMID- 21235411 TI - Interleukin-27-mediated suppression of human Th17 cells is associated with activation of STAT1 and suppressor of cytokine signaling protein 1. AB - Accumulating evidence indicates that interleukin (IL)-27, a member of the IL-12 family of cytokines, antagonizes pathological Th17 effector cell responses. Relatively little is known about the cytokines that regulate human Th17 cells. In this study, we investigated the effect of IL-27 on the differentiation of human Th17 cells and on committed memory Th17 cells. We demonstrate that IL-27 suppresses the development of human Th17 cells by downregulating retinoid orphan nuclear receptor C expression and that this inhibition is associated with the induction of the intracellular signaling factors STAT1 and induction of the suppressor of cytokine signaling protein 1. The IL-27-mediated inhibition of IL 17 is independent of IL-10. We show that IL-27 inhibits differentiation of naive T cells into IL-17(+) T cells under different Th17 polarizing conditions. IL-27 suppresses other Th17 subset cytokines such as IL-22 and IL-21 but not tumor necrosis factor-alpha. Moreover, we also show that IL-27 inhibits IL-17 production by committed Th17 memory cells, which is independent of IL-10. These studies show that IL-27 negatively regulates both the developing and committed human Th17 responses and therefore may be a promising therapeutic approach in the treatment of Th17-mediated diseases. PMID- 21235412 TI - How patients choose acupuncturists: a mixed-methods project. AB - OBJECTIVES: Patients can have difficulties choosing acupuncturists in the United Kingdom because acupuncturists are not all subject to statutory regulation. Research has identified factors that influence patients' choice of general practitioner. However, how patients choose acupuncturists has not been studied. The aim was to investigate how patients choose acupuncturists and to identify which factors might influence this choice. DESIGN: A mixed-methods design used an exploratory qualitative study followed by a quantitative study. The qualitative study explored patients' experiences of acupuncture. The quantitative vignette study investigated the impact of patient gender and practitioner factors (gender, training location, and qualifications) on choice of acupuncturist. METHODS: In the qualitative study, 35 acupuncture patients (recruited through maximum variation sampling from seven clinics and the community) participated in semistructured interviews about their acupuncture experiences. In the quantitative study, 73 participants imagined wanting to consult an acupuncturist for back pain. They rated 8 fictional acupuncturists; ratings were analyzed using analysis of covariance. RESULTS: Patients wanted qualified, personable acupuncturists and valued recommendations from trusted others. Without such recommendations, potential patients preferred female acupuncturists (F(1,69)=4.504, p<0.05) and those with medical qualifications (F(1,69)=44.832, p<0.01). CONCLUSIONS: The decision to consult a particular acupuncturist is not straightforward. Acupuncturists' trustworthiness and technical competence are important to (potential) patients; practitioner gender also influenced preferences. Patients need to be informed about proposals concerning statutory regulation in CAM and its implications; conventional practitioners might be able to better support their patients wanting to consult acupuncturists. PMID- 21235413 TI - Pandemic 2009 H1N1 influenza virus is resistant to the antiviral activity of several interferon alpha subtypes. AB - Interferons (IFNs) are critically important in the control of influenza A virus infections. To better understand the pathogenic characteristics of the pandemic 2009 H1N1 influenza virus (pH1N1) from an innate immunity viewpoint, we investigated whether in vitro pH1N1 is sensitive to the antiviral activity of IFN beta, leukocyte IFN alpha, and several IFN alpha subtypes in a human lung adenocarcinoma epithelial cell line under single-growth cycle conditions. The results showed that 50% inhibitory concentration values against pH1N1 for various type I IFN preparations were higher than those against the IFN-sensitive encephalomyocarditis virus. Leukocyte IFN alpha and IFN alpha 5, 7, 8, 10, 14, 17, and 21 subtypes also appeared to be less active against pH1N1 than the Puerto Rico/8/34 H1N1 human influenza strain A. Taken together, the results provide new insights into the contributions of the various IFN alpha subtypes toward the regulation of innate immunity against pH1N1. PMID- 21235414 TI - Factors of osteogenesis influencing various human stem cells on third-generation gelatin/beta-tricalcium phosphate scaffold material. AB - Human bone marrow-derived stem cells (hBMSCs) and adipose-derived stem cells (hASCs) have been used to regenerate bone. Both sources are claimed to have comparable osteogenic potential, but few comparative studies are available. Third generation biomaterials have been developed to reduce steps in regenerating tissues. For osteogenesis gelatin/beta-tricalcium phosphate (beta-TCP) scaffolds with incorporated controlled-release bone morphogenetic protein-2 (BMP-2) as third-generation biomaterials were recently developed. So far, few studies on protein-induced osteogenesis versus chemical-induced osteogenesis have been performed. This study evaluates the osteogenic potential of hBMSCs versus hASCs derived on gelatin/beta-TCP scaffolds in vitro under four different conditions. Gelatin/beta-TCP scaffolds with and without incorporated controlled-release BMP-2 were seeded with hBMSCs or hASCs under oscillating fluid conditions in osteogenic (OS) medium or growth medium (GM). All were evaluated radiologically (computed tomography [CT] scan), histologically, biomechanically, and for gene expression at 1, 2, 4, and 6 weeks. The highest radiological densities were seen in specimens at 6 weeks with controlled-release BMP-2, close to native bone. HBMSCs, hASCs, OS, and GM conditions resulted in similar bone formation with gelatin/beta TCP scaffolds and incorporated controlled-release BMP-2. This was confirmed histologically by Toluidine Blue and van Kossa staining and biomechanically. Gene expression studies of these specimens showed the presence of preosteoblasts, transitory osteoblasts, and secretory osteoblasts. Specimens comprised of gelatin/beta-TCP scaffolds without incorporated controlled release BMP-2 in OS medium showed lesser bone formation. hASCs and hBMSCs have similar osteogenic potential. hASCs are an attractive alternative to hBMSCs for bone regeneration using third-generation gelatin/beta-TCP scaffolds with incorporated controlled release BMP-2. PMID- 21235415 TI - Robotic radical prostatectomy in patients with high-risk disease: a review of short-term outcomes from a high-volume center. AB - PURPOSE: Patients with high-risk prostate cancer have historically been treated with multimodal therapy and considered poor candidates for minimally invasive surgery. We reviewed our experiences with robot-assisted radical prostatectomy (RARP) in patients with high-risk clinical features. MATERIALS AND METHODS: Clinical database review identified high-risk patients undergoing RARP by two high-volume robotic surgeons. D'Amico's criteria for high-risk prostate cancer were utilized: prostate-specific antigen >= 20 ng/mL, clinical stage >= T2c, or preoperative Gleason grade >= 8. About 148 patients were identified in the study group. Mean age at surgery was 60.9 years, and mean body mass index was 27.9. Mean estimated blood loss was 150 cc and the transfusion rate was 2.7%. Median hospital stay was 1 day and the rate of major complications (Clavien grade >= 3) was 3.4%. RESULTS: Bilateral nerve preservation was feasible in 28.4%, and the rate of positive surgical margins was 20.9%. Final pathology demonstrated extra capsular disease in 54.1% of patients and 12.3% had lymph node involvement. At 2 years of follow-up, 21.3% of patients had experienced biochemical recurrence or had persistent disease after treatment. Continence was 91.2% (1 pad or less) and total impotence (inability to masturbate) was 48.3%. CONCLUSIONS: RARP does not compromise oncologic or functional outcomes in patients with high-risk prostate cancer. Although long-term study is necessary to validate oncologic and functional outcomes, our data suggest that the presence of high-risk disease is not a contraindication to a minimally invasive approach for radical prostatectomy at experienced centers. PMID- 21235416 TI - Effect of Korean red ginseng on arterial stiffness in subjects with hypertension. AB - OBJECTIVES: Korean red ginseng (KRG) improves endothelial function and lower blood pressure (BP), which may affect arterial stiffness. The present study evaluated whether KRG treatment could improve arterial stiffness in subjects with hypertension. SUBJECTS AND METHODS: Eighty (80) participants with hypertension who were treated with antihypertensive agents were randomly assigned to an active (KRG 3 g/day) or a placebo treatment group in a double-blind manner. Participants were not allowed to change their antihypertensive medications. Systolic BP (SBP) and diastolic BP (DBP) were measured at baseline, and at 1, 2, and 3 months. Arterial stiffness was assessed by the measurement of brachial-ankle pulse wave velocity (baPWV) at baseline, and at 1 and 3 months. RESULTS: Thirty (30) subjects in the active group (AG) and 34 subjects in the placebo group (PG) completed 3 months of treatment and then a per-protocol analysis was done. SBP and DBP at baseline, and at 1, 2, and 3 months were not different between the AG and PG (p>0.05). After 3 months of treatment, SBP of AG was not changed from SBP at baseline. However, DBP of AG, and SBP and DBP of PG after 3 months of treatment were significantly reduced (p<0.05). baPWV of both groups was significantly reduced at 1 and 3 months (p<0.05), but was not different between the groups at each time point. Analysis after adjustment for age, time-dependent mean arterial BP, heart rate, and levels of fasting blood glucose and triglycerides showed no significant difference between AG and PG in changes of baPWV from baseline to 1 and 3 months (p>0.05). CONCLUSIONS: Three (3) months' treatment with KRG did not improve arterial stiffness in subjects with hypertension. PMID- 21235417 TI - Host response cytokine signatures in viral and nonviral acute exacerbations of chronic obstructive pulmonary disease. AB - Viruses are strongly associated with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Interferon-inducible protein-10 has been recently described as a biomarker of human rhinovirus infection, but there are no reports on the role of other immune mediators in AECOPD of viral origin. As an attempt to evaluate the differences in the systemic immune mediators profiles between AECOPD patients with presence/absence of viral infection, we measured 27 cytokines, chemokines, and cellular growth factors in the plasma of 40 patients with AECOPD needing of hospitalization by using a Luminex-based assay. These patients were screened for the presence of 16 different respiratory viruses in pharyngeal swabs. Ten healthy controls were recruited for comparison purposes. Both the group of patients with an associated viral infection (n = 11) and those with no viral infection (n = 29) showed high levels of vascular endothelial growth factor, interleukin-13 (IL-13), and IL-2. On the other hand, viral infection in AECOPD induced a coordinated response of innate immunity chemokines (eotaxin, interferon-inducible protein-10, IL-8), Th1 cytokines (IL-12p70, IL-15), and the immunomodulatory IL-10. This profile corresponds to a typical antiviral response signature previously documented for other viral infections. The identification of early cytokine signatures associated with viral infection in AECOPD could contribute to design better treatment strategies for this disease. PMID- 21235419 TI - Calcium supplementation: is there a cardiovascular risk? PMID- 21235420 TI - Menopause redefined. PMID- 21235422 TI - The DEFINE study: a bright future for CETP inhibitors? PMID- 21235423 TI - Emerging female contraceptives. AB - INTRODUCTION: Fifty years after the first contraceptive, the market remains restricted regarding composition, cost and routes of administration, and satisfying the needs of millions of women with different requirements according to their stage in life. AREAS COVERED: Women need contraception for almost 30 years of their life. Currently available contraceptives are highly effective with few side effects. This review provides information on emerging female contraceptives including some registered and others at different stages of development. Research efforts aim to reduce costs, improve acceptability and refine 'forgettable' reversible methods. Although developing and testing a new method is laborious and expensive, many new contraceptives are currently under development including different routes of administration. EXPERT OPINION: New methods should be affordable, simple to use and suitable for many women. Much work remains to be done and new methods that act on the fusion process between both gametes are desirable without affecting the hormonal milieu. PMID- 21235424 TI - Shockwave lithotripsy: arterial aneurysms and vascular complications. AB - BACKGROUND AND PURPOSE: The application of shockwave lithotripsy (SWL) in patients with arterial aneurysm remains controversial, and several case reports exist in the world literature that describe both safe use and rupture. In addition, other vascular complications have been reported. The potential for hemorrhage is affected by coagulation status and antiplatelet therapy, yet little evidence exists on their interaction with SWL. We aim to review the vascular complications after SWL. METHODS: A review of the world literature was performed in accordance with methodology that is defined by the Cochrane Collaboration. An Internet bibliographic search on MEDLINE was performed during May and June 2010, with additional hand-searching of references. The search terms lithotripsy, aneurysm, abdominal aortic aneurysm, pseudoaneurysm, hemorrhage, hematoma, coagulation, aspirin, clopidogrel, and warfarin were used. RESULTS: In reported cases, there have been 18 patients with abdominal aortic aneurysm (AAA) who have undergone SWL. Both safe and uncomplicated treatment have been reported as well as rupture of AAA. Other vascular complications after SWL have included pseudoaneurysm, venous thrombosis, arterial stenosis, and arteriovenous fistulation. Patients with hemorrhagic risk factors can undergo SWL after correction of coagulopathy. Experimental work on animal models and human tissue has evaluated the effects of SWL on the vasculature. CONCLUSION: There is currently no high-level evidence to suggest that SWL in the presence of arterial aneurysm is unsafe. Experimental work on ex vivo human tissue does not suggest that SWL is causative to aneurysm rupture. With the availability of CT imaging in modern clinical practice, aneurysms of the arterial tree should be identified as part of the investigation of urinary tract calculi. SWL can be safely performed in patients with AAA, but monitoring postprocedure is mandatory, along with access to emergency vascular surgery support; importantly, any onset of new pain or symptoms should be aggressively investigated by radiologic imaging in the first instance. PMID- 21235425 TI - Towards a near-zero recurrence rate in laparoscopic inguinal hernia repair for pediatric patients. AB - OBJECTIVE: The aim of this study was to assess whether the median or lateral umbilicus ligament covering the internal hernia opening region after the purse string knot could eliminate recurrence in laparoscopic inguinal hernia repair in pediatric patients of all ages. METHODS: About 482 laparoscopic inguinal hernia repairs in 428 children of various ages were prospectively study in our institution from January 2000 to January 2004. The patients were divided into two groups randomly. In group A, the patients were accepted laparoscopic purse-string knot closing the internal hernia opening only; in group B, the patients were accepted the median or lateral umbilicus ligament covering the internal hernia opening region after the laparoscopic purse-string knot. The data from both groups of operations were then compared. RESULTS: A total of 239 hernias were repaired in group A (214 patients), whereas 243 in group B (214 patients). The differences between the sex ratio of boys to girls (199:15 versus 197:17) and the mean ages (51.05 +/- 49.65 versus 50.59 +/- 48.87 months) in the two groups were not statistically significant. The recurrence rate in group B was lower than that in group A and was statistically significant (0.00% versus 4.18%, P < .05). There were no postoperative testicular atrophy in either group of the patients. CONCLUSION: It is possible to achieve a near-zero recurrence rate in laparoscopic hernia repair in pediatric patients of all ages, especially for the patients with large hernia sac (diameter >1.5 cm) and the age over 5 years. PMID- 21235426 TI - Incidence of upper limb oedema in patients with acute hemiparetic stroke. AB - PURPOSE: Assessment of the incidence of upper limb oedema in an acute care setting by means of clinical and volumetric evaluation. METHODS: Patients with acute hemiparetic stroke were recruited from 2006 until 2009 (n = 125). Baseline measurements consisted of the National Institute of Health Stroke Scale, Fugl Meyer Assessment Arm Section and demographic characteristics. Oedema assessment was performed at 7 days after inclusion and at 1 month and 3 months follow-up. A standardised water displacement method (objective measurement) was used to define oedema and was compared to data from visual inspection and palpation (subjective measurement). RESULTS: In literature, the incidence of upper limb oedema ranges from 16-83%, defined by a variety of definitions. Oedema incidence in this study was defined by strict criteria using water displacement and ranged from 9-13.9%, while the incidence of oedema defined by visual inspection and palpation ranged from 6-18.5% during the different stages of follow-up. The agreement (Kappa) between both measurements ranged from 0.23-0.38, which is not more than 'moderate' but comparable to the agreement of 0.34 found in literature. CONCLUSION: An objective and subjective assessment of oedema was used; the agreement between both methods was only moderate. The incidence of oedema found in this study is lower than the incidences found in literature. PMID- 21235427 TI - Tumor heterogeneity and strategies to overcome kinase inhibitor resistance in cancer: lessons from melanoma. PMID- 21235429 TI - Novel mitogen-activated protein kinase kinase inhibitors. AB - INTRODUCTION: the development of new drugs over the last few decades has targeted specific proteins thought to be a key to the disease state. MAPK kinases 1 and 2 (commonly known as MEK1-2) represent such proteins as they lie downstream of important drug targets for oncology, such as EGFR, RAS and RAF. Several MEK1-2 inhibitors are currently in Phase I and II clinical trials in oncology. AREAS COVERED: this review of current literature and recent conferences provides a background on the RAS-RAF-MEK-ERK signaling pathway and a discussion of early MEK inhibitors. The potential of MEK1-2 inhibitors for the treatment of inflammation is briefly presented. Preclinical and early clinical results are discussed for MEK inhibitors currently in development. Completed clinical trials of MEK inhibitors in oncology include some disappointments as well as some promising signs of the value of these compounds and we discuss the potential for MEK inhibitors as monotherapy and their use in drug combinations. EXPERT OPINION: the utility of MEK inhibitors as anticancer agents will depend on careful patient selection based on the presence of mutations in genes such as KRAS and BRAF, the identification of additional predictive biomarkers, and an improved understanding of the benefit of drug combinations utilizing both established and emerging therapeutics. PMID- 21235430 TI - Developments in antivirals against influenza, smallpox and hemorrhagic fever viruses. AB - INTRODUCTION: the search for effective inhibitors to multiple infectious agents including influenza, smallpox and hemorrhagic fever viruses is an area of active research as many of these agents pose dramatic health and economic challenges to the human population. Many of these infectious agents are not only endemic threats in different parts of the globe, but are also considered to have the potential of being used as bioterrorism agents. AREAS COVERED: this review focuses on inhibitors that are currently in use in the research community against specific emerging infectious agents and those that have bioterrorism potential. The paper provides information about the availability of FDA approved drugs, whenever applicable, and insights into the specific aspect of the agent life cycle that is affected by drug treatment, when known. EXPERT OPINION: the key message that is conveyed in this review is that a combination of pathogen and host-based inhibitors may have to be used for successful control of viral replication to limit the development of drug resistance. PMID- 21235428 TI - Mechanisms of drug resistance in kinases. AB - INTRODUCTION: because of their important roles in disease and excellent 'druggability', kinases have become the second largest drug target family. The great success of the BCR-ABL inhibitor imatinib in treating chronic myelogenous leukemia illustrates the high potential of kinase inhibitor (KI) therapeutics, but also unveils a major limitation: the development of drug resistance. This is a significant concern as KIs reach large patient populations for an expanding array of indications. AREAS COVERED: we provide an up-to-date understanding of the mechanisms through which KIs function and through which cells can become KI resistant. We review current and future approaches to overcome KI resistance, focusing on currently approved KIs and KIs in clinical trials. We then discuss approaches to improve KI efficacy and overcome drug resistance and novel approaches to develop less drug resistance-prone KI therapeutics. EXPERT OPINION: although drug resistance is a concern for current KI therapeutics, recent progress in our understanding of the underlying mechanisms and promising technological advances may overcome this limitation and provide powerful new therapeutics. PMID- 21235431 TI - From old to new nucleoside reverse transcriptase inhibitors: changes in body fat composition, metabolic parameters and mitochondrial toxicity after the switch from thymidine analogs to tenofovir or abacavir. AB - INTRODUCTION: Thymidine analogs zidovudine (AZT) and stavudine (d4T) have been widely used because of their antiviral activity against HIV, but at the expense of high toxicity, mainly related to mitochondrial damage. Many studies have been performed replacing AZT or d4T with newer nucleoside analogs reverse transcriptase inhibitors (NRTIs) with less toxicity, such as tenofovir (TDF) or abacavir (ABC), maintaining virological efficacy. AREAS COVERED: Relevant literature was identified using a PubMed search of articles published up to June 2010. Search terms included: 'thymidine analogs', 'stavudine', 'zidovudine', 'd4T', 'AZT', 'ZDV', 'treatment switch'. Original articles in which d4T or AZT had been replaced by TDF or ABC as switch strategies (with undetectable viral load) were reviewed where information about body fat distribution, mitochondrial functionality and/or plasma lipid parameters were available. Relevant references from these articles were also considered. Only studies performed in adult patients (18 years or older) are included. The readers will gain a better understanding of the toxicity caused by thymidine analogs, the treatment alternatives and the benefits observed after treatment switch to newer NRTIs. EXPERT OPINION: Thymidine analogs AZT and d4T yield considerable toxicity and proactive switch to newer NRTIs such as TDF or ABC is necessary in order to avoid or partially reverse such side effects. PMID- 21235432 TI - FAK and interacting proteins as therapeutic targets in pancreatic cancer. AB - Pancreatic cancer is the fourth leading cause of cancer death in the United States. Chemotherapy and radiation therapy have had minimal ability to alter the natural course of the disease. Clearly, additional agents are needed to improve outcomes in this aggressive cancer. Pancreatic cancer has been found to have several genetic alterations including activation of K-ras and inactivation of p53, p16, and DPC4. Other alterations include upregulation of angiogenic factors and matrix metalloproteinases, dysregulation of growth factor receptors, and cytoplasmic kinases including focal adhesion kinase (FAK) and src. Clinicians must translate the available knowledge of the molecular basis of this disease into rationale and effective therapeutic strategies for treatment. The role of FAK in the pathogenesis of pancreatic cancer is discussed below and efforts aimed at the development of inhibitors of FAK for this disease are reviewed. PMID- 21235434 TI - Recent advances in protein tyrosine phosphatase detection using chemical probes. AB - Protein tyrosine phosphatases (PTPs) are key regulatory enzymes in signal transduction pathways and their aberrancy has been implicated in various diseases such as cancers, metabolic syndrome, and autoimmune disorders. In spite of its great importance, determination of the functional significance of PTPs remains a major challenge, and efficient methodologies are needed to specifically delineate PTP functions. Besides the strategy to use potent and selective PTP inhibitors to study the physiological roles of the enzymes, measurement of PTP activities using specific PTP substrates or activity-based probes (ABPs) has been reported. This review focused on the recent development of small molecular probes to detect PTP activities, consisting of five sub-categories: 1. Conventional fluorescent substrates; 2. Ratiometric fluorescent PTP substrates; 3. Fluorescence substrates with selectivity to a single PTP or a class of PTPs; 4. ABPs specific for PTPs; and 5. A real-time imaging of PTP-substrate complex using a small molecule PTP probe which, offers a measurement of a real-time activity of a certain PTP in cells. PMID- 21235433 TI - Tumor-derived extracellular fragments of receptor protein tyrosine phosphatases (RPTPs) as cancer molecular diagnostic tools. AB - Receptor protein tyrosine phosphatase (RPTPs) are involved in many cellular processes, including the regulation of adhesion, migration and cellular signaling. Many RPTPs are putative tumor suppressors because of the transcriptional and translational changes observed in their expression during tumorigenesis. Recently, RPTPs were shown to be post-translationally regulated during tumorigenesis by proteolysis in a manner similar to proteolysis of the Notch receptor. There is accumulating evidence that proteolysis of RPTPs influence their cellular function and that RPTP fragments may function as oncogenes. By exploiting what is known about RPTP ligand binding domains and crystal structures of ligand-RPTP interfaces, we describe novel molecular diagnostics that have been or can be developed to identify tumor margins and target tumor tissues. PMID- 21235436 TI - Cell biological manifestations of bisdioxopiperazines treatment of human tumor cell lines in culture. AB - British developed Bisdioxopiperazine compound (Biz compounds) {ICRF-159 or ICRF 187 (razoxane, Raz)} which was the first agent ever to be observed inhibiting and controlling the spontaneous pulmonary metastases of murine Lewis Lung Carcinoma (LLC) tumor model worldwide. Since 1980, two new Biz compounds {probimane (Pro, AT-2153, MST-2) and MST-16} have been synthesized at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, PR China, based on structural modifications from British developed Biz compounds. Despite some similarities and differences of structural and pharmacological activities observed between Raz, Pro and MST-16, the systematic comparisons of their pharmacological activities and mechanisms, especially on neoplasm metastases, are still much needed. This work demonstrates that Biz compounds may inhibit tumor cell migration in vitro through a Matrigel-Coated Transwell plate assay and a wound-healing assay by using three human mammary tumor cell lines (MDA-MB-231, MDA-MB-435 and MDA-MB 468). Pro, ICRF-187 and MST-16 affect the network of actin assembly. We conclude that Biz compounds might inhibit neoplasm metastases via affecting a cascade of GTPases, cell skeleton polarizations and cell movements. PMID- 21235437 TI - Targeted therapies in metastatic melanoma: toward a clinical breakthrough? AB - Metastatic melanoma is a very aggressive cancer. Dacarbazine has been considered as the standard therapy for decades. Due to a better understanding of melanoma cells signalling and immunological response, new targeted therapies are now proposed. The efficency of these new drugs needs to be confirmed by on larger clinical trials. Ipilimumab (anti-CTLA4 monoclonal antibody) and V600-E-B-raf inhibitor have shown encouraging results, while c-KIT and MEK inhibitors are currently under evaluation. These recently published data shed the light on melanoma management. We review here the latest development of these molecules and the current perspectives in the treatment of metastatic melanoma. PMID- 21235435 TI - PTPN13/PTPL1: an important regulator of tumor aggressiveness. AB - Protein tyrosine phosphorylation plays a major role in many cellular functions implicated in cancer development and progression, but only a few of the known protein tyrosine phosphatases have yet been clearly classified as oncogenes or tumor suppressors. PTPL1 interacts with tumor-associated proteins, suggesting a link between PTPL1, the PTPN13 gene product, and tumorigenesis or cancer progression. However, the impact of PTPL1 on cancer is divided between its capacity to counteract the activity of oncogenic tyrosine kinases and its inhibitory interaction with the death receptor, Fas. In this manuscript, we review the PTPL1-interacting proteins implicated in cancer. In addition, we examine the phenotypic arguments concerning both the PTPL1/Fas interaction and the ability of PTPL1 to inhibit signaling from growth factor receptors or oncogenes with tyrosine kinase activity. Finally, we compare the alterations in expression and the genetic and epigenetic arguments supporting an oncogenic or an anti-oncogenic impact of PTPL1. PMID- 21235438 TI - Topoisomerase I inhibitors in the treatment of primary CNS malignancies: an update on recent trends. AB - High grade primary CNS gliomas hold some of the worst prognoses of any malignancy, with the vast majority of patients dying within two years of diagnosis, even with aggressive modern treatments. Surgical resection and radiotherapy are cornerstones of treatment when possible. In spite of many years of research, only recently has management with chemotherapy been able to prolong survival in patients with high grade gliomas, albeit only modestly at best. Topoisomerase I (TOP1) inhibitors target an enzyme critical for DNA replication and cell-cycle progression; they cross the blood-brain barrier and have antitumor activity against glioblastoma cells in vitro. The most frequently associated toxicities are neutropenia and diarrhea, but are often manageable. The two most used agents are irinotecan and topotecan. Due to enhanced cytochrome CY3A4/5 enzyme activity, irinotecan dose must be adjusted with concomitant enzyme inducing antiepileptic drug usage; the data is less clear regarding the effects on topotecan. Clinical trials in patients with recurrent malignant glioma have evaluated TOP1 inhibitors as monotherapy and in combination with other agents. There is evidence for using topotecan with radiotherapy. Irinotecan has limited efficacy as monotherapy, but shows promise in combination with other agents, particularly temozolomide and bevacizumab. Newer generation TOP1 inhibitors are currently being evaluated in phase I trials. TOP1 inhibitors show promising activity in patients with primary CNS malignancies and warrant further study. PMID- 21235439 TI - Discovery of allosteric inhibitors of kinesin spindle protein (KSP) for the treatment of taxane-refractory cancer: MK-0731 and analogs. AB - Current cancer chemotherapy relies heavily on cytotoxic agents, such as the taxanes and Vinca alkaloids, that interfere with the cellular machinery required for cell division and divert the cell down a pathway of programmed cell death. These antimitotic agents, or spindle poisons, target the mitotic spindle by binding to tubulin, a protein required not only for mitosis but also for structural integrity and proper function of healthy, terminally differentiated cells. To avoid side effects attributed to this nonselective mechanism of action, new targets in the mitotic pathway that act only in dividing cells were sought and a leading candidate to emerge from these efforts was kinesin spindle protein (KSP or HsEg5). KSP is a molecular motor protein that is expressed only during mitosis and controls the formation of a functional mitotic spindle. Inhibition of KSP causes mitotic arrest followed by cell death in malignant cells and thus has the potential to become a novel chemotherapeutic strategy with the potential for reduced toxicity. This article summarizes efforts carried out at Merck to discover potent, selective and water soluble KSP inhibitors that culminated in the discovery of MK-0731, the second KSP inhibitor to enter clinical trials. Of special focus in this article is how an HTS lead was optimized in apparently divergent directions, but these disparate leads converged in the design of compounds that overcame P-glycoprotein efflux and hERG channel activity, two issues that required considerable optimization within our program. PMID- 21235440 TI - Potential new agents for chronic lymphocytic leukemia treatment. AB - Chronic lymphocytic leukemia (CLL) is the most frequent type of hematological cancer in the Western World. An accumulation of leukemic cells in peripheral blood of patients is a result of apoptosis disturbances as well as an increase in germinal centers CLL cell proliferation. The differences between CLL patients in the course and response to therapy reflects personal variability between patients in their genetic material. It was documented that many sufferers from CLL are over 60 years old, and because of many countries' population obsolescence this type of leukemia could become more frequent in the future. CLL remains incurable, and the therapy regimens available at present could induce even complete remissions, but finally a relapse of the disease. The etiology of this disease is still not known, but our understanding of the processes running in CLL cells has significantly increased. A number of new agents with potential of CLL cell elimination by apoptosis or autophagy were characterized. Some of them reflect potential in cell sensitization to standard therapy. The major challenge for the future is to develop targeted anti-cancer therapy and design the optimal personalized manner of CLL treatment. A special interest is focused on anti cancer agents - natural substances of plant origin. This paper reviews chosen new anti-leukemic agents belonging to different drug-classes (new monoclonal antibodies or apoptosis-, BCR signaling- and cell cycle-related inhibitors, substances of plant origin) which are under intense investigation in preclinical studies and early clinical trials. PMID- 21235441 TI - Calculation of Young's modulus value by means of AFM. AB - In the last years, Atomic Force Microscopy (AFM) has become a powerful tool not only to study the surface morphology but also the nanomechanics of all kind of samples. In this paper, the applicability of this technique is reviewed and its basic aspects of operation, advantages and drawbacks of using the AFM probe as a picoindenter (Force Spectroscopy mode, FS-AFM) are discussed. The patents concerning picoindentation measurements are discussed in the text and special attention is paid to measurements performed on hard materials as ceramics, as they have not been as thoroughly reviewed in the literature as in the case of soft matter. The possibilities of AFM in the nanomechanics field include the quantitative determination of the Young's modulus (E) and the transition force from elastic to plastic deformation regimes, the measurement of adhesion forces and deformation mechanisms while applying vertical forces in the range from tens of pN to MUN. PMID- 21235442 TI - Pompe disease: from new views on pathophysiology to innovative therapeutic strategies. AB - Pompe disease (PD) is a metabolic myopathy caused by the deficiency of the lysosomal hydrolase acid alpha-glucosidase (GAA) and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the attenuated intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) is at present the only approved treatment for PD, in addition to supportive and physical therapies. However, ERT shows limited efficacy in some patients and does not completely correct the disease phenotype. Recently, an improved knowledge of PD pathophysiology has provided clues to explain the limitations of ERT. A mechanical effect of lysosomal inclusions on muscle contractility has been proposed as a key factor of disease resulting in a severe loss of contractility. In addition, it has been shown that secondary abnormalities of housekeeping cellular functions, such as autophagy, have an important role in the pathogenesis of cell damage in PD. Abnormalities of intra cellular trafficking of vesicles and membrane-bound proteins, such as the cation independent mannose-6-phosphate receptor, may be deleterious for the efficacy of ERT. At present, new therapeutic strategies, in addition to ERT, are under investigation. An emerging strategy for the treatment of PD is pharmacological chaperone therapy, based on the use of chaperone molecules that assist the folding of mutated enzymes and improve their stability and lysosomal trafficking. Pre-clinical studies demonstrated a synergistic effect of pharmacological chaperones and ERT. Other approaches, also in a pre-clinical stage, include substrate reduction and gene therapy. PMID- 21235443 TI - New agents and approaches to treatment in Niemann-Pick type C disease. AB - Niemann-Pick disease type C is an autosomal recessive disorder caused by mutations in either one of the two genes, NPC1 or NPC2, which encode proteins involved in the regulation of normal transport and/or processing of free cholesterol. Several types of lipids including free cholesterol (unesterified), sphingosine, sphingomyelin, phospholipids and glycosphingolipids (glucosylceramide and gangliosides GM2 and GM3) are accumulated in lysosomes and late endosomes of cells, with pronounced concentrations in the liver and the spleen. The key laboratory diagnostic test for NP-C is filliping staining of cultured skin fibroblasts from the patient, to demonstrate free cholesterol accumulation in lysosomes secondary to impaired intracellular cholesterol transport. The symptomatology and rate of disease progression are strongly influenced by age at disease onset and different clinical forms have been described on this basis: Perinatal, Early-infantile (EI), late-infantile (LI), juvenile and adult forms. Clinical symptoms include progressive neurological deterioration and visceral organomegaly. Nowadays there is no fully effective treatment, only supportive measures for relief of specific manifestations of the disease. The intervention to slow disease progression is the most promising therapy. A number of experimental disease - specific therapies, based on the molecular pathology of NP-C, have been tested in cell culture and animal models including neurosteroids, cholesterol - binding agents, curcumin and Miglustat. This paper summarizes the recent developments that have been investigated for the treatment in patients and animal models with NPC. Current therapeutic approaches have been classified based on the targeting of cellular function, the anti - apoptotic cellular mechanisms and the stem cells therapy. PMID- 21235446 TI - Mucopolysaccharidosis Type II (Hunter Syndrome): clinical picture and treatment. AB - Mucopolysaccharidosis (MPS) type II (Hunter syndrome, OMIM 309900) is an X-linked lysosomal storage disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). Major clinical manifestations include joint contractures, obstructive and restrictive airway disease, cardiac disease, skeletal deformities and often mental retardation. As with all the MPS disorders, mucopolysaccharidosis type II is a clinically heterogeneous disease in terms of the extent and rate of progression of organ impairment in affected individuals. Common causes of death, which usually occurs within the second decade of life, are obstructive airway disease and cardiac failure due to valvular dysfunction, pulmonary hypertension and myocardial disease. Patients with the more attenuated (so-called adult) form usually have a normal intelligence, but often have many complaints such as progressive loss of vision due to retinal dysfunction, spastic paresis due to myelon compression at the cranio-cerevical region, severe hip disease and cardiac complications. Clinical investigations that have been performed in the last years in a great number of patients have shown that many of these complications are still underdiagnosed and untreated. Until recently, no specific treatment was available for the affected patients; management mainly consisted of supportive care and treatment of complications. Enzyme replacement therapy with recombinant iduronate-2-sulphatase (idursulfase), however, has now been introduced. And it could be demonstrated that weekly intravenous infusions of idursulfase is able to improve many of the symptoms and signs of Hunter syndrome. This review will present the efficacy and safety data of the enzyme preparation and discuss benefits and limitations of this new therapeutic option. PMID- 21235444 TI - Therapeutic approaches to the challenge of neuronal ceroid lipofuscinoses. AB - The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 265 mutations and 38 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances. PMID- 21235447 TI - Recent advances in treatment approaches to Gaucher disease. AB - Gaucher disease is inherited as an autosomal recessive disorder. The absence of beta-glucocerebrosidase whose purpose is to cleave the glucose from ceramide results in accumulation of glucocerebroside; storage of this glycolipid results in Gaucher disease. There is tremendous clinical heterogeneity: prediction of onset of symptoms (if at all), which organs will be affected, and the degree of severity of the signs and symptoms are areas of current research. Lysosomal storage diseases may be treatable by enzyme replacement therapy. Enzyme replacement for Gaucher disease has been attempted intermittently since the middle 1970s but was not successful until removal of sugars to expose the inner mannose residues allowed the targeting of the enzyme to macrophages via mannose receptors. The use of the recombinant imiglucerase (CerezymeTM) as intravenous therapy has been safe and effective for the visceral symptoms and signs of Gaucher disease in more than 5000 patients world-wide for more than 18 years. Nonetheless, beyond enzymes not being able to traverse the blood-brain barrer, dependence on a single modality is problematic since not all patients are responders, some develop adverse events, and supply may not be forthcoming for non-medical reasons. Thus, the availability of new enzymatic preparations, velaglucerase alfa (VPRIVTM) and taliglucerase alfa (UPLYSOTM), as well as alternative modalities such as substrate reduction and pharmacological chaperones, are important additions to the management portfolio of this disease. PMID- 21235448 TI - Treatment of fabry disease: current and emerging strategies. AB - Fabry disease is an X-linked lysosomal storage disorder (LSD) due to deficiency of the enzyme alpha-galactosidase A (GLA). Absent or reduced enzyme activity leads to impaired catabolism of neutral glycosphingolipids, particularly globotriaosylceramide (Gb3), resulting in intracellular deposition of such lipids. Clinical manifestations in hemizygote males include angiokeratoma, hypohydrosis, acroparesthesia, abdominal pain, proteinuria, renal insufficiency, left ventricular hypertrophy and cerebrovascular accidents. Heterozygote women may present with mild to severe signs and symptoms. Since year 2001, enzyme replacement therapy (ERT) is the only specific treatment for Fabry disease. The beneficial effect of ERT on different organs/systems has been extensively evaluated, and an improvement in renal function, cardiac mass and quality of life has been reported. Different treatment approaches are currently on development. One of them implies the use of the active-site-specific chaperone 1 deoxygalactonojirimycin that acts facilitating folding of mutant GLA in the endoplasmic reticulum and increasing its lysosomal residual activity. Reduction of Gb3 deposits has been shown in lymphoblasts from Fabry patients with missense mutations and transgenic mouse model expressing a missense mutation GLA. Gene therapy has been also developed as a potential option for treatment of Fabry disease. This review will discuss these novel therapeutic options along with their advantages and limitations. PMID- 21235445 TI - Cell- and gene-based therapeutic approaches for neurological deficits in mucopolysaccharidoses. AB - Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases that are resulted from abnormal accumulation of glycosaminoglycans. Among the progressive multi-organ abnormalities often associated with MPS diseases, the deterioration of central nervous system (CNS) is the most challenging manifestations to be tackled, due to the impermeability of the blood-brain-barrier (BBB). Evolved with recent development in stem cell biotechnology and gene therapy, several novel experimental approaches have been investigated in animal models. In this review, we will address different approaches attempting to bypass the BBB for neuropathic MPS treatment using cell- and gene-based therapies. Several neurological findings in CNS pathophysiology emerged with therapeutic investigation will also be discussed. PMID- 21235449 TI - Mucopolysaccharidosis type III (Sanfilippo Syndrome): emerging treatment strategies. AB - Mucopolysaccharosis III (MPS III) is a lysosomal storage disorder and belongs to the group of mucopolysaccharidoses. MPS III is caused by a deficiency of one of the four enzymes catalyzing the degradation of the glycosaminoglycan heparan sulfate. MPS III is clinically characterized by progressive dementia with distinct behavioral disturbances and relatively mild somatic disease. This review will summarize and discuss the available and potential future therapeutic options for patients with MPS III. This includes enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), substrate reduction therapy (SRT), chaperone-mediated therapy, and gene therapy. Although clinical efficacy has not yet been fully demonstrated for any of these therapies, it is likely that future developments will lead to disease-modifying treatment for this devastating disease. PMID- 21235450 TI - The vasoactive role of nitric oxide: physiological and morphological aspects. AB - Nitric oxide (NO) participates in the control of the cardiovascular system where two constitutive isoforms of NO-synthase were discovered: endothelial and neuronal. Both isoforms were observed in various cells, however, endothelial NO synthase is predominantly present in the endothelium. Injury of the endothelium disturbs the balance between vasodilation and vasoconstriction and triggers different pathological alterations. In addition, whereas the intact endothelium protects vascular smooth muscle from oxidative attack, intervention in the vascular wall integrity increases the concentration of vascular superoxides, thus disturbing the effects of NO. To preserve NO-mediated vasorelaxation, different reserve mechanisms have developed. In case of damage of some endothelial receptor type, vasodilation could be ensured by activation of some other type of the present receptors. Moreover, morphological evidence demonstrated that both isoforms of NO-synthase were expressed also in smooth muscle cells and functional studies revealed that different pathological interventions in endothelial function (such as oxidative stress or hypertension) were associated with NO generation in the vascular media. In this case, the generation of NO by vascular smooth muscle may represent a physiologically relevant compensation of endothelial NO deficiency. Whereas long-term inhibition of endothelial NO synthase resulted in an unequivocal pattern of cardiovascular changes, inhibition of neuronal NO-synthase led to opposite effects, suggesting a specific position of neuronal NO-synthase in the regulation of cardiovascular tone. The specificity of endothelial or neuronal NO function seems to be related to a particular circulatory area and it is presumably determined by mutual interactions with other regulatory systems (sympathoadrenergic, renin-angiotensin, etc.). PMID- 21235452 TI - The role of brain gaseous transmitters in the regulation of the circulatory system. AB - A number of neurotransmitters, including biologically active gases namely, nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) have been postulated to play an important role in the control of the cardiovascular system by the brain. The attention of researchers has been focused on NO in particular. It has been shown that pharmacological manipulation of NO concentration in the brain produces significant changes in circulatory parameters. Furthermore, significant alterations in the brain NO system have been found in animal models of human cardiovascular diseases. These findings imply that NO in the brain may become a promising target for new treatment strategies. Although H2S and CO have also been proved to serve as transmitters in the central nervous system, their role in the neurogenic regulation of the cardiovascular system remains more obscure. Interestingly, increased synthesis of NO, H2S and CO is found in inflammation and it appears that the gases mediate some of the circulatory responses to inflammatory stimuli. In this review we discuss the role of brain gaseous transmitters in the control of the circulatory system in health and disease. PMID- 21235451 TI - Role of endothelial nitric oxide in cerebrovascular regulation. AB - Endothelial nitric oxide (NO) plays important roles in the vascular system. Animal models that show vascular dysfunction demonstrate the protective role of endothelial NO dependent pathways. This review focuses on the role of endothelial NO in the regulation of cerebral blood flow and vascular tone. We will discuss the importance of NO in cerebrovascular function using animal models with altered endothelial NO production under normal, ischemic and reperfusion conditions, as well as in hyperoxia. Pharmacological and genetic manipulations of the endothelial NO system demonstrate the essential roles of endothelial NO synthase in maintenance of vascular tone and cerebral perfusion under normal and pathological conditions. PMID- 21235453 TI - On the involvement of H2S in nitroso signaling and other mechanisms of H2S action. AB - Both endogenously produced and exogenously administered H2S exert numerous biological effects. However, the molecular mechanisms underlying these effects are not fully understood. This review surveys the biological effects of H2S and summarizes the molecular mechanisms of H2S action. It focuses on the role of H2S/HS--induced NO release from nitroso compounds, modulation of ion channels and the antioxidant and radical properties of H2S in the molecular mechanism of its effects. The potential involvement of H2S in nitroso signaling underlying its diverse biological effects is also discussed. PMID- 21235455 TI - Role of the decreased nitric oxide bioavailability in the vascular complications of diabetes mellitus. AB - This mini-review takes into consideration the physiology, synthesis and mechanisms of action of the nitric oxide (NO) and, subsequently, the causes and effects of the NO bioavailability impairment. In diabetes mellitus the reduced NO bioavailability is caused by the increased free radicals production, secondary to hyperglycemia. The reactive oxygen species oxidize the cofactors of the nitric oxide synthase, diminishing their active forms and consequently leading to a decreased NO production. Furthermore the decreased concentration of reduced glutathione results in a diminished production of nitrosoglutathione. These molecules are important intermediates of the NO pathway and physiologically activate the soluble guanylate cyclase. Their decrease in oxidative states of the cell, therefore, leads to a reduced cGMP production which represents the principal molecule that carries out NO's major effects. Finally we considered the eventual therapeutic strategies to improve NO bioavailability by acting on the causes of its decrease. Therefore the treatments proposed are based on the possibility to counteract the oxidation and, in this context, the physiopathological mechanisms strongly support the treatment with thiols. PMID- 21235456 TI - Old and new gasotransmitters in the cardiovascular system: focus on the role of nitric oxide and hydrogen sulfide in endothelial cells and cardiomyocytes. AB - The functional relevance of nitric oxide (NO) in the cardiovascular system is well established since the end of the 80', when it was firstly proposed as a key controller of vasodilation. More recent evidences, still debated and partly conflicting, point to a role of NO in the angiogenic progression. On the other hand hydrogen sulfide is a new entry as a gasotransmitter in the cardiovascular system. The variety of its biological functions seems to grow day after day. The first to be described is surely its reversible and poisoning binding of the cytochrome c oxidase that leads to impairment of the respiratory chain in mitochondria. However, sub-toxic concentrations have been later proved to be essential to maintain fundamental physiological functions in several tissues. The basal production of H2S is determined by the activity of, at least, three constitutively expressed enzymes (CBS, CSE, and 3-MPT) with tissue specificity for CBS and CSE in the central nervous and cardiovascular system, respectively. The assumption of a pivotal role of H2S in regulating physiological function is supported by the demonstration that reduced production of this gaseous molecule by CSE induces hypertension in mice. The increasing number of studies showing the regulatory functions of H2S reveals that maintaining the normal blood pressure levels is only one of its multiple biological actions. In this review, we would like to explore the recent literature on NO and H2S roles on cardiovascular system and to elucidate potential outcomes in the use of pharmacological drugs interfering with their metabolism. PMID- 21235457 TI - Current developments in the therapeutic potential of S-nitrosoglutathione, an endogenous NO-donor molecule. AB - Nitric oxide (NO) has a role in many physiological processes and its decreased concentration can lead to several pathophysiological events, therefore it is of considerable importance to find and to characterize suitable NO-donors for clinical use. S-nitrosothiols (RSNOs) are promising candidates for such therapeutics because these molecules do not appear to induce tolerance and were shown to be effective in several disease models. One of the main endogenous nitrosothiols is S-nitrosoglutathione (GSNO), which was tested as a therapeutic agent in 15 human investigations with good results. Despite the proven benefits of GSNO this molecule is not yet present in any pharmaceutical composition. The problem with the use of nitrosothiols is their fast and often unpredictable rate of decomposition in aqueous solutions. In this article we review current developments in the field which relate to the clinical applications of GSNO and other nitrosothiols in indications such as asthma, cystic fibrosis, embolization prevention or diabetic leg ulcers. The review focuses on the chemical and biological data which support the therapeutic use of GSNO and highlights areas where further research is needed. PMID- 21235458 TI - Exercise-induced modulation of endothelial nitric oxide production. AB - In the arterial wall nitric oxide (NO) is the key transmitter for endothelium dependent regulation of vascular tone. It is produced in intact endothelial cells by endothelial NO synthase (eNOS) as the key enzyme from L-arginine. Endothelial NO generation is highly regulated by mechanical, humoral, and metabolic factors. The regulation of NO synthesis occurs at different levels: ENOS gene polymorphisms are related to eNOS expression and activity and may potentially increase coronary event rate, mRNA expression is influenced by estrogen status and shear stress, mRNA stability is enhanced by vascular endothelial growth factor (VEGF), and final enzyme activity is regulated by the phosphorylation status at serine/threonine residues. Released from endothelial cells NO is rapidly transported to the neighboring vascular smooth muscle cells (VSMCs), where it induces the production of cGMP as a second messenger. CGMP in turn increases Ca2+ uptake into intracellular calcium stores thereby lowering [Ca2+]i and inducing VSMC relaxation and vasodilation. On its way to the VSMCs NO may be prematurely degraded by reactive oxygen species. On the other hand, chronic endurance exercise with regular bouts of increased laminar flow along the endothelium has the potential to increase eNOS mRNA expression and phosphorylation via AKT (protein kinase B) and to reduce oxidative stress by improving antioxidative protection. The growing knowledge about the complex regulation of NO synthesis and degradation in cardiovascular diseases and its response to exercise has led to a new understanding of the protective effects of long-term habitual physical activity against atherosclerotic heart disease and vascular aging. PMID- 21235459 TI - Cardiovascular risk and endothelial dysfunction: the preferential route for atherosclerosis. AB - The vascular endothelium plays a pivotal role in the maintenance of vessel wall integrity. In this regard, endothelial cells actively regulate vascular reactivity by responding to mechanical forces and neurohormonal mediators by releasing a variety of relaxing and contracting factors. Nitric oxide (NO), an endogenous gas synthesized by NO synthases (NOSs) is the main endothelium-derived vasodilator. Continuous production of NO by constitutive NOS maintains the vasculature in a state of vasodilation, whereas its phasic generation by inducible NOS can acutely dilate an artery in response to either physiological or pathological stimuli. Under homeostatic conditions, the endothelium maintains normal vascular tone and blood flow, and there is little or no expression of proinflammatory factors. However, both traditional and novel cardiovascular risk factors initiate a chronic inflammatory process that is accompanied by a loss of vasodilator and antithrombotic factors and an increase in vasoconstrictor and prothrombotic products. Furthermore, increased oxidative stress may result in a complete derangement of the NO system, with decreased NO bioavailability and a paradoxical NOS-related oxidant generation. Because of the antiatherogenic, antithrombotic properties of NO and the proatherogenic prothrombotic actions of endogenous oxidants, a decreased NO bioavailability with increased oxidative stress will result not only in impaired endothelium-dependent vasorelaxation but also in the acceleration of atherogenesis and onset of acute atherotrombotic events. The concepts of "endothelial dysfunction" and "endothelial activation" referring to different alterations in endothelial phenotype, may contribute to the development and clinical expression of atherosclerosis. PMID- 21235460 TI - Novel agents for the acute conversion of atrial fibrillation: focus on vernakalant. AB - Vernakalant is a novel anti-arrhythmic drug, recently approved for the cardioversion of recent-onset atrial fibrillation. Its action is mainly due to the blockade of atrial-selective channels responsible of the ultra-rapid delayed rectifier current I(Kur), but has also important interactions with other channels and currents, such as I(Na) (inward sodium current), and I(KACh) (acetylcholine regulated potassium current). Due to the relatively selective blockade of the I(Kur), vernakalant prolongs the effective refractory period of the atria with minimal effects on the ventricles, thus minimizing the risk of proarrhythmia. Thus far vernakalant has been tested in three placebo-controlled trials (ACT I, ACT II and ACT III) and in one amiodarone-controlled study (AVRO). Vernakalant has been demonstrated more effective than both placebo and amiodarone for the rapid conversion of atrial fibrillation, without significant adverse events. This article will review the recent patents on this novel atrial-selective agent, discussing its mechanisms of action and possible clinical applications in the real-world practice. PMID- 21235461 TI - Drug utilization 75% (DU75%) in 17 European hospitals (2000-2005): results from the ESAC-2 Hospital Care Sub Project. AB - The study aimed to assess 75% of drug utilization (DU75%) in participating hospitals and identify quality indicators which should be used to monitor performance within the hospitals. In the European Surveillance of Antimicrobial Consumption (ESAC; http://www.esac.ua.ac.be) project anatomic therapeutic chemical (ATC), defined daily dose (DDD) and route of administration (RoA) were used for drug categorization. Data were collected for: antibacterials for systemic use; intestinal antibiotics; rifampicin; and nitroimidazole derivatives. Each hospital's annual data were analyzed separately (hospital-year) adding up to a total of 97 hospital-year data-sets. The drug most persistently present within DU75% was ciprofloxacin (84/97 hospital-years). Co-amoxiclav was the drug which most frequently ranked first (28 times). The number of drugs constituting the DU75% by substance ranged from 7-15 (median 12) and 8-19 (median 15) by RoA which identified oral amoxicillin most frequently ranking first (17 times). In many hospitals the oral route accounted for most of the DU75%. Therefore, the extent of oral use was identified as a quality indicator which could be monitored using DU75% methodology. Since substantial variation both in extent and distribution of antibiotic use was observed, DU75% methodology is best adapted for intra-hospital consumption trend analyses or for hospitals with comparable characteristics and formularies. The number of drugs within DU75% was identified as another quality indicator. Thus, aspiring to decrease the consumption of overused drug classes should be set by the hospitals as a quality indicator on prescribing patterns. PMID- 21235462 TI - Proton pump inhibitors in pediatrics: evaluation of efficacy in GERD therapy. AB - Gastroesophageal reflux (GER) is defined as the passage of gastric contents into the esophagus. It occurs in healthy infants and can be considered physiological process. Uncomplicated GER can present with recurrent vomiting or regurgitation without any other symptoms and is usually managed by educating, reassuring, and guiding the parent without other intervention. GER disease (GERD) refers to the appearance of troublesome symptoms or complications (erosive esophagitis, ulceration, Barrett's esophagus) and may warrant acid suppression. Proton Pump Inhibitors (PPIs) are the most effective pharmacologic agents available for the treatment of children with GERD. In the pediatric practice only omeprazole, lansoprazole and esomeprazole are available over the first year of life. The empiric use in infants with nonspecific symptoms (excessive crying, regurgitation, feeding refusal, chronic cough) is frequent without randomized controlled study. Our paper will focus on the correct indications, dosages, duration of treatment and safety of PPI use in pediatric population. PMID- 21235463 TI - Bronchodilator combination therapy for the treatment of chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, and its prevalence is rising worldwide. Bronchodilators remain the cornerstone of COPD treatment, especially inhaled beta2-adrenergic receptor agonists and inhaled anticholinergics. Long-acting bronchodilators are considered more effective and convenient than short-acting bronchodilators for the maintenance treatment in patients with moderate to very severe COPD. There are currently 3 long-acting inhaled bronchodilators available in the United States: the beta2-adrenergic receptor agonists formoterol and salmeterol, and the anticholinergic, tiotropium. All 3 long-acting bronchodilators have been shown to be effective and well tolerated for the management of patients with stable COPD in clinical studies. The combination of beta2-adrenergic receptor agonists and anticholinergics has been shown to provide superior bronchodilatory effect than either agent alone, possibly because of different mechanisms of action of these agents. The current treatment guidelines recommend the use of one or more long acting bronchodilators for patients with moderate to severe stable COPD who remain symptomatic with single-agent bronchodilator therapy. The objective of this article is to review clinical data on combined bronchodilator therapy with beta2-adrenergic receptor agonists and anticholinergics in patients with COPD. PMID- 21235464 TI - Pharmacodynamic biomarkers in model-based drug development in oncology. AB - INTRODUCTION: Model-based drug development (MBDD) is recognized as an initiative able to improve success rates in the development of new anti-cancer agents. The use of pharmacodynamic (PD) biomarkers may be valuable in this context. The implementation of biomarkers in MBDD in oncology is the subject of this review. METHODS: Literature was searched for articles and relevant conference abstract concerning application of biomarkers in MBDD in oncology. First, papers are discussed concerning the use of biomarkers in modeling and simulation analyses in preclinical and early clinical phases of drug development. Subsequently, articles concerning late-stage clinical drug development are discussed. RESULTS: Only a limited set of articles and conference presentations were identified. As expected, the majority of publications are concerned with targeted anti-cancer drugs. In the early development of novel anti-cancer agents, most publications are concerned to the evaluation of dosing regimens for further clinical evaluation, or the identification of the required levels of target modulation. In general, combined analysis of clinical and preclinical data provide the most informative analyses. The use of biomarkers in late-stage drug development has mainly been confined to the prediction of phase III outcome on the basis of tumor growth data obtained from phase II trials, with tumor growth as biomarker for outcome. CONCLUSION: The use of suitable biomarkers in MBDD, has shown its merits in oncology, especially in early clinical development. Considering the low number of reports in literature, we would propose a more active use of presented techniques during all developmental phases of new anticancer agents. PMID- 21235465 TI - Comparative bioavailability study of a new formulation of injection of 75 mg diclofenac sodium in 1 ml with the conventional injection of 75 mg diclofenac sodium given in 3 ml volume. AB - OBJECTIVES: Diclofenac a non-steroidal anti-inflammatory drug (NSAID) is widely used for the management of various musculoskeletal conditions. An injectable test formulation of diclofenac sodium (75 mg/mL) was prepared to facilitate reduction in injection volume as compared to already marketed formulations of diclofenac sodium (75 mg/3 mL). The objective of this study was to compare the bioavailability of test formulation with the reference formulation given intramuscularly in healthy volunteers. METHODS: This two way randomized crossover study was performed in 14 healthy, adult, Indian, male human subjects to compare bioavailability. The formulations were administered intramuscularly (intragluteal) to the volunteers in a two way randomized fashion with a wash out period of 6 days. Blood samples were collected till 6.0 h following drug administration. The samples were analyzed using pre-validated HPLC method. RESULTS: The mean Cmax and Tmax for the test and reference formulations were 2.14 ug/mL, 1.91 ug/mL and 0.49 h, 0.50 h respectively. The mean AUC(0-t) for test and reference formulations were 3.79 ug.h/mL, and 3.43 ug.h/mL respectively. The mean AUC(0-gamma) for test and reference formulation were 4.03 ug.h/mL and 3.65 ug.h/mL respectively. The mean (90% CI) C(max), AUC(0-t) and AUC(0-gamma) ratio (Test:Reference) were 1.15 (100.25-132.99), 1.10 (100.34-119.96) and 1.09 (100.78 118.88), respectively. CONCLUSION: The test formulation shows a comparable AUC(0 t) and AUC(0-gamma) but a higher C(max) in comparison to the reference when given intra-gluteally. The lower volume of the test formulation offers advantage of injection at other sites, like deltoid region. Absence of propylene glycol in the test formulation could be advantageous in terms of improved tolerability. Hence, such formulations of previously well established molecules provide a new direction towards developing better and convenient dosing alternatives. PMID- 21235466 TI - Tigecycline treatment of critically ill patients: the LatinUser experience. AB - Tigecycline is the first of a new class of antibiotics named glycylcyclines and it was approved for the treatment of complicated intra-abdominal infections and skin and skin structure infections and community-acquired bacterial pneumonia. Notwithstanding this, the tigecycline's pharmacological and microbiological profile encourage physicians' use of the drug in other infections. The aim of this study was to characterize the indications type, pathogens, and outcomes of patients who were treated with tigecycline. We analyzed the tigecycline prescriptions in 209 patients in 23 Latin American centres using an electronic form included in the website LatinUser (http://www.clinicalrec.com.ar). Sixty-six patients (31.5%) received tigecycline for approved indications, and 143 (68.5%) for "off label" indications (47% with scientific support and 21.5% with limited or without any scientific support). The most frequent "off label" use was ventilator-associated pneumonia (VAP) (76 patients). The etiology of infections was established in 88 patients (42%). Acinetobacter spp. (54.5%, in 65% of cases carbapenems-resistant), methicillin-resistant Staphylococcus aureus (12%), and extended spectrum beta-lactamases-producing Enterobacteriaceae (10%) were the most common microorganisms isolated. Overall, attending physicians reported clinical success in 144 of the 209 patients (69%). Global mortality proportion was 35,5% (74/209 patients). Our study shows that the off label use of tigecycline is frequent, especially in VAP due to multidrug-resistant pathogens, where the therapeutic options are limited (eg: carbapenems-resistant Acinetobacter spp.). Physicians must evaluate the benefits/risks to use this antibiotic for indications that lack rigorous scientific support. PMID- 21235467 TI - A comprehensive literature search: drugs as possible triggers of Takotsubo cardiomyopathy. AB - BACKGROUND: Takotsubo cardiomyopathy (TCM) is a syndrome of transient cardiac dysfunction precipitated by intense emotional or physical stress. Excessive sympathetic stimulation is believed to be central to the pathogenesis of this condition, thus drugs with sympathetic effect could precipitate TCM. The aim of this study was to conduct a comprehensive literature search to identify drugs that could precipitate TCM. METHODS: Published case reports of TCM associated with drug-used were identified by a comprehensive literature search using the Medline/PubMed database, from January 1990 to November 2010. Search terms included Takotsubo cardiomyopathy, Tako-tsubo cardiomyopathy, stress cardiomyopathy, transient-left-ventricular ballooning syndrome, ampulla cardiomyopathy, apical ballooning syndrome, OR broken heart syndrome; together with "iatrogenic", "drug-induced", OR "induced by". Only publications in English or Spanish, in Humans, and with links to full text were retrieved. Then, articles that recognized any drug as a possible drug-induced TCM were selected. Additionally, citation lists from identified articles were subsequently reviewed to identify additional relevant articles. RESULTS: Overall, 401 different references were retrieved and 42 selected. Additionally, 5 articles were identified from citation list of selected articles. Thus, 47 articles with one report of more drugs as a possible trigger of 58 cases of SCM were reviewed, in which 20 different drugs were recognized as possible drug-induced TCM. CONCLUSION: There are some reports that linked the drug-used, mainly associated to sympathetic overstimulation, with the development of TCM. Consequently, drug induced TCM would be considered in patients with TCM, particularly those in which no clear emotional or stress trigger could be identified. PMID- 21235468 TI - Polycaprolactone fibres as a potential delivery system for collagen to support bone regeneration. AB - Poly(epsilon-caprolactone) (PCL) is biocompatible, non-immunogenic and non-toxic, and slowly degrades, allowing sufficient time for tissue regeneration. PCL has the potential for application in bone and cartilage repair as it may provide the essential structure required for bone regeneration, however, an ideal scaffold system is still undeveloped. PCL fibres were prepared using the gravity spinning technique, in which collagen was either incorporated into or coated onto the 'as spun' fibres, in order to develop novel biodegradable polymer fibres which will effectively deliver collagen and support the attachment and proliferation of human osteoblast (HOB) cells for bone regeneration. The physical and mechanical characteristics and cell fibre interactions were analysed. The PCL fibres were found to be highly flexible and inclusion of collagen did not alter the mechanical properties of PCL fibres. Overall, HOB cells were shown to effectively adhere and proliferate on all fibre platforms tested, although proliferation rates were enhanced by surface coating PCL fibres with collagen compared to PCL fibres incorporating collagen and PCL-only fibres. These findings highlight the potential of using gravity spun PCL fibres as a delivery platform for extracellular matrix proteins, such as collagen, in order to enhance cell adherence and proliferation for tissue repair. PMID- 21235469 TI - Development and evaluation of stavudine loaded injectable polymeric particulate systems. AB - Present research investigates the formulation of stavudine loaded biodegradable microspheres from different grades of Poly (D, L Lactide-co-glycolide) as a depot system for parenteral delivery. Prolonged release of stavudine facilitates reduction in symptoms of HIV infection and delay AIDS progression by reducing viral load to undetectable levels. Microspheres were prepared from PLGA 85:15 and PLGA 50:50 (RESOMER((r)) 505H) by solvent evaporation technique with different drug/polymer ratios (1:4, 1:10, 1:20, 1:50, 1:100) and a polymer solution/vehicle ratio of 1:2. The effects of various formulation variables like polymer type and concentration, surfactant concentration and drug to polymer ratio on the characteristics of microspheres were evaluated. All thirteen formulations of microspheres were evaluated for yield, entrapment efficiency, particle size and In vitro release studies. Microspheres were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), residual solvent analysis and confocal laser scanning microscopy (CLSM). Microspheres showed excellent surface topography with uniform distribution and structural integrity of the drug. Resulting microspheres showed the maximum entrapment efficiency of 68.0 +/- 1.62% and mean particle diameter below 100u. Drug release kinetics data were obtained from various kinetic models and best explained by "Higuchi Kinetic" i.e. drug release was largely governed by diffusion through water-filled pores in the matrix. Korsmeyer-Peppas equation depicted that drug release mechanism is anomalous transport, i.e. diffusion as well as polymer relaxation. Drug release from microspheres exhibited the characteristic release pattern of a monolithic matrix system with a maximum of 80 90% drug release in 6-8 weeks demonstrating the feasibility of prolonged delivery of stavudine using biodegradable microspheres for parenteral depot system. PMID- 21235470 TI - Direct compression high functionality excipient using coprocessing technique: a brief review. AB - Tablets are still the most commonly used dosage form because of the ease of manufacturing, convenience in administration, accurate dosing and excellent stability. Direct compression is the preferred method for the preparation of tablets. However, it has been estimated that less than 20 percent of the active pharmaceutical ingredients (API) can be processed into tablets via direct compression since the majority of API lack the flow, cohesion or lubricating properties required for direct compression. Increasing trends toward direct compression suggests the need for development of high functional excipients. High functionality of excipients can be obtained by development of new excipients or by particle engineering of existing excipients. Particle engineering using coprocessing provides a way to obtain an excipient with high functionality. Coprocessed excipients are the mixture of two or more excipients interacting at sub-particle level; that can provide an excipient with improved functionality as well as masking undesirable properties. Coprocessing is very cost effective method of providing high functional excipient. The present review discusses the advantages of coprocessed excipients, role of material science in coprocessing, methods of coprocessing of excipients and properties of various coprocessed excipients available in the market. PMID- 21235471 TI - Paclitaxel loaded nanosponges: in-vitro characterization and cytotoxicity study on MCF-7 cell line culture. AB - Beta cyclodextrin (beta-CD) based nanosponges were synthesized and paclitaxel inclusion complex with nanosponges were prepared using techniques of inclusion complex formation. The paclitaxel nanosponge's complexes were evaluated for their release. The nanosponges complexes were also evaluated using DSC, FTIR, and NMR techniques for confirmation of inclusion complex formation between paclitaxel and nanosponges. Particle size and morphology of paclitaxel nanosponge's complex were estimated using SEM, TEM and dynamic light scattering techniques. The particle sizes were found out to be in range of 400 to 600 nm. Cytotoxic efficacy of paclitaxel nanosponge complex was determined against MCF-7 cells and paclitaxel nanosponge's complex was found to be cytotoxic and more effective against this cell line. PMID- 21235472 TI - Interactions between novel terpenes and main components of rat and human skin: mechanistic view for transdermal delivery of propranolol hydrochloride. AB - The purpose of this study was to investigate the effectiveness and mechanism(s) of percutaneous absorption of propranolol hydrochloride (PHCL) across rat and human cadaver skin using seven novel terpenes with reference to marker terpene 1,8-cineole. In-vitro skin permeation studies were carried out via rat and human skin models. The mechanism of skin permeation of PHCL by terpenes was evaluated by FTIR, DSC, activation energy measurement and histopathological examination. Amongst the new terpenes, 1,4-cineole was found to be most effective enhancer for diffusion of PHCL through rat skin (ER=3.07) and human cadaver skin (ER=2.42) as compared to control. FTIR spectra and DSC thermogram of skin treated with aforesaid terpenes indicated that permeation occurred due to the disruption of lipid bilayers. No apparent skin irritation (erythema, edema) was observed on treatment of skin with terpenes, the irritation was higher with the beta citronellene and rose oxide. It was concluded that 1,4-cineole can be successfully used as potential permeation enhancer for PHCL. It enhanced the absorption of hydrophilic drug by extraction and disruption of lipid bilayers and keratin denaturation of stratum corneum. PMID- 21235473 TI - Aerosol delivery of antimicrobial agents during mechanical ventilation: current practice and perspectives. AB - Critically ill patients, who develop ventilator-associated pneumonia during prolonged mechanical ventilation, often require antimicrobial agents administered through the endotracheal or the tracheotomy tube. The delivery of antibiotics via the respiratory tract has been established over the past years as an alternative route in order to deliver high concentrations of antimicrobial agents directly to the lungs and avoid systemic toxicity. Since the only formal indications for inhaled/aerosolized antimicrobial agents is for patients suffering from cystic fibrosis, consequently the majority of research and published studies concerns this group of patients. Newer devices and new antibiotic formulations are currently off-label used in ambulatory cystic fibrosis patients whereas similar data for the mechanically ventilated patients do not yet exist. PMID- 21235474 TI - Dynamics of dissolution and diffusion-controlled drug release systems. AB - Analytical expressions were derived to explain the influence of the dissolution/diffusion number (Di) on the time constant and steady-state flux when dispersed drugs are released from a finite matrix. A key novelty of this work is the introduction of a single time-constant that combined the analysis of both dissolution- and diffusion-based systems. Focus is placed on systems with a constant dissolution rate and diffusion coefficient. Solutions, based on the residue theorem, were in agreement with published results describing the transport of estradiol in a polymeric matrix. The experimental cumulative amount of drug released was 0.1 mg/cm2 in 100 hours compared to 0.084 mg/cm2 predicted by the theoretical model. The process time constant, estimated from the first eigenvalue (t0) and a more accurate statistical approach (t(eff)), showed a consistent decrease with increasing Di values. For a dissolution/diffusion number of 0.21, t0 and t(eff) were estimated at 58.44 and 73.02 hrs, respectively. With the presence of a skin layer, t(eff) increased to 575.7 hrs. These results can be used to assess the relative impact of dissolution and diffusion on the time it takes drugs to attain a therapeutic level in the bloodstream. PMID- 21235475 TI - Formulation and evaluation of extended release asymmetric membrane capsules of atenolol. AB - The objective of this study was to demonstrate that the asymmetric membrane capsule can be used to deliver a poorly water soluble drug with a pH dependent solubility such as atenolol for extended periods of time by modulating solubility with organic acid. In osmotic systems, the release rate of an excipient relative to the release rate of the drug is an important factor that determines the duration of drug release. Consequently, for maintaining the desired pH over the entire period of drug dissolution a suitable thickening and suspending agent can be incorporated. By optimizing the concentration of thickening agent, it is possible to extend the availability of pH modifier in the core to provide an osmotic driving force or solubilization over the entire delivery period, so that the desired profile can be achieved for an active agent that has lower solubility characteristics. Finally, it was observed that the release rate of atenolol was influenced by the concentration of citric acid, mannitol and hydroxypropyl methylcellulose (HPMC). Results of scanning electron microscopy studies showed the formation of pores in the membrane from where the drug release occurred. The optimal formulation was found to be able to deliver atenolol at the rate of approximate zero-order up to 24 h, independent of pH of release media and agitation rate. PMID- 21235476 TI - Newer approaches for optimal bioavailability of ocularly delivered drugs: review. AB - Eye diseases can cause discomfort and anxiety in patients, with the ultimate fear of loss of vision and facial disfigurement. Many regions of the eye are relatively inaccessible to systemically administered drugs and, as a result, topical drug delivery remains the preferred route in most cases. Drugs may be delivered to treat the precorneal region for conjunctivitis and blepharitis, or to provide intraocular diseases such as glaucoma, uveitis, and cytomegalovirus retinitis. Most of the ophthalmic formulation strategies aim at maximizing ocular drug permeability through prolongation of the drug residence time in the cornea and conjunctival sac, as well as minimizing precorneal drug loss. The conventional topical ocular drug delivery systems show drawbacks such as increased precorneal elimination and high variability in efficacy. Attempts have been made to overcome these problems and enhance ocular bioavailability by the development of newer drug delivery systems. This review is concerned with classification, recent findings and applications and biocompatibility of newer drug delivery systems for the treatment of ocular diseases. PMID- 21235477 TI - Assessment of short-term changes induced by a Dermatophagoides pteronyssinus extract on asthmatic patients. Randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Once the optimal dose is reached, subcutaneous immunotherapy [SCIT] with mite extract is capable of reducing symptoms and the need for rescue medication. OBJECTIVE: To assess the capacity of a subcutaneous extract of mites [D. pteronyssinus] to bring about a reduction in concomitant medication as well as in vivo and in vitro changes in just 2-3 months of treatment in patients with allergic asthma. METHODS: A total of 45 patients with persistent mild-moderate allergic asthma due to sensitisation to D. pteronyssinus were included in a multi centre, double-blind, placebo-controlled trial. Length of treatment was 4 months. After a period for adjusting medication in order to classify asthma severity appropriately, patients were commenced on treatment of 400 or 800 g/day of budesonide as concomitant medication. RESULTS: After 4 months of treatment there were no significant changes in the budesonide dose between the active group and the placebo group. In the active group there was a significant difference between active and placebo group in sIgG4 [p=.0003], as well as a significant increase in the cutaneous tolerance index [2.81, CI 95%: 1.29 - 7.48, which was significant with a Confidence Interval of 95%]. These changes were not observed in the placebo group. CONCLUSION: After just 4 months of treatment, SCIT was capable of inducing in vivo and in vitro changes, but these changes were not reflected in improved clinical outcome within the first 4 months of therapy. PMID- 21235478 TI - Foam preparations for the treatment of ulcerative colitis. AB - Patients with ulcerative colitis uniformly have disease involving the distal colon. When patients have disease limited to the left colon or symptoms suggestive of active rectal inflammation, guidelines recommend topical rectal therapies as first-line agents either as monotherapy or in conjunction with oral products. Rectal delivery modalities offer the advantage of delivering high local concentrations of active medication to the site of maximal inflammation with minimization of systemic side effects. Methods of rectal administration include suppositories, liquid enemas and foams. Suppositories are limited to the treatment of rectal disease, and patients often have difficulty retaining the liquid enema secondary to its high volume and consistency. Rectal foams reliability extend to the descending and sigmoid colon with application. Foams are further characterized by increased viscosity, lower volumes, finer dispersion on the colonic mucosa, and increased adhesiveness to the colonic mucosa compared with liquid enemas. Additionally, rectal foam agents demonstrate equal efficacy to their liquid enema counterparts yet consistently yield better patient tolerance, lower incidence of side effects, and increased patient acceptability. Currently available agents include 5-aminosalicylic acid and corticosteroids, both first and newer generation. This review focuses on clinical trials assessing efficacy, tolerability, and patient preferences for these agents as well as describing the currently available rectal foam products. PMID- 21235480 TI - Microwave assisted synthesis and evaluation of modified pea starch as tablet superdisintegrant. AB - In the present study, cross linked sodium carboxymethylated pea starch (SCPS) was synthesized and evaluated as tablet superdisintegrant in diclofenac sodium based tablets. SCPS was synthesized using native pea starch with monochloroacetic acid and NaOH in microwave radiation environment. Finally the dried product was cross linked with phosphorous oxychloride, which produced granular highly swellable starch. SCPS with degree of substitution of 0.34 was formed and it was further evaluated as superdisintegrant in diclofenac sodium based tablets. Diclofenac sodium tablets were prepared by direct compression method with 2, 4, 6 and 8%w/w of SCPS as superdisintegrant and further comparatively evaluated for in vitro disintegration and dissolution study with Sodium starch glycolate containing tablets as reference. The results revealed that SCPS could be a promising superdisintegrant for immediate release tablets in concentration dependant manner. PMID- 21235479 TI - Characterization and in vitro evaluation of intestinal absorption of liposomes encapsulating zanamivir. AB - Zanamivir is currently used for the treatment of H1N1 and H5N1 influenza viruses. Due to its highly hydrophilic property, zanamivir has poor oral bioavailability. Liposomal formulations are known to improve oral absorption of hydrophilic drugs. The present study investigates the effect of liposomes encapsulating zanamivir on the permeation of zanamivir across Caco-2 monolayers. Among the formulations studied, neutral liposomes composed of Phospholipon((r)) 90 G and cholesterol at molar ratio of 7:3 gave the highest entrapment efficiency of zanamivir. The extrusion of liposomes loading zanamivir (LZV) resulted in the reduced-size liposomal zanamivir (RLZV), which had mean diameter at 283+/-42 nm and gave higher encapsulation efficiency of zanamivir at 34.69+/-6.37% compared to 28.32+/ 5.25%. Transport studies across Caco-2 cell monolayers showed that the apparent permeation coefficients (P(app)) of LZV and RLZV were respectively 2.2- and 3.0 fold greater than that of zanamivir solution. The P(app) of RLZV was 1.4-fold higher than that of LZV. On the basis of these results, liposomes are able to improve permeability of zanamivir across the Caco-2 monolayers, thereby possibly enhancing oral bioavailability of zanamivir. PMID- 21235481 TI - Erythropoietin encapsulation in chitosan nanoparticles and kinetics of drug release. AB - Recombinant human erythropoietin (rHu-EPO) is a glycoprotein, which is produced commercially from Chinese hamster ovary (CHO) cells. It is used for the therapy of renal anemia and chemotherapy-induced anemia in cancer patients. Recent evidence suggests that rHu-EPO exerts tissue protective effects via multiple mechanisms which include inhibition of apoptosis, promotion of angiogenesis and decreased inflammation. After intravenous (i.v.) injection, the blood concentration of rHu-EPO rapidly decreases due to proteolysis resulting in a relatively short half-life of 8.5 h, which necessitates regular dosing with intervals that do not exceed 7 days. It would be desirable to develop an encapsulated formulation providing controlled release of rHu-EPO to maintain therapeutic concentrations in plasma, and for potential tissue protective applications to maintain high local therapeutic concentrations in tissue while minimizing potential unwanted systemic effects such as polycythemia and platelet activation, both of which can predispose to intravascular thrombosis. Nanoparticle encapsulation of rHu-EPO can also allow for direct injection at sites of injury in specific tissues/organs, again minimizing systemic exposure of the drug. In this paper, we report the production of biopolymer nanoparticles by ionotropic gelation of chitosan with tripolyphosphate (TPP). The nanoparticle size distribution in aqueous solution was determined and rates of rHu-EPO release from chitosan-TPP nanoparticles were measured in PBS at 37 degrees C. It was observed that almost 30% of the encapsulated rHu-EPO was released within the first 48 hours and thereafter a linear release profile was observed for up to 2 weeks. Total drug release over 15 days was 63% of the initial amount. PMID- 21235482 TI - A novel rhodobacter sphaeroides expression system for real-time evaluation of heterologous protein expression levels. AB - Heterologous protein expression levels can not be evaluated in real-time by experimental procedures commonly used for most expression systems during host cell culture. Rb. sphaeroides has provided an ideal system for studying both photosynthesis and membrane development and exhibited potential as a novel expression system. We constructed the puc1BA and puc2BA mutant strain Rb. sphaeroides CQU68 and used it as a novel expression system to heterologously express proteins fused to beta-subunit of light-harvesting 2 complexes (LH2). The presence of LH2 with beta-subunit fusion proteins was spectrally detected by the LH2 typical absorption at ~800 nm and ~850 nm, and the formation of these complexes were further confirmed by SDS-PAGE and Western blot analysis. The expression levels of heterologous protein measured by SDS-PAGE and Western blot turned out to be higher as the typical spectral peak heights increase. These findings suggested that the production of the heterologous protein could be rapidly detected through the LH2 absorption at ~800 nm and ~850 nm. Moreover, the typical absorption could be used as a monitor for rapid and real-time evaluation of heterologous protein expression levels. PMID- 21235483 TI - Expression, purification and characterization of the Escherichia coli integral membrane protein YajC. AB - Escherichia coli YajC is a small integral membrane protein with a single transmembrane helix. The gene yajC is part of the secD operon and the protein is identified in the SecDF-YajC complex. However, the exact function of YajC remains a mystery. While its function is usually discussed in the context of the SecDF YajC complex, studies have shown that SecD/F, rather than YajC, are essential for those functions. Recently YajC is identified as the mysterious protein that co crystallized with AcrB. To further investigate the structure of YajC, we expressed and purified the protein in a detergent solubilized state. The protein assumed a folded structure containing mixed alpha/beta secondary structures, consistent with the structural prediction. Using signal Cys mutations and thiol specific probes, we found the C-terminus of YajC was cytoplasmic, while the N terminus of YajC was buried in the membrane. In addition, we expressed and purified a truncated fragment of YajC that corresponded to the C-terminal cytoplasmic domain (YajC(CT)). YajC(CT) formed a compact structure rich in beta strands and existed as a trimer. PMID- 21235484 TI - Computer-based comparison of structural features of envelope protein of Alkhurma hemorrhagic fever virus with the homologous proteins of two closest viruses. AB - The aim of this study was prediction of epitopes and medically important structural properties of protein E of Alkhurma hemorrhagic fever virus (AHFV) and comparing these features with two closely relates viruses, i.e. Kyasanur Forest disease virus (KFDV) and Tick-borne encephalitis virus (TBEV) by bioinformatics tools. Prediction of evolutionary distance, localization, sequence of signal peptides, C, N O glycosylation sites, transmembrane helices (TMHs), cysteine bond positions and B cell and T cell epitopes of E proteins were performed. 2D-MH, Virus-PLoc, Signal-CF, EnsembleGly, MemBrain, DiANNA, BCPREDS and MHCPred servers were applied for the prediction. According to the results, the evolutionary distance of E protein of AHFV and two other viruses was almost equal. In all three proteins of study, residues 1-35 were predicted as signal sequences and one asparagine was predicted to be glycosylated. Results of prediction of transmembrane helices showed one TMH at position 444-467 and the other one at position 476-490. Twelve cysteines were potentially involved to form six disulfide bridges in the proteins. Four parts were predicted as B cell epitopes in E protein of AHFV. One epitope was conserved between three proteins of study. The only conserved major histocompatibility complex (MHC) binding epitope between three viruses was for DRB0401 allele. As there are not much experimental data available about AHFV, computer-aided study and comparison of E protein of this virus with two closely related flaviviruses can help in better understanding of medical properties of the virus. PMID- 21235485 TI - 3D domain swapping provides a minor alternative refolding pathway for ribonuclease A. AB - The C-terminal beta-hairpin of RNase A contains a turn with a cis Asn113-Pro114 peptide bond. Pioneering pulsed HX experiments have shown that the C-terminal beta-hairpin forms early during refolding. This is puzzling since the Asn113 Pro114 bond is predominately trans at this stage and this conformation destabilizes the native monomer. RNase A, when refolded at high concentration, forms a series of 3D domain-swapped oligomers. In the oligomers formed by C terminal beta-strand swapping, Asn113-Pro114 is trans and permits the formation of a new intersubunit beta-sheet. We hypothesize that oligomeric species with trans Asn113-Pro114 may form during refolding. Such species could account for the HX results while comfortably accommodating Asn113-Pro114 in the trans conformation. Here, we test this hypothesis by employing chromatographic methods to detect oligomers forming in refolding conditions and find significant amounts of dimer. We propose that a 3D domain-swapped dimeric intermediate provides a minor alternative pathway for RNase A refolding. PMID- 21235486 TI - Site-directed mutagenesis to identify key residues in structure-function relationship of winged bean chymotrypsin-trypsin inhibitor and 3-D structure prediction. AB - Winged bean chymotrypsin trypsin inhibitor (WbCTI) is a Kunitz type serine protease inhibitor that inhibits both trypsin and chymotrypsin at 1:1 molar ratio. Site-directed mutagenesis study was employed to generate two mutants of WbCTI, with an aim to explore its dual inhibitory properties against the proteases. The mutants were expressed in Escherichia coli and, were purified to homogeneity using a single step immunoaffinity column. The two mutants, each containing a single mutation at the amino acid sequence positions of 63 and 64, were named as L63A and R64A, respectively. Purified L63A-WbCTI exhibited anti trypsin activity with no anti-chymotrypsin activity whereas R64A-WbCTI could inhibit chymotrypsin but not trypsin. To investigate the binding interactions between the mutated forms of WbCTI with the putative proteases, binding studies were carried out using gel filtration chromatography which further confirmed the formation of enzyme-inhibitor complexes. Finally, 3D model structure of WbCTI was designed using computer simulations which further emphasize the roles of L63 and R64 residues for dual inhibitory characteristics of WbCTI. PMID- 21235487 TI - Comprehensive profiling of the low molecular weight proteins and peptides in weak cation exchange beads human serum retentate. AB - Mass spectrometric profiling using ProteinChip and magnetic beads has rapidly grown over the past years, particularly to generate serum profiles for cancer diagnosis. The molecular weights of these distinguishing peaks are usually under 30 kDa. To identify those low molecular weight proteins and peptides is important for specific assays to be developed and increases biological insight. In this study, low molecular weight proteins and peptides from serum were purified by a combination of weak cation exchange magnetic beads and high performance liquid chromatography. The purified proteins and peptides were analyzed by 1D SDS PAGE, SELDI and LC-MS/MS. 246 proteins were identified from the HPLC fractions by LC MS/MS. 95(38.62%) proteins were first identified in serum compare with Sys BodyFluid database. 11(11/96) proteins were documented cancer associated proteins. We also observed about 109 proteins/peptides in SELDI mass spectrum, and 13 of the SELDI features were identified. PMID- 21235488 TI - Predicting protein subcellular localization by pseudo amino acid composition with a segment-weighted and features-combined approach. AB - Information of protein subcellular location plays an important role in molecular cell biology. Prediction of the subcellular location of proteins will help to understand their functions and interactions. In this paper, a different mode of pseudo amino acid composition was proposed to represent protein samples for predicting their subcellular localization via the following procedures: based on the optimal splice site of each protein sequence, we divided a sequence into sorting signal part and mature protein part, and extracted sequence features from each part separately. Then, the combined features were fed into the SVM classifier to perform the prediction. By the jackknife test on a benchmark dataset in which none of proteins included has more than 90% pairwise sequence identity to any other, the overall accuracies achieved by the method are 94.5% and 90.3% for prokaryotic and eukaryotic proteins, respectively. The results indicate that the prediction quality by our method is quite satisfactory. It is anticipated that the current method may serve as an alternative approach to the existing prediction methods. PMID- 21235489 TI - Protein acyltransferase function of purified calreticulin: the exclusive role of P-domain in mediating protein acylation utilizing acyloxycoumarins and acetyl CoA as the acyl group donors. AB - The distinct biochemical function of endoplasmic reticulum (ER) protein Calreticulin (CR) catalyzing the transfer of acyl group from acyloxycoumarin to a receptor protein was termed calreticulin transacylase (CRTAase). The present study, unlike the previous reports of others utilizing CR-deficient cells alone, dealt with the recombinant CR domains of Heamonchus contortus (rhCRTAase) in order to examine their CRTAase activity. P-domain of rhCR unlike N- and C-domains was found to be endowed with CRTAase function. We have also observed for the first time acetyl CoA, as a substrate for rhCRTAase/P-domain mediated acetylation of recombinant Schistosoma japonicum glutathione S-transferase (rGST). rhCRTAase/P-domain were also found to undergo autoacylation by acyloxycoumarins. Also, the isolated autoacylated rhCRTAase/P-domain in non-denatured form alone exhibited the ability to transfer acyl group to rGST indicating the stable intermediate nature of acylated CR. P-domain catalyzed acetylation of rGST by 7,8 Diacetoxy-4-methylcoumarin or acetyl CoA resulted in the modification of several lysine residues in common was evidenced by LC-MS/MS analysis. The putative site of the binding of acyloxycoumarins with CR was predicted by computational blind docking studies. The results showed the involvement of two lysine residues Lys 173 and Lys-174 present in P-domain for binding acyloxycoumarins and acetyl CoA thus highlighting that the active site for the CRTAase activity would reside in the P-domain of CR. Certain ER proteins are known to undergo acetylation under the physiological conditions involving acetyl CoA. These results demonstrating CRTAase mediated protein acetylation by acetyl CoA may hint at CR as the possible protein acetyltransferase of the ER lumen. PMID- 21235490 TI - Sialic acid recognition of the pandemic influenza 2009 H1N1 virus: binding mechanism between human receptor and influenza hemagglutinin. AB - Quantum mechanical fragment molecular orbital calculations have been performed for receptor binding of the hemagglutinin protein of the recently pandemic influenza 2009 H1N1, A/swine/Iowa/1930, and A/Puerto Rico/8/1934 viruses to alpha2-6 linked sialyloligosaccharides, as analogs of human receptors. The strongest receptor binding affinity was observed for the 2009/H1N1pdm. The inter fragment interaction energy analysis revealed that the amino acid mutation of 2009/H1N1pdm, Ser145Lys, was a major cause of such strong binding affinity. Strong ionic pair interaction between the sialic acid and Lys145 was observed only in the 2009/H1N1pdm, in addition to the hydrogen bond between the sialic acid and Gln226 observed in all the HAs. Therefore, pandemic 2009/H1N1pdm has been found to recognize the alpha2-6 receptor much stronger than the 1930-swine and 1934-human. PMID- 21235491 TI - Glaucoma and aging. AB - Age is an established major risk factor for glaucoma that can be used along with other data to compute chances of developing glaucoma. This leading cause of blindness is becoming increasingly more prevalent in the aging population. The characteristic progressive degeneration of the optic nerve in glaucoma is primarily caused by increased intraocular pressure yet the cause for the reduced outflow is not well understood. Early diagnosis of glaucoma remains difficult. Classic treatment can delay progression of glaucomatous optic neuropathy by lowering intraocular pressure medically or surgically. Recent insights into the age-related molecular changes of the outflow tract and retinal ganglion cells have encouraged search for new treatment approaches. New findings suggest that age related tissue changes themselves contribute significantly and are not just associated. Interdisciplinary research will be necessary to advance understanding, diagnosis and treatment of this neurodegenerative disease that has been known for more than thousand years but to this date remains a challenge. PMID- 21235493 TI - Effects of a long-term treatment with an antioxidant pyridoindole on vascular responsiveness in diabetes-induced aging rats. AB - Impaired vascular reactivity is a hallmark of cardiovascular diseases induced by diabetes, which is also an accelerated aging model. This study was designed to investigate the effect of chronic treatment of stobadine, a pyridoindole antioxidant, on vascular responsiveness in diabetic animals. Age- (13-week old) and gender-matched Wistar rats were randomly divided into control and diabetic groups. Streptozotocin (55mg/kg, i.p.) was used to induce experimental diabetes. After induction of diabetes, rats were randomly assigned for receving stobadine (24.7 mg/kg/day, p.o.) or vehicle for 8-10 months. Stobadine treatment significantly reduced the severity of hyperglycemia, heart and kidney weights, systolic blood pressure, and attenuated diabetes-induced loss in body weight gain. Increased vasoconstriction responses to phenylephrine (PE; 10(-8)-10(-5) M) and BayK-8644 (3x10(-7)-3x10(-5) M) were significantly decreased by stobadine treatment in diabetes. Although stobadine treatment increased acetylcholine (ACh; 10(-9)-10(-5) M)-induced relaxation responses, sodium nitroprusside (10(-11)-10( 6) M)-induced relaxations were not affected by the treatment or diabetes. Stobadine treatment markedly reduced A23187 (10(-9)-3x10(-6) M)-induced relaxation responses while it remained unchanged in diabetics compared to controls. The transient vasoconstriction to PE was reduced by cyclopiazonic acid (10(-6) M) or thapsigargin (TH; 10(-6) M) in all groups. TH also inhibited the relaxation to ACh (3x10(-6) M) in control and stobadine-treated diabetic groups. These results suggest that antioxidative and Ca(2+) current regulatory effects of stobadine, contribute to the mechanisms responsible for its beneficial effects in aged diabetic rats. PMID- 21235494 TI - Role of the immune system in aging and longevity. AB - The aging process is a universal, intrinsic, progressive accumulation of deleterious changes in cells and tissues that increases morbidity and leads to death. The heterogeneity of the age-related physiological changes is shown by the "biological age", which determines the rate of ageing experienced by each individual and therefore his life expectancy. According to the recent theory of oxidation-inflammation to explain the aging process, the immune system seems to be involved in the chronic oxidative and inflammatory stress conditions of aging. It has been proposed that several age-related changes in immune cell functions, which depend on the redox state of these cells, could be good markers of health, biological age and longevity. In order to identify parameters of the functional and redox situation of immune cells as markers of biological age and predictors of longevity, we have studied those parameters in human healthy centenarians, in extreme long-living mice, as models of successful aging, and in immune cells from murine models of premature immunosenescence. The aim of the present work is to review the results in humans and rodents on those parameters and their relationship with biological age and longevity, as well as to propose several strategies of lifestyle useful to improve the immune function and thus to increase the mean life span. PMID- 21235492 TI - Vitamin E and all-cause mortality: a meta-analysis. AB - The current analysis reexamines the relationship between supplemental vitamin E and all-cause mortality. All randomized, controlled trials testing the treatment effect of vitamin E supplementation in adults for at least one year were sought. MEDLINE, the Cochrane Library, and Biological Abstracts databases were searched using the terms "vitamin E," "alpha-tocopherol," "antioxidants," "clinical trial," and "controlled trial" for studies published through April 2010; results were limited to English, German, or Spanish language articles. Studies were also obtained through reference mining. All randomized controlled trials using vitamin E, with a supplementation period of at least one year, to prevent or treat disease in adults were identified and abstracted independently by two raters. Mortality data from trials with a supplementation period of at least one year were pooled. The selected trials (n = 57) were published between 1988 and 2009. Sample sizes range from 28 to 39,876 (median = 423), yielding 246,371 subjects and 29,295 all-cause deaths. Duration of supplementation for the 57 trials range from one to 10.1 years (median = 2.6 years). A random effects meta-analysis produce an overall risk ratio of 1.00 (95% confidence interval: 0.98, 1.02); additional analyses suggest no relationship between dose and risk of mortality. Based on the present meta-analysis, supplementation with vitamin E appears to have no effect on all-cause mortality at doses up to 5,500 IU/d. PMID- 21235495 TI - Sensory-dependent knowledge in young and elderly adults: arguments from the cross modal priming effect. AB - The nature of knowledge, i.e. sensory-dependent or abstract, is controversial. Growing evidence supports the existence of sensory-dependent knowledge in young individuals, but this question remains unexplored in elderly individuals. Thus the first objective of this study was to assess sensory-dependent knowledge in normal aging using a cross-modal priming paradigm. The cross-modal priming is a way to verify the nature of knowledge. However, contradictory results are reported about the existence of a cross-modal priming effect in normal aging. One possible explanation for the controversial findings is the priming task difficulty that would require too much executive resources in elderly participants and would prevent them to obtain a priming effect. Therefore, the second objective was to assess the executive involvement in the priming task. The method was based on a cross-modal priming paradigm with familiar bimodal items. First, all the sound primes were presented. For half of them, a visual abstract mask was presented simultaneously. Then, all the visual targets were processed. A battery of neuropsychological tests was administered to assess the involvement of executive functions in the priming paradigm. The results demonstrated a priming effect in the young and elderly participants, but only for the primes presented without the visual mask. The mask interference demonstrated the perceptual nature of the priming effect which supports the sensory-dependent theory of knowledge. The executive functions were correlated with the priming task only in the elderly participants. These results therefore support the task difficulty hypothesis. PMID- 21235496 TI - Role of insulin signaling in the interaction between Alzheimer disease and diabetes mellitus: a missing link to therapeutic potential. AB - Diabetes mellitus (DM) is one of the major non-genetic risk factors for Alzheimer disease (AD). However, the mechanism by which DM increases the risk of AD has not been elucidated. Here, we summarize recent findings to address this question. Whereas neuropathological studies in humans suggest that DM does not increase Abeta accumulation in the brain (a major hallmark of AD), earlier works in animal models show that Abeta does accumulate. Therefore, alternate mechanisms might exist. Recent studies using the human brain indicate that insulin signaling is impaired in the AD brain. In neurons, this insulin signaling plays a key role in modulating synaptic function and neuronal senescence besides regulating tau phosphorylation, another hallmark of AD. On the other hand, in cerebrovessels, DM causes vascular remodeling, which involves increased RAGE (receptor for advanced glycation endproducts) expression, and AD is associated with cerebrovascular amyloid angiopathy (CAA). Our recent study involving AD mice with DM has revealed that a vicious circle underlies the interaction between AD and DM. Interestingly, in our mouse model, AD increased RAGE expression, and DM worsened CAA. The contribution of vascular factors such as RAGE expression and CAA to the impairment of insulin signaling will be discussed. This impaired insulin signaling might be a possible link between AD and DM. Moreover, insulin signaling is also involved in the mechanism of aging, decreasing with an increase in age. An identification of the mechanism whereby DM modifies the pathological condition of AD through the modulation of insulin signaling is required to develop potential therapeutics for AD not only with but also without DM. PMID- 21235497 TI - The role of cellular senescence during vascular calcification: a key paradigm in aging research. AB - Vascular calcification has severe clinical consequences and is considered an accurate predictor of future adverse cardiovascular events. Vascular calcification refers to the deposition of calcium phosphate mineral, most often hydroxyapatite, in arteries. Extensive calcification of the vascular system is a key characteristic of aging. In this article, we outline the mechanisms governing vascular calcification and highlight its association with cellular senescence. This review discusses the molecular mechanisms of cellular senescence and its affect on calcification of vascular cells, the relevance of phosphate regulation and the function of FGF23 and Klotho proteins. The association of vascular calcification and cellular senescence with the rare human aging disorder Hutchison-Gilford Progeria Syndrome (HGPS) is highlighted and the mouse models used to try to determine the underlying pathways are discussed. By understanding the pathways involved in these processes novel drug targets may be elucidated in an effort to reduce the effects of cellular aging as a risk factor in cardiovascular disease. PMID- 21235498 TI - Oxidative stress and skeletal muscle dysfunction with aging. AB - With advanced of age, production of reactive oxygen species increases in muscle tissues, which causes a continuous elevation of oxidative stress in the muscle. Such oxidative stress brings damage by oxidation of cell components such as lipids, proteins, and DNA. Growing evidences suggest that oxidative stress affects energy metabolism, protein degradation, and apoptosis in the muscle via transcriptional and posttranslation regulation of key proteins, which results in loss of muscle mass and metabolic dysfunction. On the other hand, regular exercise and proper nutrition containing some antioxidant can improve the muscle function by a reduction of excessive oxidative stress. This article describes the influence of oxidative stress on the progress of age-related muscle dysfunction and reviews the effect of countermeasures such as exercise and diet. PMID- 21235500 TI - Fungal model system to understand the mechanisms unravelling the oxidative stress response. PMID- 21235501 TI - Proteomic strategies for the analysis of carbonyl groups on proteins. AB - Oxidative stress is caused by an imbalance between formation and destruction of reactive oxygen species. Analysis of the reaction products of reactive oxygen species in biomolecules is an indirect way of determining the existence of oxidative stress. In this context, the formation of carbonyl groups in proteins has been one of the most studied oxidative stress markers because of its stability and easy detection. Various proteomic tools offer great potential for the discovery of new proteins susceptible to oxidative stress, determination of quantitative changes in the profile of these modifications under different biological conditions, and characterization of the type of modification it has suffered a particular protein. This paper reviews the different approaches used for the detection of protein carbonyls and the proteomic tools that can be used to identify them. PMID- 21235502 TI - Structural and functional diversity of glutaredoxins in yeast. AB - Glutaredoxins are defined as thiol disulfide oxidoreductases that reduce disulfide bonds employing reduced glutathione as electron donor. They constitute a complex family of proteins with a diversity of enzymatic and functional properties. Thus, dithiol glutaredoxins are able to reduce disulfide bonds and deglutathionylate mixed disulfides between glutathione and cysteine protein residues. They could act regulating the redox state of sulfhydryl residues of specific proteins, while thioredoxins (another family of thiol disulfide oxidoreductases which employ NADPH as electron donor) would be the general sulfhydryl reductants. Some dithiol glutaredoxins such as human Grx2 form dimers bridged by one iron-sulfur cluster, which acts as a sensor of oxidative stress, therefore regulating the activity of the glutaredoxin. The ability to interact with iron-sulfur clusters as ligands is also characteristic of monothiol glutaredoxins with a CGFS-type active site. These do not display thiol oxidoreductase activity, but have roles in iron homeostasis. The three members of this subfamily in Saccharomyces cerevisiae participate in the synthesis of the iron-sulfur clusters in mitochondria (Grx5), or in signalling the iron status inside the cell for regulation of iron uptake and intracellular iron relocalization (Grx3 and Grx4). Such a role in iron metabolism seems to be evolutionary conserved. Fungal cells also contain membrane-associated glutaredoxins structurally and enzymatically similar to dithiol glutaredoxins, which may act as redox regulators at the early stages of the protein secretory machinery. PMID- 21235503 TI - How budding yeast sense and transduce the oxidative stress signal and the impact in cell growth and morphogenesis. AB - The eukaryotic microorganism Saccharomyces cerevisiae is a current model system in which to study the signal transduction pathways involved in the oxidative stress response. In this review we present the current evidence demonstrating that in S. cerevisiae several MAPK and signalling routes participate in this response (PKC1-MAPK, TOR, RAS-PKA-cAMP). The signalling processes converge in the activation of a number of transcription factors (Yap1, Skn7, Rlm1, Msn2/Msn4, Sfp1, among others) required for the expression of certain genes involved in the oxidative stress response. Another important output of these signalling pathways is the actin cytoskeleton, a known target for oxidation and whose organisation needs to be tightly controlled since it is essential for the integrity of the cell. We know about the existence of different levels of cross-talk between these signalling pathways, which gives strength to the enormous importance of keeping a correct redox homeostasis in cells. S cerevisiae maintains a safeguard mechanism assuring that cells always respond properly to oxidation, by means of mechanisms described in the current review. PMID- 21235504 TI - Cell integrity signaling and response to stress in fission yeast. AB - Cellular responses to external signals are regulated by conserved mitogen activated protein (MAP) kinase signaling cascades. These pathways are triggered by a vast range of stimuli. They phosphorylate numerous proteins, produce significant changes in the gene expression, and regulate diverse processes ranging from proliferation and differentiation to apoptosis in all eukaryotic cells. Three conserved MAP kinase signaling pathways have been identified in the fission yeast Schizosaccharomyces pombe. In this article, we present an overview of two of those pathways that regulate the response of fission yeast to stress and maintain cell integrity. The structure of these signaling modules and the function of the pathways, including the regulation by endogenous inhibitors, are discussed. PMID- 21235505 TI - The role of MAPK signal transduction pathways in the response to oxidative stress in the fungal pathogen Candida albicans: implications in virulence. AB - In recent years, Mitogen-Activated Protein Kinase (MAPK) pathways have emerged as major regulators of cellular physiology. In the fungal pathogen Candida albicans, three different MAPK pathways have been characterized in the last years. The HOG pathway is mainly a stress response pathway that is activated in response to osmotic and oxidative stress and also participates regulating other pathways. The SVG pathway (or mediated by the Cek1 MAPK) is involved in cell wall formation under vegetative and filamentous growth, while the Mkc1-mediated pathway is involved in cell wall integrity. Oxidative stress is one of the types of stress that every fungal cell has to face during colonization of the host, where the cell encounters both hypoxia niches (i.e. gut) and high concentrations of reactive oxygen species (upon challenge with immune cells). Two pathways have been shown to be activated in response to oxidative stress: the HOG pathway and the MKC1-mediated pathway while the third, the Cek1 pathway is deactivated. The timing, kinetics, stimuli and functional responses generated upon oxidative stress differ among them; however, they have essential functional consequences that severely influence pathogenesis. MAPK pathways are, therefore, valuable targets to be explored in antifungal research. PMID- 21235506 TI - Adaptative and developmental responses to stress in Aspergillus nidulan. AB - Development in the ascomycete A. nidulans is principally determined by environmental signals. Adaptability to oxidative stimuli can derive in changes of growth patterns and /or the activation of sexual or asexual reproductive cycles but this model fungus might also respond to high osmotic or salt concentrations, the redox state, the availability and quantity of carbon or nitrogen sources and the degree or quality of illumination. Since each cell within the colony follows a single morphogenetic program at a time, all these environmental cues might be sensed and integrated into a limited number of intracellular signals which, finally, would activate the required morphogenetic program and repress the others. This signaling mainly occurs through stress response pathways. The present review aims to summarize the available knowledge on how these pathways transduce environmental stimuli to mediate morphological changes in Aspergillus nidulans. PMID- 21235507 TI - The roles of the A- and B-chains of human relaxin-2 and -3 on their biological activity. AB - Two members of the human insulin/relaxin superfamily, relaxins-2 and 3 (H2 and H3 respectively), are separated by nearly 75 years in terms of chronological identification but are both the subject of intense recent biological study. The physiological effects of H2 relaxin include vasodilatory, anti-inflammatory, extracellular matrix remodeling, and angiogenic and anti-ischemic. Because of its potent systemic and renal vasodilatory effects, it is currently undergoing phase III clinical trial for the treatment of acute heart failure. In contrast, H3 relaxin is a highly conserved neuropeptide that has rapidly emerged as an important regulator of homeostatic physiology and complex behaviors. Because of their immense clinical potential, an understanding of the structural features that control their functions is critical for rational drug design and development. The native receptor for H2 relaxin is RXFP1. It also strongly binds to the related receptor, RXFP2. The native receptor for H3 relaxin is the unrelated receptor, RXFP3; however, it also has high affinity for another related receptor, RXFP4. Interestingly, H3 relaxin also has a high affinity for RXFP1 and can interact with RXFP2 with a significantly lower affinity. H3 relaxin thus interacts with all four of the relaxin family receptors. Previous studies have shown that H2 and H3 relaxins interact with their receptors primarily using their B-chain specific residues. However, more recent studies suggest that the role of the respective A and B chains for their activity is both peptide- and receptor dependent. This mini-review summarizes these recent findings on the structure activity relationships of H2 and H3 relaxins. PMID- 21235508 TI - Cysteine protease inhibitors: from evolutionary relationships to modern chemotherapeutic design for the treatment of infectious diseases. AB - Cysteine proteases are one of the largest groups of proteases and are involved in many important biological functions in all kingdoms of life. They are virulence factors of a range of eukaryotic, bacterial and viral pathogens and are involved in host invasion, pathogen replication and disruption of the host immune response. Their activity is regulated by a range of protease inhibitors. This review discusses the various families of cysteine protease inhibitors, their different modes of inhibition and their evolutionary relationships. These inhibitors as well as the recent discovery of propeptide and propeptide-like inhibitors provide insights into the structures that are important for particular inhibitory mechanisms, thus forming the foundation for the design of future therapeutics. PMID- 21235509 TI - Compacting proteins: pros and cons of osmolyte-induced folding. AB - Biomedical applications of osmolytes, including stabilization of protein-based pharmaceutics, preservation of living biological material and potential therapeutic prescription in vivo, are intimately related to the fact that osmolytes favour the native structure of proteins. The shift towards the native structure is associated to the compaction of the protein by a non-specific mechanism. This compaction is observed mostly for the unfolded state but also for the transition state ensemble and even for the native state. In addition, more stable three-dimensional structures are more stabilized by osmolytes if the overall protein fold is the same indicating that point mutations and osmolytes should share a similar mechanism for protein stabilization. A synergistic effect to increase protein stability between accumulation of osmolytes and protein engineering strategies seems to have operated during evolution. However, the conformational pre-organization of the unfolded state (compaction) induced by osmolytes which increases the folding rate, might lead to the accumulation of off folding pathway intermediates with non-native structure that delay folding. Also, osmolytes favor protein aggregation as an alternative way to shield protein surfaces from the solvent. The sometimes observed effect of osmolytes on the prevention of protein aggregation is apparent as they only decrease the accumulation of aggregation-competent partially unfolded states. PMID- 21235510 TI - Applications and modifications of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in peptides and peptidomimetics design and discovery. AB - Tic, short for 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, is a kind of unnatural alpha-amino acids. Due to its distinct geometrical conformation and biological activity, the structure of Tic, regarded as the surrogate of proline and the rigid analogue of phenylalanine or tyrosine, has been introduced into many compounds, which target diverse enzymes or receptors. The most successful example is that substituting the Tic residue for the proline residue of enalapril led to an approved drug quinapril. In this review, we will summarize the applications and modifications of Tic in peptides and peptidomimetics design and discovery, and hope to spark medicinal researchers' inspiration in the field of protein and peptide drug design and optimization. PMID- 21235511 TI - Erbin, a negative regulator in diverse signal pathways. AB - Erbin belongs to the LAP protein family. It represents a novel type of adaptor protein that features targeting of basolateral localization of the Her2 receptor through direct binding to the Her2 C terminus. Recent studies demonstrated that Erbin could inhibit the Ras-mediated activation of the mitogen-activated protein kinase (MAPK), nuclear factor-kappaB (NF-kappaB) and transforming growth factor beta (TGF-beta) signaling pathways. It suggests that Erbin may function as a signaling molecule. The functions of Erbin in determining cell polarity and cell adhesion have been well described. This review mainly focuses on the recent findings in regulation of signaling pathways by Erbin. PMID- 21235512 TI - Drug targeting strategies in cancer treatment: an overview. AB - Classic chemotherapy his little or no specificity for cancer cells, normally resulting in low accumulation at the tumor region (inefficacy), and in severe side effects (toxicity). This challenge has resulted in the development of several deliver strategies for chemotherapy agents to improve their concentration at the tumor site, simultaneously increasing their anticancer efficacy, while reducing the associated adverse systemic effects. In this work, the potential of drug delivery strategies involving the use of nanocarriers for controlling the biodistribution of antitumor drugs is deeply revised: passive targeting (through the enhanced permeability and retention effect, EPR effect) and active targeting (including stimuli-sensitive carriers and ligand-mediated delivery). Special attention will be also focussed on the recent approaches for overcoming multi drug resistence. Finally, a general view of the problem of "nanotoxicity" in cancer treatment is also given. PMID- 21235513 TI - Studies on synthesis, activity and binding with DNA of a new trinuclear platinum compound [{trans-PtCl(NH3)2}2{trans-Pt(thiazole)2}{H2N(CH2)(6NH2}2]Cl3(NO3). AB - A new trinuclear platinum compound [{trans-PtCl(NH(3))(2)}(2){trans-Pt(thiazole) (2)}{H(2)N(CH(2))(6)NH(2)}(2)]Cl(3) (NO(3)) has been synthesized and characterized. The activity of the compound against three human ovarian cancer cell lines A2780, A2780(cisR) and A2780(ZD0473R), its cell uptake and level of binding with DNA have been determined. JH5 is found to be less active than cisplatin against parent A2780 cell line but more active than cisplatin against the A2780(cisR) and A2780(ZD0473R) resistant cell lines indicated by the lower resistance factors. The results indicate that at the level of its activity JH5 has been better able to overcome mechanisms of resistance operating in A2780(cisR) and A2780(ZD0473R) cell lines. JH5 has higher cellular accumulation of platinum than cisplatin in the A2780(cisR) and A2780(ZD0473R) resistant cell lines but lower than cisplatin in the parents A2780 cell line. Cisplatin binds with DNA forming mainly bifunctional intrastrand 1,2-Pt(GG) and 1,2-Pt(AG) adducts that cause local bending of DNA strand. In contrast, JH5 is expected to bind with DNA to form mainly interstrand long-range G-Pt..Pt..Pt(G) adducts that would induce more of a global change in DNA conformation. PMID- 21235514 TI - N-valproyl-L-tryptophan for CNS-targeting: synthesis, characterization and efficacy in vitro studies of a new potential antiepileptic drug. AB - A new aminoacidic derivative of valproic acid (VPA) has been synthesized and characterized by analytical and spectral data. The rationale for the preparation of such potential antiepileptic agent is based on the observation that chemical combination of the anticonvulsant pharmacophore, VPA with essential aminoacids could afford more effective and less toxic actives. The synthesis, characterization, physico-chemical parameters functional for crossing Blood Brain Barrier of N-valproyl-L-tryptophan (4) are reported. The Log D (pH7.4) (0.3) indicates that (4) is adequate to cross biological membranes. Its chemical and enzymatic stability were assessed. The experiments indicate high stability of compound (4) at pH conditions of physiological fluids. Moreover, both in plasma and in cerebral enzymatic environments compound (4) doesn't undergo cleavage after 24 h. The anticonvulsant activity of the new compound was assessed against epileptic burst discharges evoked in vitro in rat hippocampal slices (Seizure like events - SLEs) and compared with that of the widely used VPA. Compound (4), even at the lower tested concentration, when compared to VPA, showed an improved protective effect against hippocampal seizures. The collected data suggest that compound (4) could be considered a very valuable candidate for subsequent in vivo evaluation as new potential antiepileptic drug. PMID- 21235515 TI - Design, synthesis and preliminary evaluation of novel imperatorin derivatives as vasorelaxant agents. AB - A series of novel imperatorin derivatives were synthesized from commercially available xanthotoxin. The in vitro pharmacological evaluation indicated that all of the compounds possessed potent vasodilatory activity. Among them, compounds (5b), (5d) and (5e) exhibited higher vasdilatory activity (with EC(50) values of 0.68 uM, 0.59 uM and 0.49 uM, respectively) than imperatorin (EC(50) = 1.12 uM). The program Volsurf was used to predict the derivatives' ADME-relevant descriptors. The results suggested that these novel compounds had a potential interest for the development of novel and potent vasorelaxant agents. PMID- 21235516 TI - Docking and molecular dynamics study on the inhibitory activity of novel inhibitors on epidermal growth factor receptor (EGFR). AB - EGFR is the cell-surface receptor. Its overexpression or overactivity has been associated with a number of cancers, including breast, lung, ovarian, and anal cancers. Many therapeutic approaches are aimed at the EGFR. A series of 2, 7 diamino-thiazolo [4,5-d] pyrimidine analogues are among the most highly potent and selective inhibitors of EGFR described to date. For in-depth investigation into the structural and chemical features responsible for the binding recognition mechanism concerned, as well as for exploring the binding pocket of these compounds, we performed a series of automated molecular docking operations. It was revealed that the binding site consisted of three main areas (P1, P2 and P3) composed of most of the hydrophobic amino acids able to accommodate the lipophilic arms of the compounds investigated. However, the solvent interface did not make much contribution to the binding of the inhibitors. The presence of residues Met793 and Asp855 may also be responsible for the binding recognition through H-bond interactions, with Phe856 through a T-shape pi-pi stacking interaction. The interaction model and pharmacophore of EGFR inhibitors were derived that can be successfully used to explain the different biologic activities of these inhibitors. Moreover, the docking results were quite robust as further validated by molecular dynamics. It is anticipated that the findings reported here may provide very useful information or clue for designing effective drugs for the therapeutic treatment of EGFR-related cancer. PMID- 21235517 TI - LYP3, a new bestatin derivative for aminopeptidase N inhibition. AB - Aminopeptidase N (APN) is a ubiquitous enzyme overexpressed on tumor cells and plays an important role in angiogenesis and metastasis of tumor. Bestatin as an effective inhibitor of aminopeptidase N is used for complementary treatment of cancer with other drugs. In this work, we reformed the structure of bestatin to a new derivative LYP3 to improve the water solubility and effectiveness. The inhibitory activity of LYP3 against APN was evaluated in vitro. PMID- 21235518 TI - Effects of quinone derivatives, such as 1,4-naphthoquinone, on DNA polymerase inhibition and anti-inflammatory action. AB - Previously, we reported that vitamin K(3), which consists of a quinone component, inhibits the activity of human DNA polymerase gamma (pol gamma). In this study, we investigated the inhibitory effects of 4 quinone derivatives (1,4-benzoquinone (BQ), 1,4-naphthoquinone (NQ), 9,10-anthraquinone (AQ) and 5,12 naphthacenequinone (NCQ)) on the activity of mammalian pols. BQ and NQ potently inhibited the activity of all the pol species: pols alpha, beta, gamma, delta, epsilon and lambda, and NQ was a stronger pol inhibitor than BQ. Because we previously found a positive relationship between pol l inhibition and anti inflammatory action, we examined whether these quinone derivatives could inhibit inflammatory responses. BQ and NQ caused a marked reduction in 12-O tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ear, although AQ and NCQ did not. In a cell culture system using mouse macrophages, NQ displayed the strongest suppression in the production of tumor necrosis factor (TNF)-alpha induced by lipopolysaccharide (LPS) among the quinone derivatives tested. Moreover, NQ was found to inhibit the action of nuclear factor (NF) kappa. In an in vivo mouse model of LPS-evoked acute inflammation, intraperitoneal injection of BQ and NQ to mice led to suppression of TNF-alpha production in serum. These anti-inflammatory responses of NQ were more potent than those of BQ. In conclusion, this study has identified several quinone derivatives, such as NQ, that are promising anti-inflammatory candidates. PMID- 21235519 TI - The effect of systematic structural modifications on the antibacterial activity of novel oxazolidinones. AB - A novel series of tetraethylene glycol (TEG) triazolyl and squaramide containing oxazolidinones were synthesized and tested for their antibacterial activity against a selected panel of Gram-positive and Gram-negative bacteria. The 4-TEG triazolyl derivatives were prepared by 'click reaction'. The introduction of the TEG and squaramide groups did not favor antibacterial activity. The three nucleoside-containing oxazolidinones were also prepared by 'click' methodology resulted in weak antibacterial activity. PMID- 21235520 TI - Menthone aryl acid hydrazones: a new class of anticonvulsants. AB - A series of ten compounds (Compounds J(1)-J(10)) of (+/-) 3-menthone aryl acid hydrazone was synthesized and characterized by thin layer chromatography and spectral analysis. Synthesized compounds were evaluated for anticonvulsant activity after intraperitoneal (i.p) administration to mice by maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) induced seizure method and minimal clonic seizure test. Minimal motor impairment was also determined for these compounds. Results obtained showed that four compounds out of ten afforded significant protection in the minimal clonic seizure screen at 6 Hz. Compound J(6), 4-Chloro-N-(2-isopropyl-5-methylcyclohexylidene) benzohydrazide was found to be the most active compound with MES ED(50) of 16.1 mg/kg and protective index (pI) of greater than 20, indicating that (+/-) 3 menthone aryl acid hydrazone possesses better and safer anticonvulsant properties than other reported menthone derivatives viz. menthone Schiff bases, menthone semicarbazides and thiosemicarbazides. PMID- 21235521 TI - Reversal of cardiac iron loading and dysfunction in thalassemic mice by curcuminoids. AB - Non-transferrin bound iron (NTBI) is found in plasma of beta-thalassemia patients and causes oxidative tissue damage. Cardiac siderosis and complications are the secondary cause of death in beta-thalassemia major patients. Desferrioxamine (DFO), deferiprone (DFP) and deferasirox (DFX) are promising chelators used to get negative iron balance and improve life quality. DFP has been shown to remove myocardial iron effectively. Curcuminoids (CUR) can chelate plasma NTBI, inhibit lipid peroxidation and alleviate cardiac autonomic imbalance. Effects of CUR on cardiac iron deposition and function were investigated in iron-loaded mice. Wild type ((mu)beta(+/+) WT) and heterozygous beta-knockout ((mu)beta(th-3/+) BKO) mice (C57BL/6) were fed with ferrocene-supplemented diet (Fe diet) and coincidently intervened with CUR and DFP for 2 months. Concentrations of plasma NTBI and malondialdehyde (MDA) were measured using HPLC techniques. Heart iron concentration was determined based on atomic absorption spectrophotometry and Perl's staining methods. Short-term electrocardiogram (ECG) was recorded with AD Instruments Power Lab, and heart rate variability (HRV) was evaluated using MATLAB 7.0 program. Fe diet increased levels of NTBI and MDA in plasma, nonheme iron and iron deposit in heart tissue significantly, and depressed the HRV, which the levels were higher in the BKO mice than the WT mice. CUR and DFP treatments lowered plasma NTBI as well as MDA concentrations (p <0.05), heart iron accumulation effectively, and also improved the HRV in the treated mice. The results imply that CUR would be effective in decreasing plasma NTBI and myocardial iron, alleviating lipid peroxidation and improving cardiac function in iron-loaded thalassemic mice. PMID- 21235522 TI - Wnt signalling: the case of the 'missing' G-protein. AB - Wnt signalling remains a hot topic for cell signalling sleuthhounds. The trail of signalling downstream of the seven-transmembrane segment Frizzleds, which bind Wnt ligands, is replete of clues [e.g. LPR5/6 (lipoprotein receptor-related protein 5/6), G-proteins or Dishevelled] and yet remains the 'final problem'. Although the heptahelical nature of Frizzleds places them well within a populous family of G-protein-coupled receptors, resistance to this theme has waxed and waned amid increasing demands for 'proof'. The Wnt Homepage (http://www.stanford.edu/group/nusselab/cgi-bin/wnt/) has acted as a dynamic real time arbiter of the controversy, highlighted by the appearance and later the disappearance of the G-protein from its central diagramming and tabulations. A recent publication in this issue of the Biochemical Journal offers a solution to the 'final problem', demonstrating under native conditions that Frizzleds expressed in mammalian brain preparations act functionally to catalyse guanine nucleotide exchange in response to stimulation with Wnt3a. Lensed from the fictional character of Sherlock Holmes, The Case of the Missing G-Protein is investigated. PMID- 21235523 TI - Cell polarity during motile processes: keeping on track with the exocyst complex. AB - Motile processes are critical for several physiological and pathological situations such as embryonic development, tumour dissemination and metastasis. Migrating cells, or developing neurons, need to establish front-rear polarity consisting of actin-driven extension of the leading edge and traffic of components that are essential for membrane extension and cell adhesion at the front. Previously, several studies have suggested that the exocyst complex is critical for the establishment and maintenance of cell polarity. This octameric complex controls the docking and insertion of exocytic vesicles to growing areas of the plasma membrane. The aim of the present review is to detail recent advances concerning the molecular and structural organization of the exocyst complex that help to elucidate its role in cell polarity. We will also review the function of the exocyst complex and some of its key interacting partners [including the small GTP-binding protein Ral, aPKCs (atypical protein kinase Cs) and proteins involved in actin assembly] in the formation of plasma extensions at the leading edge, growth cone formation during axonal extension and generation of cell movement. PMID- 21235524 TI - Optical switch probes and optical lock-in detection (OLID) imaging microscopy: high-contrast fluorescence imaging within living systems. AB - Few to single molecule imaging of fluorescent probe molecules can provide information on the distribution, dynamics, interactions and activity of specific fluorescently tagged proteins during cellular processes. Unfortunately, these imaging studies are made challenging in living cells because of fluorescence signals from endogenous cofactors. Moreover, related background signals within multi-cell systems and intact tissue are even higher and reduce signal contrast even for ensemble populations of probe molecules. High-contrast optical imaging within high-background environments will therefore require new ideas on the design of fluorescence probes, and the way their fluorescence signals are generated and analysed to form an image. To this end, in the present review we describe recent studies on a new family of fluorescent probe called optical switches, with descriptions of the mechanisms that underlie their ability to undergo rapid and reversible transitions between two distinct states. Optical manipulation of the fluorescent and non-fluorescent states of an optical switch probe generates a modulated fluorescence signal that can be isolated from a larger unmodulated background by using OLID (optical lock-in detection) techniques. The present review concludes with a discussion on select applications of synthetic and genetically encoded optical switch probes and OLID microscopy for high-contrast imaging of specific proteins and membrane structures within living systems. PMID- 21235525 TI - The multiple facets of the Golgi reassembly stacking proteins. AB - The mammalian GRASPs (Golgi reassembly stacking proteins) GRASP65 and GRASP55 were first discovered more than a decade ago as factors involved in the stacking of Golgi cisternae. Since then, orthologues have been identified in many different organisms and GRASPs have been assigned new roles that may seem disconnected. In vitro, GRASPs have been shown to have the biochemical properties of Golgi stacking factors, but the jury is still out as to whether they act as such in vivo. In mammalian cells, GRASP65 and GRASP55 are required for formation of the Golgi ribbon, a structure which is fragmented in mitosis owing to the phosphorylation of a number of serine and threonine residues situated in its C terminus. Golgi ribbon unlinking is in turn shown to be part of a mitotic checkpoint. GRASP65 also seems to be the key target of signalling events leading to re-orientation of the Golgi during cell migration and its breakdown during apoptosis. Interestingly, the Golgi ribbon is not a feature of lower eukaryotes, yet a GRASP homologue is present in the genome of Encephalitozoon cuniculi, suggesting they have other roles. GRASPs have no identified function in bulk anterograde protein transport along the secretory pathway, but some cargo specific trafficking roles for GRASPs have been discovered. Furthermore, GRASP orthologues have recently been shown to mediate the unconventional secretion of the cytoplasmic proteins AcbA/Acb1, in both Dictyostelium discoideum and yeast, and the Golgi bypass of a number of transmembrane proteins during Drosophila development. In the present paper, we review the multiple roles of GRASPs. PMID- 21235529 TI - Human platelet lysate supports ex vivo expansion and enhances osteogenic differentiation of human bone marrow-derived mesenchymal stem cells. AB - MSCs (mesenchymal stem cells) with their versatile growth and differentiation potential are ideal candidates for use in regenerative medicine and are currently making their way into clinical trials, which requires the development of xeno free protocols for their culture. In this study, MSCs were cultured in 10% FCS or 7.5% HPL (human platelet lysate)-supplemented media. We found that both groups of MSCs showed a comparable morphology, phenotype and proliferation. The percentage of cells in the S- and G2-/M-phases, however, was slightly up-regulated (P<0.01) in HPL group. HPL contains PDGF (platelet derived growth factor)-AB and IGF (insulin-like growth factor)-1. In addition, compared with FCS group, MSCs in HPL group showed an increase in osteogenic differentiation and a decrease in adipogenic differentiation. In conclusion, MSCs in HPL-supplemented media maintained similar growing potential and phenotype, while osteogenic potential was enhanced. HPL offers a promising alternative to FCS for MSC expansion for clinical application, especially in bone injury diseases. PMID- 21235526 TI - FLIP(L) induces caspase 8 activity in the absence of interdomain caspase 8 cleavage and alters substrate specificity. AB - Caspase 8 is an initiator caspase that is activated by death receptors to initiate the extrinsic pathway of apoptosis. Caspase 8 activation involves dimerization and subsequent interdomain autoprocessing of caspase 8 zymogens, and recently published work has established that elimination of the autoprocessing site of caspase 8 abrogates its pro-apoptotic function while leaving its proliferative function intact. The observation that the developmental abnormalities of caspase 8-deficient mice are shared by mice lacking the dimerization adapter FADD (Fas-associated death domain) or the caspase paralogue FLIP(L) [FLICE (FADD-like interleukin 1beta-converting enzyme)-inhibitory protein, long form] has led to the hypothesis that FADD-dependent formation of heterodimers between caspase 8 and FLIP(L) could mediate the developmental role of caspase 8. In the present study, using an inducible dimerization system we demonstrate that cleavage of the catalytic domain of caspase 8 is crucial for its activity in the context of activation by homodimerization. However, we find that use of FLIP(L) as a partner for caspase 8 in dimerization-induced activation rescues the requirement for intersubunit linker proteolysis in both protomers. Moreover, before processing, caspase 8 in complex with FLIP(L) does not generate a fully active enzyme, but an attenuated species able to process only selected natural substrates. Based on these results we propose a mechanism of caspase 8 activation by dimerization in the presence of FLIP(L), as well as a mechanism of caspase 8 functional divergence in apoptotic and non-apoptotic pathways. PMID- 21235530 TI - Clinical care of diabetic pregnancies in Northern Finland 1967-1987. AB - Diabetic pregnancies are risk pregnancies with increased perinatal mortality and perinatal morbidity. The purpose of this study was to evaluate retrospcctively the outcome of 567 diabetic pregnancies in the area of Oulu University Hospital periodically from 1967 to 1987. PMID- 21235531 TI - Bacterial vaginosis and pregnancy. AB - Bacterial vaginosis (BV) represents a disturbance in the vaginal microflora with a massive overgrowth of predominantly anaerobic bacteria resulting in a disagreeable vaginal discharge. The syndrome of BV has been described in the medical literature since the turn of the century. BV has been considered as an unpleasant but essentially harmleis disturbance of the vaginal micro-flora. However, during the last decade a number of clinical reports have appeared indicating that women with BV run an increased relative risk of postabortal pelvic inflammatory disease, preterm labor, premature rupture of the membranes and post par-tum and post-Cesarean endometritis. The present study was carried out. PMID- 21235532 TI - B cell-targeted therapy with anti-CD20 monoclonal antibody in a mouse model of Graves' hyperthyroidism. AB - Graves' disease is a B cell-mediated and T cell-dependent autoimmune disease of the thyroid which is characterized by overproduction of thyroid hormones and thyroid enlargement by agonistic anti-thyrotrophin receptor (TSHR) autoantibody. In addition to antibody secretion, B cells have recently been recognized to function as antigen-presenting/immune-modulatory cells. The present study was designed to evaluate the efficacy of B cell depletion by anti-mouse (m) CD20 monoclonal antibody (mAb) on Graves' hyperthyroidism in a mouse model involving repeated injection of adenovirus expressing TSHR A-subunit (Ad-TSHR289). We observe that a single injection of 250 ug/mouse anti-mCD20 mAb eliminated B cells efficiently from the periphery and spleen and to a lesser extent from the peritoneum for more than 3 weeks. B cell depletion before immunization suppressed an increase in serum immunoglobulin (Ig)G levels, TSHR-specific splenocyte secretion of interferon (IFN)-gamma, anti-TSHR antibody production and development of hyperthyroidism. B cell depletion 2 weeks after the first immunization, a time-point at which T cells were primed but antibody production was not observed, was still effective at inhibiting antibody production and disease development without inhibiting splenocyte secretion of IFN-gamma. By contrast, B cell depletion in hyperthyroid mice was therapeutically ineffective. Together, these data demonstrate that B cells are critical not only as antibody producing cells but also as antigen-presenting/immune-modulatory cells in the early phase of the induction of experimental Graves' hyperthyroidism and, although therapeutically less effective, B cell depletion is highly efficient for preventing disease development. PMID- 21235533 TI - Prevention of clinical and histological signs of proteolipid protein (PLP) induced experimental allergic encephalomyelitis (EAE) in mice by the water soluble carbon monoxide-releasing molecule (CORM)-A1. AB - We have evaluated the effects of the carbon monoxide-releasing molecule CORM-A1 [Na(2) (BH(3) CO(2) ); ALF421] on the development of relapsing-remitting experimental allergic encephalomyelitis (EAE) in SJL mice, an established model of multiple sclerosis (MS). The data show that the prolonged prophylactic administration of CORM-A1 improves the clinical and histopathological signs of EAE, as shown by a reduced cumulative score, shorter duration and a lower cumulative incidence of the disease as well as milder inflammatory infiltrations of the spinal cords. This study suggests that the use of CORM-A1 might represent a novel therapeutic strategy for the treatment of multiple sclerosis. PMID- 21235534 TI - Anti-thymoglobulin (ATG) treatment does not reverse type 1 diabetes in the acute virally induced rat insulin promoter-lymphocytic choriomeningitis virus (RIP LCMV) model. AB - Immune modulators such as anti-thymoglobulin (ATG) are under clinical evaluation for the treatment of type 1 diabetes (T1D). Although such agents have cured T1D in the non-obese diabetic (NOD) model, their clinical efficacy has been much lower. In order to improve the odds of successful translation from bench to bedside, we propose to evaluate this agent under more stringent conditions. Here, we evaluated the capacity of ATG to reverse T1D in the acute rat insulin promoter lymphocytic choriomeningitis virus (RIP-LCMV) model. RIP-LCMV-glycoprotein (GP) mice were treated after new-onset T1D with murine ATG antibodies. Although ATG treatment did not impair viral clearance it failed to reverse new-onset T1D in this model. The CD4:CD8 ratio was reduced drastically upon LCMV infection due to an expansion of CD8 effectors but ameliorated in ATG-treated mice. Although the percentage of CD4(+) CD25(+) regulatory T cells (T(regs) ) within the CD4(+) population was increased significantly after ATG therapy, their frequency in the periphery was reduced dramatically and never returned to normal baseline. The inability of ATG treatment to cure T1D in a stringent viral model (RIP-LCMV mice) is due at least partially to the inability to maintain or increase a sufficient CD4(+) CD25(+) T(regs) frequency, in striking contrast with what was reported in the NOD model. Our data would argue for the use of multiple animal models to assess efficacy of promising immune-based interventions and select the most potent therapies for future clinical trials. PMID- 21235535 TI - Selective expansion of merocytic dendritic cells and CD8DCs confers anti-tumour effect of Fms-like tyrosine kinase 3-ligand treatment in vivo. AB - Vaccination with autologous cancer cells aims to enhance adaptive immune responses to tumour-associated antigens. The incorporation of Fms-like tyrosine kinase 3-ligand (FLT3L) treatment to the vaccination scheme has been shown previously to increase the immunogenicity of cancer vaccines, thereby enhancing their therapeutic potential. While evidence has been provided that FLT3L confers its effect through the increase of absolute dendritic cell (DC) numbers, it is currently unknown which DC populations are responsive to FLT3L and which effect FLT3L treatment has on DC functions. Here we show that the beneficial effects of FLT3L treatment resulted predominantly from a marked increase of two specific DC populations, the CD8 DCs and the recently identified merocytic DC (mcDC). These two DC populations (cross)-present cell-associated antigens to T cells in a natural killer (NK)-independent fashion. FLT3L treatment augmented the absolute numbers of these DCs, but did not change their activation status nor their capacity to prime antigen-specific T cells. While both DC populations effectively primed CD8(+) T cell responses to cell-associated antigens, only mcDC were capable to prime CD4(+) T cells to cell-associated antigens. Consequentially, the transfer of tumour vaccine-pulsed mcDC, but not of CD8 DCs, protected mice from subsequent tumour challenge in a vaccination model and resulted in eradication of established tumours in a therapeutic approach. These results show that the beneficial effect of FLT3L is associated with the induction of mcDC and suggests that selective targeting to mcDC or instilling mcDC 'characteristics' into conventional DC populations could significantly enhance the efficacy of tumour vaccines. PMID- 21235536 TI - Association of functional polymorphisms in promoter regions of IL5, IL6 and IL13 genes with development and prognosis of autoimmune thyroid diseases. AB - To clarify the association of genetic producibility of interleukin (IL)-5, IL-6 and IL-13, which are secreted by T helper type 2 (Th2), with the development and prognosis of autoimmune thyroid disease (AITD), we genotyped IL5-746C/T, IL6 572C/G and IL13-1112C/T polymorphisms, which are functional polymorphisms in the promoter regions of the genes regulating these cytokines. Fifty-seven patients with intractable Graves' disease (GD), 52 with GD in remission, 52 with severe Hashimoto's disease (HD), 56 with mild HD and 91 healthy controls were examined in this study. The IL13-1112T allele, which correlates with higher producibility of IL-13, was more frequent in patients with GD in remission than in those with intractable GD [P=0.009, odds ratio (OR)=3.52]. The IL5-746T allele, which may correlate with lower levels of IL-5, was more frequent in patients with GD in remission than controls (P=0.029, OR=2.00). The IL6-572G allele carriers (CG and GG genotypes), which have higher producibility of IL-6, were more frequent in AITD patients (P=0.033, OR=1.75), especially in GD in remission (P=0.031, OR=2.16) and severe HD (P=0.031, OR=2.16) than in controls. Interestingly, both allele and genotype frequencies of Th2 cytokine genes were similar between GD and HD patients. In conclusion, functional polymorphisms in the genes encoding Th2 cytokines are associated differently with the development and prognosis of AITD from each other. PMID- 21235537 TI - Engagement of the B cell receptor for antigen differentially affects B cell responses to Toll-like receptor-7 agonists and antagonists in BXSB mice. AB - Nucleic acid sensors of the Toll-like receptor (TLR) family play a well established role in the pathogenesis of lupus. This is particularly true for a single-stranded RNA-sensing TLR-7 receptor, as lupus mice lacking TLR-7 show ameliorated disease. Cytosine-guanosine dinucleotide (CpG)-DNA-sensing TLR-9, conversely, has a complex regulatory role in systemic lupus erythematosus (SLE). Much less is known about whether signals through the B cell receptor for antigen (BCR) may affect the ability of B cells to respond to suboptimal TLR-7 agonists and antagonists. We studied this question in prediseased BXSB male and female B cells. We found that male B cells responded more vigorously to numerous TLR-7 ligands and this responsiveness was enhanced further upon co-engagement of the BCR. This synergy was seen primarily with the interleukin (IL)-6 secretion. A number of 32-mer inhibitory oligonucleotides (INH-ODNs) with a nuclease-resistant phosphorothioate backbone were capable of blocking TLR-7, but not BCR-induced B cell activation, with an inhibitory concentration (IC)(50) of approximately 100 nm. Surprisingly, while the presence of a single TGC motif at the 5' end of an ODN did not increase its inhibitory capacity, INH-ODNs containing multiple TGC motifs had greater inhibitory potency. When BCR and TLR-7 were co-engaged, INH ODNs showed a differential effect on B cell activation. Whereas apoptosis protection and G1-M entry completely escaped suppression, IL-6 secretion remained sensitive to inhibition, although with a 10-fold lower potency. Our results suggest that while TLR-7 antagonists may be considered as lupus therapeutics, simultaneous co-engagement of the TLR-7 and BCR might favour autoreactive B cell survival. This hypothesis needs further experimental validation. PMID- 21235539 TI - Engagement of activated Notch signalling in collagen II-specific T helper type 1 (Th1)- and Th17-type expansion involving Notch3 and Delta-like1. AB - Our previous study demonstrated that T helper (Th) cells from patients with rheumatoid arthritis (RA) display an altered expression profile of Notch receptors and enhanced activation of Notch signalling. The aim of this study was to investigate the role of distinct Notch receptors and ligands in the activation and differentiation of collagen II (CII)-reactive Th cells upon antigen-specific restimulation. Spleen mononuclear cells (SMNCs) from CII-immunized DBA/1J mice were restimulated by culturing with CII. CII-specific proliferation and differentiation of T cells were determined by tritiated thymidine ((3) [H]-TdR) incorporation and flow cytometric analysis, respectively. The mRNA expression of Notch receptors and Hes1 was assessed by real-time polymerase chain reaction (PCR). There was a clear increase in the percentage of Th1 cells and Th17 cells after CII restimulation. No significant difference was observed in the percentage of regulation T cells (T(reg) ) in SMNCs with or without CII restimulation. CII restimulation induced up-regulated transcript levels of Hes1 in CII-reactive CD4(+) T cells. The mRNA level of Notch3 was also up-regulated significantly, while the levels of the other three Notch receptors were not increased. Inhibition of Notch signalling by N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S phenylglycine t-butyl ester (DAPT) and Notch3 antibody decreased the collagen specific T cell proliferation and attenuated Th1- and Th17-type responses, while treatment with Notch ligand Delta-like 1 promoted such a response. The present study demonstrates that Notch signalling is engaged in CII-specific Th1- and Th17 type expansion in which Notch3 and Delta-like1 were involved. Selective inhibition of Notch signalling mediated by Notch3 or Delta-like1 may offer a new strategy for the treatment of RA. PMID- 21235538 TI - Quantitative and functional profiles of CD4+ lymphocyte subsets in systemic lupus erythematosus patients with lymphopenia. AB - Lymphopenia is a common clinical manifestation in patients with systemic lupus erythematosus (SLE). However, its physiopathogenic role and the contribution of different T cell subsets in this setting have not been addressed fully. The aim of this study was to characterize T cell subsets quantitatively and functionally and their association with lymphopenia and azathioprine treatment in SLE. We included 84 SLE patients and 84 healthy controls and selected 20 patients for a 6 month longitudinal analysis. Peripheral blood mononuclear cells were isolated, and T cell subsets were analysed by flow cytometry. Functional analyses included autologous and allogeneic co-cultures of T cells. Our data show persistently lower absolute numbers of CD4(+) CD25(high) T cells [regulatory T cells (T(regs) )] (1.9 versus 5.2, P < 0.01) and CD4(+) CD69(+) T cells (3.2 versus 9.3, P = 0.02) and higher activity scores (4.1 versus 1.5, P = 0.01) in SLE patients with lymphopenia compared with those without lymphopenia. Lymphopenia increased the risk for decreased numbers of CD4(+) CD25(high) cells (relative risk 1.80, 95% confidence interval 1.10-2.93; P = 0.003). In addition, azathioprine-associated lymphopenia was characterized by decreased absolute numbers of CD4(+) CD69(+) and CD4(+) interleukin (IL)-17(+) cells compared to disease activity-associated lymphopenia. Functional assays revealed that SLE effector T cells were highly proliferative and resistant to suppression by autologous T(regs) . In summary, lymphopenia was associated with deficient numbers of CD4(+) CD25(high) and CD4(+) CD69(+) cells and resistance of effector T cells to suppression by T(regs) , which could contribute to the altered immune responses characteristic of SLE. Furthermore, azathioprine treatment was associated with decreased numbers of CD4(+) CD69(+) and CD4(+) IL-17(+) cells and diminished T(reg) suppressive activity. PMID- 21235540 TI - Induction of beta-defensins by l-isoleucine as novel immunotherapy in experimental murine tuberculosis. AB - Tuberculosis is a worldwide health problem, and multidrug-resistant (MDR) and extensively multidrug-resistant (XMDR) strains are rapidly emerging and threatening the control of this disease. These problems motivate the search for new treatment strategies. One potential strategy is immunotherapy using cationic anti-microbial peptides. The capacity of l-isoleucine to induce beta-defensin expression and its potential therapeutic efficiency were studied in a mouse model of progressive pulmonary tuberculosis. BALB/c mice were infected with Mycobacterium tuberculosis strain H37Rv or with a MDR clinical isolate by the intratracheal route. After 60 days of infection, when disease was in its progressive phase, mice were treated with 250 ug of intratracheal l-isoleucine every 48 h. Bacillary loads were determined by colony-forming units, protein and cytokine gene expression were determined by immunohistochemistry and reverse transcription-quantitative polymerase chain reaction (RT-qPCR), respectively, and tissue damage was quantified by automated morphometry. Administration of l isoleucine induced a significant increase of beta-defensins 3 and 4 which was associated with decreased bacillary loads and tissue damage. This was seen in animals infected with the antibiotic-sensitive strain H37Rv and with the MDR clinical isolate. Thus, induction of beta-defensins might be a potential therapy that can aid in the control of this significant infectious disease. PMID- 21235543 TI - Gene expression analysis for the identification of selection and local adaptation in fishes. AB - In recent years, variation in gene expression has been recognized as an important component of environmental adaptation in multiple model species, including a few fish species. There is, however, still little known about the genetic basis of adaptation in gene expression resulting from variation in the aquatic environment (e.g. temperature, salinity and oxygen) and the physiological effect and costs of such differences in gene expression. This review presents and discusses progress and pitfalls of applying gene expression analyses to fishes and suggests simple frameworks to get started with gene expression analysis. It is emphasized that well-planned gene expression studies can serve as an important tool for the identification of selection in local populations of fishes, even for non traditional model species where limited genomic information is available. Recent studies focusing on gene expression variation among natural fish populations are reviewed, highlighting the latest applications that combine genetic evidence from neutral markers and gene expression data. PMID- 21235544 TI - The decline of the European eel Anguilla anguilla: quantifying and managing escapement to support conservation. AB - A method was developed to quantify the number and biomass of European eels Anguilla anguilla escaping to the ocean for breeding. The non-intrusive method, involving a fixed-position, high-frequency multi-beam sonar, permitted constant surveillance of A. anguilla movements throughout their 5 month escapement season (July to December). During this period, >1000 individuals were monitored escaping to the Atlantic Ocean from their freshwater habitat in the River Huntspill study site (Somerset, U.K.). The total length of each fish was measured using the sonar software. These measurements were then converted to an estimate of mass using a length:mass regression relationship derived from historical fyke-net data from this site, comprising c. 500 A. anguilla length:mass measurements collected over a 10 year period. The net biomass of escapement from the study site was equivalent to c. 6 kg ha-1 year-1, lower than the present European target which would require at least 7 kg ha-1 year-1 from this habitat. These findings demonstrate the capabilities of this monitoring technique and its usefulness both as a tool to assess the compliance with conservation targets and as a tool to evaluate the success of conservation measures for elusive aquatic species such as A. anguilla. PMID- 21235541 TI - Epithelial transport and deamidation of gliadin peptides: a role for coeliac disease patient immunoglobulin A. AB - In coeliac disease, the intake of dietary gluten induces small-bowel mucosal damage and the production of immunoglobulin (Ig)A class autoantibodies against transglutaminase 2 (TG2). We examined the effect of coeliac patient IgA on the apical-to-basal passage of gluten-derived gliadin peptides p31-43 and p57-68 in intestinal epithelial cells. We demonstrate that coeliac IgA enhances the passage of gliadin peptides, which could be abolished by inhibition of TG2 enzymatic activity. Moreover, we also found that both the apical and the basal cell culture media containing the immunogenic gliadin peptides were able to induce the proliferation of deamidation-dependent coeliac patient-derived T cells even in the absence of exogenous TG2. Our results suggest that coeliac patient IgA could play a role in the transepithelial passage of gliadin peptides, a process during which they might be deamidated. PMID- 21235542 TI - Somatosensory mechanisms in zebrafish lacking dorsal root ganglia. AB - Dorsal root ganglion (DRG) sensory neurons transmit all somatosensory information from the trunk region of the body. erbb3 mutant zebrafish do not form DRG neurons because the neural crest cells that generate them migrate aberrantly. Here we report that homozygous erbb3 mutants appear to swim and feed normally, and that they survive through adulthood, despite never forming DRG neurons. The source of sensory compensation in adult erbb3 mutants remains unknown, although it may be from lateral line ganglion neuromasts which are reduced, but present, in erbb3 mutants. We also provide new information about the development of DRG neurons in wild-type juvenile zebrafish. PMID- 21235545 TI - Long-term increases in young-of-the-year growth of Arctic cisco Coregonus autumnalis and environmental influences. AB - Arctic cisco Coregonus autumnalis young-of-year (YOY) growth was used as a proxy to examine the long-term response of a high-latitude fish population to changing climate from 1978 to 2004. YOY growth increased over time (r2 = 0.29) and was correlated with monthly averages of the Arctic oscillation index, air temperature, east wind speed, sea-ice concentration and river discharge with and without time lags. Overall, the most prevalent correlates to YOY growth were sea ice concentration lagged 1 year (significant correlations in 7 months; r2 = 0.14 0.31) and Mackenzie River discharge lagged 2 years (significant correlations in 8 months; r2 = 0.13-0.50). The results suggest that decreased sea-ice concentrations and increased river discharge fuel primary production and that life cycles of prey species linking increased primary production to fish growth are responsible for the time lag. Oceanographic studies also suggest that sea ice concentration and fluvial inputs from the Mackenzie River are key factors influencing productivity in the Beaufort Sea. Future research should assess the possible mechanism relating sea ice concentration and river discharge to productivity at upper trophic levels. PMID- 21235546 TI - Genetic structure and phylogeography of two freshwater fishes, Rhadinocentrus ornatus and Hypseleotris compressa, in southern Queensland, Australia, inferred from allozymes and mitochondrial DNA. AB - This study used allozyme and mtDNA variation to examine genetic structure in Rhadinocentrus ornatus and Hypseleotris compressa in southern Queensland. The aim of this study was to test the hypothesis that dispersal between coastal streams was greater in R. ornatus than in H. compressa and to test whether R. ornatus would reflect a similar pattern seen in another obligate freshwater fish in the same region, that is, R. ornatus will show genetic homogeneity among streams of the Sunshine Coast but significant differentiation among all other streams. Evidence from the current study suggests that, in R. ornatus, there was significant genetic differentiation among populations within regions, which explains why this species has very restricted dispersal abilities between streams, even between those very close to one another. On the other hand, H. compressa showed very low levels of genetic differentiation suggesting some gene flow among regions by virtue of dispersal. High levels of genetic differentiation were identified between all coastal streams in the area, including those hypothesized to have been recently connected in the Sunshine Coast area in the case of R. ornatus. PMID- 21235547 TI - Temporal and spatial variability of pelagic wild fish assemblages around Atlantic bluefin tuna Thunnus thynnus farms in the eastern Adriatic Sea. AB - The abundance and size structure of wild fishes aggregated around the sea-cages of two commercial Thunnus thynnus farms, including control locations, were assessed and compared over a 1 year period. The T. thynnus farms were located in the eastern Adriatic Sea, offshore of the islands of Ugljan and Brac. Fish assemblages were evaluated through visual census using scuba at 2 month intervals at two sites within each farm. The data suggest that wild fish assemblages at the study sites differed greatly; 20 species occurred at the Ugljan farm and 17 at the Brac farm, while only seven species were observed at the control locations. The abundance and diversity of wild fish assemblages were greater at the farms in comparison to control locations. The most abundant families were Sparidae and Belonidae (>80% of aggregated fishes). At both farms, the abundance and diversity of wild fishes were highest during summer, while diversity was lowest in winter and was mainly characterized by schools of bogue Boops boops and garfish Belone belone. Variability was also detected in spatial assemblages between farms; B. boops and B. belone were the most abundant species for the overall study at the Brac farm, while B. belone and saddled bream Oblada melanura were the most abundant at the Ugljan farm. The settlement also played a significant role in farm-associated fish assemblages, as both juveniles and advanced juveniles were common residents at farms. The majority of species which settled at the farms belonged to the sparids. Results indicate that aggregations of wild fishes at T. thynnus farms are persistent year-round, though the assemblage compositions and size structures of dominant species vary in respect to location and season. PMID- 21235548 TI - Genetic analysis of threatened Australian grayling Prototroctes maraena suggests recruitment to coastal rivers from an unstructured marine larval source population. AB - Population genetic variation of Australian grayling Prototroctes maraena was examined to determine whether the dispersal strategy of this amphidromous species favours retention of larvae and juveniles in close proximity to their natal river, or mixing of populations via marine dispersal. Variation in microsatellite and mitochondrial DNA markers was unstructured and differentiation was indistinguishable from zero across four coastal rivers spanning approximately one quarter of the continental range of the species. This result indicates that the marine larval and juvenile phase probably facilitates extensive gene flow among coastal rivers and agrees with a previous analysis of otolith chemistry that suggested larvae probably move into the sea rather than remain in estuaries. It appears likely that the dispersal strategy of P. maraena would enable recolonization of rivers that experience localized extinction provided that connectivity between freshwater habitats and the sea is sufficient to permit migration and that enough source populations remain intact to support viability of the wider population. PMID- 21235549 TI - Spawning substrata are important for breeding habitat selection but do not determine premating reproductive isolation in three sympatric Hexagrammos species. AB - Habitat use and spawning substrata were surveyed to characterize the contribution of habitat divergence to reproductive isolation in greenling Hexagrammos species. The spawning substrata and microhabitat in breeding territories differed amongst the three Hexagrammos species studied: H. octogrammus, H. agrammus and H. otakii used small red algae, surfgrass and bryozoans, respectively, as spawning substrata, and breeding territories were established in areas where those substrata were abundant. In contrast, non-territorial individuals were observed in a comparatively wider range of habitats than conspecific territories. Consequently, the distributions of non-territorial individuals of the three species partially overlapped. Since hybrids have been frequently collected, the difference in spawning substrata and the subsequent microhabitat divergence in breeding territories do not prevent females from encountering males of other species. Thus, in addition to habitat divergence, other factors such as behavioural differentiation may be needed to complete premating reproductive isolation amongst these three Hexagrammos species. PMID- 21235550 TI - Shoaling and mate choice of wild-type Tanichthys albonubes in the presence of the red fluorescent transgenic conspecifics. AB - Shoaling and sexual behaviour of wild-type male and female white cloud mountain minnow Tanichthys albonubes were measured in the presence of the red fluorescent transgenic conspecifics under laboratory conditions. Wild-type female test fish showed no significant preference, whereas wild-type male test fish preferred to be near a shoal of red transgenic fish rather than wild-type fish. When placed in a potentially reproductive context, wild-type males had a higher competitive ability over transgenic males; wild-type females spent more time with wild-type males in visually mediated experiments, but wild-type males performed more courtship displays towards transgenic females. These results suggest that the red body colouration does not appear to disturb signal communication between wild type and transgenic T. albonubes in shoaling behaviour; transgenic males have no mating advantage over wild-type males, but the red body colouration of transgenic females may affect mate choice of wild-type males. PMID- 21235551 TI - Meiobenthos provides a food resource for young cyprinids. AB - Young individuals of the bottom-biting (i.e. sediment-ingesting) common carp Cyprinus carpio and gudgeon Gobio gobio consumed significant amounts of nematodes in laboratory experiments, whereas the selective-feeding roach Rutilus rutilus did not. In mesocosm enclosure experiments in the field, C. carpio strongly decreased the nematode abundance within 4 days, whereas the bottom-biting bream Abramis brama did not affect the abundance until after 14 days. In controlled experiments with a known number of prey, C. carpio but not A. brama significantly reduced the number of nematodes, and G. gobio reduced the nematode abundance dependent on the size of the fish, with smaller fish causing a greater reduction. Cyprinus carpio consumed the nematodes and did not just mechanically kill them in the sediment, as shown by dissection of the fish intestine. Morphometric analysis of the branchial baskets indicated that the mesh width of C. carpio, but not of A. brama, is suitable for consuming meiobenthos. The results indicate that the meiobenthos is a food resource for certain bottom-feeding freshwater fishes. PMID- 21235552 TI - Microsatellite analysis of different ploidy offspring of artificial gynogenesis in Cyprinus carpio. AB - Gynogenesis was induced by using UV-irradiated spermatozoa of blunt snout bream Megalobrama amblycephala to activate eggs of common carp Cyprinus carpio. The maternal genome was then duplicated by cold shock in 0 to 4 degrees C cold water to retain the second polar body. Two kinds of fry, normal fry and abnormal tortuous fry, were hatched. Their DNA content was measured by flow cytometry. The normal fry were identified as diploid, representing the successful gynogenesis in C. carpio whereas the abnormal tortuous fry were haploid. Ten microsatellite loci were used to study the genetic diversity among C. carpio, diploid gynogenetic C. carpio and unduplicated haploid tortuous fry. The results indicated that the genetic homozygosity of gynogenetic C. carpio was significantly higher than that of C. carpio. The genetic homozygosity of the haploid C. carpio was intermediate between that of gynogenetic C. carpio and C. carpio. It might be easier for the allogenetic DNA fragments to be integrated into the haploid genome than into diploid gynogenetic genome. PMID- 21235553 TI - Spatial variation in parasite abundance: evidence of geographical population structuring in southern garfish Hyporhamphus melanochir. AB - Southern garfish Hyporhamphus melanochir were examined for metazoan parasites from nine sites in three regions (Spencer Gulf, Gulf St Vincent and northern Kangaroo Island) in South Australia to document parasite assemblages, identify candidate species suitable for use as biological tags and investigate spatial variation in parasite abundance. Four ectoparasite and 10 endoparasite species were identified representing Cestoda, Trematoda, Monogenea, Nematoda, Acanthocephala, Copepoda and Isopoda. Lernaeenicus hemirhamphi, Micracanthorhynchina hemirhamphi, Mothocya halei and Philometra sp. were suggested for 'permanent' biological markers. Multivariate discriminant function analysis showed that most sites could be distinguished based on differences in parasite abundance. Four endoparasites (Conohelmins sp., Hysterothylacium sp., M. hemirhamphi and Philometra sp.) were most important for site characterization. Limited spatial variation in permanent endoparasite abundance among localities in northern Spencer Gulf provided evidence for a distinct northern Spencer Gulf population with little interregional mixing. In contrast, considerable spatial variation in permanent endoparasite abundance between localities sampled off Kangaroo Island implied limited local movement and suggested H. melanochir may comprise a metapopulation structure. These results largely align with recent evidence from otolith chemistry that indicates fine-scale geographical population structuring in South Australian waters. PMID- 21235554 TI - Chromosomal diversification in populations of Characidium cf. gomesi (Teleostei, Crenuchidae). AB - Comparative cytogenetic studies carried out in two populations of Characidium cf. gomesi from Botucatu region, SP, Brazil, showed a similar karyotypic structure in a diploid number of 50 chromosomes, 32 metacentric and 18 submetacentric chromosomes for males and 31 metacentric and 19 submetacentric chromosomes for females as well as a ZZ-ZW sex chromosome system. Differences between both populations, however, were found in relation to the occurrence of B chromosomes and the distribution of 18S and 5S ribosomal DNA (rDNA) sites. Characidium cf. gomesi from the Alambari Stream, a component of the Tiete River basin, revealed 18S rDNA on Z and W chromosomes, while this gene was located on autosomes in the sample from the Paranapanema River basin. The 5S rDNA sites were observed in a single chromosomal pair (number 25) in the populations from Paranapanema and in two pairs in the specimens from Tiete (numbers 20 and 25). Besides that, in the sample from Paranapanema, both inter and intra-individual variations were found due to the occurrence of up to four heterochromatic supernumerary chromosomes in the cells. The life mode of this fish, restricted to headwaters and subjected to frequent breakdown into sub-populations, may have contributed to the fixation of such chromosomal differences. The karyotypic similarities found in the analysed populations, however, suggest that all are descended from the same ancestor group whereas their differences indicate that they are already existing in reproductively isolated populations. PMID- 21235555 TI - Is post-feeding thermotaxis advantageous in elasmobranch fishes? AB - The effects of post-feeding thermotaxis on ileum evacuation and absorption rates were examined in the laboratory using two elasmobranch species, the Atlantic stingray Dasyatis sabina, which inhabits thermally variable environments, and the whitespotted bamboo shark Chiloscyllium plagiosum, a stenothermic fish living on Indo-Pacific reefs. Experiments at temperatures similar to those experienced in nature revealed temperature change had no significant effect on C. plagiosum absorption or evacuation rates, suggesting stenothermic sharks cannot exploit temperature differences as a means to improve digestion efficiency. On the other hand, D. sabina showed significantly lower evacuation and absorption rates at lower temperatures. The relative decrease was greater for evacuation (Q10 = 3.08) than absorption rates (Q10 = 2.20), resulting in a significant increase in total absorption, suggesting D. sabina can benefit from using shuttling behaviour to exploit thermal variability in their environment to maximize energetic uptake. PMID- 21235556 TI - Distinguishing species of European sturgeons Acipenser spp. using microsatellite allele sequences. AB - Five microsatellite markers were analysed and their alleles were sequenced for the three sturgeon species that lived in western Europe: the European sturgeon Acipenser sturio, the Atlantic sturgeon Acipenser oxyrinchus and the Adriatic sturgeon Acipenser naccarii. A total of 94 different allele sequences were obtained. Fixed mutations in the flanking regions or in the core repeat of microsatellites provided a clear distinction between the different species. Comparison of allele sequences also provided some insights into microsatellites and the evolution of Acipenser species. These nuclear markers can be used to solve species determination problems, and combined with mitochondrial markers, will be useful to identify introgression and hybridization among the three species. Moreover, because they are short and with a limited allele size range, they are particularly suited for analysis of museum specimens or archaeological remains. PMID- 21235557 TI - Seasonal dynamics in population characteristics of European bitterling Rhodeus amarus in a small lowland river. AB - The seasonal dynamics of biological traits in a population of European bitterling Rhodeus amarus from a small river in central Europe (River Kyjovka, Czech Republic) were investigated from April 2007 to March 2008. The reproductive season lasted from early April to mid-June, with a peak in late April when > 50% of females possessed ripe eggs in their ovaries. The sex ratio was female-biased, with a higher bias following the peak in reproduction, suggesting higher mortality of males than females over the reproductive period. The population was effectively annual, with a major decrease in adult fish abundance at the end of the reproductive period. Highest relative lipid content and condition factor were observed in February, both decreasing with an increase in investment into gonads. Seasonal dynamics in somatic condition, relative lipid content and gonad mass, and their comparison with other R. amarus populations, suggest that the study population allocated a disproportionally high level of resources to reproduction. PMID- 21235558 TI - A new species of Heptapterus Bleeker 1858 (Siluriformes, Heptapteridae) from the Rio Sali basin, north-western Argentina. AB - A revision of fish specimens previously identified as Heptapterus mustelinus from the endorheic Rio Sali Basin, Tucuman, Argentina, reveals that they present several morphological differences from that species. This paper describes Heptapterus qenqo sp. nov. from the Rio Sali Basin. The new species is diagnosed by a combination of the following characters: presence of small serrae on the anterior proximal margin of the first pectoral-fin ray; anal-fin rays iv-v, 11-13 (15-17 total anal-fin rays); adipose-fin base 40.9-47.4% standard length; small eyes (7.4-14.2% head length); adipose-fin confluent to caudal fin and maxillary barbel not reaching pectoral-fin base in adults, and reaching or scarcely surpassing the first pectoral-fin ray in small juveniles. PMID- 21235559 TI - A retrospective approach to fractionize variation in body mass of Atlantic cod Gadus morhua. AB - Eggs of a single spawning batch from wild-caught Norwegian Atlantic cod Gadus morhua were hatched and first fed on either natural zooplankton or enriched rotifers Brachionus plicatilis during the larval period. Juvenile G. morhua (initial mass 14.2 g) from the two first-feeding groups were then reared for 3 months under a variety of temperature (10 and 14 degrees C) and salinity (15 and 32) combinations. All fish were individually tagged and microsatellite markers were used in a multiplex to trace the pedigree of all fish and body mass variation analysed according to different environmental and genetic sources. After the termination of the laboratory trial, the fish were transferred to land based tanks and later to sea pens and reared at ambient conditions for 26 months until they were harvested in March 2009. Growth gain from the larval and juvenile periods was persistent during the 26 months of sea pen ongrowing. The final mass of the zooplankton group was 12% higher compared to the B. plicatilis group. Similarly, rearing under a temperature of 14 degrees C and salinity of 15 during the initial 3 month period during the early juvenile stage resulted in 7-13% larger size at harvesting compared to the other three temperature and salinity combinations. The study indicates that the first-feeding method and temperature and salinity manipulation explain nearly 90% of the body mass variation explained by the model. The genetic effect (measured as body mass variation within the families studied) only accounted for c. 2% during the initial rearing period, whereas it has a large effect on growth variation (30%) during the long-term rearing at ambient conditions. Sex proportion and final maturation did not differ between family groups, and no interaction between sex and family group was seen. PMID- 21235560 TI - Trophic ecology of northern Australia's terapontids: ontogenetic dietary shifts and feeding classification. AB - The diets of 21 terapontid species from freshwater environments in northern Australia were investigated to determine the similarity and dissimilarity among species and the extent of any ontogenetic shifts. Distinct ontogenetic dietary shifts occurred in all species for which sufficient data were available, with many species passing through several discrete trophic categories during their life histories. Diets of all juvenile terapontids were similar, mainly comprising aquatic insects and zooplankton. Larger size classes of terapontids diverged into a broad spectrum of feeding groups comprising carnivorous dietary modes (including piscivory and lepidophagy), omnivory (including frugivory and consumption of allochthonous prey), herbivory and detritivory. The results indicate that the terapontids represent Australia's most trophically diverse freshwater fish family. PMID- 21235561 TI - Reproductive biology of the lesser guitarfish Zapteryx brevirostris from the south-western Atlantic Ocean. AB - This study provides the first detailed information on the reproductive biology of the lesser guitarfish Zapteryx brevirostris in the south-western Atlantic Ocean between latitudes 34 degrees and 42 degrees S. A total of 320 males (196-647 mm total length, L(T)) and 336 females (200-640 mm L(T)) were analysed. No significant differences were observed in size at 50% maturity between males (499 mm L(T)) and females (506 mm L(T)). Three seasonal patterns were related to the testes mass, the development of spermatocysts and the presence of spermatozoa in genital ducts. Females showed a 3 year reproductive cycle, with 2 years of ovarian maturation and 1 year of gestation, including a mean annual fecundity of one to two embryos. Synchronicity of both ovulating females and males with sperm in genital ducts indicated that ovulation and hence mating occurs during winter. Birth was assumed to occur during winter, but neither ovulation nor mating is simultaneous with this reproductive event. Despite its low economic value, a decline in abundance in the region, together with a low reproductive efficiency, indicates that the Z. brevirostris population should be monitored closely. PMID- 21235562 TI - Population structure, effective population size and adverse effects of stocking in the endangered Australian eastern freshwater cod Maccullochella ikei. AB - Microsatellite markers were used to examine spatio-temporal genetic variation in the endangered eastern freshwater cod Maccullochella ikei in the Clarence River system, eastern Australia. High levels of population structure were detected. A model-based clustering analysis of multilocus genotypes identified four populations that were highly differentiated by F-statistics (F(ST) = 0.09 - 0.49; P < 0.05), suggesting fragmentation and restricted dispersal particularly among upstream sites. Hatchery breeding programmes were used to re-establish locally extirpated populations and to supplement remnant populations. Bayesian and frequency-based analyses of hatchery fingerling samples provided evidence for population admixture in the hatchery, with the majority of parental stock sourced from distinct upstream sites. Comparison between historical and contemporary wild caught samples showed a significant loss of heterozygosity (21%) and allelic richness (24%) in the Mann and Nymboida Rivers since the commencement of stocking. Fragmentation may have been a causative factor; however, temporal shifts in allele frequencies suggest swamping with hatchery-produced M. ikei has contributed to the genetic decline in the largest wild population. This study demonstrates the importance of using information on genetic variation and population structure in the management of breeding and stocking programmes, particularly for threatened species. PMID- 21235563 TI - Development and characterization of 60 novel EST-SSR markers in half-smooth tongue sole Cynoglossus semilaevis. AB - Sixty novel simple sequence repeat (SSR) markers were developed from expressed sequence tags (EST) of half-smooth tongue sole Cynoglossus semilaevis exploited in the laboratory. The number of alleles, observed and expected heterozygosity per locus ranged from two to 16, from 0.0833 to 1.0000 and from 0.0816 to 0.913, respectively. Of these SSRs, 20 had significant homology to known genes by BLASTx (basic local alignment search tool x) search. For cross-species amplification, there are 53 positive amplifications in Japanese flounder Paralichthys olivaceus with 12 polymorphic loci and 51 positive amplifications in Senegalese sole Solea senegalensis with 11 polymorphic loci. These new EST-SSR markers will be useful for genetic studies and genome mapping of C. semilaevis and its closely related fishes. PMID- 21235564 TI - A planktivorous specialist turns rapacious: piscivory in invading vendace Coregonus albula. AB - Following invasion and establishment in a subarctic watercourse, small-sized vendace Coregonus albula were surprisingly found to include fish prey in their diet. The zooplankton resource was severely depleted and only made a minor dietary contribution. PMID- 21235565 TI - Feeding of sea lampreys Petromyzon marinus on minke whales Balaenoptera acutorostrata in the St Lawrence Estuary, Canada. AB - Sea lampreys Petromyzon marinus were observed on 109 occasions on 47 individual minke whales Balaenoptera acutorostrata. Bloody lesions could be identified as previous attachment sites, indicating P. marinus feeding on B. acutorostrata blood. PMID- 21235566 TI - Influence of moon phase on fish assemblages in estuarine mangrove tidal creeks. AB - Significant differences in the composition of fish assemblages during different moon phases were detected in mangrove tidal creeks of the Goiana Estuary. The numbers of Zabaleta anchovy Anchovia clupeoides, Tarpon snook Centropomus pectinatus and Guavina Guavina guavina as well as at least 15 other species showed significant changes according to moon phase and were higher in terms of individuals (32%) and mass (34%) during the new moon. PMID- 21235567 TI - DNA barcoding highlights a cryptic species of grenadier Macrourus in the Southern Ocean. AB - Although three species of the genus Macrourus are recognized in the Southern Ocean, DNA sequencing of the mitochondrial COI gene revealed four well-supported clades. These barcode data suggest the presence of an undescribed species, a conclusion supported by meristic and morphometric examination of specimens. PMID- 21235568 TI - The northernmost record of Bassanago albescens and comments on the occurrence of Rhynchoconger guppyi (Teleostei: Anguilliformes: Congridae) along the Brazilian coast. AB - The northernmost occurrence of Bassanago albescens in the western Atlantic Ocean (off the coast of Rio de Janeiro, Brazil) is presented and compared with the available data on this species. Specimens formerly identified as Rhynchoconger guppyi from off the southern Brazilian coast are regarded as B. albescens. PMID- 21235569 TI - Discrimination of two picarel species Spicara flexuosa and Spicara maena (Pisces: Centracanthidae) based on mitochondrial DNA sequences. AB - A DNA methodology based on PCR and sequencing analysis of the mtDNA 16S rRNA gene was developed for the discrimination of picarel Spicara flexuosa and blotched picarel Spicara maena (Pisces: Centracanthidae). The molecular results indicated that there is a clear discrimination between the two species, as all the individuals of S. flexuosa revealed the same 16S rDNA haplotype while the S. maena haplotype differs in 15 distinct nucleotides. PMID- 21235570 TI - How large is the world's largest fish? Measuring whale sharks Rhincodon typus with laser photogrammetry. AB - Laser photogrammetry was found to be a promising new cost-effective technique for measuring free-swimming whale sharks Rhincodon typus. Photogrammetric measurements were more precise than visual size estimates by experienced researchers, with results from the two methods differing by 9. 8 +/- 1. 1% (mean +/-s.e.). A new metric of total length and the length between the fifth gill and first dorsal fin (r2 = 0. 93) is proposed to facilitate easy, accurate length measurements of whale sharks in the field. PMID- 21235571 TI - First record of Mugil hospes in the Gulf of Mexico and its identification from Mugil curema using ctenii. AB - This study gives the first record of Mugil hospes distributed in the Gulf of Mexico. This species previously has been confused with its congener Mugil curema and can be easily differentiated by the shape of the ctenii on their scales. PMID- 21235574 TI - Adenosine A2A receptors control neuroinflammation and consequent hippocampal neuronal dysfunction. AB - The blockade of adenosine A(2A) receptors (A2AR) affords a robust neuroprotection in different noxious brain conditions. However, the mechanisms underlying this general neuroprotection are unknown. One possible mechanism could be the control of neuroinflammation that is associated with brain damage, especially because A2AR efficiently control peripheral inflammation. Thus, we tested if the intracerebroventricular injection of a selective A2AR antagonist (SCH58261) would attenuate the changes in the hippocampus triggered by intraperitoneal administration of lipopolysaccharide (LPS) that induces neuroinflammation through microglia activation. LPS administration triggers an increase in inflammatory mediators like interleukin-1beta that causes biochemical changes (p38 and c-jun N terminal kinase phosphorylation and caspase 3 activation) contributing to neuronal dysfunction typified by decreased long-term potentiation, a form of synaptic plasticity. Long-term potentiation, measured 30 min after the tetanus, was significantly lower in LPS-treated rats compared with control-treated rats, while SCH58261 attenuated the LPS-induced change. The LPS-induced increases in phosphorylation of c-jun N-terminal kinase and p38 and activation of caspase 3 were also prevented by SCH58261. Significantly, SCH58261 also prevented the LPS induced recruitment of activated microglial cells and the increase in interleukin 1beta concentration in the hippocampus, indicating that A2AR activation is a pivotal step in mediating the neuroinflammation triggered by LPS. These results indicate that A2AR antagonists prevent neuroinflammation and support the hypothesis that this mechanism might contribute for the ability of A2AR antagonists to control different neurodegenerative diseases known to involve neuroinflammation. PMID- 21235575 TI - Intracellular trafficking and secretion of cerebral dopamine neurotrophic factor in neurosecretory cells. AB - Cerebral dopamine neurotrophic factor (CDNF) is a novel evolutionary conserved protein which can protect and restore the function of dopaminergic neurons in the rat model of Parkinson's disease, suggesting that CDNF might be beneficial for the treatment of Parkinson's disease. CDNF is widely expressed in neurons in several brain regions including cerebral cortex, hippocampus, substantia nigra, striatum and cerebellum. Human CDNF is glycosylated and secreted from transiently transfected cells; however, the mechanism underlying CDNF secretion is currently unclear. In this study, we found that CDNF could be secreted primarily via the regulated secretion pathway in PC12 cells. The glycosylation of CDNF is not required for its secretion. Moreover, we identified two key subdomains in CDNF which are important for its intracellular localization and secretion. Disrupting helix-1 of CDNF significantly reduces its constitutive and regulated secretion and the helix-1 mutant is retained in the endoplasmic reticulum. Although helix-7 mutation only decreases CDNF regulated secretion and has no effect on its constitutive secretion, which is further supported by the reduction in co localization of helix-7 mutant with secretory granules. In all, these findings will advance our understanding of the molecular mechanism of CDNF trafficking and secretion. PMID- 21235576 TI - HDAC6 regulates aggresome-autophagy degradation pathway of alpha-synuclein in response to MPP+-induced stress. AB - Increasing evidence suggests that the ubiquitin-binding histone deacetylase-6 (HDAC6) plays an important role in the clearance of misfolded proteins by autophagy. In this study, we treated PC-12 cells over-expressing human mutant (A53T) alpha-synuclein (alpha-syn) and SH-SY5Y cells with MPP(+). It was found that HDAC6 expression significantly increased and mainly colocalized with alpha syn in the perinuclear region to form aggresome-like bodies. HDAC6 deficiency blocked the formation of aggresome-like bodies and interfered with the autophagy in response to MPP(+)-induced stress. Moreover, misfolded alpha-syn accumulated into the nuclei, resulting in its reduced clearance, and finally, the number of apoptotic cells significantly increased. Taken together, HDAC6 participated in the degradation of MPP(+)-induced misfolded alpha-syn aggregates by regulating the aggresome-autophagy pathway. Understanding the mechanism may disclose potential therapeutic targets for synucleinopathies such as Parkinson's disease. PMID- 21235578 TI - Advancement in carbon nanotubes: basics, biomedical applications and toxicity. AB - OBJECTIVES: Carbon nanotubes (CNTs) have attracted much attention by researchers worldwide in recent years for their small dimensions and unique architecture, and for having immense potential in nanomedicine as biocompatible and supportive substrates, as a novel tool for the delivery of therapeutic molecules including peptides, RNA and DNA, and also as sensors, actuators and composites. KEY FINDINGS: CNTs have been employed in the development of molecular electronic, composite materials and others due to their unique atomic structure, high surface area-to-volume ratio and excellent electronic, mechanical and thermal properties. Recently they have been exploited as novel nanocarriers in drug delivery systems and biomedical applications. Their larger inner volume as compared with the dimensions of the tube and easy immobilization of their outer surface with biocompatible materials make CNTs a superior nanomaterial for drug delivery. Literature reveals that CNTs are versatile carriers for controlled and targeted drug delivery, especially for cancer cells, because of their cell membrane penetrability. SUMMARY: This review enlightens the biomedical application of CNTs with special emphasis on utilization in controlled and targeted drug delivery, as a diagnostics tool and other possible uses in therapeutic systems. The review also focuses on the toxicity aspects of CNTs, and revealed that genotoxic potential, mutagenic and carcinogenic effects of different types of CNTs must be explored and overcome by formulating safe biomaterial for drug delivery. The review also describes the regulatory aspects and clinical and market status of CNTs. PMID- 21235579 TI - Low-level microbial contamination of liquid in syringe hubs leads to an unacceptable risk to the end product. AB - OBJECTIVES: The aim of this study was to assess the risk associated with microbial contamination in the hub-fluid in Luer-lock syringes to the end product, and ultimately patients. METHOD: The hub-fluid of 48 sterile syringes prefilled with broth was contaminated with a low number of Staphylococcus epidermidis or spores of Bacillus subtilis. After incubation for three weeks, the syringe fills were tested for the presence of bacterial contaminants and some syringes were used to inoculate an end product broth that was then investigated for the presence of microorganisms. KEY FINDINGS: After three weeks of incubation only 20.8% of syringe fills showed turbidity, although following further investigation 70.8% were positive for the presence of viable bacteria, whereas 95.6% of end products became contaminated following injection of the syringe fill. CONCLUSIONS: These findings add quantitative data that support the current practice of discarding syringes with residue around the cap. PMID- 21235577 TI - Decreased activity of the 20S proteasome in the brain white matter and gray matter of patients with multiple sclerosis. AB - Carbonylated (oxidized) proteins are known to accumulate in the cerebral white matter (WM) and gray matter (GM) of patients with multiple sclerosis (MS). Although oxidative stress is necessary for carbonyl generation, it is the failure of the degradation systems that ultimately leads to the build-up of carbonylated proteins within tissues. In this study, we measured the activity of the 20S proteasome and other proteolytic systems in the cerebral WM and GM of 13 MS patients and 13 controls. We report that the activities of the three peptidases of the 20S proteasome (i.e. chymotrypsin-like, caspase-like and trypsin-like) in both MS-WM and MS-GM are greatly reduced. Interestingly, neither the amount of proteasome nor the levels of the catalytic subunits (beta1, beta2, and beta5) are diminished in this disease. Proteins containing Lys-48 poly-ubiquitin also accumulate in MS tissues, indicating failure of the 26S proteasome as well. Levels of the regulatory caps 11S alpha and 19S are also lower in MS than in controls, suggesting that the activity of the more complex proteasomes may be reduced further. Finally, the activities of other proteases that might also remove oxidized proteins (calpain, cathepsin B, mitochondrial LonP) are not lessened in MS. Together, these studies suggest that direct inactivation of proteolytic centers in the 20S particle and/or the presence of specific inhibitors is the underlying cause of proteasomal dysfunction in MS. PMID- 21235580 TI - Design and development of gliclazide-loaded chitosan microparticles for oral sustained drug delivery: in-vitro/in-vivo evaluation. AB - OBJECTIVES: The objective of this study was to prepare gliclazide-chitosan microparticles with tripolyphosphate by ionic crosslinking. METHODS: Chitosan microparticles were produced by emulsification and ionotropic gelation. The effects of process variables including chitosan concentration, pH of tripolyphosphate solution, glutaraldehyde volume and release modifier agent such as pectin added to the tripolyphosphate crosslinking solution were evaluated. The microparticles were examined with scanning electron microscopy, infrared spectroscopy and differential scanning colorimetry. The serum glucose lowering effect of gliclazide microparticles was studied in streptozotocin-diabetic rabbits compared with the effect of pure gliclazide powder and gliclazide commercial tablets. KEY FINDINGS: The particle sizes of tripolyphosphate-chitosan microparticles were over the range 675-887 um and the loading efficiency of drug was greater than 94.0%. In-vivo testing of the gliclazide-chitosan microparticles in diabetic rabbits demonstrated a significant antidiabetic effect of gliclazide chitosan microparticles after 8 h that lasted for 18 h compared with gliclazide powder, which produced a maximum hypoglycaemic effect after 4 h. CONCLUSIONS: The results suggests that gliclazide-chitosan microparticles are a valuable system for the sustained delivery of gliclazide. PMID- 21235581 TI - Antioxidant multi-walled carbon nanotubes by free radical grafting of gallic acid: new materials for biomedical applications. AB - OBJECTIVES: To prove the possibility of covalently functionalizing multi-walled carbon nanotubes (CNTs) by free radical grafting of gallic acid on their surface with the subsequent synthesis of materials with improved biological properties evaluated by specific in-vitro assays. METHODS: Antioxidant CNTs were synthesized by radical grafting of gallic acid onto pristine CNTs. The synthesis of carbon nanotubes was carried out in a fixed-bed reactor and, after the removal of the amorphous carbon, the grafting process was performed. The obtained materials were characterized by fluorescence and Fourier transform infrared spectroscopy (FT-IR) analyses. After assessment of the biocompatibility and determination of the disposable phenolic group content, the antioxidant properties were evaluated in terms of total antioxidant activity and scavenger ability against 2,2'-diphenyl-1 picrylhydrazyl (DPPH), hydroxyl and peroxyl radicals. Finally the inhibition activity on acetylcholinesterase was evaluated. KEY FINDINGS: The covalent functionalization of CNTs with gallic acid was confirmed and the amount of gallic acid bound per g of CNTs was found to be 2.1+/-0.2 mg. Good antioxidant and scavenging properties were recorded in the functionalized CNTs, which were found to be able to inhibit the acetylcholinesterase with potential improved activity for biomedical and pharmaceutical applications. CONCLUSIONS: For the first time, a free radical grafting procedure was proposed as a synthetic approach for the covalent functionalization of CNTs with an antioxidant polyphenol. PMID- 21235582 TI - Platelet lysate formulations based on mucoadhesive polymers for the treatment of corneal lesions. AB - OBJECTIVES: Growth factors contained in platelet alpha-granules initiate and modulate tissue repair and are proposed for the treatment of soft and hard-tissue surgical conditions and in the management of non-healing wounds. Platelet lysate is a hemoderivative obtained from platelet-rich plasma and is capable of releasing a pool of growth factors. Many medical and surgical techniques have been proposed for the treatment of corneal lesions; management of these conditions remains problematic and healing with standard protocols is unattainable. The aim of this study was to develop formulations suitable for prolonging the contact of platelet lysate with the damaged cornea for the time necessary to exert a therapeutic effect. METHODS: Two vehicles, one based on polyacrylic acid and one based on chitosan, were autoclaved and loaded with platelet lysate and the resultant formulations were characterized for rheology, mucoadhesion, vehicle compatibility and stability. The proliferation effect was tested on two cell culture types (rabbit corneal epithelial cells and fibroblasts). An in-vitro wound-healing test was performed on fibroblasts. In both cases the formulations were compared with platelet lysate diluted with saline at the same concentration. FINDINGS: Both formulations maintained the rheological and mucoadhesive properties of the vehicles and the proliferative activity of platelet lysate. The chitosan formulation was able to significantly enhance epithelial cell growth even after storage of up to 2 weeks (in-use conditions), while the polyacrylic acid formulation was less efficient, probably due to the characteristics of the cell model used. CONCLUSIONS: The in-vitro wound-healing test performed on fibroblasts confirmed the differences between the two vehicles. The effect induced by the platelet lysate and chitosan formulation was faster than that of the polyacrylic acid formulation and complete in-vitro wound repair was achieved within 48 h. PMID- 21235583 TI - The extent of the uptake of plasmid into the skin determines the immune responses induced by a DNA vaccine applied topically onto the skin. AB - OBJECTIVES: Non-invasive immunization by application of plasmid DNA topically onto the skin is an attractive immunization approach. However, the immune responses induced are generally weak. Previously, we showed that the antibody responses induced by topical DNA vaccine are significantly enhanced when hair follicles in the application area are induced into the anagen (growth) stage by hair plucking. In the present study, we further investigated the mechanism of immune enhancement. METHODS: Three different methods--hair plucking or treatment with retinoic acid (RA) or O-tetradecanoylphorbol-13-acetate (TPA)--were used to induce mice hair follicles into the anagen stage before they were dosed with a beta-galactosidase-encoding plasmid, and the specific antibody responses induced were evaluated. KEY FINDINGS: The hair-plucking method was more effective at enhancing the resultant antibody responses. Treatment with RA or TPA caused more damage to the skin and induced more severe local inflammation than hair plucking. However, hair plucking was most effective at enhancing the uptake or retention of the DNA in the application area. CONCLUSIONS: The uptake of plasmid DNA in the application area correlated with the antibody responses induced by a topically applied DNA. PMID- 21235584 TI - Modulated pharmacokinetics and increased small intestinal toxicity of methotrexate in bilirubin-treated rats. AB - OBJECTIVES: The effect of bilirubin treatment on the pharmacokinetics and small intestinal toxicity of methotrexate was evaluated in rats, since bilirubin and its glucuronide conjugates can suppress multidrug resistance-associated protein mediated transport. METHODS: Rats were treated intravenously with bilirubin and the various clearances and tissue distribution of methotrexate were estimated under a steady-state plasma concentration. Intestinal toxicity induced by methotrexate was also evaluated by measuring the leakage of alkaline phosphatase (ALP) activity. Probenecid, an inhibitor for multidrug resistance-associated protein and organic anion transporters, was used for comparison. KEY FINDINGS: The treatment with bilirubin increased the steady-state plasma concentration and reduced biliary excretion clearance, urinary excretion clearance and intestinal exsorption clearance of methotrexate, as did treatment with probenecid. The intestinal absorption and jejunum distribution of methotrexate also significantly increased in bilirubin- and probenecid-treated rats. A greater leakage of ALP activity to the luminal fluid, with a lower ALP activity in the intestinal mucosal membrane after intestinal perfusion of methotrexate, was observed in bilirubin- and probenecid-treated rats. CONCLUSIONS: Hyperbilirubinemia, which is involved under various disease states, may increase the small intestinal accumulation and toxicities of methotrexate, since high plasma concentrations of conjugated bilirubin can suppress the function of multidrug resistance-associated proteins, which facilitate the efflux of methotrexate out of cells. PMID- 21235585 TI - Mechanism of cytochrome P450-3A inhibition by ketoconazole. AB - OBJECTIVES: Ketoconazole is extensively used as an index inhibitor of cytochrome P450-3A (CYP3A) activity in vitro and in vivo, but the mechanism of ketoconazole inhibition of CYP3A still is not clearly established. METHODS: Inhibition of metabolite formation by ketoconazole (seven concentrations from 0.01 to 1.0 um) was studied in human liver microsomes (n = 4) at six to seven substrate concentrations for triazolam, midazolam, and testosterone, and at two substrate concentrations for nifedipine. KEY FINDINGS: Analysis of multiple data points per liver sample based on a mixed competitive-noncompetitive model yielded mean inhibition constant K(i) values in the range of 0.011 to 0.045 um. Ketoconazole IC50 increased at higher substrate concentrations, thereby excluding pure noncompetitive inhibition. For triazolam, testosterone, and midazolam alpha hydroxylation, mean values of alpha (indicating the 'mix' of competitive and noncompetitive inhibition) ranged from 2.1 to 6.3. However, inhibition of midazolam 4-hydroxylation was consistent with a competitive process. Determination of K(i) and alpha based on the relation between 50% inhibitory concentration values and substrate concentration yielded similar values. Pre incubation of ketoconazole with microsomes before addition of substrate did not enhance inhibition, whereas inhibition by troleandomycin was significantly enhanced by pre-incubation. CONCLUSIONS: Ketoconazole inhibition of triazolam alpha- and 4-hydroxylation, midazolam alpha-hydroxylation, testosterone 6beta hydroxylation, and nifedipine oxidation appeared to be a mixed competitive noncompetitive process, with the noncompetitive component being dominant but not exclusive. Quantitative estimates of K(i) were in the low nanomolar range for all four substrates. PMID- 21235586 TI - Protein kinase A signalling is involved in the relaxant responses to the selective beta-oestrogen receptor agonist diarylpropionitrile in rat aortic smooth muscle in vitro. AB - OBJECTIVES: The oestrogen receptor beta (ERbeta) selective agonist diarylpropionitrile (DPN) relaxes endothelium-denuded rat aorta, but the signalling mechanism is unknown. The aim of this study was to assess whether protein kinase A (PKA) signalling is involved in DPN action. METHODS: cAMP was measured by radioimmunoassay, HSP20 phosphorylation by 2D gel electrophoresis with immunoblotting, and membrane potential and free cytosolic calcium by flow cytometry. KEY FINDINGS: DPN increased cAMP content and hyperpolarised cell membranes over the same range of concentrations as it relaxed phenylephrine precontracted aortic rings (10-300 uM). DPN-induced vasorelaxation was largely reduced by the PKA inhibitors Rp-8-Br-cAMPS (8-bromoadenosine-3', 5'-cyclic monophosphorothioate, Rp-isomer) and H-89 (N-(2-bromocynnamyl(amino)ethyl)-5 isoquinoline sulfonamide HCl) (-73%) and by the adenylate cyclase inhibitor MDL12330A (cis-N-(2-phenylcyclopentyl)-azacyclotridec-1-en-2-amine)) (-65.5%). Conversely, the PKG inhibitor Rp-8-Br-cGMP was inactive against DPN vasorelaxation. In aortic smooth muscle segments, DPN increased PKA-dependent HSP20 phosphorylation, an effect reversed by H-89. Relaxant responses to DPN were modestly antagonised (-23 to -48% reduction; n=12 per compound) by the potassium channel inhibitors iberiotoxin, PNU-37883A, 4-aminopyridine, or BaCl(2) . All four potassium channel inhibitors together reduced DPN relaxation by 86+/-9% (n=12) and fully blocked DPN hyperpolarisation. CONCLUSIONS: ERbeta-dependent relaxation of rat aortic smooth muscle evokes an adenylate cyclase/cAMP/PKA signalling pathway, likely activating the cystic fibrosis transmembrane conductance regulator chloride channel and at least four potassium channels. PMID- 21235587 TI - Comparative study of taurine and tauropyrone: GABA receptor binding, mitochondrial processes and behaviour. AB - OBJECTIVES: Taurine, a sulfur-containing amino acid, has high hydrophilicity and is poorly absorbed. Tauropyrone, a taurine-containing 1,4-dihydropyridine derivative, is suggested to have greater activity than taurine owing to improved physicochemical properties that facilitate delivery of the compound to target cells. The aim of this study was to determine whether the 1,4-dihydropyridine moiety in tauropyrone improves the pharmacological efficacy of taurine in vitro and in vivo. METHODS: The effects of taurine and tauropyrone, as well as of the 1,4-dihydropyridine moiety were compared in in-vitro experiments to determine the binding to GABA receptors and influence on mitochondrial processes (isolated rat liver mitochondria), and in in-vivo tests to assess the influence on behavioural effects caused by the GABA-A receptor ligands, bicuculline, diazepam and ethanol. KEY FINDINGS: Unlike taurine, tauropyrone did not display binding activity for the GABA-A receptor, and only taurine (but not tauropyrone) at low doses (0.1, 1.0 and 10 mg/kg) antagonised the bicuculline-induced convulsion effect. Taurine and tauropyrone had no effect on diazepam myorelaxing action, and they both exerted a comparable 'anti-ethanol' effect (shortening of the ethanol-sleeping time). Taurine and tauropyrone did not influence processes of mitochondrial bioenergetics. CONCLUSIONS: The action of tauropyrone at the level of the GABA-A receptor differs qualitatively from that of taurine, probably because of its 1,4 dihydropyridine moiety, which may hinder access to the GABA-A receptor GABA site. Tauropyrone does not show improved pharmacological efficacy in in-vitro and in vivo studies in comparison with taurine. PMID- 21235588 TI - Preparation and effects of 2,3-dehydrosilymarin, a promising and potent antioxidant and free radical scavenger. AB - OBJECTIVES: Silymarin or silybin has been effectively used for treating liver diseases and acute liver injury partly due to its antioxidant activity. In this study, 2,3-dehydrosilymarin, a compound exhibiting remarkable antiradical/antioxidant activity, was prepared from silymarin for the first time. The solubility, radical scavenging capacity and liver protecting activity of 2,3 dehydrosilymarin were studied and compared with silybin, dehydrosilybin and silymarin. METHODS: The structures of its main components were verified by ultra performance liquid chromatography/mass spectrometry (UPLC-MS) and other spectral analysis. In addition, a rapid screening method, online high-performance liquid chromatography/1,1-dipheny1-2-picrylhydrazyl (HPLC-DPPH) system, was developed for identifying the individual antioxidants in 2,3-dehydrosilymarin. KEY FINDINGS: Both in-vitro and in-vivo results markedly proved that dehydrosilymarin has decent aqueous solubility and remarkable antiradical/antioxidation capacity. Moreover, 2,3-dehydrosilybin and 2,3-dehydrosilychristin were identified to be the two major active compounds contained in 2,3-dehydrosilymarin. CONCLUSIONS: Our results suggest that 2,3-dehydrosilymarin may be a promising and potent alternative for inhibition of free radical and prevention of oxidation. PMID- 21235589 TI - Signalling pathways responsible for the methylisogermabullone-induced contraction of ileal longitudinal muscles. AB - OBJECTIVES: We have previously reported that methylisogermabullone (MIGB) stimulates small bowel motility through activation of acetylcholinergic receptors. This study investigated the cellular signalling pathways implicated in the regulation of ileal contractility by MIGB. METHODS: The ileal longitudinal muscles prepared from rats were treated with MIGB isolated from radish roots, and muscle contractility and protein expression were measured by force transducer and Western blot, respectively. KEY FINDINGS: MIGB at 30 um induced a sustained phasic contraction of ileal longitudinal muscles. Acetylcholine (ACh, 0.5 um) and MIGB stimulated translocation of protein kinase C (PKC) to cell membrane of ileal longitudinal muscles, and these stimulatory effects were remarkably attenuated by atropine (0.5 um). ACh and MIGB induced phosphorylation of ERK 1/2 and p38 MAPKs in ileal longitudinal muscles, and they also phosphorylated the caldesmon and 20 kDa regulatory light chain of myosin (MLC(20) ). Additionally, PD-98058 (10 um), a selective ERK 1/2 MAPK inhibitor, and SB-203580 (10 um), a selective p38 MAPK inhibitor, significantly reduced the MIGB-induced contraction of ileal longitudinal muscles. CONCLUSIONS: The muscarinic receptor activated by MIGB translocates the PKC to cell membrane which phosphorylates the ERK 1/2 and p38 MAPKs, resulting in subsequent phosphorylation of caldesmon and MLC(20) . These cellular events likely converge on the contraction of ileal longitudinal muscles in rats. PMID- 21235590 TI - Effects of Tween 80 on volume-regulated chloride channel and cell proliferation in rat basilar artery smooth muscle cell. AB - OBJECTIVES: We have previously found that volume-regulated chloride current (VRCC) is involved in cell cycle progression and cell proliferation. This study was to examine the effect of Tween 80, a nonionic surfactant, on VRCC and cell proliferation in rat basilar artery smooth muscle cells (BASMCs). METHODS: VRCC was recorded using a whole-cell patch clamp. Cell proliferation and cell cycle were determined by CCK-8, cell count and flow cytometry. KEY FINDINGS: The results showed that endothelin-1 promotes cell cycle transition from the G0/G1 phase to the S phase and significantly increases VRCC in BASMCs. The effect of Tween 80 on VRCC is reversible and concentration dependent. However, this chemical has no effect on the calcium-activated chloride channel. Tween 80 also concentration-dependently inhibits BASMCs proliferation and arrests cells in the G1/S checkpoint. The antiproliferative effect is paralleled with the inhibitory effect on VRCC. CONCLUSION: Our study demonstrates that the inhibitory effect of Tween 80 on VRCC contributes importantly to arrest of the cell cycle and prevention of cell proliferation. PMID- 21235591 TI - Effect and mechanism of senkyunolide I as an anti-migraine compound from Ligusticum chuanxiong. AB - OBJECTIVE: To evaluate the analgesic and anti-migraine activities of senkyunolide I from Ligusticum chuanxiong. METHODS: Mice were orally administered various doses of senkyunolide I, and their pain levels were assessed in a hot-plate test and by application of acetic acid. The levels of 5-hydroxytryptamine (5-HT), 5 hydroxytryptophan (5-HTP), 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine (NE) and dopamine (DA) in plasma and brain were assessed, and the monoamine turnover rates (5-HT/5-HTP, 5-HIAA/5-HT and NE/DA) were also calculated. RESULTS: Mice given senkyunolide I at 16 and 32 mg/kg had significantly elevated pain thresholds in the hot-plate test, and a dose of 32 mg/kg also reduced the number of abdominal writhing responses caused by acetic acid. Significant improvements were observed in the neurotransmitter levels of the drug-treated rats compared with the saline-administered controls. Compared to the rats with nitroglycerin induced migraines, the levels of nitric oxide in the plasma and whole brain of rats given senkyunolide I were lower. CONCLUSIONS: The present study suggests that senkyunolide I may be an active component of L. chuanxiong, traditionally used to treat migraine. The mechanism of pain relief in migraine model rats may be through adjusting the levels of monoamine neurotransmitters and their turnover rates, as well as decreasing nitric oxide levels in the blood and brain. Therefore, senkyunolide I may be developed as a potential treatment for migraine pain. PMID- 21235592 TI - Alcoholic extract of Cicer microphyllum augments Th1 immune response in normal and chronically stressed Swiss albino mice. AB - OBJECTIVE: The purpose of this study was to observe the effect of an alcoholic extract of Cicer microphyllum (I(3) M/38/A001) (whole plant without seeds and flowers) on the immunological parameters of sheep red blood cell immunized normal and chronically stressed Swiss albino mice. METHODS: Estimation of T-cell subsets (CD3(+) , CD4(+) /CD8(+) ), CD80/CD86, CD28, CD 69, costimulatory molecules and Th1/Th2 cytokines was carried out using a flow cytometer. This was followed by study of the delayed type hypersensitivity response, in-vitro lymphocyte proliferation assay and measurement of Th1/Th2 cytokines in isolated peripheral blood mononuclear cells by flow cytometry. An enzyme immune assay was used to analyse corticosterone levels in the serum of chronically stressed animals. KEY FINDINGS: We found that oral administration of I(3) M/38/A001 once daily at the graded doses of 6.25, 12.5, 25, 50, 100 and 200 mg/kg p.o. enhanced the proliferation and differentiation of T lymphocytes in sheep red blood cell normal and chronically stressed mice, as shown by flow cytometric analysis. The extract selectively induced type 1 immunity: it guided enhanced expression of Th1 cytokines, interferon-gamma and interleukin-2, while no significant change in interleukin-4 (Th2 cytokine) levels was observed. Confirmation of Th1 polarization was confirmed by the augmented levels of interferon-gamma and interleukin-2 in isolated peripheral blood mononuclear cells. A significant suppression of raised corticosterone levels was also observed in stressed animals, which suggests the extract's normalizing effect on the hypothalamic pituitary-adrenal axis. Co-stimulatory molecules, CD28, CD69, CD80 and CD86, which are important secondary signals for the activation of the immune system, elicited significant expression in I(3) M/38/A001 treated mice. CONCLUSION: Our studies show the immune potentiating and immune recuperative effect of the test drug in sheep red blood cell-immunized normal and chronically stressed mice. PMID- 21235593 TI - Synthesis and antimalarial activity of ethylene glycol oligomeric ethers of artemisinin. AB - OBJECTIVES: The aim of this study was to synthesize a series of ethylene glycol ether derivatives of the antimalarial drug artemisinin, determine their values for selected physicochemical properties and evaluate their antimalarial activity in vitro against Plasmodium falciparum strains. METHODS: The ethers were synthesized in a one-step process by coupling ethylene glycol moieties of various chain lengths to carbon C-10 of artemisinin. The aqueous solubility and log D values were determined in phosphate buffered saline (pH 7.4). The derivatives were screened for antimalarial activity alongside artemether and chloroquine against chloroquine-sensitive (D10) and moderately chloroquine-resistant (Dd2) strains of P. falciparum. KEY FINDINGS: The aqueous solubility within each series increased as the ethylene glycol chain lengthened. The IC50 values revealed that all the derivatives were active against both D10 and Dd2 strains. All were less potent than artemether irrespective of the strain. However, they proved to be more potent than chloroquine against the resistant strain. Compound 8, featuring three ethylene oxide units, was the most active of all the synthesized ethers. CONCLUSIONS: The conjugation of dihydroartemisinin to ethylene glycol units of various chain lengths through etheral linkage led to water-soluble derivatives. The strategy did not result in an increase of antimalarial activity compared with artemether. It is nevertheless a promising approach to further investigate and synthesize water-soluble derivatives of artemisinin that may be more active than artemether by increasing the ethylene glycol chain length. PMID- 21235594 TI - Ameliorative effects of glycyrrhizin on streptozotocin-induced diabetes in rats. AB - OBJECTIVES: Glycyrrhizin is the main water-soluble constituent of the root of liquorice (Glycyrrhiza glabra). The study investigates the effect of glycyrrhizin on streptozotocin (STZ)-induced diabetic changes and associated oxidative stress, including haemoglobin-induced free iron-mediated oxidative reactions. METHODS: Male Wistar rats were grouped as normal control, STZ-induced diabetic control, normal treated with glycyrrhizin, diabetic treated with glycyrrhizin and diabetic treated with a standard anti-hyperglycaemic drug, glibenclamide. Different parameters were studied in blood and tissue samples of the rats. KEY FINDINGS: Glycyrrhizin treatment improved significantly the diabetogenic effects of STZ, namely enhanced blood glucose level, glucose intolerant behaviour, decreased serum insulin level including pancreatic islet cell numbers, increased glycohaemoglobin level and enhanced levels of cholesterol and triglyceride. The treatment significantly reduced diabetes-induced abnormalities of pancreas and kidney tissues. Oxidative stress parameters, namely, serum superoxide dismutase, catalase, malondialdehyde and fructosamine in diabetic rats were reverted to respective normal values after glycyrrhizin administration. Free iron in haemoglobin, iron-mediated free radical reactions and carbonyl formation in haemoglobin were pronounced in diabetes, and were counteracted by glycyrrhizin. Effects of glycyrrhizin and glibenclamide treatments appeared comparable. CONCLUSION: Glycyrrhizin is quite effective against hyperglycaemia, hyperlipidaemia and associated oxidative stress, and may be a potential therapeutic agent for diabetes treatment. PMID- 21235595 TI - Structure-metabolism relationships for the glucuronidation of flavonoids by UGT1A3 and UGT1A9. AB - OBJECTIVES: This study tries to find structure-metabolism relationships between flavonoids and human UGT1A3 and UGT1A9. METHODS: The glucuronidation of flavonoids was studied with recombinant UGT1A3 and UGT1A9, and the glucuronidation activity was determined by HPLC. KEY FINDINGS: Of the flavonoids studied, it was shown for the first time that baicalein, quercetin-3-OCH(2) OCH(3) , quercetin-4'-CH(3) , quercetin-3'-OCH(3) and quercetin-3'-Br are substrates of UGT1A3. Wogonin, baicalein, quercetin-4'-Cl, quercetin-3-OCH(2) OCH(3) , quercetin-3-O-arabinoside, quercetin-4'-CH(3) , quercetin-3'-OCH(3) and quercetin-3'-Br are the newly reported substrates of UGT1A9. The preferred substrates for UGT1A3 and UGT1A9 contain the hydroxyl group at the C7-position. The glycon and the position of the B ring have conspicuous influences on the glucuronidation activity, and other chemical structures of flavonoids have minor effects. CONCLUSIONS: From the quantitative study, UGT1A9 in general has higher glucuronidation efficiency than UGT1A3. PMID- 21235596 TI - How do we prevent transfusion-associated graft-versus-host disease in children? PMID- 21235597 TI - Xenotropic murine leukemia virus-related virus (XMRV) and blood transfusion: report of the AABB interorganizational XMRV task force. PMID- 21235598 TI - Transient elastography and biomarkers for liver fibrosis assessment and follow-up of inactive hepatitis B carriers. AB - BACKGROUND: Non invasive methods for fibrosis evaluation remain to be validated longitudinally in hepatitis B. AIM: To evaluate longitudinally transient elastography (TE) and biomarkers for liver fibrosis assessment and follow-up of hepatitis B virus (HBV) inactive carriers. METHODS: Three hundred and twenty-nine consecutive HBeAg-negative HBV patients (201 inactive carriers) who underwent TE, Fibrotest and aspartate to platelet ratio index (APRI) the same day were studied. RESULTS: TE (median 4.8 vs. 6.8 kPa, P < 0.0001), Fibrotest (0.16 vs. 0.35, P < 0.0001) and APRI values (0.28 vs. 0.43, P < 0.0001) were significantly lower in inactive carriers than in the remaining patients whereas they did not differ among inactive carriers according to HBV DNA levels. In 82 inactive carriers with repeated examinations, although differences were observed among individual patients, TE values did not differ significantly over time (median intra-patient changes at end of follow-up relative to baseline: -0.2 kPa, P = 0.12). Conversely, significant fluctuations were observed for Fibrotest (+0.03, P = 0.012) and APRI (-0.01, P < 0.05). Eleven inactive carriers (5.5%) had initial elevated TE values (>7.2 kPa) confirmed during follow-up in two with significant fibrosis (F2 and F3) on liver biopsy. CONCLUSION: Non-invasive tools, particularly TE, could be useful, in addition to HBV DNA and transaminase levels, for follow-up of HBV inactive carriers as well as better selection of patients who require a liver biopsy. PMID- 21235599 TI - JAK2V617F mutation and myeloproliferative disorders in splanchnic vein thrombosis. PMID- 21235601 TI - Potential role of granulocyte/monocyte adsorptive apheresis for ulcerative colitis with concomitant CMV infection. PMID- 21235603 TI - Influenza A (H1N1)v infection in patients with inflammatory bowel disease: a case series. PMID- 21235604 TI - Mucosal healing with methotrexate in Crohn's disease: a prospective comparative study with azathioprine and infliximab. AB - BACKGROUND: Mucosal healing has become a new therapeutic goal in Crohn's disease and can be achieved with azathioprine (AZA) or biologics. Methotrexate (MTX) is an effective drug for both the induction and maintenance of remission in Crohn's disease. However, mucosal healing with MTX has been poorly investigated. AIM: To assess the mucosal healing rate in patients with Crohn's disease with clinical response to MTX as compared with AZA or infliximab (IFX). METHODS: From October 2007 to May 2009, consecutive patients with Crohn's disease were prospectively enrolled into a single-centre study when they met the following criteria: previous identification of mucosal ulcerations with ileo-colonoscopy, clinical remission within at least 3 months with MTX, AZA or IFX monotherapy, usual indication for colonoscopy in Crohn's disease (dysplasia/cancer screening, suspected stenosis) excluding assessment for mucosal healing. Mucosal healing was defined as absence of mucosal ulceration in all segments. RESULTS: Fifty-one patients with Crohn's disease (38 female; median age: 42 years) were included: 18 receiving MTX, 18 AZA and 15 IFX. Mucosal healing was achieved in 2/18 (11%) with MTX, in 9/18 (50%) with AZA (P =0.011 vs. MTX) and in 9/15 (60%) with IFX (P=0.008 vs. MTX). CONCLUSION: In patients with Crohn's disease in sustained clinical remission, mucosal healing is less frequently achieved with MTX as compared with AZA or IFX. PMID- 21235605 TI - A practice transition for the better good. PMID- 21235606 TI - Home care dental practice business and clinical guidelines. PMID- 21235607 TI - Financial--how to get paid by the patient or the facility. PMID- 21235608 TI - The evolution of a new (unofficial) specialty: dental Geriatrician. PMID- 21235609 TI - Treating patients with autism spectrum disorder--SCDA members' attitudes and behavior. AB - The goal of this study was to explore (a) the attitudes and behavior of members of the Special Care Dentistry Association (SCDA) who self-identified as treating patients with Autism Spectrum Disorders (ASD) and (b) the relationship between their professional attitudes and behaviors concerning these patients. Data were collected from 75 SCDA members who responded to an anonymous web-based survey on the SCDA website. The majority of respondents liked to treat children and adults with ASD (57%/56.9%). They treated approximately nine patients with ASD in an average week. The more they liked to treat children with ASD, the more patients with ASD they treated (r = .313; p = .018), and the more accommodations to overcome problems with communication, social interactions and aversion to change they made (r = .404; p < .001). Providers' attitudes concerning patients with ASD were quite positive and correlated with professional behavior concerning these patients. Future research should explore whether improving attitudes towards providing care for special needs patients could increase professional behavior and thus contribute to reducing the access to care problems these patients face. PMID- 21235610 TI - Dental utilization by adult Medicaid enrollees who have indicators of intellectual and developmental disabilities (IDD). AB - The purpose of this study was to determine dental utilization and type of dental services for Medicaid-enrolled adults who had been identified as having intellectual and developmental disabilities (IDD). Using Iowa claims data, the authors identified adults who met any of five IDD criteria for inclusion during calendar year 2005. Service utilization rates, including use of preventive dental, routine restorative, and complex restorative services, were determined. Approximately 60% of adults with IDD had at least one dental visit in 2005. Among adults with at least one dental visit, 83% received a preventive service, 31% a routine restorative service, and 16% a complex dental service. Those age 65 and older had fewer preventive dental services than other age groups. In Iowa, dental utilization for adults 22-64 years of age with IDD was reasonably high (64%) in 2005, but individuals over age 65 had lower utilization (45%). PMID- 21235611 TI - Salivary factors and dental plaque levels in relation to the general health of elderly residents in a long-term care facility: a pilot study. AB - The goal of this study was to examine salivary factors and formation of dental plaque in elderly subjects who were institutionalized and to relate these factors to general health and medication use. This cross-sectional study consisted of 50 elderly individuals who were institutionalized and 25 healthy young volunteers who served as a reference group. For each subject, salivary flow rates, salivary pH, and buffering capacity were assessed. Baseline Plaque Index and Plaque Formation Rate Index were used as a measure of oral hygiene. Information on each patient's general health and medication use was acquired from the institution. An evaluation of the results of this study suggests that salivary protective qualities and dental plaque levels in the elderly subjects who were institutionalized were worse than in healthy young individuals. An association between the general health of the elderly and salivary flow rate was found. PMID- 21235612 TI - Opinions on the provision of dental care in Iowa nursing homes. AB - Using a stratified random sample, a questionnaire was mailed to 400 practicing dentists and 200 directors of nursing (DONs). Response rates were 58.3% for dentists and 50% for DONs. Dentists were representative of Iowa dentists, with 85% male, mean age 49.1 years, and 22.4 years in practice. All DONs were female, with mean age of 44.9 years. Of the participating dentists, 86% had provided dental care for nursing home residents, but the majority of care was completed in dental offices. Three-quarters of dentists were somewhat/not interested in nursing home dentistry. Dentists and DONs held common perceptions of the most frequent problems related to care provision at nursing homes: low financial reimbursement, especially for Medicaid patients; no portable dental equipment; no suitable area for dentistry; dentist's preference to treat patients at their dental practice; and transportation of residents to a dental practice. Dentists and DONs had some differing perceptions about oral health care (p < .01). Minimal dental care was provided on-site at Iowa nursing homes. PMID- 21235613 TI - Use of moderate sedation for a patient with Down syndrome, intellectual disability, and Eisenmenger syndrome: a case report. AB - For patients who have Eisenmenger syndrome (ES), perioperative risks are high even for noncardiac surgery, such as dental extractions. We report on the case history of a 38-year-old male patient with Down syndrome (DS), intellectual disability (ID), and ES. The patient was scheduled for extraction of the right maxillary second molar tooth. His physical health was poor. Following oxygenation, midazolam was administered intravenously very slowly until the optimum sedative level was obtained, with a total dosage of 3.5 mg. There were no marked changes in vital signs during the perioperative period, and the patient was discharged the same day. This case suggests that moderate or conscious sedation using midazolam for dental treatment of a patient with DS, ID, and ES was well tolerated. Several critical points are presented in this review. PMID- 21235615 TI - Open or submerged healing of implants with platform switching: a randomized, controlled clinical trial. AB - AIM: The temporal pattern of bone-level alterations in conventionally restored implants is dependent upon healing mode (open or submerged). This study examined the influence of healing on marginal bone levels at implants with a medium-rough surface including the implant collar and a clearance-fit implant-abutment connection restored according to a platform-switching concept. MATERIAL AND METHODS: Two implants were placed in the posterior mandible of 21 test subjects, randomly assigned to open (OH) or submerged (SH) healing. Standardized radiographs were obtained after implant surgery, before re-entry, after crown mounting, 1 and 2 years after implant surgery, and evaluated for implant-bone level alterations (DeltaIBL). Bacterial samples of the implants' inner cavities were analysed by cultivation. STATISTICS: Brunner-Langer Model, equivalence testings by Wilcoxon's (equivalence range +/-0.4mm). RESULTS: After 2 years, DeltaIBL were -0.47+/-0.46mm (OH) and -0.54+/-0.38mm (SH). At the 1-year follow up, all implants were contaminated with bacteria. DeltaIBL (p<0.001) and the amount of bacterial contamination (p<0.001) significantly depended on time, but not on healing mode. DeltaIBL of OH and SH were equivalent at all time points (all p0.044). CONCLUSIONS: Platform-switched implants showed very limited peri implant bone-level alterations. The healing-mode neither affected the total amount nor the temporal patterns of DeltaIBL. Thus, the results for the tested implants with a non-rigid implant-abutment connection were similar to results reported previously for implants with a rigid implant-abutment connection. PMID- 21235616 TI - Effects of enamel matrix derivative on periodontal wound healing in an inflammatory environment in vitro. AB - AIM: This in vitro study was established to investigate whether the regenerative capacity of periodontal ligament (PDL) cells in the presence of enamel matrix derivative (EMD) is modulated by inflammation. MATERIALS AND METHODS: PDL cells were grown in the presence or absence of EMD under normal and inflammatory conditions for up to 14 days. In order to mimic an inflammatory environment, cells were incubated with interleukin (IL)-1beta. Cells were also exposed to transforming growth factor (TGF)-beta1 and insulin-like growth factor (IGF)-1 under both conditions. For analysis of wound healing, an in vitro wound fill assay was used. The synthesis of growth factors, markers of proliferation, and osteogenic differentiation, as well as collagen was studied by real-time polymerase chain reaction, enzyme-linked immunoassay, and immunoblotting. Mineralization was assessed by alizarine red S and von Kossa staining. RESULTS: EMD stimulated significantly the in vitro wound fill rate, cell proliferation and adhesion, synthesis of growth factors, and collagen, as well as mineralization. In the presence of IL-1beta, these EMD effects were significantly reduced. IL 1beta also inhibited significantly the wound fill rate induced by TGF-beta1 and IGF-1. CONCLUSIONS: Critical PDL cell functions that are associated with periodontal regeneration are reduced in an inflammatory environment. PMID- 21235618 TI - Haemolytic anaemia and abdominal pain--a cause not to be missed. PMID- 21235617 TI - Deaths of opiate/opioid misusers involving dihydrocodeine, UK, 1997-2007. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Dihydrocodeine (DHC) is an opioid analgesic sometimes prescribed as an alternative to other medications (e.g. methadone and buprenorphine) for opioid misuse. Its effectiveness is, however, still controversial. DHC prescription rates seem to be related to levels of DHC fatalities, possibly in relation to levels of disregard of the availability of supervised or interval dispensing of opioids, but no large-scale analysis of DHC fatalities has been carried out. We analysed here involvement of DHC in fatalities that occurred between 1997 and 2007 among individuals with a history of opiate/opioid misuse reported to the National Programme on Substance Abuse Deaths (np-SAD). WHAT THIS STUDY ADDS: DHC, either alone or in combination, was identified in 584 fatalities. Typical cases identified were males in their early thirties. In accidental overdoses, DHC, which had been prescribed to 45% of the victims, was typically identified in combination with other drugs, such as heroin/morphine, methadone and hypnotics/sedatives. Both paracetamol and antidepressants were more typically identified in combination with DHC in suicides. Opiate/opioid misusers should be educated about risks associated with polydrug intake and prescribers should carefully consider a pharmacological intervention alternative to DHC (e.g. methadone, buprenorphine) when managing and treating opiate addiction. AIMS: Although its effectiveness is somewhat controversial, it appears that dihydrocodeine (DHC) is still prescribed in the UK as an alternative to both methadone and buprenorphine for the treatment of opiate addiction. METHODS: Data covering the period 1997-2007 voluntarily supplied by coroners were analysed. All cases pertaining to victims with a clear history of opiate/opioid misuse and in which DHC, either on its own or in combination, was identified at post-mortem toxicology and/or implicated in death, were extracted from the database. RESULTS: Dihydrocodeine, either alone or in combination, was identified in 584 fatalities meeting the selection criteria. In 44% of cases it was directly implicated in the cause of death. These cases represented about 6.8% of all opiate/opioid-related deaths during this period. Typical DHC cases identified were White males in their early thirties. Accidental deaths (96%) were likely to involve DHC in combination with other psychoactives, mainly heroin/morphine, hypnotics/sedatives and methadone. Both paracetamol and antidepressants were found in proportionately more suicide cases than in accidental overdoses. DHC had been prescribed to the decedent in at least 45% of cases. CONCLUSIONS: Opiate/opioid misusers should be educated about risks associated with polydrug intake. More in particular, co-administration of DHC with heroin, methadone and benzodiazepines may increase the risk of accidental fatal overdose. Prescribers should carefully consider pharmacological intervention alternative to DHC (e.g. methadone, buprenorphine) when managing and treating opiate addiction. More resources are required to do prospective research in this area. PMID- 21235620 TI - Inhibition of paracetamol glucuronidation by tyrosine kinase inhibitors. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Clinical cases reported that fatal acute liver failure occurred when paracetamol (acetaminophen) was co administrated with some tyrosine kinase inhibitors (TKIs). The direct inhibition of UDP-glucuronosyltransferase activities has been identified as a mechanism of potentiation of paracetamol hepatotoxicity. However, the effects of TKIs on paracetamol glucuronidation are not known. WHAT THIS STUDY ADDS: * The TKIs, sorafenib, dasatinib and imatinib exhibited potent mixed inhibition against paracetamol glucuronidation in pooled human liver microsomes, implying a possible increase in paracetamol hepatotoxicity when they are co-administrated with paracetamol. AIMS We aimed to investigate the effects of tyrosine kinase inhibitors (TKIs) on paracetamol (acetaminophen) glucuronidation. METHODS: The inhibition of nine small molecule TKIs on paracetamol glucuronidation was investigated in human liver microsomes (HLMs) and recombinant human UDP glucuronosyltransferases (UGTs). RESULTS: Sorafenib, dasatinib and imatinib exhibited mixed inhibition against paracetamol glucuronidation in pooled HLMs, and potent inhibition in UGT1A9 and UGT2B15. Dasatinib and imatinib also inhibited UGT1A1-mediated paracetamol glucuronidation. Axitinib, erlotinib, gefitinib, lapatinib, nilotinib and vandetanib exhibited weak inhibition of paracetamol glucuronidation activity in HLMs. CONCLUSIONS: The inhibition of paracetamol glucuronidation by TKIs might be of particular concern when they are co-administered. PMID- 21235621 TI - Current progress in pharmacogenetics. AB - The study of genetic variation has the potential to aid understanding of the mechanisms underlying the observed inter-individual variation in drug response and by which idiosyncratic adverse effects occur. In this review, we outline current progress in pharmacogenetics using examples to highlight both mechanisms of influence of polymorphisms and research strategies for their detection. In the final sections we discuss contemporary challenges for both researchers and clinicians. PMID- 21235623 TI - Periodontal health status in the elderly with different levels of education: a 5 year follow-up study. AB - OBJECTIVE: To assess the association between the periodontal health status and level of education over a 5-year period among the elderly aged 75 years and older. BACKGROUND: Oral health among the higher educated is known to be better than among the less-well educated. On the other hand, the prevalence and severity of periodontal disease has been found to grow with increasing age. METHODS: The participants were derived from a population-based Helsinki Aging Study, a random sample of 76-, 81- and 86-year-old elderly. The 170 dentate elderly who underwent clinical oral examinations at baseline and 71 who participated in the follow-up were included in this study. The data was collected from intraoral and radiological examinations and from a structured questionnaire. RESULTS: Subjects with a higher level of education had more retained teeth than subjects with a lower level of education. According to CPITN index, better-educated participants had more healthy sextants, but they also had more sextants with periodontal pockets. Radiographic examination showed similar results. CONCLUSION: Level of education has a clear effect on the periodontal health status in the elderly. More treatment need seems to polarise into those elderly who are better educated as they retain more teeth into old age. PMID- 21235624 TI - Evaluation of partially dentate patients' knowledge about caries and periodontal disease. AB - OBJECTIVE: This investigation evaluated the knowledge of dental caries and periodontal disease among removable partial denture (RPD) wearers. METHOD: A total of 127 partially dentate patients participated in this observational study. A structured questionnaire, which included eight questions referring to knowledge about aetiology and prevention of dental caries and periodontal disease, was developed in the local language (Portuguese) and used to collect the data of all the partial denture wearers. A descriptive analysis of data was performed by means of drafting tables. RESULTS: The results demonstrated that 68.5% of patients interviewed had previously received information about oral health care. With regard to bacterial plaque, it was observed that only 34.6% reported having knowledge of this. Whereas, in relation to caries, 76.4% of the interviewees replied that they knew the meaning of this. Nevertheless, 28.3% referred to caries as a whole in the teeth, 16.5% as bad teeth and 9.4% bacteria/creatures on the teeth. Only 17.3% of the partially edentulous patients evaluated were shown to know what disease of the gingiva was. CONCLUSION: By means of the methodology applied, it could be concluded that the patients who wore RPDs presented deficient knowledge with regard to the prevention, aetiology and development of dental caries and periodontal disease. PMID- 21235622 TI - Peri-operative anaphylaxis. AB - Peri-operative anaphylaxis is an important cause for mortality and morbidity associated with anaesthesia. The true incidence is unknown and is most likely under reported. Diagnosis can be difficult, particularly as a number of drugs are given simultaneously and any of these agents can potentially cause anaphylaxis. This review covers the clinical features, differential diagnosis and management of anaphylaxis associated with anaesthesia. The investigations to confirm the clinical suspicion of anaphylaxis and further tests to identify the likely drug(s) are examined. Finally the salient features of common and rare causes including non-drug substances are described. PMID- 21235625 TI - Reoperative coronary artery bypass grafting via left thoracotomy and hypothermic fibrillation. AB - Left posterolateral thoracotomy approach for reoperative coronary artery bypass grafting (CABG) is a useful alternative to median sternotomy. We describe use of a left posterolateral thoracotomy and hypothermic fibrillation for reoperative CABG in a patient with patent bilateral internal thoracic artery grafts. PMID- 21235626 TI - Reimplantation versus remodeling: a meta-analysis. AB - BACKGROUND: Reimplantation and remodeling procedure are two different techniques for valve-sparing aortic root surgery. A number of comparative series have been published but, to date, there has been no meta-analysis comparing outcomes following the two techniques. METHODS: This meta-analysis was performed in accordance with the Cochrane Handbook for Systematic Reviews. A public domain database (MEDLINE) was searched to identify relevant series. Pooled risk ratios (RR) were calculated using fixed effects models for early (30-day) mortality, late deaths, and reoperation related to moderate or severe aortic insufficiency (AI) during follow-up. RESULTS: The search identified seven eligible series, totaling 672 patients (367 reimplantation patents). There was no significant difference in early (30-day) mortality (pooled RR 1.06; 95% CI 0.36 to 3.10; p = 0.92) and late deaths (pooled RR 0.57; 95% CI 0.18 to 1.87; p = 0.36) between reimplantation and remodeling groups. However, reimplantation technique has less chance for reoperation related to moderate or severe AI during follow-up (pooled RR 0.46; 95% CI 0.23 to 0.92; p = 0.03). CONCLUSION: Comparing with remodeling, reimplantation technique has less chance for reoperation related to moderate or severe AI during long-term follow-up. PMID- 21235627 TI - Reduction of the sinotubular junction in patients undergoing ascending aortic replacement with coexisting aortic insufficiency. AB - BACKGROUND AND AIM OF THE STUDY: Dilatation of the STJ may cause consequent aortic insufficiency (AI) in patients with normal aortic valve, in patients with ascending aortic aneurysm. In this study, we analyzed the results of ascending aorta replacement with STJ diameter reduction to correct consequent AI in patients with ascending aortic aneurysm. METHODS: Forty-five consecutive patients who had ascending aortic aneurysm underwent replacement of ascending aorta with reduction of the STJ diameter to correct AI. Mean age of the patients was 61.3 +/ 5.2. Twenty-six (57.8%) were female. Six patients had arch aneurysm. Postoperative echocardiographic studies were performed at discharge and annually thereafter. The mean duration of follow-up was 4.6 +/- 2.9 years. RESULTS: Hospital mortality rate was 4.9% (n = 2). Three patients died during follow-up. Three patients had late recurrence of AI that was caused by aortic root dilatation. One of these patients required aortic valve replacement because of severe aortic insufficiency. The five-year survival and survival free from aortic insufficiency were 91.4%+/- 5.0% and 91.2%+/- 5.1%, respectively. CONCLUSIONS: Reduction of the diameter of STJ can be used to treat AI in patients with ascending aortic aneurysm with nearly normal aortic cusps. Midterm results of this procedure are encouraging. PMID- 21235628 TI - How I do aortic valve sparing operations to treat aortic root aneurysm. PMID- 21235629 TI - Le-Compte's maneuver for relief of bronchial compression in atrial septal defect. AB - We performed anterior translocation of the pulmonary artery (Le-Compte's maneuver) in a patient with an atrial septal defect with long standing complete collapse of the left lung due to extrinsic compression of the left bronchus by a dilated pulmonary artery. Following the closure of the septal defect and anterior translocation of the pulmonary artery, there was immediate relief of airway obstruction followed by reexpansion of the collapsed lung. PMID- 21235630 TI - Allograft cardiectomy and biventricular assist device placement as a salvage maneuver in a heart transplant recipient. AB - End-stage allograft failure following cardiac transplantation is a devastating problem, and retransplantation offers the only chance for survival. We present the case of a young man with a failing cardiac allograft who underwent allograft cardiectomy, atrial pouch formation, and biventricular assist device (BiVAD) placement as a salvage maneuver. PMID- 21235631 TI - A 5-year venom immunotherapy protocol with 50 MUg maintenance dose: safety and efficacy in school children. AB - BACKGROUND: Venom immunotherapy (VIT) has been shown to be an effective and safe treatment for preventing sting-induced anaphylaxis in patients with systemic reactions to hymenoptera stings. A remaining problem is the relative effectiveness and safety of different immunotherapy protocols used with respect to maintenance dose, injection interval, and duration. OBJECTIVE: We aimed to describe a modified cluster VIT protocol with a maintenance dose of 50 MUg lasting 5 yr and to evaluate retrospectively its safety and efficacy in children. PATIENTS AND METHODS: Fifty four children 9.5+/-3.2 yr old with a history of at least one anaphylactic reaction to hymenoptera stings underwent VIT between 1995 and 2006. The identification of the offending insect(s) was based on patient's report and documented with in-vivo (SPTs and IDs) and in-vitro (RAST/CAP) test results. A modified cluster outpatient protocol lasting 5 wks, reaching a maintenance dose of 50 MUg was followed according to clinical history and test results. After the maintenance dose was achieved, the followed injection intervals were 4 wks for the first year, 5 wks for the 2nd year and 3rd year, and 6 wks for the last 2 yr. RESULTS: Of the 54 children, 52 tolerated the 50 MUg VIT protocol without side effects. Twenty one of them reported at least one field sting from at least one of the culprit, for their allergy, insects, 6+/-3.5 yr after they have started VIT treatment. In 11 of them, sting occurred 3.5+/-2.9 yr after the VIT was completed, whereas the other 10 of them during immunotherapy, 3.2+/-1.4 yr after they have started VIT. In the remaining two children, the maintenance dose was increased to 100 MUg due to systemic reactions from the VIT. The data reflect outcomes 6-16 yr after the patients' initial allergic reaction. CONCLUSION: VIT with 50 MUg maintenance dose lasting 5 yr appears to be safe and effective enough to induce tolerance in children with hymenoptera venom hypersensitivity. PMID- 21235632 TI - Analysis of genitourinary anomalies in patients with VACTERL (Vertebral anomalies, Anal atresia, Cardiac malformations, Tracheo-Esophageal fistula, Renal anomalies, Limb abnormalities) association. AB - The goal of this study was to describe a novel pattern of genitourinary (GU) anomalies in VACTERL association,which involves congenital anomalies affecting the vertebrae,anus, heart, trachea and esophagus, kidneys, and limbs.We collected clinical data on 105 patients diagnosed with VACTERL association and analyzed a subset of 89 patients who met more stringent inclusion criteria. Twenty-one percent of patients have GU anomalies, which are more severe (but not more frequent) in females. Anomalies were noted in patients without malformations affecting the renal, lower vertebral, or lower gastrointestinal systems. There should be a high index of suspicion for the presence of GU anomalies even in patients who do not have spatially similar malformations. PMID- 21235642 TI - Spo0J regulates the oligomeric state of Soj to trigger its switch from an activator to an inhibitor of DNA replication initiation. AB - Control of DNA replication initiation is essential for bacterial cells to co ordinate the faithful replication and segregation of their genetic material. The Bacillus subtilis ATPase Soj is a dynamic protein that regulates DNA replication initiation by either inhibiting or activating the DNA replication initiator protein DnaA. Here we report that the key event which switches Soj regulatory activity is a transition in its oligomeric state from a monomer to an ATP dependent homodimer capable of DNA binding. We show that the DNA binding activity of the Soj dimer is required both for activation of DNA replication initiation and for interaction with Spo0J. Finally, we demonstrate that Spo0J inhibits Soj dimerization by stimulating Soj ATPase activity. The data provide a molecular explanation for the dichotomous regulatory activities of Soj, as well as assigning unique Soj conformations to distinct cellular localization patterns. We discuss how the regulation of Soj ATPase activity by Spo0J could be utilized to control the initiation of DNA replication during the cell cycle. PMID- 21235643 TI - Cerebral and clinical effects of short-term hand immobilisation. AB - In this work, functional changes in the sensorimotor cortex following unilateral hand immobilisation were investigated in 11 healthy volunteers. Sensory and motor function of both hands was also assessed. Cortical activation was monitored with functional magnetic resonance imaging at 3 T. All examinations were performed prior to and directly after 72 h of immobilisation of the dominant hand and wrist. Following unilateral immobilisation, cortical activation increased substantially during tactile stimulation of the non-immobilised hand. This was particularly evident in the ipsilateral somatosensory cortex. Additionally, a redistribution of hemispheric dominance towards zero lateralisation was seen. A bilateral cortical activation increase was also seen during performance of a finger-tapping task by the non-immobilised hand, although this increase was less prominent than during tactile stimulation. In contrast, performance of the finger tapping task with the immobilised hand resulted in an activation decrease, predominantly in the ipsilateral sensorimotor cortex. This site was anatomically close to the regional activation increase of the non-immobilised hand. These functional changes were associated with reduced grip strength, dexterity and tactile discrimination of the immobilised hand, and simultaneously improved tactile discrimination of the non-immobilised hand. This suggests that brain adaptation following hand immobilisation includes inter-hemispheric dynamics. In summary, the improved sensory function of the non-immobilised hand following unilateral immobilisation is associated with cortical expansion, predominantly contralateral to the immobilised hand, and a redistribution of hemispheric dominance. Both cortical and clinical effects of immobilisation were identified after 72 h, suggesting rapid inter-hemispheric plasticity using existing neural substrates. PMID- 21235644 TI - A eukaryotic LOV-histidine kinase with circadian clock function in the picoalga Ostreococcus. AB - The marine environment has unique properties of light transmission, with an attenuation of long wavelengths within the first meters of the water column. Marine organisms have therefore evolved specific blue-light receptors such as aureochromes to absorb shorter-wavelength light. Here, we identify and characterize a light, oxygen, or voltage sensing (LOV) containing histidine kinase (LOV-HK) that functions as a new class of eukaryotic blue-light receptor in the pico-phytoplanktonic cell Ostreococcus tauri. This LOV-HK is related to the large family of LOV-HKs found in prokaryotes. Phylogenetic analysis indicates that the LOV domains from LOV-HKs, including O. tauri LOV-HK, and phototropins (phot; plant and green algal LOV serine/threonine kinases) have different evolutionary histories. Photochemical analysis shows that the LOV domain of LOV HK binds a flavin cofactor and absorbs blue light with a fast photocycle compared with its prokaryotic counterparts. Ostreococcus tauri LOV-HK expression is induced by blue light and is under circadian control. Further, both overexpression and downregulation of LOV-HK result in arrhythmia of the circadian reporter CCA1:Luc under constant blue light. In contrast, photochemical inactivation of O. tauri LOV-HK is without effect, demonstrating its importance for function of the circadian clock under blue light. Overexpression/downregulation of O. tauriLOV-HK alters CCA1 rhythmicity under constant red light, irrespective of LOV-HK's photochemical reactivity, suggesting that O. tauri LOV-HK also participates in regulation of the circadian clock independent of its blue-light-sensing property. Molecular characterization of O. tauri LOV-HK demonstrates that this type of photoreceptor family is not limited to prokaryotes. PMID- 21235645 TI - Hybrid embryos of Vicia faba develop enhanced sink strength, which is established during early development. AB - Selfed and crossed seeds of two homozygous Vicia faba lines served as models for the analysis of the physiological and molecular mechanisms underlying embryo heterosis. Profiles of transcripts, metabolites and seed contents of developing embryos were analysed to compare the means of reciprocally crossed and selfed seeds growing on the same mother plants. The mean weight of mature hybrid seeds was demonstrably higher, revealing mid-parent heterosis. Hybrid embryos exhibited a prolonged early phase of development and delayed onset of storage activity. Accordingly, transcript profiling indicates stimulation of cell proliferation, an effect, which is potentially mediated by activation of auxin functions within a framework of growth-related transcription factors. At the transcript level, activated cell proliferation increased assimilate uptake activity and thereby seed sink strength. This situation might finally lead to the increased size of the hybrid seeds. We conclude that hybrid seeds are characterised by accelerated growth during early development, which increases storage capacity and leads to higher metabolic fluxes. These needs are, at least partially, met by increased assimilate uptake capacity. The stimulated growth of hybrid seeds shifted metabolite profiles and potentially depleted available pools. Such metabolic shifts are most likely secondary effects resulting from the higher storage capacity of hybrid seeds, a heterotic feature, which is itself established very early in seed development. PMID- 21235646 TI - MicroRNA534a control of BLADE-ON-PETIOLE 1 and 2 mediates juvenile-to-adult gametophyte transition in Physcomitrella patens. AB - The Arabidopsis thaliana BLADE-ON-PETIOLE genes encode a pair of transcriptional coactivators that regulate lateral organ architecture by promoting cell differentiation in their proximal regions. To gain insight into the roles of BOP genes early in land plant evolution, we characterized the functions of Physcomitrella patens BOP1 and BOP2 and their negative regulator Pp-miR534a. We show that in DeltaPpMIR534a mutants lacking mature Pp-miR534a, cleavage of PpBOP1/2 is abolished, leading to elevated PpBOP1/2 transcript levels. These loss of-function mutants display an accelerated gametophore development thus correlating elevated levels of PpBOP1/2 with premature bud formation. This is further supported by our finding that exposure to cytokinin, which is known to induce bud formation on caulonema, downregulates PpMIR534a transcription and increases the accumulation of PpBOP1 in apical caulonema cells. Reporter gene fusions showed that PpMIR534a is ubiquitously expressed in protonema whereas PpBOP1/2 accumulation is restricted almost exclusively to potent caulonema apical cells and their side branch initials, but absent from differentiated cells. Together, our data propose that PpBOP1/2 act as positive regulators of protonema differentiation and that Pp-miR534a is required to control the timing of the juvenile-to-adult gametophyte transition by spatially restricting their expression to caulonema stem cells. As protonemata develop, increased cytokinin levels downregulate Pp-MIR534a transcription in these cells until a threshold level of PpBOP1/2 is reached that triggers cell differentiation and bud formation. PMID- 21235648 TI - Light exposure of Arabidopsis seedlings causes rapid de-stabilization as well as selective post-translational inactivation of the repressor of photomorphogenesis SPA2. AB - The COP1/SPA complex acts as an E3 ubiquitin ligase to repress photomorphogenesis by targeting activators of the light response for degradation. Genetic analysis has shown that the four members of the SPA gene family (SPA1-SPA4) have overlapping but distinct functions. In particular, SPA1 and SPA2 differ in that SPA1 encodes a potent repressor in light- and dark-grown seedlings, but SPA2 fully loses its function when seedlings are exposed to light, indicating that SPA2 function is hyper-inactivated by light. Here, we have used chimeric SPA1/SPA2 constructs to show that the distinct functions of SPA1 and SPA2 genes in light-grown seedlings are due to the SPA protein sequences and independent of the SPA promoter sequences. Biochemical analysis of SPA1 and SPA2 protein levels shows that light exposure leads to rapid proteasomal degradation of SPA2, and, more weakly, of SPA1, but not of COP1. This suggests that light inactivates the COP1/SPA complex partly by reducing SPA protein levels. Although SPA2 was more strongly degraded than SPA1, this was not the sole reason for the lack of SPA2 function in the light. We found that the SPA2 protein is inherently incapable of repressing photomorphogenesis in light-grown seedlings. The data therefore indicate that light inactivates the function of SPA2 through a post-translational mechanism that eliminates the activity of the remaining SPA2 protein in the cell. PMID- 21235647 TI - Arabidopsis nucleoside hydrolases involved in intracellular and extracellular degradation of purines. AB - Recently, the first plant nucleoside hydrolase, NSH1 (former designation URH1), was identified at the molecular level. This enzyme's highest hydrolysis capacity is for uridine, thereby balancing pyrimidine salvage and catabolism. NSH1 was found to be less efficient in the hydrolysis of further nucleosides. However, it remained unclear whether purine nucleosides are processed by NSH1. Moreover, the biochemical and physiological functions of further NSH isoforms in Arabidopsis has not been analyzed. Here we show that NSH1 is also able to hydrolyze xanthosine with high efficiency, and thus represents the leading activity in purine and pyrimidine breakdown in a cell. A knockout mutant for NSH1 showed symptoms of accelerated senescence, accompanied by marked accumulation of uridine and xanthosine under conditions of prolonged darkness. The closest, so far uncharacterized, homolog of NSH1, NSH2, was found to act during the late phase of senescence and may support inosine breakdown. NSH3, another NSH isoform, surprisingly functions as an extracellular, purine-specific hydrolase that is involved in degradation of extracellular nucleosides and may participate in wound and pathogen responses. PMID- 21235649 TI - BAC-recombineering for studying plant gene regulation: developmental control and cellular localization of SnRK1 kinase subunits. AB - Recombineering, permitting precise modification of genes within bacterial artificial chromosomes (BACs) through homologous recombination mediated by lambda phage-encoded Red proteins, is a widely used powerful tool in mouse, Caenorhabditis and Drosophila genetics. As Agrobacterium-mediated transfer of large DNA inserts from binary BACs and TACs into plants occurs at low frequency, recombineering is so far seldom exploited in the analysis of plant gene functions. We have constructed binary plant transformation vectors, which are suitable for gap-repair cloning of genes from BACs using recombineering methods previously developed for other organisms. Here we show that recombineering facilitates PCR-based generation of precise translational fusions between coding sequences of fluorescent reporter and plant proteins using galK-based exchange recombination. The modified target genes alone or as part of a larger gene cluster can be transferred by high-frequency gap-repair into plant transformation vectors, stably maintained in Agrobacterium and transformed without alteration into plants. Versatile application of plant BAC-recombineering is illustrated by the analysis of developmental regulation and cellular localization of interacting AKIN10 catalytic and SNF4 activating subunits of Arabidopsis Snf1-related (SnRK1) protein kinase using in vivo imaging. To validate full functionality and in vivo interaction of tagged SnRK1 subunits, it is demonstrated that immunoprecipitated SNF4-YFP is bound to a kinase that phosphorylates SnRK1 candidate substrates, and that the GFP- and YFP-tagged kinase subunits co-immunoprecipitate with endogenous wild type AKIN10 and SNF4. PMID- 21235651 TI - Members of an R2R3-MYB transcription factor family in Petunia are developmentally and environmentally regulated to control complex floral and vegetative pigmentation patterning. AB - We present an investigation of anthocyanin regulation over the entire petunia plant, determining the mechanisms governing complex floral pigmentation patterning and environmentally induced vegetative anthocyanin synthesis. DEEP PURPLE (DPL) and PURPLE HAZE (PHZ) encode members of the R2R3-MYB transcription factor family that regulate anthocyanin synthesis in petunia, and control anthocyanin production in vegetative tissues and contribute to floral pigmentation. In addition to these two MYB factors, the basic helix-loop-helix (bHLH) factor ANTHOCYANIN1 (AN1) and WD-repeat protein AN11, are also essential for vegetative pigmentation. The induction of anthocyanins in vegetative tissues by high light was tightly correlated to the induction of transcripts for PHZ and AN1. Interestingly, transcripts for PhMYB27, a putative R2R3-MYB active repressor, were highly expressed during non-inductive shade conditions and repressed during high light. The competitive inhibitor PhMYBx (R3-MYB) was expressed under high light, which may provide feedback repression. In floral tissues DPL regulates vein-associated anthocyanin pigmentation in the flower tube, while PHZ determines light-induced anthocyanin accumulation on exposed petal surfaces (bud-blush). A model is presented suggesting how complex floral and vegetative pigmentation patterns are derived in petunia in terms of MYB, bHLH and WDR co-regulators. PMID- 21235650 TI - GhMYB25-like: a key factor in early cotton fibre development. AB - MYB transcription factors have been implicated in regulation of the development of ovule epidermal cells into the elongated seed fibres of cotton. An R2R3 MYB, GhMYB25-like, identified from its reduced expression in a fibreless mutant of cotton (Xu142 fl), is here shown to play a key role in the very early stages of fibre cell differentiation. A GhMYB25-like promoter-GUS construct was expressed predominantly in the epidermal layers of cotton ovules before anthesis (-3days post-anthesis, dpa), increasing in expression in 0-dpa ovules, primarily in those epidermal cells expanding into fibres, and then in elongating fibres at +3dpa, declining thereafter. This was consistent with GhMYB25-like transcript abundance during fibre development. RNA interference suppression of GhMYB25-like resulted in cotton plants with fibreless seeds, but normal trichomes elsewhere, phenocopying the Xu142 fl mutant. Like Xu142 fl these plants had reduced expression of the fibre-expressed MYBs, GhMYB25 and GhMYB109, indicating that GhMYB25-like is upstream from those MYBs. This hierarchy was supported by the absence of any change in transcript level of GhMYB25-like in GhMYB25- and GhMYB109-silenced transgenic lines. Transgenic cotton with an additional copy of the native gene had elevated expression of GhMYB25-like in ovules, but no obvious increase in fibre initials, suggesting that there may be other factors that interact with GhMYB25-like to differentiate epidermal cells into fibre cells. PMID- 21235652 TI - What will this decade bring? PMID- 21235653 TI - Connected health and the pharmacist. PMID- 21235654 TI - Pharmacy clients' attitudes to expanded pharmacist prescribing and the role of agency theory on involved stakeholders. AB - OBJECTIVE: To examine the views of regular pharmacy clients on pharmacist prescribing and employ agency theory in considering the relationship between the stakeholders involved. METHODS: Computer assisted telephone interviews were conducted with 400 pharmacy clients recruited around Australia. Potential respondents were identified using a random number generation function in Microsoft Excel. Data were analysed with SPSS version 17 using one-way analysis of variance, principal component analysis and linear regression. The relationships between the main stakeholders involved were explored using agency theory. KEY FINDINGS: A total of 1153 answered calls recruited 400 consenting pharmacy clients. Most respondents (71%) trusted pharmacists adopting an expanded role in prescribing, however the majority (66%) supported this only after a diagnosis had been made by a doctor. Those who accepted pharmacist diagnosing and prescribing preferred that this was limited to pain management and antibiotics. Most respondents (64%) considered that expanded pharmacist prescribing would improve their access to prescription medicines, although those over 65 years of age were less supportive than younger respondents. Factors which contributed positively to clients' perception of trust in an expanded prescribing role for pharmacists were identified, and improved access to medicines was found to be the strongest predictor (P < 0.0001). CONCLUSION: Most pharmacy clients trusted pharmacists adopting an expanded prescribing role, but preferred that this was limited to doctors performing the initial diagnosis. Agency theory would conceptualize the introduction of pharmacist prescribers, as disrupting the principal (patient) agent (doctor) relationship. Its introduction would best be facilitated by careful change management. PMID- 21235655 TI - Sources of drug information for patients with chronic conditions in Alexandria, Egypt. AB - OBJECTIVES: This study sought to identify patients' perceived drug knowledge, need for more information and drug information sources, and how they varied by patient characteristics, particularly education level. METHODS: A convenience sample of 366 adult patients was interviewed when leaving 20 Egyptian pharmacies after collecting a dispensed prescription. Patients were asked about their (1) perceived knowledge of their drugs' purpose, (2) use of package inserts (PIs) to learn about side effects, contraindications and drug interactions, (3) perceived need to know more about their drugs and (4) general sources of drug information beyond healthcare providers. KEY FINDINGS: More than 30% of the patients reported that they did not know the purpose of at least one of their drugs and only read PIs selectively. Whereas 36% read about drug interactions, more reported reading about side effects (65%) and contraindications (60%) in PIs. Sixty-nine per cent of patients reported that they needed more information about their drugs. This was true for 86.8% of patients with limited education compared to 48.5% of university graduates. University graduates reported using PI topics, newspapers, internet, TV and family and friends as sources of drug information at significantly higher rates than did patients with lower levels of education. CONCLUSION: There is a need for healthcare professionals to evaluate patient comprehension and needs for drug information, especially for patients with less schooling. Healthcare providers should also consider other information sources that a patient is using. PMID- 21235656 TI - Collaboration in chronic care: unpacking the relationship of pharmacists and general medical practitioners in primary care. AB - OBJECTIVES: The objective of this research was to gain deeper understanding of the expectations, experiences and perceptions of Australian general medication practitioners (GPs) and pharmacists around collaboration in chronic illness (asthma) management in the primary care setting. METHODS: A qualitative research methodology utilising a semi-structured interview guide, based on theory and an empirical approach, was used to fulfill the objectives of this study. Face-to face interviews with pharmacists (n = 18) and GPs (n = 7) were recorded, transcribed and coded for concepts and themes. Relationships between concepts and themes were examined and used to describe the nature of collaborative relationships in the primary care setting. KEY FINDINGS: A relationship between GPs and pharmacists currently exists although there is minimal collaboration and there are several areas of practice and patient care in which the two professional groups are mismatched. At the same time, this research uncovered key aspects of the GP-pharmacist relationship, which could be used to develop more collaborative relationships in the future. The findings from this study were evaluated in light of the Collaborative Working Relationships model and published literature. CONCLUSIONS: A model for the development of GP-pharmacist relationship has been postulated which articulates the dynamic nature of professional relationship in primary care and highlights a pathway to more collaborative practice. Future research should focus on further developing this model. PMID- 21235657 TI - An assessment of dispensing practices in private pharmacies in Dar-es-Salaam, Tanzania. AB - OBJECTIVES: To assess medicine dispensing practices in private pharmacies in Dar es-Salaam, Tanzania and recommend interventions to improve practice. METHODS: A cross-sectional survey and observational study of dispensing practices among 70 pharmacies in metropolitan Dar-es-Salaam, Tanzania. KEY FINDINGS: There were 1479 dispensing encounters recorded across the 70 pharmacies. This translated to 1573 medicines dispensed. Of the medicines dispensed, 16% were anti-infectives; 45% of the dispensed medicines were requested by the client, 32% were recommended by the dispenser and only 23% were on prescriptions. The main reasons for pharmacy consultations were coughs (62%), general pain (62%) and 'flu and colds. Malaria constituted 21% of the private pharmacy visits. Of the cough encounters, 30% received antibiotics. In addition, oral antibiotics were given to 81% of the clients with diarrhoea and to 95% of those with eye and ear problems. Of the 628 clients who requested specific medicines without a prescription, only 29% were asked questions on why the medicines were required. Of the clients who bought antibiotics, 20% bought incomplete doses. In total, 1180 clients were interviewed. Of these, 35% could not repeat the instructions given to them by the dispenser. Of the 70 dispensers who gave dosage instructions, only 20% gave them according to guidelines. CONCLUSION: In Tanzania, an overwhelming proportion of medicines sold in pharmacies are dispensed without a prescription. The majority of medicines dispensed without a prescription are either requested by the client or recommended by the dispenser. When dispensing medicines, dispensers seldom give dosage instructions; when they do, the instructions are often not consistent with guidelines. A high proportion of clients seeking management of coughs and colds or for diarrhoea from private pharmacies receive antibiotics. Interventions that build the capacity of dispensers, improve the rational use of antibiotics and the management of diarrhoea in private pharmacies in Tanzania are necessary to provide consistent quality services to a populace that relies heavily on the private sector for their medications needs. PMID- 21235658 TI - Unprevented or prevented dispensing incidents: which outcome to use in dispensing error research? AB - OBJECTIVES: To compare the rate, error type, causes and clinical significance of unprevented and prevented dispensing incidents reported by Welsh National Health Service (NHS) hospital pharmacies. METHODS: Details of all unprevented and prevented dispensing incidents occurring over 3 months (September-December 2005) at five district general hospitals across Wales were reported and analysed using a validated method. Rates of unprevented and prevented dispensing incidents were compared using Mann-Whitney U test. Reported error types, contributory factors and clinical significance of unprevented and prevented incidents were compared using Fisher's exact test. KEY FINDINGS: Thirty-five unprevented and 291 prevented dispensing incidents were reported amongst 221,670 items. The rate of unprevented (16/100,000 items) and prevented dispensing incidents (131/100,000 items; P = 0.04) was significantly different. There was a significant difference in the proportions of prevented and unprevented dispensing incidents involving the wrong directions/warnings on the label (prevented, n = 100, 29%; unprevented, n = 4, 10%; P = 0.02) and the wrong drug details on the label (prevented, n = 15, 4%; unprevented, n = 6, 14%; P = 0.01). There was a significant difference in the proportions of prevented and unprevented dispensing incidents involving supply of the wrong strength (prevented, n = 46, 14%; unprevented, n = 2, 5%; P = 0.02) and issue of expired medicines (prevented, n = 3, 1%; unprevented, n = 5, 12%; P = 0.002). CONCLUSION: The use of prevented dispensing incidents as a surrogate marker for unprevented incidents is questionable. There were significant differences between unprevented and prevented dispensing incidents in terms of rate and error types. This is consistent with the medication error iceberg. Care must be exercised when extrapolating prevented dispensing incident data on error types to unprevented dispensing incidents. PMID- 21235659 TI - Incorrect drug selection at the point of dispensing: a study of potential predisposing factors. AB - OBJECTIVE: To determine potential predisposing factors to medication errors involving confusion between drug names, strengths and dosage forms. METHODS: The study analysed medication errors reported over the period January 2005 to December 2008 from the two main dispensaries of a 1200-bed NHS Foundation Hospital Trust in London. Dispensing incidents considered for analysis included all incidents involving drug name, strength and dosage label and content errors. Statistical analyses were performed using Statistica. Dispensing frequencies of the prescribed and wrongly dispensed drugs were compared by means of Wilcoxon signed-rank test, and the extent of correlation between dispensing frequency and error frequency was assessed using Spearman's rank correlation coefficient. KEY FINDINGS: The Trust recorded a total of 911 dispensing errors between 2005 and 2008. The most significant category, which accounted for 211 (23.2%) of the reported errors, involved errors in drug selection. Drug-selection errors were not random events because the plot of error frequency against the average yearly dispensing frequency for the 1000 most issued drugs showed little evidence of association (r = 0.19, P(alpha) = 0.03). There was, however, an increased likelihood of drug-selection errors occurring when the prescribed drug was dispensed with relatively low frequency and shows a significant orthographic similarity to another drug which has a higher dispensing frequency. CONCLUSION: The majority of drug-selection errors would seem to be caused by insufficient attention paid to the specified drug strength. Dispensing frequency is an important factor influencing the likelihood of a drug-selection errors occurring, but it is also shown here that a large proportion of the drug-selection errors involved specifications exhibiting high orthographic similarity. PMID- 21235660 TI - Evaluating clinical pharmacy services on a surgical patient-care area: a nurses' satisfaction survey. AB - OBJECTIVES: To determine nurses' perceptions and expectations of clinical pharmacists prior to, and 9 months after, clinical pharmacy services were introduced on two general and gastrointestinal surgery hospital wards in Canada. METHODS: A survey tool was developed based on previous research, validated to ensure reliability and accuracy, and administered to approximately 70 nurses on the surgery wards. KEY FINDINGS: Response rates for the pre and post surveys were 75% and 67% respectively. Nurses indicated that the quality of pharmacy service improved significantly from pre to post survey (85% versus 95%; P < 0.0001). There was a statistically significant increase in positive responses to seven out of eight statements such as accessibility of pharmacists, timely responses to drug-related questions, and timely delivery of unit doses and intravenous admixtures. Almost all statements about nursing staff expectations showed increases in agreement. At least 85% of nurses indicated their expectations had been met or exceeded for all but one clinical pharmacy service. A higher proportion of nurses in the post survey felt that clinical pharmacists positively impact on their roles and responsibilities as a nurse. Comments from nurses indicated enthusiastic support for clinical pharmacy services. CONCLUSIONS: A survey tool to assess the quality of pharmacy services in the hospital setting has been developed, validated, and distributed. A high level of nurses' satisfaction with the provision of new clinical pharmacy services on general surgery/gastrointestinal surgery wards was demonstrated. Nursing staff were more aware of the responsibilities of clinical pharmacists and how the clinical pharmacist role could assist them in their own nursing practice. The survey may be useful for other wards and other institutions to measure satisfaction with pharmacy services. PMID- 21235661 TI - An explanatory policy analysis of legislative change permitting pharmacists in Alberta, Canada, to prescribe. AB - OBJECTIVES: This paper provides an explanatory policy analysis of the new legislation which permits pharmacist prescribing in Alberta, Canada: the Pharmacists Profession Regulations (2006) to the Health Professions Act (1999). Its purpose is to provide useful insights for pharmacy regulatory bodies in other jurisdictions internationally that are in a position to pursue similar opportunities. METHODS: A search for government and regulatory body documents related to Alberta healthcare system and pharmacist prescribing was performed. Correspondence was initiated with authors and regulators to clarify or obtain current data. KEY FINDINGS: Research to support policy change recommendations and communication among healthcare professionals, regulators and other stakeholders is essential for developing and implementing legislative change regarding health professionals' scopes of practice at a time when legislative change is possible. Stakeholder barriers to implementation need to be identified early to provide opportunity to address and resolve. CONCLUSIONS: Collaboration between healthcare professionals, regulators and other stakeholders is essential to developing a prescribing model that can be successfully implemented when there is the opportunity for legislative change related to health professionals' scope of practice. PMID- 21235662 TI - The role of endomyocardial biopsy in ARVC: looking beyond histology in search of new diagnostic markers. AB - The Role of Endomyocardial Biopsy in ARVC. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by a high incidence of ventricular tachyarrhythmias and sudden cardiac death that appear early in the natural history of the disease and may precede significant ventricular remodeling. The classical pathology of ARVC is degeneration of right ventricular free wall myocardium and its replacement by fat and fibrous tissue. The clinical presentation may be highly variable, however, and genetic penetrance is typically low which makes definitive diagnosis difficult, especially in early stages of the disease. Endomyocardial biopsy (EMB) has not been used widely in the diagnosis of ARVC, in part because pathological changes are usually most conspicuous in the epicardium of the right ventricular free wall and tend to spare the endocardium and interventricular septum. Thus, diagnostic pathological features of ARVC are often not seen in conventional septal biopsies. Diagnostic yield may be increased by sampling the RV free wall or by using 3-dimensional electroanatomic voltage mapping to identify affected areas, but these approaches can carry increased risk and require specialized equipment and experience. Moreover, diagnostic pathological changes may not be apparent in early disease despite an increased risk of arrhythmias and sudden death. This review considers the role of EMB in the diagnosis of ARVC and highlights recent advances in identifying potential tissue biomarkers that arise early in the disease process and occur diffusely throughout the myocardium. Analysis of conventional EMB using such biomarkers could improve diagnostic sensitivity and accuracy but widespread clinical application of this approach requires further validation. PMID- 21235663 TI - Congestive heart failure after extensive catheter ablation for atrial fibrillation: prevalence, characterization, and outcome. AB - INTRODUCTION: This study sought to describe a new complication of catheter ablation for atrial fibrillation (AF): new onset congestive heart failure (CHF) after extensive ablation for AF. METHODS AND RESULTS: Data from 12 patients developing CHF after ablation were prospectively collected. All patients underwent extensive ablation for AF including circumferential pulmonary venous ablation and complex fractionated atrial electrograms guided ablation. CHF was diagnosed using the following criteria: symptoms or signs of heart failure, elevated BNP, and echocardiographic evidence of left ventricular diastolic dysfunction. Twelve patients (5 persistent and 7 permanent AF) had CHF after extensive ablation out of 484 consecutive AF patients who underwent catheter ablation (prevalence 2.5%). None of these 12 patients had CHF prior to the procedure. The mean onset of the symptoms was 39 +/- 14 hours after the index procedure. Dyspnea and pulmonary rales were the most observed symptoms or signs. White blood cell count, serum CRP, BNP, and echocardiographic parameters of left ventricular diastolic dysfunction (E/A, E/E') were significantly increased after the onset of symptoms. All patients had complete recovery with supportive therapy within 3 days of the onset of symptoms. CONCLUSIONS: In this single-center experience, CHF after extensive ablation for AF was a well-recognized complication with a relatively high incidence of 2.5%. Measurement of BNP, CRP, and E/A, E/E' is useful in managing these patients. PMID- 21235664 TI - Twelve-lead ECG interpretation in a patient with presumed left atrial flutter following AF ablation. AB - The 12-lead ECG provides valuable clues to the mechanism and origin of organized tachycardias occurring in patients after catheter ablation of atrial fibrillation. Many of these patients have cavotricuspid isthmus-dependent flutter, and therefore it is important to be aware of variations from the norm of typical flutter. Left atrial reentrant tachycardias are, however, the most common arrhythmias encountered after catheter ablation of atrial fibrillation. The underlying circuits are typically formed around anatomic obstacles such as the PV ostia or the mitral valve, and facilitated by slow conducting, low voltage isthmuses through gaps through and bordering ablation lesions. They can be recognized by the presence of 12-lead synchronous iso-electric intervals separating flutter waves. Continuous activity ECGs (without 12-lead iso-electric intervals) are typical of larger size reentrant circuits not dependent on markedly slow conducting isthmuses. Delayed bystander activity can also however obscure iso-electric intervals. The integration of informed ECG analysis with a detailed knowledge of the index ablation strategy can provide an optimum platform for successful catheter ablation of these often very symptomatic arrhythmias. PMID- 21235665 TI - Ablation efficacy and electrical morphology of a novel 18-hole open-irrigated catheter. AB - INTRODUCTION: The 6-hole open-irrigated catheter (SHOI) is increasingly used in radiofrequency (RF) ablation of arrhythmias. However, deep transmural lesions are not always achieved, and volume overload caused by irrigated ablation is another problem that should be concerned. The purpose of this study was to analyze and compare the ablation effect and electrical morphology between a novel 18-hole open-irrigated catheter (EHOI) and SHOI. METHODS AND RESULTS: The heart was exposed through a median sternotomy in 12 anesthetized dogs, and the chest cavity was filled with heparinized saline. Bipolar contact pericardial electrograms of both catheters were recorded. Lesions were created under all permutations of the following conditions: RF energy 30 and 40 W for 60 seconds, contact force at 10, 30, and 50 g, electrode orientation horizontal to the tissue, irrigation rate 10 mL/min for EHOI and 17 mL/min for SHOI. The EHOI created deeper lesions than SHOI (5.77 +/- 1.37 mm vs 4.98 +/- 1.22 mm at power of 30 W, P < 0.05; 7.16 +/- 1.15 mm vs 6.02 +/- 1.04 mm at power of 40 W, P < 0.01), and there was a trend of larger lesion volume for EHOI (312 +/- 141 mm(3) vs 259 +/- 108 mm(3) at power of 30 W, 536 +/- 200 mm(3) vs 451 +/- 180 mm(3) at power of 40 W, P > 0.05). No significant difference in electrogram morphology between 2 catheters was detected. CONCLUSIONS: The mapping electrograms of EHOI and SHOI were not significantly different. Compared with SHOI, EHOI more effectively produced deeper lesions at a lower rate of irrigation perfusion. PMID- 21235666 TI - Preprocedural predictors of atrial fibrillation recurrence following pulmonary vein antrum isolation in patients with paroxysmal atrial fibrillation: long-term follow-up results. AB - INTRODUCTION: The objective of this study was to identify the simple preprocedural parameters of atrial fibrillation (AF) recurrence following single ablation procedure in patients with paroxysmal AF during long-term follow-up period. METHODS AND RESULTS: Consecutive 474 patients (61 +/- 10 years; 364 males, left atrial (LA) diameter 37.6 +/- 5.1 mm) with drug-refractory paroxysmal AF who underwent AF ablation were analyzed. Pulmonary vein antrum isolation (PVAI), cavotricuspid isthmus line creation with bidirectional conduction block, and elimination of all non-PV triggers of AF were performed in all patients. With a mean follow-up of 30 +/- 13 months after single procedure, 318 patients (67.1%) were in sinus rhythm without any antiarrhythmic drugs. Multivariate analysis using Cox's proportional hazards model, including the age, gender, duration of AF, body mass index, LA size, left ventricular ejection fraction, and presence of hypertension and structural heart disease as variables, demonstrated that LA size was an independent predictor of AF recurrences after PVAI with a 7.2% increase in the probability for every 1 mm increase in LA diameter (P = 0.0007). When the patients were categorized into 3 groups according to the LA diameter, the patients with moderate (40-50 mm) and severe dilatation (>50 mm) had a 1.30-fold (P = 0.0131) and 2.14-fold (P = 0.0057) increase, respectively, in the probability of recurrent AF as compared with the patients with normal LA diameter (<=40 mm). CONCLUSION: In the long-term follow-up period, LA size was the best preprocedural predictor of AF recurrence following single ablation procedure in the patients with paroxysmal AF, even in the patients with a relatively small LA. PMID- 21235667 TI - Tachycardia-induced cardiomyopathy in patients with idiopathic ventricular arrhythmias: the incidence, clinical and electrophysiologic characteristics, and the predictors. AB - INTRODUCTION: Idiopathic ventricular arrhythmias in the form of monomorphic premature ventricular contractions (PVC) and/or ventricular tachycardia (VT) can cause tachycardia-induced cardiomyopathy (TICMP). The aim of this study was to determine the incidence, clinical and electrophysiologic characteristics, and the predictors of TICMP in patients with idiopathic ventricular arrhythmias. METHODS: Study population consisted of 249 consecutive patients (148 F/101 M, 45 +/- 20 y/o) with frequent PVCs and/or VT. All patients underwent transthoracic echocardiography and 24-hour Holter monitoring. TICMP was defined as left ventricular ejection fraction (LVEF) of <=50% in the absence of any detectable underlying heart disease and improvement of LVEF >=15% following effective treatment of index ventricular arrhythmia. RESULTS: Seventeen (6.8%) patients had TICMP. Patients with TICMP compared to patients with preserved LVEF were more likely to be male (65% vs 39%, P = 0.043) and asymptomatic (29% vs 9%, P = 0.018), and were more likely to have higher PVC burden (29.4 +/- 9.2 vs 8.1 +/- 7.4, P < 0.001), persistence of PVCs throughout the day (65% vs 22%, P = 0.001), and repetitive monomorphic VT (24% vs 0.9%, P < 0.001). PVC burden of 16% by ROC curve analysis best separated the patients with TICMP compared to patients with preserved LVEF (sensitivity 100%, specificity 87%, area under curve 0.96). CONCLUSIONS: TICMP was relatively common (~1 in every 15 patients) in our study population. The predictors of TICMP were male gender, absence of symptoms, PVC burden of >=16%, persistence of PVCs throughout the day, and the presence of repetitive monomorphic VT. PMID- 21235668 TI - Troubleshooting difficult transseptal catheterization. AB - Transseptal catheterization is an essential aspect of many electrophysiology studies. Difficulties may present at various stages of the procedure, especially with unique challenges posed by repeated catheterizations. More recently, technologies such as intracardiac echocardiography and radiofrequency have been employed to assist with transseptal catheterization. Integration of these tools into an organized approach for troubleshooting the difficult transseptal puncture is likely to improve procedural success and reduce the risk of serious complications such as cardiac tamponade. PMID- 21235669 TI - Effects of chronic amiodarone on the electrical restitution in the human ventricle with reference to its antiarrhythmic efficacy. AB - INTRODUCTION: Dynamic instability of ventricular refractoriness represented by electrical restitution operates synergistically with tissue heterogeneity to increase the propensity for functional reentry leading to ventricular tachycardia/fibrillation (VT/VF). Little is known about the effect of chronic amiodarone on the electrical restitution in the human ventricle. METHODS AND RESULTS: Restitution kinetics of monophasic action potential duration (MAPD(90)) in the right ventricular outflow tract (RVOT) and apex (RVA), and of inverse of conduction time from RVOT to RVA (CT(-1)), were estimated by an S1-S2 protocol in 22 patients treated with amiodarone (180 +/- 33 mg/day for 7 +/- 9 months) and in 30 without treatment. In the untreated patients, the restitution kinetics of CT( 1) was steeper in the group with structural heart disease (SHD) (UNT(SHD+), n = 18) than without SHD (UNT(SHD-), n = 12), whereas MAPD(90) restitution parameters were comparable. In the amiodarone-treated patients (all with SHD), the shortest diastolic interval to produce a ventricular response (DI(min)) was increased, the maximum slope of MAPD(90) was flattened, and the magnitude of CT(-1) restitution was reduced as compared with UNT(SHD+). Sustained VT/VF was induced in 7 of 18 UNT(SHD+) (38.9%) and in 4 of 22 amiodarone-treated patients (18.2%, P = 0.07). Concomitant presence of increased CT(-1) restitution and dispersion of MAPD(90) restitution was required for the VT/VF induction. The suppression of VT/VF in the amiodarone-treated patients was associated with a smaller magnitude of CT(-1) restitution in the presence of limited dispersion of MAPD(90) restitution. CONCLUSION: Chronic amiodarone flattens restitution kinetics of MAPD(90) and CT( 1) in the human ventricle, which could be antiarrhythmic in patients with limited tissue heterogeneity. PMID- 21235670 TI - Atrioventricular nodal reentry with retrograde lower common pathway block: a case report. AB - Retrograde lower common pathway block during AV nodal reentrant tachycardia has rarely been reported. In this report, we demonstrate retrograde ventriculoatrial block during sinus rhythm and during AV nodal reentrant tachycardia in a woman with recurrent supraventricular tachycardia. In addition, evidence of antegrade decremental lower common pathway conduction is presented that produced variable HA intervals despite a constant atrial cycle length. These features may lead to the misdiagnosis of atrial tachycardia if not recognized. PMID- 21235671 TI - Intrinsic cardiac autonomic stimulation induces pulmonary vein ectopy and triggers atrial fibrillation in humans. AB - INTRODUCTION: The induction of atrial fibrillation (AF) by pulmonary vein (PV) ectopy is well described. The triggers for these PV ectopy are not so well understood. The intrinsic cardiac autonomic nervous system (ANS) has been suggested as a potential upstream regulator that may cause PV ectopy and atrial fibrillation (AF). We hypothesized that activation of the ANS by high frequency stimulation (HFS) of atrial ganglionated plexi (GP) can initiate PV ectopy. METHODS AND RESULTS: During sinus rhythm in 12 patients undergoing ablation for paroxysmal AF, short bursts of HFS, synchronized to the local atrial refractory period, were delivered at presumed GP sites. Electrograms were recorded from catheters placed in the PV, coronary sinus (CS) and high right atrium (HRA). A total of 112 episodes of HFS were recorded, producing ectopic activity in 91 of 112 (81%) episodes. Of these 91 episodes, there were 46 episodes of isolated single ectopic beats, 5 episodes of double ectopic responses, 24 episodes of ectopy/tachycardia lasting <30 s, and 16 episodes of AF lasting >30 s. In 63 of 91 episodes, the PV catheter was placed adjacent to the stimulated GP, resulting in ectopy recorded earliest in the PV catheter in 48 of 63 (76%) episodes. In one patient, reproducible ectopy was shown to occur following AV nodal conduction delay in response to HFS. Without HFS, neither AV nodal conduction delay nor ectopy occurred. CONCLUSIONS: This study has demonstrated a direct link between activation of the intrinsic cardiac autonomic nervous system and pulmonary vein ectopy in humans. PMID- 21235672 TI - Total and interatrial epicardial adipose tissues are independently associated with left atrial remodeling in patients with atrial fibrillation. AB - INTRODUCTION: As epicardial adipose tissue (EAT) is a metabolically active visceral fat, potential interaction between EAT and myocardium is strongly suggested. The aims of this study were to determine whether the amount and regional distribution of EAT are related to the chronicity of atrial fibrillation (AF) and left atrial (LA) remodeling. METHODS AND RESULTS: This study consisted of 40 subjects with paroxysmal AF (PAF) and 40 with persistent AF (PeAF). Eighty subjects with no history of AF were enrolled as controls. Total volume of EAT (EAT(total)), regional thickness of EAT, and LA volume (LAV) were measured by multislice computed tomography. In the AF group, blood samples were drawn from coronary sinus for analysis of inflammatory cytokines including adiponectin. RESULTS: Compared with controls, AF subjects had larger LAV, EAT(total), and the thicknesses of periatrial EAT including interatrial septum (IAS). However, the thicknesses of periventricular EAT were not different between the groups. The PeAF subjects had larger LAV, EAT(total), and periatrial EAT thicknesses, higher levels of inflammatory cytokines, and lower level of adiponectin than did the PAF subjects. Adiponection level was significantly associated with EAT(total) and IAS thickness. Multivariate analysis revealed that EAT(total) (P = 0.004) and IAS thickness (P = 0.016) were independently associated with LAV. CONCLUSION: EAT(total) and thickness of periatrial EAT were significantly larger in AF subjects compared to those of the matched controls and were closely related to the chronicity of AF. Moreover, EAT(total) and IAS thickness were independently associated with LAV in subjects with AF. PMID- 21235673 TI - Three origins of focal atrial tachycardia in the lateral mitral isthmus. AB - Multiple origins of focal atrial tachycardia (AT) located at the left lateral isthmus is a rare case. We present a case of a 31-year-old female with incessant AT. During radiofrequency ablation, 3 origins of AT located in the lateral mitral ishtmus from a lower to a higher position were identified with changes of the ECG morphology and earliest activation on 3D mapping. Ablation of the AT origins can terminate the tachycardia. PMID- 21235675 TI - Autonomic tests to detect cardiac risk and their clinical practicality. PMID- 21235674 TI - Prevalence and predictors of complications of radiofrequency catheter ablation for atrial fibrillation. AB - INTRODUCTION: Up to 6% of patients experience complications after radiofrequency catheter ablation (RFA) of atrial fibrillation (AF). The purpose of this study is to determine the prevalence and predictors of periprocedural complications after RFA for AF. METHODS AND RESULTS: The subjects were 1,295 consecutive patients (age = 60 +/- 10 years) who underwent RFA (n = 1,642) for paroxysmal (53%) or persistent AF (47%) from January 2007 to January 2010. A complication occurred in 57 patients (3.5%); a vascular access complication in 31 (1.9%); pericardial tamponade in 20 (1.2%); a thromboembolic event in 4 (0.2%); deep venous thrombosis in 1 (<0.01%); and pulmonary vein stenosis in 1 patient (<0.01%). There were no procedure-related deaths. On multivariate analysis, female gender (OR = 2.27; +/-95% CI: 1.31-2.57, P < 0.01) and procedures performed in July or August (OR = 2.10; +/-95% CI: 1.16-3.80, P = 0.01) were independent predictors of any complication. For vascular complications, treatment with clopidogrel (OR = 4.40; +/-95% CI: 1.43-13.53, P = 0.01), female gender (OR = 3.65; +/-95% CI: 1.72 7.75, P < 0.01) and performing RFA in July or August (OR = 2.71; +/-95% CI: 1.25 5.87, P = 0.01) were independent predictors. The only predictor of cardiac tamponade was prior RFA (OR = 3.32; +/-95% CI: 0.95-11.61; P < 0.05). CONCLUSION: Prevalence of perioperative complications for RFA of AF is 3.5% and vascular access complications constitute the majority. The need for clopidogrel therapy should be carefully considered prior to RFA. At teaching institutions close supervision should be exercised during vascular access early in the year. Improvements in ablation technology and elimination of the need for repeat procedures may decrease the risk of pericardial tamponade. PMID- 21235676 TI - Long RP' tachycardia with an initial A-A-V activation sequence: what is the mechanism? PMID- 21235677 TI - Mitral isthmus block and coronary sinus musculature potentials. PMID- 21235678 TI - Initial results of efficacy of left linear ablation using a novel simultaneous multielectrode ablation catheter. AB - INTRODUCTION: Creating complete linear block with point-by-point ablation is challenging in the left atrium (LA). The purpose of this study was to evaluate the efficacy of LA linear ablation using a hexapolar linear multielectrode mapping/ablation catheter. METHODS AND RESULTS: Seventeen patients (age 57 +/- 10, 14 male, 6 paroxysmal AF (PAF)) were studied and underwent linear ablation at the mitral isthmus (MI) and LA roof. Ablation was performed with 90 second, 60 degrees C applications of duty-cycled bipolar/unipolar radiofrequency in a 1:1 ratio simultaneously at all selected electrode pairs. The result could not be evaluated in 2 patients because AF persisted despite cardioversion. Roof line block was confirmed in 9 of 15 (60%) patients. The mean number of applications and the procedural time with and without block was 5.4 +/- 2.4 and 4.5 +/- 2.2 applications, and 15 +/- 8 and 13 +/- 7 minutes. MI block was confirmed in 4 of 15 (27%) patients. The mean number of RF applications with and without block was 5.3 +/- 2.2 and 9.9 +/- 4.4 applications, and the procedural time was 20 +/- 9 and 27 +/- 10 minutes, respectively. For patients with underlying persistent AF, power was lower than those with PAF but improved when ablation was performed in sinus rhythm. Char was observed in 2 cases; however, no procedure-related complications were observed. CONCLUSIONS: In our initial experience, a linear multielectrode catheter using duty-cycled bipolar and unipolar RF energy was inferior to conventional single point irrigated ablation in achieving LA linear block. However, successful linear block was obtained within a short period of time, when it was achieved. PMID- 21235679 TI - T-wave amplitude variability and the risk of death in Chagas disease. AB - INTRODUCTION: Measurement of beat-to-beat T-wave amplitude variability (TWV) has been described as a promising new technique for the stratification of arrhythmic risk in postmyocardial infarction and dilated cardiomyopathy patients. Chagas disease (ChD) can lead to a potentially lethal cardiopathy that can present with ventricular arrhythmias, heart blocks, heart failure, and sudden death. The aim of the study was to evaluate the prognostic value of TWV in ChD patients in addition to traditional prognostic predictors. METHODS AND RESULTS: The study enrolled 113 ambulatory ChD patients (62 men; age: 42 +/- 9 years) in sinus rhythm and without other systemic diseases, evaluated by a standard clinical protocol. We computed TWV in 10-minute ECG recordings obtained in controlled resting conditions. TWV was defined as the median values among 8 consecutive 50 ms T-wave segments and dichotomized as either <= or > 30 MUV(2). The association of TWV and death was evaluated by Cox proportional-hazards analysis, considering other established predictors. During mean follow-up time of 106 +/- 28 months, 14 patients died. A value of median TWV > 30 MUV(2) predicts increased risk of death in a multivariate analysis (HR = 5.76, 95% CI 1.31-25.23, P = 0.014), in addition to depressed left ventricular function, presence of nonsustained ventricular tachycardia and QRS duration >133 ms. CONCLUSION: Repolarization variability, evaluated by TWV, is independently related to the risk of death in ChD. This noninvasive methodology could facilitate the identification of patients who may benefit from more aggressive therapeutic strategies. PMID- 21235680 TI - Differentiating macroreentrant from focal atrial tachycardias occurred after circumferential pulmonary vein isolation. AB - BACKGROUND: Atrial tachycardias (ATs) are commonly observed following catheter ablation of atrial fibrillation (AF). The aim of this study was to identify ECG characteristics that differentiate focal from macroreentrant ATs after circumferential pulmonary vein isolation (CPVI). METHODS AND RESULTS: One hundred and twenty ATs that occurred after CPVI were mapped using a 3-dimensional mapping system in 87 patients with AF. Further ablation was performed to eliminate the ATs. The surface ECGs of 68 ATs in 41 consecutive patients (Group 1) were analyzed retrospectively to create diagnostic algorithms. The algorithms were tested in the second 46 consecutive patients (Group 2). Patients with macroreentrant AT had lower left atrial (LA) voltage than those with focal AT (1.3 +/- 0.3 vs 1.5 +/- 0.2 mV, P = 0.01). Focal AT had a higher incidence of a positive polarity in V6 compared with macroreentrant AT (88% vs 55%, P = 0.03). The positive amplitude of the flutter/P waves in V6 was higher for focal AT than macroreentrant AT. The cycle lengths of the focal ATs were longer than those for macroreentrant AT (296 +/- 107 vs 244 +/- 25 ms, P < 0.001). Right atrial macroreentrant AT had a higher incidence of a negative polarity in at least 1 precordial lead compared with LA macroreentry. The positive flutter waves in V1 could differentiate roof/mitral isthmus dependent from non-roof/mitral isthmus dependent macroreentry. This algorithm correctly differentiated the focal from macroreentrant ATs with a sensitivity of 94%, specificity of 91%, and predictive accuracy of 92% in Group 2. CONCLUSION: Different electrophysiological properties may facilitate the differentiation between macroreentrant and focal ATs after CPVI. PMID- 21235682 TI - Antimicrobial tolerance and the significance of persister cells in recalcitrant chronic wound biofilms. AB - The application of antimicrobials in the management of wounds is a complex procedure requiring appropriate clinical decision making, judgment and a thorough understanding of antimicrobial therapies, together with their potential disadvantages. There is considerable direct and indirect evidence for the presence of bacterial biofilms in the chronic wound bed, and it has been demonstrated that bacteria within these biofilms may exhibit both specific and nonspecific antimicrobial tolerance. The antimicrobial tolerance of biofilms is a major concern in the treatment of both infected and nonhealing chronic wounds and an understanding of the mechanisms involved is of fundamental importance in managing wound infections and developing future wound management strategies. The aim of this review is therefore to provide an overview of our current understanding of the mechanisms by which bacteria in wound biofilms can resist conventional antibiotic and antibacterial therapies which is very important to wound healing. PMID- 21235683 TI - Normalization of T cell receptor repertoire diversity in patients with advanced colorectal cancer who responded to chemotherapy. AB - To investigate the correlation between normalization of T cell receptor (TCR) repertoire and remission of advanced colorectal cancer. Forty-one patients were randomly assigned to receive either folinic acid/fluorouracil/irinotecan alone (n = 20) or folinic acid/fluorouracil/irinotecan in combination with recombinant human endostatin (n = 21). Efficacy and toxicity were evaluated, and changes in TCR repertoire diversity were assessed by detecting the spectratypes of TCR complementarity-determining region three before and after several cycles of therapy. A scoring system was used to quantify changes in the TCR repertoire over time. The results demonstrated that the TCR repertoire exhibited a higher degree of normalization among patients undergoing remission relative to patients experiencing tumor progression. The results of the current study showed a positive correlation between TCR repertoire normalization and remission of colorectal cancer, suggesting that dynamic monitoring of TCR repertoire diversity may have potential prognostic value in the clinical setting. PMID- 21235684 TI - DNA glycosylase encoded by MUTYH functions as a molecular switch for programmed cell death under oxidative stress to suppress tumorigenesis. AB - 8-oxoguanine is a major base lesion in DNA or in nucleotides caused by oxidative stress, and is highly mutagenic because it can pair with adenine as well as cytosine. Adenine DNA glycosylase, encoded by the human mutY homolog gene, MUTYH, excises adenine in the nascent strand when inserted opposite 8-oxoguanine in template DNA, and thus suppresses mutagenesis caused by 8-oxoguanine that has accumulated in DNA due to oxidative stress. Several germ-line mutations in MUTYH are predisposed to MUTYH-associated polyposis, an autosomal recessive disorder characterized by multiple colorectal adenomas and carcinomas. Loss of function of MUTYH leads to an accumulation of somatic mutations in APC and KRAS genes, resulting in the development of adenomas/carcinomas. We recently demonstrated that accumulation of 8-oxoguanine in nuclear and mitochondrial DNA triggers two distinct cell death pathways that are independent of each other. Both pathways are initiated by the accumulation of MUTYH-generated single-strand breaks (SSBs) in nuclear or mitochondrial DNA. Our findings indicate that MUTYH-induced cell death due to oxidative stress results in an efficient elimination of mutagenic cells that have accumulated high levels of 8-oxoguanine in their DNAs. It is most likely that loss of function of MUTYH in stem or progenitor cells in the intestinal epithelium of MUTYH-associated polyposis patients results in escape from programmed cell death; however, accumulated 8-oxoguanine causes various mutations in APC or KRAS genes in these proliferative cells, thereby promoting tumorigenesis. We thus propose that MUTYH suppresses tumorigenesis under conditions of oxidative stress by inducing cell death and by suppressing mutagenesis. PMID- 21235685 TI - Prolonged, wireless pH-studies have a high diagnostic yield in patients with reflux symptoms and negative 24-h catheter-based pH-studies. AB - BACKGROUND: Catheter-based esophageal pH-monitoring is used to evaluate patients with suspected gastro-esophageal reflux disease (GERD); however false-negative results may occur due to poor tolerance of the catheter with reduced oral intake and activity, or high day-to-day variation in reflux and symptom events. We assessed diagnostic yield and clinical impact of prolonged, wireless pH monitoring in patients with negative results from 24-h catheter-based studies and ongoing symptoms. METHODS: Esophageal acid exposure (percentage time pH <4), Symptom Index, and Symptom Association Probability (SAP) were calculated. Diagnostic yield was assessed using Average (mean) and Worst Day (24-h period with highest acid exposure or symptom load) analyses. Outcome data were assessed 6-36 months (median 24) after initiation of definitive therapy based on physiologic testing. KEY RESULTS: Data from prolonged pH-monitoring up to 96-h (median 72-h) were available from 38 patients. Using Average and Worst Day analysis, esophageal acid exposure was pathologic in 37% and 47%, whereas SAP was positive in 34% and 63% of patients, respectively. Overall using Average and Worst Day analyses, 61% and 76% patients were diagnosed with GERD based on either pathologic acid exposure or positive symptom association. Of 12 patients that underwent antireflux surgery, 10(83%) reported a good outcome at a median 24 months follow-up. CONCLUSIONS & INFERENCES: Prolonged, wireless pH-monitoring increases test sensitivity and diagnostic yield in patients with continuing esophageal symptoms despite negative 24-h catheter-based pH-studies. Without a definitive diagnosis, many would not have received effective treatment. PMID- 21235686 TI - Genetic recombination of the hepatitis C virus: clinical implications. AB - Genetic recombination is a well-known feature of RNA viruses that plays a significant role in their evolution. Although recombination is well documented for Flaviviridae family viruses, the first natural recombinant strain of hepatitis C virus (HCV) was identified as recently as 2002. Since then, a few other natural inter-genotypic, intra-genotypic and intra-subtype recombinant HCV strains have been described. However, the frequency of recombination may have been underestimated because not all known HCV recombinants are screened for in routine practice. Furthermore, the choice of treatment regimen and its predictive outcome remain problematic as the therapeutic strategy for HCV infection is genotype dependent. HCV recombination also raises many questions concerning its mechanisms and effects on the epidemiological and physiopathological features of the virus. This review provides an update on recombinant HCV strains, the process that gives rise to recombinants and clinical implications of recombination. PMID- 21235687 TI - Prevalence and genetic diversity of waterborne pathogenic viruses in surface waters of tropical urban catchments. AB - AIMS: To study the virological quality of surface water from highly urbanized tropical water catchment areas and to determine predominant enteric viral genotypes in surface water. METHODS AND RESULTS: A wide range of human pathogenic viruses in urban surface waters was screened by nested PCR assays after concentration by ultrafiltration. Among the 84 water samples collected, at least one virus was detected in 70 (83.3%) of these samples. Noroviruses were determined to be the most prevalent enteric viruses detected in urban surface water samples, followed by astroviruses, enteroviruses, adenoviruses and hepatitis A viruses. The molecular characterization of environmental viral isolates suggested co-circulation of multiple genotypes of both noroviruses GI and GII, astroviruses and enteroviruses in urban surface waters. CONCLUSIONS: Human enteric viruses with great genetic diversity were detected in surface waters, indicating the presence of human origin of faecal contamination in highly urbanized water catchment areas. PMID- 21235688 TI - Efficient production of Al(OH)3-immobilized laccase with a Heterobasidion annosum strain selected by microplate screening. AB - AIMS: Wild-type white rot fungi are the most important production organisms for laccase, a promising oxidative biocatalyst with numerous applications. This study aimed at identifying novel highly productive strains, finding optimal cultivation conditions for laccase production and establishing a simple immobilization procedure. METHODS AND RESULTS: By using a newly developed 96-well microplate cultivation method, 23 species of white rot fungi, represented by 29 strains, were directly compared with regard to the amount of secreted laccase. Both, with glucose and spruce saw dust as growth substrate a Heterobasidion annosum strain and a Physisporinus vitreus strain were the most productive (730-2200 U l-1 of secreted laccase). Cultivation conditions for laccase production with H. annosum were optimized in larger-scale liquid cultures. Aeration with a sparger lead to a 3.8-fold increase in laccase activity when compared to nonaerated flask cultures. More than 3000 U l-1 laccase was produced in glucose medium supplemented with yeast extract and the inducer veratryl alcohol. Culture supernatant was incubated with short-range ordered Al(OH)3 particles to directly immobilize and concentrate laccase by adsorption. Active laccase was recovered in 40% yield and the Al(OH)3 adsorbed laccase was suitable for repeated decolourization of indigo carmine. CONCLUSIONS: Microplate cultivation allowed a large-scale comparison of the capacity of different fungal species for laccase production. Laccase secretion of a highly productive H. annosum strain was found to vary strongly with different cultivation conditions. Adsorption to Al(OH)3 proved to be suitable as direct immobilization technique. PMID- 21235689 TI - Alzheimer's: when memory hangs like a thread. PMID- 21235690 TI - Cardiovascular disease and the seeds of innovation: a call for papers. PMID- 21235691 TI - Statin wars: efficacy vs. cost. PMID- 21235692 TI - Cardiovascular risk estimation--what is missing? PMID- 21235693 TI - Renin-angiotensin blockade in diabetic retinopathy. PMID- 21235694 TI - Use of high-intensity statin therapy with simvastatin 80 mg and atorvastatin 80 mg in primary care. AB - AIMS: Cardiovascular disease (CVD) is the most common cause of death worldwide. Pharmaceutical risk reduction with high-intensity statin therapy is advisable for high-risk patients. Clinicians face a conflict between prescribing for cost (simvastatin 80 mg) or for efficacy (atorvastatin 80 mg). The aim of this audit was to examine the use, efficacy and tolerability of high intensity statin treatment (simvastatin 80 mg; atorvastatin 80 mg) in primary care. METHODOLOGY: Electronic medical records were examined from two general practitioners' surgeries. Analyses involved Mann-Whitney U and chi(2) tests. RESULTS: A total of 116 patients had taken simvastatin 80 mg or atorvastatin 80 mg. Patients were similar between treatment groups: mostly men (62.9%), over 60 years old (68.1%), non-smokers (81.0%) taking statins for secondary prevention (56.9%). More patients on simvastatin withdrew from treatment as a result of inefficacy (49.3% vs. 23.2%, p=0.025) compared with the atorvastatin group. Furthermore, patients on simvastatin were more likely to be failing conventional targets of lipid control, compared with patients on atorvastatin 80 mg (43.5% vs. 21.3%, p=0.006). Tolerability was similar between the two groups. DISCUSSION: UK guidelines recommend simvastatin 80 mg as an economic choice, despite scant evidence at this dose and recent safety concerns. Conversely, robust evidence exists for atorvastatin 80 mg. Head-to-head clinical trials or clinical studies comparing these agents are lacking. The present study suggests that atorvastatin 80 mg compares favourably to simvastatin in terms of efficacy and has a similar tolerability profile. CONCLUSION: This retrospective observational study suggests that despite national guidelines, atorvastatin 80 mg is used in clinical practice and is more effective and at least as well tolerated as simvastatin 80 mg. PMID- 21235695 TI - Does renin-angiotensin system blockade have a role in preventing diabetic retinopathy? A clinical review. AB - Diabetes management has increasingly focused on the prevention of macrovascular disease, in particular for type 2 diabetes. Diabetic retinopathy, one of the main microvascular complications of diabetes, is also an important public health problem. Much of the care invested in retinopathy relates to treatment rather than prevention of disease. Tight glycaemic and blood pressure control helps to reduce the risk of retinopathy, but this is not easy to achieve in practice and additional treatments are needed for both primary and secondary prevention of retinopathy. A renin-angiotensin system (RAS) has been identified in the eye and found to be upregulated in retinopathy. This has led to specific interest in the role of RAS blockade in retinopathy prevention. The recent DIRECT programme assessed use of the angiotensin receptor blocker (ARB) candesartan in type 1 and type 2 diabetes. Although the primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAS blockade. A smaller trial, RASS, reported reduced retinopathy progression in type 1 diabetes from RAS blockade with both the ARB losartan and the angiotensin converting enzyme (ACE) inhibitor enalapril. The clinical implications of these new data are discussed. PMID- 21235696 TI - Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and pioglitazone on glycemic control and measures of beta-cell function in patients with type 2 diabetes. AB - AIM/HYPOTHESIS: To assess the safety and efficacy of initial combination therapy with sitagliptin and pioglitazone compared with pioglitazone monotherapy in drug naive patients with type 2 diabetes. METHODS: A total of 520 patients were randomised to initial combination therapy with sitagliptin 100 mg q.d. and pioglitazone 30 mg q.d. or pioglitazone 30 mg q.d. monotherapy for 24 weeks. RESULTS: Initial combination therapy with sitagliptin and pioglitazone led to a mean reduction from baseline in A1C of -2.4% compared with -1.5% for pioglitazone monotherapy (p<0.001). Mean reductions from baseline were greater in patients with a baseline A1C>=10% (-3.0% with combination therapy vs. -2.1% with pioglitazone monotherapy) compared with patients with a baseline A1C<10% (-2.0% with combination therapy vs. -1.1% with pioglitazone monotherapy). Sixty percent of patients in the combination therapy group vs. 28% in the pioglitazone monotherapy group had an A1C of <7% at week 24 (p<0.001). Fasting plasma glucose decreased by -63.0 mg/dl (-3.5 mmol/l) in the combination therapy group compared with -40.2 mg/dl (-2.2 mmol/l) for pioglitazone monotherapy (p<0.001), and 2-h post meal glucose decreased by -113.6 mg/dl (-6.3 mmol/l) with combination therapy compared with -68.9 mg/dl (-3.8 mmol/l) for pioglitazone monotherapy (p<0.001). Measures related to beta-cell function also improved significantly with combination therapy compared with pioglitazone monotherapy. Combination therapy was generally well-tolerated compared with pioglitazone monotherapy, with similar incidences of hypoglycemia (1.1% and 0.8%, respectively), gastrointestinal adverse events (5.7% and 6.9%, respectively), and oedema (2.7% and 3.5%, respectively). CONCLUSION/INTERPRETATION: Initial combination therapy with sitagliptin and pioglitazone substantially improved glycemic control and was generally well-tolerated compared with pioglitazone monotherapy. PMID- 21235697 TI - Pituitary incidentalomas: a single-centre experience. AB - AIM: Pituitary incidentalomas (PIs) are diagnosed in about 10% of the patients undergoing radiological investigation for non-pituitary disorders. The aim of this study was to describe the morphological and hormonal characteristics of PIs in a cohort of patients, followed up in a single centre from 1982-2009. METHODS: Retrospective analysis of electronic medical records of patients with PIs was carried out. All patients underwent basal and dynamic evaluation of the hypothalamus-pituitary axis. Mass size was assessed at yearly intervals. RESULTS: Sixty-one patients (38 men/23 women, aged 53+/-2 years) were studied. The mean follow-up time was 48+/-8 months, and mean size of PIs was 20+/-2 mm. Twelve PIs (20%) were microadenomas, 48 (78%) were macroadenomas and one (2%) was a Rathke's cyst. The most common reasons that led to their discovery were headaches, dizziness, syncope, stroke and head injury. Forty-seven of the 61 PIs (77%) were non-functioning, 11 (18%) prolactinomas, and two (3%) GH-secreting adenomas. Hypopituitarism was present in 12% at diagnosis. Forty-eight per cent of the patients were submitted to surgery with conventional radiotherapy in 8%. Relapse in size was observed in 48% of the surgically treated patients. Of the PIs followed conservatively, 78% remained stable, 11% showed decrease and 11% increase in size during follow up. Hypopituitarism rose to 57% postoperatively. CONCLUSIONS: Majority of PIs are non-functioning adenomas that remain stable in size. Relapse in size and hypopituitarism postoperatively are common. PIs, for which conservative management was initially considered appropriate, did not progress in size. PMID- 21235698 TI - Assessing the internet prevalence of cancer. AB - INTRODUCTION: The internet is one of the most frequently accessed sources of information by patients. There is a variety of cancer-related information provided by the internet, aimed at both the general public (from official sites and non-regulated sites) and health care professionals. Little is known about whether the information provided reflects the prevalence of disease. METHODS: Searches for the 10 most common UK cancers were performed using five internet search engines. The number of relevant webpages was recorded and compared to the prevalence of each cancer according to Cancer Research UK. RESULTS: Of the 985,687,623 webpages identified, the majority were related to breast cancer (37.2%), followed by lung (16.2%) and prostate cancer (12.5%). Colorectal cancer, Oesophageal cancer and non-Hodgkin's lymphoma had the least number of websites (4.1%, 0.3% and 0.9%, respectively). There was over-representation of breast, kidney and stomach cancer with ratios of prevalence to number of websites of 1.7, 2.6 and 2.5 to 1, respectively. There was under-representation of colorectal cancer, non-Hodgkin's lymphoma and oesophageal cancer (ratios 0.2, 0.2 and 0.1, respectively). CONCLUSION: This data highlights the enormity of information available on the internet. However, there is over-representation of certain cancers (and under-representation of others) which may influence how patients perceive their illness. Healthcare professionals should be aware of the nature of information available on the internet and known when and how to direct patients to reputable sites that provide high quality information. PMID- 21235699 TI - Emerging strategies in the treatment of advanced hepatocellular carcinoma: the role of targeted therapies. AB - Hepatocellular cancer (HCC) is the fifth most common cause of cancer worldwide and its incidence is increasing as a result of the dissemination of hepatitis B and C virus infection. Surgical resection and liver transplantation are considered the only cures for HCC, but benefit approximately 10-15% of patients. In addition, radiofrequency ablation may is potentially curative for patients' with small HCC. Some patients with unresectable disease confined to the liver may benefit from embolisation or chemoembolisation. In the presence of disease not amenable to loco-regional therapy, median survival is only a few months. Current systemic therapy with cytotoxic chemotherapy induces relatively few responses and has no clear survival benefit. Current interest is focussed on the potential role of targeted therapies based on the key aspects of molecular pathogenesis of HCC, most notably sorafenib, an oral multikinase inhibitor. Recent developments discussed in this article demonstrate the potential benefits of this drug which seems destined to become first-line therapy for advanced HCC. PMID- 21235700 TI - Relationships between symptoms, symptom bother, and health-related quality of life in patients with overactive bladder taking solifenacin or placebo in the VIBRANT study. AB - AIMS: Studies of antimuscarinics for overactive bladder (OAB) typically use objective and subjective measures to assess efficacy, as each provides unique information about patient outcome. We evaluated the relationships between changes in diary-documented OAB symptoms and other patient-reported outcome (PRO) measures. METHODS: In VIBRANT, OAB patients received solifenacin (5/10 mg) or placebo for 12 weeks. During the study, patients completed 3-day bladder diaries and other generic and disease-specific PRO measures. Data from both treatment groups were combined (n=738). Categorical changes in diary variables were compared with changes in PRO measures. Partial correlations controlling for treatment and Spearman correlations were also calculated. RESULTS: Categorical improvements in diary variables were significantly associated with greater improvements in PRO measures. Pair-wise comparisons showed that patients with major symptomatic improvements had significantly greater improvements on PROs vs. those with some or no improvement. Odds ratios ranged from 1.52 to 4.09 (p<=0.002). Linear relationships between changes in PRO measures and diary variables were low to moderate but statistically significant (p<0.001). Partial correlations were highest for diary variables and OAB-Questionnaire Symptom Bother. Spearman correlations ranged from 0.170 to 0.450 (p<0.001). CONCLUSIONS: In patients with OAB, changes in objectively measured symptoms of urgency, incontinence and frequency showed low-to-moderate correlations to changes in PRO measures. While providing evidence for similar change patterns in symptoms and patient perceptions, correlations were not high, lending support to the concept that in OAB clinical trials, both bladder diaries and PRO measures are important independent measures of efficacy. PMID- 21235701 TI - Validation of a 3-item OAB awareness tool. AB - AIM: The purpose of this study was to validate a short awareness tool to assist patients in identifying if they have bothersome overactive bladder (OAB) symptoms. METHODS: This secondary analysis study utilised data from a cross sectional study of adult patients presenting for primary care visits. Patients completed an 8-item OAB screener. The clinician probed for urinary frequency, urgency, nocturia and urgency urinary incontinence. If the patient screened positive or reported the presence of at least one OAB symptom, additional questions were asked regarding lifestyle and coping issues. The clinician then diagnosed the patient as having No OAB, Possible OAB, or Probable OAB. Multivariate logistic regressions were performed to assess the feasibility of deriving a shorter screener to raise awareness of OAB among primary care patients. RESULTS: The 1,260 patients in this study were 51.6+/-17.0 years old; 62% were women; and most (89%) were Caucasian. Clinicians diagnosed 12.1% of patients with Probable OAB, 19.7% with Possible OAB and 68.3% with No OAB. The logistic regression models were performed with OAB clinical diagnosis as the dependent variable comparing No OAB versus Probable OAB. Three items which included the symptoms of urinary frequency, urinary urgency and urine loss associated with a strong desire to urinate performed well as an awareness tool. A cut-point of four provided the most appropriate sensitivity (82%) and specificity (91%) when identifying Probable OAB and yielded adequate model fit. The final 3 item OAB Awareness Tool (OAB-V3) is gender neutral. CONCLUSION: The 3-item OAB Awareness Tool (OAB-V3) correctly identified patients with symptoms of OAB with high sensitivity and specificity and can be used as a conversation starter for patients with symptoms of OAB. PMID- 21235702 TI - Preventing diabetes complications and the "glucocentric" dilemma: a word of caution. PMID- 21235703 TI - Calcium supplements and cardiovascular disease--picking the spin. PMID- 21235706 TI - Comparing health reform in the United States and New Zealand. PMID- 21235708 TI - Posteromedial diaphragmatic hernia following pediatric liver transplantation. AB - Diaphragmatic hernia is a rare complication following pediatric LT. Here, four children who developed right-sided posteromedial diaphragmatic hernias after LT are reported. The primary disease was biliary atresia in two patients, hemangioendothelioma in one, and angiosarcoma in one patient. All of the patients underwent living-donor LT using a left lateral graft. The patients presented with abdominal and/or pulmonary signs and symptoms. The diaphragmatic hernias were diagnosed at 28 days to seven months post-transplant by standard radiographs or chest CT. The defects were located at the posteromedial aspect of the diaphragm and were closed by primary closure. After diaphragm repair, the post-operative course was unremarkable and there were no recurrences. Thermal or mechanical injuries to the bare area, especially in cases of excessive adhesion between the liver and diaphragm after Kasai operation, were the possible causes of the posteromedial diaphragmatic hernia after pediatric LT. PMID- 21235709 TI - Progressive multifocal leukoencephalopathy (PML) after transplantation. PMID- 21235710 TI - Liver transplantation as a treatment option for three siblings with homozygous familial hypercholesterolemia. AB - FH is a hereditary inherited disorder of cholesterol metabolism. Homozygous form of the disease associates severe form of atherosclerotic disease. Clinicians have been tried to inhibit the progression of the homozygous FH with medical and surgical treatment. We here present three siblings with homozygous FH who were successfully treated with liver transplantation. PMID- 21235711 TI - West Nile virus encephalitis acquired via liver transplantation and clinical response to intravenous immunoglobulin: case report and review of the literature. AB - A patient developed West Nile virus (WNV) encephalitis 2 weeks after receiving a liver transplant and recovered fully, following treatment with intravenous immunoglobulin (IVIg). Laboratory testing documented transmission from the organ donor. Clinicians should be suspicious for organ-transmitted WNV in any post transplant patient who develops fever and neurological symptoms. We review previous cases of organ-transmitted WNV, the use of IVIg for WNV encephalitis, and the issue of organ donor screening. PMID- 21235712 TI - Yeast prions: could they be exaptations? The URE2/[URE3] system in Kluyveromyces lactis. AB - We examined aspects of the URE2/[URE3] prion system in Kluyveromyces lactis, which lies on a different evolutionary branch from Saccharomyces. We first analysed the polymorphism of the prion-forming domain in 38 strains. Considerable differences were found between these two genera, with little variation within K. lactis. We then analysed the regulatory function of Ure2p, using a deletion of URE2. We assessed the deregulation of two reporter genes: DAL5 and GDH2. Both were derepressed in the mutant strain, as in Saccharomyces. Finally, we tried to obtain the [URE3] prion from K. lactis. Despite the use of many different experimental conditions, we were unable to obtain a prion from Ure2p. This finding calls into question the extent to which the prion form of Ure2p may be considered an evolutionary adaptation, instead suggesting that an exaptation phenomenon may be more likely than a continuous selection history. PMID- 21235713 TI - Sp3 transcription factor is crucial for transcriptional activation of the human NOX4 gene. AB - NOX is the catalytic subunit of NADPH oxidase, the superoxide-generating enzyme. Among several isoforms of NOX, NOX4 is abundantly expressed in various tissues. To clarify the mechanisms of constitutive and ubiquitous expression of NOX4, the promoter activities of the human NOX4 gene were analyzed by reporter assays. The 5'-flanking and non-coding regions of the human NOX4 gene are known to contain multiple GC bases. Among them, three GC-boxes containing putative Sp/Klf-binding sites, which were not found in rodent genes, were suggested to be essential for the basal expression of the NOX4 gene in SH-SY5Y and HEK293 cells. Electrophoresis mobility shift assays demonstrated that Sp1 and Sp3 could bind to GC-boxes at positions -239/-227 and +69/+81 in these cells. Chromatin immunoprecipitation assays showed that Sp1 and Sp3 could also bind to GC-boxes at positions -239/-227 and +69/+81 in vivo. The promoter activity of the NOX4 gene was reduced in SH-SY5Y and HEK293 cells by transfection of an anti-Sp3 short hairpin RNA-expression plasmid. Taken together, these results suggest that Sp3 plays a key role in the expression of NOX4 in various cell lineages in humans. PMID- 21235715 TI - The benefit of combinations of oximes for the reactivating and therapeutic efficacy of antidotal treatment of sarin poisoning in rats and mice. AB - The influence of the combinations of oximes on the reactivating and therapeutic efficacy of antidotal treament of acute sarin poisoning was evaluated in this study. The ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate sarin-inhibited acetylcholinesterase and reduce acute toxicity of sarin was compared with the reactivating and therapeutic efficacy of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo methods. Studies determining percentage of reactivation of sarin-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of the combination of oximes involving HI-6 and K203 is slightly higher than the reactivating efficacy of the most effective individual oxime in diaphragm and brain but the difference between them is not significant. The ability of combination of oximes involving HI-6 and trimedoxime to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating effects of the most effective individual oxime in blood as well as tissues. Moreover, both combinations of oximes were found to be as efficacious in the reduction of acute lethal toxic effects in sarin-poisoned mice as the most effective individual oxime. A comparison of reactivating and therapeutic efficacy of individual oximes showed that the oxime HI-6 is markedly more effective than the oxime K203 and trimedoxime. Based on the obtained data, we conclude that the antidotal treatment involving chosen combinations of oximes does not significantly influence the ability of the most effective individual oxime (HI-6) to reactivate sarin-inhibited rat acetylcholinesterase and to reduce acute toxicity of sarin in mice. PMID- 21235714 TI - An enzymatic mechanism for generating the precursor of endogenous 13-cis retinoic acid in the brain. AB - 13-cis Retinoic acid (13cRA), a stereoisomeric form of retinoic acid, is naturally generated in the body and is also used clinically to treat acute promyelocytic leukemia, some skin diseases and cancer. Furthermore, it has been suggested that 13cRA modulates brain neurochemical systems because increased 13cRA levels are correlated with depression and increased suicidal tendencies. However, the mechanism for the generation of endogenous 13cRA is not well understood. The present study identified and characterized a novel enzyme in zebrafish brain, 13-cis isomerohydrolase (13cIMH) (EC 5.2.1.7), which exclusively generated 13-cis retinol and can be oxidized to 13cRA. 13cIMH shares 74% amino acid sequence identity with human retinal pigment epithelium specific 65 kDa protein (RPE65), an 11-cis isomerohydrolase in the visual cycle, and retains the key residues essential for the isomerohydrolase activity of RPE65. Similar to RPE65, 13cIMH is a membrane-associated protein, requires all-trans retinyl ester as its intrinsic substrate, and its enzymatic activity is dependent on iron. The purified 13cIMH converted all-trans retinyl ester exclusively to 13-cis retinol with K(m) = 2.6 MUm and k(cat) = 4.4 * 10(-4) .s(-1) . RT-PCR, western blot analysis and immunohistochemistry detected 13cIMH expression in the brain. These results suggest that 13cIMH may play a key role in the generation of 13cRA, as well as in the modulation of neuronal functions in the brain. PMID- 21235716 TI - Randomized, double-blinded, placebo-controlled crossover trial of treating erectile dysfunction with sildenafil after radiotherapy and short-term androgen deprivation therapy: results of RTOG 0215. AB - INTRODUCTION: Erectile dysfunction (ED) may be the most commonly observed adverse event (AE) associated with the combination of radiation therapy (RT) and androgen deprivation therapy (ADT). A significant number of men are trying phosphodiesterase type 5 inhibitors (PDE5s) such as sildenafil to treat ED, yet sildenafil studies to date shed little light on the response to ED after ADT. AIM: The purpose of this trial was to evaluate sildenafil in the treatment of ED in prostate cancer patients previously treated with external beam RT and neoadjuvant and concurrent ADT. METHODS: In this randomized, double-blinded crossover trial, eligible patients received RT/ADT for intermediate risk prostate cancer and currently had ED as defined by the International Index of Erectile Function (IIEF). Patients were randomized to 12 weeks of sildenafil or placebo followed by 1 week of no treatment then 12 weeks of the alternative. Treatment differences were evaluated using a marginal model for binary crossover data. MAIN OUTCOME MEASURES: The primary end point was improved erectile function, as measured by the IIEF. RESULTS: The study accrued 115 patients and 61 (55%) completed all three IIEF assessments. Sildenafil effect was significant (P = 0.009) with a difference in probabilities of erectile response of 0.17 (95% confidence interval: 0.06, 0.29), and 0.21 (0.06, 0.38) for patients receiving <= 120 days of ADT. However, as few as 21% of patients had a treatment-specific response, only improving during sildenafil but not during the placebo phase. CONCLUSIONS: This is the first controlled trial to suggest a positive sildenafil response for ED treatment in patients previously treated with RT/ADT, however, only a minority of patients responded to treatment. ADT duration may be associated with response and requires further study. The overall low response rate suggests the need for study of additional or preventative strategies for ED after RT/ADT for prostate cancer. PMID- 21235717 TI - Activation of NMDA receptors in lumbar spinothalamic cells is required for ejaculation. AB - INTRODUCTION: The sexual reflex ejaculation is controlled by a spinal ejaculation generator located in the lumbosacral spinal cord. A population of spinothalamic (LSt) neurons forms a key component of this generator, as manipulations of LSt cells either block or trigger ejaculation. However, it is currently unknown which afferent signals contribute to the activation of LSt cells and ejaculation. AIM: The current study tested the hypothesis that glutamate, via activation of N Methyl-D-aspartic acid (NMDA) receptors in LSt cells, is a key regulator of ejaculation. METHODS: Expression of phosphorylated NMDA receptor subunit 1 (NR1) was investigated following mating, or following ejaculation induced by electrical stimulation of the dorsal penile nerve (DPN) in anesthetized, spinalized male rats. Next, the effects of intraspinal delivery of NMDA receptor antagonist AP-5 on DPN stimulation-induced ejaculation were examined. Moreover, the ability of intraspinal delivery of NMDA to trigger ejaculation was examined. Finally, the site of action of NMDA was determined by studying effects of NMDA in male rats with LSt cell-specific lesions. MAIN OUTCOME MEASURES: Expression of NR1 and phosphorylated NR1 in LSt cells was analyzed. Electromyographic recordings of the bulbocavernosus muscle (BCM) were recorded in anesthetized, spinalized rats following stimulation of the DPN and delivery of AP-5 or NMDA. RESULTS: Results indicate that the NR1 receptors are activated in LSt cells following ejaculation in mating animals or induced by DPN stimulation in anesthetized, spinalized animals. Moreover, NR1 activation in LSt cells is an essential trigger for rhythmic BCM bursting, as DPN stimulation-induced reflexes were absent following administration of NMDA receptor antagonist in the L3-L4 spinal area, and were triggered by NMDA. NMDA effects were dependent on intact LSt cells and were absent in LSt-lesioned males. CONCLUSION: These results demonstrate that glutamate, via activation of NMDA receptors in LSt cells, is a key afferent signal for ejaculation. PMID- 21235718 TI - Intermittent androgen suppression in prostate cancer: testosterone levels and its implication. AB - INTRODUCTION: Intermittent androgen suppression (IAS) in patients affected by prostate cancer seems to lessen the severity of the side effects that are associated with continuous androgen ablation. AIM: This report monitors the effect of IAS on testosterone values, quality of life, and sexual function during phases of therapy. METHODS: A total of 100 patients entered a prospective study of IAS. Androgen blockade was prolonged until a serum prostate specific antigen (PSA) nadir was reached and then resumed for a PSA threshold of 10 ng/mL, in repeated cycles. During I phase, we assessed testosterone levels, well-being with quality-of-life score, and sexual function. MAIN OUTCOME MEASURES: All patients were followed up every 3 months with PSA and total testosterone determinations, and with quality-of-life score using a 10-point questionnaire. Side effects were assessed using yes/no questions. Sexual function was assessed using yes/no questions and in the sexually active patients with International Index of Erectile Function-5 (IIEF). RESULTS: All patients completed I cycle of treatment (I ON plus I OFF phase). During the OFF phase, 46% of patients showed low testosterone levels, while the others recovered normal testosterone concentrations at a mean of 6.2 months after therapy. There is a negative correlation between baseline PSA values and length of OFF phase and testosterone recovery, and a negative correlation between length of OFF phase and testosterone value during OFF phase. Worsening in Quality of Life (QOL) was significant during active treatment with respect to baseline, but therapy withdrawal showed a positive impact with respect to treatment period. Improvement in quality of life correlated to testosterone recovery and time to testosterone recovery. Fifty-four percent of subjects had normal sexual intercourse at therapy withdrawal, with a correspondence to time to testosterone recovery. CONCLUSIONS: Quality of life and sexual function seem to follow testosterone normalization. These results could have implications in the analysis of IAS. PMID- 21235719 TI - Programming effects of antenatal corticosteroids exposure in male sexual behavior. AB - INTRODUCTION: Brain regions implicated in sexual behavior begin to differentiate in the last trimester of gestation. Antenatal therapy with corticosteroids is often used in clinical practice during this period to accelerate lung maturation in preterm-risk pregnancies. Clinical and animal studies highlighted major behavioral impairments induced later in life by these treatments, especially when synthetic corticosteroids are used. AIM: To evaluate the implications of acute prenatal treatment with natural vs. synthetic corticosteroids on adult male rat sexual behavior and its neurochemical correlates. METHODS: Twelve pregnant Wistar rats were injected with dexamethasone (DEX-1 mg/kg), corticosterone (CORT-25 mg/kg), or saline on late gestation (pregnancy days 18 and 19). Following this brief exposure to corticosteroids, we assessed the sexual behavior of the adult male progeny and subsequently associated these behaviors with the levels of catecholamines and mRNA of dopamine and androgen receptors (AR) in brain regions relevant for sexual behavior. MAIN OUTCOME MEASURES: Sexual behavior of adult male offspring was assessed by exposure to receptive females. This was associated with serum testosterone levels and levels of catecholamines (determined by high performance liquid chromatography) and dopamine and AR mRNA expression (real-time polymerase chain reaction [PCR]) in brain regions implicated in sexual behavior. RESULTS: Prenatal DEX exposure resulted in a decreased number and increased mounts and intromissions latencies in adulthood. These findings were associated with decreased levels of serum testosterone and increased hypothalamic expression of AR mRNA. DEX animals also displayed lower dopamine levels and higher dopamine receptor mRNA expression both in hypothalamus and nucleus accumbens (NAcc). The milder phenotype of CORT animals was associated only with decreased dopamine levels in NAcc. CONCLUSION: Antenatal corticotherapy programs adult male sexual behavior through changes in specific neuronal and endocrine mediators. Importantly, equipotent doses of CORT trigger less detrimental consequences than DEX, emphasizing the differential impact of activation of the different corticosteroid receptors. PMID- 21235720 TI - Development and validation of Chinese version of female sexual function index in a Chinese population-a pilot study. AB - INTRODUCTION: Female sexual dysfunction (FSD) is a prevalent problem that has been continuously overlooked in mainland China. An assessment instrument for FSD is urgently needed. AIM: To develop and validate the Chinese version of the Female Sexual Function Index (CVFSFI) to assess FSD in China. METHODS: A total of 328 women (20-65 years old) participated in this study. The CVFSFI was developed through the procedures of translation, back translation, revision by research team, and pilot study. After an interview for clinical diagnosis of FSD based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria, all participants completed the CVFSFI for a validation study. Eighty-three women completed CVFSFI again 3-4 weeks after the first visit. Test-retest reliability was determined by Pearson product-moment correlations. Internal consistency reliability was estimated with Cronbach's alpha coefficient. Construct validity was evaluated by principal component analysis using varimax rotation. Discriminant validity was assessed with between groups analysis of variance. MAIN OUTCOME MEASURES: Including the reliability and the validity of the CVFSFI and its domains. RESULTS: A total of 172 women (52.4%) met the DSM-IV-TR criteria for diagnosis of sexual dysfunction and were included in the FSD group, while 156 (47.6%) women without FSD were included in the control group. We showed that the overall test-retest reliability coefficients were high for total CVFSFI and each domain (r at least 0.69) and the internal consistency reliability of CVFSFI was within the acceptable range (Cronbach's alpha values: from 0.69 to 0.94). Moreover, the principal component analysis with varimax rotation produced six-factor structure similar to the original FSFI. We found significant differences in both total and domain scores between FSD and control groups, demonstrating a good discriminant validity of CVFSFI. CONCLUSION: The CVFSFI is a reliable and valid questionnaire, which can be used in the assessment of FSD among Chinese women. PMID- 21235721 TI - Pedophilic behavior from brain disease. AB - INTRODUCTION: Child molestation or other pedophilic behavior may result as a consequence of a brain disorder. AIM: To characterize the mechanisms of pedophilic behavior associated with neurological diseases. METHODS: We report eight patients with pedophilic behavior as a manifestation of their brain disorder and review the literature. MAIN OUTCOME MEASURES: The sexual, neuropsychiatric, and neurological aspects of a series of patients. RESULTS: All eight developed sexual behavior toward prepubescent children in mid- to late-life coincident with the development of a neurological disorder. Five had limited insight, anxiety, or concern for their behavior and tended to have frontal lobe executive deficits. Most of this group had frontally predominant disorders. Two others retained insight and concern in the context of marked hypersexuality. This second group had treated Parkinson's disease and resembled reports of pedophilic behavior from subcortical lesions. The further presence of right temporal lobe amygdala involvement may have predisposed to specific sexual preoccupation in some patients. CONCLUSIONS: Brain disorders may release a predisposition to sexual attraction for children through disinhibition with frontal disease, sexual preoccupation with right temporal disease, or hypersexuality with subcortical disease in non-motor basal ganglia, hypothalamus, or septal nuclei. Differentiating these mechanisms of pedophilic behavior from brain disease could facilitate targeted interventions. PMID- 21235722 TI - Relationship between premature ejaculation and depression in Korean males. AB - INTRODUCTION: The psychological impacts of premature ejaculation (PE), which include guilt, anxiety, and distress, have been well established in Western countries. However, in Asia, although a substantial number of epidemiological studies have surveyed the prevalence of PE, researchers have not thoroughly investigated the relationship between PE and depression, or have defined PE properly. AIM: We studied the association between PE and depression and other psychological disturbances, in a Korean cohort by applying an appropriate definition for PE and validated outcome measures of depression. METHODS. A total of 956 males (>=20 years) were initially approached via an Internet survey company. Participants were asked to complete a questionnaire requesting detailed medical and sexual histories, which included questions from the Erectile Function Domain score in the International Index of Erectile Function (IIEF-EF) and the Beck Depression Inventory (BDI). The prevalence of PE was evaluated using two different definitions-self-assessed PE and presumed PE. Presumed PE was defined as a short ejaculation time (an estimated intravaginal ejaculatory latency time <=5 minutes), an inability to control ejaculation, and the presence of distress resulting from PE. MAIN OUTCOME MEASURES: Ejaculation-related questionnaire, the IIEF-EF, and BDI. RESULTS: A total of 334 men were evaluated. The prevalence of PE was 10.5% according to the Presumed PE definition, whereas by self-assessment, it was 25.4%. Self-assessed PE patients suffered from various psychological problems, such as depression, low self-esteem, bother, and low sexual satisfaction. Even after excluding erectile dysfunction (ED) subjects, a significant relationship was found between self-assessed PE and depression. Moreover, after further classification of the Self-assessed PE group, we found that subjects included in this group, but not in the Presumed PE group, suffered more from psychological burden than any other members of the cohort. CONCLUSION: Korean men with subjective perceptions of PE are prone to various psychological problems, which include depression. PMID- 21235723 TI - Does metabolic syndrome impair sexual function in middle- to old-aged women? AB - INTRODUCTION: To date, there are few studies dealing with the impact of metabolic syndrome (MS) on female sexual function, and the association between MS and female sexual dysfunction (FSD) in middle- to old-aged women remains unclear. AIM: To evaluate the impact of MS on sexual function in middle- to old-aged women. METHODS: From May 2009 to January 2010, we performed a cross-sectional study of sexually active women (>= 40 years old) who visited a health-screening clinic. Comprehensive history taking, anthropometric measurement, laboratory testing, and questionnaire administration were performed for each of the total 773 women enrolled. MAIN OUTCOME MEASURES: The Female Sexual Function Index (FSFI) was used to assess the key dimensions of female sexual function. RESULTS: The median age of enrolled subjects was 48 (40-65) years, and the rates of MS and FSD were 12.2% (94/773) and 54.7% (423/773), respectively. We found that the demographics of women with and without MS (P < 0.05) differed significantly from one another in terms of age, menopausal status, body mass index, educational status, household income, and urinary incontinence (UI) symptoms, although their frequency of FSD was similar (52.1% vs. 55.1%). After adjusting clinical confounders, we found that only the pain domain score was significantly different between women with MS and without MS, while the total FSFI score and other constituent domain scores showed little difference between the two groups. However, in the multivariate logistic regression model, MS and most of its components were not associated with FSD; only age, menopausal status, smoking, depression, and symptomatic UI proved to be independent risk factors for FSD (P < 0.05). CONCLUSIONS: Our study suggests that MS may have little impact on sexual function in middle- to old-aged women. Further studies with population-based and longitudinal design should be conducted to confirm this finding. PMID- 21235724 TI - The effect of prolapse surgery on vaginal sensibility. AB - INTRODUCTION: Prolapse surgery has been shown to have major impact on sexual function. Since prolapse surgery not only influences psychological factors but might also influence physiological conditions such as vaginal innervation, there is a need for objective outcome measurements to better understand the effects of prolapse surgery on sexual function. AIMS: To assess the effects of prolapse surgery with or without stress incontinence surgery on vaginal sensibility and to assess the relationship between vaginal wall sensibility and sexual well-being. METHODS: This study was performed parallel to a randomized controlled trial comparing vaginal and abdominal prolapse surgery with or without incontinence surgery in women with uterine prolapse stage 2 or more. MAIN OUTCOME MEASURES: Vaginal wall sensibility was defined as mean sensation threshold to electrical stimulation of the vaginal wall at four standardized places, measured before and 6 months after surgery. Higher sensation thresholds postsurgery relative to presurgery indicate diminished vaginal wall sensibility. Sexual function was assessed at the same time points using a questionnaire. RESULTS: Data on vaginal wall sensibility were obtained from 65 patients. The sensibility of the distal posterior (P = 0.02) and distal anterior (P = 0.10) vaginal wall decreased after vaginal surgery compared to abdominal surgery. Abdominal prolapse surgery with incontinence surgery decreased sensibility of the distal part of the anterior vaginal wall significantly more than abdominal prolapse surgery only (P = 0.01). Before surgery, vaginal wall sensibility was lower in women who reported vaginal dryness or anorgasmia. The presence of genital pain was associated with higher vaginal wall sensibility. Postoperative vaginal wall sensibility was similar in women with and without sexual problems. CONCLUSION: Vaginal prolapse surgery as well as abdominal prolapse surgery with additional incontinence surgery resulted in decreased vaginal wall sensibility. This pilot study shows no influence of the decreased vaginal wall sensibility on sexual well-being. Larger studies are needed to better understand the association between changes in vaginal wall sensibility and changes in sexual well-being. PMID- 21235725 TI - PARP inhibition restores erectile function by suppressing corporal smooth muscle apoptosis in diabetic rats. AB - INTRODUCTION: An important mechanism suggested to be responsible for diabetes associated erectile dysfunction (ED) involves increased apoptosis, increased collagen deposition, and reduced smooth muscle content in the corpus cavernosum. AIM: To determine whether the activation of the pro-apoptotic poly(adenosine diphosphate ribose) polymerase (PARP) pathway is involved in the induction of corporal apoptosis, and whether the administration of 3-aminobenzamide (3-AB), a specific PARP inhibitor, could ameliorate ED in diabetic rats. METHODS: Male Sprague-Dawley rats (8-weeks-old) were randomly divided into three groups: age matched controls (C), diabetic controls (DM), and 3-AB-treated diabetic group (DM + 3-AB). Diabetes was induced by intraperitoneal (ip) injection of streptozotocin (50 mg/kg). Eight weeks after the induction of diabetes, DM + 3-AB group treated with 3-AB (30 mg/kg/day, ip) for 4 weeks. MAIN OUTCOME MEASURES: At 12 weeks after diabetes induction, erectile function was assessed by cavernous nerve stimulation. Penile tissue was assessed for apoptosis, Masson's trichrome stain and immunohistochemical analysis for smooth muscle alpha actin. Expression of poly(ADP-ribose), phospho-protein kinase B (Akt), phospho-Bcl-2-associated death promoter (Bad), B-cell leukemia/lymphoma 2 (Bcl-2), Bcl-2-associated X Protein (Bax), and apoptosis-inducing factor (AIF) were evaluated by Western blot. Caspase-3 activity and malondialdehyde (MDA), adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide (NAD+) concentrations were also determined. RESULTS: DM group showed impaired erectile function, increased PARP activity and corporal apoptosis, and decreased smooth muscle contents. Expression of phospho Akt, phospho-Bad, Bcl-2, and concentrations of ATP and NAD+ were decreased in the DM group, whereas concentrations of MDA, expression of Bax, nuclear translocation of AIF, and caspase-3 activity were increased. Treatment with 3-AB restored erectile function and significantly reversed all molecular and histological alterations except for the increased MDA. CONCLUSION: Over-activation of penile PARP pathway in diabetic rats enhances corporal apoptosis via energy depletion, suppression of Akt phosphorylation, and activation of the mitochondrial apoptotic pathway, which results in ED; these event could be prevented by treatment with 3 AB. PMID- 21235726 TI - Combination of testosterone and vardenafil increases female sexual functioning in sub-primed rats. AB - INTRODUCTION: Hypoactive sexual desire disorder (HSDD) is a common problem in women and may have a negative impact on quality of life. A recent clinical study shows an increase in sexual drive of HSDD women after cotreatment of testosterone and vardenafil (phosphodiesterase type 5 inhibitor). AIM: In this study, we investigated the effect of testosterone and vardenafil on sexual activity in female rats. MAIN OUTCOME MEASURES: Proceptive (darts and hops), receptive (lordosis), and paced-mating (percentages after exits and contact-return latencies) behaviors were quantified. METHODS: Ovariectomized female rats, sub primed with only estradiol and fully primed with estradiol and progesterone, were tested in a paced-mating sex test and sexual behaviors were quantified. The sub primed rats are thought to model HSDD. The effect of testosterone (100 and 300 ug, subcutaneous [SC]) and vardenafil (10 mg/kg, per os [PO]) alone and testosterone (300 ug, SC) in combination with vardenafil (3 and 10 mg/kg, PO) were tested. We also studied the effects of testosterone (300 ug, SC) + intracerebroventricular (ICV) injections of vardenafil (25 and 50 ug) on sexual activity. RESULTS: No effect of testosterone and vardenafil alone was found, but cotreatment of testosterone and vardenafil (PO) caused a significant increase in proceptive and receptive behavior in the sub-primed female rats. Testosterone and vardenafil did not affect fully primed females. ICV administration of vardenafil combined with systemic testosterone, on the other hand, had no effect on sexual activity in both sub-primed and fully primed female rats. CONCLUSIONS: We conclude that cotreatment of subcutaneous testosterone and oral vardenafil increase sexual activity in sub-primed female rats. Our data supports the human finding that combination treatment of testosterone and vardenafil could be used as a new treatment for women with HSDD. PMID- 21235727 TI - Three phases of corporal tracing elicited by electrical field stimulation on rabbit corpus cavernosum smooth muscle in penile perfusion model. AB - INTRODUCTION: Nitric oxide (NO) has been shown to mediate electrical field stimulation (EFS)-caused smooth muscle relaxation. It is known that the neural control of penile erection involves adrenergic, cholinergic, and non-adrenergic non-cholinergic (NANC) neuro-effector systems; however, the effects of EFS on adrenergic and cholinergic nerves are not clear. AIMS: To elucidate EFS-induced signal transductions involved in adrenergic, cholinergic, and NANC neuro-effector systems by using an in vitro penile perfusion model. METHODS: EFS was performed on penile corpus cavernosum smooth muscle from male New Zealand White rabbits, which was pre-contracted with L-phenylephrine (10 uM). We investigated the penile tracing elicited by EFS on tissues pre-incubated with guanethidine (Guan, 50 uM), tetrodotoxin (TTX, 10 uM), Nomega nitro-L-arginine-methyl ester (L-NAME, 1 mM), atropine (50 uM), or eserine (10 uM). MAIN OUTCOME MEASURES: The time-to-peak of each phase, the percentage of relaxation, and the area under the curve (AUC). RESULTS: We discovered an extraordinary phenomenon: three distinct phases elicited by EFS. Phase I was abolished by L-NAME. Phase II was decreased by eserine and Guan, but increased by L-NAME. Phase III was abolished by atropine, but enhanced by eserine and Guan. TTX diminished all three phases. The time to reach the top of phase I was delayed by TTX. The time to attain the peak of phase II was shortened by L-NAME, but delayed by TTX and atropine. The time to reach the top of phase III was shortened by L-NAME, eserine, and Guan. AUC was significantly decreased by L-NAME and TTX. CONCLUSIONS: EFS stimulated adrenergic, cholinergic, and NANC neuro-effector systems simultaneously. Phase I was related to the NO pathway. Phase II was multiply affected by self-recovery properties, and adrenergic and cholinergic nerves. Phase III was related to cholinergic nerves. The corporal tracing elicited by EFS was the balanced result of multiple factors. PMID- 21235728 TI - Rare HLA alleles and their predicted haplotypes in Tzu Chi Taiwanese marrow donor registry. AB - The marrow donor registry of Buddhist Tzu Chi Stem Cells Centre (BTCSCC) maintained an HLA database of 291677 bone marrow volunteer donors from 1993 to 2008. From the 291677 donors we identified 28 rare alleles and discovered six novel alleles in Taiwanese. Our criterion of a rare allele was according to the definition, set by the National Marrow Donor Program (NMDP), one having a frequency of 0.002% (1/50,000) or less. The authenticity of the rare alleles was confirmed by sequence specific primer (SSP) typing protocol and/or sequence-based typing (SBT) method. This study reports the number of times the alleles were observed between 1993 and 2008, and the ethnicity of the donors carrying the rare or novel alleles. PMID- 21235729 TI - New uses for old drugs: pharmacophore-based screening for the discovery of P glycoprotein inhibitors. AB - P-glycoprotein (P-gp) is one of the best characterized transporters responsible for the multidrug resistance phenotype exhibited by cancer cells. Therefore, there is widespread interest in elucidating whether existing drugs are candidate P-gp substrates or inhibitors. With this aim, a pharmacophore model was created based on known P-gp inhibitors and it was used to screen a database of existing drugs. The P-gp modulatory activity of the best hits was evaluated by several methods such as the rhodamine-123 accumulation assay using K562Dox cell line, and a P-gp ATPase activity assay. The ability of these compounds to enhance the cytotoxicity of doxorubicin was assessed with the sulphorhodamine-B assay. Of the 21 hit compounds selected in silico, 12 were found to significantly increase the intracellular accumulation of Rhodamine-123, a P-gp substrate. In addition, amoxapine and loxapine, two tetracyclic antidepressant drugs, were discovered to be potent non-competitive inhibitors of P-gp, causing a 3.5-fold decrease in the doxorubicin GI(50) in K562Dox cell line. The overall results provide important clues for the non-label use of known drugs as inhibitors of P-gp. Potent inhibitors with a dibenzoxazepine scaffold emerged from this study and they will be further investigated in order to develop new P-gp inhibitors. PMID- 21235730 TI - Site-specific free energy changes in proteins upon ligand binding by nuclear magnetic resonance: Ca2+ -displacement by Ln3+ in a Ca2+ -binding protein from Entamoeba histolytica. AB - The study of protein-ligand interaction has been of a great interest in contemporary structural biology. The understanding of the nature of such interaction and determining the associated binding affinities are of utmost importance. Nuclear magnetic resonance has become a powerful tool in deriving information related to such interactions in proteins. Nuclear magnetic resonance data provide the site-specific information even in the case of proteins having multiple-binding sites and populations of respective species. In this communication, we set out to use such information to derive the associated microscopic binding constants. PMID- 21235731 TI - Should we listen to people affected by dementia? PMID- 21235732 TI - Occurrence of dual infection of peste-des-petits-ruminants and goatpox in indigenous goats of central India. AB - Peste-des-petits-ruminants (PPR), bluetongue (BT) and goatpox (GP) have been well recognized as causes of significant economic losses in the small ruminant population of Asia and Africa. We describe here the occurrence of these three in an outbreak noticed in non-descript goats from a subtropical region of central India. An investigation was carried out to confirm the aetiology of the heavy mortality in goats (74.6%, 112/150), with testing of samples from 12 surviving animals exhibiting mixed clinical signs indicative of PPR, BT and GP. Sandwich ELISA was used to detect PPR virus antigen and competition ELISA to detect PPR virus and BT virus antibodies. GP was confirmed on the basis of nodular lesions and an immunodiffusion assay. Eight of the 12 affected animals (66.7%) were positive for PPR virus and BT virus antibodies, and two goats (16.7%, 2/12) exhibiting clinical lesions of pox were also found positive for PPR virus/antibodies and BT virus antibodies, respectively. Although BT virus could not be identified in any sample, detection of BT virus antibodies indicated previous or possibly concurrent infection with BT virus in these goats. The N gene-based RT-PCR was used to confirm the PPR infection in these goats, and one of the amplicons was sequenced. The sequence and phylogenetic analysis revealed close proximity to PPR virus isolates from Tibet and China, with sequence homology of up to 96.9%. The sequence homology was relatively low with the majority of other Indian isolates (72.7-93.5%). The detection of this new PPR virus sequence indicates the circulation of cross-border strains in this region of India. It is presumed that the heavy mortality observed in goats is possibly attributable to the occurrence of mixed infection of PPR and GP, or PPR, BT and GP. PMID- 21235733 TI - Nogo-B is associated with cytoskeletal structures in human monocyte-derived macrophages. AB - BACKGROUND: The reticulon Nogo-B participates in cellular and immunological processes in murine macrophages. Since leukocytes are an essential part of the immune system in health and disease, we decided to investigate the expression of Nogo-A, Nogo-B and Nogo-C in different human immune cell subpopulations. Furthermore, we analyzed the localization of Nogo-B in human monocyte-derived macrophages by indirect immunofluorescence stainings to gain further insight into its possible function. FINDINGS: We describe an association of Nogo-B with cytoskeletal structures and the base of filopodia, but not with focal or podosomal adhesion sites of monocyte-derived macrophages. Nogo-B positive structures are partially co-localized with RhoA staining and Rac1 positive membrane ruffles. Furthermore, Nogo-B is associated with the tubulin network, but not accumulated in the Golgi region. Although Nogo-B is present in the endoplasmic reticulum, it can also be translocated to large cell protrusions or the trailing end of migratory cells, where it is homogenously distributed. CONCLUSIONS: Two different Nogo-B staining patterns can be distinguished in macrophages: firstly we observed ER-independent Nogo-B localization in cell protrusions and at the trailing end of migrating cells. Secondly, the localization of Nogo-B in actin/RhoA/Rac1 positive regions supports an influence on cytoskeletal organization. To our knowledge this is the first report on Nogo-B expression at the base of filopodia, thus providing further insight into the distribution of this protein. PMID- 21235734 TI - Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent. AB - BACKGROUND: Despite an ever-improving understanding of the molecular biology of cancer, the treatment of most cancers has not changed dramatically in the past three decades and drugs that do not discriminate between tumor cells and normal tissues remain the mainstays of anticancer therapy. Since Hsp90 is typically involved in cell proliferation and survival, this is thought to play a key role in cancer, and Hsp90 has attracted considerable interest in recent years as a potential therapeutic target. METHODS: We focused on the interaction of Hsp90 with its cofactor protein p60/Hop, and engineered a cell-permeable peptidomimetic, termed "hybrid Antp-TPR peptide", modeled on the binding interface between the molecular chaperone Hsp90 and the TPR2A domain of Hop. RESULTS: It was demonstrated that this designed hybrid Antp-TPR peptide inhibited the interaction of Hsp90 with the TPR2A domain, inducing cell death of breast, pancreatic, renal, lung, prostate, and gastric cancer cell lines in vitro. In contrast, Antp-TPR peptide did not affect the viability of normal cells. Moreover, analysis in vivo revealed that Antp-TPR peptide displayed a significant antitumor activity in a xenograft model of human pancreatic cancer in mice. CONCLUSION: These results indicate that Antp-TPR peptide would provide a potent and selective anticancer therapy to cancer patients. PMID- 21235736 TI - Distribution of enteric glia and GDNF during gut inflammation. AB - BACKGROUND: The enteric glia network may be involved in the pathogenesis of inflammatory bowel disease (IBD). Enteric glia cells (EGCs) are the major source of glial-derived neurotrophic factor (GDNF), which regulates apoptosis of enterocytes. The aim of the study was to determine the distribution of EGCs and GDNF during gut inflammation and to elucidate a possible diminished enteric glia network in IBD. METHODS: The expression of glial fibrillary acidic protein (GFAP) in colonic biopsies of patients with IBD, controls and patients with infectious colitis was detected by immunohistochemistry and Western blot. Tissue GDNF levels were measured by ELISA. RESULTS: The expression of GFAP and GDNF in the mucosal plexus is highly increased in the inflamed colon of patients with ulcerative colitis (UC) and infectious colitis. Although the GDNF and GFAP content are increased in Crohn's disease (CD), it is significantly less. Additionally the non inflamed colon of CD patients showed a reduced GFAP and no GDNF expression compared to controls and the non-inflamed colon of UC patients. CONCLUSIONS: GFAP and GDNF as signs of activated EGCs are increased in the inflamed mucosa of patients with UC and infectious colitis, which underline an unspecific role of EGC in the regulation of intestinal inflammation. The reduced GFAP and GDNF content in the colon of CD patients suggest a diminished EGC network in this disease. This might be a part of the pathophysiological puzzle of CD. PMID- 21235735 TI - Molecular analysis and intestinal expression of SAR1 genes and proteins in Anderson's disease (Chylomicron retention disease). AB - BACKGROUND: Anderson's disease (AD) or chylomicron retention disease (CMRD) is a very rare hereditary lipid malabsorption syndrome. In order to discover novel mutations in the SAR1B gene and to evaluate the expression, as compared to healthy subjects, of the Sar1 gene and protein paralogues in the intestine, we investigated three previously undescribed individuals with the disease. METHODS: The SAR1B, SAR1A and PCSK9 genes were sequenced. The expression of the SAR1B and SAR1A genes in intestinal biopsies of both normal individuals and patients was measured by RTqPCR. Immunohistochemistry using antibodies to recombinant Sar1 protein was used to evaluate the expression and localization of the Sar1 paralogues in the duodenal biopsies. RESULTS: Two patients had a novel SAR1B mutation (p.Asp48ThrfsX17). The third patient, who had a previously described SAR1B mutation (p.Leu28ArgfsX7), also had a p.Leu21dup variant of the PCSK9 gene. The expression of the SAR1B gene in duodenal biopsies from an AD/CMRD patient was significantly decreased whereas the expression of the SAR1A gene was significantly increased, as compared to healthy individuals. The Sar1 proteins were present in decreased amounts in enterocytes in duodenal biopsies from the patients as compared to those from healthy subjects. CONCLUSIONS: Although the proteins encoded by the SAR1A and SAR1B genes are 90% identical, the increased expression of the SAR1A gene in AD/CMRD does not appear to compensate for the lack of the SAR1B protein. The PCSK9 variant, although reported to be associated with low levels of cholesterol, does not appear to exert any additional effect in this patient. The results provide further insight into the tissue-specific nature of AD/CMRD. PMID- 21235737 TI - Genome-wide analysis of Ollier disease: Is it all in the genes? AB - BACKGROUND: Ollier disease is a rare, non-hereditary disorder which is characterized by the presence of multiple enchondromas (ECs), benign cartilaginous neoplasms arising within the medulla of the bone, with an asymmetric distribution. The risk of malignant transformation towards central chondrosarcoma (CS) is increased up to 35%. The aetiology of Ollier disease is unknown. METHODS: We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis using Affymetrix SNP 6.0 array on 37 tumours of 28 Ollier patients in combination with expression array using Illumina BeadArray v3.0 for 7 ECs of 6 patients. RESULTS: Non-recurrent EC specific copy number alterations were found at FAM86D, PRKG1 and ANKS1B. LOH with copy number loss of chromosome 6 was found in two ECs from two unrelated Ollier patients. One of these patients also had LOH at chromosome 3. However, no common genomic alterations were found for all ECs. Using an integration approach of SNP and expression array we identified loss as well as down regulation of POU5F1 and gain as well as up regulation of NIPBL. None of these candidate regions were affected in more than two Ollier patients suggesting these changes to be random secondary events in EC development. An increased number of genetic alterations and LOH were found in Ollier CS which mainly involves chromosomes 9p, 6q, 5q and 3p. CONCLUSIONS: We present the first genome-wide analysis of the largest international series of Ollier ECs and CS reported so far and demonstrate that copy number alterations and LOH are rare and non-recurrent in Ollier ECs while secondary CS are genetically unstable. One could predict that instead small deletions, point mutations or epigenetic mechanisms play a role in the origin of ECs of Ollier disease. PMID- 21235738 TI - Negative health care experiences of immigrant patients: a qualitative study. AB - BACKGROUND: Negative events are abusive, potentially dangerous or life threatening health care events, as perceived by the patient. Patients' perceptions of negative events are regarded as a potentially important source of information about the quality of health care. We explored negative events in hospital care as perceived by immigrant patients. METHODS: Semi-structured individual and group interviews were conducted with respondents about negative experiences of health care. Interviews were transcribed and analyzed using a framework method. A total of 22 respondents representing 7 non-Dutch ethnic origins were interviewed; each respondent reported a negative event in hospital care or treatment. RESULTS: Respondents reported negative events in relation to: 1) inadequate information exchange with care providers; 2) different expectations between respondents and care providers about medical procedures; 3) experienced prejudicial behavior on the part of care providers. CONCLUSIONS: We identified three key situations in which negative events were experienced by immigrant patients. Exploring negative events from the immigrant patient perspective offers important information to help improve health care. Our results indicate that care providers need to be trained in adequately exchanging information with the immigrant patient and finding out specific patient needs and perspectives on illness and treatment. PMID- 21235739 TI - Fulminant Leptospirosis (Weil's disease) in an urban setting as an overlooked cause of multiorgan failure: a case report. AB - INTRODUCTION: Leptospirosis has recently come to international attention as a globally important re-emerging infectious disease. Our case is unusual given the season, location and setting in which leptospirosis occurred. According to the New York City Board of Health, there were only two other cases of leptospirosis in New York City in the year that our patient was diagnosed. CASE PRESENTATION: A 49-year-old healthy Chinese man presented to our hospital with sepsis and multiorgan failure. The patient did not respond to antibiotics and his multiorgan failure worsened. His workup did not show any significant findings except for a positive nasopharyngeal swab result for influenza A. Later the patient developed hemoptysis with evidence of bilateral infiltrates on radiography. His status mildly improved after he was started on steroids. Eventually, a microagglutination test confirmed the presence of antibodies against Leptospira icterohaemorrhagiae. The patient subsequently recovered after a course of intravenous antibiotics. CONCLUSION: The case of fulminant leptospirosis presented here should serve to alert health care providers and the general public to the clinical importance of this severe, sometimes fatal, disease. Leptospirosis should be considered early in the diagnosis of any patient with acute, non-specific febrile illness with multiorgan system involvement or high fever in a returning traveler. In addition, not only should it be considered in tropical and rural areas between late summer to early fall, but also in any location or time if the risk factors are present. PMID- 21235740 TI - Persistent Tn polyagglutination syndrome during febrile neutropenia: a case report and review of the literature. AB - INTRODUCTION: Tn polyagglutination syndrome is a rare disorder that has been reported on only a few occasions in the literature, and, to the best of our knowledge, never before in the context of febrile neutropenia. CASE PRESENTATION: We report the case of a 26-year-old Caucasian woman who presented to our emergency department complaining of a persistent fever over the previous three days. She had a history of long-standing refractory pancytopenia with multi lineage dysplasia and severe neutropenia, but she had rarely experienced infection. The results of a physical examination and multiple laboratory tests were unremarkable. While investigating the possible causes of the refractory, long-standing pancytopenia, the possibility of a polyagglutinable state was suggested. Blood samples were sent to the laboratory for an analysis of mixed field seed lectin agglutination assay. A serum lectin panel confirmed the final diagnosis of Tn-activation. CONCLUSIONS: We should include Tn-activation in our differential whenever we encounter cases of refractory long-standing idiopathic cytopenias and inconclusive bone marrow results displaying multi-lineage dysplasia. Novel genetic techniques have recently revealed the interesting pathophysiology of this phenomenon. The recognition and inclusion of Tn polyagglutination syndrome in our differential diagnoses has important clinical implications, given its main associated features, such as severe thrombocytopenia and neutropenia, which are usually linked to a benign clinical course and prognosis. Increased awareness of the polyagglutinable disorders will potentially decrease the need for invasive and costly medical interventions and also raises the need for monitoring of this specific sub-set of patients. In addition, the study of the expression and implications of Tn, and other similar antigens, offers a fascinating perspective for the study of its role in the diagnosis, prognosis and immunotherapy of solid tumors and hematological malignancies. The infrequency with which Tn polyagglutination syndrome is encountered, its clinical features and its pathophysiology make it a formidable diagnostic challenge. PMID- 21235741 TI - Low level of physical activity in women with rheumatoid arthritis is associated with cardiovascular risk factors but not with body fat mass--a cross sectional study. AB - BACKGROUND: As many patients with rheumatoid arthritis (RA) have increased fat mass (FM) and increased frequency of cardiovascular diseases we evaluated if total physical activity (MET-hours) had impact on body composition and cardiovascular risk factors in women with RA. METHODS: Sixty-one out-ward RA women, 60.8 (57.3-64.4) years, answered a self-administered questionnaire, to estimate total daily physical activity during the previous year. Physical activity level was given as metabolic equivalents (MET) * h/day. Diet content was assessed by a food frequency questionnaire and body composition by whole-body dual-energy X-ray absorptiometry. Blood lipids and antibodies against phosphorylcholine (anti-PC) were determined. RESULTS: Forty-one percent of the women had BMI > 25, 6% were centrally obese and 80% had FM% > 30%. The median (IQR) total physical activity was 40.0 (37.4-47.7), i.e. the same activity level as healthy Swedish women in the same age. Total physical activity did not significantly correlate with disease activity, BMI or FM%. Disease activity, BMI and FM% did not differ between those in the lowest quartile of total physical activity and those in the highest quartile. However, the women in the lowest quartile of physical activity had lower HDL (p = 0.05), Apo A1 (p = 0.005) and atheroprotective natural anti-PC (p = 0.016) and higher levels of insulin (p = 0.05) and higher frequency of insulin resistance than those in the highest quartile. Women in the lowest quartile consumed larger quantities of saturated fatty acids than those in the highest quartile (p = 0.042), which was associated with high oxidized low-density lipoprotein (oxLDL). CONCLUSION: This cross sectional study demonstrated that RA women with fairly low disease activity, good functional capacity, high FM and high frequency of central obesity had the same total physical activity level as healthy Swedish women in the same age. The amount of total physical activity was not associated with functional capacity or body composition. However, low total physical activity was associated with dyslipidemia, insulin resistance, low levels of atheroprotective anti-PC and consumption of saturated fatty acids, which is of interest in the context of increased frequency of cardiovascular disease in RA. PMID- 21235742 TI - Plasma acetate, gluconate and interleukin-6 profiles during and after cardiopulmonary bypass: a comparison of Plasma-Lyte 148 with a bicarbonate balanced solution. AB - INTRODUCTION: As even small concentrations of acetate in the plasma result in pro inflammatory and cardiotoxic effects, it has been removed from renal replacement fluids. However, Plasma-Lyte 148 (Plasma-Lyte), an electrolyte replacement solution containing acetate plus gluconate is a common circuit prime for cardio pulmonary bypass (CPB). No published data exist on the peak plasma acetate and gluconate concentrations resulting from the use of Plasma-Lyte 148 during CPB. METHODS: Thirty adult patients were systematically allocated 1:1 to CPB prime with either bicarbonate-balanced fluid (24 mmol/L bicarbonate) or Plasma-Lyte 148. Arterial blood acetate, gluconate and interleukin-6 (IL-6) levels were measured immediately before CPB (T1), three minutes after CPB commencement (T2), immediately before CPB separation (T3), and four hours post separation (T4). RESULTS: Acetate concentrations (normal 0.04 to 0.07 mmol/L) became markedly elevated at T2, where the Plasma-Lyte group (median 3.69, range (2.46 to 8.55)) exceeded the bicarbonate group (0.16 (0.02 to 3.49), P < 0.0005). At T3, levels had declined but the differential pattern remained apparent (Plasma-Lyte 0.35 (0.00 to 1.84) versus bicarbonate 0.17 (0.00 to 0.81)). Normal circulating acetate concentrations were not restored until T4. Similar gluconate concentration profiles and inter-group differences were seen, with a slower T3 decay. IL-6 increased across CPB, peaking at T4, with no clear difference between groups. CONCLUSIONS: Use of acetate containing prime solutions result in supraphysiological plasma concentrations of acetate. The use of acetate-free prime fluid in CPB significantly reduced but did not eliminate large acetate surges in cardiac surgical patients. Complete elimination of acetate surges would require the use of acetate free bolus fluids and cardioplegia solutions. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12610000267055. PMID- 21235744 TI - Congenital spinal tumor in a patient with encephalocele and hydrocephalus: a case report. AB - INTRODUCTION: Encephalocele is a rare congenital abnormality of the central nervous system, where brain tissue protrudes from a defect in the skull. Some anomalies are associated with encephalocele. However, the association of spinal teratoma and encephalocele has not been reported in the English literature. CASE PRESENTATION: We report the case of an Iranian girl with a history of encephalocele surgery, who, at the age of four years, developed an intramedullary spinal teratoma, and discuss the pathogenesis of this association. CONCLUSION: To the best of our knowledge, this is the first report of an association between encephalocele and spinal teratoma. PMID- 21235743 TI - Cre-LoxP-regulated expression of monoclonal antibodies driven by an ovalbumin promoter in primary oviduct cells. AB - BACKGROUND: A promoter capable of driving high-level transgene expression in oviduct cells is important for developing transgenic chickens capable of producing therapeutic proteins, including monoclonal antibodies (mAbs), in the whites of laid eggs. Ovalbumin promoters can be used as oviduct-specific regulatory sequences in transgenic chickens, but their promoter activities are not high, according to previous reports. RESULTS: In this study, while using a previously characterized ovalbumin promoter, we attempted to improve the expression level of mAbs using a Cre/loxP-mediated conditional excision system. We constructed a therapeutic mAb expression vector, pBS-DS-hIgG, driven by the CMV and CAG promoters, in which the expression of the heavy and light chains of humanized immunoglobulin G (hIgG) is preceded by two floxed stuffer reporter genes. In the presence of Cre, the stuffer genes were precisely excised and hIgG expression was induced in pBS-DS-hIgG-transfected 293T cells. In chicken oviduct primary culture cells, hIgG was expressed after transfection of pBS-DS-hIgG together with the ovalbumin promoter-driven Cre expression vector. The expression level of hIgG in these cells was increased 40-fold over that induced directly by the ovalbumin promoter. On the other hand, hIgG was not induced by the ovalbumin promoter-driven Cre in chicken embryonic fibroblast cells. CONCLUSIONS: The Cre/loxP-based system could significantly increase ovalbumin promoter-driven production of proteins of interest, specifically in oviduct cells. This expression system could be useful for producing therapeutic mAbs at high level using transgenic chickens as bioreactors. PMID- 21235745 TI - A locally congenic backcross design in pig: a new regional fine QTL mapping approach miming congenic strains used in mouse. AB - BACKGROUND: In previous studies, a major QTL affecting fatness and growth has been mapped to pig chromosome 1q (SSC1q) using Large White - Meishan intercrosses. A higher fat depth and a larger growth rate have been reported for the allele of MS origin. Additionally the LW allele showed partial dominance effects over the MS allele for both traits. In order to refine the QTL mapping interval, advanced backcross generations were produced. Recombinant heterozygous sires were mated to LW sows in order to progeny test the sire segregation of the QTL and refine the QTL localisation. However due to the partial dominance of the LW allele, BC scheme using LW as the receiving population was not optimal. RESULTS: To overcome the difficulties related to the dominance of the LW QTL allele, a population of dams locally homozygous for the MS haplotype in the QTL region, but with an overall 29/32 LW genetic background, has been set up. Progeny testing results, using these receiver dams, were much more significant than those previously obtained with LW dams, and the SSC1 QTL interval was refined to 8 cM. Considering the results obtained, a powerful experimental design for farm animals is proposed, mimicking locally genetically identical strains used in mouse for QTL fine mapping. CONCLUSIONS: We have further characterized the fatness QTL on pig chromosome 1 and refined its map position from a 30 cM interval to a 8 cM interval, using a locally congenic BC design. We have obtained highly significant results and overcome difficulties due to the dominance of the LW allele. This design will be used to produce additional, advanced BC families to further refine this QTL localization. PMID- 21235746 TI - Hepatitis C virus genotypes circulating in district Swat of Khyber Pakhtoonkhaw, Pakistan. AB - Hepatitis C virus (HCV) is the leading cause of chronic hepatitis worldwide and its subtypes/genotypes are clinically important for clinical management and vaccine development. The present study describes frequency distribution of different HCV genotypes and their treatment status in HCV RNA positive patients from district Swat. A total of 185 HCV infected sera were analyzed by molecular genotyping assay. The most prevalent genotype was 3a (34.1%), followed by 2a (8.1%), 3b (7%) and 1a (5.4%). The samples found untypable by the present method of genotypes was 37.8% while, patients with mixed genotype infections were 7.6%. More than 80% of untypable cases were from those HCV patients who had received interferon plus ribavirin standard therapy in the past and either were non responders and were relapsed thereafter or were under treatment. In conclusion, genotype 3a is the most prevalent HCV genotype in the region. A high prevalence rate of untypable genotypes is present in treated patients that need further investigation for the successful genotyping by developing new assays or using viral sequencing method. PMID- 21235747 TI - Initial periodontal screening and radiographic findings--a comparison of two methods to evaluate the periodontal situation. AB - BACKGROUND: The periodontal screening index (PSI) is an element of the initial dental examination. The PSI provides information on the periodontal situation and allows a first estimation of the treatment required. The dental panoramic tomography (DPT) indicates the proximal bone loss, thus also allowing conclusions on the periodontal situation. In this study, the results of both methods in determining the periodontal situation are compared. METHODS: The clinical examination covered DMF-T, QHI, and PSI scores at four proximal sites per tooth; the examining dentist was unaware of the radiographic finding. Based on the PSI scores, the findings were diagnosed as follows: score 0 - 2 "no periodontitis", score 3 and 4 "periodontitis". Independent of the locality and time of the clinical evaluation, two dentists examined the DPTs of the subjects. The results were classified as follows: no bone loss = "no periodontitis", and bone loss = "periodontitis". RESULTS: 112 male subjects (age 18 to 58, O 37.7 +/- 8 years) were examined. Regarding the PSI, 17 subjects were diagnosed "no periodontitis" and 95 subjects "periodontitis". According to the evaluation of the DPTs, 70 subjects were diagnosed "no periodontitis" and 42 "periodontitis". A comparison of both methods revealed that the diagnosis "no periodontitis" corresponded in 17 cases and "periodontitis" in 42 cases (53%). In 47% (53 cases) the results were not congruent. The difference between both methods was statistically significant (p < 0.001; kappa = 0.194). CONCLUSION: The present study shows that the initial assessment of the periodontal situation significantly depends on the method of evaluation. PMID- 21235748 TI - mGlu2 metabotropic glutamate receptors restrain inflammatory pain and mediate the analgesic activity of dual mGlu2/mGlu3 receptor agonists. AB - Group II metabotropic glutamate receptors (mGluRs) couple to the inhibitory G protein Gi. The group II mGluRs include two subtypes, mGlu2 and mGlu3, and their pharmacological activation produces analgesic effects in inflammatory and neuropathic pain states. However, the specific contribution of each one of the two subtypes has not been clarified due to the lack of selective orthosteric ligands that can discriminate between mGlu2 and mGlu3 subtypes.In this study we used mGlu2 or mGlu3 knock-out mice to dissect the specific role for these two receptors in the endogenous control of inflammatory pain and their specific contribution to the analgesic activity of mixed mGlu2/3 receptor agonists.Our results showed that mGlu2-(/)- mice display a significantly greater pain response compared to their wild type littermates. Interestingly the increased pain sensitivity in mGlu2-(/)- mice occurred only in the second phase of the formalin test. No differences were observed in the first phase. In contrast, mGlu3-(/)- mice did not significantly differ from their wild type littermates in either phase of the formalin test.When systemically injected, a single administration of the mGlu2/3 agonist, LY379268 (3 mg/kg, ip), showed a significant reduction of both phases in wild-type mice and in mGlu3-(/)- but not in mGlu2-(/)- mice. However tolerance to the analgesic effect of LY379268 (3 mg/kg, ip) in mGlu3-(/)- mice developed following 5 consecutive days of injection.Taken together, these results demonstrate that: (i) mGlu2 receptors play a predominant role over mGlu3 receptors in the control of inflammatory pain in mice; (ii) the analgesic activity of mixed mGlu2/3 agonists is entirely mediated by the activation of the mGlu2 subtype and (iii) the development of tolerance to the analgesic effect of mGlu2/3 agonists develops despite the lack of mGlu3 receptors. PMID- 21235749 TI - Test-retest reliability of two instruments for measuring public attitudes towards persons with mental illness. AB - BACKGROUND: Research has identified stigmatization as a major threat to successful treatment of individuals with mental illness. As a consequence several anti-stigma campaigns have been carried out. The results have been discouraging and the field suffers from lack of evidence about interventions that work. There are few reports on psychometric data for instruments used to assess stigma, which thus complicates research efforts. The aim of the present study was to investigate test-retest reliability of the Swedish versions of the questionnaires: FABI and "Changing Minds" and to examine the internal consistency of the two instruments. METHOD: Two instruments, fear and behavioural intentions (FABI) and "Changing Minds", used in earlier studies on public attitudes towards persons with mental illness were translated into Swedish and completed by 51 nursing students on two occasions, with an interval of three weeks. Test-retest reliability was calculated by using weighted kappa coefficient and internal consistency using the Cronbach's alpha coefficient. RESULTS: Both instruments attain at best moderate test-retest reliability. For the Changing Minds questionnaire almost one fifth (17.9%) of the items present poor test-retest reliability and the alpha coefficient for the subscales ranges between 0.19 - 0.46. All of the items in the FABI reach a fair or a moderate agreement between the test and retest, and the questionnaire displays a high internal consistency, alpha 0.80. CONCLUSIONS: There is a need for development of psychometrically tested instruments within this field of research. PMID- 21235750 TI - Preliminary assessment of cardiac short term safety and efficacy of manganese chloride for cardiovascular magnetic resonance in humans. AB - BACKGROUND: Manganese based agents are intracellular and accumulate inside myocytes allowing for different imaging strategies compared to gadolinium contrasts. While previous agents release manganese very slowly in the circulation, MnCl2 allows for rapid Mn2+ uptake in myocytes, creating a memory effect that can be potentially explored. Data on animal models are very encouraging but the safety and efficacy of this approach in humans has not yet been investigated. Therefore, our objectives were to study the safety and efficacy of a rapid infusion of manganese chloride (MnCl2) for cardiovascular magnetic resonance (CMR) in humans. METHODS: Fifteen healthy volunteers underwent a CMR scan on a 1.5 T scanner. Before the infusion, cardiac function was calculated and images of a short axis mid-ventricular slice were obtained using a 2D and 3D gradient-echo inversion recovery (GRE-IR) sequence, a phase-sensitive IR sequence and a single breath-hold segmented IR prepared steady-state precession acquisition for T1 calculations. MnCl2 was infused over three minutes at a total dose of 5 MUMol/kg. Immediately after the infusion, and at 15 and 30 minutes later, new images were obtained and cardiac function re-evaluated. RESULTS: There was a significant decrease in T1 values compared to baseline, sustained up to 30 minutes after the MnCl2 infusion (pre,839 +/- 281 ms; 0 min, 684 +/- 99; 15 min, 714 +/- 168; 30 min, 706 +/- 172, P = 0.003). The 2D and 3D GRE-IR sequence showed the greatest increase in signal-to-noise ratio compared to the other sequences (baseline 6.6 +/- 4.2 and 9.7 +/- 5.3; 0 min, 11.3 +/- 4.1 and 15.0 +/- 8.7; 15 min, 10.8 +/- 4.0 and 16.9 +/- 10.2; 30 min, 10.6 +/- 5.2 and 16.5 +/- 8.3, P < 0.001 for both). There was a slight increase in systolic pressure and heart rate after three and four minutes of the infusion with normalization of these parameters thereafter. Patients showed good tolerance to MnCl2 with no major adverse events, despite all reporting transient facial flush. CONCLUSIONS: In the short term, MnCl2 appears safe for human use. It effectively decreases myocardium T1, maintaining this effect for a relatively long period of time and allowing for the development of new imaging strategies in CMR, especially in ischemia research. PMID- 21235751 TI - Comprehensive 4D velocity mapping of the heart and great vessels by cardiovascular magnetic resonance. AB - BACKGROUND: Phase contrast cardiovascular magnetic resonance (CMR) is able to measure all three directional components of the velocities of blood flow relative to the three spatial dimensions and the time course of the heart cycle. In this article, methods used for the acquisition, visualization, and quantification of such datasets are reviewed and illustrated. METHODS: Currently, the acquisition of 3D cine (4D) phase contrast velocity data, synchronized relative to both cardiac and respiratory movements takes about ten minutes or more, even when using parallel imaging and optimized pulse sequence design. The large resulting datasets need appropriate post processing for the visualization of multidirectional flow, for example as vector fields, pathlines or streamlines, or for retrospective volumetric quantification. APPLICATIONS: Multidirectional velocity acquisitions have provided 3D visualization of large scale flow features of the healthy heart and great vessels, and have shown altered patterns of flow in abnormal chambers and vessels. Clinically relevant examples include retrograde streams in atheromatous descending aortas as potential thrombo-embolic pathways in patients with cryptogenic stroke and marked variations of flow visualized in common aortic pathologies. Compared to standard clinical tools, 4D velocity mapping offers the potential for retrospective quantification of flow and other hemodynamic parameters. CONCLUSIONS: Multidirectional, 3D cine velocity acquisitions are contributing to the understanding of normal and pathologically altered blood flow features. Although more rapid and user-friendly strategies for acquisition and analysis may be needed before 4D velocity acquisitions come to be adopted in routine clinical CMR, their capacity to measure multidirectional flows throughout a study volume has contributed novel insights into cardiovascular fluid dynamics in health and disease. PMID- 21235752 TI - Protocol for shoulder function training reducing musculoskeletal pain in shoulder and neck: a randomized controlled trial. AB - BACKGROUND: Neck and shoulder complaints are common among employees in sedentary occupations characterized by intensive computer use. Such musculoskeletal pain - which is often associated with restricted range of motion and loss of muscle strength - is one of the most common conditions treated by physical therapists. The exact mechanism of neck pain is rarely revealed by clinical examination and the treatment has varied from passive rest to active treatments. Active treatments have often been divided into either training of the painful area or the surrounding musculature avoiding direct training of the painful area. Our study investigates the effect of the latter approach. METHODS/DESIGN: A randomized controlled trial of 10 weeks duration is currently being conducted. Employed office workers with severe neck-shoulder pain are randomized to 3 * 20 min shoulder function training with training supervision or to a reference group receiving advice to stay physically active. Shoulder function training primarily focuses on the serratus anterior and lower trapezius muscle with only minimal activation the upper trapezius.An announcement was sent to the administrative section of the university including jobs characterized by intensive computer work. The first 100 positive replies entered the study. Among these inclusion criteria were pain intensity in the neck/shoulder of at least 3 on a 0-9 scale. Exclusion criteria were cardiovascular disease, trauma, hypertension, or serious chronic disease. Before and after the intervention period the participants replied to a questionnaire about musculoskeletal disorders and work disability, and underwent a standardized clinical examination of the neck and shoulder girdle. Further, on a weekly basis the participants log pain intensity of the neck and shoulder during the previous week.The primary outcome measure is pain in the neck and shoulders at week 10 based on the weekly pain registration and results from the clinical examination. Secondary outcomes are strength and work disability. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT01205542. PMID- 21235753 TI - Divergent responses to peptidoglycans derived from different E. coli serotypes influence inflammatory outcome in trout, Oncorhynchus mykiss, macrophages. AB - BACKGROUND: Pathogen-associated molecular patterns (PAMPs) are structural components of pathogens such as lipopolysaccharide (LPS) and peptidoglycan (PGN) from bacterial cell walls. PAMP-recognition by the host results in an induction of defence-related genes and often the generation of an inflammatory response. We evaluated both the transcriptomic and inflammatory response in trout (O. mykiss) macrophages in primary cell culture stimulated with DAP-PGN (DAP; meso diaminopimelic acid, PGN; peptidoglycan) from two strains of Escherichia coli (PGN-K12 and PGN-O111:B4) over time. RESULTS: Transcript profiling was assessed using function-targeted cDNA microarray hybridisation (n = 36) and results show differential responses to both PGNs that are both time and treatment dependent. Wild type E. coli (K12) generated an increase in transcript number/diversity over time whereas PGN-O111:B4 stimulation resulted in a more specific and intense response. In line with this, Gene Ontology analysis (GO) highlights a specific transcriptomic remodelling for PGN-O111:B4 whereas results obtained for PGN-K12 show a high similarity to a generalised inflammatory priming response where multiple functional classes are related to ribosome biogenesis or cellular metabolism. Prostaglandin release was induced by both PGNs and macrophages were significantly more sensitive to PGN-O111:B4 as suggested from microarray data. CONCLUSION: Responses at the level of the transcriptome and the inflammatory outcome (prostaglandin synthesis) highlight the different sensitivity of the macrophage to slight differences (serotype) in peptidoglycan structure. Such divergent responses are likely to involve differential receptor sensitivity to ligands or indeed different receptor types. Such changes in biological response will likely reflect upon pathogenicity of certain serotypes and the development of disease. PMID- 21235754 TI - Single- and double-stranded DNA binding proteins act in concert to conserve a telomeric DNA core sequence. AB - BACKGROUND: Telomeres are protective cap structures at the ends of the linear eukaryotic chromosomes, which provide stability to the genome by shielding from degradation and chromosome fusions. The cap consists of telomere-specific proteins binding to the respective single- and double-stranded parts of the telomeric sequence. In addition to the nucleation of the chromatin structure the telomere-binding proteins are involved in the regulation of the telomere length. However, the telomeric sequences are highly diverged among yeast species. During the evolution this high rate of divergency presents a challenge for the sequence recognition of the telomere-binding proteins. RESULTS: We found that the Saccharomyces castellii protein Rap1, a negative regulator of telomere length, binds a 12-mer minimal binding site (MBS) within the double-stranded telomeric DNA. The sequence specificity is dependent on the interaction with two 5 nucleotide motifs, having a 6 nucleotide centre-to-centre spacing. The isolated DNA-binding domain binds the same MBS and retains the same motif binding characteristics as the full-length Rap1 protein. However, it shows some deviations in the degree of sequence-specific dependence in some nucleotide positions. Intriguingly, the positions of most importance for the sequence specific binding of the full-length Rap1 protein coincide with 3 of the 4 nucleotides utilized by the 3' overhang binding protein Cdc13. These nucleotides are very well conserved within the otherwise highly divergent telomeric sequences of yeasts. CONCLUSIONS: Rap1 and Cdc13 are two very distinct types of DNA-binding proteins with highly separate functions. They interact with the double-stranded vs. the single-stranded telomeric DNA via significantly different types of DNA binding domain structures. However, we show that they are dependent on coinciding nucleotide positions for their sequence-specific binding to telomeric sequences. Thus, we conclude that during the molecular evolution they act together to preserve a core sequence of the telomeric DNA. PMID- 21235755 TI - Spiders do not escape reproductive manipulations by Wolbachia. AB - BACKGROUND: Maternally inherited bacteria that reside obligatorily or facultatively in arthropods can increase their prevalence in the population by altering their hosts' reproduction. Such reproductive manipulations have been reported from the major arthropod groups such as insects (in particular hymenopterans, butterflies, dipterans and beetles), crustaceans (isopods) and mites. Despite the observation that endosymbiont bacteria are frequently encountered in spiders and that the sex ratio of particular spider species is strongly female biased, a direct relationship between bacterial infection and sex ratio variation has not yet been demonstrated for this arthropod order. RESULTS: Females of the dwarf spider Oedothorax gibbosus exhibit considerable variation in the sex ratio of their clutches and were infected with at least three different endosymbiont bacteria capable of altering host reproduction i.e. Wolbachia, Rickettsia and Cardinium. Breeding experiments show that sex ratio variation in this species is primarily maternally inherited and that removal of the bacteria by antibiotics restores an unbiased sex ratio. Moreover, clutches of females infected with Wolbachia were significantly female biased while uninfected females showed an even sex ratio. As female biased clutches were of significantly smaller size compared to non-distorted clutches, killing of male embryos appears to be the most likely manipulative effect. CONCLUSIONS: This represents to our knowledge the first direct evidence that endosymbiont bacteria, and in particular Wolbachia, might induce sex ratio variation in spiders. These findings are pivotal to further understand the diversity of reproductive phenotypes observed in this arthropod order. PMID- 21235756 TI - Genetic differentiation of European grayling (Thymallus thymallus) populations in Serbia, based on mitochondrial and nuclear DNA analyses. AB - BACKGROUND: The structure and diversity of grayling (Thymallus thymallus) populations have been well studied in most of its native habitat; however the southernmost populations of the Balkan Peninsula remain largely unexplored. The purpose of this study was to assess the genetic diversity of Serbian grayling populations, detect the impact of stocking and provide guidelines for conservation and management. METHODS: Eighty grayling individuals were collected from four rivers (Ibar, Lim, Drina and Rzav). The mitochondrial DNA control region (CR; 595 bp of the 3'end and 74 bp of flanking tRNA) and the ATP6 gene (630 bp fragment) were sequenced for 20 individuals (five from each locality). In addition, all individuals were genotyped with 12 microsatellite loci. The diversity and structure of the populations as well as the recent and ancient population declines were studied using specialized software. RESULTS: We detected three new haplotypes in the mtDNA CR and four haplotypes in the ATP6 gene of which three had not been described before. Previously, one CR haplotype and two ATP6 gene haplotypes had been identified as allochthonous, originating from Slovenia. Reconstruction of phylogenetic relations placed the remaining two CR haplotypes from the River Danube drainage of Serbia into a new clade, which is related to the previously described sister Slovenian clade. These two clades form a new Balkan clade. Microsatellite marker analysis showed that all four populations are genetically distinct from each other without any sign of intra population structure, although stocking of the most diverse population (Drina River) was confirmed by mtDNA analysis. Recent and historical population declines of Serbian grayling do not differ from those of other European populations. CONCLUSIONS: Our study shows that (1) the Ibar, Lim and Drina Rivers grayling populations are genetically distinct from populations outside of Serbia and thus should be managed as native populations in spite of some introgression in the Drina River population and (2) the Rzav River population is not appropriate for further stocking activities since it originates from stocked Slovenian grayling. However, the Rzav River population does not represent an immediate danger to other populations because it is physically isolated from these. PMID- 21235757 TI - Use of the atmospheric generators for capnophilic bacteria Genbag-CO2 for the evaluation of in vitro Plasmodium falciparum susceptibility to standard anti malarial drugs. AB - BACKGROUND: The aim of this study was to evaluate the cultivation system in which the proper atmospheric conditions for growing Plasmodium falciparum parasites were maintained in a sealed bag. The Genbag(r) system associated with the atmospheric generators for capnophilic bacteria Genbag CO2(r) was used for in vitro susceptibility test of nine standard anti-malarial drugs and compared to standard incubator conditions. METHODS: The susceptibility of 36 pre-identified parasite strains from a wide panel of countries was assessed for nine standard anti-malarial drugs (chloroquine, quinine, mefloquine, monodesethylamodiaquine, lumefantrine, dihydroartemisinin, atovaquone and pyrimethamine) by the standard 42-hour 3H-hypoxanthine uptake inhibition method using the Genbag CO2(r) system and compared to controlled incubator conditions (5% CO2 and 10% O2). RESULTS: The counts per minute values in the control wells in incubator atmospheric conditions (5% CO2 and 10% O2) were significantly higher than those of Genbag(r) conditions (2738 cpm vs 2282 cpm, p < 0.0001). The geometric mean IC50 estimated under the incubator atmospheric conditions was significantly lower for atovaquone (1.2 vs 2.1 nM, p = 0.0011) and higher for the quinolines: chloroquine (127 vs 94 nM, p < 0.0001), quinine (580 vs 439 nM, p < 0.0001), monodesethylamodiaquine (41.4 vs 31.8 nM, p < 0.0001), mefloquine (57.5 vs 49.7 nM, p = 0.0011) and lumefantrine (23.8 vs 21.2 nM, p = 0.0044). There was no significant difference of IC50 between the 2 conditions for dihydroartemisinin, doxycycline and pyrimethamine.To reduce this difference in term of anti-malarial susceptibility, a specific cut off was estimated for each drug under Genbag(r) conditions by regression. The cut off was estimated at 77 nM for chloroquine (vs 100 nM in 10% O2), 611 nM for quinine (vs 800 nM), 30 nM for mefloquine (vs 30 nM), 61 nM for monodesethylamodiaquine (vs 80 nM) and 1729 nM for pyrimethamine (vs 2000 nM). CONCLUSIONS: The atmospheric generators for capnophilic bacteria Genbag CO2(r) is an appropriate technology that can be transferred to the field for epidemiological surveys of drug-resistant malaria. The present data suggest the importance of the gas mixture on in vitro microtest results for anti-malarial drugs and the importance of determining the microtest conditions before comparing and analysing the data from different laboratories and concluding on malaria resistance. PMID- 21235758 TI - Full mitochondrial genome sequences of two endemic Philippine hornbill species (Aves: Bucerotidae) provide evidence for pervasive mitochondrial DNA recombination. AB - BACKGROUND: Although nowaday it is broadly accepted that mitochondrial DNA (mtDNA) may undergo recombination, the frequency of such recombination remains controversial. Its estimation is not straightforward, as recombination under homoplasmy (i.e., among identical mt genomes) is likely to be overlooked. In species with tandem duplications of large mtDNA fragments the detection of recombination can be facilitated, as it can lead to gene conversion among duplicates. Although the mechanisms for concerted evolution in mtDNA are not fully understood yet, recombination rates have been estimated from "one per speciation event" down to 850 years or even "during every replication cycle". RESULTS: Here we present the first complete mt genome of the avian family Bucerotidae, i.e., that of two Philippine hornbills, Aceros waldeni and Penelopides panini. The mt genomes are characterized by a tandemly duplicated region encompassing part of cytochrome b, 3 tRNAs, NADH6, and the control region. The duplicated fragments are identical to each other except for a short section in domain I and for the length of repeat motifs in domain III of the control region. Due to the heteroplasmy with regard to the number of these repeat motifs, there is some size variation in both genomes; with around 21,657 bp (A. waldeni) and 22,737 bp (P. panini), they significantly exceed the hitherto longest known avian mt genomes, that of the albatrosses. We discovered concerted evolution between the duplicated fragments within individuals. The existence of differences between individuals in coding genes as well as in the control region, which are maintained between duplicates, indicates that recombination apparently occurs frequently, i.e., in every generation. CONCLUSIONS: The homogenised duplicates are interspersed by a short fragment which shows no sign of recombination. We hypothesize that this region corresponds to the so-called Replication Fork Barrier (RFB), which has been described from the chicken mitochondrial genome. As this RFB is supposed to halt replication, it offers a potential mechanistic explanation for frequent recombination in mitochondrial genomes. PMID- 21235759 TI - Are old-old patients with major depression more likely to relapse than young-old patients during continuation treatment with escitalopram? AB - BACKGROUND: Escitalopram has shown efficacy and tolerability in the prevention of relapse in elderly patients with major depressive disorder (MDD). This post-hoc analysis compared time to relapse for young-old patients (n = 197) to that for old-old patients (n = 108). METHOD: Relapse prevention: after 12-weeks open-label treatment, remitters (MADRS <=12) were randomised to double-blind treatment with escitalopram or placebo and followed over 24-weeks. Patients were outpatients with MDD from 46 European centers aged >=75 years (old-old) or 65-74 years of age (young-old), treated with escitalopram 10-20 mg/day. Efficacy was assessed using the Montgomery Asberg Depression Rating Scale (MADRS). RESULTS: After open-label escitalopram treatment, a similar proportion of young-old patients (78%) and old old patients (72%) achieved remission. In the analysis of time to relapse based on the Cox model (proportional hazards regression), with treatment and age group as covariates, the hazard ratio was 4.4 for placebo versus escitalopram (chi(2) test, df = 1, chi(2)= 22.5, p < 0.001), whereas the effect of age was not significant, with a hazard ratio of 1.2 for old-old versus young-old (chi(2) test, df = 1, chi(2) = 0.41, p = 0.520). Escitalopram was well tolerated in both age groups with adverse events reported by 53.1% of young-old patients and 58.3% of old-old patients. There was no significant difference in withdrawal rates due to AEs between age groups (chi(2)-test, chi(2) = 1.669, df = 1, p = 0.196). CONCLUSIONS: Young-old and old-old patients with MDD had comparable rates of remission after open-label escitalopram, and both age groups had much lower rates of relapse on escitalopram than on placebo. PMID- 21235760 TI - Perceived morbidity and community burden after a Chikungunya outbreak: the TELECHIK survey, a population-based cohort study. AB - BACKGROUND: Persistent disabilities are key manifestations of Chikungunya virus (CHIKV) infection, especially incapacitating polyarthralgia and fatigue. So far, little is known about their impact on health status. The present study aimed at describing the burden of CHIKV prolonged or late-onset symptoms on the self perceived health of La Reunion islanders. METHODS: At 18 months after an outbreak of Chikungunya virus, we implemented the TELECHIK survey; a retrospective cohort study conducted on a random sample of the representative SEROCHIK population based survey. A total of 1,094 subjects sampled for CHIKV-specific IgG antibodies in the setting of La Reunion island in the Indian Ocean, between August 2006 and October 2006, were interviewed about current symptoms divided into musculoskeletal/rheumatic, fatigue, cerebral, sensorineural, digestive and dermatological categories. RESULTS: At the time of interview, 43% of seropositive (CHIK+) subjects reported musculoskeletal pain (vs 17% of seronegative (CHIK-) subjects, P < 0.001), 54% fatigue (vs 46%, P = 0.04), 75% cerebral disorders (vs 57%, P < 0.001), 49% sensorineural impairments (vs 37%, P = 0.001), 18% digestive complaints (vs 15%, P = 0.21), and 36% skin involvement (vs 34%, P = 0.20) on average 2 years after infection (range: 15-34 months). After controlling for confounders such as age, gender, body mass index or major comorbidities in different Poisson regression models, 33% of joint pains were attributable to CHIKV, 10% of cerebral disorders and 7.5% of sensorineural impairments, while Chikungunya did not enhance fatigue states, digestive and skin disorders. CONCLUSIONS: On average, 2 years after infection 43% to 75% of infected people reported prolonged or late-onset symptoms highly attributable to CHIKV. These manifestations carry a significant burden in the community in the fields of rheumatology, neurology and sensorineural health. PMID- 21235762 TI - The relationship between (stigmatizing) views and lay public preferences regarding tuberculosis treatment in the Eastern Cape, South Africa. AB - BACKGROUND: Tuberculosis (TB) and human immune virus/acquired immune deficiency syndrome (HIV/AIDS) stigmas affect public attitudes toward TB treatment and policy. This study examined 'stigmatizing' ideas and the view that 'TB patients should line-up in the chronic illness queue' in relation to preferences and attitudes toward TB treatment. METHODS: Data were gathered through a survey administered to respondents from 1,020 households in Grahamstown. The survey measured stigmatization surrounding TB and HIV/AIDS, and determined perceptions of respondents whether TB patients should queue with other chronically ill patients. Respondents selected support and treatment options they felt would benefit TB patients. Statistical analysis identified the prevalence of TB and HIV/AIDS stigmas. Logistic regression analyses explored associations between stigmatizing ideas, views regarding TB patients in the chronic illness queue, and attitudes toward support and treatment. RESULTS: Respondents with TB stigmatizing ideas held positive attitudes toward volunteer support, special TB queues, and treatment at clinics; they held negative attitudes toward temporary disability grants, provision of information at work or school, and treatment at the TB hospital. Respondents who felt it beneficial for TB patients to queue with other chronically ill patients conversely held positive attitudes toward provision of porridge and disability grants, and treatment at the TB hospital; they held negative attitudes toward volunteer support, special TB queues, information provision at work or school, and treatment at clinics. CONCLUSION: These results showed that two varying views related to visibility factors that expose patients to stigmatization (one characterized by TB stigma, the other by the view that TB patients should queue with other chronically ill patients) are associated with opposing attitudes and preferences towards TB treatment. These opposing attitudes complicate treatment outcomes, and suggest that complex behaviors must be taken into account when designing health policy. PMID- 21235761 TI - Treatment with a corticotrophin releasing factor 2 receptor agonist modulates skeletal muscle mass and force production in aged and chronically ill animals. AB - BACKGROUND: Muscle weakness is associated with a variety of chronic disorders such as emphysema (EMP) and congestive heart failure (CHF) as well as aging. Therapies to treat muscle weakness associated with chronic disease or aging are lacking. Corticotrophin releasing factor 2 receptor (CRF2R) agonists have been shown to maintain skeletal muscle mass and force production in a variety of acute conditions that lead to skeletal muscle wasting. HYPOTHESIS: We hypothesize that treating animals with a CRF2R agonist will maintain skeletal muscle mass and force production in animals with chronic disease and in aged animals. METHODS: We utilized animal models of aging, CHF and EMP to evaluate the potential of CRF2R agonist treatment to maintain skeletal muscle mass and force production in aged animals and animals with CHF and EMP. RESULTS: In aged rats, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater extensor digitorum longus (EDL) force production, EDL mass, soleus mass and soleus force production compared to age matched untreated animals. In the hamster EMP model, we demonstrate that treatment with a CRF2R agonist for up to 5 months results in greater EDL force production in EMP hamsters when compared to vehicle treated EMP hamsters and greater EDL mass and force in normal hamsters when compared to vehicle treated normal hamsters. In the rat CHF model, we demonstrate that treatment with a CRF2R agonist for up to 3 months results in greater EDL and soleus muscle mass and force production in CHF rats and normal rats when compared to the corresponding vehicle treated animals. CONCLUSIONS: These data demonstrate that the underlying physiological conditions associated with chronic diseases such as CHF and emphysema in addition to aging do not reduce the potential of CRF2R agonists to maintain skeletal muscle mass and force production. PMID- 21235764 TI - Parental occupational exposure to endocrine disrupting chemicals and male genital malformations: a study in the Danish National Birth Cohort study. AB - BACKGROUND: Sex hormones closely regulate development of the male genital organs during fetal life. The hypothesis that xenobiotics may disrupt endogenous hormonal signalling has received considerable scientific attention, but human evidence is scarce. OBJECTIVES: We analyse occurrence of hypospadias and cryptorchidism according to maternal and paternal occupational exposure to possible endocrine disrupting chemicals. METHODS: We conducted a follow-up study of 45,341 male singleton deliveries in the Danish National Birth Cohort during 1997-2009. Information on work during pregnancy was obtained by telephone interviews around gestational week 16. Parents' job titles were classified according to DISCO-88. A job exposure matrix for endocrine disrupting chemicals (EDCs) was implemented to assess occupational exposures. The Medical Birth and National Hospital Register provided data on congenital anomalies diagnosed at birth or during follow-up, which ended in 2009. Crude and adjusted hazard ratios (HR) were obtained from Cox regression models. RESULTS: Among all pregnancies, 6.3% were classified as possibly or probably exposed to EDCs. The most prevalent occupations conferring possible exposure were cleaners, laboratory technicians, hairdressers and agricultural workers (58% of all potentially exposed). The final cumulative incidence of cryptorchidism in boys was 2.2% (1002 cases), and of hypospadias 0.6% (262 cases). The occurrence of hypospadias increased when mothers were probably [HRa = 1.8 (95% CI 1.0-2.6)] or possibly exposed to one or more EDCs [HRa = 2.6 (95% CI 1.8-3.4). Possible paternal exposure to heavy metals increased the risk of hypospadias [HRa 2.2 (95% CI: 1.0-3.4)] and cryptorchidism [HRa 1.9 (95% CI: 1.1-2.7)]. None of the exposure groups reached statistical significance. CONCLUSION: The study provides some but limited evidence that occupational exposure to possible endocrine disrupting chemicals during pregnancy increases the risk of hypospadias. PMID- 21235763 TI - Effect of primary care physicians' use of estimated glomerular filtration rate on the timing of their subspecialty referral decisions. AB - BACKGROUND: Primary care providers' suboptimal recognition of the severity of chronic kidney disease (CKD) may contribute to untimely referrals of patients with CKD to subspecialty care. It is unknown whether U.S. primary care physicians' use of estimated glomerular filtration rate (eGFR) rather than serum creatinine to estimate CKD severity could improve the timeliness of their subspecialty referral decisions. METHODS: We conducted a cross-sectional study of 154 United States primary care physicians to assess the effect of use of eGFR (versus creatinine) on the timing of their subspecialty referrals. Primary care physicians completed a questionnaire featuring questions regarding a hypothetical White or African American patient with progressing CKD. We asked primary care physicians to identify the serum creatinine and eGFR levels at which they would recommend patients like the hypothetical patient be referred for subspecialty evaluation. We assessed significant improvement in the timing [from eGFR < 30 to >= 30 mL/min/1.73m(2)) of their recommended referrals based on their use of creatinine versus eGFR. RESULTS: Primary care physicians recommended subspecialty referrals later (CKD more advanced) when using creatinine versus eGFR to assess kidney function [median eGFR 32 versus 55 mL/min/1.73m(2), p < 0.001]. Forty percent of primary care physicians significantly improved the timing of their referrals when basing their recommendations on eGFR. Improved timing occurred more frequently among primary care physicians practicing in academic (versus non academic) practices or presented with White (versus African American) hypothetical patients [adjusted percentage(95% CI): 70% (45-87) versus 37% (reference) and 57% (39-73) versus 25% (reference), respectively, both p <= 0.01). CONCLUSIONS: Primary care physicians recommended subspecialty referrals earlier when using eGFR (versus creatinine) to assess kidney function. Enhanced use of eGFR by primary care physicians' could lead to more timely subspecialty care and improved clinical outcomes for patients with CKD. PMID- 21235765 TI - Occupational affiliation does not influence practical skills in cardiopulmonary resuscitation for in-hospital healthcare professionals. AB - BACKGROUND: D-CPR (Defibrillator Cardiopulmonary Resuscitation) is a technique for optimal basic life support during cardiopulmonary resuscitation (CPR). Guidelines recommend that healthcare professionals can perform CPR with competence. How CPR training and provision is organized varies between hospitals, and it is our impression that in Sweden this has generally improved during the last 15-20 years. However, some hospitals still do not have any AED (Automated External Defibrillators). The aim was to investigate potential differences in practical skills between different healthcare professions before and after training in D-CPR. METHODS: Seventy-four healthcare professionals were video recorded and evaluated for adherence to a modified Cardiff Score. A Laerdal Resusci Anne manikin in connection to PC Skill reporting System was used to evaluate CPR quality. A simulated CPR situation was accomplished during a 5-10 min scenario of ventricular fibrillation. Paired and unpaired statistical methods were used to examine differences within and between occupations with respect to the intervention. RESULTS: There were no differences in skills among the different healthcare professions, except for compressions per minute. In total, the number of compression per minute and depth improved for all groups (P < 0.001). In total, 41% of the participants used AED before and 96% of the participants used AED after the intervention (P < 0.001). Before intervention, it took a median time of 120 seconds until the AED was used; after the intervention, it took 82 seconds. CONCLUSION: Nearly all healthcare professionals learned to use the AED. There were no differences in CPR skill performances among the different healthcare professionals. PMID- 21235766 TI - Doses to internal organs for various breast radiation techniques--implications on the risk of secondary cancers and cardiomyopathy. AB - BACKGROUND: Breast cancers are more frequently diagnosed at an early stage and currently have improved long term outcomes. Late normal tissue complications induced by adjuvant radiotherapy like secondary cancers or cardiomyopathy must now be avoided at all cost. Several new breast radiotherapy techniques have been developed and this work aims at comparing the scatter doses of internal organs for those techniques. METHODS: A CT-scan of a typical early stage left breast cancer patient was used to describe a realistic anthropomorphic phantom in the MCNP Monte Carlo code. Dose tally detectors were placed in breasts, the heart, the ipsilateral lung, and the spleen. Five irradiation techniques were simulated: whole breast radiotherapy 50 Gy in 25 fractions using physical wedge or breast IMRT, 3D-CRT partial breast radiotherapy 38.5 Gy in 10 fractions, HDR brachytherapy delivering 34 Gy in 10 treatments, or Permanent Breast 103Pd Seed Implant delivering 90 Gy. RESULTS: For external beam radiotherapy the wedge compensation technique yielded the largest doses to internal organs like the spleen or the heart, respectively 2,300 mSv and 2.7 Gy. Smaller scatter dose are induced using breast IMRT, respectively 810 mSv and 1.1 Gy, or 3D-CRT partial breast irradiation, respectively 130 mSv and 0.7 Gy. Dose to the lung is also smaller for IMRT and 3D-CRT compared to the wedge technique. For multicatheter HDR brachytherapy a large dose is delivered to the heart, 3.6 Gy, the spleen receives 1,171 mSv and the lung receives 2,471 mSv. These values are 44% higher in case of a balloon catheter. In contrast, breast seeds implant is associated with low dose to most internal organs. CONCLUSIONS: The present data support the use of breast IMRT or virtual wedge technique instead of physical wedges for whole breast radiotherapy. Regarding partial breast irradiation techniques, low energy source brachytherapy and external beam 3D-CRT appear safer than 192Ir HDR techniques. PMID- 21235767 TI - Different level of population differentiation among human genes. AB - BACKGROUND: During the colonization of the world, after dispersal out of African, modern humans encountered changeable environments and substantial phenotypic variations that involve diverse behaviors, lifestyles and cultures, were generated among the different modern human populations. RESULTS: Here, we study the level of population differentiation among different populations of human genes. Intriguingly, genes involved in osteoblast development were identified as being enriched with higher FST SNPs, a result consistent with the proposed role of the skeletal system in accounting for variation among human populations. Genes involved in the development of hair follicles, where hair is produced, were also found to have higher levels of population differentiation, consistent with hair morphology being a distinctive trait among human populations. Other genes that showed higher levels of population differentiation include those involved in pigmentation, spermatid, nervous system and organ development, and some metabolic pathways, but few involved with the immune system. Disease-related genes demonstrate excessive SNPs with lower levels of population differentiation, probably due to purifying selection. Surprisingly, we find that Mendelian-disease genes appear to have a significant excessive of SNPs with high levels of population differentiation, possibly because the incidence and susceptibility of these diseases show differences among populations. As expected, microRNA regulated genes show lower levels of population differentiation due to purifying selection. CONCLUSION: Our analysis demonstrates different level of population differentiation among human populations for different gene groups. PMID- 21235768 TI - Informed consent for MRI and fMRI research: analysis of a sample of Canadian consent documents. AB - BACKGROUND: Research ethics and the measures deployed to ensure ethical oversight of research (e.g., informed consent forms, ethics review) are vested with extremely important ethical and practical goals. Accordingly, these measures need to function effectively in real-world research and to follow high level standards. METHODS: We examined approved consent forms for Magnetic Resonance Imaging (MRI) and functional Magnetic Resonance Imaging (fMRI) studies approved by Canadian research ethics boards (REBs). RESULTS: We found evidence of variability in consent forms in matters of physical and psychological risk reporting. Approaches used to tackle the emerging issue of incidental findings exposed extensive variability between and within research sites. CONCLUSION: The causes of variability in approved consent forms and studies need to be better understood. However, mounting evidence of administrative and practical hurdles within current ethics governance systems combined with potential sub-optimal provision of information to and protection of research subjects support other calls for more scrutiny of research ethics practices and applicable revisions. PMID- 21235769 TI - Normal social seeking behavior, hypoactivity and reduced exploratory range in a mouse model of Angelman syndrome. AB - BACKGROUND: Angelman syndrome (AS) is a neurogenetic disorder characterized by severe developmental delay with mental retardation, a generally happy disposition, ataxia and characteristic behaviors such as inappropriate laughter, social-seeking behavior and hyperactivity. The majority of AS cases are due to loss of the maternal copy of the UBE3A gene. Maternal Ube3a deficiency (Ube3a m /p+), as well as complete loss of Ube3a expression (Ube3a m-/p-), have been reproduced in the mouse model used here. RESULTS: Here we asked if two characteristic AS phenotypes - social-seeking behavior and hyperactivity - are reproduced in the Ube3a deficient mouse model of AS. We quantified social-seeking behavior as time spent in close proximity to a stranger mouse and activity as total time spent moving during exploration, movement speed and total length of the exploratory path. Mice of all three genotypes (Ube3a m+/p+, Ube3a m-/p+, Ube3a m-/p-) were tested and found to spend the same amount of time in close proximity to the stranger, indicating that Ube3a deficiency in mice does not result in increased social seeking behavior or social dis-inhibition. Also, Ube3a deficient mice were hypoactive compared to their wild-type littermates as shown by significantly lower levels of activity, slower movement velocities, shorter exploratory paths and a reduced exploratory range. CONCLUSIONS: Although hyperactivity and social-seeking behavior are characteristic phenotypes of Angelman Syndrome in humans, the Ube3a deficient mouse model does not reproduce these phenotypes in comparison to their wild-type littermates. These phenotypic differences may be explained by differences in the size of the genetic defect as ~70% of AS patients have a deletion that includes several other genes surrounding the UBE3A locus. PMID- 21235770 TI - Heath-related quality of life in Spanish breast cancer patients: a systematic review. AB - BACKGROUND: Breast cancer is one of the oncological diseases in which health related quality of life (HRQL) has been most studied. This is mainly due to its high incidence and survival. This paper seeks to: review published research into HRQL among women with breast cancer in Spain; analyse the characteristics of these studies; and describe the instruments used and main results reported. METHODS: The databases consulted were MEDLINE, EMBASE, PsycINFO, Dialnet, IBECS, CUIDEN, ISOC and LILACS. The inclusion criteria required studies to: 1) include Spanish patients, and a breakdown of results where other types of tumours and/or women from other countries were also included; and, 2) furnish original data and measure HRQL using a purpose-designed questionnaire. The methodological quality of studies was assessed. RESULTS: Spain ranked midway in the European Union in terms of the number of studies conducted on the HRQL of breast cancer patients. Of the total of 133 papers published from 1993 to 2009, 25 met the inclusion criteria. Among them, only 12 were considered as having good or excellent quality. A total of 2236 women participated in the studies analysed. In descending order of frequency, the questionnaires used were the EORTC, FACT-B, QL CA-Afex, SF-12, FLIC, RSCL and CCV. Five papers focused on validation or adaptation of questionnaires. Most papers examined HRQL in terms of type of treatment. Few differences were detected by type of chemotherapy, with the single exception of worse results among younger women treated with radiotherapy. In the short term, better results were reported for all HRQL components by women undergoing conservative rather than radical surgery. Presence of lymphedema was associated with worse HRQL. Three studies assessed differences in HRQL by patients' psychological traits. Psychosocial disorder and level of depression and anxiety, regardless of treatment or disease stage, worsened HRQL. In addition, there was a positive effect among patients who reported having a "fighting spirit" and using "denial" as a defence mechanism. One study found that breast cancer patients scored worse than did healthy women on almost all SF-12 scales. CONCLUSION: Research into health-related quality of life of breast-cancer patients is a little developed field in Spain. PMID- 21235771 TI - Relevance of JAK2V617F positivity to hematological diseases--survey of samples from a clinical genetics laboratory. AB - BACKGROUND: JAK2V617F is found in the majority of patients with Ph- myeloproliferative neoplasms (MPNs) and has become a valuable marker for diagnosis of MPNs. However, it has also been found in many other hematological diseases, and some studies even detected the presence of JAK2V617F in normal blood samples. This casts doubt on the primary role of JAK2V617F in the pathogenesis of MPNs and its diagnostic value. METHODS: In the present study, we analyzed JAK2V617F positivity with 232 normal blood samples and 2663 patient blood, bone marrow, and amniotic fluid specimens obtained from a clinical genetics laboratory by using a simple DNA extraction method and a sensitive nested allele-specific PCR strategy. RESULTS: We found JAK2V617F present in the majority (78%) of MPN patients and in a small fraction (1.8-8.7%) of patients with other specific hematological diseases but not at all in normal healthy donors or patients with non-hematological diseases. We also revealed associations of JAK2V617F with novel as well as known chromosomal abnormalities. CONCLUSIONS: Our study suggests that JAK2V617F positivity is associated with specific hematological malignancies and is an excellent diagnostic marker for MPNs. The data also indicate that the nested allele-specific PCR method provides clinically relevant information and should be conducted for all cases suspected of having MPNs as well as for other related diseases. PMID- 21235772 TI - Global analysis of estrogen receptor beta binding to breast cancer cell genome reveals an extensive interplay with estrogen receptor alpha for target gene regulation. AB - BACKGROUND: Estrogen receptors alpha (ERalpha) and beta (ERbeta) are transcription factors (TFs) that mediate estrogen signaling and define the hormone-responsive phenotype of breast cancer (BC). The two receptors can be found co-expressed and play specific, often opposite, roles, with ERbeta being able to modulate the effects of ERalpha on gene transcription and cell proliferation. ERbeta is frequently lost in BC, where its presence generally correlates with a better prognosis of the disease. The identification of the genomic targets of ERbeta in hormone-responsive BC cells is thus a critical step to elucidate the roles of this receptor in estrogen signaling and tumor cell biology. RESULTS: Expression of full-length ERbeta in hormone-responsive, ERalpha positive MCF-7 cells resulted in a marked reduction in cell proliferation in response to estrogen and marked effects on the cell transcriptome. By ChIP-Seq we identified 9702 ERbeta and 6024 ERalpha binding sites in estrogen-stimulated cells, comprising sites occupied by either ERbeta, ERalpha or both ER subtypes. A search for TF binding matrices revealed that the majority of the binding sites identified comprise one or more Estrogen Response Element and the remaining show binding matrixes for other TFs known to mediate ER interaction with chromatin by tethering, including AP2, E2F and SP1. Of 921 genes differentially regulated by estrogen in ERbeta+ vs ERbeta- cells, 424 showed one or more ERbeta site within 10 kb. These putative primary ERbeta target genes control cell proliferation, death, differentiation, motility and adhesion, signal transduction and transcription, key cellular processes that might explain the biological and clinical phenotype of tumors expressing this ER subtype. ERbeta binding in close proximity of several miRNA genes and in the mitochondrial genome, suggests the possible involvement of this receptor in small non-coding RNA biogenesis and mitochondrial genome functions. CONCLUSIONS: Results indicate that the vast majority of the genomic targets of ERbeta can bind also ERalpha, suggesting that the overall action of ERbeta on the genome of hormone-responsive BC cells depends mainly on the relative concentration of both ERs in the cell. PMID- 21235773 TI - The sex-biased brain: sexual dimorphism in gene expression in two species of songbirds. AB - BACKGROUND: Despite virtually identical DNA sequences between the sexes, sexual dimorphism is a widespread phenomenon in nature. To a large extent the systematic differences between the sexes must therefore arise from processes involving gene regulation. In accordance, sexual dimorphism in gene expression is common and extensive. Genes with sexually dimorphic regulation are known to evolve rapidly, both in DNA sequence and in gene expression profile. Studies of gene expression in related species can shed light on the flexibility, or degree of conservation, of the gene expression profiles underlying sexual dimorphism. RESULTS: We have studied the extent of sexual dimorphism in gene expression in the brain of two species of songbirds, the zebra finch (Taeniopygia guttata) and the common whitethroat (Sylvia communis), using large-scale microarray technology. Sexual dimorphism in gene expression was extensive in both species, and predominantly sex-linked: most genes identified were male-biased and Z-linked. Interestingly, approximately 50% of the male-biased Z-linked genes were sex-biased only in one of the study species. CONCLUSION: Our results corroborate the results of recent studies in chicken and zebra finch which have been interpreted as caused by a low degree of dosage compensation in female birds (i.e. the heterogametic sex). Moreover, they suggest that zebra finches and common whitethroats dosage compensate partly different sets of genes on the Z chromosome. It is possible that this pattern reflects differences in either the essentiality or the level of sexual antagonism of these genes in the respective species. Such differences might correspond to genes with different rates of evolution related to sexual dimorphism in the avian brain, and might therefore be correlated with differences between the species in sex-specific behaviours. PMID- 21235774 TI - Disrupting the rhythm of depression using Mobile Cognitive Therapy for recurrent depression: randomized controlled trial design and protocol. AB - BACKGROUND: Major depressive disorder (MDD) is projected to rank second on a list of 15 major diseases in terms of burden in 2030. The major contribution of MDD to disability and health care costs is largely due to its highly recurrent nature. Accordingly, efforts to reduce the disabling effects of this chronic condition should shift to preventing recurrence, especially in patients at high risk of recurrence. Given its high prevalence and the fact that interventions are necessary during the remitted phase, new approaches are needed to prevent relapse in depression. METHODS/DESIGN: The best established effective and available psychological intervention is cognitive therapy. However, it is costly and not available for most patients. Therefore, we will compare the effectiveness and cost-effectiveness of self-management supported by online CT accompanied by SMS based tele-monitoring of depressive symptomatology, i.e. Mobile Cognitive Therapy (M-CT) versus treatment as us usual (TAU). Remitted patients (n = 268) with at least two previous depressive episodes will be recruited and randomized over (1) M-CT in addition to TAU versus (2) TAU alone, with follow-ups at 3, 12, and 24 months. Randomization will be stratified for number of previous episodes and type of treatment as usual. Primary outcome is time until relapse/recurrence over 24 months using DSM-IV-TR criteria as assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID). For the economic evaluation the balance between costs and health outcomes will be compared across strategies using a societal perspective. DISCUSSION: Internet-based interventions might be helpful in empowering patients to become their own disease managers in this lifelong recurrent disorder. This is, as far as we are aware of, the first study that examines the (cost) effectiveness of an E-mental health program using SMS monitoring of symptoms with therapist support to prevent relapse in remitted recurrently depressed patients. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR2503. PMID- 21235775 TI - Multiplex ligation dependent probe amplification (MLPA) for rapid distinction between unique sequence positive and negative marker chromosomes in prenatal diagnosis. AB - BACKGROUND: Small supernumerary marker chromosomes (sSMC) are extra structurally abnormal chromosomes that cannot be unambiguously identified with conventional chromosome banding techniques. These marker chromosomes may cause an abnormal phenotype or be harmless depending on different factors such as genetic content, chromosomal origin and level of mosaicism. When a sSMC is found during prenatal diagnosis, the main question is whether the sSMC contains euchromatin since in most cases this will lead to phenotypic abnormalities. We present the use of Multiplex Ligation Dependent probe Amplification (MLPA) for rapid distinction between non-euchromatic and euchromatic sSMC. RESULTS: 29 well-defined sSMC found during prenatal diagnosis were retrospectively investigated with MLPA with the SALSA MLPA centromere kits P181 and P182 as well as with the SALSA MLPA telomere kits P036B and P070 (MRC Holland BV, Amsterdam, The Netherlands). All unique sequence positive sSMC were correctly identified with MLPA, whereas the unique sequence negative sSMC had normal MLPA results. CONCLUSIONS: Although different techniques exist for identification of sSMC, we show that MLPA is a valuable adjunctive tool for rapidly distinguishing between unique-sequence positive and negative sSMC. In case of positive MLPA results, genetic microarray analysis or, if not available, targeted FISH can be applied for further identification and determination of the exact breakpoints, which is important for prediction of the fetal phenotype. In case of a negative MLPA result, which means that the sSMC most probably does not contain genes, the parents can already be reassured and parental karyotyping can be initiated to assess the heritability. In the mean time, FISH techniques are needed for determination of the chromosomal origin. PMID- 21235776 TI - Chryseobacterium indologenes infection in a newborn: a case report. AB - INTRODUCTION: Chryseobacterium indologenes is an uncommon human pathogen. Most infections have been detected in hospitalized patients with severe underlying diseases who had indwelling devices implanted. Infection caused by C. indologenes in a newborn has not been previously reported. CASE PRESENTATION: We present a case of ventilator-associated pneumonia caused by C. indologenes in a full-term Caucasian newborn baby boy with congenital heart disease who was successfully treated with piperacillin-tazobactam. CONCLUSION: C. indologenes should be considered as a potential pathogen in newborns in the presence of invasive equipment or treatment with long-term broad-spectrum antibiotics. Appropriate choice of effective antimicrobial agents for treatment is difficult because of the unpredictability and breadth of antimicrobial resistance of these organisms, which often involves resistance to many of the antibiotics chosen empirically for serious Gram-negative infections. PMID- 21235777 TI - Lactase persistence genotypes and malaria susceptibility in Fulani of Mali. AB - BACKGROUND: Fulani are a widely spread African ethnic group characterized by lower susceptibility to Plasmodium falciparum, clinical malaria morbidity and higher rate of lactase persistence compared to sympatric tribes. Lactase non persistence, often called lactose intolerance, is the normal condition where lactase activity in the intestinal wall declines after weaning. Lactase persistence, common in Europe, and in certain African people with traditions of raising cattle, is caused by polymorphisms in the enhancer region approximately 14 kb upstream of the lactase gene. METHODS: To evaluate the relationship between malaria and lactase persistence genotypes, a 400 bp region surrounding the main European C/T-13910 polymorphism upstream of the lactase gene was sequenced. DNA samples used in the study originated from 162 Fulani and 79 Dogon individuals from Mali. RESULTS: Among 79 Dogon only one heterozygote of the lactase enhancer polymorphism was detected, whereas all others were homozygous for the ancestral C allele. Among the Fulani, the main European polymorphism at locus C/T-13910 was by far the most common polymorphism, with an allele frequency of 37%. Three other single-nucleotide polymorphisms were found with allele frequencies of 3.7%, 1.9% and 0.6% each. The novel DNA polymorphism T/C-13906 was seen in six heterozygous Fulani. Among the Fulani with lactase non-persistence CC genotypes at the C/T 13910 locus, 24% had malaria parasites detectable by microscopy compared to 18% for lactase persistent genotypes (P = 0.29). Pooling the lactase enhancer polymorphisms to a common presumptive genotype gave 28% microscopy positives for non-persistent and 17% for others (P = 0.11). CONCLUSIONS: Plasmodium falciparum parasitaemia in asymptomatic Fulani is more common in individuals with lactase non-persistence genotypes, but this difference is not statistically significant. The potential immunoprotective properties of dietary cow milk as a reason for the partial malaria resistance of Fulani warrant further investigation. PMID- 21235778 TI - Immunohistochemical staining of radixin and moesin in prostatic adenocarcinoma. AB - BACKGROUND: Some members of the Protein 4.1 superfamily are believed to be involved in cell proliferation and growth, or in the regulation of these processes. While the expression levels of two members of this family, radixin and moesin, have been studied in many tumor types, to our knowledge they have not been investigated in prostate cancer. METHODS: Tissue microarrays were immunohistochemically stained for either radixin or moesin, with the staining intensities subsequently quantified and statistically analyzed using One-Way ANOVA or nonparametric equivalent with subsequent Student-Newman-Keuls tests for multiple comparisons. There were 11 cases of normal donor prostates (NDP), 14 cases of benign prostatic hyperplasia (BPH), 23 cases of high-grade prostatic intraepithelial neoplasia (HGPIN), 88 cases of prostatic adenocarcinoma (PCa), and 25 cases of normal tissue adjacent to adenocarcinoma (NAC) analyzed in the microarrays. RESULTS: NDP, BPH, and HGPIN had higher absolute staining scores for radixin than PCa and NAC, but with a significant difference observed between only HGPIN and PCa (p = < 0.001) and HGPIN and NAC (p = 0.001). In the moesin-stained specimens, PCa, NAC, HGPIN, and BPH all received absolute higher staining scores than NDP, but the differences were not significant. Stage 4 moesin-stained PCa had a significantly reduced staining intensity compared to Stage 2 (p = 0.003). CONCLUSIONS: To our knowledge, these studies represent the first reports on the expression profiles of radixin and moesin in prostatic adenocarcinoma. The current study has shown that there were statistically significant differences observed between HGPIN and PCa and HGPIN and NAC in terms of radixin expression. The differences in the moesin profiles by tissue type were not statistically significant. Additional larger studies with these markers may further elucidate their potential roles in prostatic neoplasia progression. PMID- 21235779 TI - Uromodulin concentrations are not associated with incident CKD among persons with coronary artery disease. AB - BACKGROUND: A common variant of the UMOD gene was linked with prevalent chronic kidney disease (CKD) in large, genomics consortia. One community-based study found that urine concentrations of the uromodulin protein forecast risk of incident CKD. This study within persons with known coronary artery disease (CAD) evaluated whether uromodulin concentrations could distinguish CKD risk. METHODS: In the Heart and Soul Study, the UMOD snp (12917707) was genotyped in 879 individuals with baseline creatinine clearance (CrCl) measured from a 24-hour urine collection. Uromodulin protein was measured from stored urine specimens among a subset of 120 participants, balanced by genotype. Incident CKD cases (N = 102) were defined by an initial CrCl > 70 ml/min and a 5-year follow-up CrCl <60 ml/min; controls (N = 94) were matched on age, sex, and race. RESULTS: Among 527 self-described White participants with DNA, 373 (71%) were homozygous for the dominant allele (G/G), 133 (25%) were heterozygous (G/T) and only 21 (4%) were homozygous for the minor allele (T/T). The T/T genotype had an approximately 11 ml/min higher CrCl than the other 2 groups, but this difference did not reach statistical significance (p = 0.20). The T/T genotype had significantly lower uromodulin levels than the common G/G genotype, and the G/T genotype had intermediate levels. However, uromodulin concentrations were similar between cases and controls (44 vs. 48 mg/dL, p = 0.88). CONCLUSIONS: This study among a cohort of persons with established CAD found no association between urine uromodulin and incident CKD, although UMOD genotype was associated with urine uromodulin concentrations. PMID- 21235780 TI - Systematic cross-validation of 454 sequencing and pyrosequencing for the exact quantification of DNA methylation patterns with single CpG resolution. AB - BACKGROUND: New high-throughput sequencing technologies promise a very sensitive and high-resolution analysis of DNA methylation patterns in quantitative terms. However, a detailed and comprehensive comparison with existing validated DNA methylation analysis methods is not yet available. Therefore, a systematic cross validation of 454 sequencing and conventional pyrosequencing, both of which offer exact quantification of methylation levels with a single CpG dinucleotide resolution, was performed. RESULTS: To this end the methylation patterns of 12 loci (GSTpi1, p16INK4a, RASSF1A, SOCS1, MAL, hsa-mir-1-1, hsa-mir-9-3, hsa-mir 34a, hsa-mir-596, hsa-mir-663, MINT31, and LINE-1) were analyzed in ten primary hepatocellular carcinoma specimens. After applying stringent quality control criteria, 35749 sequences entered further analysis. The methylation level of individual CpG dinucleotides obtained by 454 sequencing was systematically compared with the corresponding values obtained by conventional pyrosequencing. Statistical analyses revealed an excellent concordance of methylation levels for all individual CpG dinucleotides under study (r2 = 0.927). CONCLUSIONS: Our results confirm that 454 sequencing of bisulfite treated genomic DNA provides reliable high quality quantitative methylation data and identify MAL, hsa-mir-9 3, hsa-mir-596, and hsa-mir-663 as new targets of aberrant DNA methylation in human hepatocellular carcinoma. In addition, the single molecule resolution of 454 sequencing provides unprecedented information about the details of DNA methylation pattern heterogeneity in clinical samples. PMID- 21235781 TI - Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages. AB - BACKGROUND: Exosomes are 30-100 nm membrane vesicles of endocytic origin produced by numerous cells. They can mediate diverse biological functions, including antigen presentation. Exosomes have recently been shown to contain functional RNA, which can be delivered to other cells. Exosomes may thus mediate biological functions either by surface-to-surface interactions with cells, or by the delivery of functional RNA to cells. Our aim was therefore to determine the presence of RNA in exosomes from human saliva, plasma and breast milk and whether these exosomes can be taken up by macrophages. METHOD: Exosomes were purified from human saliva, plasma and breast milk using ultracentrifugation and filtration steps. Exosomes were detected by electron microscopy and examined by flow cytometry. Flow cytometry was performed by capturing the exosomes on anti MHC class II coated beads, and further stain with anti-CD9, anti-CD63 or anti CD81. Breast milk exosomes were further analysed for the presence of Hsc70, CD81 and calnexin by Western blot. Total RNA was detected with a Bioanalyzer and mRNA was identified by the synthesis of cDNA using an oligo (dT) primer and analysed with a Bioanalyzer. The uptake of PKH67-labelled saliva and breast milk exosomes by macrophages was examined by measuring fluorescence using flow cytometry and fluorescence microscopy. RESULTS: RNA was detected in exosomes from all three body fluids. A portion of the detected RNA in plasma exosomes was characterised as mRNA. Our result extends the characterisation of exosomes in healthy humans and confirms the presence of RNA in human saliva and plasma exosomes and reports for the first time the presence of RNA in breast milk exosomes. Our results also show that the saliva and breast milk exosomes can be taken up by human macrophages. CONCLUSIONS: Exosomes in saliva, plasma and breast milk all contain RNA, confirming previous findings that exosomes from several sources contain RNA. Furthermore, exosomes are readily taken up by macrophages, supporting the notion that exosomal RNA can be shuttled between cells. PMID- 21235782 TI - Site-specific time heterogeneity of the substitution process and its impact on phylogenetic inference. AB - BACKGROUND: Model violations constitute the major limitation in inferring accurate phylogenies. Characterizing properties of the data that are not being correctly handled by current models is therefore of prime importance. One of the properties of protein evolution is the variation of the relative rate of substitutions across sites and over time, the latter is the phenomenon called heterotachy. Its effect on phylogenetic inference has recently obtained considerable attention, which led to the development of new models of sequence evolution. However, thus far focus has been on the quantitative heterogeneity of the evolutionary process, thereby overlooking more qualitative variations. RESULTS: We studied the importance of variation of the site-specific amino-acid substitution process over time and its possible impact on phylogenetic inference. We used the CAT model to define an infinite mixture of substitution processes characterized by equilibrium frequencies over the twenty amino acids, a useful proxy for qualitatively estimating the evolutionary process. Using two large datasets, we show that qualitative changes in site-specific substitution properties over time occurred significantly. To test whether this unaccounted qualitative variation can lead to an erroneous phylogenetic tree, we analyzed a concatenation of mitochondrial proteins in which Cnidaria and Porifera were erroneously grouped. The progressive removal of the sites with the most heterogeneous CAT profiles across clades led to the recovery of the monophyly of Eumetazoa (Cnidaria+Bilateria), suggesting that this heterogeneity can negatively influence phylogenetic inference. CONCLUSION: The time-heterogeneity of the amino acid replacement process is therefore an important evolutionary aspect that should be incorporated in future models of sequence change. PMID- 21235784 TI - EU-funded malaria research under the 6th and 7th Framework Programmes for research and technological development. AB - While malaria research has traditionally been strong in Europe, targeted and sustained support for cooperative malaria research at EU level, namely through the EU's 6th and 7th Framework Programmes for research and technological development, FP6 (2002-2006) and FP7 (2007-2013), has boosted both impact and visibility of European malaria research. Most of the European malaria research community is now organized under a number of comprehensive and complementary research networks and projects, assembled around four key areas: (1) fundamental research on the malaria parasite and the disease, (2) development of new malaria drugs, (3) research and development of a malaria vaccine, and (4) research to control the malaria-transmitting mosquito vector. Considerable efforts were undertaken to ensure adequate participation of research groups from disease endemic countries, in particular from Africa, with the long-term aim to strengthen cooperative links and research capacities in these countries. The concept of organizing European research through major strategic projects to form a "European Research Area" (ERA) was originally developed in the preparation of FP6, and ERA formation has now turned into a major EU policy objective explicitly inscribed into the Lisbon Treaty. EU-funded malaria research may serve as a showcase to demonstrate how ERA formation can successfully be implemented in a given area of science when several surrounding parameters converge to support implementation of this strategic concept: timely coincidence of political stimuli, responsive programming, a clearly defined--and well confined--area of research, and the readiness of the targeted research community who is well familiar with transnational cooperation at EU level. Major EU-funded malaria projects have evolved into thematic and organizational platforms that can collaborate with other global players. Europe may thus contribute more, and better, to addressing the global research agenda for malaria. PMID- 21235783 TI - Spatial and temporal variation in the kdr allele L1014S in Anopheles gambiae s.s. and phenotypic variability in susceptibility to insecticides in Western Kenya. AB - BACKGROUND: Malaria vector control in Africa depends upon effective insecticides in bed nets and indoor residual sprays. This study investigated the extent of insecticide resistance in Anopheles gambiae s.l., Anopheles gambiae s.s. and Anopheles arabiensis in western Kenya where ownership of insecticide-treated bed nets has risen steadily from the late 1990s to 2010. Temporal and spatial variation in the frequency of a knock down resistance (kdr) allele in A. gambiae s.s. was quantified, as was variation in phenotypic resistance among geographic populations of A. gambiae s.l. METHODS: To investigate temporal variation in kdr frequency, individual specimens of A. gambiae s.s. from two sentinel sites were genotyped using RT-PCR from 1996-2010. Spatial variation in kdr frequency, species composition, and resistance status were investigated in additional populations of A. gambiae s.l. sampled in western Kenya in 2009 and 2010. Specimens were genotyped for kdr as above and identified to species via conventional PCR. Field-collected larvae were reared to adulthood and tested for insecticide resistance using WHO bioassays. RESULTS: Anopheles gambiae s.s. showed a dramatic increase in kdr frequency from 1996 - 2010, coincident with the scale up of insecticide-treated nets. By 2009-2010, the kdr L1014S allele was nearly fixed in the A. gambiae s.s. population, but was absent in A. arabiensis. Near Lake Victoria, A. arabiensis was dominant in samples, while at sites north of the lake A. gambiae s.s was more common but declined relative to A. arabiensis from 2009 to 2010. Bioassays demonstrated that A. gambiae s.s. had moderate phenotypic levels of resistance to DDT, permethrin and deltamethrin while A. arabiensis was susceptible to all insecticides tested. CONCLUSIONS: The kdr L1014S allele has approached fixation in A. gambiae s.s. populations of western Kenya, and these same populations exhibit varying degrees of phenotypic resistance to DDT and pyrethroid insecticides. The near absence of A. gambiae s.s. from populations along the lakeshore and the apparent decline in other populations suggest that insecticide-treated nets remain effective against this mosquito despite the increase in kdr allele frequency. The persistence of A. arabiensis, despite little or no detectable insecticide resistance, is likely due to behavioural traits such as outdoor feeding and/or feeding on non-human hosts by which this species avoids interaction with insecticide-treated nets. PMID- 21235785 TI - Strand-specific transcriptome profiling with directly labeled RNA on genomic tiling microarrays. AB - BACKGROUND: With lower manufacturing cost, high spot density, and flexible probe design, genomic tiling microarrays are ideal for comprehensive transcriptome studies. Typically, transcriptome profiling using microarrays involves reverse transcription, which converts RNA to cDNA. The cDNA is then labeled and hybridized to the probes on the arrays, thus the RNA signals are detected indirectly. Reverse transcription is known to generate artifactual cDNA, in particular the synthesis of second-strand cDNA, leading to false discovery of antisense RNA. To address this issue, we have developed an effective method using RNA that is directly labeled, thus by-passing the cDNA generation. This paper describes this method and its application to the mapping of transcriptome profiles. RESULTS: RNA extracted from laboratory cultures of Porphyromonas gingivalis was fluorescently labeled with an alkylation reagent and hybridized directly to probes on genomic tiling microarrays specifically designed for this periodontal pathogen. The generated transcriptome profile was strand-specific and produced signals close to background level in most antisense regions of the genome. In contrast, high levels of signal were detected in the antisense regions when the hybridization was done with cDNA. Five antisense areas were tested with independent strand-specific RT-PCR and none to negligible amplification was detected, indicating that the strong antisense cDNA signals were experimental artifacts. CONCLUSIONS: An efficient method was developed for mapping transcriptome profiles specific to both coding strands of a bacterial genome. This method chemically labels and uses extracted RNA directly in microarray hybridization. The generated transcriptome profile was free of cDNA artifactual signals. In addition, this method requires fewer processing steps and is potentially more sensitive in detecting small amount of RNA compared to conventional end-labeling methods due to the incorporation of more fluorescent molecules per RNA fragment. PMID- 21235786 TI - NClassG+: A classifier for non-classically secreted Gram-positive bacterial proteins. AB - BACKGROUND: Most predictive methods currently available for the identification of protein secretion mechanisms have focused on classically secreted proteins. In fact, only two methods have been reported for predicting non-classically secreted proteins of Gram-positive bacteria. This study describes the implementation of a sequence-based classifier, denoted as NClassG+, for identifying non-classically secreted Gram-positive bacterial proteins. RESULTS: Several feature-based classifiers were trained using different sequence transformation vectors (frequencies, dipeptides, physicochemical factors and PSSM) and Support Vector Machines (SVMs) with Linear, Polynomial and Gaussian kernel functions. Nested k fold cross-validation (CV) was applied to select the best models, using the inner CV loop to tune the model parameters and the outer CV group to compute the error. The parameters and Kernel functions and the combinations between all possible feature vectors were optimized using grid search. CONCLUSIONS: The final model was tested against an independent set not previously seen by the model, obtaining better predictive performance compared to SecretomeP V2.0 and SecretPV2.0 for the identification of non-classically secreted proteins. NClassG+ is freely available on the web at http://www.biolisi.unal.edu.co/web-servers/nclassgpositive/. PMID- 21235787 TI - Main results of the ouabain and adducin for Specific Intervention on Sodium in Hypertension Trial (OASIS-HT): a randomized placebo-controlled phase-2 dose finding study of rostafuroxin. AB - BACKGROUND: The Ouabain and Adducin for Specific Intervention on Sodium in Hypertension (OASIS-HT) Trial was a phase-2 dose-finding study of rostafuroxin, a digitoxygenin derivative, which selectively antagonizes the effects of endogenous ouabain (EO) on Na+,K+-ATPase and mutated adducin. Rostafuroxin lowered blood pressure (BP) in some animal models and in humans. METHODS: OASIS-HT consisted of 5 concurrently running double-blind cross-over studies. After 4 weeks without treatment, 435 patients with uncomplicated systolic hypertension (140-169 mm Hg) were randomized to rostafuroxin (0.05, 0.15, 0.5, 1.5 or 5.0 mg/d) or matching placebo, each treatment period lasting 5 weeks. The primary endpoint was the reduction in systolic office BP. Among the secondary endpoints were diastolic office BP, 24-h ambulatory BP, plasma EO concentration and renin activity, 24-h urinary sodium and aldosterone excretion, and safety. ANOVA considered treatment sequence (fixed effect), subjects nested within sequence (random), period (fixed), and treatment (fixed). RESULTS: Among 410 analyzable patients (40.5% women; mean age, 48.4 years), the differences in the primary endpoint (rostafuroxin minus placebo) ranged from -0.18 mm Hg (P = 0.90) on 0.15 mg/d rostafuroxin to 2.72 mm Hg (P = 0.04) on 0.05 mg/d. In the 5 dosage arms combined, the treatment effects averaged 1.30 mm Hg (P = 0.03) for systolic office BP; 0.70 mm Hg (P = 0.08) for diastolic office BP; 0.36 mm Hg (P = 0.49) for 24-h systolic BP; and 0.05 mm Hg (P = 0.88) for 24-h diastolic BP. In the 2 treatment groups combined, systolic (-1.36 mm Hg) and diastolic (-0.97 mm Hg) office BPs decreased from week 5 to 10 (P for period effect <= 0.028), but carry over effects were not significant (P >= 0.11). All other endpoints were not different on rostafuroxin and placebo. Minor side-effects occurred with similarly low frequency on rostafuroxin and placebo. CONCLUSIONS: In 5 concurrently running double-blind cross-over studies rostafuroxin did not reduce BP at any dose. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT00415038. PMID- 21235788 TI - Treatment with a neutralizing anti-murine interleukin-17 antibody after the onset of coxsackievirus b3-induced viral myocarditis reduces myocardium inflammation. AB - BACKGROUND: Recently, some studies indicate that interleukin (IL)-17, known as a T cell (Th17)-derived proinflammatory cytokine, is the major mediator of tissue inflammation in inflammatory and autoimmune diseases. Viral myocarditis (VMC) is a T cell-mediated autoimmune disease, but the role for IL-17 in VMC is not well defined. RESULTS: Using IL-17 monoclonal antibody (IL-17mAb)-treated VMC mice, we tested the pathogenic role of IL-17 in the development of VMC. VMC mice were treated with monoclonal rat anti-murine IL-17 antibody (anti-IL-17) or rat IgG(2A) isotype control or phosphate-buffered solution 3 days after Coxsackievirus B3 (CVB3) injection. Normal mice without any manipulation were taken as normal control. The survival rates of mice were monitored and heart pathology was examined histologically. IL-17, IL-6, and TNF-alpha mRNA of the myocardium were assessed by semi-quantitative RT-PCR. Systemic IL-17, IL-6, and TNF-alpha level were measured by enzyme-linked immunosorbent assay, and local myocardium IL-17 expression was analyzed using immunohistochemical staining. Flow cytometric analysis was used to evaluate the frequencies of Th17 subsets in CD4(+) T cells. Results showed that neutralization of IL-17 with anti-IL-17 can ameliorate clinical symptoms, defer disease course, decrease serum IL-17 level, without declining the IL-17, IL-6 and TNF-alpha mRNA transcript level and serum IL-6, TNF-alpha level. The differentiation and proliferation of the Th17 cells were unchanged. CONCLUSIONS: Our data suggest that IL-17 is crucially involved in the pathogenesis of murine VMC, IL-17 inhibition might ameliorate the myocardium inflammation after the onset of VMC. PMID- 21235789 TI - Loss of expression of TGF-betas and their receptors in chronic skin lesions induced by sulfur mustard as compared with chronic contact dermatitis patients. AB - BACKGROUND: Sulfur mustard (SM) is a blister-forming agent that has been used as a chemical weapon. Sulfur mustard can cause damage in various organs, especially the skin, respiratory system, and eyes. Generally, the multiple complications of mustard gas result from its alkalizing potency; it reacts with cellular components like DNA, RNA, proteins, and lipid membranes.TGF-beta is a multi functional cytokine with multiple biological effects ranging from cell differentiation and growth inhibition to extracellular matrix stimulation, immunosuppression, and immunomodulation. TGF-beta has 3 isoforms (TGF-beta 1, 2, 3) and its signaling is mediated by its receptors: R1, R2 and intracellular Smads molecules.TGF-beta has been shown to have anti-inflammatory effects. TGF-betas and their receptors also have an important role in modulation of skin inflammation, proliferation of epidermal cells, and wound healing, and they have been implicated in different types of skin inflammatory disorders. METHODS: Seventeen exposed SM individuals (48.47 +/- 9.3 years), 17 chronic dermatitis patients (46.52 +/- 14.6 years), and 5 normal controls (44.00 +/- 14.6 years) were enrolled in this study.Evaluation of TGF-betas and their receptors expressions was performed by semiquantitative RT-PCR. Only TGF1 was analyzed immunohistochemically. RESULTS: Our results showed significant decreases in the expression percentages of TGF-beta 1, 2 and R1, R2 in chemical victims in comparison with chronic dermatitis and normal subjects and significant decreases in the intensity of R1 and R2 expressions in chemical victims in comparison with chronic dermatitis and normal controls. (P value < 0.05) CONCLUSIONS: TGF-betas and their receptors appear to have a noticeable role in chronic inflammatory skin lesions caused by sulfur mustard. PMID- 21235790 TI - Practices of entomophagy and entomotherapy by members of the Nyishi and Galo tribes, two ethnic groups of the state of Arunachal Pradesh (North-East India). AB - We prepared a consolidated list of edible and therapeutic insects used in Arunachal Pradesh (N.E. India) by two tribal societies (i.e., the Nyishi of East Kameng and the Galo of West Siang). The list is based on thorough, semi structured field-interviews with 20 informants of each tribal group. At least 81 species of local insects, belonging to 26 families and five orders of insects, namely Coleoptera (24 species), Orthoptera (17 species), Hemiptera (16 species), Hymenoptera (15 species) and Odonata (9 species), are being used as food among members of these two indigenous societies. However, Nyishi use overall more species of insects as food than Galo people do and consume mostly Coleoptera and Hemiptera; amongst the Galo, on the other hand, Odonata and Orthoptera dominate. The selection of the food insects amongst the Nyishi and Galo is dictated by traditional tribal beliefs as well as the taste and availability of the insects. Depending on the species, only particular or all developmental stages are consumed. Some food insects may be included in the local diet throughout the year, others only when seasonally available. Commonly specimens are being prepared for consumption by roasting, frying or boiling. Twelve species of insects are deemed therapeutically valuable by the locals and are being used by the tribes investigated to treat a variety of disorders in humans and domestic animals. Members of the Galo use a greater number of insect species for remedial purposes than the Nyishi. With the degradation of natural resources, rapid population growth, and increasing influence of 'westernization', the traditional wisdom of entomophagy and entomotherapy is at risk of being lost. There is thus an urgent need to record the role insects play as components of local diets and folk remedies and to assess insect biodiversity in the light of these uses. PMID- 21235791 TI - Molecular and biochemical characterisation of a novel mutation in POLG associated with Alpers syndrome. AB - BACKGROUND: DNA polymerase gamma (POLG) is the only known mitochondrial DNA (mtDNA) polymerase. It mediates mtDNA replication and base excision repair. Mutations in the POLG gene lead to reduction of functional mtDNA (mtDNA depletion and/or deletions) and are therefore predicted to result in defective oxidative phosphorylation (OXPHOS). Many mutations map to the polymerase and exonuclease domains of the enzyme and produce a broad clinical spectrum. The most frequent mutation p.A467T is localised in the linker region between these domains. In compound heterozygote patients the p.A467T mutation has been described to be associated amongst others with fatal childhood encephalopathy. These patients have a poorer survival rate compared to homozygotes. METHODS: mtDNA content in various tissues (fibroblasts, muscle and liver) was quantified using quantitative PCR (qPCR). OXPHOS activities in the same tissues were assessed using spectrophotometric methods and catalytic stain of BN-PAGE. RESULTS: We characterise a novel splice site mutation in POLG found in trans with the p.A467T mutation in a 3.5 years old boy with valproic acid induced acute liver failure (Alpers-Huttenlocher syndrome). These mutations result in a tissue specific depletion of the mtDNA which correlates with the OXPHOS-activities. CONCLUSIONS: mtDNA depletion can be expressed in a high tissue-specific manner and confirms the need to analyse primary tissue. Furthermore, POLG analysis optimises clinical management in the early stages of disease and reinforces the need for its evaluation before starting valproic acid treatment. PMID- 21235792 TI - Speeding up the Consensus Clustering methodology for microarray data analysis. AB - BACKGROUND: The inference of the number of clusters in a dataset, a fundamental problem in Statistics, Data Analysis and Classification, is usually addressed via internal validation measures. The stated problem is quite difficult, in particular for microarrays, since the inferred prediction must be sensible enough to capture the inherent biological structure in a dataset, e.g., functionally related genes. Despite the rich literature present in that area, the identification of an internal validation measure that is both fast and precise has proved to be elusive. In order to partially fill this gap, we propose a speed up of Consensus (Consensus Clustering), a methodology whose purpose is the provision of a prediction of the number of clusters in a dataset, together with a dissimilarity matrix (the consensus matrix) that can be used by clustering algorithms. As detailed in the remainder of the paper, Consensus is a natural candidate for a speed-up. RESULTS: Since the time-precision performance of Consensus depends on two parameters, our first task is to show that a simple adjustment of the parameters is not enough to obtain a good precision-time trade off. Our second task is to provide a fast approximation algorithm for Consensus. That is, the closely related algorithm FC (Fast Consensus) that would have the same precision as Consensus with a substantially better time performance. The performance of FC has been assessed via extensive experiments on twelve benchmark datasets that summarize key features of microarray applications, such as cancer studies, gene expression with up and down patterns, and a full spectrum of dimensionality up to over a thousand. Based on their outcome, compared with previous benchmarking results available in the literature, FC turns out to be among the fastest internal validation methods, while retaining the same outstanding precision of Consensus. Moreover, it also provides a consensus matrix that can be used as a dissimilarity matrix, guaranteeing the same performance as the corresponding matrix produced by Consensus. We have also experimented with the use of Consensus and FC in conjunction with NMF (Nonnegative Matrix Factorization), in order to identify the correct number of clusters in a dataset. Although NMF is an increasingly popular technique for biological data mining, our results are somewhat disappointing and complement quite well the state of the art about NMF, shedding further light on its merits and limitations. CONCLUSIONS: In summary, FC with a parameter setting that makes it robust with respect to small and medium-sized datasets, i.e, number of items to cluster in the hundreds and number of conditions up to a thousand, seems to be the internal validation measure of choice. Moreover, the technique we have developed here can be used in other contexts, in particular for the speed-up of stability-based validation measures. PMID- 21235793 TI - Relationship of adiposity and insulin resistance mediated by inflammation in a group of overweight and obese Chilean adolescents. AB - The mild chronic inflammatory state associated with obesity may be an important link between adiposity and insulin resistance (IR). In a sample of 137 overweight and obese Chilean adolescents, we assessed associations between high-sensitivity C-reactive protein (hs-CRP), IR and adiposity; explored sex differences; and evaluated whether hs-CRP mediated the relationship between adiposity and IR. Positive relationships between hs-CRP, IR and 2 measures of adiposity were found. Hs-CRP was associated with waist circumference (WC) in boys and fat mass index (FMI) in girls. Using path analysis, we found that hs-CRP mediated the relationship between adiposity (WC and FMI) and the homeostatic model assessment of insulin resistance (HOMA-IR) (p < 0.05) in both sexes. Our novel finding is that inflammation statistically mediated the well described link between increased adiposity and IR. PMID- 21235795 TI - Is public transport a risk factor for acute respiratory infection? AB - BACKGROUND: The relationship between public transport use and acquisition of acute respiratory infection (ARI) is not well understood but potentially important during epidemics and pandemics. METHODS: A case-control study performed during the 2008/09 influenza season. Cases (n = 72) consulted a General Practitioner with ARI, and controls with another non-respiratory acute condition (n = 66). Data were obtained on bus or tram usage in the five days preceding illness onset (cases) or the five days before consultation (controls) alongside demographic details. Multiple logistic regression modelling was used to investigate the association between bus or tram use and ARI, adjusting for potential confounders. RESULTS: Recent bus or tram use within five days of symptom onset was associated with an almost six-fold increased risk of consulting for ARI (adjusted OR = 5.94 95% CI 1.33-26.5). The risk of ARI appeared to be modified according to the degree of habitual bus and tram use, but this was not statistically significant (1-3 times/week: adjusted OR = 0.54 (95% CI 0.15-1.95; >3 times/week: 0.37 (95% CI 0.13-1.06). CONCLUSIONS: We found a statistically significant association between ARI and bus or tram use in the five days before symptom onset. The risk appeared greatest among occasional bus or tram users, but this trend was not statistically significant. However, these data are plausible in relation to the greater likelihood of developing protective antibodies to common respiratory viruses if repeatedly exposed. The findings have differing implications for the control of seasonal acute respiratory infections and for pandemic influenza. PMID- 21235794 TI - BiologicalNetworks--tools enabling the integration of multi-scale data for the host-pathogen studies. AB - BACKGROUND: Understanding of immune response mechanisms of pathogen-infected host requires multi-scale analysis of genome-wide data. Data integration methods have proved useful to the study of biological processes in model organisms, but their systematic application to the study of host immune system response to a pathogen and human disease is still in the initial stage. RESULTS: To study host-pathogen interaction on the systems biology level, an extension to the previously described BiologicalNetworks system is proposed. The developed methods and data integration and querying tools allow simplifying and streamlining the process of integration of diverse experimental data types, including molecular interactions and phylogenetic classifications, genomic sequences and protein structure information, gene expression and virulence data for pathogen-related studies. The data can be integrated from the databases and user's files for both public and private use. CONCLUSIONS: The developed system can be used for the systems-level analysis of host-pathogen interactions, including host molecular pathways that are induced/repressed during the infections, co-expressed genes, and conserved transcription factor binding sites. Previously unknown to be associated with the influenza infection genes were identified and suggested for further investigation as potential drug targets. Developed methods and data are available through the Java application (from BiologicalNetworks program at http://www.biologicalnetworks.org) and web interface (at http://flu.sdsc.edu). PMID- 21235796 TI - Timing is everything: early degradation of abscission layer is associated with increased seed shattering in U.S. weedy rice. AB - BACKGROUND: Seed shattering, or shedding, is an important fitness trait for wild and weedy grasses. U.S. weedy rice (Oryza sativa) is a highly shattering weed, thought to have evolved from non-shattering cultivated ancestors. All U.S. weedy rice individuals examined to date contain a mutation in the sh4 locus associated with loss of shattering during rice domestication. Weedy individuals also share the shattering trait with wild rice, but not the ancestral shattering mutation at sh4; thus, how weedy rice reacquired the shattering phenotype is unknown. To establish the morphological basis of the parallel evolution of seed shattering in weedy rice and wild, we examined the abscission layer at the flower-pedicel junction in weedy individuals in comparison with wild and cultivated relatives. RESULTS: Consistent with previous work, shattering wild rice individuals possess clear, defined abscission layers at flowering, whereas non-shattering cultivated rice individuals do not. Shattering weedy rice from two separately evolved populations in the U.S. (SH and BHA) show patterns of abscission layer formation and degradation distinct from wild rice. Prior to flowering, the abscission layer has formed in all weedy individuals and by flowering it is already degrading. In contrast, wild O. rufipogon abscission layers have been shown not to degrade until after flowering has occurred. CONCLUSIONS: Seed shattering in weedy rice involves the formation and degradation of an abscission layer in the flower pedicel junction, as in wild Oryza, but is a developmentally different process from shattering in wild rice. Weedy rice abscission layers appear to break down earlier than wild abscission layers. The timing of weedy abscission layer degradation suggests that unidentified regulatory genes may play a critical role in the reacquisition of shattering in weedy rice, and sheds light on the morphological basis of parallel evolution for shattering in weedy and wild rice. PMID- 21235797 TI - Human immunodeficiency virus infection and cerebral malaria in children in Uganda: a case-control study. AB - BACKGROUND: Human immunodeficiency virus (HIV)-1 infection increases the burden of malaria by increasing susceptibility to infection and decreasing the response to malarial treatment. HIV-1 has also been found to suppress the immune system and predispose to severe forms of malaria in adults. There is still a paucity of data on the association between HIV-1 infection and cerebral malaria in children. The aim of this study was to determine whether HIV-1 infection is a risk factor for cerebral malaria in children. METHOD: We conducted an unmatched case-control study, in which 100 children with cerebral malaria were compared with 132 with uncomplicated malaria and 120 with no malaria. In stratified analyses we estimated odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for age. RESULTS: HIV-1 infection was present in 9% of children with cerebral malaria compared to 2.3% in uncomplicated malaria (age-adjusted odds ratio (aOR) 5.94 (95% confidence interval (CI) 1.36-25.94, p = 0.012); and 2.5% in children with no malaria (aOR 3.85 (95% CI0.99-14.93, p = 0.037). The age-adjusted odds of being HIV-positive among children with cerebral malaria compared to the control groups (children with uncomplicated malaria and no malaria) was 4.98 (95% CI 1.54 16.07), p-value = 0.003. CONCLUSIONS: HIV-1 infection is associated with clinical presentation of cerebral malaria in children. Clinicians should ensure that children diagnosed with HIV infection are initiated on cotrimoxazole prophylaxis as soon as the diagnosis is made and caretakers counselled on the importance of adherence to the cotrimoxazole towards reducing the risk of acquiring P.falciparum malaria and associated complications such as cerebral malaria. Other malaria preventive measures such as use of insecticide-treated mosquito nets should also be emphasized during counselling sessions. PMID- 21235799 TI - A knowledge translation collaborative to improve the use of therapeutic hypothermia in post-cardiac arrest patients: protocol for a stepped wedge randomized trial. AB - BACKGROUND: Advances in resuscitation science have dramatically improved survival rates following cardiac arrest. However, about 60% of adults that regain spontaneous circulation die before leaving the hospital. Recently it has been shown that inducing hypothermia in cardiac arrest survivors immediately following their arrival in hospital can dramatically improve both overall survival and neurological outcomes. Despite the strong evidence for its efficacy and the apparent simplicity of this intervention, recent surveys show that therapeutic hypothermia is delivered inconsistently, incompletely, and often with delay. METHODS AND DESIGN: This study will evaluate a multi-faceted knowledge translation strategy designed to increase the utilization rate of induced hypothermia in survivors of cardiac arrest across a network of 37 hospitals in Southwestern Ontario, Canada. The study is designed as a stepped wedge randomized trial lasting two years. Individual hospitals will be randomly assigned to four different wedges that will receive the active knowledge translation strategy according to a sequential rollout over a number of time periods. By the end of the study, all hospitals will have received the intervention. The primary aim is to measure the effectiveness of a multifaceted knowledge translation plan involving education, reminders, and audit-feedback for improving the use of induced hypothermia in survivors of cardiac arrest presenting to the emergency department. The primary outcome is the proportion of eligible OHCA patients that are cooled to a body temperature of 32 to 34 degrees C within six hours of arrival in the hospital. Secondary outcomes will include process of care measures and clinical outcomes. DISCUSSION: Inducing hypothermia in cardiac arrest survivors immediately following their arrival to hospital has been shown to dramatically improve both overall survival and neurological outcomes. However, this lifesaving treatment is frequently not applied in practice. If this trial is positive, our results will have broad implications by showing that a knowledge translation strategy shared across a collaborative network of hospitals can increase the number of patients that receive this lifesaving intervention in a timely manner. TRIAL REGISTRATION: ClinicalTrials.gov Trial Identifier: NCT00683683. PMID- 21235800 TI - Classification of voice disorder in children with cochlear implantation and hearing aid using multiple classifier fusion. AB - BACKGROUND: Speech production and speech phonetic features gradually improve in children by obtaining audio feedback after cochlear implantation or using hearing aids. The aim of this study was to develop and evaluate automated classification of voice disorder in children with cochlear implantation and hearing aids. METHODS: We considered 4 disorder categories in children's voice using the following definitions: Level_1: Children who produce spontaneous phonation and use words spontaneously and imitatively. Level_2: Children, who produce spontaneous phonation, use words spontaneously and make short sentences imitatively. Level_3: Children, who produce spontaneous phonations, use words and arbitrary sentences spontaneously. Level_4: Normal children without any hearing loss background. Thirty Persian children participated in the study, including six children in each level from one to three and 12 children in level four. Voice samples of five isolated Persian words "mashin", "mar", "moosh", "gav" and "mouz" were analyzed. Four levels of the voice quality were considered, the higher the level the less significant the speech disorder. "Frame-based" and "word-based" features were extracted from voice signals. The frame-based features include intensity, fundamental frequency, formants, nasality and approximate entropy and word-based features include phase space features and wavelet coefficients. For frame-based features, hidden Markov models were used as classifiers and for word based features, neural network was used. RESULTS: After Classifiers fusion with three methods: Majority Voting Rule, Linear Combination and Stacked fusion, the best classification rates were obtained using frame-based and word-based features with MVR rule (level 1:100%, level 2: 93.75%, level 3: 100%, level 4: 94%). CONCLUSIONS: Result of this study may help speech pathologists follow up voice disorder recovery in children with cochlear implantation or hearing aid who are in the same age range. PMID- 21235798 TI - Analysing the eosinophil cationic protein--a clue to the function of the eosinophil granulocyte. AB - Eosinophil granulocytes reside in respiratory mucosa including lungs, in the gastro-intestinal tract, and in lymphocyte associated organs, the thymus, lymph nodes and the spleen. In parasitic infections, atopic diseases such as atopic dermatitis and asthma, the numbers of the circulating eosinophils are frequently elevated. In conditions such as Hypereosinophilic Syndrome (HES) circulating eosinophil levels are even further raised. Although, eosinophils were identified more than hundred years ago, their roles in homeostasis and in disease still remain unclear. The most prominent feature of the eosinophils are their large secondary granules, each containing four basic proteins, the best known being the eosinophil cationic protein (ECP). This protein has been developed as a marker for eosinophilic disease and quantified in biological fluids including serum, bronchoalveolar lavage and nasal secretions. Elevated ECP levels are found in T helper lymphocyte type 2 (atopic) diseases such as allergic asthma and allergic rhinitis but also occasionally in other diseases such as bacterial sinusitis. ECP is a ribonuclease which has been attributed with cytotoxic, neurotoxic, fibrosis promoting and immune-regulatory functions. ECP regulates mucosal and immune cells and may directly act against helminth, bacterial and viral infections. The levels of ECP measured in disease in combination with the catalogue of known functions of the protein and its polymorphisms presented here will build a foundation for further speculations of the role of ECP, and ultimately the role of the eosinophil. PMID- 21235801 TI - MyD88-adaptor protein acts as a preventive mechanism for memory deficits in a mouse model of Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with brain innate immune activation mainly mediated by microglia. These cells are known to be activated in the brain of AD patients and to produce inflammatory cytokines and neurotoxic molecules in response to Amyloid beta (Abeta). Activation of microglia can also promote Abeta clearance via Toll-like receptors (TLRs). Myeloid differentiation factor 88 (MyD88) is the adaptor molecule for most of these innate immune receptors, transducing the intracellular signal from TLRs to nucleus. RESULTS: Here, we report that more than 50% reduction in MyD88 expression in a mouse model of AD accelerated spatial learning and memory deficits. Brain of APPswe/PS1-MyD88+/- mice was characterized by a delay in accumulation of Abeta plaques and increased soluble levels of Abeta oligomers. Furthermore, inflammatory monocyte subset and brain IL-1beta gene expression were significantly reduced in APPswe/PS1 mice with impaired MyD88 signaling. CONCLUSIONS: These data indicate that activation of MyD88 intracellular signaling pathway, likely by TLRs, acts as a natural innate immune mechanism to restrict disease progression of APPswe/PS1 mice. PMID- 21235802 TI - Relationship between cognitive function and prevalence of decrease in intrinsic academic motivation in adolescents. AB - BACKGROUND: Decrease in intrinsic motivation is a common complaint among elementary and junior high school students, and is related to poor academic performance. Since grade-dependent development of cognitive functions also influences academic performance by these students, we examined whether cognitive functions are related to the prevalence of decrease in intrinsic academic motivation. METHODS: The study group consisted of 134 elementary school students from 4th to 6th grades and 133 junior high school students from 7th to 9th grades. Participants completed a questionnaire on intrinsic academic motivation. They also performed paper-and-pencil and computerized cognitive tests to measure abilities in motor processing, spatial construction, semantic fluency, immediate memory, short-term memory, delayed memory, spatial working memory, and selective, alternative, and divided attention. RESULTS: In multivariate logistic regression analyses adjusted for grade and gender, scores of none of the cognitive tests were correlated with the prevalence of decrease in intrinsic academic motivation in elementary school students. However, low digit span forward test score and score for comprehension of the story in the kana pick-out test were positively correlated with the prevalence of decrease in intrinsic academic motivation in junior high school students. CONCLUSIONS: The present findings suggest that decrease in capacity for verbal memory is associated with the prevalence of decrease in intrinsic academic motivation among junior high school students. PMID- 21235804 TI - Revision history aware repositories of computational models of biological systems. AB - BACKGROUND: Building repositories of computational models of biological systems ensures that published models are available for both education and further research, and can provide a source of smaller, previously verified models to integrate into a larger model. One problem with earlier repositories has been the limitations in facilities to record the revision history of models. Often, these facilities are limited to a linear series of versions which were deposited in the repository. This is problematic for several reasons. Firstly, there are many instances in the history of biological systems modelling where an 'ancestral' model is modified by different groups to create many different models. With a linear series of versions, if the changes made to one model are merged into another model, the merge appears as a single item in the history. This hides useful revision history information, and also makes further merges much more difficult, as there is no record of which changes have or have not already been merged. In addition, a long series of individual changes made outside of the repository are also all merged into a single revision when they are put back into the repository, making it difficult to separate out individual changes. Furthermore, many earlier repositories only retain the revision history of individual files, rather than of a group of files. This is an important limitation to overcome, because some types of models, such as CellML 1.1 models, can be developed as a collection of modules, each in a separate file. The need for revision history is widely recognised for computer software, and a lot of work has gone into developing version control systems and distributed version control systems (DVCSs) for tracking the revision history. However, to date, there has been no published research on how DVCSs can be applied to repositories of computational models of biological systems. RESULTS: We have extended the Physiome Model Repository software to be fully revision history aware, by building it on top of Mercurial, an existing DVCS. We have demonstrated the utility of this approach, when used in conjunction with the model composition facilities in CellML, to build and understand more complex models. We have also demonstrated the ability of the repository software to present version history to casual users over the web, and to highlight specific versions which are likely to be useful to users. CONCLUSIONS: Providing facilities for maintaining and using revision history information is an important part of building a useful repository of computational models, as this information is useful both for understanding the source of and justification for parts of a model, and to facilitate automated processes such as merges. The availability of fully revision history aware repositories, and associated tools, will therefore be of significant benefit to the community. PMID- 21235803 TI - Protective effect of Garcinia against renal oxidative stress and biomarkers induced by high fat and sucrose diet. AB - BACKGROUND: Obesity became major health problem in the world, the objective of this work was to examine the effect of high sucrose and high fat diet to induce obesity on antioxidant defense system, biochemical changes in blood and tissue of control, non treated and treated groups by administration of Garcinia cambogia, and explore the mechanisms that link obesity with altered renal function. METHODS: Rats were fed a standard control diet for 12 week (wk) or a diet containing 65% high sucrose (HSD) or 35% fat (HFD) for 8 wk and then HFD group divided into two groups for the following 4 wks. One group was given Garcinia+HFD, the second only high fat, Also the HSD divided into two groups, 1st HSD+Garcinia and 2nd HSD. Blood and renal, mesenteric, Perirenal and epididymal adipose tissues were collected for biochemical assays. RESULTS: HFD and HSD groups of rats showed a significant increase in feed intake, Body weight (BW) and body mass index (BMI). Also there were significant increases in weights of mesenteric, Perirenal and epididymal adipose tissues in HFD and HSD groups.HFD and HSD affect the kidney by increasing serum urea and creatinine levels and decreased level of nitric oxide (NO) and increased blood glucose, low density lipoproteins (LDL), triacylglycerol (TG), total cholesterol (TC) and malondialdehyde (MDA). Glucose 6-phosphate dehydrogenase (G6PD) activities were significantly decreased in HFD while there were significant increases in HSD and HSD+G groups p <= 0.05 compared with control. Moreover, renal catalase activities and MDA levels were significantly increased while NO level was lowered. These changes improved by Garcinia that decreased the oxidative stress biomarkers and increased NO level.There were significant positive correlations among BMI, kidney functions (Creatinine and urea), TG and Oxidative markers (renal MDA and catalase). CONCLUSIONS: Rats fed a diet with HFD or HSD showed, hypertriglyceridemia, increased LDL production, increased oxidative stress and renal alteration. Moreover, suggesting association between lipid peroxidation, obesity and nephropathy, while Garcinia ameliorated the damaging effects of the HFD or HSD and decreased feed intake, MDA level and decreased oxidative stress in renal tissues. PMID- 21235805 TI - Characterization of thiobarbituric acid derivatives as inhibitors of hepatitis C virus NS5B polymerase. AB - In an effort to find chemicals inhibiting the enzymatic activity of the hepatitis C virus (HCV) NS5B polymerase, a series of thiobarbituric acid derivatives were selected from a library provided by Korea Research Institute of Chemical Technology and characterized. The selected compounds exhibited IC50 values ranging from 1.7 to 3.8 MUM, and EC50 values ranging from 12.3 to 20.7 MUM against NS5B polymerase of type 1b strain. They showed little effect against type 2a polymerase. One of the compounds, G05, was selected and further characterized. It inhibited the synthesis of RNA by recombinant HCV NS5B polymerase in a dose dependent manner. The CC50 value was 77 MUM. The inhibition was in a noncompetitive manner with the substrate UTP. The compound did not inhibit the elongation step of RNA synthesis in a single-cycle processive polymerization assay. It inhibited the binding of NS5B polymerase to the template RNA in a dose dependent manner. PMID- 21235806 TI - Contribution of complement activation pathways to neuropathology differs among mouse models of Alzheimer's disease. AB - BACKGROUND: Complement proteins and activation products have been found associated with neuropathology in Alzheimer's disease (AD). Recently, a C5a receptor antagonist was shown to suppress neuropathology in two murine models of AD, Tg2576 and 3xTg. Previously, a genetic deficiency of C1q in the Tg2576 mouse model showed an accumulation of fibrillar plaques similar to the complement sufficient Tg2576, but reactive glia were significantly decreased and neuronal integrity was improved suggesting detrimental consequences for complement activation in AD. The goal of this study was to define the role of the classical complement activation pathway in the progression of pathology in the 3xTg mouse that develops tangles in addition to fibrillar plaques (more closely reflecting human AD pathology) and to assess the influence of complement in a model of AD with a higher level of complement hemolytic activity. METHODS: 3xTg mice deficient in C1q (3xTgQ-/-) were generated, and both 3xTg and 3xTgQ-/- were backcrossed to the BUB mouse strain which has higher in vitro hemolytic complement activity. Mice were aged and perfused, and brain sections stained for pathological markers or analyzed for proinflammatory marker expression. RESULTS: 3xTgQ-/- mice showed similar amounts of fibrillar amyloid, reactive glia and hyperphosphorylated tau as the C1q-sufficient 3xTg at the ages analyzed. However, 3xTg and 3xTgQ-/- on the BUB background developed pathology earlier than on the original 3xTg background, although the presence of C1q had no effect on neuropathological and pro-inflammatory markers. In contrast to that seen in other transgenic models of AD, C1q, C4 and C3 immunoreactivity was undetectable on the plaques of 3xTg in any background, although C3 was associated with reactive astrocytes surrounding the plaques. Importantly, properdin a component of the alternative complement pathway was associated with plaques in all models. CONCLUSIONS: In contrast to previously investigated transgenic models of AD, development of neuropathology in 3xTg mice, which progresses much slower than other murine models, may not be influenced by fibrillar amyloid mediated activation of the classical complement pathway, suggesting that the alternative complement pathway activation or a C3-independent cleavage of C5 could account for the detrimental effects in these mice that are prevented by the C5a receptor antagonist. Furthermore, the paucity of complement activation may be a factor in the slower kinetics of progression of pathology in the 3xTg model of this disease. PMID- 21235807 TI - Immunofluorescence analysis of duck plague virus gE protein on DPV-infected ducks. AB - BACKGROUND: In previous studies, the expression and localization characteristics of duck plague virus (DPV) gE protein have been described in cultured cells, but the properties of DPV gE protein have not been reported in vivo. Immunofluorescence analysis had been used for the detection of virus antigen, but there was no report on the use of this technique for the detection of DPV gE. In this study, we investigated the distribution of DPV gE protein on DPV-infected ducks using polyclonal antibody raised against the recombinant His-gE fusion protein by indirect immunofluorescence assay (IFA). RESULTS: The recombinant gE protein was highly immunogenicity by ELISA, and the gE was used as an antigen for the preparation of polyclonal antibody, which could be used the first antibody for further experiment to study the distribution of DPV gE protein in DPV infected tissues by indirect immunofluorescence assay. DPV gE protein were distributed in the immune organs (thymus, bursa of fabricius (BF), Harders glands, spleen), the digestive organs (liver, duodenum, jejunum, ileum), and the other parenchymatous organs (kidney, myocardium, cerebrum, and lung) of DPV infected ducks, but the positive immunofluorescence signal was not seen in the muscle and pancreas. The lymphocytes, reticulum cells, macrophages, epithelial cells, and hepatocytes served as the principal site for the localization of DPV gE antigen. Moreover, the intensity of fluorescence increased sharply from 12 to 216 h post-infection (p.i.). CONCLUSIONS: In this work, the immunogenicity of the recombinant gE protein was analyzed by ELISA, and we presented the distribution properties of DPV gE antigen in infected ducks for the first time, which may be useful for understanding the pathogenesis of DPV. These properties of the gE protein provided the prerequisite for further functional analysis. PMID- 21235808 TI - Determinants of patient satisfaction with ophthalmic services. AB - BACKGROUND: This cross-sectional study was conducted during summer 2008 at an academic ophthalmic hospital to assess patient satisfaction with care services and examine the impact of different dimensions on overall satisfaction. FINDINGS: Clients of ophthalmic services were selected by systematic random sampling. Overall satisfaction was measured as the primary outcome using a validated patient satisfaction questionnaire (PSQ-18). Different domains were evaluated using PSQ-18 (technical quality, interpersonal manner, communication, financial aspects, time spent for patients, convenience and accessibility); an additional domain, physical setting of the hospital, was evaluated by complementary questions. A general linear model was used to assess the adjusted impact of each quality dimension on the overall satisfaction. Accessibility and technical quality had the strongest association with the overall satisfaction. This regression model could predict an overall satisfaction of 60%. CONCLUSIONS: In comparable settings, if care providers wish to improve the quality of health services from a patients' perspective, they should give priority to improving accessibility and technical quality. Further studies are recommended to discover complementary predictors in formation of overall satisfaction. PREVIOUS PUBLICATION: Some parts of this article are translated form Farsi originally published in Bina Journal of Ophthalmology. (2009; 14 (3): 289-297). The original work is at: http://binajournal.org/index.php/bina/article/view/96. PMID- 21235810 TI - Navigation of total knee arthroplasty: rotation of components and clinical results in a prospectively randomized study. AB - BACKGROUND: Navigation was introduced into total knee arthroplasty (TKA) to improve accuracy of component position, function and survival of implants. This study was designed to assess the outcome of navigated TKA in comparison with conventional implantation with the focus on rotational component position and clinical mid-term results. METHODS: In a prospectively randomized single-blinded approach, 90 patients with primary gonarthrosis were assigned to three different groups. Thirty patients each were assigned to NexGen LPS without and with navigation (groups 1 and 2), and 30 patients to navigation with the Stryker Scorpio PS (group 3). The navigation system used was the imageless Stryker KneeTrac, version 1.0. Clinical outcome was assessed by a blinded observer applying the Knee Society Score (KSS) and a visual analogue scale (VAS) for pain. CT scans and radiographs were conducted prior to and 12 weeks after index surgery. RESULTS: Seventy-nine patients were available for clinical evaluation at 3 +/- 0.4 years follow-up. Four implants had to be revised for early loosening or infection (4.4%). Four patients had died and three patients were not able to follow the invitation for clinical assessment. Functional results in the KSS were significantly lower after navigated TKA. Operation time and incisions with navigation were significantly longer. Significantly less radiological outliers with navigation were found for coronal alignment of the femur, only. CONCLUSION: In this series, no beneficial effect for navigation in TKA could be shown assessing clinical data, as functional results in the presented series seemed to be lower after first generation navigated TKA. The clinical mid- to long-term value of navigation remains to be evaluated in larger patient series or meta analyses at longer follow-up. TRIAL REGISTRATION NUMBER: DRKS 00000430. PMID- 21235809 TI - Enhanced glutamate, IP3 and cAMP activity in the cerebral cortex of unilateral 6 hydroxydopamine induced Parkinson's rats: effect of 5-HT, GABA and bone marrow cell supplementation. AB - Parkinson's disease is characterized by progressive cell death in the substantia nigra pars compacta, which leads to dopamine depletion in the striatum and indirectly to cortical dysfunction. Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of Parkinson's disease and glutamate receptor mediated excitotoxicity has been suggested to be one of the possible causes of the neuronal degeneration. In the present study, the effects of serotonin, gamma-aminobutyric acid and bone marrow cells infused intranigrally to substantia nigra individually and in combination on unilateral 6 hydroxydopamine induced Parkinson's rat model was analyzed. Scatchard analysis of total glutamate and NMDA receptor binding parameters showed a significant increase in Bmax (P < 0.001) in the cerebral cortex of 6-hydroxydopamine infused rat compared to control. Real Time PCR amplification of NMDA2B, mGluR5, bax, and ubiquitin carboxy-terminal hydrolase were up regulated in cerebral cortex of 6 hydroxydopamine infused rats compared to control. Gene expression studies of GLAST, alpha-Synuclien and Cyclic AMP response element-binding protein showed a significant (P < 0.001) down regulation in 6-OHDA infused rats compared to control. Behavioural studies were carried out to confirm the biochemical and molecular studies. Serotonin and GABA along with bone marrow cells in combination showed reversal of glutamate receptors and behaviour abnormality shown in the Parkinson's rat model. The therapeutic significance in Parkinson's disease is of prominence. PMID- 21235811 TI - Neurosyphilis manifesting with unilateral visual loss and hyponatremia: a case report. AB - BACKGROUND: Syphilis is called the chameleon of the diseases due to its variety of its clinical presentations, potentially affecting every organ of the body. Incidence of this ancient disease is once again on the increase worldwide. CASE PRESENTATION: We here report an unusual case of neurosyphilis manifesting with unilateral visual loss and hyponatremia. The patient also had primary syphilitic lesions and was concomitantly diagnosed with Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection. Treatment with ceftriaxone and prednisolone, completely resolved the hyponatremia and visual acuity was partially restored. CONCLUSION: Awareness of syphilis as a differential diagnosis is important as previously unreported presentations of neurosyphilis can arise, especially in HIV infected patients. PMID- 21235812 TI - Amorphous nanosilica induce endocytosis-dependent ROS generation and DNA damage in human keratinocytes. AB - BACKGROUND: Clarifying the physicochemical properties of nanomaterials is crucial for hazard assessment and the safe application of these substances. With this in mind, we analyzed the relationship between particle size and the in vitro effect of amorphous nanosilica (nSP). Specifically, we evaluated the relationship between particle size of nSP and the in vitro biological effects using human keratinocyte cells (HaCaT). RESULTS: Our results indicate that exposure to nSP of 70 nm diameter (nSP70) induced an elevated level of reactive oxygen species (ROS), leading to DNA damage. A markedly reduced response was observed using submicron-sized silica particles of 300 and 1000 nm diameter. In addition, cytochalasin D-treatment reduced nSP70-mediated ROS generation and DNA damage, suggesting that endocytosis is involved in nSP70-mediated cellular effects. CONCLUSIONS: Thus, particle size affects amorphous silica-induced ROS generation and DNA damage of HaCaT cells. We believe clarification of the endocytosis pathway of nSP will provide useful information for hazard assessment as well as the design of safer forms of nSPs. PMID- 21235813 TI - An overview of treatment response rates to various anti-viral drugs in Pakistani hepatitis B virus infected patients. AB - Hepatitis B virus (HBV) is one of the leading health problem with up to 350 million affected people worldwide including 4.5 million only in Pakistan. It has mortality rate of 0.5 to 1.2 million per year worldwide. Pakistan lies in the endemic region with 3-5% HBV carrier rate in the country. The present article reviews the literature on the treatment response of HBV prevalent in Pakistani population. The average treatment response of Lamivudine and interferon-alpha is 25.81% and 47.95%, respectively. Peg-Interferon was shown to be not effective against the HBV/HCV (hepatitis C virus)/HDV (hepatitis Delta virus) co-infection. The present study reveals that interferon-alpha is the most effective therapy available for HBV infection prevalent in Pakistani population. Genotype C & D are the most common HBV genotypes in Pakistan and are associated with increased severity and less response to interferon therapy. This poses a great challenge for physicians and researchers and further studies are needed to describe the outcome of the current therapies recommended against HBV infection in Pakistani population. PMID- 21235814 TI - Knowledge and practice of traditional healers in oral health in the Bui Division, Cameroon. AB - BACKGROUND: The majority of Cameroonians depend on traditional medicines for their health care needs and about seven per cent of the average household health budget is spent on traditional medicines irrespective of their incomes. The aim of the present study was to determine the oral care knowledge and practices of Traditional Healers (TH) on oral health delivery in the urban and rural areas of Bui Division of Cameroon and the objectives to determine the cost of treatment and reasons why people visit TH. METHODS: The present study was cross sectional and utilized semi-structured questionnaires to collect data. RESULTS: The sample consisted of 21 TH and 52 clients of TH. Sixty two percent of the TH's were above 40 years and 90% male. The mean age was 46 years (range 20-77 years). Twenty four percent of the TH practiced as herbalists and the remainder both divination and herbalism. Sixty seven percent of people in the Bui Division, who patronize TH for their oral health needs, fall within the 20-40 year age group. There is little collaboration between the oral health workers and TH and only 6% of all patients seen by TH are referred to the dentist. Socio-cultural and economic factors affect the oral health care seeking behavior of patients in this area and only 6.5% of patients visit dental clinics. Reasons for not attending dental clinics included high cost, poor accessibility, superstition and fear. TH's are not experienced in the treatment of pulpitis - the majority of patients who presented with toothache had temporary or no relief, but despite this 67% reported being satisfied with their treatment. Sixty nine percent of the patients visited TH because of low cost - the average cost of treatment with TH (approximately $5) is very low, as compared to conventional treatment ($50). CONCLUSIONS: Traditional healers are willing to co-operate with oral health workers in improving oral health. Since they have a vital role to play in health care seeking attitudes in this community and barriers affecting the oral health seeking behaviours should be removed. Mutual cooperation, collaboration and by integrating TH into primary oral health care services needs to be increased. PMID- 21235815 TI - The use of caspase inhibitors in pulsed-field gel electrophoresis may improve the estimation of radiation-induced DNA repair and apoptosis. AB - BACKGROUND: Radiation-induced DNA double-strand break (DSB) repair can be tested by using pulsed-field gel electrophoresis (PFGE) in agarose-encapsulated cells. However, previous studies have reported that this assay is impaired by the spontaneous DNA breakage in this medium. We investigated the mechanisms of this fragmentation with the principal aim of eliminating it in order to improve the estimation of radiation-induced DNA repair. METHODS: Samples from cancer cell cultures or xenografted tumours were encapsulated in agarose plugs. The cell plugs were then irradiated, incubated to allow them to repair, and evaluated by PFGE, caspase-3, and histone H2AX activation (gammaH2AX). In addition, apoptosis inhibition was evaluated through chemical caspase inhibitors. RESULTS: We confirmed that spontaneous DNA fragmentation was associated with the process of encapsulation, regardless of whether cells were irradiated or not. This DNA fragmentation was also correlated to apoptosis activation in a fraction of the cells encapsulated in agarose, while non-apoptotic cell fraction could rejoin DNA fragments as was measured by gammaH2AX decrease and PFGE data. We were able to eliminate interference of apoptosis by applying specific caspase inhibitors, and improve the estimation of DNA repair, and apoptosis itself. CONCLUSIONS: The estimation of radiation-induced DNA repair by PFGE may be improved by the use of apoptosis inhibitors. The ability to simultaneously determine DNA repair and apoptosis, which are involved in cell fate, provides new insights for using the PFGE methodology as functional assay. PMID- 21235817 TI - Activation of the Hedgehog pathway in chronic myelogeneous leukemia patients. AB - BACKGROUND: Hedgehog (Hh) signaling pathway is involved in regulation of many tissues development and oncogenesis. Recently, Hh signaling has been identified as a required functional pathway for leukemia stem cells(LSCs), and loss of this pathway impairs leukemia progression. OBJECTIVES: The aim of this study was to determine the expression of Hedgehog signaling molecules in Chronic Myelogeneous Leukemia (CML) patients and normal people by semiquantitative polymerase chain reaction (PCR) and to correlate mRNA expression to patients' clinical data. RESULTS: Here, we showed that Sonic hedgehog (Shh), Smoothened (Smo), and Gli1 genes of Hh signaling were significantly upregulated in CML patients when compared with normal people (P < 0.001). The levels of Shh, Smo mRNA in chronic phase of CML patients were obviously lower than that in blast crisis (p < 0.05). There were no significant differences of Shh, Ptch1, Smo, Gli1 mRNA expression found when comparing CML patients of chronic phase(CP) with imatinib(IM) treated or not(p > 0.05). CONCLUSIONS: These findings suggested that activation of the Hh pathway maybe associated with CML progression. Treatment of CML with imatinib, a selective inhibitor of the BCR-ABL tyrosine kinase inhibitor, has no significant influence on the inhibition of Hh pathway of CML-CP patients. PMID- 21235816 TI - The intersection between sex and drugs: a cross-sectional study among the spouses of injection drug users in Chennai, India. AB - BACKGROUND: It is estimated that there are up to 1.1 million injection drug users (IDUs) in India; the majority are likely married. We characterize HIV, hepatitis B (HBV) and hepatitis C (HCV) prevalence and the risk environment of a sample of spouses of IDUs. METHODS: A cohort of 1158 IDUs (99% male) was recruited in Chennai, India from 2005-06. A convenience sample of 400 spouses of the male IDUs in this cohort was recruited in 2009. A risk assessment questionnaire was administered and a blood sample collected. Logistic regression was used to identify factors associated with prevalent HIV. RESULTS: Median age was 31 years; thirteen percent were widowed and 7% were not currently living with their spouse. Only 4 (1%) reported ever injecting drugs; Twenty-two percent and 25% reported ever using non-injection drugs and alcohol, respectively. The majority had one lifetime sexual partner and 37 (9%) reporting exchanging sex. Only 7% always used condoms with their regular partner. HIV, HBV and HCV prevalence were 2.5%, 3.8% and 0.5%, respectively; among spouses of HIV+ IDUs (n = 78), HIV prevalence was 10.3%. The strongest predictor of HIV was spousal HIV status (OR: 17.9; p < 0.001). Fifty-six percent of women had ever experienced intimate partner violence; Eight-six percent reported sexual violence. CONCLUSIONS: Our finding of a 10-fold higher HIV prevalence among spouses of IDUs compared with general population women indicates their vulnerability; prevalence is likely to increase given the context of low condom use and frequent sexual violence. Prevention efforts directed at IDUs should also include programs for spouses. PMID- 21235818 TI - Comparison between the disease-specific Airways Questionnaire 20 and the generic 15D instruments in COPD. AB - BACKGROUND: Given that the assessment of health-related quality of life (HRQoL) is an essential outcome measure to optimize chronic obstructive pulmonary disease (COPD) patient management, there is a need for a short and fast, reliable and valid instrument for routine use in clinical practice. The objective of this study was to analyse the relationship between the disease-specific Airways questionnaire (AQ20) and the generic 15D health-related quality of life (HRQoL) instrument simultaneously in a large cohort of patients with COPD. We also compare the HRQoL of COPD patients with that of the general population. METHODS: The AQ20 and 15D were administered to 739 COPD patients representing an unselected hospital-based COPD population. The completion rates and validity of, and correlations among the questions and dimension scores were examined. A factor analysis with varimax rotation was performed in order to find subsets of highly correlating items of the questionnaires. RESULTS: The summary scores of AQ20 and 15D were highly correlated (r = - 0.71, p < 0.01). In AQ20 over 50% of patients reported frequent cough, breathlessness during domestic work, and chest problem limiting their full enjoyment of life. 15D results showed a noteworthy decrease of HRQoL in breathing, mobility, sleeping, usual activities, discomfort and symptoms, vitality, and sexual activity (scores <= 0.75). Compared to the age- and gender-standardized Finnish general population, the COPD patients were statistically significantly worse off on 13 of 15 dimensions. CONCLUSIONS: The AQ20 and 15D summary scores are comparable in terms of measuring HRQoL in COPD patients. The data support the validity of 15D to measure the quality of life in COPD. COPD compromises the HRQoL broadly, as reflected by the generic instrument. Both questionnaires are simple and short, and could easily be used in clinical practice with high completion rates. PMID- 21235819 TI - Recruitment of representative samples for low incidence cancer populations: do registries deliver? AB - BACKGROUND: Recruiting large and representative samples of adolescent and young adult (AYA) cancer survivors is important for gaining accurate data regarding the prevalence of unmet needs in this population. This study aimed to describe recruitment rates for AYAs recruited through a cancer registry with particular focus on: active clinician consent protocols, reasons for clinicians not providing consent and the representativeness of the final sample. METHODS: Adolescents and young adults aged 14 to 19 years inclusive and listed on the cancer registry from January 1 2002 to December 31 2007 were identified. An active clinician consent protocol was used whereby the registry sent a letter to AYAs primary treating clinicians requesting permission to contact the survivors. The registry then sent survivors who received their clinician's consent a letter seeking permission to forward their contact details to the research team. Consenting AYAs were sent a questionnaire which assessed their unmet needs. RESULTS: The overall consent rate for AYAs identified as eligible by the registry was 7.8%. Of the 411 potentially eligible survivors identified, just over half (n = 232, 56%) received their clinician's consent to be contacted. Of those 232 AYAs, 65% were unable to be contacted. Only 18 AYAs (7.8%) refused permission for their contact details to be passed on to the research team. Of the 64 young people who agreed to be contacted, 50% (n = 32) completed the questionnaire. CONCLUSIONS: Cancer registries which employ active clinician consent protocols may not be appropriate for recruiting large, representative samples of AYAs diagnosed with cancer. Given that AYA cancer survivors are highly mobile, alternative methods such as treatment centre and clinic based recruitment may need to be considered. PMID- 21235820 TI - Meat consumption and risk of primary hip and knee joint replacement due to osteoarthritis: a prospective cohort study. AB - BACKGROUND: There is emerging evidence for a beneficial effect of meat consumption on the musculoskeletal system. However, whether it affects the risk of knee and hip osteoarthritis is unknown. We performed a prospective cohort study to examine the relationship between meat consumption and risk of primary hip and knee replacement for osteoarthritis. METHODS: Eligible 35,331 participants were selected from the Melbourne Collaborative Cohort Study recruited during 1990-1994. Consumption of fresh red meat, processed meat, chicken, and fish was assessed using a food frequency questionnaire. Primary hip and knee replacement for osteoarthritis during 2001-2005 was determined by linking the cohort records to the Australian National Joint Replacement Registry. RESULTS: There was a negative dose-response relationship between fresh red meat consumption and the risk of hip replacement (hazard ratio (HR) 0.94 per increase in intake of one time/week, 95% confidence interval (CI) 0.89-0.98). In contrast, there was no association with knee replacement risk (HR 0.98, 95% CI 0.94-1.02). Consumption of processed meat, chicken and fish were not associated with risk of hip or knee replacement. CONCLUSION: A high level consumption of fresh red meat was associated with a decreased risk of hip, but not knee, joint replacement for osteoarthritis. One possible mechanism to explain these differential associations may be via an effect of meat intake on bone strength and hip shape. Further confirmatory studies are warranted. PMID- 21235821 TI - Early intensive hand rehabilitation after spinal cord injury ("Hands On"): a protocol for a randomised controlled trial. AB - BACKGROUND: Loss of hand function is one of the most devastating consequences of spinal cord injury. Intensive hand training provided on an instrumented exercise workstation in conjunction with functional electrical stimulation may enhance neural recovery and hand function. The aim of this trial is to compare usual care with an 8-week program of intensive hand training and functional electrical stimulation. METHODS/DESIGN: A multicentre randomised controlled trial will be undertaken. Seventy-eight participants with recent tetraplegia (C2 to T1 motor complete or incomplete) undergoing inpatient rehabilitation will be recruited from seven spinal cord injury units in Australia and New Zealand and will be randomised to a control or experimental group. Control participants will receive usual care. Experimental participants will receive usual care and an 8-week program of intensive unilateral hand training using an instrumented exercise workstation and functional electrical stimulation. Participants will drive the functional electrical stimulation of their target hands via a behind-the-ear bluetooth device, which is sensitive to tooth clicks. The bluetooth device will enable the use of various manipulanda to practice functional activities embedded within computer-based games and activities. Training will be provided for one hour, 5 days per week, during the 8-week intervention period. The primary outcome is the Action Research Arm Test. Secondary outcomes include measurements of strength, sensation, function, quality of life and cost effectiveness. All outcomes will be taken at baseline, 8 weeks, 6 months and 12 months by assessors blinded to group allocation. Recruitment commenced in December 2009. DISCUSSION: The results of this trial will determine the effectiveness of an 8-week program of intensive hand training with functional electrical stimulation. TRIAL REGISTRATION: NCT01086930 (12th March 2010)ACTRN12609000695202 (12th August 2009). PMID- 21235822 TI - NeOProM: Neonatal Oxygenation Prospective Meta-analysis Collaboration study protocol. AB - BACKGROUND: The appropriate level of oxygenation for extremely preterm neonates (<28 weeks' gestation) to maximise the greatest chance of survival, without incurring significant morbidity, remains unknown. Infants exposed to lower levels of oxygen (targeting oxygen saturations of <90%) in the first weeks of life are at increased risk of death, cerebral palsy, patent ductus arteriosus, pulmonary vascular resistance and apnoea, whilst those maintained in higher levels of oxygen (targeting oxygen saturations of >90%) have been reported to have greater rates of morbidity including retinopathy of prematurity and chronic lung disease. In order to answer this clinical dilemma reliably, large scale trial evidence is needed. METHODS/DESIGN: To detect a small but important 4% increase in death or severe disability in survivors, over 5000 neonates would need to be recruited. As extreme prematurity affects 1% of births, such a project undertaken by one trial group would be prohibitively lengthy and expensive. Hence, the Neonatal Oxygenation Prospective Meta-analysis (NeOProM) Collaboration has been formed. A prospective meta-analysis (PMA) is one where studies are identified, evaluated, and determined to be eligible before the results of any included studies are known or published, thereby avoiding some of the potential biases inherent in standard, retrospective meta-analyses. This methodology provides the same strengths as a single large-scale multicentre randomised study whilst allowing greater pragmatic flexibility. The NeOProM Collaboration protocol (NCT01124331) has been agreed prior to the results of individual trials being available. This includes pre-specifying the hypotheses, inclusion criteria and outcome measures to be used. Each trial will first publish their respective results as they become available and the combined meta-analytic results, using individual patient data, will be published when all trials are complete. The primary outcome to be assessed is a composite outcome of death or major disability at 18 months - 2 years corrected age. Secondary outcomes include several measures of neonatal morbidity. The size of the combined dataset will allow the effect of the interventions to be explored more reliably with respect to pre-specified patient- and intervention-level characteristics. DISCUSSION: Results should be available by 2014. PMID- 21235823 TI - Adenovirus-mediated sphingomyelin synthase 2 increases atherosclerotic lesions in ApoE KO mice. AB - BACKGROUND: Sphingomyelin synthase 2 (SMS2) contributes to de novo sphingomyelin (SM) biosynthesis. Its activity is related to SM levels in the plasma and the cell membrane. In this study, we investigated the possibility of a direct relationship between SMS and atherosclerosis. METHODS: The Adenovirus containing SMS2 gene was given into 10-week ApoE KO C57BL/6J mice by femoral intravenous injection. In the control group, the Adenovirus containing GFP was given. To confirm this model, we took both mRNA level examination (RT-PCR) and protein level examination (SMS activity assay). RESULT: We generated recombinant adenovirus vectors containing either human SMS2 cDNA (AdV-SMS2) or GFP cDNA (AdV GFP). On day six after intravenous infusion of 2 * 10(11) particle numbers into ten-week-old apoE KO mice, AdV-SMS2 treatment significantly increased liver SMS2 mRNA levels and SMS activity (by 2.7-fold, 2.3-fold, p < 0.001, respectively), compared to AdV-GFP treated mice. Moreover, plasma total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), and sphingomyelin (SM) levels were significantly increased by 39% (p < 0.05), 42% (p < 0.05), 68% (p < 0.001), and 45% (p < 0.05), respectively. Plasma high-density lipoprotein cholesterol (HDL-C), phosphatidylcholine (PC), and PC/SM ratio were decreased by 42% (p < 0.05), 18% (p < 0.05), and 45% (p < 0.05), respectively. On day 30, the atherosclerotic lesions on the aortic arch of AdV-SMS2 treated mice were increased, and the lesion areas on the whole aorta and in the aortic root were significantly increased (p < 0.001). Furthermore, the collagen content in the aorta root was significantly decreased (p < 0.01). CONCLUSIONS: Our results present direct morphological evidence for the pro-atherogenic capabilities of SMS2. SMS2 could be a potential target for treating atherosclerosis. PMID- 21235824 TI - Immunoregulatory effects of AFP domains on monocyte-derived dendritic cell function. AB - BACKGROUND: Alpha-fetoprotein (AFP) is a tumor-associated glycoprotein that functions in regulation of both ontogenic and oncogenic growth. Recent study showed that AFP can induce apoptosis or impair monocyte-derived dendritic cell (MDDC) function. However, it is still unclear which AFP domain (D-AFP) plays major role in this function. RESULTS: As expected monocytes cultured in the presence of Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF) and Interleukin-4 (IL-4) developed into MDDC. Up-regulation of HLA-DR and CD11c as well as loss of CD14 molecules could be observed. Full length AFP (FL-AFP), domain 2 AFP (D2-AFP) and D3-AFP, but not D1-AFP, significantly inhibited the expression of HLA-DR high/CD11c high and CD80+/CD86 high molecules. In contrast, CD83 expression was substantially down-regulated in all samples. Expression of CD40 was significantly suppressed by FL-AFP but not by any D-AFPs. Finally, both FL-AFP and D-AFP impaired the MDDC ability to secrete IL-12 (p70). CONCLUSIONS: D2- and D3- but not D1-AFP extensively suppresses the MDDC function. All the recombinant AFP proteins impaired the ability of MDDC to secrete IL-12. PMID- 21235825 TI - Prevention of type 2 diabetes in a primary healthcare setting: three-year results of lifestyle intervention in Japanese subjects with impaired glucose tolerance. AB - BACKGROUND: A randomized control trial was performed to test whether a lifestyle intervention program, carried out in a primary healthcare setting using existing resources, can reduce the incidence of type 2 diabetes in Japanese with impaired glucose tolerance (IGT). The results of 3 years' intervention are summarized. METHODS: Through health checkups in communities and workplaces, 304 middle-aged IGT subjects with a mean body mass index (BMI) of 24.5 kg/m2 were recruited and randomized to the intervention group or control group. The lifestyle intervention was carried out for 3 years by public health nurses using the curriculum and educational materials provided by the study group. RESULTS: After 1 year, the intervention had significantly improved body weight (-1.5 +/- 0.7 vs. -0.7 +/- 2.5 kg in the control; p = 0.023) and daily non-exercise leisure time energy expenditure (25 +/- 113 vs. -3 +/- 98 kcal; p = 0.045). Insulin sensitivity assessed by the Matsuda index was improved by the intervention during the 3 years. The 3-year cumulative incidence tended to be lower in the intervention group (14.8% vs.8.2%, log-rank test: p = 0.097). In a sub-analysis for the subjects with a BMI > 22.5 kg/m2, a significant reduction in the cumulative incidence was found (p = 0.027). CONCLUSIONS: The present lifestyle intervention program using existing healthcare resources is beneficial in preventing diabetes in Japanese with IGT. This has important implications for primary healthcare based diabetes prevention. TRIAL REGISTRATION NUMBER: UMIN000003136. PMID- 21235826 TI - Area-aggregated assessments of perceived environmental attributes may overcome single-source bias in studies of green environments and health: results from a cross-sectional survey in southern Sweden. AB - BACKGROUND: Most studies assessing health effects of neighborhood characteristics either use self-reports or objective assessments of the environment, the latter often based on Geographical Information Systems (GIS). While objective measures require detailed landscape data, self-assessments may yield confounded results. In this study we demonstrate how self-assessments of green neighborhood environments aggregated to narrow area units may serve as an appealing compromise between objective measures and individual self-assessments. METHODS: The study uses cross-sectional data (N = 24,847) from a public health survey conducted in the county of Scania, southern Sweden, in 2008 and validates the Scania Green Score (SGS), a new index comprising five self-reported green neighborhood qualities (Culture, Lush, Serene, Spacious and Wild). The same qualities were also assessed objectively using landscape data and GIS. A multilevel (ecometric) model was used to aggregate individual self-reports to assessments of perceived green environmental attributes for areas of 1,000 square meters. We assessed convergent and concurrent validity for self-assessments of the five items separately and for the sum score, individually and area-aggregated. RESULTS: Correlations between the index scores based on self-assessments and the corresponding objective assessments were clearly present, indicating convergent validity, but the agreement was low. The correlation was even more evident for the area-aggregated SGS. All three scores (individual SGS, area-aggregated SGS and GIS index score) were associated with neighborhood satisfaction, indicating concurrent validity. However, while individual SGS was associated with vitality, this association was not present for aggregated SGS and the GIS-index score, suggesting confounding (single-source bias) when individual SGS was used. CONCLUSIONS: Perceived and objectively assessed qualities of the green neighborhood environment correlate but do not agree. An index score based on self reports but aggregated to narrow area units can be a valid approach to assess perceived green neighborhood qualities in settings where objective assessments are not possible or feasible. PMID- 21235828 TI - How soon to start: aspirin resumption after upper gastrointestinal bleed? PMID- 21235827 TI - Kitasato Symposium 2010: new prospects for cytokines. AB - The Second Kitasato Symposium: New Prospects for Cytokines brought together researchers and rheumatologists to consider the essential role of cytokines in health and their contributions to autoimmunity. Topics addressed during the Symposium - which was held in Berlin, Germany from 27 to 29 May 2010 - included established and new cytokine targets in arthritis and autoimmunity and innovative aspects of osteoimmunology as well as current perspectives from translational and clinical studies. The keynote lecture, delivered by George Kollias, focused on insights gained from animal models into the mechanisms of TNF function in chronic inflammation and autoimmunity. The presentations at the Symposium resulted in productive discussions regarding potential new targets for the treatment of rheumatoid arthritis and other autoimmune disorders. PMID- 21235829 TI - Clinical review: idiopathic pulmonary fibrosis acute exacerbations--unravelling Ariadne's thread. AB - Idiopathic pulmonary fibrosis (IPF) is a dreadful, chronic, and irreversibly progressive fibrosing disease leading to death in all patients affected, and IPF acute exacerbations constitute the most devastating complication during its clinical course. IPF exacerbations are subacute/acute, clinically significant deteriorations of unidentifiable cause that usually transform the slow and more or less steady disease decline to the unexpected appearance of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) ending in death. The histological picture is that of diffuse alveolar damage (DAD), which is the tissue counterpart of ARDS, upon usual interstitial pneumonia, which is the tissue equivalent of IPF. ALI/ARDS and acute interstitial pneumonia share with IPF exacerbations the tissue damage pattern of DAD. 'Treatment' with high-dose corticosteroids with or without an immunosuppressant proved ineffective and represents the coup de grace for these patients. Provision of excellent supportive care and the search for and treatment of the 'underlying cause' remain the only options. IPF exacerbations require rapid decisions about when and whether to initiate mechanical support. Admission to an intensive care unit (ICU) is a particular clinical and ethical challenge because of the extremely poor outcome. Transplantation in the ICU setting often presents insurmountable difficulties. PMID- 21235830 TI - Minimising drug errors in critically ill patients. PMID- 21235831 TI - Silencing signals in plants: a long journey for small RNAs. AB - Recent research shows that short RNA molecules act as mobile signals that direct mRNA cleavage and DNA methylation in recipient cells. PMID- 21235834 TI - Patient-ventilator interaction. Foreword. PMID- 21235833 TI - Pressure support ventilation advisory system provides valid recommendations for setting ventilator. AB - BACKGROUND: Pressure support ventilation (PSV) should be applied so that the inspiratory muscles are unloaded appropriately. We developed a computerized advisory system that assesses the load on the inspiratory muscles to spontaneously inhale, reflected by the automatically and noninvasively measured work of breathing per minute, and tolerance for that load, reflected by spontaneous breathing frequency and tidal volume, in a fuzzy-logic algorithm that provides recommendations for setting PSV. We call this a load and tolerance strategy for determining PSV. METHODS: In a clinical validation study, we compared the recommendations from our PSV advisory system to the recommendations of experienced critical-care Registered Respiratory Therapists (RRTs) for setting PSV in patients with respiratory failure. With 76 adult patients in a university medical center surgical intensive care unit receiving PSV, a combined pressure/flow sensor, positioned between the endotracheal tube and patient Y piece, sent measurements to the PSV advisory system. We compared the advisory system's recommendations (increase, maintain, or decrease the pressure support) to the RRTs' recommendations at the bedside. RESULTS: There were no significant differences between the RRTs' and the advisory system's recommendations (n = 109) to increase, maintain, or decrease PSV. The RRTs agreed with 91% of the advisory system's recommendations (kappa statistic 0.85, P < .001). The advisory system was very good at predicting the RRTs' pressure support recommendations (r(2) = 0.87, P < .02). CONCLUSIONS: A load and tolerance strategy with a computerized PSV advisory system provided valid recommendations for setting PSV to unload the inspiratory muscles, and the recommendations were essentially the same as the recommendations from experienced critical-care RRTs. The PSV advisory system operates continuously and automatically and may be useful in clinical environments where experts are not always available. PMID- 21235835 TI - Patient-ventilator interaction: the last 40 years. AB - Patient-ventilator synchrony is a complex issue affected by ventilator performance, patient characteristics, and the patient-ventilator interface. The history of patient-ventilator interaction includes avoidance of pharmacalogic paralysis, the development of spontaneous breathing systems, microprocessor technology to maximize interaction, and closed-loop control. While most clinicians agree that patient-ventilator synchrony is desirable, there remain no cause-and-effect data that asynchrony is associated with poor outcome. PMID- 21235836 TI - How often does patient-ventilator asynchrony occur and what are the consequences? AB - Mechanical ventilation can be life-saving for patients with acute respiratory failure. In between the 2 extremes of complete and no ventilatory support, both patient and machine contribute to ventilatory work. Ideally, ventilator gas delivery would perfectly match patient demand. This patient-ventilator interaction depends on how the ventilator responds to patient respiratory effort and, in turn, how the patient responds to the breath delivered by the ventilator. It is now evident that the interaction between patient and ventilator is frequently suboptimal and that patient-ventilator asynchrony is common. Its prevalence depends on numerous factors, including timing and duration of observation, technique used for detection, patient population, type of asynchrony, ventilation mode and settings (eg, trigger, flow, and cycle criteria), and confounding factors (eg, state of wakefulness, sedation). Patient ventilator asynchrony is associated with adverse effects, including higher/wasted work of breathing, patient discomfort, increased need for sedation, confusion during the weaning process, prolonged mechanical ventilation, longer stay, and possibly higher mortality. Whether asynchrony is a marker of poor prognosis or causes these adverse outcomes remains to be determined. PMID- 21235837 TI - Triggering of the ventilator in patient-ventilator interactions. AB - With current ventilator triggering design, in initiating ventilator breaths patient effort is only a small fraction of the total effort expended to overcome the inspiratory load. Similarly, advances in ventilator pressure or flow delivery and inspiratory flow termination improve patient effort or inspiratory muscle work during mechanical ventilation. Yet refinements in ventilator design do not necessarily allow optimal patient-ventilator interactions, as the clinician is key in managing patient factors and selecting appropriate ventilator factors to maintain patient-ventilator synchrony. In patient-ventilator interactions, unmatched patient flow demand by ventilator flow delivery results in flow asynchrony, whereas mismatches between mechanical inspiratory time (mechanical T(I)) and neural T(I) produce timing asynchrony. Wasted efforts are an example of timing asynchrony. In the triggering phase, trigger thresholds that are set too high or the type of triggering methods induces wasted efforts. Wasted efforts can be aggravated by respiratory muscle weakness or other conditions that reduce respiratory drive. In the post-triggering phase, ventilator factors play an important role in patient-ventilator interaction; this role includes the assistance level, set inspiratory flow rate, T(I), pressurization rate, and cycling-off threshold, and to some extent, applied PEEP. This paper proposes an algorithm that clinicians can use to adjust ventilator settings with the goal to eliminate or reduce patients' wasted efforts. PMID- 21235838 TI - Cycling of the mechanical ventilator breath. AB - Patient-ventilator interaction is a key element in optimizing mechanical ventilation. The change from inspiration to expiration is a crucial point in the mechanically ventilated breath, and is termed "cycling." Patient-ventilator asynchrony may occur if the flow at which the ventilator cycles to exhalation does not coincide with the termination of neural inspiration. Ideally, the ventilator terminates inspiratory flow in synchrony with the patient's neural timing, but frequently the ventilator terminates inspiration either early or late. Most current mechanical ventilators include adjustable cycling features that, when used in conjunction with waveform graphics, can enhance patient ventilator synchrony. PMID- 21235839 TI - Monitoring of patient-ventilator interaction at the bedside. AB - Monitoring of patient-ventilator interactions at the bedside involves evaluation of patient breathing pattern on ventilator settings. One goal of mechanical ventilation is to have ventilator-assisted breathing coincide with patient breathing. The objectives of this goal are to have patient breath initiation result in ventilator triggering without undue patient effort, to match assisted breath delivery with patient inspiratory effort, and to have assisted breathing cease when the patient terminates inspiration, thus avoiding ventilator-assisted inspiration during patient exhalation. Asynchrony can occur throughout the respiratory cycle, and this paper describes common asynchronies. The types of asynchronies discussed are trigger asynchrony (ie, breath initiation that may manifest as ineffective triggering, double-triggering, or auto-triggering); flow asynchrony (ie, breath-delivery asynchrony, which may manifest as assisted-breath delivery being faster or slower than what patient desires); and cycling asynchronies (ie, termination of assisted inspiration does not coincide with patient breath termination, which may manifest as delayed cycling or premature cycling). Various waveforms are displayed and graphically demonstrate asynchronies; basic principles of waveform interpretation are discussed. PMID- 21235840 TI - Patient-ventilator interactions: optimizing conventional ventilation modes. AB - Assisted (interactive) breathing is generally preferred to controlled breaths in patients on mechanical ventilators. Assisted breaths allow the patient's respiratory muscles to be used, and ventilatory muscle atrophy can be prevented. Moreover, the respiratory drive of the patient does not have to be aggressively blunted. However, interactive breaths need to be synchronized with the patient's efforts during the trigger, the flow delivery, and the cycling phases. Asynchrony during any of these can put an intolerable load on the respiratory muscles, leading to fatigue and the need for a high level of sedation or even paralysis. Current ventilation modes have a number of features that can monitor and enhance synchrony, including adjustment of the trigger variable, the use of pressure targeted versus fixed-flow-targeted breaths, and manipulations of the cycle variable. Clinicians need to know how to use these ventilation mode and monitor them properly, especially understanding the airway pressure and flow graphics. The clinical challenge is synchronizing ventilator gas delivery with patient effort. PMID- 21235841 TI - Closed-loop control of mechanical ventilation: description and classification of targeting schemes. AB - There has been a dramatic increase in the number and complexity of new ventilation modes over the last 30 years. The impetus for this has been the desire to improve the safety, efficiency, and synchrony of ventilator-patient interaction. Unfortunately, the proliferation of names for ventilation modes has made understanding mode capabilities problematic. New modes are generally based on increasingly sophisticated closed-loop control systems or targeting schemes. We describe the 6 basic targeting schemes used in commercially available ventilators today: set-point, dual, servo, adaptive, optimal, and intelligent. These control systems are designed to serve the 3 primary goals of mechanical ventilation: safety, comfort, and liberation. The basic operations of these schemes may be understood by clinicians without any engineering background, and they provide the basis for understanding the wide variety of ventilation modes and their relative advantages for improving patient-ventilator synchrony. Conversely, their descriptions may provide engineers with a means to better communicate to end users. PMID- 21235842 TI - Use of maximum end-tidal CO(2) values to improve end-tidal CO(2) monitoring accuracy. AB - BACKGROUND: The arterial partial pressure of CO(2) (P(aCO(2))) can be grossly estimated by the end-tidal partial pressure of CO(2) (P(ETCO(2))). This principle is used in SmartCare (Drager, Lubeck, Germany), which is an automated closed-loop system that uses P(ETCO(2)) to estimate alveolar ventilation during mechanical ventilation. OBJECTIVE: To assess whether the maximum P(ETCO(2)) value (instead of the averaged P(ETCO(2)) value) over 2-min or 5-min periods improves P(aCO(2)) estimation, and determine the consequences for the SmartCare system. METHODS: We continuously monitored breath-by-breath P(ETCO(2)) during ventilation with SmartCare in 36 patients mechanically ventilated for various disorders, including 14 patients with COPD. Data were collected simultaneously from SmartCare recordings, every 2 min or 5 min, and through a dedicated software that recorded ventilation data every 10 s. We compared the maximum and averaged P(ETCO(2)) values over 2-min and 5-min periods to the P(aCO(2)) measured from 80 arterial blood samples clinically indicated in 26 patients. We also compared SmartCare's classifications of patient ventilatory status based on averaged P(ETCO(2)) values to what the classifications would have been with the maximum P(ETCO(2)) values. RESULTS: Mean P(aCO(2)) was 44 +/- 11 mm Hg. P(aCO(2)) was higher than averaged P(ETCO(2)) by 10 +/- 6 mm Hg, and this difference was reduced to 6 +/- 6 mm Hg with maximum P(ETCO(2)). The results were similar whether patients had COPD or not. Very few aberrant values (< 0.01%) needed to be discarded. Among the 3,137 classifications made by the SmartCare system, 1.6% were changed by using the maximum P(ETCO(2)) value instead of the averaged P(ETCO(2)) value. CONCLUSIONS: Use of maximum P(ETCO(2)) reduces the difference between P(aCO(2)) and P(ETCO(2)) and improves SmartCare's classification of patient ventilatory status. PMID- 21235843 TI - Testing of nebulizers for delivering magnesium sulfate to pediatric asthma patients in the emergency department. AB - BACKGROUND: As the use of intravenous magnesium sulfate (MgSO(4)) for the treatment of refractory asthma is becoming more common, the incidence of MgSO(4) related systemic hypotension is also rising. One option is to deliver MgSO(4) via aerosol, but compared to most inhaled medications, which are active in the microgram dose range, the MgSO(4) dose requirement is in the milligram range. This, along with inefficient aerosol delivery systems, may be the reason that some studies have found lack of efficacy with aerosol MgSO(4). In preparation for a multicenter study of inhaled MgSO(4) in asthmatic children 2-17 years old, we conducted an in vitro study to choose the best MgSO(4) nebulizer system that would be effective over the entire age range. METHODS: We tested the Pari LC Star jet nebulizer, Omron MicroAir vibrating-mesh nebulizer, and the Aeroneb Go vibrating-mesh nebulizer with the Idehaler valve-less holding chamber. Aerosol delivery was via face mask. RESULTS: The Pari LC Star had an appropriate particle size distribution but a very slow aerosol output rate. The Omron MicroAir had an even slower output rate and a larger particle size distribution, which would be inappropriate for smaller children. In vitro lung deposition with the Aeroneb Go with Idehaler was 16.0 +/- 0.4 mg/min in older children and approximately a fifth of that in toddlers. CONCLUSIONS: The Aeroneb Go with Idehaler was chosen for the multicenter clinical study. PMID- 21235844 TI - Functional recovery following physical training in tracheotomized and chronically ventilated patients. AB - BACKGROUND: Rehabilitation is a non-pharmacologic therapy that can restore health and reverse the patient's disability, but the efficacy of rehabilitation in critically ill patients is not well documented. METHODS: In a prospective cohort study, we assessed whether the degree of change in functional status after comprehensive rehabilitation influenced clinical outcomes in 77 tracheotomized patients (mean +/- SD age 75 +/- 7 y) admitted for difficult weaning to our regional weaning center. The care plan, including peripheral muscle training, was delivered daily. We recorded admission demographic, anthropometric, and functional characteristics. We measured the change in basic activities of daily living score (DeltaBADL), survival, and weaning success rate as clinical outcomes. We performed the Pearson correlation analysis and linear regression, with DeltaBADL as the dependent variable, to test the predictive power of the baseline measurements. RESULTS: Sixty-seven patients (87%) survived, and 55 of them (74%) succeeded in weaning during their stay in the weaning center. The mean +/- SD DeltaBADL improvement was 2.5 +/- 2.0 points (median 2 points). Baseline performance of the latissimus dorsi predicted DeltaBADL (beta = 0.388, 95% CI 0.111-1,664, P = .03). The probability of remaining ventilator-free (P = .043) and survival (P = .001) differed across the 4 DeltaBADL categories (0 = no change, 1-2 = least improvement, and > 2 = improvement above median change). CONCLUSIONS: Mortality rate and weaning success differ according to DeltaBADL following active rehabilitation/training in tracheotomized, ventilated, difficult to-wean patients. The performance of the latissimus dorsi was the only significant predictor of change. PMID- 21235845 TI - High-frequency oscillatory ventilation in an infant with necrotizing pneumonia and bronchopleural fistula. PMID- 21235846 TI - Impact of offering continuing respiratory care education credit hours on staff participation in a respiratory care journal club. AB - BACKGROUND: Journal clubs are employed by education and healthcare institutions to facilitate learning about study design, to teach critical reading of the literature, and to help trainees and practitioners keep abreast in their fields. Our respiratory care department initiated a journal club that was open to all respiratory therapists in the community. The articles were selected by the journal club coordinator and posted on the club's web site. However, attendance remained poor despite changes in venue, time, and day of the week. In Washington State, respiratory therapists are required to obtain continuing respiratory care education credits (CRCEs), so we hypothesized that offering American Association for Respiratory Care CRCEs for journal club attendance would increase participation. METHODS: We measured journal club attendance during the 8 months preceding and the 8 months following introduction of CRCE credit for journal club attendance. The journal club meetings were held during same time frame, on the same day of the week, and in the same geographic region during the pre-CRCE and CRCE periods. Advertising for the journal club was the same during both periods as well. RESULTS: Pre-CRCE attendance ranged from 5 to 8 persons per meeting (mean +/- SD 6 +/- 1 persons), and CRCE-period attendance ranged from 7 to 10 persons (mean +/- SD 8 +/- 1) (P = .01). CONCLUSIONS: Providing CRCE credits for attendance was associated with increased participation in our departmental journal club. PMID- 21235850 TI - Transfusion therapy in the peri-operative period. PMID- 21235851 TI - Pre-operative autologous blood donation: clinical parameters and efficacy. PMID- 21235853 TI - The use of fresh-frozen bone in oral surgery: a clinical study of 14 consecutive cases. AB - BACKGROUND: Although autologous bone is considered the gold standard among the grafting materials used in implant therapy, it does have a number of drawbacks, in particular morbidity at the site of donation and the limited amount of bone available. To overcome these limitations a number of alternative bone materials have been employed in the last few years. In this study we report the results of the use of homologous fresh-frozen bone from a tissue bank in patients undergoing reconstruction of bone defects in the oral cavity. MATERIAL AND METHODS: Between June 2004 and October 2008, 14 consecutive patients underwent bone reconstruction with fresh-frozen bone from a tissue bank. Four to eight months after surgery, implants were placed in the newly formed bone. RESULTS: No problems were recorded during the post-operative course. In all cases treatment was successful and osteointegrated implants were placed in the newly formed bone after 4-8 months. All implants showed good osteointegration (100% overall success rate, mean follow up 20 months), allowing loading with a fixed cemented prosthesis. CONCLUSIONS: Our results support the previous findings that homologous fresh-frozen bone can be considered a valid alternative to autologous bone for the reconstruction of bone defects in the oral cavity in patients undergoing implant therapy. PMID- 21235854 TI - Neonatal red blood cell transfusions: searching for better guidelines. AB - BACKGROUND: Packed red blood cell (RBC) transfusions are often administered to patients in the neonatal intensive care unit. The purpose of this study was to determine whether current blood transfusion guidelines are as useful as care givers' perception in identifying patients in need of a packed RBC transfusion. DESIGN AND METHODS: Health care providers were asked to complete a pre- and post transfusion survey on neonates receiving a packed RBC transfusion. These patients were divided into three groups based on reasons for transfusion: (i) guidelines; (ii) care-givers' perceptions of need for packed RBC transfusion; or (iii) both. These three groups were further subdivided into two cohorts according to whether they had a clinical improvement or not. Demographic data and clinical variables were compared between the groups. RESULTS: Seventy-eight care-givers were surveyed. Eighteen patients (23%) were transfused based on guidelines, 36 (46%) based on care givers' perception and 24 (31%) based on both. Neonates transfused based on guidelines alone were more likely to have received the transfusion in the first week of life, had a higher pre-transfusion haematocrit, were less symptomatic and had a higher trend to require mechanical ventilation. Neonates transfused based on caregivers' perception were more likely to be on non-invasive ventilatory support and were more symptomatic. Neonates who improved after a transfusion had a lower pre-transfusion haematocrit (p=0.02), were more symptomatic (p=0.01) and were more likely to be on non-invasive ventilatory support (p=0.002) when compared to the group without a clinical improvement. The group without improvement had an increase in oxygen requirement (+2.8+/-6.4) after the transfusion (p=0.0004). Tachycardia was the most sensitive predictor of a benefit from packed RBC transfusion [OR 6.48: p=0.005]. DISCUSSION: Guidelines on when to transfuse stable growing neonates with packed RBC should be re evaluated to include more care giver judgement and perhaps be more restrictive for critically ill neonates. PMID- 21235855 TI - Coagulation factors V, VIII, and X, prothrombin time and activated partial thromboplastin time test results in thawed plasma stored at 1-6 oC for 5 days. AB - BACKGROUND: The aim of this study was to evaluate whether thawed plasma stored for 5 days at 1-6 oC is appropriate for use. MATERIALS AND METHODS: Samples taken from thawed plasma units stored for 5 days at 1-6 oC were prepared for assays of the levels of factor V, factor VIII, and factor X, and for measurements of the activated partial thromboplastin time (aPTT) and prothrombin time (PT). The results obtained were then compared with those from other similar studies. RESULTS: The average decreases in percentages of coagulation factors from day 1 to day 5 were 20% for factor V, 11% for factor X, and 25% for total factor VIII. The changes in the range of coagulation factors over the 5-day storage period were statistically significant, but the values remained within the haemostatic range. The average increases in the levels of PT and aPTT from day 1 to day 5 were also not clinically pathological. CONCLUSIONS: Thawed fresh-frozen plasma stored for 5 days at 1-6 degrees C can be used in different cases of coagulopathy and can be used as an alternative to plasma frozen within 24 hours of phlebotomy. PMID- 21235857 TI - Cardiac mechanosensitivity and stretch-activated ion channels. AB - Mechanosensitivity is a ubiquitous property of cells, and mechanosensitive ion channels (MSCs) are hypothesized to be the transducers. In the heart, MSCs are likely to account for changes in beating rate as a function of filling and for initiating stretch-induced arrhythmias (for example, following a myocardial infarction). Pharmacological agents that affect MSCs may provide a new class of antiarrhythmic drugs. (c) 1997, Elsevier Science Inc. (Trends Cardiovasc Med 1997;7:4-8). PMID- 21235858 TI - Mechanisms of Cellular Uptake of Thrombin-Antithrombin II Complexes Role of the Low-Density Lipoprotein Receptor-Related Protein as a Serpin-Enzyme Complex Receptor. AB - Serine proteinase inhibitors (serpins) such as antithrombin III inhibit target proteinases by forming a stable complexwith the enzyme. Once formed, several serpin-enzyme complexes (SECs) are removed from the circulation by a receptor, termed the SEC receptor, that is present in the liver. Until recently, the identity of this clearance receptor remained unknown; however, data are now available that strongly implicates one member of the low-density lipoprotein (LDL) receptor family as a candidate for the SEC receptor. This receptor, known as the LDL receptor-related protein (LRP), is a prominent liver receptor that is known to bind numerous ligands that include proteinase-inhibitor complexes, matrix proteins, and certain apolipoprotein E- and lipoprotein lipase-enriched lipoproteins. (c) 1997, Elsevier Science Inc. (Trends Cardiovasc Med 1997;7:9 16). PMID- 21235852 TI - Recommendations for the transfusion management of patients in the peri-operative period. I. The pre-operative period. PMID- 21235859 TI - Advances in Human Mitochondrial Diseases Molecular Genetic Analysis of Pathogenic mtDNA Mutations. AB - The mitochondrial diseases are a heterogeneous group of disorders that have been defined by specific morphological alterations in muscle and by deficits of the mitochondrial respiratory chain. The morphological hallmarks of these diseases include ragged-red fibers (an extensive proliferation of mitochondria in muscle fibers) and abnormal paracrystalline inclusions and membrane structures in mitochondria. The identification of pathogenic mutations in mitochondrial DNA (mtDNA) has resulted in a genetic classification of mitochondrial diseases. Investigations are being conducted to understand the molecular basis for the biochemical and morphological alterations of mitochondria associated with mtDNA mutations. (c) 1997, Elsevier Science Inc. (Trends Cardiovasc Med 1997;7:16-24). PMID- 21235860 TI - The current status of stenting pathobiology. AB - Stents permanently maximize the arterial lumen following percutaneous transluminal coronary angioplasty (PTCA) at the cost of a vascular injury caused by the deployment of the prosthesis. Even though clinical trials show progressive reduction of restenosis and thrombosis rates in implanted coronary stents, these two events continue to represent a potential limitation to their clinical use. This review is focused on the arterial pathobiology related to the use of permanent and temporary stents. (c) 1997, Elsevier Science Inc. (Trends Cardiovasc Med 1997;7:24-28). PMID- 21235861 TI - Expression and regulation of endothelial nitric oxide synthase. AB - Endothelium-derived nitric oxide (NO) is a key determinant of blood pressure homeostasis and platelet aggregation and is synthesized by the endothelial isoform of nitric oxide synthase (eNOS). In the vascular wall, eNOS is activated by diverse cell-surface receptors and by increases in blood flow, and the consequent generation of NO leads to vascular smooth-muscle relaxation. Endothelium-dependent vasorelaxation is deranged in a variety of disease states, including hypertension, diabetes, and atherosclerosis, but the roles of eNOS in endothelial dysfunction remain to be clearly defined. The past several years have witnessed important advances in understanding the molecular and cellular biology of eNOS regulation. In endothelial cells, eNOS undergoes a complex series of covalent modifications, including myristoylation, palmitoylation, and phosphorylation. Palmitoylation of eNOS dynamically targets the enzyme to distinct domains of the endothelial plasma membrane termed caveolae; caveolae may serve as sites for the sequestration of signal-transducing proteins and are themselves subject to dynamic regulation by ligands and lipids. Originally thought to be expressed only in endothelial cells, eNOS is now known to be expressed in a variety of tissues, including blood platelets, cardiac myocytes, and brain hippocampus. Paradigms established in endothelial cells for the molecular regulation and subcellular targeting of eNOS are being extended to the investigation of eNOS expressed in nonendothelial tissues. This review summarizes recent advances in understanding the molecular regulation of eNOS and the other NOS isoforms and identifies important parallels between eNOS and other cell signaling molecules. (c) 1997, Elsevier Science Inc. (Trends Cardiovasc Med 1997;7:28-37). PMID- 21235862 TI - Lipoprotein Modification by Advanced Glycosylation Endproducts (AGEs): Role in Atherosclerosis. AB - Recent progress in our understanding of advanced glycosylation reactions in vivo has affirmed the hypothesis that these products play an important role in the evolution of both diabetic and nondiabetic vascular disease. Utilizing newly developed advanced glycosylation end-products (AGE)-specific enzyme-linked immunosorbent assay (ELISA) techniques, AGEs have been identified to be present on a variety of vascular wall, lipoprotein, and lipid constituents. Vascular wall AGEs contribute to vascular pathology by increasing vascular permeability, enhancing subintimal protein and lipoprotein deposition, and inactivating nitric oxide. Lipid-linked AGEs present in low-density lipoprotein (LDL) also have been shown to initiate oxidative modification, promoting oxidation reactions that may proceed without the involvement of free metals or other radical generating systems. AGE-specific ELISA analysis has demonstrated a significantly increased level of AGE-modified LDL in the plasma of diabetic patients when compared to normal controls. AGE-modification impairs LDL-receptor-mediated clearance mechanisms in vivo and may contribute to elevated LDL levels in patients with diabetes. This concept has been substantiated further by the recent clinical observations that administration of the advanced glycosylation inhibitor aminoguanidine to diabetic patients significantly decreases circulating LDL levels. (Trends Cardiovasc Med 1997;7:39-47). (c) 1997, Elsevier Science Inc. PMID- 21235863 TI - Molecular advances in plasminogen activator inhibitor 1 interaction with thrombin and tissue-type plasminogen activator. AB - Plasminogen activator inhibitor 1 (PAI-1) is a glycoprotein that controls the activity of the key enzymes of the fibrinolytic system, the serine proteases tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA). Inhibition is accomplished by rapid formation of inactive, equimolar PAI 1/PA complexes. The physiological importance of PAI-1 for the fibrinolytic system has been underscored by the observation that in humans, a homozygous defect results in hemorrhagic episodes. In addition to its function in surveillance of the integrity of clots, PAI-1 efficiently inhibits the serine protease thrombin in vitro, provided that either the high molecular weight glycosaminoglycan heparin or the glycoprotein vitronectin is present. These cofactors accelerate the rate of thrombin inhibition by PAI-1 by more than two orders of magnitude. Inhibition of thrombin by PAI-1 proceeds according to a "suicide substrate mechanism," typified by a branched reaction pathway, leading either to stable PAI 1/thrombin complexes or to degradation of the inhibitor and recycling of enzyme. The cofactors heparin and vitronectin, although increasing inhibition through different mechanisms, essentially promote PAI-1 degradation by thrombin. In view of the multitude of functions attributed to thrombin, the authors propose that the relevance of thrombin inhibition by PAI-1 is to restrict its mitogenic activity, rather than to affect its coagulation function in plasma. (Trends Cardiovasc Med 1997;7:47-51). (c) 1997, Elsevier Science Inc. PMID- 21235864 TI - Molecular mechanisms linking thrombosis and angiogenesis in cancer. AB - In this brief review, the authors concentrate on selected issues related to the newly described role of tissue factor (TF), the major activator of mammalian blood coagulation, as a regulator of angiogenesis and of tumor growth and metastasis. Previously, TF had been considered strictly as the primary activator of the coagulation cascade; however, it has recently been demonstrated that overexpression of the TF gene in murine tumor cells leads to increased transcription of the gene for vascular permeability factor/vascular endothelial growth factor (VEGF), a proangiogenic factor, and decreased transcription of the gene for thrombospondin (TSP), an antiangiogenic factor. Conversely, underexpression of TF leads to decreased VEGF and increased TSP transcription. When grown in mice and compared with low TF-producing tumor cells, high TF producing tumor cells stimulate angiogenesis by approximately twofold. This effect of TF appears to be independent of its clot-promoting procoagulant activity (PCA) and suggests that TF regulates the angiogenic properties of tumor cells by altering the production of growth regulatory molecules (for example, VEGF) that can act on vascular endothelial cells (VECs). There is substantial preliminary evidence that the regulation of tumor angiogenesis can be mediated by TF via both fibrin clotting-dependent and fibrin clotting-independent mechanisms. (Trends Cardiovasc Med 1997;7:52-59). (c) 1997, Elsevier Science Inc. PMID- 21235865 TI - Defining the molecular genetic basis of idiopathic dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is a significant health care problem. The etiology is idiopathic in approximately half of the patients. Recognition that 20%-25% of idiopathic DCM cases are familial has advanced the hypothesis that single gene defects are important in the disease's pathogenesis. General linkage analyses in rare, large DCM families have determined the chromosome location of five idiopathic DCM genes. Candidate-gene mutational analyses in more typical, small pedigrees represent an alternative strategy for DCM gene identification. Human molecular genetics will play a fundamental role in defining pathogenic mechanisms for DCM with the prospect of new, molecular-based diagnostic and therapeutic approaches. (Trends Cardiovasc Med 1997;7:60-63). (c) 1997, Elsevier Science Inc. PMID- 21235866 TI - Embryonic stem cell cardiogenesis applications for cardiovascular research. AB - Mouse embryonic stem (ES) cells are pluripotent cells derived from the inner cell mass of the preimplantation blastocyst. These cells can be maintained in culture in an undifferentiated state, or they can be induced to differentiate in vitro into multiple cell types, including spontaneously beating cardiac myocytes. The ability to engineer these ES cells genetically, together with their noted rapid differentiation into cardiac myocytes in vitro, makes this a useful tool for the study of cardiac gene expression and function. This in vitro cardiogenesis system may be particularly advantageous for pharmacological studies focusing on discovery of cardioactive drugs and for specifying the functional alterations associated with ablated or mutated cardiac genes that result in a lethal phenotype in vivo. (Trends Cardiovasc Med 1997;7:63-68). (c) 1997, Elsevier Science Inc. PMID- 21235867 TI - The plasma carboxypeptidases and the regulation of the plasminogen system. AB - Central to the regulation of the plasminogen system, a proteolytic network that mediates degradation of fibrin and facilitates cell migration, is the binding of plasminogen to carboxy-terminal lysines. These residues occur either naturally on plasmin substrates or cell surfaces or are generated as a consequence of partial plasmin degradation. The basic carboxypeptidases of plasma are capable of removing such carboxy-terminal lysines. Carboxypeptidase N, which is constitutively active, suppresses plasminogen binding to cell surfaces; plasma carboxypeptidase B, which must be proteolytically activated, not only suppresses cellular binding of plasminogen but also dampens fibrinolysis. Thus, the plasma carboxypeptidases may constitute an important regulatory pathway for controlling the activity of the plasminogen system in physiologic, pathophysiologic, and pharmacologic circumstances. (Trends Cardiovasc Med 1997;7:71-75). (c) 1997, Elsevier Science Inc. PMID- 21235868 TI - Regulation of Cardiac Gene Expression by GATA-4/5/6. AB - The identification of nuclear regulatory proteins provides great promise for advancing our understanding of the transcriptional control of cardiac gene expression. Three new members of the GATA family of DNA-binding transcription factors were recently discovered and designated GATA-4/5/6. On the basis of expression patterns, the identification of candidate cardiac target genes and the current understanding of how other GATA factors function in the hematopoietic system, it appears that these genes are important for regulating programs of cardiac development and terminal differentiation. Indeed, a functional role for GATA-4/5/6 in activating the cardiac differentiation program was demonstrated in cell culture and embryonic systems; however, recent results obtained in embryonic stem (ES) cells with a targeted mutation of GATA-4 raise new questions regarding specificity of action among the three genes. The future direction of research in the field is discussed; understanding GATA-4/5/6 function and regulation is likely to provide important insight into the specification and/or differentiation of cardiac progenitors, development and morphogenesis of the heart, and regulation of cardiac-specific gene expression. (Trends Cardiovasc Med 1997;7:75 83). (c) 1997, Elsevier Science Inc. PMID- 21235869 TI - Arrhythmogenic right ventricular cardiomyopathy a still underrecognized clinic entity. AB - Arrhythmogenic right ventricular cardiomyopathy is a new morbid entity that was discovered thanks to the study of sudden death in the young. This heart muscle disease is characterized by myocardial atrophy, mostly of the right ventricle, with massive fibro-fatty infiltration, accounting for ventricular electrical instability at risk of severe arrhythmias and even cardiac arrest. The disease was found to be the major cause of sudden death in young people and athletes in the Veneto Region, Italy. A familial occurrence with autosomal dominant transmission was then discovered, and the prevalence was estimated to be higher than 1 in 5000. The disease is genetically heterogeneous: Linkage analysis, carried out in a large family with recurrence of sudden deaths, led to map the gene to chromosome 14q23-q24. Linkage analysis in a second family allowed mapping of another gene to chromosome 1q42-q43. Clinical diagnosis can be achieved through electrocardiography, echocardiography, angiocardiography, magnetic resonance imaging, and endomyocardial biopsy. Diagnostic criteria have been put forward by a committee of the International Society and Federation of Cardiology. The disease was recently included among the cardiomyopathies in the revised World Health Organization (WHO) classification. Study of the natural history allowed us to distinguish (a) a covert phase in apparently normal subjects who have a risk of abrupt electrical instability and sudden death, (b) an overt arrhythmic phase with palpitations and impending cardiac arrest, (c) congestive heart failure with pump depression, sometimes so severe as to require heart transplantation. Both the etiology and pathogenesis of the disease are unknown. In particular, the mechanisms leading to progressive loss of myocardium and fibro-fatty replacement are still speculative. Apoptosis in the right ventricle occurring not only in infancy, as in the normal heart, but also in childhood and adulthood might account for the progressive disappearance of myocardial tissue. (Trends Cardiovasc Med 1997;7:84-90). (c) 1997, Elsevier Science Inc. PMID- 21235870 TI - Prevention of restenosis future directions. AB - Restenosis remains the major limitation of percutaneous transluminal coronary angioplasty. Restenosis after balloon angioplasty is due to vascular remodeling and neointimal hyperplasia. In spite of encouraging results in animal models, most of the pharmacological trials of prevention of restenosis in humans have produced negative results. This has prompted interest in the potential role of locally delivered drugs and various balloon catheter systems that are now available to achieve local delivery of therapeutic agents at the site of arterial injury. In 1997, implantation of a coronary stent in conjunction with balloon angioplasty is performed in an increasing number of patients. Randomized studies have shown that coronary stenting may reduce the risk of restenosis. In addition, restenosis after coronary stenting is mainly due to neointimal hyperplasia. Restenosis within coronary stents might thus be much more sensitive to therapies designed to inhibit neointimal hyperplasia than restenosis after balloon angioplasty. Thus, the future prevention of restenosis might well be the combination of a mechanical device that produces the widest possible lumen and prevents vessel constriction with a pharmacologic approach to inhibit the proliferative process. (Trends Cardiovasc Med 1997;7:90-94). (c) 1997, Elsevier Science Inc. PMID- 21235871 TI - Gender and cardiovascular disease recent insights. AB - Cardiovascular disease is rare in premenopausal women compared with men in similar age groups. After menopause, however, the gender difference in cardiovascular disease diminishes, and there is an increased incidence of coronary risk and events in women. Although a number of factors contribute to the development of atherosclerotic disease in women, estrogen replacement therapy reduces cardiovascular risk. Potential molecular mechanisms for the antiatherosclerotic effects of estrogen are discussed here. It is proposed that lipid-lowering and antioxidant properties of estrogen synergize to elicit the observed vasoprotective effects. These processes are discussed in the context of balloon-injury models and hypercholesterolemia. (Trends Cardiovasc Med 1997;7:94 100). (c) 1997, Elsevier Science Inc. PMID- 21235872 TI - Molecular and cellular biology of caveolae paradoxes and plasticities. AB - Caveolae are 50-100 nm invaginations that represent an appendage or subcompartment of the plasma membrane. They are found in most cell types but are abundant in fibroblasts, adipocytes, endothelial cells, type I pneumocytes, epithelial cells, and smooth and striated muscle cells. Functionally, caveolae have been implicated in three major processes: endothelial transcytosis, potocytosis, and signal transduction. Caveolin, a 21-24 kD integral membrane protein, is a principal component of the caveolar membrane in vivo. Within caveolar microdomains, caveolin functions as a multivalent docking site for recruiting and sequestering signaling molecules. More specifically, caveolin interacts directly in a regulated manner with multiple lipid-modified signaling molecules (such as Src-tyrosine kinases, Galpha subunits, and H-Ras), preferring the inactive conformation of these molecules. Here, we present a general overview of our current knowledge of caveolae and caveolin functioning and possible implications for treatment of human disease. (Trends Cardiovasc Med 1997;7:103 110). (c) 1997, Elsevier Science Inc. PMID- 21235873 TI - Blood flow dynamics, atherosclerosis and bypass graft failure. AB - Atherosclerosis occurs at reproducible sites in the arterial tree and intimal proliferation that leads to bypass graft occlusion also show a well-defined focal distribution. These observations have led to the hypothesis that local blood flow conditions, especially low or fluctuating shear stresses, are important in the development of both disorders. Basic research using both cell culture and animal models has revealed that endothelial cell biology is very sensitive to local shear stresses and rapid progress is being made in characterizing how endothelial cells transduce shear stress. Endothelial sensitivity to shear stress affects control of hemostasis, leukocyte adherence and transmigration, growth factor production, vasomotor responses, endothelial repair and arterial wall remodeling, all of which can be expected to influence development of vascular pathologies. Also, substantial progress has been made in characterizing complex local hemodynamics at relevant arterial sites; however, further progress is needed in this area, as well as in the extrapolation of advances in basic vascular biology to human vascular disease. (Trends Cardiovasc Med 1997;7:111-118). (c) 1997, Elsevier Science Inc. PMID- 21235874 TI - Cardiac potassium channels in health and disease. AB - Cardiac K(+)currents regulate resting membrane potential and action potential duration. These tasks are accomplished for the most part by four membrane currents: an inwardly rectifying current (I(K1)), a transient outward current (I(To)), and rapid (I(Kr)), and slow (I(Ks)) delayed rectifier currents. Recent studies have revealed far greater complexity at the molecular level. I(K1) may be produced by at least three genes from the Kir 2 subfamily of the supergene Kir family. The remaining currents appear to be produced by the supergene Kvalpha family, sometimes in association with the cytoplasmic protein Kvbeta family. I(To) may be produced by the Kv4 subfamily, but members of the Kv1 subfamily could contribute, particularly if associated with Kvbeta genes. Very rapid currents could be produced by Kv1.5, but Kvs 1.2 and 2.1 might also participate. Additional levels of complexity are possible because members within a Kv subfamily may form heterotetramers, and these, in turn, may associate with different Kvbetas. The situation may be simpler for I(Kr) and I(Ks), which at present appear to be produced by the Kv HER gene and the KvLQT1 gene, respectively. Mutations of these two genes have been linked to two forms of hereditary long QT syndrome, and heterologous expression of mutant HERGs has reproduced the pathophysiological phenotype satisfactorily. Sporadic mutations in these and other cardiac K(+)channel genes may provide a basis for hypersensitivity to cardioactive or cardiotoxic drugs. (Trends Cardiovasc Med 1997;7:118-124). (c) 1997, Elsevier Science Inc. PMID- 21235875 TI - Tropomyosin structure and function new insights. AB - Cardiac muscle contraction is dependent upon a cooperative interaction between thick and thin filament sarcomeric proteins. Tropomyosin (TM), an essential thin filament protein, interacts with actin and the troponin complex to regulate contractile activity. During muscle contraction, an increase of calcium (Ca(2+)) in the myofilament space promotes binding of Ca(2+) to troponin C, which alters the conformational state of TM and facilitates acto-myosin interactions. By coupling classic genetic approaches with recent developments in transgenic animal model systems, new insights have been provided on the functional role of TM isoforms in both normal and disease states. The focus of this article is to review the current state of knowledge on TM structure and function, with a particular emphasis on myocardial expression in transgenic mouse model systems. (Trends Cardiovasc Med 1997;7:124-128). (c) 1997, Elsevier Science Inc. PMID- 21235876 TI - In vivo Echocardiographic Assessment of Left Ventricular Function in Transgenic and Gene-Targeted Mice. AB - Manipulation of the mammalian genome with transgenic and gene-targeting techniques is a powerful method for unambiguously identifying the molecular mechanisms underlying cardiac development and function. Although the small size of the mouse heart and the rapid heart rates encountered have limited echocardiographic assessment of the murine heart in the past, the use of sophisticated transducers operating at a high frequency results in highly reliable and reproducible image quality. M-mode echocardiography has been shown to provide a good correlation with gravimetrically determined left ventricular mass (LV) and to estimate accurately LV dimensions and systolic function. Doppler interrogation of transvalvular flows permits assessment of global LV systolic and diastolic function independent of ventricular geometry. Linear stress-shortening relations can be determined in the adult mouse with the use of pharmacologically induced changes in systemic arterial pressure, and these relations are capable of detecting changes in myocardial contractility in vivo, relatively independent of loading conditions. The present review focuses on the current advantages and limitations of M-mode and Doppler echocardiography to evaluate cardiac function in mice. (Trends Cardiovasc Med 1997;7:129-134). (c) 1997, Elsevier Science Inc. PMID- 21235877 TI - Adrenergic Receptors From Molecular Structure to in vivo function. AB - Adrenergic receptors form the interface between the sympathetic nervous system and the cardiovascular system as well as many endocrine and parenchymal tissues. Although several hundred G-protein-coupled receptors have been identified, adrenergic receptors, along with the visual pigment rhodopsin, have been among the most extensively studied members of this family of receptors. This review focuses on recent advances in understanding the molecular structure, function, and regulation of adrenergic receptors using in vitro systems and integrates recent transgenic animal models that were generated to study the adrenergic system in vivo. (Trends Cardiovasc Med 1997;7:137-145). (c) 1997, Elsevier Science Inc. PMID- 21235878 TI - Gene transfer strategies for augmenting cardiac function. AB - Recent transgenic as well as gene-targeted animal models have greatly increased our understanding of the molecular mechanisms of normal and compromised heart function. These studies have raised the possibility of using somatic gene transfer as a means for improving cardiac function. DNA transfer to a significant portion of the myocardium has thus far been difficult to accomplish. This review describes current efforts to achieve myocardial gene transfer in several model systems, with particular emphasis placed on adenovirus-mediated gene delivery, its possibilities, and current limitations. (Trend Cardiovasc Med 1997;7:145 150). (c) 1997, Elsevier Science Inc. PMID- 21235879 TI - Signaling pathways in failing human heart muscle cells. AB - Experimental studies have delineated important signaling pathways in cardiomyocytes and their alterations in heart failure; however, there is now evidence that these observations are not necessarily applicable to human cardiac muscle cells. For example, angiotensin II (A II) does not exert positive inotropic effects in human ventricular muscle cells, in contrast to observation in rats. Thus, it is important to elucidate cardiac signaling pathways in humans in order to appreciate the functional role of neurohumoral or mechanical stimulation in human myocardium in health and disease. In the present article, we review signal pathways in the failing human heart based on studies in human cardiac tissues and in vivo physiological studies related to A II, nitric oxide, and beta-adrenergic stimulation. (Trends Cardiovasc Med 1997; 7:151-160). (c) 1997, Elsevier Science Inc. PMID- 21235880 TI - Animal models of heart failure recent developments and perspectives. AB - Heart failure is a complex syndrome characterized by inability of the heart to supply sufficient cardiac output to meet the metabolic needs of the body. Over the past few decades, a number of animal models of heart failure have been developed to study questions that cannot be readily studied in the clinical setting. Because the syndrome of heart failure in humans has many underlying causes, ranging from primary myocardial disease (often of unknown etiology) to myocardial failure consequent to ventricular overload with secondary cardiac hypertrophy (as in hypertension, valvular heart disease, or myocardial infarction), no single animal model can successfully mimic the pathophysiology of these clinical settings. Regardless of the original cardiac abnormality, however, the end-stage heart failure syndrome generally presents a picture of cardiac dilation and circulatory congestion associated with maladaptive neurohumoral responses affecting the heart and peripheral circulation, which provide prime targets for new treatment strategies. An ideal animal model of heart failure should mimic the clinical setting as closely as possible, be accessible and reproducible, relatively stable under chronic conditions, and sufficiently economical to permit experiments in a large number of animals. In this review, we discuss the advantages and disadvantages of naturally occurring models of heart failure and models in which heart failure is induced in normal animals, focusing in particular on models that are useful for exploring disease mechanisms and interventions to prevent or treat heart failure. Much is being learned from large animals such as the dog and pig, although small animal models (rat and hamster) have many favorable features, and as genetic methods and miniaturized physiologic techniques mature, the mouse is beginning to provide gene-based models of cardiac failure aimed at better understanding of molecular mechanisms. (Trends Cardiovasc Med 1997;7:161-167). (c) 1997, Elsevier Science Inc. PMID- 21235881 TI - Advances in ultrasound methods for high-resolution imaging of the cardiovascular system. AB - Acoustic microscopy entails the use of high-frequency high-resolution ultrasound methods to produce images of sound waves reflected from or propagated through some tissue of interest. The image contrast depends on microscopic differences in the intrinsic material properties of the substance imaged, such as mass density or compressibility. Pathologic changes in cardiovascular tissues at the subcellular level can be observed with high-frequency acoustic imaging techniques, based on alterations in the structure, properties, and organization of cells and their surrounding matrix. Potential applications extend from delineation of cardiovascular development in experimental animals to clinical characterization of the composition of atherosclerotic lesions with intravascular ultrasound and estimation of the potential for plaque rupture and infarction. (Trends Cardiovasc Med 1997;7:168-174). (c) 1997, Elsevier Science Inc. PMID- 21235882 TI - Immunobiology and therapeutic applications of protein c/protein s/thrombomodulin in human and experimental allotransplantation and xenotransplantation. AB - Protein C (PC), protein S (PS), and thrombomodulin (TM) constitute a well established, physiologically important anticoagulant pathway, but they also possess significant antiinflammatory and immunoregulatory properties through their ability to regulate macrophage activation. In vivo and in vitro data concerning these antiinflammatory actions are reviewed, with an emphasis on changes in the levels of these proteins during allograft and xenograft rejection, and potential therapeutic applications arising from their exogenous administration, or genetic engineering to maintain their expression, posttransplantation. (Trends Cardiovasc Med 1997;7:174-183). (c) 1997, Elsevier Science Inc. PMID- 21235883 TI - Altering Cardiac Function via Transgenesis A Nuts and Bolts Approach. AB - Transgenesis provides a means to modify the mammalian genome. By directing expression of a engineered protein to the heart, one now is able to remodel effectively the cardiac protein profile and study the consequences of a single genetic manipulation at the molecular, biochemical, cytological, and physiologic levels. Often, a particular pathology or even a global remodeling process such as hypertrophy is accompanied by the upregulation or downregulation of a gene or set(s) of genes. What is not known is whether these changes represent a beneficial compensatory response or contribute to the continued degeneration of normal heart function. The ability to perform genetic manipulations on cardiac gene expression via transgenesis offers one a rapid and effective means of extending the correlations noted to the mechanistic level. Now, one can, in theory, express a candidate protein at a particular developmental time and determine the direct consequences of its appearance. Similarly, one can explore structure-function relationships, both between different forms of a protein family and in terms of active domains within a protein, by expressing a transgene that encodes a suitable mutation or ectopic protein isoform. This review explores the practical considerations of the transgenic approach in terms of what is important for a successful experiment from the necessary animal husbandry to designing constructs that will express at appropriate levels in the heart. (Trends Cardiovasc Med 1997;7:185-191). (c) 1997, Elsevier Science Inc. PMID- 21235884 TI - The Role of the TEF Transcription Factors in Cardiogenesis and Other Developmental Processes. AB - The development of complex tissues and organs during embryogenesis is accompanied by precise spatial and temporal gene regulation, which usually takes place at the level of transcription initiation by RNA polymerase II. Differential patterns of gene expression are controlled by the binding of combinatorial arrays of transcription factors to their cognate regulatory elements in the promoters and enhancers of target genes. Generally, these transcription factors belong to families that have arisen through gene duplication. Members of a given family can be identified by the fact that they possess a common DNA-binding domain. In this review, we present the current data arguing for the possible involvement of the TEF family of transcription factors, which contain the TEA DNA-binding domain, in cardiogenesis and in other developmental processes. (Trends Cardiovasc Med 1997;7:192-197). (c) 1997, Elsevier Science Inc. PMID- 21235885 TI - Phosphatidylinositol 3-kinase in myogenesis. AB - Phosphatidylinositol 3-kinase (PI 3-kinase) has been cloned and characterized in a wide range of organisms. PI 3-kinases are activated by a diversity of extracellular stimuli and are involved in multiple cell processes such as cell proliferation, protein trafficking, cell motility, differentiation, regulation of cytoskeletal structure, and apoptosis. It has recently been shown that PI 3 kinase is a crucial second messenger in the signaling of myogenesis. Two structurally unrelated highly specific inhibitors of PI 3-kinase-wortmannin and LY294002-block the morphological and biochemical differentiation program of different skeletal-muscle cell models. Moreover, L6E9 myoblasts overexpressing a dominant-negative mutant of PI 3-kinase p85 regulatory subunit (Deltap85) are unable to differentiate. Furthermore, PI 3-kinase is specifically involved in the insulinlike growth factor (IGF)-dependent myogenic pathway. Indeed, the ability of IGF-I, des-1,3-IGF-I, and IGF-II to promote cell fusion and muscle-specific protein expression is impaired after treatment with PI 3-kinase inhibitors or in cells overexpressing Deltap85. The identification of additional key downstream elements of the IGF/PI 3-kinase myogenic cascade is crucial to a detailed understanding of the process of muscle differentiation and may generate new tools for skeletal and cardiac muscle regeneration therapies. (Trends Cardiovasc Med 1997;7:198-202). (c) 1997, Elsevier Science Inc. PMID- 21235886 TI - Platelet Endothelial Cell Adhesion Molecule 1 (PECAM-1/CD31): A Multifunctional Vascular Cell Adhesion Molecule. AB - PECAM-1/CD31 is a member of the immunoglobulin gene superfamily found on platelets, leukocytes, and endothelial cells, where it concentrates at cell-cell borders. It has been shown to both mediate cell-cell adhesion through homophilic and heterophilic interactions and to transduce intracellular signals that upregulate the function of integrins on leukocytes. Its cellular distribution and ability to mediate adhesive and signaling phenomena suggested that PECAM-1 was a multifunctional vascular cell adhesion molecule involved in leukocyte-endothelial and endothelial-endothelial interactions. These initial suggestions have been largely confirmed as recent studies have implicated PECAM-1 in the inflammatory process and in the formation of blood vessels. As our understanding of the molecular and functional properties of PECAM-1 grows, new insights will be gained that may have therapeutic implications for cardiovascular development and disease. (Trends Cardiovasc Med 1997;7:203-210). (c) 1997, Elsevier Science Inc. PMID- 21235887 TI - Cysteine mutagenesis in the voltage-dependent sodium channel structural insights and implications. AB - The superfamily of ion channel proteins comprise multisubunit transmembrane glycoproteins that are the fundamental electrical signaling molecules in the heart and other excitable tissues. The large size and hydrophobicity of these proteins present a formidable obstacle to the generation of a crystal structure. In lieu of a high-resolution structure, complementary methods have been used to study the structure function relationships of these essential excitability proteins. Molecular cloning and biophysical analysis of heterologously expressed wild-type and mutant channel proteins have provided insights into the structural basis of the essential channel functions of permeation and gating. This powerful combination of techniques also provides dynamic structural information regarding channel proteins not likely to be forthcoming from a crystal structure. (Trends Cardiovasc Med 1997;7:211-218). (c) 1997, Elsevier Science Inc. PMID- 21235888 TI - The role of cholesteryl ester transfer protein and phospholipid transfer protein in the remodeling of plasma high-density lipoproteins. AB - Recent studies demonstrated that alterations in the size distribution of high density lipoproteins (HDLs) constitute reliable markers for the risk of coronary artery disease. These observations suggested that the determination of the size distribution of HDL subpopulations by using polyacrylamide gradient gel electrophoresis might constitute an effective tool in clinical practice for the detection of patients with elevated risk. During the last decade, concordant observations revealed that all the HDL subpopulations are metabolically interrelated, and their relative abundances are dependent on the activity of several plasma factors, among them the cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP). As reviewed in the present article, although both CETP and PLTP can promote the size redistribution or conversion of HDL, the two plasma lipid transfer proteins can alter differently the plasma HDL distribution profile through distinct mechanisms. (Trends Cardiovasc Med 1997;7:218-224). (c) 1997, Elsevier Science Inc. PMID- 21235889 TI - Cellular receptors for plasminogen activators recent advances. AB - The generation of the broad-specificity protease plasmin by the plasminogen activators urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) is implicated in a variety of pathophysiological processes, including vascular fibrin dissolution, extracellular matrix degradation and remodeling, and cell migration. A mechanism for the regulation of plasmin generation is through binding of the plasminogen activators to specific cellular receptors: uPA to the glycolipid-anchored membrane protein urokinase-type plasminogen activator receptor (uPAR) and tPA to a number of putative binding sites. The uPA-uPAR complex can interact with a variety of ligands, including plasminogen, vitronectin, and integrins, indicating a multifunctional role for uPAR, regulating not only efficient and spatially restricted plasmin generation but also having the potential to modulate cell adhesion and signal transduction. The cellular binding of tPA, although less well characterized, also has the capacity to regulate plasmin generation and to play a significant role in vessel wall biology. (Trends Cardiovasc Med 1997;7:227-234). (c) 1997, Elsevier Science Inc. PMID- 21235890 TI - Tissue factor pathway inhibitor endocytosis. AB - Tissue factor pathway inhibitor (TFPI), a 42 kD protein, provides the physiological inhibition of tissue factor initiated coagulation by inhibition of both factor Xa and factor VIIa/tissue factor. In plasma, most TFPI is lipoprotein bound with an additional "releasable" pool bound to the endothelial cell surface. TFPI clearance is via receptor mediated endocytosis into liver. Heparin sulfate proteoglycans and LRP (low density lipoprotein receptor-related protein), an extremely large (~600 kD) cell surface protein, primarily mediate this clearance, although additional TFPI binding sites and endocytosis pathways exist. (Trends Cardiovasc Med 1997; 7:234-239). (c) 1997, Elsevier Science Inc. PMID- 21235891 TI - The bernard-soulier syndrome. AB - The Bernard-Soulier syndrome (BSS) is a rare inherited disorder of platelet function due to absence or markedly decreased expression of the platelet GpIb-V IX receptor. This receptor plays a critical role in hemostasis by initiating platelet adhesion and subsequent activation at the site of vessel injury. Through its link to the platelet cytoskeleton, the GpIb-V-IX complex appears to be required to maintain normal platelet size and structure. Elucidation of the cDNA and genomic structures of the members of this complex, as well as the mutations responsible for BSS, has greatly advanced our knowledge of the structure and function of the GpIb-V-IX complex in hemostasis. (Trends Cardiovasc Med 1997;7:239-244). (c) 1997, Elsevier Science Inc. PMID- 21235892 TI - Novel stents for the prevention of restenosis. AB - Since the introduction of Interventional Cardiology in 1976, there has been rapid expansion both in its clinical application and the tools of the trade. This growth was accelerated with the introduction of the intra-coronary stent in 1987. The demonstration that stents may reduce the incidence of restenosis after percutaneous coronary revascularization has further stimulated the search for the perfect endovascular prosthesis. By creating a hybrid stent, incorporating natural coatings and local drug delivery in the design, it is hoped that the complications associated with stent thrombosis and restenosis can be eradicated. (Trends Cardiovasc Med 1997;7:245-249). (c) 1997, Elsevier Science Inc. PMID- 21235893 TI - Apoptosis and congestive heart failure. AB - Congestive heart failure (CHF) is the final clinical manifestation of a variety of cardiac (myopathies), coronary (atherosclerosis), and systemic diseases (diabetes, hypertension). Regardless of the origin of the cardiac insult, left ventricular dysfunction resulting in decreased cardiac output elicits a series of adaptational processes that attempt to compensate for some of the decrement in myocardial function. One of the key manifestations of these compensatory processes is cardiac hypertrophy, which is characterized by a marked increase in myocyte size and an increase in contractile proteins. The benefits resulting from these compensatory adaptational mechanisms, however, are only transient, and within a period of months to years, the changes induced in the myocardium fail to sustain cardiac output at a level that is sufficient to meet the demands of the body; subsequently, physical performance is impaired. Typically, progressive dilation and thinning of the left ventricle occur along with progression of CHF. The mechanisms responsible for the thinning of ventricular tissue and loss of left ventricular mass are poorly understood; traditionally, such loss has been attributed to tissue necrosis based on the morphologic observation of dead cardiac myocytes. Very recently, there have been data suggesting that apoptosis, a form of programmed cell death (PCD), occurs in the heart and may be responsible, at least in part, for the progression of CHF and the chronic loss of left ventricular function and mass. Evidence for a role of apoptosis/PCD in the progression of heart failure has been obtained from a variety of observations, including in vitro studies of cardiac myocytes in culture, experimental animal models of cardiac injury, and cardiac tissue obtained from patients with CHF. Thus, apoptosis/PCD may be a critical mechanism involved in the progressive loss of cardiac myocytes, which ultimately results in end-stage heart failure. In this brief review, the evidence for apoptosis/PCD in cardiac myocytes is presented and its potential role in the progression of CHF is analyzed. In particular, the genomic basis for apoptosis in cardiac myocytes is explored, and its relevance to the identification of novel targets for future pharmacological interventions is discussed. (Trends Cardiovasc Med 1997;7:249-255). (c) 1997, Elsevier Science Inc. PMID- 21235894 TI - Free cholesterol-induced cytotoxicity a possible contributing factor to macrophage foam cell necrosis in advanced atherosclerotic lesions. AB - A major characteristic of advanced atherosclerotic lesions is the necrotic, or lipid, core, which likely plays an important role in the clinical progression of these lesions. Recent data suggest that the necrotic core forms primarily as a consequence of macrophage foam cell necrosis. Lesional macrophages initially accumulate mostly cholesteryl esters, but macrophages in advanced lesions contain large amounts of unesterified, or free, cholesterol (FC). Although there are many theories as to why macrophage foam cells die in advanced lesions, the fact that a high FC:phospholipid (PL) ratio in cellular membranes can be toxic to cells suggests that FC-induced cytotoxicity may contribute to foam cell necrosis. The mechanism of FC cytotoxicity can be explained by disturbances in membrane protein function as a result of "stiffening" of the bilayer and by formation of intracellular FC crystals that can cause physical damage to cellular organelles. Macrophages appear to respond to FC loading by a fascinating adaptive response, namely the induction of PL biosynthesis, which initially keeps the cellular FC:PL ratio below toxic levels. Studies with cultured macrophages have demonstrated that a failure of this adaptive response leads to FC-induced foam cell cytotoxicity and necrosis, and thus a similar series of events in advanced atherosclerotic lesions could provide an explanation for the development of the necrotic core. (Trends Cardiovasc Med 1997;7: 256-263). (c) 1997, Elsevier Science Inc. PMID- 21235895 TI - Growth Hormone and Insulin-like Growth Factor 1: New Endocrine Therapies in Cardiology? AB - The hormones growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play a dominant role in whole body growth and metabolism. This is reflected in the use of human GH (hGH) in GH-deficient children to stimulate growth and in GH deficient adults to reduce visceral fat mass. Recent data suggest that hGH may improve cardiac function in patients with heart failure, so there is current interest in methods to raise GH-IGF levels, including the testing of agents that release GH from the pituitary, administering IGF-1, and most recently, long acting formulations of hGH. It is hoped that this ongoing integration of cardiology and endocrinology will uncover the pathophysiology of some cardiovascular diseases and yield new treatments based on the hormones of the GH axis. (Trends Cardiovasc Med 1997;7:264-268). (c) 1997, Elsevier Science Inc. PMID- 21235896 TI - Genetic analysis of blood vessel formation role of endothelial versus smooth muscle cells. AB - Formation of new blood vessels is vital during embryogenesis, essential for reproduction and wound healing during adulthood, and required to rescue tissue during ischemia. Neovascularization may, however, also contribute to the pathogenesis of several disorders, including tumorigenesis, diabetic vasculopathy, and chronic inflammation. Initially, blood vessels form as endothelium-lined channels by in situ differentiation of endothelial cells. Subsequently, they sprout and remodel into a highly organized and interconnected vascular network. During further maturation of the blood vessels, a sheet of primitive vascular smooth muscle cells surrounds the endothelium-lined channels, which controls endothelial cell function and provides structural support. Recent molecular analyses have identified candidate molecules that affect these processes. Their in vivo role has been further established by targeted gene manipulation in transgenic mice. This review highlights recent developments in the genetic analysis of blood vessel formation, as deduced from analysis of gene inactivated mice. (Trends Cardiovasc Med 1997;7:271-281). (c) 1997, Elsevier Science Inc. PMID- 21235897 TI - Badly engineered fibrillin lessons from molecular studies of marfan syndrome. AB - Marfan syndrome (MFS) is one of the most common inherited connective tissue disorders that severely affects the cardiovascular system. Mutations in the gene encoding fibrillin-1 (FBN1) have been shown to cause MFS as well as dominant ectopia lentis and neonatal Marfan syndrome. Fibrillin-1 is the major component of elastic fiber microfibrils in the extracellular matrix of connective tissue. Recent molecular studies have brought some light into understanding the pathogenesis of MFS, but the diagnostic problems still prevail, and targeted therapy of MFS must await better dissection of the role of fibrillin-1 in tissue phenotype using different experimental systems. (Trends Cardiovasc Med 1997;7:282 288). (c) 1997, Elsevier Science Inc. PMID- 21235898 TI - Ischemia-driven angiogenesis. AB - New blood vessels usually develop in places where they are most needed. A prime example of neovascularization representing a positive feedback response to insufficient perfusion is the development of collateral blood vessels in the ischemic myocardium and leg. The recent discoveries of hypoxia-inducible transcription and angiogenic factors have provided important mechanistic links between the metabolic consequences of ischemia and compensatory angiogenesis. Vascular endothelial growth factor (VEGF) has emerged as the key mediator of ischemia-driven angiogenesis. Environmental stresses, including hypoxia, hypoglycemia, and hypoferremia, upregulate VEGF expression at both the transcriptional and posttranscriptional levels. VEGF acts in turn on adjacent vascular beds expressing cognate receptors and induces sprouting and capillary growth toward the ischemic tissue. In addition to expanding the vasculature at sites where existing vessels have been occluded or obliterated, VEGF also functions to match the vascular density according to development and physiologic increases in oxygen consumption. Fine adjustment of the vasculature includes a step of oxygen-regulated vascular pruning mediated by VEGF in its capacity as a survival factor for newly formed vessels. Pathologic settings of ischemia-driven angiogenesis include a major component of stress-induced angiogenesis during tumor neovascularization and abnormal vessel growth associated with retinopathies. The latter represents an excessive angiogenic response to conditions of severe retinal ischemia. Further insights into the mechanism of stress-induced angiogenesis are likely to suggest new ways to augment growth of collateral vessels and to restrain unwarranted neovascularization in tumors and retinopathies. (Trends Cardiovasc Med 1997;7:289-294). (c) 1997, Elsevier Science Inc. PMID- 21235899 TI - Ordering the multiple pathways of apoptosis. AB - Apoptosis plays an important role in development, homeostasis, and disease. Current work has suggested that apoptosis can be evoked by multiple stimuli that, in turn, initiate distinct death pathways. Recently, exciting advances have been made in the understanding of biochemical pathways that regulate apoptotic processes. These pathways contain both evolutionarily conserved elements and components that are dependent on the death stimulus and cell context. Accordingly, this review focuses on the compositions and relative ordering of the apoptotic pathways in four different death paradigms: activation of receptors of the Fas ligand, destruction by cytotoxic T lymphocytes, exposure to DNA damaging agents, and loss of support by neurotrophic factors. These examples illustrate the conservation and divergence in the ways that death pathways are composed and ordered. (Trends Cardiovasc Med 1997;7:294-301). (c) 1997, Elsevier Science Inc. PMID- 21235900 TI - NADH/NADPH Oxidase and Vascular Function. AB - The vascular NADH/NADPH oxidase has been shown to be the major source of superoxide in the vessel wall. Recent work has provided insight into its structure and activity in vascular cells. This enzyme is involved in both vascular smooth muscle hypertrophy and in some forms of impaired endothelium dependent relaxation. Because oxidative stress in general participates in the pathogenesis of hypertension and atherosclerosis, the enzymes that produce reactive oxygen species may be important determinants of the course of vascular disease. (Trends Cardiovasc Med 1997;7:301-307). (c) 1997, Elsevier Science Inc. PMID- 21235901 TI - Kallistatin in blood pressure regulation transgenic and somatic gene delivery studies. AB - Kallistatin, first discovered as a human kallikrein-binding protein in the circulation, shares high homology with other plasma serine proteinase inhibitors (serpins). It forms a covalently linked complex with tissue kallikrein and inhibits kallikrein's activity. Substantial evidence has accumulated in recent years indicating that kallistatin may play a role in blood pressure regulation independent of its interaction with tissue kallikrein. Intravenous injection of kallistatin into rats and mice results in a rapid and transient reduction of blood pressure in a dose-dependent manner. Functional analysis in transgenic mice over-expressing rat kallikrein-binding protein, an analogue of human kallistatin, revealed that these mice have significantly lower blood pressure compared with control littermates. Adenovirus-mediated delivery of the human kallistatin gene can cause significant blood pressure reductions for 4 weeks in spontaneously hypertensive rats. Finally, kallistatin can induce vasorelaxation in isolated rat aortic rings and reduce renal perfusion pressure in the isolated, perfused kidney. Together, these findings suggest a direct role for kallistatin in regulating blood pressure and raise the possibility for the development of new pharmacological treatments for hypertension. (Trends Cardiovasc Med 1997;7:307 311). (c) 1997, Elsevier Science Inc. PMID- 21235902 TI - Malignant hyperthermia domain in the regulation of ca(2+) release channel (ryanodine receptor). AB - Malignant hyperthermia (MH) is a potentially lethal condition that is manifested in humans as an acute increase of body temperature in response to stress and exposure to volatile anaesthetics (halothane, enflurane) and muscle relaxants. To date, eight point mutations in the ryanodine receptor gene, the Ca(2+) release channel of the skeletal muscle sarcoplasmic reticulum, segregate with the MH phenotype, yet direct evidence linking altered [Ca(2+)](i) homeostasis to mutation in recombinant RYR has been obtained only for one such mutation. Most of these mutations appear in an "MH domain" that is localized at the NH(2) terminus of the skeletal muscle ryanodine receptor Ca(2+) channel. In this review, we summarize the available data concerning the role of the MH domain in the altered functions of the ryanodine receptor Ca(2+) channel. (Trends Cardiovasc Med 1997;7:312-316). (c) 1997, Elsevier Science Inc. PMID- 21235903 TI - Molecular and structural advances in tissue factor-dependent coagulation. AB - The tissue factor:factor VIIa (TF-F.VIIa) complex is considered the physiological initiator of blood coagulation. Besides its role in normal hemostasis, this enzyme complex has been found to play an important role in various thrombotic disorders and thus has become an attractive target for the development of new anticoagulants. Recently, significant progress has been made in regard to structural and molecular aspects of TF-VIIa-initiated coagulation. A rather complete picture on how tissue factor binds to factor VIIa has emerged and is discussed in detail in this review. Also, the combined data of the TF-F.VIIa crystal structure, of naturally occurring F.VII variants, and of mutagenesis studies provide a framework to discuss molecular aspects of the tissue factor mediated enhancement of F.VIIa catalytic efficiency and the recognition of macromolecular substrates. F.VIIa as a member of the serine protease family has an active site homologous to other coagulation factors. The release of the coordinates of the crystal structures of F.X and F.IX, together with the earlier determined thrombin structure, now allows a detailed comparison of these active centers with respect to the development of specific and potent active site inhibitors. This structural and molecular information about the TF-F.VIIa complex and other coagulation enzymes adds to our understanding of blood coagulation and should further the development of new classes of anticoagulants. (Trends Cardiovasc Med 1997;7:316-324). (c) 1997, Elsevier Science Inc. PMID- 21235904 TI - New insights into retinoid signaling in cardiac development and physiology. AB - Retinoic acid (RA) and the retinoids are potent hormones derived from the nutrient vitamin A; they bind members of the nuclear steroid receptor family (RAR, RXR), which are ligand-dependent trans-activators of target gene transcription. Although classic nutrition studies largely ignored heart as a retinoid target, recent interest in this subject stems from RA's potent cardiac teratogenicity, the identification of retinoid receptors in the heart, and the cardiac malformations observed in retinoid receptor null mutant mice. This review summarizes recent research into retinoid contributions predominantly in the embryonic heart. (Trends Cardiovasc Med 1997;7:324-329). (c) 1997, Elsevier Science Inc. PMID- 21235905 TI - Eph family receptors and ligands in vascular cell targeting and assembly. AB - Members of the Eph family of receptor tyrosine kinases determine neural cell aggregation and targeting behavior, functions that are also critical in vascular assembly and remodeling. Among this class of diverse receptors, EphA2 (Eck) and EphB1 (ELK) represent prototypes for two receptor subfamilies distinguished by high-affinity interaction with either glycerophosphatidylinositol (GPI)-linked or transmembrane ligands, respectively. EphA2 participates in angiogenic responses to tumor necrosis factor (TNF) through an autocrine loop affecting endothelial cell migration. EphB1 and its ligand Ephrin-B1 (LERK-2) are important determinants of assembly of endothelial cells from the microvasculature of the kidney, where both are expressed in endothelial progenitors and in glomerular microvascular endothelial cells. Ephrin-B1 activation of EphB1 promotes assembly of these cells into capillary-like structures. Interaction trap approaches have identified downstream signaling proteins that complex with ligand-activated EphA2 or EphB1, including nonreceptor tyrosine kinases and SH2 domain-containing adapter proteins. The Grb 10 adapter is one of a subset that binds activated EphB1, but not EphA2, defining distinct signaling mechanisms for these related endothelial receptors. On the basis of observations in vascular endothelial cells and recent results defining Eph receptor and ligand roles in neural cell targeting, we propose that these receptors direct cell-cell recognition events that are critical in vasculogenesis and angiogenesis. (Trends Cardiovasc Med 1997;7:329-334). (c) 1997, Elsevier Science Inc. PMID- 21235906 TI - Hepatic apolipoprotein B biogenesis: an update. AB - Approximately one half to two thirds of newly synthesized apolipoprotein B (apoB) in Hep G2 cells (a human hepatoma cell line) is degraded. The intracellular degradation of apoB associated with the rough endoplasmic reticulum (ER) is reviewed in the context of our current understanding of proteasome-mediated degradation of ER-associated proteins. A model of hepatic apoB biogenesis is presented. PMID- 21235907 TI - Nitric Oxide and cGMP in Regulation of Arterial Tone. AB - Nitric Oxide (NO) is an important factor in the control of vascular tone and peripheral resistance. Guanosine 3',5'-monophosphate (cGMP) mediates NO-induced vasorelaxation via multiple mechanisms, including decreased Ca(2+) entry and release, enhanced Ca(2+) extrusion, and inhibition of sensitization of myofilaments to Ca(2+) caused by some agonists such as norepinephrine (but not others such as ATP). This may result in differential effects of NO, depending on the agonist and the smooth muscle phenotype. In blood vessels exposed to inflammatory stimuli (for instance in endotoxemia), enhanced NO production causes loss of vascular reactivity to vasoconstrictor agents. This results from the induction of NO synthase activity in vascular cells, especially in the adventitia. The role of the adventitia may explain differences between large and small resistance arteries, in addition to the phenotype of smooth muscle cells. Protein-bound dinitrosyl non-heme iron complexes with thiols can be generated in arteries subsequent to the induction of NO synthase. Low molecular thiols can displace Fe-NO from these complexes, leading to activation of guanylyl cyclase and vasorelaxation. This may represent a novel mechanism of NO storage and release, enabling prolonged effects of NO in blood vessels and, perhaps, protection of vascular tissue against oxidative injury in sepsis and other inflammatory diseases. PMID- 21235908 TI - Tumor necrosis factor and endothelial cell death. AB - Tumor necrosis factor (TNF) is a multifunctional cytokine that elicits various responses in endothelial cells that can be summarized as being proinflammatory and procoagulant. Apoptosis refers to a genetically programmed form of cell death in which the cell participates in its own demise. Although TNF can activate the death pathway in normal human endothelial cells, apoptosis only results when protein synthesis is blocked. This finding indicates that TNF elicits both survival and death pathways. Endothelial cell apoptosis has been reported in various pathophysiologic situations from vascular development to immune disorders and atherosclerosis. The role of TNF-mediated endothelial death in these situations remains to be defined. PMID- 21235909 TI - Hypoxia and molecular cardiovascular medicine. AB - Hypoxia induces a cascade of physiologic responses that include glycolysis, erythropoiesis, angiogenesis, changes in adrenergic signal transduction and vascular tone, modulation of vascular cellular proliferation, and inflammation. This review addresses the recent and explosive growth in our knowledge of how vascular endothelial and smooth muscle cells actively respond to hypoxic stress, with additional focus on the roles of the NF-kappaB family of transactivation proteins in these responses. PMID- 21235910 TI - Regulation of cardiac development by receptor tyrosine kinases. AB - The development of a functional heart depends on the coordinated growth, differentiation, migration, and apoptosis of cell populations of diverse embryological origins. These processes are regulated in part by soluble polypeptide growth factors that exert their effects via binding to cell surface receptors with intrinsic tyrosine kinase activity. In particular, members of this class of receptors and their ligands have been shown to regulate the development of distinctive regions of the heart, such as the mesodermally derived cardiac myocyte, the endocardium, and outflow tract and septa, which depend on cardiac neural crest. The hepatocyte growth factor receptor, c-met the fibroblast growth factor receptors; and the neuregulin receptors have been shown to influence cardiomyocyte proliferation and/or differentiation. Receptors binding to vascular endothelial cell growth factor or angiopoietin have been implicated in the development of the endocardium. Finally, gene-targeting experiments in the mouse have demonstrated functional roles for neurotrophins and their cognate trk receptor tyrosine kinases in the development of outflow tract, septa, and valves that are structures derived from cardiac neural crest. PMID- 21235911 TI - Mutagenesis of Sarcoplasmic Reticulum Ca(2+)-ATPase. AB - Ca(2+)-ATPases of sarco(endo)plasmic reticulum utilize energy derived from hydrolysis of ATP to drive active uptake of calcium ions. Site-directed mutagenesis analysis of Ca(2+)-ATPase structure-function relationships has identified protein domains and single amino acid residues involved in the binding and occlusion of the calcium ions during translocation, as well as amino acid residues crucial to the energy-transducing intramolecular signaling that links events in the catalytic ATP hydrolysis site with rearrangements in the calcium sites. The interaction between the cardiac muscle sarcoplasmic reticulum Ca(2+) ATPase and the regulatory protein phospholamban, which mediates the activation of Ca(2+) transport by beta-agonists, has also been elucidated by mutagenesis. PMID- 21235912 TI - The role of CXC chemokines in the regulation of angiogenesis in association with lung cancer. AB - Recent evidence demonstrates that members of the CXC chemokine family can act as either angiogenic or angiostatic factors, depending on the presence of the ELR (Glu-Leu-Arg) motif in their NH(2) terminus. As such, these molecules have been shown to regulate tumor growth and metastasis in an animal model of human non small cell lung cancer. ELR-positive members (for example, IL-8) are tumor derived proteins that promote tumor growth and metastasis. Conversely, ELR negative members (for example, IP-10 and MIG) are endogenous factors that inhibit tumor growth and metastasis. The levels of these factors in human tumor specimens may have predictive value for determining which patients are at risk for developing metastasis, and alteration of these CXC chemokine levels may provide a therapeutic intervention. PMID- 21235913 TI - Reactive oxygen species as mediators of signal transduction in cardiovascular disease. AB - Reduction-oxidation (redox) reactions that generate reactive oxygen species (ROS) have been identified as important chemical processes that regulate signal transduction. Because increased ROS may be a risk factor for cardiovascular events such as unstable angina, myocardial infarction and sudden death, understanding the biological processes that generate ROS and the intracellular signals elicited by ROS will be important to gain insight into the pathogenesis of these diseases. In this review, we discuss the enzymes that generate ROS in cardiovascular tissues, the role of the mitogen-activated protein (MAP) kinase pathway in redox-sensitive signal transduction, and focus on tyrosine kinases as proximate "sensors" for redox-mediated signal events. The mechanisms by which these kinases regulate gene transcription are then discussed to provide insight into the pathogenic roles of ROS in hypertension, atherosclerosis and vascular remodeling. PMID- 21235914 TI - Embryonic Stem Cell-Derived Cardiac Differentiation: Modulation of Differentiation and "Loss-of-Function" Analysis In Vitro. AB - Mouse embryonic stem (ES) cells, when cultivated as embryo-like aggregates, are able to differentiate in vitro into derivatives of all primary germ layers. These include functionally active cardiomyocytes representing ventricle-like, atrium like, and pacemaker-like cells. During differentiation, a developmentally controlled expression pattern of cardiac-specific genes, proteins, action potentials, ion channels, and receptors is found. This developmental pattern can be modulated in vitro by differentiation factors such as retinoic acid or by "gain-of-function" and "loss-of-function" approaches. The latter strategy was successfully used for the characterization of cardiac phenotypes of beta(1) integrin-deficient ES cells after differentiation into the cardiogenic lineage. PMID- 21235915 TI - The Sarco(endo)plasmic Reticulum Ca(2+)-ATPases in the Cardiovascular System During Growth and Proliferation. AB - The sarco(endo)plasmic reticulum Ca(2+)-ATPase is present in all cell types and is essential in restoring a low cytosolic Ca(2+) concentration after cell activation. In the past years, six different isoforms encoded by three genes have been identified by cDNA cloning. Some of these isoforms are expressed in the cardiovascular system, and their expression is regulated during proliferation that occurs during ontogenic development as well as in pathological cell growth. This article reviews the new features concerning isoform diversity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase and modulation of expression of these isoforms in cardiac and vascular cells. PMID- 21235916 TI - The molecular interaction between local anesthetic/antiarrhythmic agents and voltage-gated sodium channels. AB - Local anesthetic/antiarrhythmic agents render their therapeutic effects via suppression of ionic current through voltage-gated Na channels. Recent work to understand the molecular basis of this drug-receptor interaction has exploited the combined technologies of molecular biology and electrophysiology. Despite the complexity of the effects of site-directed mutations on Na channel function and local anesthetic action, some consistent themes are emerging. Recent studies suggest that the local anesthetic compounds actively promote channel inactivation and, in doing so, function as allosteric effectors. Although the charged moiety may enter the Na channel pore, the primary mechanism whereby local anesthetic agents reduce excitability may be to induce channel inactivation. PMID- 21235917 TI - Functional Anchoring of the cAMP-Dependent Protein Kinase. AB - The precision of cAMP-responsive events is controlled in part through compartmentalization of the signal transduction machinery. Recent evidence suggests that the cAMP-dependent protein kinase (PKA) is localized to specific subcellular compartments through association with A Kinase Anchoring Proteins (AKAPs). The AKAPs now represent a functionally related family of regulatory proteins that contain a conserved PKA binding domain and unique targeting sequences that direct the PKA-AKAP complex to subcellular structures. In this review, the recent evidence suggesting that AKAPs facilitate PKA anchoring close to key membrane substrates, such as glutamate receptors, calcium-activated potassium channels, and skeletal or cardiac muscle calcium channels, is surveyed. PMID- 21235918 TI - The plakoglobin knock-out mouse: a paradigm for the molecular analysis of cardiac cell junction formation. AB - Plakoglobin (gamma-catenin), a member of the armadillo family of proteins, is a constituent of the cytoplasmic plaques of desmosomes and adherens junctions and is involved in anchorage of cytoskeletal filaments to specific cadherins. When the plakoglobin gene is ablated in mice, animals die between days 12 and 16 of embryogenesis owing to defects in heart function. Often, their heart ventricles burst, and pericardial tamponade appears to be the immediate cause of death. This tissue instability correlates with the absence of desmosomes and a redistribution of desmosomal proteins in heart, but not in epithelial organs. Plakoglobin is an essential component of cardiac desmosomes and plays a crucial role in the architecture and stabilization of heart tissue. PMID- 21235919 TI - Opioid Peptide gene expression in the myocardial cell. AB - Both kappa and delta opioid receptors have been identified in the myocardial cell. These receptors are coupled to phosphoinositide turnover and protein kinase C (PKC) activation, and their stimulation affects the cytosolic Ca(2+) and pH homeostasis as well as the contractility and the myofilament responsiveness to Ca(2+). Both the proenkephalin and the prodynorphin gene are expressed in cardiac myocytes. These cells are also able to synthetize and secrete dynorphin B, a biologically active end product of the prodynorphin gene binding selectively the kappa opioid receptor. Prodynorphin mRNA and dynorphin B expression are markedly increased in ventricular myocytes isolated from Syrian cardiomyopathic hamsters (the hypertrophic BIO 14.6 strain), as compared with normal cells. Nuclear PKC activation and intracellular Ca(2+) overload have been shown to act as the two major signaling mechanisms involved in the increase in prodynorphin gene transcription observed in cardiomyopathic myocytes. In these cells, secreted dynorphin B activates kappa opioid receptors at the cell surface and elicits an autocrine loop, leading to an increase in nuclear PKC activity and to a tonic feed-forward stimulation of prodynorphin gene transcription. The possibility that opioid genes may act in an autocrine fashion to affect myocardial Ca(2+) homeostasis, growth, and differentiation is also discussed. PMID- 21235920 TI - Peptide toxins as probes of ryanodine receptor structure and function. AB - Toxins from scorpion venom are emerging as useful ligands for structure/function studies of ryanodine receptors (RyR), the sarcoplasmic reticulum Ca(2+) release channels that elevate intracellular Ca(2+) to elicit contraction of cardiac and skeletal muscle. Imperatoxin A (IpTx(a)), a 3.7 kDa peptide from the African scorpion P. imperator, is an agonist of RyRs which, similar to the alkaloid ryanodine, binds with high affinity to the RyR protein and induces the appearance of a long-lived subconductance state. Imperatoxin I (IpTx(i)), a 15 kDa heterodimeric protein from the same venom that displays phospholipase A(2) activity, inhibits RyRs without a physical interaction with the channel protein, by releasing free fatty acids into the incubation medium. IpTx(a) and IpTx(i) are the first of a group of peptide probes of RyRs with diverse mechanism of action which overcome some of the undesirable characteristics of ryanodine. PMID- 21235921 TI - Endocytosed lysophosphatidylcholine, through the scavenger receptor, plays an essential role in oxidized low-density lipoprotein-induced macrophage proliferation. AB - The growth of cellular components is one of the characteristic events in the development of atherosclerosis. It is generally accepted that smooth muscle cells proliferate in atherosclerotic lesions. It has recently become evident that macrophage-derived foam cells also proliferate in the early stage of the atherosclerotic lesions. Our recent reports have demonstrated induction of macrophage proliferation in vitro by oxidized low density lipoprotein (Ox-LDL), in which a transport of lysophosphatidylcholine into cells by efficient endocytic uptake of Ox-LDL through the scavenger receptor pathway is important. Because macrophage-derived foam cells play an important role in the development of the early atherosclerotic lesions, it seems reasonable to expect that the Ox-LDL induced macrophage proliferation may be linked to atherosclerotic processes in vivo. PMID- 21235922 TI - Binding sites on native and multimeric vitronectin exhibit similar affinity for heparin the influence of self-association and multivalence on ligand binding. AB - A previously accepted model for the morphoregulatory activity of vitronectin is based on the idea that the heparin-binding site is buried within the circulating, monomeric form of vitronectin and that it is exposed on conversion to the multimeric form by denaturation or incorporation into the extracellular matrix. New evidence indicates that the heparin-binding sites are similarly exposed in the two forms of vitronectin and supports an alternative model for apparently altered heparin affinity. Differences in the heparin-binding properties of circulating and matrix-associated vitronectin result from an increased number of binding sites on the multivalent matrix form. By analogy with other instances in which multivalent binding interactions increase functional affinity for carbohydrates or lectins, the self-association of vitronectin into a multimeric form allows effective neutralization of heparin at the endothelial surface in the vicinity of a thrombus. PMID- 21235923 TI - The Role of Tumor Necrosis Factor-alpha Receptors in Atherosclerosis. AB - Tumor necrosis factor (TNF-alpha)-alpha is a cytokine exhibiting a plethora of activities involved in inflammation, immune regulation, and energy metabolism. TNF is produced by many cell types, including cells found in atherosclerotic lesions, such as activated monocytes or macrophages, T and B lymphocytes, mast cells, and smooth muscle cells. Two receptors mediate the functions of TNF, and both receptors are also present on cells of the artery wall and on cells involved in lesion development. Mice genetically engineered to lack expression of TNF and each of its receptors are now available and are being used to dissect the role of these molecules in protection from or development of atherosclerosis. The role of TNF receptors in atherosclerosis is the primary focus of this review. PMID- 21235924 TI - NF-kappaB Mediated Transcription in Human Monocytic Cells and Endothelial Cells. AB - Monocytes and endothelial cells become activated at sites of inflammation and contribute to the pathology of many diseases, including septic shock and atherosclerosis. In these cells, induction of genes expressing various inflammatory mediators, such as adhesion molecules, cytokines, and growth factors, is regulated by NF-kappaB/Rel transcription factors. Recent studies have identified components of the signal transduction pathways leading to the activation of NF-kappaB/Rel proteins. Inhibition of these signaling pathways provides a novel therapeutic approach to prevent inducible gene expression in both monocytes and endothelial cells. (Trends Cardiovasc Med 1998;8:138-142). (c) 1998, Elsevier Science Inc. PMID- 21235925 TI - Recent progress in the cellular and molecular biology of prostaglandin synthesis. AB - The discovery of an inducible form of prostaglandin synthase initiated a reexamination of the biochemical pathways for ligand-induced prostaglandin synthesis. As a result, new pharmaceutical agents with potential activity against pain, fever, chronic and acute inflammation, cardiovascular disorders, and colon cancer have been developed and are currently under intense investigation. Careful biochemical and pharmacologic studies of the differences between the constitutive and inducible prostaglandin synthase enzymes have suggested a previously unexpected mechanism for some of the therapeutic effects of aspirin. Identification of a new phospholipase, and recognition of its role in mast cell prostaglandin production and in transcellular prostaglandin synthesis, have identified additional potential targets for pharmacologic intervention in inflammation and other prostaglandin-mediated disorders. PMID- 21235926 TI - Cardiac Myosin-binding protein C and hypertrophic cardiomyopathy. AB - The cardiac myosin-binding protein C (MyBP-C) is a sarcomeric protein belonging to the intracellular immunoglobulin superfamily; it has both structural and regulatory roles. The gene-encoding cardiac MyBP-C in humans is located on chromosome 11p11.2, comprises over 21,000 base pairs, and contains 35 exons. Mutations have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy. Familial hypertrophic cardiomyopathy is an autosomal dominant disease characterized by ventricular hypertrophy associated with a large degree of myocardial and myofibrillar disarray. Most mutations found in the cardiac MyBP-C gene thus far are predicted to lead to an altered mRNA sequence and to produce the C-terminal truncation of the cardiac MyBP-C polypeptides lacking the myosin-binding site and also, in some cases, the titin-binding site. One might reasonably assume that the cardiac MyBP-C mutations exert their effect by altering the multimeric complex assembly of the cardiac sarcomere via the "null allele" mechanism, potentially leading to haploinsufficiency, and/or via a dominant negative effect of a misfolded RNA on the cardiac MyBP-C translation, which could interfere with the proper assembly of sarcomeric structures. These data underline the functional importance of MyBP-C in the regulation of cardiac work and provide the basis for further studies and for the production of transgenic animals for cardiac MyBP-C that will, one hopes, help to resolve the pathogenesis of chromosome-11-associated familial hypertrophic cardiomyopathy. PMID- 21235927 TI - Specificity of G(q) and G(11) Protein Signaling in Vascular Myocytes. AB - The molecular diversity of receptors and the capability of these receptors to activate multiple types of G proteins theoretically allow the transmission of signals through multiple effector pathways. In functional experiments, however, the number of possibilities may be strongly reduced. We have recently reported that in vascular myocytes, alpha(1)-adrenoceptors activate two G proteins composed of alpha(q)/beta(1)/gamma(3) and alpha(11)/beta(3)/gamma(2) subunits, leading to increase in cytoplasmic [Ca(2+)](i) concentration. Only the alpha(q) subunit transduces the signal to a phospholipase C-beta, which hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate inositol 1,4,5-trisphosphate and the subsequent release of Ca(2+) from the intracellular store. In contrast, the alpha(11) subunit activates Ca(2+) entry through a nonspecific cation channel in the presence of increased [Ca(2+)](i) level. These coupling mechanisms reveal the distinct participation of G(q) and G(11) in the regulation of vascular contractility. Specific G(q)- or G(11)-activated pathways should be taken into account to understand the various contraction profiles induced by different vasoconstrictors. PMID- 21235928 TI - Regulation of Cytoskeleton and Cell Adhesions by the Small GTPase Rho and Its Targets. AB - The Rho GTPase is a member of the Rho family, which belongs to the Ras superfamily of GTP-binding proteins. Like other GTP-binding proteins, Rho exhibits both GDP/GTP-binding activities and functions as a molecular switch, cycling between an inactive GDP-bound state and an active GTP-bound state. Rho regulates the actin cytoskeleton and cell adhesions through its specific targets. Rho is also involved in the regulation of cell morphology, cell motility, cytokinesis, and smooth muscle contraction. Until recently, however, the molecular mechanism by which Rho regulates these functions remained to be clarified. A lot of targets of Rho have recently been identified, and characterization of some of them has provided useful information for our understanding of Rho functions. This review is an attempt to focus on the roles of Rho and its targets in the regulation of the cytoskeletons and cell adhesions. PMID- 21235929 TI - Chemokines and their role in cardiovascular diseases. AB - Leukocyte infiltration into inflammatory or injured tissues requires a variety of cell-associated and soluble factors that mediate the communications between circulating leukocytes and vascular cells. During the past decade, a superfamily of polypeptide leukocyte chemoattractants known as chemokines has been identified and demonstrated to selectively induce rapid endothelial cell adhesion and transmigration of leukocyte subpopulations. Chemokines are produced by virtually every mammalian somatic cell type in response to inflammatory and immunologic stimuli and have been detected in tissues of numerous disease states characterized by infiltration of distinct leukocyte subsets. Chemokines bind and activate cell surface receptors that belong to the seven transmembrane, G protein coupled receptor superfamily. Several chemokine receptors have been identified as fusion cofactors for human immunodeficiency virus type 1 (HIV-1). Chemokines have also been shown to play a critical role in atherosclerosis and ischemic reperfusion injury. As chemokine research is a rapidly expanding area, it is the purpose of this brief review to summarize recent progress in the field and to focus on the involvement of chemokines in cardiovascular diseases. PMID- 21235930 TI - Beyond fibrinolysis: the role of plasminogen activator inhibitor-1 and vitronectin in vascular wound healing. AB - Plasminogen activator inhibitor-1 (PAI-1), as the name implies, is the primary in vivo inhibitor of both tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). PAI-1 also binds to other nonproteinase ligands, including the matrix protein vitronectin, glycosaminoglycans such as heparin, and the endocytic clearance receptor, the low-density-lipoprotein-receptor-related protein (LRP). PAI-1 belongs to the superfamily of serine proteinase inhibitors (serpins), and, like other serpins, it acts as "suicide inhibitor" that reacts only once with a target proteinase. The suicide mechanism results in irreversible modification of the serpin and an extensive change in its conformation. In the case of PAI-1, this conformational change is important not only for inhibition of the proteinase, but it also causes changes in affinity for vitronectin and LRP. These changes have important consequences for cell migration. PMID- 21235931 TI - Cardiomyocyte gap junctions: a target of growth-promoting signaling. AB - Gap junctions (GJ), composed of connexins, are membrane channels that connect and enable communication between neighboring cells and which, in addition to being essential for the coordinated electrical and contractile activity of the heart, may regulate intercellular transmission of signals affecting proliferative growth. Alterations in GJ permeability that have been associated with the regulation of growth can occur acutely through phosphorylation of connexins: fibroblast growth factor-2 (FGF-2) causes decreased coupling and increased phosphorylation of a major cardiomyocyte connexin, connexin43 (Cx43), while stimulating proliferation of cardiomyocytes. On the other hand, transforming growth factor-beta (TGFbeta) prevents the effects of FGF-2 on Cx43 phosphorylation, as well as canceling the FGF-2-induced proliferation. Parallel to its link with growth regulation, Cx43 phosphorylation emerges as a functionally important end point for delineating cardiac signal transduction pathways elicited by diverse physiologic or pathologic stimuli. PMID- 21235932 TI - Phylogenetic species concepts. PMID- 21235933 TI - Avian species described on the basis of DNA only. PMID- 21235934 TI - Precipitation and the transfer of water, nutrients and pollutants in tree canopies. AB - The functioning of a forest community depends upon the routes, rates and transformations of material flowing through it. The canopy's interaction with precipitation can result in the interception of rainfall and the scavenging of water from clouds and fog. But this movement of water through the canopy also mediates the transfer of mineral nutrients and the deposition of some atmospheric pollutants. The past decade has seen the development of increasingly complex models of transfer processes in the canopy and new methodologies for studying them. One impulse for these advances has been the need to understand not only the movement of water, nutrients and pollutants but also their reciprocal effects. Another has been the need to evaluate the nature of pollutant-induced effects with respect to the costs and effectiveness of possible remedies. PMID- 21235935 TI - Filial cannibalism in fishes: Why do parents eat their offspring? AB - Filial cannibalism (the eating of one's own offspring) occurs in a variety of taxa, but is especially prevalent in fishes with parental care. Recent research supports a central tenet of parental-investment theory; that is, parents consume their offspring when it maximizes their lifetime reproductive success. This review outlines the theoretical framework used to explain the adaptive significance of filial cannibalism, evaluates experimental studies to test some predictions of this theory and discusses how the occurrence of filial cannibalism affects other aspects of a species' reproductive ecology. PMID- 21235936 TI - Interrelationships of yuccas and yucca moths. AB - Purposeful pollination of yucca by females of a moth that produces larvae that feed on some of the seeds is a classic example of plant-animal mutualism. Recent research has focused on the complex interspecific nature of this association. Pollinators are members of two genera with different oviposition and larval biologies. There appear to be several sibling species among populations of the pollinator that were formerly considered to be a single widespread generalist, and these may include sympatric nonpollinator 'cheaters'. Bogus yucca moths, members of a third genus, which neither transport pollen nor feed in the seed but depend upon the inflorescences, are niche specific and often host-species specific and include one leaf-mining species. Their larvae can spend many years in diapause before synchronized development. PMID- 21235937 TI - Optimal allocation of resources to growth and reproduction: Implications for age and size at maturity. AB - The schedule of growth and reproduction is crucial to maximization of fitness. Models of optimal allocation of limiting resources are useful tools for predicting age and size at maturity - key components of fitness - for all lifestyles. Early models considered annual plants. Recently, they have been generalized to other short-lived organisms and also to perennials in which growth and reproduction schedules following maturation can be predicted. A review of existing models shows that differences in trophic conditions and mortality are the main sources of inter- and intraspecific variation in size. PMID- 21235938 TI - Moose and birch: How to live on low-quality diets. AB - Ten years ago, the question of forage use by moose largely focused on whether nutritive factors or secondary compounds determined their use of individual tree species. Today, it is clear that both are important. Research during the last few years has tried to explain the hierarchical decisions in the foraging patterns of moose. PMID- 21235939 TI - Ecology, mythology and the organismic way of thinking in limnology. AB - For laymen, the word 'ecology' has become naturally surrounded with mythological mist. The influence of mythological thinking on ecology as a science is not so evident, but it certainly exists and in some aspects it can hardly be overestimated. The idea of the organism as a model or matrix for shaping new knowledge about populations, communities and ecosystems is extremely important in the maintenance of mythological thinking in modern ecology. We may even consider the organismic ideas as a vehicle of mythology in modern ecology. to this article, the problem is illustrated with limnology - an advanced branch of ecology in which it is easier to see the connections and contradictions between the dominant approaches. PMID- 21235940 TI - Evolution of alternation of haploid and diploid phases in life cycles. AB - Eukaryotic sex leads to an alternation of haploid and diploid nuclear phases. Because all multicellular animals are diploid, diploidy is often considered a 'biological success' and many arguments have been advanced to explain the evolution of a prolonged diploid phase. Nevertheless, among eukaryotes three basic situations are encountered, where the vegetative individuals are diploid or haploid or both. These three basic life cycles are widely distributed among kingdoms and in some taxa the occurrence of different life cycles within the same species has been reported. This article briefly summarizes the different hypotheses on the evolution of reproductive life cycles and underlines how possibilities of variation for this trait may open new perspectives for research. PMID- 21235941 TI - Sexual preference and genetic correlations. PMID- 21235942 TI - Sexual selection: Badges and signals. PMID- 21235943 TI - Reply from christine boake. PMID- 21235944 TI - Reply from marlene zuk. PMID- 21235945 TI - Using biotic interactions to forecast the consequences of global climate change. PMID- 21235946 TI - Darwin sound on comparative method. PMID- 21235947 TI - Spatiotemporal dynamic models of plant populations and communities. AB - The idea of relating spatial patterns and temporal processes in plant community dynamics is not new, but its transformation into realistic spatiotemporal models is the result of quite recent methodological developments. There are now two classes of analytical model and a broad class of simulation models pertaining to the role of spatial structure in vegetation dynamics. They indicate that any community-dynamical theory intended to be predictive should not omit the spatial aspects of plant population dynamics, because these may radically change the conditions of persistence and coexistence. PMID- 21235948 TI - Measuring the costs of reproduction. AB - The measurement of costs of reproduction is of interest because such costs are generally assumed by life history theory. There is some controversy concerning how to measure costs: common methods include experimental manipulations of life history, such as preventing some individuals from reproducing, or estimates of genetic correlations. These two methods often yield similar results, suggesting that one can serve as a substitute for the other. There are now experiments which demonstrate that there are different mechanisms underlying the response to an experimental manipulation versus a genetic correlation, so the two methods are not equivalent in estimating costs. PMID- 21235949 TI - Evolution of insect pollination and angiosperm diversification. AB - Insect pollination is a prominent type of plant-insect mutualism that can provide clues to the nature of diffuse coevolution. A long-standing question in this field is to what extent the emergence of insect polination caused rapid diversification in the interacting organisms. Recent progress in systematics and paleontology is providing much of the information needed to address this issue. PMID- 21235950 TI - The ideal free distribution and predator-prey populations. AB - The ideal free distribution, a theoretical model of the distribution of competitors between habitat patches, has recently undergone a number of modifications and extensions. These fall into two main categories: those that assume that equilibrium is attained, and those that establish whether it is attained. The modifications suggest ways in which behavioural properties of individuals might affect the distribution of competitors, and clear a path for further empirical tests. PMID- 21235951 TI - Phylogeny and biodiversity: Conserving our evolutionary legacy. AB - Historical ecological studies provide information about the origins of species in an area and the origins of traits characterizing the interactions between those species and their environment. Incorporating this evolutionary information into conservation policies will broaden the base of options for making effective decisions about the preservation of biodiversity. PMID- 21235952 TI - Pleiotropic action of parasites: How to be good for the host. AB - Parasites reduce the reproductive output of their hosts, limit their growth, and sometimes even castrate or hill them. Under certain conditions however, a parasitized host may be better off than an uninfected one. Such 'nice' parasites have a 'pleiotropic' action on their hosts. Parasites can be pleiotropic either in space (in which case they have a beneficial effect on the host in one environment while being detrimental in another) or in time (the parasite is beneficial at one stage of the host's development and 'costly' at another stage). Such pleiotropic parasites may constitute the intermediate stage between parasitism and mutualism. PMID- 21235953 TI - Models of the evolution of phenotypic plasticity. PMID- 21235954 TI - Tropical forest exploitation. PMID- 21235955 TI - Angiosperm origins: Reply to Donoghue and Doyle. PMID- 21235957 TI - 'Biopesticides' turning into new pests? PMID- 21235956 TI - Reply from john thompson. PMID- 21235958 TI - Goose populations: Conservation, conflict and solutions. PMID- 21235959 TI - Monastic meeting questions paternity. PMID- 21235960 TI - Progress with methods for constructing evolutionary trees. AB - Evolutionists dream of a tree-reconstruction method that is efficient (fast), powerful, consistent, robust and falsifiable. These criteria are at present conflicting in that the fastest methods are weak (in their use of information in the sequences) and inconsistent (even with very long sequences they may lead to an incorrect tree). But there has been exciting progress in new approaches to tree inference, in understanding general properties of methods, and in developing ideas for estimating the reliability of trees. New phylogenetic invariant methods allow selected parameters of the underlying model to be estimated directly from sequences. There is still a need for more theoretical understanding and assistance in applying what is already known. PMID- 21235961 TI - Sex allocation in hermaphroditic plants. AB - Hermaphroditic plants allocate their reproductive resources to different functions: male, female and pollinator attraction. While earlier sex-allocation models considered only male and female functions, more recent ones can divide reproductive resources into multiple functions. The basic predictions derived from these models are similar. While most models predict sex allocation at the fruit stage (pollen and seeds), some have examined allocation at the flower stage (pollen and ovules). Selfing rate, mode of pollination and competition among offspring of the same parent are some of the factors that can influence sex allocation among populations. Although the empirical evidence lags behind the theoretical development, sex-allocation theory has been quite successful at predicting trends among populations. PMID- 21235962 TI - The Cambrian radiation of shelly fossils. AB - One of the most significant events in the history of the organic world was the acquisition by animals of the ability to build a skeleton. This is of special interest because the overwhelming majority of known major groups (phyla) acquired that ability during a very short period (five to seven million years), early in the Cambrian. Recent fossil finds, especially in northern Asia, are adding much detail to our knowledge of this period. PMID- 21235963 TI - Megapodes: Recent ideas on origins, adaptations and reproduction. AB - Some birds don't incubate their eggs using the warmth of their bodies. The megapodes have evolved a markedly different method of incubation. By making use of environmental heat, adult megapodes are emancipated from most of the usual constraints to reproductive success associated with parental care. Consequences of this unique incubation method are evident in all aspects of megapode development and behaviour. Recently, renewed interest in these birds from a number of disciplines has led to significant advances, especially in aspects associated with reproduction. Both eggs and embryos exhibit remarkable adaptations to the physiologically stressful incubation environment. The use of various types of incubation heat may also shape the mating systems of the species involved. PMID- 21235964 TI - Fisher's fundamental theorem of natural selection. AB - Fisher's Fundamental Theorem of natural selection is one of the most widely cited theories in evolutionary biology. Yet it has been argued that the standard interpretation of the theorem is very different from what Fisher meant to say. What Fisher really meant can be illustrated by looking in a new way at a recent model for the evolution of clutch size. Why Fisher was misunderstood depends, in part, on the contrasting views of evolution promoted by Fisher and Wright. PMID- 21235966 TI - Measuring reproductive costs. PMID- 21235965 TI - Statistics, costs and rationality in ecological inference. AB - The so-called 'null hypothesis' debate in ecology opened a statistical Pandora's Box. Ecologists were forced to question whether or not decades of pattern analysis had been productive. Over the past few years, the debate has expanded beyond the role of different kinds of statistical hypothesis to include the importance of different types of statistical error. Our objective in this article is to show how trends governing ecological inferences under uncertainty appear to be changing as ecologists become increasingly aware o f the potential importance of statistical errors. PMID- 21235967 TI - Kin recognition and kin discrimination. PMID- 21235968 TI - Altruistic cannibalism and superorganisms. PMID- 21235969 TI - Reply from C.j. Barnard. PMID- 21235971 TI - Inverse modelling and the global carbon cycle. PMID- 21235970 TI - Adaptive significance of avian helping behaviour. PMID- 21235972 TI - Biodiversity and ecosystem processes. PMID- 21235973 TI - The dynamics of serengeti research. PMID- 21235974 TI - Long-term population studies of seabirds. AB - Long-term studies of seabirds, some now 30-40 years old, have begun to reveal significant age-related changes in the survival and reproduction o f these long lived animals. Evidence for density-dependent regulation of seabird numbers, however, remains sparse whereas unpredictable, disastrous breeding years may be an important influence. Critical evaluation will require better data on (1) the extent of movements of seabirds between colonies, (2) the characteristics of those individuals that contribute disproportionately to the next generation, and (3) the importance of year and/or cohort effects on population processes. PMID- 21235975 TI - Marine speciation on a small planet. AB - The scale of population structure in many marine species is on the order of thousands to tens of thousands of kilometers. How does speciation take place in oceans that are only about this same size? Recent results suggest an important role for transient isolation, gamete ecology and molecular evolution at gamete recognition loci. These factors have long been appreciated by plant biologists, and are likely to be a fruitful area of research for marine biologists as well. PMID- 21235976 TI - What is a quasispecies? AB - A quasispecies is a well-defined distribution of mutants that is generated by a mutation-selection process. Selection does not act on a single mutant but on the quasispecies as a whole. Experimental systems have been designed to study quasispecies evolution under laboratory conditions. More recently, virus populations have been called quasispecies to indicate their extensive genetic heterogeneity. The most prominent examples are probably the human immunodeficiency viruses HIV-1 and HIV-2. The quasispecies nature of HIV has formed the basis of a model that provides a mechanism for the pathogenesis of acquired immunodeficiency syndrome (AIDS) in humans. This article focuses on the nature of the quasispecies concept and its implications for evolutionary biology and virology. PMID- 21235977 TI - Muroid rodents: Phylogeny and evolution. AB - The Muroidea, a group of rodents that includes mice, rats, gerbils, hamsters and others, encompasses a tremendous diversity of fairly recent geological origin. The taxonomy, systematics, phylogeny and paleontology of the muroid rodents have progressed enormously during the last two decades, and many hypotheses on their evolutionary biology have been formalized. Nevertheless, there still remain important unanswered questions - regarding, for example, local conflicts between molecular and paleontological data, or the origin of the fast rate of DNA change in rats and mice - that need more investigation. PMID- 21235978 TI - Evolution of resistance and virulence in plant-herbivore and plant-pathogen interactions. AB - Herbivores and pathogens often attack or infect the same plant parts, and the same plant traits can affect the likelihood and degree of damage. Research on plant-herbivore and plant-pathogen interactions in natural systems have, however, proceeded largely independently of each other. Our understanding of both types of plant-enemy interaction would be enhanced by greater exposure of researchers to developments in both disciplines and by more studies of interactions between pathogen and herbivore species associated with the same hosts. PMID- 21235979 TI - For adults only? Supply-side ecology and the history of larval biology. AB - When ecologists study organisms with multiphasic life cycles, they must often confront the problem of which phase to scrutinize. In principle, the dynamics and interactions of all stages could play a major role in the regulation of adult populations and species assemblages. In practice, however, the roles of larger and more sedentary phases - being easier to count and manipulate than motile propagules - have been emphasized. Nonetheless, several recent studies on the small, dispersing larval phase of marine invertebrate life cycles reach the conclusion that the spatial distribution and supply of propagules can control the distribution and abundance of populations of benthic adults. To some, the present emphasis on planktonic propagules amounts to a resurrection of ideas developed during a long and rich history of larval biology. To others, studies of demographic and ecological connections between larval and adult populations represent a substantial revision of ecological paradigms. PMID- 21235980 TI - Evolutionary consequences of basic growth equations. PMID- 21235981 TI - Reply from T.j. Case. PMID- 21235982 TI - Biogeography of island lizards. PMID- 21235983 TI - Measuring reproductive costs: Response to partridge. PMID- 21235984 TI - Reply from Michael fogarty. PMID- 21235985 TI - Marine recruitment. PMID- 21235986 TI - Plant succession and life history strategy. PMID- 21235988 TI - Hurricanes in tropical forests. PMID- 21235987 TI - Covert sex. PMID- 21235989 TI - Evolution of sex in RNA viruses. AB - Viruses can reproduce sexually. Sex in some RNA viruses is so different from sex in eukaryotes that it may have evolved independently. Yet, recent research indicates that sex in both groups can be accounted for by models of either positive or purifying selection. This review appraises the role that these types of selection may have played in the evolution of sex in RNA viruses. PMID- 21235990 TI - Intraguild predation: The dynamics of complex trophic interactions. AB - There is a long-standing debate in ecology concerning the relative importance of competition and predation in determining community structure. Recently, a novel twist has been added with the growing recognition that potentially competing species are often engaged in predator-prey interactions. This blend of competition and predation is called intraguild predation (IGP). The study of IGP will lead to a reconsideration of many classical topics, such as niche shifts, species exclusion and cascading interactions in food webs. Theoretical models suggest that a variety of alternative stable states are likely in IGP systems, and that intermediate predators should tend to be superior in exploitative competition. Many field studies support these expectations. IGP is also important in applied ecological problems, such as the conservation of endangered species and fisheries management. PMID- 21235991 TI - Foraging strategies of spiders. AB - Abundant and ecologically important in many ecosystems as predators of insects (including agricultural pests), spiders have recently gained attention as a result of a number of significant studies. In addition, because of their small size, short lifespan, and the strong influence of genetic control on their behavior, spiders are regarded with keen interest as model organisms in behavioral ecology. PMID- 21235992 TI - Use of fibrous diets by small herbivores: How far can the rules be 'bent'? AB - Allometric considerations suggest that small mammals should be unable to eat highly fibrous diets. A combination of the selective and more rapid passage of fibrous material through the gut, together with changes in gut capacity when energy requirements increase, may allow small mammals to escape these allometric constraints. Recent evidence that birds can absorb essential amino acids from the caecum (which has hitherto been considered insignificant in mammals) suggests that birds and mammals have evolved very different ways to be a herbivore. PMID- 21235993 TI - Visual textures, machine vision and animal camouflage. AB - The psychophysics of visual texture perception and texture discrimination have been investigated extensively during the past 30 years. Humans have been the main study subjects, but some research on texture perception has involved other species, and there is good reason to think that the most general results from humans apply to other vertebrates as well. Psychophysicists have suggested that some of their findings on human vision reflect adaptive 'tricks' for countering prey camouflage, but this possibility has not been widely communicated to evolutionary biologists. We review the psychophysicists' main conclusions on texture discrimination, and list additional questions that their results raise when animal coats are considered as visual textures. We also suggest ways in which advances in computer vision can be combined with psychophysics to provide new perspectives on the function of animal coat patterns. PMID- 21235994 TI - New bird species, DNA studies and type specimens. PMID- 21235995 TI - Ecology and systematics. PMID- 21235996 TI - Reply from austin hughes. PMID- 21235997 TI - Reply from R.m. Coleman and m.R. Gross. PMID- 21235999 TI - How long is the life span of a root? PMID- 21235998 TI - How to rescue the concorde fallacy. PMID- 21236000 TI - Is female sexual behaviour a neglected topic? PMID- 21236001 TI - On the origin of the genetic code. PMID- 21236002 TI - Individual voice recognition in birds. PMID- 21236003 TI - New computer architectures as tools for ecological thought. AB - Recent achievements of computer science provide unrivaled power for the advancement of ecology. This power is not merely computational: parallel computers, having hierarchical organization as their architectural principle, also provide metaphors for understanding complex systems. In this sense they might play for a science of ecological complexity a role like equilibrium-based metaphors had in the development of dynamic systems ecology. Parallel computers provide this opportunity through an informational view of ecological reality and multilevel modelling paradigms. Spatial and individual-oriented models allow application and full understanding of the new metaphors in the ecological context. PMID- 21236004 TI - Arctic biogeography: The paradox of the marine benthic fauna and flora. AB - The marine benthic fauna and flora that inhabit the shallow arctic sublittoral zone comprise a relatively young marine assemblage characterized by species of either Pacific or Atlantic affinity and notably few endemics. The young character of nearshore arctic communities, as well as their biogeographical composition, is largely a product of the Pleistocene glaciation. However, analysis of more recent collections and comparison between the origins of the benthic fauna and flora present some interesting paradoxes to biogeographers. One enigma is the low frequency of algal species with Pacific affinities in the Arctic, especially in the Chukchi, Beaufort and East Siberian Seas of the Eastern Arctic, which receive direct inputs of northward-flowing Pacific waters. In contrast, animal species with Pacific affinities are found throughout the nearshore regions of the Arctic, reaching their highest frequency in the marginal seas between the New Siberian Islands and the Canadian Archipelago. Organization of published and unpublished data, additional field collections, and the use of cladistics and molecular DNA techniques by systematists are a high priority for future research in reconstructing the evolution of the arctic biotic assemblage. PMID- 21236005 TI - Nothofagus: Evolution from a southern perspective. AB - Nothofagus holds a premier position in the study of Southern Hemisphere plant evolution and biogeography, and many have attempted to reconstruct its history. A recent surge of research on both living and fossil species has added valuable data to the debate, but has also introduced complications, including the now less certain familial relationships of the genus. The vast quantity of fossil evidence provides an extremely firm base for reconstruction of the past distribution of Nothofagus, and allows informed speculation on the time and places of origin and major speciation events. PMID- 21236006 TI - Commensal and mutualistic interactions among terrestrial vertebrates. AB - Although overlooked in many field studies, commensal and mutualistic interactions occur frequently between species of terrestrial vertebrates. Potential advantages for individuals in mixed-species associations are very diverse, and include reduction in parasite load, reduced risk of predation, and increased access to food and other resources. Recent theoretical and experimental studies reveal the prevalence of such interactions among terrestrial vertebrates, and also confirm their importance within communities thought previously to be dominated by interspecific competition. PMID- 21236007 TI - How should we define 'fitness' for general ecological scenarios? AB - Beginners in life history theory or evolutionary ecology seemingly face a variety of almost unrelated approaches. Yet the biomathematical literature of the last 10 20 years reflects the implicit acceptance of a common evolutionary framework, the core idea being that there exists a unique general fitness measure that concisely summarizes the overall time course of potential invasions by initially rare mutant phenotypes. Using such an invasion criterion to characterize fitness implicitly presupposes a scenario in which, during periods o f clear evolutionary change, the rate of evolution is set primarily by the random occurrence (and initial establishment) of favourable mutations. Evolutionarily stable life history strategies (ESSs) may then be regarded as traps for the evolutionary random walk. PMID- 21236008 TI - Beyond the prisoner's dilemma: Toward models to discriminate among mechanisms of cooperation in nature. AB - The iterated prisoner's dilemma game, or IPD, has now established itself as the orthodox paradigm for theoretical investigations of the evolution of cooperation; but its scope is restricted to reciprocity, which is only one of three categories of cooperation among unrelated individuals. Even within that category, a cooperative encounter has in general three phases, and the IPD has nothing to say about two of them. To distinguish among mechanisms of cooperation in nature, future theoretical work on the evolution of cooperation must distance itself from economics and develop games as a refinement of ethology's comparative approach. PMID- 21236009 TI - The methuselah factor: Age in cryptoendolithic communities. PMID- 21236010 TI - Persistence, drugs and rock'n'roll. PMID- 21236011 TI - When conservation goes to the dogs. PMID- 21236012 TI - Flightlessness in insects. AB - The evolution of wings is heralded as the most important event in the diversification of insects, yet flight-wing loss has occurred in nearly all pterygote insect orders. Flight loss is especially prevalent among taxa inhabiting historically stable habitats. Recent studies of wing-polymorphic species have revealed numerous selective trade-offs in the reproductive potentials of winged versus flightless forms. A diverse set of environmental factors, both biotic and abiotic, trigger flight loss in alary polyphenic taxa, presumably by influencing juvenile hormone titers. Phylogenetic comparisons promise to elucidate much about the historical contexts and consequences of flight loss. PMID- 21236013 TI - Nitrogen cycling and nitrogen saturation in temperate forest ecosystems. AB - The last decade has seen a dramatic shift in the focus of nitrogen cycling research in forest ecosystems. Concerns over nitrogen deficiencies and effects of removal in harvest have given way to concerns over excess nitrogen availability and the potential for forest decline and surface water pollution. Driving this paradigm shift is the increase in atmospheric deposition of nitrogen to forests due to industrial and agricultural activity. At the core of the new paradigm is the concept of 'nitrogen saturation' of forest ecosystems. The purpose of this review is to synthesize recent advances in research relating to nitrogen deposition effects on temperate zone forest ecosystems, and the further effects of nitrogen saturation on environmental quality. PMID- 21236014 TI - Echinoderm phylogeny: Morphology and molecules approach accord. AB - Phylogenetic relationships of echinoderms at various taxonomic levels have come under intense focus recently from both a morphological and a molecular standpoint. Initial conflict between molecular and morphological results is gradually being resolved to produce a consensus that places echinoderm Phylogeny on a new robust footing. PMID- 21236015 TI - Copying and sexual selection. AB - Recent studies of a variety of polygynously mating animals indicate that females do not always choose mates independently, but instead may copy the choices of others. Copying could serve either to increase the accuracy of mate assessment or to reduce its costs. It is also likely to affect the intensity of sexual selection. PMID- 21236016 TI - Population genetics and ecology of Artemia: Insights into parthenogenetic reproduction. AB - The relative advantages of sexual and parthenogenetic reproduction have long interested biologists and remain a central issue in ecological and evolutionary studies. Recent data on brine shrimp (Artemia) indicate that extensive ecological and genetic divergence occurs in an obligately parthenogenetic lineage. This challenges the belief that parthenogenetic lineages are evolutionary 'dead ends' and that extensive divergence is necessarily linked to recent recruitment from sexual ancestors. The molecular evidence suggests that parthenogenesis in Artemia is relatively ancient, with a single asexual lineage branching from an Old World sexual ancestor approximately five million years ago. Automictic recombination (which can occur in diploid but not polyploid parthenogenetic brine shrimp) appears to play a central role in the long-term maintenance of the parthenogenetic lineage. PMID- 21236017 TI - Pipefishes and seahorses: Are they all sex role reversed? AB - The male pregnancy of pipefishes and seahorses has led to the inference that females compete most intensely for access to mates, because males limit female reproduction. However, recent work has shown that in different species either sex may be the predominant competitor for mates. In this family, there is an apparent association between the mating pattern and the sex roles: polygamous species show reversed sex roles whereas monogamous species exhibit 'conventional' sex roles. These studies emphasize that sex role reversal is not synonymous with male parental care. PMID- 21236019 TI - Pleiotropic parasites and life history theory. PMID- 21236018 TI - Chromosome variability in tumours and cell lines. PMID- 21236020 TI - The role of scientists and foresters in the wise management of tropical forests. PMID- 21236021 TI - Experimental evolution: Replicating history. PMID- 21236022 TI - Understanding bird distributions. PMID- 21236023 TI - Endangered bryophytes in Europe. PMID- 21236024 TI - Orchid pollination biology. AB - Orchids display many unsurpassed floral specializations, as both rewarders and frauds in their interaction with animal pollinators. Accumulating evidence indicates that their floral evolution is driven by pollinator traits and that expenditure for maximized sexual reproduction is parcelled out over their lifetimes in strategies for coping with pollinator and resource limitations. Recent advances in orchid pollination biology center mainly on floral evolutionary processes, pseudocopulation and other deceptive pollination systems, and flower and fruit production in relation to costs of sexual reproduction. PMID- 21236025 TI - Seasonal drought, soil fertility and the species density of tropical forest plant communities. AB - Recent comparisons of plant species densities in tropical forest make it possible to evaluate factors that govern species richness. Contrary to earlier predictions, plant species densities are not greater on soils of relatively low fertility. In fact, the opposite trend is often observed, although the relationship between species densities and soil fertility is highly variable. However, tropical forest plant species densities consistently increase with rainfall. Species coexistence in wetter tropical forests may be facilitated by the absence of competition for moisture combined with year-round pest pressure and low understory light levels, which reduce growth rates and the potential for competition for other resources. PMID- 21236026 TI - Positive feedback in aquatic ecosystems. AB - Aquatic ecosystems offer striking examples of how positive feedback can be integral to the dynamics of complex communities. In particular, microorganisms (bacteria and protozoa) introduce a multitude of positive feedback pathways by rapidly recycling nutrients at the very base of many aquatic food webs. The relatively large magnitude of fluxes being shunted through this 'microbial loop' allows an accumulation of nutrients in localized areas, promotes a general build up of biomass, and acts as a 'life-support system' in harsh environments. In contrast to customary notions which portray positive feedback effects as undesirable, a reassessment indicates that this 'bootstrapping' can often be advantageous for many organisms. PMID- 21236027 TI - Ecological engineering - An idea whose time has come? AB - The era of cheap fossil fuels is nearing its end. industrial, agricultural and human pollutants have reached alarming levels in water, soil, air and stratosphere. Consumers no longer tolerate poisons in their food and water, are now concerned with global warming and ozone depletion, and value fields and forests for their scenery and wildlife as well as food and fibre. We are at the crossroads, searching for answers to these and many other pressing ecological problems. On one side sit 'deep ecologists' who patiently await the reactions of global Gaia. On the other sit 'biotechnologists' who would design and build new organisms and new ecosystems. The first approach is defeatist, for it awaits the decimation of the human population. The otheris activist, but will it work? Here we examine the idea of 'ecological engineering', which offers some promise of solutions to our problems if it can integrate the practical sides of ecosystem, landscape, community and population ecology with relevant formal concepts from the engineering sciences. PMID- 21236028 TI - Aerial web-weaving spiders: Linking molecular and organismal processes in evolution. AB - Aerial web-weaving spiders display a wide variety of foraging behaviors that can be tied to the evolution of one family of proteins, the silks. In some cases, the physical structure and mechanical properties of silks alone determine the ecology of spiders: the habitats in which they forage, the prey they capture and their subsequent reproductive success. Future studies that integrate research on the physical structure of silks, the molecular genetics of silk synthesis and the foraging ecology of spiders in primitive and derived phylogenetic groups could reveal how molecular and organismal processes interact in evolution. PMID- 21236029 TI - Flowering phenology: An example of relaxation of natural selection? AB - Flowering phenology has normally been viewed as fundamental to a plant species' reproductive ecology. Researchers in the field have emphasized the adaptive importance of flowering at a particular time relative to other individuals in the population, or other species in the community. An alternative view, however, is that flowering phenology is a trait that may not be under strong selection, and this may have allowed some variation to appear in populations by chance. PMID- 21236030 TI - Recurrent viruses and theories of sex. PMID- 21236031 TI - Why is sex so frequent? PMID- 21236033 TI - Kinji Imanishi and ecology in Japan. PMID- 21236032 TI - Reply from lin chao. PMID- 21236034 TI - Is there a latitudinal diversity cline in the sea? PMID- 21236035 TI - Hydrodynamics and behaviour: Transport processes in marine invertebrate larvae. PMID- 21236036 TI - Predicting biological weed control. PMID- 21236037 TI - The evolutionary ecology of corals. AB - Corals display a wide range of complex life histories. The evolutionary consequences of factors such as clonality, indeterminate growth, asexual reproduction coupled with various (sexual) breeding systems, different levels of gene flow, and strongly overlapping generations have only just begun to be explored. We identify a series of problems and areas for new research that may be resolved b y the application of novel theoretical approaches (including nonequilibrium population genetic models and demographic models incorporating modular processes such as colony fission and polyp mortality), greater in situ experimentation, long-term monitoring of population dynamics and the use of new genetic techniques. PMID- 21236038 TI - The ecology and evolution of tetracycline resistance. AB - The use of tetracycline over the past few decades has been accompanied by a drastic increase in the frequency of tetracycline resistance in a wide range of bacterial species and genera. A diversity of resistance determinants is found in the microbial world, coding for markedly different mechanisms of resistance. The recent analysis of one family of resistance determinants provides evidence for intergenic and intragenic coevolutionary changes as well as for an unusual evolutionary history of duplication and divergence in function of domains within a single locus. PMID- 21236039 TI - Landscape ecology of boreal forests. AB - It is becoming increasingly clear that densities and dynamics of various organisms often cannot be understood from the processes occurring within separate habitat patches. Effects from surrounding areas also have to be considered; a landscape perspective has to be employed. Habitat mosaics affect diversity and dynamics both in pristine and managed boreal landscapes. There is increasing interest in the landscape ecology of boreal forests and many important processes have been identified as being driven or affected by environmental heterogeneity. Comparisons between ecological processes in original and managed boreal landscapes are urgently needed. PMID- 21236040 TI - The evolutionary dynamics of polyploid plants: origins, establishment and persistence. AB - The role of polyploidy in the origin of evolutionary novelty and the maintenance of diversity in plant populations has come to be recognized as an integral component of the ecological and evolutionary dynamics of plant species populations. Recent attempts to examine the evolutionary significance of polyploidy have focused on the processes responsible for the origin of polyploid plants and the conditions that favour their establishment and persistence. The importance of these issues is not simply limited to the evolutionary dynamics of polyploidy but is, in fact, central to our understanding of the population biology processes that act on the establishment of new 'types' and the maintenance of biotic diversity at both the inter- and intraspecific levels. PMID- 21236041 TI - Evolution of correlated characters. AB - Many traits are genetically correlated with each other. Thus, selection that changes the mean value of one trait causes other traits to change as well. Recent comparative studies have emphasized the possible importance of such correlated responses in affecting the evolution of traits, including some behaviors, which are of little adaptive significance, or even maladaptive. However, it is also possible for traits with major effects on fitness, such as brain size, to evolve entirely by correlated response. Other traits that do not appear to have evolved at all may have been subject to much directional selection, simply to prevent their evolution by correlated response. The new interest in correlated responses reflects more rigorous attempts to consider the organism as a whole, rather than dissecting it into a number of questionably separable traits. PMID- 21236042 TI - The meaning of natural selection revisited at the molecular level. AB - Various molecular interaction mechanisms cause biased transmission of genes. Meiotic drive is an example of strong bias, and compartmentalization of mammalian chromosomes reflects weak bias. Such biases are the results of interaction between DNA and proteins, and should be distinguished from natural selection. Separating the effects of molecular interaction from those of natural selection, however, is often very difficult. Natural selection and molecular mechanisms interact, and our understanding of how selection works requires revision. PMID- 21236043 TI - Reply from kacelnik, bernstein and krebs. PMID- 21236044 TI - Habitat selection and predator-prey dynamics. PMID- 21236045 TI - Intuition and the logistic equation. PMID- 21236046 TI - Intuition and the logistic equation. PMID- 21236047 TI - Intuition and the logistic equation. PMID- 21236048 TI - Intuition and the logistic equation. PMID- 21236049 TI - Reply from L. Ginzburg. PMID- 21236050 TI - Intuition and the logistic equation. PMID- 21236051 TI - The calculus of conserving biological diversity. PMID- 21236052 TI - Does population viscosity promote kin selection? PMID- 21236053 TI - Achieving a sustainable biosphere: An international endeavour. PMID- 21236054 TI - Sex-ratio adjustment in solitary and social spiders. PMID- 21236055 TI - Setbacks in the search for mate-preference genes. PMID- 21236056 TI - Delayed dispersal and cooperative breeding in the seychelles warbler. PMID- 21236057 TI - Biotic feedbacks in Lake phosphorus cycles. AB - Limnologists are now reconsidering the role of the biota in the phosphorus (P) cycles of lakes. Changes in lake communities can have significant consequences for ecosystem P cycles. At seasonal timescales, the relative importance of nitrogen (N) and Pas limiting factors for primary production depends in part on zooplankton species composition. Phosphorus storage and recycling by fish and zooplankton can be large components of P budgets, and mobile consumers can be important vectors in P transport. Stability, resilience and resistance of lake P cycles may depend heavily on fluxes to and from upper trophic levels. PMID- 21236058 TI - Effects of plant species on nutrient cycling. AB - Plant species create positive feedbacks to patterns of nutrient cycling in natural ecosystems. For example, in nutrient-poor ecosystems, plants grow slowly, use nutrients efficiently and produce poor-quality litter that decomposes slowly and deters herbivores. /n contrast, plant species from nutrient-rich ecosystems grow rapidly, produce readily degradable litter and sustain high rates of herbivory, further enhancing rates of nutrient cycling. Plants may also create positive feedbacks to nutrient cycling because of species' differences in carbon deposition and competition with microbes for nutrients in the rhizosphere. New research is showing that species' effects can be as or more important than abiotic factors, such as climate, in controlling ecosystem fertility. PMID- 21236059 TI - Geographic variation in Drosophila: From molecules to morphology and back. AB - The examination of spatial variation can act as a substitute for temporal variation in population studies. Of particular use in the effort to understand the selective forces that govern spatial variation are the sibling species Drosophila melanogaster and D. simulans. Recent work at the level of both molecules and morphology has uncovered a great deal of spatial variation within and between these two species. Here we summarize these data, with reference to what they tell us about the history and nature of selection operating in these species. PMID- 21236060 TI - Doing the right thing: Ants, honeybees and naked mole-rats. AB - Traditionally the division of labour in social insects has been divided into two types: physical and temporal polyethism. New theoretical models indicate that temporal polyethism may be an emergent property rather than an organizational principle. Current research is revealing the relationship between temporal polyethism and the role of nonspecialized individuals within species of physically polymorphic social insects. PMID- 21236062 TI - Reply from m. Altmann. PMID- 21236061 TI - More covert sex: The elusive females of myrmecolacidae. AB - Among evolutionary biologists, considerable interest currently surrounds organisms that seem to be represented entirely by females. Here we discuss a less familiar problem - that of organisms in which females appear to be lacking. Our main example is the Myrmecolacidae (Strepsiptera), an unusual group of entomophagous parasites with dual hosts. Males parasitize ants and females parasitize orthopterans. Although the free-living adult males are frequently collected, the permanently endoparasitic neotenic females are elusive and are seldom encountered. PMID- 21236063 TI - Recombinant biopesticides. PMID- 21236064 TI - Phylogenetics and conservation. PMID- 21236065 TI - Why do hopping mice have such tiny testes? PMID- 21236066 TI - When hot geology meets cold climate on an island. PMID- 21236067 TI - The riches of tropical forests: Non-aimber products. PMID- 21236068 TI - Interactions between climate and terrestrial ecosystems. PMID- 21236069 TI - Toward integration of plant defence theories. PMID- 21236070 TI - Comparative evolutionary ecology of seed size. AB - A seedling's chances of establishing successfully are likely to be affected by the quantity of metabolic reserves in the seed. Seed size is thought to evolve as a compromise between producing numerous smaller seeds, each with few resources, and fewer larger seeds, each with more resources. Seed size varies 10(11)-fold across plant species, so the compromise has been struck at very different levels. These basic ideas have been accepted for 50 years, and many studies have interpreted seed size differences between species by reference to larger seed size being adaptive under a variety of hazards. However, experimental tests of the benefits of large seed size in relation to particular hazards have been rare. More experiments are now being reported, but a consistent picture has yet to emerge. There is typically at least a 10(5)-fold range of seed mass between species even within a single area, suggesting that much seed size variation is evolutionarily associated with other plant attributes. PMID- 21236071 TI - Intranuclear conflict and its role in evolution. AB - The last 20 years have seen the accumulation of a large body of information on selfish genetic elements - genes that act to further their own evolutionary interests at a cost to the individual (genome) bearing them. During the last few years, a growing number of authors have suggested that the intragenomic conflict these elements create is not just an intriguing example of natural selection in action, but a driving force behind the evolution of genetic systems. A host of phenomena, from exquisite details of gene expression to the evolution of crossing over, from the existence of syncytia during gametogenesis to the amount of DNA present in eukaryotes and the existence of multicopy genes, may all be explicable as the result of conflict within the nuclear genome. PMID- 21236072 TI - Plastid origins. AB - There has long been controversy over whether the plastids of green plants and algae, rhodophytes and chromophytes arose from a single primary endosymbiotic event or independently from several. DNA sequences from plastid genes are rapidly becoming available, but limitations of current phylogenetic inference techniques make it difficult to draw firm conclusions at present. However, it is clear that the endosymbiotic uptake of photosynthetic prokaryotes or eukaryotes has been far from unique. PMID- 21236073 TI - Physiological limits to sustainable energy budgets in birds and mammals: Ecological implications. PMID- 21236074 TI - The role of corridors in conservation: Solution or bandwagon? AB - Corridors are currently a major buzzword in conservation biology and landscape ecology. These linear landscape features may perform numerous functions, but it is their role in facilitating movement of fauna that has attracted much recent debate. The database supporting the idea of corridors acting as faunal conduits is remarkably small, and few studies have actually demonstrated that movement along corridors is important for any given species. Such data are very difficult to obtain, and conservation biologists are thus faced with the problem of whether to recommend the allocation of resources to corridors on the assumption that they may be important. PMID- 21236075 TI - Reply from grosberg and levitan. PMID- 21236076 TI - Scientific communication: The burden of responsibility. PMID- 21236077 TI - Does environmental variation maintain genetic variation? A question of scale. PMID- 21236078 TI - Anarchie in the feminine monarchiel: The case of the cape bee. PMID- 21236079 TI - Optimal memory: Toward an evolutionary ecology of animal cognition? PMID- 21236080 TI - Plant invasions, interspecific hybridization and the evolution of new plant taxa. AB - Interspecific hybridization between a native and an invading plant species, or two invading species, sometimes results in a new, sexually reproducing taxon. Several examples of such taxa have been confirmed by recent molecular and isozyme analyses. Further study of these new taxa, when recognized soon after their origin, should aim to elucidate the factors that influence their subsequent establishment and spread, thus leading to a better understanding of the processes that lead to successful speciation. Plant hybrids formed following a plant invasion provide great potential for the study of 'evolution in action'. PMID- 21236081 TI - Parasites and sex: Catching the red queen. AB - One version of the Red Queen hypothesis suggests that sexual reproduction may be an advantage in a coevolutionary arms race. Antagonistic biotic interactions, especially those between parasite and host, are thought to represent a sufficient evolutionary force to counterbalance the supposed inefficiency of sexual reproduction. Recent experimental studies demonstrate negative frequency dependent selection, increased parasite load in parthenogenetic races relative to sympatric sexual conspecifics and correlations between recombination rate and frequency of parasitic chromosomes. These studies provide strong empirical evidence that there is an important role for parasites in maintaining sex. PMID- 21236082 TI - Parent-offspring conflict: A case of arrested development. AB - The theory of parent-offspring conflict (POC) provides a plausible evolutionary foundation for the dissonant behavioral interactions commonly observed between adults and their progeny. It has been modelled extensively, but its predictions for phenotypes are murky and have been subjected to scant empirical testing. The least ambiguous cases are likely to involve taxa where offspring exert real power. Recent experimental work indicates that worker bees manipulate brood sex ratios differently from the queen. By contrast, most studies of avian brood reduction and mammalian 'weaning conflict' remain open to multiple interpretations. In general, POC may owe its current hegemony to the paucity of alternative explanations for parent-offspring squabbles. Reassessments of basic assumptions about what both parties 'really want' need to be linked to experimentation, field-oriented modelling and pluralism for this provocative theory to become broadly useful. PMID- 21236083 TI - Tissue strategies as developmental constraints: Implications for animal evolution. AB - A consideration of developmental constraints at the tissue level brings into focus the relationship between genes, cell behavior and morphological evolution. This common framework provides a rationale for phenomena as seemingly divergent as the lack of homeotic appendages in humans and the Cambrian explosion. PMID- 21236084 TI - Plant senescence. AB - Senescence is defined by evolutionary biologists as the decline in age-specific survival and fecundity that reflects declines in the performance of many different physiological functions in individuals of sufficiently advanced age. Senescence is widely recognized to occur among plants with a single reproductive event, but the extent to which senescence occurs among plants with multiple reproductive events is open to debate. The latter may show gradual or even negligible senescence. The pattern of senescence cannot readily be ascribed to either morphology or phylogeny. While it has been widely argued that clonal growth allows plants to escape senescence, this is not necessarily the case. PMID- 21236085 TI - Reply from liebherr and wagner. PMID- 21236086 TI - Flightlessness in insects. PMID- 21236087 TI - Gap size and plant defenses. PMID- 21236088 TI - Parasitizing conspecifics: Comparisons between hymenoptera and birds. PMID- 21236089 TI - Can we build an ark? PMID- 21236090 TI - Sex, statistical reasoning and other human interests. PMID- 21236091 TI - Molecular variation and evolution of viruses. PMID- 21236092 TI - Evolution and development of the vertebrate skull: The role of pattern formation. AB - The vertebrate skull is anatomically complex and phylogenetically diverse; it presents unique opportunities to examine the role of developmental processes in evolutionary change. Previous studies have largely examined phylogenetic trends in tissue composition or change in the timing of developmental events (heterochrony). Additional important insights may be gained if skull evolution and development are viewed from the standpoint of pattern formation. Contemporary models of pattern formation offer the possibility of linking developmental mechanisms of cranial morphogenesis from the level of genes, through cell biology, to adult form. PMID- 21236093 TI - The evolutionary history of the seed plant male gametophyte. AB - The role of the male gametophyte in the early history of seed plants remains an underappreciated but critical part of the evolution of a suite of characters that ultimately came to define seed plants. Recent paleobotanical discoveries and studies of extant primitive seed plant male gametophytes, when coupled with phylogenetic analyses of seed plants, provide insight into many hey events that occurred during the early evolution of seed plants. These discoveries are changing our ideas concerning the multiple origins of the sulcus (pollen grain germinal aperture) and pollen tube, the structural and physiological relationships of the male gametophyte with the host sporophyte tissues in primitive seed plants, and the evolution of siphonogamy (conduction of non-motile sperm via a pollen tube) from a zooidogamous (swimming sperm) condition. PMID- 21236094 TI - Why do females copulate repeatedly with one male? AB - For most animals, a small number of copulations is sufficient to fertilize all the eggs that a female will lay at any one time. However, in some species a very high frequency of mating occurs, indicating that individuals copulate many more times than are necessary for fertilization. If copulation behaviour carries costs, then the question arises as to how individuals of both sexes benefit from repeated matings with a single partner. For a male, a high frequency of copulation appears to be advantageous in securing or assuring paternity when his sperm is in competition with those of another male. Since copulation is likely to be as costly for females as it is for males, it is necessary to seek adaptive explanations from the female perspective. Attention is now being focused on why females should copulate repeatedly with a single male. PMID- 21236095 TI - Human dispersal and divergence. AB - Dispersal, mate exchange and behavioral innovations leading to cultural dominance and replacement have obscured some of the relationships between major linguistic groups and the biological characteristics of their speakers. Recent phylogenetic reconstructions based on nuclear and mitochondrial genes have resulted in a series of hypotheses about the spread of modern humans. These hypotheses are now being tested by linguistic reconstruction. Genes, language, archaeology and geography are sometimes congruent, but new methods to assess covariation in genetic and linguistic distances are becoming necessary. PMID- 21236096 TI - What was the evolutionary synthesis? AB - There has not been another scientific revolution that caused as much turmoil and dissension as the darwinian one. For almost 80 years it was again and again pronounced to be a failure and to be totally refuted, and at least three major alternatives were proposed to replace it. Yet, in the 1930s-1940s the opposing views were quickly and decisively refuted and a largely unified evolutionary theory emerged. Why and how this happened, however, is still rather controversial. PMID- 21236097 TI - Plant phenology: Selection and neutrality. PMID- 21236098 TI - A fed-back flow does not make a feedback. PMID- 21236099 TI - Ecological engineering. PMID- 21236100 TI - Reply from stone and weisburd. PMID- 21236101 TI - New light on forest shade. PMID- 21236102 TI - The queen of forage and the bumblebee revolution: A conference with an attitude. PMID- 21236103 TI - The continuing quest for chaos. PMID- 21236104 TI - Life on an intermittent edge. PMID- 21236105 TI - Light spectral quality, phytochrome and plant competition. AB - The light environment experienced by plants in natural vegetation is strongly dependent upon interactions with neighbors. For plants in dense stands, reduced irradiance can lead to reductions in growth and fitness. Spectral light quality is also altered beneath a leaf canopy, and can serve as an important signal of competition for light. Recent physiological studies indicate that plants can perceive the quality of light reflected from neighbors as an accurate predictor of future competition, and respond morphologically even before they are directly shaded. These findings have important implications for plant population biology, and provide a valuable opportunity for the study of adaptive plasticity. PMID- 21236106 TI - Disturbance of the phosphorus cycle: A case of indirect effects of human activity. AB - Phosphorus (P) often limits primary productivity of aquatic systems. Humans have altered the P cycle in aquatic systems, directly, by mining P-rich rock, and indirectly, through the manipulation of other element cycles and the alteration of aquatic food webs. Aquatic ecologists are becoming increasingly aware of the importance of these indirect alterations to biogeochemical cycles. Ouantitative predictions of these indirect effects will be an important focus of future studies. PMID- 21236107 TI - Evolution and progress. AB - The concept of progress is one which makes evolutionists feel very uneasy, yet it is also a concept to which they are forever returning. It is useful to make a distinction between 'comparative progress' which involves competition between groups, and 'absolute progress' which involves the climb up some objective scale. Both kinds of progress have been the subject of much debate in recent years, leading one to turn from expectations that the controversy will ever be resolved to queries about why it continues to obsess so many people. PMID- 21236108 TI - The adaptive significance of self-medication. AB - Not all pharmacists are human; other species also use medicinal substances to combat pathogens and other parasites. Self-medicating behaviour is a topic of rapidly growing interest to behaviourists, parasitologists, ethnobotanists, chemical ecologists, conservationists and physicians. Although most of the pertinent literature is anecdotal, several studies have now attempted to test the adaptive function of particular self-medicating behaviours. We discuss the results of these studies in relation to simple hypotheses that can provide a framework for future tests of self-medication. PMID- 21236109 TI - Plant-insect herbivore interactions in elevated CO(2) environments. AB - The increasing concentration of CO(2) in the atmosphere is expected to lead to global changes in the physical environment of terrestrial organisms. We are beginning to understand how these changes are transmitted into pervasive effects on the interactions between plants and their leaf-feeding insect herbivores. An elevated CO(2) atmosphere often stimulates plant carbon assimilation and growth and alters carbon allocation patterns. This, in turn, determines the quality of plants as resources for herbivorous insects. These 'quality' factors include: the concentrations of water, nitrogen and allelochemicals in host-plant leaves, and the toughness and starch and fiber content of leaf tissue. Because these parameters change in plants grown in enriched CO(2) environments, the doubled CO(2) levels anticipated for the next century will alter the dynamics of plant insect herbivore interactions because herbivore consumption, growth and fitness are affected by the typically lower quality of plants grown under these conditions. PMID- 21236110 TI - The logistic equation revisited: Final instalment. PMID- 21236111 TI - Reply from L. Ginzburg. PMID- 21236112 TI - Why cooperate? Game theory and kin selection. PMID- 21236113 TI - Biodiversity and ecosystem processes: Opportunities in Mediterranean-type ecosystems. PMID- 21236114 TI - Behavioural mechanisms in evolutionary perspective. PMID- 21236115 TI - Measuring fitness in life,,history studies. PMID- 21236116 TI - Diversity of bacterioplankton. AB - We do not know how many bacterial species exist in the world, or in any particular environment, because bacteria cannot be differentiated under the microscope; we do not even know the right order of magnitude. Thus, up to a few years ago, discussions of bacterial diversity were unwarranted. However, the development of a phylogenetic system based on rRNA sequences has provided tools to approach bacterial diversity and ecology in situ for the first time. PMID- 21236117 TI - The statistical analysis of survival in animal populations. AB - Estimating, comparing and modelling survival rates are central to population biology. However, there are many difficulties in measuring these rates in animal populations in the wild. The most relevant information is based on samples of marked individuals, i.e. capture-recapture data. In recent years, a number of new statistical approaches to the analysis of such data have been developed, permitting more sophisticated and precise measurement of survival rates. PMID- 21236118 TI - Mechanisms of sperm competition: Linking physiology and behavioural ecology. AB - Sperm competition has received a great deal of attention from behavioural ecologists because it is the ultimate form of male-male competition, and may also be important for female choice. It is becoming clear that the adaptive value of the behavioural strategies of males and females will not be fully understood until we have a better understanding of the physiological mechanisms that come into play after copulation. We now have enough information to compare the underlying mechanisms in birds and mammals and to relate these to the way in which sperm competition operates in both groups. To integrate this knowledge, the boundaries between behavioural ecology and physiology will have to be crossed in what promises to be a most fruitful enterprise. PMID- 21236119 TI - Female control of paternity. AB - Of the two components of sexual selection, female choice is much less obvious than male-male competition, and hence has always been considered to be of secondary importance. However, recent field observations and new theory have brought about a radical change of emphasis. It now appears that although a female's choice of who fathers her offspring often occurs in a subtle manner, it may be widespread and take place through a variety of behavioural and physiological mechanisms, including the manipulation of male behaviour and the selection of sperm within the female reproductive tract. PMID- 21236120 TI - The ecology of tropical rain forest canopies. AB - With the advent of increasingly sophisticated techniques for access, tropical forest canopy research has burgeoned in the last few years. Although an enormous amount of basic descriptive work remains to be done, canopy research is now entering a more advanced and ecological phase. PMID- 21236121 TI - Mutations, evolutionary theory and cancer. AB - When searching for mutations that may be responsible for tumourigenesis and interpreting their significance, molecular oncologists often make a number of implicit assumptions about how and why tumour genotypes develop. These assumptions are based on an underlying classical model of tumourigenesis. The classical model has a number of similarities to models of evolution: given the parallels between the growth of tumours and the evolution of whole organisms, this is to be expected. However, consideration of tumourigenesis as an evolutionary process also suggests some modifications that might be made to the classical model. The experimental methods and data analysis of molecular oncology must take full account of the potential contribution of evolutionary theory. As the study of mutations in cancer expands, molecular oncologists are starting to do this. PMID- 21236122 TI - Molecular interplay: One step forward, two steps back. PMID- 21236123 TI - Reply from T. Ohta. PMID- 21236124 TI - The origins of diversity in tropical rain forests. PMID- 21236125 TI - Woodland water balance. PMID- 21236126 TI - How does mast-fruiting get started? PMID- 21236127 TI - Beyond opportunism: Key principles for systematic reserve selection. AB - The intention and practice of conservation reserve selection are different. A major reason for systems of reserves is to sustain biological diversity. This involves protecting examples of as many natural features, e.g. species, communities or environments, as possible. In reality, however, new reserves have rarely been dedicated for their representation of features. Furthermore, the opportunism that has characterized the development of reserve systems can actually jeopardize the representation of all features in reserves through the inefficient allocation of limited resources. More systematic approaches are essential if reserves are to play their role in protecting biodiversity. Some basic principles for conservation planning are emerging from recent systematic procedures for reserve selection. These principles will help to link intention and practice. PMID- 21236128 TI - A revolution morphometrics. AB - We are now in the midst of a revolution in morphometric methodology. The new approaches are more effective in capturing information about the shape of an organism and result in more powerful statistical procedures for testing for differences in s shape. They are also more effective in enabling a researcher to visualize differences in shape and in suggesting simple traditional measurements that could be used in future studies. In this review we emphasize applications to exploratory studies in taxonomy and evolution. PMID- 21236129 TI - Biological invasions: Lessons for ecology. AB - Anthropogenic introduction of species is homogenizing the earth's biota. Consequences of introductions are sometimes great, and are directly related to global climate change, biodiversity AND release of genetically engineered organisms. Progress in invasion studies hinges on the following research trends: realization that species' ranges are naturally dynamic; recognition that colonist species and target communities cannot be studied independently, but that species community interactions determine invasion success; increasingly quantitative tests of how species and habitat characteristics relate to invasibility and impact; recognition from paleobiological, experimental and modeling studies that history, chance and determinism together shape community invasibility. PMID- 21236130 TI - Do grasses fight back? The case for antiherbivore defences. AB - In the past, discussion about grass-grazer interactions has tended to centre on whether they represent some sort of mutualism. However, intense grazing pressure is more likely to have selected for the presence of various antiherbivore defences in grasses. Many grasses contain silica, which functions in some cases as a physical defence. Others contain various secondary compounds which have negative effects on both invertebrate and vertebrate herbivores. Much recent evidence suggests that plants with higher levels of these defences deter herbivores more effectively than plants without them. PMID- 21236131 TI - Molecular phylogeny and the higher classification of eutherian mammals. AB - Reconstructing the evolutionary relationships among the orders of eutherian mammals constitutes a formidable phylogenetic task. It entails the identification of a single true phylogenetic tree out of 10(12)-10(28) possible ones. For almost half a century, the field of mammalian Phylogeny has been dominated by a pessimistic view, according to which the great burst of mammalian radiations more than 65 million years ago has rendered the ordinal phylogeny of mammals insolvable. In the last few years, this pessimism has started to dissipate as several superordinal relationships were identified through the use of molecular data. DNA and protein sequences have the potential to supply millions of phyloge netically useful characters, and therefore, the Phylogeny of the orders of mammals may be resolved into a consistently bifurcating tree in the not-sodistant future. PMID- 21236132 TI - Plant senescence in fire-prone perennials. PMID- 21236133 TI - Nitrogen oxide flux in tropical soils. PMID- 21236134 TI - Evidence and statistical summaries in environmental assessment. PMID- 21236135 TI - Browse and browsers: Interactions between woody plants and mammalian herbivores. PMID- 21236136 TI - Conservation biology of birds: Can we bridge the gap between head and heart? PMID- 21236137 TI - Latitudinal range fluctuations in the marine realm through geological time. AB - Our concept of polar marine faunas as having evolved in comparative isolation over long periods may need to be revised. New evidence from the Southern Ocean, in particular, suggests that a number of taxa may have had connections with lower latitude regions in the comparatively recent past. Opportunities for high-low latitude faunal interchange were enhanced considerably by reduced meridional temperature gradients over the greater part of the last 100 million years. Indeed, such is the nature and scope of past latitudinal range fluctuations that they could be major determinants of regional patterns in taxonomic diversity. PMID- 21236138 TI - Determinants of maturation in animals. AB - Maturation is a critical transition in the life cycle. Recent models have used retrospective analyses of patterns of variation in age and size at maturity in an attempt to understand the mechanisms responsible for generating phenotypic variation in maturation. Empirical work has revealed greater complexity in the biology of maturation than has been incorporated in current models, and has cast doubt on some of the assumptions and conclusions of the models. Recent insights from experimental work, coupled with theoretical advances for the analysis of growth, size and other complex characters, have great potential to elucidate evolution of maturation and how adaptive maturation phenotypes are achieved by real organisms. PMID- 21236139 TI - Assessing the role of fine roots in carbon and nutrient cycling. AB - Fine roots remain one of the most difficult and important areas to study in terrestrial ecosystems. Recent investigations have focused on carbon and nitrogen balances to assess their dynamics in natural systems. The results of these new, system-level, budgeting approaches together with those of the more conventional biomass measurement methods may provide valuable insight into fine root carbon and nutrient cycling dynamics. These findings, in turn, may facilitate a more holistic understanding of ecosystem structure and function, which is critical for the assessment and prediction of disturbances to terrestrial systems. PMID- 21236140 TI - Zooplankton body size and community structure: Effects of thermal and toxicant stress. AB - Episodic heat waves and an increase in pesticide use are widely cited as consequences of climatic warming. Recent studies show that these stressors often cause declines in the mean body size of zooplankton. Results from laboratory and field studies, as well as observations from both thermal- or toxicant-stressed natural systems, show (1) reductions in mean body size within stressed populations, or (2) changes in community composition that favor small-bodied over large-bodied species. During the past decade, it has become widely accepted that a shift in zooplankton body size can dramatically affect water clarity, rates of nutrient regeneration and fish abundances. Thus, climatic warming and associated change in pesticide use has the potential to cause striking change in the structure and functioning of temperate-zone lakes. PMID- 21236142 TI - Reply from R.L. Mumme. PMID- 21236141 TI - The future of sociobiology: Counting babies or studying proximate mechanisms. AB - Much of the debate over applying the theory of evolution to the study of human behaviour has died down because most critics now realize that the political ramifications of sociobiology are no more, or no less, than those of behaviourism, psychoanalysis or cognitive science. But controversy remains. It is scientific, and concerns the 'proper' way to do human sociobiology. I contrast the perspective of those sociobiologists who use the approach of behavioural ecology, and who have come to be known as 'darwinian anthropologists' or 'darwinian social scientists', with their critics, who refer to themselves as evolutionary or 'darwinian psychologists', describe the research methods that each uses, and ask if those issues must also be confronted by those studying animals. PMID- 21236143 TI - Group territoriality and habitat quality: What are the issues? PMID- 21236144 TI - Herbivory at the limits. PMID- 21236145 TI - Mobility limits cooperation. PMID- 21236146 TI - Striking parallels in early hominid evolution. PMID- 21236147 TI - Character displacement and replicate adaptive radiation. AB - Ecological character displacement is implicit in current views of adaptive radiation, but examples are few. The paucity of cases may be partly a problem of detection: statistical tests require that a consistent pattern of displacement be observed over independent lineages, yet opportunities for such replication may be few. Recent studies of fish in postglacial lakes and lizards on Caribbean islands reveal multiple speciation events accompanied by equivalent patterns of ecological and morphological divergence. These studies provide a wealth of new examples of apparent character displacement, and show that adaptive radiations may unfold in a predictable sequence. PMID- 21236148 TI - Models of patch dynamics in tropical forests. AB - Recent interest in the ecology and evolution of metapopulations and conservation of fragmented populations has stimulated the development of models that combine patch and population dynamics in tropical forests. One approach uses matrix models that are actual metapopulation or multi-regional demographic models. Another approach uses computer simulations to model forest succession based on the behavior of individual trees. We review applications of both types of models and suggest new combined modelling approaches. PMID- 21236149 TI - Dynamic models of behavior: An extension of life history theory. AB - Life history theory and behavioral ecology, two branches in the study of adaptation, have relied extensively on mathematical models, but have tended to employ different types of models, and different currencies of fitness. Recently, a new approach based on dynamic, state variable models has been increasingly applied to the study of behavioral adaptations. In fact, this approach amounts to a unification of life history theory and behavioral ecology, to the extent that the line separating the two fields is virtually obliterated. Dynamic models (usually solved by computer) can yield both general principles and testable, quantitative or qualitative predictions about specific behavioral and life history phenomena. PMID- 21236150 TI - Are viruses important partners in pelagic fend webs? AB - Viruses have been assumed to play a rather negligible role as partners in microbial food web dynamics. However, recent discoveries suggest that the rate of virally induced lysis of marine microbial populations may be significant. This, in turn, may have important consequences for the developing conceptual framework of the microbial food web. PMID- 21236151 TI - Anaerobes into heavy metal: Dissimilatory metal reduction in anoxic environments. AB - Within the last decade, a novel form of microbial metabolism of major environmental significance has been elucidated. In this process, known as dissimilatory metal reduction, specialized microorganisms, living in anoxic aquatic sediments and ground water, oxidize organic compounds to carbon dioxide with metals serving as the oxidant. Recent studies have demonstrated that this metabolism explains a number of important geochemical phenomena in ancient and modern sedimentary environments, affecting not only the cycling of metals but also the fate of organic matter. Furthermore, this metabolism may have practical application in remediation of environments contaminated with toxic metals and/or organics. PMID- 21236152 TI - Reply from d.w. Mock and L.s. Forbes. PMID- 21236153 TI - Parent-offspring conflict. PMID- 21236154 TI - The effects of habitat productivity on competition intensity. PMID- 21236155 TI - Female choice in birds and the cost of long tails. PMID- 21236156 TI - Can animals be spiteful? PMID- 21236157 TI - Assessing minimum viable population size: Demography meets population genetics. AB - The discussion of a population's minimum viable size provides a focus for the study of ecological and genetic factors that influence the persistence of a threatened population. There are many causes of extinction and the fate of a specific population cannot generally be predicted. This uncertainty has been dealt with in two ways: through stochastic demographic models to determine how to minimize extinction probabilities; and through population genetic theory to determine how best to maintain genetic variation, in the belief that the ability to evolve helps buffer a population against the unknown. Recent work suggests that these two very different approaches lead to very similar conclusions, at least under panmictic conditions. However, defining the ideal spatial distribution for an endangered species remains an important challenge. PMID- 21236158 TI - Transposable elements as introns: evolutionary connections. AB - Recent molecular genetic studies demonstrate that many transposable elements, when inserted into nuclear genes, can behave as introns and create novel intron processing patterns. These studies point to possible mechanisms by which transposable element insertions participate in the evolutionary diversification of gene structure, the rise of alternative splicing patterns and the production of novel regulatory interactions. Moreover, they provide us with fresh insights into the evolutionary dynamics of these mobile sequences. PMID- 21236159 TI - The relationship between body size and population abundance in animals. AB - On average, large-bodied species live at lower densities than small-bodied ones. Early studies suggested that population densities might scale so that the energy use of a population is independent of body size. However, recent work shows that, at the scale of local communities, this is rarely true and that the pattern varies among taxonomic or ecological subsets of those communities. Energetic considerations may only be relevant to the densities of more abundant species. In fact, within natural assemblages o f organisms, the underlying relationship is very variable; in subsets of those assemblages, ecological processes such as competition may structure abundance patterns. PMID- 21236160 TI - The evolutionary biology of insect hearing. AB - Few areas of science have experienced such a blending of laboratory and field perspectives as the study of hearing. The disciplines of sensory ecology and neuroethology interpret the morphology and physiology of ears in the adaptive context in which this sense organ functions. Insects, with their enormous diversity, are valuable candidates for the study of how tympanal ears have evolved and how they operate today in different habitats. PMID- 21236161 TI - Behavioural constraints and conservation biology: Conspecific attraction and recruitment. AB - Wildlife managers have devoted considerable time and research to determine how animals judge the suitability and quality of their habitat. These analyses typically center on habitat characteristics and often produce equivocal results. An additional method of habitat assessment is to examine the extent to which animals, and particularly birds, use conspecifics as cues to establishing breeding and feeding territories. Conspecifics can be indicators of habitat quality, or they might intrinsically affect reproductive success. Here we discuss the implications of conspecific attraction for biologists who wish to conserve endangered species that are living in fragmented habitats. PMID- 21236162 TI - The persistence of haplodiploidy in algae. AB - Haplodiploid life cycles are especially well represented among the eukaryotic algae. The widespread retention of haplodiploidy among diverse algal groups provides us with the opportunity to consider haplodiploidy as a stable rather than transitional life history trait and to speculate on the selective mechanisms that could be responsible for its persistence. In doing so, we could gain added insights into the evolution of sex itself. PMID- 21236163 TI - Female control of paternity: More than meets the eye. PMID- 21236164 TI - Feedback monitoring: A new way of protecting the environment. PMID- 21236165 TI - When kids just aren't worth it: Cuckoldry and parental care. PMID- 21236166 TI - Are hybridogenetic frogs cyclical parthenogens? PMID- 21236167 TI - Positive selection in a multi~gene family: Catfish olfactory receptors. PMID- 21236168 TI - Alternative equilibria in shallow lakes. AB - The turbidity of lakes is generally considered to be a smooth function of their nutrient status. However, recent results suggest that over a range of nutrient concentrations, shallow lakes can have two alternative equilibria: a clear state dominated by aquatic vegetation, and a turbid state characterized by high algal biomass. This bi-stability has important implications for the possibilities of restoring eutrophied shallow lakes. Nutrient reduction alone may have little impact on water clarity, but an ecosystem disturbance like foodweb manipulation can bring the lake back to a stable clear state. We discuss the reasons why alternative equilibria are theoretically expected in shallow lakes, review evidence from the field and evaluate recent applications of this insight in lake management. PMID- 21236169 TI - Phylogenetic relationships and evolutionary processes in East African cichlid fishes. AB - Since their discovery almost one hundred years ago, the adaptive radiations of cichlid fishes in the largest East African lakes have fascinated biologists. They are a prime example of explosive speciation. Among vertebrates, these species assemblages are the most species rich and the most diverse, morphologically, ecologically and behaviorally. Recent phylogenetic analyses of molecular data and refined knowledge about the geological history of the East African lakes are throwing new light on the evolutionary history of these extraordinary fish faunas. PMID- 21236170 TI - Microsatellites and kinship. AB - Many evolutionary studies, particularly kinship studies, have been limited by the availability of segregating genetic marker loci. Microsatellites promise to alleviate these problems. Microsatellite loci are segments of DNA with very short sequence motifs repeated in tandem; their often numerous alleles differ in the number of these repeat units. They are very common in eukaryotic DNA and can be amplified by the polymerase chain reaction, which allows the use of minute or degraded DNA samples. The alleles can be scored consistently and compared unambiguously, even across different gels. PMID- 21236171 TI - Stomatal control of transpiration. AB - The role of stomata in regulating transpiration from vegetation has historically been controversial among those working either at the single leaf, or at the extensive canopy scales. Recently, the role of unstirred air layers surrounding leaves and canopies in limiting the impact of stomatal movements on transpiration has received renewed recognition. This has led to notable progress in quantitatively describing the effectiveness of stomata in controlling transpiration and in reconciling contrasting viewpoints concerning the role of stomata at the leaf, stand and regional scales. Considerable progress has also been made in understanding how variations in aerial factors such as evaporative demand and edaphic factors such as soil water availability are sensed and transduced into appropriate stomatal regulatory responses. These developments indicate that studies carried out at multiple scales of observation are needed to understand how external environmental factors and intrinsic plant properties interact to determine the role of stomata in regulating transpiration from different types of vegetation. PMID- 21236172 TI - Adaptations and history. AB - The historical definition of adaptations has come into wide use as comparative biologists have applied methods of phylogenetic analysis to a variety of evolutionary problems. Here we point out a number of difficulties in applying historical methods to the study of adaptation, especially in cases where a trait has arisen but once. In particular, the potential complexity of the genetic correlations among phenotypic traits, performance variables and fitness makes inferring past patterns of selection from comparative data difficult. A given pattern of character distribution may support many alternative hypotheses of mechanism. While phylogenetic data are limited in their ability to reveal evolutionary mechanisms, they have always been an important source of adaptive hypotheses and will continue to be so. PMID- 21236173 TI - The biology of rarity: Patterns, causes and consequences. AB - There is a growing body of evidence suggesting that locally rare and geographically restricted species may have characteristics that differ from those of taxa that are more common. Several studies show that rare taxa have lower levels of self-incompatibility, a tendency toward asexual reproductive pathways, lower overall reproductive effort and poorer dispersal abilities. There are several mechanisms that could be responsible for such differences, but they may in practice be difficult to differentiate. Nonetheless, the documentation of recurrent rare-common differences is of vital importance because it may allow us to compensate partially for the bias of the published literature toward studies of common taxa. PMID- 21236174 TI - Geometric morphometrics: An extension of the revolution. PMID- 21236175 TI - Living dangerously but independently, or safely and contingently? PMID- 21236176 TI - The ecology and conservation management of geese. PMID- 21236177 TI - A new look at competition theory and the structure of ecological communities. PMID- 21236178 TI - Weird genetics? Evolution and nonmendelian genes. AB - It is the simplicity of traditional genetics that has endowed it with such power. Its generalisations do describe most genetic phenomena in most organisms, most of the time ... the great challenge [is] to explore the implications of the exceptions and to find new sets of even more potent rules, if any exist. PMID- 21236179 TI - Linking species and ecosystem perspectives. PMID- 21236180 TI - Dynamics of genets in cluonal plants. AB - Processes related to dispersal, recruitment and survivorship of 'genetic individuals' in clonal plants have long been considered enigmatic. Little is known of whole life-cycle dynamics in these, usually, very long-lived plants. However, inferences may be drawn from studies of specific aspects of clonal plant populations, in particular seedling recruitment, genetic structure and growth form variation. This review summarizes recent findings from such studies, and presents some conclusions concerning genet population structure and regulation, and life history evolution in clonal plants. PMID- 21236181 TI - The organization of zooplankton epibiont communities. AB - Recent findings suggest that a diverse set of interactions exists between crustacean zooplankton and the algae, protozoans and metazoans that live attached to them. The frequent molting of the crustacean exoskeleton keeps these epibiont populations in a state of constant renewal and makes this epibiont community an ideal experimental system for examining the organization of communities whose populations are distributed among ephemeral habitat patches. PMID- 21236182 TI - Geitonogamy: The neglected side of selfing. AB - Flowers of many angiosperm species are well adapted to avoid self-pollination, for instance by temporal and spatial separation of pollen and stigma within the same flower. However, such adaptations do not prevent the transfer of pollen between flowers on the same plant (geitonogamy). Recent empirical studies, aided by advances in field techniques, statistical methods and modelling, show that geitonogamy often is substantial and increases with plant size. Selfing by geitonogamy incurs a fitness cost of reduced pollen export, and recent reports show that seed set can suffer as well, even in self-incompatible species. Geitonogamy has important implications for sex-allocation theory, the evolution of dioecy and other issues in evolutionary biology. PMID- 21236183 TI - Ant-plant symbioses: Stalking the chuyachaqui. AB - According to Quechua-speaking peoples, orchard-like stands ('Supay Chacras') of two Amazonian ant-plant species are cultivated by the devil, or 'Chuyachaqui'. These "devil gardens" offer extreme examples of specializations that have evolved repeatedly in ant-plant associations. Numerous investigations are beginning to disclose the identity of the Chuyachaqui - the forces behind evolutionary specialization in ant-plant symbioses. These developments have important implications for our understanding of modes of coevolution in symbiotic mutualism, remarkable convergent similarities in the form of ant-plant symbioses on different continents, and pronounced intercontinental differences in the diversity and taxonomic composition of associates. PMID- 21236184 TI - The future of the US endangered species act. AB - The United States Endangered Species Act of J973 (ESA) is the strongest tool for protecting plants and animals in the US and has served as a model of species protection for many other nations. Because the goals of the Act - to conserve all endangered and threatened species in the US and the ecosystems upon which they depend - are widely supported among US environmentalists and biologists, it is commonly believed that these groups offer united support for the legislation. Within the US, however, vigorous debate ensues among conservation biologists as to the effectiveness of the species-oriented approach of the Act. PMID- 21236185 TI - Colonially breeding seabirds: Predators or prey? AB - The evolution of aggregation in seabirds is usually attributed to predation pressure, although many authors have argued for the role of foraging constraints to be considered. Discriminating between factors that result in group living and characteristics arising from group living has been regarded as an insoluble problem; yet it is possible to test the predictions of the different models proposed to explain colonial nesting. The resulting explanation suggests that seabird aggregations have evolved in order to utilize a dispersed and unpredictable food supply. As such, colonial nesting leads to increased vulnerability to predation, rather than being a strategy adopted to combat it. PMID- 21236186 TI - Mammalian phylogeny: Morphology and molecules. PMID- 21236187 TI - Geometric morphometrics: Reply to M. Corti. PMID- 21236188 TI - Letter. PMID- 21236189 TI - Reply from d. Graur. PMID- 21236190 TI - Rapid evolution by biological enemies. PMID- 21236191 TI - Leaf-cutting ants tease optimal foraging theorists. PMID- 21236192 TI - Fat times, lean times and competition among predators. PMID- 21236193 TI - The function and formation of buttresses. PMID- 21236194 TI - Aerobic denitrification in soils and sediments: From fallacies to factx. AB - Denitrification is the key step of the nitrogen cycle in which gaseous end products are released from the nitrate of terrestrial and aquatic environments. Although this process has always been regarded as an anaerobic one, recent research indicates that aerobic denitrification can be demonstrated with laboratory cultures and suggests that it may be widespread environmentally. Thus, denitrifying bacteria are both taxonomically and physiologically diverse, and may be predominantly aerobic. Simultaneous use of O(2) and NO(3)(-) as alternative terminal oxidants is not precluded in many bacteria, although the use of NO(3)(-) when O(2) is available is of no known advantage. PMID- 21236195 TI - Natural versus anthropogenic charge in lakes: The role of the sediment record. AB - Recent methodological developments permit the quantitative reconstruction of water chemistry variables from microfossil assemblages preserved in lake sediments. These reconstructions can be used to identify the extent and timing of disturbance to lake ecosystems. Combined with appropriate sampling strategies, lake sediments permit water chemistry variables and community rates of change to be estimated at a variety of timescales. Sediments predating major cultural impacts offer the possibility of inferring lake history before anthropogenic interference, and can, therefore, contribute to current debates about timescales of natural variance in lakes, as well as the response of lake communities to natural environmental perturbations. Such an approach has relevance to many contemporary environmental problems, e.g. acidification, eutrophication and climate change. PMID- 21236196 TI - Effects of expected global climate change on marine faunas. AB - Anthropogenically induced global climate change is likely to have a major impact on marine ecosystems, affecting both biodiversity and productivity. These changes will, in turn, have a large impact on humankind's interactions with the sea. By examining the effects of past climate changes on the ocean, as well as by determining how shifts in physical parameters of the ocean may affect physiology, biochemistry and community interactions, scientists are beginning to explore the possible effects of global climate change on marine biota. PMID- 21236197 TI - Orientation cues used by migratory birds: A review of cue-conflict experiments. AB - During the late 1960s and early 1970s the accumulating evidence of magnetic orientation forced the conclusion that the orientation of migratory birds and homing pigeons is based upon multiple stimuli. 'Cue-conflict experiments' have provided a powerful means of asking how these directional cues relate one to another. The weight of evidence suggests that in short-term orientation decision making, magnetic cues take precedence over stars, and visual information at sunset overrides both these stimuli. Recent experiments point to polarized skylight patterns as the relevant cue in dusk orientation. Although cue-conflict experiments have now been performed on a diversity of species, generalizations are weakened because of differences in experimental design, in the cues examined and in our ability to manipulate those cues. There remains a need for carefully designed comparative studies. PMID- 21236198 TI - Museums, collections and biodiversity inventories. AB - Natural history museums area at a turning point in their history. To play a central role in research on biodiversity, they must change their mode of operation and public image. Collections have grown in a haphazard manner, depending on the interests and preferences of successive curators. There is an urgent need to create international networks and standard practices among museums, to meet the challenge of the biodiversity crisis. PMID- 21236199 TI - How much do we know about the current extinction rate? AB - Since about J600, 486 animal species have been recorded extinct. This represents about 0.04% of all animal species so far described. In the same period, 600 plant species are known to have disappeared, about 0.25% of the total. These figures are much smaller than those of the Permian/ Triassic and Cretaceous/Tertiary mass extinctions. One might therefore conclude that at present life on earth is at comparatively little risk of extinction. However, there is a growing body of data to show that the converse is true. PMID- 21236201 TI - Reply from joseph bernardo. PMID- 21236200 TI - Cooperation when conditions vary. PMID- 21236202 TI - Plasticity versus genetics? PMID- 21236203 TI - Reply from david lodge. PMID- 21236204 TI - Prediction and biological invasions. PMID- 21236206 TI - High resolution pollen analysis provides new perspective on catastrophic elm decline. PMID- 21236205 TI - Unravelling Haldane's rule. PMID- 21236207 TI - Human sociobiology comes of age. PMID- 21236208 TI - Avian mating systems: The aquatic warbler is unique .... PMID- 21236209 TI - Biodiversity in ground waters. AB - Despite the importance of ground waters in the global water cycle, their ecology and biodiversity have only recently received attention. Three areas are currently being studied: (I ) the origin and colonization ground ground waters, (2) the adaptation of animals to the subterranean environment, and (3) the role of ecotone between surface and ground waters. There are still several gaps in our knowledge of groundwater biodiversity (at the genetic level, the species level, the functional group level and the ecosystem level) to which future research must be directed. PMID- 21236210 TI - Skewed birth sex ratios in primates: Should high-ranking mothers have daughters or sons? AB - Numerous studies have been published on the skewed birth sex ratios among non human primate populations. Sometimes the observed tendencies in sex ratio variations have been contradictory, and their adaptive significance has been controversial. Recent studies seem to reveal that the local resource competition among philopatric sex is the most important selective force affecting primate birth sex ratios. However, our understanding on this issue is still greatly hampered by the lack of exact knowledge on male reproductive success and the proximate mechanisms to vary sex ratios. PMID- 21236211 TI - Heterogeneity in host-parasitoid interactions: 'Aggregation of risk' and the 'CV(2) > 1 Rule'. AB - In host-parasitoid interactions the coefficient of variation (CV) of the risk of parasitism measures, at least approximately, the stabilizing influence of many forms of heterogeneity. This realization emphasizes the underlying similarity of these heterogeneities, and should end two decades of confusion about how to study them in nature. The first applications of this approach suggest that roughly one third of systems studied show substantial measurable heterogeneity. Proper use of the CV measure, however, requires that the density-dependent processes linking this static phenomenon to temporal population dynamics also be examined; this has yet to be done for any system. PMID- 21236212 TI - Entomological and mammalogical perspectives on genital differentiation. AB - When hypotheses concerning the evolution of animal genitalia are classified by their assumptions and arranged historically, key differences between the entomological and mammalogical approaches become clear. The former tradition emphasizes mechanism and the latter emphasizes species isolation. Consequently, studies of this subject often address different aspects of the question while using similar terminology, specifically, the term 'lock-and-hey'. Because genital variation represents a significant portion of animal diversity, it merits the attention and clarity of investigation given to other anatomical features. However, attempts to achieve the necessary level of clarity have been largely unsuccessful. This article promotes common terms for improved communication between researchers. PMID- 21236213 TI - Range, population abundance and conservation. AB - Several patterns in the distribution and abundance of organisms have now been documented. They include broad (but not universal) positive correlations between range sizes and population abundances; a decline in the proportion of sites occupied and in average population densities from the centre to the edge of a species' range, with either unimodal or multimodal peaks of abundance and occupancy in the core of the range; and intriguing, but still poorly documented phylogenetic effects on both range size and abundance. All these patterns require further work to establish their generality, and all of them lack generally agreed explanations. They are important, however, not only theoretically but also practically, because of the constraints and opportunities they appear to provide for the management and conservation of species. PMID- 21236214 TI - Toward a cognitive ecology. AB - The emergence of cognitive psychology as the dominant approach to understanding human behaviors and actions acknowledges the importance of internal mental operations in generating specific behavioral responses to sets of external stimuli. Traditional behaviorist interpretations that rely primarily on external inputs as the precursors of action have been largely replaced by cognitive approaches. The main intent of this article is to outline the major areas that require exploration if we wish to apply fully the principles and insight of cognitive science to behavioral ecology. PMID- 21236215 TI - Biodiversity conservation: Reserve optimization or loss minimization? PMID- 21236216 TI - Does silica defend grasses against invertebrate herbivores? PMID- 21236217 TI - Reply from C.j. Humphries. PMID- 21236218 TI - Reply from d. Bazely and m. Vicari. PMID- 21236219 TI - Infectious diseases of wildlife, in theory and in practice. PMID- 21236220 TI - Coral reefs: Health, hazards and history. PMID- 21236221 TI - How old is ancient woodland? PMID- 21236222 TI - The New Zealand biota: Historical background and new research. AB - New Zealand's origin as part of Gondwana, the composition of its ancestral biota, its geographic isolation for 80 million years, its tectonic history of changing shorelines and mountain building, and its changing climate, have all influenced the composition and distribution of its plant and animal communities, and thus its ecology and evolutionary biology. Recent DNA-sequencing studies combined with palaeogeographic analysis suggest that an Oligocene marine transgression had a major genetic bottle-neck effect on the biota and, together with recent advances in avian biogeography and paleontology, are leading to new hypotheses on the origin of many bird groups. PMID- 21236223 TI - Evolution of the moa and their effect on the New Zealand flora. AB - It is 150 years since Sir Richard Owen announced the former existence of large flightless ostrich-like birds in New Zealand based on a fragment of femur presented to him in England. Numerous studies of this extinct group of giant birds, now known by the Polynesian (plural) name 'moa', have provided much information about their effects on the flora, their recent extinction, and the evolutionary history of New Zealand and its endemic biota. Significant revision of moa taxonomy and ecology continues, and recent molecular phylogenetic analyses have stimulated new hypotheses about moa evolution. PMID- 21236224 TI - Mega-island or micro-continent? New Zealand and its fauna. AB - The terrestrial New Zealand fauna has developed on an ancient landmass of continental origins that has had an increasingly isolated existence since the late Mesozoic. As a continental remnant, New Zealand harbours survivors of many ancient lineages many of which were once far more widely distributed. But New Zealand's fauna also resembles that of an isolated archipelago: many higher taxa are missing; some have undergone extensive radiations in situ; and levels of endemism approach 100% in many groups. Ecologically, the fauna is characterized by frequent niche shifts, gigantism, and extended life histories with low reproductive rates, factors that make many species vulnerable to human disturbance. Data continue to amass supporting the ecophysiological as well as phylogenetic distinctiveness of the fauna. Described taxonomic diversity, even of terrestrial vertebrates, continues to increase. PMID- 21236225 TI - The reproductive biology of the New Zealand flora. AB - New Zealand's long isolation from other elements of Gondwanaland, oceanic climate, the unusual combination of ancient Gondwanic, tropical and more recently arrived elements in its flora, and its relatively depauperate pollinator and disperser fauna have set the stage for the evolution of a subtle, complex and distinctive reproductive biology. This contrasts markedly with the neighbouring continent of Australia where the fauna is diverse and the flowers vivid. Recent advances in understanding New Zealand's floral biology include evidence that the ancestor to the anthophytes was cosexual, with insect pollinators receiving stigmatic nectar rewards; the discovery of ground-level bat pollination in an obligate root parasite; the finding that the greater resource sensitivity of fruit set in males than in females may account for sex ratio variation in gynodioecious species; and, evidence for much more pronounced mast seeding at higher altitudes even in the absence of mammalian seed predators. PMID- 21236226 TI - Human influence on the terrestrial biota and biotic communities of New Zealand. AB - Alien plants and animals are of major economic and conservation significance in New Zealand. Plant introductions have averaged 11 species per year since European settlement in /840, and distinctive landscapes are being increasingly altered by weeds. Many introduced animals act as disease vectors or threaten native biota. Recent studies of introduced wasps show adverse effects on honey-eating and insectivorous birds. Introduced possums are now known to prey on eggs and nestlings of native birds in addition to their impact on native forests and transmittal of bovine tuberculosis. Research is increasingly focused on finding effective methods of biocontrol. PMID- 21236227 TI - Conservation and restoration of New Zealand Island ecosystems. AB - An ecological collapse has precipitated pioneering conservation initiatives in New Zealand. Many terrestrial communities in t he New Zealand archipelago have been devastated by over-exploitation, introduced mammals and habitat destruction. More recently, marine ecosystems have been depleted by over-harvesting. To mitigate against these losses, conservation in terrestrial environments has focused on protection of species and habitats. A similar approach is now under way in marine environments with the establishment of 'no-take' marine reserves. On land, conservation is now reaching beyond protection t o the eradication of pests from islands and restoration of their terrestrial ecosystems. Restoration on islands not only reduces threats to rare species; it also raises opportunities to investigate how species interact. In the sea, marine reserves not only enhance the diversity of depleted marine communities; they may also augment stocks of commercially harvested species. These initiatives provide many lessons that could be applied to degraded habitats elsewhere. PMID- 21236229 TI - Fish hybrids and the red queen. PMID- 21236228 TI - Reply from R.j. Ladle. PMID- 21236230 TI - Cladistics and convergence. PMID- 21236231 TI - Aging reduces the functionality of anti-pneumococcal antibodies and the killing of Streptococcus pneumoniae by neutrophil phagocytosis. AB - We evaluated the effect of aging on the functional activity of naturally acquired anti-pneumococcal antibodies, the function of neutrophils in phagocytic killing of opsonized pneumococci, and the complement activity. Opsonic activities of antibodies to all tested pneumococcal serotypes were significantly lower and phagocytic killing of pneumococci by neutrophils was significantly impaired among the elderly, whereas the complement activity was slightly higher in the elderly than in the young adults. The reduced functional activity of serotype-specific antibodies and the compromised function of neutrophils in the opsonophagocytosis of pneumococci are likely to contribute to the increased susceptibility of the elderly to pneumococcal diseases. PMID- 21236232 TI - Evaluation of cross-protection between O1 Manisa and O1 Campos in cattle vaccinated with foot-and-mouth disease virus vaccine incorporating different payloads of inactivated O1 Manisa antigen. AB - Serology is used to predict vaccine induced protection against challenge with a heterologous strain of the same serotype of foot-and-mouth disease virus (FMDV). To evaluate the accuracy of such predictions, we compared the protection afforded to cattle vaccinated with the O(1) Manisa strain of FMDV against challenge with either a homologous (O(1) Manisa) or a heterologous strain (O(1) Campos). Serology by virus neutralization test (VNT) using O(1) Manisa antiserum predicted an acceptable protection against such a challenge. Two experiments were carried out to compare the results for consistency. A total of 78 naive cattle were vaccinated with different antigen payloads (60-0.94 MUg) of O(1) Manisa. They were challenged by intradermolingual inoculation with live FMDV, either O(1) Manisa or O(1) Campos. Unvaccinated naive control cattle (n=20) were also challenged with either the O(1) Manisa or O(1) Campos viruses and all developed generalized FMD. The protection results for the vaccinated cattle revealed that higher payloads of O(1) Manisa vaccine were needed to protect against heterologous challenge compared to that for homologous challenge. The 50% protective dose (PD(50)) values for the vaccine in experiments 1 and 2 were found to be 28.78 and 9.44 for the homologous challenge and 3.98 and 5.01 for heterologous challenge. Furthermore, protection against O(1) Campos required a higher level of vaccine-induced antibody against this virus compared to the level of O(1) Manisa neutralizing antibody associated with protection against homologous challenge. The 50% protective level of in vitro neutralizing antibody was found to be log(10)1.827 for O(1) Campos and log(10)0.954 for O(1) Manisa based on O(1) Manisa based virus neutralization test. PMID- 21236234 TI - Evaluation of a probiotics, Bifidobacterium breve BBG-01, for enhancement of immunogenicity of an oral inactivated cholera vaccine and safety: a randomized, double-blind, placebo-controlled trial in Bangladeshi children under 5 years of age. AB - To evaluate the probiotic, Bifidobacterium breve strain Yakult (BBG-01), for safety and enhancement of immunogenicity in an oral inactivated cholera vaccine, a randomized double-blind placebo-controlled study was performed. Bangladeshi children under 5-year-old received BBG-01 or placebo for 4 weeks with two doses of oral cholera vaccine. Serum/fecal antibodies and fecal bacterial flora in the study participants were monitored. All adverse events were mild and transient and had no significant difference between the two groups. Immunological responses were similar comparing the two groups. A negative correlation between Bifidobacterium and Enterobacteriaceae in the probiotic group suggests a possible involvement of BBG-01 in alteration of the enteric bacterial flora. In conclusion, BBG-01 is well tolerated by Bangladeshi children although the post vaccinal immunostimulatory effect of BBG-01 was not evident. PMID- 21236233 TI - HelicoVax: epitope-based therapeutic Helicobacter pylori vaccination in a mouse model. AB - Helicobacter pylori is the leading cause of gastritis, peptic ulcer disease and gastric adenocarcinoma and lymphoma in humans. Due to the decreasing efficacy of anti-H. pylori antibiotic therapy in clinical practice, there is renewed interest in the development of anti-H. pylori vaccines. In this study an in silico-based approach was utilized to develop a multi-epitope DNA-prime/peptide-boost immunization strategy using informatics tools. The efficacy of this construct was then assessed as a therapeutic vaccine in a mouse model of gastric cancer induced by chronic H. pylori infection. The multi-epitope vaccine administered intranasally induced a broad immune response as determined by interferon-gamma production in ELISpot assays. This was associated with a significant reduction in H. pylori colonization compared with mice immunized with the same vaccine intramuscularly, given an empty plasmid, or given a whole H. pylori lysate intranasally as the immunogen. Total scores of gastric histological changes were not significantly different among the 4 experimental groups. These results suggest that further development of an epitope-based mucosal vaccine may be beneficial in eradicating H. pylori and reducing the burden of the associated gastric diseases in humans. PMID- 21236235 TI - Monitoring the safety of influenza A (H1N1) vaccine using web-based intensive monitoring. AB - BACKGROUND: When adjuvant vaccines against the pandemic influenza A (H1N1) virus became available after an accelerated registration process, safety issues dominated the public debate. As part of the immunisation campaign, the Dutch government installed an active monitoring of possible adverse events following immunisation (AEFIs). As part of the monitoring we conducted an anonymous prospective cohort study to identify and quantify the occurrence of AEFIs related to pandemic vaccination among the population immunised in general practice. METHOD: Adults aged 60 years and older or persons with a risk-elevating medical condition recommended for vaccination in general practice were eligible for participation. After receipt of the first pandemic vaccine the administrator handed over an information flyer of the web-based monitoring program. The patient could sign up for study participation online. Within one week, three weeks and three months after the first immunisation questions were asked about demographics and health, immunisations, injections site reactions and labeled reactions as well as other possible new AEFIs. RESULTS: In all, 3569 participants filled in the first questionnaire. Corresponding figures for the second and third questionnaires were 3395 (95.1%) and 3162 (88.6%). Mean age was 58 years (SD 15) and 50.1% was female. Main indication was 60 years or older followed by presence of pulmonary or cardiovascular disease. Of all participants, 1311 (37%) reported an AEFI. Unexpected serious reactions were not reported nor were there signals of possible new AEFIs. The occurrence of an AEFI was determined by gender, age and type of co-morbidity. CONCLUSION: The web-based intensive monitoring system among patients immunised in general practice revealed AEFIs due to pandemic vaccination in one-third of participants. There were no unexpected serious adverse events in this population. This advanced methodology can be further developed to monitor real-time use and AEFIs of vaccines. PMID- 21236236 TI - Innate immunity in DNA vaccine with Toxoplasma gondii-heat shock protein 70 gene that induces DC activation and Th1 polarization. AB - Toxoplasma gondii-derived heat shock protein 70 (T.g.HSP70) is a tachyzoite specific virulent molecule expressed before the death of hosts. We have already demonstrated the vaccine effects of T.g.HSP70 gene targeting peripheral epidermal or dermal dendritic cells (DC) to limit T. gondii loads in T. gondii-infected mice. In the present study, involvement of innate immunity in T.g.HSP70 gene vaccine-induced Th polarization at draining lymph nodes (dLN) of C57BL/6 (B6) mice and vaccine effects against toxoplasmosis have been evaluated. Compared to the mice unvaccinated or vaccinated with empty plasmid, CD11c(+) cells at the dLN from naive B6 mice expressed prominent IL-12 mRNA after the T.g.HSP70 gene vaccine. Also, CD4(+) cells at the dLN from the mice expressed prominent interferon-gamma, but not IL-4 or IL-17, mRNA at a maximum level at day 5 following vaccination. Thus, in vivo DC activation and successive early Th1 polarization were induced at the dLN of naive mice by the T.g.HSP70 gene vaccine. The DC activation and Th1 polarization were observed at the dLN from wild type (WT) and Toll-like receptor (TLR) 2-deficient mice, but not TLR4-deficient mice with B6 background by the vaccine. This T.g.HSP70 gene vaccine-induced DC activation and Th1 polarization were also observed in TRIF-deficient mice, but not MyD88-deficient mice with B6 background indicating the involvement of TLR4/MyD88 signal transduction cascade in the vaccine effects with T.g.HSP70 gene. The T.g.HSP70 gene vaccine (twice at a 2-week interval) has been shown to limit T. gondii loads in the mesenteric LN of WT, TLR2-deficient and TRIF deficient mice, but neither TLR4-deficient nor MyD88-deficient mice, at an acute phase of toxoplasmosis. The T.g.HSP70 gene vaccine also limited cyst number in the brains of WT, TLR2-deficient and TRIF-deficient mice, but not TLR4-deficient mice at a chronic phase of toxoplasmosis. Thus, innate immunity also has effects on the vaccine with T.g.HSP70 gene against acute and chronic phases of toxoplasmosis. PMID- 21236237 TI - DNA immobilization on a polypyrrole nanofiber modified electrode and its interaction with salicylic acid/aspirin. AB - A double-stranded calf thymus DNA (dsDNA) was physisorbed onto a polypyrrole (PPy) nanofiber film that had been electrochemically deposited onto a Pt electrode. The surface morphology of the polymeric film was characterized using scanning electron microscopy (SEM). The electrochemical characteristics of the PPy film and the DNA deposited onto the PPy modified electrode were investigated by cyclic voltammetry (CV), differential pulse voltammetry (DPV), and electrochemical impedance spectroscopy (EIS). Then the interaction of DNA with salicylic acid (SA) and acetylsalicylic acid (ASA), or aspirin, was studied on the electrode surface with DPV. An increase in the DPV current was observed due to the oxidation of guanine, which decreased with the increasing concentrations of the ligands. The interactions of SA and ASA with the DNA follow the saturation isotherm behavior. The binding constants of these interactions were 1.15*10(4)M for SA and 7.46*10(5)M for ASA. The numbers of binding sites of SA and ASA on DNA were approximately 0.8 and 0.6, respectively. The linear dynamic ranges of the sensors were 0.1-2MUM (r(2)=0.996) and 0.05-1mM (r(2)=0.996) with limits of detection of 8.62*10(-1) and 5.24*10(-6)MUM for SA and ASA, respectively. PMID- 21236238 TI - Differential pulse voltammetric simultaneous determination of acetaminophen and ascorbic acid using single-walled carbon nanotube-modified carbon-ceramic electrode. AB - Single-walled carbon nanotube-modified carbon-ceramic electrode (SWCNT/CCE) was employed for the simultaneous determination of acetaminophen (APAP) and ascorbic acid (AA). The SWCNT/CCE displayed excellent electrochemical catalytic activities toward APAP and AA oxidation compared with bare CCE. In the differential pulse voltammetry technique, both AA and APAP gave sensitive oxidation peaks at -62 and 302 mV versus saturated calomel electrode, respectively. Under the optimized experimental conditions, APAP and AA gave linear responses over ranges of 0.2 to 150.0 MUM (R(2)=0.998) and 5.0 to 700.0 MUM (R(2)=0.992), respectively. The lower detection limits were found to be 0.12 MUM for APAP and 3.0 MUM for AA. The investigated method showed good stability, reproducibility, and repeatability as well as high recovery in pharmaceutical and biological samples. PMID- 21236239 TI - Regulation of ultraviolet radiation induced cutaneous photoimmunosuppression by toll-like receptor-4. AB - UVB radiation is a potent immunosuppressive agent that inhibits cell-mediated immune responses. The mechanisms by which UVB radiation influences cell-mediated immune responses have been the subject of extensive investigation. However, the role of innate immunity on photoimmunological processes has received little attention. The purpose of this study was to determine whether Toll-like receptor 4 (TLR4) contributed to UV-induced suppression of contact hypersensitivity (CHS) responses. TLR4-/- and wild type C57BL/6 (TLR4+/+) mice were subjected to a local UVB immunosuppression regimen consisting of 100 mJ/cm2 UVB radiation followed by sensitization with the hapten DNFB. Wild type TLR4+/+ mice exhibited significant suppression of contact hypersensitivity response, whereas TLR4-/- developed significantly less suppression. The suppression in wild type TLR4+/+ mice could be adoptively transferred to naive syngeneic recipients. Moreover, there were significantly fewer Foxp3 expressing CD4+CD25+ regulatory T-cells in the draining lymph nodes of UV-irradiated TLR4-/- mice than TLR4+/+ mice. When cytokine levels were compared in these two strains after UVB exposure, T-cells from TLR4+/+ mice produced higher levels of IL-10 and TGF-beta and lower levels of IFN-gamma and IL 17. Strategies to inhibit TLR4 may allow us to develop immunopreventive and immunotherapeutic approaches for management of UVB induced cutaneous immunosuppression. PMID- 21236240 TI - Homologous protein subunits from Escherichia coli NADH:quinone oxidoreductase can functionally replace MrpA and MrpD in Bacillus subtilis. AB - The complex I subunits NuoL, NuoM and NuoN are homologous to two proteins, MrpA and MrpD, from one particular class of Na+/H+ antiporters. In many bacteria MrpA and MrpD are encoded by an operon comprising 6-7 conserved genes. In complex I these protein subunits are prime candidates for harboring important parts of the proton pumping machinery. Deletion of either mrpA or mrpD from the Bacillus subtilis chromosome resulted in a Na+ and pH sensitive growth phenotype. The deletion strains could be complemented in trans by their respective Mrp protein, but expression of MrpA in the B. subtilis DeltamrpD strain and vice versa did not improve growth at pH 7.4. This corroborates that the two proteins have unique specific functions. Under the same conditions NuoL could rescue B. subtilis DeltamrpA, but improved the growth of B. subtilis DeltamrpD only slightly. NuoN could restore the wild type properties of B. subtilis DeltamrpD, but had no effect on the DeltamrpA strain. Expression of NuoM did not result in any growth improvement under these conditions. This reveals that the complex I subunits NuoL, NuoM and NuoN also demonstrate functional specializations. The simplest explanation that accounts for all previous and current observations is that the five homologous proteins are single ion transporters. Presumably, MrpA transports Na+ whereas MrpD transports H+ in opposite directions, resulting in antiporter activity. This hypothesis has implications for the complex I functional mechanism, suggesting that one Na+ channel, NuoL, and two H+ channels, NuoM and NuoN, are present. PMID- 21236241 TI - Biochemical characterization of purified OmcS, a c-type cytochrome required for insoluble Fe(III) reduction in Geobacter sulfurreducens. AB - Previous studies with Geobacter sulfurreducens have demonstrated that OmcS, an abundant c-type cytochrome that is only loosely bound to the outer surface, plays an important role in electron transfer to Fe(III) oxides as well as other extracellular electron acceptors. In order to further investigate the function of OmcS, it was purified from a strain that overproduces the protein. Purified OmcS had a molecular mass of 47015 Da, and six low-spin bis-histidinyl hexacoordinated heme groups. Its midpoint redox potential was -212 mV. A thermal stability analysis showed that the cooperative melting of purified OmcS occurs in the range of 65-82 degrees C. Far UV circular dichroism spectroscopy indicated that the secondary structure of purified OmcS consists of about 10% alpha-helix and abundant disordered structures. Dithionite-reduced OmcS was able to transfer electrons to a variety of substrates of environmental importance including insoluble Fe(III) oxide, Mn(IV) oxide and humic substances. Stopped flow analysis revealed that the reaction rate of OmcS oxidation has a hyperbolic dependence on the concentration of the studied substrates. A ten-fold faster reaction rate with anthraquinone-2,6-disulfonate (AQDS) (25.2 s-1) was observed as compared to that with Fe(III) citrate (2.9 s-1). The results, coupled with previous localization and gene deletion studies, suggest that OmcS is well-suited to play an important role in extracellular electron transfer. PMID- 21236242 TI - Binding of glyceraldehyde-3-phosphate dehydrogenase to the cis-acting element of structure-anchored repression in ccn2 mRNA. AB - CCN2/connective tissue growth factor (CTGF) can be induced by hypoxia and promotes tumor angiogenesis. Our previous studies revealed that hypoxia-induced gene expression of human ccn2 mRNA is regulated post-transcriptionally in human chondrosarcoma-derived cell line, HCS-2/8, in which a minimal cis-element, entitled CAESAR, in the 3'-untranslated region (UTR) of ccn2 mRNA and a 35-kDa protein counterpart play an important role by determining the stability of ccn2 mRNA. In the present study, we identified this corresponding protein as glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by utilizing RNA affinity chromatography combined with mass spectrometry. The results of an RNA binding assay revealed the specific binding of GAPDH to this cis-element. To further characterize the interaction between GAPDH and ccn2 mRNA, we examined the roles of redox conditions and glycolytic coenzyme in the binding of GAPDH to the ccn2 mRNA. An oxidizing agent, diamide, abolished the GAPDH-RNA interaction in a concentration-dependent manner; whereas this effect could be reversed by subsequent treatment with 2-mercaptoethanol (2-ME). In addition, nicotinamide adenine dinucleotide (NAD), a coenzyme of GAPDH, inhibited the GAPDH-RNA binding. Taken together, these findings suggest that the glycolytic enzyme GAPDH regulates the gene expression of ccn2 mRNA in trans by acting as a sensor of oxidative stress and redox signals, leading to CCN2 overexpression under the condition of hypoxia and promotion of angiogenesis. PMID- 21236243 TI - Genetic association of TLR4/11367 polymorphism with late-onset Alzheimer's disease in a Han Chinese population. AB - The amyloid beta-protein (A-beta) deposits in the brains of patients with Alzheimer's disease (AD) are closely associated with innate immune responses that were assumed to play a pivotal role in the pathogenesis of AD. Toll-like receptor 4 (TLR4) is thought to contribute to Abeta clearance. Studies have reported the presence and functional significance of the TLR4/11367 polymorphism in a Han Chinese population. To evaluate the involvement of the TLR4/11367 polymorphism in the risk of late-onset Alzheimer's disease (LOAD), we performed a case-control study to analyze the genotype and allele distributions of the TLR4/11367 polymorphism in a Han Chinese population (137 LOAD cases and 137 healthy controls). There were significant differences in genotype and allele frequencies between LOAD cases and controls (genotype P<0.001, allele P<0.001). After stratification by APOE epsilon4-carrying status, the C allele of the TLR4/11367 polymorphism was still significantly associated with LOAD in APOE epsilon4 non carriers (OR=5.77, 95% CI=3.03-11.00, P<0.001) and carriers (OR=2.03, 95% CI=1.03 3.98, P=0.04). In addition, a logistic regression analysis also conferred positive association between TLR4/11367C and LOAD (dominant model: ORa=3.08, 95% CI=1.60-5.93, P=0.001; recessive model: ORa=8.79, 95% CI=3.31-23.36, P<0.001; additive model: ORa=2.75, 95% CI=1.73-4.37, P<0.001) after adjustment for age, gender, and the APOE epsilon4 carrier status. This study gives the first evidence that the TLR4/11367 polymorphism was associated with LOAD in a Han Chinese population. PMID- 21236244 TI - Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by a preferential loss of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNpc). Both glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) play key roles in maintaining the DAergic phenotype and exert a cytoprotective effect on these neurons in vivo and in vitro. However, controversy still exists regarding the relative potency of the two factors and the extent to which they act synergistically. In this study, we used a refined version of organotypic cultures as a model for PD. The neurotoxin 6-hydroxydopamine (6-OHDA) was applied unilaterally in slices of rat mesencephalon, allowing for internal controls and enabling a precise comparison between the two sides of the midbrain. We evaluated the cytoprotective and regenerative effects of BDNF, GDNF and the combination of these in terms of surviving tyrosine hydroxylase positive (TH+) cells and TH mRNA expression. Pre-, co-, or post-treatment with neurotrophic factors clearly protects DAergic neurons from cell death. Cell survival is particularly pronounced in cultures pre-treated with BDNF and is not further increased when BDNF is applied in combination with GDNF in equimolar dose. On the lesion side, surviving TH+ cells exposed to neurotrophic factors showed extensive sprouting, and BDNF treatment resulted in a two-fold increase in TH mRNA. Such effects were not seen in the absence of toxin exposure. Thus, we observed that BDNF induced an upregulation of the DAergic phenotype, which suggest a cytoprotective and regenerative effect. PMID- 21236245 TI - The evaluation of nitric oxide involvement in metrazol induced status epilepticus using multiparametric monitoring. AB - Nitric oxide (NO) has been implicated in the neuronal hyperexcitability hence its involvement in the pathophysiology of epilepsy is clear. However, some studies indicate that NO has anticonvulsant effects while others present its convulsive effects. In the present study we tested the involvement of NO in pentylenetetrazol (Metrazol) induced Status Epilepticus (SE) rats, using the nonspecific inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME) and the neuronal-specific inhibitor, 7-nitroindazole (7N1). The effects of NOS (NO synthase) inhibitors were tested, within the seizures and between them, using the Multiparametric Assembly (MPA) which continuously monitored Cerebral Blood Flow (CBF) by Laser Doppler flowmetry, mitochondrial NADH redox state by the fluorometric technique, extracellular K(+) and H(+) levels using selective mini electrodes and electrical activity (DC potential and ECoG) using special electrodes. Between seizures a trend of increase in CBF with oxidation of NADH was seen, with no change in K(+) and H(+) extracellular levels. Pre-treatment with L-NAME prevented this trend of increase in CBF whereas the injection of 7NI even decreased CBF between seizures. Within seizures, CBF increased and mitochondrial NADH was oxidized at the first seizures, while in the last seizure NADH was reduced. The use of NOS inhibitors significantly increased the degree of NADH oxidation at the latest convulsions. In conclusion our results demonstrated beneficial effect of NOS inhibitors on the brain cortex under SE induced by Metrazol, implying that they may serve as anticonvulsant drugs. PMID- 21236246 TI - Folate in smokers. AB - Blood folate concentration is decreased by tobacco smoking and presumably secondhand smoke. Because low folate concentration is associated with hyperhomocysteinemia, both are emerging as important and independent risk factors for atherosclerosis as well as prediction of early coronary artery disease. The primary cause of low folate concentration in smokers might be related to lifestyle and dietary habits. Smokers tend to consume fewer folate-rich fruits and vegetables vs non-smokers. Adverse cardiovascular health is generally attributed to toxic gases, particulates, and tars generated from tobacco smoking. Although low folate concentration and hyperhomocysteinemia are typically found in smokers, their role in this pathophysiologic process remains controversial. In fact, several studies failed to demonstrate a beneficial effect of daily folic acid supplementation as a homocysteine-lowering therapy on cardiovascular outcome even in smokers. In this review, we investigate the relationship between folate status and smoking. PMID- 21236247 TI - Cytokines in recurrent pregnancy loss. AB - BACKGROUND: Recurrent pregnancy loss (RPL) is defined as the occurrence of three or more consecutive miscarriages prior to 20 weeks gestation. Exaggerated maternal immune response to fetal antigens has been proposed to be one of the mechanisms underlying recurrent pregnancy loss. METHOD: A comprehensive literature search was conducted from the websites of the National Library of Medicine (http://www.ncbl.nlm.nih.gov) and Pubmed Central, the US National Library of Medicine's digital archive of life sciences literature (http://www.pubmedcentral.nih.gov/). The data was assessed from books and journals that published relevant articles in this field. RESULT: In normal pregnancy, tolerance of the genetically incompatible fetus by the maternal immune system depends on the interactions of an array of cytokines secreted by maternal and fetal cells at the site of implantation. Earlier research indicated that altered immunity in RPL is dominated by the Th1/Th2 hypothesis, which proposed that the fetus escapes maternal-derived T-cell responses through skewing the Th0 differentiation toward Th2 pathway which dampens pro-inflammatory Th1-type immunity. Recent studies indicate the role of proinflammatory Th17 cells and immunoregulatory Treg cells in RPL in addition to Th1/Th2 interactions. CONCLUSION: Cytokines form a complex regulatory network which maintains homeostasis between the fetal unit and the maternal immune system. If this delicate balance is adversely affected, immunoregulatory mechanisms may be insufficient to restore homeostasis and this may lead to pregnancy failure. PMID- 21236248 TI - Effect of strontium on human Runx2+/- osteoblasts from a patient with cleidocranial dysplasia. AB - Strontium represents a new generation of anti-osteoporotic agents that exert anti catabolic and anabolic effects on bone cells at once. We used strontium in vitro in order to examine its potential to stimulate bone marker transcription and hydroxyapatite formation on isolated Runx2(+/-) osteoblasts from a patient with cleidocranial dysplasia. This disease is evoked by heterozygous mutations of Runx2, an important transcription factor for osteoblast maturing and transcription of osteogenic genes, which results in insufficient gene dosage of Runx2. This genetic defect is responsible, for example, for patent fontanels, sometimes throughout the life, supernumerary teeth, and aplasia or hypoplasia of clavicles and mimics symptoms of hypophosphatasia. In this trial, we investigated the effect of strontium on gene expression of bone marker proteins, the formation of hydroxyapatite and the cell proliferation of strontium-treated Runx2(+/-) osteoblasts. Unlike normal osteoblasts, gene expression of bone marker proteins was not affected in strontium-treated Runx2(+/-) osteoblasts, while improved hydroxyapatite formation was noted in the extracellular matrix. A WST-1 cell proliferation assay with strontium-treated Runx2(+/-)-osteoblasts showed that strontium induces cell proliferation and growth. This effect might be responsible for the improved mineralisation of the extracellular matrix of strontium-treated Runx2(+/-)-osteoblasts observed. PMID- 21236249 TI - Effect of potassium channel opener pinacidil on the contractions elicited electrically or by noradrenaline in the human radial artery. AB - In order to discover an agent that can prevent spasm of the human radial artery, the aim of our study was to evaluate the effect of the K(+) channel opener, pinacidil, on contractions in the radial artery. Contractions of the radial artery were evoked by exogenously applied noradrenaline or by electrical field stimulation (EFS, 20Hz, neurogenic). Pinacidil induced concentration-dependent inhibition of both EFS- and noradrenaline-evoked contractions of the radial artery. Glibenclamide, a selective blocker of ATP-sensitive K(+) channels (Kir6.x containing subunit) antagonized in the same manner the pinacidil-induced inhibition of neurogenic contractions and contractions evoked by exogenous noradrenaline. The inhibition of pinacidil relaxation by tetraethylammonium (TEA), a blocker of Ca-sensitive K(+) (K(Ca)) channels, was more pronounced in EFS-contracted preparations. A blocker of voltage-sensitive K(+) (K(V)) channels, 4-aminopyridine (4-AP), inhibited pinacidil relaxation only in EFS-contracted preparations. In order to test the presence of different K(+) channels, immunohistochemistry of K(+) channels expression in the radial artery was performed. The vascular wall of the human radial artery showed variable positivity with the following applied antibodies: Kv1.2, Kv1.3, Kir6.1, and K(Ca)1.1. The antibodies against Kv1.6, Kv2.1, and Kir6.2 channel subunits were completely negative. These results suggest that the inhibitory effect of pinacidil on contractions of the human radial artery might be postsynaptic and associated with opening of smooth muscle Kir6.1-containing K(ATP) channels. TEA- and 4-AP-sensitive K(+) channels may also contribute to pinacidil effect in the human radial artery. PMID- 21236250 TI - Modulation of vein function by perivascular adipose tissue. AB - Although a number of studies have shown that perivascular adipose tissue (PVAT) attenuates arterial contraction through the release of perivascular-derived relaxation factors (PVRF), the role of PVAT in modulating venous function and its mechanism(s) remained unknown. Here we examined the role of PVAT in the modulation of vascular function in the inferior vena cava. Venous rings from male Wistar rats were prepared with both endothelium and PVAT intact, with either PVAT or endothelium removed, or with both endothelium and PVAT removed for functional studies. Contractile response to phenylephrine, U 46619, or 5-hydroxytryptamine was significantly attenuated in PVAT+ as compared with PVAT- veins. PVAT- vessels with intact endothelium (E+) pre-contracted with phenylephrine showed a concentration-dependent relaxation response to angiotensin 1-7 [Ang-(1-7)], and this response was abolished by the removal of endothelium, and by Ang-(1-7) (Mas) receptor antagonists D-Ala-Ang-(1-7) (A779) or D-Pro(7)-Ang-(1-7). Donor solution incubated with a PVAT+ ring induced a relaxation response in the E+ recipient vessel but not in E- recipient vessel. The use of specific channel blockers and enzyme inhibitors showed that Ang-(1-7) is a transferable PVRF that induces endothelium-dependent relaxation through NO release and activation of voltage dependent potassium (K(+)) channels (K(v)) channels. We conclude that venous PVAT attenuates agonist-induced contraction by releasing Ang-(1-7), which causes relaxation of smooth muscle through endothelial NO release and activation of K(v) channels. PMID- 21236251 TI - Amelioration effects of berberine on diabetic microendothelial injury model by the combination of high glucose and advanced glycation end products in vitro. AB - Microvascular complications are much earlier and common in diabetes. Advanced glycation end products (AGEs), together with high glucose, play a key role in the endothelial dysfunction of diabetic vascular complications. So it is of more significance to expedite the therapies to block the formation and/or the effects of AGEs. Berberine has been showed to have anti-diabetic effects, however the effects on diabetic complications were less explored, especially the effects on the microvascular complications and the formation and pathways of AGEs which have not been reported. Therefore, the present study established an in vitro model of diabetic microendothelial (microEC) injury by the combination of high glucose and AGEs to mimic the clinical situations and examine the effects and mechanisms of berberine on high glucose-AGEs-induced microEC injuries and on the formation of AGEs. We prepared AGEs, established the high glucose-AGEs injured microEC models by MTT assay, which was further supported by significantly decreased nitric oxide (NO) release, NO synthase (NOS) and thrombomodulin production with ELISA, western blot and RT-PCR analysis. Berberine treatments showed significant improvements as indicated by significantly increased NO release, NOS and thrombomodulin production. Moreover, we also observed significant inhibition effects of berberine on AGEs formation. We concluded that the in vitro model of diabetic microEC injury could be established by the combination treatments of high glucose and AGEs, while berberine could improve the diabetic microvascular injury in vitro and inhibit the formation of AGEs, suggesting the potential clinical therapies with berberine for diabetes and its vascular complications. PMID- 21236252 TI - Neuroprotective and anti-inflammatory effects of mollugin via up-regulation of heme oxygenase-1 in mouse hippocampal and microglial cells. AB - Mollugin, a bioactive phytochemical isolated from Rubia cordifolia L. (Rubiaceae), exhibits antimutagenic activity, antitumor activity, antiviral activity, and inhibitory activity in arachidonic acid- and collagen-induced platelet aggregation. In this study, we investigated the effects of mollugin as a neuroprotective agent in glutamate-induced neurotoxicity in the mouse hippocampal HT22 cell line and as an anti-inflammatory agent in lipopolysaccharide-induced microglial activation in BV2 cells. Mollugin showed potent neuroprotective effects against glutamate-induced neurotoxicity and reactive oxygen species generation in mouse hippocampal HT22 cells. In addition, the anti-inflammatory effects of mollugin were demonstrated by the suppression of pro-inflammatory mediators, including pro-inflammatory enzymes (inducible nitric oxide synthase and cyclooxygenase-2) and cytokines (tumor necrosis factor-alpha and interleukin 6). Furthermore, we found that the neuroprotective and anti-inflammatory effects of mollugin were linked to the up-regulation of the expression of heme oxygenase (HO)-1 and the activity of HO in HT22 and BV2 cells. In addition, the effects of mollugin resulted in the nuclear accumulation of nuclear factor-E2-related factor 2 (Nrf2) in HT22 and BV2 cells. Furthermore, mollugin also activated the p38 mitogen-activated protein kinase (MAPK) pathway both in HT22 and BV2 cells. These results suggest that mollugin may be a promising candidate for the treatment of neurodegenerative diseases related to neuroinflammation. PMID- 21236254 TI - Axial ligation of the high-potential heme center in an Arabidopsis cytochrome b561. AB - Arabidopsis has four putative, di-heme cytochrome b561 proteins, including one localized in the tonoplast (TCytb). From a comparative electron paramagnetic resonance (EPR), UV-Vis absorption and resonance Raman study, on wild type, H83A/H156A-TCytb and H83L/H156L-TCytb double mutants, it follows that the H83 and H156 residues are binding one of the two hemes. These measurements show that the high-potential heme site is situated at the cytoplasmic side of the membrane and allow the unambiguous differentiation between two models on the heme localization in cytochrome b561 proteins. PMID- 21236253 TI - Hypoxia-induced autophagic response is associated with aggressive phenotype and elevated incidence of metastasis in orthotopic immunocompetent murine models of head and neck squamous cell carcinomas (HNSCC). AB - Hypoxia confers resistance to chemoradiation therapy and promotes metastasis in head and neck squamous cell carcinomas (HNSCC). We investigated the effects of hypoxia in tumor phenotype using immunocompetent murine HNSCC models. Balb/c mice were injected intraorally with murine squamous cell carcinoma cells LY-2 and B4B8. Intratumoral hypoxia fraction was evaluated by the immunohistochemical detection of hypoxic probe pimonidazole and carbonic anhydrase IX (CAIX). Tumor cell apoptosis and autophagy in hypoxic areas of these tumors were examined immunohistochemically. Hypoxia-induced apoptotic and autophagic responses in vitro were examined by treating LY2 cells with CoCl(2). B4B8 tumors exhibited a non-aggressive phenotype characterized by its slow growth rate and the lack of metastatic spread. LY2 tumors demonstrated an aggressive phenotype characterized by rapid growth rate with regional and distant metastasis. Intratumoral hypoxia fraction in B4B8 tumors was significantly lower than in LY2 tumors. The hypoxic areas in B4B8 tumors exhibited increased apoptosis rate than that of LY2 tumors. In contrast, the hypoxic areas in LY2 tumors revealed autophagy. The induction of hypoxia in vitro elicited autophagy and not apoptosis in LY2 cells. The induction of autophagy coupled with blockage of apoptosis in hypoxic areas promotes tumor cell survival and confers aggressive phenotype in immunocompetent murine HNSCC models. PMID- 21236255 TI - Mechanistic characterization of sulfur transfer from cysteine desulfurase SufS to the iron-sulfur scaffold SufU in Bacillus subtilis. AB - Iron-sulfur cluster biosynthesis in Gram-positive bacteria is mediated by the SUF system. The transfer of sulfide from the cysteine desulfurase SufS to the scaffold protein SufU is one of the first steps within the assembly process. In this study, we analyzed the interaction between Bacillus subtilis SufS and its scaffold SufU. The activity of SufS represents a Ping-Pong mechanism leading to successive sulfur loading of the conserved cysteine residues in SufU. Cysteine 41 of SufU is shown to be essential for receiving sulfide from SufS, while cysteines 66 and 128 are needed for SufS/SufU interaction. In conclusion, we present the first step-by-step model for loading of the essential scaffold component SufU by its sulfur donor SufS. PMID- 21236256 TI - Actin filament associated protein mediates c-Src related SRE/AP-1 transcriptional activation. AB - AFAP is an adaptor protein involved in cytoskeletal organization and intracellular signaling. AFAP binds and activates c-Src; however, the downstream signals of this interaction remain unknown. Here we show that co-expression of AFAP and c-Src induce transcriptional activation of SRE and AP-1 in a c-Src activity dependent fashion. Structural-functional studies suggest that the proline-rich motif in the N-terminus of AFAP is critical for c-Src activation, and subsequent SRE/AP-1 transactivation and the actin-binding domain in the AFAP C-terminus is negatively involved in the regulation of AFAP/c-Src mediated SRE/AP 1 transactivation. Selective deletion of this domain enhances transactivation of SRE. We conclude that in addition to its role in the regulation of cytoskeletal structures, AFAP may also be involved in the c-Src related transcriptional activities. PMID- 21236257 TI - MicroRNA-146a regulates the maturation process and pro-inflammatory cytokine secretion by targeting CD40L in oxLDL-stimulated dendritic cells. AB - There is increasing evidence that microRNAs (miRNAs) play important roles in cell proliferation, apoptosis and differentiation that accompany inflammatory responses. However, whether miRNAs are associated with dendritic cell (DC) immuno inflammatory responses to oxidized low density lipoprotein (oxLDL) stimulation is yet unknown. Our study aims to explore the link of miRNA to lipid-overload and the immuno-inflammatory mechanism for atherosclerosis. Human primary monocyte derived DCs were transfected with miR-146a mimics and inhibitor, and then stimulated by oxLDL. For the flow cytometric analysis of the DC immunophenotype, supernatants were collected to determine inflammatory chemokine markers. Our study clearly revealed that miRNA-146a regulates the maturation process and pro inflammatory cytokine secretion in DCs by targeting CD40L in ox-LDL-stimulated DCs. PMID- 21236258 TI - LIGHT/TNFSF14 enhances adipose tissue inflammatory responses through its interaction with HVEM. AB - Obesity-induced adipose tissue inflammation is characterized by increased macrophage infiltration and cytokine production, and is associated with metabolic disorders. LIGHT/TNFSF14, a member of the TNF superfamily, plays a role in the development of various inflammatory diseases. The purpose of this study was to examine the involvement of soluble LIGHT (sLIGHT) in obesity-induced adipose tissue inflammatory responses. LIGHT gene expression on macrophages/adipocytes was upregulated by treatment with obesity-related factors. sLIGHT displayed chemotactic activity for macrophages and T cells, and enhanced inflammatory cytokine release from macrophages, adipocytes, and adipose tissue-derived SVF cells. The sLIGHT-induced inflammatory responses were blunted by neutralizing anti-HVEM antibody or knockout of HVEM, a receptor for sLIGHT. These findings indicate that sLIGHT enhances adipose tissue inflammatory responses through its interaction with HVEM. PMID- 21236260 TI - The proteome of the insoluble Schistosoma mansoni eggshell skeleton. AB - In schistosomiasis, the majority of symptoms of the disease is caused by the eggs that are trapped in the liver. These eggs elicit an immune reaction that leads to the formation of granulomas. The eggshell, which is a rigid insoluble structure built from cross-linked proteins, is the site of direct interaction between the egg and the immune system. However, the exact protein composition of the insoluble eggshell was previously unknown. To identify the proteins of the eggshell of Schistosoma mansoni we performed LC-MS/MS analysis, immunostaining and amino acid analysis on eggshell fragments. For this, eggshell protein skeleton was prepared by thoroughly cleaning eggshells in a four-step stripping procedure of increasing strength including urea and SDS to remove all material that is not covalently linked to the eggshell itself, but is part of the inside of the egg, such as Reynold's layer, von Lichtenberg's envelope and the miracidium. We identified 45 proteins of which the majority are non-structural proteins and non-specific for eggs, but are house-keeping proteins that are present in large quantities in worms and miracidia. Some of these proteins are known to be immunogenic, such as HSP70, GST and enolase. In addition, a number of schistosome-specific proteins with unknown function and no homology to any known annotated protein were found to be incorporated in the eggshell. Schistosome specific glycoconjugates were also shown to be present on the eggshell protein skeleton. This study also confirmed that the putative eggshell protein p14 contributes largely to the eggshell. Together, these results give new insights into eggshell composition as well as eggshell formation. Those proteins that are present at the site and time of eggshell formation are incorporated in the cross linked eggshell and this cross-linking does no longer occur when the miracidium starts secreting proteins. PMID- 21236259 TI - MicroRNA-221 controls expression of intercellular adhesion molecule-1 in epithelial cells in response to Cryptosporidium parvum infection. AB - Cryptosporidium parvum is a protozoan parasite that infects gastrointestinal epithelial cells and causes diarrhoeal disease in humans and animals globally. Pathological changes following C. parvum infection include crypt hyperplasia and a modest inflammatory reaction with increased infiltration of lymphocytes into intestinal mucosa. Expression of adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1), on infected epithelial cell surfaces may facilitate adhesion and recognition of lymphocytes at infection sites. MicroRNAs (miRNAs) are small RNA molecules of 23 nucleotides that negatively regulate protein-coding gene expression via translational suppression or mRNA degradation. We recently reported that microRNA-221 (miR-221) regulates ICAM-1 translation through targeting the ICAM-1 3'-untranslated region (UTR). In this study, we tested the role of miR-221 in regulating ICAM-1 expression in epithelial cells in response to C. parvum infection using an in vitro model of human biliary cryptosporidiosis. Up-regulation of ICAM-1 at both message and protein levels was detected in epithelial cells following C. parvum infection. Inhibition of ICAM-1 transcription with actinomycin D could only partially block C. parvum-induced ICAM-1 expression at the protein level. Cryptosporidium parvum infection decreased miR-221 expression in infected epithelial cells. When cells were transfected with a luciferase reporter construct covering the miR-221 binding site in the ICAM-1 3'-UTR and then exposed to C. parvum, an enhanced luciferase activity was detected. Transfection of miR-221 precursor abolished C. parvum stimulated ICAM-1 protein expression. In addition, expression of ICAM-1 on infected epithelial cells facilitated epithelial adherence of co-cultured Jurkat cells. These results indicate that miR-221-mediated translational suppression controls ICAM-1 expression in epithelial cells in response to C. parvum infection. PMID- 21236261 TI - Disseminated neoplasia in flat oysters Ostrea edulis from Galicia (NW Spain): occurrence, ultrastructural aspects and relationship with bonamiosis. AB - Disseminated neoplasia (DN) was one of the most important pathological conditions found in cultured flat oysters (Ostrea edulis) from different geographical origins grow in Galicia (NW Spain), during a two years selective breeding programme to produce oysters less susceptible to bonamiosis. Histological characteristics observed in oysters affected by DN included intense infiltration of connective tissue of various organs (gills, stomach, digestive gland and gonad) by large undifferentiated cells, with a large nucleus and a high nucleus to-cytoplasm ratio. The main ultrastructural features were predominance of euchromatin over heterochromatin that was arrayed in small clumps in the nucleus, prominent granular nucleolus, swollen mitochondria with few cristae and high number of free ribosomes in the cytoplasm. A seasonal pattern of DN prevalence was detected, with higher values in spring-summer, but there were no significant differences between geographic origins or families within these origins. However, the intensity of the disease was significantly different between origins; oysters originating outside of Galicia (particularly those originating from Ireland) were more susceptible to develop advanced DN. DN (8%) and bonamiosis (4.9%) were found concurrently in oysters. The nature and significance of this association warrants more investigation to determine its importance, if any. PMID- 21236262 TI - Elastase B of Pseudomonas aeruginosa stimulates the humoral immune response in the greater wax moth, Galleria mellonella. AB - The role of Pseudomonas aeruginosa elastase B in activation of the humoral immune response in Galleria mellonella larvae was investigated. The results of our study showed that elastase B injected at a sublethal concentration was responsible for eliciting the humoral immune response in G. mellonella larvae. The insects exhibited increased antibacterial activity, namely, we observed appearance of antimicrobial peptides and a higher level of lysozyme in cell-free hemolymph. Elastase B seems to be a more potent elicitor than thermolysin because similar maximal antibacterial activity levels were observed at a 5-fold lower concentration. We also demonstrated that there were differences in the kinetics of induction of antimicrobial activity between thermolysin and elastase B. The maximum level was observed 18h post challenge of thermolysin and 38h after injection of elastase B. It was also shown that, 24h after elastase injection, the relative levels of apoLp-III in the hemolymph significantly increased in comparison with control G. mellonella larvae. The activation of immune responses in metalloproteinase-challenged larvae involved synthesis of metalloproteinase inhibitors which increased the survival rates of insects both against the lethal dose of thermolysin as well as against viable pathogenic bacterial cells of P. aeruginosa. PMID- 21236263 TI - Augmenting beta-augmentation: structural basis of how BamB binds BamA and may support folding of outer membrane proteins. AB - beta-Barrel proteins are frequently found in the outer membrane of mitochondria, chloroplasts and Gram-negative bacteria. In Escherichia coli, these proteins are inserted in the outer membrane by the Bam (beta-barrel assembly machinery) complex, a multiprotein machinery formed by the beta-barrel protein BamA and the four peripheral membrane proteins BamB, BamC, BamD and BamE. The periplasmic part of BamA binds prefolded beta-barrel proteins by a beta-augmentation mechanism, thereby stabilizing the precursors prior to their membrane insertion. However, the role of the associated proteins within the Bam complex remains unknown. Here, we describe the crystal structure of BamB, a nonessential component of the Bam complex. The structure shows a typical eight-bladed beta-propeller fold. Two sequence stretches of BamB were previously identified to be important for interaction with BamA. In our structure, both motifs are located in close proximity to each other and contribute to a conserved region forming a narrow groove on the top of the propeller. Moreover, crystal contacts reveal two interaction modes of how BamB might bind unfolded beta-barrel proteins. In the crystal lattice, BamB binds to exposed beta-strands by beta-augmentation, whereas peptide stretches rich in aromatic residues can be accommodated in hydrophobic pockets located at the bottom of the propeller. Thus, BamB could simultaneously bind to BamA and prefolded beta-barrel proteins, thereby enhancing the folding and membrane insertion capability of the Bam complex. PMID- 21236264 TI - Symbiotic physiology promotes homeostasis in Daisyworld. AB - A connection is hypothesized between the physiological consequences of mutualistic symbiosis and life's average long-term impact on certain highly biologically conserved environmental variables. This hypothesis is developed analytically and with a variant of the Daisyworld model. Biological homeostasis is frequently effective due to co-ordination between opposing physiological "rein" functions, which buffer an organism in response to an external (often environmental) perturbation. It is proposed that during evolutionary history the pooling of different species' physiological functions in mutualistic symbioses increased the range of suboptimal environmental conditions that could be buffered against--a mutual tolerance benefit sometimes sufficient to outweigh the cost of cooperation. A related argument is that for a small number of biologically crucial physical variables (i) the difference between organism interiors and the life-environment interface is relatively low, and (ii) the biologically optimum level of that variable is relatively highly conserved across different species. For such variables, symbiosis tends to cause (at a cost) an increase in the number of environmental buffering functions per unit of selection, which in turn biases the overall impact of the biota on the state of the variable towards the biological optimum. When a costly but more temperature-tolerant and physiologically versatile symbiosis between one black (warming) and one white (cooling) "daisy" is added to the (otherwise unaltered) Daisyworld parable, four new results emerge: (1) The extension of habitability to a wider luminosity range, (2) resistance to the impact of "cheater" white daisies with cold optima, that derive short-term benefit from environmental destabilisation, (3) the capacity to maintain residual, oscillatory regulation in response to forcings that change more rapidly than allele frequencies and (crucially) (4) "succession" type dynamics in which the tolerant symbiosis colonises and to an extent makes habitable an otherwise lifeless environment, but is later displaced by free living genotypes that have higher local fitness once conditions improve. The final result is arguably analogous to lichen colonisation of the Neoproterozoic land surface, followed by the Phanerozoic rise of vascular plants. Caution is necessary in extrapolating from the Daisyworld parable to real ecology/geochemistry, but sufficiently conserved variables may be water potential, macronutrient stoichiometry and (to a lesser extent) the temperature window for metabolic activity. PMID- 21236265 TI - Mathematical modelling of hepatitis C treatment for injecting drug users. AB - Hepatitis C virus (HCV) is a blood-borne infection that can lead to progressive liver failure, cirrhosis, hepatocellular carcinoma and death. In developed countries, the majority of HCV infections are transmitted via injecting drug users (IDUs). Despite effective antiviral treatment for HCV, very few active IDUs are treated. Reluctance to treat is partially due to the risk of reinfection. We develop a mathematical model of HCV transmission amongst active IDUs, and examine the potential effect of antiviral treatment. As most mathematical models of interventions utilise a treatment function proportional to the infected population, but many policy implementations set fixed yearly targets for specific numbers treated, we study the effects of using two different treatment terms: annually treating a proportion of infecteds or a fixed number of infecteds. We examine the behaviour of the two treatment models and find different bifurcation behaviours in each case. We calculate analytical solutions for the treatment level needed for disease clearance or control, and observe that achievable levels of treatment can result in control or eradication across a wide range of prevalence levels. Finally, we calculate the sensitivity of the critical treatment threshold to the model parameters, and find that for a given observed prevalence, the injecting duration and infection risk play the most important role in determining the treatment level needed. By contrast, the sensitivity analysis indicates the presence (or absence) of immunity does not alter the treatment threshold. We conclude by discussing the public health implications of this work, and comment on the importance and feasibility of utilising treatment as prevention for HCV spread amongst IDUs. PMID- 21236266 TI - Skin capillary density and microvascular reactivity in obese subjects with and without metabolic syndrome. AB - Obesity is associated with increased cardiovascular morbidity and mortality. We hypothesized that microvascular function may be impaired in obese subjects with metabolic syndrome (OB-MetSnd) compared to obese subjects without MetSnd (OB) and healthy subjects (HS). In this cross-sectional study, we evaluated skin capillary density (SCD) in OB-MetSnd (n=20, 12 women, BMI=36.5+/-1.1kg/m(2)), OB (n=25, 16 women, BMI=34.5+/-0.7kg/m(2)), and HS (n=30, 22 women, BMI=22.8+/-0.3kg/m(2)) groups. SCD was evaluated by intravital video-microscopy at rest and after post occlusive reactive hyperemia (PORH) and venous congestion (VC). OB-MetSnd subjects exhibited significant differences in the values of MetSnd components and in leptin and HOMA-IR levels compared to OB and HS individuals. There were no differences in SCD among groups in resting conditions. The OB-MetSnd group failed to show a significant increase in the number of recruited capillaries during PORH and VC compared to the SCD evaluated at rest. A negative correlation of SCD with waist circumference, BMI, blood pressure, and HOMA-IR was observed after PORH and VC. When obese subjects were analyzed according to their HOMA-IR quartiles, a significant decrease in SCD was observed during POHR (P=0.02). Our findings showed that obese subjects have structural and functional alterations in skin microcirculation that are proportional to the increase in the degree of global and central obesity. In addition, in OB-MetSnd subjects, the cutaneous capillaries at rest are already maximally recruited, indicating an absence of functional capillary reserve. This may be related to the insulin resistance observed in OB-MetSnd individuals. PMID- 21236267 TI - Irbesartan inhibits advanced glycation end product (AGE)-induced up-regulation of vascular cell adhesion molecule-1 (VCAM-1) mRNA levels in glomerular endothelial cells. AB - Renin-angiotensin system (RAS) plays a central role in the development and progression of diabetic nephropathy. There is a growing body of evidence that advanced glycation end products (AGE) and inflammation contribute to diabetic nephropathy as well. However, the pathophysiological crosstalk between the RAS and AGE in inflammatory reactions in glomerular endothelial cells (ECs) remains unknown. In this study, we examined whether and how irbesartan, an angiotensin II type 1 receptor blocker (ARB), inhibited the AGE-induced vascular cell adhesion molecule-1 (VCAM-1) gene expression in cultured human glomerular ECs. Irbesartan or an anti-oxidant N-acetylcysteine inhibited the AGE-induced increase in reactive oxygen species (ROS) generation and subsequently blocked up-regulation of VCAM-1 mRNA levels in glomerular ECs. AGE significantly stimulated angiotensin II production by glomerular ECs. Furthermore, irbesartan completely suppressed up regulation of VCAM-1 mRNA levels in AGE plus angiotensin II-exposed glomerular ECs. Our present data suggest that there exists a crosstalk between the RAS and AGE in inflammatory reactions in glomerular ECs. Irbesartan may play a protective role against diabetic nephropathy by blocking the deleterious effects of AGE elicited angiotensin II and ROS. PMID- 21236268 TI - Abiotic stress leads to somatic and heritable changes in homologous recombination frequency, point mutation frequency and microsatellite stability in Arabidopsis plants. AB - In earlier studies, we showed that abiotic stresses, such as ionizing radiation, heavy metals, temperature and water, trigger an increase in homologous recombination frequency (HRF). We also demonstrated that many of these stresses led to inheritance of high-frequency homologous recombination, HRF. Although an increase in recombination frequency is an important indicator of genome rearrangements, it only represents a minor portion of possible stress-induced mutations. Here, we analyzed the influence of heat, cold, drought, flood and UVC abiotic stresses on two major types of mutations in the genome, point mutations and small deletions/insertions. We used two transgenic lines of Arabidopsis thaliana, one allowing an analysis of reversions in a stop codon-containing inactivated beta-glucuronidase transgene and another one allowing an analysis of repeat stability in a microsatellite-interrupted beta-glucuronidase transgene. The transgenic Arabidopsis line carrying the beta-glucuronidase-based homologous recombination substrate was used as a positive control. We showed that the majority of stresses increased the frequency of point mutations, homologous recombination and microsatellite instability in somatic cells, with the frequency of homologous recombination being affected the most. The analysis of transgenerational changes showed an increase in HRF to be the most prominent effect observed in progeny. Significant changes in recombination frequency were observed upon exposure to all types of stress except drought, whereas changes in microsatellite instability were observed upon exposure to UVC, heat and cold. The frequency of point mutations in the progeny of stress-exposed plants was the least affected; an increase in mutation frequency was observed only in the progeny of plants exposed to UVC. We thus conclude that transgenerational changes in genome stability in response to stress primarily involve an increase in recombination frequency. PMID- 21236269 TI - Icariin inhibits hydrogen peroxide-induced toxicity through inhibition of phosphorylation of JNK/p38 MAPK and p53 activity. AB - Oxidative stress caused by hydrogen peroxide (H(2)O(2)) plays an important role in the pathogenesis of Alzheimer's disease (AD). The prominent damages caused by H(2)O(2) include the ruin of membrane integrity, loss of intracellular neuronal glutathione (GSH), oxidative damage to DNA as well as the subsequent caspase-3 and p53 activation. Icariin is a flavonoid extracted from the traditional Chinese herb Epimedium brevicornum Maxim. We have previously reported that icariin has a good curative effect on patients with mild cognitive impairment (MCI), AD animal and cell models. However, the molecular mechanism of how icariin exerts neuroprotective effects is still not well understood. To address this question, we exposed undifferentiated neuronal cell lines (PC12 cells) to hydrogen peroxide (H(2)O(2)) and investigated the possible neuroprotective mechanisms of icariin. Vitamin E was used as a positive control. We observed that H(2)O(2) activated the JNK/p38 mitogen-activated protein kinase (MAPK) and induced PC12 cells apoptosis in a concentration-dependent manner. More over, we demonstrated that icariin protected PC12 cells by attenuating LDH leakage, reducing GSH depletion, preventing DNA oxidation damage and inhibiting subsequent activation of caspase-3 and p53, which are the main targets of H(2)O(2)-induced cell damage. In addition, we also found that icariin's neuroprotective effect may partly correlate with its inhibitory effect on JNK/p38 MAPK pathways. Therefore, our findings suggest that icariin is a candidate for a novel neuroprotective drug to against oxidative stress induced neurodegeneration. PMID- 21236270 TI - Acute lipophilicity-dependent effect of intravascular simvastatin in the early phase of focal cerebral ischemia. AB - The acute effects of simvastatin lactone (lipophilic) and simvastatin acid (hydrophilic) on transient focal ischemia were assessed using the isolated guinea pig brain maintained in vitro by arterial perfusion. This new model of cerebral ischemia allows the assessment of the very early phase of the ischemic process, with the functional preservation of the vascular and neuronal compartments and the blood-brain barrier (bbb). The middle cerebral artery was transiently tied for 30 min followed by reperfusion for 60 min. Statins (nanomolar doses) were administered by intravascular continuous infusion starting 60 min before ischemia induction. Brain cortical activity and arterial vascular tone were continuously recorded. At the end of the experiment immunoreactivity for microtubule associated protein 2 (MAP-2), expression of survival kinases (ERK and Akt) and total anti-oxidant capacity were assayed. Brains treated with simvastatin lactone showed i) reduced amplitude and delayed onset of ischemic depressions, ii) preservation of MAP-2 immunoreactivity, iii) activation of ERK signaling in the ischemic hemisphere and iv) increase in whole-brain anti-oxidant capacity. Treatment with the bbb-impermeable simvastatin acid was ineffective on the above mentioned parameters. Vascular resistance recordings and Akt signaling were unchanged by any statin treatment. Our findings suggest that intravascular delivered simvastatin exerts an acute lipophilicity-dependent protective effect in the early phase of cerebral ischemia. PMID- 21236271 TI - Do patients with pure alexia suffer from a specific word form processing deficit? Evidence from 'wrods with trasnpsoed letetrs'. AB - It is widely accepted that letter-by-letter reading and a pronounced increase in reading time as a function of word length are the hallmark features of pure alexia. Why patients show these two phenomena with respect to underlying cognitive mechanisms is, however, much less clear. Two main hypotheses have been proposed, i.e. impaired discrimination of letters and deficient processing of word forms. While the former deficit can easily be investigated in isolation, previous findings favouring the latter seem confounded. Applying a word reading paradigm with systematically manipulated letter orders in two patients with pure alexia, we demonstrate a word form processing deficit that is not attributable to sublexical letter discrimination difficulties. Moreover, pure alexia-like fixation patterns could be induced in healthy adults by having them read sentences including words with transposed letters, so-called 'jumbled words'. This further corroborates a key role of deficient word form processing in pure alexia. With regard to basic reading research, the present study extends recent evidence for relative, rather than precise, encoding of letter position in the brain. PMID- 21236272 TI - The acceleration of spoken-word processing in children's native-language acquisition: an ERP cohort study. AB - Healthy adults can identify spoken words at a remarkable speed, by incrementally analyzing word-onset information. It is currently unknown how this adult-level speed of spoken-word processing emerges during children's native-language acquisition. In a picture-word mismatch paradigm, we manipulated the semantic congruency between picture contexts and spoken words, and recorded event-related potential (ERP) responses to the words. Previous similar studies focused on the N400 response, but we focused instead on the onsets of semantic congruency effects (N200 or Phonological Mismatch Negativity), which contain critical information for incremental spoken-word processing. We analyzed ERPs obtained longitudinally from two age cohorts of 40 primary-school children (total n=80) in a 3-year period. Children first tested at 7 years of age showed earlier onsets of congruency effects (by approximately 70ms) when tested 2 years later (i.e., at age 9). Children first tested at 9 years of age did not show such shortening of onset latencies 2 years later (i.e., at age 11). Overall, children's onset latencies at age 9 appeared similar to those of adults. These data challenge the previous hypothesis that word processing is well established at age 7. Instead they support the view that the acceleration of spoken-word processing continues beyond age 7. PMID- 21236273 TI - Manipulations of attention dissociate fragile visual short-term memory from visual working memory. AB - People often rely on information that is no longer in view, but maintained in visual short-term memory (VSTM). Traditionally, VSTM is thought to operate on either a short time-scale with high capacity - iconic memory - or a long time scale with small capacity - visual working memory. Recent research suggests that in addition, an intermediate stage of memory in between iconic memory and visual working memory exists. This intermediate stage has a large capacity and a lifetime of several seconds, but is easily overwritten by new stimulation. We therefore termed it fragile VSTM. In previous studies, fragile VSTM has been dissociated from iconic memory by the characteristics of the memory trace. In the present study, we dissociated fragile VSTM from visual working memory by showing a differentiation in their dependency on attention. A decrease in attention during presentation of the stimulus array greatly reduced the capacity of visual working memory, while this had only a small effect on the capacity of fragile VSTM. We conclude that fragile VSTM is a separate memory store from visual working memory. Thus, a tripartite division of VSTM appears to be in place, comprising iconic memory, fragile VSTM and visual working memory. PMID- 21236274 TI - Re-examining the gesture engram hypothesis. New perspectives on apraxia of tool use. AB - In everyday life, we are led to reuse the same tools (e.g., fork, hammer, coffee maker), raising the question as to whether we have to systematically recreate the idea of the manipulation which is associated with these tools. The gesture engram hypothesis offers a straightforward answer to this issue, by suggesting that activation of gesture engrams provides a processing advantage, avoiding portions of the process from being reconstructed de novo with each experience. At first glance, the gesture engram hypothesis appears very plausible. But, behind this beguiling simplicity lies a set of unresolved difficulties: (1) What is the evidence in favour of the idea that the mere observation of a tool is sufficient to activate the corresponding gesture engram? (2) If tool use can be supported by a direct route between a structural description system and gesture engrams, what is the role of knowledge about tool function? (3) And, more importantly, what does it mean to store knowledge about how to manipulate tools? We begin by outlining some of the main formulations of the gesture engram hypothesis. Then, we address each of these issues in more detail. To anticipate our discussion, the gesture engram hypothesis appears to be clearly unsatisfactory, notably because of its incapacity to offer convincing answers to these different issues. We conclude by arguing that neuropsychology may greatly benefit from adopting the hypothesis that the idea of how to manipulate a tool is recreated de novo with each experience, thus opening interesting perspectives for future research on apraxia. PMID- 21236275 TI - Examining lateralized lexical ambiguity processing using dichotic and cross-modal tasks. AB - The individual roles played by the cerebral hemispheres during the process of language comprehension have been extensively studied in tasks that require individuals to read text (for review see Jung-Beeman, 2005). However, it is not clear whether or not some aspects of the theorized laterality models of semantic comprehension are a result of the modality of presentation. Extending earlier work examining lateralized semantic processing using lexically ambiguous words, the current experiments utilized two modified lexical-decision tasks (one fully auditory and one cross-modal) with dichotically presented target stimuli. When targets were presented to the right ear/left hemisphere there was a distinct advantage for detecting words that are associated with the dominant meaning of the ambiguous word over the subordinate meaning. In contrast, for left ear/right hemisphere trials, there was either no difference between the pattern of semantic access for dominant and subordinate meaning (dichotic only) or a processing advantage for the subordinate meaning of the ambiguous word (with cross-modal presentation). These data suggest that the complimentary hemispheric strategies that allow for semantic access are not modality specific and instead characterize how the hemispheres each contribute to comprehension for both speech and text. Thus, dichotic presentation does seem to allow for the study of subtle hemispheric difference in meaning comprehension. PMID- 21236276 TI - A role for the right superior temporal sulcus in categorical perception of musical chords. AB - Categorical perception (CP) is a mechanism whereby non-identical stimuli that have the same underlying meaning become invariantly represented in the brain. Through behavioral identification and discrimination tasks, CP has been demonstrated to occur broadly across the auditory modality, including in perception of speech (e.g. phonemes) and music (e.g. chords) stimuli. Several functional imaging studies have linked CP of speech with activity in multiple regions of the left superior temporal sulcus (STS). As language processing is generally left-hemisphere dominant and, conversely, fine-grained spectral processing shows a right hemispheric bias, we hypothesized that CP of musical stimuli would be associated with right STS activity. Here, we used functional magnetic resonance imaging (fMRI) to test healthy, musically-trained volunteers as they (a) underwent a musical chord adaptation/habituation paradigm and (b) performed an active discrimination task on within- and between-category chord pairs, as well as an acoustically-matched, more continuously-perceived orthogonal sound set. As predicted, greater right STS activity was linked to categorical processing in both experimental paradigms. The results suggest that the left and right STS are functionally specialized and that the right STS may take on a key role in CP of spectrally complex sounds. PMID- 21236277 TI - Enriched environment effects on behavior, memory and BDNF in low and high exploratory mice. AB - Environmental enrichment (EE) has been largely used to investigate behavioral modifications and neuroplasticity in the adult brain both in normal and pathological conditions. The interaction between individual behavioral traits with EE responsiveness has not been investigated within the same strain. By using two extremes of CF1 mice that differ by their exploratory behavior in the Open Field (OF) task (Kazlauckas V, 2005), denominated as Low (LE) and High (HE) Exploratory Mice, the present study evaluated if EE during adulthood could modify the putative differences between LE and HE mice on exploratory behavior, memory performance and hippocampal BDNF levels. To this end, we investigated the effect of adult LE and HE mice after 2 months of enriched or standard housing conditions on the open field, on novel object recognition, on the inhibitory avoidance task and on hippocampal BDNF immunocontent. LE showed low exploratory behavior, less retention in the inhibitory avoidance and lower hippocampal BDNF levels. EE enhanced exploratory behavior, memory performance and hippocampal BDNF levels both in LE and HE mice. Importantly, the general profile of LE mice submitted to EE was similar to HE mice housed in standard conditions. These results show that internalized behavior of LE mice can be significantly modified by exposure to an enriched environment even during adulthood. These observations may contribute to investigate biological mechanisms and therapeutical interventions for individuals with internalized psychiatric disorders. PMID- 21236279 TI - Measuring judgement bias and emotional reactivity in sheep following long-term exposure to unpredictable and aversive events. AB - Animal welfare research is now starting to measure the cognitive component of affective states in an effort to improve welfare assessments of animals. Twenty six Romane ewe lambs were trained to a spatial location task previously demonstrated to test for judgement bias in sheep. This required a go/no-go response according to the location of a bucket in a pen, with one location being positively reinforced (with a feed reward) and the other negatively reinforced (with a fan-forced blower). While training in the judgement bias arena continued, half of the sheep (n=13) were subjected to a chronic, intermittent treatment that consisted of stressful events common to production systems. After 3 weeks of treatment, all sheep were tested for biases in judgement by placing the bucket in ambiguous locations between the two learnt reference locations. The emotional reactivity, as characterised by behavioural and physiological responses, of all sheep to events that were unexpected, novel or sudden was then tested. A significant treatment * bucket location interaction was seen on day 3 with Stressed sheep approaching the bucket locations less than Control sheep (p=0.007). This may reflect a bias in judgement, however it is also possibly a treatment-induced difference in learning. Cardiac data did not indicate treatment differences, however the RMSSD of Control sheep in novel and unfamiliar situations was always higher than the Stressed animals. No meaningful treatment differences in emotional reactivity behaviours were evident. This paper provides further evidence that affective states exist and can be measured in animals. PMID- 21236278 TI - Rats' preferences for high fructose corn syrup vs. sucrose and sugar mixtures. AB - High fructose corn syrup (HFCS) has replaced sucrose in many food products, which has prompted research comparing these two sweeteners in rodents. The present study examined the relative palatability of HFCS and sucrose for rats, offering 11% carbohydrate solutions to match the content of common beverages for human consumption. The animals initially preferred HFCS to sucrose but after separate experience with each solution they switched to sucrose preference. Approximating the composition of HFCS with a mixture of fructose and glucose (55:45) yielded a solution that was less attractive than sucrose or HFCS. However, HFCS contains a small amount of glucose polymers, which are very attractive to rats. A 55:42:3 mixture of fructose, glucose and glucose polymers (Polycose) was equally preferred to HFCS and was treated similarly to HFCS in comparisons vs. sucrose. Post-oral effects of sucrose, which is 50% fructose and 50% glucose, may be responsible for the shift in preference with experience. This shift, and the relatively small magnitude of differences in preference for HFCS and sucrose, suggest that palatability factors probably do not contribute to any possible difference in weight gain responses to these sweeteners. PMID- 21236280 TI - Otitis media and associations with overweight status in toddlers. AB - INTRODUCTION: Otitis media (OM) is a significant disease that affects nearly all children early in life. Recently, childhood overweight has become an epidemic. Past research has demonstrated that a history of OM is related to food preferences and overweight through proposed physiological mechanisms. The purpose of this study was to explore the relationship between recurrent OM (ROM)/tympanostomy tube treatment and overweight status. METHODS: Data were analyzed from a prospective cohort of mothers and children recruited from 1991 1996 from a local health maintenance organization. ROM and tympanostomy tube status were obtained through a combination of physical exam and medical record abstraction. ROM and tympanostomy tube status were analyzed as categorical variables with weight-for-length (WFL) data from well child checks. Chi-square and logistic regression for univariate and multivariate analyses were performed. RESULTS: 11.4% of children had a WFL measure at two years of age >= 95 th percentile. Those children with a history of tympanostomy tube treatment had a significantly increased risk of having a WFL >= 95 th percentile after controlling for birth weight, maternal prenatal smoking, maternal education, and family income (OR 3.32, 95% CI 1.43-7.72). The alternative hypothesis that children with larger WFL at two month of age would have a greater number of OM episodes by two years of age was not significant. CONCLUSION: The findings of this study are consistent with the hypothesis and prior research that OM treated with tympanostomy tubes is associated with overweight status. PMID- 21236281 TI - Evaluation of the 'liking' and 'wanting' properties of umami compound in rats. AB - Food reward is neurologically and psychologically divided into at least two properties; 'liking' and 'wanting'. Although umami taste enhances food palatability, the liking and wanting properties of umami taste, and the underlying neural mechanisms for these properties are not clear. Here, we compared sucrose (0, 10, 30, 120 and 480 mM) and monosodium l-glutamate (MSG; 0, 10, 30, 60 and 120 mM) solutions using a taste reactivity test to evaluate liking, and fixed/progressive-ratio operant licking tasks to evaluate wanting. To determine the underlying neural mechanisms, we also conducted systemic blockade of opioid receptors in both tests. In the taste reactivity test, the hedonic reactions to 30, 60 and 120 mM MSG were greater than those to water (0mM) but lower than those to 480 mM sucrose. In the operant task, the intake, number of licks, and breakpoint to MSG reached peaks at around 60mM but they were lower than those to 30-480 mM sucrose. The systemic naloxone treatment decreased the hedonic responses to MSG and sucrose, and reduced the incentive salience of MSG but not sucrose. These findings indicate that the hedonic response and incentive salience of MSG is lower than those of sucrose when compared at the maximum response and that the incentive salience of MSG is lower than sucrose even where the hedonic response is similar. The present study also suggest that the hedonic response and incentive salience of umami compound is modulated by brain opioid signaling. PMID- 21236282 TI - GABA regulates corticotropin releasing hormone levels in the paraventricular nucleus of the hypothalamus in newborn mice. AB - The paraventricular nucleus of the hypothalamus (PVN) is a major regulator of stress responses via release of corticotropin releasing hormone (CRH) to the pituitary gland. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is characteristic of individuals with major depressive disorder (MDD). Postmortem data from individuals diagnosed with MDD show increased levels of CRH mRNA and CRH immunoreactive neurons in the PVN. In the current study, an immunohistochemical (IHC) analysis revealed increased levels of CRH in the PVN of newborn mice lacking functional GABA(B) receptors. There was no difference in the total number of CRH immunoreactive cells. By contrast, there was a significant increase in the amount of CRH immunoreactivity per cell. Interestingly, this increase in CRH levels in the GABA(B) receptor R1 subunit knockout was limited to the rostral PVN. While GABAergic regulation of the HPA axis has been previously reported in adult animals, this study provides evidence of region-specific GABA modulation of immunoreactive CRH in newborns. PMID- 21236283 TI - A simplified procedure for GC/C/IRMS analysis of underivatized 19-norandrosterone in urine following HPLC purification. AB - Nandrolone and/or its precursors are included in the World Anti-doping Agency (WADA) list of forbidden substances and methods and as such their use is banned in sport. 19-Norandrosterone (19-NA) the main metabolite of these compounds can also be produced endogenously. The need to establish the origin of 19-NA in human urine samples obliges the antidoping laboratories to use isotope ratio mass spectrometry (IRMS) coupled to gas chromatography (GC/C/IRMS). In this work a simple liquid chromatographic method without any additional derivatization step is proposed, allowing to drastically simplify the urine pretreatment procedure, leading to extracts free of interferences permitting precise and accurate IRMS analysis. The purity of the extracts was verified by parallel analysis by gas chromatography coupled to mass spectrometry with GC conditions identical to those of the GC/C/IRMS assay. The method has been validated according to ISO17025 requirements (within assay precision of +/-0.30/00 and between assay precision of +/-0.40/00). The method has been tested with samples obtained after the administration of synthetic 19-norandrostenediol and samples collected during pregnancy where 19-NA is known to be produced endogenously. Twelve drugs and synthetic standards able to produce through metabolism 19-NA have shown to present delta(13)C values around -290/00 being quite homogeneous (-28.8+/-1.5; mean+/-standard deviation) while endogenously produced 19-NA has shown values comparable to other endogenous produced steroids in the range -21 to -240/00 as already reported. The efficacy of the method was tested on real samples from routine antidoping analyses. PMID- 21236285 TI - Maternal exposure to cadmium during gestation perturbs the vascular system of the adult rat offspring. AB - Several cardiovascular diseases (CVD) observed in adulthood have been associated with environmental influences during fetal growth. Here, we show that maternal exposure to cadmium, a ubiquitously distributed heavy metal and main component of cigarette smoke is able to induce cardiovascular morpho-functional changes in the offspring at adult age. Heart morphology and vascular reactivity were evaluated in the adult offspring of rats exposed to 30ppm of cadmium during pregnancy. Echocardiographic examination shows altered heart morphology characterized by a concentric left ventricular hypertrophy. Also, we observed a reduced endothelium dependent reactivity in isolated aortic rings of adult offspring, while endothelium-independent reactivity remained unaltered. These effects were associated with an increase of hem-oxygenase 1 (HO-1) expression in the aortas of adult offspring. The expression of HO-1 was higher in females than males, a finding likely related to the sex-dependent expression of the vascular cell adhesion molecule 1 (VCAM-1), which was lower in the adult female. All these long term consequences were observed along with normal birth weights and absence of detectable levels of cadmium in fetal and adult tissues of the offspring. In placental tissues however, cadmium levels were detected and correlated with increased NF-kappaB expression--a transcription factor sensitive to inflammation and oxidative stress--suggesting a placentary mechanism that affect genes related to the development of the cardiovascular system. Our results provide, for the first time, direct experimental evidence supporting that exposure to cadmium during pregnancy reprograms cardiovascular development of the offspring which in turn may conduce to a long term increased risk of CVD. PMID- 21236284 TI - Hormone response element binding proteins: novel regulators of vitamin D and estrogen signaling. AB - Insights from vitamin D-resistant New World primates and their human homologues as models of natural and pathological insensitivity to sterol/steroid action have uncovered a family of novel intracellular vitamin D and estrogen regulatory proteins involved in hormone action. The proteins, known as "vitamin D or estrogen response element-binding proteins", behave as potent cis-acting, transdominant regulators to inhibit steroid receptor binding to DNA response elements and is responsible for vitamin D and estrogen resistances. This set of interactors belongs to the heterogeneous nuclear ribonucleoprotein (hnRNP) family of previously known pre-mRNA-interacting proteins. This review provides new insights into the mechanism by which these novel regulators of signaling and metabolism can act to regulate responses to vitamin D and estrogen. In addition the review also describes other molecules that are known to influence nuclear receptor signaling through interaction with hormone response elements. PMID- 21236286 TI - Mechanism of cytotoxic action of perfluorinated acids. III. Disturbance in Ca2+ homeostasis. AB - The global distribution of perfluorinated acids (PFAs) in industry and in household is well known. Their increasing environmental occurrence and biomagnification in the living organisms have drawn growing interests in efforts to describe precisely the mechanisms of action in vitro and in vivo. Our previous investigations widely described lipophilicity-dependent cytotoxicity of PFAs as well as the effect of perfluorination of carbon chain on depolarization of plasma membrane potential, acidification or mitochondrial dysfunctions. In this study we presented in dose- and time-dependent manner the impact of PFAs on calcium homeostasis in HCT116 cells. Comparative analysis of cytosolic [Ca2+](c) and mitochondrial calcium [Ca2+](m) carried out by flow cytometry revealed distinct uptake of calcium into mitochondria in correlation to increasing lipophilicity of PFAs. Massive accumulation of [Ca2+](m) was not accompanied by equivalent loss of [Ca2+](c). Indeed, moderate changes of [Ca2+](c) were observed after incubation with 400 MUM PFDoDA reaching 29.83% and 49.17% decrease at 4th and 72nd hour, respectively. At the same time, mitochondrial calcium uptake increased from 2- to more than 4-fold comparing with non-treated cells. Incubation with non fluorinated decanoic acid (DA) did not cause any changes in calcium homeostasis. Presented data show that PFAs-induced perturbations in calcium distribution seem to be a missing link related to mitochondria dysfunction playing a crucial role in determination of apoptotic cell death. Complete scheme for the mechanism of cytotoxic action of PFAs has been included. PMID- 21236287 TI - Arthropod venoms and cancer. AB - Many active principles produced by animals, plants and microorganisms have been employed in the development of new drugs to treat diseases such as cancer. Among the animals that produce pharmacologically active molecules capable of interfering in human cellular physiology, the highlights are venomous arthropods, such as scorpions, bees, wasps, spiders, ants and caterpillars. The substances found in the venom of these animals present great potential as anti-tumor agents. In this review, we present the main results of years of research involving the active compounds of arthropods venoms that have anti-cancer activity. PMID- 21236288 TI - Determination of sphingomyelinase-D activity of Loxosceles venoms in sphingomyelin/cholesterol liposomes containing horseradish peroxidase. AB - Based on degradation of sphingomyelin/cholesterol liposomes containing entrapped horseradish peroxidase, we evaluated the Sphingomyelinase-D (SMase-D) activity of scorpion, spider and snake venoms by monitoring spectrophotometrically the product of oxidation of HRP released. The results indicate that Loxosceles crude venoms (Loxosceles intermedia, Loxosceles laeta, Loxosceles gaucho and Loxosceles similis) displayed SMase-D activity in a concentration-dependent manner. Furthermore, this activity was blocked by the anti-loxoscelic antivenom. However, Tityus serrulatus scorpion venom, Phoneutria nigriventer spider venom and Bothrops jararaca, Crotalus durissus, Lachesis muta and Micrurus frontalis snake venoms did not show measurable SMase-D activity. PMID- 21236289 TI - Orientation tuning in the visual cortex of 3-month-old human infants. AB - Sensitivity to orientation is critical for making a whole and complete picture of the world. We measured the orientation tuning of mechanisms in the visual cortex of typically developing 3-month-olds and adults using a nonlinear analysis of the two-input steady-state Visually Evoked Potential (VEP). Two gratings, one a fixed test and the other a variable orientation masker were tagged with distinct temporal frequencies and the corresponding evoked responses were measured at the harmonics of the test and masker frequencies and at a frequency equal to the sum of the two stimulus frequencies. The magnitude of the sum frequency component depended strongly on the relative orientation of the test and masker in both infants and adults. The VEP tuning bandwidths of the 3-month-olds measured at the sum frequency were similar to those of adults, suggesting that behavioral immaturities in functions such as orientation discrimination and contour integration may result from other immaturities in long-range lateral projections or feedback mechanisms. PMID- 21236290 TI - Remapping attention in multiple object tracking. AB - Which coordinate system do we use to track moving objects? In a previous study using smooth pursuit eye movements, we argued that targets are tracked in both retinal (retinotopic) and scene-centered (allocentric) coordinates (Howe, Pinto, & Horowitz, 2010). However, multiple object tracking typically also elicits saccadic eye movements, which may change how object locations are represented. Observers fixated a cross while tracking three targets out of six identical disks confined to move within an imaginary square. The fixation cross alternated between two locations, requiring observers to make repeated saccades. By moving (or not moving) the imaginary square in sync with the fixation cross, we could disrupt either (or both) coordinate systems. Surprisingly, tracking performance was much worse when the objects moved with the fixation cross, although this manipulation preserved the retinal image across saccades, thereby avoiding the visual disruptions normally associated with saccades. Instead, tracking performance was best when the allocentric coordinate system was preserved, suggesting that targets locations are maintained in that coordinate system across saccades. This is consistent with a theoretical framework in which the positions of a small set of attentional pointers are predictively updated in advance of a saccade. PMID- 21236291 TI - Cognitive enhancers: focus on modulatory signaling influencing memory consolidation. AB - Biological research has unraveled many of the molecular and cellular mechanisms involved in the formation of long-lasting memory, providing new opportunities for the development of cognitive-enhancing drugs. Studies of drug enhancement of cognition have benefited from the use of pharmacological treatments given after learning, allowing the investigation of mechanisms regulating the consolidation phase of memory. Modulatory systems influencing consolidation processes include stress hormones and several neurotransmitter and neuropeptide systems. Here, we review some of the findings on memory enhancement by drug administration in animal models, and discuss their implications for the development of cognitive enhancers. PMID- 21236292 TI - Prenatal lipopolysaccharide treatment enhances MK-801-induced psychotomimetic effects in rats. AB - The aim of this study was to evaluate the effect of prenatal lipopolysaccharide (LPS) treatment, which is an animal developmental model of schizophrenia, on MK 801-induced psychotomimetic behavioral changes and brain aminergic system activity in adult offspring. Repeated LPS (1 mg/kg) injection in rats, that had started from 7th day of pregnancy and was continued every second day till delivery, resulted in a long-lasting disruption of prepulse inhibition (PPI) and elevation of locomotor activity in their offspring. The prenatally LPS-treated rats showed hypersensitivity to MK-801 (0.1 and 0.4 mg/kg) as evidenced by the enhancement of acoustic startle amplitude, reduced PPI, and enhanced locomotor activity. These behavioral changes were accompanied by a decrease in the dopamine and its metabolite, DOPAC concentration in the frontal cortex, enhanced dopaminergic system activity in the striatum and no changes in noradrenaline (NA) level. Furthermore, the significant augmentation of 5-HT and 5-HIAA content in the frontal cortex of females only was detected. No changes in the cortical NA tissue level were found. Summing up, the present study demonstrated that the activation of the immune system in prenatal period led to persistent behavioral hypersensitivity to psychotomimetic action of a non-competitive NMDA receptor antagonist, and attention/information processing deficits. The foregoing data indicate that prenatal administration of LPS model some of the clinical aspects of schizophrenia and these behavioral effects are connected with neurochemical changes. PMID- 21236293 TI - Granulocyte-colony stimulating factor (G-CSF) induces mechanical hyperalgesia via spinal activation of MAP kinases and PI3K in mice. AB - Granulocyte-colony stimulating factor (G-CSF) is a current pharmacological approach to increase peripheral neutrophil counts after anti-tumor therapies. Pain is most relevant side effect of G-CSF in healthy volunteers and cancer patients. Therefore, the mechanisms of G-CSF-induced hyperalgesia were investigated focusing on the role of spinal mitogen-activated protein (MAP) kinases ERK (extracellular signal-regulated kinase), JNK (Jun N-terminal Kinase) and p38, and PI(3)K (phosphatidylinositol 3-kinase). G-CSF induced dose (30-300 ng/paw)-dependent mechanical hyperalgesia, which was inhibited by local post treatment with morphine. This effect of morphine was reversed by naloxone (opioid receptor antagonist). Furthermore, G-CSF-induced hyperalgesia was inhibited in a dose-dependent manner by intrathecal pre-treatment with ERK (PD98059), JNK (SB600125), p38 (SB202190) or PI(3)K (wortmanin) inhibitors. The co-treatment with MAP kinase and PI(3)K inhibitors, at doses that were ineffective as single treatment, significantly inhibited G-CSF-induced hyperalgesia. Concluding, in addition to systemic opioids, peripheral opioids as well as spinal treatment with MAP kinases and PI(3)K inhibitors also reduce G-CSF-induced pain. PMID- 21236294 TI - Effects of the alpha- and gamma-polymorphs of glycine on the behavior of catalepsy prone rats. AB - Glycine is used to treat various health problems and is efficient in the treatment of the negative symptoms of schizophrenia. Since glycine exists as a few polymorphs, the aim of this work is to compare the effects of the alpha- and gamma-forms of glycine on the behavior of the genetic catalepsy (GC) strain of rats. Both polymorphs of glycine have been administered to rats orally as pure solid chemicals, and cataleptic behavior and behaviors in the open-field, elevated plus-maze, and light-dark box tests were studied. Both the alpha- and gamma-polymorphs of glycine increased exploratory activity in the open-field test, but only the gamma-polymorph had beneficial effects on catalepsy and exploratory activity in the light-dark box and reduced anxiety in the elevated plus-maze. PMID- 21236295 TI - Building community-engaged health research and discovery infrastructure on the South Side of Chicago: science in service to community priorities. AB - OBJECTIVE: To describe the roles community members can and should play in, and an asset-based strategy used by Chicago's South Side Health and Vitality Studies for, building sustainable, large-scale community health research infrastructure. The Studies are a family of research efforts aiming to produce actionable knowledge to inform health policy, programming, and investments for the region. METHODS: Community and university collaborators, using a consensus-based approach, developed shared theoretical perspectives, guiding principles, and a model for collaboration in 2008, which were used to inform an asset-based operational strategy. Ongoing community engagement and relationship-building support the infrastructure and research activities of the studies. RESULTS: Key steps in the asset-based strategy include: 1) continuous community engagement and relationship building, 2) identifying community priorities, 3) identifying community assets, 4) leveraging assets, 5) conducting research, 6) sharing knowledge and 7) informing action. Examples of community member roles, and how these are informed by the Studies' guiding principles, are provided. CONCLUSIONS: Community and university collaborators, with shared vision and principles, can effectively work together to plan innovative, large-scale community-based research that serves community needs and priorities. Sustainable, effective models are needed to realize NIH's mandate for meaningful translation of biomedical discovery into improved population health. PMID- 21236297 TI - Preserving protein profiles in tissue samples: differing outcomes with and without heat stabilization. AB - Post translational modification (PTM) and proteolytic processing of proteins contributes to regulation of their stability, intracellular localization and interactions with other proteins, and to direct enhancement or repression of their activity. Both PTM and proteolysis are dynamic; levels and rates change in response to changes in the cellular environment. Tissue excision, post mortem interval and subsequent methods of tissue processing for protein analysis unavoidably alter the cellular environment and therefore features of protein profiles. To aid in understanding the time frame and protein specificity of these changes and the biological and technical contributions to them, we have compared features of protein profiles in mouse hippocampus and cortex following three methods of tissue handling: immediate lysate preparation, and rapid heating to 95 degrees C and standard snap freezing in liquid nitrogen, prior to lysate preparation. In spite of the very short time frames involved, we observe protein specific differences in levels of phosphorylation, general differences in patterns of sumoylation, and specific differences in levels of proteolytic cleavage of calcineurin and the neurotrophin receptor, TRKA. These differences vary with brain region and with post excision time to processing, and highlight the challenges inherent in accurately profiling the in vivo proteome. PMID- 21236296 TI - Oligodendrogenesis in the subventricular zone and the role of epidermal growth factor. AB - Demyelinating diseases are characterized by an extensive loss of oligodendrocytes and myelin sheaths from axolemma. These neurological disorders are a common cause of disability in young adults, but so far, there is no effective treatment against them. It has been suggested that neural stem cells (NSCs) may play an important role in brain repair therapies. NSCs in the adult subventricular zone (SVZ), also known as Type-B cells, are multipotential cells that can self-renew and give rise to neurons and glia. Recent findings have shown that cells derived from SVZ Type-B cells actively respond to epidermal-growth-factor (EGF) stimulation becoming highly migratory and proliferative. Interestingly, a subpopulation of these EGF-activated cells expresses markers of oligodendrocyte precursor cells (OPCs). When EGF administration is removed, SVZ-derived OPCs differentiate into myelinating and pre-myelinating oligodendrocytes in the white matter tracts of corpus callosum, fimbria fornix and striatum. In the presence of a demyelinating lesion, OPCs derived from EGF-stimulated SVZ progenitors contribute to myelin repair. Given their high migratory potential and their ability to differentiate into myelin-forming cells, SVZ NSCs represent an important endogenous source of OPCs for preserving the oligodendrocyte population in the white matter and for the repair of demyelinating injuries. PMID- 21236298 TI - Statistical technique for analysing functional connectivity of multiple spike trains. AB - A new statistical technique, the Cox method, used for analysing functional connectivity of simultaneously recorded multiple spike trains is presented. This method is based on the theory of modulated renewal processes and it estimates a vector of influence strengths from multiple spike trains (called reference trains) to the selected (target) spike train. Selecting another target spike train and repeating the calculation of the influence strengths from the reference spike trains enables researchers to find all functional connections among multiple spike trains. In order to study functional connectivity an "influence function" is identified. This function recognises the specificity of neuronal interactions and reflects the dynamics of postsynaptic potential. In comparison to existing techniques, the Cox method has the following advantages: it does not use bins (binless method); it is applicable to cases where the sample size is small; it is sufficiently sensitive such that it estimates weak influences; it supports the simultaneous analysis of multiple influences; it is able to identify a correct connectivity scheme in difficult cases of "common source" or "indirect" connectivity. The Cox method has been thoroughly tested using multiple sets of data generated by the neural network model of the leaky integrate and fire neurons with a prescribed architecture of connections. The results suggest that this method is highly successful for analysing functional connectivity of simultaneously recorded multiple spike trains. PMID- 21236299 TI - Reliability of EMG determinism to detect changes in motor unit synchrony and coherence during submaximal contraction. AB - The determinism (DET) is a parameter used in nonlinear analysis to quantify the occurrence of recurrent patterns in a signal. Applied to the electromyographic activity (EMG), DET has been proposed as an index of motor unit synchrony in human. We have recently shown that the amount of motor unit synchronous firings above chance level was enhanced with stronger submaximal muscle contraction. Using these data, we aimed at determining if (1) EMG DET and motor unit synchrony varied in the same way and (2) EMG DET was more specifically related to the degree of oscillatory coupling between motor unit discharges. Cross-correlation and coherence analyses were applied to the discharges of 30 motor unit pairs tested at various force levels to assess the amount of synchronous impulses and the strength of oscillatory coupling in the time and frequency domains, respectively. Recurrent quantification analysis was applied to EMG activity to extract its DET. Overall, changes in EMG DET were poorly explained by changes in motor unit synchronous impulse probability (6%) and frequency (5%), and by changes in motor unit coherence in the 6-12Hz (5%) and 25-40Hz (8%) bands. Moreover, the comparison of the data obtained at the weakest and the strongest contraction levels tested with each motor unit pair showed that EMG DET remained unaltered with stronger contraction despite the occurrence of consistent changes in motor unit synchrony in both time and frequency domains. This speaks strongly against the reliability of DET in evaluating changes in motor unit synchronization during submaximal muscle contraction. PMID- 21236300 TI - High-throughput ocular artifact reduction in multichannel electroencephalography (EEG) using component subspace projection. AB - After a review of the ocular artifact reduction literature, a high-throughput method designed to reduce the ocular artifacts in multichannel continuous EEG recordings acquired at clinical EEG laboratories worldwide is proposed. The proposed method belongs to the category of component-based methods, and does not rely on any electrooculography (EOG) signals. Based on a concept that all ocular artifact components exist in a signal component subspace, the method can uniformly handle all types of ocular artifacts, including eye-blinks, saccades, and other eye movements, by automatically identifying ocular components from decomposed signal components. This study also proposes an improved strategy to objectively and quantitatively evaluate artifact reduction methods. The evaluation strategy uses real EEG signals to synthesize realistic simulated datasets with different amounts of ocular artifacts. The simulated datasets enable us to objectively demonstrate that the proposed method outperforms some existing methods when no high-quality EOG signals are available. Moreover, the results of the simulated datasets improve our understanding of the involved signal decomposition algorithms, and provide us with insights into the inconsistency regarding the performance of different methods in the literature. The proposed method was also applied to two independent clinical EEG datasets involving 28 volunteers and over 1000 EEG recordings. This effort further confirms that the proposed method can effectively reduce ocular artifacts in large clinical EEG datasets in a high-throughput fashion. PMID- 21236301 TI - OMP-ZsGreen fluorescent protein transgenic mice for visualisation of olfactory sensory neurons in vivo and in vitro. AB - Research into the biology of the mammalian olfactory system would be greatly enhanced by transgenic reporter mice with cell-specific fluorescence. To this end we previously generated a mouse whose olfactory ensheathing cells (OECs) express DsRed driven by the S100beta promoter. We present here a transgenic reporter mouse whose olfactory sensory neurons express ZsGreen, driven by the olfactory marker protein (OMP) promoter. ZsGreen was very strongly expressed throughout the cytoplasm of olfactory sensory neurons labelling them in living cells and after fixation. Labelled sensory neurons were seen in all olfactory regions in the nose and fluorescent axons coursed through the lamina propria and into the main and accessory bulbs. We developed methods for culturing embryonic and postnatal olfactory sensory neurons using these mice to visualise living cells in vitro. ZsGreen was expressed along the length of axons providing exceptional detail of the growth cones. The ZsGreen fluorescence was very stable, without fading during frequent imaging. The combination of OMP-ZsGreen and S100beta-DsRed transgenic mice is ideal for developmental studies and neuron-glia assays and they can be bred with mutant mice to dissect the roles of various molecules in neurogenesis, differentiation, axon growth and targeting and other aspects of olfactory sensory neuron and glia biology. PMID- 21236302 TI - Picornavirus non-structural proteins as targets for new anti-virals with broad activity. AB - Picornaviridae is one of the largest viral families and is composed of 14 genera, six of which include human pathogens. The best known picornaviruses are enteroviruses (including polio, PV, and rhinoviruses), foot-and-mouth disease virus (FMDV), and hepatitis A virus (HAV). Although infections often are mild, certain strains may cause pandemic outbreaks accompanied with meningitis and/or paralysis. Vaccines are available for PV, HAV and FMDV. When the oral vaccines are given to immunocompromised individuals, they may be chronically infected, and remain secretors of vaccine-derived variants of virus for years. There is no effective prophylaxis available for these or other picornaviruses. So far, only the 3C protease from viruses in three genera has been fully characterized as an anti-viral target, whereas the mode of action of compounds targeting other non structural proteins have remained largely unaddressed. Within the EU-supported FP6 project-VIZIER (Comparative Structural Genomics of Viral Enzymes Involved in Replication), the non-structural proteins were studied to identify conserved binding sites for broadly reactive anti-virals. The putative 2C helicase from echovirus-30 was shown to form ring-shaped hexamers typical for DNA-encoded SF3 helicases, and to possess ATPase activity. Hexamer formation of 2C from enterovirus 76 was in vitro shown to be dependent on the 44 N-terminal residues. Crystal structures of three enterovirus 3C proteases were solved and shown to be similar to those of other picornaviruses. A new binding site of VPg to the bottom of the thumb domain of CV-B3 3D polymerase was identified as a potential target. Broad anti-enterovirus compounds against 2C and 3A proteins were also identified, including thiazolobenzimidazoles (active against 2C) and TTP-8307 (targeting 3A). There is a need for more potent inhibitors against PV and other picornaviruses, which are potential silent reservoirs for re-emerging PV-like disease. PMID- 21236303 TI - Shedding new light on vitamin D and fatty liver disease. PMID- 21236304 TI - Viral genotype-specific role of PNPLA3, PPARG, MTTP, and IL28B in hepatitis C virus-associated steatosis. AB - BACKGROUND & AIMS: Steatosis is a prominent feature of hepatitis C, especially in patients infected with genotype 3. The analysis of genetic polymorphisms influencing steatosis in chronic hepatitis C has been limited by the studies' small sample size, and important single nucleotide polymorphisms (SNPs), such as those in the patatin-like phospholipase family 3 protein (PNPLA3), were never evaluated. METHODS: We analyzed the role of SNPs, from 19 systematically selected candidate genes, on steatosis in 626 Caucasian hepatitis C virus (HCV) infected patients. SNPs were extracted from a genome-wide association-generated dataset. Associations of alleles with the presence and/or different severity of steatosis were evaluated by univariate and multivariate logistic regression, accounting for all relevant covariates. RESULTS: The risk of steatosis was increased by carriage of I148M in PNPLA3, but only in patients with HCV genotypes non-3 (odds ratio [OR]=1.9, 95% confidence interval [CI]=1.6-2.3, p<0.001) and similar, albeit weaker associations were found for SNPs in peroxisome proliferator-activated receptor-gamma (PPARG) and interleukin-28B (IL28B). Carriage of a SNP in the microsomal triglyceride transfer protein (MTTP) increased the risk of steatosis, but only in patients with HCV genotype 3 (rs1800803, OR=3.4, 95% CI=2.4-4.9, p=0.001). CONCLUSIONS: The rs738409 SNP in PNPLA3 is associated with an increased risk of steatosis in patients infected with HCV genotypes non-3. Host genes affect steatosis depending on the infecting HCV genotype, suggesting their interaction with viral factors. PMID- 21236307 TI - Is there any association between HCV multiplication and iron induced liver injury in chronic hepatitis C? PMID- 21236308 TI - Non-invasive prediction of fibrosis in non-alcoholic fatty liver disease. PMID- 21236310 TI - Increasing hepatic arteriole wall thickness and decreased luminal diameter occur with increasing age in normal livers. AB - BACKGROUND & AIMS: There is no data to suggest that the size of bile ducts, portal venules, and hepatic arterioles varies according to age in the normal human liver. We sought to examine whether hepatic arteriolar size, wall thickness, and luminal diameter change with increasing age. METHODS: Histologically normal liver specimens from 90 live and deceased donors were separated into three groups of thirty: donor age<30, 31-60, and>60years old. Trichrome-stained slides were de-identified and assessed by a liver pathologist blinded to donor age. Morphometric measurements were taken of the hepatic arteriole, the cross-sectional diameter, and its wall thickness. The arteriole was measured at its widest diameter, the arteriolar wall at its thickest portion, and the luminal diameter between its widest points. RESULTS: There was no difference in number of arterioles or bile ducts or in arteriolar cross-sectional diameter among the groups and no correlation with age was found. An increasing arteriolar wall thickness and a decrease in luminal diameter with advancing age were noted; no difference in bile duct size among the groups was found. There was a significant difference in wall thickness/total cross-sectional diameter with extremes in age (21-30 age group vs. 71-80 age group, p=0.0009) with an accompanying significant decrease in luminal diameter/cross-sectional diameter between the same groups (p=0.00002). CONCLUSIONS: Increasing hepatic arteriolar wall thickness and decreased arteriolar cross-sectional diameter occur with increasing age in the normal human liver. PMID- 21236309 TI - Evidence of neutrophil functional defect despite inflammation in stable cirrhosis. AB - BACKGROUND & AIMS: Deranged neutrophil function in alcoholic hepatitis has been shown to be transmissible to normal neutrophils by patient plasma. The aims of this study were (i) to evaluate whether patients with stable cirrhosis have a similar transmissible neutrophil defect and (ii) to explore the possible mechanisms. METHODS: Plasma samples from 108 stable cirrhotic patients (Child A or B: 58; Child C: 50) and matched controls were incubated with normal neutrophils. Neutrophil resting respiratory burst, phagocytosis, and toll-like receptors 2, 4, and 9 expressions as well as plasma endotoxin, bacterial DNA, and cytokines were measured. In a separate study, eight patients and five controls were studied using a novel 'skin-window' technique to evaluate neutrophil function in an area of induced sterile inflammation. RESULTS: Patient plasma induced neutrophil phagocytic dysfunction was greater in patients with more severe disease and was associated with increased expression of toll-like receptors 2 and 4. An increased resting respiratory burst was observed in a subset of patients, showing higher levels of inflammatory cytokines and more pronounced phagocytic impairment. No correlation was found with endotoxemia or bacterial DNA. In patients with compensated cirrhosis and apparently normal neutrophil function, the 'skin-window' study disclosed a severe phagocytic defect at the site of inflammation. Significantly higher levels of neutrophil elastase and IL-8 were found in the blister fluid. CONCLUSIONS: Stable cirrhosis is characterized by neutrophil phagocytic dysfunction which may be subtle and only revealed in inflamed peripheral tissues where excessive inflammatory mediators continue to be released. PMID- 21236311 TI - NK cells in acute hepatitis C. PMID- 21236312 TI - Progress in the development of preventive and therapeutic vaccines for hepatitis C virus. AB - Hepatitis C virus (HCV) is a blood borne disease estimated to chronically infect 3% of the worlds' population causing significant morbidity and mortality. Current medical therapy is curative in approximately 50% of patients. While recent treatment advances of genotype 1 infection using directly acting antiviral agents (DAAs) are encouraging, there is still a need to develop vaccine strategies capable of preventing infection. Moreover, vaccines may also be used in future in combination with DAAs enabling interferon-free treatment regimens. Viral and host specific factors contribute to viral evasion and present important impediments to vaccine development. Both, innate and adaptive immune responses are of major importance for the control of HCV infection. However, HCV has evolved ways of evading the host's immune response in order to establish persistent infection. For example, HCV inhibits intracellular interferon signalling pathways, impairs the activation of dendritic cells, CD8(+) and CD4(+) T cell responses, induces a state of T-cell exhaustion and selects escape variants with mutations CD8(+) T cell epitopes. An effective vaccine will need to produce strong and broadly cross reactive CD4(+), CD8(+) T cell and neutralising antibody (NAb) responses to be successful in preventing or clearing HCV. Vaccines in clinical trials now include recombinant proteins, synthetic peptides, virosome based vaccines, tarmogens, modified vaccinia Ankara based vaccines, and DNA based vaccines. Several preclinical vaccine strategies are also under development and include recombinant adenoviral vaccines, virus like particles, and synthetic peptide vaccines. This paper will review the vaccines strategies employed, their success to date and future directions of vaccine design. PMID- 21236313 TI - Modelling foraging ants in a dynamic and confined environment. AB - In social insects, the superposition of simple individual behavioral rules leads to the emergence of complex collective patterns and helps solve difficult problems inherent to surviving in hostile habitats. Modelling ant colony foraging reveals strategies arising from the insects' self-organization and helps develop of new computational strategies in order to solve complex problems. This paper presents advances in modelling ants' behavior when foraging in a confined and dynamic environment, based on experiments with the Argentine ant Linepithema humile in a relatively complex artificial network. We propose a model which overcomes the problem of stagnation observed in earlier models by taking into account additional biological aspects, by using non-linear functions for the deposit, perception and evaporation of pheromone, and by introducing new mechanisms to represent randomness and the exploratory behavior of the ants. PMID- 21236314 TI - Disease specificity and pathologic progression of tau pathology in brainstem nuclei of Alzheimer's disease and progressive supranuclear palsy. AB - Previous studies have shown tau pathology in the inferior colliculus (IC) and superior colliculus (SC) in Alzheimer's disease (AD); however, it has not been compared to other tauopathies, such as progressive supranuclear palsy (PSP), or characterized with respect to progression of tau pathology in AD. The main purpose of this study was to investigate frequency, neuroanatomical selectivity and disease specificity of tau pathology in visual and auditory nuclei (SC and lateral geniculate body (LGB); IC and medial geniculate body (MGB), respectively). We measured phospho-tau burden with immunohistochemistry and image analysis in 26 cases of AD, 37 PSP and 11 normal controls. Tau burden was also assessed in two unrelated brainstem nuclei (substantia nigra (SN) and pedunculopontine nucleus (PPN)) of the same cases. We found tau burden to be greater in the SC of PSP compared to AD and controls. Conversely, tau burden was greater in the IC of AD compared to PSP and controls. The MGB and LGB had sparse tau pathology in both AD and PSP. This disease selectivity parallels known deficits in visual reflexes in PSP and auditory reflexes in AD. Tau burden was greater in the SC, IC, and PPN in both PSP and AD compared to controls, and greater in the SN in PSP compared to AD and controls. Although present at early Braak neurofibrillary tangle stages, the SC, IC, PPN and SN did not accumulate tau consistently until later stages. These findings support a concept of tau pathology affecting the brainstem at mid-to-late stage AD. PMID- 21236315 TI - Brain tissue energy dependence of CaM kinase IV cascade activation during hypoxia in the cerebral cortex of newborn piglets. AB - The present study aims to investigate the dependence of CaM kinase IV cascade activation during hypoxia and tests the hypothesis that hypoxia-induced tyrosine phosphorylation of CaM and CaM kinase IV, activation of CaM kinase IV and phosphorylation of CREB protein during hypoxia increases as a function of increase in cerebral tissue hypoxia as measured by decrease in tissue ATP and phosphocreatine (PCr). 3-5 days old newborn piglets were divided into normoxic (Nx, FiO2 of 0.21 for 1h) and hypoxic (Hx, FiO2 of 0.07 for 1h) groups. Cerebral tissue hypoxia was documented by determining the levels of high energy phosphates ATP and phosphocreatine (PCr). Cerebral cortical neuronal nuclei were isolated and purified, and tyrosine phosphorylation of calmodulin (Tyr99), the activator of CaM kinase IV, and CaM kinase IV determined by Western blot using anti-phospho (pTyr99)-calmodulin, anti-pTyrosine and anti-CaM kinase IV antibodies. The activity of CaM kinase IV and its consequence the phosphorylation of CREB protein at Ser133 were determined. The levels of ATP (MUmole/g brain) ranged from 3.48 to 5.28 in Nx, and 0.41 to 2.26 in Hx. The levels of PCr (MUmole/g brain) ranged from 2.46 to 3.91 in Nx and 0.72 to 1.20 in Hx. The pTyr99 calmodulin (OD x mm2) ranged from 20.35 to 54.47.60 in Nx, and 84.52 to 181.42 in Hx (r2=0.5309 vs ATP and r2=0.6899 vs PCr). Expression of tyrosine phosphorylated CaM kinase IV ranged from 32.86 to 82.46 in Nx and 96.70 to 131.62 in Hx (r2=0.5132 vs ATP and r2=0.4335 vs PCr). The activity of CaM kinase IV (pmole/mg protein/min) ranged from 1263 to 3448 in Nx and 3767 to 6633 in Hx (r2=0.7113 vs ATP and r2=0.6182 vs PCr). The expression of p-CREB at Ser133 ranged from 44.26 to 70.28 in Nx and 82.70 to 182.86 in Hx (r2=0.6621 vs ATP and r2=0.5485 vs PCr). The data show that hypoxia results in increased tyrosine phosphorylation of calmodulin (Tyr99), increased tyrosine phosphorylation of CaM kinase IV, increased activity of CaM kinase IV and increased phosphorylation of CREB at Ser133 as an inverse function of cerebral concentration of high energy phosphates, ATP and PCr. We conclude that the hypoxia-induced increased activation of CaM kinase IV cascade increases with the increase in the degree of cerebral tissue hypoxia as measured by cerebral tissue high energy phosphates in a curvilinear manner. The tyrosine kinases (Src kinase and EGFR kinase) mediated activation of CaM kinase IV cascade potentially results in increased CREB phosphorylation that triggers transcription of proapoptotic proteins during hypoxia. PMID- 21236316 TI - A functional tetranucleotide (AAAT) polymorphism in an Alu element in the NF1 gene is associated with mental retardation. AB - Mental retardation (MR) is frequent in neurofibromatosis type 1 (NF1). Allele 5 of a tetranucleotide polymorphism in an Alu element (GXAlu) localized in intron 27b of the NF1 gene has previously been associated with autism. We considered that the microsatellite GXAlu could also represent a risk factor in MR without autism. We developed a rapid method for genotyping by non-denaturing HPLC and assayed the allelic variation of GXAlu marker on in vitro gene expression in Cos 7 cells. A French population of 157 individuals (68 non syndromic non familial MR (NS-MR) patients diagnosed in the University Hospital of Tours; 89 controls) was tested in a case-control assay. We observed a significant association (chi(2)=7.96; p=0.005) between alu4 carriers (7 AAAT repeats) and MR (OR: 7.86; 95% C.I.: 2.13-28.9). The relative in vitro expression of a reporter gene encoding chloramphenicol acetyl transferase (CAT) was higher for alu4 and alu5, suggesting a regulation effect for these alleles on gene expression in vivo. Our results showed an association with a polymorphism regulating the NF1 gene or other genes during brain development. PMID- 21236317 TI - Event-related spectral perturbation induced by action-related sound. AB - It is now well established that human brain is endowed with an auditory-motor system which may depend on individual's motor experience. Here we designed an electroencephalography (EEG) experiment for investigating this dependency. A sound with not-so-obvious meaning was presented to subjects firstly. Then a visual exposure process was carried out to establish an association between the sound and action. By analyzing event-related spectral perturbation (ERSP) in the mu rhythm, we expected to find response differences in the motor cortex between the pre- and post-exposure periods. Results of 14 subjects indicated that the activation of motor cortex was stronger in the post-exposure phase. Our study suggests that the auditory-motor association can be established rapidly by a simple exposure process. PMID- 21236318 TI - The interplay of the EIIA(Ntr) component of the nitrogen-related phosphotransferase system (PTS(Ntr)) of Pseudomonas putida with pyruvate dehydrogenase. AB - BACKGROUND: Pseudomonas putida KT2440 is endowed with a variant of the phosphoenolpyruvate-carbohydrate phosphotransferase system (PTS(Ntr)), which is not related to sugar transport but believed to rule the metabolic balance of carbon vs. nitrogen. The metabolic targets of such a system are largely unknown. METHODS: Dielectric breakdown of P. putida cells grown in rich medium revealed the presence of forms of the EIIA(Ntr) (PtsN) component of PTS(Ntr), which were strongly associated to other cytoplasmic proteins. To investigate such intracellular partners of EIIA(Ntr), a soluble protein extract of bacteria bearing an E epitope tagged version of PtsN was immunoprecipitated with a monoclonal anti-E antibody and the pulled-down proteins identified by mass spectrometry. RESULTS: The E1 subunit of the pyruvate dehydrogenase (PDH) complex, the product of the aceE gene, was identified as a major interaction partner of EIIA(Ntr). To examine the effect of EIIA(Ntr) on PDH, the enzyme activity was measured in extracts of isogenic ptsN(+)/ptsN(-)P. putida strains and the role of phosphorylation was determined. Expression of PtsN and AceE proteins fused to different fluorescent moieties and confocal laser microscopy indicated a significant co-localization of the two proteins in the bacterial cytoplasm. CONCLUSION: EIIA(Ntr) down-regulates PDH activity. Both genetic and biochemical evidence revealed that the non-phosphorylated form of PtsN is the protein species that inhibits PDH. GENERAL SIGNIFICANCE: EIIA(Ntr) takes part in the node of C metabolism that checks the flux of carbon from carbohydrates into the Krebs cycle by means of direct protein-protein interactions with AceE. This type of control might connect metabolism to many other cellular functions. This article is part of a Special Issue entitled: Systems Biology of Microorganisms. PMID- 21236319 TI - A novel vanadium transporter of the Nramp family expressed at the vacuole of vanadium-accumulating cells of the ascidian Ascidia sydneiensis samea. AB - BACKGROUND: Vanadium is an essential transition metal in biological systems. Several key proteins related to vanadium accumulation and its physiological function have been isolated, but no vanadium ion transporter has yet been identified. METHODS: We identified and cloned a member of the Nramp/DCT family of membrane metal transporters (AsNramp) from the ascidian Ascidia sydneiensis samea, which can accumulate extremely high levels of vanadium in the vacuoles of a type of blood cell called signet ring cells (also called vanadocytes). We performed immunological and biochemical experiments to examine its expression and transport function. RESULTS: Western blotting analysis showed that AsNramp was localized at the vacuolar membrane of vanadocytes. Using the Xenopus oocyte expression system, we showed that AsNramp transported VO(2+) into the oocyte as pH-dependent manner above pH 6, while no significant activity was observed below pH 6. Kinetic parameters (K(m) and V(max)) of AsNramp-mediated VO(2+) transport at pH 8.5 were 90nM and 9.1pmol/oocyte/h, respectively. A rat homolog, DCT1, did not transport VO(2+) under the same conditions. Excess Fe(2+), Cu(2+), Mn(2+), or Zn(2+) inhibited the transport of VO(2+). AsNramp was revealed to be a novel VO(2+)/H(+) antiporter, and we propose that AsNramp mediates vanadium accumulation coupled with the electrochemical gradient generated by vacuolar H(+) ATPase in vanadocytes. GENERAL SIGNIFICANCE: This is the first report of identification and functional analysis on a membrane transporter for vanadium ions. PMID- 21236320 TI - The effects of cocaine on light-induced activity. AB - Cocaine is a major stimulant drug which can have rewarding and locomotor activating effects. It is used by non-addicts to enhance concentration and performance in a work or social setting. It was suggested that cocaine may amplify the impact of mood and sensory stimulation on behaviour. Here we tested whether cocaine can enhance the impact of novel sensory stimulation on exploratory locomotor activity. In this study the effects of cocaine (0, 2.5, 5.0, 10mg/kg, i.p.) on the locomotor response induced by on-off light stimulation with different light intensities (0, 22, 83, 440 lx) was investigated. Visual stimulation increased locomotor activity and grooming behaviour. Cocaine more dramatically increased locomotion and rearing behaviour but suppressed grooming. Also, visual stimulation effects on grooming were reduced by cocaine. The additive relationship between the cocaine and visual stimulation effects on locomotion and rearing combined with their opposing impact upon grooming point to independent mechanisms mediating cocaine- and visual stimulation-induced behavioural activation. PMID- 21236321 TI - Odor perception and odor awareness in congenital blindness. AB - It is generally acknowledged that people blind from birth develop supra-normal sensory abilities in order to compensate for their visual deficit. While extensive research has been done on the somatosensory and auditory modalities of the blind, information about their sense of smell remains scant. The goal of this study was therefore to compare odor perception and odor awareness in a group of 11 congenitally blind and 14 sighted control subjects. We measured odor detection threshold, odor discrimination and odor identification using the Sniffin'Sticks test. Participants also filled in the Odor Awareness Scale (OAS) to assess consciousness of olfactory sensations. Our data showed that blind subjects had a lower odor detection threshold compared to the sighted. However, no group differences were found for odor discrimination and odor identification. Interestingly, the OAS revealed that blind participants scored higher for odor awareness. The largest group differences were found for items of the OAS that measure responses to body odors and fragrances. We conclude that blind subjects rely more on their sense of smell than the sighted in order to assess their environment and to recognize places and other people. PMID- 21236322 TI - Characterization of the histidine decarboxylase gene of Staphylococcus epidermidis TYH1 coded on the staphylococcal cassette chromosome. AB - Histamine production from histidine in fermented food results in food spoilage, and is harmful to consumers. From fish-miso, we have isolated a new bacterial strain Staphylococcus epidermidis TYH1, which produced histamine under acidic condition in the medium supplemented with glucose. Using oligonucleotides deduced from the histidine decarboxylase gene (hdcA) of Lactobacillus hilgardii, about 14 kbp DNA region of the TYH1 genome was cloned and sequenced. This region contained two putative genes hdcA(TYH1) and hdcP(TYH1) encoding proteins HdcA(TYH1) (310 amino acid residues) and HdcP(TYH1) (495 residues), respectively. Nucleotide sequence around this hdc cluster showed similarity to SCCpbp4 region of S. epidermidis ATCC 12228. Downstream of the cluster, ccrA, ccrB (Type II, respectively) and pbp4 were located. The CcrA and CcrB proteins catalyzed excision of the hdc cluster from the TYH1 chromosome, upon introduction into the TYH1 strain via multicopy plasmid. When hdcA(TYH1) was expressed in Staphylococcus warneri M, histamine was extracellularly accumulated in dependence on exogenous histidine. These results indicate that the gene encoding a histidine decarboxylase resides in a movable genetic element, SCC. This new element is designated as SCChdc. PMID- 21236323 TI - Electrically enhanced solute permeation across poly(ethylene glycol)-crosslinked poly(methyl vinyl ether-co-maleic acid) hydrogels: effect of hydrogel crosslink density and ionic conductivity. AB - Swelling kinetics, ionic conductivity and electrically assisted solute permeation (theophylline, methylene blue and fluorescein sodium) of poly(ethylene glycol) (PEG) crosslinked poly(methyl vinyl ether-co-maleic acid) (PMVE/MA) hydrogels are presented. The effects of PMVE/MA concentration and PEG molecular weight (MW) on swelling behaviour and network parameters were investigated in phosphate buffered saline (pH 7.4). The percentage swelling of hydrogels increased, and the crosslink density decreased, with a decrease in PMVE/MA content and with an increase in PEG MW. The ionic conductivity of the formulation was found to increase with an increase in PEG MW. The application of an electrical current led to a significant enhancement in the rate and extent of solute permeation across the swollen hydrogels. Furthermore, it was found that the extent of solute permeation enhancement following current application was dependent upon the crosslink density and ionic conductivity of the formulation. In general, a decrease in crosslink density and an increase in ionic conductivity led to a greater enhancement in solute permeation following current application. The electro-responsive nature of these hydrogels suggests that have a potential application in electrically controlled drug delivery systems. PMID- 21236324 TI - Biophysical characterisation of GlycoPEGylated recombinant human factor VIIa. AB - The effects of GlycoPEGylation on the structural, kinetic and thermal stability of recombinant human FVIIa were investigated using rFVIIa and linear 10 kDa and branched 40 kDa GlycoPEGylated((r)) recombinant human FVIIa derivatives. The secondary and tertiary structure of rFVIIa measured by circular dichroism (CD) was maintained upon PEGylation. In contrast, the thermal and kinetic stability of rFVIIa was affected by GlycoPEGylation, as the apparent unfolding temperature T(m) measured by differential scanning calorimetry (DSC) and the temperature of aggregation, T(agg), measured by light scattering (LS) both increased with GlycoPEGylation. Both T(m) and T(agg) were independent of the molecular weight and the shape of the PEG chain. From the present biophysical characterisation it is concluded that after GlycoPEGylation, rFVIIa appears to be unaffected structurally (secondary and tertiary structure), slightly stabilised thermally (unfolding temperature) and stabilised kinetically (temperature of aggregation). PMID- 21236325 TI - A quantitative analysis of spectral mechanisms involved in auditory detection of coloration by a single wall reflection. AB - Coloration detection thresholds (CDTs) were measured for a single reflection as a function of spectral content and reflection delay for diotic stimulus presentation. The direct sound was a 320-ms long burst of bandpass-filtered noise with varying lower and upper cut-off frequencies. The resulting threshold data revealed that: (1) sensitivity decreases with decreasing bandwidth and increasing reflection delay and (2) high-frequency components contribute less to detection than low-frequency components. The auditory processes that may be involved in coloration detection (CD) are discussed in terms of a spectrum-based auditory model, which is conceptually similar to the pattern-transformation model of pitch (Wightman, 1973). Hence, the model derives an auto-correlation function of the input stimulus by applying a frequency analysis to an auditory representation of the power spectrum. It was found that, to successfully describe the quantitative behavior of the CDT data, three important mechanisms need to be included: (1) auditory bandpass filters with a narrower bandwidth than classic Gammatone filters, the increase in spectral resolution was here linked to cochlear suppression, (2) a spectral contrast enhancement process that reflects neural inhibition mechanisms, and (3) integration of information across auditory frequency bands. PMID- 21236326 TI - Recent advances in comparative hearing. PMID- 21236327 TI - Resolvability of components in complex tones and implications for theories of pitch perception. AB - This paper reviews methods that have been used to estimate the resolvability of individual partials in harmonic and inharmonic complex tones and considers the implications of the results for theories of pitch perception. The methods include: requiring comparisons of the pitch of an isolated pure tone and a partial within a complex tone as a measure of the ability to "hear out" that partial; considering the magnitude of ripples in the calculated excitation pattern of a complex tone; using a complex tone as a forward masker and using ripples in the masking pattern to estimate resolvability; measuring sensitivity to the relative phase of the components within complex tones. The measures are broadly consistent in indicating that harmonics with numbers up to about five are well resolved, but that resolution decreases for higher harmonics. Most measures suggest that harmonics with numbers above eight are poorly, if at all, resolved. However, there are uncertainties associated with each method that make the exact upper limit of resolvability uncertain. Evidence is presented suggesting a partial dissociation between resolution in the excitation pattern and the ability to hear out a partial. It is proposed that the latter requires information from temporal fine structure (phase locking). PMID- 21236328 TI - Vasorelaxation by extracts of Casimiroa spp. in rat resistance vessels and pharmacological study of cellular mechanisms. AB - AIM OF THE STUDY: Casimiroa spp. are Mexican plants traditionally used for treatment of hypertension. To study their antihypertensive action, we determined the arterial dilatation induced by extracts from leaves and seeds of Casimiroa calderoniae F. Chiang & Medrano, Casimiroa edulis Llave et Lex, and Casimiroa pubescens Ramirez. MATERIALS AND METHODS: The vascular effects of Casimiroa spp. extracts were investigated on rat caudal and aortic arteries. In addition, the extracts were characterized by HPLC using heraclenol, isopimpinellin, heraclenin and phellopterin as external standards. The methanolic extract of Casimiroa pubescens seeds (Cp12) was also studied by H-NMR and LC-MS (ESI-TOF) for the determination of casimiroin and zapotin. RESULTS: The hexanic and methanolic extracts of Casimiroa spp. (20 MUg/ml) showed vasorelaxation in arterial tissues precontracted by phenylephrine (0.5 MUM); the extracts from seeds always caused a greater relaxation in comparison to those from leaves. The most active were the methanolic seed extracts of Casimiroa edulis (Ce8) and Casimiroa pubescens (Cp12). To study the pharmacological mechanisms of vasodilatation we used various inhibitors selective to different receptor subtypes or intracellular enzymes. The vasorelaxant effect of Ce8 (20 MUg/ml) remained unaffected by the pretreatment with pyrilamine (10 MUM), an antagonist of histamine H(1) receptors, but was inhibited by atropine (0.1 MUM), a muscarinic receptor antagonist. Therefore, to determine muscarinic receptor subtypes, we used pirenzepine (1 MUM), a selective inhibitor of M(1) receptor, and 4-diphenylacetoxyl-N-methylpiperidine methiodide (DAMP, 0.01 MUM), a selective inhibitor of M(3) receptor. Only the latter reduced the vasodilatation by Ce8 and Cp12. To investigate the role of the nitric oxide synthase (NOS), we used N(G)-nitro-l-arginine methyl ester (l-NAME, 10 MUM), a selective NOS inhibitor, which decreased the dilatation induced by Ce8 and Cp12. Finally, we studied the action of (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) (ODQ, 3 MUM), a selective guanylyl cyclase inhibitor, which inhibited the dilatation by Casimiroa extracts. CONCLUSION: The data show that methanolic seed extracts of Casimiroa edulis (Ce8) and Casimiroa pubescens (Cp12) induce vasorelaxation by M(3) receptor through the activation of cGMP-dependent NO signaling. These results support the traditional use of Casimiroa decoctions for antihypertensive treatments in the Mexican ethnomedicine. PMID- 21236329 TI - Pharmacological mechanisms underlying the anti-ulcer activity of methanol extract and canthin-6-one of Simaba ferruginea A. St-Hil. in animal models. AB - RELEVANCE: Simaba ferruginea A. St-Hil. (Simaroubaceae) is a subshrub typical of the Brazilian Cerrado, whose rhizomes are popularly used as infusion or decoction for the treatment of gastric ulcers, diarrhea and fever. AIM OF THE STUDY: To evaluate the pharmacological mechanism(s) of action of the antiulcer effects of the methanol extract of Simaba ferruginea and its alkaloid canthin-6-one. MATERIALS AND METHODS: Rhizome of Simaba ferruginea was macerated with methanol to obtain the methanol extract (MESf) from which was obtained, the chloroform fraction. Canthin-6-one alkaloid (Cant) was purified and then isolated from the chloroform fraction (CFSf). The isolated Cant was identified by HPLC. Anti-ulcer assays were determined using ethanol and indomethacin-induced ulcer models in mice and rats respectively. In order to determine the probable mechanisms of actions of MESf and Cant animals were pretreated with l-NAME prior to anti-ulcer agent treatments and ulcer induction and nitric oxide (NO) level determined in order to assess NO involvement in the gastroprotective effects. Assays of malondialdehyde (MDA), myeloperoxidase (MPO), pro-inflammatory cytokines: interleukin 8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) and prostaglandin E(2) (PGE(2)) were also carried out according to previously described methods. RESULTS: The results indicate that the antiulcerogenic effects of MESf and Cant in ethanol-induced ulcer is mediated in part through increase in the production of protective endogenous NO as the antiulcerogenic activity of MESf and Cant was reduced in animals pre-treated with l-NAME. In indomethacin induced ulcer pre-treatment with MESf and Cant showed reduction in the levels of MPO and MDA in the gastric tissue, thus indicating the participation of the antioxidant mechanisms on the gastroprotective effects. The plasma levels of IL-8 in ulcerated rats with indomethacin were also reduced by Cant, but not by MESf, indicating that inhibition of this cytokine contributes to the gastroprotective effect of Cant. However MESf and Cant had no effect on the mucosal membrane levels of PGE(2), indicating that the gastroprotective effects of these agents is independent of PGE(2) modulation. CONCLUSION: The results obtained in this study with MESf and Cant added insights into the pharmacological mechanisms involved in their mode of antiulcer action. The results indicate that Cant is one of the compounds responsible for these effects. Such findings are of extreme importance in the strive for future development of potent, safer and effective antiulcer agent. The efficacy of MESf and Cant in gastroprotection shows that Simaba ferruginea might be a promising antiulcer herbal medicine, in addition to confirming the popular use of this plant against gastric ulcer models utilised in this study. PMID- 21236330 TI - Towards high-yield production of pharmaceutical proteins with plant cell suspension cultures. AB - "Molecular farming" in plants with significant advantages in cost and safety is touted as a promising platform for the production of complex pharmaceutical proteins. While whole-plant produced biopharmaceuticals account for a significant portion of the preclinical and clinical pipeline, plant cell suspension culture, which integrates the merits of whole-plant systems with those of microbial fermentation, is emerging as a more compliant alternative "factory". However, low protein productivity remains a major obstacle that limits extensive commercialization of plant cell bioproduction platform. This review highlights the advantages and recent progress in plant cell culture technology and outlines viable strategies at both the biological and process engineering levels for advancing the economic feasibility of plant cell-based protein production. Approaches to overcome and solve the associated challenges of this culture system that include non-mammalian glycosylation and genetic instability will also be discussed. PMID- 21236331 TI - Validation of a high-sensitivity assay for C-reactive protein in human saliva. AB - This study aimed to validate a high-sensitivity assay for C-reactive protein (CRP) in saliva as an alternative medium to study inflammation in large epidemiological cohorts and young people. We measured CRP in saliva and serum in 61 (29.5% males) healthy adult volunteers. We found a moderate-to-strong association between CRP measured in saliva and in serum (r=.72, p<.001). In agreement with the non-steroidal structure and the high molecular weight of CRP, we observed a low saliva-to-serum CRP ratio (1:1633.64). Furthermore, a dichotomous index of salivary CRP, equivalent to a clinically relevant serum CRP cut-off (3mg/l), was associated to known correlates of systemic inflammation (IL 6, BMI and smoking). Finally, we showed that CRP in saliva is stable at room temperature up to 8h after collection. Our study provides initial evidence suggesting that non-invasive assessment of CRP in saliva allows valid prediction of serum CRP. Salivary CRP may thus facilitate and promote research exploring the correlates of low-grade inflammation in epidemiological studies and makes it feasible to expand psychoneuroimmunology research to pediatric populations. PMID- 21236332 TI - 15-Deoxy-Delta12,14-prostaglandin J2 induces Cox-2 expression in human osteosarcoma cells through MAPK and EGFR activation involving reactive oxygen species. AB - Prostaglandins (PGs), important modulators in bone biology, may also contribute to tumor formation and progression in human osteosarcoma. 15-Deoxy-Delta(12,14) PGJ(2) (15d-PGJ(2)), a metabolite of PGD(2) and PPARgamma-ligand, exerts a panel of biological activities via receptor-dependent and -independent mechanisms. As inducible cyclooxygenase-2 (Cox-2) is a candidate inflammatory marker in human osteosarcoma and a rate-limiting enzyme in PG biosynthesis, this study aimed at investigating intracellular redox status and signaling cascades leading to Cox-2 induction in human MG-63 osteosarcoma cells. 15d-PGJ(2) induced the accumulation of reactive oxygen species (ROS) that in turn may lead to upregulation of Cox-2 via two different routes in a PPARgamma-independent manner. First, phosphorylation of p38 MAPK directly enhances Cox-2 expression by promoting mRNA stability. Second, 15d-PGJ(2) induces activation of epidermal growth factor receptors and downstream activation of Cox-2 via phosphorylation of p42/44 MAPK. Glutathione precursor molecules reversed enhanced ROS levels and Cox-2 expression. Functional activity of Cox-2 expression was tested by measurement of PGE(2) and PGF(2alpha). The synthetic compound 9,10-dihydro-15d-PGJ(2) lacking the alpha,beta-unsaturated carbonyl group in the cyclopentenone ring did not exhibit the cellular responses observed with 15d-PGJ(2). We conclude that the electrophilic carbon atom of 15d-PGJ(2) is responsible for alterations in intracellular redox status and Cox-2 expression. PMID- 21236333 TI - Vitamin C supplementation lowers urinary levels of 4-hydroperoxy-2-nonenal metabolites in humans. AB - The lack of suitable biomarkers of oxidative stress is a common problem for antioxidant intervention studies in humans. We evaluated the efficacy of vitamin C supplementation in decreasing biomarkers of lipid peroxidation in nonsmokers and in cigarette smokers, a commonly studied, free-living human model of chronic oxidative stress. Participants received ascorbic acid (500mg twice per day) or placebo for 17 days in a double-blind, placebo-controlled, randomized crossover design study. The urinary biomarkers assessed and reported herein are derived from 4-hydroperoxy-2-nonenal (HPNE) and include the mercapturic acid (MA) conjugates of 4-hydroxy-2(E)-nonenal (HNE), 1,4-dihydroxy-2(E)-nonene (DHN), and 4-oxo-2(E)-nonenol(ONO). Vitamin C supplementation decreased the urinary concentrations of both ONO-MA (p=0.0013) and HNE-MA (p=0.0213) by ~30%; however, neither cigarette smoking nor sex affected these biomarkers. In contrast, vitamin C supplementation decreased urinary concentrations of DHN-MA (three-way interaction p=0.0304) in nonsmoking men compared with nonsmoking women (p<0.05), as well as in nonsmoking men compared with smoking men (p<0.05). Vitamin C supplementation also decreased (p=0.0092) urinary total of metabolites by ~20%. Thus, HPNE metabolites can be reduced favorably in response to improved plasma ascorbic acid concentrations, an effect due to ascorbic acid antioxidant function. PMID- 21236335 TI - Gemcitabine response in pancreatic adenocarcinoma cells is synergistically enhanced by dithiocarbamate derivatives. AB - Pancreatic adenocarcinoma is a common malignancy that remains refractory to all available therapies, including the gold standard drug gemcitabine (GEM). We investigated the effect of the combination of GEM and each of the ionophore compounds pyrrolidine dithiocarbamate (PDTC) and disulfiram [DSF; 1 (diethylthiocarbamoyldisulfanyl)-N,N-diethylmethanethioamide] on p53(-/-) pancreatic adenocarcinoma cell growth. PDTC or DSF synergistically inhibited cell proliferation when used in combination with GEM by inducing apoptotic cell death. This effect was associated with an increased mitochondrial O(2)(*-) production and was further enhanced by zinc ions. Basal levels of mitochondrial O(2)(*-) or manganese superoxide dismutase (MnSOD) strictly correlated with the IC(50) for GEM or the percentage of synergism. Thus, the most relevant values of the antiproliferative synergism were obtained in GEM-resistant pancreatic adenocarcinoma cell lines. Interestingly, the GEM-sensitive T3M4 cells transfected with MnSOD expression vector showed mitochondrial O(2)(*-) and IC(50) for GEM similar to those of resistant cell lines. In vivo experiments performed on nude mice xenotransplanted with the GEM-resistant PaCa44 cell line showed that only the combined treatment with GEM and DSF/Zn completely inhibited the growth of the tumoral masses. These results and the consideration that DSF is already used in clinics strongly support the GEM and DSF/Zn combination as a new approach to overcoming pancreatic cancer resistance to standard chemotherapy. PMID- 21236336 TI - Interactions of plasmalogens and their diacyl analogs with singlet oxygen in selected model systems. AB - Plasmalogens are phospholipids containing a vinyl-ether linkage at the sn-1 position of the glycerophospholipid backbone. Despite being quite abundant in humans, the biological role of plasmalogens remains speculative. It has been postulated that plasmalogens are physiological antioxidants with the vinyl-ether functionality serving as a sacrificial trap for free radicals and singlet oxygen. However, no quantitative data on the efficiency of plasmalogens at scavenging these reactive species are available. In this study, rate constants of quenching of singlet oxygen, generated by photosensitized energy transfer, by several plasmalogens and, for comparison, by their diacyl analogs were determined by time resolved detection of phosphorescence at 1270nm. Relative rates of the interactions of singlet oxygen with plasmalogens and other lipids, in solution and in liposomal membranes, were measured by electron paramagnetic resonance oximetry and product analysis using HPLC-EC detection of cholesterol hydroperoxides and iodometric assay of lipid hydroperoxides. The results show that singlet oxygen interacts with plasmalogens significantly faster than with the other lipids, with the corresponding rate constants being 1 to 2 orders of magnitude greater. The quenching of singlet oxygen by plasmalogens is mostly reactive in nature and results from its preferential interaction with the vinyl ether bond. The data suggest that plasmalogens could protect unsaturated membrane lipids against oxidation induced by singlet oxygen, providing that the oxidation products are not excessively cytotoxic. PMID- 21236337 TI - Mechanism of lipid induced insulin resistance: activated PKCepsilon is a key regulator. AB - Fatty acids (FAs) are known to impair insulin signaling in target cells. Accumulating evidences suggest that one of the major sites of FAs adverse effect is insulin receptor (IR). However, the underlying mechanism is yet unclear. An important clue was indicated in leptin receptor deficient (db/db) diabetic mice where increased circulatory FAs was coincided with phosphorylated PKCepsilon and reduced IR expression. We report here that central to this mechanism is the phosphorylation of PKCepsilon by FAs. Kinase dead mutant of PKCepsilon did not augment FA induced IRbeta downregulation indicating phosphorylation of PKCepsilon is crucial for FA induced IRbeta reduction. Investigation with insulin target cells showed that kinase independent phosphorylation of PKCepsilon by FA occurred through palmitoylation. Mutation at cysteine 276 and 474 residues in PKCepsilon suppressed this process indicating participation of these two residues in palmitoylation. Phosphorylation of PKCepsilon endowed it the ability to migrate to the nuclear region of insulin target cells. It was intriguing to search about how translocation of phosphorylated PKCepsilon occurred without having canonical nuclear localization signal (NLS). We found that F-actin recognized phospho-form of PKCepsilon and chaperoned it to the nuclear region where it interact with HMGA1 and Sp1, the transcription regulator of IR and HMGA1 gene respectively and impaired HMGA1 function. This resulted in the attenuation of HMGA1 driven IR transcription that compromised insulin signaling and sensitivity. PMID- 21236338 TI - Mast cell transcription factors--regulators of cell fate and phenotype. AB - Transcription factors have a key role in mast cell differentiation and response of differentiated mast cells to external stimuli. During differentiation of progenitor cells to mast cells, a role for different GATA transcription factors in combination with PU.1 expression and downregulation of C/EBPalpha has been described. Notch pathway has been proposed to have a role in mast cell development. The microphthalmia-associated transcription factor expression is upregulated in later stages of mast cells differentiation, but it is not expressed in the closely related basophiles. In differentiated mast cells, there is a role for transcription factors both in determining the specific mast cell phenotype and in the response to immune stimuli such as IgE-Ag. A large number of transcription factors, including AP-1 family proteins, microphthalmia-associated transcription factor and STAT5, are modulated by these stimuli. These transcription factors and related protein modulators form a complex transcription factor network. They can form stimuli regulated specific heterodimers and common inhibitors can move from one protein to another. Transcription factors are the key regulators of mast cell physiology. Modulation of key transcription by such means as the therapeutic siRNA may hopefully allow us to modulate mast cell function, obtaining clinical benefit in a variety of diseases. This article is part of a Special Issue entitled: Mast cells in inflammation. PMID- 21236334 TI - Redox signaling in cardiac myocytes. AB - The heart has complex mechanisms that facilitate the maintenance of an oxygen supply-demand balance necessary for its contractile function in response to physiological fluctuations in workload as well as in response to chronic stresses such as hypoxia, ischemia, and overload. Redox-sensitive signaling pathways are centrally involved in many of these homeostatic and stress-response mechanisms. Here, we review the main redox-regulated pathways that are involved in cardiac myocyte excitation-contraction coupling, differentiation, hypertrophy, and stress responses. We discuss specific sources of endogenously generated reactive oxygen species (e.g., mitochondria and NADPH oxidases of the Nox family), the particular pathways and processes that they affect, the role of modulators such as thioredoxin, and the specific molecular mechanisms that are involved-where this knowledge is available. A better understanding of this complex regulatory system may allow the development of more specific therapeutic strategies for heart diseases. PMID- 21236339 TI - A targeted genetic screen identifies crucial players in the specification of the Drosophila abdominal Capaergic neurons. AB - The central nervous system contains a wide variety of neuronal subclasses generated by neural progenitors. The achievement of a unique neural fate is the consequence of a sequence of early and increasingly restricted regulatory events, which culminates in the expression of a specific genetic combinatorial code that confers individual characteristics to the differentiated cell. How the earlier regulatory events influence post-mitotic cell fate decisions is beginning to be understood in the Drosophila NB 5-6 lineage. However, it remains unknown to what extent these events operate in other lineages. To better understand this issue, we have used a very highly specific marker that identifies a small subset of abdominal cells expressing the Drosophila neuropeptide Capa: the ABCA neurons. Our data support the birth of the ABCA neurons from NB 5-3 in a cas temporal window in the abdominal segments A2-A4. Moreover, we show that the ABCA neuron has an ABCA-sibling cell which dies by apoptosis. Surprisingly, both cells are also generated in the abdominal segments A5-A7, although they undergo apoptosis before expressing Capa. In addition, we have performed a targeted genetic screen to identify players involved in ABCA specification. We have found that the ABCA fate requires zfh2, grain, Grunge and hedgehog genes. Finally, we show that the NB 5-3 generates other subtype of Capa-expressing cells (SECAs) in the third suboesophageal segment, which are born during a pdm/cas temporal window, and have different genetic requirements for their specification. PMID- 21236340 TI - Internal benchmarking of a human blood-brain barrier cell model for screening of nanoparticle uptake and transcytosis. AB - Transport of drugs across the blood-brain barrier, which protects the brain from harmful agents, is considered the holy grail of targeted delivery, due to the extreme effectiveness of this barrier at preventing passage of non-essential molecules through to the brain. This has caused severe limitations for therapeutics for many brain-associated diseases, such as HIV and neurodegenerative diseases. Nanomaterials, as a result of their small size (in the order of many protein-lipid clusters routinely transported by cells) and their large surface area (which acts as a scaffold for proteins thereby rendering nanoparticles as biological entities) offer great promise for neuro-therapeutics. However, in parallel with developing neuro-therapeutic applications based on nanotechnology, it is essential to ensure their safety and long-term consequences upon reaching the brain. One approach to determining safe application of nanomaterials in biology is to obtain a deep mechanistic understanding of the interactions between nanomaterials and living systems (bionanointeractions). To this end, we report here on the establishment and internal round robin validation of a human cell model of the blood-brain barrier for use as a tool for screening nanoparticles interactions, and assessing the critical nanoscale parameters that determine transcytosis. PMID- 21236341 TI - Estrogenic effect of the MEK1 inhibitor PD98059 on endogenous estrogen receptor alpha and beta. AB - Estrogens are key regulators in mammary development and breast cancer and their effects are mediated by estrogen receptors alpha (ERalpha) and beta (ERbeta). These two receptors are ligand activated transcription factors that bind to regulatory regions in the DNA known as estrogen responsive elements (EREs). ERalpha and ERbeta activation is subject to modulation by phosphorylation and p42/p44 MAP kinases are the best characterized ER modifying kinases. Using a reporter gene (3X-ERE-TATA-luciferase) to measure activation of endogenous ERs, we found that MEK1 inhibitor PD98059, used in concentrations insufficient to inhibit MEK1 activation of p42/p44 MAP kinases, exerted estrogenic effects on the reporter gene and on the ERE-regulated RIP 140 protein. Such estrogenic effects were observed in mammary epithelial HC11 cells and occur on unliganded ERalpha and ligand activated ERbeta. Additionally, concentrations of PD98059 able to inhibit p42/p44 phosphorylation were not estrogenic. Further, inhibition of p42 MAP kinase expression with siRNAs also resulted in loss of PD98059 estrogenic effect. In summary, PD98059 in concentrations below the inhibitory for MEK1, exerts estrogenic effects in HC11 mammary epithelial cells. PMID- 21236342 TI - Calcitriol counteracts endothelial cell pro-inflammatory processes in a chronic kidney disease-like environment. AB - In advanced chronic kidney disease (CKD), hypocalcemia, high levels of advanced glycation end products (AGEs), and parathyroid hormone (PTH) coexist and are considered to play a role in the development of chronic vasculopathies. The aim of the present study was to evaluate the impact of a CKD-like environment on cultured endothelial cell (EC) functions and to assess the impact of calcitriol on the expression of parameters such as endothelial nitric oxide synthase (eNOS), receptor of AGEs (RAGE), interleukin 6 (IL-6) and nuclear factor kappa B (NFkappaB). Human umbilical vein cord endothelial cells (HUVEC) were grown in medium containing low Ca(2+) concentration stimulated with AGE-HSA and PTH and treated with calcitriol for additional incubation. mRNA expression was established by reverse transcriptase-PCR, protein expression by Western blot analysis, IL-6 secretion by ELISA, NOS activity by conversion of [(14)C]arginine to [(14)C]citrulline and DNA-binding activity of NFkappaB-p65 assayed colorimetrically in nuclear extracts. The CKD-like environment characterized by the association of low Ca(2+) and high levels of AGEs and PTH, depressed eNOS system activity and enhanced RAGE and IL-6 expression/secretion. DNA-binding activity of nuclear NFkappaB-p65 was increased and the expression of IkappaBalpha decreased. Addition of calcitriol normalized the expression, secretion and activity of eNOS, RAGE and IL-6. The enhanced NFkappaB activity was also counteracted probably due to the increased IkappaBalpha expression. The effect of CKD-like environment on EC may partly explain the increased vasculopathies in CKD patients, in contrast to calcitriol, which suggests a vascular protective action. PMID- 21236343 TI - Characterization of activity and binding mode of glycyrrhetinic acid derivatives inhibiting 11beta-hydroxysteroid dehydrogenase type 2. AB - Modulation of intracellular glucocorticoid availability is considered as a promising strategy to treat glucocorticoid-dependent diseases. 18beta Glycyrrhetinic acid (GA), the biologically active triterpenoid metabolite of glycyrrhizin, which is contained in the roots and rhizomes of licorice (Glycyrrhiza spp.), represents a well-known but non-selective inhibitor of 11beta hydroxysteroid dehydrogenases (11beta-HSDs). However, to assess the physiological functions of the respective enzymes and for potential therapeutic applications selective inhibitors are needed. In the present study, we applied bioassays and 3D-structure modeling to characterize nine 11beta-HSD1 and fifteen 11beta-HSD2 inhibiting GA derivatives. Comparison of the GA derivatives in assays using cell lysates revealed that modifications at the 3-hydroxyl and/or the carboxyl led to highly selective and potent 11beta-HSD2 inhibitors. The data generated significantly extends our knowledge on structure-activity relationship of GA derivatives as 11beta-HSD inhibitors. Using recombinant enzymes we found also potent inhibition of mouse 11beta-HSD2, despite significant species-specific differences. The selected GA derivatives potently inhibited 11beta-HSD2 in intact SW-620 colon cancer cells, although the rank order of inhibitory potential differed from that obtained in cell lysates. The biological activity of compounds was further demonstrated in glucocorticoid receptor (GR) transactivation assays in cells coexpressing GR and 11beta-HSD1 or 11beta-HSD2. 3D-structure modeling provides an explanation for the differences in the selectivity and activity of the GA derivatives investigated. The most potent and selective 11beta-HSD2 inhibitors should prove useful as mechanistic tools for further anti-inflammatory and anti-cancer in vitro and in vivo studies. Article from the Special issue on Targeted Inhibitors. PMID- 21236344 TI - Bone metabolism and quality-of-life of postmenopausal women with invasive breast cancer receiving neoadjuvant hormonal therapy: sub-analyses from celecoxib anti aromatase neoadjuvant (CAAN) trial. AB - OBJECTIVE: Anti-aromatase therapy is important in the treatment of breast cancer in postmenopausal women but they have effects on the bone mineral density (BMD) and osteoporosis. Cyclooxygenase-2 (COX-2) inhibitors have been shown to be effective in chemoprevention in animal and clinical studies. A proof of principle study was performed to investigate the efficacy of combing anti-aromatase therapy (exemestane) and COX-2 inhibitors neoadjuvantly. The changes in the BMD, bone turnover proteins and quality-of-life (QoL) were analyzed and presented here. METHOD: 82 postmenopausal patients with histologically confirmed invasive hormone sensitive breast cancers were included for the neoadjuvant therapy (NHT). 30 patients received exemestane (EXE) 25 mg daily and celecoxib (CXB) 400 mg twice daily (group A), 24 patients received EXE 25 mg daily (group B) and 28 patients received letrozole (LET) 2.5 mg daily (group C). The same assigned treatment was intended to continue for 2 years to study the changes in the bone metabolism. BMD of 48 patients were analyzed; 23 belongs to group A, 10 to group B and 15 to group C. The serum bone turnover proteins bone-specific alkaline phosphatase (BAP) and carboxyterminal crosslinked telopeptide of type I collagen (ICTP), were measured with commercially available test kits before treatment, 3 months and 15 months after treatment. Functional Assessment of Cancer Therapy core questionnaire (FACT-G) with its additional breast cancer subscale were performed at baseline, 4, 8, and 12 weeks after NHT. RESULT: Difference between groups (p=0.007) for BMD at femur was significant. The changes of BMD in group B patients were significantly greater than patients in group A (p=0.011, CI=0.063 0.437), and group C (p=0.003, CI=0.146-0.620). The mean BAP increased from baseline in group B patients but decreased from baseline in group C patients at 3 months and 15 months. No statistical significance was found in the FACT-G scores and FACT-B scores among different groups at baseline, week 4, week 8 and week 12 after NHT. The Breast Cancer Subscale scores in group A patients were significantly higher than that of group C patients (p=0.021). After 4 weeks of NHT, negative changes of FACT-B and FACT-G scores were found in group B and C patients, but there were positive changes in group A patients. Significant differences of FACT-B score (p=0.008) and FACT-G score (p=0.019) were observed at that time point. Article from the Special issue on Targeted Inhibitors. PMID- 21236346 TI - Missense mutations in Otopetrin 1 affect subcellular localization and inhibition of purinergic signaling in vestibular supporting cells. AB - Otopetrin 1 (Otop1) encodes a protein that is essential for the development of otoconia. Otoconia are the extracellular calcium carbonate containing crystals that are important for vestibular mechanosensory transduction of linear motion and gravity. There are two mutant alleles of Otop1 in mice, titled (tlt) and mergulhador (mlh), which result in non-syndromic otoconia agenesis and a consequent balance defect. Biochemically, Otop1 has been shown to modulate purinergic control of intracellular calcium in vestibular supporting cells, which could be one of the mechanisms by which Otop1 participates in the mineralization of otoconia. To understand how tlt and mlh mutations affect the biochemical function of Otop1, we examined the purinergic response of COS7 cells expressing mutant Otop1 proteins, and dissociated sensory epithelial cells from tlt and mlh mice. We also examined the subcellular localization of Otop1 in whole sensory epithelia from tlt and mlh mice. Here we show that tlt and mlh mutations uncouple Otop1 from inhibition of P2Y receptor function. Although the in vitro biochemical function of the Otop1 mutant proteins is normal, in vivo they behave as null alleles. We show that in supporting cells the apical membrane localization of the mutant Otop1 proteins is lost. These data suggest that the tlt and mlh mutations primarily affect the localization of Otop1, which interferes with its ability to interact with other proteins that are important for its cellular and biochemical function. PMID- 21236345 TI - An APPL1/Akt signaling complex regulates dendritic spine and synapse formation in hippocampal neurons. AB - The formation and plasticity of dendritic spines and synapses, which are poorly understood on a molecular level, are critical for cognitive functions, such as learning and memory. The adaptor protein containing a PH domain, PTB domain, and leucine zipper motif (APPL1) is emerging as a critical regulator of various cellular processes in non-neuronal cells, but its function in the nervous system is not well understood. Here, we show that APPL1 localizes to dendritic spines and synapses and regulates the development of these structures in hippocampal neurons. Knockdown of endogenous APPL1 using siRNA led to a significant decrease in the number of spines as well as synapses and this defect could be rescued by expression of siRNA-resistant APPL1. Expression of exogenous APPL1 increased the spine and synaptic density and the amount of surface GluR1-containing alpha-amino 3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). Deletion of the C-terminal phosphotyrosine binding domain of APPL1, which binds the serine/threonine kinase Akt, resulted in a significant decrease in the spine and synaptic density, suggesting a role for Akt in regulating the development of these structures. Consistent with this, knockdown of Akt with siRNA or expression of dominant negative Akt led to a dramatic decrease in spine and synapse formation. In addition, APPL1 increased the amount of active Akt in spines and synapses and the effects of APPL1 on these structures were dependent on Akt, indicating that Akt is an effector of APPL1 in the regulation of these processes. Moreover, APPL1 signaling modulates spine and synapse formation through p21 activated kinase (PAK). Thus, our results indicate that APPL1 signaling through Akt and PAK is critical for spine and synaptic development and point to a role for APPL1 and its effectors in regulating cognitive function. PMID- 21236347 TI - Differential subcellular distribution of rat brain dopamine receptors and subtype specific redistribution induced by cocaine. AB - We investigated the subcellular distribution of dopamine D(1), D(2) and D(5) receptor subtypes in rat frontal cortex, and examined whether psychostimulant induced elevation of synaptic dopamine could alter the receptor distribution. Differential detergent solubilization and density gradient centrifugation were used to separate various subcellular fractions, followed by semi-quantitative determination of the relative abundance of specific receptor proteins in each fraction. D(1) receptors were predominantly localized to detergent-resistant membranes, and a portion of these receptors also floated on sucrose gradients. These properties are characteristic of proteins found in lipid rafts and caveolae. D(2) receptors exhibited variable distribution between cytoplasmic, detergent-soluble and detergent-resistant membrane fractions, yet were not present in buoyant membranes. Most D(5) receptor immunoreactivity was distributed into the cytoplasmic fraction, failing to sediment at forces up to 300,000g, while the remainder was localized to detergent-soluble membranes in cortex. D(5) receptors were undetectable in detergent-resistant fractions or raft-like subdomains. Following daily cocaine administration for seven days, a significant portion of D(1) receptors translocated from detergent-resistant membranes to detergent-soluble membranes and the cytoplasmic fraction. The distributions of D(5) and D(2) receptor subtypes were not significantly altered by cocaine treatment. These data imply that D(5) receptors are predominantly cytoplasmic, D(2) receptors are diffusely distributed within the cell, whereas D(1) receptors are mostly localized to lipid rafts within the rat frontal cortex. Dopamine receptor subtype localization is susceptible to modulation by pharmacological manipulations that elevate synaptic dopamine, however the functional implications of such drug-induced receptor warrant further investigation. PMID- 21236348 TI - Auditory cortex activation is modulated by emotion: a functional near-infrared spectroscopy (fNIRS) study. AB - Visual emotional stimuli evoke enhanced activation in early visual cortex areas which may help organisms to quickly detect biologically salient cues and initiate appropriate approach or avoidance behavior. Functional neuroimaging evidence for the modulation of other sensory modalities by emotion is scarce. Therefore, the aim of the present study was to test whether sensory facilitation by emotional cues can also be found in the auditory domain. We recorded auditory brain activation with functional near-infrared-spectroscopy (fNIRS), a non-invasive and silent neuroimaging technique, while participants were listening to standardized pleasant, unpleasant, and neutral sounds selected from the International Affective Digitized Sound System (IADS). Pleasant and unpleasant sounds led to increased auditory cortex activation as compared to neutral sounds. This is the first study to suggest that the enhanced activation of sensory areas in response to complex emotional stimuli is apparently not restricted to the visual domain but is also evident in the auditory domain. PMID- 21236349 TI - Multimodal classification of Alzheimer's disease and mild cognitive impairment. AB - Effective and accurate diagnosis of Alzheimer's disease (AD), as well as its prodromal stage (i.e., mild cognitive impairment (MCI)), has attracted more and more attention recently. So far, multiple biomarkers have been shown to be sensitive to the diagnosis of AD and MCI, i.e., structural MR imaging (MRI) for brain atrophy measurement, functional imaging (e.g., FDG-PET) for hypometabolism quantification, and cerebrospinal fluid (CSF) for quantification of specific proteins. However, most existing research focuses on only a single modality of biomarkers for diagnosis of AD and MCI, although recent studies have shown that different biomarkers may provide complementary information for the diagnosis of AD and MCI. In this paper, we propose to combine three modalities of biomarkers, i.e., MRI, FDG-PET, and CSF biomarkers, to discriminate between AD (or MCI) and healthy controls, using a kernel combination method. Specifically, ADNI baseline MRI, FDG-PET, and CSF data from 51AD patients, 99 MCI patients (including 43 MCI converters who had converted to AD within 18 months and 56 MCI non-converters who had not converted to AD within 18 months), and 52 healthy controls are used for development and validation of our proposed multimodal classification method. In particular, for each MR or FDG-PET image, 93 volumetric features are extracted from the 93 regions of interest (ROIs), automatically labeled by an atlas warping algorithm. For CSF biomarkers, their original values are directly used as features. Then, a linear support vector machine (SVM) is adopted to evaluate the classification accuracy, using a 10-fold cross-validation. As a result, for classifying AD from healthy controls, we achieve a classification accuracy of 93.2% (with a sensitivity of 93% and a specificity of 93.3%) when combining all three modalities of biomarkers, and only 86.5% when using even the best individual modality of biomarkers. Similarly, for classifying MCI from healthy controls, we achieve a classification accuracy of 76.4% (with a sensitivity of 81.8% and a specificity of 66%) for our combined method, and only 72% even using the best individual modality of biomarkers. Further analysis on MCI sensitivity of our combined method indicates that 91.5% of MCI converters and 73.4% of MCI non-converters are correctly classified. Moreover, we also evaluate the classification performance when employing a feature selection method to select the most discriminative MR and FDG-PET features. Again, our combined method shows considerably better performance, compared to the case of using an individual modality of biomarkers. PMID- 21236350 TI - Molecular phylogeny of tribe Rhipsalideae (Cactaceae) and taxonomic implications for Schlumbergera and Hatiora. AB - Tribe Rhipsalideae is composed of unusual epiphytic or lithophytic cacti that inhabit humid tropical and subtropical forests. Members of this tribe present a reduced vegetative body, a specialized adventitious root system, usually spineless areoles and flowers and fruits reduced in size. Despite the debate surrounding the classification of Rhipsalideae, no studies have ever attempted to reconstruct phylogenetic relationships among its members or to test the monophyly of its genera using DNA sequence data; all classifications formerly proposed for this tribe have only employed morphological data. In this study, we reconstruct the phylogeny of Rhipsalideae using plastid (trnQ-rps16, rpl32-trnL, psbA-trnH) and nuclear (ITS) markers to evaluate the classifications previously proposed for the group. We also examine morphological features traditionally used to delimit genera within Rhipsalideae in light of the resulting phylogenetic trees. In total new sequences for 35 species of Rhipsalideae were produced (out of 55; 63%). The molecular phylogeny obtained comprises four main clades supporting the recognition of genera Lepismium, Rhipsalis, Hatiora and Schlumbergera. The evidence gathered indicate that a broader genus Schlumbergera, including Hatiora subg. Rhipsalidopsis, should be recognized. Consistent morphological characters rather than homoplastic features are used in order to establish a more coherent and practical classification for the group. Nomenclatural changes and a key for the identification of the genera currently included in Rhipsalideae are provided. PMID- 21236353 TI - The quaternary hemoglobin conformation regulates the formation of the nitrite induced bioactive intermediate and the dissociation of nitric oxide from this intermediate. AB - Deoxyhemoglobin reduces nitrite to nitric oxide (NO). In order to study the effect of the hemoglobin quaternary conformation on the nitrite reaction, we compared T-state deoxyhemoglobin with R-state deoxyhemoglobin produced by reacting hemoglobin with carboxypeptidase-A prior to deoxygenation. The nitrite reaction with deoxyhemoglobin was followed by chemiluminescence, electron paramagnetic resonance and visible spectroscopy. The initial steps in this reaction involve the binding of nitrite to deoxyhemoglobin followed by the formation of an electron delocalized metastable intermediate that retains potential NO bioactivity. This reaction is shown by visible spectroscopy to occur 5.6 times faster in the R-state than in the T-state. However, the dissociation of NO from the delocalized intermediate is shown to be facilitated by the T quaternary conformation with a 9.6 fold increase in the rate constant. The preferred NO-release in the T-state, which has a higher affinity for the membrane, can result in the NO diffusing out of the RBC and being released to the vasculature at low partial pressures of oxygen. PMID- 21236354 TI - Curcumin-induced inhibition of proteasomal activity, enhanced HSP accumulation and the acquisition of thermotolerance in Xenopus laevis A6 cells. AB - In the present study, curcumin, a phenolic compound with anti-inflammatory, anti tumor and anti-amyloid properties, inhibited proteasomal activity and induced the accumulation of HSPs in the frog model system, Xenopus laevis. Treatment of A6 kidney epithelial cells with curcumin enhanced ubiquitinated protein levels and inhibited chymotrypsin-like activity. Furthermore, exposure of cells to 10-50 MUM curcumin for 24h induced HSP30 and HSP70 accumulation. This phenomenon was controlled at the transcriptional level since pre-treatment of cells with KNK437, a heat shock factor 1 (HSF1) inhibitor, repressed HSP accumulation. Additionally, elevation of the incubation temperature from 22 to 30 degrees C greatly enhanced the curcumin-induced accumulation of HSP30 and HSP70. Immunocytochemical analysis revealed that curcumin-induced HSP30 was detectable primarily in the cytoplasm in a punctate pattern with minimal detrimental effects on the actin cytoskeleton. Finally, prior exposure of cells to curcumin conferred a state of thermotolerance since it protected them against a subsequent cytotoxic thermal challenge. These findings are of importance given the interest in identifying agents that can upregulate HSP levels with minimal effects on cell structure or function as a therapeutic treatment of protein folding diseases. PMID- 21236355 TI - Stability and analysis of eicosanoids and docosanoids in tissue culture media. AB - Bioactive lipids derived from polyunsaturated fatty acids constitute an important set of lipid mediators with diverse homeostatic and pathophysiological activities. The role of bioactive lipids in inflammation, active resolution of inflammation, reproduction, cardiovascular biology, chronic diseases such as cancer and metabolic disorders is an active area of research. Other than the few clinically used eicosanoids such as prostaglandin F(2)alpha, prostacyclin, and prostaglandin E(2), little is known about the stability of a majority of the bioactive lipids in aqueous solutions despite their extensive use under in vitro experimental conditions. The present study evaluated the stability of eicosanoids and docosanoids as well as their parent polyunsaturated fatty acids in tissue culture media with respect to incubation time, temperature, and composition of the media using multiple reaction monitoring (MRM) LC-MS. The results provide a comprehensive and valuable data set on the stability of these bioactive lipid mediators to guide in vitro experimentation. PMID- 21236352 TI - Bidirectional metabolic regulation of neurocognitive function. AB - The efficiency of somatic energy metabolism is correlated with cognitive change over the lifespan. This relationship is bidirectional, with improved overall fitness associated with enhanced synaptic function and neuroprotection, and synaptic endangerment occurring in the context of impaired energy metabolism. In this review, we discuss recent advancements in the fields of exercise, dietary energy intake and diabetes, as they relate to neuronal function in the hippocampus. Because hippocampal neurons have energy requirements that are relatively higher than those of other brain regions, they are uniquely poised to benefit from exercise, and to be harmed by diabetes. We view exercise and dietary energy restriction as being associated with enhanced hippocampal plasticity at one end of a continuum, with obesity and diabetes accompanied by cognitive impairment at the other end of the continuum. Understanding the mechanisms for this continuum may yield novel therapeutic targets for the prevention and treatment of cognitive decline following aging, disease, or injury. PMID- 21236356 TI - Evidence for the presence of a critical disulfide bond in the mouse EP3gamma receptor. AB - To determine the contribution of cysteines to the function of the mouse E prostanoid subtype 3 gamma (mEP3gamma), we tested a series of cysteine-to-alanine mutants. Two of these mutants, C107A and C184A, showed no agonist-dependent activation in a cell-based reporter assay for mEP3gamma, whereas none of the other cysteine-to-alanine mutations disrupted mEP3gamma signal transduction. Total cell membranes prepared from HEK293 cells transfected with mEP3gamma C107A or C184A had no detectable radioligand binding. Other mutant mEP3gamma receptors had radioligand affinities and receptor densities similar to wild-type. Cell surface ELISA against the N-terminal HA-tag of C107A and C184A demonstrated 40% and 47% reductions respectively in receptor protein expression at the cell surface, and no radioligand binding was detected as assessed by intact cell radioligand binding experiments. These data suggest a key role for C107 and C184 in both receptor structure/stability and function and is consistent with the presence of a conserved disulfide bond between C107 and C184 in mouse EP3 that is required for normal receptor expression and function. Our results also indicate that if a second disulfide bond is present in the native receptor it is non essential for receptor assembly or function. PMID- 21236357 TI - Niacin promotes adipogenesis by reducing production of anti-adipogenic PGF2alpha through suppression of C/EBPbeta-activated COX-2 expression. AB - Niacin is converted to NAD and NADP in tissues, whose products are involved in a number of cellular processes; and it is associated with the regulation of adipogenesis. In this study, we identified the molecular mechanism by which niacin promotes the adipogenesis in mouse 3T3-L1 cells. When the cells were cultured with niacin, the expression of adipogenic peroxisome proliferator activated receptor gamma, CCAAT enhancer binding protein (C/EBP)alpha, and their target genes was enhanced concomitant with an increase in triglyceride storage. Moreover, niacin suppressed the expression of cyclooxygenase-2 and decreased the production of prostaglandin (PG) F(2alpha) in the early phase of adipogenesis, which PG suppresses the progression of adipogenesis via the PGF(2alpha) receptor. Furthermore, niacin decreased the C/EBPbeta level in the early phase of adipogenesis. These results indicate that niacin promoted adipogenesis by suppressing the production of the anti-adipogenic PGF(2alpha) through down regulation of C/EBPbeta-activated cyclooxygenase-2 expression in adipocytes. PMID- 21236358 TI - Analysis of omega-3 and omega-6 fatty acid-derived lipid metabolite formation in human and mouse blood samples. AB - Mass spectrometry techniques have enabled the identification of different lipid metabolites and mediators derived from omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFA) that are implicated in various biological processes. However, the broad-spectrum assessment of physiologically formed lipid metabolites and mediators in blood samples has not been presented so far. Here lipid mediators and metabolites of the n-6 PUFA arachidonic acid as well as the long-chain n-3 PUFA eicosapentaenoic acids (EPA) and docosahexaenoic acid (DHA) were measured in human blood samples as well as in mouse blood. There were detectable but mostly very low amounts of the assayed compounds in human native plasma samples, whereas in vitro activation of whole blood with the calcium ionophore A23187 led to highly significant increases of metabolite formation, with a predominance of the 12-lipoxygenase (12-LOX) products 12 hydroxyeicosatetraenoic acid (12-HETE), 12-hydroxyeicosapentaenoic acid (12-HEPE) and 14-hydroxydocosahexaenoic acid (14-HDHA). A23187 activation also led to significant increases in the formation of 5-LOX products including leukotriene B(4) (LTB(4)), leukotriene B(5) (LTB(5)) as well as of 15-LOX products and prostaglandin E(2) (PGE(2)) and thromboxane B(2) (TXB(2)). Levels were similar or even higher in A23187-activated mouse blood. The approach presented here thus provides a protocol for the comprehensive and concomitant assessment of the generation capacity of n-3 and n-6 PUFA-derived lipid metabolites as well as thromboxanes and prostaglandins in human and murine blood samples. Further studies will now have to evaluate lipid metabolite generation capacity in different physiological and pathophysiological contexts. PMID- 21236359 TI - Ceramide induces serotonin release from RBL-2H3 mast cells through calcium mediated activation of phospholipase A2. AB - Ceramide has been suggested to function as a mediator of exocytosis in response to the addition of a calcium ionophore from PC12 cells. Here, we show that although cell-permeable C(6)-ceramide or a calcium ionophore alone did not increase either the degranulation of serotonin or the release of arachidonic acid (AA) from RBL-2H3 cells, their combined effect significantly stimulated these processes in a time- and dose-dependent manner. This effect was inhibited by the presence of an exogenous calcium chelator and significantly suppressed by the CERK inhibitor (K1) and phospholipase A(2) (PLA(2)) inhibitors. Moreover, cytosolic PLA(2) GIVA (cPLA(2) GIVA) siRNA-transfected RBL-2H3 cells showed a lower level of serotonin release than scramble siRNA-transfected cells. Little is known about the regulation of degranulation proximal to the activation of cytosolic phospholipase A(2) GIVA, the initial rate-limiting step in RBL-2H3 cells. In this study, we suggest that CERK, ceramide-1-phosphate, and PLA(2) are involved in degranulation in a calcium-dependent manner. Inhibition of p44/p42 mitogen-activated protein kinase partially decreased the AA release, but did not affect degranulation. Furthermore, treatment of the cells with AA (omega-6, C20:4), not linoleic acid (omega-6, C18:2) or alpha-linolenic acid (omega-6, C18:3), induced degranulation. Taken together, these results suggest that ceramide is involved in mast cell degranulation via the calcium-mediated activation of PLA(2). PMID- 21236360 TI - Transseptal access for pulmonary vein isolation in a patient with atrial septal closure device: use of electrocautery and atrial septostomy. PMID- 21236361 TI - Venoplasty: new use for an old technique. PMID- 21236362 TI - Management and outcomes of cardiac tamponade during atrial fibrillation ablation in the presence of therapeutic anticoagulation with warfarin. AB - BACKGROUND: Cardiac tamponade (CT) is a possible complication of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF). Although the incidence of CT is not higher when RFCA is performed with a therapeutic international normalized ratio (INR), outcomes of CT are unclear. OBJECTIVE: We compared outcomes among patients with and without a therapeutic INR who developed CT as a complication of RFCA of AF. METHODS: The subjects of this retrospective study were 40 consecutive patients who developed CT during RFCA of AF at 3 centers. We divided the patients into 2 groups: RFCA performed with INR < 2 (group 1) and INR >= 2 (group 2). There were 23 patients in group 1 and 17 patients in group 2. RESULTS: Baseline clinical and procedure characteristics were not different between the 2 groups. Heparin was reversed by protamine in 83% and 94% of patients (P = .37), and warfarin was reversed by fresh frozen plasma or factor VIIa in 17% and 35% of patients (P = .27) in groups 1 and 2, respectively. All patients were successfully treated by percutaneous drainage, and none required surgical intervention. There were no significant differences in the amount of initial pericardial drainage (523 +/- 349 ml vs. 409 +/- 157 ml, P = .22) or the duration of drainage (P = .14) between the 2 groups. All patients survived to hospital discharge. Median length of hospital stay was 2 days longer in group 1 (P <.01). CONCLUSION: Cardiac tamponade is not more severe or difficult to manage in the presence of therapeutic anticoagulation with warfarin in patients undergoing RFCA of AF. PMID- 21236363 TI - Feasibility of catheter ablation of mitral annular flutter in patients with prior mitral valve surgery. AB - BACKGROUND: Mitral annular flutter (MAF) may occur after ablation of atrial fibrillation in patients with prior mitral valve (MV) replacement or repair. Percutaneous catheter ablation may be challenging owing to the presence of surgical scar and a prosthetic MV. OBJECTIVE: We examined the feasibility of and outcome after mitral isthmus ablation in patients with prior MV surgery. METHODS: Twenty-one consecutive patients (18 males, age 61 +/- 10 years) with a history of MV surgery (nine replacement, 12 repair with annuloplasty ring) underwent catheter ablation of clinical (n = 17) or easily inducible (n = 4) MAF (group 1). Patients were matched for age, gender, and ejection fraction, with 21 patients undergoing MAF ablation without prior MV surgery (group 2). Irrigated ablation was delivered endocardially in a linear fashion from the MV to the left inferior and/or to the right superior pulmonary vein and, when required, epicardially inside the coronary sinus. Isolation of all pulmonary veins was also performed. RESULTS: There was no difference in termination of tachycardia during ablation (group 1 vs. group 2; 86% vs. 71%; P = .454), achieving mitral isthmus block (71% vs. 71%; P = 1.000), or need for epicardial ablation (43% vs. 62%; P = .354) between groups. No complications occurred in either group. After a mean follow-up of 7 +/- 4 months, 15 (71%) patients in group 1 and 14 (67%) in group 2 had no recurrence of atrial arrhythmias. CONCLUSIONS: Percutaneous mitral isthmus ablation is feasible and safe in patients with prior MV replacement or repair and has comparable outcomes to patients without prior MV surgery. PMID- 21236364 TI - The evolution of gene discovery and the revelation of truth. PMID- 21236365 TI - Esophageal temperature change and esophageal thermal lesions after pulmonary vein isolation using the novel endoscopic ablation system. AB - BACKGROUND: Pulmonary vein isolation (PVI) is an established treatment option for paroxysmal atrial fibrillation. Recently, a novel endoscopic ablation system (EAS) was introduced. The incidence and severity of ablation-induced esophageal thermal lesions (ETLs) are unknown. OBJECTIVE: The purpose of this study was to investigate the incidence and severity of ablation-induced ETLs. METHODS: This prospective analysis compared two groups: group A underwent EAS-based PVI, and group B received PVI using radio frequency current (RFC). If esophageal temperature measured via an endoluminal temperature probe exceeded 38.5 degrees C, energy application was stopped immediately. Endoscopy was performed 2 days postablation. RESULTS: Forty patients (20 female, mean age 56 +/- 10 years) were treated with the EAS system (group A). In 20 patients (seven female, mean age 63 +/- 9 years) RFC-based PVI was performed (group B). Esophageal endoscopy was performed 2.1 +/- 0.8 (group A) and 2.8 +/- 1.2 days postablation (group B), respectively. In 7/40 patients (18%) in group A, thermal lesions (four thermal ulcerations, three minimal thermal lesions) were detected. In group B, 3/20 patients (15%) displayed thermal lesions (three minimal thermal lesions). All thermal lesions resolved upon repeat endoscopy performed 8 +/- 6 (group A) and 5 +/- 1 days (group B) after initial endoscopy. CONCLUSION: In the EAS group, ETLs were found in 18% of patients, as compared with in 15% in the RFC group. In patients with ETLs, ulcerations were found in 57% in the EAS group, as compared with 0% in the RFC group. This may indicate that the quality of thermal lesions is more severe in the EAS group. Further investigation is required. PMID- 21236366 TI - Airway epithelium mediates the anti-inflammatory effects of exercise on asthma. AB - Airway epithelium plays an important role in the asthma physiopathology. Aerobic exercise decreases Th2 response in murine models of allergic asthma, but its effects on the structure and activation of airway epithelium in asthma are unknown. BALB/c mice were divided into control, aerobic exercise, ovalbumin sensitized and ovalbumin-sensitized plus aerobic exercise groups. Ovalbumin sensitization occurred on days 0, 14, 28, 42, and aerosol challenge from day 21 to day 50. Aerobic exercise started on day 22 and ended on day 50. Total cells and eosinophils were reduced in ovalbumin-sensitized group submitted to aerobic exercise. Aerobic exercise also reduced the oxidative and nitrosative stress and the epithelial expression of Th2 cytokines, chemokines, adhesion molecules, growth factors and NF-kB and P2X7 receptor. Additionally, aerobic exercise increased the epithelial expression of IL-10 in non-sensitized and sensitized animals. These findings contribute to the understanding of the beneficial effects of aerobic exercise for chronic allergic airway inflammation, suggesting an immune-regulatory role of exercise on airway epithelium. PMID- 21236367 TI - Osmoprotective proteome adjustments in mouse kidney papilla. AB - The papilla of the mammalian kidney must tolerate greatly varying degrees of hyperosmotic stress during urine concentration and depending on whole organism hydration state. To identify proteome adaptations supporting cell function and survival in such a harsh environment we compared the proteome of a) the hyperosmotic renal papilla with that of adjacent iso-osmotic cortex tissue and b) the renal papilla of diuretic versus that of anti-diuretic mice. Though functionally distinct the papilla is in close physical proximity to the renal cortex, an iso-osmotic region. Proteomic differences between the papilla and cortex of C57BL6 mice were identified using two-dimensional gel electrophoresis and MALDI-TOF/TOF mass spectrometry. We found 37 different proteins characteristic of the cortex and 16 proteins over-represented in the papilla. Regional specificity was confirmed by Western blot and further substantiated by immunohistochemistry for selected proteins. Proteins that are characteristic of the renal papilla include alphaB crystallin, Hsp beta-1, Hsp90, 14-3-3 protein, glutathione S-transferase, aldose reductase, actin and tropomyosin. Gene ontology analysis confirmed a significant increase in molecular functions associated with protein chaperoning and cell stabilization. Proteins over-represented in the cortex were largely related to routine metabolism. During antidiuresis 15 different proteins changed significantly while 18 different proteins changed significantly during diuresis relative to normally hydrated controls. Changes were confirmed by Western blot for selected proteins. Proteins that are significantly altered by diuretic state are associated with cell structure (actin, tubulin), signaling (Rho GDP dissociation inhibitor, abhydrolase domain containing protein 14B), chaperone functioning (Hsp beta-1, alphaB crystallin, T complex protein-1) and anti-oxidant functions (alpha-enolase, GAPDH and LDH). Taken together our study reveals that specific proteins involved in protein folding, cytoskeletal stabilization, antioxidant responses, and stress signaling contribute greatly to the unique hyperosmotic stress resistant phenotype of the kidney papilla. PMID- 21236368 TI - Surface characteristics of acrylic modified polysulfone membranes improves renal proximal tubule cell adhesion and spreading. AB - Current polyvinylpyrrolidone-modified polysulfone (PVP-PSU) membranes in haemodialysers do not facilitate the attachment and proliferation of renal proximal tubule cells (RPTCs). For bioartificial kidney (BAK) development expensive extracellular matrices are employed to ensure the PVP-PSU membranes can serve as a substrate for RPTCs. In this study we modified PSU using an acrylic monomer (am-PSU) and polymerization using ultraviolet irradiation. We demonstrated that on adjusting the PSU or acrylic content of the membranes the wettability and surface chemistry were altered, and this affected the amount of fibronectin (Fn) that was adsorbed onto the membranes. Using an integrin blocking assay we ascertained that Fn is an important extracellular matrix component that mediates RPTC attachment. The amount of Fn adsorbed also led to different bioresponses of RPTCs, which were evaluated using attachment and proliferation assays and qualitative quantification of vinculin, focal adhesion kinase, zonula occludens and Na(+)/K(+) ATPase. Our optimized membrane, am-PSU1 (21.4% C-O groups, 19.1% PVP-PSU; contact angle 71.5-80.80, PVP-PSU: 52.4-67.50), supports a confluent monolayer of RPTCs and prevents creatinine and inulin diffusion from the apical to the basal side, meeting the requirements for application in BAKs. However, further in vivo evaluation to assess the full functionality of RPTCs on am-PSU1 is required. PMID- 21236370 TI - Safety of bisphosphonates. AB - Bisphosphonates are one of the most well studied groups of medications and they are bone specific. This tissue specificity is a rare property for a drug introduced into clinical practice as long as 40 years ago. Over the years, the therapeutic boundaries of bisphosphonates were explored and their safety profile has withstood the challenges of the harsh clinical reality and widespread use. Certainly, the esophageal or gastric irritation caused by the oral preparations is an established adverse effect, the risk of which can be reduced by the recommended routine of taking the medication. From the other reported associations with adverse events, osteonecrosis of the jaw (ONJ) and subtrochanteric fractures have attracted most of the attention mainly because their pathophysiology remains unclear. However, overall, only a very small proportion of patients treated with bisphosphonates, especially with the oral formulations, experience adverse events and the overall benefits have consistently outweighed their potential risks. Furthermore, bisphosphonates improve the quality of life in patients with metastatic bone cancer and delay the development of adverse skeletal effects. PMID- 21236371 TI - Fractured lives: you can make a bigger difference. PMID- 21236369 TI - Synthesis of metal ion-histidine complex functionalized mesoporous silica nanocatalysts for enhanced light-free tooth bleaching. AB - Several metal ion-histidine complex functionalized mesoporous silica nanoparticles (MSN) were synthesized and utilized as efficient catalysts for enhanced and light-free tooth bleaching. Fe(II), Mn(II), and Cu(II) ions were successfully immobilized in histidine-functionalized MSN and their catalytic abilities against discoloration of a dye (Orange II) in both test tubes and extracted tooth models were compared and discussed. Through direct observation of test tubes and calculation of mean color changes of extracted teeth we concluded that Fe(II)-his-MSN exhibited better catalytic competence than Mn(II)-his-MSN and Cu(II)-his-MSN because of its intrinsic redox ability. In test tubes Orange II was completely degraded within 6 h when Fe(II)-his-MSN was used as the catalyst. For the extracted tooth model the presence of Fe(II)- or Mn(II)-his-MSN significantly enhanced the efficacy of tooth bleaching for three regions, the enamel, outer dentin, and inner dentin, of stained teeth compared with H(2)O(2) alone. Furthermore, unlike current tooth bleaching techniques that need an LED or laser to catalyze H(2)O(2) bleaching, we demonstrated a light-free tooth bleaching system using Fe(II)-his-MSN as an efficient and reliable catalyst. PMID- 21236373 TI - To intubate or not to intubate? PMID- 21236374 TI - To intubate or not to intubate? PMID- 21236375 TI - Paradigm shift. PMID- 21236376 TI - Why Wait? EMS managers can proactively reduce ED delays. PMID- 21236377 TI - Pop quiz: do you know how to test your students? PMID- 21236378 TI - Back from the factory: modified ambulance makes its debut. PMID- 21236379 TI - Crisis averted: recognize the symptoms of Addison's disease. PMID- 21236381 TI - The future is now: how advanced automatic collision notification can assist in the early response, triage & care of injured patients. PMID- 21236382 TI - Unseen threats: preparing for a biological or nuclear event. PMID- 21236383 TI - Painful distractions: the importance of splinting & managing the pain associated with fractures. PMID- 21236384 TI - Toolbox trauma: power tools aren't for everyone. PMID- 21236385 TI - Preface. Immunodeficiency from two different angles. PMID- 21236386 TI - A history of bone marrow transplantation. AB - The last 40 years has seen the emergence of hematopoietic stem cell transplantation as a therapeutic modality for fatal diseases and as a curative option for individuals born with inherited disorders that carry limited life expectancy and poor quality of life. Despite the rarity of many primary immunodeficiency diseases, these disorders have led the way toward innovative therapies and further provide insights into mechanisms of immunologic reconstitution applicable to all hematopoietic stem cell transplants. This article represents a historical perspective of the early investigators and their contributions. It also reviews the parallel work that oncologists and immunologists have undertaken to treat both primary immunodeficiencies and hematologic malignancies. PMID- 21236387 TI - Hematopoietic stem cell transplantation for severe combined immune deficiency or what the children have taught us. AB - It is now more than 40 years since the first successful allogeneic hematopoietic stem cell transplantation (HSCT) for a child with severe combined immunodeficiency (SCID). In the succeeding years, HSCT for SCID patients have represented only a small portion of the total number of allogeneic HSCT performed. Nevertheless, the clinical and biologic importance of the patients transplanted for SCID has continued. SCID patients were the first to be successfully transplanted with nonsibling related bone marrow, unrelated bone marrow, T-cell depleted HSCT, and genetically corrected (gene transfer) autologous HSC. Many of the biologic insights now widely applied to allogeneic HSCT were first identified in the transplantation of SCID patients. This article reviews the clinical and biologic lessons that have been learned from HSCT for SCID patients, and how the information has impacted the general field of allogeneic HSCT. PMID- 21236388 TI - HLA-haploidentical donor transplantation in severe combined immunodeficiency. AB - Curative treatment of Severe Combined Immunodeficiency (SCID) by Hematopoietic Cell Transplantation (HCT) remains a challenge, in particular in infants presenting with serious, poorly controllable complications. In the absence of a matched family donor, HLA-haploidentical transplantation from parental donors represents a uniformly and readily available treatment option, offering a high chance to be successful. Concerning outcomes of HCT in SCID, other important parameters beside survival need to be taken into consideration, in particular the stability and robustness of the graft and its function, as well as potential late complications, related either to the disease or to the treatment. PMID- 21236389 TI - Haploidentical bone marrow transplantation in primary immune deficiency: stem cell selection and manipulation. AB - Since the early 1980s T-cell depletion has allowed haploidentical bone marrow transplantation to be performed in patients with primary immunodeficiency for whom a matched sibling donor was not available, without causing severe graft versus host disease (GVHD). This review article presents the available data in the literature on survival, GVHD, and immune reconstitution in different categories of patients, with special emphasis on the impact of different T-cell depletion methods. PMID- 21236390 TI - Bone marrow transplantation using HLA-matched unrelated donors for patients suffering from severe combined immunodeficiency. AB - Severe combined immunodeficiency (SCID) is fatal in infancy unless corrected with allogeneic bone marrow transplants (BMT), preferably from a family-related genotypically HLA-identical donor (RID) or phenotypically HLA-matched family donor (PMD). For the majority of SCID patients, such donors are not available; Therefore, parents who are HLA-haploidentical donors (HID) or HLA-matched unrelated donors (MUD) have been used. MUD BMT are associated with increased frequency of acute graft versus host disease, which can be controlled by high doses of steroids. HID BMT are associated with increased frequency of short- and long-term graft failure, need for repeated transplants, fatal pneumonitis, impaired immune reconstitution, and long-term complications, contributing to lower survival. In conclusion, the excellent long-term survival, immune reconstitution, and normal quality of life after MUD BMT suggests that in the absence of RID or PMD, MUD BMT should be offered for patients suffering from SCID. PMID- 21236392 TI - Gene therapy for primary immunodeficiencies. AB - The concept of gene therapy emerged as a way of correcting monogenic inherited diseases by introducing a normal copy of the mutated gene into at least some of the patients' cells. Although this concept has turned out to be quite complicated to implement, it is in the field of primary immunodeficiencies (PIDs) that proof of feasibility has been undoubtedly achieved. There is now a strong rationale in support of gene therapy for at least some PIDs, as discussed in this article. PMID- 21236391 TI - Purified hematopoietic stem cell transplantation: the next generation of blood and immune replacement. AB - Replacement of disease-causing stem cells with healthy ones has been achieved clinically via hematopoietic cell transplantation (HCT) for the last 40 years, as a treatment modality for a variety of cancers and immunodeficiencies with moderate, but increasing, success. This procedure has traditionally included transplantation of mixed hematopoietic populations that include hematopoietic stem cells (HSC) and other cells, such as T cells. This article explores and delineates the potential expansion of this technique to treat a variety of inherited diseases of immune function, the current barriers in HCT and pure HSC transplantation, and the up-and-coming strategies to combat these obstacles. PMID- 21236393 TI - Hematopoietic stem cell transplantation: an overview of infection risks and epidemiology. AB - Hematopoietic stem cell transplantation (HSCT) is a treatment for multiple medical conditions that result in bone marrow failure and as an antineoplastic adoptive immunotherapy for hematologic malignancies. HSCT is associated with profound compromises in host barriers and all arms of innate and acquired immunity. The degree of immune compromise varies by type of transplant and over time. Immune reconstitution occurs within several months after autologous HSCT but takes up to a year or longer after allogeneic HSCT. In those patients who develop chronic graft-versus-host disease, immune reconstitution may take years or may never completely develop. Over time, with strengthening immune reconstitution and control of graft-versus-host disease, the risk for infection dissipates. PMID- 21236394 TI - Infectious complications associated with immunomodulating biologic agents. AB - The armamentarium of biologic therapies targeting specific elements of the immune system is rapidly expanding. This review describes the spectrum of infectious complications associated to date with each of the immunomodulating biologic therapies approved by the US Food and Drug Administration. PMID- 21236395 TI - Infections in pediatric transplant recipients: not just small adults. AB - Transplantation increasingly is being used as treatment for children with end stage organ diseases, hematopoietic rescue from therapy used to treat malignancies, and as cure for primary immune deficiencies. This article reviews some of the major concepts regarding infections that complicate pediatric transplantation, highlighting differences in epidemiology, evaluation, treatment and prevention for children compared with adult recipients. PMID- 21236397 TI - Herpes viruses in transplant recipients: HSV, VZV, human herpes viruses, and EBV. AB - The herpes viruses are responsible for a wide range of diseases in patients following transplant, resulting from direct viral effects and indirect effects, including tumor promotion. Effective treatments and prophylaxis exist for the neurotropic herpes viruses HSV-1, HSV-2, varicella zoster virus, and possibly HHV 6. Antivirals seem to be less effective at prevention of the tumor-promoting effects of Epstein-Barr virus and HHV-8. Reduction in immunosuppression is the cornerstone to treatment of many diseases associated with herpes virus infections. PMID- 21236398 TI - Fungal infections in transplant and oncology patients. AB - Recent shifts in the epidemiology of invasive fungal infections (IFIs) among transplant and oncology populations have led to new recommendations on treatment; however, they have also brought new controversies. New pharmacologic therapies are being studied and guidelines for management of several IFIs have been changed accordingly. More information is being discovered about unique genetic factors that put some transplant recipients at greater risk than others for fungal infection. The role of immunomodulation continues to be investigated, and the delicate balance of maintaining some immune integrity while assuring protection of the graft remains critical. For transplant and oncology patients, the diagnosis and management of IFIs remain challenging, and improving outcomes depends on continued progress in all of these arenas. This article highlights recent advances and important factors to consider when treating transplant and oncology patients with IFIs. PMID- 21236396 TI - Cytomegalovirus in hematopoietic stem cell transplant recipients. AB - This article examines the clinical manifestations of and risk factors for cytomegalovirus (CMV). Prevention of CMV infection and disease are also explored. Antiviral resistance and management of CMV are examined. PMID- 21236399 TI - Immunotherapy and vaccination after transplant: the present, the future. AB - Vaccination and adoptive immunotherapy for herpes virus infections has become an attractive option for the control of a virus family that negatively affects transplantation. In the future, enhanced ability to select antigen-specific T cells without significant in vitro manipulation should provide new opportunities for refining and enhancing adoptive immunotherapeutic approaches. This article focuses on advances in the area of vaccinology for some of these infections and in the use of adoptive immunotherapy. At present, many of these approaches in transplant recipients have focused on infections such as human cytomegalovirus, but the opportunity to use these examples as proof of concept for other infections is discussed. PMID- 21236400 TI - The role of bile salts in digestion. AB - Bile salts (BS) are bio-surfactants present in the gastrointestinal tract (GIT) that play a crucial role in the digestion and absorption of nutrients. The importance of BS for controlled release and transport of lipid soluble nutrients and drugs has recently stimulated scientific interest in these physiological compounds. BS are so-called facial amphiphiles showing a molecular structure that is very distinct from classical surfactants. This peculiar molecular structure facilitates the formation of dynamic aggregates able to solubilise and transport lipid soluble compounds. The detergent nature of BS has been studied in the literature, mostly concentrating on the self-assembly behaviour of BS in solution but also in relation to protein denaturation and its effect on improving proteolysis. In contrast, the affinity of BS for hydrophobic phases has received less attention and studies dealing directly with the interfacial behaviour of BS are very limited in the literature. This is despite the fact that the interfacial activity of BS plays a vital role in fat digestion since it is closely involved with lypolisis. BS adsorb onto fat droplets and can remove other materials such as proteins, emulsifiers and lipolysis products from the lipid surface. The unusual surface behaviour of BS is directly related to their intriguing molecular structure and further knowledge could provide an improved understanding of lipid digestion. This review aims to combine the new insights gained into the surface properties of BS and their role in digestion. A better understanding of surface activity of BS would allow manipulation of physico-chemical and interfacial properties to modulate lipid digestion, improve bioavailability of lipid soluble nutrients and reduce absorption of saturated fats, cholesterol and trans fats. PMID- 21236401 TI - Approximately one-third of medically indicated late preterm births are complicated by fetal growth restriction. AB - OBJECTIVE: The purpose of this study was to report the frequency of fetal growth restriction (FGR) based on indication for late preterm birth (LPTB). STUDY DESIGN: Singleton live born pregnancies that were delivered from 34-36 weeks 6 days of gestation over a 1-year period at a tertiary care medical center were studied. Indications for delivery were categorized as spontaneous (spontaneous preterm birth or premature rupture of membranes), medically indicated, or elective. A customized birthweight percentile was calculated for each pregnancy; the rate of FGR was compared based on indication for LPTB. RESULTS: There were 482 LPTBs that met all criteria. Customized birthweight percentiles (median; interquartile range) were different among groups (spontaneous, 45.5%; 20.8-73.5%; medically indicated, 26.9%; 4.1-63.6%; elective, 45.9%; 22.2-78.3%; P = .001). The rate of FGR was also different among groups (spontaneous, 13%; medically indicated, 32%; elective, 21%; P = .001). CONCLUSION: With the use of customized birthweight standards, we found that FGR complicated approximately one-third of all cases of medically indicated LPTB. PMID- 21236402 TI - Interocular symmetry in peripapillary retinal nerve fiber layer thickness measured with the Cirrus HD-OCT in healthy eyes. AB - PURPOSE: To determine the cutoffs for the interocular difference in retinal nerve fiber layer (RNFL) thickness measured with Cirrus HD-OCT (Carl Zeiss Meditec, Inc) in normal eyes. DESIGN: Observational, clinical study. METHODS: Scans were acquired at 7 academic glaucoma clinics from both eyes of 284 normal subjects using the Optic Disc Cube 200 * 200 protocol. The interocular differences in RNFL thickness were calculated, and normal ranges of interocular differences were determined as the 2.5th and 97.5th percentiles. RESULTS: The average RNFL in the right eye was 0.52 MUm thicker than in the left eye; the difference was marginally significant (P = .049). The temporal, nasal, and inferior quadrants had significantly thicker RNFL in the right eye, whereas the left eye showed thicker RNFL in the superior quadrant. The 2.5th and 97.5th percentile interocular difference tolerance limits for average RNFL thickness were -7.9 MUm and 8.8 MUm, respectively. Although the difference in average RNFL thickness correlated with differences in axial length, disc area, cup-to-disc ratio, and vertical cup-to-disc ratio, only differences in axial length (beta = -0.21; P < .001) and disc area (beta = 0.17; P < .001) were associated with an interocular difference of average RNFL thickness after adjustment for each other. The interocular difference remained stable despite significant decrease in RNFL thickness with aging. CONCLUSIONS: An interocular difference in average RNFL thickness exceeding 9 MUm when measured with the Cirrus HD-OCT in normal eyes may be considered statistically significant asymmetry and may be indicative of early glaucomatous damage. PMID- 21236403 TI - Assessment of bleb morphologic features and postoperative outcomes after Ex-PRESS drainage device implantation versus trabeculectomy. AB - PURPOSE: To investigate bleb morphologic features and postoperative outcomes after Ex-PRESS drainage device (Alcon Laboratories) implantation versus trabeculectomy. DESIGN: Retrospective, consecutive case-control series. METHODS: Information was collected from the charts of 35 consecutive Ex-PRESS procedures and 35 consecutive trabeculectomy procedures with at least 2 years of follow-up. Intraocular pressure (IOP), bleb morphologic features, reduction of dependence on medication, visual recovery, number of postoperative visits, and postoperative complication rates were compared between groups. RESULTS: Average follow-up was 28 months (standard deviation, 3.23 months). Mean IOP measurements were similar after 6 months, then became slightly higher in the Ex-PRESS group at 1 year and at the final follow-up (P = .004 and P = .008, respectively). Final percent IOP lowering was similar between groups (P = .209). Unqualified success was achieved in 77.14% of Ex-PRESS and 74.29% of trabeculectomy procedures at last follow-up (P = 1.00). An additional 5.71% and 8.57% reached qualified success for Ex-PRESS and trabeculectomy surgeries, respectively (P = .99). Evaluation by the Moorfields Bleb Grading System revealed less vascularity and height but more diffuse area associated with the Ex-PRESS blebs, although these differences were absent at study completion. There were fewer cases of early postoperative hypotony and hyphema and quicker visual recovery in the Ex-PRESS group. The Ex PRESS group required fewer postoperative visits compared with the trabeculectomy group (P < .000). CONCLUSIONS: Success of Ex-PRESS surgery, as defined in our study, was similar to trabeculectomy. Final IOP measurements were slightly lower after trabeculectomy compared with Ex-PRESS. Differences in some postoperative outcomes faded with follow-up. There remains a need for long-term prospective studies comparing these 2 procedures. PMID- 21236404 TI - Ophthalmodynamometric pressure in eyes with proliferative diabetic retinopathy measured during pars plana vitrectomy. AB - PURPOSE: To measure ophthalmodynamometric pressure (ODP) during vitrectomy in patients with proliferative diabetic retinopathy (PDR). DESIGN: Prospective, interventional, consecutive case series. METHODS: This study included 75 eyes of 75 patients undergoing vitrectomy for PDR. After core vitrectomy, the intraocular pressure was gradually raised using a vented-gas forced-infusion system (VGFI), and the optic nerve head was continuously monitored through a planoconvex contact lens. When the central retinal artery or its branches on the optic nerve head showed pulsations, the pressure was recorded as ODP. Diastolic blood pressure (DBP) and systolic blood pressure (SBP) were measured at the time of ODP measurement. Multiple regression analysis was performed to investigate the relationship between ODP and various explanatory variables: DBP, SBP, age, gender, body mass index, presence of hypertension, serum hemoglobin A1c, serum total cholesterol, fasting plasma glucose, presence of rubeosis iridis, and severity of PDR. RESULTS: ODP was 63.6 +/- 11.5 mm Hg (range 15.5-84.4 mm Hg). The ODP significantly correlated with DBP (r=0.570, P<.0001) and the mean arterial blood pressure (r=0.522, P<.0001), but not with SBP (r=0.121, P=.303). Multiple regression analysis revealed that ODP had a significant correlation with DBP (P<.0001), presence of rubeosis iridis (P<.0001), and severity of PDR (P=.046). CONCLUSIONS: We measured ODP using VGFI during vitrectomy in patients with PDR. The ODP was significantly associated with DBP. The ODP was lower in patients with rubeosis iridis and severe PDR. PMID- 21236405 TI - Effects of mitomycin C on corneal endothelial cell counts in pterygium surgery: role of application location. AB - PURPOSE: To evaluate changes in corneal endothelial cell counts after pterygium surgery with application of mitomycin C (MMC) either on the perilimbal sclera or in the subconjunctival space. DESIGN: Prospective, randomized interventional study. METHODS: Fifty-six eyes of 56 patients with primary pterygium underwent excision followed by removal of subconjunctival fibrovascular tissue, 0.02% MMC application, and amniotic membrane transplantation. These were stratified randomly into 2 groups. In 1 group (n = 28), MMC was applied on the perilimbal bare sclera (sclera group), and in other group (n = 28), MMC was applied under conjunctiva, where subconjunctival fibrovascular tissue was removed (subconjunctiva group). Based on severity of pterygium fleshiness, MMC was used for 1, 3, or 5 minutes in 8, 13, and 7 eyes, respectively, in the sclera group and in 9, 13, and 6 eyes, respectively, in the subconjunctiva group. Central corneal endothelial cell counts were evaluated before and during 6 months of follow-up after surgery. RESULTS: Mean preoperative endothelial cell count was 2810 +/- 278 cells/mm(2) in the sclera group and 2857 +/- 332 cells/mm(2) in the subconjunctiva group. Mean endothelial cell losses in sclera and subconjunctiva groups were 9.7% and 9.0% at 1 week, 6.5% and 6.5% at 1 month, 4.0% and 5.0% at 3 months, and 3.4% and 4.8% at 6 months, respectively, with no statistically significant difference between the 2 groups. Longer durations of MMC application were associated with significantly greater endothelial losses in both groups. CONCLUSIONS: Regardless of application location, MMC use during pterygium surgery can cause a significant decrease in central endothelial cell count. PMID- 21236406 TI - Evaluation of intraocular lens tilt with anterior segment optical coherence tomography. AB - PURPOSE: To determine the ability of anterior segment optical coherence tomography (OCT) to detect intraocular lens (IOL) tilt evaluation in relation to the limbus. DESIGN: Observational case series. METHODS: The IOL position of 123 eyes of 92 patients was examined with anterior segment OCT (Carl Zeiss Meditec, Dublin, California, USA). All eyes underwent uneventful phacoemulsification with the IOL in the bag. Images were obtained in 4 axes (180 to 0 degrees, 225 to 45 degrees, 315 to 135 degrees, and 270 to 90 degrees). Using MatLab software version 7.1 (Mathworks), the OCT images were analyzed. The distance between the iris margin and the anterior surface of IOL, the slope ratio between IOL and limbus, and the angle (theta; position of IOL with reference to the limbus) were determined and were correlated with the astigmatism and vision. RESULTS: The mean slope of the limbus and the IOL in all axes was 0.003 +/- 0.09 and -0.002 +/- 0.12, respectively. The average slope ratio was 1.1 +/- 1 (range, -2.09 to 3.82) and the angle (theta) was 1.52 +/- 0.9 degrees (range, 0.04 to 3.6 degrees). The mean ocular residual astigmatism was 0.2379 +/- 0.469 diopters. There was no significant correlation of ocular residual astigmatism with slope ratio (r = 0.171; P = .060) and slope angle (r = -0.132; P = .147). There was significant correlation of ocular residual astigmatism with total astigmatism (r=0.602, p=0.000). The mean distances between the iris margin and the anterior surface of IOL at the pupillary plane were 0.80 +/- 0.6 mm and 0.83 +/- 0.57 mm, respectively. CONCLUSIONS: The normal in-the-bag IOL maintains an angle with reference to the limbus and a slope ratio without causing a significant tilt. Anterior segment OCT can be used as an alternative in IOL tilt evaluation by the analysis of its position in relation to the limbus. PMID- 21236407 TI - Performance of patients with deficient stereoacuity on the EYESi microsurgical simulator. AB - PURPOSE: To compare the performance of individuals with deficient stereoacuity with that of individuals with normal stereoacuity on a microsurgical task using the VRMagic EYESi Ophthalmosurgical Simulator (VRmagic Holding AG). DESIGN: Prospective, experimental study at a single institution. METHODS: Subjects with abnormal stereoacuity and controls with normal stereoacuity completed a total of 4 attempts on 2 standardized microsurgical tasks on the EYESi Simulator. Performance was quantified using a 60-point scale, and scores were compared using the Wilcoxon rank-sum test with a significance level of .05 assumed for all tests. RESULTS: Twenty-one subjects with deficient or absent stereoacuity and 21 control subjects with normal stereoacuity were included. The mean age of both groups was 31.5 years (range, 10 to 64 years). Twenty-nine (69%) participants were male. The 2 groups did not differ in age or gender. For each of the 4 module attempts, the Wilcoxon rank-sum test showed significantly better performance of individuals in the control group compared with the study group (P < .001). Additional attempts did not result in improved performance by the study group compared with the control group. No significant associations were observed between performance scores and age or gender. CONCLUSIONS: This study compared the performance of patients with deficient stereoacuity with that of those with normal stereoacuity in microsurgical tasks. Individuals with normal stereoacuity performed better than those with deficient stereoacuity in a simulated microsurgical task. A larger and more complex study may be necessary to validate the findings of the present investigations. PMID- 21236408 TI - Wound architecture of clear corneal incision with or without stromal hydration observed with 3-dimensional optical coherence tomography. AB - PURPOSE: To evaluate wound architectures of a clear corneal incision and the duration of stromal edema caused by intentional hydration in cataract surgery using 3-dimensional (3-D) cornea and anterior segment optical coherence tomography (OCT). DESIGN: Prospective, randomized study. METHODS: On 30 eyes of 23 patients, cataract surgery was performed through a clear corneal incision created with a 2.4-mm blade. After confirming the water tightness of the clear corneal incision at the end of surgery, 15 randomly selected eyes received stromal hydration, and the remaining 15 eyes did not. Using the 3-D cornea and anterior segment optical coherence tomography, wound architecture was assessed 1 day, 1 week, and 2 weeks after surgery. RESULTS: There was a statistically significant difference in corneal thickness at the clear corneal incision between eyes with and without stromal hydration 1 day and 1 week after surgery (P < .001 and P < .05, Mann-Whitney U test), but not at 2 weeks after surgery. On day 1, gaping at the epithelial side was seen in 6.7% (2 eyes), gaping at the endothelial side in 30% (9 eyes), misalignment of the roof and floor of incision in 40% (12 eyes), and local detachment of Descemet membrane in 36.7% (11 eyes). These imperfections improved with time. CONCLUSIONS: Using the 3-D cornea and anterior segment optical coherence tomography, detailed architectures of the clear corneal incision were investigated. It was found that the effect of stromal hydration lasted for at least 1 week after surgery. PMID- 21236409 TI - Polymorphisms in ARMS2 (LOC387715) and LOXL1 genes in the Japanese with age related macular degeneration. AB - PURPOSE: To determine whether polymorphisms in the ARMS2 (LOC387715) gene and the lysyl oxidase-like 1 (LOXL1) gene are associated with age-related macular degeneration (AMD) in Japanese patients. DESIGN: Clinically relevant laboratory investigation. METHODS: Forty-one unrelated Japanese subjects with dry AMD, 50 subjects with exudative (wet) AMD, and 60 subjects with polypoidal choroidal vasculopathy (PCV) were studied. The single nucleotide polymorphisms (SNPs), p.Ala69Ser of the ARMS2 gene and p.Arg141Leu of the LOXL1 gene, were amplified by polymerase chain reaction, directly sequenced, and genotyped. RESULTS: For the ARMS2 gene, the genotype frequency of the p.Ala69Ser single nucleotide polymorphism in eyes with dry AMD was not significantly different from that in the controls (P = .04), but the frequency was significantly higher in the exudative AMD group (P = 3.1 * 10(-8)) and PCV group (P = 6.9 * 10(-3)). For the LOXL1 gene, the genotype frequency of the p.Arg141Leu single nucleotide polymorphism was not statistically higher in the dry AMD and PCV groups than in the control group (dry AMD, P = .05; PCV, P = .16), but was statistically higher in the exudative AMD group (P = 6.8 * 10(-3)). Regression analyses showed significant associations between the ARMS2 gene and LOXL1 gene in patients with exudative AMD. CONCLUSIONS: The p.Ala69Ser polymorphism of the ARMS2 gene is strongly associated with exudative AMD and PCV and is associated marginally with dry AMD. The polymorphisms in the LOXL1 gene did not predispose the individual to dry AMD and PCV. These findings suggest that there is a significant association between the ARMS2 gene and LOXL1 gene in exudative AMD. PMID- 21236410 TI - Hemispherical focal macular photopic negative response and macular inner retinal thickness in open-angle glaucoma. AB - PURPOSE: To investigate in open-angle glaucoma the focal macular photopic negative response and spectral-domain optical coherence tomography measurements of retinal thicknesses in the superior and inferior macula. DESIGN: Comparative case series. METHODS: We studied 63 eyes of 63 patients with open-angle glaucoma and 41 normal eyes of 41 volunteers. Photopic negative responses were recorded using a spotlight (diameter of 15 degrees of circle), projected onto the whole or superior or inferior macula. Ganglion cell complex (nerve fiber + ganglion cell + inner plexiform layers) thickness was measured using spectral-domain optical coherence tomography. RESULTS: Mean photopic negative response amplitude over the entire macula was significantly (P < .001) decreased compared with that of controls in eyes with early (n = 24; to 62.1%), moderate (n = 21; to 57.2%), and severe (n = 18; to 49.3%) open-angle glaucoma, but not significantly different among eyes with various stages of glaucoma. Mean ganglion cell complex thickness was significantly (P < .001) decreased compared with that of controls in eyes with early (86.0%), moderate (78.3%), and severe (71.2%) glaucoma, and thinning correlated positively with glaucoma severity (P < .001). Mean photopic negative response amplitude correlated significantly (P < .001) with ganglion cell complex thickness over the whole, superior, and inferior macular areas (r = 0.57 to 0.74). In 16 eyes without visual field defect in the inferior hemifield, mean photopic negative response amplitude was 56.5% of normal (P < .001), and mean ganglion cell complex thickness in the superior macula was 92.1% of normal (P = .004). CONCLUSIONS: Focal macular photopic negative response amplitude correlates with ganglion cell complex thickness, but decreases more abruptly in early glaucoma compared with ganglion cell complex thickness. PMID- 21236411 TI - Economic evaluation of deep anterior lamellar keratoplasty versus penetrating keratoplasty in The Netherlands. AB - PURPOSE: To evaluate the cost effectiveness of deep anterior lamellar keratoplasty (DALK) versus penetrating keratoplasty (PK) in The Netherlands. DESIGN: Cost-effectiveness analysis alongside a randomized, multicenter clinical trial. METHODS: Fifty-three patients with corneal stromal pathologic features not affecting the endothelium were included with 28 patients in the DALK group and 25 in the PK group. Quality of life was measured before surgery and 3, 6, and 12 months after surgery. The main outcome measures were incremental cost effectiveness ratios per clinically improved patient on the 25-item National Eye Institute Visual Functioning Questionnaire and per patient with endothelial cell loss of maximally 20% within the first year. RESULTS: Mean total bootstrapped costs per patient were ?7607 (US$10,498) in the DALK group and ?6552 (US$9042) in the PK group. The incremental cost-effectiveness ratios were ?9977 (US$13,768) per clinically improved patient on the 25-item National Eye Institute Visual Functioning Questionnaire and ?6900 (US$9522) per patient with cell loss of maximally 20%. In patients without perforation of the Descemet membrane, the incremental cost-effectiveness ratio was ?5250 (US$7245) per patient. CONCLUSIONS: This study shows that DALK is more costly and more effective as compared with PK. Results on the 25-item National Eye Institute Visual Functioning Questionnaire were in favor of DALK, and endothelial cell loss in DALK patients remained stable after 6 months, whereas cell loss in PK patients continued. Furthermore, DALK procedures performed without perforation of the Descemet membrane were more effective. However, because it is unknown what society is willing to pay for an additional improved patient, cost effectiveness of DALK within a limited follow-up period of 12 months is unclear. Cost effectiveness of DALK may improve over time because of lower graft failure. PMID- 21236412 TI - Acquired central corneal thickness increase following removal of childhood cataracts. AB - PURPOSE: To evaluate central corneal thickness (CCT) in children with congenital/developmental cataracts before and after cataract removal, to correlate CCT with corneal diameters before cataract surgery in this same group, and to evaluate CCT over time in a separate group of children who were already aphakic or pseudophakic at study entry. DESIGN: Longitudinal study. METHODS: Children with cataract (Group 1, with pre-cataract-removal CCT) and aphakia/pseudophakia (Group 2, presenting after cataract removal) were included. CCT measurements were performed using ultrasound pachymetry. Normal fellow eyes of unilaterally affected cases served as controls. In bilateral cases, right eyes were used for analyses. RESULTS: Group 1 comprised 66 children. Before cataract surgery, unilateral cases (n = 31) showed similar CCT and strong association between the affected and fellow eyes (552.0 +/- 32.9 MUm vs 550.9 +/- 40.4 MUm, respectively; r(2) = 0.71, P = .0001). After cataract surgery, affected eyes (n = 13) showed mean CCT increase of 29.7 +/- 43.1 MUm (P = .03) while fellow eyes remained unchanged. Similarly, before cataract surgery, bilateral cases (n = 35) showed similar CCT between the right and left eyes. After cataract surgery, mean CCT increase was 27.4 +/- 39.4 MUm for first operated eyes of bilateral cases (n = 17, P = .01). Group 2 comprised 50 aphakic/pseudophakic children lacking pre cataract-removal CCT. CCT was higher in eyes with glaucoma vs those without, at both first and last measurements (DeltaCCT 58.9 +/- 27.0 MUm at first examination, P = .034, and 56.4 +/- 27.1 MUm at last examination, P = .043, respectively). There was no statistically significant CCT change over the study interval (median 28 months) for either Group 2 eyes with or those without glaucoma. CONCLUSIONS: CCT in children with cataracts increases after cataract surgery while the fellow eye remains stable. This increase seems to occur early after surgery, likely remaining stable thereafter, though glaucoma can accentuate the increase. PMID- 21236413 TI - Intravitreal ranibizumab for myopic choroidal neovascularization: factors predictive of visual outcome and need for retreatment. AB - PURPOSE: To identify predictive factors for visual outcome and need for retreatment after treating myopic choroidal neovascularization (CNV) with ranibizumab. DESIGN: A prospective interventional case series. METHODS: Sixty seven eyes of 67 patients with myopic CNV were treated with 3 intravitreal ranibizumab injections given monthly. Best-corrected visual acuity (BCVA) and optical coherence tomography-determined central macular thickness (CMT) were recorded monthly during follow-up. Fluorescein angiography changes and the number of injections needed were also assessed. RESULTS: Mean follow-up was 15.9 months. Mean BCVA improved by 7.8 letters after the first injection, 12.5 letters after 3 injections, and 12 letters by end follow-up. In 53 eyes (79.1%), BCVA improved; 40.3% gained more than 15 letters. No differences were detected in visual outcome between treatment-naive and previously treated patients. Myopic CNV area and greatest linear dimension had diminished at the study end. The mean reduction in CMT was 93.6 MUm. The mean number of injections given was 4.2. A total of 53.7% of eyes received only 3 injections. Through regression analysis, baseline BCVA (P = .006) and myopic CNV location (P = .026) were significantly correlated with BCVA at the end of follow-up. Myopic CNV location (P = .023) and prior treatment (P = .047) were significantly linked to the number of injections given. No major complications arose. CONCLUSION: An initial treatment regimen of 3 monthly ranibizumab injections seems effective and safe to treat myopic CNV. Baseline BCVA and myopic CNV location emerged as predictive factors for visual outcome. A need for retreatment was associated with myopic CNV location and prior treatment. PMID- 21236414 TI - The maximal tolerable reduction in hyperopic correction in patients with refractive accommodative esotropia: a 6-month follow-up study. AB - PURPOSE: To investigate the optimal amount of safe under-correction in patients with refractive accommodative esotropia. DESIGN: Prospective noncomparative interventional case series. METHODS: Patients with refractive accommodative esotropia wore trial glasses based on cycloplegic refraction, then -0.25 diopters (D) of minus sphere lenses were placed on both lenses of the trial glasses and the deviation was measured. Minus spheres of -0.25 D were continuously added until the angle of deviation increased; the minus spheres added just before the deviation increase were defined as the maximal tolerable amount of under correction. A total of 38 patients were prescribed under-corrected spectacles up to -1.5 D and followed for 6 months. RESULTS: Thirty-one patients underwent the maximal tolerable amount of under-correction and 7 underwent -1.5 D of under correction. A mean -0.89 D of under-correction was performed. We observed no deterioration in visual acuity, stereoacuity, or fusional ability during the follow-up period in any of the patients. Small increase in the angle of deviation of 2 prism diopters was noted in 2 patients. The mean spherical equivalent refractive error of both eyes (P = .012) and age of onset (P = .006) showed strong positive correlations with the maximal tolerable amount of under correction. CONCLUSIONS: A reduction in hyperopic correction by the maximal tolerable amount of under-correction was performed without notable short-term side effects. The spherical equivalent refractive error and age of onset appear to be useful clinical indices in determining the appropriate amount of under correction. PMID- 21236415 TI - Evaluation of long- and short-handled hand hoes for land preparation, developed in a participatory manner among women vegetable farmers in The Gambia. AB - OBJECTIVE: This study evaluated land preparation interventions (new short- and long-handled hoes), developed in a participatory manner with women vegetable farmers in West Africa, and identified indicators of long-term adoption of these interventions. METHODS: Subjects (n = 48) engaged in timed trials, alternating between using an intervention tool and their traditional hand hoe to till specified plots of land. Heart rates were measured and subjects reported the relative ergonomic comfort and safeness of the tool after each trial. Follow-up interviews and focus groups were held one, two, and three months after the trials. RESULTS: Compared to the traditional hoe, the new long-handled hoe required 22% less time (p = 0.01), while the new short hoe took 20% more time (p = 0.05) to till the standard plots in this study. Two months after the initial trials, 94% of subjects preferred the new hoes over the traditional hoe. Most subjects (75%) preferred the new short hoe over the new long hoe and thought it was faster (81%), despite measurements to the contrary. CONCLUSIONS: While the new long-handled hoe performed better in the timed trials in this study, most subjects preferred the new short-handled hoe. Subjects should be sensitized on the benefits of the long-handled hoe. PMID- 21236416 TI - Synthesis, physicochemical and spectroscopic characterization of copper(II) polysaccharide pullulan complexes by UV-vis, ATR-FTIR, and EPR. AB - Bioactive copper(II) complexes with polysaccharides, like pullulan and dextran, are important in both veterinary and human medicine for the treatment of hypochromic microcitary anemia and hypocupremia. In aqueous alkaline solutions, Cu(II) ion forms complexes with the exopolysaccharide pullulan and its reduced low-molecular derivative. The metal content and the solution composition depend on pH, temperature, and time of the reaction. The complexing process begins in a weak alkali solution (pH >7) and involves OH groups of pullulan monomer (glucopyranose) units. Complexes of Cu(II) ion with reduced low-molecular pullulan (RLMP, M(w) 6000 g mol(-1)) were synthesized in water solutions, at the boiling temperature and at different pH values ranging from 7.5 to 12. The Cu(II) complex formation with RLMP was analyzed by UV-vis spectrophotometry and other physicochemical methods. Spectroscopic characterizations (ATR-FTIR, FT-IRIS, and EPR) and spectra-structure correlation of Cu(II)-RLMP complexes were also carried out. PMID- 21236417 TI - Exploiting correlation of ECG with certain EMD functions for discrimination of ventricular fibrillation. AB - Ventricular fibrillation (VF) is a life-threatening cardiac arrhythmia. A high impulse current is required in this stage to save lives. In this paper, an empirical mode decomposition (EMD) based algorithm is presented to separate VF from other arrhythmias. The characteristics of the VF signal has high degree of similarity with the intrinsic mode functions (IMFs) of the EMD decomposition in comparison to other ECG pathologies. This high correlation between the VF signal and its certain IMFs is exploited to separate VF from other cardiac pathologies. Reliable databases are used to verify effectiveness of our algorithm and the results demonstrate superiority of our proposed technique compared to other well known techniques of VF discrimination. PMID- 21236418 TI - On the relevance of automatically selected single-voxel MRS and multimodal MRI and MRSI features for brain tumour differentiation. AB - In order to evaluate the relevance of magnetic resonance (MR) features selected by automatic feature selection techniques to build classifiers for differential diagnosis and tissue segmentation two data sets containing MR spectroscopy data from patients with brain tumours were investigated. The automatically selected features were evaluated using literature and clinical experience. It was observed that a significant part of the automatically selected features correspond to what is known from the literature and clinical experience. We conclude that automatic feature selection is a useful tool to obtain relevant and possibly interesting features, but evaluation of the obtained features remains necessary. PMID- 21236419 TI - Classification of Error-Related Negativity (ERN) and Positivity (Pe) potentials using kNN and Support Vector Machines. AB - Error processing in subjects performing actions has been associated with the Event-Related Potential (ERP) components called Error-Related Negativity (ERN) and Error Positivity (Pe). In this paper, features based on statistical measures of the sample of averaged ERP recordings are used for classifying correct from incorrect actions. Three feature selection techniques were used and compared. Classification was done by means of a kNN and a Support Vector Machines (SVM) classifier. The use of a leave-one-out approach in the feature selection provided sensitivity and specificity values concurrently higher than or equal to 87.5%, for both classifiers. The classification results were significantly better for the time window that included only the ERN, as compared to time windows including also Pe. PMID- 21236420 TI - Associations between petrol-station density and manganese and lead in the cord blood of newborns living in Taiwan. AB - Although the anti-knocking agents used in Taiwan do not contain manganese, there are relatively high concentrations of the element in diesel fuel. As such, there have been many concerns about the impact of exposure to diesel fuels on health. This study was conducted in Taiwan to investigate the relationship between the concentration of manganese in cord blood of Taiwanese newborns and the geographic density of petrol stations as a surrogate for determining manganese emissions from vehicular traffic. A total of 1526 full-term newborns without major congenital malformations were consecutively recruited from various medical facilities from May 2004 to July 2005. Questionnaires were completed by the newborns' mothers after delivery to collect information on demographic characteristics, medical history, living environment, and other factors. Cord blood samples were collected at birth and analyzed for manganese and lead using inductively coupled plasma mass spectrometry. The geographic density of petrol stations within a 10 km zone around each newborn's residence was calculated for 1343 newborns using the Arc9 Geographic Information System. The geometric means of cord blood manganese and lead concentrations were 47.0 MUg/L (GSD=1.42) and 12.6 MUg/L (GSD=1.76), respectively. After adjusting for potential confounding factors, including maternal age, and maternal education, the results of a multiple linear regression model indicated that the concentration of cord blood manganese increased monotonically with an increasing density of petrol stations. However, no such association was found for levels of lead in cord blood. Further smoothing spline model analysis indicated that a ten unit increment in petrol station density made cord blood manganese and lead levels change by factors of 1.0092 (95% CI: 1.0058, 1.0127) and 0.9994 (95% CI: 0.9890, 0.9998), respectively. This finding suggests that exposure to manganese-containing fuel from motor vehicles may result in elevated manganese levels in the fetus. Further research is warranted to explore the relationship between traffic-related manganese exposure and potential adverse effects on fetal development. PMID- 21236421 TI - Ovarian reserve and oocyte maturity in women with malignancy undergoing in vitro maturation treatment. AB - OBJECTIVE: To evaluate ovarian reserve and oocyte maturity in women with malignancy. DESIGN: A case-control study. SETTING: University teaching hospital. PATIENT(S): We evaluated all women with malignancy who underwent in vitro maturation treatment for fertility preservation from the year 2003 to 2009. The results were compared with those of an age-matched infertile control group. INTERVENTION(S): In vitro maturation treatment. MAIN OUTCOME MEASURE(S): Ovarian reserve and oocyte maturity. RESULT(S): Women with malignancy of the breast (n = 87), hematologic malignancy (n = 16), gynecologic or abdominal malignancy (n = 9), and other malignancies (n = 16) were compared with infertile control women (n = 79). The age was similar in all groups except in women with hematologic malignancy where they were younger than the control group (24.9 +/- 1.1 years vs. 30.8 +/- 0.4 years, confidence interval 4.0-9.5). Baseline FSH in this group was also lower than in the control group. Women with breast cancer had a lower number of retrieved oocytes than the control group (95% confidence interval 0-5). There were no significant differences in antral follicle count, percentage of mature oocytes on collection day, and percentage of metaphase II oocytes matured in vitro among all groups of women. CONCLUSION(S): Women with breast cancer have fewer numbers of retrieved oocytes than infertile controls. Ovarian reserve and oocyte maturity in other types of malignancy are similar to those in the control group. PMID- 21236422 TI - Testicular schistosomiasis: a case study. AB - OBJECTIVE: To report a case of testicular schistosomiasis. DESIGN: Case study. SETTING: University hospital. PATIENT(S): A 26-year-old unmarried Egyptian man presented with slowly growing painless swelling at the right hemiscrotum. INTERVENTIONS: Physical examination, scrotal ultrasonography, magnetic resonance imaging (MRI), computerized tomography, urine and semen Zeihl-Neelsen stain, stool, serum alpha-fetoprotein, FSH, LH, PRL, E2, total testosterone (T), and surgical exploration. MAIN OUTCOME MEASURE(S): Clinical, laboratory, radiologic, and histopathologic data. RESULT(S): At clinical examination, there was a large painless swelling in the right hemiscrotum with two hard masses felt subcutaneously. The transillumination test was negative with no inguinal lymphadenopathy. The left hemiscrotum revealed normal findings. Serum alpha fetoprotein, FSH, LH, total T, E2, and PRL were within normal. MRI demonstrated no masses of abnormal signal intensity or enhancement. Scrotal surgical exploration revealed discharge of thick brownish red pus with presence of two hard extratesticular scrotal masses. Histopathology of the right testis biopsy revealed reduced diameter of the seminiferous tubules with marked hypospermatogenesis where the interstitium was filled by multiple Schistosoma mansoni ova associated with granulomatous reaction compressing the tubules. CONCLUSION(S): Scrotal involvement in schistosomiasis with its variable presentations should be considered in diagnosing scrotal masses, especially in endemic areas. PMID- 21236423 TI - Hyperstimulation during IVF cycles does not modify dimensions of small subserosal and intramural leiomyomas. AB - To evaluate the influence of IVF on the dimension of leiomyomas, we selected 72 women with small intramural or subserosal leiomyomas and assessed the size of these lesions before and after the treatment cycle. The mean +/- SD diameters of the tumors at these two time points were 20.5 +/- 9.5 and 20.6 +/- 10.2 mm, respectively, thus supporting the conclusion that IVF does not influence the growth of these lesions. PMID- 21236425 TI - Monitoring the growth dynamics of somatic traits based on a semi-longitudinal study. AB - Possibilities of conducting longitudinal human growth studies are very limited, since it is necessary to monitor the probands for a long time. Another problem can be a loss of data currency, and the small size of the final sample. The solution can be a follow-up semi-longitudinal observation. This research is drawn up as a short longitudinal monitoring of 1925 children (990 boys, 935 girls), aged 6-15 years, at 20 elementary schools in four regions of the Czech Republic, which has been conducted at the same time. Data of repeatedly examined probands of a wide age range were acquired in a short time period. With the help of a linear regression model with mixed effect, the growth velocity curves of 12 somatic traits have been obtained. The timing, intensity and duration of separate growth spurts have been observed, as well as the mutual location of both points of growth velocity, local maxima and minima, and points of the maximal acceleration and deceleration. The results demonstrate that the velocity of characters with variable growth dynamics (skin-fold thicknesses, circumferences of limbs) - contrary to characters with regular growth velocity - have a higher number of partial growth spurts and an opposite course. In the period of separate growth velocity, peaks of somatic characters with regular growth dynamics reach points of partial local minima. In comparison to previous longitudinal studies of body height growth dynamics, the shift of both the beginning and the peak of boys' and girls' pubertal spurt, to a lower age can be found. PMID- 21236424 TI - Maturation and fertilization of nonhuman primate oocytes are compromised by oral administration of a cyclooxygenase-2 inhibitor. AB - OBJECTIVE: To determine if oral administration of a cyclooxygenase-2 (COX2) inhibitor affects oocyte nuclear maturation and fertilization in nonhuman primates. DESIGN: Laboratory research study. SETTING: Medical school. ANIMAL(S): Adult female cynomolgus monkeys (Macaca fascicularis). INTERVENTION(S): Monkeys received gonadotropins to stimulate multiple follicular development. An ovulatory dose of hCG was administered either alone or with oral celecoxib, a COX2 inhibitor. Oocytes were retrieved 36 hours later and exposed to sperm in vitro. MAIN OUTCOME MEASURE(S): Oocytes were assessed for nuclear status at retrieval, resumption of meiosis in vitro, and success of in vitro fertilization. RESULT(S): Treatment with hCG alone yielded oocytes that were primarily (72.9%) at the meiosis II (MII) stage of nuclear maturation; few oocytes were obtained at the germinal vesicle and germinal vesicle breakdown stages. Treatment with hCG and celecoxib yielded fewer mature (MII) oocytes (35.6%) and more oocytes at less mature stages compared with oocytes from monkeys treated with hCG alone. The majority (68.3 +/- 15.9%) of MII oocytes from monkeys treated with hCG alone fertilized in vitro, compared with only 11.0 +/- 5.9% of MII oocytes from monkeys treated with hCG and celecoxib. CONCLUSION(S): Oral administration of a COX2 inhibitor reduced the rate of oocyte nuclear maturation and the success of in vitro fertilization. Drugs of this class may block multiple essential steps in female reproduction and be effective contraceptives for women. PMID- 21236426 TI - Traumatic spinopelvic dissociation or U-shaped sacral fracture: a review of the literature. AB - Traumatic spinopelvic dissociation is a rare high-energy injury pattern, characterised by a transverse sacral fracture in conjunction with bilateral sacral fracture-dislocations. It has a high incidence of neurological complications. The true nature of the injury is easily missed and diagnosis is delayed because it commonly presents in patients with severe associated injuries. In the absence of diagnosis and treatment, it can lead to progressive deformity and chronic pain. Early realignment and fixation of the unstable lumbopelvic junction, with adjunctive decompression of compromised lumbosacral roots, are currently thought to provide the best possible environment for early mobilisation of the polytraumatised patient. Plain pelvic radiographs (anteroposterior, inlet, and outlet), lateral sacral radiograph, CT scan and reconstruction are essential to provide optimal imaging and understanding of the fracture pattern. There is no single treatment paradigm and various surgical strategies have been described in the literature. Lumbopelvic fixation or triangular osteosynthesis has recently been recommended by several authors to restore stability at the lumbosacral junction. This article presents a review of the incidence, clinical evaluation, treatment methods and outcomes of this injury pattern. PMID- 21236427 TI - Observational analysis of BOA free-papers (2001): from presentation to publication and comparison with the American Academy of Orthopaedic Surgeons (AAOS). AB - AIM: The objectives of this study were to: determine the presentation to publication conversion rate (PPCR) in peer-reviewed indexed journals of free papers and posters presented at 12-14th September 2001 British Orthopaedic Association (BOA) annual meeting and to compare the publication rate with the American Academy of Orthopaedic Surgeons (AAOS) meeting in 2001. METHODOLOGY: We looked at all presentations including both podium and poster presentations at British Orthopaedic Association meeting held in 2001 and assessed for subsequent publication as full-text article with a fixed PubMed search protocol. Once the abstract was identified as being published, we noted the name of the journal, citation, and time to presentation. The level of evidence was assigned for each abstract along the guidelines published by the centre for evidence-based medicine, Oxford, UK. This conversion rate was compared with the presentation to publication rate for the AAOS meeting in 2001. RESULTS: A total of 179 abstracts were presented at the 2001 BOA meeting. 65 of these were published as full-text articles in 30 different journals. The overall publication rate was 36.3%. The publication rate of the papers presented at AAOS annual meeting 2001 was 49% (367/756). The mean time from presentation to publication was 18.6 months (+/-9.4 months). Three fourths of them were published after 2 years of presentations (63% for AAOS). Majority of studies were either level III or IV. 14 full-text articles were published in Journal of Bone and Joint Surgery British (JBJS Br) and 8 in the Injury Journal. CONCLUSIONS: This is the first study reporting the publication rate of presentations for BOA meeting and comparing it with the publication rate of AAOS meeting in 2001. The publication rate of BOA presentations is much lower than the AAOS meeting. We believe the publication rate is an important tool in judging the quality of research work and the reputation of a scientific meeting with higher conversion rates suggesting better quality. Thus, more stringent selection criteria need to be introduced so that the selected abstracts can withstand peer-view for publication as full-text articles. PMID- 21236429 TI - Measuring safety and quality in health care: classic methods paper. PMID- 21236430 TI - Ivabradine: an hypothesis generating study--an important link between bench and bedside. PMID- 21236431 TI - The influence of tibial component fixation techniques on resorption of supporting bone stock after total knee replacement. AB - Periprosthetic bone resorption after tibial prosthesis implantation remains a concern for long-term fixation performance. The fixation techniques may inherently aggravate the "stress-shielding" effect of the implant, leading to weakened bone foundation. In this study, two cemented tibial fixation cases (fully cemented and hybrid cementing with cement applied under the tibial tray leaving the stem uncemented) and three cementless cases relying on bony ingrowth (no, partial and fully ingrown) were modelled using the finite element method with a strain-adaptive remodelling theory incorporated to predict the change in the bone apparent density after prosthesis implantation. When the models were loaded with physiological knee joint loads, the predicted patterns of bone resorption correlated well with reported densitometry results. The modelling results showed that the firm anchorage fixation formed between the prosthesis and the bone for the fully cemented and fully ingrown cases greatly increased the amount of proximal bone resorption. Bone resorption in tibial fixations with a less secure anchorage (hybrid cementing, partial and no ingrowth) occurred at almost half the rate of the changes around the fixations with a firm anchorage. The results suggested that the hybrid cementing fixation or the cementless fixation with partial bony ingrowth (into the porous-coated prosthesis surface) is preferred for preserving proximal tibial bone stock, which should help to maintain post-operative fixation stability. Specifically, the hybrid cementing fixation induced the least amount of bone resorption. PMID- 21236432 TI - Application of 1D blood flow models of the human arterial network to differential pressure predictions. AB - A new application of 1D models of the human arterial network is proposed. We take advantage of the sensitivity of the models predictions for the pressure profiles within the main aorta to key model parameter values. We propose to use the patterns in the predicted differences from a base case as a way to infer to the most probable changes in the parameter values. We demonstrate this application using an impedance model that we have recently developed (Johnson, 2010). The input model parameters are all physiologically related, such as the geometric dimensions of large arteries, various blood properties, vessel elasticity, etc. and can therefore be patient specific. As a base case, nominal values from the literature are used. The necessary information to characterize the smaller arteries, arterioles, and capillaries is taken from a physical scaling model (West, 1999). Model predictions for the effective impedance of the human arterial system closely agree with experimental data available in the literature. The predictions for the pressure wave development along the main arteries are also found in qualitative agreement with previous published results. The model has been further validated against our own measured pressure data in the carotid and radial arteries, obtained from healthy individuals. Upon changes in the value of key model parameters, we show that the differences seen in the pressure profiles correspond to qualitatively different patterns for different parameters. This suggests the possibility of using the model in interpreting multiple pressure data of healthy/diseased individuals. PMID- 21236433 TI - Flow field-flow fractionation with off-line electrothermal atomic absorption spectrometry for size characterization of silver nanoparticles. AB - Flow field-flow fractionation (Fl-FFF) with off-line electrothermal atomic absorption spectrometry (ETAAS) detection was developed and employed for particle size characterization of Ag NPs stabilized by citrate, pectin, and alginate. Citrate stabilized-Ag NPs were prepared from sodium borohydride reduction of silver nitrate. Sodium citrate was used as the capping agent to stabilize Ag NPs and prevent the aggregation process. Pectin stabilized- and alginate stabilized Ag NPs were prepared from ascorbic acid reduction of silver nitrate. Pectin and alginate were used as the capping agent for pectin stabilized- and alginate stabilized-Ag NPs, respectively. Three types of Ag NPs were characterized by using FlFFF, zeta potentiometer, and TEM technique. The mean particle sizes of Ag NPs as characterized by FlFFF were 9 nm, 19 nm, and 45 nm for citrate stabilized , pectin stabilized-, and alginate stabilized-Ag NPs, respectively, in deionized water. Further, FlFFF with ETAAS detection was employed to observe the aggregation of Ag NPs of various types in environmental water in the absence and presence of humic acid. Citrate stabilized-Ag NPs underwent aggregation more rapid than the pectin stabilized- and alginate stabilized-Ag NPs as the latter two types were sterically stabilized. Further, humic acid could prolong the stability of Ag NPs in the environment. PMID- 21236434 TI - Stir membrane liquid-liquid microextraction. AB - In this article, a novel liquid phase microextraction technique, called stir membrane liquid-liquid microextraction (SM-LLME), is presented. The new approach combines the advantages of liquid phase microextraction and stirring in the same unit allowing the isolation and preconcentration of the analytes in a simple and efficient way. In the construction of the unit, a polymeric membrane is employed to protect the small volume of the extractant phase. The extraction technique is characterized for the resolution of a model analytical problem: the determination of five selected chlorophenols in water. A two-phase extraction mode is used for the extraction of the analytes with an organic solvent in which an in situ derivatization reaction takes place. The analytes are finally analyzed by gas chromatography/mass spectrometry. All the variables involved in the extraction process have been clearly identified and optimized. The new extraction mode allows the determination of chlorophenols with limits of detection in the range from 14.8 ng/L (for 2,4,5-trichlorophenol) to 22.9 ng/L (for 3-chlorophenol) with a relative standard deviation lower than 8.7% (for 2,6-dichlorophenol). PMID- 21236435 TI - Analytical methods applied to the determination of pesticide residues in foods of animal origin. A review of the past two decades. AB - Pesticides are widely used in agriculture and can be transferred to animals in a number of ways. Consequently, reliable analytical methods are required to determine pesticide residues in foods of animal origin. The present review covers published methods and research articles (1990-2010) in which pesticide residues have been extracted from meat and meat products, milk and dairy products, fish and seafood, and eggs, then cleaned up, and isolated by chromatographic techniques to be identified and quantified by various detection methods. Recovery rates, quantification limits, the matrix effect and related parameters have all been considered. Lastly, future developments in this field are outlined. PMID- 21236436 TI - Coupling asymmetric flow-field flow fractionation and fluorescence parallel factor analysis reveals stratification of dissolved organic matter in a drinking water reservoir. AB - Using asymmetrical flow field-flow fractionation (AF4) and fluorescence parallel factor analysis (PARAFAC), we showed physicochemical properties of chromophoric dissolved organic matter (CDOM) in the Beaver Lake Reservoir (Lowell, AR) were stratified by depth. Sampling was performed at a drinking water intake structure from May to July 2010 at three depths (3-, 10-, and 18-m) below the water surface. AF4-fractograms showed that the CDOM had diffusion coefficient peak maximums between 3.5 and 2.8 x 10-6 cm2 s-1, which corresponded to a molecular weight range of 680-1950 Da and a size of 1.6-2.5 nm. Fluorescence excitation emission matrices of whole water samples and AF4-generated fractions were decomposed with a PARAFAC model into five principal components. For the whole water samples, the average total maximum fluorescence was highest for the 10-m depth samples and lowest (about 40% less) for 18-m depth samples. While humic like fluorophores comprised the majority of the total fluorescence at each depth, a protein-like fluorophore was in the least abundance at the 10-m depth, indicating stratification of both total fluorescence and the type of fluorophores. The results present a powerful approach to investigate CDOM properties and can be extended to investigate CDOM reactivity, with particular applications in areas such as disinfection byproduct formation and control and evaluating changes in drinking water source quality driven by climate change. PMID- 21236438 TI - Thin-layer chromatography with biological detection in phytochemistry. AB - Bioautography on thin-layer chromatographic (TLC) plates is a means of detecting the biological activity of a sample which has migrated on the plate with a suitable solvent. It only requires small amounts of sample and is ideal for the investigation of plant constituents, which often occur as complex mixtures. It can be used for the target-directed isolation of these constituents. In contrast to HPLC, many samples can be run at the same time on TLC. Organic solvents, which cause inactivation of enzymes or death of living organisms, can be completely removed before biological detection. Many bioassays are compatible with TLC. Antimicrobial, radical scavenging, antioxidant activities and enzyme inhibition feature among the tests that are employed. PMID- 21236437 TI - Use of countercurrent chromatography during isolation of 6-hydroxyluteolin-7-O beta-glucoside, a major antioxidant of Athrixia phylicoides. AB - Athrixia phylicoides, an indigenous South African herbal tea, has potential as a source of nutraceutical antioxidant extracts. Countercurrent chromatography (CCC) was employed as part of a multi-step process to isolate one of the major antioxidant compounds in A. phylicoides extracts. Antioxidant activity of the extracts was comparable to commercial nutraceutical extracts from Aspalathus linearis and Cyclopia spp. in a range of assays. The extracts were tested for radical scavenging (2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) di ammonium radical cation (ABTS.+) scavenging, 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) scavenging and oxygen radical absorbance capacity (ORAC)), ferric reducing antioxidant potential (FRAP) and iron chelating activity, as well as inhibition of microsomal lipid and linoleic acid emulsion oxidation. After extraction optimisation, the antioxidant activity of the major phenolic compounds in an A. phylicoides extract was determined using the on-line HPLC-diode-array DPPH and -ABTS.+ radical scavenging assays. Major compounds reported for the first time included chlorogenic acid, 1,3-dicaffeoylquinic acid, several hydroxycinnamic acid derivatives, including dicaffeoyl quinic acids, and an unidentified flavone-hexose. Finally, CCC was used in conjunction with liquid liquid partitioning and semi-preparative reversed-phase HPLC to isolate 6 hydroxyluteolin-7-O-beta-glucoside (a major antioxidant) and quercetagetin-7-O beta-glucoside (a minor compound present in CCC fraction containing 6 hydroxyluteolin-7-O-beta-glucoside) from an A. phylicoides extract. The chemical structures of the isolated compounds were confirmed by LC high-resolution electrospray ionisation MS, as well as 1H, 13C and 2D NMR spectroscopy. This is the first report of the isolation of these compounds from A. phylicoides. PMID- 21236439 TI - Enhanced fluidity liquid chromatography for hydrophilic interaction separation of nucleosides. AB - The application of enhanced fluidity liquid (EFL) mobile phases to improving isocratic chromatographic separation of nucleosides in hydrophilic interaction liquid chromatography (HILIC) mode is described. The EFL mobile phase was created by adding carbon dioxide to a methanol/buffer solution. Previous work has shown that EFL mobile phases typically increase the efficiency and the speed of the separation. Herein, an increase in resolution with the addition of carbon dioxide is also observed. This increase in resolution was achieved through increased selectivity and retention with minimal change in separation efficiency. The addition of CO2 to the mobile phase effectively decreases its polarity, thereby promoting retention in HILIC. Conventional organic solvents of similar nonpolar nature cannot be used to achieve similar results because they are not miscible with methanol and water. The separation of nucleosides with methanol/aqueous buffer/CO2 mobile phases was also compared to that using acetonitrile/buffer mobile phases. A marked decrease in the necessary separation time was noted for methanol/aqueous buffer/CO2 mobile phases compared to acetonitrile/buffer mobile phases. There was also an unusual reversal in the elution order of uridine and adenosine when CO2 was included in the mobile phase. PMID- 21236440 TI - The mass transfer kinetics in columns packed with Halo-ES shell particles. AB - The average mesopore size of the new Halo-ES-Peptide shell particles is 160 A, markedly larger than that of the classical Halo shell particles (90 A). We found that this change causes a considerable decrease of the film mass transfer resistance measured for columns packed with these particles. We analyze data obtained by systematic measurements of the C term of the van Deemter equation for the peptide beta-lipotropin (MW = 769 Da), the protein insulin (MW = 5800 Da), and a series of non-retained polystyrene standards (MW = 6400 and 13,200). The improvement in column performance is explained by an increase of the fraction of the external surface area of the shell that allows the entrance of the sample molecules inside the particle. The fraction of the shell surface accessible to a probe controls the rate of its external film mass transfer, i.e. its rate of transfer between the interstitial and the stagnant eluent. Although measurable, the increase in sample diffusivity through the porous shells does not account for the better performance of Halo-ES-peptide columns. Furthermore, the analysis of the HETPs data of small molecules (uracil, acetophenone, toluene, and naphthalene, MW< 150) reveals that the eddy diffusion (A) term of these new columns is 25% lower than that of the classical Halo columns. This result is consistent with the impact of intra-particle diffusivity on the eddy diffusion mechanism in packed columns. As shell diffusivity increases, so does the rate of transfer of sample molecules between the eluent stream-paths flowing through the packed particles and across the column diameter. Dispersion through short-range inter-channel and trans-column eddies is reduced. PMID- 21236441 TI - Influence of assembly pH on compression and Ag nanoparticle synthesis of polyelectrolyte multilayers. AB - Influence of assembly pH on compression and Ag nanoparticle synthesis of polyelectrolyte multilayers was studied using poly(diallyldimethylammonium chloride) (PDADMAC) and poly(4-styrenesulfonic acid-co-maleic acid, 1:1SS:MA) sodium salt (PSSMA 1:1) as the building blocks. The thickest multilayers turned out at pH 4. A homogeneous compression by a silicone rubber stamp increased significantly the water contact angle to a same value which was independent on the original assembly pH anymore. The multilayers assembled at pH 4 could be maximumly compressed to a ratio of 70% by a silicone rubber stamp with linear patterns, which was considerably larger than those assembled at other pHs (the compression ratio ~50%). The Ag nanoparticles were then synthesized inside the multilayers either flat compressed or not. The results showed that the compression reduced significantly the amount of Ag nanoparticles for the multilayers assembled at pH 2 and pH 4. The particle amount was also decreased significantly when the multilayers were assembled at higher pH, pH 6, for example, regardless of the compression. Substantial alteration of the multilayers in terms of the surface morphology, thickness and refractive index was found during the reduction of Ag(+) containing multilayers by NaBH(4) solution. PMID- 21236442 TI - Effects of polymer wrapping and covalent functionalization on the stability of MWCNT in aqueous dispersions. AB - The colloidal behavior of aqueous dispersions of functionalized multiwall carbon nanotubes (F-CNTS) formed via carboxylation and polymer wrapping with polyvinyl pyrrolidone (PVP) is presented. The presence of polymer on the nanotube surface provided steric stabilization, and the aggregation behavior of the colloidal system was quite different from its covalently functionalized analog. Based on hydrophobicity index, particle size distribution, zeta potential as well as the aggregation kinetics studied using time-resolved dynamic light scattering, the PVP wrapped CNT was somewhat less prone to agglomeration. However, its long-term stability was lower, and this was attributed to the partial unwrapping of the polyvinyl pyrrolidone layer on the CNT surface. PMID- 21236443 TI - Heme oxygenase-1 promoter polymorphism is a predictor of disease relapse in pancreatic neuroendocrine tumors. AB - BACKGROUND: Current available preoperative diagnostic workup is insufficient to differentiate between benign and malignant pancreatic neuroendocrine tumors (PNET). The aim of the present study was to evaluate the potential prognostic role of the promoter GTn repeat polymorphism (GTn) of the heme oxygenase-1 gene in PNET. METHODS: Tumor, metastasis, corresponding healthy tissue, and peripheral blood leukocyte DNA of 46 patients who underwent surgical resection for PNET were analyzed for GTn by PCR, capillary electrophoresis, and DNA-sequencing. The GTn was correlated to clinicopathologic parameters and clinical outcome. RESULTS: GTn was classified into short (<25) and long (>= 25) alleles and three (SS, SL, and LL) genotypes were defined. There was no difference in GTn genotype among tumor, healthy tissue, metastasis, and peripheral blood leukocyte DNA. The SS and SL genotype displayed significantly more poor differentiated tumors (P = 0.001) and higher tumor recurrence rate (P = 0.0001) compared with LL patients. The LL genotype patients presented predominantly benign PNET (P < 0.001). The LL genotype had the longest disease-free (P < 0.001) and overall survival (P = 0.006). Besides the WHO classification the GTn was identified as a strong predictor of tumor recurrence (hazard ratio 3.1, 95% confidence interval 1.3-7.3) in PNET. CONCLUSION: GTn differentiates between benign and malignant PNET and is a strong predictor of tumor recurrence. PMID- 21236444 TI - Development of a surgical educational research program-fundamental principles and challenges. AB - BACKGROUND: Surgical educational research is the scientific investigation of any aspect of surgical learning, teaching, training, and assessment. The research into development and validation of educational tools is vital to optimize patient care. This can be accomplished by establishing high quality educational research programs within academic surgical departments. This article aims to identify the components involved in educational research and describes the challenges as well as solutions to establishing a high quality surgical educational research program. METHODS: A variety of sources including journal articles, books, and online literature were reviewed in order to determine the pathways involved in conducting educational research and establishing a research program. RESULTS: It is vital to ensure that educational research is acceptable, innovative, robust in design, funded correctly, and disseminated successfully. Challenges faced by the current surgical research programs include structural organization, academic support, credibility, time, funding, relevance, and growth. The solutions to these challenges have been discussed. CONCLUSIONS: To ensure research in surgical education is of high quality and yields credible results, strong leadership in the organization of an educational research program is necessary. PMID- 21236445 TI - TAKEDA-143242 increased survival via reduced cytokines in porcine peritonitis. AB - TAKEDA-143242 (TAK-242) is a small molecule shown to inhibit lipopolysaccharide induced intracellular signaling and inflammation. In vitro studies demonstrated that TAK-242 can prevent release of TNF-alpha, IL-1beta, and IL-6 from activated macrophages of several species, including pigs. This study tested the hypothesis that TAK-242 would protect pigs from lethal gram-negative peritonitis via an anti cytokine mechanism. A validated model of porcine gram-negative peritonitis, which employs chronically inplantated cardiac transducers and aortic and pulmonary artery catheters, was used. Pigs were pretreated with TAK-242 or its vehicle via a blinding procedure prior to intraperitoneal implantation of an LD(90) dose of E. coli 0111:B4 in a fibrin clot. Ten pigs were treated with TAK-242 and nine with its vehicle. All ten TAK-242 treated pigs survived, while three of the nine vehicle treated pigs survived (P = 0.01 chi(2) test). Pulmonary artery pressure increased markedly in vehicle pigs, and this elevation was significantly (two-way ANOVA) obviated in TAK-242 treated group. Circulating levels of cytokines in vehicle treated pigs showed increased expression (3930 +/- 1770 at 1 h, 1007 +/- 400 TNF-alpha at 2 h; 719 +/- 308 of IL-1beta at 2-6 h; 33000 +/- 1000 of IL-6 at 2-4 h [pg/mL, mean +/- SEM]). Peak circulating levels of these cytokines were significantly reduced by pretreatment with TAK-242 (<25 pg/mL TNF-alpha ; <100 pg/mL IL-1beta; 0-1700 pg/mL IL-6, peak values). This study found that pretreatment with TAK-242 yielded significantly positive survival benefit in a lethal sepsis model that was associated with improved cardiovascular status and suppressed cytokine release. PMID- 21236446 TI - Brain abnormalities in neuromyelitis optica. AB - BACKGROUND: Differentiating neuromyelitis optica (NMO) from multiple sclerosis (MS) is a real challenge in the clinical field. In the past, NMO (not MS), was inferred when abnormality was not detected in the brain magnetic resonance imaging (MRI). Recently, some studies have reported abnormalities in the brain MRIs of NMO, but only few among the Asian population. The aim of this study was to evaluate the frequency of brain MRI among Korean NMO patients and characterize findings that might be helpful to distinguish NMO from MS. METHODS: Medical records, NMO-IgG, and brain MRI of 17 patients diagnosed with NMO by the revised diagnostic criteria of Wingerchuk et al. (2006) [6] from 2008 to 2010, were reviewed. RESULTS: 11 out of 17 patients (64.7%) had abnormal MRI findings. More than two lesions were detected in most patients. The majority of patients with brain MRI abnormality showed nonspecific (5 patients) or atypical (6 patients) findings. Cerebral white matter was most frequently involved (58.8%). 3 patients (17.6%) involved corpus callosum, 4 (23.5%) with internal capsule, 2 (11.8%) with cerebellum, and 3 (17.6%) with brainstem. There were 5 (29.4%) patients who met the Paty et al. criteria (1988) [15] and 3 patients (35.3%) who met the multiple sclerosis (MS) spatial distribution diagnostic criteria of Barkhof et al. (1997) [14] in their brain MRI. CONCLUSIONS: Brain abnormalities have been frequently found among Korean NMO patients and the frequencies have been reported to be higher than that of Caucasians. Current MS spatial distribution criteria, such as Paty et al. (1988) [15] or Barkhof et al. (1997) [14], are not sufficient to discriminate NMO from MS in brain MRI findings. Our results will provide valuable information that would be useful in establishing future revising criteria for NMO. PMID- 21236447 TI - Proton magnetic resonance spectroscopy of the intrinsic tongue muscles in patients with myasthenia gravis with different autoantibodies. AB - OBJECTIVE: To assess lipid composition of the intrinsic tongue muscles in patients with myasthenia gravis (MG). METHODS: This study included 15 MG patients with antibodies against muscle-specific kinase (MuSK), 15 matched MG patients with antibodies against acetylcholine receptor (AChR) and 15 matched healthy subjects. Middle posterior region of the tongue was analyzed by single voxel point-resolved proton magnetic resonance spectroscopy (MRS) using 1.5T MRI scanner. RESULTS: MRS obtained from subject with AChR MG showed a broad resonance arising from methylene groups of lipids (PMN) with no observable shoulder attributed to methyl groups (PML). Full-width at half maximum (FWHM) of PMN+PML peak showed higher value in patients with AChR MG in comparison to healthy subjects and MuSK MG patients (p<0.05). In patients with MuSK MG, the shape and FWHM of PMN+PML peak was similar as in healthy subjects (p>0.05), with tendency toward increased ratio between PMN and resonance from vinyl protons of lipids (PV). In both AChR and MuSK MG, total creatine resonance (creatine+phosphocreatine, CP) was almost absent with significant increase of PMN/CP ratio in comparison to healthy subjects (p<0.05). CONCLUSION: MRS is useful in revealing muscle lipid composition in MG. In patients with AChR MG, MRS showed increased lipid content in the tongue muscles due to the lipid migration from intra- to extramyocellular space. Finding in patients with MuSK MG might reflect intramyocellular lipid deposition in the tongue. CP decrease in tongue muscles indicated impairment of oxidative metabolism in both AChR MG and MuSK MG. PMID- 21236448 TI - Thymoma-associated myasthenia gravis without acetylcholine receptor antibodies. AB - Patients with myasthenia gravis and thymoma usually present antibodies to the acetylcholine receptor (AchR-Ab). Only two cases of thymoma-associated myasthenia gravis without AchR-Ab have been previously reported. We describe a case of seronegative thymoma-associated myasthenia gravis as a further evidence of the variability of myasthenia gravis in terms of antibody profile and thymic pathological findings. PMID- 21236449 TI - Intraoperative device closure of atrial septal defects with inferior vena cava rim deficiency: a safe alternative to surgical repair. AB - OBJECTIVE: Our objective was to evaluate the safety and feasibility of intraoperative device closure of atrial septal defects with inferior vena cava rim deficiency. METHODS: From January 2005 to December 2008, we enrolled 65 patients who had a secundum atrial septal defect with inferior vena cava rim deficiency closure in our institution. Patients were divided into 2 groups: 35 patients in group I underwent intraoperative device closure with a right lateral minithoracotomy and 30 in group II underwent open cardiac repair with a right lateral thoracotomy and cardiopulmonary bypass. Intraoperative device closure involved a minimal intercostal incision that was performed after full evaluation of the atrial septal defect by transthoracic echocardiography and the insertion of the device through the delivery sheath to occlude the atrial septal defect. RESULTS: The procedure was successful in all patients. In group I, the diameter of the atrial septal defect ranged from 30 to 44 mm (mean, 35.3 +/- 3.9 mm), and the size of the implanted occluder ranged from 34 to 48 mm (mean, 40 +/- 2.1 mm). The total occlusion rate was 82.9% immediately after the operation, 97.1% at 3 months, and 100% at 12 and 24 months of follow-up. In group II, all patients had successful closure. A follow-up period of 12 to 24 months was obtained in both groups. During the follow-up, there was no recurrence, thrombosis, or device failure. In our comparative studies, group II had significantly longer operative time, intensive care unit stay, and hospital stay than group I (P < .001). The cost of group I was less than that of group II (20,450.9 +/- 840.8 RMB vs 25,884.9 +/- 701.8; P < .001). CONCLUSIONS: Intraoperative device closure of atrial septal defects with inferior vena cava rim deficiency is a safe and feasible technique. It has the advantages of cost savings, cosmetic results, and less trauma than surgical closure. Early and midterm results are encouraging. PMID- 21236450 TI - Seabirds and chronic oil pollution: self-cleaning properties of gulls, Laridae, as revealed from colour-ring sightings. AB - Mystery oil spills off the Dutch coast affected colonial, adult Lesser Black backed Gulls prior to and within the breeding season. From colour-ringed individuals, it was demonstrated that most oiled birds survived and were clean within a few weeks and often bred successfully. Further evidence of self-cleaning properties of Larus-gulls is provided from a long-term colour-ringing project (1984-2009). In total 46 birds were reported 'oiled', two died, but the majority cleaned itself and survived for up to 20 years after being oiled. From colour ring data and 30 years of beached bird surveys (1980-2010) it is demonstrated that the effects of chronic oil pollution is larger in winter than in summer; a reflection of seasonal differences in exposure and environmental conditions. The self-cleaning properties of gulls are such that long-term survival is not necessarily jeopardized and even in a breeding season, not all is lost in case of a spill. PMID- 21236451 TI - Intensive insulin treatment increases donor site wound protein synthesis in burn patients. AB - BACKGROUND: In the treatment of burns, patients' own skin is the preferred material to cover burn wounds, resulting in the need to create a donor site wound. Enhancement of healing of the donor site wound would be beneficial in burn patients. Insulin, an anabolic agent, is used routinely to treat hyperglycemia after injury. We investigated whether intensive insulin treatment increases fractional synthesis rate (FSR) of the donor site wound protein and decreases the length of hospitalization normalized for total body surface area burned (LOS/TBSA). METHODS: FSR of the donor site wound protein was measured in pediatric patients randomized to control (n = 13) and insulin (n = 10) treatments. Depending on the postoperative day when the tracer study was done, studies were divided into "early" (days < 5) and "late" (days >= 5) periods. RESULTS: FSR of the donor site wound protein was greater in the insulin group at the "early" period of wound healing (control vs insulin, 8.2 +/- 3.8 vs 13.1 +/- 6.9% per day; P < .05); but not at the "late" (control vs insulin, 19.7 +/- 4.6 vs 16.6 +/- 4.0% per day; P > .05). Despite these differences, LOS/TBSA was not decreased in the insulin group. Correlation analyses demonstrated that, independent of the treatment regimen, FSR positively correlated (P < .05) with time after creation of the donor site and negatively correlated (P < .05) with LOS/TBSA. CONCLUSION: Insulin treatment increased FSR of the donor site wound protein in the early period of wound healing; FSR correlated with LOS/TBSA independent of the treatment regimen. PMID- 21236452 TI - A comparative study between 1 and 2 effective doses of rocuronium for intraoperative neuromonitoring during thyroid surgery. AB - BACKGROUND: The goal of this study was to explore an ideal application of rocuronium to enable adequate muscle relaxation for intubation without significantly affecting the evoked potentials measured by intraoperative neuromonitoring during thyroid surgery. METHODS: A total of 80 patients were randomized to receive 1 (group 1, n = 40) or 2 (group 2, n = 40) effective doses (ED(95)) of rocuronium to facilitate electromyographic (EMG) endotracheal tube insertion. Evoked potentials were obtained every 5 minutes by stimulating the vagus nerve between the time period of 30 and 70 minutes after administration of rocuronium. The magnitude of evoked potentials at each time point and the tracheal intubating conditions were compared between groups. Accelerometry (twitch [% TW]) was used to monitor the quantitative degree of neuromuscular transmission at the adductor pollicis muscle. RESULTS: At 30 minutes after administration of rocuronium, the rate of positive EMG response was 100% (40/40) in group 1 and 53% (21/40) in group 2 (P < .001). Positive EMG signals were obtained for all patients in group 2 until 55 minutes after administration of rocuronium. The mean amplitude detected from the time point of 30 to 60 minutes was greater in group 1 than in group 2 (P < .01). The time to tracheal intubation was 208 +/- 59 seconds in group 1 and 114 +/- 26 seconds in group 2 (P < .001). The overall intubating conditions were better in group 2 than in group 1 patients (P < .001). CONCLUSION: A total of 1 ED(95) of rocuronium (0.3 mg/kg) is an optimal dose for intraoperative neuromonitoring during thyroid surgery. Positive and high EMG signals were obtained in all patients at an early stage of operation, and satisfactory intubating conditions were achieved in most patients. PMID- 21236453 TI - Use of preoperative, 3-dimensional magnetic resonance cholangiopancreatography in pediatric choledochal cysts. AB - BACKGROUND: Standard choledochal cyst (CC) operations involve dilated extrahepatic bile duct excision followed by biloenterostomy. However, biliary variants and associated intrahepatic bile duct (IHBD) stenoses or dilatations triggering postoperative sequelae require additional procedures. The usefulness of preoperative 3-dimensional magnetic resonance cholangiopancreatography (3D MRCP) and virtual cholangioscopy (VES) for observing biliary morphology and pancreaticobiliary maljunction (PBM) was evaluated. METHODS: In 16 pediatric CC patients (age range, 4 months to 9 years; median, 3 years), visualization of PBM and aberrant bile duct anatomy and IHBD morphology at the hepatic hilum (HH), umbilical portion (UP), and posterior branch (POST) were compared between 3D-MRCP and intraoperative cholangiography (IOC). VES and intraoperative cholangioscopy (IOS) findings were compared. RESULTS: HH, UP, and POST visualization rates were 100%, 94%, and 94%, respectively, by 3D-MRCP, and 100%, 69%, and 69%, respectively, by IOC. IHBD stenosis detection rates at each region were 38%, 13%, and 13%, respectively, by 3D-MRCP, and 25%, 0%, and 9%, respectively, by IOC. IHBD dilatation detection rates at each part were 75%, 47%, and 60%, respectively, by 3D-MRCP, and 88%, 82%, and 91%, respectively, by IOC. PBM was confirmed in 56% and 93% of cases on 3D-MRCP and IOC, respectively. Both 3D-MRCP and IOC showed biliary variants in 5 cases (31%). VES showed membranous strictures at HH, UP, and POST in 6, 2, and 2 cases, respectively, whereas IOS did so at HH in 4 cases and POST in 2. CONCLUSION: Preoperative 3D-MRCP and VES accurately depict biliary morphology, allowing concrete operative planning in pediatric CC patients, complementing IOC and IOS. PMID- 21236454 TI - Enhanced recovery pathways optimize health outcomes and resource utilization: a meta-analysis of randomized controlled trials in colorectal surgery. AB - BACKGROUND: Health care systems provide care to increasingly complex and elderly patients. Colorectal surgery is a prime example, with high volumes of major procedures, significant morbidity, prolonged hospital stays, and unplanned readmissions. This situation is exacerbated by an exponential rise in costs that threatens the stability of health care systems. Enhanced recovery pathways (ERP) have been proposed as a means to reduce morbidity and improve effectiveness of care. We have reviewed the evidence supporting the implementation of ERP in clinical practice. METHODS: Medline, Embase, and the Cochrane library were searched for randomized, controlled trials comparing ERP with traditional care in colorectal surgery. Systematic reviews and papers on ERP based on data published in major surgical and anesthesiology journals were critically reviewed by international contributors, experienced in the development and implementation of ERP. RESULTS: A random-effect Bayesian meta-analysis was performed, including 6 randomized, controlled trials totalizing 452 patients. For patients adhering to ERP, length of stay decreased by 2.5 days (95% credible interval [CrI] -3.92 to 1.11), whereas 30-day morbidity was halved (relative risk, 0.52; 95% CrI, 0.36 0.73) and readmission was not increased (relative risk, 0.59; 95% CrI, 0.14-1.43) when compared with patients undergoing traditional care. CONCLUSION: Adherence to ERP achieves a reproducible improvement in the quality of care by enabling standardization of health care processes. Thus, while accelerating recovery and safely reducing hospital stay, ERPs optimize utilization of health care resources. ERPs can and should be routinely used in care after colorectal and other major gastrointestinal procedures. PMID- 21236455 TI - Posthepatectomy liver failure: a definition and grading by the International Study Group of Liver Surgery (ISGLS). AB - BACKGROUND: Posthepatectomy liver failure is a feared complication after hepatic resection and a major cause of perioperative mortality. There is currently no standardized definition of posthepatectomy liver failure that allows valid comparison of results from different studies and institutions. The aim of the current article was to propose a definition and grading of severity of posthepatectomy liver failure. METHODS: A literature search on posthepatectomy liver failure after hepatic resection was conducted. Based on the normal course of biochemical liver function tests after hepatic resection, a simple and easily applicable definition of posthepatectomy liver failure was developed by the International Study Group of Liver Surgery. Furthermore, a grading of severity is proposed based on the impact on patients' clinical management. RESULTS: No uniform definition of posthepatectomy liver failure has been established in the literature addressing hepatic surgery. Considering the normal postoperative course of serum bilirubin concentration and International Normalized Ratio, we propose defining posthepatectomy liver failure as the impaired ability of the liver to maintain its synthetic, excretory, and detoxifying functions, which are characterized by an increased international normalized ratio and concomitant hyperbilirubinemia (according to the normal limits of the local laboratory) on or after postoperative day 5. The severity of posthepatectomy liver failure should be graded based on its impact on clinical management. Grade A posthepatectomy liver failure requires no change of the patient's clinical management. The clinical management of patients with grade B posthepatectomy liver failure deviates from the regular course but does not require invasive therapy. The need for invasive treatment defines grade C posthepatectomy liver failure. CONCLUSION: The current definition of posthepatectomy liver failure is simple and easily applicable in clinical routine. This definition can be used in future studies to allow objective and accurate comparisons of operative interventions in the field of hepatic surgery. PMID- 21236456 TI - Orthopedic boot camp: examining the effectiveness of an intensive surgical skills course. AB - BACKGROUND: Changes in health care across the globe have had a profound impact on the number of hands-on surgical training opportunities that are available to residents. In the current study, we examine whether an intensive laboratory-based skills course at the start of orthopedic surgical training is an effective mechanism for teaching core technical skills. METHODS: First-year residents were divided into 3 groups (on-service, n = 8; off-service, n = 8; and a new, competency-based program that has as a major element of the curriculum a focused, intensive skills laboratory-based experience, n = 6). Baseline surgical skills were assessed prior to commencing training. The intensive skills laboratory group was then given an intensive surgical skills course, whereas the other 2 groups embarked on traditional residency. After the surgical skills course, all the residents were assessed for core surgical skills using an objective structured assessment of technical skills (OSATS) procedure. RESULTS: Pretraining scores revealed no differences between the groups of residents using both checklist (F[2,19] = 0.852, P = .442) and global rating scores (F[2,19] = 0.704, P = .507). Post-training scores revealed a significant difference, with residents from the intensive skills laboratory group performing better on both the checklists (on service = 78.9, off-service = 78.6, intensive skills laboratory = 92.3; F[2,19] = 6.914, P < .01) and global rating scores (on-service = 3.4, off-service = 3.4, intensive skills laboratory = 4.3; F[2,19] = 5.722, P < .01), than the other groups who showed no differences between them. CONCLUSION: The intensive skills course used in this study was highly effective at teaching and developing targeted surgical skills in first-year orthopedic residents. We predict that allowing residents to acquire key technical skills at the start of their training will enhance learning opportunities at later stages of training. PMID- 21236458 TI - Unilateral proptosis in a 60-year-old man. AB - A 60-year-old immunocompromised patient developed rapidly progressive proptosis that was secondary to mucormycosis. This life-threatening fungal infection usually is associated with chemosis, proptosis, ophthalmoplegia, and visual loss. The fungus may invade ocular structures, sinuses, and extend into the brain. The standard of care includes correction of the underlying condition, administration of liposomal amphotericin B with posaconazole, and surgical debridement of infected and necrotic tissue. We present a case of unilateral proptosis due to mucormycosis in an immunocompromised patient. The patient was successfully managed medically without exenteration. The indications for exenteration are currently unclear, and no clinical guidelines exist. PMID- 21236457 TI - N-myc downstream regulated gene-1 expression correlates with reduced pancreatic cancer growth and increased apoptosis in vitro and in vivo. AB - BACKGROUND: The role of N-myc downstream regulated gene-1 (NDRG1) in cancer has recently gained interest, as potential regulator of cell death and tumor suppressor. Although its normal function in the pancreas is largely unknown, loss of NDRG1 expression is associated with a more aggressive tumor phenotype and poor outcome in pancreatic cancer patients. METHODS: NDRG1 expression was determined in human pancreatic cancer samples and across a panel of 6 pancreatic cancer cell lines. HPAF-II cells were stably transfected with full-length NDRG1 (HP(NDRG1)) or the empty vector (HP(NEG)). BxPC-3 cells were silenced for NDRG1. These cells were analyzed for cell growth, cell cycle, apoptosis, and pro-apoptotic gene expression. They were transduced with lentiviral vector expressing luciferase to establish an orthotopic xenograft model. In vivo tumor growth was assessed by bioluminescence imaging. RESULTS: Growth of HP(NDRG1) was impaired in anchorage dependent and abolished in anchorage-independent assays respectively. These results were confirmed in BxPC-3 silenced for NDRG1. Growth inhibition was induced by enhanced apoptosis. Seven pro-apoptotic genes were up-regulated in HP(NDRG1) cells. In vivo, HP(NDRG1) tumors showed no growth over 6 weeks, while HP(NEG) tumors grew prominently, correlating with a 325-fold increase in light emission. CONCLUSION: In this model we found that expression of NDRG1 correlates with decreased growth in human pancreatic cancer cells in vitro and in vivo. The observation that NDRG1 completely inhibited growth in anchorage-independent assays and in vivo supports a biological function as a tumor suppressor in pancreatic cancer. PMID- 21236459 TI - Advantages and limitations of small gauge vitrectomy. AB - Small gauge vitrectomy utilizing 23- and 25-gauge instrumentation has definite advantages, but also limitations, due to the physics of smaller instruments and sutureless surgery. Higher infusion and aspiration pressures are needed to remove the vitreous using 23- and 25-gauge probes. The advantages include decreased surgical times, less tissue manipulation, reduced inflammation and pain postoperatively with more rapid visual recovery. A disadvantage is greater instrument flexion than 20-gauge probes, making small gauge vitrectomy more appropriate for indications such as vitreous opacities, epiretinal membranes, macular holes, and simple retinal detachments. There are also some increased complications related to small gauge vitrectomy, including dislocation of cannulas intraoperatively, early postoperative hypotony, choroidal detachment, and possibly an increased risk of infectious endophthalmitis. PMID- 21236460 TI - Modeling electrical response of polymer-coated SAW resonators by equivalent circuit representation. AB - The paper presents an equivalent circuit model of the polymer coated surface acoustic wave (SAW) resonators by combining coupling-of-mode (COM) description of SAW resonators and perturbation calculation of SAW propagation under polymer loading. An expression for the motional load produced by polymer coating is deduced in terms of COM parameters and polymer characteristics. In addition, expressions for the shifts in resonance frequency and attenuation due to polymer loading are obtained. Simulation results are presented for one-port and two-port resonator devices coated with viscoelastic thin polymer film. The influence of polymer film on resonator response is studied with regard to variations in film thickness and shear modulus. The model simplifies understanding of polymer-coated SAW sensors. PMID- 21236462 TI - Identification of an NTPase motif in classical swine fever virus NS4B protein. AB - Classical swine fever (CSF) is a highly contagious and often fatal disease of swine caused by CSF virus (CSFV), a positive-sense single-stranded RNA virus within the Pestivirus genus of the Flaviviridae family. Here, we have identified conserved sequence elements observed in nucleotide-binding motifs (NBM) that hydrolyze NTPs within the CSFV non-structural (NS) protein NS4B. Expressed NS4B protein hydrolyzes both ATP and GTP. Substitutions of critical residues within the identified NS4B NBM Walker A and B motifs significantly impair the ATPase and GTPase activities of expressed proteins. Similar mutations introduced into the genetic backbone of a full-length cDNA copy of CSFV strain Brescia rendered no infectious viruses or viruses with impaired replication capabilities, suggesting that this NTPase activity is critical for the CSFV cycle. Recovered mutant viruses retained a virulent phenotype, as parental strain Brescia, in infected swine. These results have important implications for developing novel antiviral strategies against CSFV infection. PMID- 21236463 TI - Transactivation of human parvovirus B19 gene expression in endothelial cells by adenoviral helper functions. AB - Human parvovirus B19 (B19V) DNA is highly prevalent in endothelial cells lining up intramyocardial arterioles and postcapillary venules of patients with chronic myocarditis and cardiomyopathies. We addressed the question of a possible stimulation of B19V gene expression in endothelial cells by infection with adenoviruses. Adenovirus infection led to a strong augmentation of B19V structural and nonstructural proteins in individual endothelial cells infected with B19V or transfected with an infectious B19V genome. Transactivation was mostly mediated at the level of transcription and not due to adenovirus-mediated induction of second-strand synthesis from the single-stranded parvoviral genome. The main adenoviral functions required were E1A and E4orf6, which displayed synergistic effects. Furthermore, a limited B19V genome replication could be demonstrated in endothelial cells and adenovirus infection induced the appearance of putative dimeric replication intermediates. Thus the almost complete block in B19V gene expression seen in endothelial cells can be abrogated by infection with other viruses. PMID- 21236464 TI - As(III) removal by hybrid reactive membrane process combined with ozonation. AB - The removal of arsenite (As(III)) was investigated using a combined ozonation reactive ceramic membrane incorporated with iron oxide nanoparticles (IONs). A disk-type gamma-Al(2)O(3) ultrafiltration membrane (CM) was covered with IONs using an annealing method. The reactive ceramic membrane (RM) was then characterized using SEM, zeta potential measurements, and pure water permeability tests. The results showed that IONs were well attached on the RM surface. In addition, doped IONs had no significant effects on the pure water permeability and the isoelectric point (IEP) of RM. Laboratory-scale experiments were subsequently conducted to investigate the impact of combined RM and ozonation processes on As(III) rejection. The experimental results revealed that As(III) rejection rate of RM with an ozonation process (92%) significantly enhanced compared with that of CM (63%). The influence of operating parameters (i.e., pH, NOM, co-existing ions and temperature) revealed that an increase of pH, a decrease of temperature and presence of NOM led to a higher As(III) rejection, whereas the presence of co-existing ions in the feed water significantly reduced the As(III) rejection; divalent counter-ions were the greatest inhibitors for As(III) rejection. Finally, a comparison of As(III) rejection in synthetic water and real groundwater confirmed the importance of real conditions in the hybrid reactive membrane process with continuous ozonation. PMID- 21236461 TI - Induction and function of virus-specific CD4+ T cell responses. AB - CD4+ T cells - often referred to as T-helper cells - play a central role in immune defense and pathogenesis. Virus infections and vaccines stimulate and expand populations of antigen-specific CD4+ T cells in mice and in man. These virus-specific CD4+ T cells are extremely important in antiviral protection: deficiencies in CD4+ T cells are associated with virus reactivation, generalized susceptibility to opportunistic infections, and poor vaccine efficacy. As described below, CD4+ T cells influence effector and memory CD8+ T cell responses, humoral immunity, and the antimicrobial activity of macrophages and are involved in recruiting cells to sites of infection. This review summarizes a few key points about the dynamics of the CD4+ T cell response to virus infection, the positive role of pro-inflammatory cytokines in the differentiation of virus specific CD4+ T cells, and new areas of investigation to improve vaccines against virus infection. PMID- 21236465 TI - Comparison of sewage sludge toxicity to plants and invertebrates in three different soils. AB - Understanding the effect of soil type on the overall toxicity of sewage sludge is one of the most important issues concerning environmental risks associated with the sewage sludge land application. The aim of the study was to determine the influence of different soils (sandy, loamy and OECD soil) on sewage sludges toxicity in relation to plants (Lepidium sativum, Sorghum saccharatum, Sinapis alba) and an invertebrate species (Heterocypris incongruens). The most evident negative influence of sewage sludges on root growth was observed in the case of OECD soil. The EC(50) values determined on the basis of the root growth inhibition of all tested plants were in the range 0.1-6.4%, 0.03-9.4% and 6.6 22.1% (% of sewage sludgekg(-1) soil) for OECD, sandy and loamy soil, respectively. Soil type also affects the sewage sludge toxicity in relation to H. incongruens. The LC(50) (mortality) values ranged from 0.26% to 11.5% depending on the sludge tested. For EC(50) (growth inhibition) values ranged from 10.7% to 36.2%. PMID- 21236466 TI - Comprehensive two-dimensional gas chromatography time of flight mass spectrometry (GC*GC-TOFMS) for environmental forensic investigations in developing countries. AB - The disposal and dumping of toxic waste is a matter of growing concern in developing countries, including South Africa. Frequently these countries do not possess access to gas chromatography-high resolution mass spectrometry (GC-HRMS) for the determination of persistent organic pollutants (POPs). This publication describes an alternative approach to the investigation of toxic waste using comprehensive gas chromatography coupled to time of flight mass spectrometry (GC*GC-TOFMS). The technology permits both comprehensive screening of toxic samples for numerous classes of organic pollutants and also quantitative analysis for the individual compounds. This paper describes the use of this technique by analysing samples obtained from a hazardous waste treatment facility in South Africa. After sampling and extraction the samples were analysed for polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs) and four dioxin-like non-ortho substituted polychlorinated biphenyls (PCBs). The quantitative values, as well as detection limits, obtained using the GC*GC-TOFMS methodology compares well with those obtained using GC-HRMS; the accepted benchmark technology for this analysis. Although GC*GC-TOFMS is not a target compound analytical technique (as is GC-HRMS), it is possible to obtain information on numerous other classes of organic pollutants present in the samples in one analytical run. This is not possible with GC-HRMS. Several different column combinations have been investigated for handling very complex waste samples and suggestions are presented for the most suitable combination. PMID- 21236467 TI - Expression of Pirh2, a p27(Kip1) ubiquitin ligase, in hepatocellular carcinoma: correlation with p27(Kip1) and cell proliferation. AB - p53-Induced ring-H2 protein (Pirh2), a recently identified ubiquitin-protein ligase, interacts with p27(Kip1) to promote ubiquitination of p27(Kip1) independently of p53. High Pirh2 and low p27(Kip1) immunoreactivity are associated with a poor prognosis in several cancers, including resistant phenotypes. In the present study, we investigated the role of Pirh2 and p27(Kip1) in human hepatocellular carcinoma (HCC) progression. Immunohistochemical analysis was performed on formalin-fixed paraffin sections of 87 specimens. Statistical analysis showed that expression of Pirh2 was negatively related to p27(Kip1) expression (r = 0.787; P < .05), and Pirh2 expression correlated significantly with histologic grade (P < .001), venous invasion (P = .004), tumor size (P = .024), and the presence of multiple tumor-bearing lymph nodes (P = .017), whereas p27(Kip1) expression correlated significantly with histologic grade (P < .001), venous invasion (P = .048), and cirrhosis (P = .028). By Kaplan-Meier analysis, the survival curves of low versus high expressers of Pirh2 and p27(Kip1) showed significant separation (P < .01). Molecular interaction could be demonstrated between Pirh2 and p27(Kip1) in three HCC cell lines. In vitro, following release of two HCC cell lines from serum starvation, the expression of Pirh2 was upregulated, whereas p27(Kip1) was downregulated. Our results suggest that Pirh2 mediates the degradation of p27(Kip1) and participates in cell proliferation in human HCC. These findings provide a rational framework for further development of Pirh2 inhibitors as a novel class of anti-tumor agents. PMID- 21236468 TI - Tongue necrosis and systemic vascular amyloidosis. AB - Tongue necrosis is a rare but dramatic clinical finding, which is most often related to infection, trauma, malignancy, or vasculitis. We describe an extremely unusual case in which systemic amyloid deposition in small arteries caused by senile systemic amyloidosis was associated with necrosis of the tongue as well as necrosis of portions of the bowel. To our knowledge, this is the first report of ischemic tongue necrosis resulting from vascular amyloidosis. PMID- 21236469 TI - Using artificial fluorescent particles as tracers of livestock wastes within an agricultural catchment. AB - Evidence for the movement of agricultural slurry and associated pollutants into surface waters is often anecdotal, particularly with relation to its 'particulate' components which receive less attention than 'bio-available' soluble phases. To assess the extent of movement of slurry particles artificial fluorescent particles were mixed with slurry and applied to a field sub-catchment within a headwater catchment. Particles were 2-60 MUm in diameter and two different densities, 2.7 and 1.2 g cm(-3) representing 'inorganic' and 'organic' material. Water samples from the field and catchment outlet were collected during two storm events following slurry application and analysed for particle and suspended sediment concentrations (SSC). SSC from the field and catchment outlet always formed clockwise hysteresis loops indicating sediment exhaustion and particles of the two densities were always found to be positively correlated. Particles from the field formed clockwise hysteresis loops during the first discharge event after slurry application, but anti-clockwise hysteresis loops during the second monitored event which indicated a depletion of readily mobilisable particles. Particles from the catchment outlet always formed anticlockwise hysteresis loops. Particle size became finer spatially, between field and catchment outlet, and temporally, between successive storm events. The results indicate that slurry particles may be readily transported within catchments but that different areas may contribute to pollutant loads long after the main peak in SSC has passed. The density of the particles did not appear to have any effect on particle transport however the size of the particles may play a more important role in the 2-60 MUm range. PMID- 21236470 TI - Abnormally high prevalence of major components of the metabolic syndrome in subjects with early-onset idiopathic venous thromboembolism. AB - BACKGROUND: Although patients with idiopathic VTE are at higher than normal risk of asymptomatic atherosclerosis and of cardiovascular events, the impact of cardiovascular risk factors on VTE is poorly understood. OBJECTIVE: To assess the prevalence of the metabolic syndrome and of its components in patients with early onset idiopathic VTE. METHODS: As many as 323 patients referred to our Thrombosis Ward for a recent (<6-months) early-onset idiopathic venous thromboembolism (VTE), were compared with 868 gender- and age-matched subjects, in whom a history of venous thrombosis had been excluded, referred during the same period time to our Ward. All had undergone a clinical assessment for smoking habits and for the presence of the components of the metabolic syndrome. RESULTS: The metabolic syndrome was detected in 76/323 cases (23.5%) and in 81/868 controls (9.3%) (p<0.001; OR:2.990; 95%C.I.:2.119-4.217). Smoking was more common in patients with idiopathic VTE than in controls. In addition to the metabolic syndrome as a whole, its major individual determinants (arterial hypertension, impaired fasting glucose plasma levels, abdominal obesity, hypertriglyceridemia, low HDL cholesterol) significantly correlated with idiopathic VTE (p always <0.05). The prevalence of thrombotic events was lower in females than in males (p=0.000; OR:2.217), the latter being most often hypertensives, smokers, hypertriglyceridemics, carriers of a metabolic syndrome and of impaired fasting glucose than females. In a multivariate analysis, arterial hypertension, impaired fasting glucose, abdominal obesity, and hypercholesterolemia independently predicted idiopathic venous events. CONCLUSIONS: Both metabolic syndrome as a whole and its major components individually considered, independently predict early-onset idiopathic VTE. PMID- 21236471 TI - Activated factor XI and tissue factor in chronic obstructive pulmonary disease: links with inflammation and thrombin generation. AB - INTRODUCTION: Increased cardiovascular mortality and risk of venous thromboembolism are serious extra-pulmonary complications of chronic obstructive pulmonary disease (COPD). Previously, circulating active tissue factor (TF) and factor XIa (FXIa) have been reported to be associated with acute coronary syndromes. OBJECTIVE: To measure plasma FXIa and active TF, prothrombin fragment 1.2 (F1.2), and markers of systemic inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], tumor necrosis factor alpha [TNFalpha] and matrix metalloproteinase 9 [MMP-9]) in 60 patients with documented stable COPD free of previous thromboembolic events. METHODS: In-house clotting assays using inhibitory monoclonal antibodies against FXIa and TF. RESULTS: FXIa was detected in 9 (15%) and TF activity in 7 (11.7%) COPD patients. Subjects positive for FXIa and/or TF (n=10; 16.7%) had higher F1.2 (median [interquartile range], 398 [216] vs 192 [42] pM, p<0.000001), fibrinogen (5.58 [2.01] vs 3.97 [2.47] g/L, p=0.0007), CRP (14.75 [1.20] vs 1.88 [2.95] mg/L, p<0.000001), IL-6 (8.14 [4.74] vs 2.45 [2.24] pg/mL, p=0.00002), and right ventricular systolic pressure (47 [15] vs 38 [12] mmHg, p=0.023), and lower vital capacity (66 [15] vs 80 [17] % predicted, p=0.04) than COPD patients without detectable FXIa and TF. COPD severity was not associated with the presence of circulating FXIa and active TF. CONCLUSIONS: This is the first study to show that active FXIa and TF are present in stable COPD patients, who exhibit enhanced systemic inflammation and thrombin generation. Our findings suggest a new prothrombotic mechanism which might contribute to elevated risk of thromboembolic complications in COPD. PMID- 21236473 TI - Robot-assisted versus total laparoscopic radical hysterectomy in early cervical cancer, a review. AB - OBJECTIVE: The aim of this study was to review current literature on total laparoscopic (TLRH) and robot-assisted radical hysterectomy (RRH) with pelvic lymphadenectomy in the treatment of early stage cervical cancer by analyzing data published in individual case series in order to compare surgical and oncological outcomes. METHODS: Up to January 2010, 27 studies were identified that met the inclusion criteria, together with our own unpublished data of patients, accounted for 342 RRH patients and 914 TLRH patients. RESULTS: There was no statistical difference between the methods in terms of age, BMI or prior abdominal surgery. Estimated mean operative time, blood loss and number of lymph nodes retrieved did not statistically differ between the RRH and TLRH method. Less blood transfusions were needed in patients treated by RRH (5.4%) versus TLRH (9.7%, p<0.05). Both methods were similar in respect to adjuvant chemo- or (chemo)radiation and recurrence rate. When complications were prioritized to severity, major post operative complications where more frequent in RRH patients (9.6%) than in TLRH patients (5.5%, p<0.05). The length of hospital stay was significantly shorter in RRH compared to TLRH treatment (3.3 versus 6.2days respectively; p:0.04). CONCLUSIONS: Robot-assisted and total laparoscopic radical hysterectomy appears to be equally adequate and feasible. RRH studies had small patient populations and further experience beyond the learning curve phase may improve operative time and complication rate. Both minimal invasive techniques should be investigated in a randomized manner. PMID- 21236472 TI - Degradation of cross-linked fibrin by leukocyte elastase as alternative pathway for plasmin-mediated fibrinolysis in sepsis-induced disseminated intravascular coagulation. AB - An alternative pathway for fibrinolysis that comprises leukocyte elastase and its interaction with the plasminogen activator-plasmin system has been suggested. Plasma levels of cross-linked fibrin degradation product by leukocyte elastase (e XDP) were significantly increased in patients with sepsis induced disseminated intravascular coagulation (DIC) compared with healthy subjects (18.6+/-19.9 vs 0.58+/-0.47U/mL, p<0.001). Twenty seven unique spots were identified from e-XDP dominant patients by immune-purification and two-dimensional difference gel electrophoresis, and they contained fibrinogen Bbeta-chain derived fragments Bbeta Asp-164, Ser-200, Gln-301, Ala-354, Ile-484 and gamma-chain derivatives gamma Val-274 at their amino-termini by acquired and processed tandem mass spectrometer. The Sequential Organ Failure Assessment Scores in patients with e XDPs levels 3-10U/mL were significantly lower than those with e-XDPs levels 3U/mL, 10-30U/mL, and 30- U/mL. The adjusted odds for 28-day mortality rate in patients with e-XDP levels less than 3U/mL (hazard ratio, 4.432; 95% CI, 1.557 12.615 [p=0.005]) were significantly higher than those in patients with e-XDP levels of 3-10U/mL. These data suggest that leukocyte elastase might contribute to the degradation of cross-linked fibrin in sepsis-induced DIC. PMID- 21236474 TI - The impact of diabetes on survival in women with ovarian cancer. AB - OBJECTIVE: Diabetes is increasingly common among cancer patients and plausible biologic mechanisms exist by which diabetes may influence cancer prognosis. We aimed to investigate the impact of diabetes on ovarian cancer outcomes. METHODS: We assessed the outcomes of 570 non-diabetic and 72 diabetic patients with epithelial ovarian, fallopian tube, and primary peritoneal cancer over a ten-year period. All inpatient and outpatient records were reviewed. The primary end points were overall and disease-free survival. RESULTS: Of the 642 cases, 11.2% had type II diabetes. Diabetics were more likely to be older, had a higher BMI (33.4 vs. 27.8), and had more comorbid conditions. Diabetics were less likely to have been surgically staged as compared to non-diabetics (p=0.04) although stage, grade, and likelihood of optimal cytoreduction were similar between groups. Over a period of 10 years, with an average of 44 months of follow-up, the median overall survival for diabetics was 1503 days. The median overall survival for non diabetics was 2464 days (log rank test, p=0.02). In a Cox proportional hazards multivariable model, diabetes remained a significant predictor of overall survival (HR=2.04, p<0.01). CONCLUSIONS: Diabetics with ovarian cancer demonstrate strikingly poorer survival. The underlying reason for this is yet unknown and deserves further attention. Differences in care, competing risks of death, and changes within the tumor biology are plausible mechanisms for the observed difference in survival. PMID- 21236475 TI - Tyrosine kinase A receptor (trkA): a potential marker in epithelial ovarian cancer. AB - OBJECTIVES: To evaluate the role of trkA receptor as a potential tumor marker in serous epithelial ovarian cancer and its relationship with the angiogenic factors expression as vascular endothelial growth factor (VEGF) and nerve growth factor (NGF). Additionally, to examine whether NGF and VEGF secreted by epithelial ovarian cancer (EOC) explants and from epithelial ovarian cancer cell line (A2780) are involved in the process of angiogenesis, such as cellular proliferation, migration and differentiation of the human endothelial cell line (EA.hy926). METHODS: The mRNA levels of VEGF, NGF and trkA receptors were measured using PCR in 60 ovarian samples. Cellular localization and semi quantitative estimation of VEGF, NGF, total trkA and p-trkA was performed using IHC in epithelial cells. NGF, total trkA and p-trkA protein were also evaluated in endothelial cells from the same tissues. Human endothelial cell line EA.hy926 was cultured with conditioned media obtained from both EOC explants and from the A2780 cell line, with or without NGF stimulus. RESULTS: Significantly higher levels of NGF, total trkA and p-trkA protein expressions were observed in epithelial and endothelial cells in poorly differentiated EOC versus normal ovary. Interestingly, the p-trkA receptor expression level showed the most significant difference and its presence was only found in borderline tumor and EOC samples indicating the importance of trkA receptor in EOC as a potential tumor marker. A significant increase in proliferation, migration and differentiation of EA.hy926 cells was observed with NGF, and this effect was significantly reverted when NGF was immuno-blocked and when a trkA inhibitor was used, showing that NGF is an important angiogenic factor in EOC by activating its trkA receptor. CONCLUSION: These results indicate that p-trkA may be considered as a new potential tumor marker in EOC, and that NGF may also act as a direct angiogenic factor in EOC. PMID- 21236476 TI - CD8+ T cells are recruited early to allergen exposure sites in atopy patch test reactions in human atopic dermatitis. PMID- 21236477 TI - Asthma control differences between inhaled corticosteroids likely related to differences in patient severity. PMID- 21236478 TI - Human TH17 cells express a functional IL-13 receptor and IL-13 attenuates IL-17A production. AB - BACKGROUND: IL-13 is a central mediator of airway responsiveness and mucus expression in patients with allergic airway inflammation, and IL-13 is currently a therapeutic target for asthma. However, little is known about how IL-13 regulates human CD4(+) T-cell lineages because IL-13 receptor (IL-13R) alpha1, a subunit of IL-13R, has not previously been reported to exist on human T cells. OBJECTIVE: We sought to determine whether human CD4(+) T(H)17 cells express IL 13Ralpha1 and whether IL-13 regulates T(H)17 cytokine production. METHODS: Naive human CD4(+) cells were isolated from whole blood, activated with anti-CD3 and anti-CD28, and polarized to T(H)1, T(H)2, T(H)17, or induced regulatory T cells in the presence of IL-13 (0-10 ng/mL). Cell supernatants, total RNA, or total protein was examined 4 days after T(H)17 polarization. RESULTS: T(H)17 cells, but not T(H)0, T(H)1, T(H)2, or induced regulatory T cells, expressed IL-13Ralpha1. IL-13 attenuated IL-17A production, as well as expression of retinoic acid related orphan receptor, runt-related transcription factor-1, and interferon regulatory factor 4 in T(H)17-polarized cells. IL-13 neither inhibited IFN-gamma production from T(H)1 cells nor inhibited IL-4 production from T(H)2 cells. Furthermore, attenuation of IL-17A production only occurred when IL-13 was present within 24 hours of T-cell activation or at the time of restimulation. CONCLUSIONS: IL-13Ralpha1 is expressed on human CD4(+) T(H)17 cells, and IL-13 attenuates IL-17A production at polarization and restimulation. Although IL-13 is an attractive therapeutic target for decreasing symptoms associated with asthma, these results suggest that therapies inhibiting IL-13 production could have adverse side effects by increasing IL-17A production. PMID- 21236479 TI - Incidence, prevalence, and trends of general practitioner-recorded diagnosis of peanut allergy in England, 2001 to 2005. AB - BACKGROUND: Previous descriptions of the epidemiology of peanut allergy have mainly been derived from small cross-sectional studies. OBJECTIVE: To interrogate a large national research database to provide estimates for the incidence, prevalence, and trends of general practitioner (GP)-recorded diagnosis of peanut allergy in the English population. METHODS: Version 10 of the QRESEARCH database was used with data from 2,958,366 patients who were registered with 422 United Kingdom general practices in the years 2001 to 2005. The primary outcome was a recording of clinician-diagnosed peanut allergy. RESULTS: The age-sex standardized incidence rate of peanut allergy in 2005 was 0.08 per 1000 person years (95% CI, 0.07-0.08), and the prevalence rate was 0.51 per 1000 patients (95% CI, 0.49-0.54). This translated into an estimated 4000 incident cases (95% CI, 3500-4600) and 25,700 prevalent cases (95% CI, 24,400-27,100) of GP-recorded diagnosis of peanut allergy in England in 2005. During the study period, the incidence rate of peanut allergy remained fairly stable, whereas the prevalence rate doubled. In those under 18 years of age, the crude lifetime prevalence rate was higher in males than females. A significant inverse relationship between prevalence and socioeconomic status was found. CONCLUSION: These data on GP recorded diagnosis of peanut allergy from a large general practice database suggest a much lower prevalence in peanut allergy than has hitherto been found. This difference may in part be explained by underrecording of peanut allergy in general practice. Further research is needed to assess the true frequency of peanut allergy in the population and whether there has been a true increase in recent years. PMID- 21236480 TI - Epidemiology of food allergy. AB - Adverse reactions to foods can occur for a variety of reasons, but a food allergy is caused by a specific immune response. Challenges to determine the prevalence of food allergy include misclassification, biased participation, lack of simple diagnostic tests, rapid evolution of disease, large numbers of potential triggers, and varied clinical phenotypes. Nonetheless, it is clear that this is a common disorder, with studies suggesting a cumulative prevalence of 3% to 6%, representing a significant impact on quality of life and costs. The inclusion of mild reactions to fruits and vegetables could result in calculation of prevalence exceeding 10% in some regions. There are data from numerous studies to suggest an increase in prevalence, but methodologic concerns warrant caution. Prevalence varies by age, geographic location, and possibly race/ethnicity. Many childhood food allergies resolve. Population-based epidemiologic studies have generated numerous novel theories regarding risks, including modifiable factors such as components of the maternal and infant diet, obesity, and the timing of food introduction. Recent and ongoing studies provide insights on risk factors, prevalence, and natural course that may inform clinical trials to improve diagnosis, prevention, and treatment. PMID- 21236481 TI - Delay in feedback repression by cryptochrome 1 is required for circadian clock function. AB - Direct evidence for the requirement of delay in feedback repression in the mammalian circadian clock has been elusive. Cryptochrome 1 (Cry1), an essential clock component, displays evening-time expression and serves as a strong repressor at morning-time elements (E box/E' box). In this study, we reveal that a combination of day-time elements (D box) within the Cry1-proximal promoter and night-time elements (RREs) within its intronic enhancer gives rise to evening time expression. A synthetic composite promoter produced evening-time expression, which was further recapitulated by a simple phase-vector model. Of note, coordination of day-time with night-time elements can modulate the extent of phase delay. A genetic complementation assay in Cry1(-/-):Cry2(-/-) cells revealed that substantial delay of Cry1 expression is required to restore circadian rhythmicity, and its prolonged delay slows circadian oscillation. Taken together, our data suggest that phase delay in Cry1 transcription is required for mammalian clock function. PMID- 21236482 TI - Initial combination antihypertensives: let's ACCELERATE. PMID- 21236483 TI - Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE): a randomised, parallel group trial. AB - BACKGROUND: Short-term studies have suggested that the use of initial combination therapy for the control of blood pressure improves early effectiveness. We tested whether a combination of aliskiren and amlodipine is superior to each monotherapy in early control of blood pressure without excess of adverse events, and if initial control by monotherapy impairs subsequent control by combination therapy. METHODS: We did a double-blind, randomised, parallel-group, superiority trial at 146 primary and secondary care sites in ten countries, with enrolment from Nov 28, 2008, to July 15, 2009. Patients eligible for enrolment had essential hypertension, were aged 18 years or older, and had systolic blood pressure between 150 and 180 mm Hg. Patients were randomly assigned (1:1:2) to treatment with 150 mg aliskiren plus placebo, 5 mg amlodipine plus placebo, or 150 mg aliskiren plus 5 mg amlodipine. Random assignment was through a central interactive voice response system and treatment allocation was masked from the patients. From 16-32 weeks, all patients received combination therapy with 300 mg aliskiren plus 10 mg amlodipine. Our primary endpoints, assessed on an intention to-treat basis (ie, in patients who received the allocated treatment), were the adjusted mean reduction in systolic blood pressure from baseline over 8 to 24 weeks, and then the final reduction at 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862. FINDINGS: 318 patients were randomly assigned to aliskiren, 316 to amlodipine, and 620 to aliskiren plus amlodipine. 315 patients initially allocated to aliskiren, 315 allocated to amlodipine, and 617 allocated to aliskiren plus amlodipine were available for analysis. Patients given initial combination therapy had a 6.5 mm Hg (95% CI 5.3 to 7.7) greater reduction in mean systolic blood pressure than the monotherapy groups (p<0.0001). At 24 weeks, when all patients were on combination treatment, the difference was 1.4 mm Hg (95% CI -0.05 to 2.9; p=0.059). Adverse events caused withdrawal of 85 patients (14%) from the initial aliskiren plus amlodipine group, 45 (14%) from the aliskiren group, and 58 (18%) from the amlodipine group. Adverse events were peripheral oedema, hypotension, or orthostatic hypotension. INTERPRETATION: We believe that routine initial reduction in blood pressure (>150 mm Hg) with a combination such as aliskiren plus amlodipine can be recommended. FUNDING: Novartis Pharma AG. PMID- 21236484 TI - Factors structuring temporal and spatial dynamics of macrobenthic communities in a eutrophic coastal lagoon (Obidos lagoon, Portugal). AB - The present work aimed to identify the main environmental drivers shaping temporal and spatial dynamics of macrobenthic communities within a eutrophic coastal lagoon. Sediments in the Obidos lagoon showed a gradient of increasing metal contamination from the inlet area to inner branches. The mid-lower lagoon area exhibited an intermediate contaminated condition between the inlet and upstream areas, suggesting that the effects of the organic loadings into the lagoon may be reflected until this area. This transitional feature was corroborated by biological data, with macrobenthic assemblages displaying characteristics of down- and upstream areas. Macrobenthic abundance peaked in winter, which was associated with a higher nutrient availability (mainly ammonium) and the proliferation of green macroalgae in mid-lower and inner lagoon areas. However, massive macroalgae growth resulted in a sharp decrease of macrobenthic diversity and abundance in spring, particularly where the higher amounts of decaying algae were detected. Higher dissimilarities between assemblages were detected during winter (and spring, for trophic composition), while in summer, differences were highly attenuated. The least contaminated area (close to the sea inlet) experienced smaller temporal variations for environmental variables, as well as the lowest temporal biological variability. This area was dominated by carnivores, which were related with increased salinity. Deposit-feeders were numerically dominant in the lagoon, being generally spread within organically enriched sandy and muddy areas. The high concentration of chlorophyll a and suspended particulate matter in water was reflected in the abundance of deposit-feeders/suspension-feeders, taking benefit of the high primary productivity. On the other hand, deposit-feeders/herbivores responded to the decay of macroalgae mats in the sediment. Biological associations varied with the biological data used (taxonomic versus trophic group composition; abundance versus biomass), highlighting the relevance of the combination of different data analysis' approaches. In general, BIOENV analysis indicated total phosphorus, biomass of Ulva, metals and organic carbon and nitrogen as being significantly influencing benthic patterns. On the other hand, discrepancies in ecological behaviours of some taxa were also detected in the present study stressing the need for additional studies on the relationships between macrobenthic communities and environmental variables. Implications of the present results for monitoring studies are discussed. PMID- 21236485 TI - Tailoring nanostructured solid-lipid carriers for time-controlled intracellular siRNA kinetics to sustain RNAi-mediated chemosensitization. AB - Use of siRNA for silencing major oncogenic/chemoresistance targets such as survivin has strong potential for cancer therapy. However, a key clinical limitation is their short action, preventing them from sustaining their therapeutic RNA-interference activity for optimal chemosensitization. This issue is tackled from the perspective of intracellular siRNA kinetics using a novel lipid-based "nanostructured siRNA carrier" (NSC), which incorporates variable amount of oil phase into the solid-lipid matrix to modify its siRNA release behaviors. We demonstrate that by manipulating the degradation responses of NSC device to lysosomal enzyme, tailoring of intracellular siRNA kinetics is achievable. A tailored NSC design delivering survivin-siRNA can extend the survivin knockdown period to 9 days, translating into steady, effective in vitro and in vivo chemosensitization of prostate cancer to docetaxel for over a week. All in all, this new NSC design provides a convenient mean to set up a clinically more appealing weekly or longer dosing cycle for siRNA therapy, which addresses a significant unmet need for prostate cancer treatment and is potentially useful for other chronic disease conditions as well. PMID- 21236486 TI - Studying placental transfer of highly purified non-dioxin-like PCBs in two models of the placental barrier. AB - Currently, toxicology and toxicokinetics of purified non-dioxin-like polychlorinated biphenyls (NDL-PCBs) are poorly characterised. Transplacental kinetics of NDL-PCBs can be studied in a variety of models, but careful validation of each model is crucial. We aimed to develop a standard operating procedure for establishing an in vitro model of the human placental barrier. Using this model, we sought to investigate placental transport kinetics of two NDL-PCB congeners. Firstly, we compared the BeWo cell line of the American Type Culture Collection with the BeWo b30 clone and determined parameters for monolayer formation. Secondly, we performed placental perfusions to validate the in vitro model. To that end, the transport of radiolabelled PCB52 and 180 was investigated in both models. We were not able to grow the ATCC cell line to confluency, but determined monolayer formation using BeWo b30. A confluent monolayer is present by day 4 post-seeding, transepithelial electrical resistance being 44.65 +/- 11.06 Omega cm(2) and sodium fluorescein transport being 4.1% +/- 0.18. Both measures can be used as indicators for monolayer formation. Results from kinetic studies in vitro and ex vivo were in excellent agreement. Both NDL PCBs crossed the placental barrier within 2.5 h. We found PCB180 to transfer more rapidly and PCB52 to associate more with placental tissue. Since transport and association patterns were similar in vitro and ex vivo, we conclude that the protocol provided here forms the basis for a good model of the placental barrier using BeWo b30. We hypothesise that the observed differences in transport and association patterns of NDL-PCBs may indicate that toxic effects of PCB52 play a more important role regarding placental function, whereas PCB180 may be of greater importance for fetal toxicity. PMID- 21236488 TI - Calcium signaling in placenta. AB - The placenta sustains the developing fetus throughout gestation and its major functions include nutrition, gas and waste exchange via a variety of passive or active mechanisms. Up to 30 g of calcium (Ca(2+)) actively crosses the trophoblast layer during human pregnancy. The Ca(2+) ion not only plays an important role for skeletal development but is also an essential second messenger. This review is intended to highlight the implications of Ca(2+) signaling during reproduction and specifically placentation. Initially, a Ca(2+) wave induces fertilization of the oocyte. The intracellular Ca(2+) concentration is key for the blastocyst implantation, proper placental development and function. Current knowledge of many proteins involved in placental Ca(2+) regulation and their function in pathologic conditions is largely limited. Recent studies, however, point to alterations in Ca(2+) homeostasis in placental pathologies such as pre-eclampsia (PE) and intrauterine growth restriction (IUGR). A broader understanding of the role of Ca(2+) signaling during human reproduction may offer insight into impaired pregnancy outcomes. PMID- 21236487 TI - IFPA Meeting 2010 Workshops Report II: Placental pathology; trophoblast invasion; fetal sex; parasites and the placenta; decidua and embryonic or fetal loss; trophoblast differentiation and syncytialisation. AB - Workshops are an important part of the IFPA annual meeting. At IFPA Meeting 2010 diverse topics were discussed in twelve themed workshops, six of which are summarized in this report. 1. The placental pathology workshop focused on clinical correlates of placenta accreta/percreta. 2. Mechanisms of regulation of trophoblast invasion and spiral artery remodeling were discussed in the trophoblast invasion workshop. 3. The fetal sex and intrauterine stress workshop explored recent work on placental sex differences and discussed them in the context of whether boys live dangerously in the womb.4. The workshop on parasites addressed inflammatory responses as a sign of interaction between placental tissue and parasites. 5. The decidua and embryonic/fetal loss workshop focused on key regulatory mediators in the decidua, embryo and fetus and how alterations in expression may contribute to different diseases and adverse conditions of pregnancy. 6. The trophoblast differentiation and syncytialisation workshop addressed the regulation of villous cytotrophoblast differentiation and how variations may lead to placental dysfunction and pregnancy complications. PMID- 21236489 TI - Effects of exogenous agmatine in human leukemia HMC-1 and HL-60 cells on proliferation, polyamine metabolism and cell cycle. AB - Impairment of agmatine homeostasis is involved in the regulation of cell proliferation in malignant solid tumors. The present study aimed at analyzing the relevance of agmatine homeostasis in pathophysiology of human leukemia. Proliferation of the human leukemia cells HMC-1 and HL-60 was determined in the absence or presence of agmatine. Apoptosis and cell cycle distribution was investigated by determination of caspase-3 activity and/or flow cytometry after staining with propidium iodide. Expression analysis was performed by qPCR and by a microarray genechip. Exogenous agmatine inhibited proliferation of both HMC-1 and HL-60 cells. The antiproliferative effect was due to interference of agmatine with the cell cycle with no evident signs of apoptosis. Comparative analysis of expression of mRNA in untreated HMC-1 cells and in non-leukemic human mast cells revealed a much lower expression of agmatinase and diamine oxidase in HMC-1 cells indicating a significantly reduced agmatine catabolism in the leukemic cells. At the mRNA level, inhibition of proliferation of both cell lines by agmatine was associated with cell type-specific alterations of the expression of enzymes of the polyamine pathway. The present results point to a significant role of agmatine homeostasis in the (patho)physiology of cell proliferation of leukemic cells, at least in HMC-1 and HL-60 cells, that may serve as a potential target for an adjuvant therapy in the treatment of human leukemia. PMID- 21236491 TI - Straylight values after refractive surgery: screening for ocular fitness in demanding professions. AB - PURPOSE: To study straylight testing as a screening method for ocular fitness after refractive surgery in demanding professions and to determine the distribution of elevations in straylight as a result of refractive surgery in a non-research setting in contrast with earlier reports in research settings. DESIGN: Cross-sectional study. PARTICIPANTS AND CONTROLS: The refractive surgery population consisted of 373 eyes in 198 subjects with a history of refractive surgery. The reference population consisted of 402 eyes in 214 young individuals without a history of refractive surgery. METHODS: Data were collected as part of routine testing at The Queen Astrid Military Hospital (Belgium), an independent military institution responsible for medical fitness examinations. Intraocular straylight was measured with the commercially available C-Quant instrument (Oculus Optikgerate GmbH, Wetzlar, Germany), using the psychophysical compensation comparison (CC) method. Fellow eyes were compared to evaluate methodological aspects. The prevalence of impairment was evaluated for 2 age independent cutoff criteria, a 2.0-fold and 3.2-fold increase, and an age dependent cutoff criterion corresponding to an increase of 0.20 log units. MAIN OUTCOME MEASURES: Methodological aspects such as repeatability, systematic differences, and distance to impaired scores, and prevalence of impaired straylight values after refractive surgery using proposed cutoff criteria. RESULTS: The CC method exhibited good repeatability, and the chance of impaired scores due to variability in measurement was small. The prevalence of impaired straylight values was minimal in the reference population. In the refractive population, 9% (33/373) of values were above the factor 2.0 criterion, 2% (7/373) were above the factor 3.2 criterion, and 12% (45/373) were 0.20 log units above the age reference. CONCLUSIONS: Straylight testing is a viable screening method for ocular fitness after refractive surgery. Patients from the general population who have undergone refractive surgery have significant elevations more frequently than surgery populations from high-quality research centers. PMID- 21236490 TI - The emergence of ADAM10 as a regulator of lymphocyte development and autoimmunity. AB - Proteolytic processing of transmembrane receptors and ligands can have a dramatic impact on cell signaling processes and subsequent cellular responses, including activation and differentiation. A member of the disintegrin and metalloproteinase family, ADAM10, has emerged as a prominent regulator of numerous receptors and ligands, including Notch and CD23. Here, we review studies resulting from the recent generation of ADAM10 conditional knockout mice which revealed a critical role for ADAM10 in Notch-dependent lymphocyte development. Additionally, we discuss results of numerous in vitro and ex vivo studies indicating that ADAM10 regulates the production of multiple secreted factors that contribute to autoimmune reactions. PMID- 21236493 TI - Examining the role of social cues in early word learning. AB - Infants watched a video of an adult pointing towards two different objects while hearing novel labels. Analyses indicated that 14- and 18-month-olds looked longer at the target object, but only 18-month-olds showed word learning. The results suggest that different types of social cues are available at different ages. PMID- 21236492 TI - A novel mutation of LAMB2 in a multigenerational mennonite family reveals a new phenotypic variant of Pierson syndrome. AB - PURPOSE: To describe a novel laminin beta-2 (LAMB2) mutation associated with nephrotic syndrome and severe retinal disease without microcoria in a large, multigenerational family with Pierson syndrome. DESIGN: Retrospective chart review and prospective family examination. PARTICIPANTS: An extended consanguineous family of 52 members. METHODS: The eyes, urine, and serum DNA were evaluated in all family members after discovering 2 patients, both younger than 10 years, with bilateral retinal detachments and concurrent renal dysfunction. Linkage analysis was performed in the 9 living affected individuals, 7 using the Illumina Human Hap370 Duo Bead Array (Illumina, San Diego, CA) and 2 using GeneChip 10K (Affymetrix, Santa Clara, CA) mapping arrays. MAIN OUTCOME MEASURES: The prevalence and severity of ocular and kidney involvement and genetic findings. RESULTS: Eleven affected family members were identified (9 living), all manifesting chronic kidney disease and bilateral chorioretinal pigmentary changes, with or without retinal detachments, but without microcoria or neurodevelopmental deficits, segregating in an autosomal recessive pattern. The causative gene was localized to a 9-Mb region on chromosome 3. Comprehensive gene sequencing revealed a novel LAMB2 variant (c.440A -> G; His147R) that was homozygous in the 9 living, affected family members, observed at a frequency of 2.1% in the Old Order Mennonite population, and absent in 91 non-Mennonite controls. The mutation is located in a highly conserved site in the N-terminal domain VI of LAMB2. CONCLUSIONS: This study describes a novel mutation of LAMB2 and further expands the spectrum of eye and renal manifestations associated with defects in the laminin beta-2 chain. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21236494 TI - Abnormal frontal cortex white matter connections in bipolar disorder: a DTI tractography study. AB - OBJECTIVE: In bipolar disorder, white matter abnormalities have been reported with region-of-interest and voxel-based methods; however, deficits in specific white matter tracts cannot be localized by these methods. Therefore, in this study, we aimed to investigate the white matter tracts that mediate connectivity of the frontal cortex using diffusion tensor imaging (DTI) tractography. METHODS: Eighteen patients with bipolar disorder and sixteen age- and gender-matched healthy subjects underwent DTI examinations. Frontal cortex white matter tracts, including the anterior thalamic radiation (ATR), uncinate fasciculus (UF), superior longitudinal fasciculus (SLF), cingulum, and inferior fronto-occipital fasciculus (IFO) were reconstructed by DTI tractography, and we calculated the mean fractional anisotropy (FA) for each fiber tract. The values were compared between groups by repeated measures analysis of variance with age and gender as covariates, which allowed us to investigate significant differences between the tracts. RESULTS: When compared with healthy controls, the patients with bipolar disorder showed significantly decreased FA in the ATR and UF, and a trend towards lower FA in the SLF and cingulum. However, there were no FA differences between groups in the IFO. CONCLUSIONS: Our study indicates that bipolar patients show abnormalities within white matter tracts connecting the frontal cortex with the temporal and parietal cortices and the fronto-subcortical circuits. These findings suggest that alterations in the connectivity of white matter tracts in the frontal cortex might contribute to the neuropathology of bipolar disorder. PMID- 21236495 TI - Why do people choose charcoal burning as a method of suicide? An interview based study of survivors in Taiwan. AB - BACKGROUND: Marked increases in the incidence of charcoal burning suicide have contributed to Taiwan's rising suicide rate in the past decade. To assess possible opportunities for intervention, we have compared survivors of suicide attempts by charcoal burning with people who ingested poisons. METHODS: We interviewed a consecutive series of suicide attempters by charcoal burning (n=37) and self-poisoning (n=38) admitted to Taipei Veterans General Hospital (TVGH) between January 2009 and March 2010. Interviews included the Structured Clinical Interview of DSMIV (SCID) and Beck Suicide Intent Scale. RESULTS: Compared to people who ingested medicines/poisons, charcoal burning suicide attempters were less likely to have a pre-existing physical illness or contact with psychiatric services prior to the attempt and more likely to be employed. Charcoal burning suicide attempters had higher levels of suicide intent (mean score 20.1) compared to people ingesting poisons (mean score 13.5) (p<0.001) and were considerably more likely to report that their choice of method was influenced by the media (87% vs. 8%), particularly the portrayal of the method as a peaceful way of dying. Charcoal burning suicides were less impulsive. LIMITATIONS: The study sample was limited to a single hospital. CONCLUSIONS: Survivors of suicide attempts by charcoal burning have high levels of intent and low levels of psychiatric contact indicating they may be more difficult to prevent than suicides by self-poisoning. Encouraging responsible media reporting of suicide and restricting the availability of charcoal may be the most promising approaches to preventing these deaths. PMID- 21236497 TI - Aggression in psychiatry wards: a systematic review. AB - Although fairly frequent in psychiatric in-patient, episodes of aggression/violence are mainly limited to verbal aggression, but the level of general health is significantly lower in nurses who report 'frequent' exposure to violent incidents, and there is disagreement between patients and staff concerning predictors of these episodes. We searched the Pubmed, Embase and PsychInfo databases for English, Italian, French or German language papers published between 1 January 1990 and 31 March 2010 using the key words "aggress*" (aggression or aggressive) "violen*" (violence or violent) and "in-patient" or "psychiatric wards", and the inclusion criterion of an adult population (excluding all studies of selected samples such as a specific psychiatric diagnosis other than psychosis, adolescents or the elderly, men/women only, personality disorders and mental retardation). The variables that were most frequently associated with aggression or violence in the 66 identified studies of unselected psychiatric populations were the existence of previous episodes, the presence of impulsiveness/hostility, a longer period of hospitalisation, non voluntary admission, and aggressor and victim of the same gender; weaker evidence indicated alcohol/drug misuse, a diagnosis of psychosis, a younger age and the risk of suicide. Alcohol/drug misuse, hostility, paranoid thoughts and acute psychosis were the factors most frequently involved in 12 studies of psychotic patients. Harmony among staff (a good working climate) seems to be more useful in preventing aggression than some of the other strategies used in psychiatric wards, such as the presence of male nurses. PMID- 21236496 TI - Pharmacological inhibition of inflammatory pathways for the prevention of preterm birth. AB - The major cause of spontaneous preterm birth (sPTB) at less than 32 weeks of gestation is intrauterine inflammation as a consequence of colonisation of the gestational membranes by pathogenic microorganisms which trigger activation of the local innate immune system. This results in release of inflammatory mediators, leukocytosis (chorioamnionitis), apoptosis, membrane rupture, cervical ripening and onset of uterine contractions. Recent PCR evidence suggests that in the majority of cases of inflammation-driven preterm birth, microorganisms are present in the amniotic fluid, but these are not always cultured by standard techniques. The nature of the organism and its cell wall constituents, residence time in utero, microbial load, route of infection and extent of tissue penetration are all factors which can modulate the timing and magnitude of the inflammatory response and likelihood of progression to sPTB. Administration of anti-inflammatory drugs could be a viable therapeutic option to prevent sPTB and improve fetal outcomes in women at risk of intrauterine inflammation. Preventing fetal inflammation via administration of placenta-permeable drugs could also have significant perinatal benefits in addition to those related to extension of gestational age, as a fetal inflammatory response is associated with a range of significant morbidities. A number of potential drugs are available, effective against different aspects of the inflammatory process, although the pathways actually activated in spontaneous preterm labour have yet to be confirmed. Several pharmacological candidates are discussed, together with clinical and toxicological considerations associated with administration of anti-inflammatory agents in pregnancy. PMID- 21236498 TI - Bone-anchored hearing aids (Baha) in congenital aural atresia: personal experience. AB - AIMS: Aural atresia is a congenital disease constituted by partial or complete lack of development of the external auditory canal, which is generally associated with malformations of the auricle and middle ear. Reconstruction of the auditory canal and correction of any deformities of the middle ear have yielded unpredictable results and variable functional outcomes, and there is a high rate of complications. Therefore, the use of bone-conduction hearing aids, such as the Baha, may represent a valid alternative for subjects who have conductive hearing loss with cochlear reserve that, as a rule, is fully conserved. The aim of this work is to reexamine our experience with the management of conductive and mixed hearing loss using the Baha system in children with bilateral aural atresia. METHODS: We examined 31 patients with bilateral congenital aural atresia in whom a Baha system had been implanted. The patients, 16 males and 15 females, were between 5 and 14 years of age (mean 8.7). The following parameters were assessed for each patient: mean preoperative air and bone conduction for frequencies between 0.5 and 4kHz; mean preoperative threshold with conventional bone conduction hearing aids; mean postoperative threshold with the Baha system; improvement in quality of life evaluated with the Glasgow Children's Benefit Inventory; rate and type of surgical complications. RESULTS: The mean preoperative air- and bone-conduction thresholds were 51.2+/-12.5 and 14.1+/ 6.3dB HL, respectively. The mean preoperative threshold with a conventional bone conduction hearing aid was 29.3+/-7.2dB HL, and the mean postoperative threshold with the Baha system was 18.1+/-7.5dB HL. Quality of life improved for all operated patients. CONCLUSIONS: The results of our study of the Baha system to treat patients with bilateral aural atresia were extremely satisfactory compared both with those of surgical reconstruction of the auditory canal and those of traditional bone-conduction hearing aids. Furthermore, great improvement was noted in quality of life, while the rate of complications was very low. Therefore, we are convinced that the Baha system is the treatment of choice for hearing loss due to bilateral congenital aural atresia. PMID- 21236499 TI - Hearing status in children with congenital cytomegalovirus: up-to-6-years audiological follow-up. AB - OBJECTIVE: To evaluate the audiological outcome of children with congenital cytomegalovirus infection. METHODS: In a prospective study, the hearing of ninety seven congenitally cytomegalovirus-infected children, born between January 2003 and July 2009, was systematically evaluated until the age of six, applying the Flemish CMV protocol. Depending on the age of the child, the protocol provides hearing evaluation by objective-, play- or conventional audiometry. Symptomatic children with hearing loss at birth were treated with ganciclovir, if parents consented. RESULTS: Seventy children had a pass on initial screening, 27 had unilateral or bilateral hearing loss. Within the normal hearing group, one asymptomatic and two symptomatic children developed late-onset hearing loss. Within the group with hearing loss, 8 children received ganciclovir, while 8 symptomatic and 11 asymptomatic children did not receive ganciclovir. As for the treated group, 37.5% of the children had stable hearing loss, one child had progressive and one child had fluctuating hearing loss. Improvement of hearing threshold occurred in 37.5% of the children. Among the untreated symptomatic children, hearing loss remained stable in 50%, while progression occurred in 37.5%. In the group of asymptomatic children with hearing loss, hearing loss was most commonly stable (72.7%). Within the group of normal hearing ears at birth (n=156), there is a significant better progression in pure tone average for ears of asymptomatic subjects in comparison to ears of symptomatic subjects (p<=0.0001). As for the group of ears with hearing loss at birth (n=38), analysis shows no evidence for a difference in pure tone average progression between the different groups (p=0.38). CONCLUSIONS: Cytomegalovirus infection may cause hearing loss, in both symptomatic and asymptomatic children. Our data show a significant difference, between both groups, in the progression of pure tone average of normal hearing ears at birth, in favor of the asymptomatic children. This is not the case for ears with hearing loss at birth. However, this may be due to the small number of ears in this group. Our data show the tendency that treatment with ganciclovir increases the likelihood of improvement and reduces the likelihood of deterioration of the hearing. PMID- 21236501 TI - Astrocyte-neuron metabolic relationships: for better and for worse. AB - In recent years, previously unsuspected roles of astrocytes have been revealed, largely owing to the development of new tools enabling their selective study in situ. These exciting findings add to the large body of evidence demonstrating that astrocytes play a central role in brain homeostasis, in particular via the numerous cooperative metabolic processes they establish with neurons, such as the supply of energy metabolites and neurotransmitter recycling functions. Furthermore, impairments in astrocytic function are increasingly being recognized as an important contributor to neuronal dysfunction and, in particular, neurodegenerative processes. In this review, we discuss recent evidence supporting important roles for astrocytes in neuropathological conditions such as neuroinflammation, amyotrophic lateral sclerosis and Alzheimer's disease. We also explore the potential for neuroprotective therapeutics based on the modulation of astrocytic functions. PMID- 21236500 TI - Non-genomic loss of PTEN function in cancer: not in my genes. AB - Loss of function of the phosphatase and tensin homolog (PTEN) tumour suppressor contributes to the development of many cancers. However, in contrast to classical models of tumour suppression, partial loss of PTEN function appears to be frequently observed in the clinic. In addition, studies of both humans and mice with reductions in PTEN gene dosage indicate that even partial loss of PTEN function is sufficient to promote some cancer types, particularly in the breast. PTEN expression appears to be tightly controlled both transcriptionally and post transcriptionally, with several recent studies implicating oncogenic microRNAs in PTEN suppression. The lipid phosphatase activity of PTEN can also be regulated post-translationally via inhibitory phosphorylation, ubiquitination or oxidation. Here we discuss these multiple mechanisms of PTEN regulation. We also put into context recent proposals that changes in this regulation can drive tumour development and address the accompanying evidence for their clinical significance. PMID- 21236502 TI - A moderate intensity exercise program did not increase the oxidative stress in older adults. AB - Oxidative damage to lipoproteins, in particular low density lipoprotein (LDL), is known to play a role in a number of diseases associated with aging such as cardiovascular disease (CVD) and dementia. Exercise can alter the balance of oxidative and anti-oxidative species within the human body and may cause oxidative damage to lipoproteins. The purpose of this study was to assess the effect of a moderate intensity exercise program on markers of oxidative stress in older age adults. Parameters of lipoprotein protein and lipid oxidation, and lipoprotein nitration were assessed in aged individuals who undertook a program of moderate physical activity for a period of 8 weeks. There were no significant changes in LDL protein oxidation or nitration which could be attributed to 8 weeks of walking exercise, however, LDL nitration was increased following acute steady state exercise (pre-: 0.34+/-0.1 vs. post-: 0.44+/-0.07 MUm/mg LDL; p=0.04). Walking at moderate intensity caused a significant weight decrease in the exercise group, but did not have any significant effect on VO2max. Exercise at this intensity was not harmful and did not increase risk factors for diseases associated with oxidative stress in the participants of the study. PMID- 21236503 TI - Malnutrition in an elderly demented population living at home. AB - Malnutrition is a frequent complication for elderly demented patients even if they live at their own home with the assistance of a caregiver. The present study evaluates nutritional characteristics of a population of 130 non institutionalized demented patients. The results show that the mini nutritional assessment (MNA) total score is inversely related with the neuro-psychiatric inventory (NPI) score and that the level of cognitive impairment is related with the nutritional status: patients with mild cognitive impairment (MCI) showed a mean MNA score higher than patients affected by Alzheimer's disease (AD) or vascular dementia (VaD). Moreover, patients depressed, with hallucinations or with behavioral disturbs are more exposed to underfeeding than only cognitively impaired subjects. In conclusion, an appropriated evaluation of nutritional status could prevent and treat nutrition-related problems even in the elderly demented patients living at home. PMID- 21236504 TI - Effect of gender on repeated coronary artery revascularization after intra coronary stenting: a meta-analysis. AB - BACKGROUND: As a risk factor of coronary artery disease (CAD), gender might be associated with the prognosis of percutaneous coronary intervention (PCI). However, there are conflicting reports in the literature regarding the role of gender on repeated coronary artery revascularization after PCI. OBJECTIVE: This meta-analysis aimed to determine whether gender influenced the incidence of repeated coronary artery revascularization after intra-coronary stenting. METHODS: We performed a meta-analysis including 13 randomized controlled trials (a total of 156,798 patients, including 107,697 men and 49,101 women) that assessed the results of target vessel revascularization (TVR), target lesion revascularization (TLR) and major adverse cardiac events (MACE) after PCI. PUBMED, MEDLINE, EMBASE and the Cochrane Database were searched for articles published in the last 10 years. RESULTS: There was no difference in the long-term incidence of TVR between males and females after PCI (16.68% vs. 16.41%; odds ratio (OR)=0.94; 95% confidence intervals (CI): 0.82-1.07; P=0.36). However, the short-term rate of TVR after PCI was significantly higher in women than that in men (4.25% vs. 3.83%; OR=0.91; 95% CI: 0.86-0.97; P<0.01). Moreover, women had higher short-term and long-term incidences of MACE than men after PCI (short term: 8.02% vs. 5.57%; P<0.01; long-term: 16.14% vs. 13.72%, P<0.01). CONCLUSIONS: The present data suggested that female sex could increase the short term incidence of repeated coronary revascularization after PCI. However, the long-term rate of repeated coronary revascularization was similar between male and female patients. PMID- 21236505 TI - Defining high-risk patients with ST-segment elevation acute myocardial infarction undergoing primary percutaneous coronary intervention: a comparison among different scoring systems and clinical definitions. AB - BACKGROUND: Identification of high-risk patients with ST-segment elevation acute myocardial infarction (STEMI) is of the utmost importance for adequate patient stratification and evaluation of additive treatments. However, there is no consensus on the optimal definition of high-risk patients. METHODS: We therefore compared 5 scoring systems in the assessment of the risk of 30-day mortality in 3214 patients with STEMI treated with primary percutaneous coronary intervention (PCI). RESULTS: Clinical scores showed a large variability in risk stratifying patients. Identification of high-risk patients ranged from 15% (PAMI score >= 9) to 66% (McNamara definition). McNamara, Antoniucci and Brodie definitions had the best sensitivity (0.87-0.88 and 95% confidence intervals (CI) ranging from 0.82 0.93) while PAMI >= 9 had the best specificity (0.87 with 95% CI of 0.86-0.88), while its sensitivity was quite low (0.42). In a sample size simulation of a trial aimed at demonstrating a 33% difference in 30-day mortality between two hypothetical treatments, the number of STEMI patients needed to be screened varied from 4712 for the Brodie definition to 9038 for the PAMI >= 9 score. CONCLUSIONS: There is a large variability in risk stratification, sensitivity, specificity and predictive values among different scoring systems. These considerations should be taken into account when designing randomised trials. PMID- 21236506 TI - Underestimation of aortic valve area in calcified aortic valve disease: effects of left ventricular outflow tract ellipticity. AB - BACKGROUND: The aortic valve area (AVA) is usually calculated using the continuity equation (CE) in which the left ventricular outflow tract (LVOT) area is estimated assuming circular geometry. We sought to evaluate the LVOT ellipticity with 64-multidetector computed tomography (MDCT) and to assess the impact of LVOT ellipticity on the evaluation of CE-based AVA in patients with calcified aortic valves. METHODS: We prospectively studied 110 patients with calcified aortic valves including 54 aortic stenosis (AS) with both 64-MDCT and transthoracic echocardiography. Double oblique transversal images for planimetry of the aortic valve and LVOT were obtained during the midsystolic phase. The short and long-axis diameters of the planimetered LVOT were measured. RESULTS: The MDCT planimetered LVOT area was underestimated by the diameter-derived (pi * r(2)) LVOT area using echocardiography (444 +/- 70 mm(2) versus 369 +/- 63 mm(2); p<0.001). The mean difference in AVA values calculated using the CE and planimetry was 0.43 +/- 0.23 cm(2) and mean measurement error of CE-based AVA was 18%. When the CE-based AVA was corrected using the MDCT planimetered LVOT area, the measurement error decreased from 28 +/- 5 to 5 +/- 2% in patients with severe aortic stenosis (AVA<1.0 cm(2)), whereas from 16 +/- 5 to 3 +/- 6% in others. CONCLUSION: Ellipticity of LVOT is associated with underestimation of AVA measurements using the CE. CE-based AVA corrected with MDCT planimetered LVOT area is useful especially in severe AS. PMID- 21236507 TI - Forgotten indices of ambulatory blood pressure profile. PMID- 21236508 TI - Unpacking the misery multiplier: how employability modifies the impacts of unemployment and job insecurity on life satisfaction and mental health. AB - Employability strongly moderates the effects of unemployment and of job insecurity on life satisfaction and mental health. Using nationally representative panel data from Australia, I find that an increase in employability from zero to 100% cancels around three quarters, in some cases more, of the detrimental effect of unemployment. Employability also matters for employees: an increase in men's employability from zero to 100% reduces the detrimental effect of job insecurity by more than half. The effects of extreme job insecurity and of unemployment are large and of comparable magnitudes. The findings are used to compute estimates of the well-being trade-off between increases in job insecurity and increases in employability, relevant to the support of "flexicurity" policies, and of the "misery multiplier", the extent to which the effect of a rise in aggregate unemployment on those becoming unemployed is supplemented by the effects on others' insecurity and employability. PMID- 21236509 TI - Challenges of Campylobacter jejuni in poultry production. PMID- 21236510 TI - The data supply chain for tracing Salmonella in pork production. PMID- 21236511 TI - Prevalence and long-term glucose metabolism evolution of post-transplant diabetes mellitus in Chinese renal recipients. AB - AIM: To assess the prevalence and predictors of post-transplant diabetes mellitus (PTDM) in Chinese renal recipients and describe their long-term evolution of glucose metabolism. METHODS: 887 non-diabetic Chinese adult renal recipients were studied retrospectively, with a median follow-up of 7 years. PTDM patients were categorized into transient PTDM and permanent PTDM. The cumulative incidence and risk factors of PTDM were estimated by Kaplan-Meier and Cox regression. RESULTS: The cumulative incidence of PTDM at 3 months, 1, 3, 5, 10, 15 and 20 years post transplant was 10.4%, 11.4%, 13.4%, 15.2%, 22.7%, 27.9% and 38.3%, respectively. 61.9% of PTDM cases were diagnosed within the first three months and 61.6% of them developed persistent diabetes in the future. Risk factors for all PTDM included older age, body mass index (BMI)>=25 kg/m(2), triglycerides>=1.5 mmol/L, rejection, the use of tacrolimus and diltiazem. The predictors of permanent PTDM included age >50 years (RR=2.322, 95% CI 1.255-4.296, P=0.007), BMI>=25 kg/m(2) (RR=1.699, 95% CI 1.014-2.846, P=0.044) and the use of tacrolimus (RR=1.835, 95% CI 1.181-2.851, P=0.007). CONCLUSIONS: Patients were most susceptible to PTDM within the first three months post-transplant and more than half of them developed persistent diabetes in the future. Age >50 years, overweight and tacrolimus application were risk factors for both PTDM and permanent PTDM. PMID- 21236512 TI - [Keratoneuritis in amebic keratitis with contact lens wear]. PMID- 21236513 TI - [Refractory anterior uveitis]. AB - Treatment of anterior uveitis should be etiological when a cause has been identified and provided for any symptomatic case, using topical corticosteroids and mydriatics/cycloplegics. Periocular and systemic agents are then used in certified cases that prove to be refractory to first-line therapy. If anterior uveitis is still rebellious to treatment, the physician should evaluate the accuracy of the present therapy in case of an unsuspected cause of uveitis, or a particularly severe or chronic intraocular inflammation. PMID- 21236514 TI - Online video improves clinical outcomes in adults with atopic dermatitis: a randomized controlled trial. AB - BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by intense pruritus that causes significant disease and psychosocial burden in patients. Patient education has the potential to improve clinical outcomes and patient knowledge of this condition. OBJECTIVES: We sought to assess the effectiveness of online video education at improving AD knowledge and disease severity compared with a written pamphlet, and to determine the usefulness and appeal of the two educational delivery vehicles. METHODS: In a randomized controlled trial, 80 participants were randomized to receive either online video-based patient education or written pamphlet education about AD and its management. We assessed AD disease severity using the patient-oriented eczema measure (POEM) scale. AD knowledge was assessed with standardized questionnaires at baseline and after the 12-week intervention. RESULTS: All participants had similar baseline knowledge and AD severity at the beginning of the study. On study completion, improvements in AD knowledge assessed by questionnaire were significantly greater in the video group than the pamphlet group (3.05 vs 1.85, P = .011). Online video-based education resulted in greater improvement in clinical outcome, as measured by POEM, compared with pamphlet-based education (POEM score reduction of 3.30 vs 1.03, P = .0043). Finally, although the usefulness of both interventions was rated equally (P = .77), the online video was significantly more appealing than the pamphlet (P = .0086). LIMITATIONS: This study is limited to AD in adults. CONCLUSION: Online video for patient education is an effective and appealing tool for improving clinical outcomes in adult patients with AD. PMID- 21236515 TI - Involving the patient to ask about hospital hand hygiene: a National Patient Safety Agency feasibility study. AB - Healthcare-associated infections (HAIs) affect at least 300,000 patients annually in the UK and represent a significant, yet largely preventable, burden to healthcare systems. Hand hygiene by healthcare workers (HCWs) is the leading prevention measure, but compliance with good practice is generally low. The UK National Patient Safety Agency surveyed the public, inpatients, and HCWs, particularly frontline clinical staff and infection control nurses, in five acute care hospitals to determine whether they agreed that a greater level of involvement and engagement with patients would contribute to increased compliance with hand hygiene and reduce HAIs. Fifty-seven percent (302/530) of the public were unlikely to question doctors on the cleanliness of their hands as they assumed that they had already cleaned them. Forty-three percent (90/210) of inpatients considered that HCWs should know to clean their hands and trusted them to do so, and 20% (42/210) would not want HCWs to think that they were questioning their professional ability to do their job correctly. Most HCWs surveyed (178/254, 71%) said that HAI could be reduced to a greater or lesser degree if patients asked HCWs if they had cleaned their hands before touching them. Inviting patients to remind HCWs about hand hygiene through the provision of individual alcohol-based hand-rub containers and actively supporting an 'It's OK to ask' attitude were perceived as the most useful interventions by both patients and HCWs. However, further work is required to refute the myth among HCWs that patient involvement undermines the doctor- or HCW-patient relationship. PMID- 21236516 TI - Sensitivity and specificity of the user-seal-check in determining the fit of N95 respirators. AB - N95 respirators are recommended by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) to prevent the inhalation of droplets which may transmit respiratory pathogens. The reliability of N95 respirators in preventing transmission depends on their fit to the wearer. Quantitative fit testing (QNFT) is the gold standard used to determine this fit objectively. The manufacturers of the respirators also recommend performing a self-reported user-seal-check to detect for leakage. This study aims to investigate the capability of the user-seal-check in determining the fit of N95 respirators by investigating the sensitivity and specificity of the user-seal check compared with QNFT. A prospective and cross-sectional research design was used. A total of 204 local Chinese undergraduate nursing students were recruited to test two commonly used respirator models (3M 1860S and 3M 1862). The results of the user-seal-check were compared with the results of the gold standard QNFT using the Condensation Nucleus Counter Fit Tester System. The sensitivity and specificity of the user-seal-check results obtained with the respirators were calculated. The results indicated low sensitivity, accuracy and predictive value of the user-seal-check in determining the fit of the N95 respirators. The user seal-check was not found to be reliable as a substitute for QNFT. The results also suggested that the user-seal-check may be unreliable for detecting gross leakage. We recommend that QNFT is used to determine the fit of N95 respirators. PMID- 21236517 TI - Out-of-hospital clinical trials: challenges in advancing the evidence base. PMID- 21236518 TI - CSF alpha-synuclein does not differentiate between parkinsonian disorders. AB - Differentiating between Parkinson's disease (PD) and atypical Parkinsonism (AP) is clinically relevant but challenging. A timely and correct diagnosis might result in better targeted treatment strategies, adequate patient counseling, and early recognition of disease-specific complications. We aimed to investigate whether cerebrospinal fluid (CSF) concentrations of alpha-synuclein are of additional diagnostic value. We examined 142 consecutive patients with parkinsonism, mean disease duration 39.7 mo (Parkinson's disease (PD), n = 58; MSA, n = 47; dementia with Lewy bodies (DLB), n = 3; VaP, n = 22; progressive supranuclear palsy (PSP), n = 10; CBD, n = 2). Gold standard was the clinical diagnosis established after 2 years of clinical follow-up. CSF concentrations of alpha-synuclein, blood pigments and the erythrocyte count were determined. No differences between CSF alpha-synuclein concentrations of patients with PD with the reference values from our laboratory were observed. We neither found significant differences between patients with PD and AP nor between AP subgroups. Adjustment for age, disease severity or presence of erythrocytes or blood pigments in CSF did not alter these results. Our results imply that CSF alpha synuclein is currently unsuitable as biomarker to differentiate between PD and AP. PMID- 21236519 TI - Weak BMAA toxicity compares with that of the dietary supplement beta-alanine. AB - beta-N-methylamino-L-alanine (BMAA) is routinely described in the literature as a potent neurotoxin and as a possible cause of neurodegenerative disorders of aging such as Alzheimer's disease, amyotrophic lateral sclerosis, and the amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS-PDC) syndrome of Guam. To test for the toxicity of BMAA against human neurons, we chose 3 standard human neuronal cell lines for examination and compared the toxicity with the muscle building nutritional supplement beta-alanine, glutamic acid, and the established excitotoxins kainic acid, quisqualic acid, ibotenic acid, domoic acid, and quinolinic acid. Neurotoxicity was measured by the standard lactic dehydrogenase release assay after 5-day incubation of NT-2, SK-N-MC, and SH-SY5Y cells with BMAA and the comparative substances. The ED(50) of BMAA, corresponding to 50% death of neurons, varied from 1430 to 1604 MUM while that of the nutritional supplement beta-alanine was almost as low, varying from 1945 to 2134 MUM. The ED(50) for glutamic acid and the 5 established excitotoxins was 200- to 360-fold lower, varying from 44 to 70 MUM. These in vitro data are in accord with previously published in vivo data on BMAA toxicity in which mice showed no pathological effects from oral consumption of 500 mg/kg/day for more than 10 weeks. Because there are no known natural sources of BMAA that would make consumption of such amounts possible, and because the toxicity observed was in the same range as the nutritional supplement beta-alanine, the hypothesis that BMAA is an environmental hazard and a contributor to degenerative neurological diseases becomes untenable. PMID- 21236520 TI - [Comparison of family functioning profile in adolescents with and without drug dependency in a high school]. AB - OBJECTIVE: To compare the family functioning profile (FFP) in adolescents addicted to drugs and those not addicted to drugs. DESIGN: Cross-sectional study comparative. SETTING: A high school in Queretaro State, Mexico. PARTICIPANTS: Study of 63 adolescents with and without addiction, of both sexes between the ages of 13 and 19, enrolled in high school; two groups formed, one not addicted to drugs (systematic probabilistic sampling was carried out); and compared with drug addicts (database). MAIN MEASUREMENTS: FFP(Alpha Cronbach 91). Descriptive and inferential statistical analysis. RESULTS: Adolescents with drug addiction (n=20), average age 17.5+/-0.4 (range 16-19), and group of non-addicts (n=43), average age 16.9+/-0.1 (range 15-18) and P=0.000. All the adolescents lived in an urban area with a predominantly simple nuclear modern, working family type. Half (50%) of addicted adolescents came from broken families P=0.002. The dispersion phase was a protective factor in preventing drug addiction in adolescents (P=0.003 OR 0.6 95% Cl;1.8-21.0). Significant statistical differences were observed in authority (OR=29.7, 95% Cl; 5.8-150.5), supervision (OR 10.3, 95% Cl; 2.8-37.2) and support (OR 0.04, 95% Cl; 5.5-109.8). The overall family dysfunctionality, (P=0.000, OR 1.8, 95% Cl; 1.3-2.3). CONCLUSION: Dysfunctional families are a risk factor for drug addiction in adolescents, when there is insufficient authority and supervision within the family. On the other hand, family support, as well as the dispersion phase, are protective factors. PMID- 21236521 TI - Preparation and in vitro screening of symmetrical bis-isoquinolinium cholinesterase inhibitors bearing various connecting linkage--implications for early Myasthenia gravis treatment. AB - Inhibitors of acetylcholinesterase are compounds widely used in the treatment of various diseases, such as Alzheimer's disease, glaucoma and Myasthenia gravis (MG). Compounds used in the therapy of MG posses a positive charge in the molecule to ensure peripheral effect of action and minimal blood-brain barrier penetration. The most prescribed carbamate inhibitors are however known for many severe side effects related to the carbamylation of AChE. This paper describes preparation and in vitro evaluation of 20 newly prepared bis-isoquinolinium inhibitors of potential concern for MG. The newly prepared compounds were evaluated in vitro on human recombinant AChE and human plasmatic butyrylcholinesterase (BChE). Their inhibitory ability was expressed as IC50 and compared to chosen standards ambenonium dichloride, edrophonium chloride, BW284c51 and ethopropazine hydrochloride. Three novel compounds presented promising inhibition (in nM range) of both enzymes in vitro better or similar to edrophonium and BW284c51, but worse to ambenonium. The novel inhibitors did not present higher selectivity toward AChE or BChE. The kinetic assay confirmed non competitive inhibition of hAChE by two selected promising novel compounds. Two newly prepared compounds were also chosen for docking studies that confirmed apparent pi-pi or pi-cationic interactions aside the cholinesterases catalytic sites. The SAR findings were discussed. PMID- 21236522 TI - The role of expert judgement and feedback in sustainable assessment: a discussion paper. AB - Skill assessment is an enduring issue for nurses both in the nursing education and practice. Emphasis is placed upon assessment for the attainment of learning outcomes within courses of education, at the expense of skill maintenance and skill development within practice. The concept of "sustainable assessment" combines and encourages both ideas and the role of judgement in assessment is crucial to this. Within courses of nursing education, skill is invariably guided and eventually assessed by the aid of an expert in the field, a connoisseur who applies the judgement of the specialist and delivers the criticism of connoisseur in the form of feedback. This paper concludes that the utilisation of this feedback to develop the students' ability to help judge their own practice is central to the notion of sustainable assessment and calls for discussion and research into this emerging field of enquiry. PMID- 21236523 TI - Nurse Practitioner preparation: is it time to move beyond masters level entry in Australia? AB - Nurse Practitioner education in Australia currently requires a post graduate qualification at masters level for endorsement by national registration bodies and entry into practice. This paper reviews the evidence and debate in America that saw the education of Nurse Practitioners advance to the doctoral level in 2004. Consideration will then be given to the similarities between the American and Australian context, in order to open the debate about whether it is timely for Australian universities to consider the need to advance Australia Nurse Practitioner education to the Doctor of Nursing Practice. PMID- 21236525 TI - One dog bite too far. PMID- 21236526 TI - Use of digastric branch of the facial nerve for identification of the facial nerve itself in parotidectomy: technical note. PMID- 21236527 TI - The influence of involuntary facial movements on craniofacial anthropometry: a survey using a three-dimensional photographic system. AB - In the modern anthropometry of complex structures, such as the face, different technical approaches for acquisition of three-dimensional data have become increasingly more common. Results of meticulous evaluations have shown high degrees of precision and accuracy under both ideal and clinical circumstances. However, the question remains as to which level of accuracy is adequate to meet clinical needs. Apart from the measuring technique itself, potential sources of error must be identified and dealt with. Subjects' involuntary facial movements can potentially influence clinical reliability. The 3dMDfaceTM system was used clinically to investigate the influence of involuntary facial movements. Other factors of influence were systematically excluded. The mean technical error of the system (0.09mm) was investigated in a previous study and taken into account for interpretation of the data. The handling of the system was straightforward for both acquisition and analysis of data. Including technical error and the influence of involuntary facial movements, the mean global error was 0.41mm (range 0-3.3). Taking into account the technical error of the system known from the previous study, involuntary facial movements account for a mean error of 0.32mm. This range of involuntary facial movements clearly exceeds the known technical error of the three-dimensional photographic system used. Given this finding, future research should shift its focus from the analysis of the technical aspects of such systems to other influential factors. PMID- 21236528 TI - Clinical outcomes of the first midwife-led normal birth unit in China: a retrospective cohort study. AB - AIMS: to report the clinical outcomes of the first six months of operation of an innovative midwife-led normal birth unit (MNBU) in China in 2008, aiming to facilitate normal birth and enhance midwifery practice. SETTING: an urban hospital with 2000-3000 deliveries per year. METHOD: this study was part of a major action research project that led to implementation of the MNBU. A retrospective cohort and a questionnaire survey were used. The data were analysed thematically. PARTICIPANTS: the outcomes of the first 226 women accessing the MNBU were compared with a matched retrospective cohort of 226 women accessing standard care. In total, 128 participants completed a satisfaction questionnaire before discharge. MAIN OUTCOME MEASURE: mode of birth and model of care. FINDINGS: the vaginal birth rate was 87.6% in the MNBU compared with 58.8% in the standard care unit. All women who accessed the MNBU were supported by both a midwife and a birth companion, referred to as 'two-to-one' care. None of the women labouring in the standard care unit were identified as having a birth companion. DISCUSSION: the concept of 'two-to-one' care emerged as fundamental to women's experiences and utilisation of midwives' skills to promote normal birth and decrease the likelihood of a caesarean section. CONCLUSION: the MNBU provides an environment where midwives can practice to the full extent of their role. The high vaginal birth rate in the MNBU indicates the potential of this model of care to reduce obstetric intervention and increase women's satisfaction with care within a context of extraordinary high caesarean section rates. IMPLICATIONS FOR PRACTICE: midwife-led care implies a separation of obstetric care from maternity care, which has been advocated in many European countries. PMID- 21236529 TI - Midwives' experiences of doula support for immigrant women in Sweden--a qualitative study. AB - OBJECTIVE: To describe and analyse midwives' experiences of doula support for immigrant women in Sweden. DESIGN: Qualitative study, analysed using content analysis. Data were collected via interviews. SETTING: Interviews were conducted at the midwives' workplaces. One midwife was interviewed at a cafe. PARTICIPANTS: Ten midwives, who participated voluntarily and worked in maternity health care in western Sweden. FINDINGS: The interview data generated three main categories. (1) 'A doula is a facilitator for the midwife' has two subcategories, 'In relation to the midwife' and 'In comparison with an interpreter', (2) 'Confident women giving support,' has two subcategories, 'Personal characteristics and attitudes' and 'Good support,' (3) 'Doulas cover shortcomings' has two subcategories, 'In relation to maternity care' and 'In relation to ethnicity'. KEY CONCLUSION AND IMPLICATIONS FOR PRACTICE: The findings of this study show that midwives experience that doulas are a facilitator for them. Doulas provide support by enhancing the degree of peace and security and improving communication with the women in childbirth. Doulas provide increased opportunities for transcultural care. They may increase childbearing women's confidence and satisfaction, help meet the diverse needs of childbearing women and improve care quality. PMID- 21236530 TI - Peer-led prenatal breast-feeding education: a viable alternative to nurse-led education. AB - OBJECTIVE: To evaluate a prenatal breast-feeding class developed and facilitated by peer Breast-feeding Buddies. DESIGN AND INTERVENTIONS: Non-equivalent control group quasi-experimental study comparing participants of the peer-led class (PLC) to those attending an established hospital-based breast-feeding nurse-led class (NLC). A brief questionnaire was completed immediately prior to the class, and telephone interviews were conducted approximately one week following the class, and one and six months post partum. SETTING AND PARTICIPANTS: 54 expectant mothers who registered for the community PLC and 55 expectant mothers who registered for the NLC. MEASUREMENTS AND FINDINGS: Breast-feeding intentions were measured at all time-points. Class evaluations, breast-feeding experiences, and breast-feeding support were measured at all post-class interviews. Both classes were considered worthwhile, but the PLC class was rated as more helpful and participants appreciated learning from the peers' personal experiences. Mothers taught by peers were more likely to access peer breast-feeding support. PLC participants initially decreased their prenatal breast-feeding duration intentions but had significantly stronger intentions to continue breast feeding at six months than did NLC mothers. KEY CONCLUSIONS: A peer-led prenatal breast feeding class is as effective as a traditional model of breast-feeding education and is a valuable tool to promote and support successful breast feeding. RECOMMENDATIONS FOR PRACTICE: Peer-led breast-feeding classes should be provided to enhance the accessibility of breast-feeding education and support for expectant mothers. PMID- 21236531 TI - Perineal pain following childbirth: prevalence, effects on postnatal recovery and analgesia usage. AB - OBJECTIVE: To establish the prevalence of perineal pain, the effects of pain on postnatal recovery, analgesia used to relieve pain and the perceived effectiveness of such analgesia at the Royal Women's Hospital, Victoria, Australia. DESIGN, SETTING AND PARTICIPANTS: We conducted structured interviews of 215 women in the postnatal ward of a tertiary hospital, within 72 hours of a vaginal birth. FINDINGS: The structured interviews revealed that 90% of women reported some perineal pain, with 37% reporting moderate or severe pain. The degree of perineal trauma predicted women's ratings of perineal pain on a visual analogue scale, with more severe trauma related to higher pain scores. Over a third of women experienced moderate or severe perineal pain, particularly when walking (33%) or sitting (39%), while 45% noted that pain interfered with their ability to sleep. Women reported moderate or severe perineal pain when they undertook activities involving feeding their infant (12%) or caring for their infant (12%). Women used a range of analgesia, including a combination of ice packs (69%), oral analgesia (75%), narcotic analgesia (4%) and anti-inflammatory suppositories (25%). The majority of women rated these forms of analgesia as effective and identified very few side effects. KEY CONCLUSIONS: Following vaginal birth, women commonly reported pain from perineal trauma. This pain affected women's ability to mobilise and was relieved by a variety of agents. Side effects from analgesia were rare. IMPLICATIONS FOR PRACTICE: The prevalence of perineal pain and the associated impact on women's recovery from childbirth warrants midwives' proactive care in offering a range of effective pain relief options to women. PMID- 21236533 TI - Effects of experimentally induced pain of the plantar soles on centre of foot pressure displacements during unperturbed upright stance. AB - BACKGROUND: Although impaired balance control during quiet standing has repeatedly been reported in persons suffering from foot pain, a better understanding of the effect of foot pain on unperturbed postural control is needed in order to propose and implement efficient podiatry treatments/interventions into clinical practice. The present study was hence designed to address this issue. METHODS: Ten young healthy adults were asked to stand upright, eyes closed, as still as possible in three experimental conditions: (1) a no-pain condition, (2) a condition when a painful stimulation was applied to the plantar surfaces of both feet, and (3) a condition in which painful stimulation was applied to another body part, the palms of both hands. The centre of foot pressure displacements was recorded using a force platform. FINDINGS: For the same perceived intensity of the pain, the severe painful stimulation applied to the plantar surfaces of both feet increased centre of foot pressure displacements, whereas the severe painful stimulation applied to the palms of both hands did not. INTERPRETATION: These results reveal the deleterious effect of experimentally induced pain on the plantar soles on unperturbed bipedal postural control. At this point, it is conceivable that these effects of experimental pain could generalise to the effects of pain in patients. Accordingly, the present findings suggest that clinical and/or instrumental interventions designed to mitigate pain in patients suffering from plantar foot pain (e.g., podiatry treatments/interventions) could improve postural control. PMID- 21236532 TI - Should extramedullary fixations for hip fractures be removed after bone union? AB - BACKGROUND: Osteosynthesis implants, which remain in the patient after fracture union to save additional surgery, may affect the strain distribution within the bone. A reduction of strain within the bone is known to result in localized bone loss ("stress shielding") and increased fracture risk. The purpose of this study was to examine whether extramedullary fixations for femoral neck fractures have to be removed after fracture union to prevent reductions in cortex strains. METHODS: In a biomechanical experiment, six pairs of human cadaver femora (mean age 56 years, range 48 to 64) were supplied with five strain gauges per bone. The bones were equally supplied with a compression hip screw or a femoral neck plate. Before surgery, after surgery and after removal of the implants, axial compression tests were conducted to measure surface strains during loading. FINDINGS: The compression hip screw reduced the amount of strain at the superior neck by 88% (P=0.015) and at the lesser trochanter by 51% (P=0.038). The femoral neck plate reduced the amount of strain at the superior neck by 89% (P=0.001), and increased the amount of strain at the inferior neck by 58% (P=0.02) and at the lesser trochanter by 63% (P=0.005). After implant removal, there was no significant difference in strain compared to pre-fracture levels, except for the compression hip screw with 21% less strain (P=0.047) at the superior neck. INTERPRETATION: Removal of osteosynthesis implants after bone union reverts bone strains to pre-fracture levels, and might prevent further bone loss induced by stress shielding. PMID- 21236534 TI - Combustion-derived substances in deep basins of Puget Sound: historical inputs from fossil fuel and biomass combustion. AB - Reconstructions of 250 years historical inputs of two distinct types of black carbon (soot/graphitic black carbon (GBC) and char-BC) were conducted on sediment cores from two basins of the Puget Sound, WA. Signatures of polycyclic aromatic hydrocarbons (PAHs) were also used to support the historical reconstructions of BC to this system. Down-core maxima in GBC and combustion-derived PAHs occurred in the 1940s in the cores from the Puget Sound Main Basin, whereas in Hood Canal such peak was observed in the 1970s, showing basin-specific differences in inputs of combustion byproducts. This system showed relatively higher inputs from softwood combustion than the northeastern U.S. The historical variations in char BC concentrations were consistent with shifts in climate indices, suggesting an influence of climate oscillations on wildfire events. Environmental loading of combustion byproducts thus appears as a complex function of urbanization, fuel usage, combustion technology, environmental policies, and climate conditions. PMID- 21236535 TI - The dynamics of arsenic in four paddy fields in the Bengal delta. AB - Irrigation with arsenic contaminated groundwater in the Bengal Delta may lead to As accumulation in the soil and rice grain. The dynamics of As concentration and speciation in paddy fields during dry season (boro) rice cultivation were investigated at 4 sites in Bangladesh and West Bengal, India. Three sites which were irrigated with high As groundwater had elevated As concentrations in the soils, showing a significant gradient from the irrigation inlet across the field. Arsenic concentration and speciation in soil pore water varied temporally and spatially; higher As concentrations were associated with an increasing percentage of arsenite, indicating a reductive mobilization. Concentrations of As in rice grain varied by 2-7 fold within individual fields and were poorly related with the soil As concentration. A field site employing alternating flooded-dry irrigation produced the lowest range of grain As concentration, suggesting a lower soil As availability caused by periodic aerobic conditions. PMID- 21236536 TI - Sources and distribution of polychlorinated-dibenzo-p-dioxins and -dibenzofurans in soil and sediment from the Yellow Sea region of China and Korea. AB - Polychlorinated-dibenzo-p-dioxins and -dibenzofurans (PCDD/Fs) were measured in soils and sediments from the Yellow Sea region. Korean soils and sediments mostly contained detectable PCDD/Fs and showed a widespread distribution among locations. Soil and sedimentary PCDD/Fs from China were comparable to or less than those in Korea. The patterns of relative concentrations of individual congeners in soils were different between the two countries, but similar in sediments. Sources of PCDD/Fs in China and Korea were found to be independent of each other and their distributions reflected matrix-dependent accumulation. Spatial distribution indicated some point sources in Korea while Chinese sources were more widespread and diffuse. PCDD/Fs measured in the coastal areas of the Yellow Sea were comparable to or less than those previously reported in for eastern Asia. However, ?TEQs in soils and sediments were near to or, in some cases exceeded environmental quality guidelines. PMID- 21236537 TI - Using deuterated PAH amendments to validate chemical extraction methods to predict PAH bioavailability in soils. AB - Validating chemical methods to predict bioavailable fractions of polycyclic aromatic hydrocarbons (PAHs) by comparison with accumulation bioassays is problematic. Concentrations accumulated in soil organisms not only depend on the bioavailable fraction but also on contaminant properties. A historically contaminated soil was freshly spiked with deuterated PAHs (dPAHs). dPAHs have a similar fate to their respective undeuterated analogues, so chemical methods that give good indications of bioavailability should extract the fresh more readily available dPAHs and historic more recalcitrant PAHs in similar proportions to those in which they are accumulated in the tissues of test organisms. Cyclodextrin and butanol extractions predicted the bioavailable fraction for earthworms (Eisenia fetida) and plants (Lolium multiflorum) better than the exhaustive extraction. The PAHs accumulated by earthworms had a larger dPAH:PAH ratio than that predicted by chemical methods. The isotope ratio method described here provides an effective way of evaluating other chemical methods to predict bioavailability. PMID- 21236538 TI - Use of virtual 3-dimensional surgery in post-traumatic craniomaxillofacial reconstruction. AB - Traumatic craniofacial injuries often present as difficult reconstructive challenges for maxillofacial surgeons. Reconstruction is often complicated by significant soft tissue loss, comminuted bony fragments, a tenuous blood supply, and wound contamination. For panfacial injuries, restoration of normal facial width, facial height, and sagittal projection may be difficult to achieve. Marked swelling may limit the surgeons' ability to palpate and recognize subtle bony defects and malunion. Furthermore, a true 3-dimensional assessment of bony alignment may not be possible with traditional surgical exposures to the craniofacial skeleton. This article builds on previous work that introduced the use of 3-dimensionally guided surgery for microvascular free-flap reconstruction of the craniofacial skeleton. Use of this technology improves the planning, timing, and overall precision of microvascular reconstructive surgery. Based on this experience, a similar approach to reconstructing patients with significant craniofacial trauma has been adopted. PMID- 21236539 TI - Orthopedic correction of growing hyperdivergent, retrognathic patients with miniscrew implants. AB - Traditional orthodontic treatments do not adequately address the skeletal problems of retrognathic, hyperdivergent, Class II adolescents; the few approaches that do address them require long-term patient compliance. This article introduces a novel approach using miniscrew implants (MSIs) and growth to treat retrognathic, hyperdivergent adolescents. Nine consecutive patients were evaluated at the start of treatment (aged 13.2 +/- 1.1 years) and again at the end of the orthopedic phase (after 1.9 +/- 0.3 years). Each patient had 2 MSIs placed in either side of the palate. Coil springs (150 g) extended from the MSIs to a rapid palatal expander, which served as a rigid segment for intruding the maxillary premolar and molars. Two additional MSIs were placed between the first mandibular molars and second premolars; coil spring (150 g) extended from the MSIs to hold or intrude the mandibular molars. Before treatment, the patients exhibited substantial and significant mandibular retrusion (Z score = -1.0), facial convexity (Z score = 0.7), and hyperdivergence (Z score = 1.6). Treatment produced consistent and substantial orthopedic effects. The chin was advanced by a mean of 2.4 mm, the sella-nasion-basion (SNB) angle increased by 2.1 degrees , the mandibular plane angle decreased by 3.9 degrees , and facial convexity decreased by approximately 3.2 degrees . Questionnaires showed that this treatment approach was not painful or uncomfortable; the majority of the patients indicated that they were very likely to recommend the treatment to others. Treatment was accomplished by titrating the amount of orthodontic intrusion performed based on the individual's growth potential. PMID- 21236540 TI - Complications in transpalatal distraction osteogenesis: a retrospective clinical study. AB - PURPOSE: Transpalatal distraction osteogenesis is a bone-borne technique to expand the maxilla and has become a routine method in treating patients with transverse maxillary hypoplasia. Limited reports concerning treatment difficulties have been published. The purpose of this study was to investigate and categorize the short- and middle-term incidence of peri- and postoperative difficulties (categorized by the classification of Paley in problems, obstacles, and complications). The signs of adverse dental and periodontal effects were established at least 1 year after removal of the distractor. PATIENTS AND METHODS: A total of 73 patients (27 male, 46 female; mean age: 28 years; range: 9 59) that underwent bone-borne SARPE in 3 centers were retrospectively investigated. Clinical follow-up was performed in 63 patients after an average period of 23.9 months (range: 6-63 months). RESULTS: Twenty-seven problems (mainly appliance related), 10 obstacles (appliance-related and asymmetric maxillary expansion), and 1 complication (premature loss of the TPD-module, due to lack of space, in a cleft patient) occurred. Clinical examination showed minimal periodontal damage (gingival recession on 15 sites and pocket depths 4-5 mm in 11 sites). In 28.6% of the incisors radiographic signs of external apical root resorption were seen. CONCLUSION: Bone-borne SARPE is a reliable technique with predictable outcomes. These results suggest that bone-borne SARPE is associated with a low incidence of dental and periodontal damage. Nevertheless, further research, preferably in randomized controlled design, is needed to evaluate the long-term effects and stability. PMID- 21236541 TI - From ear to brain. AB - In this paper Doreen Kimura gives a personal history of the "right-ear effect" in dichotic listening. The focus is on the early ground-breaking papers, describing how she did the first dichotic listening studies relating the effects to brain asymmetry. The paper also gives a description of the visual half-field technique for lateralized stimulus presentations in the visual domain, and a brief overview of asymmetry of touch and motor output. PMID- 21236542 TI - [Alteration of general state in a woman with polyethylene breast implants since 1967. About an exceptional clinical case]. AB - We report the case of a patient with mammary implants for 42 years. She presented for three years a change of the general state with clinicobiological demonstrations of indefinite origin, and a progressive bilateral increase of her mammary volume until it became exceptional. The surgery of explantation allowed the retreat of two masses of almost 6kg. The analysis did not put in evidence any malignant process but confirmed that it was about prostheses in polyethylene. In one year of recession, a considerable improvement of her general state was observed. PMID- 21236543 TI - [Necrotizing fasciitis: study of 17 cases presenting a low mortality rate]. AB - Necrotizing fasciitis is a hypodermis, muscular fascia then dermis necrotizing infection. OBJECTIVE: The originality of this study is to present a series of necrotizing fasciitis treated and followed these last five years, and to compare the therapeutic results with those of the literature. PATIENTS AND METHODS: We led a retrospective study on the patients treated for necrotizing fasciitis between 2005 and 2009 by bringing together the demographic and clinical data, the bacteriological examinations and the results of management. Follow-up data from these patients during period of study (five years) were notified. RESULTS: Seventeen patients were treated (11 men and six women). The average age of the patients was 52 years (ranging from 28 to 82 years). Risk factors of necrotizing fasciitis for our patients were: nonsteroidal anti-inflammatory drugs (82.2%), cutaneous wound (76.4%), obesity (29.4%), oto-rhino-laryngologic diseases (23.5%), alcoholic and drug addicts (23.5%), and diabetis (11.7%). The most isolated and responsible germ was Streptococcus pyogenes in 75.5% of cases. Culture of specimens collected before antibiotic treatment showed that the bacterium was sensible to the antibiotics being administered (clindamycin in 70.5% of cases). The surgical management was early done with an average delay of 2.7 days (ranging from 1 to 15 days). We observed a low mortality rate (11.7%). One patient died during the period of follow-up after one year (average follow-up of 2.0 years; 1-3 years). CONCLUSION: Contrary to the data from the literature, this study presents a decrease of the mortality in necrotizing fasciitis with an early treatment and an adequate management. The precocity and the quality of surgical procedures as well as the presence of an underlying disease are determining factors for successful management of necrotizing fasciitis. PMID- 21236544 TI - Propeller flaps: classification and clinical applications. AB - Propeller flaps feature a highly reliable reconstructive method, based on a perforator vessel. Since their introduction in 1991, a great variety of propeller flaps have been described, according to their shape and their potential of coverage. Indeed, these flaps have progressively been refined and modified, concerning their vascularity and space design. The authors present a classification of propeller flaps. This anatomical classification is necessary to understand the dissection procedure and the differences between the numerous types of propeller flaps nowadays described. It is the international classification, which should be used for the description and conception of these flaps. PMID- 21236545 TI - [The double locking face lifting]. AB - We report our favourite cervicofacial lift technique based on three principles: secondary undermining after subcutaneous canulation through two or three small incisions, a first lock at the level of any classic SMAS technique and a second subdermic lock after appropriate tension on the skin flap 1cm in front of the primary incision. We consider that this method provides the following advantages: safe undermining plane without any traction on the final scar, hair preservation, and a final natural looking consistent with the usual request in France. We therefore believe that this technique could be particularly useful for those whose experience is still limited. We report the survey of the 122 cases operated over the past five years without any major incident. Revision rate is 3.5%, but we believe it underestimates the quality of the results and efforts must be continued on the possible shortcomings of cheek ptosis, correction of naso labial fold and jowls. We recommend a medial approach for difficult necks and are reluctant to undermine extensively the mastoid area. We limit as much as possible malar lifts which recovery is sometimes difficult to manage, preferring the restoration of this area through lipofilling later complemented if necessary by one of the many fillers now available. PMID- 21236546 TI - How accurately can the aetiology of cardiac arrest be established in an out-of hospital setting? Analysis by "concordance in diagnosis crosscheck tables". AB - INTRODUCTION: Several previous studies have focused on establishing the cause of cardiac arrest (CA) during cardiopulmonary resuscitation (CPR) provided in an out of-hospital setting. OBJECTIVES: To analyze the ability of professional advanced life support providers to correctly establish the aetiology of cardiac arrest during out-of-hospital CPR. STUDY DESIGN: A retrospective cohort study analysing 211 cases of out-of-hospital cardiac arrest. METHOD: The aetiology assumed by out of-hospital physicians was compared with the diagnosis that was later established by clinicians or pathologists. RESULTS: Cases were sorted into five diagnostic groups and the overall diagnostic concordance was 74.4% (157 of 211 cases). The cardiac aetiology was presumed in 132 out of 211 patients and confirmed in 135 out of 211 patients. However, an analysis of individual cases of the cardiac causes of cardiac arrest revealed diagnostic matches in only 112 cases. Acute myocardial infarction (AMI) or pulmonary embolism (PE), both of which represent cases that can be potentially influenced by thrombolytic therapy, were presumed in 74 (53+21) and confirmed in 97 (77+20) cases, however with individual diagnostic matches in only 55 cases. CONCLUSION: This study demonstrates the importance of analysing concordance in presumed and definitive diagnosis of individual cases, since an overall comparison in a cohort of cases may be highly misleading. It introduces the method of the crosscheck table for visualization and comparison of presumed and final diagnoses. The two alternative approaches of inclusion rule for applying the thrombolytic therapy in out-of-hospital care were discussed with regard to the recent TROICA study. PMID- 21236547 TI - Therapeutic hypothermia attenuates acute lung injury in paraquat intoxication in rats. AB - AIM OF THE STUDY: Paraquat intoxication induces acute lung injury and numerous fatalities have been reported. The mechanism of toxic effect of paraquat is oxidative injury and inflammation. Therapeutic hypothermia has been known to have antioxidant and anti-inflammatory effects. This study was designed to evaluate the effect of therapeutic hypothermia on paraquat intoxication. METHODS: Male Sprague-Dawley rats were given 50 mg/kg of paraquat intraperitoneally and divided into the normothermia (36-38 degrees C) group and the hypothermia (30-32 degrees C) group after 1h of paraquat administration. The hypothermia group underwent 2 h of hypothermia followed by 2 h of rewarming. In the survival study, mortality was observed for 24 h after paraquat administration. An in the second experiment, lung tissues and plasma were harvested at 6 h after paraquat administration. RESULTS: The 12 h survival rate was significantly higher in the hypothermia group than in the normothermia group (100% vs. 50%, p<0.05), but survival rates for 24 h were not different. Acute lung injury score was lower in the hypothermia group than in the normothermia group (p<0.05). Thmalondialdehyde contents of lung tissues, plasma interleukin-6 and nitrite/nitrate concentrations were significantly decreased in the HT group compared to the NT group (p<0.05). CONCLUSION: Therapeutic hypothermia delayed early mortality and attenuated acute lung injury in paraquat intoxication. PMID- 21236548 TI - Performance of an automated external defibrillator during simulated rotor-wing critical care transports. AB - OBJECTIVE: This study aimed to evaluate whether an automated external defibrillator (AED) was accurate enough to analyze the heart rhythm during a simulated rotor wing critical care transport. We hypothesized that AED analysis of the simulated rhythms during a helicopter flight would result in significant errors (i.e., inappropriate shocks, analysis delay). METHODS: Three commercial AEDs were tested for analyzing the heart rhythm in a helicopter using a manikin and a human volunteer. Ventricular fibrillation (VF), sinus rhythm, and asystole were simulated by using an arrhythmia simulator of the manikin. The intervals from analysis to shock recommendation were collected on a stationary and in motion helicopter. Sensitivity and specificity of three AEDs were also calculated. Vibration intensities were measured with a digital vibration meter placed on the chest of the manikin/human volunteer both on the stretcher and on the floor of the helicopter. RESULTS: All AEDs correctly recommended shock delivery for the cardiac rhythms of the manikin. Sensitivity for VF was 100.0% (95% CI 91.2-100.0) and specificity for sinus rhythm and asystole were 100.0% (95% CI 91.2-100.0). Although the recorded ECG rhythms of the volunteer in an in motion helicopter showed baseline artifacts, all AEDs analyzed the cardiac rhythm of the volunteer correctly and did not recommend shock delivery. On the floor of the helicopter, the median measured vibration intensity was 6.6 m/s(2) (IQR 5.5 7.7 m/s(2)) with significantly less vibrations transmitted to the manikin/human volunteer chest (manikin median 3.1 m/s(2), IQR 2.2-4.0 m/s(2); human volunteer median 0.95 m/s(2), IQR 0.65-1.25 m/s(2)). CONCLUSION: This study suggested that current AEDs could analyze the heart rhythm correctly during simulated helicopter transport. Further studies using an animal model would be needed before applying to patients. PMID- 21236549 TI - Measuring human mast cell-mediated cytotoxicity against human tumour cells: three colour flow cytometry using monoclonal antibody target staining with annexin V / propidium iodide co-labelling of death. AB - BACKGROUND: Chromium release assay is the standard method for evaluation of cell mediated cytotoxicity, including that of mast cells. Although this is a reproducible method, it has more drawbacks than even radioactivity. In addition to the shortcoming of measuring only necrotic killing, some non-radioactive methods have not been widely used either. The numerous limitations of these methods led researchers to develop other techniques. This study describes a new flow cytometric approach that measures human mast cell-mediated cytotoxicity by marking target cells with monoclonal antibody alongside annexin V/ PI co labelling. METHODS: A colony forming unit - mast in vitro was developed from human bone marrow mononuclear cells in serum-free methylcellulose medium. Six week-old human bone marrow-derived mast cells were used as effectors, and malignant B-lymphoblastoid cell lines like Daudi / Raji cells as targets. Effectors and targets were both co-incubated for short and long-term durations, and experiments were repeated several times. Cytotoxicity was calculated by flow cytometric mast cell-mediated cytotoxicity assay. RESULTS: This method was able to clearly show mast cell-mediated cytotoxicity against human tumours. It is well known that some lymphokine-activated killer-sensitive cells are resistant to mast cell-mediated cytotoxicity. However, a different type of lymphokine activated killer-sensitive cell in this study was found to be very sensitive to mast cell mediated cytotoxicity. Moreover, this technique also allowed us to separate killing into different stages: early and late apoptosis. CONCLUSIONS: When compared to chromium release and non-radioactive methods, this method has the advantages of allowing evaluation of early apoptosis and short/long term mast cell-mediated cytotoxicity with specific target marking. PMID- 21236550 TI - Dentists' knowledge about anaphylaxis caused by local anaesthetics. AB - BACKGROUND: IgE-mediated systemic reactions to local anaesthetics may be seen- although rarely--by dentists. However, it is not known whether dentists are familiar with symptoms, signs and management of anaphylaxis. METHODS: In this study we aimed to evaluate knowledge of dentists of the symptoms and signs and current treatment of anaphylaxis. For this, some dentists working in their private offices in Istanbul were asked to complete an anonymous questionnaire with 15 questions related to anaphylaxis. RESULTS: A total of 86 dentists agreed to participate in the study. None of the attendants were completely aware of the symptoms and signs of anaphylaxis. About half of the attendants (48.8%) knew epinephrine as the first drug in the treatment of anaphylaxis and keep it in their offices (55.6%), but only one third of the dentists (31.5%) preferred intramuscular route as the most effective route for epinephrine injection. CONCLUSION: Our data show that the level of dentists' knowledge of local anaesthetics allergy and anaphylaxis is inadequate. This may endanger patients' lives. An educational programme that may improve general dentists' knowledge about local anaesthetics allergy and anaphylaxis is urgently necessary. PMID- 21236551 TI - Is it necessary to treat all asthmatic children with raised levels of exhaled nitric oxide?: treating the patient or the data. AB - BACKGROUND: The aim of the present study is to assess whether a single determination of the fraction of exhaled nitric oxide (FENO), added to the measurements usually taken during a routine checkup, helps in the prediction of the recurrence of asthma attacks in controlled patients who are not receiving any baseline treatment; and whether or not treatment of the said latent inflammation is appropriate. METHODS: Observational study of prospective cohorts. Over a period of three months, data was collected from 28 patients (6 to 14 years) who met the conditions of the inclusion criteria, with a follow up appointment after six months. RESULTS: Patients were divided into two groups: 13 with FENO values of 49 and over, and 15 with values of under 49. Five patients in the subgroup with low FENO values suffered recurrence, in contrast to only one in the group with high values. The positive predictive value of the high values of the FENO was 7.69, with no significant differences between the two groups. CONCLUSIONS: Certain doubts were raised about the usefulness of the FENO, as opposed to the traditional methods of asthma control with regard to the therapeutic management of clinically controlled patients who are not receiving treatment and who have high FENO values. It would appear unwise to recommend the systematic treatment of patients with high FENO values, when measured during a routine check-up, in cases of asthma with an allergic component and are asymptomatic or in a phase of asthma under good control. PMID- 21236552 TI - Oxidative stress status in patients with chronic idiopathic urticaria. AB - AIM: The controversial data related to oxidative stress status in patients with chronic idiopathic urticaria (CIU) have been reported. Therefore, the present study was aimed to contribute to this debate by determining oxidative stress markers along with some trace element levels in patients with CIU. METHODS: Twenty-five patients with CIU (10 males, 15 females) and 36 healthy controls were enrolled into the study. Erythrocyte lipid peroxidation status, scavenger enzyme activities and trace element levels were determined. RESULTS: While erythrocyte MDA levels, erythrocyte GSH- Px activities and erythrocyte Zn levels showed no differences between the patient and control groups, a statistically significant decrease and increase were observed in erythrocyte CuZn-SOD activities and Cu levels, respectively, in the CIU patients when compared to those of the controls (p < 0.001 for both of them). CONCLUSION: In conclusion, an oxidative burden which can be relieved by some preserved antioxidant mechanisms seems to be present in patients with CIU even if they are clinically stable and it may probably have a role in the pathogenesis. PMID- 21236553 TI - Serum heavy metal and antioxidant element levels of children with recurrent wheezing. AB - STUDY OBJECTIVES: The aim of the study is to investigate the levels of toxic heavy metals related with environmental pollution and trace elements involved in antioxidant system in children suffering from recurrent wheezing. STUDY DESIGN: One hundred children with recurrent wheezing (at least three recurrences) between the ages from 1 to 6 years took part in the study, and also 116 age- and sex- matched healthy children were involved in the study as a control group. Venous blood samples were collected and serum mercury, lead, aluminium, zinc, selenium, and copper levels were studied using ICP-MS. RESULTS: Serum lead (0.76+/-0.15 vs. 0.27+/-0.01, p:0.001) and mercury levels (1.31+/-0.15 vs 0.71+/-0.05, p<0.001) were higher in wheezy group than those acquired from the control group. Serum zinc (69.4+/-1.65 vs. 78.9+/-2.78, p:0.005) and selenium (115.6+/-1.87 vs. 125.4+/-2.94, p:0.008) levels were lower in wheezy group than those acquired from the control group. Serum zinc levels were found to be correlated with number of ARTIs (r(p):-0.332, p:0.001) and the number of wheezy attacks (r(p):-0.776, p<0.001) during the previous year in the wheezy group. CONCLUSION: Elevated levels of serum lead and mercury and low levels of zinc and selenium may suggest some disturbances in the antioxidant system in children with recurrent wheezing. This means that children with recurrent wheezing are much more susceptible to environmental pollutants and respiratory tract infections than healthy children and this heavy metal-antioxidant relationship may play a role as a contributing factor in the pathogenesis of recurrent wheezing in children. PMID- 21236554 TI - Clinical evolution of patients with respiratory allergic disease due to sensitisation to Alternaria alternata being treated with subcutaneous immunotherapy. AB - INTRODUCTION: Sensitisation to Alternaria is a cause of respiratory disease in Spain, particularly in childhood, but it is also a significant marker of the severity of this disease. Therefore, the use of an aetiological treatment (allergen specific immunotherapy) is essential, and both subjective and objective clinical parameters should be used to follow up this treatment. OBJECTIVE: This open-label, uncontrolled, observational, prospective study was designed in order to study the evolution of these patients on allergen specific immunotherapy therapy in daily clinical practice and to assess the use of different monitoring tools. MATERIAL AND METHODS: A total of 99 patients were included. They were monosensitised to this perennial allergen and treated with subcutaneous allergen specific immunotherapy. After one year of follow-up, these patients were assessed for the presence of symptoms, use of medication, clinical incidents, quality of life and asthma control. RESULTS: After one year of treatment a significant fall was observed in the use of concomitant medication (beta2-agonists: p=0.0278, inhaled corticosteroids: p=0.0007, anti-leukotrienes: p=0.0495), nasal symptoms (p=0.0081), quality of life (PAQLQ, p<0.0001) and asthma control (ACQ, p<0.0001). Twenty-one patients had to attend emergency department due to exacerbation of their allergic disease, and only one of them had to be admitted to hospital. CONCLUSION: respiratory allergic disease due to Alternaria alternata is a disease which is hard to control, and in our daily practice, the use of specific subcutaneous immunotherapy can be of significant benefit in our paediatric patients. PMID- 21236555 TI - Single port transumbilical laparoscopic surgery for adnexal lesions: a single center experience in Korea. AB - OBJECTIVES: The purpose of this study was to demonstrate the feasibility of single port transumbilical laparoscopic surgery (SPLS) for the treatment of adnexal lesions. METHODS: We have performed SPLS to treat adnexal lesions using a single three-channel port system with a wound retractor and surgical glove since October 2008. All patients who underwent SPLS for adnexal lesions between October 2008 and September 2009 were included in the study. We retrospectively reviewed their medical records and analyzed demographic data and surgical outcomes including age, medico-surgical illness, surgical indications, operative times and pathologic results. RESULTS: Eighty-six patients underwent SPLS for adnexal lesions. The median age of the patients was 31 years (range 14-78 years), the median body mass index was 21.0 kg/m(2) (range 16.7-32.2 kg/m(2)), and the median operation time was 64.5 min (range 21-176 min). The median blood loss was 10 ml (range 10-300 ml). The median length of postoperative hospital stay was 2 days (range 1-7 days). Endometriosis was the most frequently diagnosed etiology (34.9%). Other laparoscopic approaches were employed in two cases (2.3%). There were four cases (4.7%) with complications: three with pelvic infections and one with postoperative hemorrhage. CONCLUSIONS: SPLS is a feasible approach for the treatment of adnexal lesions. PMID- 21236556 TI - Open cornual resection versus laparoscopic cornual resection in patients with interstitial ectopic pregnancies. AB - OBJECTIVE: To compare laparotomy and laparoscopic management of interstitial ectopic pregnancies. STUDY DESIGN: The medical records of 109 patients diagnosed with interstitial ectopic pregnancies at the Korea University Medical Center, the Republic of South Korea, between January 1998 and October 2009 were reviewed retrospectively. Eighty-eight women were treated by open cornual resection or laparoscopic cornual resection. A case-controlled study was performed. The outcomes were operative time, length of hospital stay, estimated blood loss, blood transfusion, and complication. Nominal variables were analyzed by the Fisher's exact test or the chi(2) test. RESULTS: The frequency of cornual ectopic pregnancies was 4.31% at this medical center. In patients with a cornual resection, primary laparotomy was performed in 49 women and laparoscopy was performed in 39 women. Laparoscopy was converted to laparotomy in five patients. There were no statistically significant differences between the two groups for the mean operation time, estimated blood loss, blood loss of more than 1000 mL, blood transfusion requirements, and complications. The mean number of postoperative hospital days was shorter in the laparoscopy group than in the laparotomy group (4.53 +/- 1.44 days versus 5.89 +/- 1.86 days, respectively; P<0.001). CONCLUSION: Laparoscopic cornual resection is a safe and less invasive procedure with a reasonable complication rate and shorter hospital stay. PMID- 21236557 TI - Volumetric measurements in binary solvents: theory to experiment. AB - Interactions of proteins and protein groups with water-soluble cosolvents have been studied for the last 50 years with a variety of theoretical and experimental methods. The contribution of volumetric techniques to these studies is relatively modest, although volumetric properties of solutes are sensitive to the entire spectrum of solute-solvent and solute-cosolvent interactions. This deficiency is partly related to formidable experimental difficulties related to conducting volumetric measurements at high cosolvent concentrations and partly to the lack of the theoretical framework within which volumetric results can be rationalized in terms of solute-solvent and solute-cosolvent interactions. However, recent years have witnessed a revival of interest in application of the volumetric approach to characterization of solute-solvent interactions in protein solutions in binary mixtures. This review presents an overview of recent advances in the field, focusing on both the theoretical and the experimental developments. While presenting the current state of the art, it also outlines the strategy for future volumetric studies that will result in new insights into the old problem of interactions of proteins with protecting and denaturing osmolytes. PMID- 21236558 TI - The ratio of VEGF/PEDF expression in bone marrow mesenchymal stem cells regulates neovascularization. AB - Angiogenesis, or neovascularization, is a finely balanced process controlled by pro- and anti-angiogenic factors. Vascular endothelial growth factor (VEGF) is a major pro-angiogenic factor, whereas pigment epithelial-derived factor (PEDF) is the most potent natural angiogenesis inhibitor. In this study, the regulatory role of bone marrow stromal cells (BMSCs) during angiogenesis was assessed by the endothelial differentiation potential, VEGF/PEDF production and responses to pro angiogenic and hypoxic conditions. The in vivo regulation of blood vessel formation by BMSCs was also explored in a SCID mouse model. Results showed that PEDF was expressed more prominently in BMSCs compared to VEGF. This contrasted with human umbilical vein endothelial cells (HUVECs) where the expression of VEGF was higher than that of PEDF. The ratio of VEGF/PEDF gene expression in BMSCs increased when VEGF concentration reached 40ng/ml in the culture medium, but decreased at 80ng/ml. Under CoCl(2)-induced hypoxic conditions, the VEGF/PEDF ratio of BMSCs increased significantly in both normal and angiogenic culture media. There was no expression of endothelial cell markers in BMSCs cultured in either pro-angiogenic or hypoxia culture conditions when compared with HUVECs. The in vivo study showed that VEGF/PEDF expression closely correlated with the degree of neovascularization, and that hypoxia significantly induced pro angiogenic activity in BMSCs. These results indicate that, rather than being progenitors of endothelial cells, BMSCs play an important role in regulating the neovascularization process, and that the ratio of VEGF and PEDF may, in effect, be an indicator of the pro- or anti-angiogenic activities of BMSCs. PMID- 21236559 TI - Ligand-assisted degradation of carbon tetrachloride by microscale zero-valent iron. AB - Degradation of carbon tetrachloride (CT) by microscale zero-valent iron (ZVI) was investigated in batch systems with or without organic ligands (ethylenediaminetetraacetic acid (EDTA), citric acid, tartaric acid, malic acid and oxalic acid) at pHs from 3.5 to 7.5. The results demonstrated that at 25 degrees C, the dechlorination of CT by microscale ZVI is slow in the absence of organic ligands, with a pseudo-first-order rate constant of 0.0217 h(-1) at pH 3.5 and being further dropped to 0.0052 h(-1) at pH 7.5. However, addition of organic ligands significantly enhanced the rates and the extents of CT removal, as indicated by the rate constant increases of 39, 31, 32, 28 and 18 times in the presence of EDTA, citric acid, tartaric acid, malic acid and oxalic acid, respectively, at pH 3.5 and 25 degrees C. The effect of EDTA was most significant; the dechlorination of CT at an initial concentration of 20 mg l(-1) increased from 16.3% (no ligands) to 89.1% (with EDTA) at the end of 8h reaction. The enhanced CT degradation in the presence of organic ligands was primarily attributed to the elimination of a surface passivation layer of Fe(III) (hydr)oxides on the microscale ZVI through chelating of organic ligands with Fe(III), which maintained the exposure of active sites on ZVI surface to CT. PMID- 21236560 TI - Engineering death receptor ligands for cancer therapy. AB - CD95, TNFR1, TRAILR1 and TRAILR2 belong to a subgroup of TNF receptors which is characterized by a conserved cell death-inducing protein domain that connects these receptors to the apoptotic machinery of the cell. Activation of death receptors in malignant cells attracts increasing attention as a principle to fight cancer. Besides agonistic antibodies the major way to stimulate death receptors is the use of their naturally occurring "death ligands" CD95L, TNF and TRAIL. However, dependent from the concept followed to develop a death ligand based therapy various limiting aspects have to be taken into consideration on the way to a "bedside" usable drug. Problems arise in particular from the cell associated transmembrane nature of the death ligands, the poor serum half life of the soluble fragments derived from the transmembrane ligands, the ubiquitous expression of the death receptors and the existence of additional non-death receptors of the death ligands. Here, we summarize strategies how these limitations can be overcome by genetic engineering. PMID- 21236561 TI - Screening for large genomic rearrangements in the FANCA gene reveals extensive deletion in a Finnish breast cancer family. AB - A portion of familial breast cancer cases are caused by mutations in the same genes that are inactivated in the downstream part of Fanconi anemia (FA) signaling pathway. Here we have assessed the FANCA gene for breast cancer susceptibility by examining blood DNA for aberrations from 100 Northern Finnish breast cancer families using the MLPA method. We identified a novel heterozygous deletion, removing the promoter and 12 exons of the gene in one family. This allele was absent from 124 controls. We conclude that FANCA deletions might contribute to breast cancer susceptibility, potentially in combination with other germline mutations. To our knowledge, this is the first study reporting a large deletion in an upstream FA gene in familial breast cancer. PMID- 21236562 TI - Enhanced anti-tumor activity by the combination of TRAIL/Apo-2L and combretastatin A-4 against human colon cancer cells via induction of apoptosis in vitro and in vivo. AB - The present study indicated that the combination of TRAIL/Apo-2L and CA-4 exerted synergistic anti-proliferative effect against human colon carcinoma cells including SW-620 and HCT-116 in vitro. Moreover, the increased anti-tumor efficacy of TRAIL/Apo-2L combined with CA-4 was further validated on SW-620 xenograft model in nude mice. These enhanced anti-cancer activities were accompanied by caspase-mediated apoptosis. Furthermore, it was identified that NF kappaB as the major determinant of TRAIL/Apo-2L resistance could be blocked in cytoplasm by TRAIL/Apo-2L plus CA-4 treatment. Taken together, these findings build the rationale for further (pre)clinical development of TRAIL/Apo-2L and CA 4 against colorectal cancer. PMID- 21236563 TI - Isotypic neutralizing antibodies against mouse GCP-2/CXCL6 inhibit melanoma growth and metastasis. AB - The chemokine granulocyte chemotactic protein (GCP)-2/CXCL6 promotes tumor growth as angiogenesis inducer and neutrophil chemoattractant. The neutralizing capacity and specificity of monoclonal mouse anti-murine (mu)GCP-2/CXCL6 antibodies were evidenced by granulocyte chemotaxis and signaling assays. The half-life of the non-antigenic antibody in the blood circulation was approximately 15 days. The titers remained constant upon weekly injection. Tumor growth and lymphogenic metastases of human melanoma over-expressing muGCP-2 were reduced in mice treated with anti-muGCP-2. Moreover, the drop in muGCP-2 antibody titer correlated with the melanoma tumor size. Taken together, we show that functional blocking of GCP 2 inhibits tumor growth and metastases. PMID- 21236564 TI - A radiation-induced gene expression signature as a tool to predict acute radiotherapy-induced adverse side effects. AB - The majority of patients tolerate radiotherapy well, but some of them suffer from severe side effects. To find genes possibly predictive for radiosensitivity, mRNA profiles were generated before and 6h after in vitro irradiation with 5Gy. We analyzed lymphocytes from four head and neck and eight breast cancer patients with strong acute radiation toxicity and from 12 matching normal reacting patients in a blind study. Expression was also measured in lymphocyte subpopulations and Epstein-Barr transformed lymphocytes. Radiation response in whole lymphocyte populations was most similar to that of B cells. In peripheral blood lymphocytes of all patients; 153 genes were identified which were statistically significantly altered by a fold change of more than 50% by irradiation. The signatures of radio-responsive genes differed tremendously between primary and transformed cells. Pathway analysis revealed genes involved in p53 signalling, cell cycle control and apoptosis in response to radiation in primary lymphocytes. In these cells, a set of 67 radiation-induced genes was identified capable of differentiating between severe radiosensitive and normal reacting patients. More than one third of such classifying genes belong to the group of apoptosis or cell cycle regulating genes. The classifying potential of the expression signature has now to be validated in further patient cohorts. PMID- 21236566 TI - High mobility of SDBS-dispersed single-walled carbon nanotubes in saturated and unsaturated porous media. AB - Knowledge of the mobility of carbon nanotubes (CNTs) in porous media is very important to assess their impacts on the environment. In this study, a series of laboratory experiments were conducted to explore the transport mechanisms of sonication shortened, sodium dodecylbenzene sulfonate (SDBS) dispersed single walled nanotubes (SWNTs) in both saturated and unsaturated sand columns. Laboratory columns packed with quartz sand with different combinations of moisture content and grain-size distribution were used to examine the breakthrough behavior of the SDBS-dispersed SWNTs. Bubble column experiments were also conducted to study the interactions between the SDBS-dispersed SWNTs and the air-water interface. Packed-column experimental results showed that the SDBS dispersed SWNTs were highly mobile for most of the experimental conditions tested. The surface deposition of the SWNTs in the sand columns was low because all the interactive surfaces were negatively charged. Physical trapping was not observed for the SWNTs in the saturated porous media of different grain-size distributions because the SWNTs might orient parallel to the streamlines in flow to reduce their retention. Retention of the SWNTs in unsaturated porous media occurred only at a very low moisture content (<0.10). Otherwise, reduction in moisture content showed little impact on the retention and transport of the SWNTs in unsaturated porous media. Findings from the bubble-column experiments confirmed that the SDBS-dispersed SWNTs did not attach to the air-water interface. A mathematical model based on the advection-dispersion equation coupled with reaction-rate laws successfully described the retention and transport of the SDBS-dispersed SWNTs in both water-saturated and unsaturated columns. PMID- 21236565 TI - Extraction of gold(III) from hydrochloric acid solutions by CTAB/n-heptane/iso amyl alcohol/Na2SO3 microemulsion. AB - The extraction of Au(III) from hydrochloric acid solutions by microemulsion was studied. The extraction experiments were carried out using cetyltrimethylammonium bromide (CTAB) as surfactant and iso-amyl alcohol as co-surfactant. Au(III) was found to be extracted into the microemulsion phase due to ion pair formation such as AuCl(4)(-)CTAB(+). The influence of temperature on the extraction of Au(III) has been investigated at temperatures ranging from 288 to 313 K. Temperature was found to decrease the distribution of Au(III). Thermodynamic parameters like enthalpy and entropy of the extraction, calculated by applying Van't Hoff equation, were -36.76 kJ mol(-1) and -84.87 J mol(-1) K(-1), respectively. Furthermore, the influence of the concentrations of hydrogen ion and chloride anion on the extraction efficiency (E%) were verified. Au(III) was extracted quantitatively (E%>99%) and selectively at the whole range of HCl concentrations (0.2-5 M). Recovery of gold from electrical waste and treatment of CTAB wastewater generated from the extraction were also discussed. Thus, the extraction of Au(III) from hydrochloric acid solutions by microemulsion is an effective approach. PMID- 21236567 TI - Different solvents for the regeneration of the exhausted activated carbon used in the treatment of coking wastewater. AB - The solvents n-pentane, methylene dichloride, ethyl ether and dodecylbenzenesulphonic acid sodium were used to regenerate exhausted activated carbon used in the process of treating coking wastewater, and the efficiency, ability, and optimum conditions of the different solvents on this regeneration were investigated. The results indicate that n-pentane could effectively remove refractory organic compounds in the coking wastewater adsorbed on the surface of activated carbon and could repeatedly regenerate the exhausted activated carbon to recover its adsorption activity. Under the conditions of a regeneration time of 20 min, a regeneration temperature of 25 degrees C, an activated carbon drying time of 300 min, and an activated carbon drying temperature of 150 degrees C, n pentane had the best regeneration efficiency, at 98.27%, for exhausted activated carbon. Gas chromatography-mass spectrometry analysis results show that the nature of the activated carbon regenerated by organic solvents had no remarkable change in adsorption for the main types of organic compounds in coking wastewater. The good regenerative effect of n-pentane on the activated carbon may be due its stronger desorption of esters embedded within the internal structure of activated carbon. PMID- 21236568 TI - Aqua regia extracted metals in sediments from the industrial area and surroundings of Pancevo, Serbia. AB - Surface and buried sediments were analyzed for Ba, Ca, Cd, Co, Cr, Cu, Mn, Ni, Pb, Zn and V, as well as for total carbon and hydrogen to assess the distribution of sediment pollution due to the vicinity of the petrochemical complex. The samples, collected from 20 locations within the petrochemical complex and from 16 locations outside the complex, were aqua regia extracted and analyzed by ICP/OES. Metals were determined with an acceptable accuracy for certified metals of 82 113%. The precision for the aqua regia extraction was satisfactory, less than 20%, except for Cd where it was 28%. Comparison of the data from the petrochemical with those from the non-petrochemical areas showed different distributions of the metals. Metals that exceeded the baseline range; Ba, Cd, Cu, Zn and Pb, were detected in higher concentrations in sediments that were under the influence of the chlor-alkali plant within the petrochemical complex. Comparison with data from the petrochemical complex and its surroundings and their distribution demonstrated that the metal compositions of the sediments were modified by anthropogenic activities. PMID- 21236569 TI - Assessment of removal of components containing hazardous substances from small WEEE in Austria. AB - Minimum treatment requirements for waste electrical and electronic equipment (WEEE) established by Directive 2002/96/EC provide for the removal of specific components containing hazardous substances. To date, no comparative analysis of removal rates has been undertaken. The present paper examines the state of de pollution of sWEEE in Austrian treatment plants. The mass of selected components removed and the corresponding mass of hazardous substances is compared to estimated values for sWEEE input material. The results obtained reveal that components are only partly removed, featuring a high variation between components and plants assessed. The overall rate of removal ranged from 72% of the estimated value for batteries to 21% of the estimated value for liquid crystal panels. This implies the forwarding of substantial quantities of hazardous substances to mechanical treatment processes, particularly relevant in terms of dispersion of pollutants. Furthermore, easily releasable pollutants, such as Hg from LCD backlights, Cd from batteries or highly contaminated dust in general, pose substantial health risks for plant workers. Low removal rates of printed circuit boards, batteries and toner cartridges also lead to a reduction in quantities of valuable recyclable materials (precious metals, plastics). PMID- 21236570 TI - Adsorption-desorption properties and characterization of crosslinked Konjac glucomannan-graft-polyacrylamide-co-sodium xanthate. AB - A new flocculant, based on Konjac-graft-poly (acrylamide)-co-sodium xanthate (CKAX), was synthesized in aqueous solution using epichlorohydrin (ECH) as the cross-linker and ceric ammonium nitrate (CAN) as the initiator. X-ray diffraction indicated the existence of strong interaction between KGM and reactant, including intermolecular and intramolecular hydrogen bonds. Microscopy images exhibited the appropriate pore size and distribution, which might be related to a higher capacity of flocculation and adsorption. Thermo gravimetric analysis showed that the synthetic polymer could improve the thermo-stability of the natural polysaccharides, and there was a positive correlation between polymer residual weight and flocculation. The adsorption and desorption properties for copper ions indicated that the adsorption rate could be described by a pseudo-second-order rate model, and the Freundlich model provides the best fit for the resulting adsorption isotherm. The flocculant can be regenerated in HNO(3) solution. PMID- 21236571 TI - Recovery of struvite from animal wastewater and its nutrient leaching loss in soil. AB - Contaminants in swine wastewater were recovered in the form of struvite, a crystal of magnesium ammonium phosphate (MAP), using a newly designed process, and the leaching loss of MAP in soil was examined. The continuous flow process was operated under optimal conditions: 1.0 molar ratio of magnesium (Mg) addition with respect to orthophosphate (OP) and an aeration rate of 0.73 L/L min. Five treatments were performed with three replications for soil pH and nutrient leaching loss tests. It was found that 93% of the OP in the swine wastewater was crystallized, and the MAP crystal formation was verified by X-ray diffraction (XRD) and scanning electron microscope (SEM) analyses. The analyses revealed that the pattern of pH change and N leaching losses for MAP-treated soil were remarkably different from those for fused super phosphate (FSP)-urea-treated soils. The pH levels for the control and FSP-urea-treated soils after a five-week experiment were unchanged or slightly decreased, whereas an increase in pH was observed in the MAP-treated soils. Leaching loss of N was higher in FSP-urea treatments, with MAP treatments showing N losses of only 1.93 and 2.05%, respectively, while FSP-urea treatments showed N losses of 7.82 and 6.47%, respectively, during the same period. Phosphate (P) leaching was very slow in both MAP- and FSP-treated groups. PMID- 21236572 TI - Sorption of curium by silica colloids: effect of humic acid. AB - Sorption of curium by silica colloids has been studied as a function of pH and ionic strength using (244)Cm as a tracer. The sorption was found to increase with increasing pH and reach a saturation value of ~95% at pH beyond 5.3. The effect of humic acid on the sorption of (244)Cm onto silica was studied by changing the order of addition of the metal ion and humic acid. In general, in the presence of humic acid (2 mg/L), the sorption increased at lower pH (<5) while it decreased in the pH range 6.5-8 and above pH 8, the sorption was found to increase again. As curium forms strong complex with humic acid, its presence results in the enhancement of curium sorption at lower pH. At higher pH the humic acid present in the solution competes with the surface sites for curium thus decreasing the sorption. The decrease in the Cm sorption in presence of humic acid was found to be less when humic acid was added after the addition of curium. Linear additive model qualitatively reproduced the profile of the Cm(III) sorption by silica in presence of humic acid at least in the lower pH region, however it failed to yield quantitative agreement with the experimental results. The results of the present study evidenced the incorporation of Cm into the silica matrix. PMID- 21236573 TI - Heterogeneous photo-Fenton decolorization of methylene blue over LiFe(WO4)2 catalyst. AB - Heterogeneous photo-Fenton process using LiFe(WO(4))(2) as catalyst was studied to degrade Methylene blue (MB) dye in aqueous solution. The results indicated that LiFe(WO(4))(2) could effectively catalyze the decolorization of MB in the presence of UV light and H(2)O(2). The effects of different parameters such as amounts of catalyst, H(2)O(2) concentration, initial pH of the dye solution, initial dye concentration and UV light intensity on the decolorization efficiency of the process were investigated. It was found that LiFe(WO(4))(2) possessed a wide applicable pH range. X-ray photoelectron spectroscopy (XPS) was applied to investigate the transformation between Fe(III) and Fe(II). It was also observed that catalytic behavior could be reproduced in consecutive experiments without a considerable drop in the process efficiency. PMID- 21236574 TI - Utilization of a low cost agro-residue for production of coagulant aids and their applications. AB - Different samples of rice husk ash (RHA) and sodium silicate were prepared and characterized using FTIR, NFTIR and XRD. The selected sample of RHA was obtained by calcination of untreated rice husk (RH) in a semi-closed system at 650 degrees C. Four novel polyinorganic coagulants were also prepared, namely, poly aluminum chloride silicate, poly hydroxy aluminum sulphate silicate, poly ferric chloride silicate and poly ferric aluminum chloride silicate. Applications were carried out for the removal of some pollutants from ground, sewage and industrial waste waters. It was found that the maximum percentages removal of Fe(2+) and Mn(2+) ions in ground water reached 99 and 97%, respectively, the maximum percentage removal of, Pb(2+) ion in industrial waste water reached 97%. In addition, the maximum percentages removal of COD, BOD and TSS in sewage waste water reached 90, 92, and 93%, respectively. PMID- 21236575 TI - WITHDRAWN: Analysis of synphilin-1 and synuclein interactions by yeast two-hybrid beta-galactosidase liquid assay. AB - The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/S0304-3940(02)00253-7. The duplicate article has therefore been withdrawn. PMID- 21236576 TI - Laser assisted field evaporation of oxides in atom probe analysis. AB - We have investigated the laser assisted field evaporation phenomena of ZnO, and MgO to explore the feasibility of quantitative three dimensional atom probe analyses of insulating oxides. To assist the field evaporation of these oxides, the usage of short wavelength 343 nm ultraviolet (UV) laser was found to be more effective than 515 nm green laser. We observed field ion microscopy (FIM) image expansion and mass peak shifting when 343 nm laser was irradiated on MgO. This phenomenon can be attributed to the laser induced electron excitation which causes the reduction of the resistivity of the specimen. PMID- 21236577 TI - Toxoplasma gondii and Neospora caninum in wildlife: common parasites in Belgian foxes and Cervidae? AB - Sera from Cervidae were tested for the presence of antibodies against Neospora caninum using ELISA; and against Toxoplasma gondii using SAG1-ELISA and a commercially available agglutination test. The T. gondii seroprevalence was 52% (38/73) in roe deer (Capreolus capreolus), 0% in bred fallow deer (0/4) (Dama dama) and red deer (0/7) (Cervus elaphus). We found 2.7% of the roe deer samples and none of the bred deer samples positive for N. caninum. Brain samples from wild roe deer, red deer and red foxes (Vulpes vulpes) were tested for the presence of T. gondii and N. caninum DNA using multiplex real-time PCR. We detected T. gondii in 18.8% (57/304) of the red foxes and in 1 of the 33 deer samples. N. caninum was found in 6.6% of the red foxes and in 2 roe deer samples. Twenty-six of the T. gondii positive DNA extracts from the red fox samples were genotyped. Twenty-five were type II and only one was found to be type III. PMID- 21236578 TI - Investigations on the prevalence and potential pathogenicity of intestinal trichomonads in pigs using in situ hybridization. AB - In pigs, three different trichomonad species (Tritrichomonas foetus, Tetratrichomonas buttreyi and Tritrichomonas rotunda) have been described as commensals in the large intestine. The aim of this study was to gain further knowledge on the prevalence and pathogenicity of trichomonads in pigs by using a morphology-based approach. Chromogenic in situ hybridization (ISH) is a technique which allows direct localization of the protozoa in the intestinal tissue and correlation of the infection with pathologic changes. In the present study paraffin-wax embedded colon and ileum samples of 192 pigs were analyzed with this method. Using a probe specific for all known members of the order Trichomonadida (OT) 100 of the 192 pigs were tested positive. Thereof, about 10% showed moderate to high-grade parasitic load with trichomonads invading the lamina propria. Partial 18S ribosomal RNA gene sequencing of six of those animals showed a 100% sequence identity with T. foetus sequences. The majority of these animals were also tested positive for other enteropathogenic agents, such as Brachyspira sp., Lawsonia intracellularis, Escherichia coli, and porcine circovirus type 2. All OT positive samples were further examined with another probe complementary to all known Tritrichomonas species sequences including T. foetus, T. augusta, T. mobilensis and T. nonconforma resulting in only 48 positives. These results suggest that T. foetus may not only be considered as an intestinal commensal but rather a facultative pathogen of pigs with a tendency for tissue invasion in the presence of other agents. Furthermore, the existence of other - yet to be identified - trichomonad species in the colon of pigs was shown. PMID- 21236579 TI - Quantifying fenbendazole and its metabolites in self-medicating wild red grouse Lagopus lagopus scoticus using an HPLC-MS-MS approach. AB - On red grouse estates in the UK the nematode parasite Trichostrongylus tenuis is often controlled by application of grit medicated with the anthelmintic fenbendazole (FBZ). To date, assessment of the efficacy has been inhibited by the inability to quantify uptake of FBZ by the birds. We have developed a simple and sensitive HPLC-MS-MS method for detecting and quantifying FBZ and its metabolites from a 300 mg sample of red grouse liver. This method could be used to improve the efficacy of medicated grit treatment by allowing the identification of conditions and application methods that optimize the uptake of FBZ. With the necessary modifications, our method will also be applicable to other wildlife species where self-medication is used for parasite control. PMID- 21236580 TI - Epidemiology of bovine anaplasmosis in dairy herds from Costa Rica. AB - Bovine anaplasmosis is endemic and occurs in almost all areas of livestock production of Costa Rica. The aim of this study was to determine the seroprevalence and risk factors of anaplasmosis in dairy farms of Costa Rica by the recombinant truncated MSP-5 (rMSP-5) enzyme-linked immunosorbent assay (ELISA). Serum samples were obtained from 733 cattle from 20 commercial dairy herds of Costa Rica. The overall seroprevalence was 37.2% and herd seroprevalence ranged from 20.0 to 72.0%. The age-specific seroprevalence was 49.3% in young and 33.4% in adult animals. The main risk factors associated with seroprevalence were season of occurrence of clinical cases (rainy season) (OR=22.8), presence of tabanids (OR=9.5) and stable flies (OR=6.2), stable flies control measures (OR=3.2), non-use of ear tattoos (OR=2.8), interval of veterinary visit (<= 60 days) (OR=2.7), altitude of the farms (<800 masl) (OR=2.6) and age (<2 years) (OR=1.8). The results indicated that exposure of cattle to Anaplasma marginale is common in dairy herds of Costa Rica and endemic instability situation probably is due to inadequate vector control. PMID- 21236581 TI - Sarcocystis sinensis is an ultrastructurally distinct parasite of water buffalo that can cause foodborne illness but cannot complete its life-cycle in human beings. AB - In this study, we compared the morphology of Sarcocystis sinensis and Sarcocystis hominis, and assessed the infectiousness of S. sinensis for human volunteers. The cysts of S. sinensis were from water buffalo (Bubalus bubalis) and those of S. hominis were from cattle (Bos taurus). Transmission electron microscopy of S. sinensis cysts revealed that the cyst wall had leaning, finger-like protrusions measuring 1.44-5.08 MUm in length and without invaginations on the tip surface of the protrusions. In contrast, the cyst wall of S. hominis had upright, finger like protrusions measuring 9.43 MUm*2.42 MUm and with vesicle-like invaginations on the tip surface of the protrusions. Scanning electron microscopy revealed that surface of the protrusions was arranged as rectangles in S. sinensis, as compared to tongue-shaped in S. hominis. Other distinguishing features of S. sinensis include a thin ground substrate (GS) zone with microtubules and small, circle like structures located at the base of the protrusions. Human volunteers, after consuming S. sinensis cysts, produced no sporocysts or oocysts in feces, suggesting that humans could not serve as definitive hosts for S. sinensis. By contrast, many sporocysts and oocysts were passed in feces of a human volunteer 11-29 days after ingestion of S. hominis cysts. These results showed that S. sinensis and S. hominis are separate species and S. sinensis cannot use human being as the definitive host. PMID- 21236582 TI - Smad interacting protein 1 as a regulator of skin fibrosis in pathological scars. AB - Keloids and hypertrophic scars are significant symptomatic clinical problems characterized by the excessive and abnormal deposition of collagen-based extracellular matrix (ECM) components. However, the molecular basis of keloid and hypertrophic scar formation has not been fully elucidated. Here, we demonstrated that down-regulation of the transcription factor Smad interacting protein 1 (SIP1) could be relevant to keloid and hypertrophic scar formation. The results of the present study show that the level of SIP1 mRNA is significantly decreased in pathological scar tissues and in normal skin and pathological scar fibroblasts treated with transforming growth factor beta1 (TGF-beta1). In contrast, the expression of SIP1 mRNA is not decreased in normotrophic scar samples. The SIP1 mRNA level inversely correlates with the mRNA level of type I collagen (COL1A2) and directly correlates with the mRNA level of matrix metalloproteinase-1 (MMP1). Overexpression of SIP1 in keloid and hypertrophic scar fibroblasts represses TGF beta1-stimulated COL1A2 expression and induces MMP1 expression. Alternatively, knockdown of SIP1 in normal skin fibroblasts enhance TGF-beta1-induced COL1A2 levels. These findings suggest that SIP1 could be a regulator of skin fibrosis, and depletion of SIP1 in pathological scar tissues could result in an up regulation of collagen and down-regulation of matrix metalloproteinase, leading to an abnormal accumulation of ECM along with fibrosis and pathological scar formation. PMID- 21236583 TI - Sex differences in methamphetamine toxicity in mice: effect on brain dopamine signaling pathways. AB - Male mice were reported to display greater methamphetamine-induced neurotoxicity than females. The present study evaluated the involvement of phosphatidylinositol 3 kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK1/2) pathways in this sex-dependent methamphetamine toxicity. Intact female and male mice were administered methamphetamine (20 or 40mg/kg) and euthanized a week later. Dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) autoradiography in the lateral striatum showed a greater sensitivity in male mice treated with 20mg/kg methamphetamine compared to female mice. Striatal dopamine concentration and DAT autoradiography showed a more extensive depletion in male mice given 40mg/kg methamphetamine compared to female mice. Mice administered 40mg/kg methamphetamine showed no sex difference in striatal VMAT2 autoradiography. In the substantia nigra, DAT specific binding was decreased only in male mice treated with 40mg/kg methamphetamine and DAT mRNA levels decreased in methamphetamine-treated female and male mice. Methamphetamine-treated male mice presented a dose-dependent decrease of VMAT2 mRNA levels. Methamphetamine reduced insulin-like growth factor 1 receptor levels in females at both methamphetamine doses tested whereas it elevated G protein-coupled estrogen receptor 1 (GPER1) only in male mice. Phosphorylated Akt levels decreased only in male mice treated with 40mg/kg methamphetamine. Glycogen synthase kinase 3beta levels were reduced in male mice at both methamphetamine doses tested and in females receiving 40mg/kg. Bcl-2 levels were increased in male mice treated with methamphetamine, whereas ERK1/2 and BAD levels were unchanged. These results implicate some of the signaling pathways associated with the sex differences in methamphetamine-induced toxicity. PMID- 21236584 TI - Implementation research: Issues and prospects. AB - The concern that addiction treatment be grounded in science has been recognized and enthusiastically endorsed in both the clinical and research communities. With recognition of the gap between knowledge development and application, there has been a recent emphasis on developing strategies for more effective application, i.e., for the incorporation of evidence-based practice in routine clinical programming. This has translated to a need to develop strategies designed to achieve organizational change and a field of study whose objective is to better understand how to expedite change in treatment organizations and their clinical practices. This paper focuses on the roles and responsibilities of researchers, practitioners, and the federal government in achieving changed practice and applying new knowledge to improve treatment. Even though great strides have been made to shift the emphasis from dissemination of knowledge to its application, much still remains to be done in the development and testing of additional application strategies specific to the substance abuse treatment field. Future considerations for implementation research are discussed. PMID- 21236585 TI - Guidelines for allocating outpatient alcohol abusers to levels of care: Predictive validity. AB - The purpose of this study was to assess the predictive validity of guidelines for allocating outpatients with an alcohol-use disorder to different levels of care in routine alcohol outpatient treatment facilities. It was hypothesized that patients matched to the recommended level of care would have (a) better outcomes than patients treated at a less intensive level of care, and (b) outcomes equivalent to patients treated at a more intensive level of care. Patients at two Dutch substance-abuse treatment centers who completed intake and were allocated at either a brief or standard outpatient treatment (n=471) were followed prospectively to determine differential outcomes for those who were and were not treated at the recommended level of car. The former patients were allocated according to an algorithm based on their treatment history, addiction severity, psychiatric impairment and social stability at baseline. 52.9% of the original sample was successfully contacted for follow-up 11 months after intake. Outcome was measured in terms of self-reported alcohol use 30 days prior to follow up and changes in number of excessive and nonexcessive drinking days between intake and follow up. Only 21% of the patients were matched to the level of care according to the guidelines. Patients allocated to the recommended level of care did not have better outcomes than those treated at a less intensive level of care, but they had outcomes comparable to patients treated at a more intensive level of care. The a priori allocation guidelines were followed for only a minority of the patients, and using them did not improve treatment outcome. Further work is needed to improve the content of the treatment allocation guidelines. PMID- 21236586 TI - Injunctive norms for alcohol-related consequences and protective behavioral strategies: effects of gender and year in school. AB - Perceived drinking norms have received increased attention as one determinant of high levels of college alcohol consumption and alcohol-related problems. Excessive drinking is widely visible on college campuses, and students may therefore assume that it is peer-supported (Kitts, 2003). Research into peer relations indicates that the perceived approval of important others predicts drinking behavior (Neighbors, Lee, Lewis, Fossos, & Larimer, 2007). Neither the use of alcohol-related protective behavioral strategies nor alcohol-related negative consequences have been investigated in terms of their perceived approval. The purpose of this study was to extend previous research on injunctive norms and assess self-other discrepancies in levels of approval for campus drinking patterns, negative alcohol-related consequences, and protective behavioral strategies. Undergraduate volunteers (n=324, 61% female, 67% Caucasian) completed an online survey of drinking patterns; they rated comfort with overall campus drinking, and the acceptability of alcohol-related consequences and protective strategies for themselves and their close friends. As predicted, students expressed lower acceptance of consequences than their friends, and higher acceptance of alcohol-related protective strategies. We observed main effects of gender and year in school. Males and upperclassmen expressed higher acceptance of negative consequences for both self and others, and lower acceptance of protective strategies for both self and others. Implications for prevention programs are discussed. PMID- 21236587 TI - The effect of processing techniques and brine formulations on the development of surface sheen in enhanced beef strip loin steaks. AB - The surface sheen phenomenon in enhanced beef steaks, packaged under modified atmosphere, was studied using various combinations of processing techniques and brine formulations. There was no effect (P > 0.05) of time between enhancement and when steaks were cut on surface sheen. Beef temperature less than 0 degrees C prior to enhancement, resulted in less (P <= 0.05) sheen and less retained pump (P <= 0.05) than beef greater than 2 degrees C. Removal of phosphate from the brine resulted in lower (P <= 0.05) sheen, and the addition of lactate decreased (P <= 0.05) sheen but resulted in less (P <= 0.05) retained pump. Sheen was correlated (P <= 0.05) with pump uptake (r = 0.58) and pH (r = -0.29). Results indicate that surface sheen can be significantly affected by ingredients used, but caution must be taken as retained brine and pH can also be affected, causing secondary influences on instrumental and visual traits. PMID- 21236588 TI - Behavioural and physiological reactions of cattle in a commercial abattoir: relationships with organisational aspects of the abattoir and animal characteristics. AB - Behavioural, physiological and metabolic reactions of cattle to handling and slaughter procedures were evaluated in a commercial abattoir, from arrival until slaughter. Different genders or breeds were not subjected to the same procedures due to abattoir equipment or organisational aspects of the abattoir. Reactions to similar slaughter procedures varied according to animal characteristics and could have consequences for subsequent handling procedures. Factors that appeared to cause handling problems and vocalisation were excessive pressure during restraint, and distractions in the corridor such as noise, darkness, seeing people and activity. Post-mortem muscle metabolism depended on slaughter procedures. Following stunning or halal slaughter, some animals showed head rising movements despite the abolition of the corneal reflex, suggesting that head rising is not always indicative of consciousness. Overall, this study presents concrete data on how different types of cattle may react to slaughter procedures with a direct interest for the abattoir itself but also for scientific purposes. PMID- 21236589 TI - The effects of olive oil emulsified alginate on the physico-chemical, sensory, microbial, and fatty acid profiles of low-salt, inulin-enriched sausages. AB - This paper examines variations in the quality of low-salt, inulin enriched Pamplona-style chorizo, in which some of the pork back fat was replaced with olive oil. Four different sausage formulations were prepared in which 50% of the pork back fat was replaced with olive oil emulsified with alginate and 58% of the sodium chloride was replaced with 20% potassium chloride and 38% calcium chloride. Four lots were prepared, three with 3%, 6% and 10% proportions of added inulin were labeled O-I 3%, O-I 6% and O-I 10%, respectively; while one, lot O, was without inulin. These four formulations were compared with a control manufactured according to the traditional formula using pork back fat. The various lots were tested for proximate analysis, pH, processing loss, water activity, lactic acid bacteria, Salmonella and Listeria monocytogenes, physico chemical composition, instrumental colour (CIE L*a*b*), texture profile and fatty acid composition during mixing and at days 3, 10, 17, 24 and 31 of the drying process. A sensory evaluation was also performed by a seven-member trained panel, to obtain a descriptive analysis of the taste, texture and appearance of the product. The addition of olive oil alginate emulsion and inulin, O-I 6%, resulted in a low-salt, reduced-fat product (20% less fat than traditional sausage), richer in monounsaturated fatty acids (10%), while retaining sensory notes similar to those of the traditional chorizo used as a control and achieved a good acceptability rating. PMID- 21236590 TI - Proteomic analysis of semimembranosus and biceps femoris muscles from Bayonne dry cured ham. AB - The aim of the study was to delineate and compare the proteomic maps of two muscles of dry-cured ham: the biceps femoris and the semimembranosus. For this purpose, we used two-dimensional electrophoresis on a subcellular muscle fraction: insoluble protein in low ionic strength buffer. After protein identification by MALDI-TOF mass spectrometry and bioinformatic analyses, we found differences in expression levels in the two muscles. Seventy-three proteins or fragments were differentially expressed: 43 were over-represented in semimembranosus and 30 in biceps femoris. Although the study was performed on the insoluble protein fraction in low strength ionic buffer, protein and fragment identifications by mass spectrometry showed that most of the proteins were involved in energy metabolism. The differences observed between the two muscles can be explained by the differences in salt and moisture content in the course of dry-cured ham processing. PMID- 21236591 TI - Display life of beef packaged with an antioxidant active film as a function of the concentration of oregano extract. AB - Fresh beef steaks were packaged with a new antioxidant active system containing increasing concentrations (0.5, 1, 2 and 4%) of an oregano extract. Control samples were packaged without the active film. Additional samples were sprayed with the extract and packaged as the control samples. Packages were filled with a 80%O(2)/20%CO(2) atmosphere and displayed under illumination (14 h) at 1 +/- 1 degrees C for 28 days. Metmyoglobin formation, lipid oxidation (TBARS), instrumental colour (CIE a*) and sensory colour, discoloration, off-odour and oregano smell were determined. Active packaging significantly (P < 0.05) enhanced oxidative stability of beef steaks, depending on the oregano concentration of the active film. The display life of beef samples demonstrated that at least 1% oregano was needed for obtaining a significant increase of display life from 14 to 23 days. A concentration of 4% gave rise to unacceptable oregano smell. As a consequence, most suitable oregano extract concentrations for optimum active packaging in this system should be within the range 1-2%. PMID- 21236592 TI - Dedicated linear accelerator radiosurgery for trigeminal neuralgia: a single center experience in 179 patients with varied dose prescriptions and treatment plans. AB - PURPOSE: Dedicated linear accelerator radiosurgery (D-LINAC) has become an important treatment for trigeminal neuralgia (TN). Although the use of gamma knife continues to be established, few large series exist using D-LINAC. The authors describe their results, comparing the effects of varied target and dose regimens. METHODS AND MATERIALS: Between August 1995 and January 2008, 179 patients were treated with D-LINAC radiosurgery. Ten patients (5.58%) had no clinical follow-up. The median age was 74.0 years (range, 32-90 years). A total of 39 patients had secondary or atypical pain, and 130 had idiopathic TN. Initially, 28 patients received doses between 70 and 85 Gy, with the 30% isodose line (IDL) touching the brainstem. Then, using 90 Gy, 82 consecutive patients were treated with a 30% IDL and 59 patients with a 50% IDL tangential to the pons. RESULTS: Of 169 patients, 134 (79.3%) experienced significant relief at a mean of 28.8 months (range, 5-142 months). Average time to relief was 1.92 months (range, immediate to 6 months). A total of 31 patients (19.0%) had recurrent pain at 13.5 months. Of 87 patients with idiopathic TN without prior procedures, 79 (90.8%) had initial relief. Among 28 patients treated with 70 Gy and 30% IDL, 18 patients (64.3%) had significant relief, and 10 (35.7%) had numbness. Of the patients with 90 Gy and 30% IDL at the brainstem, 59 (79.0%) had significant relief and 48.9% had numbness. Among 59 consecutive patients with similar dose but the 50% isodoseline at the brainstem, 49 patients (88.0%) had excellent/good relief. Numbness, averaging 2.49 on a subjective scale of 1 to 5, was experienced by 49.7% of the patients, CONCLUSIONS: Increased radiation dose and volume of brainstem irradiation may improve clinical outcomes with the trade-off of trigeminal dysfunction. Further study of the implications of dose and target are needed to optimize outcomes and to minimize complications. PMID- 21236593 TI - Rectal cancer: mucinous carcinoma on magnetic resonance imaging indicates poor response to neoadjuvant chemoradiation. AB - PURPOSE: To assess response of locally advanced rectal carcinoma to chemoradiation with regard to mucinous status and local tumor invasion found at pretherapeutic magnetic resonance imaging (MRI). METHODS AND MATERIALS: A total of 88 patients were included in this prospective study of patients with advanced mrT3 and mrT4 carcinomas. Carcinomas were categorized by MRI as mucinous (mucin proportion >50% within the tumor volume), and as nonmucinous. Patients received neoadjuvant chemoradiation consisting of 50.4 Gy (1.8 Gy/fraction) and 5 fluorouracil on Days 1 to 5 and Days 29 to 33. Therapy response was assessed by comparing pretherapeutic MRI with histopathology of surgical specimens (minimum distance between outer tumor edge and circumferential resection margin = CRM, T, and N category). RESULTS: A mucinous carcinoma was found in 21 of 88 patients. Pretherapeutic mrCRM was 0 mm (median) in the mucinous and nonmucinous group. Of the 88 patients, 83 underwent surgery with tumor resection. The ypCRM (mm) at histopathology was significantly lower in mucinous carcinomas than in nonmucinous carcinomas (p <= 0.001). Positive resection margins (ypCRM <= 1 mm) were found more frequently in mucinous carcinomas than in nonmucinous ones (p <= 0.001). Treatment had less effect on local tumor stage in mucinous carcinomas than in nonmucinous carcinomas (for T downsizing, p = 0.012; for N downstaging, p = 0.007). Disease progression was observed only in patients with mucinous carcinomas (n = 5). CONCLUSION: Mucinous status at pretherapeutic MRI was associated with a noticeably worse response to chemoradiation and should be assessed by MRI in addition to local tumor staging to estimate response to treatment before it is initiated. PMID- 21236594 TI - Tumor metabolism and perfusion in head and neck squamous cell carcinoma: pretreatment multimodality imaging with 1H magnetic resonance spectroscopy, dynamic contrast-enhanced MRI, and [18F]FDG-PET. AB - PURPOSE: To correlate proton magnetic resonance spectroscopy ((1)H-MRS), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and (18)F-labeled fluorodeoxyglucose positron emission tomography ([(18)F]FDG PET) of nodal metastases in patients with head and neck squamous cell carcinoma (HNSCC) for assessment of tumor biology. Additionally, pretreatment multimodality imaging was evaluated for its efficacy in predicting short-term response to treatment. METHODS AND MATERIALS: Metastatic neck nodes were imaged with (1)H-MRS, DCE-MRI, and [(18)F]FDG PET in 16 patients with newly diagnosed HNSCC, before treatment. Short-term patient radiological response was evaluated at 3 to 4 months. Correlations among (1)H-MRS (choline concentration relative to water [Cho/W]), DCE-MRI (volume transfer constant [K(trans)]; volume fraction of the extravascular extracellular space [v(e)]; and redistribution rate constant [k(ep)]), and [(18)F]FDG PET (standard uptake value [SUV] and total lesion glycolysis [TLG]) were calculated using nonparametric Spearman rank correlation. To predict short-term responses, logistic regression analysis was performed. RESULTS: A significant positive correlation was found between Cho/W and TLG (rho = 0.599; p = 0.031). Cho/W correlated negatively with heterogeneity measures of standard deviation std(v(e)) (rho = -0.691; p = 0.004) and std(k(ep)) (rho = 0.704; p = 0.003). Maximum SUV (SUVmax) values correlated strongly with MRI tumor volume (rho = 0.643; p = 0.007). Logistic regression indicated that std(K(trans)) and SUVmean were significant predictors of short-term response (p < 0.07). CONCLUSION: Pretreatment multimodality imaging using (1)H-MRS, DCE-MRI, and [(18)F]FDG PET is feasible in HNSCC patients with nodal metastases. Additionally, combined DCE-MRI and [(18)F]FDG PET parameters were predictive of short-term response to treatment. PMID- 21236595 TI - Predicted rates of secondary malignancies from proton versus photon radiation therapy for stage I seminoma. AB - PURPOSE: Photon radiotherapy has been the standard adjuvant treatment for stage I seminoma. Single-dose carboplatin therapy and observation have emerged as alternative options due to concerns for acute toxicities and secondary malignancies from radiation. In this institutional review board-approved study, we compared photon and proton radiotherapy for stage I seminoma and the predicted rates of excess secondary malignancies for both treatment modalities. METHODS AND MATERIAL: Computed tomography images from 10 consecutive patients with stage I seminoma were used to quantify dosimetric differences between photon and proton therapies. Structures reported to be at increased risk for secondary malignancies and in-field critical structures were contoured. Reported models of organ specific radiation-induced cancer incidence rates based on organ equivalent dose were used to determine the excess absolute risk of secondary malignancies. Calculated values were compared with tumor registry reports of excess secondary malignancies among testicular cancer survivors. RESULTS: Photon and proton plans provided comparable target volume coverage. Proton plans delivered significantly lower mean doses to all examined normal tissues, except for the kidneys. The greatest absolute reduction in mean dose was observed for the stomach (119 cGy for proton plans vs. 768 cGy for photon plans; p < 0.0001). Significantly more excess secondary cancers per 10,000 patients/year were predicted for photon radiation than for proton radiation to the stomach (4.11; 95% confidence interval [CI], 3.22-5.01), large bowel (0.81; 95% CI, 0.39-1.01), and bladder (0.03; 95% CI, 0.01-0.58), while no difference was demonstrated for radiation to the pancreas (0.02; 95% CI, -0.01-0.06). CONCLUSIONS: For patients with stage I seminoma, proton radiation therapy reduced the predicted secondary cancer risk compared with photon therapy. We predict a reduction of one additional secondary cancer for every 50 patients with a life expectancy of 40 years from the time of radiation treatment with protons instead of photons. Proton radiation therapy also allowed significant sparing of most critical structures examined and warrants further study for patients with seminoma, to decrease radiation-induced toxicity. PMID- 21236596 TI - Multi-system verification of registrations for image-guided radiotherapy in clinical trials. AB - PURPOSE: To provide quantitative information on the image registration differences from multiple systems for image-guided radiotherapy (IGRT) credentialing and margin reduction in clinical trials. METHODS AND MATERIALS: Images and IGRT shift results from three different treatment systems (Tomotherapy Hi-Art, Elekta Synergy, Varian Trilogy) have been sent from various institutions to the Image-Guided Therapy QA Center (ITC) for evaluation for the Radiation Therapy Oncology Group (RTOG) trials. Nine patient datasets (five head-and-neck and four prostate) were included in the comparison, with each patient having 1-4 daily individual IGRT studies. In all cases, daily shifts were re-calculated by re-registration of the planning CT with the daily IGRT data using three independent software systems (MIMvista, FocalSim, VelocityAI). Automatic fusion was used in all calculations. The results were compared with those submitted from institutions. Similar regions of interest (ROIs) and same initial positions were used in registrations for inter-system comparison. Different slice spacings for CBCT sampling and different ROIs for registration were used in some cases to observe the variation of registration due to these factors. RESULTS: For the 54 comparisons with head-and-neck datasets, the absolute values of differences of the registration results between different systems were 2.6+/-2.1 mm (mean+/-SD; range 0.1-8.6 mm, left-right [LR]), 1.7+/-1.3 mm (0.0-4.9 mm, superior-inferior [SI]), and 1.8+/-1.1 mm (0.1-4.0 mm, anterior-posterior [AP]). For the 66 comparisons in prostate cases, the differences were 1.1+/-1.0 mm (0.0-4.6 mm, LR), 2.1+/-1.7 mm (0.0-6.6 mm, SI), and 2.0+/-1.8 mm (0.1-6.9 mm, AP). The differences caused by the slice spacing variation were relatively small, and the different ROI selections in FocalSim and MIMvista also had limited impact. CONCLUSION: The extent of differences was reported when different systems were used for image registration. Careful examination and quality assurance of the image registration process are crucial before considering margin reduction using IGRT in clinical trials. PMID- 21236597 TI - Analysis of dose at the site of second tumor formation after radiotherapy to the central nervous system. AB - PURPOSE: Second tumors are an uncommon complication of multimodality treatment of childhood cancer. The present analysis attempted to correlate the dose received as a component of primary treatment and the site of the eventual development of a second tumor. METHODS AND MATERIALS: We retrospectively identified 16 patients who had received radiotherapy to sites in the craniospinal axis and subsequently developed a second tumor. We compared the historical fields and port films of the primary treatment with the modern imaging of the second tumor locations. We classified the location of the second tumors as follows: in the boost field; marginal to the boost field, but in a whole-brain field; in a whole-brain field; marginal to the whole brain/primary treatment field; and distant to the field. We divided the dose received into 3 broad categories: high dose (>45 Gy), moderate dose (20-36 Gy), and low dose (<20 Gy). RESULTS: The most common location of the second tumor was in the whole brain field (57%) and in the moderate-dose range (81%). CONCLUSIONS: Our data contradict previous publications that suggested that most second tumors develop in tissues that receive a low radiation dose. Almost all the second tumors in our series occurred in tissue within a target volume in the cranium that had received a moderate dose (20-36 Gy). These findings suggest that a major decrease in the brain volume that receives a moderate radiation dose is the only way to substantially decrease the second tumor rate after central nervous system radiotherapy. PMID- 21236598 TI - Helical tomotherapy versus single-arc intensity-modulated arc therapy: a collaborative dosimetric comparison between two institutions. AB - PURPOSE: Both helical tomotherapy (HT) and single-arc intensity-modulated arc therapy (IMAT) deliver radiation using rotational beams with multileaf collimators. We report a dual-institution study comparing dosimetric aspects of these two modalities. METHODS AND MATERIALS: Eight patients each were selected from the University of Maryland (UMM) and the University of Wisconsin Cancer Center Riverview (UWR), for a total of 16 cases. Four cancer sites including brain, head and neck (HN), lung, and prostate were selected. Single-arc IMAT plans were generated at UMM using Varian RapidArc (RA), and HT plans were generated at UWR using Hi-Art II TomoTherapy. All 16 cases were planned based on the identical anatomic contours, prescriptions, and planning objectives. All plans were swapped for analysis at the same time after final approval. Dose indices for targets and critical organs were compared based on dose-volume histograms, the beam-on time, monitor units, and estimated leakage dose. After the disclosure of comparison results, replanning was done for both techniques to minimize diversity in optimization focus from different operators. RESULTS: For the 16 cases compared, the average beam-on time was 1.4 minutes for RA and 4.8 minutes for HT plans. HT provided better target dose homogeneity (7.6% for RA and 4.2% for HT) with a lower maximum dose (110% for RA and 105% for HT). Dose conformation numbers were comparable, with RA being superior to HT (0.67 vs. 0.60). The doses to normal tissues using these two techniques were comparable, with HT showing lower doses for more critical structures. After planning comparison results were exchanged, both techniques demonstrated improvements in dose distributions or treatment delivery times. CONCLUSIONS: Both techniques created highly conformal plans that met or exceeded the planning goals. The delivery time and total monitor units were lower in RA than in HT plans, whereas HT provided higher target dose uniformity. PMID- 21236599 TI - Curcumin regulates low-linear energy transfer gamma-radiation-induced NFkappaB dependent telomerase activity in human neuroblastoma cells. AB - PURPOSE: We recently reported that curcumin attenuates ionizing radiation (IR) induced survival signaling and proliferation in human neuroblastoma cells. Also, in the endothelial system, we have demonstrated that NFkappaB regulates IR induced telomerase activity (TA). Accordingly, we investigated the effect of curcumin in inhibiting IR-induced NFkappaB-dependent hTERT transcription, TA, and cell survival in neuroblastoma cells. METHODS AND MATERIALS: SK-N-MC or SH-SY5Y cells exposed to IR and treated with curcumin (10-100 nM) with or without IR were harvested after 1 h through 24 h. NFkappaB-dependent regulation was investigated either by luciferase reporter assays using pNFkappaB-, pGL3-354-, pGL3-347-, or pUSE-IkappaBalpha-Luc, p50/p65, or RelA siRNA-transfected cells. NFkappaB activity was analyzed using an electrophoretic mobility shift assay and hTERT expression using the quantitative polymerase chain reaction. TA was determined using the telomerase repeat amplification protocol assay and cell survival using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltertrazolium bromide and clonogenic assay. RESULTS: Curcumin profoundly inhibited IR-induced NFkappaB. Consequently, curcumin significantly inhibited IR-induced TA and hTERT mRNA at all points investigated. Furthermore, IR-induced TA is regulated at the transcriptional level by triggering telomerase reverse transcriptase (TERT) promoter activation. Moreover, NFkappaB becomes functionally activated after IR and mediates TA upregulation by binding to the kappaB-binding region in the promoter region of the TERT gene. Consistently, elimination of the NFkappaB-recognition site on the telomerase promoter or inhibition of NFkappaB by the IkappaBalpha mutant compromises IR-induced telomerase promoter activation. Significantly, curcumin inhibited IR-induced TERT transcription. Consequently, curcumin inhibited hTERT mRNA and TA in NFkappaB overexpressed cells. Furthermore, curcumin enhanced the IR-induced inhibition of cell survival. CONCLUSIONS: These results strongly suggest that curcumin inhibits IR-induced TA in an NFkappaB dependent manner in human neuroblastoma cells. PMID- 21236600 TI - Semicontinuous low-dose-rate teletherapy for the treatment of recurrent glial brain tumors: final report of a phase I/II study. AB - PURPOSE: Semicontinuous low-dose-rate teletherapy (SLDR) is a novel irradiation strategy that exploits the increased radiosensitivity of glial cells in a narrow range of reduced dose rate. We present the final report of a prospective Phase I/II study testing the feasibility of SLDR for the treatment of recurrent gliomas. METHODS AND MATERIALS: Patients with previously irradiated recurrent gliomas were enrolled from November 1993 to March 1998. Patients received SLDR, delivered 6 to 8 hours/day at a dose rate of 40 to 50 cGy/hour for a total dose of 30 to 35 Gy given over 12 days using a modified cobalt-60 treatment unit. Acute central nervous system toxicity after SLDR treatment was the primary endpoint. Overall survival was a secondary endpoint. RESULTS: Twenty patients were enrolled (14 World Health Organization Grade 4 glioma, 5 Grade 2 glioma, 1 ependymoma). No patients developed >= Grade 3 central nervous system toxicity at 3 months without radiographic evidence of tumor progression. Overall survival after SLDR was 56% at 6 months, 28% at 12 months, and 17% at 24 months. One patient survived >48 months, and 1 patient survived >60 months after SLDR treatment. Re-resection before SLDR treatment significantly improved 1-year overall survival for all patients and patients with Grade 4 glioma. CONCLUSION: The delivery of SLDR is feasible in patients with recurrent gliomas and resulted in improved outcomes for patients who underwent re-resection. There were 2 long term survivors (>48 months). This pilot study supports the notion that reduced dose rate influences the efficacy and tolerance of reirradiation in the treatment of recurrent gliomas. PMID- 21236601 TI - Imaging tumor perfusion and oxidative metabolism in patients with head-and-neck cancer using 1- [11C]-acetate PET during radiotherapy: preliminary results. AB - BACKGROUND: A growing body of in vitro evidence links alterations of the intermediary metabolism in cancer to treatment outcome. This study aimed to characterize tumor oxidative metabolism and perfusion in vivo using dynamic positron emission tomography (PET) with 1- [(11)C]-acetate (ACE) during radiotherapy. METHODS AND MATERIALS: Nine patients with head-and-neck cancer were studied. Oxidative metabolic rate (k(mono)) and perfusion (rF) of the primary tumors were assessed by dynamic ACE-PET at baseline and after 15, 30, and 55 Gy was delivered. Tumor glucose uptake (Tglu) was evaluated with [(18)F] fluorodeoxyglucose PET at baseline. Patients were grouped into complete (CR, n = 6) and partial responders (PR, n = 3) to radiotherapy. RESULTS: The 3 PR patients died within a median follow-up period of 33 months. Baseline k(mono) was almost twice as high in CR as in PR (p = 0.02) and Tglu was lower in CR than in PR (p = 0.04). k(mono) increased during radiotherapy in PR (p = 0.004) but remained unchanged in CR. There were no differences in rF between CR and PR at any dosage. k(mono) and rF were coupled in CR (p = 0.001), but not in PR. CONCLUSIONS: This study shows that radiosensitive tumors might rely predominantly on oxidative metabolism for their bioenergetic needs. The impairment of oxidative metabolism in radioresistant tumors is potentially reversible, suggesting that therapies targeting the intermediary metabolism might improve treatment outcome. PMID- 21236602 TI - Dose-escalated intensity-modulated radiotherapy is feasible and may improve locoregional control and laryngeal preservation in laryngo-hypopharyngeal cancers. AB - PURPOSE: To determine the safety and outcomes of induction chemotherapy followed by dose-escalated intensity-modulated radiotherapy (IMRT) with concomitant chemotherapy in locally advanced squamous cell cancer of the larynx and hypopharynx (LA-SCCL/H). METHODS AND MATERIALS: A sequential cohort Phase I/II trial design was used to evaluate moderate acceleration and dose escalation. Patients with LA-SCCL/H received IMRT at two dose levels (DL): DL1, 63 Gy/28 fractions (Fx) to planning target volume 1 (PTV1) and 51.8 Gy/28 Fx to PTV2; DL2, 67.2 Gy/28 Fx and 56 Gy/28 Fx to PTV1 and PTV2, respectively. Patients received induction cisplatin/5-fluorouracil and concomitant cisplatin. Acute and late toxicities and tumor control rates were recorded. RESULTS: Between September 2002 and January 2008, 60 patients (29 DL1, 31 DL2) with Stage III (41% DL1, 52% DL2) and Stage IV (52% DL1, 48% DL2) disease were recruited. Median (range) follow-up for DL1 was 51.2 (12.1-77.3) months and for DL2 was 36.2 (4.2-63.3) months. Acute Grade 3 (G3) dysphagia was higher in DL2 (87% DL2 vs. 59% DL1), but other toxicities were equivalent. One patient in DL1 required dilatation of a pharyngeal stricture (G3 dysphagia). In DL2, 2 patients developed benign pharyngeal strictures at 1 year. One underwent a laryngo-pharyngectomy and the other a dilatation. No other G3/G4 toxicities were reported. Overall complete response was 79% (DL1) and 84% (DL2). Two-year locoregional progression-free survival rates were 64.2% (95% confidence interval, 43.5-78.9%) in DL1 and 78.4% (58.1-89.7%) in DL2. Two-year laryngeal preservation rates were 88.7% (68.5 96.3%) in DL1 and 96.4% (77.7-99.5%) in DL2. CONCLUSIONS: At a mean follow-up of 36 months, dose-escalated chemotherapy-IMRT at DL2 has so far been safe to deliver. In this study, DL2 delivered high rates of locoregional control, progression-free survival, and organ preservation and has been selected as the experimental arm in a Cancer Research UK Phase III study. PMID- 21236603 TI - Investigation of the geometric accuracy of proton beam irradiation in the liver. AB - PURPOSE: To investigate the geometric accuracy of proton beam irradiation to the liver by measuring the change in Hounsfield units (HUs) after irradiation. METHODS AND MATERIALS: We examined 21 patients with liver tumors who were treated with respiratory-gated proton beam therapy (PBT). The radiation dose was 66 GyE in 12 patients and 72.6 GyE in 9 patients. Image registration and reslicing of the computed tomography (CT) results obtained within 1 month before and 3 months after PBT was performed, referring to the planning CT image. The resliced CT images obtained after PBT were subtracted from the images obtained before PBT. We investigated whether the area of the large HU change was consistent with the high dose distribution area using the location of the largest change in HU around the tumor (peak) on the subtracted CT image and the 90% dose distribution area of the planning CT image. RESULTS: The number of patients (n = 20) whose left-right peaks were within the 90% dose distribution area was significantly larger than the number of patients whose anterior-posterior peaks and superior-inferior peaks were within the 90% dose distribution area (n = 14, n = 13, p = 0.034, and p = 0.02, respectively). Twelve patients exhibited a peak within the 90% dose distribution area in all directions. Nine of the 11 patients with smaller 90% confidence intervals of the percent normalization of the beam cycle (BC; 90% BC) showed a peak within the 90% dose distribution area in six directions, and this percentage was higher than that among the patients with larger 90% BC (3/10, p = 0.03). CONCLUSION: The geometric accuracy of proton beam irradiation to the liver was higher in the left-right direction than in the other directions. Patients with an irregular respiratory rhythm have a greater risk of a reduced geometric accuracy of PBT in the liver. PMID- 21236604 TI - A phase I dose escalation study of hypofractionated IMRT field-in-field boost for newly diagnosed glioblastoma multiforme. AB - OBJECTIVES: To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. METHODS: Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4-5 acute neurotoxicity attributable to radiotherapy. RESULTS: All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. CONCLUSIONS: Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted. PMID- 21236605 TI - L-boronophenylalanine-mediated boron neutron capture therapy for malignant glioma progressing after external beam radiation therapy: a Phase I study. AB - PURPOSE: To investigate the safety of boronophenylalanine-mediated boron neutron capture therapy (BNCT) in the treatment of malignant gliomas that progress after surgery and conventional external beam radiation therapy. METHODS AND MATERIALS: Adult patients who had histologically confirmed malignant glioma that had progressed after surgery and external beam radiotherapy were eligible for this Phase I study, provided that >6 months had elapsed from the last date of radiation therapy. The first 10 patients received a fixed dose, 290 mg/kg, of L boronophenylalanine-fructose (L-BPA-F) as a 2-hour infusion before neutron irradiation, and the remaining patients were treated with escalating doses of L BPA-F, either 350 mg/kg, 400 mg/kg, or 450 mg/kg, using 3 patients on each dose level. Adverse effects were assessed using National Cancer Institute Common Toxicity Criteria version 2.0. RESULTS: Twenty-two patients entered the study. Twenty subjects had glioblastoma, and 2 patients had anaplastic astrocytoma, and the median cumulative dose of prior external beam radiotherapy was 59.4 Gy. The maximally tolerated L-BPA-F dose was reached at the 450 mg/kg level, where 4 of 6 patients treated had a grade 3 adverse event. Patients who were given >290 mg/kg of L-BPA-F received a higher estimated average planning target volume dose than those who received 290 mg/kg (median, 36 vs. 31 Gy [W, i.e., a weighted dose]; p = 0.018). The median survival time following BNCT was 7 months. CONCLUSIONS: BNCT administered with an l-BPA-F dose of up to 400 mg/kg as a 2-hour infusion is feasible in the treatment of malignant gliomas that recur after conventional radiation therapy. PMID- 21236606 TI - Staphylococcus aureus subsp. anaerobius isolates from different countries are clonal in nature. AB - Staphylococcus aureus subsp. anaerobius, a microaerophilic, catalase-negative bacteria, is the etiological agent of abscess disease, a specific chronic condition of sheep and goats, characterized by the formation of necrotic lesions that are typically located in superficial lymph nodes. In this study, molecular analysis including pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and accessory gene regulator (agr) typing was carried out on 94 S. aureus subsp. anaerobius strains isolated in different countries (79 were isolated from 35 outbreaks of the disease in Spain from 1981 to 2009, 9 were isolated in Italy, 3 in Denmark and 3 in Sudan). All of the 94 S. aureus subsp. anaerobius isolates examined belonged to one PFGE type, within which four minority subtypes were identified. Representative isolates of all PFGE subtypes as well of all countries belonged to the same sequence type (ST), ST1464, which was a singleton, and to the agr type II. Our results support the view that abscess disease is caused by a single bacterial clone worldwide. This bacterium has existed for at least a century and, thus, has undergone long-term small ruminant host restriction. PMID- 21236607 TI - Protective efficacy of H5 inactivated vaccines in meat turkey poults after challenge with Egyptian variant highly pathogenic avian influenza H5N1 virus. AB - In contrast to chickens, there is a paucity of information on the potency of H5 vaccines to protect turkeys against the highly pathogenic avian influenza (HPAI) H5N1 virus infections. In this study, 4 groups, 10 turkey poults each, were vaccinated at seven days old with one of H5N2 or H5N1 commercial vaccines or one of two prepared H5N1 vaccines from a local Egyptian variant HPAI H5N1 (EGYvar/H5N1) strain. At 35 days age, all vaccinated and 10 non vaccinated birds were challenged intranasal with 10(6) EID(50)/0.1 ml of EGYvar/H5N1. All vaccines used in this study were immunogenic in turkeys. There was no cross reaction between the commercial vaccines and the Egyptian variant H5N1 antigen as obtained by the hemagglutination inhibition test. Birds vaccinated with H5N2 vaccine were died, while other H5N1 vaccinated groups have had 20-40% mortality. The highest virus excretion was found in non-vaccinated infected and H5N2 vaccinated birds. Eleven peculiar amino acid substitutions in H5 protein of the variant strain were existed neither in the vaccine strains nor in the earliest H5N1 virus introduced into Egypt in 2006. In conclusion, single vaccination at seven days old is inadequate for protection of meat turkeys against variant HPAI H5N1 challenge and multi-dose vaccination at older age is recommended. For the foreseeable future, continuous evaluation of the current vaccines in H5N1 endemic countries in the face of virus evolution is a paramount challenge to mitigate the socio-economic impact of the virus. PMID- 21236608 TI - Three cases of oropharyngeal tularemia in Turkey. AB - OBJECTIVE: We aimed to attract our colleagues' attention to the oropharyngeal tularemia, which has been an infrequently diagnosed disease in otolaryngology clinics also becoming widespread in Turkey. METHODS: A retrospective review of database of 3 patients was performed to find patients with Tularemia. The medical files, treatment charts, serological and PCR findings and radiological (magnetic resonance imaging), histopathological records of these patients were reviewed. RESULTS: The study group consisted of 3 oropharyngeal tularemia patients. All of them presented with tonsillopharyngitis and cervical lymphadenitis and all were resistant to beta lactam or cephalosporin group antibiotics. Two patients had magnetic resonance imaging findings. All patients had positive serological tests. Strongly positive serological tests led to the diagnosis of tularemia. All patients had positive PCR and direct fluorescent antibody (DFA) test. All patients responded to systemic streptomycin treatment. CONCLUSION: In the daily practice of an otolaryngologist, it is not usual to diagnose a patient with oropharyngeal tularemia. Tularemia should be considered in the differential diagnosis of massive adenotonsillar enlargement and extensive necrotic cervical lymphadenopathy not responding to beta lactam antibiotics as a result of the rising number of tularemia outbreaks outside the classic endemic areas. PMID- 21236609 TI - Pneumolabyrinth and positional vertigo after stapedectomy. AB - Pneumolabyrinth due to late complications of stapes surgery is a rare entity. Symptoms may include various degrees of hearing loss, tinnitus and dizziness. We report the case of a 67-year-old patient who developed a unique pneumolabyrinth variant affecting the vestibule, cochlea and semicircular canals 28 years after stapedectomy. The patient presented with intractable paroxysmal positional vertigo of the lateral semicircular canal. The pneumolabyrinth was visualized by means of high resolution computed tomography. Exploratory tympanotomy findings were consistent with a perilymphatic fistula. One year after surgical treatment the subject was free of vertigo spells. Pathogenetic mechanisms are discussed. PMID- 21236610 TI - Hearing loss after noise exposure. AB - The higher field strength magnetic resonance imaging (MRI) such as 3 Tesla (T) and above generates noise that has potential detrimental effects on the hearing. Temporary threshold shifts following MRI examination have been reported for MRI with lower field strength. Such effect, however, have not been reported so far for a 3T MRI. We report a case that exemplifies the possible detrimental effects of a 3 T MRI generated noise on the auditory system. Our patient underwent investigation of his chronic backache in a 3 T MRI unit and developed hearing loss and tinnitus post-MRI examination. Hearing assessment was done using pure tone audiogram, distortion product otoacoustic emission (DPOAE) and brainstem electrical response audiometry (BERA) which revealed a unilateral sensorineural hearing loss which recovered within 3 days. However the tinnitus persisted. This is possibly a case of temporary threshold shift following noise exposure. However a sudden sensorineural hearing loss remains the other possibility. PMID- 21236611 TI - Trevor's disease (dysplasia epiphysealis hemimelica) located at the hand: case report and review of the literature. AB - Trevor's disease, also known as dysplasia epiphysealis hemimelica (DEH), is a rare developmental bone dysplasia, characterized by benign osteocartilaginous overgrowth. The lesion arises from an epiphysis. Its localization may be different, and it mostly occurs unilateral. In this report, we present a 40 years old woman suffering from Trevor's disease with unusual localization at the hand. Because of significant symptoms surgical excision was chosen. PMID- 21236612 TI - Malignant spiculated breast masses: dynamic contrast enhanced MR (DCE-MR) imaging enhancement characteristics and histopathological correlation. AB - AIM: Spiculation of breast masses is usually the result of significant desmoplastic reaction. Diminished neovascularization is expected due to sparsely dispersed tumor cells within the lesion. This feature can cause differences in enhancement patterns which can cause pitfalls while evaluating MR images as well. Aim of this study is to explore the enhancement characteristics of malignant spiculated masses and to correlate these findings with histopathological features. MATERIALS AND METHODS: Eighteen spiculated and seventeen non-spiculated masses depicted with mammography were included in the study. MR imaging was performed with 1.5 T magnet with breast coil. In MR imaging, T2-weighted turbo spin echo (TSE) with fat suppression sequence followed by pre- and post-contrast T1-weighted 3D-fast low angle shot (FLASH) sequences were used. Lesions were evaluated according to enhancement characteristics: early phase enhancement (first 2 min; less than 50%, 50-100% and more than 100%), late phase enhancement (2-6 min; persistent, plateau and washout) and inner enhancement pattern (homogenous, heterogenous and rim). Desmoplasia and lymphocyte infiltration was classified as mild, moderate and severe. MR images and histopathological findings (desmoplasia, lymphocyte infiltration and grade) of both groups were compared. RESULTS: Mean ages of patients in spiculated and non-spiculated-mass groups were 55.07 (41-71) and 47.35 (31-62), respectively. Mean diameter of lesions was 17.3mm (10-31 mm) for spiculated masses while non spiculated masses were 15.8mm (6-40 mm). There were statistically significant differences between late phase enhancement, persistent enhancement, plateau and washout (p<0.05). Intergroup comparison of desmoplasia revealed significant difference between severe versus and mild, moderate (p<0.05). CONCLUSION: Spiculated malignant lesions are supposed to contain intense desmoplastic reaction. On DCE-MR images they can show persistent enhancement pattern more often than non-spiculated lesions. PMID- 21236613 TI - A case report of cerebral air embolism after esophagogastroduodenoscopy: diagnosis and management in the emergency department. AB - BACKGROUND: Esophagogastroduodenoscopy (EGD) is a rare cause of cerebral air embolism (CAE). To our knowledge, there are only eight previously reported such cases in the history of the procedure. OBJECTIVE: To identify clinical causes of CAE that can present to the emergency department (ED) and to understand the appropriate management of CAE. CASE REPORT: A 71-year-old man presented with new onset left-sided hemiparesis and dysarthria 2h after undergoing an outpatient EGD. The patient was diagnosed with CAE in the ED after undergoing a computed tomography scan of the brain without contrast. CONCLUSION: The diagnosis of CAE is based on a thorough history and obtaining urgent radiographic imaging of the brain. The definitive treatment of CAE involves hyperbaric oxygen. PMID- 21236615 TI - Temporary axillobifemoral bypass as an adjunct to endovascular aneurysm repair using fenestrated stent grafts. AB - Prolonged endovascular procedures requiring a large diameter sheath in each groin can be associated with significant intraoperative lower limb ischemia, particularly in those with pre-existing peripheral vascular disease. We report the case of a patient who suffered severe ischemia-reperfusion injury following endovascular repair of a pararenal aortic aneurysm using a fenestrated stent graft and describe the use of temporary axillobifemoral bypass in a patient with similar comorbidities undergoing the same procedure. We propose this adjunctive technique as a means of maintaining antegrade limb perfusion and avoiding the peripheral and central metabolic consequences of ischemia-reperfusion injury. PMID- 21236616 TI - A comparison of endovascular revascularization with traditional therapy for the treatment of acute mesenteric ischemia. AB - OBJECTIVES: Few centers have adopted endovascular therapy for the treatment of acute mesenteric ischemia (AMI). We sought to evaluate the effect of endovascular therapy on outcomes for the treatment of AMI. METHODS: A single-center, retrospective cohort review was performed on all consecutive patients with thrombotic or embolic AMI presenting between 1999 and 2008. Patients with mesenteric venous thrombosis, nonocclusive mesenteric ischemia, and ischemia associated with aortic dissection were excluded. Demographic factors, preoperative metabolic status, and etiology were compared. Primary clinical outcomes included endovascular technical success, operative complications, and in hospital mortality. RESULTS: Seventy consecutive patients were identified with AMI (mean age, 64 +/- 13 years). Etiology of mesenteric ischemia was 65% thrombotic and 35% embolic occlusions. Endovascular revascularization was the preferred treatment (81%) vs operative therapy (19%). Successful endovascular treatment was achieved in 87%. Endovascular therapy required laparotomy in 69% vs traditional therapy in 100% (P < .05), with a median 52-cm necrotic bowel resected (interquartile range [IQR], 11-140 cm) vs 160 cm (IQR, 90-250 cm; P < .05), respectively. Acute renal failure and pulmonary failure occurred less frequently with endovascular therapy (27% vs 50%; P < .05 and 27% vs 64%; P < .05). Successful endovascular treatment resulted in a mortality rate of 36% compared with 50% (P < .05) with traditional therapy, whereas the mortality rate for endovascular failures was 50%. Endovascular therapy was associated with improved mortality in thrombotic AMI (odds ratio, 0.10; 95% confidence interval, 0.10-0.76; P < .05). CONCLUSIONS: Endovascular therapy has altered the management of AMI, and there are measurable advantages to this approach. Using endovascular therapy as the primary modality for AMI reduces complications and improves outcomes. PMID- 21236618 TI - The effects of operative indication and urgency of intervention on patient outcomes after thoracic aortic endografting. AB - BACKGROUND: Endovascular repair for complex thoracic aortic pathology has emerged over the past decade as an alternative to open surgical repair. Reports suggest lower morbidity and mortality rates associated with endovascular interventions. The purpose of this report was to analyze a large single institution experience in endovascular thoracic aortic repair based on clinical presentation as well as within and outside specific instructions for use. METHODS: Records of all patients undergoing thoracic aortic endografting at our institution were retrospectively reviewed for demographics, interventional indications and acuity, operative details, and clinical outcomes. Study outcomes were analyzed by clinical presentation (urgent/emergent vs elective) and aneurysm morphology that was within and outside specific instructions for use as recommended by the manufacturer. RESULTS: Between March 2006 and October 2009, 96 patients underwent thoracic endografting for aneurysm (n = 43), transection (n = 7), penetrating ulcer (n = 11), dissection (n = 19; acute = 9, chronic = 10), pseudoaneurysm (n = 11), or miscellaneous indications (n = 5). Endografting was performed with various endografts (Gore TAG: 59; Medtrontic Talent: 26; Zenith-TX2: 7; Combination: 4.Involvement of the arch (n = 42, 43.75%) was treated with subclavian artery coverage without revascularization in 13 (13.5%), debranching in 20 (20.8%), and fenestration/stenting in 9 (9.38%). Involvement of the visceral vessels (n = 24, 25%) was treated with debranching in 15 (15.6%) or fenestration/stenting in 9 (9.4%). Patients had a mean follow-up of 11.5 +/- 10.96 (range: 0-38) months. Overall mortality was 6.25% (n = 6). Mean intensive care unit stay was 6.26 +/- 8.55 (range: 1-63, median: 4) days, and hospital stay was 9.97 +/- 10.31 (range: 1-65, median: 65) days. Major complications were infrequent and included: spinal cord ischemia (n = 6, 6.25%), stroke (n = 6, 6.25%), myocardial infarction (n = 3, 3.15%), renal failure (n = 6, 6.25%), and wound complications (n = 9, 9.38%). Reoperation was required in 13 (13.54%), with early intervention in 2 (2.1%). The vast majority of patients were discharged directly to home (n = 66, 68.8%). There were no significant differences between death (1/49 [2%] vs 5/47 [10.6%], P = .07), stroke (3/49 [6%] vs 3/47 [6%], P = 1.0), or spinal cord ischemia (3/49 [6%] vs 3/47 [6%], P = 1.0) when comparing urgent/emergent presentation to elective cases, respectively. However, there were significant differences in death (6/58 [10.5%] vs 0/38 [0%], P = .04) and spinal cord ischemia (6/58 [10.5%] vs 0/38 [0%], P = .04) but not stroke (5/58 [8.8%] vs 1/38 [2.5%], P = .24] when procedures were performed outside the specific instructions for use. CONCLUSIONS: Results of this single-institution report suggest that endovascular thoracic aortic repair is a safe and effective treatment option for a variety of thoracic pathology including both elective and emergent cases. However, off-label usage of the devices is associated with a significantly higher risk of mortality and spinal cord ischemia, but the risk still appears acceptable given the majority of cases were emergent. PMID- 21236619 TI - Increased prevalence of abdominal aortic aneurysm in patients undergoing inguinal hernia repair compared with patients without hernia receiving aneurysm screening. AB - BACKGROUND: The introduction of screening programs for abdominal aortic aneurysm (AAA) is being contemplated by health services in several countries. The correlation between aortic aneurysm and abdominal wall hernias is well reported, and inguinal hernia has been identified as a risk factor for aortic aneurysm. However, the prevalence of AAA in patients with inguinal hernia has not been adequately documented. This study evaluated whether patients with inguinal hernia are at increased risk of having an AAA compared with patients without hernia receiving aneurysm screening. METHODS: Men aged >55 undergoing primary inguinal hernia repair underwent ultrasound imaging of the abdominal aorta to screen for aneurysm. A reference group was selected from men without clinical evidence of inguinal hernia participating in an AAA screening program. Prevalence and odds ratios of AAA in the two groups were calculated. RESULTS: The study cohort comprised 235 patients with inguinal hernia and 203 controls. The mean +/- SD aortic diameter was 22 +/- 9 mm in patients with inguinal hernia vs 20 +/- 6 mm for controls (P = .045). The prevalence of AAA was 8.1% in the hernia group and 3.9% in the control group (adjusted odds ratio, 3.9; 95% confidence interval, 1.6 9.5; P = .039). For aneurysms >4 cm, the prevalence was 5.1% in those with an inguinal hernia and 1.5% in those without an inguinal hernia (adjusted odds ratio, 4.7; 95% confidence interval, 1.2-18.5, P = .025). CONCLUSIONS: Inguinal hernia was a significant risk factor for AAA. Entry into a screening program of men aged >55 admitted for inguinal hernia repair should be considered. PMID- 21236620 TI - Diagnosis, management, and future developments of fibromuscular dysplasia. AB - Fibromuscular dysplasia (FMD) is a nonatherosclerotic noninflammatory vascular disease that primarily affects women from age 20 to 60, but may also occur in infants and children, men, and the elderly. It most commonly affects the renal and carotid arteries but has been observed in almost every artery in the body. FMD has been considered rare and thus is often underdiagnosed and poorly understood by many health care providers. There are, however, data to suggest that FMD is much more common than previously thought, perhaps affecting as many as 4% of adult women. When it affects the renal arteries, the most common presentation is hypertension. When it affects the carotid or vertebral arteries, the patient may present with transient ischemic attack or stroke, or dissection. An increasing number of patients are asymptomatic and are only discovered incidentally when imaging is performed for some other reason or by the detection of an asymptomatic bruit. FMD should be considered in the differential diagnosis of a young person with a cervical bruit; a "swishing" sound in the ear(s); transient ischemic attack, stroke, or dissection of an artery; or in individuals aged <= 35 years with onset hypertension. Treatment consists of antiplatelet therapy for asymptomatic individuals and percutaneous balloon angioplasty for patients with indications for intervention. Patients with aneurysms should be treated with a covered stent or open surgical repair. Little new information has been published about FMD in the last 40 years. The recently instituted International Registry for Fibromuscular Dysplasia will remedy that situation and provide observational data on a large numbers of patients with FMD. PMID- 21236621 TI - A percutaneous aortic device for cerebral embolic protection during cardiovascular intervention. AB - BACKGROUND: Embolic stroke is a major cause of morbidity in aortic and cardiac interventional procedures. Although cerebral embolic protection devices have been developed for carotid interventions and for open heart surgery, a percutaneous device for cerebral embolic protection during aortic and cardiac interventions would be desirable. METHODS: The Embrella Embolic Deflector (Embrella Cardiovascular Inc, Wayne, Pa) is a percutaneously placed embolic protection device, inserted by a 6F access in the pig's right forelimb, and deployed in the aorta, covering the brachiocephalic vessel origins. The device functions by deflecting embolic debris downstream in the aortic circulation. A swine model (n = 3) was developed for testing the deployment, retrieval, and efficacy of the device using a carotid filtration circuit for collection of emboli. Human atheromatous material was prepared as embolization particles with diameters between 150 and 600 MUm. Deflection efficiency of the device was calculated by comparing numbers of embolic particles in the carotid circulation during protected and unprotected injections. RESULTS: The device was reliably deployed, positioned, and retrieved (n = 24). There was no significant drop in blood pressure across the membrane of the device to suggest reduction of cerebral blood flow. The device did not become occluded by embolic debris despite an embolic load many times that encountered in the clinical situation. Particles entering the carotid circulation after aortic injection of emboli were reduced from 19% of total (unprotected) to 1.3% (protected, P < .0001), with 98.7% of all injected particles being deflected downstream. There was no evidence of arterial injury related to the device found at necropsy. CONCLUSION: The Embrella Embolic Deflector performs safely and reliably in the swine model of human atheroembolism. It effectively deflects almost all emboli downstream, away from the carotid circulation. The deflector shows promise as an aortic embolic protection device and merits further investigation. PMID- 21236622 TI - [Posterior reversible encephalopathy syndrome or postpartum reversible cerebral angiopathy: all postpartum headaches are not postdural puncture headaches]. PMID- 21236623 TI - Is magnesium sulfate by the intrathecal route efficient and safe? AB - The polypharmacological approach to the treatment of postoperative pain has become routine in an attempt to minimize the adverse side effects of opioids. Magnesium sulphate is a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor and thus can modify nociceptive modulation. Intravenous administration of magnesium sulphate can improve postoperative analgesia and decrease the requirement for postoperative opiates, but the effects are inconsistent and have not been reliably accompanied by a reduction in the incidence of morphine-related adverse events. Several studies have shown that the administration of magnesium by the intrathecal route is safe and, in combination with opiates, extends the effect of spinal anaesthesia in both animal and human studies. The analysis of these studies justifies further investigation of the use of magnesium sulphate by the intrathecal route. PMID- 21236624 TI - [Minutes of the 17th meeting of the anesthesia club in otorhinolaryngology]. PMID- 21236625 TI - [Spontaneous intracranial hypotension]. PMID- 21236626 TI - [Abscess-like metastases to soft tissue indicating lung cancer]. PMID- 21236627 TI - Serum metal ion concentration: comparison between small and large head metal-on metal total hip arthroplasty. AB - The purpose of this study was to compare serum metal ion concentrations (chromium and cobalt) in 3 groups, 2 with metal-on-metal articulations and a control metal on-polyethylene group. Forty-six patients with good to well-functioning hips were recruited for the study. Serum ion levels of all patients were drawn, and Harris Hip Score, University of California, Los Angeles activity score, and radiographs were performed. Serum chromium concentrations were significantly lower in the large head group compared with the small head group (P = .013). There was no difference in the cobalt concentrations between the 2 groups (P = .087). There was a significant difference between both metal-on-metal groups when compared with controls for both chromium and cobalt levels (P = .0005 and P = .0004, control vs small; P = .001 and P = .0001, control vs large, respectively). PMID- 21236628 TI - Early aseptic loosening with a precoated low-profile tibial component: a case series. AB - Between March 2007 and December 2008, we performed 529 consecutive total knee arthroplasties in 460 patients with the Zimmer (Warsaw, IN) NexGen MIS Tibial Component using a minimally invasive approach. Eight knees in 8 patients (1.5%) were revised for early aseptic loosening of the tibial component despite normal initial postoperative radiographs. Several additional patients have concerning radiographic signs of pending failure. The mean time to revision was 17 months (range, 9-31 months). Intraoperatively, in all cases, more than 50% of the tibial tray was devoid of cement and factory-applied polymethylmethacrylate. Our experience with early aseptic loosening of this tibial component has led us to discontinue its use until the etiology of the high early failure rate is able to be determined. PMID- 21236629 TI - Hospice use in Alabama, 2002-2005. AB - CONTEXT: The literature predominately describes hospice utilization among Medicare recipients, with a limited number of reports describing use among all age groups. OBJECTIVES: This study aimed to describe and compare patterns of hospice use among decedents of all ages in Alabama using a population-based approach. METHODS: We obtained death certificates for Alabama residents who died from January 1, 2002 to December 31, 2005 (n=178,420). To ascertain hospice use, we linked death certificates to the hospice administering care using state mandated listings of deaths reported by hospices. Additionally, each decedent's residence at death was geocoded and area-level socioeconomic status (SES) measures were added. RESULTS: From 2002 to 2005, a total of 43,638 Alabamians died while under hospice care, representing a quarter (24.5%) of all deaths in the state. During this four-year span, the rate of hospice use increased by nearly 15% (22.2%-25.6%). As expected, rates of hospice use increased with age at death. For the SES indicators for poverty, education, and income, rates of hospice use increased as SES improved. However, this pattern was found to vary by race and metro/nonmetro status. CONCLUSIONS: In addition to revealing racial, geographic, and other disparities in hospice care across Alabama, our results indicate usage rates in Alabama trail behind those observed nationally. We also identified previously unreported interactions between race, urbanization level, and poverty classification. Future studies should explore whether such relationships exist elsewhere and the rationale for their occurrence. PMID- 21236630 TI - Social support, world assumptions, and exposure as predictors of anxiety and quality of life following a mass trauma. AB - This study examined the influence of a mass trauma (the Virginia Tech campus shootings) on anxiety symptoms and quality of life, as well as the potential vulnerability/protective roles of world assumptions and social support. Pre trauma adjustment data, collected in the six months prior to the shooting, was examined along with two-month post-shooting data in a sample of 298 female students enrolled at the university at the time of the shootings. Linear regression analyses revealed consistent predictive roles for world assumptions pertaining to control and self-worth as well as family support. In addition, for those more severely exposed to the shooting, greater belief in a lack of control over outcomes appeared to increase vulnerability for post-trauma physiological and emotional anxiety symptoms. Implications of the results for research and intervention following mass trauma are discussed. PMID- 21236631 TI - Effects of cognitive self-consciousness on visual memory in obsessive-compulsive disorder. AB - Previous research has documented high trait cognitive self-consciousness (CSC) in obsessive-compulsive disorder (OCD). It remains unclear whether elevated CSC levels can also explain cognitive performance deficits that have frequently been found in OCD. This study examined whether experimentally heightened CSC affects visual memory performance in OCD. OCD participants and healthy controls completed a complex figure test under three experimental conditions: simultaneously focusing on their thoughts (= CSC condition), simultaneously focusing on acoustic stimuli (= dual-task condition), and without a parallel task (= standard condition). In the OCD sample both the CSC condition and the dual-task condition reduced memory performance compared to the standard condition, whereas in controls only the dual-task condition led to reduced performance. Results indicate that raising CSC in OCD has a deteriorating effect on memory encoding that parallels the effect of a secondary task. High CSC and its effects on cognitive performance might be amenable to meta-cognitive treatment approaches. PMID- 21236632 TI - Attentional processes in interactions between people with profound intellectual and multiple disabilities and direct support staff. AB - Few studies have examined joint attention in interactions with persons with profound intellectual and multiple disabilities (PIMD), despite its important role in high-quality interaction. The purpose of this study is to describe the attention-directing behaviours of persons with PIMD and their direct support staff and the attention episodes resulting from their interactions, and to understand how these variables relate to each other. Video observations of 17 staff-client dyads were coded using partial interval recording. The results showed considerable variation across individuals and dyads. In general, persons with PIMD directed the attention of staff members infrequently. The staff members frequently directed their clients' attention towards a topic of interest but did not often use the tactile modality. Within the staff-client dyad, there was not much joint attention; however, shared attention episodes occurred frequently. Shared attention and joint attention are strongly correlated. A negative correlation was found between clients not using attention-directing behaviours and staff members using tactile methods to direct the attention, and joint attention episodes. This study presents both directions for future research and practical implications. PMID- 21236633 TI - Preschool impairments in auditory processing and speech perception uniquely predict future reading problems. AB - Developmental dyslexia is characterized by severe reading and spelling difficulties that are persistent and resistant to the usual didactic measures and remedial efforts. It is well established that a major cause of these problems lies in poorly specified phonological representations. Many individuals with dyslexia also present impairments in auditory temporal processing and speech perception, but it remains debated whether these more basic perceptual impairments play a role in causing the reading problem. Longitudinal studies may help clarifying this issue by assessing preschool children before they receive reading instruction and by following them up through literacy development. The current longitudinal study shows impairments in auditory frequency modulation (FM) detection, speech perception and phonological awareness in kindergarten and in grade 1 in children who receive a dyslexia diagnosis in grade 3. FM sensitivity and speech-in-noise perception in kindergarten uniquely contribute to growth in reading ability, even after controlling for letter knowledge and phonological awareness. These findings indicate that impairments in auditory processing and speech perception are not merely an epiphenomenon of reading failure. Although no specific directional relations were observed between auditory processing, speech perception and phonological awareness, the highly significant concurrent and predictive correlations between all these variables suggest a reciprocal association and corroborate the evidence for the auditory deficit theory of dyslexia. PMID- 21236634 TI - Prevalence of intellectual disability: a meta-analysis of population-based studies. AB - Intellectual disability is an extremely stigmatizing condition and involves utilization of large public health resources, but most data about its burden is based on studies conducted in developed countries. The aim of this meta-analysis was to collate data from published literature and estimate the prevalence of intellectual disability across all such studies. The review includes studies published between 1980 and 2009, and includes data from populations that provided an overall estimate of the prevalence of intellectual disability. Meta-analysis was done using random effects to account for heterogeneity. Sub-group analyses were also done. The prevalence of intellectual disability across all 52 studies included in the meta-analysis was 10.37/1000 population. The estimates varied according to income group of the country of origin, the age-group of the study population, and study design. The highest rates were seen in countries from low- and middle income countries. Studies based on identification of cases by using psychological assessments or scales showed higher prevalence compared to those using standard diagnostic systems and disability instruments. Prevalence was higher among studies based on children/adolescents, compared to those on adults. Higher prevalence in low and middle income group countries is of concern given the limitations in available resources in such countries to manage intellectual disability. The importance of using standardized diagnostic systems to correctly estimate the burden is underlined. The public health and research implications of this meta-analysis have been discussed. PMID- 21236635 TI - Cardiac autonomic function during submaximal treadmill exercise in adults with Down syndrome. AB - This study determined whether the cardiac autonomic function of adults with Down syndrome (DS) differs from that of nondisabled persons during submaximal dynamic exercise. Thirteen participants with DS and 12 nondisabled individuals performed maximal and submaximal treadmill tests with metabolic and heart rate (HR) measurements. Spectral analysis of HR variability was performed on the last 256 consecutive R-R intervals obtained under the following conditions: (1) rest, (2) submaximal treadmill exercise (at constant relative intensity below the ventilatory threshold) and (3) recovery. Participants with DS presented lower chronotropic response than those without DS to peak and submaximal exercise (p<0.05). Nevertheless, the fractional utilization of peak HR during treadmill walking was similar between groups (~60% peak HR). Even though there were no between-group differences at rest or during recovery, the participants with DS showed a higher LF/HF ratio during exercise (p<0.05). Similarly, the LF power of participants with DS during exercise was greater than that of nondisabled participants (p<0.05). In contrast, both groups exhibited similar HF power at each physiological condition. In conclusion, these findings suggest that adults with DS demonstrate appropriate vagal withdrawal, but heightened sympathetic modulation of HR variability at ~60% of their peak HR. Despite this, the absolute change in HR from rest to exercise was attenuated in these individuals compared to persons without disabilities. This indicates that DS may be associated with poor cardiac responsiveness to changes in autonomic modulation during exercise at intensities below the ventilatory threshold. PMID- 21236636 TI - Towards a comprehensive model of stereotypy: integrating operant and neurobiological interpretations. AB - The predominant models on the emergence and maintenance of stereotypy in individuals with developmental disabilities are based on operant and neurobiological interpretations of the behavior. Although the proponents of the two models maintain largely independent lines of research, operant and neurobiological interpretations of stereotypy are not mutually exclusive. The paper reviews the two models of stereotypy and proposes an integrated model using recent findings on the neurobiology of reinforcement. The dopaminergic system and the basal ganglia are both involved in stereotypy and in reinforcement, which provides a potential link between the models. Implications of the integrated model for future research are discussed in terms of improving the assessment and treatment of stereotypy in individuals with developmental disabilities. PMID- 21236637 TI - Objective voice analysis of boys with profound hearing loss. AB - OBJECTIVES: A critical factor that affects human voice production is hearing because it provides necessary feedback for control of speech. Vocal quality of profoundly hearing-impaired children is often considered deviant from both perceptual and acoustic perspectives. The present study compares selected vocal acoustic parameters of a profound hearing loss group of boys with normal peers. METHODS: The subjects were 15 Iranian boys with profound bilateral sensorineural hearing loss and 15 Iranian normal hearing participants matched according to age and sex. The age range of the children with hearing loss was 61-81 months (M=72.26) (ie, 5.1-6.75 years, M=6.02 years) and for the normal group the age range was 61-80 months (M=71.47) (5.08-6.67 years, M=5.96 years). Each subject phonated 10 /a/ vowels with constant pitch and loudness for maximal phonation times. The mid 3-second portion of each token was analyzed using Dr. Speech 4.3u software (subprogram: Vocal Assessment; Dr. Speech, Tiger Electronics, Seattle, WA). RESULTS: There was a statistically significantly higher fundamental frequency (F0), jitter, and shimmer in the productions of the hearing loss boys compared with the normal hearing boys. Consistent with these findings was a significantly lower value for the harmonics-to-noise ratio measure for the boys with hearing loss. CONCLUSIONS: The results of the present study suggest that profoundly deaf children present with greater phonatory instability and spectral noise, with the possible inference of reduced laryngeal control relative to vocal quality. The finding of higher F0 for the boys with profound hearing loss suggests that they use a different control strategy for pitch, an area needing further study. These findings of acoustic and F0 differences of the hearing impaired boys should be kept in mind for intervention practices especially when the social impact of deafness is considered. PMID- 21236638 TI - Relationships between vocal structures, the airway, and craniocervical posture investigated using magnetic resonance imaging. AB - OBJECTIVES: Traditional voice research focuses on the vocal tract, articulators, and larynx. By ignoring their direct/indirect attachments (skull, cervical spine, and sternum) important information may be missed. We aim to investigate vocal structures within this wider context and assess the validity of this approach for subsequent voice production studies. STUDY DESIGN/METHOD: Using a cross-sectional study design, we obtained midsagittal MR images from 10 healthy adults (five males and five females) while at rest and breathing quietly. With reference points based on cephalometry, 17 craniocervical, craniocaudal, and anteroposterior variables were chosen to describe craniofacial morphology, craniocervical posture, and airway dimensions. Relationships between variables were sought using Pearson's correlation coefficient. RESULTS: We found widespread correlations relating vocal structures to the craniofacial skeleton and cervical spine (r>0.6). Increasing airway size (hyocervical distance) was associated with greater distances from the cranial base of the hyoid, larynx, epiglottis tip and uvula tip, and of C3 from the menton. A wider velopharyngeal opening was associated with a shorter and higher soft palate, and a greater (lower) craniocervical angle was associated with a wider laryngeal tube opening, narrower airway at the uvula tip and shorter distances of the hyoid and uvula tip from the cranial base. CONCLUSION: Finding widespread correlations relating vocal structures to the craniofacial skeleton and cervical spine confirms the potential of this approach to uncover functional activity during voice production and demonstrates the importance of considering vocal structures and the airway within this wider context if important information is not to be missed. PMID- 21236639 TI - Psychosocial issues after a traumatic hand injury: facilitating adjustment. AB - A hand injury has physical, psychological, and social consequences. Hand therapists play a critical role facilitating physical and psychosocial recovery and adjustment. It is important that our assessments and treatment interventions consider the whole person, are culturally relevant, and are patient centered to positively affect adjustment and improve outcomes. Psychosocial distress needs to be identified early using screening tools such as the Injured Workers Survey and the Impact of Event scale to direct treatment and refer appropriately. Peer support, either informally or during psycho-educational support groups can provide patients with valuable information, such as positive coping strategies and stress management techniques. Early participation and independence in meaningful activities ensures that important roles are preserved, which positively affects self-esteem, identity, motivation, locus of control, and outlook. Assessment tools, such as the Canadian Occupational Performance Measure and the Patient-Specific Functional Scale, can assist hand therapists in collaborating with patients to establish meaningful, culturally relevant hand therapy goals thereby facilitating successful adjustment. PMID- 21236640 TI - Transthoracic echocardiographic assessment of continuous-flow left ventricular assist devices. AB - An increasing number of patients are implanted with continuous-flow left ventricular assist devices (LVAD) for the treatment of severe congestive heart failure. In parallel with this growing experience has been an increase in knowledge of how these devices alter cardiac physiology and the important implications this has for cardiac function. Echocardiography offers the ability to provide serial noninvasive evaluation before and after LVAD implantation to document these changes, guide management decisions, and identify LVAD dysfunction. The authors detail a comprehensive assessment of LVAD function by transthoracic echocardiography. PMID- 21236642 TI - Closure of palatal fistula with buccal fat pad flap. AB - Palatal fistula as a complication of palatal surgery is difficult to manage due to the presence of fibrotic and scarred tissue and the absence of local virgin tissue. Recurrence rates are high. To investigate the efficacy of repairing small and medium sized palatal fistulas using the buccal fat pad (BFP), 20 patients (aged 2.5-19 years) with palatal fistula (10-20mm) underwent closure surgery using a pedicled BFP flap. The nasal layer was closed by a local mucosal flap (turn down flap) and the pedicled BFP flap was used for oral lining. Full epithelialization of the BFP layer was observed within 4 weeks in all patients. A 2mm defect in the anterior part of the previous fistula location remained in one case, which spontaneously healed after 2 months; all others closed successfully. Mild pain and cheek swelling occurred in 10 patients, which disappeared within 5 days with no surgical intervention. This study suggests the pedicled BFP flap is a simple and relatively secure method for palatal fistula management. It is recommended for fistulas less than 20mm in length located in the posterior two thirds of the palate. PMID- 21236643 TI - Activity of tigecycline alone and in combination with colistin and meropenem against Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae strains by time-kill assay. AB - Antibiotic combinations including tigecycline have not been studied against Klebsiella pneumoniae carbapenemase (KPC)-producing pathogens. Tigecycline alone and combined with colistin and meropenem was tested against eight genetically unrelated KPC-producing clinical strains of Enterobacteriaceae (four K. pneumoniae, two Escherichia coli, one Enterobacter cloacae and one Serratia marcescens) by time-kill assay. Tigecycline displayed a concentration-independent bacteriostatic activity in seven strains and bactericidal activity in one strain. Colistin showed bactericidal activity at 4* the minimum inhibitory concentration (MIC) in three strains and was bacteriostatic for the remaining strains and concentrations. Meropenem was bactericidal in three strains and bacteriostatic in five strains. The tigecycline+meropenem combination was not bactericidal against the four K. pneumoniae strains and was non-synergistic against all eight strains. Tigecycline+colistin was bactericidal against all strains at most time intervals and concentrations and was also synergistic at 1* and 2* MIC against most strains up to 4-8h and at 4* MIC up to 24 h against all strains. These findings suggest that, at most drug concentrations, tigecycline, colistin and meropenem as single agents do not exhibit efficient bactericidal activity against most of the KPC producing strains. Tigecycline alone might be a therapeutic option for infections caused by KPC-producers when bacteriostatic activity is adequate or combined with colistin when bactericidal activity is necessary. Additional in vivo tests are warranted to assess better the killing kinetics of tigecycline combinations against KPC-producers. PMID- 21236644 TI - Contribution of mutations in DNA gyrase and topoisomerase IV genes to ciprofloxacin resistance in Escherichia coli clinical isolates. AB - DNA gyrase (GyrA and GyrB) and topoisomerase IV (ParC and ParE) are the two essential type II topoisomerases in Escherichia coli. These enzymes act via inhibition of DNA replication. Mutations in the quinolone resistance-determining region (QRDR) of the gyrA, gyrB, parC and parE genes from clinical isolates of E. coli were determined by DNA sequencing of 54 ciprofloxacin-resistant clinical isolates from a hospital in Delhi, India. The majority of the E. coli isolates were shown to carry mutations in gyrA, parC and parE. Ciprofloxacin resistance due to accumulation of such a high number of mutations in the QRDR regions of gyrA at positions Ser83 and Asp87 and parC at position Ser80 as well as outside of the QRDR region of parE at Ser458 and Glu460 confers high-level resistance of ciprofloxacin in clinical isolates. The high frequency of occurrence of mutations in the parE gene (44.4% strains) is alarming, as topoisomerase IV is a secondary target of quinolones. PMID- 21236645 TI - A post-marketing evaluation of posaconazole plasma concentrations in neutropenic patients with haematological malignancy receiving posaconazole prophylaxis. AB - This is one of the first studies to report on therapeutic drug monitoring (TDM) of posaconazole (PCZ) for antifungal prophylaxis in patients with acute myelogenous leukaemia or myelodysplastic syndrome outside of the rigours of clinical licencing trials. A number of factors have been identified or proposed as causing poor oral absorption of PCZ. Putative PCZ concentrations have been recommended for TDM (0.5 MUg/mL or 0.7 MUg/mL). In this study, 19 (90.5%) of 21 patients failed to reach the higher putative target of 0.7 MUg/mL, and 16 patients (76.2%) failed to reach the lower target of 0.5 MUg/mL. Increasing the dose did not help four of six patients reach target concentrations. Three of the patients developed 'proven' or 'possible' fungal infections, all with PCZ concentrations <0.5 MUg/mL. Use of acid-suppressing agents appears to explain some of the poor absorption. TDM of PCZ is warranted in patients receiving this orally administered agent. PMID- 21236646 TI - MAO A VNTR polymorphism and amygdala volume in healthy subjects. AB - The X-linked Monoamine Oxidase A (MAO A) gene presents a well known functional polymorphism consisting of a variable number of tandem repeats (VNTR) (long and short variants) previously associated with altered neural function of the amygdala. Using automatic subcortical segmentation (Freesurfer), we investigated whether amygdala volume could be influenced by this genotype. We studied 109 healthy subjects (age range 18-80 years; 59 male and 50 female), 74 carrying the MAO A High-activity allele and 35 the MAO A Low-activity allele. No significant effect of the MAO A polymorphism or interaction effect between polymorphism * gender was found on amygdalar volume. Thus, our findings suggest that the reported impact of the MAO A polymorphism on amygdala function is not coupled with consistent volumetric changes in healthy subjects. Future studies are needed to investigate whether the association between volume of the amygdala and the MAO A VNTR polymorphism is influenced by social/psychological variables, such as impulsivity, trauma history and cigarette smoking behaviour, not taken into account in this work. PMID- 21236647 TI - Reduced P300 and P600 amplitude in the hollow-mask illusion in patients with schizophrenia. AB - Illusions provide a useful tool to study the mechanisms by which top-down and bottom-up processes interact in perception. Patients suffering from schizophrenia are not as subject to the hollow-mask illusion as healthy controls, since studies have shown that controls perceive a hollow mask as a normal face, while patients with schizophrenia do not. This insusceptibility to the illusion is indicating a weakened top-down processing in schizophrenia and little is understood about the neurobiology of this phenomenon. We used event-related potentials to investigate the hollow-mask illusion in patients with schizophrenia and healthy controls. We hypothesized that there would be a visible reduction of top-down processing in the patients' group and that this reduction would occur in the late stages of processing. We found significantly decreased amplitudes in the P300 and P600 components in the patients' group, indicating that visual information does not benefit from frontal, parietal or temporal activity for perceiving incoming stimuli. We propose that a deficit in functional connectivity may be responsible for impaired top-down visual processing in schizophrenia. These data further the understanding of the time course of top-down processing in patients with schizophrenia. PMID- 21236649 TI - Voxel-based morphometric analysis on the volume of gray matter in bipolar I disorder. AB - A number of previous studies have found that bipolar disorder is associated with abnormalities of brain structure. In this study we used optimized voxel-based morphometry (VBM) to compare gray matter volume between patients with bipolar I disorder and healthy controls. Twenty-four bipolar I patients (15 males and nine females) and 36 healthy controls (21 males and 15 females), who were well matched for age and gender, were scanned using structural magnetic resonance imaging. Gray matter volume was assessed and compared using optimized VBM, and the correlation between duration of illness/number of episodes and regional volumes was analyzed. There was no difference in whole-brain gray matter volume between the two groups. Optimized vVBM showed that subjects with bipolar I disorder had smaller volumes in the left inferior parietal lobule, right superior temporal gyrus, right middle frontal gyrus and left caudate. Only the volume of the right middle frontal gyrus was correlated with duration of illness and number of episodes in patients. These results suggest widespread gray matter defects in bipolar I disorder, which may play an important role in onset of the illness. PMID- 21236650 TI - Cell adhesion and locomotion on microwell-structured glass substrates. AB - The purpose of this study was to investigate the effect of microstructured material surface on cell adhesion and locomotion in real-time. ArF excimer laser direct-writing ablation was used to fabricate microwell patterns with precise control of size and spacing on glass. The influence of the ablation process parameters (laser fluence, pulse number and repetition rate) on the micromachining quality (depth, width, aspect ratio and edge effects) of the microwells was established. Human fibroblast cells, as an example of anchorage dependent cells, were seeded onto the microstructured glass substrate and time lapse microscopy was used to study cell adhesion and locomotion. The interaction with microstructured materials resulted in fibroblast cell repulsion and the cells exhibited a higher locomotion speed (75.77+/-3.36 MUm/h) on the structures in comparison with plane glass control (54.01+/-15.53 MUm/h). Further studies are needed to firmly establish the potential of microstructuring, for example, in elongating the life spans of implantable devices. PMID- 21236651 TI - Allometric variation among juvenile, adult male and female eastern bearded dragons Pogona barbata (Cuvier, 1829), with comments on the behavioural implications. AB - The functional significance of allometric change in reptiles has received limited attention and the reason for such changes has been regarded as 'obscure'. In this paper we report data on the Australian Pogona barbata, the eastern bearded dragon, from across their range and review changes in allometric growth among juveniles, and adult males and females and consider the functional relevance of these changes. There were significant differences in the population for mass, tail length, tail width, rear leg length and jaw length. These differences were consistent with differences required in locomotor performance and thus habitat use, together with access to different preferred dietary components. PMID- 21236648 TI - Time series fMRI measures detect changes in pontine raphe following acute tryptophan depletion. AB - Serotonin is synthesized from its precursor, tryptophan, by brainstem raphe neurons and their synaptic terminals in limbic regions. The omission of tryptophan from an Acute Tryptophan Depletion (ATD) diet transiently diminishes serotonin synthesis, alters raphe activity, and mimics symptoms of depression. Raphe functional magnetic resonance imaging (fMRI) poses challenges using signal averaging analyses. Time-series properties of fMRI blood oxygenation level dependent (BOLD) signals may hold promise, so we analyzed raphe signals for changes with the ATD diet. Eleven remitted (previously depressed) patients were awake with eyes-closed during seven-minute resting scans with 0.5s(-1) sampling. BOLD signal time-series data were frequency-filtered using wavelet transforms, yielding three octave-width frequency bands from 0.25 to 0.03s(-1) and an unbounded band below 0.03s(-1). Spectral power, reflecting signal information, increased in pontine raphe at high frequencies (0.25 to 0.125s(-1)) during ATD (compared to control, balanced, diet, P<0.004) but was unchanged at other frequencies. Functional connectivity, the correlation between time-series data from pairs of regions, weakened between pontine raphe and anterior thalamus at low frequencies during ATD (P<0.05). This preliminarily supports using fMRI time series features to assess pontine raphe function. Whether, and how, high frequency activity oscillations interfere with low frequency signaling requires further study. PMID- 21236652 TI - Temporal patterns of intra- and interspecific acoustic signals differ in two closely related species of Acanthoplus (Orthoptera: Tettigoniidae: Hetrodinae). AB - Males of the closely related African tettigoniids Acanthoplus discoidales and Acanthoplus longipes produce a long-lasting calling song and a short disturbance sound. The temporal patterns of the sounds were analysed in respect to species differences and song type differences. The calling songs of both species consist of impulses which are separated into verses of two syllables, with fewer impulses in the first syllable. A. longipes produces more impulses in each syllable than A. discoidales and has longer verse durations, verse intervals and syllable intervals. Also, the disturbance sounds, produced after mechanical stimulation, contain distinct verses of impulses. The disturbance sound of A. longipes has a higher number of impulses per verse than that of A. discoidales. The frequency spectra of the songs in both species have similar peak frequencies (around 12.5 kHz) and both species have their greatest hearing sensitivity in the range between 5 and 10 kHz. Females of A. longipes perform phonotaxis only to songs with a species-specific temporal pattern. By contrast, females of A. discoidales react positively to calling songs of both species. PMID- 21236653 TI - Isolation, characterization and expression analysis of the ornithine decarboxylase gene (ODC1) of the entomopathogenic fungus, Metarhizium anisopliae. AB - The gene ODC1, which codes for the ornithine decarboxylase enzyme, was isolated from the entomopathogenic fungus, Metarhizium anisopliae. The deduced amino acid sequence predicted a protein of 447 amino acids with a molecular weight of 49.3 kDa that contained the canonical motifs of ornithine decarboxylases. The ODC1 cDNA sequence was expressed in Escherichia coli cells; radiometric enzyme assays showed that the purified recombinant protein had ornithine decarboxylase activity. The optimum pH of the purified Odc1 protein was 8.0-8.5, and the optimum reaction temperature was 37 degrees C. The apparent K(m) for ornithine at a pyridoxal phosphate concentration of 20mM was 22 MUM. The competitive inhibitor of ODC activity, 1,4-diamino-2-butanone (DAB), at 0.25 mM inhibited 95% of ODC activity. The ODC1 mRNA showed an increase at the beginning of appressorium formation in vitro. During the M. anisopliae invasion process into Plutella xylostella larvae, the ODC1 mRNA showed a discrete increase within the germinating spore and during appressorium formation. The second expression peak was higher and prolonged during the invasion and death of the insect. The ODC1 gene complements the polyamine auxotrophy of Yarrowia lipolytica odc null mutant. PMID- 21236655 TI - Pharmacoeconomics in COPD and inappropriateness of diagnostics, management and treatment. AB - Chronic respiratory disorders (CRDs) concern many people and generate important health and social costs. Their global impact (particularly that of COPD) has been the subject of numerous pharmacoeconomic studies published in recent years. These studies confirm the growing impact of COPD in all countries, in terms of the patient and patient's family, and that of society as a whole. The attitude towards COPD management is still largely inadequate, from prevention to diagnosis to drug and non-pharmacologic long-term treatment. The pulmonary specialist, in cooperation with other health professionals, can play a fundamental role in detecting inappropriateness in the clinical course of COPD and provide the basis for a correct assessment of pharmacoeconomic issues. Given the increasing social impact of COPD, the meeting inspiring this review, "COPD a social disease: inappropriateness and pharmacoeconomics. The role of the specialist: present and future", Venice, Italy, 21-22 April 2010, fits in perfectly with the goals and recommendations of GARD (Global Alliance against chronic Respiratory Diseases) of the WHO. GARD has formulated working recommendations: (i) to develop national programs of prevention and control of CRDs, starting from health education campaigns and better knowledge of epidemiology, impact, and relative risk factors; (ii) to provide training and continuing education on prevention and treatment of CRDs, disseminating the existing guidelines; and (iii) to facilitate access to essential treatments and favour adherence to long-term treatment, including drug treatment and pulmonary rehabilitation, particularly amongst disadvantaged sectors of the population. PMID- 21236656 TI - Evanescent wave absorbance based fiber optic biosensor for label-free detection of E. coli at 280 nm wavelength. AB - A novel label-free technique for the detection of pathogens based on evanescent wave absorbance (EWA) changes at 280 nm from a U-bent optical fiber sensor is demonstrated. Bending a decladded fiber into a U-shaped structure enhances the penetration depth of evanescent waves and hence sensitivity of the probe. We show that the enhanced EWA response from such U-bent probes, caused by the inherent optical absorbance properties of bacterial cells or biomolecules specifically bound to the sensor surface, can be exploited for the detection of pathogens. A portable optical set-up with a UV light emitting diode, a spectrometer and U-bent fiber optic probe of 200 MUm core diameter, 0.75 mm bend radius and effective probe length of 1cm demonstrated an ability to detect less than 1000 cfu/ml. PMID- 21236654 TI - Molecular resolution of the B cell landscape. AB - The progression of hematopoietic stem cells (HSCs) to the B lymphocyte lineage requires that uncommitted progenitors successfully negotiate the transition from multipotency to unipotency, including the loss of self-renewal potential. Previous work identified essential transcription factors that mediate B lineage development. Major advances build on this knowledge and reveal coordinated changes in gene expression occurring within single cells at sequential stages in the B cell differentiation pathway. Recent studies on epigenetic mechanisms also provide a framework within which transcription factor activity, chromatin modifications, and gene expression patterns can be viewed at hierarchical levels to link genotype and phenotype. PMID- 21236657 TI - Biofunctionalized indigo-nanoparticles as biolabels for the generation of precipitated visible signal in immunodipsticks. AB - A novel class of organic nanoparticles as biolabels that can generate an instant visible signal was applied to immunodipsticks. A new principle for signal generation based on hydrolysis of colourless signal precursor molecules to produce coloured signal molecules followed by signal precipitation and localization was demonstrated. The nanoparticle biolabels were applied to sandwich immunoassays for the detection of mouse immunoglobulin G (M IgG). In the presence of M IgG, a nanoparticle-immunocomplex was formed and bound on the test zone immobilized with goat anti M IgG (Gt alpha M IgG). A blue line was developed on the test zone upon the addition of a signal developing reagent. An optical signal could be simply assessed using naked eyes or quantified using a reading device. The lowest visible signal that could be observed using naked eyes was found to be 1.25 MUg L(-1) M IgG. The nanoparticle biolabel also showed a better sensitivity (signal-to-noise ratio) compared with the conventional colloidal gold biolabel. This novel class of organic nanoparticles offers an alternative biolabel system for the development of point-of-care immunodipsticks. PMID- 21236658 TI - Intra-articular corticosteroid injections: a critical literature review with up to-date findings. AB - Intra-articular corticosteroid injections are frequently used in the management of both osteoarthritis and rheumatoid arthritis, with most evidence and articles confined to the knee joint. There are few articles that deal with intra-articular corticosteroid injections in the foot and ankle. The aim of this critical literature review is to find the most up-to-date material on intra-articular corticosteroid injections for the foot and ankle. This article will review: effects of corticosteroids; pharmacology of injectable corticosteroids; mechanism of action; indications and contraindications; agents and the dosages; adverse effects; and injection techniques. All Foreign and English language journals were searched. Please refer to Section 2 for search criteria. PMID- 21236659 TI - Footwear in the United States Army Band: injury incidence and risk factors associated with foot pain. AB - BACKGROUND: Footwear characteristics can influence, fatigue, comfort, injuries and energy cost. Members of the United States Army Band have hundreds of performances a year and these performances often include prolonged standing and marching in footwear. OBJECTIVE: The purposes of this paper are to: (1) determine injury rates before and after wearing a shoe with presumed greater cushioning and ventilation among US Army Band members, and (2) identify risk factors associated with foot pain/discomfort. METHODS: To potentially reduce injuries and improve comfort, 112 band members received shoes with an advertised increase in cushioning and ventilation. RESULTS: Injury incidence determined from medical records was 55% in the year before and 57% in the year during which band members wore the new shoes (p = 0.78). Higher risk of foot pain was associated with band unit (odds ratio (OR(Ceremonial unit/other units) = 8.6), 95% confidence interval (CI): 1.2-60.2), shoe cushioning rating (OR(poor/good) = 11.8, 95% CI: 1.5-89.7), orthotic use (OR(yes/no) = 18.5, 95% CI: 2.9-120.3), and how often band members replaced their shoes (OR(<=1 year/>2 years) = 11.5, 95% CI: 1.4-95.4). CONCLUSIONS: The new shoes did not lower injury incidence, although specific risk factors associated with foot pain/discomfort were identified. To potentially increase the cushioning and comfort, insoles may be considered. PMID- 21236660 TI - Mutant onco-proteins as drug targets: successes, failures, and future prospects. AB - Mutant onco-proteins play a direct, causal role in cancer and are therefore considered attractive drug targets. Clinical experience has supported this view, with some exceptions. However, clinical benefit has often been restricted by rapid emergence of drug-resistant clones through several distinct mechanisms. This problem can, in principle, be addressed through cocktails containing several drugs. However, the number of tumors whose survival is dependent on a single, druggable mutant onco-protein is currently unknown. The majority of tumors may be driven either by single drivers that are un-druggable, or by combinations of drivers. In both cases, new approaches will be necessary. Development of systemic RNA interference may be a solution to these problems. PMID- 21236662 TI - The effect of acid pretreatment on the anaerobic digestion and dewatering of waste activated sludge. AB - Waste activated sludge (WAS) is difficult to degrade in anaerobic digestion systems and pretreatments have been shown to speed up the hydrolysis stage. Here the effects of acid pretreatment (pH 6-1) using HCl on subsequent digestion and dewatering of WAS have been investigated. Optimisation of acid dosing was performed considering digestibility benefits and level of acid required. Pretreatment to pH 2 was concluded to be the most effective. In batch digestion this yielded the same biogas after 13 days as compared to untreated WAS at 21 days digestion. In semi-continuous digestion experiments (12 day hydraulic retention time at 35 degrees C) it resulted in a 14.3% increase in methane yield compared to untreated WAS, also Salmonella was eradicated in the digestate. Dewatering investigations suggested that the acid pretreated WAS required 40% less cationic polymer addition to achieve the same cake solid content. A cost analysis was also carried out. PMID- 21236663 TI - Microbial community analysis of an aerobic nitrifying-denitrifying MBR treating ABS resin wastewater. AB - A two-stage aerobic membrane bioreactor (MBR) system for treating acrylonitrile butadiene styrene (ABS) resin wastewater was carried out in this study to evaluate the system performance on nitrification. The results showed that nitrification of the aerobic MBR system was significant and the highest TKN removal of approximately 90% was obtained at hydraulic retention time (HRT) 18 h. In addition, the result of nitrogen mass balance revealed that the percentage of TN removal due to denitrification was in the range of 8.7-19.8%. Microbial community analysis based on 16s rDNA molecular approach indicated that the dominant ammonia oxidizing bacteria (AOB) group in the system was a beta-class ammonia oxidizer which was identified as uncultured sludge bacterium (AF234732). A heterotrophic aerobic denitrifier identified as Thauera mechernichensis was found in the system. The results indicated that a sole aerobic MBR system for simultaneous removals of carbon and nitrogen can be designed and operated for neglect with an anaerobic unit. PMID- 21236661 TI - Apoptosis and oncogenesis: give and take in the BCL-2 family. AB - The mitochondrial pathway of apoptosis constitutes one of the main safeguards against tumorigenesis. The BCL-2 family includes the central players of this pathway that regulate cell fate through the control of mitochondrial outer membrane permeabilization (MOMP), and important progress has been made in understanding the dynamic interactions between pro-apoptotic and anti-apoptotic BCL-2 proteins. In particular, recent studies have delineated a stepwise model for the induction of MOMP. BCL-2 proteins are often dysregulated in cancer, leading to increased survival of abnormal cells; however, recent studies have paradoxically shown that apoptosis induction can under some circumstances drive tumor formation, perhaps by inducing compensatory proliferation under conditions of cellular stress. These observations underline the complexity of BCL-2 protein function in oncogenesis. PMID- 21236664 TI - Design, synthesis and biological evaluation of new arylpiperazine derivatives bearing a flavone moiety as alpha1-adrenoceptor antagonists. AB - Elaborate study on the three-dimensional model of alpha(1)-adrenoceptor (alpha(1) AR) antagonists led to the development of a series of new arylpiperazine derivatives bearing a flavone nucleus as alpha(1)-AR antagonists. The in vitro activities were evaluated and compounds 1, 4, 10, 13 and 15 showed activities close to the reference compound (Prazosin). PMID- 21236665 TI - Design and regioselective synthesis of a new generation of targeted therapeutics. Part 3: Folate conjugates of aminopterin hydrazide for the treatment of inflammation. AB - Efficient syntheses of folate receptor (FR) targeting conjugates of the anti inflammatory, aminopterin hydrazide, are described. 2-{4-Benzoylamino}-5-oxo-5 {N'-[2-(pyridin-2-yldisulfanyl)-ethoxycarbonyl]-hydrazino}-pentanoic acid is synthesized from commercially available 4-[(2-amino-4-imino-3,4-dihydro-pteridin 6-yl-methyl)-amino]-benzoic acid. Conjugation of this novel, activated aminopterin hydrazide to folic acid through cysteine-terminating (C-terminus), peptide/carbohydrate spacers results in highly water soluble conjugates which allow for the release of free aminopterin hydrazide within the endosomes of targeted cells. PMID- 21236666 TI - Structure-activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists. AB - Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia. PMID- 21236667 TI - Multitargeted drugs discovery: balancing anti-amyloid and anticholinesterase capacity in a single chemical entity. AB - Memoquin (1) is a lead compound multitargeted against Alzheimer's disease (AD). It is an AChE inhibitor, free-radical scavenger, and inhibitor of amyloid-beta (Abeta) aggregation. A new series of 1 derivatives was designed and synthesized by linking its 2,5-diamino-benzoquinone core with motifs that are present in the structure of known amyloid binding agents like curcumin, the benzofuran derivative SKF64346, or the benzothiazole bearing compounds KHG21834 and BTA-1. The weaker AChE inhibitory potencies and the concomitant nearly equipotent anti amyloid activities of the new compounds with respect to 1 resulted in a more balanced biological profile against both targets. Selected compounds turned out to be effective Abeta aggregation inhibitors in a cell-based assay. By properly combining two or more distinct pharmacological properties in a molecule, we can achieve greater effectiveness compared to single-targeted drugs for investigating AD. PMID- 21236668 TI - Enediol mimics as inhibitors of the D-arabinose 5-phosphate isomerase (KdsD) from Francisella tularensis. AB - We explored the D-arabinose 5-phosphate isomerase (KdsD, E.C. 5.3.1.13) from Francisella tularensis, a highly infectious gram-negative pathogen that has raised concern as a potential bioweapon, as a target for the development of novel chemotherapeutics. F. tularensis KdsD was expressed in Escherichia coli from a synthetic gene, purified, and characterized. A group of hydroxamates designed to be mimics of the putative enediol intermediate in the enzyme's catalytic mechanism were prepared and tested as inhibitors of F. tularensis KdsD. The best inhibitor, which has an IC(50) of 7 MUM, is the most potent KdsD inhibitor reported to date. PMID- 21236669 TI - Efficient synthesis of new tetradentate ligands with potential applications for 64Cu PET-imaging. AB - We wish to report the synthesis of new tetradentate ligands in less than 3h in good to excellent yields from a commercially available compound using microwave assisted technology. First tests of complexation showed a high ability of these ligands to chelate (64)Cu(II) in very diluted medium. These new systems have the potential to be used for nuclear medicine and particularly for PET-imaging. PMID- 21236670 TI - Disease impact in chronic progressive external ophthalmoplegia: more than meets the eye. AB - We determined the extent of disease impact in 28 patients with genetically confirmed chronic progressive external ophthalmoplegia (CPEO) and compared the outcomes to those of matched myotonic dystrophy type I patients. CPEO patients reported a high frequency of severe fatigue (67.9%), pain (96.2%), depression (32.1%) and dependency in daily life (46.4%). The frequency and extent of depression were significantly higher than in DM1 patients (32.1% vs. 7.1%, p=0.040; mean Beck's depression inventory for primary care score 3.8+/-3.5 vs. 1.3+/-1.4, p=0.001), as were fatigue severity, pain intensity and extent of functional impairments. CPEO patients with polymerase gamma-1 mutations reported more functional impairments than those with mitochondrial DNA mutations. Disease impact was however not influenced by most clinical features. The present results help physicians to identify and to treat the factors that influence quality of life in CPEO patients and to provide symptomatic treatment where needed. PMID- 21236671 TI - Survivorship care after breast cancer treatment--experiences and preferences of Australian women. AB - Follow-up care after breast cancer treatment is becoming more complex as it attempts to address the long-term needs of an increasing number of survivors. Workforce issues in oncology challenge the sustainability of current specialist based care. This study explores survivors' experiences with follow-up care and attitudes to alternative models including a tailored survivorship care plan and involvement of primary care physicians and breast care nurses. Twenty women across Australia participated in semi-structured telephone interviews. All continued to attend follow-up visits with a specialist oncologist and reported a high level of satisfaction with care. Participants described a strong reliance on their specialist but were open to an increased role for their primary care physician in a shared model of care. Communication between multidisciplinary team members was perceived as an ongoing problem and there was enthusiasm for a patient-held written survivorship care plan to address this, and to meet information needs. PMID- 21236672 TI - A nonmotor microtubule binding site in kinesin-5 is required for filament crosslinking and sliding. AB - Kinesin-5, a widely conserved motor protein required for assembly of the bipolar mitotic spindle in eukaryotes, forms homotetramers with two pairs of motor domains positioned at opposite ends of a dumbbell-shaped molecule [1-3]. It has long been assumed that this configuration of motor domains is the basis of kinesin-5's ability to drive relative sliding of microtubules [2, 4, 5]. Recently, it was suggested that in addition to the N-terminal motor domain, kinesin-5 also has a nonmotor microtubule binding site in its C terminus [6]. However, it is not known how the nonmotor domain contributes to motor activity, or how a kinesin-5 tetramer utilizes a combination of four motor and four nonmotor microtubule binding sites for its microtubule organizing functions. Here we show, in single molecule assays, that kinesin-5 homotetramers require the nonmotor C terminus for crosslinking and relative sliding of two microtubules. Remarkably, this domain enhances kinesin-5's microtubule binding without substantially reducing motor activity. Our results suggest that tetramerization of kinesin-5's low-processivity motor domains is not sufficient for microtubule sliding because the motor domains alone are unlikely to maintain persistent microtubule crosslinks. Rather, kinesin-5 utilizes nonmotor microtubule binding sites to tune its microtubule attachment dynamics, enabling it to efficiently align and sort microtubules during metaphase spindle assembly and function. PMID- 21236673 TI - LUX ARRHYTHMO encodes a nighttime repressor of circadian gene expression in the Arabidopsis core clock. AB - Circadian clocks provide an adaptive advantage by allowing organisms to anticipate daily and seasonal environmental changes [1, 2]. Eukaryotic oscillators rely on complex hierarchical networks composed of transcriptional and posttranslational regulatory circuits [3]. In Arabidopsis, current representations of the circadian clock consist of three or four interlocked transcriptional feedback loops [3, 4]. Although molecular components contributing to different domains of these circuits have been described, how the loops are connected at the molecular level is not fully understood. Genetic screens previously identified LUX ARRHYTHMO (LUX) [5], also known as PHYTOCLOCK1 (PCL1) [6], an evening-expressed putative transcription factor essential for circadian rhythmicity. We determined the in vitro DNA-binding specificity for LUX by using universal protein binding microarrays; we then demonstrated that LUX directly regulates the expression of PSEUDO RESPONSE REGULATOR9 (PRR9), a major component of the morning transcriptional feedback circuit, through association with the newly discovered DNA binding site. We also show that LUX binds to its own promoter, defining a new negative autoregulatory feedback loop within the core clock. These novel connections between the archetypal loops of the Arabidopsis clock represent a significant advance toward defining the molecular dynamics underlying the circadian network in plants and provide the first mechanistic insight into the molecular function of the previously orphan clock factor LUX. PMID- 21236674 TI - View-based encoding of actions in mirror neurons of area f5 in macaque premotor cortex. AB - Converging experimental evidence indicates that mirror neurons in the monkey premotor area F5 encode the goals of observed motor acts [1-3]. However, it is unknown whether they also contribute to encoding the perspective from which the motor acts of others are seen. In order to address this issue, we recorded the visual responses of mirror neurons of monkey area F5 by using a novel experimental paradigm based on the presentation of movies showing grasping motor acts from different visual perspectives. We found that the majority of the tested mirror neurons (74%) exhibited view-dependent activity with responses tuned to specific points of view. A minority of the tested mirror neurons (26%) exhibited view-independent responses. We conclude that view-independent mirror neurons encode action goals irrespective of the details of the observed motor acts, whereas the view-dependent ones might either form an intermediate step in the formation of view independence or contribute to a modulation of view-dependent representations in higher-level visual areas, potentially linking the goals of observed motor acts with their pictorial aspects. PMID- 21236675 TI - Temporal repression of core circadian genes is mediated through EARLY FLOWERING 3 in Arabidopsis. AB - The circadian clock provides robust, ~24 hr biological rhythms throughout the eukaryotes. The clock gene circuit in plants comprises interlocking transcriptional feedback loops, reviewed in [1], whereby the morning-expressed transcription factors CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) repress the expression of evening genes, notably TIMING OF CAB EXPRESSION 1 (TOC1). EARLY FLOWERING 3 (ELF3) has been implicated as a repressor of light signaling to the clock [2, 3] and, paradoxically, as an activator of the light-induced genes CCA1 and LHY [4, 5]. We use cca1-11 lhy-21 elf3-4 plants to separate the repressive function of ELF3 from its downstream targets CCA1 and LHY. We further demonstrate that ELF3 associates physically with the promoter of PSEUDO-RESPONSE REGULATOR 9 (PRR9), a repressor of CCA1 and LHY expression, in a time-dependent fashion. The repressive function of ELF3 is thus consistent with indirect activation of LHY and CCA1, in a double-negative connection via a direct ELF3 target, PRR9. This mechanism reconciles the functions of ELF3 in the clock network during the night and points to further effects of ELF3 during the day. PMID- 21236676 TI - Regulation of stereocilia length by myosin XVa and whirlin depends on the actin regulatory protein Eps8. AB - Myosin XVa (MyoXVa) and its cargo whirlin are implicated in deafness and vestibular dysfunction and have been shown to localize at stereocilia tips and to be essential for the elongation of these actin protrusions [1-4]. Given that whirlin has no known actin-regulatory activity, it remains unclear how these proteins work together to influence stereocilia length. Here we show that the actin-regulatory protein Eps8 [5] interacts with MyoXVa and that mice lacking Eps8 show short stereocilia compared to MyoXVa- and whirlin-deficient mice. We show that Eps8 fails to accumulate at the tips of stereocilia in the absence of MyoXVa, that overexpression of MyoXVa results in both elongation of stereocilia and increased accumulation of Eps8 at stereocilia tips, and that the exogenous expression of MyoXVa in MyoXVa-deficient hair cells rescues Eps8 tip localization. We find that Eps8 also interacts with whirlin and that the expression of both Eps8 and MyoXVa at stereocilia tips is reduced in whirlin deficient mice. We conclude that MyoXVa, whirlin, and Eps8 are integral components of the stereocilia tip complex, where Eps8 is a central actin regulatory element for elongation of the stereocilia actin core. PMID- 21236677 TI - Opsin is a phospholipid flippase. AB - Polar lipids must flip-flop rapidly across biological membranes to sustain cellular life [1, 2], but flipping is energetically costly [3] and its intrinsic rate is low. To overcome this problem, cells have membrane proteins that function as lipid transporters (flippases) to accelerate flipping to a physiologically relevant rate. Flippases that operate at the plasma membrane of eukaryotes, coupling ATP hydrolysis to unidirectional lipid flipping, have been defined at a molecular level [2]. On the other hand, ATP-independent bidirectional flippases that translocate lipids in biogenic compartments, e.g., the endoplasmic reticulum, and specialized membranes, e.g., photoreceptor discs [4, 5], have not been identified even though their activity has been recognized for more than 30 years [1]. Here, we demonstrate that opsin is the ATP-independent phospholipid flippase of photoreceptor discs. We show that reconstitution of opsin into large unilamellar vesicles promotes rapid (tau<10 s) flipping of phospholipid probes across the vesicle membrane. This is the first molecular identification of an ATP independent phospholipid flippase in any system. It reveals an unexpected activity for opsin and, in conjunction with recently available structural information on this G protein-coupled receptor [6, 7], significantly advances our understanding of the mechanism of ATP-independent lipid flip-flop. PMID- 21236678 TI - Transcriptional profiling identifies TNS4 function in epithelial tubulogenesis. AB - Hepatocyte growth factor (HGF) plays central roles in tubulogenesis and metastasis [1-4]. HGF treatment of Madin-Darby canine kidney (MDCK) cells grown as cysts in three-dimensional culture induces tubulogenesis [5, 6], which like most tubulogenic processes proceeds through distinct intermediate phases. Identification of genes associated with these phases is central to understanding the molecular mechanisms of tubulogensis; however, because of inefficient, asynchronous tubule formation, isolating such genes has been unfeasible. Here we developed a synchronous, efficient tubulogenesis system and used time-course transcriptional profiling to identify genes temporally regulated in developmental intermediates. Knockdown (KD) of tensin 4 (TNS4), a particularly highly upregulated gene, leads to a decrease in formation of extensions and tubules, two sequential intermediates in tubulogenesis. Exogenous expression of TNS4 marks invasive cells in an epithelial sheet. A mutation in the SH2 domain of TNS4 prevents the transition from extension formation to invasive migration during tubule formation and leads to increased basal activation of STAT3. Exogenous expression of a constitutively active STAT3 mimics the defect by the mutation. Our study highlights the role of the TNS4-STAT3 axis in epithelial sheet invasion and tubulogenesis. PMID- 21236679 TI - Regeneration in plants and animals: dedifferentiation, transdifferentiation, or just differentiation? AB - The textbooks and literature of plant biology indicate that plant cells are totipotent, and that regeneration occurs via dedifferentiation, by which the cell and its descendents recapitulate earlier stages of development. However, recent work on the generation of callus, a presumed undifferentiated or dedifferentiated and disorganized cellular mass, indicates that the cells of callus are neither, and that callus forms predominantly from a pre-existing population of stem cells. Recent work in animal regeneration, for example in salamander limbs, also indicates that previous assumptions about the extent of dedifferentiation and pluripotency in animals are in need of critical reassessment. We review here some of these data, compare plant and animal regeneration, and argue that the importance of dedifferentiation and plasticity in regenerating systems is due for reevaluation. PMID- 21236680 TI - The justification for recombinant human bone morphogenetic protein-2 use in one- or two-level lumbar spine interbody fusions. PMID- 21236681 TI - Posterior reversible encephalopathy syndrome. AB - Posterior reversible encephalopathy syndrome (PRES) is a clinico neuroradiological entity with typical symptoms and symmetric high-signal intensity lesions in the bilateral parieto-occipital lobes on T2-weighted or fluid-attenuated inversion recovery (FLAIR) MRI. We described three patients with PRES of varied etiologies. Patient 1 was a young man with severe hypertension who presented with headache and visual disturbance. Patient 2 had leukemia and was receiving umbilical cord blood cell transplantation with immunosuppressant, and developed PRES with convulsions. Patient 3 was a pregnant woman with renal failure, who repeatedly developed PRES with convulsions. FLAIR and apparent diffusion coefficient mapping were useful in detecting PRES lesions in our patients, although diffusion-weighted imaging and CT scans had limited use in the diagnosis. Adequate and prompt treatment with antihypertensive medication immediately ameliorated the symptoms, with improvement of abnormal MRI findings. In previous reports, delayed diagnosis might have affected the prognosis. Further work on the clinical manifestations of PRES and its therapy is required. PMID- 21236682 TI - Extra-axial ependymoma mimicking a parasagittal meningioma. AB - Supratentorial ependymomas are more often found in adults than in children and are usually intra-axial. We report an extra-axial supratentorial ependymoma which mimicked the presentation of a parasagittal meningioma. The diagnosis and management of this unusual tumor is detailed. PMID- 21236683 TI - Symptom onset of spinocerebellar ataxia type 10 in pregnancy and puerperium. AB - Spinocerebellar ataxia type 10 is an autosomal dominant neurodegenerative disorder. It was initially described in Mexican families presenting with ataxia and epilepsy, with or without polyneuropathy, pyramidal signs and cognitive symptoms. The authors report three patients from the same family who were asymptomatic until gestation and puerperium, when they developed symptoms and signs suggestive of the syndrome. Genetic diagnosis was made in the three patients. The authors hypothesize that hormonal changes are likely to influence the manifestation of the condition. PMID- 21236684 TI - Persistent deficits of visual recall in Kleine-Levin syndrome. AB - Kleine-Levin syndrome (KLS) is commonly described as a self-limiting disorder exhibiting episodes of hypersomnia and psychiatric symptoms but without any enduring disabilities. Recently, some authors have reported persistent or even progressive memory deficits associated with the disorder. Nevertheless, literature about cognitive disturbances in KLS is rare. Our report describes a patient with deficits of visual and verbal recall after remission of an episode, as well as selective deficits of visual recall 6 months later. Neuropsychological testing is necessary in all patients with KLS to further characterize the profile and impact of associated cognitive deficits. PMID- 21236685 TI - Intraparenchymal temporal neurenteric cyst. AB - A 41-year-old male presented with a rare temporal intraparenchymal neurenteric cyst. A definitive preoperative diagnosis was not possible based upon the neuroradiological features. A complete excision of the cyst was achieved. Histopathology confirmed the diagnosis of a neurenteric cyst, an endodermally derived lesion of the central nervous system. PMID- 21236686 TI - Comment on "Single versus double burr hole drainage of chronic subdural hematomas". PMID- 21236687 TI - Aminopyridinecarboxamide-based inhaled IKK-2 inhibitors for asthma and COPD: Structure-activity relationship. AB - Installation of sites for metabolism in the lead compound PHA-767408 was the key focus of the IKK-2 inhaled program. This paper reports our efforts to identify a novel series of aminopyridinecarboxamide-based IKK-2 inhibitors, which display low nanomolar potency against IKK-2 with long duration of action (DOA), and metabolically labile to phase I and/or phase II metabolizing enzymes with potential capability for multiple routes of clearance. Several compounds have demonstrated their potential usefulness in the treatment of asthma and chronic obstructive pulmonary disease (COPD). PMID- 21236688 TI - Synthesis, physical-chemical characterisation and biological evaluation of novel 2-amido-3-hydroxypyridin-4(1H)-ones: Iron chelators with the potential for treating Alzheimer's disease. AB - A novel class of 2-amido-3-hydroxypyridin-4-one iron chelators is described. These compounds have been designed to behave as suitable molecular probes which will improve our knowledge of the role of iron in neurodegenerative conditions. Neurodegenerative disorders, such as Alzheimer's disease (AD) and Parkinson disease (PD), can be considered as diverse pathological conditions sharing critical metabolic processes such as protein aggregation and oxidative stress. Interestingly, both these metabolic alterations seem to be associated with the involvement of metal ions, including iron. Iron chelation is therefore a potential therapeutic approach. The physico-chemical (pK(a), pFe(3+) and logP) and biological properties (inhibition of iron-containing enzymes) of these chelators have been investigated in order to obtain a suitable profile for the treatment of neurodegenerative conditions. Studies with neuronal cell cultures confirm that the new iron chelators are neuroprotective against beta-amyloid induced toxicity. PMID- 21236689 TI - Direct determination of half-life of (214)Pb by gamma spectrometry and comparison with previous indirect measurements. AB - A new value of half-life of (214)Pb was determined using (214)Pb-enriched radioactive sources made of polyurethane foam filters treated with Rn-enriched water. Measurements based on cumulative gamma rays countings yielded a value of 27.06 (7) min. This result is 0.17 min longer than the most recent value measured by indirect methods reported in the scientific literature (Martz et al., 1991). The difference between these two measurements is caused by beta recoil whose effects in glass substrates had been neglected. PMID- 21236690 TI - The biological characterization of (99m)Tc-BnAO-NI as a SPECT probe for imaging hypoxia in a sarcoma-bearing mouse model. AB - OBJECTIVES: Tumor growth beyond the region where vascular oxygen can reach creates a hypoxic domain. In this study, BnAO, a ligand that had been labeled with (99m)Tc-pertechnetate for hypoxia imaging, was conjugated with 2 nitroimidazole to give 3,3,10,10-tetramethyl-1-(2-nitro-1H-imidazo-1-y1)-4,9 diazadodecane-2,11- dionedioxime (BnAO-NI) as a potential ligand for hypoxia detection. Pentoxifylline is a peripheral vasodilator and has been used as a radiosensitizer in tumor radiotherapy. (99m)Tc-BnAO-NI/SPECT was applied to noninvasively assess the pharmacological effect of pentoxifylline in reducing tumor hypoxia in vivo. METHODS: BnAO-NI was synthesized and formulated with methylene diphosphonate (MDP), stannous chloride and carbonate buffer to afford kits. After mixing with (99m)Tc-pertechnetate, (99m)Tc-BnAO-NI injection can be readily prepared. The partition coefficient, radiochemical purity and in vitro stability were determined. Cellular uptake of radiotracers in KHT cells under hypoxia was conducted in a CO(2) incubator at 37 degrees C under hypoxia or normoxia. A biodistribution study after intravenous injection of (99m)Tc-BnAO-NI in KHT sarcoma-implanted C3H mice was performed. The effect of pentoxifylline (100 mg/kg) on reducing tumor hypoxia was also studied. RESULTS: The radiochemical purity (RCP) of the (99m)Tc-BnAO-NI preparation was greater than 96% and stable at ambient temperature for 24h (RCP>90%). The accumulation of (99m)Tc-BnAO-NI and (99m)Tc-BnAO in KHT cells under hypoxia were 3.57 and 4.13 fold higher than those under normoxic environment, indicating unambiguous oxygen dependent uptakes of these two probes. The distribution of (99m)Tc-BnAO-NI in KHT sarcoma-bearing mice revealed rapid clearance from the blood circulation. The tumor uptake peaked at 2h post-injection (0.32 +/- 0.05%ID/g) with tumor-to-blood and tumor-to-muscle ratios of 10.32 and 3.96, respectively. The effect of pentoxifylline on the tumor blood perfusion was obvious. The tumor-to-muscle ratios at 2h post-injection of (99m)Tc-BnAO-NI with and without pentoxifylline pretreatment were 1.67 +/- 0.38 and 2.59 +/- 0.25, respectively (p = 0.025, n = 3). CONCLUSION: This study demonstrates that (99m)Tc-BnAO-NI is a hypoxia sensitive radio probe for monitoring hypoxic regions in a malignant neoplasm. However, (99m)Tc-BnAO-NI, though with higher lipophilicity than (99m)Tc-BnAO, did not achieve better specific accumulation in hypoxic tissues. (99m)Tc-BnAO NI/SPECT could be applied in clinics to noninvasively evaluate the feasibility of using pentoxifylline as a radiosensitizer by reducing tumor hypoxia in vivo. PMID- 21236691 TI - The root-hairless barley mutant brb used as model for assessment of role of root hairs in iron accumulation. AB - Main components of Strategy II mechanism for Fe uptake are secretion of chelating compounds, phytosiderophores, and specific uptake of Fe(III)-phytosiderophores complex. Since the amount of phytosiderophores secreted correlates positively with plant ability to cope with Fe shortage, a role of root hairs in enhancing root capability to store phytosiderophores under Fe stress might be envisaged. In this study the root-hairless mutant of barley (Hordeum vulgare L.) brb (bald root barley) and the wild-type genotype (cv. Pallas) were compared with respect to their capacity to respond to Fe shortage in nutrient solution. Plants were grown with Fe(III)-EDTA at 0, 0.02 and 0.08 mM, in order to reproduce severe or moderate Fe deficiency, and adequate Fe nutritional status, respectively. Analysis was performed after 11 and 14 days considering leaf Fe content, phytosiderophores release and accumulation in root tips, and 59Fe uptake. Biomass accumulation and chlorophyll content were not reduced in mutant plants as compared to wild-type ones; leaf Fe content was similar in both genotypes after 14 days of growth. Accumulation and release of phytosiderophores showed a similar trend in both genotypes when subjected to Fe limitation. Furthermore, no significant difference between the two genotypes was observed when 59Fe uptake was measured. Results seem to support the idea that the presence of root hairs and their increased production in response to low-Fe availability, while causing major modifications of root geometry, did not necessarily lead neither to an effect on growth nor on Fe uptake and accumulation in barley plants. PMID- 21236692 TI - The functions of an apple cytosolic malate dehydrogenase gene in growth and tolerance to cold and salt stresses. AB - It is well-known that cytosolic NAD-dependent malate dehydrogenase (cyMDH; l malate:NAD-oxidoreductase; EC 1.1.1.37) is an enzyme crucial for malic acid synthesis in the cytosol. Nothing is known about cyMDH in growth and stress tolerance. Here we characterised the role of the apple cyMDH gene (MdcyMDH, GenBank ID: DQ221207) in growth and tolerance to cold and salt stresses. MdcyMDH transcripts were highly accumulated in vigorously growing apple tissues, organs and suspension cells. In addition, MdcyMDH was sensitive to cold and salt stresses. MdcyMDH overexpression favourably contributed to cell and plant growth and conferred stress tolerance both in the apple callus and tomato. Taken together, our results indicated that MdcyMDH is involved in plant and cell growth as well as the tolerance to cold and salt stresses. PMID- 21236693 TI - Aortic root enlargement does not increase the surgical risk and short-term patient outcome? AB - OBJECTIVE: To analyze the short-term outcome of aortic root enlargement (ARE) using death and adverse events as end points. METHODS: From January 1999 through December 2009, 3339 patients were subjected to aortic valve replacement (AVR). A total of 678 were considered to have small aortic roots (SARs) in which an aortic prosthesis size 21 mm or smaller was implanted. ARE using a bovine pericardial patch was performed in another 218 patients, who constitute the study population. This comprised 174 females (79.8%); the mean age was 69.4 +/- 13.4 years (8-87, median 74 years), the body surface area (BSA) was 1.59 +/- 0.15m2 and the body mass index (BMI) 25.77 +/- 3.16 k gm-2, and 192 (88.5%) were in New York Heart Association (NYHA) II-III. Preoperative echocardiography revealed significant left ventricular (LV) dysfunction in 17 patients (8%), a mean aortic valve area of 0.57 +/- 0.27 cm2, and a mean gradient of 62.51 +/- 21.25 mm Hg. A septal myectomy was performed in 129 subjects (59.2%), and other associated procedures, mostly coronary artery bypass grafting (CABG), in 60 (27.5%). Bioprostheses were implanted in 161 patients (73.9%). The mean valve size was 21.9 +/- 1.0 (21-25). The mean extracorporeal circulation (ECC) and aortic clamping times were 82.8 +/- 19.8 min and 56.8 +/- 12.5 min, respectively. RESULTS: Hospital mortality was 0.9% (n=2) for ARE as compared with 0.6% (n=4) for the SAR group (p=0.8). Inotropic support was required in only 13 (5.9%) patients and the first 24-h chest drainage was 336.2 +/- 202 ml. Other complications included pacemaker implantation (7.8%), acute renal failure (10.6%), respiratory (4.1%), and CVA/transient ischemic attack (CVA/TIA) (3.2%). Postoperative echocardiographic evaluation showed a significant decrease in peak and mean aortic gradients (23.7 +/- 9.5 and 14 +/- 6.2 mm Hg, respectively, p<0.0001). The mean indexed effective orifice area (iEOA) was 0.92 +/- 0.01 cm2 m-2 (vs 0.84+/-0.07 cm2 m-2, in SAR, p<0.0001). Only 11% of patients (n=24) with ARE exhibited moderate patient prosthesis mismatch (PPM) and none had severe PPM. Mean hospital stay was 9.7 +/- 9.29 days (median 7 days). CONCLUSIONS: With the growing number of patients with degenerative aortic valve pathology, mainly an older population, sometimes with calcified and fragile aortic wall, the issue of dealing with an SAR poses the dilemma of whether to implant a smaller prosthesis and admit some degree of PPM, or to enlarge the aortic root. This study demonstrates that the latter can be done in a safe and reproducible manner. PMID- 21236694 TI - Clinical value of ESTS guidelines on preoperative lymph node staging for NSCLC. PMID- 21236695 TI - Aortic valve repair with ascending aortic aneurysms: associated lesions and adjunctive techniques. AB - OBJECTIVE: Patients with supracoronary ascending aortic aneurysms can have aortic insufficiency (AI) due to dilatation of the sinotubular junction and/or associated cusp pathology. The incidence and types of cusp lesions as well as the effect of AI severity and cusp repair techniques on outcome in this patient population is not well defined. METHODS: Since 1996, 55 patients (mean age: 65 +/ 13 years, 17 bicuspid valves) presented with supracoronary ascending aortic aneurysms and AI that was mild/moderate in 27 (49%) and severe in 28 (51%). Associated pathology included cusp prolapse in 18 (33%), cusp restriction in nine (16%) and both in three (5%). All patients underwent aortic replacement and remodeling of the sinotubular junction. Adjunctive techniques included subcommissural annuloplasty in 38(69%) and cusp repair in 28 (51%). RESULTS: AI severity was not significantly associated with the presence of cusp pathology (p=0.35). Cusp disease was present in 100% of bicuspid aortic valves compared with only 34% of trileaflet valves (p<0.001). There was no hospital mortality and overall survival was 94 +/- 4% and 75 +/- 10%, respectively, at 5 and 7 years. Freedom from re-operation was 100% at 7 years and freedom from recurrent AI (>2+) was 87 +/- 7% at 5 years. Neither the presence of preoperative severe AI, nor the need for cusp repair was predictive of late outcome. CONCLUSIONS: Cusp pathology is frequently encountered in patients with ascending aortic dilatation and AI. Severe AI is not a contraindication to valve-preserving surgery, but careful identification and repair of cusp pathology, in addition to sinotubular junction reduction, is critical for durable, long-term outcome. PMID- 21236696 TI - A 10-year angiographic follow-up of competitive flow in sequential and composite arterial grafts. AB - OBJECTIVE: Physiological reaction to competitive flow is considered as the primary mechanism of arterial graft occlusion. Reopening of graft lumen had been also reported, but details remain unknown. We sought to delineate the effect of management of the moderately stenotic targets on the occurrence of competitive flow and clinical results. METHODS: Clinical records and angiograms of 3263 bypass grafts in 852 patients, who underwent off-pump coronary revascularization using the internal thoracic artery (ITA) and radial artery without aortic manipulation since 2000, were examined. Dominant flow direction was graded as antegrade, competitive, and no flow (occlusion). Late angiography was performed in 157 patients with 561 bypass grafts for clinical reasons. The follow-up period was 55.5 +/- 31.1 months. RESULTS: The early graft patency rate was 98.0% (3197/3263). The rate of antegrade flow was 91.5% (2986/3263), while competitive flow was detected in 6.5% (211/3263). The actuarial patency rates of bypass grafts with antegrade flow were significantly higher than those with competitive flow (87.9% at 5 years and 71.3% at 8 years, vs 25.8% at 5 years and 9.2% at 8 years, p<0.0001). In the univariate and multivariate analyses for 852 patients, territory of right coronary artery (odds ratio (OR)=2.20, p=0.0002), composite radial artery (OR=1.90, p=0.03), and the distal end of the graft (OR=2.90, p=0.0003), were identified as the significant predictors of competitive flow from the target with 51-75% stenosis. Individual grafting inversely correlated with occurrence of competitive flow (OR=0.48, p=0.04). Reopening of the graft lumen associated with progression of native stenosis was not observed in these patients. CONCLUSIONS: Competitive flow can be efficiently avoided by appropriate graft arrangement and patients' selection. Selection of the target of the graft end would be crucial to achieve antegrade bypass flow and long-term patency of entire sequential bypass grafts. For the composite graft, functional recovery of the occluded graft would be extremely rare. PMID- 21236697 TI - The role of toll-like receptor mediated signalling in the pathogenesis of multiple myeloma. AB - Toll-like receptors are critical structures in sensing the invading pathogens via conserved moieties termed pathogen associated molecular patterns and in directing the innate and adaptive immune responses. Studies have shown that Toll-like receptors are not limited to normal immune cells but are expressed on tumour cells as well, including those of lymphoid neoplasms particularly B-cell malignancies, multiple myeloma and chronic lymphocytic leukemia. Neoplastic plasma cells in multiple myeloma usually show a different pattern of Toll-like receptor expression compared to normal B cells. These receptors on multiple myeloma cells, have been indicated to have a role in their proliferation, differentiation and survival, probably through induction of autocrine IL-6 secretion, and in their immunomodulatory functions. Moreover, it is speculated that these molecules may contribute to osteolytic lesions through activation of osteoclasts, and to angiogenesis through induction of pro-angiogenic factors. Knowledge on Toll-like receptor signalling in the biology of malignant plasma cells or their cellular microenvironment may give new insights into pathogenesis of multiple myeloma and may open new avenues for the therapy of this disease. PMID- 21236698 TI - Driving simulation for evaluation and rehabilitation of driving after stroke. AB - Driving is an important activity of daily living. Loss of driving privileges can lead to depression, decreased access to medical care, and increased healthcare costs. The ability to drive is often affected after stroke. In approximately 30% of stroke survivors, it is clear from the onset that driving will no longer be possible. Approximately 33% of survivors will be able to return to driving with little or no retraining, and 35% will require driving-related rehabilitation before they can resume safe driving again. The ability to drive is not routinely evaluated after stroke, and there is no established rehabilitation program for poststroke driving. When driving evaluation does occur, it is not always clear which tests are the most salient for accurately assessing poststroke driving ability. Investigators have examined the efficacy of various methodologies to predict driving performance after stroke and have found mixed results, with each method having unique weaknesses, including poor predictive ability, poor face validity, poor sensitivity or specificity, and limited reliability. Here we review common models of driving to gain insight into why single-construct visual or cognitive off-road measures are inadequate for evaluating driving, a complex and dynamic activity that involves timely interaction of multiple motor, visual, cognitive, and perceptual skills. We also examine the potential for driving simulators to overcome the problems currently faced in the evaluation and rehabilitation of driving after stroke. Finally, we offer suggestions for the future direction of simulator-based poststroke driving evaluation and training. PMID- 21236700 TI - Discriminant analysis prediction of the need for ventriculoperitoneal shunt after subarachnoid hemorrhage. AB - Shunt operations have conventionally been performed to deal with normal-pressure hydrocephalus after subarachnoid hemorrhage. The indication and timing of shunt operations are often based on clinical symptoms and head computed tomography findings, and the early identification of the need for such surgery would be advantageous. The present study examined whether this need could be predicted solely on the basis of data collected on patient admission. A total of 120 consecutive patients with subarachnoid hemorrhage who underwent radical surgery for aneurysm were analyzed for potential risk factors for the onset of hydrocephalus that could be investigated on admission. Statistically significant differences between those patients who required a shunt operation and those who did not were found in terms of age, Hunt and Kosnik grade on first visit, Glasgow Coma Scale score on first visit, Fisher group, presence/absence of hydrocephalus, presence/absence of intraventricular hemorrhage, and transverse dimension of the third ventricle and distance between lateral ventricles measured by head computed tomography scan on first visit. Discriminant analysis performed on these 8 variables yielded a single discriminant function with a high sensitivity of 85.3% and a high specificity of 87.2%. Our findings indicate that the discriminant function is capable of predicting the need for the shunt operation soon after patient admission and can shorten the waiting time for the operation, and hence can be expected to contribute to decreasing the length of hospital stay in these patients. PMID- 21236699 TI - Statins, risk of dementia, and cognitive function: secondary analysis of the ginkgo evaluation of memory study. AB - BACKGROUND: Lipid-lowering medications (LLMs) and especially statin drugs can delay cognitive decline and dementia onset in individuals with and without mild cognitive impairment (MCI) at baseline. METHODS: A longitudinal, observational study was conducted of 3069 cognitively healthy elderly patients (>=75 years of age) who were enrolled in the Ginkgo Evaluation of Memory Study. The primary outcome measure was the time to adjudicated all-cause dementia and Alzheimer dementia (AD). The secondary outcome measure was the change in global cognitive function over time measured by scores from the Modified Mini-Mental State Exam (3MSE) and the cognitive subscale of the AD Assessment Scale (ADAS-Cog). RESULTS: Among participants without MCI at baseline, the current use of statins was consistently associated with a reduced risk of all-cause dementia (hazard ratio [HR], 0.79; 95% confidence interval [95% CI], 0.65-0.96; P = .021) and AD (HR, 0.57; 95% CI, 0.39-0.85; P = .005). In participants who initiated statin therapy, lipophilic statins tended to reduce dementia risk more than nonlipophilic agents. In contrast, there was no significant association between LLM use (including statins), dementia onset, or cognitive decline in individuals with baseline MCI. However, in individuals without MCI at baseline, there was a trend for a neuroprotective effect of statins on cognitive decline. CONCLUSIONS: Statins may slow the rate of cognitive decline and delay the onset of AD and all-cause dementia in cognitively healthy elderly individuals, whereas individuals with MCI may not have comparable cognitive protection from these agents. However, the results from this observational study need to be interpreted with caution and will require confirmation by randomized clinical trials stratifying treatment groups based on MCI status at baseline. PMID- 21236701 TI - Clinical outcomes among stroke patients receiving tissue plasminogen activator therapy beyond the 3-hour time window. AB - BACKGROUND: Tissue plasminogen activator therapy (t-PA) is associated with improved neurologic outcomes and reduced disability from ischemic stroke. The current guidelines stipulate that patients receive t-PA within 3 hours of symptom onset. However, actual practice patterns vary, and little is known about patient outcomes when t-PA is received outside of the recommended time window. METHODS: We examined mean length of hospital stay, t-PA-related complications, and in hospital death by time of t-PA administration in North Carolina Stroke Care Collaborative (NCSCC) patients. The NCSCC includes 53 hospitals that enroll patients presenting with stroke-like symptoms. Of 40,907 patients enrolled between January 2005 and February 2010, 1070 (2.6%) received t-PA. Of these, 88.2% received t-PA within 3 hours of symptom onset ("early") and 30.3% received t-PA between 3 and 6 hours after symptom onset ("late"). RESULTS: Unadjusted mean length of stay (days) was longer among early patients (5.0 days; 95% confidence interval [CI], 4.7-5.3) than late patients (3.6 days; 95% CI, 3.1-4.2). t-PA related complications were similar among early (7.0%; 55/781) and late patients (6.7%; 7/102; P = .89). The proportion of in-hospital deaths was similar among late (10.5%) and early patients (12.0%). We used multivariable logistic regression to estimate odds ratios (ORs) and 95% CIs for the associations between late t-PA status and patient outcomes. CONCLUSIONS: In models controlling for age, race, sex, arrival mode, and ambulatory status on admission, late t-PA was not associated with increased odds of complications or in-hospital deaths (OR, 0.89; 95% CI, 0.49-1.62). The risks and benefits of expansion of the t-PA time window in stroke patients merit further investigation. PMID- 21236702 TI - Prevalence and association between risk factors, stroke subtypes, and abnormal ankle brachial index in acute ischemic stroke. AB - BACKGROUND: Abnormal ankle brachial index (ABI) identifies a stroke subgroup with high risk of subsequent stroke and other vascular events. There are few data regarding the prevalence of abnormal ABI in ischemic stroke in Asian countries. METHODS: We evaluated the prevalence of abnormal ABI in 747 Thai patients with ischemic stroke or transient ischemic attack and assessed the correlation of abnormal ABI with stroke risk factors and stroke subtypes. RESULTS: The prevalence of abnormal ABI (<=0.9) in ischemic stroke patients was 18.1%. Abnormal ABI in ischemic stroke patients was significantly correlated with female gender (odds ratio [OR], 1.61; confidence interval [CI], 1.09-2.40; P = .017), age >= 60 years (OR, 3.54; CI, 2.14-5.85; P < .001), and previous ischemic events, including coronary artery disease (OR, 2.55; CI, 1.47-4.43; P = .001), cerebrovascular disease (OR, 2.15; CI, 1.37-3.55; P = .002), and atrial fibrillation (OR, 1.71; CI, 1.03-2.82; P = .036). There was a significant difference in the prevalence of abnormal ABI among stroke subtypes (P < .001), which tended to be more frequent in those with large artery disease (20.4%), cardioembolic stroke (29.2%), and undetermined etiology (20.6%). CONCLUSIONS: An ABI examination should be considered in patients with ischemic stroke to facilitate the early detection and treatment of asymptomatic peripheral arterial disease and identification of excess risk for subsequent stroke or other vascular events. PMID- 21236703 TI - Gastrointestinal adverse effects of antiepileptic drugs in intractable epileptic patients. AB - Gastrointestinal (GI) discomforts are among the most common side effects of antiepileptic drugs (AEDs) that might lead to discontinuation or irregular consumption of the drugs. This study was conducted to evaluate the frequency of GI side effects of different AEDs in intractable epileptic patients treated with single or multiple drugs. GI discomfort of 100 epileptic patients (aged 35-76 years) treated with one or multiple AEDs was assessed. Seventy six patients (76%) were treated with two or more AEDs, and 24 (24%) were on monotherapy. The most common prescribed drug for monotherapy was carbamazepine and the most frequent combination was phenytoin and carbamazepine. Patients were suffering from different GI side effects including heartburn (34.6%), nausea (33.7%), constipation (26%), vomiting (22.1%), diarrhea (21.2%) and dysphagia (19.2%). Nausea and vomiting were significantly higher in patients receiving monotherapy with carbamazepine and valproic acid, respectively. When phenytoin, gabapentine, or valproic acid was added to the other AEDs, the risk of the occurrence of diarrhea, dysphagia, or heartburn was significantly increased, respectively. Addition of gabapentine to the other AEDs in multiple drug therapy was accompanied with the highest frequency of GI complications. This study indicated that GI side effects, which can affect drug absorption and utilization, were common in intractable epileptic patients with long-term AEDs treatment. This may influence the efficacy of the therapy with AEDs and enhance the probability of further attacks. PMID- 21236704 TI - Multifactorial induction of an orphan PKS-NRPS gene cluster in Aspergillus terreus. AB - Mining the genome of the pathogenic fungus Aspergillus terreus revealed the presence of an orphan polyketide-nonribosomal-peptide synthetase (PKS-NRPS) gene cluster. Induced expression of the transcriptional activator gene adjacent to the PKS-NRPS gene was not sufficient for the activation of the silent pathway. Monitoring gene expression, metabolic profiling, and using a lacZ reporter strain allowed for the systematic investigation of physiological conditions that eventually led to the discovery of isoflavipucine and dihydroisoflavipucine. Phytotoxin formation is only activated in the presence of certain amino acids, stimulated at alkaline pH, but strictly repressed in the presence of glucose. Global carbon catabolite repression by CreA cannot be abolished by positive acting factors such as PacC and overrides the pathway activator. Gene inactivation and stable isotope labeling experiments unveiled the molecular basis for flavipucine/fruit rot toxin biosynthesis. PMID- 21236705 TI - Signaling via the RIP2 adaptor protein in central nervous system-infiltrating dendritic cells promotes inflammation and autoimmunity. AB - Peripheral peptidolgycan (PGN) is present within antigen-presenting cells in the central nervous system (CNS) of multiple sclerosis (MS) patients, possibly playing a role in neuroinflammation. Accordingly, PGN is linked with disease progression in the animal model of MS, experimental autoimmune encephalomyelitis (EAE), but the role of specific PGN-sensing proteins is unknown. Here we report that the progression of EAE was dependent on the intracellular PGN sensors NOD1 and NOD2 and their common downstream adaptor molecule, receptor interacting protein 2 (RIP2; also known as RIPK2 and RICK). We found that RIP2, but not toll like receptor 2 (TLR2), played a critical role in the activation of CNS infiltrating dendritic cells. Our results suggest that PGN in the CNS is involved in the pathogenesis of EAE through the activation of infiltrating dendritic cells via NOD1-, NOD2-, and RIP2-mediated pathways. PMID- 21236706 TI - Posttranscriptional silencing of effector cytokine mRNA underlies the anergic phenotype of self-reactive T cells. AB - Self-reactive T cell clones that escape negative selection are either deleted or rendered functionally unresponsive (anergic), thus preventing them from propagating host tissue damage. By using an in vivo model, we investigated molecular mechanisms for T cell tolerance, finding that despite a characteristic inability to generate effector cytokine proteins, self-reactive T cells express large amounts of cytokine mRNAs. This disconnect between cytokine message and protein was not observed in T cells mounting productive responses to foreign antigens but, instead, was seen only in those responding to self, where the block in protein translation was shown to involve conserved AU-rich elements within cytokine 3'UTRs. These studies reveal that translation of abundant cytokine mRNAs is limited in self-reactive T cells and, thus, identify posttranscriptional silencing of antigen-driven gene expression as a key mechanism underlying the anergic phenotype of self-reactive T cells. PMID- 21236708 TI - Incidental visceral and renal artery stenosis in patients undergoing coronary angiography. AB - PURPOSE: The study aimed to examine the association between incidentally discovered mesenteric artery stenosis, renal artery stenosis (RAS) and coronary artery disease in patients undergoing coronary angiography. MATERIALS AND METHODS: We performed a prospective analysis of consecutive patients undergoing routine cardiac catheterisation. Abdominal aortograms in lateral and antero posterior view were obtained to assess arterial stenosis of the coeliac axis, superior mesenteric artery and renal arteries. Significant arterial stenosis was defined as a narrowing of at least 50% compared with the normal artery. Demographic data and cardiovascular risk factors were analysed. RESULTS: The prevalence of visceral artery stenosis (VAS) was 63/450 (14%) including 48/450 (10.6%) cases of coeliac axis stenosis and 15/450 (3.3%) cases of superior mesenteric artery stenosis. Female sex (p = 0.01), older age (p = 0.03) and the presence of coronary artery disease (p = 0.05) were significant predictors for the presence of VAS in univariate analysis. The determinants for VAS in multivariate analysis were female sex and three-vessel coronary artery disease, while two- and three-vessel coronary artery disease was significant for RAS. CONCLUSION: Screening for VAS and RAS in female patients older than 60 years with more than two diseased coronary segments could have a high diagnostic value. PMID- 21236707 TI - Abdominal aortic diameter and vascular atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. AB - OBJECTIVES: To gain insight into early mechanisms of aortic widening, we examined associations between the diameter of the abdominal aorta (AD) and cardiovascular disease (CVD) risk factors and biomarkers, as well as measures of subclinical atherosclerosis, in a multi-ethnic population. DESIGN: Cross-sectional cohort. METHODS: A total of 1926 participants (mean age 62, 50% women) underwent chest and abdomen scanning by computed tomography, ultrasound of the carotid arteries, and CVD risk factor assessment. AD was measured 5 cm above and at the bifurcation. RESULTS: In a model containing traditional CVD risk factors, biomarkers and ethnicity, only age (standardized beta = 0.97), male sex (beta = 1.88), body surface area (standardized beta = 0.92), current smoking (beta = 0.42), D-dimer levels (beta = 0.19) and hypertension (beta = 0.53) were independently and significantly associated with increasing AD (in mm) at the bifurcation; use of cholesterol-lowering medications predicted smaller AD (beta = -0.70) (P < 0.01 for all). These findings were similar for AD 5 cm above the bifurcation with one exception: compared to Caucasian-Americans, Americans of Chinese, African and Hispanic descent had significantly smaller AD 5 cm above the bifurcation (beta's = -0.59, -0.49, and -0.52, respectively, all P < 0.01), whereas AD at the bifurcation did not differ by ethnicity. Physical activity, alcohol consumption, diabetes and levels of IL-6, CRP and homocysteine were not independently associated with AD. Higher aortic and coronary artery calcium burden, but not common carotid artery intima-media thickness, were independently, but modestly (beta = 0.11 to 0.19), associated with larger AD. CONCLUSIONS: Incremental widening of the aortic diameter shared some, but not all, risk factors for occlusive vascular disease. PMID- 21236709 TI - Upregulated expression of Toll-like receptor 4 in peripheral blood of ischaemic stroke patients correlates with cyclooxygenase 2 expression. AB - OBJECTIVES: An inflammatory process following stroke in human brains and systemic inflammatory responses after stroke in humans have been reported by numerous investigators. The aim of the study was to investigate if genes involved in the cyclooxygenase 2 (COX-2) pathway are upregulated at peripheral level in patients after transient ischaemic attack (TIA) and stroke. DESIGN OF STUDY: Blood samples were obtained from two groups of patients undergoing carotid endarterectomy. The first group included 25 patients who presented TIA or ischaemic stroke. The second group included 35 patients who had an asymptomatic internal carotid artery stenosis. Total RNA was isolated and the expression of Toll-like Receptor 4 (TLR4), COX-2, membrane-associated Prostaglandin E synthase (mPGES-1), Prostaglandin E2 receptors (EP3 and EP4) was analysed by real time RT-PCR. RESULTS: Expression of COX-2 and TLR4 were significantly increased in symptomatic patients (p < 0.001). Correlation analysis showed that TLR4 expression significantly correlated with COX-2 expression (R = 0.65; p < 0.01) in ischaemic stroke patients. This correlation was not observed in TIA and asymptomatic patients. CONCLUSIONS: Our results suggest that the peripheral mechanism of inflammatory injury after stroke may be mediated by TLR4 through a COX-2 dependent pathway. PMID- 21236711 TI - Protein modeling and active site binding mode interactions of myrosinase-sinigrin in Brassica juncea--an in silico approach. AB - Myrosinase, the only known S-glycosidase, occurs particularly in Cruciferae family. It is responsible for the hydrolysis of glucosinolates and serves as a vital element of plant defense system. The biological and chemical properties of myrosinase catalyzed products of glucosinolates are well characterized. The myrosinase-protein-sequence of Brassica juncea was retrieved from NCBI database and its 3-D model was generated on the basis of crystal structure of 1MYR-A, 1E4M M and 1DWA-M chains of myrosinase from Sinapis alba by employing Modeller9v7 program. Homolog templates from S. alba exhibited 72% identity with target sequence. The model was optimized by using molecular dynamics (MD) approach together with simulated annealing (SA) methods in the same Modeller program, and eventually verified and validated on SAVES (Structure Analysis and Verification Server) and PROCHECK programs, respectively. Ramachandran plot obtained through PROCHECK program depicted that 99.8% of total residues were confined to the allowed region while only one residue (Thr92) was restrained to the disallowed region. Additionally, B. juncea myrosinase contains three disulphide bridges which were found to be conserved in S. alba homologs as well. Further, overlapping of B. juncea myrosinase with that of template protein 1MYR-A from S. alba stipulates the amino acid residues Arg115, Gln207, Thr210, Asn350, Tyr352 and Glu429 that constitute active site of the enzyme. Active site analysis also speculates the presence of a hydrophobic pocket in addition to seven N glycosylation sites. Docking studies of enzyme and substrate illuminate the interactions of various active site residues with diverse groups of sinigrin. Therefore, the present study furnishes the first significant, in silico insight into the 3-D structure, active site machinery, and enzyme-substrate interactions of B. juncea myrosinase. PMID- 21236710 TI - Transforming growth factor beta1 down-regulates Runx-2 and alkaline phosphatase activity of human dental pulp cells via ALK5/Smad2/3 signaling. AB - OBJECTIVE: Transforming growth factor beta1 (TGF-beta1) plays a role in repair and dentinogenesis in dental pulp. The purpose of this study was to study how TGF beta1 affects 2 differentiation markers, Runt-related transcription factor 2 (Runx-2) and ALP, in dental pulp cells. STUDY DESIGN: Primary-cultured human dental pulp cells were treated with TGF-beta1 with or without pretreatment and coincubation with 1,4-diamino-2,3-dicyano-1,4-bis(o-aminophenylmercapto)butadiene (U0126, a mitogen-induced extracellular kinase (MEK)/extracellular signal regulated kinase (ERK) inhibitor), Noggin (a bone morphogenetic protein inhibitor), or 4-(5-benzol[1,3]dioxol-5-yl-4-pyrldin-2-yl-1H-imidazol-2-yl) benzamide hydrate (SB431542, an activin receptor-like kinase (ALK) 5/Smad2/3 inhibitor). The differentiation status of pulp cells was evaluated by ALP staining and quantitative ALP activity assay. Changes in ALP and Runx-2 mRNA expression were determined by reverse-transcription polymerase chain reaction. RESULTS: Cells under the treatment of TGF-beta1 (5 and 10 ng/mL) showed a decrease in ALP activity and gene expression of ALP and Runx-2. Pretreatment by U0126 and Noggin was not effective to prevent the TGF-beta1-induced decline of ALP activity. Interestingly, SB431542 prevented the TGF-beta1-induced decline of ALP activity and ALP and Runx-2 gene expression. CONCLUSION: TGF-beta1 down regulates Runx-2 and ALP in human dental pulp cells via ALK5/Smad2/3 signaling. These events may play important roles at specific stages of pulpal repair and dentinogenesis. PMID- 21236712 TI - A WNK4 gene variant relates to osteoporosis and not to hypertension in the Portuguese population. AB - Germline mutations in the WNK4 gene originate Gordon syndrome or pseudohypoaldosteronism type II, a familial form of hypertension with hyperkalemia and hypercalciuria. In order to elucidate the contribution of WNK4 genetic variants to hypertension and/or osteoporosis, we analyzed 271 control individuals and a cohort of 448 hypertensive and 372 osteoporosis patients from the Portuguese population. Ten genetic variants were detected in 4.3% of the population under study, none of which revealed any significant association to the hypertension phenotype. In contrast, a rare missense alteration within exon 17 in a highly conserved arginine residue showed a possible tendency for association to the osteoporosis group. Our data suggest that WNK4 polymorphism rs56116165 is a rare allelic variant in a candidate gene with a biological function in renal calcium homeostasis that may contribute to a genetic predisposition to osteoporosis. PMID- 21236713 TI - GCKR mutations in Japanese families with clustered type 2 diabetes. AB - OBJECTIVE: The aim was to investigate the genetic background of familial clustering of type 2 diabetes. SUBJECTS AND METHODS: We recruited Japanese families with a 3-generation history of diabetes. Genome-wide linkage analysis was performed assuming an autosomal dominant model. Genes in the linkage region were computationally prioritized using Endeavour. We sequenced the candidate genes, and the frequencies of detected nucleotide changes were then examined in normoglycemic controls. RESULTS: To exclude known genetic factors, we sequenced 6 maturity onset diabetes of the young (MODY) genes in 10 familial cases. Because we detected a MODY3 mutation HNF1A R583G in one case, we excluded this case from further investigation. Linkage analysis revealed a significant linkage region on 2p25-22 (LOD score=3.47) for 4 families. The 23.6-Mb linkage region contained 106 genes. Those genes were scored by computational prioritization. Eleven genes, i.e., top 10% of 106 genes, were selected and considered primary candidates. Considering their functions, we eliminated 3 well characterized genes and finally sequenced 8 genes. GCKR ranked highly in the computational prioritization. Mutations (minor allele frequency less than 1%) in exons and the promoter of GCKR were found in index cases of the families (3 of 18 alleles) more frequently than in controls (0 of 36 alleles, P=0.033). In one pedigree with 9 affected members, the mutation GCKR g.6859C>G was concordant with affection status. No mutation in other 7 genes that ranked highly in the prioritization was concordant with affection status in families. CONCLUSIONS: We propose that GCKR is a susceptibility gene in Japanese families with clustered diabetes. The family based approach seems to be complementary with a large population study. PMID- 21236714 TI - Investigation of dogs as a reservoir of Penicillium marneffei in northern Thailand. AB - BACKGROUND: Penicillium marneffei is a dimorphic pathogenic fungus endemic in Southeast Asia that usually causes disseminated disease, mainly in immunocompromised individuals, especially those with HIV infection. Untreated cases are usually fatal. The only known natural reservoir exists in bamboo rats and there is no firm evidence that these animals are involved in direct transmission to humans. The risk of infection is not restricted to those living in endemic areas; HIV-infected individuals who travel to Southeast Asia have also become infected by P. marneffei. Hence, there must exist sources to which even tourists are exposed on a short-term basis. DESIGN AND METHODS: Penicillium is known to infect dogs and this animal is common in the streets and temple areas of Chiang Mai, where there is one of the highest incidences of P. marneffei infection in the world. Dogs have not been well studied as a possible reservoir. To investigate this possibility, we took nasal swabs from 83 outdoor dogs and performed culture and nested polymerase chain reaction (PCR) to detect P. marneffei. RESULTS: We found that approximately 13% of nasal swabs from dogs in Chiang Mai, Thailand were positive when tested by two different PCR methods, but culture results were negative. Sequencing the products from both PCR reactions showed 100% identity with P. marneffei, whereas no other known fungi shared both sequences. CONCLUSIONS: Our results suggest that dogs might be an animal reservoir for P. marneffei in northern Thailand. This observation should be confirmed by additional studies. PMID- 21236715 TI - Changes in body composition during weight loss in obese subjects in the NUGENOB study: comparison of bioelectrical impedance vs. dual-energy X-ray absorptiometry. AB - AIM: We studied the accuracy of bioelectrical impedance analysis (BIA) to assess changes in body composition during moderate weight loss in obese subjects. METHODS: Estimates of changes in fat mass (FM) and fat-free mass (FFM) by BIA were compared with those by dual-energy X-ray absorptiometry (DXA) as the reference method during a 10-week standardized weight-loss intervention. In obese women (age: 20-50 years, mean BMI: 33.8 kg/m(2)) participating in a European multicentre trial (nutrient-gene interactions in human obesity [NUGENOB]), body composition was assessed by BIA (Bodystat QuadScan 4000) and DXA (Lunar DPX-IQ at two centres, Hologic QDR 2000 at another centre) at baseline (n=131) and at week 10 (n=105) after a mean weight loss of -5.7 kg. RESULTS: At baseline, BIA significantly overestimated FFM and underestimated FM (by 1-3 kg on average) compared with DXA, and the limits of agreement were wide (mean +/- 7-8.5 kg). For body-composition changes, although biases were generally non-significant, the limits of agreement were also wide (mean +/- 3.7-4.6 kg). An FFM prediction equation for BIA data was developed in subjects scanned with Lunar instruments and cross-validated in an independent sample of 31 obese women undergoing similar weight loss. However, no major improvement in limits of agreement was found. CONCLUSION: During moderate diet-induced weight loss, the use of BIA leads to estimates of changes in body composition at the individual level that can differ substantially from those assessed by DXA, indicating that BIA and DXA cannot be used interchangeably. However, BIA in this context may be used for assessing changes in body composition at group level. PMID- 21236716 TI - Diabetes in Mozambique: prevalence, management and healthcare challenges. AB - AIM: The growing trend towards and deficient management of diabetes in Africa are important public-health challenges requiring surveillance. For this reason, this study aimed to assess the prevalence and awareness of diabetes in urban and rural Mozambique, and to describe its management. METHODS: In 2005, a representative sample of the national Mozambican adult population (n=2343) was evaluated, according to the STEPwise approach to chronic disease risk factor surveillance (STEPS). Twelve-hour fasting blood glucose (FBG) was measured, using fingertip capillary whole blood, to estimate the prevalence of impaired fasting glucose (IFG; FBG >=5.6 mmol/L and less than 6.1 mmol/L) and diabetes (FBG >=6.1 mmol/L, or treatment with insulin and/or oral blood glucose-lowering drugs). Patients' awareness and management of diabetes were assessed by questionnaire. RESULTS: The prevalence of diabetes and IFG was 2.9% [95% confidence interval (95%CI): 1.8 4.0] and 2.5% (95%CI: 1.3-3.7), respectively. Diabetes was more frequent among urban dwellers (OR=2.92, 95%CI: 1.45-5.86), mostly due to urban-rural differences in age, education, body mass index (BMI) and waist circumference (adjusted OR=2.27, 95%CI: 0.83-6.26). In all, 13% of those with diabetes were aware of their condition, 10.9% had undergone glycaemia determination during the previous year, and 9% were being treated with oral blood glucose-lowering drugs and 3% with insulin. CONCLUSION: Diabetes prevalence is low in Mozambique, but most diabetic patients were neither aware of their condition nor being treated pharmacologically, thus posing serious challenges to the provision of adequate care in an already disadvantageous context. PMID- 21236717 TI - Metformin and digestive disorders. AB - Digestive disorders (diarrhoea, vomiting) represent the most common metformin side-effects (around 30%) with this first-line drug treatment for type 2 diabetes. In healthy individuals, metformin affects glucose, vitamin B12 and the digestive uptake of bile salts. In the colon, it acts locally by modifying glucose cell metabolism. Different pathophysiological hypotheses have been proposed to explain the metformin-induced diarrhoea and vomiting, which can sometimes cause the patient to stop an effective treatment. These theories include stimulation of intestinal secretion of serotonin, changes in incretin and glucose metabolism, and bile-salt malabsorption. However, none of these hypotheses can be considered an adequate pathophysiological explanation of metformin digestive side-effects. In addition, there is a lack of experimental data to explain these highly patient-dependent adverse effects. PMID- 21236718 TI - [Radioembolisation for hepatocellular carcinoma]. AB - Hepatocellular carcinoma is now a major public health concern. In intermediate stages (one third of hepatocellular carcinoma patients), chemoembolization is the standard of care despite a poor tolerance and a moderate efficacy. Moreover, despite recent improvements, this technique seems in a dead end. Radioembolization could be an excellent tool for such patients. Currently (131)I Lipiodol, (188)Re-Lipiodol, (90)Y-glass or resin microspheres are available. More recent and promising data come from microspheres, but phase II and III studies are needed before drawing any conclusion. In the future, the combination of radioembolization with systemic chemotherapy or targeted agents (particularly antiangiogenic drugs) seems very promising. PMID- 21236719 TI - Detection and comparison of reactive oxygen species (ROS) generated by chlorophyllin metal (Fe, Mg and Cu) complexes under ultrasonic and visible-light irradiation. AB - In this paper, in order to examine the mechanisms of sonodynamic and photodynamic reactions, the chlorophyllin metal (Chl-M (M=Fe, Mg and Cu)) complexes were irradiated by ultrasound (US) and visible-light (VL), respectively, and the generation of reactive oxygen species (ROS) were detected by the method of Oxidation-Extraction Spectrometry (OES). That is, the 1,5-diphenyl carbazide (DPCI) is oxidized by the generated ROS into 1,5-diphenyl carbazone (DPCO), which can display a various visible absorption around 563 nm wavelength. Besides, some influence parameters on the generation of ROS were also reviewed. The results demonstrated an apparent synergistic effect of Chl-M and ultrasonic or visible light irradiation for the generation of ROS. Moreover, the quantities of generated ROS increase with the increase of (ultrasonic or visible-light) irradiation time and Chl-M (M=Fe, Mg and Cu) concentration. Finally, several quenchers were used to determine the kind of the generated ROS. It is wished that this paper might offer some valuable references for the study on the sonodynamic therapy (SDT) and photodynamic therapy (PDT) mechanisms and the application of Chl-M in tumor treatment. PMID- 21236720 TI - Patterns of brain atrophy in Parkinson's disease, progressive supranuclear palsy and multiple system atrophy. AB - BACKGROUND AND PURPOSE: Quantitative analysis of brain atrophy may be useful in differentiating Parkinson's Disease (PD) from Progressive Supranuclear Palsy (PSP) and parkinsonian variant of Multiple System Atrophy (MSA-P); the aim of this study was to identify the volumetric differences of subcortical structures in patients with PD, PSP and MSA-P using a novel and validated fully-automated whole brain segmentation method. METHODS: Volumetric MRIs were obtained in 72 patients with PD, 32 patients with PSP, 15 patients with MSA-P, and in 46 control subjects. Subcortical volume was measured automatically by FreeSurfer. Multivariate analysis of covariance, adjusted for intracranial volume (ICV), sex and age, was used to explore group differences. RESULTS: No volumetric differences were found between PD and controls group; otherwise the volumes of the cerebellum, the thalamus, the putamen, the pallidum, the hippocampus, and the brainstem were significantly reduced in PSP and MSA-P compared to patients with PD and control subjects. PSP and MSA-P patients only differed in thalamus volume which was smaller in PSP group (p < 0.001). Moreover, patients with PSP and MSA-P showed a ventricular system (including lateral, third and fourth ventricles) larger than that detected in PD and controls (p < 0.001). CONCLUSIONS: Volumetric data obtained with automated segmentation of cerebral regions show a significant atrophy of different brain structures in parkinsonisms rather than in PD. Our study also demonstrates that the atrophy of the thalamus only occurs in PSP while the enlargement of the whole ventricular system characterizes both PSP and MSA-P. PMID- 21236722 TI - Water quality and waterborne disease in the Niger River Inland Delta, Mali: a study of local knowledge and response. AB - This paper presents the findings of a study to assess patterns in local knowledge of and response to water quality and waterborne diseases in relation to seasonal changes in the Niger River Inland Delta. The study draws on field data collected in four villages along the Niger River in the Mopti region of Mali during September 2008. The major findings suggest: (1) water use behaviors and diarrheal disease management are influenced by the tremendous seasonal fluctuations in the riverine environment; (2) local awareness of the relationship between poor water quality, oral-fecal disease transmission, and waterborne disease is low; (3) interventions to mitigate the high incidence of childhood diarrhea and degraded water quality are limited by ongoing socio-economic, cultural, and environmental factors; and (4) women's level of health knowledge is socially and culturally dependent. PMID- 21236721 TI - Racial/ethnic residential segregation: framing the context of health risk and health disparities. AB - An increasing body of public health literature links patterns of racial/ethnic residential segregation to health status and health disparities. Despite substantial new empirical work, meaningful understanding of the pathways through which segregation operates to influence health remains elusive. The literature on segregation and health was appraised with an emphasis on select conceptual, methodological, and analytical issues. Recommendations for advancing the next generation of racial/ethnic residential segregation and health research will require closer attention to sharpening the methodology of measuring segregation, testing mediating pathways and effect modification, incorporating stronger test of causality, exploring factors of resilience in segregated areas, applying a life-course perspective, broadening the scope of the investigation of segregation to include nativity status in blacks and other racial/ethnic groups, and linking segregation measures with biological data. PMID- 21236723 TI - The metabolic interface between Pseudomonas syringae and plant cells. AB - The bacterial plant pathogen Pseudomonas syringae causes economically important diseases of a wide variety of plant species and is used as a model organism to understand the molecular basis of plant disease. Much existing research into P. syringae-plant interactions has focused on the molecular basis of plant disease resistance and the role of secreted effector proteins in the suppression of plant defences. However, researchers have speculated that the diverse array of effectors, toxins and hormones produced by this pathogen also play an important role in manipulating plant metabolism to promote infection. Recent advances in metabolomics, genomics, transcriptomics and metabolic modelling offer new opportunities to address this question and generate a system-level understanding of metabolic interactions at the host-pathogen interface. PMID- 21236724 TI - Peptide signalling in the rhizobium-legume symbiosis. AB - For two decades, signalling research in the rhizobium-legume symbiosis field has been dominated by oligosaccharide signals (mainly Nod factors and, to a lesser extent, surface polysaccharides made by the microsymbionts) and phytohormones. Recently, plant peptides have emerged as another major class of signalling molecules in the rhizobium-legume symbioses contributing to the control of nodulation, infection and bacteroid differentiation. Here we focus on three examples of symbiotically relevant peptides, namely Enod40, CLE and NCR peptides. The number of genes encoding these peptides, as well as the recent discovery of additional peptide players in the context of symbiosis, suggests that we might be seeing only the tip of the peptide iceberg in the sea of symbiotic regulations. PMID- 21236725 TI - Secretion, modification, and regulation of Ax21. AB - Innate immunity provides a first line of defense against pathogen attack and is activated rapidly following infection. Although it is now widely appreciated that host receptors of conserved microbial signatures play a key role in innate immunity in plants and animals, very little is known about the biological function of the microbially derived molecules recognized by such receptors. We have recently demonstrated that the rice XA21 receptor binds the AxY(S)22 peptide corresponding to the N-terminal region of Ax21, a type I-secreted protein that is highly conserved in all Xanthomonas species as well as in Xylella fastidiosa and the human pathogen, Stenotrophomonas maltophilia. We hypothesize that post translational modification of Ax21 is carried out by the RaxP, RaxQ, and RaxST proteins and that perception and regulation of Ax21 is controlled by the RaxR/H and PhoP/Q 2-component regulatory systems. Ax21 is predicted to serve as an inducer of quorum sensing (QS), a process where bacteria communicate with one another. Because this is the first example of a conserved microbial signature that binds a host receptor and is also predicted to serve as an inducer of QS, this work has revealed fundamental new principles governing host-microbe interactions and has provided insight into the signaling dynamics of microbial communities. PMID- 21236726 TI - IR spectroscopic analysis of polymorphism in C13H14N4O. AB - IR analysis is used here to investigate the changes in N-N, N-H, CO modes of thermally treated diphenyl carbazide (DPC) during the variation of temperature from room temperature up to ~160 degrees C. Polymorphism in DPC compound has been studied here by detecting the changes in some IR spectroscopic parameters (e.g., mode shift, band contour) during the elevation of temperature. Also, DSC, X-ray, NMR and atomic mass spectra are used as confirming tools for what is obtained by IR. All of the vibrations of DPC were found to be due to ionic fundamentals 3311 cm(-1), 3097 cm(-1), 3052 cm(-1), 1677 cm(-1), 1602 cm(-1), 1492 cm(-1), 1306 cm( 1), 1252 cm(-1), 887 cm(-1) and 755 cm(-1). The results revealed for the first time that the thermally treated DPC traverse four different phase transformations at 50 degrees C, 90 degrees C, 125 degrees C and 140 degrees C. The crystal structure was found to be amorphous, monoclinic, tetragonal, orthorhombic and amorphous within a temperature range (30 degrees C-160 degrees C). X-ray diffraction patterns support the results obtained by IR and DSC. PMID- 21236727 TI - Respiration-deficient mutants of Zymomonas mobilis show improved growth and ethanol fermentation under aerobic and high temperature conditions. AB - Respiration-deficient mutant (RDM) strains of Zymomonas mobilis were isolated from antibiotic-resistant mutants. These RDM strains showed various degrees of respiratory deficiency. All RDM strains exhibited much higher ethanol fermentation capacity than the wild-type strain under aerobic conditions. The strains also gained thermotolerance and exhibited greater ethanol production at high temperature (39 degrees C), under both non-aerobic and aerobic conditions, compared with the wild-type strain. Microarray and subsequent quantitative PCR analyses suggest that enhanced gene expression involved in the metabolism of glucose to ethanol resulted in the high ethanol production of RDM strains under aerobic growth conditions. Reduction of intracellular oxidative stress may also result in improved ethanol fermentation by RDM strains at high temperatures. PMID- 21236728 TI - Nosocomial outbreak of methicillin- and linezolid-resistant Staphylococcus epidermidis associated with catheter-related infections in intensive care unit patients. AB - A total of 128 isolates associated with catheter-related infections was recovered from 101 intensive care unit patients in a Spanish hospital during March 2008 to August 2009, and 27 of these isolates (from 21 patients) were typed as methicillin- and linezolid-resistant Staphylococcus epidermidis. Thirteen of these 21 patients (62%) had received linezolid during the 3 months preceding S. epidermidis recovery. Two closely related pulsotypes (P1a and P1b) were identified among the 27 studied isolates that belonged to the sequence type ST2 and harboured the mecA gene and the SCCmecIII type. The strains recovered from patients 1-4 (pulsotype P1a) showed the nucleotide mutation G2474T inside the amplified fragment of the 23S rRNA region and carried the aac(6')-Ie-aph(2")-Ia, ant(4'), and catA genes, whereas the strains from patients 5-21 (pulsotype P1b) showed the mutation G2603T and carried the aac(6')-Ie-aph(2")-Ia gene. None of the strains amplified the cfr gene. The ica gene and the IS256 element were detected in all strains. The emergence of 2 closely related methicillin- and linezolid-resistant S. epidermidis strains with 2 different mutations in the 23S rRNA region (G2474T and G2603T) is reported in this study as a cause of a nosocomial outbreak. The presence of G2474T or G2603T point mutations suggests that there are multiple potential sites within domain V of the 23S rRNA region at which mutations could confer resistance to linezolid in the clinical isolates. To our knowledge, this is the first report in which the G2474T mutation has been detected in domain V of the 23S rRNA gene of clinical S. epidermidis. PMID- 21236729 TI - Oral treatment with Saccharomyces cerevisiae strain UFMG 905 modulates immune responses and interferes with signal pathways involved in the activation of inflammation in a murine model of typhoid fever. AB - Salmonella spp. are Gram-negative, facultative, intracellular pathogens that cause several diarrheal diseases ranging from self-limiting gastroenteritis to typhoid fever. Previous results from our laboratory showed that Saccharomyces cerevisiae strain UFMG 905 isolated from 'cachaca' production presented probiotic properties due to its ability to protect against experimental infection with Salmonella enterica serovar Typhimurium. In this study, the effects of oral treatment with S. cerevisiae 905 were evaluated at the immunological level in a murine model of typhoid fever. Treatment with S. cerevisiae 905 inhibited weight loss and increased survival rate after Salmonella challenge. Immunological data demonstrated that S. cerevisiae 905 decreased levels of proinflammatory cytokines and modulated the activation of mitogen-activated protein kinases (p38 and JNK, but not ERK1/2), NF-kappaB and AP-1, signaling pathways which are involved in the transcriptional activation of proinflammatory mediators. Experiments in germ-free mice revealed that probiotic effects were due, at least in part, to the binding of Salmonella to the yeast. In conclusion, S. cerevisiae 905 acts as a potential new biotherapy against S. Typhimurium infection due to its ability to bind bacteria and modulate signaling pathways involved in the activation of inflammation in a murine model of typhoid fever. PMID- 21236730 TI - Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. AB - BACKGROUND: Xerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia. METHODS: We undertook a randomised controlled trial between Jan 21, 2003, and Dec 7, 2007, that compared conventional radiotherapy (control) with parotid-sparing IMRT. We randomly assigned patients with histologically confirmed pharyngeal squamous-cell carcinoma (T1-4, N0-3, M0) at six UK radiotherapy centres between the two radiotherapy techniques (1:1 ratio). A dose of 60 or 65 Gy was prescribed in 30 daily fractions given Monday to Friday. Treatment was not masked. Randomisation was by computer-generated permuted blocks and was stratified by centre and tumour site. Our primary endpoint was the proportion of patients with grade 2 or worse xerostomia at 12 months, as assessed by the Late Effects of Normal Tissue (LENT SOMA) scale. Analyses were done on an intention-to-treat basis, with all patients who had assessments included. Long-term follow-up of patients is ongoing. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN48243537. FINDINGS: 47 patients were assigned to each treatment arm. Median follow-up was 44.0 months (IQR 30.0-59.7). Six patients from each group died before 12 months and seven patients from the conventional radiotherapy and two from the IMRT group were not assessed at 12 months. At 12 months xerostomia side-effects were reported in 73 of 82 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the IMRT group than in the conventional radiotherapy group (25 [74%; 95% CI 56-87] of 34 patients given conventional radiotherapy vs 15 [38%; 23-55] of 39 given IMRT, p=0.0027). The only recorded acute adverse event of grade 2 or worse that differed significantly between the treatment groups was fatigue, which was more prevalent in the IMRT group (18 [41%; 99% CI 23-61] of 44 patients given conventional radiotherapy vs 35 [74%; 55-89] of 47 given IMRT, p=0.0015). At 24 months, grade 2 or worse xerostomia was significantly less common with IMRT than with conventional radiotherapy (20 [83%; 95% CI 63-95] of 24 patients given conventional radiotherapy vs nine [29%; 14-48] of 31 given IMRT; p<0.0001). At 12 and 24 months, significant benefits were seen in recovery of saliva secretion with IMRT compared with conventional radiotherapy, as were clinically significant improvements in dry-mouth-specific and global quality of life scores. At 24 months, no significant differences were seen between randomised groups in non xerostomia late toxicities, locoregional control, or overall survival. INTERPRETATION: Sparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life, and thus strongly supports a role for IMRT in squamous-cell carcinoma of the head and neck. FUNDING: Cancer Research UK (CRUK/03/005). PMID- 21236732 TI - Informed consent in blood transfusion: knowledge and administrative issues in Uganda hospitals. AB - Blood as a transplant is not free of risks. Clinicians and patients ought to know the parameters of a transfusion informed consent. A mixed methodology to explore patients' and clinicians' knowledge and opinions of administration and strategies to improve the transfusion informed consent process was conducted. The clinicians' level of knowledge was limited to provision of information about and the right to consent to a transfusion. They disagreed on administrative issues but had acceptable opinions on improving the process. Patients perceived this process as a way of assurance of blood safety. This process is important and should not be omitted. PMID- 21236731 TI - Pain-relieving prospects for adenosine receptors and ectonucleotidases. AB - Adenosine receptor agonists have potent antinociceptive effects in diverse preclinical models of chronic pain. By contrast, the efficacy of adenosine and adenosine receptor agonists in treating pain in humans is unclear. Two ectonucleotidases that generate adenosine in nociceptive neurons were recently identified. When injected spinally, these enzymes have long-lasting adenosine A(1) receptor-dependent antinociceptive effects in inflammatory and neuropathic pain models. Furthermore, recent findings indicate that spinal adenosine A(2A) receptor activation can enduringly inhibit neuropathic pain symptoms. Collectively, these studies suggest the possibility of treating chronic pain in humans by targeting specific adenosine receptor subtypes in anatomically defined regions with agonists or with ectonucleotidases that generate adenosine. PMID- 21236733 TI - The anterior approach to retroperitoneoscopic adrenalectomy in children: technique. AB - PURPOSE: Very limited literature exists on minimally invasive adrenalectomy in children. Retroperitoneoscopic adrenalectomy (RPA) has the advantage of avoiding intra-abdominal organ retraction, but concerns have been expressed regarding RPA on the right side. Herein, we describe the second reported experience with the anterior approach to RPA in children, which appears to overcome the limitations previously ascribed to right RPA. MATERIALS AND METHODS: Two children, aged 8 and 14-years, presented with incidental right adrenal masses. Both patients were placed in the lateral decubitus position with lumbar hyper-extension. A 5-mm, 3 port approach was used, as demonstrated in the video. RESULTS: Pathology revealed a 7-cm ganglioneuroma and a 5-cm pheochromocytoma with intact surgical margins. Operative time with these large masses and first experience with this technique was 5 h in the first case and 3.5 h in the second. No intraoperative or postoperative complications were noted, with minimal blood loss and a hospital stay of 36 h in both cases. CONCLUSION: The anterior approach to RPA is feasible even in children with a smaller retroperitoneal space and a large adrenal mass. It provides excellent exposure of the adrenal gland and vein, even on the right side. PMID- 21236734 TI - Hypospadias dilemmas: a round table. PMID- 21236735 TI - Different methods to analyze reactive oxygen species production. PMID- 21236736 TI - Similar but not identical: clinical implications for molecular studies in monozygotic discordant twins with epilepsy. PMID- 21236737 TI - Accurate verification of balloon rotation correction for the Contura multilumen device for accelerated partial breast irradiation. AB - PURPOSE: To validate a method of accurately confirming the orientation of the Contura multilumen balloon catheter before each fraction and to determine if any residual device rotation remains after adjustment. METHODS AND MATERIALS: Sixteen patients underwent CT scans before each treatment with accelerated partial breast irradiation. Before acquisition of CT scans for planning, each patient had a skin mark drawn to align with Lumen #1 (the Contura [SenoRx, Inc., Irvine, CA] has a black line on the shaft of the applicator to identify this lumen). In addition, a CT spot marker was used as a fixed reference point on the patient's skin. CT markers (used for lumen identification and reconstruction) were also used as additional reference points for distance measurements. The distances measured from the CT spot marker to the three reproducible points on the CT markers were used for balloon rotation verification. These measurements were performed for each daily fraction on reproducible CT axial views. RESULTS: Three hundred eighteen measurements were obtained. Median residual rotation for all cases was 0.2mm (standard deviation=0.797). Later fractions and skin spacing changes over time were associated with slightly greater residual rotation (Fraction #1 vs. Fraction #10, 0.1 vs. 0.3mm, p=0.05; and skin spacing change <=2 vs. >2mm, 0.2 vs. 0.5mm, p=0.0019, respectively). CONCLUSIONS: These results confirm external alignment of a skin mark with Lumen #1 (on the Contura catheter) is an accurate and reliable method to align the balloon before treatment and that no significant internal device rotation (0.2mm) is likely to occur. PMID- 21236738 TI - Daily computed tomography measurement of needle applicator displacement during high-dose-rate interstitial brachytherapy for previously untreated uterine cervical cancer. AB - PURPOSE: We investigated daily needle applicator displacement during high-dose rate interstitial brachytherapy. METHODS AND MATERIALS: Ten patients with previously untreated uterine cervical cancer received 30Gy in five fractions during 3 days of high-dose-rate interstitial brachytherapy combined with external beam radiotherapy using our unique ambulatory technique. To analyze displacement, we obtained daily computed tomography (CT) images for 147 flexible needle applicators at 21 and 45h after implantation. The distance was defined as the length between the center of gravity of titanium markers and the needle applicator tips along the daily CT axis. We adapted dwell positions of the treatment source to cover clinical target volume with a 15-mm cranial margin. RESULTS: The median displacement was 1mm (range, -6 to 12mm) at 21h and 2mm (range, -9 to 14mm) at 45h, respectively. Statistically significant caudal displacement was observed only between the displacement at 0 and 21h (p<0.0001), and not between the displacement at 21 and 45h (p=0.1). In cases with displacement of 3mm or more, we changed dwell positions to correct the treatment plan. We corrected 45 applicators (31%) at 21h and 67 (46%) at 45h. CONCLUSIONS: We investigated needle applicator displacement in our ambulatory technique using daily CT examination and considered that a 15-mm cranial margin was sufficient to cover clinical target volume. PMID- 21236739 TI - Optical and electric signals from dried oriented purple membrane of bacteriorhodopsins. AB - All the intermediates of the bacteriorhodopsin photocycle are excitable with light of suitable wavelength. This property might regulate the activity in the cells when they are exposed in the nature to high light intensity. On the other hand this property is involved in many applications. In this study the ground state and M intermediate of dried oriented samples of wild-type bacteriorhodopsin and its mutant D96N were excited with 406 nm laser flashes. Substantial M populations were generated with quasi-continuous illumination. The decay of the absorption of M intermediate had three components: their lifetimes were very different for laser flash and quasi-continuous illuminations in cases of both bacteriorhodopsin species. The optical answer for the excitation of M intermediate had a lifetime of 2.2 ms. Electric signals for M excitation had large fast negative components and small positive components in the 100 MUs time domain. The results are expected to have important implications for bioelectronic applications of bacteriorhodopsin. PMID- 21236740 TI - Determination of hippuric acid in human urine by ion chromatography with conductivity detection. AB - A simple, rapid, precise and eco-friendly ion chromatography (IC) method for the determination of hippuric acid (HA) in human urine was proposed in this paper. The separation was carried out an anion exchange column with 2.0 mmol L-1 Na2CO3 + 2.0 mmol L-1 NaHCO3 as mobile phase at the flow-rate 0.7 mL min-1. A suppressed conductivity detector was used and the detection limit was 1.0 MUg L-1 (S/N=3) for hippuric acid. The analysis time for one run was 30 min under the optimized IC condition. The recovery of hippuric acid was 93.2-98.0% while the relative standard deviation (RSD) was 1.4-2.3% by seven measurements. PMID- 21236741 TI - Free jejunal transfer for a 15-year-old girl with synovial sarcoma of the hypopharynx. AB - INTRODUCTION: Synovial sarcomas are rare, aggressive malignant soft-tissue tumours. Approximately 85-90% of synovial sarcomas occur in the extremities, with only 3% arising in the head and neck region. The hypopharynx as a site of occurrence has only rarely been reported. We describe herein our experience of free jejunal transfer for an adolescent patient with synovial sarcoma of the hypopharynx. CASE REPORT: A 15-year-old girl presented with a 2-month history of swallowing difficulties and hoarseness. Laryngoscopy revealed a mass filling the hypopharynx, almost occluding the larynx. Histological diagnosis obtained by biopsy was synovial sarcoma. The patient underwent total pharyngo-laryngo oesophagectomy and reconstruction with a free jejunal graft. Postoperative chemotherapy and radiotherapy was performed. She has been free of recurrence or metastases for 2 years and 6 months. The patient can take a normal diet without dysphagia. DISCUSSION: Synovial sarcomas are rare, malignant, soft-tissue tumours primarily affecting the extremities, with only 3% arising in the head and neck region. The cornerstone of treatment for synovial sarcomas is complete surgical resection. Recently, total pharyngo-laryngo-oesophagectomy and free jejunal transfer have become the standard technique for patients with malignancies confined to the hypopharynx because of the minimal morbidity and mortality, favourable functional outcome and low incidence of complications associated with the donor site. CONCLUSION: We report the case of a 15-year-old girl with synovial sarcoma of the hypopharynx. We performed a total pharyngo-laryngo oesophagectomy and reconstruction with a free jejunal graft. The postoperative course and the functional outcome were satisfactory. PMID- 21236742 TI - Application of various compositions of thoracodorsal perforator flap for craniofacial contour deformities. AB - BACKGROUND: Craniofacial contour defects are challenging to restore because they may involve multiple tissues and span several aesthetic subunits in a non contiguous manner. Some of these deformities may be associated with significant dead space in the region of sinus and orbit. The numerous subtle contours of the craniofacial regions must be preserved or restored to achieve a pleasing outcome. PATIENT AND RESULTS: We managed six patients with various craniofacial contour deformities as a result of hemifacial microsomia, infection, post excision of venous malformation, lipodystrophy, craniectomy for chronic frontal sinusitis and infected pneumocephalus. They were reconstructed with thoracodorsal perforator flaps bearing various components, that is, adiposal, adipofascial, dermoadiposal, adipomyofascial and osteomuscular elements. Half of the flaps were in chimaeric form. The largest flap size was 11 * 17 cm. All flaps survived and no patient required secondary contouring procedure, except for cranioplasty in one patient. CONCLUSION: The thoracodorsal perforator flap is very suitable for restoration of craniofacial contour deformities. Its advantages include: (1) ease of customisation of size and thickness, (2) several choices of donor tissue from the lateral thoracic region yielding multiple tissue components, for example, adiposal, adipofascial, dermoadiposal, adipomyofascial and osteomuscular flaps, (3) presence of adjacent perforators in the thoracodorsal system, allowing chimaeric flap configuration, thereby improving adaptation to non-contiguous contour defects, (4) ability to tailor the donor and recipient vessel size match by varying how proximal to harvest along the thoracodorsal vessels, (5) primary closure of donor site and (6) flap harvesting in supine position allowing a two team approach. PMID- 21236743 TI - Total pharyngolaryngectomy and voice reconstruction with ileocolon free flap: functional outcome and quality of life. AB - Total pharyngolaryngectomy (PL) reconstruction with an ileocolon free flap not only restores swallowing but also provides potential for speech. We report our surgical technique, functional outcome and quality of life (QoL) of 17 (15 males and two females) patients who underwent total PL/voice reconstruction with an ileocolon free flap between 2004 and 2009. The patients were retrospectively reviewed and swallowing, speech and QoL evaluated. Speech intelligibility was assessed using Hirose and Chen scoring systems, in addition to sound spectrogram analysis. QoL was evaluated using the European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) in conjunction with the disease-specific Head & Neck Cancer Module (QLQ-H&N35). The mean age of patients was 49 (range 35-69) years and the mean follow-up period was 22 (range 6-72) months. There was one partial flap failure and another flap was successfully salvaged. Swallowing function was achieved by 16 (94%) patients at 4 weeks, whilst 12 (71%) demonstrated moderate-to-excellent speech intelligibility. There were no cases of aspiration pneumonia. QLQ-C30 global QoL and functional subscales indicated patients had average-to-good functioning. Comparison of QLQ H&N35 scores with EORTC reference values indicated our patients had greater difficulty with social contact, mouth opening and weight gain. Total PL/voice reconstruction with the ileocolon free flap is a viable option in selected patients, who desire autologous voice reconstruction. A low complication rate and reasonable QoL support this reconstructive method. PMID- 21236745 TI - Midwives' support for Complementary and Alternative Medicine: a literature review. AB - OBJECTIVE: There is evidence that the use of Complementary and Alternative Medicine by childbearing women is becoming increasingly popular in industrialised countries. The aim of this is paper is to review the research literature investigating the midwives' support for the use of these therapies. METHOD: A search for relevant research published from 2000 to 2009 was undertaken using a range of databases and by examining relevant bibliographies. A total of thirteen studies were selected for inclusion in this review. RESULTS: The findings indicate that the use of Complementary and Alternative Medicine is widespread in midwifery practice. Common indications for use include; labour induction and augmentation, nausea and vomiting, relaxation, back pain, anaemia, mal presentation, perineal discomfort, postnatal depression and lactation problems. The most popular therapies recommended by midwives are massage therapy, herbal medicines, relaxation techniques, nutritional supplements, aromatherapy, homeopathy and acupuncture. Midwives support the use Complementary and Alternative Medicine because they believe it is philosophically congruent; it provides safe alternatives to medical interventions; it supports the woman's autonomy, and; incorporating Complementary and Alternative Medicine can enhance their own professional autonomy. CONCLUSIONS: There is considerable support by midwives for the use of Complementary and Alternative Medicine by expectant women. Despite this enthusiasm, currently there are few educational opportunities and only limited research evidence regarding CAM use in midwifery practice. These shortfalls need to be addressed by the profession. Midwives are encouraged to have an open dialogue with childbearing women, to document use and to base any advice on the best available evidence. PMID- 21236746 TI - Component positioning in primary total hip replacement: a prospective comparative study of two anterolateral approaches, minimally invasive versus gluteus medius hemimyotomy. AB - INTRODUCTION: One factor of implant survivorship in total hip replacement (THR) is the quality of implant choice and positioning. The purported advantages of minimally invasive approaches are faster recovery, shorter hospital stay and less per-operative blood loss. On the other hand, there have been many reports of higher complication rates, and doubts as to the quality of implant positioning. HYPOTHESIS: The quest to minimize tissue damage is at the cost of THR positioning quality. OBJECTIVES: To assess implant positioning in a prospective comparative continuous multicenter series. PATIENTS AND METHODS: Between 2008 and 2009, a prospective comparative study was conducted on a continuous series of 141 THRs. Ninety-two were performed in two centers, using a minimally invasive Watson-Jones approach; the other 49, performed in a 3rd center, used an anterolateral approach with anterior hemimyotomy. The surgeons were in all cases experienced in their technique. Short-term follow-up comprised clinical and functional (Postel Merle d'Aubigne (PMA), Harris, SF12, WOMAC) and biological assessment (serum creatine phosphokinase (CPK), myoglobinemia, hematocrit) and analysis of complications and of implant positioning on X-ray and CT-scan. RESULTS: On the Watson-Jones approach, surgery time was longer; day-1 analgesic administration was lower; PMA, Harris and WOMAC scores were better at 6 weeks; and CPK levels were lower at 24 and 48hours. There were no significant differences on the other clinical and biological criteria. Implant positioning analysis revealed significantly greater combined anteversion and greater variation in acetabular inclination mean with the Watson-Jones approach, but no differences in cup positioning, femoral stem positioning, or limb length discrepancy. DISCUSSION: The minimally invasive Watson-Jones approach provided faster recovery and less muscular damage. However, implant positioning was less precise in terms of acetabular cup inclination. LEVEL OF EVIDENCE: Level III. Prospective, comparative, non-randomized. PMID- 21236747 TI - Secondary reconstruction of burned nasal alae using rolled dermal flap with overlying full-thickness skin graft. AB - INTRODUCTION: Surgical reconstruction of the nasal tip is a very delicate procedure, as it must rebuild three different anatomical planes: mucosa, cartilage and skin with functional and aesthetic requirements. This procedure is even more difficult in burns patients, due to more limited donor sites and poor skin quality. Numerous flap options are available to reconstruct defects of the tip of the nose. The authors report their experience of nasal alar reconstruction by a scar tissue remodelling technique using a rolled dermal flap with overlying full-thickness skin graft. PATIENTS AND METHODS: The medical charts of seven patients (five women and two men with a mean age of 30) treated between 1991 and 2006 were retrospectively reviewed. Six patients presented sequelae of a facial burn and one patient had congenital facial hemiagenesis. RESULTS: Reconstruction was bilateral for all burns patients and unilateral for the patient with facial hemiagenesis. The skin graft was raised from the medial aspect of the forearm in four cases, the retroauricular region in two cases and the groin in one case. One patient required a second surgical procedure for necrosis of the nasal tip. No nasal obstruction was reported with a mean follow-up of five years (range: six months to 15 years). CONCLUSION: The rolled dermal flap with overlying full thickness skin graft is a simple and reliable procedure for reconstruction of the nasal alae. Filling of the nasal alae defect and reconstruction of all anatomical planes are achieved in a single surgical procedure. The aesthetic and functional results were satisfactory, with minimal scarring of the donor site. This technique is very suitable for the treatment of burn sequelae and can also be used to treat nasal hemiagenesis and nasal mutilation by biting or facial trauma. PMID- 21236748 TI - Titanium ossicular chain replacement prostheses: prognostic factors and preliminary functional results. AB - OBJECTIVE: To assess the efficiency of ossiculoplasty procedures with the Kurz titanium ossicular prosthesis and evaluate prognostic factors for the functional results. METHODS: Retrospective chart reviews were performed for ossiculoplasty involving Kurz titanium prostheses between 2006 and 2009 in the ENT Head and Neck Department of the hopital Nord, Marseille, France. RESULTS: The population studied was 70 patients, with 37 procedures using the partial (PORP) and 33 the total ossicular replacement prosthesis (TORP). Mean follow-up was 9 months. Pre- and postoperative audiological parameters on four frequency averages (0.5, 1, 2, and 3kHz) were compared according to AAO-HNS guidelines. A postoperative air-bone gap (ABG)<=20dB was obtained in 71.43% of the patients (86.49% for PORP, and 54.55% for TORP). The mean change in ABG was 12.45dB in cholesteatomatous otitis versus 13.41dB in non-cholesteatomatous otitis. CONCLUSION: Increasing the length of the ossicular prosthesis, especially TORP, may improve postoperative functional results. PMID- 21236749 TI - Adaptive thinking and medicine. PMID- 21236750 TI - Traces of population dynamics past. PMID- 21236751 TI - Trends in the recent history, philosophy and social studies of biology. PMID- 21236752 TI - Cannibalism among amphibian larvae: a case of good taste. PMID- 21236753 TI - New taxonomy and niche partitioning on coral reefs: jack of all trades or master of some? AB - Recent taxonomic advances are challenging widely held theories of the ecology and evolution of coral reef Invertebrates and communities. Large numbers of sibling species have been discovered across a variety of higher taxa. Differences in distribution, behavior and life history characteristics among sibling species demonstrate that niche diversification is more finely tuned, and interactions among organisms more specific, than most reef ecologists believed previously. Ecological and evolutionary understanding depends on good taxonomy. PMID- 21236754 TI - The rise of the individual-based model in ecology. AB - Recent advances of three different kinds are driving a change in the way that modelling Is being done in ecology. First, the theory of chaos tells us that short-term predictions of nonlinear systems will be difficult, and long-term predictions will be impossible. The grave Implications this has for ecology are only just beginning to be understood. Second, ecologists have started to recognize the importance of local interactions between individuals in ecological systems. And third, improvements in computer power and software are making computers more inviting as a primary tool for modelling. The combination of these factors may have far-reaching consequences for ecological theory. PMID- 21236755 TI - Phylogenetics of cytoplasmically inherited microorganisms of arthropods. AB - Associations with cytoplasmically inherited microorganisms are fundamental to the ecology and reproductive biology of many insects. Molecular phylogenetics now provides a window into the previously obscure history of these associations. This approach has recently yielded striking findings for two cases: the mutualistic endosymbionts of aphids and relatives, and some of the cytoplasmically inherited organisms that induce reproductive abnormalities in various arthropods. These examples provide useful reference points for future extensions of molecular phylogenetic methods to other prokaryote-eukaryote associations. PMID- 21236756 TI - Fluctuating asymmetry and sexual selection. AB - Behavioral ecologists are being attracted to the study of within-individual morphological variability, manifested in random deviations from bilateral symmetry, as a means of ascertaining the stress susceptibility of developmental regulatory mechanisms. Several early successes Indicate that incorporating measures of symmetry into sexual-selection studies may help link individual sexual success to a basic component of viability - developmental stability. PMID- 21236757 TI - Seabird colonies and the appeal of the Information Center Hypothesis. PMID- 21236758 TI - Vodka, meths and DNA. PMID- 21236759 TI - Reply from d. Clode. PMID- 21236761 TI - rbcL and seed-plant phylogeny. PMID- 21236760 TI - Toward a phylogenetic system of biological nomenclature. AB - Despite the widely held belief that modem biological taxonomy is evolutionary, some of the most fundamental concepts and principles in the current system of biological nomenclature are based on a nonevolutionary convention that pre-dates widespread acceptance of an evolutionary world view by more than a century. The development of a phylogenetic system of nomenclature requires reformulating these concepts and principles so that they are no longer based on the Linnean categories but on the tenet of common descent. PMID- 21236762 TI - The importance of watching birds from airplanes. PMID- 21236763 TI - Multi-century regional western spruce budworm outbreak patterns. PMID- 21236764 TI - Arctic and alpine biodiversity: patterns, causes and ecosystem consequences. PMID- 21236765 TI - Mammalian eusociality: a family affair. AB - Comparative studies of two species of mole-rat are helping to clarify the ecological correlates of mammalian eusociality. Both species live in social groups composed of close kin, within which breeding is restricted to one female and one to three males. They inhabit xeric areas with dispersed, patchy food and unpredictable rainfall. During droughts, they can neither expand their tunnel systems nor disperse. In brief periods after rain the animals must cooperate and dig furiously to locate rich food patches. By living in groups, arid-zone mole rats can take full advantage of windows of opportunity when conditions are right for burrowing. Thus, ecological factors and kin selection have apparently interacted in the evolution of eusociality in these species. PMID- 21236766 TI - Patterns and processes in communities of heirninth parasites. AB - What processes account for the structure and dynamics of helminth parasite assemblages within vertebrate and invertebrate hosts? Attempts to answer this question form the basis for the emerging subdiscipline of parasite community ecology. Negative interspecific interactions strongly affect the distribution and abundance of parasites in some systems, but only intermittently, if ever, in others. Empirical results provide only mixed support for recent theories that attempt to explain this variation. PMID- 21236767 TI - Plant chemical defense: monoterpenes and the growth-differentiation balance hypothesis. AB - Recent studies of allocation to defensive chemicals in plants have provided insights into the ecological controls over plant defensive chemicals. Both developmental and ecological studies now suggest that we can understand the factors influencing allocation to defense by examining the relative availability of resources, external needs for chemical defense, and the internal demands for growth that plants face. These studies have also shed light on one of the more popular theories in plant evolutionary ecology, the growth-differentiation balance hypothesis of plant resource allocation. PMID- 21236768 TI - Reply from B. Schmidt. PMID- 21236769 TI - Hybridogenetic frogs on an evolutionary dead end road. PMID- 21236770 TI - Bird-song as an indicator of habitat suitability. PMID- 21236771 TI - Reply from a. Kacelnik. PMID- 21236772 TI - Leaf-cutting ants may be optimal foragers. PMID- 21236773 TI - The role of museums. PMID- 21236774 TI - The role of museums. PMID- 21236775 TI - Organization of mutations along the genome: a prime determinant of genome evolution. AB - Recent advances in molecular mutagenesis reveal that two of the mechanisms which contribute to mutagen-induced point mutations, the frequency of induced DNA damage and the repair rate of this damage, vary considerably along the genome. At a grosser level of genomic resolution, cytogeneticists now distinguish several classes of chromosome bands along human chromosomes. The hot spots for X-ray induced breaks (chromosome mutations) occur in certain band classes, while the hot spots for mitomycin C-induced exchanges or melphalan-induced breaks occur in other band classes. Knowledge of these mutation patterns is modifying our concepts of genome evolution. PMID- 21236776 TI - Optimality and evolutionary genetics: complementary procedures for evolutionary analysis in behavioural ecology. AB - The concepts and tools of optimality and game theory are a major component of research in behavioural ecology. In contrast, the theory and practice of evolutionary, ecological, population and quantitative genetics have made less of an impact on those studying the evolution of animal behaviour. A more complete understanding of the evolution of behaviour can be achieved by pursuing research that combines optimality and genetics, thereby overcoming some of the limitations inherent in a single approach. PMID- 21236777 TI - Mycobacterium tuberculosis: just desserts for an ungrateful guest. AB - Myobacterium tuberculosis is the most common infectious cause of death in the world, with up to one-third of the population infected. In industrial countries infection with M. tuberculosis and tuberculosis disease has been decreasing since the 19th century. Now, however, tuberculosis disease is on the increase again, with resistance of the bacillus to available drugs spreading rapidly. This resurgence can be seen from the ecological and evolutionary point of view, where human hosts are the niche of the tuberculosis bacillus. PMID- 21236778 TI - Systematics and biodiversity. PMID- 21236779 TI - The forest architecture hypothesis for diversity maintenance. PMID- 21236780 TI - Estimating extinction rates: Joseph Banks' legacy. PMID- 21236781 TI - Ancient DNA: not quite Jurassic Park. PMID- 21236782 TI - Marine larval ecology gets a meeting of its own. PMID- 21236783 TI - Will hybrids of genetically modified crops invade natural communities? AB - A perceived danger of genetic modification of crops is that crop hybrids may not only become more-pernicious weeds of agriculture but that they may also become invasive of natural communities. New information on the extent of crop hybridization and the characteristics of modified crops is facilitating more accurate assessments of these risks. PMID- 21236784 TI - Cooperative breeding in mammals. AB - Cooperative breeding in mammals covers a diversity of breeding systems. In all cases, however, Individuals assist in the rearing of offspring other than their own. Recent research has highlighted some of the factors responsible for variation both within and between species. While it is possible to generalize about the selective pressures leading to cooperative breeding, doing so may obscure important contrasts between taxa. Of course, inclusive-fitness models explain the generalities of cooperative breeding, but differences in ecology, physiology and life history may result in distinctive processes operating in different taxa-data only likely to emerge from long-term field studies. PMID- 21236785 TI - Experimental manipulation of natural plant communities. AB - Attempts to elucidate the factors controlling the structure of plant communities have relied increasingly on field experiments. This is a powerful approach for testing theoretical predictions that offers important advantages over observational and comparative studies. However, field experiments suffer from intrinsic difficulties as well as more-easily remediable limitations. Recent progress has been made by new approaches including the use of multifactor experiments, and the development and dissemination of better statistical tools. PMID- 21236786 TI - Partitioning of reproduction in animal societies. AB - A key feature differentiating cooperative animal societies Is the apportionment of reproduction among individuals. Only recently have studies started to focus on intraspecific variability in the distribution of reproduction within animal societies, and the available data suggest that this variability might be greater than previously suspected. How can one account for intra-and interspecific variability in partitioning of reproduction? This Is one of the most intriguing problems in the study of social behaviour, and understanding the factors underlying this variability is one of the keys to understanding the properties of complex animal societies. PMID- 21236787 TI - Reply from R. Gadagkar. PMID- 21236788 TI - Spiteful animals still to be discovered. PMID- 21236789 TI - Patterns of speciation and limits to phylogenetic resolution. AB - The practice of phylogenetic systematics frequently Includes the assumption that cladogenesis occurs by a series of bifurcations. Consequently, a phylogenetic tree that includes one or more polytomous nodes is generally viewed as unresolved. However, while some polytomles surely represent a failure of resolution, others may be real or the best resolution that can be achieved. Therefore, polytomies should be considered as phylogenetic hypotheses in the same way as bifurcating topologies. PMID- 21236790 TI - Sex is for sisters: intragenomic recombination and homology-dependent mutation as sources of evolutionary variation. AB - Sex and recombination generate variation via processes that depend on an underlying complementarity between participants. Sex between DNA segments depends on their sequences having enough in common. Viewed in this way, sex does not depend on genes that originate in separate cells. Sex in the single genome uses many of the same mechanisms as intergenomic sex but has not been properly appreciated as a source of variation or as a selectable process. Mutation is the generation of new sequences rather than the novel grouping of pre-existing alleles. Mechanisms of mutation that depend on pre-existing sequence similarities in the haploid genome are a source of variation with significant and special characteristics. PMID- 21236791 TI - Relatedness and conflict over optimal group size. PMID- 21236792 TI - Hares and tortoises in Drosophila community ecology. PMID- 21236793 TI - Split sex ratios in ants with multiple mating. PMID- 21236794 TI - The science of symmetry in biology. PMID- 21236795 TI - Thermal habit, metabolic rate and the evolution of mitochondrial DNA. AB - The hallmarks of animal mitochondrial DNA (mtDNA) are a rapid rate of sequence evolution, a small genome carrying the same set of homologous genes, maternal inheritance and lack of recombination. Over the past few years, a variety of different observations has challenged these accepted notions of mitochondrial biology. Notable examples include evidence for variable rates of mtDNA sequence evolution among taxa, evidence for large and variable mitochondrial genome sizes in certain groups, and a growing number of cases in metazoans of 'paternal leakage' in the inheritance of mtDNA. Several recent studies have uncovered different lines of evidence suggesting that an organism's thermal habit, or metabolic rate, can influence the evolution of mtDNA. PMID- 21236796 TI - Patch-occupancy dynamics in fragmented landscapes. AB - Recent work on the dynamics of species living In fragmented landscapes has produced much Information on patterns of habitat patch occupancy in a wide range of organisms. Building on an elementary Markov chain model of patch occupancy, a family of Incidence-function models can be constructed for particular kinds of metapopulations. These models can be parameterized with field data on patch occupancy, and the models can be used to make quantitative predictions about specific metapopulations. This approach provides a potentially powerful tool for the management of reserve networks and species living in fragmented landscapes. PMID- 21236797 TI - Making connections in food webs. AB - Patterns in food web structure have provided an important, though contentious, testing ground for ideas about the population dynamics and energetics of multispecies systems. One of the most debated of these patterns is the apparent decrease in food web connectance as the number of species in a web Increases. Several contrasting mechanisms that might determine food web connectance have been suggested. These mechanisms, in combination with new, food web data, suggest that the conventional pattern, and explanations for it, may well be open to dispute. The true nature of the relationship between connectance and species number has implications for the explanation of other web patterns and for theories of food web structure, but a general explanation remains elusive. PMID- 21236798 TI - Transmission patterns of eukaryotic transposable elements: arguments for and against horizontal transfer. AB - Recent studies have demonstrated that several classes of transposable elements are widely distributed within eukaryotes. Horizontal transmission of these transposable elements has often been invoked In order to explain the observed variation and relationships within and between species. These same patterns of variation and relationships, however, may originate from processes that do not involve the lateral transfer of genetic material across species. PMID- 21236799 TI - Terrestrial plant tolerance to herbivory. AB - Damage to plants by herbivores is ubiquitous and sometimes severe. Tolerance is the capacity of a plant to maintain its fitness through growth and reproduction after sustaining herbivore damage. Recent physiological and ecological work indicates that tolerance mechanisms are numerous and varied. Some of the plant traits involved may reflect selection by herbivores, while others are likely to be by-products of selection for other ecological functions. Similarly, some tolerance mechanisms may participate In trade-offs with plant defence, while many do not. Regardless of its ultimate origin or physiological relationship to plant defence, tolerance often may Influence the evolution of plant defence and the composition of plant communities. PMID- 21236800 TI - Cladistics and convergence. PMID- 21236801 TI - Reply from d. Lloyd. PMID- 21236802 TI - Aerobic denitrification. PMID- 21236803 TI - Evolutionary synthesis. PMID- 21236804 TI - Parallels between the foraging strategies of ants and plants. AB - Animal and plant ecologists generally follow separate paths. This often leads to disjointed approaches to solving similar ecological problems. In the past 20 years, two related, but unconnected, research fields have undergone rapid development: modular demography, with its morphological and functional analysis of resource capture, until now basically the domain of plant ecology; and foraging theory, traditionally applied and developed in animal ecology. The results of recent research on the foraging strategies of ants and clonal plants, however, outline a general framework of functional parallels between both types of organisms that could link important aspects of animal and plant foraging ecology. PMID- 21236805 TI - Enhancing the status of population biology. PMID- 21236807 TI - Architects of sperm competition. PMID- 21236806 TI - What is a guinea-pig? PMID- 21236808 TI - Conservation and coevolutionary implications of brood parasitism by cowbirds. PMID- 21236809 TI - Exploring solutions for the tropical biodiversity crisis. PMID- 21236810 TI - The genetic, molecular and phenotypic consequences of selection for insecticide resistance. AB - Studies of insecticide resistance allow theories of the adaptive process to be tested where the selective agent, the insecticide, is unambiguously defined. Thus, the consequences of selection of phenotypic variation can be investigated in genetic, biochemical, molecular, population biological and, most recently, developmental contexts. Are the options limited biochemically and molecularly? Is the genetic mechanism monogenic or polygenic, general or population/species specific? Are fitness and developmental patterns associated? These questions of general evolutionary significance can be considered with experimental approaches to determine how insecticide resistance evolves. PMID- 21236811 TI - Centromeres: moving chromosomes through space and time. AB - Centromeres have played a pivotal role in the evolution of the eukaryote genome. Their indispensable involvement in chromosome segregation and the evolution of linkage groups throughout all eukaryotic lineages intuitively suggests conserved structure and function. Unexpectedly, recent molecular and biochemical analyses of centromeres have revealed highly divergent patterns in both DNA sequence and organization. Unlike the microtubules with which they interact, centromeres have undergone rapid diversification during evolution while retaining the same functional attributes. The most recent evidence indicates that centromeres may be species-specific entities composed of highly variable DNA families that interact with an array of non-histone proteins before attachment to the microtubules. PMID- 21236812 TI - Genetic exchange and evolutionary divergence in prokaryotes. AB - Recent work shows that genetic exchange in prokaryotes is less frequent but more promiscuous than that in eukaryotes. As a result, genetic exchange plays very different roles in determining the patterns of evolutionary divergence in these major groups. Because sexual isolation is not a prerequisite for divergence in the prokaryotic world, the biological species concept is not appropriate for bacteria. However, there is a species concept that may apply universally. PMID- 21236813 TI - Palaeontological data and identifying mass extinctions. AB - It is often assumed that mass extinctions may be read directly from the fossil record. However, recent work on the Cretaceous-Tertiary (K-T) boundary has shown the difficulty of doing this. For example, it is hard to tell whether the stratigraphic ranges of taxa are complete or not, and what the shape of an extinction really is. Range completeness may be assessed by (1) a statistical approach to the relative completeness of ranges of taxa, and (2) tests based on collecting effort near the ends of ranges. Tests carried out recently suggest that the record is good in parts and getting better. Hence, palaeontologists ought to be able to document the nature of extinction events ever more precisely. PMID- 21236814 TI - Genital morphology. PMID- 21236815 TI - Reply from R. Edwards. PMID- 21236816 TI - Genital morphology. PMID- 21236817 TI - Interpreting phenotypic variation in plants. AB - Plant ecologists and evolutionary biologists frequently examine patterns of phenotypic variation across variable environments or genetic identities. Too often, we ignore the fact that most phenotypic traits change throughout growth and development of individual plants, and that rates of growth and development are highly variable. Plants growing in different environments are likely to grow at different rates, and will be of different sizes and stages of development at a particular age. When we compare plants as a function of plant size or developmental stage, as well as a function of age, we broaden our understanding of phenotypic variation between plants. PMID- 21236818 TI - Positive interactions in communities. AB - Current concepts of the role of interspecific interactions in communities have been shaped by a profusion of experimental studies of interspecific competition over the past few decades. Evidence for the importance of positive interactions - facilitations - in community organization and dynamics has accrued to the point where it warrants formal inclusion into community ecology theory, as it has been in evolutionary biology. PMID- 21236819 TI - The tragedy of the unmanaged commons. PMID- 21236820 TI - Symmetry is in the eye of the beholder. PMID- 21236822 TI - Ecosystem response to elevated CO(2). PMID- 21236821 TI - Polyandrous parasitoids: multiple mating for variety's sake? PMID- 21236823 TI - Branching out: the new angles on molecular evolution. PMID- 21236824 TI - Levels of herbivory and parasitism in host hybrid zones. AB - Hybrid zones often are intermediate in their habitat, and have individuals that are intermediate genetically to those of either parental species. Recently, a number of studies has addressed the distribution of herbivores and parasites in hybrid zones of their hosts. Mechanisms that underlie these distributions include behavioral, environmental and genotypic differences between hybrids and their parental species. PMID- 21236825 TI - Conditional outcomes in mutualistic interactions. AB - Interspecific interactions are traditionally displayed in a grid in which each interaction is placed according to its outcome (positive, negative or neutral) for each partner. However, recent field studies consistently find the costs and benefits that determine net effects to vary greatly in both space and time, inevitably causing outcomes within most interactions to vary as well. Interactions show 'conditionality' when costs and benefits, and thus outcomes, are affected in predictable ways by current ecological conditions. The full range of natural outcomes of a given association may reveal far more about its ecological and evolutionary dynamics than does the average outcome at a given place and time. PMID- 21236826 TI - Effects of who-ecosystem manipulations on ecosystem internal processes. AB - Whole-ecosystem manipulation is a useful tool for investigating the effects of air pollution, air pollution reduction strategies and management practices on the health and productivity of forests, and has become widely used in forest ecosystem research. This review of the whole-ecosystem manipulation research gives an overview of the recent and ongoing research within this field and synthesizes the results obtained so far. PMID- 21236827 TI - Species borders: ecological and evolutionary perspectives. AB - Recent ecological studies on species borders have used a number of approaches to establish causation for specific environmental factors and to identify the traits involved. These include interspecific comparisons, detailed investigations of marginal populations, and experimental manipulation. Species borders continue to be largely ignored in evolutionary biology, although some work suggests that marginal populations may often be relatively better-adapted to unfavourable conditions but perform poorly under most other conditions. PMID- 21236828 TI - Systematics and biodiversity. PMID- 21236829 TI - Systematics and biodiversity. PMID- 21236830 TI - Systematics and biodiversity. PMID- 21236831 TI - Systematics and biodiversity. PMID- 21236832 TI - Reply from s.s. Renner and R.e. Ricklefs. PMID- 21236833 TI - Systematics and biodiversity. PMID- 21236834 TI - Cooperation or individualism: how leaf-cutting ants decide on the size of their loads. PMID- 21236835 TI - The 15% solution for preservation. PMID- 21236836 TI - Applications of the Hertzsprung-Russell star chart to ecology: reflections on the 21(st) birthday of Geographical Ecology. AB - Robert MacArthur's Geographical Ecology turned 21 last year. As it enters adulthood, we may ask whether or not it is still influencing contemporary approaches to ecology. The opening sentence, 'To do science is to search for repeated patterns, not simply to accumulate facts...', is a theme of the entire book. As ecologists, we are faced with the problem of finding patterns when there is a large number of species, an even larger number of possible pairwise interactions, and when these are dispersed across a bewildering array of habitat types. How do we look for general patterns in nature? The Hertzsprung-Russell star diagram provides an inspiring example for meeting MacArthur's challenge. PMID- 21236837 TI - 'Heads I win, tails you lose': testing directional alternative hypotheses in ecological and evolutionary research. AB - Whenever experiments make a priori predictions about the direction of change in some parameter, one-tailed test statistics offer a potentially large gain in power over the corresponding two-tailed test. This gain is rarely used in ecology and evolution because of (1) the belief that one-tailed procedures are unavailable for most statistical tests and (2) an inherent dilemma in one-tailed tests: how do we handle large parameter changes in the unanticipated direction? The first problem is a misconception, whereas the second is easily resolved by recognizing that one- and two-tailed tests are simply extremes in a continuum of testing options. PMID- 21236838 TI - Global population, food and the environment. PMID- 21236839 TI - Eye evolution: Darwin's shudder stilled. PMID- 21236840 TI - Linked sexiness and choosiness. PMID- 21236841 TI - Chaos and forecasting. PMID- 21236842 TI - Competition and coexistence in plant communities. AB - Few ecologists today doubt that competition is an important structuring factor in plant communities, but researchers disagree on the circumstances where it is most intense, and on which traits can be considered to contribute to competitive ability in different species. The distinction between a species' effect on resources and its response to reduced resource levels might help to solve these questions. Whereas classical competition theory predicts competitive exclusion of species with similar requirements, recent ideas stress that species diversity may be explained by a multitude of processes acting at different scales, and that similarities in competitive abilities often may facilitate coexistence. PMID- 21236843 TI - Interactions between aboveground herbivores and the mycorrhizal mutualists of plants. AB - Plant growth, reproduction and survival can be affected both by mycorrhizal fungi and aboveground herbivores, but few studies have examined the interactive effects of these factors on plants. Most of the available data suggest that severe herbivory reduces root colonization by vesicular-arbuscular and ectomycorrhizal fungi. However, the reverse interaction has also been documented - mycorrhizal fungi deter herbivores and interact with fungal endophytes to influence herbivory. Although consistent patterns and mechanistic explanations are yet to emerge, it is likely that aboveground herbivore-mycorrhiza interactions have important implications for plant populations and communities. PMID- 21236844 TI - Genes, trees and infections: Molecular evidence in epidemiology. AB - Molecular phylogenies constitute an important new way of tracking the progress of viral epidemics. The phylogenetic analysis of viral sequence data provides information on the origin, spread and maintenance of infections and can be used to reconstruct contact networks of infected individuals. Analysis of the branching structure of phylogenetic trees also allows inferences to be made about the rate of transmission and the distinction between endemic and epidemic infections, and provides estimates of the numbers of infected individuals. PMID- 21236845 TI - Caveat emptor: rank transform methods and interaction. AB - When distributional assumptions for analysis of variance are suspect, and nonparametric methods are unavailable, ecologists frequently employ rank transformation (RT) methods. The technique replaces observations by their ranks, which are then analysed using standard parametric tests. RT methods are widely recommended in statistics texts and in manuals for packages like SAS and IMSL. They are robust and powerful for the analysis of additive factorial designs. Recently, however, RT methods have been found to be grossly inappropriate for use with non-additive models. This severe limitation remains largely unreported outside of the theoretical statistics literature. Our goal is to explain this shortcoming of RT methods. PMID- 21236846 TI - Ethics of artificially inducing landfall by migrants. PMID- 21236847 TI - Energetic or biomass equivalence rule? PMID- 21236848 TI - Eusociality in a microtine rodent. PMID- 21236849 TI - How (not) to test an optimality model. AB - The controversy over the use of optimality models in the investigation of adaptation is long-standing. Nonetheless, little or no attention has been paid in this debate to the most important question to be asked about such models: how should the test of an optimality model be structured if the local optimality of the trait is to be assessed? Here we answer this question and describe how such a test can contribute to a test of adaptationism. PMID- 21236850 TI - Advances in marine conservation: the role of marine protected areas. AB - The world's oceans are now attracting the serious attention of conservationists. Paradoxically, as the value of marine biological diversity is recognized, the ecosystems that harbor this diversity are fast becoming degraded. New thinking about how to conserve coastal areas has resulted in protected-area models that incorporate principles of landscape ecology, adaptive and ecosystem management, and zoning in protected-area plans. PMID- 21236851 TI - Darwin, have I failed you? PMID- 21236852 TI - How do sharks orient at sea? PMID- 21236853 TI - Shortcomings of the cytochrome b gene as a molecular marker. PMID- 21236854 TI - Ecological risks of transgenic crops. PMID- 21236855 TI - Benefits, constrainsts and the evolution of the family. AB - Families form when offspring delay dispersal and remain associated with their parents into adulthood. What are the ultimate causes of such philopatry and prolonged association? Two schools of thought have emerged, providing seemingly opposing answers to this question - the 'benefits of philopatry' and the 'ecological constraints' schools. A recent threshold model for delayed dispersal helps clarify the confused semantics of these arguments and demonstrates the complimentarity of the two approaches. Many of the current advantages of family living may have evolved secondarily, however, suggesting that the initial origin of families occurred under conditions of severe competition for breeding vacancies. PMID- 21236856 TI - Sympatric speciation in animals: new wine in old bottles. AB - Recent research on natural host races and sympatric sister species, comparative phylogenetic analyses, laboratory experiments and theoretical models has greatly strengthened the case for sympatric speciation. Traits evolving in response to divergent selection experienced by subpopulations adapting to different habitats provide sufficient intrinsic premating isolation for sympatric speciation to occur. The initiation of speciation through a habitat shift in animals which mate within a preferred habitat (such as many phytophagous and parasitic invertebrates and some vertebrates, including birds) requires few genetic changes. PMID- 21236857 TI - Sexual conflict and the evolutionary ecology of mating patterns: water striders as a model system. AB - Two core ideas in the study of mating systems and sexual selection are (1) the existence of a conflict between the sexes over mating decisions, and (2) that variation in ecological conditions drives the evolution of adaptive mating strategies and the diversification of mating systems. A recent burst of experimental studies of mating behavior and sexual selection in water striders has focused on the interaction of these ideas and led to new insights into the evolutionary ecology of mating systems and sexual selection. PMID- 21236858 TI - Mother's little helpers: Patterns of male care in mammals. AB - Over the past 20 years, long-term studies have shown that mammalian fathers, brothers and even unrelated males may contribute substantially to the care of the young. Recently, more field studies of mammals with male care have further expanded interest in male care potential. Male mammals can never be sole care givers because offspring depend on maternal milk, but assistance provided by males may allow females to produce more energetically costly litters. The need for such male care contributes to the development of obligate social monogamy or communal breeding. PMID- 21236860 TI - Reply from g.a. Hoelzer and d.j. Melnick. PMID- 21236859 TI - Speciation and phylogenetic resolution. PMID- 21236861 TI - [In Process Citation] PMID- 21236862 TI - Reply from o. Judson. PMID- 21236863 TI - Individual-based models. PMID- 21236865 TI - Difficulties in deducing dynamics from static distributions. PMID- 21236864 TI - Reply from I. Hanski. PMID- 21236866 TI - Seagrass landscapes: a terrestrial approach to the marine subtidal environment. AB - Subtidal seagrass habitats are prime candidates for the application of principles derived from landscape ecology. Although seagrass systems are relatively simple compared to their terrestrial counterparts in terms of species diversity and structural complexity, seagrasses do display variation in spatial patterns over a variety of scales. The presence of a moving water layer and its influence on faunal dispersal may be a distinguishing feature impacting ecological processes in the subtidal zone. Studying seagrass-dominated landscapes may provide a novel approach to investigating questions regarding self-similarity of spatial patterns, and offers a new perspective for analysing habitat change in a variety of marine environments. PMID- 21236868 TI - National peculiarities, scientific traditions and research directions. PMID- 21236867 TI - Costs of reproduction in a historical perspective. AB - Costs of reproduction constitute a core assumption of life history theory. After reformulation by G.C. Williams, the cost hypothesis soon became a major foundation of phenotypic life history models. More-recent studies have approached reproductive costs from the perspective of quantitative genetics. Here, we present a brief historical perspective to the development of the cost of reproduction hypothesis. We evaluate the status and heuristic value of the different approaches, and outline how the approaches have originated. PMID- 21236869 TI - Early hormones and the development of phenotypic variation in tree lizards. PMID- 21236870 TI - Did Icelandic volcanic eruptions influence the post-glacial vegetational history of the British Isles? PMID- 21236871 TI - Linking human and nonhuman mating systems. PMID- 21236872 TI - The Pitcairn Islands: paradise past, paradise present? PMID- 21236873 TI - Genetic biodiversity: analysing the data. PMID- 21236874 TI - Symbionts and organelles in ancrobic protozoa and fungi. AB - The discovery of methanogenic bacteria as endosymbionts of free-living anaerobic protozoa opened new fields of research in microbial ecology, cell physiology and molecular biology. Recent information from 16S rRNA sequence studies has shown in three cases that endosymbiotic methanogenic bacteria differ from free-living species. Frequently, endosymbiotic methanogens are localized in anaerobic protozoa near hydrogenosomes - organelles that produce H2, C02 and acetate, all of which are substrates for methanogenesis. Hydrogenosomes are also present in anaerobic fungi. The current view is that the organelles are endosymbllont derived and were probably acquired on several distinct occasions during evolution. PMID- 21236875 TI - The effects of climate charge on land-atmosphere feedbacks in arctic tundra regions. AB - Recently reported high-latitude warming has the potential to affect arctic ecosystem structure and function in the short and long term. Arctic ecosystems are known sources of atmospheric CH(4), and recent CO(2) flux measurements indicate that these ecosystems are now, at least regionally, net sources of atmospheric Co(2). It appears that over the short term (decades to centuries), arctic ecosystems may represent a positive feedback on global atmospheric CO(2) concentrations and associated greenhouse gas-Induced climate change. In addition, short-term feedbacks may be large enough to affect both local and global surface temperatures. Over the long term, changes in the structure, function and composition of arctic ecosystems may increase C accumulation relatively more than the amount lost, thus restoring the sink status of arctic ecosystems. PMID- 21236876 TI - Molecular phylogeny of eukaryotes. AB - Comparisons of ribosomal RNAs and various protein coding genes have contributed to a new view of eukaryote phylogeny. Analyses of paralogous protein coding genes suggest that archaebacteria and eukaryotes are sistergroups. Sequence diversity of small subunit rRNAs in protists by far exceeds that of any multicellular or prokaryote taxon. Remarkably, a group of taxa that lack mitochondria first branches off in the small subunit rRNA tree. The later radiations are formed by a series of clades that were once thought to be more ancestral. Furthermore, tracing of the evolutionary origin of secondary endobiontic events is now possible with sequence comparisons. PMID- 21236877 TI - The use and abuse of pollinators by fungi. AB - Some fungi use flower-visiting insects to facilitate sexual reproduction or to disperse spores. These fungi have evolved elaborate techniques, such as floral mimicry and the invasion of extant flower parts, for attracting 'pollinators'. Recent research shows that fungal exploitation of pollinators has the potential to affect floral evolution, pollination ecology, plant life history traits, as well as disease-transmission dynamics and fungal evolution. PMID- 21236878 TI - Small-step invasion research. AB - Recent invasion research can be categorized broadly into two types: studies of the spatial spread, and those of the biological impact the invader has on the native biota. The first type is the most factual, and the second the most theoretical. So far, however, it is difficult to connect the two, implying that neither the spatial spread nor the species interactions can be explained in terms of each other. Recent models, analysing spatial spread, progress steadily by making small steps. PMID- 21236879 TI - Reply from a. Pomiankowski and L. Sheridan. PMID- 21236880 TI - Female choice and genetic correlations. PMID- 21236881 TI - Reply from w. Sousa. PMID- 21236883 TI - Reply from k.j. Willis. PMID- 21236882 TI - Interactive versus isolationist helminth communities reconsidered. PMID- 21236884 TI - Palaeoecology and ecology. PMID- 21236885 TI - Ecology and sustainable development. PMID- 21236886 TI - 100 issues of Tree. PMID- 21236887 TI - Spots before the eyes: molecular ecology. PMID- 21236888 TI - Ecology and paleoecology begin to merge. PMID- 21236889 TI - The evolution of behavioural ecology. PMID- 21236890 TI - Phylogenetic epidemiology lives. PMID- 21236891 TI - A new epoch in joint studies of social evolution: molecular and behavioural ecology of aphid soldiers. PMID- 21236893 TI - Graeme Caughley and the emerging science of conservation biology. PMID- 21236892 TI - Priorities in tropical biology. PMID- 21236894 TI - Chernobyl: eight years after. PMID- 21236895 TI - Future directions of global change research in terrestrial ecosystems. PMID- 21236896 TI - Defining 'Evolutionarily Significant Units' for conservation. PMID- 21236897 TI - Modelling food webs and nutrient cycling in agro-ecosystems. AB - Agricultural practices affect the spatial patterns and dynamics of the decomposition of soil organic matter and the availability of plant-limiting nutrients. The biological processes underlying these patterns and dynamics are the trophic interactions among the organisms in the soil community food web. Food web models simulate nutrient flow rates close to observed rates and clarify the role of the various groups of organisms in the cycling of nutrients. Several large interdisciplinary programs are currently focusing on these interactions, with a view to developing and managing sustainable forms of agriculture. PMID- 21236898 TI - The importance of nutrient pulses in tropical forests. AB - Recent research shows that nutrient fluxes are often pulsed In tropical forests, and that pulsed versus gradual inputs have different effects on the fates of nutrients in the ecosystem. Synchrony of nutrient mineralization with plant uptake can lower competition between microbes and plants for limiting nutrients while maintaining tight nutrient cycling, whereas asynchrony can lead to losses of nutrients from the system. Thus, nutrient pulses may play a critical role in maintaining productivity in tropical forests with tight nutrient cycling. PMID- 21236899 TI - Singing and cryptic speciation insects. AB - Biologists have long known of the existence of 'inaudible' songs in insects, but recent work has shown such substrate-borne or near-field signals to be virtually ubiquitous, and often correlated with high numbers of sibling species. In a sexual context, silent singing has the formidable advantage of privacy: neither predators nor sexual competitors can listen and disrupt. Privacy enhances species recognition by promoting signal complexity. It also encourages the evolution of intricate signals in females as well as males, leading to obligatory dueting behavior during pair formation. Current evidence suggests that song divergence in dueting taxa can facilitate rapid, sympatric speciation. PMID- 21236900 TI - Pathogens and the structure of plant communities. AB - There is increasing interest in the direct and indirect effects of pathogens and parasites on the structure of plant communities. The direct influence of pathogens is seen in cases where pathogens reduce the populations of adult and seedling plants or prevent the recruitment of seeds. Indirect effects occur when epidemic outbreaks or endemic parasites of herbivores lead to reductions in grazing pressure, which temporarily allow plants to escape from the detrimental effects of their herbivores. In both cases, the presence of pathogens can lead to changes in the relative abundance of the species in a plant community, which are discernible for many years after the initial disease outbreak has passed. PMID- 21236901 TI - Reply from N. Knowlton and j.B.C. Jackson. PMID- 21236902 TI - Taxonomy and coral reef ecology. PMID- 21236903 TI - The dynamics of parent-offspring relationships in mammals. AB - Evolutionary theories about parent-offspring relationships have predicted that young will aggressively demand food and care from their parents at the time of weaning - when the parents should, in their own interests, reserve their efforts for future offspring. Detailed studies of the behavioural development of mammals have given only limited support for these expectations. Often the mother is more amenable to the needs of her offspring than evolutionary theory predicts, and often offspring are sensitive to the state of their mother, tuning the pattern of their own development accordingly. Such aggression as is seen between mother and offspring tends to occur at stages other than weaning. The mismatch between theory and evidence may arise because a mother needs to monitor her offspring's state as well as her own and respond appropriately in order to maximize her own reproductive success. Similarly, an offspring needs to monitor its mother and prepare for the world in which it will grow up, in order to maximize its chances of surviving to breed. PMID- 21236904 TI - Bright young people, biodiversity and species lists. PMID- 21236905 TI - New directions in biogeography? AB - The deduction of biogeographic process from the study of its history is complicated by the fact that history is a singular thing. This singularity allows no estimation of the degree of determinism surrounding the realization of biogeographic processes, and consequently we know almost nothing about the generality of such deductions. Here we discuss a new approach, called 'experimental biogeography', that exploits computers to model faunal build-up repeatedly against a fixed vicariant background over ecological and evolutionary time scales. This new approach enables a biogeographer to be omniscient - to know both vicariant history and actual phylogeny. Moreover, history can be replayed repeatedly to accumulate a sample of multiple phylogenies and to estimate probability density functions for biogeographic variables. Roles of stochastic, historical and ecological processes in adaptive radiations can also be assessed. Experimental biogeography allows examination of the reliability of various methods of recovering historical patterns. PMID- 21236906 TI - Bad ecology leads to bad public policy. PMID- 21236907 TI - Molecules, museums and vouchers. PMID- 21236908 TI - Species as 'noise' in community ecology: do seaweeds block our view of the kelp forest? PMID- 21236909 TI - South Africa evolving? PMID- 21236910 TI - Frpm artificial individuals to global patterns. AB - Artificial Life is a model of biological systems that describes lives archived by computer simulation, chemical substrates or any other non-biological substrates. Artificial Life simulation adopts a bottom-up approach in which behavior of lower level entities (e.g. molecules, cells and individuals) is all that is programed; global patterns (e.g. evolutionary patterns observed at the level of the population and the community) can emerge as a result of interaction among lower level entities. Artificial Life simulations will be used not only to test ecological and evolutionary hypotheses explaining real organisms but also to show the validity of general theories, processes and concepts such as natural selection, theories of complexity, hierarchical relations and self-organization. PMID- 21236911 TI - Origin and evolution of animal hybrid species. AB - The increasing number of hybrid species, discovered in both vertebrates and invertebrates by the combined use of chromosome, allozyme and molecular markers, calls for a reevaluation of hybrid speciation and reticulate evolution In animals. The array of reproductive strategies recently detected In phylogenetically related stick Insects allows us to Investigate, using a comparative approach, questions such as the relationship between hybridization and unisexuality, and short- versus long-term evolutionary success of hybrid species. Unexpected similarities are now apparent in hybrid evolution of animals as varied as insects, snails, fish, frogs and lizards. Hybrid species may combine, to some extent, the main advantage of sex (genetic diversity) with those of clonal reproduction. This explains why these species are often so successful, and indicates a potential use of some hybrid species in experimental biology and resource management (e.g. mass production of animal proteins). PMID- 21236912 TI - Vole cycles and antipredatory behaviour. AB - During recent years the role of predation as a simple mechanism to produce cyclical population fluctuations in microtine rodent populations has gained stronger empirical and theoretical support. Predation by several generalist species produces non-cyclicity, and predation by resident specialists, such as small mustelids, produces a synchronous cyclic pattern of population fluctuations in several vole species. At the same time, behavioural ecological studies have shown that the same group of specialist predators crucial for cyclicity causes the strongest antipredatory responses in vole behaviour. Recently, breeding suppression in cyclic microtines under risk of mustelid predation has been documented both in the laboratory and in the field. This review links the new population ecological studies and modelling of cyclic microtines and their predators with recent findings on antipredatory adaptations of voles. PMID- 21236913 TI - Cytoplasmic male sterility in plants: molecular evidence and the nucleocytoplasmic conflict. AB - A much-debated issue in plant evolutionary biology concerns the maintenance of a high frequency of male sterility in natural populations. For the past decade, a theoretical framework has been provided by the concept of nucleocytoplasmic conflict. Recent molecular studies on cytoplasmic male sterility indicate that novel chimeric genes, resulting from duplications and rearrangements of mitochondrial DNA sequences, are involved In its control. Thus, male sterility, which is phenotypically the loss of the male function, is encoded by a new mitochondrial function at the molecular level. Molecular data are in agreement with theoretical models that consider cytoplasmic male sterility as a stage in the coevolution between nucleus and mitochondria, and not simply as a deleterious mitochondrial mutation. PMID- 21236914 TI - Sex and ostracods. AB - In the quest to ascertain the selective agents sustaining sex, much effort has been directed to studies of the origin and fate of asexuals. Ostracod crustaceans are of particular importance to this work, as they appear to show the highest incidence of transitions to parthenogenesis of any animal group. In addition, their excellent fossil record provides a historical perspective, suggesting that some parthenogenetic ostracods have outmanoeuvered the Red Queen for at least 70 million years. Genetic studies are now probing the basis of such persistence and are providing new direction for experimental work examining this frequent abandonment of sex. PMID- 21236915 TI - Stay with darwin. PMID- 21236916 TI - Reply from m. Brookes and a. Pomiankowski. PMID- 21236917 TI - Symmetry and sexual selection. PMID- 21236918 TI - Another solution for preserving activity and integrity? PMID- 21236919 TI - Stay with darwin. PMID- 21236920 TI - Shyness and boldness in humans and other animals. AB - The shy-bold continuum is a fundamental axis of behavioral variation in humans and at least some other species, but its taxonomic distribution and evolutionary implications are unknown. Models of optimal risk, density- or frequency-dependent selection, and phenotypic plasticity can provide a theoretical framework for understanding shyness and boldness as a product of natural selection. We sketch this framework and review the few empirical studies of shyness and boldness in natural populations. The study of shyness and boldness adds an interesting new dimension to behavioral ecology by focusing on the nature of continuous behavioral variation that exists within the familiar categories of age, sex and size. PMID- 21236921 TI - Mutualism between ecologists and ethologists? PMID- 21236922 TI - Slaying the dragon. PMID- 21236923 TI - An ecological perspective on methane emissions from northern wetlands. AB - Wetlands are significant sources of atmospheric methane, an important radiatively active 'greenhouse' gas that accounts for an estimated 12% of total greenhouse warming. Since global climate models predict the greatest temperature and precipitation changes at high latitudes, and as the largest areas of wetland (346 * 10(6)ha) are in the boreal and subarctic regions (40-70 degrees N), recent research has focused on Identifying the factors that control methane emission from northern wetlands. Over the past few years, the database has expanded tremendously, and much progress has been made in understanding the environmental controls on methane emission at small spatial and temporal scales. However, we now need to broaden our understanding of regional differences in methane emission, ecological responses of northern wetlands to climate change, and the effect of other perturbations such as drainage and flooding. PMID- 21236924 TI - The evolutionary ecology of mast seeding. AB - The past seven years have seen a revolution in understanding the causes of mast seeding In perennial plants. Before 1987, the two main theories were resource matching (i.e. plants vary their reproductive output to match variable resources) and predator satiation (i.e. losses to predators are reduced by varying the seed crop). Today, resource matching is restricted to a proximate role, and predator satiation is only one of many theories for the ultimate advantage of masting. Wind pollination, prediction of favourable years for seedling establishment, animal pollination, animal dispersal of fruits, high accessory costs of reproduction and large seed size have all been advanced as possible causes of masting. Of these, wind pollination, predator satiation and environmental prediction are important in a number of species, but the other theories have less support. In future, Important advances seem likely from quantifying synchrony within a population, and examining species with very constant reproduction between years. PMID- 21236925 TI - Animal body size distributions: patterns, mechanisms and implications. AB - Documenting the shape of the frequency distribution of species body sizes for an animal taxon appears at first sight a straightforward task. However, a variety of patterns has been reported, and a consensus is only now being reached through an understanding of how potential biases may affect observed shapes of distributions. A new body of evidence suggests that, at large scales, size distributions are right-skewed, even on logarithmic axes. If body size distributions can be described with certainty, this will allow assessment of the mechanisms proposed to generate them, and will be an important step towards understanding the structure and dynamics of animal assemblages. PMID- 21236926 TI - Evolutionary ecology of periodical insects. AB - To be periodical, a species must have a fixed life cycle length and adults must appear synchronously, reproduce only once, and die. The consequence of this life history is that, at a given location, adults of a periodical species will be absent or rare in some years and abundant in others. The relative scarcity of periodical Insect species suggests that periodicity does not evolve easily. The major obstacle to its evolution is selection favoring life cycles In which the offspring of any given female appear over a two- or three-year period. Chance events which disrupt this 'bet-hedging' strategy set the stage for periodicity. Mathematical models predict that, given certain initial conditions, intraspecific competition and predation favor its development. Recent studies suggest that periodicity is rarely perfect but that it can persist in the face of limited gene flow through time. PMID- 21236927 TI - Fossil horses, carbon isotopes and global change. AB - Between 20 and 10 million years ago, Miocene horses demonstrate rapid dental evolution from low-crowned (brachydont) to high-crowned (hypsodont) teeth. Hypsodonty is classically interpreted as an adaptive shift from browsing to grazing to exploit the spread of savanna grasses. Recent geochemical studies allow the use of carbon Isotopes to test this hypothesis. Isotopic analysis of fossil horse teeth Indicates a predominantly C(3) diet consisting of mixed browse/grass or predominantly C(3) grasses until the latest Miocene. The advent of C(4) grassland ecosystems began about 7-8 million years ago and seems related to declining equid diversity. PMID- 21236929 TI - Reply from R.j. Abbott. PMID- 21236928 TI - The landscape approach in ecology. PMID- 21236931 TI - No conflict among abundance rules. PMID- 21236932 TI - Reply from B.d. Robbins and s.s. Bell. PMID- 21236930 TI - Transgenic plants. PMID- 21236933 TI - Taxonomic minimalism. AB - Biological surveys are in increasing demand while taxonomic resources continue to decline. How much formal taxonomy is required to get the job done? The answer depends on the kind of job but it is possible that taxonomic minimalism, especially (1) the use of higher taxonomic ranks, (2) the use of morphospecies rather than species (as identified by Latin binomials), and (3) the involvement of taxonomic specialists only for training and verification, may offer advantages for biodiversity assessment, environmental monitoring and ecological research. As such, formal taxonomy remains central to the process of biological inventory and survey but resources may be allocated more efficiently. For example, if formal Identification is not required, resources may be concentrated on replication and increasing sample sizes. Taxonomic minimalism may also facilitate the inclusion in these activities of important but neglected groups, especially among the invertebrates, and perhaps even microorganisms. PMID- 21236934 TI - Plant growth and defense. PMID- 21236935 TI - Modelling social insect foraging. AB - Foraging in the social insects can be viewed as a provisioning process, in which workers are powered by one resource (e.g. nectar) to deliver another (e.g. pollen) for the colony. The rate of delivery of a resource depends on the number of workers and how hard they work, which may depend on self-feeding rate. Whether individuals sacrifice their own foraging efficiency in favour of colony performance is unclear, as theory and experiment have not yet properly addressed these issues. PMID- 21236936 TI - Ecological intelligence. PMID- 21236937 TI - Of tongues and noses: chemoreception in lizards and snakes. AB - Lizards and snakes inhabit a world so richly textured in chemical information that, as primates, we can only imagine it. Subtle nuances of chemical shading underline nearly every fundamental activity of their lives, from finding foot to finding mates. Recent work examines the nature of these chemical messages, mechanisms for their perception, the interplay of the chemical senses in the sociobiology of the group, and patterns of chemosensory evolution. Emerging is a new sense of lizard and snake behavioral complexity that belies the common notion of these animals as simple automata and points to a surprising capacity for plasticity and learning. PMID- 21236938 TI - Something borrowed, something green: lateral transfer of chloroplasts by secondary endosymbiosis. AB - New molecular data confirm what electron microscopists long suspected - fusion of two different eukaryotic cells into a single more-complex cell created novel groups of protists. By engulfing an algal cell and putting it to work as a solar powered food factory, heterotrophic protozoans became autotrophic. Drastically reduced, the engulfed cell now exists as an organelle in the host cell. Such blending of lineages was perhaps a driving force in early eukaryotic diversification. PMID- 21236939 TI - Research in large, long-term tropical forest plots. AB - The past 15 years has seen the creation oflarge (>/16 ha) permanent inventory plots in each of the major tropical forest formations of the world. Currently, six such plots have been fully mapped, and five more and under way. A standardized methodology is used at all sites - a complete census of all trees and saplings down to 1 cm in diameter - thus assuring strict comparability between sites and allowing the development of general models for the dynamics of tropical forests. The inventories aim to gather demographic information on individual tree species, to provide long-term information on forest composition so that future changes can be detected, to estimate the economic value of forest resources, to generate models of sustainable extraction, and to provide data on underused native species for use in reforestation or plantation forestry. The plots also provide data from undisturbed forest to serve as a control for anthropological and management studies of harvested forests. PMID- 21236940 TI - Multiple-trait coevolution and environmental gradients in guppies. AB - Guppies show geographical variation in many different kinds of traits. Traits covary with each other, with predation and with other environmental factors. Phenotypic correlations are often assumed to result from genetic correlations, but may also result from covariation among different sources of natural selection and interactions among the traits' functions. This network of interactions could bias the direction of evolution in characteristic ways, and suggests how intraspecific variation may give rise to interspecific variation. PMID- 21236941 TI - Are there physiological and biochemical adaptations of metabolism in deep-sea animals? AB - From the earliest observations of deep-sea animals, it was obvious that they differed in many ways from shallower-living relatives. Over the years, there has been speculation that deep-sea animals have unusually low rates of biological activity; numerous adaptive scenarios explaining this have ben offered. However, these speculations and scenarios have rarely been tested due to the difficulty of data collection and the inevitable confounding of a number of major variables which covary with depth. In recent years, study of the metabolic properties of animals of several phyla from widely differing deep-sea habitats, including the hydrthermal vents, has made it possible, using comparative approaches, to test hypotheses concerning the metabolic adaptations of deep-sea animals. PMID- 21236942 TI - Phylogeny and stratigraphy. PMID- 21236943 TI - Reply from m.R. Gross. PMID- 21236944 TI - The emergence of behavioural ecology. PMID- 21236945 TI - Reply from m.j. Benton. PMID- 21236946 TI - Reply from g.L. Bush. PMID- 21236947 TI - Scientific research traditions and collaboration in tropical ecology. PMID- 21236948 TI - Species and speciation. PMID- 21236949 TI - Plant growth and defense: reply to Herms and Mattson. PMID- 21236950 TI - Flux control at the ecosystem level. AB - The analysis of metabolic control has reached a high level of understanding of the regulation in cellular metabolic pathways. However, as soon as we leave the realm of cell compartments and enter into the demise of coordination at the organism or ecosystem level, control theory enters unstable ground. Organisms act as individuals. Here, I compare control features at different levels of organization (cell to ecosystem), to indicate how we may approach understanding of control in complex and multiple-species systems. PMID- 21236951 TI - Hormonal basis of sexual dimorphism in birds: implications for new theories of sexual selection. AB - It is widely assumed that the development of male secondary sexual traits in birds and mammals is testosterone-dependent. In birds, however, masculinity has dual origins. Male-type behaviour and morphology, such as spurs and wattles, are usually testosterone-dependent. However, showy male-type plumage is, generally, the neutral state of development. For example, castrating a peacock has no effect on his elaborate plumage whereas ovariectomizing a peahen causes her to develop showy male-type plumage. The surprising relationships between dimorphism and gonadal steroids in birds have important consequences for the current debate concerning the evolution of biological signals and, in particular, the immunocompetence-handicap principle. PMID- 21236952 TI - Comparative risk assessment and the naturalistic fallacy. PMID- 21236953 TI - Edge effects in fragmented forests: implications for conservation. AB - Edges are presumed to have deleterious consequences for the organisms that remain in forest fragments. However, there is substantial discrepancy among recent studies about the existence and intensity of edge effects. Most studies have focused on seeking simplistic and static patterns. Very few have tested mechanistic hypotheses or explored the factors that modulate edge effects. Consequently,studies are very site-specifci and their results cannot be generalized to produce a universal theory of edges. Although estimates of the intensity and impact of edge effects in fragmented forests are urgently required, little can be done to ameliorate edge effects unless their mechanics are better understood. PMID- 21236954 TI - Litter decomposition, climate and liter quality. AB - Litter decomposition is controlled by three main factors: climate, litter quality and the nature and abundance of the decomposing organisms. Climate is the dominant factor in areas subjected to unfavourable weather conditions, whereas litter quality largely prevails as the regulator under favourable conditions. Litter quality remains important until the late decomposition stages through its effects on humus formation. Interest in the role of litter decomposition in the global carbon cycle has increased recently since (1) increased atmospheric carbon dioxide will probably affect the chemical quality of litter (especially nitrogen content), and (2) global warming may enhance decomposition rates. PMID- 21236955 TI - Are natural hybrids fit or unfit relative to their parents? AB - The process of natural hybridization may produce genotypes that establish new evolutionary lineages. However, many authors have concluded that natural hybridization is of little evolutionary importance because hybrids, in general, are unfit relative to their progenitors. Deciding between these alternative conclusions requires that fitness be measured for hybrid classes and parental species. Recent analyses have found that hybrids are not uniformly unfit, but rather are genotypic classes that possess lower, equivalent or higher levels of fitness relative to their parental taxa. PMID- 21236956 TI - Tracking ecology over geological time: evolution within guilds of vertebrates. AB - Community structure, stability and change can be observed in the fossil record over timescales that far exceed what is possible in the present. Recent quantitative studies on ecological structure withion ancient guilds of various vertebrate predators, inlcuding birds, mammals and reptiles, have revealed a common pattern of iterative replacement of feeding ecomorphs over time, despite large differences in phylogenetic composition. As a result, patterns of resource division among sympatric carnivores remain stable over many millions of years and probably reflect interspecific competition and aspects of the food resource. PMID- 21236957 TI - Evaluating changes in land cover and their importance for global change. AB - During recent years, much progress has been made in integrating traditional natural science disciplines and in the developmnet of multidisciplinary models. This is crucial for an increased understanding of the dynamics of the Earth system. The domination of human activities in altering these dynamics is still increasing. However, few research projects have focused directly on understanding the motives for such intensification. It has only recently been acknowledged that improved understanding of human driving forces of global change is required to enable meaningful projections of plausible future states of the Earth system. PMID- 21236959 TI - Reply from p.h. Harvey. PMID- 21236958 TI - Synthesizing plant tolerance and avoidance of herbivory: do ecologists risk re inventing the wheel? PMID- 21236960 TI - The WORLDMAP debate. PMID- 21236961 TI - Reply from j.p. Rosenthal and p. Kotanen. PMID- 21236962 TI - Reply from p. Bateson. PMID- 21236963 TI - Parent-offspring relations in mammals. PMID- 21236964 TI - Altruism among non-relatives: alternatives to the 'Prisoner's Dilemma'. AB - Triver's model of reciprocal altruism, and its descendants based on the Prisoner's Dilemma model, have dominated thinking about cooperation and altruism between non-relatives. However, there are three alternative models of altruism directed to non-relatives. These models, which are not based on the Prisoner's Dilemma, may explain a variety of phenomena, from allogrooming among impala to helping by non-relatives in cooperatively breeding birds and mammals. PMID- 21236965 TI - UK science policy and environmental research. PMID- 21236967 TI - Entmophagous insects: progress in evolutionary and applied ecology. PMID- 21236966 TI - The measurement of stability in grasslands. PMID- 21236968 TI - Reconstructing hurricane passages over forest: a tool for understanding multiple scale responses to disturbance. PMID- 21236969 TI - Animal signals: all honesty and light? PMID- 21236970 TI - Sticklebacks: a model for behavior evolution. PMID- 21236971 TI - Molecular insights into the evolution of an enzyme; esterase6 in Drosophila. AB - It is still a suspicion among some evolutionary biologists that the incursion of molecular biology into their field will do little more than determine the DNA sequence differences underlying evolutionary changes already evident at the organismal level. Work on an esterase enzyme involved in the reproductive biology of Drosophila belies this view. Although it is already one of the most intensively studied gene - enzyme systems at an organismal level, recent molecular invetigations reveal several unexpected, and, in some cases, still inexplicable phenomena in its evolutionary history. PMID- 21236972 TI - Molecular evidence on the origin of tetrapods and the relationships of the coelacanth. AB - Coelacanths were believed to have gone extinct more than 80 million years ago - until the sensational rediscovery of one surviving member of this leneage, Latimeria chalumanae, in 1938. Since then, plaeontologists and comparative morphologists have argues whether coelacanths or lungfish (two groups of lobe finned fish) are the living sistergroup of the third extant lineage, the tetrapods. Recent molecular phylogenetic data on this debate tend to favor the hypothesis that lungfish are the closest relatives of land vertebrates. Somewhat surprisingly, the strongest molecular support for this hypothesis stems from mitochondrial rather than nuclear DNA sequences, despite the expectation that the more-slowly evolving nuclear genes should be more appropriate in addressing a phylogenetic issue involving taxonomic groups that diverged around 400 million years ago. This molecular estimate might serve as a framework to test palepntological and physiological innovations and preadaptations that allowed Devanian lobe-finned fish to colonize land. PMID- 21236973 TI - Phylogenetic tests of the sensory exploitation model of sexual selection. AB - The diverse characteristics among closely related species are often involved in communication between the sexes. The traditional view that intersexual communication behaviors evolve in a complementary way is called into question by the sensory exploitation hypothesis. By predicting a lack of coordinated evolution between signals and preferences, the sensory exploitation hypothesis is distinct from other mechanisms of sexual selection. Tests of sensory exploitation have taken a multi-disciplinary approach, with insights from sensory physiology, behavior and phylogenetic comparisons. By demonstrating that signals and receivers are not closely coupled, and that signal preference pre-dates signal origin, proponents of the model argue that sensory exploitation is an evolutionary force responsible for the diversification of intersexual communication signals. PMID- 21236974 TI - Reply from s.h. Orzack. PMID- 21236975 TI - Hormones, handicaps and bright birds. PMID- 21236976 TI - Reply from I.p.f. Owens and R.v. Short. PMID- 21236978 TI - The evolution of plant behavioural ecology. PMID- 21236977 TI - Tests of optimality models. PMID- 21236979 TI - Bryozoan sex. PMID- 21236980 TI - Transposable elements: possible catalysts of organismic evolution. AB - Mutation is the ultimate source of all genetic variation in natural populations and is generally considered a prerequisite for evolution. Although transposable elements are acknowledged as a major source of spontaneous mutations, the evolutionary significance of these mobile pieces of DNA remains the subjects of some debate. In this perspective, I discuss the biology of transposable elements with particular emphasis on their potential to produce mutations that have dramatic effecs on organismic evolution. PMID- 21236981 TI - Pheromones, social behaviour and the functions of secondary metabolism in bacteria. PMID- 21236982 TI - The evolution of parental optimism. AB - In choosing how many offspring to rear per cycle, parents commonly starts with more than they really can afford, then allow/encourage some to die. Multiple incentives for overproduction exist. By creating marginal young, parents may: (1) capitalize when unpredictable resources prove unusually rich; (2) supply these as food or servants for core brood members; and/or (3) have a stock of replacements for any core offspring that either fail to survive or develop poorly. PMID- 21236983 TI - Neogene paleoenvironmental and paleoclimatic change in southern temperate ecosystems - a southern perspective. AB - Recently, a greatly increased number of macrofossil and pollen analytical records from Australasia and southern South America has permitted, for the first time, a comprehensive overview of past vegetation and climate change in southern temperate ecosystems. While the course of Neogene climatic change has been comparable to that of the temperate northern hemisphere, a distinctive southern hemisphere vegetation has evolved, not primarily because of its common Gondwana origin, but as a consequence of the minor amplitude of Quaternary change, absence of large ice sheets, and failure of full-glacial environments to persist through interglacials. PMID- 21236984 TI - The early evolution of cellular life. AB - Recent progress in data collection and analysis has changed the study of origin of life from an area dominated by speculation into a field abundant with testable hypotheses. This review discusses advances in the following areas: the fossil recordsd; the 'retrodiction' of biochemical pathways; and contradictions between different molecular phylogenies. The latter indicates a limited number of horizontal gene transfers during the early evolution. However, these cases of horizontal gene transfer are so infrequent that they can be detected as exceptions in an otherwise coherent picture. Cases of horizontal gene transfer can be recognized within the background of the majority consensus of molecular markers. The fusion of separate lineages to form new species is revealed by the simultaneous horizontal transfer of several independent genes. PMID- 21236985 TI - Prenatal influences on reproductive life history strategies. AB - Over the past two decades, evolutionary and behavioural ecologists have become increasingly interested in the adaptive consequences of intraspecific variability in life history and behavioural strategies. Recently, behavioural endocrinologists have begun to uncover surprising relationships between levels of prenatal exposure to gonadal hormones and variation in reproductive behaviour in adulthood. Such relationships may provide a causal explanation for many variations in adult phenotype that are of insterest to behavioural and evolutionary ecologists. PMID- 21236986 TI - The potential for computer-aided identification in biodiversity research. AB - Species identification lies at the heart of most ecological studies, but it is recognized as a difficult and often frustrating task. Taxonomists have sought to overcome the difficulties of species identification by developing a range of tools and techniques that have increasingly involved the use of computers. We describe recent developments in computer-aided species identification, which have been in four main areas; multi-access keys; hypertext keys; expert systems; and neural networks. We also suggest which technique might be appropriate for a particular taxonomic group. PMID- 21236987 TI - Green algal phylogeny. AB - Studies on the fine structure of green algal cells in the 1970s fundamentally revised theories on the evolution of green algae (Division Chlorophyta) and their relation to higher and drier green plants (i.e. embryophytes or land plants). Recent molecular phylogenetic work has largely confirmed some rather unorthodox proposals about which of the green algae represent the closest living relatives of higher plants. Resolution of the most ancient divergences on the green algal land plant lineage remains elusive because of the rapidity of these evolutionary radiations and because branch topology varies with the taxa and molecular sequences sampled (as well as method of analysis). Molecular analyses within green algal groups have reinforced the value of ultrastructural characters and challenged the use of vegetative form as on overriding feature in classification. PMID- 21236988 TI - Insecticide resistance. PMID- 21236989 TI - [In Process Citation] PMID- 21236990 TI - Novelty responses: the bridge between psychology, behavioral ecology and community ecology? PMID- 21236992 TI - Behavioural ecology: concubinage before marriage? PMID- 21236991 TI - Reply from J.A. McKenzie and P. Batterham. PMID- 21236993 TI - Reply from d.s. Wilson et Al. PMID- 21236994 TI - Do plants tap SOS signals from their infested neighbours? AB - Ecologist have not been able to show unambigous evidence for the involvement of plant-to-plant signal transfer in the defence strategies of plants. However, phytopathologists and plant physiologists recently demonstrated that resistance in undamaged plants can be elicited by volatiles of plant origin. Now that empirical evidence is accumulating, there is every reason to ask why plants use the available information on the infestion status of their neighbours and to assess the fitness advantages associated with the tuning of their defence. The debate on the ecological and evolutionary significance of interplant communication needs to be revived. PMID- 21236995 TI - Protagonists of polyembryony. PMID- 21236996 TI - Sexual differences in plant developmental phenology affect plant-herbivore interactions. PMID- 21236997 TI - The keystone cops meet in Hilo. PMID- 21236998 TI - Behavioural brain research in natural and semi-natural settings. PMID- 21236999 TI - Bacteriocins: ecological and evolutionary significance. AB - Bacteriocins are compounds that are produced by bacteria and are antagonistic to other bacteria. Although they have been known for many years, recent interest in these compounds has increased because of their potential use as natural food preservatives. Although most of this research has been directed at the molecular level, a clearer picture of the ecological role played by bacteriocins in natural environments is beginning to emerge. In addition, the importance and practical implications of evolutionary aspects of bacteriocins and bacteriocin resistance are now being assessed. PMID- 21237000 TI - Detecting disease and parasite threats to endangered species and ecosystems. AB - Ecologists have recently begun to acknowledge the importance of disease and parasites in the dynamics of populations. Diseases and parasites have probably been responsible for a number of extinctions on islands and on large land masses, but the problem has only been identified in retrospect. In contrast, endemic pathogens and parasites may operate as keystone species, playing a crucial role in maintaining the diversity of ecological communities and ecosystems. Will recent advances in the understanding of parasite population biology allow us to predict threats to endangered species and communities? PMID- 21237001 TI - Virulence and transmission of infectious diseases in humans and insects: evolutionary and demographic patterns. AB - The rate and degree of proliferation of disease organisms determine their pathogenicity and the efficiency of their transmission. These traits dictate the impact of a disease on individuals as well as populations. Virulence and transmission of diseases are molded by evolutionary forces - pathogens and hosts are each selected to reproduce and persist. New ideas about the evolution of human diseases also apply to the relationships between insects and their diseases. Evidence for close associations between insects and pathogens include the viral suppression of insect molting hormones and the occurrence of latent virus that can be activated by foreign viruses. PMID- 21237002 TI - The use of chloroplast DNA polymorphism in studies of gene flow in plants. AB - In many species of plants, the dispersal of genes is mediated by the movement of both seeds and pollen. The relative contributions of seed and pollen movement to total gene flow can be difficult to estimate. Chloroplast DNA (cpDNA) may prove useful for resolving this problem. Over the past several years, studies of numerous species of plants have shown that intraspecific variation in cpDNA is often sufficiently abundant to serve as a marker for studies of gene flow. Recent theoretical models have shown that estimates of population structure based on cpDNA polymorphism should be especially sensitive to the impact of seed movement on gene flow, because cpDNA is often maternally inherited. PMID- 21237003 TI - Reply from a.j. Beattie and I. Oliver. PMID- 21237005 TI - Taxonomic minimalism. PMID- 21237004 TI - Reply from a.j. Beattie and I. Oliver. PMID- 21237006 TI - Reply from h. Ylonen. PMID- 21237007 TI - Vole cycles. PMID- 21237009 TI - Reply from T.m. Blackburn and k.j. Gaston. PMID- 21237008 TI - 'Immunocompetence': conspicuous by its absence. PMID- 21237010 TI - The evolution of body size distributions. PMID- 21237011 TI - The evolution of information storage and heredity. AB - Many important transitions in evolution are associated with novel ways of storing and transmitting information. The storage of information in DNA sequence, and its transmission through DNA replication, is a fundamental hereditary system in all extant organisms, but it is not the only way of storing and transmitting information, and has itself replaced, and evolved from, other systems. A system that transmits information can have limited heredity or indefinite heredity. With limited heredity, the number of different possible types is commensurate with, or below, that of the individuals. With indefinite heredity, the number of possible types greatly exceeds the number of individuals in any realistic system. Recent findings suggest that the emergence and subsequent evolution of very different hereditary systems, from autocatalytic chemical cycles to natural language, accompanied the major evolutionary transitions in the history of life. PMID- 21237012 TI - Adaptive phenotypic plasticity: consensus and controversy. AB - Phenotypic plasticity is an environmentally based change in the phenotype. Understanding the evolution of adaptive phenotypic plasticity has been hampered by dissenting opinions on the merits of different methods of description, on the underlying genetic mechanisms, and on the way that plasticity is affected by natural selection in a heterogeneous environment. During much of this debate, the authors of this article have held opposing views. Here, we attempt to lay out current issues and summarize the areas of consensus and controversy surrounding the evolution of plasticity and the reaction norm (the set of phenotypes produced by a genotype over a range of environments). PMID- 21237013 TI - Low impact factors of ecology journals: don't worry. PMID- 21237014 TI - Plant venereal disease: a model for integrating genetics, ecology and epidemiology. PMID- 21237015 TI - Fitness effects of sexual dimorphism in plants. PMID- 21237016 TI - Population dynamics of HIV pathogenesis. PMID- 21237017 TI - Biological consevation strategies: optimizing in situ and ex situ approaches. PMID- 21237018 TI - Sperm limitation in the sea. AB - Because sperm outnumber eggs, it is often assumed that variation in female reproductive success has little to do with male or sperm availability. Similarly for males, access to viable eggs and sperm competition are thought to drive variation in male fertilization success. These assumptions result from empirical studies on organisms with internal fertilization. However, recent evidence from free-spawning organisms suggests that sperm can often be limiting. This finding may alter our perspective on mating-system evolution, especially in externally fertilizing organisms. PMID- 21237019 TI - Birds, bugs and blood: avian parasitism and conservation. AB - Parasitism has far-reaching implications not only for the ecology and evolution of species but also for conservation. The effects of blood-feeding ectoparasites on colonially nesting bird species have been wodely studied, but recent surprising reports show that solitarily nesting species are also commonly attacked, mainly by the larvae of flies. Most bird species are solitary nesters; as their habitats are increasingly fragmented, how will the potential for such parasitism be affected? One example is that of the endangered Puerto Rican parrot (Amazona vittata), in which habitat changes have introduced a deadly parasitic fly species in a complex and unpredicted manner. As theories on habitat fragmentation outpace the data, we need to carry out more field studies of the interactions between fragmentation and parasitism, and to include parasitism in species survival and recovery plans. PMID- 21237020 TI - Meta-analysis: synthesizing research findings in ecology and evolution. AB - The growing number of empirical studies performed in ecology and evolution creates a need for quantitative summaries of research domains to generate higher order conclusions about general trends and patterns. Recent developments In meta analysis (the area of statistics that is designed for summarizing and analyzing multiple independent studies) have opened up new and exciting possibilities. Unlike more traditional qualitative and narrative reviews, meta-analysis allows powerful quantitative analyses of the magnitude of effects and has a high degree of objectivity because it is based on a standardized set of statistical procedures. The first pioneering applications in ecology and evolution demonstrate that meta-analysis is both tractable and powerful. PMID- 21237021 TI - Self-organizing systems across scales. AB - Over the past few years, ecologists have increasingly recognized the existence of strong self-reinforcing (or self-organizing) interactions within systems at a variety of scales. Positive feedback within food chains has been reported from terrestrial and aquatic ecosystems. Accumulating evidence supports the existence within communities of cooperative guilds - tit-for-tat relationships based on diffuse mutualisms and favored by environmental unpredictability. At the landscape level, both real world experience and models indicate that processes such as hydrology and the propagation of disturbance can be strongly self reinforcing (i.e. the landscape structure supports the process, and vice versa). Hence the picture emerges of a hierarchy of self-organizing systems that span food chains, communities and landscapes/regions. PMID- 21237022 TI - Reply from e-d. Schulze. PMID- 21237023 TI - Reply from e-d. Schulze. PMID- 21237024 TI - Flux control in ecosystems. PMID- 21237025 TI - Genetic correlations as tests for sensory exploitation? PMID- 21237027 TI - Sex and ostracods. PMID- 21237026 TI - Reply from j.a. Chaplin, j.e. Havel and p.d.N. Hebert. PMID- 21237028 TI - A photosynthetic ancestry for all eukaryotes? PMID- 21237029 TI - Phenotypic similarity and the evolutionary significance of countergradient variation. AB - Countergradient variation is a geographical pattern of genotypes (with respect to environments) in which genetic influences on a trait oppose environmental influences, thereby minimizing phenotypic change along the gradient. Phenotypic similarity across changing environments ought to be of intense interest because it belies considerable genotypic change. When it occurs in characters that are positively associated with fitness, countergradient variation conflicts with the hypothesis that local adaptation to one environment trades off against performance in another environment. Cases of countergradient variation therefore offer unique insight into the mechanisms that produce and maintain phenotypic similarity and/or differences along environmental gradients. PMID- 21237030 TI - Teleology, function, design and the evolution of animal behaviour. AB - Concerns about teleological language in evolutionary biology focus on the notions of function, design and adaptation. Accounts that naturalize these ideas are currently popular. In keeping with recent developments in evolutionary theory and philosophy of biology, three naturalistic analyses of function - current utility, historical function, and functions as capacities - should be differentiated. All have roles to play in biology, although the historical conception seems the most central to evolutionary theory. While rarely distinguished from function, design should be regarded as an extension of historical function. We consider the utility of this distinction for the study of behaviour. PMID- 21237031 TI - Ecological progress to meet the challenge of environmental change. PMID- 21237033 TI - A second silent spring? PMID- 21237032 TI - In search of the Holy Grail: explanations for the coexistence of plant species. PMID- 21237034 TI - Conserving livestock breed biodiversity. AB - Growing awareness of the importance of conserving the biodiversity of livestock breeds is paralleled by genetic advances that will help objective planning of conservation. Inventories of breeds, long advocated, are now being established and concepts originally formulated for the quantification of species diversity are being applied. The breeds thus conserved will provide valuable resources for the future of agriculture, especially in the developing world. PMID- 21237035 TI - How Sphagnum bogs down other plants. AB - Recent research on the organo-chemical composition of Sphagnum and on the fate of its litter has further clarified how this plant builds acidic, nutrient-poor, cold and anoxic peat bogs. The bog environment helps Sphagnum to outcompete other plants for light. Its morphology, anatomy, physiology and composition make it an effective ecosystem engineer and at the same time benefit the plant in the short term. This may have facilitated the evolution of the genus. PMID- 21237036 TI - Evolutionary neurobiology. AB - The chasm that formerly separated evolutionary biology from the research of physiologists and developmental biologists has been partially bridged in recent years. An increasing amount of research in the neurosciences makes explicit reference to issues in evolutionary biology. Much of this research is an attempt to understand structures and functions of the brain as adaptations to an animal's physical and social environment. In addition, however, some of this research at the interface of evolutionary biology and neurobiology provides information on internal evolutionary factors and the way they may constrain evolution by natural selection. PMID- 21237038 TI - Molecular coevolution and the esterase enigma. PMID- 21237037 TI - Sex determination and population biology in the hymenoptera. AB - The Hymenoptera (ants, bees, wasps and sawflies) display a great variety of social systems and sex ratios and have played a key role in the development and testing of many evolutionary models. Traditionally, considerable emphasis was placed on the fact that hymenopterans have haploid males and diploid females but it is now clear that many species also regularly produce sterile, diploid males. Recent studies explore the diverse ways in which production of these diploid males influences selection on mating systems, sex ratios and social behaviour. PMID- 21237039 TI - Species diversity and stability in grassland. PMID- 21237040 TI - Reply from j.g. Oakeshott et Al. PMID- 21237041 TI - The fitness of hybrids. PMID- 21237042 TI - Reply from s.L. Collins. PMID- 21237043 TI - A protist writes 3. PMID- 21237044 TI - Terpenoids: a plant language. PMID- 21237045 TI - Reply from m.L. Arnold and s.a. Hodges. PMID- 21237046 TI - Ecology in deep time. AB - In certain cases the extrapolation into the geological past of conditions and processes relevant to present-day ecology is not automatically valid. Do anatomical designs show improvements through time? How do we treat fossil organisms with no living parallels? What might be the influence of shifts in atmospheric composition? If the end-Cretaceous extinctions are caused by bolide impact, why does ecological trauma persist for hundreds of thousands of years? What was the ecology of the 'Cambrian explosion'? Has the role of competition been seriously underplayed? Ancient ecosystems may differ from those of today in a variety of unexpected ways. PMID- 21237047 TI - A species definition for the modern synthesis. AB - One hundred and thirty-six years since On the Origin of Species 3., biologists might be expected to have an accepted theory of speciation. Instead, there is, if anything, more disagreement about speciation than ever before. Even more surprisingly, 60 years after the biological species concept, in which species were considered to be reproductive communities isolated from other such communities, we still do not all accept a common definition of what a species is. And yet, if speciation is to be any different from ordinary evolution, we must have a clear definition of species. The emerging solution to the species problem is an updated, genetic version of Darwin's own definition. This definition is useful and is already being used in taxonomy, in biodiversity studies and in evolution. PMID- 21237048 TI - Toward an integrated epidemiology. PMID- 21237049 TI - Heat-shock proteins and thermotolerance: linking molecular and ecological perspectives. PMID- 21237050 TI - Fragrant genes help Damenwahl. PMID- 21237051 TI - Mass extinction, punctuated equilibrium and the fossil plant record. PMID- 21237052 TI - Conserving Europe's bees: why all the buzz? PMID- 21237053 TI - Pollination, seed dispersal and diversification of angiosperms. PMID- 21237054 TI - Visualizing and quantifying natural selection. AB - Modern methods of analysis are enabling researchers to study natural selection at a new level of detail. Multivariate statistical techniques can Identify specific targets of selection and provide parameter estimates that fit into equations for evolutionary change. A more Intuitive understanding of the form of selection can be provided through graphical representation of selection surfaces. Combinations of quantitative and visual analyses are providing researchers with new insights into the details of natural selection in the wild. PMID- 21237055 TI - Emerging infectious disease: what are the relative roles of ecology and evolution? AB - The increasing threat of infectious diseases in humans has renewed interest in factors leading to the emergence of new diseases and the re-emergence of familiar diseases. Examples of seemingly novel diseases currently spreading in human populations include HIV, dengue hemorrhagic fever and Lyme disease; drug resistant forms of well-known diseases such as tuberculosis are also increasing. The problem of disease emergence also extends to other animal and plant populations. In most current epidemics, ecological factors (e.g. migration, climate, agricultural practices) play a more significant role in disease emergence than evolutionary changes in pathogens or hosts. Evolutionary biologists and ecologists have much to offer to the development of strategies for the control of emerging diseases. PMID- 21237056 TI - The molecular basis of quantitative genetic variation in natural populations. AB - DNA markers allow us to study quantitative trait loci (QTL) - the genes that control adaptation and quantitative variation. Experiments can map the genes responsible for quantitative variation and address the evolutionary and ecological significance of this variation. Recent studies suggest that major genes segregate within and among natural populations. It is now feasible to study the genes that cause morphological variation, life history trade-offs, heterosis and speciation. These methods can determine the role of epistasis and genotype-by environment interaction in maintaining genetic variation. QTL mapping is an important tool used to address evolutionary and ecological questions of long standing interest. PMID- 21237057 TI - Molecular phylogeny of cetaceans prompts revision of morphological transformations. AB - The echolocating toothed whales and the filter-feeding baleen whales are traditionally considered as two monophyletic lineages that originated from the extinct cetacean suborder Archaeoceti. While current interpretation of the morphological and behavioural data sets supports toothed-whale monophyly, molecular phylogenies contradict this long-accepted taxonomic subdivision. The molecular data indicate that one group of toothed whales, the sperm whales, Is more closely related to the morphologically highly divergent baleen whales than to other odontocetes. Furthermore, these molecular analyses tentatively suggest a more recent origin of baleen whales than has been generally accepted. Although a thorough cladistic analysis of all relevant morphological data is still needed, reevaluation of some of the most important of these characters helps to reconcile the morphological and the molecular approaches. PMID- 21237058 TI - Reply from g.d. Ruxton. PMID- 21237059 TI - Chaos and scale. PMID- 21237060 TI - Chaos and scale. PMID- 21237061 TI - Biological markets. AB - In biological markets, two classes of traders exchange commodities to their mutual benefit. Characteristics of markets are: competition within trader classes by contest or outbidding; preference for partners offering the highest value; and conflicts over the exchange value of commodities. Biological markets are currently studied under at least three different headings: sexual selection, intraspecific cooperation and interspecific mutualism. The time is ripe for the development of game theoretic models that describe the common core of biological markets and integrate existing knowledge from the separate fields. PMID- 21237062 TI - Assessing weediness of transgenic crops: industry plays plant ecologist. AB - After years of experimentation and limited field testing of genetically modified crop plants, biotechnology companies in many countries are now beginning to commercialize their transgenic products. This development has shifted the focus of public concern to the procedures that governments employ in determining that a particular transgenic crop poses no risk to the environment. In this article we discuss the Information required by the US Animal and Plant Health Inspection Service (APHIS) in making this determination, and compare this with the data that have been called for by ecologists and the data presented by companies in their petitions for nonregulated status. PMID- 21237063 TI - The ecosystem management bandwagon. PMID- 21237064 TI - Social interactions, nonlinear dynamics and task allocation in groups. PMID- 21237065 TI - Climate change and tropical forests. PMID- 21237067 TI - A report from Galapagos. PMID- 21237066 TI - Haldane's rule: old theories are the best. PMID- 21237068 TI - Social life: the paradox of multiple-queen colonies. AB - The evolution of animal societies in which some individuals forego their own reproductive opportunities to help others to reproduce poses an evolutionary paradox that can be traced to Darwin. Altruism may evolve through kin selection when the donor and recipient of altruistic acts are related to each other, as generally is the case in social birds and mammals. Similarly, social insect workers are highly related to the brood they rear when colonies are headed by a single queen. However, recent studies have shown that insect colonies frequently contain several queens, with the effect of decreasing relatedness among colony members. How can one account for the origin and maintenance of such colonies? This evolutionary enigma presents many of the same theoretical challenges as does the evolution of cooperative breeding and eusociality. PMID- 21237069 TI - Rethinking complexity: modelling spatiotemporal dynamics in ecology. AB - In the past few years, part of theoretical ecology has focused on the spatiotemporal dynamics generated by simple ecological models. To a large extent, the results obtained have changed our view of complexity. Specifically, simple rules are able to produce complex spatiotemporal patterns. Consequently, some of the complexity underlying nature does not necessarily have complex causes. The emerging framework has far-reaching implications in ecology and evolution. This is improving our understanding of topics such as the problem of scales, the response to habitat fragmentation, the relationship between chaos and extinction, and how high diversity levels are supported in nature. PMID- 21237070 TI - Resource polymorphisms in vertebrates. AB - Discrete resource polymorphisms occur in various vertebrate species and probably occur more frequently than is generally appreciated. They are manifested in a number of ways, including morphological, behavioral and life history characters. Research on a number of unrelated taxa suggests that resource polymorphisms may be underestimated as a diversifying force and potentially play important roles in population divergence and initial steps in speciation. In an ecological context, they are important in resource partitioning and reducing intraspecific competition. Recent research suggests that the mechanisms maintaining these polymorphisms may be similar in diverse taxa, that phenotypic plasticity is important, and that some are under simple genetic control. PMID- 21237072 TI - Reply from j. Bruin, m.w. Sabelis and m. Dicke. PMID- 21237071 TI - The 'paradox' of polyembryony. PMID- 21237073 TI - Plants may talk, but can they hear? PMID- 21237074 TI - Testing the immunocompetence handicap theory. PMID- 21237075 TI - Reply from I.C.w. Hardy. PMID- 21237076 TI - Age and reproduction in birds - hypotheses and tests. AB - It is well known that reproductive performance improves with age in birds. Many hypotheses, involving factors such as differential survival, delayed breeding, breeding experience, foraging ability and reproductive effort, have been proposed to explain this pattern. Although these hypotheses are not mutually exclusive, they can be classified in three major groups relating to progressive appearance or disappearance of phenotypes, age-related improvements of competence, and optimization of reproductive effort. However, a closer examination of the literature reveals that only few studies have rigorously tested the hypotheses. Future work should focus on carefully designed tests that critically investigate the hypotheses. PMID- 21237077 TI - A limits-oriented approach to evolutionary ecology. AB - Evolutionary ecology focuses on optimal traits to provide a mechanistic understanding of ecological patterns. For some issues, however, It might be a mismatch to marry optimality and ecology. Given that many ecological questions involve limits (to species distributions and abundances; to species diversity), it might be useful to focus on 'limiting traits' rather than optimal traits; that is, to understand ecological limits it might be useful to identify the things that organisms do poorly, and to study constraints on the evolution of these limiting traits. While a limiting-traits approach has a long history in ecology, relatively few studies have fully applied the approach, and some ecological issues have only recently been examined from this view. PMID- 21237078 TI - Following the growth of individuals in crowded plant populations. PMID- 21237079 TI - Biodiversity and human health. PMID- 21237080 TI - Tabonuco trees, trophic manipulations and Tarzan: lizards in a tropical forest canopy. PMID- 21237081 TI - Are some plants born to burn? PMID- 21237082 TI - Unwelcome immigrants? PMID- 21237083 TI - Why is the house mouse karyotype so variable? AB - rates of robertsonian chromosomal evolution in the Western European house mouse are about two orders of magnitude greater than for most other mammals. This has resulted in a remarkable diversity of karyotypic races in a very short period of time. Recent studies are beginning to shed light on the relative contributions of mutation, drift, selection and meiotic drive in producing this pattern. PMID- 21237084 TI - The advantages of being evergreen. AB - Recent research shows that the dominance of evergreen species in nutrient-poor environments can be explained by their low nutrient loss rates. From this work It appears that the plant traits that are associated with low nutrient loss rates lead to low maximum-dry-matter production and to low rates of litter decomposition. This suggests a positive feedback between the evergreen habit and low nutrient availability. The growth characteristics of evergreens lead to a low responsiveness to environmental changes. As a result, global warming may lead to changes in the distribution of evergreens. PMID- 21237085 TI - Multi-functionality and biodiversity in arbuscular mycorrhizas. AB - Plant roots in natural ecosystems are typically colonized by a wide range of fungi. Some of these are pathogenic, others appear to be opportunistic and have no apparent impact, while mycorrhizal fungi are generally regarded as mutualistic. Of the various types of mycorrhizal fungi, the arbuscular mycorrhizal (AM) association is by far the most abundant and widespread. While the most widely accepted model of AM function depends upon plants benefiting from the facilitation of phosphorus uptake, recent data from field-based studies in temperate ecosystems indicate that only plant species with poorly branched root systems benefit from AM fungi in this way: species with highly branched root systems may benefit in other ways, such as by being protected against root pathogenic fungi. These two responses apparently represent extremes along a continuum of AM benefit determined by root system architecture. PMID- 21237086 TI - Genetic conflicts of interest in plants. AB - Several features of the reproductive biology of seed plants have recently been explained using kin-selection interpretations. The simultaneous presence of tissues with different genetic make-ups during several phases of a seed-plant's life cycle is a feature that sets the conditions for agonistic interactions among selfish genes. The available empirical evidence indicates that genetic conflicts of interest are prevalent phenomena in seed plants. Recent research on the patterns of endosperm gene transmission provides a framework for new interpretations of the role of inclusive fitness in plants. PMID- 21237087 TI - The burden is description, not identification. PMID- 21237088 TI - Parasitic infection of migratory bird species. PMID- 21237090 TI - Reply from m. Edwards and d.R. Morse. PMID- 21237089 TI - The sensory exploitation hypothesis. PMID- 21237091 TI - Comparative functional plant ecology: rationale and potentials. AB - The long tradition and early training in plant taxonomy and evolutionary theory have led to the preconceived notion among plant ecologists that plant diversity represents the sum of distinct classes, rather than a continuum of variation. Thus, broad-scale comparisons across different taxa are viewed with scepticism. Yet, the unarticulated reluctance to compare the functional properties of phototrophic organisms across broad ranges of plant types is not well-grounded. Broad comparisons are likely to capture most of the functional variance that these organisms display and lead to general conclusions, albeit sometimes imprecise for individual species. Ecological synthesis could be fostered if scientists working with the different plant types made efforts to Increase connectance between them by highlighting similarities, instead of formulating Independent theories to account for similar phenomena. PMID- 21237092 TI - Disturbed island ecology. AB - The natural occurrence of significant disturbances to the operation of insular ecosystems has tended to be downplayed in the development of island ecological theory. Despite the importance of events such as Hurricane Hugo, which in 1989 affected islands in the Caribbean, islands that are disturbed tend to be viewed as deviants from the 'true path' described by equilibrium models. However, particularly with organisms of long generation times, it is questionable whether such models are applicable. This may be as important for wildlife managers to take account of as for theorists. Disturbance regime should be incorporated into island ecological models alongside other ecological factors structuring colonization patterns and turnover. PMID- 21237093 TI - Anecdotes and the shifting baseline syndrome of fisheries. PMID- 21237094 TI - Joint 'bottom-up' and 'top-down' regulation of rocky intertidal algal beds in South Africa. PMID- 21237095 TI - Reinforcement: an idea evolving. PMID- 21237096 TI - Incorporating physiological realism into models of parasitoid feeding behaviour. PMID- 21237097 TI - Cuckoo-host coevolution: from snapshots of an arms race to the documentation of microevolution. PMID- 21237098 TI - Conservation breeding as a tool for saving animal species from extinction. AB - For nearly 3000 taxa of birds and mammals, conservation breeding may be the only possible way to avoid extinction. Today, less than 100 of these taxa have self sustaining captive populations, and even fewer have been selected for reintroduction programmes. However, recent developments in our theoretical understanding of conservation breeding, as well as in its practical application, and global organization, raise hopes for the future. PMID- 21237099 TI - The effects of natural and anthropogenic environmental changes on ecosystem processes at the catchment scale. AB - The catchment is the smallest natural unit of the landscape that combines linked terrestrial and aquatic ecosystems. The fluxes of water and elements through the catchment link the various components of the system; biotic and abiotic, terrestrial and aquatic, plants and soils, atmosphere and vegetation, soils and waters. A large amount of empirical evidence now demonstrates that the impacts of natural and anthropogenic changes on the various components of catchment ecosystems are tightly connected. PMID- 21237100 TI - Arthropod evolution: great brains, beautiful bodies. AB - While arthropod phylogeny remains controversial, comparative studies of the genetic control of segmentation and of the nervous system have begun to throw light on how mandibulate arthropods (myriapods, crustaceans and insects) reached their current level of morphological and behavioural complexity. Insects and crustaceans show remarkable similarities in the construction of their brains, suggesting that their common ancestor had typically arthropod behaviour, while developmental genetic studies are consistent with this ancestor having had distinct head, trunk and tail regions. This conclusion contrasts with the influential view, drawn from comparative embryology and functional anatomy, that insects and crustaceans evolved independently from a simple worm-like organism, perhaps resembling an annelid. PMID- 21237101 TI - Ultra-violet photoreceptors in the animal kingdom: their distribution and function. AB - Until very recently, the role of ultra-violet (UV) colour perception in vertebrate and invertebrate vision has largely been ignored. However, in the past few years, a host of detailed information has become available on the widespread distribution of UV receptors in different species - from insects to mammals - and the important functions they seem to play in navigation, foraging, intraspecies communication and the control of circadian rhythms. PMID- 21237102 TI - Reply from g. Arnqvist and d. Wooster. PMID- 21237103 TI - Statistical power of methods of meta-analysis. PMID- 21237104 TI - Serious bias in journal impact factors. PMID- 21237105 TI - The changing focus of marine mammal conservation. AB - Overexploitation has been the principal focus of marine mammal conservation. Less attention has been paid to bycatch in commercial fisheries; entanglement in lost and discarded fishing gear; food shortages owing to climate change and/or overharvesting of essential prey; point and non-point source pollution; and diseases. Also, relatively little attention has been paid to situations where marine mammals pose threats to the existence and human uses of other marine species. As overexploitation is addressed, focus must be shifted to these problems that are no less significant. PMID- 21237106 TI - Field experiments with genetically manipulated insect viruses: ecological issues. AB - Evil Oxford scientists, bent on world domination, release virus containing scorpion poison gene into English countryside. Well, not quite; but readers of the British press last summer might be forgiven for thinking that a latter-day Central Anarchist Council had taken root among the dreaming spires. The press reports concerned field experiments near Oxford of a genetically manipulated insect baculovirus by the National Environmental Research Council's (NERC) Institute for Virology and Environmental Microbiology (IVEM). But while it is easy to smile at sensational headlines, at least some of the press reporting has been accurate and informed, and raises important ecological issues - as well as questions about the regulation of experiments with genetically manipulated organisms. PMID- 21237107 TI - Marine genetics - a cautionary tale with a happy ending (so far). PMID- 21237108 TI - The lek paradox resolved? PMID- 21237109 TI - Ontogenetic contingency and the expression of plant plasticity. PMID- 21237110 TI - Microbial processes and the cycling of atmospheric trace gases. PMID- 21237111 TI - Does sex appeal to zoos? PMID- 21237112 TI - Chaos and evolution. AB - There is growing interest in applying nonlinear methods to evolutionary biology. With good reason: the living world is full of nonlinearities, responsible for steady states, regular oscillations, and chaos in biological systems. Evolutionists may find nonlinear dynamics important in studying short-term dynamics of changes in genotype frequency, and in understanding selection and its constraints. More speculatively, dynamical systems theory may be important because nonlinear fluctuations in some traits may sometimes be favored by selection, and because some long-run patterns of evolutionary change could be described using these methods. PMID- 21237113 TI - Is mitochondrial DNA a strictly neutral marker? AB - Variation and change in mitochondrial DNA (mtDNA) is often assumed to conform to a constant mutation rate equilibrium neutral model of molecular evolution. Recent evidence, however, indicates that the assumptions underlying this model are frequently violated. The mitochondria) genome may be subject to the same suite of forces known to be acting in the nuclear genome, including hitchhiking and selection, as well as forces that do not affect nuclear variation. Wherever possible, evolutionary studies involving mtDNA should incorporate statistical tests to investigate the forces shaping sequence variation and evolution. PMID- 21237114 TI - A species definition: a functional approach. PMID- 21237115 TI - Reply from p.w. Sherman and L.L. Wolfenbarger. PMID- 21237116 TI - Sensory biases and the evolution of sensory systems. PMID- 21237117 TI - Reply from j. Mallet. PMID- 21237118 TI - Correspondence. PMID- 21237120 TI - Spatial dynamics and chaos. PMID- 21237119 TI - Reply from j. Bascompte and R.v. Sole. PMID- 21237121 TI - Reinforcement in speciation. PMID- 21237122 TI - Competition or stochasticity? PMID- 21237123 TI - Sexual selection by cryptic female choice on male seminal products - a new bridge between sexual selection and reproductive physiology. AB - Selection clearly focuses on differences in reproduction, but studies of reproductive physiology generally have been carried out in a near vacuum of modern evolutionary theory. This lack of contact between the two fields may be about to change. New ideas indicate that sexual selection by cryptic female choice has affected the evolution of products in male semen that influence female reproductive behavior and physiology. PMID- 21237124 TI - The early role of nitric oxide in evolution. AB - Nitric oxide (NO), which today serves many different purposes in regulating complex cellular functions, must have played a crucial role in the early stages of the evolution of life. The formation of NO may have been a critical defence mechanism for primitive microorganisms at a time when life faced the problem of rising atmospheric levels of ozone (03) formed upon photolysis of oxygen (Oz), which occurred shortly after the development of respiration in cyanobacteria. The production of NO by organisms would have allowed neutralization of toxic 03 by chemical reaction outside the cell, thus acting as a protective mechanism against oxidative destruction, allowing evolutionary advantage. Later, NO production might have allowed the control of reactive OZ species within cells before the development of specific electron-accepting enzymes. The pathway of NO formation was then consequently developed further to serve other useful functions. Although mammalian cells produce NO from L-arginine, the origin of this ability might have arisen from the essential process of either nitrification or denitrification in prokaryotic cells. PMID- 21237125 TI - Pursuit-deterrence revisited. AB - Pursuit-deterrent signals - signals used by prey that apparently convince predators not to pursue them - were discovered 15 years ago, but their existence continues to rest on shaky empirical evidence. First, pursuit-deterrent signals are usually inferred by eliminating competing hypotheses rather than testing predictions derived from the pursuit-deterrent hypothesis directly. Second, the strength of selection pressures maintaining such signals in prey populations are unknown because behavioral ecologists infrequently observe natural predation attempts. Third, the nature of information passing between prey and predators is open to misinterpretation because measures are rarely taken to separate signals that advertise perception of the predator from those that advertise perception and the prey's condition. PMID- 21237126 TI - The long-term study of voles, mice and lemmings: homage to Robert Collett. PMID- 21237127 TI - Identification of novel antigens within the Schistosoma japonicum tetraspanin family based on molecular characterization. AB - Tetraspanins (TSPs) are proteins found on the surface of the parasite Schistosoma mansoni that have been regarded as potential protective antigens. However, divergent evolution may occur among the species of S. mansoni and Schistosoma japonicum under different environmental pressure. Thus, it was essential to characterize the S. japonicum TSP family members before selecting potential candidate TSP antigens. In this study, we used bioinformatics and experimental validation to investigate 29 TSP members from S. japonicum, including all known genes, Sj23, TE736, Sj25, and Sj-TSP-2. Five TSP members were found to be variable, and two others (Sj-tsp genes) were alternatively spliced. The phylogenetic analysis showed that schistosome TSPs were highly divergent from those of other phyla. Quantitative RT-PCR revealed that the Sj-tsp genes were differentially transcribed in the developmental stages of cercariae, schistosomula, adult worms, and eggs. Six Sj-tsp genes were significantly up regulated during the transformation from cercariae to schistosomula. Four Sj-tsp genes, including Sj-tsp-1, Sj-tsp-8, Sj-tsp-14, and Sj-tsp-26 were confirmed as potential protective antigens based on the molecular characterization. RNAi was preformed against the conserved Sj-tsp genes which were highly expressed in schistosomula to explore gene functions. These data will promote the identification of candidate antigens within the TSP family for developing novel vaccines against S. japonicum infections. PMID- 21237128 TI - Design and synthesis of a near-infrared fluorescent nanofiber precursor for detecting cell-secreted urokinase activity. AB - Abnormal proteolysis is often observed during disease progression. Up-regulation of certain tumor-associated proteases such as urokinase plasminogen activator (uPA) can be a hallmark of malignant transformation. Here we report the design and synthesis of a near-infrared nanofiber precursor (NIR-NFP) for detecting uPA activity. NIR-NFP, which is optically silent in its native state, is composed of multiple self-assembled peptide units (PEG(54)-BK(NIR664)SGRSANA-kldlkldlkldl CONH(2)). On uPA activation, NIR-NFP releases peptide fragments (PEG(54) BK(NIR664)SGR-CONH(2)) that contribute to a significant fluorescence amplification at 684nm. NIR-NFP was able to detect cell-secreted uPA from human cancer cells (SKBR-3, PANC-1, MCF-7, SKOV-3, MDA-MB-231, PC-3, and HT-1080) expressing various levels of uPA. Fluorescence changes were uPA dependent, as confirmed with both Western blot analysis and enzyme activity assay. Our data suggest that an optimized preparation may be useful for imaging uPA activity in vivo. PMID- 21237129 TI - Absorbance-based assay for membrane disruption by antimicrobial peptides and synthetic copolymers using pyrroloquinoline quinone-loaded liposomes. AB - A simple homogeneous assay for the detection of membrane permeabilization by antimicrobial peptides and synthetic copolymers is described. Liposomes encapsulating pyrroloquinoline quinone (PQQ), the prosthetic group of the apoenzyme glucose dehydrogenase (GDH), are used to detect membrane permeabilization by the antimicrobial peptides MSI-594 and MSI-78 as well as various synthetic antimicrobial copolymers in an optical microwell assay. PQQ loaded liposomes and the peptide or copolymer are added to wells of a 96-well microtiter plate. If the integrity of the liposome is compromised, the PQQ encapsulated in the liposomes is released and available for activating the apoenzyme. The release of PQQ catalyzes a color change in the presence of apo GDH, glucose, and the redox dye 1,6-dichlorophenol indophenol (DCPIP) that can be evaluated through a visual color change. For more quantitative measurements, the absorbance change over a 30min period was measured. The absorbance change is related to the activity and concentration for a given antimicrobial agent. Furthermore, by varying liposome compositions to include cholesterol, the potential toxicity of the peptide or polymer toward mammalian cells can be readily evaluated. The assay is simple and sensitive and will be useful for analyzing the membrane permeation/disruption properties of a host of antimicrobial peptides and synthetic polymers. PMID- 21237130 TI - Detection and comparison of protein-DNA interactions using DNA-BIND plate and horseradish peroxidase-based colorimetric assay. AB - We describe a procedure for detection and comparison of protein-DNA interactions using DNA-BIND plate and horseradish peroxidase (HRP)-based colorimetric assay. Amino-modified oligonucleotide was covalently immobilized on the surface of DNA BIND plate. After the complementary oligonucleotide was annealed, the plate was incubated with protein to allow sequence-specific DNA binding. Primary antibody and HRP-labeled secondary antibody were then employed, and colorimetric assay was conducted before the absorbance was read. This is a sensitive, specific, and high throughput method that has been applied not only in the detection of protein-DNA interaction but also in the quantitative comparison of DNA-binding capabilities among wild-type and mutant proteins. PMID- 21237131 TI - Glucocorticoid-induced alterations in mitochondrial membrane properties and respiration in childhood acute lymphoblastic leukemia. AB - Mitochondria are signal-integrating organelles involved in cell death induction. Mitochondrial alterations and reduction in energy metabolism have been previously reported in the context of glucocorticoid (GC)-triggered apoptosis, although the mechanism is not yet clarified. We analyzed mitochondrial function in a GC sensitive precursor B-cell acute lymphoblastic leukemia (ALL) model as well as in GC-sensitive and GC-resistant T-ALL model systems. Respiratory activity was preserved in intact GC-sensitive cells up to 24h under treatment with 100 nM dexamethasone before depression of mitochondrial respiration occurred. Severe repression of mitochondrial respiratory function was observed after permeabilization of the cell membrane and provision of exogenous substrates. Several mitochondrial metabolite and protein transporters and two subunits of the ATP synthase were downregulated in the T-ALL and in the precursor B-ALL model at the gene expression level under dexamethasone treatment. These data could partly be confirmed in ALL lymphoblasts from patients, dependent on the molecular abnormality in the ALL cells. GC-resistant cell lines did not show any of these defects after dexamethasone treatment. In conclusion, in GC-sensitive ALL cells, dexamethasone induces changes in membrane properties that together with the reduced expression of mitochondrial transporters of substrates and proteins may lead to repressed mitochondrial respiratory activity and lower ATP levels that contribute to GC-induced apoptosis. PMID- 21237132 TI - Epiregulin-dependent amphiregulin expression and ERBB2 signaling are involved in luteinizing hormone-induced paracrine signaling pathways in mouse ovary. AB - Sustained EGF receptor (EGFR) phosphorylation by de novo synthesis of EGFR ligands plays an essential role in mediating luteinizing hormone (LH)-induced ovulation process in the preovulatory follicles (POFs). In the present study, the effect of epiregulin (EREG) on oocyte maturation and ovulation was investigated using Ereg knockout (Ereg-/-) mice congenic on a C57BL/6 background. Rate of spontaneous oocyte meiotic resumption of denuded oocytes (DOs) or cumulus cell oocyte complexes (COCs) in vitro is similar between wild-type and Ereg-/- mice. However, gonadotropin-induced meiotic resumption in vivo is attenuated, and the number of COCs with expanded cumulus matrix and superovulated eggs dramatically decrease in Ereg-/- mice. Nonetheless, the number of eggs ovulated during normal estrus cycles and litter sizes in Ereg-/- mice are comparable to those of wild type littermates. In contrast to other EGFR ligands, induction of amphiregulin (Areg) mRNA is severely reduced in ovaries collected from Ereg-/- mice either after human chorionic gonadotropin (hCG) treatment in immature mice or LH surge in adults. Gonadotropin-induced EGFR and ERBB2 phosphorylation in ovaries is attenuated in immature Ereg-/- mice, and MAPK3/1 phosphorylation and prostaglandin synthase 2 (PTGS2) protein levels are reduced. This attenuation, however, is no longer detectable in adult Ereg-/- mice after LH surge. This study implicates that EREG mediates signals downstream of Areg mRNA expression and that EGFR-ERBB2 signals contributes to regulation of ovulation process. PMID- 21237133 TI - Over-expression of human carcinoma-associated antigen in intrahepatic cholangiocellular carcinoma. AB - OBJECTIVE: To investigate the expression status of human carcinoma antigen (HCA) in human cholangiocellular carcinomas, and to determine the relationship between HCA and clinical features. METHODS: Tissues from 60 intrahepatic cholangiocellular carcinoma (ICC) patients, and normal liver tissues from 20 hepatic hemangioma patients selected randomly were assayed for the expression of HCA by immunohistochemistry, and Western blots. Areas of poorly differentiated (n=20), moderately-well differentiated (n=30), highly differentiated tumors (n=10) from different cases were evaluated. Results were recorded as positive (>=5% of cells staining and staining intensity 2+ or 3+) or negative (<5% of cells staining and staining intensity<2+) and analyzed using the chi2 test. RESULTS: BCE075 and BDD048 antibodies showed similar staining patterns. The positive immunostaining of BCE075 was mainly localized in the cytoplasm and cell secretions. The staining was positive in 15% of poorly differentiated ICC, 72% of moderately-well differentiated, 100% of highly differentiated tumors. But, staining was not detected in adjacent normal tissue. The differences in HCA expression among these tissues were statistically significant. Also, we found expression of HCA to be closely associated with the degree of differentiation of ICC and tumor cell morphology. There was a correlation between expression of HCA and serum CA19-9. CONCLUSION: The data suggest that HCA is a potential marker for the diagnosis of cholangiocellular carcinoma. PMID- 21237134 TI - Changes in cytosolic glucose level in ATP stimulated live astrocytes. AB - Astrocytes which lie between brain capillaries and neuronal terminals are the primary site of glucose uptake and have a key role in coupling synaptic activity to glucose utilization in the central nervous system (CNS). We used a fluorescence resonance energy transfer (FRET) based approach to monitor cytosolic glucose in astrocytes. We determined the effect of increasing extracellular glucose concentrations on FRET ratio as a measure of increased cytosolic glucose in astrocytes. By briefly raising extracellular glucose concentration, astrocytes responded promptly by increased cytosolic glucose levels, which was manifested by decreased time-dependent FRET ratio. The FRET ratio fall-time recorded at low extracellular D-glucose concentration change (from 0 to 0.5 mM) was 53 s, whereas 17 s was recorded by raising extracellular concentration of D-glucose from 0 to 10 mM, which is likely due to facilitated d-glucose entry along the increased D glucose gradient across the plasmalemma. The relationship between the extracellular glucose concentration and the FRET ratio change is limited to the maximal ratio change, where the D-glucose plasma membrane permeability is balanced by the cytosolic utilization. We measured the effect of extracellular ATP, an important extracellular messenger for astrocyte-to-astrocyte communication, on intracellular glucose concentration. The results show that stimulation of astrocytes with ATP (1 mM) decreases cytosolic glucose concentration with a time constant of ~145 s. The mechanism of this change is discussed. PMID- 21237135 TI - Permeabilization induced by lipid II-targeting lantibiotic nisin and its effect on the bioconversion of vitamin D3 to 25-hydroxyvitamin D3 by Rhodococcus erythropolis. AB - Vitamin D3 (VD3) is a fat-soluble prohormone in mammals. VD3 is inert and must be activated by hydroxylation at the C-25 and C-1alpha positions to exert its biological activity. We recently accomplished the bioconversion of VD3 to 25(OH)VD3 with a recombinant strain of Rhodococcus erythropolis and found that the permeability of VD3 into the cytoplasm may be the rate-limiting step of 25(OH)VD3 production (Sallam et al., 2010). When the cells were treated with the lipid II-targeting lantibiotic nisin, the permeability of green chemiluminescent cyclodextrin (GCCD), which is used as a model substrate instead of VD3-partially methylated-beta-cyclodextrin (PMCD) complex, was drastically induced. Nisin also induced VD3 hydroxylation, and the rate was correlated with the expression levels of Vdh and its redox partner proteins. In the bioconversion reaction, the stability of the redox partner proteins and the additional NADH-regenerating system are crucial for VD3 hydroxylation. The degradation rate of the [2Fe-2S] cluster of ferredoxin ThcC from R. erythropolis NI86/21 is faster than that of AciB from Acinetobacter sp. OC4. Therefore, the nisin-treated R. erythropolis cells coexpressing Vdh and AciBC (1176.5 MUg) exhibited much greater 25(OH)VD3 production than the cells coexpressing Vdh and ThcCD (431.7 MUg) after four consecutive 16 h reactions. These results suggest that nisin forms nisin-lipid II pore complexes in the Rhodococcus membrane that increase the accessibility of VD3 PMCD complexes to the inside of the cells. Furthermore, nisin-treated Rhodococcus cells can be utilized for the bioconversion of other fat-soluble chemicals. PMID- 21237136 TI - What is the true enzyme kinetics in the biological system? An investigation of macromolecular crowding effect upon enzyme kinetics of glucose-6-phosphate dehydrogenase. AB - Enzyme kinetic parameters for rate equations are vital in metabolic network simulation, a major part of systems biology research efforts. Measurements of Michaelis-Menten kinetic parameters Km and Kcat have been performed for enzymes glucose-6-phosphate dehydrogenase (G6P DH) under crowded conditions using molecular crowding agents bovine serum albumin (BSA) and polyethylene glycol (PEG) of 8000 Da molecular weight. An increase in Kcat was observed at very low concentrations of crowding agent, and also at high crowder concentrations when the experiment was performed at 45 degrees C with PEG. The observed pattern in Kcat for G6P DH at high crowder concentrations has been explained via modelling using excluded volume theory. An increase in rate was observed at 45 degrees C for G6P DH versus 30 degrees C; this has been modelled via the Arrhenius equation. PMID- 21237137 TI - Preferential involvement of both ROS and ceramide in fenretinide-induced apoptosis of HL60 rather than NB4 and U937 cells. AB - Leukemic cells responding to apoptosis-inducing drugs can be varied in terms of the mechanisms of action. Fenretinide, a synthetic retinoid, is worth of study as a promising candidate for apoptosis-based therapy of leukemia. Yet, it remains unclear whether this drug exerts the similar mechanisms on different leukemic cells. Here, we report a comparative analysis of fenretinide-induced apoptosis in three acute myeloid leukemic (AML) cell lines including HL60, NB4 and U937. Through a series of antagonist assays, we revealed similarities and differences of mechanisms involved in these three cell lines. Antioxidant vitamin C completely abrogated fenretinide-induced apoptosis in all cell lines, demonstrating that ROS is an essential and common mediator. However, the apoptotic effects of fenretinide could be blocked by ceramide synthase inhibitor fumonisin B1 only in HL60 rather than the other two. Moreover, fumonisin B1 was unable to inhibit the generation of ROS in fenretinide-treated HL60 cells, indicating that ROS may function as upstream stimulus of ceramide-mediated apoptosis. These comparative results strongly suggest that the apoptotic response induced by fenretinide in HL60 involves both ROS and ceramide, whereas drug induced apoptosis in NB4 and U937 requires ROS but is independent of ceramide. Differentiated modes of action exerting on AML may guide the use of this apoptosis-inducing drug, and hence advance our knowledge about the nature of cancer-specific responses to this drug. PMID- 21237138 TI - Mean microvessel segment length and radius after embolic stroke: Comparison of magnetic resonance imaging (MRI) and laser scanning confocal microscopy (LSCM). AB - We offer a new means of noninvasively assessing mean microvessel segment length and radius after ischemic stroke. This method involves measuring changes in T2 and T2* after injecting an intravascular superparamagnetic iron oxide contrast agent and result was verified using laser scanning confocal microscopy (LSCM) of both normal brain tissue and the ischemic recovery region. Embolic stroke was induced in 8 male Wistar rats and magnetic resonance imaging (MRI) performed 1 day and 6 weeks later. On MRI taken at 6 weeks, MRI of the recovery region revealed a significant increase in mean vessel size index (VSI) (5.75 +/- 0.54 vs 4.81 +/- 0.3 9MUm; p < 0.001) and decrease in mean segment length (MSL) (16.61 +/ 2.33 vs 26.52 +/- 3.20 MUm; p < 0.001) compared to the normal contralateral hemisphere, comparable with published values. There was also a significant correlation between MSL and VSI measured by MRI vs LSCM in the recovery region and normal contralateral hemisphere (p < 0.001). Our data suggest that a) morphological changes in the microvasculature can be measured noninvasively using MRI, and b) both MRI and LSCM give comparable information about both of these important parameters. PMID- 21237139 TI - Molecular mapping of mouse brain regions innervated by leptin receptor-expressing cells. AB - Leptin acts via the long form of the leptin receptor (LepRb) on specialized sets of neurons in the brain to modulate diverse functions in concert with energy stores. Previous studies have revealed the distribution of LepRb-expressing neurons in the brain but not the regions to which LepRb neurons project to mediate downstream leptin actions. We utilized LepRb-cre in combination with cre inducible enhanced green fluorescent protein (EGFP) and farnesylated EGFP (EGFPf) mouse reporter strains to visualize LepRb neurons and their projections, respectively, throughout the brain. The areas containing LepRb soma and projections were relatively circumscribed, as many brain regions contained no detectable EGFP or EGFPf. The highest concentrations of LepRb neurons and LepRb projections were found in the hypothalamus, where the ventral premamillary (PMv), dorsomedial (DMH), and arcuate (ARC) nuclei contained the greatest number of cell bodies, in addition to substantial EGFPf-reactivity. Furthermore, both LepRb soma and projections were present in a few midbrain and brainstem nuclei. Several brain regions including the hypothalamic paraventricular nucleus (PVH), the anteroventral periventricular nucleus (AVPe), and the central nucleus of the amygdala (CeA) contained few LepRb neurons but substantial EGFPf, suggesting that these regions represent targets of LepRb neurons that lie elsewhere in the brain. In some nuclei that contained both soma and projections, the distribution of soma and projections differed, suggesting that these areas transmit leptin-encoded information in a neuroanatomically directional manner. PMID- 21237140 TI - Simultaneous detection of CYP3A5 and MDR1 polymorphisms based on the SNaPshot assay. AB - BACKGROUND: The 6986A>G polymorphism for CYP3A5 and the -129T>C, 1236C>T, 2677G>T/A, and 3435C>T polymorphisms for MDR1 are considered the major genetic factors affecting a range of drugs' metabolism and transport. Simultaneous genotyping of these five polymorphisms would be useful for estimating the therapeutic effects of their related drugs. SUBJECTS AND METHODS: We have described a SNaPshot assay that can simultaneously detect all the five polymorphisms based on multiplex PCR and minisequencing reaction. A total of 168 unrelated Chinese DNA samples were used to establish and evaluate the assay. RESULTS: The different genotypes of the five polymorphisms could be determined by peak retention time and colors. DNA sequencing was performed on samples randomly selected from each of the genotype groups detected by SNaPshot assay, and the results indicated 100% concordance. CONCLUSION: The SNaPshot assay for the CYP3A5 and MDR1 five polymorphisms detection was accurate, automated, and cost effective. PMID- 21237141 TI - Expression of neuropeptide- and hormone-encoding genes in the Ciona intestinalis larval brain. AB - Despite containing only approximately 330 cells, the central nervous system (CNS) of Ciona intestinalis larvae has an architecture that is similar to the vertebrate CNS. Although only vertebrates have a distinct hypothalamus-the source of numerous neurohormone peptides that play pivotal roles in the development, function, and maintenance of various neuronal and endocrine systems, it is suggested that the Ciona brain contains a region that corresponds to the vertebrate hypothalamus. To identify genes expressed in the brain, we isolated brain vesicles using transgenic embryos carrying Ci-beta tubulin(promoter)::Kaede, which resulted in robust Kaede expression in the larval CNS. The associated transcriptome was investigated using microarray analysis. We identified 565 genes that were preferentially expressed in the larval brain. Among these genes, 11 encoded neurohormone peptides including such hypothalamic peptides as gonadotropin-releasing hormone and oxytocin/vasopressin. Six of the identified peptide genes had not been previously described. We also found that genes encoding receptors for some of the peptides were expressed in the brain. Interestingly, whole-mount in situ hybridization showed that most of the peptide genes were expressed in the ventral brain. This catalog of the genes expressed in the larval brain should help elucidate the evolution, development, and functioning of the chordate brain. PMID- 21237143 TI - The Ca2+ increase by the sperm factor in physiologically polyspermic newt fertilization: its signaling mechanism in egg cytoplasm and the species specificity. AB - The newt, Cynops pyrrhogaster, exhibits physiological polyspermic fertilization, in which several sperm enter an egg before egg activation. An intracellular Ca(2+) increase occurs as a Ca(2+) wave at each sperm entry site in the polyspermic egg. Some Ca(2+) waves are preceded by a transient spike-like Ca(2+) increase, probably caused by a tryptic protease in the sperm acrosome at the contact of sperm on the egg surface. The following Ca(2+) wave was induced by a sperm factor derived from sperm cytoplasm after sperm-egg membrane fusion. The Ca(2+) increase in the isolated, cell-free cytoplasm indicates that the endoplasmic reticulum is the major Ca(2+) store for the Ca(2+) wave. We previously demonstrated that citrate synthase in the sperm cytoplasm is a major sperm factor for egg activation in newt fertilization. In the present study, we found that the activation by the sperm factor as well as by fertilizing sperm was prevented by an inhibitor of citrate synthase, palmitoyl CoA, and that an injection of acetyl-CoA or oxaloacetate caused egg activation, indicating that the citrate synthase activity is necessary for egg activation at fertilization. In the frog, Xenopus laevis, which exhibits monospermic fertilization, we were unable to activate the eggs with either the homologous sperm extract or the Cynops sperm extract, indicating that Xenopus sperm lack the sperm factor for egg activation and that their eggs are insensitive to the newt sperm factor. The mechanism of egg activation in the monospermy of frog eggs is quite different from that in the physiological polyspermy of newt eggs. PMID- 21237142 TI - The canonical Wnt signaling activator, R-spondin2, regulates craniofacial patterning and morphogenesis within the branchial arch through ectodermal mesenchymal interaction. AB - R-spondins are a recently characterized family of secreted proteins that activate Wnt/beta-catenin signaling. Herein, we determine R-spondin2 (Rspo2) function in craniofacial development in mice. Mice lacking a functional Rspo2 gene exhibit craniofacial abnormalities such as mandibular hypoplasia, maxillary and mandibular skeletal deformation, and cleft palate. We found that loss of the mouse Rspo2 gene significantly disrupted Wnt/beta-catenin signaling and gene expression within the first branchial arch (BA1). Rspo2, which is normally expressed in BA1 mesenchymal cells, regulates gene expression through a unique ectoderm-mesenchyme interaction loop. The Rspo2 protein, potentially in combination with ectoderm-derived Wnt ligands, up-regulates Msx1 and Msx2 expression within mesenchymal cells. In contrast, Rspo2 regulates expression of the Dlx5, Dlx6, and Hand2 genes in mesenchymal cells via inducing expression of their upstream activator, Endothelin1 (Edn1), within ectodermal cells. Loss of Rspo2 also causes increased cell apoptosis, especially within the aboral (or caudal) domain of the BA1, resulting in hypoplasia of the BA1. Severely reduced expression of Fgf8, a survival factor for mesenchymal cells, in the ectoderm of Rspo2(-/-) embryos is likely responsible for increased cell apoptosis. Additionally, we found that the cleft palate in Rspo2(-/-) mice is not associated with defects intrinsic to the palatal shelves. A possible cause of cleft palate is a delay of proper palatal shelf elevation that may result from the small mandible and a failure of lowering the tongue. Thus, our study identifies Rspo2 as a mesenchyme-derived factor that plays critical roles in regulating BA1 patterning and morphogenesis through ectodermal-mesenchymal interaction and a novel genetic factor for cleft palate. PMID- 21237144 TI - Sustained subcutaneous infusion of nicotine enhances cholinergic vasodilation in the cerebral cortex induced by stimulation of the nucleus basalis of Meynert in rats. AB - The present study examined the effects of sustained nicotine exposure on the cholinergic vasodilative system originating in the nucleus basalis of Meynert (NBM) and projecting to the cerebral cortex in rats. Rats received sustained subcutaneous nicotine (100MUg/kg/h) for 14 days. Under urethane anesthesia, the vasodilation response and acetylcholine release in the parietal cortex induced by electrical stimulation of the NBM (10-200MUA) were measured. The basal level of acetylcholine release was significantly higher in nicotine-treated rats than in saline-treated control rats. In the control rats, both the acetylcholine release and blood flow were increased by NBM stimulation in a stimulus intensity dependent manner, and a threshold of 50MUA. In nicotine-treated rats, the threshold intensity of NBM stimulation producing increases in acetylcholine release and blood flow was reduced to 20MUA. The stimulus intensity-dependent acetylcholine release and vasodilation by NBM stimulation were significantly larger in nicotine-treated rats than in control rats. We conclude that sustained subcutaneous infusion of nicotine enhances cholinergic vasodilative system in the cerebral cortex originating in the NBM. PMID- 21237145 TI - Receptor-specific functional efficacies of alkyl imidazoles as dual histamine H3/H4 receptor ligands. AB - Histamine H(3) and H(4) receptors are highly related G protein-coupled receptors. Preclinical and clinical data strongly suggest the potential therapeutic application of selectively acting histamine H(4) receptor ligands to inflammatory conditions but also hint at a certain interference of the two receptors in diseases attended with itch and pain. The aim of this investigation was to identify dual acting ligands as pharmacological tools. Receptor binding profiles of omega-(1H-imidazol-4-yl)alkyl derivatives structurally defined as amides, carbamates, esters, ethers, ketones and ureas were evaluated with respect to their potencies at histamine H(3) and H(4) receptors. A two-step screening method based on in vitro radioligand binding studies and functional [(35)S]GTPgammaS binding experiments was performed. The examined series of imidazole-containing compounds displayed both, selective histamine H(4) receptor and dual acting histamine H(3)/H(4) receptor ligands. Slight structural modifications caused major differences in selectivity profiles and on functional properties at the human histamine H(4) receptor. N-(3-(1H-Imidazol-4-yl)propyl)-2 cyclohexylacetamide 11 was identified as most potent and selective human histamine H(4) receptor ligand in this series (K(i)=45nM). Amide- and ether containing structures consistently exhibited partial agonist efficacies, whereas ureas, ketones, esters and carbamates mainly acted as antagonists and inverse agonists. We identified novel dual acting histamine H(3)/H(4) receptor ligands with varying efficacies at the histamine H(4) receptor subtype, whereas histamine H(3) receptor antagonism was kept constant, e.g. 3-(1H-imidazol-4-yl)propyl (cyclohexylmethyl)carbamate 19 or 4-(3-(3-phenylpropylthio)propyl)-1H-imidazole 30. These compounds state valuable pharmacological tools in studies of diseases, in which histamine H(3) and H(4) receptor signalling contributes to pathophysiological conditions. PMID- 21237146 TI - Levosimendan preserves the contractile responsiveness of hypoxic human myocardium via mitochondrial K(ATP) channel and potential pERK 1/2 activation. AB - This study investigated the role of levosimendan, a mitochondrial K(ATP) channel opener, during hypoxia-reoxygenation injury in human isolated tissue. The activation of preconditioning pathways, and the release of mitochondrial cytochrome c were determined. Human right atrial trabeculae were mounted in an organ bath, electrically paced and contractile force measured. Tissue was subjected to hypoxia-reoxygenation, and isoproterenol concentration-response experiments were performed as an index of contractile viability. The intracellular activities of Akt, ERK 1/2, P38, caspase 3, and cytochrome c were assayed by western blot. Following hypoxia-reoxygenation, the maximal contractile response of trabeculae to isoproterenol was significantly increased with levosimendan pretreatment compared to the hypoxia-reoxygenation control (0.88+/ 0.02 versus 0.60+/-0.01g, P<0.01). This enhanced response was blocked by 5 hydroxydecoanate (0.54+/-0.09g, P<0.01). A significant increase in both phosphorylated and total ERK 1/2 and P38 occurred at 60min reoxygenation, compared to control tissue. No difference was observed in phosphorylated or total Akt, though there was a trend for increased levels in hypoxic tissue. Cytochrome c was detected at 60min post reoxygenation, in both levosimendan treated and untreated tissue. No increase in cleaved-caspase 3 activity was observed. Our findings suggest that levosimendan preserves the contractile force to isoproterenol after hypoxia-reoxygenation, a response mediated via mK(ATP) channel activation. The significant increase in the activity of prosurvival mediators ERK 1/2 and P38 following hypoxia indicates a potential mechanism of action for levosimendan-induced cardioprotection. PMID- 21237147 TI - Interactions between modulators of the GABA(A) receptor: Stiripentol and benzodiazepines. AB - Many patients with refractory epilepsy are treated with polytherapy, and nearly 15% of epilepsy patients receive two or more anti-convulsant agents. The anti convulsant stiripentol is used as an add-on treatment for the childhood epilepsy syndrome known as severe myoclonic epilepsy in infancy (Dravet syndrome). Stiripentol has multiple mechanisms of action, both enhancing GABA(A) receptors and reducing activity of metabolic enzymes that break down other drugs. Stiripentol is typically co-administered with other anti-convulsants such as benzodiazepines which also act through GABA(A) receptor modulation. Stiripentol slows the metabolism of some of these drugs through inhibition of a variety of cytochrome P450 enzymes, but could also influence their effects on GABAergic neurotransmission. Is it rational to co-administer drugs which can act through the same target? To examine the potential interaction between these modulators, we transiently transfected HEK-293T cells to produce alpha3beta3gamma2L or alpha3beta3delta recombinant GABA(A) receptors. Using whole-cell patch clamp recordings, we measured the response to each benzodiazepine alone and in combination with a maximally effective concentration of stiripentol. We compared the responses to four different benzodiazepines: diazepam, clonazepam, clobazam and norclobazam. In all cases we found that these modulators were equally effective in the presence and absence of stiripentol. The delta-containing receptors were insensitive to modulation by the benzodiazepines, which did not affect potentiation by stiripentol. These data suggest that stiripentol and the benzodiazepines act independently at GABA(A) receptors and that polytherapy could be expected to increase the maximum effect beyond either drug alone, even without consideration of changes in metabolism. PMID- 21237148 TI - Central interleukin-10 attenuated lipopolysaccharide-induced changes in core temperature and hypothalamic glutamate, hydroxyl radicals and prostaglandin-E(2). AB - It has been documented that intravenous lipopolysaccharide (LPS) in rabbits causes fever accompanied by increased levels of extracellular glutamate, hydroxyl radicals, and prostaglandin E(2) (PGE(2)) in the hypothalamus and circulating tumor necrosis factor-alpha (TNF-alpha). This investigation was to determine whether central interleukin-10 (IL-10) exerted its antipyresis by reducing changes in circulating TNF-alpha and extracellular glutamate, hydroxyl radicals and PGE(2) in the hypothalamus. The microdialysis probes were stereotaxically and chronically implanted into the preoptic anterior hypothalamus of rabbit brain for determinating extracellular glutamate, hydroxyl radicals, and PGE(2) in situ. It was found that systemically injected LPS (2MUg/kg, intravenously) increased the levels of core temperature, and extracellular glutamate, hydroxyl radicals, and PGE(2) in the hypothalamus accompanied by increased plasma levels of TNF-alpha. Pretreatment with IL-10 (10-100ng, intracerebroventricularly) 1h before intravenous LPS significantly reduced the LPS-induced changes in extracellular glutamate, hydroxyl radicals, and PGE(2) in the hypothalamus and fever, but not the increased levels of TNF-alpha in rabbits. These findings suggested that directly injected IL-10 into the lateral cerebral ventricle 1h before intravenous LPS exerted its antipyresis by inhibiting the changes in extracellular glutamate, hydroxyl radicals and PGE(2) in the hypothalamus during LPS fever in rabbits. PMID- 21237149 TI - Effects of two oral antidiabetics, pioglitazone and repaglinide, on aconitase inactivation, inflammation and oxidative/nitrosative stress in tissues under alloxan-induced hyperglycemia. AB - Pathological changes identified in different tissues in hyperglycemic state are undoubtedly connected with increased oxidative/nitrosative stress and inflammation. In our study myeloperoxidase (MPO), nitrotyrosine and lipid peroxidation were enhanced in the heart and lung of alloxan-treated hyperglycemic animals. Additionally, pulmonary aconitase was inhibited. In the testis the changes occurred as an increase of MPO and lipid peroxidation, and as a decrease of aconitase. The effects of two different antidiabetics, the peroxisome proliferator activated receptor gamma (PPARgamma) agonist, pioglitazone, and a short acting insulin secretagogue, repaglinide, on the mentioned parameters, were investigated and compared. The insulin deficient alloxan-induced hyperglycemic animals were used to differentiate a direct anti-oxidative effect of the drugs from secondary effects mediated via increased insulin sensitivity or secretion. Pioglitazone acted by normalization of pulmonary and testicular aconitase, normalization of pulmonary and cardiac nitrotyrosine, reduction of pulmonary and testicular MPO, and by reduction of lipid peroxidation in all tissues examined. Repaglinide prevented oxidative changes by normalization of aconitase activity in the lung and testis, and by reduction of lipid peroxidation and nitrotyrosine in the heart and lung. At the same time, no effect of this drug on MPO was observed. Finally, principal component analysis was performed to explore and visualize similarities and differences of the results obtained for the both drugs. PMID- 21237150 TI - Brain alpha4beta2 nicotinic acetylcholine receptors are involved in the secretion of noradrenaline and adrenaline from adrenal medulla in rats. AB - Recently, we reported that intracerebroventricularly (i.c.v.) administered (+/-) epibatidine (a non-selective agonist of nicotinic acetylcholine receptors) elevates plasma noradrenaline and adrenaline through brain nicotinic acetylcholine receptor-mediated mechanisms in rats. In the present study, we characterized the receptors involved in these responses using selective agonists and antagonists of nicotinic acetylcholine receptor subtypes in anesthetized rats. (+/-)-Epibatidine (5 and 10nmol/animal, i.c.v.) and (-)-nicotine (250 and 500nmol/animal, i.c.v.) both elevated plasma noradrenaline and adrenaline (adrenaline>noradrenaline) but the former was more efficient than the latter. The (+/-)-epibatidine (5nmol/animal, i.c.v.)-induced elevation of plasma catecholamines was reduced by dihydro-beta-erythroidine (a selective antagonist of alpha4beta2 nicotinic acetylcholine receptors) (100 and 300nmol/animal, i.c.v.), while methyllycaconitine (a selective antagonist of alpha7 nicotinic acetylcholine receptors) (100 and 300nmol/animal, i.c.v.) had no effect on the (+/-)-epibatidine-induced responses. RJR-2403 (a selective agonist of alpha4beta2 nicotinic acetylcholine receptors) (2.5 and 5MUmol/animal, i.c.v.) elevated plasma noradrenaline and adrenaline (adrenaline>noradrenaline), while PNU-282987 (a selective agonist of alpha7 nicotinic acetylcholine receptors) (2.5 and 5MUmol/animal, i.c.v.) had no effect. Furthermore, the RJR-2403 (5MUmol/animal, i.c.v.)-induced responses were abolished by acute bilateral adrenalectomy. Immunohistochemical procedures demonstrated the expression of alpha4 and beta2 nicotinic acetylcholine receptor subunits on the spinally projecting hypothalamic paraventricular neurons. Taken together, brain alpha4beta2 nicotinic acetylcholine receptors seem to be involved in the secretion of noradrenaline and adrenaline from adrenal medulla in rats. PMID- 21237151 TI - A protease inhibitor against acute stress-induced visceral hypersensitivity and paracellular permeability in rats. AB - In the present study, we investigated the effects of camostat mesilate (CM), a synthetic protease inhibitor, on visceral sensitivity and paracellular permeability induced by the acute restraint stress. We also explored the possible mechanisms underlying these effects. The acute restraint stress was induced by wrapping the fore shoulders, upper forelimbs and thoracic trunk of Sprague-Dawley rats for 2h. Either CM (30, 100 and 300mg/kg) or saline was intragastrically administrated to the rats 30min before the acute restraint stress. Visceral perception was quantified as visceral motor response with an electromyography in a subset of rats. Paracellular permeability was determined in another subset of rats. We found that the visceral sensitivity and paracellular permeability were significantly reduced in the CM-treated rats. Moreover, the fecal protease activity was decreased in the CM-treated rats. The ZO-1 protein expression was markedly reduced by the stress treatment, but this decrease was suppressed by CM administration. Our data indicated that CM could efficiently inhibit visceral sensitivity and paracellular permeability induced by the acute restraint stress in rats. Therefore, CM might be an effective drug for the treatment of irritable bowel syndrome. PMID- 21237153 TI - GLP-1 for type 2 diabetes. AB - Glucagon-like peptide-1 (GLP-1)-based therapy of type 2 diabetes is executed either by GLP-1 receptor agonists, which stimulate the GLP-1 receptors, or by dipeptidyl peptidase-4 (DPP-4) inhibitors, which prevent the inactivation of endogenous GLP-1 thereby increasing the concentration of endogenous active GLP-1. GLP-1 activates pancreatic receptors resulting in improved glycemia through glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. There is also a potential beta cell preservation effect, as judged from rodent studies. GLP-1 receptors are additionally expressed in extrapancreatic tissue, having potential for the treatment to reduce body weight and to potentially have beneficial cardio- and endothelioprotective effects. Clinical trials in subjects with type 2 diabetes have shown that in periods of 12 weeks or more, these treatments reduce HbA(1c) by ~ 0.8-1.1% from baseline levels of 7.7-8.5%, and they are efficient both as monotherapy and in combination therapy with metformin, sulfonylureas, thiazolidinediones or insulin. Furthermore, GLP-1 receptor agonists reduce body weight, whereas DPP-4 inhibitors are body weight neutral. The treatment is safe with very low risk for adverse events, including hypoglycaemia. GLP-1 based therapy is thus a novel and now well established therapy of type 2 diabetes, with a particular value in combination with metformin in patients who are inadequately controlled by metformin alone. PMID- 21237152 TI - Purinergic signaling is required for fluid shear stress-induced NF-kappaB translocation in osteoblasts. AB - Fluid shear stress regulates gene expression in osteoblasts, in part by activation of the transcription factor NF-kappaB. We examined whether this process was under the control of purinoceptor activation. MC3T3-E1 osteoblasts under static conditions expressed the NF-kappaB inhibitory protein IkappaBalpha and exhibited cytosolic localization of NF-kappaB. Under fluid shear stress, IkappaBalpha levels decreased, and concomitant nuclear localization of NF-kappaB was observed. Cells exposed to fluid shear stress in ATP-depleted medium exhibited no significant reduction in IkappaBalpha, and NF-kappaB remained within the cytosol. Similar results were found using oxidized ATP or Brilliant Blue G, P2X(7) receptor antagonists, indicating that the P2X(7) receptor is responsible for fluid shear-stress-induced IkappaBalpha degradation and nuclear accumulation of NF-kappaB. Pharmacologic blockage of the P2Y6 receptor also prevented shear induced IkappaBalpha degradation. These phenomena involved neither ERK1/2 signaling nor autocrine activation by P2X(7)-generated lysophosphatidic acid. Our results suggest that fluid shear stress regulates NF-kappaB activity through the P2Y(6) and P2X(7) receptor. PMID- 21237154 TI - Disassembly of the JIP1/JNK molecular scaffold by caspase-3-mediated cleavage of JIP1 during apoptosis. AB - We report here the cleavage of the c-Jun N-terminal Kinase (JNK) pathway scaffold protein, JNK Interacting Protein-1 (JIP1), by caspases during both Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) and staurosporine induced apoptosis in HeLa cells. During the initiation of apoptosis, maximal JNK activation is observed when JIP1 is intact, whereas cleavage of JIP1 correlates with JNK inactivation and progression of apoptosis. JIP1 is cleaved by caspase-3 at two sites, leading to disassembly of the JIP1/JNK complex. Inhibition of JIP1 cleavage by the caspase-3 inhibitor DEVD.fmk inhibits this disassembly, and is accompanied by sustained JNK activation. These data suggest that TRAIL and staurosporine induce JNK activation in a caspase-3-independent manner and that caspase-3-mediated JIP1 cleavage plays a role in JNK inactivation via scaffold disassembly during the execution phase of apoptosis. Caspase-mediated cleavage of JIP scaffold proteins may therefore represent an important mechanism for modulation of JNK signalling during apoptotic cell death. PMID- 21237155 TI - Correlation between fetal brain activity patterns and behavioral states: an exploratory fetal magnetoencephalography study. AB - The fetal brain remains inaccessible to neurophysiological studies. Magnetoencephalography (MEG) is being assessed to fill this gap. We performed 40 fetal MEG (fMEG) recordings with gestational ages (GA) ranging from 30 to 37 weeks. The data from each recording were divided into 15 second epochs which in turn were classified as continuous (CO), discontinuous (DC), or artifact. The fetal behavioral state, quiet or active sleep, was determined using previously defined criteria based on fetal movements and heart rate variability. We studied the correlation between the fetal state, the GA and the percentage of CO and DC epochs. We also analyzed the spectral edge frequency (SEF) and studied its relation with state and GA. We found that the odds of a DC epoch decreased by 6% per week as the GA increased (P = 0.0036). This decrease was mainly generated by changes during quiet sleep, which showed 52% DC epochs before a 35 week GA versus 38% after 35 weeks (P = 0.0006). Active sleep did not show a significant change in DC epochs with GA. When both states were compared for MEG patterns within each GA group (before and after 35 weeks), the early group was found to have more DC epochs in quiet sleep (54%) compared to active sleep (42%) (P = 0.036). No significant difference in DC epochs between the two states was noted in the late GA group. Analysis of SEF showed a significant difference (P = 0.0014) before and after a 35 week GA, with higher SEF noted at late GA. However, when both quiet and active sleep states were compared within each GA group, the SEF did not show a significant difference. We conclude that fMEG shows reproducible variations in gross features and frequency content, depending on GA and behavioral state. Fetal MEG is a promising tool to investigate fetal brain physiology and maturation. PMID- 21237156 TI - Effects of fetal exposure to lipopolysaccharide, perinatal anoxia and sensorimotor restriction on motor skills and musculoskeletal tissue: implications for an animal model of cerebral palsy. AB - Cerebral palsy (CP) is a disorder of locomotion, posture and movement that can be caused by prenatal, perinatal or postnatal insults during brain development. An increased incidence of CP has been correlated to perinatal asphyxia and maternal infections during gestation. The effects of maternal exposure to low doses of bacterial endotoxin (lipopolysaccharide, LPS) on motor behavior and hind leg muscle morphology were examined in young adult rats. Prenatal exposure to LPS was also studied in association with perinatal anoxia (PA) and/or combined with subsequent sensorimotor restriction (SR) and all possible combinations of the three conditions. Rats exposed to LPS, PA and SR alone or combined (LPS + PA, LPS + SR, PA + SR, and LPS + PA + SR) showed deficits in balance and coordination when tested on the Rotarod. The SR groups, with or without other insults, (SR, LPS + SR, PA + SR, and LPS + PA + SR) exhibited the greatest motor deficits, characterized by the reduced ability to perform the horizontal ladder and suspended bar tests on postnatal day 29 (P29) and P45. Histological assessment revealed substantial morphological alterations in the slow ankle extensor soleus muscle of all SR rats. Soleus myofibers presented a reduction in cross-sectional area (CSA), an increase in sarcomere length and a decrease in sarcomere density. The CSA of the fast flexor tibialis anterior muscle was only decreased by the association of all treatments (LPS, PA, SR), but no differences were found in sarcomere length and density when compared to control. A slow-to-fast fiber type transition was only observed in the soleus and tibialis anterior muscles in the SR groups. These results suggest that exposure to LPS during the prenatal period, PA, SR alone or in combination has various degrees of consequences on motor behavior and muscle morphology. These data corroborate the concept that early experience-dependent movements play the most important role in shaping motor behavior and that reduced or anomalous sensorimotor experience can contribute to the development of aberrant motor behavior and muscle morphology. PMID- 21237157 TI - Characterisation of the membrane-extrinsic domain of the TatB component of the twin arginine protein translocase. AB - The twin arginine protein transport (Tat) system transports folded proteins across cytoplasmic membranes of bacteria and thylakoid membranes of plants, and in Escherichia coli it comprises TatA, TatB and TatC components. In this study we show that the membrane extrinsic domain of TatB forms parallel contacts with at least one other TatB protein. Truncation of the C-terminal two thirds of TatB still allows complex formation with TatC, although protein transport is severely compromised. We were unable to isolate transport-inactive single codon substitution mutations in tatB suggesting that the precise amino acid sequence of TatB is not critical to its function. PMID- 21237158 TI - The rate-limiting step of sulfiredoxin is associated with the transfer of the gamma-phosphate of ATP to the sulfinic acid of overoxidized typical 2-Cys peroxiredoxins. AB - The eukaryotic sulfiredoxin (Srx) catalyzes the reduction of overoxidized typical 2-Cys peroxiredoxins PrxSO(2) via ATP/Mg(2+)-dependent phosphorylation of the sulfinic acid group, followed by formation of a PrxSO-SSrx thiolsulfinate intermediate. Using real-time kinetics of wild-type and C84A Srxs, and pH-rate profiles with ATP/Mg(2+) analogues, we show that the rate-limiting step of the reaction is associated with the chemical process of transfer of the gamma phosphate of ATP to the sulfinic acid, in contrast to that described by Jonsson et al. Two pK(apps) of 6.2 and 7.5 were extracted from the bell-shaped pH-rate profile, corresponding to the gamma-phosphate of ATP, and to an acid-base catalyst, respectively. PMID- 21237159 TI - The chemical chaperones tauroursodeoxycholic and 4-phenylbutyric acid accelerate thyroid hormone activation and energy expenditure. AB - Exposure of cell lines endogenously expressing the thyroid hormone activating enzyme type 2 deiodinase (D2) to the chemical chaperones tauroursodeoxycholic acid (TUDCA) or 4-phenylbutiric acid (4-PBA) increases D2 expression, activity and T3 production. In brown adipocytes, TUDCA or 4-PBA induced T3-dependent genes and oxygen consumption (~2-fold), an effect partially lost in D2 knockout cells. In wild type, but not in D2 knockout mice, administration of TUDCA lowered the respiratory quotient, doubled brown adipose tissue D2 activity and normalized the glucose intolerance associated with high fat feeding. Thus, D2 plays a critical role in the metabolic effects of chemical chaperones. PMID- 21237160 TI - Glycine amide shielding on the aromatic surfaces of lysozyme: implication for suppression of protein aggregation. AB - Glycine amide (GlyAd), a typically amidated amino acid, is a versatile additive that suppresses protein aggregation during refolding, heat treatment, and crystallization. In spite of its effectiveness, the exact mechanism by which GlyAd suppresses protein aggregation remains to be elucidated. Here, we show the crystal structure of the GlyAd-lysozyme complex by high resolution X-ray crystallographic analysis at a 1.05A resolution. GlyAd bound to the lysozyme surface near aromatic residues and decreased the amount of bound waters and increased the mobility of protein. Arg and GlyAd molecules are different in binding sites and patterns from glycerol and related compounds, indicating that decreasing hydrophobic patches might be involved in suppression of protein aggregation. PMID- 21237161 TI - Rv0989c encodes a novel (E)-geranyl diphosphate synthase facilitating decaprenyl diphosphate biosynthesis in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) has a highly complex cell wall, which is required for both bacterial survival and infection. Cell wall biosynthesis is dependent on decaprenyl diphosphate as a glyco-carrier, which is hence an essential metabolite in this pathogen. Previous biochemical studies indicated (E) geranyl diphosphate (GPP) is required for the synthesis of decaprenyl diphosphate. Here we demonstrate that Rv0989c encodes the "missing" GPP synthase, representing the first such enzyme to be characterized from bacteria, and which presumably is involved in decaprenyl diphosphate biosynthesis in Mtb. Our investigation also has revealed previously unrecognized substrate plasticity of the farnesyl diphosphate synthases from Mtb, resolving previous discrepancies between biochemical and genetic studies of cell wall biosynthesis. PMID- 21237162 TI - Synechocystis sp. PCC 6803 mutant lacking both photosystems exhibits strong carotenoid-induced quenching of phycobilisome fluorescence. AB - Blue light induced quenching in a Synechocystis sp. PCC 6803 strain lacking both photosystems is only related to allophycocyanin fluorescence. A fivefold decrease in the fluorescence level in two bands near 660 and 680 nm is attributed to different allophycocyanin forms in the phycobilisome core. Some low-heat sensitive component inactivated at 53 degrees C is involved in the quenching process. Enormous allophycocyanin fluorescence in the absence of the photosystems reveals a dark stage in this quenching. Thus, we present evidence that light activation of the carotenoid-binding protein and formation of a quenching center within the phycobilisome core in vivo are discrete events in a multistep process. PMID- 21237163 TI - CTGF/CCN2 activates canonical Wnt signalling in mesangial cells through LRP6: implications for the pathogenesis of diabetic nephropathy. AB - We describe the activation of Wnt signalling in mesangial cells by CCN2. CCN2 stimulates phosphorylation of LRP6 and GSK-3beta resulting in accumulation and nuclear localisation of beta-catenin, TCF/LEF activity and expression of Wnt targets. This is coincident with decreased phosphorylation of beta-catenin on Ser 33/37 and increased phosphorylation on Tyr142. DKK-1 and LRP6 siRNA reversed CCN2's effects. Microarray analyses of diabetic patients identified differentially expressed Wnt components. beta-Catenin is increased in type 1 diabetic and UUO mice and in in vitro models of hyperglycaemia and hypertension. These findings suggest that Wnt/CCN2 signalling plays a role in the pathogenesis of diabetic nephropathy. PMID- 21237164 TI - The role of the C-terminus of human alpha-synuclein: intra-disulfide bonds between the C-terminus and other regions stabilize non-fibrillar monomeric isomers. AB - Substantial evidence implicates that the aggregation of alpha-synuclein (alphaSyn) is a critical factor in the pathogenesis of Parkinson's disease. This study focuses on the role of alphaSyn C-terminus. We introduced two additional cysteine residues at positions 107 and 124 (A107C and A124C) to our previous construct. Five X-isomers of oxidative-folded mutation of alpha-synuclein with three disulfides were isolated and their secondary structures and aggregating features were analyzed. All isomers showed similar random coil structures as wild type alpha-synuclein. However, these isomers did not form aggregates or fibrils, even with prolonged incubation, suggesting that the interactions between the C terminal and N-terminal or central NAC region are important in maintaining the natively unfolded structure of alphaSyn and thus prevent alphaSyn from changing conformation, which is a critical step for fibrillation. PMID- 21237165 TI - The promotion of neurite formation in Neuro2A cells by mouse Mob2 protein. AB - The molecular mechanism of neuritogenesis has been extensively studied but remains unclear. In this study, we identified Mob2 protein which plays a significant role in promoting neurite formation in Neuro2A (N2A) cells. Our results showed that Mob2 was expressed in developing N2A cells. To study whether Mob2 was involved in neurite formation, we downregulated Mob2 expression using RNA interference and found that neurite formation decreased in low serum induced N2A cells. In addition, we found that overexpression of Mob2 promoted neurite formation in N2A cells. Furthermore, downregulation of Mob2 expression altered the rearrangement of the actin cytoskeleton and decreased the expression of phosphorylated Moesin. Together, these results provide information on the role of Mob2 in mediating neurite formation. PMID- 21237167 TI - An alerting system improves adherence to follow-up recommendations from colonoscopy examinations. AB - BACKGROUND & AIMS: Systems are available to ensure that results of tests are communicated to patients. However, lack of adherence to recommended follow-up evaluation increases risk for adverse health outcomes and medical or legal issues. We tested the effectiveness of a novel follow-up system for patients due for surveillance colonoscopy examinations. METHODS: Electronic medical records from colonoscopies performed 5 years prior were reviewed to identify individuals due for a repeat surveillance colonoscopy examination. Patients were assigned to groups that received the standard of care or a newly developed follow-up system that included a letter to the primary care provider, 2 letters to the patient, and a telephone call to patients who had not yet scheduled an examination by the procedure due date. The primary end point was the percentage of patients who scheduled or completed the colonoscopy examination within 6 months of the due date. Secondary end points included detection rate for adenomas, sex- and ethnicity-specific follow-up rates, and patient satisfaction. RESULTS: Of 2609 patient records reviewed, 830 (31.8%) were found to be due for a surveillance colonoscopy examination in the study period. At the conclusion of the study, 241 (44.7%) patients in the intervention arm had procedures scheduled or completed, compared with 66 (22.6%) in the control group (P < .0001). The follow-up system appeared particularly effective among non-white patients; patients reported general satisfaction with the reminder program. CONCLUSIONS: A simple protocol of letters and a telephone call to patients who are due for colonoscopy examinations significantly improved adherence to endoscopic follow-up recommendations. This work provides justification for the creation of reminder systems to improve patient adherence to medical recommendations. PMID- 21237168 TI - Atrial natriuretic factor stimulates efflux of cAMP in rat exocrine pancreas via multidrug resistance-associated proteins. AB - BACKGROUND & AIMS: Atrial natriuretic factor (ANF) prevents increases in intracellular levels of cAMP that are induced by secretin in the exocrine pancreas. We investigated the contribution of cyclic adenosine monophosphate (cAMP) efflux to ANF inhibition of secretin signaling. METHODS: Intracellular and extracellular cAMP were measured by radio-binding assays in isolated pancreatic acini exposed to secretin and other secretagogues, alone or with ANF. Levels of messenger RNA for multidrug resistance-associated protein (MRP)4, MRP5, and MRP8 were measured by real-time polymerase chain reaction. MRP4 was knocked down in AR42J cells by small interfering RNA. In vivo studies were performed in rats. RESULTS: Pancreatic secretagogues increased levels of intracellular cAMP, but only secretin and vasoactive intestinal peptide promoted cAMP efflux; efflux was increased by ANF, through signaling via natriuretic peptide receptor-C and phospholipase C-protein kinase C. In time-course studies with active phosphodiesterases, levels of intracellular and extracellular cAMP increased earlier after the addition of secretin and ANF (1 min) than after the addition of secretin alone (3 min). Similar kinetic patterns occurred with a phosphodiesterase inhibitor. A probenecid-sensitive transporter mediated cAMP egression. The main cAMP transporter, MRP4, was expressed in AR42J cells and pancreas. cAMP egression occurred in AR42J cells exposed to secretin, but this response was reduced in cells that expressed MRP4 small interfering RNA. In rats, levels of cAMP in plasma and pancreatic juice increased after infusion with secretin alone or secretin plus ANF. CONCLUSIONS: ANF signals via natriuretic peptide receptor-C coupled to the phospholipase C-protein kinase C pathway to increase secretin-induced efflux of cAMP, probably through MPR-4. Cyclic AMP extrusion might be a mechanism, in addition to phosphodiesterase action, to regulate intracellular cAMP levels in pancreatic acinar cells. PMID- 21237166 TI - The epithelial barrier is maintained by in vivo tight junction expansion during pathologic intestinal epithelial shedding. AB - BACKGROUND & AIMS: Tumor necrosis factor (TNF) increases intestinal epithelial cell shedding and apoptosis, potentially challenging the barrier between the gastrointestinal lumen and internal tissues. We investigated the mechanism of tight junction remodeling and barrier maintenance as well as the roles of cytoskeletal regulatory molecules during TNF-induced shedding. METHODS: We studied wild-type and transgenic mice that express the fluorescent-tagged proteins enhanced green fluorescent protein-occludin or monomeric red fluorescent protein 1-ZO-1. After injection of high doses of TNF (7.5 MUg intraperitoneally), laparotomies were performed and segments of small intestine were opened to visualize the mucosa by video confocal microscopy. Pharmacologic inhibitors and knockout mice were used to determine the roles of caspase activation, actomyosin, and microtubule remodeling and membrane trafficking in epithelial shedding. RESULTS: Changes detected included redistribution of the tight junction proteins ZO-1 and occludin to lateral membranes of shedding cells. These proteins ultimately formed a funnel around the shedding cell that defined the site of barrier preservation. Claudins, E-cadherin, F-actin, myosin II, Rho-associated kinase (ROCK), and myosin light chain kinase (MLCK) were also recruited to lateral membranes. Caspase activity, myosin motor activity, and microtubules were required to initiate shedding, whereas completion of the process required microfilament remodeling and ROCK, MLCK, and dynamin II activities. CONCLUSIONS: Maintenance of the epithelial barrier during TNF-induced cell shedding is a complex process that involves integration of microtubules, microfilaments, and membrane traffic to remove apoptotic cells. This process is accompanied by redistribution of apical junctional complex proteins to form intercellular barriers between lateral membranes and maintain mucosal function. PMID- 21237169 TI - Dysregulated generation of follicular helper T cells in the spleen triggers fatal autoimmune hepatitis in mice. AB - BACKGROUND & AIMS: To clarify mechanisms involved in the development of autoimmune hepatitis (AIH), we recently developed a mouse model of spontaneous AIH by inducing a concurrent loss of Foxp3(+) regulatory T cells and programmed cell death 1 (PD-1)-mediated signaling. Fatal AIH in these mice was characterized by severe T-cell infiltration and huge production of antinuclear antibodies (Abs). This study aims to identify induction sites, responsible T-cell subsets, and key molecules for induction of AIH. METHODS: To develop the mouse model of AIH, neonatal thymectomy (NTx) was performed on PD-1-deficient (PD-1(-/-)) mice. We then conducted neonatal splenectomy or in vivo administration of Abs to cytokines, chemokines, or cell-surface molecules. RESULTS: In NTx-PD-1(-/-) mice, either neonatal splenectomy or in vivo CD4(+) T-cell depletion suppressed CD4(+) and CD8(+) T-cell infiltration in the liver. In the induction phase of AIH, splenic CD4(+) T cells were localized in B-cell follicles with huge germinal centers and showed the Bcl6(+) inducible costimulator (ICOS)(+) interleukin (IL) 21(+) IL-21 receptor (IL-21R)(+) follicular helper T (T(FH)) cell phenotype. Blocking Abs to ICOS or IL-21 suppressed T(FH)-cell generation and induction of AIH. In addition, IL-21 produced by T(FH) cells drove CD8(+) T-cell activation. Splenic T(FH) cells and CD8(+) T cells expressed CCR6, and CCL20 expression was elevated in the liver. Administration of anti-CCL20 suppressed migration of these T cells to the liver and induction of AIH. CONCLUSIONS: Dysregulated T(FH) cells in the spleen are responsible for the induction of fatal AIH, and CCR6-CCL20 axis dependent migration of splenic T cells is crucial to induce AIH in NTx-PD-1(-/-) mice. PMID- 21237170 TI - A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. AB - BACKGROUND & AIMS: Studies of hepatitis C virus (HCV) infection, immunopathogenesis, and resulting liver diseases have been hampered by the lack of a small animal model. We developed humanized mice with human immune system and liver tissues to improve the studies of hepatitis C virus pathogenesis and treatment. METHODS: To promote engraftment of human hepatocytes, we expressed a fusion protein of the FK506 binding protein (FKBP) and caspase 8 under control of the albumin promoter (AFC8), which induces liver cell death, in Balb/C Rag2(-/-) gammaC-null mice. Cotransplantation of human CD34(+) human hematopoietic stem cells (HSC) and hepatocyte progenitors into the transgenic mice led to efficient engraftment of human leukocytes and hepatocytes. We then infected these humanized mice (AFC8-hu HSC/Hep) with primary HCV isolates and studied HCV-induced immune responses and liver diseases. RESULTS: AFC8-hu HSC/Hep mice supported HCV infection in the liver and generated a human immune T-cell response against HCV. HCV infection induced liver inflammation, hepatitis, and fibrosis, which correlated with activation of stellate cells and expression of human fibrogenic genes. CONCLUSIONS: AFC8-hu HSC/Hep mice are a useful model of HCV infection, the immune response, and liver disease because they contain human immune system and liver cells. These mice become infected with HCV, generate a specific immune response against the virus, and develop liver diseases that include hepatitis and fibrosis. This model might also be used to develop therapeutics for HCV infection. PMID- 21237171 TI - Ion mobility separation coupled with MS detects two structural states of Alzheimer's disease Abeta1-40 peptide oligomers. AB - Mounting evidence points to the soluble oligomers of amyloid beta (Abeta) peptide as important neurotoxic species in Alzheimer's disease, causing synaptic dysfunction and neuronal injury, and finally leading to neuronal death. The mechanism of the Abeta peptide self-assembly is still under debate. Here, Abeta1 40 peptide oligomers were studied using mass spectrometry combined with ion mobility spectrometry, which allowed separation of the signals of numerous oligomers and measurement of their collisional cross-section values (Omega). For several oligomers, at least two different species of different Omega values were detected, indicating the presence of at least two families of conformers: compact and extended. The obtained results are rationalized by a set of molecular models of Abeta1-40 oligomer structure that provided a very good correlation between the experimental and theoretical Omega values, both for the compact and the extended forms. Our results indicate that mass spectrometry detects oligomeric species that are on-pathway in the process of fibril formation or decay, but also alternative structures which may represent off-pathway evolution of oligomers. PMID- 21237172 TI - Site-specific coupling and sterically controlled formation of multimeric antibody fab fragments with unnatural amino acids. AB - Immunoconjugates and multispecific antibodies are rapidly emerging as highly potent experimental therapeutics against cancer. We have developed a method to incorporate an unnatural amino acid, p-acetylphenylalanine (pAcPhe) into an antibody antigen binding fragment (Fab) targeting HER2 (human epidermal growth factor receptor 2), allowing site-specific labeling without disrupting antigen binding. Expression levels of the pAcPhe-containing proteins were comparable to that of wild-type protein in shake-flask and fermentation preparations. The pAcPhe-Fabs were labeled by reaction with hydroxylamine dye and biotin species to produce well-defined, singly conjugated Fabs. We then coupled a hydroxylamine biotin to the pAcPhe-Fab and demonstrated controlled assembly of Fabs in the presence of the tetrameric biotin-binding protein, NeutrAvidin. The position of Fab biotinylation dictates the geometry of multimer assembly, producing unique multimeric Fab structures. These assembled Fab multimers differentially attenuate Her2 phosphorylation in breast cancer cells that overexpress the Her2 receptor. Thus, an encoded unnatural amino acid produces a chemical "handle" by which immunoconjugates and multimers can be engineered. PMID- 21237173 TI - A product analog bound form of 3-oxoadipate-enol-lactonase (PcaD) reveals a multifunctional role for the divergent cap domain. AB - Lactones are a class of structurally diverse molecules that serve essential roles in biological processes ranging from quorum sensing to the aerobic catabolism of aromatic compounds. Not surprisingly, enzymes involved in the bioprocessing of lactones are often targeted for protein engineering studies with the potential, for example, of optimized bioremediation of aromatic pollutants. The enol-lactone hydrolase (ELH) represents one such class of targeted enzymes and catalyzes the conversion of 3-oxoadipate-enol-lactone into the linear beta-ketoadipate. To define the structural details that govern ELH catalysis and assess the impact of divergent features predicted by sequence analysis, we report the first structural characterization of an ELH (PcaD) from Burkholderia xenovorans LB400 in complex with the product analog levulinic acid. The overall dimeric structure of PcaD reveals an alpha-helical cap domain positioned atop a core alpha/beta-hydrolase domain. Despite the localization of the conserved catalytic triad to the core domain, levulinic acid is bound largely within the region of the active site defined by the cap domain, suggesting a key role for this divergent substructure in mediating product release. Furthermore, the architecture of the cap domain results in an unusually deep active-site pocket with topological features to restrict binding to small or kinked substrates. The evolutionary basis for this substrate selectivity is discussed with respect to the homologous dienelactone hydrolase. Overall, the PcaD costructure provides a detailed insight into the intimate role of the cap domain in influencing all aspects of substrate binding, turnover, and product release. PMID- 21237175 TI - Membrane insertion and topology of the translocating chain-associating membrane protein (TRAM). AB - The translocating chain-associating membrane protein (TRAM) is a glycoprotein involved in the translocation of secreted proteins into the endoplasmic reticulum (ER) lumen and in the insertion of integral membrane proteins into the lipid bilayer. As a major step toward elucidating the structure of the functional ER translocation/insertion machinery, we have characterized the membrane integration mechanism and the transmembrane topology of TRAM using two approaches: photocross linking and truncated C-terminal reporter tag fusions. Our data indicate that TRAM is recognized by the signal recognition particle and translocon components, and suggest a membrane topology with eight transmembrane segments, including several poorly hydrophobic segments. Furthermore, we studied the membrane insertion capacity of these poorly hydrophobic segments into the ER membrane by themselves. Finally, we confirmed the main features of the proposed membrane topology in mammalian cells expressing full-length TRAM. PMID- 21237174 TI - Initiation of translation of the FMR1 mRNA Occurs predominantly through 5'-end dependent ribosomal scanning. AB - The fragile X mental retardation 1 (FMR1) gene contains a CGG repeat within its 5' untranslated region (5'UTR) that, when expanded to 55-200 CGG repeats (premutation allele), can result in the late-onset neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome. The CGG repeat is expected to form a highly stable secondary structure that is capable of inhibiting 5'-cap-dependent translation. Paradoxically, translation in vivo is only mildly impaired within the premutation range, suggesting that other modes of translation initiation may be operating. To address this issue, we translated in vitro a set of reporter mRNAs containing between 0 and 99 CGG repeats in either native (FMR1) or unrelated (heterologous) 5'UTR context. The 5'-cap dependence of translation was assessed by inserting a stable hairpin (HP) near the 5' end of the mRNAs. The results of the current studies indicate that translation initiation of the FMR1 mRNA occurs primarily by scanning, with little evidence of internal ribosome entry or shunting. Additionally, the efficiency of translation initiation depends on transcription start site selection, with the shorter 5'UTR (downstream transcription start site I) translating with greater efficiency compared to the longer mRNA (start site III) for all CGG-repeat elements studied. Lastly, an HP previously shown to block translation gave differing results depending on the 5'UTR context, in one case initiating translation from within the HP. PMID- 21237176 TI - Symbol manipulation and rule learning in spiking neuronal networks. AB - It has been claimed that the productivity, systematicity and compositionality of human language and thought necessitate the existence of a physical symbol system (PSS) in the brain. Recent discoveries about temporal coding suggest a novel type of neuronal implementation of a physical symbol system. Furthermore, learning classifier systems provide a plausible algorithmic basis by which symbol re-write rules could be trained to undertake behaviors exhibiting systematicity and compositionality, using a kind of natural selection of re-write rules in the brain, We show how the core operation of a learning classifier system, namely, the replication with variation of symbol re-write rules, can be implemented using spike-time dependent plasticity based supervised learning. As a whole, the aim of this paper is to integrate an algorithmic and an implementation level description of a neuronal symbol system capable of sustaining systematic and compositional behaviors. Previously proposed neuronal implementations of symbolic representations are compared with this new proposal. PMID- 21237177 TI - Computational modeling of differences in the quorum sensing induced luminescence phenotypes of Vibrio harveyi and Vibrio cholerae. AB - Vibrio harveyi and Vibrio cholerae have quorum sensing pathways with similar design and highly homologous components including multiple small RNAs (sRNAs). However, the associated luminescence phenotypes of strains with sRNA deletions differ dramatically: in V. harveyi, the sRNAs act additively; however, in V. cholerae, the sRNAs act redundantly. Furthermore, there are striking differences in the luminescence phenotypes for different pathway mutants in V. harveyi and V. cholerae. However, these differences have not been connected with the observed differences for the sRNA deletion strains in these bacteria. In this work, we present a model for quorum sensing induced luminescence phenotypes focusing on the interactions of multiple sRNAs with target mRNA. Within our model, we find that one key parameter - the fold-change in protein concentration necessary for luminescence activation - can control whether the sRNAs appear to act additively or redundantly. For specific parameter choices, we find that differences in this key parameter can also explain hitherto unconnected luminescence phenotypes differences for various pathway mutants in V. harveyi and V. cholerae. The model can thus provide a unifying explanation for observed differences in luminescence phenotypes and can also be used to make testable predictions for future experiments. PMID- 21237178 TI - A statistical-reaction-diffusion approach for analyzing expansion processes. AB - In this article, we propose a method for analyzing the spatial variations in the range expansion of the pine processionary moth (PPM), an invasive species in France. Based on binary measurements - the presence or absence of PPM nests - the proposed method allows us to infer the local effect of the environment on PPM population expansion. This effect is estimated at each position x using a parameter F(x) that corresponds to the local PPM fitness. The data type and the two stage PPM life cycle make estimating this parameter difficult. To overcome these difficulties we adopt a mechanistic-statistical approach that combines a statistical model for the observation process with a hierarchical,reaction diffusion based mechanistic model for the expansion process. Bayesian inference of the parameter F(x) reveals that PPM fitness is spatially heterogeneous and highlights the existence of large regions associated with lower fitness. The factors underlying this lower fitness are yet to be determined. PMID- 21237179 TI - Sampling and assessment accuracy in mate choice: a random-walk model of information processing in mating decision. AB - Mate choice depends on mating preferences and on the manner in which mate-quality information is acquired and used to make decisions. We present a model that describes how these two components of mating decision interact with each other during a comparative evaluation of prospective mates. The model, with its well explored precedents in psychology and neurophysiology, assumes that decisions are made by the integration over time of noisy information until a stopping-rule criterion is reached. Due to this informational approach, the model builds a coherent theoretical framework for developing an integrated view of functions and mechanisms of mating decisions. From a functional point of view, the model allows us to investigate speed-accuracy tradeoffs in mating decision at both population and individual levels. It shows that, under strong time constraints, decision makers are expected to make fast and frugal decisions and to optimally trade off population-sampling accuracy (i.e. the number of sampled males) against individual-assessment accuracy (i.e. the time spent for evaluating each mate). From the proximate-mechanism point of view, the model makes testable predictions on the interactions of mating preferences and choosiness in different contexts and it might be of compelling empirical utility for a context-independent description of mating preference strength. PMID- 21237180 TI - Effects of histamine H3 receptors on chemical hyperalgesia in diabetic rats. AB - There is considerable interest in histamine H3 receptors as emerging pharmaceutical targets recently. Diabetic rats display increased pain responses following the injection of formalin into the paw suggesting the presence of hyperalgesia. In this study, the efficacy of systemic administration of selective H3 receptor agonist, immepip (1, 5 and 30 mg/kg), and antagonist, thioperamide (5, 15 and 30 mg/kg), was investigated on hyperalgesia during the formalin test in streptozocin (STZ)-induced diabetic rats. Nociceptive testing was performed in male adult Wistar rats 4 weeks after the onset of hyperglycemia. At the end of the experiment, all rats were weighed and then underwent plasma glucose measurement. Diabetes caused significant hyperalgesia during both phases of the formalin test. 5 and 30 mg/kg doses of immepip reversed chemical hyperalgesia in diabetic rats. The 1 mg dose of immepip did not alter pain behaviors in control and diabetic groups compared to the respective control ones. Immepip at any doses used in this study did not affect the body weight and plasma glucose levels of treated animals. Thioperamide alone at any doses used had no effect on formalin induced nociceptive behaviors in the control and diabetic rats. The results indicated the efficacy of immepip systemic administration in an experimental model of diabetic hyperalgesia. It may also suggest it as a promising tool for treatment of painful diabetic neuropathy. PMID- 21237181 TI - Normal form from biological motion despite impaired ventral stream function. AB - We explored the extent to which biological motion perception depends on ventral stream integration by studying LG, an unusual case of developmental visual agnosia. LG has significant ventral stream processing deficits but no discernable structural cortical abnormality. LG's intermediate visual areas and object sensitive regions exhibit abnormal activation during visual object perception, in contrast to area V5/MT+ which responds normally to visual motion (Gilaie-Dotan, Perry, Bonneh, Malach, & Bentin, 2009). Here, in three studies we used point light displays, which require visual integration, in adaptive threshold experiments to examine LG's ability to detect form from biological and non biological motion cues. LG's ability to detect and discriminate form from biological motion was similar to healthy controls. In contrast, he was significantly deficient in processing form from non-biological motion. Thus, LG can rely on biological motion cues to perceive human forms, but is considerably impaired in extracting form from non-biological motion. Finally, we found that while LG viewed biological motion, activity in a network of brain regions associated with processing biological motion was functionally correlated with his V5/MT+ activity, indicating that normal inputs from V5/MT+ might suffice to activate his action perception system. These results indicate that processing of biologically moving form can dissociate from other form processing in the ventral pathway. Furthermore, the present results indicate that integrative ventral stream processing is necessary for uncompromised processing of non-biological form from motion. PMID- 21237182 TI - A dynamic causal modeling analysis of the effective connectivities underlying top down letter processing. AB - The present study employed dynamic causal modeling to investigate the effective functional connectivity between regions of the neural network involved in top down letter processing. We used an illusory letter detection paradigm in which participants detected letters while viewing pure noise images. When participants detected letters, the response of the right middle occipital gyrus (MOG) in the visual cortex was enhanced by increased feed-backward connectivity from the left inferior frontal gyrus (IFG). In addition, illusory letter detection increased feed-forward connectivity from the right MOG to the left inferior parietal lobules. Originating in the left IFG, this top-down letter processing network may facilitate the detection of letters by activating letter processing areas within the visual cortex. This activation in turns may highlight the visual features of letters and send letter information to activate the associated phonological representations in the identified parietal region. PMID- 21237184 TI - Age-related occipito-temporal hypoactivation during visual search: relationships between mN2pc sources and performance. AB - Recently, an event-related potential (ERP) study (Lorenzo-Lopez et al., 2008) provided evidence that normal aging significantly delays and attenuates the electrophysiological correlate of the allocation of visuospatial attention (N2pc component) during a feature-detection visual search task. To further explore the effects of normal aging on the N2pc neural sources, neuromagnetic activity during the execution of a visual search task was recorded in healthy young (N=14) and older (N=20) participants by using magnetoencephalography (MEG). The possible relationships between these neural sources and overt performance were explored by assessing the co-variation between the neural N2pc activity and both the task performance and the execution in the Trail Making Test Form A (TMT-A). Results revealed that young participants showed greater activity in occipito-temporal regions than older participants during the mN2pc (magnetic counterpart of the N2pc component) latency range (190-270ms). Moreover, older participants showed reduced relative activation in the right occipito-temporal source of mN2pc. These findings suggest that the previously observed age-related changes in N2pc parameters are associated with a significant hypoactivation of occipito-temporal N2pc sources that is more marked in the right hemisphere. PMID- 21237183 TI - Spatial inhibition and the visual cortex: a magnetic resonance spectroscopy imaging study. AB - INTRODUCTION: Deficits in processing spatial information have been observed in clinical populations who have abnormalities within the dopamine (DA) system. As psychostimulants such as methamphetamine (MA) are particularly neurotoxic to the dopaminergic system it was of interest to examine the performance of MA-dependent individuals on a task of spatial attention. METHOD: 51 MA-dependent subjects and 22 age-matched non-substance abusing control subjects were tested on a Spatial Stroop attention test. MR Spectroscopy (MRS) imaging data were analyzed from 32 MA abusers and 13 controls. RESULTS: No group differences in response time or accuracy emerged on the behavioral task with both groups exhibiting equivalent slowing when the word meaning and the spatial location of the word were in conflict. MRS imaging data from the MA abusers revealed a strong inverse correlation between NAA/Cr ratios in the Primary Visual Cortex (PVC) and spatial interference (p=0.0001). Moderate inverse correlations were also seen in the Anterior Cingulate Cortex (ACC) (p=0.02). No significant correlations were observed in the controls, perhaps due to the small sample of imaging data available (n=13). DISCUSSION: The strong correlation between spatial conflict suppression and NAA/Cr levels within the PVC in the MA-dependent individuals suggests that preserved neuronal integrity within the PVC of stimulant abusers may modulate cognitive mechanisms that process implicit spatial information. PMID- 21237186 TI - Individual variation in the (patho)physiology of energy balance. AB - There are large individual differences in the susceptibility for metabolic disorders such as obesity, the metabolic syndrome and type 2 diabetes. Unfortunately, most animal studies in this field ignore the importance of individual variation which limits the face validity of these studies for translation to the human situation. We have performed a series of studies that were particularly focused on the individual differences in the (patho)physiology of energy balance. The studies were performed with passive and proactive individuals of two different rat strains: the Roman High and Low Avoidance rats and the Wild type Groningen rat. The data reveal that passive and proactive individuals differ significantly on several parameters, i.e. body composition, Hypothalamic-Pituitary-Adrenal (HPA) axis activity, plasma levels of insulin and leptin, intestinal transit time, systolic blood pressure and meal patterns. We also found that the selection line of the Roman Low Avoidance rat may be considered as a non-obese animal model for the metabolic syndrome, since these rats display, under sedentary conditions, many of the related symptoms such as hypertension, visceral adiposity and insulin resistance during an intravenous glucose tolerance test. These symptoms disappeared when the animals were allowed to exercise voluntarily in a running wheel. We conclude that experiments with passive and proactive individuals are highly relevant for studying the (patho)physiology and behavior of energy balance and the related metabolic disorders. PMID- 21237185 TI - Selective responses in right inferior frontal and supramarginal gyri differentiate between observed movements of oneself vs. another. AB - The fact that inferior frontal (IFg) and supramarginal (SMg) gyri respond to both self-generated and observed actions has been interpreted as evidence for a perception-action linking mechanism (mirroring). Yet, the brain readily distinguishes between percepts generated by one's own movements vs. those of another. Do IFg and/or SMg respond differentially to these visual stimuli even when carefully matched? We used BOLD fMRI to address this question as participants made repetitive bimanual hand movements while viewing either live visual feedback or perceptually similar, pre-recorded video of an actor. As expected, bilateral IFg and SMg increased activity during both conditions. However, right SMg and IFg responded differentially during live visual feedback vs. matched recordings. These mirror system areas may distinguish self-generated percepts by detecting subtle spatio-temporal differences between predicted and actual sensory feedback and/or visual and somatosensory signals. PMID- 21237187 TI - Methyl Vitamin B12 but not methylfolate rescues a motor neuron-like cell line from homocysteine-mediated cell death. AB - Homocysteine is an excitatory amino acid implicated in multiple diseases including amyotrophic lateral sclerosis (ALS). Information on the toxicity of homocysteine in motor neurons is limited and few studies have examined how this toxicity can be modulated. In NSC-34D cells (a hybrid cell line derived from motor neuron-neuroblastoma), homocysteine induces apoptotic cell death in the millimolar range with a TC50 (toxic concentration at which 50% of maximal cell death is achieved) of 2.2 mM, confirmed by activation of caspase 3/7. Induction of apoptosis was independent of short-term reactive oxygen species (ROS) generation. Methyl Vitamin B12 (MeCbl) and methyl tetrahydrofolate (MTHF), used clinically to treat elevated homocysteine levels, were tested for their ability to reverse homocysteine-mediated motor neuron cell death. MeCbl in the micromolar range was able to provide neuroprotection (2 h pretreatment prior to homocysteine) and neurorescue (simultaneous exposure with homocysteine) against millimolar homocysteine with an IC50 (concentration at which 50% of maximal cell death is inhibited) of 0.6 MUM and 0.4 MUM, respectively. In contrast, MTHF (up to 10 MUM) had no effect on homocysteine-mediated cell death. MeCbl inhibited caspase 3/7 activation by homocysteine in a time- and dose-dependent manner, whereas MTHF had no effect. We conclude that MeCbl is effective against homocysteine-induced cell death in motor neurons in a ROS-independent manner, via a reduction in caspase activation and apoptosis. MeCbl decreases Hcy induced motor neuron death in vitro in a hybrid cell line derived from motor neuron neuroblastoma and may play a role in the treatment of late stage ALS where HCy levels are increased in animal models of ALS. PMID- 21237188 TI - The impact of macular pigment augmentation on visual performance in normal subjects: COMPASS. AB - This study was conducted to investigate whether augmentation of macular pigment (MP) enhances visual performance (VP). 121 normal subjects were recruited. The active (A) group consumed 12 mg of lutein (L) and 1mg of zeaxanthin (Z) daily. MP optical density (MPOD) was assessed by customized heterochromatic flicker photometry. VP was assessed as best corrected visual acuity (BCVA), mesopic and photopic contrast sensitivity (CS), glare disability, photostress, and subjective visual function. Subjects were assessed at baseline; 3; 6; 12 months (V1, V2, V3 and V4, respectively). Central MPOD increased significantly in the A group (p < 0.05) but not in the placebo group (p > 0.05). This statistically significant increase in MPOD in the A group was not, in general, associated with a corresponding improvement in VP (p>0.05, for all variables), with the exception of a statistically significant time/treatment effect in "daily tasks comparative analysis" (p = 0.03). At V4, we report statistically significant differences in mesopic CS at 20.7 cpd, mesopic CS at 1.5 cpd under high glare conditions, and light/dark adaptation comparative analysis between the lower and the upper MP tertile groups (p < 0.05) Further study into the relationship between MP and VP is warranted, with particular attention directed towards individuals with low MP and suboptimal VP. PMID- 21237190 TI - The coding and updating of visuospatial memory for goal-directed reaching and pointing. AB - In this review we discuss evidence from psychophysical, electrophysiological, and neuroimaging studies that demonstrates the updating of remembered visual space in a reference frame that is centred on the eye. We then extend these findings by discussing recent work from our lab. Specifically, we address eye-centred updating of visuospatial memory for arm movements following different types of eye movements, the role of retinal versus extraretinal information in such spatial updating, and the use of allocentric versus egocentric information in coding multiple targets. We provide a conceptual model to explain the relationships among these findings. PMID- 21237191 TI - Effects of harmane and other beta-carbolines on apomorphine-induced licking behavior in rat. AB - Harmane, harmine and norharmane are beta-carboline compounds which have been referred to as inverse agonists of benzodiazepine receptors. The effect of these compounds on apomorphine-induced licking behavior was studied in rats. Subcutaneous (s.c.) injection of apomorphine (0.5 mg/kg) induced licking. The licking behavior was counted with a hand counter and recorded for a period of 75 min by direct observation. Intraperitoneal (i.p.) injections of harmane (1.25-5 mg/kg), harmine (2.5-10 mg/kg) and norharmane (1.25-5 mg/kg) significantly reduced the licking behavior. In rats pretreated with reserpine (5 mg/kg, i.p., 18 h before the test), the effects of harmane (4 mg/kg, i.p.), harmine (7.8 mg/kg, i.p.) and norharmane (2.5 mg/kg, i.p.) were unchanged. When flumazenil (2 mg/kg, i.p.) was administered 20 min before apomorphine, it was able to antagonize the effects of harmane, harmine and norharmane. It was concluded that the beta-carbolines harmane, harmine and norharmane reduce the licking behavior via an inverse agonistic mechanism located in the benzodiazepine receptors. PMID- 21237192 TI - Effect of religion on use of menthol cigarettes in African American smokers. PMID- 21237194 TI - A galectin with quadruple-domain from bay scallop Argopecten irradians is involved in innate immune response. AB - Galectins are a family of beta-galactoside-binding lectins that specifically bind to beta-galactoside residues and play crucial roles in innate immune responses of invertebrates and vertebrates. The cDNA of bay scallop Argopecten irradians galectin (designated as AiGal2) was cloned by rapid amplification of cDNA ends (RACE) method based on the expressed sequence tag (EST). The full-length cDNA of AiGal2 was of 2137 bp. The open reading frame encoded a polypeptide of 555 amino acids containing four carbohydrate-recognition domains. The deduced amino acid sequence and multi-domain organization of AiGal2 were highly similar to those of mollusk galectins. A typical galectin fold in beta-sandwich arrangement was identified in the potential tertiary structure of all the four CRDs in AiGal2. The mRNA transcripts of AiGal2 were found to be constitutively expressed in a wide range of tissues and mainly in hepatopancreas, adductor muscle and kidney. After scallops were challenged by Vibrio anguillarum or Micrococcus luteus, the mRNA expression level of AiGal2 was up-regulated significantly, while it did not changed remarkably after Pichia pastoris challenge. The recombined AiGal2 (rAiGal2) exhibited strong activity to agglutinate E. coli, V. anguillarum, Vibrio fluvialis, Edwardsiella tarda and M. luteus, and the agglutinating activities could be inhibited by both d-galactose and lactose. The in vitro encapsulation assay revealed that rAiGal2 could bind to hemocytes and enhanced its encapsulation of agarose beads. These results collectively suggested that AiGal2 functioned as a pattern recognition receptor in immune defense and contributed to the non-self recognition and elimination in cellular immune response of bay scallop. PMID- 21237193 TI - Biomarkers in aortic dissection. AB - Aortic dissection (AD) is a severe cardiovascular disease with high mortality and morbidity, which is characterized by acute onset and rapid progress. Mechanically, it has been considered that circulating blood flows into the media of the aorta through the rupture of the intima forming true and false lumens. Generally, its pathologic process is considered as follows: initially, inflammatory reaction, inflammatory cells infiltration in aortic wall, and then apoptosis of vascular smooth muscle cells, degenerating of aortic media, elastin fracture, and degradation. At last, the ingredients of the aorta are destroyed and lead to aortic dilatation, aneurysm formation, dissection and rupture. Currently, several biomarkers in peripheral blood including C-reactive protein (CRP), matrix metalloproteinases (MMPs), soluble elastin fragments (sELAF), D dimer, smooth muscle myosin heavy chain, calponin, N-terminal pro-brain natriuretic peptide (NT-proBNP), big endothelin-1 (Big ET-1), genetic markers and so on, have been demonstrated to play a major role in evaluation of AD, for example, making early diagnosis and classifying of AD. Additionally, those markers may also guide our treatment therapies and predict the prognosis. The aims of this review mainly focus on the clinical implications of the biomarkers in AD. PMID- 21237195 TI - Gene discovery, comparative analysis and expression profile reveal the complexity of the Crassostrea gigas apoptosis system. AB - Apoptosis system was reported to play important role in organism immunity, but it was a currently understudied respect in molluscan immunity studies. Base on the recent generation of ESTs in the pacific oyster, Crassostrea gigas, a survey of apoptosis-related molecules was conducted in the assembled unigenes, we found that the basic genes and domains in apoptosis-associated proteins were conserved, the overall apoptotic machinery was complex in C. gigas and that the organism had an expanded number of putative baculovirus inhibitor of apoptosis repeat domains. Moreover, four typical apoptosis-related genes were cloned in C. gigas and compared with the sequences of these genes in Drosophila melanogaster and Homo sapiens. The expression level of these four apoptosis-related genes in the hemolymph increased dramatically in the presence of the bacteria, Vibrio anguillarum, indicating their role in bacterial defense. Our results suggest that the oyster apoptosis system is not simple and cannot be represented by model invertebrates. PMID- 21237196 TI - Localization of the serine protease homolog BmSPH-1 in nodules of E. coli injected Bombyx mori larvae and functional analysis of its role in nodule melanization. AB - The molecular mechanisms underlying nodule formation and melanization, an important pathogen defense mechanism in insects, are poorly understood. In this study, we investigated the role of BmSPH-1, a catalytically inactive Bombyx mori serine protease homolog, in nodule melanization induced by injection of Escherichia coli cells into the B. mori larval hemocoel. Addition of the melanization substrate L-3,4-dihydroxyphenylalanine (DOPA) to newly formed nodules prompted nodule melanization, confirming that nodules contain activated prophenoloxidase needed for melanization. Immunoprecipitation and immunoblot studies demonstrated that BmSPH-1 interacts with BmLBP, a C-type lectin that binds Gram-negative bacteria, and that BmSPH-1 is present in a truncated, putatively activated form at the E. coli cell surface in nodules. Pretreatment of larvae with anti-BmSPH-1 serum inhibited nodule melanization in E. coli-injected larvae. These results suggest that BmSPH-1 regulates nodule melanization and is recruited into nodules from the hemolymph by BmLBP. PMID- 21237198 TI - The neuropsychiatry of neuroacanthocytosis syndromes. AB - The neuroacanthocytoses are a group of disorders characterised by peripheral blood acanthocytes, central nervous system as well as neuromuscular symptoms. These disorders uniformly result in pathology in the basal ganglia, which account for the characteristic motor symptoms such as chorea or dystonia, but may also account for the apparent elevated rates of major mental disorders in these syndromes. Elevated rates of dysexecutive syndromes, obsessive-compulsive disorder, depression and schizophrenia-like psychosis appear to occur in chorea acanthocytosis, McLeod's syndrome, pantothenate kinase-associated neurodegeneration, and Huntington's disease-like 2. Disruptions to key frontostriatal loops secondary to pathology in the striatum and pallidum appear to predispose individuals to major neuropsychiatric syndromes; however, treatment can be instituted for a number of these manifestations, which lessens the overall burden of disease in neuroacanthocytosis patients and their families. PMID- 21237189 TI - Eye movements: the past 25 years. AB - This article reviews the past 25 years of research on eye movements (1986-2011). Emphasis is on three oculomotor behaviors: gaze control, smooth pursuit and saccades, and on their interactions with vision. Focus over the past 25 years has remained on the fundamental and classical questions: What are the mechanisms that keep gaze stable with either stationary or moving targets? How does the motion of the image on the retina affect vision? Where do we look - and why - when performing a complex task? How can the world appear clear and stable despite continual movements of the eyes? The past 25 years of investigation of these questions has seen progress and transformations at all levels due to new approaches (behavioral, neural and theoretical) aimed at studying how eye movements cope with real-world visual and cognitive demands. The work has led to a better understanding of how prediction, learning and attention work with sensory signals to contribute to the effective operation of eye movements in visually rich environments. PMID- 21237199 TI - Characteristics of pregnant Japanese women who required hospitalization for treatment of pandemic (H1N1) 2009--low mortality rate may be due to early antiviral use. PMID- 21237197 TI - Self-injurious behavior in neurodevelopmental disorders: relevance of nociceptive and immune mechanisms. AB - Self-injurious behavior (SIB) among individuals with intellectual and related neurodevelopmental disorders (IDD) is a clinical challenge and scientific puzzle. The physiological mechanisms regulating the sensory components of SIB remain a mystery with no clear understanding of the underlying pathophysiology. The central dogma regarding sensory processing in general and pain in particular among individuals with IDD and chronic SIB is that sensory processing is reduced and pain is absent or blunted. In this paper, recent findings challenging some of the conventional wisdom regarding pain and sensory function among individuals with IDD and SIB are reviewed. It seems that at least a subgroup of individuals with IDD and chronic SIB may be in a physiological state similar to neuropathic pain in which hyperalgesia is mediated by plasticity mechanisms regulating inflammatory, immune, and nociceptive systems. In response to repeated tissue damage associated with chronic self-injury, innate immune cells may be producing pro-inflammatory and pro-nociceptive cytokines that act on the brain to cause sickness-like behavior and sensitize primary sensory nerve afferents contributing to pain hypersensitivity (i.e., hyperalgesia). PMID- 21237200 TI - Fungal malignant external otitis. AB - OBJECTIVE: To investigate the clinical characteristics and outcome of fungal malignant external otitis (MEO). METHODS: The files of 60 patients treated for MEO in 1990-2008 at a tertiary medical center were reviewed for clinical characteristics and outcome, and findings were compared between patients with fungal and nonfungal infection. RESULTS: Mean duration of follow-up was 4 years. Nine patients (15%) had fungal disease; the main pathogen was Candida spp. Compared with the nonfungal MEO group, patients with a fungal infection were younger at diagnosis (average 68 vs. 74 years, p = 0.01) and had more facial nerve palsies (55% vs. 14%, p = 0.01), fewer positive bacterial cultures at presentation (33% vs. 75%, p = 0.02), and higher rates of surgery (78% vs. 18%, p = 0.0008) and hyperbaric treatment (78% vs. 4%, p = 0.0001). Eighty-nine percent had persistent infection (>2 courses of systemic antibiotics before antifungal treatment) compared with 12% in the nonfungal group (p = 0.0001). Fungal disease was associated with more persistently positive imaging findings (87.5% vs. 25%, p = 0.0001). There was no significant between-group difference in survival. CONCLUSION: Fungal MEO probably occurs secondary to prolonged antibiotic treatment for bacterial MEO. The fungal disease is more invasive than the bacterial disease, although survival is the same. Treatment should be aggressive and hyperbaric oxygen therapy should be considered. PMID- 21237201 TI - Deep resequencing of serial sputum isolates of Mycobacterium tuberculosis during therapeutic failure due to poor compliance reveals stepwise mutation of key resistance genes on an otherwise stable genetic background. AB - OBJECTIVES: It has generally been held that the repeated emergence of resistance in Mycobacterium tuberculosis is due to the effects of large population sizes, slow replication, and prolonged colonization and treatment. However, there have been suggestions that its emergence is facilitated by high mutation rates due to a lack of mismatch repair, error-prone polymerases, and a potentially mutagenic host niche. Genome re-sequencing has indicated higher variability in strains with emergent resistance, but these studies have not been performed in serial isolates in which drug resistance has emerged. We have used genome re-sequencing to address the mutational processes that occur during the evolution of drug resistance during a clinical infection. METHODS: Serial isolates from a patient obtained over a 12 month period, and spanning the transition of the colonizing population from fully drug sensitive, to isoniazid resistant, to isoniazid and rifampicin (multiply drug) resistant, spanning an estimated minimum of 100 generations within the host, were deep sequenced using Illumina sequencing. The genomes were compared, and all mutations in non-repetitive sequences were identified. RESULTS: Specific mutations conferring resistance were identified. No additional mutations in non-repetitive regions were present. The mutations observed were kat S315T and rpoB D516Y. CONCLUSIONS: M. tuberculosis is relatively stable genetically within the host, and demonstrates greater stability than is suggested by in vitro studies of emergent drug resistance, or by models of hypermutability. This indicates that it is primarily the nature and duration of the infection that are sufficient to lead to the repeated emergence of drug resistance in this infection if improperly managed, and that the selective pressure of the drugs limits additional diversification. This emphasizes the central importance of maintaining therapeutic concentrations of at least two effective antibiotics for the duration of treatment to prevent the emergence of resistance. PMID- 21237202 TI - Ethanol extract from birch bark (Betula pubescens) suppresses human dendritic cell mediated Th1 responses and directs it towards a Th17 regulatory response in vitro. AB - Extracts and fractions from birch bark have been used to treat various diseases, such as skin disorders and rheumatism, and for analgesic effects. Results from studies in vitro and in vivo have shown that birch bark extracts can have immunoregulatory effects. These effects have mainly been attributed to the various triterpenes found in birch bark. The effects of birch bark from Betula pubescens on immune responses have not been reported. Ethanol extract was prepared from dry birch bark (DBBEE) and five fractions made using various ratios of dichloromethane and methanol (fractions I-V). Human monocyte-derived dendritic cells (DCs) were matured with or without DBBEE or fractions I-V at several concentrations. The effects of the extract and fractions on DC maturation were determined by measuring cytokine secretion by ELISA and expression of surface molecules by flow cytometry. DBBEE and fractions III and IV reduced DC secretion of IL-6, IL-10 and IL-12p40 and expression of CD83, CD86, CCR7 and DC-SIGN compared with control DCs. Proliferation of allogeneic CD4(+) T cells co-cultured with DCs matured with fraction IV, as measured by (3)H-thymidine incorporation, was similar to proliferation of allogeneic CD4(+) T cells co-cultured with control DCs. However, IFN-gamma secretion was reduced and IL-10 and IL-17 secretion was increased, a cytokine profile consistent with a Th17 regulatory phenotype. These results indicate that bark from Betula pubescens contains compound(s) that can modulate DCs so that their interaction with T cells leads to an immunoregulatory response. PMID- 21237203 TI - beta-cell specific overexpression of suppressor of cytokine signalling-3 does not protect against multiple low dose streptozotocin induced type 1 diabetes in mice. AB - We investigated the impact of beta-cell specific overexpression of suppressor of cytokine signalling-3 (SOCS-3) on the development of multiple low dose streptozotocin (MLDSTZ) induced Type 1 diabetes and the possible mechanisms involved. MLDSTZ treatment was administered to RIP-SOCS-3 transgenic and wild type (wt) mice and progression of hyperglycemia monitored. Isolated islets from both strains were exposed to human IL-1beta (25U/ml) or a combination of human IL 1beta (25U/ml) and murine IFN-gamma (1000U/ml) for 24h or 48h and we investigated the expression of IL-1 receptor antagonist (IL-1Ra) mRNA in islet cells and secretion of IL-1Ra into culture medium. MLDSTZ treatment caused gradual hyperglycemia both in the wt mice and in the transgenic mice with the latter tending to be more sensitive. In vitro experiments on wt and transgenic islets did not reveal any differences in sensitivity to damaging effects of STZ. Exposure of wt islets to IL-1beta or IL-1beta+IFN-gamma seemed to lead to a failing IL-1Ra response from SOCS-3 transgenic islets. It could be that an increased expression of a possible protective molecule against beta-cell destruction may lead to a dampered response of another putative protective molecule. This may have counteracted a protective effect against MLDSTZ in SOCS-3 transgenic mice. PMID- 21237205 TI - All-trans retinoic acid induces TLR-5 expression and cell differentiation and promotes flagellin-mediated cell functions in human THP-1 cells. AB - Toll-like receptor 5 (TLR-5), which is expressed on macrophages and dendritic cells (DCs), is a crucial cell surface molecule that senses microbial-associated molecular patterns and initiates host innate immune responses upon infection with invaders that express flagellin. Little information is known about the induction factors and mechanisms of TLR-5 expression. In this study, we demonstrate that all-trans retinoic acid (ATRA) significantly up-regulated TLR-5 expression in human macrophage THP-1 cells by co-activating NF-kappaB and the RARalpha receptor and inducing the differentiation of CD11b(-)CD11c(-) THP-1 cells to CD11b(+)CD11c(low) cells. Furthermore, when stimulated with flagellin, ATRA induced THP-1 cells expressed multiple cytokines, including TNF-alpha, IL-1beta, and IL-12p40, and several co-stimulatory molecules, such as CD40, CD80, CD86, and MHC class I and II. We also showed that when ATRA-induced THP-1 cells were stimulated with flagellin, the cells displayed an allostimulatory capacity rather than phagocytic activity. Taken together, our findings suggest that ATRA is a crucial immunostimulatory cofactor that induces the activation of macrophages and their subsequent differentiation into dendritic-like cells. PMID- 21237204 TI - Myeloid neoplasm-related gene abnormalities differentially affect dendritic cell differentiation from murine hematopoietic stem/progenitor cells. AB - Dendritic cells (DCs) play important roles in tumor immunology. Leukemic cells in patients with myeloid neoplasms can differentiate into DCs in vivo (referred to as in vivo leukemic DCs), which are postulated to affect anti-leukemia immune responses. We established a reproducible culture system of in vitro FLT3 ligand mediated DC (FL-DC) differentiation from murine lineage(-) Sca-1(+) c-Kit(high) cells (LSKs), which made it possible to analyse the effects of target genes on steady-state DC differentiation from hematopoietic stem/progenitor cells. Using this system, we analysed the effects of various myeloid neoplasm-related gene abnormalities, termed class I and class II mutations, on FL-DC differentiation from LSKs. All class II mutations uniformly impaired FL-DC differentiation maintaining a plasmacytoid DC (pDC)/conventional DC (cDC) ratio comparable to the control cells. In contrast, class I mutations differentially affected FL-DC differentiation from LSKs. FLT3-ITD and a constitutively active form of Ras (CA-N Ras) yielded more FL-DCs than the control, whereas the other class I mutations tested yielded less FL-DCs. Both FLT3-ITD and FLT3-tyrosine kinase domain (TKD) mutation showed a comparable pDC/cDC ratio as the control. CA-N-Ras, c-Kit-TKD, TEL/PDGFRbeta, and FIP1L1/PDGFRalpha showed a severe decrease in the pDC/cDC ratio. CA-STAT5 and CA-MEK1 severely inhibited pDC differentiation. FLT3-ITD, CA N-Ras, and TEL/PDGFRbeta aberrantly induced programmed death ligand-1 (PD-L1) expressing DCs. In conclusion, we have established a simple, efficient, and reproducible in vitro FL-DC differentiation system from LSKs. This system could uncover novel findings on how myeloid neoplasm-related gene abnormalities differentially affect FL-DC differentiation from murine hematopoietic stem/progenitor cells in a gene-specific manner. PMID- 21237206 TI - Constrained peptide models from phage display libraries highlighting the cognate epitope-specific potential of the anti-HIV-1 mAb 2F5. AB - The monoclonal antibody 2F5 (mAb 2F5), one of the most potent broadly neutralizing mAbs targeted to the HIV-1 gp41 membrane proximal exterior region (MPER), displays an unusually wide antigenic specificity, tolerating amino acid substitutions at virtually all positions of the 662-ELDKWAS-668 epitope sequence when presented by peptides. Investigating this phenomenon, Menendez et al. [22] concluded that the paratope of 2F5 contains two distinct binding compartments. One is specific and binds the DKW epitope core; the other is multi-specific and binds to the flanking DKW regions that can be distinct from the epitope sequence. Because the DKW-flanking amino acids are strongly conserved in viruses, it is not clear whether the DKW only satisfies the 2F5 epitope recognition demand. In this study, we demonstrate that the specificity of recognition of the epitope depends on the structural context in which the cognate epitope sequence is presented. The antibody does not tolerate any replacements of the DKW-flanking epitope amino acids and binds exclusively to the (L)DKWA sequence provided that it is presented by a 7-mer constrained peptide exposed by the M13 phage pIII protein. Our data propose a novel epitope recognition model in which the 2F5 mAb requires a sequence longer than DKW and no substitution of flanking amino acids for specific recognition of the peptide. Additionally, immunization data supports the notion that the binding and neutralizing immunogenic structural features of the described epitope model do not coincide. PMID- 21237207 TI - Broad spectrum reactivity versus subtype specificity-trade-offs in serodiagnosis of influenza A virus infections by competitive ELISA. AB - Avian influenza viruses (AIVs) of the H5 and H7 subtypes can cause substantial economic losses in the poultry industry and are a potential threat to public health. Serosurveillance of poultry populations is an important monitoring tool and can also be used for control of vaccination campaigns. The purpose of this study was to develop broadly reactive, yet subtype-specific competitive ELISAs (cELISAs) for the specific detection of antibodies to the notifiable AIV subtypes H5 and H7 as an alternative to the gold standard haemagglutination inhibition assay (HI). Broadly reacting monoclonal competitor antibodies (mAbs) and genetically engineered subtype H5 or H7 haemagglutinin antigen, expressed and in vivo biotinylated in insect cells, were used to develop the cELISAs. Sera from galliform species and water fowl (n=793) were used to evaluate the performance characteristics of the cELISAs. For the H5 specific cELISA, 98.1% test sensitivity and 91.5% test specificity (97.7% and 90.2% for galliforms; 98.9% and 92.6% for waterfowl), and for the H7 cELISA 97.3% sensitivity and 91.8% specificity (95.3% and 98.9% for galliforms; 100% and 82.7% for waterfowl) were reached when compared to HI. The use of competitor mAbs with broad spectrum reactivity within an AIV haemagglutinin subtype allowed for homogenous detection with high sensitivity of subtype-specific antibodies induced by antigenically widely distinct isolates including antigenic drift variants. However, a trade-off regarding sensitivity versus nonspecific detection of interfering antibodies induced by phylo- and antigenically closely related subtypes, e.g., H5 versus H2 and H7 versus H15, must be considered. The observed intersubtype antibody cross reactivity remains a disturbance variable in AIV subtype-specific serodiagnosis which negatively affects specificity. PMID- 21237208 TI - One-step reverse transcription loop-mediated isothermal amplification assay for rapid detection of Cymbidium mosaic virus. AB - Cymbidium mosaic virus (CymMV) is the most prevalent orchid virus. A single-tube one-step betaine-free reverse transcription (RT) loop-mediated isothermal amplification (LAMP) assay was developed for the rapid and easy detection of orchid-infecting CymMV. Five sets of primers were designed based on the conserved regions among various virus isolates. The specificity and the sensitivity of the assay were then evaluated using the RT-LAMP reaction. Within 1h under isothermal conditions at 60 degrees C the target viral gene was amplified successfully. This RT-LAMP assay was found to be quick, specific, sensitive and easy to perform assay that involved only one step and was simpler to carry out than alternative approaches. Thus this assay is an alternative for the rapid and easy detection of CymMV in orchids. This is first time that a RT-LAMP method for the detection of an orchid virus has been described. PMID- 21237209 TI - As the world turns: short-term human spatial memory in egocentric and allocentric coordinates. AB - We aimed to determine whether human subjects' reliance on different sources of spatial information encoded in different frames of reference (i.e., egocentric versus allocentric) affects their performance, decision time and memory capacity in a short-term spatial memory task performed in the real world. Subjects were asked to play the Memory game (a.k.a. the Concentration game) without an opponent, in four different conditions that controlled for the subjects' reliance on egocentric and/or allocentric frames of reference for the elaboration of a spatial representation of the image locations enabling maximal efficiency. We report experimental data from young adult men and women, and describe a mathematical model to estimate human short-term spatial memory capacity. We found that short-term spatial memory capacity was greatest when an egocentric spatial frame of reference enabled subjects to encode and remember the image locations. However, when egocentric information was not reliable, short-term spatial memory capacity was greater and decision time shorter when an allocentric representation of the image locations with respect to distant objects in the surrounding environment was available, as compared to when only a spatial representation encoding the relationships between the individual images, independent of the surrounding environment, was available. Our findings thus further demonstrate that changes in viewpoint produced by the movement of images placed in front of a stationary subject is not equivalent to the movement of the subject around stationary images. We discuss possible limitations of classical neuropsychological and virtual reality experiments of spatial memory, which typically restrict the sensory information normally available to human subjects in the real world. PMID- 21237210 TI - A novel role of thrombopoietin as a physiological modulator of coronary flow. AB - Thrombopoietin (TPO) is known for its ability to stimulate platelet production. However, little is currently known whether TPO plays a physiological function in the heart. The potential vasodilatory role of TPO was tested on the isolated rat heart. The expression of TPO receptor (c-mpl) and the TPO-dependent eNOS phosphorylation (P(Ser1179)) were studied on Cardiac-derived normal Human Micro Vascular Endothelial Cells (HMVEC-C) by Western blot analysis. While TPO (10-200 pg/mL) did not modify coronary flow (CF) under basal conditions, it reduced the coronary constriction caused by endothelin-1 (ET-1; 10nM) in a dose-dependent manner. This effect was blocked by both Wortmannin (100 nM) and L-NAME (100 nM); on HMVEC-C, TPO induced eNOS phosphorylation through a Wortmannin sensitive mechanism. Taken together, our data suggest a potential role of TPO as a physiological regulator of CF. By acting on specific receptors present on endothelial cells, TPO may induce PI3K/Akt-dependent eNOS phosphorylation and NO release. PMID- 21237211 TI - Upregulation of leptin-receptor in placental cells by hypoxia. AB - OBJECTIVE: Leptin and its receptor (Ob-R) are co-expressed in human placenta suggesting auto- and paracrine mechanisms of the hormone. So far it is unclear, how changes in the placental environment affect Ob-R expression. Hence, the main purpose of the study was to investigate leptin receptor expression and regulation under hypoxic conditions. The influences of hypoxia and leptin on signal transduction and cell proliferation in chorioncarcinoma cell lines as well as primary villous trophoblasts were determined. RESULTS: We found a time-dependent induction of leptin receptor mRNA and protein in placental cells under hypoxic conditions. In contrast, soluble leptin receptor expression did not change under oxygen deprivation. Leptin treatment neither activated the p42/p44 nor the STAT3 pathway in placental cells, being independent of hypoxic or normoxic conditions. Furthermore, leptin added to the culture medium in high concentrations was unable to interfere with the rate of proliferation. CONCLUSION: Our data demonstrate that hypoxia leads to an increase of Ob-R expression in placental cells. Interestingly, leptin-dependent signal transduction and proliferation remained unaffected. A possible role of the soluble leptin receptor in modulating free leptin levels will be discussed. PMID- 21237213 TI - B-type natriuretic peptide levels predict extent and severity of coronary disease in non-ST elevation coronary syndromes and normal left ventricular systolic function. AB - BACKGROUND: B-type natriuretic peptide (BNP) has been used recently as a biological marker in patients with coronary artery disease (CAD) with ST elevation, as well as without ST-elevation. BNP is able to predict systolic dysfunction, adding new prognostic information to existing traditional markers. However is not known if there is a relation between the quantity of BNP levels and the severity of coronary artery disease. METHODS: This study compared B-type natriuretic peptide (BNP) levels in patients with stable angina (SA) and acute coronary syndromes (ACS) without ST-elevation in relation to angiographic lesions using TIMI and Gensini Scores. We studied 282 patients with CAD without ST elevation and preserved systolic function. BNP samples were measured in all recruited patients within 24 hours of hospitalization. RESULTS: BNP values were progressively increased in relation to the severity of diagnosis: SA (52.6+/-49.4 pg/mL ) UA (243.3+/-212 pg/mL) NSTE-ACS (421.7+/-334 pg/mL) (p<0.0001 and p<0.007 respectively). No statistically significant difference was observed between patients with SA and controls (21.2+/-6.8 pg/mL). The analysis of BNP levels in relation to the number of involved vessels demonstrated significantly increased levels in patients with multivessel disease compared to patients with 1 or 2 vessel disease (1-86.2+/-46.3 pg/mL; 2-127+/-297 pg/mL; 3-295+/-318 pg/mL; 4 297+/-347 pg/mL p<0.001 and p<0.003). Evaluation of BNP using Gensini Score showed a strong relation between BNP and coronary disease extension (r=0.38 p<0.0001).This trend was maintained in all CAD groups (SA=r 0.54; UA r=0.36 NSTE ACS r=0.28). CONCLUSIONS: Circulating BNP levels appear elevated in ACS with diffuse coronary involvement, even in the absence of systolic dysfunction. BNP is also associated with multi-vessel disease and the extension of coronary disease. PMID- 21237212 TI - Acipimox during exercise points to an inhibitory feedback of GH on ghrelin secretion in bulimic and healthy women. AB - OBJECTIVE: Ghrelin is predominantly produced by the stomach and the growth hormone (GH)-ghrelin feedback loop between the stomach and the pituitary gland has recently been suggested. The disruption of the gut-brain axis might be involved in bulimia nervosa (BN). METHODS: We investigated responses of plasma GH, ghrelin, and neuropeptide Y (NPY) concentrations to exercise or to exercise after the administration of the antilipolytic drug Acipimox (Aci) in seven BN patients and seven healthy women (C). Aci was administered 1h before exercise (45 min, 2 W/kg of lean body mass/LBM/). Ghrelin, GH, NPY, free fatty acids (FFA) and glycerol plasma levels were measured during the test using commercial kits. RESULTS: The exercise induced an increase in plasma GH, NPY and FFA in both groups and a decrease in plasma ghrelin levels only in BN patients. Exercise after Aci administration resulted in an increase in plasma GH, and a decrease in plasma ghrelin in both groups; NPY increased more in BN patients. Exercise induced FFA increase was depressed after Aci. CONCLUSIONS: We conclude that the Aci-induced suppression in plasma ghrelin levels during exercise in both groups suggests a negative feedback of GH on ghrelin secretion. Observed changes in plasma FFA levels were not related to changes in GH and ghrelin levels. PMID- 21237214 TI - Plasma levels of n-decanoyl ghrelin, another acyl- and active-form of ghrelin, in human subjects and the effect of glucose- or meal-ingestion on its dynamics. AB - Besides n-octanoyl ghrelin (O-ghrelin), there is another acyl-form of ghrelin; n decanoyl ghrelin (D-ghrelin), which has a decanoic acid modification. In this study, we examined the kinetics of D-ghrelin immunoreactivity in human plasma in comparison to O-ghrelin or total ghrelin by using a D-ghrelin-specific radioimmunoassay. The dynamics of plasma D-ghrelin was assessed following glucose or meal-ingestion in healthy, non-obese subjects (5 males and 5 females). Correlations were also analyzed between the levels of plasma D-ghrelin and anthropometric or metabolic indicators in healthy human subjects (n=111, BMI 17.4 34.3). The plasma levels of D-ghrelin, like O- or T-ghrelin, significantly declined (p<0.05 for male and p<0.01 for female) 60 min after the ingestion of glucose in non-obese subjects. However, in the same subjects, no significant decline was noted in the levels of D-ghrelin, unlike O- or T-ghrelin, upon the meal ingestion. A significant increase was observed in the proportion of plasma D ghrelin levels to that of T-ghrelin (p<0.05) in the healthy human subjects as BMI increased, unlike the proportion of O-ghrelin to T-ghrelin, which did not change. Since D-ghrelin possesses almost the same potential as that of O-ghrelin with regard to the feeding-stimulation, these differences between the dynamics of D- and O-ghrelin in human plasma might influence appetite-control, especially in those with increased BMI. PMID- 21237215 TI - Natriuretic peptide system: a link between fat mass and cardiac hypertrophy and hypertension in fat-fed female rats. AB - The present study was designed to develop an animal model of hypertension and cardiac hypertrophy associated with obesity in female rats. Furthermore, we studied the involvement of the natriuretic peptide system in the mechanisms of these conditions. Obesity was induced in Wistar rats by a high fat diet and ovariectomy. The rats were divided into four groups: ovariectomized or sham operated with high-fat diet and ovariectomized or sham-operated with control diet. After 24 weeks of diet, rats were killed, and their tissues were removed. Cardiac atrial natriuretic peptide (ANP), clearance receptor (NPr-C) gene expression was determined by PCR. ANP concentrations were measured in plasma. Ovariectomized fat-fed rats (OF) showed increased body weight, visceral fat depot and blood pressure and decreased sodium excretion compared to other groups. Also, these rats showed higher heart-to-body weight and cell diameters of ventricular cardiomyocytes and lower cardiac ANP mRNA and plasma ANP than the control group. The adipocyte and renal NPr-C mRNA of OF rats were higher than the control group. These data showed that combined ovariectomy and high fat diet elicited obesity, hypertension and cardiac hypertrophy. These results suggest that the impairment of the natriuretic peptide system may be one of the mechanisms involved not only in development of hypertension but also in cardiac hypertrophy associated with obesity in ovariectomized rats. PMID- 21237216 TI - The role of DDX3 in regulating Snail. AB - DDX3, a DEAD box protein family member, appears to promote the progression of some cancers, which may partly result from its impedance of death receptor mediated apoptosis. We found that another mechanism by which DDX3 may aid cancer progression is by promoting increased levels of the transcription factor Snail. Snail represses expression of cellular adhesion proteins, leading to increased cell migration and metastasis of many types of cancer. Knockdown of DDX3 levels by shRNA reduced basal levels of Snail in HeLa and MCF-7 cells, and this was associated with reduced cell proliferation and migration. Snail protein and mRNA levels were increased by treatment with the HDAC inhibitors sodium butyrate or trichostatin A, and these increases were attenuated in cells with DDX3 knocked down. Treatment of cells with camptothecin was discovered to increase Snail protein levels, and this increase was diminished in cells with DDX3 knocked down. Analysis of 31 patient glioblastoma multiforme (GBM) samples revealed a significant correlation between the levels of DDX3 and Snail. Thus, DDX3 is required for basal Snail expression and increases in Snail induced by HDAC inhibitors or camptothecin, indicating that this action of DDX3 may contribute to its promotion of the progression of some cancers. PMID- 21237217 TI - Efficient colonization of plant roots by the plant growth promoting bacterium Bacillus amyloliquefaciens FZB42, engineered to express green fluorescent protein. AB - A single copy of the gfp gene linked with the P(spac) promoter and flanked by the terminal FZB42 amyE sequences was stably integrated into the chromosome of plant growth promoting bacterium Bacillus amyloliquefaciens FZB42 via homologous recombination. A spontaneous mutant, FB01mut, emitting bright fluorescence was detected among the transformants and found suitable for colonization experiments performed with Zea mays, Arabidopsis thaliana and Lemna minor. Real-time RT-PCR revealed that FB01mut expressed 2.5 times more of the gfp transcript than the original GFP-labeled strain. Confocal laser scanning microscopy of plant roots infected with gfp+ tagged FZB42 revealed that the bacterium behaves different in colonizing surfaces of plant roots of different species. In contrast to maize, FZB42 colonized preferentially root tips when colonizing Arabidopsis. FZB42 colonized heavily Lemna fronds and roots by forming biofilms consisting of extracellular matrix and cells with altered morphology. Surfactin, but no other lipopeptide or polyketide synthesized by FZB42 under laboratory conditions, was detected in extracts of Lemna plantlets colonized by FZB42. Due to its stable and long-lasting emission of bright fluorescence without antibiotic pressure FB01mut is an excellent tool for studying plant colonization under competitive, environmental conditions. PMID- 21237218 TI - Generalized semi-refolding methods for purification of the functional death domain superfamily. AB - The death domain (DD) superfamily comprising the death domain (DD) subfamily, the death effector domain (DED) subfamily, the caspase recruitment domain (CARD) subfamily and the pyrin domains (PYD) subfamily is one of the largest classes of protein interaction modules and plays a pivotal role in the apoptosis, inflammation, and immune cell signaling pathways. Despite the biological importance of the death domain superfamily, structural and in vitro biochemical studies have been limited because these domains are prone to aggregate under physiological conditions. Here, we describe a generalized method, termed semi refolding, that is particularly applicable for purification of the functional death domain superfamily. The recombinant proteins Caspase-1 CARD, AIM2 PYD, NALP3 PYD, and RIP1 DD from inclusion bodies were successfully purified using this method. PMID- 21237219 TI - Hierarchical gene synthesis using DNA microchip oligonucleotides. AB - High-cost of oligonucleotides is one of the major problems to low-cost gene synthesis. Although DNA oligonucleotides from cleavable DNA microchips has been adopted for the low-cost gene synthesis, construction of DNA molecules larger than 1 kb has been largely hampered due to the difficulties of DNA assembly associated with the negligible quantity of chip oligonucleotides. Here we report a hierarchical method for the synthesis of large genes using oligonucleotides from programmable DNA microchips. Using this hierarchical method, we successfully synthesized 1056 bp Dpo4 and 2325 bp Pfu DNA polymerase genes as models. This hierarchical strategy can be further expanded for the syntheses of multiple large genes in a scalable manner. PMID- 21237220 TI - Identification of RNF2-responding loci in long-range chromatin interactions using the novel 4C-ChIP-Cloning technology. AB - RNF2 is a core component of Polycomb repressive complex 1 (PRC1), which binds to various chromatic regions to regulate their transcriptional activity. It was recently reported that EZH2, a Polycomb group complex member, helps mediate long range chromosomal interactions in mammalian cells. The present study investigates whether RNF2-responding loci interact in long-range chromatin. The new 4C-ChIP Cloning technology was developed based on circular chromosome conformation capture (4C) and ChIP. Use of the 4C-ChIP-Cloning technology successfully identified four loci in long-range cis- or trans-interactions that were mediated by the RNF2 protein. RNAi experiments showed that RNF2 regulated the transcription levels of genes adjacent to the loci. These results suggest that RNF2 protein, as part of PRC1, mediates long-range interactions between RNF2 interation loci and regulates adjacent genes. This 4C-ChIP-Cloning technology may contribute to the study of protein-mediated long-range chromatin interactions with specific regulatory elements. PMID- 21237221 TI - Homologous overexpression of xylanase in Fusarium oxysporum increases ethanol productivity during consolidated bioprocessing (CBP) of lignocellulosics. AB - In an effort to increase ethanol productivity during the consolidated bioprocessing (CBP) of lignocellulosics by Fusarium oxysporum, we attempted the constitutive homologous overexpression of one of the key process enzymes, namely an endo-xylanase. The endo-beta-1,4-xylanase 2 gene was incorporated into the F. oxysporum genome under the regulation of the gpdA promoter of Aspergillus nidulans. The transformation was effected through Agrobacterium tumefaciens and resulted in 12 transformants, two of which were selected for further study due to their high extracellular xylanase activities under normally repressing conditions (glucose as sole carbon source). During natural induction conditions (growth on xylan) though, the extracellular enzyme levels of the transformants were only marginally higher (5-10%) compared to the wild type despite the significantly stronger xylanase 2 mRNA signals. SDS-PAGE verified enzyme assay results that there was no intracellular xylanase 2 accumulation in the transformants, suggesting the potential regulation in a post transcriptional or translational level. The fermentative performance of the transformants was evaluated and compared to that of the wild type in simple CBP systems using either corn cob or wheat bran as sole carbon sources. Both transformants produced approximately 60% more ethanol compared to the wild type on corn cob, while for wheat bran this picture was repeated for only one of them. This result is attributed to the high extracellular xylanase activities in the transformants' fermentation broths that were maintained 2-2.5-fold higher compared to the wild type. PMID- 21237222 TI - Characterisation of interaction between NS3 and NS5B protein of classical swine fever virus by deletion of terminal sequences of NS5B. AB - The NS3-NS5B interaction of classical swine fever virus (CSFV) is important for viral replication. For characterisation of the interaction between the NS3 and NS5B, a series of NS5B mutants with deletion of N-, C-terminal amino acids and quadruple alanine substitution mutations were produced. GST pull-down assays and immunoprecipitation analyses showed that NS5B and some NS5B mutants have NS3 binding activity. Further experimental data indicated that CSFV NS5B might contain two NS3 binding sites, one covering amino acids 63-99 located at the N terminal end, another covering amino acids 611-642 at the C-terminal end. Assays for RNA-dependent RNA polymerase (RdRp) activity revealed that CSFV NS3 is able to enhance the RdRp activity of NS5B and some NS5B mutants in vitro. The enhancement might be obtained by NS3 binding to the two terminal sequences of NS5B, which could be attractive targets for drug development against CSFV. PMID- 21237223 TI - Pathogenicity and complete genome sequence of a fowl adenovirus serotype 8 isolate. AB - In this study we determined and analyzed the complete nucleotide sequence of the genome of a fowl adenovirus serotype 8 (FAdV-8) isolate and examined its pathogenicity in chickens. The full genome of FAdV-8 was 44,055 nucleotides in length with a similar organization to that of FAdV-1 and FAdV-9 genomes. No regions homologous to early regions E1, E3 and E4 of mastadenoviruses were recognized. Along with FAdV-9, FAdV-8 has only one fiber gene and with regard to sequence composition and genome organization, FAdV-8 is closer to FAdV-9 than to FAdV-1. Moreover, our findings suggest that FAdV-1 of species Fowl adenovirus A as the current type species despite its historical priority is not representative of the genus Aviadenovirus, and that FAdV-8 or FAdV-9 in species Fowl adenovirus E and Fowl adenovirus D, respectively, would be more suitable for that designation. Additionally, pathogenicity of FAdV-8 was studied in specific pathogen free chickens following oral and intramuscular inoculations. Despite lack of clinical signs and pathological changes virus was found in tissues and cloacal swabs of all birds with the highest viral copy numbers present in the cecal tonsils. The highest virus titers in the feces for orally and intramuscularly inoculated chickens were recorded at days 10 and 3 post infection, respectively. PMID- 21237224 TI - Bovine leukemia virus integration site selection in cattle that develop leukemia. AB - It is essential for efficient replication of retroviruses that the viral genome is integrated into the host genome after reverse transcription. Some retroviruses are preferentially integrated into certain genomic regions that may differ depending on the disease. In this study, we analyzed the integration site of bovine leukemia virus (BLV) in leukemic cells and 55 integration sites were determined. Although the integration sites were not located in a particular chromosome, the BLV provirus was integrated into transcription units at a frequency of 43.6% (24/55) and the transcriptional direction of the provirus was in accordance with that of the integrated host genes in 62.5% (15/24). The integration sites were located in introns of the host gene, excluding only one site, which was located in downstream from a stop codon. BLV provirus was never found in a protein coding sequence (CDS) in this study. Moreover, the BLV provirus did not favor integration near transcription start sites and CpG islands, or repetitive sequences such as transposons. Therefore, the possibility that the integration of the BLV provirus disrupts the host gene is very low. Although a hot spot was not found in the BLV provirus integration sites, the provirus favored the integration into regions disadvantageous for viral gene expression since no integration site was preferentially located into/near CDS, transcription start site or CpG island. It is suggested that the integration site of the BLV provirus in leukemic cells is related to the suppression of viral gene expression. PMID- 21237225 TI - The X protein of HBV induces HIV-1 long terminal repeat transcription by enhancing the binding of C/EBPbeta and CREB1/2 regulatory proteins to the long terminal repeat of HIV-1. AB - Due to share the route of transmission, the prevalence of co-infection of hepatitis B virus (HBV) and human immunodeficiency virus-1 (HIV-1) is high with chronic HBV infection affecting nearly 10% of HIV-infected patient world wide, which has become a significant global health problem. However, the cellular and molecular mechanisms associated with HBV/HIV-1 co-infection are largely unclear. In this study, we provided evidence that HBV induces HIV-1 transcription through its X protein (HBx). We further explored the mechanism by which HBx activates HIV 1 transcription. Our results showed that C/EBP and CRE cis-regulatory elements in the long terminal repeats (LTR) of HIV-1 are required for the activation of HIV-1 transcription mediated by HBx. We also demonstrated that HBx regulates HIV-1 transcription through stimulating the binding of transcriptional regulatory proteins C/EBPbeta, CREB1, and CREB2 to HIV-1 LTR and that co-activator CBP is required for such regulation. These findings provide new insights into our understanding the effect of HBx on the activation of HIV-1 transcription and also provide evidence of the potential role of HBV in HIV-1 replication during the course of HBV/HIV-1 co-infection. PMID- 21237226 TI - Nucleoplasmic calcium regulates cell proliferation through legumain. AB - BACKGROUND & AIMS: Nucleoplasmic Ca(2+) regulates cell growth in the liver, but the proteins through which this occurs are unknown. METHODS: We used Rapid Subtraction Hybridization (RaSH) to subtract genes in SKHep1 liver cells expressing the Ca(2+) buffer protein parvalbumin (PV) targeted to the nucleus, from genes in cells expressing a mutated form of nuclear-targeted PV which has one of two Ca(2+)-binding sites inactivated. The subtraction permitted the selection of genes whose expression was affected by a small alteration in nuclear Ca(2+) concentration. RESULTS: The asparaginyl endopeptidase legumain (LGMN) was identified in this screening. When Ca(2+) was buffered in the nucleus of SKHep1 cells, LGMN mRNA was decreased by 97%, in part by a transcriptional mechanism, and decreased expression at the protein level was observed by immunoblot and immunofluorescence. Treatment with hepatocyte growth factor increased LGMN expression. Knockdown of LGMN by siRNA decreased proliferation of SKHep1 cells by ~50% as measured both by BrdU uptake and mitotic index, although an inhibitor of LGMN activity did not affect BrdU incorporation. A significant reduction in the fraction of cells in G2/M phase was seen as well. This was associated with increases in the expression of cyclins A and E. Furthermore, LGMN expression was increased in hepatocellular carcinoma cells relative to normal hepatocytes in the same specimens. CONCLUSIONS: These findings suggest a new role for LGMN and provide evidence that nuclear Ca(2+) signals regulate cell proliferation in part through the modulation of LGMN expression. Increased expression of LGMN may be involved in liver carcinogenesis. PMID- 21237227 TI - Reduced dose and duration of peginterferon alfa-2b and weight-based ribavirin in patients with genotype 2 and 3 chronic hepatitis C. AB - BACKGROUND & AIMS: There is increasing interest in identifying patients with chronic hepatitis C genotype 2 or 3 infection in whom it is possible to lower the burden of therapy while retaining high levels of efficacy. METHODS: Treatment naive patients with chronic hepatitis C genotype 2/3 infection were randomized to receive peginterferon alfa-2b (1.5MUg/kg/wk) for 24weeks (group A); peginterferon alfa-2b (1.0MUg/kg/wk) for 24weeks (group B); or peginterferon alfa-2b (1.5MUg/kg/wk) for 16weeks (group C), each in combination with weight-based ribavirin (800-1200mg/d). The study population comprised two cohorts: the Hep-Net cohort enrolled in Germany and an International cohort enrolled at study sites throughout Europe and Asia. The primary end point was sustained virological response (SVR). RESULTS: The study included 682 patients; 80.2% had genotype 3 infection. In the intent-to-treat population, SVR rates were 66.5%, 64.3%, and 56.6% in groups A, B, and C, and were similar in Asian and white patients. Treatment differences (A vs. B and A vs. C) failed to reach the predefined margin for noninferiority of -10%; and thus groups B and C failed to show noninferiority relative to group A. Among patients with undetectable HCV RNA at week 4, SVR rates were 75.3%, 75.9%, and 72.4%, respectively. Relapse rates were 17.8%, 16.3%, and 29.3%, respectively. Treatment-emergent serious adverse events were highest in group A and lowest in group C, and adverse events leading to discontinuation were similar across treatment arms. CONCLUSIONS: For patients with chronic hepatitis C genotype 2/3 infection, 24weeks of peginterferon alfa-2b (1.5MUg/kg/wk) plus weight-based ribavirin remains a standard-of-care therapy; however, treatment for 16weeks may be considered for patients with undetectable HCV RNA at week 4 of the treatment. PMID- 21237228 TI - Prodrug-based intracellular delivery of anticancer agents. AB - There are numerous anticancer agents based on a prodrug approach. However, no attempt has been made to review the ample available literature with a specific focus on the altered cell uptake pathways enabled by the conjugation and on the intracellular drug-release mechanisms. This article focuses on the cellular interactions of a broad selection of parenterally administered anticancer prodrugs based on synthetic polymers, proteins or lipids. The report also aims to highlight the prodrug design issues, which are key points to obtain an efficient intracellular drug delivery. The chemical basis of these molecular concepts is put into perspective with the uptake and intracellular activation mechanisms, the in vitro and in vivo proofs of concepts and the clinical results. Several active targeting strategies and stimuli-responsive architectures are discussed throughout the article. PMID- 21237229 TI - In vivo 6-OHDA-induced neurodegeneration and nigral autophagic markers expression. AB - Numerous reports suggest the involvement of oxidative stress in the pathogenesis of Parkinson's disease (PD), however, the crucial mechanism of the degenerative process remain unclear. Emerging evidence supports a critical role for autophagy in the pathogenic process of dopaminergic neurodegeneration. However, the definitive in vivo proof of it is currently lacking. Due to the relevance oxidative stress and chaperone-mediated autophagy (CMA) in PD pathogenesis, we investigated the expression of nigral CMA markers in 6-OHDA-lesioned hemiparkinsonian rats. Male Sprague-Dawley rats received a 6-OHDA injection (8 MUg in 4 MUl of saline with 0.02% ascorbate over 8 min) into the left medial forebrain bundle by means of a Harvard infusion pump. Following a three-week recovery period, rats exhibiting a vigorous rotational response (>100 total turns) to apomorphine (0.05 mg/kg, sc) were selected for further study. Western blotting analyses showed a decrease by 88% in TH expression levels in the striatum ipsilateral to 6-OHDA lesion (p<0.01) associated to an increase in nigral lysosomal membrane protein receptor type 2A (LAMP2A, p<0.01) and heat shock protein 90 (HSP90, p<0.01). The present results provide in vivo evidence of CMA activation in the animal model of parkinsonism in rats with a unilateral lesion of the nigrostriatal pathway induced by 6-OHDA. This widely used model offers great potential for future studies regarding new potential treatments for neurodegenerative conditions and in the investigation of signaling pathways regulating autophagy. PMID- 21237232 TI - The richness of social stimuli shapes developmental trajectories: Are laboratory mouse pups impoverished? AB - The early environment is crucial for brain and behavior development. In particular, social experiences involving the mother and the peers are critical in shaping the adult individual. Though animal models of psychiatric disorders have widely investigated the relevance of the mother-offspring interaction, the peer interaction has so far been rarely studied. The communal nest (CN) is an innovative experimental strategy that favors a more comprehensive investigation of the long-term effects of both components. CN is a rearing condition employed by up to 90% of mouse females in naturalistic settings and consists of a single nest where two or more mothers keep their pups together and share care-giving. In a CN, the developing pup is exposed to high levels of both maternal care and interaction with peers. At adulthood, these mice display relevant changes in bran function and behavior, including high levels of neural plasticity markers, such as BDNF, and elaborate adult social competences. Overall, on the one hand, CN is an experimental approach complementary to the ones currently used that allows to investigate how the early environment determines developmental trajectories. On the other, it may represent a strategy to improve the study of animal models of psychiatric disorders characterized by social dysfunction, such as major depression, autism and attention deficit hyperactivity disorder. Indeed, the more elaborate social competences shown by these mice at adulthood may allow to better characterize deficits in the social domain induced by genetic and/or environmental manipulations. PMID- 21237231 TI - Pharmacological analysis of zebrafish (Danio rerio) scototaxis. AB - The scototaxis test has been introduced recently to assess anxiety-like phenotypes in fish, including zebrafish. Parametric analyses suggest that scototaxis represents an approach-avoidance conflict, which hints at anxiety. In this model, white avoidance represents anxiety-like behavior, while the number of shuttling events represents activity. Acute or chronic fluoxetine, buspirone, benzodiazepines, ethanol, caffeine and dizocilpine were assessed using the light dark box (scototaxis) test in zebrafish. Acute fluoxetine treatment did not alter white avoidance, but altered locomotion in the higher dose; chronic treatment (2 weeks), on the other hand, produced an anxiolytic effect with no locomotor outcomes. The benzodiazepines produced a hormetic (inverted U-shaped) dose response profile, with intermediate doses producing anxiolysis and no effect at higher doses; clonazepam, a high-potency benzodiazepine agonist, produced a locomotor impairment at the highest dose. Buspirone produced an anxiolytic profile, without locomotor impairments. Moclobemide did not produce behavioral effects. Ethanol also produced a hormetic profile in white avoidance, with locomotor activation in 0.5% concentration. Caffeine produced an anxiogenic profile, without locomotor effects. These results suggest that the light-dark box is sensitive to anxiolytic and anxiogenic drugs in zebrafish. PMID- 21237230 TI - Sex-specific variation of MRI-based cortical morphometry in adult healthy volunteers: the effect on cognitive functioning. AB - Previous investigations have revealed sex-specific differences in brain morphometry. The effect of sex on cortical thickness may be influencing cognitive differences between sexes. With this exploratory study, we aimed to investigate the effect of sex in MRI-based cerebral cortex morphometry in healthy young volunteers and how the variability in cortical measures might affect cognitive functioning in men and women. 76 young healthy volunteers (45 men and 31 women) underwent a 1.5 T MR scan and 53 of them completed a comprehensive cognitive battery. Overall no gross significant differences between sexes were found in cortical thickness, surface area and curvature indexes. However, there was a significant group by hemisphere interaction in the total cortical thickness (F(1,72)=5.02; p=0.03). A greater leftward asymmetry was observed in cortical thickness in males. Only females show significant associations between cortical thickness and cognitive functioning (IQ and executive functioning). In conclusion, our findings do not support the notion of sexual dimorphism in cortical mantle morphology. The results also suggest that variability in cortical thickness may affect cognitive functioning in females but not in males. PMID- 21237233 TI - Licofelone attenuates quinolinic acid induced Huntington like symptoms: possible behavioral, biochemical and cellular alterations. AB - Cyclo-oxygenase and lipoxygenase enzymes are involved in arachidonic acid metabolism. Emerging evidence indicates that cyclo-oxygenase and lipoxygenase inhibitors prevent neurodegenerative processes and related complications. Therefore, the present study has been designed to explore the neuroprotective potential of licofelone (dual COX-2/5-LOX inhibitor) against quinolinic acid induced Huntington like symptom in rats. Intrastriatal administration of quinolinic acid significantly caused reduction in body weight and motor function (locomotor activity, rotarod performance and beam walk test), oxidative defense (as evidenced by increased lipid peroxidation, nitrite concentration and decreased endogenous antioxidant enzymes), alteration in mitochondrial enzyme complex (I, II and IV) activities, raised TNF-alpha level and striatal lesion volume as compared to sham treated animals. Licofelone (2.5, 5 and 10 mg/kg) treatment significantly improved body weight, locomotor activity, rotarod performance, balance beam walk performance, oxidative defense, mitochondrial enzyme complex activities and attenuated TNF-alpha level and striatal lesion as compared to control (quinolinic acid). The present study highlights that licofelone attenuates behavioral, biochemical and cellular alterations against quinolinic acid induced neurotoxicity and this could be an important therapeutic avenue to ameliorate the Huntington like symptoms. PMID- 21237234 TI - Alterations in the expression of neuronal chloride transporters may contribute to schizophrenia. AB - During brain development, neuronal stem cells and immature neurons express high and low levels of, respectively, the Cl(-) transporters NKCC1 and KCC2, which results in high intracellular Cl(-) concentrations. Under these circumstances chloride-flux through the GABA-A channel is from intracellular to extracellular and consequently GABA depolarizes rather than hyperpolarizes immature cells. This excitatory response is essential for neurodevelopment since it affects proliferation of the neuronal progenitor pool, neuronal differentiation, dendrite and synapse formation and integration into the existing neuronal network. In animal experiments, seizures were found to increase NKCC1 expression, lower the KCC2 expression and accelerate neuronal differentiation. An increased expression of NKCC1 and mutations of the gene have been associated with schizophrenia. Stimulation of nicotinic alpha-7 receptors on mouse hippocampal neurons increases the expression of KCC2. A microdeletion in the genomic area 15q13-14 containing the nicotine alpha7 receptor has been described in patients with mental retardation, schizophrenia and juvenile epilepsy. It is conceivable that haplotype-insufficiency of the nicotinic alpha7 receptor might lead to a reduction in KCC2 protein levels. The data indicate that all three schizophrenia risk factors, i.e. seizures, mutations in NKCC1 and nicotinic alpha-7 receptors haplotype-insufficiency contribute to higher intracellular Cl(-) concentrations, increased neuronal excitability and accelerated neuronal differentiation. Since also several other genetic risk factors for schizophrenia seem to accelerate neuronal maturation, it is hypothesized that the structural, cognitive and behavioral deficits of schizophrenia are caused be a too fast brain maturation process. PMID- 21237235 TI - The neuroprotective effects of Lonicera japonica THUNB. against hydrogen peroxide induced apoptosis via phosphorylation of MAPKs and PI3K/Akt in SH-SY5Y cells. AB - We investigated the neuroprotective effects of Lonicera japonica THUNB. (Caprifoliaceae) (LJ) extract against hydrogen peroxide (H(2)O(2)), a toxin created by oxidative stress and implicated in neurodegenerative diseases, in human SH-SY5Y neuroblastoma cells. We examined the effects of LJ against H(2)O(2) induced cytotoxicity, apoptosis, the production of reactive oxygen species (ROS), the proteolysis of cleaved poly-ADP-ribose polymerase (PARP), and the expression of Bcl-2, Bcl-xL, and cleaved caspase-3. Moreover, we attempted to determine whether LJ suppressed the phosphorylation of Akt, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 (ERK 1/2). We found that LJ improved cell viability, inhibited cytotoxicity and apoptosis, and attenuated elevations in ROS and nuclear condensation. In addition, LJ showed radical scavenging ability in 2-diphenyl-1 picrylhydrazyl (DPPH) and 2,2-azinobis-(3-ethyl-benzthiazoline-6-sulfonic acid) (ABTS) assays. Western blot data revealed that LJ inhibited H(2)O(2)-induced up- and down-regulation of cleaved PARP, cleaved caspase-3, Bcl-2, and Bcl-xL. Furthermore, LJ significantly attenuated the H(2)O(2)-induced phosphorylation of Akt, JNK, p38 MAPK, and ERK1/2. These results demonstrate that LJ possesses potent neuroprotective activity. Its potential to treat neurodegenerative diseases warrants further research. PMID- 21237236 TI - Differential expression of glutamine synthetase and cytochrome P450 isoforms in human hepatoblastoma. AB - Carcinogenesis is often linked to aberrant activation of Wnt/beta-catenin signalling, in many cases caused by activating CTNNB1 mutations (encoding beta catenin). Recently, beta-catenin was established as a decisive regulator of hepatic glutamine synthetase (GS) and cytochrome P450 (CYP) expression in mouse hepatocarcinogenesis. This study was aimed to analyse the connection of beta catenin signalling and GS/CYP expression in human paediatric tumours. Samples from 23 paediatric tumours were analysed for activating mutations in CTNNB1. Protein expression of the model beta-catenin target GS and of various CYP isoforms was analysed and correlated with CTNNB1 mutational status and histological findings. Activating CTNNB1 mutations were frequent in hepatoblastoma (80%) and nephroblastoma (31%). In CTNNB1-mutated hepatoblastoma, expression of GS was only detected in tumour areas with epithelial, not with mesenchymal differentiation. Particularly high expression of glutamine synthetase was found in hepatoblastoma cells directly neighbouring a mesenchymal-type tumour area or stroma cells, associated with above-average cell proliferation. GS expression was not observed in CTNNB1-mutated nephroblastoma. Hepatoblastoma with activated beta-catenin expressed different CYPs relevant for the metabolism of cytostatic drugs, but with high interindividual variance and heterogeneity within a single tumour. GS and different CYPs are co-expressed in hepatoblastoma with activated beta-catenin. Moreover, other factors like histological subtype of tumour cells and cell-cell-interactions at the borders between different areas of the tumours affect expression of these beta-catenin target genes. Analysis of CYP expression in resected tumour tissue might be useful for the selection of appropriate cytostatics for post-operative chemotherapy. PMID- 21237237 TI - Comparative pharmacokinetics of perfluorononanoic acid in rat and mouse. AB - Perfluorononanoic acid (PFNA) is a fluorinated organic chemical found at low levels in the environment, but is detectable in humans and wildlife. The present study compared the pharmacokinetic properties of PFNA in two laboratory rodent species. Male and female Sprague-Dawley rats were given a single dose of PFNA by oral gavage at 1, 3, or 10mg/kg, and blood was collected from the tail vein at 1, 2, 3, 4, 7, 16, 21, 28, 35, 42 and 50 days after treatment. In addition, livers and kidneys were collected for PFNA analysis at the terminal time point. CD-1 mice were given a single oral dose of PFNA of 1 or 10mg/kg, and 4 males and 4 females were killed at similar time intervals; trunk blood, liver and kidney were collected. Serum and tissue concentrations of PFNA were determined by LC-MS/MS. Serum elimination of PFNA is by and large linear with exposure doses in the rat; however, like PFOA, a major sex difference in the rate of elimination is observed, with an estimated half-life of 30.6 days for males and 1.4 days for females. PFNA is stored preferentially in the liver but not in the kidneys. In the mouse, the rates of PFNA serum elimination are non-linear with exposure dose and are slightly faster in females than males, with terminal estimated serum half life of 25.8-68.4 days and 34.3-68.9 days, respectively. PFNA is also stored preferentially in the mouse liver but not in the kidneys. Hepatic uptake appears to be more efficient and storage capacity greater in male mice than in females. These data suggest that (1) PFNA is more persistent in the mouse than in the rat; (2) there is a major sex difference in the serum elimination of PFNA in the rat, but much less so in the mouse; and (3) there is a significantly higher hepatic accumulation of PFNA in male mice than in females. PMID- 21237238 TI - Esterase metabolism of cholinesterase inhibitors using rat liver in vitro. AB - A variety of chemicals, such as organophosphate (OP) and carbamate pesticides, nerve agents, and industrial chemicals, inhibit acetylcholinesterase (AChE) leading to overstimulation of the cholinergic nervous system. The resultant neurotoxicity is similar across mammalian species; however, the relative potencies of the chemicals across and within species depend in part on chemical specific metabolic and detoxification processes. Carboxylesterases and A esterases (paraoxonases, PON) are two enzymatic detoxification pathways that have been widely studied. We used an in vitro system to measure esterase-dependent detoxification of 15 AChE inhibitors. The target enzyme AChE served as a bioassay of inhibitor concentration following incubation with detoxifying tissue. Concentration-inhibition curves were determined for the inhibitor in the presence of buffer (no liver), rat liver plus calcium (to stimulate PONs and thereby measure both PON and carboxylesterase), and rat liver plus EGTA (to inhibit calcium-dependent PONs, measuring carboxylesterase activity). Point estimates (concentrations calculated to produce 20, 50, and 80% inhibition) were compared across conditions and served as a measure of esterase-mediated detoxification. Results with well-known inhibitors (chlorpyrifos oxon, paraoxon, methyl paraoxon, malaoxon) were in agreement with the literature, serving to support the use of this assay. Only a few other inhibitors showed slight or a trend towards detoxification via carboxylesterases or PONs (mevinphos, aldicarb, oxamyl). There was no apparent PON- or carboxylesterase-mediated detoxification of the remaining inhibitors (carbofuran, chlorfenvinphos, dicrotophos, fenamiphos, methamidophos, methomyl, monocrotophos, phosphamidon), suggesting that the influence of esterases on these chemicals is minimal. Thus, generalizations regarding these metabolic pathways may not be appropriate. As with other aspects of AChE inhibitors, their metabolic patterns appear to be chemical-specific. PMID- 21237239 TI - Zebrafish (Danio rerio) embryos as a model for testing proteratogens. AB - Zebrafish embryos have been shown to be a useful model for the detection of direct acting teratogens. This communication presents a protocol for a 3-day in vitro zebrafish embryo teratogenicity assay and describes results obtained for 10 proteratogens: 2-acetylaminofluorene, benzo[a]pyrene, aflatoxin B(1), carbamazepine, phenytoin, trimethadione, cyclophosphamide, ifosfamide, tegafur and thio-TEPA. The selection of the test substances accounts for differences in structure, origin, metabolism and water solubility. Apart from 2 acetylaminofluorene, which mainly produces lethal effects, all proteratogens tested were teratogenic in zebrafish embryos exposed for 3 days. The test substances and/or the substance class produced characteristic patterns of fingerprint endpoints. Several substances produced effects that could be identified already at 1 dpf (days post fertilization), whereas the effects of others could only be identified unambiguously after hatching at >= 3 dpf. The LC50 and EC50 values were used to calculate the teratogenicity index (TI) for the different substances, and the EC20 values were related to human plasma concentrations. Results lead to the conclusion that zebrafish embryos are able to activate proteratogenic substances without addition of an exogenous metabolic activation system. Moreover, the teratogenic effects were observed at concentrations relevant to human exposure data. Along with other findings, our results indicate that zebrafish embryos are a useful alternative method for traditional teratogenicity testing with mammalian species. PMID- 21237241 TI - Brown Norway rat asthma model of diphenylmethane-4,4'-diisocyanate (MDI): determination of the elicitation threshold concentration of after inhalation sensitization. AB - Occupational exposure to polymeric diphenylmethane-diisocyanate (MDI), a known human asthmagen, can be attributed to two potential routes: the skin and the respiratory tract. While the skin as the route of sensitization was the focus of a previous investigation (Pauluhn, 2008), this paper describes a modified sensitization protocol using a 5-day inhalation exposure (days 0-4) of Brown Norway (BN) rats to two concentration x exposure time (C x t) relationships of 1000, 5000, and 10,000 mg MDI/m3 x min at exposure durations of either 10 or 360 min. Apart from the differences in the induction protocol, all other experimental variables remained identical. This was followed by four 30-min inhalation challenges to 40 mg MDI/m3 on target days 20, 25, 50, and 65. After the last challenge, changes in breathing patterns delayed in onset were recorded and allergic lung inflammation was probed by bronchoalveolar lavage (BAL). In a subsequent study groups of rats were sensitized using the 10-min C x t protocol and challenged 3-times at 40 mg MDI/m3. At the fourth challenge a dose-escalation regimen was used to determine the elicitation threshold on 'asthmatic' rats. Consistent with the skin-sensitization protocol, the most sensitive endpoints characterizing an allergic pulmonary inflammation were again BAL-neutrophils and physiological measurements showing respiratory changes delayed in onset. The dose escalation challenge yielded an elicitation threshold of 5 mg MDI-aerosol/m3 at 30 min challenge duration. In topically sensitized rats this threshold was estimated to be 3mg/m3. In summary, these data suggest the C x t product of MDI aerosol that triggers an elicitation response in 'asthmatic' rats is slightly below of that causing acute pulmonary irritation in naive rats. The high concentration delivered to the respiratory tract during the 10-min exposure period elicited a more vigorous response than the similar C x t at 360 min. Therefore, short high-level exposure patterns appear to bear a higher sensitizing potency than equal C x t products at longer exposure periods. Taking into account the respective differences in exposure intensities, the comparison of elicitation thresholds of BN rats sensitized by inhalation or skin exposure did not demonstrate essential differences. PMID- 21237240 TI - The intracellular redox stress caused by hexavalent chromium is selective for proteins that have key roles in cell survival and thiol redox control. AB - Hexavalent chromium [Cr(VI)] compounds (e.g. chromates) are strong oxidants that readily enter cells where they are reduced to reactive Cr intermediates that can directly oxidize some cell components and can promote the generation of reactive oxygen and nitrogen species. Inhalation is a major route of exposure which directly exposes the bronchial epithelium. Previous studies with non-cancerous human bronchial epithelial cells (BEAS-2B) demonstrated that Cr(VI) treatment results in the irreversible inhibition of thioredoxin reductase (TrxR) and the oxidation of thioredoxins (Trx) and peroxiredoxins (Prx). The mitochondrial Trx/Prx system is somewhat more sensitive to Cr(VI) than the cytosolic Trx/Prx system, and other redox-sensitive mitochondrial functions are subsequently affected including electron transport complexes I and II. Studies reported here show that Cr(VI) does not cause indiscriminant thiol oxidation, and that the Trx/Prx system is among the most sensitive of cellular protein thiols. Trx/Prx oxidation is not unique to BEAS-2B cells, as it was also observed in primary human bronchial epithelial cells. Increasing the intracellular levels of ascorbate, an endogenous Cr(VI) reductant, did not alter the effects on TrxR, Trx, or Prx. The peroxynitrite scavenger MnTBAP did not protect TrxR, Trx, Prx, or the electron transport chain from the effects of Cr(VI), implying that peroxynitrite is not required for these effects. Nitration of tyrosine residues of TrxR was not observed following Cr(VI) treatment, further ruling out peroxynitrite as a significant contributor to the irreversible inhibition of TrxR. Cr(VI) treatments that disrupt the TrxR/Trx/Prx system did not cause detectable mitochondrial DNA damage. Overall, the redox stress that results from Cr(VI) exposure shows selectivity for key proteins which are known to be important for redox signaling, antioxidant defense, and cell survival. PMID- 21237242 TI - Methylated 23S rRNA nucleotide m2G1835 of Escherichia coli ribosome facilitates subunit association. AB - Among 4.5 thousand nucleotides of Escherichia coli ribosome 36 are modified. These nucleotides are clustered in the functional centers of ribosome, particularly on the interface of large and small subunits. Nucleotide m(2)G1835 located on the 50S side of intersubunit bridge cluster B2 is modified by N2 methyltransferase RlmG. By means of isothermal titration calorimetry and Rayleigh light scattering, we have found that methylation of m(2)G1835 specifically enhances association of ribosomal subunits. No defects in fidelity of translation or interaction with translation GTPases could be ascribed to the ribosomes unmethylated at G1835 of the 23S rRNA. Methylation of G1835 was found to provide a significant advantage for bacteria at osmotic and oxidative stress. PMID- 21237243 TI - Molecular organization of the cullin E3 ligase adaptor KCTD11. AB - The family of human proteins containing a potassium channel tetramerization domain (KCTD) includes 21 members whose function is largely unknown. Recent reports have however suggested that these proteins are implicated in very important biological processes. KCTD11/REN, the best-characterized member of the family to date, plays a crucial role in the ubiquitination of HDAC1 by acting, in complex with Cullin3, as an E3 ubiquitin ligase. By combining bioinformatics and mutagenesis analyses, here we show that the protein is expressed in two alternative variants: a short previously characterized form (sKCTD11) composed by 232 amino acids and a longer variant (lKCTD11) which contains an N-terminal extension of 39 residues. Interestingly, we demonstrate that lKCTD11 starts with a non-canonical AUU codon. Although both sKCTD11 and lKCTD11 bear a POZ/BTB domain in their N-terminal region, this domain is complete only in the long form. Indeed, sKCTD11 presents an incomplete POZ/BTB domain. Nonetheless, sKCTD11 is still able to bind Cul3, although to much lesser extent than lKCTD11, and to perform its biological activity. The heterologous expression of sKCTD11 and lKCTD11 and their individual domains in Escherichia coli yielded soluble products as fusion proteins only for the longer form. In contrast to the closely related KCTD5 which is pentameric, the characterization of both lKCTD11 and its POZ/BTB domain by gel filtration and light scattering indicates that the protein likely forms stable tetramers. In line with this result, experiments conducted in cells show that the active protein is not monomeric. Based on these findings, homology based models were built for lKCTD11 BTB and for its complex with Cul3. These analyses indicate that a stable lKCTD11 BTB-Cul3 three-dimensional model with a 4:4 stoichiometry can be generated. Moreover, these models provide insights into the determinants of the tetramer stability and into the regions involved in lKCTD11-Cul3 recognition. PMID- 21237244 TI - Damage-specific DNA binding protein 1 (DDB1) is involved in ubiquitin-mediated proteolysis of p27Kip1 in response to UV irradiation. AB - Damage-specific DNA binding protein 1 (DDB1) is a conserved protein component of the damaged DNA binding protein complex (DDB) that recognizes UV-induced DNA lesions and initiates the nucleotide excision repair process. DDB1 is also part of an E3 ubiquitin-ligase complex that targets a variety of substrates for proteolysis including the cyclin-dependent kinase inhibitor p27(Kip1). The mechanism regulating the trafficking of DDB1 and its relationship with UV irradiation is not known, although cell cycle progression is implicated in the molecular machinery driving DDB1 into the nucleus. We evaluated the involvement of DDB1 in ubiquitination of the cdk inhibitor p27(Kip1) in response to UV irradiation. First, we observed that low and high doses of UV irradiation exert different effects on p27(Kip1) protein levels. Indeed, low but not high UV doses induced p27(Kip1) protein proteolysis in several human cell lines and UV dependent degradation is dominant over other genotoxic agents such as cisplatin. We also demonstrate that p27(Kip1) reduction is not due to transcriptional regulation and that the proteasome inhibitor MG132 affects p27(Kip1) degradation. We observed that at low UV doses the decrease in p27(Kip1) nuclear protein related with DDB1 translocation into the nucleus; conversely, high doses of UV induced p27(Kip1) accumulation and unchanged level of DDB1. The knockdown of DDB1 or Skp2 prevents UV-induced degradation of p27(Kip1) suggesting that DDB1 is essential to regulation of p27(kip1) turnover after a mild DNA damage. Our findings support the concept that DDB1 contributes to the activation of DNA repair mechanisms and could be a key factor in regulating the cell cycle in response to UV-induced DNA damage. Although the temporal order with which DDB1 contributes to ubiquitination of p27(Kip1) or initiates the nucleotide excision repair process remains to be established, our results represent a major step towards clarifying these issues. PMID- 21237245 TI - High-accuracy prediction of protein structural class for low-similarity sequences based on predicted secondary structure. AB - Information on the structural classes of proteins has been proven to be important in many fields of bioinformatics. Prediction of protein structural class for low similarity sequences is a challenge problem. In this study, 11 features (including 8 re-used features and 3 newly-designed features) are rationally utilized to reflect the general contents and spatial arrangements of the secondary structural elements of a given protein sequence. To evaluate the performance of the proposed method, jackknife cross-validation tests are performed on two widely used benchmark datasets, 1189 and 25PDB with sequence similarity lower than 40% and 25%, respectively. Comparison of our results with other methods shows that our proposed method is very promising and may provide a cost-effective alternative to predict protein structural class in particular for low-similarity datasets. PMID- 21237246 TI - Mutation in the substrate-binding site of aminopeptidase B confers new enzymatic properties. AB - Aminopeptidase B (Ap-B) catalyzes the cleavage of arginine and lysine residues at the N-terminus of various peptide substrates. In vivo, it participates notably in the miniglucagon and cholecystokinin 8 processing, but the complete range of physiological functions of Ap-B remains to be discovered. Ap-B is a member of the M1 family of Zn(2+)-metallopeptidases that are characterized by two highly conserved motives, GXMEN (potential substrate binding site) and HEXXHX(18)E (Zn(2+)-binding site). In this study, mutagenesis and molecular modelling were used to investigate the enzymatic mechanism of Ap-B. Nineteen rat Ap-B mutants of the G(298)XM(300)E(301)N(302) motif and one mutant of the HEIS(328)HX(18)E motif were expressed in Escherichia coli. All mutations except G(298)P, G(298)S, and S(328)A abolished the aminopeptidase activity. The S(328)A mutant mimics the sequence of bovine Ap-B Zn(2+)-binding site, which differs from those of other mammalian Ap-B. This mutant conserved a canonical Ap-B activity. G(298)S and G(298)P mutants exhibit new enzymatic properties such as changes in their profile of inhibition and their sensitivity to Cl(-) anions. Moreover, the G(298)P mutant exhibits new substrate specificity. A structural analysis using circular dichroism, fluorescence spectroscopy, molecular modelling and dynamics was performed to investigate the role that residue G(298) plays in the catalytic mechanism of Ap-B. Our results show that G(298) is essential to Ap-B activity and participates to the substrate specificity of the enzyme. PMID- 21237247 TI - A comprehensive study of multiple mapping and feature selection for correction strategy in the analysis of small RNAs from SOLiD sequencing. AB - High-throughput sequencing is a powerful tool for discovering and profiling microRNAs (miRNAs) to gain further insights into their biogenesis and function. Due to shorter size, short RNAs from deep sequencing dataset are prone to map to multiple loci with an equal number of mismatches, especially among multicopy miRNA precursors and homologous miRNA genes. Systematic analysis of SOLiD sequencing dataset showed that 37.94% short RNAs could simultaneously map to more than one miRNA precursor, and more short RNAs were found to have multiple genomic loci. Improper selection from candidate loci might lose some mapping information, influence miRNA expression profile or even mislead to identify novel miRNAs. A comprehensive study indicated several potential features for correction strategy: location and distribution of mismatches, quality values, expression profiles of multiple isomiRs (miRNA variants), miRNA* and moRs (miRNA-offset-RNAs) at candidate locus and in its flank sequence. Further studies should develop an approach to correct the widespread phenomenon of multiple mapping based on these features, and improve accuracy of profiling and discovering miRNAs. PMID- 21237248 TI - Molsidomine modulates the cNOS activity in an experimental model of cholinergic damage induced by 192-IgG saporin. AB - The aim of this work was to study the effect of molsidomine (MOLS), a nitric oxide (NO) donor, on the nitrergic system changes in an experimental model of cholinergic damage induced by 192 IgG saporin (SAP). Male rats were injured by intraseptal administration of SAP (0.22 MUg), after seven days, rats were administered with MOLS (4 mg/kg, i.p.) 60 min before sacrifice. Prefrontal cortex (PC), striatum (S) and hippocampus (HC) were dissected out. Results showed significant recovery of the constitutive NOS activity (cNOS) in PC and S regions by MOLS but not in HC compared against controls. SAP reduced the cellular population in the lesion site and MOLS was able to avoid the progression of damage in this area. NO donor is able to modulate the nitrergic status in an experimental model induced by SAP. PMID- 21237249 TI - Molecular characterization of an insecticide-induced novel glutathione transferase in silkworm. AB - BACKGROUND: The glutathione transferase (GST) superfamily is involved in the detoxification of various xenobiotics. We have identified a GST mRNA that was induced in the fat bodies of a silkworm strain exhibiting diazinon resistance and have investigated the enzyme properties of this GST. METHODS: A soluble recombinant protein was overexpressed in Escherichia coli. Amino acid residues of interest were changed to alanine by site-directed mutagenesis. RESULTS AND CONCLUSIONS: Phylogenetic analysis of the deduced amino acid sequence indicates that this GST belongs to an unclassified group previously reported in mosquitoes. This enzyme, named bmGSTu, has highly conserved amino acid residues, including Tyr7, Ser12 and Asn50. A recombinant bmGSTu was able to catalyze the biotranslation of glutathione with 1-chloro-2,4-dinitrobenzene, a synthetic substrate of GST. Kinetic analysis of bmGSTu mutants indicated that Tyr7, Ser12 and Asn50 are involved in enzyme function. GENERAL SIGNIFICANCE: These results support the hypothesis that bmGSTu may play a role in insecticide resistance in Bombyx mori. PMID- 21237250 TI - Identification and characterization of human PCDH10 gene promoter. AB - Recent studies have suggested roles for PCDH10 as a novel tumor suppressor gene. In our previous work, we located the core promoter of PCDH10 to a 462-bp segment of 5'-flanking region characterized by a high GC content. Here we further identified and characterized the promoter for PCDH10. Transient transfection of PC3 and LNCaP cells with a series of deleted promoter constructs indicated that the minimal promoter region was between nucleotides -144 and -99. This segment contained a CAAT box, a GT box, and a putative transcription factor binding site for AP-4. Mutational analysis identified that the CAAT box and GT box are necessary for promoter activity. Ectopic expression of NF-Ys increased reporter gene activity, whereas expression of a dominant-negative NF-YA decreased reporter gene activity. Co-transfection of Sp1/Sp3 expression plasmids enhanced reporter gene activity in a dose-dependent manner. Mithramycin A, an inhibitor of Sp-DNA interaction, reduced PCDH10 promoter activity. Electrophoretic mobility shift assays and chromatin immunoprecipitation demonstrated binding of transcription factors Sp1/Sp3 to the promoter region in vitro and in vivo. Our data show that Sp1/Sp3 and CBF/NF-Y transcription factors play a crucial role in the basal expression of the human PCDH10 gene. PMID- 21237251 TI - Pleiotropic effect of a null mutation in the cvn1 conservon of Streptomyces coelicolor A3(2). AB - The conservon (cvn) of Streptomyces species encodes a putative membrane associated signaling complex resembling the eukaryotic G-protein-coupled receptor (GPCR) system. The cvn is widely distributed in the genomes of Actinobacteria, indicating that it plays an important role in this group of bacterial species; however, the exact role of this regulatory system is hitherto poorly understood. In the present study, we generated null mutants for all 13 copies of the cvn operon distributed in the genome of Streptomyces coelicolor A3(2) and observed that the aerial mycelium formation and antibiotic production in a cvn1 mutant were markedly impaired. The cvn1 mutant formed aerial mycelium and produced actinorhodin and undecylprodigiosin at remarkably low levels on solid medium containing 1-2% glucose and at high levels on medium containing 6-10% glucose. The same phenotype as this was observed with a cvnA1 mutant. Transcriptional analyses revealed that the expression of sigU encoding a vegetative sigma factor was upregulated in the cvn1 mutant. Overexpression of rsuA encoding the sigma(SigU) antagonist restored aerial mycelium formation and pigment production in the cvn1 mutant, suggesting that the developmental defect in the cvn1 mutant is based on the high expression level of sigU. PMID- 21237252 TI - The pharmacology of Malo maxima jellyfish venom extract in isolated cardiovascular tissues: A probable cause of the Irukandji syndrome in Western Australia. AB - The in vitro cardiac and vascular pharmacology of Malo maxima, a newly described jellyfish suspected of causing Irukandji syndrome in the Broome region of Western Australia, was investigated in rat tissues. In left atria, M. maxima crude venom extract (CVE; 1-100MUg/mL) caused concentration-dependent inotropic responses which were unaffected by atropine (1MUM), but significantly attenuated by tetrodotoxin (TTX; 0.1MUM), propranolol (1MUM), Mg(2+) (6mM) or calcitonin gene related peptide antagonist (CGRP(8-37); 1MUM). CVE caused no change in right atrial rate until 100MUg/mL, which elicited bradycardia. This was unaffected by atropine, TTX, propranolol or CGRP(8-37). In the presence of Mg(2+), CVE 30 100MUg/mL caused tachycardia. In small mesenteric arteries CVE caused concentration-dependent contractions (pEC(50) 1.03+/-0.07MUg/mL) that were unaffected by prazosin (0.3MUM), omega-conotoxin GVIA (0.1MUM) or Mg(2+) (6mM). There was a 2-fold increase in sensitivity in the presence of CGRP(8-37) (3MUM). TTX (0.1MUM), box jellyfish Chironex fleckeri antivenom (92.6U/mL) and benextramine (3MUM) decreased sensitivity by 2.6, 1.9 and 2.1-fold, respectively. CVE-induced maximum contractions were attenuated by C. fleckeri antivenom (-22%) or benextramine (-49%). M. maxima CVE appears to activate the sympathetic, but not parasympathetic, nervous system and to stimulate sensory nerve CGRP release in left atria and resistance arteries. These effects are consistent with the catecholamine excess thought to cause Irukandji syndrome, with additional actions of CGRP release. PMID- 21237253 TI - Lipopolysaccharide down-regulates carbolesterases 1 and 2 and reduces hydrolysis activity in vitro and in vivo via p38MAPK-NF-kappaB pathway. AB - Carboxylesterases constitute a class of enzymes that hydrolyze drugs containing such functional groups as carboxylic acid ester, amide, and thioester. Hydrolysis of many drugs is reduced in liver diseases such as hepatitis and cirrhosis. In this study, we have demonstrated, in vitro and in vivo, treatment with LPS decreased the expression of HCE1 and HCE2 and the capacity of hydrolytic activity. In HepG2 cells, the decreased expression by LPS occurred at both mRNA and protein levels. Both HCE1 and HCE2 promoters were significantly repressed by LPS, and the repression was comparable with the decrease in HCE1 and HCE2 mRNA, suggesting the transrepression is responsible for suppressed expression. Further study showed that both PDTC, a NF-kappaB inhibitor, and SB203580, a p38MAPK inhibitor, could abolish the repression of HCE1 and HCE2 mediated by LPS, but U0126, a selective ERK1/2 inhibitor, could not do so, suggesting the repression of HCE1 and HCE2 by LPS through the p38MAPK-NF-kappaB pathway. In addition, being pretreated with LPS, HepG2 cells altered the cellular responsiveness to ester therapeutic agents, including clopidogrel (hydrolyzed by HCE1) and irinotecan (hydrolyzed by HCE2). The altered cellular responsiveness occurred at low micromolar concentrations, suggesting that suppressed expression of carboxylesterases by LPS has profound pharmacological and toxicological consequences, particularly with those that are hydrolyzed in an isoform-specific manner. This study provides new insight into the understanding of the pharmacological and toxicological effects and the mechanisms for repressing drug metabolism enzymes in inflammation. PMID- 21237254 TI - Abnormal expression of MAPK, EGFR, CK17 and TGk in the skin lesions of chloracne patients exposed to dioxins. AB - OBJECTIVE: Chloracne is one of the most sensitive and specific hallmark of dioxin intoxication. Although its clinical features are clearly described, poor understanding of the molecular pathways of dioxin-induced chloracne hampers a rational approach to therapy. The aim of the present study was to investigate the role of EGFR, MAPK, CK17, and TGk in the pathogenesis of chloracne related to dioxin exposures. METHODS: Epidermal tissues of twelve chloracne patients exposed to dioxins were compared with tissues from 12 healthy controls. These skin tissues were obtained by punch biopsies. p-EGFR and p-MAPK were examined by immunofluorescence. The mRNA and protein levels of CK17 and TGk were examined by fluorescence in situ hybridization and immunohistochemistry, respectively. RESULTS: p-EGFR and p-MAPK were found in all chloracne tissues, whereas no expression was found in the controls. CK17 mRNA and protein were also found in all chloracne lesions, but none in controls (P=0.000). TGk mRNA and protein were detected in both groups, but the distribution was distinct. The positive signals in the controls were mainly in the stratum granulosum, while in the chloracne tissues, the positive signals were found more significantly in the stratum granulosum and stratum spinosum. CONCLUSIONS: The results demonstrate that in the human skin the activation of mitogen-activated protein kinase pathway and up regulation of CK17 and TGK may play roles in the pathogenesis of chloracne related to dioxin exposures. PMID- 21237255 TI - Protection by tetrahydroxystilbene glucoside against neurotoxicity induced by MPP+: the involvement of PI3K/Akt pathway activation. AB - Oxidative stress plays an important role in the pathogenesis of Parkinson's disease (PD). 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D-glucoside (TSG), which is an active component of the rhizome extract from polygonum multiflorum, shows potent antioxidant properties. In this paper, the neuroprotective effects of TSG on 1-methyl-4-phenylpyridinium (MPP+-induced apoptosis in PC12 cells were investigated. Pretreatment with TSG markedly attenuated MPP+-induced loss of cell viability and release of lactate dehydrogenase (LDH), and reduced MPP+-induced apoptotic cell death in a dose-dependent manner. The anti-apoptotic effects of TSG were probably mediated by the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway since TSG failed to rescue cells from MPP+ injury in the presence of the PI3K inhibitor, LY294002. These results indicate that TSG affords a significant neuroprotective effect against MPP+-induced damage and apoptosis in PC12 cells. The PI3K/Akt signaling pathway might be involved in the TSG-mediated anti-apoptotic effects. PMID- 21237257 TI - Effect of casting solvent on crystallinity of ondansetron in transdermal films. AB - The purpose of the present investigation is to assess the influence of casting solvent on crystallinity of ondansetron hydrochloride in transdermal polymeric matrix films fabricated using povidone and ethyl cellulose as matrix forming polymers. Various casting solvents like chloroform (CHL), dichloromethane (DCM), methanol (MET); and mixture of chloroform and ethanol (C-ETH) were used for fabrication of the transdermal films. Analytical tools like scanning electron microscopy (SEM), X-ray diffraction (XRD) studies, differential scanning calorimetry (DSC), etc. were utilized to characterize the crystalline state of ondansetron in the film. Recrystallisation was observed in all the transdermal films fabricated using the casting solvents other than chloroform. Long thin slab looking, long wire-like or spherulite-looking crystals with beautiful impinged boundaries were observed in SEM. Moreover, XRD revealed no crystalline peaks of ondansetron hydrochloride in the transdermal films prepared using chloroform as casting solvent. The significantly decreased intensity and sharpness of the DSC endothermic peaks corresponding to the melting point of ondansetron in the formulation (specifically in CHL) indicated partial dissolution of ondansetron crystals in the polymeric films. The employed analytical tools suggested chloroform as a preferred casting solvent with minimum or practically absence of recrystallization indicating a relatively amorphous state of ondansetron in transdermal films. PMID- 21237256 TI - In vitro-in vivo correlation: perspectives on model development. AB - In vitro-in vivo correlation (IVIVC) allows prediction of the in vivo performance of a drug based on the in vitro drug release profiles. To develop an effective IVIVC, the physicochemical and biopharmaceutical properties of the drug as well as the physiological environment in the body must be taken into consideration. Key factors include drug solubility, pK(a), drug permeability, octanol-water partition coefficient and pH of environment. In general, construction of an IVIVC involves three stages of mathematical manipulation: construct a functional relationship between input (in vitro dissolution) and output (in vivo dissolution); establish a structural relationship using data collected; parameterize the unknowns in the structural model. Some key mathematical relationships used in IVIVC development are presented. The establishment of an effective IVIVC has important implications in quality control and regulatory compliance. PMID- 21237258 TI - Mathematical modeling of simultaneous drug release and in vivo absorption. AB - The attention of this review is focussed on the mathematical modeling of the simultaneous processes of drug release and absorption/distribution/metabolism/elimination (ADME processes) following different administration routes. Among all of them, for their clinical importance, the oral, transdermal and local delivery are considered. The bases of the presented mathematical models are shown after the discussion of the most relevant phenomena characterising the particular administration route considered. Then, model performances are compared to experimental evidences in order to evaluate their reliability and soundness. The most important conclusion of this review is that despite the complexity of the problem involved in the description of the fate of the drugs after their administration, the scientific community is close to the solution as witnessed by the various interesting and promising approaches here presented about the oral, transdermal and local administration routes. PMID- 21237259 TI - Self-assembly of cyclodextrin complexes: aggregation of hydrocortisone/cyclodextrin complexes. AB - Cyclodextrins (CDs) are well known functional excipients for solubilization and stabilization of drugs in aqueous formulations as well as enabling adjuncts for increasing the oral bioavailability of solid dosage forms. More recently a number of the valuable properties of these CDs have been ascribed to nanoparticulate aggregation in addition to its ability to form molecular inclusion complexes. The purpose of this study is to identify and characterize the aggregation of CD inclusion complexes with a model drug, hydrocortisone, in saturated solutions which are more relevant to drug formulation than highly dilute systems. Penetration studies of complexes through membranes and phase solubility relationships were assessed for saturated hydrocortisone solutions with the parent CDs, namely alphaCD, betaCD, gammaCD or with various water-soluble derivatives, i.e., 2-hydroxypropyl-betaCD (HPbetaCD), 2-hydroxypropyl-gammaCD (HPgammaCD) or sulfobutyl ether-beta-CD (SBEbetaCD). The data indicate that betaCD and gammaCD form micro-aggregates with hydrocortisone resulting in non linear phase-solubility relationships. By contract, the other studies of CDs or CD derivatives were found to form nanoaggregates with hydrocortisone resulting in linear solubilization relationships. Permeability profiles were evaluated for the systems formed and are described in three sections specifically a section (section I) where flux is linear (Fickian) as a function of CD concentration, a section (section II) where flux deviates in a negative fashion from linearity but still increases as the CD concentration increases and a section (section III) where flux is independent of the cyclodextrin concentration. Diminished values of flux can be interpreted based on the formation of nanoaggregates of hydrocortisone/CD complexes. Extrapolation of section I data made it possible to obtain theoretical flux values which could be used to estimate the fraction of complexes and drug which participate in aggregation. The CDs which appeared to demonstrate the lowest tendency to form complex aggregates were alphaCD and SBEbetaCD, due to their low complexation efficacy and repulsive forces, respectively. Complex aggregates with these CDs are also smaller with maximum size between 50 and 100 kDa. HPbetaCD and HPgammaCD complex aggregates manifested a maximum size above 100 kDa and the fraction of drug which participates in complex aggregation with these species is higher than for the other materials assessed. In the case of 90 mM HPgammaCD solution, data suggest that 87% of all hydrocortisone is tied up in the form of aggregates. These high concentrations were confirmed by TEM which found most particles in the 3-5 nm range but rarely particles as large as 10 and 20 nm. Speculation on the mechanism of the aggregation processes and equilibrium constants are provided but these tend to punctuate our limited understanding of these potentially important processes. PMID- 21237260 TI - Terahertz pulsed spectroscopy and imaging for pharmaceutical applications: a review. AB - The terahertz region of the electromagnetic spectrum spans the frequency range between the infrared and the microwave. Traditionally the exploitation of this spectral region has been difficult owing to the lack of suitable source and detector. Over the last ten years or so, terahertz technology has advanced considerably with both terahertz pulsed spectroscopy (TPS) and terahertz pulsed imaging (TPI) instruments now commercially available. This review outlines some of the recent pharmaceutical applications of terahertz pulsed spectroscopy and imaging. The following application areas are highlighted: (1) discrimination and quantification of polymorphs/hydrates, (2) analysis of solid form transformation dynamics, (3) quantitative characterisation of tablet coatings: off-line and on line, (4) tablet coating and dissolution, (5) spectroscopic imaging and chemical mapping. This review does not attempt to offer an exhaustive assessment of all anticipated pharmaceutical applications; rather it is an attempt to raise the awareness of the emerging opportunities and usefulness offered by this exciting technology. PMID- 21237261 TI - Pharmacological properties of Anagallis arvensis L. ("scarlet pimpernel") and Anagallis foemina Mill. ("blue pimpernel") traditionally used as wound healing remedies in Navarra (Spain). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Anagallis arvensis and Anagallis foemina are traditionally used in Navarra (Spain) for dermatological purposes regarding wound healing properties. In some cases they are also used to threat internal infections although they are known to be toxic at high doses. AIM OF STUDY: Due to lack of studies, we decided to evaluate the potential of the plants as wound healing remedies measuring antimicrobial and anti-inflammatory properties using in vitro procedures. MATERIALS AND METHODS: Antimicrobial effects were studied against four bacteria and one fungus. Anti-inflammatory properties were measured in terms of COX-1 and -2 inhibition as well as superoxide radical scavenging capacity. RESULTS: Both species exerted antimicrobial and anti-inflammatory effects. The methanolic extract obtained from Anagallis arvensis seemed to produce the highest inhibition in Candida albicans (MIC=0.31 mg/ml). Inhibition of COX-1 and -2 was also stronger for methanolic extracts whereas aqueous were revealed as better free radical scavengers. CONCLUSIONS: The study reveals that both species possess antimicrobial and anti-inflammatory activities related to their ethnomedicinal uses. PMID- 21237262 TI - Antimicrobial resistances of extraintestinal pathogenic Escherichia coli isolates from swine in China. AB - Antibiograms and relevant genotypes of porcine extraintestinal pathogenic Escherichia coli (ExPEC) isolates (n = 315) recovered between 2004 and 2007 in China were assessed. Among the 14 antimicrobials tested, the most prevalent resistance was to ampicillin, trimethoprim, sulfadimidine, tetracycline, neomycin, streptomycin, kanamycin, ciprofloxacin and ofloxacin (ranging from 81.9 to 100%). Forty-six multiresistant patterns were found. For each antimicrobial agent, ampicillin resistance was primarily mediated by bla(TEM,) streptomycin resistance by strA and strB, kanamycin/neomycin resistance by aphA1, gentamicin resistance by aac(3)-IV, quinolones resistance by mutations in gyrA, tetracycline resistance by tet(A), tet(B) and tet(G), trimethoprim resistance by dfrA7, dfrA12 and dfrA13, and sulfadimidine resistance by sul1 and sul2. Both bla(TEM-1) and bla(CTX-M-14) were found in two ESBLs-producing isolates. Strains that harbored several genes that conferred resistance to the same antimicrobial agent were often significantly more multiresistant than others. Class 1 integrons were identified in 86 (27.3%) ExPEC isolates, which harbored dfrA14, aadA2, aadA22, dfrA17, aadA5, dfrA17-aadA2, dfrA1-aadA1, dfrA12-aadA2, dfrA17-aadA5 gene cassettes in five major different variable regions, conferring resistance to trimethoprim and aminoglycosides. These results provide novel insights into the epidemiological characteristics of porcine ExPEC strains in China, and suggest the need for the prudent use of antimicrobial agents in food animals. PMID- 21237263 TI - LPS-induced CCL2 expression and macrophage influx into the murine central nervous system is polyamine-dependent. AB - Increased polyamine production is observed in a variety of chronic neuroinflammatory disorders, but in vitro and in vivo studies yield conflicting data on the immunomodulatory consequences of their production. Ornithine decarboxylase (ODC) is the rate-limiting enzyme in endogenous polyamine production. To identify the role of polyamine production in CNS-intrinsic inflammatory responses, we defined CNS sites of ODC expression and the consequences of inhibiting ODC in response to intracerebral injection of LPS+/ IFNgamma. In situ hybridization analysis revealed that both neurons and non neuronal cells rapidly respond to LPS+/-IFNgamma by increasing ODC expression. Inhibiting ODC by co-injecting DFMO decreased LPS-induced CCL2 expression and macrophage influx into the CNS, without altering LPS-induced microglial or macrophage activation. Conversely, intracerebral injection of polyamines was sufficient to trigger macrophage influx into the CNS of wild-type but not CCL2KO mice, demonstrating the dependence of macrophage influx on CNS expression of CCL2. Consistent with these data, addition of putrescine and spermine to mixed glial cultures dramatically increased CCL2 expression and to a much lesser extent, TNF expression. Addition of all three polyamines to mixed glial cultures also decreased the numbers and percentages of oligodendrocytes present. However, in vivo, inhibiting the basal levels of polyamine production was sufficient to induce expression of apolipoprotein D, a marker of oxidative stress, within white matter tracts. Considered together, our data indicate that: (1) CNS-resident cells including neurons play active roles in recruiting pro-inflammatory TREM1 positive macrophages into the CNS via polyamine-dependent induction of CCL2 expression and (2) modulating polyamine production in vivo may be a difficult strategy to limit inflammation and promote repair due to the dual homeostatic and pro-inflammatory roles played by polyamines. PMID- 21237264 TI - Decrease of lymphoproliferative response by amphetamine is mediated by dopamine from the nucleus accumbens: influence on splenic met-enkephalin levels. AB - Despite the mesocorticolimbic dopaminergic pathway being one of the main substrates underlying stimulating and reinforcing effects induced by psychostimulant drugs, there is little information regarding its role in their effects at the immune level. We have previously demonstrated that acute exposure to amphetamine (5 mg/kg, i.p.) induced an inhibitory effect on the splenic T-cell proliferative response, along with an increase in the methionine(met)-enkephalin content at limbic and immune levels, 4 days after drug administration. In this study, we investigated if a possible dopamine mechanism underlies these amphetamine-induced effects by administering D1 and D2 dopaminergic antagonists or a dopaminergic terminal neurotoxin before the drug. Pre-treatment with either SCH-23390 (0.1 mg/kg, i.p.) or raclopride (0.1 mg/kg, i.p.), a D1 or D2 dopaminergic receptor antagonist, respectively, abrogated the effects of amphetamine on the lymphoproliferative response and on met-enkephalin levels of the spleen. The amphetamine-induced increase in limbic met-enkephalin content was suppressed by SCH-23390 but not by raclopride pre-treatment. Finally, an intra accumbens 6-hydroxy-dopamine injection administered 2 weeks previously prevented amphetamine-induced effects on the lymphoproliferative response and on met enkephalin levels in the prefrontal cortex and spleen. These findings strongly suggest that D1 and D2 dopaminergic receptors are involved in amphetamine-induced effects at immune level as regards the lymphoproliferative response and the changes in spleen met-enkephalin content, whereas limbic met-enkephalin levels were modulated only by the D1 dopaminergic receptors. In addition, this study showed that a mesolimbic component modulated amphetamine-induced effects on the immune response, as previously shown at a behavioral level. PMID- 21237265 TI - Therapeutic approaches using nitric oxide in infants and children. AB - Pulmonary hypertension contributes significantly to the morbidity and mortality associated with many pediatric pulmonary and cardiac diseases. Nitric oxide, a gas molecule, is a unique pharmaceutical agent that can be inhaled and thus delivered directly to the lung. Inhaled nitric oxide was approved by the FDA in 1999 as a therapy for infants with persistent pulmonary hypertension. Since then, the use of inhaled nitric oxide has expanded to other neonatal and pediatric conditions, and our knowledge of its properties and mechanisms of action has increased tremendously. This review discusses the physiology of nitric oxide signaling, the most common indications for its clinical use, and promising new investigations that may enhance endogenous production of nitric oxide and/or improve vascular response to it. PMID- 21237267 TI - Preparation of phytantriol cubosomes by solvent precursor dilution for the delivery of protein vaccines. AB - Different delivery strategies to improve the immunogenicity of peptide/protein based vaccines are currently under investigation. In this study, the preparation and physicochemical characterisation of cubosomes, a novel lipid-based particulate system currently being explored for vaccine delivery, was investigated. Cubosomes were prepared from a liquid precursor mixture containing phytantriol or glycerylmonooleate (GMO), F127 for particle stabilisation, and a hydrotrope (ethanol or polyethylene glycol (PEG(200)) or propylene glycol (PG)). Several liquid precursors were prepared, and the effect of varying the concentrations of F127 and the hydrotrope on cubosome formation was investigated. Formulations were prepared by fragmentation for comparison. The model protein ovalbumin (Ova) was also entrapped within selected formulations. Submicron-sized particles (180-300 nm) were formed spontaneously upon dilution of the liquid precursors, circumventing the need for the preformed cubic phase used in traditional fragmentation-based methods. The nanostructure of the phytantriol dispersions was determined to be cubic phase using SAXS whilst GMO dispersions had a reverse hexagonal nanostructure coexisting with cubic phase. The greatest entrapment of Ova was within phytantriol cubosomes prepared from liquid precursors. Release of Ova from the various formulations was sustained; however, release was significantly faster and the extent of release was greater from fragmented dispersions compared to liquid precursor formulations. Taken together, these results suggest that phytantriol cubosomes can be prepared using liquid precursors and that it is a suitable alternative to GMO. Furthermore, the high entrapment and the slow release of Ova in vitro highlight the potential of phytantriol cubosomes prepared using liquid precursors as a novel vaccine delivery system. PMID- 21237266 TI - Cardiac remodeling in Drosophila arises from changes in actin gene expression and from a contribution of lymph gland-like cells to the heart musculature. AB - Understanding the basis of normal heart remodeling can provide insight into the plasticity of the cardiac state, and into the potential for treating diseased tissue. In Drosophila, the adult heart arises during metamorphosis from a series of events, that include the remodeling of an existing cardiac tube, the elaboration of new inflow tracts, and the addition of a layer of longitudinal muscle fibers. We have identified genes active in all these three processes, and studied their expression in order to characterize in greater detail normal cardiac remodeling. Using a Transglutaminase-lacZ transgenic line, that is expressed in the inflow tracts of the larval and adult heart, we confirm the existence of five inflow tracts in the adult structure. In addition, expression of the Actin87E actin gene is initiated in the remodeling cardiac tube, but not in the longitudinal fibers, and we have identified an Act87E promoter fragment that recapitulates this switch in expression. We also establish that the longitudinal fibers are multinucleated, characterizing these cells as specialized skeletal muscles. Furthermore, we have defined the origin of the longitudinal fibers, as a subset of lymph gland cells associated with the larval dorsal vessel. These studies underline the myriad contributors to the formation of the adult Drosophila heart, and provide new molecular insights into the development of this complex organ. PMID- 21237268 TI - The inhibition of human and rat 11beta-hydroxysteroid dehydrogenase 2 by perfluoroalkylated substances. AB - 11beta-Hydroxysteroid dehydrogenase 2 (11beta-HSD2) regulates active glucocorticoid access to glucocorticoid and mineralocorticoid receptors by metabolizing it to an inactive form. Perfluoroalkylated substances (PFASs) are man-made polyfluorinated compounds that are widely used and persistent in the environment. We tested the inhibitory potencies of four PFASs including perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexanesulfonate (PFHxS) and perfluorobutane sulfonate (PFBS) on human and rat 11beta-HSD2. PFOS was a potent inhibitor of both human (IC(50)=48 nM) and rat (IC(50)=293 nM) 11beta-HSD2 activities. The potencies for the inhibition of human and rat 11beta-HSD2 activities were PFOS>PFOA>PFHxS>PFBS. PFASs showed competitive inhibition of both human and rat 11beta-HSD2 activities. This observation indicates that PFOS is a potent endocrine disruptor for glucocorticoid metabolism. Article from the Special issue on Targeted Inhibitors. PMID- 21237269 TI - Fission yeast Schizosaccharomyces pombe as a new system for the investigation of corticosterone methyloxidase deficiency-causing mutations. AB - The aldosterone synthase, CYP11B2, catalyses the conversion of 11 deoxycorticosterone to aldosterone, a process that requires three steps: a hydroxylation at position 11beta to form corticosterone, another one at position 18 to produce 18-hydroxycorticosterone, and, finally, an oxidation at position 18 to form aldosterone. Aldosterone synthase deficiency usually finds its expression in infancy as a life-threatening electrolyte imbalance, caused by mutations in the CYP11B2 gene. Therefore, in depth studies of mutations and their enzymatic activities will provide information for the diagnosis and management of hypoaldosteronism caused by CYP11B2 deficiencies. Here, we report the development of a fast and cheap whole-cell technology for the enzymatic characterisation of CYP11B2 mutations. The principle of the new system is the heterologous expression of the mutants of CYP11B2 in fission yeast (Schizosaccharomyces pombe) followed by steroid bioconversion assays for the enzymatic characterisation of the investigated mutants. The new system was validated and 10 known mutations of CYP11B2 have been investigated, two of them for the first time concerning their effect on the CYP11B2 three-step reaction. The results of the fission yeast system were in good agreement with the cell culture results presenting this new system as an alternative non radioactive method that can be applied for the enzymatic characterisation of CYP11B2 mutations. PMID- 21237270 TI - Polymorphisms in STAT4 increase the risk of acute renal allograft rejection in the Chinese population. AB - Recently, the signal transducer and activator of transcription 4 (STAT4) gene have been associated with multiple autoimmune diseases. Taking into consideration that the different autoimmune diseases may share some common pathogenetic pathways, the aim of the present study was to evaluate the role of STAT4 rs7574865 polymorphism on acute allograft rejection. The present case-control study included 453 renal allograft recipients and 378 sex matched healthy controls. Genotyping was performed using a PCR based discrimination assay for the rs7574865 STAT4 SNP. No evidence of association was found between health controls and renal transplant recipients for the G/T or T/T genotype and wild type G/G. (p=0.431, two-tailed chi(2); OR=0.894, 95% CI=0.677-1.181). But among the transplant recipients, the G/T or T/T genotype was more common in transplant rejectors (acute allograft rejection) than nonrejectors who had mostly wild-type G/G genotype (p=0.003, two-tailed chi(2); OR=0.542, 95% CI=0.361-0.815). We also found a trend that the frequency of G/T or T/T genotype was also relatively more in the acute cellular mediated rejection than antibody mediated ones (p=0.049, two-tailed chi(2); OR=0.466, 95% CI=0.216-1.003). Thus, our data suggest that the rs7574865 STAT4 SNP is a genetic susceptibility variant for acute renal allograft rejection in the Chinese population. PMID- 21237271 TI - Curcumin protects against A53T alpha-synuclein-induced toxicity in a PC12 inducible cell model for Parkinsonism. AB - Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD remains incompletely understood, but it appears to involve both genetic susceptibility and environmental factors. Treatment for PD that prevents neuronal death in the dopaminergic system and abnormal protein deposition in the brain is not yet available. Evidence from human and animal studies has suggested that oxidative damage critically contributes to neuronal loss in PD. Here we test whether curcumin, a potent antioxidant compound, derived from the curry spice turmeric, can protect against mutant A53T alpha-synuclein induced cell death. We used PC12 cells that inducibly express A53T alpha synuclein. We found that curcumin protected against A53T alpha-synuclein-induced cell death in a dose-dependent manner. We further found that curcumin can reduce mutant alpha- synuclein-induced intracellular reactive oxygen species (ROS) levels, mitochondrial depolarization, cytochrome c release, and caspase-9 and caspase-3 activation. This study demonstrate that curcumin protected against A53T mutant alpha-synuclein-induced cell death via inhibition of oxidative stress and the mitochondrial cell death pathway, suggesting that curcumin may be a candidate neuroprotective agent for A53T alpha-synuclein-linked Parkinsonism, and possibly for other genetic or sporadic forms of PD. PMID- 21237272 TI - Diel variations in the selected serum immune parameters in Oreochromis mossambicus. AB - Almost all metabolic processes in an organism alternate through high and low activity phases with a regular periodicity of nearly 24h. These daily/diel variations are governed by factors such as light, weather conditions, availability of food or predator activity. The immune system in fish is expected to follow the same routine based on external cues from the environment which it lives. The present study was carried out to investigate such daily/diel variations in selected immune parameters such as serum lysozyme and peroxidases activity, total serum globulin level and peripheral blood leukocyte count in Oreochromis mossambicus. The fish were maintained in semi natural condition (i.e.12L:12D). The results showed significant rise in serum peroxidases and lysozyme between 0200 h and 0600 h of the day and serum cortisol exhibited elevated level between 2200 h and 0600 h. Total serum globulin exhibited peak concentration from 1400 h to 1800 h. Thus suggesting the possibility of rhythmic functioning of immune system in O. mossambicus. PMID- 21237273 TI - A learning-based wrapper method to correct systematic errors in automatic image segmentation: consistently improved performance in hippocampus, cortex and brain segmentation. AB - We propose a simple but generally applicable approach to improving the accuracy of automatic image segmentation algorithms relative to manual segmentations. The approach is based on the hypothesis that a large fraction of the errors produced by automatic segmentation are systematic, i.e., occur consistently from subject to subject, and serves as a wrapper method around a given host segmentation method. The wrapper method attempts to learn the intensity, spatial and contextual patterns associated with systematic segmentation errors produced by the host method on training data for which manual segmentations are available. The method then attempts to correct such errors in segmentations produced by the host method on new images. One practical use of the proposed wrapper method is to adapt existing segmentation tools, without explicit modification, to imaging data and segmentation protocols that are different from those on which the tools were trained and tuned. An open-source implementation of the proposed wrapper method is provided, and can be applied to a wide range of image segmentation problems. The wrapper method is evaluated with four host brain MRI segmentation methods: hippocampus segmentation using FreeSurfer (Fischl et al., 2002); hippocampus segmentation using multi-atlas label fusion (Artaechevarria et al., 2009); brain extraction using BET (Smith, 2002); and brain tissue segmentation using FAST (Zhang et al., 2001). The wrapper method generates 72%, 14%, 29% and 21% fewer erroneously segmented voxels than the respective host segmentation methods. In the hippocampus segmentation experiment with multi-atlas label fusion as the host method, the average Dice overlap between reference segmentations and segmentations produced by the wrapper method is 0.908 for normal controls and 0.893 for patients with mild cognitive impairment. Average Dice overlaps of 0.964, 0.905 and 0.951 are obtained for brain extraction, white matter segmentation and gray matter segmentation, respectively. PMID- 21237274 TI - Brain dynamics of upstream perceptual processes leading to visual object recognition: a high density ERP topographic mapping study. AB - Recent studies suggest that visual object recognition is a proactive process through which perceptual evidence accumulates over time before a decision can be made about the object. However, the exact electrophysiological correlates and time-course of this complex process remain unclear. In addition, the potential influence of emotion on this process has not been investigated yet. We recorded high density EEG in healthy adult participants performing a novel perceptual recognition task. For each trial, an initial blurred visual scene was first shown, before the actual content of the stimulus was gradually revealed by progressively adding diagnostic high spatial frequency information. Participants were asked to stop this stimulus sequence as soon as they could correctly perform an animacy judgment task. Behavioral results showed that participants reliably gathered perceptual evidence before recognition. Furthermore, prolonged exploration times were observed for pleasant, relative to either neutral or unpleasant scenes. ERP results showed distinct effects starting at 280 ms post stimulus onset in distant brain regions during stimulus processing, mainly characterized by: (i) a monotonic accumulation of evidence, involving regions of the posterior cingulate cortex/parahippocampal gyrus, and (ii) true categorical recognition effects in medial frontal regions, including the dorsal anterior cingulate cortex. These findings provide evidence for the early involvement, following stimulus onset, of non-overlapping brain networks during proactive processes eventually leading to visual object recognition. PMID- 21237275 TI - Longevity of the protective immune response induced after vaccination with one or two doses of AS03A-adjuvanted split H5N1 vaccine in ferrets. AB - It is crucial that a safe and effective pandemic vaccine be rapidly available to combat a new pandemic threat. In this study we investigated the magnitude and persistence of the protective efficacy induced by one or two doses (3.75 MUg HA/dose) of AS03(A)-adjuvanted H5N1 A/Indonesia/5/05 split vaccine in a lethal ferret challenge model. All ferrets that received at least one dose of adjuvanted vaccine 4 weeks before homologous challenge survived and showed reduced or undetectable virus replication in the lungs and the upper airways. Ferrets receiving two doses of adjuvanted vaccine 19 and 16 weeks before the challenge also showed high level of protection from replication in the lungs and the upper airways, albeit with only 83% survival. Animals in the control groups (non adjuvanted vaccine or saline) and animals immunized with one dose of adjuvanted vaccine administered 10 or 16 weeks before challenge showed only 17-33% survival rate after challenge. In conclusion, our observations support the possibility that a single dose of AS03(A)-adjuvanted H5N1 split vaccine can offer a rapid and short term but partial protection against disease. A second dose of the adjuvanted vaccine, which can be given with a flexible injection schedule, was shown to be essential to induce appreciable levels of antibodies and long-term protection. PMID- 21237276 TI - Nasal immunization with plasmid DNA encoding P6 protein and immunostimulatory complexes elicits nontypeable Haemophilus influenzae-specific long-term mucosal immune responses in the nasopharynx. AB - Nasal vaccination is an effective therapeutic regimen for preventing upper respiratory infection, while DNA vaccines represent a new approach for controlling infectious diseases. Here, we examined the efficacy of nasally administered DNA vaccine on upper respiratory infections. A DNA plasmid encoding the P6 outer membrane protein of nontypeable Haemophilus influenzae (NTHi) was constructed. Mice were immunized 3 times intranasally with the DNA plasmid and Matrix-M, an immunostimulatory complex adjuvant. P6-specific immune responses were examined using purified P6 protein. Nasal-associated lymphoid tissue (NALT) CD4(+) T cells were purified and incubated with feeder cells in the presence of P6, and the expression of cytokine mRNA was examined. In addition, NTHi challenges were performed and the level of NTHi was quantified in nasal washes. P6-specific nasal wash IgA and serum IgG were elevated following immunization with the DNA plasmid and Matrix-M. The number of specific IgA-producing cells increased in the nasal passages of the immunized mice. In addition to Th1 and Th2 cytokine expression, IL-17 was detected in P6-specific NALT CD4(+) T cells. Moreover, DNA vaccination enhanced bacterial clearance. These findings suggest that a successful DNA vaccination protocol has been developed for inducing in vivo immune responses against NTHi. Nasal vaccination with P6 DNA vaccine and Matrix-M might be a new effective regimen for the induction of specific protective immunity in the upper respiratory tract. PMID- 21237277 TI - Effect of vaccination of pigs against experimental infection with high and low virulence Mycoplasma hyopneumoniae strains. AB - This study investigated the infection pattern and lung lesion development in pigs caused by a low and highly virulent Mycoplasma hyopneumoniae strain at 4 and 8 weeks (w) post infection (PI). It also determined the efficacy of a commercial inactivated whole-cell vaccine against infection with each one of these M. hyopneumoniae strains. Ninety piglets free of M. hyopneumoniae were selected, and 40 of them were randomly vaccinated during their first week of life. At weaning, all piglets were allocated to 10 different groups and housed in pens with absolute filters. At 4 weeks of age, pigs were inoculated intratracheally with either a highly virulent M. hyopneumoniae strain, a low virulent strain or with sterile culture medium. Half of all animals were euthanized at 4 w PI, while the remaining half was euthanized at 8 w PI. Coughing was assessed daily, and lung lesions, immunofluorescence (IF), bacteriological analysis and nested PCR were assessed after necropsy. It was demonstrated that contrary to the highly virulent strain, the low virulent strain required more than 4 weeks PI (commonly accepted as the standard infection model) to reach maximum clinical symptoms. Vaccination significantly reduced clinical symptoms, macroscopic and microscopic lung lesions in pigs infected with the highly virulent strain. This effect was more pronounced at 4 than at 8 weeks PI. Protective efficacy was also observed in pigs infected with the low virulent strain, but the effect was less pronounced than on the highly virulent strain. PMID- 21237278 TI - Study on the protective efficacy of SA14-14-2 attenuated Japanese encephalitis against different JE virus isolates circulating in China. AB - Prior to 1976 only Japanese encephalitis virus (JEV) genotype III could be detected in China. Recently, numerous genotype I JEV strains have been isolated from JE patients, mosquitoes and pigs while genotype III strains remain present. Two kinds of JEV vaccines are currently used in China for the prevention disease: the JE live attenuated vaccine (LAV) SA14-14-2 virus and the inactivated P3 strain (IPV) vaccine. The SA14-14-2 and P3 viral strains were isolated in the year of 1953 and 1949 respectively and both belonged to the JEV genotype III. In order to evaluate the protective efficacy of both vaccines against the JEV genotype I isolates we conducted vaccination-challenge protection assays in mice. These data demonstrated that both LAV (>= 234 pfu virus) and IPV (1:5 dilution) vaccines effectively conferred protection against all 16 isolates tested following intraperitoneal (i.p.) challenge. However, when vaccinated mice were challenged via intracerebral (i.c.) injection, >= 60% LAV vaccinated animals were protected against challenge with most JEV isolates but only <= 40% protection was observed following vaccination with IPV. These results indicated that JE vaccines used in China still protected effectively against both JEV genotypes now prevalent in China and that the LAV formulation conferred higher levels of protection compared to the protection conferred by IPV. PMID- 21237279 TI - Differential roles of the phospholipase C genes in fungal development and pathogenicity of Magnaporthe oryzae. AB - Calcium plays a critical role in a variety of cellular processes in cells. However, relatively little is known about the biological effects of Ca2+ signaling on morphogenesis and pathogenesis in the rice blast fungus Magnaporthe oryzae compared to other signaling pathways. We have previously demonstrated that MoPLC1-mediated calcium regulation is important for infection-related development and pathogenicity in M. oryzae. In the present study, four genes encoding phospholipase C (PLC) isozymes (MoPLC2 to MoPLC5), which differ from MoPLC1 in their domain organization, were additionally identified. The C2 domain involved in Ca2+-dependent membrane binding is found only in MoPLC2 and MoPLC3. Detailed functional analysis using deletion mutants for MoPLC2 and MoPLC3 indicated that MoPLC2 and MoPLC3 play essential roles in development. The two deletion mutants for MoPLC2 and MoPLC3 showed reduced conidiation and a defect in appressorium mediated penetration. Reintroduction of the genes restored defects of DeltaMoplc2 and DeltaMoplc3. Notably, DeltaMoplc2 and DeltaMoplc3 mutants developed multiple appressoria on separate germ tubes of a conidium, indicating that MoPLC2- and MoPLC3-regulated signaling suppresses a feedback loop of a pathway for appressorial development. The similarity in phenotypic defects between the two mutants indicates that both MoPLC2 and MoPLC3 are important for regulation of appropriate levels of signaling molecules in a similar manner. Comparative analysis indicated that the two MoPLCs-mediated signaling pathways have interrelated, but distinct, roles in the development of M. oryzae. PMID- 21237280 TI - ATP citrate lyase is required for normal sexual and asexual development in Gibberella zeae. AB - Adenosine triphosphate (ATP) citrate lyase (ACL) is a key enzyme in the production of cytosolic acetyl-CoA, which is crucial for de novo lipid synthesis and histone acetylation in mammalian cells. In this study, we characterized the mechanistic roles of ACL in the homothallic ascomycete fungus Gibberella zeae, which causes Fusarium head blight in major cereal crops. Deletion of ACL in the fungus resulted in a complete loss of self and female fertility as well as a reduction in asexual reproduction, virulence, and trichothecene production. When the wild-type strain was spermatized with the ACL deletion mutants, they produced viable ascospores, however ascospore delimitation was not properly regulated. Although lipid synthesis was not affected by ACL deletion, histone acetylation was dramatically reduced in the ACL deletion mutants during sexual development, suggesting that the defects in sexual reproduction were caused by the reduction in histone acetylation. This study is the first report demonstrating a link between sexual development and ACL-mediated histone acetylation in fungi. PMID- 21237281 TI - Development of enzyme-linked immunosorbent assay for Delta12-prostaglandin J2 and its application to the measurement of the endogenous product generated by cultured adipocytes during the maturation phase. AB - Peroxisome proliferator-activated receptor (PPAR)gamma is a well-known master regulator for the differentiation and maturation of adipocytes. Prostaglandin (PG) D(2) can be produced in adipocytes and dehydrated to J(2) series of PGs including 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) and Delta(12)-PGJ(2), which serve as pro-adipogenic prostanoids through the activation of PPARgamma. However, the quantitative determination of Delta(12)-PGJ(2) has not been attempted during the life stage of adipocytes. In this study, we developed an enzyme-linked immunosorbent assay using mouse antiserum specific for Delta(12)-PGJ(2). According to the standard curve, the amount of Delta(12)-PGJ(2) can be measured from 0.5 pg to 14.4 ng in an assay. Our antiserum did not recognize most other prostanoids including 15d-PGJ(2), while it only showed the cross-reaction of 28% with unstable PGJ(2). This immunological assay was applied to the determination of the endogenous formation of Delta(12)-PGJ(2) in cultured 3T3-L1 adipocytes during the maturation phase. The ability of cultured adipocytes to form endogenous Delta(12)-PGJ(2) increased gradually at an earlier stage of the maturation phase and detectable at higher levels than 15d-PGJ(2). Treatment of cultured cells with either aspirin or indomethacin, a general cyclooxygenase inhibitor, significantly reduced the production of endogenous Delta(12)-PGJ(2) in the maturation medium as expected. Furthermore, we evaluated individually the exogenous effects of PGJ(2) series at various doses on adipogenesis during the maturation phase. Although Delta(12)-PGJ(2) was slightly less potent than 15d PGJ(2), each of these PGJ(2) series rescued effectively both the accumulation of fats and the gene expression of typical adipocyte-markers that were attenuated in the presence of aspirin. Taken together, our findings indicate that endogenous Delta(12)-PGJ(2) contributes substantially to the up-regulation of adipogenesis program through the activation of PPARgamma together with 15d-PGJ(2) during the maturation phase of cultured adipocytes. PMID- 21237282 TI - Role of tetraspanin CD151-alpha3/alpha6 integrin complex: Implication in angiogenesis CD151-integrin complex in angiogenesis. AB - Tetraspanin CD151 mainly associates with laminin-binding integrins and forms CD151-integrin complex. We previously reported that CD151 could be a potential target for angiogenesis, but the mechanisms involved are still unclear. This study investigated the role of CD151-integrin complex in angiogenesis and the signaling mechanisms involved. Here we showed that CD151 and CD151-AAA mutant were both well expressed at the protein level. CD151 gene transfer promoted angiogenesis and improved skin temperature of the lateral ischemic hindlimb, whereas CD151-AAA mutant abrogated the increase in capillary density and skin temperature. Further, CD151-AAA mutant failed to activate the FAK, ERK, PI3K/Akt/eNOS, and Rac1/Cdc42 signaling pathways. Moreover, CD151-AAA mutant was unavailable to promote bovine aortic endothelial cells (BAECs) proliferation and migration, in contrast to the effects of CD151. The results suggested that formation of CD151-integrin complex was likely to be a prerequisite for CD151 induced angiogenesis and signaling pathways. PMID- 21237283 TI - Phenothiazine: the seven lives of pharmacology's first lead structure. AB - Rooted in the early days of organic dye chemistry, the phenothiazine structure and its derivatives have since held a prominent place in pharmacology and biomedicine. Initially used for histochemical stains of plasmodia by Paul Ehrlich, anthelmintic and antibiotic properties of phenothiazines were globally exploited in the 1930s and 1940s. Clinical use of N-substituted phenothiazines as antihistaminics (1940s), sedatives and antipsychotics (1950s) followed and continues to this day. Recently, interest in these structures has re-emerged for a variety of fascinating features in relation to neurodegenerative disease, spearheaded by the unique redox chemistry of phenothiazine--arguably the most potent chain-breaking antioxidant ever identified. PMID- 21237284 TI - Direct and bystander effects induced by scattered radiation generated during penetration of radiation inside a water-phantom. AB - In this study, the dose distribution of photon (6 MV) and electron (22 MeV) radiation in a water-phantom was compared with the frequency of apoptotic and micronucleated cells of two human cell lines (BEAS-2B normal bronchial epithelial cells and A549 lung cancer epithelial cells). Formation of micronuclei and apoptotic-like bodies was evaluated by the cytokinesis-block micronucleus test. Measurements were performed for five different phantom depths (3-20 cm). Irradiated cells were placed in a water-phantom in three variants: directly on the axis in the beam, under shielding (only in photon radiation) and outside the beam field. The results reveal a discrepancy between the distribution of physical dose at different depths of the water-phantom and biological effects. This discrepancy is of special significance in case of cells irradiated at a greater depth or placed outside the field and under shield during the exposure to radiation. The frequency of cytogenetic damage was higher than the expected value based on the physical dose received at different depths. Cells placed outside the beam axis were exposed to scattered radiation at very low doses, so we tested if bystander effects could have had a role in the observed discrepancy between physical radiation dose and biological response. We explored this question by use of a medium-transfer technique in which medium (ICM-irradiation conditioned medium) from irradiated cells was transferred to non-irradiated (bystander) cells. The results indicate that when cells were incubated in ICM transferred from cells irradiated at bigger depths or from cells exposed outside the radiation field, the number of apoptotic and micronucleated cells was similar to that after direct irradiation. This suggests that these damages are caused by factors released by irradiated cells into the medium rather than being induced directly in DNA by X-rays. Evaluation of biological effects of scattered radiation appears useful for clinical practice. PMID- 21237285 TI - Is there a relationship between early genotoxicity and life-history traits in Vicia faba exposed to cadmium-spiked soils? AB - The Vicia faba-micronucleus test is usually performed to assess the genotoxic potential of pure substances, effluents or water extracts from soil. It is also a relevant, early biological tool to detect mutagenic substances in crude soils. Nevertheless, the physiological meaning of such DNA damage for the plant in the long term remains to be elucidated. To know more about this, two experiments were carried out with the plant model V. faba. In a preliminary short-term experiment, seeds were exposed for five days to a soil spiked with different concentrations of CdCl(2) in order to identify the concentration inducing the highest number of micronuclei without affecting plant growth. Thereafter, a long-term experiment was performed in the soil spiked with such a concentration (i.e. 510MUmol CdCl(2) per kg dry soil), in which V. faba seeds were directly sowed and allowed to grow during 151 days. As a result, Cd-spiked soil did not affect seed-emergence time nor the growth-rate of the plants for the first two months. The first signs of toxicity appeared after the 70th day of exposure. Interestingly, exposed plants produced their first flower earlier and had a longer flowering period than did control ones. Nevertheless, total flower production was less abundant in exposed plants than in control plants. Moreover, fruits appeared in control plants whereas no fruit was formed in exposed plants. At last, exposed plants showed a reduced life time. Our results suggest that the micronucleus assay can provide a predictive biomarker of long-term deleterious effects in plants. PMID- 21237286 TI - Recovery of bulky DNA adducts by the regular and a modified 32P-postlabelling assay; influence of the DNA-isolation method. AB - Bulky DNA adducts are widely used as biomarkers of human exposure to complex mixtures of environmental genotoxicants including polycyclic aromatic hydrocarbons. The 32P-postlabelling method is highly sensitive for the detection of bulky DNA adducts, but its relatively low throughput poses limits to its use in large-scale molecular epidemiological studies. The objectives of this study were to compare the impact of DNA-sample preparation with a commercial DNA isolation kit or with the classical phenol-extraction procedure on the measurement of bulky DNA adducts by 32P-postlabelling, and to increase the throughput of the 32P-postlabelling method--whilst maintaining radio-safety--by reducing the radioisotope requirement per sample. The test DNA samples were prepared from MCF-7 cells treated with benzo[a]pyrene and from human peripheral blood lymphocytes, buffy coat, and peripheral lung tissue. The modified 32P postlabelling procedure involved an evaporation-to-dryness step after the enzymatic digestions of the DNA, and radio-labelling with a reduced amount of [gamma-32P]ATP substrate in a reduced reaction volume compared with the regular method. Higher levels of DNA adducts were measured in the MCF-7 cells and in the lung-tissue samples after isolation with the kit than after solvent extraction. A seven-fold higher level of adducts was detected in the buffy-coat DNA samples isolated with the kit than with the phenol extraction procedure (p<0.001). Reduction of the amount of [gamma-32P]ATP from 50 MUCi to 25 MUCi (>6000 Ci/mmol specific radioactivity) per sample in the modified 32P-postlabelling procedure was generally applicable without loss of adduct recovery for all test samples prepared with both DNA isolation methods. The difference between the bulky DNA adduct levels resulting from the two DNA-isolation procedures requires further systematic investigation. The modified 32P-postlabelling procedure allows a 50% reduction of radioisotope requirement per sample, which facilitates increased throughput of the assay whilst maintaining radio-safety. PMID- 21237287 TI - Plasmodial ortholog of Toxoplasma gondii rhoptry neck protein 3 is localized to the rhoptry body. AB - The proteins in apical organelles of Plasmodium falciparum merozoite play an important role in invasion into erythrocytes. Several rhoptry neck (RON) proteins have been identified in rhoptry proteome of the closely-related apicomplexan parasite, Toxoplasma gondii. Recently, three of P. falciparum proteins orthologous to TgRON proteins, PfRON2, 4 and 5, were found to be located in the rhoptry neck and interact with the micronemal protein apical membrane antigen 1 (PfAMA1) to form a moving junction complex that helps the invasion of merozoite into erythrocyte. However, the other P. falciparum RON proteins have yet to be characterized. Here, we determined that "PFL2505c" (hereafter referred to as pfron3) is the ortholog of the tgron3 in P. falciparum and characterized its protein expression profile, subcellular localization, and complex formation. Protein expression analysis revealed that PfRON3 was expressed primarily in late schizont stage parasites. Immunofluorescence microscopy (IFA) showed that PfRON3 localizes in the apical region of P. falciparum merozoites. Results from immunoelectron microscopy, along with IFA, clarified that PfRON3 localizes in the rhoptry body and not in the rhoptry neck. Even after erythrocyte invasion, PfRON3 was still detectable at the parasite ring stage in the parasitophorous vacuole. Moreover, co-immunoprecipitation studies indicated that PfRON3 interacts with PfRON2 and PfRON4, but not with PfAMA1. These results suggest that PfRON3 partakes in the novel PfRON complex formation (PfRON2, 3, and 4), but not in the moving junction complex (PfRON2, 4, 5, and PfAMA1). The novel PfRON complex, as well as the moving junction complex, might play a fundamental role in erythrocyte invasion by merozoite stage parasites. PMID- 21237288 TI - Inhibition of the isoprenoid biosynthesis pathway; detection of intermediates by UPLC-MS/MS. AB - The isoprenoid biosynthesis pathway provides the cell with a variety of compounds which are involved in multiple cellular processes. Inhibition of this pathway with statins and bisphosphonates is widely applied in the treatment of hypercholesterolemia and metabolic bone disease, respectively. In addition, since isoprenylation of proteins is an important therapeutic target in cancer research there is interest in interfering with isoprenoid biosynthesis, for which new inhibitors to block farnesylation and geranylgeranylation of small GTPases are being developed. We recently developed a sensitive method using UPLC-MS/MS that allows the direct detection and quantification of all intermediates of the mevalonate pathway from MVA to GGPP which can be used to verify the specificity of inhibitors of the isoprenoid biosynthesis pathway. We here investigated the specificity of several inhibitors of the isoprenoid biosynthesis pathway in HepG2 cells, fibroblasts and lymphoblasts. The nitrogen-containing bisphosphonates pamidronate and zoledronate specifically inhibit farnesyl pyrophosphate synthase indicated by the accumulation of IPP/DMAPP. However, zaragozic acid A, a squalene synthase inhibitor, causes an increase of MVA in addition to the expected increase of FPP. Analysis of isoprenoid intermediate profiles after incubation with 6-fluoromevalonate showed a very nonspecific result with an increase in MVA, MVAP, MVAPP and IPP/DMAPP. These results show that inhibitors of a particular enzyme of the isoprenoid biosynthesis pathway can have additional effects on other enzymes of the pathway either direct or indirect through accumulation of isoprenoid intermediates. Our method can be used to test new inhibitors and their effect on overall isoprenoid biosynthesis. PMID- 21237289 TI - Mechanism of attenuation of diabetes mellitus and hypercholesterolemia induced vascular endothelial dysfunction by protein tyrosine phosphatase inhibition. AB - The study has been designed to investigate downstream mechanisms in the PTPase inhibition mediated attenuation of diabetes mellitus and hypercholesterolemia induced vascular endothelial dysfunction. Diabetes mellitus was induced in rats using streptozotocin (55 mg/kg, i.v. once), while hypercholesterolemia was produced by feeding high cholesterol diet. After 4 weeks of streptozotocin and Cholesterol rich diet administration, vascular endothelium dysfunction was assessed, in terms of attenuation of acetylcholine-induced, endothelium-dependent relaxation (Isolated Aortic Ring Preparation), a decrease in serum nitrate/nitrite level, as well as mRNA expression of eNOS (rtPCR) and disruption of integrity of vascular endothelium (Electron microscopy). After 14 days of daily administration, sodium orthovanadate (8 mg/kg, p.o., 16 mg/kg, p.o and 24 mg/kg, p.o) and atorvastatin (30 mg/kg, p.o) (positive control) significantly improved acetylcholine-induced endothelium-dependent relaxation, serum nitrate/nitrite level, mRNA expression of eNOS and maintained integrity of vascular endothelium. However, this ameliorative effect of SOV was significantly blocked by UCN-01, (PDK inhibitor) and L-NAME (Inhibitor of eNOS). Therefore, it may be concluded that sodium orthovanadate, a specific inhibitor of PTPase, may stimulate PDK and eNOS and consequently improve vascular endothelium dysfunction. Thus, inhibition of PTPase might be a useful approach in the therapeutics of vascular endothelium dysfunction. PMID- 21237290 TI - Inside-out access: a new method of lead placement for patients with central venous occlusions. AB - BACKGROUND: Physicians will increasingly encounter patients who require rhythm management devices but have venous obstructions that prevent conventional access. Alternate access options, such as thoracotomy or transiliac approaches, exist but are associated with greater cost and morbidity. OBJECTIVE: The purpose of this study is to describe a novel method of vascular access that allows prepectoral placement of conventional pacing and defibrillation leads in patients with complex central venous occlusions. METHODS: Eight patients with central venous occlusions were referred for device implantation. Inside-out central venous access (IOCVA) was obtained via a percutaneous femoral approach. A catheter dilator system was advanced via the right atrium to the most central point of venous occlusion. The occluded vein segment was punctured with a directionally guided needle, which was advanced along intravascular or extravascular tissue planes to the subclavian region. A solid wire needle was oriented toward the skin surface and advanced through the soft tissues until it exists from the body. The wire was used to pull rigid dilators through the occluded segment. Standard transvenous leads were implanted though the newly created channel. RESULTS: All patients with total central venous occlusions (4 superior vena cava, 4 brachiocephalic and bilateral subclavian) had successful, prepectoral device implants (4 left-sided, 1 single-chamber, 4 dual-chamber, 3 biventricular). No procedure-related complications occurred. All patients had normal device function at follow-up of 485 +/- 542 days. CONCLUSION: IOCVA is an effective method of pacemaker and defibrillator implantation for patients with central venous occlusions. Further clinical evaluation of this novel method is needed. PMID- 21237291 TI - Determination of drug susceptibility patterns and genotypes of Mycobacterium tuberculosis isolates from Kanpur district, North India. AB - BACKGROUND AND OBJECTIVES: Molecular typing of Mycobacterium tuberculosis isolates has greatly facilitated the understanding of tuberculosis epidemiology. This study was done to characterize prevalent M. tuberculosis genotypes in a defined area of Kanpur district, North India by spoligotyping and IS6110 Restriction Fragment Length Polymorphism (RFLP) and to correlate the genotypes identified with their drug susceptibility patterns. METHODS: Ninety-eight patients had clinical features suggestive of pulmonary tuberculosis (PTB) and out of them, 22 were new smear positive PTB (CAT I DOTS), 48 smear positive re treatment, defaulters and CAT I failure PTB (CAT II DOTS) and 28 new smear negative PTB (CAT III). Out of them, sputum culture was positive for M. tuberculosis in 74 cases. DNA was extracted from growth on Lowenstein-Jensen slants and subjected to spoligotyping. Clusters were subsequently analyzed with IS6110 RFLP. Drug susceptibility testing was done for rifampicin, isoniazid, ethambutol, ofloxacin, streptomycin and kanamycin. RESULTS: Thirty-seven spoligo patterns were observed. Predominant spoligotypes belonged to Central Asian Delhi family (33.78%), Beijing family (10.8%), East African-Indian family (5.4%), T1 family (5.4%) and U family (4.1%). RFLP analysis revealed 66% isolates had more than 10 IS6110 copies while 17% isolates each had low (1-5) and intermediate (6 9) copy numbers. All the isolates clustered by spoligotyping were identified unique by RFLP. Resistance to at least one drug was present in 35 (47.3%), out of which 8 patients belonged to CAT I and 27 to CAT II. Eleven (14.86%) were multi drug-resistant (MDR) and out of them, 6 (54.5%) isolates were of ST1/Beijing family. MDR-TB was significantly higher in Beijing strain than others (p<0.0001), however, most (83%) were from previously treated cases and thus can not be linked with recent transmission. CONCLUSION: This approach of molecular typing appears promising and merits further evaluation to study dynamics of TB transmission specially in India. PMID- 21237292 TI - Interactions of leukocytes and platelets with poly(lysine/leucine) immobilized on tetraethylene glycol-terminated self-assembled monolayers. AB - Surfaces that bind heparin are important for biomaterials for blood deheparinization. In our recent work it was demonstrated that a polypeptide composed of L-lysine and L-leucine (pKL), after immobilization onto tetra(ethylene glycol) terminated self-assembled monolayers (EG4-SAMs), can bind heparin from blood plasma in a selective, concentration-dependent way. During this work the effect of this peptide on platelet adhesion and activation and leukocyte adhesion was studied. The surface charge of these nanostructured surfaces was evaluated in order to correlate the effect of positively charged amine groups and hydrophobic methyl groups on the behavior of platelets and leukocyte adhesion. The results demonstrated that the presence of pKL decreased leukocyte adhesion to EG4-SAMs at all concentrations used. This effect is even more pronounced when surfaces were pre-immersed in heparinized plasma. In contrast, there is an increase in platelet adhesion and activation with increased percentage immobilized pKL. This effect is enhanced when surfaces were pre immersed in heparinized plasma. However, adsorbed pKL in very low amounts does not induce platelet adhesion and activation compared with EG4, even when pre immersed in plasma. Since only low pKL amounts are necessary to induce heparin selectivity, these results are promising for the development of heparin-binding biomaterials for blood deheparinization. PMID- 21237293 TI - Early dysregulation of the mitochondrial proteome in a mouse model of Alzheimer's disease. AB - Mitochondrial structural and functional alterations appear to play to an important role in the pathogenesis of Alzheimer's disease (AD). In the present study, we used a quantitative comparative proteomic profiling approach to analyze changes in the mitochondrial proteome in AD. A triple transgenic mouse model of AD (3xTg-AD) which harbors mutations in three human transgenes, APP(Swe), PS1(M146V) and Tau(P301L), was used in these experiments. Quantitative differences in the mitochondrial proteome between the cerebral cortices of 6 month-old male 3xTg-AD and non-transgenic mice were determined by using two dimensional difference gel electrophoresis (2D-DIGE) and tandem mass spectrometry. We identified 23 different proteins whose expression levels differed significantly between triple transgenic and non-transgenic mitochondria. Both down-regulated and up-regulated mitochondrial proteins were observed in transgenic AD cortices. Proteins which were dysregulated in 3xTg-AD cortices functioned in a wide variety of metabolic pathways, including the citric acid cycle, oxidative phosphorylation, pyruvate metabolism, glycolysis, oxidative stress, fatty acid oxidation, ketone body metabolism, ion transport, apoptosis, and mitochondrial protein synthesis. These alterations in the mitochondrial proteome of the cerebral cortices of triple transgenic AD mice occurred before the development of significant amyloid plaque and neurofibrillary tangles, indicating that mitochondrial dysregulation is an early event in AD. PMID- 21237294 TI - Small peptides released from muscle glycolytic enzymes during dry-cured ham processing. AB - Glycolytic enzymes are a group of sarcoplasmic enzymes responsible for the extraction of the energy available from carbohydrates. The glycolytic pathway consists of 10 enzyme-catalyzed steps. Fragments identified in this study, within the range 1100-2600 Da, correspond to glycogen phosphorylase enzyme, which catalyzes the rate limiting step in the degradation of glycogen, enzymes that catalyze steps 6-10 of glycolysis (glyceraldehyde 3-phosphate dehydrogenase, phosphoglycerate kinase, phosphoglycerate mutase, enolase, and pyruvate kinase, respectively), and lactate dehydrogenase, which catalyzes the interconversion of pyruvate and lactate. A total of 45 specific fragments of these enzymes resulting from the processing of dry-cured ham are reported for the first time in this work. This study evidences the intense proteolysis occurring in the sarcoplasmic fraction of dry-cured ham as well as facilitates the choice of the most adequate tools in the identification of naturally generated peptides through comparison between Paragon and Mascot search engines, together with UniProt and NCBInr databases. PMID- 21237295 TI - Proteome analysis of the left ventricle in the vitamin D3 and nicotine-induced rat vascular calcification model. AB - Vitamin D3 and nicotine (VDN) serve as an animal model of arterial calcification. The vascular calcification induced by the VDN model is always accompanied by compensatory left ventricular (LV) hypertrophy and impaired cardiac performance. To determine the possible mechanisms that are responsible for the effects of VDN on the LV, a 2-DE based proteomics approach was used to evaluate the changes in protein expression of the left ventricle in VDN rats, to our knowledge, for the first time. We identified sixteen proteins that were markedly altered and involved in mitochondrial function, heat shock protein activity, myocyte cytoskeleton composition and enzyme activity for energy metabolism. We describe, for the first time, a novel pathway (NDPK) that is involved in LV hypertrophy and enzyme activities of three of the sixteen clinical identified proteins: lactate dehydrogenase (LDH), SOD [Mn] and GST. PMID- 21237296 TI - 2D-DIGE analysis of phospho-enriched fractions from dasatinib-treated melanoma cell lines. AB - Current therapeutic regimes for metastatic melanoma have failed to provide robust clinical responses. Dasatinib has shown anti-proliferative and anti-invasive effects in vitro; however, not all melanoma cells tested were sensitive to dasatinib. We used 2D-DIGE analysis of phospho-enriched fractions to identify phosphoproteins involved in regulating response to dasatinib in an isogenic pair of melanoma cell lines, one sensitive to dasatinib (WM-115) and the other resistant (WM-266-4). In WM-115 cells treated with dasatinib, 18 unique protein species with altered phosphorylation levels were detected. Dasatinib treatment of WM-266-4 cells resulted in phosphoprotein alterations to four unique protein species. Four phosphorylated forms of Annexin-A2 (ANXA2) were increased in WM-115 cells treated with dasatinib, whilst dasatinib treatment did not alter ANXA2 phosphoprotein levels in WM-266-4 cells. Immunoblotting confirmed that phosphorylation of ANXA2, on tyrosine residues, was increased in WM-115 cells treated with dasatinib. Subsequent knockdown of ANXA2 by siRNA significantly inhibited proliferation of WM-115 cells but did not significantly reduce proliferation of WM-266-4 cells. Therefore, ANXA2 plays a role in regulating proliferation in dasatinib-sensitive WM-115 cells and could potentially play a role in sensitivity to dasatinib in melanoma cells. PMID- 21237297 TI - Profiling signatures of ovarian cancer tumour suppression using 2D-DIGE and 2D-LC MS/MS with tandem mass tagging. AB - Epithelial ovarian cancer (EOC) is the most common form of gynaecological malignancy in the developed world and has a poor prognosis due to its late detection. Identifying molecular markers of the disease may provide novel approaches to screening and could enable targeted treatment and the design of novel therapies. Although blood is recognized as a highly important source of disease-related biomarkers, the complexity and dynamic range of protein abundance in body fluids has hampered proteomic biomarker discovery and alternative approaches using cell models may be more successful. Herein, we have utilized two cellular models of EOC, where transfer of normal chromosome 18 material into the EOC cell lines TOV-112D and TOV-21G induced in vitro and in vivo suppression of their tumourigenic phenotype. A combination of quantitative two-dimensional difference gel electrophoresis (2D-DIGE) and two-dimensional-liquid chromatography tandem mass spectrometry (2D-LC-MS/MS) with tandem mass tagging (TMT) was employed to examine the whole cell, secreted and crude membrane proteomes of the parental and hybrid cell models to identify differentially expressed proteins as potential markers of tumour suppression. Protein changes of interest were confirmed by immunoblotting in additional hybrid and revertant cell lines where incorporated chromosome 18 material was lost. One candidate marker was also tested in sera from a set of ovarian cancer cases and controls. We have identified a list of promising candidate biomarkers for further testing and functional characterization. PMID- 21237298 TI - The endovanilloid/endocannabinoid system: a new potential target for osteoporosis therapy. AB - Human osteoclasts express functional TRPV1 channels, CB1/CB2 cannabinoid receptors and endocannabinoid/endovanilloid synthetic/catabolic enzymes. Pharmacologic manipulation of this system can modulate osteoclast activity. Here, through multidisciplinary approaches, we demonstrate that enzymes and receptors of the endocannabinoid/endovanilloid system are differently expressed in osteoclasts from menopausal women without or with osteoporosis. We report that in osteoclasts from osteoporotic patients, TRPV1 channels are upregulated and, if persistently stimulated with resiniferatoxin, become clustered to the plasma membrane while inducing a massive over-expression of CB2 receptors. By providing new evidence for a critical functional cross-talk between CB2 and TRPV1 receptors in osteoporosis, we speculate that TRPV1 desensitization, or its enhanced trafficking, together with TRPV1 agonist-induced CB2 receptor overexpression, might be critical to minimize calcium entry in osteoclasts, which could be in turn responsible of cell over-activation and higher bone resorption. Our data pave the way to the use of TRPV1 agonist together with CB2 agonists or CB1 antagonists in osteoporosis. PMID- 21237300 TI - Allyl isothiocyanate regulates caspase-1/receptor interacting protein-2 expression. AB - Isothiocyanates can inhibit nuclear factor-kappaB (NF-kappaB) activation. Interleukin (IL)-1beta activates the NF-kappaB, which in turn activates proteins involved in inflammation. IL-1beta is directly associated with caspase-1 activation. We tested the anti-inflammatory effect of allyl isothiocyanate (AITC) in mast cells. AITC suppressed the intracellular calcium level in the phorbol myristate acetate (PMA) plus calcium ionophore A23187-stimulated human mast cell line. AITC decreased PMA plus A23187-induced cystein-aspartic acid protease (caspase)-1 activity. Particularly, AITC decreased PMA plus A23187-induced caspase-1/receptor interacting protein-2 expression as well as the mRNA expression and production of IL-1beta. An in-depth research of the cellular targets of the AITC is warranted. PMID- 21237299 TI - Myeloid derived suppressor cells in human diseases. AB - Myeloid derived suppressor cells (MDSC) have been described as a heterogeneous cell population with potent immune suppressor function in mice. Limited data are available on MDSC in human diseases. Interpretation of these data is complicated by the fact that different markers have been used to analyze human MDSC subtypes in various clinical settings. Human MDSC are CD11b+, CD33+, HLA-DR(neg/low) and can be divided into granulocytic CD14- and monocytic CD14+ subtypes. Interleukin 4Ralpha, VEGFR, CD15 and CD66b have been suggested to be more specific markers for human MDSC, however these markers can only be found on some MDSC subsets. Until today the best marker for human MDSC remains their suppressor function, which can be either direct or indirect through the induction of regulatory T cells. Immune suppressor activity has been associated with high arginase 1 and iNOS activity as well as ROS production by MDSC. Not only in murine models, but even more importantly in patients with cancer, different drugs have been shown to either reverse the immune suppressor function of MDSC or directly target these cells. Systemic treatment with all-trans-retinoic acid has been shown to mature human MDSC and reverse their immune suppressor function. Alternatively, MDSC can be targeted by treatment with the multi-targeted receptor tyrosine kinase inhibitor sunitinib. This review will provide a comprehensive summary of the recent literature on human MDSC. PMID- 21237301 TI - Alteration of immune functions and Th1/Th2 cytokine balance in nicotine-induced murine macrophages: immunomodulatory role of eugenol and N-acetylcysteine. AB - The aim of this study was to evaluate the immune functions by nicotine-induced murine peritoneal macrophages, and Th1/Th2 cytokine balance in it, and concurrently to establish the immunomodulatory role of eugenol, and N acetylcysteine in nicotine-induced macrophages. Eugenol was isolated from Ocimum gratissimum, and characterized by HPLC, FTIR, and (1)H NMR. The cytotoxic effect of isolated eugenol was studied in murine peritoneal macrophages at various concentrations (0.1-50 MUg/ml) using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide. To evaluate the immunomodulatory role of eugenol and N-acetylcysteine, ROS and nitrite generations, phenotype functions by macrophages were studied. The effect of eugenol and N-acetylcysteine on the release of Th1 cytokines (TNF-alpha, IL-12) and Th2 cytokines (IL-10, TGF-beta) was measured by ELISA, and the expression of these cytokines at mRNA level were analyzed by real time PCR. Eugenol, at a dose of 15 MUg/ml, showed less cytotoxicity to the macrophages and it significantly reduced the nicotine-induced ROS, NO generation, and iNOSII expression. Similar kinds of response were observed in the presence of N-acetylcysteine (1 MUg/ml). We have found the decreased adherence, chemotaxis, phagocytosis and intracellular killing of bacteria in nicotine treated macrophages, whereas eugenol and N-acetylcysteine with nicotine treatment enhanced these cellular functions by macrophages significantly (p < 0.05). Eugenol and N-acetylcysteine were found to down regulate the Th1 cytokines in nicotine treated macrophages with concurrent activation of Th2 responses. These findings strongly enhanced our understanding of the molecular mechanism leading to nicotine-induced suppression of immune functions, and provide additional rationale for the application of anti-inflammatory therapeutic approaches by eugenol, and N-acetylcysteine for different inflammatory diseases prevention and treatment during nicotine toxicity. PMID- 21237302 TI - Tormentic acid, a triterpenoid saponin, isolated from Rosa rugosa, inhibited LPS induced iNOS, COX-2, and TNF-alpha expression through inactivation of the nuclear factor-kappab pathway in RAW 264.7 macrophages. AB - We previously reported that extract of Rosa rugosa root and its active triterpenoids constituents exhibit anti-nociceptive and anti-inflammatory effects in animal models. However, little is known about the effects and the molecular mechanism of the 19alpha-hydroxyursane-type triterpenoids. Among the tested 19alpha-hydroxyursane-type triterpenoids (kaji-ichigoside F(1), rosamultin, euscaphic acid, tormentic acid (TA)), TA was found to most potently inhibit the production of nitric oxide (NO) in RAW 264.7 cells. We investigated the anti inflammatory effects and its underlying molecular mechanisms of TA in lipopolysaccaride (LPS)-stimulated RAW 264.7 cells. TA dose-dependently reduced the productions of NO, prostaglandin E(2) (PGE(2)), and tumor necrosis factor alpha (TNF-alpha) induced by LPS. In addition, TA significantly suppressed the LPS-induced expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), and TNF-alpha at the mRNA and protein levels. Moreover, treatment with TA decreased LPS-induced DNA binding of nuclear factor-kappa B (NF-kappaB) and nuclear translocation of p65 and p50 subunits of NF-kappaB. Consistent with these findings, TA also suppressed the LPS-stimulated degradation and phosphorylation of inhibitor of kappa B-alpha (IkappaB-alpha). Taken together, these results suggest that the anti-inflammatory activity of TA is associated with the down regulation of iNOS, COX-2, and TNF-alpha through the negative regulation of the NF-kappaB pathway in RAW 264.7 cells. PMID- 21237303 TI - A single pump column-switching technique coupled with polystyrene-divinylbenzene carbon nanotubes column for the determination of trace anions in different concentrated organic matrices by ion chromatography. AB - An ion chromatographic method with on-line sample pretreatment was developed for the trace analysis of seven common anions in concentrated matrices. The pretreatment column used in this study consisted of polystyrene-divinylbenzene (PS-DVB) and multi-walled carbon nanotubes (MWCNTs). It was too hydrophobic to retain different inorganic anions, but it showed a strong affinity for organic compounds. Thus, this chromatographic system could be used to detect trace anions in organic solvents, organic acids and relevant salts. The addition of MWCNTs decreased the surface areas of stationary phases and the retention times of organic matrices were shortened. Compared with conventional column-switching technique, only a single instrument (ICS2100) was needed in this system, including a pump, a conductivity detector, an eluent generator, a six-port valve and a ten-port valve. An electrochemical self-generating suppressor (ESGS) was adopted to convert the eluent of KOH into water for the matrix elimination. Two different eluent were employed in the chromatographic system, one for separation and the other for matrix elimination. The sample pretreatment and analysis were realized simultaneously. After optimization of this system, a calibration study was conducted by preparing and analyzing eight concentrations (between 5 and 5000 MUg L(-1)) of mixture standards of seven anions in deionized water. The linearity was between 0.9990 and 0.9998, and the detection limits ranged from 0.41 to 3.17 MUg L(-1). A spiking study was performed on three representative organic chemicals with satisfactory recoveries between 88.1% and 118.5% when the concentrations of the matrices did not exceed 10 g L(-1). PMID- 21237305 TI - A review on the interrogation of peptide-metal interactions using electrospray ionization-mass spectrometry. AB - Over the years, protein interactions have been studied by many techniques to obtain a wide breadth of information. The large size and complexity of the macromolecules have caused difficulties for studying them by some techniques. In some cases, peptides, smaller and less complex biomolecules, have been found to be suitable models to mimic the interactions of entire proteins. The study of peptide-metal interaction, in particular, has proven to be fruitful to researchers across the science fields. One technique in particular, electrospray ionization-mass spectrometry (ESI-MS), has been shown to provide a great deal of information to these studies. The speed, sensitivity, and selectivity of MS, along with the information that can be interpreted from MS-based experiments, has driven this technique to the forefront for understanding the nature of peptide metal complexes. MS has allowed researchers to identify the stoichiometry of peptide-metal complexes or even mixtures of complexes. The specific amino acids in which the metal cations are bound and the degree of association in these complexes can also be determined by MS experiments. The following review discusses the ESI process and how it is ideal for studying noncovalent interactions between peptides and metals. An investigation of the qualitative and quantitative information that has been determined by ESI-MS follows for readers to realize the versatility of this technique and the diversity of information that can be obtained by a variety of related methods. PMID- 21237304 TI - Methods for measuring aptamer-protein equilibria: a review. AB - Aptamers are single stranded DNA or RNA molecules that have been selected using in vitro techniques to bind target molecules with high affinity and selectivity, rivaling antibodies in many ways. In order to use aptamers in research and clinical applications, a thorough understanding of aptamer-target binding is necessary. In this article, we review methods for assessing aptamer-protein binding using separation based techniques such as dialysis, ultrafiltration, gel and capillary electrophoresis, and HPLC; as well as mixture based techniques such as fluorescence intensity and anisotropy, UV-vis absorption and circular dichroism, surface plasmon resonance, and isothermal titration calorimetry. For each method the principle, range of application and important features, such as sample consumption, experimental time and complexity, are summarized and compared. PMID- 21237306 TI - Trace elemental analysis of airborne particulate matter using dynamic reaction cell inductively coupled plasma-mass spectrometry: application to monitoring episodic industrial emission events. AB - The elemental composition of airborne particles is being increasingly monitored since several metals have been implicated in adverse human health outcomes and environmental deterioration while simultaneously providing clues to the identity and strength of their emission sources. However, quantification of several elements and transition metals in ambient aerosols, which are typically present only at trace levels, is fraught with interferences using quadrupole inductively coupled plasma-mass spectrometry (q-ICP-MS). We report improved measurements of key aerosol elements including Al, V, Cr, Fe, Ni, Cu, and Zn in airborne coarse particulate matter (PM(10)) by exploiting ion-molecule reactions in a dynamic reaction cell (DRC) with NH(3) as the cell gas. Numerous other elements (Na, Mg, Si, K, Ca, Sc, Ti, Mn, Co, Ga, As, Se, Rb, Sr, Zr, Mo, Cd, Sn, Sb, Cs, Ba, Pb, Th, and U) and lanthanoids (Y, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu), which are important trace components used for source apportionment studies, were also measured. Inter-laboratory comparison using sector field ICP MS demonstrated the accuracy and precision of DRC-q-ICP-MS. This technique was used to determine the elemental composition of over 150 PM(10) samples collected from an industrialized region in Houston, TX. Samples were first digested using a combination of HF, HNO(3), and H(3)BO(3) in two stages in a microwave oven each with set points of 200 degrees C, 1.55 MPa (225 psig), and 20 min dwell time. Trace metals were used to identify an episodic release of particles from a local source and subsequently track the atmospheric transport of the released particles. This establishes the inherent value of such measurements to developing air quality management strategies since emission events can significantly worsen air quality over a large area. Based on our findings, we recommend continuous independent monitoring of emissions to augment existing industry self-reporting regulatory requirements. Such environmental measurements will assist in establishing industrial regulatory compliance while simultaneously providing data necessary to develop scientifically defensible air quality management strategies. PMID- 21237307 TI - Radiostrontium separation and measurement in a single step using plastic scintillators plus selective extractants. Application to aqueous sample analysis. AB - This study describes a new protocol for (90)Sr determination in water samples based on the use of a selective extractant (DtBuCH18C6) and plastic scintillator microspheres. The proposed procedure unifies chemical separation and sample measurement preparation in a single step to reduce the effort, time and reagents required for analysis. In addition, the final measurement does not produce mixed waste. The minimum activity detectable for 10 mL of sample solution is 0.46 Bq L( 1). Relative errors for the determination of (90)Sr activity in drinking, sea and river waters are less than 4%. PMID- 21237308 TI - Principal component directed partial least squares analysis for combining nuclear magnetic resonance and mass spectrometry data in metabolomics: application to the detection of breast cancer. AB - Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) are the two most commonly used analytical tools in metabolomics, and their complementary nature makes the combination particularly attractive. A combined analytical approach can improve the potential for providing reliable methods to detect metabolic profile alterations in biofluids or tissues caused by disease, toxicity, etc. In this paper, (1)H NMR spectroscopy and direct analysis in real time (DART)-MS were used for the metabolomics analysis of serum samples from breast cancer patients and healthy controls. Principal component analysis (PCA) of the NMR data showed that the first principal component (PC1) scores could be used to separate cancer from normal samples. However, no such obvious clustering could be observed in the PCA score plot of DART-MS data, even though DART-MS can provide a rich and informative metabolic profile. Using a modified multivariate statistical approach, the DART-MS data were then reevaluated by orthogonal signal correction (OSC) pretreated partial least squares (PLS), in which the Y matrix in the regression was set to the PC1 score values from the NMR data analysis. This approach, and a similar one using the first latent variable from PLS-DA of the NMR data resulted in a significant improvement of the separation between the disease samples and normals, and a metabolic profile related to breast cancer could be extracted from DART-MS. The new approach allows the disease classification to be expressed on a continuum as opposed to a binary scale and thus better represents the disease and healthy classifications. An improved metabolic profile obtained by combining MS and NMR by this approach may be useful to achieve more accurate disease detection and gain more insight regarding disease mechanisms and biology. PMID- 21237309 TI - Tracking diffusion of conditioning water in single wheat kernels of different hardnesses by near infrared hyperspectral imaging. AB - The combination of near infrared (NIR) hyperspectral imaging and chemometrics was used to follow the diffusion of conditioning water over time in wheat kernels of different hardnesses. Conditioning was attempted with deionised water (dH(2)O) and deuterium oxide (D(2)O). The images were recorded at different conditioning times (0-36 h) from 1000 to 2498 nm with a line scan imaging system. After multivariate cleaning and spectral pre-processing (either multiplicative scatter correction or standard normal variate and Savitzky-Golay smoothing) six principal components (PCs) were calculated. These were studied visually interactively as score images and score plots. As no clear clusters were present in the score plots, changes in the score plots were investigated by means of classification gradients made within the respective PCs. Classes were selected in the direction of a PC (from positive to negative or negative to positive score values) in almost equal segments. Subsequently loading line plots were used to provide a spectroscopic explanation of the classification gradients. It was shown that the first PC explained kernel curvature. PC3 was shown to be related to a moisture starch contrast and could explain the progress of water uptake. The positive influence of protein was also observed. The behaviour of soft, hard and very hard kernels was different in this respect, with the uptake of water observed much earlier in the soft kernels than in the harder ones. The harder kernels also showed a stronger influence of protein in the loading line plots. Difference spectra showed interpretable changes over time for water but not for D(2)O which had a too low signal in the wavelength range used. NIR hyperspectral imaging together with exploratory chemometrics, as detailed in this paper, may have wider applications than merely conditioning studies. PMID- 21237310 TI - Development of polymer-membrane based electrodes for suramin. AB - The development of a polymer membrane-based electrode to measure the anionic drug suramin in buffered saline and biological samples is described. A large non equilibrium, steady state EMF response is observed toward suramin, and judicious choice of the polymer membrane components allows for adjustment of the dynamic range of the electrode. The optimized membrane for use in the toxic suramin range consists of 25 wt% tridodecylmethyl ammonium chloride, 55 wt% bis-2-ethylhexyl sebacate, and 20 wt% Pellethane. Although this electrode can be used to directly quantify suramin in human plasma, determination of suramin that is not affected by the background concentration of small anions is best achieved by simple potentiometric titrations with polycationic protamine monitored with a protamine sensitive electrode. PMID- 21237311 TI - Magnetic loading of tyrosinase-Fe3O4/mesoporous silica core/shell microspheres for high sensitive electrochemical biosensing. AB - A new protocol is proposed for magnetic loading and sensitive electrochemical detection of phenol via the tyrosinase cross-linked mesoporous magnetic core/shell microspheres. The mesoporous magnetic microspheres, characterized by transmission electron microscopy, N(2) adsorption/desorption isotherms, and magnetic curve displays high capacity for enzyme immobilization and strong magnetism to adhere to the magnetic electrode surface without any additional adhesive reagent. The biosensor exhibits a wide linear response to phenol ranging from 1.0*10(-9) to 1.0*10(-5) M, a high sensitivity of 78 MUA mM(-1), a low detection limit of 1 nM, and a fast response rate (less than 5s). The proposed method is simple, rapid, inexpensive and convenient in electrode renewal, which is recommended as a promising experimental platform for wider applications in biosensing. PMID- 21237312 TI - Application of ionic-liquid supported cloud point extraction for the determination of microcystin-leucine-arginine in natural waters. AB - A cloud point extraction method has been developed using an ionic liquid (1-butyl 3-methylimidazolium hexafluorophosphate, BMiM PF(6)) for the determination of a widely studied cyanotoxin (microcystin leucine-arginine, MCLR) in natural waters. Extraction parameters such as sample pH, extraction temperature, extraction time, the amount of ionic liquid and the amount of extraction volume were investigated and optimized to achieve the maximum extraction efficiency. The results obtained indicated a good linearity with the correlation coefficient of 0.995 over the range of 0.5-50 MUg L(-1). The relative standard deviation (RSD) of the method was 7.5% (n=6). The calculated method detection limit was 0.03 MUg L(-1) (n=6). The practical applicability of the technique was demonstrated by analyzing water samples (n=9) collected from three different sites in local reservoirs. PMID- 21237313 TI - Analysis of trace metals (Cu, Cd, Pb, and Fe) in seawater using single batch nitrilotriacetate resin extraction and isotope dilution inductively coupled plasma mass spectrometry. AB - A simple and accurate low-blank method has been developed for the analysis of total dissolved copper, cadmium, lead, and iron in a small volume (1.3-1.5 mL per element) of seawater. Pre-concentration and salt-separation of a stable isotope spiked sample are achieved by single batch extraction onto nitrilotriacetate (NTA)-type Superflow((r)) chelating resin beads (100-2400 beads depending on the element). Metals are released into 0.1-0.5 M HNO(3), and trace metal isotope ratios are determined by ICPMS. The benefit of this method compared to our previous Mg(OH)(2) coprecipitation method is that the final matrix is very dilute so cone-clogging and matrix sensitivity suppression are minimal, while still retaining the high accuracy of the isotope dilution technique. Recovery efficiencies are sensitive to sample pH, number of resin beads added, and the length of time allowed for sample-resin binding and elution; these factors are optimized for each element to yield the highest recovery. The method has a low procedural blank and high sensitivity sufficient for the analysis of pM-nM open ocean trace metal concentrations. Application of this method to samples from the Bermuda Atlantic Time-Series Study station provides oceanographically consistent Cu, Cd, Pb, and Fe profiles that are in good agreement with other reliable data for this site. In addition, the method can potentially be modified for the simultaneous analysis of multiple elements, which will be beneficial for the analysis of large number of samples. PMID- 21237314 TI - Towards a selected reaction monitoring mass spectrometry fingerprint approach for the screening of oligosaccharidoses. AB - The oligosaccharidoses are a group of metabolic disorders resulting from a deficiency in enzymes responsible for the catabolism of protein bound oligosaccharides and are typified by the accumulation of corresponding sugars in the urine. Screening is typically accomplished using thin layer chromatography. However, analyte specificity can be a problem and thus complicate interpretation of results. For this reason we developed a mixed mode liquid chromatography tandem mass spectrometry assay for the screening of the oligosaccharidoses which potentially mitigates many of the problems associated with thin layer chromatography. Samples from patients previously diagnosed with I-Cell disease, mannosidosis, Pompe, galactosialidosis, and fucosidosis were derivatized with 3 methyl-1-phenyl-2-pyrazolin-5-one and subjected to analysis by liquid chromatography tandem mass spectrometry. Results were compared to normal control samples. Preliminary results suggest that each oligosaccharidoses produces a unique selected reaction monitoring fingerprint and that the developed method may be an effective screening and diagnostic tool for these disorders. PMID- 21237315 TI - An improved method of ion exchange for nitrogen isotope analysis of water nitrate. AB - Nitrate nitrogen and oxygen isotopes have been widely used to trace the nitrogen biogeochemical cycle by identifying NO(3)(-) sources. An improved method of anion exchange was developed to measure delta(15)N-NO(3)(-) in fresh water by continuous-flow elemental analyzer/isotope ratio mass spectrometry (EA-IRMS). We used a custom-built exchange resin column, a peristaltic pump and the oven-drying method in our experiments. Consequently, the amount of Ag(2)O used as a neutralizer was reduced, time was saved, and operation became simpler than before. Meanwhile, analytical precision remained identical to previous studies. KNO(3) solutions were prepared at 0.2, 5 and 25 mg-N L(-1) from KNO(3) standard salt (delta(15)N=+6.270/00), and the average delta(15)N values of the solutions after having been absorbed on and subsequently stripped from anion columns were +6.62+/-0.220/00 (n=6), +6.38+/-0.090/00 (n=6), and +6.26+/-0.070/00 (n=6), respectively. In addition, the "natural" water sample delta(15)N-NO(3)(-) showed consistency in comparison to standards, and the mean standard deviation by the different approaches was 0.080/00. Accordingly, by these improvements the anion exchange resin technique is demonstrated to be more suitable for measuring delta(15)N in NO(3)(-) than original techniques. PMID- 21237316 TI - Gold nanoparticles based chemiluminescent resonance energy transfer for immunoassay of alpha fetoprotein cancer marker. AB - In this paper, we report a new strategy of chemiluminescence resonance energy transfer (CRET) by using gold nanoparticles (AuNPs) as efficient long-range energy acceptor in sandwich immunoassays. In the design of CRET system, we chose the highly sensitive chemiluminescence (CL) reaction of luminol and hydrogen peroxide catalysed by horseradish peroxidase (HRP) because the CL spectrum of luminol (lambda(max) 425 nm) partially overlaps with the visible absorption bands of AuNPs. On the basis of CRET strategy, we developed a sandwich immunoassay of alpha fetoprotein (AFP) cancer marker. In immunoassay, two antibodies (anti-AFP-1 and anti-AFP-2) were conjugated to AuNPs and horseradish peroxidase (HRP), respectively. The sandwich-type immunoreactions between the AFP (antigen) and the two different antibodies bridged the donors (luminol) and acceptors (AuNPs), which led to the occurrence of CRET from luminol to AuNPs upon chemiluminescent reaction. We observed that the quenching of chemiluminescence signal depended linearly on the AFP concentration within a range of concentration from 5 to 70 ng mL(-1) and the detection limit of AFP was 2.5 ng mL(-1). Our method was successfully applied for determination of AFP levels in sera from cancer patients, and the results were in good agreement with ELISA assays. This approach is expected to be extended to other assay designs, that is, using other antibodies, analytes, chemiluminescent substance, and even other metallic nanoparticles. PMID- 21237317 TI - Determination of radon using solid state nuclear tracks wireless sensing method. AB - The aim of this paper is to develop a solid state nuclear tracks (SSNTs) wireless magnetoelastic sensing method for the determination of radon. In this method, wireless sensors for detecting radon are fabricated by coating polymethyl methacrylate (PMMA) film on the surface of magnetoelastic foils. The magnetoelastic sensing technique has the unique characteristic of being able to wirelessly detect resonance frequency shifts of a magnetoelastic foil in response to differences in the mass of foil. When the sensor is exposed to the environment containing radon, the PMMA film on the sensor is attacked by alpha-particles emitted from radon, generating latent SSNTs. After the sensor is chemically etched, the latent SSNTs in the PMMA film are enlarged and the sensor loses a certain mass, resulting in a shift in resonance frequency of the sensor. Consequently, the radon concentration can be determined by measuring the shift in resonance frequency. Under the conditions of the etchant concentration, etching temperature and etching time being 20% (w/w), 80 degrees C and 18 min, respectively, the linear range for the determination of radon is 1.20*10(5) to 3.60337199*10(6) Bq m(-3) h with the detection limit of 20.3*10(3) Bq m(-3) h. The method has been applied for the determination of radon in air samples with satisfactory results. PMID- 21237318 TI - Use of microperoxidase-11 to functionalize tin dioxide electrodes for the optical and electrochemical sensing of hydrogen peroxide. AB - In this paper, we employ microperoxidase MP-11 immobilized on mesoporous SnO(2) electrodes in order to study its peroxidase activity and reaction mechanism. We demonstrate the catalytic redox chemistry of the immobilized MP-11 via direct interfacial electron transfer without the use of electron mediators. By taking advantage from the optical transparency of the SnO(2) electrodes, optical absorbance spectroscopy is used in order to compliment the data information obtained from electrochemical techniques. The catalytic activity of the immobilized MP-11 is found to proceed via the Fenton reaction, yielding OH radical intermediates. We also demonstrate the viability of using this electrode system as a potential H(2)O(2) biosensor with a sensitivity range of 0.05-30 MUM. PMID- 21237319 TI - A combined photocatalytic determination system for chemical oxygen demand with a highly oxidative reagent. AB - This study focuses on the proposal and validation of a combined photocatalytic (PC) system and a three-parameterized procedure for the determination of chemical oxygen demand (COD; PcCOD(combined)), with a highly oxidative reagent utilized as a photoelectron scavenger and signal indicator. The PcCOD(combined) was the functional combination of photon-efficient thin-layer photocatalytic oxidation, conventional bulk-phase photocatalytic oxidation and photocarrier-efficient high activity photocatalytic reduction in one single photodigestion system, and consequently, this system possessed high photon-utilization efficiency, automatic stirring function and satisfactory determination characteristics. In comparison with the conventional one-parameterized procedure, the three-parameterized procedure introduces the blank and total photocatalytic reduction responses as two of the three significant analytical parameters. Under the optimized pH value of 3.0-4.5 and a rotating rate of 40 rpm, the representative KMnO(4) species was used for the PcCOD(combined) system as the combined high-activity oxidant, and a narrow and reliable analytical linear range of 0-260 mg L(-1) was achieved during the 10 min duration of the determinations. No observable interference of Cl(-) was found at concentration of the ion up to 2000 mg L(-1). A real sample analysis indicated that the measured values for the PcCOD(combined) were all within a relative deviation below 5% of COD(Cr) of the standard method, which further validates the practical feasibility of the proposed PcCOD(combined) system. PMID- 21237320 TI - An enzyme-free quartz crystal microbalance biosensor for sensitive glucose detection in biological fluids based on glucose/dextran displacement approach. AB - A sensitive and facile quartz crystal microbalance (QCM) biosensor for glucose detection in biological fluids was developed by means of a displacement-type assay mode between glucose and its analogy dextran for concanavalin A (ConA) binding sites on a graphene-based sensing platform. To construct such a displacement-based sensor, phenoxy-derived dextran (DexP) molecules were initially assembled onto the surface of graphene-coated QCM probe via pi-pi stacking interaction, and ConA molecules were then immobilized on the dextran through the dextran-ConA interaction. Upon addition of glucose, the analyte competed with the dextran for the ConA, and displaced it from the QCM probe, leading to a change in the frequency. Under optimal conditions, the frequency change relative to the basic resonant frequency was proportional to glucose concentration, and exhibited a dynamic range from 0.01 to 7.5 mM with a low detection limit (LOD) of 5.0 MUM glucose (at 3sigma). The relative standard deviations (RSDs) were below 6.2% and 9.0% for the reproducibility and selectivity of the QCM glucose sensors, respectively. In addition, the assay system was evaluated with glucose spiking samples into the distilled water and blank cattle serum, receiving in excellent correlation with the referenced values. PMID- 21237321 TI - [Epidemiology of acute coronary syndromes in France and in Europe]. AB - In France, the incidence of myocardial infarctions leading to hospitalisations can be estimated between 60,000 and 65,000 each year. With the addition of cases of unstable angina, about 80,000 to 100,000 hospital stays each year are caused by acute coronary syndromes. Cases of out-of-hospital cardiac arrest of ischaemic origin should also be taken into account when estimating the annual incidence of myocardial infarction. In Europe, a North-South gradient, and even more an East West gradient is observed for the incidence of ischaemic heart disease, with the highest figures found in central and eastern European countries. A consistent trend to a decrease in the incidence of myocardial infarction is observed on both sides of the Atlantic. In parallel, progress in the management of acute coronary syndromes has led to a marked decrease in early case fatality rates. Overall, these trends explain the spectacular decrease in cardiovascular mortality observed over the past 25 years in most European countries. Acute coronary syndromes, however, remain severe clinical conditions, which carry a high mid term and long-term morbi-mortality and deserve further efforts to develop new therapeutic tools. PMID- 21237322 TI - [Impact of genetic polymorphisms in the clinical response of oral inhibitors of the platelet P2Y12 adenosine diphosphate (ADP) receptor]. AB - Dual antiplatelet therapy with clopidogrel combined to aspirin reduces ischemic events in a wide range of patients with cardiovascular disease. However, a large interindividual variability has been observed in the pharmacodynamics response of clopidogrel with lower platelet inhibition associated with increased risk for major adverse cardiovascular events. Multiple mechanisms have been proposed for the variable response to clopidogrel, among which the impact of pharmacogenetic seems to play an important role. This article reviews the role of genetic polymorphisms in the clinical impact of oral inhibitors of the platelet P2Y12 adenosine diphosphate (ADP) receptor. PMID- 21237323 TI - [Antiplatelet agents in acute coronary syndromes. Data from the main clinical trials]. AB - Cardiovascular disease is the leading cause of early death and morbidity in developed countries and is becoming a growing problem in many developing countries. Currently, anti-coagulants play a major role in the management of the acute phase in association or not with reperfusion strategies. The combination of clopidogrel and aspirin, in accordance with the results of large randomized trials, is the treatment of reference. However two new drugs, a thienopyridine (prasugrel), and a cyclo-pentyl-triazolo-pyridine (ticagrelor) have shown their interest in major studies in comparison with clopidogrel. As a result, several effective P2Y12 receptor antagonist anti-platelet agents are now available in the therapeutic arsenal, and the cardiologist have to tailored the best drug scheme according the balance between the risk of hemorrhage and the benefits with regard to the ischemia to determine the optimal prescription for every patient. PMID- 21237324 TI - [Antiplatelet agents and diabetes mellitus]. AB - Diabetes and more specially type 2 diabetes are a major cardiovascular risk factor. The high incidence of cardiovascular thromboischemic events in type 2 diabetic patients is explained by the development of atherothrombotic lesions and by their high rate of recurrence after angioplasty but also by their high thrombogenic potential due to the association of platelet hyperactivity, hypercoagulability and hypofibrinolysis. Platelets are involved at two different levels: their hyperreactiviy but also their lower sensitivity to antiplatelets agents and specially the two main aspirin and clopidogrel. That focuses the interest of the newer antiplatelet agents (prasugrel and ticagrelor) whose efficacy seems to be less affected in the sub-group of diabetics. Besides the increased thrombo-ischemic risk in diabetics: they are also characterized by an increased hemorrhagic risk (global hemorrhagic risk and risk conferred by anti thrombotic treatments). Sub-group analysis clearly evidenced this increased hemorrhagic risk for aspirin and clopidogrel but seems to be much less for the newer antiplatelet agents (prasugrel and ticagrelor). Specific trials of primary and secondary prevention with these new agent are particularly awaited in the high risk populations specially diabetics. PMID- 21237325 TI - [2010 Congress of the French Society of Endocrinology at Deauville]. PMID- 21237326 TI - [Non thyroidal illnesses (NTIS)]. AB - Abnormalities in the circulating levels of thyroid hormones, without evidence of coexisting thyroid or pituitary gland disease can be observed in all general diseases. These nonthyroidal illnesses (NTIS) are the result of complex mechanisms that combine the effect of some drugs, cytokines, nutritional and endocrine factors at all levels of the thyrotropic axis, from the hypothalamus to the cellular transporters and nuclear receptors of thyroid hormones. The patterns of NTIS depend on the underlying disease and its severity. Thirtyfive years after the initial description, the pathophysiological significance of these anomalies remains controversial. One of the dilemma of NTIS is whether the hormone responses represent an adaptive and normal, physiologic response to conserve energy and protect against hypercatabolism in case of aggression, or whether it is a maladaptive response contributing to a worsening of the disease. This debate is not just a theoretical question, because in the first case the process must be respected, in the other case a vigorous treatment to restore circulating thyroid hormone levels is justified. There have been very few clinical studies designed to address whether the substitution with thyroid hormone is advantageous, and there is at current time no permissive evidence for the use of thyroid hormone replacement in patients with NTIS. But the clinical context, the choice of the molecule or of the dose and the way of administration were not necessarily the most relevant. Theoretically, stimulation of thyreotrope axis used a continuous infusion of TRH seems to provide clinical benefit. With the expectation that randomized clinical trials will provide demonstration of NTIS treatment efficiency, the question might remain unanswered for several more years. PMID- 21237327 TI - [New insights in growth hormone physiology and pathophysiology]. AB - This review focuses on new aspects in growth hormone (GH) biology and pathophysiology presented at the Endocrine Society's meeting, in San Diego, in June 2010. First, we will describe recent advances in the understanding of cytokine hormone signaling via STAT5 in mammary gland development, highlighting the primary role of miR193b for differentiation of mammary stem cells into alveolar progenitor cells. We will examine the potential implication of endocrine and autocrine GH for mammary gland carcinogenesis. Three novel murine models bearing tissue-specific inactivation of GH receptor or JAK2 bring new insights into the large spectrum of GH effects on energy homeostasis. We will also report new data supporting a paracrine regulation of GH secretion in women by estrogen's action in the brain. Thereafter we will question the reasons for GH abuse for doping by assessing the hormonal impact on body composition and physical performance in recreational athletes. Finally, we will discuss the controversial issue of GH replacement in acromegalic patients presenting GH deficiency after treatment of acromegaly. PMID- 21237328 TI - [Somatostatin receptor-based imaging and therapy of digestive endocrine tumors]. AB - The management of gastroenteropancreatic endocrine tumors is greatly linked to the localization of primary tumor. Morphological imaging methods are thus necessary. However, the expression of somatostatin receptors in endocrine tumors makes their detection possible thanks to radiolabeled somastotatin analogs. [(111)In-DTPA] octreotide is the main radiolabeled analog for somatostatin receptor scintigraphy. Positron emission tomography uses other tracers and currently allows improvement of the diagnosis and the tumoral staging. It also allows to affect the therapeutic management. A further step is about to be taken as far as the therapy of endocrine tumors is concerned with the peptide receptor radionuclide therapy. Those therapies are now being offered in some European and American centers for progressive metastatic tumors. Their place in the therapeutic strategy has to be defined, especially in comparison to targeted therapy. The sudden and delayed adverse events as well as the current legislation on the use of radioactive therapy-aimed products have limited their development in France so far. PMID- 21237329 TI - [Hypogonadotropic hypogonadism: new aspects in the regulation of hypothalamic pituitary-gonadal axis]. AB - Hypogonadotropic hypogonadism (HH) is defined by the absence of sex steroid synthesis associated with the lack of appropriate gonadotrophin secretion. This leads to a variable degree of impuberism, often diagnosed during childhood or adolescence. Genetics of HH involve many genes. However, molecular defects have been identified in only 30 % of patients. Kallmann syndrome (KS) is defined by the association of HH and anosmia. Six genes are involved in KS (KAL1, FGFR1, FGF8, PROK2, PROKR2 and CHD7). However, genetics of KS is complex, because of the variability of the phenotype for a similar molecular defect. Otherwise, heterozygous anomalies are frequently described. Identification in the same patient of several mutations in some of these genes (digenism) could account for this variability. Autosomal recessive transmission is frequently observed in familial cases of HH without anosmia. Molecular alterations have been identified for several neuropeptides or their corresponding receptors, which are involved in the physiology of the gonadotropic axis : GNRHR, KISS1R/GPR54, neurokinin B (TAC3), TACR3 and GNRH1 (and PROK2, PROKR2 and CHD7). Anomalies of leptin or its receptor are also involved in HH cases. A new negative regulating element has been recently identified in humans : RFRP3, which is ortholog of the avian GnIH (gonadotrophin inhibitory hormone). Recent progress about these neuropeptides leads to a new model of comprehension of the gonadotropic axis physiology, from a linear model to a network model, which regulates the central element of regulation of the gonadotropic axis, represented by the GnRH neurons. PMID- 21237330 TI - [The adult ovary is not in sleepiness: major role of forkhead proteins]. AB - The aim of this review is to underscore the major role of forkhead proteins in the adult ovary. Indeed, they revolutionize the idea of terminal differentiation of adult tissues with for example the in vivo reprogrammation of an adult organism on the one hand, and, on the other hand, the therapeutic possibilities of fertility preservation in women. In mammals, SRY, a transcription factor encoded by the Y chromosome, is responsible for the development of the undifferentiated gonads into testes. However, testis differentiation can occur in its absence. The studies of M. Treier demonstrate that FOXL2 is required to maintain the ovarian phenotype. Indeed, the absence of Foxl2 in an adult mouse ovary leads to an up regulation of testis-specific genes and a transformation of granulosa and theca cells into Sertoli-like and Leydig-like cells. The maintenance of the ovarian phenotype is an active process throughout life. Although multiple follicles are present in mammalian ovaries, most of them remain dormant. During reproductive life, some follicles are activated for development. There is an inefficient activation of dormant follicles within cryopreserved ovaries. An inhibition of the FOXO3a pathway in the mouse ovary leads to an enhancement of the activation of the dormant follicles. After transplantation, there are more preovulatory stage follicles and, after fertilization and embryo transfer, they lead to a healthy progeny. In human ovarian cortical fragments, the same inhibition and a xenotransplantation permit a development of more primordial follicles to the preovulatory stage. Thus, this treatment may be a hope to treat infertile women with cryopreserved ovaries or with a diminishing ovarian reserve. PMID- 21237331 TI - [Obesity and female reproduction]. AB - Weight, fat mass and obesity have been shown to play a major role in female reproduction. Obese women have a greater risk than nonobese women of infertility and they fail to become pregnant in both natural and assisted conception cycles. This cannot be explained only by their lack of ovulation. There are several potential mechanisms. On one hand, the endometrium seems to be partially responsible for this low fecundity in obese women. On the other hand, the oocyte seems to be implied. In a model of obese mouse, maternal obesity prior to conception is associated with altered mitochondria in mouse oocytes and an increased generation of reactive oxygen species (ROS). Furthermore, compared with controls, obese mice have significantly more decreased embryonic IGF-IR staining, smaller fetuses and smaller pups. In this model, all weaned pups have been fed with a regular diet. At 13 weeks, pups delivered from obese mice were significantly larger, and these pups demonstrated early development of a metabolic-type syndrome. These findings suggest that maternal obesity has adverse effects as early as the oocyte and preimplantation embryo stages and that these effects may contribute to lasting morbidity in offspring, underscoring the importance of optimal maternal weight and nutrition before conception. PMID- 21237332 TI - Reducing maternal mortality: a global imperative. PMID- 21237333 TI - IUD use in HIV-positive women. PMID- 21237334 TI - In-office retrieval of intrauterine contraceptive devices with missing strings. PMID- 21237335 TI - Vaginal ring contraception. AB - The contraceptive vaginal ring is a relatively new combined hormonal contraceptive method. Ethinyl estradiol and etonogestrel are rapidly absorbed through the vaginal epithelium and result in a steady serum concentration. Studies have demonstrated that the efficacy and safety of the ring are equivalent to oral contraceptives (OCs). Patients report being highly satisfied with the vaginal ring and report fewer systemic side effects than do OC users. The ring provides effective cycle control as well as symptom relief for women with menorrhagia, dysmenorrhea and polycystic ovarian syndrome. A new combined contraceptive ring containing Nestorone and ethinyl estradiol is currently being investigated in a Phase 3 trial. A progesterone-releasing vaginal ring appropriate for lactating women is available in Chile and Peru. Recent studies have demonstrated that vaginal rings can also be effective means of delivering antiretroviral drugs that provide protection from HIV. PMID- 21237336 TI - Pain control in first-trimester and second-trimester medical termination of pregnancy: a systematic review. AB - BACKGROUND: Pain is a predictable feature of medical abortion in both the first trimester and the second trimester. We sought to evaluate optimal analgesia regimens during medical abortion. STUDY DESIGN: We searched the PubMed and Cochrane databases from inception to March 2010 for publications of trials comparing methods of pain control during first-trimester medical abortion (<12 completed weeks' gestation) and second-trimester medical abortion (13-24 completed weeks' gestation). Standard data abstraction templates were used to systematically assess and summarize data. RESULTS: Of 363 articles, 10 articles reporting the results of nine studies met inclusion criteria. Heterogeneity of analgesia regimens and medical abortion protocols prevented meta-analysis. Four studies conducted in women with pregnancies <8 completed weeks' gestation found that prophylactic acetaminophen, acetaminophen+codeine, ibuprofen or alverine did not reduce medical abortion pain; however, administration of ibuprofen after onset of cramping reduced pain and subsequent analgesia use. In second-trimester medical abortion, one study found that women treated with fentanyl (50 mcg) patient-controlled analgesia (PCA) had better satisfaction and pain relief than women treated with fentanyl (25 mcg) or morphine PCA, but found no difference in delivery/demand ratio; three studies found little effect of adjuvant treatment with metoclopramide or paracervical block on pain; one study found that women at >15 weeks' gestation who received diclofenac with the first misoprostol dose required less opioid analgesia than women who received acetaminophen+codeine. CONCLUSION: Few studies examine pain management during medical abortion, and heterogeneity of existing data limits comparison. Further research is needed to determine the optimal analgesia regimens for first-trimester and second-trimester medical termination of pregnancy. To facilitate comparability of data, researchers should use contemporary medical abortion regimens, outcomes and study instruments to measure pain. PMID- 21237337 TI - Use of contraception among US women with frequent mental distress. AB - BACKGROUND: This study examines whether a woman's mental health is associated with use of contraception. STUDY DESIGN: We used national data from 2004 and 2006 to calculate the prevalence of contraceptive use among women with frequent mental distress. We examined associations among mental distress and permanent contraception and any highly or moderately effective, reversible contraceptive method. RESULTS: Women with (86%) and without (87%) frequent mental distress reported using contraception, but contraceptive type varied by mental distress and income. Among women who use contraception, those with frequent mental distress had 1.4 times higher odds (95% CI: 1.2-1.6) of using permanent contraception. Among lower income women who use reversible contraception, those with frequent mental distress had lower odds of using highly [adjusted odds ratio (aOR)=0.5, 95% CI: 0.4-0.8] and moderately (aOR=0.6, 95% CI: 0.4-0.9) effective methods than less effective methods. CONCLUSION: Contraceptive providers should consider mental health when providing counseling about contraception. PMID- 21237338 TI - Hormonal contraception use and pregnancy in adolescents with sickle cell disease: analysis of Michigan Medicaid claims. AB - BACKGROUND: Access to effective family planning is of great importance for women with sickle cell disease (SCD) due to the increased frequency of pregnancy complications. However, little is known regarding use of hormonal contraception, complications of contraception, and pregnancy in young women with SCD. STUDY DESIGN: We abstracted diagnostic codes, procedure codes and pharmacy claims from women with SCD, aged 13-21 years, enrolled in Michigan Medicaid between 1/1/2000 and 12/31/2003 with >= 9 months of continuous eligibility. RESULTS: We identified 250 women with SCD with an average period of continuous Medicaid enrollment of 20 months. Claims for hormonal contraception could be identified in only 20 patients (8%, 95% CI 5-12%). The most commonly prescribed method (n=12) was depot medroxyprogesterone (DMPA) acetate. Venous thromboembolism and osteopenia were rarely identified (n <= 10) and occurred only in women with no recorded use of hormonal contraception. In the total population, 64 patients had one pregnancy and 16 had >= 2 pregnancies during the 4-year study period. Among adolescents (13 18 years), 49 (30%) of 195 patients (95% CI 24-37%) had 59 pregnancies. By 12 weeks postpartum, few patients (n <= 10) with a record of delivery had hormonal contraception claims. CONCLUSIONS: In a publicly insured population of young women with SCD, pregnancy was more commonly identified than hormonal contraception use. Our work suggests that significant gaps may exist in family planning care for young women with SCD. PMID- 21237339 TI - Longitudinal influences of friends and parents upon unprotected vaginal intercourse in adolescents. AB - BACKGROUND: Both friends and parents may influence occurrence of adolescent sexual intercourse, but these influences have not been studied together and prospectively. STUDY DESIGN: We conducted a longitudinal analysis of a nationally representative sample of adolescents aged 15-18 years (n=6649), the National Longitudinal Study of Adolescent Health (Add Health). Baseline in-home and school interviews were conducted during 1995 and follow-up interviews in 1996. The main outcome measure was self-reported unprotected vaginal intercourse. RESULTS: In models which adjusted for age, race, parental attitudes towards contraception and pregnancy, and adolescent sexual intercourse practices at baseline, having a friend who engaged in sexual intercourse at baseline, either unprotected (OR 2.2, 95% CI 1.6-3.2) or protected (OR 1.8, 95% CI 1.4-2.4), increased the odds of unprotected intercourse vs. never intercourse in the adolescent at follow-up (p<.001). A distant relationship with the father (OR 2.4, 95% CI 1.3-4.3) vs. a close relationship at baseline also increased the odds of unprotected intercourse at follow-up compared to never intercourse (p=.028). Parental attitudes were not associated with the outcome after consideration of the adolescent's attitudes and baseline sexual practices. CONCLUSIONS: Having a friend who engages in sexual intercourse, unprotected or protected, increases the risk of unprotected intercourse. Parental attitudes are less influential after consideration of adolescent baseline attitudes and sexual practices, suggesting that parental influences are strongest before 15 years of age. Our results suggest that early intervention among both parents and adolescents may decrease the risk of unprotected intercourse. PMID- 21237340 TI - Survey of knowledge, attitudes and practices surrounding the intrauterine device in South Africa. AB - BACKGROUND: The Copper T intrauterine device (IUD) is a safe, effective, reversible contraceptive that is used widely worldwide but little in South Africa. This study assesses the knowledge, attitudes and practices of potential IUD users and health care providers to inform strategies for expanding IUD use in South Africa. STUDY DESIGN: A descriptive, cross-sectional survey was conducted among 205 clients and 32 health care providers at 12 public sector clinics in two provinces. RESULTS: Twenty-six percent of clients had heard of the IUD; of those, 9% had misconceptions or incorrect information that negatively influenced their opinion of the method. After being given a description of the Copper T IUD, 74% said they would consider using it. Provider knowledge about Copper T IUDs was inaccurate and inadequate. Providers held incorrect beliefs about IUD candidate selection and risks. Almost all providers said that they needed more training and information about the IUD. CONCLUSION: If IUD use is to be expanded in South Africa, potential users will need education about the method and providers will need training on counseling and provision. PMID- 21237341 TI - Pharmacy access to the emergency contraceptive pill: a national survey of a random sample of Australian women. AB - BACKGROUND: The emergency contraceptive pill (ECP) has the potential to assist in reducing unintended pregnancy and abortion rates. Since its rescheduling to pharmacy availability without prescription in Australia in January 2004, there is little information about Australian women's knowledge, attitudes and use of the ECP. The aim of this study was to measure the knowledge about the ECP and sociodemographic patterns of and barriers to use of the ECP. STUDY DESIGN: A cross-sectional study, using a computer-assisted telephone interview (CATI) survey conducted with a national random sample of 632 Australian women aged 16-35 years. RESULTS: Most women had heard of the ECP (95%) and 26% had used it. The majority of women agreed with pharmacy availability of the ECP (72%); however, only 48% were aware that it was available from pharmacies without a prescription. About a third (32%) believed the ECP to be an abortion pill. The most common reason for not using the ECP was that women did not think they were at risk of getting pregnant (57%). Logistic regression showed that women aged 20-29 years (OR 2.58; CI: 1.29-5.19) and 30-35 years (OR 3.16; CI: 1.47-6.80) were more likely to have used the ECP than those aged 16-19 years. Women with poor knowledge of the ECP were significantly less likely to have used it than those with very good knowledge (OR 0.28; CI: 0.09-0.77). Those in a de facto relationship (OR 2.21; CI: 1.27-3.85), in a relationship but not living with the partner (OR 2.46; 95% CI 1.31-4.63) or single women (OR 2.40; CI: 1.33-4.34) were more likely to have used the ECP than married women. CONCLUSIONS: Women in Australia have a high level of awareness of the ECP, but more information and education about how to use it and where to obtain it are still needed. PMID- 21237342 TI - Provision of the emergency contraceptive pill without prescription: attitudes and practices of pharmacists in Australia. AB - BACKGROUND: As 5 years have elapsed since the emergency contraceptive pill (ECP) was made available without prescription in Australia, information was sought about the current attitudes and practices of pharmacists in relation to their increased role in ECP provision. STUDY DESIGN: A mail survey was implemented; questionnaires were distributed to 750 pharmacies across Australia during 2008 2009. Descriptive statistics were calculated and multiple logistic regression was used to examine factors associated with declining to dispense ECP. RESULTS: Response rate was 29%. Most pharmacists used a protocol to guide ECP dispensing (77.3%) and the majority had declined ECP provision (75.1%) in certain circumstances. Many usually counselled where confidentiality could be assured (62.8%), and agreed that it is a pharmacist's role to counsel on regular contraception (81.9%). Factors significantly associated (p <=.05) with dispensing practices included pharmacists' attitudes towards acceptability of advance prescription, their age, gender and pharmacy accessibility. CONCLUSIONS: New information about Australian pharmacists' current attitudes and practices towards ECP dispensing was identified. Pharmacists had stronger, more conservative attitudes than overseas pharmacists; however, the issues that emerged were similar to those reported overseas. To address these, revised training for local pharmacists is recommended. PMID- 21237343 TI - Potent spermicidal effect of oleanolic acid 3-beta-D-glucuronide, an active principle isolated from the plant Sesbania sesban Merrill. AB - BACKGROUND: The spermicidal activity of oleanolic acid 3-beta-D-glucuronide (OAG), an active principle isolated from root extracts of Sesbania sesban, was evaluated. STUDY DESIGN: Under the Sander-Cramer test criteria, the sperm immobilizing activity of OAG was studied using highly motile rat sperm. Sperm mortality and membrane integrity were assessed by supravital staining, hypo osmotic swelling (HOS), transmission electron microscopy (TEM) and sperm membrane lipid peroxidation (LPO). In vitro microbicidal potential and hemolytic index of OAG were examined in Lactobacillus culture and rat red blood corpuscles (RBCs), respectively. Post-intravaginal OAG application, the in vivo contraceptive efficacy was evaluated in rats. Ames test determined the carcinogenic potential of OAG. RESULTS: The minimum effective concentration (MEC) of OAG was 50 mcg/mL. More than 97% of the OAG-treated sperm lost their HOS responsiveness in a dose dependent manner. TEM and LPO revealed that OAG affected the sperm membrane integrity. OAG declined fertility to zero, was nonmutagenic and was not harmful to lactobacillus. CONCLUSION: OAG has significant spermicidal activity that may be explored further. PMID- 21237344 TI - Emergency contraception in Australian community pharmacies: a simulated patient study. AB - BACKGROUND: Australia joined the worldwide movement to increase the availability of the emergency contraceptive pill (ECP) by rescheduling from Prescription to Pharmacist Only status in 2004. However a protocol developed to aid in the provision of the ECP placed extensive requirements on the pharmacist. This study investigated the provision of the ECP by community pharmacists in Sydney, Australia. STUDY DESIGN: Using a simulated patient methodology, 100 community pharmacies were visited over a five week period (Aug-Oct 2008). The simulated patient specifically requested the ECP, and details of the consultation were recorded on a standardised data collection form. RESULTS: The ECP was supplied in 95% of the pharmacies visited. Patient privacy was observed in 90% of consultations, which in general were succinct and friendly. Clinical assessment of the patient that met all the requirements was observed in 18%, partial assessment in 69%, and inadequate assessment in 13% of consultations. Provision of required information to the patient was sufficient in 42%, partial in 55%, and inadequate in 3% of consultations. CONCLUSIONS: This study highlighted a need to standardize procedures in regard to the ECP service to present a more consistent level of service to the public. Suggestions to improve the service include complete revision and simplification of the current protocol and improved training. Additionally, mandatory provision of private consultation areas and continuing professional education may facilitate and enhance quality counselling. PMID- 21237345 TI - Commentary - Lyus R, Lohr P, Prager S. Use of Mirena LNG-IUS and Paragard CuT380A intrauterine devices for nulliparous women [Contraception 2010;81:367-371]. PMID- 21237347 TI - Emergency contraception: an unresolved issue. PMID- 21237349 TI - [Affective disorders: From new models to novel treatments]. PMID- 21237350 TI - [Affective disorders: News in chronobiological models]. AB - Good news on chronobiological models of affective disorders are coming from a therapeutic innovation in the field of antidepressive action. Coming back to fundamentals by reconsidering the importance of the role of biological rhythms impairment in dysthymic pathology, a new interest bored on studies exploring short periodicities, so-called "ultradian" ones, on the basis of pharmacodynamics in the concept of therapeutic "window" of administration. The priority of circadian rhythms due to the major external biological desynchronization in depression, as well as the importance of sleep and alertness pathology, the spectacular relief of the depressive mood upon sleep deprivation, and the strong reduction of sleep need in mania, delayed exploration of ultradian exaltation of harmonic circadian components, marking a "buzz" of rhythmic structure and calling a "chronobiotic compound" which would be able to apply a "reset" to the temporal organisation. Another return to the origin leads to the experimental genomics, informing nor the "depressivity" but manic pathogenesis, in a mouse gene model which queries on the share of addictive and affective disorders. PMID- 21237351 TI - [Gene-environment interactions in affective disorders]. AB - Kindling and behavioural sensitization were probably the first among the animal models of affective disorders, to suggest that genes-environment interactions were likely to be involved in the pathophysiology of these disorders. Cross sensitization among stressors, drugs of abuse and illness episodes was deemed to be supported by the induction of a series of transcription factors, such as the proto-oncogene c-fos that subsequently alter gene expression by binding at DNA sites and inducing mRNAs for substances that may exert effects over long time periods. This was an anticipation of epigenetics which is currently defined as a functional modification to the DNA that does not involve an alteration of sequence. Epigenetic modifications are most commonly regulated by DNA methylation and histone acetylation which are usually associated with the silencing and activation of gene transcription, respectively. In animal models, it was shown that parents can actively remodel epigenetic marks, and thus affect patterns of gene expression in the offspring, whereas environmental adversity decreases parental investment in the offspring and thus alters phenotypic development. In line with this, some laboratories have sought to identify changes in gene expression in post mortem brain samples of humans with affective disorders. Finally, gene-environment interactions have been directly studied, both in animals and humans, by testing how a functional polymorphism in candidate genes would moderate the influence of stressful life events on behavioural expression. Interesting results have been found and replicated for unipolar depression, however date are scarce for bipolar disorder. Findings from these studies allow the building of more sophisticated models for unipolar and bipolar genetics. PMID- 21237352 TI - [Bipolar disorder: Continuity from child to adult?]. AB - Early onset (pediatric) bipolar disorders are still an issue of much controversy due to several clinical particularities of the thymic episodes at this age. To date, there is indeed no consensus regarding the prevalence of bipolar disorders before puberty. Diagnosis criteria in children and young adolescents remain thus elusive. The purpose of this review is to provide an overview of this issue. The idea of continuity, from childhood to adulthood, in bipolar disorders also raises important questions regarding predictive factors of bipolar disorders in adults. Studies on the childhood of bipolar adults, as well as studies on the children of bipolar parents will be reviewed, in an attempt to identify the psychopathological substrates of bipolar disorders. PMID- 21237353 TI - [Affective disorders: Evolution of nosographic models]. AB - In the history of the nosographies in psychiatry, the affective disorders were gradually distinguished from the other categories of mental disorders, until being considered as separate illness entities, such as what Kraepelin named manic depressive insanity at the end of the 19th century. The latter will be subsequently divided in two main categories, the bipolar disorder on the one hand and recurrent depression on the other hand, this separation being still current, and extensively diffused by the mean of the Diagnostic and Statistical Manual of Mental Disorders (DSM). The DSM, whose revisions largely determine the evolution of the contemporary nosographic models, mainly relies on a categorical approach of the mental disorders. The next revision will probably continue to follow this kind of approach, even if the use of dimensional components could also be developed. In the future, true nosographic advances can be waited from clinical epidemiology studies, as those which recently made it possible to highlight various sub-types of affective disorders on the basis of clinical, biographical or temperamental characteristics. Etiological approaches, centered on the pathophysiology of the affective disorders, could also contribute to build nosographic models on the basis of an objective knowledge on these diseases. PMID- 21237354 TI - [Affective disorders and antidepressant drugs: Therapeutic innovations]. AB - As it is the case in other psychiatric disorders, etiopathogenic hypotheses of depression have chiefly been shaped by the fortuitous discovery of antidepressive drugs. Reciprocally, these hypotheses have largely influenced later innovation in therapeutic drugs. In this paper, we aimed to study the development of pharmacological treatments through the different neurobiological and molecular models proposed in depressive illness through the last half-century. We first started by the monoaminergic hypothesis who postulates the existence of a deficit in monoamine transmission (norepinephrine and serotonine). We also discuss of drugs involving other neurotransmitters than the classic monoamines. If this monoaminergic hypothesis has long provided a first level of explanation for the action of antidepressant drugs, limitations have been pointed out. In the last 15 years, another model for the study of depression has clearly emanated: the stress model of depression. A possible reason for the success of this new hypothesis is its ability to provide a satisfying framework to experimental studies, in man and in animal. In this new background, numerous molecular and cellular events have been observed under the influence of stress, and these injuries appear to reverse with antidepressants. It thus seems that antidepressant agents have the ability to opposite the impact of stress through molecular actions, which directly or indirectly influence neuroplasticity. PMID- 21237356 TI - [Affective disorders and repetitive transcranial magnetic stimulation: Therapeutic innovations]. AB - Depression is the most common psychiatric disorder with a particularly important disability due to its evolution to chronicity and treatment-resistance. In the same way, the outcome of bipolar disorder is similar. Only 75% subjects remain remitted in the year following the onset of mood episode and depressive episode leads to worth responsiveness than patients in phase hypo/manic. Thus, treating mood episodes and fighting against resistant and residual symptoms or chronicity of the disorders constitute major clinical issues and economic challenges. They have generated great interest in finding new non-pharmacological approaches such as repetitive transcranial magnetic stimulation (rTMS). TMS is a non-invasive means of focal brain stimulation, rapidly fluctuating magnetic fields. Given the hypothesis that the right and left sides of the dorsolateral prefrontal cortex have opposing effects in mood control, high-frequency rTMS activates the left side and low-frequency to inhibit the right side in the treatment of depression. A literature review was conducted to study the efficacy of rTMS in the treatment of unipolar and bipolar depression, acute mania and long-term maintenance therapy. During the last decade, numerous studies including several meta-analyses have indicated the efficacy of rTMS in acute treatment of major depressive disorder. Overall, rTMS seems to be effective in the treatment of bipolar depression but further trials with larger cohorts should determine optimal parameters of stimulation. There are also few studies about rTMS in the treatment of acute mania. Protocols are reversed than in the treatment of depression. Results are promising but confounded by the presence of concurrent medications. Finally, the literature on the use of maintenance rTMS in the prevention of depressive relapse or as a mood stabiliser is limited. Nevertheless it demonstrates the importance of developing maintenance protocols to maintain the clinical improvement achieved at the end of the acute treatment. New techniques to improve the effectiveness of rTMS are already appearing. PMID- 21237355 TI - [Affective disorders, antipsychotics and mood stabilizers: Therapeutic innovations]. AB - Management of bipolar disorder has undergone many revisions in recent years as new agents and treatments have been developed and studied with variable success. In conjunction with the advent of novel therapies and indications, there has been an increase in the understanding of the phenomenology and neurobiology of bipolar disorder that has made the classification and management of the illness necessarily more sophisticated. However, there remains a significant delay of 8 years in detecting and diagnosing bipolar disorder, and a further need to improve treatments. However, this paper has emphasized the need to be aware of recent advances and the emerging uses of new pharmacological treatments in the management of bipolar disorder. It has also highlighted the need for tailoring management to the individual. In particular, the successful treatment of bipolar disorder requires achieving prophylaxis and preventing relapse. In this regard, maintenance therapy is of paramount importance, and thus the tolerability of agents needs to be considered throughout treatment and should be factored into all management decisions. At the centre is the individual with bipolar disorder and the need to maintain a healthy therapeutic relationship. However, it is important to note that the evidence synthesized in this paper serves only as a guide to the management of bipolar disorder and that, in clinical practice, all treatment recommendations require contextual interpretation, the consideration of local factors and the consultation of additional resources. PMID- 21237357 TI - [Bipolar affective disorders: Models and assessment of psychological treatments]. AB - Psychological therapies dedicated to bipolar patients have attracted major interest and many publications have been devoted to them in the last five years. The efficiency of Psychoeducation, Cognitive and behavioral therapy, Behavioral family therapy and Interpersonal and Social Rhythm Therapy, have specially been focused on. These approaches share a common background of psychoeducation and are closely linked with the transnosographical model from Zubin and Spring as well as basic behavioral and cognitive technical requirements. All these therapies focus on medication adherence, regular lifestyle, early recognition of relapse and early pharmacologic intervention. There are some differences between advantages from each approach, but the overall effect is positive in enhancing medication adherence and preventing manic relapses, and also in preventing depressive episodes and improving quality of life. These robust and corroborating results should probably be integrated in future guidelines for the management of bipolar disorders. PMID- 21237358 TI - [Interpersonal and social rhythm therapy (IPSRT)]. AB - Bipolar disorder is common, recurrent, often severe and debiliting disorder. All types of bipolar disorder have a common determinant: depressive episode. It is justify to propose a psychotherapy which shown efficacy in depression. Howewer, perturbations in circadian rhythms have been implicated in the genesis of each episode of the illness. Biological circadian dysregulation can be encouraged by alteration of time-givers (Zeitgebers) or occurrence of time-disturbers (Zeitstorers). Addition of social rhythm therapy to interpersonal psychotherapy leads to create a new psychotherapy adaptated to bipolar disorders: InterPersonal and Social Rhythm Therapy (IPSRT). IPSRT, in combinaison with medication, has demonstrated efficacy as a treatment for bipolar disorders. IPSRT combines psychoeducation, behavioral strategy to regularize daily routines and interpersonal psychotherapy which help patients cope better with the multiple psychosocial and relationship problems associated with this chronic disorder. The main issues of this psychotherapy are: to take the history of the patient's illness and review of medication, to help patient for "grief for the lost healthy self" translated in the french version in "acceptance of a long-term medical condition", to give the sick role, to examinate the current relationships and changes proximal to the emergence of mood symptoms in the four problem areas (unresolved grief, interpersonal disputes, role transitions, role deficits), to examinate and increase daily routines and social rhythms. French version of IPSRT called TIPARS (with few differences), a time-limited psychotherapy, in 24 sessions during approximatively 6 months, is conducted in three phases. In the initial phase, the therapist takes a thorough history of previous episodes and their interpersonal context and a review of previous medication, provides psychoeducation, evaluates social rhythms, introduces the Social Rhythm Metric, identifies the patient's main interpersonal problem area, and contractualizes the therapy. In the second phase, the therapist focuses work with patient toward regulating the patient's daily routines as well as resolving the interpersonal problem areas relevant to episodes (mainly interpersonal disputes and role transitions). In the third or terminaison phase, the therapist evaluates efficacy of the therapy, enhances the patient's independent functioning and develops strategies for relapse prevention. The further maintenance phase suggests differents strategies as maintenance therapy or focused intensive interventions on specific topics. PMID- 21237360 TI - Where were you? PMID- 21237361 TI - Interruptions experienced by registered nurses working in the emergency department. AB - INTRODUCTION: A descriptive, observational study was performed to determine (a) the frequency (number of interruptions per hour) that a typical ED nurse experiences interruptions, (b) the type of interruptions a typical ED nurse experiences, and (c) the percentage of interruptions that take place during medication related activities. METHODS: A convenience sample of 30 nurses from 3 emergency departments of a major metropolitan academic medical center were each observed for 120 minutes to determine how many interruptions per hour the ED nurse experienced, the type of interruptions and what percentage of these interruptions took place during medication-related activities. A data collection tool was developed to record tasks performed by the nurses and the type of interruptions experienced. Interrater reliability was established with a Kappa of 0.825. RESULTS: A total of 200 interruptions occurred during the 60 hours of observation, or 3.3 interruptions per hour per RN. Of the 20 possible types of interruptions that were identified a prior to the observation period, 11 different types of interruptions were actually observed. The majority of interruptions (95%) were related to face-to-face communications with others in the ED. The total number of interruptions related to medication activities was 55 (27.5% of the total number of interruptions). DISCUSSION: The results of this study can serve as the basis for subsequent, larger studies that examine more closely the relationship between interruptions and errors in the ED, with the ultimate goal of developing interventions to reduce medication errors and other adverse events that occur due to nurse interruptions. PMID- 21237362 TI - Evidence-based practice and family presence: paving the path for bedside nurse scientists. PMID- 21237363 TI - Barriers to screening and intervention for ED patients at risk for undiagnosed or uncontrolled hypertension. AB - OBJECTIVES: We describe clinician-reported knowledge of the Joint National Committee (JNC7) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure definitions of Stage I hypertension; perceived causes of elevated blood pressure; barriers to blood pressure re-assessment; risk of adverse events associated with the elevated blood pressure. METHODS: Health care providers from five emergency departments completed a questionnaire assessing knowledge of blood pressure criteria for hypertension, perceived causes of elevated blood pressures, barriers to re-assessment, and perceived risk of an adverse event at one year in a patient within three defined systolic and diastolic blood pressure ranges. Descriptive statistics were used to analyze the data. RESULTS: Seventy-two percent (379/524) of providers (68 attending physicians, 87 residents, 209 nurses, and 15 nurse practitioners) completed questionnaires. One hundred and four providers (27%) correctly listed the systolic and diastolic criteria for Stage 1 hypertension. Nurses and physicians rated uncontrolled, known hypertension [mean (standard deviation)] [8.7 (2.1), 8.9 (1.9)] the highest and pain [8.3 (2.3), 8.3 (2.1)] as the second highest cause of elevated BP. Nurses and physicians rated the lack of time to perform a reassessment [5.2 (3.4), 4.7 (2.8)] and a lack of adequate staffing [4.7 (3.4), 4.6 (2.9)] the highest as barriers to re-assessment. Nurses' mean adverse risk assessment twice that of physicians. DISCUSSION: Twenty seven percent of providers were aware of the JNC7 criteria and often attributed elevated blood pressures to chronic, uncontrolled hypertension, pain or anxiety. No single barrier to repeating elevated blood pressures was identified. PMID- 21237364 TI - Barriers and perceived needs for understanding and using research among emergency nurses. AB - INTRODUCTION: Nurses are involved in conducting research and incorporating evidence into their practice. However, barriers exist at the individual, unit, and organizational level related to understanding, conducting, and evaluating the evidence. The Emergency Nurses Association (ENA) conducted a study to understand levels of education in research, the extent of experience, and needs and barriers to research at the individual and organizational levels in emergency nursing. METHODS: A cross-sectional survey design was used to poll members of the ENA. A 62-item survey instrument was designed to assess five areas: 1) nurses' research values, skills, experience, and awareness; 2) organizational settings' opportunities, barriers, and limitations to research; 3) nurses' understanding and comprehension of research and evidence; 4) presentation and accessibility of research; and 5) continuing educational topics to improve knowledge of the research process. RESULTS: Respondents (n = 948) identified barriers at the individual level that included lack of knowledge about critiquing research studies and familiarity with the research process. Barriers at the unit level included obtaining help from administrators and other staff in starting a project or having the authority to change practice. Barriers at the institution level included lack of support systems such as protected time to conduct research or implement changes in practice. DISCUSSION: Emergency nurses are highly motivated and interested in learning more about conducting and utilizing research to improve practice. Perceived personal, unit-based, and organizational barriers were identified through this research in an effort to highlight areas for improvement at the local and national levels. PMID- 21237365 TI - Using action research to plan a violence prevention program for emergency departments. AB - INTRODUCTION: Although there are numerous studies that show that emergency department (ED) violence is a prevalent and serious problem for healthcare workers, there is a lack of published evaluations of interventions aimed at reducing this alarming trend. Using an action research model, the authors partnered with six hospitals to plan, implement and evaluate a violence prevention and management intervention. Phase one of this project involved gathering information from employees, managers and patients using focus groups. METHODS: Ninety-seven persons participated in one of twelve focus groups. The Haddon matrix was used to develop focus group questions aimed at gathering data about the pre-assault, during assault, and post-assault time frames and to compare these findings to planned strategies. Analysis consisted of identification of themes related to intervention strategies for patients/visitors, employees, managers, and the work environment. RESULTS: Thematic analysis results supported the relevance, feasibility, and saliency of the planned intervention strategies. With the exception of a few items, employees and managers from the different occupational groups agreed on the interventions needed to prevent and manage violence against ED workers. Patients focused on improved staff communication and comfort measures. DISCUSSION: Results support that violence in the emergency department is increasing, that violence is a major concern for those who work in and visit emergency departments, and that interventions are needed to reduce workplace violence. The Haddon matrix along with an action research method was useful to identify intervention strategies most likely to be successfully implemented and sustained by the emergency departments. PMID- 21237366 TI - Evaluating care in ED fast tracks. PMID- 21237367 TI - Detecting and treating sepsis in the emergency department. PMID- 21237368 TI - A 26-year-old woman with sudden onset cerebral edema. PMID- 21237370 TI - "Stand clear!" Tracing the practice and principles of human revival. PMID- 21237371 TI - Nursing dysphagia screening for acute stroke patients in the emergency department. PMID- 21237372 TI - Use of intravenous smart pumps for patient safety. PMID- 21237373 TI - Advocacy: nurses making a difference. PMID- 21237374 TI - Multigenerational workforce: are we using the literature effectively? PMID- 21237375 TI - Sedation and pain medications in the older adult. PMID- 21237376 TI - The effect of training programs on traditional approaches that mothers use in emergencies. AB - INTRODUCTION: The approach of the residents of central Kars, Turkey, to emergencies in our conservative district is shaped by the effect of the culture. In emergency actions, many traditional approaches are preferred, using herbs and other available materials. Some of these approaches might be directly hazardous and some create danger indirectly as they prolong the treatment period. METHODS: The study was performed using a one-group pretest/posttest design. Data were collected between June 3, 2006, and August 28, 2007. Two thousand sixty mothers completed the sociodemographic pretest and survey and attended the educational program. The final sample included 1754 mothers who completed the sociodemographic and pretest survey, attended the educational program, and completed the posttest survey. The posttest survey was administered 6 months following the educational program. RESULTS: In this study; the percentage of mothers resorting to traditional approaches in the pretest were at burns, 29.0%; lacerations, 21.4%; fractures, 25.7%; and poisoning, 45.1%; and in the posttest burns, 16.1%; lacerations, 12.7%; fractures, 15.6%; and poisoning, 34.4%. Mothers with higher educational levels were less likely to use traditional practices and the educational program significantly reduced the prevalence of using traditional practices. The training program had a positive effect in decreasing the incidence of resorting to traditional practices for certain emergencies. DISCUSSION: It was proven that the application of various harmful traditional practices had been used in first aid cases and that the rate decreased in the post training period. It is interesting to note that an additional 540 mothers who did not complete the pretest and sociodemographic questionnaire also attended the educational program because word of the program had spread throughout the region. PMID- 21237377 TI - Haiti mission--tell it from the heart. PMID- 21237379 TI - Competency and educational requirements: perspective of the rural emergency nurse. AB - INTRODUCTION: Continuing education has been associated with maintaining clinical competency for nurses. Despite this information, the availability, time, and financial support to attend continuing educational programs challenge the ability to develop, provide, or attend such programs. Before the development of methods to provide continuing educational programs to nurses working in rurally located emergency departments, a survey was developed to capture the perspective of these nurses. METHODS: An investigator-developed survey was administered to emergency nurses working within an emergency department located in a rural Midwestern state. Consent was implied upon return of the survey, and response to the survey was voluntary, in accordance with our institutional review board's policy. RESULTS: Data were obtained from 33 nurses, representing 3 different rurally located ED settings. The perceptions of the participants of this study are that maintaining clinical competency is important and that ongoing continuing education should be mandatory. DISCUSSION: These data indicate that emergency nurses in rural areas are willing to participate in ongoing education and that maintaining clinical competency is valued. Using evidence-based data to develop continuing educational programs increases the potential for the programs to be appropriate and valued and more likely to be attended by these nurses. PMID- 21237381 TI - Plant poisonings: common plants that contain cardiac glycosides. PMID- 21237380 TI - A 7-year-old child witnesses CPR. PMID- 21237382 TI - Behavioral emergencies: a closer look. PMID- 21237383 TI - Initial ECG acquisition within 10 minutes of arrival at the emergency department in persons with chest pain: time and gender differences. AB - INTRODUCTION: The American Heart Association recommends all patients presenting to the emergency department with complaints of chest pain/anginal equivalent symptoms receive an initial ECG within 10 minutes of presentation. The Synthesized Twelve-lead ST Monitoring & Real-time Tele-electrocardiography (ST SMART) study is a prospective randomized clinical trial that enrolls all subjects who call 911 for ischemic complaints in Santa Cruz County, California. ST SMART is a 5-year study ending in 2008. The primary aim of the ST SMART study is to determine whether subjects who receive prehospital ECG have more timely hospital intervention and better outcomes. OBJECTIVE: The aims of this secondary analysis of a subset of ST SMART study data were to determine (1) the rate of adherence to the American Heart Association goal in smaller community hospitals in less populous areas of receiving initial hospital ECG within the recommended 10 minutes and (2) whether there were gender differences in meeting this goal. METHODS: The dataset included patients 30 years of age and older who were transported by ambulance to 1 of 2 rural hospitals in Santa Cruz County. All patients received an initial hospital ECG after arrival at the emergency department. RESULTS: In this analysis of 425 patients (mean age, 70.4 years; 53% male), the mean time for all patients from ED arrival to initial ECG was 43 minutes (+/-145). The mean time to initial ECG was 34 minutes (+/-125) in male patients versus 53 minutes (+/-165) in female patients (Mann-Whitney test, P = .001). Forty-one percent of all patients presenting with ischemic symptoms received an initial ECG within 10 minutes of arrival. Forty-nine percent of male patients versus 32% of female patients received an initial ECG in 10 minutes or less (Fisher exact test, P = .000). CONCLUSION: In this analysis, the majority of patients with ischemic symptoms did not receive an ECG within 10 minutes of hospital presentation as recommended in evidence-based guidelines. There is a significant delay in door to time-to-ECG for women. ED nurses are in a unique position to initiate efforts to establish processes to decrease time to initial ECG for patients with ischemic symptoms. Attention to timely ECG acquisition in women may improve treatment of acute coronary syndromes in this group. PMID- 21237384 TI - Untangling health research governance in the UK. PMID- 21237385 TI - China's unhealthy relations with big tobacco. PMID- 21237386 TI - Health in Pakistan. PMID- 21237388 TI - Rani and Abhay Bang--pioneers of health care in rural India. PMID- 21237389 TI - Organ transplantation after cardiac death. PMID- 21237390 TI - Organ transplantation after cardiac death. PMID- 21237391 TI - Organ transplantation after cardiac death. PMID- 21237393 TI - Rituximab-containing therapy for chronic lymphocytic leukaemia. PMID- 21237394 TI - Rituximab-containing therapy for chronic lymphocytic leukaemia. PMID- 21237396 TI - UK Public Accounts Committee report on health inequalities. PMID- 21237397 TI - UK Public Accounts Committee report on health inequalities. PMID- 21237398 TI - Pakistan: the final frontier for a polio-free world. PMID- 21237399 TI - Trans-Pacific parallels. PMID- 21237400 TI - Use of email to acquire information from experts. PMID- 21237401 TI - Volcanic knee. PMID- 21237403 TI - A population-based case-series of Ontario patients who develop a vertebrobasilar artery stroke after seeing a chiropractor. AB - PURPOSE: The current evidence suggests that association between chiropractic care and vertebrobasilar artery (VBA) stroke is not causal. Rather, recent epidemiological studies suggest that it is coincidental and reflects the natural history of the disorder. Because neck pain and headaches are symptoms that commonly precede the onset of a VBA stroke, these patients might seek chiropractic care while their stroke is in evolution. However, very little is known about the characteristics of these patients. In fact, only small clinical case series and physician surveys have described the characteristics of chiropractic patients who later develop a VBA stroke. To date, no population based study has described this group of patients. Therefore, the objective of our study is to describe the characteristics of Ontario VBA stroke patients who consulted a chiropractor within the year before their stroke. METHODS: We conducted a population-based case series using administrative health care records of all Ontario residents hospitalized with VBA stroke between April 1, 1993, and March 31, 2002. Three databases were deterministically linked to extract the relevant information. We describe the demographic, health care utilization, and comorbidities of VBA patients. RESULTS: Ninety-three VBA stroke cases consulted a chiropractor during the year before their stroke. The mean age was 57.6 years (SD, 16.1), and 50% were female. Most cases had consulted a medical doctor during the year before their stroke, and 75.3% of patients had at least one cerebrovascular comorbidity. The 3 most common comorbidities were neck pain and headache (prevalence, 66.7%; 95% confidence interval [CI], 57.0%-76.3%), diseases of the circulatory system (prevalence, 63.4%; 95% CI, 54.8%-74.2%), and diseases of the nervous system and sense organs (prevalence, 47.3%; 95% CI, 38.7%-58.1%). CONCLUSIONS: Our population-based analysis suggests that VBA stroke patients who consulted a chiropractor the year before their stroke are older than previously documented in clinical case series. We did not find that women were more commonly affected than men. Moreover, we found that most patients had at least one cardio- or cerebrovascular comorbidity. Our analysis suggests that relying on case series or surveys of health care professionals may provide a biased view of who develops a VBA stroke. PMID- 21237402 TI - Evaluating the relationship among cavitation, zygapophyseal joint gapping, and spinal manipulation: an exploratory case series. AB - OBJECTIVE: This project determined the feasibility of conducting larger studies assessing the relationship between cavitation and zygapophyseal (Z) joint gapping following spinal manipulative therapy (SMT). METHODS: Five healthy volunteers (average age, 25.4 years) were screened and examined against inclusion and exclusion criteria. High-signal magnetic resonance imaging (MRI) markers were fixed to T12, L3, and S1 spinous processes. Scout images were taken to verify the location of the markers. Axial images of the L4/L5 and L5/S1 levels were obtained in the neutral supine position. Following the first MRI, accelerometers were placed over the same spinous processes; and recordings were made from them during side-posture positioning and SMT. The accelerometers were removed, and each subject was scanned in side-posture. The greatest central anterior to posterior Z joint spaces (gap) were measured from the first and second MRI scans. Values obtained from the first scan were subtracted from those of the second, with a positive result indicating an increase in gapping following SMT (positive gapping difference). Gapping difference was compared between the up-side (SMT) joints vs the down-side (non-SMT) joints and between up-side cavitation vs up-side noncavitation joints. RESULTS: Greater gapping was found in Z joints that received SMT (0.5 +/- 0.6 mm) vs non-SMT joints (-0.2 +/- 0.6 mm), and vertebral segments that cavitated gapped more than those that did not cavitate (0.8 +/- 0.7 vs 0.4 +/- 0.5 mm). CONCLUSIONS: A future clinical study is quite feasible. Forty subjects (30 in an SMT group and 10 in a control group) would be needed for appropriate power (0.90). PMID- 21237404 TI - Development and preliminary validation of the MedRisk instrument to measure patient satisfaction with chiropractic care. AB - OBJECTIVE: The purpose of this study is to provide preliminary information regarding the factor-structure, group- and individual-level reliability, and criterion-referenced validity of measures obtained from the MedRisk Instrument for Measuring Patient Satisfaction with Chiropractic Care. METHOD: Three hundred twenty-three subjects who had completed a course of chiropractic care responded to questionnaire in which they rated their degree of satisfaction from 1 to 5 (1 = very unsatisfied to 5 = very satisfied) for each of 20 items. Factor structure was assessed using item-correlation and exploratory factor analysis. Group-level reliability for single test administration was assessed by calculating Cronbach alpha, and individual-level reliability was determined using the standard error of measure. Criterion-referenced validity was investigated by comparing the item scores and mean scores of individual factors to global measures of satisfaction. RESULTS: Individual item scores ranged from 3.98 for "Office location was convenient" to 4.77 for "My chiropractor treats me respectfully." The items that were most highly correlated with overall patient satisfaction were "My chiropractor thoroughly explained the treatment I received" (r = 0.77) and "My chiropractor answered all of my questions" (r = 0.71). Exploratory factor analysis suggested a 2-factor solution: a 5-item "internal" factor and a 6-item "external" factor. The mean scores from these factors were correlated with the 2 global measures ranging from r = 0.68 to r = 0.80. The standard error of measure was 0.20 for the internal factor and 0.17 for the external factor. CONCLUSIONS: Preliminary assessment suggests that a 13-item version of the MedRisk instrument provides psychometrically sound measures to assess patient satisfaction with chiropractic care; however, additional confirmatory validation should be performed. PMID- 21237405 TI - Factor structure and concurrent/convergent validity of the modified somatic perception questionnaire and pain beliefs instrument. AB - OBJECTIVE: Our goal was to create a parsimonious combination of the Modified Somatic Perception Questionnaire (MSPQ) and the Pain Beliefs Screening Instrument (PBSI) through factorial structural analysis and to investigate the associations of the new scale (if unique) to disability, health condition, and quality of life report in patients with neck and low back pain scheduled for spine fusion surgery. METHODS: Factor analysis was used to refine all items within the 2 scales to 4 distinct factors: (1) somatic complaints of the head/neck, (2) somatic complaints of the gastrointestinal symptom, (3) pain beliefs and fear, and (4) self perception of serious problems. Each factor was assessed for concurrent validity with other well-established tools including the Deyo comorbidity index, the Short Form (SF)-36 mental and physical component subscales, and the Oswestry and Neck Disability Indices (ODI/NDI). RESULTS: The PBSI was fairly to moderately correlated with assessment tools of quality of life (SF-36) and disability assessment (ODI/NDI). Some of the items in the factor 1 from the MSPQ were slightly associated with the Deyo comorbidity index but not with the ODI/NDI. CONCLUSIONS: The items from the MSPQ failed to associate with measures of quality of life and disability and thus may provide only marginal value when assessing the multidimensional aspects associated with neck and low back pain. The PBSI has moderate correlation with disability assessments. Neither tool was found to strongly correlate with disability measures or with SF-36 scales (mental and physical component subscales). Additional tools may be needed to further identify the dimensions associated with chronic pain patients. PMID- 21237406 TI - Immediate effects of the audible pop from a thoracic spine thrust manipulation on the autonomic nervous system and pain: a secondary analysis of a randomized clinical trial. AB - PURPOSE: This study investigated the immediate effects of audible joint sounds following a supine T3-T4 spinal thrust manipulation on the autonomic nervous system activity using a fully automated pupillometry system in patients with chronic neck pain. An additional aim was to determine if audible sounds as perceived by the therapist were associated with the reduction of pain following manipulation. METHODS: One hundred subjects with chronic neck pain completed the study protocol. The Mann-Whitney U test was used to compare the change scores of the 3 measuring points between the one-pop and multiple-pop groups. Subjects were randomized into either a manipulation or a mobilization group. A method of automated pupillometry was used in this study to capture pupil responsiveness. RESULTS: The analysis showed that there was no significant difference between the 2 groups (P > .05). The Kruskal-Wallis test was used to compare the median change scores between the mobilization, no-pop, and pop groups. The analysis showed that there was no statistically significant difference in the amount of change in pupil diameter between the 3 groups (P > .05).The Mann-Whitney U test demonstrated that the no-pop group (P = .031) and the multiple-pop group (P = .014) had a significant reduction of pain; however, it did not reach the minimal clinically significant level of 13 mm on the visual analog scale. CONCLUSIONS: The results of this study provided evidence that the presence of joint sounds does not influence the overall activity of the autonomic nervous system following a thrust manipulation or contribute to the reduction of pain in patients with chronic neck pain. PMID- 21237407 TI - Changes in bending stiffness and lumbar spine range of movement following lumbar mobilization and manipulation. AB - OBJECTIVE: The purpose of this study was to investigate the effects of lumbar rotational manipulation and lumbar central posteroanterior mobilization on lumbar bending stiffness and flexion and extension range of motion (ROM). METHODS: A same-subject, repeated-measures, crossover design was used using 32 asymptomatic subjects (16 female and 16 male; mean [SD] age, 25.5 [4.5] years; weight, 65.7 [11.8] kg; and height, 1.70 [0.08] m). Each subject received mobilization or manipulation on 2 different occasions. Bending stiffness was calculated using a 3 point bending model using an electromagnetic tracking device and a force platform; lumbar flexion and extension ROM was measured using an electromagnetic tracking device. All variables were measured pre- and postintervention. Their effect was compared using paired t tests. RESULTS: Manipulation and mobilization did not significantly alter either bending stiffness or lumbar flexion and extension ROM (mobilization: P = .175, P = .613, and P = .535; manipulation: P = .973, P = .323, and P = .439). Bending stiffness changes were not correlated to changes in ROM (Pearson r for stiffness-flexion = -0.102, P = .586; Pearson r for stiffness-extension = 0.014, P = .941). CONCLUSIONS: Manipulation and mobilization had no significant effect on bending stiffness or flexion and extension ROM for this group of subjects. Some individual variations in effect were observed. PMID- 21237408 TI - A report of the 2009 World Games injury surveillance of individuals who voluntarily used the International Federation of Sports Chiropractic delegation. AB - OBJECTIVE: The purpose of this study was to describe the frequency and nature of injuries treated by the International Federation of Sports Chiropractic (FICS) chiropractic health care delegation at the 2009 World Games in Kaohsiung, Taiwan. METHODS: A cross-sectional study design with descriptive statistics was used to describe the standard patient care data recorded on FICS treatment forms of individuals voluntarily using FICS chiropractors. Data included patient demographics, region of the body, type of treatment provided, and pre- and posttreatment numerical pain levels. RESULTS: The FICS chiropractors recorded 1514 treatments to athletes and support personnel. There were 445 (49%) athletes and 450 (51%) nonathletes receiving care. The total number of athletes participating at the 2009 World Games was 2906 plus 2812 support staff; thus, our utilization rates are 15.31% for athletes and 16.00% for nonathletes. Total treatments were 854 for athletes and 660 for nonathletes, including follow-up care. Treatments to 17 different body regions were recorded. The highest recorded athlete treatment region was the lumbar spine at 309 (36.18%), with thoracic spine and neck being treated 195 (22.83%) and 193 (22.60%) times, respectively. Chiropractic manipulations were administered to 583 (68.27%) of the athletes treated. Mobilizations were given to 209 (24.47%), whereas 640 (74.94%) received myotherapy and 205 (24.00%) had tape applied. Pre- and posttreatment pain scales revealed that approximately 94% of patients experienced immediate improvement. CONCLUSION: These results demonstrate the findings of voluntary chiropractic care at a world-class multisport competition. PMID- 21237409 TI - Exercise therapy for office workers with nonspecific neck pain: a systematic review. AB - OBJECTIVE: The purpose of this study was to evaluate the effectiveness of various types of exercise for prevention and cure of nonspecific neck pain in office workers. METHODS: Publications between 1980 and April 2010 were systematically searched in various databases (PubMed, CINAHL Plus with full text, The Cochrane Library, Science Direct, PEDro, ProQuest, PsycNet, and Scopus). The following key words were used: neck pain, cervical pain, exercise, strengthening, stretching, endurance, office workers, visual display unit, visual display terminal, and computer users. A hand search of relevant journals was also carried out. Relevant randomized controlled trials were retrieved and assessed for methodological quality by 2 independent reviewers. The strength of the evidence was based on methodological quality and consistency of the results. RESULTS: Nine randomized controlled trials were included in this review, of which 6 were rated as high quality studies. No exercise type was identified as being effective in the prevention of nonspecific neck pain in office workers. Strong evidence was found for the effectiveness of muscle strengthening and endurance exercises in treating neck pain. Moderate evidence supported the use of muscle endurance exercise in reducing disability attributed to neck pain. CONCLUSION: Literature investigating the efficacy of exercise in office workers with nonspecific neck pain was heterogeneous. Within the limitations, for treatment of neck pain, either muscle strengthening or endurance exercise is recommended, whereas for reduction of pain related disability, muscle endurance exercise is suggested. Further research is needed before any firm conclusions regarding the most effective exercise programs for office workers can be reached. PMID- 21237411 TI - Anterior superior iliac spine asymmetry assessment on a novel pelvic model: an investigation of accuracy and reliability. PMID- 21237413 TI - CT evaluation of pulmonary venous anatomy variation in patients undergoing catheter ablation for atrial fibrillation. AB - To characterize pulmonary vein (PV) anatomy and the relative position of the PV ostia to the adjacent thoracic vertebral bodies, two readers reviewed 176 computed tomography pulmonary venous studies. PV ostial dimensions were measured and PV ovality assessed. Anatomical variations in PV drainage were noted. The position of the PV ostium relative to the nearest vertebral body edge was recorded. Right PV ostia were significantly more circular than the left (p<.001). Anatomical variability was greater for right PVs: 82% of patients had 2 ostia, 17% had 3 ostia, 0.5% had 4 ostia and 0.5% a common ostium. For left PVs, 91% of patients had 2 ostia, 8.5% a common ostium and 0.5% 3 ostia. Mean ostial distances from vertebral margin were: right PVs 3.62+/-7.48 mm; left PVs 3.84+/ 8.46 mm (p=.72). 65% of right upper PV, 60.5% of right lower PV, 51% of left upper PV and 57% of left lower PV ostia were positioned lateral to vertebral bodies. Right PV ostia are rounder than left-sided and right PV drainage is more variable. As a significant proportion of PV ostia overlap the vertebral bodies, prior anatomical evaluation by CT can assist catheter ablation procedures for atrial fibrillation (AF), especially when performed under fluoroscopy. PMID- 21237414 TI - CT Imaging findings of malignant neoplasms arising in the epigastric region in children. AB - The purpose of this article was to review the spectrum of common and rare malignant neoplasms arising in the epigastric region in children and to illustrate their characteristic computed tomography (CT) imaging features. Understanding the characteristic CT appearance of various malignant neoplasms, which can occur in the epigastric region in children, aids in accurate diagnosis and optimizes pediatric patient care. PMID- 21237415 TI - Solid-pseudopapillary neoplasm of the pancreas: spectrum of findings on multidetector CT. AB - Solid-pseudopapillary neoplasms of the pancreas are uncommon and usually occur in young women. They are generally large, encapsulated masses with mixture of solid, cystic, and hemorrhagic components. Some cases have atypical features; for example, they can form a small predominantly solid mass and produce dilatation of the main pancreatic duct. In this article we discuss and illustrate the spectrum of the appearances of this distinctive neoplasm on multidetector CT. PMID- 21237416 TI - Renal aneurysms and pseudoaneurysms. AB - Pseudoaneurysms and aneurysms are abnormal dilatations of the vessel lumen. Pseudoaneurysm is a perfused hematoma contained by the adventitia and perivascular tissues that is in communication with the lumen of an adjacent artery or vein. Aneurysm is a dilatation of the vessel lumen involving all three layers of the blood vessel wall. Renal artery aneurysms (RAA) are uncommon but the widespread use of cross-sectional imaging and incidental detection of RAA may result in an increasing number of cases diagnosed. Renal artery pseudoaneurysms are suspected in bleeding patients after penetrating renal trauma. Imaging plays a major role in the detection of renal pseudoaneurysms and aneurysms and diagnoses aneurysm rupture and active bleeding. Computed tomography (CT), magnetic resonance imaging, and digital subtraction angiography can characterize lesion size, shape, and location and identify other aneurysms and pseudoaneurysms, helping to narrow the differential diagnosis and to understand the vascular anatomy for guiding proper treatment. Endovascular treatments have contributed considerably in the management of renal pseudoaneurysms and aneurysms. The use of coil embolization or covered stent placement prevents the mortality and mobility of surgery. The article describes imaging features and the endovascular therapies to treat these vascular processes and their possible complications. PMID- 21237417 TI - Lateral ankle ligaments: MR arthrography with anatomic correlation in cadavers. AB - OBJECTIVE: The purpose of our study was to use magnetic resonance (MR) imaging and MR arthrography to demonstrate the anatomy of the lateral ankle ligaments using standard and oblique imaging planes in cadavers. MATERIAL AND METHODS: MR imaging of ten cadaveric ankles was performed before and after intra-articular administration of contrast solution. Proton-density MR images were acquired in standard and oblique imaging planes. MR imaging was correlated with anatomic sections. Measurements using oblique imaging planes were obtained to characterize the morphology of the lateral ligaments. RESULTS: The anterior talofibular ligament (ATFL) had a variable number of bands in all specimens, separated by fat signal oriented obliquely parallel to the long axis of the ligament. The fibular attachment of ATFL was located in close proximity to the fibular attachment of the distal band of the anterior tibiofibular ligament (AITFL). The angle formed by the calcaneofibular ligament (CFL) and the fibular shaft varied with different ankle positions. Special axial oblique plane best demonstrated the CFL. The posterior talofibular ligament (PTFL) was multi-fasciculated in appearance. Dorsiflexion of the ankle joint helped elongate the PTFL and best depicted this ligament in its entirety in the axial plane. CONCLUSION: Oblique imaging planes parallel to the long axis of the individual ligaments may improve visualization of the anatomy of the lateral ankle ligaments. The orientation of the lateral ankle ligaments is affected by the position of the talocrural and subtalar joints. Understanding the morphology of the lateral ankle ligaments can help radiologists diagnose abnormalities of these ligaments. PMID- 21237418 TI - PET/CT artifacts. AB - There are several artifacts encountered in positron emission tomography/computed tomographic (PET/CT) imaging, including attenuation correction (AC) artifacts associated with using CT for AC. Several artifacts can mimic a 2-deoxy-2-[18F] fluoro-d-glucose (FDG) avid malignant lesions and therefore recognition of these artifacts is clinically relevant. Our goal was to identify and characterize these artifacts and also discuss some protocol variables that may affect image quality in PET/CT. PMID- 21237419 TI - MRI findings of choroid plexus tumors in the cerebellum. AB - Choroid plexus tumors (CPTs) are uncommon primary intracranial tumors. Here, we describe two patients with CPTs of the cerebellum: one had a choroid plexus papilloma located in the left cerebellar hemisphere that presented as an irregular, lobulated and solid-cystic mass, whereas the other had a choroid plexus carcinoma that exhibited a poorly defined, mixed-intensity mass associated with invasion of adjacent brain parenchyma. Contrast-enhanced MR imaging showed prominent heterogeneous enhancement. CPTs should be considered in the differential diagnosis for irregular, heterogeneous and intensely enhancing masses that occur in the cerebellum. PMID- 21237420 TI - Multiple intra-abdominal venous thrombosis in ulcerative colitis: role of MDCT for detection. AB - Patients with ulcerative colitis are at increased risk for venous thrombosis. We report herein the case of a 28-year-old woman who developed multiple intraabdominal venous thrombosis, including partial Budd-Chiari syndrome in association with intracranial venous thrombosis and pulmonary embolism during the relapse of a known ulcerative colitis. Multidetector-row computed tomography (MDCT) allowed depiction of multiple intraabdominal sites of thrombosis including right and medial hepatic veins, left portal vein, splenic vein and left ovarian vein and demonstrated complete resolution of the multiple thrombi after anticoagulant therapy. The association of partial Budd-Chiari syndrome with other thrombi involving portal, splenic and ovarian veins in association with ulcerative colitis, has, to our knowledge never been reported yet. In addition, the potential role of MDCT in the detection of possible multiple thrombosis in patients with ulcerative colitis has never been emphasized. PMID- 21237421 TI - Celiac artery trunk thrombosis: an unusual complication of pancreatitis diagnosed on MRI. AB - Celiac artery trunk thrombosis is a rare complication of pancreatitis. Only two other cases have been reported in the English-language literature. Here, we present the clinical and multimodality imaging findings for a woman with pancreatitis who had continued pain after normalization of pancreatic enzyme levels and was unexpectedly found to have occlusion of her celiac trunk on follow up MRI. She was managed as an outpatient and had spontaneous resolution 2 weeks later. PMID- 21237422 TI - CT of unusual renal masses invading the pelvicaliceal system: potential mimics of upper tract transitional cell carcinoma. AB - Two patients with renal cell carcinoma and one patient with metastasis to the kidney from colorectal cancer are reported because all three cases manifested at computed tomography (CT) as a renal mass invading the pelvicaliceal system and radiologically simulating transitional cell carcinoma. Recognition that the CT finding of a renal mass with invasion of the pelvicaliceal system is not always indicative of a transitional cell carcinoma broadens the differential diagnosis in this setting and might potentially alter the diagnostic and therapeutic approach. PMID- 21237423 TI - Presentations and management of thyroglossal duct cyst in children versus adults: a review of 106 cases. AB - OBJECTIVE: The objective of this study was to determine the clinical presentations and management of thyroglossal duct cyst (TDC or thyroglossal tract remnant [TTR]) between children and adults and evaluate risk factors associated with recurrence after surgery for TDCs. STUDY DESIGN: A retrospective study of all patients with TDCs managed in our department from January 1998 through April 2008 was performed. All records were reviewed for age and sex, sizes and locations of cysts, diagnostic methods, surgical management, recurrences, and complications. Differences between children and adults and risk factors associated with recurrence were evaluated. RESULTS: A total of 106 patients (47 children and 59 adults) were treated for TDC. Of the children, 57.4% were male and 42.6% were female, whereas 50.8% of the adults were male and 49.2% were female. There were no significant differences in sex in either group (P > .49). The average age was 7.0 +/- 4.2 years in children and 36.0 +/- 18.0 years in adults, which demonstrates a bimodal distribution. Adults were significantly more likely than children to present with a complaint other than mass or infection (P < .01), including pain, dysphagia, dysphonia, and fistula formation. There was no significant difference in frequency of location between the adults and children. In this article, 94.9% (56/59) of the adults and 87.2% (41/47) of the children underwent a Sistrunk operation, whereas the others underwent cyst excision. There were 2 recurrences among adults and 3 among children, all of whom presented with an infected neck mass and were treated with a second Sistrunk procedure. The recurrence rates and complications between children and adults were not significantly different. CONCLUSIONS: The incidence of TDC was equal in males and females and had a bimodal distribution with similar incidence in children and adults. Adults were significantly more likely than children to present with a complaint other than mass or infection. The Sistrunk procedure is recommended as the main choice of treatment. Cyst infection may have a role in recurrence. PMID- 21237424 TI - Bilateral central ossifying fibroma affecting the mandible: report of an uncommon case and critical review of the literature. PMID- 21237425 TI - Investigation of the clinical and radiographic features of osteoarthrosis of the temporomandibular joints in adolescents and young adults. AB - OBJECTIVE: The objective of this study was to investigate the clinical and radiographic features of osteoarthrosis (OA) of the temporomandibular joints (TMJOA) in human adolescents and young adults. STUDY DESIGN: Patients (n = 4883) with temporomandibular disorders (age, 11 to 30 years) underwent clinical and radiographic examinations. The radiographic findings were classified as erosive bony changes, proliferative changes mainly, including flattening with uneven sclerosis, and osteophytes of the condyle, and bilaterally short condylar processes. In addition, we interpreted the reassessment radiographs of 156 of the patients. RESULTS: Seven hundred eleven patients had radiographic signs of OA. The frequency of OA was higher in women (563/3360, 16.8%) than in men (148/1523, 9.7%). Most patients (541/711, 76.1%) with signs of OA showed proliferative changes of OA. Moreover, 56.4% of patients with TMJOA (88/156) remained stable. CONCLUSIONS: These results suggest that although OA is an age-related disease, aging is not the crucial factor in the pathogenesis of OA. PMID- 21237426 TI - Expansive osseous dysplasia: report of 9 lesions in an African population sample and a review of the literature. AB - OBJECTIVES: The aim of this study was to report on the clinicopathologic features of osseous dysplasias (ODs) that manifest with gross expansion in a black South African hospital population sample. STUDY DESIGN: The files of 9 histology verified expansive ODs in 8 patients were reviewed. The clinical records and radiographs were analyzed and compared with reports in the literature. RESULTS: The main complaint of all patients was related to expansion of the jaw. All except 1 were female, with ages between 26 and 71 years and sizes of the lesions ranging from 4 to 15 cm. No history of similar lesions in family members was obtained. All lesions occurred in the mandible and 6 crossed the midline. The expansive growth pattern was associated with persistence of radiolucent areas in the lesions which microscopically consisted of cellular fibro-osseous tissue. Resorption of mineralized deposits by osteoclasts was prominent in the radiolucent parts of the lesion. Maturation with enlargement of the radiodense component was associated with a decrease in osteoclast activity and the formation of lobular bone masses and confluent psammomatous mineralized deposits. CONCLUSION: We propose the term "expansive osseous dysplasia" for the rare albeit important clinical subcategory of ODs that manifest with progressive jaw expansion. Suspension of osteoclast activity plays an important role in the maturation of the lesions into dense mineralized masses. PMID- 21237427 TI - The perceived prognosis of endodontic treatment and implant therapy among dental practitioners. AB - OBJECTIVE: The aims of this study were to understand if practicing dentists appreciate the difference in criteria for success used in the endodontic and implant literature, to evaluate the perceived outcome of implant therapy compared with endodontic treatment, and to evaluate current and projected utilization of implant and endodontic treatment. STUDY DESIGN: A 16-question survey was distributed to 648 dentists who graduated from the University of Connecticut Dental School over the past 30 years. RESULTS: The response rate was 47%. Forty nine percent of respondents did not know that different criteria are used in the literature to evaluate implant and root canal treatment. Thirty percent of respondents thought root canal treatment of teeth with necrotic pulp was superior to implants, and only 16% thought retreatment was preferable. CONCLUSION: A shift in utilization toward implant treatment was not found; however, a perceived superior outcome of implant compared with endodontic treatment does exist among the dental community. PMID- 21237428 TI - AADR TMD statement is timely and necessary. PMID- 21237429 TI - One has to wonder . . . PMID- 21237430 TI - New technologies on TMJ diagnosis. PMID- 21237432 TI - Atypical hard tissue formation around multiple teeth. PMID- 21237433 TI - Prospective study establishing a management plan for impacted third molar in patients undergoing hematopoietic stem cell transplantation. AB - OBJECTIVE: Although dental treatment before hematopoietic stem cell transplantation (HSCT) is essential to prevent serious infections from oral sources, the best management plan for impacted third molar (ITM) is unclear. STUDY DESIGN: This study was planned to establish a management plan for ITM. Eighty-four candidates for HSCT therapy were consecutively enrolled in the prospective trial. The management plan, which was evidence based and prospectively decided, was to extract the symptomatic ITMs and to leave the asymptomatic ones untreated, regardless of their impacted position. RESULTS: Eighty-seven ITMs were observed in 35 patients. The ITMs were in the maxilla of 25 patients and the mandible of 28 patients. Dental extraction of 7 teeth was performed in 6 patients without complications. All of the patients received the scheduled HSCT therapy and none experienced odontogenic infection while myelosuppressed. CONCLUSIONS: This management plan for ITM appears to be appropriate for pre-HSCT patients. Moreover, the experienced dental provider is suggested as a necessary and valuable part of the HSCT team. PMID- 21237434 TI - Bisphosphonates inhibit phosphorylation of signal transducer and activator of transcription 3 and expression of suppressor of cytokine signaling 3: implications for their effects on innate immune function and osteoclastogenesis. AB - OBJECTIVE: This study tested the effects of bisphosphonates (BPs) on the suppressor of cytokine signaling 3 (SOCS3) protein in macrophages. SOCS3 has been shown to regulate cell differentiation and survival; however, its potential role in mediating the effects of BPs has not been explored. STUDY DESIGN: The cell viability of murine RAW 267.4 macrophages was assessed after culturing with control medium or media containing increasing concentrations of 2 BPs (ibandronate or clodronate) for 24, 48, and 72 hours. The phosphorylation status of signal transducer and activator of transcription 3 (STAT3) and the expression of SOCS3 protein levels were determined by Western blot analysis. RESULTS: In control cultures, STAT3 phosphorylation and STAT3 and SOCS3 protein levels increased within 5 minutes after the addition of fresh medium. This increase was inhibited in cultures treated with both BPs. Macrophage cell viability also decreased after BP treatment. CONCLUSIONS: These data demonstrate that, in addition to their effects on macrophage viability, BPs can decrease STAT3 and SOCS3 expression, which are important modulators of immune responses and bone homeostasis. PMID- 21237435 TI - Comparative study of the effect of antiretroviral therapy on benign lymphoepithelial cyst of parotid glands and ranulas in HIV-positive patients. AB - OBJECTIVE: This study's aim was to assess the effect of highly active antiretroviral drugs (HAART) on benign lymphoepithelial cysts (BLEC) of the parotid and ranulas. STUDY DESIGN: The records of 10 HIV-positive patients who presented with BLEC were reviewed, and 14 HIV-positive patients who presented with ranulas were prospectively enrolled. Patients in both groups received the same combination of HAART and were clinically evaluated for the first 3 months. Patients with ranulas were followed for an additional 3 months. A clinical reduction in the size of the lesions was considered to be a positive outcome. RESULTS: All parotid glands with BLEC resolved within 3 months. No positive results were observed in ranulas during the first 3 months. However, some of the ranulas displayed a positive result after the initial 3 months of HAART. CONCLUSIONS: In contrast to BLEC, ranulas in HIV-positive patients seem to present a mixed and delayed response to HAART. PMID- 21237436 TI - CD27 and CD38 lymphocytes are detected in oral lichen planus lesions. AB - OBJECTIVE: Oral lichen planus (OLP) is a chronic disease with bandlike lymphocyte infiltration. STUDY DESIGN: To elucidate the immunologic phenotype of OLP, we analyzed the presence of CD5(+), CD20(+), CD27(+) and/or CD38(+) lymphocytes in a series of 70 atrophic OLP biopsy samples. RESULTS: CD27(+) and CD38(+) cells were present in 84% and 54% of the lesions, respectively. The lesions were graded as T cell dominant, B-cell dominant, or a mixed lesion based on CD5(+) and CD20(+) cells in the inflammatory infiltration with the following results: 26%, 7%, and 67%, respectively. CD27 expression was found in 67% of the T-cell dominant, in 80% of the B-cell dominant, and in 91% of mixed lesions. The corresponding figures for CD38 were 72%, 80%, and 62%. CONCLUSIONS: CD27(+) and CD38(+) lymphocytes represent abnormal mononuclear cell populations in atrophic OLP lesions indicating 2 forms of OLP might exist with different pathogenesis, despite similar histology and clinical behavior. PMID- 21237437 TI - Detection of TGIF1 homeobox gene in oral squamous cell carcinoma according to histologic grading. AB - OBJECTIVE: TGIF1 homeobox gene involvement in oral cancer has not yet been investigated. This study analyzed the expression of TGIF1 transcripts and protein in oral squamous cell carcinoma (OSCC). STUDY DESIGN: Snap-frozen samples from 16 patients were taken from both OSCC and nontumoral adjacent epithelium (NT) for in situ hybridization (ISH). Forty-six paraffin-embedded samples of OSCC were submitted to immunohistochemistry (IHC). A descriptive analysis of the transcript signal detection was accomplished, and TGIF1 immunoexpression was carried out considering protein levels, localization, and cellular differentiation. RESULTS: ISH reactions showed TGIF1 transcripts with a signal that was frequently intense in NT, and generally weak in OSCC, and that had stronger transcript signal in well-differentiated areas of OSCC when compared with poorly differentiated ones. IHC reactions had poorly differentiated cases associated with TGIF1 protein expression in both the nucleus and cytoplasm (P = .05, Fisher test). CONCLUSIONS: TGIF1 gain or loss of function might possibly play a role in oral cancer cell differentiation. PMID- 21237438 TI - Multifocal lateral periodontal cysts: a report of 4 cases and review of the literature. AB - Lateral periodontal cyst (LPC) is a developmental jaw cyst of odontogenic origin. It has characteristic histopathologic features that are identical to those seen in the peripherally occurring gingival cyst of adults (GCA). The polycystic variant of LPC is termed the botryoid odontogenic cyst (BOC). The histogenetic origin of LPC is probably the rests of dental lamina in the alveolar bone. In the case of BOC, it might be that several adjacent epithelial rests simultaneously undergo cystic change and eventually form a polycystic lesion. Few previous examples of multifocal occurrence of LPC can be found in the literature. We report an additional 4 patients with this rare presentation of multiple, separate LPCs, and review the literature on this topic. PMID- 21237439 TI - Use of cone-beam computed tomography in endodontics Joint Position Statement of the American Association of Endodontists and the American Academy of Oral and Maxillofacial Radiology. PMID- 21237440 TI - American Academy of Oral and Maxillofacial Radiology commentary: position papers in perspective. PMID- 21237442 TI - Integration of disparity and velocity information for haptic and perceptual judgments of object depth. AB - Do reach-to-grasp (prehension) movements require a metric representation of three dimensional (3D) layouts and objects? We propose a model relying only on direct sensory information to account for the planning and execution of prehension movements in the absence of haptic feedback and when the hand is not visible. In the present investigation, we isolate relative motion and binocular disparity information from other depth cues and we study their efficacy for reach-to-grasp movements and visual judgments. We show that (i) the amplitude of the grasp increases when relative motion is added to binocular disparity information, even if depth from disparity information is already veridical, and (ii) similar distortions of derived depth are found for haptic tasks and perceptual judgments. With a quantitative test, we demonstrate that our results are consistent with the Intrinsic Constraint model and do not require 3D metric inferences (Domini, Caudek, & Tassinari, 2006). By contrast, the linear cue integration model (Landy, Maloney, Johnston, & Young, 1995) cannot explain the present results, even if the flatness cues are taken into account. PMID- 21237441 TI - Influence of tongue/mandible volume ratio on oropharyngeal airway in Japanese male patients with obstructive sleep apnea. AB - OBJECTIVES: The objective of this study was to investigate the influence on the upper airway of the size ratio of tongue and mandible (T/M ratio) with 3D reconstructed models from computed tomography (CT) data. STUDY DESIGN: The subjects were 40 OSA male patients. The age of the patients ranged from 25 to 77 years, with an average age of 52.6 +/- 12.5 years. The body mass index (BMI) of the patients ranged from 20.1 to 35.8 kg/m(2), with an average BMI of 25.4 +/- 3.4 kg/m(2). All patients underwent a full-night polysomnography. The mean AHI for our subjects was 23.6 +/- 18.3 events per hour. CT imaging examinations were carried out in each patient. The mandible and airway volume (between posterior nasal spine [PNS] and the tip of the epiglottis) were segmented based on Hounsfield units, automatically or semi-automatically, and their volume was calculated from the number of voxels. The tongue was carefully outlined, and the inside of the tongue was smeared on each of the axial, frontal, and sagittal planes with a semi-automatic segmentation tool. The tongue/mandible (T/M) ratio was calculated from the volume of the mandible and the tongue. In addition, we investigated simple correlations between our anatomical variables and BMI, age, and AHI. RESULTS: In this study, the mean tongue and mandible volume were 79.00 +/- 1.06 cm(3) and 87.80 +/- 1.21 cm(3), respectively. As BMI increases, tongue volume increases (P = .004) and airway volume decreases (P = .021). However, no significant correlation was found between severity of OSA (AHI) and other variables. On the other hand, there was a negative correlation between airway volume and T/M ratio (P = .046). CONCLUSION: As tongue volume increases with BMI, the posterior airway is affected, and thus is likely to be involved in the development of OSA; however, in this study there was no correlation between the severity of sleep apnea (AHI) and other variables in the study. PMID- 21237443 TI - The attentional blink is diminished for targets that form coherent semantic categories. AB - Studies have shown that the attentional blink (AB) effect is diminished for intrinsically salient T2 stimuli, such as arousing, familiar, personally relevant words, or stimuli with salient low-level visual features. We examined whether the AB is diminished also for stimuli that do not have special inherent properties but are made salient by the context. One such contextual factor is the coherence of the T2 stimulus set. In three experiments, we found that the AB is diminished for stimuli that form a coherent semantic category within the T2 stimulus set. Both theoretical and practical implications are discussed. PMID- 21237445 TI - A formative approach to developing synthetic environment fidelity requirements for decision-making training. AB - This paper describes a new approach for developing design specifications for synthetic environments that support decisions making training. The approach starts by modelling the constraints governing decision-making activity in the real world. A focus is placed on what could happen in the decision-making process, rather than what does or what should. Importantly, the developed model is independent of specific actors and events, providing a robust description of the domain that remains applicable in almost all perceivable situations. By modelling the relationship between information elements, and the way decision makers develop an understanding of their environment, the approach identifies the information that may be pertinent to the decision-maker. It is contended that the approach has utility in the design of first-of-a-kind synthetic environments, as well as the evaluation of existing simulators for the specific role of decision making training. PMID- 21237446 TI - Generalization of conditioned responding: effects of autobiographical memory specificity. AB - Generalization of acquired responses appears to be a crucial, yet under investigated process in emotional disorders. Generalization occurs when a conditioned response is elicited by a stimulus different from the original conditioned stimulus. The expansion of complaints, often seen in emotional disorders, is at least in part due to processes of generalization. In the present study, generalization is approached from a memory perspective. It is hypothesized that generalization of conditioned responding is associated with autobiographical memory specificity. Higher levels of generalization are predicted for people who are characterized by limited memory specificity. In a human contingency-learning procedure, participants learned the association between two pictures of female faces and a schematic drawing of a lightning bolt. Subsequently, six morphed pictures functioning as generalization stimuli (GSs) were introduced and conditioned responses to these GSs were measured. The results showed that memory specificity was significantly associated with the extent of generalization. Participants low in autobiographical memory specificity exhibited significantly stronger conditioned responses to GSs as compared to participants high in autobiographical memory specificity. PMID- 21237447 TI - De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism. AB - BACKGROUND: Little is known about the genetics of nonsyndromic intellectual disability (NSID). Recently, we reported de novo truncating mutations in the SYNGAP1 gene of 3 of 94 NSID cases, suggesting that its disruption represents a common cause of autosomal dominant NSID. METHODS: To further explore the involvement of SYNGAP1 in NSID, we sequenced its exons and intronic boundaries in 60 additional sporadic cases of NSID, including 30 patients with autism spectrum disorders (ASD) and 9 with epilepsy, and in 380 control individuals. RESULTS: We identified de novo out-of-frame deletions in two patients with NSID and mild generalized epilepsy (c.2677delC/p.Q893RfsX184 and c.321_324delGAAG/p. K108VfsX25) and a de novo splicing mutation (c.2294 + 1G>A), which results in the creation of a premature stop codon, in a patient with NSID and autism. No splicing or truncating mutations were found in control subjects. CONCLUSIONS: We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism. PMID- 21237448 TI - A combined theoretical and spectroscopic study of 4,6-di-O-acetyl-2,3-dideoxy-D erythro-hex-2-enopyranosyl sulfamide: a novel glycosyl carbonic anhydrase IX inhibitor. AB - The novel 4,6-di-O-acetyl-2,3-dideoxy-D-erythro-hex-2-enopyranosyl sulfamide, which exhibits selectivity for inhibiting isoform IX of carbonic anhydrase as overexpressed in many tumors, has been investigated from a combined theoretical and spectroscopic point of view. The conformational study of the compound shows that the alpha-anomeric form is more stable than the beta-anomeric form from a thermodynamic point of view after including solvent effects. This fact suggests that the synthesis reaction could take place mainly under thermodynamic control as the main experimental product is the alpha-anomeric form of the sulfamide. Calculated alpha/beta ratio is about 95:5, in excellent agreement with experimental data. Optimized geometries of the alpha-anomeric form agree quite well with crystallographic data. The inclusion of a solvent has negligible effects on the conformations. A detailed analysis of some geometric parameters shed light into the conformational behavior of the sulfamide in terms of both exo and endo-anomeric effects and antiperiplanar relationships. Natural bond orbital calculations confirm those findings. Several intramolecular hydrogen bonds, characterized through the Atoms-in-Molecules theory, were found in the stable conformers. They, however, seem to play no relevant role in determining the relative stability of alpha conformers with respect to the beta ones. Calculated (1)H and (13)C NMR chemical shifts support previous findings concerning configuration and conformation assignments of the title sulfamide. The IR spectrum of the compound is recorded and reported for the first time and the assignment of some of the most important bands is accomplished with the aid of calculated harmonic vibrational frequencies. PMID- 21237449 TI - Are children with Specific Language Impairment competent with the pragmatics and logic of quantification? AB - Specific Language Impairment (SLI) is understood to be a disorder that predominantly affects phonology, morphosyntax and/or lexical semantics. There is little conclusive evidence on whether children with SLI are challenged with regard to Gricean pragmatic maxims and on whether children with SLI are competent with the logical meaning of quantifying expressions. We use the comprehension of statements quantified with 'all', 'none', 'some', 'some...not', 'most' and 'not all' as a paradigm to study whether Spanish-speaking children with SLI are competent with the pragmatic maxim of informativeness, as well as with the logical meaning of these expressions. Children with SLI performed more poorly than a group of age-matched typically-developing peers, and both groups performed more poorly with pragmatics than with logical meaning. Moreover, children with SLI were disproportionately challenged by pragmatic meaning compared to their age matched peers. However, the performance of children with SLI was comparable to that of a group of younger language-matched typically-developing children. The findings document that children with SLI do face difficulties with employing the maxim of informativeness, as well as with understanding the logical meaning of quantifiers, but also that these difficulties are in keeping with their overall language difficulties rather than exceeding them. The implications of these findings for SLI, linguistic theory, and clinical practice are discussed. PMID- 21237451 TI - Listeners' comprehension of uptalk in spontaneous speech. AB - Listeners' comprehension of phrase final rising pitch on declarative utterances, or uptalk, was examined to test the hypothesis that prolongations might differentiate conflicting functions of rising pitch. In Experiment 1 we found that listeners rated prolongations as indicating more speaker uncertainty, but that rising pitch was unrelated to ratings. In Experiment 2 we found that prolongations interacted with rising pitch when listeners monitored for words in the subsequent utterance. Words preceded by prolonged uptalk were monitored faster than words preceded by non-prolonged uptalk. In Experiment 3 we found that the interaction between rising pitch and prolongations depended on listeners' beliefs about speakers' mental states. Results support the theory that temporal and situational context are important in determining intonational meaning. PMID- 21237450 TI - The time course of anticipatory constraint integration. AB - Several studies have demonstrated that as listeners hear sentences describing events in a scene, their eye movements anticipate upcoming linguistic items predicted by the unfolding relationship between scene and sentence. While this may reflect active prediction based on structural or contextual expectations, the influence of local thematic priming between words has not been fully examined. In Experiment 1, we presented verbs (e.g., arrest) in active (Subject-Verb-Object) sentences with displays containing verb-related patients (e.g., crook) and agents (e.g., policeman). We examined patient and agent fixations following the verb, after the agent role had been filled by another entity, but prior to bottom-up specification of the object. Participants were nearly as likely to fixate agents "anticipatorily" as patients, even though the agent role was already filled. However, the patient advantage suggested simultaneous influences of both local priming and active prediction. In Experiment 2, using passive sentences (Object Verb-Subject), we found stronger, but still graded influences of role prediction when more time elapsed between verb and target, and more syntactic cues were available. We interpret anticipatory fixations as emerging from constraint-based processes that involve both non-predictive thematic priming and active prediction. PMID- 21237452 TI - Working memory, attention, and executive function in Alzheimer's disease and frontotemporal dementia. AB - Working memory deficits are a recognised feature of Alzheimer's disease (AD). They are commonly ascribed to central executive impairment and assumed to relate to frontal lobe dysfunction. Performance failures on standard tests of attention and executive function reinforce this interpretation. Nevertheless, early-onset AD patients do not show the frank behavioural changes indicative of frontal lobe dysfunction, and the characteristic functional neuroimaging changes are in posterior hemispheres rather than frontal lobes. We explored this anomaly through a comparison of working memory, attention and executive test performance in patients with AD (a 'typical' early-onset group with deficits in memory, language and perceptuospatial function and an 'amnesic' group) and frontotemporal dementia (FTD). Typical-AD and FTD patients both showed impaired performance, whereas amnesic-AD patients performed well. Despite similar quantitative performance measures, typical-AD and FTD patients showed qualitatively distinct performance profiles. Impairments in FTD patients were interpreted in 'frontal' executive terms as deficits in attention, set shifting and response inhibition. AD patients' performance appeared to be influenced by information load and was interpreted in terms of working memory capacity. In keeping with these different interpretations, neuroimaging showed characteristic frontal lobe abnormalities in FTD and temporoparietal change in typical-AD. The findings highlight the importance of the posterior hemispheres in working memory and point to a need for caution in the automatic attribution of working memory, attention and executive test failures to frontal lobe failure. They underline also the phenotypic variation within AD. PMID- 21237453 TI - Corticotropin-releasing hormone inhibits in vitro oocyte maturation in mice. AB - The expression of corticotropin-releasing hormone (CRH) receptor 1 messenger RNA in stages of follicle growth was examined by reverse transcriptase-polymerase chain reaction in long-term cultures of early preantral mouse follicles with and without CRH addition. Corticotropin-releasing hormone receptor 1 is present in stages of mouse follicle growth, whereas 10(-9), 10(-7), and 10(-6) mol/L CRH inhibits oocyte maturation in vitro, an effect reversed by antalarmin addition. PMID- 21237454 TI - Direct endoscopic necrosectomy for the treatment of walled-off pancreatic necrosis: results from a multicenter U.S. series. AB - BACKGROUND: Direct endoscopic necrosectomy (DEN) for treatment of walled-off pancreatic necrosis (WOPN) has been performed as an alternative to operative or percutaneous therapy. OBJECTIVE: To report the largest combined experience of DEN performed for WOPN. DESIGN: Retrospective chart review. SETTING: Six U.S. tertiary medical centers. PATIENTS: A total of 104 patients with a history of acute pancreatitis and symptomatic WOPN since 2003. INTERVENTIONS: DEN for WOPN. MAIN OUTCOME MEASUREMENTS: Resolution or near-resolution of WOPN without the need for surgical or percutaneous intervention and procedural complications. RESULTS: Successful resolution was achieved in 95 of 104 patients (91%). Of the patients in whom it failed, 5 died during follow-up before resolution, 2 underwent operative drainage for persistent WOPN, 1 required surgery for massive bleeding on fistula tract dilation, and 1 died periprocedurally. The mean time to resolution from the initial DEN was 4.1 months. The first debridement was performed a mean of 63 days after the initial onset of acute pancreatitis. In 73%, the entry was transgastric with median tract dilation diameter of 18 mm. The median number of procedures was 3 with 2 debridements. Complications occurred in approximately 14% and included 5 retrogastric perforations/pneumoperitoneum, which were managed nonoperatively. Univariate analysis identified a body mass index >32 as a risk factor for failed DEN. LIMITATIONS: Retrospective, highly specialized centers. CONCLUSIONS: This large, multicenter series demonstrates that transmural, minimally invasive endoscopic debridement of WOPN performed in the United States is an efficacious and reproducible technique with an acceptable safety profile. PMID- 21237455 TI - Carbon dioxide insufflation compared with air insufflation in double-balloon enteroscopy: a prospective, randomized, double-blind trial. AB - BACKGROUND: Few studies have evaluated the degree of pain, the amount of retained gas, and the safety of carbon dioxide (CO(2)) insufflation in patients undergoing double-balloon enteroscopy (DBE). OBJECTIVE: To clarify the usefulness and safety of CO(2) insufflation during DBE. DESIGN: Single-center, prospective, randomized, double-blind, controlled trial. SETTING: University hospital. PATIENTS: Forty eligible patients with small-bowel disease for whom DBE was indicated were randomized to a CO(2) insufflation (CO(2)) group or an air insufflation (air) group by means of sealed envelopes. INTERVENTION: DBE with insufflation of CO(2) or air. MAIN OUTCOME MEASUREMENTS: Efficacy evaluation was based on the degree of pain as assessed by use of a visual analog scale (VAS) and the amount of residual gas retention within the small and large bowels on radiography. The safety of CO(2) insufflation was evaluated by arterial blood gas analysis. RESULTS: Significantly fewer patients in the CO(2) group had severe pain of >= 50 mm on the VAS during DBE than in the air group (P = .02). Significantly less gas was retained in the small bowel just after and at 3 hours after DBE in the CO(2) group than in the air group (P = .003, P = .01, respectively). There was significantly less residual gas retention in the large bowel at 3 hours after DBE in the CO(2) group than in the air group (P = .02). There was no significant difference in pre-DBE and post-DBE partial pressure of oxygen in the blood (PaO(2)) and partial pressure of carbon dioxide in the blood (PaCO(2)) between groups. LIMITATIONS: Small sample size. CONCLUSION: CO(2) insufflation is a safe and useful procedure when performed during DBE. PMID- 21237456 TI - Drainage of a para-aortic abscess by transrectal endoscopic retroperitoneoscopy (with video). PMID- 21237457 TI - Radiofrequency ablation-associated necrosis of the hepatic duct confluence: re establishing biliary continuity with percutaneous cholangiographic-peroral cholangioscopic rendezvous (with videos). PMID- 21237459 TI - Safety and long-term outcomes of endoscopic papillary balloon dilation in children with bile duct stones. AB - BACKGROUND: Although experience with diagnostic and therapeutic ERCP in children is growing, little is known about the safety and technical outcomes of endoscopic papillary balloon dilation (EPBD) in pediatric patients with bile duct stones (BDSs). OBJECTIVE: To assess the safety and long-term outcomes of EPBD in pediatric patients with BDSs. DESIGN: Case study. SETTING: Tertiary referral center. PATIENTS AND INTERVENTIONS: This study involved 5 children who had BDSs combined with gallstones who underwent EPBD. MAIN OUTCOME MEASUREMENTS: Successful EPBD, successful stone removal, procedure-related complications, and long-term outcomes. RESULTS: ERCP was successful in all cases, with cannulation and subsequent EPBD. Stone removal was performed in 1 session in all patients. No EPBD-related complications were observed in any patient. After EPBD, 1 patient subsequently underwent laparoscopic cholecystectomy for gallstones. The remaining 4 were followed without surgery. In 2 patients, gallstones were spontaneously passed from the bile duct into the duodenum. During the follow-up period, over a mean of 7.1 years (range 3.7-9.3 years), no recurrence of BDSs was observed in any patient. LIMITATIONS: Small number of patients. CONCLUSIONS: Although BDSs are rare in pediatric patients, EPBD may be a safe and effective technique for the management of such stones in some children. PMID- 21237458 TI - Computer-assisted personalized sedation. AB - The American Society for Gastrointestinal Endoscopy (ASGE) Technology Committee provides reviews of new or emerging endoscopic technologies that have the potential to have an impact on the practice of GI endoscopy. Evidence-based methodology is used, with a MEDLINE literature search to identify pertinent preclinical and clinical studies on the topic, and a MAUDE (Manufacturer and User Facility Device Experience; U.S. Food and Drug Administration Center for Devices and Radiological Health) database search to identify the reported complications of a given technology. Both are supplemented by accessing the "related articles" feature of PubMed and by scrutinizing pertinent references cited by the identified studies. Controlled clinical trials are emphasized but, in many cases, data from randomized, controlled trials are lacking. In such cases, large case series, preliminary clinical studies, and expert opinions are used. Technical data are gathered from traditional and Web-based publications, proprietary publications, and informal communications with pertinent vendors. For this review, the MEDLINE database was searched through January 2010 using the keywords "computer," "computerized," "computer-assisted," "sedation," "propofol." Reports on Emerging Technology are drafted by 1 or 2 members of the ASGE Technology Committee, reviewed and edited by the committee as a whole, and approved by the Governing Board of the ASGE. These reports are scientific reviews provided solely for educational and informational purposes. Reports on Emerging Technology are not rules and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment or payment for such treatment. PMID- 21237460 TI - Scoring systems for outcome after knee injuries. AB - Outcome assessment after knee injuries and periarticular fractures are not well described in the literature. This review focuses on outcome assessment, specifically surveying various scoring systems after knee trauma. Additionally, we include a report on a series of 637 patients with multiple injuries that were re-examined at least 10 years after the inciting incident. The series includes 48 patients with lower extremity injuries isolated to the knees, and for comparison, 107 poly-traumatized patients with femoral diaphyseal fractures and no other lower extremity injuries. The outcomes were assessed utilizing the Lysholm score, the Tegner activity score, the Hannover Score for Polytrauma Outcome (HASPOC), and the 12-item short-form health survey (SF-12). We calculated correlation coefficients to compare the general health questionnaires with the more specific knee scores. For the comparison of knee injured patients with femoral shaft fracture patients, we applied the Wilcoxon test. With respect to the Tegner activity score, we observed deterioration from a mean preoperative score of 5.0, to 2.8 points at follow up. The mean Lysholm score was 81.97, ranging from 15 to 100 points. However, there was no correlation between results obtained from the Lysholm score with the results of the general health questionnaires. Although not statistically significant, the general health questionnaires (HASPOC and SF-12) trended towards a less favourable outcome for polytraumatized patients who sustained a knee injury in comparison to those with a femoral shaft fracture. In conclusion, the outcomes of knee injuries in poly-traumatized patients are rather heterogeneous, but generally are worse than in those with lower extremity injuries that spare the knee joint. PMID- 21237461 TI - Porous microcapsule formation with microsieve emulsification. AB - A simple route is presented to prepare core-shell Eudragit microcapsules through a solvent extraction method with the use of microsieve emulsification. Droplets from a solution of Eudragit FS 30D (a commercial copolymer of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1) and hexadecane in dichloromethane are dispersed into water, using a micro-engineered membrane with well-defined pores, in a cross-flow setting. The dichloromethane is extracted from the droplets, which induces demixing in the droplets, leading to a hexadecane-rich core, and an Eudragit-rich shell. The obtained microcapsules have a narrow size distribution due to the microsieve emulsification process. The capsules have a porous shell as shown by SEM and AFM measurements. Their porosity and pore size is dependent on the ratios of Eudragit and hexadecane in the dispersed phase. At pH 7.1 and above Eudragit (FS 30D) dissolves in water; this pH change is used to release the contents of the microcapsule. PMID- 21237462 TI - Dielectrophoretic alignment of metal and metal oxide nanowires and nanotubes: a universal set of parameters for bridging prepatterned microelectrodes. AB - Nanowires and nanotubes were synthesized from metals and metal oxides using templated cathodic electrodeposition. With templated electrodeposition, small structures are electrodeposited using a template that is the inverse of the final desired shape. Dielectrophoresis was used for the alignment of the as-formed nanowires and nanotubes between prepatterned electrodes. For reproducible nanowire alignment, a universal set of dielectrophoresis parameters to align any arbitrary nanowire material was determined. The parameters include peak-to-peak potential and frequency, thickness of the silicon oxide layer, grounding of the silicon substrate, and nature of the solvent medium used. It involves applying a field with a frequency >10(5) Hz, an insulating silicon oxide layer with a thickness of 2.5 MUm or more, grounding of the underlying silicon substrate, and the use of a solvent medium with a low dielectric constant. In our experiments, we obtained good results by using a peak-to-peak potential of 2.1 V at a frequency of 1.2 * 10(5) Hz. Furthermore, an indirect alignment technique is proposed that prevents short circuiting of nanowires after contacting both electrodes. After alignment, a considerably lower resistivity was found for ZnO nanowires made by templated electrodeposition (2.2-3.4 * 10(-3) Omegam) compared to ZnO nanorods synthesized by electrodeposition (10 Omegam) or molecular beam epitaxy (MBE) (500 Omegam). PMID- 21237463 TI - Mesoporous silica hybrid membranes for precise size-exclusive separation of silver nanoparticles. AB - One-dimensional (1D) nanomaterials have unique applications due to their inherent physical properties. In this study, hexagonally ordered mesoporous silica hybrid anodic alumina membranes (AAM) were synthesized using template-guided synthesis with a number of nonionic n-alkyl-oligo(ethylene oxide), Brij-type (C(x)EO(y)), which are surfactants that have different molecular sizes and characteristics. The hexagonal mesoporous silicas are vertically aligned in the AAM channels with a predominantly columnar orientation. The hollow mesostructured silicas had tunable pore diameters varying from 3.7 to 5.1 nm. In this synthesis protocol, the surfactant molecular natures (corona/core features) are important for the controlled generation of ordered structures throughout AAM channels. The development of ultrafiltration membranes composed of silica mesostructures could be used effectively in separating silver nanoparticles (Ag NPs) in both aqueous and organic solution phases. This would be relevant to the production of well defined Ag NPs with unique properties. To create a size-exclusive separation system of Ag NPs, we grafted hydrophobic trimethylsilyl (TMS) groups onto the inner pores of the mesoporous silica hybrid AAM. The immobilization of the TMS groups allowed the columnar mesoporous silica inside AAM to retain this inner pore order without distortion during the separation of solution-phase Ag NPs in organic solvents that may cause tortuous-pore membranes. Mesoporous TMS-silicas inside 1D AAM channels were applicable as a size-exclusive separation system to isolate organic solution-phase Ag NPs of uniform morphology and size. PMID- 21237464 TI - Disruption of reverse micelles and release of trapped ribonuclease A photochemically induced by Malachite Green leuconitrile derivative. AB - Photoinduced disruption of a sodium bis(2-ethylhexyl) sulfosuccinate (AOT) reverse micelle is triggered by a Malachite Green leuconitrile derivative (MGL). UV irradiation of MGL solubilized in an AOT-water-chloroform mixture creates a cationic surfactant that interacts electrostatically with the anionic AOT. We investigated the disruption of the reverse micelle by using proton nuclear magnetic resonance spectroscopy and found that UV irradiation of MGL decreases the number of water molecules solubilized in the interior of the AOT reverse micelles. Furthermore, the photoinduced disruption of the reverse micelle is shown to release ribonuclease A, which is trapped in the water in the interior of the AOT reverse micelle. This photoinduced release may offer a desirable transport system of biopolymers. PMID- 21237465 TI - Characterization of pH-induced changes in the morphology of polyelectrolyte multilayers assembled from poly(allylamine) and low molecular weight poly(acrylic acid). AB - We report characterization of pH-dependent behavior in polyelectrolyte multilayers (PEMs) fabricated from poly(allylamine) (PAH) and low molecular weight poly(acrylic acid) (PAA) synthesized by living/controlled polymerization. Exposure of these films to solutions of low pH (e.g. pH 2.0-3.2) resulted in transformations from films that were smooth and uniform to films with porous morphologies, as characterized by scanning electron microscopy (SEM). We observed large differences in both the extent of this transformation and the sizes of the pores that resulted compared to films fabricated using higher molecular weight PAA used in past studies. Whereas transformations reported in past studies generally lead to pores with sizes in the range of 0.3-2 MUm, we observed larger scale transformations and films with cell-like internal structures comprised of networks of closed pores, interconnected pores, and through-pores with sizes as large as 10-15 MUm depending on pH and the manner in which the films were incubated. Films fabricated using fluorescently end-labeled samples of PAA permitted real-time imaging of changes in internal structure using confocal microscopy (LSCM). The results of these studies also revealed large differences in the nature of these transformations when films were placed in contact with surfaces as opposed to when dipped into aqueous solutions. Our results reveal approaches that can be used to fabricate films with large pores (e.g., pores with sizes on the order of 10-15 MUm) and suggest methods that could potentially be used to generate PEMs having controlled gradients in pore size. PMID- 21237466 TI - In-pore tensile stress by drying-induced capillary bridges inside porous materials. AB - We present here some evidences that capillary liquid bridges are able to deform micrometric cylindrical pores by tensile stress. Brine-soaked filter membranes are submitted to drying conditions leading to NaCl precipitation inside the 5-10 MUm pores. A close examination demonstrated that two forms of NaCl crystallites are successively generated. First, primary cubic crystals grow, driven by the permanent evaporation. When this angular primary solid gets near the pore wall, while the evaporation makes the pore volume to be partly invaded by air, capillary liquid can bridge the now-small gap between the halite angles and the pore wall. In a second step, these small capillary bridges are frozen by a secondary precipitation event of concave-shaped NaCl. The proposed interpretation is that the liquid capillary bridges deform the host matrix of the membrane, and the situation is fossilized by the growth of solid capillary bridges. A quantitative interpretation is proposed and the consequences towards the natural media outlined. PMID- 21237467 TI - Verb production during action naming in semantic dementia. AB - In contrast with widely documented deficits of semantic knowledge relating to object concepts and the corresponding nouns in semantic dementia (SD), little is known about action semantics and verb production in SD. The degradation of action semantic knowledge was studied in 5 patients with SD compared with 17 matched control participants in an action naming task based on video clips. The pattern of errors, involving a huge proportion of generic verbs (e.g. "to remove" versus "to peel") relative to responses in control subjects, suggested a hierarchical, bottom-up deficit of action knowledge in SD patients. In addition, abnormal responses in patients consisted of verbs that were semantically related to the expected verbs produced by control subjects (e.g. "to undress" versus "to peel" for the action [To peel_orange]). This study suggests that, in SD, non-canonical responses to action naming reflect lack of both specificity and semantic relatedness relative to the expected responses. LEARNING OUTCOMES: As a result of this activity, readers will recognize that semantic word knowledge disappears in semantic dementia using video clips of object-related actions. As a result of this activity, readers will discover that this semantic impairment followed a hierarchical pattern with the more specific verbs vanishing first. PMID- 21237468 TI - Visual spatial skill: a consequence of learning to read? AB - Does learning to read influence one's visual skill? In Study 1, kindergartners from Hong Kong, Korea, Israel, and Spain were tested on word reading and a task of visual spatial skill. Chinese and Korean kindergartners significantly outperformed Israeli and Spanish readers on the visual task. Moreover, in all cultures except Korea, good readers scored significantly higher on the visual task than did less good readers. In Study 2, we followed 215 Hong Kong Chinese kindergartners across 1year, with word reading and visual skills tested twice. In this study, word reading at Time 1 by itself predicted 13% of unique variance in visual skill at Time 2. Together, these results underscore the potential importance of the process of learning to read for shaping one's visual spatial skill development. PMID- 21237469 TI - Structural brain lesions in adolescents with congenital heart disease. AB - OBJECTIVES: To assess long-term neurodevelopmental outcome of adolescents with congenital heart disease after open-heart surgery and to evaluate whether deficits are associated with cerebral injury detectable on magnetic resonance imaging (MRI). STUDY DESIGN: We conducted a cohort study with longitudinal follow up of 53 adolescents (mean age, 13.7 years; range, 11.4 to 16.9 years) who had undergone open-heart surgery with full-flow cardiopulmonary bypass during childhood and compared them with 41 age-matched controls. Assessment included conventional MRI and neurodevelopmental testing. RESULTS: MRI abnormalities were detected in 11 of the 53 patients (21%), comprising predominately white matter abnormalities and volume loss. Neurodevelopmental outcome was impaired in several domains, including neuromotor, intellectual, and executive functions, as well as visuomotor perception and integration. Adolescents with cerebral abnormalities had greater impairment in most neurodevelopmental domains compared with those without cerebral abnormalities. CONCLUSIONS: Cerebral abnormalities can be detected in a significant proportion of adolescents with corrected congenital heart disease. These abnormalities are found predominately in the white matter and are apparently of hypoxic-ischemic origin, most likely acquired during the neonatal period. PMID- 21237470 TI - COACH syndrome: an unusual cause of neonatal cholestasis. PMID- 21237471 TI - Organic and inorganic matter in Louisiana coastal waters: Vermilion, Atchafalaya, Terrebonne, Barataria, and Mississippi regions. AB - Chromophoric dissolved organic matter (CDOM) spectral absorption, dissolved organic carbon (DOC) concentration, and the particulate fraction of inorganic (PIM) and organic matter (POM) were measured in Louisiana coastal waters at Vermilion, Atchafalaya, Terrebonne, Barataria, and Mississippi River locations, in 2007-2008. The range of CDOM was 0.092 m-1 at Barataria in June 2008 to 11.225 m-1 at Mississippi in February 2008. An indicator of organic matter quality was predicted by the spectral slope of absorption coefficients from 350 to 412nm which was between 0.0087 m-1 at Mississippi in May 2008 and 0.0261 m-1 at Barataria in June 2008. CDOM was the dominant component of light attenuation at Terrebonne and Barataria. Detritus and CDOM were the primary components of light attenuation at Vermilion, Atchafalaya, and Mississippi. DOC ranged between 65 and 1235 MUM. PIM ranged between 1.1 and 426.3 mg L-1 and POM was between 0.3 and 49.6 mg L-1. PMID- 21237472 TI - Comparison of metal accumulation between 'Artificial Mussel' and natural mussels (Mytilus galloprovincialis) in marine environments. AB - The passive sampler called 'Artificial Mussel' (AM) developed by Wu et al. (2007) can provide a time-integrated estimate of metal concentrations in the marine environment, and offers a potential device to assess and compare metal concentration in different marine environments worldwide. The aim of this study was to compare metal accumulation on AM and natural mussel Mytilus galloprovincialis at three sites with different metal loads along the Portuguese coast for four months. M. galloprovincialis were placed in cages alongside AMs at each site. Samples were collected monthly and Cd, Cr, Cu, Pb, and Zn concentrations in whole soft tissues and AMs compared. For both Cu and Cd, the results were similar between AMs and natural mussels. Higher concentrations of Zn were observed in natural mussels, whereas the inverse was shown for Pb (about 10 fold higher). Our results showed that AMs are promising tools for assessing metal concentrations in marine environments. PMID- 21237473 TI - Differentiation induction of cardiac c-kit positive cells from rat heart into sinus node-like cells by 5-azacytidine. AB - Cardiac stem cells (CSCs) can differentiate into cardiac phenotypes representing early cardiomyocyte-like cells. However, CSCs-derived specification into sinus nodal cells is rarely known. Using the demethylating agent, 5-Aazacytidine (5 Aza), we tried to follow the process of cardiac specialization into sinus node like cells. The c-kit+ cells were isolated from 1-month-old rat hearts and sorted by a flow cytometry cell sorting system. Then, analyses of immunofluorescence and reverse transcription polymerase chain reaction were performed on the cells. The sorted c-kit+ cell are self-renewing and clonogenic. Some of the c-kit+ cell could spontaneously express GATA-4, cardiac troponin I (cTnI), smooth muscle actin (SMA) and CD31. At week 8, the cells treated with 10 MUM 5-Aza expressed GATA-4 and cTnI at rates of 31.4+/-2.6% and 32.6+/-8.5%. Correspondingly, the rates were 21.4+/-8.1% and 18.7+/-4.3% in the cells without 5-Aza. The difference of GATA-4 or cTnI expression rate between two groups was of significance respectively, P<0.05. The cultured cells could express mRNA of GATA4, hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) and HCN4. The mRNA expression was also up-regulated in cells treated with 10 MUM 5-Aza and growth factors. By week 2 after cell sorting, inward currents could be recorded in a fraction of the cultured cells. In conclusion, 10 MUM 5-Aza could promote the differentiation of c-kit+ cells into sinus node-like cells. 5-Aza-mediated differentiation seems to be helpful in future cell therapy for the patients suffering from loss of sinus node cells. PMID- 21237474 TI - Rapid SIV Env-specific mucosal and serum antibody induction augments cellular immunity in protecting immunized, elite-controller macaques against high dose heterologous SIV challenge. AB - Three Indian rhesus macaques, Ad-SIV primed/protein boosted and exposed twice to high-dose mucosal SIV(mac251) challenges, exhibited elite control of viremia over 6.5 years. They were negative for host factors associated with control of SIV infection. After a third intrarectal challenge with SIV(smE660), all controlled viremia, with one (macaque #5) maintaining undetectable viremia in blood. Acquisition was not blocked, but virus was contained in the jejunum and draining lymph nodes. Polyfunctional memory T cell responses and high-titered neutralizing and non-neutralizing serum and mucosal antibodies were present before and maintained post-challenge. The level of protection seen for animal #5 was predicted from analyses of gene transcription in jejunum 2 weeks post-challenge. Macaques #7 and #9, exhibiting lower pre-challenge cellular and humoral immunity, partially controlled the SIV(smE660) challenge. Initial vaccine-induced control by macaque #5 extended to the SIV(smE660) challenge due to multiple immune mechanisms that were boosted and augmented by cryptic SIV exposure. PMID- 21237475 TI - BST-2 is rapidly down-regulated from the cell surface by the HIV-1 protein Vpu: evidence for a post-ER mechanism of Vpu-action. AB - Recent evidence suggests that transmembrane domain (TMD) interactions are essential for HIV-1 Vpu-mediated antagonism of the restriction factor BST 2/tetherin. We made Vpu TMD mutants to study the mechanism of BST-2 antagonism. Vpu-I17A, -A18F, -W22L, and -S23L co-localized with BST-2 within endosomal membranes while effectively enhancing virion release and down-regulating surface BST-2. However, Vpu-A18H was confined to an endoplasmic reticulum (ER)-like distribution, resulting in impaired down-regulation of BST-2 and reduced virion release. Brefeldin A confined wild type Vpu to the ER, resulting in a similarly impaired phenotype, as did the addition of a C-terminal ER-retention signal to Vpu. We determined the half-life of cell-surface BST-2 to be ~8 hours, whereas Vpu mediated an ~80% reduction of surface BST-2 within 6 hours, suggesting that TMD interactions between Vpu and BST-2 occur within post-ER membranes to directly and rapidly remove BST-2 from the cell surface and relieve restricted virion release. PMID- 21237477 TI - Generation of neutralising antibodies against porcine endogenous retroviruses (PERVs). AB - Antibodies neutralising porcine endogenous retroviruses (PERVs) were induced in different animal species by immunisation with the transmembrane envelope protein p15E. These antibodies recognised epitopes, designated E1, in the fusion peptide proximal region (FPPR) of p15E, and E2 in the membrane proximal external region (MPER). E2 is localised in a position similar to that of an epitope in the transmembrane envelope protein gp41 of the human immunodeficiency virus-1 (HIV 1), recognised by the monoclonal antibody 4E10 that is broadly neutralising. To detect neutralising antibodies specific for PERV, a novel assay was developed, which is based on quantification of provirus integration by real-time PCR. In addition, for the first time, highly effective neutralising antibodies were obtained by immunisation with the surface envelope protein of PERV. These data indicate that neutralising antibodies can be induced by immunisation with both envelope proteins. PMID- 21237478 TI - Laccase-catalyzed oxidation of oxybenzone in municipal wastewater primary effluent. AB - Pharmaceuticals and personal care products (PPCPs) are now routinely detected in raw and treated municipal wastewater. Since conventional wastewater treatment processes are not particularly effective for PPCP removal, treated wastewater discharges are the main entry points for PPCPs into the environment, and eventually into our drinking water. This study investigates the use of laccase catalyzed oxidation for removing low concentrations of PPCPs from municipal wastewater primary effluent. Oxybenzone was selected as a representative PPCP. Like many other PPCPs, it is not recognized directly by the laccase enzyme. Therefore, mediators were used to expand the oxidative range of laccase, and the efficacy of this laccase-mediator system in primary effluent was evaluated. Eight potential mediators were investigated, and 2,2'-Azino-bis(3-ethylbenzthiazoline 6sulphonic acid) diammonium salt (ABTS), a synthetic mediator, and acetosyringone (ACE), a natural mediator, provided the greatest oxybenzone removal efficiencies. An environmentally relevant concentration of oxybenzone (43.8 nM, 10 MUg/L) in primary effluent was completely removed (below the detection limit) after two hours of treatment with ABTS, and 95% was removed after two hours of treatment with ACE. Several mediator/oxybenzone molar ratios were investigated at two different initial oxybenzone concentrations. Higher mediator/oxybenzone molar ratios were required at the lower (environmentally relevant) oxybenzone concentration, and ACE required higher molar ratios than ABTS to achieve comparable oxybenzone removal. Oxybenzone oxidation byproducts generated by the laccase-mediator system were characterized and compared to those generated during ozonation. Enzymatic treatment generated byproducts with higher mass to charge (m/z) ratios, likely due to oxidative coupling reactions. The results of this study suggest that, with further development, the laccase-mediator system has the potential to extend the treatment range of laccase to PPCPs not directly recognized by the enzyme, even in a primary effluent matrix. PMID- 21237476 TI - Influenza virus assembly and budding. AB - Influenza A virus causes seasonal epidemics, sporadic pandemics and is a significant global health burden. Influenza virus is an enveloped virus that contains a segmented negative strand RNA genome. Assembly and budding of progeny influenza virions is a complex, multi-step process that occurs in lipid raft domains on the apical membrane of infected cells. The viral proteins hemagglutinin (HA) and neuraminidase (NA) are targeted to lipid rafts, causing the coalescence and enlargement of the raft domains. This clustering of HA and NA may cause a deformation of the membrane and the initiation of the virus budding event. M1 is then thought to bind to the cytoplasmic tails of HA and NA where it can then polymerize and form the interior structure of the emerging virion. M1, bound to the cytoplasmic tails of HA and NA, additionally serves as a docking site for the recruitment of the viral RNPs and may mediate the recruitment of M2 to the site of virus budding. M2 initially stabilizes the site of budding, possibly enabling the polymerization of the matrix protein and the formation of filamentous virions. Subsequently, M2 is able to alter membrane curvature at the neck of the budding virus, causing membrane scission and the release of the progeny virion. This review investigates the latest research on influenza virus budding in an attempt to provide a step-by-step analysis of the assembly and budding processes for influenza viruses. PMID- 21237479 TI - Synthesis of the essential core of the human glycosylphosphatidylinositol (GPI) anchor. AB - The biological role of GPI anchors is of paramount importance; however, we are still far from fully understanding the structure-function relationship of these molecules. One major limiting factor has been the tiny quantities available from natural sources; obtaining homogeneous and well-defined GPI structures by synthesis, is both a challenge and an attractive goal. We report here the convergent synthesis of the essential core of the human GPI anchor 1, exploiting a common precursor to obtain the trisaccharidic donor 2 and a novel protecting groups sequence. The final product, prepared for the first time, is biologically active. PMID- 21237480 TI - Influence of electrical fields (AC and DC) on phytoremediation of metal polluted soils with rapeseed (Brassica napus) and tobacco (Nicotiana tabacum). AB - The combined use of electrokinetic remediation and phytoremediation to decontaminate soil polluted with heavy metals has been demonstrated in a laboratory-scale experiment. The plants species selected were rapeseed and tobacco. Three kinds of soil were used: un-contaminated soil from forest area (S1), artificially contaminated soil with 15mgkg(-1) Cd (S2) and multi contaminated soil with Cd, Zn and Pb from an industrial area (S3). Three treatment conditions were applied to the plants growing in the experimental vessels: control (no electrical field), alternating current electrical field (AC, 1Vcm(-1)) and direct current electrical field (DC, 1Vcm(-1)) with switching polarity every 3h. The electrical fields were applied for 30d for rapeseed and 90d for tobacco, each experiment had three replicates. After a total of 90d growth for rapeseed and of 180d for tobacco, the plants were harvested. The pH variation from anode to cathode was eliminated by switching the polarity of the DC field. The plants reacted differently under the applied electrical field. Rapeseed biomass was enhanced under the AC field and no negative effect was found under DC field. However, no enhancement of the tobacco biomass under the AC treatment was found. The DC field had a negative influence on biomass production on tobacco plants. In general, Cd content was higher in both species growing in S2 treated with AC field compared to the control. Metal uptake (Cd, Cu, Zn and Pb) per rapeseed plant shoot was enhanced by the application of AC field in all soils. PMID- 21237481 TI - Toxic responses in primary rat hepatocytes exposed with occupational dust collected from work environment of bone-based industrial unit. AB - In this in vitro study we investigated the toxic responses in hepatocytes treated with occupational dust to which workers are exposed in bone-based industrial units. The present study investigated the toxicity mechanism of bone-based occupational dust, from a particular industrial unit, on isolated rat hepatocytes. The hepatocytes were isolated by collagenase perfusion method and cell viability was determined by trypan blue exclusion and MTT [3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assay treated with occupational dust at 0.1-1.0 mgmL(-1), for 120 min. The cell viability decreased significantly in a concentration-dependent manner. Dust induced significant membrane damage measured by lactate dehydrogenase (LDH) and glutathione (GSH) release in culture media for 30-, 60- and 120 min treatment duration. The toxicity was found to be correlated with the induction of lipid peroxidation (LPO). In addition, nitric oxide (NO), and hydrogen peroxide (H(2)O(2)) generation by occupational dusts were also found to be time- and concentration-dependent. Over all the present study provides initial evidences for the toxic potential of occupational dust generated in bone-based industries and, therefore, the dust exposure to workers in unorganized industrial units should be controlled. PMID- 21237482 TI - Surface chemistry of a pine-oil cleaner and other terpene mixtures with ozone on vinyl flooring tiles. AB - Indoor environments are dynamic reactors where consumer products (such as cleaning agents, deodorants, and air fresheners) emit volatile organic compounds (VOCs) that can subsequently interact with indoor oxidants such as ozone (O(3)), hydroxyl radicals, and nitrate radicals. Typically, consumer products consist of mixtures of VOCs and semi-VOCs which can react in the gas-phase or on surfaces with these oxidants to generate a variety of oxygenated products. In this study, the reaction of a pine-oil cleaner (POC) with O(3) (100ppb) on a urethane-coated vinyl flooring tile was investigated at 5% and 50% relative humidity. These results were compared to previous alpha-terpineol+O(3) reactions on glass and vinyl surfaces. Additionally, other terpene and terpene alcohol mixtures were formulated to understand the emission profiles as seen in the POC data. Results showed that the alpha-terpineol+O(3) reaction products were the prominent species that were also observed in the POC/O(3) surface experiments. Furthermore, alpha terpineol+O(3) reactions generate the largest fraction of oxygenated products even in equal mixtures of other terpene alcohols. This finding suggests that the judicial choice of terpene alcohols for inclusion in product formulations may be useful in reducing oxidation product emissions. PMID- 21237483 TI - Hemoglobin (Hb) immobilized on amino-modified magnetic nanoparticles for the catalytic removal of bisphenol A. AB - Catalytic removal of bisphenol A from aqueous solution with hemoglobin immobilized on amino-modified magnetic nanoparticles as an enzyme catalyst was reported. The amino-modified magnetite nanoparticles were firstly prepared by the coprecipitation of Fe(2+) and Fe(3+) with NH(3).H(2)O and then modified by 3 aminopropyltriethoxysilane. The immobilization process was optimized by examining enzyme concentration, glutaraldehyde concentration, cross-link time, and immobilization time. The optimum conditions for the removal of bisphenol A with immobilized hemoglobin were also investigated. Under the optimality conditions, the removal efficiency of bisphenol A was about 80.3%. The immobilization had a beneficial effect on the stability of hemoglobin and conversions of bisphenol A. According to the proposed breakdown pathway and the intermediates, the enzyme catalytic removal of bisphenol A by the immobilized hemoglobin is considered to be an effective method. PMID- 21237485 TI - Ductal adenocarcinoma of the prostate. PMID- 21237484 TI - Potential role of minichromosome maintenance protein 2 as a screening biomarker in esophageal cancer high-risk population in China. AB - Minichromosome maintenance proteins are novel proliferative markers that have been proposed as diagnostic markers in many cancers. We evaluated the potential role of minichromosome maintenance protein 2 as a screening biomarker and compared it with proliferating cell nuclear antigen and Ki67 in a population survey of esophageal squamous cell carcinoma. A total of 299 esophageal samples from a high-risk region in China, including 171 from an endoscopy population survey, 30 from brushing cytology, and 98 from surgery and autopsy, underwent immunostaining with minichromosome maintenance protein 2, proliferating cell nuclear antigen, and Ki67 antibodies. Minichromosome maintenance protein 2 expression was confined to the proliferative compartment of normal and abnormal esophageal epithelium and particularly manifested in the surface layer of dysplasia and carcinoma in situ. The expression of proliferating cell nuclear antigen and Ki67 was positively correlated with that of minichromosome maintenance protein 2 (r(s) >0.39, P < .01); but their positive nuclei seldom reached the surface layer, and the labeling indices were significantly lower than those for minichromosome maintenance protein 2 in dysplasia (P < .05) and carcinoma in situ (P < .001). The sensitivity and specificity of minichromosome maintenance protein 2 in diagnosing dysplasia were 91.3% and 61.8%, respectively, higher than those for proliferating cell nuclear antigen (88.4% and 47.1%) and Ki67 (78.3% and 57.8%). Nine of 10 cancer and paracancerous surface-brushing samples expressed minichromosome maintenance protein 2, and the detection was higher than that for proliferating cell nuclear antigen (8/10 and 7/10) and Ki67 (7/10 and 7/10). However, none of 10 normal surface-brushing samples expressed the 3 markers. Minichromosome maintenance protein 2 is more sensitive and specific than proliferating cell nuclear antigen and Ki67 in indicating esophageal dysplasia. Minichromosome maintenance protein 2 immunostaining combined with surface brushing could be valuable in screening patients at high risk of cancer in mass surveys. PMID- 21237486 TI - Methylation status of T-lymphoma invasion and metastasis 1 promoter and its overexpression in colorectal cancer. AB - T-lymphoma invasion and metastasis 1 has been implicated in tumor invasion and metastasis. However, the regulatory mechanisms underlying aberrant T-lymphoma invasion and metastasis 1 expression in human colorectal cancer have not been well defined. To investigate the relationship between methylation status and expression levels of T-lymphoma invasion and metastasis 1 gene, methylation specific polymerase chain reaction, and immunohistochemistry staining were performed in 232 matched samples of human colorectal cancer tissue and normal colorectal mucosa. Results showed that T-lymphoma invasion and metastasis 1 protein was overexpressed in colorectal cancer, especially in metastatic cases (P < .001). The degree of T-lymphoma invasion and metastasis 1 promoter methylation was a little lower in cancer tissues than in matched normal mucosa (P < .05), and the expression level of T-lymphoma invasion and metastasis 1 was inversely related to the methylation status in cancer tissues (P < .001). Colon cancer cell lines HT29 and LS174T were treated with demethylating agent 5-aza-2' deoxycytidine, resulting in promoter hypomethylation accompanied by reexpression of T-lymphoma invasion and metastasis 1 mRNA and protein. In contrast, colon cancer cell lines SW620 and LoVo were treated with hypermethylation agent S adenosylmethionine, resulting in T-lymphoma invasion and metastasis 1 promoter hypermethylation, accompanied by suppression of T-lymphoma invasion and metastasis 1 expression and inhibition of cell growth, plate colony formation, and migration. The present study demonstrates that overexpression of T-lymphoma invasion and metastasis 1 is associated with hypomethylation status of T-lymphoma invasion and metastasis 1 promoter region in colorectal cancer tissues. It suggests that promotor hypomethylation of T-lymphoma invasion and metastasis 1 may play a role in the progression and metastasis of colorectal cancer. Pharmacologic reversal of T-lymphoma invasion and metastasis 1 promoter hypomethylation may inhibit cell proliferation and migration. PMID- 21237487 TI - Down-regulation of microRNAs of the miR-200 family and miR-205, and an altered expression of classic and desmosomal cadherins in spindle cell carcinoma of the head and neck--hallmark of epithelial-mesenchymal transition. AB - MicroRNAs are small, noncoding RNAs that regulate gene expression by posttranscriptional regulation of target genes. miR-200 family and miR-205 have been shown experimentally to regulate epithelial-mesenchymal transition. As epithelial-mesenchymal transition is the postulated pathogenetic mechanism in spindle cell carcinoma, we analyzed the expression of these microRNAs in spindle cell carcinoma of the head and neck in comparison to conventional squamous cell carcinoma of similar location and stage. We also analyzed the expression of classic and desmosomal cadherins, which are believed to be important targets during epithelial-mesenchymal transition. Forty-five cases of spindle cell carcinoma and 45 cases of squamous cell carcinoma of the head and neck were analyzed using real-time polymerase chain reaction for microRNAs, and immunohistochemistry for classic cadherins (E- and N-cadherins) and desmosomal cadherins. We found a significant down-regulation of the miR-200 family and miR 205, loss of desmosomal cadherins, and an altered expression of classic cadherins in spindle cell carcinoma in comparison to squamous cell carcinoma. Down regulation of the miR-200 family and miR-205 strongly supports the postulated role of epithelial-mesenchymal transition in spindle cell carcinoma. These microRNAs act on transcription repressors that were also up-regulated in our cases of spindle cell carcinoma, both on mRNA and on protein levels. The result is not only an altered expression of classic cadherins in adherens junctions but also a complete loss of desmosomal cadherins. PMID- 21237489 TI - Oncocytic adrenocortical neoplasms--a clinicopathologic study of 13 new cases emphasizing the importance of their recognition. AB - Oncocytic adrenocortical neoplasms (OANs) are a rare but important subtype of adrenal tumors with unique clinical and morphological features. We present 13 previously unpublished cases, of which 3 were classified as benign, 2 as having borderline malignant potential, and 8 as malignant according to the Lin-Weiss Bisceglia criteria. Seven tumors (54%) showed evidence of endocrine activity. All were composed of more than 90% oncocytes confirmed immunohistochemically using the antimitochondrial antibody mES-13 and ultrastructurally in 4 cases. Small oncocytes were a frequent finding that challenges the conventional notion of oncocytes as necessarily having abundant cytoplasm. Most cases were immunoreactive for vimentin, synaptophysin, inhibin-alpha, melan A, and calretinin, the latter being a novel finding in this group of neoplasms. Cytokeratin positivity with AE1/AE3 and CAM5.2 was variable. The literature was comprehensively reviewed to identify all cases of OANs reported to date. Hormone production is not as uncommon as previously believed, occurring in 30%. The Lin Weiss-Bisceglia criteria were retrospectively applied to all published cases with sufficient information and were shown to effectively separate tumors according to their future risk of recurrence and survival using Kaplan-Meier survival curves (log-rank test, P < .001 for both). The estimated overall median survival for malignant oncocytic neoplasms is 58 months (95% confidence interval = 27.5-88.5 months), providing the first preliminary evidence that the prognosis of malignant OANs is likely to be more favorable than conventional adrenocortical carcinomas, in which the reported median survival is between 14 and 32 months. PMID- 21237490 TI - Overexpression of cofilin 1 can predict progression-free survival in patients with epithelial ovarian cancer receiving standard therapy. AB - The aim of this study was to examine the relation between cofilin 1 expression and progression-free survival in advanced epithelial ovarian cancer. We performed quantitative reverse transcriptase polymerase chain reaction and immunohistochemical analysis in 78 patients with advanced epithelial ovarian cancer (excluding those with mucinous and clear-cell types). All patients received the standard therapy, including staging laparotomy and adjuvant chemotherapy consisting of carboplatin and paclitaxel. Of 78 samples, RNA from 62 samples was available for reverse transcriptase polymerase chain reaction analysis. We defined cofilin 1 high expression as relative gene expression equal to or higher than the median and low expression as gene expression lower than median. The progression-free survival was longer in cofilin 1 low-expression cases than in high-expression cases (P = .039). Multivariate analysis demonstrated that stage and cofilin 1 expression were significant predictors of progression-free survival. Of the 78 samples, 54 were appropriate for immunohistochemical study. In 35 of those 54 cases, cofilin 1 protein expression was detected. The progression-free survival was longer in cofilin 1 protein negative cases than in protein-positive cases (P = .042). Expression of cofilin 1 may predict the progression-free survival of patients with advanced epithelial ovarian cancer receiving standard therapy. PMID- 21237491 TI - Neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma. AB - Although extraovarian mucinous cystadenocarcinomas resemble primary ovarian carcinomas, both histologically and clinically, their specific etiology is not clear. This is the first report to show neoplastic transformation of endocervicosis into an extraovarian mucinous cystadenocarcinoma. The histologic spectrum and specific KRAS mutational analysis for this tumor were the same as for their ovarian counterparts. This supports a mullerian origin and the current approach to extrapolate the results from ovarian mucinous cystadenocarcinoma trials in prescribing treatment for patients with extraovarian mucinous cystadenocarcinomas. PMID- 21237492 TI - Can molecular markers stratify the diagnostic value of high-grade prostatic intraepithelial neoplasia? AB - The diagnostic performance of isolated high-grade prostatic intraepithelial neoplasia in prostatic biopsies has recently been questioned, and molecular analysis of high-grade prostatic intraepithelial neoplasia has been proposed for improved prediction of prostate cancer. Here, we retrospectively studied the value of isolated high-grade prostatic intraepithelial neoplasia and the immunohistochemical markers alpha-methylacyl coenzyme A racemase, Bcl-2, annexin II, and Ki-67 for better risk stratification of high-grade prostatic intraepithelial neoplasia in our local Swiss population. From an initial 165 diagnoses of isolated high-grade prostatic intraepithelial neoplasia, we refuted 61 (37%) after consensus expert review. We used 30 reviewed high-grade prostatic intraepithelial neoplasia cases with simultaneous biopsy prostate cancer as positive controls. Rebiopsies were performed in 66 patients with isolated high grade prostatic intraepithelial neoplasia, and the median time interval between initial and repeat biopsy was 3 months. Twenty (30%) of the rebiopsies were positive for prostate cancer, and 10 (15%) showed persistent isolated high-grade prostatic intraepithelial neoplasia. Another 2 (3%) of the 66 patients were diagnosed with prostate cancer in a second rebiopsy. Mean prostate-specific antigen serum levels did not significantly differ between the 22 patients with prostate cancer and the 44 without prostate cancer in rebiopsies, and the 30 positive control patients, respectively (median values, 8.1, 7.7, and 8.8 ng/mL). None of the immunohistochemical markers, including alpha-methylacyl coenzyme A racemase, Bcl-2, annexin II, and Ki-67, revealed a statistically significant association with the risk of prostate cancer in repeat biopsies. Taken together, the 33% risk of being diagnosed with prostate cancer after a diagnosis of high grade prostatic intraepithelial neoplasia justifies rebiopsy, at least in our not systematically prostate-specific antigen-screened population. There is not enough evidence that immunohistochemical markers can reproducibly stratify the risk of prostate cancer after a diagnosis of isolated high-grade prostatic intraepithelial neoplasia. PMID- 21237493 TI - Follicular programmed death 1-positive lymphocytes in the tumor microenvironment are an independent prognostic factor in follicular lymphoma. AB - We enumerated programmed death 1 (PD-1)-positive follicular helper T cells, a potentially important regulator of immune response, in the tumor microenvironment of a series of 91 newly diagnosed follicular lymphomas managed at a single institution. Clinical data were obtained for sex, age, Follicular Lymphoma International Prognostic Index (FLIPI) risk group, presence of bulky disease, presence of B symptoms, and overall survival. Immunohistochemical staining for PD 1 was performed on tissue microarray sections, and the mean number of follicular PD-1-positive cells per 9 high-power fields (1000*, 3 follicles with 3 fields per follicle) was quantified. B-cell CLL/lymphoma 2 (BCL-2) expression, CD68(+) extrafollicular lymphoma-associated macrophages, and forkhead box P3 (FOXP3)+ regulatory T cells were evaluated as reported previously. Ninety-one patients were evaluated, with a median age at diagnosis of 58 years and median survival of 11.6 years. PD-1-positive cells correlated with the number of FOXP3+ regulatory T cells (P = .01). On multivariate analysis, independent poor prognostic factors were age 55 years or greater (hazard ratio, 2.77; 95% confidence interval, 1.34 5.73; P = .006), bulky disease (hazard ratio, 2.27; 95% confidence interval, 1.03 5.00; P = .04), CD68(+) extrafollicular lymphoma-associated macrophages greater than 16.8 cells/high-power field (hazard ratio, 2.15; 95% confidence interval, 1.14-4.06; P = .02), and PD-1-positive cells greater than 35.6 cells/high-power field (hazard ratio, 1.98; 95% confidence interval, 1.09-3.60; P = .03). These factors allowed construction of a risk score defining 3 distinct prognostic groups with 10-year overall survival of 85%, 60%, and 15%. PD-1-positive follicular helper T cells and CD68(+) extrafollicular lymphoma-associated macrophages appear to predict overall survival in follicular lymphoma, and our findings support strategies aimed at modulating their function in follicular lymphoma. Future studies, performed prospectively on uniformly treated patient cohorts, should be performed to validate these findings. PMID- 21237494 TI - Erythroblastic sarcoma presenting as bilateral ovarian masses in an infant with pure erythroid leukemia. AB - Pure erythroid leukemia is a rare subtype of acute erythroid leukemia that is characterized by a predominant erythroid population, and erythroblastic sarcoma has not yet been described in the English literature. Here, we report a first case of erythroblastic sarcoma that presented as bilateral ovarian masses in a 3 1/2-month-old infant girl with pure erythroid leukemia. Bone marrow aspirate and biopsy showed that the marrow was completely replaced by large-sized blasts consistent with erythroblasts. Immunophenotypically, both the tumor cells from the ovarian mass and bone marrow blasts were positive for CD117, glycophorin A, and hemoglobin A, demonstrating erythroid differentiation. Reverse transcriptase polymerase chain reaction showed that the tumor cells from ovarian mass expressed hemoglobin F and alpha1 spectrin, confirming their erythroid lineage. Conventional karyotype of the bone marrow aspirates revealed del(6)(q23q25) and trisomy 7 in all 21 cells examined. Fluorescence in situ hybridization of the ovarian mass demonstrated loss of c-myeloblastosis viral oncogene (C-MYB) at 6q23 locus in 41% of the cells, and deletion of chromosome 7 and 7q in 37% and 66% of cells, respectively. Taken together, we showed, for the first time, that pure erythroid leukemia presented as a myeloid sarcoma in the form of ovarian masses. PMID- 21237496 TI - A case of secondary malignant giant-cell tumor of bone with p53 mutation after long-term follow-up. AB - A 46-year-old man was admitted to the hospital with a recurrent giant-cell tumor of the distal femur. This was his fourth recurrence, and it had occurred 16 years after his last treatment. The resected recurrent tumor was histologically determined to be a conventional giant-cell tumor. However, a single lung metastatic lesion and local recurrence were noticed 6 months after the resection, both of which were surgically excised. The lung lesion was histologically determined to be an implantation of giant-cell tumor, whereas the local recurrent lesion contained a clearly separated fibrosarcomatous area within the conventional giant-cell tumor. Immunohistochemistry showed diffuse and strong p53 expression in the fibrosarcomatous area. Direct sequencing revealed a p53 mutation in the sarcomatous area and a recessive mutant signal in the conventional area. The lung lesion also contained the same p53 mutation. Identification of the p53 mutation may help in diagnosing potential malignant transformation of giant-cell tumor. PMID- 21237495 TI - Active matrix metalloproteinase-2 activity discriminates colonic mucosa, adenomas with and without high-grade dysplasia, and cancers. AB - Pathologic assessment of colorectal adenomas, a complex task with significant interobserver variability, typically defines the scheduling of surveillance colonoscopies after removal of adenomas. We have characterized the activity levels of pro-matrix metalloproteinase-2, active matrix metalloproteinase-2, and matrix metalloproteinase-9 in colorectal adenomas and carcinomas as potential markers of pathologic progression during colorectal tumorigenesis. Endogenous fully activated matrix metalloproteinase-2, in particular, has been studied less frequently in adenomas due to difficulties in detection. For this report, tissues (n = 119) from 51 individuals were extracted and assayed on gelatin zymograms with digital standardization to nanogram quantities of purified active controls. Resulting data were assessed by graphical and multinomial logit regression analyses to test whether matrix metalloproteinase-2 or matrix metalloproteinase-9 activities could discriminate among 4 different types of colorectal tissue (normal mucosa, adenomas with or without high-grade dysplasia, and invasive carcinomas). Active matrix metalloproteinase-2 successfully discriminated among these tissue categories. Median activity for active matrix metalloproteinase-2 increased in a stepwise fashion with pathologic progression from normal mucosa to adenoma without high-grade dysplasia to adenoma with high-grade dysplasia to cancer. Although pro-matrix metalloproteinase-2 and pro-matrix metalloproteinase 9 activities could discriminate to some extent among tissue categories, those effects did not contribute additional information. Active matrix metalloproteinase-2 activity correlated significantly with histopathologic assessment of colorectal tissues. The ability of active matrix metalloproteinase 2 to distinguish adenomas with high-grade dysplasia from adenomas without high grade dysplasia may be particularly useful in predicting future colorectal cancer risk for an individual, thus optimizing scheduling of surveillance colonoscopies. PMID- 21237497 TI - Gastrointestinal stromal tumor presenting as a rectovaginal mass. Clinicopathologic and molecular-genetic characterization of a rare tumor with a literature review. AB - Rectal gastrointestinal stromal tumors are rare. To date, 12 gastrointestinal stromal tumors have been reported as pelvic vaginal masses. We describe a rectovaginal tumor in a 39-year-old woman. The tumor frequently recurred after multiple surgical excisions and interrupted imatinib treatment without metastasizing. Magnetic resonance tomography demonstrated a partial response under imatinib. The patient was alive with stable disease under imatinib 44 months from initial diagnosis. Molecular analysis showed a somatic 6-base pair deletion in exon 11 of c-KIT (W557_K558del) in both the primary tumor and the third recurrence; the recurrence had an additional exon 17 mutation (N822K). Comparative genomic hybridization analysis of the primary tumor showed loss of 14q and gain of 1q. Recurrence showed complete loss of nuclear p16 expression. Molecular studies and p16 status confirmed the typical characteristics of gastrointestinal stromal tumors with an aggressive phenotype underscoring the need for a special interdisciplinary treatment and for achieving complete local excision with free margins. PMID- 21237498 TI - Expression of podoplanin in thymoma: its correlation with tumor invasion, nodal metastasis, and poor clinical outcome. AB - Recent studies have shown that podoplanin overexpression is associated with lymph node metastasis and poor clinical outcome in several malignant tumors. To investigate the role of podoplanin in thymoma, we examined 111 thymomas by immunohistochemistry using monoclonal antibody D2-40, which recognizes podoplanin. The tumors consisted of 8 type A, 40 type AB, 15 type B1, 23 type B2, 15 type B3, and 10 combined thymomas according to the World Health Organization histological classification system and of 41 stage I, 28 stage II, 16 stage III, 20 stage IVa, and 6 stage IVb thymomas according to the Masaoka staging system. We have found podoplanin expression in 0 (0%) type A, 4 (10%) type AB, 4 (27%) type B1, 16 (70%) type B2, 10 (67%) type B3, and 7 (70%) combined thymomas and in 5 (12%) cases of stage I, 7 (25%) of stage II, 11 (69%) of stage III, 12 (60%) of stage IVa, and all (100%) of stage IVb thymomas. Podoplanin was significantly expressed in B2/B3/combined thymomas and advanced stage thymomas (P < .0001). On survival analysis, podoplanin expression was significantly associated with an increased risk of death for the whole group of thymomas (P = .0002), although it was not identified as an independent prognostic factor in multivariate analysis. The significant survival curve differences of podoplanin expression were also seen for stage III/IVa/IVb thymomas (P = .0409) and B2/B3/combined thymomas (P = .0478). In conclusion, D2-40 immunostaining seems to be valuable for predicting the aggressive and metastatic potential of thymomas and the prognosis of the patients. PMID- 21237500 TI - Effect of moisture and temperature variation on DOC release from a peatland: conflicting results from laboratory, field and historical data analysis. AB - Peatlands are large repositories of atmospheric carbon and concern has been raised over the stability of this carbon store because increasing dissolved organic carbon (DOC) concentrations have been observed in peatland drainage waters. A number of potential causes have been proposed in the literature, and conflicting results among studies conducted at different spatial and temporal scales suggest that the methodological approach may be an important confounding factor. The objective of this study was to determine the influence of moisture and temperature on DOC release from a south-central Ontario peatland during the fall (a major export period) following three commonly used approaches: laboratory microcosms, an intensive field study and analysis of long-term data (1980-2008). The effect of variations in temperature and moisture differed among microcosm, field study and analysis of the long-term record. Water content was important at the microcosm scale as DOC concentration and aromaticity increased with peat water-saturation. Drought caused a decrease in DOC concentration and pH, and an increase in sulphate and base cation concentrations. In contrast, the field study indicated that DOC concentration was strongly associated with temperature, and weakly correlated (negatively) with stream discharge. Average fall DOC concentration (but not export) increased over the 29 year record, and was correlated with fall discharge and precipitation (negative) and summer precipitation and fall stream pH (positive). As no common strong predictor of fall DOC was found at three scales of investigation at a single, well-studied site, it may be unreasonable to expect to identify a universal driver behind the widespread increase in DOC concentration. PMID- 21237499 TI - Relationship of aquaporin 1, 3, and 5 expression in lung cancer cells to cellular differentiation, invasive growth, and metastasis potential. AB - An oncogenic capacity of aquaporins, transmembrane channels for water, was recently proposed. This study seeks to elucidate the involvement of aquaporin 1, 3, and 5 in the development and progression of lung cancer. Expression of aquaporin 1, 3, and 5 was examined by immunohistochemistry, Western blot, and laser-captured microdissection/real-time reverse transcription polymerase chain reaction in 160 lung cancers of various histologic subtypes; and its correlation with clinicopathological factors and survival was analyzed. Aquaporin 1, 3, and 5 were expressed in tumor cells in 71%, 40%, and 56% of lung cancers, respectively. Aquaporin expressions were frequent in adenocarcinomas, whereas aquaporin 1 and 5 were negative in squamous cell carcinomas. Bronchioloalveolar carcinoma cells exhibited an apicolateral aquaporin 1 and apicolateral or basolateral aquaporin 3 localization in nonmucinous type, and apical aquaporin 1 and 5 and basolateral aquaporin 3 expression in mucinous type, which corresponded to aquaporins expression of nonneoplastic lung tissue. Basolateral aquaporin 5 expression was acquired during tumorigenesis of nonmucinous bronchioloalveolar carcinoma. In contrast, invasive adenocarcinoma tumor cells overexpressed aquaporin 1 and 5 with loss of subcellular polarization and with an intracytoplasmic distribution. Overexpression of aquaporin 1 correlated with high postoperative adenocarcinoma metastasis ratios and unfavorable disease-free survival rates (P = .031). We conclude that expression patterns of aquaporin 1, 3, and 5 in lung cancer cells are mostly associated with cellular differentiation. However, the expression of aquaporin 1 and 5 is up-regulated in invading lung cancer cells, particularly in adenocarcinomas; and the overexpression of aquaporin 1 with loss of subcellular polarization is suggested to be involved in their invasive and metastatic potential. PMID- 21237501 TI - Lack of P-selectin glycoprotein ligand-1 protects mice from thrombosis after collagen/epinephrine challenge. AB - INTRODUCTION: In thrombotic processes, during the association of leukocytes with platelets and endothelial cells, P-selectin glycoprotein ligand-1 (PSGL-1) binds to P-selectin, expressed on activated platelets and endothelial cells. Our aim was to establish the role of PSGL-1 in thrombus formation by evaluating the response to thrombotic stimuli in wild type and PSGL-1 knockout mice. MATERIALS AND METHODS: Mice were challenged by tail vein injection of (i) 15 MUg collagen plus 3 MUg epinephrine (coll/epi) (ii) 7.5 MUg collagen plus 1.5 MUg epinephrine or (iii) saline. Retro-orbital blood samples were collected in ACD anticoagulaed tubes and platelet and leukocyte counts were measured. In addition, kidneys, liver, spleen and lungs were investigated for fibrin deposition by immunohistochemistry and Western-blotting. Frozen sections were analysed for double labeling for platelet and leukocyte presence. RESULTS: After coll/epi challenge, the number of platelets and leukocytes decreased significantly in both genotypes. Lower agonist concentration resulted in an attenuated platelet decrease in PSGL-1 knockout mice compared to the controls, however changes in leukocyte and neutrophil counts were not significantly different in the two strains. In knockout mice considerably less fibrin deposition has been observed in the lungs by Western-blotting and immunohistochemistry. After coll/epi challenge the lungs of the PSGL-1 knockout animals contained both platelets and leukocytes but less thrombi has been detected than in wild-type mice. CONCLUSIONS: Our results indicate that the deficiency of PSGL-1 results in milder thrombocytopenia, less fibrin deposition and lower number of thrombosed blood vessels, suggesting that this molecule is essential for multicellular interactions during thrombus formation. PMID- 21237502 TI - Markers of fibrinolysis as predictors for maintenance of sinus rhythm after electrical cardioversion. AB - INTRODUCTION: Inflammation, endothelial dysfunction and metabolic pathways provide possible links between the inflammatory and hypofibrinolytic states in atrial fibrillation. Our aim was to explore the role of mass concentrations of PAI-1 and tPA, activities of PAI-1 and tPA as predictors of recurrence of atrial fibrillation adjusted for CRP. MATERIALS AND METHODS: The study included 129 patients with persistent atrial fibrillation. Laboratory analyses were performed including PAI-1 activity, PAI-1 mass, tPA activity, tPA mass and CRP in baseline. Patients were then randomized to atorvastatin (40 mg, two tablets once daily) or placebo, initiated at least 14 days before the elective cardioversion. Further samples and follow-up were made at day 2 and 30 days after cardioversion. RESULTS: In univariate logistic regression no fibrinolytic variable was significantly correlated with rhythm in day 30. In multivariate analysis lower PAI-1 mass was significantly associated with sinus rhythm in all models including fibrinolytic variables, CRP, metabolic components, age, hypertension and smoking. After adding treatment allocation to the fully adjusted model, PAI-1 mass remained significantly associated with sinus rhythm both at day 2 and 30 (OR 0.98; 95% CI 0.95-1.00). CONCLUSIONS: No fibrinolytic component alone was found to be a predictor of recurrence of atrial fibrillation. In multivariate models lower PAI-1 mass was associated with sinus rhythm even after adjusting for CRP, markers of the metabolic syndrome and treatment with atorvastatin. Our findings suggest a patophysiological link between AF and PAI-1 mass but the relation to inflammation remains unclear. PMID- 21237503 TI - Autofluorescence imaging can identify preinvasive or clinically occult lesions in fallopian tube epithelium: a promising step towards screening and early detection. AB - BACKGROUND: Optical imaging systems are robust, portable, relatively inexpensive, and have proven utility in detecting precancerous lesions in the lung, esophagus, colon, oral cavity and cervix. We describe the use of light-induced endogenous fluorescence (autofluorescence) in identifying preinvasive and occult carcinomas in ex vivo samples of human fallopian tube (FT) epithelium. METHODS: Women undergoing surgery for an i) ovarian mass, ii) a history suggestive of hereditary breast-ovarian cancer, or iii) known serous ovarian cancer following neoadjuvant chemotherapy (NAC) were approached for informed consent. Immediately following surgery, FT's were photographed in reflectance and fluorescence at high resolution. Images included: (1) white-light reflectance of luminal/epithelial surface; (2) narrow-band green reflectance (570 nm) (3) green autofluorescence (405/436 nm excitation); and (4) blue autofluorescence (405 nm excitation). Areas revealing a loss of natural tissue fluorescence or marked increase in tissue microvasculature were recorded and compared to final histopathologic diagnosis (SEE-FIM protocol). RESULTS: Fifty-six cases involving one or both fallopian tubes underwent reflectance and fluorescence visualization. Nine cases were excluded, either secondary to non-ovarian primary pathology (7) or excessive trauma (2) rendering tissue interpretation impossible. Of the 47 cases remaining, there were 11 high grade serous (HGS) and 9 non-serous ovarian carcinomas undergoing primary debulking surgery, 5 serous carcinomas having received NAC, 8 benign ovarian tumors, and 14 women undergoing risk-reducing bilateral salpingo oophorectomy (RRBSO). Methodology was feasible, efficient, and reproducible. TIC or carcinoma was identified in 7/11 HGS, 3/5 NAC, and 1/14 RRBSO. Optical images were reviewed to determine test positive or negative based on standardized criteria. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for the entire cohort (73%; 83%; 57%; 91%) and in a subgroup that excluded non-serous histology (87.5%; 92%; 78%; 96%). CONCLUSIONS: Abnormal FT lesions can be identified using ex vivo optical imaging technologies. With this platform, we will move towards genomic interrogation of identified lesions, and developing in vivo screening modalities via falloposcopy. PMID- 21237504 TI - Laparoscopic surgical staging of locally advanced cervix cancer (IB2 to IVA): initial experience. AB - INTRODUCTION AND OBJECTIVES: Cervical cancer incidence worldwide is about 500,000 new cases per year with most of them being detected at a locally advanced stage. Many studies have shown the need to look for extra-pelvic disease when planning appropriate therapy. We performed surgical staging by laparoscopy in 43 cases of cervical cancer at stages IB2 to IVa and evaluated our initial results. MATERIALS AND METHODS: Between February 2008 and May 2010, we selected 43 patients with histologically confirmed cervical cancer at stages IB2 to IVA with a Karnosfsky index>70. We classified the tumors according to the FIGO (International Federation of Gynecology and Obstetrics) stage and performed tomographic evaluations of the abdomen to select patients without signs of peritoneal or para aortic tumor spread. We performed a laparoscopic evaluation of the peritoneal cavity and para-aortic lymph nodes by an extra-peritoneal route. We did not use tweezers or disposable energy seals. RESULTS: The mean surgical time was 130.8min. The mean blood loss was 111.5ml. There was no conversion to laparotomy for any case. We describe a case with peritoneal implants that was classified as IVB. We removed an average of 16.4 lymph nodes; nine cases had para-aortic lymph node metastases. CONCLUSION: Laparoscopic surgical staging diagnosed 23.3% of cases with peritoneal spread of the tumor or extra-pelvic lymph node metastases. In this study, we could better define the lymph node status through laparoscopic surgical staging and could therefore recommend more suitable adjuvant therapy for patients with locally advanced cervical cancer. PMID- 21237506 TI - Antibiotic resistant bacteria as bio-indicator of polluted effluent in the green turtles, Chelonia mydas in Oman. AB - Antibiotic resistant bacteria were studied as bio-indicators of marine polluted effluents during egg-laying in green turtles. A non-invasive procedure for sampling oviductal fluid was used to test for exposure of turtles to pollution in Ras Al-Hadd, Oman, which is one of the most important nesting beaches in the world. Each sample was obtained by inserting a 15 cm sterile swab gently into the cloacal vent as the sphincter muscle is relaxed and the cloacal lining is unfolded to the outside. Forty turtles were sampled. A hundred and thirty-two species of bacteria from 7 genera were isolated. The dominant isolate was Citrobacter. Among the isolates 60.6% were multiple resistant to 15 tested antibiotics. The dominant resistance to antibiotics was ampicillin followed by streptomycin and sulphamethoxazole. Sampling oviductal fluid for resistant bacteria to antibiotics is valuable way to assess exposure to polluted effluents during feeding and migratory in turtles. Polluted effluents using bacteria as bio indicator may influence reproductive potential in this endangered species. PMID- 21237505 TI - Effects of distance from a heavily transited avenue on asthma and atopy in a periurban shantytown in Lima, Peru. AB - BACKGROUND: Proximity to roadways increases the risk of asthma in developed countries; however, relatively little is known about this relationship in developing countries, where rapid and uncontrolled growth of cities has resulted in urban sprawl and heavy traffic volumes. OBJECTIVE: We sought to determine the effect of distance from a heavily transited avenue on asthma symptoms and quantitative respiratory outcome measures in a periurban shantytown in Lima, Peru. METHODS: We enrolled 725 adolescents aged 13 to 15 years who were administered a survey on asthma symptoms and measured spirometry, response to allergy skin testing, and exhaled nitric oxide (eNO). We calculated distances from the main avenue for all households and measured indoor particulate matter in 100 households. We used multivariable regression to model the risk of asthma symptoms, risk of atopy, eNO levels, and FEV(1)/forced vital capacity ratio as a function of distance. RESULTS: Compared against 384 meters, the odds of current asthma symptoms in households living within 100 meters increased by a factor of 2 (P < .05). The odds of atopy increased by a factor of 1.07 for every 100-meter difference in the distance from the avenue (P = .03). We found an inverse relationship in prebronchodilator FEV(1)/forced vital capacity and distance to the avenue in female subjects (P = .01) but not in male subjects. We did not find an association between eNO or household particulate matter levels and distance. CONCLUSION: Living in close proximity to a high-traffic-density avenue in a periurban community in Peru was associated with a greater risk of asthma symptoms and atopy. Regulation of mobile-source pollutants in periurban areas of developing countries might help reduce the burden of asthma symptoms and atopy. PMID- 21237507 TI - Controlled architectural and chemotactic studies of 3D cell migration. AB - Chemotaxis plays a critical role in tissue development and wound repair, and is widely studied using ex vivo model systems in applications such as immunotherapy. However, typical chemotactic models employ 2D systems that are less physiologically relevant or use end-point assays, that reveal little about the stepwise dynamics of the migration process. To overcome these limitations, we developed a new model system using microfabrication techniques, sustained drug delivery approaches, and theoretical modeling of chemotactic agent diffusion. This model system allows us to study the effects of 3D architecture and chemotactic agent gradient on immune cell migration in real time. We find that dendritic cell migration is characterized by a strong interplay between matrix architecture and chemotactic gradients, and migration is also influenced dramatically by the cell activation state. Our results indicate that Lipopolysaccharide-activated dendritic cells studied in a traditional transwell system actually exhibit anomalous migration behavior. Such a 3D ex vivo system lends itself for analyzing cell migratory behavior in response to single or multiple competitive cues and could prove useful in vaccine development. PMID- 21237508 TI - Antitumor effects of YM155, a novel survivin suppressant, against human aggressive non-Hodgkin lymphoma. AB - YM155, a novel small-molecule that down-regulates survivin, exhibits broad, potent antitumor activity against a range of human tumors. We evaluated the activity of YM155 in aggressive non-Hodgkin lymphoma. In a number of diffuse large B-cell lymphoma lines, YM155 exhibited 50% growth inhibition with values between 0.23 and 3.9 nM. Within in vivo xenograft models, continuous infusion of YM155 eradicated large, established subcutaneous WSU-DLCL-2 and Ramos tumors, with sustained efficacy observed through 4 cycles of YM155 therapy. YM155 increased survival significantly versus rituximab in disseminated Ramos models. This study suggests that YM155 may represent an effective treatment for aggressive lymphomas. PMID- 21237509 TI - Treatment of invasive aspergillosis with nonmyeloablative allogeneic stem cell transplantation: one stone two birds. PMID- 21237510 TI - Sensitivity of Allium and Nicotiana in cellular and acellular comet assays to assess differential genotoxicity of direct and indirect acting mutagens. AB - We have evaluated the extent of DNA damage induced by direct and indirect mutagens by cellular and acellular comet assays in two plant systems, Nicotiana tabacum (wild type tobacco) and Allium cepa (common onion). The objectives of this study were: (1) to generate dose-response curves for DNA migration values from root and shoot nuclei of A. cepa and N. tabacum treated with the direct acting mutagens, ethyl methanesulphonate (EMS), hydrogen peroxide (H(2)O(2)) and the indirect acting mutagen, cadmium chloride (CdCl(2)), (2) to assess the differential response between isolated nuclei and nuclei of root and shoot and of both plants and (3) to examine the differences of sensitivity between direct and indirect acting mutagens by cellular and acellular comet assays. Similar sensitivities were evident in both plant systems to direct and indirect acting mutagens. The combination of cellular and acellular comet assays provided valuable insight to the mode of action of the genotoxicants used. The data obtained demonstrated the estimable capacity of the two plant systems to evaluate genotoxicity under different stress conditions and suggests Allium is a more desirable test system for rapid monitoring of genotoxicity. PMID- 21237512 TI - Blood lead levels in the adult population living in France the French Nutrition and Health Survey (ENNS 2006-2007). AB - BACKGROUND: The French Nutrition and Health Survey (ENNS) was conducted in order to describe food consumption and levels of various biomarkers in the general population. In this paper, we aimed to assess the distribution of blood lead levels (BLL) in the adult population living in France. METHOD: ENNS was a cross sectional survey carried out in the general population. Participants (18-74years of age) were sampled using a three-stage probability design stratified by geographical areas and degrees of urbanization. Collected data included biochemical samples, anthropometric measurements, socio-demographic characteristics, and environmental and occupational exposure. RESULTS: In 2006/2007, 2029 adults were included in the survey on lead. The blood lead geometric mean (GM) in the population living in France was 25.7MUg/L [24.9-26.5]. The overall prevalence of elevated BLL (>100MUg/L) was 1.7% [1.1-2.3%]. Levels were significantly higher in males than in females, and increased with age, smoking status and alcohol consumption. Other factors significantly associated with BLL were leisure activities, occupational category, age of housing unit, birth place and shellfish/crustacean consumption. CONCLUSION: For the first time a survey provides national estimates of BLL for the adult population in France. Comparison with results from a previous study among men aged 18-28years showed that the GM dropped more than 60% in the last 10years. The distribution of BLL in France was quite similar to that observed in other European countries. PMID- 21237511 TI - Transient or persistent norovirus infection does not alter the pathology of Salmonella typhimurium induced intestinal inflammation and fibrosis in mice. AB - Murine noroviruses (MNV) are currently the most prevalent viruses infecting mouse research colonies. Concurrent infection of research mice with these viruses can dramatically alter the experimental outcome in some research models, but not others. In this report, we investigated the effect of MNV1 and MNV4 on a murine model of intestinal inflammation and fibrosis induced by Salmonella typhimurium infection in C57BL/6 mice. Subsequent co-infection of these mice with MNV1 or MNV4 did not lead to major changes in histopathology, the inflammatory response, or the fibrotic response. Thus, MNV does not substantially alter all gastrointestinal research models, highlighting the importance of investigating potential alterations in the research outcome by MNV on an individual basis. We hypothesize that this is particularly important in cases of research models that use immunocompromised mice, which could be more sensitive to MNV infection induced changes. PMID- 21237513 TI - Effects of pre and postnatal exposure to low levels of polybromodiphenyl ethers on neurodevelopment and thyroid hormone levels at 4 years of age. AB - There are at present very few studies of the effects of polybromodiphenyl ethers (PBDEs), used as flame retardants in consumer products, on neurodevelopment or thyroid hormone levels in humans. The present study aims to examine the association between pre and postnatal PBDE concentrations and neurodevelopment and thyroid hormone levels in children at age 4years and isolate the effects of PBDEs from those of PCBs, DDT, DDE and HCB. A prospective birth cohort in Menorca (Spain) enrolled 482 pregnant mothers between 1997 and 1998. At 4years, children were assessed for motor and cognitive function (McCarthy Scales of Children's Abilities), attention-deficit, hyperactivity and impulsivity (ADHD-DSM-IV) and social competence (California Preschool Social Competence Scale). PBDE concentrations were measured in cord blood (N=88) and in serum of 4years olds (N=244). Among all congeners analyzed only PBDE 47 was quantified in a reasonable number of samples (LOQ=0.002ng/ml). Exposure to PBDE 47 was analyzed as a dichotomous variable: concentrations above the LOQ (exposed) and concentrations below (referents). Scores for cognitive and motor functions were always lower in children pre and postnatally exposed to PBDE47 than in referents, but none of these associations was statistically significant (beta coefficient (95%CI) of the total cognition score: -2.7 (-7.0, 1.6) for postnatal exposure, and -1.4 (-9.2, 6.5) for prenatal exposure). Postnatal exposure to PBDE 47 was statistically significantly related to an increased risk of symptoms on the attention deficit subscale of ADHD symptoms (RR (95%CI)=1.8 (1.0, 3.2)) but not to hyperactivity symptoms. A statistically significant higher risk of poor social competence symptoms was observed as a consequence of postnatal PBDE 47 exposure (RR (95%CI)=2.6 (1.2, 5.9)). Adjustment for other organochlorine compounds did not influence the results. Levels of thyroid hormones were not associated to PBDE exposure. This study highlights the importance of assessing the effects of PBDE exposure not just prenatally but also during the early years of life. In the light of current evidence a precautionary approach towards PBDE exposure of both mothers and children seems warranted. PMID- 21237514 TI - The mental health of doctor-shoppers: experience from a patient-led fee-for service primary care setting. AB - BACKGROUND: Doctor-shopping may reflect unmet patient needs and places a significant burden on health resources; however little is known about its underlying reasons and how it relates to mental illness and its recognition in an open access fee-for-service setting. METHODS: In 2003-2004, consecutive patients of 46 French general practitioners (GPs), completed in the waiting room the self report Patient Health Questionnaire and reported on service use in the past six months. During the consultation, GPs rated the severity of any physical and psychiatric disorders. RESULTS: Of 1079 patients, those rated by the GP as having a common mental disorder were significantly more likely to be doctor-shoppers but only if visiting another GP because of dissatisfaction with previous care (OR=2.3, 95% CI: 1.4-3.7). A similar trend is observed for those identified as having a common mental disorder by the Patient Health Questionnaire. Among patients with a common mental disorder, 'dissatisfied' doctor-shoppers were significantly more likely to be recognised as cases by the GP, adjusting for covariates (OR=6, 95% CI: 2.1-17.2). This was not the case for those doctor shopping for practical reasons alone. CONCLUSION: Doctor-shopping behaviour is associated with higher rates of mental illness and, among cases, an increased likelihood of recognition by the GP, only however for doctor-shoppers dissatisfied with previous care. This suggests a benefit to letting patients choose their GP as is the case in France and change if not satisfied. PMID- 21237515 TI - New generation contraceptives: interleukin 11 family cytokines as non-steroidal contraceptive targets. AB - In the 50 years since the introduction of the contraceptive pill there have been no significant breakthroughs in contraceptive technology. It is clear that the currently available contraceptives fail to meet world-wide requirements, particularly in developing countries, therefore new methods of contraception are highly desirable. Gene deletion studies in mice have identified that the two cytokines interleukin (IL) 11 and leukemia inhibitory factor (LIF) are absolutely required for embryo implantation. Studies have demonstrated that administration of long acting IL11 and LIF inhibitors blocks embryo implantation resulting in infertility in mice. Clinical studies reveal that both cytokines are important regulators of embryo implantation in humans. Preventing implantation by targeting endometrial IL11 and LIF may be useful as a pharmacological non-hormonal strategy for women. In addition, vaginal application of the IL11 or LIF inhibitor with microbicides that block sexually transmitted infections could act as dual-role contraceptives, preventing implantation and sexually transmitted infections. PMID- 21237516 TI - Evidence for an emotion maintenance deficit in schizophrenia. AB - Research has indicated that people with schizophrenia have deficits in reward representation and goal-directed behavior, which may be related to the maintenance of emotional experiences. Using a laboratory-based study, we investigated whether people with schizophrenia were able to maintain an emotional experience when given explicit instructions to do so. Twenty-eight people with schizophrenia and 19 people without completed a behavioral task judging their emotional experience of pictures held over a three second delay. This emotion maintenance task was compared to a subsequent in-the-moment emotion experience rating of each picture. In addition, all participants completed an analogous brightness experience maintenance and rating task, and patients completed a standardized visual working memory task. Participants with schizophrenia showed normal in-the-moment emotion experience of the emotion pictures; however, they showed decreased performance on emotion maintenance (for both positive and negative emotion) compared to participants without schizophrenia, even after controlling for brightness maintenance. The emotion maintenance deficit was not associated with visual brightness performance nor with performance on the visual working memory task; however, negative emotion maintenance was associated with an interview-based rating of motivation. These findings suggest that some aspects of impaired emotion maintenance in schizophrenia may be related to deficits in motivated behavior. PMID- 21237517 TI - Relationship of morningness-eveningness questionnaire score to melatonin and sleep timing, body mass index and atypical depressive symptoms in peri- and post menopausal women. AB - Previous work shows a relationship between measures of morning or evening preference (e.g., morningness-eveningness questionnaire (MEQ) scores) and melatonin and sleep timing, body mass index (BMI) and mood. This study explores the relationship of these factors to atypical depression (ATD) symptoms, particularly increased appetite and hypersomnia, in depressed and non-depressed peri- and post-menopausal women. Participants were 19 normal control subjects and 10 depressed patients, 46-72 years of age. In a university hospital setting, we administered the MEQ and Structured Interview Guide for the Hamilton Depression Rating Scale, Seasonal Affective Disorders (SIGH-SAD version), which includes a measure of ATD, 3-5 weeks before obtaining nighttime polysomnography and overnight plasma melatonin in dim light (<30lx). Scores on SIGH-SAD appetite related items were significantly correlated with MEQ, dim light melatonin onset (DLMO) time and midsleep time (MST); BMI was related to MST, sleep end time, phase-angle differences between sleep and melatonin timing, and appetite measures. Results suggest that relative to women with earlier DLMOs and MSTs, depressed peri- and post-menopausal women whose DLMOs and MSTs are phase-delayed may experience increases in appetite, hypersomnia, and BMI. These symptoms might be relieved by sleep or light manipulations that advance melatonin and sleep timing parameters. PMID- 21237518 TI - Acute disseminated encephalomyelitis (ADEM). AB - ADEM is a disease that is characterized by an inflammatory reaction and demyelination in the central nervous system, with a distinct tendency to a peripheral localization of pathological changes. ADEM happens to occur with a temporal, and probably also with a causative relationship to viral, exanthematous diseases, as well as to preventive vaccinations. However, there are still many unresolved problems with respect to the relationship of ADEM to multiple sclerosis (MS), especially in instances with a multiphasic course of the disease. Many question marks can also be raised in cases, in which the examinations were unable to determine the exact preceding or causative factor. A lot of studies on cytokines and chemokines in blood plasma and CSR from patients with ADEM have enabled investigators to get a better insight into some stages of immunopathological processes, leading to an evolvement of the disease, without a more important impact on the clinical diagnosis. PMID- 21237519 TI - Phenytoin at optimum doses ameliorates experimental autoimmune encephalomyelitis via modulation of immunoregulatory cells. AB - We investigated the optimum doses of phenytoin for treatment of myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE). Oral and intraperitoneal administrations of 0.25 to 1.0mg per mouse (12.5 50mg/kg) 3 times a week improved the clinical course. Intraperitoneal injections of 1.0mg phenytoin were the most effective, as a significant reduction in EAE severity was seen after only 2 administrations with that protocol. Treatment efficacy was associated with amelioration of cellular infiltrates in the CNS, and an increase in CD4(+)Foxp3(+) and CD4(+)CD25(+)CD127(-) regulatory T cells as well as CD8(+) suppressor/cytotoxic T cells in blood. PMID- 21237520 TI - Effect of identification and intervention age on language development for Mandarin-speaking deaf children with high family involvement. AB - OBJECTIVE: The purpose of this study is to assess the language ability between early-intervention and later-intervention Mandarin-speaking deaf children, who have normal cognition and high family involvement. MATERIALS AND METHODS: There are 29 subjects enrolled. 11 born deaf children received early intervention (7 HA and 4 CI) before 6 months old as study group. Another 18 born deaf children received later intervention (11 HA and 7 CI) between 7 and 35 months old as reference group. They were all regarded as with normal cognition and high family involvement. Their mean assessment age was 50 months old in early group and 51 months old in later group. We used several tools to test their perceptive vocabulary size, to evaluate perceptive language syntax and to compare perceptive and expressive language scores. RESULTS: Our study revealed there are significant difference between these two groups in the ability of vocabulary size, perceptive language syntax and perceptive language scores. The results showed there is no significant difference between these two groups in their expressive language scores, although their achievement score is higher in the early group. CONCLUSIONS: It clearly showed the ability of perceptive language in early intervention deaf children was better than that of later-intervention. The ability of their expressive language showed no difference between them. PMID- 21237521 TI - FOXP3+ regulatory T cells: control of FOXP3 expression by pharmacological agents. AB - Naturally arising CD4(+)CD25(+) regulatory T cells (Tregs), which specifically express the forkhead family transcription factor FOXP3, are essential for the maintenance of immunological self-tolerance and immune homeostasis. Tregs can suppress the activation, proliferation and effector function of other lymphocytes in physiological and pathological immune responses. Therefore, control of the development, survival, and function of Tregs is instrumental for effective control of immune responses. For example, cytokines such as interleukin-2 and transforming growth factor-beta, monoclonal antibodies to the Treg-associated molecules such as interleukin-2 receptor alpha chain and cytotoxic T lymphocyte associated 4, and pharmacological agents that alter signaling pathways for Treg function, can augment or dampen the suppressive activity of Tregs. How these agents control the function of Tregs at the molecular level remains to be elucidated. However, it is envisaged that pharmacological control of the function and development of Tregs by targeting FOXP3 or Treg-associated molecules will enable better control of immune responses in various clinical settings. PMID- 21237522 TI - Prediction equations and point system derived from large-scale health check-up data for estimating diabetic risk in the Chinese population of Taiwan. AB - AIM: To develop tools for predicting diabetes development in middle-aged Chinese adults living in Taiwan. METHODS: This study made use of data from 24,899 non diabetic adults aged >=35 years who received health examination service from a private health check-up clinic during the period of 1994-1996 and had one or more examinations before December 31, 2006. The proportional hazard model and the receiver operating characteristic (ROC) curve method were used respectively to construct the prediction equation and assess the model's performance. A point system is developed for the ease to calculate diabetes risk. RESULTS: Increased risk of diabetes development was associated with older age, lower education level, alcohol abstinence, abdominal obesity, elevated body mass index (BMI), blood pressure (BP), triglycerides, and impaired fasting glucose. Model 1, incorporating personal socio-demographic and lifestyle characteristics, BMI, and waist circumference (WC), had an area-under-curve (AUC) of 0.717. The AUC increased to 0.726 (model 2) when BP was introduced and to 0.823 (model 3) when both BP and clinical chemistry measures were added. The AUCs in the testing set for models 1, 2, and 3 were 0.688, 0.694, and 0.799 respectively. CONCLUSIONS: These predictive equations of diabetic risk were easy to use by clinical professions and general subjects. PMID- 21237523 TI - Reduced diffusion lung capacity in patients with type 2 diabetes mellitus predicts hospitalization for pneumonia. AB - Among 4164 patients, those with type 2 diabetes mellitus (DM) had lower lung diffusion capacity (DLCO) compared with those without DM (DLCO mean+/-SE: 15.7+/ 0.3 vs. 17.0+/-0.2 mL/min/mm Hg, p<0.01). Reduced DLCO predicted hospitalization for pneumonia independent of diabetes control, severity and co-morbidities (OR=2.4, CI 1.08-5.31). PMID- 21237525 TI - Analysis of urinary proteomic patterns for type 2 diabetic nephropathy by ProteinChip. AB - OBJECTIVE: To detect urinary proteomic profiling of patients with type 2 diabetes by using ProteinChip array technology, for searching new potential biomarkers in early diagnosis of type 2 diabetic nephropathy (T2DN). METHODS: A total of 95 urine samples from type 2 diabetic patients with normoalbuminuria (DM, n=30), microalbuminuria (DNl, n=25) and macroalbuminuria (DN2, n=20), and healthy controls (n=20) were analyzed by SELDI-TOF-MS (the surface-enhanced laser desorption/ionization time-of-flight mass spectrometry) technology combined with bioinformatics tools. RESULTS: Over 300 proteins or peptides from 1 to 80 kDa were obtained using ProteinChip. About 40 of them with the m/z values from 2008.78 to 79176.55 Da were significantly differentiated between type 2 diabetic patients and control subjects. Four proteins of mass 2797.03, 4545.77, 4984.03 and 9083.71 Da were selected as the potential biomarkers for T2DN with sensitivity of 88% and specificity of 96.7%. CONCLUSION: ProteinChip technology can help to discover new biomarkers and provide a novel non-invasive tool to early diagnosis of T2DN. PMID- 21237524 TI - Augmented NADPH oxidase activity and p22phox expression in monocytes underlie oxidative stress of patients with type 2 diabetes mellitus. AB - BACKGROUND: This study was to test the hypothesis that enhanced oxidative stress is induced in monocytes with over-activated NADPH oxidase during the development of type 2 diabetes mellitus. METHODS: Levels of glucose and lipids were analyzed in 73 diabetic patients and 36 controls. Superoxide dismutase (SOD), malondialdehyde (MDA), reactive oxygen species (ROS) and protein carbonylation were tested. Expression of NADPH oxidase was examined and p47phox translocation was assessed. RESULTS: With the abnormality of glucose and lipid metabolism, diabetic patients showed a higher oxidative stress state indicated by decreased SOD activity but elevated MDA and protein carbonylation level. Monocytes in diabetes also showed elevated ROS generation and protein carbonylation level. Furthermore, NADPH oxidase was highly activated in monocytes represented by p22phox up-regulation and p47phox translocation. Significant positive bivariate correlation was found between glucose and MDA level as well as p22phox expression. In vitro experiments also indicated that glucose could stimulate ROS generation in a NADPH oxidase dependent manner. Moreover, we carried out same measurement in 40 diabetic patients with anti-diabetic intervention and obtained the reinforced results. CONCLUSIONS: Hyperglycemia is the main factor which induces oxidative stress mainly by activation of NADPH oxidase in monocytes of diabetic patients. PMID- 21237526 TI - A comparison of autofluorescence bronchoscopy and white light bronchoscopy in detection of lung cancer and preneoplastic lesions: a meta-analysis. AB - INTRODUCTION: It is known that autofluorescence bronchoscopy (AFB) has limited value in detection of lung cancer and preneoplastic lesions. Though a substantial number of studies have evaluated the diagnostic yield of AFB, the variable estimates limited the ability to accurately assess its test performance and future role in clinical practice. The clinical utility of AFB has never been supported by a meta-analysis due to the inconsistent characteristics in some of studies. A meta-analysis was performed to re-examine the diagnostic efficiency of AFB compared with white light bronchoscopy (WLB). METHODS: Search of both MEDLINE and EMBASE database up to June 2009 was conducted and hand search was performed against the extracted reference list for relevancy. Included studies had to have a conclusive histology as diagnostic standard, and provided sufficient data to construct a 2X2 table for assessing the diagnostic yield of AFB for detection of lung cancer and preneoplastic lesions. After examining the source of variation, pooled sensitivity and specificity of AFB were estimated using a bivariate random effects regressing model and compared with that of WLB. RESULTS: Of 439 publications, 14 studies, providing 15 sets of data, were suitable for analysis. The pooled sensitivity and specificity of AFB and WLB were 0.90 (95% CI 0.84 0.93) and 0.56 (95% CI 0.45-0.66), 0.66 (95% CI 0.58-0.73) and 0.69 (95% CI 0.57 0.79). The contribution of differences in excitation light source, histological criteria and biopsy strategy was not counted as a covariate. CONCLUSIONS: The result indicated that AFB was superior to conventional WLB in detecting lung cancer and preneoplastic lesions. PMID- 21237527 TI - The addition of organic carbon and nitrate affects reactive transport of heavy metals in sandy aquifers. AB - Organic carbon introduction in the soil to initiate remedial measures, nitrate infiltration due to agricultural practices or sulphate intrusion owing to industrial usage can influence the redox conditions and pH, thus affecting the mobility of heavy metals in soil and groundwater. This study reports the fate of Zn and Cd in sandy aquifers under a variety of plausible in-situ redox conditions that were induced by introduction of carbon and various electron acceptors in column experiments. Up to 100% Zn and Cd removal (from the liquid phase) was observed in all the four columns, however the mechanisms were different. Metal removal in column K1 (containing sulphate), was attributed to biological sulphate reduction and subsequent metal precipitation (as sulphides). In the presence of both nitrate and sulphate (K2), the former dominated the process, precipitating the heavy metals as hydroxides and/or carbonates. In the presence of sulphate, nitrate and supplemental iron (Fe(OH)(3)) (K3), metal removal was also due to precipitation as hydroxides and/or carbonates. In abiotic column, K4, (with supplemental iron (Fe(OH)(3)), but no nitrate), cation exchange with soil led to metal removal. The results obtained were modeled using the reactive transport model PHREEQC-2 to elucidate governing processes and to evaluate scenarios of organic carbon, sulphate and nitrate inputs. PMID- 21237528 TI - Predictions of long-term performance of granular iron permeable reactive barriers: field-scale evaluation. AB - Long-term performance is a key consideration for the granular iron permeable reactive barrier (PRB) technology because the economic benefit relies on sustainable operation for substantial periods of time. However, predictions on the long-term performance have been limited mainly because of the lack of reliable modeling tools. This study evaluated the predictive capability of a recently-developed reactive transport model at two field-scale PRBs, both having relatively high concentrations of dissolved carbonate in the native groundwater. The first site, with 8 years of available monitoring data, was a funnel-and-gate installation, with a low groundwater velocity through the gate (about 0.12 m d( 1)). The loss in iron reactivity caused by secondary mineral precipitation was small, maintaining relatively high removal rates for chlorinated organics. The simulated concentrations for most constituents in the groundwater were within the range of the monitoring data. The second site, with monitoring data available for 5 years, was a continuous wall PRB, designed for a groundwater velocity of 0.9 m d(-1). A comparison of measured and simulated aqueous concentrations suggested that the average groundwater velocity through the PRB could be lower than the design value by a factor of two or more. The distribution and amounts of carbonate minerals measured in core samples supported the decreased groundwater velocity used in the simulation. The generally good agreement between the simulated and measured aqueous and solid-phase data suggest that the model could be an effective tool for predicting long-term performance of granular iron PRBs, particularly in groundwater with high concentrations of carbonate. PMID- 21237529 TI - Effect of charcoal amendment on adsorption, leaching and degradation of isoproturon in soils. AB - The effects of charcoal amendment on adsorption, leaching and degradation of the herbicide isoproturon in soils were studied under laboratory conditions. The adsorption data all fitted well with the Freundlich empirical equation. It was found that the adsorption of isoproturon in soils increased with the rate of charcoal amended (correlation coefficient r=0.957**, P<0.01). The amount of isoproturon in leachate decreased with the increase of the amount of charcoal addition to soil column, while the retention of isoproturon in soils increased with an increase in the charcoal content of soil samples. Biodegradation was still the most significant mechanism for isoproturon dissipation from soil. Charcoal amendment greatly reduced the biodegradation of isoproturon in soils. The half-lives of isoproturon degradation (DT(50)) in soils greatly extended when the rate of added charcoal increased from 0 to 50 g kg(-1) (for Paddy soil, DT(50) values increased from 54.6 to 71.4 days; for Alfisol, DT(50) from 16.0 to 136 days; and for Vertisol, DT(50) from 15.2 to 107 days). The degradation rate of isoproturon in soils was significantly negatively correlated with the amount of added charcoal. This research suggests that charcoal amendment may be an effective management practice for reducing pesticide leaching and enhancing its persistence in soils. PMID- 21237530 TI - Early senescence induced by 2-3H-benzoxazolinone (BOA) in Arabidopsis thaliana. AB - Measurements of chlorophyll a fluorescence, nutrient and trace elements, total protein content and malonyldialdehyde in leaves of Arabidopsis thaliana between 1 and 192 h after treatment with 0, 1 or 3 mM 2-3H-benzoxazolinone (BOA), together with imaging of chlorophyll a fluorescence and of the distributions of hydrogen peroxide and superoxide anion, suggested that the primary phytotoxic action of BOA is the induction of premature senescence, and that oxidative stress is a secondary effect that sets in a day or two later. PMID- 21237531 TI - The Solanum lycopersicum RNaseLER is a class II enzyme of the RNase T2 family and shows preferential expression in guard cells. AB - Ribonucleases (RNases) occur in different gene families, functioning in RNA processing and degradation. In this study, we report on cloning and characterization of RNaseLER, the first class II gene of the RNase T2 family in tomato (Solanum lycopersicum). The family also includes the class I members RNaseLE and RNaseLX, and the class III group of S-RNases acting in self incompatibility. The RNaseLER gene was cloned by polymerase chain reaction (PCR) assisted methods. Structural analyses of RNaseLER and homologous genes revealed unique key features of class II RNase T2 genes. RNaseLER is a single copy gene in tomato and codes for a primary protein of 260 amino acids. Subcellular localization analyzed with a RNaseLER-eYFP fusion protein and co-localization experiments revealed an intracellular accumulation in the endoplasmic reticulum. Transgenic Nicotiana benthamiana plants carrying the uidA reporter gene under the control of a 900-bp RNaseLER promoter sequence express the reporter gene predominantly in guard cells and trichomes. This previously unknown spatial expression of a RNase T2 gene is consistent with ubiquitous detection of low RNaseLER transcript abundances in almost all parts of tomato plants. As revealed by quantitative real-time RT-PCR analysis treatments with abscisic acid, ethylene or other abiotic and biotic stress factors did not affect RNaseLER expression significantly. Unlike tomato class I genes, RNaseLER represents a constitutively expressed gene with a cell-specific role in stomata and trichomes and no involvement in stress responses. PMID- 21237532 TI - Ketofol for procedural sedation? Pro and con. PMID- 21237533 TI - Enhancing functional balance and mobility among older people living in long-term care facilities. AB - This study of long-term care residents investigated whether a balance strategy training program (BSTP) developed for older people living in the community is effective in improving functional mobility and reducing falls when adapted to resident functional abilities. The BSTP was delivered twice weekly over 12 weeks. Outcome measures compared pre- and postintervention measured Timed Up and Go, Functional Reach, timed 5 sit-to-stand movements, and number of falls in 12 weeks before intervention with 12-week follow-up period. Forty-seven residents participated, 26 of whom were cognitively impaired. There was a significant improvement in all functional balance and mobility measures, but this was clinically significant only in 5 sit-to-stand time. There was no reduction in falls, although this outcome was confounded by all fallers being acutely ill at the time of falling. These results suggest participation in a BSTP by residents of long-term care improves resident functional mobility and balance. PMID- 21237534 TI - [Cocaine-induced ischemic colitis in a high-risk patient treated conservatively]. AB - Drug consumption is among the non-occlusive causes of ischemic colitis. We report a case of cocaine-induced ischemic colitis in a 34-year-old man who had undergone sigmoid resection and loop colostomy due to abdominal-pelvic injury 3 months previously. The patient presented with abdominal pain associated with diarrhea and slight transient fever of doubtful etiology and reported intranasal cocaine consumption. He was hemodynamically stable and showed no peritoneal irritation. Traces of blood were found in the colostomy bag. Colonoscopy showed ulcers and necrosis proximal to the stoma. Computed tomography angiography scan showed no abnormalities except filiform inferior mesenteric artery. The symptoms were self limiting and the patient was discharged 3 days after admission. Subsequently the colostomy was closed without complications. A high degree of suspicion is required in young patients with abdominal pain not identified by conventional methods and a recent history of drug consumption. PMID- 21237536 TI - Rethinking theory and practice: pre-registration student nurses experiences of simulation teaching and learning in the acquisition of clinical skills in preparation for practice. AB - In the United Kingdom (UK) simulation learning has been recognised in the form of a regulatory agreement that may replace hours from clinical practice. This integration has become an embedded feature of the pre-registration nursing programme at a University in the North of England, along with strategic investment in staff and simulation suites developed to underpin this curriculum change albeit in the absence of sparse empirical evidence, hence the rationale for the study which was designed to explore the relationship between simulation, theory and practice. The study features a thematic analysis of evaluation questionnaires from pre-registration student nurses (n=>500) collected over a 2 year period which informed subsequent focus group interviews to explore the themes in more detail. Consistent data findings were the students' positive response to simulation as a learning approach facilitating the application of theory in a safe controlled environment. Students reported that they felt prepared for practice, recognising that simulated learning improved their humanistic and problem solving abilities as well as the development of psychomotor, technical skills, and overall confidence. The theory-practice gap is a recurring narrative in the nursing literature, the findings of this study recognises that simulation offers an opportunity to enact the integration of theory and practice illuminating this relationship in a controlled environment thus, reinforcing the theory-practice relationship for nursing students. PMID- 21237535 TI - [Evaluation and control of hypertensive diabetics seen in Primary Care centres in Spain. BRAND II study]. AB - OBJECTIVE: We aimed to verify the level of blood pressure and glucose control and treatment in hypertensive diabetics seen in Primary Care Centres in Spain. DESIGN: Descriptive study conducted on hypertensive diabetic patients who attended primary care centres for any reason. LOCATION: Primary Care centres throughout Spain. PARTICIPANTS: The study included 6,777 patients. MEASUREMENTS: Blood pressure, weight, height, waist circumference, blood analysis and treatment were recorded RESULTS: The mean age of the sample was 64.40 (11.50) years. Mean blood glucose was 141.8 (39) mg/dl, glycosylated haemoglobin was <=7% in 45.9% of the sample, and blood pressure was under control (BP<=130/80 mmHg) in 9.8% of the patients studied. LDL Cholesterol was <=100mg/dl in 25.3% of the sample. The drugs most used to control diabetes were; sulphonylureas 2259 patients (33.3%) and biguanides 3768 patients (55.6%). A total of 556 patients were on treatment with insulin, which represented 8.2% of the population studied. The drugs most used for hypertension were; diuretics in 3395 patients (50.1%) and angiotensin converting enzyme inhibitors in 4053 patients (59.8%). CONCLUSIONS: A large proportion of hypertensive diabetics are insufficiently controlled. PMID- 21237537 TI - The postdoctoral paradox: a specification of nursing science? PMID- 21237538 TI - Maintaining power: women's experiences from labour onset before admittance to maternity ward. AB - BACKGROUND: In Sweden pregnant women are encouraged to remain at home until the active phase of labour. Recommendation is based on evidence, that women who seek care and are admitted in the latent phase of labour are subjected to more obstetric interventions and suffer more complications than women who remain at home until the active phase of labour. The aim of this study was to obtain a deeper understanding of how women, who remain at home until the active phase of labour, experience the period from labour onset until admission to labour ward. METHOD: Interviews were conducted with 19 women after they had given birth to their first child. A Constructivist Grounded theory method was used. FINDINGS: 'Maintaining power' was identified as the core category, explaining the women's experience of having enough power, when the labour started. Four related categories: 'to share the experience with another', 'to listen to the rhythm of the body', 'to distract oneself' and 'to be encased in a glass vessel', explained how the women coped and thereby maintained power. CONCLUSIONS: The first time mothers in this study, who managed to stay at home during the latent phase of labour, had a sense of power that was expressed as a driving force towards the birth, a bodily and mental strength and the right to decide over their own bodies. This implies that women who maintain power have the ability to make choices during the birth process. The professionals need to be sensitive, supportive and respectful to women's own preferences in the health-care encounter, to promote the existing power throughout the birthing process. PMID- 21237539 TI - Barriers to developing midwifery as a primary health-care strategy: a Jordanian study. AB - AIM: To identify the current barriers to developing midwifery as a primary health care strategy in Jordan and to explore the strategies to overcome these barriers. DESIGN: An exploratory design using an action research approach was undertaken. Workshop discussion groups and reflection were used to collect the data. A thematic approach was taken for the analysis. PARTICIPANTS: Data were collected from a convenience sample of 64 midwives and educators who attended workshops. FINDINGS: The professional identity and image for midwifery has been confused within a medically dominated health system and has not been seen as a primary health strategy. Midwives are not able to practice to the full role and scope of the midwife. IMPLICATIONS FOR PRACTICE: Key issues identified need to be addressed before midwifery can be part of a primary health-care strategy in Jordan. PMID- 21237540 TI - The development of research tools used in the STORK Study (the Scottish Trial of Refer or Keep) to explore midwives' intrapartum decision making. AB - OBJECTIVES: to develop appropriate tools to assess midwives' attitudes and behaviour in relation to decision making involving risk. DESIGN: a questionnaire and series of vignettes were developed and testes to explore midwives' intrapartum decision making in relation to their attitudes towards risk. An innovative online computer package was developed specifically for use in the STORK Study which enabled the programme to be very tightly controlled with limited functions accessible to participants. TESTING: a pilot study was conducted with over 50 midwives and nurses to ensure face and content validity of the vignettes and questionnaire. Initially designed to be a paper-based study, rigorous piloting highlighted the many difficulties in presenting it in that particular format. The solution to this problem was to develop the study as a secure online package. FINDINGS: online data collection provided the researchers with a greater degree of control of the data collection process, not achievable using traditional paper survey methods. Another example of this control is the immediate entry of data from participants' responses to a background database which automatically stores and backs up data this means that no additional time is required for data entry. The cost of employing an information technology professional was easily offset by the financial savings made through the limited use of stationery and postage. KEY CONCLUSIONS: although the development and testing of the research tools for the STORK Study was labour and time intensive, ultimately a questionnaire and vignette package was produced that had been rigorously tested by over 50 midwives and nurses. The researchers are confident in the reliability of the questionnaire and vignettes, as well as the validity of the data collected. The use of an online survey is clearly indicated when the population has readily available internet access, and where controlling the process of data collection is required, as such control cannot be achieved in traditional survey and questionnaire implementation. PMID- 21237541 TI - 'Not enough people to look after you': an exploration of women's experiences of childbirth in the Republic of Ireland. AB - OBJECTIVE: Women's experiences of childbirth have far reaching implications for their health and that of their babies. This paper describes an exploration of women's experiences of childbirth in the Republic of Ireland. DESIGN: A qualitative descriptive study consisting of focus group interviews (FGIs) identified important aspects of women's childbirth experiences. SETTING: Four randomly selected maternity units in the Republic of Ireland. The pilot study unit was also included in the data collection. PARTICIPANTS: A convenience sample of 25 women who volunteered to participate in five focus group interviews. Eligible participants were >18 years, able to discuss their birth experiences in English, had experienced labour, and had a live healthy baby. DATA COLLECTION: Approximately three months following the birth, data were collected using a conversational low moderator style focus group interviews. FINDINGS: Three main themes were identified, 'getting started', 'getting there' and 'consequences'. Women experienced labour in a variety of contexts and with differing aspirations. Midwives played a pivotal role in enabling or disempowering positive experiences. Control was an important element of childbirth experiences. Women often felt alone and unsupported. The busyness of the hospital units precluded women centred care both in early labour and in the period following the birth. Some women would not have another baby due to their childbirth experiences. KEY CONCLUSIONS: The context within which women give birth in the Republic of Ireland is important to their birth experiences. Although positive experiences were reported many women felt anxious and isolated. Busy environments added to women's fears and participants appeared to accept the lack of support as inevitable. Midwives play a pivotal role in helping women achieve a positive birth experience. IMPLICATIONS FOR PRACTICE: Excluding women's views from service evaluation renders an incomplete and somewhat distorted depiction of childbirth in Ireland. Although women appear to be satisfied with a live healthy baby, the process of 'getting there' has an emotional and psychological dimension that is important to the experience. Measuring the quality of maternity services must encompass recognition of psychological and emotional well-being alongside physical safety. PMID- 21237542 TI - Inside-sediment partitioning of PAH, PCB and organochlorine compounds and inferences on sampling and normalization methods. AB - Comparability of sediment analyses for semivolatile organic substances is still low. Neither screening of the sediments nor organic-carbon based normalization is sufficient to obtain comparable results. We are showing the interdependency of grain-size effects with inside-sediment organic-matter distribution for PAH, PCB and organochlorine compounds. Surface sediment samples collected by Van-Veen grab were sieved and analyzed for 16 PAH, 6 PCB and 18 organochlorine pesticides (OCP) as well as organic-matter content. Since bulk concentrations are influenced by grain-size effects themselves, we used a novel normalization method based on the sum of concentrations in the separate grain-size fractions of the sediments. By calculating relative normalized concentrations, it was possible to clearly show underlying mechanisms throughout a heterogeneous set of samples. Furthermore, we were able to show that, for comparability, screening at < 125 MUm is best suited and can be further improved by additional organic-carbon normalization. PMID- 21237543 TI - Accumulation of platinum group elements by the marine gastropod Littorina littorea. AB - The accumulation and trophic transfer of the platinum group elements (PGE): Rh, Pd and Pt; have been studied in short-term (5 day) exposures conducted in aquaria containing the marine macroalga, Ulva lactuca, and/or the grazing mollusc, Littorina littorea. Metals added to sea water (to concentrations of 20 MUg L-1) were taken up by U. lactuca in the order Rh, Pt > Pd and by L. littorea in the order Pd >= Pt >= Rh, with greatest metal accumulation in the latter generally occurring in the visceral complex and kidney. When fed contaminated alga, accumulation of Rh and Pd by L. littorea, relative to total available metal, increased by an order of magnitude, while accumulation of Pt was not readily detected. We conclude that the diet is the most important vector for accumulation of Rh and Pd, while accumulation of Pt appears to proceed mainly from the aqueous phase. PMID- 21237544 TI - A systematic review and meta-analysis of randomized controlled trials of cognitive-behavioral therapy for tinnitus distress. AB - Tinnitus is defined as a sound in the ear(s) and/or head without external origin and is a serious health concern for millions worldwide. The aim of the present study was to determine whether Cognitive Behavior Therapy (CBT) is effective in reducing distress associated with tinnitus. Randomized, controlled trials that assessed the efficacy of CBT for tinnitus-related distress in adults were identified by searching electronic databases (PsychINFO, PubMed, the Cochrane Library), and by manual searches. Fifteen studies (total of 1091 participants) were included in the meta-analysis. CBT compared with a passive and active control at post-assessment yielded statistically significant mean effect sizes for tinnitus-specific measures (Hedges's g=0.70, and Hedges's g=0.44, respectively). The average weighted pre-to-follow-up effect size for the CBT group suggested that these effects were maintained over time. Smaller but yet statistically significant effects of CBT were found for mood outcome measures. Characteristics of the studies were unrelated to effect sizes. Methodological rigor, publication bias, and a series of sensitivity analyses did not influence the findings. The results suggest that CBT is an effective treatment of tinnitus distress. However, caution is warranted given that few large-scale, well controlled trials were identified. PMID- 21237545 TI - [From microsurgery to supermicrosurgery: Experimental feasibility study and perspectives]. AB - INTRODUCTION: Supermicrosurgical techniques developed for the anastomoses less or equal to 0.5mm show convincing results in specialized centers and with an advanced instrumentation. Can we integrate supermicrosurgical training animal models in the current teaching program of microsurgery?. MATERIALS AND METHODS: Ten arterial anastomoses of the inferior epigastric artery (diameter less than or equal to 0.5mm) were performed consecutively in five rats by the same beginner operator in microsurgery, with standard microsurgical set of instruments. The intravascular stenting anastomosis method was used with 11-0 nylon sutures. The immediate patency and flap survival on postoperative day three was assessed. The duration of each anastomosis was measured. RESULTS: The mean diameter of the arteries was 0.4mm. The average time for each anastomosis was 30 minutes with a maximum of 55 minutes and a minimum of 18 minutes. The average number of stitches was 5.5. The immediate patency was 100 % with a 70 % success rate at the third day. CONCLUSIONS: There are several applications of supermicrosurgical techniques, especially in hand surgery, lymphoedema surgical treatment and for perforator-to-perforator flaps. The intravascular stenting method allows fast learning of the technique with a satisfactory success rate despite non-specific instrumentation. Furthermore, this method could easily be integrated among the microsurgical courses of many universities. PMID- 21237546 TI - [The adipose tissue transfer in the mammary parenchyma (part II): Review of the literature on the carcinologic risks]. AB - The adipose tissue transfer in the mammary parenchyma is a controversial area that generates passionate debates both in France and abroad. This second article presents a review of the literature on the interactions of fat transfer and the risk of developing breast cancer. Analysis of the results of the fundamental literature on the effects of adipose tissue in breast cancer development is troubling. At this stage, these results can not be transposed to humans as there are no studies showing a clinical correlation with suspected factors. It is difficult today to propose a pragmatic attitude on the transfer fat tissue into the breast. Given the results of the literature, we believe that the recommendations of caution of various scientific societies is well justified. The development of prospective study seems necessary to address this controversial issue. PMID- 21237547 TI - [Morel-Lavallee lesion in orthopaedic surgery (Nineteen cases)]. AB - AIMS: The object of this work is the study of especially ancient clinical forms of the effusion of Morel-Lavallee, to discuss the place of deep fascial fenestration by Ronceray and to propose criteria of therapeutic indication. PATIENTS AND METHOD: Our study concerns a continuous retrospective series over 20 years from 1989 till 2009. Eleven men and eight women, 36.7 year-old on average were treated for an effusion of Morel-Lavallee. The dominant etiology was represented by the accidents of the public highway. The collection was discovered after 41.4 days on average (extremes of 1-180 days). The volume of the collection was on average of 1237cm(3) (extremes 60cm(3)-12L). RESULTS: The conservative treatment concerned all patients who had a recent collection lower than three weeks and three others who had an ancient collection. The surgical treatment was established after all 10 times among which four in first intention and six times after failure of the previous treatment. The cure was obtained in 91% of the patients who had a recent collection by the only conservative method and among four patients by the method of Ronceray. To the three others, it was obtained after iterative unbridlings and talcage treatment. CONCLUSION: The authors insist on certain rare forms met in Africa in particular the "virtual form", the ancient forms and the too plentiful forms (12L). They plead for use deep fascial fenestrations by Ronceray for these last ones. PMID- 21237548 TI - [Fibrin sealant significantly decrease postoperative drainage in breast reconstruction by deep inferior epigastric perforator (DIEP) flap]. AB - PURPOSE: Serosanguinous drainage after breast reconstruction by deep inferior epigastric perforator (DIEP) flap constitute with the microsurgical monitoring, the main limiting factors for patient discharge. Fibrin sealant has already been studied to reduce post breast surgery drainage. The authors are presenting their experience in secondary breast reconstruction by DIEP flap with the use of sprayed fibrin sealant. PATIENTS AND METHODS: Twenty-one female patients aged 28 to 63 years old who underwent secondary breast reconstruction after mastectomy for cancer between October 2004 and June 2007 have been reviewed. These patients were separated into two groups. In group 1, patients (n=9) received two drains placed under the flap and in the axillary area. In group 2, (n=12) the DIEP flaps and thoracic areas were sprayed with fibrin sealant (Tissucol((r))) before the two drains inset. RESULTS: No adverse effect were reported, with a 36-month median follow-up. Drainages volumes or durations were not correlated to the patients' Body Mass Index (BMI). Lower drained volumes were collected from the thoracic region (372ml versus 629mL) and thoracic drains were removed earlier (5.5 days versus 6.9 days) in group 2. The length of stay was also significantly reduced after fibrin sealant use (5.5 days versus 7.22 days with P=0.0305 by log rank test). CONCLUSION: This study is a rare clinical one on fibrin sealant use to decrease postoperative drainage in breast reconstruction by DIEP flap. Fibrin sealant significantly decreased the postoperative drainage volume and duration. PMID- 21237549 TI - [Pterigium colli: secondary surgical correction of one severe case]. AB - Congenital web neck is a deformity hardly ever reported in the English literature. It is usually associated to Ulrrich-Turner syndrome. There are several options to correct this deformity, but in severe cases complete correction of the web and the abnormal back hair is not always possible. We present our experience with a secondary case where previous butterfly method was employed, a combined procedure was used achieving a satisfactory result. We considered that this technique is useful and offers an important improvement of the contour. PMID- 21237550 TI - [About an extreme case of giant lymphoedema of the upper limb: ligasure may be useful and a multidisciplinary approach is mandatory]. AB - Treatment of giant lymphoedema remains very difficult. The main problem is not only the obtention of early postoperative favorable results but to keep them long lasting. The available treatment options are numerous and often combined. The indications have to be adapted to the clinical stage of the lesion. Ligasure((r)) give us many advantages in the achievement of the surgical resection due to the quality of the lymphostasis that can be obtained and to the very limited thermic lesions caused to tissues. Long lasting postoperative physiotherapy is of first importance. We here describe a case of a giant lymphoedema of the upper limb after axillary lymph node dissection for breast cancer. The first physiotherapy failed, causing a lymphatic decompensation resulting in a lymphoedematous mass of nearly 7kg. The surgical resection with Ligasure((r)) associated to drainage and compressive physiotherapy in the long run allows to obtain good results. The late follow-up after 4 years still shows stable results. PMID- 21237551 TI - Limitations of biomarkers serum levels during pulmonary vein isolation. AB - INTRODUCTION AND OBJECTIVES: Several biomarkers have been used for evaluation and quantification of myocardial injury after effective ablation. We studied possible different thermal stability and usability of the proteins released by cardiac cells injured by different energy sources. METHODS: Firstly, we tested in vitro thermal stability of creatinine kinase (CK), myocardial bound creatinine kinase (CKMB), cardiac troponins I (cTnI) and cardiac troponins T (cTnT) in collected blood samples from 15 patients (pts) with confirmed ST-segment elevated myocardial infarction (STEMI). Secondly, the biomarkers were collected and analyzed in 82 pts treated with radiofrequency ablation (RFA) and in 79 pts treated with cryo-balloon ablation (CBA). RESULTS: In vitro experiment showed that all biomarkers were stable in low temperature of -30(o)C. Troponins were stable in the high temperatures analyzed. A substantial drop in CK and CKMB levels were measured at 50 degrees C and 40 degrees C, respectively. In vivo study showed that the increase in CKMB levels was highly significant in CBA pts only. Pathological CKMB values were observed in 24% of RFA pts and 98% of CBA pts. Pathological cTnI values were observed in all pts and the rise in cTnI levels was highly significant in both groups after ablation. CONCLUSIONS: Both in vitro and in vivo results show that CKMB cannot be used for quantitative determination of myocardial injury produced by radiofrequency energy. Only cardiac troponins reflect myocardial injury, regardless of energy source, and may be considered in future studies for comparison of biomarkers effects of cryo versus radiofrequency ablation. PMID- 21237552 TI - A comparison of paediatric airway anatomy with the SimBaby high-fidelity patient simulator. AB - BACKGROUND: The SimBaby high-fidelity patient simulator is a widely used paediatric simulator for the training of standard and critical airway management scenarios. Furthermore this simulator is frequently used for the evaluation of different airway devices and techniques. However, the anatomic structures of the SimBaby have not been compared to actual patients' anatomy. METHODS: The CT radiographic measures of the upper airway anatomy of two SimBaby simulators were compared to MRI images of the upper airway of 20 children aged 1-11 months who underwent routine MRI scans under sedation for diagnostic purposes. Various distances of the tongue, soft palate and pharynx, cross sectional areas and volumes of anatomic structures of the upper airway including the retroglossal airspace were compared. RESULTS: The SimBaby's retroglossal airspace volume greatly differed from the measurements in patients (SimBaby 5.3+/-0.4 vs. 1.9+/ 0.8 cm(3) in infants, p<0.01). Furthermore the distance from the alveolar process of the mandible to the posterior pharyngeal wall was larger in the SimBaby than in infants (5.8+/-0.1 vs. 4.5+/-0.5 cm, p<0.001) and dimensions of the epiglottis and pharynx were larger in the Simbaby. CONCLUSION: The anatomic features of the SimBaby do not adequately simulate the upper airway anatomy of infants. These results imply inadequate realism of this simulator for airway training and compromise the validity of comparative trials of different airway devices with the SimBaby as airway model. PMID- 21237554 TI - Enhanced differentiation and clonogenicity of human endometrial polyp stem cells. AB - Endometrial polyps arise from endometrial overgrowth and may cause intermenstrual bleeding, irregular bleeding, and menorrhagia. In this study, endometrial polyps were harvested from hysterectomized specimens from 6 female patients not on hormone therapy. Endometrial polyp mesenchymal stem cells (EPMSCs) were isolated and characterized. Selected cells were spindle-shaped, and expressed surface markers CD90 and CD146. The EPMSCs proliferated actively in vitro. A colony forming study demonstrates that EPMSCs had a colony-generating capacity. When cultured in a defined medium, EPMSCs can differentiate to osteoblast-, adipocyte , and neuron-like cells. No telomerase reverse transcriptase (TERT) expression was noted. Experimental results demonstrate that EPMSCs are a population of mesenchymal progenitor cells existing in human endometrial polyps that are capable of proliferation, differentiation, and colonogenicity exceeding that of bone marrow stem cells and endometrial stromal cells. These EPMSCs may be an alternative resource of adult stem cells for future regenerative therapy. PMID- 21237553 TI - Prevalence of asthma and allergies in 13- to 14-year-old adolescents and the frequency of risk factors in carriers of current asthma in Taubate, Sao Paulo, Brazil. AB - BACKGROUND: The objectives of this study were to determine the prevalence of asthma and allergies in 13- to 14-year-old adolescents in the city of Taubate, Sao Paulo, Brazil using the INTERNATIONAL STUDY OF ASTHMA AND ALLERGIES IN CHILDHOOD (ISAAC) questionnaire and to describe the presence of risk factors in current asthma carriers. METHODS: We used a cross-sectional study involving 920 adolescents who completed the ISAAC questionnaire and answered additional questions regarding smoking and the presence of pets and/or insects at home. RESULTS: The mean prevalence rate of "current asthma" was 15.3% and "asthma ever" was 6.8%. The mean prevalence rate of "current rhinitis" was 36.6% and "rhinitis ever" 37.6%. The prevalence of "eczema ever" was 16.2%. The frequency of active smoking was low (0.7%), and the presence of indoor animals (34%) and of insects (55.1%) was high. CONCLUSIONS: The prevalence of "current asthma" was twice as high as that of "asthma ever". There was no association between risk factors studied and current asthma. PMID- 21237555 TI - Genome-wide methylation analysis identifies involvement of TNF-alpha mediated cancer pathways in prostate cancer. AB - Altered signaling pathways resulting from aberrant changes in epigenetic parameters may play a pivotal role in carcinogenesis. To identify biological pathways likely to be affected by methylation-mediated alterations in gene expression in prostate cancer, we performed a genome-wide methylation analysis of 27,578 CpG sites, corresponding to 14,495 genes on a pooled sample of 12 pairs of prostate tumor and adjacent normal tissues. In all, 972 CpG sites were significantly hypermethylated while 209 sites were hypomethylated in prostate tumor tissue (FDR adjusted p-value<0.05; fold change>=2) corresponding to 1043 unique genes, which is consistent with genome-wide gene-specific hypermethylation patterns previously observed in multiple cancer models. Global hypomethylation in prostate tumor was also detected by measuring methylation changes in ALU repeat sequences. Pathway analysis of the genes with altered methylation patterns identifies the involvement of a cancer related network of genes whose activity may be heavily regulated by TNF-alpha in prostate tumorigenesis. Our results suggest that epigenetic dysregulation of cellular processes relevant to TNF-alpha dependent apoptosis and electrophile detoxification may be intimately involved in prostate carcinogenesis. These findings may lend credence to the possibility of using tumor-specific alterations in methylation patterns as biomarkers in estimating prognosis and assessing treatment options for prostate cancer. PMID- 21237556 TI - AN N-terminal Smac peptide sensitizes human prostate carcinoma cells to methyl jasmonate-induced apoptosis. AB - Although the anti-cancer agent methyl jasmonate (MJ) has been shown to selectively target malignant cells while sparing normal ones, hormone-refractory prostate cancer cells are relatively resistant to MJ than other cancer cells. In the present study, we investigated the effect of cell permeable seven-residue peptide of Smac (SmacN7), an antagonist of the inhibitor of apoptosis proteins (IAPs), on MJ-induced apoptosis. SmacN7 significantly enhanced the growth inhibition effect of MJ in human prostate cancer cells, but not in proximal tubular epithelial cells. Moreover, SmacN7 sensitizes MJ-induced apoptosis through both caspase-9-dependent and -independent pathways. Thus, blockade of the over-expressed IAPs in cancer cells could yield a potential therapeutic benefit in jasmonates-based chemotherapy. PMID- 21237557 TI - Degradation of sulfamonomethoxine with Fe3O4 magnetic nanoparticles as heterogeneous activator of persulfate. AB - Iron oxide magnetic nanoparticles (Fe(3)O(4) MNPs) can effectively activate persulfate anions (S(2)O(8)(2-)) to produce sulfate free radicals (SO(4)(-)), which are a powerful oxidant with promising applications to degrade organic contaminants. The kinetics of sulfamonomethoxine (SMM) degradation was studied in the system of Fe(3)O(4) MNPs and S(2)O(8)(2-). A complete removal of the added SMM (0.06 mmol L(-1)) was achieved within 15 min with the addition of 1.20 mmol L(-1) S(2)O(8)(2-) and 2.40 mmol L(-1) Fe(3)O(4) MNPs. There is an optimum concentration of Fe(3)O(4) MNPs because Fe(3)O(4) MNPs may also act as a SO(4)(-) scavenger at higher concentrations. It was further observed that the addition of Fe(3)O(4) MNPs in several batches for a given total amount of the activator is favorable to enhancing the degradation of SMM. A degradation mechanism was proposed on the basis of identification of the degradation intermediates of SMM with liquid chromatography combined with mass spectroscopy. PMID- 21237558 TI - Molecular dynamics study of the structures and properties of RDX/GAP propellant. AB - Molecular dynamics simulations have been performed to investigate well-known energetic material cyclotrimethylene trinitramine (RDX) crystal, glycidyl azide polymer (GAP) and RDX/GAP propellant. The results show that the binding energies on different crystalline surface of RDX change in the order of (0 1 0) > (1 0 0) > (0 0 1). The interactions between RDX and GAP have been analyzed by means of pair correlation functions. The mechanical properties of RDX/GAP propellant, i.e., elastic coefficients, modulus, Cauchy pressure, and Poisson's ratio, etc., have been obtained. It is found that mechanical properties are effectively improved by adding some amounts of GAP polymer, and the overall effect of GAP on three crystalline surfaces of RDX changes in the order of (1 0 0) > (0 1 0) > (0 0 1). The energetic properties of RDX/GAP propellant have also been calculated and the results show that compared with the pure RDX crystal, the standard theoretical specific impulse (I(sp)) of RDX/GAP propellant decrease, but they are still superior to those of double base propellant. PMID- 21237559 TI - Microfaunal indicators, Ciliophora phylogeny and protozoan population shifts in an intermittently aerated and fed bioreactor. AB - Microfauna community structure was examined in the mixed liquor of a bench-scale bioreactor equipped with an intermittent aeration and feeding system. The reactor was operated under an intermittent aeration of 25 min in every 1 h and varying feeding conditions (0.264, 0.403 and 0.773 kg BOD(5)/m(3) d). A total of 14 protozoan and metazoan taxa were identified by microscopic examination. Sessile ciliates, followed by crawling ciliates, were the major protozoan groups under 0.403 kg BOD(5)/m(3) d organic loading conditions, while sessile ciliate population was remarkably increased under an organic loading of 0.773 kg BOD(5)/m(3) d. Principal Component Analysis and Pearson correlation coefficient tests were performed in order to reveal relationships between microfauna community and operational parameters. Ciliophora specific-18S rRNA gene clone library was constructed to identify ciliate diversity under 0.773 kg BOD(5)/m(3) d organic loading conditions. Ciliophora diversity consisted of members of Aspidiscidae, Epistylidae, Opisthonectidae and Vorticellidae, with the majority of the clones being associated with the species Vorticella fusca. At least one novel phylogenetic linkage among Ciliophora was identified. Comparisons made after molecular characterization and microscopic examination of Ciliophora community showed that the estimation of broad ciliate groups is useful for ecological considerations and evaluation of the operational conditions in wastewater treatment plants. PMID- 21237560 TI - Optimization of the synthesis of a new coagulant from a tannin extract. AB - The current article studies the optimization of a new coagulant agent for water purification and wastewater remediation. Design of experiments is used for optimizing the production of this new tannin-based coagulant by using Acacia mearnsii de Wild tannin extract, NH(4)Cl and formaldehyde. The effectiveness of this product was confirmed on dye-polluted wastewater and surfactant wastewater. This cationic coagulant seems to be sensitive to temperature and tannin-NH(4)Cl ratio (g of ammonium chloride per g of tannin extract). NH(4)Cl ratio was found to be more influent than temperature and no interaction is presented between these two parameters. For each system, an optimum combination NH(4)Cl ratio and temperature was found: 24.9 degrees C and 2 g g(-1) for dye removal and 36.4 degrees C and 1.87 g g(-1) for surfactant elimination. The optimal conditions were merged to produce a combined coagulant that was tested on dye, surfactant, surface river water and municipal wastewater. Predicted levels of remediation were experimentally confirmed. PMID- 21237561 TI - Removal of nitrate from aqueous solution using cetylpyridinium bromide (CPB) modified zeolite as adsorbent. AB - Surfactant modified zeolites (SMZ) with different coverage types were prepared by loading the cetylpyridinium bromide (CPB) onto the surface of the natural zeolites. The adsorption behavior of nitrate on SMZ was investigated. Natural zeolite and SMZ with monolayer CPB coverage were inefficient for the removal of nitrate from aqueous solution. However, SMZ with patchy bilayer or bilayer CPB coverage was efficient in nitrate removal, and the nitrate adsorption capacity of SMZ increased with its CPB loading. For typical SMZ with bilayer CPB coverage, the nitrate adsorption process was well described by the pseudo-second-order kinetic model, and the experimental isotherm data fitted well with the Langmuir, Freundlich and Dubinin-Redushkevich isotherm models. Thermodynamic parameters such as Gibbs free energy change, enthalpy change and entropy change were calculated and the results showed that the adsorption of nitrate on SMZ was spontaneous and exothermic in nature. The presence of competing anions such as chloride, sulfate and bicarbonate ions slightly reduced the nitrate adsorption efficiency. Anionic exchange and electrostatic interaction were proven to be the main mechanisms that govern the adsorption of nitrate on SMZ. PMID- 21237562 TI - The relationships between low levels of urine fluoride on children's intelligence, dental fluorosis in endemic fluorosis areas in Hulunbuir, Inner Mongolia, China. AB - There has been public concern about children's intellectual performance at high levels of fluoride exposure, but few studies provide data directly to the question of whether low fluoride exposure levels less than 3.0 mg/L in drinking water adversely associated with children's intelligence. In this survey, we investigated the effects of low fluoride exposure on children's intelligence and dental fluorosis. 331 children aged from 7 to 14 were randomly recruited from four sites in Hulunbuir City, China. Intelligence was assessed using Combined Raven Test-The Rural in China while dental fluorosis was diagnosed with Dean's index. Mean value of fluoride in drinking water was 1.31+/-1.05 mg/L (range 0.24 2.84). Urine fluoride was inversely associated with IQ in the multiple linear regression model when children's age as a covariate variable was taken into account (P<0.0001). Each increase in 1 mg/L of urine fluoride associated with 0.59-point decrease in IQ (P=0.0226). Meanwhile, there was a dose-response relationship between urine fluoride and dental fluorosis (P<0.0001). In conclusion, our study suggested that low levels of fluoride exposure in drinking water had negative effects on children's intelligence and dental health and confirmed the dose-response relationships between urine fluoride and IQ scores as well as dental fluorosis. PMID- 21237563 TI - Preparation of novel nano-adsorbent based on organic-inorganic hybrid and their adsorption for heavy metals and organic pollutants presented in water environment. AB - The nanocomposites based on organic-inorganic hybrid have been attracting much attention due to their potential applications used as new type of functional materials, such as colloidal stabilizers, electro-optical devices, and nanocomposites materials. The organic-inorganic hybrid of poly(acrylic acid acrylonitrile)/attapulgite, P(A-N)/AT nanocomposites, were prepared by using in situ polymerization and composition of acrylic acid (AA) and acrylonitrile (AN) onto modified attapulgite (AT) nanoparticles. The resulting P(A-N)/AT nanocomposites were transformed into novel nano-adsorbent of poly(acrylic acid acryloamidoxime)/attapulgite by further functionalization, i.e. P(A-O)/AT nano adsorbent. The adsorption properties of P(A-O)/AT toward metal ions were determined, and the results indicated that the adsorbents with nanocomposite structure held a good of selectivity to Pb(2+) among numerous metal ions. The maximum removal capacity of Pb(2+) was up to 109.9 mg/g and it is notable to see that the adsorption removal of P(A-O)/AT nano-adsorbent for Pb(2+) could achieve more than 96.6% when the initial concentration of Pb(2+) was 120.0 mg/l. The kinetics, isotherm models, and conductivity were introduced to study the adsorption mechanism of P(A-O)/AT for Pb(2+) and it was concluded that it could be chemisorptions process and the best coordination form took place when AO:AA:Pb(2+) = 1:1:1. In addition, after simply treated with CTAB, P(A-O)/AT nano adsorbent showed better adsorption properties for phenol than the same kinds of materials. PMID- 21237564 TI - Synthesis and characterization of Zr4+, La3+ and Ce3+ doped mesoporous TiO2: evaluation of their photocatalytic activity. AB - Sol-gel method was used to synthesize Zr(4+), La(3+) and Ce(3+) doped mesoporous TiO(2) materials with different weight percentage (0.5, 1.0, 2.0 and 3.0 wt%) using triblock copolymer as the structure directing template in ethanol/water medium. Characterization revealed the isomorphic substitution of Zr(4+) ion into the lattice of TiO(2), and surface binding nature of La(3+) and Ce(3+) ions on mesoporous TiO(2). Microscopic examination confirmed the surface adsorption of foreign ion which could alter the particle morphology. The size of the particles was less than 20 nm. Photocatalytic activity of metal ions doped mesoporous TiO(2) was evaluated using aqueous alachlor as a model pollutant. It was found that 1 wt% Ce(3+) doped mesoporous TiO(2) exhibited higher activity than pure and other metal ions doped mesoporous TiO(2). The change of oxidation state of Ce(3+) is suggested to be the cause for enhanced photocatalytic activity. PMID- 21237565 TI - Selective adsorption of molybdenum(VI) from Mo-Re bearing effluent by chemically modified astringent persimmon. AB - Astringent persimmon was chemically cross-linked by formaldehyde to obtain a novel kind of adsorption gel, which was named as APF gel. The adsorption behaviors of Mo(VI) and Re(VII) along with other coexisting metals onto the APF gel were studied in the present paper. The APF gel was found to be effective for the adsorption of Mo(VI) while the gel is almost completely inert toward rhenium and calcium over the whole hydrochloric acid concentration region. The APF gel has a low affinity for iron, copper, lead, nickel, manganese and zinc ions when the concentration of HCl is higher than 1 mol/L. The gel exhibited selectivity only for Mo(VI) with a remarkably high adsorption capacity 1.05 mol/kg, and the adsorption behavior obeys the Langmuir model. According to the thermodynamic and kinetic studies, the endothermic adsorption process followed pseudo-second order kinetics. Also, its excellent adsorption characteristics for Mo(VI) were confirmed by the adsorption and elution tests using a column packed with the APF gel. The result provides a new approach for the recovery of Mo(VI) from a industrial waste effluent. PMID- 21237566 TI - Heavy metal source analysis in municipal solid waste (MSW): case study on Cu and Zn. AB - This research contributes to the knowledge of the heavy metal sources in municipal solid waste (MSW). Samples were collected from 8 cities of Zhejiang province, Eastern China. Cu and Zn, the most two conventional heavy metals with extensive distribution in many kinds of MSW components, were investigated. It shows components of kitchen waste (KW), ash (AS), plastic (PL), and paper (PA) have high universality in MSW and accounted for 55.1-95.5% in each MSW sample. Moreover, these four components are also the main heavy metal sources of MSW, which accounted for 76.3% and 82.3% contribution of the Cu and Zn contents, respectively. The Cu and Zn contents in the gross MSW sample were 41.2-1643.7 mg kg(-1) and 109.3-1077.9 mg kg(-1), respectively, which on different degree exceed the set standard for "environmental quality standard for soil" (Cu, 100 mg kg( 1); Zn, 400 mg kg(-1)) of China and have high potential of environmental risk. The heavy metal contents in the gross MSW do not have spatial variation but present high seasonal variation, significantly higher in summer than winter (P<0.01). Much more attention should be paid on the MSW management in summer to avoid heavy metal pollution. PMID- 21237567 TI - Integrating toxicity testing in the wastewater management of chemical storage terminals--a proposal based on a ten-year study. AB - Wastewater control at storage terminals of liquid chemical products in bulk is very difficult because of the variety of products handled in the facilities generating effluents of variable composition. The main objective of this work was to verify if the Vibrio fischeri acute toxicity test could be routinely included in the wastewater management of those facilities along with physical and chemical analysis in order to evaluate and improve the quality of the generated effluents. The study was performed in two phases before and after the implementation of better operational practices/treatment technologies. Chemical oxygen demand (COD) and toxicity of treated effluents did not correlate showing that effluents with low COD contain toxic substances and non-biodegradable organic matter, which may be not degraded when discharged into the aquatic environment. Segregation of influents or pre-treatment based on toxicity results and biodegradability index were implemented in the facilities generating significant improvements in the quality of final effluents with reduction of Biochemical oxygen demand (BOD) and toxicity. The integration of physical and chemical analysis with the V. fischeri toxicity test turned out to be an excellent tool for wastewater management in chemical terminals allowing rapid decision making for pollution control and prevention measures. Reuse of rain water was also proposed and when implemented by the facilities resulted in economical and environmental benefits. PMID- 21237568 TI - Effect of ketamine on endogenous pain modulation in healthy volunteers. AB - Inhibitory and facilitatory descending pathways, originating at higher central nervous system sites, modulate activity of dorsal horn nociceptive neurons, and thereby influence pain perception. Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. The N-methyl-d-aspartate receptor antagonist ketamine has a prolonged analgesic effect in chronic pain patients. This effect is due to desensitization of sensitized N-methyl-d aspartate receptors. Additionally, ketamine may modulate or enhance endogenous inhibitory control of pain perception. Diffuse noxious inhibitory control (DNIC) and offset analgesia (OA) are 2 mechanisms involved in descending inhibition. The present study investigates the effect of a ketamine infusion on subsequent DNIC and OA responses to determine whether ketamine has an influence on descending pain control. Ten healthy subjects (4 men/6 women) received a 1-hour placebo or S(+)-ketamine (40mg per 70kg) infusion on 2 separate occasions in random order. Upon the termination of the infusion, DNIC and OA responses were obtained. After placebo treatment, significant descending inhibition of pain responses was present for DNIC and OA. In contrast, after ketamine infusion, no DNIC was observed, but rather a significant facilitatory pain response (P<0.01); the OA response remained unchanged. These findings suggest that the balance between pain inhibition and pain facilitation was shifted by ketamine towards pain facilitation. The absence of an effect of ketamine on OA indicates differences in the mechanisms and neurotransmitter influences between OA and DNIC. Diffuse noxious inhibitory control responses following a 1-hour low-dose ketamine treatment displayed facilitation of pain in response to experimental noxious thermal stimulation. PMID- 21237570 TI - Quantitative atom probe analysis of carbides. AB - Compared to atom probe analysis of metallic materials, the analysis of carbide phases results in an enhanced formation of molecular ions and multiple events. In addition, many multiple events appear to consist of two or more ions originating from adjacent sites in the material. Due to limitations of the ion detectors measurements generally underestimate the carbon concentration. Analyses using laser-pulsed atom probe tomography have been performed on SiC, WC, Ti(C,N) and Ti(2)AlC grains in different materials as well as on large M(23)C(6) precipitates in steel. Using standard evaluation methods, the obtained carbon concentration was 6-24% lower than expected from the known stoichiometry. The results improved remarkably by using only the (13)C isotope, and calculating the concentration of (12)C from the natural isotope abundance. This confirms that the main reason for obtaining a too low carbon concentration is the dead time of the detector, mainly affecting carbon since it is more frequently evaporated as multiple ions. In the case of Ti(C,N) and Ti(2)AlC an additional difficulty arises from the overlap between C(2)(+), C(4)(2+) and Ti(2+) at the mass-to-charge 24 Da. PMID- 21237569 TI - Test-retest and interobserver reliability of quantitative sensory testing according to the protocol of the German Research Network on Neuropathic Pain (DFNS): a multi-centre study. AB - Quantitative sensory testing (QST) is an instrument to assess positive and negative sensory signs, helping to identify mechanisms underlying pathologic pain conditions. In this study, we evaluated the test-retest reliability (TR-R) and the interobserver reliability (IO-R) of QST in patients with sensory disturbances of different etiologies. In 4 centres, 60 patients (37 male and 23 female, 56.4+/ 1.9years) with lesions or diseases of the somatosensory system were included. QST comprised 13 parameters including detection and pain thresholds for thermal and mechanical stimuli. QST was performed in the clinically most affected test area and a less or unaffected control area in a morning and an afternoon session on 2 consecutive days by examiner pairs (4 QSTs/patient). For both, TR-R and IO-R, there were high correlations (r=0.80-0.93) at the affected test area, except for wind-up ratio (TR-R: r=0.67; IO-R: r=0.56) and paradoxical heat sensations (TR-R: r=0.35; IO-R: r=0.44). Mean IO-R (r=0.83, 31% unexplained variance) was slightly lower than TR-R (r=0.86, 26% unexplained variance, P<.05); the difference in variance amounted to 5%. There were no differences between study centres. In a subgroup with an unaffected control area (n=43), reliabilities were significantly better in the test area (TR-R: r=0.86; IO-R: r=0.83) than in the control area (TR R: r=0.79; IO-R: r=0.71, each P<.01), suggesting that disease-related systematic variance enhances reliability of QST. We conclude that standardized QST performed by trained examiners is a valuable diagnostic instrument with good test-retest and interobserver reliability within 2days. With standardized training, observer bias is much lower than random variance. Quantitative sensory testing performed by trained examiners is a valuable diagnostic instrument with good interobserver and test-retest reliability for use in patients with sensory disturbances of different etiologies to help identify mechanisms of neuropathic and non neuropathic pain. PMID- 21237571 TI - Host-parasite-environment relationship, morphology and molecular analyses of Henneguya eirasi n. sp. parasite of two wild Pseudoplatystoma spp. in Pantanal Wetland, Brazil. AB - A new myxosporean species, Henneguya eirasi n. sp., is described parasitizing the gill filaments of Pseudoplatystoma corruscans and Pseudoplatystoma fasciatum (Siluriformes: Pimelodidae) caught in the Patanal Wetland of the state of Mato Grosso, Brazil. The parasite formed white, elongated plasmodia measuring up to 3mm. Mature spores were ellipsoidal in the frontal view, measuring 37.1 +/- 1.8 MUm in total length, 12.9 +/- 0.8 MUm in body length, 3.4 +/- 0.3 MUm in width, 3.1 +/- 0.1 MUm in thickness and 24.6 +/- 2.2 MUm in the caudal process. Polar capsules were elongated and equal in size, measuring 5.4 +/- 0.5 MUm in length and 0.7 +/- 0.1 MUm in width. Polar filaments had 12-13 coils. Histopathological analysis revealed that the parasite developed in the sub-epithelial connective tissue of the gill filaments and the plasmodia were surrounded by a capsule of host connective tissue. The plasmodia caused slight compression of the adjacent tissues, but no inflammatory response was observed in the infection site. Ultrastructure analysis revealed a single plasmodial wall connected to the ectoplasmic zone through numerous pinocytotic canals. The plasmodial wall exhibited numerous projections and slightly electron-dense material was found in the ectoplasm next to the plasmodial wall, forming a line just below the wall. Partial sequencing of the 18S rDNA gene of H. eirasi n. sp. obtained from P. fasciatum resulted in a total of 1066 bp and this sequence did not match any of the Myxozoa available in the GenBank. Phylogenetic analysis revealed the Henneguya species clustering into clades following the order and family of the host fishes. H. eirasi n. sp. clustered alone in one clade, which was the basal unit for the clade composed of Henneguya species parasites of siluriform ictalurids. The prevalence of the parasite was 17.1% in both fish species examined. Parasite prevalence was not influenced by season, host sex or host size. PMID- 21237572 TI - Cytomegalovirus infection in severe burn patients monitoring by real-time polymerase chain reaction: A prospective study. AB - BACKGROUND: Cytomegalovirus (CMV) infection has been shown to occur not rarely in critically ill patients in the past decade. However, little data are available on CMV infection in burn patients whereas their susceptibility to CMV infection has been proved. METHODS: We prospectively assessed CMV viremia by real-time polymerase chain reaction and clinical outcome in immunocompetent burn patients with total burn surface area greater than 15%. RESULTS: Twenty-nine patients were enrolled. The rate of CMV infection was of 71% in CMV seropositive burn patients, and of 12.5% in CMV seronegative burn patients. CMV reactivation was associated with a higher IGS 2 score on admission. High grade CMV viremia was associated with longer mechanical ventilation duration, higher infection number, higher transfused red blood cell number, and longer ICU stays. There were no differences on mortality rate between patients with and without CMV reactivation. CONCLUSION: CMV infection rate is considerable in burn patients with TBSA greater than 15%. This infection seems to be mostly due to reactivation of latently existing virus. PMID- 21237573 TI - Anti-cancer role of SPARC, an inhibitor of adipogenesis. AB - SPARC (a secreted protein acidic and rich in cysteine) has a reputation for being potent anti-cancer and anti-obesity molecule. It is one of the first known matricellular protein that modulates interactions between cells and extracellular matrix (ECM) and is associated with the 'balance' of white adipose tissue (WAT) as well as lipogenesis and lipolysis during adipogenesis. Adipogenesis is an indication for the development of obesity and has been related to a wide variety of cancers including breast cancer, endometrial cancer, esophageal cancer, etc. Adipogenesis mainly involves ECM remodeling, changes in cell-ECM interactions, and cytoskeletal rearrangement. SPARC can also prevent hypertrophy of adipocytes and hyperplasia of adipocyte progenitors. In addition to SPARC's inhibitory role in adipogenesis, it has also been known to be involved in cell cycle, cell proliferation, cell invasion, adhesion, migration, angiogenesis and apoptosis. Molecular cancer biology and clinical biochemistry have significantly enhanced our understanding of the mechanisms that motivate the anti-cancer and anti obesity action of SPARC. Recent studies elucidating the signaling pathways that are activated by SPARC can help develop the beneficial aspects of SPARC for cancer therapy and obesity prevention. This review focuses on the anti-cancer role of SPARC as it pertains to obesity. PMID- 21237574 TI - The cortisol awakening response (CAR) across the female menstrual cycle. AB - The cortisol awakening response (CAR) has been established as a useful marker of hypothalamus-pituitary-adrenal (HPA) axis activity and has become a standard tool for stress research in ambulatory settings. Although much knowledge has been accumulated on a variety of factors modulating the CAR, the impact of the female menstrual cycle, especially during ovulation, still remains unclear. To the best of our knowledge, this is the first study that measured the CAR during menses, the follicular phase, ovulation and the luteal phase in a repeated measurement design. For this purpose, a final sample of 29 naturally cycling, healthy, non smoking, and medication-free women collected saliva samples directly after awakening as well as 30, 45, and 60 min later during each of the four different phases. To determine the timing of ovulation, an ambulatory chromatographic ovulation test kit was applied. A repeated measurements ANOVA resulted in a significant interaction effect sample * cycle phase (p=0.04), with the highest awakening response during ovulation. While awakening cortisol levels were comparable across the four cycle phases (p=n.s.), the net increase was significantly elevated during ovulation (p=0.05). Our data also confirmed earlier cross-sectional results reporting no differences in the CAR between the follicular and luteal phase. Finally, a concurrent assessment of mood applying the POMS (Profile of Mood States) yielded no differences across the four cycle phases (all p=n.s.). In sum, the present data points to the idea that the CAR is elevated during ovulation, an effect which is presumably mediated by elevated sex steroid levels during the ovulation period. PMID- 21237575 TI - Characteristics and consequences of heroin use among older adults in the United States: a review of the literature, treatment implications, and recommendations for further research. AB - This review reports on the results of a comprehensive literature search of studies examining the physical and mental health characteristics of older adults in the United States who use heroin. Multiple databases were searched for papers meeting the inclusion criteria of heroin users who were age 50 years or older. A total of 14 articles covering 9 different studies met the review inclusion criteria. All of the studies were convenience samples, and seven of the nine studies (77.8%) were entirely drawn from substance abuse treatment programs, primarily methadone maintenance programs. Findings from the qualitative studies suggest that the marginalization of older heroin users was a predominant experience that impacted the intent to seek treatment as well as treatment retention. While articles reported high levels of physical and psychological/psychiatric comorbidities with substance misuse, research on heroin use and methadone treatment among older adults is scant and the quantitative findings are inconsistent. The articles reviewed in this study demonstrate that the needs of this population will be significant, yet the development of appropriate interventions and treatment for older adult heroin users will be contingent on empirical research that adequately describes mental and physical health problems. PMID- 21237576 TI - Heat-treated and homogenised potato pulp suspensions as additives in low-fat sausages. AB - Differently homogenised and heat treated potato pulp, used as a dietary fibre additive in low-fat sausages, gave rise to an enhanced instrumentally and sensory measured firmness and compactness, respectively. This is believed to be due to the high content of insoluble fibre, which creates a fibrous network that enhances the texture of the sausage, while not interfering with the meat protein network. The process and frying losses of the sausages, using potato pulp as an additive, were not significantly different compared to the reference. Comparing the different potato pulp sausages using various kinds of heat treatment of the potato pulp significantly lowered the frying loss and increased the firmness. An explanation to these observations could be that the potato pulp exposed to shorter heat treatment compared with longer gave rise to a lower amount of amylase-leakage from the swelling starch granules caught in the potato pulp matrix. PMID- 21237577 TI - Sensory comparison of commercial low and high oxygen modified atmosphere packed sirloin beef steaks. AB - The objectives of this study were to investigate the effects of using commercially low and high modified atmosphere packaging (MAP) on quality characteristics of sirloin beef steaks. Gas mixtures used included 80% O(2):20% CO(2) (O(2)80), 70% O(2)/30% CO(2) (O(2)70) and 50% O(2)/30% CO(2):20% N(2) (O(2)50) and for commercial packs O(2)75 +/- 5%, CO(2)25 +/- 5%, <5% N(2) (O(2)Com). All samples were packed in similar tray and packaging film formats. The experimental parameters monitored included microbiological, physiochemical and sensory measurements (naive assessors). Microbial counts did not exceed the recommended legal ranges over the storage period. However the numbers of LAB (lactic acid bacteria) were the highest for commercially-packed samples (O(2)Com) in comparison to laboratory packaged samples (O(2)80, O(2)70 and O(2)50). Commercially-packaged samples eventually spoiled due to the occurrence of off flavours and off-odours and subsequently were the least acceptable to sensory naive assessors. PMID- 21237578 TI - Relationships of slice shear force and Warner-Bratzler shear force of beef strip loin steaks as related to the tenderness gradient of the strip loin. AB - This study was conducted to investigate the effects of steak location within a strip loin and USDA quality grade on muscle fiber angle, slice shear force (SSF), and Warner-Bratzler shear force (WBSF) and to determine the relationship between SSF and WBSF. Steak location influenced both SSF and WBSF values, as steaks from the anterior portion were typically tenderer than steaks from the posterior end. Although there is some discrepancy between the two shear force methods, both agree that at least the first 5 anterior-most steaks are comparable. Muscle fiber angle was affected by steak position within the strip loin, as the fiber angle shifted between steaks 7 and 8. Quality grade had a significant effect on beef tenderness for both SSF and WBSF. Finally, there was a strong relationship between lateral SSF and average WBSF (r = 0.64), which are currently the most commonly used measurements for instrumental tenderness. PMID- 21237579 TI - Prevalence and relationships of sensory taint, 5alpha-androstenone and skatole in fat and lean tissue from the loin (Longissimus dorsi) of barrows, gilts, sows, and boars from selected abattoirs in the United States. AB - This study assessed prevalence of boar taint in backfat and lean of barrows, gilts, sows, and boars, collected from abattoirs, without knowledge of the farms of origin, in different regions in the United States. Concentrations of 5alpha androstenone (liquid chromatography/mass spectroscopy) and skatole (liquid chromatography with fluorescent detection) in backfat were measured. A trained panel evaluated boar taint aroma in heated samples. Mean 5alpha-androstenone and skatole levels were low among barrows, gilts, and sows, whereas 55.8% of boars scored above a 1.0 MUg/g threshold for 5alpha-androstenone concentrations and 34.2% were above a 0.2 MUg/g threshold for skatole concentrations. Mean aroma scores for backfat and lean from barrows, gilts, and sows were low. In comparison, 59.2% of boars had elevated mean aroma scores from fat samples and 31.7% from lean. Importantly, boar taint aroma was detectable by the trained panel in at least some animals in each of the sex classes. PMID- 21237580 TI - Regulation of L-selectin expression by trauma-relevant cytokines. AB - The leukocyte adhesion molecule L-selectin is important for the rolling of neutrophil granulocytes (PMN), the first step of the cascade leading to adhesion, diapedesis, and subsequent organ dysfunction. The activation of leukocytes in the posttraumatic course is assumed to be induced by different pro-inflammatory cytokines. In the present study, we investigated the effects of stimulation with pro- and anti-inflammatory cytokines on the L-selectin surface expression on PMN. Twenty patients admitted to our institution for elective operations of the lower extremities were enrolled in a prospective clinical study. For the measurement of L-selectin expression, blood was taken before the operation (0 h), as well as 24 h and 48 h postoperatively. Without and after incubation with different pro- and anti-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6 and IL-10), the surface expression of L-selectin was detected using an anti-L-selectin-specific antibody and flow cytometry. L-selectin surface expression without any stimulation showed a non-significant increase 48 h after the operation (63.6+/-6.6 ng/ml at 0 h, 95.2+/-10.5 ng/ml at 48 h). Stimulation with TNF-alpha resulted in a significant decrease of L-selectin expression at 0 h (25.6+/-2.7 ng/ml; p<0.05) and 24 h (18.3+/-2.5 ng/ml; p<0.05), but not at 48 h (39.8+/-4.2 ng/ml). No significant differences were observed after stimulation with IL-1beta, IL-6, and IL-10 in comparison to the non-stimulated group. The study results indicate that the primary pro-inflammatory cytokine TNF-alpha regulates the L-selectin surface expression on PMN after surgical trauma. Therefore, a regulation of neutrophil activation on this level might be crucial in the development of posttraumatic complications. PMID- 21237581 TI - Hypofractionated concomitant intensity-modulated radiotherapy boost for high-risk prostate cancer: late toxicity. AB - PURPOSE: To report the acute and late toxicities of patients with high-risk localized prostate cancer treated using a concomitant hypofractionated, intensity modulated radiotherapy boost combined with long-term androgen deprivation therapy. METHODS AND MATERIALS: A prospective Phase I-II study of patients with any of the following: clinical Stage T3 disease, prostate-specific antigen level >= 20 ng/mL, or Gleason score 8-10. A dose of 45 Gy (1.8 Gy/fraction) was delivered to the pelvic lymph nodes with a concomitant 22.5 Gy prostate intensity modulated radiotherapy boost, to a total of 67.5 Gy (2.7 Gy/fraction) in 25 fractions within 5 weeks. Image guidance was performed using three gold seed fiducials. The National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, and Radiation Therapy Oncology Group late morbidity scores were used to assess the acute and late toxicities, respectively. Biochemical failure was determined using the Phoenix definition. RESULTS: A total of 97 patients were treated and followed up for a median of 39 months, with 88% having a minimum of 24 months of follow-up. The maximal toxicity scores were recorded. The grade of acute gastrointestinal toxicity was Grade 0 in 4%, 1 in 59%, and 2 in 37%. The grade of acute urinary toxicity was Grade 0 in 8%, 1 in 50%, 2 in 39%, and 3 in 4%. The grade of late gastrointestinal toxicity was Grade 0 in 54%, 1 in 40%, and 2 in 7%. No Grade 3 or greater late gastrointestinal toxicities developed. The grade of late urinary toxicity was Grade 0 in 82%, 1 in 9%, 2 in 5%, 3 in 3%, and 4 in 1% (1 patient). All severe toxicities (Grade 3 or greater) had resolved at the last follow-up visit. The 4-year biochemical disease-free survival rate was 90.5%. CONCLUSIONS: A hypofractionated intensity-modulated radiotherapy boost delivering 67.5 Gy in 25 fractions within 5 weeks combined with pelvic nodal radiotherapy and long-term androgen deprivation therapy was well tolerated, with low rates of severe toxicity. The biochemical control rate at early follow-up has been promising. Additional follow-up is needed to determine the long-term biochemical control and prostate biopsy results. PMID- 21237582 TI - Impact of primary Gleason grade on risk stratification for Gleason score 7 prostate cancers. AB - PURPOSE: To evaluate the primary Gleason grade (GG) in Gleason score (GS) 7 prostate cancers for risk of non-organ-confined disease with the goal of optimizing radiotherapy treatment option counseling. METHODS: One thousand three hundred thirty-three patients with pathologic GS7 were identified in the Duke Prostate Center research database. Clinical factors including age, race, clinical stage, prostate-specific antigen at diagnosis, and pathologic stage were obtained. Data were stratified by prostate-specific antigen and clinical stage at diagnosis into adapted D'Amico risk groups. Univariate and multivariate analyses were performed evaluating for association of primary GG with pathologic outcome. RESULTS: Nine hundred seventy-nine patients had primary GG3 and 354 had GG4. On univariate analyses, GG4 was associated with an increased risk of non-organ confined disease. On multivariate analysis, GG4 was independently associated with seminal vesicle invasion (SVI) but not extracapsular extension. Patients with otherwise low-risk disease and primary GG3 had a very low risk of SVI (4%). CONCLUSIONS: Primary GG4 in GS7 cancers is associated with increased risk of SVI compared with primary GG3. Otherwise low-risk patients with GS 3+4 have a very low risk of SVI and may be candidates for prostate-only radiotherapy modalities. PMID- 21237583 TI - Real-time in vivo dosimetry with MOSFET detectors in serial tomotherapy for head and neck cancer patients. AB - PURPOSE: A real-time dose verification method using a recently designed metal oxide semiconductor field effect transistor (MOSFET) dosimetry system was evaluated for quality assurance (QA) of intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: Following the investigation of key parameters that might affect the accuracy of MOSFET measurements (i.e., source surface distance [SSD], field size, beam incident angles and radiation energy spectrum), the feasibility of this detector in IMRT dose verification was demonstrated by comparison with ion chamber measurements taken in an IMRT QA phantom. Real-time in vivo measurements were also performed with the MOSFET system during serial tomotherapy treatments administered to 8 head and neck cancer patients. RESULTS: MOSFET sensitivity did not change with SSD. For field sizes smaller than 20 * 20 cm(2), MOFET sensitivity varied within 1.0%. The detector angular response was isotropic within 2% over 360 degrees , and the observed sensitivity variation due to changes in the energy spectrum was negligible in 6-MV photons. MOSFET system measurements and ion chamber measurements agreed at all points in IMRT phantom plan verification, within 5%. The mean difference between 48 IMRT MOSFET-measured doses and calculated values in 8 patients was 3.33% and ranged from -2.20% to 7.89%. More than 90% of the total measurements had deviations of less than 5% from the planned doses. CONCLUSION: The MOSFET dosimetry system has been proven to be an effective tool in evaluating the actual dose within individual patients during IMRT treatment. PMID- 21237584 TI - Automated planning of tangential breast intensity-modulated radiotherapy using heuristic optimization. AB - PURPOSE: To present an automated technique for two-field tangential breast intensity-modulated radiotherapy (IMRT) treatment planning. METHOD AND MATERIALS: A total of 158 planned patients with Stage 0, I, and II breast cancer treated using whole-breast IMRT were retrospectively replanned using automated treatment planning tools. The tools developed are integrated into the existing clinical treatment planning system (Pinnacle(3)) and are designed to perform the manual volume delineation, beam placement, and IMRT treatment planning steps carried out by the treatment planning radiation therapist. The automated algorithm, using only the radio-opaque markers placed at CT simulation as inputs, optimizes the tangential beam parameters to geometrically minimize the amount of lung and heart treated while covering the whole-breast volume. The IMRT parameters are optimized according to the automatically delineated whole-breast volume. RESULTS: The mean time to generate a complete treatment plan was 6 min, 50 s +/- 1 min 12 s. For the automated plans, 157 of 158 plans (99%) were deemed clinically acceptable, and 138 of 158 plans (87%) were deemed clinically improved or equal to the corresponding clinical plan when reviewed in a randomized, double-blinded study by one experienced breast radiation oncologist. In addition, overall the automated plans were dosimetrically equivalent to the clinical plans when scored for target coverage and lung and heart doses. CONCLUSION: We have developed robust and efficient automated tools for fully inversed planned tangential breast IMRT planning that can be readily integrated into clinical practice. The tools produce clinically acceptable plans using only the common anatomic landmarks from the CT simulation process as an input. We anticipate the tools will improve patient access to high-quality IMRT treatment by simplifying the planning process and will reduce the effort and cost of incorporating more advanced planning into clinical practice. PMID- 21237585 TI - Concordance between self-reports and archival records of physician visits: a case control study comparing individuals with and without alcohol use disorders in the community. AB - OBJECTIVE: The accuracy of self-reported healthcare use among individuals with alcohol use disorders (AUD) has been questioned. The present study attempts to compare the accuracy of self-reported physician visits for individuals who differ with respect to their history of AUDs. METHODS: Our data source was a 14-year follow-up of individuals interviewed at the St. Louis site of the 1981-1983 Epidemiologic Catchment Area Study (ECA). We used a case-control design (n=237) to compare the accuracy of self-reports among ECA participants with stably diagnosed AUDs (cases; n=75) to two comparison groups: those with problem/very heavy drinking (n=81) and those unaffected by alcohol (n=81). Intraclass correlation coefficients (ICC) described the concordance between self-reports and archival records of physician visits in the prior six months. We used multinomial logistic regression to identify characteristics associated with under-reporting and over-reporting, and zero-truncated Poisson regression to identify characteristics associated with discordance severity. RESULTS: Self-reports of cases had substantial concordance with physician records (ICC=0.74, CI=0.61 0.83). As compared to cases, those with problem/very heavy drinking had a significantly higher ICC, and those who were unaffected by alcohol had a significantly lower ICC. However, differences in concordance disappeared when using regression models that adjusted for factors known to affect the accuracy of self-reported healthcare use. Utilization frequency was a strong predictor of inaccurate reporting. CONCLUSIONS: These findings suggest AUD status may not independently affect the accuracy of self-reports. Counts of physician visits for those with AUD may be considered accurate when utilization frequency is low. PMID- 21237587 TI - Amplitude-integrated electroencephalography in preterm infants with cystic periventricular leukomalacia. AB - AIM: This study aimed to assess amplitude-integrated electroencephalography (aEEG) findings in preterm infants with cystic periventricular leukomalacia (cPVL) in the early neonatal period. METHODS: We analyzed five infants with cPVL, whose gestational age was between 27 and 30 weeks, and 15 matched control infants. Two-channel (C3-O1 and C4-O2) aEEG was obtained by digital conversion from a conventional electroencephalogram, which was recorded at days 0-5, 6-13, and 21-34 in each infant. We evaluated the averaged two-channel values of several measurements using visual and quantitative analyses. RESULTS: Infants with cPVL had a significant higher maximal upper-margin amplitude value, with a median of 47.5 MUV (range of 42.5-60) compared with the control infants (median, 33.8; range, 23.8-50) in the second visual-analysis record. Infants with cPVL also had a significantly higher mean upper-margin amplitude value, with a median of 18.8 MUV (range, 17.7-23.2) compared with the control infants (median, 16.3; range, 10.3-19.0) in the second quantitative-analysis record. CONCLUSIONS: We demonstrated that the upper-margin amplitude of aEEG in infants with cPVL was significantly higher than that in the control infants at 6-13 days after birth. PMID- 21237586 TI - The alcohol relapse situation appraisal questionnaire: development and validation. AB - BACKGROUND: The role of cognitive appraisal of the threat of alcohol relapse has received little attention. A previous instrument, the Relapse Situation Appraisal Questionnaire (RSAQ), was developed to assess cocaine users' primary appraisal of the threat of situations posing a high risk for cocaine relapse. The purpose of the present study was to modify the RSAQ in order to measure primary appraisal in situations involving a high risk for alcohol relapse. METHODS: The development and psychometric properties of this instrument, the Alcohol Relapse Situation Appraisal Questionnaire (A-RSAQ), were examined with two samples of abstinent adults with alcohol abuse or dependence. Factor structure and validity were examined in Study 1 (N=104). Confirmation of the factor structure and predictive validity was assessed in Study 2 (N=159). RESULTS: Results demonstrated construct, discriminant and predictive validity and reliability of the A-RSAQ. DISCUSSION: Results support the important role of primary appraisal of degree of risk in alcohol relapse situations. PMID- 21237588 TI - Early visual assessment in preterm infants with and without brain lesions: correlation with visual and neurodevelopmental outcome at 12 months. AB - BACKGROUND: Several studies have reported the development of various aspects of visual function in infancy and early childhood in both preterm and term-born infants, but only a few studies have focused on the predictive power of neonatal visual findings in infants with brain lesions. AIMS: To explore visual findings at term age, and at 3 and 12 months corrected age in preterm infants (gestational age <33 weeks) with and without brain lesions; to compare the assessment at term age and at 12 months; and to assess the relationship between visual findings and neurodevelopmental outcome at 12 months. STUDY DESIGN: Cranial ultrasound scans (US) were classified in normal, mild or major abnormalities. One-hundred and forty-five infants were assessed with age specific tests for visual function at term age, and at 3 and 12 months. Neurodevelopmental assessment (Griffiths' Scales) was performed at 12 months. RESULTS: A good correlation was found between early and late visual assessment and neurodevelopment outcome. Of the 121 infants with normal neonatal visual assessment, 119 were also normal at 12 months and 116 had normal developmental quotient. Of the 24 infants with abnormal neonatal visual assessment, 12 were also abnormal at 12 months. All the false positives had normalised by 3 months. Of the 35 infants with major US abnormalities, 20 had normal and 15 abnormal scores on the neonatal assessment. At 1 year 17 had normal and 18 abnormal scores. CONCLUSION: A normal visual assessment at term age is a good predictor of normal visual and neurodevelopmental outcome at 12 months. An abnormal visual examination in the neonatal period was a less reliable prognostic indicator, infant should be reassessed at 3 months. PMID- 21237589 TI - Effects of herbal and dietary supplements on cognition in menopause: a systematic review. AB - OBJECTIVE: Many postmenopausal women use herbal remedies and dietary supplements to counteract menopausal symptoms, including the decline in cognitive function. The aim of this systematic review is to evaluate the evidence regarding the efficacy of herbal and dietary supplements on cognition in menopause. DESIGN: Randomized clinical trials (RCTs) of herbal medicines and dietary supplements were identified using the Medline, EMBASE, AMED, PsycINFO, CINAHL and The Cochrane Library 2010 (Issue 2) electronic databases and by hand searches. Data were independently extracted and evaluated by two reviewers. Risk of bias was assessed by two independent reviewers using the Cochrane Collaboration tool. RESULTS: Twelve RCTs were included and five of these suggest that isoflavone, soy and Gingko biloba supplementation may improve cognition in postmenopausal women. However, most of the included studies had serious methodological flaws which demand a cautious interpretation of these findings. CONCLUSIONS: The evidence that herbal and dietary supplements might positively affect the cognitive decline during the menopause is not compelling. PMID- 21237590 TI - Assessing predictors of sexual function in mid-aged sexually active women. AB - OBJECTIVE: To assess predictors of sexual function in mid-aged women. METHODS: We analyzed data of 262 healthy sexually active women (40-59 years) who filled out the Female Sexual Functioning Index (FSFI), the Menopause Rating Scale (MRS) and a general questionnaire containing female/partner data. Correlations between these two measures were also analyzed. RESULTS: Significant inverse correlations were found between all FSFI and MRS scores. This was most evident for the MRS urogenital score in relation to FSFI total, pain and lubrication scores. Multiple linear regression analysis determined best model predicting total FSFI index scores that explained a 66% of the variance. In this model, MRS urogenital score was an important predictor of female sexual function (total FSFI scores) with a significant inverse relation. Additionally total FSFI scores displayed a significant positive correlation with female educational level and HT use and an inverse relation with partner age and female parity. CONCLUSION: Several female/partner factors predicted female sexual function in this mid-aged series. MRS urogenital scores significantly correlated with total FSFI scores. PMID- 21237591 TI - Controlled GPR grave research: comparison of reflection profiles between 500 and 250 MHz antennae. AB - Since ground-penetrating radar (GPR) has become a popular search option for clandestine graves, controlled research is essential to determine the numerous variables that affect grave detection. The purpose of this study was to compare GPR reflection profiles of a controlled grave containing a large pig carcass and a blank control grave at 6 months interment in a Spodosol, which is a common soil type in Florida. Data collection was performed in perpendicular orientations over the graves using both 500 and 250 MHz antennae. Since reflection profiles are used to make initial in-field assessments during a forensic search, it is important for controlled research to evaluate this imagery option. Overall, it was possible to detect the grave containing a pig carcass at 6 months interment that was buried in a Spodosol using both the 500 and the 250 MHz antennae. While the 500 MHz antenna provided more detail within the grave containing a pig carcass, including detecting a soil disturbance and the pig carcass, the 250 MHz antenna also provided excellent imagery. Either antenna would provide optimal results for the type of soil that was sampled. Furthermore, it may be possible to locate actual forensic graves in this soil type when no response from the body is noted, as there may be a discernable response from the disturbed soil within the grave shaft and a noticeable disruption of the spodic horizon. Finally, survey orientation may also affect detection. Since data collection performed in two perpendicular directions detected the pig carcass and the grave floor of the control grave, data collection for an actual search involving a body interred for a long postmortem interval should be performed in both directions when time permits. PMID- 21237592 TI - Postmortem interval of skeletal remains through the detection of intraosseal hemin traces. A comparison of UV-fluorescence, luminol, Hexagon-OBTI(r), and Combur(r) tests. AB - With the goal of obtaining additional practically applicable methods for estimating the PMI of skeletal remains, 39 samples of human and 5 samples of domestic animal long bones with known PMI (PMI=1 to approximately 2000 years) were tested with two established methods (UV-fluorescence of a freshly sawn cross section and the luminol test) and two screening tests (Hexagon-OBTI(r) test and Combur(r) test) that were being tried out in this context for the first time. The hypothesis underlying this experiment was the supposition that the PMI-related chemiluminescence of the luminol reaction for bone is based on the presence of persisting hemin from hemoglobin molecules in bone. Our results showed that lack of luminescence and reduced UV-fluorescence were more meaningful results for estimating PMI and excluding forensic relevance than a positive luminol reaction or strong UV-fluorescence, as both of the latter findings revealed the limitations of these methods in this particular context. Particularly for cases showing a positive luminol reaction, the use of additional absolute dating methods may be indicated. Against our expectations, both the Combur(r) test strips and the Hexagon-OBTI(r) test, which were both devised to demonstrate blood, delivered negative results for all samples. They are thus not suitable for estimating the PMI of skeletal remains. Future research will be necessary to elucidate whether the negative results obtained for these tests may be due to the poor solubility of potentially present hemoglobin or hemoglobin breakdown products in the Tris buffer used in this experiment. PMID- 21237593 TI - Entomotoxicology, experimental set-up and interpretation for forensic toxicologists. AB - Forensic entomotoxicology studies the usefulness of insects as alternative toxicological samples. Use of insects as alternative matrix for drug detection is well documented and recommended when conventional matrices such as blood, urine or internal organs are no longer available. However, several limitations of entomotoxicology have been highlighted, especially concerning interpretation of the drug concentrations in insects on human forensic cases. In addition, the lack of knowledge in pharmacokinetic of drugs in insects, large variability of experimental set-up and toxicological analysis compromise the utility of this science. This review focuses on the current knowledge of factors influencing drug detection in insects. Reasons for the current limitations, but also recommendations for future research are discussed and proposed in this paper. PMID- 21237594 TI - [Use of the French medico-administrative database (PMSI) to detect nosocomial infections in the University hospital of Lyon]. AB - BACKGROUND: Surveillance is an effective element in the fight against nosocomial infections, but the monitoring methods are often cumbersome and time consuming. The detection of infection in computerized databases is a means to alleviate the workload of health care teams. The objective of this study was to evaluate the performance of using discharge summaries in medico-administrative databases (PMSI) for the identification of nosocomial infections in surgery, intensive care and obstetrics. METHODS: The retrospective assessment study included patients who were hospitalized in general surgery, intensive care and obstetrics at different periods of time in 2006 and 2007 depending on the wards. Patients were monitored according to standard protocols which are coordinated at the regional level by the Southeast coordinating centre (CCLIN). The performance of identifying cases of nosocomial infection from discharge diagnoses coded by using the International Classification of Diseases (tenth revision) was evaluated by a study of sensitivity, specificity, positive and negative predictive values with their 95% confidence intervals. RESULTS: Using a limited number of diagnostic codes, the sensitivity and specificity were, respectively, 26.3% (95% CI 13.2-42.1) and 99.5% (95% 98.8-100.0) for the identification of surgical site infections. By expanding the number of diagnostic codes, the sensitivity and specificity were 78.9% (95% CI 65.8-92.1) and 65.7% (95% CI 61.0-70.3). The sensitivity and specificity for case identification of nosocomial infections in intensive care were 48.8% (95% CI 42.6-55.0) and 78.4% (95% CI 76.1-80.1), and were 42.9% (95% CI 25.0-60.7) and 87.3% (95% CI 85.2-89.3) for identification of postpartum infections. CONCLUSION: The PMSI is not a sufficiently efficient method in terms of sensitivity to be used in surveillance of nosocomial infections. A reassessment of the PMSI must be considered, with changes in coding of comorbidity that occurred in 2009. PMID- 21237595 TI - MR-imaging of the thoracic aorta: 3D-ECG- and respiratory-gated bSSFP imaging using the CLAWS algorithm versus contrast-enhanced 3D-MRA. AB - OBJECTIVE: To compare a contrast-enhanced 3D angiography (CE-3D-MRA) with the ECG and respiratory gated 3D balanced steady state free precession (bSSFP) sequence using the CLAWS algorithm (3D-bSSFP-CLAWS) with respect to acquisition time, image quality, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR). METHODS: 14 patients (4 women, mean age +/- SD: 52 +/- 18) with known or suspected thoracic aortic disease were imaged on a 1.5T scanner with both sequences. Two readers scored image quality of predefined levels of the thoracic aorta. Acquisition time, SNR and CNR were calculated for each examination. RESULTS: Image quality achieved with the 3D-bSSFP-CLAWS was scored significantly better than with the CE-3D-MRA for the aortic annulus (P = 0.003), the sinuses of Valsalva (P = 0.001), the proximal coronary arteries (P = 0.001) and the sinotubular junction (P = 0.001). Effective acquisition time for the 3D-bSSFP CLAWS and corrected acquisition time (corrected for imaging parameters) was significantly longer compared to the CE-3D-MRA (P = 0.004 and P = 0.028). SNR and CNR were significantly higher for the CE-3D-MRA (P = 0.007 and P = 0.001). CONCLUSIONS: Providing the highest scan efficiency for a given breathing pattern, image quality for the proximal ascending aorta achieved with the 3D-bSSFP-CLAWS is significantly superior in contrast to the CE-3D-MRA. PMID- 21237596 TI - Is MRI less accurate than FDG-PET/CT in diagnosing bone marrow involvement in lymphoma? PMID- 21237597 TI - Patient identification data on medical images. PMID- 21237598 TI - The value of strain ratio in differential diagnosis of thyroid solid nodules. AB - OBJECTIVE: To assess the clinical value of strain ratio in differentiating thyroid solid nodules and explore its distribution characters based on pathological results. MATERIALS AND METHODS: The study was approved by the ethic committee and the informed consents were signed. Ninety nine solid thyroid nodules (67 benign and 32 malignant) from 71 female (mean age 46.3 +/- 9.8 years) and 28 male (mean age 54.9 +/- 11.7 years) patients were evaluated. Five radiologists evaluated the nodules based on a four-degree elastography score system. Strain ratio was calculated on-line. Diagnostic performances of the two evaluations were compared using Receiver Operating Characteristic (ROC) curves. Values of different pathological nodules were compared by one-way ANOVA. RESULTS: Areas under the ROC curve (AUC) of the five readers were 0.82, 0.81, 0.79, 0.73 and 0.83, respectively. The AUC of strain ratio evaluation was higher (0.88 vs. 0.79, p < 0.001) than that of the ES score evaluation. Best cut-off points of the two evaluations were 3.5 (82% sensitivity, 72% specificity) and 4.225 (81% sensitivity, 83% specificity), respectively. Both the ES score and strain ratio were higher for malignant nodules than that for benign ones (p < 0.001). CONCLUSIONS: Strain ratio was a useful index in differential diagnosis of thyroid solid nodules. It can provide quantitative information on thyroid nodule characterization and improve diagnostic confidence. The best cut-off point for benign and malignant nodules was 4.2. PMID- 21237599 TI - Ultrasound characteristics of gouty tophi in the olecranon bursa and evaluation of their reproducibility. AB - OBJECTIVES: To describe the ultrasound characteristics of gouty tophi in the olecranon bursa and to evaluate their reproducibility. METHODS: A prospective study of the ultrasound features of 35 sites of tophi nodulations in the elbows of 31 men (mean 54.6 years). The findings were evaluated dynamically following pre-established standards. The static images were evaluated by another radiologist and were reviewed by the first examiner. RESULTS: The most frequent characteristics of tophi are: hyperechogenicity (91.7%), poorly defined contours (88.6%), multiple grouped nodules (85.6%) and heterogeneity (68.6%). Intra observer agreement is almost perfect for echogenicity (K = 1.0), moderate for the involvement of the olecranon bursa (K = 0.47) and fair for other characteristics. Inter-observer agreement is substantial for the echogenicity (K = 0.65), fair for the echotexture (K = 0.27) and the presence of a perilesional hypoechoic halo (K = 0.34) and slight for other characteristics. CONCLUSIONS: The most frequent characteristic of tophi is hyperechogenicity. The intra-observer and inter observer concordance for echogenicity are almost perfect and substantial, respectively. Knowledge of characteristics of the tophi in the elbow and their intra and inter-observer reproducibility may assist in establishing parameters for monitoring treatment and setting up criteria for differential diagnosis of processes involving the olecraneon bursa. PMID- 21237600 TI - A comparative analysis of double inversion recovery TFE and TSE sequences on carotid artery wall imaging. AB - OBJECTIVE: To analyze the characteristics of double inversion recovery (DIR) turbo field echo (TFE) and turbo spin echo (TSE) sequences and explore the value of double inversion recovery TFE sequence on carotid artery wall imaging. PATIENTS AND METHODS: 56 patients (32 males and 24 females, aged 31-76 years with a mean age of 53 years) were performed with DIR TFE and DIR TSE T1 weighted imaging (T1WI) sequences on carotid artery bifurcations. Image quality acquired by different techniques were evaluated and scored by two physicians. Whether there is significant difference is determined by SPSS 11.0 software. Paired samples t test was used for statistics. RESULTS: There was no significant difference in the image quality scores between two sequences (t = 0.880, P = 0.383 > 0.05). CONCLUSIONS: DIR TFE sequence has short scanning time and high spatial resolution. DIR TFE sequence can be used as the preferred sequence for screening carotid atherosclerotic plaque compared with DIR TSE sequence. PMID- 21237601 TI - Dual energy CT monitoring of the renal corticomedullary sodium gradient in swine. AB - OBJECTIVE: To evaluate the feasibility of dual-energy CT (DECT) for monitoring dynamic changes in the renal corticomedullary sodium gradient in swine. MATERIAL AND METHODS: This study was approved by our Institutional Animal Care and Use Committee. Four water-restricted pigs were CT-scanned at 80 and 140 kVp at baseline and at 5 min intervals for 30 min during saline or furosemide diuresis. The renal cortical and medullary CT numbers were recorded. A DECT basis material decomposition method was used to quantify renal cortical and medullary sodium concentrations and medulla-to-cortex sodium ratios at each time point based on the measured CT numbers. The sodium concentrations and medulla-to-cortex sodium ratios were compared between baseline and at 30 min diuresis using paired Student t-tests. The medulla-to-cortex sodium ratios were considered to reflect the corticomedullary sodium gradient. RESULTS: At baseline prior to saline diuresis, the mean medullary and cortical sodium concentrations were 103.8+/-8.7 and 65.3+/ 1.7 mmol/l, respectively, corresponding to a medulla-to-cortex sodium ratio of 1.59. At 30 min of saline diuresis, the medullary and cortical sodium concentrations decreased to 72.3+/-1.0 and 56.0+/-1.4 mmol/l, respectively, corresponding to a significantly reduced medulla-to-cortex sodium ratio of 1.29 (P<0.05). At baseline prior to furosemide diuresis, the mean medullary and cortical sodium concentrations were 110.5+/-3.6 and 66.7+/-4.1 mmol/l, respectively, corresponding to a medulla-to-cortex sodium ratio of 1.66. At 30 min of furosemide diuresis, the medullary and cortical sodium concentrations decreased to 68.5+/-0.3 and 58.9+/-4.0 mmol/l, respectively, corresponding to a significantly reduced medulla-to-cortex sodium ratio of 1.16 (P<0.05). One of the 4 pigs developed acute tubular necrosis likely related to prolonged hypoxia during intubation prior to the furosemide diuresis experiment. The medulla-to cortex sodium ratio for this pig, which was excluded from the mean medulla-to cortex ratio above, was 1.07 at baseline and 1.15 at 30 min following the administration of furosemide. CONCLUSION: DECT monitoring of dynamic changes in the renal corticomedullary sodium gradient after physiologic challenges is feasible in swine. PMID- 21237602 TI - Influence of hemodynamic parameters on coronary artery attenuation with 320 detector coronary CT angiography. AB - OBJECTIVES: To investigate the relationship between cardiac output, end diastolic volume and the contrast enhancement in coronary CT angiography using 320-detector CT. MATERIALS AND METHODS: A total of 38 patients underwent coronary CT angiography by using a 320-detector CT scanner (detector configuration, 320 * 0.5mm). The attenuation value of the ascending aorta at the level of the orifice of the left main trunk was measured. The cardiac output (CO), end diastolic volume (EDV) and stroke volume (SV) were measured by echocardiography. The EDV was normalized to the body surface area (BSA). The total blood volume injected from the left ventricle from the beginning of the contrast agent injection to the time of image acquisition was determined to be the total injected blood volume (TIV), which is a product of SV and the number of heart beats from the initiation of contrast agent injection to the scan. RESULTS: There was a negative correlation between the attenuation of the ascending aorta and CO (r = -0.44, P = 0.0053). However, the negative correlation between the attenuation of the ascending aorta and TIV was stronger (r = -0.52, P = 0.0007). There was a negative correlation between the attenuation of the ascending aorta and EDV/BSA (r = -0.45, P = 0.0039). CONCLUSION: In 320-detector CT, contrast enhancement in CCTA with a lesser amount of contrast medium decreases when cardiac output is high. Patients with larger EDV/BSA may also show decreased attenuation. PMID- 21237603 TI - Survey of computed tomography technique and radiation dose in Sudanese hospitals. AB - The purpose of this study was to survey technique and radiation absorbed dose in CT examinations of adult in Sudan and to compare the results with the reference dose levels. Questionnaire forms were completed in nine hospitals and a sample of 445 CT examinations in patients. Information on patient, procedure, scanner, and technique for common CT examinations were collected. For each facility, the radiation absorbed dose was measured on CT dose phantom measuring 16 cm (head) and 32 cm (body) in diameter and was used to calculate the normalized CT air kerma index. Volume CT air kerma index (CVOL), CT air kerma-length product (PKL,CT) values were calculated using the measured normalized CT air kerma index and questionnaire information. The effective dose, E estimates was determined by using PKL,CT measurements and appropriate normalized coefficients. Assuming the sample to offer a fair representative picture of CT practice patterns in Sudan, the mean CVOL and PKL,CT values were comparable or below the reference doses: 65 mGy and 758 mGy cm, respectively at head CT; 11.5 mGy and 327 mGy cm, respectively at chest CT; 11.6 mGy and 437 mGy cm, respectively at abdominal CT; and 11.0 mGy and 264 mGy cm, respectively at pelvis CT. Estimated effective doses were 1.6, 4.6, 6.6 and 4.0 mSv, respectively. The study offered a first national dose survey and provided a mean for quality control and optimization of CT practice within the country. PMID- 21237604 TI - Can left ventricular end-diastolic volumes be estimated with prospective ECG gated CT coronary angiography? AB - BACKGROUND: With the goal of minimizing patient radiation exposure, many centres have adopted prospective ECG-gated computed tomographic coronary angiography. Since image acquisition occurs only during ventricular diastasis, the ability to measure left ventricular (LV) ejection fraction (EF) and LV volumes has been lost. Given that LV volumes have prognostic value, the ability to estimate LV end diastolic volume (EDV) may be clinically desirable. OBJECTIVE: We sought to predict LV EDV using CT coronary angiography (CTA) images obtained during ventricular diastasis. METHODS: Consecutive patients who underwent retrospective ECG-gated CTA were enrolled. Images were reconstructed at the 75% phase and at end-diastole. LV and left atrial (LA) volumes were measured. RESULTS: A total of 153 consecutive patients were analyzed (mean age = 56.7 +/- 11.2 years; men = 56.2%). The mean LV EDV and EF were 144.4 +/- 40.2 mL and 63.4 +/- 9.9%, respectively. There appeared to be a very strong linear relationship between the 75% phase LV volume and LV EDV with an R(2) of 0.993. Using LV and LA volumes at the 75% phase, a prediction model of LV EDV was developed (LV EDV = (1.021 * 75% phase LV volume)+(0.259 * 75% phase LA volume), adjusted R(2) = 0.995). CONCLUSION: LV EDV can be estimated using CTA data obtained during ventricular diastasis. Further studies are needed to demonstrate that such estimates of LV EDV have incremental prognostic value over coronary artery disease severity assessment with prospective ECG-gated CTA. PMID- 21237605 TI - Optimization of mass spectral features in MALDI-TOF MS profiling of Acinetobacter species. AB - The influence of the matrix solution, sample form and deposition technique on the quality MALDI-TOF mass spectra was examined and assessed with the aim to improve MALDI-TOF MS performance for the identification of microorganisms and to enable automatic spectra acquisition. It was observed that the use of matrix compounds ferulic and sinapinic acid may result in improved mass spectral features, in terms of signal resolution and S/N ratio, as compared to alpha-cyano-4 hydroxycinnamic acid, which was, on the other hand, found to be the only matrix compound that enabled fully automatic mass spectra acquisition. The robustness of the whole sample preparation procedure was then assessed on a set of 25 strains of four Acinetobacter species. Results showed reproducible detection of subtle mass spectral differences between strains belonging to the same species, although they do not confirm the possibility of reliable strain typing. PMID- 21237606 TI - Continuous monitoring of dough fermentation and bread baking by magnetic resonance microscopy. AB - The consumer quality of baked products is closely related with dough structure properties. These are developed during dough fermentation and finalized during its baking. In this study, magnetic resonance microscopy (MRM) was employed in a study of dough fermentation and baking. A small hot air oven was installed inside a 2.35-T horizontal bore superconducting magnet. Four different samples of commercial bread mixes for home baking were used to prepare small samples of dough that were inserted in the oven and allowed to rise at 33 degrees C for 112 min; this was followed by baking at 180 degrees C for 49 min. The entire process was followed by dynamic T(1)-weighted 3D magnetic resonance imaging with 7 min of temporal resolution and 0.23*0.23*1.5 mm(3) of spatial resolution. Acquired images were analyzed to determine time courses of dough pore distribution, dough volume and bread crust thickness. Image analysis showed that both the number of dough pores and the normalized dough volume increased in a sigmoid-like fashion during fermentation and decreased during baking due to the bread crust formation. The presented magnetic resonance method was found to be efficient in analysis of dough structure properties and in discrimination between different dough types. PMID- 21237607 TI - Advances in validation, risk and uncertainty assessment of bioanalytical methods. AB - Bioanalytical method validation is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application in order to trust the critical decisions that will be made with them. Even if several guidelines exist to help perform bioanalytical method validations, there is still the need to clarify the meaning and interpretation of bioanalytical method validation criteria and methodology. Yet, different interpretations can be made of the validation guidelines as well as for the definitions of the validation criteria. This will lead to diverse experimental designs implemented to try fulfilling these criteria. Finally, different decision methodologies can also be interpreted from these guidelines. Therefore, the risk that a validated bioanalytical method may be unfit for its future purpose will depend on analysts personal interpretation of these guidelines. The objective of this review is thus to discuss and highlight several essential aspects of methods validation, not only restricted to chromatographic ones but also to ligand binding assays owing to their increasing role in biopharmaceutical industries. The points that will be reviewed are the common validation criteria, which are selectivity, standard curve, trueness, precision, accuracy, limits of quantification and range, dilutional integrity and analyte stability. Definitions, methodology, experimental design and decision criteria are reviewed. Two other points closely connected to method validation are also examined: incurred sample reproducibility testing and measurement uncertainty as they are highly linked to bioanalytical results reliability. Their additional implementation is foreseen to strongly reduce the risk of having validated a bioanalytical method unfit for its purpose. PMID- 21237608 TI - NMR techniques in biomedical and pharmaceutical analysis. AB - This article focuses on the description of some of the NMR techniques used in the field of biomedical and pharmaceutical research. Indeed, the NMR method has special characteristics which make it uniquely suitable for these kinds of studies. It is non-selective so that all the low molecular weight compounds in the sample investigated are detected simultaneously in a single run. NMR also provides rich structural information which is an important asset to characterize complex mixture components. NMR is quantitative, i.e. the area of a NMR signal is directly proportional to the number of corresponding nuclei and thus, at variance with other techniques, the response factor is not dependent on the molecular structure. It is also a non-invasive tool that permits in vivo studies in humans. Compared with other techniques, NMR is significantly insensitive, which represents the main drawback of the technique. The recent technological developments of the technique have nevertheless considerably improved its sensitivity. The first part of this article presents an overview of the advantages and limitations of NMR for in vitro quantitative analysis of complex matrices in liquid or semi-solid phases. The second part deals with the NMR-based metabolomics methodology. The third part describes the in vivo clinical magnetic resonance spectroscopy techniques. The fourth part reports some examples of NMR applications in the biomedical and pharmaceutical research fields. PMID- 21237609 TI - An overview of recent studies on the analysis of pharmaceutical polymorphs. AB - Pharmaceutical solids are well known to be able to exist in different solid-state forms and there are a wide variety of solid-state analytical techniques available to characterize pharmaceutical solids and solid-state transformations. In this review, the commonly used solid-state analytical techniques, the type of information collected, and advantages and disadvantages of each technique are discussed, with the focus on their application in solid-state characterization and monitoring solid-state transformations, such as amorphization, crystallization, hydrate formation/dehydration and cocrystal formation. The information gathered from recent literature is compiled in various tables to aid the reader to get a quick overall picture about what type of phenomena have recently been studied and which analytical technique(s) have been used. PMID- 21237611 TI - A community-based intervention to promote informed decision making for prostate cancer screening among Hispanic American men changed knowledge and role preferences: a cluster RCT. AB - OBJECTIVE: We assessed the short-term effects of a community-based intervention for Hispanic men to encourage informed decision making (IDM) about prostate cancer screening with prostate specific antigen (PSA). METHODS: All senior social and housing centers in El Paso, TX were randomized to intervention, a group-based Spanish language educational program facilitated by promotores (12 centers; 161 men) [I's], or to control, promotores-facilitated diabetes video and discussion (13 centers; 160 men) [C's]. RESULTS: Participants had low levels of schooling and baseline knowledge; 44% reported previous PSA testing. At post-test, the I's made large knowledge gains, increased their understanding that experts disagree about testing, shifted toward more active decision making roles, were more likely to believe that it is important to weigh the advantages and disadvantages of screening and to anticipate potential screening outcomes in making a decision, and were less likely to consider the screening decision easy. The I's did not change in their screening intention or the belief that choosing not to be screened could be a responsible choice. CONCLUSIONS: A community-based intervention to support IDM for prostate cancer screening can increase knowledge and may promote more active involvement in decision making about prostate cancer screening. Such an approach can increase knowledge and may promote more active involvement in decision making about prostate cancer screening. PRACTICE IMPLICATIONS: It is feasible to develop and implement a community-based intervention program to promote IDM for prostate cancer screening. PMID- 21237610 TI - Evaluating pharmacists' ability to counsel on tobacco cessation using two standardized patient scenarios. AB - OBJECTIVES: To evaluate the impact that role-playing two pre/post standardized patient scenarios within a tobacco cessation training program had on pharmacists' counseling skills. Second, to analyze the validity of the observation coding tool used to evaluate pharmacist's role-play performance. METHODS: Pharmacists performed two role-playing scenarios which incorporated national guidelines, the 5A's counseling process, and the "preparation" and "action" phases of the transtheoretical model. Pharmacists' performance was evaluated with an observation coding tool. RESULTS: Pharmacists' (n=25) counseling performance improved significantly post-training (p<0.02: Action Scenario; p<0.004: Preparation Scenario). More than 50% of pharmacists provided patient-directed tobacco consultation services in the one year following training. The observation tool score for the "action phase" scenario was highly associated with pharmacists' subsequent delivery of tobacco cessation services in community practice. CONCLUSION: Role-playing facilitated pharmacists' skill development. The evaluation tool and Action Scenario may be powerful for predicting pharmacists' delivery of tobacco cessation services. PRACTICE IMPLICATIONS: Incorporating role-playing and structured tools for performance evaluation can help enhance pharmacist performance during training and predict service delivery in community practice. Together they could facilitate tailored feedback to help pharmacists struggling with the difficult task of extending cognitive service roles in practice. PMID- 21237613 TI - WITHDRAWN: Proteome and phytochemical analysis of Cynodon dactylon leaves extract and its biological activity in diabetic rats. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.bionut.2010.09.001. The duplicate article has therefore been withdrawn. PMID- 21237612 TI - Role of MRI (magnetic resonance imaging) versus conventional imaging for breast cancer presurgical staging in young women or with dense breast. AB - AIMS: The role of magnetic resonance imaging (MRI) in the local staging of breast cancer is currently uncertain. The purpose of this prospective study is to evaluate the accuracy of preoperative MRI compared to conventional imaging in detecting breast cancer and the effect of preoperative MRI on the surgical treatment in a subgroup of women with dense breasts, young age, invasive lobular cancer (ILC) or multiple lesions. METHODS: Between January 2006 and October 2007, 91 patients with newly diagnosed breast cancer underwent preoperative clinical breast examination, mammography, bilateral breast ultrasonography and high resolution breast MRI. All patients had histologically verified breast cancer. The imaging techniques were compared using the final pathological report as gold standard. RESULTS: The sensitivity of MRI for the main lesion was 98.9%, while for multiple lesions sensitivity was 90.7% and specificity 85.4%. After preoperative MRI, 13 patients (14.3%) underwent additional fine needle/core biopsies, 9 of whom had specimen positive for cancer. Preoperative MRI changed the surgical plan in 26 patients: in 19.8% of the cases breast conservative surgery was converted to mastectomy and in 7.7% of the patients a wider excision was performed. At a mean follow-up of 48 months, 2 local recurrences occurred (local failure rate = 2.5%). CONCLUSIONS: Enhanced sensitivity of breast MRI may change the surgical approach, by increasing mastectomy rate or suggesting the need of wider local excision. MRI can play an important role in preoperative planning if used in selected patients with high risk of multifocal/multicentric lesions. However, the histologic confirmation of all suspicious findings detected by MRI is mandatory prior to definite surgery. PMID- 21237614 TI - Reversal of multidrug resistance by small interfering RNA (siRNA) in doxorubicin resistant MCF-7 breast cancer cells. AB - PURPOSE: Resistance to anticancer drugs is a serious obstacle to cancer chemotherapy. A common form of multidrug resistance (MDR) is caused by the overexpression of transmembrane transporter proteins P-glycoprotein (P-gp) and multidrug resistance-associated protein-1 (MRP1), encoded by MDR1 and MRP1 genes, respectively. These proteins lead to reduced intracellular drug concentration and decreased cytotoxicity by means of their ability to pump the drugs out of the cells. Breast cancer tumor resistance is mainly associated with overexpression of P-gp/MDR1. Although some chemical MDR modulators aim to overcome MDR by interfering functioning of P-gp, their toxicities limit their usage in clinics. Consequently, RNA interference mediated sequence specific inhibition of the expression of P-gp/MDR1 mRNA may be an efficient tool to reverse MDR phenotype and increase the success of chemotherapy. Aim of this study was resensitizing doxorubicin-resistant breast cancer cells to anticancer agent doxorubicin by selective downregulation of P-gp/MDR1 mRNA. METHODS: The effect of the selected MDR1 siRNA, and MRP1 expression after MDR1 silencing was determined by qPCR analysis. Intracellular drug accumulation and localization was investigated by confocal laser scanning microscopy after treatment with MDR1 siRNA. XTT cell proliferation assay was performed to determine the effect of MDR1 silencing on doxorubicin sensitivity. RESULTS: The results demonstrated that approximately 90% gene silencing occurred by the selected siRNA targeting MDR1 mRNA. However, the level of MRP1 mRNA did not change after MDR1 downregulation. Silencing of P-gp encoding MDR1 gene resulted in almost complete restoration of the intracellular doxorubicin accumulation and relocalization of the drug in the nuclei. Introduction of siRNA resulted in about 70% resensitization to doxorubicin. CONCLUSIONS: Selected siRNA duplex was shown to effectively inhibit MDR1 gene expression, restore doxorubicin accumulation and localization, and enhance chemosensitivity of resistant cells, which makes it a suitable candidate for therapeutic applications. PMID- 21237615 TI - Respiratory distress in Pierre Robin sequence: an experience with mandible traction by wires. AB - Congenital retrognathia and glossoptosis characterize isolated Pierre Robin sequence (iPRS); the small mandible and its retracted position cause retrodisplacement of the tongue and reduction of the oropharyngeal airway. These neonates may be affected by airway obstruction, feeding difficulties, failure to thrive, and chronic hypoxaemia. To solve the respiratory problems secondary to glossoptosis, various treatments have been described including prone positioning, a nasopharyngeal tube, glossopexy, and mandibular distraction. Over the last 28 years, the authors have treated 118 neonates and infants affected by iPRS by carrying out traction of the mandible using two parasymphyseal wires, positioned under local anaesthesia. All the procedures were successful, with no major complication. The patients' respiratory problems and apnoea disappeared suddenly after beginning traction. PMID- 21237616 TI - Utility of echocardiographic evaluation of donor hearts upon the organ procurement for heart transplantation. AB - BACKGROUND: Evaluating donor heart as accurately as possible upon the organ procurement would help lead careful post-transplant heart management. Our institution (National Cerebral and Cardiovascular Center, Osaka, Japan) has sent a transplant cardiologist upon the organ procurement for evaluating a donor heart ever since our first case of heart transplantation. METHODS: Thirteen consecutive bedside echocardiograms obtained from donors upon the organ procurement and post transplant echocardiograms obtained from their recipients were retrospectively reviewed. The impact of donor echocardiograms on their recipients' post transplant time course was analyzed and both the donor echocardiographic parameters and their recipients' parameters within 1 week after the heart transplant were compared. RESULTS: Both the left ventricular end-diastolic diameter and the ventricular wall thickness of donors correlated well with those parameters of their corresponding recipients (r(2)=0.740, p<0.0001, r(2)=0.704, p<0.0001, respectively). The information on coronary flow of the donor heart with risk factors for ischemic heart disease was useful for judging the availability for heart transplantation. The information on the pre-existing localized wall motion abnormality of donor hearts was useful for ruling out a possibility of rejection and other causes of wall motion abnormality after transplantation. The mean time required for bedside echocardiography for the donor heart was only 3.7 min. None of the recipients either developed primary graft failure or required treatment for cellular rejection. CONCLUSIONS: Detailed observation of donor hearts by bedside echocardiograms upon the organ procurement is of clinical benefit. PMID- 21237617 TI - Reduced language lateralization in first-episode medication-naive schizophrenia. AB - Diminished functional lateralization in language-related areas is found in chronic schizophrenia. It is not clear at what stage of illness these abnormalities in lateralization arise, or whether they are affected by medication. In addition, it is hypothesized that reduced language lateralization is related to positive symptoms of schizophrenia, but studies addressing this issue have yielded contradictory results. In this study we used functional MRI to measure language lateralization in 35 first-episode medication-naive schizophrenia patients and 43 matched healthy controls. Subjects performed three language tasks: a paced verb generation task, an antonym generation task, and a semantic decision task. Lateralization Index (LI) was calculated, using a relative threshold technique, in seven Regions of Interest (ROIs), including the main language-related areas and their contralateral homologues. In addition, we investigated whether language lateralization was correlated with psychotic symptoms. Across all ROIs, LI was significantly reduced in patients (p<0.001) compared to controls. Post-hoc tests revealed that this reduction was most prominent in the inferior frontal gyrus (part of Broca's area) (p=0.003) and the superior temporal gyrus (part of Wernicke's area) (p<0.001). LI was not correlated with the positive subscale of the PANSS, nor with hallucinations or disorganization. This is the first study to report reduced LI at the onset of schizophrenia, before medical treatment is initiated. PMID- 21237619 TI - On the detection of plasmidic AmpC in Enterobacteriaceae other than Escherichia spp. and Klebsiella spp. PMID- 21237620 TI - Advances in multidisciplinary and cross-species approaches to examine the neurobiology of psychiatric disorders. AB - Current approaches to dissect the molecular neurobiology of complex neuropsychiatric disorders such as schizophrenia and major depression have been rightly criticized for failing to provide benefits to patients. Improving the translational potential of our efforts will require the development and refinement of better disease models that consider a wide variety of contributing factors, such as genetic variation, gene-by-environment interactions, endophenotype or intermediate phenotype assessment, cross species analysis, sex differences, and developmental stages. During a targeted expert meeting of the European College of Neuropsychopharmacology (ECNP) in Istanbul, we addressed the opportunities and pitfalls of current translational animal models of psychiatric disorders and agreed on a series of core guidelines and recommendations that we believe will help guiding further research in this area. PMID- 21237621 TI - Shape analysis of the neostriatum in subtypes of frontotemporal lobar degeneration: neuroanatomically significant regional morphologic change. AB - Frontostriatal circuit mediated cognitive dysfunction has been implicated in frontotemporal lobar degeneration (FTLD) and may differ across subtypes of FTLD. We manually segmented the neostriatum (caudate nucleus and putamen) in FTLD subtypes: behavioral variant frontotemporal dementia, FTD, n=12; semantic dementia, SD, n=13; and progressive non-fluent aphasia, PNFA, n=9); in comparison with controls (n=27). Diagnoses were based on international consensus criteria. Manual bilateral segmentation of the caudate nucleus and putamen was conducted blind to diagnosis by a single analyst, on MRI scans using a standardized protocol. Intracranial volume was calculated via a stereological point counting technique and was used for normalizing the shape analysis. Segmented binaries were analyzed using the Spherical Harmonic (SPHARM) Shape Analysis tools (University of North Carolina) to perform comparisons between FTLD subtypes and controls for global shape difference, local significance maps and mean magnitude maps of shape displacement. Shape analysis revealed that there was significant shape difference between FTLD subtypes and controls, consistent with the predicted frontostriatal dysfunction and of significant magnitude, as measured by displacement maps. These differences were not significant for SD compared to controls; lesser for PNFA compared to controls; whilst FTD showed a more specific pattern in regions relaying fronto- and corticostriatal circuits. Shape analysis shows regional specificity of atrophy, manifest as shape deflation, with a differential between FTLD subtypes, compared to controls. PMID- 21237622 TI - Polyamidoamine dendrimers surface-engineered with biomimetic phosphorylcholine as potential drug delivery carriers. AB - Biomimetic acryloyloxyethyl phosphorylcholine (APC) was used to react with generation 5 poly(amido amine) (PAMAM) dendrimers (G5) via the Michael addition reaction between primary amino group of PAMAM dendrimers and acrylic functional group of APC. FTIR and (1)H NMR confirmed the success of surface modification of G5. The primary amino and phosphorylcholine (PC) group numbers of the surface engineered PAMAM dendrimers (G5-PC) were calculated to be 56 and 50 via (1)H NMR and potentiometric titration. Cell viability and cell morphology studies indicated that biomimetic phosphorylcholine surface engineering successfully lowered the cytotoxicity of G5 PAMAM dendrimers. The hydrophobic interior of G5 PC was used to incorporate anti-cancer drug Adriamycin (ADR) and the G5-PC showed sustained releasing behavior for ADR. Cell morphology and viability tests indicated that the drug-loaded G5-PC conjugate could effectively enter the cancer cells and inhibit the growth of cancer cells. Biomimetic phosphorylcholine surface engineered PAMAM dendrimers with lowered cytotoxicity and high cellular penetrating ability showed great potential for the biomedical applications as nanocarrier system. PMID- 21237623 TI - Cell shape and spreading of stromal (mesenchymal) stem cells cultured on fibronectin coated gold and hydroxyapatite surfaces. AB - In order to identify the cellular mechanisms leading to the biocompatibility of hydroxyapatite implants, we studied the interaction of human bone marrow derived stromal (mesenchymal) stem cells (hMSCs) with fibronectin-coated gold (Au) and hydroxyapatite (HA) surfaces. The adsorption of fibronectin was monitored by Quartz Crystal Microbalance with Dissipation (QCM-D) at two different concentrations, 20 MUg/ml and 200 MUg/ml, and the fibronectin adsorption experiments were complemented with antibody measurements. The QCM-D results show that the surface mass uptake is largest on the Au surfaces, while the number of polyclonal and monoclonal antibodies directed against the cell-binding domain (CB domain) on the fibronectin (Fn) is significantly larger on the (HA) surfaces. Moreover, a higher number of antibodies bound to the fibronectin coatings formed from the highest bulk fibronection concentration. In subsequent cell studies with hMSC's we studied the cell spreading, cytoskeletal organization and cell morphology on the respective surfaces. When the cells were adsorbed on the uncoated substrates, a diffuse cell actin cytoskeleton was revealed, and the cells had a highly elongated shape. On the fibronectin coated surfaces the cells adapted to a more polygonal shape with a well-defined actin cytoskeleton, while a larger cell area and roundness values were observed for cells cultured on the coated surfaces. Among the coated surfaces a slightly larger cell area and roundness values was observed on HA as compared to Au. Moreover, the results revealed that the morphology of cells cultured on fibronectin coated HA surfaces were less irregular. In summary we find that fibronectin adsorbs in a more activated state on the HA surfaces, resulting in a slightly different cellular response as compared to the fibronectin coated Au surfaces. PMID- 21237624 TI - A LQ-based kinetic model formulation for exploring dynamics of treatment response of tumours in patients. AB - A kinetic bio-mathematical, linear-quadratic (LQ) based model description for clonogenic survival is presented. In contrast to widely used formulations of models, a dynamic approach based on ordinary differential equations for coupling a repair model with a tumour growth model is used to allow analysis of intercellular process dynamics and submodel interference. The purpose of the model formulation is to find a quantitative framework for investigation of tumour response to radiotherapy in vivo. It is not the intention of the proposed model formulation to give a mechanistic explanation for cellular repair processes. This article addresses bio-mathematical aspects of the simplistic kinetic approach used for description of repair. The model formulation includes processes for cellular death, repopulation and cellular repair. The explicit use of the population size in the model facilitates the coupling of the sub-models including aspects of tissue dynamics (competition, oxygenation). The cellular repair is summarized by using a kinetic model for a dose equivalent Gamma describing production and elimination of sublethal lesions. This dose equivalent replaces the absorbed dose used in the common LQ- model. Therefore, this approach is called the Gamma- LQ- formulation. A comparison with two kinetic radiobiological models (the LPL model of Curtis and the compartmental model of Carlone) is carried out. The resulting differential equations are solved by numerical integration using a Runge-Kutta algorithm. The comparison reveals a good agreement between the Gamma- LQ- formulation and the models of Curtis and Carlone under certain, defined conditions: The proposed formulation leads to results which are identical to the model of Carlone over a wide range of investigated biological parameters and different fractionation schemes when using first order repair kinetics. The comparison with experimental data and the LPL- model of Curtis shows a good agreement of the Gamma- LQ- formulation using second order repair kinetics over a wide range of dose rate. Over a limited range, the use of second order repair in the Gamma- LQ- formulation approximates the same dose rate dependency of clonogenic survival using only one additional parameter to those of the common LQ model. Within the investigated range of parameters, the presented Gamma-LQ- formulation may be used to describe the in-vivo tumour response to radiation. The influence of repopulation, oxygenation and other aspects of tissue dynamics may override the differences between the intrinsic radiosensitivity yielded by each of the models. The proposed model formulation can be extended with additional static and dynamic tissue behaviours. This may be useful for the understanding of the reaction of tissues to heat (hyperthermia) or combined anti cancer treatments (chemo-radiotherapy). PMID- 21237625 TI - What sponges can tell us about the evolution of developmental processes. AB - Sponges are one of the simplest, and probably the oldest (earliest branching) multicellular lineage of extant animals. Although their embryonic development has been intensively studied in the late 19th and early 20th century, they have been mostly neglected by modern developmental biology. Recent interest in the evolution of development, aided by advances in sequencing technology, has brought the sponges back into the spotlight. It is known that the developmental toolkit of sponges includes signalling pathways, transcription factors and cell adhesion molecules that are employed during development of more complex animals (i.e. bilaterians). We are now beginning to understand how these conserved regulatory genes are used during the development of sponges. Methodological resources are now being developed for model species representing all major sponge lineages, potentially allowing us to gain insight into the evolutionary origin of animal developmental mechanisms. PMID- 21237626 TI - XCC2731, a GGDEF domain protein in Xanthomonas campestris, is involved in bacterial attachment and is positively regulated by Clp. AB - In Xanthomonas campestris pv. campestris (Xcc), which is the causative agent of black rot in crucifers, the virulence factor level is substantially decreased in the mutant deficient in RpfG, a phosphodiesterase that degrades the second messenger cyclic di-GMP. The rpfG mutant also grew in an aggregated state. It is indicated that expression of Pseudomonas GGDEF domain protein WspR (a diguanylate cyclase that synthesizes cyclic di-GMP) in wild-type Xcc can produce a phenocopy of the rpfG mutant. In this study, we showed that over-expression of GGDEF domain protein XCC2731 in wild-type Xcc caused (i) aggregation of cells, (ii) reduction in motility, and (iii) decrease in production of virulence factor extracellular enzymes and exopolysaccharides. Site-directed mutagenesis of the conserved G, G, and E residues of the GGDEF domain in XCC2731 abolished its function. The XCC2731 mutant has attenuated virulence. Furthermore, XCC2731 mutant was affected in surface attachment. Using the 5' RACE method, the XCC2731 transcription initiation site was mapped at nucleotide G, 15nt upstream of the XCC2731 start codon. Transcriptional fusion assay and gel retardation analysis indicated that Clp (cAMP receptor protein-like protein) positively regulates XCC2731 transcription in a direct manner. Reporter analysis also revealed that XCC2731 transcription is subject to catabolite repression, and reduced under conditions of oxygen limitation and high osmolarity. Our findings not only extend previous work on Clp regulation to show that it influences the expression of XCC2731 in Xcc, but also are the first to characterize the GGDEF domain protein gene expression in this phytopathogen. PMID- 21237627 TI - The Ashbya gossypii fimbrin SAC6 is required for fast polarized hyphal tip growth and endocytosis. AB - Ashbya gossypii has been an ideal system to study filamentous hyphal growth. Previously, we identified a link between polarized hyphal growth, the organization of the actin cytoskeleton and endocytosis with our analysis of the A. gossypii Wiskott-Aldrich Syndrome Protein (WASP)-homolog encoded by the AgWAL1 gene. Here, we studied the role of AgSAC6, encoding a fimbrin in polarized hyphal growth and endocytosis, and based on our functional analysis identified genetic interactions between AgSAC6 and AgWAL1. SAC6 mutants show severely reduced polarized growth. This growth phenotype is temperature dependent and sac6 spores do not germinate at elevated temperatures. Spores germinated at 30 degrees C generate slow growing mycelia without displaying polarity establishment defects at the hyphal tip. Several phenotypic characteristics of sac6 hyphae resemble those found in wal1 mutants. First, tips of sac6 hyphae shifted to 37 degrees C swell and produce subapical bulges. Second, actin patches are mislocalized subapically. And third, the rate of endocytotic uptake of the vital dye FM4-64 was reduced. This indicates that actin filament bundling, a conserved function of fimbrins, is required for fast polarized hyphal growth, polarity maintenance, and endocytosis in filamentous fungi. PMID- 21237628 TI - Role of cell wall bound calcium in Neurospora crassa. AB - Cell wall bound calcium constitutes a significant fraction (25%) of total mycelia calcium in Neurospora crassa. Wall bound calcium increases as a function of growth and calcium concentration, while cell wall bound calcium decreases in Ca free medium. Removal of wall bound calcium causes its rapid replacement from intracellular pool, inhibited by verapamil, nifedipine, concanamycin A, and wortmanin in a vacuolar mutant (Vma-5), but is unaffected by trifluoropyrazine, and calmidizoluim in a calcineurin mutant (Cnb-1) of N. crassa. Ca(2+) removal from surface with EGTA resulted in leakage of periplasmic enzymes invertase and alkaline phosphatase. Scanning and transmission electron microscopy revealed gross abnormalities represented by giant vacuoles. Toxic metal ions bound to wall fraction by displacing calcium. Our data underline the physiological importance of wall bound calcium in N. crassa. PMID- 21237629 TI - Potential application of Northern Argentine propolis to control some phytopathogenic bacteria. AB - The antimicrobial activity of samples of Northern Argentine propolis (Tucuman, Santiago del Estero and Chaco) against phytopathogenic bacteria was assessed and the most active samples were identified. Minimal inhibitory concentration (MIC) values were determined by agar macrodilution and broth microdilution assays. Strong antibacterial activity was detected against Erwinia carotovora spp carotovora CECT 225, Pseudomonas syringae pvar tomato CECT 126, Pseudomonas corrugata CECT 124 and Xanthomonas campestris pvar vesicatoria CECT 792. The most active propolis extract (Tucuman, T1) was selected to bioguide isolation and identified for antimicrobial compound (2',4'-dihydroxychalcone). The antibacterial chalcone was more active than the propolis ethanolic extract (MIC values of 0.5-1 MUg ml(-1) and 9.5-15 MUg ml(-1), respectively). Phytotoxicity assays were realized and the propolis extracts did not retard germination of lettuce seeds or the growth of onion roots. Propolis solutions applied as sprays on tomato fruits infected with P. syringae reduced the severity of disease. Application of the Argentine propolis extracts diluted with water may be promising for the management of post harvest diseases of fruits. PMID- 21237631 TI - Immunosurveillance in human non-viral cancers. AB - Immunosurveillance of infections and therefore of viral-induced cancers is well admitted but that of nonviral cancers is a matter of hot debate. In the recent years, data collected from large libraries of human cancers demonstrated that the immune contexture of the primary tumors is an essential prognostic factor for patients' disease-free and overall survival. The location in the tumor's center and invasive margin, the coordination of a memory Th1/cytotoxic T cell infiltrate, and the expression of genes involved in angiogenesis, chemotaxis, and cell adhesion are key factors for an immune control of disease progression. Systems biology predicted markers shaping an efficient immune reaction can serve as tools and targets for novel therapeutic approaches. PMID- 21237630 TI - Genetically retargeting CD8+ lymphocyte subsets for cancer immunotherapy. AB - The extraordinary sensitivity and specificity of T cells for their cognate antigen make them a highly attractive cancer therapeutic. However, the rarity of tumor-reactive T cells in cancer patients, the difficulty isolating them in sufficient numbers for adoptive immunotherapy, and the unpredictable persistence of transferred cells have been significant obstacles to broad application. Technologies that enable genetic modification of T cells have been refined and are being used to redirect the specificity of T cells to tumor antigens. An issue the field is now grappling with is how the diverse phenotypic and functional heterogeneity in T cells that could potentially be genetically modified can be capitalized upon to enhance the efficacy, safety, and reproducibility of cancer immunotherapy. PMID- 21237632 TI - Therapeutic vaccination against human papilloma virus induced malignancies. AB - Human Papilloma Virus (HPV)-induced (pre-)malignancies offer an excellent case for the rational design of immunotherapeutic strategies against cancer. Transformed cells express tumor-specific antigens of viral origin while the spontaneous antitumor response and the immunological make up of HPV-induced tumors do not differ from other immunogenic epithelial tumors. A first clinically active therapeutic HPV vaccine has been developed and clear links were found between the type and kinetics of vaccine-induced T-cell immunity. Here, we will review the mechanisms determining the success and failure of therapeutic vaccines against HPV-induced tumors, with particular emphasis on the immunological setting in which these vaccines need to work. The recent progress in therapeutic HPV vaccination will guide the development of successful vaccines in other diseases. PMID- 21237633 TI - Electrocatalytic oxidation of salicylic acid by a cobalt hydrotalcite-like compound modified Pt electrode. AB - In this paper a study of the electrocatalytic oxidation of salicylic acid (SA) at a Pt electrode coated with a Co/Al hydrotalcite-like compound (Co/Al HTLC coated Pt) film is presented. The voltammetric behaviour of the modified electrode in 0.1M NaOH shows two different redox couples: Co(II)/Co(III) and Co(III)/Co(IV). The electrocatalysis occurs at the same potential of the latter couple, showing that Co(IV) centers act as the oxidant. The CV investigation demonstrates that the process is controlled both by mass and charge transfer and that the Co(IV) centers involved in the oxidation are two for each SA molecule. The estimated value of the catalytic constant is 4*10(4) M(-1) s(-1). The determination of salicylic acid was performed both by DPV and chronoamperometry. The linearity ranges and the LOD values resulted 1*10(-5) to 5*10(-4), 5*10(-7) to 1*10(-4), 6*10(-6) and 2*10(-7) M, respectively. The Co/Al HTLC electrode has been used for SA determination in BAYER Aspirina(r) and the obtained results are consistent with an independent HPLC analysis. PMID- 21237634 TI - Real-time QCM-D monitoring of cellular responses to different cytomorphic agents. AB - Quartz crystal microbalance with dissipation monitoring (QCM-D) is used for real time in situ detection of cytoskeletal changes in live primary endothelial cells in response to different cytomorphic agents; namely, the surfactant Triton-X 100 (TX-100) and bacterial lipopolysaccharide (LPS). Reproducible dissipation versus frequency (Df) plots provide unique signatures of the interactions between endothelial cells and cytomorphic agents. While the QCM-D response for TX-100 can be described in two steps (changes in the osmotic pressure of the medium prior to observing the expected cell lysis), LPS results in a different single-phase signal. A complementary analysis is carried out to evaluate the possible competitive effects of TX-100 and LPS through the QCM-D response to BAEC stress by analyzing the Df plots obtained. Experiments with non-toxic components (fibronectin or serum) produce a different QCM-D response than that observed for the toxic chemicals, suggesting the use of Df plot signatures for the possible differentiation between cytotoxic or non-cytotoxic effects. Observations obtained by QCM-D signals are confirmed by conducting fluorescence microscopy at the same time. Our results show that a fast (few minutes) sensing response can be obtained in situ and in real-time. The conclusions from this study suggest that QCM-D can potentially be used in biodetection for applications in drug screening tests and diagnosis. PMID- 21237635 TI - Manual and manipulative therapy compared to night splint for symptomatic hallux abducto valgus: an exploratory randomised clinical trial. AB - CONTEXT: Hallux abducto valgus (HAV) is a frequent cause of great toe pain and disability, yet common treatments are only supported by mixed or equivocal research findings. Surgery often only provides modest improvement and post surgery complications may significantly hamper outcomes, implying the need for trials testing conservative treatment, such as manual and manipulative therapy, particularly in cases where surgery may be contraindicated or premature. The purpose of this exploratory trial was to test an innovative protocol of manual and manipulative therapy (MMT) and compare it to standard care of a night splint(s) for symptomatic mild to moderate HAV, with a view gather insight into the effectiveness of MMT and inform the design of a definitive trial. DESIGN: Parallel-group randomised trial set in an out-patient teaching clinic. PARTICIPANTS: A convenience sample of 75 patients was assessed for eligibility, with 30 participants (15 per group) being consented and randomly allocated to either the control group (standard care with a night splint) or the experimental group (MMT). INTERVENTION: Participants in the control group used a night splint(s) and those in the experimental group (MMT) received a structured protocol of MMT, with the participants in the experimental group receiving 4 treatments over a 2-week period. OUTCOME MEASURES: Visual analogue scale (HAV related pain), foot function index (HAV-related disability) and hallux dorsiflexion (goniometry). RESULTS: There were no participant dropouts and no data was missing. There were no statistical (p<0.05) or clinically meaningful differences (MCID<20%) between the two groups based on outcome measure scores. However, the outcome measure scores in the control group (night splint) regressed between the 1-week follow-up and 1-month follow-up, while the scores in the experimental group (MMT) were sustained up to the 1-month follow-up. The within group data analysis produced statistically and clinically significant changes from baseline to the 1-week flow-up across all outcome measures. Post hoc power analysis and sample size calculations suggest that the average between group power of this trial was approximately 60% (ES = 0.33) and that a definitive trial would require a minimum of 102 participants per group (N = 204) to achieve satisfactory power of >=80%. CONCLUSIONS: The trend in results of this trial suggest that an innovative structured protocol of manual and manipulative therapy (experimental group) is equivalent to standard care of a night splint(s) (control group) for symptomatic mild to moderate HAV in the short term. The protocol of MMT maintains its treatment effect from 1-week to 1-month follow-up without further treatment, while patients receiving standard care seem to regress when not using the night splint. Insights from this study support further testing of MMT for symptomatic mild to moderate HAV, particularly where surgery is premature or where surgical outcomes may be equivocal, and serve to inform the design of a future definitive trial. PMID- 21237636 TI - Nurse-led telephone follow-up and an educational group programme after breast cancer treatment: results of a 2 * 2 randomised controlled trial. AB - OBJECTIVE: To investigate whether frequent hospital follow-up in the first year after breast cancer treatment might partly be replaced by nurse-led telephone follow-up without deteriorating health-related quality of life (HRQoL), and whether a short educational group programme (EGP) would enhance HRQoL. PATIENTS AND METHODS: A multicentre pragmatic randomised controlled trial (RCT) with a 2*2 factorial design was performed among 320 breast cancer patients who were treated with curative intent. Participants were randomised to follow-up care as usual (3 monthly outpatient clinic visits), nurse-led telephone follow-up, or the former strategies combined with an educational group programme. The primary outcome for both interventions was HRQoL, measured by EORTC QLQ-C30. Secondary outcomes were role and emotional functioning and feelings of control and anxiety. RESULTS: Data of 299 patients were available for evaluation. There was no significant difference in HRQoL between nurse-led telephone and hospital follow-up at 12 months after treatment (p = 0.42; 95% confidence interval (CI) for difference: 1.93-4.64) and neither between follow-up with or without EGP (p = 0.86; 95% CI for difference: -3.59-3.00). Furthermore, no differences between the intervention groups and their corresponding control groups were found in role and emotional functioning, and feelings of control and anxiety (all p-values > 0.05). CONCLUSION: Replacement of most hospital follow-up visits in the first year after breast cancer treatment by nurse-led telephone follow-up does not impede patient outcomes. Hence, nurse-led telephone follow-up seems an appropriate way to reduce clinic visits and represents an accepted alternative strategy. An EGP does not unequivocally affect positive HRQoL outcomes. PMID- 21237637 TI - Differences according to educational level in the management and survival of colorectal cancer in Sweden. AB - Socioeconomic status (SES) affects survival after a cancer diagnosis. The extent to which differences in management can explain this is not known. Record-linkage between two Swedish Regional Clinical Quality Registers of colorectal cancer and a socio-economic database generated a dataset with information on diagnostic procedures, treatment and survival in patients of different educational background. Three thousand eight hundred and ninety-nine rectal cancer patients from the years 1995 to 2006 and 5715 colon cancer patients from 1997 to 2006 were evaluated. Compared to patients with high education, those with shorter education had poorer relative and overall survival (57.9% 5-year relative survival versus 63.8% in colon cancer, 58.7% versus 69.1% in rectal cancer). There were also differences in diagnostic activity with preoperative computer tomography (40% versus 47.3%) and colonoscopy (56.3% versus 62.8%) being more frequent in highly educated groups (p=0.001 and 0.037, respectively). Surgery resulting in colostomy was performed in 26.9% of rectal cancer patients of high education compared to 35.5% of those with low education (p=0.005). Although rectal cancer has poorer prognosis than colon cancer, it was noted that among the highly educated, rectal cancer patients had better survival than colon cancer patients (69.1% versus 63.8% 5-year relative survival). It thus appears that improved rectal cancer management has benefited mainly patients of middle and higher educational levels. We conclude that socioeconomic differences exist in diagnostic activity and management of colorectal cancer, which may affect survival. PMID- 21237638 TI - Primary pancreatic cystic neoplasms revisited. Part I: serous cystic neoplasms. AB - Primary pancreatic cystic neoplasms have been recognized increasingly during the two recent decades and include mainly serous cystic neoplasms, mucinous cystic neoplasms, and intraductal papillary mucinous neoplasms. Serous cystic neoplasms represent about 30% of all cystic neoplasms of the pancreas and are characterized by their microcystic appearance (on imaging, macroscopically, and microscopically) and their benign biologic behavior. Modern diagnostic methodology allows the preoperative diagnosis with an acceptable accuracy. Currently, indications for resection of serous cystic neoplasms of the pancreas include the presence of symptoms, size > 4 cm (because these 'large' neoplasms have a more rapid growth rate and probably will soon become symptomatic), and any uncertainty about the diagnosis of a serous versus a mucinous cystic neoplasm. Resection should also be considered for lesions in the body/tail of the pancreas. Conservative treatment is a reasonable option in selected patients (for example in the presence of small, asymptomatic lesions in the pancreatic head, especially in the frail or elderly patient). PMID- 21237639 TI - Nitrogen removal via nitrite pathway and the related nitrous oxide emission during piggery wastewater treatment. AB - Performance of partial nitrification (PN) via nitrite (NO(2)(-)) pathway and the related nitrous oxide (N(2)O) emission during piggery wastewater treatment was investigated. Dissolved oxygen (DO) concentration and aeration pattern were selected as operational parameters to investigate the possibility of NO(2)(-) accumulation without affecting the overall N removal. To obtain PN, aeration was done for a maximum of 3h with a stopover of oxygenation, whenever DO concentration exceeds the threshold value of 2 mg O(2)L(-1). Ammonium (NH(4)(+)) consumption ended within 2h of reaction, and at the end of NH(4)(+) oxidation, about 70-80% of N was accumulated as NO(2)(-). Using PN, an average N removal of 74-75% was observed, which is comparable to that of complete nitrification denitrification process. Regulating the aeration pattern not only benefit to the N removal in piggery wastewater, but also favoured reduction of oxygen and organic matter requirements for nitrification and denitrification. N(2)O emission was not encouraged even with 70-80% of NO(2)(-) accumulation. PMID- 21237640 TI - Triaryl (Z)-olefins suitable for radiolabeling with iodine-124 or fluorine-18 radionuclides for positron emission tomography imaging of estrogen positive breast tumors. AB - A group of (Z)-1,2-diphenyl-1-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]but-1 enes were synthesized using methodologies that will allow incorporation of a [(124)I]iodine substituent at the para-position of either the C-1 phenyl ring or the C-2 phenyl ring, or a [(18)F]OCH(2)CH(2)F substituent at the para-position of the C-2 phenyl ring. These [(124)I] and [(18)F] radiotracers are designed as potential radiopharmaceuticals to image estrogen positive breast tumors using positron emission tomography (PET). PMID- 21237641 TI - Synthesis and antitubercular evaluation of novel substituted aryl and thiophenyl tethered dihydro-6H-quinolin-5-ones. AB - A series of novel aryl and thiophenyl tethered dihydro-6H-quinolin-5-ones have been synthesized in very good yields through CeCl(3).7H(2)O-NaI catalyzed one-pot condensation of beta-enaminones derived from the respective methyl ketones; 1,3 cyclohexanedione & 5,5-dimethyl-1,3-cyclohexanedione and ammonium acetate refluxing in 2-propanol. Dihydro-6H-quinolin-5-ones 3a-f was further derivatized to the respective hydroxymethyl analogs using proline as an organocatalyst in aqueous media. Among the all 18 compounds screened for in vitro antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv (MTB), dihydro-6H-quinolin-5 ones 4e and 4f were found to be most active with MIC 3.13 MUg/mL. PMID- 21237642 TI - Synthesis and galectin-binding activities of mercaptododecyl glycosides containing a terminal beta-galactosyl group. AB - Mercaptododecyl glycosides containing a terminal beta-galactosyl group were prepared from D-galactose or from D-lactose via hexa-O-acetyl-lactal (10) as a key intermediate. Interactions of these glycolipids (5 kinds) and galectins (beta galactoside binding lectins, 6 species) were evaluated by surface plasmon resonance (SPR) method. High binding responses were observed for the lactoside, 2 deoxy-lactoside, and lactosaminide with some galectins (Gal-3, -4, -8), whereas the galactoside and 2,3-dideoxy-lactoside showed low binding activities. PMID- 21237643 TI - Selective antagonists of mouse trace amine-associated receptor 1 (mTAAR1): discovery of EPPTB (RO5212773). AB - High throughput screening of the Roche compound library identified benzanilides such as 1 and 2 as antagonists of TAAR1. Optimisation of this hit series led to the first selective TAAR1 antagonist (N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3 trifluoromethyl-benzamide EPPTB (RO5212773, 9f) having IC(50) of 28 nM at mouse TAAR1. PMID- 21237644 TI - Design and synthesis of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl cyclopropane carboxamide derivatives as novel melatonin receptor ligands. AB - Two series of 4-arylpiperidinyl amide and N-arylpiperdin-3-yl-cyclopropane carboxamide derivatives exhibiting diverse functionality at rat MT(1) and MT(2) receptors are reported. Compounds 11f and 18b (MT(1)/MT(2) agonist) have human microsomal intrinsic clearance comparable to ramelteon. PMID- 21237645 TI - Breast cancer in lupus. AB - The purpose was to evaluate the frequency of breast cancer (BC) in patients with either systemic (SLE) or incomplete lupus erythematosus (ILE), and possibly to find out immunological differences in patients with and without cancer. 133 consecutive female patients with lupus were included. The records were retrospectively analysed with respect to both malignant disease and routine laboratory parameters (e.g. autoantibodies, white blood cell counts). BC was the most common malignancy that was detected in 50% of female lupus patients with concomitant oncological disease. Other malignancies were significantly less (p < 0.001) frequent. Only ILE-patients had BC or other oncological diseases. The proportion of ILE-patients with SSA- and SSB-autoantibodies was significantly higher (p < 1.5 * 10(-10) and 9.1 * 10(-17)) in those with malignancies than without. The presented data suggest that BC is the most common malignancy in patients with ILE. SLE is no prerequisite to acquire an oncological disease. Immunological disturbances (e.g. SSA- and SSB-autoantibodies) could play a role in the oncogensis. PMID- 21237646 TI - Dual-task costs for whole trunk movement during gait. AB - The control of trunk movement plays an important role in stabilizing the head during gait. However, the effects of performing dual tasks on trunk movements during gait are unclear. We compared the effects of an arithmetic task and the colored Stroop test on trunk movement during gait in 34 healthy older adults. The participants walked 20 m normally, or while performing serial seven subtractions or the colored Stroop test. Trunk accelerations were measured using triaxial accelerometers attached to the lower and upper trunk and used to calculate trunk attenuation rate (TAR) as the reduction in acceleration from the lower to upper trunk. Both dual task conditions affected the TAR in the mediolateral and vertical directions (p<0.01), but not in the anteroposterior direction. In the mediolateral direction, the decrease in TAR was greater during the serial seven subtractions than during the Stroop test (p<0.01). In conclusion, dual task related changes of whole trunk movement during gait, particularly in the mediolateral direction, are dependent on the type of additional task. PMID- 21237647 TI - "DASH" symptoms in patients with Parkinson's disease: red flags for early cognitive decline. AB - Neuropsychiatric features in Parkinson's Disease (PD) are associated with developing dementia longitudinally. Therefore, identifying appropriate screening methods for such features, and their association with early cognitive dysfunction, may help to inform early intervention approaches. In this study, 53 PD patients without dementia underwent detailed neurological and neuropsychological assessment. The sum scores of the four items detailing Depression, Anxiety, Sleep disturbance and Hallucinosis (DASH) were calculated from the Parkinson's Disease Questionnaire (PDQ-39) and examined in relation to cognitive tasks. Results demonstrated that higher DASH scores were significantly correlated with poorer working memory and set-shifting performance, even after controlling for age, predicted intellect, depression, disease stage and duration. These data indicate that DASH symptoms are related to executive dysfunction even in non-demented patients with PD. The DASH score may represent a simple screening method for highlighting early cognitive decline, which in turn is associated with the development of dementia in PD. PMID- 21237648 TI - Validity of the Berlin Questionnaire in identifying obstructive sleep apnea syndrome when administered to the informants of stroke patients. AB - Given the high prevalence of sleep-disordered breathing (SDB) in stroke and its importance as a vascular risk factor, a clinical instrument to assess its incidence would be useful. Acute stroke patients (n=121) were stratified into high- and low-risk groups for SDB using a modified Berlin Questionnaire (BQ) administered to the informants who were living with the patient. After a minimum of 4 weeks from stroke onset, patients who were fit underwent overnight polysomnography (PSG). On stratifying risk of obstructive sleep apnea (OSA) in these patients based on the BQ, 53% belonged to the high-risk group and 47% belonged to the low-risk group. There was poor correlation between the clinical questionnaire results and PSG findings, with sensitivity of 66.7%, specificity of 55.6%, a positive predictive value of 63.4%, and a negative predictive value of 58.8%. PMID- 21237649 TI - Combination of the Williams-Isu method and the transvertebral approach to treat cervical disease. AB - In anterior fusion, we use autologous bone grafts from cervical vertebral bodies (Williams-Isu method; WI-method). To reduce the fusion level, we combine the WI method and the transvertebral approach (TVA). The wide window yielded by the removal of the bone graft from vertebral bodies at the fusion level provides for the safe decompression of neural structures. Further decompression with TVA is performed from the wide window to the adjacent level. After a two-level decompression, anterior fusion at one level is performed by autologous bone grafting. We subjected 20 patients with cervical disease to this approach. All recovered from their symptoms without surgical complications and in all patients we confirmed fusion and the retention of mobility at the TVA level. The wide operative field yielded by the WI-method is an advantage when the procedure is combined with TVA, and this technique is less invasive in patients with multilevel cervical disease. PMID- 21237650 TI - Complete preoperative embolization of hemangioblastoma vessels with Onyx 18. AB - The authors present a preliminary experience with ethyl-enevinylalcohol copolymer (Onyx) for hemangioblastoma vessel embolization before surgical resection. The patient presented with neck pain, dizziness, blurred vision, vomiting, and loss of balance. Diagnostic imaging revealed a posterior fossa cystic mass with a nodular component. Angiography demonstrated a significant vascular blush with arteriovenous shunting that was characteristic of a hemangioblastoma. Tumor vessels originating off the left posterior inferior cerebellar artery were embolized before surgery using Onyx 18 (ev3, Covidien Vascular Therapies, Mansfield, MA, USA). This resulted in complete obliteration of all tumor vessels, transforming a highly vascular tumor into an avascular mass. A safe and uneventful surgical resection was performed the next day. Onyx is a valuable embolic agent for preoperative hemangioblastoma vessel embolization. Because of its low viscosity, Onyx penetrates deeply into the tumor vasculature and allows complete obliteration of tumor vessels. Risks of the intervention have to be carefully weighed against the benefits. If preoperative embolization is indicated, the use of Onyx should be strongly considered. PMID- 21237651 TI - Delayed angiographic changes in postpartum cerebral angiopathy. AB - Postpartum cerebral angiopathy is a well-recognised subgroup of the reversible vasoconstriction syndromes. Increasingly described is a delay between clinical onset and angiographic changes. We report a patient who presented 19 days postpartum with severe thunderclap headaches, vertigo and a seizure. The clinical syndrome preceded evidence of extensive vasoconstriction on MRA imaging by 15 days; the changes were reversible at 3 months. PMID- 21237652 TI - Transvenous embolization of an intraosseous dural arteriovenous fistula of the anterior condylar vein with anomalous venous drainage causing ocular manifestations. AB - We report a patient with a rare dural arteriovenous fistula of the anterior condylar vein, who presented with unusual clinical symptoms due to the anomalous venous drainage. The patient had progressive ocular signs, a dilated venous pouch at the skull base and, on angiography, retrograde venous drainage into the superior ophthalmic vein. Transvenous embolization of the venous pouch produced complete amelioration of the ocular symptoms. Such treatment may be curative for dural arteriovenous fistulas of the anterior condylar vein. PMID- 21237654 TI - Anaphylactic reaction after fluorescein sodium administration during intracranial surgery. AB - We present a male patient who underwent a fluorescein sodium-guided brain tumor excision and experienced an anaphylactic reaction with severe hypotension and bradycardia. A 54-year-old, 70 kg man of American Society of Anesthesiologists status II was seen with a history of glioma. In the 80th minute of the operation, 20 mg/kg intravenous (i.v.) fluorescein sodium was injected after dural opening. A few minutes later, the anaphylactic reaction was diagnosed. Surgery was ended and the patient was delivered to the intensive care unit with intubation. Laboratory values were: immunoglobulin E, 332 U (upper limit 100 U); and elevated tryptase, 3.12 mg/dL. In view of the expanding use of fluorescein sodium in clinical procedures, physicians should be alerted to this rare but life threatening adverse event. PMID- 21237653 TI - Small cell lung cancer metastasis in the pituitary gland presenting with seizures and headache. AB - We report an adult female with a small cell lung cancer (SCLC) pituitary metastasis who presented with seizures and headache. While headache is a common presentation of pituitary metastases, seizures have been very rarely reported. The patient was found on MRI to have a suprasellar tumor with pituitary infundibulum involvement. She underwent endoscopic transsphenoidal resection of the tumor which was shown to be metastatic SCLC. Subsequent imaging revealed widespread systemic metastases. The patient subsequently underwent chemotherapy. PMID- 21237655 TI - An anterior expandable titanium cage in Mycobacterium avium vertebral osteomyelitis. AB - Mycobacterial infection is most commonly caused by Mycobacterium tuberculosis. M. avium and M. intracellulare are two other organisms within the Mycobacteria group often classified together as the mycobacterium avium-intracellulare complex (MAC). MAC is of low virulence and usually causes disease in immunocompromised patients such as those with the human immunodeficiency virus. Isolated vertebral osteomyelitis secondary to MAC infection is rare with only 18 previous reports, only one of which required surgical intervention. There is increasing evidence that vertebral body osteomyelitis with other pathogens can be treated with decompression, debridement and reconstruction with titanium vertebral body cages in the setting of active infection. We present a 70-year-old Caucasian male with a pathological fracture of T6 vertebral body and a kyphosis of 60 degrees and MRI findings consistent with granulomatous osteomyelitis. Vertebrectomies of T5 and T6 were performed and an expandable titanium cage was inserted with supplementary lateral fixation using plate and screws. This is the first report of a single-stage decompression and fusion with a titanium vertebral body cage for active MAC vertebral osteomyelitis. PMID- 21237656 TI - Evaluation of angiographic changes of the anterior choroidal and posterior communicating arteries for predicting cerebrovascular lesions in adult moyamoya disease. AB - To ascertain the relationship between angiographic changes of the anterior choroidal and posterior communicating arteries (AChA-PComA) and cerebrovascular lesions in adult patients with moyamoya disease (MMD), we reviewed cerebral angiograms from 132 adult patients with MMD (68 with ischemia and 64 with hemorrhage). The angiographic findings of the AChA-PComA in each symptomatic hemisphere were graded on a scale of 0 to 3. The data were statistically analyzed for correlation with cerebrovascular lesions. Extension with abnormal branches and excessive dilation of the AChA-PComA accounted for 28 of the hemorrhagic lesions (28/64, 43.8%), especially intraventricular hemorrhage (16/28, 57.1%; p<0.001). Additionally, when the occlusion was proximal to the PComA of the internal carotid artery, the posterior circulation territory was susceptible to ischemic lesions or subarachnoid hemorrhage (SAH) (p<0.001), particularly aneurysmal SAH (p<0.001). The angiographic characteristics of AChA-PComA may predict the onset of certain cerebrovascular lesions in adult patients with MMD. PMID- 21237657 TI - Lumboperitoneal shunt in a patient with Behcet's disease with medically refractory intracranial hypertension. AB - A 21-year-old male presented with severe throbbing headache, nausea, vomiting and progressive visual loss. Clinical examination revealed bilateral papilledema and left abducens nerve palsy. MRI showed findings consistent with dural sinus thrombosis. Combinging the clinical findings, MRI and a positive pathergy test, the patient was diagnosed with dural sinus thrombosis associated with Behcet's disease (BD). Despite acetazolamide, prednisone, azathioprine and repeated lumbar punctures, his signs and symptoms of intracranial hypertension gradually worsened. Therefore, lumboperitoneal shunting was planned after which rapid resolution of intracranial hypertension was observed. After reviewing similar reports, we suggest that lumboperitoneal shunt placement can be an effective treatment for patients with BD with medically refractory intracranial hypertension associated with dural sinus thrombosis. PMID- 21237658 TI - Frontal intraparenchymal schwannoma. AB - Intraparenchymal schwannomas are rare. The usual presentation is of a classical intracranial mass lesion. We report a frontal intraparenchymal schwannoma in a pediatric patient with a history of seizure. An MRI scan revealed a uniformly enhancing tumor with perilesional edema. This type of tumor is rarely found in this location. It is important to recognize and distinguish a schwannoma from other more common frontal brain tumors as the outcome is good and recurrence is rare. PMID- 21237659 TI - Posterior interbody fusion using a diagonal cage with unilateral transpedicular screw fixation for lumbar stenosis. AB - Few reports have described the combined use of unilateral pedicle screw fixation and interbody fusion for lumbar stenosis. We retrospectively reviewed 79 patients with lumbar stenosis. The rationale and effectiveness of unilateral pedicle screw fixation were studied from biomechanical and clinical perspectives, aiming to reduce stiffness of the implant. All patients were operated with posterior interbody fusion using a diagonal cage in combination with unilateral transpedicular screw fixation and had reached the 3-year follow-up interval after operation. The mean operating time was 115 minutes (range=95-150 min) and the mean estimated blood loss was 150 mL (range=100-200 mL). The mean duration of hospital stay was 10 days (range=7-15 days). Clinical outcomes were assessed prior to surgery and reassessed at intervals using Denis' pain and work scales. Fusion status was determined from X-rays and CT scans. At the final follow-up, the clinical results were satisfactory and patients showed significantly improved scores (p<0.01) either on the pain or the work scale. Successful fusion was achieved in all patients. There were no new postoperative radiculopathies, or instances of malpositioned or fractured hardware. Posterior interbody fusion using a diagonal cage with unilateral transpedicular fixation is an effective treatment for decompressive surgery for lumbar stenosis. PMID- 21237660 TI - Space-occupying cyst development in the resection cavity of malignant gliomas following Gliadel(r) implantation--incidence, therapeutic strategies, and outcome. AB - Gliadel(r) (Eisai Inc., Woodcliff Lake, NJ, USA) is the only therapeutic agent approved by the Food and Drug Administration and the European Medicines Agency for local chemotherapy of malignant gliomas. With increasing use of this treatment, characteristic side effects have become evident. While most side effects can be managed conservatively, cyst formation requires further intervention. From 2004 to 2009 at our institution 88 patients with malignant gliomas were treated with Gliadel(r). Ten patients (11%) developed a space occupying cyst in the resection cavity, seven of which caused clinical symptoms of mass effect that was most prominent 2 weeks after Gliadel(r) implantation (median=16, range=9-30). Despite dexamethasone treatment symptoms progressed, necessitating various surgical interventions. In four patients the cysts were drained percutaneously through a burrhole using a 19-gauge needle. If puncture was not possible (three patients) or not sufficient (two patients), an Ommaya reservoir was implanted for repetitive drainage. In two patients this treatment was combined with open decompression of the cyst. On average, cysts were drained three times. Eventually the symptoms subsided, corresponding to shrinkage of the cysts as shown on follow-up imaging. We describe a serious side effect of local chemotherapy, which may cause rapid clinical deterioration and require direct intervention. While reservoir implantation apparently represents a more elegant treatment option, our experience shows that draining the cyst, even only a few times, sufficiently ameliorates the symptoms and subsequently reverses and halts further cyst enlargement. PMID- 21237661 TI - A venous malformation accompanying focal cortical dysplasia resulting in a reorganization of language-eloquent areas. AB - Language functions are likely to become reorganized in patients with a congenital anomaly in the left hemisphere, especially if the lesion affects the classical Broca's or Wernicke's language areas. We describe a patient who presented with a venous malformation accompanying focal cortical dysplasias in the left frontal region. The epileptogenic zone (EZ) was localized in Broca's area, and the motor speech area was identified in the ipsilateral posterior part of the superior temporal gyrus by electrocortical stimulation. We completely resected the EZ in Broca's area. The patient was seizure-free with no post-surgical neurological deficits at last follow-up. The result of this study may help to extend the use of epilepsy surgery within eloquent areas, and also partly explain the plasticity and reshaping of the language processing functional areas associated with a congenital lesion and chronic epilepsy. PMID- 21237662 TI - Discrimination of phosphorylated double stranded DNA by naphthalene diimide having zinc(II) dipicolylamine complexes. AB - Discrimination of phosphomonoesters and phosphodiesters of DNA was attempted with naphthalene diimide carrying two zinc-dipicolylamine (Dpa) units (1). The binding constant of 1 for a self-complementary octanucleotide was 1.3*10(6)M(-1), while the value for the phosphorylated counterpart was 4.8*10(6)M(-1). This fourfold increase in the binding constant seems to stem from higher affinity of the terminal monophosphate over the phosphodiesters of DNA as the fourth ligand for the metal in 1. Likewise, the binding constant of 1 for DNase I-treated calf thymus DNA (average size 200bp) was twice as large as that for untreated DNA (1kb), possibly because the terminal phosphate groups are five times abundant in the former. These findings provide a clue to developing a system where phosphomonoesters generated upon DNA nicking are discriminated specifically from intact phosphodiesters. PMID- 21237663 TI - Identification of curcumin derivatives as human glyoxalase I inhibitors: A combination of biological evaluation, molecular docking, 3D-QSAR and molecular dynamics simulation studies. AB - Several recent developments suggest that the human glyoxalase I (GLO I) is a potential target for anti-tumor drug development. In present study, a series of curcumin derivatives with high inhibitory activity against human GLO I were discovered. Inhibition constant (K(i)) values of compounds 8, 9, 10, 11 and 13 to GLO I are 4.600MUM, 2.600MUM, 3.200MUM, 3.600MUM and 3.600MUM, respectively. To elucidate the structural features of potent inhibitors, docking-based three dimensional structure-activity relationship (3D-QSAR) analyses were performed. Satisfactory agreement between experiment and theory suggests that comparative molecular similarity index analysis (CoMSIA) modeling exhibit much better correlation and predictive power. The cross-validated q(2) value is 0.638 while no-validation r(2) value is 0.930. Integrated with docking-based 3D-QSAR CoMSIA modeling, molecular surface property (electrostatic and steric) mapping and molecular dynamics simulation, a set of receptor-ligand binding models and bio affinity predictive models for rational design of more potent inhibitors of GLO I are established. PMID- 21237664 TI - Synthesis of cross-reactive carbohydrate determinants fragments as tools for in vitro allergy diagnosis. AB - Four biotinylated tri and tetrasaccharide fragments of plant and invertebrate N glycans were synthesized using methyl tert-butyl phenyl (MBP) thioglycosides donors in order to evaluate their involvement in cross-allergies as cross reactive carbohydrate determinants (CCDs). Various levels of reactivity to anti bee and anti-HRP antibodies and with sera from allergic patients were observed when the conjugates were coated on streptavidin microplates. The results showed the potential utility of these xylosylated and fucosylated oligosaccharide fragments in determining CCD antibody epitopes. PMID- 21237665 TI - Recognition of 2'-O-methylated 3'-end of piRNA by the PAZ domain of a Piwi protein. AB - Piwi proteins are germline-specific Argonautes that associate with small RNAs called Piwi-interacting RNAs (piRNAs), and together with these RNAs are implicated in transposon silencing. The PAZ domain of Argonaute proteins recognizes the 3'-end of the RNA, which in the case of piRNAs is invariably modified with a 2'-O-methyl group. Here, we present the solution structure of the PAZ domain from the mouse Piwi protein, MIWI, in complex with an 8-mer piRNA mimic. The methyl group is positioned in a hydrophobic cavity made of conserved amino acids from strand beta7 and helix alpha3, where it is contacted by the side chain of methionine-382. Our structure is similar to that of Ago-PAZ, but subtle differences illustrate how the PAZ domain has evolved to accommodate distinct 3' ends from a variety of RNA substrates. PMID- 21237666 TI - CPB in conscious patients--surely you're joking. PMID- 21237667 TI - Intussusception-like phenomenon in acute type A aortic dissection. PMID- 21237668 TI - Repair of persistent truncus arteriosus without a conduit: sleeve resection of the pulmonary trunk from the aorta and direct right ventricle-pulmonary artery anastomosis. AB - OBJECTIVE: Establishing a new continuity between the right ventricle and the pulmonary artery is the mainstay of repair for persistent truncus arteriosus. We used the Tran Viet-Neveux technique without a Lecomte maneuver to construct the connection without a conduit. Here, we retrospectively review the mid-term surgical results to examine the effectiveness of this approach. METHODS: A cylindrical segment incorporating both pulmonary artery branches was sleeve resected from the truncal artery. The cylindrical segment was cut in the middle and two truncal arterial flaps were combined to form the posterior floor of the new pulmonary arterial trunk. The edge of the floor was attached directly to the superior margin of an oblique incision made in the left-anterior wall of the right ventricle. A polytetrafluoroethylene monocusp was attached to the lower half margin of the right ventricular incision. A large glutaraldehyde-treated pericardial patch was used to form the anterior hood of the new right ventricular outflow tract. Both great arteries were located in a normal spiral configuration. RESULTS: Ten babies (range: 3 days to 9 months of age) underwent this procedure. The Collett-Edwards classification of persistent truncus arteriosus was type I in five cases and type II in five others. There was one hospital death due to severe respiratory distress. During follow-up (36-60 months, median 54 months), only one re-operation was required to enlarge a left branch pulmonary artery stenosis. Follow-up echocardiography showed pulmonary regurgitation (mild two, moderate seven, and severe one) and mild flow acceleration in the left pulmonary artery branch and right ventricle-pulmonary artery connection in one case. CONCLUSION: This simple modification for surgical correction of persistent truncus arteriosus may be an effective alternative that overcomes conduit-related problems. PMID- 21237669 TI - Standard blood flow rates of cardiopulmonary bypass are adequate in awake on-pump cardiac surgery. AB - OBJECTIVE: Standard blood flow rates for cardiopulmonary bypass have been assumed to be the same for awake cardiac surgery with thoracic epidural anesthesia (TEA) as for general anesthesia. However, compared with general anesthesia, awake cardiac surgery with epidural anesthesia may be associated with higher oxygen consumption and may result in lactic acidosis when standard blood flow rates were used. The aim of our study was to investigate if standard blood flow rates are adequate in awake cardiac surgery. METHODS: Forty-five patients undergoing elective on-pump cardiac surgery were assigned to receive either epidural (Group TEA, n=15), combined (Group TEA-GA, n=15) or general (Group GA, n=15) anesthesia. To monitor the adequacy of standard blood flow rates, arterial lactate, acid base parameters, and central venous and jugular bulb saturation were measured at six time points (before, during, and after the surgery) in all groups. Blood flow rates were adjusted when needed. RESULTS: No lactic acidosis has developed in any group (p=NS). TEA as compared with TEA-GA and GA groups had lower central venous (67+/-4%, 75+/-11%, and 72+/-13%, respectively, p<0.05) and jugular bulb oxygen saturations during cardiopulmonary bypass (60+/-7%, 68+/-9%, and 75+/-12%, respectively, p<0.05) during the post-cardiopulmonary bypass period. The TEA group as compared with the TEA-GA and GA groups also had mild hypercapnic respiratory acidosis (56+/-10, 42+/-8, and 37+/-4 mmHg, respectively, p<0.05) and mild decrease of arterial oxygen saturation (93+/-4%, 97+/-2%, and 96+/-1%, respectively, p<0.05) at the end of surgery without any clinical consequences. Thus, no additional blood flow rates adjustments in any study group and no ventilatory support in TEA group were required. CONCLUSIONS: Under careful monitoring, the use of standard blood flow rates is adequate for patients undergoing awake on-pump normothermic cardiac surgery. PMID- 21237670 TI - Low intensity light stimulates nitrite-dependent nitric oxide synthesis but not oxygen consumption by cytochrome c oxidase: Implications for phototherapy. AB - Cytochrome c oxidase (Cco) has been reported to be a receptor for some of the beneficial effects of low intensity visible and near-infrared light on cells and tissues. Here, we have explored the role of low intensity light in affecting a newly described function of Cco, its ability to catalyze nitrite-dependent nitric oxide (NO) synthesis (Cco/NO). Using a new assay for Cco/NO we have found that both yeast and mouse brain mitochondrial Cco produce NO over a wide range of oxygen concentrations and that the rate of NO synthesis increases as the oxygen concentration decreases, becoming optimal under hypoxic conditions. Low intensity broad-spectrum light increases Cco/NO activity in an intensity-dependent fashion but has no effect on oxygen consumption by Cco. By using a series of bandpass filters and light emitting devices (LEDs) we have determined that maximal stimulation of Cco/NO activity is achieved by exposure to light whose central wavelength is 590 +/- 14 nm. This wavelength of light stimulates Cco/NO synthesis at physiological nitrite concentrations. These findings raise the interesting possibility that low intensity light exerts a beneficial effect on cells and tissues by increasing NO synthesis catalyzed by Cco and offer a new explanation for the increase in NO bioavailability experienced by tissue exposed to light. PMID- 21237671 TI - Fluorescent properties of antioxidant cysteine ABZ analogue. AB - The antioxidant properties of aminobenzamide cysteine (ABZ Cys) makes it a molecule that can potentially be used as a drug in oxidative stress related diseases and delivered in the form of a nanoparticles. Here we have studied the photo-physical properties of ABZ Cys, a fluorescent analogue of a popular antioxidant N-acetyl cysteine (NAC). We have compared ABZ Cys steady state and time-resolved fluorescence properties with its parent compounds anthranilic acid and anthranilamide in solution as well as in poly-vinyl alcohol (PVA) polymer films. ABZ Cys did not show any significant shift in absorption after entrapment in PVA film, but there was a shift towards shorter wavelengths in the emission peak compared to the phosphate buffer solution. Fluorescence lifetimes and quantum yields indicated a slight quenching of ABZ Cys fluorescence in comparison to the cysteine-less parent compounds. We also demonstrated that very low concentrations of ABZ Cys, such as 100 nM, are readily detected by a commercial spectrofluorometer. Hence we have established the possible use of ABZ Cys in biomedical applications. PMID- 21237672 TI - A chemically defined production process for highly attenuated poxviruses. AB - Highly attenuated poxviruses are promising vectors for protective and therapeutic vaccines. These vectors do not replicate in human cells and can therefore be safely given even to immunocompromised recipients. They can accommodate very large inserts and provide strong stimulation of the immune system against the vectored antigen. Disadvantages include that very high numbers of infectious units are required per dose for full efficacy. Because they are difficult to produce, improved cellular substrates and processes are urgently needed to facilitate programs intended to reach a large number of vaccinees. We have developed a fully scalable and very efficient chemically-defined production process for modified vaccinia Ankara (MVA), canarypox (CNPV, strain ALVAC) and fowlpox viruses (FPV) based on a continuous cell line. PMID- 21237673 TI - Monitoring hand flexor fatigue in a 24-h motorcycle endurance race. AB - Motorcycle riders must endure high levels of muscle tension for long periods of time, especially in their arms and forearms, when steering and using handlebar controls. Because the right hand operates the gas handle and front brakes, the present research focuses on fatigue in the right hand flexors. Ten adult riders, aged 32.5+/-5.5years, volunteered to participate in this study. During the 24h race each rider, on completion of a relay stage, visited the assessment box to do the following handgrip test sequence: (1) 10s of EMG recording at rest, (2) one 3 s maximal voluntary contraction (MVC), (3) 1min rest interval and (4) 50% MVC maintained during 10s. EMG amplitude (MP: MUV) and median and mean frequency (MF and MPF: Hz) over the superficial finger flexors were recorded during the whole handgrip test sequence with adhesive surface electrodes. MVC values were maintained during the first two relays (50-60min duration in total) and dropped gradually thereafter (p<0.01). During the monitoring of the 50% MVC, mean amplitude increased (p=0.024) while median and mean frequency tended to decrease. These results suggest fatigue is produced in motorcycle riders in a 24h race. However, the expected reduction of EMG frequency was not confirmed given to a potentially large variability. PMID- 21237674 TI - Effects of submaximal fatiguing contractions on the components of dynamic stability control after forward falls. AB - The present study aimed to investigate the effect of lower extremity muscle fatigue on the dynamic stability control of physically active adults during forward falls. Thirteen participants (body mass: 70.2kg, height: 175cm) were instructed to regain balance with a single step after a sudden induced fall from a forward-leaning position before and after the fatigue protocol. The ground reaction forces were collected using four force plates at a sampling rate of 1080Hz. Kinematic data were recorded with 12 vicon cameras operating at 120Hz. Neither the reaction time nor the duration until touchdown showed any differences (p>0.05). The ability of the subjects to prevent falling did not change after the fatigue protocol. In the fatigued condition, the participants demonstrated an increase in knee flexion during the main stance phase and an increased time to decelerate the horizontal CM motion (both p<0.05). Significant (p<0.05) decreases were seen post-fatigue in average horizontal and vertical force and maximum knee and ankle joint moments. The fatigue related decrease in muscle strength did not affect the margin of stability, the boundary of the base of support or the position of the extrapolated centre of mass during the forward induced falls, indicating an appropriate adjustment of the motor commands to compensate the deficit in muscle strength. PMID- 21237675 TI - Increased levels of interleukin-1beta and tumor necrosis factor-alpha in donor lungs rejected for transplantation. AB - BACKGROUND: Cytokine analysis of the donor lung shows significant promise as a strategy to biologically evaluate the organ before transplantation. This study compared gene expression levels of inflammatory cytokines between clinically rejected and transplanted donor lungs. METHODS: Lung tissue biopsy specimens were taken from 17 clinically unsuitable lungs and 24 transplanted donor lungs before cold flush perfusion preservation. Expression levels of interleukin (IL)-6, IL-8, IL-10, interferon-gamma, tumor necrosis factor (TNF)-alpha, and IL-1beta messenger (m)RNA were measured in a blinded fashion by quantitative real-time reverse transcription polymerase chain reaction. Prospectively collected clinical data were analyzed retrospectively and compared with cytokine expression results. The primary end point was to examine the difference of expression levels of these cytokines between rejected donor lungs and lungs used for transplantation. RESULTS: The ratio of partial pressure of oxygen/fraction of inspired oxygen, time on ventilation, infiltrates on chest X-ray images, and abnormal bronchoscopic findings for donors were statistically different between rejected and transplanted donor lungs. Comparison of gene expression levels showed that clinically rejected lungs had significantly higher levels of IL-1beta and TNF alpha than the lungs used for transplantation. Hierarchic clustering with IL 1beta and TNF-alpha showed that 4 clinically unsuitable donor lungs had very low levels of these 2 cytokines. CONCLUSION: Levels of IL-1beta and TNF-alpha are significantly higher in donor lungs rejected for transplantation using clinical criteria. However, a sub-set of non-used lungs had low levels of IL-1beta and TNF alpha and thus could potentially have been used for transplantation. In the near future, these markers could be used to assist in the lung donor selection process and to monitor organ reparative strategies. PMID- 21237676 TI - "That's not a real body": identifying stimulus qualities that modulate synaesthetic experiences of touch. AB - Mirror-touch synaesthesia is a condition where observing touch to another's body induces a subjective tactile sensation on the synaesthetes body. The present study explores which characteristics of the inducing stimulus modulate the synaesthetic touch experience. Fourteen mirror-touch synaesthetes watched videos depicting a touch event while indicating (i) whether the video induced a tactile sensation, (ii) on which side of their body they felt this sensation and (iii) the intensity of the experienced sensation. Results indicate that the synaesthetes experience stronger tactile sensations when observing touch to real bodies, whereas observing touch to dummy bodies, pictures of bodies and disconnected dummy body parts elicited weaker sensations. These results suggest that mirror-touch synaesthesia is not entirely bottom-up driven, but top-down information, such as knowledge about real and dummy body parts, also modulate the intensity of the experience. PMID- 21237677 TI - Quantitative and qualitative characterization of the acute changes in myocardial structure and function after distal coronary microembolization using MDCT. AB - RATIONALE AND OBJECTIVES: To determine the potential of multidetector computed tomography (MDCT) in assessing, at 72 hours, the effects of distal coronary microembolization on myocardial structure and function. MATERIALS AND METHODS: Microembolic material (total volume=16 mm(3) of 40-120 MUm diameter) was selectively delivered in the left anterior descending coronary artery under x-ray fluoroscopy (n = 6 pigs). After 72 hours, 64-slice MDCT was used to assess LV function, perfusion, and viability. For comparison between the measurements at 80 kV, 120 kV, and postmortem we used Bland-Altman and Pearson correlation. Histochemical and histopathological staining was used for quantitative and qualitative characterization of microinfarct. RESULTS: Cine MDCT showed the deleterious effects of microembolization on systolic wall thickening, LV volumes, and ejection fraction. Perfusion parameters, such as max upslope, peak attenuation, and time to peak, differed between microinfarct territory and remote myocardium. Inconsistency in visualizing microinfarct was observed using tube voltages of 80 kV and 120 kV. The extent of heterogeneous microinfarct was 4.5 +/ 1.0 % of LV mass at 80 kV, 6.1 +/- 0.9% LV at 120 kV, and 5.9 +/- 1.1% LV on postmortem. There was significant difference in the extent of microinfarct measured on 80 kV MDCT compared with 120 kV and postmortem. Microscopic examination revealed the random distribution of obstructed microvessels surrounded by myocardial necrosis and inflammatory cells in all animals. CONCLUSION: Both visible and nonvisible microinfarct cause perfusion deficit and LV dysfunction. MDCT is sensitive for quantifying early functional changes in LV caused by microembolization. Further improvement in spatial resolution of this technology is needed to improve visualization of microinfarct. PMID- 21237678 TI - Novel intraarterial therapy for liver cancer using ethylbromopyruvate dissolved in an iodized oil. AB - RATIONALE AND OBJECTIVES: In spite of various therapies developed, hepatocellular carcinoma still shows poor prognosis. In this study, we introduced ethylbromopyruvate (EBrP), a hydrophobic derivative of 3-bromopyruvate, as an agent for intraarterial therapy of hepatocellular carcinoma. MATERIALS AND METHODS: In in vitro study, we evaluated whether EBrP induced apoptotic cell death in Huh-BAT cells. Chemical degradation products of EBrP were identified by performing proton nuclear magnetic resonance spectroscopy and thin layer chromatography. VX2 carcinoma was implanted and grown in the liver of 25 rabbits for in vivo study. By transfemoral intraarterial approach, 0.4 mL of 10 mM and 40 mM EBrP dissolved in an iodized oil (Lipiodol) was infused into the proper hepatic artery in 8 and 10 rabbits, respectively. In the remaining seven rabbits, 0.4 mL of Lipiodol alone was intraarterially injected as a control. One week later, tumor necrosis rate was calculated with histopathologic examination and hepatotoxicity was evaluated with biochemical analysis. RESULTS: EBrP induced apoptosis in human HCC cells via mitochondrial apoptotic signaling cascades. EBrP dissociated into 3-bromopyruvate and ethanol in the aqueous environment. In VX2 liver tumor models, the group of intraarterial delivery of 40 mM EBrP/Lipiodol solution showed higher tumor necrosis rates (96.1% +/- 3.8) than the other groups (38.9% +/- 15.9 of a control, 90.5% +/- 2.9 in 10 mM) (P < .05). There was transient elevation of AST and ALT enzyme levels without any mortality. CONCLUSIONS: Intraarterial infusion of EBrP/Lipiodol solution is a feasible intraarterial therapy for liver tumors with potent antitumor effects and transient hepatotoxicity. PMID- 21237679 TI - The Possibility of differentiation between nonalcoholic steatohepatitis and fatty liver in rabbits on Gd-EOB-DTPA-enhanced open-type MRI scans. AB - RATIONALE AND OBJECTIVES: We used rabbits to investigate the possibility of differentiating between nonalcoholic steatohepatitis (NASH) and fatty liver (FL) on scans acquired by open-type- and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI). MATERIALS AND METHODS: We divided 15 adult rabbits into three equal groups; they received standard (control group), high-fat (FL) content (FL group), or choline deficient chow (NASH group). With the animals under general anesthesia we acquired scans on an open 0.3-Tesla MRI system. Signal intensity (SI) was measured before and after contrast administration and defined as SI-pre and SI post, respectively. Relative SI enhancement (Sr) was calculated using the equation: Sr = (average of three SI-post- minus average of three SI values in no signal fields)/(average of three SI-pre- minus average of three SI values in no signal fields) * 100. Maximum Sr (Srmax), the time (in seconds) required to reach Srmax (Tmax), and the difference between Srmax and Sr at 30 minutes (Sr(30m)R) were analyzed. RESULTS: Srmax was significantly higher in the NASH rabbits than the other two groups (P < .05). CONCLUSIONS: In rabbits, the Srmax value made it possible to differentiate NASH from normal and fatty liver. PMID- 21237680 TI - The role and validity of actigraphy in sleep medicine: an update. AB - Activity-based sleep-wake monitoring or actigraphy has gained a central role as a sleep assessment tool in sleep medicine. It is used for sleep assessment in clinical sleep research, and as a diagnostic tool in sleep medicine. This update indicates that according to most studies, actigraphy has reasonable validity and reliability in normal individuals with relatively good sleep patterns. The validity of actigraphy in special populations or with individuals with poor sleep or with other sleep-related disorders is more questionable. The most problematic validity issue is the low specificity of actigraphy in detecting wakefulness within sleep periods reported with certain devices or samples. Overall, the recent literature adds to previous reports in demonstrating that actigraphy is sensitive in detecting unique sleep patterns associated with specific sleep disorders as well as with other medical or neurobehavioral disorders. Furthermore, actigraphy is sensitive in detecting sleep changes associated with drug treatments and non-pharmacologic interventions. Recent developments include the development of devices specially tailored to detect periodic limb movement in sleep and the introduction of new devices and algorithms. Because of the limitations of actigraphy, it is recommended to use complementary assessment methods (objective and subjective) whenever possible. PMID- 21237681 TI - Chronic supplementation of beta-hydroxy-beta methylbutyrate (HMbeta) increases the activity of the GH/IGF-I axis and induces hyperinsulinemia in rats. AB - OBJECTIVE: Beta-hydroxy-beta-methylbutyrate (HMbeta) is a metabolite of leucine widely used for improving sports performance. Although HMbeta is recognized to promote anabolic or anti-catabolic effects on protein metabolism, the impact of its long-term use on skeletal muscle and/or genes that control the skeletal protein balance is not fully known. This study aimed to investigate whether chronic HMbeta treatment affects the activity of GH/IGF-I axis and skeletal muscle IGF-I and myostatin mRNA expression. DESIGN: Rats were treated with HMbeta (320mg/kg BW) or vehicle, by gavage, for 4 weeks, and killed by decapitation. Blood was collected for evaluation of serum insulin, glucose and IGF-I concentrations. Samples of pituitary, liver, extensor digitorum longus (EDL) and soleus muscles were collected for total RNA or protein extraction to evaluate the expression of pituitary growth hormone (GH) gene (mRNA and protein), hepatic insulin-like growth factor I (IGF-I) mRNA, skeletal muscle IGF-I and myostatin mRNA by Northern blotting/real time-PCR, or Western blotting. RESULTS: Chronic HMbeta treatment increased the content of pituitary GH mRNA and GH, hepatic IGF-I mRNA and serum IGF-I concentration. No changes were detected on skeletal muscle IGF-I and myostatin mRNA expression. However, the HMbeta-treated rats although normoglycemic, exhibited hyperinsulinemia. CONCLUSIONS: The data presented herein extend the body of evidence on the potential role of HMbeta-treatment in stimulating GH/IGF-I axis activity. In spite of this effect, HMbeta supplementation also induces an apparent insulin resistance state which might limit the beneficial aspects of the former results, at least in rats under normal nutritional status and health conditions. PMID- 21237682 TI - The severe short stature in two siblings with a heterozygous IGF1 mutation is not caused by a dominant negative effect of the putative truncated protein. AB - OBJECTIVE: While in previous studies heterozygosity for an Insulin-Like Growth Factor 1 (IGF1) defect only modestly decreased height and head circumference, we recently reported on two siblings with severe short stature with a maternally transmitted heterozygous duplication of 4 nucleotides, resulting in a frame shift and a premature termination codon in the IGF1 gene. In this paper we describe the structural and functional characteristics of the putative truncated IGF-I protein. DESIGN: Two children, their mother and maternal grandfather carried the mutation. In addition, two family members who were not affected were included in the study. Mutant (MT) IGF-I was synthesized in oxidized and reduced form using two methods. Neutral gel filtration studies were carried out with wild-type (WT) and synthetic MT IGF-I. Binding analysis of synthetic MT IGF-I to the IGF1R and insulin receptors were performed with EBNA-293 cells, stably transfected with the IGF-I receptor, and IM9 cells. L6 cells were used to examine the mitogenic potency and the potential antagonizing effect of synthetic MT IGF-I by [(3)H] thymidine incorporation assays. RESULTS: In the sera of both the carriers and non carriers the proportion of (125)I-IGF-I that was associated with the 150 kDa complex was somewhat less (varying between ~37 and ~52%) than in normal pooled serum (~53-~63%) and, instead, slightly increased amounts of radioactivity were eluted in the 40-50 kDa fraction (consisting of binary IGF-IGFBP complexes) or remained unbound. Synthetic MT IGF-I did not bind to the IGF-I receptor, nor antagonize the growth-promoting effect of IGF-I. It did bind to IGFBPs, but was barely incorporated into 150 kDa complexes. Because in all cases WT IGF-I immunoreactivity was recovered in one peak, corresponding to the MW of WT IGF-I, i.e. ~7.6 kDa, an interaction of circulating truncated mutant peptide with WT IGF I is very unlikely. CONCLUSIONS: There is no evidence that the severe short stature associated with heterozygosity for this novel IGF1 mutation in children born from a mother with the same mutation is caused by a dominant negative effect of the truncated protein. We speculate that the growth failure is caused by a combination of partial IGF-I deficiency, placental IGF-I insufficiency, and other genetic factors. PMID- 21237684 TI - Diagnosis and surgical management of a fractured atlas in a cat. AB - A 6-month-old male-castrated domestic shorthair cat was presented shortly after being bitten on the neck by a large breed dog. On presentation the cat was non ambulatory tetraparetic with preserved deep pain perception. Plain radiographs of the neck did not show any abnormalities. Computed tomography was performed and showed a right-sided depressed fracture of the dorsal lamina of the atlas. A partial dorsal laminectomy was performed to alleviate the spinal cord compression. The cat made a full recovery within 12 weeks of surgery. PMID- 21237683 TI - Identification and characterization of new long chain acyl-CoA dehydrogenases. AB - Long-chain fatty acids are an important source of energy in muscle and heart where the acyl-CoA dehydrogenases (ACADs) participate in consecutive cycles of beta-oxidation to generate acetyl-CoA and reducing equivalents for generating energy. However, the role of long-chain fatty acid oxidation in the brain and other tissues that do not rely on fat for energy is poorly understood. Here we characterize two new ACADs, ACAD10 and ACAD11, both with significant expression in human brain. ACAD11 utilizes substrates with primary carbon chain lengths between 20 and 26, with optimal activity towards C22CoA. The combination of ACAD11 with the newly characterized ACAD9 accommodates the full spectrum of long chain fatty acid substrates presented to mitochondrial beta-oxidation in human cerebellum. ACAD10 has significant activity towards the branched-chain substrates R and S, 2 methyl-C15-CoA and is highly expressed in fetal but not adult brain. This pattern of expression is similar to that of LCAD, another ACAD previously shown to be involved in long branched chain fatty acid metabolism. Interestingly, the ACADs in human cerebellum were found to have restricted cellular distribution. ACAD9 was most highly expressed in the granular layer, ACAD11 in the white matter, and MCAD in the molecular layer and axons of specific neurons. This compartmentalization of ACADs in the human central nerve system suggests that beta-oxidation in cerebellum participates in different functions other than generating energy, for example, the synthesis and/or degradation of unique cellular lipids and catabolism of aromatic amino acids, compounds that are vital to neuronal function. PMID- 21237685 TI - [Impact of nursing care on the incidence of invasive mechanical ventilation associated pneumonia]. AB - INTRODUCTION: Training health care professionals on preventive measures of ventilator-associated pneumonia (VAP) reduces the incidence of this serious adverse effect. OBJECTIVES: To evaluate the effectiveness of the non pharmacological, VAP preventive program by comparing the incidence of VAP in two periods: pre- and post- training of the nursing staff of the intensive care unit (ICU). MATERIAL AND METHODS: A comparative, observational study on the incidence of VAP and related-risk factors. Two prevalence cutoffs were used: prior to training (from October 2007 to June 2008) and post-training (from October 2008 to April 2009). The statistical analysis was performed with the SPSS v.15 statistical program, t-test or Mann-Whitney test for continuous variables and Chi square or Fisher test for qualitative variables. RESULTS: A total of 69 patients were included in the pre-training period and 71 in the post-training. Age and gender percentages were similar in both groups. There was a greater number of risk factor for VAP in the pre-training period that was statistically significant only in the case of diabetes (27.5% versus 8.4%; P=.004). There were no differences regarding the treatment administered to both groups or number of days in ICU or mechanical ventilation (MV) days. Decreased rate of 6.01 to 1.91 VAP/1.000 ventilator days in the post-training period. CONCLUSIONS: Preventive measures reduced the incidence of VAP in two samples of patients comparable in terms of risk factors. Nursing education is directly related to the results in patient safety. PMID- 21237686 TI - Treatment of endocarditis due to Proteus species: a literature review. AB - Endocarditis due to Proteus species is very rare. We report a case of endocarditis due to Proteus mirabilis that was successfully treated with ampicillin and gentamicin, and review the treatment regimens of previously published cases of Proteus endocarditis. PMID- 21237687 TI - [Evaluation of continuous education in transfusion for professionals in medical blood banks]. AB - PURPOSE OF THE STUDY: Like every actor in transfusion, staff members practising within blood banks of healthcare establishments have to follow a specific initial training and must frequently update their knowledge in blood transfusion. METHODS: To address this need from these professionals, the Etablissement francais du sang Auvergne-Loire set up training sessions which content regularly evolved according to regulation recommendations. Every cycle consists in a total of 35hours of training, divided in five one-day modules. The comparison of the evaluation questionnaires offered at the beginning and at the end of each day allowed to measure the benefits provided by every module and to compare progress according to the number of modules previously followed. The analysis of satisfaction surveys contributed to improving the education towards a high level of satisfaction of every participant. RESULTS CONCLUSION: At the end of its third year of existence, the 35hours education programme permitted to achieve a better level of training for all the staffs and the evolution towards an on-site continuing education format seems to better correspond to the personnel's expectations. PMID- 21237688 TI - [New perspectives for radiosensitization in hepatocellular carcinoma: a review of mechanisms involved in liver oncogenesis]. AB - New perspectives for radiosensitization in hepatocellular carcinoma (HCC) have emerged with the increasing knowledge of mechanisms involved in liver oncogenesis. As a matter of fact, some of these mechanisms have also a role in the response to ionizing radiation. We review some of the major molecular pathways involved in the oncogenesis of hepatocellular carcinoma. These include cellular proliferation pathways, repair systems, apoptosis, and angiogenesis. However, there are few preclinical data on concurrent targeted therapies and ionizing radiation in hepatocellular carcinoma models. Preliminary studies are ongoing. Their results might help to better define the potential benefit of such radiosensitizing strategies in the management of hepatocellular carcinoma. PMID- 21237689 TI - [Radiosensitivity of hepatocellular carcinoma]. AB - The frequency of hepatocellular carcinoma (HCC) is increasing in the western world and the role of radiotherapy is more and more discussed. Classically, hepatocellular carcinoma was considered as a radioresistant tumour: in fact, modern radiobiologic studies, performed on cell lines directly established from patients, showed that hepatocellular carcinoma has the same radiosensitivity than the other epithelial tumours. From clinical studies, its alpha/beta ratio has been estimated to be around 15 Gy. Radiosensitivity of normal hepatic parenchyma is now well evaluated and some accurate NTCP models are available to guide hepatic irradiation. The biology of hepatocellular carcinoma is also better described: the combination of radiotherapy and targeted therapies will be a promising approach in the near future. PMID- 21237690 TI - [Transarterial chemoembolization and conformal radiotherapy for hepatocellular carcinoma]. AB - Hepatocellular carcinoma is a poor prognosis tumour. The potential curative therapeutic options are orthotopic liver transplantation, surgical resection and radiofrequency ablation. Unfortunately, only a minority of patients (around 20%) are eligible for these techniques. Thus, patients can benefit from palliative options, such as transarterial chemoembolization (TACE) or sorafenib that bring only modest benefit on survival. Conformal radiotherapy allows delivering high dose radiation within a precise tumour volume while sparing the surrounding liver parenchyma. As employed in monotherapy, conformal radiotherapy is highly efficient for small size hepatocellular carcinoma (<5 cm). Above 5 cm, its efficacy is more limited but its association with TACE gives spectacular rates of complete responses. Controlled phase 2 or 3 trials are urgently warranted to define its indications in the therapeutic algorithm of hepatocellular carcinoma. PMID- 21237691 TI - [External radiotherapy for hepatocellular carcinoma]. AB - For a long time radiotherapy has been excluded from the therapeutic strategy for hepatocellular carcinoma, given its significant toxicity on the non-tumoral liver parenchyma. Conformal radiation is a recent advance in the field of radiotherapy, allowing dose escalation and combination with other therapeutic options for hepatocellular carcinoma, including trans-arterial chemo-embolization. Conformal radiotherapy is associated with interesting features, especially in cirrhotic patients: wide availability, non-invasiveness, possibility to target multiple localizations anywhere within the liver parenchyma, and favorable tolerance profile even in patients with cirrhosis and/or in a poor medical condition. Recently, radiation delivery has been optimized through several technical developments: respiratory gating and intensity-modulated radiotherapy, which allow a better focalization of the ballistics, stereotactic techniques and proton beam radiotherapy, whose availability is currently limited in Europe. Given the high response rates of hepatocellular carcinoma to radiation, conformal radiotherapy may be regarded as a curative-intent treatment for hepatocellular carcinoma, similar to surgery and per-cutaneous techniques. Yet the impact of radiotherapy has to be evaluated in randomized trials to better integrate in the complex therapeutic algorithm of hepatocellular carcinoma. PMID- 21237692 TI - [Medical therapies for hepatocellular carcinoma]. AB - Medical therapies for hepatocellular carcinoma are limited. Standard antimitotic chemotherapies and hormonotherapies are inefficient. Only sorafenib, an antiangiogenic agent inhibiting the VEGF and PDGF receptors as well as MAP kinase pathway, has shown a significant benefit on patient survival. However, its indication is restricted to patients with multifocal hepatocellular carcinoma not responding to transarterial hepatic chemoembolization or patients with hepatocellular carcinoma invading the venous portal tract or spreading to lymph nodes or as distant visceral metastasis. PMID- 21237693 TI - [High dose rate vaginal brachytherapy in endometrial cancer after surgery]. AB - PURPOSE: This study aimed at analyzing the evolution and type of recurrence in patients treated for stage I endometrial carcinomas, in order to define the respective roles of adjuvant radiotherapy and brachytherapy. PATIENTS AND METHODS: This monocentric retrospective study was conducted at Centre Alexis Vautrin, Nancy, France, between January 1995 and December 2000 on all the patients surgically treated for an endometrial cancer, and then treated with high dose rate vaginal brachytherapy. The brachytherapy was delivered in two or three fractions of 7 Gy at 5 mm from the applicator. RESULTS: In the good prognosis group, the specific and overall survivals at 5 years were respectively 96.5 and 94.2% with no local recurrence demonstrated. In the intermediate prognostic group, the specific and overall survivals at 5 years were respectively 88 and 85%, with six locoregional recurrences observed among those who did not undergo lymphadenectomy; the overall survival at 5 years was significantly decreased in the absence of external radiation. In the group of poor prognosis (stages II and III), the specific survival at 5 years was respectively 72.8 and 67 %, and the overall survival at 5 years 66.7 and 56.4%. CONCLUSION: Results for local control and survival as well as for tolerance were good. So we have decided to deliver high rate brachytherapy for all intermediate or poor prognosis patients and we have abandoned pelvic radiotherapy for good prognosis tumours (stages IA: no myometrium invasion with grade 3 and >50% of myometrium invasion with grades 1 and 2), whatever the lymph nodes surgery they had. We now propose pelvic radiotherapy only for intermediate prognosis tumours (such as IA>50% of myometrium invasion with grade 3 and IB stages), if patients did not have any lymphatic surgery, or for bad prognosis tumours. PMID- 21237694 TI - [Can or must the patient participate to risk management in radiotherapy?]. AB - PURPOSE: The present study aimed at analyzing if patient participation constitutes a promising way of improvement of patient safety, or not. The hypothesis is that patient participation is a means to develop a safety culture based on the cooperation between patients and healthcare providers, to improve patients' satisfaction and to reduce the costs associated to adverse events. PATIENTS AND METHODS: A half-day session was organized on this theme during a training of radiotherapy professionals on risk management. Professionals were first distributed in three subgroups according to their specialty (radiation oncologists, radiation physicists and medical technicians), and had to work on four main questions relating to participation, among which the collection of real situations in which patients effectively contributed (positively or negatively) to patient safety. Results were then collectively discussed. RESULTS: Patient participation allows not only to detect and recover some mistakes or errors made by the professionals (error of identity), but also to decrease patients' risk behaviors (purposely taking the place of another patient in order to be treated faster). However, it must be seen as a possibility offered to patients, and not as an obligation. CONCLUSION: Patient participation to patient safety is a field of study, which requires to be developed in order to define the conditions enhancing such participation and to implement a set of actions to improve healthcare safety by a cooperative management of this one. PMID- 21237695 TI - [4D-CT scan and radiotherapy for hepatocellular carcinoma: role in the definition of internal target volume (ITV)]. AB - PURPOSE: To evaluate the role of 4D-CT scan and the breath-related margins in the definition of internal target volume (ITV) during radiotherapy for hepatocellular carcinoma. PATIENTS AND METHODS: All patients treated for hepatocellular carcinoma that underwent a 4D-CT simulation scan were retrospectively analysed in order to assess breath-related movements of GTV in the 3-D directions. After a standard CT-scan simulation performed to contour GTV and organs at risk (OARs), a 4D-scan simulation was then realized in order to contour ITV. Margins to be added for every patient to pass from GTV to ITV were calculated and evaluated also regarding liver lobe and GTV size (< or>5 cm). RESULTS: Twenty-seven hepatocellular carcinoma patients were evaluated (total: 28 lesions). Median tumor movements in the craniocaudal, lateral and anteroposterior direction were 8.6mm (range: 0-72.9 mm), 6.5mm (range: 1-68.1mm) and 9.1mm (range: 1-34 mm), respectively. ITV had a median volume increase of 94% (range: 8-403%). CONCLUSION: Tumour breath-related displacements are significant. 4D-CT simulation scan allows to precisely define these displacements and to tailor the treatment. A precise evaluation of breath-related effects on GTV is essential, particularly with new conformal radiotherapy techniques as intensity modulated radiotherapy (IMRT) and/or stereotactic body radiotherapy. PMID- 21237696 TI - Y-STR profiling in two Afghanistan populations. AB - Afghanistan's unique geostrategic position in Eurasia has historically attracted commerce, conflict and conquest to the region. It was also an important stop along the Silk Road, connecting the far eastern civilizations with the western world. Nevertheless, limited genetic studies have been performed in Afghan populations. In this study, 17 Y-chromosomal short tandem repeat (Y-STR) loci were typed to evaluate their forensic and population genetic applications in 189 unrelated Afghan males geographically partitioned along the Hindu Kush Mountain range into north (N=44) and south (N=145) populations. North Afghanistan (0.9734, 0.9905) exhibits higher haplotype diversity than south Afghanistan (0.9408, 0.9813) at both the minimal 9-loci and 17-loci Yfiler haplotypes, respectively. The overall haplotype diversity for both Afghan populations at 17 Y-STR loci is 0.9850 and the corresponding value for the minimal 9-loci haplotypes is 0.9487. A query using of the most frequent Afghan Yfiler haplotype (7.98%) against the worldwide Y-STR haplotype reference database (YHRD) returned no profile match, indicating a high power of discrimination with 17 Y-STR loci. A median-joining network based on 15 Y-STR loci displays limited haplotype sharing between the two Afghan populations, possibly due to the Hindu Kush Mountain range serving as a natural barrier to gene flow between the two regions. PMID- 21237697 TI - School site and the potential to walk to school: the impact of street connectivity and traffic exposure in school neighborhoods. AB - The impact of neighborhood walkability (based on street connectivity and traffic exposure) within 2 km of public primary schools on children regularly walking to school was examined. The most (n=13) and least walkable (n=12) schools were selected using a school-specific 'walkability' index and a cross sectional study undertaken of Year 5, 6 and 7 children (n=1480) and consenting parents (n=1332). After adjustment, regularly walking to school was higher in children attending schools in high walkable neighborhoods (i.e, high street connectivity and low traffic volume) (Odds ratio (OR) 3.63; 95% Confidence Interval (CI) 2.01-6.56), and less likely in neighborhoods with high connectivity but high traffic volume (OR 0.32; 95% CI 0.22-0.47). Connected street networks provide direct routes to school but when designed for heavy traffic, the potential for children to walk to school is reduced. This highlights the importance of carefully considering school siting and, particularly, street design in school neighborhoods. PMID- 21237698 TI - FTIR studies of plasticized poly(vinyl alcohol)-chitosan blend doped with NH4NO3 polymer electrolyte membrane. AB - Fourier transform infrared (FTIR) spectroscopy studies of poly(vinyl alcohol) (PVA), and chitosan polymer blend doped with ammonium nitrate (NH(4)NO(3)) salt and plasticized with ethylene carbonate (EC) have been performed with emphasis on the shift of the carboxamide, amine and hydroxyl bands. 1% acetic acid solution was used as the solvent. It is observed from the chitosan film spectrum that evidence of polymer-solvent interaction can be observed from the shifting of the carboxamide band at 1660 cm(-1) and the amine band at 1591 cm(-1) to 1650 and 1557 cm(-1) respectively and the shift of the hydroxyl band from 3377 to 3354 cm( 1). The hydroxyl band in the spectrum of PVA powder is observed at 3354 cm(-1) and is observed at 3343 cm(-1) in the spectrum of the PVA film. On addition of NH(4)NO(3) up to 30 wt.%, the carboxamide, amine and hydroxyl bands shifted from 1650, 1557 and 3354 cm(-1) to 1642, 1541 and 3348 cm(-1) indicating that the chitosan has complexed with the salt. In the PVA-NH(4)NO(3) spectrum, the hydroxyl band has shifted from 3343 to 3272 cm(-1) on addition of salt from 10 to 30 wt.%. EC acts as a plasticizing agent since there is no shift in the bands as observed in the spectrum of PVA-chitosan-EC films. The mechanism of ion migration is proposed for the plasticized and unplasticized PVA-chitosan-NH(4)NO(3) systems. In the spectrum of PVA-chitosan-NH(4)NO(3)-EC complex, the doublet CO stretching in EC is observed in the vicinity 1800 and 1700. This indicates that there is some interaction between the salt and EC. PMID- 21237699 TI - Evaluation of a spectral searching algorithm for the comparison of Raman band positions. AB - Raman spectroscopic identification of unknown materials involves often the comparison of the spectrum of the unknown spectrum with previously recorded reference spectra or data from literature. However, when spectra with many Raman bands or spectra of mixtures are involved, searching can be quite complex. Different chemometrical approaches have been proposed, but these have some drawbacks. Therefore, in this paper a novel approach is proposed, which is based on a multivariate comparison of Raman band positions. Different similarity measures can be used and are evaluated with spectra of test samples that were recorded on different spectrometers, using different laser wavelengths. Moreover, this study evaluates the performances of this algorithm for identifying different compounds in mixtures, by using an iterative approach. PMID- 21237700 TI - Vibrational spectroscopy [FTIR and FTRaman] investigation, computed vibrational frequency analysis and IR intensity and Raman activity peak resemblance analysis on 4-chloro 2-methylaniline using HF and DFT [LSDA, B3LYP and B3PW91] calculations. AB - In the present study, the FT-IR and FT-Raman spectra of 4-chloro-2-methylaniline (4CH2MA) have been recorded in the range of 4000-100 cm(-1). The fundamental modes of vibrational frequencies of 4CH2MA are assigned. All the geometrical parameters have been calculated by HF and DFT (LSDA, B3LYP and B3PW91) methods with 6-31G (d, p) and 6-311G (d, p) basis sets. Optimized geometries of the molecule have been interpreted and compared with the reported experimental values for aniline and some substituted aniline. The harmonic and anharmonic vibrational wavenumbers, IR intensities and Raman activities are calculated at the same theory levels used in geometry optimization. The calculated frequencies are scaled and compared with experimental values. The scaled vibrational frequencies at LSDA/B3LYP/6-311G (d, p) seem to coincide with the experimentally observed values with acceptable deviations. The impact of substitutions on the benzene structure is investigated. The molecular interactions between the substitutions (Cl, CH(3) and NH(2)) are also analyzed. PMID- 21237701 TI - IR and Raman studies of oil and seedcake extracts from natural and genetically modified flax seeds. AB - Flax plant of the third generation (F3) overexpressing key genes of flavonoid pathway cultivated in field in 2008 season was used as the plant material throughout this study. The biochemical properties of seed, oil and seedcake extracts from natural and transgenic flax plants were compared. Overproduction of flavonoids (kaempferol), phenolic acids (coumaric, ferulic/synapic) and lignan secoisolariciresinol diglucoside (SDG) in oil and extracts from transgenic seeds has been revealed providing a valuable source of these compounds for biotechnological application. The changes in fatty acids composition and increase in their stability against oxidation along three plant generations were also detected. The analysis of oil and seedcake extracts was performed using Raman and IR spectroscopy. The wavenumbers and integral intensities of Raman and IR bands were used to identify the components of phenylpropanoid pathway in oil and seedcake extracts from control and transgenic flax seeds. The spectroscopic data were compared to those obtained from biochemical analysis. PMID- 21237702 TI - The detection of biomarkers in evaporite matrices using a portable Raman instrument under Alpine conditions. AB - The detection of relatively low concentrations of the biomarkers in experimentally prepared evaporitic matrices using a portable Raman instrument (Ahura First Defender XL equipped with a 785 nm diode laser and fixed frontal probe) under Alpine conditions was tested. The instrument was able to detect nucleobases thymine (1673 and 984 cm(-1)) and adenine (722 and 536 cm(-1)) at concentrations of 1 wt% in the gypsum matrix outdoors at a low ambient temperature of -10 degrees C and at an altitude of 2860 m(Pitztal, Austria). Amino acids glycine (1324 and 892 cm(-1)) and alanine (1357 and 851 cm(-1)) were unambiguously detected at 10 wt%. The main Raman features: strong, medium and partially weak intensity bands were observed in good agreement with the reference spectra for individual compounds (with a spectral resolution 7-10 cm(-1)) in the wavenumber range 200-1800 cm(-1). In the qualitative part of the experiment it was established that the portable instrument is able to detect the components in the mixture of three biomarkers (glycine, alanine and mellitic acid) and two evaporitic minerals unambiguously. It also detected the majority of the six similar amino acids in the mixture with gypsum and epsomite evaporitic minerals. The results obtained here demonstrate the possibility of a miniaturised Raman spectrometer to be able to cope with the various exobiologically related tasks that can be expected in the future planetary surface exploration missions. Within the payload designed by ESA and NASA for future missions, Raman spectroscopy will represent a unique research instrument. PMID- 21237703 TI - A novel use of oxidative coupling reactions for determination of some statins (cholesterol-lowering drugs) in pharmaceutical formulations. AB - New, accurate and reliable spectrophotometric methods for the assay of three statin drugs, atorvastatin calcium (AVS), fluvastatin sodium (FVS) and pravastatin sodium (PVS) in pure form and pharmaceutical formulations have been described. All methods involve the oxidative coupling reaction of AVS, FVS and PVS with 3-methyl-2-benzothiazolinone hydrazone hydrochloride monohydrate (MBTH) in the presence of Ce(IV) in an acidic medium to form colored products with lambda(max) at 566, 615 and 664 nm, respectively. Beer's law was obeyed in the ranges of 2.0-20.0, 4.9-35.4 and 7.0-30.0 MUg mL(-1) for AVS-MBTH, FVS-MBTH and PVS-MBTH, respectively. Molar absorptivities for the above three methods were found to be 3.24*10(4), 1.05*10(4) and 0.68*10(4) L mol(-1) cm(-1), respectively. Statistical treatment of the experimental results indicates that the methods are precise and accurate. The proposed methods have been applied to the determination of the components in commercial forms with no interference from the excipients. A comparative study between the suggested procedures and the official methods for these compounds in the commercial forms showed no significant difference between the two methods. PMID- 21237704 TI - Soleus H-reflex phase-dependent modulation is preserved during stepping within a robotic exoskeleton. AB - OBJECTIVE: To investigate to what extent the phase-dependent modulation of the soleus H-reflex is preserved when bilateral leg movements are electromechanically driven by a robotic exoskeleton at different levels of body weight support (BWS) in healthy subjects. METHODS: The soleus H-reflex was elicited by posterior tibial nerve stimulation with a 1-ms single pulse at an intensity that the M waves ranged from 4% to 9% of the maximal M-wave across subjects. Stimuli were randomly dispersed across the step cycle which was divided into 16 equal bins. At each bin, a maximal M-wave was elicited 100 ms after the test H-reflex and was used to normalize the associated M-wave and H-reflex. Electromyographic (EMG) activity from major hip, knee, and ankle muscles was recorded with surface bipolar electrodes. For each subject and muscle, the integrated EMG profile was established and plotted as a function of the step cycle phases. The H-reflex gain was determined as the slope of the relationship between the H-reflex and soleus EMG amplitudes at 100 ms before the H-reflex for each bin. RESULTS: During robotic assisted stepping, the phase-dependent soleus H-reflex modulation pattern was preserved and was similar at 25% and 50% BWS, a linear relationship between soleus H-reflex amplitude and background activity was found, and the reflex gain did not change with alterations of the BWS level. EMG amplitudes were smaller at 50% compared to 25% BWS. CONCLUSIONS: Body unloading, decreased EMG amplitude of ankle extensors, and reduced ankle movement are not key factors for the soleus H reflex phasic excitability to be manifested. SIGNIFICANCE: Robotic devices are utilized for rehabilitation of gait in neurological disorders. Based on our findings, spinal interneuronal circuits involved in the phase-dependent modulation of the soleus H-reflex will be engaged in a physiological manner during robotic assisted stepping in neurological disorders. PMID- 21237705 TI - Saccharomyces cerevisiae protein phosphatase Ppz1 and protein kinases Sat4 and Hal5 are involved in the control of subcellular localization of Gln3 by likely regulating its phosphorylation state. AB - A Saccharomyces cerevisiae mutant lacking PPZ1, encoding a serine/threonine protein phosphatase (PPase), is caffeine-sensitive. To clarify the function of Ppz1 in resistance to caffeine, we attempted systematically to identify protein kinase (PKase) whose disruption lead to suppression of caffeine sensitive phenotype of the ?ppz1 disruptant since disruption of PPZ1 might cause caffeine sensitivity by increasing its phosphorylated substrates and we presumed that disruption of genes for PKase sharing the substrate with Ppz1 could restore the resistance through bypassing necessity for dephosphorylation of substrates. Among the 102 viable pkase disruptions, disruption of either SAT4 or HAL5 suppressed the caffeine sensitivity phenotype and increased expression of ENA1, encoding a P type ATPase of the ?ppz1 disruptant. Because increased expression of ENA1 in the ?ppz1 disruptant was found to be suppressed by disruption of GLN3, localization and phosphorylation of Gln3 in the ?ppz1 disruptant was compared to that in the ?ppz1?sat4 and ?ppz1?hal5 double disruptants. Gln3 was found to accumulate in the nucleus in the ?ppz1 disruptant, and this nuclear localization was abolished by disruption of either SAT4 or HAL5. Interestingly, the level of Gln3 phosphorylation in the ?ppz1?sat4 and ?ppz1?hal5 disruptants decreased relative to wild type independent of caffeine. From these observations, we conclude that Ppz1 controls Gln3 localization by regulating its phosphorylation state in combination with Sat4 and Hal5. PMID- 21237706 TI - Behavioral sleep disturbances in children clinically referred for evaluation of obstructive sleep apnea. AB - OBJECTIVE/BACKGROUND: Obstructive sleep apnea (OSA) and behavioral sleep disturbances (BSD) are known to have a negative health impact on children. OSA and BSD may coexist; however, such comorbidity is not fully appreciated in clinical settings. METHODS: Patients referred for OSA evaluation completed polysomnography and the Children's Sleep Habits Questionnaire. Prevalence estimates for clinically significant BSD were computed and comorbidity of BSD and OSA was examined. Chart reviews were completed to determine if BSD were addressed in the medical treatment plan. RESULTS: Over one-half of the sample had a clinically significant BSD. Patients with comorbid OSA and BSD represented 39.46% of the sample. In 36-54% of the patients with a clinically significant BSD, no plan to treat the BSD was documented in the patient's medical record. CONCLUSIONS: Children referred for evaluation of OSA have a high likelihood of experiencing clinically significant BSD irrespective of OSA diagnosis. Sleep medicine clinicians should be careful not to overlook the potential impact of BSD even after a child has been formally diagnosed with OSA. Physician knowledge of empirically supported behavioral sleep treatments or access to behavioral sleep medicine services is an essential component of comprehensive care for children clinically referred for OSA evaluation. PMID- 21237707 TI - Intermittent exercise alters the heart rate-blood lactate relationship used for calculating the training impulse (TRIMP) in team sport players. AB - OBJECTIVES: The training impulse (TRIMP) quantifies training dose by weighting heart rate according to the relationship between fractional elevation in heart rate (DeltaHR) and blood lactate concentration (BLa). This study compared the physiological responses to intermittent and continuous exercise and their influence on TRIMP weightings. DESIGN: Repeated measures crossover. METHOD: Twelve team sport players undertook a vVO2max test and then a continuous trial (CT) and intermittent trial (IT) in a randomised order. Each trial consisted of 4*4 min stages corresponding to 25%, 50%, 75% and 100% of vVO2max. Trials were matched for distance and mean speed. RESULTS: A repeated measures ANOVA revealed higher BLa for IT at 75% vVO2max (p=0.023) and 100% vVO2max (p=0.012); higher VO(2) for IT at 25% vVO(2max) (p<0.001); higher DeltaHR for IT at 25% vVO2max (p<0.001), 75% vVO2max (p=0.03) and 100% vVO2max (p=0.018); higher TRIMP weightings for IT at 0.9 DeltaHR (p=0.018) and 1.0 DeltaHR (p=0.005). CONCLUSIONS: Intermittent exercise alters the DeltaHR-BLa relationship and TRIMP weightings at high exercise intensities. Determination of the training impulse from the DeltaHR-BLa relationship derived from a continuous exercise protocol may underestimate the exercise 'dose' of training and/or matches in team sport players. PMID- 21237708 TI - Effects of soft and semi-rigid ankle orthoses on postural sway in people with and without functional ankle instability. AB - Some studies have demonstrated improvement of postural control following use of ankle supports, whereas others reported no effect or even negative effects of bracing. The present study aimed to investigate the immediate effects of soft and semi-rigid orthosis on postural sway in patients with functional ankle instability (FAI). Twenty patients with unilateral FAI and twenty matched healthy individuals participated in the study. Balance in single limb stance on force platform with eyes-open was assessed for both legs while wearing no orthosis (control condition), soft or semi-rigid orthosis. The center of pressure (COP) measures derived from force platform signals were mean total velocity, standard deviation (SD) of velocity and phase plane portrait. A 2 * 2 * 3 (group by foot by orthotics) mixed model analysis of variance was used for statistical analysis. In the FAI group, there was a tendency to lower COP parameters while wearing either of the orthoses, with soft brace having a greater effect. For 2 dependent variables, significant effect of brace was found only for the injured limb. In the healthy group, postural sway increased from no-brace condition, to soft, to semi-rigid orthosis. Both injured and non-injured limbs of patients with FAI had greater postural sway compared to control limbs of healthy individuals. PMID- 21237709 TI - Breathlessness in cancer patients - implications, management and challenges. AB - PURPOSE OF THE REVIEW: Breathlessness in patients with advanced cancer is common. It remains a difficult symptom to improve despite recent advances in cancer treatment and the increasing evidence available. Patients and carers experience a high level of distress from this frightening symptom. There is a greater volume of evidence to guide the management of breathlessness accompanying advanced non malignant disease, as opposed to malignant disease, as most research has been conducted in this group. This article reviews the management of breathlessness in patients with cancer. METHODS: A systematic review of the literature in this area was completed. The results of the research work carried out by co-authors were also reviewed. The following databases were searched: MEDLINE, CINAHL, EMBASE, PsycINFO, the Cochrane Library. This search strategy was supplemented by hand searching references in relevant palliative care text books and by searching relevant websites. KEY RESULTS: Pharmacological and non-pharmacological measures to alleviate breathlessness are discussed in this paper. Non-pharmacological approaches are discussed in detail as these are currently the most effective for the greatest number of patients. CONCLUSIONS: The cause of breathlessness in advanced cancer patients is usually multifactorial. A combination of pharmacological with non-pharmacological approaches is essential to manage breathlessness. Breathlessness services (e.g. Breathlessness Intervention Service) can be considered to be innovative and effective models of care when provided as part of a network of services aimed at helping patients with advanced cardiorespiratory disease, including patients with advanced cancer. PMID- 21237710 TI - Understanding the role of SOX9 in acquired diseases: lessons from development. AB - The transcription factor SOX9 is crucial for multiple aspects of development. Mutations in SOX9 cause campomelic dysplasia, a haploinsufficiency disorder concordant with the expression profile of SOX9 during embryogenesis. The mechanistic understanding of development has revealed roles for SOX9 in regulating cartilage extracellular matrix (ECM) production and cell proliferation, among others. More recently, it transpires that SOX9 becomes expressed and induces destructive ECM components in organ fibrosis and related disorders. Although commonly absent from the parent cell type, SOX9 is expressed in a wide range of cancers, where it regulates cell proliferation. These data have potential diagnostic, prognostic and therapeutic relevance, suggesting that disease mechanisms might result from re-expressing this developmental transcription factor in ectopic locations. PMID- 21237712 TI - Spermatozoal RNA profiling towards a clinical evaluation of sperm quality. AB - Human spermatozoal RNAs were recently profiled using microarrays and explored as clinical markers of male infertility. An appropriate study design with a considerable number of biological replicates (sperm samples) is necessary to validate the accuracy and reproducibility of these microarray data. If the genes identified as sperm quality markers by microarray studies are successfully attributed to the pathogenesis of male infertility, then the microarray strategy may be used as a clinical diagnostic tool for male infertility. On the other hand, spermatozoal RNAs may contain not only remnant RNAs after spermatogenesis, but also RNAs that may contribute extragenomically to early embryonic development. Therefore, spermatozoal RNA profiling may enable a better understanding of what is contributed to the oocyte by sperm, in addition to their genome, to facilitate early embryonic development. PMID- 21237711 TI - Malaria crystalloids: specialized structures for parasite transmission? AB - Malaria parasites possess many unique subcellular structures and organelles that are essential for the successful completion of the complex life cycle of Plasmodium in the vertebrate host and mosquito vector. Among these are the crystalloids: transient structures whose presence is restricted to the mosquito specific ookinete and young oocyst stages of the parasite. Nearly five decades after they were first described, the crystalloids are back in the spotlight, with recent discoveries pointing to an important role in protein trafficking and sporozoite transmission that could be exploited as new targets for control of malaria transmission. PMID- 21237713 TI - Theoretical and experimental basis of slow freezing. AB - In human IVF, cryopreservation of oocytes has become an alternative to embryo storage. It has also shown enormous potential for oocyte donation, fertility preservation and animal biotechnology. Mouse oocytes have represented the elective model to develop oocyte cryopreservation in the human and over several decades their use has made possible the development of theoretical and empirical approaches. Progress in vitrification has overshadowed slow freezing to such an extent that it has been suggested that vitrification could soon become the exclusive cryopreservation choice in human IVF. However, recent studies have clearly indicated that human embryo slow freezing, a practice considered well established for decades, can be significantly improved by a simple empirical approach. Alternatively, recent and more advanced theoretical models can predict oocyte responses to the diverse factors characterizing an entire slow-freezing procedure, offering a global method for the improvement of current protocols. This gives credit to the notion that oocyte slow freezing still has considerable margins for improvement. PMID- 21237714 TI - Cellular targeting and trafficking of drug delivery systems for the prevention and treatment of MTb. AB - Targeted delivery of anti-tubercular therapeutics to alveolar macrophages via inhalation aims to achieve optimal concentration of the therapeutic in the mycobacteria's niche environment. However, several challenges need to be overcome when designing a system to achieve this targeted, intracellular delivery. The first objective is to design a system that is suitable for inhalation, i.e. it must be capable of deposition in the alveolar region of the lungs. The theme of this commentary will be on the biological barriers for intracellular targeting to alveolar macrophages once particles are deposited in the lungs with emphasis on the delivery of anti-tubercular therapy and implications for novel vaccine formulations. The commentary focuses on four key features: 1) How Mycobacterium tuberculosis enters and is trafficked through macrophages, 2) the mechanism by which current drug delivery systems (DDS) enter and are trafficked through cells and 3) How an ideal DDS for anti-tubercular therapy would be trafficked through the macrophage and 4) the potential for using DDS for novel anti-tubercular therapy and vaccine development. These four features of targeted DDS shall be discussed in relation to some new findings from our own research. PMID- 21237716 TI - Immunological correlates of protection for the RTS,S candidate malaria vaccine. PMID- 21237715 TI - Efficacy of RTS,S/AS01E malaria vaccine and exploratory analysis on anti circumsporozoite antibody titres and protection in children aged 5-17 months in Kenya and Tanzania: a randomised controlled trial. AB - BACKGROUND: RTS,S/AS01E is the lead candidate malaria vaccine. We recently showed efficacy against clinical falciparum malaria in 5-17 month old children, during an average of 8 months follow-up. We aimed to assess the efficacy of RTS,S/AS01E during 15 months of follow-up. METHODS: Between March, 2007, and October, 2008, we enrolled healthy children aged 5-17 months in Kilifi, Kenya, and Korogwe, Tanzania. Computer-generated block randomisation was used to randomly assign participants (1:1) to receive three doses (at month 0, 1, and 2) of either RTS,S/AS01E or human diploid-cell rabies vaccine. The primary endpoint was time to first clinical malaria episode, defined as the presence of fever (temperature >=37.5 degrees C) and a Plasmodium falciparum density of 2500/MUL or more. Follow up was 12 months for children from Korogwe and 15 months for children from Kilifi. Primary analysis was per protocol. In a post-hoc modelling analysis we characterised the associations between anti-circumsporozoite antibodies and protection against clinical malaria episodes. This study is registered with ClinicalTrials.gov, number NCT00380393. FINDINGS: 894 children were assigned, 447 in each treatment group. In the per-protocol analysis, 82 of 415 children in the RTS,S/AS01E group and 125 of 420 in the rabies vaccine group had first or only clinical malaria episode by 12 months, vaccine efficacy 39.2% (95% CI 19.5-54.1, p=0.0005). At 15 months follow-up, 58 of 209 children in the RTS,S/AS01E group and 85 of 206 in the rabies vaccine group had first or only clinical malaria episode, vaccine efficacy 45.8% (24.1-61.3, p=0.0004). At 12 months after the third dose, anti-circumsporozoite antibody titre data were available for 390 children in the RTS,S/AS01E group and 391 in the rabies group. A mean of 15 months (range 12-18 months) data were available for 172 children in the RTS,S/AS01E group and 155 in the rabies group. These titres at 1 month after the third dose were not associated with protection, but titres at 6.5 months were. The level of protection increased abruptly over a narrow range of antibody concentrations. The most common adverse events were pneumonia, febrile convulsion, gastroenteritis, and P falciparum malaria. INTERPRETATION: RTS,S/AS01E confers sustained efficacy for at least 15 months and shows promise as a potential public health intervention against childhood malaria in malaria endemic countries. FUNDING: PATH Malaria Vaccine Initiative (MVI), GlaxoSmithKline. PMID- 21237717 TI - Breastfeeding, triple ARV prophylaxis, and MTCT prevention. PMID- 21237718 TI - Triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of HIV-1 (Kesho Bora study): a randomised controlled trial. AB - BACKGROUND: Breastfeeding is essential for child health and development in low resource settings but carries a significant risk of transmission of HIV-1, especially in late stages of maternal disease. We aimed to assess the efficacy and safety of triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis in pregnant women infected with HIV. METHODS: Pregnant women with WHO stage 1, 2, or 3 HIV-1 infection who had CD4 cell counts of 200 500 cells per MUL were enrolled at five study sites in Burkina Faso, Kenya, and South Africa to start study treatment at 28-36 weeks' gestation. Women were randomly assigned (1:1) by a computer generated random sequence to either triple antiretroviral prophylaxis (a combination of 300 mg zidovudine, 150 mg lamivudine, and 400 mg lopinavir plus 100 mg ritonavir twice daily until cessation of breastfeeding to a maximum of 6.5 months post partum) or zidovudine and single-dose nevirapine (300 mg zidovudine twice daily until delivery and a dose of 600 mg zidovudine plus 200 mg nevirapine at the onset of labour and, after a protocol amendment in December, 2006, 1 week post-partum zidovudine 300 mg twice daily and lamivudine 150 mg twice daily). All infants received a 0.6 mL dose of nevirapine at birth and, from December, 2006, 4 mg/kg twice daily of zidovudine for 1 week after birth. Patients and investigators were not masked to treatment. The primary endpoints were HIV-free infant survival at 6 weeks and 12 months; HIV-free survival at 12 months in infants who were ever breastfed; AIDS free survival in mothers at 18 months; and serious adverse events in mothers and babies. Analysis was by intention to treat. This trial is registered with Current Controlled Trials, ISRCTN71468401. FINDINGS: From June, 2005, to August, 2008, 882 women were enrolled, 824 of whom were randomised and gave birth to 805 singleton or first, liveborn infants. The cumulative rate of HIV transmission at 6 weeks was 3.3% (95% CI 1.9-5.6%) in the triple antiretroviral group compared with 5.0% (3.3-7.7%) in the zidovudine and single-dose nevirapine group, and at 12 months was 5.4% (3.6-8.1%) in the triple antiretroviral group compared with 9.5% (7.0-12.9%) in the zidovudine and single-dose nevirapine group (p=0.029). The cumulative rate of HIV transmission or death at 12 months was 10.2% (95% CI 7.6-13.6%) in the triple antiretroviral group compared with 16.0% (12.7-20.0%) in the zidovudine and single-dose nevirapine group (p=0.017). In infants whose mothers declared they intended to breastfeed, the cumulative rate of HIV transmission at 12 months was 5.6% (95% CI 3.4-8.9%) in the triple antiretroviral group compared with 10.7% (7.6-14.8%) in the zidovudine and single-dose nevirapine group (p=0.02). AIDS-free survival in mothers at 18 months will be reported in a different publication. The incidence of laboratory and clinical serious adverse events in both mothers and their babies was similar between groups. INTERPRETATION: Triple antiretroviral prophylaxis during pregnancy and breastfeeding is safe and reduces the risk of HIV transmission to infants. Revised WHO guidelines now recommend antiretroviral prophylaxis (either to the mother or to the baby) during breastfeeding if the mother is not already receiving antiretroviral treatment for her own health. FUNDING: Agence nationale de recherches sur le sida et les hepatites virales, Department for International Development, European and Developing Countries Clinical Trials Partnership, Thrasher Research Fund, Belgian Directorate General for International Cooperation, Centers for Disease Control and Prevention, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and UNDP/UNFPA/World Bank/WHO Special Programme of Research, Development and Research Training in Human Reproduction. PMID- 21237721 TI - Improving individual measurement of postoperative pain: the pain trajectory. AB - The purpose of this study was to demonstrate a method for increasing the precision and information yield of postoperative pain assessment. We recorded pain intensity ratings over 6 days after surgery in 502 elective surgery patients and examined individual pain trajectories. A linear fit of an individual patient's scores defines a trajectory with two features: (1) the intercept or initial pain intensity; and (2) the slope, or rate of pain resolution. Three pain trajectory patterns emerged from examination of the pain trajectory slopes. Most patients (63% of the sample) demonstrated a negative slope trajectory characterized by a decline in pain intensity over days after surgery. Other patients (25% of the sample) demonstrated a flat trajectory with no meaningful change over 6 days from pain they reported initially. A third patient group (12% of the sample) had a positive slope trajectory in which pain scores increased over 6 days after surgery. Measures derived from individual pain trajectories yielded much lower standard errors of measurement and therefore had better measurement precision than did conventional pain assessment methods. Pain trajectory measures proved sufficiently precise to characterize pain patterns reliably in individual patients. PERSPECTIVE: Progress in acute pain management requires effective pain assessment. The acute pain trajectory quantifies rate of pain resolution as well as pain intensity. It affords more precise measurement than conventional pain assessment and can identify abnormal postoperative pain resolution. PMID- 21237719 TI - Babies born after diabetes in pregnancy: what are the short- and long-term risks and how can we minimise them? AB - Despite improvements in services for people with diabetes and an increased focus on care of diabetes in pregnancy, there has been no significant reduction in neonatal complications after pregnancy complicated by maternal diabetes. Some complications are severe and life threatening or lead to long-term difficulties, whilst others are transient and are unlikely to lead to long-term harm, if managed according to standard guidelines. Most neonatal complications are, in theory, avoidable by optimal diabetes care, those that arise directly as a result of poor control of diabetes in pregnancy or as a result of obstetric interventions related to maternal diabetes control. Of greater concern are iatrogenic complications that arise from decisions which have no clear rationale (e.g., 'routine' admission of a baby to a neonatal unit). Planning for neonatal management must take into account known risks and the likelihood of occurrence, start in advance of delivery, involve all relevant groups of professionals and be centred on the needs of the mother and baby and not upon historical organisational policies. PMID- 21237720 TI - Study of spontaneous recurrent seizures and morphological alterations after status epilepticus induced by intrahippocampal injection of pilocarpine. AB - Epileptic seizures are clinical manifestations of neuronal discharges characterized by hyperexcitability and/or hypersynchrony in the cortex and other subcortical regions. The pilocarpine (PILO) model of epilepsy mimics temporal lobe epilepsy (TLE) in humans. In the present study, we used a more selective approach: microinjection of PILO into the hilus of the dentate gyrus (H-PILO). Our main goal was to evaluate the behavioral and morphological alterations present in this model of TLE. Seventy-six percent of all animals receiving H-PILO injections had continuous seizures called status epilepticus (SE). A typical pattern of evolution of limbic seizures during the SE with a latency of 29.3 +/- 16.3 minutes was observed using an analysis of behavioral sequences. During the subsequent 30 days, 71% of all animals exhibited spontaneous recurrent seizures (SRSs) during a daily 8-hour videotaping session. These SRSs had a very conspicuous and characteristic pattern detected by behavioral sequences or neuroethiological analysis. Only the animals that had SE showed positive Neo-Timm staining in the inner molecular layer of the dentate gyrus (sprouting) and reduced cell density in Ammon's horn pyramidal cell subfield CA1. However, no correlation between the intensity of sprouting and the mean number and total number of SRSs was found. Additionally, using Fluoro-Jade staining, we observed neurodegeneration in the hilus and pyramidal cell subfields CA3 and CA1 24 hours after SE. These data indicate that H-PILO is a reliable, selective, efficient, low-mortality model that mimics the acute and chronic behavioral and morphological aspects of TLE. PMID- 21237722 TI - Age and gender exert differential effects on blood lipids in patients after LAGB and LRYGB. AB - BACKGROUND: Although bariatric surgery is known to exert favorable effects on dyslipidemia, few studies have systematically considered how the demographic variables might modulate the outcomes. The aim of the present study was to examine the interactive effects of gender, age, and surgery type on dyslipidimia in bariatric surgery patients at a tertiary hospital in the United States. METHODS: In a retrospective review of 294 patients who had undergone laparoscopic Roux-en-Y gastric bypass (LRYGB) or laparoscopic adjustable gastric bypass (LAGB), we examined the changes in lipid profiles and antihyperlipidemic use for <=4 years postoperatively. The data were analyzed using longitudinal mixed modeling methods, in which the effects on lipid concentrations and medication use were tested in models with gender, surgery type, age, postoperative duration, and all possible interactions entered as factors. RESULTS: Significant 2-way interactions of surgery type*time were found for total cholesterol and high density lipoprotein cholesterol, gender*time for high-density lipoprotein cholesterol, and age*time for triglycerides. A 3-way interaction of surgery type*age*time was noted for low-density lipoprotein cholesterol. For older patients, low-density lipoprotein cholesterol was reduced by 20% from baseline in the LRYGB group but did not lessen significantly in the LAGB group. In the younger patients, however, decreases from the preoperative concentrations were not evident in either surgery group. An interaction of surgery type*time on antihyperlipdemic medication use, in which values changed significantly from baseline was found in both groups. However, the pattern in the LRYGB patients opposed that in the LAGB patients. CONCLUSION: Our results have demonstrated that bariatric surgery imparts a pronounced improvement in the blood lipid profile of recipients; however, these effects might be moderated by other factors, such as age and gender, independently of the baseline weight status of the patients. PMID- 21237723 TI - Five-year follow-up after biliopancreatic diversion with duodenal switch. AB - BACKGROUND: Only limited data are available for assessing the medium and long term outcomes after bariatric surgery. We report our own long-term results after biliopancreatic diversion with duodenal switch (BPD-DS). METHODS: The data from 51 patients with a theoretical >=5-year follow-up were reviewed after BPD-DS performed from February 2002 to October 2004. The patients were assessed every 3 months during their first postoperative year, every 6 months during the second year, and annually thereafter. RESULTS: The preoperative body mass index (BMI) was 47 +/- 6.1 kg/m(2). The first 23 patients had undergone open BPD-DS. The same procedure was used (150-mL sleeve, 150-cm alimentary limb, and 100-cm common channel) for the 28 laparoscopic BPD-DS procedures, although 15 patients underwent conversion to laparotomy at the beginning of our experience. No patients died postoperatively. Of the 51 patients, 7 were not available for follow-up: 2 patients had died 9 months after BPD-DS (1 of myocardial infarction and 1 after ventral hernia repair), 1 underwent reversal, 1 refused follow-up after a complicated postoperative course, and contact was lost with 3 patients (7.8% lost to follow-up). The 5-year BMI was 31 +/- 4.5 kg/m(2), with a mean excess weight loss of 71.9% +/- 20.6%. Of the 44 patients, 7 (15.9%) had an excess weight loss of <50%; 4 of these unsatisfactory results occurred after revision BPD-DS. After primary BPD-DS, excess weight loss of 75.8% +/- 18.0% was observed. Biologic data were obtained for 85% of the patients at 5 years. The main vitamin and micronutrients parameters remained stable over time. However, a trend was seen toward an increase in the parathormone levels and difficulties in maintaining a normal vitamin D level despite updated vitamin supplementation. CONCLUSION: The results of our study have shown that BPD-DS achieves sustainable significant weight loss with >5 years of follow-up, with unsatisfactory results in <20% of cases. Although not statistically significant, revision surgery more often resulted in lesser weight loss, although this difference had almost vanished when the initial BMI was taken as a reference compared with the BMI before BPD-DS. PMID- 21237724 TI - Validation of a fully automated COMET assay: 1.75 million single cells measured over a 5 year period. AB - The COMET assay is recognized as a rapid and sensitive method in quantifying radiation induced DNA damage. We investigated the distorting influence of endogenous, assay-inherent factors onto base (single cell level) and primary outcome measures (experimental/slide level), such as olive tail moment (OTM) and percentage DNA in the tail (%tail-DNA). From 2003 to 2008, we performed the assay on lymphocytes isolated from the blood samples of 355 lung cancer patients, 170 controls, and 610 relatives, as well as one single reference individual, repeated 170 times. In total, the data from 10,016 single experiments containing around 1,750,000 cells have been included in this study. This is the first time that the endogenous variability of the COMET assay has been validated systematically on such a huge data set over a 5 year period. Assuming that the reference sample reflects assay specific white noise, we estimated a proportion of 7-95% of the variability of the outcome measures due to assay variation (white noise) depending on parameter, exposure level, and study group. The proportion of white noise was largest for the initial radiation damage. The specific endogenous factors considered attribute to 14.8% of the total variability in the primary outcome measurements of the OTM and 6.9% of the %tail-DNA. OTM turns out to be a sensitive parameter to detect variation, but is also more susceptible to disturbance caused by endogenous factors than %tail-DNA. To reduce the experimental variability in COMET assays, we recommend a highly standardized operation protocol as well as inspecting and/or adjusting the primary outcome measures according to endogenous factors before calculating secondary outcome measures, e.g. DNA repair capacity (DRC) or testing statistical inference. A human reference (HR) sample is also useful to inspect homogeneity in the temporal progression of long lasting investigations, but not for calibrating primary outcome measurements. PMID- 21237725 TI - Endonuclease VII is a key component of the mismatch repair mechanism in bacteriophage T4. AB - In previous papers we described an extra recombination mechanism in T4 phage, which contributed to general recombination only when particular mutations were used as geneticmarkers (high recombination or HR markers), whereas it was practically inactive towards other rIIB mutations (low recombination or LR markers). This marker-dependent recombination pathway was identified as a repair of mismatches in recombination heteroduplexes. We suggested that the first step in this pathway, recognition and incision of the mismatch, is performed by endonuclease VII (endo VII) encoded by the T4 gene 49. In the present paper, we tested this hypothesis in vivo. We used an experimental model system that combines site-specific double-strand breaks with the famous advantages of the recombination analysis of bacteriophage T4 rII mutants. We compared recombination of homoallelic HR and LR markers in the S17 and S17 E727 background (amber mutations in the uvsX and in the uvsX and 49 genes, respectively). In S17 crosses, the HR and LR markers retain their respective high-recombination and low recombination behavior. In S17 E727-crosses, however, the HR and LR markers show no difference in the recombination frequency and both behave as LR markers. We conclude that endo VII is the enzyme that recognizes mismatches in recombinational heteroduplexes and performs their incision. This role for endo VII was suggested previously from biochemical studies, but this is its first in vivo demonstration. PMID- 21237728 TI - Haemosuccus pancreaticus in chronic pancreatitis: direct diagnosis by CT. PMID- 21237729 TI - IL28B: A new wager in the skyline of hepatitis C virus infection. PMID- 21237726 TI - Nongradient blue native gel analysis of serum proteins and in-gel detection of serum esterase activities. AB - The objective of the present study was to analyze serum protein complexes and detect serum esterase activities using nongradient blue native polyacrylamide gel electrophoresis (BN-PAGE). For analysis of potential protein complexes, serum from rat was used. Results demonstrate that a total of 8 gel bands could be clearly distinguished after Coomassie blue staining, and serum albumin could be isolated nearly as a pure protein. Moreover, proteins in these bands were identified by electrospray mass spectrometry and low-energy collision induced dissociation (CID)-MS/MS peptide sequencing and the existence of serum dihydrolipoamide dehydrogenase (DLDH) was confirmed. For studies of in-gel detection of esterase activities, serum from rat, mouse, and human was used. In gel staining of esterase activity was achieved by the use of either alpha naphthylacetate or beta-naphthylacetate in the presence of Fast blue BB salt. There were three bands exhibiting esterase activities in the serum of both rat and mouse. In contrast, there was only one band showing esterase activity staining in the human serum. When serum samples were treated with varying concentrations of urea, esterase activity staining was abolished for all the bands except the one containing esterase 1 (Es1) protein that is known to be a single polypeptide enzyme, indicating that majority of these esterases were protein complexes or multimeric proteins. We also identified the human serum esterase as butyrylcholinesterase following isolation and partial purification using ammonium sulfate fractioning and ion exchange column chromatographies. Where applicable, demonstrations of the gel-based method for measuring serum esterase activities under physiological or pathophysiological conditions were illustrated. Results of the present study demonstrate that nongradient BN-PAGE can serve as a feasible analytical tool for proteomic and enzymatic analysis of serum proteins. PMID- 21237730 TI - [Ollier disease: benign tumours with risk of malignant transformation. A review of 17 cases]. AB - AIM: To review Ollier disease, an uncommon disease, in order to understand the clinical symptoms, diagnosis, correct treatment, and risk factors in order to prevent malignant transformation. MATERIALS AND METHODS: Seventeen cases of Ollier disease were treated between 1976 and 2006. The variables studied included: age at diagnosis and onset of malignant transformation, location of the lesion, family association with other tumours, radiological findings, treatment for the different lesions, metastatic lesions and survival. We excluded patients with Chondrosarcoma without previous diagnosis of Ollier disease. All malignant transformations were assessed by histopathology studies and radiological images. RESULTS: We include 16 cases of Ollier's and 1 of Maffucci's syndrome. The median age at diagnosis for patients having malignant transformation was 45 years, whereas the average age at diagnosis for patient without progression to malignancy was 11 years. Pathological fractures, dysmetria and deformities led to the diagnosis in young people. Benign lesions were treated with minor surgery. There were five malignancy transformations in four patients (23.5%), with the distal femur being the most frequent location for transformation to grade I chondrosarcoma. Surgery was the treatment in all of them. We found no family association with other tumours. CONCLUSIONS: Multiple enchondromatosis is a benign disease with a high risk of malignant transformation above 40 years old. Bone scintigraphy is the best tool for detecting multiple lesions and malignant transformation. Radical surgery is the only way to improve survival, and this is the reason why early diagnosis is essential. PMID- 21237731 TI - [Disaster situations. What must we know and do?]. AB - Disasters are situations or events that overwhelm local capacity and can cause great damage and human suffering. Disasters are uncommon but their consequences may be extremely serious; that is why it is absolutely necessary that health care providers become fully prepared. The paediatric population is especially vulnerable to disasters effects, and so paediatricians have to play an essential role, not only during the disaster but also previously, during disaster planning. This review aims to provide an overview of the different types of disaster, the role of paediatricians in disaster preparedness, the stages of disaster managing and finally, hospital preparedness. PMID- 21237732 TI - [The role of antibiotics in acute sinusitis: a systematic review and meta analysis]. AB - INTRODUCTION: The aim of this systematic review is to assess whether antibacterial agents are more effective than either placebo or no intervention at all in the treatment of acute bacterial sinusitis. PATIENTS AND METHODS: We reviewed the databases and search engines: PubMed, EMBASE, Cochrane Central Register of Controlled Trials and Google Scholar to identify randomized clinical trials (RCTs) in children comparing antibiotics versus placebo. Sinusitis was considered as the persistence of clinically compatible symptoms for at least 10 days. The methodological quality was assessed using the Jadad scale. Four RCTs were selected. We studied the following variables: cure, clinical improvement (on days 10 to 14), relapse-recurrence (from day 14 to day 60) and presence of adverse effects. The results were combined using meta-analysis. We used the fixed effects model or random model depending on whether or not there was heterogeneity. We estimated the combined relative risk (RR) and 95% confidence interval. RESULTS: Only two RCTs had a Jadad scale score >=3. Variable cure improvement (4 RCTs): RR 1.11 (95% CI: 0.9 to 1.3). Variable relapse-recurrence (3 RCTs): RR 0.9 (95% CI: 0.6 to 1.5). Adverse effects (4 RCTs): 2.01 (95% CI 1.1 to 3.8). CONCLUSIONS: In children with acute sinusitis, antibacterial agents at the studied doses did not appear to provide benefit in terms of cure and improvement, assessed at 10 to 14 days of follow up. Similarly, the percentage of relapse-recurrence was not lower among children who received antibiotics. Antibiotics are associated more frequently with adverse effects. PMID- 21237733 TI - [Spanish growth studies: the current situation, their effectiveness and recommendations for their use]. AB - The child growth assessment is useful not only for the follow up of children's health but also for social purposes, as an indicator of the equity advances in the world. In Spain there has been a long tradition in carrying out growth studies. During the last decade five Spanish research groups have conducted studies among the population of Andalucia, Barcelona, Bilbao, Madrid and Zaragoza. They have combined their data and have produced the "Transversal Spanish Studies 2008 and 2010" and the "Longitudinal Spanish Study 1978/2000". These studies have showed that in Spain the regional differences on growth have disappeared, and that this has had a secular trend in the last decades. The Spanish adult height has approached to other European and American countries, still below some Centre and North European countries. There are some differences between the Spanish growth studies and the multicentric World Health Organization (WHO) growth study. This is due, among other reasons, to the different criteria that are used for the sample selection. In Spain the studies are based on the "population" criteria, whereas the WHO study is based on the "socioeconomic" and "nutritional" criteria. Currently for the Spanish population is appropriate to use, as standard reference, the Spanish multicentric studies, which are the transversal as well as the longitudinal studies. Due to the recent secular trend, it would be convenient to carry out, in the future, prospective transversal growth studies, methodologically homogeneous, representatives of the different Spanish regions, and preferably made every ten to fifteen years. PMID- 21237734 TI - Fasciocutaneous flaps based on a doppler detected perforator, an illustrative series as used for burn contracture reconstruction. AB - Perforator flaps are well established as a versatile option in reconstructive surgery that provide thin, pliable cutaneous or fasciocutaneous tissue. They are particularly useful in the reconstruction of large shallow defects, such as after the release of a burn contracture, however there are situations where the additional time spent islanding these flaps may be unnecessary, and the flap is then essentially a fasciocutaneous flap based, but not islanded, on a perforator artery. This paper documents a series of 22 severe burn contractures in 17 patients reconstructed with fasciocutaneous flaps in this way. The arteries were all located pre-operatively with a hand held Doppler probe, around half at the site of a known perforator and half by systematic scanning of the surrounding skin for an ad hoc perforator. All patients achieved a good functional range of motion. There were three cases of partial superficial flap necrosis treated with split skin grafting. The functional and aesthetic outcomes were far better then those expected with split skin grafting, and published series show that contractures treated with perforator flaps are unlikely to ever need further surgery. Without islanding the flap it becomes a feasible option for reconstructing these patients even in the extremely resource poor environment in which they often present, and is an option for all plastic surgeons to consider in the reconstruction of large superficial defects. PMID- 21237735 TI - Bilateral superior epigastric pedicle perforator flaps for total chest wall coverage. AB - The superior epigastric artery (SEA), a terminal branch of the internal mammary artery, is analogous to the deep inferior epigastric artery (DIEA) in that it supplies a large number of perforators that are clustered together. This allows tissue from the superior abdomen to be used as a pedicled flap for reconstruction. A reliable and well-perfused pedicled flap can be based on this cluster of perforators, hence the term 'pedicle cluster perforator flap'. We present a case of a patient with recurrent angiosarcoma, who required total anterior chest wall reconstruction. This was achieved using bilateral pedicled SEA perforator flaps for complete coverage. To our knowledge, this is the first documented case of bilateral pedicled perforator flap reconstruction for complete chest wall reconstruction. PMID- 21237736 TI - Slip and lock: a useful addition to the plastic surgeon's armamentarium. PMID- 21237738 TI - The pea and the coconut: seed size in safe sites. PMID- 21237739 TI - Cooperative lions escape the prisoner's dilemma. PMID- 21237737 TI - Head and neck free-flap reconstruction in the elderly. AB - OBJECTIVE: To evaluate the reliability of free-flap head and neck reconstruction in the elderly. MATERIAL AND METHODS: All patients who underwent free-flap head and neck reconstruction in our institution between 2000 and 2010 were included in this retrospective study. In all, 418 patients (301 men and 117 women) were enrolled, including 95 patients aged 70 years or older (mean age=60.2+/-11.6 years). The impact of age on free-flap failure and local and general complication rates was assessed on univariate and multivariate analysis. RESULTS: Advanced age had no impact on free-flap failure and local complications rate but was correlated with a higher risk of general complications (multivariate analysis: P=0.007). A high level of comorbidity also had a significant impact on the general complications rate (multivariate analysis: P=0.001). Patients who underwent circular total pharyngolaryngectomy showed elevated risk of free-flap failure (P=0.005) and local complications (P=0.001) on multivariate analysis. CONCLUSION: Free-flap reconstruction of the head and neck is safe and reliable in the elderly. Nevertheless, meticulous patient selection, mainly based on the level of comorbidity, is necessary. PMID- 21237740 TI - Defining and mapping vegetation types in mega-diverse tropical forests. PMID- 21237742 TI - How many kinds of hantaviruses? PMID- 21237741 TI - Evolution of development: molecules, mechanisms and phylogenetics. PMID- 21237743 TI - Spatial heterogeneity in tropical forest structure: canopy palms as landscape mosaics. PMID- 21237744 TI - Symbiotic DNA in eukaryotic genomes. AB - The recent explosive growth of molecular genetic databases has yielded increasingly detailed insights into the evolutionary dynamics of eukaryotic genomes. DNA sequences with the self-encoded ability to transpose and replicate are unexpectedly abundant and widespread in eukaryotic genomes. They seem to be sexual parasites. By dispersing themselves among the chromosomes, they increase their transmission rates and can invade outcrossing populations despite reducing host fitness. Once established, molecular parasites may themselves be parasitized by other elements, and through selection for reduced virulence may become beneficial genes. Elements have been isolated at various stages in this progression, from transposons that regulate their own transposition rates, to fundamental components of eukaryotic cytology, such as telomeres. PMID- 21237745 TI - Reconstructing shifts in diversification rates on phylogenetic trees. AB - Few issues in evolutionary biology have received as much attention over the years or have generated as much controversy as those involving evolutionary rates. One unresolved issue is whether or not shifts in speclation and/or extinction rates are closely tied to the origin of 'key' innovations in evolution. This discussion has long been dominated by 'time-based' methods using data from the fossil record. Recently, however, attention has shifted to 'tree-based' methods, in which time, if It plays any role at all, is incorporated secondarily, usually based on molecular data. Tests of hypotheses about key innovations do require Information about phylogenetic relationships, and some of these tests can be implemented without any information about time. However, every effort should be made to obtain information about time, which greatly increases the power of such tests. PMID- 21237747 TI - Correspondence. PMID- 21237746 TI - Palaeo-ecophysiological perspectives on plant responses to global change. AB - Taxonomic classifications of plant species, based on morphological characteristics, provide a stable and robust approach for inferring taxonomic and phylogenetic relationships between extant and extinct species. This implies that, although evolution is a continuous process for a species, there is no whole-scale change in those suites of morphological characteristics that define higher order (genus and greater) relationships. Recent research suggests that a higher order characteristic - stomatal density - may reflect not only the atmospheric C0(2) concentration during initial evolution, but may also strongly constrain the responses of higher order plant groups to future C0(2)-enrichment. PMID- 21237748 TI - Reply from C. Wedekind and T. Seebeck. PMID- 21237749 TI - MHC and mate selection in humans? PMID- 21237750 TI - The ecology of resource polymorphism in vertebrates. PMID- 21237751 TI - The ecology of resource polymorphism in vertebrates. PMID- 21237752 TI - Polyembryony 'paradox': the case of cyclostomate Bryozoa. PMID- 21237753 TI - Polyembryony in plants: a weapon in the war over offspring numbers? PMID- 21237755 TI - Age and breeding performance in monogamous birds: the influence of pair stability. PMID- 21237754 TI - Reply from s. Skulason and T.B. Smith. PMID- 21237756 TI - What causes population cycles of forest Lepidoptera? AB - Hypotheses for the causes of regular cycles in populations of forest Lepidoptera have invoked pathogen-insect or foliage-insect interactions. However, the available data suggest that forest caterpillar cycles are more likely to be the result of interactions with insect parasitoids, an old argument that seems to have been neglected in recent years. PMID- 21237757 TI - Ecology, evolution and 1 f -noise. AB - Among ecologists, there has been a growing recognition of the importance of long term correlations In environmental time series. The family of 1 f -noises - fluctuations defined in terms of the different timescales present - is a useful approach to this problem. White noise and the random walk, the two currently favoured descriptions of environmental fluctuations, lie at extreme ends of this family of processes. Recent analyses of data, results of models, and examination of basic 1 f -noise properties, suggest that pink 1 < f noise, which lies midway between white noise and the random walk, might be the best null model of environment variation. If true, this would have important consequences for the interpretation of ecological time series and for ecological and evolutionary modelling. PMID- 21237758 TI - Inventorying and monitoring biodiversity. PMID- 21237759 TI - Ancient asexual scandals. AB - Asexual organisms that are descended from ancient asexual lineages defy current thinking on the evolution of sexual reproduction; theoreticians have been anxious to explain away their existence. However, a number of groups of organisms, from ferns to rotifers, have been suggested to be anciently asexual, and favourable evidence is being accumulated. Furthermore, new techniques for assessing claims of ancient asexuality have been proposed. Although ancient asexuals challenge current theories of sex, understanding how they manage to persist will help to explain why most organisms are sexual. PMID- 21237760 TI - Recent advances in understanding of the evolution and maintenance of sex. AB - The evolution of sex has been the focus of considerable attention during recent years. There is some consensus that the solution to the mystery is that sex either enables the creation and spread of advantageous traits (possibly parasite resistance) or helps to purge the genome of deleterious mutations. Recent experimental work has allowed testing of some of the assumptions underlying the theoretical models, most particularly whether interactions between genes are synergistic and whether the mutation rate is adequately high. However, although a variety of theories point out advantages to sex, most of them predict that a little sex and recombination can go a long way towards improving the fitness of a population, and it remains unclear why obligate sex is so common. PMID- 21237761 TI - Sexual selection. AB - Competition over mates takes many forms and has far-reaching consequences for many organisms. Recent work suggests that relative reproductive rates of males and females, sperm competition and quality variation among mates affect the strength of sexual selection. Song, other display, body size, visual ornaments and material resource offerings are often sexually selected. There is much empirical evidence of mate choice, and its evolution is clarified by mathematical models. Recent advances in theory also consider costs of choice, effects of deleterious mutations, fast and slow evolution of preferences and preferred traits, and simultaneous preferences for several traits. Contests over mates are important; so is sperm competition, scrambles, endurance rivalry, and coercion. The latter mechanisms have received less attention than mate choice. Sexual selection may explain puzzling aspects of plant pollination biology. PMID- 21237762 TI - Recent developments in sex ratio studies. AB - The allocation of resources to male and female progeny is a major component of the reproductive strategies of all sexual plants and animals. Over the past 30 years there has been intensive theoretical and experimental investigation of how natural selection moulds the sex ratio. Here, we discuss recent exciting developments and new applications of sex allocation theory and highlight some unresolved issues. PMID- 21237763 TI - Sex-determining mechanisms in animals. AB - Biological mechanisms leading to the development of males and females are extremely varied. In the XX/XY system, the male has an unequal pair of chromosomes, while in the ZZ/ZW system, the unequal pair is in the female. Sex can also be determined by the temperature of incubation. Recent research has focused on the identification of sex-determining genes, culminating in the demonstration that the Sry gene on the Y chromosome of mice can induce male development in genetically female XX mouse embryos. Nevertheless, the occurrence of phenotypes in apparent contrast to the genotype suggests that the genetic male/female switch is not simple, and there may be common features linking different sex-determining mechanisms. There is increasing evidence that such a link may be provided by the induction of growth differences, and that the primary sex difference may result from the distinction between fast versus slow growth. PMID- 21237764 TI - Animal breeding systems. AB - The study of breeding systems explores relationships between mating behaviour and parental care. Recent findings have shown that in many birds, fishes, anurans, and insects, females play a more active role than previously thought, by engaging in mate choice, mating with more than one male, and selecting genetic partners separately from social partners. Theoretical advances have improved our understanding of the effect of parental care on sex differences in mating behaviour, though less attention has been devoted to feedback in the opposite direction. The original emphasis on the role of ecology in determining breeding systems has been overshadowed by studies of individual interactions, but modern comparative techniques may provide a new fusion between ecology, life histories, and reproductive behaviour. PMID- 21237765 TI - Ecology and evolution of plant mating. AB - Plants exhibit complex mating patterns because of their immobility, hermaphroditism and reliance on vectors for pollen transfer. Research on plant mating attempts to determine who mates with whom in plant populations and how and why mating patterns become evolutionarily modified. Most theoretical models of mating-system evolution have focused on the fitness consequences of selling and outcrossing, stimulating considerable empirical work on the ecology and genetics of inbreeding depression. Less attention has been given to how the mechanics of pollen dispersal influence the transmission of self and outcross gametes. Recent work on the relation between pollen dispersal and mating suggests that many features of floral design traditionally interpreted as anti-selling mechanisms may function to reduce the mating costs associated with large floral displays. PMID- 21237766 TI - Sex against virulence: the coevolution of parasitic diseases. AB - Reciprocal selection is the underlying mechanism for host-parasite coevolutionary arms races. Its driving force is the reduction of host lifespan or fecundity that is caused by a parasite. Parasites evolve to optimize host exploitation, while hosts evolve to minimize the 'parasite-induced' loss of fitness (virulence). Research on the evolution of virulence has mostly emphasized the role of parasite evolution in determining virulence. However, host evolution, accelerated by sexual recombination, contributes to the evolution and expression of virulence as well. The Red Queen hypothesis predicts that genetic variation among host offspring facilitates selection for reduced virulence. Here, we outline a synthesis between current thinking about the evolution of virulence and the evolution of sex. PMID- 21237767 TI - Sexual selection and the brain. AB - Sex differences are intrinsically interesting, particularly in the brain. When sexually dimorphic structures mediate learning, and when such learning ability is necessary to compete for mates, then such differences are best understood within the framework of sexual selection. By categorizing recent studies of sex differences in the brain by their role in mate competition, theories of sexual selection can be used to predict and characterize the occurrence of dimorphisms among species with different mating systems. PMID- 21237768 TI - Sex and parenting: the effects of sexual conflict and parentage on parental strategies. AB - There is perhaps no more popularized aspect of animal behavior than the things parents do for offspring. Yet our understanding of the evolution of care is only rudimentary, perhaps because parental behavior is one of the most variable behavioral traits we know. Sexual reproduction, particularly in anisogamous species, has a major impact on variable patterns of care. Recent work on conflicts between the sexes over care and the consequences of variable paternity on paternal care has generated fascinating new ideas about the evolutionary forces acting on parenting. PMID- 21237769 TI - Alternative reproductive strategies and tactics: diversity within sexes. AB - Not all members of a sex behave in the same way. Frequency- and statusdependent selection have given rise to many alternative reproductive phenotypes within the sexes. The evolution and proximate control of these alternatives are only beginning to be understood. Although game theory has provided a theoretical framework, the concept of the mixed strategy has not been realized in nature, and alternative strategies are very rare. Recent findings suggest that almost all alternative reproductive phenotypes within the sexes are due to alternative tactics within a conditional strategy, and, as such, while the average fitnesses of the alternative phenotypes are unequal, the strategy is favoured in evolution. Proximate mechanisms that underlie alternative phenotypes may have many similarities with those operating between the sexes. PMID- 21237770 TI - The evolution of human sexuality. AB - The study of human sexuality from the darwinian perspective is in an explosive phase. Recent research is diverse; for instance, the dynamics of heterosexual relationships, the role of honest advertisement in attractiveness, the role of fluctuating asymmetry in sexual competition, and sexual conflict over fertilization, seen in sperm competition adaptations of men and possible cryptic sire-choice adaptation of women. Also, recent research reveals that the sexual selection that designed human secondary sexual traits was functional rather than strictly fisherian. PMID- 21237771 TI - Carabidologists and fragmented habitats. PMID- 21237772 TI - Inducible defenses and population biology. PMID- 21237773 TI - Hermes meets Aphrodite: an animal perspective. PMID- 21237775 TI - Estimating oystercatcher mortality from foraging behaviour. PMID- 21237774 TI - The rate of evolution in growing populations. PMID- 21237776 TI - Solitary chemosensory cells: why do primary aquatic vertebrates need another taste system? AB - The taste-like system of solitary chemosensory cells (SCCs) has almost eluded scientific attention. This is particularly remarkable, since recent surveys have revealed that this system of epidermal cells is widespread and abundant among the anamniotic aquatic vertebrates. In the rocklings (Gadidae, Teleostei), high densities of SCCs occur at a specialized dorsal fin. Recent evidence from this model indicates that SCCs are narrowly tuned to dilutions of fish body mucus and bile. Thus, SCCs may sample the ambient water for the upstream presence of potential competitors or predators. However, in sea robins (Triglidae, Teleostei), SCCs seem to be involved in finding food. Information from many more species is needed to explain why SCCs and taste buds have been maintained in parallel for such a long evolutionary period of time - from the age of the agnathans to that of the most advanced teleost fishes. PMID- 21237777 TI - A molecular approach to the evolution of vertebrate paired appendages. AB - Over the past few years, genes involved in the ontogenesis of tetrapod limbs have been Isolated and characterized. Some of the developmental mechanisms responsible for the morphogenesis of these complex structures can now be investigated through a new approach. In addition, these genes can serve as tools to re-evaluate some aspects of the long-standing question of the fin-to-limb transition. Comparative molecular developmental biology is providing new insight into the similarities and differences in the morphologies of these homologous structures. PMID- 21237778 TI - Pattern and process in neotropical secondary rain forests: the first 100 years of succession. AB - More and more areas of deforested wet tropical lands are being handed back to nature as their erstwhile owners abandon attempts to farm them. The resulting secondary successions offer hope that some of the unique characteristics of the original rain forests may be recovered and conserved. However, most of our understanding of what secondary tropical rain forests are and how and why they develop is limited to the first decade of a process that may last for centuries. A longer-term view indicates that the causes of change in neotropical secondary successions are similar to those operating in temperate forests, but yields sobering conclusions for conservation. PMID- 21237779 TI - The application of functional morphology to evolutionary studies. AB - Studies of functional morphology contribute in several ways to the understanding of evolutionary patterns and processes. The former include the unravelling of dependencies of characters and the construction of biomechanically feasible transformation schemes. Among the latter are the identification of structural novelties that facilitate a cascade of diverse structural changes, and the Identification of mechanisms that enable the incorporation of evolutionary novelties into the integrated organism. The study of mechanisms that maintain the match between form and function during evolutionary (and developmental) changes is a new and important area for evolutionary biologists. PMID- 21237780 TI - Ultraviolet perception. PMID- 21237781 TI - Reply from m.j. Tovee. PMID- 21237782 TI - Chromosomal variation and behavioural ecology: a challenge for mouse geneticists? PMID- 21237783 TI - Towards a behavioral ecology of ecological landscapes. AB - Recent developments in landscape-level ecological modeling rest upon poorly understood behavioral phenomena. Surprisingly, these phenomena include animal movement and habitat selection, two areas with a long history of study in behavioral ecology. A major problem in applying traditional behavioral ecology to landscape-level ecological problems is that ecologists and behaviorists work at very different spatial scales. Thus a behavioral ecology of ecological landscapes would strive to overcome this inopportune differential in spatial scales. Such a landscape-conscious behavioral undertaking would not only establish more firmly the link between behavior and ecological systems, but also catalyze the study of basic biological phenomena of Interest to behaviorists and ecologists alike. PMID- 21237784 TI - The economic value of the Earth's resources. AB - Economics is the driving force of today's widespread environmental destruction. Markets undervalue the earth's resources and compound their overuse. Since World War II the world has used resources voraciously. The situation can be described as the industrial countries overconsuming resources, which are overextracted and exported by developing countries and traded at prices that are lower than the social costs. Resource-intensive patterns of growth and trade are Inefficient for the world economy, and lead to tragic maldistribution of the Earth's riches. They should be replaced by knowledge-intensive patterns of growth. Information technology and the environmental agenda are two of the most important trends in the world economy. Together they can lead to growth that is Intrinsically compatible with the environment. PMID- 21237785 TI - Calculated risks. PMID- 21237786 TI - Cytoplasmic incompatibility in Drosophila simulans: evolving complexity. PMID- 21237787 TI - Molecular techniques in conservation and evolutionary biology: a quantum leap? PMID- 21237788 TI - Sperm caucus. PMID- 21237789 TI - Insects and ecosystem function. PMID- 21237790 TI - Combining data in phylogenetic analysis. AB - Systematists have access to multiple sources of character information in phylogenetic analysis. For example, it is not unusual to have nucleotide sequences from several different genes, or to have molecular and morphological data. How should diverse data be analyzed in phylogenetic analysis? Several methods have been proposed for the treatment of partitioned data: the total evidence, separate analysis, and conditional combination approaches. Here, we review some of the advantages and disadvantages of the different approaches, with special concentration on which methods help us to discern the evolutionary process and provide the most accurate estimates of phylogeny. PMID- 21237791 TI - The excess of transitions among nucleotide substitutions: new methods of estimating transition bias underscore its significance. AB - Estimates of transition bias provide insight into the process of nucleotide substitution, and are required in some commonly used phylogenetic methods. Transitions are favored over transversions among spontaneous mutations, and the direction and strength of selection on proteins and RNA appears to depend on mutation type. As the complexity of the nucleotide-substitution process has become apparent, problems with classical methods of estimating transition bias have been recognized. These problems arise because there Is a fundamental difference between ratios of numbers of differences among sequences and ratios of rates, and because classical methods are not easily generalized. Several new methods are now available. PMID- 21237792 TI - What we don't know about great ape variation. AB - The patterning of intraspecific variation among the great apes is proving more complex than has been recognized previously. The great ape species, as currently defined, may include markedly different subspecies, alternatively, the majority of intraspeclflc variation may be observed at the populational level within a single subspecies. Recent studies have raised a number of questions about great ape evolutionary biology. How many species of living great apes exist? What was the original dietary adaptation of gorillas? How should we define male orang-utan adulthood? PMID- 21237793 TI - How organisms respond to environmental changes: from phenotypes to molecules (and vice versa). AB - The ability of organisms to produce different phenotypes under different environmental conditions (phenotypic plasticity) has been an object of evolutionary and ecological studies since the neodarwinian synthesis. Yet, until lately, our knowledge in this field was limited to statistical approaches based on the classical tools of quantitative genetics. In recent years, however, a new dialog between organismal biologists and researchers interested in uncovering the mechanistic details of physiological and phenotypic responses has yielded several new insights. Some classic examples of phenotypic plasticity have now been traced to specific alterations in DNA transcription and RNA translation rates, and to changes in patterns of protein expression. Conversely, the explicit use of evolutionary and ecological theory is helping us to put a panoply of molecular data into a coherent historical and organismal perspective. PMID- 21237795 TI - What are 'good' species? PMID- 21237794 TI - Reply from j. Mallet. PMID- 21237796 TI - What is 'the paradox of the lek'? PMID- 21237797 TI - One picture is worth a thousand words, but there is no substitute for the real thing. PMID- 21237798 TI - Reply from g. Turner. PMID- 21237799 TI - Correspondence. PMID- 21237800 TI - The continuity of living matter and the discontinuities of its constituents: do plankton and benthos really exist? AB - Plankton and benthos are popular concepts identifying two ways of life of aquatic organisms. Their spatial separation led to the development of different sampling techniques and to separate conceptualizations of the principles governing these subsets of the aquatic environment. Reciprocal connections between plankton and benthos, however, are very strong both from a functional (energy fluxes) and a structural (life cycle dynamics) point of view. A full appreciation of such links is forcing marine ecology towards a more integrated approach. PMID- 21237801 TI - Genetic and evolutionary consequences of metapopulation structure. AB - Extinction and recolonization of populations may have various effects on the degree and distribution of genetic variation, but turnover is generally associated with low levels of among-population variation, in both 'classical' and other types of metapopulation. Therefore, adaptive evolution is unlikely to be promoted by selection among populations. Whether adaptation is promoted or slowed by population subdivision, with or without turnover, remains a subject of theoretical debate. PMID- 21237803 TI - Skimming the surface - the origin of flight in insects? PMID- 21237802 TI - Global change and ecological complexity: an international research agenda. PMID- 21237804 TI - Serengeti wild dogs: what really happened? PMID- 21237805 TI - Role-reversed risky copulation. PMID- 21237806 TI - Reproductive physiology and sperm competition in birds. PMID- 21237807 TI - Extinction filters and current resilience: the significance of past selection pressures for conservation biology. AB - There is now little reasonable doubt about the scale of the present extinction crisis: recent and ongoing rates of species loss exceed background levels by two to three orders of magnitude. Nevertheless, species differ widely in their vulnerability to current threats. Growing evidence from both palaeontology and conservation biology suggests that past events may help to explain this variation. Communities appear far more resilient to particular threats if they have faced similar challenges in the past. This intuitive but poorly reported phenomenon has potentially far-reaching implications for attempts to focus conservation efforts on those areas most at risk from contemporary human activity. PMID- 21237808 TI - Species-range-size distributions: patterns, mechanisms and implications. AB - Species-range-size distributions have received remarkably little attention in contrast to species-abundance distributions. However, recognition of the importance of regional scale phenomena for local assemblage structure, and the emergence of 'macroecology', have begun to change this situation. A growing number of studies suggests that these distributions are, in general, approximately lognormal, although interpretation is complicated by a variety of factors. Assuming the distribution pattern to be real, it can be viewed in terms of evolutionary and ecological determinants of species occurrences, although their relative significance remains unclear. The form of the distribution has a variety of important consequences, particularly for inventories of faunas and floras and for conservation. PMID- 21237809 TI - Inbreeding avoidance in animals. AB - The phenomenon of inbreeding depression is well documented and behavioral adaptations for inbreeding avoidance have been described. However, there is debate over whether inbreeding depression is always an important selective force on behavior. Here, we summarize recent evidence for inbreeding depression under natural conditions, review inbreeding avoidance mechanisms, and discuss how these are influenced by social structure. We also examine the idea that animals have evolved mechanisms to avoid outbreeding. PMID- 21237810 TI - The molecular phylogeographic bridge between deep and shallow history in continental biotas. AB - Recent studies have provided evidence that species diversity and distributions in continental biotas reflect a long history of responses (e.g. range shifts, speciation or adaptation) to habitat changes produced by geological activity over the past several million years (deep time) as well as glacial-interglacial cycles over the most recent hundreds of thousands of years (shallow time). Molecular sequences in extant taxa can be used to infer speciation and biogeographic history in deep time, as well as changes in population distributions produced by range shifts in shallow time, and thus provide a basis for constructing bridges between historical biogeographic, paleoecological and ecological biogeographic perspectives. References. PMID- 21237811 TI - Evolution and adaptive radiation of antarctic fishes. AB - There are few instances where a knowledge of the thermal physiology, habitats and lifestyles of a group of closely related species can be mapped onto a well supported phylogeny and a detailed climatic history. The unique fish fauna of the Southern Ocean, dominated by a single group of fish whose phylogeny is known from traditional and molecular techniques, provides one such opportunity. Furthermore, these fish are living at an extreme temperature for marine organisms. Physiological and molecular studies are revealing details of the mechanisms of temperature compensation and, combined with knowledge of the thermal history, are throwing new light on the process of evolution in this unique group of fish. PMID- 21237812 TI - Conservation breeding in 1995: an update. PMID- 21237813 TI - Reply from T. Ebenhard. PMID- 21237814 TI - Evolving Necker organisms. PMID- 21237815 TI - Reply from p.h. Van tienderen. PMID- 21237816 TI - Age and breeding performance in monogamous birds: the influence of mate experience. PMID- 21237817 TI - Chaos and evolution. PMID- 21237818 TI - The ecologry of anchihaline caves. AB - The dark, mostly brackish, aquatic habitats along the coasts are inhabited by a number of phylogenetically and/or biogeographically interesting animal taxa, whose ecology is poorly known. We are especially ignorant about the nature of the deoxygenated strata that occur in most of these habitats. Are these strata anoxic or only dysoxic? And how are their inhabitants adapted to low oxygen tensions? PMID- 21237819 TI - A new horizon for biological field stations and marine laboratories. PMID- 21237820 TI - Phylogeny and ecology. PMID- 21237821 TI - Evolution in fluctuating environments: a game with kin. PMID- 21237822 TI - Whorled, wiled webs. PMID- 21237823 TI - Interspecific competition reinstated as an important force structuring insect herbivore communities. PMID- 21237824 TI - Adaptive genetic structure in phytophagous insect populations. AB - Genetic variation in insect populations is frequently structured into discrete groups, or demes, that form in response to stochastic forces or natural selection. Because host-plant populations are often highly heterogeneous, phytophagous insects may form demes that are adapted to the unique traits of individual plants. Recent field experiments indicate that selection pressures imposed by host-plants can promote rapid adaptive evolution in natural insect populations at very fine spatial scales. Adaptive deme formation may be more common among endophagous insects, which feed and reside within plant tissue, than for externally feeding insects, because internal feeders experience stronger plant-mediated selection pressures. PMID- 21237825 TI - Surface-subsurface interactions in stream ecosystems. AB - Stream ecologists have recently recognized that sediments below streams play an important role in lotic ecosystems. Water flows not only across the surface of stream channels, but also through sediment interstices; consequently, surface and subsurface biogeochemical processes are linked. Recent attempts to understand the influence of subsurface processes on stream ecosystems have tried to resolve the surface-subsurface hydrologic interactions, and to gain knowledge of the ecology of subsurface organisms. PMID- 21237826 TI - Hatching asynchrony, brood reduction and other rapidly reproducing hypotheses. AB - Hatching asynchrony (extended hatching period) is apparently ubiquitous among altricial birds, and may represent a striking example of adaptive family planning. Research has focused on evaluating various benefits to resulting partial brood loss. Current conclusions fall into three major categories: that hatching asynchrony is (1) an adaptation to food availability, (2) a means of saving time, ultimately to increase lifetime reproductive success, or (3) a maladaptation. Almost every study develops a new explanation or qualifies an old one. Either most of them are wrong, or hatching asynchrony is an example of convergent evolution resulting in a behavioural trait serving many functions. PMID- 21237827 TI - Nuclear integrations: challenges for mitochondrial DNA markers. AB - The combined use of mitochondrial DNA markers and polymerase chain reaction (PCR) techniques has greatly enhanced evolutionary studies. These techniques have also promoted the discovery of mitochondrial-like sequences in the nuclear genomes of many animals. While the nuclear sequences themselves are interesting, and capable of serving as valuable molecular tools, they can also confound phylogenetic and population genetic studies. Clearly, a better understanding of these phenomena and vigilance towards misleading data are needed. PMID- 21237828 TI - Arthropod evolution: on informative data and sound methodology. PMID- 21237830 TI - Cooperation among lions: an overlooked theory. PMID- 21237829 TI - Reply from s. Legge. PMID- 21237831 TI - Is temperature-dependent sex determination in reptiles adaptive? PMID- 21237832 TI - Reply from d. Osorio et Al. PMID- 21237833 TI - Sexual and asexual reproduction in vertebrates. PMID- 21237834 TI - Insects in fragmented forests: a functional approach. AB - Insects are highly susceptible to the adverse effects of forest fragmentation. It is now beyond any doubt that fragmentation-induced changes in abundance and species richness occur in many insect groups. However, the study of insects in fragmented forests is still in its infancy and lacks real direction. Simple empirical studies are not answering the questions we most want to answer about fragmented systems. Are we in the midst of a mass-extinction crisis? What is the functional significance of the immense insect biodiversity? Does biodiversity loss affect ecosystem functioning? A more focused, functional approach to the study of forest fragmentation is required to move beyond the description of pattern and to determine how changes in insect communities affect ecosystem processes in fragmented forests. PMID- 21237835 TI - Conservation needs ethologv. AB - With the number of species and near-to-natural habitats rapidly dwindling, conservation has become an undebatable necessity. There have been some laudable, successful species conservation projects but there have also been many deplorable failures. The failures are exacerbated by limited funding. Conservationists depend on funding by national government organizations (NG0s) and by private sponsors, more than other practitioners of organismic biology do. To maximize their success, conservationists would be well advised to heed the messages resulting from animal behaviour study (i.e. ethology) and/or to involve ethologists in their projects. Here, I illustrate how ethology can benefit both in situ and ex situ conservation measures; the need for conservation-oriented behaviour research is paramount. PMID- 21237836 TI - Economics, ecology and the global biodiversity assessment. PMID- 21237837 TI - Trench warfare on the shore: interclonal aggression in sea anemones. PMID- 21237838 TI - An important confluence for stream ecology. PMID- 21237839 TI - In search of butterfly origins: morphology and molecules. PMID- 21237840 TI - Seasonal polyphenism in butterflies and natural selection. PMID- 21237841 TI - Plant evolution and the ancient greenhouse effect. PMID- 21237842 TI - Near extinction of an exploited marine invertebrate. PMID- 21237843 TI - Longevity in the deep. PMID- 21237844 TI - Haldane's rule and its legacy: Why are there so many sterile males? AB - A general pattern of animal hybridization, known as Haldane's rule, is that the XY (ZW) sex is more severely affected in its viability or fertility than the XX (ZZ) sex. Recent evidence suggests that three different forces have shaped this pattern: (1) the X chromosome and autosomes are in greater disharmony in the XY sex; (2) evolution of hybrid male sterility is greatly accelerated, at least in species with XY males; and (3) maternal-zygotic incompatibility preferentially affects the viability of the XX sex. In species with XY males, the rapid evolution toward hybrid male sterility may be responsible for the bulk of observations pertaining to Haldane's rule. One interesting and testable hypothesis is that sexual selection drives this rapid evolution. PMID- 21237846 TI - Flooding: the survival strategies of plants. AB - Floodplains and wetlands are highly suitable for plant ecological studies, whether for agricultural interests, nature conservation or basic science. Traditional work has entailed a descriptive approach at the community or individual plant level. Nowadays these studies are evolving into physiological research on relationships between flooding stress and vegetation zonation. Current experiments aim to unravel the adaptive mechanisms whereby terrestrial plants cope with the peculiar conditions of the floodplain, from the whole plant down to the cell. PMID- 21237845 TI - Developments in social terminology: semantic battles in a conceptual war. AB - The problems posed by the evolution of the diverse forms of animal sociality are among the most important and fascinating in evolutionary biology. The conceptual and terminological framework guiding studies of social evolution has been based on a particular insect model, namely, that of highly derived family-structured societies. Virtually all other social systems have been categorized as 'less social' relative to these societies. Recently, the ambiguities and constraints inherent in this hierarchical classification have led to numerous proposals to amend social terminology. What is the best framework for studying social evolution? Should the traditional classification be expanded, narrowed or abandoned altogether? In an important respect, most recent proposals present the same wine in a different bottle by retaining and recasting key terms of the traditional social-evolutionary classification. PMID- 21237847 TI - Correspondence. PMID- 21237849 TI - Valuing the earth's resources. PMID- 21237848 TI - Ancient asexuals: scandal or artifact? PMID- 21237850 TI - Reply from o.p. Judson and B.B. Normark. PMID- 21237851 TI - How effective is interdemic selection? PMID- 21237853 TI - Reply from s. Harrison and a. Hastings. PMID- 21237852 TI - Reply from g. Chichilnisky. PMID- 21237854 TI - Evolutionary ecology and the conservation of biodiversity. AB - Studies on evolving interactions among species and the coevolutionary process have suggested that the conservation of biodiversity requires a broad geographic perspective, if the 'interaction biodiversity' of the earth is to be conserved with its species diversity. Continued maintenance of the geographic mosaic of specialization, defense and population structure appears to be crucial to the coevolutionary process and the long-term persistence of some interspecific interactions. PMID- 21237855 TI - What does 'biodiversity' mean - scientific problem or convenient myth? AB - Biodiversity has become an everyday word, not just for ecologists but for politicians, the media and the general public too. But does It have a genuine scientific meaning that distinguishes it from earlier studies of diversity, or has it assumed a mythological status? PMID- 21237856 TI - Communicating ideas about humans and evolutionary theory. PMID- 21237857 TI - Evolution of avian life histories - does nest predation explain it all? PMID- 21237858 TI - VEMAP: model shootout at the sub-continental corral. PMID- 21237860 TI - Gala theory: Darwin reinforces regulation. PMID- 21237859 TI - Exploding species. PMID- 21237861 TI - Ecological immunology: costly parasite defences and trade-offs in evolutionary ecology. AB - In the face of continuous threats from parasites, hosts have evolved an elaborate series of preventative and controlling measures - the immune system - in order to reduce the fitness costs of parasitism. However, these measures do have associated costs. Viewing an individual's immune response to parasites as being subject to optimization in the face of other demands offers potential insights into mechanisms of life history trade-offs, sexual selection, parasite-mediated selection and population dynamics. We discuss some recent results that have been obtained by practitioners of this approach in natural and semi-natural populations, and suggest some ways in which this field may progress in the near future. PMID- 21237862 TI - Dispersal as a regional process affecting the local dynamics of marine and stream benthic invertebrates. AB - Recent work has shown that benthic invertebrate assemblages may be influenced in an ongoing fashion by dispersal. Water-column movements of meiofauna, juvenile insects and marine postlarvae are common and can act to alter greatly local dynamics such as predator-prey and competitive interactions in marine and stream ecosystems. These findings are important because past research on the role of dispersal in invertebrate dynamics has focused almost exclusively on how planktonic larval supply influences the establishment and maintenance of local assemblages, on the colonization of newly opened sites, or on the settlement success of new recruits. The emerging framework is that dispersal needs to be viewed as a regional process that may routinely influence local benthic dynamics, because fauna can move to and from water-column dispersal 'pools' and may do so at frequent intervals. PMID- 21237863 TI - Sources and sinks in population biology. AB - The various habitats inhabited by a given species are never of the same quality. When demographic models take into account this habitat heterogeneity, the source sink concept naturally emerges: a local demographic surplus arises in good quality habitats (source), and a local demographic deficit occurs in habitats of poor quality (sink). Within a landscape, a permanent migration of propagules or individuals from source to sink habitats may lead to a stabilization of the overall demographic system. This simple situation, explored in the recent literature, has surprising properties. In particular, it requires a change in our view of classical concepts such as ecological niche and carrying capacity, it can explain the existence and persistence of local maladaptation and it can improve conservation practice. PMID- 21237864 TI - The conservation value of small, isolated fragments of lowland tropical rain forest. AB - Deforestation is occurring at an alarming rate in the lowland tropics. In many tropical regions, rain forest is restricted to small (<100 ha), isolated fragments. While only the preservation of large areas of tropical rain forest can safeguard the complete biota, recent research has shown that a substantial number of forest species can persist for decades in fragmented forest, though large vertebrates are susceptible to habitat fragmentation. Inevitably, small fragments will become the last refuges of many rainforest species that are on the brink of extinction. In areas with little rain forest remaining, fragments can be the 'seeds' from which to re-establish extensive forest. PMID- 21237865 TI - Combining data in phylogenetic analysis. PMID- 21237866 TI - Combining data in phylogenic analysis. PMID- 21237868 TI - Reply from j.p. Huelsenbeck, j.j. Bull and C.w. Cunningham. PMID- 21237867 TI - 'Important' may not be enough to explain population cycles. PMID- 21237869 TI - Chaos and evolution. PMID- 21237870 TI - Reply from a.a. Berryman. PMID- 21237871 TI - Conserving wild dogs. PMID- 21237872 TI - Population genetics meets behavioral ecology. AB - Populations are often composed of more than just randomly mating subpopulations - many organisms from social groups with distinct patterns of mating and dispersal. Such patterns have recieved much attention in behavioral ecology, yet theories of population genetics rarely take social structures into account. Consequently, population geneticists often report high levels of apparent in breeding and concomitantly low efective sizes, even for species that avoid mating between close kin. Recently, a view of gene dynamics has been introduced that takes dispersal and social structure into account. Accounting for social structure in population genetics leads to a different perspective on how genetic variation is partitoned and the rate at which genic diversity is lost in natural populations - a view that is more consistent with observed behaviors for the minimization of inbreeding. PMID- 21237873 TI - Quantitative genetics: a promising approach for the assessment of genetic variation in endangered species. AB - The measurement of genetic variation is often an important component of endangered species management programs. Each of several tools available to measure genetic diversity has positive and negative attributes. Quantitative genetic techniques have not received much attention in the conservation field, yet they are likely to reveal variation that is most closely associated with components of fitness. In addition, quantitative genetics may not be as logistically difficult for threatened populations as was once thought. Finally, quantitative genetic models provide a better outlook for conservation programs than single-locus models. PMID- 21237874 TI - Ecosystems as conservation targets. PMID- 21237875 TI - Forced and natural molecular evolution. PMID- 21237876 TI - Meeting of the mangrovellers: the interface of biodiversity and ecosystem function. PMID- 21237877 TI - Progress and problems in arthropod phylogeny. PMID- 21237878 TI - Song and female choice: good genes and big brains? PMID- 21237879 TI - The threatened status of marine fishes. PMID- 21237880 TI - Plant diversity in mediterranean-climate regions. AB - The high plant diversity of mediterranean-climate regions has attracted much attention over the past few years. This review discusses patterns and determinants of local, differential and regional plant diversity in all five regions. Local diversity shows great variation within and between regions and explanations for these patterns invoke a wide range of hypotheses. Patterns of regional diversity are the result of differential speciation and extinction rates during the Quaternary. These rates have been influenced more by the incidence of fire and the severity of climate change than by environmental heterogeneity. All regions have a high number of rare and locally endemic taxa that survive as small populations, many of which are threatened by habitat transformation. PMID- 21237881 TI - Among-site rate variation and its impact on phylogenetic analyses. AB - Although several decades of study have revealed the ubiquity of variation of evolutionary rates among sites, reliable methods for studying rate variation were not developed until very recently. Early methods fit theoretical distributions to the numbers of changes at sites inferred by parsimony and substantially underestimate the rate variation. Recent analyses show that failure to account for rate variation can have drastic effects, leading to biased dating of speciation events, biased estimation of the transition:transversion rate ratio, and incorrect reconstruction of phylogenies. PMID- 21237882 TI - Biodiversity and the productivity and stability of ecosystems. AB - Attempts to unveil the relationships between the taxonomic diversity, productivity and stability of ecosystems continue to generate inconclusive, contradictory and controversial conclusions. New insights from recent studies support the hypothesis that species diversity enhances productivity and stability in some ecosystems, but not in others. Appreciation is growing for the ways that particular ecosystem features, such as environmental variability and nutrient stress, can influence biotic interactions. Alternatives to the diversity stability hypothesis have been proposed, and experimental approaches are starting to evolve to test these hypotheses and to elucidate the mechanisms underlying the functional role of species diversity. PMID- 21237883 TI - Aboveground net primary production decline with stand age: potential causes. AB - Aboveground net primary production (ANPP) commonly reaches a maximum in young forest stands and decreases by 0-76% as stands mature. However, the mechanism(s) responsible for the decline are not well understood. Current hypotheses for declining ANPP with stand age include: (1) an altered balance between photosynthetic and respiring tissues, (2) decreasing soil nutrient availability, and (3) increasing stomatal limitation leading to reduced photosynthetic rates. Recent empirical and modeling studies reveal that mechanisms (2) and (3) are largely responsible for age-related decline in ANPP for forests in cold environments. Increasing respiratory costs appear to be relatively unimportant in explaining declining productivity in ageing stands. PMID- 21237884 TI - Dynamic games and conditional strategies. PMID- 21237885 TI - Reply from m.R. Gross. PMID- 21237886 TI - The genetics of plasticity. PMID- 21237887 TI - Liver physiology and sex ratio biology. PMID- 21237889 TI - Reply from m. Pigliucci. PMID- 21237888 TI - Reply from h.C.j. Godfray and j.h. Werren. PMID- 21237890 TI - Value in biodiversity, ecological services and consensus. PMID- 21237891 TI - Resource competition and within-host disease dynamics. AB - The host organism is a complex mosaic of cell populations that requires adequate supplies of nutrients for maintenance, growth and proliferation. Because many nutrient requirements may be shared by host cells, pathogens and indigenous microflora, all these cells may potentially compete for growth-limiting resources. Ecological theory can explain some of the dynamics commonly seen in host-pathogen interactions; and mechanistic resource-consumer theory provides an instructive framework for viewing the disease process. PMID- 21237892 TI - Environmental anti-science. PMID- 21237893 TI - Do cells show off? Somatic selection and the nature of intercellular signalling. PMID- 21237894 TI - Restoration ecology: science, technology and society. PMID- 21237895 TI - Geomagnetic map used for long-distance navigation? PMID- 21237896 TI - Patterns in the distribution and abundance of grassland species. PMID- 21237897 TI - The evolution of insects and vertebrates: homeobox genes and homology. PMID- 21237898 TI - The dynamics of operational sex ratios and competition for mates. AB - In sexually reproducing animals, individuals of one sex may have to compete for access to mating partners of the opposite sex. The operational sex ratio (OSR) is central in predicting the intensity of mating competition and which sex is competing for which. Thanks to recent theoretical and empirical advances, particularly by exploring the concept of OSR, sexual selection studies today are becoming more fine-tuned and dynamic. The original role of parental investment in predicting sexual selection has recently been complemented by the use of sexual differences in potential reproductive rates (PRR). PMID- 21237899 TI - Plant physiological ecology of tropical forest canopies. AB - Mechanistic information about tropical canopy function is emerging at the leaf, tree, stand and landscape levels. With improved canopy access, comprehensive data are accumulating about seasonal and spatial variation in light, temperature and humidity, and corresponding variation in leaf carbon gain and water loss. At the whole-plant level, simultaneous measurements at different spatial scales have revealed the role of boundary layer dynamics in regulating transpiration. Emergent properties of canopy function are being explored through models that integrate leaf and landscape-level exchange processes. Integration of exchange processes that include functional diversity at different scales has the potential to validate regional estimates of gas exchange, which are critical to our understanding of the role of tropical forests in global atmospheric carbon balance. PMID- 21237900 TI - The population genetic consequences of habitat fragmentation for plants. AB - Habitat fragmentation reduces the size and increases the spatial isolation of plant populations. Initial predictions have been that such changes will be accompanied by an erosion of genetic variation and increased interpopulation genetic divergence due to increased random genetic drift, elevated inbreeding and reduced gene flow. Results of recent empirical studies suggest that while genetic variation may decrease with reduced remnant population size, not all fragmentation events lead to genetic losses and different types of genetic variation (e.g. allozyme and quantitative variation) may respond differently. In some circumstances, fragmentation actually appears to increase gene flow among remnant populations, breaking down local genetic structure. PMID- 21237901 TI - Ecological and conservation insights from reconstructive studies of temperate old growth forests. AB - Reconstructive studies that use paleoecological, dendroecological, historical and other approaches in order to interpret long-term ecosystem dynamics are increasingly generating valuable insights for ecologists, conservationists and foresters who are interested in the ecology, protection and management of old growth forests. In most cases, the historical context provided by these studies reveals a long-term pattern of change that challenges assumptions about the pristine condition of these systems. Ironically, it is the history of environmental fluctuations, natural disturbance processes, and subtle, often indirect, human impacts that is revealed by reconstructive work that may shape the characteristic structure, composition and ecosystem processes of old-growth forests, and that will certainly provide the greatest challenge to their future conservation and management. PMID- 21237902 TI - Microsatellites, from molecules to populations and back. AB - Population genetics studies using microsatellites, and data on their molecular dynamics, are on the increase. But, so far, no consensus has emerged on which mutation model should be used, though this is of paramount importance for analysis of population genetic structure. However, this is not surprising given the variety of microsatellite molecular motifs. Null alleles may be disturbing for population studies, even though their presence can be detected through careful population analyses, while homoplasy seems of little concern, at least over short evolutionary scales. Interspecific studies show that microsatellites are poor markers for phylogenetic inference. However, these studies are fuelling discussions on directional mutation and the role of selection and recombination in their evolution. Nonetheless, it remains true that microsatellites may be considered as good, neutral mendelian markers. PMID- 21237903 TI - Reply from j.B. Jones and R.m. Holmes. PMID- 21237904 TI - But the story gets better: subsurface invertebrates in stream ecosystems. PMID- 21237905 TI - Reply from s. Mopper. PMID- 21237907 TI - Reply from j. Ghazoul and R.k. Didham. PMID- 21237906 TI - Temporal variability and local adaptation. PMID- 21237908 TI - Biodiversity loss and ecosystem function in tropical forests. PMID- 21237909 TI - Reply from k.j. Gaston. PMID- 21237911 TI - Ethology and sea turtle conservation. PMID- 21237910 TI - Nestedness and discontinuities in species-range-size distributions. PMID- 21237912 TI - Behavioural deception. AB - Theoretical models predict that deception should occur even in stable signalling systems. Assessment of the prevalence of deception and its importance has, however, been hampered by the lack of a rigorous definition of what constitutes deception and by the anecdotal nature of much of the literature. For an interaction to qualify as deception, the receiver of the "deceptive" signal must incur a cost. While this cost is often clear in interspecific interactions, it is more difficult to evaluate in interactions between members of the same species. A systematic approach to the study of deception, including the use of experimental techniques to elicit deceptive behaviour, is now required. Such an approach may enable us to address a crucial question in social evolution - whether animals are capable of manipulating the minds of others, or merely their behaviour. PMID- 21237914 TI - International long-term ecological research: priorities and opportunities. PMID- 21237913 TI - Individual-based modelling in ecology: what makes the difference? AB - Is individual-based modelling really a new approach in ecology? A large part of the uncertainty surrounding this question is a consequence of imprecisely delimited boundaries between classical and individual-based modelling. Genuine 'individual-based' models describe a population made up of individuals that may differ from one another; they also describe changes in numbers of individuals rather than in the population density, and take resource dynamics explicitly into account. Individual-based models that fulfil these criteria will not characterize ecological systems as 'stable' systems in their ideal form, with equilibrium states represented by points in the phase space. PMID- 21237915 TI - Riding the evolutionary streetcar: where population genetics and game theory meet. PMID- 21237916 TI - Why populations do what they do. PMID- 21237918 TI - Sustainable forestry in Chilean Tierra del Fuego. PMID- 21237917 TI - Biospherics, closed systems and life support. PMID- 21237919 TI - Biodiversity knowledge in Chile: diagnosis and the first prescription. PMID- 21237920 TI - Gene-culture coevolutionary theory. AB - Gene-culture coevolutionary theory is a branch of theoretical population genetics that models the transmission of genes and cultural traits from one generation to the next, exploring how they interact. These models have been employed to examine the adaptive advantages of learning and culture, to investigate the forces of cultural change, to partition the variance in complex human behavioral and personality traits, and to address specific cases in human evolution in which there is an interaction between genes and culture. PMID- 21237921 TI - Scales of climatic variability and time averaging in Pleistocene biotas: implications for ecology and evolution. AB - Biotic responses to Pleistocene climatic fluctuations have traditionally been analyzed in the context of glacial-interglacial cycles on the scale of 10000-100 000 years. However, emerging evidence indicates that short-term, high-amplitude, climatic 'flickers', close to the limits of the resolving power of the fossil record, occurred within the glacial and interglacial substages. Because species shift geographically in response to the climate flickers, community structures are fluid, with changes absorbed ecologically and not mediated macroevolutionarily. The rapidity of these shifts may also explain anomalous fossil assemblages. PMID- 21237922 TI - The conodont controversies. AB - The discovery of fossilized conodont soft tissues has led to suggestions that these enigmatic animals were among the earliest vertebrates and that they were macrophagous, using their oropharyngeal skeletal apparatus to capture and process prey. These conclusions have proved controversial. There is now a consensus that conodonts belong within the chordates, but their position within the clade is hotly debated. Resolution of these questions has major implications for our understanding of the origin of the vertebrates and the selective pressures that led to the development of the vertebrate skeleton. PMID- 21237924 TI - Skimming and insect evolution. PMID- 21237923 TI - How do animals choose their mates? AB - How animals search for and evaluate prospective mates has, until recently, been a neglected aspect of sexual selection. Theory and field data suggest that discrimination varies with the costs and benefits of choice, but a consensus has yet to be reached on the tactics by which prospective mates are evaluated. This intriguing issue may be clarified by new studies that deal explicitly with the process of information acquisition. PMID- 21237925 TI - Reply from a. Thomas. PMID- 21237926 TI - Benthic-pelagic uncoupling of carbon flow. PMID- 21237927 TI - The eusociality continuum revisited. PMID- 21237928 TI - Reply from j.T. Costa and T.d. Fitzgerald. PMID- 21237929 TI - Reply from f. Boero et Al. PMID- 21237930 TI - Reintroduction: challenges and lessons for basic ecology. AB - Ecology is a subject where theoretical predictions are often difficult to test experimentally in the field. To address this challenge, the Ecological Society of America suggested exploiting large-scale environmental management decisions in a scientific way. This 'adaptive management' constitutes one of the purposes of the Sustainable Biosphere Initiative. Meanwhile, in the current context of the biodiversity crisis, translocations and particularly reintroductions of threatened species are becoming more numerous. It is time for ecologists and wildlife managers to collaborate on these unique opportunities for large-scale studies. PMID- 21237931 TI - Sewall wright meets artificial life: the origin and maintenance of evolutionary novelty. AB - A decade ago, Langton coined the term Artificial Life (A-Life) to identify the new field of research that is attempting to create and characterize open-ended evolving systems using diverse computer-based methods. Fruitful interactions between A-Life research and that of conventional biological sciences (B-Life) are rare. Using the framework of molecular and evolutionary genetics, we discuss some of the reasons for this lack of conceptual cross-pollination between the disciplines and we identify some potential areas for interdisciplinary collaboration. PMID- 21237932 TI - Prions and the new molecular phenetics. PMID- 21237933 TI - Population cycles revisited. PMID- 21237934 TI - Queen-male conflict over sperm use in social insects. PMID- 21237935 TI - Immunocontraception for wildlife population control. PMID- 21237936 TI - Nitrogen- or phosphorus-limited growth in herbaceous, wet vegetation: relations with atmospheric inputs and management regimes. AB - Herbaceous vegetation under temperate climatic conditions generally shows nitrogen- or phosphorus-limited plant growth, which creates conditions for a high botanical diversity. Is nitrogen (N) or phosphorus (P) the most important limiting factor, or are both generally in short supply? What are the consequences of Increased N and P inputs that result from anthropogenic disturbances? A new indicator of N or P limitation, that is, the vegetation N:P ratio, allows us to address these questions for a range of mires, dune slacks and moist grasslands. PMID- 21237937 TI - Learning from rejection: the evolutionary biology of single-locus incompatibility. AB - The self-incompatibility (S-) locus of flowering plants is among the most polymorphic known. PCR methods can now be used to estimate both the number of alleles in natural populations and their sequence diversity. The number of alleles provides an estimate of recent effective population size, thus the S locus provides a tool for examining how species characteristics affect population size. Sequence relationships among alleles provide another estimate of population size extending millions of years into the past. Relationships between S-alleles and related genes provide a means of dating the age of origin of incompatibility systems and determining which, if any, angiosperm families share incompatibility by homology. PMID- 21237938 TI - Interactions between mammals and ectomycorrhizal fungi. AB - Many ectomycorrhizal (ECM) fungi produce fruit-bodies below ground and rely on animals, especially mammals, for dispersal of spores. Mammals may therefore play an important role in the maintenance of mycorrhizal symbiosis and biodiversity of ECM fungi in many forest ecosystems. Given the pivotal role played by mycorrhizal fungi In the nutrition of their plant hosts and, possibly, in the determination of plant community structure, the ecological significance of mycophagous mammals may extend to the productivity and diversity of plant communities. Mycologists and mammalogists have been aware of the interaction between their study organisms for many years, but recent research has produced new insights Into the evolution of mammal-vectored spore dispersal among ECM fungi, the ecological importance of mycophagy to small mammals, and the effectiveness of mammals as spore-dispersal agents. PMID- 21237939 TI - Are fragments worth conserving? PMID- 21237940 TI - Reply from I.m. Turner and R.T. Corlett. PMID- 21237941 TI - Reply from C-I. Wu, N.a. Johnson and m.f. Palopoli. PMID- 21237942 TI - Haldane's rule is dead, long live Haldane's rule. PMID- 21237943 TI - Wild dogs in the Serengeti ecosystem: what really happened. PMID- 21237944 TI - Exploding bird diversity brings biological species into question. PMID- 21237945 TI - Reply from C. Dye. PMID- 21237946 TI - Preparing for the flood: evolutionary biology in the age of genomics. AB - Genome sequencing projects will soon provide a large number of gene sequences from a wide variety of species. Although the impetus of these genome projects involves biotechnology rather than evolutionary biology, several substantial evolutionary problems may potentially be addressed using genomic data. PMID- 21237947 TI - Detectability, philopatry, and the distribution of dispersal distances in vertebrates. AB - Dispersal is of central importance to population biology, behavioral ecology and conservation. However, because field studies are based on finite study areas, nearly all dispersal distributions for vertebrates currently available are biased, often highly so. The inadequacy of dispersal data obtained directly by traditional methods using population studies of marked individuals is highlighted by comparing the resulting distributions with dispersal estimates obtained by radio-tracking and by using genetic estimates of gene flow. PMID- 21237948 TI - Two truths about discounting and their environmental consequences. PMID- 21237950 TI - Staibility in coral communities: a natural experiment. PMID- 21237949 TI - Origin of metazoan phyla: Cambrian explosion or proterozoic slow burn? PMID- 21237951 TI - Timing is everything: new perspective on floral phenology. PMID- 21237952 TI - Thinking globally and team-working globally. PMID- 21237953 TI - Plant life histories: a meeting of phylogeny and ecology. PMID- 21237954 TI - Exploring nutritional biodiversity: a society is born. PMID- 21237955 TI - Begging the question: are offspring solicitation behaviours signals of need? AB - Throughout the animal kingdom, distinctive behaviour by offspring commonly precedes and accompanies their provisioning by parents. Here, we assess empirical support for the recent theory that begging advertises offspring need, that parents provision young in relation to begging intensity, and that the apparently costly nature of begging ensures the reliability of the signal. While there is some support for the predictions of honest signalling models, empirical work has also revealed a host of complexities (such as the use of multiple signals) that existing theoretical analyses have only begun to address. PMID- 21237956 TI - Recombination and clonality in natural populations of Escherichia coli. AB - Bacteria such as Escherichia coli have been commonly viewed as being primarily clonal organisms. As such, the genetic variation within clones was thought to be almost exclusively the result of the mutational process. This conclusion has recently been challenged by data from DNA sequencing studies of natural isolates that are incompatible with a primarily clonal structure. Molecular population genetic analyses of these data, including gene genealogical comparisons, have raised the possibility of a much more complex population structure that may encompass relatively frequent recombination, recurrent selective sweeps and extensive ecological population subdivision. PMID- 21237957 TI - UV-B as an environmental factor in plant life: stress and regulation. AB - Recent studies indicate that increasing solar UV-B is not merely an environmental stress for plants. Solar UV-B can cause plant morphogenetic effects, which can, in turn, modify the architecture of plants and the structure of a vegetation, In addition, UV-B radiation affect the production of various secondary metabolites (such as flavonoids, tannins and lignin) with important physiological and ecological consequences. PMID- 21237958 TI - The behavioral ecology of modern hunter-gatherers, and human evolution. AB - Modern day hunter-gatherers are an obvious source of information about human life in the past. But can modern people really tell us anything about other hominids, those represented only in the fossil record? In a world of state governments and a global economy, can present-day foragers even tell us much about life before agriculture? Some behavioral ecologists think so. Their findings show (1) that foraging practices are closely related to the character and distribution of local resources, (2) that men, women and children react to foraging opportunities quite differently, and (3) that sex and age difference in these reactions have important social causes and consequences. Some results directly challenge long held views about hunter-gatherer economics and social organization, and the scenarios of human evolution based on them. PMID- 21237959 TI - Stand up for parasites. PMID- 21237961 TI - Impact of prediation on the evolution of European bird life histories. PMID- 21237960 TI - Reply from k.h. Johnson et Al. PMID- 21237962 TI - Reply from T.e. Martin and j. Clobert. PMID- 21237963 TI - Neurodevelopmental integrity and zahavian bioacoustics. PMID- 21237964 TI - Ecological advice for the global fisher crisis. AB - Fisheries science was the precursor of population ecology and continues to contribute important theoretical advances. Despite this, fishery scientists have a poor record for applying their insights to real-world fisheries management. Is there a gulf between theory and application or does the high variability inherent in fish populations and complexity of multispecies fisheries demand a different approach to management? Perhaps the solution to the world fisheries crisis is obvious after all? PMID- 21237965 TI - Biodiversity monitoring the missing ingredients. PMID- 21237966 TI - Comparative biology and disease ecology. PMID- 21237967 TI - The breath of life - did increased oxygen levels trigger the Cambrian explosion? PMID- 21237968 TI - Addressing the gender gap in evolutionary biology. PMID- 21237969 TI - Estimating impacts of a dominant detritivore in a neotropical stream. PMID- 21237970 TI - Building phylogenies: are the big easy? PMID- 21237971 TI - Stressing the differences between male and female functions in hermaphroditic plants. PMID- 21237972 TI - Flight and echlocation in the ecology and evolution of bats. AB - Flight and echolocation are key characters distinguishing most bats from other mammals.The number of ecolological niches for bats is limited by the concurent constraints of the mammalian physiology and reproductive system and the high cost of flight and echolocation. The recent discovery of a biomechanical coupling between echolocation and flight highlights the need to incorporate both chracters as parts of a single adaptive complex in future research on the ecology and evolution of bats. PMID- 21237973 TI - Evolution of genital masculinization: why do female hyaenas have such a large 'penis'? AB - In place of a 'normal' external vagina, female spotted hyaenas bear a fully erectile, penis-sized clitoris through which they mate and give birth. Early hypotheses on the evolution of this organ have focused on its signal function, because the erect phallus is used by both sexes as part of submission or appeasement displays. However, a quite different hypothesis is suggested by recent data on the ecological function of female aggressiveness, and on the role of androgens in the development of aggressiveness and male genital development. In this view, the female phallus may have originated as an unselected side effect of selection for androgen-mediated bellicosity, a major advantage in the extraordinarily competitive hyaena social system. PMID- 21237974 TI - The population consequences of territorial behaviour. AB - Many organisms compete for space, or for resource that are linked to space. Territorial behavior in animals is one expression of competition for space. Models of competition for space seek to predict how the arrangement of individuals in a population changes as new individuals appear, others die, and neighbors interact with each other; studies of territorial behaviour examine how neighbor interactions lead animals to establish and maintain their use of space. In recent work on compition for space and on territorial behaviour, there has been a shift from simple, general models to ones that incorporate heterogeneity in the spatial and temporal distribution of resources, and in the ways individuals use resources. PMID- 21237976 TI - Reply from p. Willams et Al. PMID- 21237975 TI - Biodiversity, biospecifics, and ecological services. PMID- 21237977 TI - Reply from C. Perrings. PMID- 21237978 TI - Do all sexual signals trade off the same way? PMID- 21237979 TI - Reply from B.C. Sheldon and s. Verhulst. PMID- 21237980 TI - Reintroduction: challenges and lessons for basic ecology. PMID- 21237981 TI - Reply from f. Sarrazin and R. Barbault. PMID- 21237982 TI - Spatial self-organisation in ecology: pretty patterns or robust reality? AB - Many seemingly plausible mathematical models of small-scale ecological interactions predict the self-organisation of dynamic, coherent and large scale spatial patterns (e.g. spirals). If true, such patterns would have important ecological and evolutionary consequences. For the most part, however, empirical studies have not corroborated their existence, suggesting erroneous dynamics in the models, shortcomings in empirical methodology, or both. Arguments for categorically dismissing self-organized patterns have been based on their assumed sensitivity to symmetry-breaking stochastic noise. However, many plausible mechanisms for generating patterns are robust to noise, and consequently broken symmetry is insufficient grounds for dismissing these self-organized patterns. PMID- 21237983 TI - The embarrassment of riches: atmospheric deposition of nitrogen and community and ecosystem processes. AB - Anthropogenic sources of nitrogen have exceeded, and will continue to exceed, annual inputs of nitrogen produced by natural processes. Nitrogen enrichment may in plant tissue chemistry and microbial decomposition processes, as well as affecting rates of herbivory, all of which may be expected to result in changes in plant species assemblages Individual concepts, such as nitrogen saturation and critical load, used to describe the effects of enrichment on soil, community, ecosystm processes and species assemblages, cannot accomodate easily the range of interactions and different environmental processes. A number of approaches need to be used in tandem. Major gaps in knowledge are rates of transfer of anthropogenic nitrogen within and between different ecosystem and how these rates affect population dynamic of individual species and trophic relationships. Without this information, predictions of biological effects of enrichment are difficult to make. PMID- 21237984 TI - The new antievolution - and what to do about it. PMID- 21237985 TI - Genetics of floral symmetry revealed. PMID- 21237986 TI - An infinitude of connecting links. PMID- 21237987 TI - Characterizing human psychological adaptations. PMID- 21237988 TI - The genetic and molecular basis of developmental stability: the Lucilia story. PMID- 21237989 TI - Human perspectives on the environment. PMID- 21237990 TI - The meeting of two cultures: bridging the gap between ecology and immunology. PMID- 21237991 TI - Figs and fig pollinators: evolutionary conflicts in a coevoled mutualism. AB - Figs and fig wasps form one of the best known examples of species-specific mutualism and coevolution. Recent experiments and observations have led to a better understanding of the evolutionary processes involved in the origin and maintenance of species interactions. The observed fine-tuned traits involve not only coevolution but also selection acting on only one of the partners. Furthermore, some of the 'fine-tuned traits' appear to be be preadaptions - traits that existed before the mutalism was establised. PMID- 21237992 TI - Indiscriminate altruism: unduly nice parents and siblings. AB - Many animals can identify their relatives and bias altruistic behaviour in their favour. However, recent studies have also uncovered cases where nepotism might be expected but is weak or absent within social groups. For instance, in some bird and mammal species, males apparently feed offsping that have been sired by other males at the same rate as their own offspring. Similarly, social insect workers fail to favour more closely related individuals within their colony. Why is this so? PMID- 21237993 TI - Non-flying mammals as pollinators. AB - Non-flying mammals such as marsupials, primates and rodents have long been reported to visit flowers, but, until recently, evidence confirming their role in pollination was lacking. Three types of data have been sought in order to establish pollinator effectivness: (1) evidence of regular visitation to flowers, (2) evidence that mammals carry significant loads of pollen, and (3) experimental evidence for pollination. Here, we review recent studies that provide these data. It is now clear that many species of marsupials and primates are involved in pollination in Australia, Africa and South and Central America. We also examine earlier contentions that some plants exhibit traits that have co-evolved with non flying mammal pollinators. Much more research is still required to understand the importance of these animals in pollination. PMID- 21237994 TI - Wind as an ecological factor. AB - Wind has long been regarded as an important ecological factor in forests owing to the dramatic damage hurricanes can wreak. However, the long-term wind regime of a site also exerts a strong influence on the growth of trees. A relatively large amount is known about the acclimation of trees to wind but less about intra- or interspecific adaption to high winds. In fact, changes resulting from the effect of wind may have a greater effect on the ecology of forests than the more acute effects of destructive stroms. Improved understanding of the mechanical effects of wind is helping foresters manage their plantations and may help us to account better for local and geographical variations in forest ecology. PMID- 21237995 TI - Individual-based modelling: what is the difference? PMID- 21237996 TI - Individual-based modelling: what is the diffrence? Reply from J. Uchmamanski and V. Grimm. PMID- 21237997 TI - Hatching asynchrony in birds. PMID- 21237998 TI - Hatching asynchrony in birds Reply from M.J. Stenning. PMID- 21237999 TI - Evolution in mediterranean-climate regions Reply from R.M. Cowling. PMID- 21238000 TI - Evolution in mediterranean-climate regions. PMID- 21238001 TI - The long and short of nuclear mitochondrial DNA (Numt) lineages. PMID- 21238002 TI - The long and short of nuclear mitochondrial DNA (Numt) lineages Reply from D-X. Zhang and G.M. Hewitt. PMID- 21238003 TI - School yards and nature trails: ecology education outside the university. AB - Ecologists, conservation biologists and other natural historians increasingly recognize the need to become involved in public education. An ecologically literate public may be the 'last best hope' for a sustainable biosphere. Partnerships between ecologists and educators may be the best hope, though not the last, for moving towards an ecologically literate public. What are some practical schemes for such partnerships? We present a model for ecology education that has shown promise in several South American settings and describe its application in two quite different contexts in southern Argentina. We hope that our colleagues will ponder, criticize, modify, improve and apply the model in settings other than those we present here. PMID- 21238005 TI - Sexual cannibalism: who benefits? PMID- 21238004 TI - Are the spandrels of San Marco really panglossian pendentives? PMID- 21238006 TI - Can adaptive dynamics invade? PMID- 21238007 TI - The world conservation congress. PMID- 21238008 TI - Documenting present and past biodiversity: conservation biology meets palaeontology. PMID- 21238009 TI - Rapid reversible changes in organ size as a component of adaptive behaviour. AB - Organ structures and correlated metabolic features (e.g. metabolic rate) have often taken as fixed attributes of fully grown individual vertebrates. When measurements of these attributes became available they were often used as representative values for the species, disregarding the specific conditions during which the mesurement were made. Evidence is accumulating that the functional size of organs and aspects of the metabolic physiology of an individual may show great flexibility over timescales of weeks and even days depending on physiological status, environmental conditions and behavioural goals. This flexibility is a way for animals to cope successfully with a much wider range of conditions occurring during various life-cycle events than fixed metabolic machinery would allow. Such phenotypic flexibility is likely to be a common adaptive syndrome, typical of vertebrates living in variable environments. PMID- 21238010 TI - Competition for nitrogen between plants and soil microorganisms. AB - Experiments suggest that plants and soil microorganisms are both limited by inorganic nitrogen, even on relatively fertile sites. Consequently, plants and soil microorganisms may compete for nitrogen. While past research has focused on competition for inorganic nitrogen, recent studies have found that plants/mycorrhizae in a wide range of ecosystems can use organic nitrogen. A new view of competitive interactions between plants and soil microorganisms is necessary in ecosystem where plant uptake of organic nitrogen is observed. PMID- 21238011 TI - Environmental stochasticity and population dynamics of large herbivores: a search for mechanisms. AB - Recently, the results from several long-term individual-based population studies of ungulates have been published. One major conclusion is that the population dynamics of ungulates in predator-free environments is strongly influenced by a combination of stochastic variation in the environment, and population density. Both density dependence and environmental stochasticity operate through changes in life history traits, correlated with variation in body weight. This generates delays in the response of the population to changes in environment. In the absence of predation, a stable equilibrium is therefore unlikely to exist between an ungulate population and its food resources. This thorough understanding of the mechanisms generating population fluctuations suggests that studies of ungulates will provide an important source for examining effects of long-term changes in the environment, for instance, resulting from a climatic change. PMID- 21238012 TI - Pacific Ocean climate change: atmospheric forcing, ocean circulation and ecosystem response. AB - A major climate change event that affected atmospheric forcing, ocean circulation and ecosystem structure of the Pacific Ocean began in the mid-1970s. Changes in biomass, and presumably productivity, of the lower trophic levels (phytoplankton and Zooplankton) were directly attributed to this event. It also appears that some individual species at higher trophic levels were influenced, but cause-and effect relationships are more difficult to document at the species level. Recent work shows that at least five major pelagic ecosystems responded to this event, but in different ways, and both increases and decreases in biomass were seen. Changes of this magnitude are well documented in the paleo-oceanographic record. However, it remains to be determined to what extent the changes were caused by natural cycles versus anthropogenic change (global warming). PMID- 21238014 TI - Deception: the correct path to enlightenment? PMID- 21238013 TI - Sexual conflict resulting from adaptations to sperm competition. AB - Recent research on diverse animal taxa has revealed that male adaptations to sperm competition often lead to a conflict with female interests. That is, male attempts to increase their own fertilization success can result in a reduction of female fitness. This sexual conflict has led to selection for a variety of female adaptations that apparently reduce male-imposed costs. Understanding the causes and consequences of sexual conflict arising from adaptations to sperm competition offers much potential for new insight into the coevolution of male and female sexual strategies. PMID- 21238015 TI - Reply. PMID- 21238016 TI - Deception: the correct path to enlightenment? PMID- 21238018 TI - Sources, sinks and chaos. PMID- 21238017 TI - Reply. PMID- 21238019 TI - Sewall Wright meets artificial life. PMID- 21238021 TI - What does 'ecology' mean? PMID- 21238020 TI - Social terminology: what are words worth? PMID- 21238023 TI - Plant-soil feedback as a selective force. PMID- 21238022 TI - Sepia tones, stomatopod signals and the uses of colour. PMID- 21238024 TI - Chaos in a cup of flour. PMID- 21238025 TI - Sperm selection by females. PMID- 21238026 TI - Quick indirect interactions in intertidal food webs. PMID- 21238027 TI - Aerodynamics and insect flight. PMID- 21238028 TI - Speciation in ancient lakes. AB - About a dozen lakes in the world are up to three orders of magnitude older than most others. Lakes Tanganyika (East Africa) and Baikal (Siberia) have probably existed in some form for 12-20 million years, maybe more. Such lakes can have different origins, sizes, shapes, depths and limnologies, but, in contrast to short-lived (mostly post-glacial) lakes, they have exceptionally high faunal diversity and levels of endemicity. A multitude of and processes accounting for these explosive radiations have recently been documented, most of them based on particular groups in certain lakes, but comparative research can detect repeated patterns. No special speciafion mechanism, exclusive to ancient lakes has been demonstrated, although cases of ultra-rapid speciation have been documented. Extant diversity results not by simple accumulation, but by a complex process of immigration, speciation and extinction. PMID- 21238029 TI - Origin and evolution of the grazing guild in new world terrestrial mammals. AB - Although vertebrate herbivory has existed on land for about 300 million years, the grazingadaptation, principally developed in mammals, did not appear until the middle Cenozoic about 30 million years ago. Paleontological evidence indicates that grazing mammals diversified at the time of the spread of grasslands. Recently revised fossil calibrations reveal that the grazing mammal guild originated during the early Miocene in South America about 10-15 million years earlier than it did during the late Miocene in the northern hemisphere. Carbon isotopic analyses of extinct grazers' teeth reveal that this guild originated predominantly in C(3) terrestrial ecosystems. The present-day distribution of C(3) and C(4) grasslands evolved on the global ecological landscape since the late Miocene, after about 7 million years ago. PMID- 21238031 TI - Two beliefs about discounting and their environmental irrelevance. PMID- 21238030 TI - Self-organization in social insects. AB - Self-organization was introduced originally in the context of physics and chemistry to describe how microscopic processes give rise to macroscopic stuctures in out-of-equilibrium systems, Recent research that extends this concept to ethology suggests that it provides a concise description of a wide range of collective phenomena in animals, especially in social insects. This description does not rely on individual complexity to account for complex spatiotemporal features that emerge at the colony level, but rather assumes that intractions among simple individuals can produce highly structured collective behaviours. PMID- 21238032 TI - Is the propagation of prion molecules in different hosts an example of lamarckian inheritance? PMID- 21238033 TI - Two beliefs about discounting and their environmental irrelevance Reply from N. Henderson and W.J. Sutherland. PMID- 21238034 TI - Is the propagation of prion molecules in different hosts an example of lamarckian inheritance? Reply from M. Pagel and D.C. Krakauer. PMID- 21238036 TI - Stability and invasibility of coral communities Reply from M.D. Jennions. PMID- 21238035 TI - Stability and invasibility of coral communities. PMID- 21238037 TI - Direct and indirect estimates of dispersal distances. PMID- 21238039 TI - The state of biological knowledge. PMID- 21238038 TI - Genetics of host-parasite interactions. AB - The evolution of host susceptibility or resistance to parasites has important consequences for the evolution of parasite virulence, host sexual selection, population dynamics of both host and parasite populations, and programs of biological control. The general observation of a fraction of Individuals within a population that is not parasitized, and/or the variability in parasite intensity among hosts, may reflect several phenomena acting at different levels of ecological organization. Yet, host-parasite coevolution requires host susceptibility and parasite virulence to be genetically variable. In spite of evolutionary and epidemiological implications of genetic heterogeneities in host parasite systems, evidence concerning natural populations is still scarce. Here, we wish to emphasize why we need a better knowledge of the genetics of host parasite interaction in natural populations and to review the evidence concerning the heritability of host susceptibility or resistance to parasites in natural populations of animals. PMID- 21238040 TI - Singing in the rain forest: The duets of bay wrens. PMID- 21238041 TI - Agricultural versus ethological oceanography. PMID- 21238042 TI - Behaviour and speciation. PMID- 21238043 TI - Extending the availability of microscopic type material for taxonomy and research. PMID- 21238044 TI - The behavioural and physiological ecology of diving. AB - Recent measurements of remarkable dive performances in oceanic seabirds and marine mammals suggest the use of a range of physiological and behavioural adaptations for the parsimonious use of oxygen. Access to food at different depths may be directly related to the duration of the breath-hold, and several physiological strategies may be used to extend dive duration. But is also a growing appreciation of the importance of behavioural strategies adopted by divers to minimize the effects of physiological limitations on diving performance and to maximize acces to food. PMID- 21238045 TI - The origin and early evolutionary history of amniotes. AB - Recent phylogenetic analyses of Paleozoic tetrapods have yielded startling new insights into the origin and early evolutionary history of amniotes. The origin of this successful group involves evolutionary innovations that are associated with the development of the cleidoic egg and related reproductive strategies, and are therefore not represented directly in the fossil record. Despite this obvious difficulty, recent studies have been able to distinguish Paleozoic amniotes from their anamniotic tetrapod relatives to determine major patterns of interrelationships. PMID- 21238046 TI - Facts from feces revisited. AB - Obtaining information on wild mammal populations has been a long-standing logistical problem. However, an array of non-invasive techniques is available, including recently developed molecular genetic techniques for the analysis of feces (molecular scatology). A battery of non-invasive, molecular approaches can be used on feces, which in conjunction with conventional analysis are potentially useful for assesing genetic structure, demography and life history of mammals. Several technical problems reman before large-scale studies of feces can be undertaken productively, but already studies are providing insight into population subdivision, food habits, reproduction, sex ratio and parasitology of free-ranging populations. PMID- 21238047 TI - The new anti-evolution. PMID- 21238048 TI - Reply from k. Padian and e.C. Scott. PMID- 21238049 TI - The new anti-evolution. PMID- 21238050 TI - Darwinism and design. PMID- 21238051 TI - Hatching asynchrony in birds. PMID- 21238052 TI - Diversity in hunter-gatherer foraging. PMID- 21238053 TI - Discounting - the last word. PMID- 21238054 TI - Fluctuating around directional asymmetry? PMID- 21238055 TI - The role of theory in an emerging new plant reproductive biology. AB - Recent empirical studies hint at an end to the historical solitude between pollination and mating system approaches to plant reproductive character evolution. Now is an opportune time to distill theoretical results into comprehensible insight, and to integrate these findings into the emerging new plant reproductive biology. We outline four theoretical insights for understanding the evolution of reproductive characters, and show how these allow researchers to dissect complex ecological scenarios into clear and evolutionarily relevant components. PMID- 21238056 TI - Why are organisms usually bigger in colder environments? Making sense of a life history puzzle. AB - Environmental effects on body size are of widespread ecological and economic importance but our understanding of these effects has been obscured by an apparent paradox. Life history analysis suggests that it is adaptive for adults to emerge smaller if reared in conditions that slow down juvenile growth. However, whereas smaller adults emerge if growth is limited by food availability, the reverse is usually observed if growth is limited by temperature. The resolution of this apparent paradox may be that the response of adult size to temperature is adaptive, but is constrained by a trade-off that can be understood in terms of von Bertalanffy's classic theory of growth. Alternatively, the response may be the unavoidable consequence of a fundamental relationship between cell size and temperature. PMID- 21238058 TI - Forest turnover, diversity, and CO(2). PMID- 21238057 TI - Antarctic biology in the mainstream? PMID- 21238059 TI - Policing: it pays the strong to protect the weak. PMID- 21238060 TI - Female promiscuity and genetic incompatibility. PMID- 21238061 TI - Landscape alteration in the Americas. PMID- 21238062 TI - New tools for sex identification and the study of sex allocation in birds. AB - The recent development of simple, DNA-based methods for the determination of an individual's sex will make possible large-scale studies of sex allocation and the consequence of gender in birds. Birds provide ideal systems for studying these questions in vertebrates, as so much is known about their biology and determinants of fitness. Until recently, however, little quantitative work has been possible because of the difficulty in determining gender in most cases. Recent studies suggest that biased sex allocation be more widespread in birds than has been realized. PMID- 21238063 TI - Sex and size in cosexual plants. AB - There are conceptual and practical difficulties in measuring the exact shape of fitness-gain curves and sex allocation, and these hamper empirical testing of some of the basic predictions of sex allocation theory for plants. Nevertheless, our knowledge of the processes that shape fitness-gain curves allows us to formulate hypotheses to test predictions of sex allocation theory. One such hypothesis is that plants adjust their gender according to size. The connection between plant size and gender was generally thought to be weak. Recent data, however, suggest that size-dependent sex allocation (SDS) is a common phenomenon in hermaphrodites and other cosexual plants. PMID- 21238064 TI - The relative of species pools in determining plant species richness: an alternative explanation of species coexistence? AB - Explanations of the pattern of species have traditionally relied on small-scale, local processes occurring in ecological time. Differences in species richness have associated with different mechanisms avoiding competition, such as spatiotemporal heterogeneity (weaker competitors may find a more favourable place or time) or environmental stress (competition is assumed to be less intensive under difficult conditions). More recently, large-scale process have been taken into account, raising such questions as: which plant species may potentially grow in a certain community? Are evolutionary processes and species dispersal responsible for the differences between communities? The species-pool theory attempts to answer these general questions, and information about species pools is needed for the design of experiments where the number of species in a community is manipulated. PMID- 21238066 TI - Indiscriminate altruism - time for a more discriminating approach? PMID- 21238065 TI - Why don't birds lay more eggs? AB - Fifty years ago David Lack put forward a key hypothesis in life-history theory: that avian clutch is ultimately determined by the number of young that parents can provide with food. Since then, a plethora of brood manipulations has shown that birds can rear more young than the number of eggs they lay, and prompted a search for negative effects of increased effort on future reproduction. However, recent studies have shown that the demands of laying and incubating eggs generally omitted from experiments, could affect parental fitness. Lack's hypothesis, and the tests of its validity, need to be extended to encompass the full demands of producing and rearing the brood. PMID- 21238067 TI - Indiscriminate altruism - time for a more discriminating approach? Reply from L. Keller. PMID- 21238068 TI - Ecosystem engineering by organisms: why semantics matters. PMID- 21238070 TI - Is anything independent of selection? PMID- 21238069 TI - Ecosystem engineering by organisms: why semantics matters Reply from M. Power. PMID- 21238071 TI - Is anything independent of selection? Reply from A.I. Houston. PMID- 21238072 TI - Wind and trees. PMID- 21238073 TI - An honorary non-flying mammal pollinator. PMID- 21238074 TI - Wind and trees Reply from A.R. Ennos. PMID- 21238075 TI - Morphological approaches to measuring biodiversity. AB - Morphological diversity has the potential to provide a very useful biodiversity metric in that if emphasizes essential aspects of diversity that are not picked up by taxonomic or phylogenetic metrics. While morphological diversity metrics are used increasingly in paleobiological studies, quantitative data on the spatial distribution of morphology in modern ecosystems are scarce. The comparison between different aspects of diversity is often essential in understanding the processes underlying observed biodiversity patterns. PMID- 21238077 TI - Transdisciplinarity: transcending the disciplines. PMID- 21238076 TI - Epistasis and its consequences for the evolution of natural populations. AB - Throughout the neodarwinian synthesis, theorists have debated the role of gene interactions, or epistasis, in the evolutionary process. Unfortunately, empirical measurement of the role of epistasis in the evolution of natural populations has, until now, been difficult. Two developments in empirical approaches have occurred: (1) application of theory to the evolution of natural populations, and (2) the concurrent development of molecular marker-assisted techniques to understand the architecture of quantitative genetic variation. Thus, exciting developments in both theory and empirical data collection provide the stimulus for documenting the role of epistasis in the evolutionary process. PMID- 21238078 TI - When mothers prefer daughters over sons. PMID- 21238079 TI - Variation in blue tit breeding timetables: what factors trigger reproduction? PMID- 21238080 TI - Southern temperate biota and ecosystems: past, present and future. PMID- 21238081 TI - 'SINEs of the times' - transposable elements as clade markers for their hosts. PMID- 21238082 TI - Extraordinary sex ratios for extraordinary reasons. PMID- 21238083 TI - Speciation and signal trait genetics. PMID- 21238084 TI - Global biodiversity: is it in the mud and the dirt? PMID- 21238085 TI - Palaeontology in a molecular world: the search for authentic ancient DNA. AB - The survival of ancient DNA in specimens up to several thousands of years old is established. However, there have been several claims concerning the recovery of geologically ancient DNA from fossil material many millions of years old. The authenticity of these fossil DNA sequences is questionable on theoretical and empirical grounds, and the existence of authentic geologically ancient DNA remains to be proven. PMID- 21238086 TI - Evolution and speciation on holey adaptive landscapes. AB - Sewall Wright's powerful metaphor of rugged adaptive landscapes has formed the basis for discussing evolution and speciation for more than 60 years. However, this metaphor, with its emphasis on adaptive peaks and valleys, is to a large degree a reflection of our three-dimensional experience. Both genotypes and phenotypes of biological organisms differ in numerous characteristics, and, thus, the dimension of 'real' adaptive landscapes is much larger than three. Properties of multidimensional adaptive landscapes are very different from those of low dimension. Consequently, something that is seen as a theoretical challenge in a low-dimensional case might be a trivial problem in a multidimensional context and vice versa. In particular, the problem of how a population crosses an adaptive valley on its way from one adaptive peak to another, which Wright attempted to solve with his shifting balance theory, may be non-existent. A new framework is emerging for deepening our understanding of evolution and speciation, which provides a plausible multidimensional alternative to the conventional view of rugged adaptive landscapes. PMID- 21238087 TI - Statistical analyses of population genetic data: new tools, old concepts. AB - Several methods or tests and various software are currently being developed for analyzing data in population genetics and ecology, which often rely on computer intensive algorithms. The potential user is thus confronted with the painful experience of freedom and, in particular, has to makea priori choices between different methods. Using examples drawn from population genetics, we explain some of these recently developed tools. PMID- 21238088 TI - Reply from J-P. Rodri'guez. PMID- 21238089 TI - Conservation and animal welfare. PMID- 21238090 TI - An arid Amazon? PMID- 21238091 TI - Reply from B.B. Simpson. PMID- 21238092 TI - Is the ecology of molecules really ecology? PMID- 21238093 TI - Restoring abaptation. PMID- 21238094 TI - Food webs: a plea for parasites. AB - Parasites have the capacity to regulate host populations and may be important determinants of community structure, yet they are usually neglected in studies of food webs. Parasites can provide much of the information on host biology, such as diet and migration, that is necessary to construct accurate webs. Because many parasites have complex life cycles that involve several different hosts, and often depend on trophic interactions for transmission, parasites provide complementary views of web structure and dynamics. Incorporation of parasites in food webs can substantially after baste web properties, Including connectance, chain length and proportions of top and basal species, and can allow the testing of specific hypotheses related to food-web dynamics. PMID- 21238095 TI - Emperor ecology in the Antarctic winter. PMID- 21238097 TI - Female roles in perspective. PMID- 21238096 TI - The value of biodiversity. PMID- 21238098 TI - Reading between the lines - is allometric scaling useful? PMID- 21238099 TI - Vole cycles on Hokkaido: a time-series goldmine. PMID- 21238100 TI - The evolution of coloniality: the emergence of new perspectives. AB - The evolution of group living remains an outstanding question in evolutionary ecology. Among the most striking forms of group living are the enormous assemblages of breeders that occur in many colonial marine birds and mammals, with some colonies containing more than a million individuals breeding in close contact. Coloniality is an evolutionary puzzle because individuals pay fitness costs to breed in high densities. Despite numerous potential benefits proposed to overcome these costs, we still lack a general framework to explain coloniality. Several new hypotheses involving breeding habitat and mate selection create promising approaches for studying this enigma. PMID- 21238101 TI - Positive selection and recombination: major molecular mechanisms in colicin diversification. AB - Colicins, a family of antimicrobial proteins produced by Escherichia coli, are one of the best characterized microbial systems for studying processes of molecular diversification. Recent studies employing DNA sequence comparisons and experimental evolution suggest that positive selection and recombination play dominant roles in colicin diversification. Recombination between distantly related colicins has repeatedly generated novel classes of colicins, while positive selection for novel colicin immunity systems produces further diversity among closely related colicins. Together, these forces have resulted in a surprisingly large and diverse class of antimicrobials. Colicins are thought to play an important role in the invasion of bacteria into novel habitats. PMID- 21238102 TI - Catastrophic vegetation shifts and soil degradation in terrestrial grazing systems. AB - It has long been recognized that alternative vegetation states may occur in terrestrial grazing systems. This phenomenon may be of great importance as small environmental fluctuations may lead to relatively sudden and irreversible jumps between vegetation states. Early theoretical studies emphasized saturation of herbivore feeding to explain multiple stable states and catastrophic behaviour. Recent studies on semi-arid grasslands and arctic salt marshes, however, relate catastrophic events in these systems to plant-soil interactions. PMID- 21238103 TI - Are big trees indeed easy? PMID- 21238104 TI - Are big trees indeed easy? Reply from A. Purvis and D.L.J. Quicke. PMID- 21238105 TI - Are big trees indeed easy? Reply from D.M. Hillis. PMID- 21238106 TI - Documenting biodiversity: the need for species identifications. PMID- 21238107 TI - Documenting biodiversity: the need for species identifications Reply from M.S.Y. Lee. PMID- 21238108 TI - Ecological taxonomy: a basic tool for biodiversity conservation. PMID- 21238109 TI - Animal foraging: past, present and future. AB - Studies of foraging behaviour have proliferated over the past 30 years. Two schools of thought have emerged, one focusing on theoretical aspects (so-called 'optimal foraging theory'), the other on empirical studies. We summarize both, showing how they have evolved and begun to coalesce during the past decade. The emerging new framework is more complex than previous models, combining theory with observation. Modern phylogenetic methods promise new insights into how animal foraging has evolved. PMID- 21238110 TI - Symbiosis, fisheries and economic development on coral reefs. AB - Life-history traits of commercially important species, physiological attributes of the framework species, and characteristics of ecosystem processes make coral reefs especially vulnerable to export of biomass. Organisms in ecosystems driven by upwelling and terrestrial nutrient input are more amenable to biomass yield. Nonexportive approaches to resource management, exemplified by Palau, are compatible with the attributes of coral-reef ecosystems; they satisfy to a greater degree the economic demands and pressures of growing human populations, and they provide motivation to manage. PMID- 21238111 TI - A major transition in Darwinism. AB - Many lines of evidence indicate that in recent: years the focus of evolutionary biology has begun to shift from explaining the 'origin of species' to the modelling of processes by which autonomous entities cooperate (or are coerced) to form systems of greater complexity. If such a major shift is indeed occurring, then it should be more widely promulgated to counteract the public image of evolutionary theory, which appears to be as dogmatically simplistic today as it was a century ago. PMID- 21238112 TI - Sustainability and chaos: are they commensurable? PMID- 21238113 TI - To hide or not to hide? Refuge use in a fluctuating environment. PMID- 21238114 TI - Selfish genetic elements: long-range dynamics predicted by non-equilibrium models. PMID- 21238115 TI - Parasitoids as limiting and selective factors: can biological control be evolutionarily stable? PMID- 21238116 TI - The spped of life-history evolution. PMID- 21238117 TI - Old and new agendas for ontogeny. PMID- 21238118 TI - The diversity of speciation. PMID- 21238119 TI - Aquatic life cycle strategies: survival in a variable environment. PMID- 21238120 TI - Evolutionary aspects of ant-fungus interactions in leaf-cutting ants. AB - Leaf-cutting ants are highly successful herbivores because they are able to use a wide variety of plants as food The workers harvest and process plant material to be used as substrate for a fungus on which they feed. New hypotheses concerning the evolution of the ant-fungus relationship have now been proposed. Although the relationship between the ants and the fungus is mutualistic, if may appear that the fungus has little control over the ants. However, evidence suggests that the fungus may be exploiting the ants to provide it with substrate and antimicrobial defence. Furthermore, experimental evidence suggests that the fungus can select its substrate by controlling the foraging behaviour of the ants, by means of an ingenious chemical feedback mechanism. PMID- 21238121 TI - Patchy habitats, division of labour and growth dividends in clonal plants. AB - Natural habitats are patchy in quality. in clonal plants, resource-acquiring structures often occupy sites that differ in quality. Clonal plants can display division of labour in resource-acquisition duties, manifested as local specialization by ramets, which enhances acquisition of each resource from sites of greatest abundance. Physiological integration can re-distribute resources internally from sites of acquisition to clone parts sited where the same resources are scarce. Recent research is showing that such specialization and resource sharing is a highly efficient strategy for acquiring resources and that it can result in considerably greater growth when resources are heterogeneously distributed than when the same quantity of resources is distributed homogeneously. PMID- 21238122 TI - (Meta)population dynamics of infectious diseases. AB - The metapopulation concept provides a very powerful tool for analysing the persistence of spatially-disaggregated populations, in terms of a balance between local extinction and colonization. Exactly the same approach has been developed by epidemiologists, in order to understand patterns of diseases persistence. There is great scope for further cross-fertilization between areas. Recent work on the spatitemporal dynamics of measles illustrates that the large datasets and rich modelling literature on many infectious diseases offer great potential for developing and testing ideas about metapopulations. PMID- 21238123 TI - Intrapopulation coadaptation. PMID- 21238124 TI - Reply from C.B. Fenster, L. Chao and L.f. Galloway. PMID- 21238125 TI - Large herbivore population dynamics. PMID- 21238126 TI - Reply from B-e. Saether. PMID- 21238127 TI - The peniform clitoris of female spotted hyaenas. PMID- 21238128 TI - Reply from L.g. Frank. PMID- 21238129 TI - Discounting and conservation: another final word. PMID- 21238130 TI - Sessile animals: attached, but promiscuous? PMID- 21238131 TI - What does and should 'ecology' mean? PMID- 21238132 TI - Forest turnover, diversity and CO(2). PMID- 21238133 TI - Developmental genetics and homology: a hierarchical approach. AB - New advances in developmental genetics are providing a bridge to connect the study of development and evolution. The successful integration of these fields, however, is dependent on having a clear understanding of the concept of homology. Therefore, developmental genetic data must be placed within the context of the comparative method to provide insight into the evolutionary and developmental origins of traits. The comparative analysis of traits derived from several hierarchical levels (genes, gene expression patterns, embryonic origins and morphology) can potentially reveal scenarios of developmental integration, opportunity and constraint. Moreover, this approach has implications for resolving modern controversies surrounding the concept of homology. PMID- 21238135 TI - How much memory do tits need? PMID- 21238134 TI - Microcosmos - a review. PMID- 21238136 TI - Craning for a better view: the canopy crane network. PMID- 21238137 TI - Patterns and processes in the vertebrate digestive system. PMID- 21238138 TI - Mitochondrial Eve: the plot thickens. PMID- 21238139 TI - To introduce or not to introduce trade-offs of non-indigenous organisms. PMID- 21238140 TI - Plant responces to global changes in Co(2): unfinished business? PMID- 21238141 TI - Divergent perspectives on community convergence. AB - Recent experimental and theoretical studies of community development, as well as more general studies of complex systems, indicate that historical differences and intrinsic indeterminism can lead to long-term community divergence. This observation has sparked a series of new investivations of community structure in systems that developed under controlled or natural conditions. PMID- 21238142 TI - Reducing bias in the measurement of selection. AB - Selection on quantitative characters is commonly mesured in natural populations using regression techniques based on phenotypic covariances between traits and fitness. However, such methods do not give an accutate view of the causal relationship between the phenotype and fitness if enviornmental factors also contribute to covariances between traits and fitness. A recently developed method for estimating selection eliminates the problem of bias resulting from enviormental covariances. This underappreciated method represents a significant addition to the toolbox of evolutionary ecologist. PMID- 21238143 TI - Anaerobic eukaryote evolution: hydrogenosomes as biochemically modified mitochondria? AB - Hydrogenosomes are energy generating organelles which are found in a variety of anaerobic microbial eukaryotes. Recent data suggest that some of these hydrogenosomes may be bichemically modified mithochondria, subverting the conventional role of this compartment from one of oxidative phosphorylation, to one of hydrogen evolving fermentation. The origins of the key enzymes which are responsible for hydrogen porduction are currently obscure but they are not considered to be typical of most eukaryotes. PMID- 21238144 TI - Geometrical constraints on body size. PMID- 21238145 TI - Geometrical constraints on body size Reply from D. Atkinson and R.M. Sibly. PMID- 21238146 TI - Optimizing clutch size in birds. PMID- 21238147 TI - Optimizing clutch size in birds. PMID- 21238148 TI - Optimizing clutch size in birds Reply from P. Monaghan and R. Nager. PMID- 21238150 TI - Descriptive and predictive approaches to biodiversity measurement Reply from M. Foote and K. Roy. PMID- 21238149 TI - Descriptive and predictive approaches to biodiversity measurement. PMID- 21238151 TI - Sperm choice by females. PMID- 21238152 TI - Sperm choice by females Reply from P. Wirtz. PMID- 21238153 TI - Whither ecology? PMID- 21238154 TI - The evolutionary biology of spontaneous abortion in humans. AB - Human mothers an efficient screening system to eliminate genetically abnormal embryos. However, the incidence of certain birth defects - most notably Down's syndrome - rises with maternal age. Conventional eplanations have focused on a rising production of defective zygotes; in contrast, an evolutionary approach suggest a relaxed maternal screen. Relaxed screening potentially explains the rising incidenee of chromosomal abnormalities in live-births, the incidence of normal embryos in spontaneous abortions, and the incidence of spontaneous abortions with maternal age. If true, then restoration of the screen may be possible, reducing the incidence of birth defects. PMID- 21238155 TI - Defining and teaching environmental literacy. PMID- 21238156 TI - Variation in plant growth: from apex to ecosystem. PMID- 21238157 TI - Consistent heritability changes under poor growth conditions. PMID- 21238158 TI - Phylotypic stage or phantom: is there a highly conserved embryonic stage in vertebrates? PMID- 21238159 TI - The ant and the lion: common principles and idiosyncratic differences in social evolution. PMID- 21238160 TI - The transformation of systematics? PMID- 21238161 TI - The rise and fall of new mutations. PMID- 21238162 TI - Secondarily solitary: the evolutionary loss of social behavior. AB - Studies of social behavior frequently assume that evolution proceeds from a solitary state to a social one, and social to social lineages give rise to line are also social, excluding parasitic taxa. Recent phylogenetic studies of some bees contradict this assumption, and more examples are known or hypothesized in other animals. Social behaviour can be lost to give rise to species that are secondarily solitary. Studies of the conditions to the suppression or loss of social behavior can help to illuminate those factors that lead to its origins and maintenance. PMID- 21238163 TI - Plant functional classifications: from general groups to specific groups based on response to disturbance. AB - Predicting the effects of anthropogenic changes in climate, atmospheric composition and land use on vegetation patterns has been a central concern of recent ecological research. This aim has revived the search for classification schemes that can be to group plant species according to their response to specified environmental factors. One way forward is to adopt a hierarchical classification, where different sets of traits are examined depending on growth form. Also, at the level of interpretation, the environmental context and purpose of functional classifications need to be specified explicitly, so that global generalizations can be made by comparing across environments functional classifications derived from similar methodologies. PMID- 21238164 TI - The role of experimental microcosms in ecological research. AB - A number of recent and important developments in community ecology have been derived from experiments conducted in microcosms. Studies with microcosms have addressed a broad range of phenomena, including climate change, biodiversity, assembly rules, habitat restoration, trophic dynamics and mycorrhizal associations. The common factor linking these studies is that they manipulate an individual environmental axis and explore the role that axis plays in structuring communities. We discuss six recent studies to illustrate the use and design of microcosms for community ecology research. PMID- 21238165 TI - Evolution of antibiotic resistance. AB - World-wide spread of bacterial resistance to antimicrobial agents may limit the future progress of medicine. A huge environmental antibiotic pressure, resulting from industrial production and marketing of these drugs, has simultaneously contributed to the increase in the diversity of resistant phenotypes, to the selection of the fittest among them, and to the dispersal of resistance genes, which is expected to result in a significant acceleration of the rate of microbial evolution. Current research is focused on the mechanisms involved in the genesis, selection and dispersal of resistance genetic determinants; strategies based on molecular epidemiology and mathematical models may contribute to control or reverse the frightening trend towards a new pre-antibiotic era. PMID- 21238167 TI - Hymenopteran sex allocation. PMID- 21238166 TI - Statistical analyses of population genetic data. PMID- 21238168 TI - Reply from g.e. Heimpel. PMID- 21238169 TI - Flow cytometry for sexing birds. PMID- 21238170 TI - Reply from h. Ellegren and B.C. Sheldon. PMID- 21238171 TI - Models for the diversification of life. AB - The diversification of life through geological time a rise from presumably one species to many millions today. The diversification of marine families in the past 600 million years (Myr) appears to have followed two or three logistic curves, with equilibrium levels that lasted for up to 200 Myr. In contrast, continental organisms clearly show an exponential pattern of diversification, and although it is not clear whether the empirical diversification patterns are real or are artefacts of a poor fossil record, the latter explanation seems unlikely. Perhaps marine and continental organisms diversified in different ways, or perhaps the appearance of equilibrium patterns for marine organisms is an artefact of taxonomic structures. PMID- 21238172 TI - Why are there so many cichlid species? PMID- 21238173 TI - Ecology through the chemical looking-glass. PMID- 21238174 TI - Resurrection and time travelling: diapause in crustaceans (and others). PMID- 21238175 TI - Biosafety assessment of genetically engineered organisms in the environment. PMID- 21238176 TI - Ethology: at 50 and beyond. PMID- 21238177 TI - Counting the cost of disease resistance. PMID- 21238178 TI - Ecosystem-atmosphere CO(2) exchange: interpreting signals of change using stable isotope ratios. AB - Changes in the concentration and stable isotope ratio of atmospheric CO(2) can be used to study variations in the net exchange of carbon dioxide in terrestrial ecosystems (net difference between total photosynthesis and respiration). Changes in the timing of seasonal fluctuations in atmospheric CO(2) concentration have suggested that net uptake of carbon dioxide has been increasing in northern latitude ecosystems in association with warmer temperatures and a lengthening of the growing season. Stable isotope techniques allow a more detailed separation of differences between ecosystem photosynthesis and respiration because these two processes have contrasting effects on both the carbon and oxygen isotope ratio of atmospheric CO(2). Future applications of stable isotope analyses include documenting and monitoring the influence of global environmental change on ecosystem CO(2) exchange at regional scales (10-1000km(2)). PMID- 21238179 TI - The land flora: a phototroph-fungus partnership? AB - Numerous mutualistic associations between phototrophs and fungi exist in the extant land biota. Some are widespread, such as lichens and mycorrhizae, but some are less well known or restricted to special ecological conditions, such as endophytes in plants and algae. Recent molecular data and fossils suggest that associations arose repeatedly and that some of them are ancient, and even ancestral in the case of land plants. Mutualism, that provides various adaptations to terrestrial constraints, may have played a crucial role during terrestrialization and evolution of land phototrophs. PMID- 21238181 TI - What do we know about the performance of estimators for large phylogenies? PMID- 21238180 TI - Can elevated CO(2) affect secondary metabolism and ecosystem function? AB - It has generally been assumed that increasing atmospheric CO(2) concentrations will increase plant carbon-based secondary or structural compounds concentrations. These changes may have far-reaching consequences for herbivory and plant litter decomposition. Recent experimental results provide evidence of increases in concentrations of soluble phenolics and condensed tannins but not in lignin, structural polysaccharides or terpenes. They also show significant effects of these plant chemical changes on herbivores and little or any effects on decomposition. However, there is no consistent evidence of any of these effects at the complex long-term ecosystem level. PMID- 21238182 TI - Reply from s.e. Cates and j.L. Gittleman. PMID- 21238183 TI - Body mass allometries caused by physiological or ecological constraints? PMID- 21238184 TI - Non-invasive genetic sampling. PMID- 21238185 TI - Ancestors and taxonomy. PMID- 21238186 TI - The role of natural history collections in documenting species declines. AB - Efforts to document the decline of extant populations require a historical record of previous occurrences. Natural history museums contain such information for most regions of the world, at least at a coarse spatial scale. Museum collections have been successfully used to analyse declines in a wide range of plants and animals, at spatial scales ranging from single localities to large biotic and political regions. Natural history museum collections, when properly analysed, can be an invaluable tool in documenting changes in biodiversity during the past century. PMID- 21238187 TI - Key innovations and the ecology of macroevolution. AB - The origin or evolutionary 'success' of taxa is often attributed to key innovations-aspects of organismal phenotype that promote diversification. Different ways of delimiting taxa and measuring 'success' (i.e. number or longevity of species, morphological variety or differential control of energy) give rise to different ideas of how key innovations might operate. Key innovations may enhance competitive ability, relax adaptive trade-offs or permit exploitation of a new productive resource base. Recent key innovation studies comparing species richness in extant sister clades may miss important observations possible only with consideration of the fossil record, traditional higher taxa and phenotypic diversity. PMID- 21238188 TI - Stress response. AB - Global Ecology in Human Perspective by C.H. Southwick Oxford University Press, 1996. L16.50 hbk (xxi +392 pages) ISBN 0 19 509867 6 Ecology: A Bridge Between Science and Society by E.P. Odum Sinauer Associates, 1997. L17.95 pbk (xiv +330 pages) ISBN 0 87893 630 0. PMID- 21238189 TI - Broccoli and phyletic gradualism. AB - The Evolutionary Biology of Plants by K.J. Niklas University of Chicago Press, 1997. L51.95/$65.00 hbk, L15.95/$19.95 pbk (xix +449 pages) ISBN 0 226 58082 2/0 226 58083 0. PMID- 21238190 TI - Parallel worlds converge. AB - The Nature of Disease in Plants by R.P. Scheffer Cambridge University Press, 1997. L45.00/$64.95 hbk (ix +325 pages) ISBN 0 521 48247 X. PMID- 21238191 TI - A rare treat. AB - The Biology of Rarity: Causes and Consequences of Rare-Common Differences by W.E. Kunin and K.J. GastonChapman and Hall (Population and Community Biology Series 17), 1997. L55.00 hbk (xiv +280 pages) ISBN 0 412 63380. PMID- 21238192 TI - Adaptation and natural selection for the masses. AB - Plan and Purpose in Nature by George C. Williams Weidenfeld and Nicholson Press, 1996. L11.99 hbk (viii +191 pages) ISBN 0 297 81646 2. PMID- 21238193 TI - Miocene monkey beds. AB - Vertebrate Paleontology in the Neotropics: The Miocene Fauna of La Venta, Colombia edited by R.F. Kay et al. Smithsonian Institution Press, 1997. L62.50 hbk (xvi +592 pages) ISBN 1 56098 4 18 X. PMID- 21238194 TI - Out of control: fires and forestry in Indonesia. PMID- 21238195 TI - Genetic signatures of interpopulation dispersal. PMID- 21238196 TI - The importance of mate copying and cultural inheritance of mating preferences. PMID- 21238198 TI - Tracking migrant songbirds with stable isotopes. PMID- 21238197 TI - Scaling up the value of bioindicators. PMID- 21238199 TI - Agriculture in Nature's image. PMID- 21238200 TI - Extra-pair paternity in birds: explaining variation between species and populations. AB - Molecular techniques used to assign paternity have revealed previously unknown incidences of extra-pair paternity in socially monogamous bird species. DNA fingerprinting has now been used sufficiently often for mating-system biologists to appreciate the natural variation in the frequency of broods showing extra-pair young. The variation between species and between populations of the same species is surprisingly marked. Explaining this variation may help us to understand the factors promoting sexual selection. Recent comparative studies and detailed behavioural studies suggest that factors such as breeding density, genetic variation in the population and the intensity of sexual conflicts determine the costs and benefits to males and females of engaging in extra-pair copulations, and therefore contribute to the variation among populations. PMID- 21238201 TI - Population dynamics of large herbivores: variable recruitment with constant adult survival. AB - Recent long-term studies of population ecology of large herbivorous mammals suggest that survival of prime-aged females varies little from year to year and across populations. Juvenile survival, on the other hand, varies considerably from year to year. The pattern of high and stable adult survival and variable juvenile survival is observed in contrasting environments, independently of the main proximal sources of mortality and regardless of whether mortality is stochastic or density-dependent. High yearly variability in juvenile survival may play a predominant role in population dynamics. PMID- 21238202 TI - Evolutionary consequences of indirect genetic effects. AB - Indirect genetic effects (IGEs) are environmental influences on the phenotype of one individual that are due to the expression of genes in a different, conspecific, individual. Historically, work has focused on the influence of parents on offspring but recent advances have extended this perspective to interactions among other relatives and even unrelated individuals. IGEs lead to complicated pathways of inheritance, where environmental sources of variation can be transmitted across generations and therefore contribute to evolutionary change. The existence of IGEs alters the genotype-phenotype relationship, changing the evolutionary process in some dramatic and non-intuitive ways. PMID- 21238203 TI - Rapoport's rule: time for an epitaph? AB - The christening of the decline in the geographic extent of species from high to low latitudes as Rapoport's rule was a bold step. Allowing for a variety of potentially significant complications to the interpretation of empirical studies, evidence that this is indeed a general pattern is, at the very least, equivocal. The present taxonomically and regionally biased set of studies lend support to the recent suggestion that the pattern is a local phenomenon being expressed primarily in the Palaearctic and Nearctic above latitudes of 40-50 degrees N. Five hypotheses have been proposed to explain the generation of latitudinal declines in range size where they do occur, with the past heavy emphasis on a climatic variability mechanism being eroded. Evidence is accruing in support of more than one such mechanism. Whatever the generality of the 'rule', it has undoubtedly served to stimulate a consideration of the role of spatial variation in range sizes in several areas of research in ecology and evolution. PMID- 21238204 TI - Forest fragmentation: another perspective: reply to Laurance. PMID- 21238205 TI - Forest fragmentation: another perspective. PMID- 21238206 TI - The evolution of coloniality: does commodity selection explain it all? PMID- 21238207 TI - The evolution of coloniality: does commodity selection explain it all? Reply to Tella, Hiraldo and Donazar. PMID- 21238208 TI - Taking time with microevolution. PMID- 21238209 TI - Costs and limits of phenotypic plasticity. AB - The costs and limits of phenotypic plasticity are thought to have important ecological and evolutionary consequences, yet they are not as well understood as the benefits of plasticity. At least nine ideas exist regarding how plasticity may be costly or limited, but these have rarely been discussed together. The most commonly discussed cost is that of maintaining the sensory and regulatory machinery needed for plasticity, which may require energy and material expenses. A frequently considered limit to the benefit of plasticity is that the environmental cues guiding plastic development can be unreliable. Such costs and limits have recently been included in theoretical models and, perhaps more importantly, relevant empirical studies now have emerged. Despite the current interest in costs and limits of plasticity, several lines of reasoning suggest that they might be difficult to demonstrate. PMID- 21238210 TI - The origin of animal body plans: a study in evolutionary developmental biology, by w. Arthur, and cells, embryos and evolution, by j. Gerhart and m. Kirschner. AB - Cambridge University Press, 1997. $64.95/L45.00hbk (xii +338 pages) ISBN 0 521 55014 9 Blackwell Science, 1997. $49.50/L29.50pbk (xi +642 pages) ISBN 0 865 42574 4. PMID- 21238211 TI - Induced responses to herbivory by R. Karban and I.T. Baldwin. AB - The University of Chicago Press, 1997. $44.00/L35.25 hbk, $17.95/L14.25 pbk (x+320 pages) ISBN 0 226 42495 2/0 226 42496 0. PMID- 21238212 TI - Huxley: Evolution's High Priest by A. Desmond. AB - Michael Joseph, 1997. L20.00 hbk (xiv+370 pages) ISBN 0 7181 38821. PMID- 21238213 TI - Plant Resource Allocation, edited by F.A. Bazzaz and J. Grace. AB - Academic Press, 1997. $84.00 hbk (xi+303 pages) ISBN 0 12 083490 1. PMID- 21238214 TI - Bees see red. PMID- 21238215 TI - News from the realm of the ideal free distribution. PMID- 21238216 TI - Sperm counts. PMID- 21238217 TI - Evolution: Lost worlds. PMID- 21238218 TI - Transposable elements, gene silencing and macroevolution. PMID- 21238219 TI - European dune slacks: Strong interactions of biology, pedogenesis and hydrology. AB - Dune slacks are a unique type of wetland ecosystem, highly ranked on the international conservation agenda because of the occurrence of many rare and endangered plant species and their associated fauna. Ecologically they present some of the few examples of primary succession seres with a high degree of facilitation between functionally distinct groups of plants and a strong impact of the interannual variation of the water table. Recent research has focussed on the biological and environmental processes counteracting the rapid loss of diversity owing to human impacts along most north-west European coasts. PMID- 21238220 TI - Mistletoes as parasites: Host specificity and speciation. AB - Recent research on parasite evolution has highlighted the importance of host specialization in speciation, either through host-switching or cospeciation. Many parasites show common patterns of host specificity, with higher host specificity where host abundance is high and reliable, phylogenetically conservative host specificity, and formation of races on or in different host species. Recent advances in our understanding of host specificity and speciation patterns in a variety of animal parasites provides valuable insights into the evolutionary biology of mistletoes. PMID- 21238221 TI - Phylogenetic supertrees: Assembling the trees of life. AB - Systematists and comparative biologists commonly want to make statements about relationships among taxa that have never been collectively included in any single phylogenetic analysis. Construction of phylogenetic 'supertrees' provides one solution. Supertrees are estimates of phylogeny assembled from sets of smaller estimates (source trees) sharing some but not necessarily all their taxa in common. If certain conditions are met, supertrees can retain all or most of the information from the source trees and also make novel statements about relationships of taxa that do not co-occur on any one source tree. Supertrees have commonly been constructed using subjective and informal approaches, but several explicit approaches have recently been proposed. PMID- 21238222 TI - Reply from m.a. Jervis. PMID- 21238223 TI - Animal foraging: More than met the eye. PMID- 21238224 TI - Biological control: Disputing the indisputable. PMID- 21238225 TI - Pests of non-indigenous organisms: Hidden costs of introduction. PMID- 21238226 TI - One cell, two cell, red cell, blue cell: The persistence of a unicellular stage in multicellular life histories. AB - As developmental biologists come closer to understanding at the molecular and genetic levels how a zygote becomes an adult, it is easy to forget that the very phenomenon that gives them an occupation remains a vexing problem to evolutionary biologists: why do unicellular stages persist in life histories of multicellular organisms? There are two explanatory hypotheses. One is that a unicellular stage purges multicellular organisms of deleterious mutations by exposing offspring that are each uniformly of one genotype to selection. Another is that a one-cell stage reduces conflicts of interest among genetically different replicators within an organism. PMID- 21238227 TI - Evolution of mitotic cell-lineages in multicellular organisms. AB - Adaptive evolution in multicellular organisms is generally assumed to occur through natural selection acting differentially among the phenotypes programmed by sexually-generated zygotic genotypes. Under this view, only genetic changes in the gamete-zygote-germline-gamete cycle are considered relevant to the evolutionary process. Yet asexuality - production of progeny through proliferation of mitotic cell-lineages - is found in over one half of all eukaryotic phyla, and is likely to contribute to adaptive changes, as suggested by recent evidence from both animals and plants. Adaptive changes in mitotic lineages can be reconciled with contemporary evolutionary thought by fully abandoning the weismannian concept of individuality. PMID- 21238228 TI - Are birds dinosaurs? PMID- 21238229 TI - Sex discrimination before birth. PMID- 21238230 TI - Pollinator restoration. PMID- 21238231 TI - Searching for the role of positive interactions in plant communities. PMID- 21238232 TI - Transcending boundaries in biodiversity research. PMID- 21238233 TI - Functions of duet and solo songs of female birds. AB - Bird song is generally associated with males. In part, this reflects a bias towards studies in temperate regions, because in the tropics females of many species are regular and prolific singers. However, even among birds of temperate latitudes, females of several species occasionally sing. Recent experimental studies on female song provide some of the first tests of hypotheses to explain the functional significance of duets and obligate and facultative solo singing by females. PMID- 21238234 TI - Origins and early evolution of herbivory in tetrapods. AB - The first herbivorous tetrapods date from the Late Carboniferous, about 300 million years ago. By the Late Permian, continental ecosystems of 'modern' aspect had been established, with a vast standing crop of herbivores supporting relatively few carnivores. Processing of high-fibre plant material requires (1) structural modifications of the dentition, jaw apparatus and digestive tract and (2) the acquisition of microbial endosymbionts that produce the enzymes needed for fermentative digestion of cellulose, the principal compound of cell walls in plants. Recent phylogenetic analyses of tetrapods indicate that endosymbiotic cellulysis was acquired independently in a number of lineages during the late Palaeozoic. PMID- 21238235 TI - The evolution of recombination in changing environments. AB - Recombination generates under-represented genotypes by breaking down linkage disequilibrium between genes. Recent analyses have specified the conditions under which recombination is favored. These conditions are surprisingly sensitive to the form of selection and environmental change. This quantification makes it possible to use empirical measurements of critical parameters such as the form of epistasis, the rate of mutation, and the frequency of beneficial sweeps to assess different hypotheses for the evolution of recombination. PMID- 21238236 TI - Evolutionary explosions and the phylogenetic fuse. AB - A literal reading of the fossil record indicates that the early Cambrian (c. 545 million years ago) and early Tertiary (c. 65 million years ago) were characterized by enormously accelerated periods of morphological evolution marking the appearance of the animal phyla, and modern bird and placental mammal orders, respectively. Recently, the evidence for these evolutionary 'explosions' has been questioned by cladistic and biogeographic studies which reveal that periods of diversification before these events are missing from the fossil record. Furthermore, molecular evidence indicates that prolonged periods of evolutionary innovation and cladogenesis lit the fuse long before the 'explosions' apparent in the fossil record. PMID- 21238237 TI - Human pregnancy filtering: yesterday's news? PMID- 21238238 TI - Human pregnancy filtering: yesterday's news? PMID- 21238239 TI - Reply from L.s. Forbes. PMID- 21238240 TI - Phylotypic stage theory. PMID- 21238241 TI - Analysing diversification through time. PMID- 21238242 TI - Eggs first. PMID- 21238243 TI - Dwarf males. AB - Dwarf males are often found in species with sedentary females, where they typically cohabit in varying degrees of intimacy. This is short of true parasitism because, in return for room and board, males provide the benefit of sperm. Sexual selection rarely seems to be an option to explain male dwarfing, whereas natural selection often can. PMID- 21238244 TI - Fish migration and exploitation in the Amazon. AB - The Catfish Connection: Ecology, Migration and Conservation of Amazonian Predators by R. Barthem and M. Goulding Columbia University Press, 1997. L36.00 hbk (xvi+144 pages) ISBN 0 231 10832 X So Fruitful a Fish: Ecology, Conservation, and Aquaculture of the Amazon's Tambaqui by C. Araujo-Lima and M. Goulding Columbia University Press, 1997. L36.00 hbk (xii+191 pages) ISBN 0 231 10830 3. PMID- 21238245 TI - Measuring richness and evenness. AB - Surveying Natural Populations by L-A.C. Hayek and M.A. Buzas Columbia University Press, 1997. $69.00/L48.00 hbk, $28.00/L19.00 pbk (xvi+563 pages) ISBN 0 231 10240 2/0 231 10241 0. PMID- 21238247 TI - The elusive prospect of sustainable forestry. AB - Timber Production and Biodiversity Conservation in Tropical Rain Forests by A.G. Johns Cambridge University Press, 1997. L40.00/$69.95 hbk (xvii+225 pages) ISBN 0 521 57282 7. PMID- 21238246 TI - Vital connections. AB - Biodiversity and Human Health edited by F. Grifo and J. Rosenthal Island Press, 1997. $29.95 pbk (xviii+379 pages) ISBN 1 55963 501 9. PMID- 21238248 TI - Coping with change. AB - Extreme Environmental Change and Evolution by A.A. Hoffmann and P.A. Parsons Cambridge University Press, 1997. L55.00/$74.95 hbk, L19.95/$29.95 pbk (xii+259 pages) ISBN 0 521 44107 2/0 521 44659 7. PMID- 21238249 TI - Lost or forgotten? AB - Bonobo, the Forgotten Ape by F. de Waal University of California Press, 1997. L39.95 hbk (210 pages) ISBN 0 520 20535 9. PMID- 21238250 TI - Island cultures and ecosystems: down with harmony, up with pondfields. AB - Historical Ecology in the Pacific Islands edited by Patrick V. Kirch and Terry L. Hunt Yale University Press, 1997. $30.00 hbk (xvii+331 pages) ISBN 0 300 06603 1. PMID- 21238251 TI - Sustainable development. AB - Perspectives on Global Change: The TARGETS Approach edited by Jan Rotmans and Bert de Vries Cambridge University Press, 1997. L40.00/$69.95 hbk (xv+463 pages) ISBN 0 521 62176 3. PMID- 21238253 TI - Spatiotemporal patterns in nature. PMID- 21238252 TI - The role of the soil community in plant population dynamics. PMID- 21238254 TI - Determinants of dynamics: Population size, stability and persistence. PMID- 21238255 TI - Scaling phenomena and ecological interactions in space: Cutting to the core. PMID- 21238256 TI - From a soup or a seed? Pyritic metabolic complexes in the origin of life. AB - In the classical 'prebiotic soup' model of the origin of life, biomolecules are seen arising abiotically on the Earth and then interacting randomly in solution to form proto-cells. This model has encountered increasing difficulties, however, and recently several alternatives have been proposed. In some of these models, it is postulated that proto-cells evolved from simple biomolecular complexes originally attached to mineral surfaces, especially those of pyrite. The subsequent evolution of these complexes has been likened to embryonic development. PMID- 21238257 TI - Life history evolution of marine invertebrates: New views from phylogenetic systematics. AB - Established theories on the evolution of the diverse life histories of marine metazoans, specifically invertebrates, were developed in the absence of rigorous phylogenetic methods. With improved estimates of evolutionary relationships for various marine invertebrate groups, based on phylogenetic systematics, we can now critically evaluate the assumptions upon which these theories are based. Several studies emphasizing a phylogenetic systematics approach have recently examined the evolutionary transitions among reproductive traits and challenge us to reconsider the generality of the assumptions made about life history evolution. The results point towards exciting possibilities for a better understanding of the great diversity of reproductive and developmental modes we observe in marine invertebrates today. PMID- 21238258 TI - Generation cycles. AB - Generation cycles are population cycles with a period of roughly one generation. They have been observed in tropical pest populations and in laboratory populations. Theory suggests that they can arise both from intraspecific competition and from the influence of natural enemies, and ecological studies of populations of insects showing these cycles are starting to shed light on the mechanisms that maintain them. PMID- 21238259 TI - Archaea and the new age of microorganisms. AB - Archaea were, until recently, considered to be confined to specialized environments including those at high temperature, high salinity, extremes of pH and ambients that permit methanogenesis. Recently developed molecular methods for studying microbial ecology, which do not necessitate cell culturing, have demonstrated their presence in a wide variety of temperate and cold environments including agricultural and forest soils, fresh water lake sediments, marine picoplankton and deep-sea locations. These discoveries mark the beginning of a new era for investigating the Archaea and in particular their physiological and metabolic properties and their biological roles in complex microbial populations. PMID- 21238261 TI - The major transitions in evolution: What has driven them? PMID- 21238260 TI - Impacts of biological invasions on disturbance regimes. AB - Human management activities have altered the frequency and intensity of ecosystem disturbance often with enormous impacts on landscape structure and composition. One additional and under-appreciated way in which humans have altered disturbance regimes is through the introduction of invasive non-native species, themselves capable of modifying existing disturbance regimes or introducing entirely new disturbances. In many cases, modifications of disturbance regimes results in maintenance of ecosystems in a new or transitional state. There is now evidence that alteration of disturbance regime may be the most profound effect that a species or functional group can have on ecosystem structure and function. PMID- 21238262 TI - Reply from w.T. Wcislo and B.N. Danforth. PMID- 21238263 TI - Eusociality, life underground and parasites. PMID- 21238264 TI - Induced defenses and phenotypic plasticity. PMID- 21238265 TI - Reply from w. Wieser. PMID- 21238266 TI - Natural microcosms. PMID- 21238267 TI - Analysing diversification through time: reply to Sepkoski and Miller. PMID- 21238268 TI - Genetic estimates of population structure and gene flow: Limitations, lessons and new directions. AB - Indirect methods using genetic markers are the primary measure of gene flow levels among interbreeding populations. Results from studies employing these methods are often ambiguous and open to multiple interpretation. This is primarily due to low resolution of molecular markers and low precision of model based estimates. Studies of paternity, kinship and phylogeography generate the most reliable results. Future studies should employ more powerful analytical methods, analyse loci independently, and attempt to distinguish confounding contributions of vicariance to isolation-by-distance studies. Moreover, direct assessment of movement remains the most valid approach to many key issues in population biology. PMID- 21238270 TI - Wolbachia come of age. PMID- 21238269 TI - 'Lamarckian' mechanisms in darwinian evolution. AB - Since the Modern Synthesis, evolutionary biologists have assumed that the genetic system is the sole provider of heritable variation, and that the generation of heritable variation is largely independent of environmental changes. However, adaptive mutation, epigenetic inheritance, behavioural inheritance through social learning, and language-based information transmission have properties that allow the inheritance of induced or learnt characters. The role of induced heritable variation in evolution therefore needs to be reconsidered, and the evolution of the systems that produce induced variation needs to be studied. PMID- 21238271 TI - Local adaptation and host-parasite interactions. PMID- 21238272 TI - Establishing cryptic female choice in animals. PMID- 21238273 TI - Spiders hedge genetic bets. PMID- 21238274 TI - How to gain the benefits of sexual reproduction without paying the cost: a worm shows the way. PMID- 21238275 TI - Sperm competition in fish: 'bourgeois' males and parasitic spawning. AB - Fish exhibit an enormous variety of reproductive patterns. There is external and internal fertilization, simultaneous and sequential hermaphroditism as well as gonochorism, and an extremely widespread occurrence of parasitic reproductive behaviour among males. In most fish species there is a great size range of reproductive males, setting the stage for divergent, intraspecific reproductive patterns and an unparalleled concentration of alternative male reproductive phenotypes. Recent theoretical, empirical and comparative evidence suggests that adaptations to sperm competition in fish might be responsible for some of the most intriguing examples of reproductive design known. PMID- 21238276 TI - Social evolution in toothed whales. AB - Two contrasting results emerge from comparisons of the social systems of several odontocetes with terrestrial mammals. Researchers have identified remarkable convergence in prominent features of the social systems of odontocetes such as the sperm whale and bottlenose dolphin with a few well-known terrestrial mammals such as the elephant and chimpanzee. In contrast, studies on killer whales and Baird's beaked whale reveal novel social solutions to aquatic living. The combination of convergent and novel features in odontocete social systems promise a more general understanding of the ecological determinants of social systems in both terrestrial and aquatic habitats, as well as the relationship between relative brain size and social evolution. PMID- 21238277 TI - Hydraulic lift: a potentially important ecosystem process. AB - Hydraulic lift is the process by which some deep-rooted plants take in water from lower soil layers and exude that water into upper, drier soil layers. Hydraulic lift is beneficial to the plant transporting the water, and may be an important water source for neighboring plants. Recent evidence shows that hydraulically lifted water can promote greater plant growth, and could have important implications for net primary productivity, as well as ecosystem nutrient cycling and water balance. PMID- 21238278 TI - Statistical tests of neutrality in the age of weak selection. AB - Why review statistical tests of neutrality at a time when pan-selectionists and pan-neutralists alike seem to have been replaced by weak selectionists? First, we still don't actually know how variation is maintained at the molecular level; and second, tests of neutrality have a utility for evolutionary biologists beyond the neutralist/selectionist debate. New tests and variations on the existing tests are arising practically every month. From the complementary viewpoints of an empiricist and a theoretician, we sample the recent literature on tests of statistical neutrality and discuss the motivations, applications, assumptions, interpretations and future directions of these tests. PMID- 21238280 TI - Reply from R. Brooks. PMID- 21238279 TI - Mate copying and cultural inheritance. PMID- 21238281 TI - Polyploidy and transposons. PMID- 21238282 TI - Reply from J.F. McDonald. PMID- 21238283 TI - Too much latitude for Rapoport's rule? PMID- 21238284 TI - Reply from k.j. Gaston, T.m. Blackburn and j.I. Spicer. PMID- 21238285 TI - The case for data-less marine resource management: examples from tropical nearshore finfisheries. AB - Managing most marine finfisheries to achieve optimum yields is an unattainable dream. Protecting these resources from serious depletion through precautionary management seems the only practical option. But even this is of limited application if we demand scientific data for each managed fishery. There are too few researchers to do the work and, in any event, such research would usually not be cost-effective. Thus, we need not merely precautionary management; we need data-less management. PMID- 21238286 TI - The 'genetic benefits' of female multiple mating reconsidered. AB - In many animals, males can generally increase their fitness by mating with many mates, but females cannot produce more offspring than the number of their eggs. In spite of this restriction, females often mate with more than one male. In species without any male-provided resource benefits, females are thought to obtain some 'genetic benefits' from males that enhance offspring quality. The evolution of female multiple mating is often confused with the issue of female mate choice, but mate choice is actually possible in the single-mating situation. Therefore, we still need to explain the possible advantage of multiple mating over single mating. PMID- 21238287 TI - The greening of the land. AB - The Origin and Early Diversification of Land Plants-A Cladistic Study by P. Kenrick and P.R. Crane Smithsonian Institution Press (Smithsonian Series in Comparative Evolutionary Biology), 1997. L42.95 hbk, L21.50 pbk (xi+441 pages) ISBN 1 56098 730 8/1 56098 729 4. PMID- 21238288 TI - Useful stuff. AB - Foundations of Biophilosophy by Martin Mahner and Mario Bunge Springer-Verlag, 1997. L34.50/$54.00 hbk (xviii+423 pages) ISBN 3 540 61838 4. PMID- 21238289 TI - Rethinking tropical ecosystem management. AB - Tropical Environments: The Functioning and Management of Tropical Ecosystems by M. Kellman and R. Tackaberry Routledge, 1997. L60.00 hbk, L18.99 pbk (xix+380 pages) ISBN 0 415 11608 2/0 415 11609 0. PMID- 21238290 TI - Wetland history. AB - Wetlands of the American Midwest: A Historical Geography of Changing Attitudes by Hugh Prince The University of Chicago Press (University of Chicago Geography Research Papers), 1997. $21.00/L16.75 pbk (xiii+395 pages) ISBN 0 226 68283 8. PMID- 21238291 TI - Plant phenotypic plasticity and non-cognitive behaviour. PMID- 21238293 TI - Deep flowers for long tongues. PMID- 21238292 TI - Space invaders: modelling the distribution, impacts and control of alien organisms. PMID- 21238294 TI - Effects of herbivores on grassland plant diversity. AB - The role of herbivores in controlling plant species richness is a critical issue in the conservation and management of grassland biodiversity. Numerous field experiments in grassland plant communities show that herbivores often, but not always, increase plant diversity. Recent work suggests that the mechanisms of these effects involve alteration of local colonization of species from regional species pools or local extinction of species, and recent syntheses and models suggest that herbivore effects on plant diversity should vary across environmental gradients of soil fertility and precipitation. PMID- 21238295 TI - The demographic transition: are we any closer to an evolutionary explanation? AB - The radical shift in human reproduction in the late 19th century, known as the demographic transition, constitutes a major challenge to evolutionary approaches to human behaviour. Why would people ever choose to limit their reproduction voluntarily when, at the peak of the Industrial Revolution, resources were apparently so plentiful? Can the transition be attributed to standard life history tradeoffs, is it a consequence of cultural evolutionary processes, or is it simply a maladaptive outcome of novel and environmental social conditions? Empirical analyses and new models suggest that reproductive decision making might be driven by a human psychology designed by natural selection to maximize material wealth. If this is the case, the mechanisms governing fertility and parental investment are likely to respond to modern conditions with a fertility level much lower than that that would maximize fitness. PMID- 21238296 TI - Molecules remodel the mammalian tree. AB - DNA sequences provide a direct record of the genealogy of extant species. This tremendous reservoir of phylogenetic information is only beginning to be exploited. If progress in molecular phylogeny is being made, it should be most conspicuous amongst mammals, as their evolution is probably the best-studied. Indeed, surprising changes have recently been proposed for the tree of mammalian orders. These range from grouping whales with hippos, to placing African golden moles closer to elephants than to their fellow insectivores. PMID- 21238297 TI - Biodiversity hotspots. AB - Hotspots of biodiversity-areas particularly rich in species, rare species, threatened species, or some combination of these attributes-are increasingly being delineated to help set priorities for conservation. Only recently have we begun to test key assumptions that determine how useful a hotspot approach can be for conservation planning. The evidence suggests that although at large geographic scales hotspots do provide useful information for conservation planning, at smaller scales their value may be more limited. PMID- 21238298 TI - Extra-pair paternity in birds: 'good-genes' and something else. PMID- 21238299 TI - Extra-pair paternity in birds: 'good-genes' and something else: Reply from M. Petrie and B. Kempenaers. PMID- 21238300 TI - Key innovations? PMID- 21238301 TI - Key innovations?: Reply from J.P. Hunter. PMID- 21238302 TI - Hybrids and hybrid zones: Reply from M.G. Ritchie and N.H. Barton. PMID- 21238304 TI - Reduced supertrees. PMID- 21238303 TI - Hybrids and hybrid zones. PMID- 21238305 TI - Randomness, chaos and confusion in the study of antipredator vigilance. AB - The study of antipredator vigilance underwent a rapid and relatively recent synthesis 15-20 years ago. During the rise of behavioral ecology and sociobiology, researchers began to measure how often animals looked up from feeding. Subsequently, the field of vigilance crystallized quickly around a few striking results and an elegant theory. The convenient mathematical assumptions of this original theory continue to channel researchers' attentions today. Although data tend to match these assumptions - flock members scan independently, vigilance sequences are essentially unpredictable, and interscan intervals are highly variable - the assumptions themselves are difficult to justify. Some of our basic ideas about vigilance require detailed re-examination. PMID- 21238306 TI - Reproductive skew, concessions and limited control. AB - Models of reproductive skew in cooperative and eusocial societies suggest that dominants allow subordinates to breed to induce them to remain peaceably in the group. However, it is not yet clear how widely the assumptions of these models apply to animal societies, and many of the trends that they predict are consistent with the simpler suggestion that there is a struggle for reproduction between dominants and subordinates, whose outcome depends on the potential costs and benefits of the contest to both parties. Models of reproductive skew that incorporate contests of this kind and empirical studies that can discriminate clearly between reproductive concessions and failures of control are now needed. PMID- 21238308 TI - A lively bustle. AB - Host-Parasite Evolution: General Principles and Avian Models edited by D.H. Clayton and J. Moore Oxford University Press, 1997. L25.00 hbk (xiii +473 pages) ISBN 0 198 54892 3. PMID- 21238307 TI - Improving biological control. AB - Nature Wars: People vs. Pests by Mark L. Winston Harvard University Press, 1997. L16.50/$24.95 hbk (x +210 pages) ISBN 0 674 60541 1. PMID- 21238309 TI - A model fish. AB - Sex, Color and Mate Choice in Guppies by Anne E. Houde Princeton University Press, Monographs in Behavior and Ecology, 1997. L35.00/$49.50 hbk, L14.95/$19.95 pbk (xii +210 pages) ISBN 0 691 02790 0 / 0 691 02789 7. PMID- 21238310 TI - Space, time and statistics. AB - Spatiotemporal Models of Population and Community Dynamics by T. Czaran Chapman and Hall, Population and Community Biology Series, 1997. L59.00 hbk (xvii +284 pages) ISBN 0 412 57550 7. PMID- 21238311 TI - Of souls and skyhooks. PMID- 21238312 TI - Erratum. AB - Gadagkar, R. Trends Ecol. Evol. 13, 122-123 (March 1998). PMID- 21238313 TI - Closed areas for fisheries management-the case consolidates. PMID- 21238314 TI - To be, or to be essentially the same: the 'self-identity of ecological units'. PMID- 21238315 TI - High spatial resolution remote sensing of forest trees. PMID- 21238317 TI - Dinosaur fossils with soft parts. PMID- 21238316 TI - Mighty theories from little acorns grow: is Lyme disease risk predictable from mast-seeding by oak trees? PMID- 21238318 TI - Evolution and ecology of MHC molecules: from genomics to sexual selection. AB - In the past few years the DNA sequence database for molecules of the MHC (major histocompatibility complex) has expanded greatly, yielding a more complete picture of the long-term rates and patterns of evolution of the MHC in vertebrates. Sharing of MHC allelic lineages between long-diverged species (trans species evolution) has been detected virtually wherever it is sought, but new analyses of linked neutral regions and the complexities of sequence convergence and microrecombination in the peptide binding region challenge traditional phylogenetic analyses. Methods for estimating the intensity of selection on MHC genes suggest that viability is important, but recent studies in natural populations of mammals give inconsistent results concerning mate choice. The complex and interacting roles of microrecombination, parasite-mediated selection and mating preferences for maintaining the extraordinary levels of MHC polymorphism observed are still difficult to evaluate. PMID- 21238319 TI - The future as the key to the past for palaeobotany? AB - Continued increase in the concentration of atmospheric CO(2) and its possible effects on global climate has generated intense research interest on the likely responses of terrestrial plants and vegetation. Results from this new research provide quantitative information on plant function and growth in an environment with a high CO(2) concentration, but are also relevant to understanding plant growth in the distant past and to the techniques employed by palaeobotanists for reconstructing past climates from fossil plant remains. Experimental CO(2) enrichment of plants has demonstrated direct effects on leaf physiognomy, the tolerance of plants to low temperature and the relationship between tree rings, CO(2) and climate; it therefore signals the need for caution in interpreting palaeoclimates from fossils. PMID- 21238320 TI - Benthic suspension feeders: their paramount role in littoral marine food webs. AB - In recent years, particular attention has been paid to coupling and energy transfer between benthos and plankton. Because of their abundance, certain benthic suspension feeders have been shown to have a major impact in marine ecosystems. They capture large quantities of particles and might directly regulate primary production and indirectly regulate secondary production in littoral food chains. Suspension feeders develop dense, three-dimensional communities whose structural complexity depends on flow speed. It has been postulated that these communities can self-organize to enhance food capture and thus establish boundary systems capable of successfully exploiting a less structured system, namely, the plankton. PMID- 21238321 TI - Reply from a.L.R. Thomas. PMID- 21238323 TI - Female song for mate attraction: an overlooked phenomenon? PMID- 21238322 TI - Cambrian explosion still in the water. PMID- 21238324 TI - Shortening the phylogenetic fuse. PMID- 21238325 TI - Reply from a. Cooper and R. Fortey. PMID- 21238326 TI - Reply from N.e. Langmore. PMID- 21238327 TI - Biocontrol-risky but necessary? AB - There is currently much debate concerning the risks of biological control and the potential harmful effects of nonindigenous species introduced for controlling exotic pests. Biocontrol advocates generally appear reluctant to accept the possibility that there could be side-effects associated with biocontrol, often refuting evidence of harmful effects and suggesting that current practices are sufficient to minimize any risks. The biocontrol critics, on the other hand, although eager to provide evidence to the contrary, appear reluctant to propose any detailed, constructive criticisms or workable solutions. Here, we attempt to put these arguments into context, and suggest some directions for future research that might help to resolve some of the problems. PMID- 21238328 TI - Rapid evolution as an ecological process. AB - Rapid evolution of interspecific interactions (during a timespan of about 100 years) has the potential to be an important influence on the ecological dynamics of communities. However, despite the growing number of examples, rapid evolution is still not a standard working hypothesis for many ecological studies on the dynamics of population structure or the organization of communities. Analysis of rapid evolution as an ecological process has the potential to make evolutionary ecology one of the most central of applied biological sciences. PMID- 21238329 TI - Palaeoichthyology. AB - History of the Coelacanth Fishes by P.L. Forey Chapman & Hall, 1998. L99.00 hbk (xiii+419 pages) ISBN 412 784807. PMID- 21238330 TI - Binding up a world of wounds. AB - A World of Wounds: Ecologists and the Human Dilemma by P.R. Ehrlich Ecology Institute, Excellence in Ecology 8, 1997. DM63.00 hbk (xxiv+210 pages) ISBN 0932 2205. PMID- 21238331 TI - Two books in one: natural history and evolutionary theory. AB - Evolutionary Ecology across Three Trophic Levels: Goldenrods, Gallmakers and Natural Enemies by W.G. Abrahamson and A.E. Weis Princeton University Press, Monographs in Population Biology, 1997. $29.95/L24.95 hbk (xiii+456 pages) ISBN 0 691 01208 3. PMID- 21238332 TI - Ichthyological enthusiasm. AB - Coral Reef Fishes: Caribbean, Indian Ocean, and Pacific Ocean including the Red Sea by E. Lieske and R. Myers Princeton University Press, 1996. $35.00 hbk (400 pages) ISBN 0 691 02659 9 Air-Breathing Fishes: Evolution, Diversity, and Adaptation by J.B. Graham Academic Press, 1997. $79.95 hbk (xi+299 pages) ISBN 0 12 294860 2 The Diversity of Fishes by G.S. Helfman, B.B. Collette and D.E. Facey Blackwell, 1997. L55.00 hbk (xii+528 pages) ISBN 0 86542 256 7. PMID- 21238333 TI - Disciplining molecular evolution. AB - Molecular Evolution by W-H. Li Sinauer, 1997. L32.95 hbk (xv+487 pages) ISBN 0 87893 463 4. PMID- 21238334 TI - Networking and Iberoamerican biodiversity. PMID- 21238335 TI - The power of movement in plants. PMID- 21238336 TI - A diversity of approaches to the study of species richness. PMID- 21238337 TI - Manipulative begging calls by parasitic cuckoo chicks: why should true offspring not do the same? PMID- 21238338 TI - The end and the beginning: recoveries from mass extinctions. AB - The evolutionary consequences of mass extinctions depend as much on the processes of survival and recovery following these biotic crises as on the patterns of extinction themselves. Paleontologists are currently documenting biotic recoveries from six major mass extinctions and several smaller biotic crises. Although the immediate responses are remarkably similar after each event, with low-diversity assemblages dominated by widespread, eurytopic species, the recovery response in the long-term is more varied. Lineages that survive the extinction can lack the resilience for recovery, whereas others vanish from the fossil record seemingly to return from the dead after several million years. PMID- 21238339 TI - Emergent impacts of multiple predators on prey. AB - Although almost all prey live with many types of predator, most experimental studies of predation have examined the effects of only one predator at a time. Recent work has revealed new insights into the emergent impacts of multiple predators on prey and experimental studies have identified statistical methods for evaluating them. These studies suggest two main types of emergent effect-risk reduction caused by predator-predator interactions and risk enhancement caused by conflicting prey responses to multiple predators. Some theory and generalities are beginning to emerge concerning the conditions that tend to produce these two outcomes. PMID- 21238340 TI - Trees within trees: phylogeny and historical associations. AB - The association between two or more lineages over evolutionary time is a recurrent theme spanning several different fields within biology, from molecular evolution to coevolution and biogeography. In each 'historical association', one lineage is associated with another, and can be thought of as tracking the other over evolutionary time with a greater or lesser degree of fidelity. Examples include genes tracking organisms, parasites tracking hosts and organisms tracking geological and geographical changes. Parallels among these problems raise the tantalizing prospect that each is a special case of a more general problem, and that a single analytical tool can be applied to all three kinds of association. PMID- 21238342 TI - Why are male rotifers dwarf? PMID- 21238341 TI - Reply from j.L. Bossart and d. Pashley prowell. PMID- 21238343 TI - Is population genetics mired in the past? PMID- 21238344 TI - Reconstructing ancestral character states: a critical reappraisal. AB - Using parsimony to reconstruct ancestral character states on a phylogenetic tree has become a popular method for testing ecological and evolutionary hypotheses. Despite its popularity, the assumptions and uncertainties of reconstructing the ancestral states of a single character have received less attention than the much less challenging endeavor of reconstructing phylogenetic trees from many characters. Recent research suggests that parsimony reconstructions are often sensitive to violations of the almost universal assumption of equal probabilities of gains and losses. In addition, maximum likelihood has been developed as an alternative to parsimony reconstruction, and has also revealed a surprising amount of uncertainty in ancestral reconstructions. PMID- 21238345 TI - The enigma of frequency-dependent selection. AB - Frequency-dependent selection is so fundamental to modern evolutionary thinking that everyone 'knows' the concept. Yet the term is used to refer to different types of selection. The concept is well defined in the original context of population genetics theory, which focuses on short-term evolutionary change. The original concept becomes ambiguous, however, when used in the context of long term evolution, where density dependence becomes essential. Weak and strong frequency dependence, as distinguished in this article, refer to two very different forms of selection. PMID- 21238346 TI - Management of populations in conservation, harvesting and control. AB - Conservation, harvesting and pest control are three aspects of the same general problem: population management. All three involve intervention with the aim of regulating population size and growth in some way, yet the dissociation of these disciplines is pervasive. Recent developments and a comparison of approaches show the potential of a synthetic paradigm. PMID- 21238347 TI - Designer snails. AB - The Algorithmic Beauty of Sea Shells (2nd edn) by Hans Meinhardt Springer-Verlag, 1998. DM89.00/$54.95/L34.00 hbk (xi+236 pages) ISBN 3 540 63919 5. PMID- 21238348 TI - Natural CO(2) springs: obstacle or opportunity? AB - Plant Responses to Elevated Carbon Dioxide: Evidence from Natural Springs edited by A. Raschi, F. Miglietta, R. Tognetti and P.R. van Gardingen Cambridge University Press, 1997. L40.00/$69.95 hbk (xiv+272 pages) ISBN 0 521 58203 2. PMID- 21238349 TI - Receding black moths. AB - Melanism: Evolution in Action by Michael E.N. Majerus Oxford University Press, 1998. L55.00/$105.00 hbk, L23.95/$45.00 pbk (xiii+352 pages) ISBN 0 19 854983 0 / 0 19 854 982 2. PMID- 21238350 TI - Tropical ecology in miniature. AB - The Butterflies of Costa Rica and their Natural History. Volume II: Riodinidae. by P.J. DeVries Princeton University Press, 1997. $90.00/L70.00 hbk, $29.95/L23.95 pbk (xxvii+288 pages) ISBN 0 691 02890 7 / 0 691 02889 3. PMID- 21238351 TI - Ecosystem services, efficiency, sustainability and equity: South Africa's Working for Water programme. PMID- 21238352 TI - Action on amphibians. PMID- 21238353 TI - Mother's boy or daddy's girl? Sex determination in Hymenoptera. PMID- 21238354 TI - Fragments past, present and future. PMID- 21238355 TI - The stoop of large falcons. PMID- 21238356 TI - Butterfly battles: on conventional contests and hot property. PMID- 21238357 TI - Competition mediated by parasites: biological and theoretical progress. PMID- 21238358 TI - Chemical signals and parasite-mediated sexual selection. AB - Research into visual and acoustic signals has demonstrated that exaggerated sexual displays often provide an honest indicator of a male's resistance to parasites. Recent studies with rodents and humans now suggest that chemosensory signals also reveal a male's disease resistance and his genetic compatibility. Our understanding of sexual selection has been greatly enriched by considering the mechanisms underlying visual and acoustic displays, and recent advances in chemical communication will help to determine what kind of information is revealed by an individual's scent. PMID- 21238359 TI - Assessing ecosystem health. AB - Evaluating ecosystem health in relation to the ecological, economic and human health spheres requires integrating human values with biophysical processes, an integration that has been explicitly avoided by conventional science. The field is advancing with the articulation of the linkages between human activity, regional and global environmental change, reduction in ecological services and the consequences for human health, economic opportunity and human communities. Increasing our understanding of these interactions will involve more active collaboration between the ecological, social and health sciences. In this, ecologists will have substantive and catalytic roles. PMID- 21238360 TI - The adaptive significance of maternal effects. AB - Recently, the adaptive significance of maternal effects has been increasingly recognized. No longer are maternal effects relegated as simple 'troublesome sources of environmental resemblance' that confound our ability to estimate accurately the genetic basis of traits of interest. Rather, it has become evident that many maternal effects have been shaped by the action of natural selection to act as a mechanism for adaptive phenotypic response to environmental heterogeneity. Consequently, maternal experience is translated into variation in offspring fitness. PMID- 21238361 TI - The role of soil community in plant population dynamics: is allelopathy a key component? PMID- 21238362 TI - Reply from a.R. Watkinson. PMID- 21238363 TI - Reply from j. Bever, k.m. Westover and j. Antonovics. PMID- 21238365 TI - Quantifying brain-behavior relations in cetaceans and primates. PMID- 21238364 TI - Reply from R.C. Connor et Al. PMID- 21238366 TI - Biodiversity hotspots in the developing world. PMID- 21238367 TI - On hotspots and the use of indicators for reserve selection. PMID- 21238368 TI - Interference with ideal free models. PMID- 21238369 TI - A crisis in the making: responses of Amazonian forests to land use and climate change. AB - At least three global-change phenomena are having major impacts on Amazonian forests: (1) accelerating deforestation and logging; (2) rapidly changing patterns of forest loss; and (3) interactions between human land-use and climatic variability. Additional alterations caused by climatic change, rising concentrations of atmospheric carbon dioxide, mining, overhunting and other large scale phenomena could also have important effects on the Amazon ecosystem. Consequently, decisions regarding Amazon forest use in the next decade are crucial to its future existence. PMID- 21238370 TI - Sensory ecology, receiver biases and sexual selection. AB - During courtship, signals are sent between the sexes, and received signals contain information that forms the basis of decision making. Much is known about signal content, but less is known about signal design-what makes signals work efficiently? A consideration of design not only gives new insights into the evolution of signals (including novelty), but also allows the development of specific and testable predictions about the direction of evolution. Recently there has been increased interest in signal design, but this has resulted in some apparently divergent views in the literature. PMID- 21238371 TI - A tropical rain forest feast. AB - An Introduction to Tropical Rain Forests (2nd edn) by T.C. Whitmore Oxford Science Publications, 1998. L45 hbk, L19.50 pbk (224 pages) ISBN 0 19 850148 X/0 19 850147 1 Tropical Rain Forest: A Wider Perspective edited by F.B. Goldsmith Chapman and Hall (Conservation Biology Series) 1998. L69.00 hbk (xix+416 pages) ISBN 0 412 81510 9 Vanishing Treasures of the Philippine Rain Forest by L.R. Heaney and J.C. Rigalado Jr University of Chicago Press, 1998. L19.25/$24.00 pbk (96 pages) ISBN 0 91486819 5. PMID- 21238372 TI - Hors d'oeuvre. AB - Basic Palaeontology by M. Benton and D. Harper Addison Wesley Longman, 1997. L22.99 pbk (xv+342 pages) ISBN 0 582 22857 3. PMID- 21238373 TI - Behind the pretty face. AB - Geographic Information Systems in Ecology by Carol A. Johnston Blackwell Science, Methods in Ecology, 1998. L29.50 (256 pages) ISBN 0 632 03859 4. PMID- 21238375 TI - The lessons of palaeoecology re-taught. AB - Terrestrial Ecosystems in Changing Environments by Herman H. Shugart Cambridge University Press (Cambridge Studies in Ecology), 1998. L75.00 hbk, L27.95 pbk (xiv+537 pages) ISBN 0 521 56342 9/0 521 56523 5. PMID- 21238374 TI - Something to chew on. AB - Foraging for Survival: Yearling Baboons in Africa by Stuart A. Altmann University of Chicago Press, 1998. $70.00 hbk (xii+536 pages) ISBN 0 226 01595 5. PMID- 21238376 TI - Alternative states in shallow lakes. AB - Ecology of Shallow Lakes by Marten Scheffer Chapman and Hall (Population and Community Biology Series 22), 1998. L45.00/$79.65 hbk (xx+357 pages) ISBN 0 412 74920 3. PMID- 21238377 TI - Haunted hypotheses. AB - American Pronghorn: Social Adaptations and the Ghosts of Predators Past by J.A. Byers The University of Chicago Press, 1998. $70.00/L55.95 hbk, $23.95/L19.25 pbk (xviii+300 pages) ISBN 0 226 08698 4/0 226 08699 2. PMID- 21238378 TI - From aapa to zymogeny. AB - A Dictionary of Ecology, Evolution and Systematics (2nd edn) by R. Lincoln, G. Boxshall and P. Clark Cambridge University Press, 1998. L50.00 hbk, L17.95 pbk (ix+361 pages) ISBN 0 521 59139 2/0 521 43843 X The Encyclopedia of Ecology and Environmental Management edited by P. Calow Blackwell Science, 1998. L125.00 hbk (xv+805 pages) ISBN 0 86542 838 7. PMID- 21238379 TI - Blaming the trees: a critique of research on forest responses to high CO(2). PMID- 21238380 TI - Human influences on coastal ecosystems: does overfishing create trophic cascades? PMID- 21238381 TI - Partial local mating and the sex ratio: indirect comparative evidence. PMID- 21238382 TI - A moveable feast: the evolution of resource sharing in plant-fungus communities. PMID- 21238383 TI - Selfish genes in a social insect. PMID- 21238384 TI - Optimizing metabolic pathways. PMID- 21238385 TI - Coral diseases: what is really known? AB - Reports of new and emerging coral diseases have proliferated in recent years. Such coral diseases are often cited as contributing to coral reef decline. Many of these diseases, however, have been described solely on the basis of field characteristics, and in some instances there is disagreement as to whether an observed coral condition is actually a disease. A disease pathogen has been identified for only three coral diseases, and for only two of these has the pathogen been shown (in the laboratory) to be the disease agent. In one case, the same disease name has been used for several widely varying coral syndromes, whereas in another multiple disease names have been applied to symptoms that may be caused by a single disease. Despite the current confusion, rapid progress is being made. PMID- 21238386 TI - Genotyping, gene genealogies and genomics bring fungal population genetics above ground. AB - As ubiquitous decomposers, symbionts and parasites, fungi build populations not easily accommodated by population genetic theory. Identifying and delineating individuals and populations is often difficult, and recombination can occur in complex and variable ways. Genotyping and gene genealogies provide the framework for identifying and delineating individuals and for detecting recombination in natural populations. Expanding genomic databases now make fungi ideal subjects for tracking mutation and expression in genes of adaptive importance in experimental populations. PMID- 21238387 TI - Recent advances in South American mammalian paleontology. AB - Recently discovered deposits containing terrestrial mammal fossils, together with multidisciplinary studies of classical sequences, have yielded dramatic insights into the biotic and environmental history of South America. Notable advances include several new fossil primate taxa, an improved chronology of two major immigration events (caviomorph rodents and new world monkeys), documentation of the oldest mammalian faunas dominated by grazing taxa (which suggests that grasslands appeared at least 15 million years earlier than on other continents), evidence of early biogeographical provinciality within South America, and improved sampling of the best known Cenozoic tropical South American paleofauna. PMID- 21238388 TI - Does elevated atmospheric carbon dioxide affect arbuscular mycorrhizas? AB - It is well established that an increase in the concentration of atmospheric CO(2) stimulates plant growth. Recently, many researchers have concluded that elevated CO(2) concentrations also stimulate mycorrhizal colonization. However, new evidence suggests that the observed CO(2) effects on arbuscular mycorrhizal fungi are indirect and are a result of faster plant growth at higher CO(2) concentrations. Potential changes to species assemblages of mycorrhizal fungi could affect soil carbon storage and, consequently, the feedback effects of terrestrial soil-vegetation systems on global environmental change. PMID- 21238389 TI - Reproductive skew: disentangling concessions from control. PMID- 21238390 TI - Deep flowers for long tongues. PMID- 21238391 TI - Reply from T.h. Clutton-brock. PMID- 21238392 TI - Deep flowers for long tongues. PMID- 21238393 TI - Deep flowers for long tongues. PMID- 21238394 TI - Diversity in mimicry: paradox or paradigm? AB - Visual mimicry is a textbook case of natural selection because it is both intuitively understandable and has repeatedly evolved in a range of organisms: it is the ultimate example of parallel evolution. In many mimetic groups, particularly butterflies, a huge variety of colour patterns has arisen, even in closely related species. There has been much recent controversy over explanations of this variety. Mimicry is today a broad field of evolutionary study; here we discuss the evolution of its diversity in predator-prey systems. PMID- 21238395 TI - Dinosaurs for everyone. AB - The Complete Dinosaur edited by James O. Farlow and Michael K. Brett-Williams Indiana University Press (UK: Open University Press), 1997. L40.50/$59.95 hbk (752 pages) ISBN 0 253 33349 0. PMID- 21238396 TI - Egoism and altruism. AB - Unto Others: The Evolution and Psychology of Unselfish Behavior by E. Sober and D.S. Wilson Harvard University Press, 1998. $19.95 hbk (394 pages) ISBN 0 674 93046 0. PMID- 21238397 TI - All in the family. AB - The Evolution of Sibling Rivalry by D.W. Mock and G.A. Parker Oxford University Press, 1998. $120.00 hbk, $55.00 pbk (xiii +464 pages) ISBN 0 19 857743 5/0 19 857744 3. PMID- 21238398 TI - Questions and answers at the interface of basic and applied ecology. PMID- 21238399 TI - Rainforest plants protect their investments. PMID- 21238400 TI - Catching the Red Queen? The advice of the Rose. PMID- 21238401 TI - Tropical fish: explosions and extinctions. PMID- 21238403 TI - Paleoecology meets ecology on questions of scale. PMID- 21238402 TI - Wildlife disease ecology: from theory to policy. PMID- 21238404 TI - Understanding proboscidean evolution: a formidable task. AB - A new approach to proboscidean evolution depicts taxa in three major radiations. This approach highlights general proboscidean evolutionary trends and origins more than the specific relationships among them. Data from more than 55 million years of evolution help to interpret how the integration of primitive and derived characters was essential to proboscidean success. Only two, or perhaps three, species remain of approximately 164 that lived in the past. Extinct forms were extremely cosmopolitan, occupying a variety of habitats, from deserts to mountain tops, on all continents except Australia and Antarctica. Challenges for future investigators include a better understanding of structure and function of infrasonic call production and perception, brain features, and reproductive biology in extinct proboscideans based on inferences from living forms. PMID- 21238405 TI - Evolution and history of the western Palaearctic avifauna. AB - Recent data accumulated from fields as varied as avian palaeontology, palaeobotany, historical biogeography and molecular phylogenetics provide a completely renewed picture of the origin, evolution and distribution of modern birds. Although the origin of birds is still controversial, their Tertiary history is now well known. The reconstruction of palaeoenvironments and the identification of shifts in major vegetation belts and habitats during the Pliocene-Pleistocene epochs have added to these recent developments. Together they provide a new perspective on speciation and extinction rates since the late Pliocene and the establishment of modern avifaunas in the western Palaearctic. PMID- 21238406 TI - Changing perspectives on the origin of eukaryotes. AB - From the initial application of molecular techniques to the study of microbial organisms, three domains of life emerged, with eukaryotes and archaea as sister taxa. However, recent analyses of an expanding molecular data set reveal that the eukaryotic genome is chimeric with respect to archaea and bacteria. Moreover, there is now evidence that the primitive eukaryotic group 'Archezoa' once harbored mitochondia. These discoveries have challenged the traditional stepwise model of the evolution of eukaryotes, in which the nucleus and microtubules evolve before the acquisition of mitochondria, and consequently compel a revision of existing models of the origin of eukaryotic cells. PMID- 21238407 TI - Should females prefer dominant males? AB - It is generally believed that success in male-male competition genuinely reflects high quality and that female preference for dominant males should therefore be widespread. However, recent studies suggest that male dominance is not always attractive and that it does not necessarily predict superior parental quality, better genes or other forms of benefit to females. In fact, the costs of choosing a dominant male can sometimes outweigh the benefits. When traits selected by male male competition do not reflect overall mate quality, females are expected to use other choice cues and might occasionally prefer subordinate males. Thus, male male competition and female choice can sometimes work in different, or even opposing, directions. PMID- 21238408 TI - Ecology and speciation. AB - Recent studies on diverse taxa suggest that natural selection caused by shifts in ecology or invasions of novel habitats plays an important role in adaptive divergence and speciation. Exciting new studies integrating approaches from both the field and the laboratory suggest that ecological shifts can result in extremely rapid rates of evolutionary divergence. Although experimental approaches that link rapid ecological divergence to reproductive isolation and speciation are in their infancy, recent research indicates those approaches that will be most useful. PMID- 21238409 TI - Mast seeding and Lyme disease. PMID- 21238410 TI - Mast seeding and Lyme disease. PMID- 21238411 TI - Trace fossils and the Cambrian explosion. PMID- 21238412 TI - Reply from s. Randolph. PMID- 21238413 TI - Reply from a.L.R. Thomas. PMID- 21238414 TI - Reply from R. Fortey and a. Cooper. PMID- 21238415 TI - Frequency dependence versus optimization. PMID- 21238416 TI - Reply from m. Heino, j.a.j. Metz and v. Kaitala. PMID- 21238417 TI - Deep flowers for long tongues: reply from L.A. Nilsson. PMID- 21238418 TI - Costly sexual signals: are carotenoids rare, risky or required? AB - Theories of animal signalling emphasize the importance of costliness-to be effective, signals must be dependable; to be dependable, signals must carry costs and carotenoid-based signals are a favoured example. The traditional view that carotenoids are costly because they are scarce still carries weight. However, biomedical research has led to alternative views on costliness, mainly related to beneficial, but also to detrimental, effects of carotenoids. Recent improvements in our understanding of carotenoids suggest that the relative importance of these mechanisms will soon be determined, leading to a fresh outlook on cost-based signalling. PMID- 21238420 TI - Ultimate parasites. AB - Evolutionary Ecology of Parasites. From Individuals to Communities by Robert Poulin, Chapman & Hall, 1998. L55.00 hbk (x+212 pages) ISBN 0 412 80560 X. PMID- 21238419 TI - Family values. AB - Evolutionary Genetics (2nd edn) by J. Maynard Smith, Oxford University Press, 1998. L50.00 hbk, L19.95 pbk (368 pages) ISBN 0 19 850232 X/0 19 850231 1 Selection in Natural Populations by J.B. Mitton, Oxford University Press, 1998. L50.00 hbk (252 pages) ISBN 0 19 506352 X Progress and Prospects in Evolutionary Biology edited by J.R. Powell, Oxford University Press, 1997. L49.50 hbk (576 pages) ISBN 0 19 507691 5 Evolution on Islands edited by P.R. Grant, Oxford University Press, 1997. L24.99 pbk (348 pages) ISBN 0 19 850 1714. PMID- 21238421 TI - Bird biodiversity. AB - Endemic Bird Areas of the World. Priorities for Biodiversity Conservation by A.J. Stattersfield, M.J. Crosby, A.J. Long and D.C. Wege, Birdlife International, 1997. L37.00 pbk (860 pages) ISBN 0946 888 33 7 CDROM: Birds of the World-A Multimedia Encyclopedia, Ransom, 1997. L14.99 ISBN 1 863 89 1748. PMID- 21238422 TI - An encyclopaedia of sexuality. AB - Primate Sexuality. Comparative Studies of the Prosimians, Monkeys, Apes and Human Beings by Alan F. Dixson, Oxford University Press, 1998. L75.00 hbk, L32.50 pbk (656 pages) ISBN 0 19 850183 8/0 19 850182 X. PMID- 21238423 TI - Lobsters, moths and centipedes. AB - Arthropod Relationships edited by R.A. Fortey and H. Thomas, Kluwer Academic Publishers, 1998 (The Systematics Association Special Volume Series 55). L115 hbk (xii+383 pages) ISBN 0 412 75420 7. PMID- 21238424 TI - Treatment coverage survey after a school-based mass distribution of mebendazole: Kampot Province, Cambodia. AB - In efforts to reduce the global burden of soil transmitted helminth (STH) infections in school age children (SAC, 6-14 years old), Children Without Worms donates mebendazole to 8 countries with high prevalence of STH infections. Cambodia's national deworming program currently targets SAC through bi-annual school-based distributions of a single dose of mebendazole. A 30-cluster household survey was conducted in the rural province Kampot, to validate mebendazole treatment coverage in SAC and to assess the level of improved water supply and sanitation. Bi-annual primary school-based distributions proved to be an effective strategy in reaching school attending SAC, with treatment coverage rates between 84.1% and 88.8%. However, significantly lower rates (23.3-48.8%) were seen among SAC not enrolled in primary schools. Often members of the most marginalized families of the community, they are particularly at risk of STH infection. Methods to reach these children need to be explored to avoid treatment inequities. PMID- 21238425 TI - A Homo sapiens cytoplasmic ribosomal decoding A-site affinity screen evaluating aminoglycoside and analogue binding. AB - The potential of aminoglycoside antibiotics to induce premature stop codon read through in eukaryotic systems has been reported recently, inspiring the evaluation of structural alterations within the Homo sapiens cytoplasmic decoding center on ligand binding. Here we report the employment of an affinity screen capable of monitoring conformational changes of adenines 1492 and 1493 in solution. Thus, changes induced by the presence of a ligand can be directly translated to binding affinities for the eukaryotic decoding center. Binding data for the eukaryotic ribosomal decoding center can be easily obtained by this method and are in excellent agreement with previously reported values measured by alternative techniques. Furthermore, a good correlation is obtained between the experimental binding affinities and the biological activity of the compounds examined. In addition, illustrating the generality of the assay, unnatural rigid aminoglycoside analogues of potential therapeutic significance were evaluated. PMID- 21238426 TI - Study of interactions between DNA and aflatoxin B1 using electrochemical and fluorescence methods. AB - In this study, a carbon paste electrode modified with N-butylpyridinium hexafluorophosphate (BPPF(6)) ionic liquid and DNA was introduced as an electrochemical biosensor to study the interaction between DNA and aflatoxin B1 molecules. For this purpose, variations in oxidation peak current of guanine in various concentrations of aflatoxin B1 were measured by using the differential pulse voltammetry (DPV) method. According to this study, the binding constant of DNA-aflatoxin B1 was found to be 3.5*10(6)M(-1). This modified electrode was also used for determination of low concentrations of aflatoxin B1 by using differential pulse voltammetry. A linear dynamic range from 8.00*10(-8) to 5.91*10(-7)M and a limit of detection of 2.00*10(-8)M resulted from DPV measurements. To confirm our results, a fluorescence study was also performed. It resulted in a binding constant of 2.8*10(6)M(-1), which is in good agreement with that obtained from electrochemical study. PMID- 21238427 TI - Effects of single nucleotide changes on the binding and activity of RNA aptamers to human papillomavirus 16 E7 oncoprotein. AB - A virally-encoded oncoprotein (E7 from human papillomavirus 16, involved in the initiation of cell transformation) was the target for RNA aptamer development by the process of systematic evolution of ligands by exponential enrichment (SELEX). A number of aptamers were identified, one of which was shown to inhibit the interaction between E7 and its major binding partner, pRb. Aptamers with very similar sequences (more than 92% similarity in the random regions) did not share this activity. This study demonstrates the potential of aptamers to be highly specific, with small differences in aptamer sequence having profound effects on function. PMID- 21238428 TI - Improvement of biological and pharmacokinetic features of human interleukin-11 by site-directed mutagenesis. AB - Recombinant human interleukin-11 (rhIL-11) has been shown to increase platelet counts in animals and humans and is the only drug approved for its use in chemotherapy-induced thrombocytopenia (CIT). However, due to its serious side effects, its clinical use has been limited. The current work presents significantly improved efficacy of rhIL-11 via knowledge based re-designing process. The interleukin-11 mutein (mIL-11) was found to endure chemical and proteolytic stresses, while retaining the biological activity of rhIL-11. The improved efficacy of mIL-11 was evident after subcutaneous administration of mIL 11 and rhIL-11 in the rodent and primate models. More than three-fold increase in maximum plasma concentration (Cmax) and area-under-the curve (AUC) was observed. Furthermore, three-fold higher increase in the platelet counts was obtained after seven consecutive daily subcutaneous mIL-11 injections than that with rhIL-11. The mIL-11 demonstrated not only improved stability but also enhanced efficacy over the currently used rhIL-11 regimen, thereby suggesting less toxicity. PMID- 21238429 TI - Crystal structure of bacterial cell-surface alginate-binding protein with an M75 peptidase motif. AB - A gram-negative Sphingomonas sp. A1 directly incorporates alginate polysaccharide into the cytoplasm via the cell-surface pit and ABC transporter. A cell-surface alginate-binding protein, Algp7, functions as a concentrator of the polysaccharide in the pit. Based on the primary structure and genetic organization in the bacterial genome, Algp7 was found to be homologous to an M75 peptidase motif-containing EfeO, a component of a ferrous ion transporter. Despite the presence of an M75 peptidase motif with high similarity, the Algp7 protein purified from recombinant Escherichia coli cells was inert on insulin B chain and N-benzoyl-Phe-Val-Arg-p-nitroanilide, both of which are substrates for a typical M75 peptidase, imelysin, from Pseudomonas aeruginosa. The X-ray crystallographic structure of Algp7 was determined at 2.10A resolution by single wavelength anomalous diffraction. Although a metal-binding motif, HxxE, conserved in zinc ion-dependent M75 peptidases is also found in Algp7, the crystal structure of Algp7 contains no metal even at the motif. The protein consists of two structurally similar up-and-down helical bundles as the basic scaffold. A deep cleft between the bundles is sufficiently large to accommodate macromolecules such as alginate polysaccharide. This is the first structural report on a bacterial cell-surface alginate-binding protein with an M75 peptidase motif. PMID- 21238430 TI - The reconstituted 'humanized liver' in TK-NOG mice is mature and functional. AB - To overcome the limitations of existing models, we developed a novel experimental in vivo platform for replacing mouse liver with functioning human liver tissue. To do this, a herpes simplex virus type 1 thymidine kinase (HSVtk) transgene was expressed within the liver of highly immunodeficient NOG mice (TK-NOG). Mouse liver cells expressing this transgene were ablated after a brief exposure to a non-toxic dose of ganciclovir (GCV), and transplanted human liver cells are stably maintained within the liver (humanized TK-NOG) without exogenous drug. The reconstituted liver was shown to be a mature and functioning "human organ" that had zonal position-specific enzyme expression and a global gene expression pattern representative of mature human liver; and could generate a human-specific profile of drug metabolism. The 'humanized liver' could be stably maintained in these mice with a high level of synthetic function for a prolonged period (8 months). This novel in vivo system provides an optimized platform for studying human liver physiology, including drug metabolism, toxicology, or liver regeneration. PMID- 21238432 TI - Role of different brain areas in peripheral nerve injury-induced neuropathic pain. AB - Neuropathic pain has been described as the "most terrible of all tortures which a nerve wound may inflict" and arises as a consequence of nerve injury either of the peripheral or central nervous system. Following peripheral nerve injury, a cascade of events in the primary afferents leads to peripheral sensitization resulting in spontaneous nociceptor activity, decreased threshold and increased response to supra-threshold stimuli. A series of molecular changes in spinal cord and brain centers are associated with central sensitization which is responsible for the pain to non-injured extra-territory regions (extraterritorial pain) and contralateral parts (mirror-image pain). The peripheral nerve injury has been reported to induce neuroplastic changes in different brain regions including the anterior cingulate cortex, insular cortex, ventrolateral orbitofrontal area, amygdala, striatum, thalamus, hypothalamus, rostral ventromedial medulla, periaqueductal gray, pons (locus coeruleus), red nucleus, and medulla oblongata. The present review article discusses the involvement of these different brain areas in the development of peripheral nerve injury-induced neuropathic pain. PMID- 21238431 TI - The effect of dietary soy isoflavones before and after ovariectomy on hippocampal protein markers of mitochondrial bioenergetics and antioxidant activity in female monkeys. AB - Estrogen therapy can promote cognitive function if initiated within a 'critical window' during the menopausal transition. However, in the absence of a progestogen, estrogens increase endometrial cancer risk which has spurred research into developing estrogenic alternatives that have the beneficial effects of estrogen but which are clinically safer. Soy protein is rich in isoflavones, which are a class of potential estrogenic alternatives. We sought to determine the effects of two diets, one with casein-lactalbumin as the main protein source and the other with soy protein containing isoflavones, on protein markers of hippocampal bioenergetic capacity in adult female cynomolgus macaques (Macaca fascicularis). Further, we assessed the effects of dietary soy isoflavones before or after ovariectomy. Animals receiving soy diet premenopausally then casein/lactalbumin post-ovariectomy had higher relative hippocampal content of glycolytic enzymes glyceraldehyde 3-phosphate dehydrogenase and pyruvate dehydrogenase subunit e1alpha. Post-ovariectomy consumption of soy was associated with higher succinate dehydrogenase alpha levels and lower levels of isocitrate dehydrogenase, both proteins involved in the tricarboxylic acid cycle, significantly decreased expression of the antioxidant enzyme peroxiredoxin-V, and a non-significant trend towards decreased manganese superoxide dismutase expression. None of the diet paradigms significantly affected expression levels of oxidative phosphorylation enzyme complexes, or of mitochondrial fission and fusion proteins. Together, these data suggest that long-term soy diet produces minimal effects on hippocampal expression of proteins involved in bioenergetics, but that switching between a diet containing primarily animal protein and one containing soy isoflavones before and after menopause may result in complex effects on brain chemistry. PMID- 21238433 TI - Recognising upright and inverted faces: MEG source localisation. AB - Face recognition is a complex cognitive task that involves a distributed network of neural sources. While some components of this network have been identified, the temporal sequence of these components is not well understood. Magnetoencephalography (MEG), analyzed with a spatial filtering source localisation algorithm, was used to determine frontal contributions to face recognition. We tested 22 adults (mean age 26.3 years; 10 females). Upright and inverted faces were presented in counter-balanced blocks and subjects identified repetitions in a 1-back protocol. MEG data were recorded continuously from a 151 channel CTF machine and source localised to each participant's MRI. The classic face components, M100 and M170, were seen for upright and inverted faces with M100 localizing to bilateral occipital areas and M170 to bilateral fusiform areas. A third component, M240, showed high global field power to correctly recognised repeated faces and localised to right middle frontal and insula sources at 240 ms for upright faces and bilateral mid-frontal sources for inverted faces. The effect of repetition was examined and a source identified at 250 ms in the cingulate, for inverted faces. These results provide timing information on frontal lobe activation, seen reliably in fMRI memory studies; the immediate recognition of repeated faces activates the right frontal sources at 240-250 ms, with bilateral activation to repeated inverted faces, perhaps due to increased task difficulty. PMID- 21238434 TI - Contribution of denaturing and deodorization processes of oils to toxic oil syndrome. AB - In this article, denaturing with aniline and refining process of the oil responsible for toxic oil syndrome is briefly reviewed. The aspects considered include description of conditions of the main refining steps in relation to aniline derivatives formation, with special focus on the deodorization stage. In this last step of the refining process, an increase in the temperature, applied to such an unusual oil, could have given rise to the formation of anilides and 3 N-phenylamino-1,2-propanediol esters. PMID- 21238435 TI - Overview of strategies for addressing BRIs in drug discovery: Impact on optimization and design. AB - The sensitive and specific detection of adducts derived from reactive intermediates during discovery metabolite profiling has been made feasible by advances in LC-MS/MS instrumentation. Many companies employ screens with nucleophilic trapping agents as a routine part of early screening efforts. Although certainly not as straightforward as initial adduct detection, the positives in the profiling experiment can be followed-up with determination of exact adduct structure. This information feeds naturally into drug design efforts as the structural motifs responsible for reactive metabolite formation can be altered to reduce the property. While the process of generation of reactive metabolite data has become more straightforward, the conversion of that data into an optimization paradigm remains challenging. Recent studies have shown a very loose correlation between extent of reactive metabolite formation and observed toxicity, so setting stringent criteria likely leads to discarding compounds that would not have problems. On the other hand, the central role of reactive metabolites in most accepted mechanisms of drug-induced toxicity points to the fact that there is value in minimizing the property. Decision making based on information on reactive metabolite formation remains a difficult process in all phases of drug discovery and development. Decisions on compounds in discovery can be made based on a fixed threshold value or relative to a reference point within a chemical series, but should be made with a firm understanding of the limitation of the data. PMID- 21238437 TI - Advanced lipoxidation end-products. AB - Chemical and nonenzymatic molecular modifications induced by reactive carbonyl species (RCS) generated by peroxidation of membrane phospholipids acyl chains play a dual role as signaling molecules and as mediators of the aging process. Cytotoxic effects of RCS are due to their capacity to react with cellular constituents, forming advanced lipoxidation end-products (ALEs). Reactive carbonyl compounds are stable and can diffuse within or even escape from the cell and attack targets far from the site of formation. The consequent loss of function and structural integrity of modified biomolecules can have a wide range of downstream functional consequences and may be the cause of subsequent cellular dysfunctions and tissue damage. PMID- 21238436 TI - Enzymatic properties of ALDH1L2, a mitochondrial 10-formyltetrahydrofolate dehydrogenase. AB - 10-Formyltetrahydrofolate dehydrogenase (FDH, ALDH1L1), an abundant cytosolic enzyme of folate metabolism, shares significant sequence similarity with enzymes of the aldehyde dehydrogenase (ALDH) family. The enzyme converts 10 formyltetrahydrofolate (10-fTHF) to tetrahydrofolate and CO(2) in an NADP(+) dependent manner. The mechanism of this reaction includes three consecutive steps with the final occurring in an ALDH-homologous domain. We have recently identified a mitochondrial isoform of FDH (mtFDH), which is the product of a separate gene, ALDH1L2. Its overall identity to cytosolic FDH is about 74%, and the identity between the ALDH domains rises up to 79%. In the present study, human mtFDH was expressed in Escherichia coli, purified to homogeneity, and characterized. While the recombinant enzyme was capable of catalyzing the 10-fTHF hydrolase reaction, it did not produce detectable levels of ALDH activity. Despite the lack of typical ALDH catalysis, mtFDH was able to perform the characteristic 10-fTHF dehydrogenase reaction after reactivation by recombinant 4'-phosphopantetheinyl transferase (PPT) in the presence of coenzyme A. Using site-directed mutagenesis, it was determined that PPT modifies mtFDH specifically at Ser375. The C-terminal domain of mtFDH (residues 413-923) was also expressed in E. coli and characterized. This domain was found to exist as a tetramer and to catalyze an esterase reaction that is typical of other ALDH enzymes. Taken together, our studies suggest that ALDH1L2 has enzymatic properties similar to its cytosolic counterpart, although the inability to catalyze the ALDH reaction with short-chain aldehyde substrates remains an unresolved issue at present. PMID- 21238438 TI - Dopamine-derived biological reactive intermediates and protein modifications: Implications for Parkinson's disease. AB - Dopamine (DA) undergoes monoamine oxidase catalyzed oxidative deamination to 3,4 dihydroxyphenylacetaldehyde (DOPAL), which is metabolized primarily to 3,4 dihydroxyphenylacetic acid (DOPAC) via aldehyde dehydrogenase (ALDH). Previous studies demonstrated DOPAL to be neurotoxic, more so than DA and other metabolites, and implicated the aldehyde intermediate as a factor in the pathogenesis of Parkinson's disease (PD). However, the mechanism for generation of DOPAL at aberrant levels and the pathways for toxicity are not conclusively known. Various models for DA catabolism revealed the susceptibility of DOPAL biotransformation (e.g., ALDH) to products of oxidative stress, e.g., 4-hydroxy-2 nonenal, at physiologic/pathologic levels and agents that induce oxidative stress. An elevated concentration of DOPAL correlated with increased protein modification with subsequent work demonstrating significant reactivity of the DA derived electrophile toward protein nucleophiles compared to DA and other metabolites, e.g., DOPAC. The addition of DOPAL to proteins proceeds via reaction of the aldehyde with Lys residues, yielding a Schiff base; however, post adduction chemistry occurs for the DOPAL-modification resulting in protein cross linking. Preliminary work indicates enzymes in DA synthesis and catabolism to be cellular targets for DOPAL. Functional consequences for elevated levels of the DA derived aldehyde and protein modification may include adverse cellular effects. These data implicate DOPAL as a toxic and reactive intermediate potentially serving as a "chemical trigger" for some stage of PD pathogenesis. PMID- 21238439 TI - Effect of the omega-acylceramides on the lipid organization of stratum corneum model membranes evaluated by X-ray diffraction and FTIR studies (Part I). AB - The lipid organization in the outermost layer of the skin, the stratum corneum, is important for the skin barrier function. The stratum corneum lipids are composed of ceramides (CER), free fatty acids (FFA) and cholesterol (CHOL). In the present study Fourier transform infrared (FTIR) and small-angle X-ray scattering (SAXS) techniques were utilized to evaluate the effect of three C18 fatty acid esterified omega-acylceramides (CER EOS) on the lipid organization of stratum corneum model membranes. FTIR spectra (scissoring and rocking bands) showed as a function of temperature significant line-shape changes for both components assigned to the orthorhombic phase. Second-derivative analyzes revealed a significant decrease in the interchain coupling strength (Deltanu values) for the samples formed by CER EOS with the linoleate (CER EOS-L) and oleate (CER EOS-O) moiety around 28.5 degrees C. However, only a gradual decrease in the Deltanu values was noticed for the mixture formed with CER EOS with the stearate moiety (CER EOS-S) over the whole temperature range. In the absence of CER EOS the decrease started already at 25.5 degrees C, demonstrating that CER EOS stabilized the orthorhombic lattice. This stabilization was most pronounced for the CER EOS-S. Spectral fittings allowed to evaluate the orientation changes of the skeletal plane within the orthorhombic unit cell (theta values) for a given temperature range. From the best-fit parameters (peak area values), a decrease in the orthorhombic phase contribution to the scissoring band was also monitored as a function of the temperature. SAXS studies showed the coexistence of two lamellar phases with a periodicity of ~5.5 nm (short periodicity phase, SPP) and ~12 nm (LPP) in the presence of the CER EOS-L and CER EOS-O. However, no diffraction peaks associated to the LPP were detected for CER EOS-S. While CER EOS-S most efficiently stabilized the orthorhombic phase, CER EOS-L and CER EOS-O promoted the presence of the LPP. Therefore, the presence of all three CER EOS as observed in human stratum corneum may contribute to a proper skin barrier function. PMID- 21238440 TI - Comparison of two assays for serum 1,5-anhydroglucitol. PMID- 21238441 TI - Ionized calcium. AB - Calcium is the most abundant mineral in the human body. While most of the body's calcium is sequestered in the skeleton, the free, hydrated cation in solution is a key physiologic mediator in a host of metabolic and regulatory processes. The free cation concentration in the extracellular fluid, historically referred to as "ionized calcium" in clinical medicine, is frequently assayed in patients with suspected or known derangements of calcium metabolism. There is controversy in the literature as to whether direct measurement of ionized calcium, measurement of total (free plus chelated or protein-bound) calcium, or adjustment of total calcium for albumin concentration is the best or most practical clinical measure of calcium, as the three methods differ in costs and clinical sensitivities. This manuscript will review calcium biochemistry and homeostasis, compare the utilities of different methods of assessing calcium homeostasis, and discuss appropriate utilization of ionized calcium testing. PMID- 21238442 TI - Pregnancy-associated plasma protein A values in patients with stable cardiovascular disease: use of a new monoclonal antibody-based assay. AB - BACKGROUND: PAPP-A is promising in improving risk stratification and invasive treatment decisions in stable cardiovascular patients. We evaluated the prognostic value of pregnancy-associated plasma protein A (PAPP-A) measured by a novel assay in stable cardiovascular patients. METHODS: We investigated 228 stable cardiovascular outpatients. Blood was drawn for PAPP-A measurement after echocardiography and ergometry prior to heart catheterization. Angiographically we determined severity as well as qualitative characteristics suspect for vulnerability of coronary lesions. After 1108+/-297 days, follow-up information was obtained by questionnaire mailings and interviews by phone. RESULTS: 104 patients had coronary stenosis>=70%, 75 had B-type lesions>=50%, 46 showed complex lesions, and 68 were suspected to have vulnerable lesions. Median PAPP-A was 1.76 (interquartile range 1.21, 2.63) MUIU/ml in the entire cohort. PAPP-A concentrations did not differ in dependence on coronary artery findings. A cutpoint of 2.7 MUIU/ml was derived from receiver-operator characteristics for outcome measures. For this cutoff, Cox proportional hazard models with 19 further clinical variables showed that PAPP-A was predictive for all-cause death (HR 4.73, 95% CI 1.46-15.31, p=0.01), all-cause death or nonfatal infarction (HR 4.01, 95% CI 1.58-10.13, p=0.003) and all-cause death, nonfatal myocardial infarction or hospitalization (HR 1.96, 95% CI 1.03-3.70, p=0.04). The predictive value of PAPP-A did not change substantially after correction for values of cardiac troponin, using a highly sensitive cardiac troponin I research assay. CONCLUSIONS: PAPP-A, measured by a new, monoclonal antibody-based assay is a promising prognostic marker in patients with stable cardiovascular disease and an indication for heart catheterization. PMID- 21238443 TI - Age and gender specific pediatric reference intervals for aldolase, amylase, ceruloplasmin, creatine kinase, pancreatic amylase, prealbumin, and uric acid. AB - BACKGROUND: Reference intervals can vary based on age and gender. Proper partitioning is necessary to classify health status in different age groups. METHODS: Seven analytes; aldolase, amylase, ceruloplasmin, creatine kinase, pancreatic amylase, prealbumin and uric acid; were assayed on Roche Modular P analyzers using serum samples from 1765 children (867 females and 898 males; age range, 6 months to 17 y). Subjects 6 months up to 7 y were undergoing minor surgical procedures. Children 7 to 17 y were apparently healthy. Subjects with significant medical history or who were taking any medications were excluded. RESULTS: Separate reference intervals for boys and girls were required for 33% of the groups. Aldolase showed gender variation in the 6-8, 12-14, and 15-17 y. Amylase was the only analyte that showed no significant gender differences within any age group. Both ceruloplasmin and uric acid had significant differences between the 12-14 and 15-17 y groups. Creatine kinase exhibited statistically significant gender differences in all age groups with the exception of 6-8 y. CONCLUSION: We verified that when establishing pediatric reference intervals, partitioning by age and gender is frequently necessary. PMID- 21238444 TI - IGF-II and MMP9 as surgical repair indicators of ventricular septal defects. AB - OBJECTIVE: The insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-3 (IGFBP-3) and human growth hormone (h-GH) have been recognized as therapeutic targets for the heart disease therapy. The bioavailability and actions of insulin-like growth factors-II (IGF-II) and matrix metalloproteinase-9 (MMP9) are important for embryonic development and cardiomyocyte differentiation as well. However, the clinical manifestations following the change in the serum IGF-II and MMP9 in infants with isolated ventricular septal defect (VSD) undergoing surgical repair have not been clearly defined. STUDY DESIGN: Serum samples were collected from 72 infants: Twenty normal infants (group I) and 51 consecutive infants with echocardiography established isolated VSD (aged from 3 months to 1 year) were investigated. Among the 51 infants with VSD, 28 with shunt fraction, Qp/Qs < or = 1.5 were free of congestive heart failure symptoms (group II); 23 with shunt fraction, Qp/Qs > or = 2.0 were in congestive heart failure (group IIIa); and 23 of these 23 infants had undergone VSD repair 6 months before their second study (group IIIb). All insulin-like growth factors-II (IGF-II) and human growth hormone (h-GH), insulin like growth factor binding protein-3 (IGFBP 3) and its specific serum protease-MMP9 concentration were analyzed using ELISA and zymography, respectively. RESULTS: Serum IGF-II and MMP9 exhibited significant decreasing trends among the three groups and significantly lower concentrations of IGF-II, IGF-II/IGFBP-3 ratio and MMP9, were found only in the severe group whereas h-GH/IGF-II ratio became significantly higher in this group. Moreover, there were no significant differences in these parameters between the infants after surgical correction and the normal ones. CONCLUSIONS: The improvement in IGF-II and MMP9 serum concentration was identified in infants with VSD after surgical repair. These findings also indicate a significant relationship between IGF-II, MMP9 and VSD which might be used as diagnosis and prognosis indicators for this defect. Slight reductions in IGF-II/IGFBP3 ratio and slight increase in the h-GH/IGF-II ratio indicate mild VSD. The reductions in the MMP9, IGF-II, and IGF-II/IGFBP3 ratio plus high increase in the h-GH/IGF-II ratio indicate severe VSD. PMID- 21238445 TI - Serological surveillance and IL-10 genetic variants on anti-HBs titers: hepatitis B vaccination 20 years after neonatal immunization in Taiwan. AB - BACKGROUND: The national hepatitis B (HB) vaccination program in Taiwan that began in 1984 has resulted in a significant reduction in the carrier rate among children. However, a significant proportion of Taiwanese neonatal HB immunization recipients have exhibited low anti-HBs titers that fall to non-protective or undetectable levels. METHODS: We recruited 1677 entering freshman and graduate student participants at a Taiwanese university health center, grouped them into three age groups representing three stages of Taiwan's HB vaccination program, then conducted hepatitis B surface antigen (HBsAg) and antibodies to HBsAg (anti HBs) serological surveillances for each individual. Univariate and multivariate regression analyses of clinical characteristics and Interleukin-10 (IL-10) genetic variations were also conducted. RESULTS: A trend toward a decreasing HBsAg carrier rate was observed over the starting dates of the vaccination program (11.7%, 1.6% and 1.7% for age groups 1, 2 and 3, respectively), but we also observed an increasing rate of non-protective anti-HBs titers (15%, 26% and 50.3% for cohorts 1-3, respectively). The percentage of students with non protective anti-HBs titers increased from 23.1% for students born in 1984, to 25.2% for those born in 1985, to 39.4% for birth-year 1986 students, to 45.7% for birth-year 1987 students, and to 56.5% for birth-year 1988 students. The risk for low anti-HBs titers increased concurrently with increases in systolic blood pressure (BP), the IL-10 ATA/ACC haplotype, and the IL-10 ATA present haplotype. Risk for low anti-HBs titers decreased with concurrent decreases in glucose ante cibum (AC, before meals) and the IL-10 ACC/ACC haplotype. CONCLUSIONS: These results suggest that the genetic determinants may also contribute to variations in anti-HBs titers in immune responses to HB vaccination. PMID- 21238446 TI - Evaluation of bilirubin concentration in hemolysed samples, is it really impossible? The altitude-curve cartography approach to interfered assays. AB - BACKGROUND: Neonatal jaundice might lead to severe clinical consequences. Measurement of bilirubin in samples is interfered by hemolysis. Over a method depending cut-off value of measured hemolysis, bilirubin value is not accepted and a new sample is required for evaluation although this is not always possible, especially with newborns and cachectic oncological patients. When usage of different methods, less prone to interferences, is not feasible an alternative recovery method for analytical significance of rejected data might help clinicians to take appropriate decisions. METHODS: We studied the effects of hemolysis over total bilirubin measurement, comparing hemolysis-interfered bilirubin measurement with the non-interfered value. Interference curves were extrapolated over a wide range of bilirubin (0-30 mg/mL) and hemolysis (H Index 0 1100). RESULTS: Interference "altitude" curves were calculated and plotted. A bimodal acceptance table was calculated. Non-interfered bilirubin of given samples was calculated, by linear interpolation between the nearest lower and upper interference curves. CONCLUSIONS: Rejection of interference-sensitive data from hemolysed samples for every method should be based not upon the interferent concentration but upon a more complex algorithm based upon the concentration dependent bimodal interaction between the interfered analyte and the measured interferent. The altitude-curve cartography approach to interfered assays may help laboratories to build up their own method-dependent algorithm and to improve the trueness of their data by choosing a cut-off value different from the one ( 10% interference) proposed by manufacturers. When re-sampling or an alternative method is not available the altitude-curve cartography approach might also represent an alternative recovery method for analytical significance of rejected data. PMID- 21238447 TI - Is the accuracy of serum albumin measurements suitable for clinical application of the test? PMID- 21238448 TI - Partial loss of Ascl2 function affects all three layers of the mature placenta and causes intrauterine growth restriction. AB - Several imprinted genes have been implicated in the regulation of placental function and embryonic growth. On distal mouse chromosome 7, two clusters of imprinted genes, each regulated by its own imprinting center (IC), are separated by a poorly characterized region of 280kb (the IC1-IC2 interval). We previously generated a mouse line in which this IC1-IC2 interval has been deleted (Del(7AI) allele) and found that maternal inheritance of this allele results in low birth weights in newborns. Here we report that Del(7AI) causes a partial loss of Ascl2, a maternally expressed gene in the IC2 cluster, which when knocked out leads to embryonic lethality at midgestation due to a lack of spongiotrophoblast formation. The hypomorphic Ascl2 allele causes embryonic growth restriction and an associated placental phenotype characterized by a reduction in placental weight, reduced spongiotrophoblast population, absence of glycogen cells, and an expanded trophoblast giant cell layer. We also uncovered severe defects in the labyrinth layer of maternal mutants including increased production of the trilaminar labyrinth trophoblast cell types and a disorganized labyrinthine vasculature. Our results have important implications for our understanding of the role played by the spongiotrophoblast layer during placentation and show that regulation of the dosage of the imprinted gene Ascl2 can affect all three layers of the chorio-allantoic placenta. PMID- 21238449 TI - A single GATA factor plays discrete, lineage specific roles in ascidian heart development. AB - GATA family transcription factors are core components of the vertebrate heart gene network. GATA factors also contribute to heart formation indirectly through regulation of endoderm morphogenesis. However, the precise impact of GATA factors on vertebrate cardiogenesis is masked by functional redundancy within multiple lineages. Early heart specification in the invertebrate chordate Ciona intestinalis is similar to that of vertebrates but only one GATA factor, Ci GATAa, is expressed in the heart progenitor cells and adjacent endoderm. Here we delineate precise, tissue specific contributions of GATAa to heart formation. Targeted repression of GATAa activity in the heart progenitors perturbs their transcriptional identity. Targeted repression of endodermal GATAa function disrupts endoderm morphogenesis. Subsequently, the bilateral heart progenitors fail to fuse at the ventral midline. The resulting phenotype is strikingly similar to cardia bifida, as observed in vertebrate embryos when endoderm morphogenesis is disturbed. These findings indicate that GATAa recapitulates cell autonomous and non-cell-autonomous roles performed by multiple, redundant GATA factors in vertebrate cardiogenesis. PMID- 21238451 TI - Activation of T cell death-associated gene 8 attenuates inflammation by negatively regulating the function of inflammatory cells. AB - T cell death-associated gene 8 (TDAG8) is a G-protein-coupled receptor identified by differential mRNA display during thymocyte apoptosis induced by T cell receptor engagement. To examine the physiological role of an orphan G-protein coupled receptor TDAG8 in inflammation, we studied various immune-mediated inflammatory disease models using TDAG8-deficient mice. We found that TDAG8 deficient mice showed significant exacerbation of anti-type II collagen antibody induced arthritis and delayed-type hypersensitivity, and showed a slight exacerbation of collagen-induced arthritis. These results suggest that TDAG8 acts as a negative regulator of inflammation. PMID- 21238450 TI - Involvement of a NO-cyclic GMP-PKG signaling pathway in nitrous oxide-induced antinociception in mice. AB - The antinociceptive effect of nitrous oxide (N(2)O) is dependent on nitric oxide (NO); however, the next step in the pathway activated by NO is undetermined. The present study was conducted to test the hypothesis that a N(2)O action involves sequential activation of NO synthase, soluble guanylyl cyclase and protein kinase G to induce an antinociceptive effect in mice. The antinociceptive responsiveness of male NIH Swiss mice to N(2)O was assessed using the acetic acid abdominal constriction test. Different groups of mice were pretreated with either saline, the NO scavenger 2-(4-carboxyphenyl)-4,5-dihydro-4,4,5,5-tetramethyl-1H imidazolyl-1-oxy-3-oxide (carboxy-PTIO), the guanylyl cyclase-inhibitor 1H [1,2,4]-oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), the protein kinase G-inhibitor Rp-isomer of 8-(4-chlorophenylthio)-guanosine-3',5'-cyclic monophosphorothioate (Rp-8-pCPT-cGMPS) or the selective phosphodiesterase V-inhibitor 1,2-dihydro-2 [(2-methyl-4-pyridinyl)methyl]-1-oxo-8-(2-pyrimidinylmethoxy)-4-(3,4,5 trimethoxyphenyl)-2,7-naphthyridine-3-carboxylic acid methyl ester hydrochloride (T 0156). Vehicle (saline)-pretreated mice responded to N(2)O in a concentration dependent manner. This antinociceptive effect was antagonized by systemic pretreatment with carboxy-PTIO and ODQ and central pretreatment with Rp-8-pCPT cGMPS. In each case, the dose-response curve for N(2)O was progressively shifted to the right by increasing the dose of each pretreatment drug. On the other hand, N(2)O-induced antinociception was enhanced by systemic pretreatment with T 0156; the dose-response curve for N(2)O was shifted to the left. The ATP-sensitive potassium channel blocker glibenclamide was without influence on the antinociceptive effect of N(2)O. These results support the hypothesis that N(2)O induced antinociception in mice is mediated by a NO-cyclic GMP-PKG pathway. PMID- 21238452 TI - Chronic or high dose acute caffeine treatment protects mice against oleic acid induced acute lung injury via an adenosine A2A receptor-independent mechanism. AB - The antagonism or genetic deletion of adenosine A(2A) receptors has been shown to exacerbate tissue damage in acute lung injury. Caffeine, a widely consumed behavioral drug, acts as a non-selective antagonist of A(2A) receptor and also has additional pharmacological effects. Thus, the protective vs. deleterious effects of caffeine in acute lung injury should be evaluated. In a murine oleic acid-induced model of acute lung injury, we found that chronic caffeine treatment by drinking water (0.1g/l or 0.25g/l for 2 weeks before acute lung injury) or acute caffeine treatment at high dose (i.p. 50mg/kg, injection, 30min before acute lung injury) significantly attenuated the lung edema, hemorrhage, neutrophil recruitment as well as the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) expressions in both of the wild type (WT) and A(2A) receptor knockout (KO) mice. This profile was accompanied by increased cAMP levels and up-regulation of A2B receptor mRNAs in the lungs. In contrast, acute caffeine treatment at low dose (i.p. 5mg/kg or 15mg/kg, injection, 30min before acute lung injury) enhanced the inflammation and lung damage in WT mice with decreasing cAMP but not in A(2A) receptor KO mice. These results indicate that caffeine either enhances lung damage by antagonizing A(2A) receptor or exerts protection against lung damage via A(2A) receptor-independent mechanisms, depending on the timing of exposure (chronic vs. acute) and dose of administration (low vs. high). These findings provide new insight of caffeine in acute lung injury and highlight the potential benefit and strategy of caffeine intake or administration for preventing acute lung injury. PMID- 21238453 TI - Sex-related differences in descending norepinephrine and serotonin controls of spinal withdrawal reflex during intramuscular saline induced muscle nociception in rats. AB - Sex-associated differences in the perception and modulation of pain have widely been reported in humans as well as animals. The aim of the present study performed in conscious rats of both sexes was to systematically investigate the role of sex in endogenous descending controls of nociceptive paw withdrawal reflex during experimental muscle pain elicited by intramuscular (i.m.) injection with different doses (0.1-0.4 ml of 0.9-5.8%) of saline. Ipsilateral i.m. injection of 0.2-0.4 ml, but not 0.1 ml, isotonic (0.9%, IT) saline elicited long lasting (about 7d), secondary and contralateral mechanical hyperalgesia in female rats, whereas male rats exhibited a bilateral, short-term (less than 1d) mechanical hyperalgesia only during the exposure to 0.4 ml IT saline injection (P < 0.05). A bolus of 0.4 ml, but not 0.1-0.2 ml, IT saline significantly induced a one-week, secondary and contralateral heat hypoalgesia in both male and female rats (P < 0.05). In contrast to the IT saline injection, 0.1 ml hypertonic (5.8%, HT) saline started to evoke bilateral mechanical hyperalgesia in male and female rats. During the HT saline induced muscle nociception, mechanical hyperalgesia in female rats was greater in magnitude and longer in duration than that of in male rats (P < 0.05). Heat hypoalgesia was bilaterally found in male rats receiving either 0.2 ml or 0.4 ml HT saline injection, whereas female rats showed heat hypoalgesia, subjected only to the 0.4 ml HT saline injection (P < 0.05 and P < 0.001). Intrathecal (i.th.) administration of either 6-hydroxydopamine hydrobromide (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT) significantly attenuated the HT saline induced heat hypoalgesia, not mechanical hyperalgesia, in male rats. By contrast, in female rats i.th. 6-OHDA markedly blocked heat hypoalgesia, and mechanical hyperalgesia was prevented by 5,7-DHT treatment. It is suggested that i.m. injection of saline dose-dependently elicits ipsilateral secondary and contralateral mechanical hyperalgesia and heat hypoalgesia, which are differently modulated by descending noradrenaline (NA) and serotonin (5-HT) pathways in rats of both sexes. Importantly, the present findings here are not only consistent with our previous study indicating a supraspinal nociception discriminator with different triggering thresholds to govern peripheral A-delta and C-fiber mediated responses (You et al., 2010), but further strengthen this hypothesis that compared with male rats, supraspinal nociception discriminator in female rats exhibits a lower facilitatory threshold and a higher inhibitory threshold. This may bring our attention to better understand why females are commonly reported to be more sensitive and less tolerant to noxious stimulation. In conclusion, sex-related differences are important in descending modulations of pain and anesthesia. Less noxious stimuli could activate descending inhibition in males but not females, whereas less noxious afferents may elicit descending facilitation in female, but not male rats. Central noradrenergic and serotonergic pathways are differently involved in the action of descending modulations of nociception in rats of both sexes. PMID- 21238455 TI - Gonadotropin-releasing hormone (GnRH) modulates auditory processing in the fish brain. AB - Gonadotropin-releasing hormone 1 (GnRH1) neurons control reproductive activity, but GnRH2 and GnRH3 neurons have widespread projections and function as neuromodulators in the vertebrate brain. While these extra-hypothalamic GnRH forms function as olfactory and visual neuromodulators, their potential effect on processing of auditory information is unknown. To test the hypothesis that GnRH modulates the processing of auditory information in the brain, we used immunohistochemistry to determine seasonal variations in these neuropeptide systems, and in vivo single-neuron recordings to identify neuromodulation in the midbrain torus semicircularis of the soniferous damselfish Abudefduf abdominalis. Our results show abundant GnRH-immunoreactive (-ir) axons in auditory processing regions of the midbrain and hindbrain. The number of extra-hypothalamic GnRH somata and the density of GnRH-ir axons within the auditory torus semicircularis also varied across the year, suggesting seasonal changes in GnRH influence of auditory processing. Exogenous application of GnRH (sGnRH and cGnRHII) caused a primarily inhibitory effect on auditory-evoked single neuron responses in the torus semicircularis. In the majority of neurons, GnRH caused a long-lasting decrease in spike rate in response to both tone bursts and playbacks of complex natural sounds. GnRH also decreased response latency and increased auditory thresholds in a frequency and stimulus type-dependent manner. To our knowledge, these results show for the first time in any vertebrate that GnRH can influence context-specific auditory processing in vivo in the brain, and may function to modulate seasonal auditory-mediated social behaviors. PMID- 21238454 TI - Dll1- and dll4-mediated notch signaling are required for homeostasis of intestinal stem cells. AB - BACKGROUND & AIMS: Ablation of Notch signaling within the intestinal epithelium results in loss of proliferating crypt progenitors due to their conversion into postmitotic secretory cells. We aimed to confirm that Notch was active in stem cells (SCs), investigate consequences of loss of Notch signaling within the intestinal SC compartment, and identify the physiologic ligands of Notch in mouse intestine. Furthermore, we investigated whether the induction of goblet cell differentiation that results from loss of Notch requires the transcription factor Kruppel-like factor 4 (Klf4). METHODS: Transgenic mice that carried a reporter of Notch1 activation were used for lineage tracing experiments. The in vivo functions of the Notch ligands Jagged1 (Jag1), Delta-like1 (Dll1), Delta-like4 (Dll4), and the transcription factor Klf4 were assessed in mice with inducible, gut-specific gene targeting (Vil-Cre-ER(T2)). RESULTS: Notch1 signaling was found to be activated in intestinal SCs. Although deletion of Jag1 or Dll4 did not perturb the intestinal epithelium, inactivation of Dll1 resulted in a moderate increase in number of goblet cells without noticeable effects of progenitor proliferation. However, simultaneous inactivation of Dll1 and Dll4 resulted in the complete conversion of proliferating progenitors into postmitotic goblet cells, concomitant with loss of SCs (Olfm4(+), Lgr5(+), and Ascl2(+)). Klf4 inactivation did not interfere with goblet cell differentiation in adult wild type or in Notch pathway-deficient gut. CONCLUSIONS: Notch signaling in SCs and progenitors is activated by Dll1 and Dll4 ligands and is required for maintenance of intestinal progenitor and SCs. Klf4 is dispensable for goblet cell differentiation in intestines of adult Notch-deficient mice. PMID- 21238456 TI - Sequence comparison between three geographically distinct Spodoptera frugiperda multiple nucleopolyhedrovirus isolates: Detecting positively selected genes. AB - The complete genomic sequence of a Nicaraguan plaque purified Spodoptera frugiperda nucleopolyhedrovirus (SfMNPV) genotype SfMNPV-B was determined and compared to previously sequenced isolates from United States (SfMNPV-3AP2) and Brazil (SfMNPV-19). The genome of SfMNPV-B (132,954bp) was 1623bp and 389bp larger than that of SfMNPV-3AP2 and SfMNPV-19, respectively. Genome size differences were mainly due to a deletion located in the SfMNPV-3AP2 egt region and small deletions and point mutations in SfMNPV-19. Nucleotide sequences were strongly conserved (99.35% identity) and a high degree of predicted amino acid sequence identity was observed. A total of 145 open reading frames (ORFs) were identified in SfMNPV-B, two of them (sf39a and sf110a) had not been previously identified in the SfMNPV-3AP2 and SfMNPV-19 genomes and one (sf57a) was absent in both these genomes. In addition, sf6 was not previously identified in the SfMNPV 19 genome. In contrast, SfMNPV-B and SfMNPV-19 both lacked sf129 that had been reported in SfMNPV-3AP2. In an effort to identify genes potentially involved in virulence or in determining population adaptations, selection pressure analysis was performed. Three ORFs were identified undergoing positive selection: sf49 (pif-3), sf57 (odv-e66b) and sf122 (unknown function). Strong selection for ODV envelope protein genes indicates that the initial infection process in the insect midgut is one critical point at which adaptation acts during the transmission of these viruses in geographically distant populations. The function of ORF sf122 is being examined. PMID- 21238458 TI - Adding protease digestion to the membrane protein toolbox. PMID- 21238457 TI - Identification of a beta-lactamase inhibitory protein variant that is a potent inhibitor of Staphylococcus PC1 beta-lactamase. AB - beta-Lactamase inhibitory protein (BLIP) binds and inhibits a diverse collection of class A beta-lactamases. Widespread resistance to beta-lactam antibiotics currently limits the treatment strategies for Staphylococcus infections. The goals of this study were to determine the binding affinity of BLIP for Staphylococcus aureus PC1 beta-lactamase and to identify mutants that alter binding affinity. The BLIP inhibition constant (K(i)) for PC1 beta-lactamase was measured at 350 nM, and isothermal titration calorimetry experiments indicated a binding constant (K(d)) of 380 nM. Twenty-three residue positions in BLIP that contact beta-lactamase were randomized, and phage display was used to sort the libraries for tight binders to immobilized PC1 beta-lactamase. The BLIP(K74G) mutant was the dominant clone selected, and it was found to inhibit the PC1 beta lactamase with a K(i) of 42 nM, while calorimetry indicated a K(d) of 26 nM. Molecular modeling studies suggested that BLIP binds weakly to the PC1 beta lactamase due to the presence of alanine at position 104 of PC1. This position is occupied by glutamate in the TEM-1 enzyme, where it forms a salt bridge with the BLIP residue Lys74 that is important for the stability of the complex. This hypothesis was confirmed by showing that the PC1(A104E) enzyme binds BLIP with 15 fold greater affinity than wild-type PC1 beta-lactamase. Kinetic measurements indicated similar association rates for all complexes with variation in affinity due to altered dissociation rate constants, suggesting that changes in short range interactions are responsible for the altered binding properties of the mutants. PMID- 21238459 TI - Structural investigation of PsbO from plant and cyanobacterial photosystem II. AB - The manganese-stabilizing protein PsbO is associated with the luminal side of thylakoids close to the redox-active Mn(4)Ca cluster at the catalytically active site of photosystem II (PSII). PsbO is believed to increase the efficiency of oxygen evolution and to stabilize the Mn(4)Ca cluster against photoinhibition. Using small-angle X-ray scattering, we investigated the low-resolution structure of wild-type spinach PsbO and that of chimeric spinach PsbO fused with maltose binding protein. Small-angle X-ray scattering data revealed that both proteins are monomeric in solution, and that plant and cyanobacterial PsbO have similar structures. We show a highly efficient expression system that allows recombinant production of the active wild type and the chimeric PsbO from spinach and cyanobacteria, with yields compatible with biophysical and structural studies. The binding of spinach PsbO fused with maltose-binding protein to PSII depleted of extrinsic subunits (PSII-DeltapsbO,P,Q) was confirmed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The reconstituted PSII was shown to have similar oxygen evolution rates as obtained with wild-type spinach PsbO. PMID- 21238460 TI - Constraining enzyme conformational change by an antibody leads to hyperbolic inhibition. AB - Although it has been known for many years that antibodies display properties characteristic of allosteric effectors, the molecular mechanisms responsible for these effects remain poorly understood. Here, we describe a single-domain antibody fragment (nanobody) that modulates protein function by constraining conformational change in the enzyme dihydrofolate reductase (DHFR). Nanobody 216 (Nb216) behaves as a potent allosteric inhibitor of DHFR, giving rise to mixed hyperbolic inhibition kinetics. The crystal structure of Nb216 in complex with DHFR reveals that the nanobody binds adjacent to the active site. Half of the epitope consists of residues from the flexible Met20 loop. This loop, which ordinarily oscillates between occluded and closed conformations during catalysis, assumes the occluded conformation in the Nb216-bound state. Using stopped flow, we show that Nb216 inhibits DHFR by stabilising the occluded Met20 loop conformation. Surprisingly, kinetic data indicate that the Met20 loop retains sufficient conformational flexibility in the Nb216-bound state to allow slow substrate turnover to occur. PMID- 21238461 TI - The structural and dynamic response of MAGI-1 PDZ1 with noncanonical domain boundaries to the binding of human papillomavirus E6. AB - PDZ domains are protein interaction domains that are found in cytoplasmic proteins involved in signaling pathways and subcellular transport. Their roles in the control of cell growth, cell polarity, and cell adhesion in response to cell contact render this family of proteins targets during the development of cancer. Targeting of these network hubs by the oncoprotein E6 of "high-risk" human papillomaviruses (HPVs) serves to effect the efficient disruption of cellular processes. Using NMR, we have solved the three-dimensional solution structure of an extended construct of the second PDZ domain of MAGI-1 (MAGI-1 PDZ1) alone and bound to a peptide derived from the C-terminus of HPV16 E6, and we have characterized the changes in backbone dynamics and hydrogen bonding that occur upon binding. The binding event induces quenching of high-frequency motions in the C-terminal tail of the PDZ domain, which contacts the peptide upstream of the canonical X-[T/S]-X-[L/V] binding motif. Mutations designed in the C-terminal flanking region of the PDZ domain resulted in a significant decrease in binding affinity for E6 peptides. This detailed analysis supports the notion of a global response of the PDZ domain to the binding event, with effects propagated to distal sites, and reveals unexpected roles for the sequences flanking the canonical PDZ domain boundaries. PMID- 21238462 TI - Derivatives of Dictyostelium differentiation-inducing factors promote mitogen activated IL-2 production via AP-1 in Jurkat cells. AB - AIMS: Differentiation-inducing factors (DIFs) are chlorinated alkylphenones found in the cellular slime mold Dictyostelium discoideum. DIF derivatives exhibit antiproliferative activities and promote glucose consumption in mammalian cells in vitro. Here, we assessed the ability of DIFs to regulate the immune system in a mammalian cell-line and investigated their mechanisms of action. MAIN METHODS: We examined the effects of 30 DIF derivatives on concanavalin A-induced interleukin-2 (IL-2) production (CIIP) in Jurkat T-cells. We also examined the effects of these DIF derivatives on the activity of three transcription factors required for CIIP: namely, activator protein-1 (AP-1), nuclear factor of activated T-cells (NFAT), and nuclear factor kappa B (NFkappaB). KEY FINDINGS: A reporter gene assay suggested that 2 DIF derivatives, termed DIF-1(+1) and DIF 3(3M), significantly promoted CIIP in Jurkat cells, at least in part, by enhancing the activity of AP-1. These 2 DIF derivatives had no significant effect on concanavalin A-induced interferon-gamma production. SIGNIFICANCE: The results suggest that DIF derivatives could be developed as novel drugs for the activation of IL-2 production and resultant stimulation of the immune system. PMID- 21238463 TI - Gene therapy with hypoxia-inducible factor 1 alpha in skeletal muscle is cardioprotective in vivo. AB - AIMS: Gene therapy of a peripheral organ to protect the heart is clinically attractive. The transcription factor hypoxia-inducible factor 1 alpha (HIF 1alpha) transactivates cardioprotective genes. We investigated if remote delivery of DNA encoding for HIF-1alpha is protective against myocardial ischemia reperfusion injury in vivo. MAIN METHODS: DNA encoding for human HIF-1alpha was delivered to quadriceps muscles of mice. One week later myocardial infarction was induced and four weeks later its size was measured. Echocardiography and in vivo pressure-volume analysis was performed. Coronary vascularization was evaluated through plastic casting. HL-1 cells, transfected with either HIF-1alpha or HMOX-1 or administered bilirubin or the carbon monoxide (CO) donor CORM-2, were subjected to lipopolysacharide (LPS)-induced cell death to compare the efficacy of treatments. KEY FINDINGS: After four weeks of reperfusion post infarction, animals pretreated with HIF-1alpha showed reduced infarct size and left ventricular remodeling (p<0.05, respectively). Fractional shortening was preserved in mice pretreated with HIF-1alpha (p<0.05). Invasive hemodynamic parameters indicated preserved left ventricular function after HIF-1alpha (p<0.05), which also induced coronary vascularization (p<0.05). HIF-1alpha downstream target heme oxygenase 1 (HMOX-1) was upregulated in skeletal muscle, while serum bilirubin was increased. Transfection of HL-1 cells with HIF-1alpha or HMOX-1 and administration of bilirubin or CORM-2 comparably salvaged cells from lipopolysacharide (LPS)-induced cell death (all p<0.05). SIGNIFICANCE: HIF 1alpha gene delivery to skeletal muscle preceding myocardial ischemia reduced infarct size and postischemic remodeling accompanied by an improved cardiac function and vascularization. Similar to HIF-1alpha, HMOX-1, bilirubin and CO were protective against LPS-induced injury. This observation may have clinical potential. PMID- 21238464 TI - Resveratrol with antioxidant activity inhibits matrix metalloproteinase via modulation of SIRT1 in human fibrosarcoma cells. AB - AIMS: Resveratrol, a silent information regulator 1 (SIRT1) activator, has been reported to act as an antioxidant contained in red wine and prevent the development of cardiovascular diseases. Histone deacetylase such as SIRT1 is involved in the regulation of lifespan extension. In this study, the effect of resveratrol on matrix metalloproteinases (MMPs) that play an important role in metastasis was examined in human fibrosarcoma cell line, HT1080. MAIN METHODS: The effect of resveratrol on MMPs' activity was evaluated using gelatin zymography. Western blot analysis and RT-PCR assay were used to determine the effect of resveratrol on the expression level of MMP-9, MAPK and SIRT1 proteins and genes, respectively. KEY FINDINGS: It was observed that resveratrol exhibited not only antioxidant effects on lipid peroxidation and DNA oxidation but also inhibitory effects on the expression of MMP-2 and 9 in HT1080 cells stimulated with either phorbol myristate acetate or phenazine methosulfate. Furthermore, it was found that treatment with resveratrol decreased the level of MMP-9 expression via down-regulation of p-ERK, c-fos and p65. In addition, the level of SIRT1 gene expression was also enhanced by treatment of resveratrol alone but the level of MMP-9 gene expression was decreased. SIGNIFICANCE: These results suggest that the activation of SIRT1 in the presence of resveratrol especially inhibits the expression of MMP-9 in HT1080 cells, providing evidence that resveratrol can be a potential candidate for chemoprevention of cancer. PMID- 21238465 TI - To poly(I:C) or not to poly(I:C): advancing preclinical schizophrenia research through the use of prenatal immune activation models. AB - The neurodevelopmental hypothesis of schizophrenia has been highly influential in shaping our current thinking about modeling the disease in animals. Based on the findings provided by human epidemiological studies, a great deal of recent interest has been centered upon the establishment of neurodevelopmental rodent models in which the basic experimental manipulation takes the form of prenatal exposure to infection and/or immune activation. One such model is based on prenatal treatment with the inflammatory agent poly(I:C) (=polyriboinosinic polyribocytidilic acid), a synthetic analog of double-stranded RNA. Since its initial establishment and application to basic schizophrenia research, the poly(I:C) model has made a great impact on researchers concentrating on the neurodevelopmental and neuroimmunological basis of complex human brain disorders such as schizophrenia, and as a consequence, the model now enjoys wide recognition in the international scientific community. The present article emphasizes that the poly(I:C) model has gained such impact because it successfully accounts for several aspects of schizophrenia epidemiology, pathophysiology, symptomatology, and treatment. The numerous features of this experimental system make the poly(I:C) model a very powerful neurodevelopmental animal model of schizophrenia-relevant brain disease which is expected to be capable of critically advancing our knowledge of how the brain, following an (immune-associated) triggering event in early life, can develop into a "schizophrenia-like brain" over time. Furthermore, the poly(I:C) model seems highly suitable for the exploration of novel pharmacological and neuro immunomodulatory strategies for both symptomatic and preventive treatments against psychotic disease, as well as for the identification of neurobiological mechanisms underlying gene-environment and environment-environment interactions presumably involved in the etiology of schizophrenia and related disorders. PMID- 21238467 TI - Time and spatial attention: effects of prism adaptation on temporal deficits in brain damaged patients. AB - Growing evidence indicates that the representations of space and time interact in the brain but the exact neural correlates of such interaction remain unknown. Neuroimaging and neuropsychological studies show that processing of temporal information engages a distributed network in the right hemisphere and suggest a link between deficits in spatial attention and deficits in time perception. In the present study we used the procedure of prismatic adaptation (PA) to directionally manipulate spatial attention in order to explore the effect of attentional deviation on time perception in patients with right (RBD) vs. left (LBD) brain damage. In a first experiment, two groups of RBD and LBD patients and two groups of age-matched healthy subjects were submitted to a time reproduction task before and after rightward or leftward PA (between-group design). In a second experiment RBD and LBD patients were submitted to the same task, before and after rightward and leftward PA (within-group design). RBD but not LBD patients presented a time deficit with a clear tendency to underestimate the real time. PA inducing leftward attentional deviation biased time perception toward an underestimation in RBD patients and controls, while it was ineffective in LBD patients. PA inducing a rightward attentional deviation failed to affect time perception in either group. These results underline the effects of PA on temporal deficits in brain damaged patients. The novel finding is that, while a right hemispheric network is critical for explicit timing, a left hemispheric network is necessary for mediating the effects of prismatic adaptation on spatial and temporal perception. PMID- 21238466 TI - Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats. AB - Repeated phencyclidine (PCP) administration induces cognitive disruptions resembling those seen in schizophrenia. Alterations in glutamate transmission and gamma-aminobutyric acid (GABA) function in the prefrontal cortex (PFC) have been implicated in these PCP-induced deficits, as well as in cognitive symptoms of schizophrenia. PCP-induced cognitive deficits are reversed by chronic treatment with the atypical antipsychotic clozapine in rats. We investigated the effects of a single injection vs. repeated administration of PCP on glutamate levels in the PFC using in vivo microdialysis. Furthermore, we examined how these PCP regimens affect GABA neuronal markers in the PFC. Finally, we investigated the effects of clozapine on disruptions in glutamate levels and GABA neuronal markers induced by repeated PCP administration. Acute PCP administration (2 mg/kg) increased extracellular PFC glutamate; this increase appeared blunted, but was not eliminated, after repeated PCP pretreatment. PCP administration also strongly decreased levels of parvalbumin and glutamic acid decarboxylase-67 (two markers of GABA function) in the PFC, an effect that was maintained after a 10 day drug free washout period and unaltered by the resumption of repeated PCP injections. All of the observed PCP effects were attenuated by chronic treatment with clozapine, an atypical antipsychotic that has partial effectiveness on cognitive impairment in schizophrenia. These findings suggest that abnormal cortical glutamate transmission, possibly driven by pathological changes in GABA function in parvalbumin-positive fast-spiking interneurons, may underlie some of the cognitive deficits in schizophrenia. A better understanding of glutamate and GABA dysregulation in schizophrenia may uncover new treatment targets for schizophrenia-related cognitive dysfunction. PMID- 21238468 TI - Are all judgments created equal? An fMRI study of semantic and episodic metamemory predictions. AB - Metamemory refers to the ability of individuals to monitor and control their own memory performance. Although little theoretical consideration of the possible differences between the monitoring of episodic and of semantic knowledge has been published, results from patient and drug studies that used the "feeling of knowing" (FOK) paradigm show a selective impairment in the accuracy of episodic monitoring but not in its semantic counterpart. Similarly, neuroimaging studies provide indirect evidence for separate patterns of activation during episodic or semantic FOKs. However, the semantic-episodic distinction hypothesis has not been directly addressed. In the current event-related fMRI study, we used a within subject, within-experiment comparison of the monitoring of semantic and episodic content. Whereas the common neural correlates of episodic and semantic FOKs observed in this study generally replicate the previous neuroimaging findings, several regions were found to be differentially associated with each task. Activity of the right inferior frontal gyrus was modulated by the semantic episodic factor only during the negative predictions of retrieval, suggesting that negative predictions are based on partially distinct mechanisms during each task. A posterior midline network, known to be activated during episodic retrieval, was activated during episodic and not semantic monitoring, suggesting that episodic FOKs rely, to some extent, on common episodic retrieval processes. These findings suggest that theoretical accounts of the etiology and function of FOKs may benefit from incorporating the prediction directionality (positive/negative) and the memory domain (semantic/episodic) distinctions. PMID- 21238469 TI - Repeated social defeat increases reactive emotional coping behavior and alters functional responses in serotonergic neurons in the rat dorsal raphe nucleus. AB - Chronic stress is a vulnerability factor for a number of psychiatric disorders, including anxiety and affective disorders. Social defeat in rats has proven to be a useful paradigm to investigate the neural mechanisms underlying physiologic and behavioral adaptation to acute and chronic stress. Previous studies suggest that serotonergic systems may contribute to the physiologic and behavioral adaptation to chronic stress, including social defeat in rodent models. In order to test the hypothesis that repeated social defeat alters the emotional behavior and the excitability of brainstem serotonergic systems implicated in control of emotional behavior, we exposed adult male rats either to home cage control conditions, acute social defeat, or social defeat followed 24h later by a second social defeat encounter. We then assessed behavioral responses during social defeat as well as the excitability of serotonergic neurons within the dorsal raphe nucleus using immunohistochemical staining of tryptophan hydroxylase, a marker of serotonergic neurons, and the protein product of the immediate-early gene, c-fos. Repeated social defeat resulted in a shift away from proactive emotional coping behaviors, such as rearing (explorative escape behavior), and toward reactive emotional coping behaviors such as freezing. Both acute and repeated defeat led to widespread increases in c-Fos expression in serotonergic neurons in the dorsal raphe nucleus. Changes in behavior following a second exposure to social defeat, relative to acute defeat, were associated with decreased c-Fos expression in serotonergic neurons within the dorsal and ventral parts of the mid-rostrocaudal dorsal raphe nucleus, regions that have been implicated in 1) serotonergic modulation of fear- and anxiety-related behavior and 2) defensive behavior in conspecific aggressive encounters, respectively. These data support the hypothesis that serotonergic systems play a role in physiologic and behavioral responses to both acute and repeated social defeat. PMID- 21238470 TI - Eating rate during a fixed-portion meal does not affect postprandial appetite and gut peptides or energy intake during a subsequent meal. AB - Eating rate has recently been shown to influence energy intake and appetite during an ad libitum meal, and alter postprandial secretion of glucagon-like peptide-1 (GLP-1) and peptide-YY (PYY) following a fixed-portion meal. Whether these effects influence satiety, as measured by energy intake at the subsequent meal, is unclear. We manipulated eating rate during a fixed-portion meal in order to examine how eating behavior and associated periprandial and postprandial responses of putative endocrine mediators of appetite would affect energy intake at the following meal in fifteen non-obese (BMI<25 kg/m2) and ten obese (BMI >= 30 kg/m2) healthy adult men and women. In random order, each participant consumed a standardized, fixed-portion meal in 7 (FM), 14 (MM) or 28 (SM) minutes. Fullness, measured by the Satiety Labeled Intensity Magnitude (SLIM) scale, serum insulin, glucose, leptin, pancreatic polypeptide (PP), PYY, GLP-1, neuropeptide Y, and plasma cholecystokinin (CCK) were measured for 3h following the fixed portion meal. Ad libitum energy intake at the next meal was then measured. Eating slowly delayed time to peak fullness (P <= 0.05), but did not alter peak fullness. Peak PP concentrations were attenuated during FM compared to MM and SM (P <= 0.05) and were reached earlier during MM compared to SM (P <= 0.05). A meal by-time interaction (P <= 0.05), but no differences in AUC, peak, or time to peak were observed for CCK. No additional between meal differences in AUC, peak or time to peak for any endocrine mediator of appetite was observed. Ad libitum energy intake was not different between trials. In conclusion, the rate at which a fixed-portion meal is consumed does not appear to alter satiety despite a small effect on PP and CCK responses. PMID- 21238471 TI - A mathematical model for progression and heterogeneity in colorectal cancer dynamics. AB - This paper deals with the development of a mathematical model that describes cancer dynamics at the cellular scale. The selected case study concerns colon and rectum cancer, which originates in colorectal crypts. Cells inside the crypts are assumed to be organized according to a compartmental-like arrangement and to be homogeneously mixing. A mathematical model for cancer progression is proposed here. This model describes the generation of multiple clonal sub-populations of cells at different progression stages in a single crypt. Asymptotic analysis and simulations are developed with an exploratory aim. The obtained results offer some insights into the role played by mutation, proliferation and differentiation phenomena on cancer dynamics. In particular, the acquisition of an additional growing power and a reduction for cellular differentiation seem more likely to be the driving force behind carcinogenesis rather than an increase in the mutation rate. The mutation rate instead seems to affect progression dynamics and intra tumor heterogeneity. The role played by cells, at different differentiation stages, in the onset and progression of colorectal cancer is highlighted. The results support the fact that stem cells play a key role in cancer development and the idea that transit-amplifying cells could also take on an active role in carcinogenesis. PMID- 21238472 TI - LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects. AB - Toll-like receptors (TLRs) are the principal mediators of rapid microbial recognition: the lipopolysaccharide (LPS) receptor TLR4 seems to have a paradigmatic role. Single nucleotide polymorphisms (SNPs) in the TLR4 gene, such as +896A/G, known to attenuate receptor signaling, have been described. The +896A/G SNP is significantly less frequent in patients with myocardial infarction, Alzheimer's disease or prostate cancer, whereas it is overrepresented in centenarians. To clarify and confirm the biological effects of +896A/G SNP and its role in the pathophysiology of age-related diseases and longevity, we assessed the levels of IL-6, TNF-alpha, IL-10 and eicosanoids (LTB4 and PGE2) in LPS-stimulated whole blood samples in vitro of 50 young healthy Sicilians, screened for the presence of this SNP. To evaluate the possible influence of SNPs in PTGS2 and 5-Lo genes on eicosanoid production, the enrolled individuals were also genotyped for -765G/C PTGS2 and -1708G/A 5-Lo SNPs. Both pro-inflammatory cytokines and eicosanoids were significantly lower in carriers bearing the TLR4 mutation, whereas the anti-inflammatory IL-10 values were higher. On the basis of data reported herein, some suggestions can be drawn. First, pathogen load, by interacting with the host genotype, determines the type and intensity of inflammatory responses, according to the pro-inflammatory status and tissue injury, implicated in the pathophysiology of major age-related diseases. Second, adequate control of inflammatory response might reduce the risk of these diseases, and, reciprocally, might increase the chance of extended survival in an environment with reduced antigen (that is, pathogen) load. PMID- 21238473 TI - Synthetic cannabinoid WIN 55,212-2 mesylate enhances the protective action of four classical antiepileptic drugs against maximal electroshock-induced seizures in mice. AB - The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN- a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four classical antiepileptic drugs (carbamazepine, phenytoin, phenobarbital, and valproate) in the mouse maximal electroshock seizure (MES) model. The results indicate that WIN (10 mg/kg, i.p.) significantly enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test in mice. WIN (5 mg/kg) potentiated the anticonvulsant action of carbamazepine and valproate, but not that of phenytoin or phenobarbital in the MES test in mice. However, WIN administered alone and in combination with carbamazepine, phenytoin, phenobarbital and valproate significantly reduced muscular strength in mice in the grip-strength test. In the passive avoidance task, WIN in combination with phenobarbital, phenytoin and valproate significantly impaired long-term memory in mice. In the chimney test, only the combinations of WIN with phenobarbital and valproate significantly impaired motor coordination in mice. In conclusion, WIN enhanced the anticonvulsant action of carbamazepine, phenytoin, phenobarbital and valproate in the MES test. However, the utmost caution is advised when combining WIN with classical antiepileptic drugs due to impairment of motor coordination and long-term memory and/or reduction of skeletal muscular strength that might appear during combined treatment. PMID- 21238474 TI - Limited access ethanol drinking in the dark in adolescent and adult mice. AB - Adult risk of alcohol dependence increases the younger one first engages in intoxicating consumption. Adolescent mice drink more ethanol than do adults on a gram per kilogram basis, an increase sometimes persisting into adulthood, and this is genotype-dependent. Most studies have used 24 h two-bottle preference, with a choice between ethanol and water. We studied the developmental onset of binge drinking using limited access ethanol drinking in the dark (DID) in male and female mice. To establish age dependence in DID magnitude, we tested HS/Npt mice of 6 ages for DID for 2 weeks, and when they were 9 weeks old, we retested them for 2 weeks vs naive adult controls. Age groups drank equivalently in their first week; thus, adolescent HS/Npt mice do not show greater DID than adults. Six week old mice drank more ethanol during their second week relative to their other weeks. Ethanol DID during early adolescence (4 weeks) led to increased drinking in adulthood, as did initial DID exposure at 8 weeks. High drinking in the dark-1 (HDID-1) mice (4, 6, 9 weeks old), selectively bred for high blood ethanol after DID, were tested for 9 weeks. Mice beginning at 4 weeks generally drank more ethanol than those of other age groups. Comparison at the same ages showed that 9 week olds initiated at 4 weeks drank more ethanol than did naive 9 week olds, but all three groups of age-matched mice drank equivalent amounts once they were 10 weeks and older. The DID test is thus sensitive to developmental age. DID intakes by young adolescent HDID-1 mice were greater than intakes by older mice, like those shown by studies with two-bottle preference. Early DID led to increased drinking as adults only in HS/Npt mice. HDID-1 mice provide a useful animal model for exploring whether DID and continuous access preference drinking have parallel consequences when initiated in adolescence. PMID- 21238475 TI - Aged dogs demonstrate both increased sensitivity to scopolamine impairment and decreased muscarinic receptor density. AB - Memory deficits associated with aging and Alzheimer's disease have been linked to cholinergic dysfunction. The present study investigated this hypothesis by comparing the effects of the muscarinic cholinergic receptor antagonist scopolamine on recent memory performance and by examining muscarinic receptor density in aged and young dogs. Scopolamine (15 MUg/kg; SC) was administered prior to testing young (M=2.8 years) and aged (M=13.0 years) dogs on a delayed non-matching-to-position task (DNMP). Scopolamine significantly impaired performance of aged, but not young dogs. Muscarinic receptor density was assessed autoradiographically using the non-selective radioligand [(3)H]quinuclidinylbenzilate. Aged dogs (M=14.1 years) showed significantly decreased density of muscarinic receptors in all brain regions examined except the cerebellum compared to young dogs (M=3.7 years). The results are consistent with those seen in aged humans and Alzheimer's patients and support the hypothesis of age-dependent cholinergic dysfunction in the dog, although this was not directly determined in the current study. These findings demonstrate that markers of cholinergic hypofunction, in addition to the natural cognitive decline and amyloid pathology previously noted, are seen in canine aging. Collectively, this supports the use of the aged dog as a model for examining early pathological events in the development of Alzheimer's disease. PMID- 21238476 TI - Cannabidiol inhibits the hyperphagia induced by cannabinoid-1 or serotonin-1A receptor agonists. AB - Delta9-THC is a component of Cannabis sativa that increases food intake in animals and humans, an effect prevented by selective CB1 receptor antagonists. Cannabidiol (CBD) is another constituent of this plant that promotes several opposite neuropharmacological effects compared to Delta9-THC. CBD mechanisms of action are still not clear, but under specific experimental conditions it can antagonize the effects of cannabinoid agonists, block the reuptake of anandamide and act as an agonist of 5-HT1A receptors. Since both the cannabinoid and serotoninergic systems have been implicated in food intake control, the aim of the present work was to investigate the effects caused by CBD on hyperphagia induced by agonists of CB1 or 5-HT1A receptors. Fed or fasted Wistar rats received intraperitoneal (i.p.) injections of CBD (1, 10 and 20 mg/kg) and food intake was measured 30 min later for 1 h. Moreover, additional fed or fasted groups received, after pretreatment with CBD (20 mg/kg) or vehicle, i.p. administration of vehicle, a CB1 receptor agonist WIN55,212-2 (2 mg/kg) or a 5 HT1A receptor agonist 8-OH-DPAT (1 mg/kg) and were submitted to the food intake test for 1 h. CBD by itself did not change food intake in fed or fasted rats. However, it prevented the hyperphagic effects induced by WIN55,212-2 or 8-OH DPAT. These results show that CBD can interfere with food intake changes induced by a CB1 or 5-HT1A receptor agonist, suggesting that its role as a possible food intake regulator should be further investigate. PMID- 21238478 TI - Surface hydrophilic modification with well-defined glycopolymer for protein imprinting matrix. AB - Well-defined lactose-containing glycopolymer has been synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization with (4 cyanopentanoic acid)-4- dithiobenozoate (CAD) as chain transfer agent. The glycopolymer was introduced onto the exterior surfaces of the bovine serum albumin (BSA) imprinted polymer beads by grafting copolymerization with methyl methacrylate and ethylene glycol dimethacrylate. After alcoholysis, the hydrophilic lactose residues of glycopolymer will stretched on the surface of the MIP beads and then the hydrophilicity of the surface will be enhanced. Rebinding test shows that the glycopolymer hydrophilic modified BSA imprinted polymer presents higher performance selectivity than that of unmodified one, which means that the hydrophobic-hydrophilic balance of the imprinted polymer surface is in favor of the improvement of specific recognition property of the material. PMID- 21238477 TI - Autoshaping in adolescence enhances sign-tracking behavior in adulthood: impact on ethanol consumption. AB - Autoshaping refers to a procedure during which a cue repeatedly paired with a reward elicits a conditioned response directed at either the reward delivery location ("goal-tracking") or the cue itself ("sign- tracking"). Individual differences in expression of sign-tracking behavior may be predictive of voluntary ethanol intake. The present study was designed to explore the development of differences in sign-tracking behavior in adolescent and adult male and female rats in an 8-day autoshaping procedure. Consistency of sign-tracking and goal-tracking across age was examined by retesting adolescents again in adulthood and comparing their adult data with animals tested only as adults to explore pre-exposure effects on adult responding. In order to assess the relationship between sign-tracking and ethanol intake, voluntary ethanol consumption was measured in an 8-day, 2-hr limited access drinking paradigm following the 8-day autoshaping procedure in adulthood. Animals tested as adolescents showed notably less sign-tracking behavior than animals tested as adults, and sign-tracking behavior was not correlated across age. Animals exposed to the autoshaping procedure as adolescents demonstrated greater sign-tracking behavior as adults when compared to control animals tested only in adulthood. When examining the relationship in adulthood between sign-tracking and ethanol intake, an increase in ethanol intake among sign-trackers was found only in animals pre-exposed to autoshaping as adolescents. Whether or not these results reflect an adolescent-specific experience effect is unclear without further work to determine whether comparable pre-exposure effects are seen if the initial autoshaping sessions are delayed into adulthood. PMID- 21238479 TI - Structural analysis of a group III Glu62-phospholipase A2 from the scorpion, Mesobuthus tamulus: Targeting and reversible inhibition by native peptides. AB - Group III phospholipase A(2) enzyme transcript from the Mesobuthus tamulus (Indian red scorpion) codes for three distinct products that include a large enzymatic subunit, a pentameric peptide and a small non-enzymatic subunit. The structures of these two subunits were modeled based on their sequence identity to bee venom PLA(2) and the partial sequence of MU2 adaptin subunit of AP2 clathrin adaptor, respectively. The enzymatic subunit comprises of three helices, the calcium binding loop and a substrate binding hydrophobic channel where the structure is stabilized by four disulfide bonds. The active site of the enzyme shows a catalytic histidine residue. Interestingly, there is a conservative mutation of the conserved aspartic acid, a classical participant of catalysis in this enzyme family, to glutamic acid. However, the side chain oxygen atoms of this glutamate are oriented away from the catalytic histidine implicating the non participation of this residue in stabilizing the tautomeric conformation of the histidine. The acidic non-enzymatic subunit comprises of extensive hydrophobic residues with a conformation of an anti-parallel beta-sheets making it ideal for tissue specific targeting. The native pentapeptide with the sequence Alanine Arginine-Serine-Alanine-Arginine was docked to the enzymatic subunit. The peptide ligand occupies the hydrophobic cavity and makes a plethora of interactions with the residues in the channel, including a hydrogen bond with the crucial catalytic histidine and coordinate bond with the calcium ion. This ligand has a binding constant (K(D)) of 1.5MUM. This makes the ligand a potential reversible inhibitor, ideal to prevent the enzyme from interacting with non-specific molecules enroute to the target. The enzyme-ligand complex also provides a model to understand the stereochemistry required for the design of more potent drug molecules against such enzyme drug targets. PMID- 21238480 TI - Sterilization and protection of protein in combinations of Camellia sinensis green tea extract and gamma irradiation. AB - Sterilization of milk protein without heating is of great interest. Gamma irradiation is a very powerful method to decontaminated casein. Gamma-irradiation of proteins in aqueous media at doses higher than 5kGy is known to induce their aggregation (without oxygen) or degradation (in presence of oxygen). Camellia sinensis green tea extract addition before irradiation of caseins cow milk proteins was examined. It was found that the presence of C. sinensis green tea extract during irradiation in the presence of oxygen conditions prevented the protein aggregation even at doses higher than 10kGy, probably by scavenging oxygen radicals produced by irradiation. The protective role of C. sinensis green tea extract allowing the gamma-irradiation treatment of caseins cow milk proteins in solution, was asserted by sodium dodecyl-sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and by high performance liquid chromatography inverse phase (RP-HPLC). The total viable microorganisms content evaluated by Plate Count Agar (PCA) incubation for 12h at 37 degrees C, showed that caseins protein preparations gamma-irradiated remained sterile at a dose 2kGy in absence of C. sinensis green tea extract and at a dose lower than 2kGy in the presence of C. sinensis green tea extract. PMID- 21238481 TI - Synthesis and characterization of gum acacia inspired silica hybrid xerogels for mercury(II) adsorption. AB - In a sol-gel process, gum acacia inspired silica xerogels have been synthesized from tetraethylorthosilicate. Besides showing photoluminescence under ultraviolet excitation, the hybrid xerogels were very efficient in capturing mercury(II) from synthetic solution. To synthesize the optimum sample (in terms of Hg(II) uptake), different ratios of H(2)O:TEOS:EtOH were taken at fixed GA and catalyst concentrations where 4:1:1 ratio was found to be most favorable. Calcination in air further enhanced the mercury binding capacity of this sample. Optimum sample (H4) was obtained on calcination of the gel at 600 degrees C. The hybrids have been structurally characterized using Infrared spectroscopy, X-ray diffraction, scanning electron microscopy, thermo gravimetric analysis, photoluminescence spectroscopy and Brunauer-Emmett-Teller analysis. In a preliminary batch adsorption experiment, H4 was evaluated to be highly efficient in the removal Hg(II) from synthetic aqueous solution. PMID- 21238482 TI - Biophysical characterization of Bacillus licheniformis and Escherichia coli gamma glutamyltranspeptidases: A comparative analysis. AB - The oligomeric states of Bacillus licheniformis and Escherichia coli gamma glutamyltranspeptidases (BlGGT and EcGGT) in solution have been investigated by analytical ultracentrifugation. The results showed that BlGGT has a sedimentation coefficient of 5.12S, which can be transformed into an experimental molecular mass of approximately 62,680Da. The monomeric conformation is conserved in EcGGT. SDS-PAGE analysis and cross-linking studies further proved that the autocatalytically processed BlGGT and EcGGT form a heterodimeric association. Unfolding analyses using circular dichroism and tryptophan emission fluorescence revealed that these two proteins had a different sensitivity towards temperature- and guanidine hydrochloride (GdnHCl)-induced denaturation. BlGGT and EcGGT had a T(m) value of 59.5 and 49.2 degrees C, respectively, and thermal unfolding of both proteins was found to be highly irreversible. Chemical unfolding of BlGGT was independent to the pH value ranging from 5 to 10, whereas the pH environment was found to significantly influence the GdnHCl-induced denaturation of EcGGT. Both enzymes did not reactivate from the completely unfolded states, accessible at 6M GdnHCl. BlGGT was active in the presence of 4M NaCl, whereas the activity of EcGGT was significantly decreased at the high-salt condition. Taken together, these findings suggest that the biophysical properties of the homologous GGTs from two mesophilic sources are quite different. PMID- 21238483 TI - Epimedium polysaccharide and propolis flavone can synergistically inhibit the cellular infectivity of NDV and improve the curative effect of ND in chicken. AB - Four prescriptions, epimedium flavone plus propolis flavone (EF-PF), epimedium flavone plus propolis extracts (EF-PE), epimedium polysaccharide plus propolis flavone (EP-PF) and epimedium polysaccharide plus propolis extracts (EP-PE), were prepared and their antiviral effects were compared. In test in vitro, the four prescriptions within safety concentration scope and Newcastle disease virus (NDV) were added into cultured chick embryo fibroblast (CEF) in three modes, pre-, post adding drug and simultaneous-adding drug and virus after being mixed, the cellular A(570) values were determined by MTT method and the highest virus inhibitory rates were calculated to compare the antiviral activity of four prescriptions. In test in vivo, three hundred 21-day-old chickens were randomly divided into 6 groups and challenged with NDV except for blank control group. After 24h the chickens in four prescription groups were injected with corresponding drugs respectively, in virus control and blank control groups, with physiological saline, once a day for three successive days. On days 3, 7 and 14 after challenge, the serum antibody titer was determined. On day 15 after challenge, the mortality, morbidity and cure rate in every group were counted. The results showed that the most of A(570) values in EP-PF group were numberly or significantly larger than those of the corresponding virus control group and the highest virus inhibitory rates of EP-PF at optimal concentration group were the highest among four prescription groups in three drug-adding modes, which confirmed that EP-PF could significantly inhibit the infectivity of NDV to CEF, its action was stronger than those of other three prescriptions; in EP-PF group, the antibody titers and cure rate were the highest and the mortality and morbidity were lowest presenting numberly or significantly differences in comparison with other three prescription groups. These results indicated that epimedium polysaccharide and propolis flavone possessed synergistical action, EP PF prescription could significantly inhibit the cellular infectivity of NDV, improve the curative effect of ND in chicken and would be expected to exploit into a new-type antiviral drug. PMID- 21238484 TI - Molecular cloning and characterization of a receptor for activated protein kinase C1 (RACK1) from Chinese white shrimp; Fenneropenaeus chinensis. AB - Receptor for activated C kinase 1 (RACK1), which has seven tandem WD40 domains, is a scaffolding protein. RACK1 plays different roles by binding to different partner proteins. It is involved in hormone signaling and development, and now some evidence indicates it may have a role in innate immunity. In this paper, RACK1 cDNA from Chinese white shrimp (FcRACK1) was identified. The full length of the FcRACK1 gene is 1037 bp, including a 30 bp 5'UTR, a 957 bp ORF encoding a 318 amino acid protein, and a 50 bp 3'UTR with the polyadenylation sequence AATAAA and a poly (A) tail. The FcRACK1 protein is characterized by seven WD40 repeat domains; the ending two amino acids of each WD40 domain are WK, WD, WN, WS, WD, WD, and WQ, respectively. The length of each domain is between 30 and 44 amino acids. Multiple alignments of RACK1s showed that RACK1s are highly conserved. RT PCR showed that FcRACK1 could be detected in hemocytes, the heart, hepatopancreas, gills, stomach, intestine, and ovary. FcRACK1 in hemocytes was down-regulated after a 2h WSSV challenge, and FcRACK1 in gills was up-regulated after a 2 h Vibrio challenge. FcRACK1 in ovary went down after a 12 h Vibrio challenge and then up-regulated at 24 h. FcRACK1 in ovary was first down regulated at 2 h after a WSSV challenge and then up-regulated to the highest level at 6 h. It finally went down from 12 to 24 h. In hepatopancreas, FcRACK1 was also up-regulated by microbe challenge. Our results indicated its probable role in shrimp innate immunity. PMID- 21238485 TI - Neural processing of target distance by echolocating bats: functional roles of the auditory midbrain. AB - Using their biological sonar, bats estimate distance to avoid obstacles and capture moving prey. The primary distance cue is the delay between the bat's emitted echolocation pulse and the return of an echo. The mustached bat's auditory midbrain (inferior colliculus, IC) is crucial to the analysis of pulse echo delay. IC neurons are selective for certain delays between frequency modulated (FM) elements of the pulse and echo. One role of the IC is to create these "delay-tuned", "FM-FM" response properties through a series of spectro temporal integrative interactions. A second major role of the midbrain is to project target distance information to many parts of the brain. Pathways through auditory thalamus undergo radical reorganization to create highly ordered maps of pulse-echo delay in auditory cortex, likely contributing to perceptual features of target distance analysis. FM-FM neurons in IC also project strongly to pre motor centers including the pretectum and the pontine nuclei. These pathways may contribute to rapid adjustments in flight, body position, and sonar vocalizations that occur as a bat closes in on a target. PMID- 21238486 TI - Novel high-throughput assay to assess cellular manganese levels in a striatal cell line model of Huntington's disease confirms a deficit in manganese accumulation. AB - In spite of the essentiality of manganese (Mn) as a trace element necessary for a variety of physiological processes, Mn in excess accumulates in the brain and has been associated with dysfunction and degeneration of the basal ganglia. Despite the high sensitivity, limited chemical interference, and multi-elemental advantages of traditional methods for measuring Mn levels, they lack the feasibility to assess Mn transport dynamics in a high-throughput manner. Our lab has previously reported decreased net Mn accumulation in a mutant striatal cell line model of Huntington's disease (STHdh(Q111/Q111)) relative to wild-type following Mn exposure. To evaluate Mn transport dynamics in these striatal cell lines, we have developed a high-throughput fluorescence-quenching extraction assay (Cellular Fura-2 Manganese Extraction Assay - CFMEA). CFMEA utilizes changes in fura-2 fluorescence upon excitation at 360 nm (Ca(2+) isosbestic point) and emission at 535 nm, as an indirect measurement of total cellular Mn content. Here, we report the establishment, development, and application of CFMEA. Specifically, we evaluate critical extraction and assay conditions (e.g. extraction buffer, temperature, and fura-2 concentration) required for efficient extraction and quantitative detection of cellular Mn from cultured cells. Mn concentrations can be derived from quenching of fura-2 fluorescence with standard curves based on saturation one-site specific binding kinetics. Importantly, we show that extracted calcium and magnesium concentrations below 10 MUM have negligible influence on measurements of Mn by fura-2. CFMEA is able to accurately measure extracted Mn levels from cultured striatal cells over a range of at least 0.1-10 MUM. We have used two independent Mn supplementation approaches to validate the quantitative accuracy of CFMEA over a 0-200 MUM cellular Mn-exposure range. Finally, we have utilized CFMEA to experimentally confirm a deficit in net Mn accumulation in the mutant HD striatal cell line versus wild-type cells. To conclude, we have developed and applied a novel assay to assess Mn transport dynamics in cultured striatal cell lines. CFMEA provides a rapid means of evaluating Mn transport kinetics in cellular toxicity and disease models. PMID- 21238488 TI - Interleukin-6, a mental cytokine. AB - Almost a quarter of a century ago, interleukin-6 (IL-6) was discovered as an inflammatory cytokine involved in B cell differentiation. Today, IL-6 is recognized to be a highly versatile cytokine, with pleiotropic actions not only in immune cells, but also in other cell types, such as cells of the central nervous system (CNS). The first evidence implicating IL-6 in brain-related processes originated from its dysregulated expression in several neurological disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. In addition, IL-6 was shown to be involved in multiple physiological CNS processes such as neuron homeostasis, astrogliogenesis and neuronal differentiation. The molecular mechanisms underlying IL-6 functions in the brain have only recently started to emerge. In this review, an overview of the latest discoveries concerning the actions of IL-6 in the nervous system is provided. The central position of IL-6 in the neuroinflammatory reaction pattern, and more specifically, the role of IL-6 in specific neurodegenerative processes, which accompany Alzheimer's disease, multiple sclerosis and excitotoxicity, are discussed. It is evident that IL-6 has a dichotomic action in the CNS, displaying neurotrophic properties on the one hand, and detrimental actions on the other. This is in agreement with its central role in neuroinflammation, which evolved as a beneficial process, aimed at maintaining tissue homeostasis, but which can become malignant when exaggerated. In this perspective, it is not surprising that 'well-meant' actions of IL-6 are often causing harm instead of leading to recovery. PMID- 21238489 TI - Impaired conditioned emotional response and object recognition are concomitant to neuronal damage in the amygdala and perirhinal cortex in middle-aged ischemic rats. AB - The current study characterizes fear conditioning responses following global ischemia and evaluates neuronal damage affecting discrete extra-hippocampal areas susceptible to contribute to post ischemic emotional and memory impairments. Conditioned emotional response, Barnes Maze and object recognition tests were used to assess emotional, spatial and recognition memory, respectively. Behavioural testing was initiated in middle-aged animals (10-12 month old) 1 week following sham (n=16) or 4VO occlusion (n=18). Post-mortem cellular assessment was performed in the hippocampal CA1 layer, the perirhinal cortex and basolateral amygdala. Middle-aged ischemic animals showed impaired spatial memory in the initial three testing days in the Barnes Maze and deficit in recognition memory. Of interest, ischemic rats demonstrated a significant reduction of freezing and increased locomotion during the contextual fear testing period, suggesting reduced fear in these animals. Assessment of neuronal density 40 days following global ischemia revealed that CA1 neuronal injury was accompanied by 20-25% neuronal loss in the basolateral nucleus of the amygdala and perirhinal cortex in middle-aged ischemic compared to sham-operated animals. This study represents the first demonstration of altered conditioned fear responses following ischemia. Our findings also indicate a vulnerability of extra-hippocampal neurons to ischemic injury, possibly contributing to discrete emotional and/or memory impairments post ischemia. PMID- 21238487 TI - alpha-Synuclein, leucine-rich repeat kinase-2, and manganese in the pathogenesis of Parkinson disease. AB - Parkinson disease (PD) is the most common movement disorder. It is characterized by bradykinesia, postural instability, resting tremor, and rigidity associated with the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Another pathological hallmark of PD is the presence of alpha-synuclein proteiniacous inclusions, known as Lewy bodies and Lewy neurites, in some of the remaining dopaminergic neurons. Mounting evidence indicates that both genetic and environmental factors contribute to the etiology of PD. For example, genetic mutations (duplications, triplications or missense mutations) in the alpha synuclein gene can lead to PD, but even in these patients, age-dependent physiological changes or environmental exposures appear to be involved in disease presentation. Several additional alterations in many other genes have been established to either cause or increase the risk of parkinson disease. More specifically, autosomal dominant missense mutations in the gene for leucine-rich repeat kinase 2 (LRRK2/PARK8) are the most common known cause of PD. Recently it was shown that G2019S, the most common diseasing-causing mutant of LRRK2, has dramatic effects on the kinase activity of LRRK2: while activity of wild-type LRRK2 is inhibited by manganese, the G2019S mutation abrogates this inhibition. Based on the in vitro kinetic properties of LRRK2 in the presence of manganese, we proposed that LRRK2 may be a sensor of cytoplasmic manganese levels and that the G2019S mutant has lost this function. This finding, alongside a growing number of studies demonstrating an interaction between PD-associated proteins and manganese, suggest that dysregulation of neuronal manganese homeostasis over a lifetime can play an important role in the etiology of PD. PMID- 21238491 TI - Tropisetron increases the inhibitory effect of mild restraint on lordosis behavior of hormonally primed, ovariectomized rats. AB - Ovariectomized rats, hormonally primed with 10 MUg estradiol benzoate and 500 MUg progesterone are resistant to the lordosis-inhibiting effects of a 5 min restraint experience. However, modulation of the serotonergic (5-HT) system alters this resistance to stress. In the following experiment, ovariectomized Fischer inbred rats were hormonally primed with 10 MUg estradiol benzoate and 500 MUg progesterone. The effect of 5 min restraint on sexual behavior was examined after bilateral hypothalamic infusion or intraperitoneal (ip) treatment with the 5-HT(3) receptor antagonist, 3-tropanylindole-3-carboxylate hydrochloride (tropisetron). Infusion with 50 or 100 ng tropisetron inhibited lordosis behavior. When rats were infused with 10 or 25 ng tropisetron, rats showed normal lordosis behavior. However, when infusion with 10 or 25 ng tropisetron was combined with 5 min restraint, lordosis behavior was inhibited. These findings are consistent with prior work that has implicated hypothalamic serotonin in control of lordosis behavior and in the effect of mild restraint on the behavior. In contrast to the effects of the intracranial infusion, intraperitoneal injection with 1.0 or 2.0 mg/kg tropisetron did not amplify the effects of restraint. PMID- 21238490 TI - Neural correlates of the interactive relationship between memory deficits and depressive symptoms in nondemented elderly: resting fMRI study. AB - Prospective studies have shown an association between depressive symptoms and cognitive impairment among older adults. However, the neural correlates of this relationship are poorly understood. Our aim was to examine whether interactive effects of memory deficits and depressive symptoms are present in the memory associated functional networks, in nondemented elderly subjects. Fifteen subjects with amnestic mild cognitive impairment (aMCI) and 20 age-matched normal (CN) elderly subjects participated in this cross-sectional study. Resting-state functional connectivity MRI (R-fMRI) measured the hippocampal functional connectivity (HFC) alterations between the two groups. Voxelwise linear regression analysis was performed to correlate hippocampal network strength with the Rey Auditory Verbal Learning Test delayed recall and the Geriatric Depression Scale scores, after adjusting for age and group effects. Poorer memory performance was associated with decreased positively correlated HFC connectivity in the specific frontal lobe and default mode network (DMN) structures. Poorer memory performance also was associated with decreased anticorrelated HFC connectivity in the bilateral inferior parietal and right dorsolateral prefrontal cortices. In contrast, greater depressive symptom severity was associated with increased HFC connectivity in several frontal lobes and DMN regions. Depressive symptoms and memory functions had interactive effects on the HFC, in the frontal, temporal, and PCC structures. Our findings suggest that the R-fMRI technique can be used to examine the changes in functional neural networks where memory deficits and depressive symptoms coexist in the geriatric population. PMID- 21238492 TI - Memory enhancing effects of saffron in aged mice are correlated with antioxidant protection. AB - Brain aging is characterized by cognitive decline and memory deficits that could be the result of oxidative stress and impaired cholinergic function. In this study, the effects of a daily, 7-day, intraperitoneal administration of saffron on cognitive functions were examined in both healthy adult (4 months old) and aged (20 months old), male Balb-c mice (n=8/group), by passive avoidance test. Whole brain homogenates (minus cerebellum) were collected for examination of brain oxidative markers, caspase-3 and acetylcholinesterase (AChE) activity. Results showed that saffron-treated mice exhibited significant improvement in learning and memory, accompanied by reduced lipid peroxidation products, higher total brain antioxidant activity and reduced caspase-3 activity in both age groups of mice. Furthermore, salt- and detergent-soluble AChE activity was significantly decreased only in adult mice. Thus, we showed, for the first time, that the significant cognitive enhancement conferred by saffron administration in mice, is more closely related to the antioxidant reinforcement. Next, we compared the effect of saffron (1-250 MUg/mL), crocetin and safranal (1-125 MUM) on H(2)O(2)-induced toxicity in human neuroblastoma SH-SY5Y cells. Both saffron and crocetin provided strong protection in rescuing cell viability (MTT assay), repressing ROS production (DCF assay) and decreasing caspase-3 activation. These data, together with earlier studies suggest that crocetin is a unique and potent antioxidant, capable of mediating the in vivo effects of saffron. PMID- 21238493 TI - Brain ischemia changes the long term response to antidepressant drugs in mice. AB - Depression is a frequent but often unrecognized and under treated complication of stroke that has scarcely been investigated in animal models particularly regarding treatment issues. Using the Forced Swim Test (FST) and testing spontaneous motor activity, we studied whether a transient focal cerebral ischemia modifies mice behaviours and antidepressant drug effects. We first evaluated whether FST realized 2 days or 1 week after brain reperfusion may be routinely used in male Swiss mice previously submitted to a 15, 30 or 60-min transient occlusion of the right middle cerebral artery. We then evaluated behavioural changes up to 5 weeks in mice previously submitted to a 15-min ischemia. Behaviours according to the administration of imipramine or fluvoxamine at 1 and 5 weeks after a 15-min ischemia were finally evaluated. Transient ischemia was associated with a decrease in immobility in the FST performed 2 days after reperfusion while no changes were observed in 1 and 5 weeks post-ischemia groups. Changes were related neither to brain ischemia duration nor to infarct volume. At both 1 and 5 weeks after brain ischemia, a dramatic decrease in the antidepressant response to imipramine related to a decrease in climbing behaviour was observed while the effects of fluvoxamine were improved through an increase in both climbing and swimming. Behaviours in the FST were unrelated to any spontaneous motor activity changes. Responses to anti-depressant drugs are strongly modified in mice previously submitted to brain ischemia. Present results underline that not all antidepressant drugs are appropriate after ischemic stroke. PMID- 21238494 TI - Chronic mild stress in mice promotes cognitive impairment and CDK5-dependent tau hyperphosphorylation. AB - This study was undertaken to know whether cognition deficits produced by chronic mild stress (CMS) were associated with pathological markers of Alzheimer's disease (AD). The results show that the impairment in the Morris water maze test induced by CMS correlated with an increase in CDK5-dependent phospho-tau levels and with an increase in APP processing. Mice exposed to CMS may then constitute a non-transgenic model for sporadic forms of AD. PMID- 21238495 TI - Evaluation of chronic alcohol self-administration by a 3-bottle choice paradigm in adult male rats. Effects on behavioural reactivity, spatial learning and reference memory. AB - Chronic ethanol consumption is able to modify emotional behaviour and cognition in humans. In particular, the effects exerted by alcohol may depend on doses, time and modalities of administration. In this study we investigated, in adult male rats, ethanol self-administration and preference patterns using a 3-bottle choice paradigm with water, 10% ethanol solution, and white wine (10%, v/v), along a four-week period. The influence of alcohol free-access on novelty-induced explorative behaviour in the open field, and on spatial learning and reference memory in the Morris water maze was also evaluated. Our results indicate that: (i) rats show a higher preference for alcohol, in the first two weeks of the paradigm, displaying a higher consumption of 10% ethanol solution than white wine; in the last two weeks, they reduce their alcoholic preference, drinking the same moderate amounts of the two alcoholic beverages; (ii) at the fourth week of the free-access paradigm rats show a high explorative behaviour in the central squares of the open field and an improvement in spatial information processing in the new-place learning task of the Morris water maze. In conclusion our data suggest that, interestingly, rats exposed to the free-access paradigm were able to self-regulate their alcoholic intake, and indicated that a moderate alcohol consumption was able to induce an increase in behavioural reactivity and an enhancement in spatial learning flexibility. PMID- 21238496 TI - Theory of Mind in Parkinson's disease. AB - The ability to infer other people's mental states (i.e. Theory of Mind, ToM) is a major topic of interest in various neurological and psychiatric disorders. However, it is only recently that there has been an assessment of cognitive and affective components of ToM ability in neurodegenerative disorders. In this review, we examine studies investigating the ToM ability in Parkinson's disease (PD). Taken together, these studies provide preliminary evidence that ToM difficulties may occur in PD patients. In particular, these difficulties principally involve the cognitive component of ToM in the early stages of the disease. The spatio-temporal progression of dopamine depletion supports the hypothesis that the affective component may only be affected in the advanced stages of the disease. The relationships between executive functioning, dopaminergic therapies, and ToM in PD as well as the relationships between frontostriatal circuits and ToM processing are discussed. PMID- 21238497 TI - The cholinergic system, EEG and sleep. AB - Acetylcholine is a potent excitatory neurotransmitter, crucial for cognition and the control of alertness and arousal. Vigilance-specific recordings of the electroencephalogram (EEG) potently reflect thalamo-cortical and brainstem cortical cholinergic activity that drives theta rhythms and task-specific cortical (de-synchronisation. Additionally, cholinergic projections from the basal forebrain act as a relay centre for the brainstem-cortical arousal system, but also directly modulate cortical activity, and thus promote wakefulness or rapid-eye movement (REM) sleep. Disease states such as sleep disorders, dementia and certain types of epilepsy are a further reflection of the potent cholinergic impact on CNS physiology and function, and highlight the relevance and inter dependence of sleep and EEG. With novel technologies and computational tools now becoming available, advanced mechanistic insights may be gained and new avenues explored for diagnostics and therapeutics. PMID- 21238498 TI - Long-term effects of neonatal methamphetamine exposure on cognitive function in adolescent mice. AB - Exposure to methamphetamine during brain development impairs cognition in children and adult rodents. In mice, these impairments are greater in females than males. Adult female, but not male, mice show impairments in novel location recognition following methamphetamine exposure during brain development. In contrast to adulthood, little is known about the potential effects of methamphetamine exposure on cognition in adolescent mice. As adolescence is an important time of development and is relatively understudied, the aim of the current study was to examine potential long-term effects of neonatal methamphetamine exposure on behavior and cognition during adolescence. Male and female mice were exposed to methamphetamine (5 mg/kg) or saline once a day from postnatal days 11 to 20, the period of rodent hippocampal development. Behavioral and cognitive function was assessed during adolescence beginning on postnatal day 30. During the injection period, methamphetamine-exposed mice gained less weight on average compared to saline-exposed mice. In both male and female mice, methamphetamine exposure significantly impaired novel object recognition and there was a trend toward impaired novel location recognition. Anxiety-like behavior, sensorimotor gating, and contextual and cued fear conditioning were not affected by methamphetamine exposure. Thus, neonatal methamphetamine exposure affects cognition in adolescence and unlike in adulthood equally affects male and female mice. PMID- 21238499 TI - Ventrolateral periaqueductal gray lesion attenuates nociception but does not change anxiety-like indices or fear-induced antinociception in mice. AB - The exposure of rodents to an open elevated plus-maze (oEPM: four open arms raised from the floor) elicits naloxone-insensitive antinociception. Midazolam infusion into the dorsal portion of the periaqueductal gray (dPAG), a structure of the descending inhibitory system of pain, failed to alter oEPM-induced antinociception. Chemical lesion of dorsomedial and dorsolateral PAG attenuated defensive behavior in the standard EPM (sEPM), an animal model of anxiety, but failed to change oEPM-induced antinociception. The present study investigated the effects of bilateral lesion, with the injection of NMDA (N-methyl-D-aspartic acid), of the ventrolateral column of PAG (vlPAG) (i) on nociceptive response induced by 2.5% formalin injected into the right hind paw (nociception test) in mice exposed to the enclosed EPM (eEPM: four enclosed arms - a non-aversive situation) or to the oEPM and (ii) on anxiety indices in mice exposed to the sEPM without prior formalin injection. Results showed that oEPM-induced antinociception was not altered by lesion of vlPAG. Nevertheless, the lesion reduced the nociceptive response in mice exposed to the eEPM and increased general locomotor activity during the eEPM and oEPM exposure. Furthermore, vlPAG lesion did not alter anxiety-like indices in mice exposed to the sEPM. The results suggest that vlPAG does not play a role in oEPM-induced antinociception or in defensive reactions assessed in the sEPM. Moreover, vlPAG inactivation induces pain inhibition in mice not exposed to an aversive situation and seems to increase general activity. PMID- 21238500 TI - Serotonin transporter knockout and repeated social defeat stress: impact on neuronal morphology and plasticity in limbic brain areas. AB - Low expression of the human serotonin transporter (5-HTT) gene presumably interacts with stressful life events enhancing susceptibility for affective disorders. 5-Htt knockout (KO) mice display an anxious phenotype, and behavioural differences compared to wild-type (WT) mice are exacerbated after repeated loser experience in a resident-intruder stress paradigm. To assess whether genotype dependent and stress-induced behavioural differences are reflected in alterations of neuronal morphology in limbic areas, we studied dendritic length and complexity of pyramidal neurons in the anterior cingulate and infralimbic cortices (CG, IL), hippocampus CA1 region, and of pyramidal neurons and interneurons in the lateral (La) and basolateral (BL) amygdaloid nuclei in Golgi Cox-stained brains of male WT and 5-Htt KO control and loser mice. Spine density was analysed for IL apical and amygdaloid apical and basal pyramidal neuron dendrites. While group differences were absent for parameters analysed in CG, CA1 and amygdaloid interneurons, pyramidal neurons in the IL displayed tendencies to shorter and less spinous distal apical dendrites in 5-Htt KO controls, and to extended proximal dendrites in WT losers compared to WT controls. In contrast, spine density of several dendritic compartments of amygdaloid pyramids was significantly higher in 5-Htt KO mice compared to WT controls. While a tendency to increased spine density was observed in the same dendritic compartments in WT after stress, changes were lacking in stressed compared to control 5-Htt KO mice. Our findings indicate that disturbed 5-HT homeostasis results in alterations of limbic neuronal morphology, especially in higher spinogenesis in amygdaloid pyramidal neurons. Social stress leads to similar but less pronounced changes in the WT, and neuroplasticity upon stress is reduced in 5-Htt KO mice. PMID- 21238501 TI - Sex-specificity of associative learning-induced changes in GABAergic tonic inhibition in layer 4 neurons of mouse barrel cortex. AB - We show that in naive mice, tonic currents mediated by delta subunit-containing GABA(A) receptors in fast spiking interneurons are larger in females than in males while in regular spiking neurons such a difference was not observed. Moreover, in fast spiking interneurons, associative learning induced a larger reduction of these currents in females than in males. In contrast, in regular spiking neurons, learning similarly enhanced tonic currents in both sexes. PMID- 21238502 TI - The effects of two forms of physical activity on eyeblink classical conditioning. AB - Voluntary exercise, in the form of free access to a running wheel in the home cage, has been shown to improve several forms of learning and memory. Acrobatic training, in the form of learning to traverse an elevated obstacle course, has been shown to induce markers of neural plasticity in the cerebellar cortex in rodents. In three experiments, we examined the effects of these two forms of physical activity on delay eyeblink conditioning in rats. In Experiment 1, exercising rats were given 17 days of free access to a running wheel in their home cage prior to 10 days of delay eyeblink conditioning. Rats that exercised conditioned significantly better and showed a larger reflexive eyeblink unconditioned response to the periocular stimulation unconditioned stimulus than rats that did not exercise. In Experiment 2, exercising rats were given 17 days of free access to a running wheel in their home cage prior to 10 days of explicitly unpaired stimulus presentations. Rats that exercised responded the same to tone, light, and periocular stimulation as rats that did not exercise. In Experiment 3, acrobatic training rats were given 15 days of daily training on an elevated obstacle course prior to 10 days of eyeblink conditioning. Activity control rats underwent 15 days of yoked daily running in an open field. Rats that underwent acrobatic training did not differ in eyeblink conditioning from activity control rats. The ability to measure the learned response precisely, and the well-mapped neural circuitry of eyeblink conditioning offer some advantages for the study of exercise effects on learning and memory. PMID- 21238503 TI - Regulation of FOXO protein stability via ubiquitination and proteasome degradation. AB - Forkhead box O-class (FOXO) proteins are evolutionally conserved transcription factors. They belong to a family of proteins consisting of FOXO1, FOXO3a, FOXO4 and FOXO6 in humans. Increasing evidence suggests that FOXO proteins function as tumor suppressors by transcriptionally regulating expression of genes involved in cell cycle arrest, apoptosis, DNA repair and oxidative stress resistance. Activation of various protein kinases, including Akt, IkappaB kinase (IKK) and ERK, leads to phosphorylation of FOXO proteins and their ubiquitination mediated by E3 ligases such as SKP2 and MDM2 in human primary tumors and cancer cell lines. As a result, the tumor suppressor functions of FOXO proteins are either diminished or abrogated due to their ubiquitination-proteasome degradation, thereby favoring cell transformation, proliferation and survival. Thus, ubiquitination and proteasome degradation of FOXO proteins play an important role in tumorigenesis and represent a viable target for cancer treatment. This article is part of a Special Issue entitled: PI3K-AKT-FoxO axis in cancer and aging. PMID- 21238505 TI - Reciprocal dynamics of EEG alpha and delta oscillations during spontaneous blinking at rest: a survey on a default mode-based visuo-spatial awareness. AB - By means of a narrowband wavelet analysis (0.5-6Hz), EEG delta event-related oscillations (EROs), both time- and phase-locked to spontaneous blinking (delta blink-related oscillations or delta BROs), have recently been demonstrated. On the basis of their spatiotemporal characteristics, delta BROs have been proposed as being involved in an automatic mechanism of maintaining awareness in a visuo spatial context. The aim of the present study was: a) to investigate whether spontaneous blinking was also able to modulate alpha oscillations and, if so, b) whether this modulation was consistent with delta BROs, in order c) to acquire additional information for a better understanding of the cognitive phenomena underlying blinking. Using a broadband (0.5-100 Hz) continuous wavelet transform (CWT), we analysed a total of 189 three-second EEG epochs time-locked to the blinks of seven healthy volunteers. The EEG signals were submitted both to band pass filtered cross-trial averaging (to obtain frequency-specific BROs) and to alpha event-related synchronization/desynchronization (i.e., blink-related synchronization/desynchronization, BRS/BRD). The alpha oscillations showed: a) an early BRS; b) a BRD in the same temporal window of the delta BROs and, c) a late BRS. We postulate that: a) the early BRS represents the short-term memory maintenance of the last visually perceived trace of the surroundings; b) the alpha BRD is associated with the comparison between the newly perceived image of the environment and its mnestic representation, and, lastly, c) the late BRS is connected with neuronal recovery phenomena. PMID- 21238506 TI - Electrophysiological markers of cognitive deficits in traumatic brain injury: a review. AB - Event-related potentials (ERPs) and oscillatory activity from the human electroencephalogram (EEG) provides a rich source of data that helps elucidate specific processing impairments in TBI patients. This review will focus on some of the central and disabling cognitive deficits in TBI and how broadband ERP markers and the spectral content of the EEG can help explain abnormalities in brain function that impact upon processing speed, sustained attention, performance monitoring, inhibitory control and cognitive flexibility. Physiological signals also provide useful outcome markers in cognitive intervention studies in conjunction with behavioural endpoints. Potential rehabilitation approaches utilising electrophysiological markers of recovery are also discussed. Progress has been made in recent years in defining key pathophysiological mechanisms in the context of sensitive laboratory paradigms. However, aberrant physiological signals need to be understood more clearly in future studies in terms of the neuroanatomical impact of injury, particularly in relation to the most common type of damage in TBI, disrupting extended white matter fibres. PMID- 21238507 TI - Late cortical positivity and cardiac responsitivity in female dental phobics when exposed to phobia-relevant pictures. AB - OBJECTIVES: Dental phobia is currently classified as a specific phobia of the blood-injection-injury (BII) subtype. In another subtype, animal phobia, enhanced amplitudes of late event-related potentials have consistently been identified for patients during passive viewing of disorder-relevant pictures. However, this has not been shown for BII phobics, and studies with dental phobics are lacking. Findings on cardiac responses in BII phobia during exposure are heterogeneous, as some studies showed a diphasic pattern of heart rate acceleration and deceleration, whereas others observed pure acceleration. In contrast, heart rate increase has consistently been shown for dental phobics, resembling the reaction of animal phobics. Moreover, the BII subtype is characterized by elevated disgust reactivity whereas the role of habitual disgust proneness in dental phobia is unclear. METHODS: We recorded the electroencephalogram and the electrocardiogram from 18 dental phobic and 18 healthy women while they watched pictures depicting dental treatment, disgust, fear and neutral items. RESULTS: Phobics relative to controls showed an enhanced late positive potential (300-700 ms) and heart rate acceleration towards phobic material, reflecting motivated attention and fear. Affective ratings revealed that dental phobics experienced significantly higher levels of fear than disgust during exposure to phobia-relevant material. Patients' elevated habitual disgust proneness was restricted to specific domains, such as the oral incorporation of offensive objects. CONCLUSION: The psychophysiology of dental phobia resembles the fear-dominated subtypes of specific phobia reported in earlier studies. Future studies should continue to investigate whether the current classification of this disorder as BII phobia needs to be reconsidered. PMID- 21238508 TI - Nociceptive cortical responses during capsaicin-induced tactile allodynia in mice with spinal dorsal column lesioning. AB - We investigated nociceptive cortical responses using transcranial flavoprotein fluorescence imaging in anesthetized mice with capsaicin-induced allodynia. Tactile stimuli applied to the hindpaw produced fluorescence increases in the contralateral somatosensory cortex of naive mice. Lesioning of the ipsilateral dorsal column in the spinal cord abolished most of the cortical responses. However, the responses to the same tactile stimuli appeared again after capsaicin was injected into the hindpaw. The capsaicin treatment reduced the thresholds of the hindpaw withdrawal responses. These findings strongly suggest that the responses to tactile stimuli in the lesioned mice after capsaicin injection represented nociceptive cortical responses. PMID- 21238509 TI - A subset of MU-opioid receptor-expressing cells in the rostral ventromedial medulla contribute to thermal hyperalgesia in experimental neuropathic pain. AB - The rostral ventromedial medulla (RVM) is a major region for the descending modulation of pain at the spinal cord level, and neurons in the RVM have been implicated in the inhibition and facilitation of spinal nociceptive transmission. Although recent studies have established that the RVM facilitation of nociceptive transmission in the spinal cord contributes to neuropathic pain, the underlying mechanisms remain largely unknown. In the present study, we investigated the effects of kainic acid (KA)-induced RVM damage on neuropathic pain behavior and the expression of molecules implicated in pain modulation. KA was injected into the RVM midline region after neuropathic pain was established by chronic constrictive injury of the left sciatic nerve. Thermal hyperalgesia, but not mechanical allodynia, was persistently suppressed in the ipsilateral paw by a single KA injection into the RVM for at least the next 7 days in a rat neuropathic pain model. KA injection alone did not affect the nocifensive responses to mechanical and thermal stimuli on the intact side. Immunohistochemical analysis revealed that KA injection into the RVM significantly reduced the number of immunoreactive neurons for MU-opioid receptors, but not tryptophan hydroxylase, in association with the analgesic effect. These results suggest that a subset of RVM neurons expressing MU-opioid receptors contribute to the maintenance of thermal hyperalgesia in neuropathic pain. PMID- 21238504 TI - Control of intracellular heme levels: heme transporters and heme oxygenases. AB - Heme serves as a co-factor in proteins involved in fundamental biological processes including oxidative metabolism, oxygen storage and transport, signal transduction and drug metabolism. In addition, heme is important for systemic iron homeostasis in mammals. Heme has important regulatory roles in cell biology, yet excessive levels of intracellular heme are toxic; thus, mechanisms have evolved to control the acquisition, synthesis, catabolism and expulsion of cellular heme. Recently, a number of transporters of heme and heme synthesis intermediates have been described. Here we review aspects of heme metabolism and discuss our current understanding of heme transporters, with emphasis on the function of the cell-surface heme exporter, FLVCR. Knockdown of Flvcr in mice leads to both defective erythropoiesis and disturbed systemic iron homeostasis, underscoring the critical role of heme transporters in mammalian physiology. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21238510 TI - Connectivity pattern changes in default-mode network with deep non-REM and REM sleep. AB - Recent studies have compared default-mode network (DMN) connectivity in different arousal levels to investigate the relationship between consciousness and DMN. The comparison between the DMN in rapid eye movement (REM) sleep with that in non-REM (NREM) sleep is useful for revealing the relationship between arousal level and DMN, because the arousal level is at its lowest during deep NREM, while during REM sleep it is as high as wakefulness. Functional magnetic resonance imaging (fMRI) and polysomnogram data were acquired from participants in REM, deep NREM, and light NREM sleep, and the DMN was compared using functional connectivity analysis. Our analysis revealed that functional connectivity among the DMN core regions - the posterior cingulate cortex, rostral anterior cingulate cortex, and inferior parietal lobule - remained consistent across sleep states. In contrast, connectivity involving the DMN subsystems of REM sleep differs from that of NREM sleep, and the change well accounts for the characteristics of REM sleep. Our results suggest that both the DMN core region and subsystems may not relate to the maintenance of arousal. The DMN core network and subsystems may respectively serve to integrate brain regions and perform function specific to each level of arousal. PMID- 21238511 TI - A simple head-mountable LED device for chronic stimulation of optogenetic molecules in freely moving mice. AB - We describe a low-cost, small, remotely triggerable LED device for wireless control of transcranial optical stimulation of cortical neurons, for use in freely moving mice. The device is easily mountable on the head of a mouse with a high-polymer block. Using the Thy1-ChR2-YFP transgenic mice, we demonstrate that the device is capable of remotely triggering muscle twitches upon activation of the primary motor cortex in freely moving conditions. PMID- 21238512 TI - Protective effects of atypical antipsychotic drugs against MPP(+)-induced oxidative stress in PC12 cells. AB - Recent studies have suggested that some atypical antipsychotic drugs may have protective properties against oxidative stress. To confirm these findings, we investigated the protective effects of atypical antipsychotic drugs such as olanzapine, aripiprazole, and ziprasidone on oxidative stress induced by the N methyl-4-phenylpyridinium (MPP(+)) ion in PC12 cells. Haloperidol, a typical antipsychotic drug, was used for comparison. We determined the antioxidant effects of atypical antipsychotic drugs using a number of measures, including cell viability, the formation of reactive oxygen species (ROS), superoxide dismutase (SOD) activity and Bax levels. MPP(+) treatment induced significant loss of cell viability, the formation of ROS, reduction of SOD activity, and up regulation of Bax expression. However, olanzapine, aripiprazole and ziprasidone reversed these effects caused by MPP(+) treatment, but ziprasidone did not influence cell viability. In contrast, haloperidol did not affect all these effects. Moreover, haloperidol strongly increased the expression of Bax under MPP(+)-free conditions. Olanzapine, aripiprazole, and ziprasidone, but not haloperidol, may exert antioxidant effects through modulating ROS levels, SOD activity, and Bax expression to provide protective effects against MPP(+)-induced oxidative stress in PC12 cells. These results suggest that some atypical antipsychotic drugs have a useful therapeutic effect by reducing oxidative stress in schizophrenic patients. PMID- 21238513 TI - Expression and function of neuronal growth-associated proteins (nGAPs) in PC12 cells. AB - The growth cone plays crucial roles in neural wiring, synapse formation, and axonal regeneration. Continuous rearrangement of cytoskeletal elements and targeting of transported vesicles to the plasma membrane are essential to growth cone motility; however, the proteins directly involved in these processes and their specific functions are not well established. We recently identified 17 proteins as functional marker proteins of the mammalian growth cone and as neuronal growth-associated proteins in rat cortical neurons (nGAPs; Nozumi et al., 2009). To determine whether these 17 proteins are growth cone markers in other neuronal cell types, we examined their expression and function in PC12D cells. We found that all 17 nGAPs were highly concentrated in the growth cones of PC12D cells, and that knockdown of all of them by RNAi reduced or inhibited neurite outgrowth, indicating that all of the 17 nGAPs may be general growth cone markers. Among them, eight proteins were shown to regulate the amount of F-actin in PC12D growth cones. Two of these nGAP that are cytoskeletal proteins, Cap1 and Sept2, increased the mean growth cone area and the mean neurite length by regulating the amount of F-actin; Sept2 also induced filopodial growth. Taken together, our data suggested that some of the nGAPs were generalized markers of the growth cone in multiple neuronal cell types and some of them, such as Cap1 and Sept2, regulated growth cone morphology through rearrangement of F-actin and thereby controlled neurite outgrowth. PMID- 21238515 TI - Enhanced delivery to endothelial lysosomes by ICAM-1-targeted nanocarriers. PMID- 21238516 TI - Therapeutic vaccines and immune-based therapies for the treatment of chronic hepatitis B: perspectives and challenges. AB - The treatment of chronic hepatitis B virus (HBV) infection has greatly improved over the last 10 years, but alternative treatments are still needed. Therapeutic vaccination is a promising new strategy for controlling chronic infection. However, this approach has not been as successful as initially anticipated for chronic hepatitis B. General impairment of the immune responses generated during persistent HBV infection, with exhausted T cells not responding correctly to therapeutic vaccination, is probably responsible for the poor clinical responses observed to date. Intensive research efforts are now focusing on increasing the efficacy of therapeutic vaccination without causing liver disease. Here we describe new approaches to use with therapeutic vaccination, in order to overcome the inhibitory mechanisms impairing immune responses. We also describe innovative strategies for generating functional immune responses and inducing sustained control of this persistent infection. PMID- 21238517 TI - Let it B in viral hepatitis? PMID- 21238514 TI - Ultrasound-mediated transdermal drug delivery: mechanisms, scope, and emerging trends. AB - The use of ultrasound for the delivery of drugs to, or through, the skin is commonly known as sonophoresis or phonophoresis. The use of therapeutic and high frequencies of ultrasound (>=0.7MHz) for sonophoresis (HFS) dates back to as early as the 1950s, while low-frequency sonophoresis (LFS, 20-100kHz) has only been investigated significantly during the past two decades. Although HFS and LFS are similar because they both utilize ultrasound to increase the skin penetration of permeants, the mechanisms associated with each physical enhancer are different. Specifically, the location of cavitation and the extent to which each process can increase skin permeability are quite dissimilar. Although the applications of both technologies are different, they each have strengths that could allow them to improve current methods of local, regional, and systemic drug delivery. In this review, we will discuss the mechanisms associated with both HFS and LFS, specifically concentrating on the key mechanistic differences between these two skin treatment methods. Background on the relevant physics associated with ultrasound transmitted through aqueous media will also be discussed, along with implications of these phenomena on sonophoresis. Finally, a thorough review of the literature is included, dating back to the first published reports of sonophoresis, including a discussion of emerging trends in the field. PMID- 21238518 TI - C-reactive protein levels in relation to various features of non-alcoholic fatty liver disease among obese patients. AB - BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a major hepatic consequence of obesity. It has been suggested that the high sensitivity C reactive protein (hs-CRP) is an obesity-independent surrogate marker of severity of NAFLD, especially development of non-alcoholic steato-hepatitis (NASH), but this remains controversial. We aimed to investigate whether associations between various features of NAFLD and hs-CRP are independent of body mass index (BMI) in its broad range among obese patients. METHODS: A total of 627 obese adults (80% females), representing three cohorts from France and Belgium, had information on liver histology obtained from liver biopsies and measures of hs-CRP and BMI. We investigated whether the different features of NAFLD and BMI were associated with hs-CRP, with and without mutual adjustments using linear regression. RESULTS: BMI and hs-CRP were strongly associated. Per every 10% increase in BMI the hs-CRP level increased by 19-20% (p<0.001), and adjustment for NAFLD-stage (including no NAFLD) did not influence the association. We found no BMI-independent association between NASH and hs-CRP. However, a positive association between degree of steatosis and hs-CRP was observed (p<0.05) and this effect remained significant after adjusting for BMI, lobular inflammation, hepatocyte ballooning, and fibrosis. We found no significant associations between the other features of NAFLD and hs-CRP. CONCLUSIONS: This study indicates that it is the accumulation of fat -both in the adipose tissue and in liver steatosis- that leads to increased hs-CRP levels among obese patients. Thus, hs-CRP may be a marker of steatosis, but not of severity of NAFLD, in obese patients. PMID- 21238519 TI - Mycophenolate for the treatment of autoimmune hepatitis: prospective assessment of its efficacy and safety for induction and maintenance of remission in a large cohort of treatment-naive patients. AB - BACKGROUND & AIMS: Standard therapy for autoimmune hepatitis (AIH) is corticosteroids with or without azathioprine. However, 20% of patients do not respond or are intolerant to conventional treatment. Therefore, we evaluated prospectively the efficacy and safety of mycophenolate mofetil (MMF) in inducing and/or maintaining remission in treatment-naive AIH patients. METHODS: Fifty-nine treatment-naive patients with well defined AIH were treated with prednisolone plus 1.5-2g/d of MMF. Patients were candidates for MMF withdrawal after at least 4 years. Treatment outcomes were defined according to the International Autoimmune Hepatitis Group report. RESULTS: Treatment duration with MMF was 26months (range 3-92). Eighty-eight percent (52/59) of patients responded initially clinically and biochemically (normalization of transaminases and gamma globulins) most of them within 3months. The remaining 7 patients (12%) had partial response. In total, 59.3% (35/59) of patients had complete response (CR) with 37% (22/59) of them having achieved CR off prednisolone, while 28.8% (17/59) had initial CR with relapses. No patient was non-responder. Prednisolone withdrew in 57.6% (34/59) of patients in 8months. The only independent predictor of treatment outcome, was gamma-GT (baseline gamma-GT, p=0.008 and gamma-GT on month 24, p<0.05). Severe side effects leading to MMF discontinuation occurred in only 3.4% (2/59) of patients. Six patients (2 according to protocol and 4 for personal reasons), stopped treatment with MMF, but 3 relapsed. CONCLUSIONS: MMF seems safe and effective as first-line therapy in inducing and maintaining remission in treatment-naive patients with AIH, having a significant and rapid steroid sparing effect as attested by the fact that so far, 37% (22/59) of AIH patients achieved CR off prednisolone. PMID- 21238520 TI - Natural history of chronic hepatitis B in Euro-Mediterranean and African countries. AB - Data derived from population, case-control, and cohort studies conducted in several Euro-Mediterranean and African countries disclose impressive similarities in the age and modes of hepatitis B virus (HBV) transmission and in the prevalence, duration, and outcome of the four phases of the natural history of chronic infection. Perinatal HBV infection is rare while the vast majority of chronic infections originate from horizontal HBV transmission to infants and children. HBeAg loss and seroconversion to anti-HBe occur in a few years time, usually during the second decade of life. HBeAg-negative/anti-HBe-positive chronic hepatitis B (CHB), predominates in these countries being 7-9 times more frequent than HBeAg-positive CHB. The predominance of HBeAg-negative CHB is largely linked to the molecular characteristics of HBV genotype D prevailing in European and African countries of the Mediterranean basin and of genotype E and subgenotype A1 that prevail in the other parts of Africa. The molecular characteristics of the African subgenotype A1 differ from those of European subgenotype A2 explaining the fact that patients infected subgenotype A1 demonstrate an earlier loss of HBeAg and seroconversion to anti-HBe during the natural course of HBV infection compared to those infected with subgenotype A2. It is proposed that the molecular characteristics of HBV genotypes and subgenotypes prevailing in Euro-Mediterranean and African countries acting in concert with host and environmental factors largely determine the natural history of chronic HBV infection and its significant differences from countries of HBV genotype C and B and of subgenotype Ae predominance. The knowledge of the natural history of chronic HBV infection in Euro-Mediterranean and African countries combined with wide screening programs for prompt recognition and treatment of chronic HBV infection both in its HBeAg-positive and -negative immune reactive phases can be expected to increase the efficacy of current and future therapeutic strategies. PMID- 21238521 TI - Reactive oxygen species in the normal and acutely injured liver. PMID- 21238522 TI - Alternative thinking about starting points of obesity. Development of child taste preferences. AB - Food marketers are at the epicenter of criticism for the unfolding obesity epidemic as societies consider banning advertising to children and taxing "junk" foods. While marketing's role in obesity is not well understood, there is clear evidence that children are regularly targeted with calorie-dense, nutrient-poor food. Much of the past research seeks to understand how marketing influences brand preference and child requests. The authors argue that understanding palate development offers new insights for discussion. Two studies consider whether a sugar/fat/salt (SFS) palate is linked to children's knowledge of food brands, experience with products, and advertising. In study 1, the authors develop a survey measure of taste preferences and find that a child's SFS palate (as reported by parents) relates significantly to children's self-reported food choices. Study 2 examines how knowledge of certain branded food and drinks is related to palate. Findings show that children with detailed mental representations of fast-food and soda brands--developed via advertising and experience--have higher scores on the SFS palate scale. PMID- 21238523 TI - The food choice kaleidoscope. A framework for structured description of product, place and person as sources of variation in food choices. AB - Despite a wide range of research approaches already being used to study eating and drinking, this complex aspect of human activity lacks conceptualisation and methodology for structured description of food choices. This paper introduces a metaphoric framework--the food choice kaleidoscope--as an approach to such inquiry. It conceptualises individual food choice events (or eating occasions) as being shaped by three main factors--product, person and place--and provides a descriptive approach through which patterns and variability in food choice events can be observed. The factors can be studied separately or in combination to reveal the joint influence of product, place and/or person factors. The approach is 'data hungry' and requires information about large numbers of eating occasions obtained for a variety of foods/beverage in a variety of situations. Using information about ~5800 eating occasions obtained from 25 New Zealand women who self-completed 24-h recall diaries, the kaleidoscopic approach is illustrated. The data are analysed in relation to 30 food/beverage categories and 37 contextual (or 'place') variables, and at the level of individual participants. Results are presented that document: product-to-product variability in who eats/drinks what and where/how it is consumed; place-to-place variation in what is consumed and by whom; and person-to-person variability in what is consumed and where/how it is consumed. The most significant insight to emerge is the considerable heterogeneity that is hidden beneath the average patterns, and that average values may be inappropriate/irrelevant for this type of data. PMID- 21238524 TI - Does negative mood drive the urge to eat? The contribution of negative mood, exposure to food cues and eating style. AB - The current study investigated whether negative mood alone, or in conjunction with exposure to food cues, influences the urge to eat. Female participants (N=160) were allocated to either a negative or neutral mood induction procedure followed by exposure to either a preferred food cue or a non-food cue. Participants reported their urge to eat at baseline, following the mood induction procedure, and following the cue exposure, as well as completing measures of restrained and disinhibited eating. Contrary to prediction, urge to eat decreased following the mood induction procedure for those in the negative mood condition. This was not influenced by eating style (i.e., restrained or disinhibited eaters). Urge to eat subsequently increased following exposure to the food, but not the non-food, cue. This effect was moderated by negative mood and eating style with disinhibited eating being positively associated with urge to eat for those women in the negative mood condition. These findings suggest that negative mood plays a role in the tendency to overeat, but only in the context of personally desirable food cues and for a subgroup of women with a history of disinhibited eating. PMID- 21238525 TI - Determinants of consumer understanding of health claims. AB - The new EU regulation on nutrition and health claims states that claims can be permitted only if they can be expected to be understood by consumers. Investigating determinants of consumer understanding of health claims has therefore become an important topic. Understanding of a health claim on a yoghurt product was investigated with a sample of 720 category users in Germany. Health claim understanding was measured using open answers, which were subsequently content analysed and classified by comparison with the scientific dossier of the health claim. Based on this respondents were classified as safe, risky or other. In addition to the open questions on claim understanding, respondents rated a number of statements on claim interpretation for agreement and completed scales on interest in healthy eating, attitude to functional foods, and subjective knowledge on food and health. Results showed that respondents with a positive attitude to functional foods are more likely to be classified as risky with regard to their claim understanding, whereas respondents with negative or neutral attitudes are more likely to be classified into the other category. Implications for testing claim understanding are discussed. PMID- 21238526 TI - Ascorbate uptake is decreased in the hippocampus of ageing rats. AB - Ascorbate, an intracellular antioxidant, has been considered critical for neuronal protection against oxidant stress, which is supported especially by in vitro studies. Besides, it has been demonstrated an age-related decrease in brain ascorbate levels. The aims of the present study were to investigate ascorbate uptake in hippocampal slices from old Wistar rats, as well as its neuroprotective effects in in vitro and in vivo assays. Hippocampal slices from male Wistar rats aged 4, 11 and 24 months were incubated with radiolabeled ascorbate and incorporated radioactivity was measured. Hippocampal slices from rats were incubated with different concentrations of ascorbate and submitted to H(2)O(2) induced injury, cellular damage and S100B protein levels were evaluated. The effect of chronic administration of ascorbate on cellular oxidative state and astrocyte biochemical parameters in the hippocampus from 18-months-old Wistar rats was also studied. The ascorbate uptake was decreased in hippocampal slices from old-aged rats, while supplementation with ascorbate (2 weeks) did not modify any tested oxidative status in the hippocampus and the incubation was unable to protect hippocampal slices submitted to oxidative damage (H(2)O(2)) from old rats. Our data suggest that the decline of ascorbate uptake might be involved in the brain greater susceptibility to oxidative damage with advancing age and both in vitro and vivo assays suggest that ascorbate supplementation did not protect hippocampal cells. PMID- 21238529 TI - Prevalence of traumatic brain injury in incarcerated groups compared to the general population: a meta-analysis. AB - Traumatic brain injury can cause numerous behavioral abnormalities including aggression, violence, impulsivity, and apathy, factors that can be associated with criminal behavior and incarceration. To better characterize the association between traumatic brain injury and incarceration, we pooled reported frequencies of lifetime traumatic brain injury of any severity among incarcerated samples and compared the pooled frequency to estimates of the lifetime prevalence of traumatic brain injury in the general population. We found a significantly higher prevalence of traumatic brain injury in the incarcerated groups compared to the general population. As such, there appears to be an association between traumatic brain injury and incarceration. PMID- 21238530 TI - Effects of constant daylight exposure during early development on marmoset psychosocial behavior. AB - Due to global industrialization, the light cycle is shifting to longer daytime. Mounting evidence indicates that social developmental disorders may correlate with longer periods of daytime in childhood. However, the exact mechanisms of this link remain unclear. To examine the impact of longer day-time on psychosocial development, we developed a novel non-human primate model, using the common marmoset (Callithrix jacchus) reared under constant daylight from birth. Marmosets were reared individually by human nursing under constant light (LL) during varying periods in juvenile development, and their behaviors were compared with those of normal day-night cycle (LD) marmosets by multivariate analysis based on principal component analysis (PCA). LL marmosets elicited egg-like calls (e-call) less in juvenile period, and displayed side-to-side shakes of the upper body with rapid head rotation through adulthood frequently. Based on the PCA, these behaviors were interpreted as 'alert' or 'hyperactive' states. Additionally, behavioral development of marmosets reared under constant dark (DD) was markedly different from both LD and LL marmosets, suggesting the fundamental importance of daylight-dependent neuronal and endocrine processes and entrainment by a constant 24-hour light/dark cycle on psychosocial behavior development. PMID- 21238531 TI - Clinical evaluation of Er,Cr:YSGG and GaAlAs laser therapy for treating dentine hypersensitivity: A randomized controlled clinical trial. AB - OBJECTIVE: The advent of dental lasers has raised another possible treatment option for dentine hypersensitivity (DH) and has become a research interest in the last decades. The aim of this randomized, controlled, double-blind, split mouth, clinical study was to evaluate and compare the desensitizing effects of erbium, chromium-doped:yttrium, scandium, gallium and garnet (Er,Cr:YSGG) to galium-aluminium-arsenide (GaAlAs) laser on DH. METHODS: Fifty-one patients participated in this study for a total of 174 teeth. DH was assessed for all groups with a visual analog scale. For each patient, the teeth were randomized to three groups. In the diode laser group, sensitive teeth were irradiated with the GaAlAs laser at 8.5J/cm(2) energy density. In the Er,Cr:YSGG laser group, sensitive teeth were irradiated with Er,Cr:YSGG laser in the hard tissue mode using a none-contact probe at an energy level of 0.25W and repetition rate of 20Hz, 0% water and 10% air. In the control group no treatment was performed. Treatment time was 60s for GaAlAs laser and 30s for Er,Cr:YSGG laser. RESULTS: When compared with the control group and baseline data, in both laser groups, laser irradiation provided a desensitizing effect immediately after treatment and this effect was maintained throughout the study (p<0.05). No significant differences between Er,Cr:YSGG and GaAlAs laser groups were found at any follow up examination (p>0.05). CONCLUSION: Based on these findings, it may be concluded that both Er,Cr:YSGG and GaAlAs lasers were effective in the treatment of DH following a single application. PMID- 21238533 TI - Cord blood transplantation and stem cell regenerative potential. AB - The past 20 years of experience with umbilical cord blood transplantation have demonstrated that cord blood is effective in the treatment of a spectrum of diseases, including hematological malignancies, bone marrow failure, hemoglobinopathies, and inborn errors of metabolism. Cord blood can be obtained with ease and then safely cryopreserved for either public or private use without loss of viability. As compared to other unrelated donor cell sources, cord blood transplantation allows for greater human leukocyte antigen disparity without a corresponding increase in graft-vs.-host disease. Moreover, cord blood has a lower risk of transmitting infections by latent viruses and is less likely to carry somatic mutations than other adult cells. Recently, multiple populations of stem cells with primitive stem cell properties have been identified from cord blood. Meanwhile, there is an increasing interest in applying cord blood mononuclear cells or enriched stem cell populations to regenerative therapies. Accumulating evidence has suggested functional improvements after cord blood transplantation in various animal models for treatments of cardiac infarction, diabetes, neurological diseases, etc. In this review, we will summarize the most recent updates on clinical applications of cord blood transplantation and the promises and limitations of cell-based therapies for tissue repair and regeneration. PMID- 21238532 TI - Identification and isolation from either adult human bone marrow or G-CSF mobilized peripheral blood of CD34(+)/CD133(+)/CXCR4(+)/ Lin(-)CD45(-) cells, featuring morphological, molecular, and phenotypic characteristics of very small embryonic-like (VSEL) stem cells. AB - OBJECTIVE: Recently, we demonstrated that normal human bone marrow (hBM)-derived CD34(+) cells, released into the peripheral blood after granulocyte colony stimulating factor mobilization, contain cell subpopulations committed along endothelial and cardiac differentiation pathways. These subpopulations could play a key role in the regeneration of post-ischemic myocardial lesion after their direct intracardiac delivery. We hypothesized that these relevant cells might be issued from very small embryonic-like stem cells deposited in the BM during ontogenesis and reside lifelong in the adult BM, and that they could be mobilized into peripheral blood by granulocyte colony-stimulating factor. MATERIALS AND METHODS: Samples of normal hBM and leukapheresis products harvested from cancer patients after granulocyte colony-stimulating factor mobilization were analyzed and sorted by multiparameter flow cytometry strategy. Immunofluorescence and reverse transcription quantitative polymerase chain reaction assays were performed to analyze the expression of typical pluripotent stem cells markers. RESULTS: A population of CD34(+)/CD133(+)/CXCR4(+)/Lin(-) CD45(-) immature cells was first isolated from the hBM or from leukapheresis products. Among this population, very small (2-5 MUm) cells expressing Oct-4, Nanog, and stage specific embryonic antigen-4 at protein and messenger RNA levels were identified. CONCLUSIONS: Our study supports the hypothesis that very small embryonic-like stem cells constitute a "mobile" pool of primitive/pluripotent stem cells that could be released from the BM into the peripheral blood under the influence of various physiological or pathological stimuli. In order to fully support that hBM and leukapheresis product-derived very small embryonic-like stem cells are actually pluripotent, we are currently testing their ability to differentiate in vitro into cells from all three germ layers. PMID- 21238534 TI - Theoretical approach to modelling and analysis of the bioprocess with product inhibition and impulse effect. AB - This work presents the first mathematical model of a bioprocess with product inhibition and impulse effect. To begin with, an exemplary mathematical bioprocess model with product inhibition and impulse effect is formulated. Then, according to the model, the analysis of bioprocess stability is presented. The article expresses the product oscillation period, which provides the precise feeding time frame for the regulator bioprocess to achieve an equivalent stable output as that of a bioprocess with impulse effect in the same production environment. Moreover, in this work, the optimization of the production process with respect to the tunable parameters is investigated, and analytical expressions of their optimal values are provided. Numerical simulations using biological data are presented to illustrate the main results. PMID- 21238535 TI - Regulation of Ca(2+)-entry in pancreatic alpha-cell line by transient receptor potential melastatin 4 plays a vital role in glucagon release. AB - Elevation in the intracellular Ca(2+) concentration stimulates glucagon secretion from pancreatic alpha-cells. The Transient Receptor Potential Melastatin 4 channel (TRPM4) is critical for Ca(2+) signaling. However, its role in glucagon secreting alpha-cells has not been investigated. We identified TRPM4 gene expression and protein in the alphaTC1-6 cell line using RT-PCR and immunocytochemistry. Furthermore, we performed a detailed biophysical characterization of the channel using the patch-clamp technique to confirm that currents typical for TRPM4 were present in alphaTC1-6 cells. To investigate TRPM4 function, we generated a stable knockdown clone using shRNA and a lentiviral vector. Inhibition of TRPM4 significantly reduced the responses to different agonists during Ca(2+) imaging analysis with Fura-2AM. The reduction in the magnitude of Ca(2+) signals resulted in decreased glucagon secretion. These results suggested that depolarization by TRPM4 may play an important role in controlling glucagon secretion from alpha-cells and perhaps glucose homeostasis. PMID- 21238536 TI - Administration of a gonadotropin-releasing hormone agonist affects corpus luteum vascular stability and development and induces luteal apoptosis in a rat model of ovarian hyperstimulation syndrome. AB - Ovarian hyperstimulation syndrome (OHSS) is a complication of ovarian stimulation with gonadotropins followed by the administration of human chorionic gonadotropin (hCG) to trigger the final steps of oocyte maturation. Gonadotropin-releasing hormone (GnRH) analogs are thought to be effective in preventing this complication and a clinical trial has found a lower incidence of OHSS in patients treated with these molecules. Our aim was to analyze the in vivo effect of a GnRH I agonist on corpus luteum development and regression, ANGPT-1, ANGPT-2 and Tie-2 protein expression and luteal blood vessel stabilization, the expression of the steroidogenic acute regulatory protein (StAR) and the cytochrome P450 side-chain cleavage enzyme (P450scc) and cell proliferation, in ovaries from an OHSS rat model. To this end immature female Sprague-Dawley rats were hyperstimulated and treated with a GnRH-I agonist from the start of pregnant mare serum gonadotropin (PMSG) administration until the day of hCG injection for 5 consecutive days. Blood and tissue samples were collected 48h after hCG injection. Vascular endothelial growth factor VEGF levels were evaluated in the peritoneal fluid by ELISA. Serum progesterone and estradiol were measured by RIA. Histological features of sectioned ovaries were assessed in hematoxylin and eosin (H&E) stained slides. Luteal blood vessel stability, cell proliferation and apoptosis were assessed by immunohistochemistry for SMCA, PCNA, and TUNEL, respectively. P450scc, StAR, FLK-1, ANGPT-1, ANGPT-2, Tie-2 and PCNA protein levels were evaluated by Western blot from dissected corpora lutea (CL). The treatment with the GnRH-I agonist significantly decreased serum progesterone and estradiol levels as well as P450scc and StAR protein expression in the untreated OHSS group. In addition, the agonist significantly decreased the number of CL in the OHSS group, as compared with the untreated OHSS group. In the OHSS group, the area of periendothelial cells in the CL was larger than that of the control group. However, the treatment with the GnRH-I agonist significantly reduced the area of periendothelial cells in the CL in the OHSS group. The luteal levels of ANGPT-1 and its receptor Tie-2 significantly increased in the OHSS group when compared with the control group. Conversely, the administration of the GnRH-I agonist significantly decreased the levels of these factors in the CL from the OHSS group, as compared with the untreated OHSS group. In addition, the treatment with the GnRH-I agonist reduced the diameter of CL and decreased CL cell proliferation as compared with that observed in the untreated OHSS group. Finally, the GnRH-I agonist increased apoptosis in the CL from the OHSS group. In conclusion, these results show that GnRH-I agonist exerts diverse actions on the CL from a rat OHSS model. The decrease in P450scc, StAR, ANGPT-1 and Tie-2 expression, blood vessel stability and luteal proliferation leads to CL regression in the ovaries from OHSS rats. Moreover, our results suggest that the downregulation of ANGPT-1 and its receptor is a possible mechanism whereby GnRH-I agonists could prevent early OHSS. PMID- 21238537 TI - Development of steroid sulfatase inhibitors. AB - Hydrolysis of biologically inactive steroid sulfates to unconjugated steroids by steroid sulfatase (STS) is strongly implicated in rendering estrogenic stimulation to hormone-dependent cancers such as those of the breast. Considerable progress has been made in the past two decades with regard to the discovery, design and development of STS inhibitors. We outline historical aspects of their development, cumulating in the discovery of the first clinical trial candidate STX64 (BN83495, Irosustat) and other sulfamate-based inhibitors. The development of reversible STS inhibitors and the design of dual inhibitors of both aromatase and STS is also discussed. PMID- 21238538 TI - Progesterone induces expression of the prolactin receptor gene through cooperative action of Sp1 and C/EBP. AB - Prolactin (Prl) and progesterone (P) cooperate synergistically during mammary gland development and tumorigenesis. We hypothesized that one mechanism for these effects may be through mutual induction of receptors (R). EpH4 mouse mammary epithelial cells stably transfected with PR-A express elevated levels of PrlR mRNA and protein compared to control EpH4 cells that lack the PR. Likewise, T47D human breast cancer cells treated with P overexpress the PrlR and activate PrlR promoter III. PrlR promoter III does not contain a classical P response element but contains several binding sites for transcription proteins, including C/EBP, Sp1 and AP1, which may also interact with the PR. Using promoter deletion and site directed mutagenesis analyses as well as gel shift assays, cooperative activation of the C/EBP and adjacent Sp1A, but not the Sp1B or AP1, sites by P is shown to confer P responsiveness leading to increased PrlR transcription. PMID- 21238539 TI - Human growth hormone receptor gene expression is regulated by Gfi-1/1b and GAGA cis-elements. AB - Human growth hormone receptor (hGHR) gene regulation is complex: mRNAs are transcribed from multiple variant (V) 5'UTR exons, several ubiquitously while others only in the postnatal hepatocyte. The liver-specific V1 exon promoter contains Gfi-1/1b repressor sites adjacent to a GAGA box, a GH response element (GHRE) in several mammalian genes. GAGA boxes are also present in the ubiquitously expressing V3 exon promoter. Heterologous sites in bovine, ovine and murine GHR genes suggest conserved roles. GAGA factor stimulated V1 and V3 promoters while Gfi-1/1b repressed basal and GAF-stimulated V1 transcription. HGH treatment of HepG2 cells resulted in a new complex forming with V3 GAGA elements, suggesting a functional GHRE. Data suggest liver-specific V1 transcription is regulated by inhibitory Gfi-1/1b and stimulatory GAGA cis-elements and Gfi-1/1b may control the lack of V1 expression in fetal liver, hepatic tumours and non hepatic tissues. In addition, hGH may regulate hGHR expression through V3 GAGA boxes. PMID- 21238540 TI - Anti-inflammatory effects of yerba mate extract (Ilex paraguariensis) ameliorate insulin resistance in mice with high fat diet-induced obesity. AB - The aim of the present study was to evaluate the effects of yerba mate extract upon markers of insulin resistance and inflammatory markers in mice with high fat diet-induced obesity. The mice were introduced to either standard or high fat diets. After 12 weeks on a high fat diet, mice were randomly assigned to one of the two treatment conditions, water or yerba mate extract at 1.0 gkg(-1). After treatment, glucose blood level and hepatic and soleus muscle insulin response were evaluated. Serum levels of TNF-alpha and IL-6 were evaluated by ELISA, liver tissue was examined to determine the mRNA levels of TNF-alpha, IL-6 and iNOS, and the nuclear translocation of NF-kappaB was determined by an electrophoretic mobility shift assay. Our data show improvements in both the basal glucose blood levels and in the response to insulin administration in the treated animals. The molecular analysis of insulin signalling revealed a restoration of hepatic and muscle insulin substrate receptor (IRS)-1 and AKT phosphorylation. Our data show that the high fat diet caused an up-regulation of the TNF-alpha, IL-6, and iNOS genes. Although after intervention with yerba mate extract the expression levels of those genes returned to baseline through the NF-kappaB pathway, these results could also be secondary to the weight loss observed. In conclusion, our results indicate that yerba mate has a potential anti-inflammatory effect. Additionally, these data demonstrate that yerba mate inhibits hepatic and muscle TNF-alpha and restores hepatic insulin signalling in mice with high fat diet-induced obesity. PMID- 21238541 TI - Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of JNK and NF-kappaB activation in a rat model of amyloid-beta-induced Alzheimer's disease. AB - This study is to examine if hydrogen-rich saline reduced amyloid-beta (Abeta) induced neural inflammation and oxidative stress in a rat model by attenuation of activation of JNK and NF-kappaB. Sprague-Dawley male rats (n=18, 280-330 g) were divided into three groups, sham operated, Abeta1-42 injected and Abeta1-42 plus hydrogen-rich saline treated animals. Hydrogen-rich saline (5 ml/kg, i.p., daily) was injected for 10 days after intraventricular injection of Abeta1-42. The levels of IL-1beta were assessed by ELISA analysis, 8-OH-dG by immunohistochemistry in the brain slides, and JNK and NF-kappaB by immunohistochemistry and western blotting. After Abeta1-42 injection, the level of IL-1beta, 8-OH-dG, JNK and NF-kappaB all increased in brain tissues, while hydrogen-rich saline treatment decreased the level of IL-1beta, 8-OH-dG and the activation of JNK and NF-kappaB. In conclusion, hydrogen-rich saline prevented Abeta-induced neuroinflammation and oxidative stress, possibly by attenuation of activation of c-Jun NH2-terminal kinase (JNK) and nuclear factor-kappaB (NF kappaB) in this rat model. PMID- 21238542 TI - Over-expression of alpha-synuclein 98 triggers intracellular oxidative stress and enhances susceptibility to rotenone. AB - The alpha-synuclein protein is a major component of Lewy bodies found in the brains of patients with Parkinson's disease (PD). Recently, alpha-synuclein 98 (alpha-syn98), a small isoform of the wild type protein was isolated. The neurotoxicity of this protein was assessed by over-expressing alpha-syn98 in dopaminergic cells. Enhanced expression of alpha-syn98 was insufficient to adversely affect the survival of neurons or to promote aggregation of the protein. However, when exposed to rotenone, alpha-syn98 over-expressing dopaminergic cells demonstrated significantly increased cytotoxicity and aggregate formation. Furthermore, we found enhanced basal ROS production and MDA levels in alpha-syn98 over-expressing neurons. High basal oxidative stress induced by alpha-syn98, combined with oxidative stress caused by rotenone treatment, promoted aggregate formation and significantly decreased cell viability. These data indicate that alpha-syn98 can enhance the susceptibility of dopaminergic neurons to oxidative insults by raising steady-state levels of oxidative stress. PMID- 21238543 TI - Time series analysis of postural responses to combined visual pitch and support surface tilt. AB - The purpose of using time-series analyses is to provide interpretation of information on curves or functions, such as dynamic, biomechanical data. We evaluated the application of one method of time-series analysis for assessing changes in postural responses when exposed to a continuously rotating visual field combined with a tilted support surface. Functional Principal Component Analysis (fPCA) was applied to center of mass (CoM) trajectories collected from 22 young adults (20-39 y.o.) on a fixed surface or following a 3 degree (30 degrees /s) dorsiflexion tilt of the support surface combined with continuous upward or downward pitch rotation of the visual field at 30 and 45 degrees /s. The usefulness of this analytical tool is that each curve is treated as a distinct observation by itself, allowing for traditional PCA to be applied to the analysis of curves. Results of the fPCA highlighted 5 distinct time periods in the CoM curves that explained 91% of the variability in the data. These periods in which the young adults altered their CoM in response to visual field motion would not have been identified if we had relied on the onset and offset of the transient disturbance to distinguish responses. Young adults significantly displaced their CoM in response to visual motion over both the period of support surface tilt and while the support surface returned to a neutral position. Our results indicate that fPCA is a viable method when applied to the small but complex changes that emerge in postural data and might allow for a better understanding of time dependent processes occurring with pathology and intervention. PMID- 21238544 TI - Effect of glycogen synthase kinase 3 beta-mediated presenilin 1 phosphorylation on amyloid beta production is negatively regulated by insulin receptor cleavage. AB - Presenilin 1 (PS1), a causative molecule of familial Alzheimer's disease (AD), is known to be an unprimed substrate of glycogen synthase kinase 3 beta (GSK3beta) [Twomey and McCarthy (2006) FEBS Lett 580:4015-4020] and is phosphorylated at serine 353, 357 residues in its cytoplasmic loop region [Kirschenbaum et al. (2001) J Biol Chem 276:7366-7375]. In this report, we investigated the effect of PS1 phosphorylation on AD pathophysiology and obtained two important results--PS1 phosphorylation increased amyloid beta (Abeta) 42/40 ratio, and PS1 phosphorylation was enhanced in the human AD brains. Interestingly, we demonstrated that PS1 phosphorylation promoted insulin receptor (IR) cleavage and the IR intracellular domain (IR ICD) generated by gamma-secretase led to a marked transactivation of Akt (PKB), which down-regulated GSK3beta activity. Thus, the cleavage of IR by gamma-secretase can inhibit PS1 phosphorylation in the long run. Taken together, our findings indicate that PS1 phosphorylation at serine 353, 357 residues can play a pivotal role in the pathology of AD and that the dysregulation of this mechanism may be causally associated with its pathology. PMID- 21238545 TI - Triterpenes and steroids from the roots of Scorzonera austriaca. AB - A new D:B-friedoolean-type triterpene, 3beta-acetoxyglutin-5(10)-en-6-oxo (1), together with seventeen known compounds (2-18) was isolated from the roots of Scorzonera austriaca. Their structures were elucidated mainly by NMR and HR-ESI MS, as well as on comparison with the reported data. Cytotoxicities of compounds 2, 4, 6, 10-14 and 16 against selected cancer cells of human promyelocytic leukemia (HL-60) and human hepatoma (BEL-7404) were measured in vitro. PMID- 21238546 TI - A novel cyclopropyl-containing fatty acid glucoside from the seeds of Litchi chinensis. AB - 3,12-Dihydroxy-cis-3,4-methylenedodecanoic acid 3-O-beta-d-glucopyranoside, trivially named litchioside C (1), the first cyclopropyl-containing fatty acid glycoside, was isolated along with three previously uncharacterized galactosylacylglycerols from the seeds of Litchi chinensis. Its structure was established on the basis of spectroscopic analysis including HRESIMS and 2D NMR spectra. Its antioxidant and antibacterial activities were evaluated and its biogenetic pathway was discussed. PMID- 21238547 TI - A new diarylheptanoid from the rhizomes of Zingiber mekongense. AB - A new diarylheptanoid, (3S,5S)-3,5-diacetoxy-1,7-bis(3,4,5 trimethoxyphenyl)heptane (1), together with the known docosyl trans-ferulate (2), (1S,2S,4S)-p-menthan-1,2,4-triol (3), 5alphaH-eudesmane-4alpha,11-diol (4), 5alphaH-eudesmane-4beta,11-diol (5), 4alpha,10beta-dihydroxy-1betaH,5alphaH-guaia 6-ene (guaianediol) (6), (+)-galanolactone (7), (E)-labda-8(17),12(13)-dien-15,16 olide (8), labda-8(17),13(14)-dien-15,16-olide (9), 3,5-dihydroxy-7,4' dimethoxyflavone (10) and 3,5,3'-trihydroxy-7,4'-dimethoxyflavone (11) were isolated from the rhizomes of Zingiber mekongense. Their structures were determined by spectroscopic methods. The stereochemistry of 1 was proved through chemical conversion. Compounds 1, 4-7 and 9-11 exhibited anti-HIV-1 activities in the anti-syncytium assay using (?Tat/rev)MC99 virus and 1A2 cell line system, while only compounds 7 and 11 were found active in the HIV-1 reverse transcriptase assay. PMID- 21238548 TI - Correlations between camptothecin and related metabolites in Camptotheca acuminata reveal similar biosynthetic principles and in planta synergistic effects. AB - Camptothecin (CPT), 9-methoxycamptothecin (9-MeO-CPT), and 10-hydroxycamptothecin (10-OH-CPT) are potent antineoplastic metabolites. We analyzed these metabolites in Camptotheca acuminata sampled from Germany and China, using LC-MS/MS and LC ESI-HRMS/MS, coupled with chemometrics. Multivariate analysis revealed that fresh stems of C. acuminata from China had the highest comprehensive metabolite load. Significant positive correlations of CPT with 9-MeO-CPT and 10-OH-CPT were observed by Kruskal's multidimensional scaling and principal component analysis. Linear discriminant analysis and hierarchical agglomerative cluster analysis revealed that C. acuminata from China was separated from others. These positive correlations indicate that these metabolites are biosynthesized similarly and operate synergistically in planta. PMID- 21238549 TI - A new dimeric resveratrol from the roots of Shorea roxburghii. AB - A new resveratrol dimer, roxburghiol A (1) together with eleven known compounds were isolated from the roots of Shorea roxburghii. Their structures were identified on the basis of spectroscopic evidence and physicochemical properties. All isolated compounds were evaluated for their cytotoxicity (KB and HeLa cells). Compounds 8 and 9 showed potent cytotoxicity against both KB and HeLa cell lines with IC(50) values of 6.5, 8.5 and 8.7, 10.1 MUg/mL, respectively. PMID- 21238550 TI - Sesquiterpenes from Vladimiria souliei and their inhibitory effects on NO production. AB - As a part of our ongoing search for plant-derived compounds that inhibit nitric oxide production, the methanol extract of the roots of Vladimiria souliei was found to show significant inhibitory effects on INF-gamma-induced nitric oxide production in murine macrophage RAW264.7 cells. Bioactivity-guided isolation of the extract yielded two most active sesquiterpenes, including a new compound, named souliene A (1) and alismol (2). Their structures were elucidated by spectroscopic methods (IR, ESIMS, HRESIMS, 1D and 2D NMR). Two isolates showed promising inhibitory effects on INF-gamma-induced nitric oxide production in murine macrophage RAW264.7 cells. PMID- 21238551 TI - Spatial serial conditioning maintained with minimal temporal contingency. AB - Two experiments used a spatial serial conditioning paradigm to assess the effectiveness of spatially informative conditioned stimuli in eliciting tracking behavior in pigeons. The experimental paradigm consisted of the simultaneous presentation of 2 key lights (CS2 and CTRL), followed by another key light (CS1), followed by food (the unconditioned stimulus or US). CS2 and CTRL were presented in 2 of 3 possible locations, randomly assigned; CS1 was always presented in the same location as CS2. CS2 was designed to signal the spatial, but not the temporal locus of CS1; CS1 signaled the temporal locus of the US. In experiment 1, differential pecking on CS2 was observed even when CS2 was present throughout the interval between consecutive presentations of CS1, but only in a minority of pigeons; prevalence of differential pecking was enhanced when CS2 duration was halved. A control condition verified that pecking on CS2 was not due to temporal proximity between CS2 and US. Experiment 2 demonstrated the reversibility of spatial conditioning between CS2 and CTRL. Asymptotic performance never involved tracking CTRL more than CS2 for any of 16 pigeons. It is inferred that pigeons learned the spatial association between CS2 and CS1, and that temporal contingency facilitated its expression as tracking behavior. PMID- 21238552 TI - Quantitative, steady-state properties of Catania's computational model of the operant reserve. AB - Catania (2005) found that a computational model of the operant reserve (Skinner, 1938) produced realistic behavior in initial, exploratory analyses. Although Catania's operant reserve computational model demonstrated potential to simulate varied behavioral phenomena, the model was not systematically tested. The current project replicated and extended the Catania model, clarified its capabilities through systematic testing, and determined the extent to which it produces behavior corresponding to matching theory. Significant departures from both classic and modern matching theory were found in behavior generated by the model across all conditions. The results suggest that a simple, dynamic operant model of the reflex reserve does not simulate realistic steady state behavior. PMID- 21238553 TI - A comparison of explicitly unpaired treatment and extinction: recovery of sign tracking within a context renewal design. AB - The present experiment compared the effectiveness of explicitly unpaired treatment and extinction in preventing the recovery of sign-tracking within a context renewal design. Three groups of rats were first trained on a sign tracking procedure in Context A where insertions of a retractable lever were paired with food. In a second phase, the sign-tracking response was eliminated. One group received standard extinction of the CS in Context B, while another group received explicitly unpaired treatment in Context B where food was presented only during inter-trial intervals (and not paired with the lever). A third group received this explicitly unpaired treatment in Context A. After the sign-tracking response was eliminated, all groups received a test session in Context A where the lever was presented alone and no food was delivered at any time. Significantly more responding occurred in the group that received explicitly unpaired treatment in Context B than in either of the other groups. This demonstrates that there are situations where explicitly unpaired treatment is less effective than extinction in preventing the reappearance of previously eliminated responding. PMID- 21238554 TI - Associative symmetry in a spatial sample-response paradigm. AB - Symmetry has been difficult to observe in nonhumans mainly because they seem to perceive stimuli as a conjunction of visual, spatial, and temporal characteristics. When such characteristics are controlled, symmetry does emerge in nonhumans (cf. Frank and Wasserman, 2005; Urcuioli, 2008). Recently, however, Garcia and Benjumea (2006) reported symmetry in pigeons without controlling for temporal order. The present experiments explored their paradigm and the ingredients for their success. Experiments 1 and 2 sought to replicate their findings and to examine different symmetry measures. We found evidence for symmetry using non-reinforced choice probe tests, a latency-based test, and a reinforced consistent versus inconsistent manipulation. Experiment 3 adapted their procedure to successive matching to evaluate their contention that a choice between at least two comparisons is necessary for symmetry to emerge. Contrary to their prediction, symmetry was observed following go/no-go training. Our results confirm Garcia and Benjumea's findings, extend them to other test and training procedures, and once again demonstrate symmetry in the absence of language. PMID- 21238555 TI - Conceptual thresholds for same and different in old-(Macaca mulatta) and new world (Cebus apella) monkeys. AB - Learning of the relational same/different (S/D) concept has been demonstrated to be largely dependent upon stimulus sets containing more than two items for pigeons and old-world monkeys. Stimulus arrays containing several images for use in same/different discrimination procures (e.g. 16 identical images vs. 16 nonidentical images) have been shown to facilitate and even be necessary for learning of relational concepts (Flemming et al., 2007; Wasserman et al., 2001; Young et al., 1997). In the present study, we investigate the threshold at which a new world primate, the capuchin (Cebus apella) may be able to make such a discrimination. Utilizing a method of increasing entropy, rather than conventional procedures of decreasing entropy, we demonstrate unique evidence that capuchin monkeys are readily capable of making 2-item relational S/D conditional discriminations. In another experiment, we examine the supposed level of difficulty in making S/D discriminations by rhesus monkeys (Macaca mulatta). Whereas pigeons (Columba livia) and baboons (Papio papio) have shown marked difficulty simultaneously discriminating same from different arrays at all when composed of fewer than 8 items each, rhesus monkeys seem to understand that pairs of stimuli connote sameness and difference just the same (Flemming et al., 2007). With sustained accurate performance of 2-item S/D discriminations, both experienced and task-naive rhesus monkeys appear quite certain in their conceptual knowledge of same and different. We conclude that learning of the same/different relational concept may be less dependent upon high levels of entropy contrast than originally hypothesized for nonhuman primates. PMID- 21238557 TI - 4-Methylbenzophenone and benzophenone are inactive in the micronucleus assay. AB - Many materials in contact with food, including printing inks, the lack of deeper knowledge about possible toxic effects is a problem. Furthermore, some of these substances are not only produced for packaging of foods, they are produced for a variety of purposes and are not meant to come into direct contact with foodstuffs. Two examples on such chemicals in printing inks are benzophenone and 4-methylbenzophenone. Recently, authorities reported that high levels of the photoinitiator 4-methylbenzophenone had been detected in cereal products. Based on this information we have studied 4-methylbenzophenone and the chemically similar benzophenone using the micronucleus assay in vivo and in vitro. To increase the sensitivity we have used the in vivo flow cytomer-based micronucleus assay in mouse. Although doses up to lethality were used and an average of hundred thousand young erythrocytes, polychromatic erythrocytes, analysed from each animal, no genotoxic effect occurred. The 4-methylbenzophenone was also analysed in the in vitro micronucleus assay, using human lymphocytes. The result does not show any dose-related effect. These results show that the occurrence of 4-methylbenzophenone that so far has been detected in foodstuff does not increase the cancer risk through chromosome breaks or mal-distribution of chromosomes. PMID- 21238556 TI - Upregulation of heme oxygenase-1 as an adaptive mechanism for protection against crotonaldehyde in human umbilical vein endothelial cells. AB - Crotonaldehyde, a highly reactive alpha, beta-unsaturated aldehyde, is a ubiquitous environmental pollutant and a product of endogenous lipid peroxidation. It is also a major component of cigarette smoke and is present in many foods and beverages, and has also been linked to development of various diseases. Activation of endothelial cells by stimuli such as cigarette smoke is an important risk factor for cardiovascular diseases, including atherosclerosis. Heme oxygenase-1 (HO-1) is a protective antioxidant enzyme with a critical role in resistance to oxidative stress and other cellular functions. In this study, we examined the effects of crotonaldehyde on HO-1 induction and determined the signaling pathways in human umbilical vein endothelial cells (HUVECs). Inhibition of the protein kinase C-delta (PKC-delta) and p38 pathways resulted in significant blockage of crotonaldehyde-mediated HO-1 induction. Crotonaldehyde treatment caused a dramatic increase in translocation of NF-E2 related factor (Nrf2), leading to induction of HO-1. In addition, small interfering RNA knockdown of Nrf2 and treatment with the specific HO-1 inhibitor ZnPP exhibited an obvious increase of apoptosis of crotonaldehyde-treated HUVECs. Taken together, our results demonstrated that crotonaldehyde-induced HO-1 expression is mediated by the PKC-delta-p38 MAPK-Nrf2-HO-1 pathway in HUVECs, which is an adaptive response to oxidative stress. PMID- 21238558 TI - Cardiac-specific overexpression of metallothionein rescues nicotine-induced cardiac contractile dysfunction and interstitial fibrosis. AB - Cigarette smoking is a devastating risk factor for cardiovascular diseases and nicotine is believed the main toxin component responsible for the toxic myocardial effects of smoking. Nonetheless, neither the precise mechanism of nicotine-induced cardiac dysfunction nor effective treatment is elucidated. The aim of this study was to evaluate the impact of cardiac-specific overexpression of heavy metal scavenger metallothionein on myocardial geometry and mechanical function following nicotine exposure. Adult male friend virus B (FVB) wild-type and metallothionein mice were injected with nicotine (2 mg/kg/d) intraperitoneally for 10 days. Mechanical and intracellular Ca2+ properties were examined. Myocardial histology (cross-sectional area and fibrosis) was evaluated by hematoxylin and eosin (H&E) and Masson trichrome staining, respectively. Oxidative stress and apoptosis were measured by fluoroprobe 5-(6)-chloromethyl 2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA) fluorescence and caspase 3 activity, respectively. Nicotine exposure failed to affect the protein abundance of metallothionein. Our data revealed reduced echocardiographic contractile capacity (fractional shortening), altered cardiomyocyte contractile and intracellular Ca2+ properties including depressed peak shortening amplitude, maximal velocity of shortening/relengthening, resting and electrically-stimulated rise in intracellular Ca2+, as well as prolonged duration of relengthening and intracellular Ca2+ clearance in hearts from nicotine-treated FVB mice, the effect of which was ameliorated by metallothionein. Biochemical and histological findings depicted overt accumulation of reactive oxygen species (ROS), apoptosis and myocardial fibrosis without any change in myocardial cross-sectional area following nicotine treatment, which was mitigated by metallothionein. Taken together, our findings suggest the antioxidant metallothionein may reconcile short-term nicotine exposure-induced myocardial contractile dysfunction and fibrosis possibly through inhibition of ROS accumulation and apoptosis. PMID- 21238559 TI - Macrophages and liposomes in inflammatory disease: friends or foes? AB - Liposome-encapsulated corticosteroids have shown to exert strong beneficial effects in inflammatory diseases, such as arthritis and cancer. To extend the clinical applicability of these potent nanomedicines, the therapeutic effect of dexamethasone phosphate loaded long-circulating liposomes (LCL-DXP) was evaluated in animal models of multiple sclerosis (MS) and Crohn's disease (CD). In mice with experimental autoimmune encephalitis (EAE), a model for MS, treatment with LCL-DXP, but not free DXP, resulted in a decrease in disease activity when compared to PBS treated mice. In contrast, in mice with chronic DSS-induced colitis, a model for CD, treatment with LCL-DXP did not induce an improvement, but in fact worsened the fecal blood loss after treatment, indicating an aggravation of the disease. It is hypothesized that modulation of macrophage polarization towards a M2 phenotype underlies the efficacy of corticosteroid based drug delivery systems, which is supported by the presented data. On the one hand, M1 polarized macrophages are part of the pathogenesis of MS; the modulation to M2-polarization by LCL-DXP is therefore beneficial. On the other hand, M1 polarized intestinal macrophages fulfill a protective and inflammation suppressing role in intestinal homeostasis; changing their phenotype to M2 causes reduced protection to invading microorganisms, leading to a more severe intestinal inflammation. These findings therefore indicate that the interplay between the specific phenotype of macrophages and the specific inflammatory context of the inflammatory disease in question may be an important determining factor in the therapeutic applicability of liposomal corticosteroids in inflammatory disease. PMID- 21238560 TI - Controlled release of linear-dendritic hybrids of carbosiloxane dendrimer: the effect of hybrid's amphiphilicity on drug-incorporation; hybrid-drug interactions and hydrolytic behavior of nanocarriers. AB - Dendritic micelles formed from amphiphilic dendritic ABA triblock copolymers based on organic linear poly(ethylene oxide) and inorganic dendritic block containing silicon atoms (OSC-D(Gn)-PEO-D(Gn)-CSO, n=1-3)(1) were evaluated as drug delivery vehicles for a drug in both lipophilic and hydrophilic forms. The physical parameters of the drug-incorporated carriers including the influences of drug:carrier ratio, the release kinetics of the drugs from the micellar solution were measured. The apparent partition constant of drug between the carriers and the external medium was studied as well. It was observed that the loading efficiency and hydrolytic behavior of the hybrids depend on several factors, such as type of interaction between host and guest molecules, generation of the dendritic copolymers and pH. The release profiles of the drugs from the micelle solution were found to be a slow steady release at pH 1, 7.4 and 10. Investigation of the drug release dynamics in buffered media at pH 7.4 showed that the drug released through the carriers with slight deviation follow Fickian and Case II diffusion mechanisms for drugs in lipophilic and hydrophilic forms, respectively. PMID- 21238561 TI - An oil-free microemulsion for intravenous delivery of diallyl trisulfide: formulation and evaluation. AB - The aim of the present study was to develop an oil-free o/w microemulsion, Cremophor EL:ethanol-propylene glycol:saline, for diallyl trisulfide (DATS) for intravenous (i.v.) administration to modify the safety and pharmacokinetics of DATS. The ternary diagram was constructed to identify the regions of dilutable microemulsions, and the optimal composition of microemulsion was determined by evaluation of injection safety such as hemolysis, intravenous stimulation and injection anaphylaxis compared to commercial formulation Chentian((r)). Promising microemulsion with modified injection safety was developed that could incorporate 100 mg/g of DATS. The droplet size of the microemulsion was about 26 nm in diameter with narrow distribution (polydispersity index: 0.14). Acute toxicity test showed that median lethal dose (LD(50)) of DATS microemulsion was 1.69-fold higher than that of Chentian((r)). Pharmacokinetics was assessed by comparing with the commercial injection after intravenous administration to rats at a dose of 30 mg/kg. The developed microemulsion showed significant higher area under the drug concentration-time curve and lower clearance and distribution volume than those of Chentian((r)) (p<0.05). This helped DATS to reach higher level in vessel, and circulate in the blood stream for a longer time resulting in better therapeutic effect. In conclusion, microemulsion would be a promising intravenous delivery system for DATS. PMID- 21238562 TI - Sustained-release of protein from biodegradable sericin film, gel and sponge. AB - A silk protein, sericin, contains 18 kinds of amino acids, mostly polar side chains forming a complex of three principal polypeptides. The major polypeptides exhibit hydrophobic characteristics by forming a beta-sheet structure in a hydrate state. As a drug-releasing biomaterial made by an aqueous process without using any cross linker, sericin is expected to form various hydrophobic dosage forms. However, its dosage form, with respect to the molecular weight and concentration of sericin, and its biodegradation behavior has not been studied in detail. In this study, the film, gel and sponge of sericin were prepared and examined to determine the release properties of the charged protein, fluorescein isothiocyanate-albumin (FA). The film and gel, as solid and semisolid forms, respectively, were also evaluated for their biodegradation behavior. For in vitro release, FA was sustained-released from these preparations. The concentration and dosage form markedly affected FA release. For in vivo biodegradation, the sericin preparations implanted subcutaneously in rats gradually decreased in size and weight. Histological examination indicated no marked inflammation at the site. As for in vivo release, FA remained for 3-6 weeks or more in rats. These findings suggest that sericin is suitable for use as a drug-releasing biomaterial. PMID- 21238563 TI - Peripheral perception mechanism of ultrasonic hearing. AB - Ultrasound can be perceived by bone conduction, and its characteristics differ from those of air-conducted audible sound (ACAS) in some respects. Despite many studies on ultrasonic hearing, the details have not yet been clarified. In this study, to elucidate the perception mechanism, the masking of bone-conducted ultrasound (BCU) produced by ACAS and the sensitivity of BCU in hearing impaired subjects were evaluated. We found that BCU was masked by high frequency ACAS, especially in the frequency range of 10-14 kHz. The most effective masker frequency depended on masker intensity. For hearing impaired subjects, the pure tone thresholds at 1-8 kHz and the maximum audible frequencies at cut-off intensities of 70-100 dB HL were significantly associated with the BCU threshold (p < 0.01 or p < 0.05). No subjects with estimated total loss of the inner hair cell system in the cochlear basal turn could hear BCU. These results suggest the peripheral perceptual region to be located in the cochlea. The results of masking show the faster excitation spread to the lower frequency range, depending on the intensity. This faster excitation spread may be due to nonlinearity in cochlear mechanics, which may work even without cochlear amplifier, and induce unique characteristics of BCU. PMID- 21238564 TI - Industrial-scale manufacturing of pharmaceutical-grade bioactive peptides. AB - Recent studies have shown that most peptide sequences encrypted in food proteins confer bioactive properties after release by enzymatic hydrolysis. Such bioactivities, which include antithrombotic, antihypertensive, immunomodulatory and antioxidant properties, are among the traits that are of biological significance in therapeutic products. Bioactive peptides could therefore serve as potential therapeutic agents. Moreover, research has shown that peptide therapeutics are toxicologically safe, and present less side effects when compared to small molecule drugs. However, the major conventional methods i.e. the synthetic and biotechnological methods used in the production of peptide therapeutics are relatively expensive. The lack of commercially-viable processes for large-scale production of peptide therapeutics has therefore been a major hindrance to the application of peptides as therapeutic aids. This paper therefore discusses the plausibility of manufacturing pharmaceutical-grade bioactive peptides from food proteins; the challenges and some implementable strategies for overcoming those challenges. PMID- 21238565 TI - New insights on culture and calcium signalling in neurons and astrocytes from epileptic patients. AB - Primary brain cell cultures are a useful tool for understanding the physiopathology of epilepsy and for searching new potential antiepileptic drugs. These cell types are usually prepared from murine species and few human models have been described. The main goal of this study is the establishment of experimental conditions to isolate and culture neurons and astrocytes from human brain and to test its functionality. The tissues came from antiepileptic drug resistant epileptic patients undergoing surgery. Human neurons and astrocytes were isolated following an enzymatic and mechanical dissociation protocol. Cultures were viable for 3-6 weeks. Cytological characterization was performed by immunocytochemistry using specific antibodies against both neuron (anti-NeuN) and astrocyte (anti-GFAP) protein markers. In order to test their viability and functionality, cells were loaded with the fluorescent calcium probe fura-2 and variations in cytosolic calcium concentrations ([Ca2+]c) were measured by cell imaging. [Ca2+]c increases were evoked upon cell stimulation with high K+ (KCl 75 mM), glutamate (500 MUM) or bicuculline (100 MUM). Interestingly, spontaneous [Ca2+]c transients were also observed in some neuron-like cells. A novel unreported finding in this study has been the incorporation of human serum that was critical for cell functionality. The setting of these human cultures open the opportunity to new insights on culture and calcium signalling studies on the mechanism(s) of cell resistance to antiepileptic drugs, as well as to studies on plasticity, maturation and possible neurite emission for graft studies. PMID- 21238566 TI - Assessment of immune response of the B subunit of Shiga toxin fused to AAF adhesin of enteroaggregative Escherichia coli. AB - Shiga toxin is a member of AB toxin family and is composed of an A subunit which mediated toxicity and a homopentameric protein responsible for toxin binding and internalization into target cells. Another group of diarrheagenic Escherichia coli, enteroaggregative E. coli (EAEC) is a group of E. coli with aggregative adherence to epithelial cells, which play an important role in its pathogenesis. In the present investigation, the immune response of recombinant hybrid peptide composed of B subunit of Shiga toxin (StxB) and Aggregative Adherence Fimbriae (AAF) of EAEC (B-AAF/I, B-AAF/II) that elicited protective response was further characterized. The assessment of IgG subclasses (IgG1 and IgG2a) and cytokine production by these peptides indicated that although the hybrid peptides could induce immune response, but two adhesins behave differently in this regard. Lymphocyte proliferation assay and IFN-gamma production were highly significant for B-AAF/II. Overall, based on the data obtained from this study it seems that mixed population of Th1-Th2 type of immune responses were induced by these hybrid peptides, which probably lead to observed protective response. In the present study, it is shown that the two hybrid peptides i.e. B-AAF/I and B-AAF/II, could be a promising strategy to make more effective and powerful vaccine. PMID- 21238567 TI - Pili of oral Streptococcus sanguinis bind to salivary amylase and promote the biofilm formation. AB - Streptococcus sanguinis is a member of oral streptococci and one of the most abundant species found in oral biofilm called dental plaque. Colonization of the oral streptococci on the tooth surface depends on the adhesion of bacteria to salivary components adsorbed to the tooth surface. Recently, we identified unique cell surface long filamentous structures named pili in this species. Herein, we investigated the role of S. sanguinis pili in biofilm formation. We found that pili-deficient mutant, in which the genes encoding the three pilus proteins PilA, PilB and PilC have been deleted, showed an impaired bacterial accumulation on saliva-coated surfaces. Confocal microscopic observations suggested that the mutant was incapable of producing typical three-dimensional layer of biofilm. Ligand blot analysis showed that the ancillary pilus proteins PilB and PilC bound to human whole saliva. Additional analysis demonstrated that PilC bound to multiple salivary components, and one of which was found to be salivary alpha amylase. These results indicate that pilus proteins are members of saliva-binding proteins of oral S. sanguinis, and suggest the involvement of pili in its colonization on saliva-coated tooth surfaces and in the human oral cavity. PMID- 21238568 TI - Evaluation of Cryptococcus neoformans galactoxylomannan-protein conjugate as vaccine candidate against murine cryptococcosis. AB - Galactoxylomannan (GalXM) is a complex polysaccharide produced by the human pathogenic fungus Cryptococcus neoformans that mediates profound immunological derangements in murine models. GalXM is essentially non-immunogenic and produces immune paralysis in mice. Previous studies have attempted to enhance immunogenicity by conjugating GalXM to a protein carrier, but only transient antibody responses were elicited. Here we report the generation of two GalXM conjugates with bovine serum albumin (BSA) and protective antigen (PA) of Bacillus anthracis, respectively, using 1-cyano-4-dimethylaminopyridinium tetrafluoroborate (CDAP) as the cyanylating reagent. Both conjugates induced potent and sustained antibody responses as detected by both cross antigen-based and CovaLink direct ELISAs. We confirmed the specificity of the response to GalXM by inhibition ELISA and immunofluorescence. The isotype composition analysis revealed that IgG and IgM were abundant in the immune sera against GalXM, consistent with the induction of a T cell-dependent response. IgG1 was the predominant IgG subclass against GalXM, while immunization with Quil A as adjuvant elicited a significantly higher production of IgG2a than with Freund's adjuvant. Immune sera were not opsonic for C. neoformans and there was no survival difference between immune and non-immune mice challenged with C. neoformans. These results demonstrated the effectiveness of the GalXM-protein conjugate to induce robust immune responses although no evidence was obtained that such responses contributed to host defense. PMID- 21238569 TI - Effects of herpes simplex virus type 2 glycoprotein vaccines and CLDC adjuvant on genital herpes infection in the guinea pig. AB - Genital herpes simplex virus (HSV) infections are common but results from vaccine trials with HSV-2 glycoprotein D (gD) have been disappointing. We therefore compared a similar HSV gD2 vaccine, to a further truncated gD2 vaccine, to a vaccine with gD2 plus gB2 and gH2/gL2 and to a vaccine with only gB2 and gH2/gL2 in a guinea pig model of genital herpes. All vaccines were administered with cationic liposome-DNA complexes (CLDC) as an adjuvant. All vaccines significantly decreased the severity of acute genital disease and vaginal virus replication compared to the placebo group. The majority of animals in all groups developed at least one episode of recurrent disease but the frequency of recurrent disease was significantly reduced by each vaccine compared to placebo. No vaccine was significantly more protective than gD2 alone for any of the parameters described above. No vaccine decreased recurrent virus shedding. When protection against acute infection of dorsal root ganglia and the spinal cord was evaluated all vaccines decreased the per cent of animal with detectable virus and the quantity of virus but again no vaccine was significantly more protective than another. Improvements in HSV-2 vaccines may require inclusion of more T cell targets, more potent adjuvants or live virus vaccines. PMID- 21238570 TI - Immunization with DnaJ (hsp40) could elicit protection against nasopharyngeal colonization and invasive infection caused by different strains of Streptococcus pneumoniae. AB - Increasing mortality, morbidity and economic costs have been paid to pneumococcal diseases every year. Currently, vaccination is the most promising strategy to reduce the occurrence of pneumococcal infection. In this study, we investigated the protective efficacy of immunization with recombinant DnaJ (hsp40) protein against infections of different serotypes of Streptococcus pneumoniae. We demonstrated that mucosal immunization with DnaJ antigen could induce both systemic and mucosal antibodies for DnaJ and stimulate the release of high levels of IL-10, IFN-gamma and IL-17A. Moreover, this mucosal vaccination could reduce nasal or lung colonization of pneumococcus and elicit protection against different serotypes of invasive pneumococcal infections. As well, we found that intraperitoneal immunization with DnaJ could also protect against invasive infections caused by different serotypes of pneumococcus, and passive immunization with antibodies specific for DnaJ confirmed that this protection was antibody-mediated. Our results therefore support the potential of DnaJ as a conserved pneumococcal protein vaccine. PMID- 21238571 TI - Emerging and continuing trends in vaccine opposition website content. AB - CONTEXT: Anti-vaccination websites appeal to persons searching the Internet for vaccine information that reinforces their predilection to avoid vaccination for themselves or their children. Few published studies have systematically examined these sites. OBJECTIVES: The aim of this study was to employ content analysis as a useful tool for examining and comparing anti-vaccination websites for recurring and changing emphases in content, design, and credibility themes since earlier anti-vaccination website content analyses were conducted. METHODS: Between February and May 2010, using a commonly available search engine followed by a deep web search, 25 websites that contained anti-vaccination content were reviewed and analyzed for 24 content, 14 design, and 13 credibility attributes. RESULTS: Although several content claims remained similar to earlier analyses, two new themes emerged: (1) the 2009 H1N1 epidemic threat was "manufactured," and (2) the increasing presence of so-called "expert" testimony in opposing vaccination. CONCLUSION: Anti-vaccination websites are constantly changing in response to the trends in public health and the success of vaccination. Monitoring the changes can permit public health workers to mount programs more quickly to counter the opposition arguments. Additionally, opposition claims commonly appeal to emotions whereas the supporting claims appeal to reason. Effective vaccine support may be better served by including more emotionally compelling content. PMID- 21238572 TI - Immunogenicity, reactogenicity and safety of the human rotavirus vaccine RIX4414 oral suspension (liquid formulation) in Finnish infants. AB - The lyophilized formulation of a human rotavirus vaccine, RotarixTM (RIX4414) is highly immunogenic. In order to comply with the World Health Organization's (WHO) recommendation, a liquid formulation of the vaccine that does not require reconstitution was developed. The immunogenicity, reactogenicity and safety of the liquid formulation were compared with lyophilized formulation in two Finnish studies. In Study A infants aged 6-12 weeks received two doses of the lyophilized or liquid formulation of the vaccine or placebo following a 0,1 month schedule. In Study B, infants aged 10-17 weeks received two doses of either liquid or lyophilized formulation of the vaccine. In both studies, anti-rotavirus IgA antibodies were assessed pre-vaccination and one month post-Dose 2. In Study A, the anti-rotavirus seroconversion rate was 90% (95% CI: 81.2-95.6%) and 83.7% (95% CI: 74.2-90.8%) in the groups that received the liquid and the lyophilized formulation of RIX4414, respectively; the respective anti-rotavirus IgA seroconversion rates in Study B were 88.6% (95% CI: 86.1-90.8%) and 90.5% (95% CI: 86.2-93.8%). Reactogenicity and safety profiles of the two vaccine formulations were similar. Liquid formulation of the rotavirus vaccine allows greater flexibility in supply and reduces logistical costs. PMID- 21238573 TI - Pandemic H1N1 vaccine requires the use of an adjuvant to protect against challenge in naive ferrets. AB - In the context of an A/H1N1 influenza pandemic situation, this study demonstrates that heterologous vaccination with an AS03-adjuvanted 2008/2009 seasonal trivalent and pandemic H5N1 monovalent split vaccine conferred partial protection in influenza-naive ferrets after challenge with the influenza pandemic H1N1 A/The Netherlands/602/09 virus. Further, unlike saline control and non-adjuvanted vaccine, it was shown that immunization of naive ferrets with an AS03-adjuvanted pandemic H1N1 A/California/7/09 influenza split vaccine induced increased antibody response and enhanced protection against the challenge strain, including significant reduction in viral shedding in the upper respiratory tract and reduced lung pathology post-challenge. These results show the need for vaccination with the adjuvanted vaccine to fully protect against viral replication and influenza disease in unprimed ferrets. PMID- 21238575 TI - In vitro micronuclei tests to evaluate the genotoxicity of surface water under the influence of tanneries. AB - Leather manufacturing has a high potential for environmental pollution due to hides and chemicals that are not completely absorbed during the tanning process. This study aims to investigate the mutagenic potential of surface water samples from Cadeia and Feitoria rivers (RS, Brazil) in areas influenced by tanneries and leather footwear industry. Micronucleus assays using V79 cells and human lymphocytes were used. Cells were exposed to surface water collected bimonthly from three sites for a year, totaling six samples. Significant MN induction in human lymphocytes was shown by 83% of samples from sites FEI001 and CAD001 located downstream from the industrial area, followed by FEI004 (33%), upstream. Only a single sample from site FEI004 showed a positive response for MN in V79 cells. Thirteen discordant and five concordant responses were found between the two in vitro tests. Mutagenic agents were found at the sites where chemical quality was worst, corroborating studies on chronic toxicity, oxidative stress and mutagenicity performed in this area. The assay using human lymphocytes was more sensitive than V79 cells to detect the contaminants from this area, showing that it is an excellent biomarker of environmental genotoxicity. PMID- 21238574 TI - A highly optimized DNA vaccine confers complete protective immunity against high dose lethal lymphocytic choriomeningitis virus challenge. AB - Protection against infection is the hallmark of immunity and the basis of effective vaccination. For a variety of reasons there is a great demand to develop new, safer and more effective vaccine platforms. In this regard, while 'first-generation' DNA vaccines were poorly immunogenic, new genetic 'optimization' strategies and the application of in vivo electroporation (EP) have dramatically boosted their potency. We developed a highly optimized plasmid DNA vaccine that expresses the lymphocytic choriomeningitis virus (LCMV) nucleocapsid protein (NP) and evaluated it using the LCMV challenge model, a gold standard for studying infection and immunity. When administered intramuscularly with EP, robust NP-specific cellular and humoral immune responses were elicited, the magnitudes of which approached those following acute LCMV infection. Furthermore, these responses were capable of providing 100% protection against a high-dose, normally lethal virus challenge. This is the first non-infectious vaccine conferring complete protective immunity up to 8 weeks after vaccination and demonstrates the potential of 'next-generation' DNA vaccines. PMID- 21238576 TI - Relative embryotoxicity of two classes of chemicals in a modified zebrafish embryotoxicity test and comparison with their in vivo potencies. AB - The zebrafish embryotoxicity test (ZET) is a fast and simple method to study chemical toxicity after exposure of the complete vertebrate embryo during embryogenesis in ovo. We developed a novel quantitative evaluation method to assess the development of the zebrafish embryo based on specific endpoints in time, the general morphology score (GMS) system. For teratogenic effects a separate scoring list was developed. The relative effects of eight glycol ethers and six 1,2,4-triazole anti-fungals were evaluated in this system and results were compared with in vivo developmental toxicity potencies. Methoxyacetic acid and ethoxyacetic acid appeared as the most potent glycol ether metabolites, inducing growth retardation and malformations. Other glycol ethers showed no developmental toxicity. Flusilazole appeared the most potent triazole, followed by hexaconazole, cyproconazole, triadimefon, myclobutanil and triticonazole, respectively. In general, the potency ranking of the compounds within their class in the ZET was comparable to their in vivo ranking. In conclusion, the ZET with the GMS system appears an efficient and useful test system for screening embryotoxic properties of chemicals within the classes of compounds tested. This alternative test method may also be useful for the detection of embryotoxic properties of other classes of chemicals. PMID- 21238577 TI - The kinetic study of the inhibition of human cholinesterases by demeton-S-methyl shows that cholinesterase-based titration methods are not suitable for this organophosphate. AB - The organophosphorus insecticide, demeton-S-methyl (DSM), is considered as a good surrogate of the highly toxic nerve agent VX for skin absorption studies due to similar physico-chemical properties and in vitro percutaneous penetration profile. But, when skin distribution was estimated by measuring inhibition of cholinesterase activity, the results were poorly reproducible. The various grades of commercial DSM solutions were suspected to be the origin of the discrepancies. This hypothesis was tested by measuring inhibition of human acetyl- and butyrylcholinesterase by two commercial DSM solutions. The inhibition rate was independent on the enzyme concentration confirming pseudo-first order conditions. But complete inhibition of butyrylcholinesterase activity was achieved only when the DSM concentration was at least 1500-fold higher than the enzyme concentration. Besides, complete inhibition of acetylcholinesterase was never achieved. Mass spectrometry analysis of the inhibited butyrylcholinesterase adducts identified monomethoxyphosphorylated-serine, the aged product of inhibition by DSM or a derivative with a modified leaving group. Neither spontaneous reactivation nor aging of the dimethoxyphosphorylated-serine could account for the inhibition kinetics observed, suggesting an overly complicated kinetic scheme not compatible with the requirement of a titration experiment. In conclusion, cholinesterase-based analytical methods should be avoided for DSM titration in skin penetration studies. PMID- 21238578 TI - Exercise and leukocyte interchange among central circulation, lung, spleen, and muscle. AB - Circulating leukocytes increase rapidly with exercise then quickly decrease when the exercise ends. We tested whether exercise acutely led to bidirectional interchange of leukocytes between the circulation and the lung, spleen, and active skeletal muscle. To accomplish this it was necessary to label a large number of immune cells (granulocytes, monocytes, and lymphocytes) in a way that resulted in minimal perturbation of cell function. Rats were injected intravenously with a single bolus of carboxyfluorescein diacetate succinamidyl ester (CFSE) dye which is rapidly and irreversibly taken up by circulating cells. The time course of the disappearance of labeled cells and their reappearance in the circulation following exercise was determined via flow cytometry. The majority of circulating leukocytes were labeled at 4h. post-injection and this proportion slowly declined out to 120 h. At both 24 and 120 h, running resulted in an increase in the proportion of labeled leukocytes in the circulation. Analysis of the skeletal muscle, spleen and lung indicated that labeled leukocytes had accumulated in those tissues and were mobilized to the circulation in response to exercise. This indicates that there is an ongoing exchange of leukocytes between the circulation and tissues and that exercise can stimulate their redistribution. Exchange was slower with muscle than with spleen and lung, but in all cases, influenced by exercise. Exercise bouts redistribute leukocytes between the circulation and the lung, spleen and muscle. The modulatory effects of exercise on the immune system may be regulated in part by the systemic redistribution of immune cells. PMID- 21238579 TI - Characterization of the threshold for NAD(P)H:quinone oxidoreductase activity in intact sulforaphane-treated pulmonary arterial endothelial cells. AB - Treatment of bovine pulmonary arterial endothelial cells in culture with the phase II enzyme inducer sulforaphane (5MUM, 24h; sulf-treated) increased cell lysate NAD(P)H:quinone oxidoreductase (NQO1) activity by 5.7 +/- 0.6 (mean +/- SEM)-fold, but intact-cell NQO1 activity by only 2.8 +/- 0.1-fold compared to control cells. To evaluate the hypothesis that the threshold for sulforaphane induced intact-cell NQO1 activity reflects a limitation in the capacity to supply NADPH at a sufficient rate to drive all the induced NQO1 to its maximum activity, total KOH-extractable pyridine nucleotides were measured in cells treated with duroquinone to stimulate maximal NQO1 activity. NQO1 activation increased NADP(+) in control and sulf-treated cells, with the effect more pronounced in the sulf treated cells, in which the NADPH was also decreased. Glucose-6-phosphate dehydrogenase (G-6-PDH) inhibition partially blocked NQO1 activity in control and sulf-treated cells, but G-6-PDH overexpression via transient transfection with the human cDNA alleviated neither the restriction on intact sulf-treated cell NQO1 activity nor the impact on the NADPH/NADP(+) ratios. Intracellular ATP levels were not affected by NQO1 activation in control or sulf-treated cells. An increased dependence on extracellular glucose and a rightward shift in the K(m) for extracellular glucose were observed in NQO1-stimulated sulf-treated vs control cells. The data suggest that glucose transport in the sulf-treated cells may be insufficient to support the increased metabolic demand for pentose phosphate pathway-generated NADPH as an explanation for the NQO1 threshold. PMID- 21238580 TI - Primary role of mitochondrial Rieske iron-sulfur protein in hypoxic ROS production in pulmonary artery myocytes. AB - This study was designed to determine whether: (1) hypoxia could directly affect ROS production in isolated mitochondria and mitochondrial complex III from pulmonary artery smooth muscle cells (PASMCs) and (2) Rieske iron-sulfur protein in complex III might mediate hypoxic ROS production, leading to hypoxic pulmonary vasoconstriction (HPV). Our data, for the first time, demonstrate that hypoxia significantly enhances ROS production, measured by the standard ROS indicator dichlorodihydrofluorescein/diacetate, in isolated mitochondria from PASMCs. Studies using the newly developed, specific ROS biosensor pHyPer have found that hypoxia increases mitochondrial ROS generation in isolated PASMCs as well. Hypoxic ROS production has also been observed in isolated complex III. Rieske iron-sulfur protein silencing using siRNA abolishes the hypoxic ROS formation in isolated PASM complex III, mitochondria, and cells, whereas Rieske iron-sulfur protein overexpression produces the opposite effect. Rieske iron-sulfur protein silencing inhibits the hypoxic increase in [Ca(2+)](i) in PASMCs and hypoxic vasoconstriction in isolated PAs. These findings together provide novel evidence that mitochondria are the direct hypoxic targets in PASMCs, in which Rieske iron sulfur protein in complex III may serve as an essential, primary molecule that mediates the hypoxic ROS generation, leading to an increase in intracellular Ca(2+) in PASMCs and HPV. PMID- 21238582 TI - Quercetin-iron chelates are transported via glucose transporters. AB - Flavonoids are well-known antioxidants and free radical scavengers. Their metal binding activity suggests that they could be effective protective agents in pathological conditions caused by both extracellular and intracellular oxidative stress linked to metal overload. Quercetin is both a permeant ligand via glucose transport proteins (GLUTs) and a high-affinity inhibitor of GLUT-mediated glucose transport. Chelatable "free iron" at micromolar concentrations in body fluids is a catalyst of hydroxyl radical (OH(*)) production from hydrogen peroxide. A number of flavonoids, e.g., quercetin, luteolin, chrysin, and 3,6 dihydroxyflavone, have been demonstrated to chelate intracellular iron and suppress OH(*) radical production in Madin Darby canine kidney cells. The most effective chelation comes from the flavonone B ring catechol found in both quercetin and luteolin. We show here that quercetin concentrations of <1MUM can facilitate chelatable iron shuttling via GLUT1 in either direction across the cell membrane. These siderophoric effects are inhibited by raised quercetin concentrations (>1MUM) or GLUT inhibitors, e.g., phloretin or cytochalasin B, and iron efflux is enhanced by impermeant extracellular iron chelators, either desferrioxamine or rutin. This iron shuttling property of quercetin might be usefully harnessed in chelotherapy of iron-overload conditions. PMID- 21238583 TI - Receptor specific crosstalk and modulation of signaling upon heterodimerization between beta1-adrenergic receptor and somatostatin receptor-5. AB - In the present study we describe heterodimerization, trafficking, coupling to adenylyl cyclase and signaling in HEK-293 cells cotransfected with human somatostatin receptor 5 (hSSTR5) and beta(1)-adrenergic receptor (beta(1)AR). hSSTR5/beta(1)AR exists as heterodimers in basal conditions which was further enhanced upon synergistic activation of both receptors. Activation of either beta(1)AR or hSSTR5 displayed dissociation of heterodimerization. In cotransfectants, beta(1)AR effect on cAMP was predominant; however, blocking beta(1)AR with antagonist resulted in 60% inhibition of forskolin-stimulated cAMP in the presence of hSSTR5 agonists. cAMP/PKA pathway in cotransfected cells was regulated in receptor-specific manner, in contrast, the status of pERK1/2 and pPI3K/AKT was predominantly regulated by hSSTR5. The expression levels of phosphorylated NFAT remained unchanged indicating blockade of calcineurin mediated dephosphorylation and nuclear translocation of NFAT, the process predominantly regulated by pJNK in SSTR5 dependent manner. Taken together, the functional consequences of results described here might have relevance in the cardiovascular system where SSTR and AR subtypes play important roles. PMID- 21238581 TI - Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. AB - Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and initiating tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB1 and CB2 G-protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types 1 and 2 diabetes, atherosclerosis, Alzheimer disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain. PMID- 21238584 TI - Alteration of Golgi structure in senescent cells and its regulation by a G protein gamma subunit. AB - Cellular senescence is a process wherein proliferating cells undergo permanent cell cycle arrest while remaining viable. Senescence results in enhanced secretion of proteins that promote cancer and inflammation. We report here that the structure of the Golgi complex which regulates secretion is altered in senescent cells. In cells where senescence is achieved by replicative exhaustion or in cells wherein senescence has been induced with BrdU treatment dependent stress, the Golgi complex is dispersed. The expression of a G protein gamma subunit, gamma11, capable of translocation from the plasma membrane to the Golgi complex on receptor activation increases with senescence. Knockdown of gamma11 or overexpression of a dominant negative gamma3 subunit inhibits Golgi dispersal induced by senescence. Overall these results suggest that in cellular senescence an upregulated G protein gamma subunit mediates alterations in the structure of the Golgi. PMID- 21238585 TI - CD44-mediated elongated T cell spreading requires Pyk2 activation by Src family kinases, extracellular calcium, phospholipase C and phosphatidylinositol-3 kinase. AB - The proline-rich tyrosine kinase 2, Pyk2, is a focal adhesion related kinase expressed in T cells that is tyrosine phosphorylated and activated by integrin, chemokine or T cell receptor stimulation. Ligation of the cell adhesion molecule CD44 also induces Pyk2 phosphorylation and T cell spreading, and this is negatively regulated by the protein tyrosine phosphatase CD45. Here, we identify the activation requirements for Pyk2 and demonstrate its requirement for CD44 mediated elongated T cell spreading. Upon CD44-mediated cell spreading, Pyk2 was recruited to CD44 clusters in both CD45(+) and CD45(-) T cells, yet was more strongly phosphorylated in T cells lacking CD45. In these cells, Pyk2 phosphorylation was dependent on Src family kinase activity and required actin polymerisation, phosphatidylinositol-3 kinase and phospholipase C activity as well as extracellular calcium. Inhibition of any of these events prevented Pyk2 phosphorylation and T cell spreading. Transfection of a truncated form of Pyk2 lacking the kinase domain, PRNK, inhibited CD44-mediated cell spreading, demonstrating an important role for Pyk2. However, inhibition of microtubule turnover by Taxol prevented elongated T cell spreading but did not affect Pyk2 phosphorylation, indicating that microtubule reorganisation is downstream, or independent, of Pyk2 phosphorylation. Together this demonstrates that multiple factors are required for CD44-induced Pyk2 activation, which plays a critical role in CD44-mediated elongated T cell spreading. PMID- 21238586 TI - Ultrasound-mediated destabilization and drug release from liposomes comprising dioleoylphosphatidylethanolamine. AB - Novel sonosensitive doxorubicin-containing liposomes comprising dioleoylphosphatidylethanolamine (DOPE) as the main lipid constituent were developed and characterized in terms of ultrasound-mediated drug release in vitro. The liposome formulation showed high sonosensitivity; where approximately 95% doxorubicin was released from liposomes after 6min of 40kHz US exposure in buffered sucrose solution. This represented a 30% increase in release extent in absolute terms compared to liposomes comprising the saturated lipid analogue distearoylphosphatidylethanolamine (DSPE), and a 9-fold improvement in release extent when compared to standard pegylated liposomal doxorubicin, respectively. Ultrasound release experiments in the presence of serum showed a significantly reduction in sonosensitivity of DSPE-based liposomes, whilst the release properties of DOPE-based liposomes were essentially maintained. Dynamic light scattering measurements and cryo-transmission electron microscopy of DOPE-based liposomes after ultrasound treatment indicated liposome disruption and formation of various lipid structures, corroborating the high release extent. The results point to the potential of DOPE-based liposomes as a new class of drug carriers for ultrasound-mediated drug delivery. PMID- 21238587 TI - Combinational RNAi gene therapy of hepatocellular carcinoma by targeting human EGFR and TERT. AB - Both human telomerase reverse transcriptase (hTERT) and epidermal growth factor receptor (hEGFR) are ideal targets for RNA interference (RNAi)-based gene therapy of hepatocellular carcinoma. Two shRNA expression plasmids pU6-shTERT and pU6 shEGFR targeting hTERT and hEGFR, respectively, were separately formulated as pegylated immuno-lipopolyplexes, a novel non-viral gene delivery system. In vitro studies showed that when pU6-shTERT and pU6-shEGFR were combined and applied to SMMC-7721 cells, there was a significant additive effect on cytotoxicity as well as cell apoptosis, compared to pU6-shTERT or pU6-shEGFR alone, with a cell viability of 50.9+/-7.4%, 79.2+/-3.6% and 77.1+/-3.6%, respectively, and with a cell apoptotic rate of 44.8+/-0.9%, 25.1+/-0.4% and 29.5+/-0.8%, respectively. In vivo study in SMMC-7721 xenograft tumor model demonstrated that intravenous administration of PILP-formulated pU6-shTERT and pU6-shEGFR caused an additive effect on tumor growth inhibition, compared to pU6-shTERT or pU6-shEGFR alone, with a tumor growth inhibition rate of 74.0%, 36.3% and 46.1%, respectively, which is consistent with the downregulated EGFR and TERT mRNA expression. The results suggest that combinational RNAi gene therapy of hepatocellular carcinoma by targeting human EGFR and TERT with pegylated immuno-lipopolyplexes is a new and good strategy. PMID- 21238588 TI - Enteric-coated tablets improve oral bioavailability of DX-9065, a novel anticoagulant. AB - Oral bioavailability of DX-9065, a factor Xa inhibitor, was only 3% when it was administered as a conventional capsule formulation in fasted humans, and was further reduced to about one-tenth when it was administered to fed humans. The poor absorption of DX-9065 probably resulted from its low membrane permeability and its electrostatic interaction with bile acid. We designed enteric-coated tablets with the expectation that this pharmaceutical technology will prevent DX 9065 from interacting with bile acid. More than 85% of DX-9065 was released from the tablet coated with hypromellose acetate succinate within 10min in simulated intestinal fluid (pH 6.8). Monkey experiments demonstrated that AUC of DX-9065 after oral administration of its enteric-coated tablet was about 5 times that of its aqueous solution in the fasted state. The food effect on drug absorption was also reduced when DX-9065 was administered as an enteric-coated tablet. The average ratio of AUC in a fed state to that in a fasted state was approximately 0.5, even though the ratio was 0.1 when the enteric-coated tablet was substituted with the drug solution. Enteric coating could be a useful method for improving oral absorption of DX-9065 with reduced food effects on drug absorption. PMID- 21238589 TI - High-frequency (80-500 Hz) oscillations and epileptogenesis in temporal lobe epilepsy. AB - High-frequency oscillations (HFOs), termed ripples (80-200 Hz) and fast ripples (250-600 Hz), are recorded in the EEG of epileptic patients and in animal epilepsy models; HFOs are thought to reflect pathological activity and seizure onset zones. Here, we analyzed the temporal and spatial evolution of interictal spikes with and without HFOs in the rat pilocarpine model of temporal lobe epilepsy. Depth electrode recordings from dentate gyrus (DG), CA3 region, subiculum and entorhinal cortex (EC), were obtained from rats between the 4th and 15th day after a status epilepticus (SE) induced by i.p. injection of pilocarpine. The first seizure occurred 6.1 +/- 2.5 days after SE (n = 7 rats). Five of 7 animals exhibited interictal spikes that co-occurred with fast ripples accounting for 4.9 +/- 4.6% of all analyzed interictal spikes (n = 12,886) while all rats showed interictal spikes co-occurring with ripples, accounting for 14.3 +/- 3.4% of all events. Increased rates of interictal spikes without HFOs in the EC predicted upcoming seizures on the following day, while rates of interictal spikes with fast ripples in CA3 reflected periods of high seizure occurrence. Finally, interictal spikes co-occurring with ripples did not show any specific relation to seizure occurrence. Our findings identify different temporal and spatial developmental patterns for the rates of interictal spikes with or without HFOs in relation with seizure occurrence. These distinct categories of interictal spikes point at dynamic processes that should bring neuronal networks close to seizure generation. PMID- 21238590 TI - Noggin and Wnt3a enable BMP4-dependent differentiation of telencephalic stem cells into GluR-agonist responsive neurons. AB - Early telencephalic development is dependent on the spatially and temporally coordinated regulation by essential signaling factors. For example, members of the Bone Morphogenetic Protein (BMP) family, such as BMP4, are crucial for proper development of dorsal telencephalic structures. Stimulation of multipotent telencephalic neural stem cells (NSCs) with BMP4 induces differentiation primarily into astrocytic and mesenchymal cells. However, BMP4-mediated mesenchymal differentiation is inhibited at certain culture conditions of NSCs, corresponding to in vivo developmental contexts. These inhibitory mechanisms are not fully understood and the terminal fate of non-astrocytic BMP4 treated NSCs under these conditions is unclear. Here we show that secreted factors inhibited BMP4-mediated mesenchymal differentiation of telencephalic NSCs. BMP4 mediated a dramatic and direct up-regulation of endogenous noggin levels, that in turn exerted a concentration-dependent inhibition of BMP4-mediated mesenchymal differentiation of NSCs. Instead, BMP4 exposure of NSCs induced neuronal differentiation in mesenchyme-preventing conditions, whereas treatment with recombinant noggin alone did not. Wnt signaling is known to be essential for the development of neurons derived from the dorsal telencephalon, and co-stimulation of NSCs with BMP4+Wnt3a resulted in a synergistic effect yielding significantly increased number of mature neurons compared to stimulation with each factor alone. Thus whereas only a subset of BMP4-induced neurons derived from telencephalic NSCs, responded to glutamate receptor (GluR) agonists, over 80% of BMP4+Wnt3a-induced neurons responded appropriately to GluR-agonists. Our results increase the understanding of the role for BMP4 in differentiation of telencephalic multipotent progenitors, and reveal novel implications for noggin and Wnt3a in these events. PMID- 21238591 TI - GABAergic neurons expressing p75 in rat substantia innominata and nucleus basalis. AB - In vitro findings suggested a role for the p75 neurotrophin receptor in the maturation of GABAergic neurons residing in the basal forebrain (BF), a brain area known to have p75 expression only on cholinergic neurons. We document here the presence of GABAergic neurons which express p75 in the BF in vivo. Colocalization of p75 with the cholinergic marker choline-acetyltransferase (ChAT) and/or the GABAergic marker glutamic acid decarboxylase-67 (GAD67) was investigated in the BF at birth, at two weeks, and in adulthood. A subset of GAD67(+) neurons was p75(+) (p75(+)/GAD67(+)) but ChAT(-) in the substantia innominata and nucleus basalis magnocellularis at birth, whereas all p75(+)/GAD67(+) neurons were also ChAT(+) from two weeks onward. These phenotypic features suggest that a subpopulation of GABAergic neurons could be sensitive to neurotrophins during brain maturation. To unravel this issue, we then pursued a functional analysis by assessing p75 expression profile, and its modulation by nerve growth factor (NGF) or brain-derived neurotrophic factor (BDNF) in primary BF cell cultures. NGF increased p75 expression exclusively in cholinergic neurons, whereas BDNF induced p75 expression only in a subset of GABAergic neurons (p75(+)/GAD67(+)/ChAT(-)) through a p75- and tyrosine-kinase-dependent mechanism. The latter findings point to a selective role of BDNF in the induction of p75 expression in BF GABAergic neurons. Altogether these results confirm the role of neurotrophins in the developing and mature circuitry of GABAergic neurons in the BF regions. PMID- 21238592 TI - Combining computational modeling with sparse and low-resolution data. PMID- 21238593 TI - Consistent spectral predictors for dynamic causal models of steady-state responses. AB - Dynamic causal modelling (DCM) for steady-state responses (SSR) is a framework for inferring the mechanisms that underlie observed electrophysiological spectra, using biologically plausible generative models of neuronal dynamics. In this paper, we examine the dynamic repertoires of nonlinear conductance-based neural population models and propose a generative model of their power spectra. Our model comprises an ensemble of interconnected excitatory and inhibitory cells, where synaptic currents are mediated by fast, glutamatergic and GABAergic receptors and slower voltage-gated NMDA receptors. We explore two formulations of how hidden neuronal states (depolarisation and conductances) interact: through their mean and variance (mean-field model) or through their mean alone (neural mass model). Both rest on a nonlinear Fokker-Planck description of population dynamics, which can exhibit bifurcations (phase transitions). We first characterise these phase transitions numerically: by varying critical model parameters, we elicit both fixed points and quasiperiodic dynamics that reproduce the spectral characteristics (~2-100 Hz) of real electrophysiological data. We then introduce a predictor of spectral activity using centre manifold theory and linear stability analysis. This predictor is based on sampling the system's Jacobian over the orbits of hidden neuronal states. This predictor behaves consistently and smoothly in the region of phase transitions, which permits the use of gradient descent methods for model inversion. We demonstrate this by inverting generative models (DCMs) of SSRs, using simulated data that entails phase transitions. PMID- 21238594 TI - Dynamic causal modeling of cortical activity from the acute to the chronic stage after stroke. AB - Functional neuroimaging studies frequently demonstrated that stroke patients show bilateral activity in motor and premotor areas during movements of the paretic hand in contrast to a more lateralized activation observed in healthy subjects. Moreover, a few studies modeling functional or effective connectivity reported performance-related changes in the motor network after stroke. Here, we investigated the temporal evolution of intra- and interhemispheric (dys-) connectivity during motor recovery from the acute to the early chronic phase post stroke. Twelve patients performed hand movements in an fMRI task in the acute (<=72 hours) and subacute stage (2 weeks) post-stroke. A subgroup of 10 patients participated in a third assessment in the early chronic stage (3-6 months). Twelve healthy subjects served as reference for brain connectivity. Changes in effective connectivity within a bilateral network comprising M1, premotor cortex (PMC), and supplementary motor area (SMA) were estimated by dynamic causal modeling. Motor performance was assessed by the Action Research Arm Test and maximum grip force. Results showed reduced positive coupling of ipsilesional SMA and PMC with ipsilesional M1 in the acute stage. Coupling parameters among these areas increased with recovery and predicted a better outcome. Likewise, negative influences from ipsilesional areas to contralesional M1 were attenuated in the acute stage. In the subacute stage, contralesional M1 exerted a positive influence on ipsilesional M1. Negative influences from ipsilesional areas on contralesional M1 subsequently normalized, but patients with poorer outcome in the chronic stage now showed enhanced negative coupling from contralesional upon ipsilesional M1. These findings show that the reinstatement of effective connectivity in the ipsilesional hemisphere is an important feature of motor recovery after stroke. The shift of an early, supportive role of contralesional M1 into enhanced inhibitory coupling might indicate maladaptive processes which could be a target of non-invasive brain stimulation techniques. PMID- 21238595 TI - Age-related alterations in the modular organization of structural cortical network by using cortical thickness from MRI. AB - Normal aging is accompanied by various cognitive functional declines. Recent studies have revealed disruptions in the coordination of large-scale functional brain networks such as the default mode network in advanced aging. However, organizational alterations of the structural brain network at the system level in aging are still poorly understood. Here, using cortical thickness, we investigated the modular organization of the cortical structural networks in 102 young and 97 normal aging adults. Brain networks for both cohorts displayed a modular organization overlapping with functional domains such as executive and auditory/language processing. However, compared with the modular organization of young adults, the aging group demonstrated a significantly reduced modularity that might be indicative of reduced functional segregation in the aging brain. More importantly, the aging brain network exhibited reduced intra-/inter-module connectivity in modules corresponding to the executive function and the default mode network of young adults, which might be associated with the decline of cognitive functions in aging. Finally, we observed age-associated alterations in the regional characterization in terms of their intra/inter-module connectivity. Our results indicate that aging is associated with an altered modular organization in the structural brain networks and provide new evidence for disrupted integrity in the large-scale brain networks that underlie cognition. PMID- 21238596 TI - Image analysis and statistical inference in neuroimaging with R. AB - R is a language and environment for statistical computing and graphics. It can be considered an alternative implementation of the S language developed in the 1970s and 1980s for data analysis and graphics (Becker and Chambers, 1984; Becker et al., 1988). The R language is part of the GNU project and offers versions that compile and run on almost every major operating system currently available. We highlight several R packages built specifically for the analysis of neuroimaging data in the context of functional MRI, diffusion tensor imaging, and dynamic contrast-enhanced MRI. We review their methodology and give an overview of their capabilities for neuroimaging. In addition we summarize some of the current activities in the area of neuroimaging software development in R. PMID- 21238598 TI - Functional analysis of the chicken PPARgamma gene 5'-flanking region and C/EBPalpha-mediated gene regulation. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma) and CCAAT/enhancer binding protein-alpha (C/EBPalpha) are the master regulators of adipogenesis. The regulatory mechanism of PPARgamma and C/EBPalpha gene expression is clear in mammals, however, little is known in chicken. The aim of the present study was to characterize chicken PPARgamma promoter and investigate whether PPARgamma could be regulated by C/EBPalpha in chickens. A 2-kb nucleotide sequence upstream of the start codon of chicken PPARgamma gene was cloned and characterized by using bioinformatics and experimental approaches. This 2-kb promoter region exhibited strong promoter activity in DF1 cells. The reporter gene assay showed that the chicken C/EBPalpha could activate PPARgamma gene promoter. Further study by electrophoretic mobility shift assay and mutational analysis revealed that the chicken C/EBPalpha could directly bind to and regulate the PPARgamma gene promoter. Our results demonstrate that PPARgamma can be directly regulated by C/EBPalpha in chickens. PMID- 21238597 TI - Radial diffusivity predicts demyelination in ex vivo multiple sclerosis spinal cords. AB - OBJECTIVE: Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords. BACKGROUND: In MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans. METHODS: DTI was performed at 4.7 T on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate-severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. RESULTS: Within ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate-severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p=0.091). CONCLUSIONS: Increased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity can serve as a marker of overall tissue integrity within chronic MS lesions. This study provides pathologic foundation for on-going in vivo DTI studies in MS. PMID- 21238600 TI - Japanese encephalitis virus: from genome to infectome. AB - Japanese encephalitis virus (JEV) is an arbovirus belonging to the family Flaviviridae. It is maintained in a zoonotic cycle involving pigs, ardeid birds and Culex species of mosquitoes. Humans are accidental/dead end hosts of JEV infection because they cannot sustain high viral titers. Factors affecting the clinical manifestations and pathogenesis of JEV infection are not well understood. Though, vaccines are currently available against JEV, it has to be further improved. Here we review the literature on the JEV life cycle, pathogenesis and host immune responses to JEV infection. PMID- 21238601 TI - Junin virus. A XXI century update. AB - Junin virus of the Arenaviridae family is the etiological agent of Argentine hemorrhagic fever, a febrile syndrome causing hematological and neurological symptoms. We review historical perspectives of current knowledge on the disease, and update information related to the virion and its potential pathogenic mechanisms. PMID- 21238599 TI - Phylogenetic lineage and pilus protein Spb1/SAN1518 affect opsonin-independent phagocytosis and intracellular survival of Group B Streptococcus. AB - Opsonin-independent phagocytosis of Group B Streptococcus (GBS) is important in defense against neonatal GBS infections. A recent study indicated a role for GBS pilus in macrophage phagocytosis (Maisey et al Faseb J 22 2008 1715-24). We studied 163 isolates from different phylogenetic backgrounds and those possessing or lacking the gene encoding the pilus backbone protein, Spb1 (SAN1518, PI-2b) and spb1-deficient mutants of wild-type (WT) serotype III-3 GBS 874391 in non opsonic phagocytosis assays using J774A.1 macrophages. Numbers of GBS phagocytosed differed up to 23-fold depending on phylogenetic background; isolates possessing spb1 were phagocytosed more than isolates lacking spb1. Comparing WT GBS and isogenic spb1-deficient mutants showed WT was phagocytosed better compared to mutants; Spb1 also enhanced intracellular survival as mutants were killed more efficiently. Complementation of mutants restored phagocytosis and resistance to killing in J774A.1 macrophages. Spb1 antiserum revealed surface expression in WT GBS and spatial distribution relative to capsular polysaccharide. spb1 did not affect macrophage nitric oxide and TNF-alpha responses; differences in phagocytosis did not correlate with N-acetyl d glucosamine (from GBS cell-wall) according to enzyme-linked lectin-sorbent assay. Together, these findings support a role for phylogenetic lineage and Spb1 in opsonin-independent phagocytosis and intracellular survival of GBS in J774A.1 macrophages. PMID- 21238602 TI - Phenylurea herbicides induce cytogenetic effects in Chinese hamster cell lines. AB - The intensive use of herbicides over the last few decades has caused a general increase of environmental pollution. It is thus very important to evaluate the possible genotoxic properties of these chemical compounds as well as identifying their mode of action. Phenylurea herbicides are selective agents widely used for the control of infestant plants. Of these herbicides, which are widely used in agriculture, we analysed four of the less intensively studied molecules. More precisely, we investigated the genotoxic effects of fenuron, chlorotoluron, diuron, and difenoxuron by analyses of chromosomal aberrations (CAs) and sister chromatid exchange (SCE) in exposed mammalian cells. We used the Chinese hamster ovary (CHO) and epithelial liver (CHEL) cell lines, endowed with the absence or the presence, respectively, of an enzymatic system to activate pro-mutagenic compounds. Our results show that all herbicides tested induce, at high concentrations, an increasing number of CAs in non-metabolising CHO cells. Instead, in the exposed CHEL cell line, the four herbicides induced CAs also at the lowest dose-level. In the CHEL cells, a statistically significant increase of SCE was also observed. The phenylurea herbicides showed direct genotoxic activity, but the cytogenetic effects were greatly enhanced after metabolic conversion. These data, together with other information on phenylurea herbicides, are of great interest from the environmental point of view, and for human health. In fact, intensive use of herbicides contaminates soil, surface water, groundwater and agricultural products, and thus should be taken in particular consideration not only for those initiatives to specifically protect exposed workers, but also to safeguard the health of consumers of agricultural products. PMID- 21238603 TI - A core in vitro genotoxicity battery comprising the Ames test plus the in vitro micronucleus test is sufficient to detect rodent carcinogens and in vivo genotoxins. AB - In vitro genotoxicity testing needs to include tests in both bacterial and mammalian cells, and be able to detect gene mutations, chromosomal damage and aneuploidy. This may be achieved by a combination of the Ames test (detects gene mutations) and the in vitro micronucleus test (MNvit), since the latter detects both chromosomal aberrations and aneuploidy. In this paper we therefore present an analysis of an existing database of rodent carcinogens and a new database of in vivo genotoxins in terms of the in vitro genotoxicity tests needed to detect their in vivo activity. Published in vitro data from at least one test system (most were from the Ames test) were available for 557 carcinogens and 405 in vivo genotoxins. Because there are fewer publications on the MNvit than for other mammalian cell tests, and because the concordance between the MNvit and the in vitro chromosomal aberration (CAvit) test is so high for clastogenic activity, positive results in the CAvit test were taken as indicative of a positive result in the MNvit where there were no, or only inadequate data for the latter. Also, because Hprt and Tk loci both detect gene-mutation activity, a positive Hprt test was taken as indicative of a mouse-lymphoma Tk assay (MLA)-positive, where there were no data for the latter. Almost all of the 962 rodent carcinogens and in vivo genotoxins were detected by an in vitro battery comprising Ames+MNvit. An additional 11 carcinogens and six in vivo genotoxins would apparently be detected by the MLA, but many of these had not been tested in the MNvit or CAvit tests. Only four chemicals emerge as potentially being more readily detected in MLA than in Ames+MNvit--benzyl acetate, toluene, morphine and thiabendazole--and none of these are convincing cases to argue for the inclusion of the MLA in addition to Ames+MNvit. Thus, there is no convincing evidence that any genotoxic rodent carcinogens or in vivo genotoxins would remain undetected in an in vitro test battery consisting of Ames+MNvit. PMID- 21238604 TI - Exposure to asbestos: correlation between blood levels of mesothelin and frequency of micronuclei in peripheral blood lymphocytes. AB - Inhalation of asbestos, a mineral extensively used in a variety of applications, is strongly associated with malignant mesothelioma (MM), a fatal cancer of the pleura. Soluble mesothelin-related peptides (SMRP) are a promising biomarker suggested for the screening of MM in healthy asbestos-exposed subjects. In the present study a comparison of micronucleus (Mn) frequencies in peripheral blood lymphocytes (PBL) between 44 asbestos-exposed and 22 control individuals has been performed, and the correlation with serum SMRP has been examined. SMRP levels were found to be significantly higher in subjects exposed to asbestos and in their various subgroups than in controls. Concerning micronucleated lymphocytes, a statistically significant difference from controls was seen in the percentages of both micronucleated mononucleated lymphocytes (MnMNL) and micronucleated binucleated lymphocytes (MnBNL), but the difference was markedly higher for the percentage of micronucleated polynucleated lymphocytes (MnPNL). With respect to the correlation between the frequency of the three types of micronucleated lymphocytes and serum-SMRP values of asbestos-exposed subjects, it was statistically significant for MnMNL, but not for MnBNL and MnPNL. PMID- 21238605 TI - Watching intracellular lipolysis in mycobacteria using time lapse fluorescence microscopy. AB - The fact that Mycobacterium tuberculosis mobilizes lipid bodies (LB) located in the cytosol during infection process has been proposed for decades. However, the mechanisms and dynamics of mobilization of these lipid droplets within mycobacteria are still not completely characterized. Evidence in favour of this characterization was obtained here using a combined fluorescent microscopy and computational image processing approach. The decrease in lipid storage levels observed under nutrient depletion conditions was correlated with a significant increase in the size of the bacteria. LB fragmentation/condensation cycles were monitored in real time. The exact contribution of lipases in this process was confirmed using the lipase inhibitor tetrahydrolipstatin, which was found to prevent LB degradation and to limit the bacterial cell growth. The method presented here provides a powerful tool for monitoring in vivo lipolysis in mycobacteria and for obtaining new insights on the growth of cells and their entry into the dormant or reactivation phase. It should be particularly useful for studying the effects of chemical inhibitors and activators on cells as well as investigating other metabolic pathways. PMID- 21238606 TI - Design and validation of the biliary atresia research consortium histologic assessment system for cholestasis in infancy. AB - BACKGROUND & AIMS: Pathologists participating in the National Institutes of Health-sponsored Biliary Atresia Research Consortium (BARC) developed and then evaluated a standardized system for histologic reporting of liver biopsies from infants with cholestasis. METHODS: A set of 97 anonymous liver biopsy samples was sent to 10 pathologists at BARC centers. A semiquantitative scoring system that had 16 histologic features was developed and then used by the pathologists, who had no knowledge of clinical history, imaging results, or laboratory data. Interobserver agreement was evaluated statistically. Agreement on scoring of each feature and on the pathologists' diagnosis, compared with the final clinical diagnosis, was evaluated by using weighted kappa statistics. RESULTS: There was moderate to substantial interobserver agreement in identification of bile plugs in ducts, giant-cell transformation, extramedullary hematopoiesis, and bile duct proliferation. The pathologists' diagnosis of obstruction in clinically proven cases of biliary atresia (BA) ranged from 79%-98%, with a positive predictive value of 90.7%. Histologic features that best predicted BA, on the basis of logistic regression, included bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis (each P<.0001). CONCLUSIONS: The BARC histologic assessment system identified features of liver biopsies from cholestatic infants, with good interobserver agreement, that might be used in diagnosis and determination of prognosis. The system diagnosed BA with a high level of sensitivity and identified infants with biliary obstruction with reasonable interobserver agreement. However, distinguishing between BA and disorders such as total parenteral nutrition-associated liver disease and alpha(1)-antitrypsin deficiency is not possible without adequate clinical information. PMID- 21238607 TI - Screening-identified celiac disease: who needs treatment and when? PMID- 21238608 TI - Increased mortality and length of stay among patients with inflammatory bowel disease and hospital-acquired infections: effect of risk adjustment. PMID- 21238609 TI - Are colorectal cancer screening recommendations for first-degree relatives of patients with adenomas too aggressive? AB - Consensus guidelines of the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology recommend first degree relatives of individuals diagnosed with an adenoma before age 60 should be screened every 5 years with colonoscopy starting at age 40. This is the identical recommendation for those with a first-degree relative diagnosed with colorectal cancer (CRC) before age 60. There is good evidence that first-degree relatives of individuals diagnosed with CRC before age 60 are at substantially increased risk for developing cancer at a young age. However, it is unclear whether an individual with a first-degree relative with an adenoma diagnosed before age 60 is at increased risk of CRC. Because not all adenomas portend the same cancer risk in the individual who has the adenoma, they would not be expected to portend the same risk in their first-degree relatives. Because of these uncertainties, the US Preventive Services Task Force does not recommend more aggressive screening of first-degree relatives of individuals with an adenoma. The adenoma detection rate for individuals 50 to 59 years old without a first-degree relative with CRC is sufficiently high (approximately 25%-30%) that almost half the population would be high risk on the basis of one first-degree relative having an adenoma. Given the weakness of evidence supporting the guidelines, suboptimal levels of screening in the general population, and lack of resources to comply with the recommendation, first-degree relatives of individuals with adenomas should be screened as average-risk persons until more compelling data are available to justify more aggressive screening. PMID- 21238610 TI - Unfulfilled wishes by gastric electrical stimulation. PMID- 21238611 TI - Hepatocellular carcinoma with sternal metastasis. PMID- 21238612 TI - Unusual abdominal tumor: peritoneal mesothelioma. PMID- 21238613 TI - Patients often go without effective new treatments, especially in rare disease patient populations where profit potential is limited. PMID- 21238614 TI - Madres para la Salud: design of a theory-based intervention for postpartum Latinas. AB - BACKGROUND: Weight gain in young women suggests that childbearing may be an important contributor to the development of obesity in women. Depressive symptoms can interfere with resumption of normal activity levels following childbirth or with the initiation of or adherence to physical activity programs essential for losing pregnancy weight. Depression symptoms may function directly to promote weight gain through a physiologic mechanism. Obesity and its related insulin resistance may contribute to depressed mood physiologically. Although physical activity has well-established beneficial effects on weight management and depression, women tend to under participate in physical activity during childbearing years. Further, the mechanisms underpinning the interplay of overweight, obesity, physical activity, depression, and inflammatory processes are not clearly explained. OBJECTIVES: This report describes the theoretical rationale, design considerations, and cultural relevance for "Madres para la Salud" [Mothers for Health]. DESIGN AND METHODS: Madres para la Salud is a 12 month prospective, randomized controlled trial exploring the effectiveness of a culturally specific intervention using "bouts" of physical activity to effect changes in body fat, systemic and fat tissue inflammation, and postpartum depression symptoms in sedentary postpartum Latinas. SUMMARY: The significance and innovation of Madres para la Salud includes use of a theory-driven approach to intervention, specification and cultural relevance of a social support intervention, use of a Promotora model to incorporate cultural approaches, use of objective measures of physical activity in post partum Latinas women, and the examination of biomarkers indicative of cardiovascular risk related to physical activity behaviors in postpartum Latinas. PMID- 21238615 TI - Potentiation of the hypoxic ventilatory response by 1 day of hyperoxia in neonatal rats. AB - The O(2) sensitivity of the neonatal rat carotid body is increased after 1 day in moderate hyperoxia (60% O(2)) (Donnelly et al., 2009). We investigated whether this enhanced peripheral chemosensitivity increases the hypoxic ventilatory response (HVR) and tested the hypothesis that this plasticity is mediated by the superoxide anion. Neonatal rats (7 d old) were injected with saline or MnTMPyP, a superoxide scavenger, and placed into 60% O(2) for 23-28h. Baseline ventilation was reduced and the acute HVR (12% O(2)) was enhanced in hyperoxia-treated rats relative to age-matched controls; MnTMPyP did not block these effects. An additional group of rats was studied after only 30min in 60% O(2). This shorter exposure had no effect on normoxic ventilation or the HVR. We conclude that 1 d, but not 30min, of 60% O(2) augments the HVR of neonatal rats and that production of the superoxide anion does not contribute to this plasticity. PMID- 21238616 TI - Both PDI and PDIp can attack the native disulfide bonds in thermally-unfolded RNase and form stable disulfide-linked complexes. AB - Protein disulfide isomerase (PDI) and its pancreatic homolog (PDIp) are folding catalysts for the formation, reduction, and/or isomerization of disulfide bonds in substrate proteins. However, the question as to whether PDI and PDIp can directly attack the native disulfide bonds in substrate proteins is still not answered, which is the subject of the present study. We found that RNase can be thermally unfolded at 65 degrees C under non-reductive conditions while its native disulfide bonds remain intact, and the unfolded RNase can refold and reactivate during cooling. Co-incubation of RNase with PDI or PDIp during thermal unfolding can inactivate RNase in a PDI/PDIp concentration-dependent manner. The alkylated PDI and PDIp, which are devoid of enzymatic activities, cannot inactivate RNase, suggesting that the inactivation of RNase results from the disruption of its native disulfide bonds catalyzed by the enzymatic activities of PDI/PDIp. In support of this suggestion, we show that both PDI and PDIp form stable disulfide-linked complexes only with thermally-unfolded RNase, and RNase in the complexes can be released and reactivated dependently of the redox conditions used. The N-terminal active site of PDIp is essential for the inactivation of RNase. These data indicate that PDI and PDIp can perform thiol disulfide exchange reactions with native disulfide bonds in unfolded RNase via formation of stable disulfide-linked complexes, and from these complexes RNase is further released. PMID- 21238617 TI - Purification, characterization and thermal inactivation kinetics of a non regioselective thermostable lipase from a genotypically identified extremophilic Bacillus subtilis NS 8. AB - Thermostable lipase produced by a genotypically identified extremophilic Bacillus subtilis NS 8 was purified 500-fold to homogeneity with a recovery of 16% by ultrafiltration, DEAE-Toyopearl 650M and Sephadex G-75 column. The purified enzyme showed a prominent single band with a molecular weight of 45 kDa. The optimum pH and temperature for activity of lipase were 7.0 and 60 degrees C, respectively. The enzyme was stable in the pH range between 7.0 and 9.0 and temperature range between 40 and 70 degrees C. It showed high stability with half lives of 273.38 min at 60 degrees C, 51.04 min at 70 degrees C and 41.58 min at 80 degrees C. The D-values at 60, 70 and 80 degrees C were 788.70, 169.59 and 138.15 min, respectively. The enzyme's enthalpy, entropy and Gibb's free energy were in the range of 70.07-70.40 kJ mol(-1), -83.58 to -77.32 kJ mol(-1)K(-1) and 95.60-98.96 kJ mol(-1), respectively. Lipase activity was slightly enhanced when treated with Mg(2+) but there was no significant enhancement or inhibition of the activity with Ca(2+). However, other metal ions markedly inhibited its activity. Of all the natural vegetable oils tested, it had slightly higher hydrolytic activity on soybean oil compared to other oils. On TLC plate, the enzyme showed non-regioselective activity for triolein hydrolysis. PMID- 21238618 TI - IFN-gamma enhances HOS and U2OS cell lines susceptibility to gammadelta T cell mediated killing through the Fas/Fas ligand pathway. AB - Osteosarcoma is the second highest cause of cancer-related death in children and adolescents, partly due to dysfunction of the Fas/FasL signaling pathway, which leads to develop fatal metastasis. Since presenting no or low levels of Fas expression, resisting Fas ligand-induced apoptosis, and lack of FasL in the host environment, osteosarcoma cells always promote metastases growth and proliferate in the lungs. Therefore, agents, which up-regulate tumor cell surface Fas expression and function, in combination with immune cells, may be effective in treating osteosarcoma, especially lung metastases. The aim of this work was to investigate the effect of gammadelta T cells in combination with IFN-gamma in treating osteosarcoma in vitro. In the present study, we found that IFN-gamma up regulated the expression of Fas in osteosarcoma cell lines, HOS and U2OS, resulting in an enhanced susceptibility of cells to gammadelta T cells lyses. Moreover, this cytotoxicity was prevented by treatment with FasL-blocking antibodies. These data suggest that adoptive transfer of gammadelta T cells in combination with IFN-gamma may substantially increase anti-osteosarcoma activities and represent a novel strategy for osteosarcoma adjunct immunotherapy. PMID- 21238619 TI - Lower prevalence of circulating invariant natural killer T (iNKT) cells in patients with acute myocardial infarction undergoing primary coronary stenting. AB - Invariant natural killer T cells are a unique lymphocyte subtype that can recognize lipid antigens presented by CD1d and release pro-atherogenic cytokines such as interferon-gamma. We studied the importance of iNKT cells, other lymphocyte cell types and CD11b in the peripheral blood of patients diagnosed with acute myocardial infarction (AMI) before and after primary coronary stenting. Lymphocyte population profiles and CD11b were compared between patients with AMI and healthy control subjects using flow cytometry. Both the absolute number and cell fractions of iNKT, CD3+CD4+ lymphocytes were significant lower in AMI patients than health controls. The cell fraction of NK cells was also reduced, while there was a significant increase in the cell fractions and absolute numbers of CD3+CD8+ lymphocytes, B lymphocytes and mean fluorescence intensity values of labeled CD11b. The number of iNKT cells was significantly and positively correlated with cholesterol and low-density lipoprotein levels in blood samples from AMI patients before primary coronary stenting. Logistic regression analysis demonstrated that the absolute number of iNKT cells was a significant independent predictor for restenosis during the 243 day post operative follow-up. This study demonstrates that iNKT cell number may be a useful predictor of clinical outcome in AMI patients with primary coronary stenting. PMID- 21238620 TI - Identification of myeloid-derived suppressor cells and T regulatory cells in lung microenvironment after Urethane-induced lung tumor. AB - Tumor growth occurs by the imbalance between cells with effector function and cells with suppressor/regulatory functions. To investigate this scenario we administered the chemical carcinogen Urethane in BALB/c mice and followed these animals during 120 days to observe lung tumor development. In another set of experiments the same protocol was performed with the harvest of spleen, lung and blood at 20 and 30 days after Urethane injection. The lung was used for histology, spleen cells were evaluated for IFN-gamma production, and serum nitrite was measured as an indirect form of nitric oxide (NO) evaluation. The spleen and lung-infiltrating cells were evaluated by flow cytometry for CD11b+Gr 1+ myeloid suppressor cells and CD4+FoxP3+ T regulatory cells. Urethane led to lung nodules development after 120 days and the time point evaluation showed that splenocytes stimulated ex vivo expressed higher levels of IFN-gamma 20 days after the chemical injection. Also, the level of nitric oxide in serum was higher after 20 days of Urethane injection. There was no statistical difference in spleen cells percentages for CD11b+Gr-1+ and CD4+Foxp3+ in all groups. However, lung infiltrating cells presented early (20 days) a higher expression of CD11b+Gr-1+ suggesting suppression at this site. In conclusion, it was possible to observe two distinct events at the very early time point after Urethane injection. In periphery there was an increase at the effector immune response (as depicted by IFN-gamma-producing cells) and in tumor development site there was an increase at the suppressor cell (CD11b+Gr-1+) phenotype. Suppressor/regulatory cells are targets for cancer therapy. PMID- 21238621 TI - Oral administration of ginsenoside Rh1 inhibits the development of atopic dermatitis-like skin lesions induced by oxazolone in hairless mice. AB - In the present study, we examined the inhibitive effect of ginsenoside Rh1 on oxazolone-induced atopic dermatitis-like skin lesions in hairless mice. Oral administration of ginsenoside Rh1 improved clinical symptoms, and it was confirmed by histophathological analysis. In ginsenoside Rh1 (20mg/kg) group, ear swellings and ear weights were significantly lower than the control group. Moreover, elevation of IL-6 and total IgE levels in serum were suppressed by ginsenoside Rh1 (20mg/kg). In addition, ginsenoside Rh1 (20mg/kg) significantly increased mRNA expression of IFNgamma and Foxp3, and slightly decreased IL-4 expression in draining lymph nodes. The results suggest that ginsenoside Rh1 can alleviate inflammatory symptoms in atopic dermatitis (AD) by reduction of IgE and IL-6 levels in peripheral blood, increase of Foxp3 expression in draining lymph nodes and suppression of inflammation in skin regions. Indeed, ginsenoside Rh1 exhibited therapeutic possibility in immune disorders. PMID- 21238623 TI - Superoxide dismutase and cytochrome P450 isoenzymes might be associated with higher risk of renal cell carcinoma in male patients. AB - Literature data support the hypothesis that oxidative stress and the accompanying antioxidant defense might play an important role in renal cell carcinoma (RCC) growth and progression. It is also known that the incidence of renal tumors is two times higher in men than in women. Thus, the aim of this study was to determine whether the oxidant/antioxidant profile of renal cell carcinoma tissue, adjacent to tumor tissue and nontumor tissue was different in male and female patients. Significantly higher lipid peroxidation (LPO) in renal cell carcinoma tissue compared to nontumor tissue was demonstrated only in male patients. Besides, gender-related difference in copper zinc superoxide dismutase (CuZnSOD) and manganese superoxide dismutase (MnSOD) in nontumor and renal cell carcinoma tissue was obtained at the level of transcription, translation and activity of these antioxidant isoenzymes. Morever, we demonstrated that the gene expression of 3 CYPs out of 7 was altered; CYP2D6 mRNA was decreased in both sexes while gender-related suppression of mRNA for CYP2E1 (women) and CYP2C19 (men) was observed. Taken together, these parameters might be potentially responsible for higher risk of renal cell carcinoma in men than in women. PMID- 21238622 TI - Inhibition of IgE-mediated secretion from human basophils with a highly selective Bruton's tyrosine kinase, Btk, inhibitor. AB - The study of receptor-mediated signaling in human basophils is often limited by the availability of selective pharmacological agents. The early signaling reaction mediated by FcepsilonRI aggregation is thought to require the activity of Bruton's tyrosine kinase (btk), an enzyme that has been identified as important in B cells signaling because mutations lead to X-linked agammaglobulinemia. This study uses the btk selective irreversible inhibitor, PCI 32765, to explore the role of btk in a variety of functions associated with the activation of human basophils. Nine endpoints of basophil activation were examined: induced cell surface expression of CD63, CD203c, CD11b; induced secretion of histamine, LTC4, IL-4 and IL-13; the cytosolic calcium response; and the induced loss of syk kinase. Four stimuli were examined; anti-IgE antibody, formyl-met-leu-phe (FMLP), C5a and IL-3. For stimulation with anti-IgE, PCI-32765 inhibited CD63, histamine, LTC4 and IL-4 secretion with an IC50 of 3-6 nM (with 100% inhibition at 50 nM) and it inhibited CD203c and CD11b and the cytosolic calcium response with and IC50 of 30-40 nM. Fifty percent occupancy of btk with PCI-32765 occurred at ~10nM. Consistent with btk functioning downstream or in parallel to syk activation, PCI-32765 did not inhibit the loss of syk induced by anti-IgE in overnight cultures. Finally, PCI-32765 did not significantly inhibit basophil activation by FMLP or C5a and did not inhibit IL-13 release induced by IL-3. These results suggest that btk is specifically required for IgE-mediated activation of human basophils. PMID- 21238624 TI - Laparostomy closure in stage 4S neuroblastoma. AB - Laparostomy in children is a rare procedure, and there is little in the literature as to the best method for closure in children with an open abdomen. We describe 2 cases with stage 4S neuroblastoma that required emergency decompressive laparostomy. Both cases highlight advantages and disadvantages with known techniques for achieving skin and fascia closure. We believe this to be the first report of a combination of extracellular matrix mesh and vacuum therapy for successful fascial and skin closure in stage 4S neuroblastoma. PMID- 21238625 TI - Excision of extensive metastatic dysgerminoma to control refractory hypercalcaemia in a child at high risk for tumour-lysis syndrome. AB - Hypercalcaemia is a rare life-threatening complication of paediatric cancer that is commoner in haematological than solid malignancies and associated rarely with acute renal failure. Often refractory to medical therapy, control of hypercalcaemia in children with solid tumours may necessitate excision of localised tumours or urgent chemotherapy for metastatic ones. We present a child with refractory hypercalcaemia, bulky chemosensitive metastatic tumours and acute renal failure in whom chemotherapy posed high-risk of tumour lysis syndrome (TLS). Resection of the metastatic tumours successfully normalised the hypercalcaemia and represents a practical alternative control strategy in cases at high risk of TLS. PMID- 21238626 TI - Epithelial cyst of the spleen with foci of ectopic liver. AB - Epithelial cysts account for about 20% of all splenic cysts. Their pathogenesis is unclear, and different authors have proposed many hypotheses. It has been suggested that they are derived from embryonal epithelial inclusions during splenic development, from invagination of capsular surface mesothelium in splenic sulci with subsequent metaplasia, or from trauma. Moreover, a congenital, genetic, or teratomatous origin has also been hypothesized. We describe an unusual case of epithelial splenic cyst with mature liver foci in its wall. This finding supports its possible dysontogenetic origin. PMID- 21238627 TI - Endovascular papillary angioendothelioma (Dabska tumor): underrecognized malignant tumor in childhood. AB - Endovascular papillary angioendothelioma, or Dabska tumor, was first presented in 1969 by Maria Dabska where she presented cases occurring in 6 children. The tumor was described as being a low-grade angiosarcoma characterized by papillary endovascular proliferations of atypical endothelial cells and anastomosing vascular channels within the dermis. Since its original description, only 30 case reports have been written describing the varying presentation, clinical course, and histopathology of this tumor. This case report documents the presentation and management of endovascular papillary angioendothelioma in a young male and reviews the current literature. Because more cases of EPAs are reported, perhaps a more standard approach to accurate diagnosis and treatment with surgical intervention and pathologic recognition via microscopy and immunohistochemistry can be determined. PMID- 21238628 TI - Transvesical resection of a mucocele after laparoscopically assisted anorectal pull-through for imperforate anus with rectobulbar urethral fistula. AB - Mucocele formation is a rare complication after imperforate anus repair. Abdominal cyst enucleation or resection, transrectal resection by a posterior sagittal approach, and perineal cyst resection are the standard surgical options. The authors report the first patient who underwent transvesical mucocele resection. PMID- 21238629 TI - Isolated gastric varices with upper gastrointestinal bleeding 11 years after distal pancreatectomy for ruptured pancreatic pseudocyst. AB - Isolated gastric varices with upper gastrointestinal bleeding are an unusual event, particularly in children in whom obstruction of the splenic vein is an infrequent occurrence. We describe a 19-year-old man with bleeding isolated gastric varices 11 years after he underwent distal pancreatectomy with preservation of the spleen for a ruptured pancreatic pseudocyst. The disorder was cured with splenectomy. PMID- 21238630 TI - Heterotopic gastric mucosa of the upper esophagus following repair of esophageal atresia with tracheoesophageal fistula. AB - A term female newborn underwent uncomplicated repair of esophageal atresia with tracheoesophageal fistula (type C) then coarctation of the aorta. Subsequently, she developed symptomatic esophageal strictures, which required serial dilations. In addition, she suffered feeding intolerance from esophageal dysmotility and gastroesophageal reflux disease, necessitating Nissen fundoplication with gastrostomy. At 6 years of age, surveillance esophagogastroduodenoscopy revealed mild stenosis and heterotopic gastric mucosa of the upper esophagus at the level of the anastomosis. This is the second report of heterotopic gastric mucosa of the upper esophagus at the level of the anastomosis following repair of esophageal atresia with tracheoesophageal fistula. PMID- 21238631 TI - Preoperative embolization of giant sacrococcygeal teratoma in a premature newborn. AB - Resection of a large vascular sacrococcygeal teratoma (SCT) in a newborn has the potential to be a fatal procedure caused by hemolysis, rupture, or bleeding of the tumor. Usually, most blood supply of an SCT is derived from the middle sacral artery. As soon as these arteries have been ligated, further blood loss is minimal. There is only one previous presentation about preoperative embolization of these arteries. We present a case in which the feeding arteries of a giant SCT were embolized in an infant born at 30 weeks and 3 days of gestation. Although bleeding during the surgery was minimal, continuous need of transfusions and life threatening hyperkalemia created severe problems during surgery, until tumor resection was completed. This is the smallest reported patient in whom SCT was preoperatively treated by embolization. PMID- 21238632 TI - Hepatic angiosarcoma of childhood: a case report and review of literature. AB - Angiosarcomas are rare tumors that predominantly affect adults. Hepatic angiosarcoma in a child is an extremely rare event and is associated with a poor prognosis. Herein, we report our experience in a case of hepatic angiosarcoma in a child who presented with a huge unresectable mass that underwent liver transplantation. PMID- 21238633 TI - The development and translation of the tissue-engineered vascular graft. AB - This lecture will define the classic tissue engineering paradigm, describe cell trafficking with regard to neotissue formation, and explain the role of the host in neotissue formation. PMID- 21238634 TI - Translating innovation: Beethoven, Gross, Krummel, and Georgeson. PMID- 21238635 TI - Technical aspects of fetal endoscopic tracheal occlusion for congenital diaphragmatic hernia. AB - In isolated congenital diaphragmatic hernia, prenatal prediction is made based on measurements of lung size and the presence of liver herniation into the thorax. A subset of fetuses likely to die in the postnatal period is eligible for fetal intervention that can promote lung growth. Rather than anatomical repair, this is now attempted by temporary fetal endoscopic tracheal occlusion (FETO). Herein we describe purpose-designed instruments that were developed thanks to a grant from the European Commission. The feasibility and safety of FETO have now been demonstrated in several active fetal surgery programs. The most frequent complication of the procedure is preterm premature rupture of the membranes, which is probably iatrogenic in nature. It does have an impact on gestational age at delivery and complicates balloon removal. FETO is associated with an apparent increase in survival compared with same severity controls, although this needs to be evaluated in a formal trial. The time has come to do so. PMID- 21238637 TI - Protocolized management of infants with congenital diaphragmatic hernia: effect on survival. AB - BACKGROUND/PURPOSE: In 2006, we introduced a new protocol for congenital diaphragmatic hernia (CDH) management featuring nitric oxide in the delivery room, gentle ventilation, lower criteria for extracorporeal membrane oxygenation (ECMO), and appropriately timed operative repair on ECMO. Our goals were to assess outcomes after institution of this protocol and to compare results with historical controls. METHODS: Charts were reviewed of all newborns admitted to a large metropolitan children's hospital from 2002 to 2009 with a diagnosis of CDH. Data were recorded regarding delivery, ECMO, operative repair, length of stay, comorbidities/anomalies, complications, and survival. Postprotocol outcomes were compared to those from the preprotocol era and to data from the international CDH Registry. RESULTS: Comparison of the protocolized group (n = 43) to the historical group (n = 51) revealed no significant differences in gestational age, birth weight, Apgar scores, or comorbidities. New treatment strategies substantially improved survival to discharge (67% preprotocol, 88% postprotocol; P = .015). Among ECMO patients, survival increased to 82% (20% preprotocol; P = .002). CONCLUSIONS: Our new protocol significantly improved survival to discharge for newborns with CDH. Institution of such a protocol is valuable in improving outcomes for patients with CDH and merits consideration for widespread adoption. PMID- 21238636 TI - Submucosal gland development in the human fetal trachea xenograft model: implications for fetal gene therapy. AB - BACKGROUND/PURPOSE: Our previous work in a human-fetal trachea xenograft model suggests potential benefits of treating cystic fibrosis in utero. The target for postnatal gene therapy in cystic fibrosis is tracheal submucosal glands (SMGs). The aim of this study was to determine if SMG development in our model recapitulates normal trachea development and its validity for studying fetal gene transfer. METHODS: Fetal tracheas were divided into developmental phases: early, mid, and late. Fetal tracheas were xenografted onto immunocompromised mice and analyzed for SMG developmental staging and mucopolysaccharide production. RESULTS: There were no significant differences in gland number, size, or density from early through late phase between groups. Xenografted tracheas demonstrated a similar progression through the stages of SMG development as controls after an initial phase shift. Control and xenografted tracheas demonstrated characteristic patterns of acidic mucin production at the base of the SMGs. CONCLUSIONS: Fetal trachea xenograft SMG recapitulates normal development and is a valid model for studying human fetal gene transfer. The accessibility of SMG stem cells in early tracheal development may afford a unique window of opportunity for gene transfer. This model has the benefit of providing access to human fetal tracheas in vivo and permits the study of novel fetal gene therapy strategies. PMID- 21238638 TI - Decreased cerebral oxygen saturation during thoracoscopic repair of congenital diaphragmatic hernia and esophageal atresia in infants. AB - BACKGROUND/PURPOSE: Congenital diaphragmatic hernia (CDH) and esophageal atresia with tracheoesophageal fistula (EA/TOF) can be repaired thoracoscopically, but this may cause hypercapnia, acidosis, and reduced cerebral oxygenation. We evaluated the effect of thoracoscopy in infants on cerebral oxygen saturation (cSO(2)), arterial blood gases, and carbon dioxide (CO(2)) absorption. METHODS: Eight infants underwent thoracoscopy (6 CDH and 2 EA/TOF). Serial arterial blood gases were taken. Regional cSO(2) was measured using near-infrared spectroscopy. Absorption of insufflated CO(2) was calculated from exhaled (13)CO(2)/(12)CO(2) ratio measured by mass spectrometry. RESULTS: CO(2) absorption increased during thoracoscopy with a maximum 29% +/- 6% of exhaled CO(2) originating from the pneumothorax. Paco(2) increased from 9.4 +/- 1.3 kPa at the start to 12.4 +/- 1.0 intraoperatively and then decreased to 7.6 +/- 1.2 kPa at end of operation. Arterial pH decreased from 7.19 +/- 0.04 at the start to 7.05 +/- 0.04 intraoperatively and then recovered to 7.28 +/- 0.06 at end of operation. Cerebral hemoglobin oxygen saturation decreased from 87% +/- 4% at the start to 75% +/- 5% at end of operation. This had not recovered by 12 (74% +/- 4%) or 24 hours (73% +/- 3%) postoperatively. CONCLUSIONS: This preliminary study suggests that thoracoscopic repair of CDH and EA/TOF may be associated with acidosis and decreased cSO(2). The effects of these phenomena on future brain development are unknown. PMID- 21238639 TI - Long term follow-up in high-risk congenital diaphragmatic hernia survivors: patching the diaphragm affects the outcome. AB - BACKGROUND/PURPOSE: The increased survival rate reached in infants with congenital diaphragmatic hernia (CDH) has shown a concomitant increase in late morbidity. A recent report from CDH Study Group showed that dimension of diaphragmatic defect is the only independent risk factor of mortality. However, the influence of defect size on late morbidity is still controversial. The aim of the study was to evaluate the influence of patch repair (proxy of diaphragmatic defects size) on midterm morbidity. METHODS: All high-risk (prenatal diagnosis and/or respiratory symptoms within 6 hours of life) CDH survivors treated at our institution from 2004 to 2008 were followed up in a multidisciplinary outpatient clinic as part of a longitudinal prospective study. Auxological, gastroesophageal, pulmonary, and orthopedic evaluations were performed at 6, 12, and 24 months of age. Patient outcomes were compared with respect to +/- patch repair. RESULTS: Of 70 survivors, 61 (87%) were enrolled and prospectively evaluated in follow-up. Poorer auxological outcome, increased rate of gastroesophageal reflux, and altered pulmonary function test were observed during follow-up. CONCLUSIONS: Patch repair correlates with higher pulmonary, auxological, and gastroesophageal morbidity without increasing chest wall deformities at long-term follow-up. PMID- 21238640 TI - Preclinical regulatory validation of an engineered diaphragmatic tendon made with amniotic mesenchymal stem cells. AB - PURPOSE: Under a Food and Drug Administration directive, we examined definite long-term safety and efficacy aspects of an engineered diaphragmatic tendon graft as a regulatory prerequisite for clinical trials. METHODS: Newborn lambs (N = 27) underwent partial diaphragmatic replacement with a Teflon patch, a composite acellular bioprosthesis, or the same bioprosthesis seeded with autologous amniotic mesenchymal stem cells processed under Good Manufacturing Practice guidelines. Multiple safety and efficacy analyses were performed at different time points up to 14 months of age (ovine adulthood). RESULTS: There was no mortality. None of the blood tests or full body autopsy specimens showed any abnormality. There was a significantly higher failure rate in animals that received an acellular bioprosthetic graft vs an engineered graft, with no significant differences between Teflon and acellular bioprosthetic implants. Tensile strength and total collagen levels were significantly higher in engineered grafts than in acellular bioprosthetic grafts. On histology, lysozyme and myeloperoxidase stainings were unremarkable in all grafts. CONCLUSIONS: Diaphragmatic repair with a clinically viable autologous tendon engineered with amniotic mesenchymal stem cells leads to improved outcomes when compared with an equivalent acellular bioprosthesis, with no local or systemic adverse effects. Clinical trials of engineered diaphragmatic repair appear practicable within regulatory guidelines. PMID- 21238641 TI - Expression of Iroquois genes is up-regulated during early lung development in the nitrofen-induced pulmonary hypoplasia. AB - BACKGROUND/PURPOSE: Iroquois homeobox (Irx) genes have been implicated in the early lung morphogenesis of vertebrates. Irx1-3 and Irx5 gene expression is seen in fetal lung in rodents up to day (D) 18.5 of gestation. Fetal lung in Irx knockdown mice shows loss of mesenchyme and dilated airspaces, whereas nitrofen induced hypoplastic lung displays thickened mesenchyme and diminished airspaces. We hypothesized that the Irx genes are up-regulated during early lung morphogenesis in the nitrofen-induced hypoplastic lung. METHODS: Pregnant rats were exposed either to olive oil or nitrofen on D9. Fetal lungs harvested on D15 were divided into control and nitrofen groups; and the lungs harvested on D18 were divided into control, nitrofen without congenital diaphragmatic hernia (CDH[ ]), and nitrofen with CDH (CDH[+]). Irx gene expression levels were analyzed by reverse transcriptase polymerase chain reaction. Immunohistochemistry was performed to evaluate protein expression of Irx family. RESULTS: Pulmonary Irx1-3 and Irx5 messenger RNA expression levels were significantly up-regulated in nitrofen group compared with controls at D15. On D15, Irx immunoreactivity was increased in nitrofen-induced hypoplastic lung compared with controls. CONCLUSION: Overexpression of Irx genes in the early lung development may cause pulmonary hypoplasia in the nitrofen CDH model by inducing lung dysmorphogenesis with thickened mesenchyme and diminished airspaces. PMID- 21238642 TI - Serial amnioinfusions prevent fetal pulmonary hypoplasia in a large animal model of oligohydramnios. AB - BACKGROUND/PURPOSE: Severe neonatal pulmonary hypoplasia incurs mortality rates approaching 71% to 95%. We sought to determine the utility of serial amnioinfusions through a subcutaneously implanted intraamniotic catheter to prevent pulmonary hypoplasia in fetal obstructive uropathy. METHODS: Fetal lambs (n = 32) were divided into 3 groups. Group I (n = 12) underwent a sham operation, group II (n = 15) underwent a complete urinary tract obstruction via ligation of the urachus and urethra with a subcutaneous tunneled intraamniotic port-a-cath without amnioinfusions, and group III (n = 5) underwent a creation of a complete urinary tract obstruction with a port-a-cath as described in group II with serial amnioinfusions. Lung tissue was analyzed by lung volume to body weight ratios and stereology. Statistical analysis was performed by analysis of variance and Bonferroni comparisons (P < .05). RESULTS: Obstructed fetuses grossly had smaller lungs than treated and control animals. Lung volume to body weight ratios were statistically significant between groups. Airspace fractions were comparable between groups I and III (average = 0.53 and 0.55, respectively), although both were significantly greater than group II (average = 0.48) (P = .049). CONCLUSIONS: Serial amnioinfusions through an intraamniotic port-a-cath prevented pulmonary hypoplasia in an ovine model of complete obstructive uropathy. The use of an easily accessible device for amnioinfusions may be a viable option to treat oligohydramnios. PMID- 21238643 TI - First reported experience with intramuscular diaphragm pacing in replacing positive pressure mechanical ventilators in children. AB - PURPOSE: Diaphragm pacing (DP) has been shown to successfully replace mechanical ventilators for adult tetraplegic patients with chronic respiratory insufficiency. This is the first report of DP in ventilator-dependent children. METHODS: This was a prospective interventional experience under institutional review board approval. Diaphragm pacing involves outpatient laparoscopic diaphragm motor point mapping to identify the site where stimulation causes maximum diaphragm contraction with implantation of 4 percutaneous intramuscular electrodes. Diaphragm conditioning ensues to wean the child from the ventilator. RESULTS: Six children were successfully implanted ranging from 5 to 17 years old with the smallest 15 kg in weight. Length of time on mechanical ventilation ranged from 11 days to 7.6 years with an average of 3.2 years. In all patients, DP provided tidal volumes above basal needs. Five of the patients underwent a home-based weaning program, whereas one patient who was implanted only 11 days post spinal cord injury never returned to the ventilator with DP use. Another patient was weaned from the ventilator full time but died of complications of his underlying brain stem tumor. The remaining patients weaned from the ventilator for over 14 hours a day and/or are actively conditioning their diaphragms. CONCLUSION: Diaphragm pacing successfully replaced mechanical ventilators, which improves quality of life. PMID- 21238644 TI - Vertical expandable prosthetic titanium rib device insertion: does it improve pulmonary function? AB - PURPOSE: Vertical expandable prosthetic titanium rib (VEPTR) insertion and expansion has been advocated to increase thoracic volume and pulmonary function in patients with thoracic insufficiency syndrome. We reviewed our experience with VEPTR implantation to determine if lung function and growth is augmented, to determine the children's functional status, and if the scoliosis is controlled. METHODS: From 2006 to 2010, 29 insertions and 57 expansions were performed in 26 patients at our institution. Demographic data were reviewed in conjunction with complications, scoliosis angles, pulmonary function tests (PFTs), and computed tomography-guided 3D reconstructions to determine lung volumes; and quality of life scores were determined using a modified Scoliosis Research Society (SRS) questionnaire preoperatively and postoperatively. The groups were also stratified by age (because of lung growth potential), disease (congenital or infantile scoliosis, Jeune syndrome, neuromuscular, other structural thoracic disorders), and sex. Analyses using SPSS (SPSS, Chicago, Ill) were performed with P < .05 considered significant. RESULTS: Each patient underwent 3.03 +/- 1.8 surgeries, spending 0.97 +/- 1.8 days in the intensive care unit and 4.41 +/- 6 days in the hospital for each procedure. Mean age was 90.7 +/- 41 months. Of the 36 complications, most were because of infection (12), half requiring operative repair (hardware removal). The average PFT percent predicted values for forced expiratory volume in 1 second, forced vital capacity, and RV were 54.6 +/- 22, 58.1 +/- 24, and 145.3 +/- 112, respectively, preoperatively and 51.8 +/- 20, 55.9 +/- 20, and 105.6 +/- 31, respectively, postoperatively. The lung volumes measured by computed tomography when corrected for age do not increase significantly postoperatively. The mean Cobb measurement for the preoperative major curves was 64.7 degrees and postoperatively was 46.1 degrees for those curves measured preoperatively, for a 29% curve improvement. All postoperative curves had a mean of 56.4 degrees and 58.1 degrees at final follow-up, a 3% curve increase. The SRS scores for patients remained unchanged and no statistical difference was seen from preoperative to postoperative values. No statistically significant difference was seen in complications, PFT (forced expiratory volume in 1 second, forced vital capacity, RV), lung volumes, scoliosis angles, and SRS scores between sex, age, and disease categories. CONCLUSION: There was mild improvement in scoliosis angles but no improvement in lung function and volume. Scoliosis Research Society scores indicate that the children have near normal function both before and after VEPTR placement. Pulmonary function, lung volume, and patient subjective assessments did not increase dramatically after VEPTR placement, although scoliosis angles improved. PMID- 21238645 TI - Necrotizing enterocolitis is associated with neonatal intestinal injury. AB - PURPOSE: We hypothesized that a subset of premature newborns has subclinical, intestinal mucosal compromise that predisposes to the development of necrotizing enterocolitis (NEC) days or weeks later. METHODS: Fifty-five newborns of 23 to 36 weeks' gestational age were identified, and urine was collected over the first 90 hours of life. The urinary concentration of intestinal fatty acid binding protein (iFABP(u)), a sensitive marker for intestinal injury, was determined. The diagnosis of NEC was based upon clinical condition, pathology, and/or imaging findings. RESULTS: Neonatal iFABP(u) exceeded 800 pg/mL in 27 subjects, including 9 of 9 who subsequently developed stage 2 or 3 NEC. This degree of iFABP(u) elevation, but not asphyxia, was significantly associated with the development of NEC (P < .01). CONCLUSION: In this population of premature newborns, there was a substantial incidence of intestinal mucosal compromise. All infants who subsequently developed stage 2 or 3 NEC had an elevated iFABP(u). This finding suggests a model for the pathogenesis of some cases of NEC, whereby perinatal mucosal injury predisposes to further damage when feedings are initiated. In addition, neonatal iFABP(u) assessment may represent a tool to identify infants at the highest risk for NEC and allow for the institution of focused, preventive measures. PMID- 21238646 TI - Effects of multidisciplinary prenatal care and delivery mode on gastroschisis outcomes. AB - BACKGROUND/PURPOSE: This study examined the effects of multidisciplinary prenatal care and delivery mode on gastroschisis outcomes, with adjustment for key confounding variables. METHODS: This retrospective cohort study included all gastroschisis patients treated at a single tertiary children's hospital between 1999 and 2009. Prenatal care, delivery mode (vaginal vs cesarean section before labor vs after labor), patient characteristics, and clinical outcomes were determined by chart review. Time to discontinuation of parenteral nutrition (PN) was the primary outcome of interest. Effects of multidisciplinary prenatal care and delivery mode were evaluated using Cox proportional hazards regression models that included gestational age, birth weight, sex, concomitant intestinal complications, and year of admission. RESULTS: Of 167 patients included, 46% were delivered vaginally, 69% received multidisciplinary prenatal care, and median time to PN discontinuation was 38 days. On multivariable modeling, gestational age, uncomplicated gastroschisis, and year of admission were significant predictors of early PN independence. Delivery mode and prenatal care had no independent effect on outcomes, although patients receiving multidisciplinary prenatal care were more likely to be born at term (49% vs 27%, P = .01). CONCLUSIONS: Gestational age and intestinal complications are the major determinants of outcome in gastroschisis. Multidisciplinary prenatal care may facilitate term delivery. PMID- 21238647 TI - Conditional mutation of fibroblast growth factor receptors 1 and 2 results in an omphalocele in mice associated with disruptions in ventral body wall muscle formation. AB - BACKGROUND/PURPOSE: We observed that fibroblast growth factor receptors 1 and 2 (Fgfr1, Fgfr2) are expressed during abdominal wall development in mice and hypothesized that conditional mutation of these genes would result in abdominal wall defects. METHODS: Section in situ hybridizations were performed for Fgfr1 and Fgfr2 on wild-type embryos at embryonic day (E) 11.5 and E13.5. Conditional mutation of Fgfr1and Fgfr2 was achieved with a tamoxifen inducible Cre at E8.5. Litters were harvested at E17.5, whole mount photographs were taken, and paraffin sections were generated and stained with hematoxylin and eosin. RESULTS: Fgfr1 was expressed in ectoderm, lateral plate mesoderm, and myoblasts, whereas Fgfr2 was expressed almost exclusively in the early dermis and ectoderm of the abdominal wall. Conditional mutation of both Fgfr2 alleles and one Fgfr1 allele resulted in omphalocele in 38.7% of mutants. Histologic examination in mutants demonstrated disruptions in dermal and muscle development. CONCLUSIONS: Mutant embryos with omphalocele arising from mutation in Fgfr1 and Fgfr2 exhibit disruptions in the development of the secondary abdominal wall structures. These findings are consistent with a model of ventral abdominal wall development in which organization of the muscles and connective tissue (secondary abdominal wall structures) is influenced by positional information emanating from the primary abdominal wall. PMID- 21238648 TI - Local control, survival, and operative morbidity and mortality after re resection, and intraoperative radiation therapy for recurrent or persistent primary high-risk neuroblastoma. AB - BACKGROUND/PURPOSE: Patients with locally recurrent or persistent high-risk neuroblastoma are difficult to treat. We describe our experience using intraoperative radiation therapy (IORT) after re-resection in this high-risk population. METHODS: We retrospectively reviewed 44 consecutive patients who received IORT at our institution between April 2000 and September 2009 after gross total resection of recurrent/persistent tumor. Specifically, we evaluated local recurrence rates, complications, and overall survival. RESULTS: The median age at diagnosis was 41.5 months. Median follow-up after IORT was 10.5 months. Each patient received prior chemotherapy and surgery, while 94.5% had previous external beam radiation therapy. MYCN was amplified in 34% of patients. There were no operative or postoperative deaths, and 18 patients (40.9%) had postoperative complications. There was a 50.4% probability of local control. MYCN amplification did not affect local control (local recurrence rate of 53.9% vs 52.4%, P = .89). Median overall survival was 18.7 months (95% confidence interval, 11.7-25.6 months). Mean survival for MYCN-amplified patients was 13.0 vs 39.2 months for those without MYCN amplification (P = .035). CONCLUSIONS: Intraoperative radiation therapy after re-resection of locally recurrent/persistent neuroblastoma results in a reasonable rate of local control with acceptable morbidity and survival. This approach should be considered in this high-risk population. PMID- 21238649 TI - Resectability and operative morbidity after chemotherapy in neuroblastoma patients with encasement of major visceral arteries. AB - BACKGROUND/PURPOSE: Image-defined vessel encasement is a significant risk factor for surgical complications and incomplete resection for intermediate-risk tumors. We sought to examine the impact of vessel encasement on complications or resectability in intermediate-risk or high-risk patients after neoadjuvant chemotherapy. METHODS: We retrospectively reviewed 207 consecutive patients with circumferential encasement of the renal vessels, celiac axis, and/or superior mesenteric artery (SMA) who underwent resection between 1991 and 2009. Specifically, we evaluated resection rates, complications, and outcome. RESULTS: Median age at diagnosis was 3.0 years, and 79% of patients had stage 4 disease. Of known MYCN status, 23.4% had MYCN amplification. Vessel encasement included renal vessels, celiac axis, or SMA alone in 107, 7, and 4 patients, respectively. Both the renal vessels and celiac axis were encased in 5 patients, renal vessels and SMA in 7 patients, and celiac axis and SMA in 14 patients. Sixty-three patients had all 3 vessels encased. The gross total resection (GTR) rate was 94%. No operative or postoperative deaths occurred. The overall complication rate was 34.8% (n = 72). Overall 5-year survival (+/- SEM) was 67.4% (+/- 7.4%). CONCLUSION: Encasement of major visceral arteries in patients with neuroblastoma who have received chemotherapy does not preclude gross total resection. PMID- 21238650 TI - Selective inhibition of cyclooxygenase-2 suppresses metastatic disease without affecting primary tumor growth in a murine model of Ewing sarcoma. AB - BACKGROUND/PURPOSE: Mammalian target of rapamycin suppression by rapamycin inhibits tumor growth and neovascularization via cyclooxygenase-2 (COX-2) downregulation with no effect on lung metastases. We hypothesize that combining a selective COX-2 antagonist (celecoxib) with rapamycin would decrease lung metastases. METHODS: Ewing sarcoma cells (SK-NEP-1) were surgically implanted into the left kidney of athymic mice (n = 40). The mice were divided into 4 treatment groups (control, rapamycin only, celecoxib only, and combination) and then killed at 6 weeks. Primary tumors were weighed. Vasculature was examined using lectin angiography and immunohistochemistry, and lung metastases were examined using H&E and CD99 immunostaining. Tumor weight and lung metastases were analyzed. RESULTS: Mean primary tumor weights were significantly reduced in the rapamycin-treated groups but not in the celecoxib-only group. Lectin angiography and endothelial markers immunostaining showed markedly decreased vascularity in the rapamycin-treated groups but not in the celecoxib-only group. Celecoxib treated groups showed significantly fewer mice with lung metastases than non celecoxib-treated groups. CONCLUSION: Celecoxib prevents lung metastasis in a murine model of Ewing sarcoma with no effect on tumor size or neovascularization. Cyclooxygenase-2 may represent a future potential target for metastatic disease prevention. PMID- 21238651 TI - Pediatric American College of Surgeons National Surgical Quality Improvement Program: feasibility of a novel, prospective assessment of surgical outcomes. AB - PURPOSE: The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) provides validated assessment of surgical outcomes. This study reports initiation of an ACS NSQIP Pediatric at 4 children's hospitals. METHODS: From October 2008 to June 2009, 121 data variables were prospectively collected for 3315 patients, including 30-day outcomes and tailoring the ACS NSQIP methodology to children's surgical specialties. RESULTS: Three hundred seven postoperative complications/occurrences were detected in 231 patients representing 7.0% of the study population. Of the patients with complications, 175 (75.7%) had 1, 39 (16.9%) had 2, and 17 (7.4%) had 3 or more complications. There were 13 deaths (0.39%) and 14 intraoperative occurrences (0.42%) detected. The most common complications were infection, 105 (34%) (SSI, 54; sepsis, 31; pneumonia, 13; urinary tract infection, 7); airway/respiratory events, 27 (9%); wound disruption, 18 (6%); neurologic events, 8 (3%) (nerve injury, 4; stroke/vascular event, 2; hemorrhage, 2); deep vein thrombosis, 3 (<1%); renal failure, 3 (<1%); and cardiac events, 3 (<1%). Current sampling captures 17.5% of cases across institutions with unadjusted complication rates ranging from 6.8% to 10.2%. Completeness of data collection for all variables exceeded 95% with 98% interrater reliability and 87% of patients having full 30 day follow-up. CONCLUSION: These data represent the first multiinstitutional prospective assessment of specialty-specific surgical outcomes in children. The ACS NSQIP Pediatric is poised for institutional expansion and future development of risk-adjusted models. PMID- 21238652 TI - Surgical intervention in the setting of parenteral nutrition-associated cholestasis may exacerbate liver injury. AB - PURPOSE: This study compares postoperative markers of liver injury in patients receiving intravenous fish oil (IFO) with parenteral nutrition (PN)-associated cholestasis (PNAC) to patients with resolved PNAC. METHODS: A retrospective review of all cholestatic-IFO patients undergoing abdominal laparotomy between March 1, 2007, and July 1, 2009, led to inclusion of 23 patients who collectively underwent 27 abdominal operations (13 pre-PNAC resolution and 14 post-PNAC resolution). Direct bilirubin (DB), total bilirubin, and alanine aminotransferase levels were examined over time in relation to operations. The time to resume presurgical trend of decreasing DB was calculated. RESULTS: Sixty-nine percent (9/13) of pre-PNAC resolution procedures were associated with postoperative increase in DB compared with 7% (1/14) of post-PNAC resolution procedures associated with a recurrence of cholestasis (P = .02; odds ratio, 29.3; 95% confidence interval, 2.79-306.8). The median time to return to the preoperative downward trend of DB was 21 days. CONCLUSIONS: Operations before PNAC resolution may be associated with an increased postoperative DB, possibly reflecting an exacerbation of liver injury. Operations post-PNAC resolution on IFO had a comparatively low incidence of postoperative cholestasis recurrence. Excepting clinical indication otherwise, it may be advisable to delay surgical intervention in the setting of PNAC in certain cases. PMID- 21238653 TI - Experience performing 64 consecutive stapled intestinal anastomoses in small children and infants. AB - BACKGROUND/PURPOSE: Intestinal anastomosis in children has traditionally been performed using hand-sewn techniques. Little data exist evaluating the efficacy of stapled intestinal anastomoses in the infant and pediatric populations. METHODS: A review of a 5-year experience using a mechanical stapler to treat 64 consecutive children requiring intestinal anastomoses was performed. An intestinal stapler was used to complete a side-to-side functional end-to-end anastomosis. Postoperative outcomes and modifications made to the technique were identified. RESULTS: Since 2004, 64 children (median age, 3 months; range, newborn to 24 months) underwent procedures requiring intestinal anastomosis. Twenty-six children (41%) were 1 week or less in age. Twenty-seven children (42%) underwent a stoma closure using a stapler. Thirty-seven children (58%) underwent bowel resection and stapled anastomosis in treating a variety of surgical disorders. Complications included wound infection (n = 2) and anastomotic stricture (n = 1). No issues suggesting anastomotic dilatation and subsequent stasis/overgrowth were identified. CONCLUSIONS: These results suggest that stapled bowel anastomosis is an effective approach applicable to a variety of surgical diseases in newborns and infants. PMID- 21238654 TI - Results of a longitudinal study of rigorous manuscript submission guidelines designed to improve the quality of clinical research reporting in a peer-reviewed surgical journal. AB - BACKGROUND/PURPOSE: In an effort to improve the reporting quality of clinical research, the Journal of Pediatric Surgery instituted specific reporting guidelines for authors beginning June 2006. This study was conducted to evaluate whether these guidelines improved reporting of observational studies. METHODS: The Guidelines for the Reporting of Clinical Research Data (Guidelines) included 23 criteria in 3 subcategories: Methods, Results, and More than one treatment group. Reporting quality was evaluated by determining the percentage of criteria met. Seventy-three articles before implementation and 147 articles after implementation were independently assessed by 2 reviewers. RESULTS: Mean global composite scores increased from 72.2 pre-Guidelines to 80.1 post-Guidelines (P < .0001). Scores increased in each subcategory: Methods, 71.9 to 78.6 (P < .0001); Results, 77.2 to 83.0 (P = .002); and More than one treatment group, 40.0 to 70.6 (P = .0003). Post-Guidelines implementation scores have increased over time. CONCLUSIONS: The introduction of the Guidelines resulted in significant improvement in the quality of reporting in the Journal. The low cost vs the benefit suggests that the Guidelines can be an effective way to improve reporting quality in nonrandomized studies. We encourage further efforts to increase inclusion of reporting criteria as well as evaluation and improvement of the Guidelines. We suggest that editors of other surgical publications consider implementing analogous guidelines. PMID- 21238655 TI - Toward effective pediatric minimally invasive surgical simulation. AB - BACKGROUND/PURPOSE: Simulation is increasingly being recognized as an important tool in the training and evaluation of surgeons. Currently, there is no simulator that is specific to pediatric minimally invasive surgery (MIS). A fundamental technical difference between adult and pediatric MIS is the degree of motion scaling. Smaller instruments and areas of dissection under greater optical magnification require finer, more precise hand movements. We hypothesized that this can be used to detect differences in skills proficiency between pediatric and general surgeons. METHODS: We programmed a virtual reality simulation of intracorporeal suturing with modes that used motion scaling to mimic conditions of either adult or pediatric MIS. The participants consisted of pediatric and general surgeons who wore motion-sensing gloves. Metrics included time elapsed, penetration errors, tool movement smoothness, hand movement smoothness, and gesture level proficiency. RESULTS: For all measures, pediatric surgeons demonstrated superior proficiency on exercises conducted in pediatric conditions (P < .05). Performance in adult conditions was similar between the 2 groups. CONCLUSION: Pediatric surgeons possess unique skills compared with general surgeons that relate to the technical challenges they routinely face, reinforcing the need for a surgical simulator specific to pediatric MIS. This validates our simulator and the manipulation of motion scaling as a useful training tool. PMID- 21238656 TI - Redilation of bowel after intestinal lengthening procedures--an indicator for poor outcome. AB - BACKGROUND/PURPOSE: Despite a good understanding of short-term outcomes of the longitudinal intestinal lengthening and tailoring (LILT) and serial transverse enteroplasty (STEP) procedures, limited data exist on long-term complications. METHODS: This is a 15-year single-institution retrospective chart review of patients who underwent an intestinal lengthening procedure (ILP). Long-term ILP related complications, their interval to development, patients' ability to wean off parenteral nutrition (PN), and the need for further procedures were analyzed. RESULTS: Of 119 patients with short bowel syndrome, 14 had undergone an ILP. Seven patients had an LILT, and 9 patients had a STEP, including repeat ILPs on the same patient. Overall, 93% of patients had complications. Four patients in the LILT group and 3 patients in the STEP group weaned off PN. Eight patients (57%) experienced bowel redilation after their ILP. The 2 deaths in the study came from this group. Seven required another abdominal operation and only one weaned off PN. There were no significant differences in mean bowel length between the redilated group and the non-re-dilated group. CONCLUSIONS: Complications are common after ILPs, and patients who redilated their bowel after ILP did clinically worse than those who did not. PMID- 21238657 TI - Elements of successful intestinal rehabilitation. AB - PURPOSE: The optimal therapy for intestinal failure (IF) is unknown. The results of a systematic, protocol-driven management strategy by a multidisciplinary team are described. METHODS: Intestinal failure was defined as bowel length of less than 40 cm or parenteral nutrition (PN) for more than 42 days. A multidisciplinary team and protocol to prevent PN-associated liver disease (PNALD) were instituted in 2006. Data were gathered prospectively with consent and ethics board approval. RESULTS: From 1998 to 2006, 33 patients were treated (historical cohort) with an overall survival of 72%. Rotating prophylactic antibiotics for bacterial overgrowth were given to 27% of patients; 6% had lipid sparing PN, and none received fish oil-based lipids. Median time to intestinal rehabilitation was 7 +/- 3.1 months, and 27% of patients who developed PNALD died. From 2006 to 2009, 31 patients were treated. Seventy-seven percent received PAB; 60%, lipid-sparing PN; and 47%, parenteral fish oil emulsion. Eighty-seven percent weaned from PN at 3.9 +/- 3.8 months, and no patients developed PNALD with 100% survival. Novel lipid therapies were associated with changes in essential fatty acid profile and one case of clinical essential fatty acid deficiency. CONCLUSION: The institution of a multidisciplinary team and a protocol-driven strategy to prevent PNALD improves survival in IF. Further studies are recommended. PMID- 21238658 TI - Laparoscopic adjustable gastric banding in adolescents: short-term results. AB - PURPOSE: Children and adolescents who fail to lose weight through diet and exercise programs have been offered weight loss surgery for several years. We report our early results on laparoscopic adjustable gastric banding (LAGB) in 100 teenagers. METHODS: Candidates for surgery underwent rigorous assessment for medical eligibility, compliance, and psychological well-being. Patients who met criteria and were approved by our team were offered LAGB. Postoperatively, patients were followed monthly until steady weight loss was achieved, then every 3 months thereafter. RESULTS: One hundred patients aged 14 to 19 years underwent LAGB. Preoperative average weight was 136.7 kg, and median body mass index was 48.7. Comorbid medical conditions were common. Five reoperations were performed for port site bleeding, hiatal hernia repair, possible intestinal obstruction, and port slippage. Eighty-seven patients were followed for a minimum of 6 months. Average weight loss at 6 months was 12.4 (range, 33.2 to 16.2) kg, and average change in body mass index was 4.4 (range, 11.8 to -5.6). CONCLUSION: Laparoscopic adjustable gastric banding may be performed safely in adolescents, and short-term results suggest that LAGB may serve as an important tool to help them lose weight. PMID- 21238660 TI - The significance of first rib fractures in children. AB - PURPOSE: The purpose of the study was to determine if first rib fractures are associated with an increased incidence of thoracic vascular injury in pediatric patients. METHODS: The medical records of all children diagnosed with a first rib fracture or a central vascular injury after blunt trauma treated at a state designated level 1 pediatric trauma center from 2000 to 2009 were reviewed. RESULTS: Thirty-three children (0.27% of patients; mean age, 10.9 +/- 0.9 years) were identified with either a first rib fracture or thoracic vascular injury owing to blunt trauma. Thirty-two children had a first rib fracture, and only 1 child (3%) had significant thoracic vascular injury. Mediastinal abnormalities (indistinct aortic knob) were identified in 3 children, 2 with first rib fracture on initial chest radiograph. Despite a normal cardiovascular examination result, 25 (74%) children with a normal mediastinum on screening chest radiograph underwent computed tomography. No child with a normal mediastinum on initial chest radiograph was found to have associated intrathoracic injuries requiring further intervention. In children with first rib fractures and a normal mediastinum by screening chest x-ray, the negative predictive value for thoracic vascular injury was 100%. CONCLUSIONS: Children with first rib fractures without mediastinal abnormality on chest radiograph require no further workup for thoracic vascular injury. PMID- 21238659 TI - Minimal vs extensive esophageal mobilization during laparoscopic fundoplication: a prospective randomized trial. AB - PURPOSE: Laparoscopic Nissen fundoplication has been traditionally performed with extensive esophageal dissection to create 2 to 3 cm of intraabdominal esophagus. Retrospective data have suggested that minimal esophageal mobilization may reduce the risk of postoperative herniation of the wrap into the lower mediastinum. To compare complete esophageal dissection to leaving the phrenoesophageal attachment intact, we conducted a 2-center, prospective, randomized trial. METHODS: After obtaining permission/assent, patients were randomized to circumferential division of the phrenoesophageal attachments (MAX) or minimal mobilization with no violation of the phrenoesophageal membrane (MIN). A contrast study was performed at 1 year. The primary outcome variable was postoperative wrap herniation. RESULTS: One hundred seventy-seven patients were enrolled in the study (MIN, n = 90; MAX, n = 87) from February 2006 to May 2008. There were no differences in demographics or operative time. Contrast studies were performed in 64 MIN and 71 MAX patients, respectively. The transmigration rate was 30% in the MAX group compared with 7.8% in the MIN group (P = .002). The reoperation rate was 18.4% in the MAX group and 3.3% in the MIN group (P = .006) CONCLUSIONS: Minimal esophageal mobilization during laparoscopic fundoplication decreases postoperative wrap transmigration and the need for a redo operation. PMID- 21238661 TI - Prospective validation of an abbreviated bedrest protocol in the management of blunt spleen and liver injury in children. AB - PURPOSE: The aim of this study was to validate the safety, and quantify the impact of, an abbreviated protocol for blunt spleen/liver injury (BSLI), we instituted a prospective study with early ambulation. METHODS: Following institutional review board approval, data were collected prospectively in all patients with BSLI up to 8 weeks after discharge. There were no exclusion criteria, and patient accrual was consecutive. Bedrest was restricted to 1 night for grade I and II injuries and 2 nights for grade III or higher. RESULTS: A total of 131 patients with BSLI were enrolled. Injuries included isolated spleen in 72 (55%), liver only in 55 (42%), and both in 4 (3%). One splenectomy was required for a grade 5 injury. Transfusions were used in 24 patients, with 18 patients undergoing transfusion because of injured solid organ. Bedrest was applicable to 110 patients (84%), for which the mean grade of injury was 2.6 and mean bedrest was 1.6 days. The need for bedrest was the limiting factor for length of stay in 86 patients (66%). There were 2 deaths, and no patients were readmitted. CONCLUSIONS: An abbreviated protocol of 1 night of bedrest for grade I and II injuries and 2 nights for grade III or higher can be safely used, resulting in dramatic decreases in hospitalization compared with the current American Pediatric Surgical Association recommendations. PMID- 21238662 TI - Partial splenectomy for hereditary spherocytosis: a multi-institutional review. AB - BACKGROUND/PURPOSE: Partial splenectomy has emerged as a surgical option for selected children with hereditary spherocytosis, with the goal of reducing anemia while preserving splenic function. This multi-institutional study is the largest series to date examining outcomes data for partial splenectomy in patients with hereditary spherocytosis. METHODS: Data were collected retrospectively from 5 North American pediatric hospitals. Sixty-two children underwent partial splenectomy for hereditary spherocytosis between 1990 and 2008. RESULTS: At 1 year following partial splenectomy, mean hemoglobin significantly increased by 3.0 +/- 1.4 g/dL (n = 52), reticulocyte count decreased by 6.6% +/- 6.6% (n = 41), and bilirubin level decreased by 1.3 +/- 0.9 mg/dL (n = 25). Patients with poor or transient hematologic response were found to have significantly more splenic regeneration postoperatively compared with patients with a durable clinical response (maximal spleen dimension, 9.0 +/- 3.4 vs 6.3 +/- 2.2 cm). Clinically significant recurrence of anemia or abdominal pain led to completion splenectomy in 4.84% of patients. No patients developed postsplenectomy sepsis. CONCLUSIONS: Our multi-institutional review indicates that partial splenectomy for hereditary spherocytosis leads to sustained and clinically significant improvement in hematologic profiles and clinical symptoms in most patients. Our data support partial splenectomy as an alternative for selected children with hereditary spherocytosis. PMID- 21238663 TI - Intrasphincteric botulinum toxin decreases the rate of hospitalization for postoperative obstructive symptoms in children with Hirschsprung disease. AB - BACKGROUND: Although most children with Hirschsprung disease do well after pull through surgery, some continue to have persistent obstructive symptoms. The purpose of this study was to evaluate the effect of intrasphincteric botulinum toxin in the management of these children. METHODS: A retrospective review of patients with Hirschsprung disease treated over 10 years was performed. RESULTS: Twenty-two patients who had previously undergone pull-through surgery received a median number of 2 botulinum toxin injections (range, 1-23). The number of hospitalizations for obstructive symptoms significantly decreased from preinjection (median, 1.5; interquartile range [IQR], 1-3) to postinjection (median, 0; IQR, 0-1) (P = .0003). The number of injections was lower in children with a rectosigmoid transition zone (median, 1 injection; IQR, 1-3.5) than in those with long-segment disease (median, 3 injections; IQR, 1-15) (P = .04). Eighty percent of patients had a good response to the first dose of botulinum toxin, and 69% of them required additional injections. There were no short-term or long-term complications related to botulinum toxin. CONCLUSIONS: Intrasphincteric botulinum toxin significantly decreased the need for obstruction related hospitalization in children who had undergone pull-through surgery for Hirschsprung disease. Botulinum toxin should be strongly considered in the management algorithm for postoperative obstructive symptoms in children with Hirschsprung disease. PMID- 21238664 TI - Glowing in the dark: time of day as a determinant of radiographic imaging in the evaluation of abdominal pain in children. AB - BACKGROUND/PURPOSE: Although ultrasound is often the preferred pediatric imaging study, many institutions lack ultrasound access at night; and computerized tomography (CT) becomes the only radiological method available for evaluation of appendicitis in children. The purpose of this study was to characterize patterns of daytime and nighttime use of ultrasound or CT for evaluation of pediatric appendicitis and to measure consequent differences in radiation exposure and cost. METHODS: A retrospective chart review of patients evaluated for appendicitis from October 2004 to October 2009 (N = 535) was performed to evaluate daytime and nighttime use of ultrasound and CT for pediatric patients. RESULTS: Average age was 10.2 years (range, 3-17 years). During the day, 6 times as many ultrasounds were performed as CTs (230 vs 35). At night, half as many ultrasounds were performed (50 vs 110). Average radiation dose per child during the day was significantly lower than at night (day, 0.52 mSv per patient; night, 2.75 mSv per patient). Average radiology costs were lower for daytime patients ($2491.06 day vs $4045.00 night; P < .05). CONCLUSIONS: Dependence on CT at night results in higher average radiation exposure and cost. Twenty-four-hour ultrasound availability would decrease radiation exposure and cost of evaluation of children presenting with appendicitis. PMID- 21238665 TI - An evidence-based clinical protocol for diagnosis of acute appendicitis decreased the use of computed tomography in children. AB - PURPOSE: The increased use of computed tomography (CT) to diagnose appendicitis in children has led to a concern for the possibility of increased CT-related cancer morbidity. We designed a clinical protocol for the diagnosis and treatment of appendicitis in children in an attempt to decrease the use of CT scans at our institution. METHODS: Patients who had surgical consultation for suspected appendicitis were placed on the clinical protocol. Data concerning diagnosis and treatment were collected prospectively. Retrospective data from patients admitted to our institution with acute appendicitis before the clinical protocol were collected as historical controls. RESULTS: One hundred twelve patients were diagnosed and treated by our protocol between June and November 2009. Of these, 100 patients underwent an appendectomy for acute appendicitis. They were compared with 146 patients from 2007. In-house CT use decreased from 71.2% to 51.7% (P = .01). Preoperative ultrasound use increased from 2.7% to 21% (P < .001). The negative appendectomy rate increased (6.8% vs 11%, P = .25). CONCLUSIONS: Our findings suggest that the implementation of an evidence-based clinical protocol for the diagnosis and treatment of acute appendicitis in children may safely decrease the use of CT scans and increase the use of ultrasound. PMID- 21238666 TI - Do patients with Down syndrome develop appendicitis? AB - BACKGROUND/PURPOSE: Given the number of individuals with Down syndrome (DS) and the high incidence of acute appendicitis (AA) in the general population, one would expect a certain number of patients with DS to develop AA. However, clinical experience suggests that AA is uncommon in patients with DS. This study was undertaken to determine whether the incidence of AA is significantly decreased in patients with DS. METHODS: A 13-year cross-sectional study of the state's hospital discharge database was performed to estimate the annual incidence of AA in patients with DS and in the general population. Estimates were generated for both pediatric (0-17 years) and adult (>= 18 years) populations and were compared using 95% confidence intervals (CIs). In addition, the authors' hospital database was queried over a 10-year time frame. RESULTS: Incidence estimates of AA in children with DS and in the general pediatric population were 2.5 and 8.9 per 1000, respectively. In adults, the incidence estimates were 2.7 and 5.7 per 1000. CONCLUSIONS: The incidence of AA is markedly lower in patients with DS than in the general population. Although the biological basis for this remains unknown, this information is relevant in the evaluation of the acute abdomen in patients with DS. PMID- 21238667 TI - Restorative proctocolectomy with and without protective ileostomy in a pediatric population. AB - PURPOSE: This study aim was to review outcomes of pediatric patients after restorative proctocolectomy with or without a protective ileostomy in the treatment of ulcerative colitis and polyposis syndromes. METHODS: All patients who underwent rectal mucosectomy with ileal pouch reservoir and hand-sewn ileal pouch anal anastomosis (IPAA) during 19-year period were reviewed retrospectively. RESULTS: Eighty-three patients with ulcerative colitis and 7 patients with polyposis syndromes (ages 2.0-21.8 years) were reviewed. Sixty eight patients underwent IPAA without diverting ileostomy. Fifty-six patients underwent restorative proctocolectomy as single-stage procedures, and 12 had abdominal colectomy and subsequent definitive IPAA without diverting ileostomy. Nineteen patients had IPAA with diverting ileostomy and subsequent closure of ileostomy. Three-stage procedures were performed in 3 cases. An ileal pouch leak or pelvic abscess occurred in 2 patients. Surgical pouch revision for retraction, efferent limb syndrome, prolapse, pouchitis, or perirectal infections occurred in 19 (6/62 J-pouch, 13/28 S-pouch). Fourteen patients (5/22 with diversion, 9/68 without diversion) developed small bowel obstruction. Overall, daytime and nighttime continence was excellent with rare nocturnal evacuations. CONCLUSIONS: Restorative proctocolectomy without protective ileostomy is not associated with an increased morbidity, even in patients with active colitis, and may be appropriate most patients. PMID- 21238668 TI - The predictive value of preoperative fluorine-18-L-3,4-dihydroxyphenylalanine positron emission tomography-computed tomography scans in children with congenital hyperinsulinism of infancy. AB - BACKGROUND/PURPOSE: In congenital hyperinsulinism (CHI) of infancy, the use of preoperative fluorine-18-L-3,4-dihydroxyphenylalanine-positron emission tomography-computed tomography ((18)F-DOPA-PET-CT) scan has recently been reported. The aim of this study was to evaluate the accuracy of this technique in discriminating between diffuse and focal CHI and the anatomical localization of focal lesions. METHODS: Between 2006 and 2010, (18)F-DOPA-PET scan was performed in 19 children with CHI (median age, 2 months; range, 1-12 months) who were not responding to medical therapy and underwent laparoscopic or open surgery. The findings of (18)F-DOPA-PET scan were correlated with histology. RESULTS: In 5 children, (18)F-DOPA-PET scan showed diffuse pancreatic uptake, confirmed at histology and supporting the genetic suspicion of diffuse disease. In 14 children, (18)F-DOPA-PET scan indicated focal pancreatic uptake, which corresponded to histology. However, in 5 patients (36%), (18)F-DOPA-PET scan was inaccurate in defining the location of the lesion (n = 3), size of the lesion (n = 1), or both location and size (n = 1), leading to an inaccurate pancreatic resection. CONCLUSIONS: Fluorine-18-L-3,4-dihydroxyphenylalanine-positron emission tomography-computed tomography scan discriminates between diffuse and focal forms of CHI. In focal forms, (18)F-DOPA-PET scan is useful in 2/3 of patients in defining the site and dimension of the focal lesion. Intraoperative histologic confirmation of complete focal lesion resection is needed. PMID- 21238669 TI - Hepaticoduodenostomy vs hepaticojejunostomy for reconstruction after resection of choledochal cyst. AB - PURPOSE: Roux-en-Y hepaticojejunostomy (HJ) is currently the favored reconstructive procedure after resection of choledochal cysts. Hepaticoduodenostomy (HD) has been argued to be more physiologically and technically easier but is feared to have associated complications. Here we compare outcomes of the 2 procedures. METHODS: A retrospective chart review identified 59 patients who underwent choledochal cyst resection within our institution from 1999 to 2009. Demographic and outcome data were compared using t tests, Mann-Whitney U tests, and Pearson chi(2) tests. RESULTS: Fifty-nine patients underwent repair of choledochal cyst. Biliary continuity was restored by HD in 39 (66%) and by HJ in 20 (34%). Open HD patients required less total operative time than HJ patients (3.9 vs 5.1 hours, P = .013), tolerated a diet faster (4.8 days compared with 6.1 days, P = .08), and had a shorter hospital stay (7.05 days for HD vs 9.05 days for HJ, P = .12). Complications were more common in HJ (HD = 7.6%, HJ = 20%, P = .21). Three patients required reoperation after HJ, but only one patient required reoperation after HD for a stricture (HD = 2.5%, HJ = 20%, P = .037). CONCLUSIONS: In this series, HD required less operative time, allowed faster recovery of bowel function, and produced fewer complications requiring reoperation. PMID- 21238670 TI - Extrahepatic portal vein thrombosis after umbilical catheterization: is it a good choice for Rex shunt? AB - BACKGROUND: Extrahepatic portal vein thrombosis (EHPVT) is an important cause of portal hypertension in children. Rex shunt has been used successfully to treat these patients. METHODS: We report our experience in 19 infants and children (5 months to 14 years) with HPVT eligible for a mesenteric-portal surgical shunt with left internal jugular vein autograft. Eight children had idiopathic EHPVT, nine had post-umbilical catheterization EHPVT, one had portal vein agenesis, and one had posttransplant EHPVT. RESULTS: It was possible to perform the Rex shunt in all patients except for 8 of 9 cases in the post-umbilical catheterization EHPVT group. A Warren procedure was performed in 4 of those patients and a proximal splenorenal shunt in 1. Current follow-up ranges from 3 to 26 months. Shunt thrombosis occurred in one patient with portal vein agenesis and associated cardiac anomaly. Portal hypertension has significantly improved after surgery. None of our patients have experienced new bleeding episodes until now. CONCLUSIONS: The Rex shunt should be considered in the treatment of children with idiopathic EHPVT experiencing repeated gastrointestinal bleeding episodes refractory to endoscopic treatment. Nevertheless, the role of this operation for children with post-umbilical catheterization EHPVT is yet to be clearly evaluated. PMID- 21238671 TI - A critical review of premature infants with inguinal hernias: optimal timing of repair, incarceration risk, and postoperative apnea. AB - BACKGROUND/PURPOSE: This study evaluated the optimal timing for repair, incarceration risk, and postoperative apnea rate in premature infants with inguinal hernias. METHODS: This was a retrospective review of premature infants undergoing inguinal hernia repairs from 2006 to 2008. RESULTS: One hundred seventy-two patients were identified. Mean gestational age was 30.7 weeks, and mean birth weight was 1428 g. At repair, mean postconceptional age was 46.6 weeks with mean weight of 3688 g. Elective repairs were performed on 127 patients. Thirty-five patients were discharged with a known hernia, and none developed incarceration. No postoperative apnea episodes occurred in any of these 127 patients. Forty-five patients had herniorrhaphy before discharge from the neonatal intensive care unit (NICU) with a median postoperative hospitalization of 8 days (2-51 days). Thirteen percent required prolonged (>48 hours) intubation after repair. Of 172 patients, 8 (4.6%) developed incarcerated hernia. Five incarcerations occurred in the NICU before discharge, and 3 patients had incarceration as their initial presentation. CONCLUSIONS: There is minimal risk of postoperative apnea for premature infants undergoing elective inguinal hernia repair. The risk of incarceration in premature infants discharged from the NICU with a known hernia is low. Herniorrhaphy before discharge from the NICU was associated with a prolonged hospital stay. PMID- 21238672 TI - Outcomes research in pediatric surgery. Part 1: overview and resources. AB - Outcomes research in pediatric surgery can be defined as the analysis of pediatric surgical outcomes and their predictors at different levels in the health care delivery system. The objectives of this article are to understand the differences between outcomes research and clinical trials as well as to gain familiarity with public multispecialty and specialty-specific databases. The utility of outcomes research extends to benchmarking the quality of care, refinement of management strategies, patient education, and marketing. Assessment of the integration of a new surgical technique into the health care system is best determined by examining a population-based registry, whereas comparative efficacy of surgical procedures is best assessed by randomized clinical trials. In the first part of this 2-part series, an overview and brief outline of available resources for outcomes research in pediatric surgery are reviewed. In part 2, a template is presented on how to structure and design an outcomes research question. PMID- 21238673 TI - Outcomes research in pediatric surgery. Part 2: how to structure a research question. AB - Innovative treatments and procedures are essential to the advancement of surgery. Outcomes research provides the mechanism to analyze these new treatments as they enter clinical practice and evaluate them against established therapies. Information gained through this methodology is essential because new techniques and innovations often gain rapid acceptance before clinical trials can be conducted to assess them. Increasing national emphasis is placed on comparative effectiveness as health care costs rise. Surgeons must take the lead in surgical outcomes and comparative effectiveness research, with the goal of identifying the most efficient and effective treatment for our patients. The authors show how to structure and design a research project involving pediatric surgical outcomes. The model consists of the following 3 phases: (1) study design, (2) data preparation, and (3) data analysis. The model we present provides the reader with a basic format and research structure to serve as a guide to performing high quality surgical outcomes research. PMID- 21238675 TI - Stump appendicitis in children. AB - Stump appendicitis is a delayed complication of incomplete appendectomy. Reinflammation of possible residual appendiceal tissue should be considered in patients with right lower quadrant pain and a surgical history of appendectomy. In this report, we present 3 cases of stump appendicitis in children. PMID- 21238676 TI - Preliminary resuscitation for perforated necrotizing enterocolitis: 2 cases treated with initial direct peritoneal resuscitation. AB - We used peritoneal infusions of 2.5% dextrose solution as an adjunct to resuscitation of 2 very low-birth-weight infants having perforated necrotizing enterocolitis. This was repeated every 12 hours for 7 days before and 1 day after extensive bowel resection. The designation of this research method has been termed direct peritoneal resuscitation. We discuss our observations and the evolution of this technique from studies in the animal laboratory to a recent trial in patients with abdominal trauma. We propose that the early response benefit of this preoperative resuscitation seen in our 2 cases be investigated by others. Prospective controlled trials could then be considered for those high risk patients having diffuse disease and shock. PMID- 21238677 TI - Spontaneous gall bladder perforation: a rare condition in the differential diagnosis of acute abdomen in children. AB - Gallbladder perforation is very rare in children and almost exclusively is a complication of cholecystitis, which accompanies severe inflammation of the gallbladder with or without cholelithiasis. Here we present 4 cases of spontaneous gall bladder perforation, which should be kept in mind as a condition for inclusion in the differential diagnosis of an acute abdomen in children. PMID- 21238678 TI - Partial umbilical exstrophy with cecal patch and intact hindgut entering a cloaca: a new variant. AB - Variants of cloaca and exstrophy are difficult to explain and manage. We describe a female neonate having partial umbilical exstrophy with a cecal patch in the bladder and an intact distal hindgut that was expressed as a cloaca. The baby was managed by ileostomy and bladder closure without separating the cecal patch from the bladder. The possible embryological origin of this abnormality is discussed, and the literature is reviewed. PMID- 21238679 TI - A unique case of rhabdoid tumor presenting as hemoperitoneum in an infant. AB - We report the first pediatric case of an extrarenal, noncentral nervous system, diffusely metastatic, gastrointestinal rhabdoid tumor in a 106-day-old, previous 25-week preterm infant. The unusual clinical presentation, the diagnosis, and biology of this tumor as well as the etiology of hemoperitoneum in neonates and infants are discussed. PMID- 21238680 TI - An unusual presentation of a congenital intrahepatic arterioportal fistula in an infant with Down syndrome. AB - Congenital intrahepatic arterioportal fistula is a rare entity that most often presents with symptoms of portal hypertension and malabsorption. We discuss a patient who presented with distributive shock, congestive heart failure, pulmonary hypertension, ascites, and a history of severe constipation. PMID- 21238681 TI - Unusual coexistence of caudal duplication and caudal regression syndromes. AB - Caudal duplication syndrome includes anomalies of the genitourinary system, gastrointestinal tract, and the distal neural tube. Caudal regression syndrome presents with lumbosacral hypogenesis, anomalies of the lower gastrointestinal tract, genitourinary system, and limb anomalies. Both happen as a result of insult to the caudal cell mass. We present a child having features consistent with both entities. PMID- 21238682 TI - Split-appendix technique for simultaneous appendicovesicostomy and appendicocecostomy. AB - PURPOSE: Surgical treatment of urinary and fecal incontinence with appendicocecostomy (AC) and appendicovesicostomy (AV) has high success in achieving continence. Usually, the appendix can only be used for one of these, requiring the second channel to be constructed from alternative tissue. We describe our outcomes using the split-appendix technique for simultaneous creation of AC and AV. METHODS: We reviewed records for all patients that underwent simultaneous AC and AV from the appendix alone from 1999 to 2009. When anatomy permitted, the appendix was divided into 2. The proximal end was kept in continuity with the cecum for an AC, whereas the distal end was used for AV. The appendiceal length, continence status, and subsequent need for surgical revision were recorded. RESULTS: Of 394 children who underwent reconstructive surgery with a Mitrofanoff channel, 43 patients (11%) used the split-appendix technique. After a mean follow-up of 40 months, 43 of 43 ACs and 41 of 43 AVs are continent. Of the 86, 16 (19%) channels created required surgical revision. CONCLUSIONS: The channels created from split-appendix technique have outcomes and revision rates comparable with those of other described techniques. This technique is applicable to a minority of children undergoing continent reconstruction; however, it has the benefit of avoiding a bowel resection and its accompanying risks. PMID- 21238683 TI - Thoracoscopic cartilage resection with partial perichondrium preservation in unilateral pectus carinatum: preliminary results. AB - BACKGROUND/PURPOSE: Although minimally invasive repair of pectus excavatum has gained worldwide acceptance, treatment of pectus carinatum is mostly performed with open procedures. Different minimally invasive alternatives have been proposed in the last few years, including subpectoral CO(2) dissection and intrathoracic compression (Abramson technique), or conservative procedures, as dynamic compression system. Recently, another surgical technique has been proposed for the treatment of unilateral pectus carinatum, consisting of a thoracoscopic approach and multiple cartilage incisions. The aim of this work is to present our modification to this approach. METHODS: We have modified this technique by introducing complete cartilage resection of all anomalous costal cartilages, performed thoracoscopically. Three thoracoscopic ports were used. Cartilage is removed progressively using a rongeur and preserving the anterior perichondrium. RESULTS: We have performed this technique in 4 patients during the last year. Follow-up ranged from 6 to 14 months. No intraoperative or postoperative complications were observed. The results, assessed by the patients themselves, were good in 2 cases, quite good in one, and fair in the first patient of our series, who was reoperated using a classical open approach. Pain was well controlled without the need of an epidural catheter. CONCLUSION: Thoracoscopic cartilage resection with perichondrium preservation can be considered as feasible alternative for the treatment of unilateral pectus carinatum. PMID- 21238684 TI - Pneumatosis intestinalis and portal venous gas resulting from acute diarrheal illness: clinical picture in an infant. PMID- 21238692 TI - Life after promotion: self-reported professional development needs and career satisfaction of associate professors. PMID- 21238699 TI - Interruption of placental blood flow during labor: potential systemic and cerebral organ consequences. AB - Interruption of placental blood during labor, also termed "asphyxia," affects approximately 3 of every 1000 term infants. The systemic and cerebral consequences of asphyxia are in part related to circulatory adaptive responses, which in turn are modulated by the severity and duration of the insult. Long-term neurological outcome has been well categorized, whereas the systemic consequences remain unclear. PMID- 21238700 TI - Functional echocardiography in assessment of the cardiovascular system in asphyxiated neonates. AB - Perinatal asphyxia commonly results in multi-organ damage, and cardiovascular dysfunction is a frequent association. Myocardial damage, right ventricular dysfunction, abnormal circulatory transition, and impaired autoregulation may all contribute to postnatal neurological damage. Adequate monitoring and appropriate targeted treatment therefore are essential after an asphyxial insult. Standard methods of cardiovascular monitoring in the neonate have limitations. Point of care ultrasound scanning or functional echocardiography offers extra information to assist the clinician in identifying when there is significant cardiovascular impairment, classifying the underlying abnormal physiology and potentially targeting appropriate therapy, thereby optimizing the post-insult cerebral blood flow and oxygen delivery. PMID- 21238701 TI - Pulmonary hypertension and the asphyxiated newborn. AB - Persistent pulmonary hypertension of the newborn may occur with perinatal asphyxia, either because of direct effects of hypoxia/ischemia on pulmonary arterial function or indirectly because both are associated with meconium aspiration syndrome or perinatal sepsis/pneumonia. Therapies for persistent pulmonary hypertension of the newborn have the potential to affect cerebral function and cerebral perfusion in infants with hypoxic ischemic encephalopathy. Our literature review concludes that hyperventilation should be avoided, bicarbonate therapy is unproven, and hypoxia and hyperoxia should both be avoided. Nitric oxide improves pulmonary artery pressure and systemic perfusion. The effects of inotropic agents on cerebral perfusion or outcomes are uncertain. PMID- 21238702 TI - Ischemia-reperfusion and neonatal intestinal injury. AB - We review research relating ischemia/reperfusion to injury in the neonatal intestine. Epidemiologic evidence suggests that the most common form of necrotizing enterocolitis is not triggered by a primary hypoxic-ischemic event. Its late occurrence, lack of preceding ischemic events, and evidence for microbial and inflammatory processes preclude a major role for primary hypoxic ischemia as the sentinel pathogenic event. However, term infants, especially those with congenital heart disease who have development of intestinal necrosis, and those preterm infants with spontaneous intestinal perforations, are more likely to have intestinal ischemia as a primary component of their disease pathogenesis. PMID- 21238703 TI - Acute kidney injury post neonatal asphyxia. AB - Acute kidney injury (AKI) is a common consequence of perinatal asphyxia, occurring in up to 56% of these infants. A major difficulty in diagnosing this condition is the lack of a consensus definition of neonatal AKI, largely because of a dearth of specific measurable variables and biochemical markers. This review will discuss the current evidence regarding the epidemiology, investigation, and treatment of AKI in the asphyxiated neonate. Particular emphasis will be given to the investigation of renal function in the neonate and to potential biomarkers that may aid the clinician in the diagnosis of renal injury in this population. PMID- 21238704 TI - Effect of stress on the hypothalamic-pituitary-adrenal axis in the fetus and newborn. AB - The hypothalamic-pituitary-adrenal (HPA) axis is essential for maintaining homeostasis in the fetus and newborn. A proportion of extremely preterm infants suffer from transient adrenocortical insufficiency of prematurity. Although these infants have suboptimal adrenocortical response to stress in the first week of life, the HPA axis adapts rapidly, and most exhibit an adequate response by day 14. An attenuated cortisol response in preterm infants might be protective against intracranial bleeding. Severe hypoxic-ischemic encephalopathy is a potent stimulus to the HPA axis. Chronic intrauterine hypoxemia can up-regulate the setpoint of the HPA axis and augments adrenal steroidogenic production, resulting in sustained elevation of circulating cortisol levels. PMID- 21238705 TI - Hypothermia after perinatal asphyxia: selection for treatment and cooling protocol. AB - Three large randomized controlled trials have demonstrated benefits from 3 days of cooling to 33-34 degrees C after perinatal asphyxia. No serious adverse effects were documented. The trials excluded many infants for hypothermia (HT) therapy, including those of age >6 hours and those with prematurity of <36 weeks gestation, abnormal coagulation, persistent pulmonary hypertension, and congenital abnormalities. This article considers whether the foregoing trial exclusion criteria are feasible given current knowledge and evidence. HT affects the validity of some outcome predictors (eg, clinical examination, amplitude integrated electroencephalography), but not of magnetic resonance imaging. HT is a time-critical emergency treatment after perinatal asphyxia that requires optimal collaboration among local hospitals, transport teams, and cooling centers. PMID- 21238706 TI - Oxygen supplementation in the delivery room: updated information. AB - Resuscitation is the most common procedure performed in neonatology. However, new contributions based on scientific evidence challenge the traditional procedures. Of these new contributions, the use of room-air instead of 100% oxygen and titration of the oxygen inspiratory fraction according to oximetry and heart rate represent a new approach in the resuscitation of both term and preterm newborns. PMID- 21238707 TI - Hypoxic-ischemic encephalopathy: challenges in outcome and prediction. AB - The outcomes of hypoxic-ischemic encephalopathy vary between death and intact survival. The spectrum of long-term morbidity in survivors ranges from mild motor and cognitive deficits to cerebral palsy and severe cognitive deficits. Our literature review reinforces the notion that the spectrum of hypoxic-ischemic encephalopathy outcomes represents a continuum, which has important implications for the prediction of outcome and the indications for intervention. We summarize predictive criteria at 3 time points: the first 6 hours of life, 6-72 hours of life, and at hospital discharge. In this era of neuroprotection, predictive models that aid therapeutic decision making, including the withdrawal of support, need to be revised. PMID- 21238708 TI - Shock: a common consequence of neonatal asphyxia. AB - Neonatal asphyxia is associated with multi-organ hypoxia-ischemia and subsequent dysfunction. The cardiovascular system is frequently affected, causing signs of shock and complicating the neonatal circulatory transition. Hypothermia therapy can improve outcome from neonatal asphyxia without adversely affecting cardiovascular stability. Therapy directed at the cardiovascular system can improve short-term measures of systemic blood flow, but to date has not been demonstrated to improve long-term outcome. PMID- 21238709 TI - Hemostasis and platelet dysfunction in asphyxiated neonates. AB - Hemostasis is the balance between bleeding and clotting and includes coagulation and fibrinolysis with platelet interactions. Despite developmental hemostasis that describes the major differences between neonates and older children and adults, neonates do not have increased bleeding or clotting unless clinical situations disturb the "balance." Perinatal asphyxia alters the balance of hemostasis, resulting in abnormalities that may result in bleeding and thrombosis. The following discussion will describe normal hemostasis, laboratory measures of hemostasis, developmental hemostasis, and the effects of asphyxia on hemostasis. PMID- 21238710 TI - Is it better to be injured when you are pregnant? PMID- 21238711 TI - Pregnancy is protective. PMID- 21238712 TI - Hospital-level variability in incisional hernia repair technique affects patient outcomes. AB - BACKGROUND: Mesh placement during ventral incisional hernia repair has been shown to result in superior outcomes; however, significant variation persists in the adoption of this technique. We performed a multi-institutional study to understand how variation in surgical technique influences outcomes. METHODS: This study is a retrospective, facility-level analysis of incisional hernia repairs performed at 16 veteran's administration medical centers between 1997 and 2002. Operative notes and a postoperative course were physician-abstracted from the medical record. Hospital rates for the type of hernia repair, mesh placement, and recurrence were calculated. Spearman's correlation and generalized linear models were performed. RESULTS: A total of 1,612 incisional hernia repairs with a median follow-up of 66.2 months were included in the study. The mean rate of mesh implantation was 63.7% but ranged from 37.5% to 90%. The 5-year recurrence rate was 25.6% and ranged from 16.0% to 38.4%. The rate of mesh use for the incisional hernia repair at the hospital level was associated significantly with the hospital recurrence rate for all cases (R(2) = .27; P = .04) and elective cases (R(2) = .31; P = .02). For every 10% increase in the rate of mesh placement, a corresponding 3.1% decrease was noted in the recurrence rates (P = .001). The hospital rate of mesh use was not associated significantly with rates of complications or patient satisfaction. CONCLUSION: Hospitals that adopted a higher rate of mesh repair for incisional hernia repairs had lower recurrence rates. These data support that the efficacy of mesh repair previously proven in clinical trials is highly translatable to effective practice in the field. Continued studies on the attributable risk of complications to mesh placement are ongoing. PMID- 21238713 TI - Editorial response: Let's get started. PMID- 21238714 TI - ACTH-dependent Cushing syndrome: The potential benefits of simultaneous bilateral posterior retroperitoneoscopic adrenalectomy. PMID- 21238716 TI - Evaluation of oxygen pressurized microwave-assisted digestion of botanical materials using diluted nitric acid. AB - The feasibility of diluted nitric acid solutions for microwave-assisted decomposition of botanical samples in closed vessels was evaluated. Oxygen pressurized atmosphere was used to improve the digestion efficiency and Al, Ca, K, Fe, Mg and Na were determined in digests by inductively coupled plasma optical emission spectrometry (ICP OES). Efficiency of digestion was evaluated taking into account the residual carbon content (RCC) and residual acidity in digests. Samples were digested using nitric acid solutions (2, 3, 7, and 14 mol L(-1) HNO(3)) and the effect of gas phase composition inside the reaction vessels by purging the vessel with Ar (inert atmosphere, 1 bar), air (20% of oxygen, 1 bar) and pure O(2) (100% of oxygen, 1 bar) was evaluated. The influence of oxygen pressure was studied using pressures of 5, 10, 15 and 20 bar. It was demonstrated that a diluted nitric acid solution as low as 3 mol L(-1) was suitable for an efficient digestion of sample masses up to 500 mg of botanical samples using 5 bar of oxygen pressure. The residual acidities in final digests were lower than 45% in relation to the initial amount of acid used for digestion (equivalent to 1.3 mol L(-1) HNO(3)). The accuracy of the proposed procedure was evaluated using certified reference materials of olive leaves, apple leaves, peach leaves and pine needles. Using the optimized conditions for sample digestion, the results obtained were in agreement with certified values. The limit of quantification was improved up to a factor of 14.5 times for the analytes evaluated. In addition, the proposed procedure was in agreement with the recommendations of the green chemistry once it was possible to obtain relatively high digestion efficiency (RCC<5%) using only diluted HNO(3), which is important to minimize the generation of laboratory residues. PMID- 21238715 TI - Biological monitoring of 3-phenoxybenzoic acid in urine by an enzyme-linked immunosorbent assay. AB - An enzyme-linked immunosorbent assay (ELISA) method was employed for determination of the pyrethroid biomarker, 3-phenoxybenzoic acid (3-PBA) in human urine samples. The optimized coating antigen concentration was 0.5 ng/mL with a dilution of 1:4000 for the 3-PBA antibody and 1:6000 for the enzyme conjugate. Urine samples were hydrolyzed with concentrated hydrochloric acid; extracted with dichloromethane and solvent-exchanged into a methanol/buffer solution, prior to analysis in a 96-microwell plate immunoassay. Quantitative recoveries of 3-PBA were obtained for fortified urine samples by ELISA (92+/-18%) as well as by gas chromatography/mass spectrometry (GC/MS) (90+/-13%). The overall method precision of these samples was within +/-20% for both the ELISA and GC/MS methods. Analytical results from over one hundred urine samples showed that the ELISA and GC/MS data were highly correlated, with a correlation coefficient of 0.95. At the 10 ng/mL comparative concentration level, the false positive rate was 0% and the false negative rate was 0.8% for ELISA when using GC/MS as the reference method. The ELISA method has a suitable low detection limit for 3-PBA to assess pyrethroid exposures in non-occupational settings. PMID- 21238717 TI - Azo calix[4]arene based neodymium(III)-selective PVC membrane sensor. AB - We found that the PVC membrane, containing azo calix[4]arene is a suitable ionophore, exhibited a Nernstian response for neodymium (Nd(3+)) ions (with slope of 19.8+/-0.2 mV decade(-1) for the triply charged ion) over a wide linear range of 4.0*10(-8) to 1.0*10(-1) mol L(-1) with a detection limit 1.0*10(-8) mol L( 1), a relatively fast response time, in the whole concentration range (<10 s), and a considerable life time at least for four months in the pH range of 4.0-8.0. Furthermore, the electrode revealed high selectivity with respect to all the common alkali, alkaline earth, transition and heavy metal ions, including the members of the lanthanide family other than Nd(3+). Concerning its applications, it was effectively employed for the determination of neodymium ions in industrial waste water as well as in lake water. PMID- 21238718 TI - CdSe quantum dots capped PAMAM dendrimer nanocomposites for sensing nitroaromatic compounds. AB - The detection of nitroaromatic compounds, best known as raw materials in explosives preparations, is important in many fields including environmental science, public security and forensics. CdSe quantum dots capped with PAMAM-G(4) dendrimer were synthetized in water and used for the detection of trace amounts of three nitroaromatic compounds: 4-methoxy-2-nitrophenol (MNP), 2-amine-5-chloro 1,3-dinitrobenzene (ACNB) and 3-methoxy-4-nitrobenzoic acid (MNB). To increase the apparent water solubility of these compounds alpha-cyclodextrin (alpha-CD) was used to promote the formation of inclusion complexes. The studied nitroaromatic compounds (plus alpha-CD) significantly quenched the fluorescence intensity of the nanocomposite with linear Stern-Volmer plots. The Stern-Volmer constants (standard deviation in parenthesis) were: MNB, K(SV)=65(5)*10(4) M(-1); ACNB, K(SV)=19(2)*10(4) M(-1); and, MNP, K(SV)=33(1)*10(2) M(-1). These constants suggest the formation of a ground state complex between the nitroaromatric compounds and the sensor which confers a relatively high analytical sensitivity. The detection sensibilities are about 0.01 mg L(-1) for MNB and ACNB and about 0.1 mg L(-1) for MNP. No interferences or small interferences are observed for trinitrotoluene [K(SV)=10(2)*10(2)*M(-1)], 2,4-dinitrotoluene [K(SV)=20(3)*10 M( 1)], 2,6-dinitrotoluene [K(SV)=11(4)*10 M(-1)] and nitrobenzene [K(SV)=2(1)*10(3)*M(-1)]. PMID- 21238719 TI - Optical supermicrosensor responses for simple recognition and sensitive removal of Cu (II) Ion target. AB - The field of optical chemosensor technology demands a simple yet general design for fast, sensitive, selective, inexpensive, and specific recognition of a broad range of toxic metal ions. The suitable accommodation of chromogenic receptors onto ordered porous carriers have led to selective and sensitive chemosensors of target species. In this study, we offer real evidence on the potential use of two and three-dimensional (2D and 3D) ordered supermicroporous monoliths as selective shape and size carriers for immobilizing the chromogenic probe. Among all the chemosensors, 3D supermicropore has exhibited easy accessibility of target ions, such as ion transports and high affinity responses of receptor-metal analyte binding events. This leads to an optical color signal that is easily generated and transduced even at trace levels of Cu(II) target ions. The supermicrosensors have shown the ability to create Cu(II) ion-sensing responses up to nanomolar concentrations (~10(-9) mol/dm(3)) with rapid response time (in the order of seconds). Supermicrosensors have the ability to create easily modified sensing systems with multiple regeneration/reuse cycles of sensing systems of Cu(II) analytes. The simple treatment using ClO(4)(-) anion as a stripping agent has removed effectively the Cu(II) ions and formed a "metal-free" probe surface. The supermicrosensors have exhibited the specificity behavior permitting Cu(II) ion-selective determination in real-life samples, such as in wastewater, despite the presence of active component species. Extensive analytical results indicate that the use of the supermicrosensor as Cu(II) ion strips for field screening can be a time- and cost-alternative tool to current effective laboratory assays. PMID- 21238720 TI - Chemometric models for the quantitative descriptive sensory analysis of Arabica coffee beverages using near infrared spectroscopy. AB - Mathematical models based on chemometric analyses of the coffee beverage sensory data and NIR spectra of 51 Arabica roasted coffee samples were generated aiming to predict the scores of acidity, bitterness, flavour, cleanliness, body and overall quality of coffee beverage. Partial least squares (PLS) were used to construct the models. The ordered predictor selection (OPS) algorithm was applied to select the wavelengths for the regression model of each sensory attribute in order to take only significant regions into account. The regions of the spectrum defined as important for sensory quality were closely related to the NIR spectra of pure caffeine, trigonelline, 5-caffeoylquinic acid, cellulose, coffee lipids, sucrose and casein. The NIR analyses sustained that the relationship between the sensory characteristics of the beverage and the chemical composition of the roasted grain were as listed below: 1 - the lipids and proteins were closely related to the attribute body; 2 - the caffeine and chlorogenic acids were related to bitterness; 3 - the chlorogenic acids were related to acidity and flavour; 4 - the cleanliness and overall quality were related to caffeine, trigonelline, chlorogenic acid, polysaccharides, sucrose and protein. PMID- 21238721 TI - Rhodamine-based chemosensing monolayers on glass as a facile fluorescent "turn on" sensing film for selective detection of Pb2+. AB - Rhodamine-based chemosensors 1 and 2 were synthesized and self-assembled onto glass surfaces for the selective fluorescent sensing of Pb(2+). The immobilized chemosensors showed fluorescent responses that were turned-on with Pb(2+) in CH(3)CN, selectively over various metal ions. The Pb(2+)-selective fluorescent switch of the immobilized chemosensors was also reversible, allowing for repeated use for Pb(2+) detection. PMID- 21238722 TI - Ultrasonic frequency analysis of antibody-linked hydrogel biosensors for rapid point of care testing. AB - Analyte quantification in highly scattering media such as tissue, blood, and other biological fluids is challenging using conventional spectroscopic methods. Ultrasound easily penetrates these opaque samples, yet currently provides little chemical information. We have developed a general approach for creating hydrogel biosensors based on antibody-linked cellulose polymers. Target recognition induces changes to the sensor stiffness and size, which is accompanied by characteristic changes to a measured ultrasonic frequency profile. Using this technique, nM sensitivity for acetaminophen is demonstrated in a series of biofluids including whole blood, blood plasma, saliva, and urine. Likewise, this methodology is attractive for point of care diagnostics due to the short measurement time, simple methodology which excludes pretreatment of samples, and has minimal chemical or buffer requirements. PMID- 21238723 TI - Ultrasonic quantification using smart hydrogel sensors. AB - Analyte quantification in samples with extensive matrix effects can be challenging using conventional analytical techniques. Ultrasound has been shown to easily penetrate samples that can be difficult to measure optically or electrochemically, though it provides little chemical information. Recent ultrasound contrast agents provide highly localized contrast within a sample based on concentration. We have developed a general approach for creating smart biosensors based on molecularly imprinted hydrogel polymers that recognize and bind a target analyte, changing ultrasonic properties with analyte concentration. Multilinear analyte calibration in hydrogel solutions provided quantification of the chosen analyte, theophylline, from 8.4 MUM to 6.1 mM with a high degree of linearity (correlation coefficient exceeding 0.99). Simultaneous quantification of both theophylline and of an interfering species, caffeine, was also carried out, providing an avenue for simultaneous analyte analysis with one smart biosensor that can be dispersed and remotely detected. PMID- 21238724 TI - Determination of imipramine and trimipramine by capillary electrophoresis with electrochemiluminescence detection. AB - The tricyclic antidepressants (TCA) imipramine (Imi) and trimipramine (Tri) were successfully analyzed by capillary electrophoresis (CE) coupling with Tris(2,2 bipyridyl) ruthenium(II)-based (Ru(bpy)(3)(2+)) end-column electrochemiluminescence (ECL) detection. The addition of beta-CD to the running buffer was found to enable baseline separation of the two analytes and the addition of acetonitrile (ACN) as an organic additive to improve the repeatability and sensitivity of the CE method. Under the optimized separation and detection conditions (50mM PBS (pH=7.0) and 2mM Ru(bpy)(3)(2+) in the ECL detection cell, 20 mM Tris (pH=2.0), 0.2 mM beta-CD and 20% ACN (v/v) as running buffer), wide linear ranges of 0.1-5 MUM and 0.1-5 MUM were achieved, with the correlation coefficients of 0.9990 (n=8) and 0.9980 (n=8) for Imi and Tri, respectively. Detection limits 5 nM and 1 nM (S/N=3) were obtained for Imi and Tri, respectively. The method was also successfully applied for the determination of Imi in pharmaceutical dosage form. PMID- 21238725 TI - Covalent immobilization of horseradish peroxidase via click chemistry and its direct electrochemistry. AB - A simple and versatile approach for covalent immobilization of redox protein on solid surface via self-assembled technique and click chemistry is reported. The alkynyl-terminated monolayers are obtained by self-assembled technique, then, azido-horseradish peroxidase (azido-HRP) was covalent immobilized onto the formed monolayers by click reaction. The modified process is characterized by reflection absorption infrared spectroscopy (RAIR), surface-enhanced Raman scattering spectroscopy (SERS) and electrochemical methods. All the experimental results suggest that HRP is immobilized onto the electrode surface successfully without denaturation. Furthermore, the immobilized HRP shows electrocatalytic reduction for H(2)O(2), and the linear range is from 5.0 to 700 MUM. The heterogeneous electron transfer rate constant k(s) is 1.11 s(-1) and the apparent Michaelis Menten constant is calculated to be 0.196 mM. PMID- 21238726 TI - A novel glucose sensor based on ordered mesoporous carbon-Au nanoparticles nanocomposites. AB - Ordered mesoporous carbon-Au nanoparticles (OMC-Au) nanocomposites were synthesized by a one-step chemical reduction route. Due to the large surface area and high conductivity of OMC, good biocompatibility of OMC and Au nanoparticles, a mediator-free glucose biosensor was fabricated by immobilizing glucose oxidase (GOD) on the OMC-Au nanocomposites modified glassy carbon (GC) electrode. Direct electron transfer between GOD and the electrode was achieved and the electron transfer rate constant (k(s)) was calculated to be 5.03 s(-1). The Michalis Menten constant (K(M)(app)) value of GOD immobilized on the OMC-Au/GC electrode surface was found to be 0.6 mM. The glucose biosensor exhibits a linear range from 0.05 to 20.0 mM. This biosensor also shows good reproducibility, excellent stability and the negligible interferences from ascorbic acid and uric acid. PMID- 21238727 TI - Solvent (ionic liquid) impregnated resin-based extraction coupled with dynamic ultrasonic desorption for separation and concentration of four herbicides in environmental water. AB - A new method was developed for the determination of monolinuron, propazine, linuron, and prebane in environmental water samples. The solvent (ionic liquid) impregnated resin (IL-SIR)-based extraction coupled with dynamic ultrasonic desorption (DUSD) was applied to the separation and concentration of the analytes. The high performance liquid chromatography (HPLC) was applied to the determination of the analytes. The ionic liquid [C(6)MIM][PF(6)] was immobilized on Diaion HP20 resin by immersing the resin in ethanol solution containing [C(6)MIM][PF(6)]. The effect of extraction parameters, including pH value of sample solution, salt concentration in sample and extraction time, and elution conditions, including the concentration of ethanol in elution solvent, the flow rate of elution solvent and the ultrasonic power, were examined and optimized. The limits of detection and quantification for the analytes were in the range of 0.15-0.29 MUg L(-1) and 0.51-0.98 MUg L(-1), respectively. Some environmental water samples were analyzed and the analytical results were satisfactory. PMID- 21238728 TI - An emphatic orthogonal signal correction-support vector machine method for the classification of tissue sections of endometrial carcinoma by near infrared spectroscopy. AB - A new application of emphatic orthogonal signal correction (EOSC) for baseline correction of near infrared spectra from reflectance measurements of tissue sections is introduced. EOSC was evaluated and compared with principal component orthogonal signal correction (PC-OSC) by using support vector machine (SVM) classifiers. In addition, some exemplary synthetic data sets were created to characterize EOSC coupled to SVM for classification. Orthogonal experimental design coupled with analysis of variance (ANOVA) was used to determine the significant parameters for optimization, which were the OSC method and number of components for the model. EOSC combined with the SVM gave better predictions with respect to a larger number of components and was not as susceptible to overfitting the data as the classifier built with PC-OSC data. These results were supported by simulations using synthetic data sets. EOSC is a softer signal correction approach that retains more signal variance which was exploited by the SVM. Classification rates of 93+/-1% were obtained without orthogonal signal correction with the SVM. PC-OSC and EOSC data gave similar peak prediction accuracies of 94+/-1%. The key advantages demonstrated by EOSC were its resistance to overfitting, fine-tuning capability or softness, and the retention of spectral features after signal correction. PMID- 21238729 TI - A nonenzymatic sensor for xanthine based on electrospun carbon nanofibers modified electrode. AB - Xanthine (Xa) determination is of considerable importance in clinical analysis and food quality control. Therefore, a sensitive nonenzymatic amperometric sensor for Xa based on carbon nanofibers (CNFs) has been proposed. The CNFs, which were prepared by electrospinning technique and subsequent thermal treatment, were used to modify carbon paste electrode (CNF-CPE) to construct the amperometric sensor device without any oxidation pretreatment. In application to Xa electrochemical determination, the CNF-CPE exhibited high electrocatalytic activity and fast amperometric response. Various experimental parameters, such as pH and applied potential were optimized. Under the optimal conditions, the dynamic linear range of Xa was 0.03-21.19 MUM (R=0.9992) with the detection limit low to 20 nM (S/N=3). With good selectivity and sensitivity, the present system was successfully applied to estimate the freshness of fish and determine Xa in human urine, which provides potential application in food quality control and clinical analysis. PMID- 21238730 TI - Considerations for potency equivalent calculations in the Ah receptor-based CALUX bioassay: normalization of superinduction results for improved sample potency estimation. AB - The chemically activated luciferase expression (CALUX) system is a mechanistically based recombinant luciferase reporter gene cell bioassay used in combination with chemical extraction and clean-up methods for the detection and relative quantitation of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related dioxin like halogenated aromatic hydrocarbons in a wide variety of sample matrices. While sample extracts containing complex mixtures of chemicals can produce a variety of distinct concentration-dependent luciferase induction responses in CALUX cells, these effects are produced through a common mechanism of action (i.e. the Ah receptor (AhR)) allowing normalization of results and sample potency determination. Here we describe the diversity in CALUX response to PCDD/Fs from sediment and soil extracts and not only report the occurrence of superinduction of the CALUX bioassay, but we describe a mechanistically based approach for normalization of superinduction data that results in a more accurate estimation of the relative potency of such sample extracts. PMID- 21238731 TI - Ultrasensitively sensing acephate using molecular imprinting techniques on a surface plasmon resonance sensor. AB - An ultrathin molecularly imprinted polymer film was anchored on an Au surface for fabricating a surface plasmon resonance sensor sensitive to acephate by a surface bound photo-radical initiator. The polymerization in the presence of acephate resulted in a molecular-imprinted matrix for the enhanced binding of acephate. Analysis of the SPR wavenumber changes in the presence of different concentrations of acephate gave a calibration curve that included the ultrasensitive detection of acephate by the imprinted sites in the composite, K(ass) for the association of acephate to the imprinted sites, 7.7*10(12) M(-1). The imprinted ultrathin film revealed impressive selectivity. The selectivity efficiencies for acephate and other structurally related analogues were 1.0 and 0.11-0.37, respectively. Based on a signal to noise ratio of 3, the detection limits were 1.14*10(-13) M for apple sample and 4.29*10(-14) M for cole sample. The method showed good recoveries and precision for the apple and cole samples spiked with acephate solution. This suggests that a combination of SPR sensing with MIP film is a promising alternative method for the detection of organophosphate compounds. PMID- 21238732 TI - Determination of As(III) by anodic stripping voltammetry using a lateral gold electrode: experimental conditions, electron transfer and monitoring of electrode surface. AB - The aim of this work is to evaluate the efficiency of the determination of As(III) by anodic stripping voltammetry (ASV) using a lateral gold electrode and to study the modifications of the electrode surface during use. Potential waveforms (differential pulse and square wave), potential scan parameters, deposition time, deposition potential and surface cleaning procedure were examined for they effect on arsenic peak intensity and shape. The best responses were obtained with differential pulse potential wave form and diluted 0.25 M HCl as supporting electrolyte. The repeatability, linearity, accuracy and detection limit of the procedure and the interferences of cations and anions in solution were evaluated. The applicability of the procedure for As(III) determination in drinking waters was tested. Cyclic voltammetry (CV) was used to study the electrochemical behaviour of As(III) and for the daily monitoring of electrode surface. Also scanning electron microscopy (SEM) analysis was used to control the electron surface. Finally we evaluated the possibility to apply the equations valid for flow systems also to a stirred system, in order to calculate the number of electrons transferred per molecule during the stripping step. PMID- 21238733 TI - Fast and accurate peanut allergen detection with nanobead enhanced optical fiber SPR biosensor. AB - This paper is the first report of a fiber optic SPR biosensor with nanobead signal enhancement. We evaluated the system with a bioassay for the fast and accurate detection of peanut allergens in complex food matrices. Three approaches of an immunoassay to detect Ara h1 peanut allergens in chocolate candy bars were compared; a label-free assay, a secondary antibody sandwich assay and a nanobead enhanced assay. Although label-free detection is the most convenient, our results illustrate that functionalized nanobeads can offer a refined solution to improve the fiber SPR detection limit. By applying magnetite nanoparticles as a secondary label, the detection limit of the SPR bioassay for Ara h1 was improved by two orders of magnitude from 9 to 0.09 MUg/mL. The super paramagnetic character of the nanoparticles ensured easy handling. The SPR fibers could be regenerated easily and one fiber could be reused for up to 35 times without loss of sensitivity. The results were benchmarked against a commercially available polyclonal ELISA kit. An excellent correlation was found between the Ara h1 concentrations obtained with the ELISA and the concentrations measured with the SPR fiber assay. In addition, with the SPR fiber we could measure the samples twice as fast as compared to the fastest ELISA protocol. Since the dipstick fiber has no need for microchannels that can become clogged, time consuming rinsing step could be avoided. The linear dynamic range of the presented sensor was between 0.1 and 2 MUg/mL, which is considerably larger than the ELISA benchmark. PMID- 21238734 TI - Simultaneous determination of aflatoxins and ochratoxin A in baby foods and paprika by HPLC with fluorescence detection: a single-laboratory validation study. AB - Mycotoxins are toxic secondary metabolites of fungal origin, the major mycotoxins of food concern are aflatoxins and ochratoxin A. Due to the wide range of matrices susceptible to mycotoxin contamination, the possible co-occurrence, and the very wide range of concentration, validated versatile multi-mycotoxin and multi-matrix methods are strongly requested. A reversed phase HPLC method for the simultaneous determination of aflatoxins and ochratoxin A in baby foods and paprika was set up. Three bulk samples were prepared according to commercial availability, one for paprika and for baby foods, two different bulks were set, a corn based and a multi-cereal based baby food. A single-laboratory validation was performed, for each investigated level ten analyses were performed, relative standard deviations of repeatability (RSD(r)) and recovery factors were calculated; RSD(r) values ranged from 2% to 10% for AFB(1) and from 3% to 10% for OTA, while the recovery factors ranged from 86% to 96% for AFB(1) and from 77% to 96% for OTA. The checked compliance of the RSD(r) and recovery with the values reported in the current EU Regulations confirmed the fitting for purpose of the method. Limit of detection and LoQ values of the method were respectively 0.002 and 0.020 MUg/kg for AFB(1) and 0.012 and 0.080 MUg/kg for OTA in baby foods; and 0.002 and 0.200 MUg/kg for AFB(1) and 0.012 and 0.660 MUg/kg for OTA in paprika. The current method represents a good example of the possibility of a multi mycotoxin and/or a multi-matrix analysis depending on the laboratory research or official control purposes. PMID- 21238735 TI - Determination of antihypertensive and anti-ulcer agents from surface water with solid-phase extraction-liquid chromatography-electrospray ionization tandem mass spectrometry. AB - Pharmaceuticals are emerging contaminants in surface water and they must be measured to follow their effects on the aquatic environment. We developed a solid phase extraction and liquid chromatography-electrospray ionization tandem mass spectrometry (SPE-LC-ESI-MS/MS) method for the determination of twenty-six pharmaceutical compounds - which belong to antihypertensive and anti-ulcer agents - from surface water samples. The selection of pharmaceuticals was based on usage frequency in Hungary. During method development Oasis HLB, SampliQ Polymer SCX and Si-SCX SPE cartridges were tested. As LC eluent ammonium formate, ammonium acetate buffers at pH 3 and 5 were investigated and for quantitation both matrix matched and internal standard calibration was used. For matrix effect assessment post-extraction spike method was applied which can separate the extraction efficiency from ion suppression for better determination of recovery. Method detection limits (MDLs) varied between 0.2 and 10 ng/L. Precision of the method, calculated as relative standard deviation (RSD), ranged from 0.2 to 14.6% and from 1.2 to 22.4% for intra- and inter-day analysis, respectively. The method was applied to analyze Danube water samples. Measured average concentrations varied between 2 and 39 ng/L for eleven compounds and another one could be detected under LOQ. PMID- 21238736 TI - Development and validation of a GC-MS method for rapid determination of galanthamine in Leucojum aestivum and Narcissus ssp.: a metabolomic approach. AB - Galanthamine, an acetylcholinesterase inhibitor marketed as a hydrobromide salt for the treatment of Alzheimer's disease, is obtained from some Amaryllidaceae plants. A new method was developed and validated for its quantification by GC-MS in different plant sources: bulbs and leaves from Narcissus confusus; bulbs from N. pseudonarcissus cv. Carlton; and leaves and in vitro cultures from L. aestivum. Samples (50 mg) were extracted with methanol (1 mL) for 2 h, then aliquots of the extracts were silylated and analyzed by GC-MS. The calibration line was linear over a range of 15-800 MUg galanthamine/sample, ensuring an analysis of samples with a content of 0.03-1.54% analyte referred to dry weight. The recovery was generally more than 95%. Good inter- and intra assay precision was observed (RSD<3%). Principal component analysis of GC-MS chromatograms allowed discrimination of the plant raw material with respect to species, organs and geographical regions. The analytical method developed in this study proved to be simple, sensitive and far more informative than the routine analytical methods (GC, HPLC, CE and NMR), so it may be useful for quality control of plant raw materials in the pharmaceutical industry. PMID- 21238737 TI - A non-radioactive assay for precise determination of intracellular levels of imatinib and its main metabolite in Bcr-Abl positive cells. AB - Multidrug resistance (MDR) is often associated with overexpression of the P glycoprotein (P-gp, ABCB1). It was demonstrated that the P-gp mediated efflux decreases the drug concentration in cancer cells which results in the failure of chemotherapy. However, the MDR phenotype in cancer cells obviously involves various mechanisms. Therefore, if we want to estimate a contribution of the P-gp expression to the MDR phenotype, a clear quantitative relationship between the intracellular drug level and cell sensitivity must be established. To achieve this goal, a sensitive and non-radioactive assay for precise determination of intracellular levels of imatinib and its main metabolite N-desmethyl imatinib (CGP 74588) has been developed. The assay is based on an optimised extraction of cells with 4% formic acid after their separation from the growth medium by centrifugation through a layer of silicone oil. Cell extracts are subsequently analyzed by LC/MS/MS. Calibration curves were linear from 1 to 500 nmol/l for imatinib and from 2 to 500 nmol/l for CGP 74588, with correlation coefficients (r(2)) better than 0.998 and 0.996, respectively. The limit of quantitation (LOQ) was 1 nmol/l for imatinib and 2 nmol/l for CGP 74588. Our method has been successfully applied to the determination of intracellular levels of imatinib in sensitive K562 and their resistant variant, K562/Dox cells. PMID- 21238738 TI - Indirect voltammetric detection of fluoride ions in toothpaste on a comb-shaped interdigitated microelectrode array. AB - A novel technique based on dynamic electrochemistry for the detection of fluoride ions was developed. It is based on its strong complexation with ferric ion. Formed fluoroferric complex is cathodically inactive at the potential of the reduction of free ferric aquo ion. The voltammetric and amperometric response of platinum comb-shaped interdigitated microelectrode array is decreased after fluoride addition. This decrease serves for the quantification of fluoride ions added to the solution. The detection limit of 4.5*10(-5) mol dm(-3) was achieved when one of the segments of interdigitated microelectrode array (IDA) was used as an indicating electrode. The detection limit is about one order of magnitude lower than in the case of conventional platinum macroelectrode. In comparison with ISE electrodes this method is faster and also avoiding large error resulting from the antilogarithmization of ISE Nerstian response. The method was applied to the analysis of toothpaste. PMID- 21238739 TI - Electrochemical properties of a fully integrated, singlewalled carbon nanotube coplanar three-electrode system on glass substrate. AB - Fully integrated carbon nanotube-based three-electrode electrochemical systems were photolithographically prepared on glass substrates and electrochemically characterized. O(2) plasma treatment of the transferred single-walled carbon nanotube (SWCNT) film was voltammetrically optimized in terms of applied plasma power and the elapsed time. The patterned thin film Ag layer was chemically oxidized in an acidic solution for various dip times to form a chlorinated Ag layer. The Nernstian behavior of as-prepared and seven-day-aged Ag/AgCl thin-film electrodes was investigated for optimization, and the electrode's electrochemical attributes were compared to a commercial reference electrode. A quality control evaluation and a performance assessment of the fully integrated SWCNT-transferred sensing systems were performed using cyclic voltammetry. The proposed SWCNT-based three-electrode device exhibited clear electrochemistry under voltammetric conditions, and is therefore a candidate for use in all electrochemical biosensors. PMID- 21238740 TI - Synthesis of polypyrrole nanoparticles and its grafting with silica gel for selective binding of chromium(VI). AB - Polypyrrole nanoparticles of desired structure have been synthesized through simple micelle technique. It is then grafted with functionalized silica gel to develop a novel organic-inorganic hybrid material. The role of dimethyl dichloro silane (coupling agent) in grafting is demonstrated. The nanoparticles are characterized by TEM, SEM and TGA. Grafting reactions are evaluated by spectral (FTIR) analysis and chemical test. The Cr(VI) binding behavior of the composite is studied in various pH of the medium. The selectivity in binding Cr(VI) is monitored. The metal ion adsorption capacity and surface area of the material are found to be 38 mg/g and 235 m(2)/g, respectively. PMID- 21238741 TI - Online preconcentration in capillary electrophoresis with contactless conductivity detection for sensitive determination of sorbic and benzoic acids in soy sauce. AB - A sensitive method of online preconcentration followed by capillary electrophoresis with capacitively coupled contactless conductivity detection (CE C(4)D) is evaluated as a novel approach for the determination of benzoic acid and sorbic acid in soy sauce. The online preconcentration technique, namely field enhanced sample injection, coupled with CE-C(4)D were successfully developed and optimized. In order to reduce the complex matrix interference resulting from the constituents of soy sauce, a suitable sample clean-up procedure was also investigated for real sample pretreatment. Under optimized conditions, sorbic acid and benzoic acid were well separated within 10 min, and the detection limits were 0.05 MUM (5.6 MUg L(-1)) and 0.08 MUM (9.8 MUg L(-1)), respectively. The accuracy was tested by spiking 10.0 mg L(-1) and 100.0 mg L(-1) of standards in the soy sauce samples, and the recoveries were 95-99%, respectively. Results of this study show a great potential for the proposed method as a tool for the fast screening of benzoic acid and sorbic acid in a complex matrix. PMID- 21238742 TI - Fabrication of new solid state phosphate selective electrodes for environmental monitoring. AB - A highly selective and sensitive phosphate sensor has been fabricated by constructing a crystal disk consisting of variable mixtures of aluminium powder (Al), aluminium phosphate (AlPO(4)) and powdered copper (Cu). The membrane sensor exhibits linear potential response in the concentration range of 1.0*10(-1) to 1.0*10(-6) mol L(-1). The proposed sensor also exhibits a fast response time of <60s. Its detection limit is lower than 1.0*10(-6) mol L(-1). The electrode has a long lifetime and can be stored in air when not in use. The selectivity of the sensor with respect to other common ions is excellent. PMID- 21238743 TI - A cation exchange resin bead-based microscale electrolytic suppressor for capillary ion chromatography. AB - A cation exchange resin (CER) bead-based microscale electrolytic suppressor for capillary ion chromatography (CIC) has been fabricated and evaluated. Relative to common ion exchange membrane, the use of CER beads presents a simple way to fabricate a microscale suppressor due to its small surface area and spherical shape. The internal volume of the device is ~600 nL, which matches the requirements by CIC. Continuous online regeneration is readily achieved using pure water or diluted sulfuric acid as the regenerant. The use of a cation exchange functionalized monolithic segment inserted between two CER beads greatly reduces the electrical resistance and improves the suppression efficiency. The device works well only in the electrolytic mode, chemical regeneration alone is ineffective. The suppressed background is ~3 MUS/cm for 10mM KOH eluent generated online by a microscale KOH electrolytic generator operated at the flow rate of 3 MUL/min. The preliminary application for capillary ion chromatography has been demonstrated. PMID- 21238744 TI - Electrochemical impedance spectroscopy detection of lysozyme based on electrodeposited gold nanoparticles. AB - A simple, highly sensitive, and label-free electrochemical impedance spectroscopy (EIS) aptasensor based on an anti-lysozyme-aptamer as a molecular recognition element, was developed for the detection of lysozyme. Improvement in sensitivity was achieved by utilizing gold nanoparticles (AuNPs), which were electrodeposited onto the surface of a gold electrode, as a platform for immobilization of the aptamer. To quantify the amount of lysozyme, changes in the interfacial electron transfer resistance (R(et)) of the aptasensor were monitored using the redox couple of an [Fe(CN)(6)](3-/4-) probe. The R(et) increased with lysozyme concentration. The plot of R(et) against the logarithm of lysozyme concentration is linear over the range from 0.1 pM to 500 pM with a detection limit of 0.01 pM. The aptasensor also showed good selectivity for lysozyme without being affected by the presence of other proteins. PMID- 21238745 TI - Bicontinuous gyroidal mesoporous carbon matrix for facilitating protein electrochemical and bioelectrocatalytic performances. AB - A strategy of protein-entrapment in bicontinuous gyroidal mesoporous carbon (BGMC) nanocomposite films is described. Herein, the quasi-reversible electron transfer of redox proteins (such as glucose oxidase and myoglobin) is probed and the associated biocatalytic activity is revealed. The apparent heterogeneous electron transfer rate constant of the immobilized glucose oxidase is up to 9.4 s(-1), much larger than those in carbon nanotubes and some conventional mesoporous carbons. The BGMC based glucose biosensor enables the determination of glucose at a potential of 0.6 V (vs. SCE). Its detection limit is 1.0*10(-5) M (signal-to-noise ratio, S/N=3), the linear response is up to 7.49 mM and the detection sensitivity is 52.5 nA mM(-1) Furthermore, a series of BGMCs with different pore sizes is designed and synthesized using sucrose or phenol formaldehyde resin to study the influences of pore sizes and carbon sources on the immobilization of redox proteins and on the heterogeneous electron transfer. PMID- 21238746 TI - Tris(hydroxymethyl)aminomethane-modified magnetic microspheres for rapid affinity purification of lysozyme. AB - A novel affinity purification method for lysozyme (LZM) based on functionalized magnetic microspheres was developed. Tris(hydroxymethyl)aminomethane (Tris) modified magnetic microspheres with specific affinity toward LZM were prepared using Tris as ligand and silica-coated magnetic microshperes as support. Transmission electron microscopy and magnetic property measurement results showed that the Tris-modified magnetic microspheres have a very good core-shell structure and high magnetization.The maximum binding capacity of LZM was about 108.6 mg/g magnetic microspheres. LZM purified from chicken egg white had high purity and well-maintained activity of 8140 U/mg. This magnetic-mediated LZM purification strategy has advantages of high efficiency, low cost and easy operation. PMID- 21238747 TI - Identification of impurities in polymyxin B and colistin bulk sample using liquid chromatography coupled to mass spectrometry. AB - The European Pharmacopoeia (Ph. Eur.) describes liquid chromatography-ultraviolet (LC-UV) methods using C(18) stationary phases for the analysis of polymyxin B and colistin. Several unknown impurities were detected in commercial samples of those polypeptide complexes. However, the Ph. Eur. does not specify any related substances for polymyxin B and colistin. Since both methods use non-volatile buffers, the mobile phases were incompatible with mass spectrometry (MS). For the identification of related substances in bulk samples by LC/MS, volatile mobile phase systems were developed. However, the LC/MS methods (with volatile additives) showed inferior chromatographic separation compared to the LC-UV method (with non-volatile additives). Moreover, previously identified impurities by LC/MS could not be assigned in LC-UV methods as the separation in both systems was different. In this study, known impurities were traced in the LC-UV methods and new impurities present in polymyxin B and colistin bulk samples were characterized. To achieve this, each peak from the non-volatile system was collected separately and reinjected into an LC system with a volatile mobile phase coupled to MS. This way, collected impurity peaks were rechromatographed on a reversed phase column in order to separate the analyte from the buffer salts. Using this method, out of 39 peaks, five novel related substances were characterized in a polymyxin B bulk sample. Fourteen impurities, which were already reported in the literature were traced as good as possible in the LC-UV method. In the case of colistin, a total of 36 peaks were investigated, among which four new compounds. Additionally, 30 known impurities were traced in the LC UV method. PMID- 21238748 TI - New methods applicable for calibration of indicator electrodes. AB - The new methods applicable for calibration of indicator electrodes, based on standard addition and standard subtraction methods, are suggested. Some of the methods enable the slope of an indicator electrode and equivalence volume V(eq) to be determined simultaneously from a single set of potentiometric titration data. Some other methods known hitherto were also taken into account. A new model, based on a standard addition method, applicable also in nonlinear range for the ISE slope (S) is suggested, and its applicability was confirmed experimentally in calibration of calcium ISE. PMID- 21238749 TI - Kinetic catalytic determination of trace levels of iodide based on the oxidation of basic dyes with hydrogen peroxide monitored potentiometrically using simple PVC electrodes. AB - Four sensitive catalytic potentiometric methods have been developed for trace levels determination of iodide based on its catalytic effects on the oxidation of four dyes: viz. variamine blue (VB), rhodamine B (RB), methylene blue (MB) and malachite green (MG), with H(2)O(2) in H(3)PO(4) medium at 25+/-0.5 degrees C. The catalyzed reaction rates were estimated potentiometrically by monitoring the potential of the corresponding dye-PVC ion selective electrodes. To select the optimized reaction conditions offering the highest sensitivity of the method, parallel studies were carried out on each dye catalyzed reaction including: the effect of reactant concentration, reaction medium and temperature. The working calibration curves were linear over the concentration range from 0.32 to 2.54 mg L(-1) iodide for VB method and from 3.2 to 12.7 mg L(-1) for other ones. The tolerance limits of more than 20 interfering species were listed indicating the high selectivity of the method. Trace iodide in edible salt and pharmaceutical samples was determined without the need for separation or preconcentration procedures. PMID- 21238750 TI - Alternative approach to post column online isotope dilution ICP-MS. AB - An alternative post column online double isotope dilution inductively coupled plasma mass spectrometry (ID-ICP-MS) method was developed. The resulting equation allows a straightforward calculation of the mass concentration of the analyte in the sample from the measured isotope ratio chromatogram. The use of a balance to determine and monitor the mass flow of the spike and a solution of the species under investigation as the reference are the two core components of this new method. Changes in the viscosity of the system eluent-analyte-spike will not affect the results due to the direct determination of the mass flow rate. The use of the species under investigation as the reference makes the method independent of the injected volume. To simplify matters, the integration of the isotope ratio chromatogram was done with Excel using Simpson's rule instead of sophisticated programs for transformation and integration. The advantages of the new approach were demonstrated with the help of the determination of selenomethionine in the selenized yeast reference material SELM-1 with liquid chromatography coupled to ICP-MS (HPLC ID-ICP-MS) applying the new online double IDMS method. PMID- 21238751 TI - Pesticide residue analysis of fruit juices by LC-MS/MS direct injection. One year pilot survey. AB - For this work, thirteen types of fruit juices (orange, pineapple, peach, apple, multifruit, mango, strawberry, tomato, pear, mandarin, grape, banana and grapefruit) were selected to develop an analytical method for the analysis of 53 pesticides by direct injection in LC-MS/MS. The preparation of the samples was very simple: an aliquot of the juice was centrifuged and it was ten-times diluted prior to analysis, which allowed reducing considerably the time and cost of the analyses. Besides, dilution of the samples permits reducing the amount of matrix going into the system, and thus, decreasing the matrix effects, so common in this type of commodities, opening the possibility to perform quantification with solvent based standards. Validation of the method was carried out in accordance with EU guidelines. Calibration curves covering three orders of magnitude were performed, and they were linear over the concentration range studied for all the matrices (from 0.1 to 100 MUg L(-1)). Practical limits of quantification were in the low MUg L(-1) range, far below the maximum residue levels (MRLs) of the EU regulations, which do not set specific MRLs for juices, and in this cases of processed food, MRLs of the raw product are applied. Repeatability of the instrumental method was studied in all matrices, obtaining good intra- and inter day relative standard deviations (RSDs). The proposed method was applied to 106 real fruit juice samples purchased in different local markets during a one-year survey in order to validate the suitability for routine analysis. 43% of the analysed samples gave positive results (higher than the practical limits of quantification). PMID- 21238752 TI - Screening of non-polar heterocyclic amines in urine by microextraction in packed sorbent-fluorimetric detection and confirmation by capillary liquid chromatography. AB - A rapid and simple procedure for the direct screening of urine samples is described. The method involves microextraction in a packed sorbent (MEPS) that is on-line coupled to a capillary liquid chromatograph with fluorimetric detection. The overall arrangement works as a screening/confirmatory system for monitoring non-polar heterocyclic aromatic amines (HAAs) in urine samples. This configuration allows the selective retention of HAAs from urine on a C(18) MEPS cartridge integrated in the needle of a micro-well plate autosampler. Retained HAAs were eluted with methanol/water (90:10, v/v) and directly injected into the fluorimetric detector. This screening method provides a yes/no binary response that may require confirmation. The samples for which the concentration of HAAs was close to or above the established threshold limit (30 ng mL(-1)) were subjected to capillary liquid chromatography (CLC) for confirmation purposes. A mobile phase of acetonitrile and triethylamine (25 mM) at pH 2.5, through a gradient of composition at a flow rate of 20 MUL min(-1), resulted in good separations between the analytes in less than 11 min. This confirmation method allowed the determination of the analytes in the 10-100 ng mL(-1) range for harmane and norharmane and from 20 to 200 ng mL(-1) for 3-amino-1,4-dimethyl-5H pyrido-[4,3-b] indole (Trp-P-1), 3-amino-1-methyl-5H-pyrido-[4,3-b] indole (Trp-P 2), 2-amino-9H-pyrido-[2,3-b] indole (AalphaC) and 2-amino-3-methyl-9H-pyrido [2,3-b] indole (MeAalphaC), with relative standard deviation (RSD) values between 2.12% and 3.73%, and limits of detection between 1.6 and 5.6 ng mL(-1) for all the HAAs. PMID- 21238753 TI - Comparison of ISO-GUM and Monte Carlo methods for the evaluation of measurement uncertainty: application to direct cadmium measurement in water by GFAAS. AB - The propagation stage of uncertainty evaluation, known as the propagation of distributions, is in most cases approached by the GUM (Guide to the Expression of Uncertainty in Measurement) uncertainty framework which is based on the law of propagation of uncertainty assigned to various input quantities and the characterization of the measurand (output quantity) by a Gaussian or a t distribution. Recently, a Supplement to the ISO-GUM was prepared by the JCGM (Joint Committee for Guides in Metrology). This Guide gives guidance on propagating probability distributions assigned to various input quantities through a numerical simulation (Monte Carlo Method) and determining a probability distribution for the measurand. In the present work the two approaches were used to estimate the uncertainty of the direct determination of cadmium in water by graphite furnace atomic absorption spectrometry (GFAAS). The expanded uncertainty results (at 95% confidence levels) obtained with the GUM Uncertainty Framework and the Monte Carlo Method at the concentration level of 3.01 MUg/L were +/-0.20 MUg/L and +/-0.18 MUg/L, respectively. Thus, the GUM Uncertainty Framework slightly overestimates the overall uncertainty by 10%. Even after taking into account additional sources of uncertainty that the GUM Uncertainty Framework considers as negligible, the Monte Carlo gives again the same uncertainty result (+/-0.18 MUg/L). The main source of this difference is the approximation used by the GUM Uncertainty Framework in estimating the standard uncertainty of the calibration curve produced by least squares regression. Although the GUM Uncertainty Framework proves to be adequate in this particular case, generally the Monte Carlo Method has features that avoid the assumptions and the limitations of the GUM Uncertainty Framework. PMID- 21238754 TI - Quantitative colorimetric-imaging analysis of nickel in iron meteorites. AB - A quantitative analytical imaging approach for determining the nickel content of metallic meteorites is proposed. The approach uses a digital image of a series of standard solutions of the nickel-dimethylglyoxime coloured chelate and a meteorite sample solution subjected to the same treatment as the nickel standards for quantitation. The image is processed with suitable software to assign a colour-dependent numerical value (analytical signal) to each standard. Such a value is directly proportional to the analyte concentration, which facilitates construction of a calibration graph where the value for the unknown sample can be interpolated to calculate the nickel content of the meteorite. The results thus obtained were validated by comparison with the official, ISO-endorsed spectrophotometric method for nickel. The proposed method is fairly simple and inexpensive; in fact, it uses a commercially available digital camera as measuring instrument and the images it provides are processed with highly user friendly public domain software (specifically, ImageJ, developed by the National Institutes of Health and freely available for download on the Internet). In a scenario dominated by increasingly sophisticated and expensive equipment, the proposed method provides a cost-effective alternative based on simple, robust hardware that is affordable and can be readily accessed worldwide. This can be especially advantageous for countries were available resources for analytical equipment investments are scant. The proposed method is essentially an adaptation of classical chemical analysis to current, straightforward, robust, cost effective instrumentation. PMID- 21238755 TI - A simple double-bead sandwich assay for protein detection in serum using UV-vis spectroscopy. AB - In this study a double-bead sandwich assay, employing magnetic nanoparticles and gold nanoparticles is proposed. The magnetic nanoparticles allow specific capturing of the analyte in biological samples, while the optical properties of the gold nanoparticles provide the signal transduction. We demonstrated that a major improvement in the assay sensitivity was obtained by selecting an optimal gold nanoparticle size (60 nm). A detection limit of 5-8 ng/mL, a sensitivity of 0.6-0.8 (pg/mL)(-1) and a dynamic range of 3 orders of magnitude were achieved without any further amplification using the detection of prostate specific antigen in serum as a model system. The proposed assay has the ability to be easily implemented within a microfluidic device for point-of-care applications whereby the readout can be executed by a fast and cheap optical measurement. PMID- 21238756 TI - Breath analysis by optical fiber sensor for the determination of exhaled organic compounds with a view to diagnostics. AB - Breath analysis constitutes a promising tool in clinical and analytical fields due to its high potential for non-invasive diagnostics of metabolic disorders and monitoring of disease status. An optical fiber (OF) sensor has been developed for determination of volatile organic compounds (ethane, pentane, heptane, octane, decane, benzene, toluene and styrene) in human breath for clinical diagnosis. The analytical system developed showed a high performance for breath analysis, inferred for the analytical signal intensity and stability, linear range, and detection limits ranging from 0.8 pmol L(-1), for heptane, and to 9.5 pmol L(-1), for decane. The OF sensor also showed advantageous features of near real-time response and low instrumentation costs, besides showing an analytical performance equivalent to the breath analysis by gas chromatography-mass spectrometry (GC MS), used as the reference method. PMID- 21238757 TI - Capillary zone electrophoresis for U(VI) and short chain carboxylic acid sorption studies on silica and rutile. AB - Capillary zone electrophoresis was used to study the uranyl and short chain carboxylic acid sorption on silica and rutile. The separation and the simultaneous determination (in a single run) of a number of short chain carboxylic acids (oxalic, formic, acetic and propionic) and U(VI) with direct UV detection is developed for the analysis of solutions after the sorption experiments. The reverse polarity mode is used (the injection is performed at the negative end). The matrix effect of Si(IV) (possible silica dissolution product) and perchlorate (added for constant ionic strength in sorption experiments) on the separation of U(VI) and organic acids is investigated. The influence of methanol addition in carrier electrolyte on the separation selectivity of given analytes is also studied. Under the chosen conditions (carbonate buffer (ionic strength of 0.1M), pH 9.8, 0.15 mM of tetradecyltrimethylammonium bromide, 25% (v/v) of methanol) the calibration curves are plotted. They are linear in two ranges of concentration from ~1*10(-5) to ~1*10(-3) M for oxalate, acetate, propionate, U(VI) and ~1*10(-4) to ~1*10(-3) for formate. The accuracy of the procedure is checked by the "added-found" method in simulation solutions. The relative standard deviations of the concentrations found are within the range of 1-10% and the recovery is in the range of 90-115%. This method is applied for the analysis of aqueous samples issued from sorption experiments on silica and rutile. The obtained results indicate that the given organic acids decrease uranium sorption both on silica and rutile. These experiments demonstrate that short chain carboxylic acids can influence the mobility and the chemistry of U(VI) in the environment. PMID- 21238758 TI - Simultaneous determination of potassium guaiacolsulfonate, guaifenesin, diphenhydramine HCl and carbetapentane citrate in syrups by using HPLC-DAD coupled with partial least squares multivariate calibration. AB - A simple and rapid analytical procedure was proposed for the determination of chromatographic peaks by means of partial least squares multivariate calibration (PLS) of high-performance liquid chromatography with diode array detection (HPLC DAD). The method is exemplified with analysis of quaternary mixtures of potassium guaiacolsulfonate (PG), guaifenesin (GU), diphenhydramine HCI (DP) and carbetapentane citrate (CP) in syrup preparations. In this method, the area does not need to be directly measured and predictions are more accurate. Though the chromatographic and spectral peaks of the analytes were heavily overlapped and interferents coeluted with the compounds studied, good recoveries of analytes could be obtained with HPLC-DAD coupled with PLS calibration. This method was tested by analyzing the synthetic mixture of PG, GU, DP and CP. As a comparison method, a classsical HPLC method was used. The proposed methods were applied to syrups samples containing four drugs and the obtained results were statistically compared with each other. Finally, the main advantage of HPLC-PLS method over the classical HPLC method tried to emphasized as the using of simple mobile phase, shorter analysis time and no use of internal standard and gradient elution. PMID- 21238759 TI - A new potentiometric sensor for the determination of alpha-amylase activity. AB - A platinum redox sensor for the direct potentiometric determination of alpha amylase concentration has been described. The sensor measured the amount of triiodide released from a starch-triiodide complex, which was correlated with the alpha-amylase activity after biocatalytic starch degradation. The composition and stability of the potassium triiodide solution was optimized. The starch-triiodide complex was characterized potentiometrically at variable starch and triiodide concentrations. The response mechanism of the platinum redox sensor towards alpha amylase was proposed and the appropriate theoretical model was elaborated. The results obtained using the redox sensor exhibited satisfactory accuracy and precision and good agreement with a standard spectrophotometric method and high sensitive fully automated descret analyser method. The sensor was tested on pure alpha-amylase (EC 3.2.1.1, Fluka, Switzerland), industrial granulated alpha amylase Duramyl 120 T and an industrial cogranulate of protease and alpha-amylase Everlase/Duramyl 8.0 T/60 T. The detection limit was found to be 1.944 mU for alpha-amylase in the range of 0-0.54 U (0-15 MUg), 0.030 mKNU for Duramyl 120 T in the range of 0-9.6 mKNU (0-80 MUg) and 0.032 mKNU for Everlase/Duramyl 8.0 T/60 T in the range of 0-9.24 mKNU (0-140 MUg). PMID- 21238760 TI - Evaluation of various QuEChERS based methods for the analysis of herbicides and other commonly used pesticides in polished rice by LC-MS/MS. AB - Four different extraction and clean-up protocols based on the QuEChERS method were compared for the development of an optimized sample preparation procedure for the multiresidue analysis of 16 commonly applied herbicides in rice crops using LC-QqQ/MS. Additionally the methods were evaluated for the analysis of 26 insecticides and fungicides currently used in rice crops. The methods comprise, in general, the hydratation of the sample with water followed by the extraction with acetonitrile, phase separation with the addition of different salts and finally a clean-up step with various sorbents. Matrix effects were evaluated for the 4 studied methods using LC-QqQ/MS. Additionally LC-TOF/MS was used to compare the co-extractants obtained with the four assayed methodologies. Thirty-six pesticides presented good performance with recoveries in the range 70-120% and relative standard deviations below 20% using 7.5 g of milled polished rice and the buffered acetate QuEChERS method without clean-up at both fortification levels: 10 and 300 MUg kg(-1). The other six pesticides presented low recovery rates, nevertheless all these analytes could be analyzed with at least one of the other three studied procedures. PMID- 21238761 TI - Optimization of a pharmaceutical freeze-dried product and its process using an experimental design approach and innovative process analyzers. AB - The aim of the present study was to examine the possibilities/advantages of using recently introduced in-line spectroscopic process analyzers (Raman, NIR and plasma emission spectroscopy), within well-designed experiments, for the optimization of a pharmaceutical formulation and its freeze-drying process. The formulation under investigation was a mannitol (crystalline bulking agent) sucrose (lyo- and cryoprotector) excipient system. The effects of two formulation variables (mannitol/sucrose ratio and amount of NaCl) and three process variables (freezing rate, annealing temperature and secondary drying temperature) upon several critical process and product responses (onset and duration of ice crystallization, onset and duration of mannitol crystallization, duration of primary drying, residual moisture content and amount of mannitol hemi-hydrate in end product) were examined using a design of experiments (DOE) methodology. A 2 level fractional factorial design (2(5-1)=16 experiments+3 center points=19 experiments) was employed. All experiments were monitored in-line using Raman, NIR and plasma emission spectroscopy, which supply continuous process and product information during freeze-drying. Off-line X-ray powder diffraction analysis and Karl-Fisher titration were performed to determine the morphology and residual moisture content of the end product, respectively. In first instance, the results showed that - besides the previous described findings in De Beer et al., Anal. Chem. 81 (2009) 7639-7649 - Raman and NIR spectroscopy are able to monitor the product behavior throughout the complete annealing step during freeze-drying. The DOE approach allowed predicting the optimum combination of process and formulation parameters leading to the desired responses. Applying a mannitol/sucrose ratio of 4, without adding NaCl and processing the formulation without an annealing step, using a freezing rate of 0.9 degrees C/min and a secondary drying temperature of 40 degrees C resulted in efficient freeze-drying supplying end products with a residual moisture content below 2% and a mannitol hemi-hydrate content below 20%. Finally, using Monte Carlo simulations it became possible to determine how varying the factor settings around their optimum still leads to fulfilled response criteria, herewith having an idea about the probability to exceed the acceptable response limits. This multi-dimensional combination and interaction of input variables (factor ranges) leading to acceptable response criteria with an acceptable probability reflects the process design space. PMID- 21238762 TI - Determination and importance of temperature dependence of retention coefficient (RPHPLC) in QSAR model of nitrazepams' partition coefficient in bile acid micelles. AB - Linear dependence between temperature (t) and retention coefficient (k, reversed phase HPLC) of bile acids is obtained. Parameters (a, intercept and b, slope) of the linear function k=f(t) highly correlate with bile acids' structures. Investigated bile acids form linear congeneric groups on a principal component (calculated from k=f(t)) score plot that are in accordance with conformations of the hydroxyl and oxo groups in a bile acid steroid skeleton. Partition coefficient (K(p)) of nitrazepam in bile acids' micelles is investigated. Nitrazepam molecules incorporated in micelles show modified bioavailability (depo effect, higher permeability, etc.). Using multiple linear regression method QSAR models of nitrazepams' partition coefficient, K(p) are derived on the temperatures of 25 degrees C and 37 degrees C. For deriving linear regression models on both temperatures experimentally obtained lipophilicity parameters are included (PC1 from data k=f(t)) and in silico descriptors of the shape of a molecule while on the higher temperature molecular polarisation is introduced. This indicates the fact that the incorporation mechanism of nitrazepam in BA micelles changes on the higher temperatures. QSAR models are derived using partial least squares method as well. Experimental parameters k=f(t) are shown to be significant predictive variables. Both QSAR models are validated using cross validation and internal validation method. PLS models have slightly higher predictive capability than MLR models. PMID- 21238763 TI - Powdered activated carbons as effective phases for bar adsorptive micro extraction (BAMUE) to monitor levels of triazinic herbicides in environmental water matrices. AB - Bar adsorptive micro-extraction using three powdered activated carbons (ACs) as adsorbent phases followed by liquid desorption and high performance liquid chromatography with diode array detection (BAMUE(ACs)-LD/HPLC-DAD), was developed to monitor triazinic herbicides (atrazine, simazine and terbutylazine) in environmental water matrices. ACs used present apparent surface areas around 1000 m(2) g(-1) with an important mesoporous volume and distinct surface chemistry characteristics (pH(PZC) ranging from 6.5 to 10.4). The textural and surface chemistry properties of the ACs adsorbent phases were correlated with the analytical data for a better understanding of the overall enrichment process. Assays performed on 10 mL water samples spiked at the 10.0 MUg L(-1) levels under optimized experimental conditions yielded recoveries around 100% for the three herbicides under study. The analytical performance showed good precision (RSD<15.0%), convenient detection limits (~0.1 MUg L(-1)) and suitable linearity (1.0-12.0 MUg L(-1)) with good correlation coefficients (r(2)>0.9914). By using the standard addition method, the application of the present method on real water matrices, such as surface water and wastewater, allowed very good performances at the trace level. The proposed methodology proved to be a suitable sorptive extraction alternative for the analysis of priority pollutants with polar characteristics, showing to be easy to implement, reliable, sensitive and requiring a low sample volume to monitor triazinic compounds in water matrices. PMID- 21238764 TI - Comparative evaluation of antioxidant capacities of thiol-based antioxidants measured by different in vitro methods. AB - Thiol-type compounds are an important class of strong antioxidants and main determinants of total antioxidant capacity (TAC) of cellular homogenates. The TAC of thiol mixtures and the corresponding TEAC (trolox equivalent antioxidant capacity) values of individual thiols were determined by the CUPRAC (CUPric Reducing Antioxidant Capacity) method, and the results were compared with those found by reference assays for method validation. Synthetic mixtures of thiols were prepared, and the expected and found TAC values (in mM trolox (TR) equivalents) of these mixtures showed a good agreement. The technique of standard additions was performed for thiol mixtures and human serum, and the absorbance results confirmed that apparent chemical deviations from Beer's law were absent in the system. The CUPRAC results were compared with those of reference methods, namely 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS)/persulphate and Ferric Reducing Antioxidant Power (FRAP). As being a most important thiol ( SH) peptide at in vivo conditions, glutathione (GSH) showed a TEAC value of 0.57 in the CUPRAC method, as opposed to the corresponding value (1.51) in the ABTS/persulphate method. The ABTS/persulphate result was not in accordance with the reversible 1-e oxidation of GSH to the corresponding disulfide that is expected to occur under physiological conditions. FRAP did not give consistent results, and even at relatively high concentrations of GSH, the TEAC(FRAP) value was only 0.07. The thiol-type antioxidant-bearing pharmaceuticals of Brunac eye drop, Trom and Mentopin effervescent tablets containing N-acetyl-L-cysteine (NAC) were assayed with HPLC for comparison, and the obtained results for NAC were in accordance with those found with CUPRAC. PMID- 21238765 TI - Quantitative LIBS analysis of vanadium in samples of hexagonal mesoporous silica catalysts. AB - The method for the analysis of vanadium in hexagonal mesoporous silica (V-HMS) catalysts using Laser Induced Breakdown Spectrometry (LIBS) was suggested. Commercially available LIBS spectrometer was calibrated with the aid of authentic V-HMS samples previously analyzed by ICP OES after microwave digestion. Deposition of the sample on the surface of adhesive tape was adopted as a sample preparation method. Strong matrix effect connected with the catalyst preparation technique (1st vanadium added in the process of HMS synthesis, 2nd already synthesised silica matrix was impregnated by vanadium) was observed. The concentration range of V in the set of nine calibration standards was 1.3-4.5% (w/w). Limit of detection was 0.13% (w/w) and it was calculated as a triple standard deviation from five replicated determinations of vanadium in the real sample with a very low vanadium concentration. Comparable results of LIBS and ED XRF were obtained if the same set of standards was used for calibration of both methods and vanadium was measured in the same type of real samples. LIBS calibration constructed using V-HMS-impregnated samples failed for measuring of V HMS-synthesized samples. LIBS measurements seem to be strongly influenced with different chemical forms of vanadium in impregnated and synthesised samples. The combination of LIBS and ED XRF is able to provide new information about measured samples (in our case for example about procedure of catalyst preparation). PMID- 21238766 TI - Column-switching linked to large sample volumes to preconcentrate beta-blockers at trace levels in environmental water. AB - This paper describes about an automated on-line enrichment method for the simultaneous determination of seven beta-blockers in river water using a short liquid chromatography column for preconcentration coupled with LC-DAD. The method performs the preconcentration of 30 mL of river water samples (5% organic modifier) using a 50 mm*4.6 mm C18 column for enrichment and a 150 mm*4.6 mm C18 column for separation, allowing the determination of beta-blockers at trace levels in river water. The analytical procedure was developed by optimizing the breakthrough parameters (flow rate, time of preconcentration and percentage of organic modifier added to the sample) in order to achieve the maximum sensitivity, and by optimizing the mobile phase (composition and flow rate) to get adequate separation of the components in a reasonable analysis time. Under the optimized conditions, the method was validated with respect to linearity, precision, limits of detection, limits of quantification and accuracy. Detection and quantitation limits ranged between 0.1 and 3.1 and between 1.0 and 5.0 ng mL( 1), respectively, whereas the RSD on inter-day precision was below 8%. To cope with the matrix effect in the determination of these drugs in river water samples, the standard addition methodology was successfully applied. Recoveries ranging from 81 to 115% proved the accuracy of the methodology proposed in this work. PMID- 21238767 TI - Directly suspended droplet microextraction combined with single drop back extraction as a new approach for sample preparation compatible with capillary electrophoresis. AB - A simple and novel method of directly suspended droplet microextraction (DSDME) combined with single drop back-extraction prior to capillary electrophoresis (CE) measurement is developed. In this technique, DSDME was firstly carried out under the maximum stirring rate for a desired time. Then, an aqueous droplet as back extractive phase suspended at the needle tip was immersed in droplet of organic phase for back-extracted. After extraction, the aqueous droplet was transferred into a suitable vial and injected into CE for analysis. Three alkaloids were selected as model compounds for developing and evaluating the method performance. Under the optimum conditions, the enrichment factors ranged from 231 to 524. The relative standard deviations for five replicates were in the range of 4.8-8.1%. The calibration graph was linear in the range of 20-1000 ng mL(-1) yielding correlation coefficients higher than 0.9983. The limit of detections varied from 8.1 to 14.1 ng mL(-1). Human urine samples were spiked with three alkaloids standard to assess the matrix effects and satisfactory results were obtained. The advantages of this method are simplicity of operation, rapid detection, low cost, high enrichment factor and little solvent consumption. PMID- 21238768 TI - The preparation of glutathione-capped CdTe quantum dots and their use in imaging of cells. AB - In this paper, different sizes of glutathione-capped CdTe (GSH/CdTe) quantum dots (QDs) have been prepared directly in aqueous solution. The QDs have tunable fluorescence in the range of 510-670 nm, and they also have high photoluminescence quantum yield (PLQY) without any postpreparative treatment. Furthermore, the QDs have strong resistance to photobleaching, and they also have to be considered as cytocompatible. In addition, for the first time, folic acid was covalently conjugated to the GSH/CdTe QDs for imaging of cancer cells, demonstrating their potentially broad application as biolabels. PMID- 21238769 TI - Sulfur determination in coal using molecular absorption in graphite filter vaporizer. AB - The vaporization of sulfur containing samples in graphite vaporizers for atomic absorption spectrometry is accompanied by modification of sulfur by carbon and, respectively, appearance at high temperature of structured molecular absorption in 200-210 nm wavelength range. It has been proposed to employ the spectrum for direct determination of sulfur in coal; soundness of the suggestion is evaluated by analysis of coal slurry using low resolution CCD spectrometer with continuum light source coupled to platform or filter furnace vaporizers. For coal in platform furnace losses of the analyte at low temperature and strong spectral background from the coal matrix hinder the determination. Both negative effects are significantly reduced in filter furnace, in which sample vapor efficiently interacts with carbon when transferred through the heated graphite filter. The method is verified by analysis of coals with sulfur content within 0.13-1.5% (m/m) range. The use of coal certified reference material for sulfur analyte addition to coal slurry permitted determination with random error 5-12%. Absolute and relative detection limits for sulfur in coal are 0.16 MUg and 0.02 mass%, respectively. PMID- 21238770 TI - Selective colorimetric sensing of Cu2+ using triazolyl monoazo derivative. AB - Although the high sensitivity, high selectivity and fast response make emission (fluorescence) based technique as one of the most promising tool for developing the chemosensors for metal ions, the past few years have witnessed a demand for the absorption based chemosensors for paramagnetic heavy metal ions, especially Cu(2+). Being paramagnetic, Cu(2+) leads to the low signal outputs ("turn-off") caused by decreased emission which may sometimes give false positive response, rendering the emission based technique less reliable for analytical purposes. Herein, we report synthesis and characterization of a hetarylazo derivative, characterized by a strong charge-transfer band which gets attenuated convincingly in the presence of Cu(2+) leading to distinct naked-eye color change (yellow to purple), and to a lesser extent in the presence of Cd(2+), Zn(2+), Co(2+), Pb(2+), Fe(2+), Ni(2+), Fe(3+) and Hg(2+) for which the naked eye sensitivity was comparatively (w.r.t. Cu(2+)) much less. No response was observed for the other metal ions including Li(+), Na(+), K(+), Mg(2+), Ca(2+), Ba(2+), Mn(2+), Ag(+), Zn(2+), Cd(2+), Pb(2+), and lanthanides Ce(3+), La(3+), Pr(3+), Eu(3+), Nd(3+), Lu(3+), Yb(3+), Tb(3+), Sm(3+), Gd(3+). The proposed sensing mechanism has been ascribed to the stabilization of LUMO after complexation with Cu(2+) and a 1:1 stoichiometry has been deduced. PMID- 21238771 TI - Quantification of N-acetylcysteine in pharmaceuticals using cobalt phthalocyanine modified graphite electrodes. AB - Flow injection analysis (FIA) with amperometric detection was employed for the quantification of N-acetylcysteine (NAC) in pharmaceutical formulations, utilizing an ordinary pyrolytic graphite (OPG) electrode modified with cobalt phthalocyanine (CoPc). Cyclic voltammetry was used in preliminary studies to establish the best conditions for NAC analysis. In FIA-amperometric experiments the OPG-CoPc electrode exhibited sharp and reproducible current peaks over a wide linear working range (5.0*10(-5)-1.0*10(-3) mol L(-1)) in 0.1 mol L(-1) NaOH solution. High sensitivity (130 mA mol(-1) cm(2)) and a low detection limit (9.0*10(-7) mol L(-1)) were achieved using the sensor. The repeatability (R.S.D.%) for 13 successive flow injections of a solution containing 5.0*10(-4) mol L(-1) NAC was 1.1%. The new procedure was applied in analyses of commercial pharmaceutical products and the results were in excellent agreement with those obtained using the official titrimetric method. The proposed amperometric method is highly suitable for quality control analyses of NAC in pharmaceuticals since it is rapid, precise and requires much less work than the recommended titrimetric method. PMID- 21238772 TI - Determination of uric acid and creatinine in human urine using hydrophilic interaction chromatography. AB - Uric acid is the end-product of purine metabolism and a major antioxidant in humans. The concentrations of uric acid in plasma and urine are associated with various diseases and routinely measured in clinical and biomedical laboratories using enzymatic conversion and colorimetric measurement. In this study a hydrophilic interaction chromatographic (HILIC) method was developed for simultaneous determination of uric acid and creatinine, a biomarker of urine dilution and renal function, in human urine. Urine samples were pretreated by dilution, protein precipitation, centrifugation and filtration. Uric acid and creatinine were separated from other components in urine samples and quantified using HILIC chromatography. A linear relationship between the ratio of the peak area of the standards to that of the internal standard and the concentration of the standards was obtained for both uric acid and creatinine with the square of correlation coefficients >0.999 for both analytes. The detection limits were 0.04 MUg/mL for creatinine and 0.06 MUg/mL for uric acid. The described HILIC method has proved to be simple, accurate, robust and reliable. PMID- 21238773 TI - A new device for magnetic stirring-assisted dispersive liquid-liquid microextraction of UV filters in environmental water samples. AB - A new method based on dispersive liquid-liquid microextraction (DLLME) in combination with high-performance liquid chromatography (HPLC) has been developed for the analysis of UV filters. A specially designed flask, which has two narrow open necks with one of them having a capillary tip, was employed to facilitate the DLLME process. By adopting such a device, the extraction and subsequent phase separation were conveniently achieved. A binary solvent system of water sample and low-density extraction solvent (1-octanol) was used for the DLLME and no disperser solvent was involved. The extraction was accelerated by magnetic agitation of the two phases. After extraction, phase separation of the extraction solvent from the aqueous sample was easily achieved by leaving the extraction system statically for a while. No centrifugation step involving in classical DLLME was necessary. The analyte-enriched phase, floating above the sample solution, was elevated and concentrated into the narrow open tip of the flask by adding pure water into it via the other port, which was withdrawn with a microsyringe for the subsequent HPLC analysis. Under the optimized conditions, the limits of detection for the analytes were in range of 0.2-0.8ngmL(-1) .The linearity ranges were 8-20,000 ng mL(-1) for HB, 7-20,000 ng mL(-1) for DB, 8 10,000 ng mL(-1) for BP and 5-20,000 ng mL(-1) for HMB, respectively. Enrichment factors ranging from 59 to 107 folders were obtained for the analytes. The relative standard deviations (n=3) at a spiked level of 80 ng mL(-1) were between 1.4 and 4.8%. The proposed magnetic stirring-assisted DLLME method was successfully applied to the analysis of lake water samples. PMID- 21238774 TI - CdTe quantum dots as a highly selective probe for prion protein detection: colorimetric qualitative, semi-quantitative and quantitative detection. AB - CdTe quantum dots (QDs) were used as a highly selective probe for the detection of prion protein. Orange-emitting precipitates appeared within 30s of the addition of recombination prion protein (rPrP) to a solution of green-emitting CdTe QDs. This allowed colorimetric qualitative and semi-quantitative detection of rPrP. The decrease in fluorescence intensity of the supernatant could be used for quantitative detection of rPrP. The fluorescence intensity of the supernatant was inversely proportional to the rPrP concentration from 8 to 200 nmol L(-1) (R(2)=0.9897). Transmission electron microscopy results showed that fibrils existed in the precipitates and these were partly transformed to amyloid plaques after the addition of rPrP. PMID- 21238775 TI - Development of metal complex imprinted solid-phase microextraction fiber for 2,2' dipyridine recognition in aqueous medium. AB - In this paper, a novel metal complex imprinted polymer (CIP) coated solid-phase microextraction (SPME) fiber was prepared which could recognize the complex template [Cu(OAc)(2)(2,2'-dipyridine)] in aqueous medium. The saturating adsorption capacity of CIP-coated fiber was 2.2 and 2.6 times greater than those of molecularly imprinted polymer (MIP) coated fiber and nonimprinted polymer (NIP) coated fiber, respectively. Extraction conditions that influenced the recognition performance of CIP-coated fiber were investigated including pH, extraction solvent, metal ion species, etc. The ligand selectivity was also evaluated and discussed. The results demonstrated that CIP-coated fiber had better binding affinity for 2,2'-dipyridine compared to its structure analogues. The recognition ability of CIP coating was stable and effective in aqueous medium while MIP coating showed weak imprinting effect due to disturbance from protic solvent. 2,2'-dipyridine extracted by CIP-coated fiber using HPLC/UV detection resulted in a linear range of 10-200 MUg/L with a detection limit of 2.0 MUg/L. The proposed method was successfully applied to the analysis of 2,2'-dipyridine in spiked tap water, laboratory wastewater and human urine samples with recoveries 80.3-103.3% and RSDs 5.5-8.9%. PMID- 21238776 TI - A novel small molecule fluorescent sensor for Zn2+ based on pyridine-pyridone scaffold. AB - The development of a water-soluble and small molecular weight fluorescent probe, 3-(4-methoxyphenyl)-4-(methylsulfanyl)-6-(pyridin-2-yl)pyridin-2(1H)-one (3), for detecting Zn(2+) based on pyridine-pyridone skeleton is reported. We observed a clear chelation enhanced fluorescence effect of 3 in the presence of Zn(2+). Other fluorescent properties of 3 are discussed. PMID- 21238777 TI - Determination of melamine in dairy products by an electrochemiluminescent method combined with solid-phase extraction. AB - An electrochemiluminescence (ECL) enhancement method combined with solid-phase extraction has been developed for the determination of melamine in dairy products. It was found that melamine in a strong base solution is able to enhance the ECL of Ru(bpy)(3)(2+) at glass carbon electrode. The optimum experimental conditions for the determination of trace melamine by ECL, such as scan mode and scan rate of the applied potential, the type of buffer solutions and their pH conditions, were investigated. Under optimized conditions, the enhanced ECL intensity was linearly proportional to the logarithm of melamine concentration in the range of 0.01-1.0 ppb, and the detection limit was 0.003 ppb. The method has been successfully demonstrated to determine melamine in dairy products including liquid milk, yogurt and milk powder samples. The relative standard deviations ranging from 5.3% to 11.2% and the recoveries from 95.2% to 102.4% were acquired by this method. A possible mechanism for the ECL enhancement effect was also proposed. PMID- 21238778 TI - Samarium (III) adsorption on bentonite modified with N-(2-hydroxyethyl) ethylenediamine. AB - A new material has been synthesized using dry process to activate bentonite followed by N-(2-hydroxyethyl) ethylenediamine connecting chlorosilane coupling agent. The synthesized new material was characterized by elemental analysis, FT IR and thermogravimetry which proved that bentonite was successfully modified. The most interesting trait of the new material was its selective adsorption for rare earth elements. A variety of conditions of the new material were investigated for adsorption. The optimal conditions were determined with respect to pH and shaking time. Samarium (Sm) was quantitatively adsorbed at pH 4 and shaking time of 2 min onto the new material. Under these conditions the maximum static adsorption capacity of Sm(III) was found to be 17.7 mg g(-1). The adsorbed Sm(III) ion were quantitatively eluted by 2.0 mL 0.1 mol L(-1) HCl and 5% CS (NH(2))(2) solution. According to IUPAC definition, the detection limit (3sigma) of this method was 0.60 ng mL(-1). The relative standard deviation (RSD) under optimum conditions was less than 3% (n=8). The new material also was applied for the preconcentration of trace Sm(III) in environmental samples with satisfactory results. PMID- 21238779 TI - High throughput tryptic digestion via poly (acrylamide-co-methylenebisacrylamide) monolith based immobilized enzyme reactor. AB - A poly (acrylamide-co-methylenebisacrylamide) (poly (AAm-co-MBA)) monolith was prepared by thermal polymerization in the 100 or 250 MUm i.d. capillary. The monolithic support was activated by ethylenediamine followed by glutaraldehyde. Trypsin was then introduced to form an immobilized enzyme reactor (IMER). The prepared IMER showed a reliable mechanical stability and permeability (permeability constant K=2.65*10(-13) m(2)). With BSA as the model protein, efficient digestion was completed within 20s, yielding the sequence coverage of 57%, better than that obtained from the traditional in-solution digestion (42%), which took about 12h. Moreover, BSA down to femtomole was efficiently digested by the IMER and positively identified by matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). To test the applicability of IMER for complex sample profiling, proteins extracted from Escherichia coli were digested by the IMER and further analyzed by nanoreversed phase liquid chromatography-electrospray ionization-mass spectrometry (nanoRPLC-ESI-MS/MS). In comparison to in-solution digestion, despite slightly fewer proteins were positively identified at a false discovery rate (FDR) of ~1% (333 vs 411), the digestion time used was largely shortened (20s vs 24 h), implying superior digestion performance for the high throughput analysis of complex samples. PMID- 21238780 TI - Overall calibration procedure via a statistically based matrix-comprehensive approach in the stir bar sorptive extraction-thermal desorption-gas chromatography-mass spectrometry analysis of pesticide residues in fruit-based soft drinks. AB - Stir bar sorptive extraction (SBSE)-thermal desorption (TD) procedure combined with gas chromatography mass spectrometry (GC-MS) and the statistical variance component model (VCM) is applied to the determination of semi-volatile compounds including organochlorine and organophosphorus pesticides in various synthetic and real fruit-based soft drink matrices. When the matrix effects are corrected using isotopically labelled or non labelled internal standard, but matrix/calibration run-induced deviations are still present in the measurements, the adoption of a variance component model (VCM) in the quantitative analysis of various matrices via an overall calibration curve is successful. The method produces an overall calibration straight line for any analyte accounting for the uncertainty due to all the sources of uncertainty, namely matrix-induced deviations, calibration runs performed at different times, measurement errors. Small increases in the detection limits and in uncertainty in the concentration values obtained in the inverse regression face favourably the decrease in times and costs for routine analyses. PMID- 21238781 TI - Determination of linuron in water and vegetable samples using stripping voltammetry with a carbon paste electrode. AB - A carbon paste electrode was used for the electrochemical determination of linuron concentrations in water and vegetable extracts. Optimal conditions were established with respect to electrode activation (electrochemical pretreatment), time accumulation, potential accumulation, scan rate, and pH. The limit of detection achieved with a pre-concentration step was 23.0 MUg L(-1). Recovery measurements in vegetable extract and natural water samples were in the range of 98-103%, indicating that the proposed electrochemical method can be employed to analyze linuron in these matrices. The determination results were in good agreement with HPLC results. PMID- 21238782 TI - Urinary signature of anabolic steroids and glucocorticoids in humans by LC-MS. AB - A metabonomic strategy based on LC-MS was employed to investigate the metabolic profile of urine samples from 20 athletes who had been tested positive for corticoids and anabolic steroids and 29 controls. In this aim, different sample preparations and chromatographic conditions were compared. The acquired LC-MS data of doped athletes and controls were subjected to analysis of variance (ANOVA) and principal component analysis (PCA). Using this approach, molecular signature of human urine was obtained showing that metabonomics could be a complementary tool to discriminate different urinary profiles and to track down metabolic changes in humans. PMID- 21238783 TI - Gemifloxacin mesylate (GFM) stability evaluation applying a validated bioassay method and in vitro cytotoxic study. AB - The validation of a microbiological assay applying the cylinder-plate method to determine the quinolone gemifloxacin mesylate (GFM) content is described. Using a strain of Staphylococcus epidermidis ATCC 12228 as the test organism, the GFM content in tablets at concentrations ranging from 0.5 to 4.5 MUg mL(-1) could be determined. A standard curve was obtained by plotting three values derived from the diameters of the growth inhibition zone. A prospective validation showed that the method developed is linear (r=0.9966), precise (repeatability and intermediate precision), accurate (100.63%), specific and robust. GFM solutions (from the drug product) exposed to direct UVA radiation (352 nm), alkaline hydrolysis, acid hydrolysis, thermal stress, hydrogen peroxide causing oxidation, and a synthetic impurity were used to evaluate the specificity of the bioassay. The bioassay and the previously validated high performance liquid chromatographic (HPLC) method were compared using Student's t test, which indicated that there was no statistically significant difference between these two validated methods. These studies demonstrate the validity of the proposed bioassay, which allows reliable quantification of GFM in tablets and can be used as a useful alternative methodology for GFM analysis in stability studies and routine quality control. The GFM reference standard (RS), photodegraded GFM RS, and synthetic impurity samples were also studied in order to determine the preliminary in vitro cytotoxicity to peripheral blood mononuclear cells. The results indicated that the GFM RS and photodegraded GFM RS were potentially more cytotoxic than the synthetic impurity under the conditions of analysis applied. PMID- 21238784 TI - Simple spectrophotocolorimetric method for quantitative determination of gold in nanoparticles. AB - A simple spectrophotocolorimetric method devoted to the measurement of gold content in nanoparticles (NPs) was developed. It includes two steps: (i) metal gold NPs (Au NPs) are oxidized into the AuCl(4)(-) anion using a 5*10(-2) M HCl 1.5*10(-2) M NaCl-7*10(-4) M Br(2) solution, next (ii) AuCl(4)(-) concentration is measured using a spectrophotometric assay based on the reaction of AuCl(4)(-) with the cationic form of Rhodamine B to give a violet ion pair complex. This latter is extracted with diisopropyl ether and the absorbance of the organic complex is measured at 565 nm. The method is linear in the range 6-29 MUM of AuCl(4)(-) with a limit of detection of 4.5MUM. The analytical method was optimized with respect of bromine excess to obtain complete Au NPs oxidation. The method was applied to two types of Au NPs currently under investigation: citrate stabilized Au NPs and Au NPs capped with dihydrolipoic acid (Au@DHLA). Both the gold content of Au NPs and the concentration of NPs (using NP diameter measured by transmission electron microscopy) have been calculated. PMID- 21238785 TI - The medical center core facility is the natural domain of the pathology department. PMID- 21238786 TI - Histologic characteristics of non-microsatellite-instable colon adenomas correlate with distinct molecular patterns. AB - Colon carcinogenesis encompasses the stepwise accumulation of genomic aberrations correlated with the transition of aberrant crypt-adenoma-carcinoma. Recent data have revealed that, in addition to the microsatellite-instable phenotype, the chromosome instability pathway, representing four fifth of the colon carcinoma, could be involved in heterogeneous molecular alterations. Our project was aimed at determining the existence of distinct molecular subtypes in 159 non microsatellite-instable colon polyps and their correlation with histology and dysplasia, using allelotyping, MGMT promoter gene methylation status, and K-RAS mutation analyses. Allelic imbalance, MGMT methylation, and K-RAS mutations arise in 62%, 39%, and 32% of polyps, respectively. Only 14% of polyps had no alterations. A 2-way hierarchical clustering analysis of the allelic imbalances identified subgroups of polyps according to their allelic imbalance frequency and distribution. Not only tubulovillous adenoma but also high-grade adenomas were correlated with high global allelic imbalance frequency (P = .005 and P = .003), with allelic imbalance at microsatellites targeting chromosomes 1, 6, and 9. In conclusion, the data presented in this study show that a large heterogeneity exists in the molecular patterns of alterations in precancerous colon lesions, favoring different modes of tumor initiation. Therefore, molecular alterations correlated with tubulovillous-type and high-grade dysplasia could represent targets identifying predictive factors of progression. PMID- 21238787 TI - Toluene optic neurotoxicity: magnetic resonance imaging and pathologic features. AB - Toluene, a colorless liquid found in glues, paints, and industrial products, is lipid soluble and rapidly absorbed by the lipid-rich central nervous system. Prolonged exposure through occupation or purposeful inhalation may lead to neurologic abnormalities. Two men presented with multifocal central nervous system defects and bilateral optic neuropathy of unclear etiology. After numerous diagnostic tests, including brain magnetic resonance imaging, lumbar puncture, hematologic studies, and in one patient a brain biopsy, chronic inhalation of toluene was found to be the cause. Timely diagnosis is important because patients may experience improvement in neurologic and ocular manifestations with cessation of exposure, whereas continued inhalant abuse or exposure can result in permanent loss of neurologic function. PMID- 21238788 TI - Characterization of the presence of Foxp3(+) T cells from patients with different clinical forms of Chagas' disease. PMID- 21238789 TI - Anaplastic lymphoma kinase expression in neuroblastomas and its relationship with genetic, prognostic, and predictive factors. PMID- 21238790 TI - Healing rate and post-obturation pain of single- versus multiple-visit endodontic treatment for infected root canals: a systematic review. AB - INTRODUCTION: The choice of single- versus multiple-visit root canal treatment for infected teeth is in dispute. The purpose of this systematic review was to compare the healing rate and post-obturation pain of single- versus multiple visit root canal treatment for teeth with infected root canals. METHODS: An exhaustive literature search combined with specified inclusion criteria was performed to identify randomized or quasi-randomized controlled trials (RCTs or quasi-RCTs), comparing root canal treatment in single and multiple appointments (2 or more visits) in patients with infected root canals. RESULTS: Ten RCTs were identified and included in this review. Of these, 6 compared the healing rate and 5 compared the prevalence of post-obturation pain in single- and multiple-visit root canal treatment on teeth with infected root canals. No significant difference was observed in the healing rate between single- versus multiple-visit root canal treatment, as well as the incidence of medium-term post-obturation pain. As to the short-term follow up, the prevalence of post-obturation pain was significantly lower in single-visit than in multiple-visit group. CONCLUSIONS: On the basis of current studies, the healing rate of single- and multiple-visit root canal treatment is similar for infected teeth. Patients experience less frequency of short-term post-obturation pain after single-visit than those having multiple visit root canal treatment. PMID- 21238791 TI - Evaluation of the delivery of mesenchymal stem cells into the root canal space of necrotic immature teeth after clinical regenerative endodontic procedure. AB - INTRODUCTION: Immature teeth with open apices treated with conventional nonsurgical root canal treatment often have a poor prognosis as a result of the increased risk of fracture and susceptibility to recontamination. Regenerative endodontics represents a new treatment modality that focuses on reestablishment of pulp vitality and continued root development. This clinical procedure relies on the intracanal delivery of a blood clot (scaffold), growth factors (possibly from platelets and dentin), and stem cells. However, to date, the clinical presence of stem cells in the canal space after this procedure has not been demonstrated. The purpose of this clinical study was to evaluate whether regenerative endodontic procedures are able to deliver stem cells into the canal space of immature teeth in young patients and to identify the possible tissue origin for these cells. METHODS: After informed consent, the first appointment consisted of NaOCl irrigation and treatment with a triple antibiotic paste. One month later, the root canal space was irrigated with sterile saline, and bleeding was evoked with collection of samples on paper points. Real-time reverse transcription polymerase chain reaction and immunocytochemistry were conducted to compare the gene transcripts and proteins found in the root canal sample with levels found in the systemic circulation. RESULTS: Molecular analyses of blood collected from the canal system indicated the significant accumulation of transcripts for the stem cell markers CD73 and CD105 (up to 600-fold), compared with levels found in the systemic blood. Furthermore, this effect was selective because there was no change in expression of the differentiation markers ALK-P, DSPP, ZBTB16, and CD14. Histologic analyses demonstrated that the delivered cells expressed both CD105 and STRO-1, markers for a subpopulation of mesenchymal stem cells. CONCLUSIONS: Collectively, these findings demonstrate that the evoked bleeding step in regenerative procedures triggers the significant accumulation of undifferentiated stem cells into the canal space where these cells might contribute to the regeneration of pulpal tissues seen after antibiotic paste therapy of the immature tooth with pulpal necrosis. PMID- 21238792 TI - Caries susceptibility of endodontically versus nonendodontically treated teeth. AB - INTRODUCTION: The aim of the present investigation was to evaluate the caries susceptibility of endodontically versus nonendodontically treated teeth in relation to dental plaque-related factors. METHODS: Twenty patients with 2 endodontically treated teeth (ETT) each were examined regarding cariogenic microflora of proximal plaque, in situ plaque pH drop after a sucrose rinse (Stephan curve), and de novo plaque formation. Recurrent caries and the quality of the coronal fillings/crowns of these teeth were also evaluated. ETT were compared with contralateral, nonendodontically treated teeth (NETT). RESULTS: Irrespective to the type of restoration, Streptococcus mutans count, de novo plaque formation, and recurrent caries were higher on the surface of ETT compared with NETT (P < .05). Moreover, the initial (resting) pH in plaque was significantly lower (P < 0.05) in ETT. CONCLUSIONS: ETT showed an increased susceptibility to caries as a result of either alteration in their biological environment or inadequacy of the marginal fit of the dental restoration. Clinicians should be aware of this risk. PMID- 21238793 TI - Comparison of the in vivo antimicrobial effectiveness of sodium hypochlorite and chlorhexidine used as root canal irrigants: a molecular microbiology study. AB - INTRODUCTION: The purpose of this clinical study was to compare the antimicrobial effects of 2.5% sodium hypochlorite (NaOCl) and 0.12% chlorhexidine digluconate (CHX) when used as irrigants during treatment of teeth with apical periodontitis. METHODS: Forty-seven single-rooted single-canal teeth with necrotic pulps and asymptomatic apical periodontitis were selected for this study according to stringent inclusion/exclusion criteria. Bacterial samples were taken at the baseline (S1) and after (S2) chemomechanical preparation using 2.5% NaOCl (n = 30) or 0.12% CHX (n = 17) as the irrigant. Bacterial, archaeal, and fungal presence was evaluated by broad-range polymerase chain reaction (PCR), whereas bacterial identifications were performed by a closed-ended reverse-capture checkerboard approach targeting 28 candidate endodontic pathogens. RESULTS: All S1 samples were PCR positive for bacterial presence but negative for both archaea and fungi. Both NaOCl- and CHX-based protocols were significantly effective in reducing the bacterial levels and number of taxa. No significant differences were observed between them in all tested parameters including the incidence of negative PCR results in S2 (40% for NaOCl vs 47% for CHX, p = 0.8), reduction in the number of taxa per canal (p = 0.3), and reduction in the bacterial levels (p = 0.07). The most prevalent taxa in S2 samples from the NaOCl group were Propionibacterium acnes, Streptococcus species, Porphyromonas endodontalis, and Selenomonas sputigena. In the CHX group, the most prevalent taxa in S2 were Dialister invisus, Actinomyces israelii, Prevotella baroniae, Propionibacterium acidifaciens, and Streptococcus species. CONCLUSIONS: Treatment protocols using irrigation with either NaOCl or CHX succeeded in significantly reducing the the number of bacterial taxa and their levels in infected root canals, with no significant difference between these substances. PMID- 21238794 TI - Comparison of periapical radiography and limited cone-beam computed tomography in mandibular molars for analysis of anatomical landmarks before apical surgery. AB - INTRODUCTION: The purpose of the present study was to evaluate the detectability and dimensions of periapical lesions, the relationship of the mandibular canal to the roots of the respective teeth, and the dimension of the buccal bone by using limited cone-beam computed tomography (CBCT) in comparison to conventional periapical (PA) radiographs for evaluation of mandibular molars before apical surgery. METHODS: The study comprised 38 molars with 75 roots. The type of PA lesion as diagnosed on PA radiographs was compared with the type of lesion seen on sagittal and coronal CBCT sections. The distances of the apices of the first mandibular molars and basal border of the PA lesion to the coronal lining of the mandibular canal were assessed with PA radiographs and corresponding sagittal and coronal CBCT images. Furthermore, coronal CBCT images were used to measure the distance from the apices to the buccal bone surface and the corresponding width of the cortical bone plate. RESULTS: Of 58 detected PA lesions, 15 (25.9%) lesions diagnosed with sagittal CBCT slices were missed with PA radiography. The distance between the apices and the upper border of the mandibular canal was only measurable in 24 of 68 radiographs (35.3%) by using PA images. The cortical bone wall had a mean thickness of 1.7 mm, whereas the total buccal bone wall (cortical and spongious) measured 5.3 mm on average. CONCLUSIONS: The present study highlights the advantages of using limited CBCT for treatment planning in mandibular molars before apical surgery. PMID- 21238795 TI - Prevalence of taurodont and pyramidal molars in a German population. AB - INTRODUCTION: The purpose of this retrospective study was to assess the prevalence of taurodont and pyramidal molars among a German dental school patient population. METHODS: A total of 800 patients' full-mouth periapical radiographs were screened. The radiographs were evaluated under optimal conditions using double magnifying glasses. A total of 4,885 molars (including third molars) were evaluated. The relative incidence and the correlations regarding the location of taurodont and pyramidal teeth (right versus left side and maxillary versus mandibular) were analyzed using the chi-square test. RESULTS: Eighteen patients were found to have a taurodont molar (13 women and 5 men [p = 0.097]). Fifteen patients were found to have a pyramidal molar (11 women and 4 men [p = 0.124]). The overall incidence of patients with taurodont molars was 2.25% and with pyramidal molars 1.88%, respectively. The prevalence of taurodont molars from all teeth examined was 0.61%, and the prevalence of pyramidal molars was 0.50%. No significant differences were obtained regarding the location of the affected teeth (p > 0.05). CONCLUSIONS: The occurrence of taurodont or pyramidal molars among this German population was rare. PMID- 21238796 TI - Comparison of endotoxin levels in previous studies on primary endodontic infections. AB - BACKGROUND: This study was performed to determine which of the quantitative methods, namely, chromogenic endpoint, chromogenic kinetic, and turbidimetric kinetic ones, best fit for the analysis of primary endodontic infections. METHODS: Twenty-one root canals with apical periodontitis were sampled with paper points. The same sample was analyzed by means of the endpoint chromogenic Limulus amebocyte lysate (LAL) assay (QCL), quantitative kinetic chromogenic LAL assay (KQCL), and kinetic turbidimetric LAL assay (Turbidimetric). RESULTS: All three LAL methods were effective in the recovery of endotoxin from root canal infection. Regardless of the method tested, endotoxin was detected in 100% of the root canals (21/21). The KQCL assay yielded a median value of endotoxin of 7.49 EU/mL, close to and not significantly different from those for the turbidimetric test (9.19 EU/mL) (both kinetic methods) (p > 0.05). In contrast, the endpoint QCL showed a median value of 34.20 EU/mL (p < 0.05). The comparison of the three methods revealed that both turbidimetric and KQCL methods were more precise, with best reproducibility (the coefficient variation between analysis of the root canal and its duplicate was lower than 10%). The inhibition/enhancement assay indicated a good interaction between the root canal samples with the turbidimetric method. CONCLUSION: This study has revealed that quantitative kinetic-turbidimetric and kinetic-chromogenic LAL methods are best fitted for the analysis of endotoxins in root canal infection, both being more precise and allowing better reproducibility compared with the endpoint-QCL assay. PMID- 21238797 TI - Observer ability to detect ex vivo simulated internal or external cervical root resorption. AB - INTRODUCTION: The objective of this study was to assess observer ability to detect ex vivo simulated internal and external cervical root resorption. METHODS: A total of 90 single-rooted mandibular anterior teeth were split along the coronal plane. By using a 0.5-mm diameter round bur, 50 of the teeth were drilled to simulate resorptive cavities (25 internal and 25 external cervical resorption), and the remaining 40 teeth were left without surface defects. The sectioned teeth were rejoined and placed in the alveolar sockets of a dry human mandible in groups of 6 and imaged with intraoral film by using 3 different angulations and with a cone-beam computed tomography (CBCT) unit. Film and CBCT image sets were evaluated twice by 3 separate observers. Teeth were scored for the presence and location of resorption by using a 5-point scale. Intraobserver and interobserver kappa coefficients and Az values were calculated for each observer and image set. Differences between modalities were compared by using z statistics, with the significance level set at alpha = 0.05. RESULTS: Both intraobserver and interobserver agreements were statistically higher (p < .05) for the Iluma CBCT images than for the intraoral images. Az values for CBCT images were also statistically higher (p < .05) than for film images for all observers and readings. In addition, kappa and Az values of external cervical resorption cavities were statistically higher (p < .05) than those of internal cervical resorption cavities for all observers, image types, and readings. CONCLUSIONS: High-resolution Iluma CBCT images performed better than film in the ex vivo detection and localization of simulated internal and external cervical root resorption. PMID- 21238798 TI - Immunohistochemical expression of Notch signaling in the lining epithelium of periapical cysts. AB - INTRODUCTION: In this study we evaluated the immunohistochemical expression of the receptors Notch 1 and Notch 2, the ligand Delta 1, and the transcription factors HES 1 and HES 5 in the epithelium of well-defined periapical cysts. METHODS: Immunohistochemistry was carried out on 55 formalin-fixed and paraffin embedded, well-defined periapical cysts with minimum inflammation, obtained from the archival tissue database of the Department of Oral Pathology and Surgery. Western blotting was performed to evaluate the specificity of the anti-Notch antibody and the expression of Notch signaling in 5 fresh-frozen periapical cysts. The levels of staining intensity were estimated by the performance of a semiautomated image analysis system. Descriptive statistic of mean values obtained by computerized image analysis method was performed. RESULTS: Immunostaining reaction of all Notch signaling components was observed in the cytoplasm and/or the cytoplasmic membrane in the majority of epithelial cells of periapical cysts. Nuclear staining was observed occasionally in all cases. Notch 2 showed strong staining in 52.83% of the cases, followed by Notch 1 (35.85%), HES 1 and HES 5 moderate staining in 72.73% and 57.69% of the cases, respectively, and Delta 1 weak staining in 58.33% of the cases. No statistical correlation was found between the antibodies and the sex or the age of the study group. CONCLUSIONS: Notch is an evolutionarily conserved signaling mechanism that regulates cell fate decisions during development and postnatal life in organisms as diverse as worms, flies, and humans. The present observations indicate that Notch pathway is active downstream in the lining epithelium of periapical cysts, suggesting an involvement of this pathway in periapical cyst growth and expansion. PMID- 21238799 TI - Effect of fluocinolone acetonide on human dental pulp cells: cytotoxicity, proliferation, and extracellular matrix formation. AB - INTRODUCTION: The goal of vital pulp therapy is to maintain pulp vitality and function. Fluocinolone acetonide is a potent topical glucocorticoid used in the treatment of skin disorders and oral lesions that could possibly be used to resolve inflammation and stimulate the healing process of inflamed dental pulp. The purpose of this study was to investigate the effects of fluocinolone acetonide (0.1-50 MUmol/L) on cytotoxicity, cell proliferation, and fibronectin and type I collagen synthesis in human dental pulp cells (HDPCs). METHODS: HDPCs were prepared from freshly extracted human third molars. MTT assay was used to determine toxicity and cell proliferation. Western blot analysis was performed to detect fibronectin and type I collagen synthesis. RESULTS: Low concentrations of fluocinolone acetonide were not only nontoxic but also significantly stimulated cell proliferation (P < .05). Fluocinolone acetonide significantly stimulated fibronectin and type I collagen synthesis (P < .05). CONCLUSIONS: Low concentrations (0.1-10 MUmol/L) of fluocinolone acetonide might have the potential to stimulate healing of inflamed dental pulp. PMID- 21238800 TI - Inflammation triggers constitutive activity and agonist-induced negative responses at M(3) muscarinic receptor in dental pulp. AB - The purpose of this study was to investigate whether the inflammation of rat dental pulp induces the muscarinic acetylcholine receptor (mAChR) constitutive receptor activity. Pulpitis was induced with bacterial lipolysaccharide in rat incisors dental pulp. Saturation assay with [(3)H]-quinuclidinyl benzilate ([(3)H] QNB), competitive binding with different mAChR antagonist subtypes, and nitric oxide synthase (NOS) activity were performed. A drastic change in expression and response to mAChR subtypes was observed in pulpitis. Inflamed pulp expressed high number of M(3) mAChR of high affinity, whereas the M(1) mAChR is the main subtype displayed in normal pulp. Consistent with the identification of the affinity constant (Ki) of M(3) and Ki of M(1) in both pulpitis and in normal pulps are the differences in the subtype functionality of these cells. In pulpitis, pilocarpine (1 * 10(-11) mol/L to 5 * 10(-9) mol/L) exerted an inhibitory action on NOS activity that was blocked by J 104129 fumarate (highest selective affinity to M(3) mAChR). In normal pulps, pilocarpine (1 * 10(-11) mol/L to 5 * 10(-9) mol/L) has no effect. NOS basal activity was 5.9 times as high in pulpitis as in the normal pulp as a result of the activation of inducible NOS. The irreversible pulpitis could induce a mAChR alteration, increasing the high-affinity receptor density and transduction-coupling efficiency of inducible NOS activity, leading to a spontaneously active conformation of the receptor. Pilocarpine acting as an inverse agonist might be useful therapeutically to prevent necrosis and subsequent loss of dental pulp. PMID- 21238801 TI - Calcium hydroxide inactivates lipoteichoic acid from Enterococcus faecalis through deacylation of the lipid moiety. AB - INTRODUCTION: Lipoteichoic acid (LTA) is a major virulence factor of Enterococcus faecalis that is closely associated with refractory apical periodontitis. Recently, we have shown that calcium hydroxide, a commonly used intracanal medicament, abrogated the ability of LTA to stimulate the production of tumor necrosis factor alpha in a murine macrophage line, RAW 264.7. Because calcium hydroxide could potentially modify the glycolipid moiety of LTA, we examined if calcium hydroxide inactivates LTA through deacylation of the LTA. METHODS: LTA was prepared from E. faecalis by organic solvent extraction followed by chromatography with the hydrophobic-interaction column and the ion-exchange column. RAW 264.7 cells were stimulated with intact LTA or calcium hydroxide treated LTA for 24 hours, and the productions of nitric oxide (NO) and chemokines interferon-gamma-induced protein (IP-10) and macrophage inflammatory protein 1alpha (MIP-1alpha) were determined. The glycolipid structure of LTA was analyzed using matrix-assisted laser desorption ionization-time of flight mass spectrometry and thin layer chromatography (TLC). RESULTS: The production of NO, IP-10, and MIP-1alpha was augmented in LTA-stimulated cells, whereas no such effect was observed upon stimulation with calcium hydroxide-pretreated LTA. Mass spectrometry showed that intact glycolipids of LTA yielded distinct mass peaks at 930 to 1,070 mass over charge (m/z) units, corresponding to dihexosyl diacylglycerol consisting of two acyl chains with chain lengths of C(16) to C(22) and with one or two unsaturated double bonds. However, those peaks were not observed in the mass spectra of the calcium hydroxide-treated LTA. Furthermore, free fatty acids released from the calcium hydroxide-treated LTA were detected using TLC. CONCLUSION: We suggest that calcium hydroxide attenuates the inflammatory activity of E. faecalis LTA through deacylation of the LTA. PMID- 21238802 TI - An animal model to study regenerative endodontics. AB - INTRODUCTION: A growing body of evidence is demonstrating the possibility for regeneration of tissues within the pulp space and continued root development in teeth with necrotic pulps and open apices. There are areas of research related to regenerative endodontics that need to be investigated in an animal model. The purpose of this study was to investigate ferret cuspid teeth as a model to investigate factors involved in regenerative endodontics. METHODS: Six young male ferrets between the ages of 36-133 days were used in this investigation. Each animal was anesthetized and perfused with 10% buffered formalin. Block sections including the mandibular and maxillary cuspid teeth and their surrounding periapical tissues were obtained, radiographed, decalcified, sectioned, and stained with hematoxylin-eosin to determine various stages of apical closure in these teeth. RESULTS: The permanent mandibular and maxillary cuspid teeth with open apices erupted approximately 50 days after birth. Initial signs of closure of the apical foramen in these teeth were observed between 90-110 days. Complete apical closure was observed in the cuspid teeth when the animals were 133 days old. CONCLUSIONS: Based on the experiment, ferret cuspid teeth can be used to investigate various factors involved in regenerative endodontics that cannot be tested in human subjects. The most appropriate time to conduct the experiments would be when the ferrets are between the ages of 50 and 90 days. PMID- 21238803 TI - Cytotoxicity of Portland cement with different radiopacifying agents: a cell death study. AB - INTRODUCTION: The aim of this study was to investigate the cytotoxicity of white Portland cement (PC) alone or associated with bismuth oxide (PCBi), zirconium oxide (PCZir), and calcium tungstate (PCCa) in 2 cell lineages. METHODS: Murine periodontal ligament cells (mPDL) and rat osteosarcoma cells (ROS 17/2.8) were exposed for 24 hours to specific concentrations of fresh PC and PC associations with radiopacifiers. Zinc oxide-eugenol cement and hydrogen peroxide treatment were applied as cytotoxic positive controls. Cell viability after incubation with the cements was assessed by mitochondrial dehydrogenase enzymatic assay. Cell morphology was microscopically analyzed by cresyl violet staining, and the mechanism of cell death was determined by acridine orange/ethidium bromide methodology. All data were analyzed statistically by analysis of variance and Tukey post hoc test (P < .05). The correlation among cell death by apoptosis or necrosis and pH values was established by Pearson linear coefficient. RESULTS: The mitochondrial dehydrogenase enzymatic assay only revealed significant cell death rate at high concentrations of cement elutes. PC alone was not cytotoxic, even at 100 mg/mL. Microscopic images showed that none of the PC formulations caused damage to any cell lines. Statistical analysis of apoptosis/necrosis data demonstrated that PC and PC plus radiopacifying agents promoted significant necrosis cell death only at 100 mg/mL. CONCLUSIONS: The mPDL cells were more sensitive than ROS17/2.8. The results showed that PC associated with bismuth oxide, zirconium oxide, or calcium tungstate is not cytotoxic to mPDL or ROS17/2.8. Zirconium oxide and calcium tungstate might be good alternatives as radiopacifying agents. PMID- 21238804 TI - Zinc chloride for odontogenesis of dental pulp stem cells via metallothionein up regulation. AB - INTRODUCTION: Previous studies have shown that zinc chloride (ZnCl(2)) can induce metallthionein (MT) in the liver and kidney to protect tissues against toxicants and shows a better corneal wound healing than conventional drugs do. We hypothesized that ZnCl(2) can promote odontogenesis of dental pulp stem cells (DPSCs) via MT. The purpose of this study was to investigate the effects of ZnCl(2) on human DPSCs and the expression of MT. METHODS: DPSCs were isolated by flow cytometry with selective surface marker CD146 and STRO-1. After they grew into confluence, DPSCs were induced into odontoblasts with or without ZnCl(2) supplemented in the culture medium for 21 days. The effect of ZnCl(2) on DPSCs differentiation was examined followed by alkaline phosphatase staining/activity and quantitative real-time polymerase chain reaction analysis. RESULTS: By treating DPSCs with ZnCl(2), the duration of mineralization was shortened and expressions of differentiation markers into odontoblasts were more significant than those without ZnCl(2) stimulation. Besides, the MT gene expression was increased with the increasing expressions of odontoblasts' markers after treated with ZnCl(2). CONCLUSION: This was the first report that ZnCl(2) could promote odontoblastic differentiation of DPSCs through the up-regulation of gene MT. PMID- 21238806 TI - A high-resolution computed tomographic study of changes in root canal isthmus area by instrumentation and root filling. AB - INTRODUCTION: The aim of this study was to obtain a three-dimensional analysis of the isthmus area of the mesiobuccal root canal system in mandibular molars using high-resolution micro-computed tomography (MU-CT) scanning and to measure the amount of debris and root filling material in the isthmus after instrumentation/irrigation and root filling. METHODS: Mandibular molars with two separated mesial root canals (10 teeth) were scanned by using the Skyscan 1172 MU CT system (Skyscan, Aartselaar, Belgium) before and after instrumentation and after filling using the Thermafil root filling technique. An isthmus was defined as the ribbon-shaped or thin connecting structure between two root canals after instrumentation. The characteristics of the isthmuses were quantitatively monitored during the whole treatment. The images were segmented and quantified. The surface area of the isthmus, volume of debris after rotary instrumentation, and volume of the filled space in the isthmus after obturation were evaluated. RESULTS: Of the seven mesial roots, two had isthmus/anastomoses somewhere along its length in the apical 5 mm, and five had an isthmus that was continuous all the way from the coronal part to the apical part. The average percentage of isthmus surface area and isthmus volume after instrumentation was 21.4% and 9.4% of the whole root canal system, respectively. About 35.2% of the isthmus volume was filled with apparent hard tissue debris after instrumentation/irrigation. The average percentage of volume of filling material in the isthmus areas was significantly lower (57.5%) than in the main root canals (98.5%, p < 0.001). CONCLUSIONS: A considerable amount of dentin debris is produced and packed into the isthmus area during rotary instrumentation of mesial canals of lower molars despite continuous irrigation during and after instrumentation. The debris may partly prevent penetration of the filling material and sealer into the isthmus area. PMID- 21238805 TI - Endodontic photodynamic therapy ex vivo. AB - INTRODUCTION: The objective of this study was to evaluate the antimicrobial effects of photodynamic therapy (PDT) on infected human teeth ex vivo. METHODS: Fifty-two freshly extracted teeth with pulpal necrosis and associated periradicular radiolucencies were obtained from 34 subjects. Twenty-six teeth with 49 canals received chemomechanical debridement (CMD) with 6% NaOCl, and 26 teeth with 52 canals received CMD plus PDT. For PDT, root canal systems were incubated with methylene blue (MB) at concentration of 50 MUg/mL for 5 minutes, followed by exposure to red light at 665 nm with an energy fluence of 30 J/cm(2). The contents of root canals were sampled by flushing the canals at baseline and after CMD alone or CMD+PDT and were serially diluted and cultured on blood agar. Survival fractions were calculated by counting colony-forming units (CFUs). Partial characterization of root canal species at baseline and after CMD alone or CMD+PDT was performed by using DNA probes to a panel of 39 endodontic species in the checkerboard assay. RESULTS: The Mantel-Haenszel chi(2) test for treatment effects demonstrated the better performance of CMD+PDT over CMD (P = .026). CMD+PDT significantly reduced the frequency of positive canals relative to CMD alone (P = .0003). After CMD+PDT, 45 of 52 canals (86.5%) had no CFUs as compared with 24 of 49 canals (49%) treated with CMD (canal flush samples). The CFU reductions were similar when teeth or canals were treated as independent entities. Post-treatment detection levels for all species were markedly lower for canals treated by CMD+PDT than they were for those treated by CMD alone. Bacterial species within dentinal tubules were detected in 17 of 22 (77.3%) and 15 of 29 (51.7%) canals in the CMD and CMD+PDT groups, respectively (P = .034). CONCLUSIONS: Data indicate that PDT significantly reduces residual bacteria within the root canal system, and that PDT, if further enhanced by technical improvements, holds substantial promise as an adjunct to CMD. PMID- 21238808 TI - Surface changes of mineral trioxide aggregate after the application of bleaching agents: electron microscopy and an energy-dispersive X-ray microanalysis. AB - INTRODUCTION: The aim of this study was to investigate the changes in the surface structure and chemical composition after applying bleaching agents to completely hardened mineral trioxide aggregate. METHODS: A total of 12 samples of MTA blocks were divided into three groups, two different bleaching agents, and a control group. The surface structure was observed using a scanning electron microscope. The changes in elemental composition were analyzed by an energy-dispersive x-ray microanalysis (EDX) system. RESULTS: The surface of the MTA covered with each bleaching agent changed in terms of both color and structure compared with the control. EDX showed that both bleaching agents affected the elemental distribution. A decrease in Ca and an increase in Si were shown, and this tendency was especially pronounced in the higher hydrogen peroxide concentration group. CONCLUSIONS: The acidic conditions induced by bleaching agents brought about the deterioration of the MTA surface. These findings suggest that MTA is an insufficient barrier against tooth bleaching. PMID- 21238807 TI - Adhesion of Epiphany self-etch sealer to dentin treated with intracanal irrigating solutions. AB - INTRODUCTION: This in vitro study assessed the adhesion of Epiphany self-etch (SE) root canal sealer to dentin treated with different irrigation regimens. METHODS: Flat dentin surfaces were obtained from human third molar teeth; smear layer was created on each sample. Five groups of 10 samples each were conditioned with one of the following regimens: (1) deionized water for 10 minutes; (2) 5% sodium hypochlorite (NaOCl) for 10 minutes; (3) 5% NaOCl for 10 minutes and then 10% sodium ascorbate (Na-Ascr) for 10 minutes; (4) 5% NaOCl for 10 minutes and then 2% chlorhexidine (CHX) for 5 minutes; or (5) 5% NaOCl for 10 minutes and then 10% Na-Ascr for 10 minutes, followed by 2% CHX for 5 minutes. The conditioned dentin surfaces were dried with absorbent paper points. The Epiphany SE sealer was placed on each dentin surface with the use of hollow stainless steel tubes with specific diameter and height. The samples were stored in 100% humidity at 37 degrees C for 7 days and then tested for shear bond strength in a universal testing machine. RESULTS: Shear bond strength data were analyzed by one way analysis of variance and Tukey post hoc tests (P < .05). There were statistically significant differences among the groups. CONCLUSIONS: NaOCl decreased the bond strength of Epiphany SE sealer to dentin, whereas the use of Na-Ascr reversed this negative effect of NaOCl. CHX had neither negative nor positive influence on the bond strength. PMID- 21238809 TI - Efficacy of sonic and ultrasonic activation for removal of calcium hydroxide from mesial canals of mandibular molars: a microtomographic study. AB - BACKGROUND: The purpose of this study was to use micro-computed tomography (micro CT) scanning to evaluate the efficacy of sonic and passive ultrasonic irrigation (PUI) on calcium hydroxide (Ca[OH](2)) removal and to measure the volume and percentage of Ca(OH)(2) remaining in the root canal system. METHODOLOGY: The root canals of 46 extracted human mandibular molar teeth were prepared with rotary instruments and randomly assigned to two experimental groups (n = 40) as well as positive and negative controls (n = 6). In each experimental group, 20 teeth were assigned to each irrigation protocol, sonic or passive ultrasonic irrigation. All experimental teeth and the positive controls were filled with Ca(OH)(2), whereas the negative control teeth did not receive Ca(OH)(2). All teeth were scanned using micro-CT scanning to determine the dressing volume. After 7 days, the Ca(OH)(2) was removed in the experimental groups using rotary instrumentation only, and the teeth were again scanned using micro-CT scanning to calculate volume and percentage of Ca(OH)(2) removed. Positive control teeth were not subjected to rotary instrumentation. Experimental samples were then irrigated using either sonic or passive ultrasonic and the volume of remaining Ca(OH)(2) was calculated using micro-CT. RESULTS: Remnants of Ca(OH)(2) were found in all experimental groups. No Ca(OH)(2) was found in the negative controls, whereas a mean of 8.7 mm(3) of Ca(OH)(2) was recorded in the positive controls. Rotary plus passive ultrasonic irrigation removed significantly more Ca(OH)(2) (85.7%) than rotary plus sonic irrigation (71.5%) (p < 0.001). CONCLUSIONS: The combination of rotary instrumentation and passive ultrasonic activation for 3 periods of 20 seconds results in significantly lower amounts of Ca(OH)(2) remnants in the canal compared with sonic irrigation. PMID- 21238810 TI - Evaluation of the effect of intrinsic material properties and ambient conditions on the dimensional stability of white mineral trioxide aggregate and Portland cement. AB - INTRODUCTION: A number of factors affect the dimensional stability of a material. These factors include curing conditions, material solubility, leaching, and time. The aim of this study was to evaluate the restrained dimensional change in the vertical direction as a function of the ambient conditions, fluid uptake, solubility, and leaching of white mineral trioxide aggregate (MTA) and Portland cement stored in Hank's balanced salt solution (HBSS) over a period of 28 days. METHODS: The dimensional change in the vertical direction over a 28-day period was determined using a linear variable differential transducer (LVDT) on laterally restrained test samples. The fluid uptake and solubility of both MTA and Portland cement was also evaluated. The leaching in water and HBSS was assessed using inductively coupled plasma. RESULTS: MTA was more soluble than Portland cement. Both materials absorbed water and physiological solution, with Portland cement displaying a lower uptake than MTA. Both cements exhibited a net expansion when in contact with a physiological solution and released high levels of calcium. MTA leached bismuth. Both calcium and bismuth ion release was higher in HBSS than in water. Phosphorus ions in HBSS were depleted when in contact with both MTA and Portland cement. CONCLUSIONS: The MTA was very susceptible to ambient conditions. The addition of bismuth oxide to MTA reduced the leaching of calcium hydroxide, increased the material solubility, and caused deterioration in material dimensional stability. Further research is necessary to establish the material porosity and its effect on the dimensional stability. PMID- 21238811 TI - A novel urethane acrylate-based root canal sealer with improved degree of conversion, cytotoxicity, bond strengths, solubility, and dimensional stability. AB - INTRODUCTION: We have developed new urethane acrylate-based root canal sealers using polycarbonate (PC) as polyol and 2,2-azobis(2-methyl)butyronitrile (AMBN) as a thermal initiator. The purpose of this study was to compare the properties among a group of seven sealers: (1) polybutyleneadipate (PBA) with 2,2-azobis isobutyronitrile (AIBN), (2) PBA-AMBN, (3) PC-AIBN, (4) PC-AMBN, (5) AH Plus (Dentsply DeTrey GmbH, Konstanz, Germany), (6) Epiphany (Pentron Clinical Technologies, Wallingford, CT), and (7) EndoREZ (Ultradent Products, Inc, South Jordan, UT). METHODS: Attenuated total reflectance-Fourier transforming infrared spectroscopy was used to analyze the degree of conversion. Cytotoxicity was evaluated using MTT assay. In addition, push-out bond strength, solubility, and dimensional stability were investigated. RESULTS: Urethane acrylate-based root canal sealers behaved better than Epiphany and EndoREZ for the properties evaluated in this study. The PC-AMBN sealer exhibited the highest degree of conversion even in the apical third, and its cytotoxicity for nonsetting and aged specimens at 24 hours was comparable to AH Plus sealer. In addition, the PC-AMBN sealer with zinc oxide/thermoplastic polyurethane cones had a significantly higher bond strength than AH Plus with gutta percha. Solubility and dimensional changes of the PC-AMBN sealer conformed to the American National Standards Institute/American Dental Association (ANSI/ADA) standard 57. CONCLUSIONS: The PC AMBN sealer has great potential for use in endodontic therapy. PMID- 21238812 TI - Evaluation of rat alveolar bone response to Angelus MTA or experimental light cured mineral trioxide aggregate using fluorochromes. AB - INTRODUCTION: The aim of this study was to evaluate the rat alveolar bone response after the implantation of experimental light-cured mineral trioxide aggregate (MTA) or Angelus MTA (Angelus, Londrina, Parana, Brazil) by histological and fluorescence analysis. METHODS: Thirty Wistar Albino rats were divided into three groups. In the control group, empty polyethylene tubes were inserted into the rat alveolar sockets immediately after extraction. In the other groups, the tubes were filled with light-cured MTA or Angelus MTA. Five animals from each group were injected with calcein on day 7, alizarin on day 14, and oxytetracycline on day 21. On day 30, these animals were killed, and the right hemimaxillas were removed and histologically processed. Half of the maxillas were processed and stained with hematoxylin and eosin. The remaining maxillas were processed for fluorescence analysis and stained with Stevenel blue and alizarin red. New bone was histomorphometrically evaluated using a Merz grid. RESULTS: The light-cured MTA presented a similar response when compared with Angelus MTA; it was characterized by a mild inflammatory response and complete bone healing. In the light-cured MTA group, the fluorescence areas were more evident at 21 days, showing an increase in bone formation. However, dystrophic mineralization was observed only with Angelus MTA. CONCLUSIONS: It was concluded that both materials present a similar inflammatory response and bone healing, but dystrophic mineralization was observed only with Angelus MTA. PMID- 21238813 TI - Scanning electron microscopic investigation of the effectiveness of phosphoric acid in smear layer removal when compared with EDTA and citric acid. AB - INTRODUCTION: The smear layer adheres to dentinal surface, thus occluding the dentinal tubules. Because this layer disfavors the penetration of irrigant solutions and root canal fillings, it should be removed. The aim of this study was to compare the effectiveness of 37% phosphoric acid with that of 17% EDTA and 10% citric acid in the removal of smear layer. MATERIALS AND METHODS: Fifty-two maxillary single-rooted human canines were accessed and instrumented. Between each instrument used, the canals were irrigated with sodium hypochlorite. After instrumentation, the teeth were irrigated with distilled water and then divided into groups according to the time and substances employed. The substances used were 17% EDTA, 10% citric acid, and 37% phosphoric acid solution and gel. The experimental time periods were of 30 seconds, 1 minute, and 3 minutes. The samples were prepared and observed by means of scanning electron microscopy. Three photomicrographs (2,000*) were recorded for each sample regarding the apical, middle, and cervical thirds. A score system was used to evaluate the images. RESULTS: None of the substances analyzed in this study was effective for removing the smear layer at 30 seconds. In the 1-minute period, the phosphoric acid solution showed better results than the other substances evaluated. In the 3 minute period, all the substances worked well in the middle and cervical thirds although phosphoric acid solution showed excellent results even in the apical third. CONCLUSIONS: These findings point toward the possibility that phosphoric acid solution could be a promising agent for smear layer removal. PMID- 21238814 TI - Case of Ewing's sarcoma misdiagnosed as a periapical lesion of maxillary incisor. AB - Ewing's sarcoma (ES) belongs to the group II neuroectodermal tumors. They usually occur in diaphyses of long bones, ribs, and pelvis and are rare in head and neck bones, with only 30 cases reported. The mandible is more affected than the maxilla. ES is also the second most common primary malignant bone tumor found in children, after leukemia and osteosarcomas, but they are rare in adults. The following is a report of a new case of ES localized in the maxilla occurring in a 25-year-old man who had been misdiagnosed with an odontogenic infection. The patient was treated successfully, with a 2-year follow-up, by using a combination of aggressive systemic chemotherapy and surgery with primary reconstruction of the defect, avoiding the use of radiotherapy. PMID- 21238815 TI - Revitalization of tooth with necrotic pulp and open apex by using platelet-rich plasma: a case report. AB - INTRODUCTION: A growing body of evidence is demonstrating the possibility for regeneration of tissues within the pulp space and continued root development in teeth with necrotic pulps and open apexes. The purpose of this case report is to add a regenerative endodontic case to the existing literature about using platelet-rich plasma (PRP). METHODS: An 11-year-old boy whose maxillary second premolar tooth had been accidently extracted and immediately replanted developed pulpal necrosis and symptomatic apical periodontitis. After preparing an access cavity, its necrotic pulp was removed. The canal was irrigated with 5.25% NaOCl solution and dried with paper points. A triple antibiotic mixed with distilled water was packed in the canal and left for 22 days. Twenty milliliters of whole blood was drawn from the patient's forearm for preparation of PRP. After removal of the antibiotic mixture, the PRP was injected into the canal space up to the cementoenamel junction level. Three millimeters of grey mineral trioxide aggregate was placed directly over the PRP clot. Three days later, the tooth was double-sealed with permanent filling materials. RESULTS: Clinical examination 5 1/2 half months later revealed no sensitivity to percussion or palpation tests. Radiographic examination of this tooth showed resolution of the periapical lesion, further root development, and continued apical closure. Sensitivity tests with cold and an electric pulp test elicited a positive response similar to those found in the first premolar tooth. CONCLUSIONS: On the basis of short-term results of the present case, it appears that regeneration of vital tissues in a tooth with necrotic pulp and a periapical lesion is possible; PRP is potentially an ideal scaffold for this procedure. PMID- 21238816 TI - Interdisciplinary management of impacted maxillary central incisor with dilacerated crown. AB - INTRODUCTION: Dilaceration of the permanent teeth usually occurs because of trauma to their deciduous predecessors. Dilaceration in the crown is rare compared with that in the root and is more common in the maxillary and mandibular incisors. Generally, surgical exposure of the tooth followed by orthodontic traction or extraction of the tooth is the the choice of treatment. METHODS: This article highlights a surgical-endodontic approach to the management of the left permanent maxillary central incisor with dilaceration of the crown. RESULTS: The 1-year follow-up showed good stability of the prosthesis and good periodontal health. CONCLUSIONS: Surgical resection of the crown followed by endodontic treatment and restoration is a viable and rapid option for the management of crown dilaceration. PMID- 21238819 TI - Assessing the evidence: clinical research trends in dermatology over a 10-year period. PMID- 21238820 TI - Nicolau syndrome following subcutaneous glatiramer-acetate injection. PMID- 21238821 TI - Disseminated follicular eruption during therapy with the MEK inhibitor AZD6244. PMID- 21238822 TI - Effect of adapalene on cetuximab-induced painful periungual inflammation. PMID- 21238823 TI - Update on morphea: part I. Epidemiology, clinical presentation, and pathogenesis. AB - Morphea, also known as localized scleroderma, is a rare fibrosing disorder of the skin and underlying tissues. Morphea is differentiated from systemic sclerosis based on the absence of sclerodactyly, Raynaud phenomenon, and nailfold capillary changes. Patients with morphea commonly have systemic symptoms, such as malaise, fatigue, arthralgias, and myalgias, as well as positive autoantibody serologies. However, involvement of morphea is almost uniformly limited to those tissues derived from the mesoderm. The underlying pathogenesis of morphea is incompletely understood at this time, but ultimately results in an imbalance of collagen production and destruction. PMID- 21238824 TI - Update on morphea: part II. Outcome measures and treatment. AB - Morphea is a rare fibrosing disorder of the skin and underlying tissues. The underlying pathogenesis of morphea is not completely understood at this time, but ultimately results in an imbalance of collagen production and destruction. Evidence-based treatment options of morphea are limited secondary to the rarity of the disease, and the lack of universally used validated outcome measures. The most commonly used outcome measures are skin scores, computerized surface area measurement, durometer, cutometer, thermography, and ultrasound measurements. The Localized Scleroderma Cutaneous Assessment Tool is a promising recently validated skin scoring tool that allows differentiation between activity and damage, is sensitive to change, and requires no additional equipment. The most robust data in the treatment of morphea exists for methotrexate in combination with systemic steroids and ultraviolet A1. PMID- 21238825 TI - The use of oral midazolam for perioperative anxiolysis of healthy patients undergoing Mohs surgery: conclusions from randomized controlled and prospective studies. AB - BACKGROUND: Anxiety can complicate any outpatient procedure by causing elevation in blood pressure and heart rate with resultant increase in intraoperative and postoperative bleeding. Anxiety may also reduce patient satisfaction with the surgical experience. Midazolam is an efficacious short-acting benzodiazepine with an excellent safety record. However, little experience is documented on the use of midazolam in outpatient dermatologic surgery. OBJECTIVE: To establish the safety and efficacy of oral midazolam in healthy patients undergoing Mohs micrographic surgery. METHODS: Patients undergoing outpatient Mohs surgery were randomized in a double-blind, placebo-controlled study of single-dose midazolam for efficacy and safety in producing anxiolysis of short duration. A subpopulation of patients was evaluated prospectively in a nonrandomized arm of the study. Data on vital signs, anxiety, adverse events, and overall satisfaction were collected and compared using analysis of covariance model. RESULTS: Forty four patients were randomized and 31 patients were enrolled in the prospective arm. Socioeconomic and surgical characteristics were similar among the groups. At 60 minutes, there was a clinically and statistically significant reduction in anxiety and alertness in both randomized and prospective arms. There were no major adverse events. Patients in all 3 groups were equally satisfied with their experience. LIMITATIONS: Few patients with high perioperative anxiety were willing to participate in a randomized controlled trial of anxiolytic medication. CONCLUSIONS: Midazolam is safe and efficacious in perioperative anxiolysis for healthy patients undergoing outpatient Mohs micrographic surgery. Midazolam offers the benefits of amnesia, reduced alertness, and reduced blood pressure with no clinically significant adverse effects. PMID- 21238826 TI - Correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent basal cell carcinoma. AB - BACKGROUND: The type of treatment for a basal cell carcinoma (BCC) depends on the histologic subtype. Histologic examination is usually performed on incisional biopsy specimens. In primary BCC, the histologic subtype is correctly identified with a punch biopsy in 80.7% of cases. In recurrent BCC, correct identification is more difficult because of discontinuous growth caused by scar formation. Because an aggressive histologic subtype has a significantly higher risk for recurrence in these tumors, the histologic subtype is at least as important in recurrent BCC as it is in primary BCC. OBJECTIVE: To investigate the correlation between histologic findings on punch biopsy specimens and subsequent excision specimens in recurrent BCC. Furthermore, we sought to clarify how often an aggressive histologic subtype was missed, based on the punch biopsy specimen. METHODS: We compared the histologic subtype in a punch biopsy specimen with the subsequent excision specimen in recurrent BCC. All BCCs were coded and judged randomly by the same dermatopathologist. RESULTS: In 24 of 73 investigated BCCs (32.9%), the histologic subtype of the initial biopsy did not match with the histologic subtype of the subsequent excision. Of the 37 excised BCCs with an aggressive histologic subtype, 7 (19%) were missed by the initial punch biopsy. LIMITATIONS: Intraobserver variation may have affected the results of this study. CONCLUSIONS: Discriminating tumors with any aggressive growth is relevant for treatment. However, in recurrent BCC, the histology of the biopsy specimen does not always correlate with the histology of the definitive excision. This may have important therapeutic implications. PMID- 21238827 TI - D2-40 lymphatic marker for detecting lymphatic invasion in thin to intermediate thickness melanomas: association with sentinel lymph node status and prognostic value-a retrospective case study. AB - BACKGROUND: Sentinel lymph node (SLN) status is the greatest prognostic factor of morbidity in melanoma. D2-40 antibody specifically marks lymphatic endothelium and has been used for identifying lymphatic invasion (LI) in multiple cancers. OBJECTIVE: We sought to determine the relationship between melanoma lymphatic invasion (as detected using D2-40 on primary melanoma biopsies/excisions) and the presence or absence of melanoma in subsequent SLN biopsy. METHODS: We retrospectively evaluated LI using D2-40 on primary biopsies/excisions from patients with thin to intermediate thickness (Breslow thickness: <=2.0 mm) melanomas, who underwent lymphatic mapping and SLN biopsy, and whose SLN status was known. Sixty-four cases met the criteria and were available for analysis. We analyzed patient age, patient sex, mitotic rate, ulceration, tumor depth, and D2 40 detected LI as predictors of SLN status. RESULTS: Lymphatic invasion detection increased from 3.1% using hematoxylin and eosin only to 21.9% using D2-40. Twelve of 14 patients with D2-40 LI were SLN positive (positive predictive value, 85.7%). D2-40 LI was detected in the primary biopsy specimen of 12 of 18 patients with a positive SLN (sensitivity 66.7%). Of 50 patients without D2-40 LI, 44 were SLN negative (negative predictive value, 88.0%). Of 46 SLN-negative patients, 44 did not have D2-40 LI (specificity, 95.7%). LIMITATIONS: Results are retrospective and limited to SLN biopsy performed at one institution. CONCLUSIONS: On univariate and multivariate analysis, D2-40-detected LI was the most significant predictor of SLN status. D2-40 antibody staining to detect lymphatic invasion should be incorporated in routine melanoma biopsy evaluation. PMID- 21238828 TI - "Clark/dysplastic" nevi with florid fibroplasia associated with pseudomelanomatous features. AB - BACKGROUND: Melanocytic nevi may exhibit histologic features in common with cutaneous melanoma, creating diagnostic difficulties. OBJECTIVE: We sought to assess the clinical behavior of melanocytic nevi with pseudomelanomatous features in association with dermal fibrosis. METHODS: Forty-two melanocytic nevi with pronounced fibrosis and associated pseudomelanomatous changes were collected and studied clinically and histologically. RESULTS: The fibrosis was centrally located and laminated in appearance. It imparted a trizonal appearance: a junctional component with prominent single cells and/or irregular nests, underlying fibrosis, and a mature dermal component. No recurrence or metastases were evident over an average follow-up period of 2 years. LIMITATIONS: The follow up period was short. CONCLUSIONS: The central location and laminated appearance of the fibrosis suggest that this may represent the extreme end of a spectrum of fibroplastic changes in "Clark/dysplastic" nevi. Adjacent features of "Clark/dysplastic" nevi and limitation of pseudomelanomatous features to the perifibrotic focus are important in accurately identifying these lesions. Although melanocytic nevi with exaggerated fibroplasia may show foci with melanoma-like features, they do not appear to exhibit aggressive clinical behavior. PMID- 21238829 TI - Kaposi sarcoma and quinine: a potentially overlooked triggering factor in millions of Africans. AB - Kaposi sarcoma (KS)-associated herpesvirus, also known as human herpesvirus 8, is necessary but not sufficient for the development of KS. Lytic reactivation of human herpesvirus 8 may be important in KS pathogenesis. KS and its causative agent, KS-associated herpesvirus, have distinctive largely unexplained geographic distributions. We note the recent "oncoweed" hypothesis of biologic plants in the environment accounting for this reactivation. We believe that quinine and its derivatives might better explain the epidemiology of KS than oncoweeds. Indeed, we propose an "oncodrug" hypothesis, specifically with regard to quinine and its derivatives, a linkage first advanced by one of us (V. R.) and associates in 1984. PMID- 21238830 TI - Genital protection in phototherapy units. PMID- 21238831 TI - Unconflicted. PMID- 21238832 TI - Desmoplastic trichoepithelioma. PMID- 21238833 TI - Toward a molecular understanding of cellulite: facts, controversies, and future directions. PMID- 21238834 TI - Update on the characterization of Staphylococcus aureus skin infections in a pediatric dermatology tertiary health care outpatient facility: antibiotic susceptibility patterns and decreased methicillin resistance. PMID- 21238835 TI - Sentinel node biopsy not standard of care for melanoma. PMID- 21238836 TI - Histologic variants of periungual fibromas in tuberous sclerosis complex. PMID- 21238837 TI - No differences in serum selenium levels and blood glutathione peroxidase activities in patients with vitiligo compared with healthy control subjects. PMID- 21238838 TI - Serum homocysteine as a biomarker of vitiligo vulgaris severity: a pilot study. PMID- 21238839 TI - Kaposi sarcoma presenting as a cutaneous horn. PMID- 21238840 TI - Metastatic Crohn disease: clearance with metronidazole. PMID- 21238841 TI - Gianotti-Crosti syndrome associated with herpes simplex virus type 1 gingivostomatitis. PMID- 21238842 TI - All of us. PMID- 21238843 TI - Prognostic factors in patients with buccal squamous cell carcinoma: 10-year experience. AB - PURPOSE: Squamous cell carcinoma (SCC) of the buccal mucosa accounts for 23% to 37% of all intraoral cancer cases in Taiwan. Because of the high recurrence rate and invasive tumor behavior, the prognosis is generally poor. The aim of this study was to evaluate the prognostic significance of clinicopathologic factors on survival rates for patients with buccal SCC in a medical center in central Taiwan. MATERIALS AND METHODS: Between March 1995 and December 2002, patients admitted to hospital and diagnosed as having buccal SCC were enrolled in the study. There were 415 patients (406 men and 9 women) 25 to 84 years old (mean age, 51.1 +/- 11.4 years). The chart records were retrospectively reviewed. Relevant clinical features in each patient, such as primary tumor size, tumor stage, initial treatment modalities, surgical margin status, cervical nodal metastasis status, and histopathologic grade, were compared for survival analysis. RESULTS: Three hundred ninety-four patients received surgical intervention. Univariate analysis of relevant prognostic factors showed that positive surgical margin, positive cervical nodal metastasis, positive extracapsular spread, larger tumor, and advanced tumor stage were associated with poor prognosis. Multivariate analysis identified the factors that independently influenced the survival rate as advanced stage disease (stage III: relative risk [RR], 3.09; P = .006; stage IV: RR, 4.64; P < .001), positive surgical margin (RR, 2.02; P = .001), and extracapsular spread of cervical lymph node metastasis (RR, 6.89; P < .001). CONCLUSIONS: This study represents the largest series in the literature and highlights the importance of tumor stage, surgical margin status, and extracapsular spread of cervical nodal metastasis as the most important prognostic factors in patients with buccal SCC. PMID- 21238844 TI - Sinus graft with safescraper: 5-year results. AB - PURPOSE: In the procedure of sinus floor elevation, autogenous bone, allogenic grafts, and several other bone substitutes are used. However, autogenous bone is still considered the gold standard. Donor sites for autogenous bone are generally the iliac crest, oral cavity, calvarium bone, and tibia. In this work the experience with the use of a Safescraper device for harvesting of autogenous bone is reported and a decision-making algorithm for grafting in sinus floor elevation procedures is proposed. MATERIALS AND METHODS: Forty sinus augmentation procedures were performed in 34 patients. All sinuses were filled with a mixture of autogenous bone and bovine hydroxyapatite. A Safescraper device was used to harvest autologous bone from the maxillary area. Platelet-rich plasma was used to sustain bone placement. Sixty-five dental implants were placed at 4 months with a flapless procedure. A clinical and radiological 5-year retrospective case series of a cohort is reported. RESULTS: In all cases new bone formation was confirmed radiologically and implant placement was performed successfully. Analysis of samples obtained by biopsy with histology and microcomputed tomography showed the presence of mature bone. Healing problems were observed in only 1 case. CONCLUSIONS: Sinus augmentation with bone grafts obtained from oral cavity with a bone scraper device has the advantage of providing autogenous bone without the need for an extra surgical approach. This procedure yields satisfactory results in bone formation, implant survival, and patient satisfaction. When combined with a flapless approach for implant placement, a decrease in the morbidity of the entire process is achieved. PMID- 21238845 TI - Minimum criteria for immediate provisionalization of single-tooth dental implants in extraction sites: a 1-year retrospective study of 100 consecutive cases. AB - PURPOSE: Minimum criteria were used in the placement of 100 consecutive provisional restorations on single-tooth dental implants placed into extraction sites within 3 days of surgery. MATERIALS AND METHODS: Provisional restorations were placed on 4.1- and 4.8-mm diameter standard ITI (Straumann, Waltham, MA) implants in the anterior mandible and maxilla in 100 treatment sites over a 3 year period. Provisionals were placed despite low insertion torque values of 15 N cm or 50 implant stability quotient using radiofrequency analysis. Implants had final impressions for definitive restorations done 8 to 12 weeks after implant placement. All patients were recalled 1 year after restoration and evaluated according to parameters suggested by Albrektsson et al (Int J Oral Maxillofac Implants 1:11, 1986). RESULTS: One implant was not osseointegrated. The remaining implants were judged successful at the 1-year recall appointment. CONCLUSION: Immediate provisionalization of implants placed into fresh extraction sites can be effective even when minimal provisionalization criteria are met. PMID- 21238846 TI - Implant-box mandible: dislocation of an implant into the mandible. PMID- 21238847 TI - Prevalence, location, and size of maxillary sinus septa: panoramic radiograph versus computed tomography scan. AB - PURPOSE: To determine the prevalence, location, and size of maxillary sinus septa, and to compare the results of panoramic radiographs and computed tomography (CT) scans. MATERIALS AND METHODS: This study included 30 patients, 17 women and 13 men, with a mean age of 50.9 years (range, 28-73 years), undergoing treatment planning for implant-supported restorations in the maxilla. Three observers analyzed the panoramic radiographs, the conventional CT scans in acetate, and the Implametric 3-dimensional CT (3Dent, Valencia, Spain). The maxillary sinus septa of each patient and the type of septa, as well as its location and size, were recorded. RESULTS: In 60 maxillary sinuses, panoramic radiographs showed 32 septa (53.3%); CT in acetate showed 42 septa (70%); and Implametric 3-dimensional CT showed 40 septa (66.7%). Most septa (60%) were located in the middle region of the maxillary sinus, 22.5% in the posterior region, and 17.5% in the anterior region. The mean height of the septa was 4.78 +/- 1.76 mm. Panoramic radiographs led to an erroneous diagnosis in 46.5% of the cases. CONCLUSIONS: Maxillary sinus septa are a frequent anatomic variation. They can be found in any of the maxillary sinus regions independently of patient edentulism. The panoramic radiograph can lead to false-positive and false negative findings in the visualization of septa in almost half of cases. Therefore, whenever a maxillary sinus lift is planned, a thorough study of the affected sinus should be made using CT. PMID- 21238848 TI - Computerized navigation for immediate loading of dental implants with a prefabricated metal frame: a feasibility study. AB - PURPOSE: To study the probability of using Image Guided Implantology (IGI) for planning and execution of a dental plan of 3 implants in a geometric pattern that fits a prefabricated metal frame accurately, simulating provisional restoration in immediate loading. MATERIAL AND METHODS: Ten mandible models were imaged by standard computed tomography. Three implants, two in the premolar and one in the molar area on each side of the jaws, were planned by use of the IGI system (Image Navigation Ltd, Moshav Ora, Israel). Two millimeter drilling and subsequent 3 millimeter widening drilling was performed with the real-time computerized navigation technology in the 120 sampling sites. In each step, parallel pins were inserted, and metal gauging frames with preplanned holes of incremental diameters and in the predefined geometric pattern were placed on the pins to evaluate the precision of fit. RESULTS: Full success was obtained in fitting all three 3-mm pins, with frames having clearance of 0.5 or 1 mm, and in matching pairs of pins 2 or 3 mm in diameter at clearances of 0.5 mm or greater. With more constrained clearances, matching of all 3 pins was 80% and 95% successful with 2-mm pins (clearance of 0.25 and 0.5 mm, respectively) and 60% and 95% successful with 3-mm pins (clearance of 0 and 0.25 mm, respectively). Some laterality bias was observed. CONCLUSIONS: This preliminary study shows that the IGI system enables accurate planning of implant number and location to be achieved together with planning for a prefabricated metal frame for immediate loading. PMID- 21238849 TI - Orthognathic surgery in cherubism. PMID- 21238850 TI - Use of a second fiberoptic bronchoscope to guide oral fiberoptic intubation in 2 patients with existing vocal cord injury. PMID- 21238851 TI - Diversity in oral and maxillofacial surgery. PMID- 21238852 TI - Informed consent: dissimilar linguistic barriers in different societies. PMID- 21238853 TI - Concerns about anesthetizing palatal tissues. PMID- 21238854 TI - The pronociceptive effect of proteinase-activated receptor-4 stimulation in rat knee joints is dependent on mast cell activation. AB - Proteinase-activated receptor-4 (PAR(4)) is a G-protein-coupled receptor activated by serine proteinases released during tissue repair and inflammation. We have previously shown that PAR(4) activation sensitises articular primary afferents leading to joint pain. This study examined whether mast cells contribute to this PAR(4)-induced sensitisation and consequent heightened pain behaviour. The expression of PAR(4) on synovial mast cells was confirmed with immunofluorescent staining of rat knee joint sections. Electrophysiological recordings were made from joint primary afferents in male Wistar rats during both nonnoxious and noxious rotations of the knee. Afferent firing rate was recorded for 15 minutes after close intra-arterial injection of 10(-9) to 10(-5)mol of the PAR(4) activating peptide, AYPGKF-NH(2), or the inactive peptide, YAPGKF-NH(2) (100-MUl bolus). Rats were either naive or pretreated with the mast cell stabilise, cromolyn (20mg/kg). Mechanical withdrawal thresholds were determined using a dynamic planter aesthesiometer and weight bearing determined using an incapacitance tester. These behavioural measurements were taken before and after intra-articular AYPGKF-NH(2), or the inactive peptide, YAPGKF-NH(2) (100MUg). Local administration of AYPGKF-NH(2) caused a significant increase in joint primary afferent firing rate and pain behaviour compared with the control peptide YAPGKF-NH(2). These effects were blocked by pretreatment with cromolyn. These data reveal that PAR(4) is expressed on synovial mast cells and the activation of PAR(4) has a pronociceptive effect that is dependent on mast cell activation. Proteinase-activated receptor-4 is expressed on synovial mast cells, and the activation of Proteinase-activated receptor-4 has a pronociceptive effect that is dependent on mast cell activation. PMID- 21238855 TI - The role of working memory in the attentional control of pain. AB - Attention is acknowledged as an important factor in the modulation of pain. A recent model proposed that an effective control of pain by attention should not only involve the disengagement of selective attention away from nociceptive stimuli, but should also guarantee that attention is maintained on the processing of pain-unrelated information without being recaptured by the nociceptive stimuli. This model predicts that executive functions are involved in the control of selective attention by preserving goal priorities throughout the achievement of cognitive activities. In the present study, we tested the role of working memory in the attentional control of nociceptive stimuli. In the control condition, participants had to discriminate the color of visually presented circles preceded by tactile distracters. In some trials (20%), tactile stimuli were replaced by novel nociceptive distracters in order to manipulate the attentional capture. In the working memory condition, participants had to respond to the visual stimulus presented one trial before, and were thus required to maintain the color of the visual stimulus in working memory during the entire inter-trial time interval. Results showed that, while novel nociceptive stimuli induced greater distraction than regular tactile stimuli in the control condition, the distractive effect was suppressed in the working memory condition. This suggests that actively rehearsing the feature of pain-unrelated and task relevant targets successfully prevents attention from being captured by novel nociceptive distracters, independently of general task demands. Working memory can help to inhibit the involuntary capture of attention by pain by preserving cognitive goal priorities. PMID- 21238856 TI - Herpes zoster vaccination among adults aged 60 years and older, in the U.S., 2008. AB - BACKGROUND: Shingles (herpes zoster [HZ]) is a localized, generally painful and debilitating disease that occurs most frequently among older adults. It is caused by reactivation of varicella-zoster virus. HZ causes substantial morbidity, especially among older adults. The vaccine to prevent HZ was approved by Food and Drug Administration and recommended by the Advisory Committee for Immunization Practices for people aged >=60 years in 2006 (these recommendations were published in 2008). PURPOSE: To examine HZ vaccination among people aged >=60 years in the U.S. in 2008. METHODS: Data from the 2008 National Health Interview Survey among people aged >=60 years were analyzed in 2010. Multivariable logistic regression and predictive marginal analyses were conducted to identify factors independently associated with HZ vaccination. Potential missed opportunities also were assessed. RESULTS: By 2008, only 6.7% (95% CI=5.9%, 7.6%) of adults aged >=60 years reported having had HZ vaccination. The level of HZ vaccination coverage was lower (4.7%) among people aged 60-64 years compared to people aged 65-74 years (7.4%); 75-84 years (7.6%); and >=85 years (8.2%). Coverage was statistically higher for non-Hispanic whites (7.6%) compared with non-Hispanic blacks (2.5%) and Hispanics (2.1%). Among people aged >=60 years who reported never receiving HZ vaccination, 95.1% reported at least one missed opportunity to be vaccinated. People more likely to report ever having been vaccinated were older, female, non-Hispanic white, married, more educated, and reporting received influenza vaccination in the past year. CONCLUSIONS: By 2008, HZ vaccination coverage was 6.7%. The coverage level was low among all groups, but it was lowest among minority groups. Increased efforts are needed to remove barriers and to enable HZ vaccination among all adults aged >=60 years. PMID- 21238857 TI - Measuring the quality of public open space using Google Earth. AB - BACKGROUND: Proximity to public open space, such as parks and other green spaces, has considerable health benefits, and people have been shown to be more likely to use such space for physical activity if it is of high quality. This paper describes a new remote-assessment approach that makes use of Google Earth Pro (the free version of this program is Google Earth) to provide rapid and inexpensive measurement of the quality of public open space. PURPOSE: The aim of the study was to assess the correlation between assessments of the quality of public open space using (1) the remote method (making use of Google Earth Pro) and (2) direct observation with a well-established measure of quality, the Public Open Space Tool (POST). METHODS: Fifty parks selected from the southwest part of Sydney, Australia, were assessed in 2009 with the remote method (using Google Earth Pro), and scores were compared with those obtained from direct observation of the same parks using POST. The time taken to conduct the assessments using each method was also recorded. Raters for each method were blind to scores obtained from using the other method. Analyses were conducted in 2009. RESULTS: The Spearman correlation coefficient between the quality scores obtained for the 50 parks using the remote method and direct observation was 0.9 (p<0.0001). The remote method took 4 hours, whereas direct observation took 42 hours, showing the remote method to be much faster and more resource efficient for the measurement of the quality of physical activity-related environments. CONCLUSIONS: The remote assessment method provides, for the first time, the capacity to assess the quality of large numbers of parks and other green spaces without the need for in person visits, dramatically reducing the time required for environmental audits of public open space. PMID- 21238858 TI - Obesity-promoting food environments and the spatial clustering of food outlets around schools. AB - BACKGROUND: The increasing prevalence of overweight and obesity in school-aged children is potentially linked to contextual influences such as the food environment around schools. The proximity of fast-food and convenience stores to schools may enhance access to unhealthy foods and have a negative impact on diet. PURPOSE: This study used spatial cluster analysis to determine whether food outlets are clustered around schools and evaluated the extent of food outlet clustering by school and school neighborhood sociodemographic characteristics. METHODS: The locations in 2008 of all schools, fast-food outlets, and convenience stores in five urban regions across New Zealand were geocoded. Using GIS analysis conducted in 2009, the number and proportion of outlets within 400-m and 800-m road distance around each school was calculated. The spatial clustering of food outlets within 1.5 km of schools was determined using a multi-type K-function. Food outlet type, school level, SES, the degree of population density, and commercial land use zoning around each school were compared. RESULTS: Primary/intermediate schools had a total proportion of 19.3 outlets per 1000 students within 800 m compared to 6.6 for secondary schools. The most socially deprived quintile of schools had three times the number and proportion of food outlets compared to the least-deprived quintile. There was a high degree of clustering of food outlets around schools, with up to 5.5 times more outlets than might be expected. Outlets were most clustered up to 800 m from schools and around secondary schools, socially deprived schools, and schools in densely populated and commercially zoned areas. CONCLUSIONS: Food environments in New Zealand within walking proximity to schools are characterized by a high density of fast-food outlets and convenience stores, particularly in more-socially deprived settings. These obesogenic environments provide ready access to obesity promoting foods that may have a negative impact on student diet and contribute to inequalities in health. PMID- 21238859 TI - Mandatory menu labeling in one fast-food chain in King County, Washington. AB - BACKGROUND: As part of a comprehensive effort to stem the rise in obesity, King County, Washington, enforced a mandatory menu-labeling regulation requiring all restaurant chains with 15 or more locations to disclose calorie information at the point of purchase beginning in January 2009. PURPOSE: The purpose of this study is to quantify the impact of the King County regulation on transactions and purchasing behavior at one Mexican fast-food chain with locations within and adjacent to King County. METHODS: To examine the effect of the King County regulation, a difference-in-difference approach was used to compare total transactions and average calories per transaction between seven King County restaurants and seven control locations focusing on two time periods: one period immediately following the law until the posting of drive-through menu boards (January 2009 to July 2009) and a second period following the drive-through postings (August 2009 through January 2010). Analyses were conducted in 2010. RESULTS: No impact of the regulation on purchasing behavior was found. Trends in transactions and calories per transaction did not vary between control and intervention locations after the law was enacted. CONCLUSIONS: In this setting, mandatory menu labeling did not promote healthier food-purchasing behavior. PMID- 21238861 TI - Disaster preparedness among medically vulnerable populations. AB - BACKGROUND: Vulnerable populations such as those with poor health, disabilities, and chronic diseases are at an increased risk of adverse health outcomes resulting from natural disasters. PURPOSE: The objective of this study was to examine the association of general health status, disability status, and chronic disease status, respectively, with disaster preparedness, among Behavioral Risk Factor Surveillance System (BRFSS) survey respondents. METHODS: BRFSS data were obtained for six states that implemented the optional general preparedness module from 2006 through 2008. Three dependent variables were analyzed, including presence of four preparedness items (i.e., food, water, flashlight, radio); emergency evacuation plan; and 3-day supply of medication. Primary independent variables included perceived health status, disability status, and number of chronic diseases. Data were analyzed in 2010 and accounted for BRFSS complex sampling design. RESULTS: Respondents with fair/poor perceived health (OR=0.76, 95% CI=0.65, 0.89); a disability (activity limitation; OR=0.81, 95% CI=0.73, 0.90); and three or more chronic diseases (OR=0.77, 95% CI=0.58, 1.02) were less likely to have all four preparedness items than their healthier counterparts. However, all these groups were more likely to have a 3-day supply of medication than their healthier counterparts. Results varied for presence of an emergency evacuation plan. CONCLUSIONS: Vulnerable populations were generally less likely to have household preparedness items but more likely to have medication supplies than their counterparts. Public health officials should target these groups to increase levels of disaster preparedness. PMID- 21238860 TI - Adulthood stressors, history of childhood adversity, and risk of perpetration of intimate partner violence. AB - BACKGROUND: More than half a million U.S. women and more than 100,000 men are treated for injuries from intimate partner violence (IPV) annually, making IPV perpetration a major public health problem. However, little is known about causes of perpetration across the life course. PURPOSE: This paper examines the role of "stress sensitization," whereby adult stressors increase risk for IPV perpetration most strongly in people with a history of childhood adversity. METHODS: The study investigated a possible interaction effect between adulthood stressors and childhood adversities in risk of IPV perpetration, specifically, whether the difference in risk of IPV perpetration associated with past-year stressors varied by history of exposure to childhood adversity. Analyses were conducted in 2010 using de-identified data from 34,653 U.S. adults from the 2004 2005 follow-up wave of the National Epidemiologic Survey on Alcohol and Related Conditions. RESULTS: There was a significant stress sensitization effect. For men with high-level childhood adversity, past-year stressors were associated with an 8.8 percentage point (pp) increased risk of perpetrating compared to a 2.3 pp increased risk among men with low-level adversity. Women with high-level childhood adversity had a 14.3 pp increased risk compared with a 2.5 pp increased risk in the low-level adversity group. CONCLUSIONS: Individuals with recent stressors and histories of childhood adversity are at particularly elevated risk of IPV perpetration; therefore, prevention efforts should target this population. Treatment programs for IPV perpetrators, which have not been effective in reducing risk of perpetrating, may benefit from further investigating the role of stress and stress reactivity in perpetration. PMID- 21238862 TI - Use of standing orders for adult influenza vaccination a national survey of primary care physicians. AB - BACKGROUND: Influenza vaccination of adults remains below recommended levels. Standing orders programs (SOPs) that allow nonphysician medical staff to assess eligibility and administer vaccines without an individualized physician's order are a proven method to increase vaccination rates. However, recent data on their use are not available. PURPOSE: Investigators surveyed primary care physicians nationwide in 2009 to assess factors related to awareness and use of SOPs. METHODS: Using the AMA Master List, a stratified random sample of U.S. family physicians (n=820) and general internists (n=820) was selected to receive a mailed questionnaire. The inclusion criterion was providing primary care to adults in an office-based practice. The primary outcome measure, analyzed in 2010, was consistent use of SOPs. RESULTS: The survey response rate was 67% (1015/1517). Forty-two percent of respondents who immunized adults in their practices reported consistent use of SOPs. Those physicians differed in several dimensions, including awareness of recommendations and regulations regarding SOPs for vaccines, size and type of practice, number and level of training of clinical staff, attributes of the staff. The two variables in logistic regression models that were associated with the highest likelihood of using SOPs were awareness of recommendations to use them (OR=3.0; 95% CI=2.2, 4.1) and agreement with their effectiveness (OR=2.7, 95% CI=1.9, 3.8). CONCLUSIONS: Fewer than half of physicians report using SOPs for influenza vaccination, a number that is not much higher than it was about a decade ago. Approaches to increase use of SOPs are needed. PMID- 21238863 TI - Economic analysis of physical activity interventions. AB - BACKGROUND: Numerous interventions have been shown to increase physical activity but have not been ranked by effectiveness or cost. PURPOSE: This study provides a systematic review of physical activity interventions and calculates their cost effectiveness ratios. METHODS: A systematic literature review was conducted (5579 articles) and 91 effective interventions promoting physical activity were identified, with enough information to translate effects into MET-hours gained. Cost-effectiveness ratios were then calculated as cost per MET-hour gained per day per individual reached. Physical activity benefits were compared to U.S. guideline-recommended levels (1.5 MET-hours per day for adults and 3.0 MET-hours per day for children, equivalent to walking 30 and 60 minutes, respectively). RESULTS: The most cost-effective strategies were for point-of-decision prompts (e.g., signs to prompt stair use), with a median cost of $0.07/MET hour/day/person; these strategies had tiny effects, adding only 0.2% of minimum recommended physical activity levels. School-based physical activity interventions targeting children and adolescents ranked well with a median of $0.42/MET-hour/day/person, generating an average of 16% of recommended physical activity. Although there were few interventions in the categories of "creation or enhanced access to places for physical activity" and "community campaigns," several were cost effective. The least cost-effective categories were the high intensity "individually adapted behavior change" and "social support" programs, with median cost-effectiveness ratios of $0.84 and $1.16 per MET-hour/day/person. However, they also had the largest effect sizes, adding 35%-43% of recommended physical activity, respectively. Study quality was variable, with many relying on self-reported outcomes. CONCLUSIONS: The cost effectiveness, effect size, and study quality should all be considered when choosing physical activity interventions. PMID- 21238864 TI - Diabetes and prediabetes: screening and prevalence among adults with coronary heart disease. AB - BACKGROUND: Clinical performance measures recommend that nondiabetic patients with coronary heart disease (CHD) be screened for diabetes every 3 years. PURPOSE: The purpose of this study is to report the prevalence of diabetes and prediabetes among U.S. adults aged >=35 years with CHD and to determine factors associated with not receiving recommended diabetes screenings. METHODS: The Behavioral Risk Factor Surveillance System (BRFSS) is an annual state-based telephone survey of non-institutionalized U.S. adults. Information on prediabetes prevalence was collected for 33 states in 2008; data analysis was conducted in 2009. The prevalence of diabetes and prediabetes among adults aged >=35 years with CHD (n=20,618) and prevalence of diabetes screening among nondiabetic adults with CHD (n=14,335) were assessed. Multivariate logistic regression was used to calculate the odds of not being screened for diabetes in the past 3 years while controlling for other factors. RESULTS: Among adults with CHD, 30.7% (95% CI=29.4%, 32.1%) reported being diagnosed with diabetes and 10.0% (95% CI=9.2%, 10.8%) reported prediabetes. Among nondiabetic adults with CHD, 25.4% (95% CI=23.9%, 26.9%) reported not being screened for diabetes in the past 3 years. Those with no recent routine checkup and those with no health insurance had the highest odds of no recent diabetes screening. CONCLUSIONS: The prevalence of diabetes and prediabetes is substantial among adults with CHD and likely underestimated because of suboptimal screening. One of four nondiabetic adults with CHD reported not being screened for diabetes in the past 3 years. PMID- 21238865 TI - Food insecurity and weight status among U.S. children and families: a review of the literature. AB - CONTEXT: Food insecurity disproportionately affects U.S. demographic groups of children and adult family members at the highest risk for obesity and may lead to weight gain through various pathways. This article reviews research regarding the relationship between food insecurity and weight status, and the potential role of federal food and nutrition assistance programs. EVIDENCE ACQUISITION: A search for relevant peer-reviewed research studies among U.S. children and nonelderly adults, published between 2000 and March 2010, identified 42 studies regarding the relationship between food insecurity and weight status. There were 22 studies regarding the potential role of food and nutrition assistance programs. EVIDENCE SYNTHESIS: Among children and men, support for an association between food insecurity and weight status has been mixed. Women who experience food insecurity are more likely to be overweight or obese compared to women with adequate household resources for food; however, there is little evidence that food insecurity promotes increased weight gain over time. Long-term participation in the Supplemental Nutrition Assistance Program may increase risk for excess weight gain. CONCLUSIONS: Additional research addressing the limitations of current studies is needed to fully understand the observed linkages between food insecurity and risk for obesity. Nevertheless, there is substantial evidence these nutritional problems coexist, and it is critical that future efforts to eliminate hunger consider opportunities to promote healthy food choices and physical activity. Evaluations of policy changes and other intervention strategies are needed to determine the potential for food and nutrition assistance programs to more effectively reduce obesity among participants. PMID- 21238866 TI - Sedentary behaviors and health outcomes among adults: a systematic review of prospective studies. AB - CONTEXT: Nowadays, people spend a substantial amount of time per day on sedentary behaviors and it is likely that the time spent sedentary will continue to rise. To date, there is no review of prospective studies that systematically examined the relationship between diverse sedentary behaviors and various health outcomes among adults. PURPOSE: This review aimed to systematically review the literature as to the relationship between sedentary behaviors and health outcomes considering the methodologic quality of the studies. EVIDENCE ACQUISITION: In February 2010, a search for prospective studies was performed in diverse electronic databases. After inclusion, in 2010, the methodologic quality of each study was assessed. A best-evidence synthesis was applied to draw conclusions. EVIDENCE SYNTHESIS: 19 studies were included, of which 14 were of high methodologic quality. Based on inconsistency in findings among the studies and lack of high-quality prospective studies, insufficient evidence was concluded for body weight-related measures, CVD risk, and endometrial cancer. Further, moderate evidence for a positive relationship between the time spent sitting and the risk for type 2 diabetes was concluded. Based on three high-quality studies, there was no evidence for a relationship between sedentary behavior and mortality from cancer, but strong evidence for all-cause and CVD mortality. CONCLUSIONS: Given the trend toward increased time in sedentary behaviors, additional prospective studies of high methodologic quality are recommended to clarify the causal relationships between sedentary behavior and health outcomes. Meanwhile, evidence to date suggests that interventions aimed at reducing sedentary behavior are needed. PMID- 21238867 TI - Constraints and barriers to public health adaptation to climate change: a review of the literature. AB - Public health adaptation to climate change is an important issue and inevitably is needed to address the adverse health impacts of climate change over the next few decades. This paper provides an overview of the constraints and barriers to public health adaptation and explores future research directions in this emerging field. An extensive literature review was conducted in 2010 and published literature from 2000 to 2010 was retrieved. This review shows that public health adaptation essentially can operate at two levels, namely, adaptive-capacity building and implementation of adaptation actions. However, there are constraints and barriers to public health adaptation arising from uncertainties of future climate and socioeconomic conditions, as well as financial, technologic, institutional, social capital, and individual cognitive limits. The opportunities for planning and implementing public health adaptation are reliant on effective strategies to overcome these constraints and barriers. It is proposed here that high research priority should be given to multidisciplinary research on the assessment of potential health impacts of climate change, projections of health impacts under different climate and socioeconomic scenarios, identification of health co-benefits of mitigation strategies, and evaluation of cost-effective public health adaptation options. PMID- 21238869 TI - A 2020 vision for educating the next generation of public health leaders. AB - To meet the dynamic and evolving challenges of public health in the 21st century, our society should foster the next generation of public health leaders. We offer a vision for doing so, by introducing prevention literacy and education from the earliest possible starting point and then broadening these concepts throughout the educational ladder. Making this societal commitment now to nurture such future leaders should make the country healthier by 2020 and beyond. PMID- 21238868 TI - Estimating the population impact of preventive interventions from randomized trials. AB - Growing concern about the limited generalizability of trials of preventive interventions has led to several proposals concerning the design, reporting, and interpretation of such trials. This paper presents an epidemiologic framework that highlights three key determinants of population impact of many prevention programs: the proportion of the population at risk who would be candidates for a generic intervention in routine use, the proportion of those candidates who are actually intervened on through a specific program, and the reduction in incidence produced by that program among recipients. It then describes how the design of a prevention trial relates to estimating these quantities. Implications of the framework include the following: (1) reach is an attribute of a program, whereas external validity is an attribute of a trial, and the two should not be conflated; (2) specification of a defined target population at risk is essential in the long run and merits greater emphasis in the planning and interpretation of prevention trials; (3) with due attention to sampling frame and sampling method, the process of subject recruitment for a trial can yield key information about quantities that are important for assessing its potential population impact; and (4) exclusions during subject recruitment can be conceptually separated into intervention-driven, program-driven, and trial-design-driven exclusions, which have quite different implications for trial interpretation and for estimating population impact of the intervention studied. PMID- 21238870 TI - Healthy People 2020 and Education for Health: what are the objectives? AB - The Education for Health framework is designed as an educational roadmap for Healthy People 2020. It aims to connect the educational phases and suggests overall educational strategies needed to educate health professionals and the public to achieve a healthier America. The framework seeks to develop a seamless approach to prevention and population health education from Pre-K through graduate school. The framework is built on national movements in health literacy, undergraduate public health education and evidence-based thinking. It envisions a coordinated set of learning objectives divided into Pre-K through Grade 12, 2 year and 4-year colleges, and graduate education in the health professions as well as for health education for the community-at-large. The Healthy People Curriculum Task Force, a consortium of eight health professions education associations, has developed the framework and connected the framework with new and revised educational objectives of Healthy People 2020. The Task Force envisions a decade-long process to define and implement specific learning outcomes that can be integrated across the educational continuum. Interprofessional prevention education, in which health professionals learn and practice together, is seen by the Task Force as a key method for implementation. Understanding the roles played by a range of clinical health professions is also essential to communication and understanding. Healthy People 2020 and its new and revised educational objectives provide a vehicle for promoting the discussion and experimentation that will be needed to achieve an integrated and seamless approach to education for health for the American public as well as for health professionals. PMID- 21238871 TI - Evidence-based health promotion programs for schools and communities. AB - Healthy People 2020 includes an objective to increase the proportion of elementary, middle, and senior high schools that provide comprehensive school health education to prevent health problems in the following areas: unintentional injury; violence; suicide; tobacco use and addiction; alcohol or other drug use; unintended pregnancy, HIV/AIDS, and sexually transmitted infections (STI); unhealthy dietary patterns; and inadequate physical activity. These specific goals are part of the efforts of Healthy People 2020 to increase the proportion of elementary, middle, and senior high schools that have health education goals or objectives that address the knowledge and skills articulated in the National Health Education Standards. A focus on Pre-K through 12 health education is a prerequisite for the implementation of a coordinated, seamless approach to health education as advocated by the Healthy People Curriculum Task Force and incorporated into the Education for Health framework. To help accomplish these goals, this article views the role of education as part of the broader socioecologic model of health. A comprehensive literature review was undertaken to identify evidence-based, peer-reviewed programs, strategies, and resources. The results of this review are presented organized as sexual health, mental and emotional health, injury prevention, tobacco and substance abuse, and exercise and healthy eating. Evidence-based implementation strategies, often considered the missing link, are recommended to help achieve the Healthy People 2020 objective of increasing the prevalence of comprehensive school health education programs designed to reduce health risks for children. PMID- 21238872 TI - Community colleges and public health: making the connections. AB - Community colleges, in collaboration with public health agencies, can advance public health education by reaching a diverse student body, integrating public health into general education, and providing specialized associate degrees that serve workforce needs. Career ladders that include transferability of coursework to 4-year institutions and continuing education, including certificate programs, are key to success of these efforts. Community, or 2-year, colleges are well positioned to connect components of the Healthy People Curriculum Task Force's Education for Health framework by providing general education core courses in public health, epidemiology, and global health compatible with the educated citizen and public health movement. To serve specific workforce needs, associate degree programs are proposed, including environmental health, public health preparedness, public health informatics, and pre-health education. A generalist option designed for transfer to public health and related majors at 4-year institutions is also recommended. PMID- 21238873 TI - Undergraduate public health at 4-year institutions: it's here to stay. AB - Undergraduate public health education at 4-year institutions, those with and without graduate public health education, has grown rapidly during the first decade of the 21st century since the IOM recommended that "all undergraduates have access to education in public health." Much of this growth has been guided by the Educated Citizen and Public Health initiative, a collaboration of arts and sciences and public health educators that encourages introductory course work in public health, epidemiology, and global health plus undergraduate minors and majors in public health. The Educated Citizen and Public Health model, as opposed to existing professional models, envisions core public health education based on the Association of American Colleges and Universities' Liberal Education and America's Promise essential learning outcomes that encourage experiential learning, evidence-based thinking, a global and community focus, plus integration and synthesis. Public health education in this model provides solid generalist grounding for graduate education in public health as well as a range of graduate disciplines from the health professions to international affairs and from law to business. In addition, it helps ensure a broad range of college graduates who understand and support public health approaches. The Healthy People 2020 objective to increase the proportion of 4-year colleges and universities that offer minor or major in public health should help propel additional growth, especially in 4-year colleges without graduate public health education. Integrative curricula designed as part of the reform of undergraduate education provide opportunities to make evidence-based public health approaches available to a large number of undergraduates. PMID- 21238874 TI - Using the Clinical Prevention and Population Health Curriculum Framework to encourage curricular change. AB - The Healthy People Curriculum Task Force was established in 2002 to encourage implementation of Healthy People 2010 Objective 1.7: "To increase the proportion of schools of medicine, schools of nursing and health professional training schools whose basic curriculum for healthcare providers includes the core competencies in health promotion and disease prevention." In 2004, the Task Force published a Clinical Prevention and Population Health Curriculum Framework ("Framework") to help each profession assess and develop more robust approaches to this content in their training. During the 6 years since the publication of the Framework, the Task Force members introduced and disseminated it to constituents, facilitated its implementation at member schools, integrated it into initiatives that would influence training across schools, and adapted and applied the Framework to meet the data needs of the Healthy People 2010 Objective 1.7. The Framework has been incorporated into initiatives that help promote curricular change, such as accreditation standards and national board examination content, and efforts to disseminate the experiences of peers, expert recommendations, and activities to monitor and update curricular content. The publication of the revised Framework and the release of Healthy People 2020 (and the associated Education for Health Framework) provide an opportunity to review the efforts of the health professions groups to advance the kind of curricular change recommended in Healthy People 2010 and Healthy People 2020 and to appreciate the many strategies required to influence health professions curricula. PMID- 21238875 TI - Model approaches for advancing interprofessional prevention education. AB - Healthy People 2010 included an objective to "increase the proportion of ... health professional training schools whose basic curriculum for healthcare providers includes the core competencies in health promotion and disease prevention." Interprofessional prevention education has been seen by the Healthy People Curriculum Task Force as a key strategy for achieving this objective and strengthening prevention content in health professions education programs. To fulfill these aims, the Association for Prevention Teaching and Research sponsored the Institute for Interprofessional Prevention Education in 2007 and in 2008. The institutes were based on the premise that if clinicians from different professions are to function effectively in teams, health professions students need to learn with, from, and about students from other professions. The institutes assembled interprofessional teams of educators from academic health centers across the country and provided instruction in approaches for improving interprofessional prevention education. Interprofessional education also plays a key role in implementation of Healthy People 2020 Education for Health framework. The delivery of preventive services provides a nearly level playing field in which multiple professions each make important contributions. Prevention education should take place during that phase of the educational continuum in which the attitudes, skills, and knowledge necessary for both effective teamwork and prevention are incorporated into the "DNA" of future health professionals. Evaluation of the teams' educational initiatives holds important lessons. These include allowing ample time for planning, obtaining student input during planning, paying explicit attention to teamwork, and taking account of cultural differences across professions. PMID- 21238876 TI - The roles of healthcare professionals in implementing clinical prevention and population health. AB - Across the health disciplines, clinical prevention and population health activities increasingly are recognized as integral to the practice of their professions. Most of the major clinical health professions organizations have begun incorporating clinical prevention and population health activities and services into educational curricula, the accreditation process, and training to affect clinical practice. Students in each health profession need to understand the roles played by those in other health professions. This understanding is a prerequisite for better communication and collaboration among the professions and for accomplishing the educational objectives included in Healthy People 2020 and organized using the Education for Health framework. To help accomplish these goals, this article summarizes each health profession's contributions to the field of prevention and population health, explains how the profession contributes to interprofessional education or practice, reviews specific challenges faced in the provision of these types of services, and highlights future opportunities to expand the provision of these services. Several general themes emerge from a review of the different health professions' contributions to this area. First, having well-trained prevention and population health professionals outside of the traditional public health field is important because prevention and population health activities occur in almost all healthcare settings. Second, because health professionals work in interprofessional teams in the clinical setting, training and educating all health professionals within interprofessional models would be prudent. Third, in order to expand services, reimbursement for health promotion counseling, preventive medicine, and disease management assistance needs to be appropriate for each of the professions. PMID- 21238877 TI - Caffeinated alcoholic beverages: an emerging public health problem. PMID- 21238878 TI - Bumps on the road to preparedness. PMID- 21238879 TI - Unraveling the paradox of concurrent food insecurity and obesity. PMID- 21238880 TI - Measuring the quality of public open space using Google Earth: a commentary. PMID- 21238881 TI - [Quarterly Medical Review: an international flavour in La Presse Medicale]. PMID- 21238883 TI - Should we routinely measure portal pressure in patients with cirrhosis, using hepatic venous pressure gradient (HVPG) as guidance for prophylaxis and treatment of bleeding and re-bleeding? Yes! AB - Portal hypertension is key to the natural history of cirrhosis. The standard way to assess portal hypertension is the hepatic venous pressure gradient (HVPG). HVPG has been convincingly shown to be a strong predictor of variceal bleeding and survival. In addition, it has been shown to predict other portal hypertension related clinical events, to include fluid retention and hepatic encephalopathy. Finally, HVPG is the only suitable tool to assess the response of portal hypertension to medical treatment. Thus, although not necessarily easy to measure, HVPG provides the clinician with information which is prognostically crucial and otherwise unobtainable. PMID- 21238884 TI - Should we routinely measure portal pressure in patients with cirrhosis, using hepatic venous pressure gradient (HVPG) as a guide for prophylaxis and therapy of bleeding and rebleeding? No. AB - Portal hypertension (PH) is a severe complication of liver cirrhosis. Measurement of the degree of portal hypertension is usually performed by measuring the hepatic venous pressure gradient (HVPG) which is the difference between the free hepatic venous pressure (FHVP) and the wedged hepatic venous pressure (WHPG). The HVPG accurately reflects the degree of PH in the majority of liver diseases. PH is defined by an increase of HVPG values above the normal upper limit of 5 mm Hg, while clinically significant PH is defined by an HVPG to >=10 mm Hg. Although measurement of HVPG potentially has several applications, in clinical practice its major use has been related to the assessment of hemodynamic response to pharmacological therapy, in order to evaluate the efficacy of treatment and to predict the risk of rebleeding from esophageal varices. When properly performed, HVPG is a reliable, safe and good predictive tool in the management of portal hypertension. However, the need for appropriate equipment, sufficient and reliable operators and costs, have discouraged its use outside Liver Units specifically devoted to the clinical management of portal hypertension. This has diminished its applicability. Combining its use with transjugular liver biopsy and using the prognostic value of HVPG may help encourage its use. PMID- 21238885 TI - The oral glucose tolerance test (OGTT) revisited. AB - The oral glucose tolerance test (OGTT) has been the mainstay for diagnosing diabetes for decades. Recently, the American Diabetes Association (ADA) suggested abandoning the OGTT, while resorting to a simpler screening test, exclusively based on baseline fasting blood glucose concentration. This review article rewinds the history of OGTT and its recent advancements, and compares its power in detecting early diabetes with that of fasting blood glucose alone. The key point is that there are more diabetics originating from a population with normal fasting blood glucose than from subjects with impaired fasting glucose, those who can be detected by the new ADA recommendations. Conversely, the OGTT detects more efficiently early diabetes as well as subjects with IGT, as the glycemia at the second hour seems crucial as a diagnostic tool. We discuss the different significance of fasting versus second hour glycemia during OGTT, according to different mechanisms of glucose homeostasis. Finally, we provide recent evidence on very simple additional information that can be obtained from the OGTT, which renders this test even more useful, discussing pathophysiologic significance. PMID- 21238886 TI - Mundane, yet challenging: the assessment of malnutrition in inflammatory bowel disease. AB - Protein-energy malnutrition (PEM) is defined as a "state of nutrition in which a deficiency or excess (or imbalance) of energy, protein, and other nutrients causes measurable adverse effects on tissue/body form (body shape, size and composition) and function, and clinical outcome". Although this definition resulted from a long discussion among experts, it lacks concise assessment criteria. Essential to an effective practice of nutrition support, however, is the ability to identify who actually needs medical nutrition therapy. Patients with active inflammatory bowel disease (IBD) are a high risk group for protein energy malnutrition, with a prevalence ranging up to 75%. PMID- 21238887 TI - Ex-vivo red blood cells generation: a step ahead in transfusion medicine? AB - Blood transfusion and especially red blood cell (RBC) transfusion is an essential therapeutic act because it might be life-saving in several situations such as massive bleeding or as prolonged quality-of-life therapies in patients with chronic anemic disorders. Although the need for blood is thereby widespread, there is however a major imbalance between demand and supply of donors, so that there is a mounting research to develop suitable surrogates for human donated blood. Functional RBCs have already been generated from a variety of cellular progenitors (i.e., somatic stem cells, human embryonic stem cells and induced pluripotent stem cells) and synthetic biomaterials. Although these types of "artificial blood" carry several advantages over donated blood, including larger supply, lower risk of blood-borne pathogens transmission, no risk of immune incompatibility using group O, RhD-negative RBCs, and extended survival of stored RBCs, their efficacy has not been extensively tested thus far in clinical trials. Therefore, while it seems premature at this point in time to conclude that ex vivo manufacturing of blood might be the definitive solution to the current shortage of blood supply, it represents however a valuable starting point for translational research in transfusion medicine. PMID- 21238888 TI - Drug-induced acute pancreatitis related to medications commonly used in gastroenterology. AB - BACKGROUND: With the growing number of pharmacological agents available nowadays, the gastrointestinal drug-induced side effects become more common than ever. However, drug-induced pancreatitis belongs to rather seldom reported adverse drug reactions, probably because of the difficulty in proving the relationship between an inflammation of the pancreas and the pharmacotherapy with a certain drug. AIM: The aim of this review is to draw attention to an infrequent but real problem of drug-induced acute pancreatitis associated with medications commonly used in the treatment of gastrointestinal disorders. METHODOLOGY: For the purpose of that the PubMed database was searched using the keywords "drug-induced pancreatitis", "drug-associated pancreatitis", "acute pancreatitis", "pancreatitis" in various combinations and relevant literature was reviewed. RESULTS: A substantial number of drugs commonly prescribed for gastrointestinal disorders are known to cause acute pancreatitis. Case reports and review articles published so far draw attention to medications already known to cause drug-induced pancreatic damage as well as implicate new drugs. Generally, the etiopathological mechanisms involved in drug-induced pancreatitis remain unclear. It is difficult to establish or rule out definitely such unwanted event, especially in patients taking numerous medications prescribed for multiple comorbidities. CONCLUSION: Pharmacological agents are among etiologic factors that should be considered in all patients presenting with signs and symptoms consistent with acute pancreatitis. The diagnosis of drug-induced AP is often difficult to established. Therefore a high index of suspicion and thorough drug history are crucial for making the final diagnosis. PMID- 21238889 TI - Antiplatelet therapy in the perioperative period. AB - The current practice of withdrawing aspirin 7-10 days preoperatively may be dangerous in certain groups of patients. The risk of cardiovascular events increases 3-fold after aspirin withdrawal. The average time between aspirin withdrawal and the manifestation of acute coronary syndrome is 8 to 11 days. The withdrawal of clopidogrel earlier than 4-6 weeks after bare metal stent implantation or less than 12 months after drug-eluting stent implantation is very risky and poses a high risk of stent thrombosis and high perioperative mortality. Continuing aspirin perioperatively leads to a 1.5-fold increase in perioperative bleeding complications but it does not lead to a higher severity of bleeding complications or higher mortality. The article analyzes current European and American guidelines for perioperative antiplatelet treatment and suggests an algorithm based on the guidelines to help make clinical decisions. PMID- 21238890 TI - Heart failure patients selection for cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is an established treatment for refractory chronic heart failure (CHF) patients with ventricular dyssynchrony. The patient selection for this therapy remains the basis for response improvement. Various parameters, methods and technology for identification of appropriate patient are under research. The influences of age and gender, disease progress stage such as mild and late stage CHF including right ventricular dysfunction, dyssynchrony and scar identified by imaging techniques like echocardiography, magnetic resonance and nuclear imaging, and atrial fibrillation on CRT benefits were respectively discussed. This review summarizes the current advancement in these areas. PMID- 21238891 TI - Design of medical devices--a home perspective. AB - Health care services are moving out to the community and into the home; e-health services, remote monitoring technology and self-management are replacing hospitalization and visits to medical clinics and custom-tailored medicines are making inroads into normative treatment. These developments have great implications for the scope and design of home health care equipment. The paper discusses the unique nature of home medical devices, from a human-environment machine perspective, focusing on the nature of users, environment and tasks performed. We call for increased awareness and active continuous involvement of health care personnel together with bioengineers, human factors experts, architects, designers and end users--patients and caregivers--in defining the objectives of health care devices and services at home in terms of "all family" use, integrated into the overall surroundings ("smart home"), and as part of a collaborative patient-physician disease management team. PMID- 21238892 TI - Medication discrepancies at discharge from an internal medicine service. AB - BACKGROUND: Medication errors most commonly occur at the time of medication prescribing and particularly at the moment of the transitions of care. The objectives of this study were to identify and characterize the discrepancies between the physicians' discharge medication orders and the medication lists at admission obtained by an internal medicine specialist physician in a general internal medicine service. METHODS: This descriptive, retrospective, study was carried out at a tertiary care university teaching hospital in Spain. It was based on the review of non selected, consecutive, hospital discharge reports. Discrepancies were identified, categorized and characterized through the analysis of the information (medication lists, laboratory tests results, diagnosis, and clinical evolution) contained in them. RESULTS: We analyzed 954 discharge reports. In the medication reconciliation process, we find discrepancies in 832 (87.2%) of them. Justified discrepancies were found in 828 (86.8%) reports and unjustified discrepancies in 52 (5.4%). Omission of a medication was the most frequent medication error detected in 86.4% of cases, followed by incomplete prescription (9.6%). The number of diagnosis, the length of hospital stay and the number of permanent medications at admission were the characteristics of cases associated with medication discrepancies in multivariate linear regression (P<0.01). CONCLUSIONS: Although considering the limitations in its design, it is remarkable the low number of medication errors detected in our study. Appropriate routines to ensure an accurate medication history collection and a methodical elaboration of the medication list at discharge, when performed by trained internists, are important for an adequate medication reconciliation process. PMID- 21238893 TI - Mortality and complications in very old patients (90+) admitted to departments of internal medicine in Spain. AB - SUMMARY: Patients over 90 years of age (the "very elderly") account for an increasing number of admissions to departments of internal medicine (IM). The aim of this study was to analyse the demographic data, hospitalization characteristics, medical complications, and predictors of mortality in patients over 90 admitted to IM departments. MATERIAL AND METHODS: All patients admitted to IM departments in Spain between the years 2005 and 2007 were analysed. Clinical and demographic data were compared with records from "younger elderly" patients (65-90). RESULTS: During the study period, there were 1,567,659 patient admissions to IM departments in Spain, and 90,679 (5.8%) were older than 90. Hospital mortality occurred in 22.3% of very elderly patients. The main predictors for hospital death were pressure ulcer (Odds Ratio [OR] 1.55, CI95% 1.45-1.66), thromboembolic disease (OR 1.83, CI95% 1.61-2.09), nosocomial pneumonia (OR 2.53, CI95% 2.39-2.69), hip fracture (OR 2.20, CI95% 1.53-3.18), male gender (OR 1.06, CI95% 1.03-1.10), age (OR 1.05, CI95% 1.04-1.06), dementia (OR 1.13, CI95% 1.08-1.18), cancer (OR 1.60, CI95% 1.51-1.71), acute respiratory failure (OR 1.83, CI95% 1.76-1.89), acute infectious disease (OR 2.30, IC95% 2.11 2.52), and Charlson comorbidity index (OR 1.21, CI95% 1.16-1.26). CONCLUSIONS: Very elderly patients represent a large and growing fraction of the total admissions to IM departments in Spain. They are at higher risk for complications during their hospital stay and mortality rate is double that of the younger elderly. PMID- 21238894 TI - Mortality rates and modes of death in heart failure patients with reduced versus preserved systolic function. AB - BACKGROUND: There are conflicting reports regarding the characteristics and mortality rates of heart failure patients with preserved (HFPSF) vs. reduced systolic left ventricular function (SHF). METHODS: We evaluated the clinical profiles, mortality rates and modes of death in 481 consecutive symptomatic heart failure patients. In 317(66%) patients LVEF was <40% (SHF), and in 164(34%) LVEF>=40% (HFPSF). RESULTS: Compared to the HFPSF group, SHF patients were predominantly younger males with ischemic etiology and less cardiovascular comorbidities such as obesity, hypertension, diabetes mellitus and atrial fibrillation. Over a mean follow-up period of 2 years, 148(31%) patients died. Overall mortality was similar between the two groups: 53(32%) HFPSF patients and 95(30%) SHF patients died (p=0.6), even after adjusting for baseline variables, including age, gender and comorbidities (hazard ratio 1.09; 95% confidence interval 0.74-1.61; p=0.67). In contrast to the similar mortality rates, the modes of death were different. SHF patients had higher death rates due to pump failure compared to the HFPSF group {32/95(34%) vs. 9/53(17%) patients, p=0.03}. A trend towards higher rate of non-cardiac death was observed in HFPSF group {33/53(62%) patients vs. 45/95(47%) patients, respectively, p=0.08}. The prevalence of arrhythmic death was similar in both groups {17/95(18%) vs. 10/53(19%) patients, p=0.9}. CONCLUSIONS: Although the characteristics of HFPSF and SHF patients are distinctively different, the mortality rates are similar. The mode of death is different among the two groups of patients, as pump failure death is significantly higher in SHF patients, while non-cardiac mortality is more prevalent in HFPSF patients. PMID- 21238895 TI - Prognosis of patients with haematological malignancies admitted to the intensive care unit: Sequential Organ Failure Assessment (SOFA) trend is a powerful predictor of mortality. AB - BACKGROUND: The prognosis of patients with haematological malignancies who are admitted to the ICU is generally poor. In order to optimize care, it is important to be able to determine which patients are most likely to benefit from continuation of treatment after ICU admission. METHODS: Data of 86 patients with a haematological malignancy consecutively admitted to the ICU of Maastricht University Medical Centre were examined in a retrospective cohort study in order to identify clinically useful prognostic parameters. RESULTS: ICU mortality was 56% and in-hospital mortality was 65%. Non-survivors had higher APACHE-II and SOFA scores compared with survivors (32+/-8.0 versus 25+/-6.5 and 11.5+/-3.1 versus 8.5+/-3.0, respectively). The mortality rate was significantly higher in patients with an increasing SOFA score (>=2 points) compared with patients with an unchanged or decreasing SOFA score (72% versus 58% and 21%, respectively). Mortality was also higher in patients requiring invasive mechanical ventilation or inotropic/vasopressor therapy. CONCLUSION: The mortality rate among patients with haematological malignancies who are admitted to the ICU is high and mainly associated with the severity of illness, as reflected by more severe and worsening organ failure and a need for mechanical ventilation or inotropic/vasopressor therapy. Several factors appear to be associated with a poor outcome, but no absolute predictors of mortality could be identified, although the results suggest that changes in the SOFA score during the stay in the ICU can be helpful in the decision making about the continuation or discontinuation of treatment. PMID- 21238896 TI - Myocardial iron overload assessed by magnetic resonance imaging (MRI)T2* in multi transfused patients with thalassemia and acquired anemias. AB - BACKGROUND: Cardiac complications secondary to iron overload remain a significant matter in patients with transfusion dependent anemias. PATIENTS AND METHODS: To evaluate cardiac siderosis, Magnetic resonance imaging T2* (MRI T2*) was performed in 3 cohorts of transfusion dependent patients: 99 with thalassemia major (TM), 20 with thalassemia intermedia (TI), and 10 with acquired anemias (AA). Serum ferritin was measured and all patients underwent echocardiographic evaluation. RESULTS: In TM patients cardiac T2* pathologic values (below 20 ms) were found in 37 patients. Serum ferritin was negatively associated with age (r= 0.32, p=0.001) and weakly with T2* values (r=-0.19, p=0.057). A positive correlation was found between T2* and LVEF (r=0.27, p=0.006). Out of 37 patients with T2*<20 ms, 18 (48%) had serum ferritin values<1000 ng/ml. In TI cohort, 3 patients had cardiac T2* pathologic values. In AA cohort, pathologic T2* values were found in 2 patients, who received 234 and 199 PRBC units, respectively, and were both on chelation therapy (in one patient ferritin value was 399 ng/ml). T2* values were negatively associated, but not significantly, with the number of PRBC transfused (r=-0.53, p=0.07). CONCLUSION: In our experience, 37% of TM patients had a myocardial iron overload assessed by MRI T2*; this value is higher than in TI patients. Serum ferritin measurement was a poor predictor of myocardial siderosis. In patients with AA, more than 200 PRBC units transfused were required to induce cardiac hemosiderosis, in spite of chelation therapy and, in one patient, of normal ferritin values. PMID- 21238897 TI - Cross-sectional epidemiology of hepatitis C virus detection and treatment in HIV infected patients. AB - BACKGROUND: Sustained virologic response to peginterferon plus ribavirin reduces liver-related complications and mortality in patients co-infected with HIV and hepatitis C virus. Therefore, the presence of any barriers to start hepatitis C virus therapy should be identified and eliminated in order to recruit all eligible patients. METHODS: Cross-sectional study. In a HIV referral clinic we assessed the proportion of patients eligible for hepatitis C virus evaluation and treatment according to consensus guidelines. RESULTS: We identified 134 patients with hepatitis C virus and HIV co-infection. Twenty-one patients were excluded from the analysis due to never attending the HIV clinic (n=12) or having hepatitis C virus RNA not detectable (n=9). In the remaining 113 patients, only 61% had identification of hepatitis C virus genotype and quantification of hepatitis C viral load. Thirty-six patients started peginterferon plus ribavirin, and 16 (44%) achieved sustained virologic response. Seventy-seven patients did not receive treatment for hepatitis C virus due to the presence of medical contraindications (n=22), provider barriers (n=15), or patient barriers (n=40). Multivariate analysis identified lower education degree (odds ratio: 4.53; 95% confidence intervals: 1.36-15.16, p=0.014) and patient civil status single, separated or widower (odds ratio: 4.81; 95% confidence intervals: 1.54-14.99, p=0.007) as the independent determinants associated to not initiating therapy for hepatitis C virus infection in patients with barriers. CONCLUSION: A minor proportion of HIV-infected patients received appropriate assessment and treatment for hepatitis C virus infection. Social disadvantages require multidisciplinary models of health care to improve hepatitis C virus treatment initiation and success. PMID- 21238898 TI - Epstein Barr virus hepatitis. AB - OBJECTIVES: Epstein-Barr Virus (EBV) infection has the potential to establish life-long, benign infections in their hosts. Although biochemical evidence of hepatocellular damage is common, jaundice is uncommon and complete recovery is the rule. The present study describes clinical characteristics and changes of liver function tests during the course of infectious mononucleosis. PATIENTS AND METHODS: All immunocompetent patients with hepatic dysfunction associated with acute EBV infection, cared for at the University Hospital of Heraklion, over a 6 year period, were identified and retrospectively studied. RESULTS: The study included 41 patients with a median age of 18.5 (15-51) years. Aspartate aminotransferase (AST) and alanine-aminotransferase (ALT) were increased in an average maximum of 5-fold. Both transaminase levels started to rise 2 days after the clinical onset of the disease, and returned to normal after a period of 20 days. Alkaline-phosphatase (ALP), gamma-glutamyltransferase (gamma-GT) and bilirubin levels also increased above the normal values during the course of the disease and returned to normal after a period of 20, 30 and 22 days respectively. The changes of mean AST and ALT levels over time were statistically significant, while those of mean ALP, gamma-GT and bilirubin levels over time were not. Anicteric cholestatic liver disease was observed in 24 patients (59%), while icteric only in 2 (6%). CONCLUSION: Liver involvement in acute EBV infection represents mild and self-limited hepatitis with predominantly cholestatic features. PMID- 21238899 TI - Serum surrogate markers of liver fibrosis in primary biliary cirrhosis. AB - BACKGROUND: Hyaluronan, leptin, laminin and collagen IV have been used extensively for the assessment of liver fibrosis. The aim of this study was to assay these markers in the peripheral and hepatic vein blood of primary biliary cirrhosis (PBC) patients and to study their ability to discriminate early from advanced disease. METHODS: Sera from 62 PBC patients were compared to 60 controls, 44 chronic Hepatitis C, 38 hepatocellular carcinoma and 34 viral cirrhosis patients. Serum from the hepatic vein of 15 cirrhotic PBC patients and 17 patients with viral cirrhosis was also assayed. RESULTS: All disease groups had significantly increased levels of hyaluronan and collagen IV, compared to controls, while laminin was significantly increased only in viral cirrhosis. Hyaluronan levels were statistically different between early (54.5 ng/ml; 95%CI 27.3-426.9) and late PBC (154.5 ng/ml; 95%CI 55.3-764.4, p<0.05). The area under the curve (AUC) for the identification of late PBC was 0.74 for hyaluronan, 0.63 for leptin, 0.59 for laminin and 0.70 for collagen IV. Hyaluronan had high sensitivity and NPV in identifying late stages of PBC (96% and 90%, respectively). Short term UDCA had no effect on these markers. CONCLUSION: No single measurement can differentiate between advanced and early fibrosis in PBC. However serum hyaluronan is a promising single serum marker for longitudinal studies in PBC. PMID- 21238900 TI - Obesity and fat distribution as predictors of aortoiliac peripheral arterial disease in middle-aged men. AB - BACKGROUND: Peripheral arterial disease (PAD) in the aortoiliac segment is found in nearly a half of patients with PAD. The aim of this study was to estimate the influence of obesity and fat distribution on the occurrence of aortoiliac PAD in middle-aged men. METHODS: This case-control study included 204 middle-aged men (mean 58+/-7 years; range 45-70 years): 102 patients with aortoiliac PAD and 102 healthy controls without PAD. Aortoiliac PAD was diagnosed by ankle-brachial index (ABI) and angiography. Body mass index (BMI) was categorized as: normal weight, overweight, and obese. Percents of body fat were grouped according to quartile distribution. The relationship between anthropometrics and aortoiliac PAD was estimated by multivariate logistic regression. RESULTS: Patients with aortoiliac PAD had higher body mass index, waist circumference, waist-hip ratio and percent of body fat. A strong correlation between all anthropometric parameters and ABI index and mean angiographic score was shown among patients with PAD. Multivariate regression, adjusted for blood pressure and cholesterol level, identified being overweight, body fat over 26.5% and WHR over 1.02 as predictors for aortoiliac PAD. Body fat over 26.5% and WHR over 1.02 remained significant after further adjustment for blood pressure, cholesterol and body mass index. CONCLUSION: This study has identified the quantity of fat tissue (body fat over 26.5%) and its visceral distribution (waist-hip ratio over 1.02) as predictors of aortoiliac PAD in middle-aged men. Body mass index, a crude indicator of obesity, should be combined with these parameters when assessing the risk for aortoiliac PAD. PMID- 21238901 TI - Impact of diabetes on outcome in patients with non-ST-elevation myocardial infarction. AB - BACKGROUND: Diabetes mellitus contributes to the increase of cardiovascular deaths worldwide. Despite continuous treatment evolution, patients with diabetes suffering from an acute coronary syndrome still have a high morbidity and mortality. We aimed to analyze the impact of diabetes on one-year outcome in an unselected patient population with non-ST-elevation myocardial infarction (non STEMI). METHODS: Retrospective analysis of 847 unselected patients with non STEMI. We compared the baseline characteristics, treatment and outcome of patients versus those without diabetes. RESULTS: A total of 138 patients had diabetes (16%) and 709 (84%) had no diabetes. Patients with diabetes were older, often had hypertension, hyperlipidemia, previous myocardial infarction and Killip class >=2 on admission. Approximately 80% of both patients, with and without diabetes, underwent diagnostic coronary angiography. Multivessel disease was more present among patients with diabetes, but patients with diabetes were treated more often conservatively. At one-year follow up rates of death and major adverse cardiac events were significantly higher in patients with diabetes compared to those without diabetes (8% vs. 3%; P=0.001 and 23% vs. 14%; P=0.008, respectively). Even after adjustment for differences in baseline characteristics, diabetes remained an independent predictor of mortality (OR: 2.25; CI95%: 1.05 3.91). CONCLUSIONS: In an unselected patient population with non-STEMI, patients with diabetes have higher risk factors on admission, less often undergo coronary revascularisation and have worse outcome at one-year follow-up. Diabetes is an independent predictor of one-year mortality in patients with non-STEMI. PMID- 21238902 TI - Adherence to antihypertensive therapy affects Ambulatory Arterial Stiffness Index. AB - BACKGROUND: A major contributor to poor blood pressure (BP) control is nonadherence to therapy, which remains poorly recognized by physicians. The prevention of hypertension-induced changes in arterial wall, namely increased arterial stiffness and peripheral vascular resistance, is a reasoned adequate end point of hypertension treatment. Indirect measurement of these arterial factors can be derived from the analysis of 24-hour Ambulatory BP Monitoring (24 h-ABPM). This pilot study evaluated the association between antihypertensive therapy adherence and 24 h-ABPM-derived parameters in hypertensive patients. METHODS: We studied 42 hypertensive patients (70+/-10 years) in chronic antihypertensive therapy. Patients were divided according to the Morisky Medication Adherence Scale (MMAS) in Low-Adher (MMAS <6) and High-Adher (MMAS 6-8) groups. The Ambulatory Arterial Stiffness Index (AASI) and its symmetric calculation (Sym_AASI) were derived from 24 h-ABPM. A bivariate logistic regression analysis was performed to evaluate the predictive value of MMAS for increased AASIs (i.e. above the median). RESULTS: Low-Adher group (n=17) showed higher AASIs compared to High-Adher group (n=25). The two groups were similar in terms of BP burden at the 24 h-ABPM. AASIs were inversely related to MMAS. MMAS resulted a predictor for both increased AASI (O.R. 0.49, 95% CI 0.31-0.76, P<0.01) and increased Sym_AASI (O.R. 0.67, 95% CI 0.47-0.95, P=0.026). After adjustment for PP, age and nocturnal diastolic BP reduction, MMAS persisted as an inverse predictor only of increased AASI. MMAS was also related to the diastolic vs systolic BP correlation coefficient r. CONCLUSIONS: Low adherence to antihypertensive therapy seems to be associated with increased standard AASI. In this setting, AASI could represent an additional information derived from the 24 h-ABPM in hypertensive patient evaluation. PMID- 21238903 TI - Association of apolipoprotein A5 gene promoter region -1131T>C with risk of stroke in Han Chinese. AB - BACKGROUND: Ischemic stroke is a suddenly developing temporary or often permanent damage of the brain. Several candidate genes have been shown to have an impact in the pathogenesis of ischemic stroke. Recently, the -1131T>C polymorphism in apolipoprotein A5 (APOA5) gene has been reported to be associated with ischemic stroke in different racial groups, but no data is available currently in Han Chinese. Our study is to investigate the association between the APOA5 gene polymorphism -1131T>C and the susceptibility to ischemic stroke in Han Chinese. METHODS: 310 controls and 342 patients with classified ischemic stroke were performed to detect the -1131T>C alleles genotyped by polymerase chain reaction restriction fragment length polymorphism analysis in independent case-control study. RESULTS: TG levels of subjects carrying -1131C allele were elevated compared to the subjects with -1131T allele in all ischemic stroke subgroups and in controls. The serum TC, LDL-C and HDL-C levels did not differ between subjects with T or C alleles in each group. The overall distribution of APOA5 -1131T>C genotype among stroke patients and controls was significantly different (P<0.01). Frequencies of CC homozygote and C allele were significantly higher in all stroke subgroups than those in control group. After adjustment for conventional risk factors, logistic regression analysis showed that C allele carrier (CC+CT) of 1131T>C was an independent risk factor for all stroke subgroups (P<0.05). CONCLUSIONS: APOA5 gene -1131T>C polymorphism is independently associated with the development of ischemic stroke in Chinese Han population, and CC homozygote may have a promoting effect on ischemic stroke. PMID- 21238904 TI - Hemoglobin, erythropoietin and systemic inflammation in exacerbations of chronic obstructive pulmonary disease. AB - BACKGROUND: Systemic inflammation may represent a possible cause of anemia. Previous data support that anemic patients with COPD present high erythropoietin (EPO) levels, suggestive of EPO resistance, possibly mediated through inflammatory mechanisms. OBJECTIVES: We aimed to determine whether systemic inflammation, which is usually up-regulated during exacerbations of COPD (ECOPD) is associated with low hemoglobin levels expressing erythropoietin resistance. METHODS: Hemoglobin (Hb), EPO and serum biomarkers of systemic inflammation [CRP, TNF-alpha, fibrinogen and IL-6] were assessed at three time points (admission, resolution and stable phases) in a selected cohort of 93 COPD patients. RESULTS: Hemoglobin levels were significantly lower on admission compared to resolution and stable phases (median 12.1 g/dl [interquartile ranges 11.2-12.7], vs 13.5 [12.4-14.3] vs 13.4 [12.7-14.08], respectively p=0.002), whereas EPO was significantly higher on admission compared to resolution and stable phases. A negative association between Hb and IL-6 and a positive association between EPO and IL-6 were observed only during the acute phase of exacerbation. EPO and Hb were negatively associated during the acute phase, whereas they were positively associated during discharge and stable phase. CONCLUSIONS: In this observational study we have shown that during admission for ECOPD Hb levels are decreased and EPO levels are increased. We have also identified a negative association between Hb and EPO. The above association is mainly related to increased IL-6 levels, indicating a possible EPO resistance through the mechanism of increased systemic inflammatory process. PMID- 21238905 TI - Elevated NT-proBNP levels should be interpreted in elderly patients presenting with dyspnea. AB - BACKGROUND: B-type natriuretic peptide (BNP) assay is a useful tool in order to diagnose dyspnea due to congestive heart failure (CHF). On the other hand many other diseases could affect BNP levels. The aim of this study was to investigate a group of elderly patients admitted to an Internal Medicine unit because of dyspnea. PATIENTS AND METHODS: NT-proBNP was assessed in 132 consecutive patients aged 80+/-6 years because of dyspnea. History data, anthropometric, clinical and biochemical parameters were collected. Renal function was assessed by the CKD-EPI formula. Diagnosis of pulmonary disease such as infections and chronic obstructive disease was considered and was analyzed as a single parameter. Statistical analysis was carried out dividing patients with high NT-proBNP from those with normal NT-proBNP according to the Januzzi cut-off. RESULTS: NT-proBNP was higher than the normal reference values in 68.7% of patients and its levels increased in the 5 different stages of chronic kidney disease. Subjects with high NT-proBNP had lower haemoglobin levels (11.6+/-2.1 vs 12.8+/-1.9 g/dl, p=0.003), higher prevalence of atrial fibrillation (54.3 vs 25%, p=0.001), and lower prevalence of pulmonary diseases (29.7 vs 57.5%, p=0.005). Logistic regression analysis showed that NT-proBNP levels were independently associated with haemoglobin (OR 1.307 95% CI 1.072-1.593, p=0.008) and pulmonary diseases (OR 3.069 95% CI 1.385-6.801, p=0.006). CONCLUSIONS: A disease different from CHF appears to affect NT-proBNP plasma levels. Therefore, determination of its levels does not seem to help clinicians in the definition of dyspnea in elderly people with different comorbidities. PMID- 21238906 TI - Diagnostic value of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in patients with fever of unknown origin. AB - BACKGROUND: While fever of unknown origin (FUO) remains a challenging problem in clinical practice, fluorine-18 fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) has been considered helpful in diagnosing its cause. The present study is set to evaluate the diagnostic value of PET/CT for patients with FUO. METHODS: We analyzed the records of 48 patients with FUO (34 men and 14 women; mean age of 57-year-old with a range between 24- and 82 year-old). The patients were examined by (18)F-FDG PET/CT and the results were compared to a final diagnosis that was established by additional procedures. RESULTS: A final diagnosis was established for 36 patients (75%). Among them, 15 patients had infectious diseases, 12 patients had malignancies, and 9 patients had non-infectious inflammatory diseases. Thirty-two abnormal PET/CT results correctly revealed the source of fever (true-positives). Abnormal PET/CT results were considered false-positives for 8 patients without diagnoses. Normal PET/CT results in 4 patients with no diagnoses were classified as true-negatives. Four patients with normal PET/CT results with diagnosed cause for FUO were considered false-negatives. Therefore, PET/CT had a positive predictive value of 80%, a negative predictive value of 50%, a sensitivity of 89%, and a specificity of 33% in patients with FUO. CONCLUSIONS: Our study demonstrated that FDG-PET/CT is a valuable imaging tool for the identification of the etiology in patients with FUO. The results suggest that this procedure may be considered as a second-line test, especially when conventional structural imaging was normal or unable to distinguish lesions from benign and malignant. PMID- 21238907 TI - Homeopathy, a tremendous opportunity for medicine! PMID- 21238909 TI - Detection of chronic kidney disease in hospitalized patients: is one estimating glomerular filtration rate equation better than another? PMID- 21238911 TI - Ventilation/perfusion scanning still has a role in the work-up of suspected pulmonary embolism. PMID- 21238913 TI - NTx as marker for bone resorption in CKD. PMID- 21238914 TI - Chromosomal abnormalities in renal cell carcinoma variants detected by Urovysion fluorescence in situ hybridization on paraffin-embedded tissue. AB - Urovysion fluorescence in situ hybridization (UVFISH) identifies malignant cells in urine by detecting specific urothelial carcinoma-related chromosomal abnormalities. Some renal carcinomas (RCCs) share overlapping chromosomal aberrations with urothelial carcinoma. Malignant renal cells that are shed in urine can potentially cause a positive UVFISH result. We evaluated UVFISH in RCCs to determine its potential applicability to the diagnosis and grading of RCCs. Paraffin blocks from 39 RCCs (25 clear cell, 9 papillary, 2 chromophobe, and 3 sarcomatoid) and 15 controls (5 renal oncocytomas and 10 urothelial carcinomas) were tested. Of the RCCs, 15 (40%) were UVFISH-positive (9/25 [40%] clear cell, 3/9 [30%] papillary, 1/2 [50%] chromophobe, and 2/3 [67%] sarcomatoid carcinoma) and 24 (60%) were negative. Of the 15 controls, 8 (~50%) were UVFISH-positive (2/5 [40%] oncocytomas and 6/10 [60%] urothelial carcinomas) and 7 (~50%) were UVFISH-negative. Polysomy of chromosome 17 showed a statistically significant correlation with RCC subtype, being absent in most of the clear cell RCCs (P = .0096) compared with other RCCs. Polysomy of chromosome 7 was more frequent in high-grade than low-grade RCC (P = .0197) and more likely in high-grade clear cell than low-grade clear cell RCC (P = .0120). In conclusion, we showed that RCC has overlapping chromosomal abnormalities with urothelial carcinoma and can cause a positive UVFISH result. This has implications for the interpretation of Urovysion in patients whose urine contains malignant cells but who have negative cystoscopy and a concomitant renal mass. The chromosomal abnormalities observed in RCC are not distinct from those in urothelial carcinoma; therefore, UVFISH cannot distinguish these tumor types, nor can it type or grade RCC. PMID- 21238917 TI - Shedding light on mammalian microautophagy. AB - ESCRT complexes are implicated in mediating membrane protein degradation, whereas hsc70 mediates cytosolic protein degradation via chaperone-mediated autophagy. In this issue of Developmental Cell, Sahu et al. (2011) describe in mammalian cells the involvement of ESCRT complexes and hsc70 in the degradation of cytosolic proteins in a process resembling microautophagy. PMID- 21238915 TI - New developments in the molecular pathogenesis of head and neck tumors: a review of tumor-specific fusion oncogenes in mucoepidermoid carcinoma, adenoid cystic carcinoma, and NUT midline carcinoma. AB - Tumor-specific chromosomal rearrangements often produce potent fusion oncogenes, which induce tumorigenesis by 2 alternative mechanisms: deregulation of the cell cycle resulting in gene overexpression or gene fusion resulting in a hybrid, chimeric oncogene. Tumor-specific recurrent chromosomal translocations and novel fusion oncogenes in aggressive head and neck malignancies have diagnostic, therapeutic, and prognostic implications. Recently, pathognomonic fusion transcripts have been identified in various uncommon, aggressive head and neck malignancies, including mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), and NUT midline carcinoma (NMC). The t(11;19)(q12;p13) translocation in MEC results in fusion of the MECT1 gene at 19p13 and the MAML2 gene at 11q21. The MECT1-MAML2 fusion transcript, present in more than half of MECs, is associated with lower histologic grades and improved survival, suggesting both diagnostic and prognostic roles in clinical management. The t(6;9)(q22-23;p23-24) translocation in ACC results in fusion of the MYB gene at 6q22-23 and the NFIB gene at 9p23-24. The MYB-NFIB fusion transcript, present in at least one third of salivary ACCs, can be detected by new reverse transcription polymerase chain reaction screening methods, and has emerged as a potential therapeutic target. The t(15;19)(q14;p13.1) translocation in NMC results in fusion of the NUT gene at 15q14 and the BRD4 gene at 19p13.1. This occurs in two thirds of NMC. Because NMC lacks characteristic clinicopathologic features and established therapeutic options, the BRD4-NUT fusion transcript may represent both a diagnostic marker and an optimal target for disease-specific drug therapy. Moreover, immunohistochemical advances have yielded a promising new monoclonal antibody against the NUT antigen, which may improve NMC diagnosis. Next-generation sequencing methods, such as the use of massively parallel and paired-end sequencing in the study of cancer genomes, will likely disclose novel fusion transcripts in more human malignancies. Hopefully, as technological advances unravel the molecular pathogenesis of aggressive carcinomas, diagnostic and therapeutic options will evolve to improve clinical outcomes. PMID- 21238918 TI - MicroRNAs sculpt gene expression in embryonic development: new insights from plants. AB - Zygotic microRNAs coordinate the clearance of maternal mRNA in animals to facilitate developmental transitions. In a recent issue of Genes and Development, Nodine and Bartel (2010) uncover a reciprocal function in plants, where miRNA-156 preemptively represses genes that function later in development to prevent premature developmental transitions. PMID- 21238919 TI - Epigenetic memory meets G2/M: to remember or to forget? AB - The histone H3 lysine 27 (H3K27) methyltransferase EZH2 is essential for stem cell maintenance and proliferation. Recent insights suggest that the cyclin dependent kinase CDK1 phosphorylates EZH2 at specific threonine residues by sensing developmental cues to mediate self-renewal or differentiation during G2/M phase. PMID- 21238920 TI - A receptor for meningococcus: eliciting beta-arrestin signaling for barrier breaching. AB - In a recent issue of Cell, Coureuil et al. (2010) show that type IV pili of Neisseria meningitidis-the causative bacterium of cerebrospinal meningitis-bind to the endothelial beta2-adrenoceptor and elicit biased beta-arrestin signaling resulting in microvilli formation and paracytotic bacterial migration. PMID- 21238921 TI - Whence directionality: guidance mechanisms in solitary and collective cell migration. AB - As individual cells or groups of cells move through the complex environment of the body, their migration is affected by multiple external cues. Some cues are diffusible signaling molecules, and some are solid biophysical features. How do cells respond appropriately? This perspective discusses the relationship between guidance input and the cellular output, considering effects from classical chemotaxis to contact-dependent guidance. The influences of membrane trafficking and of imposed constraints on directional movement are also considered. New insights regarding guidance and dynamic cell polarity have emerged from examining new cell migration models and from re-examining well known ones with new approaches and new tools. PMID- 21238923 TI - Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B. AB - Robo4 is an endothelial cell-specific member of the Roundabout axon guidance receptor family. To identify Robo4 binding partners, we performed a protein protein interaction screen with the Robo4 extracellular domain. We find that Robo4 specifically binds to UNC5B, a vascular Netrin receptor, revealing unexpected interactions between two endothelial guidance receptors. We show that Robo4 maintains vessel integrity by activating UNC5B, which inhibits signaling downstream of vascular endothelial growth factor (VEGF). Function-blocking monoclonal antibodies against Robo4 and UNC5B increase angiogenesis and disrupt vessel integrity. Soluble Robo4 protein inhibits VEGF-induced vessel permeability and rescues barrier defects in Robo4(-/-) mice, but not in mice treated with anti UNC5B. Thus, Robo4-UNC5B signaling maintains vascular integrity by counteracting VEGF signaling in endothelial cells, identifying a novel function of guidance receptor interactions in the vasculature. PMID- 21238922 TI - MicroRNA-9 reveals regional diversity of neural progenitors along the anterior posterior axis. AB - Neural progenitors self-renew and generate neurons throughout the central nervous system. Here, we uncover an unexpected regional specificity in the properties of neural progenitor cells, revealed by the function of a microRNA--miR-9. miR-9 is expressed in neural progenitors, and its knockdown results in an inhibition of neurogenesis along the anterior-posterior axis. However, the underlying mechanism differs--in the hindbrain, progenitors fail to exit the cell cycle, whereas in the forebrain they undergo apoptosis, counteracting the proliferative effect. Among several targets, we functionally identify hairy1 as a primary target of miR 9, regulated at the mRNA level. hairy1 mediates the effects of miR-9 on proliferation, through Fgf8 signaling in the forebrain and Wnt signaling in the hindbrain, but affects apoptosis only in the forebrain, via the p53 pathway. Our findings show a positional difference in the responsiveness of progenitors to miR 9 depletion, revealing an underlying divergence of their properties. PMID- 21238924 TI - PI4P and Rab inputs collaborate in myosin-V-dependent transport of secretory compartments in yeast. AB - Cell polarity involves transport of specific membranes and macromolecules at the right time to the right place. In budding yeast, secretory vesicles are transported by the myosin-V Myo2p to sites of cell growth. We show that phosphatidylinositol 4-phosphate (PI4P) is present in late secretory compartments and is critical for their association with, and transport by, Myo2p. Further, the trans-Golgi network Rab Ypt31/32p and secretory vesicle Rab Sec4p each bind directly, but distinctly, to Myo2p, and these interactions are also required for secretory compartment transport. Enhancing the interaction of Myo2p with PI4P bypasses the requirement for interaction with Ypt31/32p and Sec4p. Together with additional genetic data, the results indicate that Rab proteins and PI4P collaborate in the association of secretory compartments with Myo2p. Thus, we show that a coincidence detection mechanism coordinates inputs from PI4P and the appropriate Rab for secretory compartment transport. PMID- 21238925 TI - KIF16B/Rab14 molecular motor complex is critical for early embryonic development by transporting FGF receptor. AB - Kinesin-mediated membrane trafficking is a fundamental cellular process, but its developmental relevance is little understood. Here we show that the kinesin-3 motor KIF16B/Rab14 complex acts in biosynthetic Golgi-to-endosome traffic of the fibroblast growth factor receptor (FGFR) during early embryonic development. Kif16b(-/-) mouse embryos failed in developing epiblast and primitive endoderm lineages and died in the peri-implantation stage, similar to previously reported FGFR2 knockout embryos. KIF16B associated directly with the Rab14-GTP adaptor on FGFR-containing vesicles and transported them toward the plasma membrane. To examine whether the nucleotide state of Rab14 serves as a switch for transport, we performed Rab14-GDP overexpression. This dominant negative approach reproduced the whole putative sequence of KIF16B or FGFR2 deficiency: impairment in FGFR transport, FGF signaling, basement membrane assembly by the primitive endoderm lineage, and epiblast development. These data provide one of the first pieces of genetic evidence that microtubule-based membrane trafficking directly promotes early development. PMID- 21238926 TI - Brat promotes stem cell differentiation via control of a bistable switch that restricts BMP signaling. AB - Drosophila ovarian germline stem cells (GSCs) are maintained by Dpp signaling and the Pumilio (Pum) and Nanos (Nos) translational repressors. Upon division, Dpp signaling is extinguished, and Nos is downregulated in one daughter cell, causing it to switch to a differentiating cystoblast (CB). However, downstream effectors of Pum-Nos remain unknown, and how CBs lose their responsiveness to Dpp is unclear. Here, we identify Brain Tumor (Brat) as a potent differentiation factor and target of Pum-Nos regulation. Brat is excluded from GSCs by Pum-Nos but functions with Pum in CBs to translationally repress distinct targets, including the Mad and dMyc mRNAs. Regulation of both targets simultaneously lowers cellular responsiveness to Dpp signaling, forcing the cell to become refractory to the self-renewal signal. Mathematical modeling elucidates bistability of cell fate in the Brat-mediated system, revealing how autoregulation of GSC number can arise from Brat coupling extracellular Dpp regulation to intracellular interpretation. PMID- 21238927 TI - Ras effector switching promotes divergent cell fates in C. elegans vulval patterning. AB - The C. elegans vulva is patterned by epidermal growth factor (EGF) activation of Ras to control 1 degrees fate, and 1 degrees fate induces antagonistic Notch dependent 2 degrees fate. Furthermore, a spatial EGF gradient, in addition to inducing 1 degrees fate, directly contributes to 2 degrees fate via an unknown pathway. We find that in addition to its canonical effector, Raf, vulval Ras utilizes an exchange factor for the Ral small GTPase (RalGEF), such that Ras RalGEF-Ral antagonizes Ras-Raf pro-1 degrees fate activity. Consistent with its restricted expression pattern, Ral participates in EGF pro-2 degrees activity. Thus, we have delineated a Ras effector-switching mechanism whereby position within the morphogen gradient dictates that Ras effector usage is switched to RalGEF from Raf to promote 2 degrees instead of 1 degrees fate. Our observations define the utility of Ras effector switching during normal development and may provide a possible mechanistic basis for cell and cancer-type differences in effector dependency and activation. PMID- 21238928 TI - Rheb1 is required for mTORC1 and myelination in postnatal brain development. AB - mTor kinase is involved in cell growth, proliferation, and differentiation. The roles of mTor activators, Rheb1 and Rheb2, have not been established in vivo. Here, we report that Rheb1, but not Rheb2, is critical for embryonic survival and mTORC1 signaling. Embryonic deletion of Rheb1 in neural progenitor cells abolishes mTORC1 signaling in developing brain and increases mTORC2 signaling. Remarkably, embryonic and early postnatal brain development appears grossly normal in these Rheb1f/f,Nes-cre mice with the notable exception of deficits of myelination. Conditional expression of Rheb1 transgene in neural progenitors increases mTORC1 activity and promotes myelination in the brain. In addition the Rheb1 transgene rescues mTORC1 signaling and hypomyelination in the Rheb1f/f,Nes cre mice. Our study demonstrates that Rheb1 is essential for mTORC1 signaling and myelination in the brain, and suggests that mTORC1 signaling plays a role in selective cellular adaptations, rather than general cellular viability. PMID- 21238929 TI - Cooperative regulation of growth by Yorkie and Mad through bantam. AB - The Dpp and Fat-Hippo signaling pathways both regulate growth in Drosophila. Dpp is a BMP family ligand and acts via a Smad family DNA-binding transcription factor, Mad. Fat-Hippo signaling acts via a non-DNA-binding transcriptional coactivator protein, Yorkie. Here, we show that these pathways are directly interlinked. They act synergistically to promote growth, in part via regulation of the microRNA gene bantam, and their ability to promote growth is mutually dependent. Yorkie and Mad physically bind each other, and we identify a 410 bp minimal enhancer of bantam that responds to Yorkie:Mad in vivo and in cultured cells, and show that both Yorkie and Mad associate with this enhancer in vivo. Our results indicate that in promoting the growth of Drosophila tissues, Fat Hippo and Dpp signaling contribute distinct subunits of a shared transcriptional activation complex, Yorkie:Mad. PMID- 21238930 TI - Antagonistic growth regulation by Dpp and Fat drives uniform cell proliferation. AB - We use the Dpp morphogen gradient in the Drosophila wing disc as a model to address the fundamental question of how a gradient of a growth factor can produce uniform growth. We first show that proper expression and subcellular localization of components in the Fat tumor-suppressor pathway, which have been argued to depend on Dpp activity differences, are not reliant on the Dpp gradient. We next analyzed cell proliferation in discs with uniformly high Dpp or uniformly low Fat signaling activity and found that these pathways regulate growth in a complementary manner. While the Dpp mediator Brinker inhibits growth in the primordium primarily in the lateral regions, Fat represses growth mostly in the medial region. Together, our results indicate that the activities of both signaling pathways are regulated in a parallel rather than sequential manner and that uniform proliferation is achieved by their complementary action on growth. PMID- 21238932 TI - Modifications of nuclear DNA and its regulatory proteins. Preface. PMID- 21238931 TI - Microautophagy of cytosolic proteins by late endosomes. AB - Autophagy delivers cytosolic components to lysosomes for their degradation. The delivery of autophagic cargo to late endosomes for complete or partial degradation has also been described. In this report we present evidence that distinct autophagic mechanisms control cytosolic protein delivery to late endosomes and identify a microautophagy-like process that delivers soluble cytosolic proteins to the vesicles of late endosomes/multivesicular bodies (MVBs). This microautophagy-like process has selectivity and is distinct from chaperone-mediated autophagy that occurs in lysosomes. Endosomal microautophagy occurs during MVB formation, relying on the ESCRT I and III systems for formation of the vesicles in which the cytosolic cargo is internalized. Protein cargo selection is mediated by the chaperone hsc70 and requires the cationic domain of hsc70 for electrostatic interactions with the endosomal membrane. Therefore, we propose that endosomal microautophagy shares molecular components with both the endocytic and autophagic pathways. PMID- 21238934 TI - Complex assemblies of factors IX and X regulate the initiation, maintenance, and shutdown of blood coagulation. AB - Blood hemostasis is accomplished by a complex network of (anti-)coagulatory and fibrinolytic processes. These physiological processes are implemented by the assembly of multiprotein complexes involving both humoral and cellular components. Coagulation factor X, and particularly, factor IX, exemplify the dramatic enhancement that is obtained by the synergistic interaction of cell surface, inorganic and protein cofactors, protease, and substrate. With a focus on structure-function relationship, we review the current knowledge of activity modulation principles in the coagulation proteases factors IX and X and indicate future challenges for hemostasis research. This chapter is organized by describing the principles of hierarchical activation of blood coagulation proteases, including endogenous and exogenous protease activators, cofactor binding, substrate specificities, and protein inhibitors. We conclude by outlining pharmaceutical opportunities for unmet needs in hemophilia and thrombosis. PMID- 21238935 TI - Structure and proteolytic properties of ADAMTS13, a metalloprotease involved in the pathogenesis of thrombotic microangiopathies. AB - ADAMTS13 is a 190-kDa zinc protease encoded by a gene located on chromosome 9q34. This protease specifically hydrolyzes von Willebrand factor (VWF) multimers, thus causing VWF size reduction. ADAMTS13 belongs to the A Disintegrin And Metalloprotease with ThromboSpondin type 1 repeats (ADAMTS) family, involved in proteolytic processing of many matrix proteins. ADAMTS13 consists of numerous domains, including a metalloprotease domain, a disintegrin domain, several thrombospondin type 1 (TSP1) repeats, a cysteine-rich domain, a spacer domain, and two CUB (Complement c1r/c1s, sea Urchin epidermal growth factor, and Bone morphogenetic protein) domains. ADAMTS13 cleaves a single peptide bond (Tyr(1605) Met(1606)) in the central A2 domain of the VWF molecule. This proteolytic cleavage is essential to reduce the size of ultralarge VWF polymers, which, when exposed to high shear stress in the microcirculation, are prone to form platelets clumps, which cause severe syndromes called thrombotic microangiopathies (TMAs). In this chapter, we (a) discuss the current knowledge of structure-function aspects of ADAMTS13 and its involvement in the pathogenesis of TMAs, (b) address the ongoing controversies, and (c) indicate the direction of future investigations. PMID- 21238936 TI - Thrombin as an anticoagulant. AB - Thrombosis is the most prevalent cause of fatal diseases in developed countries. An antithrombotic agent that can be administered to patients with severe acute thrombotic diseases without the risk of causing hemorrhage, as experienced with antithrombotic/thrombolytic therapy in the treatment of acute ischemic stroke or systemic anticoagulants like heparin, would likely revolutionize the treatment of cardiovascular and cerebrovascular diseases. Thrombin remains at the forefront of cardiovascular medicine and a major target of antithrombotic and anticoagulant therapies, due to its involvement in thrombotic deaths. Heparins and direct thrombin inhibitors currently used in the treatment of acute thrombotic complications, especially in the venous circulation, are plagued by complications related to dosage and bleeding. A new strategy of intervention has been proposed in recent years aiming at modulating, rather than inhibiting, thrombin function. Specifically, efforts have been directed toward finding ways of exploiting the anticoagulant function of thrombin unleashed by the activation of protein C, either using small modulators or protein engineering. The ability of thrombin to activate protein C coexists with its procoagulant and prothrombotic functions, mediated respectively by cleavage of fibrinogen and the protease-activated receptor 1 (PAR1). A strategy that inhibits thrombin at the active site abrogates the procoagulant and prothrombotic functions, but also shuts down activity toward the anticoagulant protein C. On the other hand, a strategy that selectively compromises fibrinogen and PAR1 recognition may take advantage of the anticoagulant and cytoprotective functions of activated protein C and prove of interest for in vivo applications. This chapter summarizes current protein engineering efforts to convert thrombin into a potent and safe anticoagulant for in vivo applications. PMID- 21238937 TI - Regulation of proteases by protein inhibitors of the serpin superfamily. AB - The serpins comprise an ancient superfamily of proteins, found abundantly in eukaryotes and even in some bacteria and archea, that have evolved to regulate proteases of both serine and cysteine mechanistic classes. Unlike the thermodynamically determined lock-and-key type inhibitors, such as those of the Kunitz and Kazal families, serpins use conformational change and consequent kinetic trapping of an enzyme intermediate to effect inhibition. By combining interactions of both an exposed reactive center loop and exosites outside this loop with the active site and complementary exosites on the target protease, serpins can achieve remarkable specificity. Together with the frequent use of regulatory cofactors, this permits a sophisticated time- and location-dependent mode of protease regulation. An understanding of the structure and function of serpins has suggested that they may provide novel scaffolds for engineering protease inhibitors of desired specificity for therapeutic use. PMID- 21238938 TI - Multiple roles of metalloproteinases in neurological disorders. AB - Once thought to mainly act in brain to remodel the extracellular matrix, the family of metalloproteinases is important in many normal and pathological processes in the nervous system. Matrix metalloproteinases (MMPs) and A disintegrin and metalloproteinases (ADAMs) are the two major families of metalloproteinases in the brain. MMPs are comprised of several related enzymes that act on extracellular molecules. Normally, they are important in angiogenesis and neurogenesis in development. In neuroinflammatory illnesses, they disrupt the basal lamina and tight junction proteins to open the blood-brain barrier (BBB). ADAMs are important in neuroinflammation through activation of tumor necrosis factor-alpha (TNF-alpha) and their action as secretases that modulate the action of receptors on the cell surface. Four tissue inhibitors of metalloproteinases (TIMPs) are the main inhibitors of the MMPs and ADAMs. Recently, MMPs were found to affect DNA repair processes by an unexpected intranuclear action. MMPs and ADAMs have been implicated in the pathophysiology of neurodegenerative diseases such as Alzheimer's disease and vascular cognitive impairment. Growing literature on the functions of MMPs and ADAMs in the central nervous system is opening up new and exciting areas of research that may lead to novel approaches to treatment of neurological diseases. PMID- 21238939 TI - Regulation of caspases in the nervous system implications for functions in health and disease. AB - Caspases, initially identified as a family of proteases regulating cell death, have been found to have nonapoptotic functions as well. Some family members are critical for mediating programmed cell death in development. After development, caspases are downregulated in the nervous system, but continue to perform important nonapoptotic functions relevant for neurogenesis and synaptic plasticity. In neurodegenerative diseases, where aberrant neuronal death is an outstanding feature, there is an increase in caspase activity. The specific caspase death pathways leading to dysfunction and death have still not been fully clarified, despite the plethora of scientific literature addressing these issues. In this chapter, we will present the current knowledge of caspase activation and activity pathways, the current tools for examining caspases, and functions of caspases in the nervous system in health and in disease. Alzheimer's Disease, the most common neurodegenerative disorder, and cerebral ischemia, the most common cause of neurologic death, are used to illustrate our current understanding of death signaling in neurodegenerative diseases. A better understanding of how caspases function in health and disease would provide appropriate specific targets for the development of therapeutic interventions for these diseases. Life and death are exquisitely regulated at the cellular level from development through maturity. During development, neuronal death is the major factor shaping the nervous system. This death is mainly caspase-mediated apoptosis. Once the waves of developmental death have passed (death occurs at different times in different parts of the nervous system), there is downregulation of the death machinery, as the postmitotic neurons should live for the life of the organism. Aberrant neuronal death is a major part of neurodegenerative disorders, but there is still no clear understanding of the processes leading to the phenotypes of the various diseases. Even the type of death that occurs continues to be debated, whether it is apoptotic, necrotic, or autophagic, or some combination of these death mechanisms. Here, we will discuss the role that the caspases play in neuronal function, dysfunction, and death. First, we will discuss the regulation of caspase activation and activity. We will examine the current understanding of caspase function in developmental neuronal death and then illustrate the role of caspases in neuronal death in disease employing two diseases of neuronal loss, Alzheimer's Disease (AD), which is the most common chronic neurodegenerative disorder, and cerebral ischemia/stroke, the third most common cause of death in Western society, which is an acute neuronal disorder with chronic sequelae. PMID- 21238933 TI - Membrane-anchored serine proteases in health and disease. AB - Serine proteases of the trypsin-like family have long been recognized to be critical effectors of biological processes as diverse as digestion, blood coagulation, fibrinolysis, and immunity. In recent years, a subgroup of these enzymes has been identified that are anchored directly to plasma membranes, either by a carboxy-terminal transmembrane domain (Type I), an amino-terminal transmembrane domain with a cytoplasmic extension (Type II or TTSP), or through a glycosylphosphatidylinositol (GPI) linkage. Recent biochemical, cellular, and in vivo analyses have now established that membrane-anchored serine proteases are key pericellular contributors to processes vital for development and the maintenance of homeostasis. This chapter reviews our current knowledge of the biological and physiological functions of these proteases, their molecular substrates, and their contributions to disease. PMID- 21238940 TI - Understanding how hepatitis C virus builds its unctuous home. AB - Hepatitis C virus genome replication occurs in endoplasmic reticulum-derived membrane compartments, but it is unknown how these structures arise. In this issue of Cell Host & Microbe, Reiss and colleagues (2011) show that the virus recruits a specific lipid kinase to replication sites, stimulates its kinase activity, and alters the phospholipid profile of replication compartments. PMID- 21238941 TI - SIV envelope acquires a nefarious habit. AB - Deletion of the nef gene from macaque simian immunodeficiency virus (SIVmac) attenuates its ability to cause disease. Pathogenic viruses occasionally emerge in macaques infected with Nef-deleted SIVmac, with some genetic determinants mapping to the envelope (env) gene. An intriguing new study shows that these changes endow Env with a Nef-like ability to counteract tetherin/BST2 (Serra Moreno et al., 2011). PMID- 21238942 TI - RNA virus harnesses microRNAs to seize host translation control. AB - Picornaviruses have evolved elaborate strategies to subvert host translation. In this issue of Cell Host and Microbe, Ho et al. (2011) report that enterovirus infection induces the synthesis of a transcription factor that enhances the synthesis of microRNA-141, which suppresses translation of the cap-binding protein, eIF4E, mRNA to inhibit cap-dependent translation. PMID- 21238943 TI - Super-resolution dissection of coordinated events during malaria parasite invasion of the human erythrocyte. AB - Erythrocyte invasion by the merozoite is an obligatory stage in Plasmodium parasite infection and essential to malaria disease progression. Attempts to study this process have been hindered by the poor invasion synchrony of merozoites from the only in vitro culture-adapted human malaria parasite, Plasmodium falciparum. Using fluorescence, three-dimensional structured illumination, and immunoelectron microscopy of filtered merozoites, we analyze cellular and molecular events underlying each discrete step of invasion. Monitoring the dynamics of these events revealed that commitment to the process is mediated through merozoite attachment to the erythrocyte, triggering all subsequent invasion events, which then proceed without obvious checkpoints. Instead, coordination of the invasion process involves formation of the merozoite erythrocyte tight junction, which acts as a nexus for rhoptry secretion, surface protein shedding, and actomyosin motor activation. The ability to break down each molecular step allows us to propose a comprehensive model for the molecular basis of parasite invasion. PMID- 21238944 TI - Virulence of Mycobacterium tuberculosis depends on lipoamide dehydrogenase, a member of three multienzyme complexes. AB - Mycobacterium tuberculosis (Mtb) adapts to persist in a nutritionally limited macrophage compartment. Lipoamide dehydrogenase (Lpd), the third enzyme (E3) in Mtb's pyruvate dehydrogenase complex (PDH), also serves as E1 of peroxynitrite reductase/peroxidase (PNR/P), which helps Mtb resist host-reactive nitrogen intermediates. In contrast to Mtb lacking dihydrolipoamide acyltransferase (DlaT), the E2 of PDH and PNR/P, Lpd-deficient Mtb is severely attenuated in wild type and immunodeficient mice. This suggests that Lpd has a function that DlaT does not share. When DlaT is absent, Mtb upregulates an Lpd-dependent branched chain keto acid dehydrogenase (BCKADH) encoded by pdhA, pdhB, pdhC, and lpdC. Without Lpd, Mtb cannot metabolize branched-chain amino acids and potentially toxic branched-chain intermediates accumulate. Mtb deficient in both DlaT and PdhC phenocopies Lpd-deficient Mtb. Thus, Mtb critically requires BCKADH along with PDH and PNR/P for pathogenesis. These findings position Lpd as a potential target for anti-infectives against Mtb. PMID- 21238945 TI - Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment. AB - Hepatitis C virus (HCV) is a major causative agent of chronic liver disease in humans. To gain insight into host factor requirements for HCV replication, we performed a siRNA screen of the human kinome and identified 13 different kinases, including phosphatidylinositol-4 kinase III alpha (PI4KIIIalpha), as being required for HCV replication. Consistent with elevated levels of the PI4KIIIalpha product phosphatidylinositol-4-phosphate (PI4P) detected in HCV-infected cultured hepatocytes and liver tissue from chronic hepatitis C patients, the enzymatic activity of PI4KIIIalpha was critical for HCV replication. Viral nonstructural protein 5A (NS5A) was found to interact with PI4KIIIalpha and stimulate its kinase activity. The absence of PI4KIIIalpha activity induced a dramatic change in the ultrastructural morphology of the membranous HCV replication complex. Our analysis suggests that the direct activation of a lipid kinase by HCV NS5A contributes critically to the integrity of the membranous viral replication complex. PMID- 21238947 TI - Enterovirus-induced miR-141 contributes to shutoff of host protein translation by targeting the translation initiation factor eIF4E. AB - Viruses rely on the host translation machinery to complete their life cycles. Picornaviruses use an internal ribosome entry site to initiate cap-independent protein translation and in parallel host cap-dependent translation is shut off. This process is thought to occur primarily via cleavage of host translation initiation factors eIF4GI and eIF4GII by viral proteases. Here we describe another mechanism whereby miR-141 induced upon enterovirus infection targets the cap-dependent translation initiation factor, eIF4E, for shutoff of host protein synthesis. Knockdown of miR-141 reduces viral propagation, and silencing of eIF4E can completely reverse the inhibitory effect of the miR-141 antagomiR on viral propagation. Ectopic expression of miR-141 promotes the switch from cap-dependent to cap-independent translation. Moreover, we identified a transcription factor, EGR1, which is partly responsible for miR-141 induction in response to enterovirus infection. Our results suggest that upregulation of miR-141 upon enterovirus infection can facilitate viral propagation by expediting the translational switch. PMID- 21238946 TI - Compensatory changes in the cytoplasmic tail of gp41 confer resistance to tetherin/BST-2 in a pathogenic nef-deleted SIV. AB - Tetherin (BST-2 or CD317) is an interferon-inducible transmembrane protein that inhibits virus release from infected cells. Whereas HIV-1 Vpu and HIV-2 Env counteract human tetherin, most SIVs use Nef to antagonize the tetherin proteins of their nonhuman primate hosts. Here, we show that compensatory changes in the cytoplasmic domain of SIV gp41, acquired by a nef-deleted virus that regained a pathogenic phenotype in infected rhesus macaques, restore resistance to tetherin. These changes facilitate virus release in the presence of rhesus tetherin, but not human tetherin, and enhance virus replication in interferon-treated primary lymphocytes. The substitutions in gp41 result in a selective physical association with rhesus tetherin, and the internalization and sequestration of rhesus tetherin by a mechanism that depends on a conserved endocytosis motif in gp41. These results are consistent with HIV-2 Env antagonism of human tetherin and suggest that the ability to oppose tetherin is important for lentiviral pathogenesis. PMID- 21238949 TI - Ultrasound biomicroscopic imaging of iris melanoma: a clinicopathologic study. AB - PURPOSE: To demonstrate the correlation of ultrasound biomicroscopy (UBM) features of iris melanoma with histopathology. DESIGN: Retrospective analysis of medical records. METHODS: The medical records of patients that underwent surgery for iris melanoma at the Princess Margaret Hospital, University of Toronto, from June 1990 to October 1998 were reviewed. The clinical features, as well as the UBM findings prior to surgical intervention, were evaluated. The anatomic features noted on UBM were correlated with histopathologic features seen in the surgical specimens. RESULTS: Fourteen cases met the inclusion criteria and were included in the final analysis. The ultrasound acoustic characteristics showed a broad spectrum of findings among iris melanomas. Tumor acoustic parameters correlated well with histologic features, including tumor vascularity, surface plaque, extrascleral extension, ciliary body involvement, and integrity of iris pigment epithelium. CONCLUSIONS: UBM is a useful imaging technique for the in vivo assessment of primary iris melanoma and can provide detailed imaging of the tumor's interface with the angle structures. The preoperative assessment of these tumors by UBM may aid the surgeon in choosing the most appropriate technique to ensure total removal. PMID- 21238950 TI - Weight matters: physical and psychosocial well being of persons with spinal cord injury in relation to body mass index. AB - OBJECTIVE: To examine the relationship of body mass index (BMI) with multiple health indices among persons with spinal cord injury (SCI). DESIGN: Multicenter cross-sectional study. SETTING: A total of 16 SCI Model Systems throughout the United States. PARTICIPANTS: A total of 1107 men and 274 women (N=1381), mean age +/- SD, 43.1+/-14.6 years (tetraplegia, 56.9%; complete injuries, 50.2%; mean years since injury +/- SD, 7.8+/-8.6), who received follow-up in 2006 to 2009, were classified into 1 of the 4 BMI categories-underweight, normal, overweight, and obese-based on self-reported height and measured weight. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Rehospitalization, pain, self-perceived health, FIM, Craig Handicap Assessment and Reporting Technique, Patient Health Questionnaire-9 (PHQ-9), and the Diener's Satisfaction With Life Scale (SWLS). RESULTS: The prevalence of underweight, overweight, and obesity was 7.5%, 31.4%, and 22.1%, respectively, which varied by age, sex, marital status, education, and neurologic impairment. For those with tetraplegia and functional motor-complete injuries, rehospitalization occurred more frequently among obese persons, while days rehospitalized were the longest among underweight persons. Pain was more severe in those classified as obese. Community mobility was lower in the underweight, overweight, and obese groups than in those with normal weight. There was no significant association between BMI and self-perceived health, FIM, PHQ-9, and SWLS beyond the effect of neurologic impairment. CONCLUSIONS: Prevention and intervention directed at those significantly overweight or underweight deserve consideration as priorities in the continuity of care for persons with SCI. Efforts should be targeted particularly to those at higher risk, including persons with more severe injuries, who are less educated, and who are living alone. PMID- 21238948 TI - Comparative RNAi screening reveals host factors involved in enterovirus infection of polarized endothelial monolayers. AB - Enteroviruses, including coxsackievirus B (CVB) and poliovirus (PV), can access the CNS through the blood brain barrier (BBB) endothelium to cause aseptic meningitis. To identify cellular components required for CVB and PV infection of human brain microvascular endothelial cells, an in vitro BBB model, we performed comparative RNAi screens and identified 117 genes that influenced infection. Whereas a large proportion of genes whose depletion enhanced infection (17 of 22) were broadly antienteroviral, only 46 of the 95 genes whose depletion inhibited infection were required by both CVB and PV and included components of cell signaling pathways such as adenylate cyclases. Downregulation of genes including Rab GTPases, Src tyrosine kinases, and tyrosine phosphatases displayed specificity in their requirement for either CVB or PV infection. These findings highlight the pathways hijacked by enteroviruses for entry and replication in the BBB endothelium, a specialized and clinically relevant cell type for these viruses. PMID- 21238952 TI - Mutual exclusivity in autism spectrum disorders: testing the pragmatic hypothesis. AB - While there is ample evidence that children treat words as mutually exclusive, the cognitive basis of this bias is widely debated. We focus on the distinction between pragmatic and lexical constraints accounts. High-functioning children with autism spectrum disorders (ASD) offer a unique perspective on this debate, as they acquire substantial vocabularies despite impoverished social-pragmatic skills. We tested children and adolescents with ASD in a paradigm examining mutual exclusivity for words and facts. Words were interpreted contrastively more often than facts. Word performance was associated with vocabulary size; fact performance was associated with social-communication skills. Thus mutual exclusivity does not appear to be driven by pragmatics, suggesting that it is either a lexical constraint or a reflection of domain-general learning processes. PMID- 21238951 TI - Rumination as a transdiagnostic factor in depression and anxiety. AB - The high rate of comorbidity among mental disorders has driven a search for factors associated with the development of multiple types of psychopathology, referred to as transdiagnostic factors. Rumination is involved in the etiology and maintenance of major depression, and recent evidence implicates rumination in the development of anxiety. The extent to which rumination is a transdiagnostic factor that accounts for the co-occurrence of symptoms of depression and anxiety, however, has not previously been examined. We investigated whether rumination explained the concurrent and prospective associations between symptoms of depression and anxiety in two longitudinal studies: one of adolescents (N=1065) and one of adults (N=1317). Rumination was a full mediator of the concurrent association between symptoms of depression and anxiety in adolescents (z=6.7, p< .001) and was a partial mediator of this association in adults (z=5.6, p< .001). In prospective analyses in the adolescent sample, baseline depressive symptoms predicted increases in anxiety, and rumination fully mediated this association (z=5.26, p< .001). In adults, baseline depression predicted increases in anxiety and baseline anxiety predicted increases in depression; rumination fully mediated both of these associations (z=2.35, p= .019 and z=5.10, p< .001, respectively). These findings highlight the importance of targeting rumination in transdiagnostic treatment approaches for emotional disorders. PMID- 21238953 TI - Plasticity of human spatial cognition: spatial language and cognition covary across cultures. AB - The present paper explores cross-cultural variation in spatial cognition by comparing spatial reconstruction tasks by Dutch and Namibian elementary school children. These two communities differ in the way they predominantly express spatial relations in language. Four experiments investigate cognitive strategy preferences across different levels of task-complexity and instruction. Data show a correlation between dominant linguistic spatial frames of reference and performance patterns in non-linguistic spatial memory tasks. This correlation is shown to be stable across an increase of complexity in the spatial array. When instructed to use their respective non-habitual cognitive strategy, participants were not easily able to switch between strategies and their attempts to do so impaired their performance. These results indicate a difference not only in preference but also in competence and suggest that spatial language and non linguistic preferences and competences in spatial cognition are systematically aligned across human populations. PMID- 21238954 TI - Karl Kleist: A Nazi behind the map? PMID- 21238955 TI - Urinary trichloroacetic acid levels and semen quality: a hospital-based cross sectional study in Wuhan, China. AB - Toxicological studies indicate an association between exposure to disinfection by products (DBPs) and impaired male reproductive health in animals. However, epidemiological evidence in humans is still limited. We conducted a hospital based cross-sectional study to investigate the effect of exposure to DBPs on semen quality in humans. Between May 2008 and July 2008, we recruited 418 male partners in sub-fertile couples seeking infertility medical instruction or assisted reproduction services from the Tongji Hospital in Wuhan, China. Major semen parameters analyzed included sperm concentration, motility, and morphology. Exposure to DBPs was estimated by their urinary creatinine-adjusted trichloroacetic (TCAA) concentrations that were measured with the gas chromatography/electron capture detection method. We used linear regression to assess the relationship between exposure to DBPs and semen quality. According to the World Health Organization criteria (<20 million/mL for sperm concentration and <50% motile for sperm motility) and threshold value recommended by Guzick (<9% for sperm morphology), there were 265 men with all parameters at or above the reference values, 33 men below the reference sperm concentration, 151 men below the reference sperm motility, and 6 men below the reference sperm morphology. The mean (median) urinary creatinine-adjusted TCAA concentration was 9.2 (5.1) MUg/g creatinine. Linear regression analyses indicated no significant association of sperm concentration, sperm count, and sperm morphology with urinary TCAA levels. Compared with those in the lowest quartile of creatinine adjusted urinary TCAA concentrations, subjects in the second and third quartiles had a decrease of 5.1% (95% CI: 0.6%, 9.7%) and 4.7% (95% CI: 0.2%, 9.2%) in percent motility, respectively. However, these associations were not significant after adjustment for age, abstinence time, and smoking status. The present study provides suggestive but inconclusive evidence of the relationship between decreased sperm motility and increased urinary TCAA levels. The effect of exposure to DBPs on human male reproductive health in Chinese populations still warrants further investigations. PMID- 21238956 TI - Polychlorinated biphenyls and non-Hodgkin's lymphoma: a case-control study in Northern Italy. AB - BACKGROUND: Polychlorinated biphenyls (PCBs) have been hypothesized to increase the risk of non-Hodgkin lymphoma (NHL), although conclusive evidence is still lacking. High levels of PCBs were found in soil in some areas close to a PCB producing factory in Brescia, North Italy. We conducted a population-based case control study among residents of the town to investigate the possible association between PCB pollution and NHL in this area. METHODS: We included both incident and deceased NHL cases, and a random sample of the town residents as controls, frequency matched to cases as regards age and gender. Exposure to PCBs was estimated on the basis of the lifetime residential history of cases and controls in four different areas of the town-A, B and C (polluted areas) and D (control area). RESULTS: A total of 495 cases (287 incident cases) and 1467 controls were enrolled. Positive associations were found between NHL and having resided for at least 10 years in the area A, the most polluted area (odds ratio, OR=1.8; p=0.02) and for having resided in any of the polluted areas considered together (A+B+C) (OR=1.4; p=0.08). However, no associations were evident for having resided 20 years or longer in the polluted areas or when analyzing the association with each subject's main residence in his/her lifetime. CONCLUSION: This study provides some evidence for an association between PCB exposure and NHL, though results should be considered with caution in the absence of individual biological measures of exposure. PMID- 21238957 TI - Iatrogenic portobiliary fistula complicating endoscopic stenting of a pancreatic cyst, with possible carcinoma: a case report. PMID- 21238958 TI - Successful endoscopic treatment of intraductal extension of a villous adenoma with high-grade dysplasia, with 3-year follow-up. PMID- 21238959 TI - Feasibility of EUS-guided injection of irinotecan-loaded microspheres into the swine pancreas. AB - BACKGROUND: LC beads (Biocompatibles International plc) are designed for the time released delivery of the chemotherapeutic agent irinotecan into focal, hypervascularized, hepatic tumors. OBJECTIVE: To determine the feasibility of EUS guided injection of LC beads (with/without irinotecan) into the swine pancreas. DESIGN: Survival animal study. SETTING: Academic center. SUBJECTS: This study involved 12 Yorkshire swine. INTERVENTION: LC beads without irinotecan and loaded with up to 300 mg of irinotecan were injected under EUS guidance with a 19-gauge needle into the tail of the pancreas. CT scanning and necropsy with histology were performed at day 7. MAIN OUTCOME MEASUREMENTS: Feasibility of the injections, gross and microscopic evidence of pancreatic inflammation, and clinical tolerance by the animals. RESULTS: After injection of LC beads with/without irinotecan, in 10 of 12 animals an intrapancreatic, hyperechoic focus with an average diameter of 2.2 cm was visible by EUS, and a hypodense area in the tail of the pancreas was visible by contrast CT. In 2 animals (1 with irinotecan and 1 without) no beads were seen on CT. In 10 of 12 animals, a depot of beads was located in the tail of the pancreas on gross inspection and histology. Drug depot with only localized pancreatic tissue reactions was seen on histopathologic review. LIMITATIONS: Animal study. CONCLUSION: The EUS-guided injection of LC beads (with/without irinotecan) into the pancreas of the pig is feasible and safe. This technique is a potential minimally invasive local treatment option for locally advanced pancreatic cancer. PMID- 21238960 TI - Hyperostosis frontalis interna - a marker of social status? Evidence from the Bronze-Age "high society" of Qatna, Syria. AB - In 1719 Morgagni described a condition, today known as hyperostosis frontalis interna (HFI), as one sign within a triad consisting of HFI, virilism, and obesity. Today, HFI is predominantly found in older women. Although the etiology of HFI has not yet been determined precisely, the condition has been linked to metabolic disorders. HFI is reported to be rare in the archaeological record and the frequency of the condition is thought to have increased during the 19th and 20th centuries. We present preliminary results on the occurrence of HFI in the commingled human bone assemblage from "tomb VII" discovered underneath the Bronze Age royal palace of the ancient city of Qatna, Syria. A preliminary minimal number of individuals of 70 has been estimated for the as yet not fully analyzed skeletal remains. Skull fragments of nine individuals exhibit endocranial bone formations consistent with HFI. Rarity of stress indicators in the skeletons, the rich grave goods, and the burial place within the area of the Royal palace are suggestive of a high social status and an economically favorable situation of the buried individuals. Assuming that their life style included a high calorie diet in combination with little physical activity, acquired metabolic disorders may have been present in many individuals. The comparatively high number of individuals presenting HFI in the studied sample might therefore be viewed as being related to their high social status. Multiple occurrences of HFI in archaeological skeletal assemblages might serve as a proxy for social status. PMID- 21238961 TI - An ontogenetic approach to facial variation in three Native American populations. AB - Various explanations have been formulated regarding high levels of craniofacial variation among Native American populations but the contribution of developmental processes to the establishment of these patterns of variation remains unknown. In this study, we compare facial morphology in ontogenetic series of three Native South American populations, one hunter-gatherer group and two farmer groups, in order to test the null hypothesis that indicates that the pattern of facial differentiation between populations does not change during ontogeny. If diet related factors contribute to outline facial morphology, it is likely to find greater differences between hunter-gatherer and both farmer groups than between two groups of farmers and this differentiation is expected to increase with age, especially in those structures that are influenced by the mechanical load of mastication. According to our results, hunter-gatherers clearly differ from the two groups of farmers. Non-heritable factors linked to diet, such as nutritional content of food, may increase differentiation across ontogeny in some cases. However, as hunter-gatherers were clearly separated from farmer populations during entire postnatal ontogeny, an important proportion of size variation may not necessarily reflect eco-sensitive changes. Consequently, the hypothesis cannot be completely rejected. PMID- 21238963 TI - Predictors of 5 year survival following hip fracture. AB - BACKGROUND: This study aims to assess the mortality associated with hip fracture at 5 years in a geriatric population, and evaluate the influence of age, cognitive state, mobility and residential status on long term survival after hip fracture. METHODS: A prospective audit was carried out of all patients with a hip fracture admitted to a university hospital over a 4 year period. Data from 2640 patients were analysed and multivariate analysis used to indicate the important variables predicting mortality. Patients fulfilling the criteria of age<80 years, Abbreviated Mental Test Score (AMT)>=7/10, independently mobile and admitted from own home were put into group A (low risk group). Patients not meeting the criteria were placed into group B (high risk group). RESULTS: 2640 patients fitted the inclusion criteria, 482 in group A and 2158 in group B. 850 patients (43.1%) died in their first year following hip fracture. 302 patients (63%) of group A were still alive at 5 years in comparison with only 367 (17%) of group B. Overall, 669 (25%) patients survived for 5 years. Increased survival was shown for the following variables: age<80 years RR 5.27 (p<0.01), AMT>=7/10 RR 6.03 (p<0.01), independent mobility RR 2.63 (p<0.01) and admitted from own home RR 4.52 (p<0.01). CONCLUSIONS: These findings will allow for early recognition of those patients with an increased chance of long-term survival following hip fracture. Such patients may be suitable for surgical treatment, such as total hip replacement, which has a good long-term outcome. PMID- 21238965 TI - Impact of the tension-free vaginal tape obturator procedure on sexual function in women with stress urinary incontinence. AB - OBJECTIVE: To evaluate prospectively the impact of the tension-free vaginal tape obturator (TVT-O) procedure on sexual function in women with stress urinary incontinence (SUI). METHODS: The present prospective study included women with SUI and no concomitant prolapse who underwent a TVT-O procedure at Fuzhou General Hospital in Fuzhou, Fujian, China. Before and 6 months after surgery, the patients had their sexual function evaluated using the Female Sexual Function Index (FSFI) questionnaire. Only sexually active women were included in the final analysis. RESULTS: Among the 55 sexually active patients, 21.8% had coital incontinence, which was cured in 11 of 12 patients (91.7%). More than half (54.5%) the women reported an improvement in sexual function after surgery and 45.5% reported no change. No statistically significant difference was found between preoperative and postoperative total or domain (desire, arousal, lubrication, orgasm, satisfaction, and pain) scores on the FSFI. CONCLUSION: The TVT-O procedure in women with SUI did not significantly affect sexual function. Further studies are needed to verify the findings and compare the impact of TVT-O on sexual function with that of other anti-incontinence procedures. PMID- 21238966 TI - Urodynamic and clinical effects of transvaginal mesh repair for severe cystocele with and without urinary incontinence. AB - OBJECTIVE: To demonstrate the urodynamic and clinical effects of transvaginal polypropylene mesh repair (TVM) for severe cystocele with or without stress urinary incontinence (SUI). METHODS: One hundred women with severe cystocele who underwent transvaginal cystocele repair using a tension-free polypropylene mesh were included in a retrospective study. A simultaneous transobturator tape (TOT) procedure was performed in 24 patients with concurrent urodynamic stress incontinence (USI). Postoperative follow-up examinations included urodynamic testing, pelvic organ prolapse quantification, and urogynecologic questionnaire. RESULTS: Mean follow-up was 35 months (range, 13-68 months). At 3-6 months after surgery, 2 (8.3%) of the 24 patients with USI who had undergone TVM and TOT had persistent SUI. Of the 30 women with occult USI who had undergone TVM alone, 6 (20%) developed symptomatic SUI and 9 (30%) had asymptomatic SUI. Thirteen (28.3%) of the 46 patients without USI developed postoperative SUI. The 1-year results showed de novo SUI in 10 (10%) women, recurrent cystocele in 6 (6%), and mesh erosions in 5 (5%). Four (13.3%) of the 30 patients engaging in sexual activity had dyspareunia. CONCLUSION: TVM is effective and safe in patients with severe cystocele, but may have an impact on voiding and sexual activity. PMID- 21238967 TI - Factors predicting the response to biofeedback-assisted pelvic floor muscle training for urinary incontinence. AB - OBJECTIVE: To evaluate the efficacy of biofeedback-assisted pelvic floor muscle training (PFMT) for urinary incontinence and to determine the patient characteristics predictive of success. METHODS: Clinical and physiologic data of 86 patients with urinary incontinence who had received biofeedback-assisted PFMT were analyzed retrospectively. The clinical response was determined to be a success (requiring no more therapy) or a failure (requiring surgery or other medical therapy) at 3 months after completion of treatment. RESULTS: The success group included 57% of the enrolled patients. In the univariate analysis, the following factors had P values of less than 0.20: alcohol consumption, detrusor overactivity, type of urinary incontinence, and the change in the average amplitude of tonic contraction before treatment and after the 8th session of biofeedback-assisted PFMT. In the multiple logistic regression analysis, the only independent predictive factor of a successful response was a significant change in the average tonic contraction before treatment and after the 8th session (odds ratio, 1.661; 95% confidence interval, 1.015- 2.721). CONCLUSION: After biofeedback-assisted PFMT, 57% of patients with urinary incontinence required no further therapy. Increased pelvic floor muscle activity after the 8th session of PFMT predicted a successful response to treatment. PMID- 21238968 TI - Characterization of branched ultrahigh molar mass polymers by asymmetrical flow field-flow fractionation and size exclusion chromatography. AB - The molar mass distribution (MMD) of synthetic polymers is frequently analyzed by size exclusion chromatography (SEC) coupled to multi angle light scattering (MALS) detection. For ultrahigh molar mass (UHM) or branched polymers this method is not sufficient, because shear degradation and abnormal elution effects falsify the calculated molar mass distribution and information on branching. High temperatures above 130 degrees C have to be applied for dissolution and separation of semi-crystalline materials like polyolefins which requires special hardware setups. Asymmetrical flow field-flow fractionation (AF4) offers the possibility to overcome some of the main problems of SEC due to the absence of an obstructing porous stationary phase. The SEC-separation mainly depends on the pore size distribution of the used column set. The analyte molecules can enter the pores of the stationary phase in dependence on their hydrodynamic volume. The archived separation is a result of the retention time of the analyte species inside SEC-column which depends on the accessibility of the pores, the residence time inside the pores and the diffusion ability of the analyte molecules. The elution order in SEC is typically from low to high hydrodynamic volume. On the contrary AF4 separates according to the diffusion coefficient of the analyte molecules as long as the chosen conditions support the normal FFF-separation mechanism. The separation takes place in an empty channel and is caused by a cross-flow field perpendicular to the solvent flow. The analyte molecules will arrange in different channel heights depending on the diffusion coefficients. The parabolic-shaped flow profile inside the channel leads to different elution velocities. The species with low hydrodynamic volume will elute first while the species with high hydrodynamic volume elute later. The AF4 can be performed at ambient or high temperature (AT-/HT-AF4). We have analyzed one low molar mass polyethylene sample and a number of narrow distributed polystyrene standards as reference materials with known structure by AT/HT-SEC and AT/HT-AF4. Low density polyethylenes as well as polypropylene and polybutadiene, containing high degrees of branching and high molar masses, have been analyzed with both methods. As in SEC the relationship between the radius of gyration (R(g)) or the molar mass and the elution volume is curved up towards high elution volumes, a correct calculation of the MMD and the molar mass average or branching ratio is not possible using the data from the SEC measurements. In contrast to SEC, AF4 allows the precise determination of the MMD, the molar mass averages as well as the degree of branching because the molar mass vs. elution volume curve and the conformation plot is not falsified in this technique. In addition, higher molar masses can be detected using HT-AF4 due to the absence of significant shear degradation in the channel. As a result the average molar masses obtained from AF4 are higher compared to SEC. The analysis time in AF4 is comparable to that of SEC but the adjustable cross-flow program allows the user to influence the separation efficiency which is not possible in SEC without a costly change of the whole column combination. PMID- 21238969 TI - Characterisation of methacrylate monoliths for bacteriophage purification. AB - Binding of three different bacteriophages (phages), namely T7, lambda and M13 on methacrylate monoliths was investigated. Phage M13 exhibited the highest dynamic binding capacity of 4.5*10(13) pfu/mL while T7 and lambda showed capacity of 1*10(13) pfu/mL, all corresponding to values of around 1mg/mL. Interestingly, capacity for lambda phage was increased 5-fold by increasing NaCl concentration in a loaded sample from 0 to 0.2M while there was a constant capacity decrease for T7 and M13 phages. Under optimal conditions, recovery for all three phages approached 100%. Measurement of a pressure drop increase during loading enabled estimation of adsorbed phage layer thickness. At a maximal capacity it was calculated to be around 50 nm for T7 phage and 60 nm for lambda phage matching closely capside size thus indicating monolayer adsorption while 80 nm layer thickness was estimated for M13 phage showing its orientation along the pore. PMID- 21238970 TI - Polyethylenimine-modified metal oxides for fabrication of packed capillary columns for capillary electrochromatography and capillary liquid chromatography. AB - The need for novel packing materials in both capillary electrochromatography (CEC) and capillary liquid chromatography (CLC) is apparent and the development towards more selective, application-oriented chromatographic phases is under progress world-wide. In this study we have synthesized new polyethyleneimine (PEI) functionalized Mn(2)O(3), SiO(2), SnO(2), and ZrO(2) particles for the fabrication of packed capillary columns for CEC and CLC. The nanocasting approach was successful for the preparation of functionalized metal oxide materials with a controlled porosity and morphology. PEI functionalization was done using ethyleneimine monomers to create particles which are positively charged in aqueous solution below pH 9. This functionalization allowed the possibility to have both hydrophobic (due to its alkyl chain) and ionic interactions (due to positively charged amino groups) with selected compounds. For comparison aminopropyl-functionalized silica was also synthesized and tested. Both slurry pressure and electrokinetic packing procedures used gave similar results, but fast sedimentation of the material caused some problems during the packing. The high stability and wide pH range of PEI-functionalized SiO(2) material, with potential for hydrophobic and electrostatic interactions, proved to be useful for the CEC and CLC separation of some model acidic and neutral compounds. PMID- 21238971 TI - Macroscopic investigation of the transient hydrodynamic memory behavior of preparative packed chromatography beds. AB - The goal of the present work was to examine the hydrodynamic behavior of preparative scale packed chromatography beds during long-term cyclical operation at high loads using an experimental set-up with a high resolution measuring device of bed height. One agarose-based resin and one methacrylic-based resin were examined in a 140 mm column. Both resins exhibited hysteresis behavior during compression/relaxation cycles. The hystereses were less pronounced with decreasing hydrodynamic stress rate. The occurrence of hystereses was an indication for hydrodynamic memory behavior of the chromatography packing. During long-term cyclical operation at high loads of the column filled with methacrylic resin, oscillations of the steadily with time decreasing flow rate were observed for the first time. These oscillations were attributed to the viscoelasticity of the polymer particles network representing a system with materials with fading memory. Such nonlinear systems with feed-back are known to exhibit inherent self oscillations. A decoupling of the two processes of bed compression and decrease of bed permeability was observed. The presented results explain why preparative packed-bed chromatography often yields unsatisfactory reproducible data and why unwanted phenomena like medium wall detachment or other symptoms of deteriorated chromatography beds are frequently observed. PMID- 21238972 TI - Direct determination of hydrogen cyanide in cigarette mainstream smoke by ion chromatography with pulsed amperometric detection. AB - The determination of hydrogen cyanide in cigarette mainstream smoke has been achieved by ion chromatography (IC) with pulsed amperometric detection (PAD). The proposed method of totally trapping whole cigarette mainstream smoke by Cambridge filters, which are treated with sodium hydroxide/ethanol solution, possesses the advantage of fast analysis time over the widespread used solution absorption method. The possible co-existing interferents are evaluated under the optimized detection conditions and excellent recoveries of cyanide are obtained. The cyanide content of absorption solution can be directly determined by the optimized IC-PAD method without any pretreatments. The linear range is 0.0147 2.45 MUg/mL with R2 value of 0.9997. The limit of the detection is 3 MUg/L for a 25 MUL injection loop. The overall relative standard deviation of the method is less than 5.20% and the recovery range from 94.3% to 101.0%. The results obtained from the developed method are in good agreement with that of continuous flow analyzer (CFA) method. PMID- 21238973 TI - Assessing deaf and hearing children's communication in Brazil. AB - In Brazil there are no specific tests for either signed or spoken language for deaf children. A protocol evaluating communicative abilities independent of modality of communication (sign language or spoken language), and comprising assessments of (a) pragmatic profile; (b) modality of communication and linguistic level; (c) complexity of communication; and (d) style and efficacy of communication between parent and child was administered to 127 deaf and hearing children. The children, aged 3-6 years old, were distributed in three groups: 20 with severe hearing loss, 40 with profound hearing loss and 67 normally hearing. Deaf children were found to be delayed, independent of their linguistic level and preferred modality of communication. The protocol in this study proved to be an useful instrument for gathering relevant information about the three groups of preschool children's communicative abilities, and particularly suitable for use in countries where standardized assessments are not available. LEARNING OUTCOMES: The reader will be introduced to the use of an assessment protocol comprising its development, application and data analysis. The reader will be informed about assessment of deaf children's preferred modality of communication, by the participation of a bilingual (sign language user) professional. Communication abilities can be assessed independently of the linguistic modality. In developing countries in general, where simple and easy to administer assessments tools are scarce, such a protocol is of specific value. PMID- 21238974 TI - Immunocytochemical detection of Rhodococcus equi in tracheal washes of foals. AB - The aim of the present study was to develop an immunocytochemical procedure for the early detection and demonstration of Rhodococcus equi in smears of tracheal aspirates taken from live foals in field conditions. Tracheal wash samples were collected from thoroughbred foals, aged 1-5 months and located in studs around Bursa and Istanbul, Turkey. Some foals were suspected of having R. equi infection on the basis of clinical examination (n=56) and others were unaffected control animals (n=54). Serum samples were also collected from each foal for testing for the presence of R. equi-specific antibody by enzyme linked immunosorbent assay (ELISA). Thirty-six of the control foals (66.7%) and 37 of the affected foals (66.1%) were seropositive for R. equi. Immunocytochemical labelling was detected in the smears from 73.2% of the affected foals and 70.4% of the control foals. For both ELISA and immunocytochemistry (ICC), there was no significant difference between the affected and control foals (P>0.05) and there was no significant difference between the two test modalities (P>0.05). ICC may therefore have similar diagnostic utility when compared with ELISA. There is no clear relationship between clinical signs and ELISA or ICC positivity. PMID- 21238975 TI - CDX-2 and HER-3 expression in canine gastric and colorectal adenocarcinomas. AB - CDX-2 is used as a specific cell marker for human intestinal adenocarcinoma. In human studies, HER-3 overexpression predicts poor survival for patients with various cancers including gastric cancer. Gastrointestinal adenocarcinoma is less common in dogs than in man and the expression of immunological markers by the canine tumours has not yet been extensively studied. CDX-2 and HER-3 expression was determined in 18 canine gastrointestinal adenocarcinomas: 13 were of colorectal origin and five were of gastric origin. CDX-2 expression was predominantly observed in the nuclei of normal colonic epithelium and in neoplastic epithelium and neoplastic gastric epithelial cells that which had metastasized to the gastric lymph node. CDX-2 was expressed in 11 of 13 (84.6%) colorectal adenocarcinomas and in all five (100%) gastric adenocarcinomas. HER-3 was consistently expressed in the cytoplasm of neoplastic epithelial cells. HER-3 expression was detected in 12 of 13 (92.3%) colorectal and in all five (100%) gastric adenocarcinomas. CDX-2 and HER-3 may be useful markers for canine gastrointestinal adenocarcinoma. PMID- 21238976 TI - Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers. AB - INTRODUCTION: We studied moxifloxacin-induced QT prolongation and proportion of categorical QTc outliers when 5 methods of QT measurement were used to analyze electrocardiograms (ECGs) from a thorough QT study. METHODS: QT interval was measured by the threshold, tangent, superimposed median beat, automated global median beat, and longest QT methods in a central ECG laboratory in 2730 digital ECGs from 39 subjects during placebo and moxifloxacin treatment. RESULTS: All 5 methods were able to demonstrate statistically significant moxifloxacin-induced QTcF prolongation. However, lower bound of 95% 1-sided confidence interval of QTcF prolongation did not exceed 5 milliseconds with the longest QT method. More QTcF outliers were observed with the longest QT and tangent methods, whereas the other 3 methods were comparable. QTcF values greater than 500 milliseconds were observed only with moxifloxacin by the tangent method, and with moxifloxacin and placebo by the longest QT method. CONCLUSION: The method of QT measurement must be considered when interpreting individual thorough QT/QTc studies. PMID- 21238977 TI - Investigating the links between the subcomponents of executive function and academic achievement: a cross-cultural analysis of Chinese and American preschoolers. AB - Little is known about how components of executive function (EF) jointly and uniquely predict different aspects of academic achievement and how this may vary across cultural contexts. In the current study, 119 Chinese and 139 American preschoolers were tested on a battery of EF tasks (i.e., inhibition, working memory, and attentional control) as well as academic achievement tasks (i.e., reading and mathematics). Results demonstrate that although working memory performance in both cultures was comparable, Chinese children outperformed American children on inhibition and attentional control tasks. In addition, the relation between components of EF and achievement was similar in the two countries. Working memory uniquely predicted academic achievement, with some intriguing patterns in regard to tasks requiring complex processing. Inhibition uniquely predicted counting but did not uniquely predict calculation. Attentional control predicted most aspects of achievement uniformly and was the most robust predictor for reading in both countries. In sum, the data provide insight into both cultural variability and consistency in the development of EF during early childhood. PMID- 21238978 TI - Preschoolers search for hidden objects. AB - The issue of whether young children use spatio-temporal information (e.g., movement of objects through time and space) and/or contact-mechanical information (e.g., interaction between objects) to search for a hidden object was investigated. To determine whether one cue can have priority over the other, a dynamic event that put these cues into conflict was created, with only spatio temporal information being valid. The 3-year-olds used in the study were found to use the valid spatio-temporal cue exclusively and seemed to ignore the contact mechanical cue. Both search behavior and eye tracking during the event support the view of a sophisticated sensitivity to the validity of a cue in indicating a target's hidden location. PMID- 21238979 TI - Low Apgar scores and risk of childhood attention deficit hyperactivity disorder. AB - OBJECTIVE: To examine whether low Apgar scores at 5 minutes are associated with increased risks of attention deficit hyperactivity disorder (ADHD). STUDY DESIGN: We conducted a nationwide population-based cohort study of all 980 902 singletons born in Denmark from 1988 to 2001. All children were monitored from 3 years of age until a first International Classification of Diseases diagnosis of hyperkinetic disorder, a first medication for ADHD, migration, death, or the end of 2006, whichever came first. We used Cox regression models to examine the association between Apgar scores at 5 minutes and ADHD. RESULTS: Apgar scores were inversely associated with risk of ADHD (hazard ratio 0.92; 95% CI: 0.88 0.96, P trend < .001). Compared with children with Apgar scores of 9 or 10 at 5 minutes, the risk for ADHD was 75% higher in children with Apgar scores of 1 to 4 (hazard ratio 1.75; 95% CI: 1.15 to 2.11) and 63% higher for those with Apgar scores of 5 to 6 (95% CI: 1.25 to 2.11). CONCLUSIONS: A low Apgar score was associated with an increased risk of ADHD in childhood. Low Apgar scores and ADHD may share common causes or a low Apgar score reflects at least one causal pathway leading to ADHD. PMID- 21238980 TI - A normal capillary refill time of <= 2 seconds is associated with superior vena cava oxygen saturations of >= 70%. AB - OBJECTIVE: To test the hypothesis that a normal capillary refill time (CRT) <= 2 seconds is associated with superior vena cava oxygen saturation (ScvO2) >= 70% in critically ill children. STUDY DESIGN: Two-year, prospective study in a tertiary level pediatric intensive care unit. Whenever ScvO2 measurements were obtained, central (forehead/sternum) and peripheral (finger/toe) CRTs were concomitantly assessed. RESULTS: Central and peripheral CRTs <= 2 seconds were both associated with ScvO2 >= 70% (P < .01). Sensitivity/specificity analyses revealed that central CRT <= 2 seconds demonstrated a sensitivity of 84.4%, specificity of 71.4%, positive predictive value of 93.1%, and negative predictive value of 50.0% in predicting ScvO2 >= 70%. Peripheral CRT <= 2 seconds had a sensitivity of 71.9%, specificity of 85.7%, positive predictive value of 95.8%, and negative predictive value of 40.0% in predicting ScvO2 >= 70%. CONCLUSIONS: A normal CRT <= 2 seconds can be predictive of ScvO2 >= 70%. Our study corroborates the recommendations of the Pediatric Advanced Life Support curricula targeting a normal CRT <= 2 seconds as a therapeutic endpoint for goal-directed shock resuscitation. This clinical target remains particularly relevant in community hospitals when the ability to obtain central venous catheter access may be limited and ScvO2 data unavailable. PMID- 21238981 TI - The impact of in utero exposure to diabetes on childhood body mass index growth trajectories: the EPOCH study. AB - OBJECTIVE: To examine associations between exposure to maternal diabetes in utero and body mass index (BMI) growth trajectories from birth through 13 years of age among a diverse cohort of youth. STUDY DESIGN: Mixed linear effects models were constructed to assess differences in BMI and BMI growth velocity from birth through 13 years of age for 95 subjects exposed to diabetes in utero and 409 unexposed subjects enrolled in a retrospective cohort study. RESULTS: The overall BMI growth trajectory (adjusted for sex and race/ethnicity) was not significantly different for exposed and unexposed subjects from birth through 26 months of age (P = .48). However, the overall growth trajectory from 27 months of age through 13 years differed by exposure status (P = .008), adjusted for sex and race/ethnicity. The difference was primarily due to a significantly higher BMI growth velocity among exposed youth between 10 and 13 years, increasing by 4.56 kg/m2 compared with 3.51 kg/m2 in the unexposed (P = .005). Control for demographic variables, socioeconomic factors, and maternal prepregnancy BMI did not alter the observed associations. CONCLUSIONS: Exposure to maternal diabetes in utero accelerates BMI growth in late childhood, thus increasing long-term obesity risk. PMID- 21238983 TI - Oxygenation with T-piece versus self-inflating bag for ventilation of extremely preterm infants at birth: a randomized controlled trial. AB - OBJECTIVE: To investigate whether infants < 29 weeks gestation who receive positive pressure ventilation (PPV) immediately after birth with a T-piece have higher oxygen saturation (SpO2) measurements at 5 minutes than infants ventilated with a self inflating bag (SIB). STUDY DESIGN: Randomized, controlled trial of T piece or SIB ventilation in which SpO2 was recorded immediately after birth from the right hand/wrist with a Masimo Radical pulse oximeter, set at 2-second averaging and maximum sensitivity. All resuscitations started with air. RESULTS: Forty-one infants received PPV with a T-piece and 39 infants received PPV with a SIB. At 5 minutes after birth, there was no significant difference between the median (interquartile range) SpO2 in the T-piece and SIB groups (61% [13% to 72%] versus 55% [42% to 67%]; P = .27). More infants in the T-piece group received oxygen during delivery room resuscitation (41 [100%] versus 35 [90%], P = .04). There was no difference in the groups in the use of continuous positive airway pressure, endotracheal intubation, or administration of surfactant in the delivery room. CONCLUSION: There was no significant difference in SpO2 at 5 minutes after birth in infants < 29 weeks gestation given PPV with a T-piece or a SIB as used in this study. PMID- 21238984 TI - Vitamin D deficiency is associated with altered hematologic indexes in very low birth weight infants. PMID- 21238985 TI - The challenge of communicating cardiovascular risk information to our patients. PMID- 21238986 TI - The relationship between early concentrations of 25 blood proteins and cerebral white matter injury in preterm newborns: the ELGAN study. AB - OBJECTIVE: To evaluate whether concentrations of inflammation-related proteins are elevated in the blood of preterm newborns who develop cerebral white matter damage. STUDY DESIGN: We measured 25 proteins in blood collected on days 1, 7, and 14 from 939 infants born before the 28th week of gestation. Brain ultrasound scans were read by at least two sonologists, who agreed on the presence or absence of lesions. A protein concentration was considered elevated if it was in the highest quartile for gestational age and the day on which the specimen was collected. RESULTS: In time-oriented models, elevated concentrations of vascular endothelial growth factor receptor 1, serum amyloid A, and macrophage inflammatory protein 1beta on day 1 and interleukin-8 on day 7 were associated with increased risk of ventriculomegaly. Elevated concentrations of macrophage inflammatory protein 1beta on day 1 and intercellular adhesion molecule 1 on day 7 were associated with increased risk of an echolucent lesion. Infants with elevated concentrations of inflammation-related proteins on two separate days were at significantly increased risk for ventriculomegaly, but at only modestly increased risk for an echolucent lesion. CONCLUSIONS: Concentrations of inflammation-related proteins in the circulation in the first days after preterm birth provide information about the risk of sonographic white matter damage. The inflammatory process might begin in utero. PMID- 21238988 TI - Symptomatic vocal cord paresis/paralysis in infants operated on for esophageal atresia and/or tracheo-esophageal fistula. AB - OBJECTIVES: To describe the prevalence and pathogenesis of symptomatic vocal cord paresis/paralysis (VCP) in patients treated for esophageal atresia (EA), tracheo esophageal fistula (TEF) or both. STUDY DESIGN: Retrospective study of all patients treated for EA/TEF in our center (1995 to 2009). Patients with and without symptomatic VCP were compared for gestational age, birth weight, associated anomalies, referrals, long-gap EA (> 3 cm or 3 vertebral bodies), cervical esophagostomy, anastomotic leakage, length of ventilation, and major cardiac surgery. Prevalence or median (IQR) is reported. RESULTS: Of 174 patients, 7 (4%) had symptomatic VCP. Prevalence of referrals (5/7 versus 21/167; P = .0009), long gap (5/7 versus 41/167; P = .0146), previous cervical esophagostomy (5/7 versus 7/167; P < .0001), and anastomotic leakage (3/7 versus 10/167; P = .0097) was higher, and ventilation longer (8.5 days [7.0 to 15.5] versus 6.0 days (5.0 to 7.0); P = .0072) in patients with VCP. CONCLUSIONS: In infants treated for EA/TEF, VCP should be ruled out in case of persistent respiratory morbidity or, when present, cautiously monitored. Surgical risk factors should be actively controlled. Further studies are needed to define the prevalence of acquired and congenital VCP in patients with EA/TEF. PMID- 21238987 TI - Subclinical atherosclerosis in Latino youth: progression of carotid intima-media thickness and its relationship to cardiometabolic risk factors. AB - OBJECTIVE: To assess carotid artery intima-media thickness (CIMT) change over 2 years in overweight Latino adolescents and examine its relationship to cardiometabolic risk. STUDY DESIGN: Seventy-two healthy overweight male and female Latino adolescents (mean age, 14.5 +/- 1.7 years; mean body mass index, 31.5 +/- 6.9 kg/m(2)) were evaluated at baseline and 2 years later for CIMT by high-resolution B-mode ultrasound, the metabolic syndrome and its features, body composition by dual-energy x-ray absorptiometry and magnetic resonance imaging, glucose/insulin measures by fasting blood, and oral and intravenous glucose tolerance tests. RESULTS: Baseline CIMT did not differ from 2-year follow-up; however, 38 participants increased CIMT (0.017 +/- 0.003 mm; +2.8%) and 34 decreased or remained the same (-0.019 +/- 0.002 mm; -3.1%). ANCOVA analyses showed that participants with CIMT progression had higher baseline low-density lipoprotein (LDL)-cholesterol and total cholesterol (91.3 +/- 3.4 and 150.3 +/- 3.9 mg/dL) compared with those with CIMT non-progression (78.1 +/- 3.6 and 135.6 +/- 4.2 mg/dL, P < .05), independent of sex, baseline CIMT, age, and height. In multivariate regression, LDL-cholesterol was the sole predictor of CIMT progression, but the effect was small (odds of CIMT progression increased by 3% for each 1 mg/dL higher baseline LDL-cholesterol; 95% CI, 1.004 to 1.006, P = .03). CONCLUSIONS: These results indicate a high variability in the magnitude of CIMT change in growing overweight Latino youth and support the use of LDL cholesterol to assess subclinical atherosclerosis risk in this population. PMID- 21238990 TI - How do we identify infectious agents that trigger Guillain-Barre syndrome, Fisher syndrome and Bickerstaff brainstem encephalitis? PMID- 21238989 TI - Twelve-month prevalence of psychiatric disorders and treatment-seeking among Asian Americans/Pacific Islanders in the United States: results from the National Epidemiological Survey on Alcohol and Related Conditions. AB - To compare the 12-month prevalence of psychiatric disorders in Asian Americans/Pacific Islanders in contrast to non-Hispanic whites; and further compare persistence and treatment-seeking rates for psychiatric disorders among Asian American/Pacific Islanders and non-Hispanic whites, analyses from the 2001 2002 National Epidemiologic Survey on Alcohol and Related Conditions, Wave 1 (n=43,093) were conducted for the subsample of 1332 Asian Americans/Pacific Islanders (596 men and 736 women) and 24,507 non-Hispanic whites (10,845 men and 13,662 women). The past 12-month prevalence for any psychiatric disorder was significantly lower in Asian American/Pacific Islander males and females than non Hispanic white males and females. Asian American/Pacific Islander males were less likely than non-Hispanic white males to have any mood, anxiety, substance use, and personality disorders, whereas the prevalence of mood disorders among Asian American/Pacific Islander females did not differ from those of non-Hispanic white females. In some cases, such as drug use disorders, both male and female Asian Americans/Pacific Islanders were more likely to have more persistent disorders than non-Hispanic whites. Compared to non-Hispanic white females, Asian American/Pacific Islander females had lower rates of treatment-seeking for any mood/anxiety disorders. Although less prevalent than among non-Hispanic whites, psychiatric disorders are not uncommon among Asian Americans/Pacific Islanders. The lower treatment-seeking rates for mood/anxiety disorders in Asian American/Pacific Islander females underscore the unmet needs for psychiatric service among this population. PMID- 21238991 TI - Editorial comment. PMID- 21238992 TI - Terminology and details of the diagnostic process for testis cancer. AB - PURPOSE: We examined the process and causes of diagnostic delay, defined as the interval from symptom onset to diagnosis, for testis (germ cell) cancer and the change with time. Diagnostic delay influences disease burden and may be subdivided into symptomatic interval, defined as symptom onset to first presentation, and diagnostic interval, defined as first presentation to diagnosis. MATERIALS AND METHODS: We performed a single center review of 100 consecutive cases. Diagnostic delay in weeks, and symptomatic and diagnostic intervals in days were calculated, and related factors were recorded. Previous reports by the senior author (JT) in the same health care system allowed the examination of change during 2 decades. RESULTS: Mean+/-SD diagnostic delay was 12.5+/-17.4 weeks (median 6, range 1 to 104), a substantial decrease in the mean of 10 months reported by one of us (JT) in 1987. Mean symptomatic interval was 65.4+/-100.9 days (median 29, range 0 to 720). Mean diagnostic interval was 21.9+/-63.5 days (median 7, range 1 to 540). Symptomatic interval exceeded or was equal to diagnostic interval in 80 men. CONCLUSIONS: This terminology allows detailed examination of the diagnostic process for testis cancer. Aberrant diagnostic delay for testis cancer is decreasing and is now dominated by patient dependent factors. Select cases suggest that physician error remains a factor in a minority. PMID- 21238994 TI - Impact of caseload on total hospital charges: a direct comparison between minimally invasive and open radical prostatectomy--a population based study. AB - PURPOSE: We tested the relationship between caseload and total hospital charges after stratifying by minimally invasive and open radical prostatectomy. MATERIALS AND METHODS: We evaluated 1,188 vs 3,354 men treated with minimally invasive vs open radical prostatectomy in the Florida Hospital Inpatients data file in 2008. Caseload was defined as the count of procedures performed by each surgeon between the study start on January 1, 2008 and the date of each procedure. Patients were divided into tertiles based on their procedure specific caseload. Univariate and multivariate analysis was done to address the relation between caseload and total hospital charges for the minimally invasive and open procedures. Covariates were patient age, race, comorbidity, and length of stay. RESULTS: Median total hospital charges for minimally invasive and open radical prostatectomy were $33,234 and $33,674, respectively (p=0.03). Median total hospital charges in the low, intermediate and high minimally invasive vs open procedure caseload tertiles were $41,765, $34,799 and $28,780 vs $35,642, $34,726 and $32,726, respectively. On multivariate analysis with the high minimally invasive caseload tertile as the reference category the increments of the probability of charges in excess of the 2008 median of $33,588 were 3.9 and 8.1-fold for the intermediate and low caseload minimally invasive procedures, and 2.5, 3.6 and 2.8-fold for the high, intermediate and low caseload open procedures, respectively (each p<0.001). CONCLUSIONS: Overall median total hospital charges are virtually the same for minimally invasive and open radical prostatectomy. However, total hospital charges for the minimally invasive procedure have a more sensitive caseload effect, as evidenced by the wider distribution of the median of minimally invasive caseload specific total hospital charges vs that of open radical prostatectomy. The high caseload minimally invasive procedure resulted in the lowest total hospital charges relative to all other minimally invasive and open radical prostatectomy categories. PMID- 21238995 TI - Nonphysician provider fellowship training: meeting patient needs in a time of physician shortages. PMID- 21238996 TI - Editorial comment. PMID- 21238993 TI - Early termination of a trial of mycophenolate mofetil for treatment of interstitial cystitis/painful bladder syndrome: lessons learned. AB - PURPOSE: We evaluated the efficacy and tolerability of mycophenolate mofetil in patients with treatment refractory interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: A total of 210 patients with interstitial cystitis/painful bladder syndrome were to be randomized into a multicenter, placebo controlled trial using a 2:1 randomization. Participants in whom at least 3 interstitial cystitis/painful bladder syndrome specific treatments had failed and who had at least moderately severe symptoms were enrolled in a 12-week treatment study. The primary study end point was the global response assessment. Secondary end points were general and disease specific symptom questionnaires, and voiding diaries. RESULTS: Only 58 subjects were randomized before a black box warning regarding mycophenolate mofetil safety was issued by the manufacturer in October 2007. The trial was halted, and interim analysis was performed and presented to an independent data and safety monitoring board. Six of the 39 subjects (15%) randomized at study cessation were considered responders for mycophenolate mofetil compared to 3 of 19 controls (16%, p=0.67). Secondary outcome measures reflected more improvement in controls. CONCLUSIONS: In a randomized, placebo controlled trial that was prematurely halted mycophenolate mofetil showed efficacy similar to that of placebo to treat symptoms of refractory interstitial cystitis/painful bladder syndrome. The results of this limited study cannot be used to confirm or refute the hypothesis that immunosuppressive therapy may be beneficial to at least a subgroup of patients with interstitial cystitis/painful bladder syndrome. Despite study termination lessons can be gleaned to inform future investigations. PMID- 21238997 TI - Nocturia: escaping the "prostate-centric" approach. PMID- 21238998 TI - Evaluation of prostate specific antigen acceleration for prostate cancer diagnosis. AB - PURPOSE: Prostate specific antigen acceleration can be calculated as the slope of log prostate specific antigen vs time, where log is the natural logarithm. We determined the best interval in which prostate specific antigen acceleration can be calculated with the best result in terms of specificity and sensitivity for prostate cancer diagnosis. MATERIALS AND METHODS: Entered in the study were 741 men who underwent transrectal ultrasound guided prostate biopsy with 12 or more cores and at least 3 prior consecutive prostate specific antigen measurements in at least 365 days. Prostate specific antigen acceleration was calculated as the slope of log prostate specific antigen vs time using a minimum of 3 prostate specific antigen measurements. Acceleration was evaluated at different intervals, including within 1 year (365 days), 2 years (730 days), 3 years (1,095 days), 4 years (1,460 days), 5 years (1,825 days) and 6 years (2,190 days) before the last measurement. RESULTS: A total of 255 cancers (34.4%) were found. On ROC analysis the AUC of prostate specific antigen acceleration (0.728, 95% CI 0.694-0.760) was better than that of prostate specific antigen, prostate specific antigen velocity and prostate specific antigen doubling time. The highest AUC of prostate specific antigen kinetics was for prostate specific antigen acceleration calculated within 3 to 4 years (731 to 1,460 days) before the last measurement. CONCLUSIONS: Three or more prostate specific antigen measurements within 3 to 4 years (731 to 1,460 days) before the last measurement enabled more accurate calculation of prostate specific antigen acceleration than measurement within 1 to 2 years (0 to 730 days). PMID- 21239001 TI - Editorial comment. PMID- 21239002 TI - Comorbidity, treatment and mortality: a population based cohort study of prostate cancer in PCBaSe Sweden. AB - PURPOSE: We examined associations among comorbidity, treatment decisions and mortality in patients with prostate cancer. MATERIALS AND METHODS: A total of 77,536 men diagnosed with prostate cancer between 1997 and 2006 were identified in PCBaSe Sweden from the National Prostate Cancer Register of Sweden. Logistic, Cox and competing risk regression were used to assess associations among Charlson comorbidity index, treatment and mortality. The Charlson comorbidity index was categorized into no (0), mild (1) and severe comorbidity (2+). RESULTS: In men with low risk prostate cancer 5,975 of the 13,245 (45.1%) patients without comorbidity underwent radical prostatectomy compared to 256 of the 1,399 (18.9%) men with severe comorbidity. Following adjustment for age and period of diagnosis, radical prostatectomy was less likely to be offered to men with severe comorbidity (OR 0.48, 95% CI 0.41-0.55). In men with high risk prostate cancer, radiotherapy was more common (range 7.7% to 21.3%) than radical prostatectomy (range 3.0% to 11.2%) regardless of comorbidity burden. All cause and competing cause but not prostate cancer specific mortality were increased in men with severe comorbidity (all cause HR 1.99, 95% CI 1.93-2.05; competing cause sHR 2.66, 95% CI 2.56-2.78; prostate cancer specific sHR 0.98, 95% CI 0.93-1.03). The cumulative probability of prostate cancer death given no death from competing causes was significantly higher in men with severe comorbidity in all risk groups (p<0.01). CONCLUSIONS: Comorbidity affects treatment choices, and is associated with all cause, competing cause and conditional prostate cancer specific mortality. An increased conditional prostate cancer specific mortality in men with severe comorbidity may reflect less aggressive treatment, impaired tumor defense, lifestyle factors and poor general health behavior. PMID- 21239003 TI - Salvage radical prostatectomy following primary high intensity focused ultrasound for treatment of prostate cancer. AB - PURPOSE: High intensity focused ultrasound for the treatment of primary prostate cancer is increasing in a subset of men seeking definitive treatment with reduced morbidity. We review outcomes in men undergoing salvage radical prostatectomy after failed whole gland high intensity focused ultrasound. MATERIALS AND METHODS: Prospective data were collected for men presenting with an increasing prostate specific antigen and biopsy proven prostate cancer after high intensity focused ultrasound from 2007 to 2010 who underwent salvage open radical prostatectomy with a 22-month median followup, including prostate specific antigen, prostate volume, pathology results, continence and erectile function. RESULTS: Data for 15 men were available, including median age 64 years (IQR 55 69), Gleason score before high intensity focused ultrasound of 6 (8), Gleason score 7 (7), median cores positive 39% (IQR 17%-63%) and median prostate specific antigen 7 ng/ml (IQR 5-8). Whole gland high intensity focused ultrasound achieved median nadir prostate specific antigen 1.1 ng/ml (IQR 0.5-3.1). Biopsy after high intensity focused ultrasound demonstrated Gleason score 6 (in 3 patients), 7 (9) and 8/9 (3), and 42% (IQR 25%-50%) cores positive and a median time from high intensity focused ultrasound to radical prostatectomy of 22 months (IQR 7-26). Perioperative morbidity was limited to 1 transfusion in a patient with a rectal injury. Pathologically extensive periprostatic fibrosis was found with persistent prostate cancer, as pT3 disease (in 9 of 14), Gleason scores 6 (2), 7 (9) and 8 of 9 (4), with focally positive margins in 3 of 11 (pT3a). Postoperative prostate specific antigen was unrecordable in 14 of 15 patients with further treatment in 2. Postoperative continence (more than 12 months of followup) yielded no pad use in 6 of 10 men with universally poor erectile function. CONCLUSIONS: Radical prostatectomy as salvage is feasible for men in whom high intensity focused ultrasound failed, but with a higher morbidity than for primary surgery. Pathology results are alarming given the number of cases with extraprostatic extension yet early followup data suggest acceptable oncologic control. These results should be factored in when counseling men who wish to undergo primary high intensity focused ultrasound. PMID- 21239004 TI - Editorial comment. PMID- 21239005 TI - Editorial comment. PMID- 21239006 TI - D'Amico risk stratification correlates with degree of suspicion of prostate cancer on multiparametric magnetic resonance imaging. AB - PURPOSE: We determined whether there is a correlation between D'Amico risk stratification and the degree of suspicion of prostate cancer on multiparametric magnetic resonance imaging based on targeted biopsies done with our electromagnetically tracked magnetic resonance imaging/ultrasound fusion platform. MATERIALS AND METHODS: A total of 101 patients underwent 3 Tesla multiparametric magnetic resonance imaging of the prostate, consisting of T2, dynamic contrast enhanced, diffusion weighted and spectroscopy images in cases suspicious for or with a diagnosis of prostate cancer. All prostate magnetic resonance imaging lesions were then identified and graded by the number of positive modalities, including low-2 or fewer, moderate-3 and high-4 showing suspicion on multiparametric magnetic resonance imaging. The biopsy protocol included standard 12-core biopsy, followed by real-time magnetic resonance imaging/ultrasound fusion targeted biopsies of the suspicious magnetic resonance lesions. Cases and lesions were stratified by the D'Amico risk stratification. RESULTS: In this screening population 90.1% of men had a negative digital rectal examination. Mean+/-SD age was 62.7+/-8.3 years and median prostate specific antigen was 5.8 ng/ml. Of the cases 54.5% were positive for cancer on protocol biopsy. Chi-square analysis revealed a statistically significant correlation between magnetic resonance suspicion and D'Amico risk stratification (p<0.0001). Within cluster resampling demonstrated a statistically significant correlation between magnetic resonance suspicion and D'Amico risk stratification for magnetic resonance targeted core biopsies and magnetic resonance lesions (p<0.01) CONCLUSIONS: Our data support the notion that using multiparametric magnetic resonance prostate imaging one may assess the degree of risk associated with magnetic resonance visible lesions in the prostate. PMID- 21239007 TI - Editorial comment. PMID- 21239008 TI - Predicting 15-year prostate cancer specific mortality after radical prostatectomy. AB - PURPOSE: Long-term prostate cancer specific mortality after radical prostatectomy is poorly defined in the era of widespread screening. An understanding of the treated natural history of screen detected cancers and the pathological risk factors for prostate cancer specific mortality are needed for treatment decision making. MATERIALS AND METHODS: Using Fine and Gray competing risk regression analysis we modeled clinical and pathological data, and followup information on 11,521 patients treated with radical prostatectomy at a total of 4 academic centers from 1987 to 2005 to predict prostate cancer specific mortality. The model was validated on 12,389 patients treated at a separate institution during the same period. Median followup in the modeling and validation cohorts was 56 and 96 months, respectively. RESULTS: The overall 15-year prostate cancer specific mortality rate was 7%. Primary and secondary Gleason grade 4-5 (each p<0.001), seminal vesicle invasion (p<0.001) and surgery year (p=0.002) were significant predictors of prostate cancer specific mortality. A nomogram predicting 15-year prostate cancer specific mortality based on standard pathological parameters was accurate and discriminating with an externally validated concordance index of 0.92. When stratified by patient age at diagnosis, the 15-year prostate cancer specific mortality rate for pathological Gleason score 6 or less, 3+4, 4+3 and 8-10 was 0.2% to 1.2%, 4.2% to 6.5%, 6.6% to 11% and 26% to 37%, respectively. The 15-year prostate cancer specific mortality risk was 0.8% to 1.5%, 2.9% to 10%, 15% to 27% and 22% to 30% for organ confined cancer, extraprostatic extension, seminal vesicle invasion and lymph node metastasis, respectively. Only 3 of 9,557 patients with organ confined, pathological Gleason score 6 or less cancer died of prostate cancer. CONCLUSIONS: Poorly differentiated cancer and seminal vesicle invasion are the prime determinants of prostate cancer specific mortality after radical prostatectomy. The prostate cancer specific mortality risk can be predicted with remarkable accuracy after the pathological features of prostate cancer are known. PMID- 21239009 TI - Inguinal recurrence following therapeutic lymphadenectomy for node positive penile carcinoma: outcome and implications for management. AB - PURPOSE: We investigated the treatment results and outcomes of patients with pathological node positive penile carcinoma who experienced an inguinal recurrence after therapeutic lymphadenectomy, and determined the clinicopathological features predictive of such recurrences. MATERIALS AND METHODS: Data of 161 patients with pN+ penile carcinoma were analyzed. Ipsilateral postoperative radiotherapy was given if histopathology revealed 2 or more metastases and/or extranodal extension. Medium observed followup was 60 months. The 5-year incidence of inguinal recurrence was estimated using a competing risk analysis considering death a competing risk. RESULTS: An inguinal recurrence developed in 26 patients following lymphadenectomy after a median of 5.3 months. The overall estimated 5-year inguinal recurrence rate was 16%. Of the 26 patients with inguinal recurrence ipsilateral adjuvant radiotherapy was indicated in 22 but given in 11. The other 11 patients had recurrence in the groin before the start of adjuvant radiotherapy. Median survival after inguinal recurrence was 4.5 months. Only 2 of 26 patients (8%) underwent successful salvage after inguinal recurrence. Pronounced differences in estimated recurrence rates were found among several clinicopathological variables indicating extensive penile cancer. Patients with 3 or more unilateral metastatic inguinal nodes and/or extranodal extension and/or pelvic nodal involvement defined a subgroup with high risk pN+ penile cancer. CONCLUSIONS: Most inguinal recurrence following therapeutic lymphadenectomy in pN+ penile carcinoma occurs within a short time. Patients experiencing such a recurrence have a poor outcome with limited salvage options. Patients with 3 or more unilateral metastatic inguinal nodes and/or extranodal extension and/or pelvic nodal involvement represent a high risk group that may benefit from multimodality treatment. PMID- 21239011 TI - Use of abiraterone for prostate cancer. PMID- 21239010 TI - Urinary pH is highly associated with tumor recurrence during intravesical mitomycin C therapy for nonmuscle invasive bladder tumor. AB - PURPOSE: In recent years some reports have suggested without any significant evidence that mitomycin C instillation would be more effective with urinary alkalinization. We investigated the association between urinary pH and the efficiency of mitomycin C instillation. MATERIALS AND METHODS: We identified 130 patients treated with transurethral resection of a bladder tumor and adjuvant intravesical mitomycin C instillation between 1985 and 2008 at Keio University Hospital. Urinary pH was determined in 124 of the 130 patients just before mitomycin C administration during the scheduled instillation period. These 124 patients were assigned to groups according to urinary pH in increments of 0.5 and the association between urinary pH and clinicopathological characteristics was evaluated. RESULTS: Mean+/-SD urinary pH was 5.77+/-0.05 (range 5.00 to 7.66) during the scheduled instillation period. Urinary pH was 5.00 to 5.49, 5.50 to 5.99, 6.00 to 6.49, 6.50 to 6.99 and 7.00 in 39, 46, 25, 7 and 7 patients, respectively. Patients were further divided into 2 groups by urinary pH using a cutoff of 5.5, including 39 with pH less than 5.5 and 85 with pH 5.5 or more. Age, gender, tumor grade, primary/recurrent disease, pathological stage and the presence or absence of concomitant carcinoma in situ were not significantly difference between the 2 groups. Multivariate analysis revealed that categorical urinary pH was an independent risk factor for tumor recurrence (HR 1.75, p=0.032). Three and 5-year recurrence-free rates were 64.2% and 52.9% in patients with pH 5.5 or greater, and 41.9% and 38.4% in those with pH less than 5.5, respectively (p=0.046). Multivariate analysis showed that the HR of urinary pH for tumor recurrence was 1.84 and 2.54 at the 5.4 and 5.2 cutoffs, respectively. CONCLUSIONS: Results suggest that urinary pH more than 5.5 is associated with a decreased risk of tumor recurrence in patients treated with intravesical mitomycin C for nonmuscle invasive bladder cancer. Monitoring urinary pH during mitomycin C adjuvant treatment and modifying pH for urine alkalization may improve the therapeutic efficacy of mitomycin C instillation. PMID- 21239012 TI - Novel therapeutic strategies for castration resistant prostate cancer: inhibition of persistent androgen production and androgen receptor mediated signaling. AB - PURPOSE: Androgen receptor signaling remains essential for many prostate cancers that have progressed despite androgen deprivation therapy. After medical or surgical castration persistent though not insignificant low levels of androgens are produced from nongonadal sources, such as the adrenal glands. Some castration resistant prostate cancers acquire the ability to convert adrenal steroids to androgens, maintaining levels sufficient to activate androgen receptor. Inhibition of persistent androgen production and androgen receptor mediated signaling are relevant therapeutic strategies for castration resistant prostate cancer. MATERIALS AND METHODS: The scientific foundation of and clinical experience with secondary hormonal therapy as well as the development of new investigational agents for castration resistant prostate cancer, specifically selective cytochrome p450 17 inhibitors and second generation antiandrogens, are discussed. RESULTS: Selective inhibition of cytochrome p450 17 has emerged as an important therapeutic pathway for castration resistant prostate cancer. The selective cytochrome p450 17 inhibitor abiraterone acetate showed promising activity and tolerability in phase I-II trials. Phase III studies are underway in men with chemotherapy naive castration resistant prostate cancer as well as those with progression after docetaxel based chemotherapy. TAK-700 and TOK-001 (formerly VN124-1) are novel selective cytochrome p450 17 inhibitors that recently entered phase I/II evaluation. MDV3100 is a second generation antiandrogen that blocks androgen receptor signaling by inhibiting nuclear translocation of the ligand-receptor complex. Clinical data on MDV3100 are encouraging and support continued phase III study. CONCLUSIONS: Novel therapies for castration resistant prostate cancer that target persistent androgen production and androgen receptor mediated signaling have demonstrated promising activity in many men with castration resistant prostate cancer and may redefine the clinical management of these patients. PMID- 21239013 TI - Renal oncocytosis: management and clinical outcomes. AB - PURPOSE: Renal oncocytosis is a rare pathological condition in which renal parenchyma is diffusely involved by numerous oncocytic nodules in addition to showing a spectrum of other oncocytic changes. We describe our experience with renal oncocytosis, focusing on management and outcomes. MATERIALS AND METHODS: A total of 20 patients with a final pathological diagnosis of renal oncocytosis from July 1995 through June 2009 were included in the analysis. Patient demographics, intraoperative variables and postoperative outcomes are reported. RESULTS: Median age at nephrectomy was 71 years (IQR 59-75). Of the patients 15 (75%) had bilateral disease. There were 23 operations (9 right side, 14 left side) performed on 20 patients, and of these procedures 13 (57%) were partial nephrectomies and 10 (43%) were radical nephrectomies. Median dominant tumor mass diameter was 4.1 cm (IQR 3-6.4, range 1 to 14.6). The most common dominant tumor histology was hybrid tumor between oncocytoma and chromophobe renal cell carcinoma in 13 of 23 specimens (57%), followed by chromophobe renal cell carcinoma in 6 (26%), oncocytoma in 3 (13%) and conventional renal cell carcinoma in 1 (4%). Ten patients (50%) had preexisting chronic kidney disease before nephrectomy and chronic kidney disease developed in 5 more after surgery. After a median followup of 35 months no patients had metastatic disease. CONCLUSIONS: Patients with renal oncocytosis usually present with multiple and bilateral renal nodules. Half of the patients had chronic kidney disease at diagnosis and 25% had new onset of chronic kidney disease. No patient had distant metastatic disease during followup. Our management approach is to perform partial nephrectomy when possible and then use careful surveillance of the remaining renal masses. PMID- 21239014 TI - Identification of high risk pathological node positive penile carcinoma: value of preoperative computerized tomography imaging. AB - PURPOSE: Patients with penile carcinoma, and 3 or more histopathologically proven unilateral metastatic inguinal nodes, and/or extranodal extension, and/or pelvic metastasis are considered a subgroup with prognostically unfavorable parameters for disease specific death and local recurrence after inguinal lymphadenectomy. We established radiographic criteria for the preoperative identification of such patients. MATERIALS AND METHODS: Preoperative diagnostic computerized tomography studies of 30 patients with penile carcinoma with proven unilateral or bilateral lymph node metastasis were reviewed independently by 2 radiologists blinded for patient data. All computerized tomography images were analyzed per side (60). Several radiographic criteria were assessed for regional lymph nodes with short axis diameter 8 mm or greater and/or central nodal necrosis. Sides were characterized as high risk if histopathology revealed 3 or more metastatic inguinal nodes and/or extranodal extension and/or pelvic nodal involvement. RESULTS: Histopathological nodal involvement was found in 38 sides (63%) including 22 sides (37%) defined as high risk. The presence of central nodal necrosis and/or irregular nodal border of the regional lymph nodes on the preoperative computerized tomography identified the high risk subgroup with a sensitivity of 95% (21 of 22) and a specificity of 82% (31 of 38). All 7 sides falsely designated as high risk harbored inguinal metastases but they were classified as low risk. The interobserver agreement of each radiographic parameter was almost perfect. CONCLUSIONS: The presence of central nodal necrosis and/or an irregular nodal border of the regional lymph nodes on preoperative computerized tomography images are accurate and reproducible criteria to identify high risk pathological node positive penile cancer. These criteria can be used for risk stratification and patient counseling. PMID- 21239016 TI - Editorial comment. PMID- 21239017 TI - Efficacy of a second line luteinizing hormone-releasing hormone agonist after advanced prostate cancer biochemical recurrence. AB - PURPOSE: Men with castrate resistant prostate cancer have limited treatment options. Although luteinizing hormone-releasing hormone agonists are in the same class, they are slightly different in their pharmacology. We determined whether rechallenging patients with prostate cancer, who were receiving a luteinizing hormone-releasing hormone analogue but had progression, with a different luteinizing hormone-releasing hormone analogue (goserelin or leuprolide acetate) would result in a prostate specific antigen response. Secondary objectives were to calculate the PSA response and determine whether sequence order impacted the response. MATERIALS AND METHODS: We performed a retrospective, ethics approved review of the records of patients with prostate cancer at multiple institutions who received a luteinizing hormone-releasing hormone analogue (goserelin or leuprolide acetate), experienced progression, as measured by 2 consecutive prostate specific antigen increases, and were rechallenged with the other analogue (goserelin or leuprolide acetate). Prostate specific antigen and relevant clinical data were obtained and statistical analysis was done. RESULTS: Of 39 available men 27 (69%) had decreased prostate specific antigen after 3 months of switching regimens. The median change in prostate specific antigen was 1.5 (IQR -10.0, 0.8), indicating a statistically significant decrease (p=0.01). The median percent prostate specific antigen change for leuprolide acetate to goserelin was -69.3% (IQR -81.5, 26.2) and for goserelin to leuprolide acetate it was -6.4% (IQR -61.7, 21.8, p=0.05). Median time to a subsequent prostate specific antigen increase was 5.2 months (95% CI 3.5-17.4). CONCLUSIONS: Prostate specific antigen decreased after switching luteinizing hormone-releasing hormone therapies. This decrease appeared most significant in the group that switched from leuprolide acetate to goserelin. The duration of response after switching was approximately 5 months. The study is limited by its retrospective nature but should encourage prospective evaluation of this observation. PMID- 21239018 TI - Stem cell therapy for the bladder--where do we stand? PMID- 21239019 TI - Buccal mucosa: good but not perfect. PMID- 21239020 TI - The quest for improved management of penile cancer. PMID- 21239021 TI - Cost-effectiveness of prostate specific antigen screening in the United States: extrapolating from the European study of screening for prostate cancer. AB - PURPOSE: Preliminary results of the European Randomized Study of Screening for Prostate Cancer showed a decrease in prostate cancer specific mortality associated with prostate specific antigen screening. We evaluated the cost effectiveness of prostate specific antigen screening using data from the European Randomized Study of Screening for Prostate Cancer protocol when extrapolated to the United States. MATERIALS AND METHODS: We used previously reported Surveillance, Epidemiology and End Results-Medicare data and a nationwide sample of employer provided estimates of costs of care for patients with prostate cancer. The European data were used in accordance with the study protocol to determine the costs and cost-effectiveness of prostate specific antigen screening. RESULTS: The lifetime cost of screening with prostate specific antigen, evaluating abnormal prostate specific antigen and treating identified prostate cancer to prevent 1 death from prostate cancer was $5,227,306 based on the European findings and extrapolated to the United States. If screening achieved a similar decrease in overall mortality as the decrease in prostate cancer specific mortality in the European study, such intervention would cost $262,758 per life-year saved. Prostate specific antigen screening reported in the European study would become cost effective when the lifelong treatment costs were below $1,868 per life-year, or when the number needed to treat was lowered to 21 or fewer men. CONCLUSIONS: The lifelong costs of screening protocols are determined by the cost of treatment with an insignificant contribution from screening costs. We established a model that predicts the minimal requirements that would make screening a cost-effective measure for population based implementation. PMID- 21239022 TI - Editorial comment. PMID- 21239023 TI - Effects of family history and genetic polymorphism on the cost-effectiveness of chemoprevention with finasteride for prostate cancer. AB - PURPOSE: Improvement in the cost-effectiveness of chemoprevention for prostate cancer could be realized through the identification of patients at higher risk. We estimated the cost-effectiveness of prostate cancer chemoprevention across risk groups defined by family history and number of risk alleles, and the cost effectiveness of targeting chemoprevention to higher risk groups. MATERIALS AND METHODS: We developed a probabilistic Markov model to estimate costs, survival and quality adjusted survival across risk groups for patients receiving or not receiving chemoprevention with finasteride. The model uses data from national cancer registries, online sources and the medical literature. RESULTS: The incremental cost-effectiveness of 25 years of chemoprevention with finasteride in patients 50 years old was an estimated $89,300 per quality adjusted life-year (95% CI $58,800-$149,800), assuming finasteride decreased all grades of prostate cancer by 24.8%. Among patients with a positive family history (without genetic testing) chemoprevention provided 1 additional quality adjusted life-year at a cost of $64,200. Among patients with a negative family history at $400 per person tested, the cost-effectiveness of genetically targeted chemoprevention ranged from $98,100 per quality adjusted life-year when limiting finasteride to individuals with 14 or more risk alleles, to $103,200 per quality adjusted life year when including those with 8 or more risk alleles. CONCLUSIONS: Although there are small differences in the cost-effectiveness of genetically targeted chemoprevention strategies in patients with a negative family history, genetic testing could reduce total expenditures if used to target chemoprevention for higher risk groups. PMID- 21239024 TI - Low dose computerized tomography for detection of urolithiasis--its effectiveness in the setting of the urology clinic. AB - PURPOSE: Low dose noncontrast computerized tomography is becoming a common imaging tool to diagnose urolithiasis. We investigated its usefulness as a diagnostic tool in the outpatient setting. MATERIALS AND METHODS: A total of 62 patients with suspected urolithiasis underwent standard renal stone protocol computerized tomography with a tube current of 160 mA. Images were modified by adding image noise to simulate tube currents of 70, 100 and 130 mA. Three urologists independently interpreted the original and simulated dose scans for stone number, location and associated signs of obstruction. In addition, the investigators rated the ease of interpreting the scans and their overall level of confidence. RESULTS: There were no statistically significant differences in interobserver and intra-observer variability for stone detection or obstruction signs except significant interobserver variability in hydronephrosis and intra observer variability in stranding categories. Each 1 mm increase in stone size increased the likelihood of a concordant response 3.55, 2.7 and 2-fold when reducing the tube current level by 19%, 38% and 56%, respectively (p=0.001, 0.008 and 0.021, respectively). Multiple stones or index stone location were not associated with agreement. The overall level of confidence decreased with lower simulated doses, particularly in the bony pelvis (p<0.02). CONCLUSIONS: Low dose computerized tomography may serve as an effective tool in the setting of the urology clinic in patients with urolithiasis. This imaging tool can better assess urolithiasis and associated obstruction than plain abdominal radiographs, but it may be problematic with small stones (less than 2 mm) and evidence of distal ureteral obstruction. Its effectiveness as a long-term followup tool requires further prospective trials. PMID- 21239025 TI - [CONSORT 2010 Declaration: updated guideline for reporting parallel group randomised trials]. PMID- 21239027 TI - Weight, body composition and handgrip strength among pulmonary tuberculosis patients: a matched cross-sectional study in Mwanza, Tanzania. AB - This study aimed to estimate deficits in weight, arm fat area (AFA), arm muscle area (AMA) and handgrip strength among smear-positive pulmonary TB (PTB+) patients starting treatment. We conducted a cross-sectional study among PTB+ patients and age- and sex-matched neighborhood controls. HIV status, anthropometric measurements and handgrip strength were determined. Deficits in weight, AFA, AMA and handgrip strength associated with PTB+ and HIV were estimated using multiple regression analysis. We recruited 355 pairs of PTB+ patients and controls. PTB+ was associated with deficits of 10.0kg (95% CI 7.3; 12.7) in weight and 6.8kg (95% CI 5.2; 8.3) in handgrip strength among females and 9.1kg (95% CI 7.3; 10.9) in weight and 6.8kg (95% CI 5.2; 8.4) in handgrip strength among males. In both sexes, PTB+ was associated with deficits in AFA and AMA. Among females, HIV was associated with deficits in AMA and handgrip strength, but the deficit in handgrip strength was larger among PTB+ patients (3.2kg 95% CI 1.3; 5.2) than controls (-1.6kg 95% CI -4.8; 1.5) (interaction, P=0.009). These findings suggest that deficits in weight and handgrip strength among patients starting TB treatment are severe. Thus, nutritional support may be necessary to ensure reversal of the deficits, and may improve treatment outcomes. PMID- 21239026 TI - [Clinical features of patients with hypertriglyceridemia referred to lipid units: registry of hypertrigliceridemia of the Spanish Arteriosclerosis Society]. AB - BACKGROUND AND OBJECTIVE: to show clinical features of subjects with hypertriglyceridemia (HTG) referred to the Lipid Units associated to Spanish Arteriosclerosis Society (ULSEA). PATIENTS AND METHOD: it is a prospective, cross sectional, multicentric study of patients with serum Tgs > 200mg/dL, recruited from January 2007 to December 2008. Demographic, drug therapies, anthropometrical, main diagnosis and biochemical parameters were registered. RESULTS: We included 1,033 men and 361 women, 50+/-12 years-old. Vascular disease, smoking, alcohol intake and liver steatosis were more prevalent in men than in women; by contrast, hypertension, diabetes and abdominal obesity were they in women. Regular physical exercise and a healthy diet were kept sparsely. Most patients suffered from a primary HTG (54%), mainly familial combined hyperlipidemia or familial hypertriglyceridemia. Obesity, alcohol intake and diabetes were the most common secondary forms of HTG. Among patients, 27% were diet-only treated, 44% received drugs in monotherapy and 24% drugs in combinations. CONCLUSIONS: Although primary forms of HTG are common, we show here a high prevalence of secondary forms and conditions worsening the HTG, being smoking and alcohol intake in men and abdominal obesity and diabetes in women. Even though most patients are drug-treated, diet and regular exercise recommendations should be clearly improved. PMID- 21239028 TI - Trends of mycobacterial clinical isolates in Taiwan. AB - Non-tuberculous mycobacteria (NTM) can cause chronic pulmonary infection, however, NTM infection is generally overlooked. This retrospective study analyzed the frequencies of Mycobacterium tuberculosis complex (MTBC) and NTM clinical isolates from 99 200 specimens of patients suspected with pulmonary mycobacterial infection in Taiwan from 2002-2007. A total of 8024 mycobacterial isolates, including 5349 MTBC and 2675 NTM, were obtained from the 99 200 specimens in the study period. The overall mycobacterial isolation rate was 8.09% (8024/99 200), and the overall MTBC and NTM isolation rate was 5.39% (5349/99 200) and 2.7% (2675/99 200), respectively. Notably, the prevalence of NTM isolates among the identified mycobacteria strains was increased 2.6 fold from 2002 (17.54%, 147/838) to 2007 (45.80%, 659/1439). The frequencies of MTBC and NTM isolates showed a reciprocal trend: the NTM isolation rates were steadily increasing while the overall mycobacterial isolation rates remained stable over the study period. Our results suggest that the diagnosis, identification and susceptibility tests for NTM should be standardized and integrated in clinical routines, for providing the information of NTM infection and prescribing clinical treatment in a more precise and efficient way to reduce the increasing NTM in the studied area. PMID- 21239029 TI - Cellular factors in plant virus movement: at the leading edge of macromolecular trafficking in plants. AB - To establish systemic infection, plant viruses must be localized to the correct subcellular sites to accomplish replication and then traffic from initially infected cells into neighboring cells and even distant organs. Viruses have evolved various strategies to interact with pre-existing cellular factors to achieve these functions. In this review we discuss plant virus intracellular, intercellular and long-distance movement, focusing on the host cellular factors involved. We emphasize that elucidating viral movement mechanisms will not only shed light on the molecular mechanisms of infection, but will also contribute valuable insights into the regulation of endogenous macromolecular trafficking. PMID- 21239030 TI - Targeting the hepatitis B virus precore antigen with a novel IgNAR single variable domain intrabody. AB - The Hepatitis B virus precore protein is processed in the endoplasmic reticulum (ER) into secreted hepatitis B e antigen (HBeAg), which acts as an immune tolerogen to establish chronic infection. Downregulation of secreted HBeAg should improve clinical outcome, as patients who effectively respond to current treatments (IFN-alpha) have significantly lower serum HBeAg levels. Here, we describe a novel reagent, a single variable domain (V(NAR)) of the shark immunoglobulin new antigen receptor (IgNAR) antibodies. V(NAR)s possess advantages in stability, size (~14 kDa) and cryptic epitope recognition compared to conventional antibodies. The V(NAR) domain displayed biologically useful affinity for recombinant and native HBeAg, and recognised a unique conformational epitope. To assess therapeutic potential in targeting intracellular precore protein to reduce secreted HBeAg, the V(NAR) was engineered for ER-targeted in vitro delivery to function as an intracellular antibody (intrabody). In vitro data from HBV/precore hepatocyte cell lines demonstrated effective intrabody regulation of precore/HBeAg. PMID- 21239032 TI - Characterization of host genetic expression patterns in HIV-infected individuals with divergent disease progression. AB - The course of HIV-1 infection shows a variety of clinical phenotypes with an important involvement of host factors. We compare host gene expression patterns in CD3+ T cells from two of these phenotypes: long-term non-progressor patients (LTNP) and matched control patients with standard HIV disease progression. Array analysis revealed over-expression of 322 genes in progressors and 136 in LTNP. Up regulated genes in progressors were mainly implicated in the regulation of DNA replication, cell cycle and DNA damage stimulus and mostly localized into cellular organelles. In contrast, most up-regulated genes in LTNP were located at the plasmatic membrane and involved in cytokine-cytokine receptor interaction, negative control of apoptosis or regulation of actin cytoskeleton. Regarding gene interactions, a higher number of viral genes interacting with cellular factors were seen in progressors. Our study offers new comparative insights related to disease status and can distinguish differentiated patterns of gene expression among clinical phenotypes. PMID- 21239031 TI - The structure of avian polyomavirus reveals variably sized capsids, non-conserved inter-capsomere interactions, and a possible location of the minor capsid protein VP4. AB - Avian polyomavirus (APV) causes a fatal, multi-organ disease among several bird species. Using cryogenic electron microscopy and other biochemical techniques, we investigated the structure of APV and compared it to that of mammalian polyomaviruses, particularly JC polyomavirus and simian virus 40. The structure of the pentameric major capsid protein (VP1) is mostly conserved; however, APV VP1 has a unique, truncated C-terminus that eliminates an intercapsomere connecting beta-hairpin observed in other polyomaviruses. We postulate that the terminal beta-hairpin locks other polyomavirus capsids in a stable conformation and that absence of the hairpin leads to the observed capsid size variation in APV. Plug-like density features were observed at the base of the VP1 pentamers, consistent with the known location of minor capsid proteins VP2 and VP3. However, the plug density is more prominent in APV and may include VP4, a minor capsid protein unique to bird polyomaviruses. PMID- 21239034 TI - A two-class population balance equation yielding bimodal flocculation of marine or estuarine sediments. AB - Bimodal flocculation of marine and estuarine sediments describes the aggregation and breakage process in which dense microflocs and floppy macroflocs change their relative mass fraction and develop a bimodal floc size distribution. To simulate bimodal flocculation of such sediments, a Two-Class Population Balance Equation (TCPBE), which includes both size-fixed microflocs and size-varying macroflocs, was developed. The new TCPBE was tested by a model-data fitting analysis with experimental data from 1-D column tests, in comparison with the simple Single Class PBE (SCPBE) and the elaborate Multi-Class PBE (MCPBE). Results showed that the TCPBE was the simplest model that is capable of simulating the major aspects of the bimodal flocculation of marine and estuarine sediments. Therefore, the TCPBE can be implemented in a large-scale multi-dimensional flocculation model with least computational cost and used as a prototypic model for researchers to investigate complicated cohesive sediment transport in marine and estuarine environments. Incorporating additional biological and physicochemical aspects into the TCPBE flocculation process is straight-forward also. PMID- 21239033 TI - Multiple HIV-1 infections with evidence of recombination in heterosexual partnerships in a low risk Rural Clinical Cohort in Uganda. AB - We report on the frequency of multiple infections, generation of recombinants and consequences on disease progression in 35 HIV-1 infected individuals from 7 monogamous and 6 polygamous partnerships within a Rural Clinical Cohort in Uganda. The env-C2V3, gag-p24 and pol-IN genes were sequenced. Single genome amplified half genome sequences were used to map recombination breakpoints. Three participants were dually infected with subtypes A and D, one case with subtype A and A/D recombinant and the fifth with 2 phylogenetically distinct A/D recombinants. Occurrence of A/D recombination was observed in two multiple infected individuals. Rate of late stage WHO events using Cox regression was 3 times greater amongst multiple infected compared to singly infected individuals (hazard ratio 3.35; 95% CI 1.09, 10.3; p=0.049). We have shown that polygamous relationships involving subtype discordant partnerships was a major contributor of multiple infections with generation of inter subtype recombinants in our cohort. PMID- 21239035 TI - An examination of the mechanisms for stable foam formation in activated sludge systems. AB - Screening pure cultures of 65 mycolic acid producing bacteria (Mycolata) isolated mainly from activated sludge with a laboratory based foaming test revealed that not all foamed under the conditions used. However, for most, the data were generally consistent with the flotation theory as an explanation for foaming. Thus a stable foam required three components, air bubbles, surfactants and hydrophobic cells. With non-hydrophobic cells, an unstable foam was generated, and in the absence of surfactants, cells formed a greasy surface scum. Addition of surfactant converted a scumming population into one forming a stable foam. The ability to generate a foam depended on a threshold cell number, which varied between individual isolates and reduced markedly in the presence of surfactant. Consequently, the concept of a universal threshold applicable to all foaming Mycolata is not supported by these data. The role of surfactants in foaming is poorly understood, but evidence is presented for the first time that surfactin synthesised by Bacillus subtilis may be important. PMID- 21239036 TI - Gravity drainage of activated sludge: new experimental method and considerations of settling velocity, specific cake resistance and cake compressibility. AB - A laboratory scale setup was used for characterization of gravitational drainage of waste activated sludge. The aim of the study was to assess how time of drainage and cake dry matter depended on volumetric load, SS content and sludge floc properties. It was demonstrated that activated sludge forms compressible cakes, even at the low pressures found in gravitational drainage. The values of specific cake resistance were two to three orders of magnitude lower than those obtained in pressure filtration. Despite the compressible nature of sludge, key macroscopic parameters such as time of drainage and cake solid content showed simple functional dependency of the volumetric load and SS of a given sludge. This suggests that the proposed method may be applied for design purposes without the use of extensive numerical modeling. The possibilities for application of this new technique are, among others, the estimation of sludge drainability prior to mechanical dewatering on a belt filter, or the application of surplus sludge on reed beds, as well as adjustments of sludge loading, concentration or sludge pre-treatment in order to optimize the drainage process. PMID- 21239037 TI - Assessing sediment hazard through a weight of evidence approach with bioindicator organisms: a practical model to elaborate data from sediment chemistry, bioavailability, biomarkers and ecotoxicological bioassays. AB - Quality assessments are crucial to all activities related to removal and management of sediments. Following a multidisciplinary, weight of evidence approach, a new model is presented here for comprehensive assessment of hazards associated to polluted sediments. The lines of evidence considered were sediment chemistry, assessment of bioavailability, sub-lethal effects on biomarkers, and ecotoxicological bioassays. A conceptual and software-assisted model was developed with logical flow-charts elaborating results from each line of evidence on the basis of several chemical and biological parameters, normative guidelines or scientific evidence; the data are thus summarized into four specific synthetic indices, before their integration into an overall sediment hazard evaluation. This model was validated using European eels (Anguilla anguilla) as the bioindicator species, exposed under laboratory conditions to sediments from an industrial site, and caged under field conditions in two harbour areas. The concentrations of aliphatic hydrocarbons, polycyclic aromatic hydrocarbons and trace metals were much higher in the industrial compared to harbour sediments, and accordingly the bioaccumulation in liver and gills of exposed eels showed marked differences between conditions seen. Among biomarkers, significant variations were observed for cytochrome P450-related responses, oxidative stress biomarkers, lysosomal stability and genotoxic effects; the overall elaboration of these data, as those of standard ecotoxicological bioassays with bacteria, algae and copepods, confirmed a higher level of biological hazard for industrial sediments. Based on comparisons with expert judgment, the model presented efficiently discriminates between the various conditions, both as individual modules and as an integrated final evaluation, and it appears to be a powerful tool to support more complex processes of environmental risk assessment. PMID- 21239038 TI - Disruption of zebrafish (Danio rerio) reproduction upon chronic exposure to TiO2 nanoparticles. AB - As common engineered nanomaterials, TiO(2) nanoparticles (nTiO(2)) are usually perceived as non-toxic, and have already been widely used in many products and applications. Such a perception might have been shaped by some short-term studies that revealed no/low toxicity of nTiO(2) to cells and eco-relevant organisms. However, given the ultimate release of nTiO(2) into the aquatic environment, which can act as a sink for engineered nanoparticles, their long-term impact on the environment and human health is still a concern and deserves more research efforts. Here, for the first time, we demonstrate that chronic exposure of zebrafish to 0.1 mg L(-1) nTiO(2), can significantly impair zebrafish reproduction. For instance, there was a 29.5% reduction in the cumulative number of zebrafish eggs after 13 weeks of nTiO(2) exposure. Thus, we provided timely information on indicating a serious risk of reproductive impairment of environments contaminated with low levels of nTiO(2) on aquatic organisms, leading to alterations in population dynamics and aquatic ecosystem balance, and thus warrants a careful scrutiny on toxicity assessment of nTiO(2), especially their long-term impact. PMID- 21239039 TI - The role of Aster amellus Linn. in the degradation of a sulfonated azo dye Remazol Red: a phytoremediation strategy. AB - Phytoremediation is a novel and promising approach for the treatment of pollutants. This study did explore the potential of Aster amellus Linn. to decolorize a sulfonated azo dye Remazol Red (RR), a mixture of dyes and a textile effluent. Induction in the activities of lignin peroxidase, tyrosinase, veratryl alcohol oxidase and riboflavin reductase was observed during RR decolorization, suggesting their involvement in the metabolism of RR. UV-Visible absorption spectrum, HPLC and FTIR analysis confirmed the degradation of RR. Four metabolites after the degradation of the dye were identified as 2-[(3 diazenylphenyl) sulfonyl] ethanesulfonate, 4-amino-5-hydroxynaphthalene-2,7 disulfonate, naphthalene-2-sulfonate and 3-(1,3,5-triazin-2 ylamino)benzenesulfonate by using GC/MS. Textile effluent and mixture of dyes showed 47% and 62% decrease respectively in American Dye Manufacturers Institute value. BOD of textile effluent and mixture of dyes were reduced by 75% and 48% respectively, COD of industrial effluent and mixture of dyes was reduced by 60% and 75% and TOC was reduced by 54% and 69% respectively after the treatment by A. amellus for 60 h; this indicated that the plant can be used for cleaning textile effluents. Toxicity study revealed the phytotransformation of RR into non-toxic products. PMID- 21239040 TI - Limitations of reverse polyethylene samplers (RePES) for evaluating toxicity of field contaminated sediments. AB - Passive samplers are used to measure dissolved nonionic organic contaminants (NOCs) in environmental media. More recently, reverse polyethylene samplers (RePES) have been used with spiked sediments to recreate interstitial water exposure concentrations and observed toxicity. In the present study, RePES were used with field contaminated sediments. The RePES was not capable of recreating the pattern of toxicity with the amphipod and mysid observed with intact field sediments. Decreased survival in the RePES exposures as compared to the whole sediment exposures was most likely caused by an overexposure to NOCs due to a lack of surrogate black carbon in the RePES system. As an alternative, aqueous phase studies were performed in which polyethylene was allowed to equilibrate with slurries of intact sediments for 3 weeks. Three weeks was found to be an insufficient amount of time for the polyethylene to equilibrate with the sediment. An additional study demonstrated 3 months was sufficient for lower contaminant concentrations, but might not be an adequate amount of time for more highly contaminated sediments. The aqueous phase transfer approach may be useful if equilibration is sufficiently long, although this length of time may be impractical for use in certain applications, such as toxicity identification evaluations (TIEs). PMID- 21239041 TI - Adsorptive removal of As(III) by biogenic schwertmannite from simulated As contaminated groundwater. AB - This study investigates synthesis of biogenic schwertmannite by Acidithiobacillus ferrooxidans and its role and mechanism in adsorption of As(III) from water. Results indicate that schwertmannite particles formed through oxidation of ferrous sulfate by A. ferrooxidans cells for different times vary greatly in size and in morphology. The hedge-hog like schwertmannite formed after reaction for 72h are aggregative spheroid particles with a diameter of approximately 2.5MUm and its chemical formula can be expressed as Fe(8)O(8)(OH)(4.42)(SO(4))(1.79). Batche studies show that both Freundlich and Langmuir model are suitable for describing the adsorption behavior of As(III) on schwertmannite at pH 7.5 and As(III) in simulated groundwater can be effectively removed by biogenic schwertmannite with a maximum adsorption capacity of 113.9mg As(III) g(-1) and the optimal pH is in the range of 7-10. The arsenic removal is hardly affected by the competing anions often observed in groundwater unless the mole concentration of PO(4)(3-) and SO(4)(2-) in groundwater are 75 or 750 times higher than As(III), respectively. The mechanism of As(III) adsorption on biogenic schwertmannite involves ligand exchanges between arsenic species and surface hydroxyl group and sulfate. In addition, experiments show that As(III)-sorbed biogenic schwertmannite aged in deionized water at 25 degrees C exhibits no mineralogy phase changes even after ageing at pH 6.0 and 8.5 for 90d. PMID- 21239042 TI - Ozone-enhanced catalytic oxidation of monochlorobenzene over iron oxide catalysts. AB - In this study, we examined the experimental catalytic oxidation of gaseous monochlorobenzene (MCBz) with O3 over Fe2O3 in a packed bed reactor to investigate the feasibility of economical low temperature decomposition at a high space velocity (SV). We investigated the effects of several reaction parameters (temperature, O3 concentration, and SV) on the MCBz oxidation. At 150 degrees C, the conversion of MCBz over Fe2O3 in the absence of O3 was only 3%; it increased to 91% over Fe2O3 in the presence of 1,200 ppm of O3 at a high SV of 83 s(-1). A long-term operation study revealed that the conversion of MCBz was stable for more than 96 h. In the steady state, the carbon and chlorine balances were 88% and 86%, respectively. Applying a Langmuir-Hinshelwood kinetic model, we estimated an activation energy of 16.7 kJ mol(-1) for MCBz oxidation over Fe2O3 in the presence of O3. PMID- 21239043 TI - Significance of dysadherin and E-cadherin expression in differentiated-type gastric carcinoma with submucosal invasion. AB - Dysadherin is a cancer-associated cell membrane glycoprotein that down-regulates E-cadherin and plays important roles in tumor progression and metastasis. Differentiated-type gastric carcinoma can be classified into 2 histologic subtypes according to the presence of poorly differentiated components: a mixed type (differentiated carcinoma with poorly differentiated components) and a pure type (purely differentiated-type adenocarcinoma). We studied the clinicopathologic features of 318 cases of differentiated-type gastric carcinoma with submucosal invasion and evaluated the immunohistochemical expression of dysadherin and E-cadherin. We also evaluated 46 cases of metastatic lymph nodes. Tumors with combined dysadherin-positive (>=50%) expression and E-cadherin negative (<50%) expression had significantly higher proportions of the moderately differentiated type, deeper submucosal invasion, positivity of lymphatic permeation, and positivity of lymph node metastasis than tumors with other combinations of dysadherin and E-cadherin expression (P = .0009, P = .0015, P = .0273, and P = .0187, respectively). Moreover, the frequency of dysadherin positive (>=50%) expression was higher in the mixed type (60.3%) than in the pure type (12.4%) (P < .0001), whereas the frequency of E-cadherin-negative (<50%) expression was higher in the mixed type (84.5%) than in the pure type (50.5%) (P < .0001). The frequency of dysadherin expression in the metastatic lymph nodes (80.4%) was significantly higher than that in the primary tumors (45.7%) (P = .001). Dysadherin-positive (>=50%) expression and E-cadherin-negative (<50%) expression may be correlated with the mixed type. Combined dysadherin-positive (>=50%) expression and E-cadherin-negative (<50%) expression may be valuable information for predicting aggressive tumor behavior. PMID- 21239044 TI - Central nervous system marginal zone B-cell lymphoma associated with Chlamydophila psittaci infection. AB - Extranodal marginal zone B-cell lymphomas are linked to bacterial infections that vary according to the anatomical site. The occurrence of these lymphomas in the central nervous system is a very rare event, and the identification of specific bacteria in this setting has not been previously addressed. Herein, we report for the first time a case of primary central nervous system marginal zone B-cell lymphoma involving the choroid plexus associated with Chlamydophila psittaci infection. No concomitant ocular involvement was detected. C psittaci was identified with 3 independent methods, and through immunohistochemistry, it was visualized in the cytoplasm of monocytes/macrophages present within lymphomatous tissues. This observation points toward the opportunity to investigate the prevalence of C psittaci infection in central nervous system lymphomas, particularly in those with low-grade histologic features. PMID- 21239045 TI - Mammalian target of rapamycin regulates expression of beta-catenin in hepatocellular carcinoma. AB - Although evidence has shown that both the mammalian target of rapamycin and beta catenin are involved in hepatocellular carcinoma, little is known about their relationship in pathogenesis of hepatocellular carcinoma. To investigate the expression of phosphorylated mammalian target of rapamycin and beta-catenin and their prognostic impacts, as well as their relationship in hepatocellular carcinoma, we analyzed 63 human hepatocellular carcinoma samples by immunohistochemistry. Phosphorylated mammalian target of rapamycin cytoplasmic and beta-catenin cytoplasmic/nuclear-positive immunoreactivities were observed in 63.5% (40/63) and 55.6% (35/63) of the hepatocellular carcinoma specimens, respectively. Significant associations were found between cytoplasmic beta catenin and phosphorylated mammalian target of rapamycin expression and tumor size (both P < .01) and metastasis (P < .01 and P < .05, respectively). In addition, beta-catenin expression in the cytoplasm was closely associated with the expression of phosphorylated mammalian target of rapamycin. To further explore the relationship between mammalian target of rapamycin and beta-catenin, hepatocellular carcinoma HepG2 and Hep3B cells were treated with beta-catenin siRNA and mammalian target of rapamycin inhibitor, rapamycin; and the expression of phosphorylated mammalian target of rapamycin and beta-catenin in cells was then measured by Western blot. The activity of Wnt/beta-catenin signaling pathway was also assessed by luciferase reporter assay. The cell viability and proliferation were evaluated by thiazolyl blue tetrazolium bromide assay and [(3)H]-thymidine incorporation assay. The results showed that the level of beta catenin protein expression was markedly decreased by rapamycin in HepG2 and Hep3B cells. The reduction of beta-catenin and mammalian target of rapamycin resulted in inhibition of cell viability proliferation, but the combination of reduction of beta-catenin and mammalian target of rapamycin did not show a synergistic effect on the inhibition of cell viability and proliferation in HepG2 and Hep3B cells. In conclusion, the present study showed that, for the first time, mammalian target of rapamycin regulated the expression level of beta-catenin in hepatocellular carcinoma. Both mammalian target of rapamycin and beta-catenin play important roles in the growth, metastasis, and prognosis of hepatocellular carcinoma. PMID- 21239046 TI - Air pollution and meteorological processes in the growing dryland city of Urumqi (Xinjiang, China). AB - Seven years (2000-2006) of monthly PM10 (particulate matter, d <= 10 MUm), SO2, and NO2 concentrations are reported for Urumqi, the capital of Xinjiang in NW China. Considerably high mean annual concentrations have been observed, which ranged between 150 and 240 MUg m-3 (PM10, 31 and 50 MUg m-3 (NO2), and 49 and 160 MUg m-3 (SO2). The shapes of seasonal variation of all pollutants were remarkably similar; however, winter/summer ratios of concentrations were quite different for PM10 (2-3) and NO2 (~4) compared to SO2 (up to 30). Very high consumption rates of fossil fuels for energy generation and domestic heating are mainly responsible for high annual pollution levels, as well as the (very) high winter/summer ratios. Detailed analysis of the 2000-2006 records of Urumqi's meteorological data resulted in inter-annual and seasonal frequency distributions of (a) (surface) inversion events, (b) heights of surface inversions, (c) stability classes of Urumqi's boundary layer, and (d) the "Air Stagnation Index (ASI)". Urumqi's boundary layer is shown to be characterized by high mean annual and seasonal frequencies of (surface) inversions and by the dominance of stable dispersion classes. A further outcome of the meteorological analysis is the proof of Urumqi's strong diurnal wind system, which might have particularly contributed to the stabilization of the nocturnal boundary layer. Annual and seasonal variations of pollutant's concentrations are discussed in the context of occurrences of inversions, boundary layer, stability classes, and ASI. The trend of Urumqi's air pollution indicates a strong increase of mean annual concentrations 2000-2003, followed by a slight increase during 2003-2006. These are in strong contrast to (a) the growth of Urumqi's fleet of motor vehicles and (b) to the growing number of stable regimes of Urumqi's boundary layer climate during same period. It is concluded that the (regional and) local administrative technical countermeasures have efficiently lowered Urumqi's air pollution levels. PMID- 21239047 TI - Synergistic toxic effect of nano-TiO and As(V) on Ceriodaphnia dubia. AB - Due to the active development and application of nanotechnology, engineered nanomaterials (ENMs) are becoming a new class of environmental pollutants that may significantly impact the environment and human health. While many toxicity investigations have been conducted, there is little information about the synergistic effect of ENMs and other toxic compounds in the environment. In order to extend this knowledge, the combined effect of TiO2 nanoparticles (n-TiO2) and As(V) were investigated. High concentrations of As(V) can accumulate on the n TiO2 surface. Cultured Ceriodaphnia dubia (C. dubia) species were used to examine the synergistic toxic effect through exposure to 1) n-TiO2 suspensions, 2) As(V) solutions, and 3) mixtures of n-TiO2 and As(V) suspensions. Results showed that n TiO2 alone was not toxic when the concentration was less than 400 mg/L and that the 24-hour median lethal concentration (LC50) of As(V) alone was 3.68+/ 0.22mg/L. However, in the presence of low concentrations of n-TiO2, the toxicity of As(V) increased significantly. At the same initial As(V) concentration, the toxicity of n-TiO2 first increased, reached a maximum, and then decreased with an increase in n-TiO2 concentration. Hydrodynamic size and sorption capacity were most important parameters for toxicity. PMID- 21239048 TI - A phase II trial of carboplatin and docetaxel followed by radiotherapy given in a "Sandwich" method for stage III, IV, and recurrent endometrial cancer. AB - OBJECTIVE: To determine feasibility and efficacy of administering docetaxel and carboplatin chemotherapy followed by pelvic radiotherapy and then consolidation chemotherapy in patients with advanced or recurrent endometrial cancer. METHODS: Patients with surgically staged III-IV (excluding IIIA from positive cytology alone) endometrial cancer or biopsy confirmed recurrent disease were eligible. Treatment consisted of 3 cycles of docetaxel (75 mg/m2) and carboplatin (AUC 6) on a q21 day schedule followed by involved field irradiation (45 Gy)+/- brachytherapy and three additional cycles of docetaxel and carboplatin. Kaplan Meier (KM) methods estimated overall survival (OS) and progression free survival (PFS). RESULTS: Forty-two patients enrolled, 7 did not complete therapy. 95% (39/41) had primary disease. Median age=58 years (range: 21-81 years). 78% (32/41)=endometrioid histology. Stages=10 IIIA, 21 IIIC, 1 IVA, 7 IVB, (recurrent=1 IC, 1 IIA). There were 23 non-hematologic and 14 grade 3 and 16 grade 4 hematologic toxicities. Seven patients died following treatment with a median follow-up of 28 months (range: 7-70 months). KM estimates and 95% confidence intervals for OS at 1 year were 95% (82-99%), at 3 years 90% (75-96%), and at 5 years 71% (45-86%). Of the 39 with primary disease, 11 progressed or died within 5 years of study enrollment. KM estimates and 95% confidence intervals for PFS at 1 year were 87% (72-94%), at 3 years 71% (51-83%), and at 5 years 64% (42-80%). CONCLUSIONS: "Sandwiching" radiation between chemotherapy for advanced or recurrent endometrial cancer merits further development based on the reported PFS and OS. PMID- 21239049 TI - Treatment of vulvar intraepithelial neoplasia with topical imiquimod: seven years median follow-up of a randomized clinical trial. AB - OBJECTIVE: Recently we reported on the efficacy of imiquimod for treating vulvar intraepithelial neoplasia (VIN) in a placebo-controlled, double-blinded randomized clinical trial (RCT). Four weeks after treatment, a complete response was observed in 35% of patients and a partial response in 46%. All complete responders remained disease-free at 12 months follow-up. In the current investigations, we assessed long-term follow-up at least 5 years after the initial RCT. METHODS: Twenty-four of 26 imiquimod-treated patients who had participated in the initial RCT were seen for follow-up. Primary endpoint was durability of clinical response to imiquimod assessed by naked eye vulvar examination and histology. Long-term clinical response was correlated to lesion size before start of the initial RCT. Secondary endpoints were mental health, global quality of life, body image and sexual function in relation with long-term clinical response. RESULTS: Median follow-up period was 7.2 years (range 5.6-8.3 years). VIN recurred in one of nine complete responders. Of the initial partial responders, two became disease-free after additional imiquimod treatment. In the other partial responders, VIN recurred at least once after the initial RCT. In long-term complete responders, lesion size at study entry was smaller and these patients had a significantly better global quality of life at follow-up than patients with residual disease and/or recurrence after imiquimod treatment. CONCLUSIONS: In case of a complete response, imiquimod is effective in the long term. Furthermore, patients with a long-term complete response had a significantly better global quality of life than patients who recurred after imiquimod treatment. PMID- 21239050 TI - Tying up loose threads in delivery of a newborn care package. PMID- 21239053 TI - Addressing the complexity of cardiovascular disease by design. PMID- 21239052 TI - Improvement of perinatal and newborn care in rural Pakistan through community based strategies: a cluster-randomised effectiveness trial. AB - BACKGROUND: Newborn deaths account for 57% of deaths in children younger than 5 years in Pakistan. Although a large programme of trained lady health workers (LHWs) exists, the effectiveness of this training on newborn outcomes has not been studied. We aimed to evaluate the effectiveness of a community-based intervention package, principally delivered through LHWs working with traditional birth attendants and community health committees, for reduction of perinatal and neonatal mortality in a rural district of Pakistan. METHODS: We undertook a cluster randomised trial between February, 2006, and March, 2008, in Hala and Matiari subdistricts, Pakistan. Catchment areas of primary care facilities and all affiliated LHWs were used to define clusters, which were allocated to intervention and control groups by restricted, stratified randomisation. The intervention package delivered by LHWs through group sessions consisted of promotion of antenatal care and maternal health education, use of clean delivery kits, facility births, immediate newborn care, identification of danger signs, and promotion of careseeking; control clusters received routine care. Independent data collectors undertook quarterly household surveillance to capture data for births, deaths, and household practices related to maternal and newborn care. Data collectors were masked to cluster allocation; those analysing data were not. The primary outcome was perinatal and all-cause neonatal mortality. Analysis was by intention to treat. This trial is registered, ISRCTN16247511. FINDINGS: 16 clusters were assigned to intervention (23,353 households, 12,391 total births) and control groups (23,768 households, 11,443 total births). LHWs in the intervention clusters were able to undertake 4428 (63%) of 7084 planned group sessions, but were only able to visit 2943 neonates (24%) of a total 12,028 livebirths in their catchment villages. Stillbirths were reduced in intervention clusters (39.1 stillbirths per 1000 total births) compared with control (48.7 per 1000; risk ratio [RR] 0.79, 95% CI 0.68-0.92; p=0.006). The neonatal mortality rate was 43.0 deaths per 1000 livebirths in intervention clusters compared with 49.1 per 1000 in control groups (RR 0.85, 0.76-0.96; p=0.02). INTERPRETATION: Our results support the scale-up of preventive and promotive maternal and newborn interventions through community health workers and emphasise the need for attention to issues of programme management and coverage for such initiatives to achieve maximum potential. FUNDING: WHO; Saving Newborn Lives Program of Save the Children USA, funded by the Bill & Melinda Gates Foundation. PMID- 21239054 TI - Secreted Gaussia luciferase as a sensitive reporter gene for in vivo and ex vivo studies of airway gene transfer. AB - The cationic lipid GL67A is one of the more efficient non-viral gene transfer agents (GTAs) for the lungs, and is currently being evaluated in an extensive clinical trial programme for cystic fibrosis gene therapy. Despite conferring significant expression of vector-specific mRNA following transfection of differentiated human airway cells cultured on air liquid interfaces (ALI) cultures and nebulisation into sheep lung in vivo we were unable to detect robust levels of the standard reporter gene Firefly luciferase (FLuc). Recently a novel secreted luciferase isolated from Gaussia princeps (GLuc) has been described. Here, we show that (1) GLuc is a more sensitive reporter gene and offers significant advantages over the traditionally used FLuc in pre-clinical models for lung gene transfer that are difficult to transfect, (2) GL67A-mediated gene transfection leads to significant production of recombinant protein in these models, (3) promoter activity in ALI cultures mimics published in vivo data and these cultures may, therefore, be suitable to characterise promoter activity in a human ex vivo airway model and (4) detection of GLuc in large animal broncho alveolar lavage fluid and serum facilitates assessment of duration of gene expression after gene transfer to the lungs. In summary, we have shown here that GLuc is a sensitive reporter gene and is particularly useful for monitoring gene transfer in difficult to transfect models of the airway and lung. This has allowed us to validate that GL67A, which is currently in clinical use, can generate significant amounts of recombinant protein in fully differentiated human air liquid interface cultures and the ovine lung in vivo. PMID- 21239055 TI - A technical note to improve the reporting of studies of the human placenta. AB - Human placentas studied after normal and abnormal pregnancies require author attention to a number of variables derived from clinical chart review. We herein provide a Table listing many of the key variables that might be confounders for clinical studies of the human placenta. As Editors for Placenta, we respectfully request our authors to cite this Technical Note in Methods of submitted papers and include the Table provided herein, and as a download in Instructions for authors, in Supplementary material for any manuscript submission related to the human placenta. This request is optional for authors and is part of an experiment we will trial for the next three years, with the goal of improving the science reported in Placenta. PMID- 21239056 TI - BCR-ABL1 mutations in patients with imatinib-resistant Philadelphia chromosome positive leukemia by use of the PCR-Invader assay. AB - BCR-ABL1 kinase domain mutations were evaluated in 60 imatinib-resistant patients with Philadelphia-positive (Ph(+)) leukemia using PCR-Invader assay and direct sequencing. In chronic myelogenous leukemia (CML)--chronic phase (CP), 5 had P loop mutations and 3 had T315I mutations. CML-CP patients with high Sokal score showed significantly higher incidence of mutations. P-loop mutations were associated with higher risk of disease progression. In CML-advanced phase, P-loop mutations and T315I mutation were associated with significantly shorter survival. In Ph(+) acute lymphoblastic leukemia, overall survival was poor irrespective of mutational status. The PCR-Invader assay is useful for screening of mutations and prediction of prognosis. PMID- 21239057 TI - Polymorphisms in integrin genes and lymphoma risk. AB - Immune deficiency is one of the best characterized and strongest known risk factors for non-Hodgkin lymphoma (NHL). We studied the association between single nucleotide polymorphisms (SNPs) in integrin genes that are important components in human innate immunity and the risk of NHL in a population-based case-control study of women in Connecticut, USA. A total of 373 tag SNPs in 33 gene regions were included in the analysis of 448 cases and 525 controls. The ADAM19 rs11466782 SNP was associated with an increased risk of lymphoma (OR, 1.73; 95% CI, 1.28-2.35; Padditive=0.0004), and the ICAM3 rs2304240 (OR, 0.67; 95% CI, 0.52 0.86; Padditive=0.002) and the PTGDR rs708486 SNPs (OR, 0.75; 95% CI, 0.63-0.90; Padditive=0.002) were associated with reduced risk of lymphoma. Two gene regions (ADAM19 (P=0.009) and ICAM3 (P=0.009)) displayed global associations with lymphoma risk at the P<0.01 level. While our results suggest that genetic polymorphisms in integrin genes may play a role in the genesis of lymphoma in women, they should be viewed as exploratory until they are replicated in additional populations. PMID- 21239058 TI - 8p11 Myeloproliferative syndrome with BCR-FGFR1 rearrangement presenting with T lymphoblastic lymphoma and bone marrow stromal cell proliferation: a case report and review of the literature. PMID- 21239059 TI - Biochemical response of amphipods (Gammarid: Paramorea) in a sediment laboratory exposure from Ushuaia Bay, Beagle Channel. AB - A coastal system (Ushuaia Bay, Argentina) impacted by anthropogenic activities was studied by the response of local amphipods (Parmorea sp., Gammaridae) to the exposure of coastal sediments in a laboratory assay. Four coastal areas with different loadings of contaminants and one considered as reference were studied. Organic matter, carbohydrates, proteins and heavy metals were measured in sediment samples. Organisms were exposed to sediments for seven days and catalase (CAT), glutathione S-transferase (GST), acetylcholinesterase (AChE) and lipid peroxidation (LPO) were measured afterward. Amphipods exhibited an activation of GST and inhibition of AChE in most impacted areas. Principal Component Analysis (PCA) was conducted in order to associate the biological responses with sediment metal concentration and its eutrophicated status. Levels of Cd and Cr were associated with the inhibition of AChE and with the enhancement of GST. CAT and LPO were enhanced in most areas, but no link was found with the contaminants studied by PCA, suggesting that other parameters present in sediments not included in the PCA affect the amphipods. The most impacted area corresponds to Nautical Club station, with a highly eutrophicated status and high content of metals, where amphipods after the exposure were affected in a biochemical level. PMID- 21239060 TI - The influence of water temperature on induced liver EROD activity in Atlantic cod (Gadus morhua) exposed to crude oil and oil dispersants. AB - Juvenile Atlantic cod were exposed to either the water-accommodated fraction (WAF) or the chemically enhanced water-accommodated fraction (CEWAF) of Mediterranean South American (MESA), a medium grade crude oil at three different temperatures. Two concentrations of each mixture were tested, 0.2% and 1.0% (v/v) at 2, 7 and 10 degrees C. Corexit 9500 was the chemical dispersant tested. The liver enzyme ethoxyresorufin-O-deethylase (EROD) was measured during a 72-h exposure. The WAF of oil had significant (P<0.05) effect on enzyme activity compared to controls at only one sampling time: 48 h at 10 degrees C. Exposure of CEWAF of oil resulted in significantly (P<0.05) elevated EROD activity compared to controls. The level of EROD induction was temperature related with higher induction being observed in cod exposed to CEWAF at higher temperatures. Total polycyclic aromatic hydrocarbon (PAH) concentrations in exposure water were significantly higher in chemically dispersed mixtures. While PAH concentrations were lower in the 2 degrees C water compared to 7 or 10 degrees C (8.7 vs 11.9 MUg mL(-1)), the level of EROD induction was approximately 9 and 12 times lower at 2 degrees C compared to 7 or 10 degrees C, respectively, suggesting the metabolic rate of the cod plays a role in the enzyme response. These data suggest the risk of negative impacts associated with exposure to chemically dispersed oil may be affected by water temperature and that risk assessment of potential effects of WAF or CEWAF should consider the effects of water temperature on the physiology of the fish as well as the effectiveness of dispersants. PMID- 21239061 TI - Prenatal mercury exposure in a multicenter cohort study in Spain. AB - BACKGROUND: Mercury is a ubiquitous heavy metal that may negatively affect human health. It is desirable to investigate mercury exposure in vulnerable populations. OBJECTIVE: To determine the concentrations of total mercury (T-Hg) in cord blood and to evaluate the role of maternal fish consumption in a Spanish mother and child cohort. METHODS: A total of 1883 mother and child pairs from a population-based cohort were included between 2004 and 2008. T-Hg concentrations were measured in whole cord blood and maternal seafood consumption was ascertained by means of a food-frequency questionnaire. Linear regression was used in stratified analyses, while a joint model was adjusted using a mixed effects linear model. RESULTS: Maternal daily seafood consumption was 78g/d and the geometric mean for T-Hg was 8.2MUg/L. Maternal fish intake during pregnancy, mother's age, country of origin, educational level, employment status and parity, as well as area of study and season of delivery, were associated with cord blood T-Hg levels. A doubling in consumption of large oily fish was associated with an increase of 11.4% (95%CI: 3.8 to 19.6%) in cord blood T-Hg levels, followed by an increase of 8.4% (95%CI: 5.7 to 11.2%) in the case of canned tuna and 8.3% (95%CI: 5.5 to 11.1%) in that of lean fish. CONCLUSION: A high proportion of newborns had elevated concentrations of cord blood T-Hg according to the current US-EPA reference dose (5.8MUg/L for methylmercury). Mercury concentrations were related to maternal fish consumption, with large oily fish being the main contributor. PMID- 21239062 TI - Concentrations and loadings of polybrominated diphenyl ethers in dust from low income households in California. AB - California residents may experience the highest polybrominated diphenyl ether (PBDE) flame retardant exposures in the United States, the nation with the highest body burdens worldwide. It is hypothesized that Californians' high exposures are due to the state's strict furniture flammability standards. Ingestion of PBDE-contaminated dust, to which children may be particularly susceptible, is a dominant exposure pathway. Low-income populations may also face disparately high exposures due to the presence of older, deteriorated or poorly manufactured furniture treated with PBDEs. We collected up to two dust samples per home (54 samples total), several days apart, from low-income California households in the urban community of Oakland (n=13 homes) and the agricultural community of Salinas (n=15 homes). We measured BDE-47, BDE-99 and BDE-100, the major constituents of the penta-PBDE flame retardant formulation commonly used in furniture. All three PBDE congeners were detected in every sample with concentrations (loadings) ranging from 185 to 126,000ng/g (621-264,000ng/m(2)), 367-220,000ng/g (1550-457,000ng/m(2)), and 84-41,100ng/g (257-85,700ng/m(2)) for BDE-47, BDE-99 and BDE-100, respectively. Median concentrations (loadings) observed in Salinas homes for BDE-47, BDE-99 and BDE-100 were 3100ng/g (10,800ng/m(2)), 5480ng/g (19,500ng/m(2)), and 1060ng/g (3810ng/m(2)), respectively, and in Oakland homes 2780ng/g (10,700ng/m(2)), 4450ng/g (19,100ng/m(2)), and 1050ng/g (4000ng/m(2)), respectively. Maximum concentrations for BDE-47 and BDE-99 are the highest reported to date. Indoor concentrations and loadings did not significantly differ between communities; concentrations and loadings were strongly correlated between collections for all three congeners (Spearman rho=0.79-0.97, p<0.002). We estimated non-dietary ingestion of each congener for one child in each home (n=28 children) and found that estimated intake for BDE-47 and BDE-99 exceeded the U.S. Environmental Protection Agency's recommended chronic reference dose for three and five children, respectively. Children's estimated intake via dust ranged from 1.0 to 599ng/kg/day, 2.0 1065ng/kg/day and 0.5-196ng/kg/day for BDE-47, BDE-99 and BDE-100, respectively. In order to mitigate these exposures, future research must address the factors that contribute to PBDE exposures in low-income homes. PMID- 21239051 TI - Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. AB - BACKGROUND: We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. METHODS: We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). FINDINGS: In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4.98*10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7.62*10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. INTERPRETATION: Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. FUNDING: The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix. PMID- 21239063 TI - Identification of pleasant, neutral, and unpleasant odors in schizophrenia. AB - Recent work on odor hedonics in schizophrenia has indicated that patients display abnormalities in hedonic judgments of odors in comparison to healthy comparison participants. In the current study, identification accuracy for pleasant, neutral, and unpleasant odors in individuals with schizophrenia and healthy controls was examined. Thirty-three schizophrenia patients (63% male) and thirty one healthy volunteers (65% male) were recruited. The groups were well matched on age, sex, and smoking status. Participants were administered the University of Pennsylvania Smell Identification Test, which was subsequently divided into 16 pleasant, 15 neutral, and 9 unpleasant items. Analysis of identification z-scores for pleasant, neutral, and unpleasant odors revealed a significant diagnosis by valence interaction. Post-hoc analysis revealed that schizophrenia participants made more identification errors on pleasant and neutral odors compared to healthy controls, with no differences observed for unpleasant odors. No effect was seen for sex. The findings from the current investigation suggest that odor identification accuracy in patients is influenced by odor valence. This pattern of results parallels a growing body of literature indicating that patients display aberrant pleasantness ratings for pleasant odors and highlights the need for additional research on the influence of odor valence on olfactory identification performance in individuals with schizophrenia. PMID- 21239064 TI - Immunoprotection against toxic biomarkers is retained during Parkinson's disease progression. AB - The aim was to ascertain any possible linkage between humoral immune responses to principal biomarkers (alpha-synuclein monomers, its toxic oligomers or fibrils, dopamine and S100B) and cellular immunity in Parkinson's disease development. There were elevated autoantibody titers to alpha-synuclein monomers, oligomers plus fibrils in 72%, 56%, and 17% of Parkinsonian patients respectively with a 5 year disease duration. Additionally, there were increased titers to dopamine and S100B (96% and 89%) in the 5-year patient group. All of these values subsided in 10-year sufferers. Furthermore, CD3+, CD4+, CD8+ T-lymphocyte and B-lymphocyte subsets declined in the patient cohort during Parkinsonism indicating disease associated reductions in these lymphocyte subsets. PMID- 21239065 TI - Is there any developmental relationship between mastoid pneumatization and adenoid tissue volume? AB - OBJECTIVE: The aim of this study was to investigate the developmental relationship between adenoid tissue volume and mastoid air cell volume, using a 3D reconstruction technique. STUDY DESIGN: Cross-sectional retrospective study. SUBJECTS AND METHODS: Multislice computed tomography (MSCT) images were obtained using three-dimensional (3D) reconstruction and volume-rendering techniques (VRT). The subjects were 63 boys and 37 girls, 3-16 years of age. The volumes of bilateral mastoid air cells and adenoids marked in axial-coronal-sagittal planes were calculated. The patients were grouped into three categories according to adenoid tissue volume, total mastoid volume (TMV), and age. RESULTS: No significant difference was noted between the right mastoid volume (RMV) and the left mastoid volume (LMV) or between age and sex (p=0.368; p=0.549; p=0.454). The incremental increase in adenoid tissue volume did not correlate with TMV (r= 0.161, r=-0.279, r=0.015). The incremental increase in TMV did not correlate with the volume of adenoid tissue (r=0.024, r=0.148, r=0.017). CONCLUSIONS: No significant correlation was obtained between the incremental increase in adenoid tissue volume and TMV or the incremental increase in TMV and adenoid tissue volume. There does not seem to be a developmental relationship between adenoid tissue volume and TMV. PMID- 21239066 TI - Management of subglottic cysts with Mitomycin-C-A case series and literature review. AB - OBJECTIVES: To describe the management and outcomes of seven infants with subglottic cysts. To assess the role of Mitomycin-C in the management of subglottic cysts. To discuss the relationship of subglottic cysts with gastro esophageal reflux. To extensively review the literature on subglottic cysts. DESIGN: Retrospective case series and literature review. METHODS: Case series of seven children with subglottic cysts at a tertiary care hospital. Charts were reviewed to determine birth history, gender, intubation history, comorbidities, age at presentation, presenting symptoms, interventions and follow-up. RESULTS: Between 2001 and 2009, seven patients aged 4-13 months were diagnosed with and treated for subglottic cysts. All children had a history of intubation and had evidence of gastro-esophageal reflux. All children were treated with endoscopic marsupialization (CO(2)-laser, cupped forceps) or bronchoscopic rupture; with or without concomitant topical Mitomycin-C therapy. Infants were followed clinically and with interval endoscopy with a minimum follow-up of 6 weeks. No patients receiving topical post-marsupialization Mitomycin-C (0/4) had cyst recurrence. Those patients who did not receive Mitomycin-C therapy recurred more frequently (66% - 2/3). Cysts ruptured with the bronchoscope tip recurred (66% - 2/3) more often than cysts undergoing endoscopic marsupialization (0/6). The one bronchoscopic rupture case that did not recur was the one in which Mitomycin-C was used concomitantly. Patient follow-up was at 2, 4 and 6 weeks post-procedure. CONCLUSION: Endoscopic marsupialization is the treatment of choice for subglottic cysts. Gastro-esophageal reflux has a strong association with subglottic cysts. The post-marsupialization application of Mitomycin-C may have a role in reducing the recurrence rate and scarring after surgical treatment of subglottic cysts. PMID- 21239067 TI - Dizziness in 10 year old children: an epidemiological study. AB - OBJECTIVE: Current data about the prevalence and characteristics of dizziness in the paediatric population is very limited and the generalisability of extant studies to the UK population has not been explored. Our study aims to provide a robust estimate of the prevalence of dizziness in 10 year old children in the UK, to describe the characteristics of this dizziness and to explore whether this dizziness is socially patterned. METHODS: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) was analysed (N=13,988). A total of 6965 of these children attended for a balance assessment session at age 10. Those who reported rotary vertigo were interviewed about their symptoms. Logistic regression was used to explore whether dizziness at age 10 is socially patterned. RESULTS: A total of 400 children reported rotary vertigo, giving a prevalence estimate of 5.7% [CI 5.2, 6.3%]. 13.1-20.6% of children reported experiencing their dizziness between 1 and 4 times a week (depending on the symptom). 51.5% of children had to stop what they were doing because of the dizziness making them feel unwell. A total of 60% of children reported headache as an accompanying symptom, tentatively suggesting a diagnosis of migraine, although there was no association between reports of headache and a maternal family history of migraine. 20.3% of children with dizziness also reported tinnitus and 17.3% reported that their hearing changed when they were dizzy. CONCLUSIONS: Dizziness in 10 year old children is not uncommon and in about half limits current activities. Rotary vertigo is commonly accompanied by dizziness of another description and also by headache. There is no evidence that dizziness at this age is socially patterned. PMID- 21239068 TI - The rate-corrected QT interval calculated from 24-hour Holter recordings may serve as a significant arrhythmia risk stratifier in heart failure patients. PMID- 21239070 TI - Alpine "P" waves in a case of restrictive cardiomyopathy. PMID- 21239069 TI - The Ghent Marfan Trial--a randomized, double-blind placebo controlled trial with losartan in Marfan patients treated with beta-blockers. AB - BACKGROUND: Aortic root dilation, dissection and rupture are major clinical problems in Marfan syndrome (MFS). Although beta-blockers remain the standard of preventive treatment, preliminary results from animal studies and a selected group of severely affected MFS children show significant benefit from treatment with losartan, an angiotensin II receptor blocker with TGF-beta inhibiting potential. Large-scale human trials are now needed to confirm these results. This trial aims to evaluate the combined effect of both drugs. METHODS: We are conducting a prospective randomized placebo controlled double blind phase III study aiming to include 174 MFS patients (age >= 10 years and z-score >= 2). Patients already taking beta-blockers are randomized for weight-adjusted treatment with losartan versus placebo. The primary endpoint is decrease in aortic root growth rate. Secondary endpoints are aortic dissection/surgery, progression of aortic/mitral regurgitation, arterial stiffness, left ventricular systolic/diastolic function, quality of life and genetic modifiers. Echocardiography, vascular echo-Doppler and quality of life assessment will be performed at baseline and at 6-monthly follow-ups for 3 years. MRI evaluation will be performed at baseline and at the end of the trial. CONCLUSION: This trial will study new therapeutic strategies for the prevention of serious cardiovascular complications in MFS. The uniqueness in our trial is that the additive effect of losartan and beta-blocker will be evaluated in a large spectrum of disease severity. A combination of ultrasound and MRI will allow detailed evaluation of anatomic and functional properties of the aorta and left ventricle. PMID- 21239071 TI - Partial least squares analysis of the association between metabolic factors and left ventricular mass among Taiwanese adolescents. PMID- 21239072 TI - Left atrial remodeling and reduced atrial pump function after chronic right ventricular apical pacing in patients with preserved ejection fraction. AB - BACKGROUND: This prospective study was to examine the impact of right ventricular apical (RVA) pacing on atrial remodeling and function. METHODS AND RESULTS: 103 patients (age 70 +/- 11 years; 53 men) with preserved left ventricular (LV) ejection fraction (LVEF>45%) who received RVA pacing had Doppler echocardiography performed at baseline and after one year follow up. At one year follow up, left atrial (LA) volumes (pre-atrial contraction volume and the minimal volume) and their indexes were significantly increased with reduction in passive emptying fraction and total emptying fraction (all p<0.05). LA segmental tissue velocities - mean peak systolic (Sm-la), peak early diastolic (Em-la) and late diastolic (Am la) - were also significantly reduced (all p<0.001). A reduction of Am-la>30% occurred in 24% of patients, and was more prevalent in patients with an elevation of LV filling pressure (E/e'>15) at one year (44.1% vs. 11.7%, chi(2)=12.75, p<0.001) as well as those with a reduction of LVEF >= 5% (34.0% vs. 14.3%, chi(2)=5.140, p=0.023). By multivariate regression analysis, E/e'>15 at one year (odds ratio [OR] 5.213; 95% confidence interval [CI] 1.778-15.281) and reduction of LVEF >= 5% (OR 3.181; 95% CI 1.045-9.686) were independent predictors of reduction of Am-la>30%. CONCLUSIONS: Chronic RVA pacing results in LA remodeling and reduced atrial function. This is related to elevated filling pressures and impairment of LV systolic function. PMID- 21239073 TI - Risk of atrial fibrillation according to the initial presentation of a preexcitation syndrome. AB - BACKGROUND: Atrioventricular reentrant tachycardia (AVRT) is frequent in Wolff Parkinson-White syndrome (WPW). Atrial fibrillation (AF) is rare. The purpose of the study was to determine the factors of spontaneous AF in WPW according to the initial presentation. METHODS AND RESULTS: Electrophysiological study (EPS) was performed among 709 patients with a preexcitation syndrome. First event was AF in 44 patients. Remaining patients were studied for AVRT (314), syncope (94), adverse presentation without AF (9) or systematically (248 asymptomatic patients). Patients with AF were older than other patients (44 +/- 16 years vs 34.5 +/- 17) (0.0003); maximal rate conducted over accessory pathway (AP) was higher in patients with AF than in other patients except in adverse presentation (0.0002); AVRT was induced more frequently in patients with AF than in asymptomatic patients (57% vs 14.5%) but less than in patients with AVRT (89%). AF was induced more frequently in patients with AF than in other patients except in adverse presentation (<0.0001). During follow-up AF occurred more frequently in patients with AF (5; 11%) than in patients with AVRT (7; 2%), with syncope (1%) and asymptomatic patients (4; 1.6%). Older age predicted recurrence (54 +/- 16 vs 40 +/- 17). CONCLUSIONS: AF was the first event in only 6% of patients with WPW and was a rare event in other patients. They are older but 10% are less than 18 years and have a more rapid conduction over AP than other patients. PMID- 21239074 TI - Late microvascular obstruction after acute myocardial infarction: relation with cardiac and inflammatory markers. AB - OBJECTIVES: We sought to assess the relation of late microvascular obstruction (l MVO) size as quantified by cardiac magnetic resonance (CMR) imaging with cardiac and inflammatory marker concentrations after acute myocardial infarction (AMI). METHODS: CMR was performed in 118 consecutive patients within 8 days after successful interventional reperfused first acute ST-elevation AMI. Infarct volumes and l-MVO sizes were calculated from late enhancement (LE) sequences and functional parameters were determined from short-axis cine MR sequences. Creatine kinase (CK) and cardiac troponin T (cTnT), high-sensitivity C-reactive protein (hs-CRP) as well as lactate dehydrogenase (LD) concentrations were determined serially from day 1 to day 4 after symptom onset. RESULTS: L-MVO was detected in 66/118 patients (55.9%) and comprised 18.2 +/- 10% of infarct size and 4.7 +/- 3% of left ventricle myocardial mass. Each single-point, peak and cumulative release concentration of cTnT (r=0.44 to 0.73, p<0.0001), CK (r=0.21 to 0.76, p<0.0001), LD (r=0.36 to 0.82, all p<0.0001) as well as hs-CRP single-point values as assessed from day 1 to day 4 and its peak and cumulative release concentrations (r=0.24 to 0.49, p<0.003) significantly correlated with l-MVO size. Receiver operating curve (ROC) analysis indicated a cut-off value of 4.7 MUg/l cTnT to best identify the presence of l-MVO (area under the curve (AUC) 0.904; 95% CI: 0.85-0.95; p<0.0001). CONCLUSION: L-MVO sizes significantly correlate with cardiac and inflammatory marker concentrations as determined early after AMI. cTnT concentration of >4.7 MUg/l could help to identify patients in whom l-MVO is present. PMID- 21239075 TI - The EFFect of hIgh-dose ClopIdogrel treatmENT in patients with clopidogrel resistance (the EFFICIENT trial). AB - OBJECTIVES: The aim of this study was to evaluate the effect of high-dose clopidogrel continuation treatment on the development of MACCE after elective PCI in patients with clopidogrel resistance. METHODS: The study group consisted of 192 patients. Of these, 98 participants without resistance served as the control group (Group 1) and received 75 mg/day clopidogrel for 1 month. Ninety-four patients with resistance were randomly divided into two groups: 47 patients in the standard-dose group (Group 2) received 75 mg/day continuation therapy, whereas 47 patients in the high-dose group (Group 3) received 150 mg/day continuation therapy for 1 month. Clopidogrel resistance was evaluated with the VerifyNow P2Y12 test. Patients with a platelet inhibition value lower than 40% were classified as resistant. RESULTS: During the 6-month follow-up for MACCE, the event-rate in Group 2 was significantly higher than both Groups 1 and 3 (Group 1 vs Group 2; p=0.019, Group 1 vs Group 3; p=0.82, Group 2 vs Group 3; p=0.045). Total bleeding rate in all groups were similar (Group 1 vs Group 2; p=0.54, Group 1 vs Group 3; p=0.27, Group 2 vs Group 3; p=0.16). The rate of NACE was similar in all groups (Group 1 vs Group 2; p=0.08, Group 1 vs Group 3; p=0.50, Group 2 vs Group 3; p=0.39). CONCLUSION: In patients who underwent elective PCI and had clopidogrel resistance, high-dose clopidogrel continuation therapy was more efficient in preventing MACCE than the standard dose. High-dose continuation therapy did not increase the risk of bleeding complication (The EFFICIENT Trial; ClinicalTrials.gov number: NCT01032668). PMID- 21239076 TI - A meta-analysis comparing the effect of PCV2 vaccines on average daily weight gain and mortality rate in pigs from weaning to slaughter. AB - The aim of this investigation was, through a meta-analysis, to review the published literature concerning the effect of PCV2 vaccination on the average daily weight gain (ADG) and on the mortality rate in pigs from weaning to slaughter. The review was restricted to studies investigating the effect of vaccines against PCV2 published from 2006 to 2008, identified using computerised literature databases. Only studies that met the following criteria were included: commercial vaccines were used, pigs or pens were assigned randomly to vaccination versus control groups in herds naturally infected with PCV2, and vaccinated and non-vaccinated pigs were housed together. Furthermore, it was a requirement that sample size, age at vaccination, and production period were stated. The levels of ADG and mortality rate had to be comparable to those seen in modern intensive swine production. In total, 107 studies were identified; 70 were excluded because they did not fulfil the inclusion criteria and 13 were identical to results published elsewhere. A significant effect of PCV2 vaccination on ADG was found for pigs in all production phases. The largest increase in ADG was found for finishing pigs (41.5g) and nursery-finishing pigs (33.6g) with only 10.6g increase in the nursery pigs. Mortality rate was significantly reduced for finishing pigs (4.4%) and nursery-finishing pigs (5.4%), but not for nursery pigs (0.25%). Herds negative for PRRS had a significantly larger increase in ADG compared to herds positive for PRRS. The PRRS status had no effect on mortality rate. PMID- 21239077 TI - Integrating surveillance and biosecurity activities to achieve efficiencies in national avian influenza programs. AB - Based on the HPAI experience, efforts to improve global capacity to prevent and control zoonotic diseases should consider new and more efficient models for integrating prevention and surveillance activities. PMID- 21239078 TI - The effect of local kinematic changes on anticipation judgments. AB - Skilled tennis players rely on a more global than local perceptual strategy when anticipating an opponent's shot direction in tennis (Williams, Huys, Canal Bruland, & Hagemann, 2009). Global perceptual strategy refers to the pick-up of dynamic information across different body areas rather than from a single source such as the arm or racket. We extend previous work by examining the spatiotemporal characteristics of visual information pick-up when anticipating shot direction in tennis. We perturbed information from various body locations by interchanging the dynamics of selected areas with those from strokes played to the opposite side of the court. In addition, we presented each manipulation under four different temporal occlusion conditions (from 240 ms prior to racket-ball contact) to examine the time course of information extraction. Skilled tennis players outperformed less skilled counterparts in predicting shot direction, even at early phases of the opponent's motion. Moreover, skilled players showed significant decrements in performance when the arms and racket were perturbed, highlighting the relevance of distal information when anticipating opponents' intentions. PMID- 21239080 TI - Does viral gastroenteritis really increase the reports of Clostridium difficile infection? PMID- 21239079 TI - Potential celiac disease in type 1 diabetes: a multicenter study. AB - AIMS: To describe the prevalence of potential celiac disease (pot-CD) in young patients with type 1 diabetes mellitus (T1DM) and characterize their clinical features. METHODS: This cross-sectional multicenter study involved 8717 T1DM patients from 31 Italian centers. Information was collected on the total number of T1DM patients, CD patients and pot-CD patients. The following data were collected on pot-CD patients: gender, age at T1DM diagnosis, age at the first CD serological positivity, presence of CD-related symptoms, presence of other autoimmune disorders and treatment with gluten free diet (GFD). One thousand three-hundred-sixty-one patients who were positive for CD serology were the control group. RESULTS: CD serological positivity was found in 7.2% T1DM patients. Prevalence of pot-CD was 12.2% (n=77) among CD positive patients: symptoms were present in 12/77; a third autoimmune disorder was found in 15 patients. Prevalence of pot-CD in the control population was 8.4% (n=114; p=0.005). No difference was found with regard to clinical features. Only few symptomatic patients were on GFD both in T1DM and control patients. CONCLUSIONS: A higher prevalence of pot-CD was found in T1DM patients, that may be ascribed to the routine screening, although the influence of genetic factors cannot be excluded. PMID- 21239081 TI - Prevalence and predictors of nasal and extranasal staphylococcal colonization in patients presenting to the emergency department. AB - STUDY OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common causes of skin and soft tissue infections in patients presenting to the emergency department (ED). The prevalence of asymptomatic MRSA colonization in ED patients is less well described, particularly in the absence of a skin and soft tissue infection-related complaint. The goals of this study are to assess the prevalence of nasal and extranasal staphylococcal colonization in ED patients, evaluate risk factors, and molecularly characterize the strains. METHODS: We performed active surveillance for methicillin-susceptible S aureus (MSSA) and MRSA colonization in 400 subjects presenting to an urban ED. Risk factor assessment was performed and culture testing was conducted on anterior nares, oropharynx, palms, groin, perirectal area, wounds, and catheter insertion sites. Multiplex polymerase chain reaction was used to identify the USA300/400 clonal types. RESULTS: The prevalence of colonization with MSSA was 39% (95% confidence interval 34.2% to 44.0%), and prevalence of colonization with MRSA was 5% (95% confidence interval 3.1% to 7.6%). Among MRSA-colonized subjects, an extranasal site tested positive in 80% of subjects, and 45% had exclusive extranasal colonization. USA300 was identified in 55% of MRSA-colonized subjects. The main risk factors for MRSA colonization included HIV infection, diabetes, and participation in contact sports. CONCLUSION: The overall prevalence of MRSA colonization in this ED population was lower than that reported in other high risk ambulatory care settings. However, extranasal colonization was present in more than half of MRSA-colonized subjects, and USA300 was the predominant clonal type. PMID- 21239082 TI - A randomized controlled trial of incision and drainage versus ultrasonographically guided needle aspiration for skin abscesses and the effect of methicillin-resistant Staphylococcus aureus. AB - STUDY OBJECTIVE: The incidence of skin and soft tissue infections has increased dramatically during the last decade, in part because of increased prevalence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). Incision and drainage is considered the primary intervention; however, some clinicians prefer ultrasonographically guided needle aspiration because it represents a less invasive alternative. Our hypothesis is that ultrasonographically guided needle aspiration is equivalent to incision and drainage in treating simple skin and soft tissue abscesses. METHODS: This study was a nonblinded randomized controlled trial. Patients with uncomplicated superficial abscesses were randomized to incision and drainage with packing or ultrasonographically guided needle aspiration. Purulence obtained from the abscess was cultured to identify the causative organism. Bedside ultrasonography was performed pre- and postintervention to confirm the presence or absence of an abscess cavity. Patients were followed up at 48 hours (in person by a clinician) and on day 7 (telephone follow-up by research staff). The primary outcome was a combination of sonographic resolution and clinical resolution of the signs and symptoms of ongoing infection at day 7. The signs and symptoms of ongoing infection include increasing pain, erythema, and the presence of pus. Resolution was assessed with both sonographic resolution (day 0 and day 2) and improvement of clinical symptoms (day 2) and resolution of clinical symptoms (day 7) without further intervention. RESULTS: A total of 101 patients were enrolled, 54 incision and drainage and 47 ultrasonographically guided needle aspiration patients. At initial presentation, 60% (95% confidence interval [CI] 45% to 70%) of needle aspirations yielded little or no purulence, despite sonographic visualization of an abscess cavity and sonographic guidance during the procedure. The overall success of ultrasonographically guided needle aspiration was 26% (95% CI 18% to 44%) compared with 80% (95% CI 66% to 89%) success in patients randomized to incision and drainage. The difference between groups was 54% (95% CI 35% to 69%). Overall success of both incision and drainage and ultrasonographically guided needle aspiration was lower in patients with CA-MRSA. Patients with CA-MRSA (n=33) were less likely to receive successful drainage with needle aspiration (8% versus 55%) or incision and drainage (61% versus 89%). The difference for needle aspiration and incision and drainage was 47% (95% CI 15% to 57%) and 28% (95% CI 4% to 45%), respectively. CONCLUSION: Ultrasonographically guided needle aspiration is insufficient therapy for skin abscesses. The presence of CA-MRSA decreases the success of both incision and drainage and ultrasonographically guided needle aspiration. PMID- 21239083 TI - Spatial variation and geographic-demographic determinants of out-of-hospital cardiac arrests in the city-state of Singapore. AB - STUDY OBJECTIVE: Our primary objective is to calculate the relative risk of cardiac arrests at the development guide plan (DGP) (equivalent to census tract) level in a city-state, Singapore, and examine its relationship with key area level population characteristics. METHODS: This was an observational ecological study design. We calculated the relative risk as the ratio of the observed and population standardized expected counts of out-of-hospital cardiac arrests in Singapore, aggregated at DGP level. Data were collected from October 2001 to October 2004. We used conditional autoregressive spatial models to examine the predictors of increased risk at the DGP level. RESULTS: We found a spatial distribution of cardiac arrests, with an unexpected cluster caused by nonresident arrests occurring at the international airport. The risk of out-of-hospital cardiac arrest more than doubled, 2.35 (95% confidence interval [CI] 1.28 to 4.48), for each 5-point increase in the proportion of people aged 65 years and older. For each 5-point increase in the proportion of Chinese individuals living in a DGP, the risk of out-of-hospital cardiac arrest was reduced by a factor of 0.8 (95% CI 0.7 to 0.9). The risk of out-of-hospital cardiac arrest increased by 1.49-fold (95% CI 1.18 to 1.82) for every 5-point increase in the proportion of households with no family nucleus (live alone). When restricted to residential cases of out-of-hospital cardiac arrest, none of the variables remained significant, possibly because of small sample size. CONCLUSION: The risk of cardiac arrests could be related to the age and racial and family structure of DGPs in Singapore. This article models how such data can help to direct public health education, cardiopulmonary resuscitation training, and public access defibrillation programs in other health systems. PMID- 21239084 TI - Blood culture contamination with Enterococci and skin organisms: implications for surveillance definitions of primary bloodstream infections. AB - Enterococci are a common cause of bacteremia but are also common contaminants. In our institution, approximately 17% of positive blood cultures with enterococci are mixed with skin organisms. Such isolates are probable contaminants. The specificity of the current definition of primary bloodstream infection could be increased by excluding enterococci mixed with skin organisms. PMID- 21239085 TI - Mindfulness meditation to improve care quality and quality of life in long-term care settings. AB - Quality of long-term care has been the focus of 2 recent Institute of Medicine reports: "Improving the Quality of Long-Term Care"(1) and "Improving the Quality of Care in Nursing Homes."(2) Although there has been some improvement in care quality since regulatory reforms were enacted in 1987,(3) poor care persists.(4) Certified nursing assistants (CNAs) are challenged in the provision of optimal care by chronic stress in the workplace, leading to absenteeism, reduced job satisfaction, and increased turnover.(5-7) Mindfulness training, which cultivates a practice of being present in the moment, recognizing stressful situations when they arise, and responding to stress in an adaptive manner,(8) holds promise as a simple, inexpensive approach to reduce CNA stress and improve quality of care and quality of life for residents in long-term care settings. Formal and informal mindfulness practices can readily be incorporated into CNA educational programs. PMID- 21239086 TI - [Health of family physicians: do we practice what we preach?]. AB - AIMS: To describe the lifestyle of primary care physicians, their adherence to cancer screening tests and to describe basic aspects of occupational, mental and sexual health. DESIGN: Cross-sectional study. SETTING: Primary Care. Health Area 7, Madrid. PARTICIPANTS: Family Physicians. METHODS: An anonymous survey sent through the internal mail was completed by the participants. The questionnaire was based on the Cardiovascular Disease Prevention European Guidelines, Health Prevention and Promotion Activities Program (Programa de Actividades Preventivas y de Promocion de la Salud) and the World Health Organisation document on physical activity and health. The Hamilton Anxiety Scale was used to measure anxiety. RESULTS: A total of 114 primary care physicians participated in the study. The average years of medical practice was 18.29 years (SD: 8.2). Adherence to cardiovascular screening was 70%. Adherence to cervix, breast and colorectal cancer screening was of 73%, 86% and 24%, respectively. Vaccination records were up to date in 51.8% of the participants. A total of 81.6% had a stable sexual partner and 75.2% were satisfied with their sexual relationships. The condom was always used by just 21.1% of the participants. Hamiltons anxiety scale was abnormal in 74.3% of the physicians, but 90.4% reported to feel good or very good. CONCLUSIONS: Adherence to cardiovascular and female cancer screening is adequate, but insufficient in colorectal cancer. Vaccination among the participants was adequate. PMID- 21239087 TI - [Bullous skin rash in a 61-year-old man]. PMID- 21239088 TI - Numeracy skills of nursing students. AB - Research has highlighted poor mathematical ability amongst qualified and student nurses. Three major classifications of errors: i)conceptual, ii)arithmetical and iii)computational have been identified. These errors involve being unable to formulate an equation from information given, unable to operate a given equation, or simple arithmetical errors respectively. The objective of this study was to determine if a sample of Australian second year undergraduate nursing students, from the state of Victoria, could accurately calculate drug dosages and perform some basic mathematical calculations that would be required in the workplace. A descriptive survey collecting demographical data, attitudes towards drug calculation performance and basic mathematical and drug calculation questions was administered to the 52 undergraduate nurses who participated in the study. The average score was 56.1%. Interestingly 63.5% of the students denied any drug calculations issues. On average those who completed a minimum of year 12 mathematics, or who had entered the course directly from secondary education achieved scores over 50%. Of all the errors that occurred 36.0% were conceptual, 38.9% were arithmetical and 25.1% were computational. Some Victorian nursing students currently have deficiencies in performing accurate calculations, with both arithmetical and conceptual errors, indicating fundamental flaws in their mathematical understanding and demonstrating an unacceptable level to practice safely. PMID- 21239089 TI - The infection control education needs of nursing students: an interview study with students and mentors. AB - AIM: To identify and explore the infection prevention and control education needs of nursing students as perceived by students and mentors. METHODS: Semi structured interviews were undertaken with 31 nursing students within one large university and 32 nurse mentors in one large NHS Trust. Interview transcripts were analysed using framework analysis. RESULTS: There were perceived deficits in both levels of knowledge and clinical skills but the emphasis placed on these differed between nursing students and nurse mentors. The use of small group and interactive methods for teaching and learning was preferred, in particular to encourage less confident students to participate more. Assessments in practice placements of specific skills were identified as a good teaching and learning tool by both students and mentors. Infection prevention and control education was considered to be a joint responsibility between the university and Trust, though there was acknowledgement that this joint working was not always evident. Clinical credibility was considered particularly important by mentors in those who teach students. CONCLUSION: There may be deficits in the education provided to nursing students in this area. Teaching and learning preferences and strategies for improving some areas of teaching and learning have been identified and several areas for future research have been suggested. PMID- 21239091 TI - A structured review of journal articles reporting outcomes using the University of Washington Quality of Life Scale. AB - The University of Washington Quality of Life Scale (UW-QoL) is one of the most frequently reported health-related quality of life (HR-QoL) questionnaires in head and neck cancer, and since its first publication in 1993 has been used in many different cohorts. There is a considerable amount of information to assimilate and, to date, we know of no attempt that has been made to summarise publications specific to its use in a peer review journal. The aim of this review was to systematically search published papers that report its use, identify common themes, and present a tabulated summary. Several search engines were used (PubMed, Medline, Medical-Journals.com, eMedicine), and 222 abstracts were found and hand searched. A total of 66 papers were eligible for inclusion, 21 on functional outcome, 25 on predictors of HR-QoL, 19 on development or validation of the questionnaire, and one clinical trial. The review includes a diversity of studies and a range of HR-QoL outcomes following head and neck cancer. It provides clinicians and their colleagues in multidisciplinary teams with a source of quick reference to relevant papers reporting the UW-QoL, and gives a short summary of the pertinent conclusions drawn from each paper. PMID- 21239090 TI - Effect of a high protein meat diet on muscle and cognitive functions: a randomised controlled dietary intervention trial in healthy men. AB - BACKGROUND: Recommendations to use other criteria than N-balance for defining protein requirements have been proposed. However, little evidence to support other measures such as physiological functions is available. OBJECTIVE: To investigate the effects of a usual (UP) versus a high protein (HP) diet on muscle function, cognitive function, quality of life and biochemical regulators of protein metabolism. DESIGN: A randomised intervention study was conducted with 23 healthy males (aged 19-31 yrs). All subjects consumed a Usual Protein (UP) diet (1.5 g protein/kg BW) for a 1-wk run-in period before the intervention period where they were assigned to either a UP or a High Protein (HP) diet (3.0 g protein/kg BW) for 3-wks with controlled intake of food and beverages. Blood and urine samples were taken along with measurements of physiological functions at baseline and at the end of the intervention period. RESULTS: The HP group improved their reaction time significantly compared with the UP group. Branched chain amino acids and phenylalanine in plasma were significantly increased following the HP diet, which may explain the improved reaction time. CONCLUSION: Healthy young males fed a HP diet improved reaction time. No adverse effects of the HP diet were observed. This trial was registered at www.clinicaltrials.gov as NCT00621231. PMID- 21239094 TI - The rationale, implementation, and effect of the Medicare CKD education benefit. AB - Although it affects <1% of the US population, stage 4 chronic kidney disease (CKD) has increased in prevalence in the United States, grown 67% between the early 1990s and the first part of this decade. It is important to consider new strategies to slow or halt this increase. A frameshift in patient care delivery is underway in kidney health care in the United States with a Medicare education benefit for patients with stage 4 CKD. This Medicare benefit is a unique program that has the potential to inform patients and families about CKD and prepare them for transitions in health states and kidney health care. For the greatest value of this benefit to be realized, it is critical for the health care community to accurately gauge patient understanding of CKD and provide curricula that are comprehensible and actionable for patients. This type of benefit is patient centered, yet it will succeed only with a willingness to review its effectiveness and revise it if needed. PMID- 21239093 TI - Role of nutritional status and inflammation in higher survival of African American and Hispanic hemodialysis patients. AB - BACKGROUND: Observational studies indicate greater survival in African American and Hispanic maintenance hemodialysis patients compared with their non-Hispanic white counterparts, although African Americans have shorter life expectancy than whites in the general population. We hypothesized that this apparent survival advantage is due to a more favorable nutritional/inflammatory profile in minority hemodialysis patients. STUDY DESIGN: We examined the association between race/ethnicity and 5-year survival before and after adjustment for case-mix and surrogates of the malnutrition-inflammation complex syndrome (MICS) using Cox regression with or without matched sampling in a large cohort of adult hemodialysis patients. SETTING & PARTICIPANTS: 124,029 adult hemodialysis patients, including 16% Hispanics, 49% non-Hispanic whites, and 35% African Americans. PREDICTORS: Race/ethnicity before and after adjustment for MICS, including values for body mass index, serum albumin, total iron-binding capacity, ferritin, creatinine, phosphorus, calcium, bicarbonate, white blood cell count, lymphocyte percentage, hemoglobin, and protein intake. OUTCOMES: 5-year (July 2001 to June 2006) survival. RESULTS: In dialysis patients, blacks and Hispanics had lower mortality overall than non-Hispanic whites after traditional case-mix adjustment. However, after additional control for MICS, Hispanics had mortality similar to non-Hispanic whites, and African Americans had even higher mortality. Unadjusted, case-mix-, and MICS-adjusted HRs for African Americans versus whites were 0.68 (95% CI, 0.66-0.69), 0.89 (95% CI, 0.86-0.91), and 1.06 (95% CI, 1.03 1.09) in the unmatched cohort and, 0.95 (95% CI, 0.90-0.99), 0.89 (95% CI, 0.84 0.94), and 1.16 (95% CI, 1.07-1.26) in the matched cohort, and for Hispanics versus whites, 0.66 (95% CI, 0.64-0.69), 0.84 (95% CI, 0.81-0.87), and 0.97 (95% CI, 0.94-1.00) in the unmatched cohort and 0.89 (95% CI, 0.84-0.95), 0.88 (95% CI, 0.83-0.95), and 0.98 (95% CI, 0.91-1.06) in the matched cohort, respectively. LIMITATIONS: Adjustment cannot be made for unmeasured confounders. CONCLUSIONS: Survival advantages of African American and Hispanic hemodialysis patients may be related to differences in nutritional and inflammatory status. Further studies are required to explore these differences. PMID- 21239095 TI - Early dialysis in Britain: Leeds and beyond. AB - In parallel with the experience in most countries, early clinical experiments with dialysis in Britain did not lead to general adoption of the treatment. After a decade, dialysis for acute kidney failure was re-established at Leeds General Infirmary under the direction of Dr Frank Parsons, who had been inspired by Dr John Merrill in Boston. The intervening period was not characterized by indifference to kidney failure, but was devoted to defining acute kidney failure and successfully applying "conservative" measures, such as dietary regimens based on the scientific understanding and teaching of the time. The circumstances influencing the start of dialysis therapy at Leeds in 1956 and subsequent events up to the early 1960s are discussed in relation to the national medical scene. PMID- 21239096 TI - Effect of sevelamer and calcium-based phosphate binders on coronary artery calcification and accumulation of circulating advanced glycation end products in hemodialysis patients. AB - BACKGROUND: Some trials have indicated that coronary artery calcification progresses more slowly in sevelamer-treated dialysis patients than in those using calcium-based binders. Effects of phosphate binders on circulating advanced glycation end products (AGEs) are unknown. STUDY DESIGN: Randomized trial with parallel-group design. SETTING & PARTICIPANTS: 183 adult (aged >20 years) patients on maintenance hemodialysis therapy at 12 dialysis facilities with a mean vintage of 118 +/- 89 (median, 108) months. Dialysate calcium concentration was 2.5 mEq/L, and dietary calcium was not controlled. INTERVENTION: Patients were randomly assigned to 12 months of treatment with sevelamer (n = 91) or calcium carbonate (n = 92). OUTCOMES & MEASUREMENTS: Primary outcome measures were change from baseline in coronary artery calcification score (CACS) determined at study entry and completion using multislice computed tomography and the proportion of patients with a >= 15% increase in CACS. Blood parameters were determined at study entry and 2-week intervals, and levels of plasma pentosidine, a representative AGE, were determined at study entry, 6 months, and study completion. RESULTS: 79 (86.8%) and 84 (91.3%) patients in the sevelamer and calcium-carbonate arms completed the treatment, respectively. Both binders were associated with an increase in mean CACS: 81.8 (95% CI, 42.9-120.6) and 194.0 (139.7-248.4), respectively (P < 0.001 for both). After adjustment for baseline values, the increase in the sevelamer group was 112.3 (45.8-178) less (P < 0.001). Percentages of patients with a >= 15% increase in CACS were 35% of the sevelamer group and 59% of the calcium-carbonate group (P = 0.002). Plasma pentosidine levels increased with calcium carbonate but not [corrected] sevelamer treatment (P < 0.001). Sevelamer use was associated with decreased risk of a >= 15% increase in CACS regardless of baseline blood parameters, pentosidine level, and CACS. LIMITATIONS: Treatment duration was relatively short, some sevelamer treated patients (7 of 79) received calcium carbonate, and washout could not be performed. CONCLUSIONS: The data suggest that sevelamer treatment slowed the increase in CACS and suppressed AGE accumulation. PMID- 21239098 TI - Predictors of body dissatisfaction and disordered eating in middle-aged women. AB - The purpose of the present article was to review empirical research on the factors associated with body dissatisfaction and disordered eating in middle-aged women. All of the factors identified are relevant to both of these significant women's health issues, suggesting that they are strongly linked. Most correlates and risk factors are similar to those found in younger women and encompass biological (e.g., body mass index), psychological (e.g., internalization of the thin ideal), and sociocultural influences (e.g., weight-related teasing). Additional factors of relevance to middle-aged women are menopausal status and aging anxiety, which reflect the distinct developmental challenges faced by women during midlife. PMID- 21239097 TI - Novel therapeutic approaches to lupus glomerulonephritis: translating animal models to clinical practice. AB - Systemic lupus erythematosus is a chronic autoimmune disease frequently affecting the kidney. Renal involvement is characterized by glomerular immune complex deposits and proliferative glomerulonephritis progressing to glomerulosclerosis and kidney failure. The development of systemic lupus erythematosus is regulated genetically, and lupus susceptibility genes have been linked to immune hyper responsiveness and loss of immune regulation. In addition to the systemic immune defects, recent studies in animal models show that susceptibility to lupus nephritis is influenced by intrinsic renal factors. Thus, renal cell responses to immune-mediated glomerular injury determine disease outcome. This supports the idea that future treatments for lupus nephritis need to focus on regulating end organ responses. The feasibility of this approach has been shown in animal models of kidney disease. For more than 50 years, the emphasis in management of lupus nephritis has been suppression of autoimmune responses and systemic control of inflammation. This review describes recently developed targeted drug delivery technologies and potential targets that can regulate glomerular cell responses, offering a novel therapeutic approach for lupus nephritis. PMID- 21239099 TI - Predictors of psychological treatment noncompletion among sexual offenders. AB - Research indicates that sexual offenders who do not complete their treatment are more likely to reoffend than are those who do complete it (Hanson et al., 2002; Losel & Schmucker, 2005). Several investigators have attempted to identify the characteristics of those individuals who do not complete treatment, most likely with the aim of preventing recidivism and the disastrous consequences that offenders' behavior has for their victims and for society at large. The objective of the present article is to review studies of treatment noncompletion among sexual offenders. We found that between 15% and 86% of sexual offenders do not complete treatment. In addition, results of the 18 studies reviewed diverge to the point where it is difficult to draw unequivocal conclusions about the variables related to the phenomenon. Only antisocial personality disorder and certain features of antisocial personality disorder appear to be related consistently and significantly to the discontinuation of treatment. These features are conceptualized under the three principles of effective treatment for general offenders. We present an analysis of the methodological limitations common to all of the studies reviewed in order to explain why confusion seems to reign supreme in the literature in this area at the present time, and we offer recommendations for future research in light of these limitations. PMID- 21239100 TI - Effects of early prevention programs on adult criminal offending: a meta analysis. AB - This meta-analysis investigated the long term effects of prevention programs conducted during early and middle childhood on criminal offending during adulthood. The analyses included 3611 participants in 9 programs. The effect size for adult criminal offending was significant, but small in magnitude (OR=1.26; 95% CI=1.06-1.50, p=.011). The effects of the programs on positive outcomes (academic attainment and involvement in productive activity, such as being engaged in school or work) were somewhat larger and more consistent than effects on crime (OR=1.36, 95% CI=1.20-1.55, p<.001). Several participant and program characteristics moderated the effectiveness of (early) prevention. Children who were more at-risk and those from a lower SES benefited more. Shorter, but more intensive programs, and programs that focus on social and behavioral skills, rather than on academic skills or family support, tend to produce larger effects. Taken together, these results indicate that early prevention programs can help put children on a more positive developmental trajectory that is maintained into adulthood, but there is still no convincing evidence that they can prevent adult crime. Implications of the findings for research, policy and clinical practice are discussed. PMID- 21239101 TI - Family medicine, 'La Herencia' and breast cancer; understanding the (dis)continuities of predictive genetics in Cuba. AB - Building on social science research examining the relationship between genetic knowledge, identity and the family this paper takes the cultural context of Cuba as a site for critical ethnographic engagement. The paper makes use of research working with a range of Cuban public and genetic professionals as part of a collaborative research project exploring the social and cultural context of health beliefs about breast cancer. It illuminates the contrasting ways in which genomic knowledge linked to an increased risk of breast cancer is perceived, communicated, and acted upon. It is argued that the particular meaning and significance of genetic risk linked to breast cancer in this context must be examined in relation to long standing institutional practices relating to public health care provision. The focus on 'the family' in the provision of Cuban health provides a particularly viable foundation for the expansion of what is described as 'community genetics', including the collation of family history details for common complex diseases such as breast cancer. Nevertheless specific public perceptions of risk related to breast cancer and the difficulties of discussing a diagnosis of cancer openly in the family point to the very specific challenges for the translation and application of predictive interventions in Cuba. In summary the dynamic interrelationship between public health, perceptions of risk or health beliefs about the causes of the disease and attitudes towards cancer diagnosis within the family point to both continuities and discontinuities in the way that genomic interventions linked to breast cancer are unfolding as part of a dynamic yet still ostensibly socialist project of health care in Cuba. PMID- 21239102 TI - University of the Pacific/Highland Hospital oral and maxillofacial surgery training program. PMID- 21239103 TI - Correlation of thrombomodulin expression and occlusion of the uterine artery for the treatment of leiomyoma. AB - OBJECTIVES: To determine the difference in thrombomodulin expression in the myometrium and in myoma; and to understand the correlation of anticoagulation/fibrinolytic function and the mechanism of uterine artery occlusion in the treatment of leiomyoma. STUDY DESIGN: Immunohistochemistry, western blotting and fluorescence quantitative polymerase chain reaction were used to investigate thrombomodulin protein expression and gene transcription in 15 female patients. RESULTS: Thrombomodulin was mainly expressed in endotheliocytes in the two types of tissues. According to western blotting data, the relative expression of protein of the myometrium was 1.49 times higher than that of the myoma. This difference was significant (P < 0.01). The relative transcription of thrombomodulin mRNA was 1.28 times higher in myometrial tissue than in myomal tissue (P < 0.05). CONCLUSIONS: Anticoagulation/fibrinolytic functions may be higher in the myometrium than in fibroids. This may be an important explanation for the mechanism of uterine artery occlusion. PMID- 21239104 TI - Can emerging level 1 evidence "discourage" elective nephron-sparing surgery for small renal tumors? PMID- 21239105 TI - Mozart, the brain, and the bladder: clinical usefulness of near-infrared spectroscopy for the detection of detrusor overactivity. PMID- 21239106 TI - New hydroxypyridinone-functionalized sepharoses as sorbing agents for hard metal ions. AB - Two new polymeric matrices functionalized with 3-hydroxy-4-pyridinone chelating units (HP-NH-SEPH and HP-C=NH-SEPH) have been prepared and studied for their chelating ability towards a set of metal ions (e.g. Fe(III), Al(III), and Th(IV)). Both matrices demonstrated excellent ability to complex these metal ions, but HP-NH-SEPH evidenced higher chelating capacity than HP-C=NH-SEPH. The corresponding metal-complex gels presented high stability in the pH range 3-7, and their chelating capacity followed the order, Fe(III)~Th(IV)>Al(III), in agreement with previously reported thermodynamics of the corresponding monomeric ligand-metal complexes in aqueous solution. These functionalized supports also showed capacity to be regenerated and reused. Thus, there are good perspectives for potential environmental and medical applications of these new metal sorbents. PMID- 21239107 TI - Liquid phase hydrodechlorination of chlorophenols at lower temperature on a novel Pd catalyst. AB - Pd catalyst supported on mesoporous silica-carbon nano-composite (Pd/MSCN) was prepared by the method of wet impregnation, and its activity for hydrodechlorination (HDC) of 2-chlorophenol, 4-chlorophenol and 2,4 dichlorophenol was evaluated at 258-313 K under ordinary hydrogen pressure by using triethylamine (Et(3)N) as a base additive. XRD analysis indicates that Pd/MSCN catalyst possesses the ordered mesostructure. Meanwhile, the results from TEM and H(2) chemisorption analysis indicate the high dispersion of Pd on MSCN with Pd nanoparticles whose average size is 3.2 nm. For the first time, the high activity of nano-size Pd on MSCN for HDC of chlorophenols was observed at 258 K. In addition, it was found that the inhibition effect of Et(3)N on HDC existed obviously, and can be efficiently reduced by stepwise addition of Et(3)N. The correlations of the dielectric constants of base and the polarity of solvent to the activity of Pd/MSCN for HDC of chlorophenols were obtained. PMID- 21239108 TI - The situation of hazardous chemical accidents in China between 2000 and 2006. AB - From the aspects of the total quantity of accidents, regional inequality, enterprises scale and environmental pollution accidents, this study makes an analysis of hazardous chemical accidents in China for the period spanning from 2000 to 2006. The following results are obtained: firstly, there were lots of accidents and fatalities in hazardous chemical business, i.e., the number of casualty accidents fluctuated between 200 and 600/year, the number of fatality fluctuated between 220 and 1100/year. Secondly, the accident rate in developed southeast coastal areas, e.g., Guangdong, Zhejiang and Jiangsu, was far higher than that in the northwest regions, e.g., Xizang, Xinjiang, and Qinghai. Thirdly, nearly 80% of dangerous chemical accidents had occurred in small and medium-sized enterprises (SMEs). Finally, various sudden environmental pollution accidents resulted from hazardous chemicals were frequent in recent years, causing a huge damage to human and property. Then, based on the readjustment of economic structure in the last decades, the development status of Occupational Health and Safety (OHS) in SMEs and other factors, the paper explores the main causes, which offers valuable insight into measures that should be taken to reduce hazardous chemical accidents. PMID- 21239110 TI - Role of peripheral 5-HT(4), 5-HT(6), and 5-HT(7) receptors in development and maintenance of secondary mechanical allodynia and hyperalgesia. AB - The role of 5-hydroxytryptamine (5-HT)(4), 5-HT(6), and 5-HT(7) receptors in formalin-induced secondary allodynia and hyperalgesia in rats was assessed. Formalin produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term secondary mechanical allodynia and hyperalgesia. Pretreatment (-10min) with cromoglycate (195-1950nmol/paw) partially inhibited acute nociceptive behaviors and completely prevented secondary allodynia and hyperalgesia on day 6 after injection. Ipsilateral peripheral pretreatment with the selective 5-HT(4) (ML-10302, 1-100nmol/paw), 5-HT(6) (EMD-386088, 0.001 0.01nmol/paw), and 5-HT(7) (LP-12, 0.01-100nmol/paw) receptor agonists significantly increased secondary allodynia and hyperalgesia in both paws. In contrast, ipsilateral peripheral pretreatment with the selective 5-HT(4) (GR 125487, 1-100nmol/paw), 5-HT(6) (SB-258585, 0.00001-0.001nmol/paw), and 5-HT(7) (SB-269970, 0.1-10nmol/paw) receptor antagonists significantly prevented formalin induced secondary allodynia and hyperalgesia in both paws. The pronociceptive effect of ML-10302 (100nmol/paw), EMD-386088 (0.01nmol/paw), and LP-12 (100nmol/paw) were completely prevented by GR-125487 (5-HT(4) antagonist, 1nmol/paw), SB-258585 (5-HT(6) antagonist, 0.00001nmol/paw), and SB-269970 (5 HT(7), antagonist, 0.01nmol/paw), respectively. Ipsilateral peripheral posttreatment with cromoglycate or GR-125487 (1-100nmol/paw), SB-258585 (0.001 0.1nmol/paw), and SB-269970 (0.1-10nmol/paw) reversed formalin-induced secondary allodynia and hyperalgesia in both paws. Results suggest that a barrage of afferent input induced by 5-HT at peripheral 5-HT(4), 5-HT(6), and 5-HT(7) receptors participate in the development and maintenance of formalin-induced long term secondary allodynia and hyperalgesia in the rat. 5-hydroxytryptamine (5-HT) released in peripheral tissues after formalin injection sensitized primary afferent neurons via 5-HT(4), 5-HT(6), and 5-HT(7) receptors, leading to development and maintenance of secondary allodynia and hyperalgesia. PMID- 21239109 TI - Evaluation of menstrual cycle effects on morphine and pentazocine analgesia. AB - Studies have demonstrated menstrual cycle influences on basal pain perception, but direct evidence of menstrual cycle influences on analgesic responses has not been reported in humans. Our aim was to determine whether the magnitude of morphine and pentazocine analgesia varied across the menstrual cycle. Sixty-five healthy women, 35 taking oral contraceptives (OC) and 30 normally cycling (NOC), underwent experimental pain assessment both before and after intravenous administration morphine (0.08mg/kg) or pentazocine (0.5mg/kg) compared to saline placebo. Both active drug and placebo were administered once during the follicular phase and once during the luteal phase. Measures of heat, ischemic, and pressure pain sensitivity were obtained before and after drug administration. Change scores in pain responses were computed to determine morphine and pentazocine analgesic responses, and medication side effects were recorded. The data were analyzed using mixed-model analyses of variance. NOC women showed slightly greater heat pain sensitivity in the follicular vs luteal phase, while the reverse pattern emerged for OC women (P=0.046). Also, OC women showed lower pressure pain thresholds compared to NOC women (P<0.05). Regarding analgesic responses, NOC women showed greater morphine analgesia for ischemic pain during the follicular vs the luteal phase (P=0.004). Likewise, side effects for morphine were significantly higher in NOC women in the follicular phase than in the luteal phase (P=0.02). These findings suggest that sex hormones may influence opioid responses; however, the effects vary across medications and pain modalities and are likely to be modest in magnitude. Limited menstrual cycle effects on baseline pain responses were observed; however, morphine analgesia and side effects were greater during the follicular phase. PMID- 21239111 TI - Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states. AB - Spinal cord injury (SCI) commonly results in the development of neuropathic pain, which can dramatically impair the quality of life for SCI patients. SCI-induced neuropathic pain can be manifested as both tactile allodynia (a painful sensation to a non-noxious stimulus) and hyperalgesia (an enhanced sensation to a painful stimulus). The mechanisms underlying these pain states are poorly understood. Clinical studies have shown that gabapentin, a drug that binds to the voltage gated calcium channel alpha-2-delta-1 subunit (Ca(v)alpha2delta-1) proteins is effective in the management of SCI-induced neuropathic pain. Accordingly, we hypothesized that tactile allodynia post SCI is mediated by an upregulation of Ca(v)alpha2delta-1 in dorsal spinal cord. To test this hypothesis, we examined whether SCI-induced dysregulation of spinal Ca(v)alpha2delta-1 plays a contributory role in below-level allodynia development in a rat spinal T9 contusion injury model. We found that Ca(v)alpha2delta-1 expression levels were significantly increased in L4-6 dorsal, but not ventral, spinal cord of SCI rats that correlated with tactile allodynia development in the hind paw plantar surface. Furthermore, both intrathecal gabapentin treatment and blocking SCI induced Ca(v)alpha2delta-1 protein upregulation by intrathecal Ca(v)alpha2delta-1 antisense oligodeoxynucleotides could reverse tactile allodynia in SCI rats. These findings support that SCI-induced Ca(v)alpha2delta-1 upregulation in spinal dorsal horn is a key component in mediating below-level neuropathic pain states, and selectively targeting this pathway may provide effective pain relief for SCI patients. Spinal cord contusion injury caused increased calcium channel Ca(v)alpha2delta-1 subunit expression in dorsal spinal cord that contributes to neuropathic pain states. PMID- 21239113 TI - A nationwide study of three invasive treatments for trigeminal neuralgia. AB - Invasive procedures for treatment of trigeminal neuralgia (TGN) include percutaneous radiofrequency thermocoagulation (PRT), partial sensory rhizotomy (PSR), and microvascular decompression (MVD). Using a nationwide discharge registry from The Netherlands, we assessed the frequency of use and patient characteristics, and evaluated treatment failure for each patient undergoing PRT, PSR, or MVD from January 2002 through December 2004. Only patients without a procedure in the year prior were included. Primary outcome was readmission for repeat procedures for TGN or known complications within 1year. Comparability of patient populations was assessed through propensity scores based on hospital, age, sex, and comorbidity. Conditional logistic regression matched on propensity score was used to calculate relative risks (RR) with 95% confidence intervals (CIs) for repeat procedures or complications. During the study period, 672 patients with TGN underwent PRT, 39 underwent PSR, and 87 underwent MVD. Hospital type was the predominant determinant of procedure type; age, sex, and comorbidity were weak predictors. The RR for repeat procedures for PSR was 0.21 (95% CI: 0.07 to 0.65) and for MVD was 0.13 (95% CI: 0.05 to 0.35) compared with PRT (RR 1). For complications, the RR of PSR was 5.36 (95% CI: 1.46 to 19.64) and of MVD was 4.40 (95% CI: 1.44 to 13.42). Sex, urbanization, and comorbidity did not influence prognosis, but hospital and surgical volume did. In conclusion, although PSR and MVD are associated with a lower risk of repeat procedure than PRT, they seem to be more prone to complications requiring hospital readmission. Microvascular decompression and partial sensory rhizotomy are associated with a lower risk of undergoing a repeat procedure compared with percutaneous radiofrequency thermocoagulation but are more prone to complications requiring readmission to hospital. PMID- 21239112 TI - Role for peroxynitrite in sphingosine-1-phosphate-induced hyperalgesia in rats. AB - Sphingosine-1-phosphate (S1P) is an important mediator of inflammation recently shown in in vitro studies to increase the excitability of small-diameter sensory neurons, at least in part, via activation of the S1P(1) receptor subtype. Activation of S1PR(1) has been reported to increase the formation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide (O(2)(.-)) and nitric oxide synthase (NOS)-derived nitric oxide (NO). This process favors the formation of peroxynitrite (ONOO(-) [PN]), a potent mediator of hyperalgesia associated with peripheral and central sensitization. The aims of our study were to determine whether S1P causes peripheral sensitization and thermal hyperalgesia via S1PR(1) activation and PN formation. Intraplantar injection of S1P in rats led to a time-dependent development of thermal hyperalgesia that was blocked by the S1PR(1) antagonist W146, but not its inactive enantiomer W140. The hyperalgesic effects of S1P were mimicked by intraplantar injection of the well characterized S1PR(1) agonist SEW2871. The development of S1P-induced hyperalgesia was blocked by apocynin, a NADPH oxidase inhibitor; N(G)-nitro-l arginine methyl ester, a nonselective NOS inhibitor; and by the potent PN decomposition catalysts (FeTM-4-PyP(5+) and MnTE-2-PyP(5+)). Our findings provide mechanistic insight into the signaling pathways engaged by S1P in the development of hyperalgesia and highlight the contribution of the S1P(1) receptor-to-PN signaling in this process. Sphingosine-1-phosphate (S1P)-induced hyperalgesia is mediated by S1P1 receptor activation and mitigated by inhibition or decomposition of peroxynitrite, providing a target pathway for novel pain management strategies. PMID- 21239114 TI - Persistent pain after joint replacement: prevalence, sensory qualities, and postoperative determinants. AB - Persistent postsurgical pain is a prevalent but underacknowledged condition. The aim of this study was to assess the prevalence, sensory qualities, and postoperative determinants of persistent pain at 3 to 4years after total knee replacement (TKR) and total hip replacement (THR). Patients completed a questionnaire with included the Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) Pain Scale, PainDetect Questionnaire, Short-Form McGill Pain Questionnaire, and questions about general health and socioeconomic status. A total of 632 TKR patients and 662 THR patients completed a questionnaire (response rate of 73%); 44% of TKR patients and 27% of THR patients reported experiencing persistent postsurgical pain of any severity, with 15% of TKR patients and 6% of THR patients reporting severe-extreme persistent pain. The persistent pain was most commonly described as aching, tender, and tiring, and only 6% of TKR patients and 1% of THR patients reported pain that was neuropathic in nature. Major depression and the number of pain problems elsewhere were found to be significant and independent postoperative determinants of persistent postsurgical pain. In conclusion, this study found that persistent postsurgical pain is common after joint replacement, although much of the pain is mild, infrequent, or an improvement on preoperative pain. The association between the number of pain problems elsewhere and the severity of persistent postsurgical pain suggests that patients with persistent postsurgical pain may have an underlying vulnerability to pain. A small percentage of patients have severe persistent pain after joint replacement, and this is associated with depression and the number of pain problems elsewhere. PMID- 21239115 TI - RNA interference-mediated gene silence of the NR1 subunit of the NMDA receptor by subcutaneous injection of vector-encoding short hairpin RNA reduces formalin induced nociception in the rat. AB - There is accumulating evidence to implicate the importance of N-methyl-d aspartate (NMDA) receptors to the induction and maintenance of central sensitization during pain states. However, the use of NMDA receptor antagonists can often be limited by serious central nervous system side effects. The development of peripheral NMDA receptor antagonists that do not interfere with central glutamate processing can avoid adverse effects of the central nervous system. RNA interference is an evolutionarily conserved mechanism for silencing gene expression in which a targeted mRNA is degraded by a double-stranded RNA sequence known as a small interfering RNA (siRNA). siRNAs can be derived from short hairpin (sh) RNAs, which can be expressed from plasmids or viral vectors to achieve long-term gene silencing. In this study, we examined the effect of gene silence and antinociception on formalin-induced pain by subcutaneous injection of vector-encoding shRNA targeting the NR1 subunit of the NMDA receptor. The results revealed that subcutaneous injection of vector-expressing NR1 shRNA could effectively diminish the nociception induced by formalin stimuli and inhibit gene expression of NR1 evidenced by a decreased level of mRNA and protein. The effect of antinociception and inhibition of NR1 expression by NR1 shRNA persisted for about 14days. The data suggest that NR1 shRNA has therapeutic potential to provide long-term treatment of pathological pain that is induced or maintained by peripheral nociceptor activity. Subcutaneous injection of NR1 short hairpin RNA has the therapeutic potential of providing long-term treatment of pathological pain that is induced or maintained by peripheral nociceptor activity. PMID- 21239116 TI - Effects of laser pulsing on analysis of steels by atom probe tomography. AB - When performing atom probe tomography analysis, laser pulsing was found very helpful for some types of steels, which are prone to premature sample failure under voltage pulsing. Rather accurate chemical compositions for both matrix and precipitates were obtained by voltage- and laser-pulsed mode. Some special issues on the effects of laser are discussed. A simple correction based on the (13)C(n+) and (10)B(n+) peak was used to quantify C in the carbide (M(23)C(6), M = Fe, Cr, Mo) and B in the boride (M(3)B(2), M = Mo, Fe, Cr, V). The mass resolution in laser mode is sufficient to resolve (56)Fe(2+) and (14)N(2)(1+) at 28Da. Small peak shifts were found in the spectrum due to reflectron aberrations. PMID- 21239117 TI - Atom probe tomography and transmission electron microscopy characterisation of precipitation in an Al-Cu-Li-Mg-Ag alloy. AB - State-of-the art atom probe tomography (APT) combined with transmission electron microscopy (TEM) were used to investigate the microstructure at different stages of the ageing process of an alloy of composition (at%) Al-1.68%Cu-4.62%Li-0.33%Mg 0.1%Ag. These alloys were shown to exhibit a complex microstructure of T(1) plates and several metastable phases, including theta' and S. We will highlight the early stages of clustering, precipitate interactions and possible solute segregation at the matrix/precipitate interfaces and detail the chemical composition of the different phases. PMID- 21239118 TI - Association of secondhand smoke exposure with nicotine dependence among Black smokers. AB - INTRODUCTION: Exposure to secondhand smoke (SHS) is influenced by norms and regulations, socioeconomic status and immediate personal interactions. SHS exposure may occur in various settings, including the living space, workplace, and other social environments. This study examines the association between exposure to SHS and nicotine dependence among current smokers. METHODS: A cross sectional sample of 246 Black (60% male and 40% female) current smokers age 40 and older, from Baltimore, Maryland and Washington, D.C, responded to an interviewer-administered questionnaire. We examined nicotine dependence using clinical guidelines based on the Diagnostic and Statistical Manual of Mental Disorders, Text Revision (2000). We performed multivariate logistic regression to assess the association between SHS and nicotine dependence. RESULTS: SHS exposure in the current home environment and exposure in settings outside the home, as well as difficulty to quit smoking and heaviness of smoking, were associated with nicotine dependence. After adjustment for age, gender, education, income, employment status, current alcohol consumption, history of marijuana use, and number of cigarettes smoked per day; exposure to SHS at home only, and in both current home environment and other settings, continued to be associated with clinically-defined nicotine dependence (OR=2.25; 95% CI 1.05, 4.86 vs. OR=2.31; 95% CI 1.03, 5.18), respectively. DISCUSSION: These findings highlight the relative importance of examining SHS exposure in personal (residential and automobile) and public (workplace and outdoor) settings by current smokers. Promotion of smoke-free environments may reduce the prevalence of nicotine dependence among current smokers. PMID- 21239119 TI - Differences in smoking expectancies in smokers with and without a history of major depression. AB - Adults with depression evidence higher rates of smoking and lower quit rates than adults without depression. Little is known about the relationship between depression and smoking beliefs which are associated with both smoking and smoking cessation behavior. The primary aim of this study was to examine whether adult smokers with and without a history of major depressive disorder (MDD) differ in their endorsement of smoking expectancies. The secondary aim of the study was to examine whether there were interactions of depression and gender on the endorsement of expectancies. Adult cigarette smokers participating in a clinical trial of Selegiline hydrochloride for smoking cessation were classified as having a history of depression (MDD+, n=26) or no history of depression (MDD-, n=75). History of depression and smoking expectancies were assessed prior to randomization into the clinical trial. There was a main effect of depression on 7 out of 10 of the assessed beliefs. MDD+ smokers, compared to MDD- smokers, more strongly endorsed beliefs that smoking reduces negative affect, boredom, and cravings; smoking increases stimulation and social facilitation; smoking helps to manage cravings and weight; and that the taste is enjoyable. The main effect of gender and the interactive effect of depression and gender were not significant. Incorporating expectancies into cognitive-behavioral treatments for smoking cessation may be useful for smokers with a history of depression. PMID- 21239120 TI - A healthier oil combination and konjac gel as functional ingredients in low-fat pork liver pate. AB - Healthier lipid pates were formulated by reducing the fat content and/or replacing the pork backfat by a healthier oil combination (olive, linseed and fish oils) and konjac gel (0-15%). The reformulation results were evaluated by composition (proximate analysis and fatty acid profile), technological properties (emulsion stability, colour, and texture), microbiological and sensory parameters of the pates. Pates with partial or total replacement of pork backfat had lower levels of saturated fatty acids (SFA) (27.4% and 21.3%) and monounsaturated fatty acids (MUFA) (49.8% and 42.5%), and higher levels of polyunsaturated fatty acids (PUFA) (22.4% and 35.6%) compared with control pates (32.2%, 58.2% and 9.04% respectively). The n-6/n-3 PUFA ratio was decreased from 6.78 (in control pates) to 0.79 and 0.48 when partial and total pork backfat respectively was replaced by a healthier oil combination. Although emulsion stability was affected by the formulation, in general all pates had good fat and water binding properties. The fat reduction produced a softer and more spreadable pate, although no effect on penetration parameters was observed after by pork fat replacement by a healthier oil combination. The addition of 15% of konjac gel produced stiffer structures (as compared with 0 and 7%) which are very close to those of the control samples. No microbiological limitations were produced by the reformulation process, obtaining pates with acceptable sensory characteristics, similar to the control sample. PMID- 21239121 TI - Determinants of the underreporting of alcohol consumption by HIV/HCV co-infected patients during face-to-face medical interviews: the role of the physician. AB - OBJECTIVES: The objective of this study was to assess to what extent HIV/HCV co infected patients underreport alcohol use to their physician with respect to self reports from self-administered questionnaires (SAQ) and identify correlates of alcohol underreporting during face-to-face medical interviews (FMI). DESIGN: ANRS CO13-HEPAVIH is a French multi-center cohort of HIV/HCV co-infected patients. METHODS: Data were collected at enrolment using both SAQ and FMI while clinical data were retrieved from medical records. Alcohol consumption was assessed through SAQ and compared with FMI patient reports. Correlates of underreporting alcohol consumption during FMI with respect to SAQ were identified using logistic regression analysis. RESULTS: Among 544 patients, 37% were classified as alcohol abusers according to AUDIT-C in the SAQ. During FMI, 14% underreported alcohol consumption. The following correlates were independently associated with underreporting alcohol consumption in FMI: not receiving HIV treatment, being followed up by a hepatologist for HCV infection and reporting a history of injecting drug use. CONCLUSIONS: These results highlight the difficulties in alcohol consumption assessment which HCV specialists may face when suggesting to their HIV/HCV co-infected patients that they cease drinking completely. Patient awareness about the real need to reduce their alcohol use before starting HCV therapy may also contribute to underreporting. Innovative strategies for alcohol risk-reduction, including the promotion of controlled consumption and access to multidisciplinary teams, should be implemented for HIV/HCV co-infected patients in order to reduce barriers to HCV treatment. PMID- 21239122 TI - Presence of the oral bacterium Capnocytophaga canimorsus in the tooth plaque of canines. AB - Capnocytophaga canimorsus is a potentially pathogenic microorganism when transmitted to humans from the oral cavity of canines. Although there is some knowledge about the frequency of occurrence in canines, it is uncertain whether there is a correlation between its occurrence and lifestyle, health, or breed of dog. Samples of tooth plaque from a total of 131 canines were collected, cultured on selective media, and tested using physiological and molecular analyses to help discern the presence of C. canimorsus. Phylogenetic analyses determined that 49.2% of canines sampled carried a species of Capnocytophaga and 21.7% of the canines sampled in this study carried C. canimorsus. Statistical analyses found that male dogs and those that are neutered and spayed are more likely to host Capnocytophaga species. The data also suggested that breed was a statistically significant predictor of C. canimorsus, with the smaller breeds more likely to carry the potential pathogen. In addition, three "human" species of Capnocytophaga; C. ochracea, C. haemolytica, and one isolate of either C. gingivalis or C. granulosa were cultured from five canines. Sixteen canines sampled carried an unidentified Capnocytophaga species, with the sequences from all isolates forming a well-defined phylogenetic clade with 100% bootstrap support that may well represent a new species of Capnocytophaga. PMID- 21239123 TI - Age estimation using cytochrome c oxidase activity analysis. AB - Recently, in the field of forensic medicine the number of unidentified cadavers has increased due to mass disasters and international terrorism. In addition to the conventional anthropological methods, a simple and precise method to estimate the age of these unidentified cadavers to assist in the personal identification is necessary. On the other hand, many researchers have reported that mitochondrial respiratory activity decreases with aging because of the production of reactive oxidative species in the process of ATP generation. Therefore, it may be possible for us to estimate human age by analyzing mitochondrial activity. In this report we attempted to analyze cytochrome c oxidase (CCO) activity, and the amount of protein and mRNA expression in various aged rats. The age of human subjects was estimated through the analysis of human CCO activity from 28 actual forensic cases. The CCO activity, the amount of protein and the mRNA expression increased in the 3rd week and decreased afterwards in rats. Furthermore, human CCO activity was decreased gradually with aging. Therefore, CCO activity analysis may be useful for age estimation in forensic cases. PMID- 21239124 TI - Surgical treatment of acute recurrent throat infections in children. AB - OBJECTIVE: The purpose of this study was to define the contribute of surgery and watchful waiting in the treatment of feverish episodes and other clinical manifestations related to acute recurrent throat infections in children. METHODS: An observational, retrospective and multi-centric study was carried out on 407 subjects, aged 2-11, with a minimum two-year follow-up. Chi square test and Fisher's test were used for the statistical analysis. RESULTS: Watchful waiting prevented, similarly to surgery, recurrences of feverish episodes, but did not favourably impact on other clinical manifestations (respiratory obstruction, otitis media, group A beta hemolyticus streptococcus positive laboratory findings) as compared to surgery (p<0.001). CONCLUSIONS: The higher effectiveness of surgical treatment, as compared to watchful waiting, was documented in the study patients, considering all the clinical manifestations related to acute recurrent throat infections. PMID- 21239125 TI - Management of metastasis to the thyroid gland. AB - We present 4 cases with metastasis to the thyroid gland (MTG), and discussed the diagnosis and treatment of MTG. It is not always easy to correctly diagnose MTG from primary thyroid cancer. Although fine needle aspiration biopsy is useful for the diagnosis of MTG, it is important to take other imaging studies and/or tumor marker into consideration. Thyroidectomy for MTG is controversial, but the good indication of thyroidectomy is considered for the patient whose primary tumor is controllable. Thyroidectomy may also be useful even for the patient with uncontrollable disease to prevent respiratory and swallowing problems caused by MTG. PMID- 21239126 TI - Efficacy and tolerability of modified Atkins diet in Japanese children with medication-resistant epilepsy. AB - Ten Japanese patients aged 1.5-17years with medication-resistant epilepsy were placed on the modified Atkins diet (MAD) for 3weeks during admission to our hospital. Dietary carbohydrate was restricted to 10g per day. We studied the efficacy of the diet regarding the seizure frequency and tolerability of the diet at the end of the 3weeks on the diet. Those who decided to continue the MAD at the time of discharge were followed up in the out-patient clinic to observe the effect of the diet on the seizure frequency. Three of the 10 patients could not continue the diet during the 3-week admission; one had rotavirus enterocolitis and the other 2 disliked the diet. Among the remaining 7 patients who could continue the diet for 3weeks, 3 achieved the seizure reduction; 2 became seizure free and 1 showed about 75% reduction in the seizure frequency within 10days on the diet. All of these 3 patients continued the diet after the 3-week admission. The other 4 patients did not show a reduction of the seizure frequency by the end of the 3weeks on the diet. Two of them discontinued the diet on discharge. The remaining 2 still continued the diet at home and one became seizure-free 3months after the start of the diet. In total, 4 of 10 patients achieved>75% reduction in the seizure frequency, although relapse occurred in 2 of the patients, at 5months and 2years after seizure reduction, respectively. The MAD was effective and well tolerated in children with medication-resistant epilepsy in Japan. PMID- 21239128 TI - [Efficacy of first-line radiation for non-resectable carotid paraganglioma]. AB - BACKGROUND: Carotid paragangliomas are rare. Surgical resection is the primary treatment. However, when surgery is impossible, radiation therapy is an alternative potentially enabling local control with less morbidity. We report a case of good local control of an unresectable paraganglioma after external beam radiation. CASE REPORT: A 72-year-old-woman, had a 4-year history of right facial palsy associated with pulsatile tinnitus, episodic ear bleeding and ipsilateral hearing loss. Physical examination revealed a retro-mandibular and sub-mastoid pulsatile mass. Magnetic resonance imaging showed a large carotid paraganglioma involving the temporal bone. Since surgical resection was impossible, our patient was given external beam radiation therapy at a dose of 60 Gy. At 12 months follow up, local control was good without significant toxicity. CONCLUSION: External beam radiation therapy seems to be a good alternative therapy for local control of carotid paragangliomas if surgical resection is impossible. PMID- 21239127 TI - [Direct inhibitors of thrombin, hirudin, bivalirudin, and dabigatran etexilate]. AB - Thrombin inhibition is an important objective in the prevention and treatment of thrombosis. A new molecule, dabigatran etexilate or Pradaxa((r)), has been recently licensed for thromboprophylaxis in major orthopedic surgery in several countries but not in the USA. In contrast, the FDA has approved it for prevention in patients with non-valvular atrial fibrillation. This new orally active anticoagulant is being developed for the treatment of venous thromboembolism and acute coronary syndromes in patients with non-valvular atrial fibrillation. Dabigatran is a reversible inhibitor of free thrombin and clot-bound thrombin. An oral thrombin inhibitor melagatran is no longer available due to hepatic toxicity. Several other thrombin inhibitors are used via parenteral administration: lepirudine and desirudine, bivalirudine and argatroban. They are mostly given to patients with heparin-induced thrombocytopenia (HIT). Bivalirudine is used for acute coronary syndrome in patients undergoing percutaneous interventions. The main pharmacologic characteristics of thrombin inhibitor agents are presented focusing on dabigatran etexilate and including the main results of clinical trials. PMID- 21239129 TI - Estimation of the left ventricular diastolic function with cardiac MDCT: correlation of the slope of the time-enhancement-curve with the mitral annulus diastolic velocity. AB - Patients with diastolic heart failure tend to have a poor outcome, similar to that for patients with systolic heart failure. The aim of this study was to explore the ability of MDCT to estimate the left ventricular diastolic function. Thirty patients with suspected coronary artery disease underwent MDCT and echocardiography. The early transmitral flow velocities (E) and the velocity of mitral annulus early diastolic motion (e') were measured in order to evaluate the diastolic function. The scanning delay of CT was determined using a test injection technique. The aortic enhancement was measured over the aortic-root lumen, and it was plotted over time to yield a time-enhancement-curve. A gamma variate function was then fit to the time-enhancement-curve and thereafter both the 'slope' of enhancement for each patient and the region of interest [ROI] were calculated. According to a univariate analysis, the slope of the time-enhancement curve was found to correlate with the e' (r = 0.686, P = 0.000) and E/e' (r = 0.482, P = 0.007), however, no significant correlation was observed with the systolic parameters of the left ventricle. These results indicate that the slope of the time-enhancement-curve in the aorta significantly correlates with e', i.e. the diastolic parameters, which are independent of the systolic parameters. Based on these findings, we propose that the slope of the time-enhancement-curve may serve as a parameter for the left ventricular diastolic function on MDCT. PMID- 21239130 TI - Local thermal ablation of renal cell carcinoma. AB - PURPOSE: With evolving local thermal ablation technology, the clinical application of thermal ablation has been actively investigated in the treatment for renal cell carcinoma. We review the evolution and current status of radiofrequency ablation and microwave ablation for renal cell carcinoma. MATERIALS AND METHODS: All articles published in English on radiofrequency ablation or microwave ablation as a treatment for renal cell carcinoma were identified with a MEDLINE(r) and PubMed(r) search from 1990 to 2010. RESULTS: Local thermal ablation has several advantages, including keeping more normal renal units, relatively simple operation, easy tolerance, fewer complications, a shorter hospitalization and convalescence period. Long-term data has determined radiofrequency ablation is responsible for poor surgical candidates with renal cell carcinoma, however, tumor size, location and shape might affect the efficacy of radiofrequency ablation. Microwave ablation can induce large ablation volumes and yield good local tumor control. Associated complications appear to be low. CONCLUSIONS: Local ablative approaches seem to represent an attractive alternative to extirpative surgery for the treatment of small renal neoplasms in select patients. Potential developments include concepts to improve the accuracy and effectiveness of thermal ablation by improving the guiding, monitoring capabilities and detection capacity of multi-center lesions to provide at least equivalent cancer control to conventional surgery. PMID- 21239131 TI - Comparison of neutral and positive enteral contrast media for MDCT enteroclysis. AB - OBJECTIVE: To compare neutral and positive enteral contrast media for MDCT enteroclysis (MDCTE) in various small bowel diseases. MATERIALS AND METHODS: 40 patients with suspicion of small bowel diseases were divided randomly into two equal groups. In one group, water was used as neutral enteral contrast and in other group, 2% water soluble iodinated contrast was used as positive enteral contrast. All MDCTE were done on a 16-slice multidetector row CT unit. The findings of MDCTE were compared with the standards of reference. RESULTS: There were 12 cases of abdominal tuberculosis (30%), 5 cases of bowel masses (12%), 4 cases of Crohn's disease (10%), 3 cases of small bowel adhesions (7%), 2 cases of midgut volvulus (5%), 2 cases of segmental enteritis (5%) and 12 of all cases (30%) were normal. There was no statistically significant difference between neutral and positive enteral contrast with regards to bowel distention, contrast reflux and evaluation of duodenum. Abnormal bowel wall enhancement was appreciated only with use of neutral enteral contrast (n=12). Evaluation of ileocaecal junction was possible in all 20 patients (100%) with positive enteral contrast but in only 17 patients (85%) with neutral enteral contrast. Overall sensitivity and specificity of MDCTE with use of neutral contrast medium (100 and 88% respectively) was greater for evaluation of small bowel diseases, when compared to MDCTE using positive enteral contrast medium (92.8 and 83.3% respectively). CONCLUSIONS: Water is a good enteral contrast medium for MDCT enteroclysis examination and allows better evaluation of abnormal bowel wall enhancement. Ileocaecal junction evaluation is better with positive enteral contrast medium. PMID- 21239132 TI - Tapping the potential of intact cell mass spectrometry with a combined data analytical approach applied to Yersinia spp.: detection, differentiation and identification of Y. pestis. AB - In the everyday routine of an analytic lab, one is often confronted with the challenge to identify an unknown microbial sample lacking prior information to set the search limits. In the present work, we propose a workflow, which uses the spectral diversity of a commercial database (SARAMIS) to narrow down the search field at a certain taxonomic level, followed by a refined classification by supervised modelling. As supervised learning algorithm, we have chosen a shrinkage discriminant analysis approach, which takes collinearity of the data into account and provides a scoring system for biomarker ranking. This ranking can be used to tailor specific biomarker subsets, which optimize discrimination between subgroups, allowing a weighting of misclassification. The suitability of the approach was verified based on a dataset containing the mass spectra of three Yersinia species Yersinia enterocolitica, Y. pseudotuberculosis and Yersinia pestis. Thereby, we laid the emphasis on the discrimination between the highly related species Yersinia pseudotuberculosis and Y. pestis. All three species were correctly identified at the genus level by the commercial database. Whereas Y. enterocolitica was correctly identified at the species level, discrimination between the highly related Y. pseudotuberculosis and Y. pestis strains was ambiguous. With the use of the supervised modelling approach, we were able to accurately discriminate all the species even when grown under different culture conditions. PMID- 21239133 TI - Effectiveness and impact of networked communication interventions in young people with mental health conditions: a systematic review. AB - OBJECTIVE: Examine the effectiveness and impacts of the networked communication technologies used by health care professionals for the treatment of adolescents/young adults with mental health disorders. METHODS: Nine electronic databases were searched. Quantitative and qualitative study designs were included, technologies were described and a narrative synthesis of all included studies was undertaken. RESULTS: 20,925 papers were identified from which 12 interventions met the inclusion criteria. Three categories of networked communication were identified: email and/or web-based electronic diary (n=6); videoconference (n=5); and virtual reality (n=1). Three studies reported statistically significant improvements in symptoms post intervention; all involved email communication. Patients were willing to use networked communication in routine care in nine studies. CONCLUSIONS: Networked communication technologies can increase the opportunity for communication between patient and health care professionals. Limited improvements in quality of life and continuity of care for patients were reported. Patients and health care professionals expressed some satisfaction with technologies. Further research exploring concerns over privacy and security is needed. PRACTICE IMPLICATIONS: Networked communication technologies have the potential to be a useful addition to mental health services delivery, however the impact and effectiveness of these technologies is inconclusive. PMID- 21239134 TI - Health information seeking: a review of measures and methods. AB - OBJECTIVE: Outlines the methods and measures commonly used to study active health information seeking and prescribes important considerations in advancing the study of patient information seeking. METHODS: A systematic review of the literature from 1978 to 2010. A single bibliometric database, PsychInfo, identified 648 articles of health information seeking. The 129 articles included in the review were coded by type of sample, measures (n=12) utilized to study health information seeking, and types of study methods (n=5). RESULTS: A majority of studies used non-clinical samples and measured general health information seeking (i.e., whether the participant engaged in a search for health information) through cross-sectional study designs. CONCLUSIONS: There are varying samples, measures, and designs used to identify those who do or do not seek health information. Future research should look into how health information seeking influences health management and should uncover the social and relational functions of health information seeking using more advanced (and less routinely applied) measures and methods of studying health information seeking. PRACTICE IMPLICATIONS: More people are actively searching for health information and health providers should address this in their discussions with patients. PMID- 21239135 TI - Slicing it thin: new methods for brief sampling analysis using RIAS-coded medical dialogue. AB - OBJECTIVE: To explore the relationship between one-minute slices and full-session interaction and the predictive validity of the slices to ratings of affect and rapport. METHODS: Third-year medical students (n=253) were videotaped during an OSCE. All interaction was coded using the Roter Interaction Analysis System (RIAS) and samples were drawn at minutes 1, 5, and 9 and extracted from the coded database. The slices were related in multivariate analysis to full-session interaction, corrected for slice content, and correlated with affect ratings of participants and independently rated judgments of rapport. RESULTS: One-minute slices explained 33% of full-session variance in student interaction and 30% of variance in standardized patient interaction. Slices were significantly correlated with affective ratings of participants and independent judgments of rapport in a similar pattern as full-session interaction analysis. CONCLUSIONS: One-minute slices of interaction can provide a meaningful degree of insight into OSCE session communication with both concurrent and predictive validity to ratings of session affect and rapport. PRACTICE IMPLICATIONS: Evidence of concurrent and predictive validity further supports use of this approach as a research tool that provides an efficient means of analyzing processes of care, examining variation in communication throughout a visit and predicting visit outcomes. PMID- 21239136 TI - When chest pain reveals a Fabry disease. PMID- 21239137 TI - [Intramedullary tuberculoma diagnosis and treatment: interest of neurosurgery?]. PMID- 21239138 TI - [Rectus sheath hematoma: A lethal but unknown condition in liver cirrhotic patients]. PMID- 21239139 TI - [Giant cell arteritis-related upper/lower limb vasculitis]. AB - Upper/lower limb vasculitis has been considered an uncommon manifestation of giant cell arteritis, occurring in 3 to 16% of patients. Upper/lower limb vasculitis is still associated with significant morbidity, leading to limb/toe amputation in 5.6 to 15.8% of patients. Yearly clinical vascular examination should be performed systematically to screen upper/lower limb vasculitis at an early stage in patients with giant cell arteritis. Duplex ultrasound has proved to be a reliable non-invasive imaging method for detecting arterial stenoses of the upper/lower limbs in patients with giant cell arteritis. Patients with giant cell arteritis-related upper/lower limb vasculitis should undergo routine investigations to detect underlying aortic complications, concomitant aortic localizations being encountered in more than 50% of cases. Prednisone is the first-line therapy at an initial dose of 0.7-1 mg/kg daily. Prevention of platelet aggregation with low-dose aspirin is potentially effective in preventing ischemic complications of GCA. The indication of surgical therapy should be based on the severity of giant cell arteritis-related upper/lower limb clinical symptoms to avoid unnecessary morbidity in the course of interventional therapy. PMID- 21239140 TI - A review of behavioral interventions for the treatment of aggression in individuals with developmental disabilities. AB - Aggression can present as a significant problem behavior in individuals with a diagnosis of developmental disability. Much research has focused on the prevalence of aggression in individuals with varying degrees of severity of intellectual disability (AD), autism spectrum disorders (ASD) and co-morbidity of ID and ASD. Research has also focused on the impact of aggressive behavior on individuals' development including cognitive, adaptive and social functioning. The literature on Applied Behavior Analysis provides abundant examples of various interventions that are effective in reducing or eliminating aggressive behavior across a range of ages and degrees of developmental disabilities. Many interventions report success using antecedent alterations, reinforcement-based strategies and consequence manipulations. The current review provides a focused, comprehensive examination of aggressive behavior intervention research for individuals with developmental disabilities aged 3-18 years published between 1980 and 2009. PMID- 21239141 TI - Bottom-up learning of explicit knowledge using a Bayesian algorithm and a new Hebbian learning rule. AB - The goal of this article is to propose a new cognitive model that focuses on bottom-up learning of explicit knowledge (i.e., the transformation of implicit knowledge into explicit knowledge). This phenomenon has recently received much attention in empirical research that was not accompanied by a corresponding work effort in cognitive modeling. The new model is called TEnsor LEarning of CAusal STructure (TELECAST). In TELECAST, implicit processing is modeled using an unsupervised connectionist network (the Joint Probability EXtractor: JPEX) while explicit (causal) knowledge is implemented using a Bayesian belief network (which is built online using JPEX). Every task is simultaneously processed explicitly and implicitly and the results are integrated to provide the model output. Here, TELECAST is used to simulate a causal inference task and two serial reaction time experiments. PMID- 21239142 TI - A Peer Review Intervention for Monitoring and Evaluating sites (PRIME) that improved randomized controlled trial conduct and performance. AB - OBJECTIVE: Good clinical practice (GCP) guidelines emphasize trial site monitoring, although the implementation is unspecified and evidence for benefit is sparse. We aimed to develop a site monitoring process using peer reviewers to improve staff training, site performance, data collection, and GCP compliance. STUDY DESIGN AND SETTING: The Peer Review Intervention for Monitoring and Evaluating sites (PRIME) team observed and gave feedback on trial recruitment and follow-up appointments, held staff meetings, and examined documentation during annual 2-day site visits. The intervention was evaluated in the ProtecT trial, a UK randomized controlled trial of localized prostate cancer treatments (ISRCTN20141297). The ProtecT coordinator and senior nurses conducted three monitoring rounds at eight sites (2004-2007). The process evaluation used PRIME report findings, trial databases, resource use, and a site nurse survey. RESULTS: Adverse findings decreased across all sites from 44 in round 1 to 19 in round 3. Most findings related to protocol adherence or site organizational issues, including improvements in eligibility criteria application and data collection. Staff found site monitoring acceptable and made changes after reviews. CONCLUSION: The PRIME process used observation by peer reviewers to improve protocol adherence and train site staff, which increased trial performance and consistency. PMID- 21239143 TI - Optimizing vs. matching: response strategy in a probabilistic learning task is associated with negative symptoms of schizophrenia. AB - Previous research indicates that behavioral performance in simple probability learning tasks can be organized into response strategy classifications that are thought to predict important personal characteristics and individual differences. Typically, relatively small proportion of subjects can be identified as optimizers for effectively exploiting the environment and choosing the more rewarding stimulus nearly all of the time. In contrast, the vast majority of subjects behaves sub-optimally and adopts the matching or super-matching strategy, apportioning their responses in a way that matches or slightly exceeds the probabilities of reinforcement. In the present study, we administered a two choice probability learning paradigm to 51 individuals with schizophrenia (SZ) and 29 healthy controls (NC) to examine whether there are differences in the proportion of subjects falling into these response strategy classifications, and to determine whether task performance is differentially associated with symptom severity and neuropsychological functioning. Although the sample of SZ patients did not differ from NC in overall rate of learning or end performance, significant clinical differences emerged when patients were divided into optimizing, super-matching and matching subgroups based upon task performance. Patients classified as optimizers, who adopted the most advantageous learning strategy, exhibited higher levels of positive and negative symptoms than their matching and super-matching counterparts. Importantly, when both positive and negative symptoms were considered together, only negative symptom severity was a significant predictor of whether a subject would behave optimally, with each one standard deviation increase in negative symptoms increasing the odds of a patient being an optimizer by as much as 80%. These data provide a rare example of a greater clinical impairment being associated with better behavioral performance. PMID- 21239144 TI - ADAMTSL3 as a candidate gene for schizophrenia: gene sequencing and ultra-high density association analysis by imputation. AB - We previously reported an association with a putative functional variant in the ADAMTSL3 gene, just below genome-wide significance in a genome-wide association study of schizophrenia. As variants impacting the function of ADAMTSL3 (a disintegrin-like and metalloprotease domain with thrombospondin type I motifs like-3) could illuminate a novel disease mechanism and a potentially specific target, we have used complementary approaches to further evaluate the association. We imputed genotypes and performed high density association analysis using data from the HapMap and 1000 genomes projects. To review all variants that could potentially cause the association, and to identify additional possible pathogenic rare variants, we sequenced ADAMTSL3 in 92 schizophrenics. A total of 71 ADAMTSL3 variants were identified by sequencing, many were also seen in the 1000 genomes data, but 26 were novel. None of the variants identified by re sequencing was in strong linkage disequilibrium (LD) with the associated markers. Imputation analysis refined association between ADAMTSL3 and schizophrenia, and highlighted additional common variants with similar levels of association. We evaluated the functional consequences of all variants identified by sequencing, or showing direct or imputed association. The strongest evidence for function remained with the originally associated variant, rs950169, suggesting that this variant may be causal of the association. Rare variants were also identified with possible functional impact. Our study confirms ADAMTSL3 as a candidate for further investigation in schizophrenia, using the variants identified here. The utility of imputation analysis is demonstrated, and we recommend wider use of this method to re-evaluate the existing canon of suggestive schizophrenia associations. PMID- 21239145 TI - The association between general psychological distress and delusional-like experiences: a large population-based study. AB - BACKGROUND: Delusional-like experiences (DLE) are prevalent in the community, and are associated with the both clinical and subclinical depression and anxiety. The aim of this study was to explore the association between general psychological distress and DLE adjusting for the presence of psychiatric disorders in a large population-based sample. METHODS: Subjects were drawn from the Australian National Survey of Mental Health and Wellbeing 2007 (n=8841). DLE were assessed using a modified World Mental Health Composite International Diagnostic Interview (CIDI) schedule, and psychological distress was measured using the Kessler-10 (K10) short questionnaire. We examined the relationship between DLE and quartiles of K10 scores using logistic regression, adjusting for depression and anxiety disorders, and other potential confounding factors. The analyses were also repeated in the subgroup of the sample who were free of lifetime clinical diagnoses. RESULTS: Of the participants, 776 (8.4%) endorsed one or more DLE. Individuals with moderate and severe psychological distress were two to three times more likely to endorse DLE. The association remained significant after adjusting for potential confounding factors, and in the subgroup of the population who remained after excluding those who met criteria for lifetime diagnosis for any mental disorder. CONCLUSION: While DLE have traditionally been associated with psychotic disorders, our results suggest that they are associated with non-specific psychological distress in otherwise-well individuals. PMID- 21239146 TI - Rising incidence of Staphylococcus aureus with reduced susceptibility to vancomycin and susceptibility to antibiotics: a global analysis 2004-2009. AB - During 2004-2009, 20004 isolates of Staphylococcus aureus were collected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T.). Of these isolates, 8249 (41.2%) were meticillin-resistant S. aureus (MRSA) and 11755 (58.8%) were meticillin-susceptible S. aureus (MSSA). A total of 4.0%, 5.3% and 3.0% of all S. aureus, MRSA and MSSA isolates, respectively, exhibited vancomycin minimum inhibitory concentrations (MICs) >= 2 MUg/mL. Whilst no vancomycin-resistant S. aureus were encountered in this study and the majority of these isolates remained susceptible to vancomycin at the Clinical and Laboratory Standards (CLSI) breakpoint of 2 MUg/mL, the total number of isolates with MICs creeping up to 2 MUg/mL and above increased in all S. aureus from 4.0% in 2004 to 7.7% in 2009 (P < 0.001). Moreover, in MRSA this phenotype increased from 5.6% in 2004 to 11.1% in 2009 (P < 0.001). The increase was also notable for MSSA, which rose from 2.6% in 2004 to 5.6% in 2009 (P < 0.001). Of the 12 antibiotics tested, linezolid, minocycline, tigecycline and vancomycin were the most active agents by susceptibility against all S. aureus, all MRSA and all MSSA isolates. Against MRSA isolates with vancomycin MICs >= 2 MUg/mL, susceptibility to vancomycin decreased from 100% in 2004 to 95.77% in 2009 (P > 0.05). Similarly, in MSSA isolates susceptibility to vancomycin decreased from 100% in 2004 to 91.07% in 2009 (P > 0.05). These data suggest that although the number of isolates of S. aureus with reduced susceptibility to vancomycin has increased significantly from 2004 to 2009, this upward creep of MICs has not yet impacted significantly on the overall susceptibility of vancomycin against either MRSA or MSSA. PMID- 21239147 TI - Kinetics of 1H->13C NMR cross-polarization in polymorphs and solvates of the antipsychotic drug olanzapine. AB - The (1)H->(13)C NMR cross-polarization (CP) was studied under magic-angle spinning at 7.5 kHz in various crystal forms of the antipsychotic drug olanzapine: two polymorphs (metastable I and stable II) and eight solvates containing organic solvent and water molecules. The CP kinetics followed the non classical I-I(*)-S model, in which CP begins in a spin cluster of proximate abundant spins I(*) and rare spins S, then is controlled by spin diffusion of the abundant spins I from bulk to the I(*) spins of the spin cluster and finally is governed by spin-lattice relaxation of the abundant spins in the rotating frame. The corresponding CP kinetics parameters were determined and analyzed. It was demonstrated that the, lambda and T(df) values (the CP time constant, the cluster composition parameter and the (1)H spin-diffusion constant, respectively) were very useful to discriminate the functional groups, especially in the 3D parameter space. In order to conveniently analyze the large amount (175) of the collected CP parameters, the number of the observed variables was reduced using the principal component (PC) analysis. The 2D plot of PC2 vs. PC1 showed adequate separation of the CH(3), CH(2), CH and C cases (C stands for carbons without adjacent hydrogens). It was demonstrated that those cases were located along the PC1 axis in the order of increasing (1)H-(13)C dipolar couplings: C0 and <0.2), intermediate (0.2-0.65) and high risk (>0.65)] and ypN staging [ypN0, ypN1, ypN2 and ypN3] with multivariate Cox regression analysis. RESULTS: When using the LNR classification, 88 patients were categorised as zero, 91 as low, 82 as intermediate and 53 as high risk. For classic ypN staging, 88 were ypN0, 126 ypN1, 58 ypN2 and 42 ypN3. Compared to the low risk category, LNR zero corresponded to an adjusted hazard ratio [HRadj] of 0.4 (95%CI, 0.2-0.9), intermediate risk LNR to a HRadj of 1.2 (0.7-2.2) and high risk LNR to a HRadj of 2.7 (1.5-5.0). Similarly, the ypN0 category corresponded to a HRadj of 0.3 (0.2-0.7), ypN2 to a HRadj 1.1 (0.6-2.0) and ypN3 to a HRadj 2.2 (1.3-3.8) compared to ypN1 patients. CONCLUSION: Lymph node status after neoadjuvant chemotherapy predicts overall survival. In patients treated with neoadjuvant chemotherapy, LNR does not seem to be superior to classic ypN staging. PMID- 21239166 TI - The prevalence of premalignant gastric lesions in asymptomatic patients: predicting the future incidence of gastric cancer. AB - BACKGROUND: Helicobacter pylori is the main risk-factor for gastric cancer through a cascade from gastritis through atrophic gastritis (AG), intestinal metaplasia (IM), dysplasia (DYS) to malignancy. The presence of these lesions in the general population predicts the gastric cancer incidence in the coming decades. Prevalence data are mostly obtained from serological studies and endoscopy data in symptomatic patients. AIM: To investigate the prevalence of H. pylori infection and its related gastric changes in asymptomatic subjects. METHODS: 383 Patients undergoing routine colonoscopy were included. All subjects underwent upper GI endoscopy and completed the Gastrointestinal Symptom Rating Scale (GSRS). Biopsies were taken from antrum and corpus. RESULTS: H. pylori infection was present in 22%. Non-Caucasian subjects had a significantly higher H. pylori prevalence (p < 0.001). AG, IM and DYS were together found in 9.3% of subjects. Subjects with AG, IM or DYS were significantly older (p < 0.001). No differences were found with respect to gender, presence of GI symptoms as scored by GSRS, lifestyle and medication use. CONCLUSIONS: The prevalence of premalignant gastric lesions is considerable in general Western population with increasing age as the main risk factor. One time screening for premalignant lesions at the age of 60 years is a reasonable strategy since the numbers found imply that gastric cancer will remain a prevalent disease. PMID- 21239167 TI - TLR-3 polymorphism is an independent prognostic marker for stage II colorectal cancer. AB - BACKGROUND: Clinicopathologic stage is still the main parameter to evaluate the prognosis of newly diagnosed colorectal cancer (CRC) patients. Although molecular markers have been suggested for follow up of treated CRC patients, their complete clinical application is still under evaluation. MATERIALS AND METHODS: To evaluate the association of immune-related genes with CRC prognosis and survival, a total of 19 single nucleotide polymorphisms (SNPs) were genotyped in 614 German patients within the Kiel cohort (POPGEN). RESULTS: A promoter variant (rs1800872) in the Interleukin-10 (IL-10) gene was associated with an increased lymph node metastasis involvement [odds ratio (OR) = 2.1, 95% confidence interval (CI) = 1.03-4.2, for carriers of the TT genotype]. More importantly, among 582 followed up patients the SNP rs3775291 in the toll-like receptor 3 (TLR-3) gene was associated with CRC specific survival (150 events). Patients carrying the TT genotype had a 93% increased risk of death compared with the CC carriers [hazard ratio (HR) = 1.93, 95% CI 1.14-3.28]. The observed effect of the TLR-3 variant was restricted to stage II patients (HR = 4.14, 95% CI 1.24-13.84) and to patients who did not receive adjuvant therapy (HR = 3.2, 95% CI 1.4-7.7). CONCLUSIONS: Our results may provide additional candidates for risk assessment in stage II CRC patients for treatment decision. Further validation of the presented findings is warranted. PMID- 21239168 TI - Effect of low dissolved oxygen on simultaneous nitrification and denitrification in a membrane bioreactor treating black water. AB - Effect of low dissolved oxygen on simultaneous nitrification and denitrification was evaluated in a membrane bioreactor treating black water. A fully aerobic membrane bioreactor was operated at a sludge age of 60 days under three low dissolved oxygen (DO) levels below 0.5mg/L. It sustained effective simultaneous nitrification/denitrification for the entire observation period. Nitrification was incomplete due to adverse effects of a number of factors such as low DO level, SMPs inhibition, alkalinity limitation, etc. DO impact was more significant on denitrification: Nitrate was fully removed at low DO level but the removal was gradually reduced as DO was increased to 0.5mg/L. Nitrogen removal remained optimal within the DO range of 0.15-0.35 mg/L. Experimental results were calibrated and simulated by model evaluation with the same model coefficients. The model defined improved mass transfer with lower affinity coefficients for oxygen and nitrate as compared to conventional activated sludge. PMID- 21239169 TI - Comparison between UV spectroscopy and Nirs to assess humification process during sewage sludge and green wastes co-composting. AB - The humification of organic matter during composting was studied by the quantification and monitoring of the evolution of humic substances (Humic Acid-HA and Fulvic Acid-FA) by UV spectra deconvolution (UVSD) and near-infrared reflectance spectroscopy (NIRS) methods. The final aim of this work was to compare UVSD to NIRS method, already applied on the same compost samples in previous studies. Finally, UVSD predictions were good for HA and HA/FA (r(2) of 0.828 and 0.531) but very bad for FA (r(2) of 0.092). In contrary, all NIRS correlations were accurate and significant with r(2) of 0.817, 0.806 and 0.864 for HA, FA and HA/FA ratio respectively. From these results, HA/FA ratio being a well-used index of compost maturity, UVSD and NIRS represent two invaluable tools for the monitoring of the composting process. However, we can note that NIRS predictions were more accurate than UVSD calibrations. PMID- 21239170 TI - Relative quantitative PCR to assess bacterial community dynamics during biodegradation of diesel and biodiesel fuels under various aeration conditions. AB - The degradation of diesel fuel, B20 blend and biodiesel in liquid cultures by a seven-member bacterial consortium was compared under conditions with full aeration or with limited aeration with nitrate added as main electron acceptor. Community dynamics was assessed employing real-time PCR and the ddCt method for relative quantification. Biodegradation rates increased with increasing biodiesel content, but were significantly reduced under conditions with nitrate. Despite large variations in biodegradation rates, magnitude changes in population numbers were typically observed only from zero to one order, regardless the type of fuel and electron acceptor. Only Comamonadaceae and Variovorax sp. distinctly preferred aerobic conditions, and during aerobic growth showed suppression as fuel contained more biodiesel. Thus, the consortium is relatively stable and most of the degraders can shift their metabolism from hydrocarbons to biodiesel. The stability of the consortium is of interest in the context of biodiesel-mediated biodegradation of petroleum hydrocarbons. PMID- 21239171 TI - When microbial conversations get physical. AB - It is widely accepted that microorganisms are social beings. Whereas communication via chemical signals (e.g. quorum sensing) has been the focus of most investigations, the use of physical signals for microbial cell-cell communication has received only limited attention. In this Opinion article, I postulate that physical modes of microbial communication could be widespread in nature. This is based on experimental evidence on the microbial emission and response to three physical signals: sound waves, electromagnetic radiation and electric currents. These signals propagate rapidly, and even at very low intensities, they provide useful mechanisms when a rapid response is required. I also make some suggestions for promising future research avenues that could provide novel and unsuspected insights into the physical nature of microbial signaling networks. PMID- 21239172 TI - The spectrum of psychogenic non-epileptic seizures and comorbidities seen in an epilepsy monitoring unit. AB - We sought to study characteristics of patients presenting with psychogenic non epileptic seizures (PNES), with and without major psychiatric comorbidity. A total of 39 patients who were diagnosed with PNES in a tertiary care setting were studied, and those patients with and without axis I psychiatric disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) were compared. The mean time in confirming the diagnosis was 9 years. More than half the patients were taking anti-epileptic medications when they presented for video-electroencephalographic monitoring. The mean monitoring time required to capture a PNES was 0.6 days. Comorbid chronic medical conditions were found in 38.5% and axis I-psychiatric diagnoses in 48.7%. There were no significant differences in characteristics between those with and without major psychiatric comorbidities. PMID- 21239173 TI - Neoplastic meningitis presenting with acute cerebellar ataxia. AB - Acute cerebellar ataxia is a rare initial presenting feature of neoplastic meningitis (NM), particularly in gastric cancer. The authors report a 61-year-old woman with acute cerebellar ataxia secondary to NM from gastric cancer, which was not accompanied by other symptoms commonly associated with NM at initial presentation. It is suggested that NM should be considered in the differential diagnosis of cancer patients with acute cerebellar ataxia. PMID- 21239174 TI - A patient with brucellar cervical spondylodiscitis complicated by epidural abscess. AB - Brucellar cervical spondylodiscitis and epidural abscess are serious medical conditions that can cause permanent neurological deficits. Fortunately, they are rare. We report a 34-year-old male patient, complaining of fever and neck pain and stiffness, with increased deep tendon reflexes. A lumbar puncture was normal. Brucella species organisms were isolated from blood cultures, and the Rose-Bengal test and the standard tube agglutination (STA) test were positive. The diagnosis was made on MRI. The patient was treated with doxycycline and rifampin daily for 16 weeks. On day 51 of treatment, the patient had no symptoms and his physical and neurological examinations were normal. His repeat cervical MRI was almost normal. The STA test was negative at week 20. It is important to consider brucellar cervical spondylodiscitis with epidural abscess in endemic regions. PMID- 21239175 TI - Amoxicillin-induced acute aseptic meningitis. AB - A 58-year-old man presented to the hospital with fever and headache after amoxicillin intake. Physical examination, laboratory, and a cranial CT scan were unremarkable. Cerebrospinal fluid (CSF) testing revealed lymphocytic pleocytosis. After discontinuation of amoxicillin and symptomatic care, the patient quickly improved. Interestingly, he had had two prior episodes of aseptic meningitis that were probably also related to the administration of amoxicillin. Aseptic meningitis can be caused by multiple non-infectious conditions including drugs, malignancy, and autoimmune diseases. We report a case associated with amoxicillin that meets the criteria of drug-induced aseptic meningitis. Considering the wide utilization of amoxicillin, healthcare providers should be aware of it as a possible cause of drug-induced aseptic meningitis. PMID- 21239177 TI - Self-consistent charging in dielectric films under defocused electron beam irradiation. AB - We clarify the transient and equilibrium charging characteristics of grounded dielectrics due to low-energy defocused electron beam irradiation by a three dimensional self-consistent simulation model. The model incorporates the electron scattering, transport and trapping. Results show that some electrons can arrive at the grounded substrate due to the internal field and density gradient, forming the leakage current. The transient charging process tends to equilibrium as the surface potential decreases and the leakage electron current increases. The positive and negative space charges are distributed alternately along the beam incident direction. In the equilibrium state, the surface potential and leakage electron current decrease to stable values with increasing film thickness and the trap density, but with decreasing electron mobility. Moreover, the surface potential of the dielectric thin film exhibits a maximum negative value with variation of the beam energy; for example, under the condition of the film thicknesses 0.5 MUm and 2 MUm, the maximum negative values of surface potentials are -13 V and -98 V in beam energies 2 keV and 3.5 keV, respectively. However, for the thick film, the surface potential decreases with the increase in beam energy. PMID- 21239178 TI - Sublingual mucosa: A new vaccination route for systemic and mucosal immunity. AB - Needle-free vaccine delivery has become a global priority, both to eliminate the risk of improper and unsafe needle use and to simplify vaccination procedures. In pursuit of greater ease of vaccination, a number of needle-free delivery routes have been explored, with mucosal routes being perhaps the most prominent. Since the vaccine administration route significantly affects immune responses, numerous researchers are attempting to develop alternative vaccine delivery methods including a mucosal route. My group's recent studies demonstrate the potential of the sublingual (s.l.) route for delivering vaccines capable of inducing mucosal as well as systemic immune responses. Sublingual administration conferred effective protection against a lethal challenge with influenza virus (H1N1) or genital papillomavirus. Moreover, CCR7-CCL19/CCL21-regulated dendritic cells are responsible for activation of T and B cells following s.l. administration. This review highlights current knowledge about the safety and effectiveness of s.l. vaccination and describes how s.l. vaccination can induce both systemic and mucosal immunity. PMID- 21239176 TI - APOBEC3G: a double agent in defense. AB - APOBEC3G (A3G) is an effective cellular host defense factor under experimental conditions in which a functional form of the HIV-encoded protein Vif cannot be expressed. Wild-type Vif targets A3G for proteasomal degradation and when this happens, any host defense advantage A3G might provide is severely diminished or lost. Recent evidence cast doubt on the potency of A3G in host defense and suggested that it could, under some circumstances, promote the emergence of more virulent HIV strains. In this article, I suggest that it is time to recognize that A3G has the potential to act as a double agent. Future research should focus on understanding how cellular and viral regulatory mechanisms enable the antiviral function of A3G, and on the development of novel research reagents to explore these pathways. PMID- 21239179 TI - Extremely low frequency electromagnetic field exposure does not modulate toll like receptor signaling in human peripheral blood mononuclear cells. AB - The effects of extremely low frequency electromagnetic fields (ELF-EMF) on human health remain unclear. It has been reported that ELF-EMF may modulate the innate immune response to microorganisms in animal models and mammalian cell-lines. With the recently gained insight in innate immune signaling and the discovery of pattern recognition, we aim to study whether ELF-EMF modulates innate inflammatory signaling pathways. We used human peripheral blood mononuclear cells (PBMCs), isolated from blood from healthy volunteers, which we stimulated with specific TLR2 and TLR4 ligands, and with several microorganisms. The cells were subsequently exposed in B(dc)=3 MUT to a highly controlled and standardized ELF EMF signal (20-5000Hz, B(ac)=5 MUT, 30 min) and cytokine production was measured at different time points after stimulation. No significant difference in immune response, as reflected by IL-1beta, IL-6, TNFalpha, IL-8 and IL-10 production, could be detected after stimulation with LPS (TLR4 ligand), Pam3Cys (TLR2 ligand) or a panel of heat killed microorganisms: Mycobacterium tuberculosis, Salmonella typhimurium, Candida albicans, Aspergillus fumigatus and Staphylococcus aureus (multiple TLR ligands). We therefore conclude that under our experimental conditions, ELF-EMF does not modulate the innate immune response of human primary cells after TLR stimulation in vitro. PMID- 21239180 TI - Upregulation of TLR2 expression on G-CSF-mobilized peripheral blood stem cells is responsible for their rapid engraftment after allogeneic hematopoietic stem cell transplantation. AB - Granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cells (PBSCs) are more frequently used as the cellular source in allogeneic hematopoietic stem cell transplantation (HSCT) than bone marrow stem cells (BMSCs) because they promote more rapid engraftment and immune reconstitution. However, the underlying mechanism for this is not fully understood. Here, we investigated the role of Toll-like receptor 2 (TLR2) on PBSCs in promoting rapid engraftment after allogeneic HSCT. We found that PBSCs highly expressed TLR2 in comparison to BMSCs, and TLR2 was directly induced by G-CSF signaling. Treatment with the TLR2 ligand, Pam(3)CSK(4) (PAM), more efficiently induced myeloid differentiation of PBSCs than BMSCs. Similarly, endogenous TLR2 ligands from the serum of recipients of allogeneic transplantation more rapidly stimulated myeloid differentiation of PBSCs compared with BMSCs. PAM treatment of TLR2(-/-) syngeneic recipient mice transplanted with PBSCs resulted in significantly elevated numbers of PBSC-derived myeloid cells and spleen colony formation compared with controls. Our results demonstrate that TLR2 signaling in PBSCs correlates with their ability to rapidly differentiate into myeloid cells, resulting in improved engraftment. Thus, TLR2 may be a novel target for increasing the efficiency of allogeneic HSCT by overcoming engraftment failure or delayed engraftment. PMID- 21239181 TI - Influence of inflammation on total energy expenditure in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: Studies show that inflammation can contribute to an increase in resting energy expenditure in patients with chronic kidney disease; however, findings about total energy expenditure (TEE) have not been reported. The aim of this study was to evaluate the effects of inflammation on TEE and physical activity energy expenditure in hemodialysis (HD) patients. DESIGN: This was a cross-sectional study. SETTING: This study was conducted from Hopital Edouard Herriot, Lyon, France. PATIENTS: This study included 24 HD patients and 18 healthy subjects. MAIN OUTCOME MEASURE: TEE and step counts were measured over a 7-day period by the SenseWear Pro2 Armband in 24 HD patients (15 patients with C-reactive protein <5 mg/L, aged 67.0 +/- 14.7 years, and 9 with C-reactive protein >5 mg/L, aged 69.0 +/- 18.0 years) and compared with 18 healthy subjects (62.3 +/- 15.3 years). RESULTS: Mean estimated TEE measured with SenseWear Pro2 Armband was significantly lower (25.5 +/- 4.1 kcal/kg/day) in patients with inflammation when compared with those without inflammation (32.0 +/- 6.7 kcal/kg/day) and with healthy subjects (31.8 +/- 7.0 kcal/kg/day) (P = .012). There was a difference in the physical activity (step counts) between patient groups (P < .05). Healthy subjects and patients without inflammation walked more (8,107 +/- 5,419 and 6,016 +/- 3,752 steps/day, respectively) as compared with patients with inflammation (2,801 +/- 2,754 steps/day, P = .001). CONCLUSION: Our findings suggest that patients with inflammation have a lower TEE when compared with healthy subjects and patients without inflammation. TEE is influenced by physical activity because patients with inflammation appear to be less active. PMID- 21239182 TI - Serum creatinine improves body mass index survival prediction in hemodialysis patients: a 1-year prospective cohort analysis from the ARNOS study. AB - OBJECTIVE: This study sought to better characterize the relationships between body mass index (BMI) and lean body mass (LBM) as assessed by serum creatinine (SCr) and mortality. DESIGN: The data were collected from a prospective prevalent cohort in maintenance hemodialysis patients. SETTING: The study was carried out in 25 dialysis units in Rhones Alpes area (France and Switzerland). PATIENT: A total of 1,205 patients were followed up for 1-year, starting July 1, 2005. OUTCOME: Mortality as well as clinical and biological routine parameters were recorded. Kaplan-Meier, Cox model, Log rank test were used for the statistical analysis. RESULTS: We found that SCr was a strong predictor of mortality (P < .001), whereas BMI was not. Additionally, higher BMI lost its protective effect when it was associated with low SCr. Survival was strongly reduced in patients having a predialysis SCr <717 MUmol/L in patients with a BMI >23 (P < .001). CONCLUSION: BMI should not be used by itself but in conjunction with SCr as a surrogate of LBM to improve its morbid-mortality predictive power. LBM should also be taken into account in further survival studies carried out in hemodialysis patients. PMID- 21239183 TI - A pilot study on the relation between dietary calcium and clinical parameters in renal transplant recipients. AB - OBJECTIVE: This aim of this study was to evaluate the association between dietary calcium and variables that include body mass index, abdominal obesity, metabolic profile, and blood pressure levels in renal transplant patients. DESIGN: A cross sectional study was conducted. SETTING: Eligible patients were recruited from renal transplant outpatient clinics at Pedro Ernesto University Hospital, Rio de Janeiro, Brazil. PATIENTS: A total of 40 men and 34 women aged >18 years who had received kidney transplants in the past >=12 months were included in this study. INTERVENTION: All patients underwent clinical, dietary, anthropometric, and biochemical evaluation. RESULTS: Participants were classified into the following 2 groups on the basis of their mean dietary calcium intake: group A (<600 mg/day) and group B (>=600 mg/day). Patients in group B presented significantly lower levels of waist circumference and waist-to-hip ratio as compared with those in group A (P = .04 and P = .005, respectively), after adjusting for confounding variables such as energy intake, gender, age, physical activity, time since transplantation, and prednisone dose. After controlling for potential confounders, including energy intake and physical activity, subjects in group B had a lower odds ratio for prevalent abdominal obesity as compared with those in group A (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = .04). Body mass index was significantly lower in patients with higher calcium intake; however, this difference did not reach statistical significance after adjustments for confounding factors. Metabolic profile and blood pressure levels were similar in both groups. CONCLUSION: The findings of the present study suggest that a higher dietary calcium intake may be associated with lower abdominal adiposity in renal transplant patients. PMID- 21239184 TI - Vitamin D: the iceberg nutrient. AB - The understanding of vitamin D's role in human health has recently expanded. It is now recognized as more than a hormone activated in the kidney only for calcium homeostasis. It is metabolized and used by virtually every cell in the body. Patients with chronic kidney disease have a deficit in their kidney production of 1,25(OH)(2)D and have classically been treated with calcitriol or its active analogues. Despite often having lower systemic levels of 1,25(OH)(2)D, patients with chronic kidney disease retain the capability of extra renal production of 1,25(OH)(2)D. This has far reaching implications for their health. This review examines clinical trials and observations in 3 areas that impact chronic kidney disease patients. Cancer, cardiovascular disease and infections are responsible for much of the morbidity and mortality in this patient population. We will discuss vitamin D's role in these disease states with a focus on the chronic kidney disease patient. PMID- 21239185 TI - Association of self-reported physical activity with laboratory markers of nutrition and inflammation: the Comprehensive Dialysis Study. AB - OBJECTIVE: Patients on dialysis maintain extremely low levels of physical activity. Prior studies have demonstrated a direct correlation between nutrition and physical activity but provide conflicting data on the link between inflammation and physical activity. Using a cohort of patients new to dialysis from the Comprehensive Dialysis Study (CDS), we examined associations of self reported physical activity with laboratory markers of nutrition and inflammation. DESIGN, SETTING, AND PATIENTS: Between June 2005 and June 2007, CDS collected data on self-reported physical activity, nutrition, and health-related quality of life from patients starting dialysis in 296 facilities located throughout the United States. Baseline serum samples were collected from participants in a nutrition sub-study of CDS. MEASURES: Serum albumin and prealbumin were measured as markers of nutrition, and C-reactive protein (CRP) and alpha-1-acid glycoprotein as markers of inflammation. Self-reported physical activity was characterized by the maximum activity score (MAS) and adjusted activity score (AAS) of the Human Activity Profile. RESULTS: The mean age of participants in the analytic cohort (n = 201) was 61 years. The MAS and AAS were below the 10th and first percentile, respectively, in comparison with healthy 60 year-old norms. Both activity scores were directly correlated with albumin (r(2) = 0.3, P < .0001) and prealbumin (r(2) = 0.3, P < .0001), and inversely correlated with CRP (AAS: r(2) = -0.2, P = .01; MAS: r(2) = -0.1, P = .08). In multivariate analyses adjusting for age, gender, race/ethnicity, diabetes status, and center, both activity scores were directly correlated with prealbumin and inversely correlated with CRP. CONCLUSIONS: Patients new to dialysis with laboratory-based evidence of malnutrition and/or inflammation are likely to report lower levels of physical activity. PMID- 21239186 TI - Appetite and gastrointestinal symptoms in chronic hemodialysis patients. AB - OBJECTIVE: The aim of the present cross-sectional study was to assess the association between self-reported appetite and gastrointestinal symptoms in chronic hemodialysis patients. DESIGN: A cross-sectional study was carried out. SETTING: The study was carried out at an outpatient hemodialysis service center. PATIENTS: A total of 110 patients were included in this study. INTERVENTION: The first question of the Hemodialysis Study Appetite questionnaire was used to assess the appetite of the HD patients. The multiple-choice answers for the first question "During the past week, how would you rate your appetite?" were as follows: (1) very good, (2) good, (3) fair, (4) poor, or (5) very poor. At the same time, each patient was invited to answer the following questions: Did you have any of the following symptoms (hiccups, feeling full after a few bites of food, nausea, vomiting, indigestion, abdominal pain, bloating, and constipation) in the last 2 weeks? Are there particular foods that you used to like but now do not? Did you have changes in smell in the last 2 weeks? Did you have taste changes in the last 2 weeks? MAIN OUTCOME MEASURE: Possible associations between appetite and gastrointestinal symptoms were assessed in this study. RESULTS: In 52 (47.2%) HD patients, the appetite was very good or good (group A), in 28 (25.4%) fair (group B), and in 30 (27.3) poor or very poor (group C). The most frequent symptoms were bloating and constipation. The frequency of food aversion and early satiety were 23.6% and 18.2%, respectively. The frequency of changes in smell and taste were 3.6% and 7.2%, respectively. The frequency of early satiety, food aversion, changes in smell and taste was significantly higher in group C as compared with group A. Similarly, the frequency of early satiety, food aversion, and changes in taste were higher in group B than in group A. The other frequencies did not differ significantly among group A, B, and C. CONCLUSION: Food aversion, early satiety, changes in taste and smell were significantly more frequent in HD patients with poor or very poor appetite as compared with those with good or very good appetite. PMID- 21239187 TI - Megestrol acetate use in hypoalbuminemic dialysis patients. PMID- 21239189 TI - A traveling team concept to expedite the transfer and management of unstable patients in cardiopulmonary shock. AB - Emergent mechanical support with transfer of patients in acute cardiopulmonary shock to specialty centers for definitive management is often required at non transplant centers. An alternative approach to the traditional "hub and spoke" model is presented. A team of health care specialists from our hospital is deployed to the community hospital for stabilization, possible implantation, and transfer of patients to our tertiary care facility. Patient assessment can be made with intervention, allowing stabilization and safe transfer by our team to our institution. This method provides tertiary level care at the referring hospital and may improve survival for a sub-set of patients in the community hospital setting. PMID- 21239188 TI - A polymorphism linked to elevated levels of interferon-gamma is associated with an increased risk of cytomegalovirus disease among Caucasian lung transplant recipients at a single center. AB - BACKGROUND: Single-nucleotide polymorphisms (SNPs) associated with active cytomegalovirus (CMV) infections after lung transplantation have not been identified. METHODS: SNPs associated with varying levels of interferon (IFN) gamma (+874T/A), tumor necrosis factor-alpha (-308G/A), interleukin-10 (-1082G/A, -819C/T, -592C/A) and interleukin-6 (-174G/C) were characterized for 170 Caucasian lung transplant recipients who received alemtuzumab induction and valganciclovir prophylaxis against CMV. RESULTS: Patients were followed for a median of 34 months post-transplant, and 66% (113 of 170), 24% (40 of 170) and 10% (17 of 170) had no CMV infection, CMV viremia and CMV disease, respectively. Median times to CMV viremia and disease were 7 and 10 months, respectively. For each gene, there was no significant deviation from Hardy-Weinberg equilibrium. Independent risk factors for the development of CMV disease were IFN-gamma +874 T/T genotype (associated with high levels of IFN-gamma production), CMV donor positive/recipient-negative (D(+)/R(-)) serostatus and acute cellular rejection requiring augmented immunosuppression (p = 0.001, 0.003 and 0.049, respectively). The association between IFN-gamma +874 T/T genotype and CMV disease was most striking among R(+) patients (p = 0.02). D(+)/R(-) serostatus was also a significant risk factor for CMV viremia (p = 0.0005). IFN-gamma +874 T/T genotype was associated with significantly lower peak CMV viral loads (p = 0.03). There were no associations between tumor necrosis factor-alpha, interleukin-10 or interleukin-6 SNPs and CMV infections. CONCLUSION: A genetic predisposition to elevated IFN-gamma levels may play a dual role in controlling active CMV infection among lung transplant recipients receiving alemtuzumab induction and valganciclovir prophylaxis, limiting the extent of viral replication in serum but increasing the risk of CMV disease. PMID- 21239190 TI - Efficacy and tolerability of a red-vine-leaf extract in patients suffering from chronic venous insufficiency--results of a double-blind placebo-controlled study. AB - OBJECTIVES: The aim of this study was to investigate the effect of a red-vine leaf extract (AS195, Antistax((r)), Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany) on the volume of the leg and clinical symptoms in patients with chronic venous insufficiency (CVI). DESIGN, MATERIALS AND METHODS: A multicentre, randomised, double-blind and placebo-controlled study was carried out with 720 mg AS195 per day over 12 weeks in CVI patients (CEAP Grades 3-4a) and moderate-to-severe clinical symptoms. Efficacy endpoints were changes in limb volume determined by water displacement volumetry, clinical CVI symptoms assessed on a 10-cm visual analogue scale and global efficacy evaluations. RESULTS: The full-analysis set included 248 patients (placebo: n = 122; AS195: n = 126). After 12 weeks, AS195 significantly reduced lower limb volume by a mean of 19.9 standard error (SE) 8.9 ml over placebo (95% confidence interval (CI): -37.5, 2.3; p = 0.0268; analysis of covariance, ANCOVA). The standardised effect size of 0.28 for volume reduction indicates a clinically relevant effect. On Day 84, the symptom of 'pain in the legs' assessed by visual analogue scale decreased in the AS195 group compared with the placebo group: mean difference -6.6 SD 3.3 mm (95% CI: -13.1,-0.1; p = 0.047). Other symptoms showed no significant change. The tolerability of AS195 was similar to that of placebo. CONCLUSIONS: AS195 treatment for 84 days resulted in an approximately 20 ml reduction of limb volume in the active treatment group compared with the placebo group. Patients reported subjective improvement following treatment with AS195 compared with placebo. However, patients' overall rating of efficacy did not correlate well with measured reductions in limb volume. TRIAL REGISTRATION: ClinicalTrials.gov NCT00855179. PMID- 21239191 TI - Odontogenic tumors: a 5-year retrospective study in a Brazilian population and analysis of 3406 cases reported in the literature. AB - OBJECTIVE: The objective of this study was to analyze the frequency and distribution of odontogenic tumors in Fortaleza, Brazil, and compare the findings with those reported in the literature. STUDY DESIGN: A total of 6231 oral lesions retrieved from 5 anatomic pathology services in Fortaleza, Brazil, over a 5-year period, were reviewed. In addition, the literature was searched for studies on odontogenic tumors (OTs) according to the 2005 WHO classification. RESULTS: Within the total 6231 oral lesions, 185 (2.97%) were OTs, all benign. OTs presented a female predilection, with a male:female ratio of 0.62:1.00. These neoplasms occurred over a wide range of ages (1 to 78 years), with a mean of 30.5 years. Ameloblastomas, keratocystic odontogenic tumors, and odontomas were the most frequent OT types. CONCLUSIONS: OTs are rare neoplasms and appear to show geographic variations. In Fortaleza, Brazil, they are more common in female patients, with ameloblastoma followed by keratocystic odontogenic tumors as the most frequent OTs. PMID- 21239192 TI - The efficacy of EMG, jaw tracking, and joint sound recording technologies in the evaluation of TMD. PMID- 21239193 TI - Canine bacterial urinary tract infections: new developments in old pathogens. AB - Uncomplicated bacterial urinary tract infections (UTIs) occur commonly in dogs. Persistent or recurrent infections are reported less frequently. They typically occur in dogs with an underlying disease and are sometimes asymptomatic, especially in dogs with predisposing chronic disease. Escherichia coli is the organism most frequently cultured in both simple and complicated UTIs. Organisms such as Enterococcus spp. and Pseudomonas spp. are less common in uncomplicated UTI, but become increasingly prominent in dogs with recurrent UTI. The ability of bacteria to acquire resistance to antimicrobials and/or to evade host immune defence mechanisms is vital for persistence in the urinary tract. Antimicrobial therapy limitations and bacterial strains with such abilities require novel control strategies. Sharing of resistant bacteria between humans and dogs has been recently documented and is of particular concern for E. coli O25b:H4-ST131 strains that are both virulent and multi-drug resistant. The epidemiology of complicated UTIs, pathogenic traits of uropathogens and new therapeutic concepts are outlined in this review. PMID- 21239194 TI - T2 distribution mapping profiles with phase-encode MRI. AB - Two 1-D phase-encode sequences for T2 mapping, namely CPMG-prepared SPRITE and spin-echo SPI, are presented and compared in terms of image quality, accuracy of T2 measurements and the measurement time. The sequences implement two different approaches to acquiring T2-weighted images: in the CPMG-prepared SPRITE, the T2 weighting of magnetization precedes the spatial encoding, while in the spin-echo SPI, the T2-weighting follows the spatial encoding. The sequences are intended primarily for T2 mapping of fluids in porous solids, where using frequency encode techniques may be problematic either due to local gradient distortions or too short T2. Their possible applications include monitoring fluid-flow processes in rocks, cement paste hydration, curing of rubber, filtering paramagnetic impurities and other processes accomplished by changing site-specific T2. PMID- 21239195 TI - Number of portal tract macrophages correlates with the modified hepatic activity index in chronic hepatitis C infection. AB - The Ishak modified hepatic activity index (mHAI) is widely used to score disease activity in chronic hepatitis C infection. However, the scoring of the mHAI components is subjective and prone to interobserver variation. Liver injury results in increased numbers of portal tract macrophages, which are easily identified via periodic acid-Schiff with diastase digestion stain. Evaluation of 30 liver biopsies from patients with chronic hepatitis C revealed increasing numbers of portal tract macrophages as scores of liver inflammation increased. Specifically, the number of PASD-positive portal tract macrophages per centimeter of biopsy length correlated with the level of portal inflammation and total mHAI score, and these correlations were statistically significant (P = .039 and .029, respectively). Although the portal macrophage count appeared to correlate with the interface activity and lobular necroinflammatory score, this did not meet statistical significance (P = .073 and .079, respectively). Interobserver agreement by kappa analysis was greater for the portal macrophage count than for any individual component of the mHAI score. In summary, the number of periportal ceroid-laden macrophages correlates with liver inflammation as measured using the mHAI, with better interobserver agreement. This technique may serve as a useful adjunct to the mHAI in the assessment of liver injury in hepatitis C. PMID- 21239196 TI - Oncocytoma of the kidney with prominent intracytoplasmic lumina. AB - Oncocytoma is a histologically distinctive neoplasm of the kidney, with a well recognized cytoarchitectural appearance. On occasion, however, renal oncocytomas are known to exhibit unusual morphologic features that may pose diagnostic difficulties. We present the clinical and pathologic details of an oncocytoma of the kidney with an unusual histologic appearance imparted by the presence of large numbers of prominent intracytoplasmic lumens. Morphologically, the neoplasm was composed of uniform polygonal cells with copious amounts of granular, eosinophilic cytoplasm, round nuclei, and prominent nucleoli, exhibiting an organoid pattern of growth. Intracytoplasmic lumina of varying size were present throughout the tumor. There were no mitotic figures or areas of necrosis present. The diagnosis of oncocytoma was supported by immunohistochemical and ultrastructural studies. By electron microscopy, the intracytoplasmic lumens appeared as membrane bound spaces with associated microvilli. The presence of intracytoplasmic lumina in a significant proportion of cells is an uncommon feature of renal oncocytoma which can generate problems in diagnosis. Awareness of this phenomenon should allow for improved recognition of oncocytomas exhibiting this type of unusual morphology. PMID- 21239197 TI - Extraoral plasmablastic lymphoma with intravascular component and MYC translocation. AB - Plasmablastic lymphoma (PBL) is an uncommon, clinically aggressive, Epstein-Barr virus-driven B-cell lymphoma that was initially described in tumors of relatively young human immunodeficiency virus-positive men. Subsequent to initial reports, the clinical and pathological spectrum of this disease has been expanded such that, now, PBL is recognized to be a heterogeneous disease entity. Plasmablastic lymphoma has been seen in clinical settings outside those initially reported and has been shown to demonstrate a variety of morphologic patterns. We describe a case of extraoral PBL in an human immunodeficiency virus-infected patient with a computed tomography-identified heterogeneously enhancing mass in the stomach. Histologically, a prominent intravascular component was identified. Fluorescent in situ hybridization analysis for MYC/IGH (immunoglobulin heavy chain) rearrangement t(8;14) identified fusion signals, confirming the presence of MYC rearrangement. The presence of a prominent intravascular in our case is unique. To our knowledge, these findings have not been observed in the previous reports of PBL. The observation of this vascular component supports the heterogeneity of PBL and may be an indicator of tumor aggressiveness. We were able to demonstrate the MYC/IGH rearrangement in our case of PBL. The interplay between Epstein-Barr virus and this MYC rearrangement may be similar to what is observed in Burkitt lymphoma, another clinically aggressive non-Hodgkin lymphoma. PMID- 21239198 TI - Growth hormone can improve insulin resistance and differentiation in pancreas of senescence accelerated prone male mice (SAMP8). AB - OBJECTIVE: The aim of the present study was to investigate the effect of aging on several parameters related to glucose metabolism, proliferation and differentiation in the pancreas and how GH administration to old SAMP8 mice could affect these parameters. MATERIALS AND METHODS: Pancreas samples were obtained from two types of male mice models: senescence-accelerated prone (SAMP8) and senescence-accelerated-resistant (SAMR1) mice SAMP8 and SAMR1 mice and the influence of exogenous administration of GH (2mgs.c./kg/day) on SAMP8 mice. RNA was isolated from pancreas samples of male mice using the kit RNeasy total RNA kit Ref. 50974104 (Qiagen). Insulin was measured in plasma by RIA kit and glucose was measured in plasma by an assay kit. RESULTS: Aging decreases the expression of differentiation in the pancreas of Pdx-1, FoxO 1 and FoxO 3A but not of Sirt 1 or of the expression of the proliferative genes PCNA and Sei1. The expression of glucagon and GLUT2 were increased with aging and no differences were observed in somatostatin and insulin expressions. Insulin levels in plasma were increased with aging in SAMP8 mice. IGF-1 expression was reduced with aging. The treatment with GH was able to increase the expression of Sirt 1, Pdx-1, FoxO 3A and IGF-1. On the other hand, the treatment decreased the expression of glucagon, GLUT2, somatostatin and insulin, furthermore GH was able to decrease the plasma levels of insulin in old male SAMP8 mice (p<0.0004). CONCLUSION: The present study has shown that aging is associated with significant alterations in the relative expression of pancreatic genes involved in insulin secretion as well as in the differentiation and in the intra islet glucose metabolism. According to our results, GH administration to old SAMP8 mice was able to improve the pancreatic function of the old SAMP8 mice and to decrease insulin and glucagon expressions in the pancreas improving instead insulin levels and glucose metabolism. PMID- 21239199 TI - Ronidazole pharmacokinetics after intravenous and oral immediate-release capsule administration in healthy cats. AB - Ronidazole (RDZ) is an effective treatment for feline Tritrichomonas foetus infection, but has produced neurotoxicity in some cats. An understanding of the disposition of RDZ in cats is needed in order to make precise dosing recommendations. Single-dose pharmacokinetics of intravenous (IV) RDZ and immediate-release RDZ capsules were evaluated. A single dose of IV RDZ (mean 9.2mg/kg) and a 95mg immediate-release RDZ capsule (mean 28.2mg/kg) were administered to six healthy cats in a randomized crossover design. Plasma samples were collected for 48 h and assayed for RDZ using high pressure liquid chromatography (HPLC). Systemic absorption of oral RDZ was rapid and complete, with detection in the plasma of all cats by 10 min after dosing and a bioavailability of 99.64 (+/-16.54)%. The clearance of RDZ following IV administration was 0.82 (+/-0.07) ml/kg/min. The terminal half-life was 9.80 (+/ 0.35) and 10.50 (+/-0.82) h after IV and oral administration, respectively, with drug detectable in all cats 48h after both administrations. The high oral bioavailability of RDZ and slow elimination may predispose cats to neurotoxicity with twice-daily administration. Less frequent administration should be considered for further study of effective treatment of T foetus-infected cats. PMID- 21239200 TI - Congenital diaphragmatic eventration in two closely related British Shorthair cats. AB - Two closely related British Shorthair cats, which died after surgery performed in the dorsal position, were presented for dissection. In both, a thin, flaccid, enlarged transparent tendinous diaphragmatic portion protruded cranially into the thoracic cavity, forming a cupola in which left, right medial and quadrate hepatic lobes were encased in both cats and the stomach in one cat. Microscopically, no muscle fibres were observed in the membrane, but numerous hepatocytes and bile ducts were incorporated in its central part. The anomaly was diagnosed as a congenital diaphragmatic eventration. PMID- 21239201 TI - [Detection of risks for the safety of the patients in the implementation of continuous techniques of extracorporeal depuration (CTED)]. AB - INTRODUCTION: Continuous techniques of extracorporeal depuration (CTED) manage high volumes of fluid exchange and extensive control of its safety is required. OBJECTIVE: To detect the risks of CTED and to determine its frequency per patient. MATERIAL AND METHODS: An observational, retrospective study was performed. Inclusion criteria were patients admitted from January 2009 to December 2009, with CTED in the Polyvalent Intensive Care Unit (ICU) of the Hospital 12 de Octubre. We previously identified 10 risks that were detectable in the clinical records. We analyzed demographic and treatment variables. The quantitative variables were expressed as mean+/-SD and the qualitative ones as absolute and relative frequencies. ANALYSIS: SPSS 15.0((r)). RESULTS: A total of 54 patients (11.7%), with ages 59.78+/-14.8, 42 men (77.8%) were included. In 81.4%, the indication was acute kidney failure; 80.3% were treated with hemodiafiltration. Mean hours of CTED were 112.9+/-139.9 and the medium of 2 filters per patient (recommended intakes 0-31). Risk/patient rate was: 100% of patients without monitoring of the Mg and P, and 3.7% (n=2) urea; in 16 (29.6%), there was coagulation of the circuit prior to 24 hours and in 25 (46.3%) the blood could not be returned; in 14 (29.3%), written regime was always lacking on the order for treatment. The dose was not reflected on the patient's chart in 2 (3.7%); in 3 patients (5.6%) with coagulation disorder, anticoagulants were prescribed in the circuit. In 1 (1.9%) bleeding was observed and in 10 (18.5%) there was mild hypothermia (35-32 degrees C). CONCLUSIONS: A standardized monitoring of the Mg and P is required. The therapy should be prescribed in the medical treatment. The technique needs to be improved in order to prolong its duration and avoid blood losses. PMID- 21239202 TI - Diagnosis of anal human papillomavirus infection: polymerase chain reaction or cytology? AB - OBJECTIVES: To investigate the relationship between human immunodeficiency virus (HIV)-positive and HIV-negative patients engaging in promiscuous behaviors and anal human papillomavirus (HPV) infection diagnosed by polymerase chain reaction (PCR) and cytology. METHODS: Fifty-six HIV-positive patients and 49 HIV-negative patients who engaged in sexually promiscuous behavior were enrolled in the study. We performed cytological exams using the Pap smear and PCR for HPV-DNA detection, with identification of oncogenic strains. The 2001 Bethesda System terminology was used for the cytological exams. We also evaluated the immunologic status of the HIV-infected patients. RESULTS: PCR positivity for HPV-DNA was higher in the group of HIV-positive patients than in the group of HIV-negative patients with a statistically significant difference. In contrast we did not find any statistically significant difference by cytological exam. Oncogenic strains were equally distributed in the two groups. CONCLUSIONS: Our results indicate the importance of the cytological exam for anal HPV screening in the population at high risk of sexually transmitted disease and that HPV-DNA PCR can be used only as adjunct test. PMID- 21239203 TI - [Sorafenib and radiotherapy association for hepatocellular carcinoma]. AB - Conformal radiotherapy is a promising therapeutic strategy for hepatocellular carcinoma (HCC), producing local control rates above 90% within the radiation beam. However, survival after radiotherapy remains limited by the high frequency of intra- and extra-hepatic recurrences, which occurs in 40-50 and 20-30% of cases, respectively. Sorafenib (BAY43-9006, Nexavar; Bayer, West Haven, CT) is a small-molecule inhibitor that demonstrated potent activity to target v-raf murine sarcoma oncogene homolog B1 (BRAF) and VEGFR tyrosine kinases. Sorafenib is the only drug that demonstrated effectiveness to increase overall survival in advanced or metastatic hepatocellular carcinoma. The rationale to combine radiotherapy with sorafenib is the following: (1) targeting RAS-RAF-MAPK and VEGFR signaling pathways, which are specifically activated after exposure to radiation, and responsible for radio-resistance phenomenon; (2) enhancing the oxygen effect through normalization of the surviving tumor vasculature; and (3) synchronization of the cell cycle. Sorafenib and radiotherapy represent complementary strategies, as radiotherapy may be useful to prolong the effect of sorafenib through control of the macroscopic disease, when sorafenib may target latent microscopic disease. Sorafenib and radiotherapy associations are thus based on a relevant biological and clinical rationale and are being evaluated in ongoing phase I-II trials. PMID- 21239204 TI - Stereotactic radiation therapy and selective internal radiation therapy for hepatocellular carcinoma. AB - Recent technological advances allow precise and safe radiation delivery in hepatocellular carcinoma. Stereotactic body radiotherapy is a conformal external beam radiation technique that uses a small number of relatively large fractions to deliver potent doses of radiation therapy to extracranial sites. It requires stringent breathing motion control and image guidance. Selective internal radiotherapy or radioembolization refers to the injection of radioisotopes, usually delivered to liver tumors via the hepatic artery. Clinical results for both treatments show that excellent local control is possible with acceptable toxicity. Most appropriate patient populations and when which type of radiation therapy should be best employed in the vast therapeutic armamentarium of hepatocellular carcinoma are still to be clarified. PMID- 21239205 TI - [Epidemiology, natural history and pathogenesis of hepatocellular carcinoma]. AB - Hepatocellular carcinoma (HCC) is the main type of primary liver cancers and the third most common cause of cancer mortality worldwide. In France, rising number between 5000 and 6000 cases are diagnosed each year. The major risk factor for hepatocellular carcinoma is chronic hepatitis: viral hepatitis B, viral hepatitis C, consumption of alcohol, hemochromatosis. Hepatocellular carcinoma is closely associated to liver cirrhosis, which is a true precancerous state. Because hepatocarcinogenesis is a long and heterogeneous process, there is still much to understand. Many genetic and epigenetic alterations are described leading to changes in cellular signalling cascades involved in regulation of growth, differentiation, apoptosis, motility. Hepatitis viruses play a direct oncogenic role through the interaction between viral and cellular proteins, which control cell homeostasis, or by the integration of hepatitis B virus genome into the host genome. Furthermore, hepatitis viruses play an indirect oncogenic role by causing chronic inflammation and hepatocyte regeneration related to viral hepatopathy. In expectation of a better understanding of hepatocarcinogenesis and new treatments, prevention from risk factors and ultrasonographic screening of patients with cirrhosis should increase prognosis. PMID- 21239206 TI - Sonolytic degradation of endocrine disrupting chemical 4-cumylphenol in water. AB - The sonolytic degradation of endocrine disrupting compound 4-cumylphenol (4-CyP) in aqueous solution was investigated. The influence of operating parameters for sonication process such as 4-CyP initial concentration, frequency, power, pH, temperature and saturating gas was examined. The extent of degradation was inversely proportional to the initial substrate concentration. The rate of 4-CyP degradation was frequency dependent. The degradation rate increased proportionally with increasing ultrasonic power from 20 to 100 W and temperature in the range of 20-50 degrees C. The most favorable degradation pH was acidic media. Destruction in the presence of saturating gas follows the order: argon>air>nitrogen. The 4-CyP degradation was inhibited in the presence of nitrogen gas owing to the free radical scavenging effect in vapor phase within the bubbles of cavitation. The ultrasonic degradation of 4-CyP was clearly promoted in the presence of bromide anions and the promoting effect on degradation increased with increasing bromide concentration. At low 4-CyP concentration (0.05 mg L(-1)), bicarbonate ion drastically enhanced the rate of 4 CyP degradation. Experiments conducted using pure and natural water demonstrated that the sonolytic treatment was more efficient in the natural water compared to pure water. PMID- 21239207 TI - Real time monitoring of progressive damage during loading of a simplified total hip stem construct using embedded acoustic emission sensors. AB - Acoustic emission (AE) is a non-destructive technique that is capable of passively monitoring failure of a construct with excellent temporal resolution. Previous investigations using AE to monitor the integrity of a total hip replacement (THR) have used surface mounted sensors; however, the AE signal attenuates as it travels through materials and across interfaces. This study proposes that directly embedded sensors within the femoral stem of the implant will reduce signal attenuation effects and eliminate potential complications and variability associated with fixing the sensor to the sample. Data was collected during in vitro testing of implanted constructs, and information from both embedded and externally mounted AE sensors was compared and corroborated by micro Computed Tomography (micro-CT) images taken before and after testing. The results of this study indicate that the embedded sensors gave a closer corroboration to observed damage using micro-CT and were less affected by unwanted noise sources. This has significant implications for the use of AE in assessing the state of THR constructs in vitro and it is hypothesised that directly embedded AE sensors may provide the first steps towards an in vivo, cost effective, user friendly, non destructive system capable of continuously monitoring the condition of the implanted construct. PMID- 21239209 TI - Computed tomography characterisation of additive manufacturing materials. AB - Additive manufacturing, covering processes frequently referred to as rapid prototyping and rapid manufacturing, provides new opportunities in the manufacture of highly complex and custom-fitting medical devices and products. Whilst many medical applications of AM have been explored and physical properties of the resulting parts have been studied, the characterisation of AM materials in computed tomography has not been explored. The aim of this study was to determine the CT number of commonly used AM materials. There are many potential applications of the information resulting from this study in the design and manufacture of wearable medical devices, implants, prostheses and medical imaging test phantoms. A selection of 19 AM material samples were CT scanned and the resultant images analysed to ascertain the materials' CT number and appearance in the images. It was found that some AM materials have CT numbers very similar to human tissues, FDM, SLA and SLS produce samples that appear uniform on CT images and that 3D printed materials show a variation in internal structure. PMID- 21239208 TI - The effect of blood pressure calibrations and transcranial Doppler signal loss on transfer function estimates of cerebral autoregulation. AB - There are methodological concerns with combined use of transcranial Doppler (TCD) and Finapres to measure dynamic cerebral autoregulation. The Finapres calibration mechanism ("physiocal") causes interruptions to blood pressure recordings. Also, TCD is subject to signal loss due to probe movement. We assessed the effects of "physiocals" and TCD signal loss on transfer function estimates in recordings of 45 healthy subjects. We added artificial "physiocals" and removed sections of TCD signal from 5 min Finapres and TCD recordings. We also compared transfer function results from 5 min time series with time series as short as 1 min. Accurate transfer function estimates can be achieved in the 0.03-0.07 Hz band using beat by-beat data with linear interpolation, while data loss is less than 10s. At frequencies between 0.07 and 0.5 Hz, transfer function estimates become unreliable with 5s of data loss every 50s. 2s data loss only affects frequency bands above 0.15Hz. Finally, accurate transfer function assessment of autoregulatory function can be achieved from time series as short as 1min, although gain and coherence tend to be overestimated at higher frequencies. PMID- 21239210 TI - How common and what are the determinants of sub-optimal care for Parkinson's disease patients: the Milton Keynes community study. AB - OBJECTIVES: Limited data currently exists within the UK addressing the level of Parkinson's disease (PD) healthcare provision. We investigated whether care for PD patients in a UK community met national guidelines, and the determinants of sub-optimal care for this patient group. METHODS: 340 PD patients were identified from a population of 242,606 (crude prevalence 140 per 100,000 (95% CI 126-156 per 100,000), age-adjusted prevalence 199 per 100,000 (95% CI 178-221 per 100,000)). 248 out of 340 (73%) PD patients identified took part, completing rating scales assessing cognitive, non-motor and sociodemographic variables. RESULTS AND CONCLUSIONS: 9% of patients had never seen a neurologist for their PD and 18.5% were sub-optimally managed; defined as (a) delay between initial diagnosis and first consultation by a specialist >1 year and (b) patients who had not had specialist PD review for >1 year. Older age, poor cognition and worse mobility were major factors in determining sub-optimal care whilst lower education level and tremor as initial symptom were more modest predictors. 20% of patients had been started on dopaminergic therapies including ergot-derived agonists by their GP prior to referral and less than a third had seen allied health professionals throughout their illness. Further work is required to test whether these findings are generalizable across the country and identify what can be done to ensure equal access to specialist care so that all PD patients have access to best practice. PMID- 21239211 TI - Hospital admissions of young persons for illicit drug use or abuse: does neighborhood of residence matter? AB - Adolescence constitutes a period of risk for drug use and drug use disorders. Previous research, largely focused on individual risk factors, has failed to include neighborhood structure in the study of determinants of youth drug use or abuse. A cohort of 76,693 adolescents ages 13-15 from 586 urban neighborhoods in Sweden were followed up for 12 years, from age 16 to age 28. Multilevel modeling was used to analyze neighborhood variations in hospital admissions due to illicit drug use or abuse. We found a variation of 8% by neighborhood economic status and the risk of being admitted to hospital increased 73% in low-compared to high income neighborhoods. Our results suggest that neighborhood of residence in adolescence plays a significant role in predicting future health-related behaviors and that the need for drug abuse interventions at a neighborhood level is compelling. PMID- 21239212 TI - Sounds and scents in (social) action. AB - Although vision seems to predominate in triggering the simulation of the behaviour and mental states of others, the social perception of actions might rely on auditory and olfactory information not only when vision is lacking (e.g. in congenitally blind individuals), but also in daily life (e.g. hearing footsteps along a dark street prompts an appropriate fight-or-fly reaction and smelling the scent of coffee prompts the act of grasping a mug). Here, we review recent evidence showing that non-visual, telereceptor-mediated motor mapping might occur as an autonomous process, as well as within the context of the multimodal perceptions and representations that characterize real-world experiences. Moreover, we discuss the role of auditory and olfactory resonance in anticipating the actions of others and, therefore, in shaping social interactions. PMID- 21239214 TI - Light-dependent gene regulation in nonphototrophic bacteria. AB - Bacteria sense and respond to light, a fundamental environmental factor, by employing highly evolved machineries and mechanisms. Cellular systems exist to harness light energy usefully as in phototrophic bacteria, to combat photo oxidative damage stemming from the highly reactive species generated on absorption of light energy, and to link the light stimulus to DNA repair, taxis, development, and virulence. Recent findings on the genetic response to light in nonphototrophic bacteria highlight the ingenious transcriptional regulatory mechanisms and the panoply of factors that have evolved to perceive and transmit the signal, and to bring about finely tuned gene expression. PMID- 21239215 TI - Host-microbe interactions: ever increasing complexity. PMID- 21239213 TI - Control of protein function by reversible NE-lysine acetylation in bacteria. AB - Recently published work indicates that reversible N(E)-lysine (N(E)-Lys) acetylation of proteins in bacteria may be as diverse, and as important for cellular function, as it has been reported in eukaryotes for the last five decades. In addition to biochemical and genetic approaches, proteomic studies have identified N(E)-Lys acetylation of proteins and enzymes involved in diverse cellular activities such as transcription, translation, stress response, detoxification, and especially carbohydrate and energy metabolism. These findings provide a platform for elucidating the molecular mechanisms behind modulation of enzyme activity by N(E)-Lys acetylation, as well as for understanding how the prokaryotic cell maintains homeostasis in a changing environment. PMID- 21239216 TI - TD-DFT investigation of triple-stranded helicates with bis(benzene-o-dithiolato) ligands. AB - The electronic spectra of triple-stranded complexes of Ti(IV) with bis(benzene-o dithiolato) ligands (H(4)-L(1)=1,2-bis(2,3-dimercaptobenzamido)ethane; H(4) L(2)=1,2-bis(2,3-dimercaptobenzamido)benzene) were investigated at the TD-DFT level of theory employing B3LYP/LANL2DZ. The influence of the nature (aliphatic or aromatic) of the spacer bridging both {Ti(S(2)C(6)H(3))(3)} units on the absorptive features of the dinuclear complexes was also studied. B3LYP/LANL2DZ leads to spectra accounting for four absorption bands. At the lowest-energy region, the most important transitions are due to ligand-to-metal charge transfer (LMCT), in which out-of-plane ligand-centered orbitals and titanium-based MOs are involved. In going to the blue-region, a third band was detected with excitations showing an important contribution from ligand-to-ligand charge transfer (LLCT) and indeed, a combined LMCT+LLCT character has been considered. This observation seems to arise from a decrease in the metallic character of the LUMO-derivatives involved in the excitations. The origin of the absorption band at the highest energy part of the spectrum is assigned to a LLCT. The influence of the nature of the spacer on the molar absorption coefficients (E) for this band has been clearly observed. The complex bearing aliphatic spacer shows E of about 5 E+4 M( 1) cm(-1), while the one containing an aromatic spacer present a value of E of about 2 E+5 M(-1) cm(-1). PMID- 21239217 TI - Fluorescence spectroscopic investigation of the interaction between triphenyltin and humic acids. AB - The interaction between triphenyltin (TPT) and humic acid (HA) was investigated using UV-vis and fluorescence spectra techniques. The experimental results showed that the fluorescence quenching of HA by TPT was a result of the interaction of TPT with HA. The binding constant K(b) and corresponding thermodynamic parameters were measured at different temperatures. The binding of TPT molecule to HA is a spontaneous molecular interaction procedure in which entropy increased and Gibbs free energy decreased. Hydrophobic interaction force plays a major role in stabilizing the TPT-HA complex. The three-dimensional fluorescence contour spectra revealed that TPT could enter into the hydrophobic cavities in some domain of HA. PMID- 21239218 TI - ESR, electrochemical, molecular modeling and biological evaluation of 4 substituted and 1,4-disubstituted 7-nitroquinoxalin-2-ones as potential anti Trypanosoma cruzi agents. AB - Electrochemical and ESR studies were carried out in this work with the aim of characterizing the reduction mechanisms of 4-substituted and 1,4-disubstituted 7 nitroquinoxalin-2-ones by means of cyclic voltammetry in DMSO as aprotic solvent. Two reduction mechanisms were found for these compounds: the first, for compounds bearing a labile hydrogen by following a self-protonation mechanism (ECE steps), and the second, for compounds without labile hydrogen, based on a purely electrochemical reduction mechanism (typical of nitroheterocycles). The electrochemical results were corroborated using ESR spectroscopy allowing us to propose the hyperfine splitting pattern of the nitro-radical, which was later corroborated by the ESR simulation spectra. All these compounds were assayed as growth inhibitors against Trypanosoma cruzi: first, on the non-proliferative (and infective) form of the parasite (trypomastigote stage), and then, the ones that displayed activity, were assayed on the non-infective form (epimastigote stage). Thus, we found four new compounds highly active against T. cruzi. Finally, molecular modeling studies suggest the inhibition of the trypanothione reductase like one of the possible mechanisms involved in the trypanocidal action. PMID- 21239219 TI - Enhancing fluorescence intensity of Ellagic acid in Borax-HCl-CTAB micelles. AB - Ellagic acid (C(14)H(6)O(8)), a naturally occurring phytochemical, found mainly in berries and some nuts, has anticarcinogenic and antioxidant properties. It is found that fluorescence of Ellagic acid (EA) is greatly enhanced by micelle of cetyltrimethylammonium bromide (CTAB) surfactant. Based on this effect, a sensitive proposed fluorimetric method was applied for the determination of Ellagic acid in aqueous solution. In the Borax-HCl buffer, the fluorescence intensity of Ellagic acid in the presence of CTAB is proportional to the concentration of Ellagic acid in range from 8.0*10(-10) to 4.0*10(-5) mol L(-1); and the detection limits are 3.2*10(-10) mol L(-1) and 5.9*10(-10) mol L(-1) excited at 266 nm and 388 nm, respectively. The actual samples of pomegranate rinds are simply manipulated and satisfactorily determined. The interaction mechanism studies argue that the negative EA-Borax complex is formed and solubilized in the cationic surfactant CTAB micelle in this system. The fluorescence intensity of EA enhances because the CTAB micelle provides a hydrophobic microenvironment for EA-Borax complex, which can prevent collision with water molecules and decrease the energy loss of EA-Borax complex. PMID- 21239220 TI - The complexation of a novel squaric bis(thiosemicarbazone); 3,4 bis{[(aminothioxomethyl)amino]azamethylene}cyclobut-ene-1,2-diol. AB - A novel chelating agent (Sqtsc; H(4)L) bearing both hard and soft donor atoms was synthesized by the condensation of squaric acid with thiosemicarbazide. The ligand has two symmetrical sets of donor atoms (SNO), therefore, it was allowed to react with the metal ions at the mole ratio 2:1 (M:L). Mono- and bi-nuclear chelates were obtained in which the ligand showed a variety of modes of bonding viz. (OO)(2-), (SNNS)(2-) and (SNO)(2-) per each metal ion supporting the ambidentate and flexidentate characters of the ligand. The mode of bonding and basicity of the ligand depend mainly on the type of the metal cation and its counter anion. All the obtained complexes have the preferable O(h)-geometry except the VO(II)-complex (7) which has also the preferable square pyramid geometry. Structural elucidation was achieved via elemental and spectral data. PMID- 21239221 TI - A practical synthesis of novel alpha-dibromoalkyl- and trimethylsilylmethyl aminoboranes and derivatives. AB - Addition of LDA to a mixture of trimethylborate and dibromomethane in THF at a temperature of -78 degrees C leads to the formation of dibromomethyllithium and its capture by borate ester. ClB(OMe)(2) converts the resulting borate salt to dimethoxy(dibromomethyl)borane 2. N,N-Dimethylamino(methoxy)(dibromomethyl)borane 3 and N,N-bis(dimethylamino)(dibromomethyl)borane 4 were prepared by an amination reaction between N,N-dimethylaminotrimethylsilane and dimethoxy(dibromomethyl)borane 2. To obtain dichlorotrimethylsilylmethylborane 7 not containing the alpha-halomethyl group, N,N bis(dimethylamino)(trimethylsilylmethyl)borane 5 was first obtained from the reaction of ClB(NMe(2))(2) with an organolithium reagent. Dimethoxy(trimethylsilylmethyl)borane 6 was then prepared by methoxylation of compound 5. Finally, compound 7 was prepared by chlorination of 6 using BCl(3). The chemical structures of these compounds were determined using (13)C, (1)H, (11)B NMR and GC/MS/MS techniques. PMID- 21239222 TI - Thermochromism of perylenes: dynamics in aromatics. AB - A thermal equilibrium between planar and skew perylene derivatives induces thermochromism and may modulate molecular recognition. Thus, the long-lasting discussion about the geometry of perylene could be solved in terms of this equilibrium. Extension to other aromatics and practical applications such as for non contact fluorescence thermometers are discussed. PMID- 21239223 TI - Vestibular neuritis has selective effects on air- and bone-conducted cervical and ocular vestibular evoked myogenic potentials. AB - OBJECTIVE: To characterise the changes in cervical (cVEMP) and ocular (oVEMP) vestibular evoked myogenic potentials to different stimuli in patients with vestibular neuritis (VN). METHODS: cVEMPs and oVEMPs were recorded using air conducted (AC; clicks and short tone bursts) and bone-conducted (BC; lateral impulses and taps) stimuli in VN patients (n=23) and normals (n=40). RESULTS: AC evoked cVEMPs revealed few abnormalities, significantly less than for AC evoked oVEMPs (cVEMP: 22% vs oVEMP: 68%, P<0.001). Lateral impulses showed high rates of abnormalities (74% vs 70%, P>0.05) for both reflexes. Although forehead taps produced low rates of abnormalities for both reflexes (33% vs 13%, P>0.05), response amplitudes were smaller from the affected ear (P<0.05). CONCLUSIONS: AC stimuli were associated with low abnormality rates of cVEMPs, consistent with sparing of inferior nerve function in VN, but frequent abnormalities of oVEMPs. The high rates of abnormalities shown for lateral impulses suggest a dependence on superior nerve (i.e. utricular) afferents for both oVEMPs and cVEMPs. SIGNIFICANCE: Lateral impulses behave as expected for utricular function and AC cVEMPs for saccular function. The AC evoked oVEMP seems to depend on the integrity of the superior vestibular nerve, possibly due to saccular afferents travelling in it. PMID- 21239224 TI - Cytotoxicity evaluation of reactive metabolites using rat liver homogenate microsome-encapsulated alginate gel microbeads. AB - We present an improved cytotoxicity test for reactive metabolites, in which the S9 microsomal fraction of rat liver homogenate is encapsulated in alginate gel microbeads to avoid cytotoxic effects of S9-self-generated toxicants, microsomal lipid peroxides. The S9-encapsulated gel microbeads were prepared by a coaxial two-fluid nozzle and surfaces of the microbeads were coated with poly-L-lysine (PLL). Although the initial metabolic rate of the S9-encapsulated gel microbeads was about 20% slower than that of bare S9, the microbeads prevented the leakage of microsomal lipid peroxides thanks to the dense alginate and PLL polymer networks. In fact, the half maximal effective concentration of the indirect mutagen cyclophosphamide on NIH3T3 cells in the presence of the S9-encapsulated gel microbeads was about 5 times higher than that in the presence of bare S9. Use of the S9-encapsulated gel microbeads enabled the more accurate evaluation of the cytotoxicity of the reactive metabolites without the S9-based cytotoxicity. PMID- 21239225 TI - Characterization of rpoH in Acetobacter pasteurianus NBRC3283. AB - The RpoH in Acetobacter pasteurianus NBRC3283 was characterized. It was revealed that the rpoH controls the expression of groEL, dnaKJ, grpE, and clpB to different extents. In addition, the rpoH disruption mutant became apt to be affected by heat, ethanol, and acetic acid, indicating its importance in acetic acid fermentation. PMID- 21239226 TI - A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. AB - BACKGROUND: Restless legs syndrome (RLS) is a chronic disease, which is managed with palliative medications that are likely to be required for a patient's lifetime. It is, therefore, important to know the long-term consequences of these treatments. Currently, the most commonly prescribed treatment for RLS is one of the dopamine (DA) agonists. Most of what we understand about efficacy and side effects of the DA agonists are, however, derived from relatively short-term studies. This is particularly a problem since these medications produce in some patients a significant increase or augmentation of RLS symptoms known to occur during the first 2 years of treatment and perhaps even later in treatment. The primary aim of this study was to determine the long-term efficacy (10-year) for commonly used RLS medication types: dopaminergic agonists and opioids. METHODS: Records of all RLS patients treated in one tertiary care center with pramipexole, pergolide or methadone during the years 1997-2007 were reviewed. The duration and reason for any discontinuation of treatment and medication doses were recorded. RESULTS: Annual rates for discontinuing treatment persisted for up to 10 years of treatment and were fairly constant after the first year at 9% for pramipexole, 8% for pergolide, and 0% for methadone. Similarly, annual augmentation rates were fairly constant after the first year and persisted for up to 10 years at 7% for pramipexole, 5% for pergolide, and 0% for methadone. The percentage continuing on the treatment medication for over 5 years was 58% for pramipexole and 35% for pergolide. CONCLUSIONS: The DA agonists appear to have a limited period of clinical utility for many patients. Severe augmentation, while not common in any 1 year, can develop even after years on the medication. Methadone, in contrast, shows neither augmentation nor major problems with continued efficacy after the first year of treatment. PMID- 21239227 TI - Emerging diversity within chrysophytes, choanoflagellates and bicosoecids based on molecular surveys. AB - In recent years, a substantial amount of data on aquatic protists has been obtained from culture-independent molecular approaches, unveiling a large diversity and the existence of new lineages. However, sequences affiliated with minor groups (in terms of clonal abundance) have often been under-analyzed, and this hides a potentially relevant source of phylogenetic information. Here we have searched public databases for 18S rDNA sequences of chrysophytes, choanoflagellates and bicosoecids retrieved from molecular surveys of protists. These three groups are often considered to account for most of the heterotrophic flagellates, an important functional component in microbial food webs. They represented a significant fraction of clones in freshwater studies, whereas their relative clonal abundance was low in marine studies. The novelty displayed by this dataset was notable. Most environmental sequences were distant to sequences of cultured organisms, indicating a significant bias in the representation of taxa in culture. Moreover, they were often distant to sequences from other molecular surveys, suggesting an insufficient sequencing effort to characterize the in situ diversity of these groups. Phylogenetic trees with complete sequences present the most accurate representation of the diversity of these groups, with the emergence of several new clades formed exclusively by environmental sequences. Exhaustive data mining in sequence databases allowed the identification of new diversity hidden inside chrysophytes, choanoflagellates and bicosoecids. PMID- 21239228 TI - Barcoding diatoms: exploring alternatives to COI-5P. AB - Diatoms are a diverse lineage with species that can be difficult to identify or cryptic, but DNA barcoding, a molecular technique, can assist identification and facilitate studies of speciation and biogeography. The most common region used for DNA barcoding, COI-5P, can distinguish diatom species, but has not displayed universality (i.e., successful PCR amplification from diverse taxa). Therefore, we have assessed the following alternative markers: ~1400bp of rbcL; 748bp at the 3' end of rbcL (rbcL-3P); LSU D2/D3 and UPA. Sellaphora isolates were used to determine each marker's ability to discriminate among closely related species and culture collection material was utilized to explore further marker universality. All of the alternative markers investigated have greater universality than COI 5P. Both full and partial (3P) rbcL regions had the power to discriminate between all species, but rbcL-3P can be sequenced more easily. LSU D2/D3 could distinguish between all but the most closely related species (96%), whereas UPA only distinguished 20% of species. Our observations suggest that rbcL-3P should be used as the primary marker for diatom barcoding, while LSU D2/D3 should be sequenced as a secondary marker to facilitate environmental surveys. PMID- 21239230 TI - Cryopreservation of ovarian tissue for a decade in Denmark: a view of the technique. AB - This paper presents the Danish 10-year experience (1999-2009) with cryopreservation (n=386) and autotransplantation of ovarian tissue (n=18). Before applying the technique to humans, the method was thoroughly tested and validated. The cryoprotectant solution was chosen after histological evaluation of mouse and human ovarian tissue after freezing with four different combinations of cryoprotectants. Viability was confirmed by transplantation of frozen-thawed human ovarian tissue (n=49) to oophorectomized Nude mice. Viability after transport of fresh tissue 4-5h prior to freezing had previously been validated. Overnight transport of fresh ovarian tissue prior to cryopreservation was evaluated when human ovarian tissue was kept on ice for 20h and then cryopreserved. The thawed ovarian tissue was transplanted to an oophorectomized Nude mouse and histology confirmed viability. In Denmark 12 women have received a total of 18 autotransplantations of ovarian tissue. All women resumed ovarian function and three healthy babies were born to two women. In both women, the tissue was transported on ice for 4-5h prior to cryopreservation. Ovarian tissue cryopreservation is an important method for fertility preservation; however, before applying the method clinically, each laboratory should perform thorough validation of their technique. PMID- 21239229 TI - Seeking common pathophysiology in asthma, atopy and sinusitis. AB - Asthma and chronic sinusitis are inexplicably common airway diseases that are linked to atopy and allergic inflammation. T helper type 2 (Th2) cells and the associated cytokines are believed to play crucial pathogenic roles in asthma, but the environmental factors that instigate allergic airway disease remain poorly understood. Environmental proteinases are highly allergenic and are candidate inducers of airway Th2 responses. Determining the proteinases and their sources that are relevant to airway disease, however, remains challenging. In this Opinion, we summarize the evidence that implicates fungi as both a relevant source of allergenic proteinases and a potential cause of asthma, atopy and chronic sinusitis through airway infection. Clarification of the extrinsic causes of these processes will markedly improve diagnosis, prognosis and therapy. PMID- 21239232 TI - Offering patients choices: a pilot study of interactions in the seizure clinic. AB - Using conversation analysis (CA), we studied conversations between one United Kingdom-based epilepsy specialist and 13 patients with seizures in whom there was uncertainty about the diagnosis and for whom different treatment and investigational options were being considered. In line with recent communication guidance, the specialist offered some form of choice to all patients: in eight cases, a course of action was proposed, to be accepted or rejected, and in the remaining five, a "menu" of options was offered. Even when presenting a menu, the specialist sometimes conveyed his own preferences in how he described the options, and in some cases the menu was used for reasons other than offering choice (e.g., to address patient resistance). Close linguistic and interactional analysis of clinical encounters can show why doctors may feel they are offering choices when patients report that the decision was clinician dominated. PMID- 21239231 TI - Molecular determinant-based typing of KIR alleles and KIR ligands. AB - Killer cell immunoglobulin-like receptors (KIRs) regulate NK cell function. KIRs and their HLA ligands are highly polymorphic in nature with substantial allelic polymorphism. At present, there is a lack of an expedient method for KIR and HLA allele typing with relevant functional information. Here, we developed a single nucleotide polymorphism (SNP) assay to type various allele groups of KIR2DL1 with distinct functional properties based on polymorphism at position 245. We also established a SNP assay to type different KIR ligands based on polymorphism at position 77 in HLA-C and position 83 in HLA-B and -A. Our SNP assays for KIR and KIR ligand typing are much cheaper and faster than existing high-resolution typing. Importantly, our high-throughput methods provide readouts that are informative in predicting NK cell activity in health, disease, and transplantation. PMID- 21239233 TI - Anticonvulsant activity of BmK AS, a sodium channel site 4-specific modulator. AB - The anticonvulsant activity of BmK AS, a sodium channel site 4-selective modulator purified from scorpion venom (Buthus martensi Karsch), was investigated in unanesthetized rats with acute pentylenetetrazole (PTZ)- and pilocarpine induced seizures. Rats were microinjected in the CA1 region with either saline or BmK AS, followed by epileptogenic doses of PTZ or pilocarpine 30 minutes later. The anticonvulsant efficacy of BmK AS in PTZ- or pilocarpine-evoked seizure-like behavior and cortical epileptiform EEG activity was assessed. Intrahippocampal injections of BmK AS (0.05-1 MUg in 1 MUL) produced dose-dependent anticonvulsant activity in the PTZ model, suppressing seizure-associated behavior and reducing both the number and duration of high-amplitude, high-frequency discharges (HAFDs) on the EEG. In contrast, BmK AS did not affect the epileptiform EEG in the pilocarpine model over the same dose range, although it did increase the latency to status epilepticus onset and slightly, but significantly, reduced the seizure score. In summary, our results demonstrate that the sodium channel site 4 selective modulator BmK AS is an effective inhibitor of PTZ- but not pilocarpine induced acute seizures. These results indicate that BmK AS may serve as a novel probe in exploring the role of different sodium channel subtypes in an epileptogenic setting and as a potential lead in developing antiepileptic drugs specifically for the therapy of sodium channel site 4-related epilepsy. PMID- 21239234 TI - Heterology tolerance and recognition of mismatched base pairs by human Rad51 protein. AB - Human Rad51 (hRad51) promoted homology recognition and subsequent strand exchange are the key steps in human homologous recombination mediated repair of DNA double strand breaks. However, it is still not clear how hRad51 deals with sequence heterology between the two homologous chromosomes in eukaryotic cells, which would lead to mismatched base pairs after strand exchange. Excessive tolerance of sequence heterology may compromise the fidelity of repair of DNA double-strand breaks. In this study, fluorescence resonance energy transfer (FRET) was used to monitor the heterology tolerance of human Rad51 mediated strand exchange reactions, in real time, by introducing either G-T or I-C mismatched base pairs between the two homologous DNA strands. The strand exchange reactions were much more sensitive to G-T than to I-C base pairs. These results imply that the recognition of homology and the tolerance of heterology by hRad51 may depend on the local structural motif adopted by the base pairs participating in strand exchange. AnhRad51 mutant protein (hRad51K133R), deficient in ATP hydrolysis, showed greater heterology tolerance to both types of mismatch base pairing, suggesting that ATPase activity may be important for maintenance of high fidelity homologous recombination DNA repair. PMID- 21239235 TI - Enantioselective separation and electrochemical sensing of D- and L-tryptophan at ultratrace level using molecularly imprinted micro-solid phase extraction fiber coupled with complementary molecularly imprinted polymer-fiber sensor. AB - Highly efficient enantioselective separation and quantitative recoveries of D- and L-tryptophan in aqueous and real samples can be achieved, with a monolithic molecularly imprinted polymeric fiber that serves both for micro-solid phase extraction and ultratrace sensing, without any false-positive (non-specific) contribution and cross-reactivity, in the range of 0.15-30.00 ng mL(-1) with detection limit as low as 0.0261 ng mL(-1) (relative standard deviation=0.64%, signal/noise=3). The proposed method combining molecularly imprinted micro-solid phase extraction fiber and a complementary molecularly imprinted polymer-carbon composite fiber sensor is proven to be useful for clinical diagnosis of stress related diseases caused by acute tryptophan depletion. PMID- 21239236 TI - Identification of carotenoid pigments and their fatty acid esters in an avian integument combining HPLC-DAD and LC-MS analyses. AB - Yellow-orange-red ornaments present in the integuments (feathers, bare parts) of birds are often produced by carotenoid pigments and may serve to signal the quality of the bearer. Although carotenoid esterification in tissues is a common phenomenon, most of the work on avian carotenoids has been focused on the identification of free forms or have been done after sample saponification. Here we determined free and esterified carotenoid composition in a bird species with red ornaments: the red-legged partridge (Alectoris rufa). Carotenoids from leg integument were extracted and processed by TLC to separate three major carotenoid groups (free form, mono- and diesters with fatty acids), whereas saponified extracts gave only free forms of carotenoids. TLC fractions were then analyzed by HPLC-DAD with C18 phase column for a preliminary identification of carotenoid groups. The final characterization of free carotenoids and its esters with fatty acids was performed with direct extracts analyzed by LC-MS and LC-MS/MS with a C30 phase, always with a system coupled to DAD. The main carotenoid (lambda(max) 478 nm and [M+H](+) at m/z 597.2) was identified as astaxanthin by comparison with standards. A second carotenoid (lambda(max) between 440 and 480 nm and [M+H](+) at m/z 581.3) was not identified among any of the commercially available carotenoid standards, although it could correspond to pectenolone according to its fragmentation pattern. Both the unidentified carotenoid and astaxanthin formed monoesters with fatty acids, but only astaxanthin was in its diesterified form. Monoesters were mainly formed with palmitic, stearic, oleic and linoleic acids. Complementary analyses of fatty acid composition in partridge integument by GC-MS revealed high amounts of these and other fatty acids, such as myristic, arachidic and docosanoic acids. The combination of HPLC-DAD and LC-MS/MS spectra was especially useful to identify the carotenoids present in the esterified forms and the probable masses of the fatty acids included in them, respectively. PMID- 21239238 TI - A rapid and accurate UPLC/MS/MS method for the determination of benzodiazepines in human urine. AB - A rapid, sensitive, and specific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) assay method for simultaneous determination of 13 benzodiazepine compounds in human urine was developed and validated. Aliquots of 0.5 mL of urine specimens were used for the analysis and the benzodiazepines were extracted by single step methanol (containing 0.2% formic acid) precipitation and then separated on a BEH C18 (50 mm * 2.1 mm, 1.7 MUm) analytical column with the temperature maintained at 45 degrees C. The mobile phases consisted of methanol and water (both containing 0.2% formic acid) and the flow rate was 0.4 mL/min. The TQ detector, equipped with an electrospray ionization ion source, was set up with a positive mode. The acquisitions were performed in multiple-reaction monitoring (MRM) and the limit of quantification was 20 ng/mL for all of the 13 compounds. The low limits of detections (LODs) of the benzodiazepines in this method were between 0.5 and 2 ng/mL. The chromatographic separation time was 4 min and calibration curves in human urine were generated over the range of 20 2000 ng/mL. The method validation parameters such as accuracy, precision, carryover, recovery, stability, and specificity for all of the 13 compounds were within the acceptable range. This method is suitable for the high throughput screening of benzodiazepines in clinical laboratories. PMID- 21239237 TI - Combination of HPLC chromatogram and hypoglycemic effect identifies isoflavones as the principal active fraction of Belamcanda chinensis leaf extract in diabetes treatment. AB - In previous study, we demonstrated the hypoglycemic effect of aqueous extract of Belamcanda chinensis leaves in rats. Here, we separated the aqueous extract of B. chinensis leaves and investigated the spectrum-effect relationships between HPLC chromatograms and hypoglycemic activities of different isolates from B. chinensis leaf extract. Sequential solvent extraction with petroleum ether, chloroform, acetic ester and n-butanol provided several isolates showing similar hypoglycemic activities, making it difficult to discriminate the active fractions. Stepwise elution through HP20 macroporous resin by water, 40% and 95% ethanol provided isolates with distinct hypoglycemic activities, representing a simple, rapid and efficient preparative separation method. Combination of HPLC chromatogram and pharmacological effect targeted a hypoglycemic activity-related region in HPLC chromatogram. Each peak in this region was analyzed by UV spectrum scan. Most of them were flavonoids in which tectoridin and swertisin were known flavonoids with anti-diabetic activities. In together, this work provides a general model of combination of HPLC chromatography and pharmacological effect to study the spectrum-effect relationships of aqueous extract from B. chinensis leaves, which can be used to find principle components of B. chinensis on pharmacological activity. PMID- 21239239 TI - Treatment of gastrointestinal angiodysplasia and unmet needs. AB - BACKGROUND: Gastrointestinal angiodysplasia (GIAD) may either be asymptomatic or induce overt or obscure bleeding with a high risk of recurrence. Numerous therapeutic options are available but evidence bases are lacking. AIM: We conducted a comprehensive review of pharmacological and endoscopic treatments for previous or active bleeding GIAD and established the unmet needs of the clinicians. METHODS: Clinical trials, series, and reports, having been selected through PubMed inquiry, manual searching, and reference list reviewing, were classified by levels of evidence. RESULTS: Controlled studies focusing on GIAD treatment, excluding other GI vascular malformations, are rare. Endoscopic destruction, preferably using non-contact endoscopic techniques, is most often proposed as a first-line treatment for GIAD (expert level). In addition, APC is preferred over Nd:Yag laser due to the lower risk of perforation (expert level). Pharmacological treatments for GIAD are considered either when endoscopy fails to access the AD or in order to prevent rebleeding for "chronic bleeding patients." Octreotide and oestroprogestative treatments are the best evaluated drugs; however, no appropriate comparison on cost-effectiveness and tolerance has been performed. CONCLUSIONS: The most effective therapeutic strategy for bleeding GIAD is currently inconclusive, and new trials should be performed to address unmet needs. PMID- 21239240 TI - Desmoid-type chest wall fibromatosis. A six cases series. AB - PURPOSE OF THE STUDY: Desmoid-type fibromatosis is a fibroblastic proliferation that develops in the deep soft tissues and is characterized by infiltrative growth and a tendency towards local recurrence but does not metastasize. Fibromatosis of the chest wall is rare, representing only 10 to 20% of all deep fibromatoses. CASE REPORT: We report a six cases series of fibromatosis of the chest wall treated at our institution between 1996 and 2009. There were five men and one woman with a mean age of 42.2. Swelling of the chest wall was the most frequent symptom. Imaging showed an expansive homogeneous mass, invading the rib (four cases) or the sternum (two cases). Surgical resection was performed in all cases. The outcome was favorable (five cases) or marked by local recurrence (one case). DISCUSSION: Although it is considered to be a benign lesion, this tumor can be locally very aggressive, and has a high local recurrence rate depending upon the efficacy of surgical resection. PMID- 21239241 TI - Non-simultaneous bilateral hip fracture: epidemiologic study of 241 hip fractures. AB - INTRODUCTION: Hip fractures are an important public health problem given their growing incidence as well as their functional and vital repercussions. With longer survival, patients with a contralateral fracture are increasingly numerous. The objective of this study was to investigate the bilateralization of hip fractures in terms of anatomic location and time to the second fracture. HYPOTHESIS: Contralateral fractures are of the same anatomical type as the primary fractures. PATIENTS AND METHODS: This was a retrospective epidemiological study on all patients managed for hip fractures between January 2007 and May 2008. Each case of bilateralization was studied. RESULTS: We included 241 patients in the study. The mean age at occurrence of the primary fracture was 83.3 years (range, 60-99 years). The distribution showed 45.6% true femoral neck fractures and 54.4% trochanteric fractures. Twenty-six of the 241 patients had already suffered from a hip fracture (10.8%). This fracture was the same type as the recent fracture in 80.8% of the cases. The mean time between the two fractures was 5.6 years (range, 1-277 months). DISCUSSION: The contralateral fractures were the same anatomical type as the primary fracture in eight out of ten patients and the symmetry remains intact in 64-83% depending on the series. The fracture occurred on average within 5 years of the first hip fracture. In cases of asymmetry, the second fracture was more often a trochanteric fracture. The causes explaining this symmetry are several and are poorly known. The risk factors are numerous and their prevention is essential (acting on the patient's environment to prevent falls, rehabilitation to reestablish autonomy after the first fracture, and preventive treatment of osteoporosis), although these notions are often ignored by surgeons. LEVEL OF EVIDENCE: IV, retrospective study. PMID- 21239243 TI - Phosphoinositide-generated second messengers in cardiac signal transduction. AB - Hokin and Hokin were the first to demonstrate that tissue inositol phospholipid (phosphoinositide, PI) turnover was increased by hormone treatment. Twenty years later, Michell published a seminal review in which he suggested a relationship between stimulated inositol phospholipid metabolism and Ca(2+) mobilization. The biochemical link between these two events was subsequently identified by Berridge and colleagues as inositol trisphosphate (InsP(3)), a Ca(2+)-mobilizing ligand that is formed by the breakdown of phosphatidylinositol bisphosphate (PIP(2)). The other product of inositol phospholipid hydrolysis, diacylglycerol, activates a Ca(2+)-sensitive phospholipid-dependent protein kinase, protein kinase C, which has been considered as a potential regulator of cardiac ion channels, inotropic state, and gene expression. This review summarizes our current state of knowledge concerning the formation of phosphoinositide-generated second messengers in cardiac cells and their potential role in mediating functional responses in the myocardium. PMID- 21239242 TI - Balancing sensitivity and specificity: sixteen year's of experience from the mammography screening programme in Copenhagen, Denmark. AB - AIM: To report on sensitivity and specificity from 7 invitation rounds of the organised, population-based mammography screening programme started in Copenhagen, Denmark, in 1991, and offered biennially to women aged 50-69. Changes over time were related to organisation and technology. METHODS: Individualized data were retrieved on outcome of screening mammography, assessment, surgery, and interval cancers. European Guideline performance indicators were calculated, supplemented with false positive and interval cancer rates per 1000 screens. False positive tests were divided into those sorted out at assessment (Type 1) and at surgery (Type 2). RESULTS: In total, 1392 invasive breast cancers/ductal carcinoma in situ cases (DCIS) were diagnosed, giving an overall detection rate of 7.6 per 1000 screens. Of 5178 false positive tests, 4666 were Type 1 and 512 Type 2. The 468 interval cancers constituted 25% of all breast cancers (=screen detected+interval cancer). Almost all outcome measures were well within the desirable level of the European Guidelines. Risk of Type 2 false positive tests was positively associated with detection rate especially at initial screen, and interval cancer rate was negatively associated with detection rate. This association was decoupled after introduction of high resolution ultrasound and stereotactic breast biopsies, resulting in a Benign-to-Malignant-Ratio (BMR) of 1:11.40. CONCLUSION: Mammography screening is a delicate balance between benefits and risks. Increase in detection rate came at cost of increase in risk of benign biopsies. Introduction of new technologies broke this pattern and a slight increase in detection rate coincided with an unprecedentedly low BMR. PMID- 21239245 TI - Macrophage scavenger receptors and atherosclerosis. AB - The fatty streak is the earliest visible atherosclerotic lesion. Microscopically, this lesion consists of a subendothelial collection of macrophage foam cells that are characterized by their content of numerous lipid droplets. Investigations into the mechanisms responsible for foam cell formation have led to the identification of macrophage scavenger receptors that are capable of recognizing and internalizing modified forms of low-density lipoprotein (LDL). The recent cloning of a macrophage scavenger receptor that is capable of recognizing acetylated and oxidized LDL has permitted the application of molecular approaches to the study of scavenger receptor expression and the determinants of ligand recognition. These studies suggest the possibility that treatment strategies that inhibit LDL modification or influence macrophage gene expression might be effective in the prevention or treatment of atherosclerosis. PMID- 21239244 TI - Protein S and protein C Biochemistry, physiology, and clinical manifestation of deficiencies. AB - Protein C and protein S are two plasma proteins that participate in an anticoagulant pathway. Protein C circulates as an inactive precursor that is converted to an active serine protease by a complex between thrombin and the endothelial cell-surface protein thrombomodulin. Activated protein C and protein S form an anticoagulant complex on cell surfaces that inactivates two of the regulatory proteins of coagulation, factors Va and VIIIa. Activated protein C is then cleared from the circulation by a relatively slow inactivation by alpha(1) antitrypsin and the protein C inhibitor. Deficiencies in protein C and protein S are associated with thrombotic complications. With protein S, this can arise as the result of a deficiency in protein S synthesis, proteolytic cleavage, and/or due to an increase in binding to the complement regulatory protein C4bBP, which behaves like an acute phase reactant. Inflammatory mediators not only elevate C4bBP levels, but also lead to downregulation of thrombomodulin expression. Animal experiments suggest that activated protein C and protein S may be effective and safe antithrombotic agents. PMID- 21239246 TI - Cardiomyocyte growth regulation by Ca(2+)-calmodulin. AB - Elevation of intracellular free Ca(2+) concentrations is a common early cellular action of a variety of agents that induce cardiac myocyte hypertrophy. This observation, plus the large body of evidence that implicates Ca(2+)-calmodulin (CaM) in cell-cycle control in other cells, prompted us to evaluate the role of the CaM signal-transducing pathway in cardiomyocyte growth regulation. Toward that end, several lines of transgenic mice were generated to express elevated levels of CaM in cardiac myocytes during development. Constitutive overexpression of CaM in the hearts of transgenic mice induced both hyperplastic and hypertrophic growth of cardiac myocytes; some characteristics and potential mechanisms of this growth response are the subjects of the present review. PMID- 21239247 TI - Control of cardiac muscle cell division. AB - Division and proliferation of the terminally differentiated ventricular heart muscle cell in the adult mammal is not activated after injury such as that caused by a myocardial infarction. We do not understand how mitosis is irreversibly blocked in these myocytes during early development. Mammalian cardiac muscle, unlike skeletal muscle, cannot regenerate. Knowledge of the mechanisms that control the cardiac myocyte cell cycle would allow us to design reagents or procedures to initiate repair or regeneration of the adult myocardium following injury. Ideally, we would like to be able to revert cardiac muscle cells in intact heart muscle to the biochemical state they were in during early fetal growth when they were actively dividing and proliferating. This article briefly reviews what is currently known about the mechanism which so tightly suppresses the mitotic activity of these highly differentiated cells. PMID- 21239248 TI - Expression and regulation of the renin gene. AB - Elucidating the expression and regulation of the renin gene has been the focus of intense investigation because of its participation in the renin-angiotensin system and its links to hypertension. Since the cloning of the first complementary DNA (cDNA) encoding mouse submandibular gland renin over a decade ago, a great deal of progress has been made toward understanding the expression and regulation of renin in a number of species. These include the isolation of cDNA and genomic clones for interspecific renin genes, the demonstration of primary expression in tissues where only renin activity data were previously reported, and, more recently, the development of tools to examine specifically the mechanisms of renin transcription and regulation, and to define the role played by the renin-angiotensin system in the pathogenesis of hypertension. PMID- 21239249 TI - Regulatory mechanisms for skeletal muscle differentiation and their relevance to gene expression in the heart. AB - The discovery of the MyoD family of skeletal muscle-specific regulatory factors, which bind DNA and activate muscle-specific transcription in collaboration with widely expressed factors, has led to dramatic progress toward understanding the mechanisms responsible for activation of muscle-specific gene expression during differentiation of skeletal muscle. In contrast, relatively little is known of the mechanisms responsible for activation and maintenance of cardiac muscle transcription. Many muscle-specific genes that are directly regulated by the MyoD family in skeletal muscle are also expressed in the heart, which does not express known members of the MyoD family. The different embryonic origins of skeletal and cardiac muscle and the differences in responsiveness of skeletal and cardiac muscle-specific genes to growth factor signals suggest that, if MyoD-like proteins participate in cardiac muscle development, they are likely to be expressed much earlier in development than the MyoD family and may have diverged substantially from these skeletal muscle regulatory proteins. Regulatory pathways independent of or in addition to those controlled by MyoD-like proteins appear more likely to be involved in specification of the cardiac muscle developmental program. PMID- 21239250 TI - Ischemic preconditioning Nature's own cardioprotective intervention. AB - A brief exposure to ischemia paradoxically makes the heart better able to withstand a subsequent ischemic insult. This phenomenon has been termed ischemic preconditioning. Recent studies indicate that occupancy of A(1)-type adenosine receptors is the trigger for the preconditioning response, but the ultimate mechanism remains elusive. This review will examine what is known about ischemic preconditioning, including the scope and magnitude of the protection that is realized, its possible mechanism, and its clinical relevance. PMID- 21239251 TI - Gene expression in cardiac hypertrophy. AB - Cardiac hypertrophy due to hemodynamic overload is a harbinger of morbidity and mortality in humans. The development of hypertrophy involves both quantitative and qualitative changes in gene expression that are thought to produce an enlarged organ more capable of meeting its new functional requirements. The genes are normal, but the way in which they are regulated is modified. Analysis of these changes and the mechanisms involved are essential if we are to understand the role that hypertrophy plays in the pathogenesis of heart failure. PMID- 21239252 TI - Antithrombotic agents from salivary glands of hematophagous animals. AB - The introduction of thrombolytic agents and adjunctive anticoagulant therapy in acute myocardial infarction and heparin-aspirin combinations in unstable angina have resulted in major gains in the acute management of these disorders; however, it is widely believed that available therapeutic agents, such as streptokinase and tissue plasminogen activator (t-PA), anticoagulants, such as heparin, and antiplatelet agents, such as aspirin, may not possess the optimal efficacy and safety profile. A major surge was initiated to identify alternative thrombolytic and antithrombotic drugs, and as a part of these efforts the isolation and characterization of protein salivary anticoagulants from hematophagous animal species has assumed importance. In the following, we briefly review these proteins and the development of peptides and peptidomimetic compounds based on their structures and discuss the potential utility of these compounds in cardiovascular disease therapy. PMID- 21239253 TI - New concepts regarding constriction within a stenosis Influence of intraluminal pressure changes. AB - Morphologic and clinical studies clearly show that most human coronary lesions exhibit vasomotion. Variable ischemic thresholds, ischemia unrelated to workload, and variant angina further prove the presence of vasoconstriction in coronary artery disease. While vasoconstriction is important in the presentation of coronary artery disease, the unique type of contraction present in an arterial stenosis has been only recently examined. In normal large conduit arteries, the afterload opposing smooth muscle contraction is the intraluminal pressure, which remains relatively constant. In stenotic arteries, as the artery constricts, the pressure (or afterload) opposing smooth muscle shortening decreases, leading to exaggerated constriction and augmented arterial narrowing. Physiologically, this implies that a unique type of contraction ("heterotonic") occurs within an arterial stenosis. Clinically, this type of contraction might explain the exaggerated shortening observed within an arterial stenosis. It also suggests that stenotic pressure is an important variable in the pathophysiology and potential treatment of angina pectoris. PMID- 21239254 TI - Antimyosin scintigraphy in cardiovascular diseases. AB - Antimyosin antibody is highly specific for in vivo delineation of acute myocyte necrosis as only irreversibly damaged myocytes with sarcolemmal disruption will enable access of the administered antibody to the once-privileged intracellular antigen-myosin. Thus, antimyosin radiolabeled with either indium-111 or technitium-99m has been used for the noninvasive diagnosis of myocyte necrosis associated with acute myocardial infarction, myocarditis, heart transplant rejection, as well as in other cardiac disorders such as rheumatic carditis or adriamycin cardiotoxicity. The sensitivity of antimyosin scintigraphy for these disorders has been reported to be 90%-100%. The final verdict on its full potential must await extensive clinical use. PMID- 21239255 TI - Letter to the editor. PMID- 21239256 TI - Letter to the editor. PMID- 21239257 TI - Peripartum vascular collapse Dissection of a genetic disease. PMID- 21239258 TI - Genetic regulation of endothelin-1 in vascular endothelial cells. AB - Endothelin-1 (ET-1) is a potent vasoconstrictor and smooth muscle cell mitogen synthesized and secreted by endothelial cells. This vasoactive peptide is genetically regulated by many of the cytokines, hormones, and physical forces that are involved in vascular disease processes. Transcriptional regulation of the ET-1 gene depends upon the cis-acting elements of the ET-1 promoter and their interaction with the protooncogene products Fos and Jun as well as other DNA binding proteins. PMID- 21239259 TI - Cardiac sodium channel structure and function. AB - The upstroke of the action potential in heart cells, as in nerve and skeletal muscle cells, is due to the movement of sodium ions through ion-selective channels in the surface membrane. Voltage-dependent sodium channels in the heart, while sharing many common electrophysiologic characteristics with sodium channels in nerve and skeletal muscle, are distinctive in that they also contribute current to the plateau phase of the action potential and have unique sensitivities to channel-active toxins and drugs, most notably the local anesthetic-type antiarrhythmic agents. With the recent cloning and functional expression of the rat and human cardiac sodium channel genes, we are now in a position to understand better the molecular mechanisms responsible for the unique characteristics of sodium channels in the heart. PMID- 21239260 TI - Genetic lipid disorders in cardiovascular disease. AB - Familial lipoprotein disorders are seen in approximately half of the patients with premature coronary artery disease. The molecular basis for most of these disorders is poorly understood. Several (usually) rare genetic disorders affecting the genes for apolipoproteins AI-CIII-AIV, (a), B and E; lipoprotein receptors such as the low-density lipoprotein receptor or lipoprotein-processing enzymes (lecithin-cholesterol-acyltransferase) are associated with coronary artery disease. The characterization of these unusual extreme lipoprotein defects enables a better understanding of normal lipoprotein physiology and the role of lipoproteins and apolipoproteins in the pathophysiology of arteriosclerosis. PMID- 21239261 TI - Immune cytokines and cardiac disease. AB - In conditions such as idiopathic dilated congestive cardiomyopathy associated with lymphocytic myocarditis and cardiac allograft rejection, the immune system can reversibly impair cardiac function. Cytokines interleukin-1 and tumor necrosis factor disrupt beta-adrenergic signal transduction and agonist stimulation of contractility. Identification of this reversible effect potentially offers a novel pathophysiologic mechanism for producing cardiac injury. PMID- 21239262 TI - The use of isolated myocytes to evaluate myocardial remodeling. AB - It has been postulated that changes in the gross anatomic features of the heart due to various hemodynamic alterations (for example, pressure or volume overloading) are mirrored by specific changes in myocyte shape. The development of the isolated cardiac myocyte preparation has been instrumental in providing a more consistent and expeditious means for assessing changes in cellular dimensions. Data obtained from isolated myocytes collected from adult rats with various types of hemodynamic overloading confirm that cell shape changes in a consistent and predictable manner and that hypertrophy, rather than hyperplasia, is responsible for the increase in cardiac mass. The use of isolated myocytes should provide answers to many other questions regarding ventricular remodeling. PMID- 21239263 TI - Limitations of cineangiography Impact of new technologies for image processing and quantitation. AB - In coronary cineangiography, all components of the imaging chain are potential sources of image distortion. An understanding of these limitations is important to the understanding of the utility and limitations of digital techniques for image processing and for quantitative assessment of arterial dimensions. PMID- 21239264 TI - The long-QT syndrome Genetic considerations. AB - The familial long-QT syndrome (LQTS) is an infrequently occurring disorder in which affected family members have QT prolongation on the ECG, often associated with recurrent syncope and fatal ventricular arrhythmias. Autosomal recessive and autosomal dominant modes of inheritance were suggested by the pattern of occurrence of this disorder in the first reported LQTS families. Statistical genetic analysis (segregation analysis) has substantiated a major gene effect on QTc length in two large pedigrees. Gene linkage studies have uncovered tight linkage between a DNA marker at the Harvey ras-1 locus on chromosome 11 and LQTS in one large pedigree, substantiating a genetic basis of this disorder. PMID- 21239265 TI - Strategies for the design of novel thrombolytic and antithrombolytic agents. AB - Recent advances in our understanding of thrombosis and thrombolysis have led to the design of new thrombolytic agents and regimens that may offer improved efficacy. In general, these new approaches specifically target pivotal steps in thrombus formation or lysis. The goal is to reduce adverse side effects (such as bleeding complications) that result from development of a lytic state or that result from a failure to maintain patency (as characterized by rethrombosis). The points in the coagulation cascade that are susceptible to inhibition, as well as the proposed agents for intervention, are discussed in this review. PMID- 21239266 TI - Growth factors, cytokines, and vascular injury. AB - Restenosis after angioplasty can be considered as the undesirable consequence of the vascular response to injury. The repair process, which manifests as smooth muscle cell hyperplasia and extracellular matrix deposition, is controlled by growth factors and cytokines from a variety of sources. Vascular smooth muscle cells themselves synthesize mitogens, such as platelet-derived growth factor and insulinlike growth factor I, which synergize to promote medial cell proliferation. Additionally, growth factors such as fibroblast growth factor are probably released by trauma from damaged smooth muscle cells or from the matrix that surrounds them. The abundance and cellular distribution of cell membrane receptors for the various growth factors is also modulated after arterial injury, and probably plays a role in determining the characteristics and magnitude of the proliferative response. It is becoming increasingly apparent that multiple redundant and often overlapping control mechanisms are involved in modulating restenosis. As the sequence of signaling events is unraveled, and antagonists to the critical mediators are developed, it is likely that more effective treatment protocols will become available to improve the long-term outcome of angioplasty procedures. PMID- 21239267 TI - The tissue renin-angiotensin systems in cardiovascular disease. AB - The renin-angiotensin system, in its classic definition, is known as an endocrine system that exerts its actions through the effector peptide, angiotensin II, in various organs to act as a vasoconstrictor and a regulator of salt and volume homeostasis. The availability of more sensitive methods to study the biochemistry and pharmacology as well as the molecular biology of the RAS has expanded our knowledge of the system and provided new perspectives of autocrine and paracrine functions of the RAS in cardiovascular regulation. One of the more exciting of these recently described actions is the possible involvement of the RAS in the adaptive processes related to cardiovascular hypertrophy and angiogenesis. PMID- 21239268 TI - Adenosine receptors and cardiovascular function. AB - Adenosine exerts pronounced cardiac and vascular effects. Distinct receptors, present on the endothelium and vascular and cardiac myocytes, mediate the various cardiovascular effects of adenosine. The A(1) and the A(2) subtypes of adenosine receptor are coupled to different G proteins, second messengers, and physiologic responses. Recent cloning of the two subtypes of adenosine receptor should enhance our understanding of the structure, function, and regulation of these receptors and should facilitate discovery of new subtypes that may be expressed in a tissue-specific manner. These molecular advances should also provide insights into the mechanism of the cardiovascular action of adenosine, which is gaining greater clinical usefulness. PMID- 21239269 TI - Modulation of the cell membrane expression of the kininogens regulates the rate of bradykinin delivery to cells. AB - The kininogens were first recognized as the parent molecules for bradykinin. Their relative physiologic importance in plasma hemostasis and fibrinolysis and tissue cysteine protease inhibition has not been clarifed. Recent studies on the structure and function of the plasma kininogens, their interaction with cells of the intravascular compartment, and clinical investigations on contact system activation have refocused the physiologic importance of these proteins to kinin delivery for the maintance of vasodilatory tone. Kininogen expression on platelets slows the rate of kinin liberation, and kinins upregulate kininogen expression on endothelial cells. Regulation of kinin delivery by influencing kininogen expression may provide for new agents to manipulate blood pressure. PMID- 21239271 TI - A young woman with syncope and sudden death What molecular mechanisms could be involved? PMID- 21239270 TI - Myocardial phospholipases A(2) and their membrane substrates. AB - Many of the adverse sequelae of acute myocardial ischemia result from the degradation of sarcolemmal phospholipid constituents mediated by the activation of intracellular phospholipases. The consequent deleterious changes in sarcolemmal membrane properties precipitate ischemic membrane dysfunction resulting in electrophysiologic alterations and myocytic cell death. In myocardium, the overwhelming majority of phospholipase activity is catalyzed by a novel class of calcium-independent plasmalogen-selective phospholipases A(2) that is rapidly and reversibly activated within minutes of myocardial ischemia. Elucidation of the molecular mechanisms underlying the regulation of these phospholipases A(2) will define novel therapeutic targets that can potentially be pharmacologically manipulated to attenuate the deleterious effects of ischemia and reperfusion on myocardial function. PMID- 21239272 TI - Highlights from the 1991 scientific session of the International Society for Heart Research Meeting. PMID- 21239273 TI - Embryonic stem cells as a model for cardiogenesis. AB - Embryonic stem (ES) cells are derived from the inner cell mass of mouse blastocysts. These cells, when placed upon a suitable fibroblast feeder layer, continue to proliferate without overt differentiation and remain totipotent. Cells in this state are competent for gene targeting via homologous recombination. Hence, they hold the possibility of developing defined animal models of human cardiovascular disease. When removed from the feeder layer, ES cells undergo differentiation and development into large, multicellular structures, termed embryoid bodies (EBs). Morphologic, biochemical, and molecular genetic analyses indicate that during EB development some early aspects of cardiogenesis are recapitulated. Thus, EB development in culture is useful for studying certain early cardiogenic events. PMID- 21239274 TI - Connexins and the heart. AB - Gap junctions are specialized regions of adjoining cell membranes composed of numerous intercellular low-resistance channels. In the heart, these channels electrotonically couple adjacent myocytes and synchronize the cardiac action potential. Signaling through gap junction channels may also influence embryogenesis and development. Recent studies have identified the connexin gene family whose protein products assemble to form gap junction channels. Studies of connexin gene expression and function are providing new insights into the behavior of gap junction channels in the heart. PMID- 21239275 TI - Cardiac myocyte interconnections at gap junctions Role in normal and abnormal electrical conduction. AB - Slow conduction leading to reentrant ventricular tachycardias in patients with healed myocardial infarcts appears to depend primarily on alterations in intercellular coupling at gap junctions of myocytes bordering the infarct scar. Results of correlative morphometric and electrophysiologic studies indicate that the elongated shape of individual myocytes, their complex overlapped packing in myocardium, and the number and distribution of gap junctions that electrically couple myocytes are all important structural determinants of anisotropic patterns of current spread in normal myocardium. Alterations of these structural features likely contribute to electrophysiologic derangements critical in reentrant arrhythmogenesis. Recent observations that cardiac myocytes may be coupled by multiple gap junction channel proteins having unique electrophysiologic properties provide new insights into potential mechanisms regulating intercellular current transfer in the heart. PMID- 21239276 TI - Proto-oncogenes and cardiac development. AB - Proto-oncogene products participate in signaling processes that extend from the cell surface to the nucleus. Recent investigations have focused attention on the role that proto-oncogenes play in the proliferation, differentiation, and hypertrophic growth of cardiac myocytes. Such studies suggest a cause-and-effect relationship between aberrations in proto-oncogene expression and abnormalities in myocyte growth and differentiation. PMID- 21239277 TI - The role of the autonomic nervous system in sudden cardiac death. AB - The autonomic nervous system exerts a modulating effect on the risk of sudden cardiac death (SCD) in the setting of ischemic heart disease. The mechanism by which sympathetic tone increases the risk of ventricular arrhythmias is not known, though regional sympathetic denervation at and apical to the site of transmural infarction may result in regional supersensitivity to circulating catecholamines and play a role in ventricular arrhythmogenesis. [(123)I]MIBG scintigraphy enables noninvasive determination of regional cardiac denervation and may be a useful tool for probing the role of sympathetic nervous system in SCD. Increased vagal tone is generally protective against SCD. Newer tests such as baroreflex slope testing and various techniques for determination of heart rate variability, which provide indices of vagal tone, may have greater predictive value and are powerful tools in assessing the role of autonomic nervous system in SCD. PMID- 21239278 TI - Tissue factor pathway inhibitor and the revised hypothesis of blood coagulation. AB - The recent rediscovery, isolation, and characterization of an endogenous coagulation inhibitor termed tissue factor pathway inhibitor (TFPI) has provided new insight into the regulation of in vivo coagulation. TFPI is a multivalent, Kunitz-type, protease inhibitor that directly binds and inactivates factor Xa and, in a factor-Xa-dependent fashion, produces feedback inhibition of the factor VIIa-tissue factor catalytic complex. The demonstrated in vitro properties of TFPI have led to the formulation of a revised theory of blood coagulation. In the revised model, coagulation proceeds through a single pathway rather than the alternative and redundant "extrinsic" and "intrinsic" pathways that had previously been postulated. PMID- 21239279 TI - Wisdom of the walrus. PMID- 21239280 TI - Two brothers with unexplained cardiomegaly Initial clues to the molecular basis of a hereditary cardiac disease. PMID- 21239281 TI - Signal transduction through G proteins in the cardiac myocyte. AB - The membrane of the cardiocyte contains a large variety of molecules whose function is to transmit signals from outside the cell to inside. The signals are initiated by receptors for a variety of agonists and propagated by a family of heterotrimeric G proteins to ion channels and intracellular enzymes. The large complement of receptors, G proteins, and effectors found in the cardiocyte raises fundamental questions about the mechanisms that assure the precision and timing of the heart cell's response to external stimuli. PMID- 21239282 TI - Cardiac sodium-calcium exchange research New directions. AB - The sarcolemmal Na(+)-Ca(2+) exchanger is the dominant myocardial Ca(2+) efflux mechanism and has a central role in the regulation of contractility. Physiologic and molecular advances in Na(+)-Ca(2+) exchange research have led a resurgence of interest in this system. Molecular cloning of the exchanger has recently been accomplished, and information on the molecular structure and reaction mechanism is forthcoming. PMID- 21239283 TI - Thromboxane biosynthesis and metabolism in relation to cardiovascular risk factors. AB - Enhanced platelet biosynthesis of thromboxane A(2) is associated with several cardiovascular risk factors, as a consequence of a direct effect on platelet biochemistry and/or some form of endothelial dysfunction. Moreover, episodic increases in thromboxane biosynthesis occur in acute coronary and cerebral ischemic syndromes. Thromboxane-dependent platelet activation represents an important mechanism that amplifies the consequences of acute vascular lesions as well as those of longstanding metabolic or hemodynamic disturbances, and results in increased risk of vascular occlusive events. PMID- 21239284 TI - Digitalis and baroreflexes in heart failure. AB - A physiologic hallmark of heart failure is neurohumoral excitation, due in large part to abnormalities in baroreflex control of the circulation. New experimental and clinical evidence suggests that digitalis glycosides, long considered important inotropic agents in the management of heart failure, also have important autonomic actions and may play a major role as neural sensitizing agents in this clinical disorder. PMID- 21239285 TI - Commitment and differentiation of cardiac myocytes. AB - This article reviews what is known about the earliest stages of heart development focusing on the periods of commitment and differentiation of cardiac progenitor cells and their molecular regulation. The pathway from precursor to differentiated cardiac myocyte is crucial to forming a normal, functional heart. Congenital cardiac abnormalities are some of the most common, estimated at 5-8 per 1000 live births worldwide. These conditions affect mortality and morbidity of patients as infants, children, and adults. Knowledge of what steps are critical to normal heart development would lead to earlier diagnosis and possibly repair of these defects. PMID- 21239286 TI - Nicotine and coronary heart disease. AB - Nicotine may contribute to accelerated atherogenesis by inducing hyperlipidemia, injuring endothelial cells, and/or promoting thrombosis, although the evidence is not conclusive. Nicotine is likely to contribute to acute ischemic events in people who already have coronary heart disease via adverse effects on systemic hemodynamics, by promoting thrombosis, constricting coronary arteries, and/or facilitating arrhythmogenesis. Pharmacodynamic studies suggest that nicotine inhaled in cigarette smoke may have different cardiovascular effects than that absorbed more slowly, as from nicotine gum or transdermally. The safety of chronic nicotine exposure, such as with medicinal use of nicotine, cannot be predicted and requires empiric evaluation. PMID- 21239287 TI - The electrophysiology of the cardiac sodium channel. AB - Conduction in most regions of the heart is sustained by transient increases in membrane permeability to Na(+). The application of contemporary biophysical and molecular biologic techniques demonstrates that permeability to Na(+) depends on a distinct protein that forms ion-selective channels in the membrane. These channels are believed to be the site of action of the local anesthetic class of antiarrhythmic drugs. More detailed studies of the structure and function of the Na channel hold the prospect for a clearer understanding of the mechanisms and treatment of some arrhythmias. PMID- 21239288 TI - Thrombomodulin Biology and potential cardiovascular applications. AB - Thrombomodulin on endothelial surfaces is the major cofactor for the activation of the anticoagulant protein C by thrombin. Recent studies of the structure and regulation of thrombomodulin provide important clues as to its mechanism of action. These studies should enable the rational use of thrombomodulin as a therapeutic agent to inhibit coagulation either by infusion of thrombomodulin or its derivatives, or by pharmacologic alteration of cellular levels. PMID- 21239289 TI - The role of end-systolic pressure-volume analysis in clinical assessment of ventricular function. AB - Over the past two decades, the end-systolic pressure-volume relationship (ESPVR) has undergone intensive investigation assessing its role as an index of ventricular contractile function and performance. From this investigation, we have learned that the ESPVR accurately assesses acute changes in contractility and is especially useful in the research setting where cardiac load can be controlled and altered. However, the need to alter load to develop the relationship and the dependence of ESPVR on cardiac mass limits broad clinical usage of the tool. PMID- 21239290 TI - Molecular mechanisms of skeletal muscle adaptations to exercise. AB - The strength and oxidative capacity of skeletal muscle are major determinants of physical performance, whether in elite athletes or in patients with congestive heart failure or other circulatory disorders. Exercise training augments the functional capacity of skeletal muscle, in part by altering the abundance of proteins essential for contraction and energy metabolism. These adaptations result from exercise-induced changes in the abundance of specific mRNA transcripts, suggesting that gene transcription is an important target for signaling pathways that couple contractile activity to changes in muscle phenotype. Understanding the genetic control mechanisms involved in the adaptive capacity of skeletal muscle could lead to novel approaches to the therapy of patients with cardiovascular disease, either by improving peripheral utilization of oxygen in patients with limited cardiac output or by contributing to the successful application of skeletal muscle grafts to assist the failing heart. PMID- 21239291 TI - The antithrombotic effects of organic nitrates. AB - The antianginal mechanism of organic nitrates is attributed to their vasodilatory action(s). In this article, the authors review the in vitro and in vivo data implicating an antiplatelet mechanism of action for organic nitrates that may contribute to their antiischemic properties. PMID- 21239292 TI - Transesophageal echocardiography state of the art. AB - Transesophageal echocardiography (TEE) is a recently popularized ultrasonic imaging technique that provides high-resolution anatomic and physiologic information due to the probe's proximity to cardiac structures. Although TEE has been available in a single-plane, two-dimensional format for many years, widespread enthusiasm for the technique has only recently developed with the addition of Doppler technology, improved image resolution, and biplanar imaging. Because of the relatively late clinical interest in TEE, literature detailing the technique's utility is at present somewhat limited. There is already good evidence documenting TEE's value in assessment of mitral valve prosthetic function, valvular regurgitation, aortic dissection, left atrial thrombus, and intraoperative monitoring of left ventricular segmental wall motion and mitral valve repair. In addition, the list of proven indications is rapidly growing. This article summarizes the present state of TEE imaging and indicates future directions of TEE clinical applicability. PMID- 21239293 TI - Gene transfer into cardiac myocytes in vivo. AB - The ability to express recombinant genes in cardiac myocytes in vivo holds promise for the treatment of a number of inherited and acquired diseases of the cardiovascular system. Several groups have demonstrated recently that plasmid DNA is taken up and expressed in cardiac myocytes following injection into the left ventricular wall in vivo. Recombinant genes introduced into cardiac myocytes by this technique are expressed for at least 6 months after injection, and appear to be regulated normally by humoral signals. In addition to its potential for somatic gene therapy, this method should prove useful for studies of transcriptional regulation in the heart. PMID- 21239294 TI - Polypeptide growth factors and atherosclerosis. AB - The lesions of atherosclerosis represent a specialized response to chronic inflammation resulting from agents that injure endothelial cells or cause endothelial cell dysfunction. Numerous growth-regulatory molecules, both stimulatory and inhibitory in nature, play critical roles in inducing the flbroproliferative response that contributes to the formation of the advanced lesion of atherosclerosis, the fibrous plaque. These molecules are key factors in determining whether the potentially occlusive fibrous plaque lesions of atherosclerosis will progress, regress, or remain unchanged. PMID- 21239295 TI - Neutrophil and endothelial changes in reperfusion injury. AB - Reperfusion of the ischemic myocardium alleviates the hypoxic insult, but promotes the influx of neutrophils. The rapidity and site-specificity of neutrophil accumulation, initially noted as adhesion to the vascular endothelium, implies functional alterations in the endothelium, which subserve neutrophil sequestration and reperfusion injury. Elucidation of the underlying mechanisms that predispose one to endothelial dysfunction, leukocyte sequestration, and neutrophil-mediated exacerbation of myocardial injury may provide a basis for the development of adjunctive pharmacologic therapies to enhance the benefits of restoring blood flow to the ischemic heart. PMID- 21239296 TI - Mechanisms of coronary artery spasm. AB - Coronary artery spasm, the pathogenic mechanism most frequently observed in the syndrome of Prinzmetal's variant angina, appears to be caused by a local, nonspecific smooth muscle hyperreactivity. The relationship between coronary atherosclerosis, endothelial dysfunction, and coronary artery spasm is still speculative. Coronary artery spasm should be distinguished from other forms of coronary vasoconstriction, which may also play a role in angina pectoris. Occlusive coronary spasm causes complete interruption of coronary blood flow and may contribute to thrombus formation. Segmental coronary hyperreactivity may also be a component of acute coronary syndromes. PMID- 21239297 TI - Lipoprotein(a) as a cardiovascular risk factor. AB - Lipoprotein(a) [Lp(a)] is a class of lipoprotein particles having the lipid composition of plasma low-density lipoprotein (LDL), but with a distinct protein moiety comprised of two proteins linked together by a disulfide bridge. The two proteins are apoB100, the protein moiety of LDL, and apo(a), a heavily glycosylated protein that is specific for Lp(a). Apo(a) has a strong structural similarity to plasminogen and has a wide-size polymorphism that has a genetic origin and is partially responsible for the size and density heterogeneity of Lp(a). High plasma levels of Lp(a) are associated with an increased risk for cardiovascular disease that is related to the atherogenic and thrombogenic potentials of this lipoprotein enhanced by the presence of other risk factors, among which are high plasma levels of LDL or low levels of high-density lipoprotein. The factors determining the plasma levels of Lp(a) have not been clearly identified except for an association with different alleles of the apo(a) gene, which is located in the long arm of chromosome 6. Currently there are no generally accepted ways to normalize the plasma levels of Lp(a) by either dietary and/or pharmacologic means. Until further progress in this area is made, patients with high plasma levels of Lp(a) should be advised to correct modifiable risk factors in order to decrease the cardiovascular pathogenicity of this lipoprotein class. PMID- 21239298 TI - Nuclear magnetic resonance spectroscopic investigations of the human myocardium. AB - Magnetic resonance spectroscopy is a noninvasive technique for measuring the concentration of metabolites both in vivo and in solutions. The technique exploits the nuclear spin of certain isotopes, and measurements of signals from the nuclei of phosphorus atoms ((31)P) have provided much new information about high-energy phosphates and reaction fluxes in energy provision and utilization. The method has been systematically applied in the isolated heart preparation and the surgically exposed heart, and the effects of ischemia and other interventions have been documented. In humans, the ratio of phosphocreatine to adenosine triphosphate in the heart that has been determined both at rest and during exercise has been shown to be a sensitive index for impairment in cardiac metabolism in patients with myocardial hypertrophy due to aortic valve disease and during hand-grip exercise in patients with ischemia. It is now practical to use (31)P magnetic resonance spectroscopy to extend our understanding of myocardial metabolism in health and disease and to assess the response to therapy and the rejection of the transplanted heart. PMID- 21239299 TI - Intravascular ultrasound imaging. AB - Intravascular ultrasound imaging is a useful and promising modality that is capable of demonstrating the structure of blood vessel walls. It also provides a quantitative assessment of the amount of atheroma present that cannot be visualized by angiography. This article reviews the basic principles of intravascular ultrasound imaging and describes the clinical studies after balloon angioplasty evaluated by intravascular ultrasound imaging. PMID- 21239300 TI - Implantable devices in the coronary artery from metal to genes. AB - Preliminary data from nonrandomized clinical trials suggest that, in selected subgroups of patients, the implantation of endovascular stents may improve the initial results of coronary dilatation, may successfully treat arterial dissection and abrupt closure, and may reduce the incidence of recurrent stenosis. The widespread use of stents remains limited, however, by the need for intensive anticoagulation to prevent arterial thrombosis. The development of sustained-release drug delivery systems and gene-transfer technology may enable local delivery of antithrombotic and antiproliferative therapies that would greatly increase the safety and applicability of these devices. PMID- 21239301 TI - Reperfusion-induced injury manifestations, mechanisms, and clinical relevance. AB - Although reperfusion is an absolute prerequisite for the survival of ischemic tissue, it is not necessarily without hazard. Many (but not all) cardiologists are of the opinion that some component of reperfusion may be detrimental and able to inflict injury over and above that attributable to the ischemia. In this article, we define four sequelae of reperfusion that might be designated as "reperfusion injury," we identify possible underlying mechanisms, and we consider whether any of these forms of reperfusion injury are of clinical relevance. PMID- 21239302 TI - Heat shock and adaptive response to ischemia. AB - A mild heat treatment is known to confer a transient protection to cells against a subsequent lethal heat shock. This phenomenon is better known as thermotolerance and seems to be mediated by the expression of a group of proteins, the heat-shock proteins. Recent studies have shown that a heat-shock pretreatment improves postischemic recovery in an isolated perfused rat heart model. In the present brief review, we cover the more recent findings related to heat shock and the adaptive response that it may produce in the cardiac cell against ischemic stress. PMID- 21239303 TI - Homocysteine as a risk factor for cardiovascular disease. AB - Homocysteine is an amino acid that appears to damage the vascular endothelium and promote thrombosis. The most frequent causes of hyperhomocyst(e)inemia are the inherited defect of the enzyme cystathinonine B-synthase and nutritional deficiency of vitamin B(12) or folate. Hyperhomocyst(e)inemia is associated, perhaps causally, with atherosclerotic vascular disease. Interactions with risk factors such as cigarette smoking, hyperlipidemia, and hypertension are possible, but not yet defined. Dietary supplementation with vitamin B(12), folate, and other substances can reduce homocysteine levels. Such simple measures may reduce the risk of vascular disease in hyperhomocyst(e)inemic subjects. PMID- 21239304 TI - Generation and control of cardiac pacing the pacemaker current. AB - Several currents contribute to the electrical activity of mammalian pacemaker cells. Of these, the hyperpolarization-activated current, i(f), is involved in the generation of the diastolic depolarization phase, and therefore has a main role in controlling the most peculiar feature of these cells: their ability to beat spontaneously and to drive the heartbeat. More than this, i(f) represents the key mechanism by which sympathetic and parasympathetic stimuli regulate, via the diastolic depolarization phase, the pacing frequency of sinoatrial node cells and thus the heart rate. This is achieved through regulation of adenylyl-cyclase activity and of intracellular cAMP, which is the second messenger in i(f) modulation. A fine regulation of i(f) is thus the basis by which epinephrine and acetylcholine exert their fine control on cardiac rhythm. PMID- 21239305 TI - Development and role of coronary collaterals. AB - The collateral circulation that develops in response to gradual and progressive coronary artery occlusion can maintain the structural and functional integrity of the subtended myocardium to an astonishing degree, provided the speed of the stenosing process is not too great. Collateral development occurs by recapitulation of ontogeny: patterns of morphogenic gene expression normally active only during embryonic development are recalled for vasculogenesis (large vessel formation, as in human and canine collaterals) and angiogenesis (capillary sprouting, as in human and porcine hearts). Vascular cell proliferation is induced by ischemia-related growth factor production. However, tissue growth alone is not enough for vasculogenesis (it would by itself cause lumen reduction). Remodeling, that is, the controlled destruction and complete reconstruction of the enlarged vessel, takes place involving the concerted action of proteases. For unknown reasons, the growth-remodeling process provides only ~50% of the blood-conducting capacity of the large vessel it has replaced. This leaves room for improvement by somatic gene therapy and by drugs to be developed. PMID- 21239306 TI - Hirudin and other thrombin inhibitors experimental results and potential clinical applications. AB - Thrombosis results from the activation of the hemostatic system by pathologic stimuli. It is a dynamic process that involves various blood cells and proteins, the nature of blood flow, and substrate characteristics. The classic description of the hemostatic system encompasses the coagulation and fibrinolytic systems, the platelets, and the endothelium. Thrombin plays a central role in thrombus formation, interacting with the components of the hemostatic system and vessel wall. PMID- 21239307 TI - Endothelium-derived vasoactive factors and their role in the coronary circulation. AB - The endothelium-due to its strategic anatomic position between the circulating blood and vascular smooth muscle-plays an important functional role in the coronary circulation. Endothelial cells release factors interfering with coagulation, platelet function, vascular tone, and growth. Endothelium-derived nitric oxide (NO) is the endogenous nitrovasodilator that is a potent inhibitor of platelet function and vasodilator. Together with prostacyclin, NO plays an important protective role in preventing platelet adhesion, aggregation, and coronary vasospasm. Endothelial cells also are a source of contracting factors such as endothelin-1, thromboxane A(2), and endoperoxides. Cardiovascular risk factors (hyperlipidemia, hypertension, and diabetes) inhibit the formation of endothelium-derived relaxing factors and promote that of contracting factors. In coronary arteries with advanced atherosclerosis, endothelial function is severely impaired. The reduced release of endothelium-derived NO is associated with an increased platelet-vessel-wall interaction and, in turn, platelet activation and vasospasm, both known events in coronary artery disease. PMID- 21239308 TI - Genetics of hypertension A multidisciplinary challenge. AB - Hypertension is a prevalent complex polygenic disease mandating directive concerted multidisciplinary efforts in the dissection of its genetic basis. Identification of the genes involved in the etiology of genetic hypertension (hypertension genes) will lead to an elucidation of primary pathogenic mechanisms of hypertension, target organ complications, and interactions with environmental factors. This can thus form the basis for directive integrated management of hypertension. PMID- 21239309 TI - Molecular and cellular biology of adrenergic receptors. AB - Adrenergic receptors form the interface between the sympathetic nervous system and the cardiovascular system. Genomic or cDNA clones for 8 types of mammalian adrenergic receptors have been obtained. Much has been learned about the structure and functional properties of the beta(2)-adrenergic receptor. Less is known about the functional properties and the physiologic role of the other adrenergic receptors. Further progress in this field may lead to the development of more selective drugs to modify the physiologic processes controlled by these receptors. PMID- 21239310 TI - Metabolic and diagnostic significance of creatine kinase isoenzymes. AB - Creatine kinase isoenzyme content is frequently used to assess the state of differentiation of muscle and neural tissue and following release into plasma as diagnostic markers for acute myocardial infarction, skeletal muscle disease, and neurologic injury. The establishment of thrombolytic therapy as the standard of care for acute myocardial infarction and new information on the tissue distribution of creatine kinase isoenzymes has necessitated the development of more rapid assays for the diagnosis of infarction and expanded the potential use of these isoenzymes as markers for other disease states. PMID- 21239311 TI - New developments in antihypertensive drugs. AB - New developments in antihypertensive drug treatment include optimizing the use of established drugs, the introduction of novel compounds, and a renewed appreciation that hypertension is but one of various cardiovascular risk factors that must be addressed in managing the patient with raised blood pressure. Thus, the approach used must be tailored to the individual patient both in terms of drug choice and dose as well as preventive measures. New drug development depends very much on improving our understanding of the pathophysiologic mechanisms involved in hypertension and seems likely to be applied at the level of the renin angiotensin system and other local factors governing vascular smooth muscle function. PMID- 21239312 TI - Serotonin receptors Therapeutic prospects in cardiovascular disease. AB - Serotonin is widely distributed throughout the body, can have potent and profound effects on the cardiovascular system, and may be involved in the pathophysiology of several cardiovascular disease states. Recent advances in the classification of serotonin receptors, along with the identification of selective drug tools for some of these receptor types, enables the putative role of different serotonin receptor subtypes in both the etiology and treatment of disease states to be explored. This review considers the potential therapeutic application of selective serotonin receptor agonists and antagonists in cardiovascular disease. PMID- 21239313 TI - Pathogenetic and therapeutic implications of calcitonin-gene-related peptide in the cardiovascular system. AB - Calcitonin-gene-related peptide (CGRP) is one of the recently discovered endogenous peptides with potent cardiovascular effects in humans and in animals. Its powerful vasodilating action in addition to its direct positive inotropic effect on the heart, plus its presence in perivascular nerve endings in the heart and the latest demonstration of specific receptors in the human heart, suggest important physiologic and therapeutic roles for CGRP in cardiovascular diseases. PMID- 21239314 TI - Cardiac transplant graft arteriosclerosis. AB - Transplant-associated coronary arteriosclerosis is an obstructive, proliferative lesion that forms in the coronary arteries of transplanted hearts, often within months, and is the most frequent single cause of late posttransplant death. Graft arteriosclerosis has uncertain risk factors, is difficult to diagnose because of the denervation of the transplanted heart, and is difficult to treat because of its diffuse nature, with frequent involvement of intramural as well as extramural vessels. Graft arteriosclerosis is morphologically distinct from the usual form of coronary atherosclerosis, with T-lymphocytes and macrophages in the portions of the lesion immediately beneath an intact endothelium. Nevertheless, like typical atherosclerosis, the obstructive lesions are largely composed of smooth muscle cells and the extracellular matrix that they produce. Immunologic mechanisms likely contribute to graft arteriosclerosis, possibly through cytokine driven smooth muscle cell proliferation, stimulated by a localized chronic cell mediated immune response analogous to delayed type hypersensitivity. PMID- 21239315 TI - Cardiovascular research in transgenic animals. AB - The ability to alter specifically the expression or activity of known gene products in intact animals provides a powerful experimental system to study pathophysiology. These animal models can now be readily generated using transgenic technology. Traditional transgenic approaches rely on gain-of-function alterations, and several experimental paradigms have recently been established based on this attribute. These include assessment of promoter function, overexpression of physiologically important gene products, targeted oncogenesis, and insertional mutagenesis. Technical and practical issues relevant to the generation of such models are discussed here. In addition, several recent transgenic models germane to the cardiovascular system are presented. These experiments provide exciting new model systems to study clinical issues that heretofore have been difficult, if not impossible, to address. PMID- 21239316 TI - Serine protease inhibitors (serpins). AB - Inhibition of serine proteases by serpins (serpin: serine protease inhibitor) is a key mechanism for the control of proteolysis in thrombosis, shock, and inflammation. The various members of the serpin gene superfamily (alpha(1) antitrypsin, ovalbumin, C1-inhibitor, antithrombin III, alpha(2)-antiplasmin, type-1 plasminogen-activator inhibitor, and so forth) have many characteristics in common. In this article, we review the biochemistry and cell biology of serpins, and we discuss their clinical importance and therapeutic potential. PMID- 21239317 TI - GMP-140, a receptor that mediates interactions of leukocytes with activated platelets and endothelium. AB - GMP-140, a membrane glycoprotein located in secretory granules of platelets and endothelium, is rapidly redistributed to the cell surface following cellular activation. GMP-140 promotes rapid adhesion of neutrophils and monocytes to activated endothelium at sites of tissue injury as well as platelet-leukocyte interactions in areas of inflammation and hemorrhage. Like other leukocyte adhesion molecules, GMP-140 may also be involved in inflammatory disorders such as reperfusion injury. Further study of the structure and function of GMP-140 and related receptors may lead to development of new drugs that block leukocyte adhesion in human disease. PMID- 21239318 TI - Thromboxane-A(2)/prostaglandin-H(2) receptors Characterization and antagonism. AB - Thromboxane A(2) (TXA(2)) is a potent vasoconstrictor and platelet aggregator whose synthesis is increased in a variety of cardiovascular diseases. TXA(2) receptor antagonists have been used to (a) establish a pathophysiologic role for TXA(2) in a variety of cardiovascular diseases, (b) subtype platelet and vascular receptors, (c) elucidate structural characteristics of the receptor, and (d) aid in its purification. However, much still remains to be learned about the structure and function of TXA(2) receptors. PMID- 21239319 TI - Calcium and ischemic injury. AB - Ischemia increases [Ca(2+)](i) in cardiac myocytes despite the initial decrease in force development observed. This increased [Ca(2+)](i) contributes to myocyte injury by diverse mechanisms, including activation of proteases and phospholipases, and mitochondrial injury. Increased [Ca(2+)](i) may also contribute to reperfusion injury by causing hypercontracture when ATP is resynthesized to allow Ca(2+)-induced cycling of the myofilament cross-bridges. In addition, enhanced cellular Ca uptake by Na-Ca exchange, resulting in Ca(2+) loading of mitochondria or other intracellular organelles during reperfusion, may alter postreperfusion recovery. Thus, alterations in Ca(2+) homeostasis probably contribute to ischemic injury; however, other injury pathways not involving an increase in [Ca(2+)](i) or total cellular Ca content are also undoubtedly important. PMID- 21239320 TI - Leukocyte adhesion molecules and myocardial ischemia. AB - Current evidence strongly indicates that neutrophils contribute to the injury seen after ischemia and reperfusion of various tissues. Potentially important therapeutic targets are the specific adhesion mechanisms supporting neutrophil extravasation and secretory activity. Several such mechanisms have been characterized recently at a molecular level in vitro, and warrant investigation in relevant models of human disease. PMID- 21239321 TI - Fluorescence spectroscopy in cardiovascular disease Fundamental concepts and clinical applications. AB - Laser-induced fluorescence spectroscopy can distinguish atherosclerotic from normal arteries by their characteristic fluorescence spectra. The ability to perform remote spectroscopy through optical fibers can be incorporated into a "smart" laser angioplasty system. By detecting the presence of atherosclerosis, and by signaling completion of plaque ablation, fluorescence spectroscopy could guide selective laser ablation of atherosclerotic plaques. This guidance capability could result in safe and effective laser angioplasty systems. PMID- 21239322 TI - Plasminogen activator inhibitors. AB - Plasminogen activator inhibitors (PAIs) regulate plasminogen activation in normal and pathologic processes. Plasminogen activator inhibitor 1 (PAI-1) is the major physiologic inhibitor of both tissue-type and urokinase-type plasminogen activators. It is a highly regulated single-chain glycoprotein, whose overexpression in vivo impairs the fibrinolytic balance and correlates with thrombotic disorders. Recent clinical observations suggest an association between elevated plasma PAI-1 and symptomatic coronary artery occlusive disease or deep venous thrombosis. Recognition of the clinical relevance of PAIs and timely assessment of the fibrinolytic capacity in patients at risk may have therapeutic implications. PMID- 21239323 TI - Dopamine receptor agonists in cardiovascular medicine. AB - The cardiovascular and renal effects of dopamine are mediated through peripheral catecholamine receptors. Knowledge of the receptor type responsible for each of the actions of dopamine leads to its rational use clinically and to understanding the hemodynamic actions of the newer dopamine receptor agonists recently introduced into clinical trials. Several of the newer agonists have profiles of receptor activities that differ from dopamine, and early clinical studies indicate that they will have different therapeutic indications and applications. PMID- 21239324 TI - Restenosis following coronary balloon angioplasty Role of smooth muscle cell proliferation. AB - Restenosis following successful coronary balloon angioplasty remains one of major limitations of this procedure. It is now known that intimal hyperplasia is the primary cause of restenosis. Angioplasty injury of arteries causes activation of platelets, injury and necrosis of smooth muscle and endothelial cells, and leukocyte infiltration. These events result in the production and release of factors that stimulate smooth muscle cell proliferation and subsequently lead to intimal hyperplasia. A number of antiproliferative agents have been found to be effective in inhibiting intimal hyperplasia. It is hoped that an effective pharmacologic approach toward preventing restenosis may be found in the near future. PMID- 21239325 TI - Fish oil and vascular disease. AB - Dietary n-3 fatty acids have potent biologic effects on cells of the blood and the vasculature. Many of these actions could ultimately prove medically useful, with potential therapeutic impact on atherogenesis, thrombosis, or vascular reactivity. Although a few clinical trials of fish oil have been reported in humans (for example, prevention of reocclusion after coronary angioplasty), results have not yet been definitive. Until additional information is available, the use of fish-oil supplements for treatment or prophylaxis of cardiovascular disease is not warranted. PMID- 21239326 TI - Cardiovascular effects of platelet-activating factor. AB - Platelet-activating factor (PAF) is a unique biologically active phospholipid that is synthesized by many cells and tissues and has actions far more diverse than just platelet activation. PAF is probably a mediator of the normal inflammatory and thrombotic responses. Inappropriate or excessive production of PAF can lead to vascular injury, particularly via its proinflammatory effects, and marked hemodynamic derangements. There is evidence that PAF may play a role in clinical syndromes of shock, infarction, and reperfusion injury. Antagonists of the PAF receptor have been developed and have therapeutic potential in these common life-threatening disorders. PMID- 21239327 TI - Use of skeletal muscle grafts for cardiac assist. AB - Skeletal muscle is a potential power source for cardiac assist. Two approaches have been used to harvest this power: dynamic cardiomyoplasty, which involves the application of a muscle directly to the heart to support cardiac contractile function; and the construction of skeletal muscle pouches or ventricles, which are used as separate pumps working either in parallel or in series with the heart. These techniques may represent an alternate therapeutic approach in patients with end-stage heart disease or in infants with certain congenital heart anomalies. PMID- 21239328 TI - Intravascular stents. AB - Intravascular stents have been developed to address acute arterial closure and restenosis, the major limitations of percutaneous transluminal coronary angioplasty (PTCA). Metallic stents in human clinical trials have shown efficacy in treating acute closure and, in selected patients, lowering the restenosis rate. This review delineates the characteristics of the ideal stent and examines ongoing clinical trials that are evaluating various stent prototypes. Developmental stents that use radiopaque and bioabsorbable materials are presented. The potential role for intravascular stents as vehicles for localized drug delivery and gene therapy is discussed. PMID- 21239329 TI - The role of the automatic implantable cardioverter-defibrillator (AICD) in the treatment of medically refractory ventricular arrhythmias. AB - After 6 years of widespread clinical use, the role of the automatic implantable cardioverter-defibrillator (AICD) is well defined in some circumstances and less well defined in others. In the next year, the second generation of this device will become available, incorporating antitachycardia pacing algorithms and programmable delivered-energy capabilities into the basic defibrillator system. As a prelude to this development, this article addresses the current status and future role of the AICD in the overall therapeutic armamentarium for the treatment of ventricular tachycardia and presentation of sudden death. PMID- 21239330 TI - Echo-Doppler in the diagnosis and management of congenital heart disease. AB - Advancements in echo-Doppler technology now provide the capability for both high quality anatomic imaging as well as the assessment of cardiac flows and hemodynamics. Given these capabilities, and the potentially complex nature of all congenital heart lesions, echo-Doppler is well suited for the diagnostic assessment of congenital heart disease. As a noninvasive, reliable, and relatively inexpensive tool, it is well suited for the longitudinal follow-up of patients with treated and untreated congenital heart lesions. Recent experience with intraoperative imaging has indicated that direct epicardial echo-Doppler examination provides clinically useful information for the surgeon treating congenital heart lesions. Echo-Doppler examination continues to evolve into a primary modality for the recognition, evaluation, and treatment of congenital heart disease. PMID- 21239331 TI - Genetic abnormalities in apolipoprotein B. AB - Recent studies have demonstrated that mutations in the apolipoprotein (apo-) B gene can cause significant alterations in blood cholesterol levels. A variety of apo-B gene mutations that prevent the translation of a full-length apo-B molecule can lead to low blood cholesterol levels. A missense mutation in the apo-B gene has been described that prevents the binding of the apo-B100-containing lipoproteins to the low-density lipoprotein receptor, thereby causing them to be cleared slowly from the plasma. This mutation results in high blood cholesterol levels. Analyzing the different apo-B gene mutations has increased our understanding of the wide variation in cholesterol levels in the general population and has increased our understanding of the structure and function of apo-B. PMID- 21239332 TI - Cardiovascular effects of pulmonary hypertension. AB - Right ventricular dysfuction is the most significant cardiovascular effect of pulmonary hypertension. A variety of techniques to evaluate right ventricular dysfuction have been examined. but, due to the complex geometry of the right ventricle, the optimal method has yet to be established. Vasodilator therapy has been shown to be beneficial in improving cardiovascular function in some patients. Echocardiography holds promise in evaluating response to therapy nonivasively. PMID- 21239333 TI - Physiologic assessment of coronary artery stenosis severity. AB - For over a quarter-century, selective coronary arteriography has remained the ultimate diagnostic test for assessing the significance of atherosclerotic lesions in the coronary circulation of humans. Despite the development of many noninvasive techniques designed to assess effects of limitations in the ability to augment coronary flow on myocardial perfusion, function, and metabolism, the coronary arteriogram has maintained its clinical position of preeminence. PMID- 21239334 TI - T-lymphocyte interactions in cardiac transplant rejection. AB - Transplant rejection is a complex cascade of cellular and molecular inflammatory events triggered by the recognition of donor antigens by the recipient immune system. The interaction between T-cell receptors on "helper" T cells and donor antigen confers specificity of the response, whereas accessory cell interactions and growth factor (lymphokine) secretion regulate the variety of cellular responses. An understanding of these cellular and molecular interactions may promote new therapeutic strategies. PMID- 21239335 TI - Genesis and "suicide" of eicosanoid biosynthetic enzymes. AB - Biologically active eicosanoids are substances that initiate, aggravate, or sustain thrombosis and inflammation. Prominent in this regard are thromboxane A(2), a potent coronary vasoconstrictor and platelet-aggregating factor and leukotriene B(4), a potent leukocyte chemotactic agent. Pharmacologic restraint of their formation may be beneficial. Recent research on the natural regulation of their formation recognizes the importance of two processes: the genesis of enzymes and proteins that amplify eicosanoid formation and the "suicide" inactivation that accompanies this formation. The balance of genesis-"suicide" of eicosanoid biosynthetic enzymes offers a new way to raise questions about the role of eicosanoids in cardiac disorders. PMID- 21239336 TI - Comparison of ionic and low-osmolar contrast media during cardiac catheterization. AB - The use of nonionic contrast agents during cardiac catheterization decreases the incidence of both major and minor cardiovascular complications when compared with ionic contrast. Hemodynamic and electrophysiologic effects are less profound especially in patients who have severe coronary artery disease or left ventricular dysfunction. Sparse data exist comparing ionic and nonionic contrast in patients undergoing percutaneous transluminal coronary angioplasty. No clinical evidence suggests that nonionic contrast agents are less nephrotoxic than ionic contrast though patients with significant baseline renal dysfunction (creatinine > 3.0) might benefit. The incidence of thrombotic events appears to be similar for both types of agents. Finally, the risk reduction of cardiovascular events must be weighed against markedly higher costs. PMID- 21239337 TI - G proteins and low-molecular-weight GTP-binding proteins in platelets. AB - Platelets contain at least two distinct families of proteins that can bind GTP: the G proteins and the low-molecular-weight GTP-binding proteins. G proteins are heterotrimeric regulatory proteins that mediate the interaction between cell surface receptors and the enzymes that generate second messengers during platelet activation. At least five different G proteins have been identified in platelets. The low-molecular-weight GTP-binding proteins range in size from 21 to 28 kDa. Little is known for certain about their function, but at least 15 such proteins have been identified in platelets, many of which have been shown to be homologous to the products of the ras protooncogene. In cells other than platelets, low molecular-weight GTP-binding proteins have been implicated in protein transport, cell activation events, and malignant transformation. Their role in platelets is unknown. PMID- 21239338 TI - The polymerase chain reaction (PCR) and cardiovascular diagnosis. AB - The polymerase chain reaction (PCR) is a recently discovered technique of molecular biology that has revolutionized both basic science and clinical research laboratories. Its beautiful simplicity derives from its ability to geometrically amplify a single copy of a DNA sequence to millions of copies in a matter of hours. PCR thus allows both the molecular biologist to clone genes and the clinical pathologist to screen blood samples for human immunodeficiency virus, with rapidity and ease never before available. In this brief review we will discuss the basic technique of the PCR, its applications in the basic science and clinical areas, and further emphasize its current and potential roles in cardiovascular medicine. PMID- 21239339 TI - Percutaneous coronary angioscopy Current status and future directions. AB - Major advances in catheter technology and miniaturization of fiberoptics have allowed clinical percutaneous coronary angioscopy to become a reality. Percutaneous angioscopy yields highly detailed images of intracoronary morphology and pathology. Ongoing clinical trials are investigating the feasibility, safety, and clinical utility of coronary angioscopy, particularly in relation to interventional techniques such as percutaneous coronary angioplasty and the identification of intracoronary thrombi. PMID- 21239340 TI - Gene transfer and cardiovascular disease. AB - Through the introduction of foreign DNA into somatic cells, the aim of gene therapy is to correct or prevent disorders caused by the absence or malfunction of genes within a diseased individual. Expression of recombinant genes at specific sites within the vasculature can provide insights into vascular biology and potential treatments for various cardiovascular disorders. In our studies, we have developed methods for the transfer of recombinant genes into the endothelium and vascular smooth muscle cells by using retroviral vectors and liposomal transfection. Although these techniques are still in the formative stages, gene transfer into the endothelium and other vascular cells is a new approach to the treatment of vascular diseases, including atherosclerosis and restenosis. PMID- 21239341 TI - Analysis of local gene expression in human atherosclerotic plaques by in situ hybridization. AB - In situ hybridization is an invaluable tool for the examination of gene expression in human atherosclerotic plaques, and therefore is useful for research into the underlying mechanisms of atherogenesis. Information obtained using this technique includes determining not only the presence or absence of a specific mRNA in a tissue sample, but also the type of cell expressing the gene of interest. Cells containing platelet-derived growth factor (PDGF) mRNA were identified in carotid endarterectomy specimens by in situ hybridization. Mesenchymal-appearing intimal cells, the major cell type containing PDGF mRNAs and expressing PDGF, were often found associated with focal regions of organizing thrombus. It is suggested that organization of thrombi resulting from plaque rupture or intraplaque hemorrhage of the vasa vasorum may contribute to the episodic growth of the atherosclerotic plaque through an influence on these cells. PMID- 21239342 TI - Cell proliferation in human atherosclerosis. AB - Despite the assumed proliferative nature of human atherosclerosis, very few studies exist that measure the actual proliferative rates in human arterial tissue. Recent proliferation-specific antibodies show very low rates of cell proliferation, as might be expected for a disease that takes numerous years to become clinically evident. These levels of proliferation are similar to animal models of hypercholesterolemia-induced atherosclerosis, and are unlike other models of acute mechanical injury to the artery wall. Proliferative activity in atherosclerotic plaques is seen among both smooth muscle cells and mononuclear inflammatory cells. PMID- 21239343 TI - Antiplatelet and anticoagulant therapy during coronary thrombolysis. AB - Plasminogen activators reduce mortality in patients with acute myocardial infarction primarily by inducing reperfusion at a time when the myocardium is still viable. Consequently, important determinants of the clinical response to thrombolytic therapy include the patency rate, the timing of reperfusion, and the frequency of coronary reocclusion. With present thrombolytic agents, coronary patency is not achieved in 30%-50% of patients and reperfusion is often delayed for more than 60 min after initiating thrombolytic therapy. Even in those that achieve patency, reperfusion flow, an important determinant of myocardial salvage, may be limited by incomplete clot lysis and residual coronary stenosis. Finally, reocclusion has been reported in 15%-25% of patients and has serious clinical consequences. Experimental and clinical evidence suggests that many of these problems reflect ongoing platelet activation and thrombosis. Thus, there is a rational basis to assume that the clinical benefit of thrombolytic therapy will be enhanced by the addition of antiplatelet and anticoagulant agents. PMID- 21239344 TI - New directions in thrombolytic therapy Molecular mutants and biochemical conjugates. AB - The currently available thrombolytic agents are widely perceived to be suboptimal in terms of both efficacy and safety. This perception has in turn stimulated efforts to design and construct novel plasminogen activators endowed with improved biochemical and pharmacologic properties. There is as yet no consensus as to the properties of an "ideal" thrombolytic agent, and the failure of comparative clinical trials to identify a superior agent has contributed to the controversy. Although an improved plasminogen activator has not yet been constructed, it is clear that efforts to do so have advanced our knowledge of the complex structure-function relationships within plasminogen activators. PMID- 21239345 TI - Lipid abnormalities in myocardial cell injury. AB - Considerable evidence indicates that abnormalities in fatty acid and phospholipid metabolism are important in the pathogenesis of the membrane dysfunction that leads to irreversible myocardial cell injury during myocardial ischemia and related conditions. Membrane dysfunction is mediated by phospholipid degradation and by the accumulation of amphipathic lipid species, including free fatty acids, long-chain acyl-coenzyme A esters, long-chain acylcarnitines, and lipid peroxides. Accumulation of free arachidonic acid, a fatty acid normally stored in membrane phospholipids, is a sensitive indicator of phospholipid degradation. Ongoing work is aimed at defining mechanisms of the phospholipid alterations that appear to involve phospholipase-mediated phospholipid catabolism and impaired phospholipid synthesis. PMID- 21239346 TI - Transcriptional control of muscle proteins. AB - The development of a muscle cell from a precursor cell involves a massive adjustment of gene expression such that over 50 previously silent genes are expressed to produce the muscle proteins required for contractile functions. In differentiated muscle, hormonal and physiologic stimuli modify the expression of these proteins primarily at the level of transcription. How does the cell regulate the switching on and switching off of specific genes to produce the muscle phenotype and respond to new conditions? PMID- 21239348 TI - Survival. PMID- 21239349 TI - The flower code and cancer development. AB - It has been postulated that the preliminary steps of cancer known as "cancerization field" could be mediated by a competitive mechanism among mutated and wild-type cells. Cell competition is a process of selection among populations of cells with different fitness: the best adapted cells (winners) survive and proliferate in the tissue at the expense of the less well adapted cells (losers), and these loser cells are eliminated from the tissue by apoptosis. However, the molecular mechanisms mediating this process and the genes involved are still unknown. A mechanism of cell-to-cell communication during cell competition known as the "flower code" has been recently proposed to distinguish loser from winner cells: fwe(ubi) isoform is expressed ubiquitously in the imaginal disc while fwe(Lose) isoforms are expressed specifically during cell competition in the cells to be eliminated. Cell competition has been postulated to have implications in development, tissue homeostasis, regeneration and tumour development; the process of cell competition does not affect the total cell number and organ morphology is maintained because winner cells compensate for the loss. A role of cell competition as the mechanism occurring during initial stages of tumour formation is currently under study. PMID- 21239350 TI - Using living cells to transport therapeutic genes for cancer treatment. AB - One of the key problems in cancer gene therapy is the inefficient delivery of therapeutic transgenes to tumour sites, after the systemic injection of the viral vector. Hence, new vector discovery is extremely important for the improvement of gene therapy results. Previously, mammalian cells were proposed as new vector systems; however with recent advances in stem cell research this modality makes them more suitable candidates. Tumours are composed of both malignant and benign cells. As "benign" cell types are able to form blood vessels, and stroma, it has been hypothesised that exogenously administrated cells of a different kind would preferentially engraft at the stromal tumour site and could deliver cancer gene therapy vectors to tumours. PMID- 21239351 TI - Electrochemotherapy for treatment of skin and soft tissue tumours. Update and definition of its role in multimodal therapy. AB - Electrochemotherapy (ECT) is a therapeutical procedure based on the induction of cell membrane electroporation, by cell exposure to electric fields lasting a few microseconds, combined with the local or systemic administration of cytotoxic drugs, with an intracellular target and high intrinsic efficacy, but poor cell membrane permeability. ECT is an effective local therapy for any histological tumour that has been used clinically since 2005 and is currently in use in 83 centres all over Europe. In the literature, ECT as a local oncological treatment shows an objective response between 70 and 90% in mucocutaneous primary and metastatic lesions, is cost effective and has few local and systemic side effects. In this manuscript, we present an overview of the European experience in ECT, as well as our own experience in a specialised Spanish oncological centre and in a basic oncological unit in Nicaragua. The purpose is to reflect on the role that this procedure could have in the treatment of skin and mucosal cancer as part of a multidisciplinary approach. PMID- 21239353 TI - Correction of systematic set-up error in breast and head and neck irradiation through a no-action level (NAL) protocol. AB - PURPOSE: To quantify systematic and random patient set-up errors in breast and head and neck conventional irradiation and to evaluate a no-action level (NAL) protocol for systematic set-up error off-line correction in head and neck cancer and breast cancer patients. MATERIAL AND METHODS: Verification electronic portal images of orthogonal set-up fields were obtained daily for the initial four consecutive fractions for 20 patients treated for breast cancer and for 20 head and neck cancer patients. The calculated systematic error was used to shift the isocentre accordingly on the fifth treatment day. From then until the end of the treatment course, pair orthogonal portal images of set-up fields were obtained weekly. To assess the impact of the protocol, pre- and post-correction systematic errors were compared and PTV margins were estimated before and after correction using published margin recipes. RESULTS: Population systematic set-up error decreased in the breast cancer patient group after the implementation of NAL protocol from 4.0 to 1.7 mm on the x-axis, from 4.7 to 2.1 mm on the y-axis and from 2.8 to 0.9 mm on the z axis. The percentage of patients with individual systematic set-up error reduction was 80%, 90% and 80% on the x-, y and z-axes respectively. Population systematic set-up error decreased also in the head and neck cancer patient group from 2.3 to 1.1 mm on the x-axis, from 1.6 to 1.4 mm on the y-axis and from 1.7 to 0.7 mm on the z-axis. The percentage of patients with individual systematic set-up error reduction was 70%, 65% and 85% on the x-, y- and z-axes respectively. Margin reduction achievable with NAL protocol implementation on the x-, y- and z-axes was 6.3, 7.2 and 4.8 mm for breast cancer patients and 3.3, 0.6 and 2.8 mm for head and neck cancer patients. CONCLUSION: NAL off-line protocol is useful for systematic set-up error correction and PTV margin reduction in conventional breast and head and neck irradiation. PMID- 21239352 TI - Gallbladder carcinoma incidentally encountered during laparoscopic cholecystectomy: how to deal with it. AB - Gallbladder cancer (GBC), characterised by rapid progression and a poor prognosis with a high mortality rate, is a complex disease to treat. Incidental gallbladder carcinoma (IGBC) is defined as carcinoma of the gallbladder suspected for the first time during cholecystectomy or accidentally found on histological examination of the gallbladder. With the increasingly widespread acceptance of laparoscopic cholecystectomy (LC) and difficulties in diagnosing GBC preoperatively, the number of cases of IGBC during and after LC has increased. However, management of IGBC is a difficult issue in the absence of established guidelines. Problems associated with IGBC related to LC are the decisions of whether, when and how to perform additional surgery. Controversy remains regarding the effectiveness of additional resection in different stages of GBC. This review gives an overview of IGBC related to LC, and further discusses the preoperative, intraoperative and postoperative diagnosis and management of IGBC during LC. PMID- 21239355 TI - The EORTC Quality of Life questionnaire for patients with colorectal cancer: EORTC QLQ-CR29 validation study for Spanish patients. AB - INTRODUCTION: The EORTC Quality of Life (QL) Group has developed a questionnaire the EORTC QLQ-CR29- for evaluating QL in colorectal cancer. The aim of this study is to assess the psychometric properties of the EORTC QLQCR29 when applied to a sample of Spanish patients. MATERIALS AND METHODS: Eighty-four locally advanced rectal cancer patients in the treatment follow-up period after receiving surgery and neoadjuvant chemoradiotherapy were included in the study. Seventy subjects also had adjuvant chemotherapy. Patients completed both the EORTC QLQC30 and the QLQ-CR29 once. The psychometric evaluation of the questionnaire's structure, reliability, and convergent, divergent and known-groups validity was performed. RESULTS: Multitrait scaling analysis showed that three of the multi-item scales met the standards of convergent and discriminant validity. These same scales reached the 0.7 Cronbach's coefficient criterion or were close to it. In both analyses exceptions were observed in the blood and mucus in stool scale. Correlations between the scales of the QLQC30 and the module were low (r<0.02) in most cases. A few areas with more related content had higher correlations (r<0.05). Group comparison analyses showed differences in QL between groups of patients based on age, comorbidity, performance status, receipt of adjuvant chemotherapy and surgery modality. CONCLUSIONS: The EORTC QLQ-CR29 is a reliable and valid instrument when applied to a sample of Spanish rectal cancer patients. These results are in line with those of the EORTC validation study. PMID- 21239354 TI - In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines. AB - INTRODUCTION: Chemotherapy for advanced well-differentiated carcinoids is characterised by low response rates and short duration of responses. The present study aimed to assess the in vitro activity of novel platinum-based chemotherapeutic drugs in combination with dichloroacetate (DCA), a sensitiser to apoptosis, against lung carcinoid cell lines. METHODS: Three permanent cell lines (UMC-11, H727 and H835) were exposed to 14 different established cytotoxic drugs and the novel platinum-based compounds as satraplatin, JM118 and picoplatin in combination with DCA, and viability of the cells was measured using a tetrazoliumbased dye assay. RESULTS: With exception of the highly chemoresistant UMC- 11 line, the carcinoid cell lines (H727, H835) were sensitive to the majority of chemotherapeutics in vitro. Among the platinum-based drugs, carboplatin and oxaliplatin showed highest efficacy. H835 cells growing as multicellular spheroids were 2.7-8.7-fold more resistant to picoplatin, satraplatin and its metabolite compared to single cell suspensions. DCA (10 mM) inhibited the growth of UMC- 11 cells by 22% and sensitised these highly resistant cells to carboplatin, satraplatin and JM118 1.4-2.4-fold. CONCLUSION: The highly resistant UMC-11 lung carcinoid cells are sensitive to carboplatin, oxaliplatin and the satraplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs. PMID- 21239356 TI - Clinical-therapeutic management of thoracoscopy in pleural effusion: a groundbreaking technique in the twenty-first century. AB - INTRODUCTION: The aim of this study was to investigate the effectiveness of thoracoscopy in the diagnosis of non-affiliated pleural effusions (PE). MATERIAL AND METHODS: A five-year prospective study including data from 110 patients that were clinically diagnosed as benign (14.5%), malign (34.5%) and non-affiliated (50.9%). PE in patents without oncology disease and negative biopsy or cytology were considered as benign. Malignant diagnosis was established according to a pleural biopsy, compatible cytology and/or clinical features. Remaining cases were considered as non-affiliated. Thoracoscopy was done under local anaesthesia and sedation. RESULTS: Thoracoscopy confirmed previous clinical diagnosis of benignity and malignity. Regarding non-affiliated patients, 30.35% were diagnosed after thoracoscopy as unspecific pleuritis, 17.86% mesothelioma and 1.79% pleural tuberculosis (TBC). The other 48.21% of patients reported as non-affiliated were diagnosed with pleural carcinoma. Statistical analysis did not reveal differences between frequencies analysed. CONCLUSIONS: Our results indicate that thoracoscopy is a cost-effective and reliable technique for obtaining histological diagnosis in PE and also allows a directed pleurodesis if indicated. PMID- 21239357 TI - Open-label trial on efficacy and security of treatment with gemcitabine and oral modulation with tegafur and levofolinic acid (GEMTG) in patients with advanced pancreatic cancer. AB - AIM: Advanced pancreatic cancer has a bad prognosis, with a median overall survival (OS) no longer than 4-6 months. Since the end of last century, monotherapy with gemcitabine has remained the elective therapy, but new schedules are needed in order to improve these results. We aim to evaluate the efficacy of tegafur and levofolinic acid (LV) associated with gemcitabine, as well as its toxicity, progression-free survival and OS in advanced pancreatic cancer. PATIENTS AND METHODS: An open-label, multicentric, prospective, non-controlled trial was carried out on patients with advanced or disseminated pancreatic cancer. Gemcitabine 1250 mg/m2 was administered on the 1st and 8th days of the cycle, tegafur 750 mg/m2/day for 21 consecutive days and LV 25 mg/day continuously, every 28 days, with a maximum of six cycles. The primary variable was tumour overall response rate (ORR). Secondarily, time to progression (TTP), OS and scheme toxicity were determined. RESULTS: Forty patients were recruited; the male/female ratio was 30:10, with a mean age of 61 years. Forty percent had a Karnofsky index of 90% or 100%. Only 11 patients (27%) completed the six cycles of treatment, but more than 50% received three or more cycles. Dose intensity was 89.56% for gemcitabine and 87.36% for tegafur. Efficacy ORR was 22.5% (CI 95%, 6 37%). TTP was 3.87 months (CI 95%, 2.1-5.6), time to treatment failure was 2.97 months (CI 95%, 2.43-4.67) and OS 6.3 months (CI 95%, 4-7). The chemotherapeutic combination was well accepted; most haematologic and non-haematologic toxicities were grade 1 or 2. The most prevalent grade 3/4 toxicities were asthenia (30%), liver biochemistry disorders (25%), diarrhoea (15%) and stomatitis (12%). CONCLUSIONS: The administration of gemcitabine, associated with oral tegafur and leucovorin, has activity against advanced pancreatic cancer, with an adequate toxicity profile. PMID- 21239360 TI - Monthly unannounced pill counts for monitoring HIV treatment adherence: tests for self-monitoring and reactivity effects. AB - BACKGROUND: Unannounced home-based pill counts conducted in person or on the telephone are reliable and valid for monitoring medication adherence. However, expecting to have one's pills counted, organizing medications for pill counts, and increased attention from the person conducting the pill counts may have reactive effects and inadvertently improve adherence. The current study determined whether monthly unannounced pill counts conducted by telephone influence adherence over time. METHODS: Two prospective cohorts, one drawn from a social support condition in a behavioral intervention trial (n=186) and the other an observational study (n=187), were followed for 12 months and 8 months, respectively. Medication adherence was monitored using monthly unannounced pill counts conducted by telephone. In addition, blood plasma viral load was collected at the final pill count for the observational cohort. RESULTS: Analyses did not indicate increases in medication adherence over time for antiretroviral or psychiatric medications among men, women, people with detectable and undetectable viral loads, and various medication regimens. CONCLUSIONS: Unannounced pill counts conducted by telephone do not demonstrate reactivity effects and remain a viable, unobtrusive, objective method of monitoring medication adherence. PMID- 21239361 TI - Factors associated with seroconversion after standard dose hepatitis B vaccination and high-dose revaccination among HIV-infected patients. AB - BACKGROUND: Patients with HIV-infection often respond poorly to vaccination. We sought to determine rates of seroconversion among HIV-infected patients receiving the hepatitis B vaccine and for non-responders who received high-dose revaccination. METHODS: A single-center retrospective chart review was performed. Patients received either a series of Engerix-B (20 mcg) or Twinrix (standard dose vaccine [SDV]). A subset of non-responders received a higher 40 mcg dose series of Engerix-B (high-dose revaccination [HDR]). RESULTS: 215 patients received SDV with an overall response rate of 46.5%. Among the 115 non-responders, 30 received HDR with an overall response rate of 66.7%. Factors associated with response to SDV included younger age (odds ratio [OR]/1 year=0.97, P=.03), higher CD4 at first dose (OR/100 CD4=1.13, P=.02), and receipt of Twinrix versus Engerix-B (OR=2.3, P=.003). Higher CD4 at first dose was also associated with response to HDR (OR/100 CD4=2.0, P=.02). All factors remained independently associated with response to SDV and HDR on multivariable analysis. CONCLUSIONS: HDR appears to be a viable strategy to achieve seroconversion among HIV-infected patients who fail to respond to SDV. Higher CD4 at vaccination, younger age, and receipt of Twinrix were independently associated with SDV seroconversion. PMID- 21239358 TI - Treatment change in pregnancy is a significant risk factor for detectable HIV-1 RNA in plasma at end of pregnancy. AB - PURPOSE: To investigate the risk factors for an HIV-1 RNA plasma viral load above 400 copies/mL in the third trimester of pregnancy. METHODS: Data from a large national study were used. The possible determinants were assessed in univariate analyses and in a multivariate logistic regression model in order to adjust for possible confounders. RESULTS: Among 662 pregnancies followed between 2001 and 2008, 131 (19.8%) had an HIV-1 plasma copy number above 400/mL at the third trimester of pregnancy. In the multivariate analysis, the variables significantly associated with this occurrence were earlier calendar year (adjusted odds ratio [AOR] per additional calendar year, 0.70; 95% CI, 0.63-0.77; P<.001), lower CD4 count at enrollment (AOR per 100 cells lower, 1.18; 95% CI, 1.09-1.27; P<.001), HIV-1 RNA levels above 400 copies per mL at enrollment (AOR, 2.23; 95% CI, 1.50 3.33; P<.001), and treatment modification during pregnancy (AOR, 1.66; 95% CI, 1.07-2.57; P=.024). CONCLUSIONS: Treatment changes in pregnancy significantly increase the risk of an incomplete viral suppression at the end of pregnancy. In HIV-infected women of childbearing age, proper preconception care, which includes the preferential prescription of regimens with the best safety profile in pregnancy, is likely to prevent an incomplete viral suppression at the end of pregnancy. PMID- 21239362 TI - Effect of gender and calendar year on time to and duration of virologic suppression among antiretroviral-naive HIV-infected individuals initiating combination antiretroviral therapy. AB - PURPOSE: To determine the effects of gender and calendar year on time to and duration of virologic suppression among HIV-infected antiretroviral-naive individuals initiating combination antiretroviral therapy (cART). METHODS: Ontario Cohort Study antiretroviral-naive participants who initiated cART after December 31, 1998, and who had >=2 follow-up viral loads were included. Multivariable Cox proportional hazard models were used to estimate the effects of gender and calendar year on times to virologic suppression and rebound. RESULTS: Of the 840 patients, 81% were male (median age 40 years; interquartile range [IQR], 34-46). Time to virologic suppression was shorter among women (hazard ratio [HR]=1.27, P=.01) and in more recent calendar time periods (2002-2004: HR, 1.04, P=.67; 2005-2006: HR, 1.22, P=.06; 2007-2008: HR, 1.36, P=.004) compared to 1999-2001 after adjusting for age and type of cART regimens. Women had shorter times to virologic rebound (HR, 1.57; P<.01) after adjusting for age, injection drug use, and type of cART regimen. However, 14/18 (78%) women suspected to be taking cART only for prevention of mother-to-child transmission of HIV experienced virologic rebound compared to 28% of women who required cART for their own health, suggesting that the increased rate of virologic rebound was due to women stopping ART at the termination of a pregnancy if they did not need it for their own health. Rates of rebound did not differ by calendar year period. CONCLUSION: Time to virologic suppression has steadily decreased over time while duration of suppression remained stable. Time to virologic suppression was shorter for women than for men, whereas durability of virologic suppression was slightly longer for men than women. However, gender differences in virologic rebound were likely due to women discontinuing cART at the end of the pregnancy if it was not needed for their own health. PMID- 21239363 TI - The relationship of CCR5 antagonists to CD4+ T-cell gain: a meta-regression of recent clinical trials in treatment-experienced HIV-infected patients. AB - PURPOSE: Lower CD4+ T-cell counts are related to increased morbidity and mortality despite virologic suppression. CCR5 antagonists are associated with robust CD4+ T-cell responses. We examined the relationship of CCR5 antagonists to CD4+ T-cell gains. DESIGN: Meta-regression of recent phase 2-3 trials evaluating new antiretroviral agents in treatment-experienced subjects. METHODS: We analyzed the relationship of CCR5 antagonists to CD4+ T-cell count increase 24 weeks after initiating the new regimen using a linear model with generalized estimating equations controlling for differing rates of virologic suppression. Each treatment group was treated as a data point weighted by sample size. RESULTS: We included 46 treatment groups from 17 trials (11 groups from 5 trials used CCR5 antagonists). Controlling for average baseline HIV-1 RNA and proportion of subjects achieving HIV-1 RNA <50 copies/mL, use of a CCR5 antagonist was associated with an additional significant CD4+ T-cell gain of +30/MUL (95% CI, 19 42) at 24 weeks compared to treatment groups not using a CCR5 antagonist. CONCLUSIONS: Use of a CCR5 antagonist was associated with an enhanced CD4+ T-cell count response independent of virologic suppression. This observation supports further evaluation of CCR5 antagonists in patients with discordant immunologic and virologic responses to ART. PMID- 21239365 TI - Semantic feature analysis treatment for aphasic word retrieval impairments: what's in a name? AB - This article delineates differences among treatment paradigms that have been called semantic feature analysis treatment and reviews the outcomes of these treatment studies regarding improved naming of treated items, maintenance of treatment effects over time, and generalized improvement to untreated items. Differences in outcomes among the treatment paradigms highlight the importance of using different names for different treatment paradigms. PMID- 21239364 TI - Broca's area: rethinking classical concepts from a neuroscience perspective. AB - Just about one and one-half centuries ago, Paul Broca identified the posterior third left frontal convolution of the human brain as a critical area for speech production. Although years of cerebrovascular accident localization studies partially confirmed Broca's claim, recent years have seen a clarification and expansion of the role Broca's area plays in serial processing of language and speech as well as a probable role in nonlinguistic processing. This article will review some of the more recent anatomical and physiological research, including lesion studies, imaging research, and interoperative electrocortical stimulation studies. The article will summarize the research on the role of the human inferior frontal gyrus in lexical, phonologic, and grammatical production, the so called "mirror mechanism" and other aspects of cognitive processing and motor execution. PMID- 21239366 TI - Oral reading for language in aphasia (ORLA): evaluating the efficacy of computer delivered therapy in chronic nonfluent aphasia. AB - PURPOSE: This study examined the efficacy of a treatment, Oral Reading for Language in Aphasia (ORLA), delivered by computer to individuals with chronic nonfluent aphasia and compared its efficacy with the same treatment delivered by a speech-language pathologist (SLP). METHOD: With ORLA, the person with aphasia systematically and repeatedly reads aloud sentences, first in unison and then independently. Following a no-treatment period, 25 individuals with chronic nonfluent aphasia were randomly assigned to receive 24 sessions of ORLA, 1-3 times per week, either by computer or by the SLP. RESULTS: For participants receiving computer ORLA, change made on the Western Aphasia Battery Aphasia Quotient (WAB-AQ) during the treatment phase was larger than the change made during the no-treatment phase. Positive effect sizes for change during treatment compared with change during the no-treatment phase were obtained and were benchmarked as medium or large for the WAB-AQ and discourse measures. There was no significant difference between outcomes for computer ORLA compared with SLP ORLA. CONCLUSION: Low-intensity ORLA, delivered by computer to individuals with chronic nonfluent aphasia, is efficacious and may be equivalent to ORLA delivered by an SLP. PMID- 21239359 TI - A randomized, placebo-controlled trial of abacavir intensification in HIV-1 infected adults with virologic suppression on a protease inhibitor-containing regimen. AB - BACKGROUND AND OBJECTIVE: Maximizing the durability of viral suppression is a key goal of antiretroviral therapy. The objective of AIDS Clinical Trials Group Study 372A was to determine whether the intensification strategy of adding abacavir to an effective indinavir-dual nucleoside regimen would delay the time to virologic failure. METHODS: Zidovudine-experienced subjects (n=229) on therapy with indinavir + zidovudine + lamivudine with plasma HIV-1 RNA levels<500 copies/mL were randomized to abacavir 300 mg twice daily or placebo. The primary endpoint was the time to treatment failure, defined as a composite of confirmed virologic failure (2 consecutive HIV-1 RNAs>200 copies/mL) and treatment discontinuation. RESULTS: At baseline, the study population was 88% male with a median age of 41 years and median CD4 cell count of 250/mm3. Median follow-up was 4.4 years. The primary endpoint was reached in 61/116 of abacavir versus 62/113 of placebo recipients (P=.77); virologic failure occurred in 34/116 and 42/113 patients, respectively (P=.22). There were no differences in the proportions of subjects with plasma HIV-1 RNA levels below 50 copies/mL, in CD4 cell count increases, nor adverse events between the arms. In the study, 17% of subjects developed nephrolithiasis, 2% experienced abacavir hypersensitivity, and 4.8% experienced at least 1 serious cardiovascular event (7 [6%] in the abacavir arm, 4 [3.5%] in the placebo arm). In additional secondary and post hoc analyses, rates of intermittent viremia, suppression below a plasma HIV-1 RNA level of 6 copies/mL, and HIV-1 proviral DNA levels in peripheral blood mononuclear cells were not significantly different in the 2 arms. CONCLUSIONS: The strategy of intensification with abacavir in patients who are virologically suppressed on a stable antiretroviral regimen does not confer a clinical or virologic benefit. As antiretroviral regimens have become more potent since this trial was completed, it will be even more difficult to prove that late intensification of already virologically suppressed patients will add benefit. However, studies are warranted with drugs with new mechanisms of action to determine whether the level of persistent viremia below 50 copies/ mL can be further reduced and what influence this may have on latent HIV reservoirs. PMID- 21239368 TI - The ICF framework and third party disability: application to the spouses of persons with aphasia. AB - The World Health Organization's (WHO) International Classification of Functioning, Disability and Health (ICF) provides a framework for understanding functioning and disability of persons with a health condition. WHO refers to "third party disability" as the study of the life functioning of family members when faced with a health condition of their significant others. The spouses of persons with aphasia (PWAs) have been referred to as the "hidden victims" of aphasia. Traditionally, rehabilitation and societal efforts have been directed solely at the person who has the overt disability. Although it has been long acknowledged that the spouses of PWAs can also have significant difficulties, the focus and resources of therapy are usually not provided to address spouses' problems directly. In addition, PWAs depend on their communicative environments to maintain and develop the skills learned in therapy. The long-term outcomes of aphasia therapy are greatly influenced by being in a facilitative environment. Thus, understanding and providing appropriate intervention and support services for spouses may help not only the spouses but also the PWAs to have positive long term outcomes. This article examines whether the ICF framework can be used to study third party disability of the spouses of PWAs and how the ICF could be used to develop clinically applicable research in this crucial area. PMID- 21239367 TI - Profile of life participation after stroke and aphasia. AB - This study sought to obtain authentic information about life participation after stroke and aphasia. An interview was conducted with 40 individuals from diverse backgrounds and living in 2 geographic locations who had aphasia of at least 9 months. Participants were interviewed using the Profile of Functional Activities and Life Participation (PFALP), a semistructured, conversational approach to obtain self-reported information about a person's life participation profile. Life participation profiles were unique for each participant. Overall, participants reported having difficulty with many activities for which they judged themselves to be moderately impaired and for which they reported low performance satisfaction. Interview data provided information about participation restrictions related to communication and other areas. Results highlight the need for personally relevant follow-up assessment of life participation among people with chronic aphasia to identify and guide viable interventions that extend beyond the traditional scope of care. PMID- 21239369 TI - Lost and found. PMID- 21239370 TI - Attention deficits after incident stroke in the acute period: frequency across types of attention and relationships to patient characteristics and functional outcomes. AB - BACKGROUND: Attention deficits are common post stroke and result in poorer functional outcomes. This study examined the frequency of attention deficits after incident stroke and their correlates. METHOD: Attention of 94 stroke survivors was assessed using the Bells test, Trails Making Test A/B, 2.4- and 2.0 second trials of the Paced Auditory Serial Addition Test (PASAT), and Integrated Auditory Visual Continuous Performance Test (IVA-CPT) within 3 weeks post stroke. Wider functioning was assessed using the Medical Short Form-36 (SF-36) Physical and Mental Component Summary scores (PCS and MCS), London Handicap Scale, Modified Rankin Scale, General Health Questionnaire-28, and Cognitive Failures Questionnaire (CFQ). RESULTS: Most participants were impaired or very impaired on the IVA-CPT (z scores ? 3 SDs below normative mean) but not other attention measures. Functional independence and cognitive screening test (Mini-Mental State Examination) performance were significantly related to IVA-CPT, Trails A/B, and Bells tests but not PASAT. Better performance across the Bells test was related to better SF-36 PCS, whereas Trails A and the PASAT were related to SF-36 MCS. Better CFQ naming was related to Trails B, whereas worse CFQ memory was related to better PASAT performance. CONCLUSION: Attention deficits are common post stroke, though frequency varies widely across the forms of attention assessed, with tests of neglect and speeded attention tasks being linked to quality of life. This variability of performance and linking to wider outcomes suggests the need for comprehensive assessment of attention and that attention is a viable target for rehabilitative efforts. PMID- 21239371 TI - How much change in the stroke impact scale-16 is important to people who have experienced a stroke? AB - BACKGROUND: The Stroke Impact Scale-16 (SIS-16) is used clinically and in research to measure quality of life after stroke. There are no studies that have estimated how much change on the SIS-16 is an important amount of change. The aim of this study was to estimate the minimal clinically important difference (MCID) of the SIS-16. METHOD: SIS-16 scores of participants receiving services at 2 outpatient physical therapy clinics who met inclusion and exclusion criteria (n = 36) were taken at baseline and discharge. At discharge, participants and their physical therapists rated their perceived amount of recovery on a Global Rating of Change (GROC) scale. Estimated MCID values were calculated for the SIS-16 using receiver operating characteristics curves with the GROC as anchors. RESULTS: There was no difference in baseline characteristics between participants who reported important improvement and those who did not. There was a fair relationship between change in SIS-16 scores and participants' (0.41) and physical therapists' (0.38) GROC scores. Change in SIS-16 scores was significantly greater in participants who reported an important amount of change on the GROC scale and those who did not. Estimated MCID of the SIS-16 ranged from 9.4 to 14.1 depending on the anchor. CONCLUSION: The estimated MCID values presented in this study provide a way for clinicians to evaluate meaningful change in individual patients and for researchers to evaluate meaningful change between groups. PMID- 21239372 TI - A preliminary qualitative analysis of the impact of hope on stroke recovery in women. AB - PURPOSE: The purpose of this study was to explore the perceived influence of hope on stroke recovery in women who were at least 6 months post stroke. METHOD: Ten women were recruited from a midsize community in southwestern Ontario, Canada. The main research question was to determine what factors influence hope in the later stages of recovery. RESULTS: These women described hope as an integral factor in fostering optimal recovery beyond 1 year post stroke. Specifically, 3 interconnected factors (ie, external, internal, and personal) worked in conjunction to foster hope in these women post stroke. CONCLUSION: Understanding the influence of hope in long-term recovery is important for health care practitioners and support systems to foster maximal recovery in survivors of stroke. PMID- 21239373 TI - Using metrics to describe the participative stances of members within discussion forums. AB - BACKGROUND: Researchers using forums and online focus groups need to ensure they are safe and need tools to make best use of the data. We explored the use of metrics that would allow better forum management and more effective analysis of participant contributions. OBJECTIVE: To report retrospectively calculated metrics from self-harm discussion forums and to assess whether metrics add to other methods such as discourse analysis. We asked (1) which metrics are most useful to compare and manage forums, and (2) how metrics can be used to identify the participative stances of members to help manage discussion forums. METHODS: We studied the use of metrics in discussion forums on self-harm. SharpTalk comprised five discussion forums, all using the same software but with different forum compositions. SharpTalk forums were similar to most moderated forums but combined support and general social chat with online focus groups discussing issues on self-harm. Routinely recorded time-stamp data were used to derive metrics of episodes, time online, pages read, and postings. We compared metrics from the forums with views from discussion threads and from moderators. We identified patterns of participants' online behavior by plotting scattergrams and identifying outliers and clusters within different metrics. RESULTS: In comparing forums, important metrics seem to be number of participants, number of active participants, total time of all participants logged on in each 24 hours, and total number of postings by all participants in 24 hours. In examining participative stances, the important metrics were individuals' time logged per 24 hours, number of episodes, mean length of episodes, number of postings per 24 hours, and location within the forum of those postings. Metric scattergrams identified several participative stances: (1) the "caretaker," who was "always around," logged on for a much greater time than most other participants, posting but mainly in response to others and rarely initiating threads, (2) the "butterfly," who "flitted in and out," had a large number of short episodes, (3) two "discussants," who initiated many more discussion threads than anybody else and posted proportionately less in the support room, (4) "here for you," who posted frequently in the support room in response to other participants' threads, and (5) seven "people in distress," who posted many comments in the support room in comparison with their total postings and tended to post on their own threads. CONCLUSIONS: Real-time metrics may be useful: (1) by offering additional ways of comparing different discussion forums helping with their management, and (2) by identifying participative stances of individuals so allowing better moderation and support of forums, and more effective use of the data collected. For this to happen, researchers need to publish metrics for their discussion forums and software developers need to offer more real-time metrics facilities. PMID- 21239374 TI - Assessing the acceptability and usability of an interactive serious game in aiding treatment decisions for patients with localized prostate cancer. AB - BACKGROUND: Men diagnosed with localized prostate cancer face a potentially life altering treatment decision that can be overwhelming. Enhancing patient knowledge through education can significantly reduce feelings of uncertainty while simultaneously increasing confidence in decision making. Serious games have been shown in other populations to increase health knowledge and assist with the health decision-making process. We developed an interactive serious game, Time After Time, which translates evidence-based treatment outcome data into an accessible and understandable format that men can utilize in their prostate cancer treatment decision-making process. The game specifically aims to raise men's awareness and understanding of the impact of health-related quality of life issues associated with the major treatment options and to enrich their conversations with their health care providers. OBJECTIVE: This study determined the acceptability and usability of the alpha version of Time After Time, an interactive decision aid for men diagnosed with localized prostate cancer, in order to inform future iterations of the serious game. METHODS: The study employed a mixed methods approach to assess the acceptability and usability of the Time After Time serious game using qualitative focus groups and a quantitative Likert scale survey. RESULTS: A total of 13 men who had already completed treatment for localized prostate cancer completed the survey and participated in focus group meetings. The majority of the study participants rated Time After Time as an appropriate decision tool for localized prostate cancer and verified that it meets its goals of increasing focus on side effects and generating questions for the patient's health care team. However, participants also expressed concerns about game usability and the diversity of information covered regarding treatment options and potential treatment outcomes. CONCLUSIONS: Serious games are a promising approach to health education and decision support for older men. Participants were receptive to the idea of a serious game as a decision aid in localized prostate cancer. However, usability issues are a major concern for this demographic, as is clarity and transparency of data sources. PMID- 21239375 TI - The rate of nitrite reduction in leaves as indicated by O2 and CO2 exchange during photosynthesis. AB - Light response (at 300 ppm CO(2) and 10-50 ppm O(2) in N(2)) and CO(2) response curves [at absorbed photon fluence rate (PAD) of 550 MUmol m(-2) s(-1)] of O(2) evolution and CO(2) uptake were measured in tobacco (Nicotiana tabacum L.) leaves grown on either NO(3)(-) or NH(4)(+) as N source and in potato (Solanum tuberosum L.), sorghum (Sorghum bicolor L. Moench), and amaranth (Amaranthus cruentus L.) leaves grown on NH(4)NO(3). Photosynthetic O(2) evolution in excess of CO(2) uptake was measured with a stabilized zirconia O(2) electrode and an infrared CO(2) analyser, respectively, and the difference assumed to represent the rate of electron flow to acceptors alternative to CO(2), mainly NO(2)(-), SO(4)(2-), and oxaloacetate. In NO(3)(-)-grown tobacco, as well as in sorghum, amaranth, and young potato, the photosynthetic O(2)-CO(2) flux difference rapidly increased to about 1 MUmol m(-2) s(-1) at very low PADs and the process was saturated at 50 MUmol quanta m(-2) s(-1). At higher PADs the O(2)-CO(2) flux difference continued to increase proportionally with the photosynthetic rate to a maximum of about 2 MUmol m(-2) s(-1). In NH(4)(+)-grown tobacco, as well as in potato during tuber filling, the low-PAD component of surplus O(2) evolution was virtually absent. The low-PAD phase was ascribed to photoreduction of NO(2)(-) which successfully competes with CO(2) reduction and saturates at a rate of about 1 MUmol O(2) m(-2) s(-1) (9% of the maximum O(2) evolution rate). The high-PAD component of about 1 MUmol O(2) m(-2) s(-1), superimposed on NO(2)(-) reduction, may represent oxaloacetate reduction. The roles of NO(2)(-), oxaloacetate, and O(2) reduction in the regulation of ATP/NADPH balance are discussed. PMID- 21239376 TI - Water deficits uncouple growth from photosynthesis, increase C content, and modify the relationships between C and growth in sink organs. AB - In plants, carbon (C) molecules provide building blocks for biomass production, fuel for energy, and exert signalling roles to shape development and metabolism. Accordingly, plant growth is well correlated with light interception and energy conversion through photosynthesis. Because water deficits close stomata and thus reduce C entry, it has been hypothesised that droughted plants are under C starvation and their growth under C limitation. In this review, these points are questioned by combining literature review with experimental and modelling illustrations in various plant organs and species. First, converging evidence is gathered from the literature that water deficit generally increases C concentration in plant organs. The hypothesis is raised that this could be due to organ expansion (as a major C sink) being affected earlier and more intensively than photosynthesis (C source) and metabolism. How such an increase is likely to interact with C signalling is not known. Hence, the literature is reviewed for possible links between C and stress signalling that could take part in this interaction. Finally, the possible impact of water deficit-induced C accumulation on growth is questioned for various sink organs of several species by combining published as well as new experimental data or data generated using a modelling approach. To this aim, robust correlations between C availability and sink organ growth are reported in the absence of water deficit. Under water deficit, relationships weaken or are modified suggesting release of the influence of C availability on sink organ growth. These results are interpreted as the signature of a transition from source to sink growth limitation under water deficit. PMID- 21239378 TI - Molecular characterization and functional analysis of the beta-galactosidase gene during Coffea arabica (L.) fruit development. AB - beta-D-Galactosidase (EC 3.2.1.23) has been detected in several plant species, and is characterized in different organs and tissues by its ability to hydrolyse terminal non-reducing beta-D-galactosyl residues from beta-D-galactoside polymers. In the present paper the cloning and the biochemical and molecular characterization of Coffea arabica beta-galactosidase expressed in the pericarp and the endosperm of coffee fruits in all phases of ripeness are described. It was found that coffee beta-galactosidase is not evenly transcribed throughout fruit ripening, oscillating with two distinct peaks: the first peak when immature fruits are at the active growing stage and the second when fully developed coffee fruits are completely ripe. Both in vitro enzymatic activity of coffee fruit protein extracts and in vivo histochemical assay of freshly harvested coffee fruits confirmed the uneven transcription of beta-galactosidase as fruit maturation advanced. Partial genomic DNA sequencing indicated a complex arrangement of nine putative exons. In silico translation of the cloned coding sequences clearly revealed the cloned gene as beta-galactosidase, with the presence of a signal peptide directing the enzyme to the apoplast. Two isoforms were distinguished by sequencing reverse transcription-PCR transcripts, one expressed in young and adult leaves and another in stems, petals, and coffee fruit endosperm and pericarp. Southern blot analysis indicates that there are at least two copies of this gene in the C. arabica genome that could explain the presence of two beta-galactosidase isoforms. PMID- 21239379 TI - Food standards: the cacophony of governance. AB - Although long distance trade in food goes back at least as far as Columbus, the recent wave of food globalization is unprecedented in human history. But despite the existence of the Codex Alimentarius, the Food and Agriculture Organization, and the World Trade Organization, there is no central authority that governs the many facets of food. Instead, we have arrived at a food network that is governed by a plethora of public and private standards including those for productivity, food safety, food quality, packaging, and nutritional value. However, standards are both epistemological and ontological devices; they make the realities that they claim to describe. Moreover, once accepted they tend to become 'second nature,' often obscuring growing problems and conflicts, including (perhaps especially) those arising out of the very standards themselves. On the one hand, standards for productivity obscure the weak and rapidly eroding premises on which current productivity is based. On the other hand, standards for quality tend to rigidify production regimes. Both tend to inhibit innovations of the sort necessary for us to realize food security globally. PMID- 21239377 TI - A holistic view of nitrogen acquisition in plants. AB - Nitrogen (N) is the mineral nutrient required in the greatest amount and its availability is a major factor limiting growth and development of plants. As sessile organisms, plants have evolved different strategies to adapt to changes in the availability and distribution of N in soils. These strategies include mechanisms that act at different levels of biological organization from the molecular to the ecosystem level. At the molecular level, plants can adjust their capacity to acquire different forms of N in a range of concentrations by modulating the expression and function of genes in different N uptake systems. Modulation of plant growth and development, most notably changes in the root system architecture, can also greatly impact plant N acquisition in the soil. At the organism and ecosystem levels, plants establish associations with diverse microorganisms to ensure adequate nutrition and N supply. These different adaptive mechanisms have been traditionally discussed separately in the literature. To understand plant N nutrition in the environment, an integrated view of all pathways contributing to plant N acquisition is required. Towards this goal, in this review the different mechanisms that plants utilize to maintain an adequate N supply are summarized and integrated. PMID- 21239380 TI - Involvement of cytosolic ascorbate peroxidase and Cu/Zn-superoxide dismutase for improved tolerance against drought stress. AB - In order to understand the role of cytosolic antioxidant enzymes in drought stress protection, transgenic tobacco (Nicotiana tabacum cv. Xanthi) plants overexpressing cytosolic Cu/Zn-superoxide dismutase (cytsod) (EC 1.15.1.1) or ascorbate peroxidase (cytapx) (EC 1.11.1.1) alone, or in combination, were produced and tested for tolerance against mild water stress. The results showed that the simultaneous overexpression of Cu/Znsod and apx or at least apx in the cytosol of transgenic tobacco plants alleviates, to some extent, the damage produced by water stress conditions. This was correlated with higher water use efficiency and better photosynthetic rates. In general, oxidative stress parameters, such as lipid peroxidation, electrolyte leakage, and H(2)O(2) levels, were higher in non-transformed plants than in transgenic lines, suggesting that, at the least, overexpression of cytapx protects tobacco membranes from water stress. In these conditions, the activity of other antioxidant enzymes was induced in transgenic lines at the subcellular level. Moreover, an increase in the activity of some antioxidant enzymes was also observed in the chloroplast of transgenic plants overexpressing cytsod and/or cytapx. These results suggest the positive influence of cytosolic antioxidant metabolism on the chloroplast and underline the complexity of the regulation network of plant antioxidant defences during drought stress. PMID- 21239381 TI - CONSTANS and the evolutionary origin of photoperiodic timing of flowering. AB - A network of promoting and inhibiting pathways that respond to environmental and internal signals controls the flowering transition. The outcome of this regulatory network establishes, for any particular plant, the correct time of the year to flower. The photoperiod pathway channels inputs from light, day length, and the circadian clock to promote the floral transition. CONSTANS (CO) is a central regulator of this pathway, triggering the production of the mobile florigen hormone FT (FLOWERING LOCUS T) that induces flower differentiation. Because plant reproductive fitness is directly related to its capacity to flower at a precise time, the photoperiod pathway is present in all known plant species. Recent findings have stretched the evolutionary span of this photophase signal to unicellular algae, which show unexpected conserved characteristics with modern plant photoperiodic responses. In this review, a comparative description of the photoperiodic systems in algae and plants will be presented and a general role for the CO family of transcriptional activators proposed. PMID- 21239382 TI - Nitrate transceptor(s) in plants. AB - The availability of mineral nutrients in the soil dramatically fluctuates in both time and space. In order to optimize their nutrition, plants need efficient sensing systems that rapidly signal the local external concentrations of the individual nutrients. Until recently, the most upstream actors of the nutrient signalling pathways, i.e. the sensors/receptors that perceive the extracellular nutrients, were unknown. In Arabidopsis, increasing evidence suggests that, for nitrate, the main nitrogen source for most plant species, a major sensor is the NRT1.1 nitrate transporter, also contributing to nitrate uptake by the roots. Membrane proteins that fulfil a dual nutrient transport/signalling function have been described in yeast and animals, and are called 'transceptors'. This review aims to illustrate the nutrient transceptor concept in plants by presenting the current evidence indicating that NRT1.1 is a representative of this class of protein. The various facets, as well as the mechanisms of nitrate sensing by NRT1.1 are considered, and the possible occurrence of other nitrate transceptors is discussed. PMID- 21239383 TI - ABC transporters coordinately expressed during lignification of Arabidopsis stems include a set of ABCBs associated with auxin transport. AB - The primary inflorescence stem of Arabidopsis thaliana is rich in lignified cell walls, in both vascular bundles and interfascicular fibres. Previous gene expression studies demonstrated a correlation between expression of phenylpropanoid biosynthetic genes and a subset of genes encoding ATP-binding cassette (ABC) transporters, especially in the ABCB/multi-drug resistance/P glycoprotein (ABCB/MDR/PGP) and ABCG/pleiotropic drug resistance (ABCG/PDR) subfamilies. The objective of this study was to characterize these ABC transporters in terms of their gene expression and their function in development of lignified cells. Based on in silico analyses, four ABC transporters were selected for detailed investigation: ABCB11/MDR8, ABCB14/MDR12, ABCB15/MDR13, and ABCG33/PDR5. Promoter::glucuronidase reporter assays for each gene indicated that promoters of ABCB11, ABCB14, ABCB15, and ABCG33 transporters are active in the vascular tissues of primary stem, and in some cases in interfascicular tissues as well. Homozygous T-DNA insertion mutant lines showed no apparent irregular xylem phenotype or alterations in interfascicular fibre lignification or morphology in comparison with wild type. However, in abcb14-1 mutants, stem vascular morphology was slightly disorganized, with decreased phloem area in the vascular bundle and decreased xylem vessel lumen diameter. In addition, abcb14-1 mutants showed both decreased polar auxin transport through whole stems and altered auxin distribution in the procambium. It is proposed that both ABCB14 and ABCB15 promote auxin transport since inflorescence stems in both mutants showed a reduction in polar auxin transport, which was not observed for any of the ABCG subfamily mutants tested. In the case of ABCB14, the reduction in auxin transport is correlated with a mild disruption of vascular development in the inflorescence stem. PMID- 21239384 TI - Chronic kidney disease is prevalent in Chinese patients admitted with verified cerebrovascular lesions and predicts short-term prognosis. AB - OBJECTIVE: Recent studies have identified chronic kidney disease (CKD) as an important risk factor for vasculopathies. While the link between CKD and cardiovascular events is well established, the link with cerebrovascular lesions (CVL) has been less well described. METHODS: We studied the prevalence and prognostic importance of CKD in 1014 incident Chinese patients admitted with verified computerized tomography (CT) or magnetic resonance imaging (MRI) CVL (within the last 7 days). Laboratory data included the urinary microalbumin-to creatinine ratio, routine urinalysis, fasting plasma glucose, serum creatinine, uric acid and other measures. Estimated glomerular filtration rate was calculated (using the modification of diet in renal disease formula) and CKD stages were classified according to kidney disease outcome quality initiative (K/DOQI) guidelines. Patients were followed for 30 days and any neurological sequelae were recorded. RESULTS: A total of 1014 patients were enrolled (455 females, aged 68.56 +/- 12.17 years). Among these, 708 had ischemic stroke, 197 hemorrhagic stroke and 109 had transient cerebral ischemic attack. Microalbuminuria was detected in 11.2% of patients, while 24.8% had proteinuria. Of all patients, 6.90% had Stage 1, 14.69% Stage 2, 21.60% Stage 3, 2.56% Stage 4 and 1.97% had Stage 5, giving a total prevalence of CKD at 47.7%. In logistic regression, proteinuria (odds ratio = 1.69), hyperglycemia (odds ratio = 1.67) and anemia (odds ratio = 1.37) were independent predictors for risk of sequelae at 30 days for both ischemic and non-ischemic CVL. CONCLUSION: We report a high prevalence of CKD among Chinese patients with incident CVL. Proteinuria, hyperglycemia and anemia were prognostic factors in these patients. PMID- 21239385 TI - Nutritional vitamin D in dialysis patients: what to D-iscern? PMID- 21239386 TI - TLR-4+ peripheral blood monocytes and cardiovascular events in patients with chronic kidney disease--a prospective follow-up study. AB - BACKGROUND: Atherosclerosis is an inflammatory process mediated by circulating immune cells, including monocytes. There is accumulating evidence for the involvement of Toll-like receptor 4 (TLR-4) as a mediator of atherogenesis. METHODS: We evaluated the association between CD14+/TLR-4+ monocytes in peripheral blood (flow cytometry) and future cardiovascular events (CVE), e.g. myocardial infarction, percutaneous transluminal coronary angioplasty (including stenting), aortocoronary bypass, stroke and angiographically verified stenosis of peripheral arteries and cardiovascular (CV) death, in 191 patients with chronic kidney disease Stage V receiving hemodialysis therapy. RESULTS: At baseline, CD14+/TLR-4+ monocytes correlated significantly with age (r = 0.2; P = 0.007), high-sensitivity C-reactive protein (r = 0.2; P = 0.008) and mean arterial pressure (r = -0.2; P = 0.02), but not with gender (P = 0.5), smoking (P = 0.6) and the presence of diabetes (P = 0.5). During a median follow-up period of 36 [1 54] months, 79 (41%) patients experienced a CVE. A total of 55 patients died during the follow-up period, 25 of those due to a confirmed CV cause. Log-rank test did not reveal statistical significance for TLR-4+ monocytes concerning incident CVE (P = 0.3), CV death (P = 0.85) and overall death (P = 0.8). In a multiple Cox-regression analysis, we identified age (P = 0.003) and smoking (P = 0.001) as the only independent variables associated with incident CVE. CONCLUSIONS: Unexpectedly, we could not detect an association between CD14+/TLR 4+ monocytes and incident CVE as well as CV death in stable hemodialysis patients. Further studies have to clarify the potential role of this cell population for CV outcome in this population. PMID- 21239387 TI - The prevalence and meaning of eosinophilia in renal diseases on a nephrology consultation service. AB - BACKGROUND: In recent years, we have come to understand that the eosinophil is more than the end point in clearance of parasitic infection or a maladaptive response to asthma and allergic reactions. Since eosinophilia has been reported to be common in renal diseases, we thought that an evaluation of the associations of eosinophilia on a renal consultation service would add some value to the understanding of their role in renal disease. METHODS: This was a prospective cross-sectional study of 1339 consecutive patients referred to the nephrology service after hospitalization who were evaluated for the relationship of the amount of serum eosinophils to their diagnosis, gender, age and the presence of autoimmune disease, cancer, infection, liver disease, pleural effusions, allergies and use of prednisone, beta-blockers or beta agonists, in addition to the total white blood count, urine protein, serum concentration creatinine and phosphorus levels and estimated glomerular filtration rate. RESULTS: The presence of vascular disease correlated the most strongly with increased eosinophil count (partial correlation coefficient, r = 0.18, P = 0.006), followed by pleural effusions (r = 0.17, P = 0.001), while total white cell count (r = -0.18, P = 0.008) and administration of beta-blockers (r = -0.13, P = 0.047) demonstrated significant inverse correlations and the presence of autoimmune disease, cancer, allergies, proteinuria and serum phosphorus concentration demonstrated no significant correlation. CONCLUSION: There are multiple associations with increased eosinophil counts in patients seen on a nephrology consultant service; however, their presence appears less often in association with allergies or uremia and more often with vascular disease. PMID- 21239388 TI - Recent and rapid speciation with limited morphological disparity in the genus Rattus. AB - Recent and rapid radiations provide rich material to examine the factors that drive speciation. Most recent and rapid radiations that have been well characterized involve species that exhibit overt ecomorphological differences associated with clear partitioning of ecological niches in sympatry. The most diverse genus of rodents, Rattus (66 species), evolved fairly recently, but without overt ecomorphological divergence among species. We used multilocus molecular phylogenetic data and five fossil calibrations to estimate the tempo of diversification in Rattus, and their radiation on Australia and New Guinea (Sahul, 24 species). Based on our analyses, the genus Rattus originated at a date centered on the Pliocene-Pleistocene boundary (1.84-3.17 Ma) with a subsequent colonization of Sahul in the middle Pleistocene (0.85-1.28 Ma). Given these dates, the per lineage diversification rates in Rattus and Sahulian Rattus are among the highest reported for vertebrates (1.1-1.9 and 1.6-3.0 species per lineage per million years, respectively). Despite their rapid diversification, Rattus display little ecomorphological divergence among species and do not fit clearly into current models of adaptive radiations. Lineage through time plots and ancestral state reconstruction of ecological characters suggest that diversification of Sahulian Rattus was most rapid early on as they expanded into novel ecological conditions. However, rapid lineage accumulation occurred even when morphological disparity within lineages was low suggesting that future studies consider other phenotypes in the diversification of Rattus. PMID- 21239389 TI - Towards a more nuanced understanding of the relationship between sex-biased gene expression and rates of protein-coding sequence evolution. AB - Genes that are differentially expressed between the sexes (sex-biased genes) are among the fastest evolving genes in animal genomes. The majority of sex-biased expression is attributable to genes that are primarily expressed in sex-limited reproductive tissues, and these reproductive genes are often rapidly evolving because of intra- and intersexual selection pressures. Additionally, studies of multiple taxa have revealed that genes with sex-biased expression are also expressed in a limited number of tissues. This is worth noting because narrowly expressed genes are known to evolve faster than broadly expressed genes. Therefore, it is not clear whether sex-biased genes are rapidly evolving because they have sexually dimorphic expression, because they are expressed in sex limited reproductive tissues, or because they are narrowly expressed. To determine the extend to which other confounding variables can explain the rapid evolution of sex-biased genes, I analyzed the rates of evolution of sex-biased genes in Drosophila melanogaster and Mus musculus in light of tissue-specific measures of expression. I find that genes with sex-biased expression in somatic tissues shared by both sexes are often evolving faster than non-sex-biased genes, but this is best explained by the narrow expression profiles of sex-biased genes. Sex-biased genes in sex-limited tissues in D. melanogaster, however, evolve faster than other narrowly expressed genes. Therefore, the rapid evolution of sex biased genes is limited only to those genes primarily expressed in sex-limited reproductive tissues. PMID- 21239390 TI - Chromosome size in diploid eukaryotic species centers on the average length with a conserved boundary. AB - Understanding genome and chromosome evolution is important for understanding genetic inheritance and evolution. Universal events comprising DNA replication, transcription, repair, mobile genetic element transposition, chromosome rearrangements, mitosis, and meiosis underlie inheritance and variation of living organisms. Although the genome of a species as a whole is important, chromosomes are the basic units subjected to genetic events that coin evolution to a large extent. Now many complete genome sequences are available, we can address evolution and variation of individual chromosomes across species. For example, "How are the repeat and nonrepeat proportions of genetic codes distributed among different chromosomes in a multichromosome species?" "Is there a general rule behind the intuitive observation that chromosome lengths tend to be similar in a species, and if so, can we generalize any findings in chromosome content and size across different taxonomic groups?" Here, we show that chromosomes within a species do not show dramatic fluctuation in their content of mobile genetic elements as the proliferation of these elements increases from unicellular eukaryotes to vertebrates. Furthermore, we demonstrate that, notwithstanding the remarkable plasticity, there is an upper limit to chromosome-size variation in diploid eukaryotes with linear chromosomes. Strikingly, variation in chromosome size for 886 chromosomes in 68 eukaryotic genomes (including 22 human autosomes) can be viably captured by a single model, which predicts that the vast majority of the chromosomes in a species are expected to have a base pair length between 0.4035 and 1.8626 times the average chromosome length. This conserved boundary of chromosome-size variation, which prevails across a wide taxonomic range with few exceptions, indicates that cellular, molecular, and evolutionary mechanisms, possibly together, confine the chromosome lengths around a species-specific average chromosome length. PMID- 21239391 TI - Molecular evolution of the toll-like receptor multigene family in birds. AB - Toll-like receptors (TLR) are membrane-bound sensors of the innate immune system that recognize invariant and distinctive molecular features of invading microbes and are also essential for initiating adaptive immunity in vertebrates. The genetic variation at TLR genes has been directly related to differential pathogen outcomes in humans and livestock. Nonetheless, new insights about the impact of TLRs polymorphism on the evolutionary ecology of infectious diseases can be gained through the investigation of additional vertebrate groups not yet investigated in detail. In this study, we have conducted the first characterization of the entire TLR multigene family (N = 10 genes) in non-model avian species. Using primers targeting conserved coding regions, we aimed at amplifying large segments of the extracellular domains (275-435 aa) involved in pathogen recognition across seven phylogenetically diverse bird species. Our analyses suggest avian TLRs are dominated by stabilizing selection, suggesting that slow rates of nonsynonymous substitution help preserve biological function. Overall, mean values of omega (= d(n)/d(s)) at each TLR locus ranged from 0.196 to 0.517. However, we also found patterns of positive selection acting on specific amino acid sites that could be linked to species-specific differences in pathogen-associated molecular pattern recognition. Only 39 of 2,875 (~1.35%) of the codons analyzed exhibited significant patterns of positive selection. At least one half of these positively selected codons can be mapped to putative ligand-binding regions, as suggested by crystallographic structures of TLRs and their ligands and mutagenic analyses. We also surveyed TLR polymorphism in wild populations of two bird species, the Lesser Kestrel Falco naumanni and the House Finch Carpodacus mexicanus. In general, avian TLRs displayed low to moderate single nucleotide polymorphism levels and an excess of silent nucleotide substitutions, but also conspicuous instances of positive directional selection. In particular, TLR5 and TLR15 exhibited the highest degree of genetic polymorphism and the highest occurrence of nonconservative amino acid substitutions. This study provides critical primers and a first look at the evolutionary patterns and implications of TLR polymorphism in non-model avian species and extends the list of candidate loci for avian eco-immunogenetics beyond the widely employed genes of the Major Histocompatibility Complex (MHC). PMID- 21239392 TI - Human locomotor adaptive learning is proportional to depression of cerebellar excitability. AB - Human locomotor adaptive learning is thought to involve the cerebellum, but the neurophysiological mechanisms underlying this process are not known. While animal research has pointed to depressive modulation of cerebellar outputs, a direct correlation between adaptive learning and cerebellar depression has never been demonstrated. Here, we used transcranial magnetic stimulation to assess excitability changes occurring in the cerebellum and primary motor cortex (M1) after individuals learned a new locomotor pattern on a split-belt treadmill. To control for potential changes associated to task performance complexity, the same group of subjects was also assessed after performing 2 other locomotor tasks that did not elicit learning. We found that only adaptive learning resulted in reduction of cerebellar inhibition. This effect was strongly correlated with the magnitude of learning (r = 0.78). In contrast, M1 excitability changes were not specific to learning but rather occurred in association with task complexity performance. Our results demonstrate that locomotor adaptive learning in humans is proportional to cerebellar excitability depression. This finding supports the theory that adaptive learning is mediated, at least in part, by long-term depression in Purkinje cells. This knowledge opens the opportunity to target cerebellar processes with noninvasive brain stimulation to enhance motor learning. PMID- 21239393 TI - Microanatomical correlates of cognitive ability and decline: normal ageing, MCI, and Alzheimer's disease. AB - Few microanatomical measures have been reliably correlated with cognitive measures in aging and Alzheimer's disease (AD), particularly in the early stages of degeneration, such as mild cognitive impairment (MCI). However, cortical minicolumn organization has been shown to correlate with cognitive ability in aging monkeys, and the present study extends this finding to humans. We have previously reported that minicolumn spacing of cells in human association cortex is selectively reduced in normal aging (minicolumn thinning). The present study found that such measures detected early disease changes in MCI as well as further minicolumn thinning and disruption in AD. Plaques, tangles, and minicolumns were quantified, postmortem, for 20 controls, 10 MCI, and 20 AD subjects. Minicolumn changes were correlated with premortem cognitive scores (mini-mental state examination and verbal fluency). Two regions were studied from each brain: association cortex in the planum temporale (BA22) and primary auditory cortex (BA41). The relationship between minicolumns and cognitive function was strongest in association cortex, whereas in primary auditory cortex, it appeared to be an epiphenomenon of overall brain atrophy. Microanatomical changes reflecting selective regional vulnerability to AD pathology and differential involvement in the cognitive deficit of AD are therefore detectable in the early stage of MCI. PMID- 21239394 TI - A comparative in vitro study of frictional resistance between lingual brackets and stainless steel archwires. AB - Friction between archwires and labial brackets has received considerable attention; however, information on the frictional behaviour of commercially available lingual brackets is limited. The aim of this study was to investigate the frictional resistance resulting from a combination of lingual orthodontic brackets (7th Generation, STb, Magic, and In-Ovation L) and stainless steel archwires at 0, 5, and 10 degrees of second-order angulation. Each bracket type (n = 30) was tested with three different sizes of archwires. Static and kinetic frictional forces were evaluated with a universal testing machine. Statistical analysis of the data was performed with non-parametric Kruskal-Wallis and Dunn's multiple comparison tests. All tested brackets showed higher frictional forces as the wire size and second-order angulation increased. The lowest friction was found with In-Ovation L brackets and 0.016 inch archwires at 0 degrees angulation, and the greatest friction with a combination of STb brackets and 0.017 * 0.025 inch archwires at 10 degrees angulation. For all combinations, Magic and In-Ovation L brackets showed lower frictional resistance when compared with 7th Generation and STb brackets. The slot width (occluso-gingival dimension) of the brackets, measured using the optics of a microhardness machine, showed that all brackets were oversized and that Magic brackets had the largest slot width. Surface roughness of the brackets investigated using atomic force microscopy and scanning electron microscopy, demonstrated that the 7th Generation brackets had the greatest surface roughness. PMID- 21239395 TI - A follow-up study of early interceptive treatment of primary anterior crossbites. AB - The purpose of this study was to investigate the outcome of early interceptive treatment of primary anterior crossbites with posterior occlusal acrylic resin blocks in combination with a 2 * 4 appliance, and to examine the differences in craniofacial morphology between the stable and relapse groups. Lateral cephalograms of 46 subjects (17 males and 29 females; average mean age 4 years 2 months +/- 5 months) with a primary anterior crossbite were obtained before (T0) and immediately after (T1) treatment and at a 6 year follow-up (T2). The patients were assigned to either a stable (n = 35; 13 males and 22 females) or a relapse (n = 11; 4 males and 7 females) group according to the amount of overjet when the permanent incisors had erupted. The differences in craniofacial morphology between the groups were compared using a two-tailed t-test. The results revealed that the relapse subjects had a more forward position of the mandible relative to the cranial base and maxilla, a longer mandible and an increased gonial angle at T0. At T1, both groups had a positive overjet, but the treatment changes were different. Between T1 and T2, the maxillary length (A'-Ptm') increased less in the relapse group, the angle between the posterior border of the mandibular ramus and SN plane (Ram-SN) decreased and gonial angle increased and vice versa in the stable group. When posterior bite raising and 2 * 4 appliance therapy are used to correct primary anterior crossbites, all patients showed an immediate positive treatment response, whereas approximately one-quarter of subjects relapsed into a reverse overjet when the permanent incisors had erupted, mainly because of a more severe Class III craniofacial morphology at T1 and unfavourable growth during T1 T2. PMID- 21239396 TI - In vitro study of force decay of latex and non-latex orthodontic elastics. AB - The aim of this study was to evaluate the force decay of two brands of orthodontic elastics, both offering latex and non-latex products. Samples were subjected to continuous stretching, measuring force at 5 seconds, 8 hours, and 24 hours in both dry and wet conditions. Five hundred samples were used, GAC(r) and Lancer(r) 0.25 inch and 4 oz, divided into testing sample sizes of n = 25 per group. For the dry test, elastics were kept stretched to three times their internal diameter for 5 seconds (initial force), 8 hours, and 24 hours; for the wet test, they were stretched for 8 and 24 hours. Both brands showed initial forces significantly greater than those specified by the manufacturers (P < 0.05). Comparing wet/dry conditions, there was a greater force loss in the wet medium than the dry. As for elastic composition (latex or non-latex), the only significant difference found was between Lancer elastics with and without latex in dry conditions, force loss being greater for latex-free elastics. Comparing brands, there was greater force loss with GAC than with Lancer. Comparing elastic force at the eight-hour mark and the twenty-four hour mark to the initial force (only in wet conditions), GAC latex and non-latex and Lancer latex elastics showed significantly less force at eight and twenty four hours than initially. On the other hand, Lancer non-latex was the only type of elastics that did not show a significant decrease in its initial elastic characteristics at eight hours in wet conditions. Nevertheless, Lancer non-latex did show significantly less force in wet conditions at twenty four-hours than the forces observed initially and at eight-hours. PMID- 21239397 TI - A systematic review of the efficacy of oral appliance design in the management of obstructive sleep apnoea. AB - Oral appliances (OAs) are increasingly advocated as a treatment option for obstructive sleep apnoea (OSA). However, it is unclear how their different design features influence treatment efficacy. The aim of this research was to systematically review the evidence on the efficacy of different OAs on polysomnographic indices of OSA. A MeSH and text word search were developed for Medline, Embase, Cinahl, and the Cochrane library. The initial search identified 1475 references, of which 116 related to studies comparing OAs with control appliances. Among those, 14 were randomized controlled trials (RCTs), which formed the basis of this review. The type of OA investigated in these trials was mandibular advancement devices (MADs), which were compared with either inactive appliances (six studies) or other types of MADs with different design features. Compared with inactive appliances, all MADs improved polysomnographic indices, suggesting that mandibular advancement is a crucial design feature of OA therapy for OSA. The evidence shows that there is no one MAD design that most effectively improves polysomnographic indices, but that efficacy depends on a number of factors including severity of OSA, materials and method of fabrication, type of MAD (monobloc/twin block), and the degree of protrusion (sagittal and vertical). These findings highlight the absence of a universal definition of treatment success. Future trials of MAD designs need to be assessed according to agreed success criteria in order to guide clinical practice as to which design of OAs may be the most effective in the treatment of OSA. PMID- 21239398 TI - Infusion reactions to the chimeric EGFR inhibitor cetuximab--change to the fully human anti-EGFR monoclonal antibody panitumumab is safe. PMID- 21239399 TI - Salvage combination chemotherapy with floxuridine, dactinomycin, etoposide, and vincristine (FAEV) for patients with relapsed/chemoresistant gestational trophoblastic neoplasia. AB - BACKGROUND: Although most patients with gestational trophoblastic neoplasia (GTN) are cured by conventional chemotherapy, some develop drug resistance or relapse. The use of new combination drugs has been studied to treat those with resistant or relapsed disease. We evaluated the results of floxuridine, dactinomycin, etoposide, and vincristine (FAEV) chemotherapy in patients with relapsed/chemoresistant GTN. PATIENTS AND METHODS: Clinical data and outcome of the patients with relapsed/chemoresistant GTN from 1 January 2005 to 30 June 2008 were retrospectively reviewed. Eligible patients had received at least one cycle of FAEV chemotherapy. The primary end points were response rate and toxicity of FAEV regimen; the secondary end point was assessment of clinical predictors of response. RESULTS: In total, 91 patients were included. Fifty-five of these patients (60.4%) achieved serologic complete remission (SCR), 29 patients had no response, 7 patients experienced recurrent grade >=3 or intolerable toxicity. SCR of FAEV chemotherapy was significantly associated with number of previous chemotherapy regimens (<=2) in multivariate analysis (P = 0.005). The most serious adverse events were greater than or equal to grade 3 neutropenia (26.4%), febrile neutropenia (6.6%), and greater than or equal to grade 3 thrombocytopenia (3.3%). CONCLUSION: FAEV is an effective regimen with manageable toxicity for patients with relapsed/chemoresistant GTN. Further studies of this regimen are warranted. PMID- 21239400 TI - Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology. AB - BACKGROUND: The introduction of molecular targeted agents (e.g., monoclonal antibodies or kinase inhibitors) and cancer vaccines has raised the question whether alternate clinical trial designs, including window trials, are better suited to evaluate such new molecular entities (NMEs) and improve their approval rates. In window trials, patients receive an NME for a window of time before starting standard treatment allowing the evaluation of an NME in tumors unperturbed by previous therapies. METHODS: A systematic literature search was conducted to identify window trials in adult and pediatric oncology. RESULTS: Twenty-nine window trials were identified and reviewed, 13 in pediatric and 16 in adult oncology. Most of the trials (20/29) tested cytotoxics known to have activity in other clinical situations. In contrast to trials with pretreated patients, the window trials established the antitumor activity of melphalan, topotecan, epirubicin and etoposide in untreated patients with rhabdomyosarcoma or small-cell lung cancer. In window trials with ineffective or modestly active NMEs, we found no indication of a significant negative effect on overall survival for participating patients. CONCLUSIONS: Provided close safety monitoring and careful patient selection, window trials are a safe option to investigate potential clinical activity of NMEs. PMID- 21239401 TI - Exposure to acrylamide and human cancer--a review and meta-analysis of epidemiologic studies. AB - BACKGROUND: Acrylamide has been associated to cancer risk in rodents, but data on humans are inconclusive. We thus carried out a critical review and meta-analysis of studies of exposure to acrylamide and cancer. METHODS: We identified 586 publications, 25 presented relevant results. We conducted meta-analyses of studies of dietary intake based on random-effects models by calculating pooled relative risks (RR) and the corresponding 95% confidence intervals (CI). We combined results of occupational studies according to a fixed-effect model. RESULTS: The summary RRs for an increase of 10 MUg/day of acrylamide intake were close to unity for all the cancers considered, ranging from 0.98 for esophageal cancer to 1.01 for colon, endometrial, ovarian and kidney cancer. None of the estimates was significant. Exclusion of one case-control study from Sweden resulted in a summary RR of kidney cancer of 1.04 (95% CI 1.00-1.08). The combined standardized mortality ratios for high occupational exposure were 1.67 (95% CI 0.83-2.99) for pancreatic cancer and 2.22 (95% CI 0.81-4.84) for kidney cancer. CONCLUSIONS: Available studies consistently suggest a lack of an increased risk of most types of cancer from exposure to acrylamide. The main association that requires further monitoring involves kidney cancer. PMID- 21239402 TI - Free mobility of medical oncologists across the European Union: still a false myth. PMID- 21239403 TI - Stability of HER2-positive status in breast carcinoma: a comparison between primary and paired metastatic tumors with regard to the possible impact of intervening trastuzumab treatment. AB - BACKGROUND: To date, the stability of human epidermal growth factor receptor 2 (HER2)-positive primary breast carcinomas during disease progression and the role of intervening trastuzumab treatment in the loss of HER2-positive status in paired metastases remain under-investigated. MATERIALS AND METHODS: Sixty-six patients with HER2-positive primary carcinoma and paired metastasis were evaluated. We examined the overall agreement of the HER2 status and compared the status agreement between 38 trastuzumab-treated patients and 28 trastuzumab-naive control patients. The impact of chemotherapy, endocrine therapy, metastatic site (locoregional or distant), and time to relapse (>=5 or <5 years) on the HER2 status change was assessed. RESULTS: Fifty-six (84.9%) patients had HER2 status agreement between paired tumors; 10 patients had HER2-positive-to-negative conversion. The agreement rate in the trastuzumab-treated group and in the control group was comparable (86.8% versus 82.1%) (P = 0.858). Chemotherapy, endocrine therapy, metastatic site, and time to relapse did not significantly affect HER2 stability in either group. In the discordant tumor pairs, variations in testing methods and borderline scores were common. CONCLUSIONS: HER2-positive status remained unchanged in most paired metastases. Loss of HER2-positive status did not seem to be affected by trastuzumab treatment. Differences in testing and interpretation may account for the discordance in some cases. PMID- 21239404 TI - Prognostic electrocardiographic parameters in patients with suspected myocarditis. AB - AIMS: The objective of this study was to investigate the prognostic value of electrocardiographic (ECG) parameters for outcome in patients acutely admitted with myocarditis without previous heart failure who underwent endomyocardial biopsy. METHODS AND RESULTS: Between 1995 and 2009, 186 consecutive patients (age: 43.4 +/- 13.9 years) acutely admitted with clinically suspected myocarditis were enrolled and followed up for a mean of 55.1 +/- 105.1 months. Electrocardiograms recorded before myocardial biopsy were analysed for rhythm, conduction times, signs of hypertrophy, and repolarization abnormalities. The primary endpoint was time to cardiac death or heart transplantation. The mean QRS duration was 90.3 +/- 24.3 ms; 158 patients had a normal QRS duration (<120 ms) and 21 patients had a prolonged QRS duration (>= 120 ms). During follow-up, 15.8% of patients with a normal QRS duration reached the primary endpoint compared with 42.8% of patients with a prolonged baseline QRS duration [hazard ratio (HR) 3.43; 95% confidence interval (CI) 1.78-6.01; P < 0.001]. The increased risk predicted by a prolonged QRS duration was robust after adjusting for covariates (HR 2.83; CI 1.07-7.49; P = 0.012). A QTc prolongation >= 440 ms (P = 0.011), an abnormal QRS axis (P = 0.012), and premature ventricular beats (P = 0.018) were significant monovariate predictors but did not prove to be independent predictors for survival in multivariate analysis. Q-waves and repolarization abnormalities were neither associated with the primary endpoint nor with immunohistological signs of inflammation. Other ECG parameters were not significantly related to outcome. CONCLUSION: A prolonged QRS duration is an independent predictor for cardiac death or heart transplantation in patients with suspected myocarditis. PMID- 21239405 TI - Serial assessment of the electrocardiographic strain pattern for prediction of new-onset heart failure during antihypertensive treatment: the LIFE study. AB - AIMS: Although the presence of the electrocardiographic (ECG) strain pattern has been associated with an increased risk of developing heart failure (HF), the relationship of regression vs. persistence vs. development of new ECG strain to subsequent HF is unclear. METHODS AND RESULTS: Electrocardiographic strain was evaluated at baseline and at year-1 in 7265 hypertensive patients without HF treated with atenolol- or losartan-based regimens. During 3.9 +/- 0.7 years of follow-up after the year-1 ECG, 154 patients (2.1%) were hospitalized for HF. Five-year HF incidence was lowest in patients with no ECG strain (1.6%), intermediate in patients with regression of strain (5.4%), and highest in patients with persistent (7.1%) or new strain (7.0%; P< 0.0001 across groups). In the Cox multivariable analyses adjusting for the known predictive value of in treatment ECG left ventricular hypertrophy by the Cornell product and Sokolow Lyon voltage, in-treatment QRS duration, systolic and diastolic pressure, incident myocardial infarction and atrial fibrillation, randomized treatment and other risk factors for HF, regression of strain [hazards ratio (HR) 2.4, 95% confidence interval (CI) 1.2-5.0], persistence of strain (HR 1.9, 95% CI 1.2 3.2), and development of new ECG strain (HR 2.3, 95% CI 1.2-4.4) were all independently associated with an increased risk of new HF compared with the absence of ECG strain on both baseline and year-1 ECGs. CONCLUSION: The development of new ECG strain or persistence of ECG strain between baseline and year-1 is associated with an increased risk of HF. The regression of ECG strain between baseline and year-1 does not convey a decreased risk of HF. CLINICAL TRIALS REGISTRATION: http://clinicaltrials.gov/ct/show/NCT00338260. PMID- 21239407 TI - Correlated responses of root growth and sugar concentrations to various defoliation treatments and rhythmic shoot growth in oak tree seedlings (Quercus pubescens). AB - BACKGROUND AND AIMS: To understand whether root responses to aerial rhythmic growth and contrasted defoliation treatments can be interpreted under the common frame of carbohydrate availability; root growth was studied in parallel with carbohydrate concentrations in different parts of the root system on oak tree seedlings. METHODS: Quercus pubescens seedlings were submitted to selective defoliation (removal of mature leaves, cotyledons or young developing leaves) at appearance of the second flush and collected 1, 5 or 10 d later for morphological and biochemical measurements. Soluble sugar and starch concentrations were measured in cotyledons and apical and basal root parts. KEY RESULTS: Soluble sugar concentration in the root apices diminished during the expansion of the second aerial flush and increased after the end of aerial growth in control seedlings. Starch concentration in cotyledons regularly decreased. Continuous removal of young leaves did not alter either root growth or apical sugar concentration. Starch storage in basal root segments was increased. After removal of mature leaves (and cotyledons), root growth strongly decreased. Soluble sugar concentration in the root apices drastically decreased and starch reserves in the root basal segments were emptied 5 d after defoliation, illustrating a considerable shortage in carbohydrates. Soluble sugar concentrations recovered 10 d after defoliation, after the end of aerial growth, suggesting a recirculation of sugar. No supplementary recourse to starch in cotyledons was observed. CONCLUSIONS: The parallel between apical sugar concentration and root growth patterns, and the correlations between hexose concentration in root apices and their growth rate, support the hypothesis that the response of root growth to aerial periodic growth and defoliation treatments is largely controlled by carbohydrate availability. PMID- 21239406 TI - The nuclear envelope in the plant cell cycle: structure, function and regulation. AB - BACKGROUND: Higher plants are, like animals, organisms in which successful completion of the cell cycle requires the breakdown and reformation of the nuclear envelope in a highly controlled manner. Interestingly, however, while the structures and processes appear similar, there are remarkable differences in protein composition and function between plants and animals. SCOPE: Recent characterization of integral and associated components of the plant nuclear envelope has been instrumental in understanding its functions and behaviour. It is clear that protein interactions at the nuclear envelope are central to many processes in interphase and dividing cells and that the nuclear envelope has a key role in structural and regulatory events. CONCLUSION: Dissecting the mechanisms of nuclear envelope breakdown and reformation in plants is necessary before a better understanding of the functions of nuclear envelope components during the cell cycle can be gained. PMID- 21239408 TI - Casparian bands occur in the periderm of Pelargonium hortorum stem and root. AB - BACKGROUND AND AIMS: Casparian bands are characteristic of the endodermis and exodermis of roots, but also occur infrequently in other plant organs, for example stems and leaves. To date, these structures have not been detected in phellem cells of a periderm. The aim of this study was to determine whether Casparian bands occur in phellem cells using tests that are known to detect Casparian bands in cells that also contain suberin lamellae. Both natural periderm and wound-induced structures were examined in shoots and roots. METHODS: Using Pelargonium hortorum as a candidate species, the following tests were conducted: (1) staining with berberine and counterstaining with aniline blue, (2) mounting sections in concentrated sulphuric acid and (3) investigating the permeability of the walls with berberine as an apoplastic, fluorescent tracer. KEY RESULTS: (1) Berberine-aniline blue staining revealed a modification in the radial and transverse walls of mature phellem cells in both stems and roots. Three days after wounding through to the cortex of stems, the boundary zone cells (pre-existing, living cells nearest the wound) had developed vividly stained primary walls. By 17 d, staining of mature phellem cells of wound-induced periderm was similar to that of natural periderm. (2) Mature native phellem cells of stems resisted acid digestion. (3) Berberine was excluded from the anticlinal (radial and transverse) walls of mature phellem cells in stems and roots, and from the wound-induced boundary zone. CONCLUSIONS: Casparian bands are present in mature phellem cells in both stems and roots of P. hortorum. It is proposed that Casparian bands act to retard water loss and pathogen entry through the primary cell walls of the phellem cells, thus contributing to the main functions of the periderm. PMID- 21239409 TI - Does diet influence physical performance in community-dwelling older people? Findings from the Hertfordshire Cohort Study. AB - BACKGROUND: recent studies suggest that diet may affect the physical performance of older adults, but the impact of variations in the UK diet on physical performance has not been assessed. OBJECTIVE: to examine relationships between diet and physical performance in community-dwelling older men and women. SETTING AND PARTICIPANTS: a total of 628 men and women aged 63-73 years who were taking part in the Hertfordshire Cohort Study. METHODS: diet was assessed using an administered food frequency questionnaire; physical performance was assessed by the time taken to complete a 3-m walk, chair-rise test and one-legged balance test. RESULTS: in women, higher intakes of the antioxidant nutrients, beta carotene and selenium, were associated with shorter 3-m walk times; higher beta carotene and vitamin C intakes were associated with shorter chair-rise times (all P < 0.05). Higher vitamin D intakes and percentage energy from protein were also associated with faster 3-m walk times (both P < 0.05), but they were not related to chair-rise time. There were no associations between any measure of dietary intake and balance in the women studied. After adjustment for the effects of confounding influences, we found no associations between diet and physical performance among men. CONCLUSIONS: these data indicate that variations in the diets of community-dwelling older women may be linked to differences in physical performance, but further work is needed to determine the role of variations in diet on physical performance and its decline with age among older adults in the UK. PMID- 21239410 TI - Exploring patterns of daily physical and sedentary behaviour in community dwelling older adults. AB - BACKGROUND: recent evidence suggests that the interaction between periods of sedentary and activity behaviour is important for health; providing distinctive information to assessment of activity alone. This study quantified activity and sedentary behaviour in older, community-dwelling adults. METHODS: fifty-six community-dwelling older adults with an average age 79 (SD) years wore an ActivPAL accelerometer for 7 days and were assessed for a range of motor, cognitive and affective characteristics. Seven variables derived from accelerometry considered to represent four characteristics of habitual behaviour (volume, frequency, intensity and variability) were submitted to principal components factor analysis (PCA). Factor scores were retained and used as dependent variables in regression analysis. RESULTS: three significant orthogonal factors emerged from the PCA, accounting for 80% of the variance in test scores: 'walking behaviour' which accounted for 39% of variance in the model; 'sedentary behaviour' explaining 24.3% of total variance; and 'postural transitions' which accounted for 16.7% of total variance. For the regression analysis, younger age and lower body mass index (BMI) emerged as significant predictors of physical behaviour, explaining 36% of the total variance. For postural transitions, lower BMI was the unique contributor, explaining 15% of total variance. Significant predictors of sedentary behaviours were not identified. CONCLUSIONS: walking, sedentary and transitory behaviours are distinct from each other, and together explain daily function. Further research on a larger sample is indicated to explore the characteristics that explain these behaviours, in particular the interplay between sedentary behaviour and periods of physical activity. PMID- 21239411 TI - Vascular cognitive impairment in small vessel disease: clinical and neuropsychological features of lacunar state and Binswanger's disease. AB - BACKGROUND: ischaemic cerebrovascular small vessel disease (SVD) is a prevalent and under-diagnosed condition that triggers vascular cognitive impairment (VCI). OBJECTIVE: to describe the neuropsychological and clinical profiles in SVD (Binswanger's disease, BD; lacunar state, LS) from the clinician's perspective at the VCI stage. METHODS: a total of 1257 patients admitted to a tertiary center with a diagnosis of stroke, neuroradiological vascular disease, cognitive impairment/dementia, during a 13-year period were investigated. We prospectively assessed cognition in a subset of 141 patients with VCI (LS n = 28, BD n = 69, large vessel disease-LVD-n = 44) with MMSE, CAMDEX-H, WAIS-R, EXIT-25 and Trail making test. RESULTS: executive dysfunction (ECD) (n = 89, 91.7% versus n = 10, 22.7%; P < 0.001) and gait disturbances (n = 74, 76.3% versus n = 15, 34.1%; P < 0.001) characterized SVD. Prior strokes (n = 9, 9.3% versus n = 23, 52.3%; P < 0.001) and embologenous cardiopathy (n = 39, 40.2% versus n = 28, 63.6%; P < 0.04) featured LVD cases. BD was defined by hypertension (n = 52, 75.4% versus n = 30, 44.1%; P < 0.001), ECD (n = 65, 94.2% versus n = 34, 47.2%; P < 0.001) and VCI onset with cognitive impairment but not strokes (n = 44, 63.8% versus n = 34, 50%; P < 0.01). CONCLUSIONS: ECD and a frontal gait are SVD's clinical landmarks in our sample. LS and BD cases share a similar cognitive profile. PMID- 21239412 TI - High-risk syndrome for neuromyelitis optica: a descriptive and comparative study. AB - BACKGROUND: Neuromyelitis optica (NMO) frequently begins with a monofocal episode of optic neuritis or myelitis. A concept named high-risk syndrome (HRS) for NMO has been proposed for patients with monofocal episodes and NMO-IgG antibodies. OBJECTIVE: To describe HRS patients and compare them with NMO patients. METHODS: We identified 30 patients with HRS: 18 with extensive myelitis (HRM) and 12 with optic neuritis (HRON), in a database pooling patients from 25 centres in France. Clinical, laboratory/magnetic resonance imaging (MRI) data and outcome were analysed and compared with a national cohort of 125 NMO patients extracted from the same database. RESULTS: Mean follow-up was 4.8 years. Mean age at onset was 42.8 years (range: 12.4-70) with a female:male ratio of 0.9. Asymptomatic lesions were report on visual evoked potentials in 4/8 tested HRM patients and on spinal cord MRI in 2/7 HRON patients. Three patients died, two owing to a cervical lesion. HRS and NMO patients had similar clinical/paraclinical data, except for a predominance of men in the HRS group and a later mean age at onset in the HRM subgroup. CONCLUSION: The description of HRS patients is compatible with a monofocal form of NMO. Asymptomatic lesions could be included in a new set of NMO diagnostic criteria. PMID- 21239413 TI - Association of IL2RA polymorphisms with susceptibility to multiple sclerosis is not explained by missense mutations in IL2RA. AB - Genome-wide association studies have identified an association between two intronic single nucleotide polymorphisms (SNPs), rs12722489 and rs2104286, in the interleukin-2 receptor alpha-chain gene (IL2RA) and susceptibility to multiple sclerosis (MS). We studied these SNPs in association with susceptibility to and severity of MS in a population-based cohort of 220 patients from Olmsted County, Minnesota, compared with 442 matched controls. We sequenced the exons, splice sites and 5' and 3' untranslated regions in 27 randomly selected MS patients (powered for allele frequency>=0.04) to search for mutations. No novel missense mutation was identified. Two patients (7.5%) had an exon 2 SNP (rs4308625) and two patients had an exon 4 SNP (rs2228149), both synonymous. PMID- 21239414 TI - Distributed changes in default-mode resting-state connectivity in multiple sclerosis. AB - BACKGROUND: The default-mode network (DMN) has been increasingly recognized as relevant to cognitive status. OBJECTIVES: To explore DMN changes in patients with relapsing-remitting (RR) multiple sclerosis (MS) and to relate these to the cognitive status. METHODS: Eighteen cognitively impaired (CI) and eighteen cognitively preserved (CP) RRMS patients and eighteen healthy controls (HCs), matched for age, sex and education, underwent neuropsychological evaluation and anatomical and resting-state functional MRI (rs-fMRI). DMN functional connectivity was evaluated from rs-fMRI data via independent component analysis. T2 lesion load (LL) was computed by a semi-automatic method and global and local atrophy was estimated by SIENAX and SPM8 voxel-based morphometry analyses from 3D T1 images. RESULTS: When the whole group of RRMS patients was compared with HCs, DMN connectivity was significantly weaker in the anterior cingulate cortex, whereas it was significantly weaker in the core but stronger at the periphery of the posterior cingulate cortex. These findings were more evident in CP than CI patients. Observed DMN changes did not correlate with global atrophy or T2-LL, but were locally associated with regional grey matter loss. CONCLUSION: Relapsing remitting multiple sclerosis patients show a consistent dysfunction of DMN at the level of the anterior node. DMN distribution changes in the posterior node may reflect a possible compensatory effect on cognitive performance. PMID- 21239415 TI - Mistreatment and psychological well-being among older adults: exploring the role of psychosocial resources and deficits. AB - OBJECTIVES: To examine the relationships between psychosocial resources and deficits, elder mistreatment, and psychological well-being. METHODS: We used a representative sample of 2,744 older adults aged 57-85 years in the United States from the National Social Life, Health and Aging Project. We examined reports of any mistreatment (verbal, financial, or physical) and multiple types of mistreatment. RESULTS: Lower levels of positive support, higher levels of criticism from close relationships, and feelings of social isolation are positively associated with self-reported mistreatment experience. As suggested by the stress process theory, those who reported mistreatment experience also reported lower levels of global happiness and higher levels of psychological distress. There is also some evidence for the buffering hypothesis--levels of global happiness are higher and levels of psychological distress are lower for older adults who reported any mistreatment if they also reported more positive social support, social participation, and feelings of social connection. DISCUSSION: Older adults with fewer psychosocial resources or more psychosocial deficits seem to be more vulnerable to mistreatment, and mistreatment seems particularly detrimental to psychological well-being for these people. PMID- 21239416 TI - The Palisades: an interdisciplinary wellness model in senior housing. AB - PURPOSE: The conceptual model and implementation strategies for a university private housing collaboration in a multilevel housing campus for older adults are described. The faculty and private developers viewed senior housing as an opportunity for people to downsize their space in order to upsize their lives within a community rich with resources to support their developmental needs. METHODS: A wellness program that includes assessments developed and performed by a multidisciplinary team provides the basis for the development of resources and interventions aimed at upsizing residents' lives. Semi-annual assessments and feedback sessions provide the residents with opportunities to set and revise goals and to work with members of the team to identify resource needs. RESULTS: After the first year, the wellness assessment scheduling and protocol were streamlined and recruitment barriers were addressed. The addition of a system for providing feedback to residents about their assessment results enhanced the meaning and value of the process. IMPLICATIONS: The Palisades team hopes to assist in promoting similar projects designed to positively impact wellness in older adults. PMID- 21239417 TI - What can alcohol researchers learn from research about the relationship between macro-level gender equality and violence against women? AB - AIMS: This systematic review focuses on research about macro-level gender equality and violence against women (VAW) and identifies conceptually and theoretically driven hypotheses as well as lessons relevant for alcohol research. Hypotheses include: amelioration--increased equality decreases VAW; backlash- increased equality increases VAW; and convergence--increased equality reduces the gender gap; and hypotheses that distinguish between relative and absolute status, with relative status comparing men's and women's status and absolute status measuring women's status without regard to men. METHODS: Systematic review of studies published through June 2009 identified through PubMed and Web of Science, as well as citing and cited articles. RESULTS: A total of 30 studies are included. Of 85 findings examining amelioration/backlash, 25% support amelioration, 22% backlash; and 53% are null. Of 13 findings examining convergence, 31% support and 23% are inconsistent with convergence; 46% are null. CONCLUSION: Neither the existence nor the direction of the equality and VAW relationship can be assumed. This suggests that the relationship between macro level gender equality and alcohol should also not be assumed, but rather investigated through research. PMID- 21239418 TI - Quantitative review of operative management of hallux rigidus. AB - INTRODUCTION: Surgical techniques for the management of hallux rigidus include cheilectomy, Keller resection arthroplasty, arthrodesis, Silastic implantation, phalangeal or metatarsal osteotomy, capsular arthroplasty, partial or total joint replacement, interposition arthroplasty. However, the optimal management is controversial. SOURCES OF DATA: We performed a comprehensive search of CINAHL, Embase, Medline and the Cochrane Central Registry of Controlled Trials, from inception of the database to 2 November 2010. Sixty-nine articles published in peer reviewed journals were included in this comprehensive review. AREAS OF AGREEMENT: Cheilectomy and first metatarsal or phalangeal corrective osteotomy may provide better outcome for patients with early and intermediate hallux rigidus (Stages I-II), while arthrodesis or arthroplasty are indicated to manage more severe conditions. The Coleman Methodology Score showed great heterogeneity in terms of study design, patient characteristics, management methods and outcome assessment and generally low methodological quality. AREAS OF CONTROVERSY: Definitive conclusions on the use of these techniques for routine management of patients with hallux rigidus are not possible. Given the limitations of the published literature, especially the extensive clinical heterogeneity, it is not possible to compare outcomes of patients undergoing different surgical procedures and determine clear guidelines. GROWING POINTS: To assess whether benefits from surgery, validated and standardized measures should be used to compare the outcomes of patients undergoing standard surgical procedures. RESEARCH: There is a need to perform appropriately powered randomized clinical trials of using standard diagnostic assessment, common and validated scoring system comparing reported outcomes and duration of follow-up >2 years. PMID- 21239419 TI - Unexplained sudden cardiac death: an opportunity to identify hereditary cardiac arrhythmias. PMID- 21239420 TI - Clinical trials on transcatheter aortic valve implantation cannot be compared because of inconsistent endpoints. PMID- 21239422 TI - Resource implications of inter-facility transport between emergency departments in Hong Kong. AB - BACKGROUND: The Inter-facility Transport (IFT) service provided by the Emergency Department (ED) is a vital service in Hong Kong. Patients need to be rapidly transported over distances to access appropriate healthcare facilities. METHODS: This study aims 1. to examine the resource utilisation of IFT accompanied by ED staff and 2. to analyse the crude, fixed and variable costs of IFT. A retrospective review was conducted of all IFT from Alice Ho Miu Ling Nethersole Hospital in the New Territories of Hong Kong where ED staff accompanied patients from 1 January 2006 to 31 December 2008. Descriptive analysis was used to evaluate the crude, fixed and variable costs per year for providing an ED-based IFT service. RESULTS: There were 337 transports accompanied by either medical or nursing staff from the ED that accounted for around 2% of all IFT. The most common indication for mobilising the transport team was an unstable clinical condition that required neurosurgical care. The average transport service time was 57.7 min per transport (SD 11.0). Resource utilisation consisted of fixed and variable costs that summed up to a cost of HKD $87,224.3 (USD $11,182.6) per year and the crude cost of providing IFT service by the ED was HKD$852.2 (USD $109.3) per patient. CONCLUSION: The crude cost of providing IFT service by the ED was reasonable and acceptable. PMID- 21239423 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 1. Alpha-blockers increase the chances of a successful trial without catheter after acute urinary retention. PMID- 21239425 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 2. GlideScope in the emergency department. PMID- 21239426 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 3. Elevation of serum magnesium may improve clinical outcome after aneursymal subarachnoid haemorrhage. PMID- 21239427 TI - Towards evidence-based emergency medicine: best BETs from the Manchester Royal Infirmary. BET 4. Cylinder plaster versus cricket pad splint in uncomplicated patellar fractures. PMID- 21239429 TI - Modulation of the tyrosine kinase receptor Ret/glial cell-derived neurotrophic factor (GDNF) signaling: a new player in reproduction induced anterior pituitary plasticity? AB - During gestation, parturition, and lactation, the endocrine axis of the dam must continually adapt to ensure the continual and healthy development of offspring. The anterior pituitary gland, which serves as the endocrine interface between the brain and periphery, undergoes adaptations that contribute to regulation of the reproductive axis. Growth factors and their receptors are potential candidates for intrapituitary and paracrine factors to participate in the functional and anatomical plasticity of the gland. We examined the involvement of the growth factor glial cell-derived neurotrophic factor (GDNF) and its receptor tyrosine kinase rearranged during transfection (Ret) in the physiological functional and anatomical plasticity of the anterior pituitary gland. We found that variations in both expression and subcellular localization of Ret during gestation and lactation are temporally correlated with changes in pituitary gland function. We showed that Ret/GDNF signaling could endorse two different functional roles depending on the physiological status. At the end of lactation and after weaning, Ret was colocalized with markers of apoptosis. We found that Ret could therefore act as a physiological dependence receptor capable of inducing apoptosis in the absence of GDNF. In addition, we identified the follicullostellate cell as a probable source for intrapituitary GDNF and proposed GDNF as a potential physiological modulator of endocrine cell function. During all stages studied, we showed that acute application of GDNF to pituitary slices was able to modulate both positively and negatively intracellular calcium activity. Altogether our results implicate Ret/GDNF as a potent pleiotropic factor able to influence pituitary physiology during a period of high plasticity. PMID- 21239430 TI - Exposure to diethylstilbestrol during embryonic and larval stages of medaka fish (Oryzias latipes) leads to sex reversal in genetic males and reduced gonad weight in genetic females. AB - Molecular and cellular mechanisms involved in artificially induced ovarian differentiation were analyzed by exposing embryos of medaka (Oryzias latipes) to a potent nonsteroidal estrogen, diethylstilbestrol (DES). Embryos were exposed for short-exposure (SE) [from 0 to 8 d postfertilization (dpf)] and long-exposure (LE) periods (from 0 to 18/28 dpf) to 1 ng/ml of DES, and status of sexual differentiation in somatic and germ cells of these gonads was analyzed at 8, 18, and 28 dpf by histology, cell proliferation assays, TUNEL assay, and in situ hybridization using sex-specific somatic and germ cell markers. Additionally, gonads of exposed fry were examined after withdrawal of DES to see whether effects of DES in exposed fish were reversible or not. DES induced germ cell proliferation and meiosis in XY fry of SE and LE groups. However, SE induced only a partial reduction in expression of gonadal soma-derived factor, the male dominant somatic cell marker, and was not sufficient to induce ovarian development after withdrawal of DES. On the contrary, LE resulted in complete loss of such male-specific gene expression in somatic cells of XY gonads, and these gonads underwent sustained ovarian development even after withdrawal of DES. Importantly, LE to DES affected germ cell proliferation in XX gonads adversely during early stages of sexual differentiation, leading to reduced gonad weight in adulthood. Interestingly, apoptosis was not the cause for reduction in germ cell number. Taken together, these results indicated that DES exposure has long-lasting effects on the gonadal development in genetic males (sex reversal) and females (reduced gonad weight) of medaka. PMID- 21239431 TI - In vivo activity of the thyroid hormone receptor beta- and alpha-selective agonists GC-24 and CO23 on rat liver, heart, and brain. AB - Thyroid hormone analogs with selective actions through specific thyroid hormone receptor (TR) subtypes are of great interest. They might offer the possibility of mimicking physiological actions of thyroid hormone with receptor subtype or tissue specificity with therapeutic aims. They are also pharmacological tools to dissect biochemical pathways mediated by specific receptor subtypes, in a complementary way to mouse genetic modifications. In this work, we studied the in vivo activity in developing rats of two thyroid hormone agonists, the TRbeta selective GC-24 and the TRalpha-selective CO23. Our principal goal was to check whether these compounds were active in the rat brain. Analog activity was assessed by measuring the expression of thyroid hormone target genes in liver, heart, and brain, after administration to hypothyroid rats. GC-24 was very selective for TRbeta and lacked activity on the brain. On the other hand, CO23 was active in liver, heart, and brain on genes regulated by either TRalpha or TRbeta. This compound, previously shown to be TRalpha-selective in tadpoles, displayed no selectivity in the rat in vivo. PMID- 21239433 TI - Activation of the cholinergic antiinflammatory pathway ameliorates obesity induced inflammation and insulin resistance. AB - Obesity is associated with a chronic inflammatory state characterized by adipose tissue macrophage infiltration and inflammation, which contributes to insulin resistance. The cholinergic antiinflammatory pathway, which acts through the macrophage alpha7-nicotinic acetylcholine receptor (alpha7nAChR), is important in innate immunity. Here we show that adipose tissue possesses a functional cholinergic signaling pathway. Activating this pathway by nicotine in genetically obese (db/db) and diet-induced obese mice significantly improves glucose homeostasis and insulin sensitivity without changes of body weight. This is associated with suppressed adipose tissue inflammation. In addition, macrophages from alpha7nAChR-/- [alpha7 knockout (alpha7KO)] mice have elevated proinflammatory cytokine production in response to free fatty acids and TNFalpha, known agents causing inflammation and insulin resistance. Nicotine significantly suppressed free fatty acid- and TNFalpha-induced cytokine production in wild type (WT), but not alpha7KO macrophages. These data suggest that alpha7nAChR is important in mediating the antiinflammatory effect of nicotine. Indeed, inactivating this pathway in alpha7KO mice results in significantly increased adipose tissue infiltration of classically activated M1 macrophages and inflammation in alpha7KO mice than their WT littermates. As a result, alpha7KO mice exhibit more severely impaired insulin sensitivity than WT mice without changes of body weight. These data suggest that the cholinergic antiinflammatory pathway plays an important role in obesity-induced inflammation and insulin resistance. Targeting this pathway may provide novel therapeutic benefits in the prevention and treatment of obesity-induced inflammation and insulin resistance. PMID- 21239434 TI - Changes in gene expression during pituitary morphogenesis and organogenesis in the chick embryo. AB - The anterior pituitary gland plays an important role in the regulation of many physiological processes. Formation of Rathke's pouch (RP), the precursor of the anterior pituitary, involves evagination of the oral ectoderm in a multi-step process regulated by cell interactions, signaling pathways, and transcription factors. Chickens are an excellent model to study development because of the availability of large sample sizes, accurate timing of development, and embryo accessibility. The aim of this study was to quantify mRNA expression patterns in the developing chicken anterior pituitary to evaluate the chicken embryo as a model for mammalian pituitary development. The expression profiles of 16 genes differentially expressed in RP and neuroectoderm were determined in this study. Among these, Pitx1, Pitx2, and Hesx1 mRNA levels were high on embryonic days (e) 2.5 to e3 in RP and decreased during development. Expression of Pit1 and Tbx19 mRNA in RP reached the highest levels by e7 and e6.5, respectively. Levels of glycoprotein subunit alpha mRNA increased beginning at e4. FGF8 mRNA showed the highest expression at e3 to e3.5 in neuroectoderm. BMP2 showed slight decreases in mRNA expression in both tissues during development, while Isl1 and Noggin mRNA expression increased in later development. Taken together, we present the first quantitative transcriptional profile of pituitary organogenesis. Our results will help further understanding of the functional development of this gland. Moreover, because of the high similarity in gene expression patterns observed between chicken and mouse, chickens could serve as an excellent model to study genetic and molecular mechanisms underlying pituitary development. PMID- 21239432 TI - Aldosterone production in human adrenocortical cells is stimulated by high density lipoprotein 2 (HDL2) through increased expression of aldosterone synthase (CYP11B2). AB - Adrenal aldosterone production is regulated by physiological agonists at the level of early and late rate-limiting steps. Numerous studies have focused on the role of lipoproteins including high-density lipoprotein (HDL) as cholesterol providers in this process; however, recent research suggests that HDL can also act as a signaling molecule. Herein, we used the human H295R adrenocortical cell model to study the effects of HDL on adrenal aldosterone production and CYP11B2 expression. HDL, especially HDL2, stimulated aldosterone synthesis by increasing expression of CYP11B2. HDL treatment increased CYP11B2 mRNA in both a concentration- and time-dependent manner, with a maximal 19-fold increase (24 h, 250 MUg/ml of HDL). Effects of HDL on CYP11B2 were not additive with natural agonists including angiotensin II or K(+). HDL effects were likely mediated by a calcium signaling cascade, because a calcium channel blocker and a calmodulin kinase inhibitor abolished the CYP11B2-stimulating effects. Of the two subfractions of HDL, HDL2 was more potent than HDL3 in stimulating aldosterone and CYP11B2. Further studies are needed to identify the active components of HDL, which regulate aldosterone production. PMID- 21239435 TI - Gonadotropin-releasing hormone-II increases membrane type I metalloproteinase production via beta-catenin signaling in ovarian cancer cells. AB - GnRH-II is produced by ovarian cancer cells and enhances their invasiveness in vitro. In our studies of OVCAR-3 and CaOV-3 ovarian cancer cell lines, GnRH-II treatment induced phosphorylation of Akt and glycogen synthase kinase (GSK)3beta, as well as beta-catenin accumulation in the nucleus, and the latter was reduced by small interfering RNA (siRNA)-mediated depletion of the GnRH receptor. The phosphatidylinositol 3 kinase (PI3K)/Akt pathway is involved in beta-catenin dependent signaling, and pretreatment of these human ovarian cancer cells with a PI3K/Akt inhibitor, LY294002, attenuated GnRH-II-stimulated phosphorylation of GSK3beta and inhibited GnRH-II-induced invasion. It also attenuated GnRH-II induced trans-activation of a beta-catenin-dependent reporter gene, most likely because GSK3beta phosphorylation promotes translocation of beta-catenin to the nucleus. Membrane type I matrix metalloproteinase (MT1-MMP) contributes to tumor progression directly, or by processing the latent MMP-2 zymogen, and is a known target of beta-catenin signaling. When OVCAR-3 and CaOV-3 cells were treated with GnRH-II, MT1-MMP levels increased approximately 3-fold, whereas siRNA-mediated depletion of GnRH receptor or pretreatment with LY294002 abrogated this. In addition, lithium chloride, which increases GSK3beta phosphorylation and the nuclear translocation of beta-catenin, increased MT1-MMP levels in these ovarian cancer cells. By contrast, depletion of beta-catenin by siRNA treatment abolished GnRH-II-induced MT1-MMP synthesis and reduced their invasive potential. Furthermore, siRNA-mediated reduction of MT1-MMP levels reduced GnRH-II-induced invasion in ovarian cancer cells. We therefore conclude that GnRH-II stimulates the PI3K/Akt pathway, and the phosphorylation of GSK3beta, thereby enhancing the beta-catenin-dependent up-regulation of MT1-MMP production, which contributes to ovarian cancer metastasis. PMID- 21239436 TI - Participation of Akt, menin, and p21 in pregnancy-induced beta-cell proliferation. AB - beta-Cell mass increases during pregnancy to accommodate for insulin resistance. This increase is mainly due to beta-cell proliferation, a process that requires intact prolactin receptor (Prlr) signaling. Signaling molecules that are known to regulate beta-cell proliferation include Jak2, Akt, the tumor suppressor menin, and cell cycle proteins. Whether these pathways are involved in prolactin mediated beta-cell proliferation is unknown. Using the heterozygous prolactin receptor-null (Prlr(+/-)) mice, we isolated pancreatic islets from both Prlr(+/+) and Prlr(+/-) mice on d 0 and 15 of pregnancy and examined the expression levels of these signaling molecules. In the wild-type mice (Prlr(+/+)), both phospho Jak2 and phospho-Akt expression in pancreatic islets increased during pregnancy, which were attenuated in the pregnant Prlr(+/-) mice. During pregnancy, menin expression was reduced by 50 and 20% in the Prlr(+/+) and the Prlr(+/-) mice, respectively, and the pregnant Prlr(+/-) mice had higher islet p18 levels than the Prlr(+/+) mice. Interestingly, between d 0 and 15 of pregnancy, expression of cyclin inhibitory protein p21(cip) was increased in the Prlr(+/+) mice, but this increase was blunted in the Prlr(+/-) mice. Lastly, we did not find any difference in the expression levels of cyclins D1, D2, and inhibitory kinases between the pregnant Prlr(+/+) and Prlr(+/-) mice. Therefore, we conclude that during pregnancy, placental hormones act through the prolactin receptor to increase beta-cell mass by up regulating beta-cell proliferation by engaging Jak2, Akt, menin/p18, and p21. Future studies will determine the relative contribution of these molecules in maintaining normal glucose homeostasis during pregnancy. PMID- 21239437 TI - Hypermethylation of hepatic glucokinase and L-type pyruvate kinase promoters in high-fat diet-induced obese rats. AB - Obesity-dependent insulin resistance and type 2 diabetes mellitus are closely associated with decreased glucose utilization and down-regulation of hepatic glycolytic enzymes expression. Previously, we showed that DNA hypermethylation is involved in age-dependent susceptibility to hepatic insulin resistance and diabetes. However, what we cannot distinguish is whether the age-related obesity contributes to DNA hypermethylation in those natural aging rats. In the present study, we hypothesize that DNA methylation plays a crucial role in the regulation of glycolytic enzymes in the high-fat diet-induced obesity. Here, we report that DNA hypermethylation is correlated with a decline in hepatic glucokinase (Gck) and L-type pyruvate kinase (LPK) expression in high-fat diet-induced obese rats as compared with the control diet group. Down-regulation of Gck and LPK expression are reversed by the 5-aza-2'-deoxycytidine in the cell model of steatosis. These novel observations indicate that DNA methylation is involved in the development of metabolic diseases, such as obesity, insulin resistance, type 2 diabetes mellitus, and nonalcoholic steatohepatitis, suggesting that the hypermethylation level of Gck and LPK promoters may be a useful parameter for the evaluation of obesity-induced insulin resistance and fatty liver. PMID- 21239438 TI - Characterization of the hyperphagic response to dietary fat in the MC4R knockout mouse. AB - Defective melanocortin signaling causes hyperphagic obesity in humans and the melanocortin-4 receptor knockout mouse (MC4R(-/-)). The human disease most commonly presents, however, as haploinsufficiency of the MC4R. This study validates the MC4R(+/-) mouse as a model of the human disease in that, like the MC4R(-/-), the MC4R(+/-) mouse also exhibits a sustained hyperphagic response to dietary fat. Furthermore, both saturated and monounsaturated fats elicit this response. N-acylphosphatidylethanolamine (NAPE) is a signaling lipid induced after several hours of high-fat feeding, that, if dysregulated, might explain the feeding behavior in melanocortin obesity syndrome. Remarkably, however, MC4R(-/-) mice produce elevated levels of NAPE and are fully responsive to the anorexigenic activity of NAPE and oleoylethanolamide. Interestingly, additional differences in N-acylethanolamine (NAE) biochemistry were seen in MC4R(-/-) animals, including reduced plasma NAE levels and elevated hypothalamic levels of fatty acid amide hydrolase expression. Thus, while reduced expression of NAPE or NAE does not explain the high-fat hyperphagia in the melanocortin obesity syndrome, alterations in this family of signaling lipids are evident. Analysis of the microstructure of feeding behavior in response to dietary fat in the MC4R(-/-) and MC4R(+/-) mice indicates that the high-fat hyperphagia involves defective satiation and an increased rate of food intake, suggesting defective satiety signaling and enhanced reward value of dietary fat. PMID- 21239439 TI - Brain-derived neurotrophic factor/tyrosine kinase B signaling regulates human trophoblast growth in an in vivo animal model of ectopic pregnancy. AB - Although medical treatment of unruptured ectopic pregnancy using methotrexate has been established, development of more potent and safer medical treatment is needed due to limited indications and side effects of methotrexate. Brain-derived neurotrophic factor (BDNF) signals through its receptor tyrosine kinase B (TrkB) to regulate the growth of malignant trophoblastic, choriocarcinoma cell. We investigated possible involvement of this signaling system in nonmalignant human trophoblast growth in both ectopic and intrauterine pregnancy. Here, we demonstrated the expression of BDNF in syncytiotrophoblasts and extravillous trophoblasts (EVTs) together with TrkB in cytotrophoblasts and EVTs in human placental villi during both normal and ectopic pregnancies. Treatment of cultured villous explants with soluble TrkB ectodomain or a Trk receptor inhibitor K252a suppressed cytotrophoblast differentiation by inhibiting EVT outgrowth reflected by decreased levels of an EVT marker, human leukocyte antigen-G. These inhibitors also decreased cytotrophoblast proliferation and cellular viability based on histopathological analyses and monitoring glucose metabolism, together with increased apoptosis in cytotrophoblasts based on in situ terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate nick end labeling and caspase-3/7 assays. After xenotransplantation of human placental villi into SCID mice as an in vivo model of ectopic pregnancy, treatment with K252a suppressed transplanted villi growth as reflected by decreased cytotrophoblast differentiation and proliferation, reduced tissue levels of chorionic gonadotropin-beta, and increased apoptosis and caspase-3/7 activities. Thus, paracrine signaling by the BDNF/TrkB system is important for human cytotrophoblast differentiation, proliferation, and survival, and inhibition of BDNF/TrkB signaling in cytotrophoblasts could provide a novel medical treatment for ectopic pregnancy. PMID- 21239440 TI - Antidiabetic properties of the histamine H3 receptor protean agonist proxyfan. AB - Proxyfan is a histamine H3 receptor protean agonist that can produce a spectrum of pharmacological effects including agonist, inverse agonist, and antagonist. We have discovered that proxyfan (10 mg/kg orally) significantly improved glucose excursion after an ip glucose tolerance test in either lean or high fat/cholesterol diet-induced obese mice. It also reduced plasma glucose levels comparable to that of metformin (300 mg/kg orally) in a nongenetic type 2 diabetes mouse model. The dose-dependent decrease in glucose excursion correlated with inhibition of ex vivo H3 receptor binding in the cerebral cortex. In addition, glucose levels were significantly reduced compared with vehicle-treated mice after intracerebroventricular administration of proxyfan, suggesting the involvement of central H3 receptors. Proxyfan-induced reduction of glucose excursion was not observed in the H3 receptor knockout mice, suggesting that proxyfan mediates this effect through H3 receptors. Proxyfan reduced glucose excursion by significantly increasing plasma insulin levels in a glucose independent manner. However, no difference in insulin sensitivity was observed in proxyfan-treated mice. The H1 receptor antagonist chlorpheniramine and the H2 receptor antagonist zolantidine had modest effects on glucose excursion, and neither inhibited the glucose excursion reduced by proxyfan. The H3 receptor antagonist/inverse agonist, thioperamide, had weaker effects on glucose excursion compared with proxyfan, whereas the H3 receptor agonist imetit did not affect glucose excursion. In conclusion, these findings demonstrate, for the first time, that manipulation of central histamine H3 receptor by proxyfan can significantly improve glucose excursion by increasing plasma insulin levels via a glucose independent mechanism. PMID- 21239442 TI - Corticosteroid regulation of P-glycoprotein in the developing blood-brain barrier. AB - The early fetal brain is susceptible to teratogens in the maternal circulation, because brain microvessel expression of drug efflux transporter, P-glycoprotein (P-gp), is very low. However, there is a dramatic up-regulation of brain microvessel P-gp in late gestation. This study investigated the role of cortisol and dexamethasone in this up-regulation of fetal brain microvessel P-gp expression. Primary brain endothelial cell (BEC) cultures derived from gestational d (GD)40, GD50, GD65 (term, ~68 d) and postnatal d 14 male guinea pigs were treated with varying doses (10(-8) to 10(-5) m) of cortisol, dexamethasone, and aldosterone. After treatment, P-gp function was assessed using calcein-acetoxymethyl ester (P-gp substrate; 1 MUm for 1 h) and measuring BEC accumulation of calcein. Corticosteroid treatment of BECs derived from postnatal d 14 resulted in increased P-gp activity. BECs derived from GD65 (near term) responded similarly, but these cells were extremely sensitive to the effects of mineralocorticoid receptor agonists (cortisol and aldosterone). BECs derived from GD50 displayed dose-dependent increases in P-gp function with dexamethasone (P < 0.05) and a trend towards increased function with cortisol. Cells derived from GD40 were unresponsive to all treatments. In conclusion, P-gp function in BECs is more responsive to glucocorticoids (GCs) in late gestation. Therefore, the late gestational surge in fetal plasma GCs, which parallels the increase in brain microvessel P-gp expression, may contribute to this P-gp up-regulation. Further, synthetic GCs (administered to pregnant women at risk of preterm delivery) may increase the protective capacity of the developing fetal blood-brain barrier, depending on the timing of GC exposure. PMID- 21239441 TI - Differential and complementary effects of glucose and prolactin on islet DNA synthesis and gene expression. AB - The mechanisms by which lactogenic hormones promote beta-cell expansion remain poorly understood. Because prolactin (PRL) up-regulates beta-cell glucose transporter 2, glucokinase, and pyruvate dehydrogenase activities, we reasoned that glucose availability might mediate or modulate the effects of PRL on beta cell mass. Here, we used male rat islets to show that PRL and glucose have differential but complementary effects on the expression of cell cyclins, cell cycle inhibitors, and various other genes known to regulate beta-cell replication, including insulin receptor substrate 2, IGF-II, menin, forkhead box protein M1, tryptophan hydroxylase 1, and the PRL receptor. Differential effects on gene expression are associated with synergistic effects of glucose and PRL on islet DNA synthesis. The effects of PRL on gene expression are mirrored by beta cell overexpression of signal transducer and activator of transcription 5b and are opposed by dexamethasone. An ad-small interfering RNA specific for cyclin D2 attenuates markedly the effects of PRL on islet DNA synthesis. Our studies suggest a new paradigm for the control of beta-cell mass and insulin production by hormones and nutrients. PRL up-regulates beta-cell glucose uptake and utilization, whereas glucose increases islet PRL receptor expression and potentiates the effects of PRL on cell cycle gene expression and DNA synthesis. These findings suggest novel targets for prevention of neonatal glucose intolerance and gestational diabetes and may provide new insight into the pathogenesis of beta-cell hyperplasia in obese subjects with insulin resistance. PMID- 21239443 TI - Kisspeptin is essential for the full preovulatory LH surge and stimulates GnRH release from the isolated ovine median eminence. AB - Kisspeptins are the product of the Kiss1 gene and potently stimulate GnRH secretion. In sheep, Kiss1 mRNA-expressing cells are found in the arcuate nucleus (ARC) and dorsal-lateral preoptic area and both appear to mediate the positive feedback effect of estradiol to generate the preovulatory GnRH/LH surge. To determine the role of kisspeptin in transmitting estrogen-positive feedback in the hypothalamus, we administered the kisspeptin antagonist p-271 to ewes subjected to an estradiol benzoate-induced LH surge. Kisspeptin antagonist treatment significantly attenuated these LH surges. We further examined the response to kisspeptin treatment prior to the LH surge. Kisspeptin significantly stimulated GnRH secretion into the hypophysial portal system, but the response to kisspeptin was similar in luteal and late-follicular phase ewes. Kiss1r mRNA expression in GnRH neurons was also similar across the estrous cycle. To examine alternative pathways for kisspeptin stimulation of GnRH neurons, we examined the origin of kisspeptin neuronal fibers in the external zone of the median eminence (ME) using neuronal tracing and immunohistochemical techniques. ARC populations of kisspeptin neurons project fibers to the ME. Finally, we showed kisspeptin stimulates GnRH release from ovine ME-cultured explants. This suggests direct kisspeptin to GnRH terminal-to-terminal communication within the ME. Overall, these data indicate an essential role for kisspeptin in receiving stimulatory estrogen signals and generating the full positive feedback GnRH/LH surge. Kisspeptin neurons of the ARC project to the external zone of the ME and kisspeptin acts upon the GnRH fibers at this level. PMID- 21239444 TI - Premature ovarian failure in mice with oocytes lacking core 1-derived O-glycans and complex N-glycans. AB - Premature ovarian failure (POF) affects up to 1.4% of women under the age of 40 yr and less than 30% of cases have a known cause. Here we describe a new mouse model of POF resulting from oocyte-specific ablation of core 1-derived (mucin) O glycans and complex and hybrid N-glycans. Females carrying floxed alleles of both the C1galt1 (T-syn) and Mgat1 glycosyltransferase genes and a ZP3Cre transgene, generate oocytes lacking complex O- and N-glycans following oocyte-specific deletion at the primary follicle stage. We previously showed that few double mutant females are fertile, and those produce only a single small litter. Here we show that ovarian function declined rapidly in double-mutant females with less than 1% ovulating at 11 wk of age after superovulation with exogenous gonadotropins. Ovary weight was significantly decreased in double-mutant females by 3 months of age, consistent with a decrease in the number of developing follicles. FSH levels in double-mutant females were elevated at 3 months of age, and testosterone and inhibin A were decreased, showing that the loss of complex N and O-glycans from oocyte glycoproteins affected hypothalamic-pituitary-gonadal feedback loops. The absence of developing follicles, ovary dysfunction, reduced testosterone and inhibin A, and elevated FSH in double-mutant females lacking C1galt1 and Mgat1 in oocytes represents a new mouse model for the study of follicular POF. PMID- 21239445 TI - Reactive oxygen species play an essential role in IGF-I signaling and IGF-I induced myocyte hypertrophy in C2C12 myocytes. AB - IGF-I induces skeletal muscle hypertrophy by stimulating protein synthesis and suppressing the protein degradation pathway; the downstream signaling pathways Akt-mammalian target of rapamycin (mTOR)-p70-kDA-S6-kinase (p70S6K), and Forkhead box O1 (FoxO1) play essential roles in this regulation. Reactive oxygen species (ROS) modulate the signaling of various growth factors via redox regulation. However, the role of ROS in IGF-I signaling is not fully understood. In this study, we investigated whether ROS regulate the signaling and biological action of IGF-I in C2C12 myocytes. We found that IGF-I induces ROS in C2C12 myocytes. While treatment with H(2)O(2) significantly enhanced IGF-I-induced phosphorylation of the IGF-I receptor (IGF-IR), IGF-IR phosphorylation was markedly attenuated when cells were treated with antioxidants. The downstream signaling pathway, Akt-mTOR-p70S6K was subsequently down-regulated. Furthermore, the phosphorylation of FoxO1 by IGF-I decreased concomitantly with the restoration of the expression of its target genes, Atrogin-1 and muscle RING finger 1, which are related to muscle atrophy. Nox4 knockdown, which is reportedly to produce ROS in insulin signaling, attenuated IGF-I-induced IGF-IR phosphorylation, indicating that Nox4 is involved in the regulation of IGF-I signaling. Importantly, antioxidant treatments inhibited IGF-I-induced myocyte hypertrophy, demonstrating that ROS are necessary for IGF-I-induced myocyte hypertrophy in vitro. These results indicate that ROS play an essential role in the signaling and biological action of IGF-I in C2C12 myocytes. PMID- 21239446 TI - Rapid detection of genetic variants in hypertrophic cardiomyopathy by custom DNA resequencing array in clinical practice. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease (1/500) and the most common cause of sudden cardiac death in young people. Pathogenic mutation detection of HCM is having a growing impact on the medical management of patients and their families. However, the remarkable genetic and allelic heterogeneity makes molecular analysis by conventional methods very time-consuming, expensive and difficult to realise in a routine diagnostic molecular laboratory. METHOD AND RESULTS: The authors used their custom DNA resequencing array which interrogates all possible single-nucleotide variants on both strands of all exons (n=160), splice sites and 5'-untranslated region of 12 HCM genes (27 000 nucleotides). The results for 122 unrelated patients with HCM are presented. Thirty-three known or novel potentially pathogenic heterozygous single-nucleotide variants were identified in 38 patients (31%) in genes MYH7, MYBPC3, TNNT2, TNNI3, TPM1, MYL3 and ACTC1. CONCLUSIONS: Although next-generation sequencing will replace all large-scale sequencing platforms for inherited cardiac disorders in the near future, this HCM resequencing array is currently the most rapid, cost-effective and reasonably efficient technology for first-tier mutation screening of HCM in clinical practice. Because of its design, the array is also an appropriate tool for initial screening of other inherited forms of cardiomyopathy. PMID- 21239447 TI - What did we learn from the genome-wide association study for tuberculosis susceptibility? PMID- 21239448 TI - A totally thoracoscopic approach for pulmonary anatomic segmentectomies. AB - Reported experience with video-assisted anatomic pulmonary segmentectomy is still limited. Over a 28-month period, totally thoracoscopic (TT) anatomic segmentectomies, i.e. using only endoscopic instrumentation and video-display without utility incision, were attempted on 50 patients (25 males and 25 females), aged 18-81 years (mean: 57 years). The indication was a clinical N0 non small cell lung carcinoma in 25 cases, a solitary metastasis in nine cases and a benign lesion in 16 cases. The following segmentectomies were performed: right apicosuperior (9) right superior (6), right basilar (7), lingula sparing left upper lobectomy (7), left apicosuperior (4), lingula (4), left superior (6) and left basilar (7). It was associated with a radical lymphadenectomy in 20 cases. There was one conversion to thoracotomy. The mean operative time was 188+/-54 min, the mean intraoperative blood loss was 91+/-82 ml (range: 0-450 ml). There were four minor postoperative complications (11.7%). The median postoperative stay was 5.6+/-2.4 days. Out of the 25 patients operated on for a cN0 lung carcinoma, two were finally upstaged to N2. TT anatomic pulmonary segmentectomies are feasible and safe. PMID- 21239449 TI - Negative-pressure pulmonary edema presented with concomitant spontaneous pneumomediastinum: Moore meets Macklin. AB - Negative-pressure pulmonary edema is an unusual complication mainly associated with general anesthesia. It is caused by excessive negative intrathoracic pressure following a deep inspiration against an acute airway obstruction. The resultant decreased intrathoracic pressure amplifies venous return to the right heart and increases pulmonary capillary wedge pressure that can be further amplified by massive sympathetic discharge due to hypoxia. The combination of increased venous return and pulmonary capillary wedge pressure favours the shift of fluid into the pulmonary interstitium with resultant pulmonary edema. Conversely, spontaneous pneumomediastinum (SP) results from alveolar rupture following an excessive positive intrathoracic pressure. The air leaks out of the alveoli and along the perivascular space toward the mediastinum. We experienced a case of negative pulmonary edema which presented in association with SP. Pneumomediastinum is probably caused by an excessive positive intrathoracic pressure for a subsequent expiration against a closed airway. In the present case, both complications resolved with conservative management. PMID- 21239450 TI - Oxidized regenerated cellulose in cardiac computer tomography imaging. AB - Oxidized regenerated cellulose is widely used as a bioabsorbable topical hemostatic agent. Postoperative visualization of this material through routine chest imaging, such as conventional radiography, computer tomography (CT), magnetic resonance imaging as well as sonography, may prove difficult and, to our knowledge, is not described in the literature. We describe a case where the mediastinal packing with SurgicelTM Nu-KnitTM after a mitral valve repair procedure led to a delayed obstruction of the superior vena cava, necessitating a re-thoracotomy and curettage of the hemostatic material. The hemostatic agent was not prospectively interpreted as the cause of a severe upper inflow restriction, despite repeated imaging. Retrospectively, the hemostatic material as a cause of the upper inflow obstruction could have been identified earlier if its presence would have been known to the radiologist. We strongly recommend that the surgeon inform the radiologist that such materials were used to improve the diagnostic yield of CT interpretation. PMID- 21239451 TI - Real-time three-dimensional transoesophageal echocardiography during percutaneous transcatheter occlusion of mitral periprosthetic paravalvular leak. AB - We present the case of an 86-year-old female patient with a history of mitral valve replacement due to relevant stenosis. After surgery, an increasing periprosthetic valvular leak (PVL) became obvious causing regurgitation and an increasing haemolysis. Conventional two-dimensional transoesophageal echocardiography (2D TEE) showed a defect of 15 mm length located from the lateral to the posterior circumference subdivided by two surgical sutures into three parts. The patient refused additional surgical therapy. Hence, we suggested a percutaneous transcatheter occlusion of the leakage with a 12 * 5 mm Amplatzer((r)) Vascular Plug III device (AVP) (AGA Medical Corporation, Plymouth, MA, USA). The placement of the device was supported indispensably by real-time three-dimensional TEE. The device occluded the leakage nearly completely and downgraded the regurgitation from moderate to neglectable. Also haemolytic parameters improved significantly. V-wave decreased promptly from 70 to 35 mmHg after placing AVP. Percutaneous closure of PVL by AVP, a self-expandable nitinol device approved for peripheral vessel occlusion, is described in limited cases with more or less successful results. It is graded as a technically demanding procedure reserved to poor surgical candidates. The main challenge is finding and intubating the leakage and the correct placement of the device. Three-dimensional TEE seems to be superior to conventional 2D TEE as it allows an easier guidance of the device into the defect. Hence, it is strongly recommended for this intracardiac intervention. PMID- 21239452 TI - Left ventricular myxoma in a child: a case report. AB - Left ventricular myxoma are quite rare and have not been reported in children. We report a left ventricular myxoma arising from interventricular septum in a 12 year-old girl who presented with history of single episode of syncope while playing in school. General examination of the child did not reveal any abnormality except a grade II/VI systolic murmur in left parasternal area. Transthoracic echocardiography revealed a round pedunculated mass (18 * 30 mm) in left ventricle arising from middle of interventricular septum with a pedicle measuring 4 mm at its base. The tumour was projecting through aortic valve in systole. Syncope in this case was probably due to obstruction of left ventricular outflow tract by myxoma leading to a decrease in cardiac output. Complete excision of myxoma was done through transmitral approach. PMID- 21239453 TI - Impact of clinical pharmacy services on patients in an outpatient chemotherapy academic clinic. AB - BACKGROUND: Assessing the role of the pharmacist in an outpatient oncology clinic requires quantification of parameters that are important to the patient and the healthcare system. Patient evaluations not only serve as benchmarks for a process; but may also predict behavior such as utilization of care, continuity with the provider, and compliance. PURPOSE: To identify the role of the patient pharmacist relationship and enhance patient satisfaction with care, a survey tool was developed and utilized. METHODS: A 20-item, 2-page survey tool was developed and administered to oncology patients actively receiving treatment at the Cancer Therapy & Research Center (CTRC) in San Antonio, Texas. Following approval from the Investigational Review Board, survey distribution began on December 1, 2009 and continued through February 2010. Basic social and demographic data were collected. Satisfaction with pharmacy service was assessed with questions on a Likert ranking scale detailing time spent with pharmacists, knowledge of medication therapy, willingness to pay for clinical pharmacy services, etc. The primary outcome was the impact of the pharmacist-patient relationship assessed by examining the interaction between time spent with pharmacist, understanding of medications, and desire for future pharmacy counseling services. RESULTS: A total of 77 surveys were administered and collected. Of the patients surveyed, 86% stated that it is important for patients to discuss their treatment with a pharmacist and 76% requested pharmacy follow-up at future visits. CONCLUSION: This cross-sectional survey reveals that patients are interested in visiting with a pharmacist regularly during chemotherapy treatment and patients may be willing to pay for pharmacy counseling services. PMID- 21239454 TI - Respiratory and gastrointestinal epithelial modulation of the immune response during viral infection. AB - Respiratory and enteric viral infections cause significant morbidity and mortality world-wide and represent a major socio-economic burden. Many of these viruses have received unprecedented public and media interest in recent years. A popular public misconception is that viruses are a threat to which the human body has only limited defences. However, the majority of primary and secondary exposures to virus are asymptomatic or induce only minor symptoms. The mucosal epithelial surfaces are the main portal of entry for viral pathogens and are centrally involved in the initiation, maintenance and polarisation of the innate and adaptive immune response to infection. This review describes the defences employed by the epithelium of the respiratory and gastrointestinal tracts during viral infections with focus on epithelial modulation of the immune response at the innate/adaptive interface. PMID- 21239455 TI - Proteinase-activated receptor 2 activation promotes an anti-inflammatory and alternatively activated phenotype in LPS-stimulated murine macrophages. AB - Proteinase-activated receptor 2 (PAR(2)), a 7-transmembrane G protein-coupled receptor, contributes to inflammation either positively or negatively in different experimental systems. Previously, we reported that concurrent activation of PAR(2) and TLRs in human lung and colonic epithelial cells resulted in a synergistic increase in NF-kappaB-mediated gene expression, but a down regulation of IRF-3-mediated gene expression. In this study, the effect of PAR(2) activation on LPS-induced TLR4 signaling was examined in primary murine macrophages. The PAR(2) activation of wild-type macrophages enhanced LPS-induced expression of the anti-inflammatory cytokine, IL-10, while suppressing gene expression of pro-inflammatory cytokines, TNF-alpha, IL-6, and IL-12. Similar PAR(2)-mediated effects on LPS-stimulated IL-10 and IL-12 mRNA were also observed in vivo. In contrast, PAR 2-/- macrophages exhibited diminished LPS-induced IL-10 mRNA and protein expression and downstream STAT3 activation, but increased KC mRNA and protein. PAR(2) activation also enhanced both rIL-4- and LPS-induced secretion of IL-4 and IL-13, and mRNA expression of alternatively activated macrophage (AA-M) markers, e.g. arginase-1, mannose receptor, Ym-1. Thus, in the context of a potent inflammatory stimulus like LPS, PAR(2) activation acts to re establish tissue homeostasis by dampening the production of inflammatory mediators and causing the differentiation of macrophages that may contribute to the development of a Th2 response. PMID- 21239456 TI - Down-regulation of NF-kappaB signalling by polyphenolic compounds prevents endotoxin-induced liver injury in a rat model. AB - Activation of NF-kappaB has been reported to play a key role in causing endotoxin induced hepatic damage through enhanced production of reactive oxygen species and pro-inflammatory mediators. In this context, the potential of polyphenolic phytochemicals in preventing endotoxin-induced liver damage remains unclear. Here, we demonstrate that catechin and quercetin have the potential to down regulate the initial signalling molecule NF-kappaB which may further inhibit the downstream cascade including TNF-alpha and NO. These results were confirmed using N-nitro-L-arginine methyl ester (L-NAME), the inhibitor of inducible nitric oxide synthase (iNOS) along with the biochemical and histological alterations occurring in the presence and absence of supplementation with both the polyphenols. However, catechin was found to be more effective than quercetin against endotoxin induced liver injury. These findings suggest that these polyphenols may form a pharmacological basis for designing a therapeutic agent against endotoxin mediated oxidative damage. PMID- 21239457 TI - Gene expression profiles of RAW264.7 macrophages stimulated with preparations of LPS differing in isolation and purity. AB - Lipopolysaccharide is a major component of the cell wall of Gram-negative bacteria and a potent stimulator of innate immune response via TLR4. Studies on the LPS action both in vivo and in vitro have used different preparations of LPS, including ultra-pure LPS (LIST) and a less pure but less expensive form (Sigma) isolated from Escherichia coli serotype O111:B4. The difference between the effects of these compounds has not been well studied although this information is important in understanding TLR stimulation. In this study, we compared response of RAW264.7 macrophage cells treated LIST or Sigma LPS for 6 h and 24 h. Gene expression data were analyzed to identify specific genes and pathways that are in common and unique to the two LPS preparations. Seven hundred fifty-five genes were differentially expressed at 6 h in response to Sigma LPS and 973 were differentially expressed following LIST LPS treatment, with 503 in common. At 24 h, Sigma LPS induced or repressed 901 genes while 1646 genes were differentially regulated by LIST LPS treatment; 701 genes were shared by two forms of LPS. Although considerably more genes were differentially expressed in response to LIST LPS, similar molecular pathways and transcriptional networks were activated by the two LPS preparations. We also treated bone marrow-derived macrophages (BMMs) from three strains of mice with different concentrations of LIST and Sigma LPS and showed that BMMs produced more IL-6 and TNF-alpha in response to LIST LPS at low LPS concentrations but, at higher LPS concentrations, more cytokines were produced in response to stimulation by Sigma LPS. Together, these findings suggest that, despite activation of similar molecular pathways by LIST and Sigma LPS preparations, residual protein impurities in the Sigma LPS preparation may nevertheless influence the transcriptional profile attributed to TLR4 stimulation. PMID- 21239458 TI - Expression of integrins and Toll-like receptors in cervical cancer: effect of infectious agents. AB - We hypothesized that development of cervical cancer is associated with alterations in the expression of innate immune receptors, i.e. integrins and TLRs, and that these alterations can be induced by infectious agents. We have studied the expression of these proteins in cervical biopsy tissues and cervical cancer-derived cell lines HeLa, CaSki, SiHa, C-33 A, and ME180. Immunohistochemistry analysis demonstrated an increase in integrin alphav, beta3, beta4, and beta6 expression in the epithelium during the development of cervical cancer. A clear trend towards higher expression of integrin beta6 in cell lines harbouring human papillomavirus (HPV) genetic material, compared to HPV-negative C-33 A, was observed. To investigate whether bacterial infection can alter the expression of TLRs and integrins, we infected HeLa cells by two pathogens, Escherichia coli and Pseudomonas aeruginosa, using a common bacterium of the female genital tract, Lactobacillus reuteri, as a control. Infection with E. coli or P. aeruginosa, but not with L. reuteri, significantly altered the expression of TLR and integrins, particularly of TLR4 and integrin beta6. Considering that both integrin beta6 and TLR4 play important roles in tumorigenesis, our data suggest that bacterial infection may trigger cancer development in HPV-infected cervical epithelium. PMID- 21239459 TI - Adipocyte-macrophage interaction may mediate LPS-induced low-grade inflammation: potential link with metabolic complications. AB - Chronic low-grade infection has been suggested to be associated with metabolic disorder such as diabetes. However, the molecular mechanism underlying this important association is largely unknown. The only clue established so far is that many subjects exhibit elevated levels of C-reactive protein as measured by highly sensitive assay. Here, we hypothesized that adipocyte-macrophage interaction plays a key role in amplifying such low grade infection to the level of influencing metabolic disorders. The presence of macrophages in abdominal adipose tissues was investigated by immunohistochemistry. To see whether molecules associated with acute phase protein, LPS signaling, and persistent recruitment of monocytes, are produced at higher amounts in adipocytes co cultured with macrophages stimulated with low concentration of LPS (1 ng/ml), we measured serum amyloid A (SAA), LPS binding protein (LBP), soluble CD14 (sCD14), and RANTES levels in culture supernatant of co-cultures. Lastly, we investigated in vivo effect of low-grade LPS infusion on the production of these molecules using obese model mice. The macrophages were certainly identified in abdominal adipose tissues. Investigated molecules, especially LBP, SAA, and RANTES were produced at higher amounts in co-cultures stimulated with LPS compared with the cells without LPS. The ob/ob, and high-fat diet-induced obesity mice produced higher amounts of LBP, SAA, and RANTES one day after LPS infusion (1 ng/ml/g body weight) compared with ob/- and normal-fat fed control mice. Thus, adipocytes and infiltrated macrophages, and their interaction with low endotoxin stimulation appear to play an important role in amplifying and maintaining LPS-induced low grade inflammation. PMID- 21239460 TI - The role of DNA sensing and innate immune receptor TLR9 in otitis media. AB - Otitis media (OM), a common infectious disease in children, is associated with bacterial middle ear (ME) infection. Toll-like receptors (TLRs) are important mediators of innate immune responses, and TLR9 specifically recognizes the unmethylated cytidine-phosphate-guanosine (CpG) motifs in bacterial DNA. Additional sensors of foreign DNA have recently been identified. The role of DNA sensing and TLR9 was investigated in a murine model of OM induced by non-typeable Haemophilus influenzae (NTHi). Expression of genes related to DNA-sensing pathways involved in innate immunity was assessed via DNA microarray, qPCR and immunohistochemistry. Middle ear responses to NTHi were examined in wild-type and TLR9(-/-) mice by histopathology and bacterial culture. Expression of TLR9 signaling genes was modestly up-regulated during OM, as was TLR9 protein in both ME mucosal cells and infiltrating leukocytes. However, genes known to be regulated by CpG DNA were dramatically up-regulated, as were genes involved in DNA sensing by DIA, Pol-III and AIM2. Toll-like receptor 9 deletion significantly prolonged the inflammatory response induced by NTHi in the ME and delayed bacterial clearance. The results suggest that DNA sensing via TLR9 plays a role in OM pathogenesis and recovery. Alternative forms of DNA sensing may also contribute to OM. PMID- 21239462 TI - Cholecystokinin and hypothalamic corticotrophin-releasing factor participate in endotoxin-induced hypophagia. AB - Cholecystokinin (CCK) provides a meal-related signal that activates brainstem neurons, which have reciprocal interconnections with the hypothalamic paraventricular nucleus. Neurons that express corticotrophin-releasing factor (CRF) in the hypothalamus possess anorexigenic effects and are activated during endotoxaemia. This study investigated the effects of CCK(1) receptor blockade on lipopolysaccharide (LPS)-induced hypophagia and hypothalamic CRF neuronal activation. Male Wistar rats were pretreated with a specific CCK(1) receptor antagonist (devazepide; 1 mg kg(-1); i.p.) or vehicle; 30 min later they received LPS (100 MUg kg(-1); i.p.) or saline injection. Food intake, corticosterone responses and Fos-CRF and Fos-alpha-melanocyte-stimulating hormone (alpha-MSH) immunoreactivity in the hypothalamus and Fos-tyrosine hydroxylase immunoreactivity in the nucleus of the solitary tract (NTS) were evaluated. In comparison with saline treatment, LPS administration decreased food intake and increased plasma corticosterone levels, as well as the number of Fos-CRF and Fos- tyrosine hydroxylase double-labelled neurons in vehicle-pretreated rats; no change in Fos-alpha-MSH immunoreactivity was observed after LPS injection. In saline-treated animals, devazepide pretreatment increased food intake, but it did not modify other parameters compared with vehicle-pretreated rats. Devazepide pretreatment partly reversed LPS-induced hypophagia and Fos-CRF and brainstem neuronal activation. Devazepide did not modify the corticosterone and Fos-alpha MSH responses in rats treated with LPS. In conclusion, the present data suggest that LPS-induced hypophagia is mediated at least in part by CCK effects, via CCK(1) receptor, on NTS and hypothalamic CRF neurons. PMID- 21239463 TI - Respiratory responses to hypercapnia and hypoxia in mice with genetic ablation of Kir5.1 (Kcnj16). AB - Inward rectifier (Kir) potassium channels contribute to the control of electrical activity in excitable tissues and their activity is modulated by many biochemical factors, including protons. Heteromeric Kir4.1-Kir5.1 channels are highly pH sensitive within the physiological range of pH changes and are strongly expressed by the peripheral chemosensors as well as in the brainstem pH-sensitive areas which mediate respiratory responses to changes in blood and brain levels of P(CO(2))/[H(+)]. In the present study, Kir5.1 knockout mice (Kir5.1(-/-)) were used to determine the role of these channels in the chemosensory control of breathing. We found that Kir5.1(-/-) mice presented with persistent metabolic acidosis and a clear respiratory phenotype. Despite metabolic acidosis, ventilation at rest and in hyperoxic hypercapnia were similar in wild-type and Kir5.1(-/-) mice. Ventilatory responses to hypoxia and normoxic hypercapnia were significantly reduced in Kir5.1(-/-) mice; however, carotid body chemoafferent responses to hypoxia and CO(2) were not affected. In the in situ brainstem-spinal cord preparations with denervated peripheral chemoreceptors, resting phrenic nerve activity and phrenic nerve responses to respiratory acidosis or isohydric hypercapnia were also similar in Kir5.1(-/-) and wild-type mice. In in situ preparations of Kir5.1(-/-) mice with intact peripheral chemoreceptors, application of CN(-) resulted in a significantly reduced phrenic nerve response, suggesting that the relay of peripheral chemosensory information to the CNS is compromised. We suggest that this compensatory modulation of the peripheral chemosensory inputs develops in Kir5.1(-/-) mice in order to counteract the effect of continuing metabolic acidosis on the activity of the peripheral chemoreceptors. These results therefore suggest that despite their intrinsic pH sensitivity, Kir4.1-Kir5.1 channels are dispensable for functional central and peripheral respiratory chemosensitivity. PMID- 21239464 TI - Impact of age on critical closing pressure of the cerebral circulation during dynamic exercise in humans. AB - Limited information is available regarding cerebral vascular responses to dynamic exercise in older adults. We examined the influence of age on exercise-induced changes in the critical closing pressure (CCP) of the cerebral vasculature. Twelve young and twelve older subjects performed two bouts of steady-state cycling at low and moderate intensities (30 and 50% heart rate reserve). Mean arterial pressure (MAP), middle cerebral artery blood velocity (MCA V) and partial pressure of end-tidal carbon dioxide ( ) were measured. The CCP was estimated by linear extrapolation of pairs of systolic and diastolic blood pressure and MCA V waveforms. Exercise-induced increases in MAP were greater in older subjects (P < 0.01), while mean MCA V (MCA V(mean)) responses to exercise were similar between groups (P = 0.59). The CCP was elevated from rest during low and moderate-intensity exercise in both groups (moderate exercise: young, +13 +/ 2 mmHg and older, +22 +/- 2 mmHg; P < 0.01), with the older subjects exhibiting greater increases in CCP during both exercise intensities (moderate exercise: young, +43 +/- 9% rest versus older, +153 +/- 45% rest; P = 0.04). In contrast, cerebral vascular conductance index (MCA V(mean)/MAP; CVCi) was only decreased during moderate exercise in older subjects (P < 0.01) and CVCi was not altered from rest in young subjects during low- or moderate-intensity cycling. No age group differences were observed in at rest or during two intensities of exercise (P = 0.40). These data demonstrate that older subjects exhibit larger exercise induced increases in CCP and decreases in CVCi. Thus, ageing is associated with greater increases in cerebral vascular tone during low- and moderate-intensity dynamic exercise. PMID- 21239465 TI - Intracellular compartmentalization of skeletal muscle glycogen metabolism and insulin signalling. AB - The interest in skeletal muscle metabolism and insulin signalling has increased exponentially in recent years as a consequence of their role in the development of type 2 diabetes mellitus. Despite this, the exact mechanisms involved in the regulation of skeletal muscle glycogen metabolism and insulin signalling transduction remain elusive. We believe that one of the reasons is that the role of intracellular compartmentalization as a regulator of metabolic pathways and signalling transduction has been rather ignored. This paper briefly reviews the literature to discuss the role of intracellular compartmentalization in the regulation of skeletal muscle glycogen metabolism and insulin signalling. As a result, a hypothetical regulatory mechanism is proposed by which cells could direct glycogen resynthesis towards different pools of glycogen particles depending on the metabolic needs. Furthermore, we discuss the role of skeletal muscle transverse tubules as potential modulators of tissue insulin responsiveness. PMID- 21239466 TI - Expectations about and impact of the Liverpool Care Pathway for the dying patient in an Italian hospital. AB - This study is aimed at exploring the expectations about and the impact on healthcare staff of the Liverpool Care Pathway for the dying patient (LCP) in an Italian hospital. Qualitative information was derived from four focus group (FG) meetings that were carried out separately by profession and scheduled before the beginning and after the end of the implementation process of the Italian version of LCP for hospitals (LCP-I). Interview topics concerned end-of-life care related problems and expectations about the impact of the LCP-I programme. Tape recordings of the FGs were transcribed verbatim, and transcripts analysed independently by two research psychologists using thematic analysis. Five major topics were identified: managing pain and discontinuing inappropriate treatments, communicating with patients, communicating with relatives, communicating between professionals and practical issues. As compared with those reported in the initial FGs, responses from the final FGs highlighted that physicians felt more confident with pain management and with discontinuing inappropriate treatment, and were more inclined to recognize the value of the nurses' work. Nurses underlined advantages in using pro re nata medication, but stressed lack of personnel and time as obstacles in consistent improvement of end-of-life care. All participants seemed to acquire greater awareness of their difficulties in communication and, paradoxically, became more uncertain of their ability to liaise with dying patients and their families. LCP-I implementation may improve both knowledge about physical symptom management and professional awareness of the problems related to emotional and informative support in end-of-life care. PMID- 21239467 TI - Care or custody? An evaluation of palliative care in prisons in North West England. AB - This study aimed to evaluate health professionals' views about palliative care provision in prisons in the counties of Cumbria and Lancashire in the North West of England. Seventeen prison healthcare staff and nine specialist palliative care staff participated in semi-structured interviews and 16 prison healthcare staff completed a questionnaire designed to measure knowledge, skills and confidence in relation to palliative care. The findings highlighted tensions between the philosophies of care and custody, and the many challenges in providing palliative care in a custodial setting. This paper presents two illustrative case study examples, and suggests ways in which some of these challenges can be overcome in practice. PMID- 21239469 TI - Prevalence of intimate partner violence among migrant and native women attending general practice and the association between intimate partner violence and depression. AB - OBJECTIVE: To explore the prevalence of intimate partner violence (IPV) of women (aged >18 years) attending general practice and to assess the association between IPV and depression. METHODS: A cross-sectional survey was conducted within 15 general practices across Rotterdam. The study population was all women older than 18 years of age attending general practice. Women were screened for sociodemographic factors, IPV and depression using the Composite Abuse Scale and the Beck Depression Inventory. RESULTS: This study had a response rate of 63% (221 of 352 women). Two hundred and fourteen women were included in the study of whom 41% were migrants. Thirty per cent of the women attending general practise ever experienced IPV. Migrants experienced IPV 1.5 times more often compared to Dutch women. A significant association between IPV and depression was found. Half of the abused women were suffering from a depression. More than three-quarter of depressed women ever experienced IPV. CONCLUSIONS: IPV is common in women attending general practice and it is significantly associated with depression. To improve recognition of abused women, doctors should ask depressed women if they ever experienced IPV. PMID- 21239468 TI - A mutate-and-map strategy accurately infers the base pairs of a 35-nucleotide model RNA. AB - We present a rapid experimental strategy for inferring base pairs in structured RNAs via an information-rich extension of classic chemical mapping approaches. The mutate-and-map method, previously applied to a DNA/RNA helix, systematically searches for single mutations that enhance the chemical accessibility of base pairing partners distant in sequence. To test this strategy for structured RNAs, we have carried out mutate-and-map measurements for a 35-nt hairpin, called the MedLoop RNA, embedded within an 80-nt sequence. We demonstrate the synthesis of all 105 single mutants of the MedLoop RNA sequence and present high-throughput DMS, CMCT, and SHAPE modification measurements for this library at single nucleotide resolution. The resulting two-dimensional data reveal visually clear, punctate features corresponding to RNA base pair interactions as well as more complex features; these signals can be qualitatively rationalized by comparison to secondary structure predictions. Finally, we present an automated, sequence blind analysis that permits the confident identification of nine of the 10 MedLoop RNA base pairs at single-nucleotide resolution, while discriminating against all 1460 false-positive base pairs. These results establish the accuracy and information content of the mutate-and-map strategy and support its feasibility for rapidly characterizing the base-pairing patterns of larger and more complex RNA systems. PMID- 21239470 TI - Diagnosing acute coronary syndrome in primary care: comparison of the physicians' risk estimation and a clinical decision rule. AB - BACKGROUND: Diagnosing acute coronary syndrome (ACS) in a primary care setting poses a diagnostic dilemma for physicians. OBJECTIVE: We directly compared the diagnostic accuracy of a clinical decision rule (CDR) based on history taking and physical examination in suspected ACS with the risk estimates of the attending GP. METHODS: In a prospective multicenter study, patients suspected of ACS were included by the GP. GPs were asked to estimate the probability (0%-100%) of the presence of ACS. GPs collected patient data, but they were not aware of the CDR and did not score the patient accordingly. RESULTS: Two hundred and ninety-eight patients were included (52% female, mean age 66 years, 22% ACS). The area under the receiver operating characteristic (ROC) curve (AUC) was 0.75 [95% confidence interval (CI) 0.68-0.82] for the GP risk estimate and 0.66 (95% CI 0.58-0.73) for the CDR. There was an agreement between the risk estimation of the GP and a CDR in 51% and the prevalence of ACS in predefined low-, intermediate- and high-risk groups was similar for the GP and CDR estimates. In the low-risk group, according to the GP, four patients (8.2%) suffered an ACS. These four patients were all identified by the decision rule as high risk. CONCLUSIONS: The GP classified patients as ACS or no ACS more adequately than the CDR, judged by the AUC. However, the use of a CDR in patients that are considered at low risk for ACS by the GP could reduce the amount of missed myocardial infarctions. PMID- 21239471 TI - Germline competency of parthenogenetic embryonic stem cells from immature oocytes of adult mouse ovary. AB - Parthenogenetic embryonic stem cells (pESCs) have been generated in several mammalian species from parthenogenetic embryos that would otherwise die around mid-gestation. However, previous reports suggest that pESCs derived from in vivo ovulated (IVO) mature oocytes show limited pluripotency, as evidenced by low chimera production, high tissue preference and especially deficiency in germline competence, a critical test for genetic integrity and pluripotency of ESCs. Here, we report efficient generation of germline-competent pESC lines (named as IVM pESCs) from parthenogenetic embryos developed from immature oocytes of adult mouse ovaries following in vitro maturation (IVM) and artificial activation. In contrast, pESCs derived from IVO oocytes show defective germline competence, consistent with previous reports. Further, IVM pESCs resemble more ESCs from fertilized embryos (fESCs) than do IVO pESCs on genome-wide DNA methylation and global protein profiles. In addition, IVM pESCs express higher levels of Blimp1, Lin28 and Stella, relative to fESCs, and in their embryoid bodies following differentiation. This may indicate differences in differentiation potentially to the germline. The mechanisms for acquisition of pluripotency and germline competency of IVM pESCs from immature oocytes remain to be determined. PMID- 21239472 TI - 6-Thioguanine reactivates epigenetically silenced genes in acute lymphoblastic leukemia cells by facilitating proteasome-mediated degradation of DNMT1. AB - Thiopurines including 6-thioguanine ((S)G), 6-mercaptopurine, and azathioprine are effective anticancer agents with remarkable success in clinical practice, especially in effective treatment of acute lymphoblastic leukemia (ALL). (S)G is understood to act as a DNA hypomethylating agent in ALL cells, however, the underlying mechanism leading to global cytosine demethylation remains unclear. Here we report that (S)G treatment results in reactivation of epigenetically silenced genes in T leukemia cells. Bisulfite genomic sequencing revealed that (S)G treatment universally elicited demethylation in the promoters and/or first exons of the genes that were reactivated. (S)G treatment also attenuated the expression of histone lysine-specific demethylase 1 (LSD1), thereby stimulating lysine methylation of the DNA methylase DNMT1 and triggering its degradation via the ubiquitin-proteasomal pathway. Taken together, our findings reveal a previously uncharacterized but vital mechanistic link between (S)G treatment and DNA hypomethylation. PMID- 21239473 TI - The HIF-1-inducible lysyl oxidase activates HIF-1 via the Akt pathway in a positive regulation loop and synergizes with HIF-1 in promoting tumor cell growth. AB - Adaptation to hypoxia is a driving force for tumor progression that leads to therapy resistance and poor clinical outcome. Hypoxic responses are mainly mediated by hypoxia-inducible transcription factor-1 (HIF-1). One critical HIF-1 target mediating tumor progression is lysyl oxidase (LOX), which catalyzes cross linking of collagens and elastin in the extracellular matrix, thereby regulating tissue tensile strength. Paradoxically, LOX has been reported to be both upregulated and downregulated in cancer cells, especially in colorectal cancer. Thus, we hypothesized that LOX might regulate expression of HIF-1 to create a self-timing regulatory circuit. Using human colorectal carcinoma cell lines in which HIF-1 and LOX expression could be modulated, we showed that LOX induction enhanced HIF-1 expression, whereas LOX silencing reduced it. Mechanistic investigations revealed that LOX activated the PI3K (phosphoinositide 3-kinase) Akt signaling pathway, thereby upregulating HIF-1alpha protein synthesis in a manner requiring LOX-mediated hydrogen peroxide production. Consistent with these results, cancer cell proliferation was stimulated by secreted and active LOX in an HIF-1alpha-dependent fashion. Furthermore, nude mice xenograft assays established that HIF-1 potentiated LOX action on tumor growth in vivo. Taken together, these findings provide compelling evidence that LOX and HIF-1 act in synergy to foster tumor formation, and they suggest that HIF-1/LOX mutual regulation is a pivotal mechanism in the adaptation of tumor cells to hypoxia. PMID- 21239476 TI - Statistical design considerations in animal studies published recently in cancer research. PMID- 21239475 TI - CCT241533 is a potent and selective inhibitor of CHK2 that potentiates the cytotoxicity of PARP inhibitors. AB - CHK2 is a checkpoint kinase involved in the ATM-mediated response to double strand DNA breaks. Its potential as a drug target is still unclear, but inhibitors of CHK2 may increase the efficacy of genotoxic cancer therapies in a p53 mutant background by eliminating one of the checkpoints or DNA repair pathways contributing to cellular resistance. We report here the identification and characterization of a novel CHK2 kinase inhibitor, CCT241533. X-ray crystallography confirmed that CCT241533 bound to CHK2 in the ATP pocket. This compound inhibits CHK2 with an IC(50) of 3 nmol/L and shows minimal cross reactivity against a panel of kinases at 1 MUmol/L. CCT241533 blocked CHK2 activity in human tumor cell lines in response to DNA damage, as shown by inhibition of CHK2 autophosphorylation at S516, band shift mobility changes, and HDMX degradation. CCT241533 did not potentiate the cytotoxicity of a selection of genotoxic agents in several cell lines. However, this compound significantly potentiates the cytotoxicity of two structurally distinct PARP inhibitors. Clear induction of the pS516 CHK2 signal was seen with a PARP inhibitor alone, and this activation was abolished by CCT241533, implying that the potentiation of PARP inhibitor cell killing by CCT241533 was due to inhibition of CHK2. Consequently, our findings imply that CHK2 inhibitors may exert therapeutic activity in combination with PARP inhibitors. PMID- 21239478 TI - Industrial differences in female fertility treatment rates--a new approach to assess differences related to occupation? AB - AIMS: Infertility is highly prevalent and 16-26% of women trying to achieve a pregnancy experience infertility in one or more periods. Several exposures in the work environment have been hypothesized to affect female reproduction. This study aimed to estimate relative rates (RR) of female fertility treatment in the 57 industrial groups in Denmark. METHODS: The closed cohort of all 20-39 year old economically active women in Denmark by January 2001 (n = 567,816) were followed up for hospital contacts due to infertility from 2001 to 2005 as registered in the Danish Occupational Hospital Register. Age-standardized relative rates for being diagnosed as infertile were estimated by industry. Further standardization with respect to socioeconomic status was also performed. RESULTS: In total, 12,575 women were diagnosed with infertility during the follow-up period. Three industries presented with statistically significant elevations in age standardized RRs: hospitals (RR = 1.27, 95% confidence interval (CI): 1.20-1.35), general and dental practice (RR = 1.17, 95% CI: 1.02-1.35) and other health care (RR = 1.24, 95% CI: 1.09-1.41). Standardization for socioeconomic status rendered two industries that were statistically significantly elevated: manufacture of wood and wood products (RR = 1.20, 95% CI: 1.02-1.42) and hospitals (RR = 1.17, 95% CI: 1.10-1.24). CONCLUSIONS: Interpretation of the results is complex, since the relative contributions to the observed inequalities of the work environment and, for example, differences in inclination to start a family or in proneness to seek treatment are difficult to resolve. Withstanding shortcomings and limitations, register data of fertility treatment offers a possibility to suggest industries for further investigation of reproductive health. PMID- 21239477 TI - Genome-scale RNAi on living-cell microarrays identifies novel regulators of Drosophila melanogaster TORC1-S6K pathway signaling. AB - The evolutionarily conserved target of rapamycin complex 1 (TORC1) controls cell growth in response to nutrient availability and growth factors. TORC1 signaling is hyperactive in cancer, and regulators of TORC1 signaling may represent therapeutic targets for human diseases. To identify novel regulators of TORC1 signaling, we performed a genome-scale RNA interference screen on microarrays of Drosophila melanogaster cells expressing human RPS6, a TORC1 effector whose phosphorylated form we detected by immunofluorescence. Our screen revealed that the TORC1-S6K-RPS6 signaling axis is regulated by many subcellular components, including the Class I vesicle coat (COPI), the spliceosome, the proteasome, the nuclear pore, and the translation initiation machinery. Using additional RNAi reagents, we confirmed 70 novel genes as significant on-target regulators of RPS6 phosphorylation, and we characterized them with extensive secondary assays probing various arms of the TORC1 pathways, identifying functional relationships among those genes. We conclude that cell-based microarrays are a useful platform for genome-scale and secondary screening in Drosophila, revealing regulators that may represent drug targets for cancers and other diseases of deregulated TORC1 signaling. PMID- 21239479 TI - Incentivizing deceased organ donation: a Swedish priority-setting perspective. AB - AIMS: The established deceased organ donation models in many countries, relying chiefly on altruism, have failed to motivate a sufficient number of donors. As a consequence organs that could save lives are routinely missed leading to a growing gap between demand and supply. The aim of this paper is twofold; firstly to develop a proposal for compensated deceased organ donation that could potentially address the organ shortage; secondly to examine the compatibility of the proposal with the ethical values of the Swedish healthcare system. METHODS: The proposal for compensating deceased donation is grounded in behavioural agency theory and combines extrinsic, intrinsic and signalling incentives in order to increase prosocial behaviour. Furthermore the compatibility of our proposal with the values of the Swedish healthcare system is evaluated in reference to the principles of human dignity, needs and solidarity, and cost effectiveness. RESULTS: Extrinsic incentives in the form of a 5,000 compensation towards funeral expenses paid to the estate of the deceased or family is proposed. Intrinsic and signalling incentives are incorporated by allowing all or part of the compensation to be diverted as a donation to a reputable charity. The decision for organ donation must not be against the explicit will of the donor. CONCLUSIONS: We find that our proposal for compensated deceased donation is compatible with the values of the Swedish healthcare system, and therefore merits serious consideration. It is however important to acknowledge issues relating to coercion, commodification and loss of public trust and the ethical challenges that they might pose. PMID- 21239480 TI - Anti-hepatotoxic effects of 3,4-methylenedioxyphenol and N-acetylcysteine in acutely acetaminophen-overdosed mice. AB - 3,4-Methylenedioxyphenol (sesamol) is effective against acetaminophen-induced liver injury in rats. Whether sesamol's anti-hepatotoxic effect is comparable to that of N-acetylcysteine has never been studied. We investigated the anti hepatotoxic effects of sesamol and N-acetylcysteine on acetaminophen-induced hepatotoxicity in mice. Equimolar doses (1 mmol/kg) of sesamol and N acetylcysteine significantly inhibited acetaminophen (300 mg/kg)-increased serum aspartate transaminase and alanine transaminase levels 6 h post-administration. Sesamol and N-acetylcysteine maintained hepatic glutathione levels and inhibited lipid peroxidation. Moreover, the combination of sesamol and N-acetylcysteine antagonistically inhibited sesamol's protection against acetaminophen-induced liver injury. We conclude that the protective effect of sesamol against acetaminophen-induced liver damage is comparable to that of N-acetylcysteine by maintaining glutathione levels and inhibiting lipid peroxidation in mice. PMID- 21239481 TI - Fenvalerate induced hepatic oxidative stress in selenium- and/or iodine-deficient rats. AB - Considering the potential adverse effects of selenium and iodine deficiencies, and frequency of intensive but improper use of insecticides, this study was designed to evaluate the effects of a pyrethroid insecticide, fenvalerate, on the oxidant/antioxidant status of liver using a rat model of iodine and/or selenium deficiency. The study was conducted on eight groups of 3-week old Wistar rats. Iodine and/or selenium deficiency was introduced by feeding the animals with a diet containing <0.005 mg selenium/kg and/or supplying with 1% sodium perchlorate containing drinking water for a period of 7 weeks. Fenvalerate exposure (100 mg/kg/d, i.p., for the last 7 days) in normal rats increased hepatic glutathione peroxidase activity and lipid peroxidation, decreased glutathione content, but did not change the activities of catalase or any of the superoxide dismutase forms; in iodine-deficient animals caused only the elevation of lipid peroxidation; in selenium-deficient animals and in combined iodine/selenium deficiency decreased glutathione peroxidase, increased catalase activities and lipid peroxidation, and decreased all the forms of superoxide dismutase activity only in combined deficiency. These results suggested that fenvalerate is an oxidant stress inducer in rat liver, and its potential effects on pro oxidant/antioxidant balance may also be important for human populations, particularly with iodine and/or selenium deficiencies. PMID- 21239482 TI - Free radical scavenging and antiacetylcholinesterase activities of Origanum majorana L. essential oil. AB - In the present study, Origanum majorana L. essential oil (EO) was analyzed by gas chromatography-mass spectrometry (GC-MS) and evaluated for free radical scavenging and anticholinesterase activities. GC-MS analysis revealed the presence of 4-terpineol (29.97%), gamma-terpinene (15.40%), trans-sabinene hydrate (10.93), alpha-terpinene (6.86%), 3-cycolohexene-1-1 methanal,a,a4 trimethyl-,(S)-(CAS) (6.54%), and sabinene (3.91%) as main constituents. Origanum majorana L. EO exhibited concentration-dependent inhibitory effects on 2,2' diphenylpicrylhydrazyl (DPPH(*)), hydroxyl radical, hydrogen peroxide, reducing power, and lipid peroxidation with IC(50) values of 58.67, 67.11, 91.25, 78.67, and 68.75 ug/mL, respectively; while the IC(50) values for the standard trolox were noted to be 23.95, 44.97, 51.30, 42.22, and 52.72 ug/mL, respectively. Interestingly, cholinesterase inhibitory activity was also found with IC(50) values of 36.40 ug/mL. We can conclude that the marjoram EO has a significant potential to be used as a natural antioxidant and anti-AChE. PMID- 21239483 TI - Arfaptins are localized to the trans-Golgi by interaction with Arl1, but not Arfs. AB - Arfaptins (arfaptin-1 and arfaptin-2/POR1) were originally identified as binding partners of the Arf small GTPases. Both proteins contain a BAR (Bin/Amphiphysin/Rvs) domain, which participates in membrane deformation. Here we show that arfaptins associate with trans-Golgi membranes. Unexpectedly, Arl1 (Arf like 1), but not Arfs, determines the trans-Golgi association of arfaptins. We also demonstrate that arfaptins interact with Arl1 through their BAR domain containing region and compete for Arl1 binding with golgin-97 and golgin 245/p230, both of which also bind to Arl1 through their GRIP (golgin 97/RanBP2/Imh1p/p230) domains. However, arfaptins and these golgins show only limited colocalization at the trans-Golgi. Time-lapse imaging of cells overexpressing fluorescent protein-tagged arfaptins and golgin-97 reveals that arfaptins, but not golgin-97, are included in vesicular and tubular structures emanating from the Golgi region. These observations indicate that arfaptins are recruited onto trans-Golgi membranes by interacting with Arl1, and capable of inducing membrane deformation via their BAR domains. PMID- 21239484 TI - Arginine deficiency causes runting in the suckling period by selectively activating the stress kinase GCN2. AB - Suckling "F/A2" mice, which overexpress arginase-I in their enterocytes, develop a syndrome (hypoargininemia, reduced hair and muscle growth, impaired B-cell maturation) that resembles IGF1 deficiency. The syndrome may result from an impaired function of the GH-IGF1 axis, activation of the stress-kinase GCN2, and/or blocking of the mTORC1-signaling pathway. Arginine deficiency inhibited GH secretion and decreased liver Igf1 mRNA and plasma IGF1 concentration, but did not change muscle IGF1 concentration. GH supplementation induced Igf1 mRNA synthesis, but did not restore growth, ruling out direct involvement of the GH IGF1 axis. In C2C12 muscle cells, arginine withdrawal activated GCN2 signaling, without impacting mTORC1 signaling. In F/A2 mice, the reduction of plasma and tissue arginine concentrations to ~25% of wild-type values activated GCN2 signaling, but mTORC1-mediated signaling remained unaffected. Gcn2-deficient F/A2 mice suffered from hypoglycemia and died shortly after birth. Because common targets of all stress kinases (eIF2alpha phosphorylation, Chop mRNA expression) were not increased in these mice, the effects of arginine deficiency were solely mediated by GCN2. PMID- 21239485 TI - Impact of the metabolic activity of Streptococcus thermophilus on the colon epithelium of gnotobiotic rats. AB - The thermophilic lactic acid bacterium Streptococcus thermophilus is widely and traditionally used in the dairy industry. Despite the vast level of consumption of S. thermophilus through yogurt or probiotic functional food, very few data are available about its physiology in the gastrointestinal tract (GIT). The objective of the present work was to explore both the metabolic activity and host response of S. thermophilus in vivo. Our study profiles the protein expression of S. thermophilus after its adaptation to the GIT of gnotobiotic rats and describes the impact of S. thermophilus colonization on the colonic epithelium. S. thermophilus colonized progressively the GIT of germ-free rats to reach a stable population in 30 days (10(8) cfu/g of feces). This progressive colonization suggested that S. thermophilus undergoes an adaptation process within GIT. Indeed, we showed that the main response of S. thermophilus in the rat's GIT was the massive induction of the glycolysis pathway, leading to formation of lactate in the cecum. At the level of the colonic epithelium, the abundance of monocarboxylic acid transporter mRNAs (SLC16A1 and SLC5A8) and a protein involved in the cell cycle arrest (p27(kip1)) increased in the presence of S. thermophilus compared with germ-free rats. Based on different mono-associated rats harboring two different strains of S. thermophilus (LMD-9 or LMG18311) or weak lactate producing commensal bacteria (Bacteroides thetaiotaomicron and Ruminococcus gnavus), we propose that lactate could be a signal produced by S. thermophilus and modulating the colon epithelium. PMID- 21239486 TI - Dissecting the metabolic roles of pteridine reductase 1 in Trypanosoma brucei and Leishmania major. AB - Leishmania parasites are pteridine auxotrophs that use an NADPH-dependent pteridine reductase 1 (PTR1) and NADH-dependent quinonoid dihydropteridine reductase (QDPR) to salvage and maintain intracellular pools of tetrahydrobiopterin (H(4)B). However, the African trypanosome lacks a credible candidate QDPR in its genome despite maintaining apparent QDPR activity. Here we provide evidence that the NADH-dependent activity previously reported by others is an assay artifact. Using an HPLC-based enzyme assay, we demonstrate that there is an NADPH-dependent QDPR activity associated with both TbPTR1 and LmPTR1. The kinetic properties of recombinant PTR1s are reported at physiological pH and ionic strength and compared with LmQDPR. Specificity constants (k(cat)/K(m)) for LmPTR1 are similar with dihydrobiopterin (H(2)B) and quinonoid dihydrobiopterin (qH(2)B) as substrates and about 20-fold lower than LmQDPR with qH(2)B. In contrast, TbPTR1 shows a 10-fold higher k(cat)/K(m) for H(2)B over qH(2)B. Analysis of Trypanosoma brucei isolated from infected rats revealed that H(4)B (430 nM, 98% of total biopterin) was the predominant intracellular pterin, consistent with a dual role in the salvage and regeneration of H(4)B. Gene knock out experiments confirmed this: PTR1-nulls could only be obtained from lines overexpressing LmQDPR with H(4)B as a medium supplement. These cells grew normally with H(4)B, which spontaneously oxidizes to qH(2)B, but were unable to survive in the absence of pterin or with either biopterin or H(2)B in the medium. These findings establish that PTR1 has an essential and dual role in pterin metabolism in African trypanosomes and underline its potential as a drug target. PMID- 21239487 TI - Reconstitution of insulin action in muscle, white adipose tissue, and brain of insulin receptor knock-out mice fails to rescue diabetes. AB - Type 2 diabetes results from an impairment of insulin action. The first demonstrable abnormality of insulin signaling is a decrease of insulin-dependent glucose disposal followed by an increase in hepatic glucose production. In an attempt to dissect the relative importance of these two changes in disease progression, we have employed genetic knock-outs/knock-ins of the insulin receptor. Previously, we demonstrated that insulin receptor knock-out mice (Insr( /-)) could be rescued from diabetes by reconstitution of insulin signaling in liver, brain, and pancreatic beta cells (L1 mice). In this study, we used a similar approach to reconstitute insulin signaling in tissues that display insulin-dependent glucose uptake. Using GLUT4-Cre mice, we restored InsR expression in muscle, fat, and brain of Insr(-/-) mice (GIRKI (Glut4-insulin receptor knock-in line 1) mice). Unlike L1 mice, GIRKI mice failed to thrive and developed diabetes, although their survival was modestly extended when compared with Insr(-/-). The data underscore the role of developmental factors in the presentation of murine diabetes. The broader implication of our findings is that diabetes treatment should not necessarily target the same tissues that are responsible for disease pathogenesis. PMID- 21239488 TI - Fructose 1-phosphate is the preferred effector of the metabolic regulator Cra of Pseudomonas putida. AB - The catabolite repressor/activator (Cra) protein is a global sensor and regulator of carbon fluxes through the central metabolic pathways of gram-negative bacteria. To examine the nature of the effector (or effectors) that signal such fluxes to the protein of Pseudomonas putida, the Cra factor of this soil microorganism has been purified and characterized and its three-dimensional structure determined. Analytical ultracentrifugation, gel filtration, and mobility shift assays showed that the effector-free Cra is a dimer that binds an operator DNA sequence in the promoter region of the fruBKA cluster. Furthermore, fructose 1-phosphate (F1P) was found to most efficiently dissociate the Cra-DNA complex. Thermodynamic parameters of the F1P-Cra-DNA interaction calculated by isothermal titration calorimetry revealed that the factor associates tightly to the DNA sequence 5'-TTAAACGTTTCA-3' (K(D) = 26.3 +/- 3.1 nM) and that F1P binds the protein with an apparent stoichiometry of 1.06 +/- 0.06 molecules per Cra monomer and a K(D) of 209 +/- 20 nM. Other possible effectors, like fructose 1,6 bisphosphate, did not display a significant affinity for the regulator under the assay conditions. Moreover, the structure of Cra and its co-crystal with F1P at a 2-A resolution revealed that F1P fits optimally the geometry of the effector pocket. Our results thus single out F1P as the preferred metabolic effector of the Cra protein of P. putida. PMID- 21239489 TI - Cortisol synthesis in epidermis is induced by IL-1 and tissue injury. AB - Glucocorticoids (GCs) are known inhibitors of wound healing. In this study we report the novel finding that both keratinocytes in vitro and epidermis in vivo synthesize cortisol and how this synthesis regulates wound healing. We show that epidermis expresses enzymes essential for cortisol synthesis, including steroid 11 beta-hydroxylase (CYP11B1), and an enzyme that controls negative feedback mechanism, 11beta-hydroxysteroid dehydrogenase 2 (11betaHSD2). We also found that cortisol synthesis in keratinocytes and skin can be stimulated by ACTH and inhibited by metyrapone (CYP11B1 enzyme inhibitor). Interestingly, IL-1beta, the first epidermal signal of tissue injury, induces the expression of CYP11B1 and increases cortisol production by keratinocytes. Additionally, we found induction of CYP11B1 increased production of cortisol and activation of GR pathway during wound healing ex vivo and in vivo using human and porcine wound models, respectively. Conversely, inhibition of cortisol synthesis during wound healing increases IL-1beta production, suggesting that cortisol synthesis in epidermis may serve as a local negative feedback to proinflammatory cytokines. Local GCs synthesis, therefore, may provide control of the initial proinflammatory response, preventing excessive inflammation upon tissue injury. Inhibition of GC synthesis accelerated wound closure in vivo, providing the evidence that modulation of cortisol synthesis in epidermis may be an important regulatory mechanism during wound healing. PMID- 21239490 TI - Gcn1 and actin binding to Yih1: implications for activation of the eIF2 kinase GCN2. AB - Yeast Yih1 protein and its mammalian ortholog IMPACT, abundant in neurons, are inhibitors of Gcn2, a kinase involved in amino acid homeostasis, stress response, and memory formation. Like Gcn2, Yih1/IMPACT harbors an N-terminal RWD domain that mediates binding to the Gcn2 activator Gcn1. Yih1 competes with Gcn2 for Gcn1 binding, thus inhibiting Gcn2. Yih1 also binds G-actin. Here, we show that Yih1-actin interaction is independent of Gcn1 and that Yih1-Gcn1 binding does not require actin. The Yih1 RWD (residues 1-132) was sufficient for Gcn2 inhibition and Gcn1 binding, but not for actin binding, showing that actin binding is dispensable for inhibiting Gcn2. Actin binding required Yih1 residues 68-258, encompassing part of the RWD and the C-terminal "ancient domain"; however, residues Asp-102 and Glu-106 in helix3 of the RWD were essential for Gcn1 binding and Gcn2 inhibition but dispensable for actin binding. Thus, the Gcn1- and actin binding sites overlap in the RWD but have distinct binding determinants. Unexpectedly, Yih1 segment 68-258 was defective for inhibiting Gcn2 even though it binds Gcn1 at higher levels than does full-length Yih1. This and other results suggest that Yih1 binds with different requirements to distinct populations of Gcn1 molecules, and its ability to disrupt Gcn1-Gcn2 complexes is dependent on a complete RWD and hindered by actin binding. Modeling of the ancient domain on the bacterial protein YigZ showed peculiarities to the eukaryotic and prokaryotic lineages, suggesting binding sites for conserved cellular components. Our results support a role for Yih1 in a cross-talk between the cytoskeleton and translation. PMID- 21239491 TI - Mechanisms involved in the coordinate regulation of mTORC1 by insulin and amino acids. AB - In this study, we explored the coordinate regulation of mTORC1 by insulin and amino acids. Rat livers were perfused with medium containing various concentrations of insulin and/or amino acids. At fasting (1*) or 2* (2*AA) concentrations of amino acids, insulin maximally stimulated Akt phosphorylation but had no effect on global rates of protein synthesis. In the absence of insulin, 4*AA produced a moderate stimulation of protein synthesis and activation of mTORC1. The combination of 4*AA and insulin produced a maximal stimulation of protein synthesis and activation of mTORC1. These effects were accompanied by decreases in raptor and PRAS40 and an increase in RagC associated with mTOR (mammalian target of rapamycin). The studies were extended to a cell culture model in which mTORC1 activity was repressed by deprivation of leucine and serum, and resupplementation with the amino acid and insulin acted in an additive manner to restore mTORC1 activation. In deprived cells, mTORC1 was activated by expressing either constitutively active (ca) Rheb or a caRagB.caRagC complex, and coexpression of the constructs had an additive effect. Notably, resupplementation with leucine in cells expressing caRheb or with insulin in cells expressing the caRagB.caRagC complex was as effective as resupplementation with both leucine and insulin in non-transfected cells. Moreover, changes in mTORC1 activity correlated directly with altered association of mTOR with RagB/RagC, Rheb, raptor, and PRAS40. Overall, the results suggest that amino acids signal through the Rag complex and insulin through Rheb to achieve coordinate activation of mTORC1. PMID- 21239492 TI - pH-dependent cargo sorting from the Golgi. AB - The vacuolar proton-translocating ATPase (V-ATPase) plays a major role in organelle acidification and works together with other ion transporters to maintain pH homeostasis in eukaryotic cells. We analyzed a requirement for V ATPase activity in protein trafficking in the yeast secretory pathway. Deficiency of V-ATPase activity caused by subunit deletion or glucose deprivation results in missorting of newly synthesized plasma membrane proteins Pma1 and Can1 directly from the Golgi to the vacuole. Vacuolar mislocalization of Pma1 is dependent on Gga adaptors although no Pma1 ubiquitination was detected. Proper cell surface targeting of Pma1 was rescued in V-ATPase-deficient cells by increasing the pH of the medium, suggesting that missorting is the result of aberrant cytosolic pH. In addition to mislocalization of the plasma membrane proteins, Golgi membrane proteins Kex2 and Vrg4 are also missorted to the vacuole upon loss of V-ATPase activity. Because the missorted cargos have distinct trafficking routes, we suggest a pH dependence for multiple cargo sorting events at the Golgi. PMID- 21239493 TI - Structural basis for two-component system inhibition and pilus sensing by the auxiliary CpxP protein. AB - Bacteria are equipped with two-component systems to cope with environmental changes, and auxiliary proteins provide response to additional stimuli. The Cpx two-component system is the global modulator of cell envelope stress in gram negative bacteria that integrates very different signals and consists of the kinase CpxA, the regulator CpxR, and the dual function auxiliary protein CpxP. CpxP both inhibits activation of CpxA and is indispensable for the quality control system of P pili that are crucial for uropathogenic Escherichia coli during kidney colonization. How these two essential biological functions of CpxP are linked is not known. Here, we report the crystal structure of CpxP at 1.45 A resolution with two monomers being interdigitated like "left hands" forming a cap shaped dimer. Our combined structural and functional studies suggest that CpxP inhibits the kinase CpxA through direct interaction between its concave polar surface and the negatively charged sensor domain on CpxA. Moreover, an extended hydrophobic cleft on the convex surface suggests a potent substrate recognition site for misfolded pilus subunits. Altogether, the structural details of CpxP provide a first insight how a periplasmic two-component system inhibitor blocks its cognate kinase and is released from it. PMID- 21239494 TI - Lys-63-specific deubiquitination of SDS3 by USP17 regulates HDAC activity. AB - SDS3 is a key component of the histone deacetylase (HDAC)-dependent Sin3A co repressor complex, serving to maintain its HDAC activity. Here, we report both exogenous and endogenous functional interaction between deubiquitinating enzyme USP17 and human SDS3 by MALDI-TOF-MS, co-immunoprecipitation assay, and GST pull down assay. In this study, we demonstrated that SDS3 readily undergoes endogenous polyubiquitination, which is associated specifically with Lys-63-branched polyubiquitin chains and not with Lys-48-branched polyubiquitin chains. Further, we also demonstrated that USP17 specifically deubiquitinates Lys-63-linked ubiquitin chains from SDS3 and regulates its biological functions. The deubiquitinating activity of USP17 on SDS3 negatively regulates SDS3-associated HDAC activity. The constitutive expression of USP17 and its substrate SDS3 was involved in the inhibition of anchorage-independent tumor growth and blocks cell proliferation, leading to apoptosis in cervical carcinoma cells. Furthermore, we showed that USP17 and SDS3 mutually interact with each other to regulate cancer cell viability. These data support the possibility that SDS3, being a substrate of USP17, may play an important role in developing a novel therapeutic means to inhibit specific HDAC activities in cancer. PMID- 21239495 TI - Presenilins promote the cellular uptake of copper and zinc and maintain copper chaperone of SOD1-dependent copper/zinc superoxide dismutase activity. AB - Dyshomeostasis of extracellular zinc and copper has been implicated in beta amyloid aggregation, the major pathology associated with Alzheimer disease. Presenilin mediates the proteolytic cleavage of the beta-amyloid precursor protein to release beta-amyloid, and mutations in presenilin can cause familial Alzheimer disease. We tested whether presenilin expression affects copper and zinc transport. Studying murine embryonic fibroblasts (MEFs) from presenilin knock-out mice or RNA interference of presenilin expression in HEK293T cells, we observed a marked decrease in saturable uptake of radiolabeled copper and zinc. Measurement of basal metal levels in 6-month-old presenilin 1 heterozygous knock out (PS1(+/-)) mice revealed significant deficiencies of copper and zinc in several tissues, including brain. Copper/zinc superoxide dismutase (SOD1) activity was significantly decreased in both presenilin knock-out MEFs and brain tissue of presenilin 1 heterozygous knock-out mice. In the MEFs and PS1(+/-) brains, copper chaperone of SOD1 (CCS) levels were decreased. Zinc-dependent alkaline phosphatase activity was not decreased in the PS null MEFs. These data indicate that presenilins are important for cellular copper and zinc turnover, influencing SOD1 activity, and having the potential to indirectly impact beta amyloid aggregation through metal ion clearance. PMID- 21239496 TI - H3K36 methylation antagonizes PRC2-mediated H3K27 methylation. AB - H3K27 methylation mediated by the histone methyltransferase complex PRC2 is critical for transcriptional regulation, Polycomb silencing, Drosophila segmentation, mammalian X chromosome inactivation, and cancer. PRC2-mediated H3K27 methylation can spread along the chromatin and propagate the repressive chromatin environment; thus, chromatin components that antagonize the activity of PRC2 are important for restraining Polycomb silencing. Here we report that in HeLa cells, H3 histones unmethylated at Lys-36 are mostly methylated at Lys-27, with the exception of newly synthesized H3. In addition, K27me3 rarely co-exists with K36me2 or K36me3 on the same histone H3 polypeptide. Moreover, PRC2 activity is greatly inhibited on nucleosomal substrates with preinstalled H3K36 methylation. These findings collectively identify H3K36 methylation as a chromatin component that restricts the PRC2-mediated spread of H3K27 methylation. Finally, we provide evidence that the controversial histone lysine methyltransferase Ash1, a known Trithorax group protein that antagonizes Polycomb silencing in vivo, is an H3K36-specific dimethylase, not an H3K4 methylase, further supporting the role of H3K36 methylation in antagonizing PRC2-mediated H3K27 methylation. PMID- 21239497 TI - Crystal structure of the human histone methyltransferase ASH1L catalytic domain and its implications for the regulatory mechanism. AB - Absent, small, or homeotic disc1 (Ash1) is a trithorax group histone methyltransferase that is involved in gene activation. Although there are many known histone methyltransferases, their regulatory mechanisms are poorly understood. Here, we present the crystal structure of the human ASH1L catalytic domain, showing its substrate binding pocket blocked by a loop from the post-SET domain. In this configuration, the loop limits substrate access to the active site. Mutagenesis of the loop stimulates ASH1L histone methyltransferase activity, suggesting that ASH1L activity may be regulated through the loop from the post-SET domain. In addition, we show that human ASH1L specifically methylates histone H3 Lys-36. Our data implicate that there may be a regulatory mechanism of ASH1L histone methyltransferases. PMID- 21239498 TI - Parathyroid hormone-responsive Smad3-related factor, Tmem119, promotes osteoblast differentiation and interacts with the bone morphogenetic protein-Runx2 pathway. AB - The mechanisms whereby the parathyroid hormone (PTH) exerts its anabolic action on bone are incompletely understood. We previously showed that inhibition of ERK1/2 enhanced Smad3-induced bone anabolic action in osteoblasts. These findings suggested the hypothesis that changes in gene expression associated with the altered Smad3-induced signaling brought about by an ERK1/2 inhibitor would identify novel bone anabolic factors in osteoblasts. We therefore performed a comparative DNA microarray analysis between empty vector-transfected mouse osteoblastic MC3T3-E1 cells and PD98059-treated stable Smad3-overexpressing MC3T3 E1 cells. Among the novel factors, Tmem119 was selected on the basis of its rapid induction by PTH independent of later increases in endogenous TGF-beta. The levels of Tmem119 increased with time in cultures of MC3T3-E1 cells and mouse mesenchymal ST-2 cells committed to the osteoblast lineage by BMP-2. PTH stimulated Tmem119 levels within 1 h as determined by Western blot analysis and immunocytochemistry in MC3T3-E1 cells. MC3T3-E1 cells stably overexpressing Tmem119 exhibited elevated levels of Runx2, osteocalcin, alkaline phosphatase, and beta-catenin, whereas Tmem119 augmented BMP-2-induced Runx2 levels in mesenchymal cells. Tmem119 interacted with Runx2, Smad1, and Smad5 in C2C12 cells. In conclusion, we identified a Smad3-related factor, Tmem119, that is induced by PTH and promotes differentiation in mouse osteoblastic cells. Tmem119 is an important molecule in the pathway downstream of PTH and Smad3 signaling in osteoblasts. PMID- 21239499 TI - Plasminogen/plasmin modulates bone metabolism by regulating the osteoblast and osteoclast function. AB - The contribution of plasminogen (Plg)/plasmin, which have claimed to be the main fibrinolytic regulators in the bone metabolism, remains unclear. This study evaluated how the absence of Plg affects the function of osteoblast (OB) and osteoclast (OC). There was a larger population of pre-OCs in bone marrow-derived cells from the Plg(-/-) mice than the population of that from the WT mice. In addition, the absence of Plg suppressed the expression of osteoprotegerin in OBs. Moreover, an exogenous plasmin clearly induced the osteoprotegerin expression in Plg(-/-) OBs. The osteoclastogenesis of RAW264.7 mouse monocyte/macrophage lineage cells in co-culture with OBs from the Plg(-/-) mice was significantly accelerated in comparison with that in co-culture with OBs from the WT mice. Intriguingly, the accelerated OC differentiation of RAW264.7 cells co-cultured with Plg(-/-) OBs was clearly suppressed by the treatment of an exogenous plasmin. Consequently, Plg(-/-) mice display decreased bone mineral density. These findings could eventually lead to the development of new clinical therapies for bone disease caused by a disorder of the fibrinolytic system. PMID- 21239500 TI - Stress chaperone GRP-78 functions in mineralized matrix formation. AB - Mineralized matrix formation is a well orchestrated event requiring several players. Glucose-regulated protein-78 (GRP-78) is an endoplasmic reticulum chaperone protein that has been implicated in functional roles ranging from involvement in cancer biology to serving as a receptor for viruses. In the present study we explored the role of GRP-78 in mineralized matrix formation. Differential expression of GRP-78 mRNA and protein was observed upon in vitro differentiation of primary mouse calvarial cells. An interesting observation was that GRP-78 was identified in the secretome of these cells and in the bone matrix, suggesting an extracellular function during matrix formation. In vitro nucleation experiments under physiological concentrations of calcium and phosphate ions indicated that GRP-78 can induce the formation of calcium phosphate polymorphs by itself, when bound to immobilized type I collagen and on demineralized collagen wafers. We provide evidence that GRP-78 can bind to DMP1 and type I collagen independent of each other in a simulated extracellular environment. Furthermore, we demonstrate the cell surface localization of GRP-78 and provide evidence that it functions as a receptor for DMP1 endocytosis in pre osteoblasts and primary calvarial cells. Overall, this study represents a paradigm shift in the biological function of GRP-78. PMID- 21239501 TI - Delta-like 1 serves as a new target and contributor to liver fibrosis down regulated by mesenchymal stem cell transplantation. AB - Chronic liver injury always progresses to fibrosis and eventually to cirrhosis, a massive health care burden worldwide. Delta-like 1 (Dlk1) is well known as an inhibitor of adipocyte differentiation. However, whether it is involved in liver fibrosis remains unclear. Here, we provide the first evidence that Dlk1 is a critical contributor to liver fibrosis through promoting activation of hepatic stellate cells (HSCs) during chronic liver injury. We found that upon liver injury, Dlk1 was dramatically induced and initially expressed in hepatocytes and then into the HSCs by a paracrine manner. It leads to the activation of HSCs, which is considered to be a pivotal event in liver fibrogenesis. Two forms (~50 and ~25 kDa) of the Dlk1 protein were detected by Western blot analysis. In vitro administration of Dlk1 significantly promoted HSC activation, whereas in vivo knockdown of Dlk1 dramatically inhibited HSC activation and the subsequent fibrosis. The large soluble form (~50 kDa) of Dlk1 was shown to contribute to HSC activation. We were encouraged to find the Dlk1-promoted HSC activation and liver fibrosis can be depressed by transplantation of bone marrow-mesenchymal stem cells (BM-MSCs). Furthermore, we demonstrated that FGF2 was up-regulated in BM MSCs under injury stimulation, and it probably participated in the inhibition of Dlk1 by BM-MSCs. Our findings provide a novel role of Dlk1 in liver fibrosis leading to a better understanding of the molecular basis in fibrosis and cirrhosis and also give insights into the cellular and molecular mechanisms of MSC biology in liver repair. PMID- 21239502 TI - Resveratrol-mediated SIRT-1 interactions with p300 modulate receptor activator of NF-kappaB ligand (RANKL) activation of NF-kappaB signaling and inhibit osteoclastogenesis in bone-derived cells. AB - Resveratrol is a polyphenolic phytoestrogen that has been shown to exhibit potent anti-oxidant, anti-inflammatory, and anti-catabolic properties. Increased osteoclastic and decreased osteoblastic activities result in bone resorption and loss of bone mass. These changes have been implicated in pathological processes in rheumatoid arthritis and osteoporosis. Receptor activator of NF-kappaB ligand (RANKL), a member of the TNF superfamily, is a major mediator of bone loss. In this study, we investigated the effects of resveratrol on RANKL during bone morphogenesis in high density bone cultures in vitro. Untreated bone-derived cell cultures produced well organized bone-like structures with a bone-specific matrix. Treatment with RANKL induced formation of tartrate-resistant acid phosphatase-positive multinucleated cells that exhibited morphological features of osteoclasts. RANKL induced NF-kappaB activation, whereas pretreatment with resveratrol completely inhibited this activation and suppressed the activation of IkappaBalpha kinase and IkappaBalpha phosphorylation and degradation. RANKL up regulated p300 (a histone acetyltransferase) expression, which, in turn, promoted acetylation of NF-kappaB. Resveratrol inhibited RANKL-induced acetylation and nuclear translocation of NF-kappaB in a time- and concentration-dependent manner. In addition, activation of Sirt-1 (a histone deacetylase) by resveratrol induced Sirt-1-p300 association in bone-derived and preosteoblastic cells, leading to deacetylation of RANKL-induced NF-kappaB, inhibition of NF-kappaB transcriptional activation, and osteoclastogenesis. Co-treatment with resveratrol activated the bone transcription factors Cbfa-1 and Sirt-1 and induced the formation of Sirt-1 Cbfa-1 complexes. Overall, these results demonstrate that resveratrol-activated Sirt-1 plays pivotal roles in regulating the balance between the osteoclastic versus osteoblastic activity result in bone formation in vitro thereby highlighting its therapeutic potential for treating osteoporosis and rheumatoid arthritis-related bone loss. PMID- 21239503 TI - A novel 3-hydroxyproline (3Hyp)-rich motif marks the triple-helical C terminus of tendon type I collagen. AB - Because of its unique physical and chemical properties, rat tail tendon collagen has long been favored for crystallographic and biochemical studies of fibril structure. In studies of the distribution of 3-hydroxyproline in type I collagen of rat bone, skin, and tail tendon by mass spectrometry, the repeating sequences of Gly-Pro-Pro (GPP) triplets at the C terminus of alpha1(I) and alpha2(I) chains were shown to be heavily 3-hydroxylated in tendon but not in skin and bone. By isolating the tryptic peptides and subjecting them to Edman sequence analysis, the presence of repeating 3-hydroxyprolines in consecutive GPP triplets adjacent to 4-hydroxyproline was confirmed as a unique feature of the tendon collagen. A 1960s study by Piez et al. (Piez, K. A., Eigner, E. A., and Lewis, M. S. (1963) Biochemistry 2, 58-66) in which they compared the amino acid compositions of rat skin and tail tendon type I collagen chains indeed showed 3-4 residues of 3Hyp in tendon alpha1(I) and alpha2(I) chains but only one 3Hyp residue in skin alpha1(I) and none in alpha2(I). The present work therefore confirms this difference and localizes the additional 3Hyp to the GPP repeat at the C terminus of the triple helix. We speculate on the significance in terms of a potential function in contributing to the unique assembly mechanism and molecular packing in tendon collagen fibrils and on mechanisms that could regulate 3-hydroxylation at this novel substrate site in a tissue-specific manner. PMID- 21239504 TI - Novel chemosensitive single-nucleotide polymorphism markers to targeted regimens in metastatic colorectal cancer. AB - PURPOSE: Methods for predicting individual responsiveness to targeted chemotherapy are urgently needed, considering the frequent resistance and extremely high cost. EXPERIMENTAL DESIGN: A chemosensitive single-nucleotide polymorphism (SNP) discovery schema is presented that utilizes (i) genome-wide SNP screening with a human SNP array and an in vitro chemosensitivity assay in 118 colorectal cancers, (ii) clinical association analysis in the other 98 patients who had received chemotherapy for metastatic cancer, and (iii) biological utility assessment using cell viability assays of transfected colorectal cancer (CRC) cells. RESULTS: Nine SNPs related to bevacizumab and cetuximab regimen sensitivity were chosen during screening. Overall responses for bevacizumab regimens revealed that patients carrying the TT genotype at ANXA11 rs1049550 or at least one G allele at LINS1 rs11247226 seemed greater chemosensitive than those carrying at least one C allele or the AA genotype, respectively (P < 0.05). For cetuximab regimens, patients carrying the GG genotype at DFNB31 rs2274159 or LIFR rs3729740 seemed greater chemosensitive than those carrying at least one A allele (P = 0.025 and P = 0.07). Cytotoxicity analyses showed that all RKO and HCT116 CRC clones transfected with the G allele at LIFR rs3729740 and the C allele at ISX rs361863 were more sensitive to cetuximab regimens than those with the A and T allele, respectively (P <= 0.001 0.024). CONCLUSIONS: Chemosensitive SNP markers were identified using a novel three-step process. The candidate marker LIFR rs3729740 and possibly ISX rs361863 will hopefully predict responsive patients to cetuximab regimens, although further validation is needed in large cohorts. PMID- 21239505 TI - KRAS mutation is associated with lung metastasis in patients with curatively resected colorectal cancer. AB - PURPOSE: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse. EXPERIMENTAL DESIGN: One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n = 65), lung (n = 50), and brain (n = 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n = 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial. RESULTS: In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P = 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P < 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR = 2.1; 95% CI, 1.2 to 3.5, P = 0.007) but not liver relapse in patients from the VICTOR trial. CONCLUSIONS: KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies. PMID- 21239506 TI - The role of MafA in regulating cytokine expression in pancreatic beta cells. PMID- 21239508 TI - Curcumin and Alzheimer disease: this marriage is not to be performed. PMID- 21239511 TI - Characterization of highly efficacious allosteric agonists of the human calcium sensing receptor. AB - We discovered structurally novel human calcium-sensing receptor (CaSR) allosteric agonists and compared their pharmacology to phenylalkylamine calcimimetics. 1 Benzothiazol-2-yl-1-(2,4-dimethyl-phenyl)-ethanol (AC-265347) activated CaSR signaling in cellular proliferation and phosphatidylinositol (PI) hydrolysis assays with potencies of 30 and 10 nM, respectively. (S)-1-Benzothiazol-2-yl-1 (2,4-dimethyl-phenyl)-ethanol) [(S)-AC-265347], the S-enantiomer of AC-265347, was approximately 10- to 20-fold more potent than (R)-1-benzothiazol-2-yl-1-(2,4 dimethyl-phenyl)-ethanol) [(R)-AC-265347]. The phenylalkylamines cinacalcet and calindol had activity similar to that of AC-265347 in cellular proliferation assays but less activity in PI assays. All compounds had reduced activity when extracellular Ca(2+) was removed, indicating that they cooperate with Ca(2+) to activate CaSRs, and all activated CaSR isoforms with the N-terminal extracellular domain deleted, indicating that they interact with the transmembrane domains. In both cases, AC-265347 and therefore (S)-AC-265347 were significantly more efficacious than the phenylalkylamines. Mutations E837A(7.39) and I841A(7.43) strongly reduced phenylalkylamine-induced signaling, but not AC-265347- or (S)-AC 265347-induced signaling, suggesting different modes of binding. AC-265347 and (S)-AC-265347 stimulated significantly greater responses than cinacalcet or calindol at each of four loss-of-function human polymorphic CaSR variants. AC 265347 did not inhibit the CYP2D6 cytochrome P450 isozyme, unlike cinacalcet, which is a potent CYP2D6 inhibitor. In rats, AC-265347, (S)-AC-265347, and (R)-AC 265347 each reduced serum parathyroid hormone (PTH) with a rank order potency correlated with their in vitro potencies. AC-265347 and (S)-AC-265347 also reduced plasma ionizable calcium ([Ca(2+)](o)). AC-265347 was orally active, and its plasma concentrations correlated well with its effects on serum PTH. Thus, these highly efficacious CaSR allosteric agonists represent leads for developing therapeutic agents with potential advantages over existing therapies. PMID- 21239510 TI - Cevimeline-induced monophasic salivation from the mouse submandibular gland: decreased Na+ content in saliva results from specific and early activation of Na+/H+ exchange. AB - Cevimeline and pilocarpine are muscarinic agonists used clinically to treat dry mouth. In this study, we explored fluid secretion from mouse submandibular glands to determine the mechanism of cevimeline, pilocarpine, and an experimentally used agent carbachol. Cevimeline evoked almost the same amount of secretion at concentrations from 30 MUM to 1 mM. Pilocarpine also induced secretion at a concentration as low as 1 MUM and was the most powerful secretagogue at 10 MUM. Secretion was induced by carbachol at 0.1 MUM, with maximum secretion at 1.0 MUM. Cevimeline induced monophasic secretion at all concentrations tested, whereas higher concentrations of pilocarpine and carbachol induced secretion with variable kinetics, i.e., an initial transient high flow rate, followed by decreased secretion after 2 to 3 min. In the presence of an epithelial Na(+) channel blocker, amiloride, neither carbachol nor pilocarpine affected the Na(+) level of secreted saliva; however, it significantly increased the Na(+) content of cevimeline-induced saliva. The intracellular Ca(2+) response of acinar cells was almost identical among all three agents, although recovery after drug removal was slower for cevimeline and pilocarpine. A profound decrease in intracellular pH was observed during pilocarpine and carbachol treatment, whereas intracellular acidification induced by cevimeline was only seen in the presence of a Na(+)/H(+) exchange inhibitor. When external HCO(3)(-) was removed, cevimeline-induced saliva significantly decreased. These findings suggest that cevimeline specifically activates Na(+)/H(+) exchange and may promote Na(+) reabsorption by stabilizing epithelial sodium channel activity. PMID- 21239512 TI - Smoking induces bimodal DNA damage in mouse lung. AB - To clarify the relationship between DNA damage and free radical generation caused by smoking in vivo, DNA damage was investigated in the mouse lung by single-cell gel electrophoresis assay after exposure to cigarette smoke (CS) or gas phase cigarette smoke (GPCS). Although GPCS did not induce DNA lesions, bimodal peaks of DNA damage were detected in mouse lung exposed to CS, one immediately after exposure and another 15 min later. Pretreatment with a specific hydroxyl radical (*OH) scavenger completely prevented both types of DNA damage induced by CS. Electron spin resonance (ESR) study of the kinetics of free radical generation in CS or GPCS revealed that *OH could be detected immediately after the spin trapping of CS without chelators (first *OH generation), whereas *OH was also generated gradually with a time lag when the spin trapping was performed with chelators (second *OH generation). Our ESR study also indicated that the first *OH peak was probably generated from H(2)O(2) via a metal-independent pathway, whereas the second *OH peak might have been generated from H(2)O(2) and other sources via at least two different metal-masked pathways. The bimodal DNA damage induced in lung by smoking appears to be the result of a time lag between the first *OH generation and second *OH generation after exposure to the tar in CS. PMID- 21239513 TI - Innate immune activity in plaque of patients with untreated and L-thyroxine treated subclinical hypothyroidism. AB - CONTEXT: A strong association between subclinical hypothyroidism (SCH) and atherosclerotic diseases, independent of the traditional risk factors, was noted. OBJECTIVE: The objective of the study was to evaluate the association between SCH and the inflammatory potential of atherosclerotic plaques as well as the role of L-T(4) replacement therapy (LTR) on regulation of plaque inflammation. EXPERIMENTAL DESIGN AND MAIN OUTCOME MEASURES: We examined the differences in macrophage content, proinflammatory cytokine infiltration, and oxidative stress between asymptomatic carotid plaques of patients with and without SCH and LTR. SETTING AND PARTICIPANTS: Plaques were obtained from 23 SCH patients with LTR (treated), 34 untreated SCH patients, and 30 control patients without SCH enlisted to undergo carotid endarterectomy for extracranial high-grade (>70%) internal carotid artery stenosis. Plaques were analyzed for macrophages, T lymphocytes, human leukocyte antigen (HLA)-DR(+) cells, nuclear factor-kappaB (NF kappaB), inhibitory-kappaBbeta (IkappaBbeta), TNF-alpha, nitrotyrosine, matrix metalloproteinase-9 (MMP-9), and collagen content (immunohistochemistry and ELISA). RESULTS: Compared with control plaques, SCH plaques had more macrophages, T lymphocytes, and HLA-DR(+) cells, TNF-alpha, NF-kappaB, markers of oxidative stress (nitrotyrosine and O(2-) production), and MMP-9 (P < 0.01, for all), along with a lesser collagen content and IkappaBbeta levels (P < 0.001). Compared with plaques from treated patients, plaques from untreated patients had more macrophages, T lymphocytes, HLA-DR(+) cells, TNF-alpha, NF-kappaB (P < 0.001), nitrotyrosine, O(2-) production, and MMP-9 (P < 0.01, for all), along with a lesser collagen content and IkappaBbeta levels (P<0.001). CONCLUSIONS: These data suggest a potential interplay between SCH and inflammatory activity in atherosclerotic plaque progression toward instability. Moreover, LTR might contribute to plaque stabilization by inhibiting the innate immunity-dependent plaque rupture in patients with SCH. PMID- 21239514 TI - SHBG, sex hormones, and inflammatory markers in older women. AB - CONTEXT: In premenopausal and older women, high testosterone and estradiol (E2) and low SHBG levels are associated with insulin resistance and diabetes, conditions characterized by low-grade inflammation. OBJECTIVE: The aim of the study was to examine the relationship between SHBG, total testosterone, total E2, and inflammatory markers in older women. DESIGN AND PATIENTS: We conducted a retrospective cross-sectional study of 433 women at least 65 yr old from the InCHIANTI Study, Italy, who were not on hormone replacement therapy or recently hospitalized and who had complete data on SHBG, testosterone, E2, C-reactive protein (CRP), IL-6, soluble IL-6 receptor (sIL-6r), and TNF-alpha. Relationships between sex hormones and inflammatory markers were examined by multivariate linear regression analyses adjusted for age, body mass index, smoking, insulin, physical activity, and chronic disease. RESULTS: In fully adjusted analyses, SHBG was negatively associated with CRP (P = 0.007), IL-6 (P = 0.008), and sIL-6r (P = 0.02). In addition, testosterone was positively associated with CRP (P = 0.006), IL-6 (P = 0.001), and TNF-alpha (P = 0.0002). The negative relationship between testosterone and sIL-6r in an age-adjusted model (P = 0.02) was no longer significant in a fully adjusted model (P = 0.12). E2 was positively associated with CRP (P = 0.002) but not with IL-6 in fully adjusted models. In a final model including E2, testosterone, and SHBG, and all the confounders previously considered, SHBG (0.23 +/- 0.08; P = 0.006) and E2 (0.21 +/- 0.08; P = 0.007), but not testosterone (P = 0.21), were still significantly associated with CRP. CONCLUSION: In late postmenopausal women not on hormone replacement therapy, SHBG and E2 are, respectively, negative and positive, independent and significant correlates of a proinflammatory state. PMID- 21239515 TI - Clinical review: Intravenous glucocorticoids for Graves' orbitopathy: efficacy and morbidity. AB - CONTEXT: The administration of iv glucocorticoid pulses has been advocated as a treatment approach for patients with inflammatory and moderate to severe Graves' orbitopathy (GO). This review offers an update on this controversial regimen. EVIDENCE ACQUISITION: PubMed and the MeSH-Database were searched (with no temporal limit) for the following topics: management of active and severe GO; glucocorticoid therapy of GO; iv glucocorticoid administration; mechanism and pharmacokinetics of iv glucocorticoids; and adverse events, morbidity, and mortality of iv glucocorticoids. The articles were evaluated according to their setting and study design. EVIDENCE SYNTHESIS: All randomized and uncontrolled trials, consensus statement, systematic reviews, and meta-analyses dealing with the efficacy and morbidity of iv glucocorticoids in GO were identified. CONCLUSIONS: The current first-line treatment for active, moderate-to-severe GO is a 12-wk course of high-dose iv glucocorticoid pulses. The response rate of this regimen is approximately 80%. Intravenous glucocorticoids have a statistically significant advantage over oral treatment and cause significantly fewer adverse events. However, major side effects related to preexisting diseases, administered dose, and treatment schedule have been reported. The morbidity and mortality of iv glucocorticoid therapy are 6.5 and 0.6%, respectively. Thus, careful patient selection is warranted. Before iv glucocorticoid administration, patients should be screened for recent hepatitis, liver dysfunction, cardiovascular morbidity, severe hypertension, inadequately managed diabetes, and glaucoma. The cumulative dose should not exceed 8 g, and with the exception of sight-threatening GO the single doses preferably should not be administered on consecutive days. Monthly monitoring during subsequent treatment is warranted. PMID- 21239517 TI - Surgical results of thyroid nodules according to a management guideline based on the BRAF(V600E) mutation status. AB - CONTEXT: In Korea, where PTC comprises about 90-95% of the reported thyroid cancers, the prevalence of BRAF(V600E) mutation in papillary thyroid carcinoma (PTC) is above 80%. OBJECTIVE: We analyzed the surgical result according to a management guideline based on the BRAF(V600E) mutation status of thyroid nodules. DESIGN: A total of 865 thyroid nodules were prospectively analyzed for their cytology and BRAF(V600E) mutation status by pyrosequencing. For the patients who had a diagnosis of atypical cells of undetermined significance (ACUS), we recommended surgery when there was positivity for BRAF(V600E) mutation or the nodules were clinically suspicious. RESULTS: Among 865 cases, 504, 141, 54, 140, 10, and 16 were diagnosed as benign, ACUS, suspicious for malignancy, malignant, suspicious for follicular neoplasm, and nondiagnostic, respectively. None of the 504 benign, 45 (31.9%) of the 141 ACUS, 46 (85.2%) of the 54 suspicious for malignancy, 129 (92.1%) of the 140 malignant, and one (10%) of the 10 suspicious for follicular neoplasm cases showed BRAF(V600E) mutation. Surgery was recommended to all 45 patients with BRAF(V600E) mutation-positive ACUS nodules; among them, 30 patients underwent surgery, 29 had PTC, and one had nodular hyperplasia. All the patients diagnosed as suspicious for malignancy or malignant were advised to undergo an operation, and they turned out to have PTCs regardless of their BRAF(V600E) mutation status. CONCLUSIONS: We found that performing BRAF(V600E) mutation analysis on the fine-needle aspiration biopsy specimens was of great help to make a therapeutic decision for thyroid nodules when the fine needle aspiration biopsy results were equivocal. PMID- 21239516 TI - Sterol O-acyltransferase 1 (SOAT1, ACAT) is a novel target of steroidogenic factor-1 (SF-1, NR5A1, Ad4BP) in the human adrenal. AB - CONTEXT: Steroidogenic factor-1 (SF-1, NR5A1, Ad4BP) is a master regulator of adrenal development and steroidogenesis. Defects in several known targets of SF-1 can cause adrenal disorders in humans. OBJECTIVE: We aimed to identify novel targets of SF-1 in the human adrenal. These factors could be important regulators of adrenal development and steroidogenesis and potential candidates for adrenal dysfunction. DESIGN: A gene discovery strategy was developed based on bidirectional manipulation of SF-1. Overexpression or knockdown of SF-1 in NCI H295R human adrenocortical cells was used to identify a subset of positively regulated SF-1 targets. RESULTS: This approach identified well-established SF-1 target genes (STAR, CYP11A) and several novel genes (VSNL1, ZIM2, PEG3, SOAT1, and MTSS1). Given its role in cholesterol metabolism, sterol O-acyltransferase 1 (SOAT1, previously referred to as acyl-Coenzyme A:cholesterol acyltransferase 1, ACAT) was studied further and found to be expressed in the developing human fetal adrenal cortex. We hypothesized that impaired SOAT1 activity could result in adrenal insufficiency through reduced cholesteryl ester reserves or through toxic destruction of the adrenal cells during development. Therefore, mutational analysis of SOAT1 in a cohort of 43 patients with unexplained adrenal insufficiency was performed but failed to reveal significant coding sequence changes. CONCLUSIONS: Our reverse discovery approach led to the identification of novel SF-1 targets and defined SOAT1 as an important factor in human adrenal steroidogenesis. SF-1-dependent up-regulation of SOAT1 may be important for maintaining readily-releasable cholesterol reserves needed for active steroidogenesis and during episodes of recurrent stress. PMID- 21239518 TI - Inhibition of DPP-4 with vildagliptin improved insulin secretion in response to oral as well as "isoglycemic" intravenous glucose without numerically changing the incretin effect in patients with type 2 diabetes. AB - BACKGROUND AND AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors block the degradation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. The aim of the present study was to quantitatively assess the incretin effect after treatment with the DPP-4 inhibitor vildagliptin (V) or placebo (P) in patients with type 2 diabetes. MATERIALS AND METHODS: Twenty-one patients (three women, 18 men) with type 2 diabetes previously treated with metformin (mean age, 59 yr; body mass index, 28.6 kg/m(2); glycosylated hemoglobin, 7.3%) were studied in a two-period crossover design. They received 100 mg V once daily or P for 13 d in randomized order. The incretin effect was measured on d 12 (75-g oral glucose) and d 13 ("isoglycemic" iv glucose) based on insulin and C-peptide determinations and insulin secretion rates (ISR). RESULTS: V relative to P treatment significantly increased intact incretin concentrations after oral glucose and insulin secretory responses to both oral glucose and isoglycemic iv glucose (e.g. AUC(ISR oral), by 32.7%, P = 0.0006; AUC(ISR iv), by 33.1%, P = 0.01). The numerical incretin effect was not changed (IE(ISR), V vs. P, 35.7 +/- 4.9 and 34.6 +/- 4.0%, P = 0.80). CONCLUSIONS: DPP-4 inhibition augmented insulin secretory responses both after oral glucose and during isoglycemic iv glucose infusions, with no net change in the incretin effect. Thus, slight variations in basal incretin levels may be more important than previously thought. Or, DPP-4 inhibitor-induced change in the incretin-related environment of islets may persist overnight, augmenting insulin secretory responses to iv glucose as well. Alternatively, yet unidentified mediators of DPP 4 inhibition may have caused these effects. PMID- 21239519 TI - Interaction between testosterone and growth hormone on whole-body protein anabolism occurs in the liver. AB - CONTEXT: GH and testosterone both exert protein-anabolic effects and may act synergistically. Liver and muscle are major sites of protein metabolism. OBJECTIVE: Our objective was to determine whether the site of GH and testosterone interaction on protein metabolism is primarily hepatic or extrahepatic. DESIGN: In this open-label randomized crossover study, the impact on whole-body protein metabolism of oral (solely hepatic testosterone exposure) and transdermal (systemic testosterone exposure) testosterone replacement in the presence or absence of GH was compared. PATIENTS AND INTERVENTION: Eleven hypopituitary men with GH and testosterone deficiency were randomized to 2-wk treatments with transdermal testosterone (10 mg) or oral testosterone (40 mg), with or without GH replacement (0.6 mg/d). The dose of testosterone administered orally achieves physiological portal testosterone concentrations without spillover into the systemic circulation. MAIN OUTCOME MEASURES: Whole-body leucine turnover was measured, from which leucine rate of appearance (LRa), an index of protein breakdown, and leucine oxidation (Lox), a measure of irreversible protein loss, were estimated at the end of each treatment. RESULTS: In the absence of GH, neither transdermal nor oral testosterone affected LRa or Lox. GH therapy significantly increased LRa, an effect equally reduced by transdermal and oral testosterone administration. GH replacement alone did not significantly change Lox, whereas addition of testosterone treatment reduced Lox, with the effect not significantly different between transdermal and oral testosterone. CONCLUSIONS: In the doses used, testosterone stimulates protein anabolism by reducing protein breakdown and oxidation only in the presence of GH. Because the net effect on protein metabolism during GH therapy is not different between systemic and solely hepatic testosterone administration, we conclude that the liver is the primary site of this hormonal interaction. PMID- 21239520 TI - RSK4 inhibition results in bypass of stress-induced and oncogene-induced senescence. AB - p90 Ribosomal S6 kinase (RSK) 4 is a serine-threonine kinase that belongs to the p90RSK family. RSK4 has been proposed as a tumor suppressor gene, related with anti-invasive activity, inhibition of the RAS-mitogen-activated protein kinase (MAPK) pathway and induction of senescence. Despite the related findings, little is known about RSK4 effectors. In human tumors, RSK4 is downregulated even in some benign lesions, such as colon adenomas and breast papillomas, indicating that RSK4 inhibition could be an early event in cellular transformation. For cells to achieve immortality and transformation, it is believed that they must override senescence. In the present study, we found that when RSK4 is inhibited in vitro using short hairpin RNA technology, cells can bypass stress-induced senescence and oncogene-induced senescence: normal human fibroblasts grew following oxidative stress, induction of DNA damage and KRAS(V12) or BRAF(E600) overexpression. To investigate the RSK4 effectors, we used short hairpin RNA or inhibitor molecules against major senescence mediators. We found that RSK4 induced senescence is mediated through p21, but is independent of p16, p38MAPKs and induction of reactive oxygen species, delimiting RSK4 signaling. These data support the importance of RSK4 for regulating senescence and indicate that downregulation of this kinase could be an important element in facilitating cell transformation. PMID- 21239521 TI - Invited commentary: (Mass) Imprisonment and (Inequities in) Health. AB - The US imprisonment rate has increased dramatically since the mid-1970s, precipitating tremendous interest in the consequences of having ever been imprisoned for the marginal men for whom contact with prisons and jails has become commonplace. The article by Spaulding et al. in this issue of the Journal (Am J Epidemiol. 2011;173(5):479-487) makes a substantial contribution to research in this area by demonstrating for the first time that the small short term benefits of imprisonment with regard to mortality risk are far outweighed by the much larger long-term mortality costs of having ever been imprisoned. Yet it remains unclear whether contact with the penal system causes the associations therein. In this commentary, the author addresses some of the obstacles to causal inference that exist in this research area and highlights one way to overcome them. He then suggests that future research might focus on 1) the consequences of mass imprisonment for health inequities among adult men and 2) the spillover effects of mass imprisonment for persons who are also affected by the penal system-the families, friends, and communities prisoners leave behind. PMID- 21239522 TI - Prisoner survival inside and outside of the institution: implications for health care planning. AB - The life expectancy of persons cycling through the prison system is unknown. The authors sought to determine the 15.5-year survival of 23,510 persons imprisoned in the state of Georgia on June 30, 1991. After linking prison and mortality records, they calculated standardized mortality ratios (SMRs). The cohort experienced 2,650 deaths during follow-up, which were 799 more than expected (SMR = 1.43, 95% confidence interval (CI): 1.38, 1.49). Mortality during incarceration was low (SMR = 0.85, 95% CI: 0.77, 0.94), while postrelease mortality was high (SMR = 1.54, 95% CI: 1.48, 1.61). SMRs varied by race, with black men exhibiting lower relative mortality than white men. Black men were the only demographic subgroup to experience significantly lower mortality while incarcerated (SMR = 0.66, 95% CI: 0.58, 0.76), while white men experienced elevated mortality while incarcerated (SMR = 1.28, 95% CI: 1.10, 1.48). Four causes of death (homicide, transportation, accidental poisoning, and suicide) accounted for 74% of the decreased mortality during incarceration, while 6 causes (human immunodeficiency virus infection, cancer, cirrhosis, homicide, transportation, and accidental poisoning) accounted for 62% of the excess mortality following release. Adjustment for compassionate releases eliminated the protective effect of incarceration on mortality. These results suggest that the low mortality inside prisons can be explained by the rarity of deaths unlikely to occur in the context of incarceration and compassionate releases of moribund patients. PMID- 21239524 TI - Stability of mouse oocytes at -80 degrees C: the role of the recrystallization of intracellular ice. AB - The germplasm of mutant mice is stored as frozen oocytes/embryos in many facilities worldwide. Their transport to and from such facilities should be easy and inexpensive with dry ice at -79 degrees C. The purpose of our study was to determine the stability of mouse oocytes with time at that temperature. The metaphase II oocytes were cryopreserved with a vitrification solution (EAFS10/10) developed by M Kasai and colleagues. Two procedures were followed. In one, the samples were cooled at 187 degrees C/min to -196 degrees C, warmed to -80 degrees C, held at -80 degrees C for 1 h to 3 months, and warmed to 25 degrees C at one of three rates. With the highest warming rate (2950 degrees C/min), survival remained at 75% for the first month, but then slowly declined to 40% over the next 2 months. With the slowest warming (139 degrees C/min), survival was only ~ 5% even at 0 time at -80 degrees C. In the second procedure, the samples were cooled at 294 degrees C/min to -80 degrees C (without cooling to 196 degrees C) and held for up to 3 months before warming at 2950 degrees C/min. Survival was ~ 90% after 7 days and dropped slowly to 35% after 3 months. We believe that small non-lethal quantities of intracellular ice formed during the cooling and that the intracellular crystals increased to a damaging size by recrystallization during the 3 month's storage at -80 degrees C. From the practical point of view, this protocol yields sufficient stability to make it feasible to ship oocytes worldwide in dry ice. PMID- 21239525 TI - Formation of nucleoli in interspecies nuclear transfer embryos derived from bovine, porcine, and rabbit oocytes and nuclear donor cells of various species. AB - The most successful development of interspecies somatic cell nuclear transfer (iSCNT) embryos has been achieved in closely related species. The analyses of embryonic gene activity in iSCNT embryos of different species combinations have revealed the existence of significant aberrations in expression of housekeeping genes and genes dependent on the major embryonic genome activation (EGA). However, there are many studies with successful blastocyst (BL) development of iSCNT embryos derived from donor cells and oocytes of animal species with distant taxonomical relations (inter-family/inter-class) that should indicate proper EGA at least in terms of RNA polymerase I activation, nucleoli formation, and activation of genes engaged in morula and BL formation. We investigated the ability of bovine, porcine, and rabbit oocytes to activate embryonic nucleoli formation in the nuclei of somatic cells of different mammalian species. In iSCNT embryos, nucleoli precursor bodies originate from the oocyte, while most proteins engaged in the formation of mature nucleoli should be transcribed from genes de novo in the donor nucleus at the time of EGA. Thus, the success of nucleoli formation depends on species compatibility of many components of this complex process. We demonstrate that the time and cell stage of nucleoli formation are under the control of recipient ooplasm. Oocytes of the studied species possess different abilities to support nucleoli formation. Formation of nucleoli, which is a complex but small part of the whole process of EGA, is essential but not absolutely sufficient for the development of iSCNT embryos to the morula and BL stages. PMID- 21239526 TI - Histone exchange activity and its correlation with histone acetylation status in porcine oocytes. AB - In mammalian oocytes, histone H3 and histone H4 (H4) in the chromatin are highly acetylated at the germinal vesicle (GV) stage, and become globally deacetylated after GV breakdown (GVBD). Although nuclear core histones can be exchanged by cytoplasmic free histones in somatic cells, it remains unknown whether this is also the case in mammalian oocytes. In this study, we examined the histone exchange activity in maturing porcine oocytes before and after GVBD, and investigated the correlations between this activity and both the acetylation profile of the H4 N-terminal tail and the global histone acetylation level in the chromatin. We injected Flag-tagged H4 (H4-Flag) mRNA into GV oocytes, and found that the Flag signal was localized to the chromatin. We next injected mRNAs of mutated H4-Flag, which lack all acetylation sites and the whole N-terminal tail, and found that the H4 N-terminal tail and its modification were not necessary for histone incorporation into chromatin. Despite the lack of acetylation sites, the mutated H4-Flag mRNA injection did not decrease the acetylation level on the chromatin, indicating that the histone exchange occurs partially in the GV chromatin. In contrast to GV oocytes, the Flag signal was not detected on the chromatin after the injection of H4-Flag protein into the second meiotic metaphase oocytes. These results suggest that histone exchange activity changes during meiotic maturation in porcine oocytes, and that the acetylation profile of the H4 N-terminal tail has no effect on histone incorporation into chromatin and does not affect the global level of histone acetylation in it. PMID- 21239527 TI - Effect of epidermal growth factor-like peptides on pig cumulus cell expansion, oocyte maturation, and acquisition of developmental competence in vitro: comparison with gonadotropins. AB - The aim of this work was to assess the FSH-stimulated expression of epidermal growth factor (EGF)-like peptides in cultured cumulus-oocyte complexes (COCs) and to find out the effect of the peptides on cumulus expansion, oocyte maturation, and acquisition of developmental competence in vitro. FSH promptly stimulated expression of amphiregulin (AREG) and epiregulin (EREG), but not betacellulin (BTC) in the cultured COCs. Expression of AREG and EREG reached maximum at 2 or 4 h after FSH addition respectively. FSH also significantly stimulated expression of expansion-related genes (PTGS2, TNFAIP6, and HAS2) in the COCs at 4 and 8 h of culture, with a significant decrease at 20 h of culture. Both AREG and EREG also increased expression of the expansion-related genes; however, the relative abundance of mRNA for each gene was much lower than in the FSH-stimulated COCs. In contrast to FSH, AREG and EREG neither stimulated expression of CYP11A1 in the COCs nor an increase in progesterone production by cumulus cells. AREG and EREG stimulated maturation of oocytes and expansion of cumulus cells, although the percentage of oocytes that had reached metaphase II was significantly lower when compared to FSH-induced maturation. Nevertheless, significantly more oocytes stimulated with AREG and/or EREG developed to blastocyst stage after parthenogenetic activation when compared to oocytes stimulated with FSH alone or combinations of FSH/LH or pregnant mares serum gonadotrophin/human chorionic gonadotrophin. We conclude that EGF-like peptides do not mimic all effects of FSH on the cultured COCs; nevertheless, they yield oocytes with superior developmental competence. PMID- 21239528 TI - Expression and effect of resistin on bovine and rat granulosa cell steroidogenesis and proliferation. AB - Resistin, initially identified in adipose tissue and macrophages, was implicated in insulin resistance. Recently, its mRNA was found in hypothalamo-pituitary axis and rat testis, leading us to hypothesize that resistin may be expressed in ovary. In this study, we determined in rats and cows 1) the characterization of resistin in ovary by RT-PCR, immunoblotting, and immunohistochemistry and 2) the effects of recombinant resistin (10, 100, 333, and 667 ng/ml) +/- IGF1 (76 ng/ml) on steroidogenesis, proliferation, and signaling pathways of granulosa cells (GC) measured by enzyme immunoassay, [(3)H]thymidine incorporation, and immunoblotting respectively. We observed that resistin mRNA and protein were present in several bovine and rat ovarian cells. Nevertheless, only bovine GC abundantly expressed resistin mRNA and protein. Resistin treatment decreased basal but not IGF1 induced progesterone (P<0.05; whatever the dose) and estradiol (P<0.005; for 10 and 333 ng/ml) production by bovine GC. In rats, resistin (10 ng/ml) increased basal and IGF1-induced progesterone secretion (P<0.0001), without effect on estradiol release. We found no effect of resistin on rat GC proliferation. Conversely, in cows, resistin increased basal proliferation (P<0.0001; for 100 667 ng/ml) and decreased IGF1-induced proliferation of GC (P<0.0001; for 10-333 ng/ml) associated with a decrease in cyclin D2 protein level (P<0.0001). Finally, resistin stimulated AKT and p38-MAPK phosphorylation in both species, ERK1/2-MAPK phosphorylation in rats and had the opposite effect on the AMPK pathway (P<0.05). In conclusion, our results show that resistin is expressed in rat and bovine ovaries. Furthermore, it can modulate GC functions in basal state or in response to IGF1 in vitro. PMID- 21239529 TI - In vivo function of airway epithelial TLR2 in host defense against bacterial infection. AB - Decreased Toll-like receptor 2 (TLR2) expression has been reported in patients with chronic obstructive pulmonary disease and in a murine asthma model, which may predispose the hosts to bacterial infections, leading to disease exacerbations. Since airway epithelial cells serve as the first line of respiratory mucosal defense, the present study aimed to reveal the role of airway epithelial TLR2 signaling to lung bacterial [i.e., Mycoplasma pneumoniae (Mp)] clearance. In vivo TLR2 gene transfer via intranasal inoculation of adenoviral vector was performed to reconstitute TLR2 expression in airway epithelium of TLR2(-/-) BALB/c mice, with or without ensuing Mp infection. TLR2 and lactotransferrin (LTF) expression in airway epithelial cells and lung Mp load were assessed. Adenovirus-mediated TLR2 gene transfer to airway epithelial cells of TLR2(-/-) mice reconstituted 30-40% TLR2 expression compared with TLR2(+/+) cells. Such airway epithelial TLR2 reconstitution in TLR2(-/-) mice significantly reduced lung Mp load (an appropriate 45% reduction), coupled with elevated LTF expression. LTF expression in mice was shown to be mainly dependent on TLR2 signaling in response to Mp infection. Exogenous human LTF protein dose dependently decreased lung bacterial load in Mp-infected TLR2(-/-) mice. In addition, human LTF protein directly dose-dependently decreased Mp levels in vitro. These data indicate that reconstitution of airway epithelial TLR2 signaling in TLR2(-/-) mice significantly restores lung defense against bacteria (e.g., Mp) via increased lung antimicrobial protein LTF production. Our findings may offer a deliverable approach to attenuate bacterial infections in airways of asthma or chronic obstructive pulmonary disease patients with impaired TLR2 function. PMID- 21239530 TI - Lung-derived soluble mediators are pathogenic in ventilator-induced lung injury. AB - Ventilator-induced lung injury (VILI) due to high tidal volume (V(T)) is associated with increased levels of circulating factors that may contribute to, or be markers of, injury. This study investigated if exclusively lung-derived circulating factors produced during high V(T) ventilation can cause or worsen VILI. In isolated perfused mouse lungs, recirculation of perfusate worsened injury (compliance impairment, microvascular permeability, edema) induced by high V(T). Perfusate collected from lungs ventilated with high V(T) and used to perfuse lungs ventilated with low V(T) caused similar compliance impairment and permeability and caused a dose-dependent decrease in transepithelial electrical resistance (TER) across rat distal lung epithelial monolayers. Circulating soluble factors derived from the isolated lung thus contributed to VILI and had deleterious effects on the lung epithelial barrier. These data demonstrate transferability of an injury initially caused exclusively by mechanical ventilation and provides novel evidence for the biotrauma hypothesis in VILI. Mediators of the TER decrease were heat-sensitive, transferable via Folch extraction, and (following ultrafiltration, 3 kDa) comprised both smaller and larger molecules. Although several classes of candidate mediators, including protein cytokines (e.g., tumor necrosis factor-alpha, interleukin-6, macrophage inflammation protein-1alpha) and lipids (e.g., eicosanoids, ceramides, sphingolipids), have been implicated in VILI, only prostanoids accumulated in the perfusate in a pattern consistent with a pathogenic role, yet cyclooxygenase inhibition did not protect against injury. Although no single class of factor appears solely responsible for the decrease in barrier function, the current data implicate lipid-soluble protein-bound molecules as not just markers but pathogenic mediators in VILI. PMID- 21239531 TI - Long-term failure of alveologenesis after an early short-term exposure to a PDGF receptor antagonist. AB - Survivors of moderate-to-severe bronchopulmonary dysplasia have impaired alveologenesis lasting at least into early adult life. The mechanisms underlying this long-term effect are unknown. We hypothesized that short-term inhibition of growth factor-mediated early alveolar formation would result in a long-term impairment of subsequent alveologenesis. Neonatal rats were injected daily with the platelet-derived growth factor (PDGF) receptor antagonist, imatinib mesylate, from day 1-7 of life, to inhibit the early alveolar formation occurring by in growth of secondary crests into precursor saccules. The pups were then allowed to recover for 7, 14, 21, or 58 days. In imatinib-treated pups, DNA synthesis in total lung cells, and specifically in cells of secondary crests, was reduced at day 8 of life, had rebounded on day 14 of life but was then again reduced by day 28 of life. At day 8 of life, imatinib-treated pups had impaired alveologenesis as reflected by a decrease in secondary crests, an increase in alveolar size, and an overall decrease in both estimated alveolar number and generations compared with age-matched controls. No meaningful recovery was observed, even after a 21- or 58-day recovery period. The lungs of imatinib-treated pups had increased fibulin-5 content and an abnormal deposition of elastin. We conclude that reduced signaling through the PDGF pathways, at an early stage of alveologenesis, can result in long-lasting changes in lung architecture. A likely mechanism is through impaired formation of the elastin scaffold required for alveolarization. PMID- 21239532 TI - Cytoprotective effects of albumin, nitrosated or reduced, in cultured rat pulmonary vascular cells. AB - S-nitrosoalbumin (SNO-Alb) has been shown to be an efficacious cytoprotective molecule in acute lung injury, as well as ischemia-reperfusion injury in heart and skeletal muscle. Nonetheless, limited information is available on the cellular mechanism of such protection. Accordingly, we investigated the protective effects of SNO-Alb [ and its denitrosated congener, reduced albumin (SH-Alb) ] on tert-butyl hydroperoxide (tBH)-mediated cytotoxicity in cultured rat pulmonary microvascular endothelial cells (RPMEC), as well as hydrogen sulfide (H(2)S)-mediated cytotoxicity in rat pulmonary artery smooth muscle cells (RPASMC). We noted that tBH caused a concentration-dependent necrosis in RPMEC, and pretreatment of RPMEC with SNO-Alb dose-dependently decreased the sensitivity of these cells to tBH. A component of SNO-Alb cytoprotection was sensitive to N(G)-nitro-L-arginine methyl ester and was associated with activation of endothelial nitric oxide synthase (eNOS), phenomena that could be reproduced with pretreatment with SH-Alb. Exogenous H(2)S caused concentration-dependent apoptosis in RPASMC due to activation of ERK1/2 and p38, as well as downregulation of Bcl-2. Pretreatment with SNO-Alb reduced H(2)S-mediated apoptosis in a concentration-dependent manner that was associated with SNO-Alb mediated inhibition of activation of ERK1/2 and p38. Pretreatment with SNO-Alb reduced toxicity of 1 mM sodium hydrosulfide in an N(G)-nitro-L-arginine methyl ester-sensitive fashion in RPASMC that expressed gp60 and neuronal NOS and was capable of transporting fluorescently labeled SH-Alb. Therefore, SNO-Alb is cytoprotective against models of oxidant-induced necrosis (tBH) and inhibitors of cellular respiration and apoptosis (H(2)S) in both pulmonary endothelium and smooth muscle, respectively, and a component of such protection can be attributed to a SH-Alb-mediated activation of constitutive NOS. PMID- 21239533 TI - T-bet is induced by interferon-gamma to mediate chemokine secretion and migration in human airway smooth muscle cells. AB - An inappropriate balance between T-helper (Th)1 and Th2 cytokine production underlies inflammatory changes that result in airway disease. Expression of the T box transcription factor T-bet regulates differentiation of Th cells and production of Th1 cytokines, particularly IFNgamma. T-bet-deficient mice develop airway hyperreactivity, undergo airway remodeling, and exhibit defects in IFNgamma production while overproducing Th2 cytokines. T-bet is also reduced in the airways of asthmatic patients, suggesting loss of T-bet expression or activity promotes development of inflammatory airway disease. We present novel data demonstrating T-bet expression is induced in human airway smooth muscle cells (ASMC) by IFNgamma. This IFNgamma-stimulated expression of T-bet is dependent on signaling through JAK2 and signal transducers and activators of transcription 1 (STAT1) and activates T-bet-dependent DNA binding activity. Expression of T-bet stimulates IFNgamma-stimulated IFNgamma expression, secretion, and promoter activity, while inhibiting IFNgamma-stimulated release of chemokines including monocyte chemoattractant protein (MCP)-1/CCL2, regulated on activation normal T-expressed and secreted (RANTES)/CCL5, and eotaxin/CCL11. This is accompanied by changes in expression of the chemokine receptors CCR3 and IL12Rbeta2 and TNFalpha. T-bet expression also reduces chemotactic migration of ASMC in response to serum and PDGF, which contributes to airway hyperplasia. These results are the first to identify T-bet expression and activity in a structural cell of the lung and may provide new insights into therapeutic targets for inflammatory airway disease. PMID- 21239534 TI - LPS-induced decrease in intracellular labile zinc, [Zn]i, contributes to apoptosis in cultured sheep pulmonary artery endothelial cells. AB - A role in signal transduction for a vanishingly small labile pool of intracellular zinc ([Zn](i)) has been inferred by the sensitivity of various physiological pathways to zinc chelators such as N,N,N',N'-tetrakis(2 pyridylmethyl)ethylenediamine (TPEN) and/or associations with changes in nonprotein-bound zinc-sensitive fluorophores. Although we (44) reported that LPS induced apoptosis in cultured sheep pulmonary artery endothelial cells (SPAEC) was exacerbated by TPEN, 1) we did not detect acute (30 min) changes in [Zn](i), and 2) it is unclear from other reports whether LPS increases or decreases [Zn](i) and whether elevations or decreases in [Zn](i) are associated with cell death and/or apoptosis. In the present study, we used both chemical (FluoZin-3 via live cell epifluorescence microscopy and fluorescence-activated cell sorting) and genetic (luciferase activity of a chimeric reporter encoding zinc-sensitive metal-response element and changes in steady-state mRNA of zinc importer, SLC39A14 or ZIP14) techniques to show that LPS caused a delayed time-dependent (2 4 h) decrease in [Zn](i) in SPAEC. A contributory role of decreases in [Zn](i) in LPS-induced apoptosis (as determined by caspase-3/7 activation, annexin-V binding, and cytochrome c release) in SPAECs was revealed by mimicking the effect of LPS with the zinc chelator, TPEN, and inhibiting LPS- (or TPEN)-induced apoptosis with exogenous zinc. Collectively, these are the first data demonstrating a signaling role for decrease in [Zn](i) in pulmonary endothelial cells and suggest that endogenous levels of labile zinc may affect sensitivity of pulmonary endothelium to the important and complex proapoptotic stimulus of LPS. PMID- 21239535 TI - CTGF disrupts alveolarization and induces pulmonary hypertension in neonatal mice: implication in the pathogenesis of severe bronchopulmonary dysplasia. AB - The pathological hallmarks of bronchopulmonary dysplasia (BPD), one of the most common long-term pulmonary complications associated with preterm birth, include arrested alveolarization, abnormal vascular growth, and variable interstitial fibrosis. Severe BPD is often complicated by pulmonary hypertension characterized by excessive pulmonary vascular remodeling and right ventricular hypertrophy that significantly contributes to the mortality and morbidity of these infants. Connective tissue growth factor (CTGF) is a multifunctional protein that coordinates complex biological processes during tissue development and remodeling. We have previously shown that conditional overexpression of CTGF in airway epithelium under the control of the Clara cell secretory protein promoter results in BPD-like architecture in neonatal mice. In this study, we have generated a doxycycline-inducible double transgenic mouse model with overexpression of CTGF in alveolar type II epithelial (AT II) cells under the control of the surfactant protein C promoter. Overexpression of CTGF in neonatal mice caused dramatic macrophage and neutrophil infiltration in alveolar air spaces and perivascular regions. Overexpression of CTGF also significantly decreased alveolarization and vascular development. Furthermore, overexpression of CTGF induced pulmonary vascular remodeling and pulmonary hypertension. Most importantly, we have also demonstrated that these pathological changes are associated with activation of integrin-linked kinase (ILK)/glucose synthesis kinase-3beta (GSK-3beta)/beta-catenin signaling. These data indicate that overexpression of CTGF in AT II cells results in lung pathology similar to those observed in infants with severe BPD and that ILK/GSK-3beta/beta-catenin signaling may play an important role in the pathogenesis of severe BPD. PMID- 21239537 TI - Hypoxia-inducible factor-1alpha mediates TGF-beta-induced PAI-1 production in alveolar macrophages in pulmonary fibrosis. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha), a transcription factor that functions as a master regulator of oxygen homeostasis, has been implicated in fibrinogenesis. Here, we explore the role of HIF-1alpha in transforming growth factor-beta (TGF-beta) signaling by examining the effects of TGF-beta(1) on the expression of plasminogen activator inhibitor-1 (PAI-1). Immunohistochemistry of lung tissue from a mouse bleomycin (BLM)-induced pulmonary fibrosis model revealed that expression of HIF-1alpha and PAI-1 was predominantly induced in alveolar macrophages. Real-time RT-PCR and ELISA analysis showed that PAI-1 mRNA and activated PAI-1 protein level were strongly induced 7 days after BLM instillation. Stimulation of cultured mouse alveolar macrophages (MH-S cells) with TGF-beta(1) induced PAI-1 production, which was associated with HIF-1alpha protein accumulation. This accumulation of HIF-1alpha protein was inhibited by SB431542 (type I TGF-beta receptor/ALK receptor inhibitor) but not by PD98059 (MEK1 inhibitor) and SB203580 (p38 MAP kinase inhibitor). Expression of prolyl hydroxylase domain (PHD)-2, which is essential for HIF-1alpha degradation, was inhibited by TGF-beta(1), and this decrease was abolished by SB431542. TGF beta(1) induction of PAI-1 mRNA and its protein expression were significantly attenuated by HIF-1alpha silencing. Transcriptome analysis by cDNA microarray of MH-S cells after HIF-1alpha silencing uncovered several pro-fibrotic genes whose regulation by TGF-beta(1) required HIF-1alpha, including platelet-derived growth factor-A. Taken together, these findings expand our concept of the role of HIF 1alpha in pulmonary fibrosis in mediating the effects of TGF-beta(1) on the expression of the pro-fibrotic genes in activated alveolar macrophages. PMID- 21239536 TI - Nitric oxide suppression of cellular proliferation depends on cationic amino acid transporter activity in cytokine-stimulated pulmonary endothelial cells. AB - Inducible nitric oxide (NO) synthase (iNOS) is a stress response protein upregulated in inflammatory conditions, and NO may suppress cellular proliferation. We hypothesized that preventing L-arginine (L-arg) uptake in endothelial cells would prevent lipopolysaccharide/tumor necrosis factor-alpha (LPS/TNF)-induced, NO-mediated suppression of cellular proliferation. Bovine pulmonary arterial endothelial cells (bPAEC) were treated with LPS/TNF or vehicle (control), and either 10 mM L-leucine [L-leu; a competitive inhibitor of L-arg uptake by the cationic amino acid transporter (CAT)] or its vehicle. In parallel experiments, iNOS or arginase II were overexpressed in bPAEC using an adenoviral vector (AdiNOS or AdArgII, respectively). LPS/TNF treatment increased the expression of iNOS, arginase II, CAT-1, and CAT-2 mRNA in bPAEC, resulting in greater NO and urea production than in control bPAEC, which was prevented by L leu. LPS/TNF treatment resulted in fewer viable cells than in controls, and LPS/TNF-stimulated bPAEC treated with L-leu had more viable cells than LPS/TNF treatment alone. LPS/TNF treatment resulted in cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase expression, which was attenuated by L-leu. AdiNOS reduced viable cell number, and treatment of AdiNOS transfected bPAEC with L-leu preserved cell number. AdArgII increased viable cell number, and treatment of AdArgII transfected bPAEC with L-leu prevented the increase in cell number. These data demonstrate that iNOS expression in pulmonary endothelial cells leads to decreased cellular proliferation, which can be attenuated by preventing cellular L-arg uptake. We speculate that CAT activity may represent a novel therapeutic target in inflammatory lung diseases characterized by NO overproduction. PMID- 21239538 TI - Cell deformation at the air-liquid interface induces Ca2+-dependent ATP release from lung epithelial cells. AB - Extracellular nucleotides regulate mucociliary clearance in the airways and surfactant secretion in alveoli. Their release is exquisitely mechanosensitive and may be induced by stretch as well as airflow shear stress acting on lung epithelia. We hypothesized that, in addition, tension forces at the air-liquid interface (ALI) may contribute to mechanosensitive ATP release in the lungs. Local depletion of airway surface liquid, mucins, and surfactants, which normally protect epithelial surfaces, facilitate such release and trigger compensatory mucin and fluid secretion processes. In this study, human bronchial epithelial 16HBE14o(-) and alveolar A549 cells were subjected to tension forces at the ALI by passing an air bubble over the cell monolayer in a flow-through chamber, or by air exposure while tilting the cell culture dish. Such stimulation induced significant ATP release not involving cell lysis, as verified by ethidium bromide staining. Confocal fluorescence microscopy disclosed reversible cell deformation in the monolayer part in contact with the ALI. Fura 2 fluorescence imaging revealed transient intracellular Ca(2+) elevation evoked by the ALI, which did not entail nonspecific Ca(2+) influx from the extracellular space. ATP release was reduced by ~40 to ~90% from cells loaded with the Ca(2+) chelator BAPTA-AM and was completely abolished by N-ethylmalemide (1 mM). These experiments demonstrate that in close proximity to the ALI, surface tension forces are transmitted directly on cells, causing their mechanical deformation and Ca(2+) dependent exocytotic ATP release. Such a signaling mechanism may contribute to the detection of local deficiency of airway surface liquid and surfactants on the lung surface. PMID- 21239539 TI - Quantifying mitochondrial and plasma membrane potentials in intact pulmonary arterial endothelial cells based on extracellular disposition of rhodamine dyes. AB - Our goal was to quantify mitochondrial and plasma potential (Deltapsi(m) and Deltapsi(p)) based on the disposition of rhodamine 123 (R123) or tetramethylrhodamine ethyl ester (TMRE) in the medium surrounding pulmonary endothelial cells. Dyes were added to the medium, and their concentrations in extracellular medium ([R(e)]) were measured over time. R123 [R(e)] fell from 10 nM to 6.6 +/- 0.1 (SE) nM over 120 min. TMRE [R(e)] fell from 20 nM to a steady state of 4.9 +/- 0.4 nM after ~30 min. Protonophore or high K(+) concentration ([K(+)]), used to manipulate contributions of membrane potentials, attenuated decreases in [R(e)], and P-glycoprotein (Pgp) inhibition had the opposite effect, demonstrating the qualitative impact of these processes on [R(e)]. A kinetic model incorporating a modified Goldman-Hodgkin-Katz model was fit to [R(e)] vs. time data for R123 and TMRE, respectively, under various conditions to obtain (means +/- 95% confidence intervals) Deltapsi(m) (-130 +/- 7 and -133 +/- 4 mV), Deltapsi(p) (-36 +/- 4 and -49 +/- 4 mV), and a Pgp activity parameter (K(Pgp), 25 +/- 5 and 51 +/- 11 MUl/min). The higher membrane permeability of TMRE also allowed application of steady-state analysis to obtain Deltapsi(m) (-124 +/- 6 mV). The consistency of kinetic parameter values obtained from R123 and TMRE data demonstrates the utility of this experimental and theoretical approach for quantifying intact cell Deltapsi(m) and Deltapsi(p.) Finally, steady-state analysis revealed that although room air- and hyperoxia-exposed (95% O(2) for 48 h) cells have equivalent resting Deltapsi(m), hyperoxic cell Deltapsi(m) was more sensitive to depolarization with protonophore, consistent with previous observations of pulmonary endothelial hyperoxia-induced mitochondrial dysfunction. PMID- 21239540 TI - Autoregulation of nodulation interferes with impacts of nitrogen fertilization levels on the leaf-associated bacterial community in soybeans. AB - The diversities leaf-associated bacteria on nonnodulated (Nod(-)), wild-type nodulated (Nod(+)), and hypernodulated (Nod(++)) soybeans were evaluated by clone library analyses of the 16S rRNA gene. To analyze the impact of nitrogen fertilization on the bacterial leaf community, soybeans were treated with standard nitrogen (SN) (15 kg N ha(-1)) or heavy nitrogen (HN) (615 kg N ha(-1)) fertilization. Under SN fertilization, the relative abundance of Alphaproteobacteria was significantly higher in Nod(-) and Nod(++) soybeans (82% to 96%) than in Nod(+) soybeans (54%). The community structure of leaf-associated bacteria in Nod(+) soybeans was almost unaffected by the levels of nitrogen fertilization. However, differences were visible in Nod(-) and Nod(++) soybeans. HN fertilization drastically decreased the relative abundance of Alphaproteobacteria in Nod(-) and Nod(++) soybeans (46% to 76%) and, conversely, increased those of Gammaproteobacteria and Firmicutes in these mutant soybeans. In the Alphaproteobacteria, cluster analyses identified two operational taxonomic units (OTUs) (Aurantimonas sp. and Methylobacterium sp.) that were especially sensitive to nodulation phenotypes under SN fertilization and to nitrogen fertilization levels. Arbuscular mycorrhizal infection was not observed on the root tissues examined, presumably due to the rotation of paddy and upland fields. These results suggest that a subpopulation of leaf-associated bacteria in wild type Nod(+) soybeans is controlled in similar ways through the systemic regulation of autoregulation of nodulation, which interferes with the impacts of N levels on the bacterial community of soybean leaves. PMID- 21239541 TI - The EIIABMan phosphotransferase system permease regulates carbohydrate catabolite repression in Streptococcus gordonii. AB - Commensal oral streptococci play critical roles in oral biofilm formation and promote dental health by competing with, and antagonizing the growth of, pathogenic organisms, such as Streptococcus mutans. Efficient utilization of the spectrum of carbohydrates in the oral cavity by commensal streptococci is essential for their persistence, and yet very little is known about the regulation of carbohydrate catabolism by these organisms. Carbohydrate catabolite repression (CCR) in the abundant oral commensal Streptococcus gordonii strain DL 1 was investigated using the exo-beta-D-fructosidase gene (fruA) and a fructose/mannose sugar:phosphotransferase (PTS) enzyme II operon (levDEFG) as model systems. Functional studies confirmed the predicted roles of FruA and LevD in S. gordonii. ManL, the AB domain of a fructose/mannose-type enzyme II PTS permease, contributed to utilization of glucose, mannose, galactose, and fructose and exerted primary control over CCR of the fruA and levD operons. Unlike in S. mutans, ManL-dependent CCR was not sugar specific, and galactose was very effective at eliciting CCR in S. gordonii. Inactivation of the apparent ccpA homologue of S. gordonii actually enhanced CCR of fruA and levD, an effect likely due to its demonstrated role in repression of manL expression. Thus, there are some similarities and fundamental differences in CCR control mechanisms between the oral pathogen S. mutans and the oral commensal S. gordonii that may eventually be exploited to enhance the competitiveness of health-associated commensals in oral biofilms. PMID- 21239542 TI - Abundance, diversity, and activity of ammonia-oxidizing prokaryotes in the coastal Arctic ocean in summer and winter. AB - Ammonia oxidation, the first step in nitrification, is performed by certain Beta- and Gammaproteobacteria and Crenarchaea to generate metabolic energy. Ammonia monooxygenase (amoA) genes from both Bacteria and Crenarchaea have been found in a variety of marine ecosystems, but the relative importance of Bacteria versus Crenarchaea in ammonia oxidation is unresolved, and seasonal comparisons are rare. In this study, we compared the abundance of betaproteobacterial and crenarchaeal amoA genes in the coastal Arctic Ocean during summer and winter over 2 years. Summer and winter betaproteobacterial amoA clone libraries were significantly different, although the gene sequences were similar to those found in temperate and polar environments. Betaproteobacterial and crenarchaeal amoA genes were 30- to 115-fold more abundant during the winter than during the summer in both years of the study. Archaeal amoA genes were more abundant than betaproteobacterial amoA genes in the first year, but betaproteobacterial amoA was more abundant than archaeal amoA the following year. The ratio of archaeal amoA gene copies to marine group I crenarchaeal 16S rRNA genes averaged 2.9 over both seasons and years, suggesting that ammonia oxidation was common in Crenarchaea at this location. Potential nitrification rates, as well as the total amoA gene abundance, were highest in the winter when competition with phytoplankton was minimal and ammonium concentrations were the highest. These results suggest that ammonium concentrations were important in determining the rates of ammonia oxidation and the abundance of ammonia-oxidizing Betaproteobacteria and Crenarchaea. PMID- 21239543 TI - Detection of Shiga toxin-producing Escherichia coli serotypes O26:H11, O103:H2, O111:H8, O145:H28, and O157:H7 in raw-milk cheeses by using multiplex real-time PCR. AB - Shiga toxin (Stx)-producing Escherichia coli (STEC) strains are a diverse group of food-borne pathogens with various levels of virulence for humans. In this study, we describe the use of a combination of multiple real-time PCR assays for the screening of 400 raw-milk cheeses for the five main pathogenic STEC serotypes (O26:H11, O103:H2, O111:H8, O145:H28, and O157:H7). The prevalences of samples positive for stx, intimin-encoding gene (eae), and at least one of the five O group genetic markers were 29.8%, 37.3%, and 55.3%, respectively. The H2, H7, H8, H11, and H28 fliC alleles were highly prevalent and could not be used as reliable targets for screening. Combinations of stx, eae variants, and O genetic markers, which are typical of the five targeted STEC serotypes, were detected by real-time PCR in 6.5% of the cheeses (26 samples) and included stx-wzx(O26)-eae-beta1 (4.8%; 19 samples), stx-wzx(O103)-eae-epsilon (1.3%; five samples), stx ihp1(O145)-eae-gamma1 (0.8%; three samples), and stx-rfbE(O157)-eae-gamma1 (0.3%; one sample). Twenty-eight immunomagnetic separation (IMS) assays performed on samples positive for these combinations allowed the recovery of seven eaebeta1 positive STEC O26:H11 isolates, whereas no STEC O103:H2, O145:H28, or O157:H7 strains could be isolated. Three stx-negative and eaebeta1-positive E. coli O26:[H11] strains were also isolated from cheeses by IMS. Colony hybridization allowed us to recover STEC from stx-positive samples for 15 out of 45 assays performed, highlighting the difficulties encountered in STEC isolation from dairy products. The STEC O26:H11 isolates shared the same virulence genetic profile as enterohemorrhagic E. coli (EHEC) O26:H11, i.e., they carried the virulence associated genes EHEC-hlyA, katP, and espP, as well as genomic O islands 71 and 122. Except for one strain, they all contained the stx1 variant only, which was reported to be less frequently associated with human cases than stx2. Pulsed field gel electrophoresis (PFGE) analysis showed that they displayed high genetic diversity; none of them had patterns identical to those of human O26:H11 strains investigated here. PMID- 21239544 TI - Contribution of the Klebsiella pneumoniae capsule to bacterial aggregate and biofilm microstructures. AB - We studied the interaction between capsule production and hydrodynamic growth conditions on the internal and macroscopic structure of biofilms and spontaneously formed aggregates of Klebsiella pneumoniae. Wild-type and capsule deficient strains were studied as biofilms and under strong and mild hydrodynamic conditions. Internal organization of multicellular structures was determined with a novel image-processing algorithm for feature extraction from high-resolution confocal microscopy. Measures included interbacterial spacing and local angular alignment of individual bacteria. Macroscopic organization was measured via the size distribution of aggregate populations forming under various conditions. Compared with wild-type organisms, unencapsulated mutant organisms formed more organized aggregates with less variability in interbacterial spacing and greater interbacterial angular alignment. Internal aggregate structure was not detectably affected by the severity of hydrodynamic growth conditions. However, hydrodynamic conditions affected both wild-type and mutant aggregate size distributions. Bacteria grown under high-speed shaking conditions (i.e., at Reynolds' numbers beyond the laminar-turbulent transition) formed few multicellular aggregates while clumpy growth was common in bacteria grown under milder conditions. Our results indicate that both capsule and environment contribute to the structure of communities of K. pneumoniae, with capsule exerting influence at an interbacterial length scale and fluid dynamic forces affecting overall particle size. PMID- 21239545 TI - Ammonium availability affects the ratio of ammonia-oxidizing bacteria to ammonia oxidizing archaea in simulated creek ecosystems. AB - The ammonia-oxidizing microbial community colonizing clay tiles in flow channels changed in favor of ammonia-oxidizing bacteria during a 12-week incubation period even at originally high ratios of ammonia-oxidizing archaea to ammonia-oxidizing bacteria (AOB). AOB predominance was established more rapidly in flow channels incubated at 350 MUM NH(4)(+) than in those incubated at 50 or 20 MUM NH(4)(+). Biofilm-associated potential nitrification activity was first detected after 28 days and was positively correlated with bacterial but not archaeal amoA gene copy numbers. PMID- 21239546 TI - Survival of Escherichia coli, Enterococci, and Campylobacter spp. in sheep feces on pastures. AB - The survival of enteric bacteria in 10 freshly collected sheep fecal samples on pastures was measured in each of four seasons. Ten freshly collected feces were placed on pasture, and concentrations of Escherichia coli, enterococci, and Campylobacter spp. were monitored until exhaustion of the fecal samples. In all four seasons, there was an increase in enterococcal concentrations by up to 3 orders of magnitude, with peak concentrations recorded between 11 and 28 days after deposition. E. coli concentrations increased in three out of four seasons by up to 1.5 orders of magnitude, with peak concentrations recorded between 8 and 14 days after deposition. The apparent growth of E. coli and enterococci was strongly influenced by the initial water content of the feces and the moisture gained during periods of rehydration following rainfalls. Conversely, the results suggested that dehydration promoted inactivation. Campylobacter spp. did not grow and were rapidly inactivated at a rate that tended to be faster at higher temperatures. Pulsed-field gel electrophoresis (PFGE) of a selection of Campylobacter spp. suggested that these survival data are applicable to a range of Campylobacter spp., including the most frequently isolated PFGE genotype from sheep in New Zealand, and to genotypes previously observed to cause disease in humans. The results of this study are currently being incorporated into a fecal microbe reservoir model that is designed to assist water managers' abilities to estimate microbial loads on pastures grazed by sheep, including the influence of factors such as rainfall and temperature. PMID- 21239547 TI - Stress survival islet 1 (SSI-1) survey in Listeria monocytogenes reveals an insert common to listeria innocua in sequence type 121 L. monocytogenes strains. AB - Listeria monocytogenes strains (n = 117) were screened for the presence of stress survival islet 1 (SSI-1). SSI-1(+) strains (32.5%) belonged mainly to serotypes 1/2c, 3b, and 3c. All sequence type 121 (ST-121) strains included (n = 7) possessed homologues to Listeria innocua genes lin0464 and lin0465 instead of SSI 1. PMID- 21239548 TI - Detection of Cryptosporidium molnari oocysts from fish by fluorescent-antibody staining assays for cryptosporidium spp. affecting humans. AB - Three direct fluorescent-antibody staining assay kits for the detection of zoonotic Cryptosporidium species were used to detect Cryptosporidium molnari from Murray cod, and the cryptosporidia were characterized by using small-subunit (SSU) ribosomal DNA (rDNA). To facilitate rapid diagnosis of infection, this study demonstrated that all three kits detected fresh C. molnari and two kits detected formalin-fixed oocysts. PMID- 21239549 TI - Diversity of multidrug-resistant salmonella enterica strains associated with cattle at harvest in the United States. AB - The prevalence and diversity of multidrug-resistant (MDR) Salmonella enterica strains associated with cattle at harvest in the United States were examined. Hides and carcasses of cattle were sampled at processing plants (n = 6) located in four geographically distant regions from July 2005 to April 2006. The mean prevalences of Salmonella on hides, preevisceration carcasses (immediately after hide removal), and postintervention carcasses (in the chiller and after the full complement of interventions) were 89.6%, 50.2%, and 0.8%, respectively. The values for MDR Salmonella enterica strains (defined as those resistant to two or more antimicrobials) as percentages of Salmonella prevalence were 16.7% (95% confidence interval [CI], 8.3 to 25.1%; median percent prevalence, 6.9%), 11.7% (95% CI, 4.4 to 19.0%; median, 4.8%), and 0.33% (95% CI, -0.3 to 0.70%; median, 0%), respectively. In this study, 16,218 Salmonella hide and carcass isolates were screened for antimicrobial resistance. Of these, 978 (6.0%) unique MDR S. enterica isolates were identified and serotyped and their XbaI pulsed-field gel electrophoresis (PFGE) profiles determined. The predominant MDR S. enterica serotypes observed were Newport (53.1%), Typhimurium (16.6%), and Uganda (10.9%). Differences in MDR S. enterica prevalence were detected, and PFGE analysis revealed both epidemic clusters (profiles found in plants in multiple regions/seasons) and endemic clusters (profiles observed in plants in limited regions/seasons) within several of the MDR serotypes examined. Despite these differences, multiple-hurdle processing interventions employed at all plants were found to be quite effective and decreased Salmonella carcass contamination by 98.4% (95% CI, 97.6 to 99.7%). PMID- 21239550 TI - Entianin, a novel subtilin-like lantibiotic from Bacillus subtilis subsp. spizizenii DSM 15029T with high antimicrobial activity. AB - Lantibiotics, such as nisin and subtilin, are lanthionine-containing peptides that exhibit antimicrobial as well as pheromone-like autoinducing activity. Autoinduction is specific for each lantibiotic, and reporter systems for nisin and subtilin autoinduction are available. In this report, we used the previously reported subtilin autoinduction bioassay in combination with mass spectrometric analyses to identify the novel subtilin-like lantibiotic entianin from Bacillus subtilis subsp. spizizenii DSM 15029(T). Linearization of entianin using Raney nickel-catalyzed reductive cleavage enabled, for the first time, the use of tandem mass spectrometry for the fast and efficient determination of an entire lantibiotic primary structure, including posttranslational modifications. The amino acid sequence determined was verified by DNA sequencing of the etnS structural gene, which confirmed that entianin differs from subtilin at 3 amino acid positions. In contrast to B. subtilis ATCC 6633, which produces only small amounts of unsuccinylated subtilin, B. subtilis DSM 15029(T) secretes considerable amounts of unsuccinylated entianin. Entianin was very active against several Gram-positive pathogens, such as Staphylococcus aureus and Enterococcus faecalis. The growth-inhibiting activity of succinylated entianin (S-entianin) was much lower than that of unsuccinylated entianin: a 40-fold higher concentration was required for inhibition. For succinylated subtilin (S subtilin), a concentration 100-fold higher than that of unsuccinylated entianin was required to inhibit the growth of a B. subtilis test strain. This finding was in accordance with a strongly reduced sensing of cellular envelope stress provided by S-entianin relative to that of entianin. Remarkably, S-entianin and S subtilin showed considerable autoinduction activity, clearly demonstrating that autoinduction and antibiotic activity underlie different molecular mechanisms. PMID- 21239551 TI - Persistence of free-living protozoan communities across rearing cycles in commercial poultry houses. AB - The introduction and survival of zoonotic bacterial pathogens in poultry farming have been linked to bacterial association with free-living protozoa. To date, however, no information is available on the persistence of protozoan communities in these environments across consecutive rearing cycles and how it is affected by farm- and habitat-specific characteristics and management strategies. We therefore investigated the spatial and temporal dynamics of free-living protozoa in three habitats (pipeline, water, and miscellaneous samples) in three commercial poultry houses across three rearing cycles by using the molecular fingerprinting technique denaturing gradient gel electrophoresis (DGGE). Our study provides strong evidence for the long-term (ca. 6-month) persistence of protozoa in broiler houses across consecutive rearing cycles. Various free-living protozoa (flagellates, ciliates, and amoebae), including known vectors of bacterial pathogens, were observed during the down periods in between rearing cycles. In addition, multivariate analysis and variation partitioning showed that the protozoan community structure in the broiler houses showed almost no change across rearing cycles and remained highly habitat and farm specific. Unlike in natural environments, protozoan communities inside broiler houses are therefore not seasonal. Our results imply that currently used biosecurity measures (cleaning and disinfection) applied during the down periods are not effective against many protozoans and therefore cannot prevent potential cross contamination of bacterial pathogens via free-living protozoa between rearing cycles. PMID- 21239552 TI - Comprehensive approaches to molecular biomarker discovery for detection and identification of Cronobacter spp. (Enterobacter sakazakii) and Salmonella spp. AB - Cronobacter spp. (formerly Enterobacter sakazakii) and Salmonella spp. are increasingly implicated internationally as important microbiological contaminants in low-moisture food products, including powdered infant formula. Estimates indicate that 40 to 80% of infants infected with Cronobacter sakazakii and/or Salmonella in the United States may not survive the illness. A systematic approach, combining literature-based data mining, comparative genome analysis, and the direct sequencing of PCR products of specific biomarker genes, was used to construct an initial collection of genes to be targeted. These targeted genes, particularly genes encoding virulence factors and genes responsible for unique phenotypes, have the potential to function as biomarker genes for the identification and differentiation of Cronobacter spp. and Salmonella from other food-borne pathogens in low-moisture food products. In this paper, a total of 58 unique Salmonella gene clusters and 126 unique potential Cronobacter biomarkers and putative virulence factors were identified. A chitinase gene, a well-studied virulence factor in fungi, plants, and bacteria, was used to confirm this approach. We found that the chitinase gene has very low sequence variability and/or polymorphism among Cronobacter, Citrobacter, and Salmonella, while differing significantly in other food-borne pathogens, either by sequence blasting or experimental testing, including PCR amplification and direct sequencing. This computational analysis for Cronobacter and Salmonella biomarker identification and the preliminary laboratory studies are only a starting point; thus, PCR and array-based biomarker verification studies of these and other food borne pathogens are currently being conducted. PMID- 21239553 TI - Persistent infection or successive reinfection of deer mice with Bartonella vinsonii subsp. arupensis. AB - Bartonella infections are common in rodents. From 1994 to 2006, longitudinal studies of a rodent community, consisting mainly of deer mice (Peromyscus maniculatus), were conducted in southwestern Colorado to study hantaviruses. Blood samples from deer mice captured one or more times during the period 2003 to 2006 (n = 737) were selected to study bartonellae in deer mice. Bartonellae were found to be widely distributed in that population, with an overall prevalence of 82.4% (607/737 mice). No correlation was found between bartonella prevalence and deer mouse weight or sex. Persistent or successive infections with bartonellae were observed in deer mice captured repeatedly, with a prevalence of 83.9% (297/354), and the infection appeared to last for more than 1 year in some of them. Persistent infection with bartonellae may explain the high prevalence of these bacteria in deer mice at this site and, perhaps, elsewhere. Genetic analysis demonstrated that deer mouse-borne bartonella isolates at this site belong to the same species, B. vinsonii subsp. arupensis, demonstrating a specific relationship between B. vinsonii subsp. arupensis and deer mice. PMID- 21239554 TI - Differentiation of "Candidatus Liberibacter asiaticus" isolates by variable number tandem-repeat analysis. AB - Four highly polymorphic simple sequence repeat (SSR) loci were selected and used to differentiate 84 Japanese isolates of "Candidatus Liberibacter asiaticus." The Nei's measure of genetic diversity values for these four SSRs ranged from 0.60 to 0.86. The four SSR loci were also highly polymorphic in four isolates from Taiwan and 12 isolates from Indonesia. PMID- 21239555 TI - Gene cluster conferring streptomycin, sulfonamide, and tetracycline resistance in Escherichia coli O157:H7 phage types 23, 45, and 67. AB - Multidrug resistance to streptomycin, sulfonamide, and tetracycline (AMR-SSuT) was identified in 156 of 171 isolates of Escherichia coli O157:H7 of phage types 23, 45, and 67. In 154 AMR-SSuT isolates, resistance was encoded by strA, strB, sul2, and tet(B), which in 59 of 63 tested isolates were found clustered together on the chromosome within the cdiA locus. PMID- 21239557 TI - Fate of Mycobacterium avium subsp. paratuberculosis after application of contaminated dairy cattle manure to agricultural soils. AB - Details regarding the fate of Mycobacterium avium subsp. paratuberculosis (basonym, Mycobacterium paratuberculosis) after manure application on grassland are unknown. To evaluate this, intact soil columns were collected in plastic pipes (lysimeters) and placed under controlled conditions to test the effect of a loamy or sandy soil composition and the amount of rainfall on the fate of M. paratuberculosis applied to the soil surface with manure slurry. The experiment was organized as a randomized design with two factors and three replicates. M. paratuberculosis-contaminated manure was spread on the top of the 90-cm soil columns. After weekly simulated rainfall applications, water drainage samples (leachates) were collected from the base of each lysimeter and cultured for M. paratuberculosis using Bactec MGIT ParaTB medium and supplements. Grass was harvested, quantified, and tested from each lysimeter soil surface. The identity of all probable M. paratuberculosis isolates was confirmed by PCR for IS900 and F57 genetic elements. There was a lag time of 2 months after each treatment before M. paratuberculosis was found in leachates. The greatest proportions of M. paratuberculosis-positive leachates were from sandy-soil lysimeters in the manure treated group receiving the equivalent of 1,000 mm annual rainfall. Under the higher rainfall regimen (2,000 mm/year), M. paratuberculosis was detected more often from lysimeters with loamy soil than sandy soil. Among all lysimeters, M. paratuberculosis was detected more often in grass clippings than in lysimeter leachates. At the end of the trial, lysimeters were disassembled and soil cultured at different depths, and we found that M. paratuberculosis was recovered only from the uppermost levels of the soil columns in the treated group. Factors associated with M. paratuberculosis presence in leachates were soil type and soil pH (P < 0.05). For M. paratuberculosis presence in grass clippings, only manure application showed a significant association (P < 0.05). From these findings we conclude that this pathogen tends to move slowly through soils (faster through sandy soil) and tends to remain on grass and in the upper layers of pasture soil, representing a clear infection hazard for grazing livestock and a potential for the contamination of runoff after heavy rains. PMID- 21239556 TI - Seasonal changes of freshwater ammonia-oxidizing archaeal assemblages and nitrogen species in oligotrophic alpine lakes. AB - The annual changes in the composition and abundance of ammonia-oxidizing archaea (AOA) were analyzed monthly in surface waters of three high mountain lakes within the Limnological Observatory of the Pyrenees (LOOP; northeast Spain) using both 16S rRNA and functional (ammonia monooxygenase gene, amoA) gene sequencing as well as quantitative PCR amplification. The set of biological data was related to changes in nitrogen species and to other relevant environmental variables. The whole archaeal assemblage was dominated by phylotypes closely related to the crenarchaeal 1.1a group (58% +/- 18% of total 16S rRNA gene sequences), and consistent structural changes were detected during the study. Water temperature was the environmental variable that better explained spring, summer, and winter (ice-covered lakes) archaeal assemblage structure. The amoA gene was detected year round, and seasonal changes in amoA gene composition were well correlated with changes in the archaeal 16S rRNA gene pool. In addition, copy numbers of both the specific 1.1a group 16 rRNA and archaeal amoA genes were well correlated, suggesting that most freshwater 1.1a Crenarchaeota had the potential to carry out ammonia oxidation. Seasonal changes in the diversity and abundance of AOA (i.e., amoA) were better explained by temporal changes in ammonium, the substrate for nitrification, and mostly nitrite, the product of ammonia oxidation. Lacustrine amoA gene sequences grouped in coherent freshwater phylogenetic clusters, suggesting that freshwater habitats harbor typical amoA containing ecotypes, which is different from soils and seas. We observed within the freshwater amoA gene sequence pool a high genetic divergence (translating to up to 32% amino acid divergence) between the spring and the remaining AOA assemblages. This suggests that different AOA ecotypes are adapted to different temporal ecological niches in these lakes. PMID- 21239558 TI - Terminal oxidase diversity and function in "Metallosphaera yellowstonensis": gene expression and protein modeling suggest mechanisms of Fe(II) oxidation in the sulfolobales. AB - "Metallosphaera yellowstonensis" is a thermoacidophilic archaeon isolated from Yellowstone National Park that is capable of autotrophic growth using Fe(II), elemental S, or pyrite as electron donors. Analysis of the draft genome sequence from M. yellowstonensis strain MK1 revealed seven different copies of heme copper oxidases (subunit I) in a total of five different terminal oxidase complexes, including doxBCEF, foxABCDEFGHIJ, soxABC, and the soxM supercomplex, as well as a novel hypothetical two-protein doxB-like polyferredoxin complex. Other genes found in M. yellowstonensis with possible roles in S and or Fe cycling include a thiosulfate oxidase (tqoAB), a sulfite oxidase (som), a cbsA cytochrome b(558/566), several small blue copper proteins, and a novel gene sequence coding for a putative multicopper oxidase (Mco). Results from gene expression studies, including reverse transcriptase (RT) quantitative PCR (qPCR) of cultures grown autotrophically on either Fe(II), pyrite, or elemental S showed that the fox gene cluster and mco are highly expressed under conditions where Fe(II) is an electron donor. Metagenome sequence and gene expression studies of Fe-oxide mats confirmed the importance of fox genes (e.g., foxA and foxC) and mco under Fe(II)-oxidizing conditions. Protein modeling of FoxC suggests a novel lysine-lysine or lysine arginine heme B binding domain, indicating that it is likely the cytochrome component of a heterodimer complex with foxG as a ferredoxin subunit. Analysis of mco shows that it encodes a novel multicopper blue protein with two plastocyanin type I copper domains that may play a role in the transfer of electrons within the Fox protein complex. An understanding of metabolic pathways involved in aerobic iron and sulfur oxidation in Sulfolobales has broad implications for understanding the evolution and niche diversification of these thermophiles as well as practical applications in fields such as bioleaching of trace metals from pyritic ores. PMID- 21239559 TI - Inhibition of Streptococcus mutans biofilm formation by Streptococcus salivarius FruA. AB - The oral microbial flora consists of many beneficial species of bacteria that are associated with a healthy condition and control the progression of oral disease. Cooperative interactions between oral streptococci and the pathogens play important roles in the development of dental biofilms in the oral cavity. To determine the roles of oral streptococci in multispecies biofilm development and the effects of the streptococci in biofilm formation, the active substances inhibiting Streptococcus mutans biofilm formation were purified from Streptococcus salivarius ATCC 9759 and HT9R culture supernatants using ion exchange and gel filtration chromatography. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry analysis was performed, and the results were compared to databases. The S. salivarius HT9R genome sequence was determined and used to indentify candidate proteins for inhibition. The candidates inhibiting biofilms were identified as S. salivarius fructosyltransferase (FTF) and exo-beta-d-fructosidase (FruA). The activity of the inhibitors was elevated in the presence of sucrose, and the inhibitory effects were dependent on the sucrose concentration in the biofilm formation assay medium. Purified and commercial FruA from Aspergillus niger (31.6% identity and 59.6% similarity to the amino acid sequence of FruA from S. salivarius HT9R) completely inhibited S. mutans GS-5 biofilm formation on saliva-coated polystyrene and hydroxyapatite surfaces. Inhibition was induced by decreasing polysaccharide production, which is dependent on sucrose digestion rather than fructan digestion. The data indicate that S. salivarius produces large quantities of FruA and that FruA alone may play an important role in multispecies microbial interactions for sucrose-dependent biofilm formation in the oral cavity. PMID- 21239560 TI - Molecular epidemiology of Salmonella enterica serovar typhimurium isolates from cattle in hokkaido, Japan: evidence of clonal replacement and characterization of the disseminated clone. AB - The molecular epidemiology of 545 Salmonella enterica serovar Typhimurium isolates collected between 1977 and 2009 from cattle in Hokkaido, Japan, was investigated using pulsed-field gel electrophoresis (PFGE). Nine main clusters were identified from 116 PFGE patterns. Cluster I comprised 248 isolates, 243 of which possessed a sequence specific to definitive phage type 104 (DT104) or U302. The cluster I isolates were dominant in 1993 to 2003, but their numbers declined beginning in 2004. Beginning in 2002, an increase was observed in the number of cluster VII isolates, consisting of 21 PFGE patterns comprising 165 isolates. A total of 116 isolates representative of the 116 PFGE profiles were analyzed by multilocus variable-number tandem-repeat analysis (MLVA). Other than two drug sensitive isolates, 19 isolates within cluster VII were classified in the same cluster by MLVA. Among the cluster VII isolates, an antibiotic resistance type showing resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, tetracycline, kanamycin, cefazolin, and sulfamethoxazole-trimethoprim and a resistance type showing resistance to ampicillin, streptomycin, sulfonamides, tetracycline, and kanamycin were found in 23 and 125 isolates, respectively. In the 19 isolates representative of cluster VII, the bla(TEM-1) gene was found on a Salmonella serotype Typhimurium virulence plasmid, which was transferred to Escherichia coli by electroporation along with resistance to two to four other antimicrobials. Genomic analysis by subtractive hybridization and plasmid analysis suggested that the bla(TEM-1)-carrying virulence plasmid has a mosaic structure composed of elements of different origin. These results indicate an emerging multidrug-resistant S. Typhimurium clone carrying a virulence-resistance plasmid among cattle in Hokkaido, Japan. PMID- 21239561 TI - A new wine Saccharomyces cerevisiae killer toxin (Klus), encoded by a double stranded rna virus, with broad antifungal activity is evolutionarily related to a chromosomal host gene. AB - Wine Saccharomyces cerevisiae strains producing a new killer toxin (Klus) were isolated. They killed all the previously known S. cerevisiae killer strains, in addition to other yeast species, including Kluyveromyces lactis and Candida albicans. The Klus phenotype is conferred by a medium-size double-stranded RNA (dsRNA) virus, Saccharomyces cerevisiae virus Mlus (ScV-Mlus), whose genome size ranged from 2.1 to 2.3 kb. ScV-Mlus depends on ScV-L-A for stable maintenance and replication. We cloned and sequenced Mlus. Its genome structure is similar to that of M1, M2, or M28 dsRNA, with a 5'-terminal coding region followed by two internal A-rich sequences and a 3'-terminal region without coding capacity. Mlus positive strands carry cis-acting signals at their 5' and 3' termini for transcription and replication similar to those of killer viruses. The open reading frame (ORF) at the 5' portion codes for a putative preprotoxin with an N terminal secretion signal, potential Kex2p/Kexlp processing sites, and N glycosylation sites. No sequence homology was found either between the Mlus dsRNA and M1, M2, or M28 dsRNA or between Klus and the K1, K2, or K28 toxin. The Klus amino acid sequence, however, showed a significant degree of conservation with that of the product of the host chromosomally encoded ORF YFR020W of unknown function, thus suggesting an evolutionary relationship. PMID- 21239562 TI - Quantification of ventricular resynchronization reserve by radionuclide phase analysis in heart failure patients: a prospective long-term study. AB - BACKGROUND: Phase analysis, developed to assess dyssynchrony from ECG-gated radionuclide ventriculography, has shown promising results. We hypothesized that quantifying the cardiac resynchronization reserve, that is, the extent of response to cardiac resynchronization therapy (CRT), by radionuclide imaging could potentially identify patients who are best suited for CRT. METHODS AND RESULTS: Seventy-four patients ages 64.8+/-10.1 years were prospectively studied from July 2004 to July 2006, of whom 62.2% and 37.8%, respectively, were in New York Heart Association class 3 and 4. Mean QRS width was 173+/-25 ms. ECG-gated radionuclide ventriculography to quantify interventricular and intraventricular dyssynchrony was performed at baseline with and without CRT and at the 3-month follow-up visit. Amino-terminal-pro-brain natriuretic peptide (NT-pro-BNP) levels were also determined at baseline and at 3 months. During a mean follow-up of 10.1+/-7.6 months, there were 37 (50%) clinical events that defined the nonresponder group, including cardiac death or readmission for worsening heart failure. In multivariate Cox model analysis, higher NT-pro-BNP blood levels were associated with a significant increase in the risk for event (hazard ratio=1.085 for a 100 pg/L increase in NT-pro-BNP; 95% confidence interval, 1.014 to 1.161). Each 10 degrees elevation in intraventricular dyssynchrony was associated with a decrease in the risk of events (hazard ratio=0.456, 95% confidence interval, 0.304 to 0.683). Receiver operating characteristic curve analysis demonstrated that an interventricular dyssynchrony cutoff value of 25.5 degrees for intraventricular synchrony yielded 91.4% sensitivity and 84.4% specificity for predicting a good response to CRT. CONCLUSIONS: The quantification of interventricular dyssynchrony with radionuclide phase analysis suggests that early postimplantation interventricular dyssynchrony may provide identification of CRT responders. PMID- 21239563 TI - Virgibacillus alimentarius sp. nov., isolated from a traditional Korean food. AB - A novel, Gram-positive, rod-shaped, motile, endospore-forming, halophilic bacterial strain, J18(T), was isolated from a traditional salt-fermented seafood made of gizzard shad in Korea. Colonies were convex, cream-coloured and 1.0-2.0 mm in diameter after incubation for 3 days on marine agar. Growth occurred at pH 7.0-11.0 (optimum, pH 10.0), at 4-40 degrees C (optimum, 37 degrees C) and in the presence of 0-30% NaCl (optimum, 9-10%). On the basis of 16S rRNA gene sequence analysis, strain J18(T) was related most closely to Virgibacillus byunsanensis ISL-24(T) (96.3% similarity), Virgibacillus carmonensis LMG 20964(T) (96.2%), Virgibacillus halodenitrificans DSM 10037(T) (96.0%), Virgibacillus arcticus Hal 1(T) (95.5%) and Virgibacillus necropolis LMG 19488(T) (95.5%). The major fatty acids were anteiso-C(15:0) and anteiso-C(17:0). The DNA G+C content of strain J18(T) was 37.0 mol%. The cell-wall peptidoglycan was of the meso diaminopimelic acid type. The major quinone was menaquinone 7 (MK-7). Based on phenotypic, chemotaxonomic and phylogenetic data, strain J18(T) is considered to represent a novel species of the genus Virgibacillus, for which the name Virgibacillus alimentarius sp. nov. is proposed. The type strain is J18(T) (=KACC 14624(T) =JCM 16994(T)). PMID- 21239564 TI - Pyrococcus yayanosii sp. nov., an obligate piezophilic hyperthermophilic archaeon isolated from a deep-sea hydrothermal vent. AB - An obligate piezophilic anaerobic hyperthermophilic archaeon, designated strain CH1(T), was isolated from a hydrothermal vent site named 'Ashadze', which is located on the Mid-Atlantic Ridge at a depth of 4100 m. Enrichment and isolation of the strain were carried out at 95 degrees C under a hydrostatic pressure of 42 MPa. Cells of strain CH1(T) were highly motile irregular cocci with a diameter of ~1-1.5 um. Growth was recorded at 80-108 degrees C (optimum 98 degrees C) and at pressures of 20-120 MPa (optimum 52 MPa). No growth was observed under atmospheric pressures at 60-110 degrees C. Growth was observed at pH 6.0-9.5 (optimum 7.5-8.0) and in 2.5-5.5% (w/v) NaCl (optimum 3.5%). Strain CH1(T) was strictly anaerobic and grew on complex proteinaceous substrates, such as yeast extract, Peptone, and casein, as well as on sucrose, starch, chitin, pyruvate, acetate and glycerol without electron acceptors. The G+C content of the genomic DNA was 49.0+/-0.5 mol%. Analysis of 16S rRNA gene sequences revealed that strain CH1(T) belongs to the genus Pyrococcus. Based on its physiological properties and similarity levels between ribosomal proteins, strain CH1(T) represents a novel species, for which the name Pyrococcus yayanosii sp. nov. is proposed. The type strain is CH1(T) (=JCM 16557). This strain is also available by request from the Souchotheque de Bretagne (catalogue LMBE) culture collection (collection no. 3310). PMID- 21239565 TI - Aquisphaera giovannonii gen. nov., sp. nov., a planctomycete isolated from a freshwater aquarium. AB - As part of a study of the diversity of planctomycetes, two novel strains, designated OJF2(T) and OJF8, were isolated from the sediments of a freshwater aquarium. The organisms were chemoheterotrophic, spherical and pink-pigmented, had an optimum growth temperature of about 30-35 degrees C and an optimum pH for growth of around 7.5-8.5. The predominant fatty acids were C(18:1)omega9c and C(16:0). The two strains were able to assimilate several sugars and organic acids. 16S rRNA gene sequence analysis confirmed the affiliation of these organisms to the phylum 'Planctomycetes'; they showed highest similarity to the type strains of Singulisphaera acidiphila (92.4%) and Isosphaera pallida (91.9%). On the basis of physiological, biochemical and chemotaxonomic characteristics, strains OJF2(T) and OJF8 are considered to represent a novel species of a new genus of the order Planctomycetales, for which the name Aquisphaera giovannonii gen. nov., sp. nov. is proposed. The type strain of Aquisphaera giovannonii is OJF2(T) (=CECT 7510(T) =DSM 22561(T)). PMID- 21239566 TI - Acinetobacter rudis sp. nov., isolated from raw milk and raw wastewater. AB - Two bacterial strains, G30(T) and A1PC16, isolated respectively from raw milk and raw wastewater, were characterized using a polyphasic approach. Chemotaxonomic characterization supported the inclusion of these strains in the genus Acinetobacter, with Q-8 and Q-9 as the major respiratory quinones, genomic DNA G+C contents within the range observed for this genus (38-47 mol%) and C(16:0), C(18:1)omega9c and C(16:1)omega7c/iso-C(15:0) 2-OH as the predominant fatty acids. The observation of 16S rRNA gene sequence similarity lower than 97% with other Acinetobacter species with validly published names led to the hypothesis that these isolates could represent a novel species. This hypothesis was supported by comparative analysis of partial sequences of the genes rpoB and gyrB, which showed that strains G30(T) and A1PC16 did not cluster with any species with validly published names, forming a distinct lineage. DNA-DNA hybridizations confirmed that the two strains were members of the same species, which could be distinguished from their congeners by several phenotypic characteristics. On the basis of these arguments, it is proposed that strains G30(T) and A1PC16 represent a novel species, for which the name Acinetobacter rudis sp. nov. is proposed. The type strain is strain G30(T) (=LMG 26107(T) =CCUG 57889(T) =DSM 24031(T) =CECT 7818(T)). PMID- 21239567 TI - Micrococcus lactis sp. nov., isolated from dairy industry waste. AB - A Gram-positive, yellow-pigmented, actinobacterial strain, DW152(T), was isolated from a dairy industry effluent treatment plant. 16S rRNA gene sequence analysis indicated that strain DW152(T) exhibited low similarity with many species with validly published names belonging to the genera Micrococcus and Arthrobacter. However, phenotypic properties including chemotaxonomic markers affiliated strain DW152(T) to the genus Micrococcus. Strain DW152(T) had ai-C(15:0) and i-C(15:0) as major cellular fatty acids, and MK-8(H(2)) as the major menaquinone. The cell wall peptidoglycan of strain DW152(T) had l-lysine as the diagnostic amino acid and the type was A4alpha. The DNA G+C content of strain DW152(T) was 68.0 mol%. In 16S rRNA gene sequence analysis, strain DW152(T) exhibited significant similarity with Micrococcus terreus NBRC 104258(T), but the mean value of DNA-DNA relatedness between these strains was only 42.3%. Moreover, strain DW152(T) differed in biochemical and chemotaxonomic characteristics from M. terreus and other species of the genus Micrococcus. Based on the above differences, we conclude that strain DW152(T) should be treated as a novel species of the genus Micrococcus, for which the name Micrococcus lactis sp. nov. is proposed. The type strain of Micrococcus lactis sp. nov. is DW152(T) (=MTCC10523(T) =DSM 23694(T)). PMID- 21239568 TI - A comparative study of the accuracy and reliability of multidetector computed tomography and cone beam computed tomography in the assessment of dental implant site dimensions. AB - OBJECTIVES: The aim of this study was to investigate the accuracy and reliability of linear measurements of edentulous ridges recorded from 16-row multidetector CT (MDCT) images and cone beam CT (CBCT) images acquired using a flat panel detector (FPD) with a large field of view (FOV), both independently and in comparison with each other. METHODS: Edentulous areas of human dry skulls were marked with gutta percha markers to standardize the plane of the transverse cross-sections and path of measurements. The skulls were imaged using a 16-row MDCT scanner and a CBCT device with a large FOV and a FPD. Ridge dimensions were recorded from reformatted sections by two observers and compared with measurements recorded directly from the bone. The measurement errors and intra and interexaminer reliability were calculated for each modality and compared with each other. RESULTS: The overall mean of the absolute errors was 0.75 mm for MDCT and 0.49 mm for CBCT. The mean of the CBCT absolute errors was smaller than that of the MDCT absolute errors for the overall data, as well as for the site-specific data. The intraexaminer reliability score was 0.994 for MDCT and 0.995 for CBCT. The interexaminer reliability was 0.985 for MDCT and 0.958 for CBCT. CONCLUSIONS: Both MDCT and CBCT were associated with a clinically and statistically significant measurement error. CBCT measurements were significantly more accurate than those of MDCT. The measurements recorded from both modalities had a high inter and intraexaminer reliability. Accuracy of measurements was found to be more operator dependent with CBCT than with MDCT. PMID- 21239569 TI - Magnification rate of digital panoramic radiographs and its effectiveness for pre operative assessment of dental implants. AB - OBJECTIVES: The purpose of this study was to determine the accuracy and effectiveness of digital panoramic radiographs for pre-operative assessment of dental implants. METHODS: We selected 86 patients (221 implants) and calculated the length of the planned implant based on the distance between a selection of critical anatomical structures and the alveolar crest using the scaling tools provided in the digital panoramic system. We analysed the magnification rate and the difference between the actual inserted implant length and planned implant length according to the location of the implant placement and the clarity of anatomical structures seen in the panoramic radiographs. RESULTS: There was no significant difference between the planned implant length and actual inserted implant length (P > 0.05). The magnification rate of the width and length of the inserted implants, seen in the digital panoramic radiographs, was 127.28 +/- 13.47% and 128.22 +/- 4.17%, respectively. The magnification rate of the implant width was largest in the mandibular anterior part and there was a significant difference in the magnification rate of the length of implants between the maxilla and the mandible (P < 0.05). When the clarity of anatomical structures seen in the panoramic radiographs is low, the magnification rate of the width of the inserted implants is significantly higher (P < 0.05), but there is no significant difference between the planned implant length and actual inserted implant length according to the clarity of anatomical structures (P < 0.05). CONCLUSIONS: Digital panoramic radiography can be considered a simple, readily available and considerably accurate pre-operative assessment tool in the vertical dimension for dental implant therapy. PMID- 21239570 TI - The value of magnetic resonance arthrography of the temporomandibular joint in imaging disc adhesions and perforations. AB - OBJECTIVES: This study attempted to validate MR arthrography (MRAr) of the temporomandibular joint (TMJ) in detecting the position, integrity and relations of the articular disc and retrodiscal tissue. METHODS: A total of 20 TMJs from 10 patients with severe TMJ dysfunction underwent MRI and MRAr. A paramagnetic contrast medium was injected into the upper joint compartment to observe possible adhesions and/or leakage into the lower compartment. 15 TMJs were surgically or arthroscopically explored and restored. RESULTS: MRAr was approximately in the same diagnostic value as MRI when locating position, but superior in detecting disc perforations (eight TMJs) and adhesions (seven TMJs) appearing together in four cases. Surgery confirmed radiological findings in all but one case, where arthroscopy and surgery failed to confirm a disc perforation indicated by MRAr. CONCLUSIONS: TMJ MRAr may simultaneously reveal adhesions and perforations. Sensitivity and the probability of false-positive results require further study. PMID- 21239571 TI - Preliminary results of a study comparing conventional radiography with phase contrast radiography for assessing root morphology of mandibular third molars. AB - OBJECTIVES: The aim of this study was to evaluate the usefulness of phase contrast radiography for assessing root morphology of mandibular third molars in comparison with conventional radiography. METHODS: We studied 37 extracted mandibular third molars. One oral surgeon compared the number of roots and root curvature of the extracted teeth on conventional radiographs with those on phase contrast images. RESULTS: The number of roots and root curvature on conventional images differed significantly from those on phase-contrast images. CONCLUSIONS: Our results suggest the possibility that phase-contrast radiography is more useful than conventional radiography for assessing the root morphology of mandibular third molars. PMID- 21239572 TI - Evaluation of effective dose from a RANDO phantom in videofluorography diagnostic procedures for diagnosing dysphagia. AB - OBJECTIVES: Videofluorography (VF) is useful for diagnosing dysphagia; however, few reports have investigated appropriate effective doses for VF. The present study aimed to estimate the effective radiation dose in VF for diagnosis of dysphagia. METHODS: Radiation doses to tissues and organs were measured using the anthropomorphic RANDO woman phantom as an equivalent to the human body. Effective doses were estimated according to the recommendations of the International Commission on Radiological Protection (ICRP) 60 in 1990 and IRCP 103 in 2007. The tissues measured were those recommended by ICRP 60 and ICRP 103 including gonads (ovaries and testes), red bone marrow and tissues in which excessive radiation commonly causes malignant tumours including lung, thyroid gland, stomach, large intestine, liver, oesophagus, bladder, breast, bone marrow, skin, brain and salivary gland. Skin dose was also measured using thermoluminescent dosimeters. RESULTS: Using ICRP 103, the effective dose was estimated as 118.1 MUSv at a tube voltage of 50 kV and 82.4 MUSv at 45 kV. However, using ICRP 60 the effective dose for 1 min of VF was estimated at 62.4 MUSv and 47.2 MUSv under the same exposure conditions. CONCLUSIONS: Using ICRP 103, the effective dose for VF per examination at a total estimation time of 1 min was estimated as approximately 2.5-8.3 times that observed for digital panoramic radiography and 1/12 to 3 times depending on the measurement device for cone beam CT (CBCT). This value can be decreased in the future using a smaller irradiation field and decreased time for examination in VF in the future. PMID- 21239573 TI - A comparison between bitewing radiographs taken with rectangular and circular collimators in UK military dental practices: a retrospective study. AB - OBJECTIVES: The aim of this study was to determine any increase in the incidence of cone cut errors that adversely affected diagnostic yield resulting in more retakes using rectangular collimation with film holders in bitewing radiography. Comparisons were also made with other positioning errors that occurred when bitewings were taken with circular collimation, with and without film holders. METHODS: A preliminary questionnaire was used to determine the year that rectangular collimation was adopted by military dental practice. 3 time-framed subsets, each of 1000 bitewing radiographs, were identified: subset 1, films taken with circular collimators without film holders; subset 2, films taken with circular collimators with film holders; and subset 3, films taken with rectangular collimators with film holders. Each subset was assessed for positioning errors of cone cut, horizontal overlap, vertical distortion and film centring. The chi(2) test was used to test significant differences amongst the three subsets. RESULTS: The use of film holders with circular collimation significantly reduced the incidence of cone cut errors from 21.7% to 3.3%. There was an increase in the incidence of cone cut errors from 3.3% to 20.9% when rectangular collimation was used, but the actual number considered "rejects" was very small, only 0.1% (1 in 1000 films) in subset 2 and 0.3% (3 of 1000 films) in subset 3, when assessed for diagnostic yield. CONCLUSIONS: This study provides evidence that rectangular collimation did not significantly affect the diagnostic yield of bitewing radiographs despite the presence of cone cut. Therefore, all practitioners should adopt rectangular collimation. PMID- 21239574 TI - Pneumatization of the articular eminence on cone beam computed tomography: prevalence, characteristics and a review of the literature. AB - OBJECTIVES: The aim of this study was to determine the prevalence and characteristics of pneumatized articular eminence (PAT) by cone beam CT (CBCT) and to present a review of the PAT literature. METHODS: A retrospective study was performed using sagittal and coronal CBCT images of 514 patients in the Department of Oral and Maxillofacial Radiology, Ataturk University, Turkey. Age and gender were recorded for all patients and, for the cases of PAT, laterality and types were also recorded. The chi(2) test was used. RESULTS: Of the 514 patients, 41 (8.0%) had PAT, of whom 25 were female (61.0%) and 16 were male (39.0%). This difference was not statistically significant (P > 0.05). The age range of the patients with PAT was 15-62 years (mean 30.6 +/- 11.4). Of the 41 patients, 31 (75.6%) had unilateral and 10 (24.4%) had bilateral PAT. 17 (41.5%) PATs were unilocular and 24 (58.5%) were multilocular. CONCLUSIONS: It is possible that PAT is a more frequent condition than is commonly perceived. In differential diagnosis of suspected cases or in cases for which surgical treatment is planned, panoramic radiographs should be supplemented with CBCT. PMID- 21239575 TI - A manufacturer's role in reducing the dose of cone beam computed tomography examinations: effect of beam filtration. AB - OBJECTIVES: The dosimetry of the Kodak 9500 cone beam CT (CBCT) unit (Carestream Health, Rochester, NY) was measured before and after installation of copper filtration. METHODS: Dosimetry of a pre-production Kodak 9500 CBCT unit was compared with a current production unit with 0.4 mm of added filtration and increased kVp. Thermoluminescent dosimeter 100 chips were placed at 24 locations in a RANDO (radiation analogue dosimetry) head phantom (Nuclear Associates, Hicksville, NY). Small, medium and large adult default exposure settings were used in separate dosimeter runs for large and medium field of view (FOV) examinations with both units. Equivalent dose and effective dose were calculated using International Commission on Radiological Protection (ICRP) 1990 and 2007 tissue weights. RESULTS: Estimations of risk using 2007 ICRP calculations increased by an average of 77% for large FOV scans and 125% for the medium FOV scans in comparison with 1990 calculations. With added filtration, effective dose for medium FOV examinations for default settings were: small adult 76 uSv, medium adult 98 uSv, and large adult 166 uSv. Effective doses for large FOV examinations were: small adult 93 uSv, medium adult 163 uSv, and large adult 260 uSv. Effective dose was reduced by an average of 43% in examinations made with increased filtration and adjusted kVp. CONCLUSION: The manufacturer's installation of additional filtration with the adjustment of kVp in the Kodak 9500 CBCT unit resulted in significant patient dose reductions for examinations at all adult default settings. PMID- 21239576 TI - Early victims of X-rays: a tribute and current perception. AB - X-rays were discovered in 1895 and since then much has been written about Wilhelm Roentgen and the events surrounding the discovery. However, there have been only scattered references in the literature about the early workers who dedicated their life, and death, to X-rays. Radiology has come of age since then. Large exposure times have been reduced to milliseconds and there has been a change from analogue to digital. The advent of new and rapidly developing modalities and the ubiquitous presence of cone beam CT (CBCT) highlight the need to remember the early victims of X-rays, especially with the lack of universal guidelines for taking a CBCT scan. The aim of this article is to alert the oral radiologist to exposing patients irrespective of need, and to pay respect to the victims on the 116(th) anniversary of the discovery of X-rays. PMID- 21239577 TI - A case of desmoplastic ameloblastoma arising in the maxillary alveolus: the origin and time-course changes in the early stage of tumour development observed on dental radiographs. AB - In this article we report a case of desmoplastic ameloblastoma in which chronological changes in the early development can be observed on dental radiographs. The tumour grew very slowly and did not appear to have a strong potential for local extension like typical ameloblastomas. Radiological findings of our case suggest the tumour arose from the periodontal membrane. However, it was not possible to obtain conclusive histopathological evidence. PMID- 21239578 TI - Treatment of a branchial sinus tract by sclerotherapy. AB - A 16-year-old female presented with a sinus on the skin just medial to the right clavicle, which had discharged clear fluid on a daily basis for a number of years. A sinogram was performed and showed a long sinus tract extending from the region of the right clavicle to the lateral pharyngeal wall. Surgical treatment would have required an extensive procedure and seemed inappropriate in view of the relatively mild symptoms the patient was experiencing. Instead sclerotherapy was used to induce healing of the lesion. This was performed using 3% sodium tetradecyl sulphate foam delivered via a catheter along the entire length of the tract. There were no immediate complications from this procedure and on review at 1 and 6 weeks post-procedure the patient reported a significant improvement in the fluid discharge. At 1 year post-procedure this improvement had been sustained. The patient did report an occasional discharge from the sinus tract orifice at the base of her neck, but she did not feel that this was a significant problem and declined any further treatment. PMID- 21239579 TI - Two DNA translocases synergistically affect chromosome dimer resolution in Bacillus subtilis. AB - In Bacillus subtilis, chromosome dimers that block complete segregation of sister chromosomes arise in about 15% of exponentially growing cells. Two dedicated recombinases, RipX and CodV, catalyze the resolution of dimers by site-specific recombination at the dif site, which is located close to the terminus region on the chromosome. We show that the two DNA translocases in B. subtilis, SftA and SpoIIIE, synergistically affect dimer resolution, presumably by positioning the dif sites in close proximity, before or after completion of cell division, respectively. Furthermore, we observed that both recombinases, RipX and CodV, assemble on the chromosome at the dif site throughout the cell cycle. The preassembly of recombinases probably ensures that dimer resolution can occur rapidly within a short time window around cell division. PMID- 21239580 TI - Absence of diauxie during simultaneous utilization of glucose and Xylose by Sulfolobus acidocaldarius. AB - Sulfolobus acidocaldarius utilizes glucose and xylose as sole carbon sources, but its ability to metabolize these sugars simultaneously is not known. We report the absence of diauxie during growth of S. acidocaldarius on glucose and xylose as co carbon sources. The presence of glucose did not repress xylose utilization. The organism utilized a mixture of 1 g/liter of each sugar simultaneously with a specific growth rate of 0.079 h(-1) and showed no preference for the order in which it utilized each sugar. The organism grew faster on 2 g/liter xylose (0.074 h(-1)) as the sole carbon source than on an equal amount of glucose (0.022 h( 1)). When grown on a mixture of the two carbon sources, the growth rate of the organism increased from 0.052 h(-1) to 0.085 h(-1) as the ratio of xylose to glucose increased from 0.25 to 4. S. acidocaldarius appeared to utilize a mixture of glucose and xylose at a rate roughly proportional to their concentrations in the medium, resulting in complete utilization of both sugars at about the same time. Gene expression in cells grown on xylose alone was very similar to that in cells grown on a mixture of xylose and glucose and substantially different from that in cells grown on glucose alone. The mechanism by which the organism utilized a mixture of sugars has yet to be elucidated. PMID- 21239581 TI - The sporulation protein SirA inhibits the binding of DnaA to the origin of replication by contacting a patch of clustered amino acids. AB - Bacteria regulate the frequency and timing of DNA replication initiation by controlling the activity of the replication initiator protein DnaA. SirA is a recently discovered regulator of DnaA in Bacillus subtilis whose synthesis is turned on at the start of sporulation. Here, we demonstrate that SirA contacts DnaA at a patch of 3 residues located on the surface of domain I of the replication initiator protein, corresponding to the binding site used by two unrelated regulators of DnaA found in other bacteria. We show that the interaction of SirA with domain I inhibits the ability of DnaA to bind to the origin of replication. DnaA mutants containing amino acid substitutions of the 3 residues are functional in replication initiation but are immune to inhibition by SirA. PMID- 21239582 TI - Sulfate-driven elemental sparing is regulated at the transcriptional and posttranscriptional levels in a filamentous cyanobacterium. AB - Sulfur is an essential nutrient that can exist at growth-limiting concentrations in freshwater environments. The freshwater cyanobacterium Fremyella diplosiphon (also known as Tolypothrix sp. PCC 7601) is capable of remodeling the composition of its light-harvesting antennae, or phycobilisomes, in response to changes in the sulfur levels in its environment. Depletion of sulfur causes these cells to cease the accumulation of two forms of a major phycobilisome protein called phycocyanin and initiate the production of a third form of phycocyanin, which possesses a minimal number of sulfur-containing amino acids. Since phycobilisomes make up approximately 50% of the total protein in these cells, this elemental sparing response has the potential to significantly influence the fitness of this species under low-sulfur conditions. This response is specific for sulfate and occurs over the physiological range of sulfate concentrations likely to be encountered by this organism in its natural environment. F. diplosiphon has two separate sulfur deprivation responses, with low sulfate levels activating the phycobilisome remodeling response and low sulfur levels activating the chlorosis or bleaching response. The phycobilisome remodeling response results from changes in RNA abundance that are regulated at both the transcriptional and posttranscriptional levels. The potential of this response, and the more general bleaching response of cyanobacteria, to provide sulfur-containing amino acids during periods of sulfur deprivation is examined. PMID- 21239583 TI - Gene expression profiling of Corynebacterium glutamicum during Anaerobic nitrate respiration: induction of the SOS response for cell survival. AB - The gene expression profile of Corynebacterium glutamicum under anaerobic nitrate respiration revealed marked differences in the expression levels of a number of genes involved in a variety of cellular functions, including carbon metabolism and respiratory electron transport chain, compared to the profile under aerobic conditions using DNA microarrays. Many SOS genes were upregulated by the shift from aerobic to anaerobic nitrate respiration. An elongated cell morphology, similar to that induced by the DivS-mediated suppression of cell division upon cell exposure to the DNA-damaging reagent mitomycin C, was observed in cells subjected to anaerobic nitrate respiration. None of these transcriptional and morphological differences were observed in a recA mutant strain lacking a functional RecA regulator of the SOS response. The recA mutant cells additionally showed significantly reduced viability compared to wild-type cells similarly grown under anaerobic nitrate respiration. These results suggest a role for the RecA-mediated SOS response in the ability of cells to survive any DNA damage that may result from anaerobic nitrate respiration in C. glutamicum. PMID- 21239584 TI - Structural and mechanical properties of Klebsiella pneumoniae type 3 Fimbriae. AB - This study investigated the structural and mechanical properties of Klebsiella pneumoniae type 3 fimbriae, which constitute a known virulence factor for the bacterium. Transmission electron microscopy and optical tweezers were used to understand the ability of the bacterium to survive flushes. An individual K. pneumoniae type 3 fimbria exhibited a helix-like structure with a pitch of 4.1 nm and a three-phase force-extension curve. The fimbria was first nonlinearly stretched with increasing force. Then, it started to uncoil and extended several micrometers at a fixed force of 66 +/- 4 pN (n = 22). Finally, the extension of the fimbria shifted to the third phase, with a characteristic force of 102 +/- 9 pN (n = 14) at the inflection point. Compared with the P fimbriae and type 1 fimbriae of uropathogenic Escherichia coli, K. pneumoniae type 3 fimbriae have a larger pitch in the helix-like structure and stronger uncoiling and characteristic forces. PMID- 21239585 TI - Effects of metal on the biochemical properties of Helicobacter pylori HypB, a maturation factor of [NiFe]-hydrogenase and urease. AB - The biosyntheses of the [NiFe]-hydrogenase and urease enzymes in Helicobacter pylori require several accessory proteins for proper construction of the nickel containing metallocenters. The hydrogenase accessory proteins HypA and HypB, a GTPase, have been implicated in the nickel delivery steps of both enzymes. In this study, the metal-binding properties of H. pylori HypB were characterized, and the effects of metal binding on the biochemical behavior of the protein were examined. The protein can bind stoichiometric amounts of Zn(II) or Ni(II), each with nanomolar affinity. Mutation of Cys106 and His107, which are located between two major GTPase motifs, results in undetectable Ni(II) binding, and the Zn(II) affinity is weakened by 2 orders of magnitude. These two residues are also required for the metal-dependent dimerization observed in the presence of Ni(II) but not Zn(II). The addition of metals to the protein has distinct impacts on GTPase activity, with zinc significantly reducing GTP hydrolysis to below detectable levels and nickel only slightly altering the k(cat) and K(m) of the reaction. The regulation of HypB activities by metal binding may contribute to the maturation of the nickel-containing enzymes. PMID- 21239586 TI - The Escherichia coli K-12 MntR miniregulon includes dps, which encodes the major stationary-phase DNA-binding protein. AB - Escherichia coli MntR protein is the Mn(2+)-responsive transcriptional repressor of the MntH manganese transporter. We have used chromatin immunoprecipitation to determine the distribution of Mn(2+)-MntR across the entire E. coli chromosome in vivo, and we report that MntR binds to only four targets, adjacent to the mntH, mntR, yebN, and dps genes. Unexpectedly, we found that dps expression is directly repressed by Mn(2+)-MntR. PMID- 21239587 TI - A processive glycosyltransferase involved in glycolipid synthesis during phosphate deprivation in Mesorhizobium loti. AB - Natural habitats are often characterized by a low availability of phosphate. In plants and many bacteria, phosphate deficiency causes different physiological responses, including the replacement of phosphoglycerolipids in the membranes with nonphosphorous lipids. We describe here a processive glycosyltransferase (Pgt) in Mesorhizobium loti (Rhizobiales) involved in the synthesis of di- and triglycosyldiacylglycerols (DGlycD and TGlycD) during phosphate deprivation. Cells of the corresponding Deltapgt deletion mutant are deficient in DGlycD and TGlycD. Additional Pgt-independent lipids accumulate in Mesorhizobium after phosphate starvation, including diacylglyceryl trimethylhomoserine (DGTS) and ornithine lipid (OL). The accumulation of the nonphosphorous lipids during phosphate deprivation leads to the reduction of phosphoglycerolipids from 90 to 50%. Nodulation experiments of Mesorhizobium wild type and the Deltapgt mutant with its host plant, Lotus japonicus, revealed that DGlycD and TGlycD are not essential for nodulation under phosphate-replete or -deficient conditions. Lipid measurements showed that the Pgt-independent lipids including OL and DGTS accumulate to higher proportions in the Deltapgt mutant and therefore might functionally replace DGlycD and TGlycD during phosphate deprivation. PMID- 21239588 TI - Genetic analysis of the protein shell of the microcompartments involved in coenzyme B12-dependent 1,2-propanediol degradation by Salmonella. AB - Hundreds of bacterial species use microcompartments (MCPs) to optimize metabolic pathways that have toxic or volatile intermediates. MCPs consist of a protein shell encapsulating specific metabolic enzymes. In Salmonella, an MCP is used for 1,2-propanediol utilization (Pdu MCP). The shell of this MCP is composed of eight different types of polypeptides, but their specific functions are uncertain. Here, we individually deleted the eight genes encoding the shell proteins of the Pdu MCP. The effects of each mutation on 1,2-PD degradation and MCP structure were determined by electron microscopy and growth studies. Deletion of the pduBB', pduJ, or pduN gene severely impaired MCP formation, and the observed defects were consistent with roles as facet, edge, or vertex protein, respectively. Metabolite measurements showed that pduA, pduBB', pduJ, or pduN deletion mutants accumulated propionaldehyde to toxic levels during 1,2-PD catabolism, indicating that the integrity of the shell was disrupted. Deletion of the pduK, pduT, or pduU gene did not substantially affect MCP structure or propionaldehyde accumulation, suggesting they are nonessential to MCP formation. However, the pduU or pduT deletion mutants grew more slowly than the wild type on 1,2-PD at saturating B(12), indicating that they are needed for maximal activity of the 1,2-PD degradative enzymes encased within the MCP shell. Considering recent crystallography studies, this suggests that PduT and PduU may mediate the transport of enzyme substrates/cofactors across the MCP shell. Interestingly, a pduK deletion caused MCP aggregation, suggesting a role in the spatial organization of MCP within the cytoplasm or perhaps in segregation at cell division. PMID- 21239589 TI - Bistability in myo-inositol utilization by Salmonella enterica serovar Typhimurium. AB - The capability of Salmonella enterica serovar Typhimurium strain 14028 (S. Typhimurium 14028) to utilize myo-inositol (MI) is determined by the genomic island GEI4417/4436 carrying the iol genes that encode enzymes, transporters, and a repressor responsible for the MI catabolic pathway. In contrast to all bacteria investigated thus far, S. Typhimurium 14028 growing on MI as the sole carbon source is characterized by a remarkable long lag phase of 40 to 60 h. We report here that on solid medium with MI as the sole carbon source, this human pathogen exhibits a bistable phenotype characterized by a dissection into large colonies and a slow-growing bacterial background. This heterogeneity is reversible and therefore not caused by mutation, and it is not observed in the absence of the iol gene repressor IolR nor in the presence of at least 0.55% CO(2). Bistability is correlated with the activity of the iolE promoter (P(iolE)), but not of P(iolC) or P(iolD), as shown by promoter-gfp fusions. On the single-cell level, fluorescence microscopy and flow cytometry analysis revealed a gradual switch of P(iolE) from the "off" to the "on" status during the late lag phase and the transition to the log phase. Deletion of iolR or the addition of 0.1% NaHCO(3) induced an early growth start of S. Typhimurium 14028 in minimal medium with MI. The addition of ethoxyzolamide, an inhibitor of carboanhydrases, elongated the lag phase in the presence of bicarbonate. The positive-feedback loop via repressor release and positive induction by bicarbonate-CO(2) might allow S. Typhimurium 14028 to adapt to rapidly changing environments. The phenomenon described here is a novel example of bistability in substrate degradation, and, to our knowledge, is the first demonstration of gene regulation by bicarbonate CO(2) in Salmonella. PMID- 21239590 TI - Core and panmetabolism in Escherichia coli. AB - Escherichia coli exhibits a wide range of lifestyles encompassing commensalism and various pathogenic behaviors which its highly dynamic genome contributes to develop. How environmental and host factors shape the genetic structure of E. coli strains remains, however, largely unknown. Following a previous study of E. coli genomic diversity, we investigated its diversity at the metabolic level by building and analyzing the genome-scale metabolic networks of 29 E. coli strains (8 commensal and 21 pathogenic strains, including 6 Shigella strains). Using a tailor-made reconstruction strategy, we significantly improved the completeness and accuracy of the metabolic networks over default automatic reconstruction processes. Among the 1,545 reactions forming E. coli panmetabolism, 885 reactions were common to all strains. This high proportion of core reactions (57%) was found to be in sharp contrast to the low proportion (13%) of core genes in the E. coli pangenome, suggesting less diversity of metabolic functions compared to that of all gene functions. Core reactions were significantly overrepresented among biosynthetic reactions compared to the more variable degradation processes. Differences between metabolic networks were found to follow E. coli phylogeny rather than pathogenic phenotypes, except for Shigella networks, which were significantly more distant from the others. This suggests that most metabolic changes in non-Shigella strains were not driven by their pathogenic phenotypes. Using a supervised method, we were yet able to identify small sets of reactions related to pathogenicity or commensalism. The quality of our reconstructed networks also makes them reliable bases for building metabolic models. PMID- 21239592 TI - The effect of feeling stereotyped on social power and inhibition. AB - An experience sampling study examined the degree to which feeling stereotyped predicts feelings of low power and inhibition among stigmatized and nonstigmatized individuals. For 7 days, participants with a concealable (gay and lesbian), a visible (African American), or no identifiable stigma recorded feelings of being stereotyped, of powerlessness, and of inhibition immediately following social interactions. For members of all three groups, feeling stereotyped was associated with more inhibition, and this relation was partially mediated by feeling low in power. Although stigmatized participants reported feeling stereotyped more often than nonstigmatized participants, they reacted less strongly to the experience, consistent with the presence of buffering mechanisms developed by those living with stigma. African Americans appeared to buffer the impact of feeling stereotyped more effectively than gay and lesbian participants, an effect that was partly attributable to African Americans' higher identity centrality. PMID- 21239591 TI - From "in the air" to "under the skin": cortisol responses to social identity threat. AB - The authors examined women's neuroendocrine stress responses associated with sexism. They predicted that, when being evaluated by a man, women who chronically perceive more sexism would experience more stress unless the situation contained overt cues that sexism would not occur. The authors measured stress as the end product of the primary stress system linked to social evaluative threat-the hypothalamic-pituitary-adrenal cortical axis. In Study 1, female participants were rejected by a male confederate in favor of another male for sexist reasons or in favor of another female for merit-based reasons. In Study 2, female participants interacted with a male confederate who they learned held sexist attitudes or whose attitudes were unknown. Participants with higher chronic perceptions of sexism had higher cortisol, unless the situation contained cues that sexism was not possible. These results illustrate the powerful interactive effects of chronic perceptions of sexism and situational cues on women's stress reactivity. PMID- 21239593 TI - Reducing exposure to trust-related risks to avoid self-blame. AB - Three studies demonstrated that anticipated self-blame elicits more conservative decisions about risks that require trust than about otherwise economically identical risks that do not. Participants were more reluctant to invest money in a company when it risked failure due to fraud versus low consumer demand (Study 1), and to risk points in an economic game when its outcome ostensibly depended on another participant versus chance (Studies 2 and 3). These effects were mediated by anticipated self-blame (Studies 1 and 2). Additionally, participants who actually experienced a loss felt more self-blame when the loss violated their trust and became even more conservative in subsequent risk decisions relative to participants whose loss did not violate their trust (Study 3). No support emerged for alternative explanations based on either the perceived probability of incurring a loss or an aversion to losses that profit others. The motivational power of trust violations is discussed. PMID- 21239594 TI - Sex differences in romantic attachment: a meta-analysis. AB - This article presents the first meta-analysis of sex differences in the avoidance and anxiety dimensions of adult romantic attachment, based on 113 samples (N = 66,132) from 100 studies employing two-dimensional romantic attachment questionnaires (Experiences in Close Relationships, Experiences in Close Relationships-Revised, and Adult Attachment Questionnaire). Overall, males showed higher avoidance and lower anxiety than females, with substantial between-study heterogeneity. Sex differences were much larger in community samples (bivariate D = .28) than in college samples (D = .12); web-based studies showed the smallest sex differences (D = .07) in the opposite direction. Sex differences also varied across geographic regions (overall Ds = .10 to .34). Sex differences in anxiety peaked in young adulthood, whereas those in avoidance increased through the life course. The relevance of these findings for evolutionary models of romantic attachment is discussed, and possible factors leading to underestimation of sex differences are reviewed. PMID- 21239595 TI - Making up for lost opportunities: the protective role of downward social comparisons for coping with regrets across adulthood. AB - Two longitudinal studies showed that if adults confront low opportunities to overcome regrets, downward social comparisons can exert self-protective functions across the adult life span, irrespective of age (Study 1 N = 104 young and older adults, Study 2 N = 51 older adults). Both studies found that downward relative to upward social comparisons were associated with improvements in participants' positive (but not negative) affect, if they perceived low as opposed to high opportunities to overcome regrets. Moreover, Study 2 showed that this beneficial effect on change in positive affect mediated the experience of fewer cold symptoms over time. Supplemental analyses further indicated that the mechanism linking social comparison processes and opportunities with positive (but not negative) affect was associated with the capacity for goal reengagement. In addition, these analyses showed that the obtained effects were largely unrelated to the severity of regret-related consequences and thus ruled out an alternative explanation of the findings. PMID- 21239596 TI - Responding to partners' expression of anger: the role of communal motivation. AB - The effects of communal motivation on reactions to relationship partners' expressed anger were examined. In Study 1, married couples reported on the communal strength of their marriage, their expressions of anger to their spouse, and relationship satisfaction. In Study 2, college students reported on the communal strength of their best friendships, those friends' expressions of anger, and their evaluations of and provision of support to those friends. In Study 3, communal motivation toward a stranger who expressed mild anger was manipulated and evaluation of that stranger was measured. In all three studies, low communal motivation was associated with more negative evaluations of angry partners, lower relationship satisfaction, and, in Study 2, lower support provision. In contrast, when communal motivation was high, these decreases either did not occur (Studies 1 and 3) or were diminished (Study 2), and in Study 2, partners' anger was associated with increased provision of social support. PMID- 21239597 TI - Attachment and the management of empathic accuracy in relationship-threatening situations. AB - The current studies tested how attachment orientations are related to empathic accuracy (i.e., the accuracy with which one infers a partner's private thoughts and feelings) during attachment-relevant discussions. In Study 1, married couples were videotaped discussing a severe or a less severe relationship issue that involved intimacy or jealousy. In Study 2, dating couples were videotaped trying to resolve a relationship conflict. Consistent with the revised empathic accuracy model, highly avoidant individuals were less empathically accurate in both studies. Relative to less anxious persons, highly anxious individuals were more empathically accurate when discussing intimacy issues that posed a potential threat to their relationship (in Study 1) and when they were rated as more distressed when discussing a relationship conflict (in Study 2). The findings are discussed in terms of how highly anxious and highly avoidant people differentially manage empathic accuracy to regulate negative affect and facilitate their interpersonal goals. PMID- 21239598 TI - Daily cognitive appraisals, daily affect, and long-term depressive symptoms: the role of self-esteem and self-concept clarity in the stress process. AB - The current study investigated how self-esteem and self-concept clarity are implicated in the stress process both in the short and long term. Initial and 2 year follow-up interviews were completed by 178 participants from stepfamily unions. In twice-daily structured diaries over 7 days, participants reported their main family stressor, cognitive appraisals (perceived stressor threat and stressor controllability), and negative affect. Results of multilevel modeling indicated that high self-esteem ameliorated the effect of daily negative cognitive appraisals on daily negative affect. Self-concept clarity also buffered the effect of low self-self-esteem on depressive symptoms 2 years later. Our findings point to the vulnerability of those having low self-esteem or low self concept clarity in terms of both short- and long-term adaptation to stress. They indicate the need for the consideration of such individual differences in designing stress management interventions. PMID- 21239599 TI - A meta-analytic investigation of the relationship of state and trait anxiety to performance on figural and verbal creative tasks. AB - Extensive research suggests when and how anxiety has debilitating or facilitating effects on routine cognitive tasks or motor tasks. However, research examining anxiety's relation to performance on creative tasks such as divergent thinking and artistic tasks is less conclusive despite a rather substantial literature. The authors' meta-analytic investigation of 59 independent samples finds that anxiety is significantly and negatively related to creative performance. In addition, the findings provide insights into factors such as task complexity, type of task (i.e., figural or verbal), and type of anxiety (i.e., state or trait) that moderate the relationship between anxiety and creativity-all of which are consistent with the idea that anxiety and creativity present competing cognitive demands. In addition to identifying gaps in the literature such as the need for research using a two-component model of anxiety in relation to creativity, the authors' results have practical implications for those seeking to increase individual creativity. PMID- 21239600 TI - The role of depressogenic personality and attachment in the intergenerational similarity of depressive symptoms: a study with early adolescents and their mothers. AB - Parental depression has been identified as a risk factor for psychopathology in children, and for child depression in particular. Increasingly, research is addressing the underlying psychological processes that may explain the intergenerational similarity of depressive symptoms. In the present study, we aim to investigate the role of two theoretically relevant vulnerability factors in this intergenerational similarity, that is, (a) dimensions of depressogenic personality (i.e., sociotropy and autonomy) and (b) dimensions of attachment (i.e., anxiety and avoidance). Results in a sample of early adolescents and their mothers show significant intergenerational similarity in both sets of vulnerabilities. Moreover, the intergenerational similarity of both vulnerability factors was found to account for the association between mothers' and children's depressive symptoms. Within each generation there were also meaningful and specific associations between dimensions of depressogenic personality and dimensions of attachment, with sociotropy being primarily related to anxiety and with autonomy being primarily related to avoidance. PMID- 21239602 TI - Measurement of the airway surface liquid volume with simple light refraction microscopy. AB - In the cystic fibrosis (CF) lung, the airway surface liquid (ASL) volume is depleted, impairing mucus clearance from the lung and leading to chronic airway infection and obstruction. Several therapeutics have been developed that aim to restore normal airway surface hydration to the CF airway, yet preclinical evaluation of these agents is hindered by the paucity of methods available to directly measure the ASL. Therefore, we sought to develop a straightforward approach to measure the ASL volume that would serve as the basis for a standardized method to assess mucosal hydration using readily available resources. Primary human bronchial epithelial (HBE) cells cultured at an air liquid interface develop a liquid meniscus at the edge of the culture. We hypothesized that the size of the fluid meniscus is determined by the ASL volume, and could be measured as an index of the epithelial surface hydration status. A simple method was developed to measure the volume of fluid present in meniscus by imaging the refraction of light at the ASL interface with the culture wall using low-magnification microscopy. Using this method, we found that primary CF HBE cells had a reduced ASL volume compared with non-CF HBE cells, and that known modulators of ASL volume caused the predicted responses. Thus, we have demonstrated that this method can detect physiologically relevant changes in the ASL volume, and propose that this novel approach may be used to rapidly assess the effects of airway hydration therapies in high-throughput screening assays. PMID- 21239603 TI - Fluorinated groups mediate the immunomodulatory effects of volatile anesthetics in acute cell injury. AB - Volatile anesthetics are known to attenuate inflammatory response and tissue damage markers in acute organ injury. It is unclear whether these beneficial effects of volatile anesthetics are mediated by the ether basic structure or by characteristics of their halogenations. We describe in an in vitro model of acute inflammation in pulmonary cells that halogenation (fluorinated carbon groups) is responsible for the immunomodulatory effects. The inflammatory response after coexposure to endotoxin and sevoflurane, diethyl-ether, or various water-soluble molecules carrying trifluorinated carbon (CF(3)) groups was evaluated in pulmonary epithelial and endothelial cells and in neutrophils. In epithelial and endothelial cells, expression of inflammatory mediators to LPS stimulation was dose-dependently decreased upon exposure to sevoflurane and other molecules with CF(3) groups. This was not observed for diethyl-ether or structure-similar nonfluorinated molecules. In neutrophils, chemotactic activity, as well as expression of surface CD11b and CD62L, was positively modified by molecules carrying CF(3) groups. Cytotoxicity could be excluded. These findings for the first time reveal in an in vitro model of acute inflammation that the immunomodulatory effects are not limited to volatile anesthetics but are associated with a much broader class of CF(3) group-containing molecules. The immunomodulatory effects could now be provided in a hydrophilic, injectable formulation for the treatment of patients suffering from acute organ injury, such as acute lung injury, in environments not suitable for volatile anesthetics. PMID- 21239604 TI - Up-regulation of MUC18 in airway epithelial cells by IL-13: implications in bacterial adherence. AB - Airway bacterial infections are a major problem in lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. Increased Th2 cytokines, such as IL-13, are observed in lung diseases and may contribute to bacterial infections. How Th2 cytokines affect bacterial infection remains unknown. MUC18, an adhesion molecule shown to be involved in the pathogenesis of malignant melanoma, has been recently identified in airway epithelial cells of patients with COPD. We investigated MUC18 regulation by IL-13 and the role of MUC18 in bacterial adherence to epithelial cells. Human airway tissues, brushed bronchial epithelial cells from normal subjects and subjects with asthma, and epithelial cell lines (e.g., HEK293 cells) were used to study the regulation of MUC18 by IL-13 and the involvement of MUC18 in bacterial (e.g., Mycoplasma pneumoniae [Mp] and nontypeable Haemophilus influenzae [NTHi]) adherence to epithelial cells. Asthmatic bronchial epithelium expressed higher levels of MUC18 than normal bronchial epithelium. IL-13 increased MUC18 in cultured bronchial epithelial cells from normal subjects and particularly from subjects with asthma. IL-13-induced MUC18 expression may be modulated in part through transcription factor specificity protein 1. Overexpression of human MUC18 in HEK293 cells increased cell-associated Mp and NTHi levels. Moreover, MUC18 was shown to directly interact with Mp and NTHi. These results for the first time show that an allergic airway milieu (e.g., IL-13) increases MUC18 expression, which may contribute to increased bacterial infection/colonization in asthma and other lung diseases. PMID- 21239605 TI - A20 regulation of nuclear factor-kappaB: perspectives for inflammatory lung disease. AB - Persistent activation of NF-kappaB is central to the pathogenesis of many inflammatory lung disorders, including cystic fibrosis, asthma, and chronic obstructive pulmonary disease. A20 is an endogenous negative regulator of NF kappaB signaling, which has been widely described in autoimmune and inflammatory disorders, including diabetes and Crohn's disease, but which has received little attention in terms of chronic lung disorders. This review examines the existing body of research on A20 regulation of NF-kappaB signaling and details the mechanism and regulation of A20 action focusing, where possible, on pulmonary inflammation. A20 and its associated signaling molecules are highlighted as being of potential therapeutic interest for the treatment of inflammatory disorders, and a proposed model of A20 activity in inflammatory lung disease is provided. PMID- 21239606 TI - Neonatal hyperoxia contributes additively to cigarette smoke-induced chronic obstructive pulmonary disease changes in adult mice. AB - The extent by which early postnatal lung injury contributes to the development of chronic obstructive pulmonary disease (COPD) in the adult is unclear. We hypothesized that exposure to hyperoxia during early postnatal life can augment lung changes caused by adult chronic cigarette smoke (CS) exposure. C57BL/6J mice (1 d old) were exposed to hyperoxia (O(2)) for 5 days. At 1 month of age, half of the O(2)-exposed mice and half of the control mice were placed in a CS chamber for 6 months. After exposure to CS, mice underwent quasi-static pressure-volume curve and mean chord length measurements; quantification of pro-Sp-c expression; and measurement of lung IL-8/ KC, CXCR2/IL8Ralpha, TNF-alpha, and IL-6 mRNA by real-time PCR. Adult mice exposed to O(2)+CS had significantly larger chord length measurements (P < 0.02) and lung volumes at 35 cm H(2)O (P < 0.05) compared with all other groups. They also had significantly less pro-Sp-c protein and surfactant protein C mRNA expression (P < 0.003). Mice exposed to O(2)+CS and CS-only mice had significantly higher lung resistance and longer mean time constants (P < 0.01), significantly more inflammatory cells in the bronchoalveolar lavage fluid (P < 0.03), and significantly higher levels of lung CXCR2/IL8Ralpha mRNA compared with mice not exposed to smoke (P < 0.02). We conclude that exposure to early postnatal hyperoxia contributed additively to CS induced COPD changes in adult mice. These results may be relevant to a growing population of preterm children who sustained lung injury in the newborn period and may be exposed to CS in later life. PMID- 21239607 TI - Aggravation of bleomycin-induced pulmonary inflammation and fibrosis in mice lacking peroxiredoxin I. AB - Oxidative stress plays an important role in the pathogenesis of acute lung injury and pulmonary fibrosis. Peroxiredoxin (Prx) I is a cellular antioxidant enzyme induced under stress conditions. In the present study, the protective effects of Prx I on the development of bleomycin-induced acute pulmonary inflammation and pulmonary fibrosis were investigated using Prx I-deficient mice. Survival of Prx I-deficient mice after bleomycin administration was significantly lower than that of wild-type mice, corresponding with enhanced acute pulmonary inflammation and fibrosis. The level of inflammatory cytokines and chemokines, such as TNF-alpha, macrophage inflammatory protein-2, and monocyte chemotactic protein-1, was significantly elevated in the bronchoalveolar lavage fluid of Prx I-deficient mice after bleomycin administration. Furthermore, the level of 8-isoprostane, an oxidative stress marker, and the concentration and alveolar macrophage expression of macrophage migration inhibitory factor were elevated in the lungs of Prx I deficient mice after bleomycin administration. The exacerbation of bleomycin induced pulmonary inflammation and fibrosis in Prx I-deficient mice was inhibited by treatment with N-acetyl-L-cysteine, a radical scavenger, or with (S,R)-3-(4 hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, a tautomerase inhibitor of macrophage migration inhibitory factor. These findings suggest that mice lacking Prx I are highly susceptible to bleomycin-induced pulmonary inflammation and fibrosis because of increases in pulmonary oxidant levels and macrophage migration inhibitory factor activity in response to bleomycin. PMID- 21239608 TI - Innate immune response to influenza A virus in differentiated human alveolar type II cells. AB - Alveolar Type II (ATII) cells are important targets for seasonal and pandemic influenza. To investigate the influenza-induced innate immune response in those cells, we measured the global gene expression profile of highly differentiated ATII cells infected with the influenza A virus at a multiplicity of infection of 0.5 at 4 hours and 24 hours after inoculation. Infection with influenza stimulated a significant increase in the mRNA concentrations of many host defense related genes, including pattern/pathogen recognition receptors, IFN, and IFN induced genes, chemokines, and suppressors of cytokine signaling. We verified these changes by quantitative real-time RT-PCR. At the protein level, we detected a robust virus-induced secretion of the three glutamic acid-leucine-arginine (ELR)-negative chemokines CXCL9, CXCL10, and CXCL11, according to ELISA. The ultraviolet inactivation of virus abolished the chemokine and cytokine response. Viral infection did not appear to alter the differentiation of ATII cells, as measured by cellular mRNA and concentrations of surfactant proteins. However, viral infection significantly reduced the secretion of surfactant protein (SP)-A and SP-D. In addition, influenza A virus triggered a time-dependent activation of phosphatidylinositol 3-kinase signaling in ATII cells. The inhibition of this pathway significantly decreased the release of infectious virus and the chemokine response, but did not alter virus-induced cell death. This study provides insights into influenza-induced innate immunity in differentiated human ATII cells, and demonstrates that the alveolar epithelium is a critical part of the initial innate immune response to influenza. PMID- 21239609 TI - Aurora kinase B activity is modulated by thyroid hormone during transcriptional activation of pituitary genes. AB - Covalent histone modifications clearly play an essential role in ligand-dependent transcriptional regulation by nuclear receptors. One of the predominant mechanisms used by nuclear receptors to activate or repress target-gene transcription is the recruitment of coregulatory factors capable of covalently modify the amino terminal ends of histones. Here we show that the thyroid hormone (T3) produces a rapid increase in histone H3Ser10 phosphorylation (H3Ser10ph) concomitant to the rapid displacement of the heterochromatin protein 1beta (HP1beta) to the nuclear periphery. Moreover, we found that T3-mediated pituitary gene transcription is associated with an increase in H3Ser10ph. Interestingly, the Aurora kinase B inhibitor ZM443979 abolishes the effect of T3 on H3Ser10ph, blocks HP1beta delocalization, and significantly reduces ligand-dependent transactivation. Similar effects were shown when Aurora kinase B expression was abrogated in small interfering RNA assays. In an effort to understand the underlying mechanism by which T3 increases H3Ser10ph, we demonstrate that liganded thyroid hormone receptor directly interacts with Aurora kinase B, increasing its kinase activity. Moreover, using chromatin immunoprecipitation assays, we have shown that Aurora kinase B participates of a mechanism that displaces HP1beta from promoter region, thus preparing the chromatin for the transcriptional activation of T3 regulated genes. Our findings reveal a novel role for Aurora kinase B during transcriptional initiation in GO/G1, apart from its well-known mitotic activity. PMID- 21239610 TI - Glucocorticoid-mediated repression of the oncogenic microRNA cluster miR-17~92 contributes to the induction of Bim and initiation of apoptosis. AB - Synthetic glucocorticoids were one of the first effective treatments for lymphoid malignancies because of their ability to induce apoptosis and are still used in combination with other chemotherapeutic agents. Up-regulation of Bim, a proapoptotic member of the B-cell lymphoma-2 family, is an important mediator of glucocorticoid-induced apoptosis. Although glucocorticoids are known to elevate Bim mRNA and protein, little is known about the mechanism. Here, we report that glucocorticoids repress the expression of the microRNA cluster miR-17~92, which results in elevated Bim protein expression as a mechanism by which glucocorticoids induce Bim. Using a luciferase-Bim 3' untranslated region construct, we demonstrate that glucocorticoids mediate Bim induction posttranscriptionally after miR-17~92 repression, resulting in increased Bim protein expression. Overexpression of miR-17~92 microRNAs decreases Bim induction and attenuates glucocorticoid-mediated apoptosis. Conversely, knockdown of miR 17~92 increases Bim protein expression and glucocorticoid-mediated apoptosis. These findings indicate that endogenous levels of miR-17~92 repress Bim expression in T-cell lymphoid malignancies and that glucocorticoids induce Bim expression via down-regulation of the miR-17~92 microRNA cluster. Our findings present a novel mechanism that contributes to the up-regulation of Bim and induction of apoptosis in lymphocytes after glucocorticoid treatment. Furthermore, our work demonstrating that inhibition of miR-17~92 increases glucocorticoid-induced apoptosis highlights the potential importance of miR-17~92 as a therapeutic target in leukemias and lymphomas. PMID- 21239611 TI - Suppression of BMP-Smad signaling axis-induced osteoblastic differentiation by small C-terminal domain phosphatase 1, a Smad phosphatase. AB - Bone morphogenetic proteins (BMPs) induce osteoblastic differentiation in myogenic cells via the phosphorylation of Smads. Two types of Smad phosphatases- small C-terminal domain phosphatase 1 (SCP1) and protein phosphatase magnesium dependent 1A--have been shown to inhibit BMP activity. Here, we report that SCP1 inhibits the osteoblastic differentiation induced by BMP-4, a constitutively active BMP receptor, and a constitutively active form of Smad1. The phosphatase activity of SCP1 was required for this suppression, and the knockdown of SCP1 in myoblasts stimulated the osteoblastic differentiation induced by BMP signaling. In contrast to protein phosphatase magnesium-dependent 1A, SCP1 did not reduce the protein levels of Smad1 and failed to suppress expression of the Id1, Id2, and Id3 genes. Runx2-induced osteoblastic differentiation was suppressed by SCP1 without affecting the transcriptional activity or phosphorylation levels of Runx2. Taken together, these findings suggest that SCP1 may inhibit the osteoblastic differentiation induced by the BMP-Smad axis via Runx2 by suppressing downstream effector(s). PMID- 21239612 TI - Role of reactive oxygen species in injury-induced insulin resistance. AB - Acute insulin resistance is common after injury, infection, and critical illness. To investigate the role of reactive oxygen species (ROS) in critical illness diabetes, we measured hepatic ROS, which rapidly increased in mouse liver. Overexpression of superoxide dismutase 2, which decreased mitochondrial ROS levels, protected mice from the development of acute hepatic insulin resistance. Insulin-induced intracellular signaling was dramatically decreased, and cellular stress signaling was rapidly increased after injury, resulting in the hyperglycemia of critical illness diabetes. Insulin-induced intracellular signaling, activation of stress (c-Jun N-terminal kinase) signaling, and glucose metabolism were all normalized by superoxide dismutase 2 overexpression or by pretreatment with antioxidants. Thus, ROS play an important role in the development of acute hepatic insulin resistance and activation of stress signaling after injury. PMID- 21239614 TI - Progesterone receptor activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells. AB - We previously showed that progesterone (P4) inhibited the proliferation of human umbilical vein endothelial cells (HUVECs) through a p53-dependent pathway. Now we investigated further the molecular mechanism underlying the hormone activity. In cultured HUVECs, P4 increased the protein levels of phosphorylated Src (p-Src), Raf-1, and ERK. The levels of p-Src and p-Src-progesterone receptor complex in HUVECs were increased by P4 treatment. These effects were blocked by pretreatment with a progesterone receptor antagonist, RU486. The P4-induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors. Moreover, administration with cSrc antisense oligonucleotide prevented the P4-induced increases of the levels of p53 mRNA and protein. These data suggest that P4 induced up-regulation of p53 might be mediated through activation of cSrc. Pretreatment with Src kinase inhibitors also prevented P4-induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated ERK. Transfection with dominant-negative ERK2 prevented the P4 induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation. P4 also increased nuclear factor-kappaB (NF-kappaB) nuclear translocation and NF-kappaB binding onto the p53 promoter. These effects were abolished by pretreatment with ERK inhibitors. The P4-induced up-regulation of the p53 promoter activity was prevented by preadministration with dominant negative ERK2 or NF-kappaB inhibitors. Taken together, our data suggest that the cSrc/Kras/Raf-1/ERK2/NF-kappaB signaling pathway contributes to the P4-induced up regulation of p53 in HUVECs. These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs. PMID- 21239613 TI - Dynamic chromatin modifications control GnRH gene expression during neuronal differentiation and protein kinase C signal transduction. AB - GnRH, a neuropeptide produced by rare, specialized hypothalamic secretory neurons, is critical for reproduction. During development, GnRH gene expression increases as neurons migrate from the olfactory placode to the hypothalamus, with highest levels in the mature, postmitotic state. While neuronal differentiation is known to be controlled by chromatin modulations, the role of chromatin dynamics in GnRH gene regulation has not been studied. Here, we use mature and immature GnRH neuronal cell models to show that both neuron-specific and protein kinase C regulation of GnRH expression are mediated by chromatin structure and histone modifications. Only in GT1-7 mature GnRH neuronal cells did GnRH regulatory elements display high sensitivity to DNase and enrichment of active histone markers histone-H3 acetylation and H3 lysine 4 trimethylation (H3K4-Me3), as well as RNA polymerase II (RNAPII) binding and enhancer RNA transcription. In contrast, H3K9-Me2, a marker of inactive chromatin, was highest in nonneuronal cells, low in GT1-7 cells, and intermediate in immature GnRH neuronal cells. The chromatin of the GnRH gene was therefore active in mature GnRH neuronal cells, inactive in nonneuronal cells, but not fully inactive in immature GnRH neuronal cells. Activation of protein kinase C (PKC) potently represses GnRH expression. PKC activation caused closing of the chromatin and decreased RNAPII occupancy at the GnRH minimal promoter (-278/-97). At GnRH-Enhancer-1 (-2404/-2100), PKC activation decreased phosphorylated-RNAPII binding, enhancer RNA transcription, and H3 acetylation, and reciprocally increased H3K9-Me2. Chromatin modifications therefore participate in the dynamic regulation and specification of GnRH expression to differentiated hypothalamic neurons. PMID- 21239615 TI - Nr4a1 siRNA expression attenuates alpha-MSH regulated gene expression in 3T3-L1 adipocytes. AB - Several recent investigations have underscored the growing role of melanocortin signaling in the peripheral regulation of lipid, glucose, and energy homeostasis. In addition, the melanocortins play a critical role in the central control of satiety. These observations, and the latest reports highlighting the emerging role of the nuclear hormone receptor (NR) 4A subgroup in metabolism, have prompted us to investigate the cross talk between [Nle(4), d-Phe(7)] (NDP)-alpha MSH and Nr4a signaling in adipose. We have shown that NDP-MSH strikingly and preferentially induces the expression of the NR4A subgroup (but not any other members of the NR superfamily) in differentiated 3T3-L1 adipocytes. Utilization of quantitative PCR on custom-designed metabolic TaqMan low-density arrays identified the concomitant and marked induction of the mRNAs encoding Il-6, Cox2, Pdk4, and Pck-1 after NDP-MSH treatment. Similar experiments demonstrated that the mRNA expression profile induced by cAMP and NDP-MSH treatment displayed unique but also overlapping properties and suggested that melanocortin-mediated induction of gene expression involves cAMP-dependent and -independent signaling. Nr4a1/Nur77 small interfering RNA (siRNA) expression suppressed NDP-MSH-mediated induction of Nr4a1/Nur77 and Nr4a3/Nor-1 (but not Nr4a2/Nurr1). Moreover, expression of the siRNA-attenuated NDP-MSH mediated induction of the mRNAs encoding Il-6, Cox2/Ptgs2, and Pck-1 expression. In addition, Nur77 siRNA expression attenuated NDP-MSH-mediated glucose uptake. In vivo, ip administration of NDP-MSH to C57 BL/6J (male) mice significantly induced the expression of the mRNA encoding Nur77 and increased IL-6, Cox2, Pck1, and Pdk4 mRNA expression in (inguinal) adipose tissue. We conclude that Nur77 expression is necessary for MSH mediated induction of gene expression in differentiated adipocytes. Furthermore, this study demonstrates cross talk between MSH and Nr4a signaling in adipocytes. PMID- 21239616 TI - Specific histone lysine 4 methylation patterns define TR-binding capacity and differentiate direct T3 responses. AB - The diversity of thyroid hormone T(3) effects in vivo makes their molecular analysis particularly challenging. Indeed, the current model of the action of T(3) and its receptors on transcription does not reflect this diversity. Here, T(3)-dependent amphibian metamorphosis was exploited to investigate, in an in vivo developmental context, how T(3) directly regulates gene expression. Two, direct positively regulated T(3)-response genes encoding transcription factors were analyzed: thyroid hormone receptor beta (TRbeta) and TH/bZIP. Reverse transcription-real-time quantitative PCR analysis on Xenopus tropicalis tadpole brain and tail fin showed differences in expression levels in premetamorphic tadpoles (lower for TH/bZIP than for TRbeta) and differences in induction after T(3) treatment (lower for TRbeta than for TH/bZIP). To dissect the mechanisms underlying these differences, chromatin immunoprecipitation was used. T(3) differentially induced RNA polymerase II and histone tail acetylation as a function of transcriptional level. Gene-specific patterns of TR binding were found on the different T(3) -responsive elements (higher for TRbeta than for TH/bZIP), correlated with gene-specific modifications of H3K4 methylation (higher for TRbeta than for TH/bZIP). Moreover, tissue-specific modifications of H3K27 were found (lower in brain than in tail fin). This first in vivo analysis of the association of histone modifications and TR binding/gene activation during vertebrate development for any nuclear receptor indicate that chromatin context of thyroid-responsive elements loci controls the capacity to bind TR through variations in histone H3K4 methylation, and that the histone code, notably H3, contributes to the fine tuning of gene expression that underlies complex physiological T(3) responses. PMID- 21239617 TI - Research resource: nuclear receptor atlas of human retinal pigment epithelial cells: potential relevance to age-related macular degeneration. AB - Retinal pigment epithelial (RPE) cells play a vital role in retinal physiology by forming the outer blood-retina barrier and supporting photoreceptor function. Retinopathies including age-related macular degeneration (AMD) involve physiological and pathological changes in the epithelium, severely impairing the retina and effecting vision. Nuclear receptors (NRs), including peroxisome proliferator-activated receptor and liver X receptor, have been identified as key regulators of physiological pathways such as lipid metabolic dysregulation and inflammation, pathways that may also be involved in development of AMD. However, the expression levels of NRs in RPE cells have yet to be systematically surveyed. Furthermore, cell culture lines are widely used to study the biology of RPE cells, without knowledge of the differences or similarities in NR expression and activity between these in vitro models and in vivo RPE. Using quantitative real time PCR, we assessed the expression patterns of all 48 members of the NR family plus aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator in human RPE cells. We profiled freshly isolated cells from donor eyes (in vivo), a spontaneously arising human cell line (in vitro), and primary cell culture lines (in vitro) to determine the extent to which NR expression in the cultured cell lines reflects that of in vivo. To evaluate the validity of using cell culture models for investigating NR receptor biology, we determined transcriptional activity and target gene expression of several moderately and highly expressed NRs in vitro. Finally, we identified a subset of NRs that may play an important role in pathobiology of AMD. PMID- 21239618 TI - The nuclear receptor corepressor (NCoR) controls thyroid hormone sensitivity and the set point of the hypothalamic-pituitary-thyroid axis. AB - The role of nuclear receptor corepressor (NCoR) in thyroid hormone (TH) action has been difficult to discern because global deletion of NCoR is embryonic lethal. To circumvent this, we developed mice that globally express a modified NCoR protein (NCoRDeltaID) that cannot be recruited to the thyroid hormone receptor (TR). These mice present with low serum T(4) and T(3) concentrations accompanied by normal TSH levels, suggesting central hypothyroidism. However, they grow normally and have increased energy expenditure and normal or elevated TR-target gene expression across multiple tissues, which is not consistent with hypothyroidism. Although these findings imply an increased peripheral sensitivity to TH, the hypothalamic-pituitary-thyroid axis is not more sensitive to acute changes in TH concentrations but appears to be reset to recognize the reduced TH levels as normal. Furthermore, the thyroid gland itself, although normal in size, has reduced levels of nonthyroglobulin-bound T(4) and T(3) and demonstrates decreased responsiveness to TSH. Thus, the TR-NCoR interaction controls systemic TH sensitivity as well as the set point at all levels of the hypothalamic pituitary-thyroid axis. These findings suggest that NCoR levels could alter cell specific TH action that would not be reflected by the serum TSH. PMID- 21239619 TI - Assembly of the photosynthetic apparatus. PMID- 21239620 TI - Mechanisms linking drought, hydraulics, carbon metabolism, and vegetation mortality. PMID- 21239621 TI - Identification and characterization of thioredoxin h isoforms differentially expressed in germinating seeds of the model legume Medicago truncatula. AB - Thioredoxins (Trxs) h, small disulfide reductases, and NADP-thioredoxin reductases (NTRs) have been shown to accumulate in seeds of different plant species and play important roles in seed physiology. However, little is known about the identity, properties, and subcellular location of Trx h isoforms that are abundant in legume seeds. To fill this gap, in this work, we characterized the Trx h family of Medicago truncatula, a model legume, and then explored the activity and localization of Trx h isoforms accumulating in seeds. Twelve Trx h isoforms were identified in M. truncatula. They belong to the groups previously described: h1 to h3 (group I), h4 to h7 (group II), and h8 to h12 (group III). Isoforms of groups I and II were found to be reduced by M. truncatula NTRA, but with different efficiencies, Trxs of group II being more efficiently reduced than Trxs of group I. In contrast, their insulin disulfide-reducing activity varies greatly and independently of the group to which they belong. Furthermore, Trxs h1, h2, and h6 were found to be present in dry and germinating seeds. Trxs h1 and, to a lesser extent, h2 are abundant in both embryonic axes and cotyledons, while Trx h6 is mainly present in cotyledons. Thus, M. truncatula seeds contain distinct isoforms of Trx h that differ in spatial distribution and kinetic properties, suggesting that they play different roles. Because we show that Trx h6 is targeted to the tonoplast, the possible role of this isoform during germination is finally discussed. PMID- 21239622 TI - Plastid biotechnology: food, fuel, and medicine for the 21st century. PMID- 21239623 TI - Tracking Glideosome-associated protein 50 reveals the development and organization of the inner membrane complex of Plasmodium falciparum. AB - The most deadly of the human malaria parasites, Plasmodium falciparum, has different stages specialized for invasion of hepatocytes, erythrocytes, and the mosquito gut wall. In each case, host cell invasion is powered by an actin-myosin motor complex that is linked to an inner membrane complex (IMC) via a membrane anchor called the glideosome-associated protein 50 (PfGAP50). We generated P. falciparum transfectants expressing green fluorescent protein (GFP) chimeras of PfGAP50 (PfGAP50-GFP). Using immunoprecipitation and fluorescence photobleaching, we show that C-terminally tagged PfGAP50-GFP can form a complex with endogenous copies of the linker protein PfGAP45 and the myosin A tail domain-interacting protein (MTIP). Full-length PfGAP50-GFP is located in the endoplasmic reticulum in early-stage parasites and then redistributes to apical caps during the formation of daughter merozoites. In the final stage of schizogony, the PfGAP50 GFP profile extends further around the merozoite surface. Three-dimensional (3D) structured illumination microscopy reveals the early-stage IMC as a doubly punctured flat ellipsoid that separates to form claw-shaped apposed structures. A GFP fusion of PfGAP50 lacking the C-terminal membrane anchor is misdirected to the parasitophorous vacuole. Replacement of the acid phosphatase homology domain of PfGAP50 with GFP appears to allow correct trafficking of the chimera but confers a growth disadvantage. PMID- 21239624 TI - Nhe1 is essential for potassium but not calcium facilitation of cell motility and the monovalent cation requirement for chemotactic orientation in Dictyostelium discoideum. AB - In Dictyostelium discoideum, extracellular K+ or Ca2+ at a concentration of 40 or 20 mM, respectively, facilitates motility in the absence or presence of a spatial gradient of chemoattractant. Facilitation results in maximum velocity, cellular elongation, persistent translocation, suppression of lateral pseudopod formation, and myosin II localization in the posterior cortex. A lower threshold concentration of 15 mM K+ or Na or 5 mM Ca2+ is required for chemotactic orientation. Although the common buffer solutions used by D. discoideum researchers to study chemotaxis contain sufficient concentrations of cations for chemotactic orientation, the majority contain insufficient levels to facilitate motility. Here it has been demonstrated that Nhe1, a plasma membrane protein, is required for K+ but not Ca2+ facilitation of cell motility and for the lower K+ but not Ca2+ requirement for chemotactic orientation. PMID- 21239625 TI - Depletion of mitochondrial acyl carrier protein in bloodstream-form Trypanosoma brucei causes a kinetoplast segregation defect. AB - Like other eukaryotes, trypanosomes have an essential type II fatty acid synthase in their mitochondrion. We have investigated the function of this synthase in bloodstream-form parasites by studying the effect of a conditional knockout of acyl carrier protein (ACP), a key player in this fatty acid synthase pathway. We found that ACP depletion not only caused small changes in cellular phospholipids but also, surprisingly, caused changes in the kinetoplast. This structure, which contains the mitochondrial genome in the form of a giant network of several thousand interlocked DNA rings (kinetoplast DNA [kDNA]), became larger in some cells and smaller or absent in others. We observed the same pattern in isolated networks viewed by either fluorescence or electron microscopy. We found that the changes in kDNA size were not due to the disruption of replication but, instead, to a defect in segregation. kDNA segregation is mediated by the tripartite attachment complex (TAC), and we hypothesize that one of the TAC components, a differentiated region of the mitochondrial double membrane, has an altered phospholipid composition when ACP is depleted. We further speculate that this compositional change affects TAC function, and thus kDNA segregation. PMID- 21239626 TI - Role of glucose in the expression of Cryptococcus neoformans antiphagocytic protein 1, App1. AB - The cryptococcus-specific protein antiphagocytic protein 1 (App1) regulates Cryptococcus neoformans virulence by controlling macrophage-driven fungal phagocytosis. This is accomplished through complement receptors (CR), specifically CR3. When inhaled, C. neoformans can cause a life-threatening meningoencephalitis in immunocompromised patients. Because glucose starvation can significantly change the gene expression and virulence of C. neoformans and because App1 is critical for phagocytosis in the lung-a low-glucose environment we investigated the role of glucose in App1 expression. We found that App1 was upregulated dramatically under low-glucose conditions, and it was upregulated when C. neoformans cells were incubated in bronchoalveolar lavage (BAL) fluid, serum, and cerebrospinal fluid, which are low-glucose environments. Characterization of App1's regulation based on mammalian lung physiology revealed that App1 is upregulated via both increases in transcription and increases in mRNA stability. Our data provide new insights regarding C. neoformans adaptations to low-glucose environments. PMID- 21239627 TI - Neuregulin-1beta regulation of embryonic endothelial progenitor cell survival. AB - Endothelial progenitor cells (EPCs) are mobilized into the vascular space and home to damaged tissues, where they promote repair in part through a process of angiogenesis. Neuregulins (NRGs) are ligands in the epidermal growth factor family that signal through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3, and erbB4) and regulate endothelial cell biology, promoting angiogenesis. Stimuli such as ischemia and exercise that promote EPC mobilization also induce cleavage and release of transmembrane NRG from cardiac microvascular endothelial cells (CMECs). We hypothesized that NRG/erbB signaling may regulate EPC biology. Using an embryonic (e)EPC cell line that homes to and repairs injured myocardium, we were able to detect erbB2 and erbB3 transcripts. Identical receptor expression was found in EPCs isolated from rat bone marrow and human whole blood. NRG treatment of eEPCs induces phosphorylation of kinases including Akt, GSK-3beta, and Erk1/2 and the nuclear accumulation and transcriptional activation of beta-catenin. NRG does not induce eEPC proliferation or migration but does protect eEPCs against serum deprivation-induced apoptosis. These results suggest a role for tissue-derived NRG in the regulation of EPC survival. PMID- 21239628 TI - Isoform-selective 5'-AMP-activated protein kinase-dependent preconditioning mechanisms to prevent postischemic leukocyte-endothelial cell adhesive interactions. AB - We previously demonstrated that preconditioning induced by ethanol consumption at low levels [ethanol preconditioning (EPC)] or with 5-aminoimidazole-4-carboxamide 1-beta-d-ribofuranoside (AICAR-PC) 24 h before ischemia-reperfusion prevents postischemic leukocyte-endothelial cell adhesive interactions (LEI) by a mechanism that is initiated by nitric oxide formed by endothelial nitric oxide synthase. Recent work indicates that 1) ethanol increases the activity of AMP activated protein kinase (AMPK) and 2) AMPK phosphorylates endothelial nitric oxide synthase at the same activation site seen following EPC (Ser1177). In light of these observations, we postulated that the heterotrimeric serine/threonine kinase, AMPK, may play a role in triggering the development of the anti inflammatory phenotype induced by EPC. Ethanol was administered to C57BL/6J mice by gavage in the presence or absence of AMPK inhibition. Twenty-four hours later, the numbers of rolling and adherent leukocytes in postcapillary venules of the small intestine were recorded using an intravital microscopic approach. Following 45 min of ischemia, LEI were recorded after 30 and 60 min of reperfusion or at equivalent time points in control animals. Ischemia-reperfusion induced a marked increase in LEI relative to sham-operated control mice. The increase in LEI was prevented by EPC, an effect that was lost with AMPK inhibition during the period of ethanol exposure. Studies conducted in AMPK alpha(1)- and alpha(2)-knockout mice suggest that the anti-inflammatory effects of AICAR are not dependent on which isoform of the catalytic alpha-subunit is present because a deficiency of either isoform results in a loss of protection. In sharp contrast, EPC appears to be triggered by an AMPK alpha(2)-isoform-dependent mechanism. PMID- 21239629 TI - Heme oxygenase metabolites inhibit tubuloglomerular feedback in vivo. AB - Tubuloglomerular feedback (TGF) is a renal autoregulatory mechanism that constricts the afferent arteriole in response to increases in distal NaCl. Heme oxygenases (HO-1 and HO-2) release carbon monoxide (CO) and biliverdin, which may help control renal function. We showed in vitro that HO products inhibit TGF; however, we do not know whether this also occurs in vivo or the mechanism(s) involved. We hypothesized that in vivo HO-1 and HO-2 in the nephron inhibit TGF via release of CO and biliverdin. We first performed laser capture microdissection followed by real-time PCR and found that both HO-1 and HO-2 are expressed in the macula densa. We next performed micropuncture experiments in vivo on individual rat nephrons, adding different compounds to the perfusate, and found that an HO inhibitor, stannous mesoporphyrin (SnMP), potentiated TGF (P < 0.05, SnMP vs. control). The CO-releasing molecule (CORM)-3 partially inhibited TGF at 50 MUmol/l (P < 0.01, CORM-3 vs. control) and blocked it completely at higher doses. A soluble guanylyl cyclase (sGC) inhibitor, LY83583, blocked the inhibitory effect of CORM-3 on TGF. Biliverdin also partially inhibited TGF (P < 0.01, biliverdin vs. control), most likely attributable to decreased superoxide (O(2)(-)) because biliverdin was rendered ineffective by tempol, a O(2)(-) dismutase mimetic. We concluded that HO-1 and HO-2 in the nephron inhibit TGF by releasing CO and biliverdin. The inhibitory effect of CO on TGF is mediated by the sGC/cGMP signaling pathway, whereas biliverdin probably acts by reducing O(2)(-). PMID- 21239630 TI - High-fat diet is associated with blunted splanchnic sympathoinhibitory responses to gastric leptin and cholecystokinin: implications for circulatory control. AB - Gastric leptin and cholecystokinin (CCK) act on vagal afferents to induce cardiovascular effects and reflex inhibition of splanchnic sympathetic nerve discharge (SSND) and may act cooperatively in these responses. We sought to determine whether these effects are altered in animals that developed obesity in response to a medium high-fat diet (MHFD). Male Sprague-Dawley rats were placed on a low-fat diet (LFD; n = 8) or a MHFD (n = 24) for 13 wk, after which the animals were anesthetized and artificially ventilated. Arterial pressure was monitored and blood was collected for the determination of plasma leptin and CCK. SSND responses to leptin (15 MUg/kg) and CCK (2 MUg/kg) administered close to the coeliac artery were evaluated. Collectively, MHFD animals had significantly higher plasma leptin but lower plasma CCK levels than LFD rats (P < 0.05), and this corresponded to attenuated or reversed SSND responses to CCK (LFD, -21 +/- 2%; and MHFD, -12 +/- 2%; P < 0.05) and leptin (LFD, -6 +/- 2%; and MHFD, 4 +/- 1%; P < 0.001). Alternatively, animals on the MHFD were stratified into obesity prone (OP; n = 8) or obesity-resistant (OR; n = 8) groups according to their weight gain falling within the upper or lower tertile, respectively. OP rats had significantly higher resting arterial pressure, adiposity, and plasma leptin but lower plasma CCK compared with LFD rats (P < 0.05). The SSND responses to CCK or leptin were not significantly different between OP and OR animals. These results demonstrate that a high-fat diet is associated with blunted splanchnic sympathoinhibitory responses to gastric leptin and CCK and may impact on sympathetic vasomotor mechanisms involved in circulatory control. PMID- 21239631 TI - Endothelial ischemia-reperfusion injury in humans: association with age and habitual exercise. AB - Advancing age is a major risk factor for coronary artery disease. Endothelial dysfunction accompanied by increased oxidative stress and inflammation with aging may predispose older arteries to greater ischemia-reperfusion (I/R) injury. Because coronary artery ischemia cannot be induced safely, the effects of age and habitual endurance exercise on endothelial I/R injury have not been determined in humans. Using the brachial artery as a surrogate model of the coronary arteries, endothelial function, assessed by brachial artery flow-mediated dilation (FMD), was measured before and after 20 min of continuous forearm occlusion in young sedentary (n = 10, 24 +/- 2 yr) and middle-aged (n = 9, 48 +/- 2 yr) sedentary adults to gain insight into the effects of primary aging on endothelial I/R injury. Young (n = 9, 25 +/- 1 yr) and middle-aged endurance-trained (n = 9, 50 +/- 2 yr) adults were also studied to determine whether habitual exercise provides protection from I/R injury. Fifteen minutes after ischemic injury, FMD decreased significantly by 37% in young sedentary, 35% in young endurance trained, 68% in middle-aged sedentary, and 50% in middle-aged endurance-trained subjects. FMD returned to baseline levels within 30 min in young sedentary and endurance-trained subjects but remained depressed in middle-aged sedentary and endurance-trained subjects. Circulating markers of antioxidant capacity and inflammation were not related to FMD. In conclusion, advancing age is associated with a greater magnitude and delayed recovery from endothelial I/R injury in humans. Habitual endurance exercise may provide partial protection to the endothelium against this form of I/R injury with advancing age. PMID- 21239632 TI - Nicotine aggravates the brain postischemic inflammatory response. AB - A substantial body of evidence suggests that nicotine adversely affects cerebral blood flow and the blood-brain barrier and is a risk factor for stroke. The present study investigated the effect of nicotine on cerebrovascular endothelium under basal and ischemia/reperfusion injury under in vivo condition. Nicotine (2 mg/kg sc) was administered to mice over 14 days, which resulted in plasma nicotine levels of ~100 ng/ml, reflecting plasma concentrations in average to heavy smokers. An analysis of the phenotype of isolated brain microvessels after nicotine exposure indicated higher expression of inflammatory mediators, cytokines (IL-1beta, TNF-alpha, and IL-18), chemokines (CCL2 and CX(3)CL1), and adhesion molecules (ICAM-1, VCAM-1, and P-selectins), and this was accompanied by enhanced leukocyte infiltration into brain during ischemia/reperfusion (P < 0.01). Nicotine had a profound effect on ischemia/reperfusion injury; i.e., increased brain infarct size (P < 0.01), worse neurological deficits, and a higher mortality rate. These experiments illuminate, for the first time, how nicotine regulates brain endothelial cell phenotype and postischemic inflammatory response at the brain-vascular interface. PMID- 21239633 TI - [Ca2+]i signaling vs. eNOS expression as determinants of NO output in uterine artery endothelium: relative roles in pregnancy adaptation and reversal by VEGF165. AB - Pregnancy is a time of greatly increased uterine blood flow to meet the needs of the growing fetus. Increased uterine blood flow is also observed in the follicular phase of the ovarian cycle. Simultaneous fura-2 and 4,5 diaminofluoresceine (DAF-2) imaging reveals that cells of the uterine artery endothelium (UA Endo) from follicular phase ewes produce marginally more nitric oxide (NO) in response to ATP than those from luteal phase. However, this is paralleled by changes in NO in response to ionomycin, suggesting this is solely due to higher levels of endothelial nitric oxide synthase (eNOS) protein in the follicular phase. In contrast, UA Endo from pregnant ewes (P-UA Endo) produces substantially more NO (4.62-fold initial maximum rate, 2.56-fold overall NO production) in response to ATP, beyond that attributed to eNOS levels alone (2.07 fold initial maximum rate, 1.93-fold overall with ionomycin). The ATP-stimulated intracellular free calcium concentration ([Ca(2+)](i)) response in individual cells of P-UA Endo comprises an initial peak followed by transient [Ca(2+)](i) bursts that are limited in the luteal phase, not altered in the follicular phase, but are sustained in pregnancy and observed in more cells. Thus pregnancy adaptation of UA Endo NO output occurs beyond the level of eNOS expression and likely through associated [Ca(2+)](i) cell signaling changes. Preeclampsia is a condition of a lack of UA Endo adaptation and poor NO production/vasodilation and is associated with elevated placental VEGF(165). While treatment of luteal NP-UA Endo and P-UA Endo with VEGF(165) acutely stimulates a very modest [Ca(2+)](i) and NO response, subsequent stimulation of the same vessel with ATP results in a blunted [Ca(2+)](i) and an associated NO response, with P-UA Endo reverting to the response of luteal NP-UA Endo. This demonstrates the importance of adaptation of cell signaling over eNOS expression in pregnancy adaptation of uterine endothelial function and further implicates VEGF in the pathophysiology of preeclampsia. PMID- 21239634 TI - Acute antioxidant supplementation and skeletal muscle vascular conductance in aged rats: role of exercise and fiber type. AB - Age-related increases in oxidative stress contribute to impaired skeletal muscle vascular control. However, recent evidence indicates that antioxidant treatment with tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) attenuates flow mediated vasodilation in isolated arterioles from the highly oxidative soleus muscle of aged rats. Whether antioxidant treatment with tempol evokes similar responses in vivo at rest and during exercise in senescent individuals and whether this effect varies based on muscle fiber type composition are unknown. We tested the hypothesis that redox modulation via acute systemic tempol administration decreases vascular conductance (VC) primarily in oxidative hindlimb locomotor muscles at rest and during submaximal whole body exercise (treadmill running at 20 m/min, 5% grade) in aged rats. Eighteen old (25-26 mo) male Fischer 344 x Brown Norway rats were assigned to either rest (n = 8) or exercise (n = 10) groups. Regional VC was determined via radiolabeled microspheres before and after intra-arterial administration of tempol (302 MUmol/kg). Tempol decreased mean arterial pressure significantly by 9% at rest and 16% during exercise. At rest, similar VC in 26 out of 28 individual hindlimb muscles or muscle parts following tempol administration compared with control resulted in unchanged total hindlimb muscle VC (control: 0.18 +/- 0.02; tempol: 0.17 +/- 0.05 ml.min(-1).100 g(-1).mmHg(-1); P > 0.05). During exercise, all individual hindlimb muscles or muscle parts irrespective of fiber type composition exhibited either an increase or no change in VC with tempol (i.e., ?11 and <->17 muscles or muscle parts), such that total hindlimb VC increased by 25% (control: 0.93 +/- 0.04; tempol: 1.15 +/- 0.09 ml.min(-1).100 g(-1).mmHg(-1); P <= 0.05). These results demonstrate that acute systemic administration of the antioxidant tempol significantly impacts the control of regional vascular tone in vivo presumably via redox modulation and improves skeletal muscle vasodilation independently of fiber type composition during submaximal whole body exercise in aged rats. PMID- 21239635 TI - Treatment of diabetic rats with a peroxynitrite decomposition catalyst prevents induction of renal COX-2. AB - Cyclooxygenase (COX)-2 expression is increased in the kidney of rats made diabetic with streptozotocin and associated with enhanced release of prostaglandins stimulated by arachidonic acid (AA). Treatment of diabetic rats with nitro-L-arginine methyl ester (L-NAME) to inhibit nitric oxide synthase or with tempol to reduce superoxide prevented these changes, suggesting the possibility that peroxynitrite (ONOO) may be the stimulus for the induction of renal COX-2 in diabetes. Consequently, we tested the effects of an ONOO decomposition catalyst, 5,10,15,20-tetrakis(N-methyl-4'-pyridyl)porphyrinato iron(III) (FeTMPyP), which was administered for 3-4 wk after the induction of diabetes. FeTMPyP treatment normalized the twofold increase in the expression of nitrotyrosine, a marker for ONOO formation, in the diabetic rat and prevented the increase in renal COX-2 expression without modifying the two- to threefold increases in renal release of prostaglandins PGE(2) and 6-ketoPGF(1alpha) in response to AA. FeTMPyP treatment of diabetic rats reduced the elevated creatinine clearance and urinary excretion of TNF-alpha and transforming growth factor (TGF)-beta, suggesting a renoprotective effect. Double immunostaining of renal sections and immunoprecipitation of COX-2 and nitrotyrosine suggested nitration of COX-2 in diabetic rats. In cultured human umbilical vein endothelial cells (HUVECs) exposed to elevated glucose (450 mg/dl) or ONOO derived from 3 morpholinosydnonimine (SIN-1), expression of COX-2 was increased and was prevented when endothelial cells were treated with FeTMPyP. These results indicate that elevated glucose increases the formation of ONOO, which contributes to the induction of renal COX-2 in the diabetic rat. PMID- 21239636 TI - Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression. AB - There is emerging evidence that aldosterone can promote diastolic dysfunction and cardiac fibrosis independent of blood pressure effects, perhaps through increased oxidative stress and inflammation. Accordingly, this investigation was designed to ascertain if mineralocorticoid receptor blockade improves diastolic dysfunction independently of changes in blood pressure through actions on myocardial oxidative stress and fibrosis. We used young transgenic (mRen2)27 [TG(mRen2)27] rats with increases in both tissue ANG II and circulating aldosterone, which manifests age-related increases in hypertension and cardiac dysfunction. Male TG(mRen2)27 and age-matched Sprague-Dawley rats were treated with either a low dose (~1 mg.kg(-1).day(-1)) or a vasodilatory, conventional dose (~30 mg.kg(-1).day(-1)) of spironolactone or placebo for 3 wk. TG(mRen2)27 rats displayed increases in systolic blood pressure and plasma aldosterone levels as well as impairments in left ventricular diastolic relaxation without changes in systolic function on cine MRI. TG(mRen2)27 hearts also displayed hypertrophy (left ventricular weight, cardiomyoctye hypertrophy, and septal wall thickness) as well as fibrosis (interstitial and perivascular). There were increases in oxidative stress in TG(mRen2)27 hearts, as evidenced by increases in NADPH oxidase activity and subunits as well as ROS formation. Low-dose spironolactone had no effect on systolic blood pressure but improved diastolic dysfunction comparable to a conventional dose. Both doses of spironolactone caused comparable reductions in ROS/3-nitrotryosine immunostaining and perivascular and interstitial fibrosis. These data support the notion mineralocorticoid receptor blockade improves diastolic dysfunction through improvements in oxidative stress and fibrosis independent of changes in systolic blood pressure. PMID- 21239638 TI - Atrial tachycardia/fibrillation in the connexin 43 G60S mutant (Oculodentodigital dysplasia) mouse. AB - Atrial fibrillation (AF), the most common cardiac arrhythmia seen in general practice, can be promoted by conduction slowing. Cardiac impulse conduction depends on gap junction channels, which are composed of connexins (Cxs). While atrial Cx40 and Cx43 are equally expressed, AF studies have primarily focused on Cx40 reductions. The G60S Cx43 mutant (Cx43(G60S/+)) mouse model of Oculodentodigital dysplasia has a 60% reduction in Cx43 in the atria. Cx43(G60S/+) mice were compared with Cx40-deficient (Cx40(-/-)) mice to determine the role of Cxs in atrial tachycardia/fibrillation (AT/F). Intracardiac electrophysiological studies were done in 6-mo-old male C57BL/6 Cx43(G60S/+) mutant, littermate (Cx43(+/+)), Cx40(-/-), and C57BL/6 wild-type (WT) mice. AT/F induction used an extra stimulus during sinus rhythm, programmed electrical stimulation, or burst pacing (1-ms pulses, 50-Hz, 400-ms train) in the absence and presence of carbachol (CCh). Atrial effective refractory periods did not differ between strains. Cx43(G60S/+) mice were more susceptible to induction of sustained AT/F (duration >2 min, 9 of 12; maximum >35 min) compared with Cx43(+/+) mice (3 of 11; chi(2) = 5.24; P = 0.02). CCh enhanced sustained AT/F susceptibility in WT (from 1 of 12 without, to 7 of 10 with CCh; chi(2) = 8.98; P < 0.01) but not in Cx40(-/-) mice (1 of 13 without vs. 2 of 9 with CCh; chi(2) = 0.95; P = NS). The pattern of epicardial recordings during AT/F in Cx43(G60S/+) mice was left preceding right, with left atrial fractionated activation patterns consistent with clinical observations of AF. In conclusions, while Cx43(G60S/+) mice had severe AT/F, Cx40(-/-) mice were resistant to CCh-induced AT/F. PMID- 21239637 TI - Blood flow dynamics of one cardiac cycle and relationship to mechanotransduction and trabeculation during heart looping. AB - Analyses of form-function relationships during heart looping are directly related to technological advances. Recent advances in four-dimensional optical coherence tomography (OCT) permit observations of cardiac dynamics at high-speed acquisition rates and high resolution. Real-time observation of the avian stage 13 looping heart reveals that interactions between the endocardial and myocardial compartments are more complex than previously depicted. Here we applied four dimensional OCT to elucidate the relationships of the endocardium, myocardium, and cardiac jelly compartments in a single cardiac cycle during looping. Six cardiac levels along the longitudinal heart tube were each analyzed at 15 time points from diastole to systole. Using image analyses, the organization of mechanotransducing molecules, fibronectin, tenascin C, alpha-tubulin, and nonmuscle myosin II was correlated with specific cardiac regions defined by OCT data. Optical coherence microscopy helped to visualize details of cardiac architectural development in the embryonic mouse heart. Throughout the cardiac cycle, the endocardium was consistently oriented between the midline of the ventral floor of the foregut and the outer curvature of the myocardial wall, with multiple endocardial folds allowing high-volume capacities during filling. The cardiac area fractional shortening is much higher than previously published. The in vivo profile captured by OCT revealed an interaction of the looping heart with the extra-embryonic splanchnopleural membrane providing outside-in information. In summary, the combined dynamic and imaging data show the developing structural capacity to accommodate increasing flow and the mechanotransducing networks that organize to effectively facilitate formation of the trabeculated four-chambered heart. PMID- 21239640 TI - 20-Hydroxyeicosatetraenoic acid synthesis is increased in human neutrophils and platelets by angiotensin II and endothelin-1. AB - The cytochrome P-450 arachidonic acid metabolite 20-HETE is central to the regulation of vascular tone, renal function, and blood pressure and is synthesized in the rat kidney in response to angiotensin II (ANG II) and endothelin-1 (ET-1). There are very few studies examining the cellular synthesis of 20-HETE in humans. We aimed to measure human neutrophil and platelet 20-HETE levels under basal conditions and after ANG II, ET-1, and calcium ionophore (CaI). 20-HETE was measured in human platelets and neutrophils after saline (control), CaI (2.5 MUg/ml), and ANG II or ET-1 (10 nmol/l-1 MUmol/l) incubations. The effect of cells, which were preincubated with the omega hydroxylase inhibitor N-hydroxy-N'-(4-butyl-2-methylphenyl) (HET0016, 10 nM), ANG II types 1 or 2 (AT(1) or AT(2)) receptor inhibition with irbesartan (1 MUmol/l) or PD-123319 (1 MUmol/l), or endothelin receptor subtypes A or B (ET(A) or ET(B)) receptor inhibition with BQ-123 or BQ-778 (100 nmol/l), was studied. Neutrophil and platelet content and release of 20-HETE was significantly increased by CaI and blocked by the omega-hydroxylase inhibitor HET0016. ANG II and ET-1 significantly increased neutrophil and platelet content and release of 20-HETE. ANG II increased 20-HETE via the AT(2) receptor. ET-1 increased 20-HETE through the ET(B) receptor in platelets and both the ET(A) and ET(B) receptors in neutrophils. These studies show that human platelets and neutrophils synthesize 20-HETE in response to ANG II and ET-1. 20-HETE synthesis in both cell types was predominantly mediated via the AT(2) and ET(B) receptors. Stimulation via these receptor pathways has generally been thought to be cardioprotective and requires further studies in clinical situations associated with low-grade inflammation or where ANG II and ET-1 are elevated to clarify the role of 20-HETE. PMID- 21239639 TI - Active tension adaptation at a shortened arterial muscle length: inhibition by cytochalasin-D. AB - Unlike the static length-tension curve of striated muscle, airway and urinary bladder smooth muscles display a dynamic length-tension curve. Much less is known about the plasticity of the length-tension curve of vascular smooth muscle. The present study demonstrates that there were significant increases of ~15% in the phasic phase and ~10% in the tonic phase of a third KCl-induced contraction of a rabbit femoral artery ring relative to the first contraction after a 20% decrease in length from an optimal muscle length (L(0)) to 0.8-fold L(0). Typically, three repeated contractions were necessary for full length adaptation to occur. The tonic phase of a third KCl-induced contraction was increased by ~50% after the release of tissues from 1.25-fold to 0.75-fold L(o). The mechanism for this phenomenon did not appear to lie in thick filament regulation because there was no increase in myosin light chain (MLC) phosphorylation to support the increase in tension nor was length adaptation abolished when Ca(2+) entry was limited by nifedipine and when Rho kinase (ROCK) was blocked by H-1152. However, length adaptation of both the phasic and tonic phases was abolished when actin polymerization was inhibited through blockade of the plus end of actin by cytochalasin-D. Interestingly, inhibition of actin polymerization when G-actin monomers were sequestered by latrunculin-B increased the phasic phase and had no effect on the tonic phase of contraction during length adaptation. These data suggest that for a given level of cytosolic free Ca(2+), active tension in the femoral artery can be sensitized not only by regulation of MLC phosphatase via ROCK and protein kinase C, as has been reported by others, but also by a nonmyosin regulatory mechanism involving actin polymerization. Dysregulation of this form of active tension modulation may provide insight into alterations of large artery stiffness in hypertension. PMID- 21239642 TI - Glutathione-indole-3-acetonitrile is required for camalexin biosynthesis in Arabidopsis thaliana. AB - Camalexin, a major phytoalexin in Arabidopsis thaliana, consists of an indole ring and a thiazole ring. The indole ring is produced from Trp, which is converted to indole-3-acetonitrile (IAN) by CYP79B2/CYP79B3 and CYP71A13. Conversion of Cys(IAN) to dihydrocamalexic acid and subsequently to camalexin is catalyzed by CYP71B15. Recent studies proposed that Cys derivative, not Cys itself, is the precursor of the thiazole ring that conjugates with IAN. The nature of the Cys derivative and how it conjugates to IAN and subsequently forms Cys(IAN) remain obscure. We found that protein accumulation of multiple glutathione S-transferases (GSTs), elevation of GST activity, and consumption of glutathione (GSH) coincided with camalexin production. GSTF6 overexpression increased and GSTF6-knockout reduced camalexin production. Arabidopsis GSTF6 expressed in yeast cells catalyzed GSH(IAN) formation. GSH(IAN), (IAN)CysGly, and gammaGluCys(IAN) were determined to be intermediates within the camalexin biosynthetic pathway. Inhibitor treatments and mutant analyses revealed the involvement of gamma-glutamyl transpeptidases (GGTs) and phytochelatin synthase (PCS) in the catabolism of GSH(IAN). The expression of GSTF6, GGT1, GGT2, and PCS1 was coordinately upregulated during camalexin biosynthesis. These results suggest that GSH is the Cys derivative used during camalexin biosynthesis, that the conjugation of GSH with IAN is catalyzed by GSTF6, and that GGTs and PCS are involved in camalexin biosynthesis. PMID- 21239643 TI - The submergence tolerance regulator SUB1A mediates crosstalk between submergence and drought tolerance in rice. AB - Submergence and drought are major constraints to rice (Oryza sativa) production in rain-fed farmlands, both of which can occur sequentially during a single crop cycle. SUB1A, an ERF transcription factor found in limited rice accessions, dampens ethylene production and gibberellic acid responsiveness during submergence, economizing carbohydrate reserves and significantly prolonging endurance. Here, we evaluated the functional role of SUB1A in acclimation to dehydration. Comparative analysis of genotypes with and without SUB1A revealed that SUB1A enhanced recovery from drought at the vegetative stage through reduction of leaf water loss and lipid peroxidation and increased expression of genes associated with acclimation to dehydration. Overexpression of SUB1A augmented ABA responsiveness, thereby activating stress-inducible gene expression. Paradoxically, vegetative tissue undergoes dehydration upon desubmergence even though the soil contains sufficient water, indicating that leaf desiccation occurs in the natural progression of a flooding event. Desubmergence caused the upregulation of gene transcripts associated with acclimation to dehydration, with higher induction in SUB1A genotypes. SUB1A also restrained accumulation of reactive oxygen species (ROS) in aerial tissue during drought and desubmergence. Consistently, SUB1A increased the abundance of transcripts encoding ROS scavenging enzymes, resulting in enhanced tolerance to oxidative stress. Therefore, in addition to providing robust submergence tolerance, SUB1A improves survival of rapid dehydration following desubmergence and water deficit during drought. PMID- 21239645 TI - Pollen tubes lacking a pair of K+ transporters fail to target ovules in Arabidopsis. AB - Flowering plant reproduction requires precise delivery of the sperm cells to the ovule by a pollen tube. Guidance signals from female cells are being identified; however, how pollen responds to those cues is largely unknown. Here, we show that two predicted cation/proton exchangers (CHX) in Arabidopsis thaliana, CHX21 and CHX23, are essential for pollen tube guidance. Male fertility was unchanged in single chx21 or chx23 mutants. However, fertility was impaired in chx21 chx23 double mutant pollen. Wild-type pistils pollinated with a limited number of single and double mutant pollen producing 62% fewer seeds than those pollinated with chx23 single mutant pollen, indicating that chx21 chx23 pollen is severely compromised. Double mutant pollen grains germinated and grew tubes down the transmitting tract, but the tubes failed to turn toward ovules. Furthermore, chx21 chx23 pollen tubes failed to enter the micropyle of excised ovules. Green fluorescent protein-tagged CHX23 driven by its native promoter was localized to the endoplasmic reticulum of pollen tubes. CHX23 mediated K(+) transport, as CHX23 expression in Escherichia coli increased K(+) uptake and growth in a pH dependent manner. We propose that by modifying localized cation balance and pH, these transporters could affect steps in signal reception and/or transduction that are critical to shifting the axis of polarity and directing pollen growth toward the ovule. PMID- 21239648 TI - Essential tools of the trade. PMID- 21239649 TI - Hypoxic-ischaemic brain injury. AB - Hypoxic-ischaemic brain injury is common and usually due to cardiac arrest or profound hypotension. The clinical pattern and outcome depend on the severity of the initial insult, the effectiveness of immediate resuscitation and transfer, and the post-resuscitation management on the intensive care unit. Clinical assessment is difficult and so often these days compromised by sedation, neuromuscular blockade, ventilation, hypothermia and inotropic management. Investigations can add valuable information, in particular brain MRI shows characteristic patterns depending on the severity of the injury and the timing of imaging. EEG patterns may also suggest the possibility of a good outcome. There is no entirely reliable algorithm of clinical signs or investigations which allow a definitive prognosis but the combination of careful repeated observations and appropriate ancillary investigations allows the neurologist to give an informed and accurate opinion of the likely outcome, and to advise on management. Overall, the prognosis is extremely poor and only a quarter of patients survive to hospital discharge, and often even then with severe neurological or cognitive deficits. PMID- 21239650 TI - Creutzfeldt-Jacob disease mimics, or how to sort out the subacute encephalopathy patient. AB - Sporadic Creutzfeldt-Jacob disease (CJD) is a rare untreatable neurodegenerative disease which every neurologist will occasionally encounter during their career. However, it is likely to appear on their differential diagnosis list significantly more frequently. Numerous conditions can present with subacute encephalopathy which might be sporadic CJD and this article explores these diagnoses. It includes the commonest sporadic CJD mimics which are neurodegenerative, and highlights the relatively rare treatable mimics which must not be missed. It discusses relevant investigations, including serum antibodies, CSF, electroencephalography and MR brain imaging, and strategies when preliminary investigations fail to support sporadic CJD but no alternative diagnosis is readily apparent. PMID- 21239646 TI - Malate plays a crucial role in starch metabolism, ripening, and soluble solid content of tomato fruit and affects postharvest softening. AB - Despite the fact that the organic acid content of a fruit is regarded as one of its most commercially important quality traits when assessed by the consumer, relatively little is known concerning the physiological importance of organic acid metabolism for the fruit itself. Here, we evaluate the effect of modifying malate metabolism in a fruit-specific manner, by reduction of the activities of either mitochondrial malate dehydrogenase or fumarase, via targeted antisense approaches in tomato (Solanum lycopersicum). While these genetic perturbations had relatively little effect on the total fruit yield, they had dramatic consequences for fruit metabolism, as well as unanticipated changes in postharvest shelf life and susceptibility to bacterial infection. Detailed characterization suggested that the rate of ripening was essentially unaltered but that lines containing higher malate were characterized by lower levels of transitory starch and a lower soluble sugars content at harvest, whereas those with lower malate contained higher levels of these carbohydrates. Analysis of the activation state of ADP-glucose pyrophosphorylase revealed that it correlated with the accumulation of transitory starch. Taken together with the altered activation state of the plastidial malate dehydrogenase and the modified pigment biosynthesis of the transgenic lines, these results suggest that the phenotypes are due to an altered cellular redox status. The combined data reveal the importance of malate metabolism in tomato fruit metabolism and development and confirm the importance of transitory starch in the determination of agronomic yield in this species. PMID- 21239652 TI - Stem cells as a resource for regenerative neurology. AB - Public and media interest in the potential applications of stem cells in regenerative neurology has led to growing hope and expectation. This interest is heightened by the current paucity of treatments available for neurodegenerative diseases and their generally poor prognosis. Patient discussions about stem cells are therefore a common occurrence in clinical practice, requiring neurologists to offer clear and accurate information. In the context of a complex and rapidly evolving field, this can be extremely challenging. Here we address issues around stem cell populations relevant to regenerative neurology, including the opportunities they offer for research and their potential application as direct therapies, concluding with a pragmatic assessment of the likely clinical benefits of stem cell research. PMID- 21239653 TI - John Hughlings Jackson and our understanding of the epilepsies 100 years on. AB - The term Jacksonian epilepsy was coined by Jean Martin Charcot following John Hughlings Jackson's 1870 paper 'A study of convulsions', where he had defined a convulsion as "a symptom resulting from an occasional, an excessive and a disorderly discharge of nerve tissue on muscles". His earlier writings had included cases of syphilis related epilepsy, and the introduction of the first successful antiepileptic drugs-the bromides. Based on careful clinical observation or, as Hughlings Jackson himself put it, on the "experiments performed by disease", 'A study of convulsions' was a synthesis of those previous reports which has contributed to our practical understanding of epilepsy, a contribution which continues to inform our thinking to the present day. PMID- 21239654 TI - Multiple retinal emboli in a case of acute stroke. PMID- 21239655 TI - Thinking outside of the box. PMID- 21239656 TI - Lao People's Democratic Republic. PMID- 21239657 TI - The bare essentials: head injury. PMID- 21239658 TI - Volar locking plate implant prominence and flexor tendon rupture. AB - BACKGROUND: Flexor tendon injury is a recognized complication of volar plate fixation of distal radial fractures. A suspected contributing factor is implant prominence at the watershed line, where the flexor tendons lie closest to the plate. METHODS: Two parallel series of patients who underwent volar locked plating of distal radial fractures from 2005 to 2008 and with at least six months of follow-up were retrospectively reviewed. Group 1 included seventy-three distal radial fractures that were treated by three orthopaedic hand surgeons with use of a single plate design at one institution, and Group 2 included ninety-five distal radial fractures that were treated by four orthopaedic hand surgeons with use of a different plate design at another institution. On the postoperative lateral radiographs, a line was drawn tangential to the most volar extent of the volar rim, parallel to the volar cortical bone of the radial shaft. Plates that did not extend volar to this line were recorded as Grade 0. Plates volar to the line, but proximal to the volar rim, were recorded as Grade 1. Plates directly on or distal to the volar rim were recorded as Grade 2. RESULTS: In Group 1, the average duration of follow-up was thirteen months (range, six to forty-nine months). Three cases of flexor tendon rupture were identified among seventy-three plated radii (prevalence, 4%). Grade-2 plate prominence was found in two of the three cases with rupture and in forty-six cases (63%) overall. In Group 2, the average duration of follow-up was fifteen months (range, six to fifty-six months). There were no cases of flexor tendon rupture and no plates with Grade-2 prominence among ninety-five plated radii. CONCLUSIONS: Flexor tendon rupture after volar plating of the distal part of the radius is an infrequent but serious complication. The plate used in Group 1 is prominent at the watershed line of the distal part of the radius, which may increase the risk of tendon injury. We found no ruptures in Group 2, perhaps as a result of the lower profile of the plate. Further studies are needed before recommending one plate over another. Regardless of plate selection, surgeons should avoid implant prominence in this area. PMID- 21239659 TI - Quality defects in market beef and dairy cows and bulls sold through livestock auction markets in the Western United States: II. Relative effects on selling price. AB - Relative effects of Beef Quality Assurance (BQA)-related defects in market beef and dairy cows and bulls on selling price at auction was evaluated during 2008. The presence and severity of 23 BQA-related traits were determined during sales in Idaho, California, and Utah. Overall, 18,949 unique lots consisting of 23,479 animals were assessed during 125 dairy sales and 79 beef sales. Mean sale price +/- SD (per 45.5 kg) for market beef cows, beef bulls, dairy cows, and dairy bulls was $45.15 +/- 9.42, $56.30 +/- 9.21, $42.23 +/- 12.26, and $55.10 +/- 9.07, respectively. When combined, all recorded traits explained 36% of the variation in selling price in beef cows, 35% in beef bulls, 61% in dairy cows, and 56% in dairy bulls. Premiums and discounts were determined in comparison with a "par" or "base" animal. Compared with a base BCS 5 beef cow (on a 9-point beef scale), BCS 1 to 4 cows were discounted (P < 0.0001), whereas premiums (P < 0.05) were estimated for BCS 6 to 8. Compared with a base BCS 3.0 dairy cow (on a 5 point dairy scale), more body condition resulted in a premium (P <= 0.001), whereas a less-than-desirable BCS of 2.0 or 2.5 was discounted (P < 0.0001). Emaciated or near-emaciated cows (beef BCS 1 or 2; dairy BCS 1.0 or 1.5) were discounted (P < 0.0001). Compared with base cows weighing 545 to 635 kg, lighter BW beef cows were discounted (P < 0.0001), whereas heavier beef cows received (P < 0.05) a premium. Compared with a base dairy cow weighing 636 to 727 kg, lighter BW cows were discounted (P < 0.0001), whereas heavier cows (727 to 909 kg) received a premium (P < 0.01). Beef and dairy cows with any evidence of lameness were discounted (P < 0.0001). Presence of ocular neoplasia in the precancerous stage discounted (P = 0.05) beef cows and discounted (P < 0.01) dairy cows, whereas at the cancerous stage, it discounted (P < 0.0001) all cows. Hide color influenced (P < 0.0001) selling price in beef cattle but had no effect (P = 0.17) in dairy cows. Animals that were visibly sick were discounted (P < 0.0001). Results suggest that improving BCS and BW, which producers can do at the farm or ranch level, positively affects sale price. Furthermore, animals that are visibly sick or have a defect associated with a possible antibiotic risk will be discounted. Ultimately, animals with minor quality defects should be sold in a timely manner before the defect advances and the discount increases. PMID- 21239660 TI - Survey of quality defects in market beef and dairy cows and bulls sold through livestock auction markets in the Western United States: I. Incidence rates. AB - A survey was conducted to quantify incidence of Beef Quality Assurance (BQA) related defects in market beef and dairy cows and bulls selling at auction during 2 seasons in 2008. Twenty-three BQA-related traits were evaluated by 9 trained personnel during sales at 10 livestock auction markets in Idaho (n = 5; beef and dairy), California, (n = 4; dairy only), and Utah (n = 1; beef and dairy). Overall, 18,949 unique lots (8,213 beef cows, 1,036 beef bulls, 9,177 dairy cows, and 523 dairy bulls,) consisting of 23,479 animals (9,299 beef cows, 1,091 beef bulls, 12,429 dairy cows, and 660 dairy bulls) were evaluated during 125 sales (64 spring, 61 fall) for dairy and 79 sales (40 spring, 39 fall) for beef. The majority of market beef cows and bulls (60.9 and 71.3%, respectively) were predominantly black-hided, and the Holstein hide pattern was observed in 95.4 and 93.6% of market dairy cows and bulls, respectively. Market cattle weighed 548 +/- 103.6 kg (beef cows), 751 +/- 176.1 kg (beef bulls), 658 +/- 129.7 kg (dairy cows), and 731 +/- 150.8 kg (dairy bulls). Most beef cows (79.6%) weighed 455 to 726 kg, and most beef bulls (73.8%) weighed 545 to 954 kg, respectively. Among market beef cattle, 16.0% of cows and 14.5% of bulls weighed less than 455 and 545 kg, respectively, and 63.7% of dairy cows and 81.5% of dairy bulls weighed 545 to 817 kg or 545 to 954 kg, respectively. However, 19.5% of dairy cows and 13.1% of dairy bulls weighed less than 545 kg. Mean BCS for beef cattle (9-point scale) was 4.7 +/- 1.2 (cows) and 5.3 +/- 0.9 (bulls), and for dairy cattle (5 point scale) was 2.6 +/- 0.8 (cows) and 2.9 +/- 0.6 (bulls). Some 16.5% of beef cows and 4.1% of beef bulls had a BCS of 1 to 3, whereas 34.8% of dairy cows and 10.4% of dairy bulls had a BCS of 2 or less. Emaciation (beef BCS = 1, dairy BCS = 1.0) or near-emaciation (beef BCS = 2, dairy BCS = 1.5) was observed in 13.3% of dairy cows and 3.9% of beef cows. Among beef cattle, 15.1% of cows and 15.4% of bulls were considered lame. In contrast, 44.7% of dairy cows and 26.1% of dairy bulls were lame. Ocular neoplasia (cancer eye) was observed in only 0.6% of beef cows, 0.3% of beef bulls, 0.3% of dairy cows, and 0.0% of dairy bulls. However, among animals with ocular neoplasia, it was cancerous in 34.4% of beef bulls, 48.0% of dairy cows, and 73.3% of beef cows. In conclusion, numerous quality defects are present in market beef and dairy cattle selling at auction in the Western United States, which could influence their value at auction. PMID- 21239661 TI - Horse species symposium: a novel approach to monitoring pathogen progression during uterine and placental infection in the mare using bioluminescence imaging technology and lux-modified bacteria. AB - Uterine and placental infections are the leading cause of abortion, stillbirth, and preterm delivery in the mare. Whereas uterine and placental infections in women have been studied extensively, a comprehensive examination of the pathogenic processes leading to this unsatisfactory pregnancy outcome in the mare has yet to be completed. Most information in the literature relating to late-term pregnancy loss in mares is based on retrospective studies of clinical cases submitted for necropsy. Here we report the development and application of a novel approach, whereby transgenically modified bacteria transformed with lux genes of Xenorhabdus luminescens or Photorhabdus luminescens origin and biophotonic imaging are utilized to better understand pathogen-induced preterm birth in late term pregnant mares. This technology uses highly sensitive bioluminescence imaging camera systems to localize and monitor pathogen progression during tissue invasion by measuring the bioluminescent signatures emitted by the lux-modified pathogens. This method has an important advantage in that it allows for the potential tracking of pathogens in vivo in real time and over time, which was hitherto impossible. Although the application of this technology in domestic animals is in its infancy, investigators were successful in identifying the fetal lungs, sinuses, nares, urinary, and gastrointestinal systems as primary tissues for pathogen invasion after experimental infection of pregnant mares with lux modified Escherichia coli. It is important that pathogens were not detected in other vital organs, such as the liver, brain, and cardiac system. Such precision in localizing sites of pathogen invasion provides potential application for this novel approach in the development of more targeted therapeutic interventions for pathogen-related diseases in the equine and other domestic species. PMID- 21239662 TI - Genetic parameters of insect bite hypersensitivity in Dutch Friesian broodmares. AB - Insect bite hypersensitivity (IBH) is a seasonal allergic skin disease in horses caused by bites of certain Culicoides spp. The aim of our study was to investigate the maternal effect on IBH and to estimate the heritability and repeatability of IBH in the Dutch Friesian horse population. Data consisted of 3,453 Dutch Friesian broodmares with 3,763 visual observations on IBH clinical symptoms scored by 12 inspectors during organized foal inspections in 2004 and 2008. Nine percent of the mares (n = 310) were scored in both years. Mares descended from 144 sires and 2,554 dams and 26.2% of the dams (n = 669) had more than 1 offspring in the data set (range: 2 to 6). Insect bite hypersensitivity was analyzed as a binary trait with a threshold animal model with and without a maternal effect, using a Bayesian approach. Observed IBH prevalence in Dutch Friesian broodmare population was 18.2%. Heritability on the liability scale was 0.16 (SD = 0.06); heritability on the observed scale was 0.07; and repeatability was 0.89 (SD = 0.03). Maternal effect was 0.17 (SD = 0.06) and significantly differed from zero, although the animal model without a maternal effect fitted the data better. These results show that genetic and permanent environmental factors affect IBH in Dutch Friesian horses. The dam affected the IBH development of her offspring through an additive genetic influence but also by being part of their rearing environment. PMID- 21239663 TI - New insights into the pathogenesis of cystic follicles in cattle: microarray analysis of gene expression in granulosa cells. AB - Ovarian follicular growth and development are regulated by extraovarian and intraovarian factors, which influence granulosa cell proliferation and differentiation. However, the molecular mechanisms that drive follicular growth are not completely understood. Ovarian follicular cysts are one of the most common causes of reproductive failure in dairy cattle. Nevertheless, the primary cause of cyst formation has not been clearly established. A gene expression comparison may aid in elucidating the causes of ovarian cyst disease. Our objective was to identify differentially expressed genes in ovarian granulosa cells between normal dominant and cystic follicles of cattle. Granulosa cells and follicular fluid were isolated from dominant and cystic follicles collected via either ultrasound-guided aspiration from dairy cows (n = 24) or slaughterhouse ovaries from beef cows (n = 23). Hormonal analysis for progesterone, estradiol, and androstenedione in follicular fluid was performed by RIA. Total RNA was extracted and hybridized to 6 Affymetrix GeneChip Bovine Genome Arrays (Affymetrix, Santa Clara, CA). Abundance of mRNA for differentially expressed selected genes was determined through quantitative real-time reverse transcription PCR. Follicular cysts showed greater (P < 0.05) progesterone, lesser (P < 0.05) estradiol, and no differences (P > 0.10) in androstenedione concentrations compared with noncystic follicles. A total of 163 gene sequences were differentially expressed (P < 0.01), with 19 upregulated and 144 downregulated. From selected target genes, quantitative real-time reverse transcription PCR confirmed angiogenin, PGE(2) receptor 4, and G-protein coupled receptor 34 genes as upregulated in cystic follicles, and Indian hedgehog protein precursor and secreted frizzled-related protein 4 genes as downregulated in cystic follicles. Further research is required to elucidate the role of these factors in follicular development and cyst formation. PMID- 21239664 TI - Genome-wide association studies for feedlot and growth traits in cattle. AB - A genome wide-association study for production traits in cattle was carried out using genotype data from the 10K Affymetrix (Santa Clara, CA) and the 50K Illumina (San Diego, CA) SNP chips. The results for residual feed intake (RFI), BW, and hip height in 3 beef breed types (Bos indicus, Bos taurus, and B. indicus * B. taurus), and for stature in dairy cattle, are presented. The aims were to discover SNP associated with all traits studied, but especially RFI, and further to test the consistency of SNP effects across different cattle populations and breed types. The data were analyzed within data sets and within breed types by using a mixed model and fitting 1 SNP at a time. In each case, the number of significant SNP was more than expected by chance alone. A total of 75 SNP from the reference population with 50K chip data were significant (P < 0.001) for RFI, with a false discovery rate of 68%. These 75 SNP were mapped on 24 different BTA. Of the 75 SNP, the 9 most significant SNP were detected on BTA 3, 5, 7, and 8, with P <= 6.0 * 10(-5). In a population of Angus cattle divergently selected for high and low RFI and 10K chip data, 111 SNP were significantly (P < 0.001) associated with RFI, with a false discovery rate of 7%. Approximately 103 of these SNP were therefore likely to represent true positives. Because of the small number of SNP common to both the 10K and 50K SNP chips, only 27 SNP were significantly (P < 0.05) associated with RFI in the 2 populations. However, other chromosome regions were found that contained SNP significantly associated with RFI in both data sets, although no SNP within the region showed a consistent effect on RFI. The SNP effects were consistent between data sets only when estimated within the same breed type. PMID- 21239665 TI - Ultrasonographic assessment of liver dimensions in dairy cows with different hepatic triacylglycerol content. AB - The objective of this study was to investigate the relationship between hepatic triacylglycerol content (TAG) and hepatic size and shape assessed by transcutaneous ultrasonography in dairy cows. In a second part, the usefulness of ultrasonographic measurements pertaining to the size and shape of the liver for the diagnosis of fatty liver was evaluated. Transcutaneous ultrasonographic examination of the liver was carried out in 133 German Holstein cows (BW: 578 +/- 6 kg; age: 5 +/- 0.2 yr; withers height: 145 +/- 0.3 cm). The size of the liver, angle of the ventral liver margin, and thickness of the liver over the portal vein and caudal vena cava were measured in the 10th and 11th intercostal spaces via ultrasonography. As the gold standard, TAG was determined enzymatically in liver biopsies. Hepatic TAG ranged from 5 to 292 mg/g of liver fresh weight (FW). Cows were allocated to 4 groups according to their hepatic TAG content (TAG >=150 mg/g of FW, n = 32; >=100 to 150 mg/g of FW, n = 34; >=50 to 100 mg/g of FW, n = 38; <50 mg/g of FW, n = 29). Weak to moderate correlations (r = 0.26 to 0.49) between the ultrasonographic liver measurements and hepatic TAG indicated an increased size and angle of the liver with increasing hepatic fat accumulation. All mean liver ultrasonographic measurements revealed differences between TAG classes (P < 0.001), with the greatest values in cows with hepatic TAG concentrations >=150 mg/g of FW. Stepwise multiple linear regression for hepatic TAG prediction (r(2) = 0.34, P < 0.001) and stepwise discriminant analysis used only ultrasonographic measurements obtained via the 10th intercostal space and age. Regression analysis revealed that TAG prediction widely overestimated measured TAG in the low TAG range and underestimated TAG in the high TAG range. The sensitivity and specificity based on discriminant analysis for differentiation of the TAG groups were 0.61 and 0.61 (<50 vs. >=50 mg/g of FW), 0.67 and 0.71 (<50 vs. >=100 mg/g of FW), 0.83 and 0.82 (<50 vs. >=150 mg/g of FW), 0.70 and 0.77 (<100 vs. >=100 mg/g of FW), and 0.83 and 0.85 (<100 vs. >=150 mg/g of FW), respectively. Results revealed that with a hepatic TAG content of approximately 100 mg/g of FW, the liver increased in size and its margins became rounded. Pronounced increases in the size and thickness of the liver and in the angle of the liver occurred only in cows with very severe fatty liver (TAG >=150 mg/g of FW). However, the determination of ultrasonographic measurements of liver size and shape appeared to be of limited diagnostic value in the recognition of fatty liver because of increased interindividual variance in dairy cows. PMID- 21239666 TI - A single nucleotide polymorphism set for paternal identification to reduce the costs of trait recording in commercial pig breeding. AB - In animal breeding, recording of correct pedigrees is essential to achieve genetic progress. Markers on DNA are useful to verify the on-farm pedigree records (parental verification) but can also be used to assign parents retrospectively (parental identification). This approach could reduce the costs of recording for traits with low incidence, such as those related to diseases or mortality. In this study, SNP were used to assign the true sires of 368 purebred animals from a Duroc-based sire line and 140 crossbred offspring from a commercial pig population. Some of the sires were closely related. There were 3 full sibs and 17 half sibs among the true fathers and 4 full sibs and 35 half sibs among all putative fathers. To define the number of SNP necessary, 5 SNP panels (40, 60, 80, 100, and 120 SNP) were assembled from the Illumina PorcineSNP60 Beadchip (Illumina, San Diego, CA) based on minor allele frequency (>0.3), high genotyping call rate (>=90%), and equal spacing across the genome. For paternal identification considering only the 66 true sires in the data set, 60 SNP resulted in 100% correct assignment of the sire. By including additional putative sires (n = 304), 80 SNP were sufficient for 100% correct assignment of the sire. The following criteria were derived to identify the correct sire for the current data set: the logarithm of odds (LOD) score for assigning the correct sire was >=5, the number of mismatches was <=1, and the difference in the LOD score between the first and the second most likely sire was >5. If the correct sire was not present among all putative sires, the mean LOD for the most likely sire was close to zero or negative when using 100 SNP. More SNP would be needed for paternal identification if the number of putative sires increased and the degree of relatedness was greater than in the data set used here. The threshold for the number of mismatches can be adjusted according to the practical situation to account for the trade-off between false negatives and false positives. The latter can be avoided efficiently, ensuring that the correct father is being sampled. Nevertheless, a restriction on the number of putative sires is advisable to reduce the risk of assigning close relatives. PMID- 21239667 TI - Companion animals symposium: development of the mammalian gastrointestinal tract, the resident microbiota, and the role of diet in early life. AB - Mammalian gastrointestinal (GI) development is guided by genetic determinants established during the evolution of mammals and matched to the natural diet and environment. Coevolution of the host GI tract (GIT) and the resident bacteria has resulted in commensal relationships that are species and even individual specific. The interactions between the host and the GI bacteria are 2-way and of particular importance during the neonatal period, when the GIT needs to adapt rapidly to the external environment, begin processing of oral foods, and acquire the ability to differentiate between and react appropriately to colonizing commensal and potentially pathogenic bacteria. During this crucial period of life, the patterns of gene expression that determine GI structural and functional development are modulated by the bacteria colonizing the previously sterile GIT of fetuses. The types and amounts of dietary inputs after birth influence GI development, species composition, and metabolic characteristics of the resident bacteria, and the interactions that occur between the bacteria and the host. This review provides overviews of the age-related changes in GIT functions, the resident bacteria, and diet, and describes how interactions among these 3 factors influence the health and nutrition of neonates and can have lifelong consequences. Necrotizing enterocolitis is a common GI inflammatory disorder in preterm infants and is provided as an example of interactions that go awry. Other enteric diseases are common in all newborn mammals, and an understanding of the above interactions will enhance efforts to support neonatal health for infants and for farm and companion animals. PMID- 21239668 TI - The sentinel fat pads: the relationship of the ROOF and SOOF to the temporal nerve in facial rejuvenation. AB - BACKGROUND: A great number of studies have reported on the temporal branch anatomy and its relationship to the fascial layers and various fat pads of the temporal region, but no article has included information on the relationship of the temporal nerve to the retro-orbicularis oculi fat (ROOF) and/or the suborbicularis oculi fat (SOOF). OBJECTIVES: The authors report the results of a series of human cadaver temporal nerve dissections, with particular attention paid to its relation to the ROOF and the SOOF. The results of a literature review and a subsequent open browlift are also reported to confirm the results of the cadaver study. METHODS: Dissection was performed on 15 fresh human cadavers, for a total of 29 hemifaces. The course and relationships of the temporal nerve branch to the fascia, fat pads, and landmarks in the temporal region were noted and detailed. A thorough review was also performed for 23 articles, to compare the author's anatomical findings with data in the previous literature. RESULTS: During cadaver dissection, the temporal branch was found to lie on the undersurface of the superficial temporal fascia. In the supraorbital area, the ROOF existed in the loose areolar plane or deep layer of the superficial temporal fascia, with the temporal nerve branch directly superficial to it. The temporal branch passed lateral to the SOOF in its superiomedial course at the level of the zygoma. These findings were later confirmed during an in vivo open browlift as well. CONCLUSIONS: The ROOF was formerly unrecognized as an important sentinel marker for possible injury to the temporal nerve branch during browlift. However, this cadaver study and its accompanying literature comparisons show that browlift dissection, whether endoscopic or open, should aim to keep the ROOF fat in the superficial plane, ensuring that the nerve branch is safe from iatrogenic injury. PMID- 21239669 TI - Visual loss after blepharoplasty: incidence, management, and preventive measures. AB - BACKGROUND: Although rare, instances of visual loss after cosmetic blepharoplasty have been previously reported in the literature. OBJECTIVES: The goal of this study is to summarize the existing literature and report the results of a physician survey in order to provide appropriate guidelines for preventing, diagnosing, and treating this unfortunate complication. METHODS: A 13-question survey was sent to all members of the American Society for Aesthetic Plastic Surgery (ASAPS) and the British Association of Aesthetic Plastic Surgery (BAAPS). Surgeons were queried about their number of years in surgical practice, their average annual caseload of blepharoplasties, and the number of cases of visual loss. The survey also contained questions about the type of anesthesia administered, surgical technique, the presence of risk factors or comorbidities in patients, symptoms, time of presentation, management, and final outcome. RESULTS: A total of 648 responses were received from ASAPS members and 72 from BAAPS members. The overall number of blepharoplasties reported by these respondents was 752,816. Thirty-nine cases of visual loss were reported: 25 permanent and 14 temporary. According to this, the overall incidence of visual loss following blepharoplasty was calculated at 0.0052% (five of 100,000 cases, or one in 20,000). Permanent visual loss was calculated at 0.0033% (three in 100,000, or one in 30,000) and temporary visual loss at 0.0019% (two in 100,000, or one in 50,000). The most common symptoms in affected patients were pain and pressure. Development of symptoms was reported to occur within the first 24 hours, with two peaks: intraoperative to one postoperative hour, and six to 12 postoperative hours. Hypertension was the most common risk factor for postoperative visual loss. Retrobulbar hemorrhage was reported to be the main cause of blindness. The most common management technique reported was orbital decompression, followed by steroids and canthotomy. CONCLUSIONS: According to this study, blindness after blepharoplasty is a rare event. However, every step should be taken to prevent it. Prevention should begin in the preoperative period and should continue intraoperatively and postoperatively. Once the diagnosis of impending visual loss is made, it should be treated as a true surgical emergency, since early treatment has proven beneficial. PMID- 21239670 TI - The endonasal lateral crural underlay and sandwich grafts. AB - BACKGROUND: Previously, the problem created by overly convex, wide, and robust lower lateral cartilages (LLC) required an external or endonasal approach with delivery. Although this method has proven invaluable, it may not be indicated in all patients with large tips, specifically those with overly convex LLC or with thin skin and robust LLC. OBJECTIVE: The authors present the results of their straightforward technique for narrowing the bulbous tip through an endonasal nondelivery approach that reinforces the nasal airway while at the same time preventing alar notching, lateral crus recurvature, and bossa formation. METHODS: From August 2008 to February 2010, 29 patients underwent endonasal lateral crural underlay and sandwich graft with the authors' technique. All patients had medium to thin skin and prominent, bulbous, symmetric LLC. Three of the patients presented for secondary rhinoplasty. The authors identified no specific contraindications for this procedure. All patients who remained for follow-up were given a questionnaire that analyzed their nasal tip satisfaction on a five point categorical scale at seven separate points of follow-up. RESULTS: Among the 27 patients who remained for follow-up, the results were highly satisfactory, mostly satisfactory, or satisfactory in 25 of the 27 cases (as indicated by patient survey). The two remaining patients requested a thinner nasal tip. No significant complications were noted. CONCLUSIONS: The lateral lower crural underlay sandwich graft is an adjunct to the traditional endonasal approach, further enhancing and expanding the possible outcomes. It appears to equal the predictability and stability identified with traditional tip-narrowing techniques in the external approach but with less operative time, less surgical dissection, and presumably less edema, thereby allowing us to better meet our patients' demands. PMID- 21239671 TI - Unfavorable outcomes with vertical reduction mammaplasty: part II. AB - BACKGROUND: Vertical reduction mammaplasty is a procedure that has steadily increased in popularity in the United States. Although numerous techniques exist for performing this operation, the adverse outcomes are similar in nature regardless of the approach. The authors previously evaluated patient satisfaction with vertical reduction mammaplasty in 260 consecutive patients in Part I. OBJECTIVE: This study evaluates the unfavorable outcomes encountered by the authors in the same patients included in Part I and examines the range of complications seen in other studies. METHODS: The authors reviewed the charts of 260 consecutive patients who underwent vertical reduction mammaplasty by the senior author at one of four institutions. All surgeries were performed through a superior pedicle vertical incision technique with varying amounts of liposuction. RESULTS: Unfavorable outcomes at our institution included scarring (10%), necrosis (1.92%), wound dehiscence (10%), areola asymmetry (6.54%), breast distortion or asymmetry (15%), and hematoma or seroma formation (1.54%). The results varied greatly in severity and necessity of intervention. CONCLUSIONS: While there is a wide spectrum of complication rates among the different techniques of vertical reduction, the outcomes are often similar. The authors have observed these complications in a broad patient demographic and believe that the examples provided in this article can be extrapolated to other vertical incision techniques. An assessment of these complications is necessary to provide patients with proper preoperative counseling about the risks and consequences of these potential sequelae. In our experience, more significant resection and suction produced less cosmetically favorable results. PMID- 21239673 TI - Breast implant surface development: perspectives on development and manufacture. AB - Capsular contracture poses a significant clinical and scientific research challenge for breast surgeons. Some researchers have pointed to the surface features of implant devices as being responsible for the potential tightening and hardening of the surrounding capsule. In this article, the authors review the history and development of breast implant design, specifically the data supporting improvements that have potential to mitigate the incidence of capsular contracture. The literature suggests that development of new implant surfaces designed to reduce a patient's foreign body response will improve the safety profile of implant devices and increase patient satisfaction in the long-term. PMID- 21239672 TI - Hyaluronan, TSG-6, and inter-alpha-inhibitor in periprosthetic breast capsules: reduced levels of free hyaluronan and TSG-6 expression in contracted capsules. AB - BACKGROUND: The exact mechanism of capsular contracture (CC) is still unknown. The covalent modification of hyaluronan (HA) with the heavy chains (HC) of inter alpha-inhibitor (IalphaI) has been identified as an important pathway in inflammation and tissue remodeling, where HC.HA formation is catalyzed by TSG-6 (the protein product of tumor necrosis factor stimulated gene-6). OBJECTIVE: The authors quantitatively assess the correlation between severity of CC (measured by Baker grade) and expression of HA, TSG-6, and IalphaI (ie, the polypeptides HC1, HC2, and bikunin) in periprosthetic breast capsules. METHODS: Immunofluorescent staining for HA, TSG-6, HC1, HC2, and bikunin was carried out on periprosthetic breast capsules (n = 7) of each Baker grade from four anatomical locations. Quantitative analysis was performed to identify differences in staining intensity. Real-time quantitative polymerase chain reaction (RT-qPCR) was performed to determine differences in TSG-6 gene expression levels. RESULTS: Severity of contracture was associated with reduced staining for both free HA (Pearson correlation coefficient, r = -0.645, P < .001) and TSG-6 (r = -0.642, P = .002). RT-qPCR showed a significant negative correlation between severity of contracture and TSG-6 gene expression levels (r = -0.750, P = .001). CONCLUSIONS: The negative correlation between TSG-6 expression levels and severity of CC suggests a possible protective role for TSG-6 in the context of CC formation, and this may have a clinically relevant role in prevention of breast CC. PMID- 21239674 TI - Oncologic risks of autologous fat grafting to the breast. AB - As the frequency of fat grafting to the breast has increased, some investigators have raised the possibility that this procedure may potentially increase the risks associated with breast cancer. Their concerns included not only interference with cancer detection, but also promotion of tumor formation or recurrence mediated by mechanisms such as aromatase expression, angiogenesis, and tumor stromal cells. However, published clinical studies describing outcomes of fat grafting to the breast in more than 2000 patients have not reported any increase in new or recurrent cancers. The reason for this apparent disconnect may lie in the small sample sizes and relatively short follow-up, but it may also reside in the considerable gap between laboratory studies or theoretical considerations suggesting potential risks and the actual clinical practice. This review discusses potential risks of current and novel approaches to autologous fat grafting to the breast within the context of both the underlying science and clinical practice. PMID- 21239675 TI - Water-assisted liposuction for body contouring and lipoharvesting: safety and efficacy in 41 consecutive patients. AB - BACKGROUND: Water-assisted liposuction (WAL) is a new technique for body contouring and fat harvesting that relies on a fan-shaped jet of tumescent solution to anesthetize fatty for liposuction and grafting. As with any new technology, safety and efficacy are paramount. OBJECTIVE: The author evaluates the technique and outcomes for small-to-moderate volume liposuction cases treated with WAL in an office setting. METHODS: Forty-one consecutive patients were treated with WAL (Body-Jet; Human Med, Eclipse Ltd., Dallas, Texas) in the author's private practice for mild-to-moderate body contouring. Patients were given local anesthesia (standardized tumescent solutions) during all three phases of the surgery. During the latter two phases, irrigation of tumescent solution was accompanied simultaneously by suction aspiration. Fat harvesting was accomplished by collecting and separating the aspirated adipose tissue in a sterile container, without need for washing or centrifugation. Fat grafting by microdroplet technique was performed within two hours of collection. Fat aliquots from five randomly-selected patients were assessed with a trypan blue dye exclusion test within one hour and again six to eight hours after collection. RESULTS: A total of 37 females and four males underwent WAL in this series; average body mass index (BMI) was 25.5. Among the 41 patients, 166 areas involving twelve anatomic sites were treated. Patients were divided into two groups based on the volume of treatment: Group 1 contained 19 patients with small volume WAL and Group 2 had 22 cases of moderate-volume WAL. All patients experienced uneventful recovery periods with minimal side effects and no significant complications. Although large volumes of tumescent solution were required during the three phases of the technique, the total volume of infiltration almost equaled the final volume of aspiration. The average infiltration-to-aspiration ratio was 1.1 to 1.0 in all cases over both groups. On the other hand, the average infiltration-to-fat ratio was 2.8 to 1.0 in Group l and 2.4 to 1.0 in Group 2. Lidocaine dosage averaged 10.5mg/kg in Group 1 and 20.0mg/kg in Group 2. Patients were monitored for at least 24 hours without adverse signs or symptoms that required fluid resuscitation, blood transfusions, or interventional treatments for lidocaine side effects or toxicity. Twenty-three patients elected to save their fat for autologous fat grafting in nine anatomical sites with thirty-nine procedures. The augmented sites were clinically assessed between three and eight months postoperatively. Trypan blue dye exclusion testing indicated that about 90% of adipocytes expelled the dye after one hour of extraction, while an estimated 10% of cells per patient were observed to be free of dye six to eight hours after removal. CONCLUSIONS: The amount of instilled tumescent fluid, lidocaine dosage, and aspiration volumes appeared to be safe, with minimal blood loss in small and moderate volume liposuction cases. The early experience with fat grafting was encouraging, but requires more sophisticated evaluation, longer follow-up, and a larger number of cases. PMID- 21239677 TI - Nonsurgical rejuvenation of the aging face with injectable poly-L-lactic acid for restoration of soft tissue volume. AB - BACKGROUND: Characteristics of the aging face include soft tissue atrophy, loss of skin elasticity resulting in excess facial skin, and gravitational descent or ptosis of facial soft tissues. Poly-L-lactic acid (PLLA) is a synthetic biodegradable polymer that provides soft tissue augmentation through stimulation of an inflammatory tissue response with subsequent collagen deposition. OBJECTIVE: The authors discuss the special considerations inherent in facial aging, describe the mechanism of action and indications for a new PLLA filler under consideration for Food and Drug Administration (FDA) approval (Sculptra Aesthetic, sanofi-aventis US, Bridgewater, New Jersey), and detail the results of a two-year off-label pilot study with the product. METHODS: The senior author (LAC) treated 106 patients with PLLA in an off-label indication, as part of a pilot study while Sculptra Aesthetic was being evaluated for FDA approval for cosmetic indications. All patients were followed up for two years to help develop a protocol for injection technique. RESULTS: The age range of patients in this series was 40 to 78 years. Three patients were male and 103 were female. Patients received an average injection of 1.6 vials per session, over an average of 2.3 sessions, to achieve volume restoration in the tear trough, midface, malar region, nasolabial folds, prejowl area, mandibular border, and mandibular angle. The authors we achieved 100% follow-up with 99.1% patient satisfaction. The rate of nodule formation was 4.7% at a minimum follow-up of two years. CONCLUSIONS: Because of its unique mechanism of action, PLLA for nonsurgical facial rejuvenation requires meticulous injection technique with special considerations for optimizing outcomes and minimizing adverse events. PMID- 21239676 TI - A technique for filling the temples with highly diluted hyaluronic acid: the "dilution solution". AB - BACKGROUND: Hollow temples are a common sign of aging, contributing to the upper face appearing "pinched" and the brows appearing short and ptotic. Many treatments have been described for this area, including fat injections and implants. However, traditional injection techniques have not proven entirely satisfactory in correcting the problem without resulting irregularities. OBJECTIVES: The author describes a technical refinement wherein diluted hyaluronic acid (HA) fillers are injected into the temple. METHODS: Thus far, a series of 40 patients has been treated over 18 months with the author's technique, which involves diluting the HA filler by a ratio of approximately two to one (diluent to filler) and injecting the temple as evenly as possible. As the saline component absorbs, the filling material is distributed more evenly in the temple than with undiluted filler. RESULTS: Patients experienced improved results, with a smoother appearance to the brow. There were no instances of complications requiring dissolution of the product with hyaluronidase. Irregularities proved minor and easily correctable; no intravascular complications were noted in this series of patients. Clinical photographs demonstrate improvement in the "pinched" upper face and an apparent elongation of the brows. The author estimates, based on prior experience, that duration of effect will be approximately two to three years. CONCLUSIONS: Dilution of the HA fillers administered for brow treatment results in a more even distribution of the product and a lower morbidity than previously described techniques, making temple treatment far easier than in the past. PMID- 21239678 TI - Etiology, prevention, and treatment of dermal filler complications. AB - The availability of dermal fillers for multiple cosmetic indications has led to a dramatic increase in their application. Although fillers are generally regarded as safe tools for soft tissue augmentation, complications can occur. Therefore, to describe and review the complications associated with the currently-available dermal filling agents, the authors conducted a literature review in peer-reviewed journals and present the reported complication rates. They also describe current strategies to avoid, diagnose, and manage complications if they do occur. PMID- 21239679 TI - A cross-case comparison of hypothermia prevention methods and continuous improvement culture between aesthetic plastic surgery sites. AB - The Patient Safety Committee of The American Society for Aesthetic Plastic Surgery (ASAPS) has initiated a new patient safety training program. The pilot module of this program will focus on hypothermia prevention, with the goal of decreasing the negative effects of hypothermia for surgery patients. Previous literature has shown that hypothermia can result in a higher incidence of surgical wound infections and longer postanesthesia recovery times, among other adverse effects. Therefore, educating medical personnel on patient safety techniques like hypothermia prevention is important for achieving positive patient outcomes. However, organizational research indicates that implementing and sustaining improvements system-wide requires a "continuous improvement culture." Earlier research has identified concepts such as double-loop learning, problem-solving, error management, and organizational routines as key elements of a continuous improvement culture. Antecedent to the ASAPS training program, a case study analysis of three surgery practices was performed to better understand the relationship between organizational structure, hypothermia domain knowledge, and continuous improvement culture characteristics. The data analysis indicates a positive correlation between hypothermia prevention and elements of a continuous improvement culture. These findings suggest that a patient safety training program, which includes learning objectives directed at improving organizational culture in addition to specific research-based preventative techniques, is more likely to achieve sustained improvements in patient outcomes than training focused on preventative techniques alone. PMID- 21239680 TI - Evidence-based medicine in aesthetic surgery. PMID- 21239681 TI - So you want to be an evidence-based plastic surgeon? A lifelong journey. PMID- 21239682 TI - Monoclonal tumor origin is an underlying misconception of the RESIC approach. PMID- 21239684 TI - Increased plasma soluble uPAR level is a risk marker of respiratory cancer in initially cancer-free individuals. AB - BACKGROUND: Soluble urokinase plasminogen activator receptor (suPAR) is a stable plasma biomarker associated with inflammation and disease. This study tested the association between suPAR levels and incident respiratory, gastrointestinal, or other types of cancer in initially cancer-free individuals from a general population-based prospective study. METHODS: Baseline plasma samples, baseline characteristics, and follow-up data were available from 2,656 individuals from the population-based Danish MONICA10 (MONItoring trends and determinants of CArdiovascular disease) study, followed for a median of 12.6 years. Cancer was diagnosed according to international classification of diseases (ICD) 8 and ICD 10 codes and suPAR levels were measured using a commercially available ELISA. The association of suPAR levels with incident cancer during follow-up was analyzed using Cox regression, adjusted for established risk factors and the inflammatory markers C-reactive protein (CRP) and leukocyte numbers. RESULTS: suPAR levels ranged from 0.6 to 22 ng/mL and median suPAR level was 4.01 ng/mL. An increase of 1 ng/mL in baseline suPAR was associated with adjusted HR of 1.61 (95% CI: 1.23 2.11, P < 0.001), 0.92 (95% CI: 0.69-1.24, P = 0.59), and 1.33 (95% CI: 1.13 1.58, P < 0.001) of being diagnosed with respiratory, gastrointestinal, and other cancer types, respectively. CONCLUSION: Elevated suPAR levels were associated with increased risk of incident respiratory cancer and other types of cancer, but not gastrointestinal cancers, independently of established risk factors, CRP, and leukocyte numbers. IMPACT: These findings suggest that inflammation is involved in cancer development. Risk algorithms based on established risk factors and risk associated biomarkers should be developed and evaluated in large, general population-based studies. We suggest suPAR as a candidate for evaluation in cancer risk algorithms. PMID- 21239683 TI - Trinitrophenyl derivatives bind differently from parent adenine nucleotides to Ca2+-ATPase in the absence of Ca2+. AB - Trinitrophenyl derivatives of adenine nucleotides are widely used for probing ATP binding sites. Here we describe crystal structures of Ca(2+)-ATPase, a representative P-type ATPase, in the absence of Ca(2+) with bound ATP, trinitrophenyl-ATP, -ADP, and -AMP at better than 2.4-A resolution, stabilized with thapsigargin, a potent inhibitor. These crystal structures show that the binding mode of the trinitrophenyl derivatives is distinctly different from the parent adenine nucleotides. The adenine binding pocket in the nucleotide binding domain of Ca(2+)-ATPase is now occupied by the trinitrophenyl group, and the side chains of two arginines sandwich the adenine ring, accounting for the much higher affinities of the trinitrophenyl derivatives. Trinitrophenyl nucleotides exhibit a pronounced fluorescence in the E2P ground state but not in the other E2 states. Crystal structures of the E2P and E2 ~ P analogues of Ca(2+)-ATPase with bound trinitrophenyl-AMP show that different arrangements of the three cytoplasmic domains alter the orientation and water accessibility of the trinitrophenyl group, explaining the origin of "superfluorescence." Thus, the crystal structures demonstrate that ATP and its derivatives are highly adaptable to a wide range of site topologies stabilized by a variety of interactions. PMID- 21239685 TI - Survival following non-small cell lung cancer among Asian/Pacific Islander, Latina, and Non-Hispanic white women who have never smoked. AB - BACKGROUND: Lung cancer is the leading cause of cancer death among U.S. Asian/Pacific Islander (API) and Latina women despite low smoking prevalence. This study examined survival patterns following non-small cell lung cancer in a population-based sample of lung cancer cases from the San Francisco Bay Area Lung Cancer Study (SFBALCS). METHODS: Women diagnosed with lung cancer from 1998 to 2003 and 2005 to 2008 and identified through the Greater Bay Area Cancer Registry were telephone-screened for eligibility for the SFBALCS. The screener data were linked to the cancer registry data to determine follow-up. This analysis included 187 non-Hispanic (NH) white, 23 U.S.-born Latina, 32 foreign-born Latina, 30 U.S. born API, and 190 foreign-born API never-smokers diagnosed with lung cancer and followed through 2008. RESULTS: All-cause survival was poorer among APIs [HR=1.7 (95% CI: 1.0-2.8) among U.S.-born APIs and HR=1.2 (95% CI: 0.9-1.5) among foreign born APIs] and Latinas [HR=2.1 (95% CI: 1.2-3.6) among U.S.-born Latinas; HR=1.4 (95% CI: 0.9-2.3) among foreign-born Latinas] relative to NH whites. These survival differences were not explained by differences in selected sociodemographic or clinical factors. CONCLUSIONS: Further research should focus on factors such as cultural behaviors, access to or attitudes toward health care, and genetic variations as possible explanations for these striking racial/ethnic differences. IMPACT: Latina and API female never-smokers diagnosed with lung cancer were up to two times more likely to die than NH whites, highlighting the need for additional research to identify the underlying reasons for the disparities and heightened clinical awareness. PMID- 21239686 TI - Plasma isoflavones and the risk of lung cancer in women: a nested case-control study in Japan. AB - BACKGROUND: Although several epidemiologic studies have found that isoflavone intake assessed by questionnaire is associated with a decreased risk of lung cancer, no prospective study has investigated this association using blood concentrations of isoflavones. METHODS: We conducted a nested case-control study within a population-based prospective cohort study. A total of 24,127 women aged 40 to 69 years who returned the baseline questionnaire and provided blood samples were observed from 1990 through 2006. During a median follow-up period of 13.5 years, 126 newly diagnosed lung cancer cases were identified. For each case, we selected two controls matched for age, area, smoking status, and condition of blood draw. A conditional logistic regression model was used to estimate the odds ratios (ORs) and 95% CIs of lung cancer in relation to plasma concentrations of genistein, daidzein, glycitein, equol, and total isoflavones. RESULTS: After exclusion of 20 lung cancer cases diagnosed in the first 3 years after blood collection, an inverse association was found between plasma genistein concentration and lung cancer risk. The multivariate-adjusted OR (95% CI) of lung cancer in the highest quintile of plasma genistein concentration as compared with that in the lowest quintile was 0.31 (0.12, 0.86; P for trend=0.085). Other isoflavones and total isoflavones were not associated with a significant decrease in the risk of lung cancer. CONCLUSION: Plasma genistein concentration was inversely associated with lung cancer risk in Japanese women. IMPACT: Our data support the previously observed association between isoflavone intake and lung cancer risk. PMID- 21239687 TI - Red meat, dietary nitrosamines, and heme iron and risk of bladder cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). AB - BACKGROUND: Previous epidemiologic studies found inconsistent results for the association between red meat intake, nitrosamines [NDMA: N-nitrosodimethylamine, and ENOC (endogenous nitroso compounds)], and the risk of bladder cancer. We investigated the association between red meat consumption, dietary nitrosamines, and heme iron and the risk of bladder cancer among participants of the European Prospective Investigation into Cancer and Nutrition (EPIC). METHODS: Data on food consumption and complete follow-up for cancer occurrence were available for a total of 481,419 participants, recruited in 10 European countries. Estimates of HRs were obtained by proportional hazard models, stratified by age at recruitment, gender, and study center and adjusted for total energy intake, smoking status, lifetime intensity of smoking, duration of smoking, educational level, and BMI. RESULTS: After a mean follow-up of 8.7 years, 1,001 participants were diagnosed with bladder cancer. We found no overall association between intake of red meat (log2 HR: 1.06; 95% CI: 0.99-1.13), nitrosamines (log2 HR: 1.09; 95% CI: 0.92-1.30 and HR: 0.98; 95% CI: 0.92-1.05 for ENOC and NDMA, respectively) or heme iron (log2 HR: 1.05; 95 CI: 0.99-1.12) and bladder cancer risk. The associations did not vary by sex, high- versus low-risk bladder cancers, smoking status, or occupation (high vs. low risk). CONCLUSIONS: Our findings do not support an effect of red meat intake, nitrosamines (endogenous or exogenous), or heme iron intake on bladder cancer risk. PMID- 21239689 TI - An appraisal of the evidence underlying performance measures for community acquired pneumonia. AB - Numerous organizations use performance measures to monitor the quality of care provided for a variety of clinical conditions. An appraisal of the evidence underlying such performance measures has never been reported. Our objective was to estimate the effects of interventions recommended by performance measures and to determine the quality of evidence from which those estimates derive, using the Joint Commission and the Centers for Medicare and Medicaid Services' performance measures for community-acquired pneumonia (CAP) as examples. We performed systematic reviews of the literature to identify evidence related to the performance measures for CAP. Metaanalyses were then performed to estimate the absolute and relative effects of the interventions recommended by the performance measures. The Grading Recommendations, Assessment, Development, and Evaluation system was used to determine the quality of evidence. The estimated effects favored the interventions recommended by five of the six performance measures. These included pneumococcal vaccination (incidence of pneumococcal pneumonia: relative risk [RR], 0.43; 95% confidence interval [CI], 0.24-0.75), blood cultures, antibiotic administration within 6 hours, use of a guideline-compliant antibiotic regimen, and influenza vaccination (incidence of symptomatic influenza: RR, 0.30; 95% CI, 0.22-0.40). However, among these performance measures, only influenza vaccination was supported by high-quality evidence. One step smoking cessation counseling was contradicted by moderate-quality evidence (smoking quit rate: RR, 1.05; 95% CI, 0.90-1.22). The evidence supporting performance measures is frequently not of high quality and occasionally contradictory. PMID- 21239688 TI - Physicians' colorectal cancer screening discussion and recommendation patterns. AB - BACKGROUND: Primary care physician (PCP) actions are pivotal to colorectal cancer (CRC) screening performance, and guidelines recommend discussion with patients about test options and potential benefits and harms. This article profiles patterns of discussion about and recommendations for screening and explores potential associations with multilevel factors (patient, clinician, practice, and environment). METHODS: In 2009, we analyzed data from 1,266 physicians responding to the 2006-2007 National Survey of Primary Care Physicians' Recommendations and Practices for Breast, Cervical, Colorectal, and Lung Cancer Screening (absolute response rate=69.3%; cooperation rate=75.0%). Descriptive statistics examined physicians' reports of discussion and recommendations. Multivariate analyses assessed the associations of these practices with multilevel factors. RESULTS: Although few respondents reported discussion of all options, 46% usually discuss more than one option; the vast majority of these respondents discuss fecal occult blood testing (FOBT) and colonoscopy (49%) or FOBT, sigmoidoscopy, and colonoscopy (32%). Of physicians who discuss more than one option, a majority reported usually recommending one or more test options, most commonly colonoscopy alone (43%) and FOBT and colonoscopy (43%). Several personal characteristics (specialty), perceived patient characteristics (prefer physician to decide), practice characteristics (geographic location), and community barriers (specialist availability) were independently associated with discussion and/or recommendation patterns. CONCLUSIONS: PCPs do not discuss the full menu of test options, but many report selecting one or two options for discussion and recommendation. To ensure that patients' perspectives and concerns are elicited and considered, patient decision-making approaches should be considered. IMPACT: Attention to informed decision making in CRC screening will be important for enhancing patient-centered quality care. PMID- 21239690 TI - High prevalence of pulmonary tuberculosis and inadequate case finding in rural western Kenya. AB - RATIONALE: Limited information exists on the prevalence of tuberculosis and adequacy of case finding in African populations with high rates of HIV. OBJECTIVES: To estimate the prevalence of bacteriologically confirmed pulmonary tuberculosis (PTB) and the fraction attributable to HIV, and to evaluate case detection. METHODS: Residents aged 15 years and older, from 40 randomly sampled clusters, provided two sputum samples for microscopy; those with chest radiograph abnormalities or symptoms suggestive of PTB provided one additional sputum sample for culture. MEASUREMENTS AND MAIN RESULTS: PTB was defined by a culture positive for Mycobacterium tuberculosis or two positive smears. Persons with PTB were offered HIV testing and interviewed on care-seeking behavior. We estimated the population-attributable fraction of HIV on prevalent and notified PTB, the patient diagnostic rate, and case detection rate using provincial TB notification data. Among 20,566 participants, 123 had PTB. TB prevalence was 6.0/1,000 (95% confidence interval, 4.6-7.4) for all PTB and 2.5/1,000 (1.6-3.4) for smear positive PTB. Of 101 prevalent TB cases tested, 52 (51%) were HIV infected, and 58 (64%) of 91 cases who were not on treatment and were interviewed had not sought care. Forty-eight percent of prevalent and 65% of notified PTB cases were attributable to HIV. For smear-positive and smear-negative PTB combined, the patient diagnostic rate was 1.4 cases detected per person-year among HIV-infected persons having PTB and 0.6 for those who were HIV uninfected, corresponding to case detection rates of 56 and 65%, respectively. CONCLUSIONS: Undiagnosed PTB is common in this community. TB case finding needs improvement, for instance through intensified case finding with mobile smear microscopy services, rigorous HIV testing, and improved diagnosis of smear-negative TB. PMID- 21239691 TI - Involvement of endothelial apoptosis underlying chronic obstructive pulmonary disease-like phenotype in adiponectin-null mice: implications for therapy. AB - RATIONALE: Chronic obstructive pulmonary disease is frequently complicated with comorbidities, such as cardiovascular disease, osteoporosis, and body weight loss, but the causal link remains unclear. OBJECTIVES: To investigate the role of adiponectin in the pathogenesis of chronic obstructive pulmonary disease and its potential use in therapy. METHODS: Adiponectin localization and dynamics in the lung were analyzed in an elastase-induced emphysema model. Next, the lung of adiponectin-knockout mice, extrapulmonary effects, and the underlying mechanism were investigated. Finally, we tested whether exogenous adiponectin could ameliorate the emphysematous change in adiponectin-knockout mice. MEASUREMENTS AND MAIN RESULTS: Adiponectin expression in lung vasculature and plasma concentration of adiponectin were reduced after elastase-instillation. Notably, adiponectin-knockout mice showed progressive alveolar enlargement and increased lung compliance. They further exhibited not only systemic inflammation, but also extrapulmonary phenotype, such as body weight loss, fat atrophy, and osteoporosis. Moreover, endothelial apoptosis was enhanced in the lungs of adiponectin-knockout mice, as evidenced by caspase-3 activity. Consistent with this, expressions of vascular endothelial growth factor receptor-2 and platelet endothelial cell adhesion molecule-1 on endothelial cells were decreased in the adiponectin-knockout mice. Finally, adenovirus-mediated adiponectin supplementation ameliorated the emphysematous phenotype. CONCLUSIONS: Adiponectin knockout mice develop progressive chronic obstructive pulmonary disease-like phenotype with systemic inflammation and extrapulmonary phenotypes. Hypoadiponectinemia could thus play a critical role in the progression of chronic obstructive pulmonary disease and concomitant comorbidities through endothelial dysfunction. Together, adiponectin could be a novel target for chronic obstructive pulmonary disease therapy. PMID- 21239692 TI - Biomechanical comparison of anatomic double-bundle, anatomic single-bundle, and nonanatomic single-bundle anterior cruciate ligament reconstructions. AB - BACKGROUND: Although both anatomic double-bundle and single-bundle anterior cruciate ligament reconstruction procedures are in use, it remains controversial whether the anatomic double-bundle procedure is biomechanically superior. HYPOTHESIS: The anatomic double-bundle procedure would be better than both laterally placed anatomic and nonanatomic transtibial single-bundle procedures at restoring to normal the tibial anterior translation, internal rotation, and pivot shift instability. It was also hypothesized that tibial internal rotation would be closer to normal after laterally placed anatomic single-bundle reconstruction than after the nonanatomic reconstruction. STUDY DESIGN: Controlled laboratory study. METHODS: Eight cadaveric knees were mounted in a 6 degrees of freedom rig and tested using the following loading conditions: 90-N anterior and posterior tibial forces, 5-N.m internal and external tibial rotation torques, and a simulated pivot-shift test. Tibiofemoral kinematics during the flexion-extension cycle were recorded with an optical tracking system for (1) intact, (2) anterior cruciate ligament-deficient knee, (3) anatomic double-bundle reconstruction, (4) nonanatomic single-bundle reconstruction, and (5) laterally placed single-bundle reconstruction. RESULTS: Rotational laxity with internal tibial torque and anterior laxity in the simulated pivot shift were significantly less in the double-bundle reconstruction and laterally placed single-bundle reconstruction compared with the nonanatomic single-bundle reconstruction. There were no significant differences between the 3 procedures when anterior and posterior tibial translation forces and external rotation torques were applied. In addition, there were no significant differences between the double-bundle reconstruction and laterally placed single-bundle reconstruction. CONCLUSION: The postoperative rotational and pivot-shift laxity after anatomic double-bundle anterior cruciate ligament reconstruction was significantly better than that after nonanatomic single-bundle reconstruction. However, there were no significant differences between the double-bundle reconstruction and laterally placed single-bundle reconstruction. CLINICAL RELEVANCE: This work suggests that a single-bundle reconstruction may be better able to control both knee laxity and pivot-shift instability if the femoral tunnel is moved to a more lateral position and that then the double-bundle reconstruction may not offer significant further advantages. PMID- 21239693 TI - Mortality of one-week-old chickens during naturally occurring Marek's disease virus infection. AB - Marek's disease (MD) is a disease of chickens that occurs worldwide and has serious economic consequences. MD can present as one of several forms, with the most commonly occurring forms being the lymphoproliferative diseases. Under experimental conditions, an early mortality syndrome has been recognized following infection by some but not all strains of MD virus (MDV). This is the first report of a confirmed case of mortality due to naturally occurring MDV infection in 1-week-old, nonvaccinated, chickens. Necrotizing lesions were observed in the bursa of Fabricius, lung, duodenum, jejunum, and proventriculus, and large intranuclear inclusion bodies were a striking feature in tissues with lesions in all birds. Immunohistochemical staining for the pp38 protein of MDV revealed abundant pp38 antigen in the affected tissues, confirming the presence of MDV within the lesions. PCR yielded an amplicon with 97% homology to the meq gene of MDV. No evidence of co-infection by either of the immunosuppressive agents chicken anemia virus and infectious bursal disease virus was detected. PMID- 21239694 TI - Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cells. AB - The transcription factor PU.1 occupies a central role in controlling myeloid and early B-cell development, and its correct lineage-specific expression is critical for the differentiation choice of hematopoietic progenitors. However, little is known of how this tissue-specific pattern is established. We previously identified an upstream regulatory cis element whose targeted deletion in mice decreases PU.1 expression and causes leukemia. We show here that the upstream regulatory cis element alone is insufficient to confer physiologic PU.1 expression in mice but requires the cooperation with other, previously unidentified elements. Using a combination of transgenic studies, global chromatin assays, and detailed molecular analyses we present evidence that PU.1 is regulated by a novel mechanism involving cross talk between different cis elements together with lineage-restricted autoregulation. In this model, PU.1 regulates its expression in B cells and macrophages by differentially associating with cell type-specific transcription factors at one of its cis-regulatory elements to establish differential activity patterns at other elements. PMID- 21239695 TI - The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. AB - Given the significant activity and tolerability of bendamustine, rituximab, and bortezomib in patients with relapsed indolent and mantle cell non-Hodgkin lymphoma, and laboratory studies suggesting synergistic activity, we conducted a multicenter phase 2 study of the bendamustine/bortezomib/rituximab combination. Patients with relapsed or refractory indolent and mantle cell lymphoma with adequate organ function were treated with bendamustine 90 mg/m2 days 1 and 4; rituximab 375 mg/m2 day 1, and bortezomib 1.3 mg/m2 days 1, 4, 8, 11. Six 28-day cycles were planned. Thirty patients (7 with mantle cell lymphoma) were enrolled and treated. Eight patients experienced serious adverse events, including one event of grade 5 sepsis. Common nonhematologic adverse events were generally grade 1 or grade 2 and included nausea (50%), neuropathy (47%), fatigue (47%), constipation (40%), and fever (40%). Of 29 patients evaluable for efficacy, 24 (83%) achieved an objective response (including 15 with complete response). With median follow-up of 24 months, 2-year progression-free survival is 47% (95% confidence interval, 25%-69%). On the basis of these promising results, the US cooperative groups have initiated randomized trials to evaluate this regimen in follicular and mantle cell lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00547534. PMID- 21239696 TI - HDAC11 plays an essential role in regulating OX40 ligand expression in Hodgkin lymphoma. AB - In Hodgkin lymphoma (HL), the malignant cells are surrounded by a large number of reactive infiltrating inflammatory cells, including OX40-expressing T cells and interleukin 10 (IL-10)-producing regulatory T (T-reg) cells. These T-reg cells can suppress the immune response and thus contribute to the maintenance of immune tolerance and to insufficient antitumor response. The engagement of OX40L with the OX40 receptor is essential for the generation of antigen-specific memory T cells and for the induction of host antitumor immunity. In the present study, we investigated whether histone deacetylase inhibitors (HDACis) may induce a favorable antitumor immune response by regulating the expression of OX40L in HL. We found that HDACis up-regulated OX40L surface expression in HL cell lines in a dose-dependent manner. Small interfering RNAs (siRNAs) that selectively inhibited HDAC11 expression, significantly up-regulated OX40L and induced apoptosis in HL cell lines, and silencing HDAC11 transcripts increased the production of tumor necrosis-alpha (TNF-alpha) and IL-17 in the supernatants of HL cells. Furthermore, HDACI-induced OX40L inhibited the generation of IL-10-producing type 1 T-reg cells. These results demonstrate for the first time that HDAC11 plays an essential role in regulating OX40L expression. Pharmacologic inhibition of HDAC11 may produce a favorable antitumor immune response in patients with HL. PMID- 21239698 TI - Phase 1 and pharmacokinetic study of bolus-infusion flavopiridol followed by cytosine arabinoside and mitoxantrone for acute leukemias. AB - Flavopiridol is a protein bound, cytotoxic, cyclin-dependent kinase inhibitor. Flavopiridol given by 1-hour bolus at 50 mg/m(2) daily 3 times followed by cytosine arabinoside and mitoxantrone (FLAM) is active in adults with poor-risk acute leukemias. A pharmacologically derived "hybrid" schedule (30-minute bolus followed by 4-hour infusion) of flavopiridol was more effective than bolus administration in refractory chronic lymphocytic leukemia. Our phase 1 trial "hybrid FLAM" in 55 adults with relapsed/refractory acute leukemias began at a total flavopiridol dose of 50 mg/m(2) per day 3 times (20-mg/m(2) bolus, 30 mg/m(2) infusion). Dose-limiting toxicity occurred at level 6 (30-mg/m(2) bolus, 70-mg/m(2) infusion) with tumor lysis, hyperbilirubinemia, and mucositis. Death occurred in 5 patients (9%). Complete remission occurred in 22 (40%) across all doses. Overall and disease-free survivals for complete remission patients are more than 60% at more than 2 years. Pharmacokinetics demonstrated a dose-response for total and unbound plasma flavopiridol unrelated to total protein, albumin, peripheral blast count, or toxicity. Pharmacodynamically, flavopiridol inhibited mRNAs of multiple cell cycle regulators, but with uniform increases in bcl-2. "Hybrid FLAM" is active in relapsed/refractory acute leukemias, with a recommended "hybrid" dose of bolus 30 mg/m(2) followed by infusion of 60 mg/m(2) daily for 3 days. This clinical trial is registered at www.clinicaltrials.gov as #NCT00470197. PMID- 21239697 TI - Functional study of the vitamin K cycle in mammalian cells. AB - We describe a cell-based assay for studying vitamin K-cycle enzymes. A reporter protein consisting of the gla domain of factor IX (amino acids 1-46) and residues 47-420 of protein C was stably expressed in HEK293 and AV12 cells. Both cell lines secrete carboxylated reporter when fed vitamin K or vitamin K epoxide (KO). However, neither cell line carboxylated the reporter when fed KO in the presence of warfarin. In the presence of warfarin, vitamin K rescued carboxylation in HEK293 cells but not in AV12 cells. Dicoumarol, an NAD(P)H-dependent quinone oxidoreductase 1 (NQO1) inhibitor, behaved similarly to warfarin in both cell lines. Warfarin-resistant vitamin K epoxide reductase (VKOR-Y139F) supported carboxylation in HEK293 cells when fed KO in the presence of warfarin, but it did not in AV12 cells. These results suggest the following: (1) our cell system is a good model for studying the vitamin K cycle, (2) the warfarin-resistant enzyme reducing vitamin K to hydroquinone (KH2) is probably not NQO1, (3) there appears to be a warfarin-sensitive enzyme other than VKOR that reduces vitamin K to KH2, and (4) the primary function of VKOR is the reduction of KO to vitamin K. PMID- 21239699 TI - Impact of beta2 integrin deficiency on mouse natural killer cell development and function. AB - Natural killer (NK) cells are innate immune cells that express members of the leukocyte beta2 integrin family in humans and mice. These CD11/CD18 heterodimers play critical roles in leukocyte trafficking, immune synapse formation, and costimulation. The cell-surface expression of one of these integrins, CD11b/CD18, is also recognized as a major marker of mouse NK-cell maturation, but its function on NK cells has been largely ignored. Using N-ethyl-N-nitrosourea (ENU) mutagenesis, we generated a mouse carrying an A -> T transverse mutation in the Itgb2 gene, resulting in a mutation that prevented the cell-surface expression of CD18 and its associated CD11a, CD11b, and CD11c proteins. We show that beta2 integrin-deficient NK cells have a hyporesponsive phenotype in vitro, and present an alteration of their in vivo developmental program characterized by a selective accumulation of c-kit(+) cells. NK-cell missing-self recognition was partially altered in vivo, whereas the early immune response to mouse cytomegalovirus (MCMV) infection occurred normally in CD18-deficient mice. Therefore, beta2 integrins are required for optimal NK-cell maturation, but this deficiency is partial and can be bypassed during MCMV infection, highlighting the robustness of antiviral protective responses. PMID- 21239700 TI - Prevalence of 25-hydroxyvitamin D deficiency in subgroups of elderly persons with anemia: association with anemia of inflammation. AB - Anemia and vitamin D deficiency are conditions that both result in significant morbidity and increase with age. The potential relationship between them remains poorly understood, particularly in the elderly. We used the Third National Health and Nutrition Examination Survey to examine the association of vitamin D deficiency with anemia subtypes in persons aged >= 60 years. Vitamin D deficiency was defined as serum levels < 20 ng/mL, and anemia was defined according to World Health Organization criteria. Vitamin D deficiency was associated with anemia prevalence independent of age, sex, or race/ethnicity (odds ratio, 1.47; 95% confidence interval, 1.06-2.05; P = .02) and varied significantly by anemia subtype (P overall = .003). The prevalence of vitamin D deficiency was 33.3% in the nonanemic population, 56% in anemia of inflammation (AI; P = .008), and 33.0% in unexplained anemia (P = .55). Non-Hispanic blacks had a 7-fold increased risk of AI compared with whites, and this was partially attenuated after adjusting for vitamin D deficiency. These data show that vitamin D deficiency is associated with specific subtypes of anemia in the elderly, especially in those with AI. Vitamin D may suppress inflammatory pathways, and studies to determine whether vitamin D supplementation ameliorates AI are warranted. PMID- 21239701 TI - CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients. AB - Erdheim-Chester disease (ECD) is a rare form of non-Langerhans histiocytosis, with noncodified therapeutic management and high mortality. No treatment has yet been shown to improve survival in these patients. We conducted a multicenter prospective observational cohort study to assess whether extraskeletal manifestations and interferon-alpha treatment would influence survival in a large cohort of ECD patients. To achieve this goal, we thoroughly analyzed the clinical presentation of 53 patients with biopsy-proven ECD, and we performed a survival analysis using Cox proportional hazard model. Fifty-three patients (39 men and 14 women) with biopsy-proven ECD were followed up between November 1981 and November 2010. Forty-six patients (87%) received interferon-alpha and/or PEGylated interferon-alpha. Multivariate survival analysis using Cox proportional hazard model revealed that central nervous system involvement was an independent predictor of death (hazard ratio = 2.51; 95% confidence interval, 1.28-5.52; P = .006) in our cohort. Conversely, treatment with interferon-alpha was identified as an independent predictor of survival (hazard ratio = 0.32; 95% confidence interval, 0.14-0.70; P = .006). Although definitive confirmation would require a randomized controlled trial, these results suggest that interferon-alpha improves survival in ECD patients. This may be seen as a significant advance, as it is the first time a treatment is shown to improve survival in this multisystemic disease with high mortality. PMID- 21239702 TI - CD8+CD44(hi) but not CD4+CD44(hi) memory T cells mediate potent graft antilymphoma activity without GVHD. AB - Allogeneic hematopoietic cell transplantation can be curative in patients with leukemia and lymphoma. However, progressive growth of malignant cells, relapse after transplantation, and graft-versus-host disease (GVHD) remain important problems. The goal of the current murine study was to select a freshly isolated donor T-cell subset for infusion that separates antilymphoma activity from GVHD, and to determine whether the selected subset could effectively prevent or treat progressive growth of a naturally occurring B-cell lymphoma (BCL(1)) without GVHD after recipients were given T cell-depleted bone marrow transplantations from major histocompatibility complex-mismatched donors. Lethal GVHD was observed when total T cells, naive CD4(+) T cells, or naive CD8(+) T cells were used. Memory CD4(+)CD44(hi) and CD8(+)CD44(hi) T cells containing both central and effector memory cells did not induce lethal GVHD, but only memory CD8(+) T cells had potent antilymphoma activity and promoted complete chimerism. Infusion of CD8(+) memory T cells after transplantation was able to eradicate the BCL(1) lymphoma even after progressive growth without inducing severe GVHD. In conclusion, the memory CD8(+) T-cell subset separated graft antilymphoma activity from GVHD more effectively than naive T cells, memory CD4(+) T cells, or memory total T cells. PMID- 21239703 TI - Prediction of the fetal status in noninvasive management of alloimmune thrombocytopenia. AB - Fetal/neonatal alloimmune thrombocytopenia is the most common cause of severe thrombocytopenia in the fetus and in an otherwise healthy newborn. To counter the consequences of severe fetal thrombocytopenia, antenatal therapies have been implemented. Predictive parameters for fetal severe thrombocytopenia are important for the development of noninvasive strategy and tailored intervention. We report here data concerning 239 pregnancies in 75 HPA-1bb women. Analysis of the index cases (diagnosis of fetal/neonatal alloimmune thrombocytopenia) did not show any significant correlation between the severity of the disease and the maternal genetic background (ABO blood group and HLA-DRB3 allele). Subsequent pregnancies were managed, and therapy effectiveness was evaluated. The highest mean newborn platelet count was observed for a combination of intravenous immunoglobulin and steroids (135 * 109/L; 54 newborns) compared with intravenous immunoglobulin alone (89 * 109/L; 27 newborns). The maternal anti-HPA-1a antibody concentration measured before any treatment and before 28 weeks of gestation was predictive of the fetal status. The weighted areas under curves of the maternal alloantibody concentrations were predictive of therapy response. To conclude, this large retrospective survey gives new insights on maternal predictive parameters for fetal status and therapy effectiveness allowing noninvasive strategies. PMID- 21239704 TI - VEGF and FGF prime vascular tube morphogenesis and sprouting directed by hematopoietic stem cell cytokines. AB - Here, we demonstrate a novel, direct-acting, and synergistic role for 3 hematopoietic stem cell cytokines: stem cell factor, interleukin-3, and stromal derived factor-1alpha, in controlling human endothelial cell (EC) tube morphogenesis, sprouting, and pericyte-induced tube maturation under defined serum-free conditions in 3-dimensional matrices. Angiogenic cytokines such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) alone or VEGF/FGF combinations do not support these responses. In contrast, VEGF and FGF prime EC responses to hematopoietic cytokines via up-regulation of c-Kit, IL-3Ralpha, and C-X-C chemokine receptor type 4 from either human ECs or embryonic quail vessel explants. In support of these findings, EC Runx1 is demonstrated to be critical in coordinating vascular morphogenic responses by controlling hematopoietic cytokine receptor expression. Combined blockade of hematopoietic cytokines or their receptors in vivo leads to blockade of developmental vascularization in quail embryos manifested by vascular hemorrhage and disrupted vascular remodeling events in multiple tissue beds. This work demonstrates a unique role for hematopoietic stem cell cytokines in vascular tube morphogenesis and sprouting and further demonstrates a novel upstream priming role for VEGF and FGF to facilitate the action of promorphogenic hematopoietic cytokines. PMID- 21239707 TI - Motor imagery ability in patients with early- and mid-stage Parkinson disease. AB - BACKGROUND: Motor imagery has recently gained attention as a promising new rehabilitation method for patients with neurological disorders. Up to now, however, it has been unclear whether this practice method can also be successfully applied in the rehabilitation of patients with Parkinson disease (PD). OBJECTIVE: This study aimed to investigate whether the motor imagery ability of patients with PD is still intact despite basal ganglia dysfunctioning. METHODS: A total of 14 patients with early- and mid-stage PD (Hoehn and Yahr 1-3) and 14 healthy controls were evaluated by means of an extensive imagery ability assessment battery, consisting of 2 questionnaires, the Chaotic Motor Imagery Assessment battery, and a test based on mental chronometry. RESULTS: PD patients performed the imagery tasks more slowly than controls, but the motor imagery vividness and accuracy of most patients were well preserved. CONCLUSIONS: These results are promising regarding the potential use of motor imagery practice in the rehabilitation of patients with PD. PMID- 21239706 TI - The reproducibility and convergent validity of the walking index for spinal cord injury (WISCI) in chronic spinal cord injury. AB - BACKGROUND: The Walking Index for Spinal Cord Injury II (WISCI II) is a hierarchical scale that measures improvements in walking following spinal cord injury (SCI). The WISCI II has good face validity, concurrent validity, and reliability following acute SCI; however, psychometric properties need to be determined for chronic SCI. Because prior studies have demonstrated a relationship between lower-extremity motor scores (LEMS) and walking, outcome measures for walking should demonstrate a linkage between the underlying impairment (weakness) and walking-convergent validity. OBJECTIVE: To determine convergent validity and reproducibility of the WISCI II. METHODS: Self-selected and maximum WISCI levels were assessed for 76 patients with chronic SCI (34 paraplegia, 42 tetraplegia); 10-m walking speeds were calculated. Convergent validity was assessed by correlating WISCI II levels to LEMS and walking speed. Reproducibility was assessed with the intraclass correlation coefficient (ICC) and the smallest real difference (SRD). RESULTS: Convergent validity of the self selected and maximum WISCI II with LEMS was moderate for paraplegia (rho = 0.479 and rho = 0.533) and strong for tetraplegia (rho = 0.852 and rho = 0.816). Tetraplegia, but not paraplegia, demonstrated convergent validity of walking speed at the self-selected and maximum WISCI levels with LEMS (rho = 0.752 and rho = 0.813). WISCI reproducibility was excellent (self-selected ICC = 0.994; maximum ICC = 0.995), resulting in SRDs of 0.785 (self-selected) and 0.597 (maximum), suggesting that a change of one WISCI level can be interpreted as real in a chronic patient. CONCLUSIONS: Results suggest that the WISCI II should be a very useful outcome measure for detecting changes in walking function following chronic SCI. PMID- 21239708 TI - Characterization of Trex1 induction by IFN-gamma in murine macrophages. AB - 3' Repair exonuclease (Trex1) is the most abundant mammalian 3' -> 5' DNA exonuclease with specificity for ssDNA. Trex1 deficiency has been linked to the development of autoimmune disease in mice and humans, causing Aicardi-Goutieres syndrome in the latter. In addition, polymorphisms in Trex1 are associated with systemic lupus erythematosus. On the basis of all these observations, it has been hypothesized that Trex1 acts by digesting an endogenous DNA substrate. In this study, we report that Trex1 is regulated by IFN-gamma during the activation of primary macrophages. IFN-gamma upregulates Trex1 with the time course of an early gene, and this induction occurs at the transcription level. The half-life of mRNA is relatively short (half-life of 70 min). The coding sequence of Trex1 has only one exon and an intron of 260 bp in the promoter in the nontranslated mRNA. Three transcription start sites were detected, the one at -580 bp being the most important. In transient transfection experiments using the Trex1 promoter, we have found that two IFN-gamma activation site boxes, as well as an adaptor protein complex 1 box, were required for the IFN-gamma-dependent induction. By using EMSA assays and chromatin immune precipitation assays, we determined that STAT1 binds to the IFN-gamma activation site boxes. The requirement of STAT1 for Trex1 induction was confirmed using macrophages from Stat1 knockout mice. We also establish that c-Jun protein, but not c-Fos, jun-B, or CREB, bound to the adaptor protein complex 1 box. Therefore, our results indicate that IFN-gamma induces the expression of the Trex1 exonuclease through STAT1 and c-Jun. PMID- 21239710 TI - Elevated IL-7 availability does not account for T cell proliferation in moderate lymphopenia. AB - Lymphopenia-induced proliferation (LIP) is a proliferative program initiated in response to T cell insufficiency caused by acute or chronic immunodepletion. Studies of lymphopenic mice have demonstrated that the cytokine IL-7 and TCR signaling are critical for LIP. We examined how these two factors impact T cell proliferation following transfer into moderately lymphopenic mice. In this study, we show that moderate lymphopenia (~25% of wild-type lymphocytes) of IL-7Ralpha knock-in mutant (IL-7Ralpha(449F)) mice supports T cell proliferation, although with decreased frequency and kinetics compared with cells transferred to severely lymphopenic (5% of wild-type lymphocytes) IL-7Ralpha(-/-) hosts. Although previous studies have demonstrated that elevated IL-7 levels play an important role in LIP, IL-7 availability was not elevated in IL-7Ralpha(449F) mice. However, moderate lymphopenia increased access of transferred T cells to self peptide presented on APCs that can trigger TCR signaling and proliferation. Importantly, we did not detect significant changes in TCR Vbeta usage of proliferated T cells recovered from either moderately or severely lymphopenic hosts. Our work demonstrates that polyclonal T cells retain a diverse TCR repertoire following proliferation mediated by either self-peptide-MHC interaction alone or in combination with IL-7, and that T cell reconstitution is most efficient in the presence of increased IL-7 availability. PMID- 21239709 TI - Hapten application to the skin induces an inflammatory program directing hapten primed effector CD8 T cell interaction with hapten-presenting endothelial cells. AB - Contact hypersensitivity is a CD8 T cell-mediated response to hapten sensitization and challenge of the skin. Effector CD8 T cell recruitment into the skin parenchyma to elicit the response to hapten challenge requires prior CXCL1/KC-directed neutrophil infiltration within 3-6 h after challenge and is dependent on IFN-gamma and IL-17 produced by the hapten-primed CD8 T cells. Mechanisms directing hapten-primed CD8 T cell localization and activation in the Ag challenge site to induce this early CXCL1 production in response to 2,4 dinitrofluorobenzene were investigated. Both TNF-alpha and IL-17, but not IFN gamma, mRNA was detectable within 1 h of hapten challenge of sensitized mice and increased thereafter. Expression of ICAM-1 was observed by 1 h after challenge of sensitized and nonsensitized mice and was dependent on TNF-alpha. The induction of IL-17, IFN-gamma, and CXCL1 in the challenge site was not observed when ICAM-1 was absent or neutralized by specific Ab. During the elicitation of the contact hypersensitivity response, endothelial cells expressed ICAM-1 and produced CXCL1 suggesting this as the site of CD8 T cell localization and activation. Endothelial cells isolated from challenged skin of naive and sensitized mice had acquired the hapten and the ability to activate hapten-primed CD8 T cell cytokine production. These results indicate that hapten application to the skin of sensitized animals initiates an inflammatory response promoting hapten-primed CD8 T cell localization to the challenge site through TNF-alpha-induced ICAM-1 expression and CD8 T cell activation to produce IFN-gamma and IL-17 through endothelial cell presentation of hapten. PMID- 21239711 TI - Involvement of CD56brightCD11c+ cells in IL-18-mediated expansion of human gammadelta T cells. AB - gammadelta T cells are considered to be innate lymphocytes that play an important role in host defense against tumors and infections. We recently reported that IL 18 markedly amplified gammadelta T cell responses to zoledronate (ZOL)/IL-2. In an extension of this finding, we analyzed the mechanism underlying the IL-18 mediated expansion of gammadelta T cells. After incubation of PBMCs with ZOL/IL 2/IL-18, the majority of the cells expressed gammadelta TCR, and the rest mostly exhibited CD56(bright)CD11c(+) under the conditions used in this study. CD56(bright)CD11c(+) cells were derived from a culture of CD56(int)CD11c(+) cells and CD14(+) cells in the presence of IL-2 and IL-18 without the addition of ZOL. They expressed IL-18Rs, HLA-DR, CD25, CD80, CD83, CD86, and CD11a/CD18. In addition, they produced IFN-gamma, TNF-alpha, but not IL-12, when treated with IL 2/IL-18, and they exerted cytotoxicity against K562 cells, thus exhibiting characteristics of both NK cells and dendritic cells. Incubation of purified gammadelta T cells with CD56(bright)CD11c(+) cells in the presence of ZOL/IL-2/IL 18 resulted in the formation of massive cell clusters and led to the marked expansion of gammadelta T cells. However, both conventional CD56( /int)CD11c(high) dendritic cells induced by GM-CSF/IL-4 and CD56(+)CD11c(-) NK cells failed to support the expansion of gammadelta T cells. These results strongly suggest that CD56(bright)CD11c(+) cells play a key role in the IL-18 mediated proliferation of gammadelta T cells. PMID- 21239712 TI - CSF-1-dependent red pulp macrophages regulate CD4 T cell responses. AB - The balance between immune activation and suppression must be regulated to maintain immune homeostasis. Tissue macrophages (MPhis) constitute the major cellular subsets of APCs within the body; however, how and what types of resident MPhis are involved in the regulation of immune homeostasis in the peripheral lymphoid tissues are poorly understood. Splenic red pulp MPhi (RPMs) remove self Ags, such as blood-borne particulates and aged erythrocytes, from the blood. Although many scattered T cells exist in the red pulp of the spleen, little attention has been given to how RPMs prevent harmful T cell immune responses against self-Ags. In this study, we found that murine splenic F4/80(hi)Mac-1(low) MPhis residing in the red pulp showed different expression patterns of surface markers compared with F4/80(+)Mac-1(hi) monocytes/MPhis. Studies with purified cell populations demonstrated that F4/80(hi)Mac-1(low) MPhis regulated CD4(+) T cell responses by producing soluble suppressive factors, including TGF-beta and IL-10. Moreover, F4/80(hi)Mac-1(low) MPhis induced the differentiation of naive CD4(+) T cells into functional Foxp3(+) regulatory T cells. Additionally, we found that the differentiation of F4/80(hi)Mac-1(low) MPhis was critically regulated by CSF-1, and in vitro-generated bone marrow-derived MPhis induced by CSF-1 suppressed CD4(+) T cell responses and induced the generation of Foxp3(+) regulatory T cells in vivo. These results suggested that splenic CSF-1-dependent F4/80(hi)Mac-1(low) MPhis are a subpopulation of RPMs and regulate peripheral immune homeostasis. PMID- 21239713 TI - Mast cells as sensors of cell injury through IL-33 recognition. AB - In response to cell injury, caused, for example, by trauma, several processes must be initiated simultaneously to achieve an acute inflammatory response designed to prevent sustained tissue damage and infection and to restore and maintain tissue homeostasis. Detecting cell injury is facilitated by the fact that damaged cells release intracellular molecules not normally present in the extracellular space. However, potential underlying mechanisms for the recognition of endogenous danger signals released upon cell injury have yet to be elucidated. In this study, we demonstrate that mast cells, potent promoters of acute inflammation, play a key role in responding to cell injury by recognizing IL-33 released from necrotic structural cells. In an in vitro model of cell injury, this recognition was shown to involve the T1/ST2 receptor and result in the secretion of proinflammatory leukotrienes and cytokines by mouse mast cells. Remarkably, of all of the components released upon necrosis, our results show that IL-33 alone is a key component responsible for initiating proinflammatory responses in mast cells reacting to cell injury. Our findings identify IL-33 as a key danger signal released by necrotic structural cells capable of activating mast cells, thus providing novel insights concerning the role of mast cells as sensors of cell injury. PMID- 21239714 TI - An essential role of STIM1, Orai1, and S100A8-A9 proteins for Ca2+ signaling and FcgammaR-mediated phagosomal oxidative activity. AB - Phagocytosis is a process of innate immunity that allows for the enclosure of pathogens within the phagosome and their subsequent destruction through the production of reactive oxygen species (ROS). Although these processes have been associated with increases of intracellular Ca(2+) concentrations, the mechanisms by which Ca(2+) could regulate the different phases of phagocytosis remain unknown. The aim of this study was to investigate the Ca(2+) signaling pathways involved in the regulation of FcgammaRs-induced phagocytosis. Our work focuses on IgG-opsonized zymosan internalization and phagosomal ROS production in DMSO differentiated HL-60 cells and neutrophils. We found that chelation of intracellular Ca(2+) by BAPTA or emptying of the intracellular Ca(2+) store by thapsigargin reduced the efficiency of zymosan internalization. Using an small interfering RNA strategy, our data establish that the observed Ca(2+) release occurs through two isoforms of inositol 1,4,5-triphosphate receptors, ITPR1 and ITPR3. In addition, we provide evidence that phagosomal ROS production is dependent on extracellular Ca(2+) entry. We demonstrate that the observed Ca(2+) influx is supported by ORAI calcium release-activated calcium modulator 1 (Orai1) and stromal interaction molecule 1 (STIM1). This result suggests that extracellular Ca(2+) entry, which is required for ROS production, is mediated by a store-operated Ca(2+) mechanism. Finally, our data identify the complex formed by S100A8 and S100A9 (S100 calcium-binding protein A8 and A9 complex), two Ca(2+) binding proteins, as the site of interplay between extracellular Ca(2+) entry and intraphagosomal ROS production. Thus, we demonstrate that FcgammaR-mediated phagocytosis requires intracellular Ca(2+) store depletion for the internalization phase. Then phagosomal ROS production requires extracellular Ca(2+) entry mediated by Orai1/STIM1 and relayed by S100A8-A9 as Ca(2+) sensor. PMID- 21239715 TI - Dendritic cell-specific ICAM-3-grabbing nonintegrin expression on M2-polarized and tumor-associated macrophages is macrophage-CSF dependent and enhanced by tumor-derived IL-6 and IL-10. AB - Dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN; CD209) is a human pathogen-attachment C-type lectin with no obvious murine ortholog and for which ligation leads to enhanced anti-inflammatory cytokine release and altered proinflammatory cytokine production. Although induced by IL-4 in monocytes and considered as a DC marker, DC-SIGN expression on human APCs under homeostatic conditions is so far unexplained. We report in this study that M-CSF enhances DC SIGN expression on in vitro derived anti-inflammatory macrophages and that M-CSF mediates the induction of DC-SIGN by fibroblast- and tumor cell-conditioned media. The M-CSF-inducible DC-SIGN expression along monocyte-to-macrophage differentiation is dependent on JNK and STAT3 activation, potentiated by STAT3 activating cytokines (IL-6, IL-10), and abrogated by the M1-polarizing cytokine GM-CSF. In pathological settings, DC-SIGN expression is detected in tumor tissues and on ex vivo-isolated CD14(+) CD163(+) IL-10-producing tumor-associated macrophages. Importantly, DC-SIGN Abs reduced the release of IL-10 from macrophages exposed to Lewis(x)-expressing SKBR3 tumor cells. These results indicate that DC-SIGN is expressed on both wound-healing (IL-4-dependent) and regulatory (M-CSF-dependent) alternative (M2) macrophages and that DC-SIGN expression on tumor-associated macrophages might help tumor progression by contributing to the maintenance of an immunosuppressive environment. PMID- 21239716 TI - Basic calcium phosphate crystals induce monocyte/macrophage IL-1beta secretion through the NLRP3 inflammasome in vitro. AB - Basic calcium phosphate (BCP) crystals are associated with severe osteoarthritis and acute periarticular inflammation. Three main forms of BCP crystals have been identified from pathological tissues: octacalcium phosphate, carbonate substituted apatite, and hydroxyapatite. We investigated the proinflammatory effects of these BCP crystals in vitro with special regard to the involvement of the NLRP3-inflammasome in THP-1 cells, primary human monocytes and macrophages, and mouse bone marrow-derived macrophages (BMDM). THP-1 cells stimulated with BCP crystals produced IL-1beta in a dose-dependent manner. Similarly, primary human cells and BMDM from wild-type mice also produced high concentrations of IL-1beta after crystal stimulation. THP-1 cells transfected with short hairpin RNA against the components of the NLRP3 inflammasome and mouse BMDM from mice deficient for NLRP3, apoptosis-associated speck-like protein, or caspase-1 did not produce IL 1beta after BCP crystal stimulation. BCP crystals induced macrophage apoptosis/necrosis as demonstrated by MTT and flow cytometric analysis. Collectively, these results demonstrate that BCP crystals induce IL-1beta secretion through activating the NLRP3 inflammasome. Furthermore, we speculate that IL-1 blockade could be a novel strategy to inhibit BCP-induced inflammation in human disease. PMID- 21239717 TI - Presentation of soluble antigens to CD8+ T cells by CpG oligodeoxynucleotide primed human naive B cells. AB - Naive B lymphocytes are generally thought to be poor APCs, and there is limited knowledge of their role in activation of CD8(+) T cells. In this article, we demonstrate that class I MHC Ag presentation by human naive B cells is enhanced by TLR9 agonists. Purified naive B cells were cultured with or without a TLR9 agonist (CpG oligodeoxynucleotide [ODN] 2006) for 2 d and then assessed for phenotype, endocytic activity, and their ability to induce CD8(+) T cell responses to soluble Ags. CpG ODN enhanced expression of class I MHC and the costimulatory molecule CD86 and increased endocytic activity as determined by uptake of dextran beads. Pretreatment of naive B cells with CpG ODN also enabled presentation of tetanus toxoid to CD8(+) T cells, resulting in CD8(+) T cell cytokine production and granzyme B secretion and proliferation. Likewise, CpG activated naive B cells showed enhanced ability to cross-present CMV Ag to autologous CD8(+) T cells, resulting in proliferation of CMV-specific CD8(+) T cells. Although resting naive B cells are poor APCs, they can be activated by TLR9 agonists to serve as potent APCs for class I MHC-restricted T cell responses. This novel activity of naive B cells could be exploited for vaccine design. PMID- 21239718 TI - IL-33 activates B1 cells and exacerbates contact sensitivity. AB - B1 B cells produce natural IgM and play a critical role in the early defense against bacterial and viral infection. The polyreactive IgM also contributes to the clearance of apoptotic products and plays an important role in autoimmune pathogenesis. However, the mechanism of activation and proliferation of B1 cells remains obscure. In this study, we report that IL-33, a new member of IL-1 family, activates B1 cells, which express the IL-33 receptor alpha, ST2. IL-33 markedly activated B1 cell proliferation and enhanced IgM, IL-5, and IL-13 production in vitro and in vivo in a ST2-dependent manner. The IL-33-activated B1 cell functions could be largely abolished by IL-5 neutralization and partially reduced by T cell or mast cell deficiency in vivo. ST2-deficient mice developed less severe oxazolone-induced contact sensitivity (CS) than did wild-type (WT) mice. Furthermore, IL-33 treatment significantly exacerbated CS in WT mice with enhanced B1 cell proliferation and IgM and IL-5 production. Moreover, IL-33 activated B1 cells from WT mice could adoptively transfer enhanced CS in ST2(-/-) mice challenged with IL-33. Thus, we demonstrate, to the best of our knowledge, a hitherto unrecognized mechanism of B1 cell activation and IL-33 function, and suggest that IL-33 may play an important role in delayed-type hypersensitivity. PMID- 21239719 TI - Proteasome inhibition with bortezomib depletes plasma cells and autoantibodies in experimental autoimmune myasthenia gravis. AB - Bortezomib, an inhibitor of proteasomes, has been reported to reduce autoantibody titers and to improve clinical condition in mice suffering from lupus-like disease. Bortezomib depletes both short- and long-lived plasma cells; the latter normally survive the standard immunosuppressant treatments targeting T and B cells. These findings encouraged us to test whether bortezomib is effective for alleviating the symptoms in the experimental autoimmune myasthenia gravis (EAMG) model for myasthenia gravis, a disease that is characterized by autoantibodies against the acetylcholine receptor (AChR) of skeletal muscle. Lewis rats were immunized with saline (control, n = 36) or Torpedo AChR (EAMG, n = 54) in CFA in the first week of an experimental period of 8 wk. After immunization, rats received twice a week s.c. injections of bortezomib (0.2 mg/kg in saline) or saline injections. Bortezomib induced apoptosis in bone marrow cells and reduced the amount of plasma cells in the bone marrow by up to 81%. In the EAMG animals, bortezomib efficiently reduced the rise of anti-AChR autoantibody titers, prevented ultrastructural damage of the postsynaptic membrane, improved neuromuscular transmission, and decreased myasthenic symptoms. This study thus underscores the potential of the therapeutic use of proteasome inhibitors to target plasma cells in Ab-mediated autoimmune diseases. PMID- 21239720 TI - Cutting Edge: Selective role of ubiquitin in MHC class I antigen presentation. AB - The importance of ubiquitination in MHC class I-restricted Ag processing remains unclear. To address this issue, we overexpressed wild-type and dominant-negative lysineless forms of ubiquitin (Ub) in mammalian cells using an inducible vaccinia virus system. Overexpression of the lysineless Ub nearly abrogated polyubiquitination and potently inhibited epitope presentation from a cytosolic N end rule substrate as well as endoplasmic reticulum (ER)-targeted model Ags. In contrast, there was little impact on Ag presentation from cytosolic proteins. These trends were location dependent; redirecting cytosolic Ag to the ER rendered presentation lysineless Ub-sensitive, whereas retargeting exocytic Ag to the cytosol had the inverse effect. This dichotomy was further underscored by small interfering RNA knockdown of the ER-associated Ub ligase Hrd1. Thus, Ub-dependent degradation appears to play a major role in the MHC class I-restricted processing of ER-targeted proteins and a more restricted role in the processing of cytosolic proteins. PMID- 21239721 TI - TRIF is a critical survival factor in viral cardiomyopathy. AB - TRIF is a member of the innate immune system known to be involved in viral recognition and type I IFN activation. Because IFNs are thought to play an important role in viral myocarditis, we investigated the role of TRIF in induced myocarditis in mice. Whereas C57BL/6 (wild-type) mice showed only mild myocarditis, including normal survival postinfection with coxsackievirus group B serotype 3 (CVB3), infection of TRIF(-/-) mice led to the induction of cardiac remodeling, severe heart failure, and 100% mortality (p < 0.0001). These mice showed markedly reduced virus control in cardiac tissues and cardiomyocytes. This was accompained with dynamic cardiac cytokine activation in the heart, including a suppression of the antiviral cytokine IFN-beta in the early viremic phase. TRIF(-/-) myocytes displayed a TLR4-dependent suppression of IFN-beta, and pharmacological treatment of CVB3-infected TRIF(-/-) mice with murine IFN-beta led to improved virus control and reduced cardiac inflammation. Additionally, this treatment within the viremic phase of myocarditis showed a significant long term outcome indexed by reduced mortality (20 versus 100%; p < 0.001). TRIF is essential toward a cardioprotection against CVB3 infection. PMID- 21239723 TI - Evolution of phlebology: the journal of venous disease. PMID- 21239722 TI - A role for autophagic protein beclin 1 early in lymphocyte development. AB - Autophagy is a highly regulated and evolutionarily conserved process of cellular self-digestion. Recent evidence suggests that this process plays an important role in regulating T cell homeostasis. In this study, we used Rag1(-/-) (recombination activating gene 1(-/-)) blastocyst complementation and in vitro embryonic stem cell differentiation to address the role of Beclin 1, one of the key autophagic proteins, in lymphocyte development. Beclin 1-deficient Rag1(-/-) chimeras displayed a dramatic reduction in thymic cellularity compared with control mice. Using embryonic stem cell differentiation in vitro, we found that the inability to maintain normal thymic cellularity is likely caused by impaired maintenance of thymocyte progenitors. Interestingly, despite drastically reduced thymocyte numbers, the peripheral T cell compartment of Beclin 1-deficient Rag1( /-) chimeras is largely normal. Peripheral T cells displayed normal in vitro proliferation despite significantly reduced numbers of autophagosomes. In addition, these chimeras had greatly reduced numbers of early B cells in the bone marrow compared with controls. However, the peripheral B cell compartment was not dramatically impacted by Beclin 1 deficiency. Collectively, our results suggest that Beclin 1 is required for maintenance of undifferentiated/early lymphocyte progenitor populations. In contrast, Beclin 1 is largely dispensable for the initial generation and function of the peripheral T and B cell compartments. This indicates that normal lymphocyte development involves Beclin 1-dependent, early stage and distinct, Beclin 1-independent, late-stage processes. PMID- 21239724 TI - Novel anticoagulants: a discussion of clinical use in the treatment and prevention of venous thromboembolism. AB - Traditional therapeutic oral anticoagulation strategies often require invasive dosing or monitoring. Vitamin K antagonists (VKAs) have a large number of interactions, delayed onset requires frequent dose monitoring, and they have a small margin between therapeutic dose and bleeding complications. Novel oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, are being developed to prevent those VKAs drawbacks. Besides oral bioavailability, those compounds are designed to require minimal to no monitoring and have a favourable safety profile. This review reports efficacy and safety data of these compounds throughout clinical development, as well as new approaches for oral pharmacological management of venous thromboembolism. PMID- 21239725 TI - How many patients do I need? Sample size and power calculations. PMID- 21239728 TI - Classic major histocompatibility complex class I molecules: new actors at the neuromuscular junction. AB - The presence and function of immune molecules in the central nervous system (CNS) have been under debate for a long time. There is mounting evidence that molecules fundamental for immune function are indeed expressed by both neurons and glia and that such molecules may have important nonimmunological function for the organization and stability of synaptic connections. Here, we present data showing that the classic form of major histocompatibility complex (MHC) class I molecules is expressed in spinal motoneurons, in particular in their axons and presynaptically at their synapses with skeletal muscles, the neuromuscular junctions (NMJs). The expression is strongly increased after axon lesion in the peripheral nerve. In the absence of classic MHC I, the organization of NMJs is disturbed with NMJs in higher numbers than normal, thereby equipping single muscle fibers with multiple NMJs. It is suggested that these effects are mediated by the classic MHC class I in the motor axons, possibly through effects mediated by the peripherally myelinating Schwann cells, which express receptors for classic MHC class I. The presence of immune molecules normally used by other cells for antigen presentation in peripheral motor axons may have implications for the onset of specific motoneuron disease. PMID- 21239726 TI - Radio-frequency stylet ablation for incompetent perforating veins. PMID- 21239729 TI - Dendritic spine plasticity: new regulatory roles of dynamic microtubules. AB - Dendritic spines are small actin-rich protrusions that form the postsynaptic part of most excitatory synapses. They play critical roles in synaptic function and exhibit a striking degree of structural plasticity, which is closely linked to changes in strength of synaptic connections. Here the authors summarize recent work that has revealed an important relationship between the microtubule and actin cytoskeleton in controlling spine morphology and plasticity. Dynamic microtubules and the proteins that specifically associate with the growing microtubule plus-ends recently emerged as temporal and spatial regulators of actin organization, which controls dynamic changes in structure and function of dendritic spines. PMID- 21239732 TI - Shape-specific polymeric nanomedicine: emerging opportunities and challenges. AB - Size and shape are fundamental properties of micro/nanoparticles that are critically important for nanomedicine applications. Extensive studies have revealed the effect of particle size on spherical particles with respect to circulation, extravasation and distribution in vivo. In contrast, the importance of particle shape has only recently begun to emerge. For example, cylindrically shaped filomicelles (diameter 22-60 nm, length 8-18 MUm) have shown persistent blood circulation for up to one week after intravenous injection, much longer than their spherical counterparts. Disc-shaped nanoparticles have demonstrated higher in vivo targeting specificity to endothelial cells expressing intercellular adhesion molecule receptors in mice than spherical particles of similar size. In this Minireview, we will discuss the recent advances in the fabrication of shape-specific nanoparticles and their unique biological and pharmacological properties. Computational models are presented to provide mechanistic understanding of the shape effects on cell targeting under flow conditions. Shape-specific nanoparticles have the potential to significantly improve the performance of nanomedicine in diagnostic imaging and targeted drug delivery applications. PMID- 21239731 TI - Experimental models of Rett syndrome based on Mecp2 dysfunction. AB - Rett syndrome (RTT) is a neurodevelopmental disorder predominantly occurring in females with an incidence of 1:10,000 births and caused by sporadic mutations in the MECP2 gene, which encodes methyl-CpG-binding protein-2, an epigenetic transcription factor that binds methylated DNA. The clinical hallmarks include a period of apparently normal early development followed by a plateau and then subsequent frank regression. Impaired visual and aural contact often lead to an initial diagnosis of autism. The characterization of experimental models based on the loss-of-function of the mouse Mecp2 gene revealed that subtle changes in the morphology and function of brain cells and synapses have profound consequences on network activities that underlie critical brain functions. Furthermore, these experimental models have been used for successful reversals of RTT-like symptoms by genetic, pharmacological and environmental manipulations, raising hope for novel therapeutic strategies to improve the quality of life of RTT individuals. PMID- 21239734 TI - Persistent enteric mycobacterial infection enhances sensitivity to acute mucosal injury. AB - Antigen presenting cells such as intestinal macrophages are dynamic effector cells that play a critical role in maintaining mucosal homeostasis. However, it is not known how occult intestinal infections alter the response of the intestinal mucosa to subsequent intestinal injury. The aim of this study was to evaluate how persistent subclinical intestinal infection with Mycobacterium avium subsp. paratuberculosis (Map) would influence acute dextran sulfate sodium (DSS) mediated intestinal inflammation. BALB/c mice were infected intraperitoneally with Map. Following an incubation period of 90 d, mice were administered 2% DSS in the drinking water for six days. Prior to and during treatment with DSS, mice were evaluated for clinical signs of disease and body weights were recorded. At termination of the experiment, body weights, frequency of rectal blood, and gross and histological cecal lesions were evaluated, and tissues were collected for isolation of Map. Subclinical and persistent intestinal Map infection was established based on the absence of both weight loss and rectal blood and the isolation of Map from the small and large intestines in mice infected with Map only. Following treatment with DSS, Map-infected mice had increased weight loss, increased frequency of rectal blood, and exacerbation of gross lesions and increased cecal lesion scores. Also, there was a significant reduction in Map isolated from the small intestines of Map-infected and DSS-treated mice. In conclusion, subclinical Map infection sensitizes the host to enhanced acute DSS mediated intestinal inflammation. PMID- 21239733 TI - Overexpression of histone variant H2A.1 and cellular transformation are related in N-nitrosodiethylamine-induced sequential hepatocarcinogenesis. AB - Histones through a complex repertoire of non-allelic variants and their post translational modifications regulate gene expression. Though alterations in histone-modifying enzymes and post-translational modifications of histones have been studied in cancer, expression of histone variants has not been clearly associated with dedifferentiation and malignant transformation of hepatocyte in vivo. In the present work, the pattern of variants of histones was investigated during N-nitrosodiethylamine (NDEA)-induced hepatocarcinogenesis. Our studies show for the first time in vivo overexpression of a major histone H2A variant H2A.1 and a decrease in H2A.2 at protein and mRNA levels by sodium dodecyl sulfate-Acetic acid-Urea-Triton (SDS-AUT) two-dimensional gel electrophoresis followed by matrix-assisted-laser desorption/ionization time-of-flight (TOF)/TOF mass spectrometry and reverse transcriptase-polymerase chain reaction analysis during sequential development of hepatocellular carcinoma (HCC). H2A.1 and H2A.2 are highly homologous, replication-dependent, non-allelic variants of histone H2A differing at only three amino acid positions. Our results of increase in proliferating cell nuclear antigen expression indicate that with increase in replicating population of transformed cells in HCC, H2A.1 expression increases, suggesting association of H2A.1 overexpression with hyper-proliferation of hepatocytes during cellular dedifferentiation and progressive transformation of normal liver to preneoplastic and neoplastic stages of HCC. PMID- 21239735 TI - Hepatitis B x-interacting protein induces HepG2 cell proliferation through activation of the phosphatidylinositol 3-kinase/Akt pathway. AB - Hepatitis B x-interacting protein (HBXIP), a co-factor of survivin, was originally identified by its binding with the C-terminus of the hepatitis B virus x protein (HBx). We have recently shown that HBXIP promotes the growth of both normal liver cells and hepatoma cells in vitro, but the molecular mechanisms of this have not been documented. In this study, we investigated the potential effects of HBXIP on the proliferation of HepG2 cells and the intracellular signaling pathway mediating these changes. Over-expression of the HBXIP gene promoted the proliferation of HepG2 cells, as shown by the MTT assay. We also showed that HBXIP induced cellular accumulation in the S phase concomitantly with up-regulation of cyclinD(1) and down-regulation of p21 and p53 levels. Moreover, HBXIP over-expression cells showed activation of the PI3K/Akt pathway; this activation was accompanied by an increase in phosphorylation of glycogen synthase kinase 3beta. LY294002, a specific inhibitor of PI3K, blocked HBXIP-stimulated Akt phosphorylation and suppressed the cell cycle promotion induced by HBXIP in HepG2 cells. The increase in cyclinD(1) protein levels induced by HBXIP was inhibited when cells were incubated with LY294002. In conclusion, our data suggest that the proliferation of HepG2 cells promoted by HBXIP is associated with activation of the PI3K/Akt signaling pathway. PMID- 21239736 TI - The activation of leptin-mediated survivin is limited by the inducible suppressor SOCS-3 in MCF-7 cells. AB - Although leptin has been found to be implicated in obesity-related breast carcinogenesis in postmenopausal women, the molecular mechanisms involved are yet to be defined. Recently, the antiapoptotic gene survivin has been recognized as a target gene for leptin in breast cancer. The aim of this study was to investigate the effect of leptin on the expression of survivin and on the transcriptional activity of its promoter in MCF-7 breast cancer cells. We also studied the potential involvement of SOCS-3 (a negative regulator of leptin's main signaling pathway JAK2/STAT3) in the expression of leptin-mediated survivin. Our results showed a significant increase in the mRNA (dose-dependent increase of 40-70%) and protein expression levels of survivin 24 h post-leptin treatment, which was followed by a significant decrease at 48 and 72 h (of 60-70%). In accordance, a chromatin immunoprecipitation assay revealed an initial strong binding of STAT3 to the survivin promoter, which was no longer detected after 24 h. Myc/mad/max network proteins and histone H3 acetylation status were not found to contribute to the expression of leptin-mediated survivin. Furthermore, a protein immunoprecipitation assay detected an enhanced SOCS-3 binding to the long isoform of leptin's receptor (Ob-Rb) 48 and 72 h after leptin administration, thus conferring inhibition to leptin signaling. In conclusion, our findings suggest, for the first time to our knowledge, that the effect of leptin on the antiapoptotic gene survivin is limited by the inhibitory role of SOCS-3 in the leptin-activated JAK2/STAT3 signaling pathway in MCF-7 breast cancer cells. PMID- 21239737 TI - Biocompatibility study of glycofurol in rat brains. AB - Glycofurol (GF) has been used clinically as a solvent for parenteral drug delivery systems. However, the application and toxicity of GF in the brain have not been reported. This study was carried out to assess the systemic and neurologic reactions of GF in rats upon intracranial injection. Hematological and neuropathological assessments of rats were performed during the acute, subacute and chronic period after the injection. Injection of the GF solution (GF 25 MUL + PBS 25 MUL) into the brain cortex showed that it did not cause any deaths or clinical neurobehavioral abnormalities. At the same volume as phosphate-buffered saline (PBS) injection, it had mild effects on all hematological data and histopathology of brain tissues. Nevertheless, histomorphologic assessments of the brain tissues treated with PBS 70 MUL revealed different tissue responses compared with those of 70 MUL GF solution (30 MUL + PBS 40 MUL) where tissues around the administration site showed elevated polymorphonuclear leukocytes, macrophages and gliosis. These results demonstrated that the GF solution (GF 25 MUL + PBS 25 MUL) administration was well tolerated and caused minor inflammatory responses of cerebral cortex. This suggests possibilities of GF for drug delivery systems in the brain parenchymal tissues. PMID- 21239738 TI - CD44 mediates oligosaccharides of hyaluronan-induced proliferation, tube formation and signal transduction in endothelial cells. AB - Oligosaccharides of hyaluronan (o-HA) can induce angiogenesis and the growth and tube formation of vascular endothelial cells (ECs) in particular. As the major o HA receptor, CD44 has been implicated in EC function, but its role in mediating o HA-induced EC proliferation and tube formation remains unclear. In this study, we investigated the role of CD44 in o-HA-induced proliferation and tube formation of human umbilical vein endothelial cells (HUVECs) and explored the molecular mechanisms underlying the angiogenesis process. A CD44 siRNA was delivered into HUVECs by electroporation and o-HA-induced proliferation and tube formation capacity of CD44-silenced or control HUVECs were assessed by methylthiazolyldiphenyl-tetrazolium bromide (MTT) and Matrigel assays. Furthermore, the changes in Src, focal adhesion kinase (FAK) and extracellular signal-regulated kinase1 and 2 (ERK1/2) phosphorylation, as well as the expression of c-jun and c-fos were examined by Western blot and realtime polymerase chain reaction assays. Our results demonstrated that 10 MUg/mL o-HA obviously induced the proliferation and tube formation in HUVECs, and stimulated the phosphorylation of Src, FAK and ERK1/2 and upregulation of c-jun and c-fos, which could be inhibited by CD44 silencing. Altogether our data suggest that CD44 functions to initiate tyrosine phosphorylation of Src, FAK and ERK1/2, and upregulates the expression of c-jun and c-fos, thus mediating o-HA-induced proliferation and tube formation in HUVECs. PMID- 21239739 TI - Effect of Perilla frutescens var. acuta Kudo and rosmarinic acid on allergic inflammatory reactions. AB - Allergy is characterized by an overreaction of the immune system. Perilla frutescens leaf extract has been reported to exhibit antiallergic inflammatory activity. To investigate precisely the effect and mechanism of 30% ethanol extract powder of P. frutescens var. acuta Kudo (EPPF) and rosmarinic acid (RA), a component of EPPF in allergic rhinitis and rhinoconjunctivitis, the antiallergic effects of EPPF and RA were analyzed using in vivo and in vitro models. Cytokine production was analyzed by means of an enzyme-linked immunosorbent assay. Cytokine expression was analyzed via reverse transcription polymerase chain reaction and Western blotting. Transcription factor and caspase 1 activity were analyzed by a luciferase assay and caspase-1 assay, respectively. The number of nasal, ear and eye rubs after an ovalbumin (OVA) challenge in OVA sensitized mice was significantly higher than that in OVA-unsensitized mice. Increased number of rubs was inhibited by administration of EPPF or RA. Increased levels of IgE in the serum, spleen and nasal mucosa of OVA-sensitized mice were reduced by EPPF or RA administration. The histamine level was also reduced by EPPF or RA administration in the serum of OVA-sensitized mice. Protein levels and mRNA expressions of interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha were inhibited by EPPF or RA administration in the nasal mucosa tissue or spleen of OVA-sensitized mice. In EPPF or RA-administered mice, the mast cell and eosinophil infiltration increase as caused by OVA-sensitization was decreased. In addition, EPPF or RA inhibited both cyclooxygenase-2 protein expression and caspase-1 activity in the same nasal mucosa tissue. In activated human mast cells, nuclear factor-kappa B (NF-kappaB)/Rel A and caspase-1 activation increased, whereas NF-kappaB/Rel A and caspase-1 activation was inhibited after a treatment of EPPF or RA. These results indicate that EPPF and RA ameliorate allergic inflammatory reactions such as allergic rhinitis and allergic rhinoconjunctivitis. PMID- 21239740 TI - Motor and behavioral changes in rats with adenine-induced chronic renal failure: influence of acacia gum treatment. AB - Chronic renal failure (CRF) either occurring naturally in humans or induced surgically in rats causes alterations in behavior and motor functions. However, the effect of chemically induced CRF in rats on behavior is not known. We induced CRF in rats by feeding adenine (0.75% w/w, four weeks) and investigated the effect of the ensuing CRF on a depression model (forced swimming test, FST), analgesia (mechanical nociception), neuromuscular coordination (Rota-rod test) and motor activity (activity meter test). Further, we investigated the effect of giving acacia gum (AG, 10% w/v) in the drinking water concomitantly with adenine using the above models. AG has been previously shown to ameliorate the severity of CRF in humans and rats. Adenine-induced CRF significantly increased the plasma concentrations of urea and creatinine, and reduced creatinine clearance. Additionally, it significantly reduced motor activity and increased immobility time in the FST, suggesting a depressant-like effect. Both of these actions were significantly antagonized by AG treatment. Adenine insignificantly reduced the mechanical nociceptive threshold by 15%. The results of the tests for neuromuscular coordination were inconclusive. In conclusion, adenine-induced CRF caused motor and behavioral alterations, and these were significantly mitigated by administration of AG. PMID- 21239741 TI - Exercise with angina and cramp? PMID- 21239742 TI - Clinical features of lupus cystitis complicated with hydroureteronephrosis in a Chinese population. AB - OBJECTIVE: Lupus cystitis is a relatively rare complication of systemic lupus erythematosus (SLE). The clinical characterization of it remains obscure. We sought to provide insight for timely recognition and diagnosis of lupus cystitis, and for efficacious management of this disease entity. METHODS: The clinical files of 18 patients with lupus cystitis treated at Peking Union Medical College Hospital were reviewed. Clinical manifestations, laboratory investigations, therapeutic measurements, and clinical outcomes were analyzed. RESULTS: There were both male and female patients with a wide range of ages. The interval from onset of SLE to hydroureteronephrosis varied from 0 to 5 years. The most common clinical presentations were gastrointestinal (GI) symptoms, while urinary symptoms were less common and relatively mild. Lupus nephritis often presented concomitantly with lupus cystitis but was relatively less active pathologically. Laboratory findings showed a high rate of positive anti-SSA. Therapy of prednisone plus cyclophosphamide was effective for lupus cystitis. Delayed diagnosis and treatment may lead to irreversible obstructive uropathy and permanent loss of renal function. CONCLUSION: Lupus cystitis may not be so rare as has been thought. The diagnosis of lupus cystitis should be considered when patients with SLE present with GI symptoms, and therapy should begin as early as possible. PMID- 21239743 TI - Prevalence of clinically significant improvement following total knee replacement. AB - OBJECTIVE: Although total knee replacement (TKR) has a high reported success rate, the pain relief and functional improvement after surgery vary. The purpose of our retrospective cohort study was to determine the prevalence of patients showing no clinically important improvement 1 year after TKR, and patient factors that may predict this outcome. METHODS: We reviewed primary TKR registry data that were collected from 2 academic hospitals: the Toronto Western Hospital and the Hamilton Health Sciences Henderson Hospital in Ontario, Canada. Relevant covariates including demographic data, body mass index, and comorbidity were recorded. Knee joint pain and functional status were assessed at baseline and at 1-year followup with the Western Ontario McMaster University Osteoarthritis Index (WOMAC) and Oxford Knee Score (OKS) to measure the change using the minimal clinically important difference (MCID). Logistic regression modeling was used to identify the predictors of interest. RESULTS: Overall, 11.7% (373/3177) of patients reported no clinically important improvement 1 year after surgery. Logistic regression modeling showed that a greater patient age independently predicted no clinically important improvement on the WOMAC scale 1 year after surgery (p = 0.0003), while being male independently predicted no clinically important improvement on the OKS 1 year after surgery (p = 0.008). CONCLUSION: Awareness of the prevalence of patients who may show no clinically important improvement and factors that predict this outcome will help patients and surgeons set realistic expectations of surgery. PMID- 21239744 TI - Early prediction of increased arterial stiffness in patients with chronic inflammation: a 15-year followup study of 108 patients with rheumatoid arthritis. AB - OBJECTIVE: Patients with rheumatoid arthritis (RA), a chronic inflammatory disease, have increased cardiovascular morbidity and mortality. We investigated whether early markers of RA inflammatory disease activity could predict later increased levels of pulse-wave velocity (PWV) and augmentation index (AIx), 2 measures of arterial stiffness. METHODS: In total 238 patients with early RA were followed longitudinally and 108 were available for the 15-year followup examination. Comprehensive baseline clinical and radiographic data were collected in 1992. Arterial stiffness, measured as AIx and PWV (Sphygmocor apparatus), was recorded at the 15-year followup. Adjusted logistic univariate and multivariate analyses were performed with levels of AIx and PWV as the dependent variables, and variables reflecting baseline RA disease activity as possible predictors. The validity of the final models was examined in linear regression analyses. RESULTS: Baseline C-reactive protein (CRP) above the median predicted increased AIx (OR 3.52, 95% CI 1.04-11.90) and PWV (OR 4.84, 95% CI 1.39-16.83) at the 15-year assessment in multivariate models. Patients with elevated baseline CRP had significantly higher AIx (beta = 2.67, 95% CI 0.06-5.31, p = 0.045) and lnPWV (beta = 0.08, 95% CI 0.01-0.14, p = 0.02) after 15 years, after adjustments for age, sex, heart rate (AIx only) and mean arterial pressure. CONCLUSION: Inflammation early in the RA disease course was associated with increased AIx and PWV after 15 years. These findings support the importance of early control of the inflammatory process in patients with RA. PMID- 21239745 TI - Cartilage destruction is partly induced by the internal proteolytic enzymes and apoptotic phenomenon of chondrocytes in relapsing polychondritis. AB - OBJECTIVE: We analyzed 9 cases by immunohistochemical studies in order to elucidate the mechanisms of cartilage destruction in relapsing polychondritis (RP), which often involves the external auricle and respiratory tract through immunological disorder. METHODS: Cartilage tissues were obtained during surgical operations. Cell species in the granulation tissues, especially near the cartilage, were identified by cell-surface markers [CD3, CD4, CD8, CD20, CD45 (LCA), and CD68]. The proteolytic enzymes expressed in the cells in the perichondral granulation and in chondrocytes themselves were analyzed by immunohistochemical studies using anti-matrix metalloproteinase (MMP) -1, -3, -8, -9, and -13, and cathepsin D, K, L, and elastase antibodies. Apoptosis and nitric oxide (NO), an apoptosis-related factor, were also examined using ApopTag and antinitrotyrosine antibody, respectively. RESULTS: Among cell species that infiltrated in perichondral granulation, LCA, CD68 (monocytes/macrophages), and CD4 cells were dominant in number; MMP-8, MMP-9, and elastase were expressed only in the perichondral granulation; whereas MMP-3 and cathepsin K and L were detected in both chondrocytes and granulations. Out of 9 cases examined, 6 revealed apoptotic cells in excess of 50% of chondrocytes. There was a strong correlation between the number of apoptotic cells and the number of MMP-3 positive (r = 0.83) and cathepsin K-positive cells (r = 0.92). Abundant NO expressing cells were observed in the chondrocytes in degenerated cartilage, similar to apoptosis. CONCLUSION: Cartilage destruction in polychondritis is induced not only by perichondral inflammation, but also by intrinsic factors expressed in chondrocytes themselves, including certain kinds of proteolytic enzymes and apoptosis. PMID- 21239746 TI - Validation of the functional assessment of chronic illness therapy-fatigue scale in patients with moderately to severely active systemic lupus erythematosus, participating in a clinical trial. AB - OBJECTIVE: Fatigue is a common symptom of systemic lupus erythematosus (SLE). Our objective was to validate the 13-item Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale in patients with SLE. METHODS: The FACIT-Fatigue, Medical Outcomes Study Short-Form-36 (SF-36) questionnaire, Brief Pain Inventory (BPI), and Patient Global Assessment Visual Analog Scale (Patient-GA) were completed at baseline and at Weeks 12, 24, and 52 by patients with moderately to severely active extrarenal SLE. The patients were participating in a rituximab clinical trial. The British Isles Lupus Assessment Group (BILAG) disease activity index and the Physician Global Assessment Visual Analog Scale (Physician-GA) were completed by physicians at the same visits. RESULTS: At baseline, 254 patients completed the FACIT-Fatigue scale. Cronbach's alpha was > 0.95 at all visits. In cross-sectional analyses, FACIT-Fatigue scores differentiated between groups defined by BILAG General domain ratings. FACIT-Fatigue had moderate-high correlations (r = 0.5-0.8) with SF-36, BPI, and Patient-GA, but poor correlations with BILAG total score and Physician-GA (r = 0.1-0.3). At Weeks 12, 24, and 52, mean FACIT-Fatigue scale improvement was higher in patients who improved versus those who remained unchanged on the BILAG General domain. FACIT-Fatigue scale scores remained stable for patients with worsened BILAG General domain ratings compared to baseline. Distribution and anchor-based estimates suggested a minimally important difference (MID) range of 3-6 points. CONCLUSION: The FACIT Fatigue scale is a valid and responsive measure of fatigue in patients with SLE. MID in this SLE sample is similar to that derived previously in other populations. Since few patients experienced worsening BILAG General and Musculoskeletal domains in this study, further research is warranted to evaluate the responsiveness of FACIT-Fatigue to worsening of these domains. PMID- 21239747 TI - Paternal exposure to methotrexate and pregnancy outcomes. AB - OBJECTIVE: To assess the risk of major malformation in the case of paternal exposure to methotrexate (MTX) at the time of conception. METHODS: Using prospective data of our Teratology Information Service, we analyzed outcomes of paternal MTX exposure at the time of conception or up to 3 months before conception. RESULTS: We report on the outcomes of 42 pregnancies involving 40 men treated with MTX at the time of conception. Twenty-three men were treated for an inflammatory disease (54.8%), 9 for psoriasis (21.4%), and 8 for a malignant disease (19.0%). Weekly dosages varied between 7.5 mg and 30 mg. The pregnancies resulted in 36 live births, 3 spontaneous abortions, and 3 voluntary abortions. No congenital malformation was observed at birth. CONCLUSION: Based on our results and case reports in literature, paternal MTX exposure at the time of conception does not seem to raise any major concern for offspring. PMID- 21239748 TI - Comparison of certolizumab pegol with other anticytokine agents for treatment of rheumatoid arthritis: a multiple-treatment Bayesian metaanalysis. AB - OBJECTIVE: To compare the clinical efficacy of certolizumab pegol (CZP) with that of other anticytokine agents indicated for the treatment of rheumatoid arthritis (RA) with identical therapeutic indication (anti-tumor necrosis factor-alpha, anti-interleukin 1 or 6), with the objective of determining the noninferiority of CZP. METHODS: A systematic review was performed to identify randomized controlled trials that assessed the efficacy of anticytokine agents in combination with conventional disease-modifying antirheumatic drugs (DMARD) after 6 months of treatment, using the American College of Rheumatology (ACR) response criteria, in patients with RA who have shown inadequate response to DMARD including methotrexate. Indirect treatment comparisons were carried out by a multiple treatment Bayesian random-effects metaanalysis. Data were analyzed using the Markov chain Monte Carlo simulation. Noninferiority of CZP was assessed in comparison with a predefined equivalence margin of 5%. RESULTS: Nineteen placebo controlled studies were identified: 14 evaluated the efficacy of 5 anti-TNF-alpha agents (infliximab, etanercept, adalimumab, golimumab, CZP) and 5 evaluated efficacy of 2 anti-interleukin agents (anakinra, tocilizumab). Every treatment showed significant efficacy versus placebo in individual studies. The multiple treatment metaanalysis showed a highest OR for CZP on ACR20 response. Metaanalysis indicates that the efficacy of CZP according to ACR20 response is superior to that of infliximab, adalimumab, and anakinra, and equivalent or superior to that of etanercept, golimumab, and tocilizumab. According to ACR50 response, the efficacy of CZP is equivalent or superior to that of all other anticytokines. CONCLUSION: Results of this original multiple-treatment Bayesian metaanalysis indicate that certolizumab pegol is at least as efficacious as the preexisting antirheumatic anticytokine biotherapies. PMID- 21239749 TI - Plasma platelet-derived microparticles in patients with connective tissue diseases. AB - OBJECTIVE: To clarify the role of platelet-derived microparticles (PDMP), which are small vesicles with thrombotic and immunological properties, in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), dermatomyositis/polymyositis (PM/DM), and mixed connective tissue disease (MCTD). METHODS: Plasma levels of PDMP were measured by ELISA, and compared among patients with one of the 4 diseases. Association of PDMP levels with clinical characteristics and medication of the patients was also examined. RESULTS: PDMP levels were higher in patients with MCTD and SSc than in controls. Multiple linear regression analysis revealed that patients with Raynaud's phenomenon (RP) showed higher PDMP levels than those without. PDMP levels in individual patients did not fluctuate significantly over several months. CONCLUSION: PDMP level is associated with MCTD, SSc, and RP, and could be a novel marker for RP. PMID- 21239750 TI - Association of IRF5 polymorphisms with susceptibility to macrophage activation syndrome in patients with juvenile idiopathic arthritis. AB - OBJECTIVE: Systemic-onset juvenile idiopathic arthritis (systemic JIA) and macrophage activation syndrome (MAS), the most devastating complication of systemic JIA, are characterized by abnormal levels of proinflammatory cytokines. Interferon regulatory factor 5 (IRF5) is a member of the IRF family of transcription factors, and acts as a master transcription factor in the activation of genes encoding proinflammatory cytokines. Polymorphisms in the IRF5 gene have been associated with susceptibility to autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Our aim was to assess associations of IRF5 gene polymorphisms with susceptibility to systemic JIA and MAS. METHODS: Three IRF5 single-nucleotide polymorphisms (rs729302, rs2004640, and rs2280714) were genotyped using TaqMan assays in 81 patients with systemic JIA (33 with MAS, 48 without) and 190 controls. RESULTS: There were no associations of the IRF5 gene polymorphisms or haplotypes under study with susceptibility to systemic JIA. There was a significant association of the rs2004640 T allele with MAS susceptibility (OR 4.11; 95% CI 1.84, 9.16; p = 0.001). The IRF5 haplotype (rs729302 A, rs2004640 T, and rs2280714 T), which was reported as conferring an increased risk of SLE, was significantly associated with MAS susceptibility in patients with systemic JIA (OR 4.61; 95% CI 1.73, 12.3; p < 0.001). CONCLUSION: IRF5 gene polymorphism is a genetic factor influencing susceptibility to MAS in patients with systemic JIA, and IRF5 contributes to the pathogenesis of MAS in these patients. PMID- 21239751 TI - Surgery for shoulder osteoarthritis: a Cochrane systematic review. AB - OBJECTIVE: To determine the benefits and harm of surgery for shoulder osteoarthritis (OA). METHODS: We performed a Cochrane Systematic Review of clinical trials of adults with shoulder OA, comparing surgical techniques [total shoulder arthroplasty (TSA), hemiarthroplasty, implant types, and fixation] to placebo, sham surgery, nonsurgical modalities, and no treatment. We also reviewed trials that compared various surgical techniques, reporting patient-reported outcomes (pain, function, quality of life, etc.) or revision rates. We calculated the risk ratio for categorical outcomes and mean differences for continuous outcomes with 95% CI. RESULTS: There were no controlled trials of surgery versus placebo or nonsurgical interventions. Seven studies with 238 patients were included. Two studies compared TSA to hemiarthroplasty (n = 88). Significantly worse scores on the 0-100 American Shoulder and Elbow Surgeons scale (mean difference, -10.05 at 24-34 mo; 95% CI -18.97 to -1.13; p = 0.03) and a nonsignificant trend toward higher revision rate in hemiarthroplasty compared to TSA (relative risk 6.18; 95% CI 0.77 to 49.52; p = 0.09) were noted. With 1 study providing data (n = 41), no differences were noted between groups for pain scores (mean difference 7.8; 95% CI -5.33 to 20.93), quality of life on Medical Outcomes Study Short-Form 36 physical component summary (mean difference 0.80; 95% CI 6.63 to -8.23), and adverse events (relative risk 1.2; 95% CI 0.4 to 3.8). CONCLUSION: TSA was associated with better shoulder function, with no other demonstrable clinical benefits compared to hemiarthroplasty. More studies are needed to compare clinical outcomes between them and comparing shoulder surgery to sham, placebo, and other nonsurgical treatment options. PMID- 21239752 TI - Antinuclear antibodies and clinical associations in a british cohort with limited cutaneous systemic sclerosis. AB - OBJECTIVE: To assess the prevalence of disease-specific autoantibodies in patients with limited cutaneous systemic sclerosis (lcSSc). METHODS: Sera from 180 patients with lcSSc were analyzed for antinuclear antibody (ANA). Clinical characteristics were compared in the presence or absence of specific autoantibodies. RESULTS: SSc-specific antibodies were detected in 135 patients (75%). Associations were found between anticentromere antibody and age at lcSSc diagnosis, telangiectasia, reduced creatinine clearance, and selective reduction in DLCO, and between antitopoisomerase-I and pulmonary fibrosis. CONCLUSION: The majority of patients with lcSSc belong to distinctive serologic subsets, potentially with prognostic significance. PMID- 21239753 TI - Malignancies in juvenile idiopathic arthritis: a preliminary report. AB - OBJECTIVE: To present preliminary data on incidence of malignancy in juvenile idiopathic arthritis (JIA), compared to general population rates. METHODS: We examined cancer occurrence within JIA registries at 3 Canadian pediatric rheumatology centers. The subjects in the clinic registries were linked to regional tumor registries to determine the occurrence of invasive cancers over the observation period (spanning 1974-2006). The total number of cancers expected was determined by multiplying the person-years in the cohort by age, sex, and calendar year-specific cancer rates. The standardized incidence ratio (SIR, ratio of cancers observed to expected) was generated, with 95% confidence intervals. RESULTS: The study sample consisted of 1834 patients. The female proportion was 67.6%; average age at entry to cohort was 8.6 years (SD 5.1). The majority were Caucasian. Subjects contributed 22,341 patient-years (average 12.2, SD 7.8). Within this observation period, one invasive cancer occurred, compared to 7.9 expected (SIR 0.12, 95% CI 0.0, 0.70). This was a hematological cancer (Hodgkin's lymphoma), representing a SIR for hematological malignancies of 0.76 (95% CI 0.02, 4.21). CONCLUSION: Only one invasive cancer was identified in this large sample of individuals with JIA, observed for an average of 12.2 years each. These data suggest that, at least in the initial years following diagnosis of JIA, the risk of invasive cancers overall is not markedly increased. The results do not rule out the possibility of a baseline increased risk of hematological malignancies. PMID- 21239754 TI - Increased expression of B cell activation factor supports the abnormal expansion of transitional B cells in systemic lupus erythematosus. AB - OBJECTIVE: To examine the relationship between interferon-alpha (IFN-alpha) and dysregulation of B cell activation factor (BAFF) and specific B cell phenotypes in systemic lupus erythematosus (SLE). METHODS: Four-color flow cytometry was used to examine the peripheral B cell populations in patients with SLE. RNA was isolated from the peripheral blood of 87 patients and BAFF expression was determined by quantitative polymerase chain reaction (PCR) and normalized to GAPDH. The expression levels of 5 IFN-responsive genes (LY6E, OAS1, IFIT1, ISG15, and MX1) were determined by quantitative PCR and totaled to generate a global IFN score. The correlations were examined between peripheral B cell populations (including transitional, pregerminal, plasmablasts, and memory) and the expression of BAFF and the global IFN score. RESULTS: Examination of the peripheral B cell populations in SLE demonstrated a relative expansion of the transitional B cell and plasmablast compartment and a reduction in the memory B cell population. Expressions of BAFF and global IFN score were elevated in patients with SLE compared to healthy controls. A strong positive correlation was noted between BAFF expression and the relative proportion of late transitional (T2) B cells. The proportions of more mature B cell phenotypes did not correlate with BAFF expression. The global IFN score was strongly associated with the level of BAFF expression and moderately correlated with the proportion of late transitional B cells. CONCLUSION: The findings suggest that elevated BAFF expression supports expansion of the T2 B cell compartment and contributes to a breach in tolerance in patients with SLE. PMID- 21239755 TI - Functional polymorphisms of the coagulation factor II gene (F2) and susceptibility to systemic lupus erythematosus. AB - OBJECTIVE: Two F2 functional polymorphisms, rs1799963 (G20210A) and rs3136516 (A19911G), are known to be associated with elevated levels/activity of prothrombin (encoded by F2) and risk of thrombosis. Since patients with systemic lupus erythematosus (SLE) have high risk of thrombosis and accelerated atherosclerosis and also high prevalence of anti-prothrombin antibodies, we hypothesized that these two F2 polymorphisms could affect risk of SLE. METHODS: We investigated these polymorphisms in 627 women with SLE (84% Caucasian Americans, 16% African Americans) and 657 female controls (78% Caucasian Americans, 22% African Americans). RESULTS: While the rs1799963 A allele was almost absent in African Americans, it was present at ~2% frequency in Caucasian Americans and showed no significant association with SLE. The rs3136516 G allele frequency was significantly higher in Caucasian SLE cases than in controls (48.4% vs 43.7%, respectively) with a covariate-adjusted odds ratio (OR) of 1.22 (95% CI 1.03-1.46, p = 0.023). The association was replicated in African Americans (rs3136516 G allele frequency 91.2% in cases vs 82.2% in controls) with an adjusted OR of 1.96 (95% CI 1.08-3.58, p = 0.022). Stratification of Caucasian SLE patients based on the presence or absence of cardiac and vascular events (CVE) revealed stronger association with the CVE-positive SLE subgroup than the CVE-negative SLE subgroup (OR 1.42 vs 1.20). Prothrombin activity measurements in a subset of SLE cases demonstrated higher activity in the carriers of the rs3136516 G allele. CONCLUSION: Our results suggest a potential role for prothrombin and the crosstalk between hemostatic and immune/inflammatory systems in SLE and SLE-associated cardiovascular events, which warrants further investigation in independent samples. PMID- 21239756 TI - Assessment of subclinical vascular disease associated with ankylosing spondylitis. AB - OBJECTIVE: Studies indicate that ankylosing spondylitis (AS), as well as rheumatoid arthritis, may be associated with accelerated atherosclerosis and vascular disease. We assessed endothelial dysfunction, carotid atherosclerosis, and aortic stiffness in AS in context with clinical and laboratory measurements. METHODS: Forty-three patients with AS and 40 matched healthy controls were studied. We assessed common carotid intima-media thickness (ccIMT), flow-mediated vasodilation (FMD), and pulse-wave velocity (PWV) in association with age, disease duration, smoking habits, body mass index, patient's assessment of pain and disease activity, Bath AS Disease Activity Index, Bath AS Functional Index (BASFI), metric measurements, erythrocyte sedimentation rate, C-reactive protein, and HLA-B27 status. RESULTS: We found impaired FMD (6.85 +/- 2.98% vs 8.30 +/- 3.96%; p = 0.005), increased ccIMT (0.65 +/- 0.15 vs 0.54 +/- 0.15 mm; p = 0.01), and higher PWV (8.64 +/- 2.44 vs 8.00 +/- 1.46 m/s; p = 0.03) in patients with AS compared to controls, respectively. We also found that ccIMT negatively correlated with FMD (r = -0.563; p = 0.0001) and positively correlated with PWV (r = 0.374; p = 0.018). Both ccIMT and PWV correlated with disease duration (r = 0.559; p = 0.013 and r = 0.520; p = 0.022, respectively), BASFI (r = 0.691; p = 0.003 and r = 0.654; p = 0.006), decreased lumbar spine mobility (r = -0.656; p = 0.006 and r = -0.604; p = 0.013), chest expansion (r = -0.502; p = 0.047 and r = 0.613; p = 0.012), and increased wall-occiput distance (r = 0.509; p = 0.044 and r = 0.614; p = 0.011). CONCLUSION: In this well characterized AS population, impaired FMD and increased ccIMT and PWV indicate abnormal endothelial function and increased atherosclerosis and aortic stiffness, respectively. The value of noninvasive diagnostic tools needs to be further characterized. PMID- 21239757 TI - Identify biomarkers of neuropsychiatric systemic lupus erythematosus by matrix assisted laser desorption/ionization time-of-flight mass spectrometry combined with weak cation magnetic beads. AB - OBJECTIVE: To identify proteomic biomarkers in cerebrospinal fluid (CSF) and develop a diagnostic proteomic model for neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: CSF proteomic spectra were generated by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) combined with weak cation exchange (WCX) magnetic beads. The spectra were taken from 27 patients with NPSLE before and after treatment, and 27 controls including 17 patients with scoliosis and 10 patients with SLE but without neuropsychiatric manifestation. Discriminating peaks were processed by Biomarker Patterns Software to build a decision tree model for NPSLE classification. In addition, CSF samples of 12 patients with NPSLE, 12 patients with lumbar disc herniation, and 9 patients with other neurological conditions were used as a blind test group to verify the accuracy of the model. RESULTS: Twelve discriminating mass-to-charge (m/z) peaks were identified between NPSLE and controls: m/z peaks 7740, 11962, 8065, 7661, 6637, 5978, 11384, 11744, 8595, 10848, 7170, and 5806. The diagnostic decision tree model, built with a panel of m/z peaks 8595, 7170, 7661, 7740, and 5806, recognized NPSLE with both sensitivity and specificity of 92.6%, based on training group samples, and sensitivity and specificity of 91.7% and 85.7%, respectively, based on the blind test group. In addition, the root node m/z peak 8595 protein, which was downregulated in the CSF of patients with NPSLE after treatment, was identified and confirmed as ubiquitin by immunoprecipitation and ELISA. CONCLUSION: Potential CSF biomarkers for NPSLE are identified by MALDI-TOF-MS combined with WCX magnetic beads. The novel diagnostic proteomic model with m/z peaks 8595, 7170, 7661, 7740, and 5806 is highly sensitive and relatively specific for NPSLE diagnosis. The level of ubiquitin in CSF is a promising biomarker for active NPSLE. PMID- 21239758 TI - Use of serum clara cell 16-kDa (CC16) levels as a potential indicator of active pulmonary fibrosis in systemic sclerosis. AB - OBJECTIVE: To clarify the clinical significance of concentrations of serum Clara cell 16-kDa protein (CC16; previously denoted CC10) in the diagnosis and monitoring of pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc); and to compare CC16 levels with levels of the current most reliable serum markers for PF, such as Krebs von den Lungen-6 (KL-6) antigen and surfactant protein-D (SP-D). METHODS: Serum levels of CC16, KL-6, and SP-D were determined by ELISA in 92 patients with SSc, 20 patients with systemic lupus erythematosus (SLE), and 20 healthy controls. In a retrospective longitudinal study, correlation of serum CC16 levels with the activity of PF was assessed in 16 SSc patients with PF. RESULTS: Although CC16 levels were higher in patients with SSc than in SLE patients or healthy controls, the difference was not significant. Increased serum CC16 levels were associated with involvement of PF, especially active PF, as well as KL-6 and SP-D. Receiver operating characteristic curve analysis revealed that the utility of CC16 is slightly inferior to KL-6, but was comparable with that of SP-D for detecting PF in patients with SSc. In the longitudinal study, serum levels of CC16, KL-6, and SP-D were significantly decreased in the inactive disease phase compared to the active disease phase. CONCLUSION: CC16 levels can be used as a potential serum biomarker for PF in addition to KL-6 and SP-D in patients with SSc. PMID- 21239759 TI - Incidence and mortality of treated primary Sjogren's syndrome in Taiwan: a population-based study. AB - OBJECTIVE: To estimate the incidence and mortality of treated primary Sjogren's syndrome (pSS) by sex and age group in Taiwan. METHODS: We used claims data of the Bureau of National Health Insurance (NHI) of Taiwan from 2005 to 2007 for analysis. According to the NHI, pSS is classified as one of the financially catastrophic illnesses and patients with pSS could be exempted from copayment of all medical costs. To obtain a catastrophic illness certificate (CIC) for pSS, patients are required to meet the criteria of the American-European Consensus Group for pSS, and are reviewed by a committee. Patients approved for receipt of a CIC for pSS for the first time were defined as incident cases of treated pSS. RESULTS: A total of 3352 incident cases occurred between 2005 and 2007. The estimated mean annual incidence was 6.0 per 100,000 inhabitants (95% CI 5.8-6.2) for both sexes, 11.0 (95% CI 10.6-11.4) for women and 1.1 (95% CI 1.0-1.2) for men, with a female/male ratio of 9.9 (95% CI 8.8-11.1). Incidence increased with age, peaking at age 55-64 years in women and 65-74 years in men. The mortality rate was 33.4 per 1000 case person-years for men and 11.4 for women, with a male/female rate ratio of 2.9 (95% CI 1.7-5.3). CONCLUSION: The incidence of treated pSS in women is 10 times that in men. Nevertheless, pSS mortality in men is 3 times that in women. PMID- 21239760 TI - Valproic acid suppresses interleukin-1beta-induced microsomal prostaglandin E2 synthase-1 expression in chondrocytes through upregulation of NAB1. AB - OBJECTIVE: Microsomal prostaglandin E(2) synthase-1 (mPGES-1) catalyzes the terminal step in the biosynthesis of PGE(2). Early growth response factor-1 (Egr 1) is a key transcription factor in the regulation of mPGES-1, and its activity is negatively regulated by the corepressor NGF1-A-binding protein-1 (NAB1). We examined the effects of valproic acid (VA), a histone deacetylase inhibitor, on interleukin 1beta (IL-1beta)-induced mPGES-1 expression in human chondrocytes, and evaluated the roles of Egr-1 and NAB1 in these effects. METHODS: Chondrocytes were stimulated with IL-1 in the absence or presence of VA, and the level of mPGES-1 protein and mRNA expression were evaluated using Western blotting and real-time reverse-transcription polymerase chain reaction (PCR), respectively. mPGES-1 promoter activity was analyzed in transient transfection experiments. Egr 1 and NAB1 recruitment to the mPGES-1 promoter was evaluated using chromatin immunoprecipitation assays. Small interfering RNA (siRNA) approaches were used to silence NAB1 expression. RESULTS: VA dose-dependently suppressed IL-1-induced mPGES-1 protein and mRNA expression as well as its promoter activation. Treatment with VA did not alter IL-1-induced Egr-1 expression, or its recruitment to the mPGES-1 promoter, but prevented its transcriptional activity. The suppressive effect of VA requires de novo protein synthesis. VA induced the expression of NAB1, and its recruitment to the mPGES-1 promoter, suggesting that NAB1 may mediate the suppressive effect of VA. Indeed, NAB1 silencing with siRNA blocked VA-mediated suppression of IL-1-induced mPGES-1 expression. CONCLUSION: VA inhibited IL-1-induced mPGES-1 expression in chondrocytes. The suppressive effect of VA was not due to reduced expression or recruitment of Egr-1 to the mPGES-1 promoter and involved upregulation of NAB1. PMID- 21239761 TI - Clinical spectrum, treatment, and outcome of patients with type II mixed cryoglobulinemia without evidence of hepatitis C infection. AB - OBJECTIVE: The clinical spectrum, etiologies, and best therapeutic approaches of type II mixed cryoglobulinemia (MC) not associated with hepatitis C virus (HCV) infection have been poorly described to date. We studied the clinical presentation and outcome of patients with type II MC with no evidence of HCV. METHODS: This was a multicenter retrospective study on the clinical presentation and outcome of patients with type II MC without evidence of HCV infection. Only patients with symptomatic MC were included. RESULTS: Thirty-three patients were included (median followup 67.2 mo). Extensive investigations for associated diseases were performed at presentation. MC was related to an autoimmune disease in 14 patients, to a lymphoid malignancy in 4 patients, and to an infectious disease in 2 patients, while MC was classified as essential (primary) in 13. Essential MC tended to be more severe than secondary disease with, in particular, more frequent renal and peripheral nerve involvement. Most patients were treated with steroid with or without immunosuppressive agents, mainly cyclophosphamide. These treatments were unable to induce sustained remission. One patient was successfully treated with lenalidomide. Seven patients with nonmalignant MC were treated with rituximab; 2 had a sustained complete remission, 3 improved greatly but relapsed within 5 months, and 2 experienced a disease flare. CONCLUSION: An important proportion of non HCV-related type II MC remains essential. Efforts should be made to find other etiologies than HCV, because treatments with steroid and immunosuppressants are not satisfactory, especially in severe forms. In these situations anti-CD20 therapy may present the best option but should be used with caution. New agents such as lenalidomide remain to be evaluated. PMID- 21239762 TI - Standards for education and credentialing in critical care medicine. PMID- 21239763 TI - The brain-bone-blood triad: traffic lights for stem-cell homing and mobilization. AB - Navigation of transplanted stem cells to their target organs is essential for clinical bone marrow reconstitution. Recent studies have established that hematopoietic stem cells (HSCs) dynamically change their features and location, shifting from quiescent and stationary cells anchored in the bone marrow to cycling and motile cells entering the circulation. These changes are driven by stress signals. Bidirectional migrations to and from the bone marrow are active processes that form the basis for HSC transplantation protocols. However, how and why HSCs enter and exit the bone marrow as part of host defense and repair is not fully understood. The development of functional, preclinical, immune-deficient NOD/SCID (non-obese diabetic-severe combined immunodeficiency) mice transplantation models has enabled the characterization of normal and leukemic human HSCs and investigation of their biology. Intensive research has revealed multiple tasks for the chemokine SDF-1 (stromal cell-derived factor-1, also known as CXCL12) in HSC interactions with the microenvironment, as well as the existence of overlapping mechanisms controlling stress-induced mobilization and enhanced HSC homing, sequential events of major physiological relevance. These processes entail dynamically interacting, multi-system aspects that link the bone marrow vasculature and stromal cells with the nervous and immune systems. Neural cues act as an external pacemaker to synchronize HSC migration and development to balance bone remodeling via circadian rhythms in order to address blood and immune cell production for the physiological needs of the body. Stress situations and clinical HSC mobilization accelerate leukocyte proliferation and bone turnover. This review presents the concept that HSC regulation by the brain-bone blood triad via stress signals controls the bone marrow reservoir of immature and maturing leukocytes. PMID- 21239764 TI - Minimal residual disease in acute lymphoblastic leukemia. AB - In patients with acute lymphoblastic leukemia (ALL), treatment response is increasingly evaluated with minimal residual disease (MRD) assays. ALL cells can be recognized by their clonal rearrangement of immunoglobulin and T-cell receptor genes, expression of gene fusions, and leukemia-associated immunophenotypes. Assays based on polymerase chain reaction or flow cytometry can detect one ALL cell among 10,000 to 100,000 normal cells in clinical samples. The vast majority of cases have antigen-receptor gene rearrangements and leukemia immunophenotypes for MRD monitoring; about half of the cases currently have suitable gene fusions. The clinical significance of MRD has been conclusively demonstrated in both childhood and adult ALL. In most studies, MRD positivity is defined by the presence of 0.01% or more ALL cells; the risk of relapse is generally proportional to the level of MRD, particularly when measured during or at the end of remission-induction therapy. The prevalence of MRD during early therapy differs among genetic and biologic ALL subtypes. However, being a measurement of drug resistance in vivo and reflecting multiple cellular, host, and treatment variables, MRD is typically an independent prognostic factor. MRD is now used in several clinical trials for risk assignment and to guide clinical management overall. The time points at which MRD testing is performed and the threshold levels that trigger treatment intensification vary according to the methodology available, the results of preclinical correlative studies, and protocol design. PMID- 21239765 TI - Treating the "older" adult with acute lymphoblastic leukemia. AB - Acute lymphoblastic leukemia (ALL) in adults is a rare disease. The results of therapy remain unsatisfactory, and progress has been relatively slow. This article will focus on curative therapy in patients aged 30 to 60 years, but will also discuss the management of elderly patients with ALL. Recent large trials have increased our knowledge of the factors that determine outcome, and have clarified the role of blood and marrow transplantation in the management of this disease. These trials have also highlighted the major issues we need to focus on if we are to improve outcomes. This article describes the results of chemotherapy and blood and marrow transplantation for Philadelphia chromosome negative and positive adult ALL in the "older" adult patient, but also critically examines the major controversies and suggests how they might be resolved. The role of allografting in adult ALL is comprehensively discussed. Results of recent studies on T-cell ALL and reduced-intensity allografting are reviewed. A better understanding of the biology of the disease (including gene profiling) may allow individualization of therapy and, in time, targeted therapy. PMID- 21239766 TI - Adolescents and young adults with acute lymphoblastic leukemia. AB - During the last decade, increasing attention has been paid to a unique group of patients with acute lymphoblastic leukemia (ALL) who lie at the crossroad of therapeutic care by pediatric and adult hematologists/oncologists. ALL is a disease that affects infants, children, adolescents, and adult patients. With current therapies, the vast majority of children with ALL are now long-term survivors; unfortunately, the same good results have not yet been obtained for adults with ALL. This review will describe current controversies surrounding the treatment of adolescents and young adults with ALL--a group who finds themselves in the transition from "pediatric" to "adult" treatment approaches. The review focuses on recent insights into disease biology, prognostic factors, and treatment outcomes that have led to a series of prospective clinical trials specifically designed for adolescents and younger adults (AYAs) with ALL. These trials have been designed to provide important new clinical, psychosocial, and biological insights, and to further improve the survival of this challenging and unique group of patients. PMID- 21239767 TI - Telomere biology and telomere diseases: implications for practice and research. AB - The recent recognition of genetic defects in telomeres and telomere repair in multiple human diseases has practical implications for hematologists and oncologists and their patients; consequences for future clinical research in hematology and other subspecialties; and even importance in the interpretation of animal experiments involving cell propagation. Telomere diseases include constitutional marrow failure as dyskeratosis congenita, some apparently acquired aplastic anemia, myelodysplasia and acute myeloid leukemia; pulmonary fibrosis; and hepatic nodular regenerative hyperplasia and cirrhosis. Accelerated telomere attrition is a likely pathophysiology of cancer arising from chronic inflammation. Telomerase can be modulated by sex hormones, which may explain the activity of androgens in marrow failure. Measurement of telomere length of peripheral blood leukocytes is a simple screening clinical assay. Detection of a mutation in a patient has implications for therapy, prognosis, monitoring, and genetic counseling. For research in hematology and oncology, telomere biology could be assessed as a risk for secondary malignancies and in graft-versus-host disease, for progression in a variety of blood cancers, and as potentially modifiable by hormone replacement strategies. PMID- 21239768 TI - Aplastic anemia: first-line treatment by immunosuppression and sibling marrow transplantation. AB - Newly diagnosed aplastic anemia is a serious condition, with more than 75% (higher in young patients) becoming long-term survivors if diagnosed and treated appropriately. First-line treatment approaches include immunosuppressive treatment using the combination of antithymocyte globulin and cyclosporine A for patients without a sibling donor and HLA identical sibling transplant for patients younger than age 40 with a donor. Best transplant strategies have been defined and include conditioning with cyclophosphamide and antithymocyte globulin, marrow as a stem cell source, and graft-versus-host diease prophylaxis using cyclosporine A and methotrexate. It is against these standard treatment approaches that any therapeutic progress has to be measured. PMID- 21239769 TI - Alternative donor transplantation for aplastic anemia. AB - Patients with severe aplastic anemia who do not have a human leukocyte antigen (HLA)-identical sibling generally receive immunosuppressive therapy as a first line therapy, with allogeneic transplantation being reserved for those who do not have an adequate sustained response. Barriers to the use of unrelated-donor transplantation for aplastic anemia include identifying a suitable alternative donor, and risks of graft failure, regimen-related toxicity, and graft-versus host disease (GVHD). Despite the more than 14 million adults registered with donor registries worldwide, only approximately 50% of patients of Caucasian descent will have an available and fully HLA-matched unrelated adult donor; the rate is substantially lower for non-Caucasians. While umbilical cord blood allows transplantation with greater donor-recipient HLA disparity (without excessive risk of GVHD), risks of graft failure and transplant-related mortality are higher than after transplantation of adult donor grafts. Among patients with a suitable donor, recent changes in pre-transplant conditioning regimens have lowered the risks of organ toxicity and graft failure. Although advances in donor HLA typing and selection practices and improved GVHD prophylaxis have lowered the risk, GVHD remains an important obstacle to long-term symptom-free survival. Despite these limitations, unrelated-donor transplantation offers the best chance of long-term survival for many patients in whom current immunosuppression strategies are not effective. Wider applicability of alternative-donor transplantation for aplastic anemia will require better approaches to prevent graft failure and GVHD and to expand the pool of unrelated-donor grafts. This includes exploring strategies to effectively use alternative grafts such as umbilical cord blood. PMID- 21239770 TI - New prognostic markers in acute myeloid leukemia: perspective from the clinic. AB - Acute myeloid leukemia (AML) is a disease with marked heterogeneity in both response to therapy and survival. Cytogenetics, age, and performance status have long determined prognosis and therapy. The advent of molecular diagnostics has heralded an explosion in new prognostic factors, including gene mutations in KIT, FLT3 (Fms-like tyrosine kinase 3), NPM1 (nucleophosmin 1), and CEBPA (CCAAT enhancer-binding protein-alpha). Microarray technology can now identify unique gene expression signatures associated with prognosis. Similarly microRNA expression, single nucleotide polymorphism arrays, and DNA methylation signatures have recently described important new prognostic subgroups of AML, and are contributing to our understanding of AML disease biology. Combined with proteomic profiling, these technologies have helped identify new targets and signaling pathways, and may soon help to identify individual patients likely to benefit from specific therapies, including allogeneic hematopoietic cell transplantation. In summary, new clinical and molecular prognostic markers have begun to significantly improve our understanding of AML biology. We are now close to a time when we will be able to use these prognostic factors and technologies to identify new targets for therapy and to determine who may benefit from that therapy, and ultimately change how we treat individual patients with AML. PMID- 21239771 TI - New trends in the standard of care for initial therapy of acute myeloid leukemia. AB - In younger patients with acute myeloid leukemia (AML), initial treatment has provided very good control of the disease. Induction therapy has used combination chemotherapy, with anthracycline and cytarabine as the foundation. Recent trials support dose intensification of anthracycline in induction. Intensive postremission therapy further contributes to improving survival. The addition of targeted therapy with gemtuzumab ozogamicin to standard therapy has not improved on these outcomes. Newer agents targeted to specific molecular abnormalities or survival mechanisms in the leukemic cell are being studied as future additions to the current standard therapy. PMID- 21239772 TI - Treating the elderly patient with acute myelogenous leukemia. AB - Decisions regarding the optimal treatment of acute myelogenous leukemia in the elderly patient requires the consideration of multiple factors. Population-based studies have demonstrated that, for all age groups, aggressive therapy results in improved survival and quality of life when compared with palliative care. The optimal induction and postremission regimen for older patients has yet to be determined. Furthermore, not all patients are candidates for such therapy. Consideration of patient and disease-related factors can help to determine the appropriateness of intensive therapy in a given patient. For those patients for whom aggressive induction therapy does not seem to be in their best interest, novel agents are being investigated that will hopefully address the issues of induction death and early relapse associated with these patient populations. PMID- 21239773 TI - Novel insights into the biology of CLL. AB - Significant advancements in the care of patients with chronic lymphocytic leukemia (CLL) have occurred over the past decade. Nonetheless, CLL remains incurable outside of allogeneic transplantation. CLL is the most common leukemia in the United States and Europe, and new treatments and therapeutic strategies are clearly needed. To address this need, the pathogenesis of CLL has been an area of intense ongoing investigation. These international efforts illuminate a complex biology that is reliant on the interplay of inherited, environmental, and host factors. This broad review will discuss the recent advances in our understanding of CLL biology including the elucidation of inherited and acquired genetic changes; the role of the B-cell receptor and B-cell receptor signaling; CLL cell kinetics; and the interactions in the microenvironment between CLL cells, other immune cells, and stromal elements. This improved understanding of disease pathogenesis is facilitating the development of novel therapeutic treatment strategies. PMID- 21239774 TI - Prognostic markers and stratification of chronic lymphocytic leukemia. AB - Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies and is characterized by a tremendously variable clinical course. Additionally, whereas the median age at diagnosis is 72 years, CLL is diagnosed with increasing frequency in younger patients. Given the toxicities associated with currently available therapies, being able to predict which patients will need treatment could play a significant role in preserving bone marrow function and reducing morbidity and mortality. While a great many prognostic markers have been identified that predict outcomes for patients with CLL. Learning how to use these prognostic markers to provide patient care is more difficult. PMID- 21239775 TI - Treatment of younger patients with chronic lymphocytic leukemia. AB - Younger patients (defined as patients younger than 50-55 years of age) represent a small group of newly diagnosed patients with chronic lymphocytic leukemia, accounting only for 10% to 20% of newly diagnosed cases. However, once these patients become symptomatic and require treatment, their life expectancy is significantly reduced. Therapeutic approaches for younger patients should be directed at improving survival by achieving a complete remission and, where possible, eradicating minimal residual disease. Chemoimmunotherapy combinations carry the highest response rates and are commonly offered to younger patients. Additional strategies that should be considered for younger patients include early referral for stem-cell transplantation and clinical trials of consolidation therapy to eliminate minimal residual disease. PMID- 21239776 TI - Evidence-based mini-review: the role of alkylating agents in the initial treatment of chronic lymphocytic leukemia patients with the 11q deletion. AB - A 55-year-old man presented with fever, night sweats, and weight loss of about 20 lbs. in the prior 6 months. Physical examination revealed multiple cervical, axillary, and inguinal lymphadenopathy. The spleen was enlarged. A complete blood count revealed leukocytosis with absolute lymphocytosis: 30,000/MUL. Peripheral blood-flow cytometric analysis showed a clonal lymphocyte population with immunophenotypes positive for CD5, CD20(dim), and monotypic kappa light chain. Fluorescence in situ hybridization (FISH) analysis revealed del(11q22.3), but negative for t(11:14). What should be used to treat his chronic lymphocytic leukemia (CLL) disease? PMID- 21239777 TI - Upcoming diagnostic and therapeutic developments in classical Hodgkin's lymphoma. AB - With improvements in therapy, increasing dose intensity, early recognition of toxicity, and enhanced supportive care, current outcomes in patients with classical Hodgkin's lymphoma (HL) may be superior to disease-free and overall survival (OS) predicted by existing prognostic models, including the International Prognostic Score (IPS). The addition of biologic markers to recognized clinical prognostic factors, including those of the IPS, may to improve patient risk stratification and guide therapy in the future. However, the identification of these markers has been problematic due to the lack of large, confirmatory prospective trials, reproducibility and feasibility of the assays, and failure to improve upon already recognized clinical risk factors. One biomarker in particular, CD68, present on tumor infiltrating macrophages and detectable by immunohistochemical staining, is significantly associated with both shortened progression-free and disease-specific survivals in patients with HL at diagnosis and at relapse. In addition, less than 5% CD68+ cells correlates with a 100% disease-specific survival in patients with early-stage HL. CD68 represents just one of the many prognostic markers that could eventually be used to risk stratify therapy. In addition, biologic markers may not only serve as prognostic markers, but also as therapeutic targets in HL. This review examines current data using the IPS to determine patient outcome, discuss several potential biologic prognostic markers, and summarize new therapies that are currently in clinical development in HL. PMID- 21239778 TI - The past: what we have learned in the last decade. AB - Hodgkin lymphoma (HL) has become a curable malignancy for most patients during the last decades. However, many controversies still exist on the optimal strategy of how to cure our patients. The key question is how to balance the risks and toxicities of chemotherapy and radiotherapy against the need for a definite treatment for early or advanced-stage HL patients. However, although many studies have been conducted and reported during the past decade, interpretation of their results and treatment recommendations might vary significantly in different countries. For example, early-stage HL might be divided into two different subgroups: early favorable and early unfavorable or not. Treatment of early-stage HL might include radiotherapy ("combined modality") or not. Depending on the extent of radiotherapy, the schedule and number of chemotherapy cycles are also questioned. For advanced-stage HL, the situation is not much different. Compared with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), the more aggressive escalated BEACOPP regimen (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) is highly effective, but also raises concern due to excessive toxicity. Thus, there is a controversy about the standard of care for advanced HL patients. Because no mature results comparing these approaches with each other are currently available, it remains our duty to share the preliminary information with our patients and to figure out the most appropriate individual treatment strategy. Of course, the discussion of these issues is influenced by experiences and preferences. In contrast, in this article, we will try to focus on the available scientific evidence regarding the first-line treatment of HL. Of course, focusing on the last decade necessarily exclude the most recent results from ongoing studies. Thus, even though this article comprises treatment recommendations for HL patients, the best treatment certainly still is within properly designed prospective clinical trials. PMID- 21239779 TI - The present: optimizing therapy--too much or too little? AB - Despite the use of less toxic chemotherapy and more limited doses and fields of radiation, the prognosis for patients with all stages of classical Hodgkin lymphoma (HL) has continued to improve over the last 20 years. The challenge today is better identification of prognostic markers that will allow even further reduction of therapy in the most favorable subsets and new approaches for those who have a high risk of failure with current approaches. Most ongoing clinical trials for newly diagnosed HL base therapy decisions on the result of an interim restaging PET/CT, de-escalating for early responders and escalating for patients with a suboptimal response. While awaiting the results of these important trials, the debates rage on regarding the use of consolidative radiotherapy in early stage HL and the use of escalated BEACOPP in advanced stage disease. Unfortunately, we still face the very difficult decision with nearly every patient with HL of "too much," risking long-term consequences, or "too little," risking relapse and the need for additional toxic therapy. At present, we need to make these very difficult initial treatment decisions with inadequate data, but reassured by the excellent outcomes for most patients and encouraged by the new agents available for those who fail first-line therapy. PMID- 21239780 TI - Assessing new therapies and their overall impact in myelofibrosis. AB - Clinical management of myelofibrosis (MF)--whether primary or arising from an antecedent myeloproliferative neoplasm (post-essential thrombocythemia/polycythemia vera MF)--is currently in a period of transition that began with the discovery of the JAK2-V617F mutation 5 years ago. Selective JAK2 inhibitors have been developed, and clinical trials thus far have demonstrated that several of these agents meaningfully reduce MF-associated splenomegaly and constitutional symptoms. JAK2 inhibitors have durable benefits, act across the spectrum of MF subtypes, and provide a level of symptomatic benefit not seen with previous generations of nontargeted therapies. However, the JAK2 inhibitors can cause anemia and/or gastrointestinal disturbance, and their impact on JAK2 allele burden and the natural history is not yet fully defined. Several additional therapies that do not directly target JAK2 (eg, immunomodulatory drugs, histone deacetylase inhibitors, and inhibitors of the mammalian target of rapamycin [mTOR]) may ameliorate MF-associated anemia and morbidity-inducing symptoms. Balancing the potential benefits of these new agents against the risks and benefits of allogeneic stem cell transplantation (which can be curative, but carries a high risk of treatment-associated morbidity and mortality) requires an accurate estimation of the prognosis for an individual patient. Enhanced prognostic modeling systems are helping us to better characterize prognosis in MF patients not only at diagnosis, but also along the dynamic and variable course of the illness. Future advancements in the efficacy of MF-targeted therapy will likely arise from new pathogenetic insights and from combining JAK2 inhibitors with other agents. PMID- 21239781 TI - Chronic myeloid leukemia 2010: where are we now and where can we go? AB - Chronic myeloid leukemia is a model of how the molecular understanding of a disease can provide the platform for therapy and diagnostics. Clinicians are now empowered with first- and second-generation tyrosine kinases, as well as molecular tools to monitor disease and characterize resistance. However, there are still unanswered questions regarding optimization of therapy, the utility of molecular monitoring, and the search (or need) of "cure" that bears thought. In this review, we will discuss these issues, as they provide a roadmap for what may lie ahead in the therapy of other hematologic malignancies, particular the other myeloproliferative syndromes, where specific genetic lesions, and targeted therapy, are now being realized. PMID- 21239782 TI - Rethinking disease definitions and therapeutic strategies in essential thrombocythemia and polycythemia vera. AB - The seminal discovery of the JAK2V617F mutation, which is highly prevalent in Philadelphia-negative myeloproliferative disorders, now renamed neoplasms, triggered an almost unprecedented explosion of interest and data in the field. Descriptions of additional mutations in exon 12 of JAK2, at position 515 in MPL, and a number of other mutations at low frequency followed these discoveries. These advances in our understanding of molecular pathogenesis of these conditions coincided with the publication of results from two major clinical studies, ECLAP and PT-1, which contributed important clinical insights and facilitated significant correlative data collection. This article, focusing mainly upon essential thrombocythemia and polycythemia vera, reviews four major themes: the impact upon classification of these disorders considering a radical review of current terminology, and then three areas pertinent to clinical management: the indications for cytoreductive therapy in which the key targets are to reduce thrombohemorrhagic complications, relieve disease-related symptoms, and minimize the risk of transformation to secondary myeloid malignancy such as myelodysplasia, leukemia, and secondary myelofibrosis; and second reviewing current and, last, future therapeutic options, in particular interferon and JAK2 inhibitors. PMID- 21239783 TI - Thrombocytopenia in the intensive care unit patient. AB - The many comorbidities in the severely ill patient also make thrombocytopenia very common (~40%) in intensive care unit patients. The risk of bleeding is high with severe thrombocytopenia and is enhanced in intensive care patients with mild or moderately low platelet counts when additional factors are present that interfere with normal hemostatic mechanisms (eg, platelet function defects, hyperfibrinolysis, invasive procedures, or catheters). Even if not associated with bleeding, low platelet counts often influence patient management and may prompt physicians to withhold or delay necessary invasive interventions, reduce the intensity of anticoagulation, order prophylactic platelet transfusion, or change anticoagulants due to fear of heparin-induced thrombocytopenia. One approach to identify potential causes of thrombocytopenia that require specific interventions is to consider the dynamics of platelet count changes. The relative decrease in platelet counts within the first 3 to 4 days after major surgery is informative about the magnitude of the trauma or blood loss, whereas the dynamic of the platelet count course thereafter shows whether or not the physiologic compensatory mechanisms are working. A slow and gradual fall in platelet counts developing over 5 to 7 days is more likely to be caused by consumptive coagulopathy or bone marrow failure, whereas any abrupt decrease (within 1-2 days) in platelet counts manifesting after an initial increase in platelet counts approximately 1 to 2 weeks after surgery strongly suggests immunologic causes, including heparin-induced thrombocytopenia, other drug-induced immune thrombocytopenia, and posttransfusion purpura. PMID- 21239784 TI - Thrombosis in cancer: an update on prevention, treatment, and survival benefits of anticoagulants. AB - Thromboembolism is a common, complex, and costly complication in patients with cancer. Management has changed significantly in the past decade, but remains firmly dependent on the use of anticoagulants. Low-molecular-weight heparin is the preferred anticoagulant for prevention and treatment, although its limitations open opportunities for newer oral antithrombotic agents to further simplify therapy. Multiple clinical questions remain, and research is focusing on identifying high-risk patients who might benefit from primary thromboprophylaxis, treatment options for those with established or recurrent thrombosis, and the potential antineoplastic effects of anticoagulants. Risk-assessment models, targeted prophylaxis, anticoagulant dose escalation for treatment, and ongoing research studying the interaction of coagulation activation in malignancy may offer improved outcomes for oncology patients. PMID- 21239785 TI - Evidence-based mini-review: should all patients with idiopathic venous thromboembolic events be screened extensively for occult malignancy? PMID- 21239786 TI - Recombinant factor VIIa: an assessment of evidence regarding its efficacy and safety in the off-label setting. AB - Recombinant human factor VIIa (rFVIIa) is approved by the US Food and Drug Administration for use in the setting of hemorrhage associated with factor VIII or factor IX inhibitors in patients with congenital or acquired hemophilia. This indication represents only a small number of bleeding conditions. Since it became available, rFVIIa has been increasingly used in the management of off-label indications, ranging from emergent hemostasis in traumatic hemorrhage to prophylactic hemostasis in patients undergoing major surgery. Prominent off-label indications include the management of patients with coagulopathies, such as occurs in trauma patients experiencing massive and uncontrolled hemorrhage, and in patients undergoing cardiovascular surgery with cardiopulmonary bypass. Other occasions for use occur in patients with intact coagulation systems, with nontraumatic intracranial hemorrhage being the most common in this group. Uncertainties regarding the efficacy and safety associated with use of rFVIIa in these off-label scenarios have led to evidence-based assessments of patient outcomes, including mortality, the rate of thromboembolic adverse events, and posttreatment functional status. We review the evidence regarding the efficacy and safety of this important, but controversial, hemostatic agent in the off label setting. PMID- 21239787 TI - Pregnancy and commonly used drugs in hematology practice. AB - When a woman suffering from a hematological condition is contemplating pregnancy, she may need to continue the use of medications that do not have sufficient evidence of fetal safety. We discuss the evidence existing for some therapies of major hematological conditions in the context of major principles in clinical teratology. It is critical to always balance the potential fetal risks of the drug in question against the maternal and fetal risks of the untreated hematological condition. PMID- 21239788 TI - Consultative hematology: the pregnant patient pregnancy loss. AB - The presence of antiphospholipid antibodies has been associated with an increased risk of recurrent pregnancy loss, and there is evidence to suggest that antithrombotic therapy improves the likelihood of a successful outcome in affected women. Recent studies suggest an association between hereditary thrombophilia and pregnancy loss, although a causal role remains controversial. Although the available data are limited and flawed, there is increasing use of antithrombotic therapy in thrombophilic women with a history of pregnancy failure. Given the absence of proven effective therapy in women with unexplained recurrent loss, there is also growing pressure to intervene with antithrombotics in women with no known underlying thrombophilia. This article reviews the evidence for an association between thrombophilia and recurrent pregnancy loss and the data regarding the use of antithrombotic therapy for prevention of loss an area that remains particularly challenging because of the paucity of good quality data upon which to base clinical decisions. PMID- 21239789 TI - Evidence base for the management of venous thromboembolism in pregnancy. AB - Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of maternal mortality during pregnancy. DVT and PE are commonly suspected due to many mimicking signs and symptoms that are normal in pregnancy. However, validated diagnostic approaches are lacking, and a fear of teratogenic/oncogenic exposure from imaging procedures affects the acceptability of diagnostic approaches used for VTE during pregnancy. DVT and PE treatment in pregnancy is also challenging due to this lack of validated diagnostic approaches, changes in maternal physiology, and the need for intact hemostasis at the time of delivery/epidural analgesia. Prevention requires an optimal balancing of absolute increased bleeding risk from pharmacologic thromboprophylaxis and the absolute benefit of reduced DVT and PE, which, while serious, are relatively uncommon. PMID- 21239790 TI - Preparing basic and translational grant proposals: thoughts from the trenches. AB - Written primarily for first-time applicants, this overview is a collection of tips intended to convey an approach to grant writing based on the experience of the author. Therefore, it is not a comprehensive review and it does not supplant the numerous treatises on grant writing, which cover everything from writing style and grammar to details regarding individual granting mechanisms and agencies. Rather, it is a brief overview of the grant writing process from conception to submission. PMID- 21239791 TI - Tips for writing successful patient-oriented research career development awards. AB - Preparing a career development award can be an immensely satisfying experience and a great boost to a research career if successful, or it can seem like a miserable waste of time if unsuccessful. This paper highlights tips for the preparation of patient-oriented career development awards and provides references for grant-writing guidance. Patient-oriented research is defined as "research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator directly interacts with human subjects. This area of research includes: 1) mechanisms of human disease; 2) therapeutic interventions; 3) clinical trials, and; 4) the development of new technologies." PMID- 21239792 TI - Hematology grants workshop. AB - In this yearly update on grant writing, we attempt to provide the attendee/reader with advice from "senior" investigators concerning the application process for external grant funds. While focused particularly on federal (National Institutes of Health, NIH) grants, the advice is generally applicable to any competitive grant-funding mechanism. Drs. Stephanie Lee and Jeffrey Molldrem have provided very thorough advice on clinical and basic grant applications and tips for those early in their careers. The session will include ample time for questions and answers, with key staffers from NIH in attendance. PMID- 21239793 TI - The aging patient with hemophilia: complications, comorbidities, and management issues. AB - Improvements in hemophilia care and antiviral treatments have resulted in increases in median life expectancy for persons with congenital hemophilia A and B. Currently, 2% of hemophilia A and B patients surveyed in US comprehensive hemophilia treatment centers are 65 years of age or older and 15% are 45 years or older. Many of the complications of hemophilia, including intracranial hemorrhage, joint disease, and inhibitor development, increase with increasing age. Hepatocellular carcinoma and end-stage liver disease are increasing in the older hemophilia population due to infection with hepatitis C (HCV) and HCV/HIV coinfection. Older hemophilia patients also now face the same medical conditions associated with aging in the general population, including cardiovascular disease and cancer. Complex hemostatic management, sometimes in conjunction with antithrombotic management, with extensive cross-specialty clinical and laboratory coordination may be required for the care of the older hemophilia patient. Because elderly hemophilia patients currently represent a small portion of the overall hemophilia population, there is little in the way of clinical data to guide recommendations. Registry databases and cooperative group studies are needed for the development of evidence-based guidelines for the older hemophilia population, which is anticipated to expand in the future. PMID- 21239795 TI - Hemophilia: new protein therapeutics. AB - Therapeutic advances for patients with hemophilia have resulted in reduced mortality, improved joint outcomes, safety from blood-transmitted pathogens, improved quality of life, and a normalized life span in the developed world. The production of recombinant coagulation factors has increased the worldwide capacity for replacement therapy and facilitated aggressive prophylactic therapy. However, this has come at significant cost, and barriers remain to broad application of prophylaxis. Recombinant DNA technology remains a promising platform to develop novel hemophilia therapeutics with improved functional properties to try to overcome some of these remaining barriers. Bioengineering strategies have produced novel therapeutics with increased production efficiency, increased potency and resistance to inactivation, prolonged plasma half-lives, and reduced immunogenicity. Alternative nonbiologic therapies may lead to new treatment paradigms. The current pipeline of new technologies and products is promising and growing with several agents already advancing from preclinical to clinical trials. PMID- 21239794 TI - Alternative strategies for gene therapy of hemophilia. AB - Hemophilia A and B are monogenic disorders that were felt to be ideal targets for initiation of gene therapy. Although the first hemophilia gene therapy trial has been over 10 years ago, few trials are currently actively recruiting. Although preclinical studies in animals were promising, levels achieved in humans did not achieve long-term expression at adequate levels to achieve cures. Transplantation as a source of cellular replacement therapy for both hemophilia A and B have been successful following liver transplantation in which the recipient produces normal levels of either factor VIII (FVIII) or factor IX (FIX). Most of these transplants have been conducted for the treatment of liver failure rather than for "curing" hemophilia. There are a variety of new strategies for delivering the missing clotting factor through ectopic expression of the deficient protein. One approach uses hematopoietic stem cells using either a nonspecific promoter or using a lineage-specific promoter. An alternative strategy includes enhanced expression in endothelial cells or blood-outgrowth endothelial cells. An additional approach includes the expression of FVIII or FIX intraarticularly to mitigate the intraarticular bleeding that causes much of the disability for hemophilia patients. Because activated factor VII (FVIIa) can be used to treat patients with inhibitory antibodies to replacement clotting factors, preclinical gene therapy has been performed using platelet- or liver-targeted FVIIa expression. All of these newer approaches are just beginning to be explored in large animal models. Whereas improved recombinant replacement products continue to be the hallmark of hemophilia therapy, the frequency of replacement therapy is beginning to be addressed through longer-acting replacement products. A safe cure of hemophilia is still the desired goal, but many barriers must still be overcome. PMID- 21239796 TI - Duration of anticoagulation: applying the guidelines and beyond. AB - Despite an improved understanding of the risk factors underlying venous thromboembolism (VTE), extensive clinical investigation, and detailed clinical guidelines, the decision to extend anticoagulation indefinitely for an individual patient with VTE is often problematic. Patients with VTE in association with major surgery, trauma, immobilization, or pregnancy are at relatively low risk of recurrence and generally do not require more than 3 to 6 months of anticoagulant therapy. For patients with a first unprovoked, or idiopathic, episode of VTE, an individualized approach should be taken in deciding on the duration of anticoagulation based on the patient's recurrence and bleeding risk, as well as their personal preference. Although the presence of genetic thrombophilic disorders (factor V Leiden and prothrombin G20210A gene mutations; deficiencies of antithrombin, protein C, and protein S) predispose patients to a first episode of VTE, there is inconsistent data on whether testing for these defects changes patient outcomes or should alter their management. In patients with a single unprovoked VTE, measurement of D-dimer several weeks following the completion of anticoagulant therapy appears useful in stratifying patients with a first unprovoked episode of VTE with regard to recurrence risk. Through a series of clinical vignettes, the utility of the laboratory in risk-stratifying patients with respect to recurrence risk will be discussed, along with decision making regarding the duration of anticoagulation. The potential impact of having a nonremovable inferior vena caval filter will also be addressed. PMID- 21239797 TI - The post-thrombotic syndrome. AB - The post-thrombotic syndrome (PTS) is an important chronic complication of deep vein thrombosis (DVT). The present review focuses on risk determinants of PTS after DVT and available means to prevent and treat PTS. More than one-third of patients with DVT will develop PTS, and 5% to 10% of patients develop severe PTS, which can manifest as venous ulcers. PTS has an adverse impact on quality of life as well as significant socioeconomic consequences. The main risk factors for PTS are persistent leg symptoms 1 month after acute DVT, anatomically extensive DVT, recurrent ipsilateral DVT, obesity, and older age. Subtherapeutic dosing of initial oral anticoagulation therapy for DVT treatment may also be linked to subsequent PTS. By preventing the initial DVT and DVT recurrence, primary and secondary prophylaxis of DVT will prevent cases of PTS. Daily use of elastic compression stockings for 2 years after proximal DVT appears to reduce the risk of PTS; however, uncertainty remains regarding optimal duration of use, optimal compression strength, and usefulness after distal DVT. The cornerstone of managing PTS is compression therapy, primarily using elastic compression stockings. Venoactive medications such as aescin and rutosides may provide short term relief of PTS symptoms. Further studies to elucidate the pathophysiology of PTS, to identify clinical and biological risk factors, and to test new preventive and therapeutic approaches to PTS are needed. PMID- 21239799 TI - Long-term physiological side effects after allogeneic bone marrow transplantation. AB - Allogeneic bone marrow transplantation (allo-BMT) or stem cell transplantation has the potential to cure a significant proportion of patients with otherwise fatal diseases. At present, immediate survival is no longer the sole concern after allo-BMT, because many patients can survive the acute complications of the procedure and remain free of their original disease for several years. Although long-term allo-BMT survivors generally enjoy good health, for many others cure or control of the underlying disease is not accompanied by full restoration of health. The long-term physiologic effects after allo-BMT include nonmalignant organ or tissue dysfunction; changes in quality of life; infections related to delayed, or abnormal, immune reconstitution; and secondary cancers. These long term complications and the features of chronic graft-versus-host disease (GVHD) symptoms are heterogeneous in nature, time of onset, duration, and severity. The underlying origin of these complications is often multifactorial, with chronic GVHD being the most challenging risk factor. The main aims of this review are to present transplant physicians and health care providers with an overview of these malignant and nonmalignant late complications, with a special focus on chronic GVHD. A close partnership between the transplant center, organ-specific specialties, and local primary care providers is a key component of preventive medicine. The patient can play a major role through engagement in health maintenance behaviors. PMID- 21239798 TI - Warfarin versus new agents: interpreting the data. AB - Stroke prevention in atrial fibrillation (AF) is a rapidly expanding indication for lifelong oral anticoagulation. The vitamin K antagonists (VKAs) effectively prevent stroke, but are notoriously difficult to manage and are associated with frequent adverse events. These factors account for the widespread underuse of warfarin for patients with AF who are qualified candidates for therapy. New oral anticoagulants with different mechanisms of action are beginning to exit phase III trials and may replace the VKAs for a number of indications, especially AF. The oral direct thrombin and Xa inhibitors are furthest along in development. Dabigatran etexilate, a thrombin inhibitor, has recently shown excellent outcomes in the prevention of stroke in patients with AF. The oral Xa inhibitors are still in phase III trials for stroke prevention in AF, but results from trials for other indications look promising. These short-acting, short-duration, unmonitored drugs are not without limitations and potential adverse effects. The perceived drawbacks of the VKAs may actually be assets in the management of patients with AF, and the pros and cons of each class of drug must be taken into account as physicians consider or patients request transition to a new class of oral anticoagulants. PMID- 21239800 TI - Comorbidities and hematopoietic cell transplantation outcomes. AB - Conventional allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment option for various hematological diseases due, in part to high-dose conditioning and, in part, to graft-versus-tumor effects. Reduced-intensity or non-myeloablative conditioning regimens have relied mostly on graft-versus-tumor effects for disease control, and their advent has allowed relatively older and medically infirm patients to be offered allo-HCT. However, both HCT modalities have been associated with organ toxicities and graft-versus host disease, resulting in substantial non-relapse mortality. It has become increasingly important to optimize pre-transplant risk assessment in order to improve HCT decision making and clinical trial assignments. Single-organ comorbidity involving liver, lung, heart, or kidney before HCT has been traditionally found to cause organ toxicity after HCT. Recent efforts have resulted in the advent of a weighted scoring system that could sensitively capture multiple-organ comorbidities prior to HCT. The HCT-comorbidity index (HCT CI) has provided better prediction of HCT-related morbidity and mortality than other non-HCT-specific indices. Subsequent studies, with the exception of a few studies with modest numbers of patients, have confirmed the prognostic importance of the HCT-CI. Further, the HCT-CI has been consolidated with various disease specific and patient-specific risk factors to refine assignments of patients to the appropriate HCT setting. Ongoing studies are addressing prospective validation of the HCT-CI, furthering our understanding of biological aging, and enhancing the applicability of the HCT-CI comorbidity coding. Future knowledge of the impacts of multiple comorbidities on post-HCT toxicities might guide new prophylactic and therapeutic interventions to lessen the procedure's mortality. PMID- 21239802 TI - Host factors for risk and survival in lymphoma. AB - All cancers arise from complex interactions between aspects of the patient (host) biology and the environment. Once tumors arise, they frequently remain dependent on interactions with their microenvironment for their growth and proliferation. In this review, we examine the contributions of the host genetics and environmental exposures to the development of lymphoma. We will further examine the interactions of the tumor and the microenvironment that influence tumor growth and proliferation. PMID- 21239801 TI - Health-related quality of life following allogeneic hematopoietic stem cell transplantation. AB - It is common knowledge that an allogeneic hematopoietic stem cell transplantation (HSCT) will have an enormous impact on the lives of transplant recipients and their families. Once an appropriate donor is identified, the curative potential of this treatment often drives the decision to proceed knowing that there will be intense physiologic toxicities and adverse effects on health-related quality of life (HRQL). Twenty-five years ago, HRQL was identified as an efficacy parameter in the evaluation of new anticancer drug therapy. Overall, the evidence suggests that an allogeneic HSCT has a significant impact on the overall HRQL of recipients, which is a result of decrements across all dimensions, including a significant symptom profile. The degree of impact on overall HRQL and the multiple dimensions varies across the transplant trajectory. Specific HRQL dimensions, such as physical function and symptoms, are easily incorporated into a clinician's assessment whereas other dimensions (eg, psychosocial) are less commonly integrated. The translation of HRQL results to improve clinical practice is not well established. Clinicians are often uncertain when to assess the scope of HRQL and how to interpret the information in a clinically meaningful way. The purpose of this review is to highlight the quality-of-life effects of allogeneic HSCT and discuss application into clinical practice. PMID- 21239803 TI - Novel agents for follicular lymphoma. AB - Unlabeled and radiolabeled anti-CD20 monoclonal antibodies have had a significant impact in the care of patients with follicular lymphoma (FL) over the past decade. More recently, bendamustine has demonstrated activity in refractory FL, and has been explored as initial therapy and in novel combinations. Whereas outcomes for this patient population have significantly improved, there remains substantial unmet need for patients who require more effective and better tolerated therapies. Novel anti-CD20 antibodies and other immunotherapies against different B-cell antigens are under active investigation. The proteosome inhibitor bortezomib and the immunomodulatory agent lenalidomide have demonstrated single-agent activity and are currently in randomized trials. Other novel compounds have demonstrated activity in broad-based clinical studies in B cell malignancies. However, considerable challenges remain in efficiently demonstrating which patient subsets can benefit from these novel compounds and which combinations may have the greatest clinical benefit in further improving outcomes for patients with FL. PMID- 21239806 TI - Anemia of inflammation. AB - Inflammation arising from various etiologies, including infection, autoimmune disorders, chronic diseases, and aging, can promote anemia. The anemia of inflammation (AI) is most often normocytic and normochromic and is usually mild. Characteristic changes in systemic iron handling, erythrocyte production, and erythrocyte life span all contribute to AI. The preferred treatment is directed at the underlying disease. However, when the inflammatory insult is intractable, or the cause has not been diagnosed, there are limited options for treatment of AI. Because anemia is a comorbid condition that is associated with poor outcomes in various chronic disease states, understanding its pathogenesis and developing new tools for its treatment should remain a priority. Hepcidin antimicrobial peptide has taken center stage in recent years as a potent modulator of iron availability. As the technology for quantitative hepcidin analysis improves, hepcidin's role in various disease states is also being revealed. Recent insights concerning the regulatory pathways that modify hepcidin expression have identified novel targets for drug development. As the field advances with such therapeutics, the analysis of the impact of normalized hemoglobin on disease outcomes will confirm whether anemia is a reversible independent contributor to the morbidity and mortality associated with inflammatory diseases. PMID- 21239805 TI - Anemia in elderly patients: an emerging problem for the 21st century. AB - Anemia is a significant problem in elderly patients. Although many anemic elderly patients can be diagnosed with nutritional deficiency, anemia of chronic inflammation or comorbid diseases that explain their decreased hematocrit, the etiology of anemia in a significant fraction remains obscure. There is evidence to suggest that the hematopoietic stem cell displays increasing erythropoietin (EPO) resistance with age. EPO levels rise in elderly, nonanemic patients, and it is hypothesized that there is an interplay between this rising demand for EPO and the decreasing ability of the aging kidney to produce adequate hormone to meet that need. There is further considerable evidence that aging is associated with increased proinflammatory cytokine expression and that many of these cytokines can contribute to EPO insensitivity. Consequently, genetic variation in the expression of these proinflammatory cytokines may influence the development of anemia in elderly patients, both through induction of hepcidin expression (anemia of inflammation) and through cytokine suppression of erythroid colony formation. The impact of inflammatory mediators, EPO insensitivity, and other factors that may act on the hematopoietic stem cell to decrease erythropoiesis are under active study and should serve to elucidate the pathophysiology of this important cause of morbidity and mortality in elderly individuals. A better understanding of the pathophysiology of anemia in elderly patients should provide critical entry points for interventions that will improve survival and quality of life in the aging population. PMID- 21239804 TI - Signal transduction inhibitor therapy for lymphoma. AB - Current research in lymphoma is focused on two areas of lymphoma biology-the signal transduction pathways used to maintain the growth of malignant lymphocytes and the role of the tumor microenvironment in lymphoma growth and survival. This review focuses on three signaling pathways: the phosphatidylinositol 3 kinase/mammalian target of rapamycin (PI3K/mTOR) pathway, the B-cell receptor/spleen tyrosine kinase (BCR/Syk) pathway, and the protein kinase C-beta (PKC-beta) pathway, known to be important to lymphoma cells. The mTOR inhibitors temsirolimus and everolimus have demonstrated antitumor activity in all types of lymphoma, the Syk inhibitor fostamatinib has activity in diffuse large B-cell lymphoma and chronic lymphocytic leukemia, and the PKC-beta inhibitor enzastaurin is being used as consolidation therapy after remission in diffuse large B-cell lymphoma. This review discusses the biology behind the development of each new agent and the results of initial clinical trials. The goal is to provide the hematologist/oncologist background information on these new agents and understand their current and potential role in the management of patients. PMID- 21239807 TI - Hematologic disorders after solid organ transplantation. AB - The evaluation of hematologic disorders after solid organ transplantation (SOT) must take into account issues unique to the post-transplant setting that influence the development of anemia and single or multi-lineage cytopenias. Attention to the time of onset of cytopenia(s) is important, because the disorders of passenger lymphocyte syndrome, transplant-related thrombotic microangiopathy, hemophagocytic syndrome, and graft-versus-host disease typically occur during the first few months after SOT, and post-transplant lymphoproliferative disorder usually occurs within the first year. Drug-related anemia and cytopenia(s) occur due to a variety of mechanisms, including drug induced hemolysis and marrow suppression and perturbation of T-cell subsets by the immunosuppressive agents, leading to immune dysregulation and autoimmunity. Viral infections can cause direct suppression of hematopoiesis, and a variety of opportunistic infections can precipitate acquired hemophagocytic syndrome, a frequently lethal systemic inflammatory disorder. Early investigation of pancytopenia by bone marrow biopsy is warranted, because it is often the presenting symptom of one or multiple life-threatening pathologies after SOT, such as graft-versus host disease, post-transplant lymphoproliferative disorder, hemophagocytic syndrome, or severe opportunistic infections, and these entities may have a better prognosis if early interventions are undertaken. PMID- 21239808 TI - Systemic light-chain amyloidosis: advances in diagnosis, prognosis, and therapy. AB - Systemic light-chain amyloidosis (AL) is caused by misfolded immunoglobulin light chain proteins that aggregate and deposit as unique fibrils, ultimately leading to organ failure and death. Recent developments that have significantly aided the management of patients with AL include diagnostic techniques for definitive typing of amyloid deposits by use of laser microdissection with mass spectrometry and customized protein bioinformatics, and validated staging and response-scoring systems that improve clinical trial design. The widespread use of cardiac biomarker staging and serum-free light-chain levels to evaluate response to therapy has also improved care. Standard therapies such as oral melphalan and dexamethasone or autologous stem cell transplant continue to be important options, while thalidomide and its analogs, lenalidomide and pomalidomide, and the proteasome-inhibitor bortezomib have activity in AL and have expanded our armamentarium. Continued improvement in outcomes, however, will require the commitment and cooperation of pharmaceutical companies, regulatory agencies, academic investigators, and cooperative groups/consortia. This effort will involve the conduct of well-designed clinical trials of new agents and combinations within a modern framework that categorizes the study populations of patients with AL, defines the end points appropriate to those populations and to the different phases of clinical trials, employs the newly available staging and response criteria, and standardizes adverse event reporting. PMID- 21239809 TI - Monoclonal gammopathy of undetermined significance and smoldering myeloma: new insights into pathophysiology and epidemiology. AB - Routine screening for monoclonal gammopathy of undetermined significance (MGUS) is not indicated. Despite this fact, MGUS is a common finding in medical practice. Almost all individuals diagnosed with MGUS represent incidental cases diagnosed when physicians order serum protein electrophoresis, immunofixation, or both, as part of the work-up of a number of common symptoms and laboratory abnormalities. In the absence of reliable molecular predictors of outcome, the detection of an early precursor state typically imposes a complex situation for the patient and the responsible physician-usually, it leads to a lot of questions that lack clear answers. In the past years, several novel insights have been gained in the area of multiple myeloma (MM) precursor disease. This review focuses on results from recent investigations and discusses implications for diagnostic work-up, clinical management, and patient counseling. More specifically, it sheds light on the following commonly asked questions by patients and physicians: i) what is the risk of progression from precursor to full-blown MM, and are there ways to risk-stratify patients?; ii) is MM always preceded by a precursor state, and is there anything that could or should be done to delay or prevent progression?; and iii) why do some individuals develop MM precursor diseases, and is there a reason to screen the family? PMID- 21239810 TI - Relapsed multiple myeloma. AB - Advances in treatment options for patients with multiple myeloma have made a significant impact on the overall survival of patients and have helped achieve levels of response and duration of remission previously not achievable with standard chemotherapy-based approaches. These improvements are due, in large part, to the development of the novel agents thalidomide, bortezomib, and lenalidomide, each of which has substantial single-agent activity. In addition, a large number of second-generation agents are also in clinical development, such that the repertoire of available treatment options continues to expand. To better interpret clinical trials performed in the relapsed setting, it is important that definitions of relapse categories are used to help better pinpoint the specific benefit for a given therapy, especially in the combination therapy setting as it aids in determining if ongoing work should be continued or abandoned for a given new agent. Insights from preclinical modeling and in vitro work have identified several new combinations, new targets and second- or third-generation versions of existing targets that hold great promise in the setting of relapsed myeloma. Combinations of thalidomide, bortezomib, and lenalidomide with conventional agents or among each other have resulted in enhanced response rates and efficacy. Clinical trials of agents such as carfilzomib, pomalidomide, vorinostat, panobinostat, and elotuzomab are just a few of the many exciting new compounds that are being tested in phase 1 and phase 2 clinical trials for relapsed patients. Further clinical and translational testing are critical to better understanding how best to combine these new agents, as well as identifying patient populations that may best benefit from treatment with these developing new agents. PMID- 21239811 TI - Evidence-based mini-review: treatment options for patients with relapsed/refractory myeloma previously treated with novel agents and high-dose chemotherapy and autologous stem-cell transplantation. PMID- 21239814 TI - Allogeneic hematopoietic stem-cell transplantation for myelodysplastic syndrome. AB - Transplantation is the only known cure for myelodysplastic syndrome (MDS). While some comparative analyses have demonstrated early transplantation to be the preferred strategy for all MDS patients, many of these analyses are biased. Using newly identified prognostic factors and models, a rational approach to transplantation can be undertaken. Factors such as transfusion dependency, cytogenetics, medical comorbidity, and World Health Organization (WHO) histologic subtype should all be considered when deciding on the role of transplantation for the MDS patient. Unresolved issues in transplantation include the impact of pre transplant tumor debulking with traditional chemotherapeutic agents or the new DNA hypomethylating agents, and the optimal timing of reduced-intensity conditioning transplantation for older patients or for those with medical comorbidities. PMID- 21239812 TI - How much? How frequent? How long? A clinical guide to new therapies in myelodysplastic syndromes. AB - Advances in the treatment of myelodysplastic syndromes (MDSs) over the last decade have given patients and their hematologists a multitude of treatment options. Therapeutic options now exist that reduce disease-related symptoms, improve quality of life, and alter the natural history of the disease. Three drugs are now specifically Food and Drug Administration-approved for treatment of MDS: (1) azacitidine, (2) decitabine, and (3) lenalidomide. Clinical results with each of these agents, plus results with immunosuppressive therapy, are reviewed to guide clinical decision making. Although each therapy has made a substantial impact in improving the care of patients with MDS, unfortunately MDS treatment in 2010 ultimately fails in most patients, but these therapies provide a foundation on which we can build to further improve outcomes. PMID- 21239813 TI - Evidence-based mini-review: Should patients over the age of 60 with INT-2 or high risk myelodysplastic syndrome undergo allogeneic stem cell transplantation prior to progression to acute myelogenous leukemia? AB - CASE: A 65-year-old male who was previously in good health presented to his primary care physician with increasing fatigue over several months. He was found to be anemic (hemoglobin 7.5 mg/dL) and neutropenic (absolute neutrophil count 1000/MUL). Further laboratory investigation showed an elevated erythropoietin level and normal iron stores. Bone marrow biopsy revealed dysplasia in two lineages and 8% blasts. Cytogenetic studies showed a clone with loss of 7q. He required red blood cell transfusions approximately every 2 weeks. He was started on hypomethylating agent treatment and referred for consultation regarding the role of hematopoietic stem cell transplantation. HLA typing results demonstrated that he had an HLA-identical sibling. PMID- 21239815 TI - Prognosis of myelodysplastic syndromes. AB - The myelodysplastic syndromes (MDS) are a very complex group of hematopoietic disorders. The degree of complexity relates not only to the intrinsic pathobiological characteristics of the disease, but also to the group of patients whom it affects most frequently: older individuals or those who have been exposed to prior forms of chemotherapy. It is therefore crucial to develop clinical tools to predict with a certain degree of precision the prognosis and outcome for patients with specific subtypes of MDS in specific clinical situations. At the present time, patients with MDS are diagnosed using a set of well-established histopathological criteria. Prognosis is established using classifications that include morphological features, percentage of blasts, and clinical and molecular characteristics such as peripheral cytopenias and cytogenetics. The International Prognostic Scoring System (IPSS) is a classic example of this type of classification. Over the last 5 years, there has been an intense effort to develop new prognostic systems for MDS, and new molecular alterations with potential prognostic value have been discovered. Over the same period of time, several new therapeutic interventions have been developed for patients with MDS. Biomarkers of response to these agents, in particular for the hypomethylating agents, are needed to predict clinical benefit. This review summarizes current prognostic models of MDS and new molecular alterations with potential prognostic potential. PMID- 21239816 TI - Clinical use of intravenous iron: administration, efficacy, and safety. AB - This section reviews the history, pharmacology, administration, efficacy, and toxicity of intravenous iron. Intravenous iron offers advantages over oral iron for the treatment of iron deficiency anemia across a wide range of disease states associated with absolute and functional iron deficiency. However, there remain concerns about the acute safety profiles of the available preparations and the potential for long-term toxicity with their repeated administration. Seven intravenous iron formulations are available. Confusion concerning the relative toxicities of the different formulations abounds. The similarities and differences are discussed. Iron repletion has been associated with adverse outcomes in infections. The relationship, if any, between intravenous iron administration and infections is reviewed. The potential advantages of total dose infusion (TDI), complete repletion in a single setting, are highlighted. A new paradigm for iron replacement therapy in iron deficiency anemia is presented. PMID- 21239817 TI - Iron deficiency and heart disease: ironclad evidence? AB - Patients with heart failure have elevated levels of circulating inflammatory cytokines and commonly have iron deficiency anemia or anemia of chronic inflammation. Clinical trials in patients with congestive heart failure and iron deficiency have demonstrated that intravenous iron treatment appears to improve subjective and objective outcomes. Most patients in these trials were not anemic or only had mild anemia, and hemoglobin concentration rose only slightly after treatment with iron. Experimental evidence demonstrates that iron is a cofactor for muscle function, which could explain the improvement in clinical outcomes. Many questions remain to be answered to understand the role of iron therapy in patients with congestive heart failure. PMID- 21239818 TI - Parenteral iron therapy in cancer-associated anemia. AB - Anemia is common in cancer patients. Its cause is multifactorial, so a brief workup is always necessary to rule out simple, reversible causes. Anemia of chronic disease/inflammation and chemotherapy-induced anemia are the most common causes. Symptomatic or clinically severe anemia may require treatment with blood transfusion or an erythropoiesis-stimulating agent (ESA). If ESA therapy is chosen, developing evidence now suggests that, similar to chronic renal failure patients on hemodialysis, the addition of intravenous iron can improve the response to ESA because of iron-restricted erythropoiesis, even in the iron replete patient. PMID- 21239819 TI - Childhood myelodysplastic syndrome: focus on the approach to diagnosis and treatment of juvenile myelomonocytic leukemia. AB - Expansion of myeloid blasts with suppression of normal hematopoiesis is a hallmark of acute myeloid leukemia (AML). In contrast, myeloproliferative neoplasms (MPNs) are clonal disorders characterized by overproliferation of one or more lineages that retain the ability to differentiate. Juvenile myelomonocytic leukemia (JMML) is an aggressive MPN of childhood that is clinically characterized by the overproduction of monocytic cells that can infiltrate organs, including the spleen, liver, gastrointestinal tract, and lung. Major progress in understanding the pathogenesis of JMML has been achieved by mapping out the genetic lesions that occur in patients. The spectrum of mutations described thus far in JMML occur in genes that encode proteins that signal through the Ras/mitogen-activated protein kinase (MAPK) pathways, thus providing potential new opportunities for both diagnosis and therapy. These genes include NF1, NRAS, KRAS, PTPN11, and, most recently, CBL. While the current standard of care for patients with JMML relies on allogeneic hematopoietic stem-cell transplant, relapse is the most frequent cause of treatment failure. Rarely, spontaneous resolution of this disorder can occur but is unpredictable. This review is focused on the genetic abnormalities that occur in JMML, with particular attention to germ-line predisposition syndromes associated with the disorder. Current approaches to therapy are also discussed. PMID- 21239820 TI - Pediatric acute lymphoblastic leukemia: is there still a role for transplant? AB - Constant questioning of the applicability of transplant for any diagnosis is appropriate. This is particularly necessary in fields such as pediatric leukemia, in which significant progress in therapy and risk classification is being made. Outcomes with chemotherapy are constantly improving, and donor availability and transplant outcomes are also better. It is important to be aware of likely outcomes when counseling families and recommending therapy, and to consider issues of likely late side effects. Biological studies that predict prognosis, for example, array-based studies, hold hope of identifying the children destined to relapse at the outset of disease. However, a rigorous approach must be taken in determining whether transplant does improve outcome whenever this strategy is applied. PMID- 21239821 TI - Treatment of pediatric chronic myeloid leukemia in the year 2010: use of tyrosine kinase inhibitors and stem-cell transplantation. AB - Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the only proven cure for chronic myeloid leukemia (CML), a rare malignancy in childhood. With the excellent results induced by the tyrosine kinase inhibitor (TKI) imatinib in adults in the last decade, the appropriate management of children with CML has also changed radically, and only a minority are now transplanted as a front-line treatment. Data on pediatric experiences with imatinib in CML from controlled trials remain very limited, but this review of available data describes the role of imatinib in children with CML, addressing: 1) the starting dose; 2) pharmacokinetics in childhood; 3) possible adverse effects, with a focus on the still-growing skeleton; 4) early monitoring of treatment efficacy in an attempt to avoid failure; 5) the timing of allo-SCT in children; and 6) treatment of CML relapse after allo-SCT. Because the characteristics of CML in children seem to overlap extensively with what is described in adult internal medicine, most answers and pediatric algorithms are adapted from the treatment of CML in adults. Today in 2010, allo-SCT in children should be postponed until CML becomes refractory to imatinib. The approach for young patients with suboptimal responses is unclear because data on the efficacy and safety of second-generation TKIs in childhood are almost entirely missing. Other than being included in a formal trial on second-generation TKIs, allo-SCT for patients failing imatinib remains the first choice. PMID- 21239822 TI - Immune thrombocytopenia. AB - Immune thrombocytopenia (ITP) comprises a heterogeneous group of disorders characterized by autoimmune-mediated platelet destruction and impairment of thrombopoiesis. ITP may occur in the absence of an evident predisposing etiology (primary ITP) or secondary to a growing list of associated conditions (secondary ITP), and must be differentiated from other causes of thrombocytopenia. This review focuses on primary ITP in adults. The traditional goal of therapy in this population is to achieve a hemostatic platelet count of 30*10(9)/L or above for most patients while minimizing treatment-related morbidity. This approach has been called into question by the recent advent of well-tolerated and effective agents for the management of ITP, including pulse-dose dexamethasone, rituximab, and the thrombopoietin receptor agonists. Recent studies suggest the potential for aggressive therapy at the time of diagnosis to alter the natural history of ITP and point to the importance of quality-of-life considerations in therapeutic decision making. PMID- 21239823 TI - Evidence-based mini-review: Is indium-labeled autologous platelet scanning predictive of response to splenectomy in patients with chronic immune thrombocytopenia? AB - Clinical scenario: An otherwise healthy 25-year-old woman returns to your office for management of chronic primary immune thrombocytopenia. She was diagnosed 6 months earlier and continues to require prednisone 15 mg daily and periodic infusions of intravenous immunoglobulin to maintain a hemostatic platelet count. You discuss second-line treatment options, including splenectomy. The patient asks if there are any means by which to predict likelihood of response to splenectomy. You have heard about the use of indium-labeled autologous platelet scanning for this purpose and wonder what the evidence shows. PMID- 21239824 TI - Understanding and evaluating platelet function. AB - The contribution of platelets to normal hemostasis and vascular disease is well described. However, recent studies make it clear that much remains to be learned about platelet activation at the single cell and the molecular level, and about the contribution of platelets to inflammation, tumor angiogenesis, and embryonic development. This article is divided into two themes. The first is an overview of current knowledge of the mechanisms that drive platelet function in vivo and a brief summary of some of the emerging ideas that are modifying older views. The second theme is a consideration of the strengths and weaknesses of the tools we have as hematologists to assess platelet function in the clinical setting, identify mechanisms, and evaluate the impact of antiplatelet agents. PMID- 21239825 TI - Thrombocytopenia in pregnancy. AB - Thrombocytopenia occurs commonly during pregnancy, and may result from diverse etiologies. Awareness of these many causes facilitates proper diagnosis and management of thrombocytopenia in the pregnant setting. Some causes of thrombocytopenia are unique to pregnancy and may not be familiar to hematologists. In the review, we will discuss the differential diagnosis of thrombocytopenia in pregnancy, and the pathogenesis of selected thrombocytopenic disorders. Considerations for optimal management of the pregnant patient with thrombocytopenia will also be described. PMID- 21239827 TI - Sickle-cell pain: advances in epidemiology and etiology. AB - New epidemiological findings recast pain in sickle-cell disease (SCD) as being more often a chronic manifestation than was previously thought, although acute pain is still the hallmark of the disease. SCD pain intensity, the number of painful locations, and the frequency of hospitalizations due to SCD pain may worsen with age. In adults and even in children, the quantity and severity of SCD pain may be vastly underestimated, because most of the "iceberg" of SCD pain is "submerged" at home, and only the tip of the iceberg is seen by health care providers when acute SCD care is rendered in emergency rooms and hospitals. Implications of this "iceberg phenomenon" are significant for clinicians, researchers, employers, policy makers, and the public. Nevertheless, both emergency room and hospital utilization for SCD pain remain prevalent. Often, utilization recurs early, perhaps emblematic of poor acute pain management. New data show the protean impacts of SCD pain on health-related quality of life, sleep, and psychological and social health. The relationship of the severity of SCD pain to the severity of underlying sickle vasculopathy is unclear, but epidemiologic evidence and patient descriptors suggest a temporal evolution of pain mechanisms. At first, increasingly worse nociceptive pain from vaso occlusion and local lesions may evolve over the first two decades of life. Then, in the third and following decades, central neuropathic pain may also evolve due to past and continuing nociceptive stimuli. New findings confirm environmental contributors to SCD pain, including seasonal (colder) temperatures, barometric pressure, and wind speed. PMID- 21239826 TI - Neurobiological mechanisms of pain in sickle cell disease. AB - Pain is a frequent complaint of people living with sickle cell disease (SCD); however, the neurobiology of pain in SCD remains poorly understood. Whereas this pain has been thought to be primarily related to visceral and somatic tissue injury subsequent to vaso-occlusion events, emerging evidence from human and animal studies has suggested that a component of SCD pain may be related to neuropathic processes. Significant knowledge has been obtained from studies of molecular and neurobiological mechanisms leading to and maintaining neuropathic pain. Some of the most promising evidence has implicated major roles of protein kinase C and Ca2+/calmodulin-dependent protein kinase II, and their interaction with the N-methyl-D-aspartate receptors and the transient receptor potential vanilloid 1 receptor in the development of neuropathic pain. The latest evidence from our studies suggests that these pathways are important for SCD pain as well. Coupled with emerging animal models of SCD pain, we can now start to elucidate neurobiological mechanisms underlying pain in SCD, which may lead to better understanding and effective therapies. PMID- 21239828 TI - Evidence-based mini-review: Are systemic corticosteroids an effective treatment for acute pain in sickle cell disease? AB - An 18-year-old African-American male with sickle cell disease (SCD) is admitted to the hospital with a vaso-occlusive pain crisis affecting his chest and right upper extremity. He has a history of asthma but does not have a fever or respiratory symptoms, and a chest X-ray is negative for an infiltrate. He is treated with intravenous fluids and morphine. You are asked about the potential efficacy of systemic corticosteroids as an adjunctive treatment for pain control. PMID- 21239830 TI - Dealing with neuropathy in plasma-cell dyscrasias. AB - Peripheral neuropathy (PN) is a frequent complication of plasma-cell dyscrasias such as monoclonal gammopathy of undetermined significance, multiple myeloma, Waldenstrom's disease, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, Castleman's disease, and light chain amyloidosis. PN can be associated with the underlying disease or it can related to the treatment. The novel immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib have changed the standard treatment of multiple myeloma. Treatment-related PN induced by thalidomide (TiPN) or bortezomib (BiPN) has become the most frequent cause of symptomatic polyneuropathy in multiple myeloma and related diseases. Dealing with PN has become a major challenge in current clinical practice for multiple myeloma patients. This review deals with practical issues such as etiology, incidence, symptoms, and clinical management of treatment-emergent PN. The major focus of the hematologist should be on the prevention of PN, primarily by frequent monitoring of the patient and by timely and adequate dose reduction of thalidomide and bortezomib. Thalidomide should not be given for periods longer than 18 months, and if it is, then patients should be carefully monitored with a low threshold for discontinuation in the face of any emergent neuropathy. In the case of BiPN, the dose of bortezomib should be reduced and/or the administration interval should be prolonged from biweekly to weekly. Adequate pain management and supportive care require a multidisciplinary approach involving the treating physician, expert nursing staff, and a neurologist as clinically indicated. PMID- 21239829 TI - Sickle-cell trait: novel clinical significance. AB - There is a long-standing controversy in the literature as to whether sickle-cell trait (SCT) should be viewed as a benign carrier state or as an intermediate disease phenotype. Because SCT is routinely detected by neonatal screening for sickle-cell disease, it becomes imperative that consensus on this issue be achieved in order to provide the best medical advice to affected individuals. The issue of selective screening in the post-neonatal period was thrust into the limelight recently by the National Collegiate Athletic Association's recommendation that its member colleges and universities test student-athletes to confirm their carrier status if not already known. The stated goal of this recommendation was to prevent exercise-related sudden death in athletes with SCT. We review some of the reported complications of SCT for which new information has emerged, focusing particularly on venous thromboembolism and renal manifestations. PMID- 21239831 TI - Renal insufficiency and failure. AB - Renal impairment is a common complication of multiple myeloma. Chronic renal failure is classified according to glomerular filtration rate as estimated by the MDRD (modification of diet in renal disease) formula, while RIFLE (risk, injury, failure, loss and end-stage renal disease) and AKIN (acute renal injury network) criteria may be used for the definition of the severity of acute renal injury. Novel criteria based on estimated glomerular filtration rate measurements are proposed for the definition of the reversibility of renal impairment. Renal complete response (CRrenal) is defined as sustained (i.e., lasting at least 2 months) improvement of creatinine clearance (CRCL) from under 50 mL/min at baseline to 60 mL/min or above. Renal partial response (PRrenal) is defined as sustained improvement of CRCL from under 15 mL/min at baseline to 30 to 59 mL/min. Renal minor response (MRrenal) is defined as sustained improvement of the baseline CRCL of under 15 mL/min to 15 to 29 mL/min or, if baseline CRCL was 15 to 29 mL/min, improvement to 30 to 59 mL/min. Bortezomib with high-dose dexamethasone is considered the treatment of choice for myeloma patients with renal impairment and improves renal function in most patients. Although there is limited experience with thalidomide, this agent can be administered at the standard dosage to patients with renal failure. Lenalidomide, when administered at reduced doses according to renal function, is effective and can reverse renal impairment in a subset of myeloma patients. PMID- 21239832 TI - Thrombosis in multiple myeloma. AB - Patients with multiple myeloma (MM) are at an increased risk of venous and arterial thrombosis. The pathogenesis remains unclear, but probably involves several factors such as activation of procoagulant factors, acquired activated protein C resistance, and inflammation. In addition to general risk factors for venous thromboembolism, such as older age, immobility, surgery, and inherited thrombophilia, there are some MM-specific and treatment-related factors that contribute to the increased risk. The risk for venous thromboembolism is high when patients are treated with thalidomide or lenalidomide in combination with dexamethasone or multi-agent chemotherapy. Thromboprophylaxis should be given in these settings. Which agent is the most appropriate is a matter of debate, but aspirin, low-molecular-weight heparin, and warfarin all seem to be effective. This review discusses risk factors for thromboembolism in MM and general, disease specific and treatment-related mechanisms for thrombosis. Recommendations for thromboprophylaxis are described and treatment choices for venous thrombosis in MM patients are reviewed. PMID- 21239833 TI - Genetic therapy for beta-thalassemia: from the bench to the bedside. AB - Beta-thalassemia is a genetic disorder with mutations in the beta-globin gene that reduce or abolish beta-globin protein production. Patients with beta thalassemia major (Cooley's anemia) become severely anemic by 6 to 18 months of age, and are transfusion dependent for life, while those with thalassemia intermedia, a less-severe form of thalassemia, are intermittently or rarely transfused. An allogeneically matched bone marrow transplant is curative, although it is restricted to those with matched donors. Gene therapy holds the promise of "fixing" one's own bone marrow cells by transferring the normal beta globin or gamma-globin gene into hematopoietic stem cells (HSCs) to permanently produce normal red blood cells. Requirements for effective gene transfer for the treatment of beta-thalassemia are regulated, erythroid-specific, consistent, and high-level beta-globin or gamma-globin expression. Gamma retroviral vectors have had great success with immune-deficiency disorders, but due to vector-associated limitations, they have limited utility in hemoglobinopathies. Lentivirus vectors, on the other hand, have now been shown in several studies to correct mouse and animal models of thalassemia. The immediate challenges of the field as it moves toward clinical trials are to optimize gene transfer and engraftment of a high proportion of genetically modified HSCs and to minimize the adverse consequences that can result from random integration of vectors into the genome by improving current vector design or developing novel vectors. This article discusses the current state of the art in gene therapy for beta-thalassemia and some of the challenges it faces in human trials. PMID- 21239834 TI - Update on iron chelators in thalassemia. AB - Over the past four decades, there have been dramatic improvements in survival for patients with thalassemia major due in large measure to improved iron chelators. Two chelators are approved for use in the United States and Canada, parenteral deferoxamine and oral deferasirox. Three are available in much of the rest of the world, where oral deferiprone is also approved (in the United States, deferiprone is only available in studies, for emergency use, or on a "compassionate-use" basis). Many trials and worldwide clinical experience demonstrate that each of the three drugs can chelate and remove iron, and thereby prevent or improve transfusional hemosiderosis in thalassemia patients. However, the chelators differ strikingly in side-effect profile, cost, tolerability and ease of adherence, and (to some degree) efficacy for any specific patient. The entire field of chelator clinical trials suffers from the fact that each drug (as monotherapy or in combination) has not been tested directly against all of the other possibilities. Acknowledging the challenges of assessing chelators with diverse properties and imperfect comparative data, the purpose of this review is to summarize the last 4 years of studies that have improved our understanding of the applications and limitations of iron chelators in various settings for thalassemia patients, and to point out areas for much-needed future research. PMID- 21239835 TI - Hematopoietic stem cell transplantation in thalassemia. AB - Almost 30 years have passed since the first successful hematopoietic stem cell transplantation in thalassemia and that first patient is now a healthy young adult with a completely normal life. Since that time, more than 3000 such transplants have been performed worldwide. This review provides a brief history of hematopoietic stem cell transplantation in thalassemia and reassesses current clinical results with the objective to provide outcome predictions based on modern transplant technologies. The role of hematopoietic stem cell transplantation in the oral chelation era and implications for possible closure in the approach to future gene therapy will also be discussed. PMID- 21239836 TI - Trauma blood management: avoiding the collateral damage of trauma resuscitation protocols. AB - The use of high ratios of red blood cells to platelets and plasma in trauma resuscitation protocols is quickly gaining favor in civilian trauma centers. The use of higher ratios of coagulation factors to red blood cells has been shown to improve outcomes in both military and civilian centers, but does the evidence support the use of a 1:1:1 ratio, as has been suggested? There is growing evidence that the use of such high ratios may be excessive and potentially harmful, and there has not been enough emphasis on the other components of evidence-based "damage control" resuscitation. PMID- 21239838 TI - Logistics of massive transfusions. AB - Care of the patient with massive bleeding involves more than aggressive surgery and infusion of large amounts of blood products. The proper management of massive transfusions-whether they are in trauma patients or other bleeding patients requires coordination of the personnel in the surgical suite or the emergency department, the blood bank, and laboratory. PMID- 21239837 TI - Optimal use of blood products in severely injured trauma patients. AB - Injury is the leading cause of life years lost in the United States, and uncontrolled hemorrhage is the leading cause of potentially preventable death. Traditionally, these patients have been serially resuscitated with large volumes of crystalloid and/or colloids and red blood cells, followed by smaller amounts of plasma and platelets. Transfusion data coming first from the ongoing war in Iraq and Afghanistan and followed by multiple civilian studies have brought into question this tradition-based practice. Numerous recent retrospective single and multicenter studies have associated improved outcomes with earlier and increased use of plasma and platelets. These data have stimulated significant interest in studying massively transfused trauma patients. Most clinicians have concluded that the optimal timing and quantity of blood products in the treatment of hypothermic, coagulopathic, and acidotic trauma patients are unclear. Although there are strongly held opinions and long-standing traditions in their use, there are little quality data within which to logically guide resuscitation therapy. A multicenter prospective observational study is ongoing, and randomized trials are planned. This review will address the issues raised previously and describe recent trauma patient outcome data utilizing predetermined plasma:platelet:red blood cell transfusion ratios, and possibilities for future transfusion products and research. PMID- 21239839 TI - High cytogenetic or molecular genetic risk acute myeloid leukemia. AB - Resistance, manifested as failure to enter remission despite living long enough to do so or as relapse from remission, is the principal cause of therapeutic failure in acute myeloid leukemia, even in patients age >= 75. Recently, a "monosomal karyotype" in acute myeloid leukemia blasts has been found to be a principal predictor of resistance. It is also clear that patients with a normal karyotype, and other intermediate prognosis karyotypes, can be placed into a high risk group based on the absence of a mutation in the NPM1 gene or the presence of an internal tandem duplication (ITD) of the Fms-like tyrosine kinase 3 gene (FLT3) gene, particularly if there is loss of the wild-type FLT3 allele. The effects of other genetic abnormalities have been inconsistent, perhaps reflecting differences in expression of the abnormality and its translation into protein. Several reports have shown the prognostic potential of profiling global gene expression, micro-RNA expression, DNA methylation, and proteomics. Although routine application of these approaches is still premature, pretreatment assessment of the nucleophosmin 1 (NPM1) mutation and FLT3 ITD status, as well as cytogenetics, should be routine. These results can be used to guide the choice of remission induction therapy, for example, by placing patients with monosomal karyotype or FLT3 ITDs on clinical trials. Allogeneic hematopoietic cell transplant in first complete remission is generally indicated for high-risk patients. However, new approaches are needed to reduce the high rates of relapse, even after hematopoietic cell transplant. PMID- 21239840 TI - Understanding and managing ultra high-risk chronic lymphocytic leukemia. AB - Modern treatment approaches such as chemoimmunotherapy (e.g., fludarabine/cyclophosphamide/rituximab or FCR) are highly effective in the majority of chronic lymphocytic leukemia (CLL) patients. However, there remains a small but challenging subgroup of patients who show ultra high-risk genetics (17p deletion, TP53 mutation) and/or poor response to chemoimmunotherapy. The median life expectancy of these patients is below 2 to 3 years with standard regimens. Accordingly, CLL with the 17p deletion (and likely also with sole TP53 mutation) should be treated with alternative strategies. While p53 defects appear to play a central role in our understanding of this ultra high-risk group, at least half of the cases will not be predictable based on existing prognostic models. Current treatment approaches for patients with p53 defects or poor response to chemoimmunotherapy should rely on agents acting independently of p53, such as alemtuzumab, lenalidomide, flavopiridol, and a growing number of novel compounds (or combinations thereof) currently available in clinical trials. Poor survival times of patients with ultra high-risk CLL suggest that eligible patients should be offered consolidation with reduced-intensity allogeneic stem-cell transplantation or experimental approaches in clinical trials. PMID- 21239841 TI - Ultra high-risk myeloma. AB - Ultra high-risk myeloma can be defined as myeloma leading to death within 24 months. Despite tremendous improvements in the past decade (especially because of the availability of novel drugs such as thalidomide, bortezomib, and lenalidomide), these patients still represent 15% to 20% of the patients. Many prognostic factors can help to define these patients, including age, renal insufficiency, poor performance status, comorbidities, International Staging System (ISS) stage 3, high proliferation, leukemic presentation, and acquired genetic changes, as defined by interphase fluorescence in situ hybridization or genomics. Several combinations of these prognostic parameters can define ultra high-risk patients, making a universal therapeutic proposal almost impossible. However, focusing on fit patients with ISS 3, high proliferation, and poor-risk genetic changes, these patients should probably benefit from dose-dense and prolonged therapeutic schemas, ideally within prospective trials. PMID- 21239842 TI - Fluoride excess and periostitis in transplant patients receiving long-term voriconazole therapy. AB - BACKGROUND: We describe a heart transplant patient with painful periostitis and exostoses who was receiving long-term therapy with voriconazole, which is a fluoride-containing medication. Elevated plasma and bone fluoride levels were identified. Discontinuation of voriconazole therapy led to improvement in pain and reduced fluoride and alkaline phosphatase levels. METHODS: To determine whether voriconazole is a cause of fluoride excess, we measured plasma fluoride levels in 10 adult post-transplant patients who had received voriconazole for at least 6 months and 10 post-transplant patients who did not receive voriconazole. To assess the effect of renal insufficiency on fluoride levels in subjects receiving voriconazole, half were recruited on the basis of a serum creatinine level of >=1.4 mg/dL on their most recent measurement, whereas the other 5 subjects receiving voriconazole had serum creatinine levels <1.4 mg/dL. All control subjects had serum creatinine levels of >=1.4 mg/dL. Patients were excluded from the study if they received a fluorinated pharmaceutical other than voriconazole. RESULTS: All subjects who received voriconazole had elevated plasma fluoride levels, and no subjects in the control group had elevated levels (14.32 MUmol/L +/- 6.41 vs 2.54 +/- 0.67 MUmol/L; P<.001). Renal function was not predictive of fluoride levels. Plasma fluoride levels remained significantly higher in the voriconazole group after adjusting for calcineurin inhibitor levels and doses. Half of the voriconazole group subjects had evidence of periostitis, including exostoses in 2 patients. Discontinuation of voriconazole therapy in patients with periostitis resulted in improvement of pain and a reduction in alkaline phosphatase and fluoride levels. CONCLUSIONS: Voriconazole is associated with painful periostitis, exostoses, and fluoride excess in post-transplant patients with long-term voriconazole use. PMID- 21239843 TI - Treatment of endogenous fungal endophthalmitis: focus on new antifungal agents. AB - Endogenous fungal endophthalmitis, involving only the chorioretinal structures or extending to involve the vitreous (vitritis), is a sight-threatening infection requiring early appropriate therapy. Endophthalmitis is a relatively frequent complication of candidemia and less commonly occurs in patients who have invasive aspergillosis. Because the eye is a protected compartment, penetration of systemically administered antifungal agents is highly variable. In the posterior segment of the eye, amphotericin B (AmB) achieves very poor concentrations, but fluconazole concentrations are high. Among newer antifungal agents, voriconazole shows the most promise, because therapeutic concentrations for most Candida and Aspergillus species are achieved in the vitreous, and its antifungal activity is broad. In contrast, neither posaconazole nor the 3 echinocandins achieve adequate therapeutic concentrations in the vitreous. For sight-threatening macular involvement and vitritis, intravitreal injection of either AmB or voriconazole is helpful to achieve high local antifungal activity as quickly as possible. We review the available evidence regarding the most appropriate use of antifungal agents for endogenous fungal endophthalmitis, with the emphasis on treatment of infections due to Candida species. PMID- 21239844 TI - A method for accurate modelling of the crystal response function at a crystal sub level applied to PET reconstruction. AB - Positron emission tomography (PET) images suffer from low spatial resolution and signal-to-noise ratio. Accurate modelling of the effects affecting resolution within iterative reconstruction algorithms can improve the trade-off between spatial resolution and signal-to-noise ratio in PET images. In this work, we present an original approach for modelling the resolution loss introduced by physical interactions between and within the crystals of the tomograph and we investigate the impact of such modelling on the quality of the reconstructed images. The proposed model includes two components: modelling of the inter crystal scattering and penetration (interC) and modelling of the intra-crystal count distribution (intraC). The parameters of the model were obtained using a Monte Carlo simulation of the Philips GEMINI GXL response. Modelling was applied to the raw line-of-response geometric histograms along the four dimensions and introduced in an iterative reconstruction algorithm. The impact of modelling interC, intraC or combined interC and intraC on spatial resolution, contrast recovery and noise was studied using simulated phantoms. The feasibility of modelling interC and intraC in two clinical (18)F-NaF scans was also studied. Measurements on Monte Carlo simulated data showed that, without any crystal interaction modelling, the radial spatial resolution in air varied from 5.3 mm FWHM at the centre of the field-of-view (FOV) to 10 mm at 266 mm from the centre. Resolution was improved with interC modelling (from 4.4 mm in the centre to 9.6 mm at the edge), or with intraC modelling only (from 4.8 mm in the centre to 4.3 mm at the edge), and it became stationary across the FOV (4.2 mm FWHM) when combining interC and intraC modelling. This improvement in resolution yielded significant contrast enhancement, e.g. from 65 to 76% and 55.5 to 68% for a 6.35 mm radius sphere with a 3.5 sphere-to-background activity ratio at 55 and 215 mm from the centre of the FOV, respectively, without introducing additional noise. Patient images confirmed the usefulness of interC and intraC modelling for improving spatial resolution and contrast. Based on Monte Carlo simulated data, we conclude that four-dimensional modelling of the inter- and intra-crystal interactions during the reconstruction process yields a significantly improved contrast to noise ratio and the stationarity of the spatial resolution in the reconstructed images. PMID- 21239845 TI - Investigating the temporal resolution limits of scintillation detection from pixellated elements: comparison between experiment and simulation. AB - This study investigates the physical limitations involved in the extraction of accurate timing information from pixellated scintillation detectors for positron emission tomography (PET). Accurate physical modeling of the scintillation detection process, from scintillation light generation through detection, is devised and performed for varying detector attributes, such as the crystal element length, light yield, decay time and surface treatment. The dependence of light output and time resolution on these attributes, as well as on the photon interaction depth (DoI) of the annihilation quanta within the crystal volume, is studied and compared with experimental results. A theoretical background which highlights the importance of different time blurring factors for instantaneous ('ideal') and exponential ('realistic') scintillation decay is developed and compared with simulated data. For the case of a realistic scintillator, our experimental and simulation findings suggest that dependence of detector performance on DoI is more evident for crystal elements with rough ('as cut') compared to polished surfaces (maximum observed difference of 64% (25%) and 22% (19%) in simulation (measurement) for light output and time resolution, respectively). Furthermore we observe distinct trends of the detector performance dependence on detector element length and surface treatment. For short crystals (3 * 3 * 5 mm(3)) an improvement in light output and time resolution for 'as cut' compared to polished crystals is observed (3% (7%) and 9% (9%) for simulation (measurement), respectively). The trend is reversed for longer crystals (3 * 3 * 20 mm(3)) and an improvement in light output and time uncertainty for polished compared to 'as cut' crystals is observed (36% (6%) and 40% (20%) for simulation (measurement), respectively). The results of this study are used to guide the design of PET detectors with combined time of flight (ToF) and DoI features. PMID- 21239846 TI - Comparison of GATE/GEANT4 with EGSnrc and MCNP for electron dose calculations at energies between 15 keV and 20 MeV. AB - The GATE Monte Carlo simulation platform based on the GEANT4 toolkit has come into widespread use for simulating positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging devices. Here, we explore its use for calculating electron dose distributions in water. Mono-energetic electron dose point kernels and pencil beam kernels in water are calculated for different energies between 15 keV and 20 MeV by means of GATE 6.0, which makes use of the GEANT4 version 9.2 Standard Electromagnetic Physics Package. The results are compared to the well-validated codes EGSnrc and MCNP4C. It is shown that recent improvements made to the GEANT4/GATE software result in significantly better agreement with the other codes. We furthermore illustrate several issues of general interest to GATE and GEANT4 users who wish to perform accurate simulations involving electrons. Provided that the electron step size is sufficiently restricted, GATE 6.0 and EGSnrc dose point kernels are shown to agree to within less than 3% of the maximum dose between 50 keV and 4 MeV, while pencil beam kernels are found to agree to within less than 4% of the maximum dose between 15 keV and 20 MeV. PMID- 21239847 TI - Quantitative assessments of burn degree by high-frequency ultrasonic backscattering and statistical model. AB - An accurate and quantitative modality to assess the burn degree is crucial for determining further treatments to be properly applied to burn injury patients. Ultrasounds with frequencies higher than 20 MHz have been applied to dermatological diagnosis due to its high resolution and noninvasive capability. Yet, it is still lacking a substantial means to sensitively correlate the burn degree and ultrasonic measurements quantitatively. Thus, a 50 MHz ultrasound system was developed and implemented to measure ultrasonic signals backscattered from the burned skin tissues. Various burn degrees were achieved by placing a 100 degrees C brass plate onto the dorsal skins of anesthetized rats for various durations ranged from 5 to 20 s. The burn degrees were correlated with ultrasonic parameters, including integrated backscatter (IB) and Nakagami parameter (m) calculated from ultrasonic signals acquired from the burned tissues of a 5 * 1.4 mm (width * depth) area. Results demonstrated that both IB and m decreased exponentially with the increase of burn degree. Specifically, an IB of -79.0 +/- 2.4 (mean +/- standard deviation) dB for normal skin tissues tended to decrease to -94.0 +/- 1.3 dB for those burned for 20 s, while the corresponding Nakagami parameters tended to decrease from 0.76 +/- 0.08 to 0.45 +/- 0.04. The variation of both IB and m was partially associated with the change of properties of collagen fibers from the burned tissues verified by samples of tissue histological sections. Particularly, the m parameter may be more sensitive to differentiate burned skin due to the fact that it has a greater rate of change with respect to different burn durations. These ultrasonic parameters in conjunction with high-frequency B-mode and Nakagami images could have the potential to assess the burn degree quantitatively. PMID- 21239848 TI - An automatic contour propagation method to follow parotid gland deformation during head-and-neck cancer tomotherapy. AB - We developed an efficient technique to auto-propagate parotid gland contours from planning kVCT to daily MVCT images of head-and-neck cancer patients treated with helical tomotherapy. The method deformed a 3D surface mesh constructed from manual kVCT contours by B-spline free-form deformation to generate optimal and smooth contours. Deformation was calculated by elastic image registration between kVCT and MVCT images. Data from ten head-and-neck cancer patients were considered and manual contours by three observers were included in both kVCT and MVCT images. A preliminary inter-observer variability analysis demonstrated the importance of contour propagation in tomotherapy application: a high variability was reported in MVCT parotid volume estimation (p = 0.0176, ANOVA test) and a larger uncertainty of MVCT contouring compared with kVCT was demonstrated by DICE and volume variability indices (Wilcoxon signed rank test, p < 10(-4) for both indices). The performance analysis of our method showed no significant differences between automatic and manual contours in terms of volumes (p > 0.05, in a multiple comparison Tukey test), center-of-mass distances (p = 0.3043, ANOVA test), DICE values (p = 0.1672, Wilcoxon signed rank test) and average and maximum symmetric distances (p = 0.2043, p = 0.8228 Wilcoxon signed rank tests). Results suggested that our contour propagation method could successfully substitute human contouring on MVCT images. PMID- 21239849 TI - Evaluation of the tissue reaction to a new bilayered collagen matrix in vivo and its translation to the clinic. AB - This study evaluates a new collagen matrix that is designed with a bilayered structure in order to promote guided tissue regeneration and integration within the host tissue. This material induced a mild tissue reaction when assessed in a murine model and was well integrated within the host tissue, persisting in the implantation bed throughout the in vivo study. A more porous layer was rapidly infiltrated by host mesenchymal cells, while a layer designed to be a barrier allowed cell attachment and host tissue integration, but at the same time remained impermeable to invading cells for the first 30 days of the study. The tissue reaction was favorable, and unlike a typical foreign body response, did not include the presence of multinucleated giant cells, lymphocytes, or granulation tissue. In the context of translation, we show preliminary results from the clinical use of this biomaterial applied to soft tissue regeneration in the treatment of gingival tissue recession and exposed roots of human teeth. Such a condition would greatly benefit from guided tissue regeneration strategies. Our findings demonstrate that this material successfully promoted the ingrowth of gingival tissue and reversed gingival tissue recession. Of particular importance is the fact that the histological evidence from these human studies corroborates our findings in the murine model, with the barrier layer preventing unspecific tissue ingrowth, as the scaffold becomes infiltrated by mesenchymal cells from adjacent tissue into the porous layer. Also in the clinical situation no multinucleated giant cells, no granulation tissue and no evidence of a marked inflammatory response were observed. In conclusion, this bilayered matrix elicits a favorable tissue reaction, demonstrates potential as a barrier for preferential tissue ingrowth, and achieves a desirable therapeutic result when applied in humans for soft tissue regeneration. PMID- 21239850 TI - Adjuvant effect of liposome in chicken result from induction of nitric oxide. AB - Intranasal delivery of liposome-encapsulated inactivated Newcastle Disease virus (NDV) is known to be an effective vaccine for inducing immunity in the respiratory tract from our previous reports. Four-week-old specific pathogen-free chickens were intranasally immunized with NDV entrapped in phosphatidylcholine liposomes (PC-Lip). The mucosal levels of anti-NDV s-immunoglobulin A (IgA), serum IgG, a high hemagglutination inhibition titer (1:640), and the high survival rate with the PC-Lip vaccine were comparable to those of our previous report. The immune mechanisms of the PC-Lip adjuvant were determined by in vitro cellular experiments using the NO production of chicken spleen macrophages. The most important finding of this study was proving that macrophages were stimulated by PC-Lip via the extracellular regulated kinase (ERK) 1/2 and nuclear factor (NF)-kappaB activation pathways. This finding may be useful for developing potent mucosal vaccine delivery systems in the future. PMID- 21239851 TI - Plasma fetuin-A is associated with the severity of cognitive impairment in mild to-moderate Alzheimer's disease. AB - The significance of vascular risk factors in the development and progression of Alzheimer's disease (AD) is now widely recognized. Fetuin-A is an abundant plasma protein that predicts vascular risk in a variety of clinical settings. In the context of cerebral ischemia, fetuin-A appears to be anti-inflammatory. Given the apparent importance of neuroinflammation in cognitive decline, we analyzed fetuin A concentrations and pro-inflammatory cytokine levels in a cohort of 34 patients with mild-to-moderate AD, and compared these to age-matched controls. Further, we analyzed the relationship between plasma fetuin-A concentration and a measure of cognitive impairment using multivariate regression modeling. Plasma fetuin-A concentrations were lower in the patient group (p = 0.006) compared with controls and were significantly correlated with Mini-Mental State Examination (MMSE) score (r = 0.504, p = 0.002). Fetuin-A concentration was also significantly and inversely correlated with plasma TNF-alpha concentration (r = -0.496, p = 0.003). The association between MMSE performance and fetuin-A was maintained even after multivariate adjustment for other risk factors including TNF-alpha (adjusted R2 total = 0.371). Using this model, plasma fetuin-A concentration explained 21% of the variance in MMSE scores. Further studies are needed to evaluate whether fetuin-A is related to the progression and pathogenesis of AD. PMID- 21239852 TI - Transgenic AD model mice, effects of potential anti-AD treatments on inflammation, and pathology. AB - The deposition of amyloid-beta (Abeta) peptides in plaques and intracellular neurofibrillary tangles are the two main characteristic pathological features of Alzheimer's disease (AD). Significantly, plaques are surrounded by activated astrocytes, microglia, and possibly, macrophages, and it has been suggested that this activity contributes to the pathology. Whether this will lead to a decrease or an increase in the amount of Abeta deposition is not clear. To investigate the relation between amyloid neuropathology and inflammation, we examined the changes in amyloid pathology in the hippocampus and neocortex following three anti inflammatory treatments aimed at reducing the amyloid burden. In these studies we treated mice with different non-steroidal anti-inflammatory drugs for several months (i.e., from 8 through 14 months of age), and studied the Abeta pathology and inflammation in the brain. Sham treatment and flurbiprofen treatment did not affect Abeta pathology, and a low dose HCT 1026 (10 mg/kg; a nitric oxide donating flurbiprofen analog that has additional useful properties, including a remarkable gastrointestinal safety) did not affect pathology either, however a higher dose of HCT 1026 (30 mg/kg) did reduce the Abeta load. Furthermore, this treatment reduced the amount of microglial activation surrounding plaques. In contrast, the low dose of HCT 1026 increased GFAP activation, but did not change microglial activation. Together the data indicate that changing the activity of glial cells can lead to both a decrease of the amyloid burden, and to detrimental changes, likely caused by the interplay between the activation levels of astrocytes and microglial cells. PMID- 21239854 TI - Neural correlates of episodic memory in behavioral variant frontotemporal dementia. AB - Impaired episodic memory is currently an exclusion criterion for behavioral variant frontotemporal dementia (bv-FTD), although prior studies have shown that neuropsychological memory performance varies from very impaired to intact in such patients. Our study investigated i) whether this variability might be due to the admixture of true bv-FTD and phenocopy syndrome patients and ii) the neural correlates of episodic memory deficits in bvFTD. Groups of patients with true bvFTD (n = 14), phenocopy syndrome (n = 6), Alzheimer's disease (AD) (n = 14), and healthy controls (n = 15) underwent memory testing and had MRI scanning with ratings of regional brain atrophy. Phenocopy patients did not differ to controls on memory scores or atrophy ratings. By contrast, bvFTD and AD patients were impaired on both measures in comparison to controls and more importantly, bvFTD and AD did not differ on memory scores. Atrophy patterns differed, with AD showing typical medial temporal lobe atrophy, while bvFTD patients had predominantly prefrontal cortex atrophy. In bvFTD neuropsychological memory performance correlated with frontal atrophy ratings while in AD significant correlations were found between memory and both medial temporal lobe and frontal atrophy ratings. Taken together, out data shows that bvFTD patients can show a similar degree of episodic memory impairment on neuropsychological tests to AD patients, however, the neural correlates differ. The previously variable reported memory performance in bvFTD is likely due to the inclusion of phenocopy patients, who are mostly undistinguishable from controls. These findings have implications for the diagnosis of bvFTD. PMID- 21239855 TI - Persistent post-operative cognitive decline: naked truth, invisibility cloak or the "Emperor's new clothes"? PMID- 21239853 TI - Blocking the apolipoprotein E/amyloid-beta interaction reduces fibrillar vascular amyloid deposition and cerebral microhemorrhages in TgSwDI mice. AB - The accumulation of amyloid-beta (Abeta) peptides as toxic oligomers, amyloid plaques, and cerebral amyloid angiopathy (CAA) is critical in the pathogenesis of Alzheimer's disease (AD). The binding of Abeta peptides to apolipoprotein E (ApoE) plays an important role in modulation of amyloid deposition and clearance. We have shown that blocking the Abeta/ApoE interaction with Abeta(12-28P), a nontoxic blood-brain-barrier permeable and non-fibrillogenic synthetic peptide, constitutes a novel therapeutic approach for AD by reducing Abeta parenchymal deposition. In the present study, we investigate this therapeutic effect on CAA in the transgenic (Tg) AD mice model (TgSwDI), which expresses Swedish (K670N/M671L), Dutch (E693Q)/Iowa (D694N) AbetaPP mutations. These mice develop abundant CAA beginning at the age of 6 months. Behavioral results show that Abeta(12-28P) treated TgSwDI AD mice performed the same as wild-type mice, whereas vehicle treated TgSwDI were impaired in spatial memory. Furthermore, this treatment resulted in a significant reduction of total amyloid burden, especially the fibrillar vascular amyloid burden, which importantly was accompanied by a reduction in microhemorrhages and neuroinflammation. Measurement of Abeta levels in the brain homogenate revealed a significant decrease in both the total amount of Abeta and Abeta oligomer levels in Abeta(12-28P) treated TgSwDI mice. These findings suggest that blocking the Abeta/ApoE interaction is a highly effective therapeutic approach for vascular amyloid deposition, in contrast to some other therapeutic approaches. PMID- 21239856 TI - The effect of metals on spatial memory in a transgenic mouse model of Alzheimer's disease. AB - The amyloid-beta protein (Abeta) is a metalloprotein with affinity for the metal ions zinc (Zn), copper (Cu), and iron (Fe), which are found in high concentrations in the plaques of Alzheimer's disease (AD). Increasing attention is focused on the role of these metals in AD, and much of the evidence suggests a dyshomeostasis between these metal ions may significantly affect Abeta aggregation and deposition in the brain. While the effect of these metals on Abeta has been shown in vitro, there is less behavioral data supporting a direct role in cognitive impairment. In order to investigate the cognitive consequences of metal dyshomeostasis, we sought to directly increase metal levels in the brain by dietary means in a transgenic mouse model (Tg2576). We have now examined the effect of increased Zn (10 ppm) and Fe (10 ppm) levels in the drinking water in the Tg2576 mouse. Since increased dietary Zn can lead to Cu deficiency, a Zn group supplemented with copper was also examined (Zn (10 ppm)+Cu (0.025 ppm)). Significant increases in latency and fewer platform crossings on probe trials, which are considered measures of spatial memory impairment, were seen in both Fe and Zn supplemented transgenic mice, compared to those raised on lab water. No significant differences were seen between the Zn + Cu group and in transgenic mice raised on lab water. These data suggest that the negative consequences of Zn may be due to a reduction in copper levels and, therefore, an imbalance between these metal ions rather than a direct effect of increased Zn. PMID- 21239857 TI - Survival of batch numbers within dental implants following incineration as an aid to identification. AB - Dental implants have become a popular choice of treatment in replacing individual lost teeth or entire dentitions. The physical properties of high corrosion resistance, high structural strength and high melting point, suggest the retention of intact implants following most physical assaults. As the implants are machine made, they lack the individualisation required for their use as identifiers of the deceased, however the StraumannTM Company (Waldenburg, Switzerland) has recently released information that within the chamber of their implants they have laser etched batch numbers. The number of implants with the same batch number varies from 24 to 2400. The purpose of this study was to ascertain if the batch number was still identifiable following intense heat exposure in a furnace. A StraumannTM Standard Plus 3.3 x 8 mm implant, with no healing cap nor abutment attached was incinerated to 1125 degrees Celsius. Another StraumannTM Standard Plus 3.3 x 8 mm implant was also incinerated in the same way as the first implant but with an abutment attached. The results indicated that the first implant had totally oxidised within the internal chamber whilst the second implant following the removal of the abutment revealed an intact identifiable batch number. If the companies constructing implants were to place individual serial numbers rather than batch numbers on these implants then the potential exists for a new approach to be established for the identification of the deceased. PMID- 21239858 TI - Age estimation from dental cementum incremental lines and periodontal disease. AB - Age estimation by counting incremental lines in cementum added to the average age of tooth eruption is considered an accurate method by some authors, while others reject it stating weak correlation between estimated and actual age. The aim of this study was to evaluate this technique and check the influence of periodontal disease on age estimates by analyzing both the number of cementum lines and the correlation between cementum thickness and actual age on freshly extracted teeth. Thirty one undecalcified ground cross sections of approximately 30 um, from 25 teeth were prepared, observed, photographed and measured. Images were enhanced by software and counts were made by one observer, and the results compared with two control-observers. There was moderate correlation ((r)=0.58) for the entire sample, with mean error of 9.7 years. For teeth with periodontal pathologies, correlation was 0.03 with a mean error of 22.6 years. For teeth without periodontal pathologies, correlation was 0.74 with mean error of 1.6 years. There was correlation of 0.69 between cementum thickness and known age for the entire sample, 0.25 for teeth with periodontal problems and 0.75 for teeth without periodontal pathologies. The technique was reliable for periodontally sound teeth, but not for periodontally diseased teeth. PMID- 21239859 TI - Sex discrimination potential of permanent maxillary molar cusp diameters. AB - The purpose of the present investigation was to assess the potential usefulness of permanent maxillary molar cusp diameters for sex discrimination of poorly preserved skeletal remains. Cusp diameters were measured from standardized occlusal view photographs in a sample of black South Africans consisting of 130 males and 105 females. Results demonstrated that all cusp dimensions for both first and second maxillary molars exhibited significant sexual dimorphism (p < 0.001). Univariate and multivariate discriminant function equations permitted low to moderate classification accuracy in discriminating sex (58.3%-73.6%). The allocation accuracies for cusp diameter measurements were as high as, and even surpassed, those observed for conventional crown length and breadth dimensions of the same teeth. The most accurate result (73.6%, with a sex bias of only 0.5%) was obtained when all cusp diameters from both maxillary molars were used concurrently. However, only slightly less accurate results (~70.0%) were achieved when selected dimensions from only one of the molars, or even a single cusp, were utilized. Although not as reliable at predicting sex as other skeletal elements in black South Africans, the derived odontometric standards can be used with highly fragmentary skeletal material, as well as immature remains in which crown formation of the maxillary molars is complete. PMID- 21239860 TI - Dental age estimation based on third molar eruption in First Nation people of Canada. AB - Forensic age estimation of living subjects has become an increasing focus of interest in modern society. One main criterion for dental age estimation in the relevant age group is the evaluation of third molar eruption. The importance of ethnic variation in dental development requires population specific data for dental age evaluation. In the present study, we determined the stages of third molar eruption in 347 female and 258 male First Nations people of Canada aged 11 to 29 years based on radiological evidence from 605 conventional orthopantomograms. The results presented here provide data on the age of alveolar, gingival, and complete eruption of the third molars in the occlusal plane that can be used for forensic estimation of the minimum and most probable ages of investigated individuals. PMID- 21239861 TI - Dental anomalies and their value in human identification: a case report. AB - Forensic odontology and anthropology provide valuable support with regard to human identification. In some cases, when soft tissue is destroyed, carbonized or absent for whatever reason, bones and teeth become the only source of information about the identity of the deceased. In human identification, anything different, such as variation from normality, becomes an important tool when trying to establish the identity of the deceased. This paper illustrates a positive identification case achieved by the diagnosis of an anomaly of tooth position, with confirmation using skull-photo superimposition. Even though forensic science presents modern techniques, in this particular case, the anomalous position of the canine played a key role on the identification, showing that the presence of a forensic dentist on the forensic team can be of great value. PMID- 21239862 TI - Matching simulated antemortem and post-mortem dental radiographs from human skulls by dental students and experts: testing skills for pattern recognition. AB - The aim of this study was to evaluate the ability of undergraduate dental students to match simulated ante- and post-mortem radiographs in human skulls with experts as controls for the 1)number of post-mortem images needed for a match, 2)accuracy of the matches, and 3)time spent for a match. A film bitewing was recorded in each side of 51 dentate dry human skulls (a.m.-images) and digital images of the teeth were recorded using a sensor (p.m.-images). 102 correctly matching and 102 non-matching image pairs were constructed. Ten students and three experts scored the image pairs as: certain match, certain non match, or uncertain. None of the experts but half of the students made false positive scores. Half of the students performed just as accurately as the experts. All students (except one who made 8 FPs) asked for more p.m.-images than did the experts before deciding on a match, however, all students, but one, also spent less time per image pair than did the experts before deciding on a match (P<0.001). This simulated test sample may identify dental students and dentists with abilities for pattern recognition and thus help in the decision on who might be included as part of a forensic dental team when extra help is needed. PMID- 21239863 TI - Utility of ELISA optical density values and clinical scores for the diagnosis of and thrombosis prediction in heparin-induced thrombocytopenia. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction caused by antibodies to the heparin/platelet factor 4 (PF4) complex, resulting in thrombocytopenia and prothrombotic state. HIT diagnosis is challenging and depends on clinical presentation and laboratory tests. We investigated the usefulness of clinical scores and heparin/PF4 ELISA optical density (OD) as a diagnostic marker and thrombosis predictor in HIT. METHODS: We analyzed 92 patients with suspected HIT. The heparin/PF4 antibody was measured using a commercial ELISA kit (GTI, USA). For each patient, the 4 T's score and Chong's score were calculated. RESULTS: Of the 92 patients, 28 were anti-heparin/PF4 seropositive. The 4 T's score and Chong's score showed good correlation (r=0.874). The 4 T's score and OD values showed good performance for diagnosis of the definite and unlikely HIT groups; however, OD levels showed better sensitivity (93.8%) than the 4 T's score used alone (62.5%). Of the 92 patients, 26 developed thrombosis. The OD values were significantly higher in patients with thrombosis than in those without thrombosis (0.52 vs. 0.22, P<0.001). Patients with high OD values (OD>0.4) had an increased risk of thrombosis (adjusted odds ratio 9.44 [3.35-26.6], P<0.001) and a shorter 250-day thrombosis-free survival (32.1% vs. 54.7%, P=0.012). CONCLUSIONS: ELISA OD values in combination with clinical scoring can improve the diagnosis of and thrombosis prediction in HIT. More attention should be paid to the use of clinical scores and OD values as thrombosis predictors in HIT. PMID- 21239864 TI - Acute promyelocytic leukemia presenting with central nervous system involvement: a report of 2 cases. AB - Central nervous system (CNS) involvement in acute promyelocytic leukemia (APL) is rare, and the presence of CNS symptoms at the time of diagnosis of APL is even rarer. We report 2 cases of APL presenting with CNS involvement. A 43-yr-old woman presented with easy bruising and stuporous mentality. Her complete blood count (CBC) revealed leukocytosis with increased blasts. Bone marrow (BM) analysis was carried out, and the diagnosis of APL was confirmed. This was done by cytogenetic analysis and demonstration of PML-RARalpha rearrangement by reverse transcriptase PCR in the BM cells. A lumbar puncture was performed to investigate the cause of her stuporous mentality, and her cerebrospinal fluid (CSF) analysis revealed 97% leukemic promyelocytes. Despite systemic and CNS therapy, she died due to septic shock by infection and rapid disease progression only 3 days after her admission. Another patient, a 3-yr-old girl, presented with easy bruising and epistaxis, and her CBC showed pancytopenia with increased blasts. BM studies confirmed APL. Quantitative PCR for PML-RARalpha in the BM cells revealed a PML-RARalpha/ABL ratio of 0.33 and CSF analysis revealed 9.5% leukemic promyelocytes (2 of 21 cells). She received induction chemotherapy and intrathecal therapy and achieved complete remission (CR) in the BM and CNS. She has been maintained in the CR status for the past 31 months. Thus, patients with APL must be evaluated for CNS involvement if any neurological symptoms are present at the time of diagnosis. PMID- 21239865 TI - A case of therapy-related acute lymphoblastic leukemia with t(11;19)(q23;p13.3) and MLL/MLLT1 gene rearrangement. AB - Therapy-related ALL (t-ALL) is a rare secondary leukemia that develops after chemotherapy and/or radiotherapy for primary malignancies. Chromosomal 11q23 abnormalities are the most common karyotypic alterations in t-ALL. The t(11;19)(q23;p13) aberration is extremely rare and has not been confirmed at the molecular genetic level. Here, we report a case of t-ALL with t(11;19)(q23;p13.3) and MLL-MLLT1 (alias ENL) gene rearrangement confirmed by cytogenetic analysis, multiplex reverse transcription-PCR (multiplex RT-PCR), and DNA sequencing in a patient who had undergone treatment for breast cancer. A 40-yr-old woman developed acute leukemia 15 months after undergoing 6 cycles of adjuvant chemotherapy (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2), radiation therapy (dose, 5,900 cGy), and anticancer endocrine therapy with tamoxifen. The complete blood cell counts and bone marrow examination showed increased blasts and the blasts showed B lineage immunophenotype (positive for CD19, CD34, and cytoplasmic CD79a). Cytogenetic analysis revealed the karyotype 47,XX,+X,t(11;19)(q23;p13.3)[4]/46,XX[16]. FISH analyses, multiplex RT-PCR, and DNA sequencing confirmed the MLL-MLLT1 gene rearrangement. The patient underwent induction chemotherapy with fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD) and achieved complete remission. Subsequently, she underwent consolidation chemotherapy, but died of brain ischemia in the pons and the region of the middle cerebral artery. To our knowledge, this is the first case report of t-ALL with t(11;19)(q23;p13.3) and the MLL-MLLT1 gene rearrangement. PMID- 21239866 TI - A case of monoclonal gammopathy in extranodal marginal zone B-cell lymphoma of the small intestine. AB - Monoclonal gammopathy occurs in one-third of the patients with mucosa-associated lymphoid tissue lymphoma (MALT lymphoma). However, monoclonal gammopathy has been rarely reported in Korea. Paraprotenemia accompanying MALT lymphoma is strongly correlated with involvement of the bone marrow, and this involvement leads to the progression of the disease. Here, we present a case of a 66-yr-old man diagnosed with IgM monoclonal gammopathy and stage IV extranodal marginal zone lymphoma of the small intestine, with the involvement of the bone marrow. PMID- 21239867 TI - The effects of anti-insulin antibodies and cross-reactivity with human recombinant insulin analogues in the E170 insulin immunometric assay. AB - BACKGROUND: Insulin assays are affected by varying degrees of interference from anti-insulin antibodies (IAs) and by cross-reactivity with recombinant insulin analogues. We evaluated the usefulness of the E170 insulin assay by assessing IA effects and cross-reactivity with 2 analogues. METHODS: Sera were obtained from 59 type 2 diabetes patients receiving continuous subcutaneous insulin infusion and 18 healthy controls. Insulin levels were determined using an E170 analyzer. To investigate the effects of IAs, we performed IA radioimmunoassays, and analyzed the differences between directly measured insulin (direct insulin) and polyethylene glycol (PEG)-treated insulins (free, IA-unbound; total, IA-bound and unbound insulin). We performed in-vitro cross-reactivity tests with insulin aspart and insulin glulisine. RESULTS: In IA-positive patients, E170 free insulin levels measured using the E170 analyzer were significantly lower than the direct insulin levels. The mean value of the direct/free insulin ratio and IA-bound insulin, which were calculated as the difference between total and free insulin, increased significantly as endogenous IA levels increased. The E170 insulin assay showed low cross-reactivities with both analogues (< 0.7%). CONCLUSIONS: IAs interfered with E170 insulin assay, and the extent of interference correlated with the IA levels, which may be attributable to the increase in IA-bound insulin, and not to an error in the assay. The E170 insulin assay may measure only endogenous insulin since cross-reactivity is low. Our results suggest that the measurement of free insulin after PEG pre-treatment could be useful for beta cell function assessment in diabetic patients undergoing insulin therapy. PMID- 21239868 TI - Distribution of virulence genes in spa types of methicillin-resistant Staphylococcus aureus isolated from patients in intensive care units. AB - BACKGROUND: Various virulence factors and superantigens are encoded by mobile genetic elements. The relationship between clonal background and virulence factors differs in different geographic regions. We compared the distribution and relationship of spa types and virulence genes among methicillin-resistant Staphylococcus aureus (MRSA) strains isolated from a tertiary hospital in 2000-01 and 2007-08. METHODS: In 2000-01 and 2007-08, 94 MRSA strains were collected from 3 intensive care units at a Korean tertiary hospital. We performed spa typing and multiplex PCR for 19 superantigen genes. RESULTS: Relatively frequent spa types were t037 (40.5%), t002, t601, and t2138 in 2000-01, and t2460 (43.9%), t002, t037, t601, t324, and t2139 in 2007-08. We identified 4 novel spa types, 2 of which were designated as t5076 and t5079. Superantigen profiles were closely linked to spa types. For example, sea, sek, and seq superantigen genes were mainly detected in t037 strains. CONCLUSIONS: Major spa types differed depending on study periods, and the distribution of superantigen genes correlated with spa type. PMID- 21239870 TI - Plant root hair in tap water: a potential cause for diagnostic confusion. AB - Plant root hairs are commonly found artifacts in parasitology specimens and may be confused with helminthes by an untrained eye. We report a case of brain tuberculoma where the tissue sample was contaminated with root hair derived from tap water; the presence of this root hair, which mimicked a larva, led to diagnostic confusion. Therefore, tap water should be considered a source of root hair and vegetable matter. PMID- 21239869 TI - Application of single-nucleotide polymorphism and mycobacterial interspersed repetitive units-variable number of tandem repeats analyses to clinical Mycobacterium tuberculosis isolates from Korea. AB - BACKGROUND: Single-nucleotide polymorphism (SNP) analysis is a powerful strategy for large-scale molecular population studies examining phylogenetic relationships among bacterial strains. Mycobacterial interspersed repetitive units-variable number of tandem repeats (MIRU-VNTR) can be easily digitized to share data among laboratories. This study applied SNP and MIRU-VNTR analyses for molecular strain typing of Mycobacterium tuberculosis isolates collected throughout Korea. METHODS: We studied 102 clinical M. tuberculosis isolates, including 6 paired strains, collected from 11 university hospitals in Korea in 2008 and 2009. SNPs were detected using hairpin primer assays, and then, MIRU-VNTR analysis was performed. RESULTS: Thirty-five SNPs contained polymorphisms that helped differentiate the 96 tested isolates. The isolates were classified into 15 clusters. The Beijing family strains were distributed within closely related clusters in the SNP dendrogram. For MIRU-VNTR analysis, the 96 isolates were divided into 12 groups. The discriminatory index in 8 of these groups (MIRU-10, 23, -26, and -31; ETR-A, -B, -C, and -F) was high (Hunter-Gaston diversity index > 0.6). Unlike the SNP method, MIRU-VNTR analysis did not identify any notable localizations of Beijing or non-Beijing family isolates in specific clusters. CONCLUSIONS: SNP and MIRU-VNTR analyses are surrogate molecular strain-typing methods for M. tuberculosis in Korea where Beijing family isolates are predominant. PMID- 21239871 TI - Bacteremia caused by Corynebacterium amycolatum with a novel mutation in gyrA gene that confers high-level quinolone resistance. AB - Although Corynebacterium amycolatum can cause opportunistic infections, it is commonly considered as contaminant. In this report, we present a case of bacteremia caused by C. amycolatum with a novel mutation in the gyrA gene that confers high-level quinolone resistance to the organism. PMID- 21239872 TI - Miller-Dieker syndrome with der(17)t(12;17)(q24.33;p13.3)pat presenting with a potential risk of mis-identification as a de novo submicroscopic deletion of 17p13.3. AB - Miller-Dieker syndrome involves a severe type of lissencephaly, which is caused by defects in the lissencephaly gene (LIS1). We report the case of a female infant with der(17)t(12;17)(q24.33;p13.3)pat caused by an unbalanced segregation of the parental balanced translocation of 17p with other chromosomes. The proband presented with facial dysmorphism, arthrogryposis, and intrauterine growth retardation. Most cases of Miller-Dieker syndrome have a de novo deletion involving 17p13.3. When Miller-Dieker syndrome is caused by an unbalanced translocation, mild-to-severe phenotypes occur according to the extension of the involved partner chromosome. However, a pure partial monosomy derived from a paternal balanced translocation is relatively rare. In this case, the submicroscopic cryptic deletion in the proband was initially elucidated by FISH, and karyotype analysis did not reveal additional chromosome abnormalities such as translocation. However, a family history of recurrent pregnancy abnormalities strongly suggested familial translocation. Sequential G-banding and FISH analysis of the father's chromosomes showed that the segment of 17p13.3->pter was attached to the 12qter. Thus, we report a case that showed resemblance to the findings in cases of a nearly pure 17p deletion, derived from t(12;17), and delineated by whole genome array comparative genomic hybridization (CGH). If such cases are incorrectly diagnosed as Miller-Dieker syndrome caused by de novo 17p13.3 deletion, the resultant improper genetic counseling may make it difficult to exactly predict the potential risk of recurrent lissencephaly for successive pregnancies. PMID- 21239873 TI - Clinical, biochemical and genetic analyses in two Korean patients with medium chain acyl-CoA dehydrogenase deficiency. AB - Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive hereditary metabolic disorder of mitochondrial fatty acid beta-oxidation. It is characterized by hypoketotic hypoglycemia, hyperammonemia, seizure, coma, and sudden infant death syndrome-like illness. The most frequently isolated mutation in the acyl-CoA dehydrogenase, medium-chain (ACADM) gene of Caucasian patients with MCADD is c.985A>G, but ethnic variations exist in the frequency of this mutation. Here, we describe 2 Korean pediatric cases of MCADD, which was detected during newborn screening by tandem mass spectrometry and confirmed by molecular analysis. The levels of medium-chain acylcarnitines, including octanoylcarnitine (C8), hexanoylcarnitine (C6), and decanoylcarnitine (C10), were typically elevated. Molecular studies revealed that Patient 1 was a compound heterozygote for c.449_452delCTGA (p.Thr150ArgfsX4) and c.461T>G (p.L154W) mutations, and Patient 2 was a compound heterozygote for c.449_452delCTGA (p.Thr150ArgfsX4) and c.1189T>A (p.Y397N) mutations. We detected asymptomatic patients with MCADD by using a newborn screening test and confirmed it by ACADM mutation analysis. This report presents evidence of the biochemical and molecular features of MCADD in Korean patients and, to the best of our knowledge, this is the first report of the c.461T>G mutation in the ACADM gene. PMID- 21239874 TI - 14-3-3sigma (sigma) regulates proliferation and differentiation of multipotent p63-positive cells isolated from human breastmilk. AB - The mammary gland is a dynamic organ that only undergoes complete differentiation during pregnancy. Differentiation is fuelled by asymmetric division of stem cells that reside in normally quiescent niches in the resting gland in response to pregnancy-associated hormones. Loss of regulation of stem cells is believed to underlie some breast cancers. This process is poorly understood in humans since it is difficult to extract stem cells from the lactating gland. We have identified a p63-positive population in breastmilk that proliferates and differentiates into at least two separate mammary lineages in culture. Nuclear translocation of p63 coincides with expression of the cell-cycle arrest protein 14-3-3sigma (Sigma) and precedes differentiation. Transient down-regulation of Sigma promotes maintenance of the p63-positive population without affecting normal differentiation. We propose that p63-postive cells from breastmilk represent a novel source of cells to model regulation of mammary gland development and tumorigenesis. PMID- 21239875 TI - Release the ink4a/arf growth suppression by "u" and "me"? PMID- 21239876 TI - The emerging role of maternal phosphatidylinositol 3 kinase (PI3K) signaling in manipulating mammalian preimplantation embryogenesis. PMID- 21239877 TI - Metabolic cues from the microenvironment act as a major selective factor for cancer progression and metastases formation. PMID- 21239878 TI - Inhibition of Smad3 activity by cyclin D-CDK4 and cyclin E-CDK2 in breast cancer cells. PMID- 21239879 TI - Breast cancer go sMAD: cyclin towards aggressive phenotypes. PMID- 21239880 TI - Targeting the metabolic flexibility of cancer cells: straighten up and die right. PMID- 21239881 TI - Hypoxia: are stem cells in it for the long run? AB - Adult stem cells must persist throughout life to ensure continuous replenishment of dead or damaged cells in various tissues of the body. While numerous studies have already begun to identify some of the factors and mechanisms that regulate long term function and survival of stem cells, there is still much to learn in this regard. A growing body of evidence suggests that various types of stem cells exist in a hypoxic microenvironment, which may be conducive to stem cell longevity. We have recently shown that the oxygen dependent transcription factor hypoxia inducible factor 1alpha (Hif1alpha) is essential for maintenance of functional levels of telomerase in murine embryonic stem cells (mES). Importantly, long-term proliferation of mES cells with reduced Hif1alpha levels led to telomere shortening and ultimately cell senescence. Studies by others over the past 10 years has also indicated that hypoxia and Hif expression are essential for self-renewal and are involved in the regulation of proliferation for some types of stem cells. We now report our view regarding the effects and mechanisms by which hypoxia may regulate the long-term maintenance of stem cell populations. PMID- 21239882 TI - PRIMA-1Met/APR-246 induces wild-type p53-dependent suppression of malignant melanoma tumor growth in 3D culture and in vivo. AB - Disseminating malignant melanoma is a lethal disease highly resistant to radio- and chemotherapy. Therefore, the development of new treatment strategies is strongly needed. Tumor suppressor p53-mediated apoptosis is essential for the response to radio- and chemotherapy. Although p53 is not frequently mutated in melanoma, it is inactivated by integrin alphav-mediated signaling, as we previously demonstrated 1, which may account, at least partially, for increased apoptosis resistance of malignant melanoma. In this study we addressed the question whether functional restoration of p53 by APR-246 (PRIMA-1Met), which can reactivate mutant p53 and induce massive apoptosis in cancer cells, is able to restore the function of inactive p53 in melanoma. Using a three-dimensional collagen gel (3D-collagen) to culture melanoma cells carrying wild-type p53, we found that APR-246 treatment resulted in activation of p53, leading to increased expression of p53 pro-apoptotic targets Apaf1 and PUMA and activation of caspase- 9 and -3. Moreover, APR-246 triggered melanoma cell apoptosis that was mediated by p53 and caspase 9. Importantly, APR-246 treatment also suppressed human melanoma xenograft tumors in vivo in a p53-dependent manner. Thus, wild-type p53 reactivation may provide a novel approach for malignant melanoma treatment, with APR-246 as a candidate drug for such a development. PMID- 21239884 TI - The role of BAFF-R dysregulation in B-lymphoid lineage malignancies. PMID- 21239883 TI - S. pombe replication protein Cdc18 (Cdc6) interacts with Swi6 (HP1) heterochromatin protein: region specific effects and replication timing in the centromere. AB - Heterochromatin in S. pombe is associated with gene silencing at telomeres, the mating locus and centromeres. The compact heterochromatin structure raises the question how it unpacks and reforms during DNA replication. We show that the essential DNA replication factor Cdc18 (CDC6) associates with heterochromatin protein 1 (Swi6) in vivo and in vitro. Biochemical mapping and mutational analysis of the association domains show that the N-terminus of Cdc18 interacts with the chromoshadow domain of Swi6. Mutations in Swi6 that disrupt this interaction disrupt silencing and delay replication in the centromere. A mutation cdc18-I43A that reduces Cdc18 association with Swi6 has no silencing defect at the centromere, but changes Swi6 distribution and accelerates the timing of centromere replication. We suggest that fine tuning of Swi6 association at replication origins is important for negative as well as positive control of replication initiation. PMID- 21239885 TI - Overlapping and distinct pRb pathways in the mammalian auditory and vestibular organs. AB - Retinoblastoma gene (Rb1) is required for proper cell cycle exit in the developing mouse inner ear and its deletion in the embryo leads to proliferation of sensory progenitor cells that differentiate into hair cells and supporting cells. In a conditional hair cell Rb1 knockout mouse, Pou4f3-Cre-pRb(-/-), pRb(-/ ) utricular hair cells differentiate and survive into adulthood whereas differentiation and survival of pRb(-/-) cochlear hair cells are impaired. To comprehensively survey the pRb pathway in the mammalian inner ear, we performed microarray analysis of (pRb(-/-) cochlea and utricle. The comparative analysis shows that the core pathway shared between pRb(-/-) cochlea and utricle is centered on E2F, the key pathway that mediates pRb function. A majority of differentially expressed genes and enriched pathways are not shared but uniquely associated with pRb(-/-) cochlea or utricle. In pRb(-/-) cochlea, pathways involved in early inner ear development such as Wnt/beta-catenin and Notch were enriched, whereas pathways involving in proliferation and survival are enriched in pRb(-/-) utricle. Clustering analysis showed that the pRb(-/-) inner ear has characteristics of a younger control inner ear, an indication of delayed differentiation. We created a transgenic mouse model (ER-Cre-pRb(flox/flox)) in which Rb1 can be acutely deleted postnatally. Acute Rb1 deletion in the adult mouse fails to induce proliferation or cell death in inner ear, strongly indicating that Rb1 loss in these postmitotic tissues can be effectively compensated for, or that pRb-mediated changes in the postmitotic compartment result in events that are functionally irreversible once enacted. This study thus supports the concept that pRb-regulated pathways relevant to hair cell development, encompassing proliferation, differentiation and survival, act predominantly during early development. PMID- 21239886 TI - The elusive role of the SPRY2 domain in RyR1. AB - The second of three SPRY domains (SPRY2, S1085 -V1208) located in the skeletal muscle ryanodine receptor (RyR1) is contained within regions of RyR1 that influence EC coupling and bind to imperatoxin A, a toxin probe of RyR1 channel gating. We examined the binding of the F loop (P1107-A1121) in SPRY2 to the ASI/basic region in RyR1 (T3471-G3500, containing both alternatively spliced (ASI) residues and neighboring basic amino acids). We then investigated the possible influence of this interaction on excitation contraction (EC) coupling. A peptide with the F loop sequence and an antibody to the SPRY2 domain each enhanced RyR1 activity at low concentrations and inhibited at higher concentrations. A peptide containing the ASI/basic sequence bound to SPRY2 and binding decreased ~10-fold following mutation or structural disruption of the basic residues. Binding was abolished by mutation of three critical acidic F loop residues. Together these results suggest that the ASI/basic and SPRY2 domains interact in an F loop regulatory module. Although a region that includes the SPRY2 domain influences EC coupling, as does the ASI/basic region, Ca2+ release during ligand- and depolarization-induced RyR1 activation were not altered by mutation of the three critical F loop residues following expression of mutant RyR1 in RyR1-null myotubes. Therefore the electrostatic regulatory interaction between the SPRY2 F loop residues (that bind to imperatoxin A) and the ASI/basic residues of RyR1 does not influence bi-directional DHPR-RyR1 signaling during skeletal EC coupling, possibly because the interaction is interrupted by the influence of factors present in intact muscle cells. PMID- 21239887 TI - Nicotinic acetylcholine receptors containing the alpha4 subunit are critical for the nicotine-induced reduction of acute voluntary ethanol consumption. AB - Recently, we investigated the molecular mechanisms of the smoking cessation drug varenicline, a nicotinic acetylcholine receptor (nAChR) partial agonist, in its ability to decrease voluntary ethanol intake in mice. Previous to our study, other labs had shown that this drug can decrease ethanol consumption and seeking in rat models of ethanol intake. Although varenicline was designed to be a high affinity partial agonist of nAChRs containing the alpha4 and beta2 subunits (designated as alpha4beta2*), at higher concentrations it can also act upon alpha3beta2*, alpha6*, alpha3beta4* and alpha7 nAChRs. Therefore, to further elucidate the nAChR subtype responsible for varenicline-induced reduction of ethanol consumption, we utilized a pharmacological approach in combination with two complimentary nAChR genetic mouse models, a knock-out line that does not express the alpha4 subunit (alpha4 KO) and another line that expresses alpha4* nAChRs hypersensitive to agonist (the Leu9'Ala line). We found that activation of alpha4* nAChRs was necessary and sufficient for varenicline-induced reduction of alcohol consumption. Consistent with this result, here we show that a more efficacious nAChR agonist, nicotine, also decreased voluntary ethanol intake, and that alpha4* nAChRs are critical for this reduction. PMID- 21239888 TI - Molecular pathogenesis of cervical cancer. AB - INTRODUCTION: Cervical cancer is a sexually transmitted disease that results from infection with oncogenic types of human papillomavirus (HPV). Oncogenic HPV DNA is found in over 95% of invasive cervical cancers worldwide. Cervical cancer is a leading cause of cancer deaths in developing countries because of high HPV infection rates and lack of comprehensive cervical Pap smear testing of susceptible women. Vaccination against HPV prevents the acquisition of cervical dysplastic lesions among eligible women who have not already acquired the vaccine specific HPV types. METHODS: Literature review of the epidemiology, infection cycle, viral gene function and current vaccines related to the oncogenic types of the human papillomavirus (HPV). CONCLUSION: Enhanced understanding of HPV and population-based measures offer the best hope of limiting worldwide mortality due to cervical cancer. The development of therapeutic cervical cancer vaccines and/or virus-targeted drug therapies would be a giant step forward. PMID- 21239889 TI - Transforming blood vessels into bone. PMID- 21239890 TI - Screening for modulators of cisplatin sensitivity: unbiased screens reveal common themes. AB - Cisplatin is a widely used chemotherapeutic agent to treat a variety of solid tumors. The cytotoxic mode of action of cisplatin is mediated by inducing conformational changes in DNA including intra- and inter-strand crosslink adducts. Recognition of these adducts results in the activation of the DNA damage response resulting in cell cycle arrest, repair, and potentially, apoptosis. Despite the clinical efficacy of cisplatin, many tumors are either intrinsically resistant or acquire resistance during treatment. The identification of cisplatin drug response modulators can help us understand these resistance mechanisms, provide biomarkers for treatment strategies, or provide drug targets for combination therapy. Here we discuss functional genetic screens, including one performed by us, set up to identify genes whose inhibition results in increased sensitivity to cisplatin. In summary, the validated genes identified in these screens mainly operate in DNA damage response including nucleotide excision repair, translesion synthesis, and homologous recombination. PMID- 21239892 TI - Medication persistence in the treatment of HIV infection: a review of the literature and implications for future clinical care and research. AB - Persistence, continuous treatment with a prescribed medication or intervention, is an important, but underrecognized aspect of medication treatment, especially for HIV. In contrast to adherence, which measures the percentage of patient behavior to a prescribed therapy, persistence measures the duration during which a patient remains on a prescribed therapy. Decreased persistence for HIV treatment, or shorter duration on therapy, is associated with increased rates of virological failure, development of antiretroviral resistance, and increased morbidity and mortality. Additionally, frequency and duration of nonpersistent episodes rather than adherence may be a better predictor of clinical outcomes in HIV-infected patients on certain regimens. In this review, we codify the constructs of persistence and adherence, and further define persistence as either patient or regimen persistence. Furthermore, current literature on the clinical consequences of and factors associated with suboptimal persistence is summarized. Finally, methods to measure persistence as well as interventions that may improve persistence and clinical outcomes are suggested. PMID- 21239891 TI - FcRn overexpression in mice results in potent humoral response against weakly immunogenic antigen. AB - The neonatal Fc receptor (FcRn) regulates IgG and albumin homeostasis, mediates maternal IgG transport, is active in phagocytosis and delivers antigen for presentation. We have previously shown that transgenic (tg) mice that have been created to overexpress bovine FcRn (bFcRn) demonstrate increased half-life of mouse IgG, significantly increased antigen-specific IgG in serum and augmented expansion of antigen-specific B cells and plasma cells after immunization. One of the interesting questions surrounding this enhanced immune response is whether these tg mice could effectively induce immune response to weakly immunogenic antigens. To address this question, we immunized these bFcRn tg mice with a conserved hemagglutinin subunit 2 (HA2)-based synthetic peptide that was recently found to be effectively targeted by neutralizing antibodies. Using an ELISA system, we found that, whereas wild-type mice showed a weak immune response and developed only a de minimis amount of antibody against the epitope, FcRn over expressing animals mounted a robust reaction expressed in specific antibody titers on day 28 that continued to rise through day 50. Consistent with our previous data, the enhanced immune response resulting from the FcRn overexpression was also associated with a substantial increase in the number of spleen derived B cells, dendritic cells, granulocytes and plasma cells. Based on this evidence, we propose that tg mice that overexpress bFcRn offer major advantages in monoclonal antibody production because the tg mice would allow the generation of antibodies (hybridomas) to weakly immunogenic antigens that otherwise would be difficult or even impossible to make. PMID- 21239893 TI - Tracking the biological risk of coronary artery disease in HIV-infected individuals: the case of circulating endothelial progenitor cells. PMID- 21239894 TI - SENSE makes us rethink the second-generation nonnucleoside reverse transcriptase inhibitor etravirine's place in HIV-1 treatment. PMID- 21239895 TI - The imperative to respond with appropriate and timely interventions to mass rape in conflict-affected areas. PMID- 21239896 TI - A comparison of patients' attitudes to antiretroviral toxicities between the UK and Uganda. PMID- 21239897 TI - Inappropriate claim of 'failure of ritonavir-boosted lopinavir monotherapy in HIV' in the Monotherapy Switzerland/Thailand (MOST) trial. PMID- 21239898 TI - Differentiation and apoptosis in pilomatrixoma. AB - We carried out a histopathologic study of pilomatrixoma, a benign skin tumor, and also examined apoptosis and hair differentiation with the aim to understand the presence of amorphous debris and cyst formation in the tumor. Among 16 cases of pilomatrixoma examined, 11 were at the early regressive stage and 5 were at the late regressive stage according to the classification by Kaddu et al. In the former cases, tumor nests were basically composed of basophilic, transitional, and shadow cells. Cyst formation was evident in all cases and squamoid epithelium was observed in 4 cases at the early regressive stage. Amorphous debris was found in all cases including those at the late regressive stage. Immunohistochemical analysis revealed positive reaction products for beta-catenin and Lef-1 in basophilic and transitional cells, although their distribution differed. Immunoreactivity for beta-catenin was observed in the lower transitional cells, whereas immunoreactivity for Lef-1 was also evident in the upper transitional cells. Positive reactions for hair keratins were found in the cytoplasm of transitional and shadow cells, but not in the amorphous debris. Examination by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method revealed positive reactions in transitional and some shadow cells. These results suggest that in pilomatrixoma, production of hair keratin and induction of apoptosis may occur at the same time, and that unlike the normal hair follicle irregular expression of beta-catenin and Lef-1 results in the appearance of amorphous debris and cyst formation. PMID- 21239900 TI - Basal cell carcinoma-associated pseudocarcinomatous hyperplasia. PMID- 21239901 TI - Introduction. PMID- 21239902 TI - The genetic basis of addiction and relevant cellular mechanisms. PMID- 21239903 TI - Management of substance abuse in the hospital setting. PMID- 21239904 TI - Anesthesia for opiate detoxification and the ibogaine controversy. PMID- 21239905 TI - The anesthetic implications of alcoholism. PMID- 21239906 TI - The anesthetic implications of illicit opioid abuse. PMID- 21239907 TI - Cocaine and the club drugs. PMID- 21239908 TI - The perioperative implications of tobacco, marijuana, and other inhaled toxins. PMID- 21239909 TI - Drugs, alcohol, pregnancy, and the fetal alcohol syndrome. PMID- 21239910 TI - Drug abuse in the chronic pain patient. PMID- 21239911 TI - Perioperative implications of buprenorphine maintenance treatment for opioid addiction. PMID- 21239912 TI - The drug seeking anesthesia care provider. PMID- 21239913 TI - Propofol abuse. PMID- 21239915 TI - Skull deformities at a crossroads: the need for new directions. PMID- 21239916 TI - Deformational plagiocephaly: a look into the future. PMID- 21239917 TI - Current concepts in deformational plagiocephaly. PMID- 21239918 TI - Craniofacial implants success in facial rehabilitation. AB - The use of craniofacial implants is an effective treatment for patients with deformities, burns, and cancer sequelae. The sites with the most successful implants are the auricular, nasal, and orbital regions. Furthermore, other factors can affect the implant longevity such as irradiated area, surgical technique, bone quality and quantity, macrostructure and microstructure of the implant, maintenance, and systemic factors. PMID- 21239919 TI - In situ fronto-orbital advancement with medial orbital osteotomies for trigonocephaly-associated hypotelorism. AB - In treating trigonocephaly, the value of direct surgical correction of orbital hypotelorism is controversial. In many cases of hypotelorism, the distance between the orbits increases over time after traditional fronto-orbital advancement. Still, more severe hypotelorism is not fully corrected and may benefit from a more definitive surgical intervention. We describe an in situ fronto-orbital advancement that improves severe hypotelorism and simplifies the surgical treatment of trigonocephaly. The key modification to traditional fronto orbital advancement is an in situ medial orbital osteotomy that extends along the medial orbit, posterior to the medial canthus, and then across the inferior orbital rim into the piriform aperture. The procedure is indicated only in patients with more severe hypotelorism on physical examination. Rather than creating a freely removable bandeau during the operation, the bone segment composed of the supraorbital bar and superior orbits remains attached at the medial canthi. A midline osteotomy allows the respective orbital segments to be independently mobilized with the medial canthi left attached, and the space between them widened with gentle lateral traction and placement of an interpositional bone graft. Concomitantly, the lateral orbits and lateral supraorbital bar are contoured, advanced, and fixed with resorbable plates and screws. Representative results are shown. In situ fronto-orbital advancement with medial orbital osteotomies is a safe, efficient, and relatively simple technique that results in immediate improvement of hypotelorism and may be a worthwhile maneuver to consider in selected cases. PMID- 21239920 TI - Analysis of the jugular foramen in pediatric patients with craniosynostosis. AB - INTRODUCTION: Intracranial hypertension due to craniosynostosis is a dreaded potential complication that affects the developing brain. We hypothesized that craniosynostotic patients have significantly reduced jugular foramen (JF) when compared with age-matched controls. This may partially account for the observed increase in intracranial pressure (ICP) seen in some of these patients. We also estimated the potential effects on ICP using the Hagen-Poiseuille equation. MATERIALS AND METHODS: Two institutional review board-approved groups were included in this study. Group 1 consists of 14 randomly selected craniosynostotic patients (7 boys and 7 girls; mean age, 9.33 mo; range, 0.6-21 mo). Group 2, the control group, consists of 27 children without craniosynostosis (13 boys and 14 girls; mean age, 8.71 mo; range, 0.23-45 mo). The same neuroradiologist used axial computed tomographic scans to measure the greatest anterior-posterior (AP) and lateral diameters of the jugular bulb. RESULTS: The right JF AP diameter is 23.02% smaller in group 1 than in group 2 (P = 0.0066, 2-tailed t-test). The left JF AP diameter was also smaller for group 1 but was not statistically significant (P = 0.257, 2-tailed t-test). Group 1 also had a nonsignificant increase in both lateral diameters (P > 0.05). DISCUSSION: The study showed a significant decrease (23.02%) in the right JF AP dimension in children with craniosynostosis. On the basis of the Hagen-Poiseuille equation, a 23.02% AP diameter reduction in 1 JF may theoretically increase the ICP 63.5% or 6.35 mm Hg, keeping all other variables, such as blood flow, constant. Although not supported by aspect ratio analysis, the slight increase in the lateral diameters of the patients' JFs may lessen this effect. PMID- 21239921 TI - Inferior bundle (fourth band) of the buccinator and the incisivus labii inferioris muscle. AB - The aim of this study was to clarify the morphologic and spatial relationships of the inferior bundle of the buccinator and the incisivus labii inferioris muscle (ILI) and their surrounding structures. The inferior bundle of the buccinator and the ILI were investigated in 40 hemifaces from Korean cadavers. The inferior bundle (or fourth band) of the buccinator muscle was observed in 14 (35%) of the 40 specimen sides. The ILI was found in 39 (97.5%) of the 40 specimen sides. The spatial relationships of the ILI with the buccinator muscle and the orbicularis oris muscle were classified into 4 categories based on the existence of the inferior bundle of the buccinator. These observations indicate that the lower portion of the buccinator including the third and fourth inferior bundles and the ILI could affect the alveolar bone of the mandible or occlusion during these muscular movements. PMID- 21239922 TI - Location of supraorbital foramen/notch and infraorbital foramen with reference to soft- and hard-tissue landmarks. AB - The purpose of the present study was to determine the locations of the supraorbital foramen (SOF) and the infraorbital foramen (IOF) relative to soft- and hard-tissue landmarks. It will provide more accurate data for dental and facial surgery. Twenty embalmed adult cadavers (40 sides; 16 men, 4 women) were dissected to expose the SOFs and IOFs, and another 46 skulls (92 sides) were also measured for further study. The locations of the SOFs and IOFs were evaluated with direct and photographic measurements. The data gained were analyzed by statistical method. The horizontal distances between the SOFs/IOFs and the medial canthus to the distance between the medial canthus and the lateral canthus ratios have been measured, and their confidence intervals are 0.22 to 0.31 and 0.34 to 0.49, respectively, and their linear regression equations are EF = 0.58 CF + 25.02 (unit: mm) and EF = 0.51 DG + 24.20 (unit: mm). The vertical distance between IOFs/SOFs and the medial/lateral canthi are 25.09 +/- 3.36 mm/23.91 +/- 3.31 mm and 25.75 +/- 3.34 mm/26.93 +/- 3.88 mm, respectively. The horizontal angle between IOFs/SOFs and the medial/lateral canthi are 72.54 +/- 7.13 degrees, 66.77 +/- 5.17 degrees, 47.45 +/- 6.57 degrees, 54.69 +/- 8.38 degrees, respectively. Based on the hard tissues, The SOF localized 20.55 +/- 3.24 mm medial and 13.78 +/- 2.60 mm superior to the zygomaticofrontal suture. And the horizontal angle between them is 56.04 +/- 6.87 degrees. The IOF localized 18.52 +/- 2.30 mm medial and 30.79 +/- 3.29 inferior to the zygomaticofrontal suture. The horizontal angle between them is 31.06 +/- 4.33 degrees. We also found that most (96.81%) of the IOFs were located below the middle line of the zygomatic arch. These results may provide more detailed information about the locations of SOF and IOF. And they will facilitate prediction of the locations of IOF and SOF in clinical procedure. PMID- 21239923 TI - Morphometry of the ear in north Sudanese subjects with Down syndrome: a three dimensional computerized assessment. AB - Down syndrome (DS) is the most frequent live-born autosomal aneuploidy in humans. Scanty data on the craniofacial phenotype of African subjects with DS have been published so far. We wanted to detail the morphologic characteristics of the ears in north Sudanese subjects with DS. The three-dimensional coordinates of 13 soft tissue landmarks on the ears were obtained using a laser scanner in 64 north Sudanese subjects with DS aged 4 to 34 years and in 682 sex- and age-matched control subjects. From the landmarks, left and right linear distances (ear width and length), ratios (ear width-to-ear length), areas (ear area), angles (angle of the auricle vs the facial midplane), and the three-dimensional symmetry index were calculated. Distances, angles, areas, and ratios were computed. Subject and reference data were compared by computing z scores and calculating Student t tests. Ear width, length, and area were significantly (Student t test, P < 0.001) smaller in the subjects with DS than in the reference subjects. On the right side of the face, the subjects with DS had larger ear width-to-ear length ratios and larger angles of the auricle versus the facial midplane than the reference subjects. The three-dimensional symmetry index was significantly larger in the reference subjects. In conclusion, ear dimensions, position, and shape significantly differed in subjects with DS when compared with sex-, age-, and ethnic group-matched control subjects. PMID- 21239924 TI - Relation of the mandibular body and ramus in Treacher Collins syndrome. AB - BACKGROUND: Treacher Collins syndrome is associated with a clockwise mandibular deformity (Plast Reconstr Surg 2008;121:77e-84e). We hypothesize that the Treacher Collins mandible exhibits a more obtuse relation between the body and the ramus compared with unaffected subjects. The purpose of this study was to objectively analyze the body-ramus relation in Treacher Collins compared with control subjects and to investigate the effect of age. METHODS: This was a retrospective analysis involving three-dimensional computed tomography (CT) scans. Demographic and CT scan information was obtained for Treacher Collins and control subjects. Measurements were performed on the IDXrad platform. The ramus body angle (RBA) was defined as the intersection of the anterior ramus with the tangent from the alveolar process of the mandible. The mandibular plane angle (MPA) was measured in standard fashion. Left and right hemimandibles were analyzed. Statistical analysis involved the paired t-test (P < 0.005 significance). Subgroups based on age, younger than 3 years and older than 12 years, were then compared, within and between groups. RESULTS: Three-dimensional CT scans were identified in 18 Treacher Collins (36 sides) and 24 control (48 sides) subjects. The MPA was excluded in 6 Treacher Collins and 2 control hemimandibles for absent centric occlusion. The Treacher Collins group consisted of 7 females and 11 males, ranging in age from 0.66 to 204 months (mean, 91.6 months). The control cohort included 13 females and 11 males, aged 0.26 to 204 months (mean, 111.5 months). The mean RBAs for the Treacher Collins and comparison groups were 150.28 and 114.2 degrees (P < 0.0001). The mean MPAs were 38.25 and 31.9 degrees for the Treacher Collins group and control subjects, respectively (P < 0.0001). In children younger than 3 years, the RBAs were 154.40 and 119.36 degrees, and for patients older than 12 years, the RBAs were 148.40 and 111.75 degrees for the Treacher Collins group and control subjects (both P < 0.0001). Comparing Treacher Collins younger than 3 years with those older than 12 years, the mean RBAs were not statistically different at 154.40 and 148.40 degrees (P = 0.1869). Among control subjects younger than 3 years compared with older than 12 years, the RBAs approached significance, but not statistically at 119.36 and 111.75 degrees (P = 0.0122). Notably, among control subjects, the MPA did statistically flatten with increasing age, showing 37.36 and 29.50 degrees (P = 0.0011). CONCLUSIONS: The clockwise relation of the mandibular body relative to the ramus is objectively documented in Treacher Collins subjects. This relation persists despite increasing age, in distinction to control subjects where the mandibular plane flattens in adolescence. PMID- 21239925 TI - Morphometric analysis of the Korean mandibular ramus for distraction osteogenesis using micro-computed tomography. AB - When performing distraction osteogenesis, the osteotomy is normally applied to the cortical bone posterior to the mandibular second molar. We measured the topographic thickness of the cortical and trabecular bone of the mandibular ramus and at the mandibular canal (MC) to provide crucial anatomic data aimed at minimizing complications and elucidating the most appropriate site for placing the distractor. Forty sides of the mandibles were prepared from 20 Korean cadavers (10 men and 10 women with a mean age of 68 years). The specimens were scanned and reconstructed into three-dimensional images using a micro-computed tomography system. Coronal and horizontal sectional images of the mandibular ramus were taken at thickness intervals of 2 mm from the reconstructed three dimensional images. Image analysis software was used to measure the thicknesses of the cortical and trabecular bone and to identify the locations of the MC within the body and the mandibular ramus on each section. The mean thicknesses of the buccal cortical plate, trabecular bone, and lingual cortical plate were 2.9 mm (men, 3.0 mm; women, 2.8 mm), 9.1 mm (men, 9.8 mm; women, 8.5 mm), and 2.2 mm (men, 2.3 mm; women, 2.1 mm), respectively. The distance from the buccal surface of the mandible to the MC increased from 5.3 to 10.0 mm (men, 5.3-10.0 mm; women, 5.3-9.1 mm) when moving progressively anterosuperior from the mandibular angle region. Morphometric analyses of the mandibular ramus can provide crucial data when performing mandibular osteotomy and locating an appropriate placement site for a distractor device during the distraction-osteogenesis procedure. PMID- 21239926 TI - Autologous cranial particulate bone graft: an experimental study of onlay cranioplasty. AB - The purpose of this study was to determine whether particulate bone graft maintains its volume when used for onlay cranioplasty. Twenty-five adult, male, New Zealand white rabbits were divided into 5 groups (n = 5/group). Groups 1 to 3 were controls: group 1, untreated; group 2, sham procedure; and group 3, burring the cortical surface. Group s 4 and 5 had augmentation of the parietal bones with particulate graft harvested from the frontal bone with a brace and bit. The particulate graft was placed on native parietal bone (group 4) or on parietal bone that had been abraded to punctuate bleeding with an electric burr (group 5). Volume maintenance and osseointegration of the grafts were determined by micro computed tomography and histology. At 16 weeks postoperatively, the mean (SD) volumes of the parietal bones in control groups 1, 2, and 3 were 555.8 (29.2), 550.8 (36.8), and 539.0 (39.0) mm, respectively. Immediately after cranioplasty, the mean (SD) volumes of augmented parietal bone were 846.0 (10.8) mm for group 4 and 831.8 (11.8) mm for group 5. Sixteen weeks postoperatively, 100% of the group 4 grafts had resorbed (551.8 [SD, 24.0] mm), and parietal volume was no different from controls (P = 0.89). Group 5 maintained 54.2% of volume (695.6 [SD, 22.0] mm), which was greater than those of the controls (P < 0.0001). Particulate graft may be used for onlay cranioplasty if the recipient site is burred. Approximately one half of the onlay graft is resorbed, and its original shape is not maintained. PMID- 21239927 TI - Expression of transforming growth factor-beta-responsive smads in cranial suture development and closure. AB - The transforming growth factor-beta (TGF-beta) family of extracellular signaling molecules is heavily involved in developmental events, including patterning, formation, maintenance, and closure of the cranial suture. Several studies have demonstrated that TGF-betas are temporally and spatially localized to the suture and play a pivotal role in sutural state. These signals are translated into intracellular activity through a family of proteins known as smads. There are 8 known smads, with smads 1, 5, and 8 transducing BMP signals and smads 2 and 3 transducing TGF-beta signals. Dimerization of any of these smads and smad 4 is necessary for phosphorylation and activation. Although many studies have delineated the presence of TGF-beta during suture closure, no studies have determined smad activity. It was hypothesized that smad activity would change during sutural closure. Reverse transcription-polymerase chain reaction was used to determine whether TGF-beta-responsive smads were present in the suture at which point they were immunohistochemically localized. A rat model was used in which the posterior intrafrontal suture fused during neonatal days 16 to 22. Time points before and after this event were analyzed for changes in smad expression and function. It was determined from these experiments that (1) the TGF-beta responsive smads 2, 3, and 4 are all present in the suture; (2) smads 2 and 4 are distributed in the region of the osteogenic front of the suture; and (3) smad 2/4 activity decreases in areas in which presumptive bone will form. These results add to the knowledge present about sutural development and may provide news targets to which therapeutics can be developed. PMID- 21239928 TI - Influence of mixing blood with calcium phosphate bone paste on hardening. AB - Calcium phosphate bone paste (CPP) has been recently introduced as a reconstructive material in craniofacial surgery. However, we observed that mixing of blood and CPP tended to interfere with CPP hardening. In addition, CPP mixed with blood tended to be absorbed postoperatively. Hence, we used a rabbit model and applied CPP mixed with blood over defects in the skull to investigate the influence of blood on CPP. Calcium phosphate bone paste was mixed with blood for 1 minute and applied to the defects in the calvarial bone of rabbits. At 4 and 24 postoperative weeks, we histologically evaluated morphologic changes in the hydroxyapatite (HA). Our study revealed that HA was not absorbed when a small quantity of blood (15%) was mixed with CPP. However, HA was absorbed almost entirely when a large quantity of blood (30%) was mixed with CPP. In addition, we found that the porosity of HA was increased by the mixture of a small quantity of blood into CPP, and this addition stimulated osteogenesis in HA. PMID- 21239929 TI - Long-term treatment outcome of presurgical nasoalveolar molding in patients with unilateral cleft lip and palate. AB - PURPOSE: The purpose of this study was to evaluate the long-term effectiveness of presurgical nasoalveolar molding (PNAM) in patients with unilateral cleft lip and palate (UCLP). METHODS: Twenty-five patients with UCLP treated by either PNAM or non-PNAM therapy between 1998 and 2003 were recruited in the study. During the clinical examination and data analysis, the evaluators were blinded to which patients received PNAM. The patients were reviewed clinically, and their facial morphology was captured with a three-dimensional scanner. Their dental arch configuration and occlusion were recorded by plaster dental models. After the patient evaluations and measurements were completed, the patient list was unblinded. There were 20 patients in the PNAM group and 5 patients in the non PNAM group. Fisher exact tests and Wilcoxon rank sum tests were used to compare the outcomes. RESULTS: Clinically, the improvement in the PNAM group was most evident in nasal and lip anatomy. However, there were no statistically significant differences between the 2 groups on each of the measurements on three dimensional facial images and dental models. CONCLUSIONS: Our study suggests a trend toward a long-term clinical improvement in nasal and lip anatomy of UCLP patients treated with PNAM. However, these improved results were not confirmed by three-dimensional stereophotography. There was no statistically significant difference in the long-term three-dimensional anthropometric measurements and dental model analysis between the PNAM group and the non-PNAM group. PMID- 21239930 TI - Kimura disease in the parotid gland. AB - Kimura disease (KD) is a rare entity that occurs primarily in Asian people characterized histopathologically by a lymph-folliculoid granuloma with infiltration of the mass and the surrounding tissues by eosinophils, often with concomitant peripheral blood eosinophilia and elevated serum immunoglobulin E, generally seen in the head and neck region, especially preauricular area. In this article, we present the case of a 14-year-old male patient with KD on his left parotid area. The clinical, radiologic, surgical, and pathologic findings of KD are discussed in this article. PMID- 21239931 TI - Correction of large facial encephalocele with bilateral rare craniofacial clefts. AB - Treatment of Tessier number 3, 11 craniofacial clefts represent a surgical challenge with complex bone and soft tissue deficits of the lip, cheek, medial orbit, and forehead. The severity of the presenting defect will ultimately determine the number of reconstructive stages required as well as the timing of each stage. Initial surgery in infancy is aimed at functional correction. We present the case of a patient with an expanding fronto-orbital encephalocele, a right number 3, 11 cleft and a left number 3, 10 cleft. The initial procedure repaired the encephalocele and reconstructed the supraorbital and forehead regions. Subsequent surgeries corrected the bilateral facial clefts with cleft lip repair, rotation of the forehead and nasal unit, cheek advancement, and a lower eyelid transposition flap. PMID- 21239932 TI - Advanced and prospective technologies for potential use in craniofacial tissues regeneration by stem cells and growth factors. AB - The processes of craniofacial tissues development and regeneration are largely dependent on sequential and reciprocal interactions between mesenchymal and epithelial components. These processes involve a series of inductive and permissive interactions that result in the determination, differentiation, and organization of craniofacial tissues. Stem cells and growth factors represent a very interesting research field for craniofacial tissues regeneration. They represent a potential key component in autologous graft for craniofacial tissues regeneration. An ideal goal of oral-craniofacial dental reconstructive therapy is to establish treatment modalities that predictably restore functional tissues. One major area of focus has been that of dental materials with marked improvements in the design of materials used to restore teeth/periodontium/bone lost as a consequence of disease or disorders. Interest in these technologies continues to increase in dental application as a substitute for traditional treatments and artificial components. Recent progress in the studies of molecular basis of tooth development, adult stem cell biology, and regeneration will provide fundamental knowledge for the realization of human craniofacial tissues regeneration in the near future. PMID- 21239933 TI - Synchronous squamous cell carcinoma and chronic lymphocytic leukemia of the palate. AB - Although multiple synchronous malignancies of the same histological type have been described frequently in the upper aerodigestive tract, this is a less frequent phenomenon when dealing with tumors of different lineage. We present a case of a man who developed simultaneously an oral squamous cell carcinoma and chronic lymphocytic lymphoma of the palate without any previous risk factors. To the best of our knowledge, this is the first case well documented in the literature of synchronous oral squamous cell carcinoma and chronic lymphocytic lymphoma of the palate in the same sample. The presence of multiple primary malignancies of different histological types not only complicates the treatment but also worsens the prognosis of the patient. PMID- 21239934 TI - Upper airway volume after Le Fort III advancement in subjects with craniofacial malformation. AB - AIM: There are no quantitative standards for the volumetric measurements of the airway space after Le Fort III advancement. Computed tomographic (CT) scans have provided the opportunity to compare with the accuracy of real anatomic changes, thus the functional improvements, resulting after a surgical treatment. MATERIALS AND METHODS: Three-dimensional CT scans processed by Digital Imaging and Communications in Medicine files in Dolphin 3D software were used to assess the airway space volume in 4 subjects affected by craniofacial syndromic malformations treated with Le Fort III advancement. The preoperative (T0) and postoperative (T1: 6 mo after surgery) three-dimensional craniofacial CT scans of the subjects were collected and retrospectively analyzed. Image segmentation of the anatomic structures of interest and the three-dimensional graphic rendering were done by using the Dolphin Imaging Plus 11.0 software. RESULTS: The airway space volume was significantly increased after surgery (mean [SD]: from 9166.57 [1861.48] mm to 15,300.45 [5114.09] mm; P < 0.01). The sagittal surfaces had an expansion from 798.92 (74.88) to 1151.45 (218.47) mm. The coronal surfaces grew from 226.75 (62.85) to 390.42 (102.21) mm, and axial surfaces increased 473.32 (62.34) to 676.00 (151.07) mm from T0 to T1. CONCLUSIONS: In conclusion, this study showed an increase in the upper airway space volume in white subjects after Le Fort III advancement. PMID- 21239935 TI - Divided parietal bone in plagiocephaly. AB - Supernumerary cranial sutures represent a rare cause of plagiocephaly. In the case of an extra suture dividing the parietal bone, the presenting features are often inconsistent with the typical presentation of deformational or synostotic plagiocephaly. Disagreement exists as to how the presence of this suture affects the shape of the skull. We present a case of a supernumerary suture in the parietal bone leading to plagiocephaly and discuss the role this suture plays in cranial growth. PMID- 21239936 TI - A peculiar orbital roof blow-in fracture. AB - An orbital blow-in fracture is defined as a displaced fracture of the orbital rim or wall when the fractured bone fragment is pulled into the orbit, resulting in a decreased orbital volume. Orbital blow-in fractures is generally localized at the orbital roof. Surgical treatment is required and should be early to avoid any damage to the visual. We report a peculiar case of indirect blow-in orbital roof fracture associated with fracture of the parietal bone. PMID- 21239938 TI - Simultaneous reconstruction of medial canthal area and both eyelids with a single transverse split forehead island flap. AB - In this report, we are presenting a case in which we have split the paramedian forehead flap, thus providing 2 axially perfused skin flaps for simultaneous reconstruction of the upper and lower lid structures after resection of basal cell carcinoma from the left medial canthal area. We found that split forehead flap seems to be a favorable option for simultaneous reconstruction of the upper and lower eyelid defects by enabling nicely vascularized and abundant amount of regional skin. PMID- 21239937 TI - Congenital cystic eye: from prenatal diagnosis to therapeutic management and surgical treatment. AB - Only 28 cases of congenital cystic eye have been reported in the literature. The main issue in such cases is differential diagnosis between this malformation and different cystic malformations and masses of the orbital cavity and eyeball, the most common of which is microphthalmia with cyst. Both malformations arise from incomplete closure of the fetal optic vesicle in different stages of embryonic development. We present a case of congenital cystic eye, associated with coloboma and corneal dermoid of the fellow eye and with left brachiocephaly, discussing differential diagnosis with microphthalmia with cyst and illustrating the treatment we planned and performed. The patient first underwent a surgical excision of the left corneal dermoid, then a resection of the right orbital cyst. The last step was to perform a craniotomy and cranial vault remodeling. All the operations were planned and performed using a team approach. The team comprised an ophthalmologist, a plastic surgeon, and a neurosurgeon, and the result was a successful outcome. PMID- 21239939 TI - Assessment of the functionality of the pectoralis major myocutaneous flap skin paddle. AB - INTRODUCTION: The pectoralis major myocutaneous flap (PMMF) is commonly used for oral cavity reconstruction, yet its impact on function (intelligible speech, swallowing, mastication, tongue mobility, oral competence, and mouth opening) has rarely been studied or reported in the literature. PURPOSE: This study assessed the long-term functional outcome of oral cavity reconstruction with PMMF, placing particular emphasis in its correlation with size of the skin paddle and volume of the flap. MATERIALS AND METHODS: Twenty-five patients who underwent reconstruction of compound defects of the oral cavity that involved floor of mouth, buccal mucosa, alveolar ridge, retromolar area, lateral tongue, and continuity of mandible were assessed and followed up for up to 4 years. Assessment of function was based on predetermined clinical parameters along with consecutive measurements of skin paddle size. RESULTS: At 6 months, the size of the skin paddles averaged a 37% decrease in size, along with a marked reduction in the mass effect from the flap. Tongue mobility was considered good in all patients. Speech was considered intelligible in 84% of patients, of which 16% required some concentration to understand. Initial complaints of difficulty swallowing resolved in every patient and mouth opening in all patients returned to their preoperative state. These findings were maintained consistently throughout the follow-up period. Flap complications, consisting of partial skin paddle necrosis, occurred in 4 patients (16%), but healed after local debridement. Intraoral hair in the skin paddle was present in 5 men who did not receive postoperative radiotherapy. CONCLUSIONS: Reconstruction of the oral cavity (including defects with partial involvement of the tongue and continuity of mandible) can be predictably accomplished using PMMF. These procedures are associated mostly with minor and temporary disruption of function and quality of life and few complications. PMID- 21239940 TI - Spontaneous nonpulsatile aneurysm of the superficial temporal artery mimicking a subcutaneous mass lesion. AB - True superficial temporal artery (STA) aneurysms are extremely rare and usually atherosclerotic in origin. Here the authors report a 62-year-old man with a nonpulsatile mass lesion at the trace of the right STA that was surgically excised with a preoperative diagnosis of subcutaneous mass lesion, preoperatively and histopathologically found out to be a thrombosed true STA aneurysm. Preoperative evaluation, differential diagnosis, and management of such lesions are discussed. PMID- 21239945 TI - Face, brain, and veins: a new perspective for multiple sclerosis onset. PMID- 21239946 TI - The new gold standard in infusion nursing. PMID- 21239947 TI - The Patient Protection and Affordable Care Act: the opportunities for nurses: Craven & Ober Policy Strategists, LLC. PMID- 21239948 TI - Recent efforts and available technologies for safety in delivery of blood products. AB - Over the past few decades, many efforts to improve the safety of blood products have concentrated on the reduction of transfusion-associated infectious diseases, particularly human immunodeficiency virus and hepatitis C. As health care enters a time of significant economic changes and governmental agencies develop guidances to improve patient safety, new efforts are being implemented and new technologies are being developed to ensure safe delivery of blood products. This article outlines the structure of agencies responsible for blood safety in the United States, reviews the fairly recent implementation of a blood product bar code labeling system (ISBT 128) in the United States, describes safety efforts at the level of the hospital transfusion service, and reviews some of the emerging technologies for safety in blood delivery at the bedside. PMID- 21239950 TI - Pediatric central line: bundle implementation and outcomes. AB - Central vascular catheters are an integral part of caring for a pediatric intensive care patient, providing hemodynamic monitoring capabilities, reliable vascular access for hydration, medication administration, and blood sampling. However, central vascular catheters put the patient at risk for central line associated bloodstream infections (CLABSIs). In 2010, the Centers for Medicare & Medicaid Services added CLABSI to the list of "never events." This article discusses the measures one hospital implemented to reduce the CLABSI rate, and the research that supports this evidence-based practice. PMID- 21239949 TI - Recombinant infusion therapies indicated for bleeding disorders. AB - Hemophilia is a genetic condition that causes prolonged bleeding in those affected after surgeries, dental procedures, and injuries. It has been treated with a variety of products in the modern era, with some of the treatments causing serious viral infections. The development of recombinant-factor products has led to longer life expectancy and better quality of life for those affected. The objectives of this article are to review the epidemiology and pathophysiology of hemophilia A and B and von Willebrand's disease and to outline the development of treatment products, along with the advantages and disadvantages of each product. Research on newer products is progressing at a rapid pace. The article will also discuss some of the newer products currently in development. PMID- 21239951 TI - Reducing blood-culture contamination through an education program. AB - A blood culture is the cornerstone of an established etiological diagnosis of septicemia. Although it is not currently possible to eliminate blood-culture contamination, many interventions have been shown to reduce contamination rates. Retrospective data analysis through an initial audit with major departments at one hospital, including the intensive care unit and emergency department, showed that the blood-culture contamination rate was 4.8%, which is more than the set standard (ie, less than 3%). A decrease in blood-culture contamination rates from the initial 4.8% to less than 3% was obtained with a supervised training and evaluation program through collaborative efforts of the nursing and laboratory departments. PMID- 21239952 TI - The effects of virtual intravenous and patient simulator training compared to the traditional approach of teaching nurses: a research project on peripheral i.v. catheter insertion. AB - Teaching intravenous (i.v.) catheter insertion where nurses "see one, do one, and teach one" is standard protocol, yet it allows little opportunity for practice. This study assesses the effectiveness of using mannequins and simulators to train nurses. Participants were randomly assigned to an experimental or a control group for training, and afterward they completed an i.v. insertion survey for each peripheral i.v. they performed. There was a significant relationship between the number of i.v. insertion attempts and the type of training, Chi (1, N = 41) = 4.19, P = .041, phi = 0.32, and a significant difference in the number of i.v. insertion attempts between the 2 groups, U = 143, P = .043. PMID- 21239953 TI - Making clinical decision support more supportive. PMID- 21239955 TI - What's new in Shock, February 2011? PMID- 21239954 TI - The contribution of geography to black/white differences in the use of low neonatal mortality hospitals in New York City. AB - BACKGROUND: Racial differences in the use of high-quality hospital care contribute to racial disparities in mortality for very low birth weight (VLBW) neonates. OBJECTIVES: We explored the role that geographic distribution of hospitals plays in the racial disparity in the use of top-tier hospitals by mothers of VLBW neonates in New York City. RESEARCH DESIGN: Retrospective analysis of Vital Statistics and administrative databases. SUBJECTS: VLBW deliveries in New York City from 1996 to 2001 to non-Hispanic Black (n = 4947) and non-Hispanic White (n = 1615) mothers. RESULTS: Black mothers were less likely to deliver in a top-tier hospitals (White = 44%, Black = 28%; P < 0.001) and top-tier hospitals were less likely to be located in Black mothers' neighborhoods (White = 40%, Black = 33%; P < 0.001). Distance, however, did not contribute to the disparity in use of top-tier hospitals. Non-Hispanic Black mothers lived marginally closer to a top-tier hospital than non-Hispanic White mothers (0.65 miles closer; P < 0.001), and mothers of both the races often bypassed their neighborhood hospital (Black = 62% bypassed, White = 71%; P < 0.001). Inattention to recommended prenatal behaviors was associated with using a closer hospital, suggesting that geographic proximity was most important to mothers of vulnerable neonates. Purported measures of hospital quality such as Neonatal Intensive Care Unit level and volume were more strongly associated with use of hospital for White mothers than for Black mothers. CONCLUSIONS: The influence of geography on the use of top-tier hospitals for mothers of VLBW neonates is complex. Other personal and hospital characteristics, not just distance or geography, also influenced hospital use in New York City. PMID- 21239956 TI - Cidofovir may be deleterious in BK virus-associated nephropathy. PMID- 21239958 TI - Pancreas transplantation after combined heart-kidney transplantation. PMID- 21239959 TI - Mycosis as a cause of secondary sclerosing cholangitis requiring liver retransplantation. PMID- 21239960 TI - Single-site laparoscopic living donor nephrectomy offers comparable perioperative outcomes to conventional laparoscopic living donor nephrectomy at a higher cost. PMID- 21239961 TI - Syngeneic islet transplantations into the submandibular gland of mice. PMID- 21239962 TI - Allospecific regulatory effects of sirolimus and tacrolimus in the human mixed lymphocyte reaction. AB - BACKGROUND: Tacrolimus (TAC) and sirolimus (SRL), two commonly used immunosuppressive agents, have demonstrated contrasting immunoregulatory effects. We recently described factors affecting the generation of allospecific CD4CD25 forkhead/winged helix transcription factor P3 (FOXP3) T-regulatory (Treg) cells in mixed lymphocyte reaction (Treg MLR) and now report additional findings on the effects of TAC and SRL. METHODS: TAC, SRL, or media without agents were added separately to MLRs using human leukocyte antigen two DR-matched and -mismatched healthy volunteers and prekidney transplant donor/recipient pairs. Concentrations correlated with subtherapeutic and therapeutic blood levels. Stimulation indices of H-TDR uptake, cell proliferation, and the generation of carboxy-fluorescein diacetate succinimidyl ester (CFSE) labeled CD4CD25FOXP3 cells by flow cytometry were initially compared. Each group of (non-CFSE labeled) MLR-generated cells were then added as third components to CFSE-labeled responding cells in freshly prepared primary MLRs, to determine allospecific and nonspecific inhibitory and Treg recruitment effects. RESULTS: TAC inhibited stimulation indices and CD4CD25 FOXP3 cell generation in both human leukocyte antigen DR-matched and -mismatched pairs, particularly at therapeutic levels (>=5 ng/mL). SRL had an equivalent effect in matched pairs but was associated with a significantly higher %generation of CD4CD25FOXP3 cells than TAC. SRL-MLR-generated Tregs added as third components allospecifically inhibited MLR proliferation and recruited additional CFSE-labeled autologous Tregs compared with addition of TAC- or media MLR-generated Tregs. CONCLUSIONS: Calcineurin and mammalian target of rapamycin inhibitors have disparate effects on allospecific Treg generation using the Treg MLR. This assay can thereby be helpful in assessing allospecific regulatory effects of diverse immunosuppressive agents. PMID- 21239964 TI - Don'T stop believing: be sure to read page 2. PMID- 21239963 TI - Supplemental vitamin D and calcium in the management of African Americans with heart failure having hypovitaminosis D. AB - INTRODUCTION: A dyshomeostasis of macro- and micronutrients, including vitamin D and oxidative stress, are common pathophysiologic features in patients with congestive heart failure (CHF). In African Americans (AA) with CHF, reductions in plasma 25(OH)D are of moderate-to-marked severity (<20 ng/mL) and may be accompanied by ionized hypocalcemia with compensatory increases in serum parathyroid hormone (PTH). The management of hypovitaminosis D in AA with CHF has not been established. METHODS: Herein, a 14-week regimen: an initial 8 weeks of oral ergocalciferol (50,000 IU once weekly); followed by a 6-week maintenance phase of cholecalciferol (1400 IU daily); and a CaCO3 (1000 mg daily) supplement given throughout was designed and tested. Fourteen AA patients having a dilated (idiopathic) cardiomyopathy with reduced ejection fraction (EF, <35%) were enrolled: all completed the initial 8-week course; and 12 complied with the full 14 weeks. At baseline, 8 and/or 14 weeks, serum 25(OH)D and PTH; serum 8 isoprostane, a biomarker of lipid peroxidation, and echocardiographic EF were monitored. RESULTS: Reduced 25(OH)D at entry (14.4 +/- 1.3 ng/mL) was improved (P < 0.05) in all patients at 8 weeks (30.7 +/- 3.2 ng/mL) and sustained (P < 0.05) at 14 weeks (30.9 +/- 2.8 ng/mL). Serum PTH, abnormally increased in 5 patients at baseline (104.8 +/- 8.2 pg/mL), was reduced at 8 and 14 weeks (74.4 +/- 18.3 and 73.8 +/- 13.0 pg/mL, respectively). Plasma 8-isoprostane at entry (136.1 +/- 8.8 pg/mL) was reduced at 14 weeks (117.8 +/- 7.8 pg/mL; P < 0.05), whereas baseline EF (24.3 +/- 1.7%) was improved (31.3 +/- 4.3%; P < 0.05). CONCLUSIONS: Thus, the 14-week course of supplemental vitamin D and CaCO3 led to healthy 25(OH)D levels in AA with heart failure having vitamin D deficiency of moderate to-marked severity. Albeit a small patient population, the findings suggest that this regimen may attenuate the accompanying secondary hyperparathyroidism and oxidative stress and improve ventricular function. PMID- 21239965 TI - Neuroprotective effect of orexin-A is mediated by an increase of hypoxia inducible factor-1 activity in rat. AB - BACKGROUND: Recent studies suggest that the novel neuropeptide orexin-A may play an essential role during neuronal damage. However, the function of orexin-A during brain ischemia remains unclear. Recently, hypoxia-inducible factor-1alpha (HIF-1alpha) was shown to be activated by orexin-A. The aim of the current study is to test the hypothesis that administration of exogenous orexin-A can attenuate ischemia-reperfusion injury through the facilitation of HIF-1alpha expression. METHODS: Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion for 120 min. Rats were treated with different doses of orexin-A or vehicle before the ischemia and at the onset of reperfusion. To investigate the action of HIF-1alpha in the neuroprotective effects of orexin-A, the HIF-1alpha inhibitor YC-1 was used alone or combined with orexin-A. Neurologic deficit scores and infarct volume were assessed. Brains were harvested for immunohistochemical staining and western blot analysis. RESULTS: Orexin-A significantly ameliorated neurologic deficit scores and reduced infarct volume after cerebral ischemia reperfusion. Administration of 30 MUg/kg orexin-A showed optimal neuroprotective effects. This effect was still present 7 days after reperfusion. Furthermore, orexin-A decreased the number of apoptotic cells and significantly enhanced HIF-1alpha expression after cerebral ischemia reperfusion. Moreover, the facilitation of HIF-1alpha expression was accompanied with inhibition of von Hippel-Lindau expression. Administration of HIF-1alpha inhibitor suppressed the increase of HIF-1alpha and reversed the neuroprotective effects of orexin-A. CONCLUSIONS: Orexin-A has a neuroprotective effect against cerebral ischemia-reperfusion injury. These effects may be mediated through the HIF-1alpha pathway. PMID- 21239966 TI - Midazolam impairs immune functions: it's time to take care of dendritic cells. PMID- 21239967 TI - Targeting Hypoxia-induced Inflammation. PMID- 21239968 TI - Efficacy, safety, and pharmacokinetics of sugammadex for the reversal of rocuronium-induced neuromuscular blockade in elderly patients. AB - BACKGROUND: The management of elderly patients can be challenging for anesthesiologists for many reasons, including altered pharmacokinetics and dynamics. This study compared the efficacy, safety, and pharmacokinetics of sugammadex for moderate rocuronium-induced neuromuscular blockade reversal in adult (aged 18-64 yr) versus elderly adult (aged 65 yr or older) patients. METHODS: This phase 3a, multicenter, parallel-group, comparative, open-label study enrolled 162 patients aged 18 yr and older, American Society of Anesthesiologists class 1-3, scheduled for surgery with general anesthesia and requiring neuromuscular blockade. After anesthesia induction, patients received rocuronium, 0.6 mg/kg, before tracheal intubation, with maintenance doses of 0.15 mg/kg as required. At the end of surgery, patients received sugammadex, 2.0 mg/kg, at reappearance of the second twitch of the train-of-four (TOF) for reversal. The primary efficacy variable was time from sugammadex administration to recovery of the TOF ratio to 0.9 or greater. Pharmacokinetics and safety were also evaluated. RESULTS: Overall, 150 patients were treated and had at least one postbaseline efficacy assessment; 48 were aged 18-64 yr (adult), 62 were aged 65 74 yr (elderly), and 40 were aged 75 yr or older (old-elderly). The geometric mean time (95% confidence interval) from sugammadex administration to recovery of the TOF ratio to 0.9 increased with age, from 2.3 (2.0-2.6) min (adults) to 2.9 (2.7-3.2) min (elderly/old-elderly groups combined). Recovery of the TOF ratio to 0.9 was estimated to be 0.7 min faster in adults compared with patients aged 65 yr or older (P = 0.022). Sugammadex was well tolerated by all patients. CONCLUSION: Sugammadex facilitates rapid reversal from moderate rocuronium induced neuromuscular blockade in adults of all ages. PMID- 21239969 TI - Lipid emulsion reverses Levobupivacaine-induced responses in isolated rat aortic vessels. AB - BACKGROUND: The goal of this in vitro study was to investigate the effects of lipid emulsion (LE) on local anesthetic levobupivacaine-induced responses in isolated rat aorta and to determine whether the effect of LE is related to the lipid solubility of local anesthetics. METHODS: Isolated rat aortic rings were suspended for isometric tension recording. The effects of LE were determined during levobupivacaine-, ropivacaine-, and mepivacaine-induced responses. Endothelial nitric oxide synthase and caveolin-1 phosphorylation was measured in human umbilical vein endothelial cells treated with levobupivacaine alone and with the addition of LE. RESULTS: Levobupivacaine produced vasoconstriction at lower, and vasodilation at higher, concentrations, and both were significantly reversed by treatment with LE. Levobupivacaine and ropivacaine inhibited the high potassium chloride-mediated contraction, which was restored by LE. The magnitude of LE-mediated reversal was greater with levobupivacaine treatment than with ropivacaine, whereas this reversal was not observed in mepivacaine-induced responses. In LE-pretreated rings, low-dose levobupivacaine- and ropivacaine induced contraction was attenuated, whereas low-dose mepivacaine-induced contraction was not significantly altered. Treatment with LE also inhibited the phosphorylation of endothelial nitric oxide synthase induced by levobupivacaine in human umbilical vein endothelial cells. CONCLUSIONS: These results indicate that reversal of levobupivacaine-induced vasodilation by LE is mediated mainly through the attenuation of levobupivacaine-mediated inhibition of L-type calcium channel-dependent contraction and, in part, by inhibition of levobupivacaine induced nitric oxide release. LE-mediated reversal of responses induced by local anesthetics may be related to their lipid solubility. PMID- 21239970 TI - More on transfusion and adverse outcome: it's time to change. PMID- 21239971 TI - Association between intraoperative blood transfusion and mortality and morbidity in patients undergoing noncardiac surgery. AB - BACKGROUND: The impact of intraoperative erythrocyte transfusion on outcomes of anemic patients undergoing noncardiac surgery has not been well characterized. The objective of this study was to examine the association between blood transfusion and mortality and morbidity in patients with severe anemia (hematocrit less than 30%) who are exposed to one or two units of erythrocytes intraoperatively. METHODS: This was a retrospective analysis of the association of blood transfusion and 30-day mortality and 30-day morbidity in 10,100 patients undergoing general, vascular, or orthopedic surgery. We estimated separate multivariate logistic regression models for 30-day mortality and for 30-day complications. RESULTS: Intraoperative blood transfusion was associated with an increased risk of death (odds ratio [OR], 1.29; 95% CI, 1.03-1.62). Patients receiving an intraoperative transfusion were more likely to have pulmonary, septic, wound, or thromboembolic complications, compared with patients not receiving an intraoperative transfusion. Compared with patients who were not transfused, patients receiving one or two units of erythrocytes were more likely to have pulmonary complications (OR, 1.76; 95% CI, 1.48-2.09), sepsis (OR, 1.43; 95% CI, 1.21-1.68), thromboembolic complications (OR, 1.77; 95% CI, 1.32-2.38), and wound complications (OR, 1.87; 95% CI, 1.47-2.37). CONCLUSIONS: Intraoperative blood transfusion is associated with a higher risk of mortality and morbidity in surgical patients with severe anemia. It is unknown whether this association is due to the adverse effects of blood transfusion or is, instead, the result of increased blood loss in the patients receiving blood. PMID- 21239972 TI - State-specific effects of sevoflurane anesthesia on sleep homeostasis: selective recovery of slow wave but not rapid eye movement sleep. AB - BACKGROUND: Prolonged propofol administration does not result in signs of sleep deprivation, and propofol anesthesia appears to satisfy the homeostatic need for both rapid eye movement (REM) and non-REM (NREM) sleep. In the current study, the effects of sevoflurane on recovery from total sleep deprivation were investigated. METHODS: Ten male rats were instrumented for electrophysiologic recordings under three conditions: (1) 36-h ad libitum sleep; (2) 12-h sleep deprivation followed by 24-h ad libitum sleep; and (3) 12-h sleep deprivation, followed by 6-h sevoflurane exposure, followed by 18-h ad libitum sleep. The percentage of waking, NREM sleep, and REM sleep, as well as NREM sleep delta power, were calculated and compared for all three conditions. RESULTS: Total sleep deprivation resulted in significantly increased NREM and REM sleep for 12-h postdeprivation. Sevoflurane exposure after deprivation eliminated the homeostatic increase in NREM sleep and produced a significant decrease in the NREM sleep delta power during the postanesthetic period, indicating a complete recovery from the effects of deprivation. However, sevoflurane did not affect the time course of REM sleep recovery, which required 12 h after deprivation and anesthetic exposure. CONCLUSION: Unlike propofol, sevoflurane anesthesia has differential effects on NREM and REM sleep homeostasis. These data confirm the previous hypothesis that inhalational agents do not satisfy the homeostatic need for REM sleep, and that the relationship between sleep and anesthesia is likely to be agent and state specific. PMID- 21239973 TI - Pain medicine: repairing a fractured dream. PMID- 21239974 TI - Perioperative nerve injury after total knee arthroplasty: regional anesthesia risk during a 20-year cohort study. AB - BACKGROUND: Perioperative nerve injury (PNI) is one of the most debilitating complications after total knee arthroplasty (TKA). Although regional anesthesia (RA) techniques reduce pain and improve functional outcomes after TKA, they may also contribute to PNI. The objective of this study was to test the hypothesis that PNI risk differs among patients according to RA use during TKA. METHODS: All patients aged at least 18 yr who underwent elective TKA from January 1988 to July 2007 were retrospectively identified. The primary outcome variable was the presence of a new PNI documented within 3 months of the procedural date. Age, sex, body mass index, type of procedure, tourniquet time, type of anesthesia, and use of peripheral nerve blockade were evaluated as potential risk factors for PNI using multivariable logistic regression. RESULTS: Ninety-seven cases of PNI were identified among 12,329 patients. Overall incidence of PNI was 0.79% (95% CI, 0.64-0.96%). PNI was not associated with peripheral nerve blockade (odds ratio [OR], 0.97) or type of anesthesia (OR, 1.10 [neuraxial vs. general]; OR, 1.82 [combined vs. general]). Risk for PNI decreased with age (OR, 0.68 [per decade]; P < 0.001) but increased with tourniquet time (OR, 1.28 [per 30-min increase]; P = 0.003) and bilateral procedures (OR, 2.51; P < 0.001). Patients with PNI who underwent peripheral nerve blockade were less likely to have complete neurologic recovery (OR, 0.37; P = 0.03). CONCLUSIONS: Risk for PNI after TKA was unchanged by the use of RA techniques. This finding supports the notion that the known benefits of RA for patients undergoing TKA can be achieved without increasing risk of neurologic injury. However, in rare situations when PNI occurs, complete recovery may be less likely if it develops after peripheral nerve blockade. PMID- 21239975 TI - Meta-analysis of thoracic epidural anesthesia versus general anesthesia for cardiac surgery. AB - BACKGROUND: A combination of general anesthesia (GA) with thoracic epidural anesthesia (TEA) may have a beneficial effect on clinical outcomes after cardiac surgery. We have performed a meta-analysis to compare mortality and cardiac, respiratory, and neurologic complications in patients undergoing cardiac surgery with GA alone or a combination of GA with TEA. METHODS: Randomized studies comparing outcomes in patients undergoing cardiac surgery with either GA alone or GA in combination with TEA were retrieved from PubMed, Science Citation index, EMBASE, CINHAL, and Central Cochrane Controlled Trial Register databases. RESULTS: The search strategy yielded 1,390 studies; 28 studies that included 2,731 patients met the selection criteria. Compared with GA alone, the combined risk ratio for patients receiving GA with TEA was 0.81 (95% CI: 0.40-1.64) for mortality, 0.80 (95% CI: 0.52-1.24) for myocardial infarction, and 0.59 (95% CI: 0.24-1.46) for stroke. The risk ratios for the respiratory complications and supraventricular arrhythmias were 0.53 (95% CI: 0.40-0.69) and 0.68 (95% CI: 0.50 0.93), respectively. CONCLUSIONS: This meta-analysis showed that the use of TEA in patients undergoing cardiac surgery reduces the risk of postoperative supraventricular arrhythmias and respiratory complications. The sparsity of events precludes conclusions about mortality, myocardial infarction, and stroke, but the estimates suggest a reduced risk after TEA. The risk of side effects of TEA, including epidural hematoma, could not be assessed with the current dataset, and therefore TEA should be used with caution until its benefit-harm profile is further elucidated. PMID- 21239976 TI - Thoracic epidural anesthesia for cardiac surgery: a randomized trial. AB - BACKGROUND: The addition of thoracic epidural anesthesia (TEA) to general anesthesia (GA) during cardiac surgery may have a beneficial effect on clinical outcomes. TEA in cardiac surgery, however, is controversial because the insertion of an epidural catheter in patients requiring full heparinization for cardiopulmonary bypass may lead to an epidural hematoma. The clinical effects of fast-track GA plus TEA were compared with those of with fast-track GA alone. METHODS: A randomized controlled trial was conducted in 654 elective cardiac surgical patients who were randomly assigned to combined GA and TEA versus GA alone. Follow-up was at 30 days and 1 yr after surgery. The primary endpoint was 30-day survival free from myocardial infarction, pulmonary complications, renal failure, and stroke. RESULTS: Thirty-day survival free from myocardial infarction, pulmonary complications, renal failure, and stroke was 85.2% in the TEA group and 89.7% in the GA group (P = 0.23). At 1 yr follow-up, survival free from myocardial infarction, pulmonary complications, renal failure, and stroke was 84.6% in the TEA group and 87.2% in the GA group (P = 0.42). Postoperative pain scores were low in both groups. CONCLUSIONS: This study was unable to demonstrate a clinically relevant benefit of TEA on the frequency of major complications after elective cardiac surgery, compared with fast-track cardiac anesthesia without epidural anesthesia. Given the potentially devastating complications of an epidural hematoma after insertion of an epidural catheter, it is questionable whether this procedure should be applied routinely in cardiac surgical patients who require full heparinization. PMID- 21239977 TI - Epidurals for cardiac surgery: can we substantially reduce surgical morbidity or should we focus on quality of recovery? PMID- 21239979 TI - A clinician's guide to patient selection for watchful waiting management of inguinal hernia. AB - OBJECTIVE: The goal of this study was to assist surgeons in managing patients with minimally symptomatic inguinal hernia by identifying characteristics that predict crossover to surgery or worsening of hernia symptoms. BACKGROUND: Randomized trials have suggested that watchful waiting management of minimally symptomatic inguinal hernia is an acceptable alternative to surgical repair. However, these trials found that roughly a quarter of patients would elect for repair in the first 2 years, suggesting that not all patients are good candidates for watchful waiting. METHODS: The 336 patients randomized to watchful waiting in the American College of Surgeons Watchful Waiting Hernia Trial constituted the study population. Preoperative patient characteristics were used to predict 2 outcomes, either crossover to surgery or the development of hernia pain limiting activities and/or crossover to surgery. Patients in our study were part of a previously registered randomized trial: NCT00263250. RESULTS: At 2 years, 72 patients crossed over to surgery, with pain with strenuous activities [odds ratio (OR), 1.3 per 10-mm visual analog scale pain scale], chronic constipation (OR, 4.9), prostatism (OR, 2.9), being married (OR, 2.3), and good health [OR, 3.0 American Society of Anesthesiologists Class (ASA) 1 vs 2], predicting crossover. An additional 28 patients developed pain, limiting their activities, with pain during strenuous activities (OR, 1.3 per 10-mm visual analog scale) and chronic constipation (OR, 4.5), predicting the combined outcome of pain limiting activities and/or crossover to surgery. Higher levels of activity reduced the risk (OR, 0.95) of this combined outcome. CONCLUSIONS: Readily identifiable patient characteristics can predict those patients with minimally symptomatic inguinal hernia who are likely to "fail" watchful waiting hernia management. Consideration of these factors will allow surgeons to optimally tailor hernia management. PMID- 21239980 TI - Accuracy of gadofosveset-enhanced MRI for nodal staging and restaging in rectal cancer. AB - OBJECTIVE: To prospectively assess the accuracy of gadofosveset-enhanced magnetic resonance imaging (MRI) for nodal staging and restaging in rectal cancer. BACKGROUND: Accurate preoperative assessment of nodal disease in rectal cancer impacts treatment management. Staging with modern imaging techniques (computed tomography, MRI and endorectal ultrasound) is insufficiently accurate for clinical decision making. This study aims to assess the accuracy of MRI using a novel lymph node magnetic resonance contrast, gadofosveset, for nodal staging and restaging in rectal cancer using a per node comparison with histology as the reference standard. METHODS: Sixty-eight patients underwent gadofosveset-enhanced MRI at 1.5T. Twenty-six patients (primary staging group I) were treated with total mesorectal excision (with or without preoperative 5 * 5 Gy) and 42 (restaging group II) underwent a long course of chemoradiation followed by a restaging MRI and resection. Nodes were scored as benign or malignant by 2 radiologists (experienced and junior reader) first on standard MRI, then on gadofosveset-enhanced MRI. For group I the primary staging MRI was compared with histology. In group II the second, restaging MRI was compared with histology. RESULTS: For the experienced reader, sensitivity, specificity, and area under the ROC-curve (AUC) improved from 76%, 82% and 0.84 on standard MRI to 80%, 97% and 0.96 on gadofosveset-MRI (P < 0.001). For the junior reader results improved from 69%, 85%, and 0.85 on standard MRI to 70%, 95%, and 0.93 on gadofosveset-MRI (P = 0.03). Interobserver agreement was good on both standard MRI (kappa 0.73) and gadofosveset-MRI (kappa 0.71). CONCLUSIONS: This study shows high reproducibility and significantly improved accuracy compared to standard MRI for gadofosveset enhanced MRI for nodal staging and restaging in rectal cancer. PMID- 21239983 TI - Computed tomographic angiography for blunt cerebrovascular injuries: don't throw out the baby with the bathwater. PMID- 21239984 TI - The hypertonic saline trial: a possible downside to the gold standard of double blinding. PMID- 21239987 TI - Hedgehog inhibition with cyclopamine represses tumor growth and prolongs survival in a transgenic mouse model of islet cell tumors. AB - BACKGROUND: Blockade of aberrant hedgehog (Hh) activation has recently been proposed as a therapeutic target, but effects in models of islet cell tumors have not been examined. In this study, we address the role of the Hh pathway in tumor progression of murine islet cell tumors. METHODS: To assess in vivo effects, Rip1Tag2 mice were treated with vehicle or cyclopamine (25 mg/kg/d) (n = 10 in each group). The effect of hedgehog pathway inhibition on survival was determined by continuous application of the small molecule smoothened antagonist cyclopamine. RESULTS: Hh-inhibition was confirmed by downregulation of Hh-target genes. Cyclopamine response was associated with increased apoptosis, decreased tumor cell proliferation and reduced tumor volume. Furthermore, hedgehog inhibition with cyclopamine significantly prolonged median survival in the used transgenic mouse model (102 vs 124 days; P = 0.02). CONCLUSIONS: Thus, Hh inhibitors may provide a new paradigm for therapy of islet cell tumors in various stages, particularly their use in conjunction with conventional antimetabolites should be further evaluated. PMID- 21239988 TI - Utility of a wireless, handheld monitoring system in the management of hemophilia patients. AB - Optimal management of hemophilia requires precise monitoring and thorough compliance with prescribed treatment. However, keeping track of these data using traditional paper log books is often challenging for young patients. We conducted a pilot study with 52 patients at three hemophilia treatment centers to determine whether the use of a wireless, handheld monitoring system would improve patients' record keeping and communication with their healthcare team. At the conclusion of the 3-month testing period, surveys completed by all participating patients and clinicians demonstrated that such a device can facilitate and enhance both patient self-management and communication between clinician and patient. PMID- 21239989 TI - Recurrence of perinatal lethal osteogenesis imperfecta in sibships: parsing the risk between parental mosaicism for dominant mutations and autosomal recessive inheritance. AB - PURPOSE: Recurrence of lethal osteogenesis imperfecta in families results from either dominant (parental mosaicism) or recessive inheritance. The proportion of these two mechanisms is not known, and determination of the contribution of each is important to structure genetic counseling for these families. METHODS: We measured the recurrence rate of lethal osteogenesis imperfecta after the birth of an affected infant. We determined the rate of parental mosaicism in a subset of families in which we had identified dominant mutations. In 37 families in which two or more affected infants were born, we identified mutations and determined the proportion that resulted from recessive inheritance. RESULTS: The recurrence rate after the first affected pregnancy was 1.3%. The rate of parental mosaicism in families in which a dominant mutation was identified in a first affected child was 16%. In 37 families with two affected infants, 26 had dominant mutations, seven had recessive mutations, and we failed to find mutations in four. The overall recurrence rate for couples after two or more affected infants was 32%; 27% for families with parental mosaicism, 31% for recessive mutations, and 50% for families with no identified mutation. CONCLUSIONS: In most populations, recurrence of lethal osteogenesis imperfecta usually results from parental mosaicism for dominant mutations, but the carrier frequency of recessive forms of osteogenesis imperfecta will alter that proportion. Mutation identification is an important tool to assess risk and facilitate prenatal or preimplantation diagnosis. PMID- 21239990 TI - Integrated analysis of unclassified variants in mismatch repair genes. AB - PURPOSE: Lynch syndrome is a genetic disease that predisposes to colorectal tumors, caused by mutation in mismatch repair genes. The use of genetic tests to identify mutation carriers does not always give perfectly clear results, as happens when an unclassified variant is found. This study aimed to define the pathogenic role of 35 variants present in MSH2, MLH1, MSH6, and PMS2 genes identified in our 15-year case study. METHODS: We collected clinical and molecular data of all carriers, and then we analyzed the variants pathogenic role with web tools and molecular analyses. Using a Bayesian approach, we derived a posterior probability of pathogenicity and classified each variant according to a standardized five-class system. RESULTS: The MSH2 p.Pro349Arg, p.Met688Arg, the MLH1 p.Gly67Arg, p.Thr82Ala, p.Lys618Ala, the MSH6 p.Ala1236Pro, and the PMS2 p.Arg20Gln were classified as pathogenic, and the MSH2 p.Cys697Arg and the PMS2 p.Ser46Ile were classified as likely pathogenic. Seven variants were likely nonpathogenic, 3 were nonpathogenic, and 16 remained uncertain. CONCLUSION: Quantitative assessment of several parameters and their integration in a multifactorial likelihood model is the method of choice for classifying the variants. As such classifications can be associated with surveillance and testing recommendations, the results and the method developed in our study can be useful for helping laboratory geneticists in evaluation of genetic tests and clinicians in the management of carriers. PMID- 21239991 TI - Implementation science for the US President's Emergency Plan for AIDS Relief (PEPFAR). PMID- 21239992 TI - Cancer in HIV-infected persons from the Caribbean, Central and South America. AB - BACKGROUND: HIV-infected individuals have heightened cancer risk. With the advent of highly active antiretroviral therapy (HAART), the frequency of some AIDS defining cancers (ADC) has decreased although certain non-AIDS-defining cancers (NADC) are becoming more frequent. Cancers among HIV-infected individuals in Latin American and the Caribbean have not yet been carefully studied. METHODS: Cancer cases among the Caribbean, Central and South American network for HIV Research (CCASAnet) cohort were identified reviewing clinical records and pre existing databases. RESULTS: There were 406 cancers reported: 331 ADC (224 Kaposi sarcomas and 98 non Hodgkin lymphomas). Most frequent NADC (n = 75) were Hodgkin lymphoma and skin cancers. Seventy-three percent of NADC and 45% of ADC were diagnosed >1 year after HIV diagnosis. Fifty-six percent of ADC occurred before HAART start. Median time from HAART start until cancer diagnosis was 2.5 years for NADC and 0.5 years for ADC (P = <0.001). Within 3372 HAART starters, 158 were diagnosed with 165 cancers (82.4% ADC); 85 cases were previous to or concomitant with HAART initiation. Incidence of cancer after HAART initiation in 8080 person years of follow-up was 7.2 per 1000 person-years (95% confidence interval = 5.5 to 9.3) for ADC and 2.7 (95% confidence interval = 1.8 to 4.1) for NADC; incidence was higher in the first 2 months, particularly for ADC (47.6). A pre HAART ADC was a predictor of mortality after adjusting for age, sex, and CD4 at HAART initiation. CONCLUSIONS: ADC were the most frequent cancers in this region and were often diagnosed close to HIV diagnosis and HAART start. Incidence of cancer was highest around HAART initiation. PMID- 21239993 TI - Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals: a systematic review and meta-analysis. AB - OBJECTIVE: To determine whether interferon-gamma release assays (IGRAs) improve the identification of HIV-infected individuals who could benefit from latent tuberculosis infection therapy. DESIGN: Systematic review and meta-analysis. METHODS: We searched multiple databases through May 2010 for studies evaluating the performance of the newest commercial IGRAs (QuantiFERON-TB Gold In-Tube [QFT GIT] and T-SPOT.TB [TSPOT]) in HIV-infected individuals. We assessed the quality of all studies included in the review, summarized results in prespecified subgroups using forest plots, and where appropriate, calculated pooled estimates using random effects models. RESULTS: The search identified 37 studies that included 5736 HIV-infected individuals. In three longitudinal studies, the risk of active tuberculosis was higher in HIV-infected individuals with positive versus negative IGRA results. However, the risk difference was not statistically significant in the two studies that reported IGRA results according to manufacturer-recommended criteria. In persons with active tuberculosis (a surrogate reference standard for latent tuberculosis infection), pooled sensitivity estimates were heterogeneous but higher for TSPOT (72%; 95% confidence interval [CI], 62-81%) than for QFT-GIT (61%; 95% CI, 47-75%) in low /middle-income countries. However, neither IGRA was consistently more sensitive than the tuberculin skin test in head-to-head comparisons. Although TSPOT appeared to be less affected by immunosuppression than QFT-GIT and the tuberculin skin test, overall, differences among the three tests were small or inconclusive. CONCLUSIONS: Current evidence suggests that IGRAs perform similarly to the tuberculin skin test at identifying HIV-infected individuals with latent tuberculosis infection. Given that both tests have modest predictive value and suboptimal sensitivity, the decision to use either test should be based on country guidelines and resource and logistic considerations. PMID- 21239994 TI - The impact of the AIDS Drug Assistance Program (ADAP) on use of highly active antiretroviral and antihypertensive therapy among HIV-infected women. AB - OBJECTIVES: To evaluate the association between enrollment into an AIDS Drug Assistance Program (ADAP) and use of highly active antiretroviral therapy (HAART) and antihypertensive therapy. METHODS: Cross-sectional analyses of data were performed on HAART-eligible women enrolled in the California (n = 439), Illinois (n = 168), and New York (n = 487) Women's Interagency HIV Study sites. A subset of HIV-infected women with hypertension (n = 395) was also analyzed. Unadjusted and adjusted backward stepwise elimination logistic regression measured the association between demographic, behavioral, and health service factors and nonuse of HAART or antihypertensive medication. RESULTS: In adjusted analysis of HAART nonuse, women without ADAP were significantly more likely not to use HAART (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.5-3.7) than women with ADAP. In adjusted analysis of antihypertensive medication nonuse, women without ADAP had an increased but not significant odds of antihypertensive medication nonuse (OR, 2.4; 95% CI, 0.93-6.0) than women with ADAP. CONCLUSIONS: Government funded programs for prescription drug coverage such as ADAP may play an important role in how HIV-positive women access and use essential medications for chronic diseases. PMID- 21239995 TI - Low lopinavir plasma or hair concentrations explain second-line protease inhibitor failures in a resource-limited setting. AB - BACKGROUND: In resource-limited settings, many patients, with no prior protease inhibitor (PI) treatment on a second-line, high genetic barrier, ritonavir boosted PI-containing regimen have virologic failure. METHODS: We conducted a cross-sectional survey to investigate the aetiology of virologic failure in 2 public health antiretroviral clinics in South Africa documenting the prevalence of virologic failure (HIV RNA load >500 copies/mL) and genotypic antiretroviral resistance; and lopinavir hair and plasma concentrations in a nested case-control study. RESULTS: Ninety-three patients treated with a second-line regimen including lopinavir boosted with ritonavir were included, of whom 50 (25 cases, with virologic failure and 25 controls) were included in a nested case control study. Of 93 patients, 37 (40%) had virological failure, only 2 of them had had major PI mutations. The negative predictive values: probability of failure with lopinavir plasma concentration >1 ug/mL or hair concentrations >3.63 ng/mg for virologic failure were 86% and 89%, and positive predictive values of low concentrations 73% and 79%, respectively, whereas all virologic failures with HIV RNA loads above 1000 copies per milliliter, of patients without PI resistance, could be explained by either having a low lopinavir concentration in plasma or hair. CONCLUSIONS: Most patients who fail a lopinavir/ritonavir regimen, in our setting, have poor lopinavir exposure. A threshold plasma lopinavir concentration (indicating recent lopinavir/ritonavir use) and/or hair concentration (indicating longer term lopinavir exposure) are valuable in determining the aetiology of virologic failure and identifying patients in need of adherence counselling or resistance testing. PMID- 21239997 TI - Changing pattern of lymphoma subgroups at a tertiary academic complex in a high prevalence HIV setting: a South African perspective. AB - BACKGROUND: HIV infection has been associated with an increased risk of non Hodgkin lymphoma, particularly in the first world. Despite the high burden of HIV infection in sub-Saharan regions, published data on HIV and malignancies are sparse from these areas. MATERIALS AND METHODS: We recently published data on lymphomas diagnosed from January 2004 to December 2006, at a single center in Johannesburg, to serve as a baseline for long-term comparison during the period of highly active antiretroviral therapy rollout. We report a retrospective analysis of the follow-up data collected from January 2007 to December 2009 at the Johannesburg academic hospital complex (Gauteng, South Africa). RESULTS: There were 2225 new diagnoses of lymphoproliferative disorders made during 2007 2009 as compared with 1897 cases diagnosed during 2004-2006. A significant increase in both high-grade B-cell lymphomas and Hodgkin lymphoma was documented during 2007-2009. This was associated with a statistically significant increase in HIV prevalence in those tested (from 44.3% in 2004-2006 to 62.0% in 2007 2009). HIV-positive patients presented at a statistically significantly younger median age and showed a relative overrepresentation of females when compared with HIV-negative patients. HIV-positive patients were diagnosed at later stages of HIV infection when compared with patients in the first world. CONCLUSIONS: The pattern of lymphoma subtypes and the demographics of the patients diagnosed have altered in association with significantly increased HIV prevalence. These changes have important public health implications. In particular, scale-up and earlier access to highly active antiretroviral therapy is essential with continued monitoring as access to therapy improves. PMID- 21239996 TI - Systemic and mucosal differences in HIV burden, immune, and therapeutic responses. AB - BACKGROUND: Mucosal tissues represent major targets for HIV transmission but differ in susceptibility and reservoir function by unknown mechanisms. METHODS: In a cross-sectional study, HIV RNA and infectious virus were compared between oral and genital compartments and blood in HIV-infected women, in association with clinical parameters, copathogens, and putative innate and adaptive HIV inhibitors. RESULTS: HIV RNA was detectable in 24.5% of women from all 3 compartments, whereas 45% had RNA in only 1 or 2 sites. By comparison, infectious HIV, present in blood of the majority, was rare in mucosal sites. Innate mediators, secretory leukocyte protease inhibitor and thrombospondin, were highest in mucosae. Highly active antiretroviral therapy was associated with an 80% decreased probability of shedding. Multivariate logistic regression models revealed that mucosal HIV RNA was associated with higher plasma RNA, infectious virus, and total mucosal IgA, but not IgG. There was a 37-fold increased probability of detecting RNA in both genital and oral specimens (P = 0.008; P = 0.02, respectively) among women in highest versus lowest IgA tertiles. CONCLUSIONS: Mucosal sites exhibit distinct characteristics of infectious HIV, viral shedding, and responses to therapy, dependent upon both systemic and local factors. Of the putative innate and adaptive mucosal defense factors examined, only IgA was associated with HIV RNA shedding. However, rather than being protective, there was a striking increase in probability of detectable HIV RNA shedding in women with highest total IgA. PMID- 21239998 TI - CD40L-containing virus-like particle as a candidate HIV-1 vaccine targeting dendritic cells. AB - The central role of dendritic cell (DC) in mounting an immune response to a novel antigen is now well established. We sought to demonstrate the use of a particular vaccine strategy based on directing HIV-1 Gag proteins to DCs in conjunction with an activation signal. CD40L was expressed on the surface of virus-like particles (VLPs) to target HIV-1 Gag antigens to the CD40 receptor on DCs, whereas CD40L CD40 interaction would also result in cellular activation. Multiple CD40L VLP constructs were made and evaluated in vitro and in vivo. Indeed, one VLP that expressed CD40L to the highest level showed greatest capacity to activate DCs in vitro. Correspondingly, this CD40L-VLP also proved to be most immunogenic in mice in raising both humoral and cellular responses to HIV-1 Gag. Confirmatory studies were performed to demonstrate the increased immunogenicity of CD40L-VLP is no longer observed when tested in CD40-/- mice. Our findings lend support to the belief that vaccine strategies that both target and activate DCs could yield a superior immune response. PMID- 21240000 TI - Do fentanyl and morphine influence body temperature after severe burn injury? AB - Fentanyl lacks the antiinflammatory properties of morphine. Morphine attenuates the inflammatory response through differential stimulation of MU-receptor subtypes. Patients who receive morphine during coronary artery bypass graft have been shown to experience less postoperative fever than those who receive fentanyl. Patients who receive continuous fentanyl infusions in increased room temperatures after thermal injury may be at increased risk to experience higher body temperature than those who receive morphine. The records of 28 patients with >20%TBSA burn in 30 intensive care unit rooms (13 received fentanyl and 15 received morphine or hydromorphone) and 12 trauma patients who received fentanyl in 22 degrees C intensive care unit rooms were reviewed. Mean maximum core temperature and percentage of temperature recordings > 39 degrees C in the first 48 hours of admission were compared between burn patients who received fentanyl, those who did not, and with trauma patients. Burn patients exposed to fentanyl experienced significantly higher temperatures (40.1 +/- 0.9 degrees C) compared with those given morphine (38.7 +/- 0.8 degrees C) and compared with trauma patients (37.5 +/- 2.4 degrees C), P < .01 and P < .001, respectively. Burn patients on fentanyl had temperatures > 39 degrees C for a higher percentage of time (33 +/- 27%) than those without fentanyl (7.2 +/- 13%) and trauma patients (1 +/- 2.8%), P < .01 and P < .001, respectively. No differences in other medications administered, acute physiology and chronic health evaluation II scores, or the number of infections that could account for temperature disparities between groups existed. Burn patients who receive fentanyl in 30 degrees C rooms experience higher body temperatures and are febrile for a higher percentage of time than those receiving morphine only. Morphine has well established antiinflammatory properties and likely attenuates the postburn inflammatory response more than fentanyl, resulting in lower body temperatures. This phenomenon needs to be further investigated in additional studies. PMID- 21239999 TI - Combinations of 3-hydroxyphthalic anhydride-modified ovalbumin with antiretroviral drug-based microbicide candidates display synergistic and complementary effects against HIV-1 infection. AB - BACKGROUND: The development of a safe, effective, and affordable microbicide to prevent the sexual transmission of HIV combination is urgently needed. Our previous studies demonstrated that 3-hydroxyphthalic anhydride-modified chicken ovalbumin (HP-OVA) exhibited potent antiviral activity against a broad spectrum of HIV, simian immunodeficiency virus, and herpes simplex virus, making it a promising candidate as a component of combination microbicide. We intended to evaluate potential the synergistic anti-HIV-1 effect of HP-OVA in combination with antiretroviral drug (ARV)-based microbicide candidates. METHODS: The antiviral activity of HP-OVA and the ARVs, including HIV-1 entry inhibitors (T20, C52L, NB64, NBD556, AMD3100, and Maraviroc) and reverse transcriptase inhibitors (Tenofovir, UC781, and TMC120), tested alone or in combination, against HIV-1 X4 and R5 viruses, including some drug-resistant strains, was determined in MT-2 and peripheral blood mononuclear cells using p24 assay. The immune responses induced by HP-OVA that was applied in the vaginas of rats were detected by enzyme-linked immunosorbent assay. RESULTS: When each of these ARV-based microbicide candidates was combined with HP-OVA, synergistic activity was observed against infection by both X4 and R5 strains, and the degree of synergy differed in each case. HP-OVA was highly effective against several ARV-resistant HIV-1 strains, suggesting that combining HP-OVA with these ARV-based microbicide candidates might work cooperatively against both drug-sensitive and -resistant HIV-1 strains. Human body fluids and human proteins had little or no effects on HP-OVA-mediated inhibitory activity against HIV-1 infection. HP-OVA formulated in the universal gel maintained its antiviral activity for at least 1 month and only induced weak immune responses after its multiple applications in the vaginas of rats. CONCLUSIONS: Synergistic and complementary effects against infection by a broad spectrum of HIV-1 strains were observed by combining HP-OVA with the ARV-based microbicide candidates. These findings provide a sound scientific platform for the development of a safe, effective, and affordable combination microbicide to prevent the sexual transmission of HIV and other sexually transmissible viruses. PMID- 21240001 TI - Computer decision support software safely improves glycemic control in the burn intensive care unit: a randomized controlled clinical study. AB - The optimal method for glycemic control in the critically burned patient is unknown. The purpose of this randomized controlled study was to determine the safety and efficacy of computer decision support software (CDSS) to control serum glucose concentration in a burn intensive care unit. Eighteen adult burn/trauma patients receiving continuous insulin infusion were initially randomized to receive glucose management by a traditional paper protocol or a computer protocol (CP) for 72 hours and then crossed over to the alternate method for an additional 72 hours. Time in target glucose range (range: 80-110 mg/dl) was higher in the CP group (47 +/- 17% vs 41 +/- 16.6%; P <= .05); time over target range was not significantly reduced in the CP group (49 +/- 17.8% vs 54 +/- 17.1%; P = .08); and no difference was noted in time under target range of 80 mg/dl (CP: 4.5 +/- 2.8%, paper protocol: 4.8 +/- 3.3%; P = .8), less than 60 mg/dl (P = .7), and less than 40 mg/dl (P = 1.0). Severe hypoglycemic events (<40 mg/dl) did not differ from the CP group compared with historical controls for patients receiving no insulin (P = .6). More glucose measurements were performed in the CP group (P = .0003), and nursing staff compliance with CP recommendations was greater (P < .0001). Glycemic control using CDSS is safe and effective for the critically burned patient. Time in target range improved without increase in hypoglycemic events. CDSS enhanced consistency in practice, providing standardization among nursing staff. PMID- 21240002 TI - Select practices in management and rehabilitation of burns: a survey report. AB - The purpose of this study is to document the organization and current practices in physical rehabilitation across burn centers. An online survey developed for the specific purposes of this study sought information regarding a) logistics of the burn center; b) inpatient and outpatient treatment of patients with burn injury; and c) specific protocols in the treatment of a few complications secondary to burn injuries. Of the 159 responses received, 115 were received from the United States, 20 from Australia, 16 from Canada, and 7 from New Zealand. The overall sample included responses from 76 physical therapists (PTs) and 78 occupational therapists. Seventy-three of those surveyed considered themselves primarily a burn therapist. Nurses (86%) were reported as primarily responsible for wound care of inpatients, followed by wound care technicians (24%). Ninety seven percent of the therapists reported following their own treatment plans. The trunk and areas of head and neck were treated by both PTs and occupational therapists, whereas the lower extremities continue to be treated predominantly by PTs. Some common practices regarding treatment of a few complications secondary to burn injuries such as splinting to prevent contractures, treatment of exposed or ruptured extensor tendons, exposed Achilles tendons, heterotopic ossification, postoperative ambulation, conditioning, scar massage, and use of compression garments are described. Opportunities exist for 1) developing a common document for practice guidelines in physical rehabilitation of burns; and 2) conducting collaborative studies to evaluate treatment interventions and outcomes. PMID- 21240004 TI - Gender differences in recovery goals in patients after acute myocardial infarction. AB - PURPOSE: : While cardiac rehabilitation has been established as an essential part of comprehensive cardiac care, participation rates for female patients are substantially lower than for male patients. Lower referral rates and higher ages of female patients partly explain this underutilization. Gender differences in recovery goals of cardiac patients have not been examined. METHODS: : Five hundred ninety patients (22.2% women) admitted to the hospital because of an acute myocardial infarction answered a questionnaire regarding 24 goals in 5 domains of recovery (physical functioning, risk-factor modification, psychological well-being, independence in daily life, and return to work). In addition, psychological symptoms and medical data were assessed. Gender differences were tested by using chi and Student t tests, as well as multivariate logistic and linear regression models. RESULTS: : Gender differences were found in 7 of the 24 recovery goals. After adjustment for psychosocial and clinical characteristics, women still reported a higher importance of "performance of household duties" (odds ratio [OR] = 8.62; 95% confidence interval [CI], 5.43 13.66), "independence in activities of daily living" (OR = 2.38; CI, 1.58-3.59), and "emotional equilibrium" (OR = 1.58, CI, 1.01-2.46). Men rated "physical endurance" and "reducing strain at workplace" as more important goals (OR = 0.64; CI, 0.42-0.97 and OR = 0.39; CI, 0.17-0.93). Except for psychological distress, gender differences in health status were not related to differences in goals. CONCLUSIONS: : Gender roles and differences in social-life conditions may have an important influence on the recovery goals of patients after an acute myocardial infarction. Recovery goals should be explored when planning intervention programs for individual patients. PMID- 21240003 TI - Respiratory and skeletal muscle strength in chronic obstructive pulmonary disease: impact on exercise capacity and lower extremity function. AB - PURPOSE: We sought to quantify the impact of respiratory muscle and lower extremity strength on exercise capacity and lower extremity function (LEF) in patients with chronic obstructive pulmonary disease (COPD). METHODS: In 828 persons with COPD, we assessed the impact of reduced respiratory (maximum inspiratory pressure, MIP) and lower extremity muscle strength (quadriceps strength, QS) on exercise capacity (6-minute walk test, 6MWT), and LEF (short physical performance battery). Multiple regression analyses taking into account key covariates, including lung function and smoking, tested the associations between muscle strength and exercise and functional capacity. RESULTS: For each 0.5 SD decrement in QS, men walked 18.3 m less during 6MWT (95% confidence interval [CI], -24.1 to -12.4); women 25.1 m less (95% CI, -31.1 to -12.4). For each 0.5 SD decrement in MIP, men walked 9.4 m less during 6MWT (95% CI, -15.2 to -3.6); women 8.7 m less (95% CI, -14.1 to -3.4). For each 0.5 SD decrease in QS, men had a 1.32 higher odds (95% CI, 1.11-1.15) of poor LEF; women had a 1.87 higher odds (95% CI, 1.54-2.27). Lower MIP (per 0.5 SD) was associated with increased odds of poor LEF in women (odds ratio = 1.18; 95% CI, 1.00-1.39), but not in men (odds ratio = 1.10; 95% CI, 0.93-1.31). CONCLUSIONS: In COPD, reduced respiratory and lower extremity muscle strength are associated with decreased exercise and functional capacity. Muscle weakness is likely an important component of impairment and disability in patients with COPD. PMID- 21240005 TI - Clinical and functional predictors of health-related quality of life during cardiac rehabilitation. AB - PURPOSE: This is a retrospective and descriptive analysis of demographic and clinical factors common among cardiac rehabilitation patients with high versus low perceptions of health-related quality of life(HRQOL). In addition, we describe the characteristics that are predictive of greater improvements in HRQOL during cardiac rehabilitation. METHODS: We included 970 patients (63.6 10.6 years; 71% male patients) referred to a 12-week program between 1996 and 2006 who all completed a HRQOL questionnaire at baseline and program completion.Patients were divided into 4 quartiles based on HRQOL scores at program entry. The Kruskall-Wallis test and chi2 analyses determined differences between quartiles for continuous and categorical variables,respectively. In addition, regression models predicted changes in HRQOL during the course of the cardiac rehabilitation program. RESULTS: At program entry, quartile differences were found for diagnosis (P = .04), number of risk factors (P < .01), self-efficacy (P < .001), and caloric expenditure (P = .05). Significant predictors of change included baseline HRQOL sores, flexibility, and left ventricular ejection fraction (R2 = 0.50; P = .001). CONCLUSIONS: The factors found that related to baseline HRQOL and were predictive of the change in HRQOL were primarily clinical and functional in nature. This suggests that those who have greater physical functionality, the confidence to perform physical tasks, and are not limited clinically, may more readily adapt to cardiac rehabilitation and progress more rapidly. Those patients with the poorest exercise capacities at entrance to the program tended to make the greatest gains in HRQOL. PMID- 21240006 TI - Prevalence of obstructive sleep apnea in a patient population undergoing cardiac rehabilitation. AB - OBJECTIVES: : The primary objective of this study was to determine the prevalence of undiagnosed or untreated obstructive sleep apnea (OSA) in patients undergoing cardiac rehabilitation. METHODS: : A total of 132 consecutive patients were screened by Berlin Questionnaire to determine the presence or absence of OSA. RESULTS: : Fourteen patients did not consent to participate. Of the remaining 118 patients, 20 (17%) were found to have a preexisting formal diagnosis of OSA. Of the remaining 98 patients (69 males and 29 females), 43 (44%) were found to have a high probability of OSA as predicted by the Berlin Questionnaire. There was no significant difference in the prevalence (P < .05) between males (29/69, 42%) and females (14/29, 48%) who were predicted to have OSA. Similarly, no significant differences were observed in the ages or body mass index between OSA and non-OSA patients. A significantly greater frequency (P < .05) of coronary artery disease was observed in the OSA group than in the non-OSA group. CONCLUSIONS: : Overall, the rate of preexisting and predicted OSA (53%) suggests a high prevalence of OSA in patients with cardiovascular diseases in a cardiac rehabilitation setting. Moreover, the high rate of undiagnosed OSA, as suggested by the Berlin Questionnaire, further adds to the growing literature that a large number of patients with significant cardiovascular disease carry the burden of sleep disordered breathing. PMID- 21240009 TI - Ileal immune dysregulation in necrotizing enterocolitis: role of CD40/CD40L in the pathogenesis of disease. AB - OBJECTIVES: CD40, a co-stimulatory molecule, plays a critical role in coordinating enteric inflammatory immune responses. In necrotizing enterocolitis (NEC), upregulation of IL-10, a CD40-modulated cytokine, has been described, but the role of the IL-10 receptor (IL-10Rbeta), CD40, and its ligand CD40L in disease pathogenesis is unknown. The study herein investigates ileal expression of CD40, CD40L, and IL-10R in a rat model of NEC. SUBJECTS AND METHODS: NEC was induced in newborn rats using established methods of formula feeding, asphyxia, and cold stress. Expression of CD40, CD40L, IL-10Rbeta, and other proinflammatory molecules, including Toll-like receptor-4 (TLR-4) and IL-18, was assessed by immunoblotting. Tissue infiltration by macrophages, monocytes, and T cells was examined by confocal immunohistochemistry. RESULTS: Ileum from rat pups with NEC showed increased expression of TLR-4, IL-18, and IL-10Rbeta. Sections from both NEC and control pups demonstrated preservation of ileal cells expressing CD40/CD40L. The distal ileum of controls expressed both CD40 and CD40L; conversely, neither molecule was detected in ileal tissue from NEC pups. Additional studies showed that treatment with epidermal growth factor (EGF), previously shown to ameliorate the severity of NEC in an animal model, did not restore CD40 expression. CONCLUSIONS: Ileal cytokine dysregulation, manifested by decreased CD40/CD40L and increased IL-10Rbeta expression, may be involved in the pathogenesis of NEC. Dampened CD40 signaling may be related to enhanced IL-10 expression and a suppressed T-cell response to injury. We speculate that augmenting CD40-CD40L interactions may achieve a protective effect in this NEC model. PMID- 21240011 TI - Addition of polydextrose and galactooligosaccharide to formula does not affect bacterial translocation in the neonatal piglet. AB - OBJECTIVES: The aim of the study was to determine the effect of polydextrose (PDX) and galactooligosaccharide (GOS) on bacterial translocation (BT) in neonatal piglets. MATERIALS AND METHODS: Piglets (n = 36) were randomized 12 hours after birth to receive total enteral nutrition (TEN) as formula; TEN + GOS (4 g/L), TEN + PDX (4 g/L), or TEN + GOS + PDX (2 g/L each) for 7 days or were supported by total parenteral nutrition (TPN) as a positive control for BT (n = 8). Blood, spleen, liver, and mesenteric lymph node (MLN) samples were cultured for aerobic and anaerobic bacteria. Colon microbiota 16S rDNA was measured by polymerase chain reaction. Myeloperoxidase activity and tumor necrosis factor alpha expression were measured in ileum and ascending colon. RESULTS: Among the enterally fed groups, no difference was seen in the Lactobacillus and Bacteroides 16S rDNA copies per gram of colonic contents, yet total bacterial levels were lower (P < 0.05) in the TEN + GOS group compared with TEN alone. Bacteria were detected in the blood, liver spleen, and MLN of TPN piglets. In contrast, bacterial counts were predominantly detected in the MLN of TEN piglets, at much lower levels than in TPN, and levels were not affected by GOS and PDX addition. TPN piglets had elevated (P < 0.05) ileal myeloperoxidase activity and a trend in elevated ascending colon tumor necrosis factor-alpha expression (P = 0.1). CONCLUSIONS: PDX and GOS added to formula do not induce BT in healthy piglets. Low levels of bacteria in MLN of healthy neonatal piglets may reflect mucosal sampling rather than pathological BT. PMID- 21240010 TI - Esophageal impedance monitoring for gastroesophageal reflux. AB - Dual pH-multichannel intraluminal impedance (pH-MII) is a sensitive tool for evaluating overall gastroesophageal reflux disease, and particularly for permitting detection of nonacid reflux events. pH-MII technology is especially useful in the postprandial period or at other times when gastric contents are nonacidic.pH-MII was recently recognized by the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition as being superior to pH monitoring alone for evaluation of the temporal relation between symptoms and gastroesophageal reflux. In children, pH-MII is useful to correlate symptoms with reflux (particularly nonacid reflux), to quantify reflux during tube feedings and the postprandial period, and to assess efficacy of antireflux therapy. This clinical review is simply an evidence-based overview addressing the indications, limitations, and recommended protocol for the clinical use of pH-MII in children. PMID- 21240012 TI - Relations of steatosis type, grade, and zonality to histological features in pediatric nonalcoholic fatty liver disease. AB - BACKGROUND: The relations between hepatic steatosis and histological features of hepatocyte injury in children with nonalcoholic fatty liver disease have yet to be examined. The aims of the present study were to establish associations between steatosis amount, type, and distribution in a well-characterized group of children with biopsy-proven nonalcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: One hundred eight children with NAFLD seen in 5 centers were studied. Clinical and laboratory data were collected. Hematoxylin-eosin and Masson trichrome stains were evaluated by 2 expert liver pathologists. Steatosis grade (0-3), type (macrovesicular, microvesicular, or mixed), and zone (1, 3, azonal, or panacinar) were determined. The NAFLD activity score and fibrosis stage were determined. RESULTS: Median patient age was 12 years and median body mass index was 31 kg/m. Fibrosis was present in 87%. The median NAFLD activity score was 4. Mild, moderate, and severe steatosis were present in 42%, 34%, and 24% of biopsies, respectively. Macrovesicular steatosis was present in 81% and mixed steatosis was present in 19%. Panacinar distribution of steatosis was most frequent (40%), followed by azonal (27%). Steatosis grade positively correlated with portal inflammation (P = 0.018). Azonal distribution positively correlated with presence of hepatocyte ballooning (P = 0.03). Biopsies with mixed steatosis were approximately 20 times more likely to have megamitochondria than those with macrovesicular steatosis alone (95% confidence interval 2.3-204.9). There was no relation between steatosis amount, type, or distribution to fibrosis stage. CONCLUSIONS: Specific histological patterns of steatosis in children are associated with histological markers of steatohepatitis. Ballooning and portal inflammation correlated well with features of steatosis. PMID- 21240013 TI - Prolapse gastropathy. PMID- 21240014 TI - Acetaminophen pharmacokinetics in children with nonalcoholic fatty liver disease. AB - OBJECTIVES: : The aim of the study was to evaluate UDP-glucuronyltransferase activity and the pharmacokinetics of a single oral dose of acetaminophen (APAP) in children with nonalcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: : Twelve boys 10 to 17 years old with biopsy-proven NAFLD and 12 age- and sex matched controls without NAFLD were recruited. Following administration of a single oral dose of APAP (5 mg/kg, maximum 325 mg), APAP and its glucuronide metabolite (APAP-G) were measured in plasma, urine, and sputum at various intervals up to 24 hours. The activity of UDP-glucuronyltransferase was estimated by the plasma ratio of APAP-G to APAP at 4 hours. RESULTS: : Following administration of APAP, children with NAFLD had significantly higher concentrations of APAP-G in serum (P = 0.0071) and urine (P = 0.0210) compared with controls. No significant differences in APAP pharmacokinetics parameters were observed between the 2 groups. CONCLUSIONS: : APAP glucuronidation is altered in children with fatty liver disease. Despite the altered disposition of this metabolite, the pharmacokinetics of a single 5 mg/kg dose of APAP is the same in children with NAFLD as in children with normal liver function. PMID- 21240015 TI - Early high calcium and phosphorus intake by parenteral nutrition prevents short term bone strength decline in preterm infants. AB - BACKGROUND AND AIM: Very premature newborns have an increased risk of low bone mass and metabolic bone disease. Most longitudinal studies report a significant decline in bone strength in the first weeks after birth. The aim of the study was to evaluate whether higher early calcium (Ca) and phosphorus (P) intake delivered by parenteral nutrition (PN) can prevent bone strength decline in preterm infants, within the first weeks after birth. PATIENTS AND METHODS: This was a randomized controlled trial of consecutively admitted neonates born with <= 33 weeks of gestational age, assigned to receive either Ca 45 mg . kg-1 . day-1 (low dose [LD]) or Ca 75 mg . kg-1 . day-1 (high dose [HD]) by PN. P was added to the PN solutions at a fixed Ca:P ratio (mg) of 1.7:1. Bone strength was assessed by the speed of sound (SOS) using the quantitative ultrasound method. Measurements were performed weekly from birth until discharge. Low bone strength (SOS < 10th centile of reference values) was the main outcome. RESULTS: Eighty-six infants were enrolled, 40 assigned to LD group and 46 to HD group. Mean (standard error) gestational age was 29.6 weeks (2.1) and birth weight was 1262 g (0.356). In the HD group, the SOS values never fell below those recorded at birth and, up to the sixth week of life, low bone strength was significantly less frequent as compared with that in the LD group, in spite of progressive reduction in parenteral mineral intake and/or establishment of full enteral feeding. CONCLUSIONS: Early assigned parenteral intake of Ca 75 mg . kg-1 . day-1 and P 44 mg . kg-1 . day-1 significantly contributed to preventing short-term bone strength decline in preterm infants. PMID- 21240016 TI - Balloon-occluded retrograde transvenous obliteration treats hepatic dysfunction and gastric varices. PMID- 21240017 TI - Hepatic venous outflow obstruction complicating Churg-Strauss syndrome in a 5 year-old child. PMID- 21240018 TI - Optimisation of the reflux-symptom association statistics for use in infants being investigated by 24-hour pH impedance. AB - BACKGROUND AND AIM: pH-impedance monitoring is used to diagnose symptomatic gastroesophageal reflux (GER) based on symptom association probability (SAP). Current criteria for calculation of SAP are optimised for heartburn in adults. Infants, however, demonstrate a different symptom profile. The aim of the present study was to optimise criteria for calculation of SAP in infants with GER disease. PATIENTS AND METHODS: Ten infants referred for investigation of symptomatic reflux were enrolled. GER episodes were recorded using a pH-impedance probe, which remained in place for 48 hours. During the test, cough, crying, and regurgitation were marked. Impedance recordings were analysed for the occurrence of bolus reflux episodes. SAP for behaviors following reflux episodes was separately calculated for day 1 and day 2 using automated reporting software, which enabled the time window used for SAP calculations to be modified from 15 to 600 seconds. Day-to-day agreement of SAP was assessed by calculating the 95% limits of agreement (mean difference +/- 1.96 standard deviations of differences) and their confidence intervals. RESULTS: The number of bolus GER episodes and symptom episodes reported did not differ from day to day. The best agreement in SAP between the 2 days was found using time intervals of 2 minutes for cough, 5 minutes for crying, and 15 seconds and/or 2 to 5 minutes for regurgitation. CONCLUSIONS: We conclude that the standard 2-minute time interval is appropriate for the investigation of cough and regurgitation symptoms. The day-to-day agreement of SAP for crying was poor using standard criteria, and our results suggest increasing the reflux-symptom association time interval to 5 minutes. PMID- 21240019 TI - Successful treatment of autoimmune hepatitis with methotrexate. PMID- 21240020 TI - Infliximab-induced psoriasis in children with inflammatory bowel disease. AB - Infliximab is frequently used to treat both inflammatory bowel disease (IBD) and psoriasis. We reviewed the medical records of 73 children with IBD receiving infliximab therapy and identified 6 (8%) cases of infliximab-induced psoriasis. Five (83%) had Crohn disease and 4 (67%) were girls. The psoriatic lesions appeared on the face (n = 5; 83%) and perineum (n = 1; 17%). A median of 13 doses were administered during a median duration of 21 months. All of the patients were continued on infliximab to maintain clinical remission of IBD. Educating children with IBD and their caregivers about this paradoxical phenomenon and periodic dermatology evaluation may promote patient care. PMID- 21240021 TI - Inlet patch: clinical presentation and outcome in children. AB - OBJECTIVES: An inlet patch (IP) is defined as heterotopic gastric mucosa located in the proximal esophagus. Little information is available in children. The aim of this retrospective study was to assess clinical significance, endoscopic and histological characteristics, and natural history of IP in children. PATIENTS AND METHODS: This retrospective multicenter study included all of the cases of IP recorded in 7 tertiary French pediatric gastrointestinal centers. Information about demographics, clinical symptoms, endoscopic characteristics, histology, treatment, and evolution was collected. RESULTS: Fifteen children were included (8 boys, 7 girls). The median age at diagnosis was 9.5 years (range 3.3-15 years). Five children had esophageal atresia and 9 had gastroesophageal reflux. Only 1 child was asymptomatic. Digestive symptoms (dysphagia, food impaction) were noted in 14 patients and respiratory or ear, nose, and throat symptoms in 6. At endoscopy, IP was characterized by a small, round salmon-pink lesion of the proximal esophagus. Helicobacter pylori was found in 2 patients. Proton pump inhibitor treatment was initiated in 14 children for a mean duration of 4.7 months (range 1-12 months). Two patients were lost to follow-up. Clinical symptoms disappeared in 5 patients and decreased in 3 others. One case of hematemesis was noted after a mean follow-up of 9 months. Recurrent symptoms were noted in 2 patients after treatment discontinuation. CONCLUSIONS: IP is an uncommon but almost certainly underrecognized lesion in children, and may be the cause of digestive and respiratory symptoms in some children. PMID- 21240022 TI - Evaluations of psychological preparation for children undergoing endoscopy. AB - We provided psychological preparation to children who were hospitalized for endoscopy. We performed a multifaceted evaluation of the effects of the preparation to identify appropriate methods for individual children. The subjects were 20 children, ages 4 to 15 years (average 9.9 years), who were divided into 3 groups according to the preparation methods. From our study, we suggest that it is important to discuss the preparation methods for medical procedures using methods appropriate to the level of cognitive development of each individual child. PMID- 21240023 TI - Double-blind, placebo-controlled antibiotic treatment study of small intestinal bacterial overgrowth in children with chronic abdominal pain. AB - BACKGROUND AND OBJECTIVES: Chronic abdominal pain (CAP) in children may be a precursor to irritable bowel syndrome (IBS) in adults. The prevalence of abnormal lactulose breath tests (LBT) suggesting small intestinal bacterial overgrowth (SIBO) has been reported as 91% in children with CAP and 35% in healthy controls. In addition, patients with IBS with SIBO who responded to nonabsorbable antibiotic treatment with normalization of LBT reported 75% global improvement in symptoms. The aim of the study was to test whether treatment with a nonabsorbable antibiotic may reduce symptoms in children with CAP. METHODS: Seventy-five children ages 8 to 18 years with CAP based on Rome II criteria were enrolled. Subjects underwent baseline LBT and completed symptom-based questionnaires. They were then randomized in a 2:1, double-blind fashion to receive a 10-day course of 550 mg of rifaximin or placebo 3 times per day (t.i.d.). LBT and questionnaires were repeated 2 weeks after treatment. RESULTS: Forty-nine children received rifaximin and 26 received placebo. There were no differences in demographics between groups. Ninety-four percent who received rifaximin and 92% who received placebo had abnormal baseline LBT, suggesting SIBO (not significant [NS]). There was no significant difference in symptom improvement between groups; however, only 20% of children treated with rifaximin achieved a normalized repeat LBT, demonstrating successful treatment of SIBO. CONCLUSIONS: Similar to adults with IBS, the prevalence of abnormal LBT suggesting SIBO in children with CAP is high; however, treatment with 10 days of rifaximin has low efficacy in normalizing LBT in this group. Additional studies are needed to determine whether a treatment approach with higher efficacy would lead to improvement in children with CAP. PMID- 21240024 TI - Colonic hyperactivity results in frequent fecal soiling in a subset of children after surgery for Hirschsprung disease. AB - BACKGROUND AND AIM: Fecal soiling is a challenging problem in some children after pull-through surgery for Hirschsprung disease (HSCR). The prevailing perception is that soiling results from overflow incontinence; however, its treatment with laxatives yields mixed results. Colonic manometry studies are reported to be normal in most patients in this population. The interpretation of these findings does not support the physiology of fecal overflow incontinence in these children. The aim of the present study was to define the physiology underlying daily, frequent fecal soiling in children after surgery for HSCR using manometric techniques. PATIENTS AND METHODS: Four pediatric motility centers in the United States participated in the study; medical records and manometric tracings (anorectal and colonic) of children (n = 59; 6.5 years; 48 boys) who had pull through surgery for HSCR and presented with daily, frequent fecal soiling were examined. Children referred for evaluation of constipation who had normal colonic manometry served as controls (n = 25; 6.7 years; 12 boys). The patients with HSCR were divided into 2 groups (Hirschsprung disease groups 1 and 2 [HD1, HD2]) based on the absence or presence of high-amplitude propagated contractions (HAPCs). A control group that included children with chronic constipation was also studied. We compared the mean HAPC frequency between the HD2 and control groups. RESULTS: HD1 included 21 patients who had no HAPCs in fasting or postprandial periods. HD2 included 38 patients who had an average of 0.07 HPACs/min while fasting and 0.13/min in the postprandial state. In this subset the number of HAPCs in the fasting state (P = 0.04) and the postprandial state (P < 0.001) was greater when compared with controls. Additionally, there was a significant increase in HAPCs/min from the fasting to the postprandial state (P = 0.01). In the HD2 group 40% had colonic hyperactivity. CONCLUSIONS: Daily, frequent fecal soiling after pull-through surgery for HSCR may be due to colonic hyperactivity in some children. It is imperative that this unique subset be identified because the management strategy would include avoidance of laxatives, contrary to standard current practice. PMID- 21240025 TI - A biopsy is not always necessary to diagnose celiac disease. AB - OBJECTIVES: Small intestinal histology is the criterion standard for the diagnosis of celiac disease (CD). However, results of serological tests such as anti-endomysium antibodies and anti-tissue transglutaminase antibodies (tTGA) are becoming increasingly reliable. This raises the question of whether a small intestinal biopsy is always necessary. The aim of the present study was, therefore, to investigate whether a small intestinal biopsy can be avoided in a selected group of patients. PATIENTS AND METHODS: Serology and histological slides obtained from 283 pediatric patients suspected of having CD were examined retrospectively. The response to a gluten-free diet (GFD) in patients with a tTGA level >= 100 U/mL was investigated. RESULTS: A tTGA level >= 100 U/mL was found in 128 of the 283 patients. Upon microscopic examination of the small intestinal epithelium, villous atrophy was found in 124 of these patients, confirming the presence of CD. Three patients had crypt hyperplasia or an increased number of intraepithelial lymphocytes. In 1 patient no histological abnormalities were found. This patient did not respond to a GFD. CONCLUSIONS: Pediatric patients with a tTGA level >= 100 U/mL in whom symptoms improve upon consuming a GFD may not need a small intestinal biopsy to confirm CD. PMID- 21240026 TI - Constipation and colonic transit times in children with morbid obesity. AB - OBJECTIVES: The aim of the study was to determine the frequency of functional constipation according to the Rome III criteria in children with morbid obesity and to evaluate by measuring colonic transit times (CTTs) whether decreased colonic motility is present in these children. PATIENTS AND METHODS: Ninety-one children with morbid obesity ages 8 to 18 years, entering a prospective, randomized controlled study evaluating the effect of an outpatient versus inpatient treatment program of obesity, participated. All of the children filled out a standardized questionnaire regarding their bowel habits, and CTTs were measured using radioopaque markers. Food diaries were also recorded to evaluate their diet. RESULTS: A total of 19 children (21%) had functional constipation according to the Rome III criteria, whereas 1 child had functional nonretentive fecal incontinence. Total CTT exceeded 62 hours in only 10.5% of the children with constipation, and among them, 2 had a total CTT of >100 hours. In the nonconstipated group 8.3% had a delayed CTT. Furthermore, no difference was found between the diet of children with or without constipation, specifically not with respect to fiber and fat intake. CONCLUSIONS: Our study confirms a high frequency of functional constipation in children with obesity, using the Rome III criteria. However, abnormal colonic motility, as measured by CTT, was delayed in only a minority of patients. No relation was found between constipation in these children and fiber or fat intake. PMID- 21240027 TI - Effect of various warm-up devices on bat velocity of intercollegiate baseball players. AB - A variety of warm-up devices are available to baseball players to use before their game at-bat. Past baseball research evaluating warm-up devices indicates that implements that are +/-12% of standard game bat weight produce the greatest bat velocities for high school and intercollegiate players. The purpose of this study was to examine the effect of various warm-up devices on bat velocity (BV) of intercollegiate baseball players. Twenty-two Division I intercollegiate baseball players (age = 20.0 +/- 1.5 years, height = 182.6 +/- 8.3 cm, body mass = 91.4 +/- 11.4 kg, lean body mass = 78.8 +/- 8.9 kg, % body fat = 13.6 +/- 3.8) participated in a warm-up with 1 of 10 weighted devices on separate days. Each of the 10 testing sessions consisted of a standardized warm-up, 3 dry swings as hard as possible with the assigned warm-up device, 2 comfortable dry swings with a standard game baseball bat followed by 3 game swings (20-second rest between swings) while hitting a baseball off of a batting tee with the same standard game baseball bat. Results indicated that there were no statistically significant differences in BV after using any of the 10 warm-up devices. For male intercollegiate baseball players, results indicate that warm-up devices varying from 623.7 to 2,721.5 g (22-96 oz.) did not change mean BV of a standard game baseball bat, suggesting that intercollegiate players can use any of the 10 warm up devices in the on-deck circle and maintain their BV. Therefore, personal preference as to which warm-up implement to use in the on-deck circle is advised. PMID- 21240028 TI - Reliability and validity of a new repeated agility test as a measure of anaerobic and explosive power. AB - The aim of this study was to evaluate the reliability and validity of a repeated modified agility test (RMAT) to assess anaerobic power and explosiveness. Twenty seven subjects (age: 20.2 +/- 0.9 years, body mass: 66.1 +/- 6.0 kg, height: 176 +/- 6 cm, and body fat: 11.4 +/- 2.6%) participated in this study. After familiarization, subjects completed the RMAT consisting of 10 * 20-m maximal running performances (moving in forward, lateral, and backward) with ~25-second recovery between each run. Ten subjects performed the RMAT twice separated by at least 48 hours to evaluate relative and absolute reliability and usefulness of the test. The criterion validity of the RMAT was determined by examining the relationship between RMAT indices and the Wingate anaerobic test (WAT) performances and both vertical and horizontal jumps. Reliability of the total time (TT) and peak time (PT) of the RMAT was very good, with intraclass correlation coefficient > 0.90 and SEM < 5% and low bias. The usefulness of TT and PT of the RMAT was rated as "good" and "OK," respectively. The TT of the RMAT had significant correlations with the WAT (peak power: r = -0.44; mean power: r = -0.72), vertical jumps (squat jump: r = -0.50; countermovement jump: r = -0.61; drop jump (DJ): r = -0.55; DJ with dominant leg: r = -0.72; DJ with nondominant leg: r = -0.53) and 5 jump test (r = -0.56). These findings suggest that the RMAT is a reliable and valid test for assessing anaerobic power and explosiveness in multisprint sport athletes. Consequently, the RMAT is an easily applied, inexpensive field test and can provide coaches and strength and conditioning professionals with relevant information concerning the choice and the efficacy of training programs. PMID- 21240030 TI - Lower extremity biomechanics during weightlifting exercise vary across joint and load. AB - The purpose of this study was to determine the effect of load on lower extremity biomechanics during the pull phase of the clean. Kinematic and kinetic data of the 3 joints of the lower extremity were collected while participants performed multiple sets of cleans at 3 percentages: 65, 75, and 85% of 1 repetition maximum (1RM). General linear models with repeated measures were used to assess the influence of load on angular velocities, net torques, powers, and rates of torque development at the ankle, knee, and hip joint. The results suggest that the biomechanical demands required from the lower extremities change with the lifted load and to an extent depend on the respective joint. Most notably, the hip and knee extended significantly faster than the ankle independent of load, whereas the hip and ankle generally produced significantly higher torques than the knee did. Torque, rate of torque development (RTD), and power were maximimal at 85% of 1RM for the ankle joint and at 75% of 1RM for the knee joint. Torque and RTD at the hip were maximal at loads >75% of 1RM. This study provides important novel information about the mechanical demands of a weightlifting exercise and should be heeded in the design of resistance training programs. PMID- 21240029 TI - Psychophysiological effects of preperformance massage before isokinetic exercise. AB - Sports massage provided before an activity is called pre-event massage. The hypothesized effects of pre-event massage include injury prevention, increased performance, and the promotion of a mental state conducive to performance. However, evidence with regard to the effects of pre-event massage is limited and equivocal. The exact manner in which massage produces its hypothesized effects also remains a topic of debate and investigation. This randomized single-blind placebo-controlled crossover design compared the immediate effects of pre-event massage to a sham intervention of detuned ultrasound. Outcome measures included isokinetic peak torque assessments of knee extension and flexion; salivary flow rate, cortisol concentration, and alpha-amylase activity; mechanical detection thresholds (MDTs) using Semmes-Weinstein monofilaments and mood state using the Profile of Mood States (POMS) questionnaire. This study showed that massage before activity negatively affected subsequent muscle performance in the sense of decreased isokinetic peak torque at higher speed (p < 0.05). Although the study yielded no significant changes in salivary cortisol concentration and alpha amylase activity, it found a significant increase in salivary flow rate (p = 0.03). With the massage intervention, there was a significant increase in the MDT at both locations tested (p < 0.01). This study also noted a significant decrease in the tension subscale of the POMS for massage as compared to placebo (p = 0.01). Pre-event massage was found to negatively affect muscle performance possibly because of increased parasympathetic nervous system activity and decreased afferent input with resultant decreased motor-unit activation. However, psychological effects may indicate a role for pre-event massage in some sports, specifically in sportspeople prone to excessive pre-event tension. PMID- 21240031 TI - Specificity of jumping, sprinting, and quick change-of-direction motor abilities. AB - Despite being addressed in a number of previous studies, the controversy regarding the generality vs. specificity of jumping, sprinting, and change-of direction speed (CODS) abilities still remains unresolved. Here, we tested the hypotheses that jumping, sprinting, and CODS represent separate and specific motor abilities, and that the jumping ability based on concentric and slow stretch-shortening cycle (SSC) is relatively independent of the same ability based on fast SSC. Eighty-seven male college athletes performed 3 concentric/slow SSC and 3 fast SSC jump tests, 4 sprint tests, and 3 CODS tests. The hypotheses were tested by means of the principal component factor analysis (PCA). The applied procedure reduced the greater number of manifest variables to a smaller number of independent latent dimensions or factors and, thereafter, assessed the relationships among them. The PCA revealed a relatively simple and consistent structure consisting of 4 separate factors that explained nearly 80% of variance of the applied tests. The factors appeared to correspond to the sprinting ability, concentric/slow SSC jumping ability, fast SSC jumping ability, and CODS ability. Further analyses revealed that the extracted factors were mainly independent, because they shared only between 6 and 23% of the common variance. These results supported our hypotheses regarding the specificity of jumping, sprinting, and CODS abilities, and specificity of the concentric/slow SSC and fast SSC jumping abilities. Coaches and strength and conditioning professionals should, therefore, use separate performance tests for the assessment of the studied abilities. PMID- 21240033 TI - An automated analyzer provides clinically concordant results to manual back titration for quantitation of bicarbonate in pancreatic juice. AB - OBJECTIVES: Secretin pancreatic function tests play an important role in the diagnosis of chronic pancreatitis. Back titration is the standard method for measurement of bicarbonate in pancreatic juice but is time consuming and manually performed. Use of an autoanalyzer for this purpose is not validated. METHODS: Bicarbonate concentrations in secretin-stimulated pancreatic juice specimens were quantitated by manual back titration, a clinical chemistry autoanalyzer (automated bicarbonate, Roche Cobas c501, Roche Diagnostics, Indianapolis, Ind), and a blood gas analyzer (calculated bicarbonate, GEM 3000, Instrumentation Laboratories, Bedford, Mass). Kappa statistic analysis, Bland-Altman analysis, and Lin concordance correlation coefficients were calculated. RESULTS: Ninety specimens from 31 subjects were included. Using a bicarbonate concentration of 80 mEq/L as a cutoff value, there was poor agreement between back titration and calculated bicarbonate (kappa = 0.188); however, only 1 specimen showed discrepancy between back titration and automated bicarbonate (kappa = 0.977). The limit of agreement between the back titration and automated bicarbonate was -9.0 to + 8.3 mEq/L. The Lin concordance correlation coefficient between the 2 methods was 0.931 (P < 0.001). CONCLUSIONS: There is strong concordance between manual back titration and chemistry autoanalyzer methods for measurement of bicarbonate concentrations in pancreatic juice. Autoanalyzers may replace back titration for this purpose. Blood gas analyzers are unsuitable. PMID- 21240032 TI - Effect of different obesogenic diets on pancreatic histology in Ossabaw miniature swine. AB - OBJECTIVE: Obesity is a factor in the outcome and severity of pancreatic conditions. We examined the effect of hypercaloric diets on the pancreata of Ossabaw swine, a large animal model of metabolic syndrome and obesity. METHODS: Swine were fed with 1 of 4 diets: high-fructose (n = 9), atherogenic (n = 10), modified atherogenic (n = 6), or eucaloric standard diet (n = 12) for 24 weeks. Serum chemistries were measured, and pancreata were examined for histological abnormalities including steatosis, inflammation or fibrosis, insulin content, and oxidative stress. RESULTS: The fructose, atherogenic, and modified atherogenic diet groups exhibited obesity, metabolic syndrome, islet enlargement, and significantly increased pancreatic steatosis (22.9% +/- 7.5%, 19.7% +/- 7.7%, and 38.7% +/- 15.3% fat in total tissue area, respectively) compared with controls (9.3% +/- 1.9%; P < 0.05). The modified atherogenic diet group showed significantly increased oxidative stress levels as evidenced by elevated serum malondialdehyde (3.0 +/- 3.3 vs 1.5 +/- 0.3 MUmol/L in controls; P = 0.006) and pancreatic malondialdehyde (0.1 +/- 0.12 vs 0.04 +/- 0.01 nmol/mg protein in controls; P = 0.01). None of the swine exhibited pancreatitis or cellular injury. CONCLUSIONS: Ossabaw swine fed with a modified atherogenic diet developed significant pancreatic steatosis and increased oxidative stress, but no other histological abnormalities were observed. PMID- 21240034 TI - Oxygenation of the portal vein by intraperitoneal administration of oxygenated perfluorochemical improves the engraftment and function of intraportally transplanted islets. AB - OBJECTIVES: One of the major obstacles for successful intraportal islet transplantation (IPIT) is early graft loss due to hypoxia. We therefore examined the effect of intraperitoneal oxygenated perfluorochemical (PFC) on oxygenation of the portal vein with respect to islet engraftment and function after IPIT in a rat model. METHODS: First, we measured the oxygen tension and saturation in the portal vein of Lewis rats before and after intraperitoneal injection of oxygenated PFC. Second, blood glucose levels, glucose tolerance, and the number of surviving islets were measured after IPIT with oxygenated PFC (group 1), with PFC saturated by nitrogen (group 2), and without any PFC (control). RESULTS: Both oxygen tension and saturation in the portal vein significantly increased after injection of oxygenated PFC. In IPIT, the functional success rate in group 1 was 83.3%, compared with 16.7% in group 2 and 16.7% in the control. On the 28th posttransplantation day, the number of engrafted islets in the liver in group 1 (12.8 [SD, 3.3]) was significantly higher than that in group 2 (4.7 [SD, 3.0]) and in the control group (6.5 [SD, 3.3]). CONCLUSIONS: We clearly demonstrated the effect of intraperitoneal oxygenated PFC on oxygenation of the portal vein, resulting in better IPIT outcomes. PMID- 21240035 TI - Abdominal distension: an important feature in human parechovirus infection. AB - A total of 8 infants presenting with sepsis-like illness were diagnosed to have human parechovirus (HPeV) infection; of which, 5 had abdominal distension and 6 had an erythematous rash. A combination of abdominal distension and erythematous rash was observed in 4 infants. The abdominal symptoms can be very prominent and signs could be confused with acute surgical conditions. Although fever and central nervous symptoms are important features, a red rash with abdominal distension and a low C-reactive protein value and lymphocyte count can be clues to recognize this infection. PMID- 21240036 TI - Photoreceptor reconstitution correlates with visual improvement after intravitreal bevacizumab treatment of choroidal neovascularization secondary to traumatic choroidal rupture. PMID- 21240038 TI - Vitrectomy associated with internal limiting membrane peeling remains a very challenging procedure with variable outcomes. PMID- 21240039 TI - The effect of intravitreal bevacizumab in the treatment of Coats disease in children. PMID- 21240041 TI - Sutureless phacoemulsification with transpupillary removal of silicone oil and intracapsular intraocular lens implantation using illuminated 23-gauge infusion system. PMID- 21240042 TI - Prolonged gas tamponade is used for a variety of vitreoretinal repair procedures. PMID- 21240043 TI - Hyalocytes: essential cells of the vitreous cavity in vitreoretinal pathophysiology? AB - PURPOSE: To review the present understanding of hyalocytes. METHODS: A review of recent studies that investigated the roles of hyalocytes in the pathophysiology of the vitreous cavity. RESULTS: Studies on immunocytochemistry and chimeric mice with green fluorescent protein transgenic mice show that hyalocytes belong to the monocyte/macrophage lineage and derive from bone marrow. The effects of hyalocytes on the vitreous cavity environment can be divided into three categories: synthesis of extracellular matrix, regulation of the vitreous cavity immunology, and modulation of inflammation. In noninflamed eyes, vitreous cavity is an immune-privileged site that is maintained by a system called vitreous cavity-associated immune deviation, in which hyalocytes play the role of antigen presenting cells. However, cultured hyalocytes proliferate in response to inflammatory molecules and secrete vascular endothelial growth factor and urokinase-type plasminogen activator. A collagen gel embedded with hyalocytes contracts over time, which is enhanced by transforming growth factor-beta but is inhibited by Rho kinase inhibitor. These results suggest that hyalocytes can be an exacerbating factor in inflamed eyes. Clinically, hyalocytes are frequently found in the surgically removed specimens of epiretinal membrane or proliferative vitreoretinopathy. CONCLUSION: Elucidating the properties of hyalocytes is important to understand the biology of vitreous cavity and to develop novel treatments for vitreoretinal diseases. PMID- 21240045 TI - Subsequent vertebral fracture after vertebroplasty: incidence and analysis of risk factors. AB - STUDY DESIGN: A retrospective review and analysis of consecutive patients who underwent single-level vertebroplasty at our institute between March 2002 and March 2006. OBJECTIVE: To analyze the risk factors for subsequent fractures after vertebroplasty and to predict the postoperative fracture-free time and rate. The effect of bone cement volume injected was also evaluated. SUMMARY OF BACKGROUND DATA: Previous studies of subsequent fractures after vertebroplasty showed conflicting conclusions about risk factors. The frequency of refracture also varied, ranging from 12% to 52%. Most new fractures occurred at adjacent levels, with different risk factors identified. No data were available on the effect of injected bone cement volume, and no consensus had been reached as to the optimal cement volume. METHODS: All enrolled patients were treated with single-level vertebroplasty and followed a standardized postoperative care protocol. Data from medical records and radiographs were collected and analyzed. Variables included patient constitutional factors, radiographic parameters, and volume of injected bone cement. RESULTS: A total of 166 patients (76 men, 90 women) with a mean age of 73.4 years were enrolled in this study. The mean follow-up time was 15.3 months. The overall refracture rate was 38%, with a mean fracture-free interval of 32 months. Both a greater volume of bone cement injected and a greater degree of vertebral height restored contributed significantly to the risk of subsequent adjacent fracture. No risk factor for subsequent remote fracture was identified. A greater volume of bone cement injected was positively correlated with deformity correction after vertebroplasty. CONCLUSION: Most subsequent fractures occurred at the adjacent level within the first 3 months. Patient preoperative condition did not help predict refracture. Although a greater volume of bone cement injected when performing vertebroplasty contributed to the risk of subsequent adjacent fracture, it resulted in a greater improvement of kyphosis. PMID- 21240044 TI - Human disc nucleus properties and vertebral endplate permeability. AB - STUDY DESIGN: Experimental quantification of relationships between vertebral endplate morphology, permeability, disc cell density, glycosaminoglycan (GAG) content, and degeneration in samples harvested from human cadaveric spines. OBJECTIVE: To test the hypothesis that variation in endplate permeability and porosity contributes to changes in intervertebral disc cell density and overall degeneration. SUMMARY OF BACKGROUND DATA: Cells within the intervertebral disc are dependent on diffusive exchange with capillaries in the adjacent vertebral bone. Previous findings suggest that blocked routes of transport negatively affect disc quality, yet there are no quantitative relationships between human vertebral endplate permeability, porosity, cell density, and disc degeneration. Such relationships would be valuable for clarifying degeneration risk factors and patient features that may impede efforts at disc tissue engineering. METHODS: Fifty-one motion segments were harvested from 13 frozen cadaveric human lumbar spines (32-85 years) and classified for degeneration using the magnetic resonance imaging-based Pfirrmann scale. A cylindrical core was harvested from the center of each motion segment that included vertebral bony and cartilage endplates along with adjacent nucleus tissue. The endplate mobility, a type of permeability, was measured directly using a custom-made permeameter before and after the cartilage endplate was removed. Cell density within the nucleus tissue was estimated using the picogreen method, while the nuclear GAG content was quantified using the dimethylmethylene blue technique. Specimens were imaged at 8 MUm resolution using microCT; bony porosity was calculated. Analysis of variance, linear regression, and multiple comparison tests were used to analyze the data. RESULTS.: Nucleus cell density increased as the disc height decreased (R2 = 0.13; P = 0.01) but was not related to subchondral bone porosity (P > 0.5), total mobility (P > 0.4), or age (P > 0.2). When controlling for disc height, however, a significant, negative effect of age on cell density was observed (P = 0.03). In addition to this, GAG content decreased with age nonlinearly (R2 = 0.83, P < 0.0001) and a cell function measurement, GAGs/cell, decreased with degeneration (R2 = 0.24; P < 0.0001). Total mobility (R2 = 0.14; P < 0.01) and porosity (R2 = 0.1, P < 0.01) had a positive correlation with age. CONCLUSION: Although cell density increased with degeneration, cell function indicated that GAGs/cell decreased. Because permeability and porosity increase with age and degeneration, this implies that cell dysfunction, rather than physical barriers to transport, accelerates disc disease. PMID- 21240046 TI - Intraoperative disc herniation during posterior spinal fusion for correction of Scheuermann's Kyphosis. AB - STUDY DESIGN: A retrospective case report. OBJECTIVE: To report a previously unpublished complication associated with surgical correction of Scheuermann's kyphosis (SK). SUMMARY OF BACKGROUND DATA: Recently, a review of a large Scoliosis Research Society database reported a 1.9% risk of neurologic injury during surgical correction of SK. Typically, changes in neurophysiological monitoring are attributed to hypoperfusion of the spinal cord during deformity correction and can be treated by elevating the mean arterial blood pressure or by decreasing the amount of correction. However, other reversible etiologies of neurologic compromise theoretically exist as well. SK is associated with degenerative changes in the intervertebral disc, and an intraoperative neural compromise could be due to disc herniations during application of powerful deformity corrective forces. METHODS: The patient's medical history, physical examination, and diagnostic studies were retrospectively reviewed. RESULTS: We encountered a previously unreported complication of intraoperative disc herniation causing neural compromise during deformity correction of SK. A 17-year old patient developed a T10-T11 herniated nucleus pulposus during posterior spinal fusion for SK. We postulate that abnormal intervertebral disc degeneration associated with SK and significant pressure on the middle spinal column during application of the cantilever correction maneuver contributed to the disc herniation, which resulted in acute unilateral leg pain and weakness. To our knowledge, no reported case of this phenomenon has been documented in the literature. CONCLUSION: Surgeons should consider acute disc herniation as a possible etiology for intraoperative neurophysiologic changes. PMID- 21240047 TI - Questionnaires to examine Back Pain Beliefs held by health care professionals: a psychometric evaluation of Simplified Chinese versions. AB - STUDY DESIGN: Observational cross-sectional study. OBJECTIVE: To perform a psychometric evaluation of Simplified Chinese versions of back pain beliefs questionnaires for use in health care professionals living in mainland China. SUMMARY OF BACKGROUND DATA: Back pain beliefs are of importance in the development of chronic low back pain (LBP) and disability. Different types of beliefs exist with regard to LBP and these include inevitable consequences of LBP and fear-avoidance beliefs. LBP beliefs held by health care providers are also known to influence their patients' pain beliefs and can contribute to the development of chronic LBP and disability. At present, validated questionnaires such as the Back Beliefs Questionnaire, Health Care Providers' Pain and Impairment Relationship Scale, and Fear-Avoidance Beliefs Questionnaire are commonly used to investigate back pain beliefs held by health care professionals working in western countries. There are no published nor validated Simplified Chinese versions to allow investigation of back pain beliefs in health care professionals living in mainland China. METHODS: The English versions of the earlier mentioned questionnaires were translated and culturally adapted into Simplified Chinese using the double-back-translation method. A psychometric evaluation of the translated questionnaires was conducted on 65 health care professionals (rehabilitation medicine specialists, osteopaths, and nurses), with and without LBP, practicing in Shanghai, China. The questionnaires were completed twice within 7- to 10-day period. RESULTS: The Back Beliefs Questionnaire, Health Care Providers' Pain and Impairment Relationship Scale, and Fear-Avoidance Beliefs Questionnaire (work and physical subscales) had acceptable internal consistency (Cronbach alpha range: 0.70-0.87) and construct validity (r = 0.40 0.49, P < 0.05), good reproducibility (Intraclass correlation coefficients, ICC(2,1) range: 0.85-0.93) and an absence of any floor or ceiling effects. CONCLUSION: This study showed that the Simplified Chinese versions of back pain beliefs questionnaires are valid and reliable. Therefore, these questionnaires can be used in research involving Chinese health care professionals living in mainland China. PMID- 21240048 TI - The influence of alendronate on spine fusion in an osteoporotic animal model. AB - STUDY DESIGN: A posterolateral lumbar fusion model in osteoporotic rats. OBJECTIVE.: To assess the effect of alendronate on spine fusion in an osteoporotic animal model. SUMMARY OF BACKGROUND DATA: The effect of alendronate on spine fusion is still controversial. Also, there are no studies using an osteoporotic animal model to assess the effect of alendronate on spine fusion. METHODS: Forty-six female Sprague-Dawley rats underwent either sham-operation (sham) (N = 24) or bilateral ovariectomy (OVX)(N = 22). Eight weeks after the first surgery, animals underwent intertransverse spine fusion at L4-L5. Animals received saline or alendronate 70 MUg/kg/wk by subcutaneous administration once a week for 8 weeks after spinal arthrodesis. All animals were divided into four groups: sham-control, sham-alendronate, OVX-control, and OVX-alendronate. After that the animals were killed and the fusion mass was assessed by radiographic, peripheral quantitative computed tomography (pQCT) scanning, and biomechanical and histologic analysis. RESULTS: In the radiographic study and the pQCT scanning, the area of fusion masses of animals treated with alendronate was considerably larger and denser than that of the control animals in both sham and OVX groups. In the biomechanical study, the ultimate load of the fusion mass of alendronate-treated animals was higher than that of control animals in the osteoporotic groups. Histologic analysis of sagittal sections of fusion mass revealed greater new bone formation in alendronate-treated animals in osteoporotic models and significant inhibition of osteoclasts among the grafted area of alendronate-treated animals compared with the control models. CONCLUSION: Alendronate was effective for radiologic, biomechanical, and histologic success of spine fusion in an osteoporotic animal model. Though much of the graft bone was not resorbed, alendronate increased biomechanical strength with ingrowth of new bone formation in osteoporotic animals. This study suggests the alendronate may improve spine fusion healing in the presence of osteoporosis. PMID- 21240049 TI - Acute cervical spinal cord injury complicated by preexisting ossification of the posterior longitudinal ligament: a multicenter study. AB - STUDY DESIGN: Retrospective multicenter study. OBJECTIVE: To review the clinical characteristics of traumatic cervical spinal cord injury (SCI) associated with ossification of the posterior longitudinal ligament (OPLL). SUMMARY OF BACKGROUND DATA: Despite its potentially devastating consequences, there is a lack of information about acute cervical SCI complicated by OPLL. METHODS: This study included consecutive patients with acute traumatic cervical SCI (Frankel A, B, and C) who were admitted within 48 hours of injury to 34 spine institutions across Japan. For analysis of neurologic outcome, patients who had completed at least a 6-month follow-up were included. Neurologic improvement was defined as at least one grade conversion in Frankel grade. RESULTS: A total of 453 patients were identified (367 men, 86 women; mean age, 59 years). OPLL was found in 106 (23%) patients (87 men, 19 women; mean age, 66 years). Most of the patients with OPLL (94 of 106) were without bone injury, presenting with incomplete SCI. The prevalence of OPLL reached 34% in SCI without bone injury. The cause of SCI was predominantly falls (74%). Only 25% of the patients were aware of OPLL. Half of the OPLL patients reported gait disturbance before injury. Forty-eight (52%) OPLL patients without bone injury underwent surgery (median, 13.5 days after injury), mostly laminoplasty. Overall, no significant difference was noted in neurologic improvement between surgery group and conservative group. However, further stratification showed that surgery was associated with greater neurologic recovery in patients who had gait disturbance before injury (P = 0.04). CONCLUSION: Prevalence of OPLL among cervical SCI was alarmingly high, especially in those without bone injury. Most of cervical SCI associated with OPLL were incomplete, without bone injury, and caused predominantly by low-energy trauma. The majority of the patients were unaware of OPLL. Surgery produced better neurologic recovery in patients who had gait disturbance before injury. PMID- 21240050 TI - Postoperative surgical site infections in patients undergoing spinal tumor surgery: incidence and risk factors. AB - STUDY DESIGN: We conducted a retrospective, case control study on patients undergoing surgery for spinal tumors. OBJECTIVE.: Our aim was to determine the incidence and to identify risk factors for surgical site infections (SSIs) in patients undergoing surgery for spinal tumors. SUMMARY OF BACKGROUND DATA: SSIs after spinal tumor surgery may be particularly devastating as they may add to substantial surgical morbidity and may further exacerbate already existing neurologic deficits. Incidence and risk factors predisposing to SSIs in patients undergoing surgery for spinal tumors are not well studied yet. METHODS: Between January 1995 and February 2008, 971 procedures for spinal tumors were performed on 739 patients. Excluding sacral tumors from the current study, 895 procedures on 678 patients were reviewed to identify those cases with SSIs. Furthermore, 65 infected cases and a randomly selected subset of 162 controls were analyzed by logistic regression modeling to identify the risk factors associated with SSIs. RESULTS: There were 678 patients that were included in this study with 364 men (54%) and 314 women (46%), with an average age of 47.2 year. Sixty-five patients who developed SSIs underwent a total of 162 procedures including 78 procedures for wound debridement and washout. The incidence of SSIs was 8.89% for primary nonbony spinal tumors, 9.5% for metastatic spinal tumors, and 13.7% for primary bony spinal tumors. Staphylococcus aureus was the most commonly isolated organism (n = 22 of 65, 33%). In the multivariate logistic regression model, previous spinal surgeries, complex plastic closures, increasing number of comorbidities, presence of a hospital acquired infection at the time of a previous surgery, and increasing duration of hospital stay during primary surgery were significantly associated with increased likelihood of developing postoperative SSIs. CONCLUSION: Surgery for spine tumors appears to be associated with a higher incidence of SSI than nontumor spine surgery. Identification of perioperative risk factors will help delineate this subset of patients with high risk for developing SSIs thus potentially allowing perioperative modification for such factors, which may lead to an overall better clinical outcome and patient satisfaction. PMID- 21240051 TI - Reliability and validity of a new objective tool for low back pain functional assessment. AB - STUDY DESIGN: Classification and functional assessment model for nonspecific low back pain (LBP) patients and controls on the basis of kinematic analysis parameters. OBJECTIVE: Develop a logistic regression model using kinematic analysis variables to (1) discriminate between LBP patients and controls and (2) obtain objective parameters for LBP functional assessment. SUMMARY OF BACKGROUND DATA: Functional assessment of spinal disorders has been carried out traditionally by means of subjective scales. Objective functional techniques have been developed, which usually involve the application of external loads or the analysis of highly standardized trunk flexion-extension maneuvers. Few studies have used everyday activities such as sit-to-stand or lifting an object from the ground. They have shown that the motion patterns of LBP patients differ from those of healthy subjects. Nevertheless, very few studies have tried to correlate objective findings to the results of subjective scales, and no previous study has developed a LBP classification and functional assessment model on the basis of kinematic analysis of everyday activities. METHODS: Sixteen controls and 39 LBP patients performed a sit-to-stand task, and lifted three different weights from a standing position. The vertical forces exerted and the relative positions of the lower limb and the cervical, thoracic, lumbar, and sacroiliac regions were recorded. Reliability was determined from repetitions of the tests performed by the control group. Binary logistic regression analyses were computed. The results of the selected regression equation were correlated to the Oswestry Disability Index scale results, to check the validity of the procedure for the measurement of functional disability. RESULTS: Reliability of the parameters was good. The selected regression model used two variables, and correctly classified 97.3% of the patients. High correlations were found between the results of this regression equation and the Oswestry Disability Index scale. CONCLUSION: It is possible to distinguish LBP patients from healthy subjects by means of the biomechanical analysis of everyday tasks. This kind of analysis can produce objective and reliable indexes about the patients' degree of functional impairment. PMID- 21240052 TI - Comparison of percutaneous and open anterior screw fixation in the treatment of type II and rostral type III odontoid fractures. AB - STUDY DESIGN: Prospective controlled study of the clinical and radiographic results of a group of 42 cases having undergone anterior screw fixation for type II and rostal type III odontoid fractures. OBJECTIVE: The objective of this study is to determine the safety and efficacy of percutaneous anterior screw fixation as an alternative new technique in the management of type II and rostal type III odontoid fractures. SUMMARY OF BACKGROUND DATA: Minimally invasive spinal techniques have only recently been developed. However, clinical and radiographic outcome of minimally invasive anterior screw fixation for odontoid fractures has been evaluated in very few studies. There have been no prospective clinical reports published on the comparison of percutaneous anterior screw fixation for type II and "shallow" type III odontoid fractures or a traditional open manner. METHODS: Forty-two patients, 26 men and 16 women, with an average age of 47.1 years (32-65) were prospectively evaluated. All patients underwent percutaneous anterior screw fixation(n = 19) or open screw fixation (n = 23). The following data were compared between the two groups: operative time, blood loss, radiograph exposure time, the clinical and radiographic results, and complications. Radiologic examination of the cervical spine with plain radiographs was performed at 3, 6, and 12 months after surgery. RESULTS: In comparison with open fixation group, percutaneous fixation group had significantly less operating time and less blood loss. The radiation time and clinical outcome were basically identical in two groups. Radiographic evaluation showed satisfactory bony union and no evidence of abnormal movement at the fracture site in both percutaneous fixation group (18 of 19 cases) and open fixation group (22 of 23 cases). Two cases of postoperative dysphagia occurred in open screw fixation group. CONCLUSION: Percutaneous anterior screw fixation is a safe and reliable procedure for treatment of type II and rostral type III odontoid fractures with potential advantages. PMID- 21240053 TI - Analysis of preexistent vertebral rotation in the normal infantile, juvenile, and adolescent spine. AB - STUDY DESIGN: Vertebral rotation was systematically analyzed in the normal, nonscoliotic thoracic spine of children aged 0 to 16 years. Subgroups were created to match the infantile, juvenile, and adolescent age groups according to the criteria of the Scoliosis Research Society. OBJECTIVE: To determine whether a distinct pattern of vertebral rotation in the transverse plane exists in the normal, nonscoliotic infantile, juvenile, and adolescent spine. SUMMARY OF BACKGROUND DATA: We assume that, once the spine starts to deteriorate into a scoliotic deformity, it will follow a preexisting rotational pattern. Recently, we identified a rotational pattern in the normal nonscoliotic adult spine that corresponds to the most common curve types in adolescent idiopathic scoliosis. In infantile idiopathic scoliosis, curves are typically left sided and boys are affected more often than girls, whereas in adolescent idiopathic scoliosis, the thoracic curve is typically right sided and predominantly girls are affected. The present study is the first systematic analysis of vertebral rotation in the normal children's spine. METHODS: Vertebral rotation in the transverse plane of T2-T12 was measured by using a semiautomatic method on 146 computed tomographic scans of children (0-16 years old) without clinical or radiologic evidence of spinal pathology. Scans were mainly made for reasons such as recurrent respiratory tract infections, malignancies, or immune disorders. Vertebral rotational patterns were analyzed in the infantile (0-3-year-old), juvenile (4-9 year-old), and adolescent (10-16-year-old) boys and girls. RESULTS: In the infantile spine, vertebrae T2-T6 were significantly rotated to the left (P < 0.001). In the juvenile spine, T4 was significantly rotated to the left. In the adolescent spine, T6-T12 were significantly rotated to the right (P <= 0.001). Rotation to the left was more pronounced in infantile boys than in the girls (P = 0.023). In juvenile and adolescent children, no statistical differences in rotation were found between the sexes. CONCLUSION: These data support the hypothesis that the direction of the spinal curve in idiopathic scoliosis is determined by the built-in rotational pattern that the spine exhibits at the time of onset. The well-known predominance of right-sided thoracic curves in adolescent idiopathic scoliosis and left-sided curves in infantile idiopathic scoliosis can be explained by the observed patterns of vertebral rotation that preexist at the corresponding age. PMID- 21240054 TI - Sagittal decompensation after corrective osteotomy for lumbar degenerative kyphosis: classification and risk factors. AB - STUDY DESIGN: A retrospective study OBJECTIVE: To classify the types and identify related factors on sagittal decompensation after corrective osteotomy for lumbar degenerative kyphosis (LDK). SUMMARY OF BACKGROUND DATA: There has been a skeptical view of surgical treatment of LDK owing to loss of sagittal balance even after correction of kyphosis. However, there had been no report on the classification and risk factors of sagittal decompensation. METHODS: A total of 23 LDK patients who had undergone corrective osteotomy were enrolled. The mean follow-up period was 45.7 months. Radiographic parameters including sagittal balance, the cross-sectional area of paravertebral muscles, were analyzed. We classified the type of sagittal decompensation into thoracic (Group T) and lumbar decompensation (Group L) with a reference line from the posterosuperior corner of the sacrum to the center of the T12-L1 disc. The type of sagittal decompensation was defined with the location of T1 and the reference line at the last follow-up radiographs. RESULTS: The mean number of fusion segments was 7.7. Sagittal balance improved from 26.4 cm to 4 cm immediately after operation but deteriorated to 11.2 cm at the last follow-up. The decompensation was greater in Group T (11 cases) than in Group L (12 cases) (9.1 cm vs. 5.2 cm, P = 0.03). The comparative analysis showed significant differences between groups T and L in thoracic kyphosis at the last follow-up (Group T:L = 40.5 degrees :27.5 degrees , P = 0.04), preoperative thoracic kyphotic angle (Group T:L = 19.6 degrees :-1 degrees , P = 0.01), mean ratio of cross-sectional area of paravertebral muscles to intervertebral disc in T12-L1, and incidence of the preoperative compensatory thoracic lordosis (Group T:L = 27.3%:100%, P = 0). CONCLUSION: The mean sagittal decompensation after corrective osteotomy for LDK was 38.3%. The etiology was loss of lumbosacral lordosis in Group L and progression of kyphosis at the proximal unfused segments in addition to lumbosacral loss in Group T. The decompensation was greater in the thoracic type than in the lumbar type and was considered relevant to a large preoperative thoracic kyphotic angle, absence of compensatory thoracic lordosis, and atrophy of paravertebral muscles. PMID- 21240055 TI - Cyclosporine and lactation: when the mother is willing to breastfeed. AB - We describe a woman treated with cyclosporine after renal transplantation who commenced breastfeeding of her newborn infant. The child had no apparent clinical adverse effects to cyclosporine. To confirm the safety of breastfeeding and guide the patient and her clinician, cyclosporine concentrations in maternal blood, breast milk, and infant blood were measured. Maternal cyclosporine concentration (1-hour postdose) was 49 MUg/L, and the breast milk cyclosporine concentration (2 hour postdose) was 46 MUg/L. Infant cyclosporine blood concentration shortly after breastfeeding was undetectable (<10 MUg/L). Analysis revealed that the estimated infant exposure to cyclosporine via breast milk was minimal and provided reassurance to continue breastfeeding in this case. PMID- 21240056 TI - Urine analysis of 3,4-methylenedioxypyrovalerone in opioid-dependent patients by gas chromatography-mass spectrometry. AB - A gas chromatography-mass spectrometry (GCMS) procedure was developed for the quantitative analysis of the new designer drug methylenedioxypyrovalerone (MDPV) in urine together with the common stimulants amphetamine, methamphetamine, and methylenedioxymethamphetamine (MDMA). The procedure involved electron ionization (EI) GCMS in the selected ion monitoring (SIM) mode after liquid-liquid extraction with toluene and derivatization with heptafluorobutyric acid anhydride. All MDPV findings were confirmed by positive chemical ionization GCMS in SIM mode. Positive chemical ionization-GCMS allowed the protonated molecule M+H+ m/z 276 to be used as a target ion with 3 abundant fragments as qualifier ions. By electron ionization-GCMS, the limit of quantification (LOQ) for MDPV was 0.02 mg/L; and for amphetamine, methamphetamine, and MDMA, the LOQ was 0.05 mg/L. The method was applied to monitoring urine samples from opioid-dependent patients undergoing opioid substitution treatment. Nine of the 34 urine samples (26%) analyzed were MDPV positive by the GCMS procedure. The positive samples were obtained from 2 female and 7 male patients with a mean age of 31 years. The median (range) MDPV concentration was 0.16 mg/L (0.04-3.9 mg/L) based on the 7 samples for which a numeric value was obtained, whereas the concentration was below the LOQ but above the limit of detection in 2 samples. The method revealed amphetamine in approximately 40% of the cases, and there was no statistical difference between the MDPV-positive and MDPV-negative groups. Urine amphetamine concentrations were on average 10 times higher than those of MDPV. The opioid dependent patients used MDPV mainly as a substitute for amphetamine, judging from the laboratory findings of this study and the information from our patients. PMID- 21240057 TI - Systematic review of thiopurine methyltransferase genotype and enzymatic testing strategies. AB - BACKGROUND: An increased understanding of the genetic basis of disease creates a demand for personalized medicine and more accurate testing for diagnosis and treatment. Thiopurine methyltransferase (TPMT) plays an important role in the metabolism of thiopurine drugs used in pediatric leukemia, rheumatoid arthritis, and inflammatory bowel disease. The objective was to review the literature systematically to ascertain the performance characteristics of current genotype and enzymatic testing technologies for TPMT. METHODS: A systematic review of the literature was conducted to describe TPMT testing technologies. Eligible studies evaluated either a TPMT genotype or TPMT phenotype technology in comparison to a reference standard and expressed results in terms of sensitivity and specificity or positive/negative predictive value. The laboratory technique was recorded, and the quality of the identified studies was assessed using a modified Critical Appraisal Skills Program tool. RESULTS: Seventeen studies were reviewed. The sensitivity and specificity of the genotype test ranged from 55% to 100% and from 94% to 100%, respectively. The sensitivity and specificity of the phenotype test ranged from 92% to 100% and from 86% to 98%, respectively. A variety of laboratory techniques were employed. Reviewed studies were of low methodological quality. CONCLUSIONS: The systematic review of TPMT test strategies found that available technologies demonstrated high values for sensitivity and specificity, however, there was a lack of a single gold standard and most studies were of poor quality. Disregard for study sample size and confounding factors such as concurrent medications and blood transfusions were the main contributors to low quality. There were also inconsistencies in the selection of a reference standard which complicated the interpretation of the findings. PMID- 21240058 TI - Molecular classification of breast cancer: is it time to pack up our microscopes? AB - Breast cancer is a heterogeneous disease. The traditional classification uses morphology to divide tumours into distinct categories with differing prognosis and behavior. Despite providing high quality data cheaply, it has limitations and hence there has been a hope that the new molecular methods may help to refine the classification systems. Much has been learned in the last few years however, the molecular taxonomy is still in evolution and likely to change over the coming years. Whether the molecular classification is as useful for special subtypes of breast cancers as it has been for ductal carcinoma, no special type, remains to be determined. PMID- 21240059 TI - The evolution of the histology in pleomorphic xanthoastrocytomas in children: a study of 15 cases. AB - AIMS: To review the clinicopathological spectrum and evolution of the histology of pleomorphic xanthoastrocytomas (PXAs) seen at a single children's hospital. METHODS: PXAs were selected from the Royal Children's Hospital archives over 30 years. The clinical features and pathology were reviewed, specifically checking the histological variation between areas, and the changes between biopsies. RESULTS: Fifteen patients were identified. Ten had repeat biopsies. Eleven patients did not show histological features of anaplasia. Of these eleven, three did not show the characteristic histological features, which developed 3 and 11 years later in repeat biopsies in two. Seven showed uncommon potentially confusing histology. One died, one had stable disease and one had progressive disease. Three with incomplete initial surgery remained in complete remission following more surgery, radiotherapy and chemotherapy when the tumours progressed, up to 11 years later. Four patients did show anaplasia, with abrupt change from typical PXA in two, and years following initial biopsy in one. Of these four patients, three died, one with extensive metastasis. CONCLUSIONS: PXA should be considered in superficial cerebral tumours composed only of compact bundles of glial fibrillary acidic protein positive spindle cells with inconspicuous mitosis, even when the highly characteristic features of this tumour are not seen. The prominent variation in histology makes small biopsies difficult for diagnosis and assessing anaplasia. Patients with non-anaplastic tumours can often be salvaged by more treatment for tumour progression. PMID- 21240060 TI - INI1 immunohistochemical expression in glioblastoma: correlation with MGMT gene promoter methylation status and patient survival. AB - AIMS: INI1 expression and its correlation with MGMT gene promoter methylation status and follow-up was investigated in 77 surgically removed glioblastomas then treated with radiotherapy (RT) or RT plus temozolomide (TMZ). METHODS: INI1 was determined by immunohistochemistry and MGMT by methylation-specific PCR. RESULTS: INI1 was expressed in 83.1% of cases. The median overall survival (OS) was 13.6 months in INI1+ tumours and 7.2 months in INI1- tumours. 31.3% of patients with INI1+ tumours were alive compared with 15.4% of patients with INI1- tumours. MGMT methylation was detected in 31.2% of cases. OS was significantly different between patients with methylated tumours and un-methylated tumours (p < 0.04), and between patients with RT+ TMZ and RT alone (p < 0.001). Considering both treatment and MGMT, the difference in OS was significant (p < 0.002). The difference in OS according to MGMT and INI1 was significant (p < 0.04). The longest median OS was recorded among methylated and INI1+ tumours. Among un methylated tumours, the median OS was 11.1 months in INI1+ and 6.5 months in INI1 tumours. No patients were alive with un-methylated and INI1- tumours. CONCLUSIONS: Loss of INI1 immunohistochemical expression in glioblastoma may be indicating an underlying molecular aberration accounting for the more aggressive clinical behaviour. PMID- 21240061 TI - Histopathological regression grading versus staging of rectal cancer following radiotherapy. AB - AIMS: To compare histological grading of rectal cancer radiotherapy response with pathological staging as a prognostic indicator. METHODS: Histological tumour regression was five tier graded in 102 rectal cancer patients treated with preoperative radiotherapy [short course (n = 34), long course (n = 68)]. Differences between these grades and between the two radiotherapy regimes were assessed. These variables, pTMN staging and others were correlated with relapse free survival at 3 years. RESULTS: 22 patients suffered disease recurrence and four died during a mean post-operative follow-up of 40.3 months. There were 52 good responders (tumour regression grades 1-3) and 50 poor responders (tumour regression grades 4-5). Regression was greater following the long course regime (p < 0.0001). Otherwise, there were no significant differences between the response groups and between the two regimes, including the number of lymph nodes found in the resected bowel. Only the pN status correlated with relapse free survival on multivariate analysis (p = 0.0004; HR = 4.26, 95%CI = 1.66-10.93 for pN2 versus pN0). CONCLUSIONS: The number of lymph nodes found for staging was not influenced by either the extent of primary tumour regression or the type of radiotherapy. pN status, but not tumour regression grade, is a reliable predictor of survival. PMID- 21240062 TI - Sclerosing nodular lesions of the gastrointestinal tract containing large numbers of IgG4 plasma cells. AB - BACKGROUND: Hyalinised fibrous nodules have been encountered within the gastrointestinal tract (GIT) and been labelled as reactive nodular fibrous tumours. Several have a history of abdominal surgery and/or sepsis that acts as a precipitating cause for the fibrosis. Recently, much attention has been focused on IgG4 related fibrosing lesions that are typically associated with a high population of IgG4 positive plasma cells and tissue fibrosis. There may be attendant elevated serum IgG4 levels and associated autoimmune disease. METHODS: We present four patients with well-circumscribed fibrous nodular lesions occurring in the GIT. Tissue was formalin fixed after microwave antigen retrieval and H&E stains and immunohistochemistry were performed. IgG4/IgG ratios were calculated from the three high power fields containing the densest concentration of positive plasma cells. RESULTS: The patients were two females (45 and 56 years) and two males (47 and 60 years) who presented with gastric (2 cases), caecal and sigmoid flexure involvement. One case had four lesions while the other three cases were solitary nodules. Two patients had coexistent autoimmune disease. All lesions were nodular and composed of paucicellular, hyalinised fibrous tissue associated with chronic inflammation. In all lesions the plasma cell population was strongly IgG4 positive. CONCLUSIONS: This paper describes unique, well-circumscribed sclerosing nodules containing IgG4 positive plasma cells within the bowel wall that may cause mucosal polypoid lesions. It is possible that these lesions may be related to the spectrum of IgG4 related sclerosing disease or belong to a separate subset of inflammatory reactive conditions that are rich in IgG4 plasma cells. PMID- 21240063 TI - Adenocarcinomas associated with perianal fistulae in Crohn's disease have a rectal, not an anal, immunophenotype. AB - AIMS: Perianal fistulae are often observed in patients with Crohn's disease (CD), although the development of associated adenocarcinomas is very rare. The origin of adenocarcinomas in perianal fistulae associated with CD remains controversial and includes adjacent anal glands or rectal mucosa. Here, we attempted to determine the origin. METHODS: We performed immunohistochemical analysis on seven cases of adenocarcinomas in perianal fistulae associated with CD using antibodies against mucins (MUCs), cytokeratins (CKs) and the intestine-specific transcription factor CDX2. RESULTS: MUC2 and CK20 were expressed in all seven adenocarcinomas examined. MUC5AC/CLH2, MUC5AC/HGM and CDX2 were positive in four (57%), five (71%), and five (71%) adenocarcinomas, respectively. These proteins were positive in rectal mucosa, and negative in the anal glands. Six of seven adenocarcinomas (86%) were negative for CK7. CK7 was expressed in the anal glands, but not in rectal mucosa. CONCLUSIONS: Adenocarcinomas in perianal fistulae associated with CD showed immunohistochemical phenotypes similar to those of rectal-type mucosa, rather than the anal glands. The adenocarcinomas might originate from cells migrating from the adjacent rectal mucosa to the CD associated perianal fistulae. PMID- 21240064 TI - Quantitative analysis of the expression of TGF-alpha and EGFR in papillary thyroid carcinoma: clinicopathological relevance. AB - AIMS: There are no quantitative data on the mRNA expression of epidermal growth factor receptor (EGFR) and transformation growth factor alpha (TGF-alpha) in thyroid carcinoma. The aims of this study were to detect, quantify and analyse the clinicopathological correlations of the expression of these genes in a large cohort of patients with thyroid carcinoma. METHODS: EGFR and TGF-alpha expression were investigated using real time quantitative polymerase chain reaction and immunohistochemistry on 71 papillary thyroid carcinomas (PTCs), 68 paired non cancer thyroid tissues adjacent to the PTC and 20 benign thyroid lesions. RESULTS: TGF-alpha and EGFR mRNA increased in PTC when compared with benign thyroid lesions. In many PTCs with high level of expression of TGF-alpha and EGFR mRNA, the morphological non-cancer tissue adjacent to the cancer also showed high levels of expression of these mRNAs. The levels of expression of mRNA of TGF alpha and EGFR correlated with each other and with the level of protein expression. The level of expression of TGF-alpha mRNA was significantly related to lymphovascular permeation while the expression of EGFR mRNA was related to the pathological subtype of PTC and cancer recurrence. CONCLUSIONS: TGF-alpha and EGFR were overexpressed, correlated with each other and associated with the pathological parameters in papillary thyroid carcinoma. The results provide information for management of thyroid cancer in the era of gene targeting therapy. PMID- 21240065 TI - Inflammatory monomorphic undifferentiated sarcoma with distinct clinical and pathological features: a 'new' entity? AB - AIM: To describe two patients with a highly aggressive, apparently 'new' and rare soft tissue and bone malignancy of childhood and early adult life that we have named inflammatory monomorphic undifferentiated sarcoma. METHODS AND RESULTS: Two histologically identical tumours located in the proximal humerus and the anterior chest wall of males aged 6 and 31 presented as solitary, painful, tender, necrotising, masses, associated with fever, leukocytosis and negative microbiological cultures. The extensively necrotic resected tumours consisted of large, monomorphic epithelioid cells with vesicular nuclei, prominent eosinophilic nucleoli, and abundant eosinophilic cytoplasm surrounded by numerous neutrophils and eosinophils which formed sterile microabscesses. Immunohistochemical and ultrastructural studies revealed no specific differentiation. Both tumours were very aggressive, with early local recurrence, metastasis to regional and distant lymph nodes and viscera, and no response to several different chemotherapeutic regimens. CONCLUSION: A careful review of the literature led us to believe that inflammatory monomorphic undifferentiated sarcoma may represent a rare and distinct clinicopathological entity that does not appear to have been previously described. PMID- 21240066 TI - Plasmablastic lymphoma involving the penis: a previously unreported location of a case with aberrant CD3 expression. AB - Lymphomas of the penis are rare and can either arise at this site or be a manifestation of systemic disease. We report the case of an elderly man with a plasmablastic lymphoma (PBL) involving the uncircumcised penile prepuce. The neoplasm was composed of plasmablasts positive for monotypic immunoglobulin lambda light chain, CD3, CD79a, CD138 and Epstein-Barr virus encoded RNA (EBER), and was negative for CD2, CD5, CD7, CD20, and PAX5. This case is highly unusual for at least two reasons. The penile foreskin is a rare location for lymphoma and PBL at this site has not been reported. Secondly, the tumour was shown by immunohistochemistry to be positive for the T-cell marker CD3. Lineage ambiguity in terminally differentiated B-cell lymphomas has been reported to be closely related with immune compromise and is associated with Epstein-Barr virus infection. The literature on penile lymphomas is also reviewed. PMID- 21240067 TI - Improved identification of Gordonia, Rhodococcus and Tsukamurella species by 5' end 16S rRNA gene sequencing. AB - OBJECTIVES: The identification of fastidious aerobic Actinomycetes such as Gordonia, Rhodococcus, and Tsukamurella has remained a challenge leading to clinically significant misclassifications. This study is intended to examine the feasibility of partial 5'-end 16S rRNA gene sequencing for the identification of Gordonia, Rhodococcus, and Tsukamurella, and defined potential reference sequences for species from each of these genera. METHODS: The 16S rRNA gene sequence based identification algorithm for species identification was used and enhanced by aligning test sequences with reference sequences from the List of Prokaryotic Names with Standing in Nomenclature. RESULTS: Conventional PCR based 16S rRNA gene sequencing and the alignment of the isolate 16S rRNA gene sequence with reference sequences accurately identified 100% of clinical strains of aerobic Actinomycetes. While partial 16S rRNA gene sequences of reference type strains matched with the 16S rRNA gene sequences of 19 isolates in our data set, another 13 strains demonstrated a degree of polymorphism with a 1-4 bp difference in the regions of difference. CONCLUSIONS: 5'-end 606 bp 16S rRNA gene sequencing, coupled with the assignment of well defined reference sequences to clinically relevant species of bacteria, can be a useful strategy for improving the identification of clinically relevant aerobic Actinomycetes. PMID- 21240068 TI - Age-specific prevalence of herpes simplex viruses in Melbourne. AB - AIMS: To characterise the epidemiology of anogenital herpes in Melbourne by detailing the age-specific prevalence of herpes simplex virus (HSV) 1 and HSV 2. METHODS: A cross-sectional study of 2055 anogenital specimens assayed by polymerase chain reaction (PCR) for HSV 1 and 2 at Melbourne Pathology from 1 August 2004 to 11 May 2005 was conducted. Results were analysed by age and sex. RESULTS: PCR demonstrated HSV 1 in 44.1% of all anogenital herpes cases. The relative prevalence of HSV 1 decreased as a function of increasing age. In patients under the age of 20, 18.2% of cases of anogenital herpes were due to HSV 2, as compared with 84.6% in patients over the age of 50. CONCLUSIONS: In this study population a clear relationship is seen between age and relative frequency of HSV 1 and 2 as a cause of anogenital herpes. HSV 2 accounts for only a small proportion of infections in younger patients. PMID- 21240069 TI - Follicular dendritic cell sarcoma of the lung: a report of two cases highlighting its pathological features and diagnostic pitfalls. PMID- 21240070 TI - Pulmonary haptoglobin: a new marker for adenocarcinomas of the lung? PMID- 21240071 TI - Determination of a molecular signature of acute T-cell-mediated renal allograft rejection using quantitative real-time RT-PCR of 45 genes on a low density array. PMID- 21240072 TI - Cytotoxic T-cell lymphoma complicating common variable immunodeficiency. PMID- 21240073 TI - Mutational analysis of mononucleotide repeats in XRCC2 and XRCC6 in cancers with microsatellite instability. PMID- 21240075 TI - CBS gene mutations found in a Chinese pyridoxine-responsive homocystinuria patient. PMID- 21240074 TI - Aggressive angiomyxoma of the sphenoidal sinus. PMID- 21240076 TI - Transient monoclonal gammopathy in a patient with scrub typhus. PMID- 21240077 TI - Immunohistochemistry for PMS2 and MSH6 alone can replace a four antibody panel for mismatch repair deficiency screening in colorectal adenocarcinoma. PMID- 21240079 TI - Paraprotein interferences in routine laboratory assays. PMID- 21240080 TI - Living and working longer with cancer. PMID- 21240081 TI - Smoking cessation for older people: neither too little nor too late. AB - Community nurses are uniquely placed to facilitate smoking cessation with older people. Older people who smoke in the home expose not only themselves to the many health risks associated with tobacco use but also partners, children and grandchildren through second-hand smoke. Yet research has found that community nurses have several concerns about raising the issue of smoking in the home with older people including taking away one of their few pleasures; fear that the damage is done; damaging the professional relationship and a lack of knowledge about smoking cessation advice and services. In this article the authors acknowledge and challenge these concerns to encourage community nurses to embed smoking cessation in their daily practice with older people. PMID- 21240082 TI - Education in geriatric medicine for community hospital staff. AB - Community hospitals provide many services for older people. They are mainly managed by nursing staff, with some specialist input. Little is known about education provided in these facilities. Most education in geriatric medicine is provided in hospitals, despite most elderly care being provided in the community. The authors surveyed senior nursing staff in Irish community hospitals to examine this area in more detail. Staff in all 18hospitals in the Health Service Executive (South) area were invited to participate. The response rate was 100%. Sixteen of the 18 respondents (89%) felt staff did not have enough education in geriatric medicine. Just over half of hospitals had regular staff education sessions in the area, with a minority of sessions led by a geriatrician, and none by GPs. Geriatrician visits were valued, but were requested only every 1-3 months. Staff identified challenging behaviour and dementia care as the areas that posed most difficulty. PMID- 21240083 TI - Exploring the concept of quality care for the person who is dying. AB - The concept of good quality care for the patient who is dying is diverse and complex. Many of the actions that are being taken to increase the quality of care of the dying patient are based around outcome, uniformity of service and standardization of process. There are two main areas that are referred to when dealing with care of the dying patient; end-of-life care and palliative care. High quality end-of-life care is increasingly recognized as an ethical obligation of health-care providers, clinicians and organizations, and yet there appears little evidence from the patients' perspective. There are many national and local initiatives taking place to improve the quality of care people receive towards the end of their life. This being said initiatives alone will not achieve good quality care and deliver good patient experiences. Only clinicians working at the front line can truly influence the way in which quality is improved and good experiences delivered. PMID- 21240084 TI - Reflect for success: recommendations for mentors managing failing students. AB - Failing a student nurse for not meeting clinical competency on a practice placement can be a distressing and traumatic event for both student and community nurse mentor. This paper describes how a reflective model can be used to support practitioners' to come to terms with the decision and action of failing a student and dealing with the aftermath of the final interview. PMID- 21240085 TI - The Health and Social Care Act 2008. AB - Several inquiry reports have shown that there is still a need to further improve health and social care and strengthen public confidence in these services. The reports have particularly emphasized the need for stricter regulation of health and adult social care providers and the need to use statutory powers to ensure compliance with quality and safety standards.This article outlines how the provisions of the Health and Social Care Act 2008 aim to address this need to further regulate quality and safety standards in health and social care. PMID- 21240086 TI - Cuts, concerns and compromise: standards must not be jeopardized. AB - One month into the Right Nurse, Right Skills Campaign, Rosemary Cook summarizes the evidence gathered so far and urges managers and team members to share their views. PMID- 21240087 TI - Achieving excellence in postgraduate community nurse practice placements. AB - This qualitative research using focus groups and an online questionnaire into excellent postgraduate community nurse placements concluded that student trainees need to be ensured of diverse and new experiences besides being recognized by practice staff as already qualified nurses with an array of existing experience. Their community practice teacher trainers need to be trained to cope with postgraduate versus pre-registration needs and especially aware of tailoring nurse experiences to the individual. This requires a finer awareness of their knowledge and student status along with ambivalent needs requiring guidance but space to work independently. Delphi Experts concluded trainer motivation and support most crucial elements in postgraduate placements along with clarity of expectations. Basic introduction and administration sets learning in motion and Start right, stay right! is a catchword to abide by. PMID- 21240088 TI - Decision making within a community provider organization. AB - AIM: To explore community nurses' experiences of decision making within the community provider organization. BACKGROUND: Recent changes in health care with an increasing number of patients being cared for outside of institutions can put considerable pressure on the nurse with respect to decision making. METHODS: In depth interviews were performed with 6 registered nurses in two communities. The interviews were analysed by means of phenomenological hermeneutics. RESULTS: The community nurses' experiences of decision making were interpreted as spiders or octopuses, consultants and troubleshooters. The subthemes were; networking and structuring, responsibility, availability and knowledge, assessment power, information selection, avoiding rules and bypassing managers. In accordance with hermeneutical phenomenology, the findings were discussed and explained with reference to Ofstad's philosophy of freedom to make decisions. CONCLUSION: In their decision making, community nurses are committed to finding administrative solutions that satisfy patient needs. PMID- 21240089 TI - Prioritizing COPD care. PMID- 21240098 TI - Limits to autonomy and personalization. PMID- 21240099 TI - The use of bevacizumab for the treatment of colorectal cancer. PMID- 21240100 TI - What is the real cost of bevacizumab for patients with advanced bowel cancer? PMID- 21240101 TI - The mourning before: can anticipatory grief theory inform family care in adult intensive care? AB - Although anticipatory grief is a much-debated and critiqued bereavement concept, it does offer a way of understanding and exploring expected loss that may be helpful in certain situations. In end-of-life care in adult intensive care units, families often act as proxy decision makers for patients in the transition from curative treatment efforts to planned treatment withdrawal. Despite there being a developed evidence base to inform care of families at this time, few of the clinical studies that provided this evidence were underpinned by bereavement theory. Focusing on end-of-life intensive care practices, this paper integrates work on anticipatory grief and family interventions to present a family-centred framework of care. Through this it is argued that the complex needs of families must be more comprehensively understood by doctors and nurses and that interventions must be more systematically planned to improve quality end-of-life care for families in this setting. PMID- 21240102 TI - Psychological distress in Icelandic patients with repeated recurrences of cancer. AB - AIM: The main aim was to investigate differences between the psychological distress of patients with a first diagnosis of cancer, those experiencing their first recurrence, and those experiencing later recurrences. Little is known about the development of cancer patients' psychological distress and whether it becomes more severe with greater incidence of recurrence. METHOD: A total of 218 patients from 3 oncology outpatient clinics in Iceland were assessed with the Brief Symptom Inventory Scale 18 (BSI 18). RESULTS: Several aspects of cancer patients' psychological distress seem to positively correlate with number of recurrences, and women experience a recurrence of cancer differently to men. CONCLUSION: Health-care professionals need to be aware of patients' likely distress levels at different stages of their illness and the ways in which their gender might affect their psychological state. PMID- 21240103 TI - Nurses' and care workers' attitudes toward death and caring for dying older adults in Japan. AB - Registered nurses (RNs) and care workers (CWs) have important roles in providing end-of-life care to older adults, but little is known about the attitudes of RNs and CWs in Japan. In this study, 464 RNs and CWs working in facilities in Japan were asked to complete a self-administered questionnaire that included the Frommelt Attitude Toward Care of the Dying Scale, Form B, Japanese version (FATCOD-Form B-J) and the Death Attitude Profile (DAP), Japanese version. A total of 388 (83.6%) questionnaires were returned, and 367 (79.1%) were fully completed. The final sample included 190 RNs and 177 CWs. Multiple regression analysis showed that better attitudes toward caring for the dying were positively associated with seminar attendance and negatively associated with fear of death. PMID- 21240104 TI - Psychological contracts of hospice nurses. AB - Psychological contracts have been described as individuals' beliefs regarding the obligations, expectations, and contributions that exist between them and their employer. They can be influenced by the organization's culture and philosophy, through human resources policies, and through the employee's personality and characteristics. Owing to the recent economic crisis, hospices in the UK are currently in a transitional phase and are being expected to demonstrate efficiencies that might be more in line with a business model than a health-care environment. This may conflict with the philosophical views of hospice nurses. To support nurses through this transition, it might be helpful to understand the antecedents of hospice nurses' behaviour and how they construct their psychological contracts. Failure to offer adequate support might lead to negative outcomes such as a desire to leave the organisation, poorer quality work, or disruptive behaviour. This study used a modified grounded theory approach involving in-depth interviews to explore the context and content of the psychological contracts of hospice nurses in the UK. Four main themes emerged: the types of psychological contracts formed, how the contracts are formed, their contents, and the breaches and potential violations the nurses perceive. PMID- 21240105 TI - Maintaining hope when close to death: insight from cancer patients in palliative home care. AB - PURPOSE: This article reports the social and psychological processes that 11 cancer patients receiving palliative home care used to keep their hope alive. METHOD: The patients described their ways of dealing with hope in interviews and diaries, and it was from these accounts that the processes were extracted, using a grounded theory methodology. RESULTS: Two main processes emerged: maintaining life and preparing for death. When the patients focused on maintaining life, they tried to preserve its meaning and to communicate with others about life and death. They found it helpful to shift their focus and to involve fellow 'travellers' in their journey. To prepare for death was to take responsibility for the future and to see possibilities of living on even after death. CONCLUSION: This paper revealed two parallel and interdependent processes used by patients in the palliative care phase to maintain hope and respond to living close to death. PMID- 21240106 TI - Development of palliative care in nursing homes: evaluation of a Danish project. AB - BACKGROUND: There is a general lack of research regarding the palliative care of nursing home residents and professional education in palliation in Denmark. Qualification requirements need to be established, best practices must be spread, and a systematic approach to providing competent palliative care in nursing homes must be found. PURPOSE: The purpose of this study was to evaluate an attempt to develop--through three pedagogical methods--the palliative care competencies of the personnel and make organizational improvements at three Danish nursing homes. METHOD: A process-based, user-oriented evaluation method was used. Twenty-two nursing home employees and five teachers participated in five focus group interviews. RESULTS: Both the nursing home employees and the teachers felt that the project as a whole, and the three methods used, contributed to an improvement in the staff 's palliative care competencies and the organization. CONCLUSION: The study exposes the barriers to improving Danish palliative care provision and factors required for development to succeed. It highlights the need for recognition by colleagues, active involvement of nursing home managers, and a certain understanding of the methods, including the importance of prioritizing practice-based competence training. PMID- 21240108 TI - The 21st century doctor. PMID- 21240109 TI - Medication adherence and patient choice in mental health. PMID- 21240111 TI - Gluteus medius tears: an under-diagnosed pathology. AB - Tears of the gluteus medius tendon contribute to greater trochanteric pain syndrome, but they are often overlooked as a cause of lateral hip pain and tenderness. This review presents the relevant anatomy, pathophysiology, diagnostic workup, differential diagnosis and management of these tears. PMID- 21240112 TI - Peripheral muscle dysfunction and chronic obstructive pulmonary disease. AB - Chronic obstructive pulmonary disease is a systemic disease that includes significant adverse effects on muscle function, with varied changes to the structure and metabolism of the peripheral muscles. This review evaluates the evidence for the mechanisms that mediate these changes and the significance of the diminished muscle function. PMID- 21240113 TI - Trampolining injuries. AB - Trampoline-related injuries have increased dramatically over the last few years. This article presents a review of the literature summarizing the different types and mechanisms of sustaining such injuries and looks at current recommendations to prevent them. PMID- 21240114 TI - Ophthalmic manifestations of giant cell arteritis. AB - This article reviews the ophthalmic manifestations of giant cell arteritis. An overview of giant cell arteritis as a disease spectrum is presented with special emphasis on the ophthalmic involvement. PMID- 21240115 TI - Wernicke's encephalopathy: a preventable cause of maternal death. AB - Wernicke's encephalopathy is a rare cause of maternal death. It is a difficult diagnosis to make but prevention and treatment is straightforward. Severe thiamine deficiency causes Wernicke-Korsakoff syndrome. Correct diagnosis and treatment with thiamine will decrease the case fatality rate. PMID- 21240116 TI - How will health-care organizations meet venous thromboembolism targets? AB - Health-care organizations need to develop a strategy to ensure that all hospitalized patients receive appropriate thromboprophylaxis. This review describes an evidence-based model which could improve service delivery, meet national targets, save money and reduce the incidence of hospital-acquired venous thromboembolism. PMID- 21240117 TI - Dyslexia. AB - Despite over 100 years of research, dyslexia continues to be controversial because of the failure to agree on a definition and underlying causes, as well as the funding implications. This article identifies evidence-based factors that influence the development of reading and may cause difficulties, and the areas of continuing controversy. PMID- 21240118 TI - Can an understanding of transactional analysis improve postgraduate clinical supervision? AB - Clinical supervision in postgraduate medical training is vital in producing competent and safe health-care practitioners. Effective communication between supervisors and trainees at an interpersonal and professional level determines the quality of the supervision process. Transactional analysis, a theory of personality, can be used to enhance understanding of interpersonal interactions and improve the outcomes of clinical training. PMID- 21240119 TI - Pierre Franco: master surgeon in the 16th century. PMID- 21240120 TI - Aortic dissection and cytomegalovirus activation: a possible link? PMID- 21240121 TI - Myxoedematous pre-coma and heart failure. PMID- 21240123 TI - Something to remember... PMID- 21240122 TI - Tonsillectomy: a routine procedure? PMID- 21240126 TI - Should echocardiography become a core skill for intensivists? PMID- 21240127 TI - Abnormal saline: redressing the balance. PMID- 21240128 TI - Dizziness in the elderly. PMID- 21240129 TI - Paediatric supracondylar fractures of the humerus: acute assessment and management. PMID- 21240130 TI - Imaging the small bowel. PMID- 21240131 TI - Learning to value disability. PMID- 21240132 TI - Advanced level nursing. PMID- 21240133 TI - Attitudes to sexuality of patients with learning disabilities: a review. AB - OBJECTIVE: A critical review of the literature to determine the attitudes of staff and families towards the sexuality of adults who have learning disabilities. DESIGN: An evidence-based practice literature search of all published studies conducted since 2000. This included a comprehensive review of books, electronic databases, grey literature and hand-searching. Four key studies were identified and subjected to critical analysis. METHOD OF CRITIQUE: The four key studies yielded were critically analysed using a framework developed by Parahoo (2006). This critiquing tool identifies seven key areas: title, abstract, literature review, methodology, data analysis and results, discussion and interpretation, and conclusions and recommendations. RESULTS: All four studies uniquely addressed similar issues in practice; there are areas of bias and concerns about the reliability of some of the studies critiqued. Similar themes were identified, suggesting that the results could be replicated in further studies. Education for staff was a key theme throughout the studies. CONCLUSIONS: Education for staff is vital to ensure that a consistent approach is taken to support adults who have learning disabilities to express their sexuality. In order to facilitate the changes required in practice, leadership, education and a support network are required. Recommendations from this review include training on leadership and on the sexuality of adults with learning disabilities for all staff. PMID- 21240134 TI - The Valued People Project: users' views on learning disability nursing. AB - A well-educated and trained workforce is undoubtedly crucial to the development of quality care for people with learning disabilities. Notwithstanding this, and unsure as to the need to continue to commission educational programmes for one part of this workforce-pre-registration learning disability nursing-South Central Strategic Health Authority commissioned the Valued People Project to undertake a detailed strategic review of educational commissioning, along with a review of the specialist learning disability health workforce more generally. This project has recently been completed, and provides a unique evidence-based expert evaluation of the future strategic direction of education commissioning and leadership for workforce issues in specialist learning disability services, as well as the wider NHS workforce. This is the first in a series of articles that reports on one aspect of the project: the focus group work undertaken with parents and relatives of people with learning disabilities, and people with learning disabilities themselves, as to the need and type of health workforce needed to support them in the future. The article concludes by identifying the key messages of importance from parents and people with learning disabilities concerning the future specialist and wider NHS workforce. PMID- 21240135 TI - Colostomy, management and quality of life for the patient. AB - The aim of this article is to describe the development and use of a new and unique continence control device (CCD). The Vitala TM CCD is a pouchless ostomy device that seals against the stoma and prevents the passage of stool, while allowing the release and deodorization of flatus. This will enable many end colostomates to control their effluent. It is the first non-invasive product to temporarily meet the colostomate's need of faecal continence. The reasons why people receive stomas and the different products available for their management will be explored in this article. Issues with regard to quality of life and the patient experience are discussed in the context of results from a VitalaTM CCD phase III 12-hour study. Two short case studies are also presented to illustrate how VitalaTM CCD can be used by ostomates experiencing functional and/or psychological problems to improve quality of life by allowing them to regain continence for up to 12 hours. PMID- 21240136 TI - Management of COPD using the Roper-Logan-Tierney framework. AB - This article reviews the health condition of a patient with chronic obstructive pulmonary disease (COPD). It discusses the use of the Roper-Logan-Tierney activities of daily living framework model, in conjunction with the nursing process to identify the patient's main priorities for nursing care. COPD is the fifth most common cause of morbidity and mortality in the UK. It is a chronic illness often caused by smoking. The disease is a life-long illness and can affect all aspects of the person's life. Furthermore, exacerbations are often poorly controlled resulting in more frequent admissions to hospital, placing more pressure on patients, nurses and healthcare services. Aspects of care related to breathing, eating and drinking, and maintaining a safe environment are explored. The nursing process, as a systemic tool, can help in identifying and understanding the individual needs of patients and aid in establishing patient centred therapeutic care. PMID- 21240137 TI - Balloon gastrostomy tubes for long-term feeding in the community. AB - AIM: Dysphagic patients with functional guts often receive nutritional and hydration support through enteral feeding tubes. These include percutaneous endoscopic gastrostomy (PEG) and radiologically inserted gastrostomy (RIG) tubes. The balloon gastrostomy tube (BGT) as a primary tube of choice in tube-fed patients, including head and neck cancer patients, offers a new approach to enteral tube feeding in the community. There are complications associated with the use of enteral feeding tubes. This study compared the complication rates and the costs of PEG tubes and BGTs in patients on long-term enteral feeding in the community and looked at the possible use of BGTs as an alternative to PEG tubes. METHODS: The records of all 15 BGT-fed patients on the caseload and 15 randomly selected PEG tube-fed patients were reviewed. The study was based on two consecutive visits to these patients. Tube and stoma complications were clinically scored in order of increasing severity (0-10) and statistically tested. The prevalence of stoma and tube complications was expressed in percentages. RESULTS: There was no significant difference (P>0.05) in the overall clinical scores between BGT-fed and PEG tube-fed patients at both initial and final visits. However, with regard to specific complications-infected sites, tube dislodgement, overgranulation, and infection with overgranulation-significant differences were observed between the two groups of patients at the initial and final visits. In addition, the total costs of inserting and managing BGTs were significantly higher than those for PEG tubes. CONCLUSIONS: Although BGTs may be used as analternative to PEG tubes in patients on long-term enteral feeding in the community, the higher cost of using BGTs over PEG tubes should be considered when selecting feeding tubes for these patients. PMID- 21240138 TI - Building the future: children's views on nurses and hospital care. AB - Healthcare policies such as standard 7 of the National Service Framework for Children, Young People and Maternity Services and the new NMC standards for pre registration nursing programmes emphasise the need for universities and their partner trusts to engage with patients and the public in developing both nurse training courses and services. This article describes a two-arm study into the views and experiences of children with regard to hospitals. Conducted as part of an ongoing commitment to the reconfiguration of children's services and the development of a new undergraduate children's nursing programme, the study collected data from 61 children in two children's hospitals in the south of England and from eight members of a city youth parliament. AIMS: The study sought to involve child users in service planning through two objectives: 1) to ascertain the views of children and young people on what skills, knowledge and attitudes, children's nurses of the future will need to care for sick children and their families; and 2) to seek the views of young people on what children think about before being admitted to hospital, and subsequently as inpatients. METHOD: The study used a draw and write/tell technique. The main outcome measures were description and analysis of those attributes which children believe nurses of the future should possess, and of those factors which inhibit or enhance childhood hospital admission. RESULTS: A number of themes emerged from analysis of the data: notably that children's nurses of the future should be skilled in both verbal and non-verbal communication, as well as having fundamental clinical skills. Issues relating to children about to be admitted to hospital included being scared or worried, and fear of the unknown, while concerns after admission to hospital related to the care environment, social needs, and individual/ personal needs and requirements. CONCLUSIONS: This patient and public involvement study revealed a number areas that children and young people believe to be important for the future training of children's nurses. Additionally, the factors which children consider inhibit or enhance the experience of hospital admission have been identified. PMID- 21240139 TI - Campus living: segregation or creating a true community? PMID- 21240140 TI - Writing for professional publication. Part 5: creating interest. AB - The first four parts of this series on writing for professional publication focused on the research and preparation required before beginning to write a potential article. In this fifth part of the series, John Fowler, an experienced nursing lecturer and author, explores the final step in preparation for writing: that of creating interest. PMID- 21240141 TI - Advanced-level nursing: a benchmark for patient care. PMID- 21240142 TI - Monitoring health services' use of the Mental Health Act. AB - John Tingle discusses the Care Quality Commission's first report on the exercise of its functions in keeping under review the operation of the Mental Health Act 1983. PMID- 21240143 TI - Liberating the NHS: a brave new world, or litigation nightmare? AB - The coalition Government, in its White Paper Equity and Excellence: Liberating the NHS and in the subsequent paper Liberating the NHS: the new Legislative Framework has advanced its proposals for NHS restructuring. These proposals are intended to provide much enhanced roles for GPs in relation to the commissioning of NHS services in the future. This article explores these proposals and considers whether they can be seen as a return to the 1990s and the approach of the NHS Community Care Act 1990. It also explores the nature of these greater responsibilities and some of the problems that this may give rise to in the future. PMID- 21240144 TI - Cleansing stations. PMID- 21240145 TI - Nursing concerns for 2011. PMID- 21240146 TI - 3-Acetyloxy-2-cyano-2-(alkylaminocarbamoyl)propyl groups as biodegradable protecting groups of nucleoside 5'-mono-phosphates. AB - Thymidine 5'-bis[3-acetyloxy-2-cyano-2-(2-phenylethylcarbamoyl)propyl]phosphate (1) has been prepared and the removal of phosphate protecting groups by hog liver carboxyesterase (HLE) at pH 7.5 and 37 degrees C has been followed by HPLC. The first detectable intermediates are the (R(P))- and (S(P))-diastereomers of the monodeacetylated triester 14, which subsequently undergo concurrent retro-aldol condensation to diester 4 and enzyme-catalyzed hydrolysis to the fully deacetylated triester 15. The former pathway predominates, representing 90% of the overall breakdown of 14. The diester 4 undergoes the enzymatic deacetylation 700 times less readily than the triester, but gives finally thymidine 5' monophosphate as the desired main product. To elucidate the potential toxicity of the electrophilic 2-cyano-N-(2-phenylethyl)acrylamideby-product 17 released upon the deprotection, the hydrolysis of 1 has also been studied in the presence of glutathione (GSH). PMID- 21240147 TI - Homopolymerization of ethylene, 1-hexene, styrene and copolymerization of styrene with 1,3-cyclohexadiene using (eta5-tetramethylcyclopentadienyl)dimethylsilyl(N Ar')amido-TiCl2/MAO (Ar'=6-(2-(diethylboryl)phenyl)pyrid-2-yl, biphen-3-yl). AB - The propensity of a half-sandwich (eta5-tetramethylcyclopentadienyl) dimethylsilylamido Ti(IV)-based catalyst bearing an auxiliary diethylboryl protected pyridyl moiety (Ti-8), activated by methylaluminoxane (MAO) to homopolymerize alpha-olefins such as ethylene, 1-hexene and styrene as well as to copolymerize styrene with 1,3-cyclo-hexadiene is described. The reactivity of Ti 8 was investigated in comparison to a 6-(2-(diethylboryl)phenyl)pyrid-2-yl-free analogue (Ti-3). PMID- 21240148 TI - Phytochemical and cytotoxic investigations of Alpinia mutica rhizomes. AB - The methanol and fractionated extracts (hexane, ethyl acetate and water) of Alpinia mutica (Zingiberaceae) rhizomes were investigated for their cytotoxic effect against six human carcinoma cell lines, namely KB, MCF7, A549, Caski, HCT116, HT29 and non-human fibroblast cell line (MRC 5) using an in vitro cytotoxicity assay. The ethyl acetate extract possessed high inhibitory effect against KB, MCF7 and Caski cells (IC50 values of 9.4, 19.7 and 19.8 ug/mL, respectively). Flavokawin B (1), 5,6-dehydrokawain (2), pinostrobin chalcone (3) and alpinetin (4), isolated from the active ethyl acetate extract were also evaluated for their cytotoxic activity. Of these, pinostrobin chalcone (3) and alpinetin (4) were isolated from this plant for the first time. Pinostrobin chalcone (3) displayed very remarkable cytotoxic activity against the tested human cancer cells, such as KB, MCF7 and Caski cells (IC50 values of 6.2, 7.3 and 7.7 ug/mL, respectively). This is the first report of the cytotoxic activity of Alpinia mutica. PMID- 21240149 TI - Lamotrigine adjunctive therapy to lithium and divalproex in depressed patients with rapid cycling bipolar disorder and a recent substance use disorder: a 12 week, double-blind, placebo-controlled pilot study. AB - OBJECTIVE: To pilot the efficacy and safety data of lamotrigine adjunctive therapy to lithium and divalproex in patients with rapid-cycling bipolar disorder (RCBD) and a recent substance use disorder (SUD). METHOD: Structured clinical interviews were used to ascertain DSM-IV diagnosis of RCBD, SUDs, and other Axis I disorders. Patients who did not meet the criteria for a bimodal response after up to 16-weeks of open-label treatment with lithium plus divalproex, as measured by MADRS (Montgomery-Asberg Depression Rating Scale) <= 19, YMRS ( Young Mania Rating Scale) <= 12 and GAF (Global Assessment of Functioning) = 51 for 4 weeks, were randomized to a 12- week, double-blind addition of lamotrigine or placebo to lithium plus divalproex. Primary and secondary outcomes were analyzed with ANCOVA, t-test, or chi-square/Fisher's exact. RESULTS: Of 98 patients enrolled into the study, 36 were randomized to receive lamotrigine (n = 18) or placebo (n +/- 18), and 8 patients per arm completed the study. No patient discontinued due to adverse events. The change in MADRS total score from baseline to endpoint was 9.1 +/- 11.2 in lamotrigine-treated patients versus -4.5 +/- 13.1 in placebo treated patients (p = 0.27). There were no significant differences in changes in YMRS total scores and rates of response or remission. CONCLUSIONS: Lamotrigine adjunctive therapy was well tolerated in patients previously non-responsive to initial treatment of lithium plus divalproex. A larger study is warranted to determine the efficacy and safety of adjunctive lamotrigine versus placebo in RCBD with a recent SUD. PMID- 21240150 TI - Metabolic syndrome with different antipsychotics: a multicentre cross-sectional study. AB - OBJECTIVE: High prevalence of metabolic syndrome (MS) and related metabolic disturbances in patients with schizophrenia and bipolar affective disorder have been in main focus of interest in recent years since the introduction of second generation antipsychotics. This study aims to examine these questions: 1) Is there a relation between antipsychotic treatment and MS prevalence? 2) Which antipsychotic users have higher MS prevalence? 3) Do patients on antipsychotic polytherapy have higher rates of MS than patients on antipsychotic monotherapy? 4) Which metabolic parameters are considerably disturbed on which antipsychotic users? METHODS: 242 Patients with schizophrenia, schizoaffective disorder and bipolar disorder without any other psychiatric comorbidity according to DSM-IV and using the same antipsychotic(s) and/or mood stabilizers at least for the last 6 months included to the final assessment. RESULTS: The sample was divided into 7 drug groups. The MS prevalence was highest in the combined antipsychotic (AA) group (48.1%) according to ATP III criteria. According to IDF criteria clozapine (C) group had the highest MS prevalence (74%). CONCLUSIONS: When metabolic parameters evaluated overall, metabolic risk with antipsychotics is found to be highest in clozapine group, followed by combined AP group. Olanzapine and risperidone have intermediate risk while zuclopentixole has lowest. PMID- 21240151 TI - A failed 6-week,randomized, double-blind, placebo-controlled study of once-daily extended release quetiapine fumarate in patients with acute schizophrenia: lessons learned. AB - OBJECTIVE: To demonstrate the efficacy of once-daily extended release quetiapine fumarate (quetiapine XR) versus placebo in adults with acute exacerbation of schizophrenia. METHODS: A 6-week, double-blind, randomized, placebo-controlled study. In- or out-patients with a DSM-IV diagnosis of schizophrenia were randomized to fixed-dose quetiapine XR 400, 600, or 800 mg/day, quetiapine immediate release (IR) 800 mg/day, or placebo. Primary endpoint was change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 6. Other efficacy assessments included Clinical Global Impressions (CGI) of Severity (CGI-S) and of Improvement (CGI-I) ratings. Safety assessments included adverse event (AE) reporting and laboratory measures. RESULTS: 565 patients were randomized; 333 (58.9%) completed the study. Greater numeric improvements in PANSS total score were seen for quetiapine XR (all doses) and quetiapine IR versus placebo at Week 6; the differences were not statistically significant. Secondary efficacy endpoint results were similar. There was not a high placebo response in this study, but rather an attenuation of drug effect. In general, quetiapine XR was well tolerated over 6-weeks' treatment; there were no unexpected AEs. CONCLUSION: The efficacy of quetiapine XR (400, 600, and 800 mg/day) was not established at Week 6. Quetiapine IR, an agent with established efficacy in schizophrenia, also did not separate from placebo at endpoint. Therefore, this is considered a failed study and possible reasons for this are discussed. Quetiapine XR was generally well tolerated and its safety profile was consistent with the known profile of quetiapine. PMID- 21240152 TI - Efficacy of high-dose aripiprazole for treatment-resistant schizoaffective disorder: a case report. AB - Aripiprazole is an atypical neuroleptic with a unique mechanism of action. According to the package insert, the maximum recommended dose for aripiprazole is 30 mg/day. In clinical practice, off-label prescribing of medications, including the use of doses that exceed the manufacturer's recommendations, is not uncommon. Most premarketing studies are designed principally to demonstrate safety, efficacy, and tolerability and often exclude many patients who are treated after a drug has been released.To report a case with treatment-resistant schizoaffective disorder in which a patient tolerated and responded to high-dose aripiprazole; an objective is to discuss the use of aripiprazole dosages at higher than those recommended in the product's labelling. PMID- 21240153 TI - Complete resolution of clozapine-induced sialorrhea with low dose trihexyphenidyl. AB - Clozapine-induced sialorrhea (CIS) is a frequently occurring debilitating adverse effect. Although various treatment options exist, none has been proved to be distinctly superior to others. We report a case of CIS that responded to low dose of trihexyphenidyl (2 mg/day). PMID- 21240154 TI - Antidepressant induced apathy responsive to dose reduction. AB - Apathy has a significant negative impact on the quality of life. It can be a part of other axis I and axis III disorders such as depression. It has also been reported as a treatment emergent side effect of SSRI drugs. A 48 year old male with diagnosis of personality change due to medical condition and depressive symptoms was started on Sertraline. Although his depressive symptoms, impulse control and his irritability improved significantly he became quite apathetic. This responded positively to a reduction in the dose of sertraline. Since apathy can be a residual symptom of depression it may be a valid consideration to increase the dose of the SSRI. However if apathy was not a significant part of depressive syndrome prior to SSRI treatment then antidepressant treatment emergent apathy needs to be considered and one option is to reduce the dose of the SSRI. Other options appear to be addition of other pharmacological agents such as stimulants, dopamine agonists, acetylcholinesterase inhibitors and NMDA antagonists. PMID- 21240155 TI - Instability of human rotavirus G genotypes circulating in a rural area of Bangladesh. AB - A total of 280 fecal specimens from patients with acute gastroenteritis attending one rural hospital (Dharmapasha health complex, Sunamgonj) in Bangladesh from August 2004 to May 2006 were tested for rotavirus by Polyacrylamide Gel Electrophoresis (PAGE). The diversity of rotavirus was investigated using electropherotyping and reverse transcription-PCR amplification of the VP7 and VP4 genes. The electrophoretic patterns of dsRNA of rotavirus showed 9 different migrations (6 long and 3 short) by PAGE. In the year 2004-2006, group A rotavirus was detected in 112 out of 280(40.0%) specimens. G and P genotyping was performed among the 46 representative positive specimens, 20(43.5%) were emerging strain G9P[8], which were associated with VP6 genotype II (subgroup II), and NSP4 genotype B, followed by 16(34.8%) G2P[4], 8(17.4%) G1P[8] and 2(4.4%) G4P[8] strains. G9P[8] was found to be the most predominant strain in 2004, but the prevalence rate abruptly decreased during the period 2005-2006. In addition G2P[4] was the most prevalent strain in 2005 and 2006. G1P[8] was less prevalent in the study period then the previous years. Nucleotide Sequence identity of VP7 gene of G9 rotaviruses were higher than 99.4% with each other and all the G9 rotavirus strains in this study clustered in a single branch of the phylogenetic tree. Nucleotide sequence identity of complete VP4 gene of P[8] rotaviruses were more than 99.7% with each other and all the P[8] rotavirus strains in this study grouped in a single cluster suggesting recent emergence from a common ancestor. An important finding of this study is that the genetic profile of rotavirus is changing within very short period in Bangladesh and continued surveillance of the circulating strains is necessary to detect new strains or new variants which can escape immune protection induced by available vaccines. PMID- 21240156 TI - Epidemiological determinants of psoriasis. AB - A cross-sectional study was conducted on 102 cases having clinical manifestation of psoriasis with a view to evaluate the epidemiological determinants of psoriasis. Psoriasis constituted 1.49% of the total dermatological disorder. Seventy patients (68.6%) were males and thirty two (31.4%) were females with a male to female ratio of 2.18:1. The mean age was 30.76+/-13.17 years in male and 26.94+/-14.94 years in female. Sixteen (15.7%) patients had one or more family member having psoriasis with male and female in equal frequency. Regarding precipitating factors, psoriasis was developed after trauma in 4.9%, infection 3.9%, stressful life events 6.9% and drugs 2.9%; and was exacerbated after trauma in 5.9%, infection 5.9%, stressful life events 35.3% and drugs 12.7%. The disease showed improvement in summer (27.5%) and found deteriorated in winter (47.1%). Sunlight had beneficial effect in 33.3% of cases. During pregnancy improvement was observed in 50% but flare up in 22.2% of cases. Fifty percent of patients were smokers, 41.2% were non-smokers and 13.7% were ex-smokers. Forty percent had Body Mass Index (BMI) between 22 to 26 Kg/m2, 40.2% had less than 22 Kg/m2 and 15.7% had above 26 Kg/m2. It was concluded that the prevalence of psoriasis among dermatological patients was similar to results reported in Turkey and in Northern India. The precipitating factors, such as smoking, stressful life events, infection, trauma, sunlight, pregnancy, drugs, and seasonal variations could influence the development of psoriasis and affect its clinical expression. PMID- 21240157 TI - Comparison between ultrasound and plain X-ray in evaluating the cause of shoulder pain. AB - Painful shoulder is a common painful condition among patients. Apart from acute traumatic lesions such as fractures, dislocations, contusions, sprains and ruptured tendons, 85 to 90% of painful shoulders are due to adhesive capsulitis, acute or chronic calcific tendinitis, bursitis, bicipital tendinitis and lesions of the musculotendinous cuff. Arthritis is the cause of less than 5% of painful shoulders. For evaluating conditions of shoulder joint, X-ray has been regarded as only method of choice for long time. Magnetic resonance imaging (MRI) is an alternative procedure but the cost limits its utilization especially in Bangladesh. Ultrasonography is an effective imaging modality in the evaluation of both rotator and non-rotator cuff disorders. Because of low cost and availability, it can be an alternative procedure for the diagnosis of painful shoulder. The present study was conducted to assess ultrasonography as a useful modality in evaluating cases of shoulder pain and to compare the findings with X ray findings. Thirty two patients with shoulder pain were evaluated by X-ray and Ultrasonography (USG). Clinical diagnosis was done for correlation. To identify the cause of shoulder pain, 100% patients were found normal in plain X-ray. On Ultrasonography (USG) 12.5% patients had displaced long head of biceps, 21.9% had biceps tendinitis, and 3.1% had bursitis. In the assessment of shoulder pathology, USG had a sensitivity of 73.3%, specificity of 88.2%, Positive predictive value (PPV) of 84.6%, Negative predictive value (NPV) of 78.9% and an accuracy of 81.3%. USG is a useful modality for evaluation the shoulder joint in case of painful shoulder even plain X-ray is non conclusive. PMID- 21240158 TI - A feeding aid prosthesis for a preterm baby with cleft lip and palate. AB - Cleft lip and palate is a common congenital defect of human being. If a child is born with congenital cleft palate defect, it is very painful to their parents. They are very much worried about the feeding of their baby. In this situation feeding aid prosthesis is the only treatment of choice. The feeding aid prosthesis helps not only feeding the baby but also help to develop proper articulation of speech. The article describes an advanced clinical and laboratory technique for the fabrication of a feeding aid prosthesis for new born baby. 9 infants who were suffering from congenital cleft lip and palate defect and a 9 month old baby with acquired palatal defect (acid-victim) were included in this study. All of them had treated with feeding aid prosthesis for feeding till palatoplasty was done. The feeding aid prosthesis was fabricated with acrylic resin and finally relined with soft lining materials. The impression of the palate was taken with heavy body silicon putty with the help of modeling wax custom tray. Data were collected before and after prosthesis on the basis of feeding time, amount of consumption of milk and growth pattern of the infants with their height and weight. Out of ten babies, 30% rejected the prostheses and 70% had accepted and used the prostheses until they were fit for palatoplasty. Growth of the babies was significantly improved who accepted the prosthesis than who rejected the prosthesis. PMID- 21240159 TI - Endoscopic dacryocystorhinostomy. AB - Dacryocystorhinostomy (DCR) is the treatment of distal nasolacrimal duct blockage. It has got many advantages of over external DCR with higher patient's acceptance. Twenty one consecutive cases of endoscopic DCR were studied during the period of two and a half years with a mean follow up period of 13.12 months (SD=7.05). The mean age of cases was 42.95 years (SD=14.49). In most of the cases the cause was either idiopathic (71.43%) or inflammatory (23.81%). The techniques used for making bony window were chisel-hammer (19.50%), powered drill (23.81%), Kerrison punch forceps (14.29%) or combination of powered drill and Kerrison punch forceps (42.86%). Silicon stent was used in 71.43% cases. There was no significant peroperative complication; premature extrusion of stent (4.76%), synaechia (9.52%), excessive granulation tissue formation (9.52%) and stomal stenosis with recurrence of symptoms (9.52%) were the complications noticed here. Anatomical success with patent stoma was observed in 90.48% cases but symptomatic improvement with dry comfortable eyes were seen in 86% cases. There was no statistically significant difference of outcome between this study and that of recently published studies (p>0.05). Some comparative studies showed both higher and lower success rates of endoscopic DCR than external procedure but there was no significant difference (p>0.05). PMID- 21240160 TI - Male sub-fertile patients in a tertiary hospital. AB - Estimated prevalence of subfertility is 10% of couples; 35 40% male, 40 50% female and remainder involve both sexes. We analyzed semen of 50 sub-fertile male subjects attending infertility unit outpatient department, Department of Obstetrics and Gynaecology, Bangabandhu Sheikh Mujib Medical University, between July 2007 and December 2008, to establish cause of their problem and initiate treatment regimen to correct their problem. Mean age was 32.68 years, known medical disorders was present in 6(6% history of mumps, 4% history of orchitis, 2% diabetes), 28% were smokers, and none was drug addict. Semen analysis: mean+/ SD semen volume 1.94+/-1.08 ml, concentration 19.43+/-25.18 106/ml, motility 24.04+/-26.49%, rapid linearity 13.10+/-15.74%, slow linearity 8.16+/-8.65%, non progressive 2.74+/-6.23%, immotile 33.68+/-33.06%, morphology 21.62+/-26.15%, head abnormality 21.06+/-24.72%, midpiece abnormality 14.04+/-17.12%, and tail and other abnormalities 10.90+/-17.28%. Agglutination was seen in 2%. Diagnosis was 42% azoospermia, 4% normozoospermia, 12% oligoasthenozoospermia, 10% asthenozoospermia, 18% oligozoospermia, 10% oligozoospermia with reduced motility, 2% each oligozoospermia with infection and astheno and teratozoospermia. PMID- 21240161 TI - Bancroftian elephantiasis in Nilphamari, Bangladesh. AB - The parasitic nematodes Wuchereria bancrofti, causes a dreadful disease in humans known as lymphatic filariasis, which afflicts more than 250 million people in tropical countries. Twelve districts with about 20 million people are endemic out of 64 districts in Bangladesh affecting more on Northern districts. This study was done in the Nilphamari, Kisorgonj and Sayedpur Thana under Nilphamari district, which is the most endemic for filariasis. In the present study, nineteen unions were investigated. Average 1.34% people were infected with filariasis (0.87% male and 1.81% female) out of 2,32,005 populations in those area. The highest percentage of infected unions was Alam Biditor (1.35%) under Kisorgonj Thana and lowest infected unions was Khatamadhupur (0.21%) under Sayedpur Thana. Among the affected people, 69.48% were poor, 28.88% were middle class and 1.63% was rich. The age group, 26-45 years, showed the highest rate (53.07%) of infection and the age group, 6-15 years, showed the lowest rate (1.92%) of infection. The relationships between infection status of male and female were statistically significant. PMID- 21240162 TI - Blood conservation strategies for reducing peri-operative blood loss in open heart surgery. AB - Defects in hemostasis are frequently seen in open heart surgery. Strategies should be reviewed about the peri-operative blood loss and conservation of blood here. In this study, comparison among three agents (Aprotinin, Tranaexaemic Acid & Epsilon Amino Caproic Acid) is done to reduce the peri-operative blood loss in open-heart surgery. Ninety male and female patients within 20-60 years of age were selected who underwent conventional cardiac surgery and anesthesia with Cardio-pulmonary-bypass for common open heart surgeries (ASD, VSD, AVR, etc) and randomly divided into three groups 30 patients in each. Group A, B, C was administered Inj. Aprotinin, Tranaexaemic acid & EACA respectively. Perioperative hemodynamic parameters and blood loss in suction bottle & drainage tube were noted until the 3rd POD. Requirement of blood transfusion, heparin, protamine and blood derived products were also noted. Activated clotting time was documented in the perioperative period. Clinically relevant outcome like re-exploration, mechanical ventilation, morbidities, mortality etc were also verified. Data were analyzed and results were calculated with student's T test & ANOVA. The groups were matched regarding recorded peri-operative variables. Peri-operative blood loss is significantly reduced (p<0.05) both in the Aprotinin and Tranexamic acid groups. Renal dysfunction was reported in 20% of aprotinin patients, 14.29% of tranexaemic acid patients and 18.51% of EACA patients. A conclusion was drawn from the study that Tranexamic acid can significantly reduce the peri-operative blood loss in open heart surgery cases and that it can be preferred as an agent of choice in blood conservation strategy in these cases. PMID- 21240163 TI - Risk factors, morbidity and mortality of neonatal tetanus. AB - A retrospective study was conducted to identify the risk factors, mortality and morbidity of neonatal tetanus in an Infectious Disease Hospital, Mohakhali, Dhaka, Bangladesh, the only referral hospital in the country of its kind. Hospital records of all cases of neonatal tetanus admitted over one year period from 1st May 2008 and 30th April 2009 were analyzed. Demographic data, clinical presentation, progression, hospital stay and outcome were evaluated. Overall mortality was found 52.9%. Hospital stay among the patients was 11.00 +/- 8.37 days. Among the patients about two third had unsatisfactory outcome and only 6(35.3%) patients recovered completely. The retrospective study identified that mortality due to neonatal tetanus was very high and the common morbidities were lock jaw, inability to suck, abdominal rigidity, convulsion, fever, irritability etc. It has been explored that low socioeconomic conditions, mothers' illiteracy, lack of antenatal care and involvement of untrained persons during delivery of baby and unclean cord care practices were the important factors contributing to neonatal tetanus. A further study with a larger sample size is recommended for evaluating the findings of the study and formulating the possible preventive strategies against neonatal tetanus. PMID- 21240164 TI - Status of HIV infection among the pregnant women attending in outpatient department. AB - Human immunodeficiency virus (HIV) infection has been spreading rapidly in the developing countries and vertical transmission also taking place. This study has been done to find out the prevalence of HIV infection among the pregnant women, so that necessity of routine screening test can be identified. It is a cross sectional study. Five hundred two pregnant women were included. Three ml venous blood was taken and then HIV screening test was done by ELISA method. All reactive tests were confirmed by Western blot antibody testing. The positive cases were followed up and necessary treatment was given. Delivery was conducted in this hospital. Baby's blood was tested to see vertical transmission after 18 months. Most of the subject were educated housewife, mean age was 25 years. Six (6%) husband was overseas service holder, 12% were smoker and 1.6% had drug addiction. Eight (8%) subject had previous history of blood transfusion and 49% subject or her husband had history of surgery or got parental therapy. 2% subject gave the history of familial disharmony and 2% had multiple sex partners. HIV infection was found in 2 patients (0.4%). Both of them got infection from their husband. One husband was over seas service holder and another one was injecting drug user. For the prevention of spread, reduction of vertical transmission and providing early management to the positive patient all pregnant women should be screened for HIV routinely. PMID- 21240165 TI - Tuberculous pleural effusion. AB - Despite prevention programs, tuberculosis is still endemic in developing countries. Extrapulmonary tuberculosis is increasing globally in the face of recent emergence of Human Immunodeficiency Virus (HIV) infection. Pleural tuberculosis is a common problem in daily clinical practice. We assessed 26 cases of tuberculous pleural effusion admitted in Bangabandhu Sheikh Mujib Medical University from 2002 to 2007. The diagnosis was based upon clinical examination, tuberculin reaction, imaging, pleural fluid analysis and response to antitubercular chemotherapy a surrogate clinical determinant. Apparently promising newer biochemical pleural fluid measurements were not utilized due to a number of limitations. The presenting symptoms found in this prospective analysis are fever (100%), nonproductive cough (73%), pleuritic chest pain (38%), loss of weight (38%) and shortness of breath (38%). A high index of suspicion after confident exclusion of malignancy and pneumonia is a clue to diagnosis. Out of 80 cases of extrapulmonary tuberculosis admitted during the study period, tuberculous pleural effusion constitutes 32.50%. PMID- 21240166 TI - Value of dysmorphic red cells and G1 cells by phase contrast microscopy in the diagnosis of glomerular diseases. AB - The morphology of red cells by phase-contrast microscopy (PCM) is a useful diagnostic marker for glomerular haematuria. This study evaluated the value of urinary dysmorphic red cells and G1 cells (special type of dysmorphic red cell) count by PCM providing a simple, cost effective and low risk technique in the diagnosis of glomerular diseases. Urine samples of 120 patients with haematuria and proteinuria were examined and the percentage of dysmorphic red cells and G1 cells were calculated. Cases were divided into two groups; group I (>20% dysmorphic red cells- glomerular group) and group II (<=20% dysmorphic red cells as non glomerular group). Renal histopathology was used as the gold standard method for the diagnosis of glomerulonephritis. Results from PCM showed a sensitivity of 92.7%, specificity 100% by the detection of dysmorphic red cell while by the detection of G1 cells, a sensitivity of 97.6% and specificity 100% were observed. The percentage of G1 cells is superior to counting dysmorphic red cells. The high sensitivity of phase contrast microscopy confirms its usefulness for the detection of dysmorphic red cells and G1 cells that can guide clinicians in the identification of the site of haematuria using non invasive tests. PMID- 21240167 TI - Serum adiponectin in patients with coronary heart disease. AB - Adiponectin is an adipocyte derived hormone, a modulator of lipid metabolism and systemic inflammation. It has potential anti-atherogenic property. Adiponectin is present in low concentration in patients with obesity, insulin resistance (IR), Type 2 diabetes mellitus (T2DM) and coronary heart disease (CHD). In this case control study, we studied the association of Serum adiponectin with CHD. Sixty four subjects were enrolled. Consecutive 31 CHD patients (Group I) and 33 healthy controls (Group II) were included. Serum adiponectin & lipid profile were estimated in all. Serum adiponectin was significantly lower in CHD patients (3.90+/-2.21MUg/ml) in comparison with controls (5.09+/-2.13MUg/ml)(P<0.05). There was no significant difference of any fraction of lipid profile between cases and controls. Significant negative correlation was observed between Serum adiponectin and Serum triacylglyceride (STG) in cases (P<0.01). It may be concluded that low serum adiponectin may have some important role in development of CHD and probably low adiponectin and dyslipidemia are linked in the development of atherosclerosis. Further study is recommended with larger sample size to explore the role of hypoadiponectinemia in the causation of CHD. PMID- 21240168 TI - Maternal complications in twin pregnancies. AB - Twin pregnancy is a high-risk pregnancy as it is associated with significant increase in the perinatal mortality and morbidity and maternal mortality and morbidity. This study was carried out to determine the maternal complications related with twin pregnancy. This was a cross-sectional observational study among all women with twin pregnancy, both booked (patients who had at least three visits to antenatal care were considered as booked) and unbooked, admitted in Institute of Post Graduate Medicine and Research, Dhaka now Bangabandhu Sheikh Mujib Medical University. Out of 3675 deliveries 53(1.4%) patients had twin pregnancy during a period of two years beginning from September 1996 to August 1998. Out of 53 patients, 34(64.2%) were multipara and 19(35.8%) were primipara. Most of the patients were between 22-29(67.9%) years group. The duration of gestations was 32-36 weeks for 17(32.1%) patients, 37-40 weeks for 30(56.6%) patients. Maternal complications were noticed as anaemia in 19(35.8%) patients, hypertension in 12(22.6%) patients, post-partum haemorrhage (PPH) in 10(18.9%) patients, hyperemesis gravidarum in 4(7.5%), polyhydramnios in 3(5.7%) patients, ante-partum haemorrhage (APH) in 3(5.7%) patients, premature rupture of membranes (PROM) in 2(3.8%) patients, gestational diabetes in 3(5.7%) patients, urinary tract infection (UTI) in 2(3.8%) patients, complications of operative delivery in 2(3.8%) patients. There was no maternal death in our study. Twin Pregnancy is a high-risk pregnancy associated with significant increase in maternal mortality and morbidity. With aggressive management of complications such as preterm labour, foetal distress, hypertension, APH, PPH, premature rupture of membranes etc morbidity and mortality can be improved. PMID- 21240169 TI - The outcome of kidney transplants with multiple renal arteries. AB - The use of grafts with multiple renal arteries has been considered a relative contraindication because of the increased incidence of vascular and urologic complications. The aim of this retrospective study is to determine whether the kidney grafts with multiple arteries have any adverse effect upon post transplant graft and patient survival. After reviewing the records of 35 adult kidney transplants done consecutively at Bangabandhu Sheik Mujib Medical University over a period of 3 years (Jan 2005 to Dec 2007). Mean age of recipients. 43.46+/-12.11 years and donors 40.33+/-11.46 years. Twenty patients (Group A) had grafts with single renal artery and 15 patients (Group B) had grafts with multiple renal arteries. The incidence of vascular complications, ureteral complications, post surgical haemorrhage, mean serum creatinine level and acute tubular necrosis in both Group A & B were observed. Complications developed in 15(43%) patients in this series. In Group A, 1(5%) developed post operative bleeding cause perinephric hematoma, 1(5%) technical obstruction of ureter, 1(5%) sloughed ureter, graft nephrectomy 1(5%) and acute tubular necrosis 1(5%) patient. In Group B, 2(13%) patients developed hematoma, urine leak 3(20%), sloughed ureter 1(6%), graft nephrectomy 1(6%) and acute tubular necrosis 3(20%) patients. Though the kidney grafts with multiple renal arteries have been considered a relative contraindication because of the increased risk of complication. In this series incidence of complication was 43%. The higher rate probably reflects the small number of living related donors. PMID- 21240170 TI - Postoperatve pain relief in children after subumbilical surgeries-a comparison between caudal bupivacaine and bupivacaine-clonidine. AB - In a randomised case control study in children undergoing elective subumbilical surgery, we have assessed the clinical value of bupivacaine and bupivacaine clonidine mixture for caudal analgesia. Sixty children aged 2-10 years, were allocated randomly to two equal groups (n=30) to receive 0.25% bupivacaine 1ml/kg (Group I) and 0.25% bupivacaine 1ml/kg with clonidine 2MUg/kg (Group II). The baseline haemodynamic parameters, heart rate and blood pressure were recorded. Intraoperatively children in both groups maintained haemodynamic stability and required less amount of muscle relaxant. Duration of analgesia in minutes was assessed by the time interval between the caudal extradural injection and the first analgesic demand by the patient. It was significantly longer (p=0.000) in Group II (712 +/- 15.30 minutes) as compared with Group I (246 +/- 8.74 minutes). Group II required significantly less supplementary analgesia after operation. There was no significant difference in the incidence of side effects between the two groups. Group I received more doses of diclofenac suppository in first 24 postoperative hours. We conclude that, when added to bupivacaine, clonidine improves the duration of caudal analgesia in children undergoing subumbilical surgery. PMID- 21240171 TI - Palliative care out patient consultation service in a teaching hospital in Bangladesh. AB - Palliative care is a newly emerging subspecialty in Bangladesh. The aims of this study were i) to determine the characteristics, types of referral, disease pattern and insight about the disease and ii) to estimate the prevalence of pain and other common symptoms in a population of patients with advanced incurable state of cancer and attending the newly established palliative care out patient clinic. The data were collected at the outpatient clinic during first consultation using a modified structured data collection sheet from the Institute of Palliative Medicine (IPM) in Calicut, Keralla, India. Two hundred and three patients with mean age 50 years, diagnosed as suffering from incurable cancer were seen during a period of 21 months from October 2007 to June 2009. Most of the patients were from less privileged socioeconomic group (86%), stays with family (99%), already know about their disease status and prognosis (62%). Referred from other disciplines formed the major group (72%) of this population. All of them had been under treatment for variable period ranging from one month to four years. The most common five symptoms noted by the service providers were pain (89%), loss of appetite (61%), sleeplessness (55%), lack of energy (47%) and constipation (44%). Population based studies are required to determine the actual magnitude of sufferers and suffering in spite of the availability of global knowledge and skill to reduce these sufferings of the incurably ill members of the society. PMID- 21240172 TI - Comparison between bipolar diathermy tonsillectomy and cold dissection tonsillectomy. AB - A prospective study was carried out in the department of otolaryngology-Head & Neck Surgery, Bangabandhu Sheikh Mujib Medical University (BSMMU) and Bangladesh Medical college Hospital, Dhaka. From January, 2007 to January, 2009 to compare between Bipolar Diathermy Tonsillectomy and Cold Dissection Tonsillectomy. Two hundred patients were divided equally into two groups- bipolar diathermy tonsillectomy and cold dissection tonsillectomy. The two groups were compared in age and sex distribution but there was no significant difference (p>0.05) between the two groups. Operative time, operative blood loss, postoperative pain, diet intake, activity level and complications were compared in the two groups. Operative time and blood loss was significantly less in the diathermy group which was highly significant (p<0.001). No significant difference (p>0.05) in the postoperative pain was observed. Percentage of normal diet taken was higher in the diathermy group on the 1st day and lower on the 7th day while the difference was not statistically significant (p>0.05). No significant difference (p>0.05) was noted between the two groups in terms of postoperative activity and postoperative blood loss. Operative blood loss & time was significantly less in bipolar diathermy tonsillectomy. So it is a safe technique and can be used safely with less morbidity & complication. PMID- 21240173 TI - Role of discrimination indices in differentiation of beta thalassaemia trait and iron deficiency anaemia. AB - Iron deficiency anaemia (IDA) and beta thalassaemia trait (BTT) are the most common causes of microcytic hypochromic anaemias. Several discrimination indices have been introduced to discriminate quickly these similar entities via parameters obtained from automated cell counter. The purpose of the study was to evaluate the value of five discrimination indices in differentiation of BTT and IDA. This study consists of 57 cases of BTT and 72 cases of IDA. Five discrimination indices evaluated in this study for differentiation of BTT and IDA were red blood cell (RBC) count, red blood cell distribution width index (RDWI), Green & King Index (G & K), Mentzer index (MI) and England & Fraser (E & F) index. Sensitivity, specificity, positive and negative predictive values and Youden's index (YI) had been calculated. RBC count and RDWI appears to be reliable and useful index for the differentiation of BTT and IDA, as both of the indices had more than 80% sensitivity, specificity in differentiation of IDA and BTT. Patients with microcytic hypochromic anaemia could be easily screened out for BTT and IDA through these discrimination indices in the absence of other complicated diseases. PMID- 21240174 TI - Association between bacterial vaginosis and preterm delivery. AB - Bacterial vaginosis (BV) is one of most common presentation in women of reproductive age, and its prevalence is relatively high in the obstetric population which is responsible for preterm delivery. The present study tried to explore the association of BV with preterm delivery, and included 100 pregnant women aged 15 to 35 years, between 28 36 weeks of gestation, with abnormal vaginal discharge and clinically suspected of BV, attending obstetrics outpatient department of BSMMU were selected for the study, divided into two groups based on Amsel clinical criteria (63 culture negative and 37 culture positive for BV). Mean +/- SD age of BV negative and positive subjects was 24.59 +/- 5.18 and 23.89 +/- 4.77 years respectively (statistically no significant difference). Likewise, socioeconomic status, educational status and gravida did not show statistically any significant difference between groups. Significantly high number of BV positive women delivered prematurely (73%) compared to BV negative (25.4%) (p<0.001). Mean +/- SD gestational age also differed significantly 37.49 +/- 2.53 vs. 35.24 +/- 2.33 weeks (p<0.001). Our study supported that abnormal bacterial colonization, indicative of bacterial vaginosis, is strongly associated with preterm delivery. PMID- 21240175 TI - Characteristics of infertile couples. AB - The objective of the study was to evaluate the sociodemographic characteristics and to find out the causes of infertility among the couple attending out patient department of infertility unit in Bangabandhu Sheikh Mujib Medical University (BSMMU) from January to December 2007. This is a descriptive observational study. Data were analyzed done manually and statistical analysis was calculated by Statistical package for social sciences (SPSS) program. During this period 3184 patients were attended out patient department (OPD) of infertility unit (IU-I & II). Among them primary infertility was present in 1971(61.90%) and secondary infertility in 1213(38%) cases. One thousand four hundred and two (1402) patient's complete data were reviewed from OPD register book of IU-I. The mean duration of the infertility was 4.7(4.52) years. The mean age of female patient was 26.5+/-5.35 years. The mean age of male patient was 34.56+/-6.33 years. A positive male factor problem alone was found in 13% couples, female factors in 71.46% couples and unexplained infertility in 15.47% couples. Among the male factor Oligozoospermia (33.33%) was the most common cause of male infertility. Anovulation (52.16%) was the most common cause of female infertility and major cause of anovulation was Polycystic ovary syndrome (PCOS) (29.90%). Fibroid uterus, Bilateral tubal block and Pelvic inflammatory disease (PID) were significantly (p<0.001) higher in secondary infertility. Endometriosis and unexplained infertility were significantly (p<0.001) higher in primary infertility. Distribution of other causes of infertility was same for both primary and secondary infertility. PMID- 21240176 TI - Human thelaziasis in Bangladesh. AB - Very few cases of Human Thelaziasis are reported worldwide. This is the first case of its kind from Bangladesh. A 58 years old man was admitted to Ophthalmology department of Mymensingh Medical College Hospital, Mymensingh, with itching, redness, foreign body sensation, lacrimation & filamentary discharge from right eye (R/E). He had visual acuity <6/60, conjunctival congestion & advanced bi-headed pterygium of R/E. After exposure of R/E ball with universal eye's speculum, a thin white nematode was found into the right lower conjunctival fornix. It was taken out by a plain forceps, placed into a bottle containing Hartman's solution & immediately sent to Microbiology department of Mymensingh Medical College for proper identification. Subsequently with the joint collaboration & detailed examination by the Parasitology department of Bangladesh Agricultural University (BAU), Mymensingh, the nematode was identified as an adult Thelazia callipaeda worm. PMID- 21240177 TI - POEMS Syndrome. AB - A 49 years old male patient admitted with 2 years history of lower extremity symmetrical sensorimotor polyneuropathy, sclerodermic skin change, erectile dysfunction, hepatosplenomegaly and monoclonal gammopathy. The clinical evaluation met the criteria for the diagnosis of (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) POEMS syndrome. The patient was treated with corticosteroid and melphelan and responded well. We present a case different from the other cases with severe unusual burning sensation all over the body, which was his sole complaint and with this complaint he visited lot of doctors including psychiatrist. PMID- 21240178 TI - Acute lymphoblastic leukaemia presenting with severe hypercalcaemia. AB - Acute lymphoblastic leukaemia (ALL) is the most common malignancy in children. Usually ALL children present with pallor, fever, bleeding, infection, lymphadenopathy and hapatosplenomegaly. Very rarely ALL patients may present with hypercalcaemia and osteolytic lesions. A five year old boy was referred and transferred to the paediatric ward of Bangabandhu Sheikh Mujib Medical University, Dhaka with the complaints of pain in the hip joint, generalized pain all over the body and very high calcium level. He was severely pale, the total leukocyte count was normal with normal distribution. Platelet count was also normal. There were some atypical lymphocytes. Radiology showed extensive osteolytic lesions. Considering all these findings, a bone marrow study was done, which was compatible with ALL. Flow-cytometry was also done and it confirmed the diagnosis as common ALL. PMID- 21240179 TI - A 30 year old female with lower abdominal lump. AB - A female of 30 years of age, hailing from Narayangonj, Dhaka got admitted herself into Dhaka medical College & Hospital on 25.10.08 with the complaints of a lump in the lower abdomen for 1 year and pain in the lower abdomen for the same duration. Local examination reveals a lump in the lower abdomen which is intra abdominal, 10cm * 12cm in size. CT scan of Abdomen reveals a solid mass measuring (12 * 9 * 8.5) cm is seen in left side of abdominal cavity extending up to pelvic cavity. FNAC of abdominal lump shows sheets of mesothelial cells and few small clusters of regular epithelial like cells. Laparotomy was done on 27.11.08 under G/A & reveals a solid mass measuring about 10 * 8cm size & was well encapsulated, adherent with omentum found in the lower abdomen. Few mesenteric lymph nodes were enlarged. The mass was gently separated from the omentum ensuring adequate haemostasis. Post-operative period was uneventful. Histopathology report shows neoplasm composed of plump of fibroblasts arranged in broad sweeping fascicles and infiltrate into adjacent tissue consistent with fibromatosis. The patient was discharged with advice on 10th post operative day. PMID- 21240180 TI - Oral squamous cell carcinoma in a 10 year old boy. AB - Squamous cell carcinoma of the oral cavity a type of Oral Cancer in young patients is a very rare occurrence particularly during the first decade of life. Oral cancer is predominantly an aggressive neoplasm of middle-aged people where 96% of the patients are more than 40 years of age and it occurs mainly due to the excessive consumption of tobacco and alcohol. In South-East Asia it has a higher rate of occurrence than the rest of the world, partly due to increased consumption of chewing tobacco and various harmful spices, areca nuts and betel quids. These rare varieties of aggressive neoplasm commonly affect tongue and lip. This report describes a case of squamous cell carcinoma in a 10 year old boy who had an exophytic type of granulomatous lesion with some indurated borders which diffusely involved the left side of the hard palate, alveolar mucosa, left maxillary antrum and aggressively emerged within the left orbit by engulfing the left inferior rectus muscle. The purpose of this case report is to provide information that younger group can suffer from oral squamous cell carcinoma though it is very rare and this younger group would appear to have a biologically more aggressive tumor and they require more complex treatment. The role of more aggressive initial therapy must be considered. PMID- 21240181 TI - Intrathoracic kidney in adult with an abnormal presentation. AB - Intra thoracic kidney is a rare congenital anomaly. Pathologically thoracic renal ectopia is due to eventration of the diaphragm. Usually symptoms appear in infancy and rarely in adult with respiratory problems and with organ involved. This only patient presented with left sided chest pain and abdominal discomfort at the age of 52 years having repeated previous similar attack in the department of Cardiology. Chest X ray and ultrasonography of whole abdomen was done along with other routine investigations, which reveals an ectopic and elevated left kidney. Five percent of the renal ectopia is intrathoracic kidney. It usually is symptomatic in infantile age but adult presentation is also found. PMID- 21240182 TI - Congenital aneurysm of the left atrium. AB - Isolated left atrial (LA) aneurysm is a rare condition, whereas LA aneurysm secondary to other causes is a fairly common condition. A case of large left atrial aneurysm presented with features of heart failure with cardiac arrhythmia and an abnormal cardiac silhouette on chest X-ray. A 14 years old girl presented with palpitation at rest, shortness of breath, productive cough and bilateral leg swelling for last 8 months. There was no history of chest pain, hemoptysis, syncope, prolonged fever, and rheumatic fever. She was mildly anemic, had raised JVP and mild bilateral pedal edema. There was left parasternal heave, soft S1, loud P2 and a pansystolic murmur of grade 3/6 over mitral area radiating to the left axilla. ECG showed multifocal atrial tachycardia (MAT), chest X-ray showed cardiomegaly with bulging of the left heart border with upper lobe diversion. Echo-Doppler study showed hugely dilated LA (115 mm in diameter), dilated left ventricle, Grade-2+ mitral regurgitation (MR), mild tricuspid regurgitation (TR) and mild pulmonary hypertension with normal appearing mitral, aortic and tricuspid and pulmonary valves. The patient was diagnosed as a case of congenital aneurysm of LA. PMID- 21240183 TI - Methicillin resistant Staphylococcus aureus - an overview. AB - Staphylococcus aureus strains those are resistant to methicillin are referred to as Methicillin resistant Staphylococcus aureus. These express mecA gene to produce altered penicillin binding protein. At present Methicillin resistant Staphylococcus aureus has been increasing as a serious nosocomial and community pathogen having the property of multi drug resistant. Humans are the natural reservoir for Staphylococcus aureus and asymptomatic colonization is far more common than infection. Many hospitals of different country of the world including Bangladesh are struggling with increasing number of this versatile pathogen. Early and specific diagnosis is important to ensure a favourable outcome. In this paper we attempted to explore history, prevalence, transmission, risk factors, pathogenicity, laboratory diagnosis, prevention and control of Methicillin resistant Staphylococcus aureus as a critical review to provide some new upgrade regarding this super bug. PMID- 21240184 TI - Chest pain in children: an update. AB - Chest pain is a common symptom for children and adolescents. It is the second most frequent complaint leading to referral to paediatric cardiologist, murmurs being the largest. The most common cause of chest pain prompting a child to visit a physician is idiopathic chest pain (21-59%). Other disorders are pulmonary (12 24%), psychologic (17-19%), musculoskeletal (7-16%), gastrointestinal (5-7%), cardiac (1-4%) and miscellaneous (2-4%). Most children with chest pain have normal physical findings. Careful physical examination can reveal important clues and save much unnecessary investigations. When an organic cause is found for the pain then specific treatment is commenced. Depending on the circumstances, a therapeutic trial may be warranted, for example use of an inhaled bronchodilator 15-20 minutes before exercise for suspected exercise induced asthma, use of adequate anti-reflux medication for gastro-oesophageal reflux disease or non steroidal anti-inflammatory medication for musculoskeletal pain. Where an organic cause is not considered to be present, explanation and reassurance can reduce anxiety and decrease the severity of the symptoms. This article specifically deals with problems of chest pain in children and approach to such problems in the form of relevant investigations and management. PMID- 21240185 TI - Near peer teaching in South Asia: a buzz word or ground reality? PMID- 21240186 TI - Bangladesh insulin guideline (premix) for type 2 diabetes. PMID- 21240187 TI - Cdc42-dependent formation of the ZO-1/MRCKbeta complex at the leading edge controls cell migration. AB - Zonula occludens (ZO)-1 is a multi-domain scaffold protein known to have critical roles in the establishment of cell-cell adhesions and the maintenance of stable tissue structures through the targeting, anchoring, and clustering of transmembrane adhesion molecules and cytoskeletal proteins. Here, we report that ZO-1 directly binds to MRCKbeta, a Cdc42 effector kinase that modulates cell protrusion and migration, at the leading edge of migrating cells. Structural studies reveal that the binding of a beta hairpin from GRINL1A converts ZO-1 ZU5 into a complete ZU5-fold. A similar interaction mode is likely to occur between ZO-1 ZU5 and MRCKbeta. The interaction between ZO-1 and MRCKbeta requires the kinase to be primed by Cdc42 due to the closed conformation of the kinase. Formation of the ZO-1/MRCKbeta complex enriches the kinase at the lamellae of migrating cells. Disruption of the ZO-1/MRCKbeta complex inhibits MRCKbeta mediated cell migration. These results demonstrate that ZO-1, a classical scaffold protein with accepted roles in maintaining cell-cell adhesions in stable tissues, also has an active role in cell migration during processes such as tissue development and remodelling. PMID- 21240188 TI - Interaction between the helicases genetically linked to Fanconi anemia group J and Bloom's syndrome. AB - Bloom's syndrome (BS) and Fanconi anemia (FA) are autosomal recessive disorders characterized by cancer and chromosomal instability. BS and FA group J arise from mutations in the BLM and FANCJ genes, respectively, which encode DNA helicases. In this work, FANCJ and BLM were found to interact physically and functionally in human cells and co-localize to nuclear foci in response to replication stress. The cellular level of BLM is strongly dependent upon FANCJ, and BLM is degraded by a proteasome-mediated pathway when FANCJ is depleted. FANCJ-deficient cells display increased sister chromatid exchange and sensitivity to replication stress. Expression of a FANCJ C-terminal fragment that interacts with BLM exerted a dominant negative effect on hydroxyurea resistance by interfering with the FANCJ-BLM interaction. FANCJ and BLM synergistically unwound a DNA duplex substrate with sugar phosphate backbone discontinuity, but not an 'undamaged' duplex. Collectively, the results suggest that FANCJ catalytic activity and its effect on BLM protein stability contribute to preservation of genomic stability and a normal response to replication stress. PMID- 21240189 TI - The Arabidopsis CUL4-DDB1 complex interacts with MSI1 and is required to maintain MEDEA parental imprinting. AB - Protein ubiquitylation regulates a broad variety of biological processes in all eukaryotes. Recent work identified a novel class of cullin-containing ubiquitin ligases (E3s) composed of CUL4, DDB1, and one WD40 protein, believed to act as a substrate receptor. Strikingly, CUL4-based E3 ligases (CRL4s) have important functions at the chromatin level, including responses to DNA damage in metazoans and plants and, in fission yeast, in heterochromatin silencing. Among putative CRL4 receptors we identified MULTICOPY SUPPRESSOR OF IRA1 (MSI1), which belongs to an evolutionary conserved protein family. MSI1-like proteins contribute to different protein complexes, including the epigenetic regulatory Polycomb repressive complex 2 (PRC2). Here, we provide evidence that Arabidopsis MSI1 physically interacts with DDB1A and is part of a multimeric protein complex including CUL4. CUL4 and DDB1 loss-of-function lead to embryo lethality. Interestingly, as in fis class mutants, cul4 mutants exhibit autonomous endosperm initiation and loss of parental imprinting of MEDEA, a target gene of the Arabidopsis PRC2 complex. In addition, after pollination both MEDEA transcript and protein accumulate in a cul4 mutant background. Overall, our work provides the first evidence of a physical and functional link between a CRL4 E3 ligase and a PRC2 complex, thus indicating a novel role of ubiquitylation in the repression of gene expression. PMID- 21240253 TI - Evaluation of the prognostic significance of MSMB and CRISP3 in prostate cancer using automated image analysis. AB - Despite prostate cancer being the most frequent cancer in men in the Western world, tissue biomarkers for predicting disease recurrence after surgery have not been incorporated into clinical practice. Our group has previously identified beta-microseminoprotein (MSMB) and cysteine-rich secretory protein-3 (CRISP3) as independent predictors of biochemical recurrence after radical prostatectomy. The purpose of the present study was to use automated image analysis, enabling quantitative determination of MSMB and CRISP3 expressions in a large cohort and to validate the previous findings. MSMB and CRISP3 protein expressions were assessed on tissue microarrays constructed from 3268 radical prostatectomy specimens. Whole-slide digital images were captured, and a novel cytoplasmic algorithm was used to develop a quantitative scoring model for cytoplasmic staining. Classification regression tree analysis was used to group patients, with different risk for biochemical recurrence, depending on level of protein expression. Patients with tumors expressing high levels of MSMB had a significantly reduced risk for biochemical recurrence after radical prostatectomy (HR=0.468; 95% CI 0.394-0.556; P<0.001). Multivariate analysis adjusted for clinicopathological parameters revealed that MSMB expression was an independent predictor of decreased risk of recurrence (HR=0.710; 95% CI 0.578-0.872; P<0.001). We found no correlation between CRISP3 expression and biochemical recurrence. In this current study, we applied a novel image analysis on a large independent cohort and successfully verified that MSMB is a strong independent factor, predicting favorable outcome after radical prostatectomy for localized prostate cancer. PMID- 21240254 TI - Downregulation of CASR expression and global loss of parafibromin staining are strong negative determinants of prognosis in parathyroid carcinoma. AB - Parathyroid carcinoma is associated with mutations in the HRPT2/CDC73 gene and with decreased parafibromin and calcium-sensing receptor (CASR) expression, but in some cases establishing an unequivocal diagnosis remains a challenge. The aim of our study was to evaluate the prognostic value of CASR and parafibromin expression and of HRPT2/CDC73 mutations in patients with an established diagnosis of parathyroid carcinoma. Data on survival and disease-free survival were obtained from hospital records of 23 patients with an established diagnosis of parathyroid carcinoma in whom CASR and parafibromin expression and HRPT2/CDC73 mutation analyses were available from paraffin-embedded pathological specimens. Kaplan-Meier curves were used for survival analysis. Downregulation of CASR expression, global loss of parafibromin staining and a HRPT2/CDC73 mutation were, respectively, found in 7 (30%), 13 (59%) and 4 (17%) patients, and were associated with, respectively, 16-fold, 4-fold and 7-fold increased risk of developing local or distant metastasis. These findings suggest that although downregulation of CASR expression, global loss of parafibromin staining and mutations in the HRPT2/CDC73 gene are tools of proven value to assist in establishing a diagnosis of parathyroid carcinoma, their absence does not exclude it. Notwithstanding, we demonstrate a significant added value of these markers as strong determinants of increased malignant potential and thus as negative prognostic markers in this malignancy. PMID- 21240255 TI - Amplification of the ch19p13.2 NACC1 locus in ovarian high-grade serous carcinoma. AB - On the basis of digital karyotyping, we have identified a new, discrete amplified region at ch19p13.2 in a high-grade ovarian serous carcinoma. To further characterize this region, we determined the frequency and biological significance of ch19p13.2 amplification by analyzing 341 high-grade serous carcinomas from The Cancer Genome Atlas (TCGA) and found an increased DNA copy number at this locus in 18% of cases. We correlated the DNA and RNA copy number by analyzing the TCGA data set for all amplified genes and detected seven genes within ch19p13.2 that were significantly correlated (R>=0.54) and were, in fact, listed as the top 100 potential 'driver' genes at a genome-wide scale. Interestingly, one of the seven genes, NACC1, encoding NAC1 was previously reported to be involved in the development of tumor recurrence in ovarian serous carcinoma and to have a causal role in the development of paclitaxel resistance. Therefore, we selected NACC1 for validation in an independent cohort. On the basis of fluorescence in situ hybridization, we found that 35 (20%) of 175 high-grade serous carcinomas had an increased DNA copy number at the NACC1 locus, and those amplified cases were associated with early disease recurrence within 6 months (P=0.013). A significantly high level of NAC1 protein expression based on immunohistochemistry was detected in amplified tumors as compared with non-amplified tumors (P<0.005). In summary, our data suggest that amplification at the ch19p13.2 NACC1 locus, leading to NAC1 overexpression, is one of the molecular genetic alterations associated with early tumor recurrence in ovarian cancer. PMID- 21240256 TI - Improved demonstration of immunohistochemical prognostic markers for survival in follicular lymphoma cells. AB - Follicular lymphoma (FL) is one of the most common forms of the low-grade non Hodgkin's lymphoma in adults, with a characteristic translocation, t(14;18)(q32;q21) that deregulates the expression of the BCL2 gene. The clinical course of FL patients is variable, whereby a subset of patients survive for long periods even without relapses, whereas the majority have frequent relapses with shorter survival. We have analyzed a series of 186 FLs, studying the correlation between clinical outcome and the tumor cell expression of a set of immunohistochemical markers, using an automated procedure for tissue microarrays to reduce the subjectivity of scoring. The results identified several markers associated with differences in overall survival (OS) in univariate analyses, such as Cyclin E, Mdm2, CD10, p21, IgD, Bcl-xL, CD30, and E2F6. Cases with a higher level of expression of Cyclin E, Mdm2, p21, IgD, Bcl-xL, CD30, and E2F6 were associated with a significantly shorter OS. On the other hand, strong CD10 expression was linked to a significantly better outcome. A Cox model was then constructed, integrating the Follicular Lymphoma International Prognostic Index (FLIPI) score and a restricted selection of three immunohistochemical markers: Cyclin E, Mdm2, and CD10 expression. A potentially useful finding is that the integrated FLIPI plus immunohistochemical model can be used to identify a subset of 26 patients (almost 20% of the total series), with a survival probability of 100% at 5 years. This not only confirms that a group of FL cases may have a very good clinical course, but also indicates that this group can be identified using this integrated clinical and immunohistochemical approach. PMID- 21240257 TI - Benign mucocele-like lesions of the breast: revisited. AB - Mucocele-like lesions of the breast are ruptured ducts that discharge their contents into the stroma. They constitute a spectrum from benign to atypical to malignant. The current management of these lesions diagnosed on core biopsy is excision. The goal of our study was to evaluate the necessity of this practice for benign mucocele-like lesions. Retrospective review of the pathology database from 1 January 2000 to 1 June 2008 identified 61 cases, with follow-up information available in 50 cases. Clinical, radiological, and pathological information was correlated. Core biopsies were reviewed to confirm the diagnosis and verify previous biopsy site. In all, 45 patients underwent surgery, whereas 5 patients were followed for >1 year and remained stable. Patient's ages ranged from 44 to 76 years. Most benign mucoceles were diagnosed stereotactically while targeting calcifications (93.3%); rarely, the lesion was a sonographically detected mass. Most excisions had no residual mucocele (37/45=82%). In seven cases (15.6%), atypical duct hyperplasia was present, three with residual mucocele. In one case, the residual mucocele showed a continuum from florid to atypical duct hyperplasia at the core biopsy site. The other six cases showed atypical duct hyperplasia adjacent to but not directly at the core biopsy site. The sizes of the benign mucoceles ranged from incipient to 0.6 cm, all containing calcifications except one, which was incidental. Radiological-pathological correlation was concordant in all cases except one with suspicious calcification, which was ductal carcinoma in situ on excision. In this series, the largest of its kind, the upstage rate of benign mucoceles diagnosed on core biopsy was 17.8%. With the exception of the ductal carcinoma in situ case, no radiological or morphological features were predictive of atypia. Thus, because of associated atypical duct hyperplasia, sampling reasons, and intralesional heterogeneity, we continue to recommend excision of benign mucocele-like lesions diagnosed on core biopsy. PMID- 21240258 TI - Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor. AB - The aim of this study was to relate the density of tumor infiltrating T cells to cancer-specific survival in colorectal cancer, taking into consideration the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) screening status. The T-cell marker CD3 was stained by immunohistochemistry in 484 archival tumor tissue samples. T-cell density was semiquantitatively estimated and scored 1-4 in the tumor front and center (T cells in stroma), and intraepithelially (T cells infiltrating tumor cell nests). Total CD3 score was calculated as the sum of the three CD3 scores (range 3-12). MSI screening status was assessed by immunohistochemistry. CIMP status was determined by quantitative real-time PCR (MethyLight) using an eight-gene panel. We found that patients whose tumors were highly infiltrated by T cells (total CD3 score >=7) had longer survival compared with patients with poorly infiltrated tumors (total CD3 score <=4). This finding was statistically significant in multivariate analyses (multivariate hazard ratio, 0.57; 95% confidence interval, 0.31-1.00). Importantly, the finding was consistent in rectal cancer patients treated with preoperative radiotherapy. Although microsatellite unstable tumor patients are generally considered to have better prognosis, we found no difference in survival between microsatellite unstable and microsatellite stable (MSS) colorectal cancer patients with similar total CD3 scores. Patients with MSS tumors highly infiltrated by T cells had better prognosis compared with intermediately or poorly infiltrated microsatellite unstable tumors (log rank P=0.013). Regarding CIMP status, CIMP low was associated with particularly poor prognosis in patients with poorly infiltrated tumors (multivariate hazard ratio for CIMP-low versus CIMP-negative, 3.07; 95% confidence interval, 1.53-6.15). However, some subset analyses suffered from low power and are in need of confirmation by independent studies. In conclusion, patients whose tumors are highly infiltrated by T cells have a beneficial prognosis, regardless of MSI, whereas the role of CIMP status in this context is less clear. PMID- 21240259 TI - Structure of human O-GlcNAc transferase and its complex with a peptide substrate. AB - The essential mammalian enzyme O-linked beta-N-acetylglucosamine transferase (O GlcNAc transferase, here OGT) couples metabolic status to the regulation of a wide variety of cellular signalling pathways by acting as a nutrient sensor. OGT catalyses the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP GlcNAc) to serines and threonines of cytoplasmic, nuclear and mitochondrial proteins, including numerous transcription factors, tumour suppressors, kinases, phosphatases and histone-modifying proteins. Aberrant glycosylation by OGT has been linked to insulin resistance, diabetic complications, cancer and neurodegenerative diseases including Alzheimer's. Despite the importance of OGT, the details of how it recognizes and glycosylates its protein substrates are largely unknown. We report here two crystal structures of human OGT, as a binary complex with UDP (2.8 A resolution) and as a ternary complex with UDP and a peptide substrate (1.95 A). The structures provide clues to the enzyme mechanism, show how OGT recognizes target peptide sequences, and reveal the fold of the unique domain between the two halves of the catalytic region. This information will accelerate the rational design of biological experiments to investigate OGT's functions; it will also help the design of inhibitors for use as cellular probes and help to assess its potential as a therapeutic target. PMID- 21240260 TI - Modelling the long QT syndrome with induced pluripotent stem cells. AB - The ability to generate patient-specific human induced pluripotent stem cells (iPSCs) offers a new paradigm for modelling human disease and for individualizing drug testing. Congenital long QT syndrome (LQTS) is a familial arrhythmogenic syndrome characterized by abnormal ion channel function and sudden cardiac death. Here we report the development of a patient/disease-specific human iPSC line from a patient with type-2 LQTS (which is due to the A614V missense mutation in the KCNH2 gene). The generated iPSCs were coaxed to differentiate into the cardiac lineage. Detailed whole-cell patch-clamp and extracellular multielectrode recordings revealed significant prolongation of the action-potential duration in LQTS human iPSC-derived cardiomyocytes (the characteristic LQTS phenotype) when compared to healthy control cells. Voltage-clamp studies confirmed that this action-potential-duration prolongation stems from a significant reduction of the cardiac potassium current I(Kr). Importantly, LQTS-derived cells also showed marked arrhythmogenicity, characterized by early-after depolarizations and triggered arrhythmias. We then used the LQTS human iPSC-derived cardiac-tissue model to evaluate the potency of existing and novel pharmacological agents that may either aggravate (potassium-channel blockers) or ameliorate (calcium-channel blockers, K(ATP)-channel openers and late sodium-channel blockers) the disease phenotype. Our study illustrates the ability of human iPSC technology to model the abnormal functional phenotype of an inherited cardiac disorder and to identify potential new therapeutic agents. As such, it represents a promising paradigm to study disease mechanisms, optimize patient care (personalized medicine), and aid in the development of new therapies. PMID- 21240261 TI - Radical-mediated enzymatic carbon chain fragmentation-recombination. AB - The radical S-adenosylmethionine (S-AdoMet) superfamily contains thousands of proteins that catalyze highly diverse conversions, most of which are poorly understood, owing to a lack of information regarding chemical products and radical-dependent transformations. We here report that NosL, involved in forming the indole side ring of the thiopeptide nosiheptide (NOS), is a radical S-AdoMet 3-methyl-2-indolic acid (MIA) synthase. NosL catalyzed an unprecedented carbon chain reconstitution of L-tryptophan to give MIA, showing removal of the Calpha-N unit and shift of the carboxylate to the indole ring. Dissection of the enzymatic process upon the identification of products and a putative glycyl intermediate uncovered a radical-mediated, unusual fragmentation-recombination reaction. This finding unveiled a key step in radical S-AdoMet enzyme-catalyzed structural rearrangements during complex biotransformations. Additionally, NosL tolerated fluorinated L-tryptophan as the substrate, allowing for production of a regiospecifically halogenated thiopeptide that has not been found among the more than 80 members of the naturally occurring thiopeptide family. PMID- 21240262 TI - The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. AB - Cancer stem cells (CSCs), or tumor-initiating cells, are involved in tumor progression and metastasis. MicroRNAs (miRNAs) regulate both normal stem cells and CSCs, and dysregulation of miRNAs has been implicated in tumorigenesis. CSCs in many tumors--including cancers of the breast, pancreas, head and neck, colon, small intestine, liver, stomach, bladder and ovary--have been identified using the adhesion molecule CD44, either individually or in combination with other marker(s). Prostate CSCs with enhanced clonogenic and tumor-initiating and metastatic capacities are enriched in the CD44(+) cell population, but whether miRNAs regulate CD44(+) prostate cancer cells and prostate cancer metastasis remains unclear. Here we show, through expression analysis, that miR-34a, a p53 target, was underexpressed in CD44(+) prostate cancer cells purified from xenograft and primary tumors. Enforced expression of miR-34a in bulk or purified CD44(+) prostate cancer cells inhibited clonogenic expansion, tumor regeneration, and metastasis. In contrast, expression of miR-34a antagomirs in CD44(-) prostate cancer cells promoted tumor development and metastasis. Systemically delivered miR-34a inhibited prostate cancer metastasis and extended survival of tumor bearing mice. We identified and validated CD44 as a direct and functional target of miR-34a and found that CD44 knockdown phenocopied miR-34a overexpression in inhibiting prostate cancer regeneration and metastasis. Our study shows that miR 34a is a key negative regulator of CD44(+) prostate cancer cells and establishes a strong rationale for developing miR-34a as a novel therapeutic agent against prostate CSCs. PMID- 21240263 TI - Time-lapse imaging of disease progression in deep brain areas using fluorescence microendoscopy. AB - The combination of intravital microscopy and animal models of disease has propelled studies of disease mechanisms and treatments. However, many disorders afflict tissues inaccessible to light microscopy in live subjects. Here we introduce cellular-level time-lapse imaging deep within the live mammalian brain by one- and two-photon fluorescence microendoscopy over multiple weeks. Bilateral imaging sites allowed longitudinal comparisons within individual subjects, including of normal and diseased tissues. Using this approach, we tracked CA1 hippocampal pyramidal neuron dendrites in adult mice, revealing these dendrites' extreme stability and rare examples of their structural alterations. To illustrate disease studies, we tracked deep lying gliomas by observing tumor growth, visualizing three-dimensional vasculature structure and determining microcirculatory speeds. Average erythrocyte speeds in gliomas declined markedly as the disease advanced, notwithstanding significant increases in capillary diameters. Time-lapse microendoscopy will be applicable to studies of numerous disorders, including neurovascular, neurological, cancerous and trauma-induced conditions. PMID- 21240264 TI - The Ngal reporter mouse detects the response of the kidney to injury in real time. AB - Many proteins have been proposed to act as surrogate markers of organ damage, yet for many candidates the essential biomarker characteristics that link the protein to the injured organ have not yet been described. We generated an Ngal reporter mouse by inserting a double-fusion reporter gene encoding luciferase-2 and mCherry (Luc2-mC) into the Ngal (Lcn2) locus. The Ngal-Luc2-mC reporter accurately recapitulated the endogenous message and illuminated injuries in vivo in real time. In the kidney, Ngal-Luc2-mC imaging showed a sensitive, rapid, dose dependent, reversible, and organ- and cell-specific relationship with tubular stress, which correlated with the level of urinary Ngal (uNgal). Unexpectedly, specific cells of the distal nephron were the source of uNgal. Cells isolated from Ngal-Luc2-mC mice also revealed both the onset and the resolution of the injury, and the actions of NF-kappaB inhibitors and antibiotics during infection. Thus, imaging of Ngal-Luc2-mC mice and cells identified injurious and reparative agents that affect kidney damage. PMID- 21240265 TI - IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. AB - Polymorphisms in the gene encoding the transcription factor IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Here we show that IRF5 expression in macrophages was reversibly induced by inflammatory stimuli and contributed to the plasticity of macrophage polarization. High expression of IRF5 was characteristic of M1 macrophages, in which it directly activated transcription of the genes encoding interleukin 12 subunit p40 (IL 12p40), IL-12p35 and IL-23p19 and repressed the gene encoding IL-10. Consequently, those macrophages set up the environment for a potent T helper type 1 (T(H)1)-T(H)17 response. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively. Our data suggest a critical role for IRF5 in M1 macrophage polarization and define a previously unknown function for IRF5 as a transcriptional repressor. PMID- 21240266 TI - Efficient mucosal vaccination mediated by the neonatal Fc receptor. AB - Almost all infectious diseases are initiated at mucosal surfaces, yet intramuscular or subcutaneous vaccination usually provides only minimal protection at sites of infection owing to suboptimal activation of the mucosal immune system. The neonatal Fc receptor (FcRn) mediates the transport of IgG across polarized epithelial cells lining mucosal surfaces. We mimicked this process by fusing a model antigen, herpes simplex virus type-2 (HSV-2) glycoprotein gD, to an IgG Fc fragment. Intranasal immunization, together with the adjuvant CpG, completely protected wild-type, but not FcRn knockout, mice after intravaginal challenge with virulent HSV-2 186. This immunization strategy induced efficient mucosal and systemic antibody, B- and T-cell immune responses, with stable protection for at least 6 months after vaccination in most of the immunized animals. The FcRn-IgG transcellular transport pathway may provide a general delivery route for subunit vaccines against many mucosal pathogens. PMID- 21240267 TI - Regulation of transcription by unnatural amino acids. AB - Small-molecule regulation of gene expression is intrinsic to cellular function and indispensable to the construction of new biological sensing, control and expression systems. However, there are currently only a handful of strategies for engineering such regulatory components and fewer still that can give rise to an arbitrarily large set of inducible systems whose members respond to different small molecules, display uniformity and modularity in their mechanisms of regulation, and combine to actuate universal logics. Here we present an approach for small-molecule regulation of transcription based on the combination of cis regulatory leader-peptide elements with genetically encoded unnatural amino acids (amino acids that have been artificially added to the genetic code). In our system, any genetically encoded unnatural amino acid (UAA) can be used as a small molecule attenuator or activator of gene transcription, and the logics intrinsic to the network defined by expanded genetic codes can be actuated. PMID- 21240268 TI - Structure of UvrA nucleotide excision repair protein in complex with modified DNA. AB - One of the primary pathways for removal of DNA damage is nucleotide excision repair (NER). In bacteria, the UvrA protein is the component of NER that locates the lesion. A notable feature of NER is its ability to act on many DNA modifications that vary in chemical structure. So far, the mechanism underlying this broad specificity has been unclear. Here, we report the first crystal structure of a UvrA protein in complex with a chemically modified oligonucleotide. The structure shows that the UvrA dimer does not contact the site of lesion directly, but rather binds the DNA regions on both sides of the modification. The DNA region harboring the modification is deformed, with the double helix bent and unwound. UvrA uses damage-induced deformations of the DNA and a less rigid structure of the modified double helix for indirect readout of the lesion. PMID- 21240269 TI - Crystal structure of autotaxin and insight into GPCR activation by lipid mediators. AB - Autotaxin (ATX, also known as Enpp2) is a secreted lysophospholipase D that hydrolyzes lysophosphatidylcholine to generate lysophosphatidic acid (LPA), a lipid mediator that activates G protein-coupled receptors to evoke various cellular responses. Here, we report the crystal structures of mouse ATX alone and in complex with LPAs with different acyl-chain lengths and saturations. These structures reveal that the multidomain architecture helps to maintain the structural rigidity of the lipid-binding pocket, which accommodates the respective LPA molecules in distinct conformations. They indicate that a loop region in the catalytic domain is a major determinant for the substrate specificity of the Enpp family enzymes. Furthermore, along with biochemical and biological data, these structures suggest that the produced LPAs are delivered from the active site to cognate G protein-coupled receptors through a hydrophobic channel. PMID- 21240270 TI - A processed noncoding RNA regulates an altruistic bacterial antiviral system. AB - The >= 1030 bacteriophages on Earth relentlessly drive adaptive coevolution, forcing the generation of protective mechanisms in their bacterial hosts. One such bacterial phage-resistance system, ToxIN, consists of a protein toxin (ToxN) that is inhibited in vivo by a specific RNA antitoxin (ToxI); however, the mechanisms for this toxicity and inhibition have not been defined. Here we present the crystal structure of the ToxN-ToxI complex from Pectobacterium atrosepticum, determined to 2.75-A resolution. ToxI is a 36-nucleotide noncoding RNA pseudoknot, and three ToxI monomers bind to three ToxN monomers to generate a trimeric ToxN-ToxI complex. Assembly of this complex is mediated entirely through extensive RNA-protein interactions. Furthermore, a 2'-3' cyclic phosphate at the 3' end of ToxI, and catalytic residues, identify ToxN as an endoRNase that processes ToxI from a repetitive precursor but is regulated by its own catalytic product. PMID- 21240271 TI - Structural basis of substrate discrimination and integrin binding by autotaxin. AB - Autotaxin (ATX, also known as ectonucleotide pyrophosphatase/phosphodiesterase-2, ENPP2) is a secreted lysophospholipase D that generates the lipid mediator lysophosphatidic acid (LPA), a mitogen and chemoattractant for many cell types. ATX-LPA signaling is involved in various pathologies including tumor progression and inflammation. However, the molecular basis of substrate recognition and catalysis by ATX and the mechanism by which it interacts with target cells are unclear. Here, we present the crystal structure of ATX, alone and in complex with a small-molecule inhibitor. We have identified a hydrophobic lipid-binding pocket and mapped key residues for catalysis and selection between nucleotide and phospholipid substrates. We have shown that ATX interacts with cell-surface integrins through its N-terminal somatomedin B-like domains, using an atypical mechanism. Our results define determinants of substrate discrimination by the ENPP family, suggest how ATX promotes localized LPA signaling and suggest new approaches for targeting ATX with small-molecule therapeutic agents. PMID- 21240272 TI - Structural basis for the assembly of the SMRT/NCoR core transcriptional repression machinery. AB - Eukaryotic transcriptional repressors function by recruiting large coregulatory complexes that target histone deacetylase enzymes to gene promoters and enhancers. Transcriptional repression complexes, assembled by the corepressor NCoR and its homolog SMRT, are crucial in many processes, including development and metabolic physiology. The core repression complex involves the recruitment of three proteins, HDAC3, GPS2 and TBL1, to a highly conserved repression domain within SMRT and NCoR. We have used structural and functional approaches to gain insight into the architecture and biological role of this complex. We report the crystal structure of the tetrameric oligomerization domain of TBL1, which interacts with both SMRT and GPS2, and the NMR structure of the interface complex between GPS2 and SMRT. These structures, together with computational docking, mutagenesis and functional assays, reveal the assembly mechanism and stoichiometry of the corepressor complex. PMID- 21240273 TI - Ephaptic coupling of cortical neurons. AB - The electrochemical processes that underlie neural function manifest themselves in ceaseless spatiotemporal field fluctuations. However, extracellular fields feed back onto the electric potential across the neuronal membrane via ephaptic coupling, independent of synapses. The extent to which such ephaptic coupling alters the functioning of neurons under physiological conditions remains unclear. To address this question, we stimulated and recorded from rat cortical pyramidal neurons in slices with a 12-electrode setup. We found that extracellular fields induced ephaptically mediated changes in the somatic membrane potential that were less than 0.5 mV under subthreshold conditions. Despite their small size, these fields could strongly entrain action potentials, particularly for slow (<8 Hz) fluctuations of the extracellular field. Finally, we simultaneously measured from up to four patched neurons located proximally to each other. Our findings indicate that endogenous brain activity can causally affect neural function through field effects under physiological conditions. PMID- 21240274 TI - A wireless multi-channel neural amplifier for freely moving animals. AB - Conventional neural recording systems restrict behavioral experiments to a flat indoor environment compatible with the cable that tethers the subject to recording instruments. To overcome these constraints, we developed a wireless multi-channel system for recording neural signals from rats. The device takes up to 64 voltage signals from implanted electrodes, samples each at 20 kHz, time division multiplexes them into one signal and transmits that output by radio frequency to a receiver up to 60 m away. The system introduces <4 MUV of electrode-referred noise, comparable to wired recording systems, and outperforms existing rodent telemetry systems in channel count, weight and transmission range. This allows effective recording of brain signals in freely behaving animals. We report measurements of neural population activity taken outdoors and in tunnels. Neural firing in the visual cortex was relatively sparse, correlated even across large distances and was strongly influenced by locomotor activity. PMID- 21240275 TI - Mutations of the SLX4 gene in Fanconi anemia. AB - Fanconi anemia is a rare recessive disorder characterized by genome instability, congenital malformations, progressive bone marrow failure and predisposition to hematologic malignancies and solid tumors. At the cellular level, hypersensitivity to DNA interstrand crosslinks is the defining feature in Fanconi anemia. Mutations in thirteen distinct Fanconi anemia genes have been shown to interfere with the DNA-replication-dependent repair of lesions involving crosslinked DNA at stalled replication forks. Depletion of SLX4, which interacts with multiple nucleases and has been recently identified as a Holliday junction resolvase, results in increased sensitivity of the cells to DNA crosslinking agents. Here we report the identification of biallelic SLX4 mutations in two individuals with typical clinical features of Fanconi anemia and show that the cellular defects in these individuals' cells are complemented by wildtype SLX4, demonstrating that biallelic mutations in SLX4 (renamed here as FANCP) cause a new subtype of Fanconi anemia, Fanconi anemia-P. PMID- 21240276 TI - Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia. AB - The evolutionarily conserved SLX4 protein, a key regulator of nucleases, is critical for DNA damage response. SLX4 nuclease complexes mediate repair during replication and can also resolve Holliday junctions formed during homologous recombination. Here we describe the phenotype of the Btbd12 knockout mouse, the mouse ortholog of SLX4, which recapitulates many key features of the human genetic illness Fanconi anemia. Btbd12-deficient animals are born at sub Mendelian ratios, have greatly reduced fertility, are developmentally compromised and are prone to blood cytopenias. Btbd12(-/-) cells prematurely senesce, spontaneously accumulate damaged chromosomes and are particularly sensitive to DNA crosslinking agents. Genetic complementation reveals a crucial requirement for Btbd12 (also known as Slx4) to interact with the structure-specific endonuclease Xpf-Ercc1 to promote crosslink repair. The Btbd12 knockout mouse therefore establishes a disease model for Fanconi anemia and genetically links a regulator of nuclease incision complexes to the Fanconi anemia DNA crosslink repair pathway. PMID- 21240277 TI - SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype. AB - DNA interstrand crosslink repair requires several classes of proteins, including structure-specific endonucleases and Fanconi anemia proteins. SLX4, which coordinates three separate endonucleases, was recently recognized as an important regulator of DNA repair. Here we report the first human individuals found to have biallelic mutations in SLX4. These individuals, who were previously diagnosed as having Fanconi anemia, add SLX4 as an essential component to the FA-BRCA genome maintenance pathway. PMID- 21240278 TI - Real-time multimodal optical control of neurons and muscles in freely behaving Caenorhabditis elegans. AB - The ability to optically excite or silence specific cells using optogenetics has become a powerful tool to interrogate the nervous system. Optogenetic experiments in small organisms have mostly been performed using whole-field illumination and genetic targeting, but these strategies do not always provide adequate cellular specificity. Targeted illumination can be a valuable alternative but it has only been shown in motionless animals without the ability to observe behavior output. We present a real-time, multimodal illumination technology that allows both tracking and recording the behavior of freely moving C. elegans while stimulating specific cells that express channelrhodopsin-2 or MAC. We used this system to optically manipulate nodes in the C. elegans touch circuit and study the roles of sensory and command neurons and the ultimate behavioral output. This technology enhances our ability to control, alter, observe and investigate how neurons, muscles and circuits ultimately produce behavior in animals using optogenetics. PMID- 21240279 TI - Optogenetic manipulation of neural activity in freely moving Caenorhabditis elegans. AB - We present an optogenetic illumination system capable of real-time light delivery with high spatial resolution to specified targets in freely moving Caenorhabditis elegans. A tracking microscope records the motion of an unrestrained worm expressing channelrhodopsin-2 or halorhodopsin in specific cell types. Image processing software analyzes the worm's position in each video frame, rapidly estimates the locations of targeted cells and instructs a digital micromirror device to illuminate targeted cells with laser light of the appropriate wavelengths to stimulate or inhibit activity. Because each cell in an unrestrained worm is a rapidly moving target, our system operates at high speed (~50 frames per second) to provide high spatial resolution (~30 MUm). To test the accuracy, flexibility and utility of our system, we performed optogenetic analyses of the worm motor circuit, egg-laying circuit and mechanosensory circuits that have not been possible with previous methods. PMID- 21240280 TI - A transgenic mouse for in vivo detection of endogenous labeled mRNA. AB - Live-cell single mRNA imaging is a powerful tool but has been restricted in higher eukaryotes to artificial cell lines and reporter genes. We describe an approach that enables live-cell imaging of single endogenous labeled mRNA molecules transcribed in primary mammalian cells and tissue. We generated a knock in mouse line with an MS2 binding site (MBS) cassette targeted to the 3' untranslated region of the essential beta-actin gene. As beta-actin-MBS was ubiquitously expressed, we could uniquely address endogenous mRNA regulation in any tissue or cell type. We simultaneously followed transcription from the beta actin alleles in real time and observed transcriptional bursting in response to serum stimulation with precise temporal resolution. We tracked single endogenous labeled mRNA particles being transported in primary hippocampal neurons. The MBS cassette also enabled high-sensitivity fluorescence in situ hybridization (FISH), allowing detection and localization of single beta-actin mRNA molecules in various mouse tissues. PMID- 21240281 TI - RNAi screening for fat regulatory genes with SRS microscopy. AB - Identification of genes regulating fat accumulation is important for basic and medical research; genetic screening for those genes in Caenorhabditis elegans, a widely used model organism, requires in vivo quantification of lipids. We demonstrated RNA interference screening based on quantitative imaging of lipids with label-free stimulated Raman scattering (SRS) microscopy, which overcomes major limitations of coherent anti-Stokes Raman scattering microscopy. Our screening yielded eight new genetic regulators of fat storage. PMID- 21240282 TI - Green light stimulates terahertz emission from mesocrystal microspheres. AB - The discovery of efficient sources of terahertz radiation has been exploited in imaging applications, and developing a nanoscale terahertz source could lead to additional applications. High-frequency mechanical vibrations of charged nanostructures can lead to radiative emission, and vibrations at frequencies of hundreds of kilohertz have been observed from a ZnO nanobelt under the influence of an alternating electric field. Here, we observe mechanical resonance and radiative emission at ~ 0.36 THz from core-shell ZnO mesocrystal microspheres excited by a continuous green-wavelength laser. We find that ~ 0.016% of the incident power is converted into terahertz radiation, which corresponds to a quantum efficiency of ~ 33%, making the ZnO microspheres competitive with existing terahertz-emitting materials. The mechanical resonance and radiation stem from the coherent photo-induced vibration of the hexagonal ZnO nanoplates that make up the microsphere shells. The ZnO microspheres are formed by means of a nonclassical, self-organized crystallization process, and represent a straightforward route to terahertz radiation at the nanoscale. PMID- 21240283 TI - Synthetic RNA-protein complex shaped like an equilateral triangle. AB - Synthetic nanostructures consisting of biomacromolecules such as nucleic acids have been constructed using bottom-up approaches. In particular, Watson-Crick base pairing has been used to construct a variety of two- and three-dimensional DNA nanostructures. Here, we show that RNA and the ribosomal protein L7Ae can form a nanostructure shaped like an equilateral triangle that consists of three proteins bound to an RNA scaffold. The construction of the complex relies on the proteins binding to kink-turn (K-turn) motifs in the RNA, which allows the RNA to bend by ~ 60 degrees at three positions to form a triangle. Functional RNA protein complexes constructed with this approach could have applications in nanomedicine and synthetic biology. PMID- 21240285 TI - Large field-induced strains in a lead-free piezoelectric material. AB - Piezoelectric materials exhibit a mechanical response to electrical inputs, as well as an electrical response to mechanical inputs, which makes them useful in sensors and actuators. Lead-based piezoelectrics demonstrate a large mechanical response, but they also pose a health risk. The ferroelectric BiFeO(3) is an attractive alternative because it is lead-free, and because strain can stabilize BiFeO(3) phases with a structure that resembles a morphotropic phase boundary. Here we report a reversible electric-field-induced strain of over 5% in BiFeO(3) films, together with a characterization of the origins of this effect. In situ transmission electron microscopy coupled with nanoscale electrical and mechanical probing shows that large strains result from moving the boundaries between tetragonal- and rhombohedral-like phases, which changes the phase stability of the mixture. These results demonstrate the potential of BiFeO(3) as a substitute for lead-based materials in future piezoelectric applications. PMID- 21240286 TI - Nucleation of nuclear bodies by RNA. AB - The biogenesis of the many functional compartments contained in the mammalian cell nucleus is poorly understood. More specifically, little is known regarding the initial nucleation step required for nuclear body formation. Here we show that RNA can function as a structural element and a nucleator of nuclear bodies. We find that several types of coding and noncoding RNAs are sufficient to de novo assemble, and are physiologically enriched in, histone locus bodies (with associated Cajal bodies), nuclear speckles, paraspeckles and nuclear stress bodies. Formation of nuclear bodies occurs through recruitment and accumulation of proteins resident in the nuclear bodies by nucleating RNA. These results demonstrate that transcription is a driving force in nuclear body formation and RNA transcripts can function as a scaffold in the formation of major nuclear bodies. Together, these data suggest that RNA-primed biogenesis of nuclear bodies is a general principle of nuclear organization. PMID- 21240287 TI - Transient photoinduced 'hidden' phase in a manganite. AB - Photoinduced phase transitions are of special interest in condensed matter physics because they can be used to change complex macroscopic material properties on the ultrafast timescale. Cooperative interactions between microscopic degrees of freedom greatly enhance the number and nature of accessible states, making it possible to switch electronic, magnetic or structural properties in new ways. Photons with high energies, of the order of electron volts, in particular are able to access electronic states that may differ greatly from states produced with stimuli close to equilibrium. In this study we report the photoinduced change in the lattice structure of a charge and orbitally ordered Nd(0.5)Sr(0.5)MnO(3) thin film using picosecond time-resolved X ray diffraction. The photoinduced state is structurally ordered, homogeneous, metastable and has crystallographic parameters different from any thermodynamically accessible state. A femtosecond time-resolved spectroscopic study shows the formation of an electronic gap in this state. In addition, the threshold-like behaviour and high efficiency in photo-generation yield of this gapped state highlight the important role of cooperative interactions in the formation process. These combined observations point towards a 'hidden insulating phase' distinct from that found in the hitherto known phase diagram. PMID- 21240288 TI - Experimental analysis of charge redistribution due to chemical bonding by high resolution transmission electron microscopy. AB - The electronic charge density distribution or the electrostatic atomic potential of a solid or molecule contains information not only on the atomic structure, but also on the electronic properties, such as the nature of the chemical bonds or the degree of ionization of atoms. However, the redistribution of charge due to chemical bonding is small compared with the total charge density, and therefore difficult to measure. Here, we demonstrate an experimental analysis of charge redistribution due to chemical bonding by means of high-resolution transmission electron microscopy (HRTEM). We analyse charge transfer on the single-atom level for nitrogen-substitution point defects in graphene, and confirm the ionicity of single-layer hexagonal boron nitride. Our combination of HRTEM experiments and first-principles electronic structure calculations opens a new way to investigate electronic configurations of point defects, other non-periodic arrangements or nanoscale objects that cannot be studied by an electron or X-ray diffraction analysis. PMID- 21240289 TI - Creation and control of a two-dimensional electron liquid at the bare SrTiO3 surface. AB - Many-body interactions in transition-metal oxides give rise to a wide range of functional properties, such as high-temperature superconductivity, colossal magnetoresistance or multiferroicity . The seminal recent discovery of a two dimensional electron gas (2DEG) at the interface of the insulating oxides LaAlO(3) and SrTiO(3) (ref. 4) represents an important milestone towards exploiting such properties in all-oxide devices. This conducting interface shows a number of appealing properties, including a high electron mobility, superconductivity and large magnetoresistance, and can be patterned on the few nanometre length scale. However, the microscopic origin of the interface 2DEG is poorly understood. Here, we show that a similar 2DEG, with an electron density as large as 8*10(13) cm(-2), can be formed at the bare SrTiO(3) surface. Furthermore, we find that the 2DEG density can be controlled through exposure of the surface to intense ultraviolet light. Subsequent angle-resolved photoemission spectroscopy measurements reveal an unusual coexistence of a light quasiparticle mass and signatures of strong many-body interactions. PMID- 21240290 TI - Ultralow-voltage field-ionization discharge on whiskered silicon nanowires for gas-sensing applications. AB - Several hundred million volts per centimetre of electric-field strength are required to field-ionize gas species. Such fields are produced on sharp metallic tips under a bias of a few kilovolts. Here, we show that field ionization is possible at dramatically lower fields on semiconductor nanomaterials containing surface states, particularly with metal-catalysed whiskers grown on silicon nanowires. The low-voltage field-ionization phenomena observed here cannot be explained solely on the basis of the large field-amplification effect of suspended gold nanoparticles present on the whisker tips. We postulate that field penetration causes upward band-bending at the surface of exposed silicon containing surface states in the vicinity of the catalyst. Band-bending enables the valence electron to tunnel into the surface states at reduced fields. This work provides a basis for development of low-voltage ionization sensors. Although demonstrated on silicon, low-voltage field ionization can be detected on any sharp semiconductor tip containing proper surface states. PMID- 21240292 TI - Could using the zona pellucida bound sperm for intracytoplasmic sperm injection (ICSI) enhance the outcome of ICSI? PMID- 21240291 TI - CABYR binds to AKAP3 and Ropporin in the human sperm fibrous sheath. AB - Calcium-binding tyrosine phosphorylation-regulated protein (CABYR) is a highly polymorphic calcium-binding tyrosine- and serine-/threonine-phosphorylated fibrous sheath (FS) protein involved in capacitation. A putative domain (amino acids 12-48) homologous to the regulatory subunit of type II cAMP-dependent protein kinase A (RII) dimerisation and A kinase-anchoring protein (AKAP)-binding domains of protein kinase A at the N-terminus suggests that CABYR may self assemble and bind to AKAPs. Moreover, there is evidence that CABYR has limited interaction with AKAPs. However, further evidence and new relationships between CABYR and other FS proteins, including AKAPs, will be helpful in understanding the basic physiology of FS. In this study, a new strategy for co immunoprecipitation of insoluble proteins, as well as the standard co immunoprecipitation method in combination with mass spectrometry and western blot, was employed to explore the relationship between CABYR, AKAP3 and Ropporin. The results showed that AKAP3 was co-immunoprecipitated with CABYR by the anti CABYR-A polyclonal antibody, and, conversely, CABYR was also co immunoprecipitated with AKAP3 by the anti-AKAP3 polyclonal antibody. Another RII like domain containing protein, Ropporin, was also co-immunoprecipitated with CABYR, indicating that Ropporin is one of CABYR's binding partners. The interactions between CABYR, AKAP3 and Ropporin were confirmed by yeast two-hybrid assays. Further analysis showed that CABYR not only binds to AKAP3 by its RII domain but binds to Ropporin through other regions besides the RII-like domain. This is the first demonstration that CABYR variants form a complex not only with the scaffolding protein AKAP3 but also with another RII-like domain-containing protein in the human sperm FS. PMID- 21240293 TI - A self-reported long-term follow-up of patients operated with either shortening techniques or a TachoSil grafting procedure. AB - The aim of this article is to analyse the long-term results of different surgical techniques for correction of penile deviations in Peyronie's disease. Patients who underwent surgery for a penile deviation in Peyronie's disease between 1997 and 2007 were included into this study. Cases were retrospectively analysed by chart review. The current situation was evaluated by a 16-item standardized questionnaire addressing penile straightness, sensation, length, sexual function and satisfaction. Ninety patients were contacted with a return rate of 75 (83%) evaluable questionnaires. Thirty-two patients were operated by shortening techniques (STs) with either Schroeder-Essed (n=16) or Nesbit (n=16). Forty-three were operated by a plaque in-/excision and defect covering by TachoSil method (TM). Both groups were similar regarding age (ST 56 years, TM 57 years), comorbidities, mean preoperative erection hardness score (EHS; 3.1 ST, 3.4 TM) and time of follow-up (total mean, 63 months). Preoperatively ST patients had significantly less plaques (P<0.05) and a lower deviation angle in comparison to TM patients (ST 56 degrees versus TM 74 degrees ; P< 0.001). Still TM patients reported slightly better straightening results, but a significantly lower mean EHS (ST 3.3 versus TM 2.6; P<0.001) during the follow-up. Satisfaction rates were similar in both groups. In conclusion, both techniques revealed to be safe and sustainable successful in penile straightening with better functional outcome of patients operated by STs. PMID- 21240294 TI - Cancer cell migration: when red light switched to green. PMID- 21240297 TI - Reflections of a former vice president on long-time cardiac experiences. AB - Editor's Note: Mr. Cheney, 46th vice president of the United States, was the featured guest speaker at the third annual Baylor Health Care System Foundation Heart and Vascular Dinner on April 7, 2009, at the home of Kathy and Harlan Crow (Figures 1 and 2). Previous speakers were former Senator Bob Dole and Denton Cooley, MD. Cheney spoke about his experiences with cardiovascular disease, his 40-year career in public service, and the challenges facing health care. Mr. Cheney has had four heart attacks and numerous other cardiovascular episodes, beginning with his first heart attack when he was 37 years old. The Foundation's Heart and Vascular Campaign, which has raised more than $11.2 million toward its $20 million fundraising goal, supports eight cardiology fellows and four residents in vascular surgery, as well as cardiovascular research at Baylor University Medical Center at Dallas, Baylor Hamilton Heart and Vascular Hospital, and The Heart Hospital Baylor Plano. PMID- 21240295 TI - The number of spermatozoa collected with testicular sperm extraction is a novel predictor of intracytoplasmic sperm injection outcome in non-obstructive azoospermic patients. AB - The purpose of this study was to determine the relationships between monitors of spermatogenesis and predictors of the intracytoplasmic sperm injection (ICSI) outcome in patients with non-obstructive azoospermia (NOA) undergoing testicular sperm extraction (TESE). Seventy-nine patients with NOA (mean age: 43.6+/-5.2 years), each of whom yielded (97 000+/-3040) spermatozoa with conventional TESE, were considered in our analysis. Their partners (mean age: 35.8+/-5.1 years) underwent a total of 184 ICSI cycles; 632 oocytes were collected, 221 oocytes were injected, 141 oocytes were fertilized, 121 embryos were obtained, 110 embryos were transferred, 14 clinical pregnancies were achieved and only one miscarriage occurred. Multivariate regression analysis indicated relationships between the percentage of fertilized oocytes, transferred embryos and clinical pregnancies with the following variable values: female partner's age, number of spermatozoa collected, testicular volume, male partner's levels of follicle stimulating hormone (FSH), number of oocytes collected, number of oocytes injected and number of ICSI cycles. A significant inverse relationship was found between female partner's age or male partner's FSH levels and biochemical pregnancies. A significant direct relationship emerged between the number of ICSI cycles and the percentage of oocytes fertilized, embryos transferred and biochemical pregnancies, and between the number of spermatozoa collected per testicular biopsy and biochemical pregnancies. The number of spermatozoa was positively linked to the number of clinical pregnancies, independent of the number of ICSI cycles and the number of oocytes collected/injected. The number of spermatozoa collected, FSH level and testicular volume are monitors of spermatogenesis linked to ICSI success. PMID- 21240298 TI - Light chain amyloidosis: a case presentation and review. PMID- 21240296 TI - Adeno associated viral vector-delivered and hypoxia response element-regulated CD151 expression in ischemic rat heart. AB - AIM: The aim of this study was to improve the delivery efficacy and target specificity of the pro-angiogenic gene CD151 to the ischemic heart. METHODS: To achieve the inducible expression of adeno-associated viral (AAV)-delivered CD151 gene in only the ischemic myocardium, we generated an AAV construct in which CD151 expression can be controlled by the hypoxia response element (HRE) sequence from the human Enolase gene. The function of this vector was examined in rat H9C2 cardiac myoblasts and in ischemic rat myocardium. The expression of CD151 in the areas of ischemic myocardium was confirmed at the mRNA level by real-time PCR and on the protein level by Western blot, whereas the CD151 expression in the microvessels within the areas of ischemic myocardium was detected by immunohistochemistry. RESULTS: HRE significantly enhances the expression of CD151 under hypoxic conditions or in the ischemic myocardium, and forced CD151 expression increases the number of microvessels in the ischemic myocardium. CONCLUSION: The AAV-mediated, HRE regulated delivery of the CD151 gene shows higher expression in the ischemic myocardium and more efficiently targets CD151 to the hypoxic regions after myocardial infarction. PMID- 21240299 TI - Type I second-degree atrioventricular block and intermittent left posterior fascicular block in a 26-year-old woman with an inferoposterior acute myocardial infarct. PMID- 21240300 TI - The use of probiotics in the prevention of necrotizing enterocolitis in preterm infants. PMID- 21240301 TI - Future economic damages. PMID- 21240302 TI - Facts and ideas from anywhere. PMID- 21240304 TI - Scalp lesions and hair loss. PMID- 21240303 TI - Chest wall chondrosarcoma. PMID- 21240306 TI - Stress ulcer prophylaxis in the intensive care unit. PMID- 21240305 TI - Accelerated junctional rhythm, isorhythmic atrioventricular dissociation, and hidden P waves. PMID- 21240307 TI - Facts and ideas from anywhere. PMID- 21240309 TI - First recognized episode of atrioventricular reciprocating tachycardia 10 hours after coronary artery bypass grafting in a 42-year-old man. PMID- 21240308 TI - Blanched fingers. PMID- 21240310 TI - Postoperative glycemic control in cardiac surgery patients. AB - Glycemic control in postoperative cardiac patients is necessary to improve outcomes in wound infection and overall mortality. In recent years, clinical trials evaluating blood glucose control in critically ill patients advocated for intense blood glucose management and found a significant reduction in morbidity and mortality. Some organizations published recommendations regarding blood glucose management in critically ill patients reflecting this information. However, recent clinical trials evaluating blood glucose target ranges in critically ill patients have found conflicting results, which has prompted reevaluation of current goals and guidelines, allowing for less stringent blood glucose target ranges. With the inconsistency of clinical trials evaluating a target blood glucose range for critically ill patients, specifically postoperative cardiac surgery patients, the target blood glucose range is still not clearly defined. Additional comparisons of specific glucose ranges would allow for a clearer definition of recommended blood glucose goals to target in postoperative cardiac patients. PMID- 21240311 TI - Texas Medical Board investigations revisited. PMID- 21240313 TI - Tributes to robert w. Jackson, MD. PMID- 21240312 TI - Facts and ideas from anywhere. PMID- 21240314 TI - Tributes to barry w. Uhr, MD. PMID- 21240315 TI - Concomitant endometrial and pancreatic cancers. PMID- 21240316 TI - Wegener's granulomatosis presenting as a large solitary cavitary mass. PMID- 21240317 TI - Electrocardiogram after 2 weeks of diarrhea. PMID- 21240319 TI - Facts and ideas from anywhere. PMID- 21240318 TI - New drugs approved in 2009. PMID- 21240320 TI - Warfare, genocide, and ethnic conflict: a Darwinian approach. AB - As the 21st century dawns, I reflect on the history of humankind with growing concern about the need to understand the underlying biological and cultural roots of ethnic conflict and warfare. In the many studies of human conflict, innate biological predispositions have been neglected. This article is the third part of a series of seminars for medical residents at the University of Texas Southwestern Medical School at Dallas (see http://adarwinstudygroup.org/). The series starts with in-depth coverage of Darwinian natural and sexual selection, with examples from the domestication of animals and plants and the crisis of antibiotic resistance. The series strives to show how biology has been neglected in the study of the we-they orientation of human behavior, with its devastating consequences. The subject material is profoundly disturbing, as it looks at "human nature" and contrasts the "dark side" of human behavior with the opposite, profoundly caring and loving side. PMID- 21240321 TI - Absolutely the last word on physical diagnosis: Not! PMID- 21240322 TI - Recurrent thyroid cancer with changing histologic features. AB - We present the case of a 57-year-old woman diagnosed with breast cancer and a thyroid mass that was suspicious for cancer. The breast cancer was estrogen and progesterone receptor negative, HER2/neu borderline, with a high proliferative index. Treatment of this cancer took precedence. Nine months later, a total thyroidectomy was done for papillary thyroid cancer with metastases to 2 of 8 perithyroid lymph nodes. Postoperative radioactive iodine ablation was given. Recurrent thyroid disease was found in the right neck 1 year later and was resected; no radioactive iodine was given at that time. After 21/2 years, the cancer recurred as a more highly aggressive, undifferentiated anaplastic thyroid carcinoma. Treatment is discussed. PMID- 21240323 TI - Bigeminal rhythm IV. PMID- 21240324 TI - Responsibility for the acts of others. PMID- 21240325 TI - Facts and ideas from anywhere. PMID- 21240326 TI - Coming of age in the emergency room. PMID- 21240327 TI - Ectopic adrenocorticotropic hormone syndrome: a diagnostic challenge and review of the literature. AB - We present a case of a 60-year-old woman who initially presented with pneumonia and abdominal pain and was diagnosed with ectopic adrenocorticotropic hormone (ACTH) syndrome secondary to small cell lung cancer. We review published literature and summarize the typical challenges in the diagnosis and treatment of ectopic ACTH syndrome. Recent research has shed new light on the mechanism of ectopic ACTH production and provided a potential new target for treatment. PMID- 21240328 TI - Cystic meningioma: unusual imaging appearance of a common intracranial tumor. AB - Meningiomas are common tumors of the central nervous system that account for approximately 15% of all intracranial tumors and are the most common extra-axial neoplasm. Most meningiomas are benign, although atypical and malignant meningiomas also exist. Typical imaging characteristics include a well circumscribed, homogeneously enhancing, extra-axial mass on both computed tomography and magnetic resonance imaging. The presence of an associated cyst is an uncommon imaging feature that may make it difficult to distinguish the tumor from a primary intra-axial glial neoplasm. The presence of peritumoral edema can also be a misleading finding. We present a case of a woman who presented with a history of multiple recent falls, decreased energy, and increased somnolence and was found to have a "cystic meningioma." Typical imaging characteristics, histologic subtypes, treatment, and prognosis are also discussed. PMID- 21240329 TI - Tall R waves in leads V(1) to V(3). PMID- 21240330 TI - Patient-controlled analgesia: Is it worth the painful prescribing process? PMID- 21240331 TI - Facts and ideas from anywhere. PMID- 21240332 TI - [Hypoglycemia in the diabetes treatment - risk minimization with dipeptidyl peptidase-4 inhibitors]. AB - After metformin, with insulin in patients with severe hyperglycemia, current recommendations on treatment for type 2 diabetes suggest several pharmacotherapies, including sulfonylureas, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors and others. Among them, recent data emphasize the effectiveness at a lower risk for hypoglycemia of dipeptidyl peptidase-4 inhibitors compared to other drug groups. One particular drug from this group, sitagliptin offers sound effectiveness, safety and tolerability resulting in good glycemic control at a very low risk for hypoglycemia. This review explores available evidence on the optimal treatment for type 2 diabetes regarding glycemic control with minimal risk for hypoglycemia based on evidence from clinical trials and meta-analyses within the context of the current treatment recommendations by the Spanish Society of Diabetes. PMID- 21240334 TI - Comparative analysis of the effect of cytokines on the thymus, adrenal glands, and spleen in rats with various behavioral characteristics. AB - We compared the effect of a pro-inflammatory cytokine IL-1beta and anti inflammatory cytokine IL-4 on the state of stress-marker organs in rats with various behavioral characteristics in the open-field test. Intraperitoneal injection of the cytokines was followed by a slight decrease in the relative weight of the thymus, adrenal glands, and spleen in behaviorally active and, especially, in passive animals. These changes are probably associated with the effect of the test immunomodulators on apoptosis and migration of cells of the immunocompetent organs. Pretreatment with IL-1beta and IL-4 was shown to prevent involution of the thymus and spleen in rats during acute stress on the model of immobilization with simultaneous electrocutaneous stimulation. Hence, these cytokines have the same effects on functional state of stress-marker organs in animals. IL-1beta and IL-4 have a greater effect in passive rats than in active specimens, which reflects specific features of immune mechanisms in animals with different emotional reactivity. PMID- 21240335 TI - Role of the brain dopaminergic and opioid system in the regulation of "child's" (maternal bonding) behavior of newborn albino rats. AB - Administration of D(2) receptor antagonist clebopride in a dose not affecting locomotor activity was followed by a decrease in maternal bonding behavior of 10 day-old and 15-day-old albino rat pups. D(1) receptor antagonist SCH23390 had a stimulatory effect only on the behavior of 10-day-old newborns. Opioid peptide beta-casomorphin-7 abolished the effect of clebopride in rat pups of the older age group. PMID- 21240336 TI - Irreversible amnesia in rats and edible snails under conditions of associative memory reconsolidation disturbance caused by NMDA-glutamate receptor antagonist. AB - The effect of MK-801, an antagonist to NMDA-glutamate receptors, on reconsolidation of olfactory discrimination task in rats and taste discrimination in edible snails was examined. Twenty-four hours after conditioning, the animals received a single systemic injection of MK-801 followed by a reminding conditional stimulus. Disturbances in retrieval of the acquired task were observed 10 days after injection followed by a reminding procedure. Repeated conditioning of these animals did not restore the task. Injection of MK-801 without reminding stimulation had no effect on task retention. Thus, disturbances of NMDA-dependent reconsolidation of the associative memory in animals of different taxonomic groups irreversibly eliminated long-term memory. PMID- 21240337 TI - Phospholipid composition of erythrocytes and glutathione redox system in rats during adaptation to cholesterol load. AB - We studied phospholipid composition of erythrocytes and the state of the glutathione redox system in rats during adaptation to cholesterol load for 180 days. The adaptive response is formed during the period from day 30 to day 90 of cholesterol load and is associated with increased relative content of phosphatidylethanolamine and phosphatidylinositol, activation of glutathione redox system enzymes (glutathione reductase and glutathione peroxidase), and enhanced production of glutathione. PMID- 21240338 TI - Possible mechanisms for the effect of protein sensitization on functional properties of the isolated m. soleus and m. EDL from mice. AB - We studied possible involvement of ATP in the influence of protein sensitization on contractile function and non-quantum secretion in the end-plate of isolated skeletal muscles from mouse leg. The dynamic vector of muscle contraction force was shown to correlate with changes in non-quantum secretion of acetylcholine under various conditions of experimental pathology. However, the degree of these changes was lower in sensitized animals. It can be hypothesized that the ATP induced variability in functional properties of slow muscles during protein sensitization reflects the development of resistance to external loads. The adaptive changes in fast muscles during protein sensitization are not associated with the ATP-mediated mechanisms of excitation. PMID- 21240339 TI - Effect of acute alloxan diabetes on ischemic and reperfusion arrhythmias in rats with different activity of nitric oxide system. AB - Similar degree of glycemia (28-31 mmol/liter) and similar mortality (37-42%) were revealed in August rats exhibiting enhanced activity of NO system and in Wistar rats 3 weeks after alloxan treatment. Under conditions of myocardial ischemia caused by 10-min coronary artery ligation, the intensity of arrhythmias did not differ from the control in Wistar rats with diabetes mellitus and increased in August rats. Under conditions of reperfusion, diabetes produced an antiarrhythmic effect in Wistar rats and did not affect arrhythmia in August rats. Plasma concentrations of nitrates and nitrites in Wistar and August rats increased by 82 and 143%, respectively, compared to the control. The level of hemoxygenase-1 (hsp32) in the myocardium remained unchanged in Wistar rats and decreased by 26% in August rats. Thus, the absence of antiarrhythmic effect of acute diabetes in August rats is probably related to elevated NO content and reduced antioxidant activity. PMID- 21240340 TI - Effects of dalargin on free radical processes in the blood of rats exposed to moderate hypothermia. AB - Moderate hypothermia stimulates LPO processes in rat plasma and erythrocytes and simultaneously increases antioxidant activity in the plasma and SOD activity erythrocyte. Dalargin prevents stimulation of LPO in the blood in hypothermia by reducing the generation of active oxygen species and maintaining the level of low molecular antioxidants. PMID- 21240341 TI - Catalytic characteristics of NADP-isocitrate dehydrogenase from the liver of rats in health and after injection of TNF-alpha and melatonin treatment. AB - Activity of NADP-dependent isocitrate dehydrogenase (EC 1.1.1.42) increases and the catalytic characteristics of the enzyme isolated from the liver of rats are changed under conditions of apoptosis induction in comparison with these characteristics in health. Injection of melatonin induced a trend to normalization of kinetic parameters of catalytic activity and of some regulatory characteristics of the enzyme. PMID- 21240342 TI - Effects of lipoic acid on proliferation and apoptosis of liver cells in rats with metabolic stress. AB - Lipoic acid stimulated expression of heat shock proteins 25, 70, and 90 in liver cells of Wistar rats with metabolic stress (5 days of food deprivation followed by complete resumption of nutrition). Lipoic acid in a dose of 25 mg/kg reduced proliferation of hepatic lymphocytes during fasting, while after resumption of feeding it stimulated hepatocyte proliferation due to differentiated regulation of the expression of cyclin D1 and Rb protein in these cell populations. PMID- 21240343 TI - Study of anti-ischemic effect of afobazole in experimental myocardial infarction. AB - Seven-day treatment of rats with experimental myocardial infarction with afobazole (5-ethoxy-2-[2-morpholino)-ethylthio] benzimidasole dihydrochloride) resulted in shrinkage of the ischemic damage area in the heart, stimulation of reparative processes in the myocardium, and prevention of postinfarction remodeling of the left ventricle. Anti-ischemic effect of afobazole in experimental myocardial infarction is presumably due to its interactions with sigma(1) receptors. PMID- 21240344 TI - Mechanisms of hyperglycemic effect of calcitonin. AB - We studied the effect of calcitonin on blood glucose level, total calcium content, and the main stages of carbohydrate metabolism: absorption in the intestine, transport from the blood to tissues, tissue sensitivity to insulin in the whole organism, glycogen content, and activity of glucose-6-phosphate dehydrogenase and lactate dehydrogenase in the liver. A hyperglycemic effect of calcitonin was demonstrated, a close negative correlation was found between glucose level and total calcium content (r=-0.834, p<0.02). Calcitonin had no effect on glucose absorption in the small intestine and its transport from the blood to tissues (glucose consumption by peripheral tissues at the organism level), but reduced glycogen content in the liver and increased activities of glucose-6-phosphate dehydrogenase and lactate dehydrogenase. PMID- 21240345 TI - Glucural (amigluracyl) improves survival of isolated rat hepatocytes in suspension. AB - Nonsteroid anti-inflammatory drug glucural (water-soluble N-methyl-D-glucosamine complex with 6-methyluracyl) improves survival of isolated rat hepatocytes stored in suspension. This effect of glucural is presumably explained by its membranotropism. PMID- 21240346 TI - Effect of pro- and antioxidants on insulin sensitivity and glucose tolerance. AB - We studied the correlation between the effect of alpha-lipoic acid, emoxipin, reamberin, and mexidol on LPO in vitro and the action of these drugs on insulin sensitivity and tolerance to glucose load in vivo. It was found that the preparations producing prooxidant effect in vitro (alpha-lipoic acid and reamberin) are characterized by pronounced insulin-potentiating activity, but only slightly increase (alpha-lipoic acid) or even decrease (reamberin) tolerance to glucose load. 3-Hydroxypyridine derivatives (emoxipin and mexidol) producing an antioxidant effect in vitro increase glucose tolerance, but exhibit relatively weak insulin-potentiating activity. These results suggest that differential use of the studied drugs in patients with diabetes mellitus depending on the type of the disease and individual insulin requirement is a promising trend in medical studies. PMID- 21240347 TI - Nootropic activity of extracts from wild and cultivated Alfredia cernua. AB - Antihypoxic and nootropic activities of extracts from aerial parts of wild and cultivated Alfredia cernua (L.) Cass. were studied on the models of pressure chamber hypoxia, open field test, and passive avoidance conditioning. The extracts of Alfredia cernua promoted retention of the orientation reflex and passive avoidance conditioned response and normalized orientation and exploratory activities disordered as a result of hypoxic injury. The efficiency of the extracts was superior to that of piracetam by the effect on retention of passive avoidance response throughout the greater part of the experiment. Nootropic activity of cultivated Alfredia cernua was not inferior to that of the wild plant. PMID- 21240348 TI - Pharmacological correction of the negative effects of acetylsalicylic acid on the energy production system. AB - Experiments of outbred rats with modeled xenobiotic load with acetylsalicylic acid (250 mg/kg for 7 days) revealed inhibition of mitochondrial respiration rate in states of rest and active phosphorylation, inhibition of succinate-dependent oxidation pathway, and a decrease in energization of organelles in the heart. For correction of the observed changes in energy production, succinic acid was preventively administered in a dose of 50 mg/kg for 7 days, which abolished the negative metabolic shifts in myocardial mitochondria. Comparison of pharmacokinetics of acetylsalicylic acid and acetylsalicylic acid against the background of succinate treatment performed on rabbits revealed complete coincidence of the studied parameters, which attests to the possibility of prevention of mitochondrial dysregulations with this Krebs cycle intermediate. PMID- 21240349 TI - Effect of acetylcholine on mortality of mice from sepsis and proinflammatory cytokine production. AB - Experiments on outbred mice showed that acetylcholine chloride in a dose of 20 mg/kg 6 h after subcutaneous injection significantly reduces mortality of mice from sepsis induced by intraperitoneal injection of 2*10(9) E. coli bacterial bodies and the blood levels of proinflammatory cytokines TNF-alpha, IL-1beta, and IL-6. PMID- 21240350 TI - Mechanisms of protective effect of Dicarbamin on the blood system in cytostatic treatment. AB - The effect of Dicarbamin preparation on hemopoiesis suppressed with cyclophosphamide was studied in animal experiments. It was shown that Dicarbamin produced a protective effect on granulocytic hemopoietic steam. This property of the preparation is determined by both protection of immature granulocytic cells at early terms after cytostatic treatment and more active maturation of neutrophils in the bone marrow due to enhanced secretion of humoral factors by elements of hemopoietic environment at late terms of the experiment. PMID- 21240351 TI - Effects of bacterial endotoxin on alpha-synuclein expression in the lymph node leukocytes of rats. AB - The effects of bacterial LPS on the expression of early apoptosis marker (annexin V) and immunoreactive alpha-synuclein in mononuclear leukocytes of the mesenteric lymph nodes of rats were studied in vivo and in vitro. Injection of LPS increased the number of lymphocytes with high expression of immunoreactive alpha-synuclein in cell nucleus and cytoplasm (by 68.6+/-8.1%) and stimulated apoptosis in this population (by 96.0+/-3.6% of the control). The expression of alpha-synuclein in macrophages increased only in the cytoplasm and this increase was not paralleled by stimulation of apoptosis in these cells. The data indicate that LPS-induced elevation of alpha-synuclein in lymphocytes is a component of the mechanism of programmed death in these cells. The increase of alpha-synuclein expression in macrophages can be related to processes associated with their stimulation. PMID- 21240353 TI - Apolipoprotein E gene polymorphism in men with coronary atherosclerosis in Siberia. AB - Polymorphism of coding fragment of APOE gene was analyzed in two groups of men. The main group consisted of 77 residents of the West Siberian region aged 45-65 years with coronary atherosclerosis (documented by coronary angiography) without acute coronary syndrome with stable effort angina, functional class II-IV. The reference group consisted of 350 residents of Novosibirsk, aged 45-69 years. Statistically significant associations between genotypes of APOE gene coding part polymorphism and some key lipid risk factors (blood total and LDL cholesterol, atherogenic index, etc.) for coronary atherosclerosis were found in male residents of the West Siberian region. Elevated total mean level of cholesterol was detected in male residents of Novosibirsk with the APOE genotypes containing epsilon4 allele. PMID- 21240352 TI - Modulation of reparative regeneration and CD117 expression by liver cells after partial hepatectomy in mice. AB - The effects of 3-aminophthalhydrazide and carrageenan on reparative regeneration and expression of CD117 by liver cells after partial hepatectomy were studied in mice. 3-Aminophthalhydrazide stimulated regeneration of the liver and increased the count of CD117(+) hepatocytes. By contrast, carrageenan inhibited liver reparation and CD117 expression. PMID- 21240354 TI - Changes in bone marrow and peripheral compartments of the erythron under the effect of tumor cells in indolent non-Hodgkin lymphomas and multiple myeloma. AB - Here we present the results of pathomorphological study of erythron cells from patients with indolent non-Hodgkin lymphomas and multiple myeloma. The revealed associations suggest that tumor cells can modulate the bone marrow and peripheral compartment of the erythron in lymphoproliferative diseases leading to quantitative and morphological changes in bone marrow erythrokaryocytes and peripheral blood erythrocytes. Clinical and pathomorphological markers of dyshemopoiesis associated with the presence of anemia were identified in indolent non-Hodgkin lymphomas. In multiple myeloma, a correlation between the parameters of bone marrow and peripheral compartments of the erythron and structural modifications of myeloma cells infiltrating the bone marrow was revealed. PMID- 21240355 TI - Effect of magnetic fields on antioxidant system enzymes in mice with Ehrlich ascites carcinoma. AB - The combination of weak steady-state and weak low-frequency alternating magnetic fields activates SOD in Ehrlich ascites carcinoma cells and catalase in liver cells by 3.7 and 1.3 times, respectively (p<0.05), which can result from enhanced production of ROS induced by combined exposure to magnetic fields with the specified parameters. PMID- 21240356 TI - Clinical significance of the content of biomolecular markers in invasive front of colon carcinomas. AB - We studied the expression of beta-catenin, matrix metalloproteinase 9, collagen IV, and laminin in invasive front of primary colon adenocarcinomas and their metastases in lymph nodes and liver. Intensive expression of matrix metalloproteinase 9 in zones of invasive growth of the tumor was associated with enhanced accumulation of beta-catenin in the nuclei of tumor cells in peripheral zones of 28% studied tumors. The presence of nuclear beta-catenin and increased content of metalloproteinase 9 in the tumor were associated with abnormal accumulation of laminin in cell cytoplasm and with the absence of collagen IV containing basal membranes. These changes were typical of tumors with high invasive and metastatic potential. Our findings suggest that beta-catenin, matrix metalloproteinase 9, laminin, and collagen IV are important predictors of clinical course of rectal cancer and that the peculiarities of protein expression related to the risk of liver metastases have concordant patterns and are most pronounced in invasive front of the tumor. PMID- 21240357 TI - Effect of dinitrosyl iron complexes on platelet aggregation induced by HeLa cervical carcinoma cells. AB - We studied the effect of dinitrosyl iron complexes with glutathione ligands on platelet aggregation with HeLa tumor cells. It was shown that dinitrosyl iron complexes not only inhibited cell aggregation, but being added at early stages can also block this process. These findings dictate further studies of dinitrosyl iron complexes as a compound reducing metastasizing and thrombus-formation in tumor patients. PMID- 21240358 TI - Effect of the peptide bronchogen (Ala-Asp-Glu-Leu) on DNA thermostability. AB - Thermodynamic parameters of DNA melting in the presence of a peptide bronchogen in various concentrations were estimated on a differential scanning microcalorimeter. Bronchogen was shown to serve as a DNA-stabilizing agent. Bronchogen increased the melting temperature of DNA from calf thymus and mouse liver by 3.1 degrees C in a narrow range of r (molar ratio of bronchogen/DNA b.p., 0.01-0.055). A further increase in r was not accompanied by changes in the melting temperature. The complex melting enthalpy (DeltaH(melt)) remained unchanged in this range of r (0.01-1.0). DeltaH(melt) for DNA from the thymus and mouse liver was 11.4 and 12.7 cal/g, respectively. Our results indicate that bronchogen is not an adenine-thymine-specific or guanine-cytosine-specific ligand. The type of binding is considered as strong and occasional. The binding occurs with both strands of DNA (mainly with nitrogen bases). PMID- 21240359 TI - Morphological study of the main mechanisms of myometrium involution after repeated pregnancies in mice. AB - Elimination of "excessive" myocytes and their structures during involution of the myometrium after the first and third pregnancies was realized by clasmocytosis (eliminating the greatest volume of myocyte cytoplasm fragments), apoptosis, and necrosis (equal percentage by volume). In contrast to the first pregnancy, involution after the third one was not over by day 10 because of inhibited elimination of functionally lost myocytes by necrosis and apoptosis mechanisms. Presumably, this was caused by slower hydrolysis of apoptotic bodies by macrophages. The concentration of macrophages in the myometrium on day 10 of the involution period in females after the third delivery was 4-fold higher than in intact mice and in females after the first delivery during the same period. PMID- 21240360 TI - Reparative regeneration of rat fetal liver after partial hepatectomy. AB - A reproducible model of fetal liver regeneration was created. Resection of 20% liver was carried out in rat fetuses on day 17 of prenatal development. The organ weight was restored after 2 days at the expense of an increase in hepatocyte mitotic activity; cell hypertrophy was minor. After recovery, the cell composition of the operated liver did not differ from the control, i.e. the regeneration was organotypical. PMID- 21240361 TI - Pathomorphological study of the pancreas during phospholipase A2-induced experimental pancreatic necrosis. AB - The pathomorphogenesis of experimental acute pancreatic necrosis induced by administration of phospholipase A2 into the pancreatic tissue is characterized by pathomorphological signs of hemorrhagic pancreatic necrosis (total necrosis and purulent fusion of some acini and massive hemorrhages in the interlobular and intralobular interstitial tissue) and fatty pancreatic necrosis (necrobiotic and necrotic changes in acinar cells that spread from the peripheral area and form the demarcation line). PMID- 21240363 TI - Relationship between myogenic reaction and autoregulation of cerebral circulation. AB - Dilatation of rat pial arterioles at constant arteriolar wall strain during autoregulation of cerebral circulation was shown by the method of biomicroscopy. Wavelet-analysis of cerebral blood flow oscillations during this period revealed increased oscillation amplitude in the endothelial and neurogenic frequency ranges and unchanged amplitude at myogenic frequency range. These findings probably attest to the leading role of myogenic reaction in the autoregulation. PMID- 21240364 TI - Manifestation of adaptive changes during combined development of postinfarction remodeling of the heart and diabetes mellitus. AB - Oxidative phosphorylation in isolated cardiomyocytes was studied under conditions of postinfarction remodeling and diabetes mellitus. Oxidation-phosphorylation uncoupling in the mitochondria in this disease combination was less pronounced than in each of these diseases alone. Combined development of the diseases was paralleled by less severe hyperglycemia and myocardial hypertrophy and lesser body weight loss. Presumably, combination of coronary occlusion and diabetes mellitus stimulates the adaptive changes in cardiomyocytes as early as at the level of mitochondrial energy metabolism. PMID- 21240365 TI - Experimental study of corrective effects of human umbilical blood nuclears under conditions of a posthemorrhagic state. AB - Intravenous transfusion of nucleated cells from human umbilical cord blood (10(6)/ml saline) to female rats 3 h after massive blood loss produced a pronounced corrective effect (day 5): alleviates posthemorrhagic changes and normalizes hemoconcentration parameters, metabolic disorders, and behavioral reactions. PMID- 21240366 TI - Variability of microsomal oxidation and porphyrin metabolism in rats. AB - An inverse relationship between erythropoiesis intensity and microsomal oxidation level has been detected during the early postnatal period in rats with high resistance to hypoxia. PMID- 21240367 TI - Anticoagulant effects of thioanalogs of thrombin-binding DNA-aptamer and their stability in the plasma. AB - In order to create effective therapeutically significant oligonucleotide structures, a series of analogs of thrombin-binding aptamer d(GGTTGGTGTGGTTGG) containing thiophosphoryl substitutions were synthesized. The anticoagulation effects of the resultant thrombin-binding aptamer analogs were evaluated and the effects of local thiomodifications on their structure and function were studied, including the effects on stability in blood plasma and resistance to DNA nucleases. A promising modified oligonucleotide (LL11) was found with the structure modified only in TT loops. It retains antithrombin properties of thrombin-binding aptamer, but is more resistant to biodegradation. PMID- 21240368 TI - Expression of mitochondrial uncoupling protein UCP2 in the brain of rats after hippocampal injury inflicted by kainic acid. AB - The expression of mitochondrial protein UCP2 and cytochrome C-oxidase subunit III genes in the hippocampus and prefrontal cortex was evaluated by real-time PCR 3 and 7 days after microinjection of kainic acid into the dorsal hippocampus. In contrast to cytochrome C-oxidase subunit III mRNA, the level of UCP2 mRNA in the hippocampus increased 1 week after microinjection of kainic acid. The expression of both genes in the prefrontal cortex did not differ from the control. Presumably, activation of UCP2 synthesis in hippocampal injury indicates the neuroprotective effects of this protein. PMID- 21240369 TI - Effects of short-term exposure to haloperidol and reserpine on dopamine turnover in nigrostriatal system in rat brain. AB - Spectrophotometric methods were employed to determine activity of dopamine metabolism enzymes, tyrosine hydroxylase and monoamine oxidase B, in nigrostriatal structures of the brain in Wistar rats after short-term (60 min) haloperidol or reserpine treatment. Activating effect of the test compounds on dopamine synthesis, more pronounced in the caudate nucleus, was demonstrated. Utilization of monoamine oxidase B transmitter was activated by haloperidol, but not reserpine. Some peculiarities of response of the nigrostriatal system structures to the test compounds were noted. We hypothesized the presence of a phase of dopamine metabolism activation, aimed at maintenance of dopamine transmission and nervous system adaptation at early terms after reserpine and haloperidol administration. PMID- 21240370 TI - Peculiarities of the effect of terahertz radiation at nitric oxide frequencies on gaseous and electrolyte composition of the blood in different types of stress. AB - We studied the effect of terahertz radiation at NO frequencies 150.176-150.664 GHz on gaseous and electrolyte composition of the blood in albino rats during stress. Partial or complete recovery of the studied parameters of blood gases and electrolytes in stressed animals was observed after 15- and 30-min terahertz irradiation at NO frequencies, respectively. PMID- 21240371 TI - Effect of IL-1beta receptor antagonist on lipid peroxidation in the liver in stress. AB - The content of molecular LPO products increased in the liver of rats exposed to daily 1-h immobilization. IL-1beta receptor antagonist limited the stress-induced intensification of LPO. PMID- 21240372 TI - Role of thiol-disulfide system in mechanisms of functional changes in neutrophils under conditions of oxidative stress. AB - We studied the state of the thiol-disulfide system (contents of reduced and oxidized glutathione, their ratio, and concentrations of protein SH-groups and protein-bound glutathione) and functional properties of neutrophils (production of hydroxyl radicals, IL-8, and TNF-alpha and myeloperoxidase activity) from healthy donors under conditions of oxidative stress in vitro induced by H(2)O(2)in a final concentration of 200 MUM and from patients with community acquired pneumonia. We evaluated the role of reduced and protein-bound glutathione in the regulation of functional state of blood neutrophils from patients with community-acquired pneumonia and during oxidative stress in vitro under conditions cell incubation with N-ethylmaleimide or 1,4 dithioerythritolsulfhydryl, the blocker and protector of sulfhydryl groups, respectively. PMID- 21240373 TI - Participation of L-type voltage-gated calcium channels in facilitation of long term potentiation during the formation of morphine dependence in rats. AB - Parameters of long-term potentiation in the system mossy fibers-CA3 pyramidal neurons in hippocampal slices in experimental animals vary during the formation of chronic opiate dependence. During the first day of morphine treatment, the value of potentiation was significantly lower than in controls. Starting from day 8 and at early stages of dependence (days 25-29), facilitation of long-term potentiation was recorded. Incubation of the slices with L-type Ca(2+)-channel blocker nifedipine did not change the response to the test stimuli and did not affect potentiation induction in hippocampal slices from control and morphine treated animals. Nifedipine had no effect on long-term potentiation of mossy fibers in the control and at early terms of morphine treatment, but significantly reduced its facilitation at later terms. PMID- 21240374 TI - Ammonia redistribution from the gastrointestinal tract to general circulation after intraperitoneal injection of cyclophosphamide to rats. AB - Ammonia level in the blood increased within 3 h after intraperitoneal injection of cyclophosphamide in doses of 200, 600, and 1000 mg/kg: by 1.4, 1.8, and 2.5 times in the blood from v. portae, by 1.5, 2.1, and 3.3 times in the blood from v. cava caud. caudally to vv. renales orifice, and by 1.8, 2.7, and 4.2 times, respectively, in the same vein cranially to vv. hepaticae. A positive portocaval gradient of ammonia concentration was abolished. Blood concentrations of glutamine and urea increased less markedly than those of ammonia. Ammonia and glutamine accumulation in isotonic saline injected to animals intraperitoneally 2.5 h after cyclophosphamide was stimulated depending on the drug dose. Blood concentrations of cytolysis markers (lactate dehydrogenase and alanine and aspartate transaminases) increased. Ammonia, glutamine, and urea concentrations in the blood remained high 18 h after injection of cyclophosphamide, the glutamine/ammonia ratio increased. These data indicate that a single intraperitoneal injection of cyclophosphamide to rats in doses of 200-1000 mg/kg disorders detoxification and stimulates transperitoneal diffusion of ammonia from the digestive tract to the posterior vena cava basin with the development of hyperammoniemia. PMID- 21240375 TI - Comparative efficiency of succinate-containing antihypoxants in traumatic toxicosis. AB - Experiments on Wistar rats showed the development of endotoxicosis 12 h after severe compression injury. Endotoxicosis manifested in disorders in bromosulfaleine excretion from the blood, increase of blood urea, uric acid, creatinine, and potassium levels and aminotransferase activities. Injection of succinate-containing antihypoxants (reamberine, cytoflavin, metaprot plus, succinamic acid 2-amino-4-acetylthiasolo[5,4-b]indole) directly after decompression promoted recovery of liver function, prevented the development of hyperfermentemia and renal failure as a result of reduced blood levels of potassium and non-protein nitrogen. The protective effect of the drugs in traumatic toxicosisdecreased in the following order: metaprot plus>cytoflavin>2 amino-4-acetylthiasolo[5,4-b]indole succinaminic acid>reamberine. PMID- 21240376 TI - Some aspects of toxicological activity of kardosten after chronic 6-month administration to rats. AB - Chronic treatment of rats with kardosten for 6 months had a positive effect on some ECG values and behavior without disordering the hepatorenal functions. All effects of the drug observed during a course of treatment were leveled and the parameters reached the basal values within 2 weeks after drug discontinuation, this confirming its safety. PMID- 21240377 TI - Effects of 5-HT2A receptor stimulation and blocking on immune response. AB - Experiments on CBA mice showed that selective stimulation of 2A serotonin receptors with DOI agonist (1 mg/kg) led to suppression of the immune response and reduction of the spleen and peripheral blood CD8(+)T cell counts with the cytotoxic/suppressor function. Selective blockade of these receptors with ketanserin (1 mg/kg) had an opposite effect: immunostimulation with an increase in CD8(+)T cell count in the spleen. These data indicate the involvement of 2A serotonin receptors in immunosuppressive mechanisms of serotoninergic system. PMID- 21240378 TI - Monitoring of the effect of low-intensity laser radiation with constant pulse generation on neutrophil granulocytes in vitro. AB - We studied the effect of low-intensity laser radiation with constant pulse generation on bactericidal activity of neutrophilic granulocytes, in particular, on their capacity to form extracellular structures, so-called extracellular neutrophil traps. It was found that exposure to low-intensity laser radiation with constant pulse generation enhanced bactericidal activity of neutrophilic granulocytes, which manifested in the increase of the percent of neutrophils forming extracellular neutrophil traps. PMID- 21240379 TI - Effect of selective agonist of serotonin 5-HT1A receptors on defensive behavior in mice with different predisposition to catalepsy. AB - We studied the effect of activation of serotonin 5-HT1A receptors with selective agonist 8-OH-DPAT (0.1, 0.5, and 1.0 mg/kg) on intraspecies aggression and freezing reaction (catalepsy) in male mice of catalepsy-resistant AKR/J and two catalepsy-prone strains CBA/Lac and congenic AKR.CBA-D13Mit76. The latter strain differs from AKR strain only by terminal chromosome 13 fragment transferred from CBA strain and containing a locus determining predisposition to catalepsy and a gene encoding 5-HT1A receptor. 8-OH-DPAT in a low dose (0.1 mg/kg) affecting primarily presynaptic receptors suppressed aggressive behavior in CBA mice, but had no effect on the time of cataleptic freezing. At the same time, this dose of the drug produced no significant effect on aggression in AKR and AKR.CBA-D13Mit76 mice, but significantly attenuated freezing in AKR.CBA-D13Mit76 mice. High doses of 8-OH-DPAT (0.5 and 1 mg/kg) which affected mainly postsynaptic receptors inhibited catalepsy in CBA and AKR.CBA-D13Mit76 mice and in a dose of 1 mg/kg it suppressed aggression in all tested mouse strains. We concluded that the genome of the recipient strain (AKR) modulated the involvement of 5-HT(1A) receptors into the regulation of aggression and catalepsy in mice. PMID- 21240380 TI - Hormonal reaction of the testes to chorionic gonadotropin in CBA/Lac and PT mice: effects of the dose and time after treatment. AB - Testosterone concentrations in the blood of CBA/Lac and PT mice and its content in the testes under normal conditions and during stimulation with chorionic gonadotropin were measured by enzyme immunoassay. Genetic differences in reactivity of the testes to chorionic gonadotropin were revealed: PT mice were characterized by more pronounced hormonal reaction compared to CBA/Lac mice. An optimal dose of chorionic gonadotropin (10 U) and time interval (120 min) for evaluation of potentialities of testicular hormonal function were determined. PMID- 21240381 TI - Changes in tissue metalloproteinase inhibitor-1 and matrix metalloproteinases during tumor development and metastasizing in mice. AB - Tissue inhibitor of matrix metalloproteinases type 1, inhibiting the majority of matrix metalloproteinases, can both suppress and stimulate tumor growth. The concentrations and activities of tissue matrix metalloproteinase inhibitor-1 were measured in C57Bl/6 mice during progression and metastasizing of Lewis lung adenocarcinoma. Activities of matrix metalloproteinases in tumor tissue of mice were lower than in liver and lung tissues of intact animals. Serum concentration of tissue inhibitor increased significantly during the development of Lewis lung adenocarcinoma. Macrophage depression (injection of gadolinium chloride associated with a decrease in metastasis number) decreased serum concentration of tissue inhibitor, but it did not attain the control level observed in intact mice. These findings attest to a pleiotropic antitumor effect of tissue matrix metalloproteinase inhibitor-1 reflecting disorders in matrix metalloproteinase regulation during the progress of Lewis lung adenocarcinoma in mice. PMID- 21240382 TI - Expression of molecular markers in the tumor and survival prognosis in osteosarcoma. AB - Immunohistochemical study of p53, VEGF, Flt-1/VEGFR1 Ab-1, EGFR, HER-2/neu, Bax, and Cox-2 expression in osteosarcomas was carried out in 40 patients aged 16-70 years. Expression of p53 was detected in 27.5% tumors, VEGF in 15%, Flt-1/VEGFR1 Ab-1 in 97.5%, EGFR in 52.5%, HER-2/neu in 32.5%, Bax in 77.8%, and Cox-2 in 32.3% tumors. Multifactorial analysis showed that the expression of HER-2/neu (p=0.004), p53 (p=0.01), and Cox-2 (p=0.04) in osteosarcomas significantly correlated with unfavorable prognosis for overall survival, while HER-2/neu (p=0.02) and Cox-2 (p=0.003) with relapse-free survival. Analysis of HER-2/neu, p53, and Cox-2 expression in the primary tumor should be taken into consideration in the treatment of patients with osteosarcoma. PMID- 21240383 TI - Evaluation of the proportion of hormonal and progenotoxic effects of estrogens and glucose in cancer patients. AB - he progenotoxic (G, generation of reactive oxygen forms in mononuclears) and hormonal (H, reactive insulinemia) effects of oral glucose, on the one hand, and the same effects of estradiol (10(-8)and 10(-5)M) in vitro on blood mononuclears (G: by comet tail length; H: by expression of AMP kinase and TNF and IL-6 secretion), on the other, were compared with consideration for the concepts on endocrine genotoxic switch-over in patients with breast cancer and endometrial cancer in remission. Coculturing of mononuclears with estradiol in general led to an increase in comet tail and was associated with a trend to more intense expression of AMP kinase and IL-6 secretion. The reaction to estradiol (primarily in a concentration of 10(-8)M) evaluated by the expression of AMP kinase and TNF secretion was more intensive than the reaction evaluated by comet tail lengths or by percentage of cells with comets in women with predominating progenotoxic effect of glucose vs. hormonal effect. This fact can be used as a landmark in search for means for optimization of the status and proportion of effects in the estrogen and glucose systems. PMID- 21240384 TI - Role of glycogen in processes of cerebellar glial cells under conditions of its damage with sodium nitrite. AB - Ultrastructure of processes of glial cell, astrocytes of the molecular layer of cerebellar cortex in Rana temporaria frog, under conditions of damage to the cerebellum caused by NO-generating compound sodium nitrite was studied under an electron microscope. It was found that astrocytes have at least two types of processes: the first (fibrillar) primarily contained numerous fibrils and few glycogen granules and the second (granular) primarily containing glycogen granules. In the presence of NO-generating compound in toxic doses, fibrillar processes are damaged or completely degrade more rapidly than granular ones. The processes containing glycogen can protect both damaged synapses and individual synaptic buttons by forming a compact structure, wrapping, around them. We analyzed the possible role of glycogen of cerebellar glial cell processes in neuroglial interactions in the presence of sodium nitrite. PMID- 21240385 TI - Effects of infant rat fostering in artificially formed litters on the development of brain, adrenals and gonads. AB - Morphometric and histochemical properties of neurons in the frontoparietal and parietal lobes and CA1 hippocampal area, thickness of the neocortex, histochemical and morphometric properties of adrenals and gonads, and concentrations of sex hormones were compared in 40-day rats fostered in artificially formed (experimental group) and natural (control) litters. Animals of the experimental group had lower body and brain weight, thickness of the neocortex in the parietal lobe, sizes of nuclei and cytoplasm of layer 2 and layer 5 neurons of the frontoparietal and parietal lobes and in the hippocampus, lower NADPH-dehydrogenase activity in the hippocampus, and lower NADH- dehydrogenase activity in layer 2 neurons of the parietal lobe in comparison with control rats. RNA concentration in neuronal cytoplasm in neocortex and hippocampus was higher in rats from experimental group, than in animals from the control group. Higher estradiol concentration, higher activity of 3beta hydroxysteroiddehydrogenase in thecal cells of ovarian follicles were found in females from experimental group; decreased testicle weight, reduced diameter of seminiferous tubules, reduced activity of 3beta-hydroxysteroiddehydrogenase in Leydig's cells, and trend forward lowering of testosterone concentration were found in males from experimental group. PMID- 21240386 TI - Enhanced sensitivity of nucleoli in human proliferating cells to inhibition of protein synthesis with anisomycin. AB - We describe the reaction of nuclei in cultured human cells from different tissues to inhibition of total protein synthesis with anisomycin - ribotoxin, which is now considered as a potential antitumor drug. It was shown that nucleoli in sensitive cells demonstrate typical reaction: under the action of the inhibitor, labile nucleolar protein, a component of RNA polymerase I transcription complex (previously called A3 antigen), rapidly migrates from the nucleolus to numerous discrete foci in the nucleoplasm. These changes are specific for translation suppression and are not induced by other influences on the cells. Migration of A3 antigen into the nucleoplasm manifests primarily in cells at the stage of DNA replication and is absent in resting cells. These results suggest that localization of A3 antigen can be a marker of artificial suppression of translation in proliferating human cells in vitro. PMID- 21240387 TI - Role of nitric oxide in the regulation of mechanosensitive ionic channels in cardiomyocytes: contribution of NO-synthases. AB - The role of NO in the regulation of currents passing through ion channels activated by cell stretching (mechanically gated channels, MGC), particularly through cation-selective K(+)-channels TRPC6, TREK1 (K(2P)2.1), and TREK2 (K(2P)10.1), was studied on isolated mouse, rat, and guinea pig cardiomyocytes using whole-cell patch-clamp technique. In non-deformed cells, binding of endogenous NO with PTIO (2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-1 oxy-3-oxide) irreversibly shifted the diastolic membrane potential towards negative values, modulates K(ir)-channels by reducing I(K1), and blocks MGC. Perfusion of stretched cells with PTIO solution completely blocked MG-currents. NO-synthase inhibitors L-NAME and L-NMMA completely blocked MGC. Stretching of cardiomyocytes isolated from wild type mice and from NOS1(-/-)- and NOS2(-/-)- knockout mice led to the appearance in MG-currents typical for the specified magnitude of stretching, while stretching of cardiomyocytes from NOS3(-/-)- knockout mice did not produce in MG-current. These findings suggest that NO plays a role in the regulation of MGC activity and that endothelial NO-synthase predominates as NO source in cardiomyocyte response to stretching. PMID- 21240388 TI - Development and characterization of Thy*IkappaBalpha-SI transgenic mice. AB - We developed and characterized a new transgenic model where NF-kappaB activity is inhibited only in mature neurons. Transgenic mouse strain Thy*IkappaBalpha-SI was created using trans-dominant super inhibitor NF-kappaB (IkappaBalpha-SI), which is a multimutant form of IkappaBalpha inhibitory protein cloned into specific neutral Thy-1.2 cassette. Detailed molecular analysis showed that the transgene and its product (IkappaBalpha-SI protein) are expressed in the nervous system of transgenic mice. In situ hybridization showed that Thy*IkappaBalpha-SI in the nervous system is expressed exclusively in neurons. The developed model provides wide opportunities for studying functional role of NF-kappaB in mature neurons in the central and peripheral nervous system in vivo. PMID- 21240389 TI - Evaluation of morphometric parameters of native blood cells by atomic force microscopy. AB - We propose and tested a method for studies of native blood cells by atomic-force microscopy in a humid chamber preserving viability, size, and shape of biological objects. The method has some advantages over scanning in a liquid cell: it allows studying non-fixed blood samples in the form of suspension of live cells and excludes mechanical and chemical influences on the cells. PMID- 21240390 TI - A selective etching phenomenon on {001} faceted anatase titanium dioxide single crystal surfaces by hydrofluoric acid. AB - A selective etching phenomenon on {001} faceted anatase TiO(2) single crystal surfaces by HF and associated etching mechanism are reported. Density functional theory (DFT) calculations reveal that HF stabilizes the grown {001} facets at low concentrations, but selectively destroys the grown {001} facets at high concentrations. PMID- 21240391 TI - Kinetic stability of water-dispersed oil droplets encapsulated in a polyelectrolyte multilayer shell. AB - The original theoretical model of polyelectrolyte adsorption onto water-dispersed colloid particles is extended to the system of polydisperse droplets of sunflower oil. Polycation (poly(allylamine hydrochloride)) and polyanion (poly(sodium 4 styrenesulfonate)) are taken in the theoretically projected concentrations to perform Layer-by-Layer assembly of a multilayer shell on the surface of oil droplets preliminary stabilized with a protein emulsifier (bovine serum albumin). The velocity of gravitational separation in suspension of encapsulated oil droplets is theoretically predicted and experimentally measured depending on the coating shell's thickness, aiming to clarify the mechanism to control over the separation process. Combining the theory and experimental data, the mass density of a polyelectrolyte multilayer shell assembled in a Layer-by-Layer fashion is obtained. Polyelectrolyte multilayer coated oil droplets are characterized by means of zeta-potential, and particle size measurements, and visualized by scanning electron microscopy. PMID- 21240392 TI - Self-renewal of the human gastric epithelium: new insights from expression profiling using laser microdissection. AB - The gastric mucosa is subject to continual bidirectional renewal by differentiation from stem and transit amplifying cells. It was the aim of this study to characterize the self-renewal of the human gastric mucosa and its two major types of glands in the fundus and antrum, respectively. Three characteristic regions (pit, proliferative, and lower neck regions) were isolated from fundic and antral units by the use of laser microdissection, and expression profiles concerning 15 marker genes were generated by RT-PCR analysis. The surface mucous cells (SMCs) of fundic and antral units differed in their expression of at least four secretory genes, i.e., gastric lipase, TFF3, FCGBP, and lysozyme. The maturation of mucous neck cells was shown to occur stepwise, first towards a mucous phenotype followed by a serous differentiation step. Also, a stepwise maturation of both the antral SMCs and antral gland cells was observed. Additionally, the presence of gastric lipase was also demonstrated for the first time in antral gland cells. In conclusion, the different expression profiles of SMCs of the fundic and antral units could be the basis for the different self-renewal rates of fundic and antral SMCs and could influence the spatial organization of the bacterial microbiota within the various parts of the gastric mucosa. PMID- 21240393 TI - Understanding the role of carbamate reactivity in fatty acid amide hydrolase inhibition by QM/MM mechanistic modelling. AB - QM/MM modelling of FAAH inactivation by O-biphenyl-3-yl carbamates identifies the deprotonation of Ser241 as the key reaction step, explaining why FAAH is insensitive to the electron-donor effect of conjugated substituents; this may aid design of new inhibitors with improved selectivity and in vivo potency. PMID- 21240394 TI - Theoretical study of the source-drain current and gate leakage current to understand the graphene field-effect transistors. AB - We designed acene molecules attached to two semi-infinite metallic electrodes to explore the source-drain current of graphene and the gate leakage current of the gate dielectric material in the field-effect transistors (FETs) device using the first-principles density functional theory combined with the non-equilibrium Green's function formalism. In the acene-based molecular junctions, we modify the connection position of the thiol group at one side, forming different electron transport routes. The electron transport routes besides the shortest one are defined as the cross channels. The simulation results indicate that electron transport through the cross channels is as efficient as that through the shortest one, since the conductance is weakly dependent on the distance. Thus, it is possible to connect the graphene with multiple leads, leading the graphene as a channel utilized in the graphene-based FETs in the mesoscopic system. When the conjugation of the cross channel is blocked, the junction conductance decreases dramatically. The differential conductance of the BA-1 is nearly 7 (54.57 MUS) times as large as that of the BA-4 (7.35 MUS) at zero bias. Therefore, the blocked graphene can be employed as the gate dielectric material in the top-gated graphene FET device, since the leakage current is small. The graphene-based field effect transistors fabricated with a single layer of graphene as the channel and the blocked graphene as the gate dielectric material represent one way to overcome the problem of miniaturization which faces the new generation of transistors. PMID- 21240395 TI - Exciton coupling in coordination compounds. AB - This Perspective reviews the impact of exciton coupling on the spectroscopic properties of coordination compounds. Exciton coupling features arise in electronic absorption and circular dichroism spectra when chromophores are brought into close spatial proximity, for example by coordination to a metal centre. The analysis of these features can reveal much information such as the geometry of a complex and its absolute configuration. The extension of the exciton coupling model to polynuclear metallosupramolecular arrays is discussed. PMID- 21240396 TI - Studying Smad2 intranuclear diffusion dynamics by mathematical modelling of FRAP experiments. AB - We combine Fluorescence Recovery After Photobleaching (FRAP) experiments with mathematical modelling to study the dynamics inside the nucleus of both the TGF beta-sensitive transcriptional regulator Smad2, and Green-Fluorescent Protein (GFP). We show how combining modelling with bleaching strips of different areas allows a rigorous test of whether or not a protein is moving via diffusion as a single species. As noted recently by others, it is important to consider diffusion during the bleaching process. Neglecting it can cause serious error. Also, it is possible to use the bleaching process itself to provide an extra consistency test to the models predicting the recovery. With our method we show that the dynamics of GFP are consistent with it diffusing as a single species in a uniform environment in which flow is negligible. In contrast, the dynamics of the intracellular signal transducer Smad2 are never consistent with it moving as a single species via simple diffusion in a homogeneous environment without flow. Adding TGF-beta slows down the dynamics of Smad2 but even without TGF-beta, the Smad2 dynamics are influenced by one or more of: association, flow, and inhomogeneity in space of the dynamics. We suggest that the dynamics inside cells of many proteins may be poorly described by simple diffusion of a single species, and that our methodology provides a general and powerful way to test this hypothesis. PMID- 21240397 TI - Polymer based chemical delivery to multichannel capillary patterned cells. AB - In order to match the controllability of traditional pipetting with the advantages of microfluidics, we introduce the concept of polymer based chemical delivery to multichannel capillary patterned cells. Here we demonstrate that UV polymerized hydrogel can be used as a miniature pipet to deliver picolitre chemical quantities to multichannel capillary patterned cells. PMID- 21240398 TI - Deuterium kinetic isotope effects on the gas-phase reactions of C2H with H2(D2) and CH4(CD4). AB - Kinetics of the ethynyl (C(2)H) radical reactions with H(2), D(2), CH(4) and CD(4) was studied over the temperature range of 295-396 K by a pulsed laser photolysis/chemiluminescence technique. The C(2)H radicals were generated by ArF excimer-laser photolysis of C(2)H(2) or CF(3)C(2)H and were monitored by the chemiluminescence of CH(A(2)Delta) produced by their reaction with O(2) or O((3)P). The measured absolute rate constants for H(2) and CH(4) agreed well with the available literature data. The primary kinetic isotope effects (KIEs) were determined to be k(H(2))/k(D(2)) = 2.48 +/- 0.14 and k(CH(4))/k(CD(4)) = 2.45 +/- 0.16 at room temperature. Both of the KIEs increased as the temperature was lowered. The KIEs were analyzed by using the variational transition state theory with semiclassical small-curvature tunneling corrections. With anharmonic corrections on the loose transitional vibrational modes of the transition states, the theoretical predictions satisfactorily reproduced the experimental KIEs for both C(2)H + H(2)(D(2)) and C(2)H + CH(4)(CD(4)) reactions. PMID- 21240399 TI - 4-Mercaptopyridine on Au(111): a scanning tunneling microscopy and spectroscopy study. AB - The adsorption of 4-mercaptopyridine (4MPy) molecules on reconstructed Au(111) is investigated by Scanning Tunneling Microscopy (STM) and Spectroscopy (STS) at low temperature and under ultra-high vacuum (UHV) conditions. As made visible by STM, at low coverage (<10%) 4MPy adsorbs preferentially at elbow sites of the Herringbone reconstruction and at step edges of the Au(111). Increasing coverage (but still <30%) results in formation of molecular chains followed, at even higher coverage, by a 3-dimensional growth. Detailed analysis of z-V spectroscopy (ramping the tunneling bias V while keeping the tunneling current constant) provides information on the bias dependent apparent height of a single 4MPy/Au(111) as well as on the local density of states (LDOS) of single and chain 4MPy molecules in comparison to the bare Au(111) surface revealing a significant shift of the lowest unoccupied molecular orbital (LUMO) towards lower energy for molecules within chains. Additionally, the data provide no evidence that for these samples prepared in UHV the adsorption of 4MPy on Au(111) requires mediating Au adatoms. Also, clear indications are given that the adsorption does not induce a strong reduction of the Au DOS close to its Fermi energy. Finally, in context of the apparent STM height of 4MPy molecules, the behavior of the differential barrier height Phi(diff)(V) = (?(z)?(V)I/?(V)I)(2) on bare Au(111) and 4MPy/Au(111) is analyzed and the corresponding experimental values are applied to recover the LDOS of the molecule for unoccupied states according to a previously published numerical recipe [B. Koslowski, H. Pfeifer and P. Ziemann, Phys. Rev. B, 2009, 80, 165419 and M. Ziegler, N. Neel, A. Sperl, J. Kroger, and R. Berndt, Phys. Rev. B, 2009, 80, 125402]. In this way, one obtains a spectrum comprising a constant DOS of the Shockley-like surface state of Au(111) and a Lorentzian line attributed to the LUMO of 4MPy. PMID- 21240400 TI - The synthesis and photophysical properties of peripherally and non-peripherally substituted ball-type Mg(II) and Zn(II) phthalocyanines. AB - Newly synthesized ball-type Zn(II) and Mg(II) phthalocyanines containing four 1,1'-binaphthol substituents at peripheral and non-peripheral positions are presented. The structures of the synthesized compounds were characterized by using elemental analysis, UV-vis, FT-IR, (1)H-NMR and mass spectroscopies. The Phi(F) values were 0.33, 0.08, 0.20 and 0.08 for 6-9, respectively. The Phi(T) values were 0.56, 0.85, 0.64 and 0.88 for 6-9, respectively. All the complexes showed reasonably large triplet lifetimes with tau(T) values of 710 (6), 170 (7), 1490 (8) and 380 MUs (9) in DMSO. These complexes offer potential as photosensitizers in photodynamic therapy. PMID- 21240402 TI - Electronic coherences and vibrational wave-packets in single molecules studied with femtosecond phase-controlled spectroscopy. AB - Employing femtosecond pulse-shaping techniques we investigate ultrafast, coherent and incoherent dynamics in single molecules at room temperature. In first experiments single molecules are excited into their purely electronic 0-0 transition by phase-locked double-pulse sequences with pulse durations of 75 fs and 20 nm spectral band width. Their femtosecond kinetics can then be understood in terms of a 2-level system and modelled with the optical Bloch equations. We find that we observe the coherence decay in single molecules, and the purely electronic dephasing times can be retrieved directly in the time domain. In addition, the Rabi-frequencies and thus the transition dipole moments of single molecules are determined from these data. Upon excitation of single molecules into a vibrational level of the electronically excited state also incoherent intra-molecular vibrational relaxation is recorded. Increasing the spectral band width of the excitation pulses to up to 120 nm (resulting in a transform-limited pulse width of 15 fs) coherent superpositions of excited state vibrational modes, i.e. vibrational wave packets, are excited. The wave-packet oscillations in the excited state potential energy surface are followed in time by a phase-controlled pump-probe scheme, which permits to record wave packet interference, and to determine the energies of vibrational modes and their coupling strengths to the electronic transition. PMID- 21240401 TI - Linking amyloid protein aggregation and yeast survival. AB - Protein aggregation and amyloid formation lie behind an increasing number of human diseases. Here we describe the application of an "aggregation reporter", in which the test protein is fused to dihydrofolate reductase, as a general method to assess the intracellular solubility of amyloid proteins in eukaryotic background. Because the aggregation state of the target protein is linked directly to yeast cells survival in the presence of methotrexate, protein solubility can be monitored in vivo without the requirement of a functional assay for the protein of interest. In addition, the approach allows the in vivo visualization of the cellular location and aggregated state of the target protein. To demonstrate the applicability of the assay in the screening of genes or compounds that modulate amyloid protein aggregation in living cells, we have used as models the Alzheimer's amyloid beta peptide, polyglutamine expansions of huntingtin, alpha-synuclein and non-aggregating variants thereof. Moreover, the anti-aggregational properties of small molecules and the effects of the yeast protein quality control machinery have also been evaluated using this method. PMID- 21240403 TI - Design, modeling and characterization of microfluidic architectures for high flow rate, small footprint microfluidic systems. AB - We propose a strategy for optimizing distribution of flow in a microfluidic chamber for microreactor, lateral flow assay and immunocapture applications. It is aimed at maximizing flow throughput, while keeping footprint, cell thickness, and shear stress in the distribution channels at a minimum, and offering a uniform flow field along the whole analysis chamber. In order to minimize footprint, the traditional tree-like or "rhombus" design, in which distribution microchannels undergo a series of splittings into two subchannels with equal lengths and widths, was replaced by a design in which subchannel lengths are unequal, and widths are analytically adapted within the Hele-Shaw approximation, in order to keep the flow resistance uniform along all flow paths. The design was validated by hydrodynamic flow simulation using COMSOL finite element software. Simulations show that, if the channel is too narrow, the Hele-Shaw approximation loses accuracy, and the flow velocity in the chamber can fluctuate by up to 20%. We thus used COMSOL simulation to fine-tune the channel parameters, and obtained a fluctuation of flow velocity across the whole chamber below 10%. The design was then implemented into a PDMS device, and flow profiles were measured experimentally using particle tracking. Finally, we show that this system can be applied to cell sorting in self-assembling magnetic arrays, increasing flow throughput by a factor 100 as compared to earlier reported designs. PMID- 21240404 TI - An indole-linked C8-deoxyguanosine nucleoside acts as a fluorescent reporter of Watson-Crick versus Hoogsteen base pairing. AB - Pyrrole- and indole-linked C(8)-deoxyguanosine nucleosides act as fluorescent reporters of H-bonding specificity. Their fluorescence is quenched upon Watson Crick H-bonding to dC, while Hoogsteen H-bonding to G enhances emission intensity. The indole-linked probe is ~ 10-fold brighter and shows promise as a fluorescent reporter of Hoogsteen base pairing. PMID- 21240405 TI - A natural product-like inhibitor of NEDD8-activating enzyme. AB - The natural product-like 6,6"-biapigenin has been identified as only the second inhibitor of NEDD8-activating enzyme using virtual screening. This compound was active in enzyme and cell-based assays, with potency in the micromolar range. PMID- 21240406 TI - Optical imaging of excited-state tautomerization in single molecules. AB - Tautomerism process of single fluorescent molecules was studied by means of confocal microscopy in combination with azimuthally or radially polarized laser beams. During a tautomerism process the transition dipole moment (TDM) of a molecule changes its orientation which can be visualized by the fluorescence excitation image of the molecule. We present experimental and theoretical studies of two porphyrazine-type molecules and one type of porphyrin molecule: a symmetrically substituted metal-free phthalocyanine and porphyrin, and nonsymmetrically substituted porphyrazine. In the case of phthalocyanine the fluorescence excitation patterns show that the angle between the transition dipole moments of the two tautomeric forms is near 90 degrees , in agreement with quantum chemical calculations. For porphyrazine we find that the orientation change of the TDM is less than 60 degrees or larger than 120 degrees , as theoretically predicted. Most of the porphyrin molecules show no photoinduced tautomerization, while for 7% of the total number of investigated molecules we observed excitation patterns of two different trans forms of the same single molecule. We demonstrate for the first time that a molecule, undergoing a tautomerism process stays in one tautomeric trans conformation during a time comparable with the acquisition time of one excitation pattern. This allowed us to visualize the existence of each of the two trans forms of one single porphyrin molecule, as well as the sudden switching between these tautomers. PMID- 21240407 TI - Zebrafish as a good vertebrate model for molecular imaging using fluorescent probes. AB - Fluorescent probes have been used extensively to monitor biomolecules and biologically relevant species in vitro and in vivo. A new trend in this area that has been stimulated by the desire to obtain more detailed information about the biological effects of analytes is the change from live cell to whole animal fluorescent imaging. Zebrafish has received great attention for live vertebrate imaging due to several noticeable advantages. In this tutorial review, recent advances in live zebrafish imaging using fluorescent probes, such as fluorescent proteins, synthetic fluorescent dyes and quantum dots, are highlighted. PMID- 21240408 TI - Functionalized mesoporous silica nanoparticle-based visible light responsive controlled release delivery system. AB - A supramolecular assembly for visible light responsive release of cargo molecules is presented. Sulforhodamine 101 was loaded inside the mesopores of mercaptopropyl-functionalized mesoporous silica nanoparticles (MP-MSN) and entrapped by mercaptopropyl-coordinated Ru(bpy)(2)(PPh(3))-moieties. Irradiation with visible light triggers the release of capping species and loaded molecules. PMID- 21240409 TI - Cyclometalated [Os(C-N)x(N-N)(3-x)]m+ mimetics of tris(2,2' bipyridine)osmium(II): covering a 2 V potential range by known (x = 0, 1) and new (x = 2, 3) species (C-N = o-2-phenylpyridinato). AB - Electrochemical studies of [Os(C-N)(x)(N-N)(3-x)](m+) (1) consisting of known Os(II) species with x = 0 (a) and 1 (b) and crystallographically characterized new Os(III) bis- and tris-metalacycles with x = 2 (c) and 3 (d) (N-N = 2,2' bipyridine, (-)C-N = 2-phenylpyridinato) revealed a Nernstian behavior in MeCN. A stepwise replacement of neutral N-N ligands by three anionic C-N donors covers a 2 V potential range from -1 to +1 V vs. Ag/AgCl for the Os(III)/Os(II) feature. PMID- 21240410 TI - Copper(II) and iron(II) ion sensing with semiconducting polymer dots. AB - This communication describes a simple platform that employs carboxyl functionalized semiconducting polymer dots as a fluorescent probe for sensitive ratiometric Cu(2+) and Fe(2+) detection, in which the sensing mechanism is based on aggregation-induced fluorescence quenching. PMID- 21240411 TI - New biocompatible thermo-reversible hydrogels from PNiPAM-decorated amyloid fibrils. AB - New biocompatible temperature-responsive hydrogels have been obtained by using unprecedented low concentration of amyloid fibril-PNiPAM hybrids. The viscoelasticity of the hydrogels can be finely controlled by tuning the PNiPAM layers without changing the structure or concentration of the amyloid fibrils. PMID- 21240412 TI - Thermoresponsive poly(N-vinyl caprolactam)-coated gold nanoparticles: sharp reversible response and easy tunability. AB - Narrowly distributed poly(N-vinyl caprolactam) obtained by the MADIX/RAFT process was used for the preparation of novel thermoresponsive gold nanoparticles presenting a sharp reversible response to temperature, which can be easily modulated near the physiological temperature by simply changing the polymer molecular weight or concentration. PMID- 21240413 TI - Hypervalent neutral O-donor ligand complexes of silicon tetrafluoride, comparisons with other group 14 tetrafluorides and a search for soft donor ligand complexes. AB - The hypervalent adducts of SiF(4), trans-[SiF(4)(R(3)PO)(2)] (R = Me, Et or Ph), cis-[SiF(4){R(2)P(O)CH(2)P(O)R(2)}] (R = Me or Ph), cis-[SiF(4)(pyNO)(2)] and trans-[SiF(4)(DMSO)(2)] have been prepared from SiF(4) and the ligands in anhydrous CH(2)Cl(2), and characterised by microanalysis, IR and VT multinuclear ((1)H, (19)F, (31)P) NMR spectroscopy. The NMR studies show extensive dissociation at ambient temperatures in non-coordinating solvents, but mixtures of cis and trans isomers of the monodentate ligand complexes were identified at low temperatures. Crystal structures are reported for trans-[SiF(4)(R(3)PO)(2)] (R = Me or Ph), and cis-[SiF(4)(pyNO)(2)]. The GeF(4) analogues cis [GeF(4){R(2)P(O)(CH(2))(n)P(O)R(2)}] (R = Me or Ph, n = 1; R = Ph, n = 2) were similarly characterised and the structures of cis-[GeF(4){R(2)P(O)CH(2)P(O)R(2)}] (R = Me or Ph) determined. The reaction of R(3)AsO (R = Me or Ph) with SiF(4) does not give simple adducts, but forms [R(3)AsOH](+) cations as fluorosilicate salts. SiF(4) adducts of some ether ligands (including THF, 12-crown-4) were also characterised by (19)F NMR spectroscopy in solution at low temperatures (~190 K), but are fully dissociated at room temperature. Attempts to isolate, or even to identify, SiF(4) adducts with phosphine or thioether ligands in solution at 190 K were unsuccessful, contrasting with the recent isolation and detailed characterisation of GeF(4) analogues. The chemistry of SiF(4) with these oxygen donor ligands, and with soft donors (P, As, S or Se), is compared and contrasted with those of GeF(4), SnF(4) and SiCl(4). The key energy factors determining stability of these complexes are discussed. PMID- 21240414 TI - Spin frustration in a Cu(II)3 triangle frustrated? AB - A spiral hexanuclear antiferromagnetic Cu(II) complex with a [Cu(3)(MU(2) NO)(3)(MU(3)-O)] triangular core has direct metal spin coupling through diazine (MU(2)-NN), oxime (MU(2)-NO) and oxide/hydroxide (MU(3)-O) bridges. Spin frustration, expected in the triangular core, is suppressed (frustrated) by the bridging antiferromagnetic connections to the external metals, and so any residual spin in the triangle effectively cannot be stabilized. PMID- 21240415 TI - Non-innocent reactivity of bis-phosphinimine pincer ligands in palladium complexes. AB - Although the Pd complex of the bis-phosphinimine pincer ligand 1,3 C(6)H(3)(CH(2)N=PPh(3))(2) is accessible, this ligand is also non-innocent in the formation of a phosphinimine-aminophosphine pincer complex; as well, both complexes undergo hydride abstraction generating unique formally cationic ligand complexes. PMID- 21240416 TI - Alginate stabilized silver nanocube-Rh6G composite as a highly selective mercury sensor in aqueous solution. AB - Alginate-stabilized silver nanocubes are synthesized via a reduction method and are characterized by UV-Vis and fluorescence spectroscopies, SEM, AFM and HRTEM analyses. A silver nanocubes (Ag NCbs) based sensor for detecting Hg2+ ions in aqueous solution has been developed using Rh6G as an external spectroscopic probe. Using this system, Hg2+ ions (as low as 1*10(-10) mol L(-1)) are recognized in aqueous media via a colorimetric method with very high selectivity and sensitivity over other metal ions namely Fe2+, Zn2+, Pb2+, Cu2+, Sn2+, Cd2+, Ni2+, and Co2+. PMID- 21240417 TI - Nanoscale electrical probing of heterogeneous ceramics: the case of giant permittivity calcium copper titanate (CaCu3Ti4O12). AB - Scanning Probe Microscopy with conductive tips has been used to image and study the dielectric properties of giant permittivity CaCu3Ti4O12 ceramics at the nanoscale. Since measurements are generally carried out on sections of a sample, particular attention has been devoted to possible artefacts due to surface imperfections, such as substantial surface roughness and/or contamination that can result in controversial interpretation, particularly at nanometric spatial dimensions. A reliable surface investigation has been carried out after the definition of both the physical and geometrical unbiased criteria to avoid any artefacts due to surface roughness and/or anomalous tip-sample contact variations. The presence of insulating grain boundaries and the measurement of a depletion layer at the grain-grain boundary interfaces unambiguously demonstrate the relevance of the Internal Barrier Layer Capacitor effect, among all the proposed physical mechanisms, to explain the giant dielectric behaviour. Such imaging provided a clear correlation between the macroscopic dielectric properties and the nanometric structure at the interfaces. Moreover, the "general criteria" for reliable nanoelectrical characterization as well as the related measurement resolution have been defined. PMID- 21240418 TI - Pyrrolyl-, 2-(2-thienyl)pyrrolyl- and 2,5-bis(2-thienyl)pyrrolyl-nucleosides: synthesis, molecular and electronic structure, and redox behaviour of C5 thymidine derivatives. AB - A series of modified nucleosides based on thymidine have been prepared by Pd catalysed cross-coupling between N-alkyl-alkynyl functionalised pyrrolyl- (py), 2 (2-thienyl)pyrrolyl- (tp) or 2,5-bis(2-thienyl)pyrrolyl (tpt) groups with 5-iodo 2'-deoxyuridine. The length of the alkyl chain linking the nucleoside and pyrrolyl-containing unit, N(CH(2))(n)C[triple bond, length as m-dash]C-nucleoside (where n = 1-3) was also varied. The compounds have been characterised by (1)H NMR, ES-MS, UV-vis, cyclic voltammetry (CV) and, in some cases, single-crystal X ray diffraction. Cyclic voltammetry studies demonstrated that all the py-, tp- and tpt-alkynyl derivatives 1-7 can be electrochemically polymerised to form conductive materials. It was found that increasing the N-alkyl chain length in these cases resulted in only minor changes in the oxidation potential. The same behaviour was observed for the tp- and tpt-modified nucleosides 9-12; however, the py-derivative, 8, produced a poorly conducting material. DFT calculations on the one-electron oxidised cation of the modified nucleosides bearing tp or tpt showed that spin density is located on the pyrrolyl and thienyl units in all cases and that the coplanarity of adjacent rings increases upon oxidation. In contrast, in the corresponding pyrrolyl cases the spin density is distributed over the whole molecule, suggesting that polymerisation does not occur solely at the pyrrolyl-Calpha position and the conjugation is interrupted. PMID- 21240419 TI - Hypervalent organochalcogenanes as inhibitors of protein tyrosine phosphatases. AB - A series of organochalcogenanes was synthesized and evaluated as protein tyrosine phosphatases (PTPs) inhibitors. The results indicate that organochalcogenanes inactivate the PTPs in a time- and concentration-dependent fashion, most likely through covalent modification of the active site sulfur-moiety by the chalcogen atom. Consequently, organochalcogenanes represent a new class of mechanism-based probes to modulate the PTP-mediated cellular processes. PMID- 21240420 TI - Observation of content and heterogeneity of poly-beta-hydroxybutyric acid (PHB) in Legionella bozemanii by vibrational spectroscopy. AB - Information on how cells respond to their environment, interact with each other, or undergo complex processes such as cellular differentiation or gene expression has been obtained mostly by interference from population-level data. Individual microorganisms, even those on supposedly "clonal" populations, may differ widely from each other in terms of their genetic composition, physiology, biochemistry, or behaviours. This genetic and phenotypic heterogeneity has important practical consequences for a number of relevant interests, including antibiotic or biocide resistance, the productivity and stability of industrial fermentations, the efficacy of food preservatives, and the potential of pathogens to cause disease. Here we introduce vibrational spectroscopy to characterize Legionella bozemanii with respect to its content of poly-hydroxybutyric acid (PHB) and its distribution on both the population level and the single cell level. PMID- 21240421 TI - In situ Raman imaging of astaxanthin in a single microalgal cell. AB - Raman imaging is shown to be a highly selective and sensitive method of studying in situ and in vivo astaxanthin distribution, concentration and molecular structure in the cyst form of the unicellular microalgae Haematococcus pluvialis. PMID- 21240422 TI - A catechol biosensor based on a gold nanoparticles encapsulated-dendrimer. AB - Tyrosinase has been immobilized on a Au nanoparticles encapsulated-dendrimer bonded conducting polymer on a glassy carbon electrode for the estimation of catechol. The modified electrode was characterized by cyclic voltammetry and AFM techniques. The principle of catechol estimation was based on the reduction of biocatalytically liberated quinone species at +0.2 V versus Ag/AgCl (3 M KCl), with good stability, sensitivity, and featuring a low detection limit (about 0.002 MUM) and wide linear range (0.005 MUM-120 MUM). The electrochemical redox peak of catechol on the GCE/PolyPATT/Den(AuNPs)/tyrosinase was also investigated. A response time of 7 s, reusability up to 5 cycles and a shelf life of more than 2 months under refrigerated conditions were reported. Various parameters influencing biosensor performance have been optimized including pH, temperature, and applied potential. The utility and application of this nanobiosensor was tested in a real water samples. PMID- 21240423 TI - Development of double cylindrical dielectric barrier discharge ion source. AB - This paper deals with the dielectric barrier discharge (DBD) ion source composed of the outer cylindrical dielectric tube and the inner grounded metallic tube electrode. The sample gas is supplied through the inner ceramic tube. In this ion source, the DBD plasma is localized in the DBD tube so that the sample gases can be ionized just outside of the ceramic tube by the DBD excited helium gas without being exposed in the plasma jet. Besides, ambient air does not take part in the ionization of the sample vapor because ionization takes place inside the DBD ion source. Thus, this method is totally free from contaminants in ambient air. It was found that this ion source is capable of soft, high-sensitivity, and reproducible ionization. Application of this technique to the analysis of methamphetamine, carbaryl and basil leaf was given. PMID- 21240424 TI - Rhodamine hydrazone derivatives as Hg2+ selective fluorescent and colorimetric chemosensors and their applications to bioimaging and microfluidic system. AB - In this paper, we report new rhodamine hydrazone derivatives bearing thiol and carboxylic acid groups as selective fluorescent and colorimetric chemosensors for Hg(2+). The ring-opening process of spirolactam enables the large fluorescent enhancement and colorimetric change upon the addition of Hg(2+). The sample containing Hg(2+) was mixed with one of the chemosensors in a microchannel where the sensor was examined using confocal laser scanning microscopy. A plot of the fluorescent intensities of both chemosensors versus the log concentration of Hg(2+) exhibited a linear response (r(2)=0.95) in the range of 1 nM-1 MUM, and the detection limits were 1 nM and 4.2 nM, respectively. Both chemosensors also enable the visualization of Hg(2+) accumulated in the nematode Caenorhabditis elegans previously exposed to nanomolar concentrations of Hg(2+). PMID- 21240425 TI - Antibody-based multiplex analysis of structurally closely related chiral molecules. AB - Four class-specific and stereoselective antibodies were labeled with different fluorophores to enable simultaneous quantification of the enantiomers of phenylalanine and phenyllactic acid. Using fluorescence immunoassays and microarrays, sensitive detection of each analyte was possible even in the presence of a large excess of the other structurally similar molecules. PMID- 21240426 TI - Fluorescence imaging of hydroxyl radicals at superhydrophobic gold flower-like surface in photocatalytic system. AB - A new and facile assay for hydroxyl radicals in photocatalytic systems is reported for the first time that is based on the fluorescence imaging of increasing hydrophilic regions through the highly selective hydroxyl radical induced lateral remote oxidation of superhydrophobic 1-octadecanethiol molecules at gold flower-like surface in the designed photomask setup. PMID- 21240427 TI - Transfer of lipid and phase reorganisation in self-assembled liquid crystal nanostructured particles based on phytantriol. AB - The internal structure of dispersed liquid crystal nanostructured particles of the V(2) and H(2) phases, termed cubosomes and hexosomes respectively, is integral to their application in the pharmaceutical, agricultural and food industries. However the nanostructure is susceptible to change upon incorporation of other lipids and hence it is important to understand the potential for interparticle lipid transfer for such particles when they encounter a particle of dissimilar lipid content. Using time resolved synchrotron small angle X-ray scattering, we have investigated the transfer of material between cubosomes composed of phytantriol with three different particle types of dissimilar composition, (i) hexosomes and (ii) emulsified microemulsion composed of phytantriol and vitamin E acetate, and (iii) cubosomes prepared from glycerol monooleate. It was found that material was transferred between the different dispersed nanostructured particles, with the transfer being caused by compositional ripening. Somewhat counter-intuitively the transfer was bidirectional with phytantriol being more rapidly transferred than the minor component vitamin E acetate. The greater lipophilicity of vitamin E acetate supports previous studies suggesting greater mobility for the less lipophilic components, regardless of the more efficient transfer route to achieve uniform composition. When particles comprising lipids with similar lipophilicities were mixed, the transfer was limited and did not achieve completion; a phase change between cubic nanostructures required to achieve complete mixing provides an apparent barrier to further compositional ripening. The conclusions from this study provide additional support to lipid transfer mechanisms, and highlight some subtleties in using dissimilar lipid mixtures in e.g. food applications. PMID- 21240428 TI - Periodic nanoscale structures on polyimide surfaces generated by temporally tailored femtosecond laser pulses. AB - A strong influence of different pulse durations and double pulse delay times on the formation of periodic surface structures on polyimide were observed employing ultrashort laser pulses tailored on a sub-picosecond and picosecond time scale. Multi-photon, defect-related excitation mechanisms and thermal expansion of the polymer lattice correlated to a loss of long range order and polarisation memory were considered. PMID- 21240429 TI - C-H oxidation by platinum group metal oxo or peroxo species. AB - While C-H oxidation by ruthenium oxo compounds has been broadly applied in organic synthesis, examples of C-H oxidation by metal oxo complexes from the rest of the platinum group are still rare. We survey the preparation and reactivity of these late-transition metal oxo and peroxo complexes in this tutorial review. PMID- 21240430 TI - Control of the stereo-selectivity of styrene epoxidation by cytochrome P450 BM3 using structure-based mutagenesis. AB - The potential of flavocytochrome P450 BM3 (CYP102A1) from Bacillus megaterium for biocatalysis and biotechnological application is widely acknowledged. The catalytic and structural analysis of the Ala82Phe mutant of P450 BM3 has shown that filling a hydrophobic pocket near the active site improved the binding of small molecules, such as indole (see Huang et al., J. Mol. Biol., 2007, 373, 633) and styrene. In this paper, additional mutations at Thr438 are shown to decrease the binding of and catalytic activity towards laurate, whereas they significantly increased the stereo-specificity of styrene epoxidation. Production of R-styrene oxide with 48% and 64% e.e., respectively, was achieved by the Ala82Phe-Thr438Leu and Ala82Phe-Thr438Phe mutants. These structure-based mutants of P450 BM3 illustrate the promise of rational design of synthetically useful biocatalysts for regio- and stereo- specific mono-oxygenation reactions. PMID- 21240431 TI - Amphiphilic antioxidants from "cashew nut shell liquid" (CNSL) waste. AB - Hydrogenated cardanol and cardols, contained in industrial grade cardanol oil and obtained by distillation of the raw "cashew nut shell liquid" (CNSL), are easily transformed into efficient 4-thiaflavane antioxidants bearing a long alkyl chain on A ring and a catechol group on B ring. PMID- 21240432 TI - Facile construction of non-precious iron nitride-doped carbon nanofibers as cathode electrocatalysts for proton exchange membrane fuel cells. AB - We demonstrate a facile construction of iron nitride-doped carbon nanofiber by effectively utilizing the existing slit pores and rough edges along the inner wall of the substrate as originated by virtue of its cup-stack structure for effectively increasing the number of active sites and consequently the oxygen reduction activity. PMID- 21240433 TI - Dynamic wetting of a fluoropolymer surface by ionic liquids. AB - The spontaneous spreading of ionic liquids on a fluoropolymer surface (Teflon AF1600) in air is investigated by high-speed video microscopy. Six ionic liquids (EMIM BF(4), BMIM BF(4), OMIM BF(4), EMIM NTf(2), BMIM NTf(2) and HMIM NTf(2)) are used as probe liquids. The dependence of the dynamic contact angle on contact line velocity is interpreted with a hydrodynamic model and a molecular-kinetic model. The usefulness of the hydrodynamic model is rather limited. There is a good correspondence between the molecular dimensions of the liquids and the physical parameters of the molecular-kinetic model. The viscous and molecular kinetic contributions to energy dissipation are calculated, revealing that energy is dissipated in the bulk as well as at the contact line during dynamic wetting. There are wide ramifications of these results in areas ranging from lubrication and biology to minerals processing and petroleum recovery. PMID- 21240434 TI - Optical fluid and biomolecule transport with thermal fields. AB - A long standing goal is the direct optical control of biomolecules and water for applications ranging from microfluidics over biomolecule detection to non equilibrium biophysics. Thermal forces originating from optically applied, dynamic microscale temperature gradients have shown to possess great potential to reach this goal. It was demonstrated that laser heating by a few Kelvin can generate and guide water flow on the micrometre scale in bulk fluid, gel matrices or ice without requiring any lithographic structuring. Biomolecules on the other hand can be transported by thermal gradients, a mechanism termed thermophoresis, thermal diffusion or Soret effect. This molecule transport is the subject of current research, however it can be used to both characterize biomolecules and to record binding curves of important biological binding reactions, even in their native matrix of blood serum. Interestingly, thermophoresis can be easily combined with the optothermal fluid control. As a result, molecule traps can be created in a variety of geometries, enabling the trapping of small biomolecules, like for example very short DNA molecules. The combination with DNA replication from thermal convection allows us to approach molecular evolution with concurrent replication and selection processes inside a single chamber: replication is driven by thermal convection and selection by the concurrent accumulation of the DNA molecules. From the short but intense history of applying thermal fields to control fluid flow and biological molecules, we infer that many unexpected and highly synergistic effects and applications are likely to be explored in the future. PMID- 21240435 TI - Copper(II)-terbium(III) single-molecule magnets linked by photochromic ligands. AB - Two assemblies composed of single-molecule magnets (SMMs) linked by photochromic ligands, [Cu(II)(2)Tb(III)(2)(L)(2)(NO(3))(2)(dae-o)(2)].2(n-BuOH) (1) and {[Cu(II)Tb(III)(L)(n-BuOH)(0.5)](2)(dae-c)(3)}.5(DMF).4(n-BuOH).2(H(2)O) (2), were synthesized by reacting the SMM [Cu(II)Tb(III)(L)(NO(3))(3)] (H(2)L = 1,3 bis((3-methoxysalicylidene)amino)propane) and photochromic molecules, H(2)dae-o and H(2)dae-c, which are open- and closed-ring isomers of 1,2-bis(5-carboxyl-2 methyl-3-thienyl)perfluoropentene (H(2)dae), respectively. 1 has a tetranuclear ring-like structure comprised of two [CuTb] units and two dae-o(2-) ligands. On the other hand, 2 has a one-dimensional ladder-type structure involving the [CuTb] and dae-c(2-) units in a 3 : 2 ratio. Magnetic studies revealed that 1 and 2 had ferromagnetic interactions between the Cu(II) and Tb(III) ions and that both compounds exhibited frequency dependence of ac susceptibilities owing to freezing the magnetization of the [CuTb] SMM. Upon irradiation with ultraviolet light and visible light, an absorption band at ~600 nm changed, indicating that photochromic reactions involving the dae(2-) ligands occurred. After irradiation, the magnetic behaviour of 1 did not change, whereas magnetic behaviour of 2 changed, due to the modification of intermolecular environment. PMID- 21240437 TI - Rheo-attenuated total reflectance infrared spectroscopy: a new tool to study biopolymers. AB - Whilst rheology is the reference technique to study the mechanical properties of unspun silk, we know little of the structure and the dynamics that generate them. By coupling infrared spectroscopy and shearing forces to study silk fibroin conversion, we are introducing a novel tool to address this gap in our knowledge. Here the silk conversion process has been studied dynamically using polarized attenuated total reflectance Fourier transform infrared spectroscopy whilst applying shear, thus revealing silk protein conformation and molecular orientation in situ. Our results show that the silk conversion process starts with a pre-alignment of the proteins followed by a rapid growth of the beta-sheet formation and then a subsequent deceleration of the growth. We propose that this tool will provide further insight into not only silk but any biopolymer solution, opening a new window into biological materials. PMID- 21240436 TI - Aggregation-induced emission enhancement of polycyclic aromatic alkaloid derivatives and the crucial role of excited-state proton-transfer. AB - Aggregation-induced emission enhancement (AIEE) phenomenon is observed in the polycyclic aromatic alkaloid derivatives due to the configuration changes in the excited state, which is attributed to intramolecular proton-transfer and the formation of a new structure of enol form. PMID- 21240438 TI - Environment-sensitive amphiphilic fluorophore for selective sensing of protein. AB - Here we report the selective sensing of BSA (bovine serum albumin) by 8 (alkoxy)quinoline-based fluorescent probes, via non-covalent interactions. The weak fluorescence of these probes in aqueous solution showed a dramatic increase in quantum yield and lifetime upon binding with BSA, while the responses to various other proteins/enzymes used were negligible under similar experimental conditions. The emission of the probe is affected by the interplay with BSA but not with tryptophan amino acid suggesting that the microenvironment created by the macromolecule induces some change in their excited-state properties. Binding site assignment by a known site-selective binding ligand enabled us to conclude that the compounds predominantly bind at site I of BSA. The changes in fluorescence intensity and the position of emission maxima of compounds in presence of BSA along with the increase in steady state anisotropy values well reflect the nature of binding and location of the probe inside the protein environment. Compounds interact with BSA efficiently and exhibit site selectivity and thus have the potentiality to serve as an efficient and selective sensor of protein. PMID- 21240439 TI - Pseudo Jahn-Teller origin of cis-trans and other conformational changes. The role of double bonds. AB - Based on the pseudo Jahn-Teller effect (PJTE) theory, an approach is developed to rationalize and predict the conformations and conformational changes in molecular systems with a common pattern, a double bond. It is shown that starting with the high-symmetry geometry of the environment (in many cases D(2d)), the double bond descends from an e(2) electronic configuration (e is a twofold degenerate MO) which produces a variety of PJT distortions, the main of which is the rotational (b(1)) transformation D(2d) -> D(2h) accompanied by the formation of the double bond. Further PJT interactions with higher energy E-states may trigger additional distortions which in D(2h) symmetry are classified as in-plane (e(i)) cis and trans, and out-of-plane (e(o)) chair and boat. The realization of these conformations depends on the positions of the excited E-states and the PJTE parameter values. The two emerging PJTE problems, ((3)A(2) + (3)E(1) + (3)E(2)) ? (e(i) + e(o)) and ((1)A(1) + (1)B(1) + (1)B(2) + (1)E(1) + (1)E(2)) ? (b(1) + e(i) + e(o)), are formulated in the matrix form and provide a general picture of the ground and excited adiabatic potential energy surfaces. Following this scheme in combination with ab initio calculations, the possible conformations and conformational transitions are analyzed for several specific systems including (in increasing complexity) N(2)H(2), C(2)H(4), N(2)(NH(2))(2) and N(2)(C(6)H(5))(2) (azobenzene). The family of molecular systems with a double bond is vast, but the importance of the PJT approach developed here is also in its general validity as it can be applied to any other systems. PMID- 21240440 TI - A comparative analysis of the UV/Vis absorption spectra of nitrobenzaldehydes. AB - In a joint experimental and theoretical study, the UV/Vis absorption spectra of the three isomers (ortho, meta, para) of nitrobenzaldehyde (NBA) were analyzed. Absorption spectra are reported for NBA vapors, cyclohexane and acetonitrile solutions. All spectra are poor in vibronic structure and hardly affected in shape by the surroundings (vapor or solution). Moderate solvatochromic shifts of ~ -0.2 eV are measured. For all isomers vertical transition energies, oscillator strengths, and excited state dipole moments were computed using the MS CASPT2/CASSCF and CC2 methods. Based on these calculations the experimental transitions were assigned. The spectra of all isomers are characterized by weak (epsilon(max) ~ 100 M(-1) cm(-1)) transitions around 350 nm (3.6 eV), arising from npi* absorptions starting from the lone pairs of the nitro and aldehyde moieties. The next band of intermediate intensity peaking around 300 nm (4.2 eV, epsilon(max) ~ 1000 M(-1) cm(-1)) is dominated by pipi* excitations within the arene function. Finally, strong absorptions (epsilon(max) ~ 10,000 M(-1) cm(-1)) were observed around 250 nm (5.0 eV) which we ascribe to pipi* excitations involving the nitro and benzene groups. PMID- 21240441 TI - Chemistry, physico-chemistry and applications linked to biological activities of beta-glucans. AB - beta-Glucans is the common name given to a group of chemically heterogeneous polysaccharides. They are long- or short-chain polymers of (1-->3)-beta-linked glucose moieties which may be branched, with the branching chains linked to the backbone by a (1-->6)-beta linkage. beta-(1-->3)-Glucans are widely distributed in bacteria, algae, fungi and plants, where they are involved in cell wall structure and other biological function. beta-Glucans have been shown to provide a remarkable range of health benefits, and are especially important against the two most common conventional causes of death in industrialized countries, i.e. cardiovascular diseases (where they promote healthy cholesterol and blood glucose levels) and cancer (where they enhance immune system functions). This Highlight provides a comprehensive and up-to-date commentary on beta-glucans, their chemistry, physico-chemistry, functional role in immunological responses, and possible applications as therapeutic tools. In addition, we discuss the mechanism behind their health benefits, which are not yet fully understood. PMID- 21240442 TI - Bio-functionalization of metal-organic frameworks by covalent protein conjugation. AB - Bioconjugation of functional proteins onto metal-organic frameworks (MOFs) has been achieved using activation of pendent linking groups of the organic linkers on the surface of MOFs. Fluorescent microscopy revealed successful conjugation of an enhanced fluorescent protein onto MOFs. In addition, Candida-antarctica-lipase B-conjugated MOFs showed no loss of enantioselectivity and activity in transesterification of (+/-)-1-phenylethanol. PMID- 21240443 TI - Diastereoselective synthesis of the indeno-tetrahydropyridine core bearing a diaryl-substituted stereogenic quaternary carbon center of haouamine B. AB - The characteristic indeno-tetrahydropyridine core of cytotoxic haouamine B (2) was efficiently synthesized featuring the diastereoselective construction of a diaryl-substituted stereogenic quaternary center by an intramolecular Pd catalyzed alpha-C-arylation and subsequent direct conversion of the vinylogous imide function into the C2-C25 double bond by TsNHNH(2). PMID- 21240444 TI - Entropy-driven molecular switch and signal amplification for homogeneous SNPs detection. AB - An approach was developed to rapidly and sensitively detect SNP in homogeneous solution based on an entropy-driven molecular switch and isothermal polymerase amplification reaction without addition of exogenous primers. PMID- 21240445 TI - The role of hydroxyl groups in low temperature carbon monoxide oxidation. AB - Using the unique ability of inelastic neutron scattering spectroscopy to quantify surface hydroxyls, it is shown that two hydroxyls are essential for the low temperature oxidation of CO over a model palladium catalyst. PMID- 21240446 TI - Engineering arginine cross-linked mercaptoundecanoic acid CdSe/CdS/ZnS quantum dots for two-photon imaging of live cancer cells. AB - Low toxicity arginine cross-linked mercaptoundecanoic acid CdSe/CdS/ZnS quantum dots were synthesized for two-photon imaging of live cancer cells. PMID- 21240447 TI - Influence of ion pairing on the oxidation of iodide by MLCT excited states. AB - The oxidation of iodide to diiodide, I(2)(-), by the metal-to-ligand charge transfer (MLCT) excited state of [Ru(deeb)(3)](2+), where deeb is 4,4' (CO(2)CH(2)CH(3))(2)-2,2'-bipyridine, was quantified in acetonitrile and dichloromethane solution at room temperature. The redox and excited state properties of [Ru(deeb)(3)](2+) were similar in the two solvents; however, the mechanisms for excited state quenching by iodide were found to differ significantly. In acetonitrile, reaction of [Ru(deeb)(3)](2+*) and iodide was dynamic (lifetime quenching) with kinetics that followed the Stern-Volmer model (K(D) = 1.0 +/- 0.01 * 10(5) M(-1), k(q) = 4.8 * 10(10) M(-1) s(-1)). Excited state reactivity was observed to be the result of reductive quenching that yielded the reduced ruthenium compound, [Ru(deeb(-))(deeb)(2)](+), and the iodine atom, I. In dichloromethane, excited state quenching was primarily static (photoluminescence amplitude quenching) and [Ru(deeb(-))(deeb)(2)](+) formed within 10 ns, consistent with the formation of ion pairs in the ground state that react rapidly upon visible light absorption. In both solvents the appearance of I(2)(-) could be time resolved. In acetonitrile, the rate constant for I(2)(-) growth, 2.2 +/- 0.2 * 10(10) M(-1) s(-1), was found to be about a factor of two slower than the formation of [Ru(deeb(-))(deeb)(2)](+), indicating it was a secondary photoproduct. The delayed appearance of I(2)(-) was attributed to the reaction of iodine atoms with iodide. In dichloromethane, the growth of I(2)(-), 1.3 +/- 0.4 * 10(10) M(-1) s(-1), was similar to that in acetonitrile, yet resulted from iodine atoms formed within the laser pulse. These results are discussed within the context of solar energy conversion by dye-sensitized solar cells and storage via chemical bond formation. PMID- 21240448 TI - sp hybridization in free carbon nanoparticles--presence and stability observed by near edge X-ray absorption fine structure spectroscopy. AB - The presence and stability of sp hybridized atoms in free carbon nanoparticles was investigated by NEXAFS spectroscopy. The experiments show that a predominant fraction of carbon atoms is found in linear sp-chains and that conversion into sp(2) structures proceeds already at low temperature and in the gas phase. PMID- 21240449 TI - Synergy between quantum dots and 1,10-phenanthroline-copper(II) complex towards cleaving DNA. AB - We have found that the DNA cleaving activity of quantum dots and 1,10 phenanthroline-Cu(II) complex is significantly enhanced when they are combined. PMID- 21240450 TI - Quantum dot photoluminescence lifetime-based pH nanosensor. AB - The first CdSe/ZnS quantum dot photoluminescence lifetime-based pH nanosensor has been developed. The average lifetime of mercaptopropionic acid-capped QD nanosensors showed a linear response in the pH range of 5.2-6.9. These nanosensors have been satisfactorily applied for pH estimation in simulated intracellular media, with high sensitivity and high selectivity toward most of the intracellular components. PMID- 21240451 TI - 'Shape effects' in metal oxide supported nanoscale gold catalysts. AB - We report the activity of shape-controlled metal oxide (CeO(2), ZnO and Fe(3)O(4)) supported gold catalysts for the steam reforming of methanol (SRM) and the water gas shift (WGS) reactions. Metal oxide nanoshapes, prepared by controlled hydrolysis and thermolysis methods, expose different crystal surfaces, and consequently disperse and stabilize gold differently. We observe that similar to gold supported on CeO(2) shapes exposing the {110} and {111} surfaces, gold supported on the oxygen-rich ZnO {0001} and Fe(3)O(4) {111} surfaces shows higher activity for the SRM and WGS reactions. While the reaction rates vary among the Au-CeO(2), Au-ZnO and Au-Fe(3)O(4) shapes, the apparent activation energies are similar, indicating a common active site. TPR data further indicate that the reaction lightoff coincides with the activation of Au-O-M species on the surface of all three oxide supports evaluated here. Different shapes contain a different number of binding sites for the gold, imparting different overall activity. PMID- 21240452 TI - New strategy to construct fused/bridged/spiro carbocyclic scaffolds based on the design of novel 6-C synthon precursor. AB - In this article we report a new strategy to build fused/spiro/bridged carbocyclic systems with a novel 6-C synthon from readily available diallyl diacetates through the sequential Pd-catalyzed double allyl alkylation and Diels-Alder annulation. Further exploration on the application of this strategy can construct useful complex scaffolds. PMID- 21240453 TI - Pesticide exposure and risk of Parkinson's disease--a population-based case control study evaluating the potential for recall bias. AB - OBJECTIVE: The aim of this study was to investigate whether pesticide exposure was associated with Parkinson's disease in a population-based case-control study in British Columbia, Canada. METHODS: Patients reimbursed for anti-parkinsonian agents were identified and screened for eligibility as cases. Controls were selected from the universal health insurance database, frequency-matched to the case sample on birth year, gender, and geographic region. A total of 403 cases and 405 controls were interviewed about their job, medical and personal habits histories, and beliefs about disease risk factors. Among those reporting pesticide exposure, an occupational hygiene review selected participants exposed "beyond background" (ie, above the level expected in the general population). Unconditional logistic regression was used to estimate associations for different pesticide categories. RESULTS: Of the cases, 74 (18%) self-reported pesticide exposure and 37 (9%) were judged to be exposed beyond background. Self-reported exposure was associated with increased risk [odds ratio (OR) 1.76, 95% confidence interval (95% CI) 1.15-2.70], however the risk estimate was reduced following the hygiene review when restricted to those considered exposed (OR, 1.51, 95% CI, 0.85-2.69). When agricultural work was added to the model, the risk for hygiene reviewed pesticide exposure was not elevated (OR 0.83, 95% CI 0.43-1.61), but agricultural work was (OR 2.47, 95% CI 1.18-5.15). More than twice as many cases as controls thought chemicals cause Parkinson's disease. Discussion This study provides little support for pesticide exposure as a cause of Parkinson's disease. The observed pattern of step-wise decreases in risk estimates might indicate differential recall by case status. The relationship to agricultural jobs suggests that farming exposures--other than pesticides--should be considered as risk factors for Parkinson's disease. PMID- 21240454 TI - Early stages of melanoma on the limbs of high-risk patients: clinical, dermoscopic, reflectance confocal microscopy and histopathological characterization for improved recognition. AB - Early stages of 36 melanomas on limbs were morphologically characterised. Most occurred in high-risk patients (multiple and/or familial melanoma) attending a referral unit for melanoma and pigmented lesions. None of the tumours was clinically suspicious for melanoma (mean diameter of 4.3 mm). The tumours were classified into four dermoscopic groups: (i) prominent network (n = 16); (ii) delicate network (n = 5); (iii) hypo-pigmentation with dotted vessels (n = 10); and (iv) diffuse light pigmentation with perifollicular pigmentation (n = 5). Confocal microscopy performed in 12 cases allowed the identification of atypical, single cells within epidermal layers. Histopathology showed marked large atypical cells in a pagetoid spreading pattern in most cases. Significant associations were detected between the third dermoscopic group and naevoid histological appearance and delay in detection, and between the fourth group and lentigo maligna-like features. Dermoscopy allowed an increase in the suspicious threshold in these difficult melanomas in high-risk patients and enabled the subclassification of early melanomas on the limbs, with a correct confocal and histopathological correlation. Although the biological behaviour of these incipient tumours remains uncertain, the most appropriate treatment seems to be recognition and proper excision. PMID- 21240455 TI - Significant immediate and long-term improvement in quality of life and disease coping in patients with vitiligo after group climatotherapy at the Dead Sea. AB - Quality of life in patients with vitiligo is impaired. This study explored the immediate effect of 20 days of climatotherapy at the Dead Sea on quality of life, coping with the disease, general well-being and individual stress levels in a group of 71 patients with vitiligo and 42 matched controls. The long-term effect was assessed after 12 months in 33/71 patients and 12/42 controls. Study instruments were Dermatology Life Quality Index, Beck Depression Inventory and the Adjustment to Chronic Skin Disorders Questionnaire. Stress measurements were based on cortisol and beta-endorphin concentrations in saliva samples. Quality of life was significantly improved at day 20 at the Dead Sea compared with day 1, and this was still significant after 12 months. Moreover, social anxiety/avoidance, anxious-depressive mood and helplessness as measured by the Adjustment to Chronic Skin Disorders Questionnaire were significantly reduced. There was no difference in levels of cortisol and beta-endorphin between patients and controls, indicating that stress per se is not a significant contributor in vitiligo. In conclusion, therapy in patient groups offers an effective tool for long-lasting improvement in quality of life and patients' well-being. PMID- 21240456 TI - An ethanol extract of Iris nertschinskia induces p53-dependent apoptosis in the MCF7 human breast cancer cell line. AB - Iris nertschinskia, an ornamental plant, is utilized in traditional East Asian medicine for the treatment of skin diseases. However, the biological activity underlying its therapeutic effects remains to be established. In this study, we investigated the anti-tumor effect of the plant extract on MCF7 human breast cancer cells. An ethanol extract of Iris nertschinskia triggered cell death in a dose-dependent manner. Moreover, treatment with the extract promoted p53 phosphorylation in MCF7 cells. Increased phosphorylation of p53, in turn, led to induction of Bax protein, a key regulator of p53-dependent apoptotic cell death, as well as of caspase-7 cleavage in MCF7 cells. Consistently, cells treated with p53-specific siRNA or the caspase inhibitor, Z-VAD, resisted apoptotic cell death induced by the Iris nertschinskia extract. Our results suggest that p53 sensitizes tumor cells to the ethanol extract of Iris nertschinskia by Bax protein induction and caspase-dependent apoptosis. PMID- 21240457 TI - Novel therapeutic potential in targeting microtubules by nanoparticle albumin bound paclitaxel in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) shows low response to most conventional chemotherapies. To facilitate target identification for novel therapeutic development, we deployed gene expression profiling on 43 paired HCC tumors and adjacent non-tumoral liver, which is also considered as the pre-malignant liver lesion. In conjunction with ontology analysis, a major functional process found to play a role in the malignant transformation of HCC was microtubule-related cellular assembly. We further examined the potential use of microtubule targeting taxane drugs, including paclitaxel and docetaxel, and compared with findings to results from doxorubicin, a common chemotherapeutic agent used in HCC. Recent studies showed that drug delivery by nanoparticles have enhanced efficacy with reduced side effects. In this regard, the nanoparticle albumin-bound (nab) paclitaxel was also examined. In a panel of HCC cell lines studied, a high sensitivity towards taxane drugs was generally found, although the effect from nab-paclitaxel was most profound. The nab-paclitaxel showed an effective IC50 dose at 15-fold lower than paclitaxel alone or the derivative analogue docetaxel, and ~450-fold less compared to doxorubicin. Flow cytometric analysis confirmed a cell cycle blockade at the G2/M phase and increased apoptosis following nab paclitaxel treatment. In vivo animal studies also showed that nab-paclitaxel readily inhibited xenograft growth with less toxicity to host cells compared to other anti-microtubule drugs and doxorubicin. Gene silencing of the microtubule regulatory gene STMN1 by RNAi suggested a distinct synergistic effect in the combined treatment with nab-paclitaxel. Our findings in this study highly suggest that the microtubule assembly represents a promising therapeutic target development in HCC. PMID- 21240458 TI - Flexible hysteroscopy with narrow band imaging (NBI) for endoscopic diagnosis of malignant endometrial lesions. AB - Narrow band imaging (NBI) for detection of blood vessels and microstructures on the mucosal surface is used in gastrointestinal endoscopy since it can improve qualitative diagnosis and detection of lesion. However, there are no studies on flexible hysteroscopy using NBI. We performed flexible hysteroscopy with NBI for outpatients to investigate the sensitivity and specificity of endoscopic diagnosis of malignant endometrial lesions. Of patients who attended our hospital for suspected lesions in the uterine cavity between April 2009 and May 2010, 104 subjects underwent hysteroscopy with NBI, in addition to white light. Using the pathological diagnosis as the gold-standard, we evaluated the sensitivity and specificity of NBI hysteroscopy for detecting atypical endometrial hyperplasia (AEH) or carcinoma. The results were also compared with historical data (n=209) for conventional hysteroscopy using white light only in 2008. The sensitivities were 97.2% [95% confidence interval (95% CI): 90.3-99.7%] and 82.6% (95% CI: 74.4 89.0%) for NBI hysteroscopy and conventional hysteroscopy, respectively. The 95% CIs for the two methods did not overlap and the sensitivity of lesion detection was higher with NBI hysteroscopy. Specificities were comparable, 90.6% (95% CI: 75.0-98.0%) and 85.1% (95% CI: 76.3-91.6%) between the methods. NBI hysteroscopy has increased sensitivity for detection of atypical endometrial hyperplasia (AEH) or carcinoma. A comparison with historical data suggested that NBI may be useful for diagnosis of malignant endometrial lesions. As far as we are aware, this is the first evaluation of flexible hysteroscopy with NBI for diagnosis of malignant endometrial lesions. PMID- 21240459 TI - Epigenetic regulation of the potential tumor suppressor gene, hLHX6.1, in human cervical cancer. AB - It is well known that the Homo sapiens LIM homeobox domain 6 gene (hLHX6), a putative transcription regulator, controls the differentiation and development of neural and lymphoid cells, particularly in the central nervous system. In this study, we investigated hLHX6.1 (an isoform of hLHX6), which functions as a tumor suppressor gene in the cervix. Firstly, the methylation levels of the hLHX6 and hLHX6.1 promoters were investigated in 8 cervical cancer cell lines and human tissue samples with a distinctive degree of malignant transformation. In spite of the presence of multiple cytosine guanine dinucleotides (CpG islands) in 2 proximal promoters of the hLHX6 and hLHX6.1 genes, only the hLHX6.1 promoters were found to be mostly hypermethylated and associated with transcriptional silencing by promoter methylation, whereas the hLHX6 promoters were not. Methylation levels in the hLHX6.1 promoter were also found to be strongly related to cervical cancer development. The level of hLHX6.1 gene expression was found to be relatively high in normal cells, in which the hLHX6.1 promoter was mostly unmethylated. However, the hLHX6.1 gene expression was down-regulated or undetectable in cervical cancer cell lines and cancer tissues, in which the hLHX6.1 promoter was hypermethylated. This epigenetic alteration in the hLHX6.1 promoter begins at a relatively early stage, suggesting its potential as a biomarker for the early diagnosis and prevention of cervical cancer. Moreover, the overexpression of the hLHX6.1 gene in cervical cancer cells suppressed the tumorigenic phenotype, as shown by soft agar colony formation and migration assays, suggesting that hLHX6.1 could be a new tumor suppressor gene in the cervix. PMID- 21240460 TI - Anti-proliferative potential of curcumin in androgen-dependent prostate cancer cells occurs through modulation of the Wingless signaling pathway. AB - Activation of the Wingless (Wnt)/beta-catenin signaling pathway contributes to prostate tumorigenesis and metastasis. Depending of the stage of prostate cancer development, current drug therapies are of limited efficiency, so that prevention with natural compounds appears as an attractive strategy especially due to the slow progressive development of prostate cancer. We report here that the chemopreventive agent curcumin from the rhizome of Curcuma longa was able to affect cell proliferation of androgen-dependent prostate cancer through the induction of cell cycle arrest in G2 and modulation of Wnt signaling. Curcumin decreases the level of Tcf-4, CBP and p300 proteins implicated in the Wnt transcriptional complex that leads to the decrease of beta-catenin/Tcf-4 transcriptional activity and of the expression of beta-catenin target genes (cyclin D1 and c-myc). Subsequent cell death induction is linked to autophagy. Interestingly, in androgen-independent prostate cancer cells, curcumin does not affect Wnt/beta-catenin transcriptional activity. Altogether our results suggest that curcumin is an interesting chemopreventive agent for early stage prostate cancer. PMID- 21240461 TI - Cancer-associated fibroblasts correlate with poor prognosis in rectal cancer after chemoradiotherapy. AB - Cancer-associated fibroblasts (CAFs) in the stroma play an important role in influencing the proliferation, invasion and metastasis of cancer cells. Fibroblast activation protein-alpha (FAP-alpha) is known as a marker of CAFs, while stromal cell-derived factor-1 (SDF-1) is primarily expressed by CAFs. Herein, we investigated whether the expression levels of these genes are associated with clinical outcome after pre-operative chemoradiotherapy (CRT) in rectal cancer patients. We obtained total RNA from residual cancer stroma using microdissection from a total of 52 rectal cancer specimens from patients who underwent pre-operative CRT, we performed transcriptional analyses, and the serum protein concentrations in 40 matched microdissected specimens were measured by enzyme-linked immunosorbent assay. Additionally, we sought to clarify the location of FAP-alpha and SDF-1 expression using immunohistochemical staining. Of the 52 patients, 15.6 and 36.8% showed detectable FAP-alpha and SDF-1 mRNA expression, respectively. A significant correlation was observed between stromal FAP-alpha and SDF-1 mRNA levels. Moreover, there was a significant correlation between stromal SDF-1 gene expression levels and serum protein levels. Patients who developed distant recurrences after CRT had positive expression of both genes (P<0.05). The positive expression of both genes was also associated with poor probability of recurrence-free and overall survival (P<0.05). Patients with elevated serum SDF-1 levels had equally poor overall survival as those with positive stromal SDF-1 gene expression (P<0.05). In immunohistochemistry, both FAP-alpha and SDF-1 expression was observed in certain activated fibroblasts. In conclusion, FAP-alpha and SDF-1 expression was shown to be involved in tumor re growth and recurrence in rectal cancer patients treated with pre-operative CRT. PMID- 21240462 TI - Increase in clusterin forms part of the stress response in Hodgkin's lymphoma. AB - Clusterin (also called APOJ, SGP-2, XIP8) has thus far been only partially characterized in lymphomas contrary to other types of cancer. Its expression has been reported only for anaplastic large cell lymphomas and, more recently, in mycosis fungoides. Here, we demonstrate an up-regulation of intracellular clusterin in Hodgkin's lymphoma (HL)-derived cell lines L-428, KM-H2 and L-540, caused by different stimuli such as IFN-gamma, doxorubicin and X-rays. These stimuli are relevant for the pathophysiology and therapy of HL and represent a first step in the characterisation of this glycoprotein known to have a role in drug chemoresistance. p53 up-regulation accompanies increases in clusterin levels accordingly with the onset of apoptosis. We also show that the cells secrete more clusterin after treatment with doxorubicin, which is consistent with the observed intracellular increase. These observations suggested that the levels of circulating clusterin should also be measured in the peripheral blood from HL patients both at the time of diagnosis and after two cycles of chemotherapy. In a preliminary study on patient sera we observed that an increase in clusterin is correlated with positron emission tomography (PET) positivity after two cycles of chemotherapy. PMID- 21240463 TI - mTOR inhibitors show promising in vitro activity in bladder cancer and head and neck squamous cell carcinoma. AB - Bladder cancer and head and neck squamous cell carcinoma (HNSCC) are frequent but lack efficient therapies especially in advanced disease. Almost no studies on mTOR function and inhibition in these tumor entities have been reported. We examined the gene and protein expression levels of mTOR and its activated form (pmTOR) in three human bladder carcinoma cell lines (RT-4, T24, EJ28) and three HNSCC cell lines (PCI-1, PCI-13, BHY). Furthermore, the consequences of mTOR inhibition by mTOR-specific siRNAs and the mTOR inhibitor temsirolimus were analysed in vitro using immunohistochemical Ki-67 staining, mTOR and pmTOR western blot analysis, MTT assay, as well as cell cycle analysis with flow cytometry. Especially pmTOR protein expression levels showed marked differences between cell lines. siRNA transfection was associated with dose-dependent target protein reduction but not proliferation inhibition or apoptosis. On the contrary, temsirolimus significantly reduced cell viability and induced apoptosis and cell cycle arrest. According to these data, bladder cancer and HNSCC are promising tumor entities for mTOR inhibition with temsirolimus. PMID- 21240464 TI - Effects of bevacizumab in mouse model of endometrial cancer: Defining the molecular basis for resistance. AB - Endometrial cancer is the most frequent gynecologic cancer in women. Long-term outcomes for patients with advanced stage or recurrent disease are poor. Targeted molecular therapy against the vascular endothelial growth factor (VEGF) and its receptors constitute a new therapeutic option for these patients. The goal of our study was to assess the potential effectiveness of inhibition of VEGF/VEGFR signaling in a xenograft model of endometrial cancer using bevacizumab (Avastin, a humanized antibody against VEGFA). We also aimed to identify molecular markers of sensitivity or resistance to this agent. We show that bevacizumab retards tumor growth in athymic mice by inhibiting molecular components of signaling pathways that sustain cell survival and proliferation. We also demonstrate that resistance to bevacizumab may involve up-regulation of anti-apoptotic genes and certain proto-oncogenes. We propose that down-regulation of ARHGAP6 and MMP15 transcripts indicates that tumors are sensitive to bevacizumab whereas inhibition of PKCdelta- or S6K-dependent signaling and up-regulation of TNFRS4 or MMP13 and MMP14 mark a developing resistance to bevacizumab therapy. Interestingly, the significant activation of c-Jun oncogene detected in bevacizumab-treated tumors suggests that, in endometrial cancers, the c-Jun-mediated pathway(s) contribute to bevacizumab resistance. PMID- 21240466 TI - Integrated Testing Strategy (ITS) - Opportunities to better use existing data and guide future testing in toxicology. AB - The topic of Integrated Testing Strategies (ITS) has attracted considerable attention, and not only because it is supposed to be a central element of REACH, the ambitious European chemical regulation effort. Although what ITSs are supposed to do seems unambiguous, i.e. speeding up hazard and risk assessment while reducing testing costs, not much has been said, except basic conceptual proposals, about the methodologies that would allow execution of these concepts. Although a pressing concern, the topic of ITS has drawn mostly general reviews, broad concepts, and the expression of a clear need for more research on ITS. Published research in the field remains scarce. Solutions for ITS design emerge slowly, most likely due to the methodological challenges of the task, and perhaps also to it its complexity and the need for multidisciplinary collaboration. Along with the challenge, ITS offer a unique opportunity to contribute to the Toxicology of the 21st century by providing frameworks and tools to actually implement 21st century toxicology data in the chemical management and decision making processes. Further, ITS have the potential to significantly contribute to a modernization of the science of risk assessment. Therefore, to advance ITS research we propose a methodical approach to their design and will discuss currently available approaches as well as challenges to overcome. To this end, we define a framework for ITS that will inform toxicological decisions in a systematic, transparent, and consistent way. We review conceptual requirements for ITS developed earlier and present a roadmap to an operational framework that should be probabilistic, hypothesis-driven, and adaptive. Furthermore, we define properties an ITS should have in order to meet the identified requirements and differentiate them from evidence synthesis. Making use of an ITS for skin sensitization, we demonstrate how the proposed ITS concepts can be implemented. PMID- 21240465 TI - CIAPIN1 confers multidrug resistance through up-regulation of MDR-1 and Bcl-L in LoVo/Adr cells and is independent of p53. AB - Recent investigations discovered that CIAPIN1 might be another drug resistance associated molecule in cancer cells. However, the underlying mechanisms of CIAPIN1-related multidrug resistance (MDR) remain elusive. In the present study, we investigated the role and possible mechanisms of CIAPIN1 in MDR of human colon carcinoma LoVo/Adr cells which express the wild-type p53 gene. By using small interference RNA and gene transfection techniques, we found that knockdown of CIAPIN1 expression re-sensitized LoVo/Adr cells to anti-cancer drugs and up regulation of CIAPIN1 in sensitive LoVo cells resulted in a distinct MDR phenotype. We further revealed that CIAPIN1 conferred the MDR phenotype in LoVo/Adr cells through up-regulating expression of MDR-1 (P-gp) and Bcl-xL. Finally, by analyzing the effect of inactivation of wild-type p53 on CIAPIN1 induced up-regulation of P-gp and Bcl-xL, we determined that CIAPIN1 could exhibit its MDR-related function independently of the p53 signaling pathway. Overall, the results presented here further suggest that over-expression of CIAPIN1 is an important mechanism of drug resistance in human cancers, even if not the sole one. PMID- 21240467 TI - A mechanistic redefinition of adverse effects - a key step in the toxicity testing paradigm shift. AB - The efforts of the committee that produced the report on Toxicity Testing in the 21st Century reflected the need to look at the issue of assessing risks to humans from exposure to various chemicals through a lens of 21st century biology. The problem - determining if there is a risk of specific exposures - is as old as humanity; every generation brings its own perspective and tools for examining the problem and coming to answers and solutions. Bringing this generation's tools to bear requires us to see the problem of chemical risk assessment in a different light, both in terms of testing of toxicity pathways in vitro and in the interpretation of the tests for estimating whether exposures will be safe. One key issue will be to assess when pathway perturbations are believed to be excessive, i.e., when they are deemed adverse. Redefinition of adversity based on in vitro testing will require a new perception of dose response functions as probabilities of failures, with multiple underlying processes acting sequentially and in parallel leading to failure at a cellular and an organism level. These dose response relationships for adversity will also require a computational systems biology approach for examining toxicity pathway dynamics and stress pathway overload. While the overall approach of defining adversity for in vitro endpoints and using this definition of adversity for risk assessment can be painted in broad brush strokes, as we have done here for DNA-reactive compounds, it will take implementation with a series of prototypes to show the process in practice. PMID- 21240468 TI - Evidence-based toxicology - the toolbox of validation for the 21st century? AB - Validation has become a primary driver of the evolution of toxicological methods. Agreement at OECD level currently requires validation of new approaches for consideration in test guideline development. Several examples of this exist. However, the toxicology in the 21(st) century movement, prompted by the 2007 NRC/NAS vision document, might lead to a revolutionary change in the toxicological toolbox. The challenge is whether the validation process, as it has been formalized over the last two decades, meets the needs for this paradigm shift.The concept of evidence-based medicine (EBM) has emerged from clinical medicine, which retrospectively assesses the evidence of adequacy of a given approach. This is not typically done in prospective studies - the equivalent of validation studies might be multicenter randomized trials. Evidently, where such unambiguous evidence is available, no other assessment is necessary. EBM, however, has developed procedures, including meta-analysis, to collect and evaluate all the available evidence where no such definitive study is available. The recent successful introduction of retrospective validation, i.e. the collection and evaluation of existing evidence from various sources, represents a step in this direction. Here, we will explore new toxicological approaches via evidence-based toxicology (EBT). PMID- 21240469 TI - Courage for simplification and imperfection in the 21st century assessment of "Endocrine disruption". AB - "Endocrine disruption" is a public and political buzzword that has and is still receiving high media attention. Based on the latter, numerous tiered testing strategies have evolved that should ensure that humans will not run a health risk due to the voluntary or involuntary exposure to endocrine active compounds (EAS). An analysis of the currently available knowledge on EAS mediated endocrine disruption in humans demonstrates that there are very few EAS that causally induce endocrine disruptive effects. Conversely, the association EAS exposure with increased risk or incidences of endocrine disruptive effects in humans are difficult to reconcile with the results from animal studies. Consequently, the analysis of the traditional and historically grown tiered approach in EAS testing, often at very high doses or concentrations, demonstrates that the likelihood of detecting EAS with true potential for endocrine disruption in humans is very low, primarily due to inherent differences between the surrogate species and the human, and will provide for a high number of false-positives commensurate with low efficiency, high cost, and often violently disputed interpretations of what the data would mean for human risk assessment. It is thus proposed that EAS testing for putative endocrine disruption in humans and qualitative and quantitative evaluation for risk assessment purposes should be entirely focused on human data, and derived from a combination of in silico and in vitro systems, PBPK modeling, metabonomic or genomic profiling of human tissue, realistic human EAS exposure, dose-effect principles and adverse effect scenarios, human patient or exposure cohort datasets, etc. Animals models should be used only where specific pathways in endocrine physiology and thus development and reproduction is nearly identical to the situation in the human, thereby guaranteeing that causal exposure and effect relationships in the animals can be extrapolated to the human. PMID- 21240470 TI - Comparative analysis of the revised Directive 2010/63/EU for the protection of laboratory animals with its predecessor 86/609/EEC - a t4 report. AB - On 8th September 2010 the long process of revising the EU Directive for the protection of laboratory animals was concluded. Here a comparative evaluation of the new and old Directive is provided. While its ultimate goal is to replace the use of animals, the new Directive acknowledges that animals, including nonhuman primates, are still needed for scientific purposes today. Importantly, animals have an intrinsic value, which must be respected. There are some major advances for animal welfare, many of which had however already been common practice in the more progressive Member States. The new Directive prohibits new, more progressive legislation if not already in place and thus harmonises but also freezes the 27 Member States at a relatively high level. The revision was an important opportunity for the European Commission, on the one side to demonstrate its commitment to improve human health and safety by enabling animal testing and on the other side to improve animal health and welfare by setting minimum standards. By this Directive Europe is again taking a leading role in research and development for new non-animal tests and technologies by introducing a series of measures that strengthen the evaluation of the need of animal use in each case. It also represents a formal implementation of the 3Rs principle (Replacement, Reduction and Refinement of animal tests) put forward by Russel and Burch 1959. PMID- 21240471 TI - Dying to learn: the supply and use of companion animals in U.S. colleges and universities. AB - Americans consider dogs and cats as household pets, but many are harmed and killed for teaching and training purposes, despite the availability of alternatives. A review of 92 U.S. public college and university Institutional Animal Care and Use Committee (IACUC) 2005-2007 records indicates that 52% are using live and dead dogs and cats, and 26% are using live dogs and cats in harmful teaching exercises in undergraduate life science, veterinary, and medical education. In specific cases, IACUCs are failing to minimize animal use and suffering in education as required by the Animal Welfare Act (AWA). Sources of dogs and cats for education include Class A and Class B dealers, and United States Department of Agriculture (USDA) 2005-2007 inspections reveal repeated violations and inhumane treatment. Regardless, dealers continue to sell thousands of dogs and cats, many whom were former pets, annually to universities for use in education. A growing number of universities, however, are changing their policies and replacing harmful animal use with pedagogically sound alternatives. PMID- 21240472 TI - Food for thought ... considerations and guidelines for basic test method descriptions in toxicology. AB - The development and application of new test systems and test methods is central to the progress of in vitro toxicology. In order to live up to the future challenges, it is important to use the vast knowledge of adjoining fields, such as cell biology or developmental biology, and to attract specialists from such areas to develop new methods. Not all of them bring with them the necessary experience and training required for the development of toxicological test systems. Thus, promising new biological test systems sometimes still require additional considerations to become successful. Sometimes even the referees of scientific journals and their editors seem to lack judgement guidelines for minimum performance standards. Here we provide a list of points to be considered for the establishment of a test method. The chapters range from the explanation of the meaning of positive controls, performance standards or signal-noise ratios to a discussion of statistical considerations, suitable solvents and data display formats. The considerations are simple and expressed in a non-mathematical format, with a strong focus on plausibility and common sense. The major intention of this article is to provide a compilation of important issues requiring consideration. Whether they apply to a specific system and whether action is required must be determined by individual judgement. PMID- 21240473 TI - [On water, salt and more ... infusion therapy for neonates, infants and children]. PMID- 21240474 TI - [Basal cell carcinoma and stem cell markers : Contribution to possible histogenesis?]. AB - The prevalence and incidence of basal cell carcinoma are on the rise. Yet, its histogenesis is still controversial. Hitherto discussed concepts are largely based on morphological analogies. Historically, basal cell carcinoma was named after its similarity to the epidermal basal cell layer which is viewed as its histogenetic origin. On the other hand, a primitive follicular origin is postulated due to the morphological similarity of basal cell carcinoma to the embryonic hair germ. In 1990, the hair follicle bulge was characterized as the anatomical niche for follicular stem cells. Early studies employing stem cell markers suggested a follicular origin of basal cell carcinoma. Since then an explosion of stem cell markers has occured in dermatology. In this review, the stem cell markers employed in the examination of basal cell carcinoma up to now are critically evaluated. Initially, studies on the histogenesis of this common dermatological tumor are reviewed. PMID- 21240475 TI - [Treatment of small-cell lung cancer]. AB - Treatment of small cell lung cancer (SCLC) is based on the stage of disease. While combination of chemo- and radiotherapy preferably as concomitant chemoradiotherapy represents standard treatment in patients with locally advanced tumors (UICC stage I-III), patients with metastatic disease (stage IV) should be treated with an established platinum based chemotherapy regimen. After chemotherapy and in case of an achieved tumor response treatment should be completed by an adjuvant radiation of the brain in patients with adequate performance status. In patients with a very early stage of disease without involvement of lymph node metastasis a surgical approach in combination with an adjuvant chemotherapy can be discussed. In patients with relapsed tumors second line therapies like the topoisomerase I inhibitor Topotecan have proven efficacy. Up to now neither molecular targeted therapies nor cytotoxic or immunological maintenance strategies have provided any benefit to patients with SCLC. PMID- 21240476 TI - Rat neonatal beta cells lack the specialised metabolic phenotype of mature beta cells. AB - AIMS/HYPOTHESIS: Fetal and neonatal beta cells have poor glucose-induced insulin secretion and only gain robust glucose responsiveness several weeks after birth. We hypothesise that this unresponsiveness is due to a generalised immaturity of the metabolic pathways normally found in beta cells rather than to a specific defect. METHODS: Using laser-capture microdissection we excised beta cell enriched cores of pancreatic islets from day 1 (P1) neonatal and young adult Sprague-Dawley rats in order to compare their gene-expression profiles using Affymetrix U34A microarrays (neonatal, n = 4; adult, n = 3). RESULTS: Using dChip software for analysis, 217 probe sets for genes/38 expressed sequence tags (ESTs) were significantly higher and 345 probe sets for genes/33 ESTs significantly lower in beta cell-enriched cores of neonatal islets compared with those of adult islets. Among the genes lower in the neonatal beta cells were key metabolic genes including mitochondrial shuttles (malate dehydrogenase, glycerol-3-phosphate dehydrogenase and glutamate oxalacetate transaminase), pyruvate carboxylase and carnitine palmitoyl transferase 2. Differential expression of these enzyme genes was confirmed by quantitative PCR on RNA from isolated neonatal (P2 until P28) and adult islets and with immunostaining of pancreas. Even by 28 days of age some of these genes were still expressed at lower levels than in adults. CONCLUSIONS/INTERPRETATION: The lack of glucose responsiveness in neonatal islets is likely to be due to a generalised immaturity of the metabolic specialisation of pancreatic beta cells. PMID- 21240478 TI - Uptake and intracellular localization of submicron and nano-sized SiO2 particles in HeLa cells. AB - Engineered amorphous silica nanoparticles (SiO(2)-NPs) are widely used in dyes, varnishes, plastics and glue, as well as in pharmaceuticals, cosmetics and food. Novel composite SiO(2)-NPs are promising multifunctional devices and combine labels for subsequent tracking and are functionalized e.g. to specifically target cells to deliver their cargo. However, biological and potential toxic effects of SiO(2)-NPs are insufficiently understood. The aim of this study was to determine the uptake and fate of SiO(2)-NPs in mammalian cells. Also, silica submicron particles (SiO(2)-SMPs) were included in the studies in order to identify effects, which are only observed for nano-sized SiO(2) particles. Fluorescently labelled SiO(2)-NPs (nominal size 70 nm) and SiO(2)-SMPs (nominal size 200 and 500 nm) were used to examine cytotoxicity, cellular uptake and localization in human cervical carcinoma cells (HeLa). Particle uptake and intracellular localization in mitochondria, endosomes, lysosomes and nuclei were studied by wide field and confocal laser scanning fluorescence microscopy. Physicochemical characterization of SiO(2)-NPs by transmission electron microscopy and dynamic light scattering revealed a spherical morphology and a monodisperse size distribution. In the presence of serum, all SiO(2) particles are non-toxic. However, in the absence of serum SiO(2)-NPs but not SiO(2)-SMPs are highly toxic. SiO(2) particles, irrespective of size, were detected in the cytosol and accumulated in endosomal compartments of HeLa cells. No accumulation of SiO(2) particles in nuclei or mitochondria of HeLa cells could be observed. In contrast to SiO(2)-SMPs, SiO(2)-NPs are preferentially localized in lysosomes. PMID- 21240477 TI - Oleate-mediated activation of phospholipase D and mammalian target of rapamycin (mTOR) regulates proliferation and rapamycin sensitivity of hepatocarcinoma cells. AB - AIMS/HYPOTHESIS: A high-fat diet and obesity are associated with increased risk of liver cancer. Because increased delivery of NEFA to the liver occurs in these conditions, we investigated the involvement of the unsaturated fatty acid oleate in hepatocarcinoma cell proliferation using human-derived hepatocarcinoma cell lines as model systems. METHODS: Western blotting, FACS analysis and [(3)H]thymidine incorporation were used to study the signalling pathways and the proliferation of cells cultured for up to 72 h with or without a concentration of oleate considered to be relevant to human pathophysiology (50 MUmol/l) or a concentration considered elevated (1 mmol/l). RESULTS: In HepG2 cells, proliferation was increased in the presence of 50 MUmol/l oleate, but was decreased at 1 mmol/l. This differential effect was correlated with the activation of the mammalian target of rapamycin complex 1 (mTORC1) and with increased translation of cell cycle regulators. Oleate-mediated mTORC1 activation required phospholipase D activation, which produces phosphatidic acid and is known to render mTORC1 rapamycin resistant. Remarkably, rapamycin resistance was found to affect specifically the mTORC1/eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) branch of the mTORC1 pathway in the presence of 50 MUmol/l oleate. Furthermore, inhibition of phosphatidic acid production abolished oleate induced increases in mTORC1 activity and cyclin A production. Importantly, the same differential effects of oleate on mTORC1 activation, cell cycle regulators and rapamycin resistance were found in SK-Hep1 cells. CONCLUSIONS/INTERPRETATION: Oleate stimulates mTORC1 activation and rapamycin resistance. We propose that rapamycin-derived mTOR inhibitors are likely to be of limited therapeutic use to restrain hepatic tumour growth, particularly in the context of associated obesity. PMID- 21240479 TI - Purification and characterization of a cytotoxic neurotoxin-like protein from Naja haje haje venom that induces mitochondrial apoptosis pathway. AB - This study reported the purification and characterization of a cytotoxic, neurotoxin-like protein derived from the venom of the Egyptian cobra Naja haje haje, Elapidae family, and explored their mechanistic role in the cell death. The protein purification was performed through ion-exchange chromatography and gel filtration chromatography and was characterized by SDS-PAGE, amino acid sequencing, and mass spectrum analysis. The antitumor activity of Naja haje venom (NHV) and its fractions (NHVI, NHV-Ia, NHV-Ib, NHV-Ic, NHV-II, NHV-III, and NHV IV) were tested against different human cancer cell lines. The molecular cascade of cell death was explored through evaluation of apoptosis/necrosis ratio, DNA fragmentation, histone deacetylase (HDAC) activity, mitochondrial transmembrane potential (Deltapsi(m)), cytochrome c release, total caspases, caspase-3, caspase 9, and cell cycle analysis by flow cytometry. Most of the separated fractions possessed variable cytotoxic effect against different cancer cells. The most potent antitumor fraction was NHV-Ic due to its ability to induce DNA damaging and fragmentation that was associated with a significant induction of apoptosis via mitochondrial pathway and disturbed cell cycle phases as well as an inhibition of HDAC activity. NHV-Ic induced the mitochondrial pathway initially by the impairment of Deltapsi(m) besides the DNA damage and in response to that the mitochondria-released cytochrome c that may in turn activated total caspases, caspase-3 and caspase-9 in lymphoblastic leukemia 1301 cells. The partial amino acid sequencing of NHV-Ic revealed 100, 95.65, and 91.3% homology with the Long neurotoxin 1 from Naja haje anchietae (Angolan cobra), Naja haje haje (Egyptian cobra), and Boulengerina annulata annulata (banded water cobra), respectively. PMID- 21240480 TI - Comparative lung bioavailability of fluticasone/salmeterol via a breath-actuated spacer and conventional plastic spacers. AB - PURPOSE: This study compares the in vivo relative lung bioavailability of Hydrofluoroalkane (HFA) Seretide delivered via unprimed and unwashed Aerochamber Plus (AP) or Volumatic (VM) spacers, a integrated breath-actuated vortex Synchro Breathe (SB) device and an Evohaler pMDI (EH) device using adrenal suppression and early fall in serum potassium (K) as surrogates for respirable dose. METHODS: Seventeen healthy volunteers completed this randomised double-blind, double-dummy crossover study. Single doses of placebo/Seretide 250 (total dose ex valve fluticasone 2000 mcg/salmeterol 200 mcg) were administered via the devices. Overnight urinary cortisol/creatinine (OUCC) and serum K were measured at baseline and after each dose. RESULTS: Significant suppression of OUCC and K occurred from baseline with the SB, AP and VM but not with the EH devices. The geometric mean fold suppression (95% confidence interval, p) was: EH, 1.59 (0.80 3.14, p=0.40); AP, 4.26 (3.01-6.02, p<0.001); VM, 3.11 (1.99-4.78, p<0. 001); SB, 3.29 (2.04-5.24, p<0.001). For K, the arithmetic mean fall (mmol/l) (95% confidence interval; p) was: EH, -0.10 (-0.25-0.05, p=0.18); AP, -0.23 (-0.41 to 0.04, p=0.02); VM, -0.22 (-0.44 to -0.01, p=0.04); SB, -0.28 (-0.42 to -0.13, p=0.001). CONCLUSIONS: The breath-actuated SB device was comparable to 'out of the box' small and large volume spacers and produced similar improvements in relative systemic lung bioavailability for fluticasone and salmeterol. PMID- 21240481 TI - Medication incidents reported to an online incident reporting system. AB - AIMS: Approximately 20% of deaths from adverse events are related to medication incidents, costing the NHS an additional L500 million annually. Less than 5% of adverse events are reported. This study aims to assess the reporting rate of medication incidents in NHS facilities in the north east of Scotland, and to describe the types and outcomes of reported incidents among different services. Furthermore, we wished to quantify the proportion of reported incidents according to the reporters' profession. METHODS: A retrospective description was made of medication incidents reported to an online reporting system (DATIX) over a 46 month-period (July 2005 to April 2009). Reports originated from acute and community hospitals, mental health, and primary care facilities. RESULTS: Over the study period there were 2,666 incidents reported with a mean monthly reporting rate of 78.2/month (SD+/-16.9). 6.1% of all incidents resulted in harm, with insulin being the most commonly implicated medication. Nearly three-quarters (74.2%, n=1,978) of total incidents originated from acute hospitals. Administration incidents were implicated in the majority of the reported medication incidents (59%), followed by prescribing (10.8%) and dispensing (9.9%), while the nondescript "other medication incidents" accounted for 20.3% of total incidents. The majority of reports were made by nursing and midwifery staff (80%), with medical and dental professionals reporting the lowest number of incidents (n=56, 2%). CONCLUSIONS: The majority of medication incidents in this study were reported by nursing and midwifery staff, and were due to administration incidents. There is a clear need to elucidate the reasons for the limited contribution of the medical and dental professionals to reporting medication incidents. PMID- 21240482 TI - Distinctive responses of metabolically active microbiota to acidification in a thermophilic anaerobic digester. AB - Acidification is one of the most common and serious problems inducing process failure in anaerobic digesters. The production of volatile fatty acids (VFAs) mainly triggers acidic shock. However, little is known about the bacteria involved in the processes of acidogenic metabolism, such as fermentation and reductive acetogenesis. Here, the metabolic responses of a methanogenic community to the acidification and resulting process deterioration were investigated using transcriptional profiling of both the 16S rRNA and formyltetrahydrofolate synthetase (FTHFS) genes. The 16S rRNA-based analyses demonstrated that the dynamic shift of bacterial populations was closely correlated with reactor performance, especially with VFA accumulation levels. The pH drop accompanied by an increase in VFAs stimulated the metabolic activation of an uncultured Chloroflexi subphylum I bacterium. The subphylum has been characterized as a fermentative carbohydrate degrader using culture- and molecular-based ecophysiological assays. At the beginning of VFA accumulation, FTHFS genes were expressed; the transcripts were derived from phylogenetically predicted homoacetogens, suggesting that reductive acetogenesis was operated by hitherto unidentified bacteria. When acetate concentrations were high, the FTHFS expression ceased and Thermoanaerobacterium aciditolerans proliferated selectively. This thermoacidophilic bacterium would play a decisive role in acetate production via fermentative metabolism. The results of this study reveal for the first time that an uncultured Chloroflexi, T. aciditolerans, and novel homoacetogens were metabolically associated with acidic shock and subsequent VFA accumulation in an anaerobic digester. PMID- 21240483 TI - Quantitative assessment of MLAA-34 expression in diagnosis and prognosis of acute monocytic leukemia. AB - MLAA-34 is a newly identified monocytic leukemia-associated antigen. Previous data indicated that MLAA-34 might be a novel anti-apoptosis factor related closely to carcinogenesis or progression of acute monocytic leukemia. The over expression of MLAA-34 is intuitively expected to be associated with unfavorable clinical features in acute myeloid leukemia. However, there have been no clinical studies about the prognostic relevance of MLAA-34 expression in human malignancies. This study was done to investigate the clinical relevance of the expression of MLAA-34 in de novo acute myeloid leukemia. In 126 patients with de novo acute myeloid leukemia, the level of MLAA-34 expression and protein expression ratio were determined by using quantitative reverse transcriptase-PCR and western blot, respectively. The results were analyzed with respect to the patients' clinical features and treatment outcomes. Both MLAA-34 expression rates and expression levels were found to be higher in patients with the French American-British classification subtype M5, and the expression levels were also higher in patients with a leukocyte number of >= 20 * 10(9)/L and patients with extramedullary disease. In addition, MLAA-34 over-expression (>= median expression) was associated with an unfavorable day 7 response to induction chemotherapy and also associated with a poor survival rate. In multivariate analysis, high MLAA-34 levels was independently associated with a poorer relapse free survival and overall survival in AML patients. In conclusion, our data indicate that MLAA-34 may be used as a prognostic marker for treatment decision making in acute monocytic leukemia through validation by further studies. PMID- 21240484 TI - Suppression of T-cell responses by tumor metabolites. AB - Tumor cells have developed multiple mechanisms to escape T-cell-mediated immune recognition. Recent work has revealed that the altered tumor metabolism depletes essential nutrients or leads to the accumulation of immunosuppressive metabolites in the tumor microenvironment. In this review, we discuss the suppressive activity of some metabolic key players, which are upregulated in human tumor cells, including indolamine-2,3-dioxygenase (IDO), arginase, inducible nitric oxide synthetase (iNOS), and lactate dehydrogenase (LDH)-A, on the adaptive immune system. A better understanding of the impact of metabolic alterations of tumor cells on effector T-cell functions could lead to new therapeutic strategies to improve the efficacy of cancer immunotherapy. PMID- 21240485 TI - Immunocompetent cell functions in Ph+ acute lymphoblastic leukemia patients on prolonged Imatinib maintenance treatment. AB - Imatinib mesylate (Imatinib) is a potent inhibitor of defined tyrosine kinases and is effectively used for the treatment of malignancies characterized by the constitutive activation of these tyrosine kinases, such as Philadelphia chromosome-positive (Ph(+)) leukemias and gastrointestinal stromal tumors. Suppressive as well as stimulating effects of this drug on T lymphocytes or dendritic cells (DC), which play a major role in immune tumor surveillance, have been reported. For this reason, we questioned whether Imatinib could also affect the phenotypic and functional properties of these subpopulations in Ph(+) acute lymphoblastic leukemia (ALL) patients on prolonged Imatinib maintenance treatment. Circulating T lymphocytes and NK cells from Imatinib-treated Ph(+) ALL patients showed a subset distribution comparable to that of healthy donors. In addition, T-cell immunomodulant cytokine production (IFN-gamma, TNF-alpha) and proliferative responses were not impaired. A normal monocyte-derived DC differentiation and apoptotic body loading capacity was also observed in the majority of Imatinib-treated patients. In contrast, an impairment in the DC intracellular production of IL-12 was recorded, although this was not observed when normal DC were exposed in vitro to Imatinib. Finally, in vivo Imatinib treatment did not affect the T-lymphocyte proliferation and IFN-gamma production induced by leukemic apoptotic body-loaded DC, underling the potential capability of these cells to generate a specific immune response against tumoral antigens. Taken together, these findings provide evidence that immunotherapeutic approaches aimed at controlling residual disease in Ph(+) ALL patients in hematologic remission are not jeopardized by the long-term administration of Imatinib. PMID- 21240486 TI - Chemotherapy-resistant osteosarcoma is highly susceptible to IL-15-activated allogeneic and autologous NK cells. AB - High-grade osteosarcoma occurs predominantly in adolescents and young adults and has an overall survival rate of about 60%, despite chemotherapy and surgery. Therefore, novel treatment modalities are needed to prevent or treat recurrent disease. Natural killer (NK) cells are lymphocytes with cytotoxic activity toward virus-infected or malignant cells. We explored the feasibility of autologous and allogeneic NK cell-mediated therapies for chemotherapy-resistant and chemotherapy sensitive high-grade osteosarcoma. The expression by osteosarcoma cells of ligands for activating NK cell receptors was studied in vitro and in vivo, and their contribution to NK cell-mediated cytolysis was studied by specific antibody blockade. Chromium release cytotoxicity assays revealed chemotherapy-sensitive and chemotherapy-resistant osteosarcoma cell lines and osteosarcoma primary cultures to be sensitive to NK cell-mediated cytolysis. Cytolytic activity was strongly enhanced by IL-15 activation and was dependent on DNAM-1 and NKG2D pathways. Autologous and allogeneic activated NK cells lysed osteosarcoma primary cultures equally well. Osteosarcoma patient-derived NK cells were functionally and phenotypically unimpaired. In conclusion, osteosarcoma cells, including chemoresistant variants, are highly susceptible to lysis by IL-15-induced NK cells from both allogeneic and autologous origin. Our data support the exploitation of NK cells or NK cell-activating agents in patients with high-grade osteosarcoma. PMID- 21240487 TI - Targeting NKT cells and PD-L1 pathway results in augmented anti-tumor responses in a melanoma model. AB - Invariant or Type 1 NKT cells (iNKT cells) are a unique population of lymphocytes that share characteristics of T cells and natural killer (NK) cells. Various studies have shown that positive costimulatory pathways such as the CD28 and CD40 pathways can influence the expansion and cytokine production by iNKT cells. However, little is understood about the regulation of iNKT cells by negative costimulatory pathways. Here, we show that in vivo activation with alpha-GalCer results in increased cytokine production and expansion of iNKT cells in the absence of programmed cell death ligand-1 (PD-L1, B7-H1, and CD274). To study whether PD-L1 deficiency on NKT cells would enhance antigen-specific T-cell responses, we utilized CD8(+) OT-1 OVA transgenic T cells. alpha-GalCer enhanced the expansion and cytokine production of OT-1 CD8(+) cells after adoptive transfer into wild-type recipients. However, this expansion was significantly enhanced when OT-1 CD8(+) T cells were adoptively transferred into PD-L1(-/-) recipients. To extend these results to a tumor model, we used the B16 melanoma system. PD-L1(-/-) mice given dendritic cells loaded with antigen and alpha GalCer had a significant reduction in tumor growth and this was associated with increased trafficking of antigen-presenting cells and CD8(+) T cells to the tumors. These data demonstrate that abrogating PDL1:PD-1 interactions during the activation of iNKT cells amplifies an anti-tumor response when coupled with DC vaccination. PMID- 21240488 TI - Reduced tumorigenesis of EG7 after interleukin-10 gene transfer and enhanced efficacy in combination with intratumorally injection of adenovirus-mediated lymphotactin and the underlying mechanism. AB - Although interleukin-10 (IL-10) is commonly regarded as an immunosuppressive cytokine, a wealth of evidence is accumulating that IL-10 also possesses some immunostimulating antitumor properties. Previous studies demonstrated that forced expression of the IL-10 gene in tumor cells could unexpectedly produce antitumor effects. In this study, we explored the tumorigenesis of EG7 cells transduced with IL-10 gene. In vivo, IL-10 gene transfer reduced tumorigenic capacity of EG7 cells and prolonged survival of the EG7 tumor-bearing mice. It was found that the cytotoxicities of cytotoxic T lymphocytes (CTL) and natural killer cells (NK cells) were enhanced. Assessment of the immune status of the animals showed prevalence of a systemic and tumor-specific Th2 response (high levels of IL-4 and IL-10). To improve the therapeutic efficacy, we combined with intratumoral injection of adenovirus-mediated lymphotactin (Ad-Lptn) into the overestablished EG7 tumor model. More significant inhibition of tumor growth were observed in EG7 tumor-bearing mice that received combined treatment with IL-10 and Lptn gene than those of mice treated with IL-10 or Lptn gene alone. The highest NK cells and CTL activity was induced in the combined therapy group, increasing the production of IL-2 and interferon-gamma (IFN-gamma) significantly but decreasing the expression of immune suppressive cells (CD4(+)Foxp3(+) Treg cells and Gr1(+)CD11b(+) MDSCs). The necrosis of tumor cells was markedly observed in the tumor tissues, accompanying with strongest expression of Mig (monokine induced by interferon gamma) and IP-10 (interferon-inducible protein 10), weakest expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinases-2 (MMP 2). In vivo, depletion analysis demonstrated that CD8(+) T cells and NK cells were the predominant effector cell subset responsible for the antitumor effect of IL-10 or Lptn gene. These findings may provide a potential strategy to improve the antitumor efficacy of IL-10 and Lptn. PMID- 21240490 TI - Long-term response after 6-year treatment with anakinra and onset of focal bone erosion in neonatal-onset multisystem inflammatory disease (NOMID/CINCA). AB - The exact elucidation of skeletal and cartilagineous involvement in neonatal onset multisystem inflammatory disease (NOMID) is still poorly known, and there are few data providing the long-term response to treatment with the available interleukin-1 inhibitors. We present here a 13-year-old boy with NOMID treated with anakinra and low-dose methylprednisolone since he was 7 years old for an overall period of 6 years. Every clinical manifestation was highly responsive to interleukin-1 blockade, with the exception of his bone abnormalities. At the comparison of radiography and magnetic resonance imaging of his knees made respectively at 7 and 13 years, we noticed a bone erosion on the posterior surface of the patella combined with the progression of distal femoral overgrowth and endosteal thinning of both meta-epiphyses. This report must encourage clinicians in a precocious institution of interleukin-1 antagonists to thwart the occurrence of irreversible bone changes. PMID- 21240491 TI - Hypertrichosis after surgery for cubital tunnel syndrome. PMID- 21240489 TI - Heterotopic ossifications following implant surgery--epidemiology, therapeutical approaches and current concepts. AB - The pathophysiology of heterotopic ossification (HO) is still ill-understood. Several risk factors such as osteoarthritis, male gender and injury patterns like traumatic brain injury and severe soft tissue damage have been described. Furthermore, the pathophysiology of local and systemic factors has been investigated leading to an extended knowledge especially on the molecular level. Knowledge of the involved cell types and mediators led to the now widely used prophylactic and therapeutic strategies to prevent heterotopic ossifications. Out of these findings, the beneficial effects of NSAIDs and radiotherapy on HO prophylaxis have been proven for a number of indications such as total hip arthroplasty and acetabular surgery. However, there is little information about the potential effects on heterotopic ossifications around the elbow. Surgical treatment may be considered in some cases, but there are only limited indications. Generally, only clinically relevant bone formations should be resected. Following surgical resection, beneficial effects on range of motion and pain relief has been described. An accurate perioperative regimen is crucial and includes prophylactic medication. In combination with radiotherapy, low recurrence rates were described but there are still controversies about the optimal timing for surgical resection. PMID- 21240492 TI - Young males with primary lymphoma of bone presenting with musculoskeletal pain are prone to be misdiagnosed as ankylosing spondylitis: a case report. AB - Primary lymphoma of bone (PLB) is an uncommon clinical entity. Pain in the skeleton and pelvis is a frequent complaint which may be partly relieved by nonsteroidal anti-inflammatory drugs. So, the patients suffering from PLB are easily referred to the rheumatologist and often be misdiagnosed as rheumatic diseases. Here, we described a case of PLB presenting with rheumatic pain. PMID- 21240493 TI - Pilot study: possible association of IL10 promoter polymorphisms with CRMO. PMID- 21240494 TI - Successful treatment of sepsis-induced disseminated intravascular coagulation in a patient with idiopathic thrombocytopenic purpura using recombinant human soluble thrombomodulin. AB - Disseminated intravascular coagulation (DIC) may complicate a variety of disorders that contribute to mortality, particularly those related to bleeding. It is therefore very difficult to manage DIC in patients with known bleeding disorders. We treated a 62-year-old woman with idiopathic thrombocytopenic purpura (ITP) complicated with sepsis-induced DIC. She had been diagnosed with ITP 8 months prior to admission. Laboratory tests showed an elevation of d-dimer and endotoxin, while pyelonephritis was shown by abdominal computed tomography. Escherichia coli was detected by blood culture. Based on these findings, the patient was diagnosed with sepsis-induced DIC due to urinary tract infection. Thrombocytopenia was refractory despite the use of antibiotics and platelet transfusion, but it was promptly improved in response to recombinant human soluble thrombomodulin (rTM). We suggest that rTM provides a new therapeutic strategy for DIC patients with high hemorrhagic risk. PMID- 21240495 TI - "Heterozygous versus homozygous" should be applied for complex diseases. PMID- 21240496 TI - Association between circulatory levels of vitamin D and radiographic hand osteoarthritis. AB - The aim is to evaluate the association between the serum level of vitamin D and prevalence and severity of radiographic hand OA. The study population comprised Chuvashians (91 men with a mean age of 46.24 (20-75) and 99 women with a mean age of 44.94 (18-74)). OA was evaluated for 14 joints of each hand using Kellgren and Lawrence's (K-L) scoring method and osteophytes (OS) scores. The following four outcomes were used: two indices of the number of affected joints (Num-KL and Num OS) representing severity of hand OA and two indices of the presence of at least one affected joint (dichotomous indices) (Dich-KL and Dich-OS). Vitamin D (25(OH)D) level was assessed by radioimmunoassay. Statistical analyses included multiple linear and logistic regressions and one-way ANOVA. Linear regression models showed no significant association between the circulating levels of vitamin D and Num-KL (P = 0.781) or Num-OS (P = 0.338). The logistic regression models showed similar results: Dich-KL: (0.935 (0.864, 1.011), P = 0.093) and Dich-OS: (0.966 (0.896, 1.043), P = 0.378). Results of one-way ANOVA showed no differences in age, sex, and BMI-adjusted Num-KL between individuals with normal levels of vitamin D and those with a vitamin D deficiency (F = 0.023, P = 0.878). Similar results were received when adjusted Num-OS scores were compared (F = 1.553, P = 0.214). After adjustment for age, sex, and BMI, no association was found between the serum level of vitamin D and prevalence and severity of radiographic hand OA evaluated using K-L or osteophyte scores. PMID- 21240497 TI - Interleukin 8 gene 2767 A/G polymorphism is associated with increased risk of nephritis in children with Henoch-Schonlein purpura. AB - The objective of this study is to investigate the association between IL-8 gene 2767 G/A polymorphism and clinical features, kidney involvement and prognosis in childhood Henoch Schnolein purpura (HSP). A total of 115 patients with HSP (59 male, 56 female) were included in the study with age at diagnosis between 2 and 17 years (8.0 +/- 3.0). Hundred and eight healthy adults were included in the study as controls. The patients had been followed up for kidney involvement for at least 6 months and in average 8.2 +/- 7.5 months. Interleukin 8 (IL-8) gene 2767 G/A polymorphism was studied by PCR-RFLP method. Frequency of the "A" allele was 0.37 in the patient group, whereas it was 0.36 in the control group. The difference was not statistically significant (P = 0.696). No association was detected between the IL-8 gene G/A polymorphism and the clinical, laboratory, and demographic data related to the patients with HSP. Kidney involvement was more common in those with the G/A polymorphism of the IL-8 gene. While a 0.44 frequency of the "A" allele was detected in those with kidney involvement, this rate was 0.29 in those with no kidney involvement (P = 0.046). Follow-up of those with the "A" allele revealed higher proteinuria (P = 0.023, odds ratio 0.176, 95% CI 0.034-0.917) and higher creatinine levels (P = 0.049, odds ratio 0.024, 95% CI 0.036-0.094). These results suggest that the kidney involvement is more common in patients with the "A" allele, and degree of proteinuria and creatinine levels is higher in these patients at follow-up. PMID- 21240498 TI - Lack of association between plasminogen activator inhibitor type-1 (PAI-1) gene 4G/5G polymorphism and osteoarthritis. AB - This study was conducted in Turkish osteoarthritis patients to determine the frequency of 4G/5G polymorphism genotypes of plasminogen activator inhibitor type 1 gene and to examine the role of this polymorphism in osteoarthritis development. Genomic DNA obtained from 200 persons (140 patients with osteoarthritis and 60 healthy controls) was used in the study. DNA was amplified by polymerase chain reaction using 4G allele- and 5G allele-specific primers. Polymerase chain reaction products were assessed with CCD camera by being exposed to 2% agarose gel electrophoresis. No statistically significant difference between the groups with respect to genotype distribution was found (P > 0.05) in the study. The 4G allele frequency was indicated as 44% and 5G allele was as 56% in patients, whereas this was 45-55% in the control group. This study has established that 4G/5G polymorphism genotypes of plasminogen activator inhibitor type-1 gene do not play a role in the development of osteoarthritis in the Turkish population. PMID- 21240499 TI - Beta2-glycoprotein I gene polymorphisms Val247Leu and Trp316Ser in Spanish patients with primary antiphospholipid syndrome. AB - The significance of beta2-glycoprotein I (beta2GPI) polymorphisms in the production of anti-beta2GPI and other antiphospholipid autoantibodies (aPL) and in the pathogenesis of primary antiphospholipid syndrome (PAPS) is not well understood. We performed a study comparing the distribution of polymorphisms at codons 247 (Val247Leu) and 316 (Trp316Ser) of the beta2GPI gene in a Caucasian Spanish population of PAPS patients and healthy controls, and then making correlations with the development of anti-beta2GPI antibodies and other aPL and associated clinical manifestations. A total of 57 PAPS patients and 100 control subjects were included. In the analysis of Val247Leu polymorphism, alleles (V and L) and genotypes (V/V, V/L, L/L) were similarly distributed in PAPS patients and controls (P = 0.66 and P = 0.22, respectively). Regarding Trp316Ser polymorphism, we found a higher percentage of patients with respect to controls expressing S allele (11.4 vs. 5%, P = 0.02) and T/S genotype (22.8 vs. 10%, P = 0.02). However, when we compared T/T and T/S genotypes in PAPS patients, we found no differences regarding generation of anti-beta2GPI, other aPL and clinical manifestations favoring any genotype. Our findings suggest that among Spanish Caucasians, polymorphisms at codon 247 (Val247Leu) do not seem to influence PAPS pathogenesis. On the contrary, polymorphisms at codon 316 (Trp316Ser), by means of an increased S allele and T/S genotype presence in Spanish Caucasian patients, might play a role in the pathogenic development of PAPS, although mechanism would not involve an increased production of anti-beta2GPI and other aPL. PMID- 21240500 TI - Association between clinical parameters and amyloid-positive area in gastroduodenal biopsy in reactive amyloidosis associated with rheumatoid arthritis. AB - Our study was aimed to clarify an association between gastrointestinal (GI) amyloid-positive area and various kinds of factors including renal function in reactive amyloidosis associated with rheumatoid arthritis (RA). Twenty-five patients with an established diagnosis of reactive AA amyloidosis participated in the study between January 1989 and December 2009. Each patient satisfied the 1987 American Rheumatism Association criteria for RA. All patients showed amyloid deposits in both of GI and renal tissues. The average amyloid-deposited area was 2.2% in renal tissues and 3.7% in GI tissues although the difference was not statistically significant. Twenty-two patients out of 25 patients showed less than 5% of amyloidosis in renal tissues and nineteen patients showed 5% of amyloidosis in GI tissues. In 5 out of a total of 25 cases, the amyloid-deposited area in GI tissues was lesser than that in renal tissues. Mesangial proliferative glomerulonephritis, thin basement membrane disease (TBMD) and membranous nephropathy were frequently combined with renal amyloidosis. For statistical analyses, renal and GI tissues of % amyloid-positive areas were transformed to common logarithmic values (Log(10)%amyloid), since the histograms showed log normal distribution. Clinical data were assessed by patient record at the time of GI biopsy. The correlation between Log(10)%GI-amyloid and age, creatinine (Cr), creatinine clearance (Ccr), blood urea nitrogen (BUN), and estimated glomerular filtration rate (eGFR) were not significantly associated with Log(10)%GI-amyloid in crude correlation analyses and also in sex- and age-adjusted linear regression analyses. Although GI biopsy was not correlated with clinical factors, GI amyloid positive areas were larger than renal amyloid-positive areas. Endoscopic screening of the upper GI tract is common in Japan, and amyloid-deposited area in GI tissues was sufficient to use for the diagnosis of amyloidosis compared with renal tissues in terms of convenience and sensitivity. PMID- 21240501 TI - Anxious personality is a risk factor for developing complex regional pain syndrome type I. AB - The aim of this study was to investigate the role of psychological factors in the development of complex regional pain syndrome (CRPS) type I following the fracture of the distal radius. Fifty patients (average age 57.70 +/- 13.43 years) with a distal radius fracture were enrolled in the present study. All of the patients were treated by closed reduction and cast immobilization. The Toronto Alexithymia Scale-20, Anxiety Sensitivity Index, State-Trait Anxiety Inventory, and Beck Depression Inventory were used to determine the patients' psychological features 2 days after the fracture. The patients were followed for 2 months after cast immobilization was completed using the International Association for the Study of Pain criteria to diagnose CRPS type I. CRPS type I developed in 13 (26%) patients of the 32 (34.4%) female patients and 18 (11.1%) male patients. The risk of CRPS type I was significantly increased in patients with high trait anxiety scores (P = 0.038). The results show that, after fracturing the distal radius, patients who have an anxious personality have a higher risk of developing CRPS type I. Following these patients closely for the development of CRPS type I may be advantageous for early preventative and therapeutic interventions. PMID- 21240502 TI - Greek NHS capacity constraints regarding intravenous treatment for rheumatoid arthritis patients. AB - Intravenous (iv) infusion of biologic agents is a highly effective therapeutic option for active rheumatoid arthritis (RA). In Greece, it is mandatory that all infusions are administered in a hospital setting; therefore, they are strongly correlated with the system's capacity in terms of resources. The objective of this paper was to assess the capacity of the Greek National Health System (NHS) hospitals to meet current/projected demand for iv treatment of RA patients. Semi qualitative interviews on the basis of a strictly structured questionnaire were conducted with the Heads of all NHS RA infusion sites to record available resources, service utilization and ability to meet current/projected demand. Out of 31 NHS infusion sites, 28 responded (90.3%). On average, 41.6% of Greek NHS RA patients are treated with a biologic agent and 61.5% of respondents stated that available resources are insufficient to meet current demand. The most important constraints in selection order were as follows: space (93%), staff (89.5%), equipment (61.5%) and working hours (57%). Fifty-six percent of respondents stated that they may decline treatment to patients due to constraints. Overall, respondents estimated that the number of iv patients could be increased by 104%, were there no capacity constraints. An important proportion of the estimated 40.000 RA patients in Greece, for whom iv biologic treatment in the hospital setting is essential for disease control, may be declined treatment due to constraints in RA-specific resources. Rationalization and reallocation of NHS resources is required to ensure equity in access to effective treatment for all RA patients. PMID- 21240503 TI - Treatment of refractory adult-onset Still's disease with tocilizumab: report of two cases and review of the literature. AB - Adult-onset Still's disease (AOSD) is empirically treated with nonsteroidal anti inflammatory drugs, corticosteroids, conventional disease-modifying antirheumatic drugs, tumor necrosis factor-blocking agents or anakinra. The monoclonal anti interleukin (IL)-6 antibody tocilicumab (TOC) has recently been approved for the treatment of rheumatoid arthritis and may be an attractive therapeutic option for AOSD as well. We report two AOSD patients treated with TOC and review of the current data on the use of TOC in AOSD. TOC was applied to the first patient after failure of cloroquin, methotrexate, adalimumab and etanercept. The second patient received TOC because of inefficacious methotrexate treatment. TOC was well tolerated by both the patients, and no clinically significant side effects occurred. Including these two cases, a total of seven AOSD patients have been successfully treated with TOC so far. TOC may be a promising treatment option for AOSD patients refractory to conventional disease-modifying antirheumatic drugs anakinra and tumor necrosis factor-[Formula: see text]. PMID- 21240504 TI - The ossification diathesis in the Medici family: DISH and other features. AB - The Medici family ruled Florence for most of the period from the 1430s to the 1730s, with the senior (primogenito) branch predominating until the line ended in the 1530s and the cadet (secondogenito) branch predominating thereafter. Recent studies have identified a familial syndrome consisting of cutaneous symptoms, peripheral arthropathy and spinal ankylosis in the primogenito branch of the family, and the presence of diffuse idiopathic skeletal hyperostosis (DISH) in two members of the secondogenito branch. These findings raise the question of whether DISH was also a component of the primogenito familial syndrome. The present study provides a further specification of the ossification diathesis in the familial syndrome of the primogenito branch of the Medici family. Recently discovered photographs of exhumed Medici skeletons from the primogenito line are examined, with a focus on spinal, sacro-iliac and peripheral ossifications. These observations are supplemented with published reports of radiological, histological and macroscopic studies of the skeletons. Our interpretations of the ossification data relating to the primogenito branch of the Medici family are supportive of a diagnosis of DISH. DISH was one component of the triple pathology identified as a syndrome in the fifteenth century primogenito Medici line. As a diagnosis of DISH has recently been proposed for two sixteenth century members of the secondogenito branch of the family, it appears that the same condition affected both branches of the Medici lineage, without excluding other forms of undifferentiated joint and spondylarthropathies. PMID- 21240505 TI - Does the greater number of lymph nodes removed during standard lymph node dissection predict better patient survival following radical cystectomy? AB - PURPOSE: To determine whether the number of lymph nodes (LNs) removed during radical cystectomy (RC) and pelvic LN dissection (LND) is associated with patient survival. METHODS: Data on 450 patients who underwent RC and standard bilateral pelvic LND for urothelial bladder cancer without receiving neoadjuvant chemotherapy were reviewed. The extent of LND included common iliac artery bifurcation proximally, genitofemoral nerve laterally and the pelvic floor caudally. The impact of the number of LNs removed, analyzed as both continuous and categorical variables, on cancer-specific survival (CSS) and recurrence-free survival (RFS) was analyzed. RESULTS: The median number of LNs removed was 18 (mean 19.6, range 10-94). Of total 450 patients, 129 (28.7%) had node-positive (N +) disease. For entire patients, the number of LNs removed was not associated with CSS and RFS in the analysis with continuous variable (P = 0.715; P = 0.442, respectively), quartiles (P = 0.924; P = 0.676, respectively), or <18 versus >=18 LNs removed (5-year CSS rates: 67.0% vs. 69.4%, P = 0.679; 5-year RFS rates = 59.4% vs. 60.6%, P = 0.725, respectively). Similarly, the number of LNs removed was not associated with CSS and RFS in both N0 and N + patients, and in each T stage. Multivariate analyses showed that T stage and lymphovascular invasion were significant predictors for survival in N0 patients, whereas adjuvant chemotherapy and LN density were predictors for survival in N + patients. CONCLUSIONS: If meticulous LND was performed based on standardized LND template during RC, the number of LNs removed was not associated with patient survival. PMID- 21240506 TI - Prognostic relevance of number and bilaterality of positive surgical margins after radical prostatectomy. AB - PURPOSE: Positive surgical margin (PSM) status following radical prostatectomy (RP) is a well-established prognostic factor. The aim of the present study is to evaluate whether number of PSMs or bilaterality of PSMs might have prognostic significance for biochemical recurrence (BCR) in the population with a PSM status following RP. METHODS: We evaluated 1,395 RP pathology reports from our center between 1980 and 2006. All patients who underwent (neo)-adjuvant therapy were excluded, leaving a cohort of 1,009 patients, with 249 (24.7%) subjects having a PSM at RP of whom 29.4% had multiple PSMs (>= 2 sites), while 13.6% had bilateral PSMs. Median follow-up was 40 months (range 0-258 months). We used BCR-free survival as the primary study outcome. BCR was defined as any rise in PSA above or equal to 0.2 ng/ml. RESULTS: Of patients with a PSM status, 41% (95% CI: 33 49%) developed BCR within 5 years, compared to 12% (95% CI: 9-15%) in the population without a PSM. Multivariable analysis identified PSA at diagnosis and RP Gleason score as independent predictive factors for BCR. Increasing number and/or bilaterality of PSM did not lead to significant higher rates of BCR. CONCLUSION: In patients with a PSM, the number of positive sites or bilaterality of PSM status does not add prognostic information for risk of BCR. Survival curve slopes were different for patients with bilateral PSM, showing a significant tendency to progress to BCR earlier during follow-up than patients with unilateral PSM. PMID- 21240507 TI - Coronary sinus ostium: the key structure in the heart's anatomy from the electrophysiologist's point of view. AB - There are no research studies that comprehensively analyze, with computed tomography, the coronary sinus (CS) ostium with respect to its importance for some electrophysiological procedures paying special attention to the Thebesian valve (ThebV). Our aim was to evaluate the characteristic features of the CS anatomy, which can be useful for electrophysiologists using multislice computed tomography (MSCT). An additional aim was to create a tomographic classification of ThebV types. Included into the study were 150 patients (aged 59.7 +/- 11.4; 105M) (43 with heart failure). Due to the suspicion of coronary artery disease, 64-slice MSCT (Toshiba, Aquilion 64) was performed in all patients. All measurements and the search for the ThebV were performed on multiplanar reconstructions in axial projection at 0.5-mm slice thickness. The average diameter of CS ostium was 14.2 +/- 3.5 mm and the angle of entrance of the CS to the right atrium was 112 degrees +/- 11 degrees . Seven variants of the ThebV were introduced and six of them were confirmed in this group. The following frequency of variants of ThebV was confirmed: E, 11.3%; D, 10.6%; A1, 8.7%; A2, 7.4%; C, 6.0%; B2, 2.0%. A statistically significant correlation between age and the size of CS ostium was found (r = 0.25; p < 0.05). It is possible to visualize and evaluate the CS including measurements and ThebV evaluation in MSCT. Six anatomical variants of the valve were found. MSCT can potentially provide valuable knowledge before the CS cannulation. PMID- 21240508 TI - Influence of fastigial nucleus stimulation on heart rate variability of surgically induced myocardial infarction rats: fastigial nucleus stimulation and autonomous nerve activity. AB - Electrical stimulation of the rostal cerebellar fastigial nucleus (FNS) has been proved to have neuroprotective effects, but it is not known whether FNS also has a cardioprotective effect. One hundred Sprague-Dawley rats were randomly allocated into four groups, including a sham-operation group (Sham group), rats whose coronary arteries were ligated but the FNs were sham stimulated (AMI group), rats in which both coronary arteries were ligated and FNs were stimulated (FNS group), and rats whose fastigial nuclei were lesioned 5 days before ligation, then their coronary arteries were ligated and FNs were stimulated (FNL group). Heart rate variability parameters were monitored 6 h, 24 h, 7 days and 21 days after ligation, and mortality rates, hemodynamic parameters and infarction sizes were compared after 21 days. FNS improved the survival of rats, and this may be due to the increased vagal and decreased sympathetic tone. FN stimulation does not affect infarction size and hemodynamic parameters. FN stimulation may have a protective effect on surgically induced myocardial infarction rats. PMID- 21240509 TI - Video-assisted microsurgical transoral approach to the craniovertebral junction: personal experience in childhood. AB - PURPOSE: This paper outlines the perspectives of transoral craniosurgery for anterior craniovertebral junction (CVJ) compressive abnormalities in the specific subset of paediatric patients. In particular we analyzed the opportunity for endoscopic video-assisted approach to the CVJ along with neuronavigation for anterior decompression by the transoral approach in paediatric patients. METHODS: Among 30 patients ranging 6-78 years undergoing CVJ decompressive procedures, we operated transorally 3 paediatric patients (ranging 11-15 years) by using open access, microsurgical technique, neuronavigation, and endoscopy. RESULTS: The microscope was the main stone of the transoral procedure; a complete CVJ decompression was accomplished in all the cases by using the 30-degree endoscope that allowed to identify residual compression not clearly visible by using the microscope alone. The use of an angled-lens endoscope can significantly improve the exposure of the clivus without splitting the soft palate. CONCLUSIONS: Endoscopically assisted transoral surgery represents an emerging alternative to the standard microsurgical approach to the anterior CVJ. Used in conjunction with traditional microsurgery and intraoperative fluoroscopy, endoscopy provides information for a better decompression with a reduced need for extensive soft palate splitting, no need for hard-palate resection, or extended maxillotomy. Transoral video-assisted microsurgical approach should be considered the gold standard especially in the paediatric patient. PMID- 21240510 TI - The oculomotor nerve: anatomic relationship with the floor of the third ventricle. AB - PURPOSE: Endoscopic third ventriculostomy (ETV) has become first-line treatment for obstructive hydrocephalus. Many complications have been described, but the literature about oculomotor palsy after ETV is scarce. Therefore we undertook an anatomical study of the relationship of the oculomotor nerve to the floor of the third ventricle. METHODS: Distances and angles between the third nerve and the bottom of the third ventricle were studied both in two cadaver heads and in high definition CISS images in 16 MRI scans. The angles of the trajectories putting the nerve at risk or not were compared. Finally, in a retrospective analysis of intraoperative images the appearance of the membranous portion of the floor was defined and if visible, the distance of the third nerve to the midline was estimated by comparing with the 8-mm balloon catheter. RESULTS: The course of the third nerve is approximately 8 mm laterally and approximately 17 mm caudally distant from the midpoint of the floor of the third ventricle. The angle of the trajectory to damage the third nerve is at least 12 degrees greater than any safe angle of ETV trajectory through a normal burr hole. CONCLUSIONS: The third nerve is not always visible during ETV procedures, but the angular and linear measurements imply that the risk to damage the nerve should be relatively small. Confirmation of these data in hydrocephalic patients with distorted anatomy is needed. PMID- 21240511 TI - Atopic dermatitis in dogs is associated with a high heterogeneity in the distribution of protein-bound lipids within the stratum corneum. AB - The stratum corneum (SC) was taken from five atopic dogs by tape stripping (12 strips) of non-lesional areas of the abdomen. The free and protein-bound lipids were extracted and analyzed by thin-layer chromatography after fractionation on aminopropyl-bonded silica gel columns. A very frequent feature was the heterogeneity in the lipid content of consecutive layers. This was even more accentuated for the covalently bound lipids, with variations from one layer to another in the concentrations of cholesterol, omega hydroxylated ceramides and omega hydroxylated long-chain fatty acids. Among the free lipids, large amounts of glucosylceramides were present in canine atopic SC although they are nearly absent from the SC of normal dogs. A heterogeneous distribution of lipids was seen in canine atopic SC. These results suggest that strikingly deep variations occur in the lipid metabolism of keratinocytes in the skin of atopic dogs. In order to gain insight into this phenomenon, further studies should be focused on the activity of enzymes involved in both biosynthetic and catabolic processes. PMID- 21240512 TI - Breast tumor kinase (Brk/PTK6) plays a role in the differentiation of primary keratinocytes. AB - Breast Tumor Kinase (Brk/PTK6) has a relatively limited expression profile in normal tissue. Its expression is restricted to epithelial cells that are differentiating such as those in the epidermis, and Brk expression appears to be absent from proliferating cells in normal tissue. Also, there is now some evidence to suggest that Brk plays a functional role in the differentiation of the keratinocytes in the epidermis. We have, therefore, investigated the role that Brk/PTK6 plays in normal human primary keratinocytes by suppressing protein levels using RNA interference. We show that as primary human keratinocytes are induced to differentiate in vitro, Brk levels decrease. Decreasing Brk protein levels lead to an increase in the number of cells with a permeable plasma membrane, a decrease in epidermal growth factor receptor (EGFR) and a parallel increase in keratin 10 levels, but classical markers of apoptosis or terminal differentiation are not affected. We propose Brk, Keratin 10 and EGFR are co regulated during differentiation and that manipulating Brk expression can influence the differentiation of normal primary human keratinocytes. PMID- 21240513 TI - Asiaticoside suppresses collagen expression and TGF-beta/Smad signaling through inducing Smad7 and inhibiting TGF-betaRI and TGF-betaRII in keloid fibroblasts. AB - Asiaticoside (ATS) isolated from the leaves of Centella asiatica possesses strong wound-healing properties and reduces scar formation. However, the specific effects of asiaticoside on the formation of keloidal scars remain unknown. In the present study, we evaluated the in vitro effects of asiaticoside on the proliferation, collagen expression, and transforming growth factor (TGF) beta/Smad signaling of keloid-derived fibroblasts. Fibroblasts isolated from keloid tissue and normal skin tissues were treated with asiaticoside at different concentrations. Afterwards, they were subjected to RT-PCR and Western blot analyses. The inhibitory effects of asiaticoside on fibroblast viability were assayed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Asiaticoside decreased fibroblast proliferation in a time- and dose dependent manner. It also inhibited type I and type III collagen protein and mRNA expressions. In addition, asiaticoside reduced the expression of both TGF-betaRI and TGF-betaRII at the transcriptional and translational level. Moreover, it increased the expression of Smad7 protein and mRNA. However, asiaticoside did not influence the expression of Smad2, Smad3, Smad4, phosphorylated Smad2, and phosphorylated Smad3. Taken together, these results suggest that asiaticoside could be of potential use in the treatment and/or prevention of hypertrophic scars and keloids. PMID- 21240514 TI - Isolation and identification of a distinct side population cancer cells in the human epidermal squamous cancer cell line A431. AB - Side population (SP) cells have been suggested to be multipotent cancer stem cells. To address whether SP cells exist in epidermal squamous cancer cell line A431, A431 cells dyed with Hoechst 33342 were sorted through flow cytometry. The SP cells were then analyzed by colony-forming and cell proliferation assay. Further, tumorigenicity and microarray analysis were used to compare biological difference between SP and non-SP (NSP) cells. Our results showed that SP cells existed in the A431 cell line, showing higher proliferating and colony-forming ability than NSP cells. Tumors generated from SP cells were larger than those from the NSP cells in NOD/SCID mice. The mRNA microarray profiling revealed that five cancer marker gene expressions were up-regulated and one tumor suppressor gene expression was down-regulated. These findings suggest that SP cells in A431 could contribute to self-renewal, neoplastic transformation, and cancer metastasis of human epidermal squamous cell carcinoma. PMID- 21240515 TI - Relationships between metastasis-associated protein (MTA) 1 and lymphatic metastasis in tonsil cancer. AB - We evaluated immunohistochemically the expression profiles of metastasis associated protein (MTA) 1 and their associations with lymph node metastasis in tonsil cancer. Immunohistochemical analysis of 43 tonsillar neoplasm tissues was performed using antibodies raised to MTA1. Depth of tumor invasion, lymph node metastasis, and clinical outcomes were assessed. Clinical N0 patients were divided into two groups: N0a, negative for MTA1; N0b, positive for MTA1. Occult node metastasis was reevaluated according to the revised clinical N staging system taking account of MTA1 expression. The expression rate of MTA1 was 41.9%. There was a significant correlation between the expression of MTA1 and lymph node metastasis (P = 0.034*). MTA1 had a sensitivity of 53.3% and a specificity of 84.6% for identification of cervical metastases. When cN0b patients were considered to be N+, the recalculated rate of occult metastasis fell from 50% to 7.6% (the false-positive rate remained unchanged). MTA1 was found to be a useful molecular marker to predict lymphatic metastasis in tonsil cancer. PMID- 21240516 TI - The cadherin-catenin complex in nasopharyngeal carcinoma. AB - Abnormal Wnt signaling and impaired cell-cell adhesion due to abnormal E-cadherin and beta-catenin function have been implicated in many cancers, but have not been fully explored in nasopharyngeal carcinoma. The aim of this study was to analyze beta-Catenin cellular location and E-cadherin expression levels in nasopharyngeal carcinoma. E-cadherin expression levels were also correlated with clinical data and underlying pathology. beta-Catenin and E-cadherin expression were examined in 18 nasopharyngeal carcinoma and 7 non-tumoral inflammatory pharynx tissues using immunohistochemical methods. Patient clinical data were collected, and histological evaluation was performed by hematoxylin/eosin staining. beta-catenin was detected in membrane and cytoplasm in all cases of nasopharyngeal carcinoma, regardless of histological type; in non-tumoral tissues, however, beta-catenin was observed only in the membrane. As for E-cadherin expression levels, strong staining was observed in most non-tumoral tissues, but staining was only moderate in nasopharyngeal carcinoma tissues. E-cadherin expression was associated with beta-catenin localization, study group, metastatic disease, and patient outcomes. Reduced levels of E-cadherin protein observed in nasopharyngeal carinoma may play an important role in invasion and metastasis. Cytoplasmic beta-catenin in nasopharyngeal carcinoma may impair cell-cell adhesion, promoting invasive behavior and a metastatic tumor phenotype. PMID- 21240517 TI - Volume reduction in subcortical regions according to severity of Alzheimer's disease. AB - We investigated whether there exists a hierarchical vulnerability of subcortical structures with respect to the severity of Alzheimer's disease (AD). A total of 236 subjects (179 with AD and 57 with normal cognition) underwent 1.5-T magnetic resonance (MR) imaging. The volumes of the five subcortical structures (amygdala, thalamus, putamen, globus pallidus, and caudate nucleus) and hippocampus were analyzed using a large deformation diffeomorphic metric mapping algorithm. The volume changes were evaluated according to the Clinical Dementia Rating (CDR). Correlation between the volumes of the subcortical structures and scores of the cognitive domain-specific neuropsychological tests were evaluated. Volume loss of the amygdala occurred even in the very mild stage of AD (CDR 0.5), as did volume loss in the hippocampus. Similar reductions in volume occurred in the thalamus and putamen, however during the mild (CDR 1) and moderate (CDR 2) stages of AD, respectively. The globus pallidus and caudate nucleus remained devoid of changes until the moderate stage of AD (p < 0.01). Volume loss in those subcortical structures correlated with the neuropsychological test scores (p < 0.01). Our results suggest that there is a hierarchical vulnerability in subcortical structures according to the clinical severity of AD and that subcortical volume reductions correlate with cognitive impairment. PMID- 21240518 TI - Impact of fatigue on the efficacy of rehabilitation in multiple sclerosis. AB - Fatigue is considered to be one of the most common and disabling symptoms among individuals with multiple sclerosis (MS). The aim of this study is to investigate if an intensive, short-term inpatient rehabilitation program is able to improve fatigue in MS, and if fatigue is able to negatively influence the clinical and functional outcome of rehabilitation in MS. One-hundred eighty six consecutively recruited MS patients underwent an intensive, short-term inpatient rehabilitation program. Sixty-four of them were selected for this study according to our inclusion criteria and compared to a control group of 22 MS patients who did not follow a rehabilitation program. We measured fatigue symptoms with the Fatigue Severity Scale (FSS) before and after rehabilitation, and classified patients into fatigued (FMS) in the case of an FSS score >=36 and into non-fatigued MS (NFMS) in the case of an FSS <36. Expanded Disability Status Scale (EDSS) and Functional Independence Measure (FIM) were used as clinical outcome measures of the efficacy of the rehabilitation program. In our sample, an intensive, short term rehabilitation treatment is able to determine a significant reduction of fatigue symptoms compared to untreated MS patients (p < 0.0001); however, the presence of fatigue at the beginning of the rehab program seems not to have any impact on the clinical and functional outcome of rehabilitation. An intensive inpatient rehabilitation trial decreases symptom of fatigue in MS patients; furthermore fatigue seems not to modify the amelioration of disability and impairment determined by a rehabilitation program. PMID- 21240519 TI - A case-control study of beneficial and adverse effects of 2-octyl cyanoacrylate tissue adhesive for episcleral explants in retinal detachment surgery. PMID- 21240520 TI - Amelioration of selenite toxicity and cataractogenesis in cultured rat lenses by Vitex negundo. AB - PURPOSE: Recent evidence suggests that oxidative stress plays a significant role in the development of cataract. The present study sought to evaluate the efficacy of flavonoid fraction of Vitex negundo (FVN) in preventing the toxicity induced by sodium selenite in vitro culture condition. METHODS: Enucleated rat lenses were maintained in organ culture containing DMEM medium alone (G I), supplemented with 0.1mM sodium selenite (G II), sodium selenite + 20 MUg/ml quercetin (G III) and sodium selenite + 50 MUg/ml FVN (G IV). Treatment was from the second to fifth day, while selenite administration was done on the third day. After the experimental period, lenses were taken out and the activities of superoxide dismutase (SOD), catalase, Ca(2+) ATPase, levels of reduced glutathione (GSH), calcium, reactive oxygen species (ROS), thiobarbituric acid reactive substances (TBARS), and sulfhydryl content were studied. RESULTS: Morphological examination revealed dense vacuolization and loss of cortical transparency in G II compared to control and treated group. The mean activities of the enzymes SOD, catalase and Ca(2+) ATPase, levels of GSH and sulfhydryl content were significantly reduced in lenses of G II compared to control. In addition, the mean levels of ROS, calcium and TBARS were elevated in G II compared to control. However, these changes were modulated by FVN treatment to further strengthen its protective role over selenite cataract. CONCLUSION: These results suggest that FVN treatment prevented selenite toxicity and cataractogenesis by maintaining antioxidant status, calcium homeostasis, protecting sulfhydryl group, and decreasing oxidative stress in lens, which may be due to its protective effects. PMID- 21240521 TI - The contrasting effect of estrogen on mRNA expression of VEGF in bovine retinal vascular endothelial cells under different oxygen conditions. AB - OBJECTIVE: To investigate the influence of Estradial (E(2)) at physiological concentration on mRNA expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1alpha(HIF-alpha1) in bovine retinal vascular endothelial cells (BRECs) under different oxygen conditions. METHODS: The mRNA expression of VEGF, HIF-1alpha in BRECs was studied by quantitative reverse transcription PCR (qRT-PCR), and protein levels were assayed by Western Blot. Different concentrations of E(2) (10(-12), 10(-10), 10(-8) mol/l) and estrogen receptor antagonist Tamoxifen (10(-7) mol/l) were added into the cell culture medium of different groups, while the phosphate-buffered saline (PBS) was added in the control group instead. Culture conditions were set to be under normoxia and hypoxia. The results of each group were detected after 8 hours and 24 hours. RESULTS: (1) Under hypoxia, gene expression of VEGF, HIF-1alpha in BRECs increased more than that of the control group (P < 0.05). There is evident positive correlation between the mRNA and protein levels of VEGF and HIF-1alpha (r = 0.82). (2) Treated with 10(-8) mol/l E(2,) the expression of VEGF mRNA was increased in a time-dependent manner (P < 0.05). Treated with the indicated to concentrations of E(2) (10(-12 ~ -8) mol/l) under normoxia for twenty-four hours, the mRNA expression of VEGF in BRECs was increased in a dose-dependent manner (P < 0.05), whereas E(2) did not influence the mRNA expression of HIF-1alpha (P > 0.05). (3) Under hypoxia , E(2) reduced the mRNA and protein levels of HIF-1alpha and VEGF in a concentration-dependent manner (P < 0.05), and the decrease developed in a time-dependent manner (P < 0.05). (4) An overdose of tamoxifen (10(-7) mol/l) reversed the effect of E(2) (10(-8) mol/l) (P < 0.05). CONCLUSIONS: E(2) increases the gene expression of VEGF in BRECs under normoxia, whereas E(2) reduces the gene expression of VEGF in BRECs through HIF-1alpha under hypoxic conditions in a dose-dependent and time-dependent manner. The contrasting effect of E(2) on mRNA expression of VEGF may play a prophylactic role in retinopathy of prematurity (ROP). PMID- 21240522 TI - Diagnostic ability of retinal ganglion cell complex, retinal nerve fiber layer, and optic nerve head measurements by Fourier-domain optical coherence tomography. AB - PURPOSE: To evaluate the diagnostic ability of Fourier-domain optical coherence tomography (FD-OCT) measurements in glaucoma patients, patients with ocular hypertension, and normal subjects. METHODS: Ninety-three participants with open angle glaucoma (OAG), 58 patients with ocular hypertension (OHT), and 60 healthy control subjects were included in the study. All study participants underwent FD OCT imaging. Retinal ganglion cell complex (GCC), macular thickness, peripapillary retinal nerve fiber layer thickness (RFNL), and optic nerve head parameters (ONH) were measured in each participant. The diagnostic ability was evaluated using area under the receiver operating characteristics curves (AUROC). RESULTS: Glaucoma patients showed a significant reduction in GCC and macular retinal thickness compared to patients with OHT and normal subjects. No differences in GCC were found between the patients with OHT and normal subjects. The best diagnostic ability in the comparison between glaucoma and normal subjects after adjusting for age was found for cup-to-disc ratio (AUROC = 0.848), RNFL average thickness (AUROC = 0.828), and GCC global loss volume (AUROC = 0.805). The diagnostic power of the best GCC, RNFL, and ONH parameter did not show differences beyond random variation (p > 0.05). CONCLUSIONS: Imaging of the GCC using FD-OCT (RTVue-100) has a comparable diagnostic ability to RNFL and ONH measurements in distinguishing between glaucoma patients and healthy subjects. No differences were found between patients with OHT and normal subjects with regard to ONH, RNFL, and GCC parameters. PMID- 21240523 TI - Caspase-3-independent photoreceptor degeneration by N-methyl-N-nitrosourea (MNU) induces morphological and functional changes in the mouse retina. AB - BACKGROUND: Retinal degeneration is followed by significant changes in the structure and function of photoreceptors in humans and several genetic animal models. However, it is not clear whether similar changes occur when the degeneration is induced pharmacologically. Therefore, our aim was to investigate the influence of retinotoxic N-methyl-N-nitrosourea (MNU) on the function, morphology and underlying molecular pathways of programmed cell death. METHODS: C57/BL6 mice were injected with different doses of MNU, and function was determined by analysing optokinetic reflex measurements and cued water maze results at several time points post-injection. Morphometric measurements were also taken from H&E-stained paraffin eye sections. TUNEL-positive cells and caspase-3 and -6 were detected by immunohistochemistry. To assess the molecular changes leading to cell death, qRT-PCR from neurosensory retina mRNA was performed. RESULTS: The application of MNU led to an instant decrease in function and a delayed decrease in the thickness of the retinal outer nuclear layer. These responses were observed in the absence of any structural changes in the retinal pigment epithelium. The degeneration of the photoreceptor cell layer was highest with 60 mg/kg MNU. The assessment of TUNEL-positive cells visualised cell death after treatment, but no detectable caspase-3 activity was observed concomitant with these changes. qRT-PCR revealed the possible involvement of the inflammatory mediator caspase-1 and endoplasmic reticulum stress-mediated apoptosis by caspase 12. CONCLUSION: MNU leads to the dose-dependent degeneration of photoreceptor cells in mice by caspase-3-independent pathways and is, therefore, a suitable model to study retinal degeneration in an animal model. PMID- 21240524 TI - Surface quality of human corneal lenticules after femtosecond laser surgery for myopia comparing different laser parameters. AB - BACKGROUND: To determine the surface characteristics of human corneal lenticules after femtosecond laser surgery for myopia. METHODS: The Carl Zeiss Meditec AG VisuMax(r) femtosecond laser system was used for refractive correction called Femtosecond Lenticule Extraction on 24 myopic eyes. The surface regularity on the refractive corneal lenticules recovered was evaluated by assessing scanning electron microscopy images using an established scoring system. Three different energy levels 150, 180, and 195 nJ were compared (n = 8 in each group). RESULTS: Surface irregularities were caused by tissue bridges, cavitation bubbles, or scratches. The surface regularity index (R(2) = 0.74) decreased as pulse energy increased. The average surface regularity score obtained was 7.5 for 150 nJ, 7.25 for 180 nJ, and 6.25 for 195 nJ. CONCLUSIONS: The human corneal lenticules created with the VisuMax(r) femtosecond laser system are of predictable, good quality surface. This study shows the influence of pulse energy on surface regularity in human eyes. Further studies should focus on optimization of laser parameters as well as surgical technique to improve the regularity of the corneal stromal bed and so make the advantages of the femtosecond laser technology over conventional techniques clearer in the future. PMID- 21240525 TI - PI3K/Akt pathway mediates high glucose-induced lipogenesis and extracellular matrix accumulation in HKC cells through regulation of SREBP-1 and TGF-beta1. AB - Previous studies have shown that high glucose stimulates renal SREBP-1 gene expression and increases renal tubular cells lipid metabolism, however, the mechanisms remain elusive. In the present study we demonstrated that PI3K/Akt pathway was activated in human renal proximal tubular cell line (HKC) exposed to high glucose accompanied with up-regulation of SREBP-1, TGF-beta1, lipid droplets deposits and extracellular matrix production. Inhibition of PI3K/Akt pathway by chemical LY294002 or specific short hairpin RNA (shRNA) vector prevented SREBP-1 and TGF-beta1 up-regulation, as well as ameliorated HKC cells lipogenesis and extracellular matrix accumulation. These findings indicate that PI3K/Akt pathway potentially mediates high glucose-induced lipogenesis and extracellular matrix accumulation in HKC cells. PMID- 21240526 TI - Evaluation of the association studies of single nucleotide polymorphisms and hepatocellular carcinoma: a systematic review. AB - PURPOSE: For decades of years, hundreds of candidate gene-based association studies explored the relationship between single nucleotide polymorphisms (SNPs) and hepatocellular carcinoma (HCC). There was no systematic review summarized the results of these association studies of candidate SNPs and HCC to date. In order to summarize the results of the association studies, we conducted a concise systematic review. METHODS: By searching Pubmed database before October 2010, we reviewed all the association studies about candidate SNPs and HCC. If the eligible study number on a given SNP was more than three, we conducted a meta analysis. We reported here only the overall positive-association results with statistical significance and evaluated the reliability of the associations by using false-positive report probability (FPRP) analysis and the Venice guidelines on genetic epidemiology studies. RESULTS: Six SNPs of five genes (rs1800562 of HFE, rs17868323 and rs11692021 of UGT1A7, rs2279744 of MDM2, rs1143627 of IL-1B, and rs4880 of MnSOD) showed overall significant associations with HCC. The eligible number of the studies varied from three to nine. Two SNPs (rs1800562 of HFE and rs2279744 of MDM2) passed the FPRP threshold (FPRP < 0.20). According to the Venice guidelines, the associations between the two SNPs (rs1800562 and rs2279744) and HCC were of moderate evidence. CONCLUSIONS: Two SNPs (rs1800562 of HFE and rs2279744 of MDM2) were associated with HCC with moderate epidemiological evidence and deserve further study and additional biological and clinical assessment. PMID- 21240527 TI - Pauci-immune crescentic glomerulonephritis complicating Sjogren's syndrome in a 12-year-old girl. PMID- 21240528 TI - Long-term risk of chronic kidney disease in unilateral multicystic dysplastic kidney. AB - The clinical spectrum of renal dysplasia includes the non-functioning multicystic dysplastic kidney (MCDK). We report our experience of the outcome of unilateral MCDK and its contralateral kidney in 101 children with the diagnosis of MCDK from 1985 to 2009. Data collected included urine protein/creatinine ratio, estimated GFR (eGFR), blood pressure, surgical intervention, renal length and abnormalities of the contralateral kidney, and the involution rate. There was a predominance of left-sided MCDK. Diagnosis was made prenatally in 86.7%. Contralateral abnormalities included vesicoureteral reflux (16.8%), UPJ obstruction (4.1%), and megaureter (2.4%). Complete involution of MCDK occurred within 5 years in 60%. Compensatory hypertrophy of the contralateral kidney to >97% occurred in 74.1%. Nephrectomy was performed in 19.8%. There was an increased risk of chronic kidney disease (CKD) stage >= 2, and hypertension in those with contralateral abnormalities (p<0.0001; p<0.001 respectively). In those without contralateral abnormalities, hyperfiltration with mean eGFR of 149 +/- 13 ml/min/1.73 m(2) was seen in 32% and proteinuria in 9.8%. There was a significantly inverse relationship between proteinuria and eGFR (p<0.0001). In conclusion, children with contralateral abnormalities are at risk for developing decreased kidney function, whereas a substantial number of patients with no obvious contralateral abnormalities have markers of renal injury. Therefore, systematic follow-up of all patients is recommended. PMID- 21240529 TI - Development of a clinical prediction rule to identify patients with neck pain who are likely to benefit from home-based mechanical cervical traction. AB - The objective of the study was to identify the population of patients with neck pain who improved with home-based mechanical cervical traction (HMCT). A prospective cohort study was conducted in a physical therapy clinic at a local hospital. Patients with neck pain referred to the clinic for physical therapy were included in the study. A HMCT program was given to participants for 2 weeks. The patient's demographic data, Numerical Pain Scale (NPS) score, Neck Disability Index (NDI) and Fear-Avoidance Beliefs Questionnaire score were collected, and standard physical examination of the cervical spine was conducted before intervention. The NPS score, NDI and a global rating of perceived improvement were collected after the intervention was completed. A total of 103 patients participated in the study and 47 had a positive response to HMCT. A clinical prediction rule with four variables (Fear-Avoidance Beliefs Work Subscale score < 13, pre-intervention pain intensity >= 7/10, positive cervical distraction test and pain below shoulder) was identified. With satisfaction of at least three out of four variables (positive likelihood ratio = 4.77), the intervention's success rate increased from 45.6% to over 80%. It appears that patients with neck pain who are likely to respond to HMCT may be identified. PMID- 21240530 TI - Long-term results of surgery for lumbar spinal stenosis: a randomised controlled trial. AB - We randomised a total of 94 patients with long-standing moderate lumbar spinal stenosis (LSS) into a surgical group and a non-operative group, with 50 and 44 patients, respectively. The operative treatment comprised undercutting laminectomy of stenotic segments, augmented with transpedicular-instrumented fusion in suspected lumbar instability. The primary outcome was the Oswestry disability index (ODI), and the other main outcomes included assessments of leg and back pain and self-reported walking ability, all based on questionnaire data from 85 patients at the 6-year follow-up. At the 6-year follow-up, the mean difference in ODI in favour of surgery was 9.5 (95% confidence interval 0.9-18.1, P-value for global difference 0.006), whereas the intensity of leg or back pain did not differ between the two treatment groups any longer. Walking ability did not differ between the treatment groups at any time. Decompressive surgery of LSS provided modest but consistent improvement in functional ability, surpassing that obtained after non-operative measures. PMID- 21240531 TI - The patterns and risk factors of hearing loss following microvascular decompression for hemifacial spasm. AB - OBJECTIVE: The aim of this study was to reveal the risk factors including intraoperative brain stem auditory evoked potential (BAEP) changes and to define parameter and warning values of BAEP beyond which the probability of hearing impairment rises significantly. METHODS: From April 1997 to February 2009, 1156 patients underwent microvascular decompression (MVD) for hemifacial spasm (HFS) and their medical records and audiologic data. The intraoperative BAEP monitoring was performed in all operations during surgery from the time of administration of general anesthesia until the time of skin closure. Pure tone audiometry (PTA) and Speech Discrimination Score (SDS) were performed on all patients before and after surgery for categorizing the patterns of hearing loss. There were 825 females and 331 males with a mean age of 48.7 years (range 17-75 years). The mean symptom duration was 67.8 months (range 1-420 months). RESULTS: At the 1-year follow-up examination, 1091 (94.4%) patients of the total 1156 patients exhibited a cured state, and 65 (5.6%) patients had residual spasms. Hearing loss occurred in 46 patients (3.9%). In 26 patients, PTA was decreased more than 15 dB with a proportional decrease of the SDS. In 10 patients, poor SDS without hearing loss occurred. Total deafness was developed in 10 patients. A higher incidence of BAEP change and a poor recovery especially amplitude in wave V during surgery was observed in patients with poor SDS (eight patients) and total deafness (seven patients) (p = 0.000). Reduction of amplitude more than 50% in wave V was a strong indicator for a worse outcome of the hearing capacity. The difference in other risk factors according to hearing loss pattern was not statistically significant (p > 0.05). Only female was significant (p = 0.005). CONCLUSIONS: The intraoperative BAEP change and a poorer recovery, especially reduction of amplitude more than 50% in wave V, was a strong indicator for a worse outcome of the hearing capacity. Vigilant intraoperative monitoring of the BAEP and adequate steps for recovery of the BAEP change could prevent hearing loss after MVD for HFS. PMID- 21240532 TI - Chemical reactivity of Synechococcus sp. PCC 7002 and Synechocystis sp. PCC 6803 hemoglobins: covalent heme attachment and bishistidine coordination. AB - In the absence of an exogenous ligand, the hemoglobins from the cyanobacteria Synechocystis sp. PCC 6803 and Synechococcus sp. PCC 7002 coordinate the heme group with two axial histidines (His46 and His70). These globins also form a covalent linkage between the heme 2-vinyl substituent and His117. The in vitro mechanism of heme attachment to His117 was examined with a combination of site directed mutagenesis, NMR spectroscopy, and optical spectroscopy. The results supported an electrophilic addition with vinyl protonation being the rate determining step. Replacement of His117 with a cysteine demonstrated that the reaction could occur with an alternative nucleophile. His46 (distal histidine) was implicated in the specificity of the reaction for the 2-vinyl group as well as protection of the protein from oxidative damage caused by exposure to exogenous H(2)O(2). PMID- 21240533 TI - The tetranuclear copper active site of nitrous oxide reductase: the CuZ center. AB - This review focuses on the novel CuZ center of nitrous oxide reductase, an important enzyme owing to the environmental significance of the reaction it catalyzes, reduction of nitrous oxide, and the unusual nature of its catalytic center, named CuZ. The structure of the CuZ center, the unique tetranuclear copper center found in this enzyme, opened a novel area of research in metallobiochemistry. In the last decade, there has been progress in defining the structure of the CuZ center, characterizing the mechanism of nitrous oxide reduction, and identifying intermediates of this reaction. In addition, the determination of the structure of the CuZ center allowed a structural interpretation of the spectroscopic data, which was supported by theoretical calculations. The current knowledge of the structure, function, and spectroscopic characterization of the CuZ center is described here. We would like to stress that although many questions have been answered, the CuZ center remains a scientific challenge, with many hypotheses still being formed. PMID- 21240534 TI - Characterization of carrageenan extracted from Hypnea bryoides in Oman. AB - Carrageenophyte red seaweed from Oman, Hypnea bryoides, extracted using three different processes: an aqueous, a mild alkaline, and a more vigorous alkaline extraction was investigated. The resulting extract precipitated by alcohol was subject to chemical and rheological measurements. The total carbohydrate [ranged from 36.78 to 41.65 g/100 g], and ash [39.04 to 43.11 g/100 g] were the most abundant components in H. bryoides and contrary to the two, lipid content was found at a minimum [ranging from 2.95 to 3.38 g/100 g]. Alkali treatment with NaOH allowed complete conversion of kappa (kappa) carrageenan form as detected by FTIR analysis. Total yield by alkali treatments gave higher yields (33%) compared with aqueous treatments (12%). However, subsequent aqueous treatment produced mixed carrageenan (MU and kappa) with higher molecular weight compared with the alkali treatments which produced single carrageenan form (kappa) with molecular weight of 4.1 * 10(5) Da. The effects of thermal history on gel-sol and sol-gel transition were investigated by differential scanning calorimeter (DSC) and rheology on a pure sample and 1.5% kappa-carrageenan mixture added with 30 mM KCl. Transition temperatures from DSC and rheology showed comparable results and were in good agreement with those previously reported. PMID- 21240535 TI - Musculokeletal: what's different in children? Jumping from pool to pool; falls and slips; elbow hurts. PMID- 21240536 TI - Transcript profiling of chitosan-treated Arabidopsis seedlings. AB - In nature, plants can recognize potential pathogens, thus activating intricate networks of defense signals and reactions. Inducible defense is often mediated by the detection of microbe or pathogen associated molecular pattern elicitors, such as flagellin and chitin. Chitosan, the deacetylated form of chitin, plays a role in inducing protection against pathogens in many plant species. We evaluated the ability of chitosan to confer resistance to Botrytis cinerea in Arabidopsis leaves. We subsequently treated Arabidopsis seedlings with chitosan and carried out a transcript profiling analysis using both ATH1 GeneChip microarrays and quantitative RT-PCR. The results showed that defense response genes, including camalexin biosynthesis genes, were up-regulated by chitosan, both in wild-type and in the chitin-insensitive cerk1 mutant, indicating that chitosan is perceived through a CERK1-independent pathway. PMID- 21240537 TI - Afferent baroreflex failure and tako-tsubo cardiomyopathy. PMID- 21240538 TI - The circadian pattern of cardiac autonomic modulation in a middle-aged population. AB - OBJECTIVES: To examine the circadian pattern of cardiac autonomic modulation (CAM) and its attributes in general population. METHODS: We obtained 24-h beat-to beat RR data using a high resolution 12-lead Holter ECG in a community-dwelling sample of 115 non-smokers. We performed heart rate variability (HRV) analysis on the normal RRs from each 5-min segment to obtain time-specific HRV indices: high (HF; 0.15-0.40 Hz) and low (LF; 0.04-0.15 Hz) frequency powers, standard deviation of RR intervals (SDNN), and the square root of the mean of the sum of the squared differences of the adjacent RR intervals (RMSSD). For each individual, we fit the segment-specific HRV data to a cosine periodic function, and estimated 3 individual-level cosine function parameters to quantify the circadian variation: the mean (M), amplitude (A), and acrophase (theta). We then used a random-effects meta-analysis to summarize the M, A, and theta, and their 95% confidence intervals (CI). RESULTS: The mean age was 56 (SD 8) years, with 63% female and 76% white. The averages of M, A and theta (95%CI) of log HF were 3.59 (3.43-3.76) ms(2), 0.61 (0.54-0.68) ms(2), and 3:10 (2:25-3:55) AM, respectively, and that of RMSSD were 22.3 (20.5-24.1) ms, 6.5 (5.4-7.5) ms, 3:45 (2:55-4:35) AM, respectively. Older age is associated with lower mean of HRV. Males have higher oscillation amplitude than females. The acrophase of LF/HF was earlier in females than in males, and in younger individuals than in older individuals. CONCLUSIONS: The circadian pattern of CAM can be quantified by 3 cosine parameters of HRV, which are correlated with age and gender. PMID- 21240539 TI - Characterization of a human tumorsphere glioma orthotopic model using magnetic resonance imaging. AB - Magnetic resonance imaging (MRI) is the imaging modality of choice by which to monitor patient gliomas and treatment effects, and has been applied to murine models of glioma. However, a major obstacle to the development of effective glioma therapeutics has been that widely used animal models of glioma have not accurately recapitulated the morphological heterogeneity and invasive nature of this very lethal human cancer. This deficiency is being alleviated somewhat as more representative models are being developed, but there is still a clear need for relevant yet practical models that are well-characterized in terms of their MRI features. Hence we sought to chronicle the MRI profile of a recently developed, comparatively straightforward human tumor stem cell (hTSC) derived glioma model in mice using conventional MRI methods. This model reproduces the salient features of gliomas in humans, including florid neoangiogenesis and aggressive invasion of normal brain. Accordingly, the variable, invasive morphology of hTSC gliomas visualized on MRI duplicated that seen in patients, and it differed considerably from the widely used U87 glioma model that does not invade normal brain. After several weeks of tumor growth the hTSC model exhibited an MRI contrast enhancing phenotype having variable intensity and an irregular shape, which mimicked the heterogeneous appearance observed with human glioma patients. The MRI findings reported here support the use of the hTSC glioma xenograft model combined with MRI, as a test platform for assessing candidate therapeutics for glioma, and for developing novel MR methods. PMID- 21240540 TI - Influence of Methylobacterium on iron translocation in plants. AB - Iron metabolism in plants is essential to maintain optimal growth and iron nutrition is dependent on uptake of iron from the environment and movement of iron in the plant tissues. We have examined the translocation of iron in plant leaves following foliar application of FeEDTA to Vicia faba and Zea mays. Using radiolabeled iron, we observed that iron translocation is stimulated by products of Methylobacterium mesophylicum and by the cytokinin, kinetin. When cytokinins were applied to leaves along with (55)FeEDTA, the rate of iron translocation was greater than in controls without cytokinin addition. Since recent studies indicate that M. mesophylicum is widely distributed in the environment as a pyllospheric bacterium, this organism may have an important role in enhancing translocation of nutrients in plant leaves. PMID- 21240541 TI - Crystal structure and mode of action of a class V chitinase from Nicotiana tabacum. AB - A class V chitinase from Nicotiana tabacum (NtChiV) with amino acid sequence similar to that of Serratia marcescens chitinase B (SmChiB) was expressed in E. coli and purified to homogeneity. When N-acetylglucosamine oligosaccharides [(NAG)(n)] were hydrolyzed by the purified NtChiV, the second glycosidic linkage from the non-reducing end was predominantly hydrolyzed in a manner similar to that of SmChiB. NtChiV was shown to hydrolyze partially N-acetylated chitosan non processively, whereas SmChiB hydrolyzes the same substrate processively. The crystal structure of NtChiV was determined by the single-wavelength anomalous dispersion method at 1.2 A resolution. The protein adopts a classical (beta/alpha)8-barrel fold (residues 1-233 and 303-348) with an insertion of a small (alpha + beta) domain (residues 234-302). This is the first crystal structure of a plant class V chitinase. The crystal structure of the inactive mutant NtChiV E115Q complexed with (NAG)4 was also solved and exhibited a linear conformation of the bound oligosaccharide occupying -2, +1, +2, and +3 subsites. The complex structure corresponds to an initial state of (NAG)4 binding, which is proposed to be converted into a bent conformation through sliding of the +1, +2, and +3 sugar units to -1, +1, and +2 subsites. Although NtChiV is similar to SmChiB, the chitin-binding domain is present in the C-terminus of the latter, but not in the former. Aromatic amino acid residues found in the substrate binding cleft of SmChiB, including Trp97, are substituted with aliphatic residues in NtChiV. These structural differences appear to be responsible for NtChiV being a non-processive enzyme. PMID- 21240542 TI - Nationwide rates of conversion from laparoscopic or vaginal hysterectomy to open abdominal hysterectomy in Germany. AB - The aim of this study was to provide population-based German-wide hysterectomy rates based on the national hospitalization file and to estimate the rate of conversion from laparoscopical or vaginal hysterectomy to open abdominal hysterectomy. Nationwide population-based DRG (diagnosis related groups) data of the years 2005 and 2006 were used to calculate hysterectomy rates by indication group and type of surgical approach. Overall 305,015 hysterectomies were performed during the study period (4.5 out of 1,000 women aged 20 years or more). The hysterectomy rate for benign diseases of the genital tract among women aged 20 years or more (3.6 out of 1,000 women) is higher than in Sweden but lower than in the US or Australia. Only 6 and 5% of all hysterectomies were performed by laparoscopically assisted vaginal hysterectomy and laparoscopic hysterectomy, respectively. Twenty-six percent of hysterectomies for benign diseases among women aged 50 years or more included bilateral oophorectomy. 10% of laparoscopical hysterectomies and 1% of vaginal hysterectomies necessitated a conversion to an abdominal hysterectomy. For both types of hysterectomies, the conversion rates were highest for primary malignant genital tract cancer and other cancers compared to the other indication groups. Whereas the conversion rate for laparoscopical hysterectomies increased by age, this rate did not change by age for vaginal hysterectomies. Conversion from laparoscopically or vaginal hysterectomy to open abdominal hysterectomy is associated with the indication and type of hysterectomy started with and is considerably higher for laparoscopic than vaginal hysterectomies. PMID- 21240543 TI - Bioinformatic identification of novel protein phosphatases in the dog genome. AB - Protein kinases and protein phosphatases constitute about 2-4% of the genes in a typical eukaryotic genome. Protein phosphatases are important players in many cellular processes such as proliferation, differentiation, cell adhesion, and motility. In this study, we identified, classified, and analyzed protein phosphatase complement of the dog genome. In this article, we report the identification of at least 178 putative protein phosphatases in dog which include 51 PSTPs, 112 PTPs, and 15 Asp-based protein phosphatases. Interestingly, we found at least five novel protein phosphatases in dog, namely DUSP5L, DUSP18L, MTMR9L, MTMR12L, and PPP6CL which are not present in human, mouse, rat, and cow. In addition, we found PTP4A1-rt, a retro-transposed copy of the PTP4A1 gene, in chromosome 27. Furthermore, we modeled three-dimensional structures of the catalytic domains of these putative protein phosphatases and aligned them to see the structural similarities between them. We docked PPP2CA with okadaic acid and calculated the value of affinity energy as -8.8 kcal/mol. Our nucleotide substitution rate study revealed that apparently none of the phosphatase family is under significantly higher evolutionary pressure. PMID- 21240544 TI - Recombinant scorpion insect excitatory toxin BmK IT accelerates the growth of insect Spodoptera frugiperda 9 cells. AB - Several scorpion insect toxins are selectively active on the lepidopterous and dipterous insects. The gene encoding insect excitatory neurotoxin (BmK IT) from the scorpion Buthus martensii Karsch was expressed in Escherichia coli BL21(DE3) at a high level of 3 mg/0.5 L using the prokaryotic expression system pTWIN1. Colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), whole-cell patch-clamp technique and immunofluorescence assays were used to evaluate the toxicity of rBmK IT to insect Spodoptera frugiperda 9 (Sf9) cells and to analyze the potential mechanism of this toxicity. rBmK IT accelerated the growth of Sf9 cells in a dose-dependent manner. Voltage-gating sodium channel activity could not be detected in Sf9 cells using a whole-cell patch-clamp technique. However, immunofluorescence analysis clearly showed co-localization of tetrodotoxin (TTX) and rBmK IT on the Sf9 cell membrane, which demonstrated that rBmK IT could bind to and act on the voltage-gated sodium channels on the Sf9 cells by the high affinity action power. The findings presented in this study are essential for further study of this peptide. PMID- 21240547 TI - Mobilizing communities to implement evidence-based practices in youth violence prevention: the state of the art. AB - Community mobilization can increase the effective implementation of evidence based practices (EBPs) in youth violence prevention. These strategies bring together people and organizations in a community to try to solve or reduce a problem. They help communities address the challenges of identifying EBPs, disseminating them to local decision-makers, and then implementing and sustaining them if they are successful. Science-based systems for implementing EBPs such as PROSPER and Communities That Care can help to integrate this complex work in communities. Further insight about implementing EBPs in youth violence prevention is being developed through the CDC-funded Academic Centers for Excellence in Youth Violence Prevention. Community mobilization approaches for seven of these programs are discussed, highlighting successful approaches and challenges encountered. PMID- 21240546 TI - Antihypertensive drugs and inflammation in acute ischemic stroke as a predictor factor of future cardiovascular mortality. AB - The beneficial effects of antihypertensive drugs in secondary stroke prevention could not be based on their effects on lowering hypertension only.In this prospective study, the status of blood pressure, treatment regimens, new atherothrombotic event, blood sampling for hs-CRP and fibrinogen were asked at initial visit, 6th, and 12th months in 226 patients with atherothrombotic stroke.Eighty-seven percent of patients had an antihypertensive regimen, but hypertension control was achieved in 34.1% of patients.Neither use of six different antihypertensive drug regimens nor the change in blood pressure levels showed any difference on new atherothrombotic events, outcomes or survival rates.On the other hand, the higher levels of hs-CRP at baseline were found to be associated with higher mortality rates (p=0.020).Our findings emphasize the predictive role of inflammation in future cardiovascular mortality in patients with acute ischemic stroke, indicating that inflammatory mediators underlying the atherothrombotic process play a more important role than it is assumed. PMID- 21240548 TI - Psycho-social processes in dealing with legal innovation in the community: insights from biodiversity conservation. AB - Mitigation measures for tackling the consequences of a changing climate will involve efforts of various types including the conservation of affected ecosystems. For this, communities throughout the world will be called on to change habits of land and water use. Many of these changes will emerge from the multilevel governance tools now commonly used for environmental protection. In this article, some tenets of a social psychology of legal innovation are proposed for approaching the psycho-social processes involved in how individuals, groups and communities respond to multilevel governance. Next, how this approach can improve our understanding of community-based conservation driven by legal innovation is highlighted. For this, the macro and micro level processes involved in the implementation of the European Natura 2000 Network of Protected Sites are examined. Finally, some insights gained from this example of multilevel governance through legal innovation will be enumerated as a contribution for future policy making aimed at dealing with climate change consequences. PMID- 21240550 TI - A survey on draught animal technology (DAT) in EN-Nhoud area, North Kordofan State, Sudan. AB - Draught animal technology (DAT) can potentially play a central role in agriculture transformation for traditional farmers. This study surveyed the state of DAT in En-Nhoud area, North Kordofan State, Sudan in an attempt to have a clear view of the changes brought about by introducing the technology. The study followed the cross-sectional survey design. Farmers were selected from ten clusters (villages) and data were collected using questionnaires and face to face interviews with farmers in addition to group discussions with them and the different actors in the field. The results showed that farmers appreciate the role played by DAT, but they highlighted the need for further capacity building and technical backup. Harnessing issues are not well understood and applied by the farmers. The different actors involved in DAT in the area lack networking and coordination, and this reflected on the many problems and constraints faced by the farmers. PMID- 21240549 TI - Invasion of Trypanosoma cruzi into host cells is impaired by N propionylmannosamine and other N-acylmannosamines. AB - The etiologic agent of Chagas' disease, Trypanosoma cruzi, is widely distributed in South America, affecting millions of people with thousands of deaths every year. Adherence of the infectious trypomastigote to host cells is mediated by sialic acid. T. cruzi cannot synthesize sialic acids on their own but cleave them from the host cells and link them to glycans on the surface of the parasites using the trans-sialidase, a GPI-anchored enzyme. The infectivity of the protozoan parasites strongly depends on the activity of this enzyme. In this report, we investigated whether the transfer of sialic acids from the host to the parasites can be attenuated using novel sialic acid precursors. The cell line 86 HG-39 was infected with T. cruzi and treated with defined N-acylmannosamine analogues bearing an elongated N-acyl side-chain. By treatment of these cells the number of T. cruzi infected cell was reduced up to 60%. We also showed that the activity of the bacterial sialidase C was reduced with N-glycan substrates with elongated N-acyl side chains of the terminal sialic acids. The affinity of this sialidase decreased with the length of the N-acyl side-chain. The data presented suggest that N-acyl modified sialic acid precursors can change the transfer of sialic acids leading to modification of infection. Since the chemotherapy of this disease is inefficient and afflicted by side effects, the need of effective drugs is lasting. These findings propose a new path to prevent the dissemination of T. cruzi in the human hosts. These compounds or further modified analogues might be a basis for the search of new agents against Chagas' disease. PMID- 21240551 TI - Development and validation of the Mental Health Attitude Survey for Police. AB - Police officers often lack sufficient mental health training and knowledge of mental illness to manage the risks associated with emotionally disturbed person (EDP) encounters. Still, it is not clear how much mental health training police officers actually need and, to date, there are no measures for police departments to use to determine officer attitudes toward dealing with EDPs. This led to the development of the Mental Health Attitude Survey for Police (MHASP), a modification and compilation of previously developed and newly developed items, which can be used to measure the effectiveness of mental health crisis training curricula in improving police attitudes toward persons with mental illnesses. A sample of 412 police officers from a major city police department in the northeast anonymously completed the MHASP. The results provide good evidence that the MHASP is a reliable and initially validated measure of police attitudes toward persons with mental illnesses. PMID- 21240552 TI - Emergency commitment of people residing in assisted living facilities. AB - The objective of this study was to describe emergency commitment of people from assisted living facilities (ALFs) and to discuss relevant policy issues. This study used statewide, archival emergency commitment data from July 2000 through June 2008. During the 1 year from July 07 through June 08 there were 3,061 people with 4,163 emergency commitments from ALFs. Some individuals had more than one emergency commitment during the year, with 20% having between 2 and 9 emergency commitments from ALFs. Some of these individuals also had substantial numbers of emergency commitments in the 7 years from July 2000 through June 2007. Discussed are possible factors related to emergency commitment from ALFs and the need for additional research on these topics. This includes availability of mental health services for these populations, the role of client characteristics, and how licensing of ALFs relates to emergency commitment of ALF residents. PMID- 21240553 TI - Therapists talk about the engagement process. AB - 'Engagement' and 'treatment engagement' are terms that frequently appear in the mental health literature, and are operationalized differently across studies. A clearer understanding and conceptualization of engagement would enhance research and practice. Six focus groups were conducted with community mental health therapists (n = 41) to learn how they define engagement, the barriers to engagement they experience, and the strategies they use to enhance engagement. In some aspects, their definition of engagement was similar to the helping alliance. However, therapists viewed engagement as much more than the relationship; it is a complex process that is affected by many factors, including agency policies and practices. Suggestions are made to advance the study of how clinical and organizational factors affect engagement. PMID- 21240554 TI - Cardiovascular risk factors in patients with schizophrenia receiving continuous medical care. AB - Modifiable risk factors for cardiovascular disease were assessed among individuals with schizophrenia receiving continuous (i.e. 24-h) medical care. Participants tended to have higher levels of risk factors than for the general population. They had similar levels of risk factors as for previous UK studies of patients not receiving continuous care, except they tended to have higher smoking rates and lower physical activity levels, although statistical comparisons were not possible. Among patients with schizophrenia receiving continuous medical care interventions for health behavior change may need to be further prioritized and there is a need to capitalize on the ready availability of social support in these settings. PMID- 21240555 TI - Resilience and distress: Israelis respond to the disengagement from Gaza and the second Lebanese war. AB - Resilience and distress in Israeli society were assessed at three points in time: before and after the Israeli disengagement from Gaza, and after the second Lebanese war. A random sample of 366 Israelis was assessed for nation-related anxiety and hostility, personal resources and post-traumatic symptoms. The lowest levels of anxiety were observed at the second time point, after the disengagement. Respondents with high-resilience profiles showed lower levels of post-traumatic symptoms and higher levels of personal resources. The findings underscore Israelis' resilience and the importance of personal resources in ongoing nationally stressful situations. PMID- 21240557 TI - Emergency preparedness training of tribal community health representatives. AB - This study describes the development and evaluation of online Public Health Emergency Preparedness (PHEP) training adapted to the learning styles and needs of tribal Community Health Representatives (CHRs). Working through a university tribal community college partnership, the Arizona Center for Public Health Preparedness at the University of Arizona and Dine College of the Navajo Nation delivered a blended online and face-to-face public health preparedness certificate program based on core public health emergency preparedness competencies. This program was carefully adapted to meet the environmental and learning needs of the tribal CHRs. The certificate program was subsequently evaluated via a scenario-based decision-making methodology. Significant improvements in five of six competency areas were documented by comparison of pre and post-certificate training testing. Based on statistical support for this pedagogical approach the cultural adaptations utilized in delivery of the certificate program appear to be effective for PHEP American Indian education. PMID- 21240556 TI - Preventing early child maltreatment: implications from a longitudinal study of maternal abuse history, substance use problems, and offspring victimization. AB - In the interest of improving child maltreatment prevention science, this longitudinal, community based study of 499 mothers and their infants tested the hypothesis that mothers' childhood history of maltreatment would predict maternal substance use problems, which in turn would predict offspring victimization. Mothers (35% White/non-Latina, 34% Black/non-Latina, 23% Latina, 7% other) were recruited and interviewed during pregnancy, and child protective services records were reviewed for the presence of the participants' target infants between birth and age 26 months. Mediating pathways were examined through structural equation modeling and tested using the products of the coefficients approach. The mediated pathway from maternal history of sexual abuse to substance use problems to offspring victimization was significant (standardized mediated path [ab] = .07, 95% CI [.02, .14]; effect size = .26), as was the mediated pathway from maternal history of physical abuse to substance use problems to offspring victimization (standardized mediated path [ab] = .05, 95% CI [.01, .11]; effect size = .19). There was no significant mediated pathway from maternal history of neglect. Findings are discussed in terms of specific implications for child maltreatment prevention, including the importance of assessment and early intervention for maternal history of maltreatment and substance use problems, targeting women with maltreatment histories for substance use services, and integrating child welfare and parenting programs with substance use treatment. PMID- 21240558 TI - Correlates of unintended birth among low-income Hispanic immigrants at high risk for depression. AB - Hispanic women, a large and growing ethnic minority group in the U.S., have an unintended birth rate over twice the national average. However, little is known about unintended birth among Hispanic immigrants. The purpose of this study is to determine the sociodemographic, including immigration-related, correlates of unintended birth in this population. Data were collected as part of a preventive intervention among pregnant Hispanic immigrants at increased risk for depression (n = 215). The correlates of women's self-reported pregnancy intention (intended, mistimed, unwanted) were examined using multinomial logistic regression. Similar to nationally representative findings, unintended birth was more common among younger women, single women and women not cohabiting with their partners, and women with more children. Additionally, women who had immigrated to the U.S. less than 1 year ago had almost a 4 times greater risk of a mistimed birth (RRR = 3.82, P < 0.05) compared to women who immigrated 1-4 years ago. Women with greater social support scores had a reduced chance of mistimed (RRR = 0.98, P < 0.10) and unwanted (RRR = 0.97, P < 0.05) birth. The findings have implications for development of effective and culturally appropriate family planning programs. They suggest that interventions should target young women, women who have achieved their desired family size, and very recent immigrants. PMID- 21240559 TI - Highly-compliant, microcable neuroelectrodes fabricated from thin-film gold and PDMS. AB - Bio-electrodes have traditionally been made of materials such as metal and silicon that are much stiffer than the tissue from which they record or stimulate. This difference in mechanical compliance can cause incomplete or ineffective contact with the tissue. The electrode stiffness has also been hypothesized to cause chronic low-grade injury and scar-tissue encapsulation, reducing stimulation and recording efficiency. As an initial step to resolve these issues with electrode performance, we have developed and characterized electrically-functional, low-Young's modulus, microcable-shaped neuroelectrodes and demonstrated electrophysiological recording functionality. The microcable geometry gives the electrodes a similar footprint to traditional wire and microwire neuroelectrodes, while reducing the difference in Young's modulus from nervous tissue by orders of magnitude. The electrodes are composed of PDMS and thin-film gold, affording them a high-level of compliance that is well suited for in vivo applications. The composite Young's modulus of the electrode was experimentally determined to be 1.81 +/- 0.01 MPa. By incorporating a high-tear strength silicone, Sylgard 186, the load at failure was increased by 92%, relative to that of the commonly used Sylgard 184. The microcable electrodes were also electromechanically tested, with measurable conductivity (220 kOmega) at an average 8% strain (n = 2) after the application of 200% strain. Electrophysiological recording is demonstrated by wrapping the electrode around a peripheral nerve, utilizing the compliance and string-like profile of the electrode for effective recording in nerve tissue. PMID- 21240560 TI - Impact of computer-assisted data collection, evaluation and management on the cancer genetic counselor's time providing patient care. AB - Cancer genetic counseling sessions traditionally encompass collecting medical and family history information, evaluating that information for the likelihood of a genetic predisposition for a hereditary cancer syndrome, conveying that information to the patient, offering genetic testing when appropriate, obtaining consent and subsequently documenting the encounter with a clinic note and pedigree. Software programs exist to collect family and medical history information electronically, intending to improve efficiency and simplicity of collecting, managing and storing this data. This study compares the genetic counselor's time spent in cancer genetic counseling tasks in a traditional model and one using computer-assisted data collection, which is then used to generate a pedigree, risk assessment and consult note. Genetic counselor time spent collecting family and medical history and providing face-to-face counseling for a new patient session decreased from an average of 85-69 min when using the computer-assisted data collection. However, there was no statistically significant change in overall genetic counselor time on all aspects of the genetic counseling process, due to an increased amount of time spent generating an electronic pedigree and consult note. Improvements in the computer program's technical design would potentially minimize data manipulation. Certain aspects of this program, such as electronic collection of family history and risk assessment, appear effective in improving cancer genetic counseling efficiency while others, such as generating an electronic pedigree and consult note, do not. PMID- 21240561 TI - Do perioperative blood transfusions influence prognosis of gastric cancer patients? Analysis of 927 patients and interactions with splenectomy. AB - BACKGROUND: This study was to assess the influence of perioperative blood transfusions on the prognosis of patients undergoing a potentially curative resection for gastric cancer and to investigate the interaction between transfusions and splenectomy. MATERIALS AND METHODS: Between January 1990 and December 2005, 927 patients from 6 Italian tertiary referral centers underwent curative resections for gastric cancer. Clinical and pathologic variables were prospectively collected. The influence of perioperative blood transfusions on survival were evaluated by univariate and multivariate analysis. Moreover, the influence of splenectomy both in transfused and nontransfused patients undergoing total gastrectomy was also evaluated. RESULTS: The overall 5-year survival was 54.6%. The 5-year survival rate in transfused patients (n = 327) was 50.6% compared with 56.6% in nontransfused patients (n = 600) (P = .094). In the subgroup of patients who underwent total gastrectomy with spleen preservation (n = 209), 5-year survival rate was 46% and 51.4% in transfused and nontransfused patients, respectively (P = .418); those who underwent total gastrectomy with splenectomy (n = 199) presented a 5-year survival rate of 45% in transfused group compared with 39.1% in nontransfused patients (P = .571). CONCLUSIONS: Our study indicates a slightly, but not significantly, negative effect of allogeneic blood transfusion on prognosis of gastric cancer patients. In the subgroup of patients who underwent total gastrectomy, splenectomy seems to invert this mild effect, with a positive influence on overall survival. PMID- 21240562 TI - Risk factors, prognosis, and management of early and late intrahepatic recurrence after resection of primary clear cell carcinoma of the liver. AB - BACKGROUND: Primary clear cell carcinoma of the liver (PCCCL) is an uncommon variant of hepatocellular carcinoma (HCC). The prognostic factors influencing its recurrence and survival are not clarified. This study is to evaluate the predictive factors, the therapy, and prognosis of intrahepatic recurrences after resection of PCCCL. METHODS: A total of 214 PCCCL patients treated by curative resection from January 1996 to March 2006 were retrospectively analyzed. Intrahepatic recurrences were classified into early (<=1 year) and late (>1 year) recurrences. RESULTS: The 1-, 3-, and 5-year overall survival (OS) rates for PCCCL patients were significantly better than those of HCC patients (P = .001). Serum a-fetoprotein (AFP) level, tumor size, liver cirrhosis, and vascular invasion were independent risk factors for both OS and disease-free survival (DFS) of PCCCL. Early and late intrahepatic recurrences developed in 28 patients and 71 patients, respectively. In multivariate analysis, ALT level and vascular invasion were independent risk factors for early recurrence, whereas age was the only significant risk factor for late recurrence. OS of late-recurrence group was significantly better than that of early-recurrence group (P = .001), and re resection rate was higher in late than in early-recurrence group (P = .04). The 1 , 3-, and 5-year OS of patients with recurrence who received curative treatment was comparable to those who never had tumor recur (P = .71). CONCLUSION: PCCCL has a better prognosis and tends to recur later than HCC. Early and late recurrences of PCCCL are linked to different predictive factors. The time to recurrence and feasibility of curative treatment are the best determinants for the prognosis. PMID- 21240563 TI - An exclusion principle and the importance of mobility for a class of biofilm models. AB - Much of the earth's microbial biomass resides in sessile, spatially structured communities such as biofilms and microbial mats, systems consisting of large numbers of single-celled organisms living within self-secreted matrices made of polymers and other molecules. As a result of their spatial structure, these communities differ in important ways from well-mixed (and well-studied) microbial systems such as those present in chemostats. Here we consider a widely used class of 1D biofilm models in the context of a description of their basic ecology. It will be shown via an exclusion principle resulting from competition for space that these models lead to restrictions on ecological structure. Mathematically, this result follows from a classification of steady-state solutions based on a 0 stability condition: 0-stable solutions are in some sense determined by competitive balance at the biofilm base, whereas solutions that are not 0-stable, while less dependent on conditions at the biofilm base, are unstable at the base. As a result of the exclusion principle, it is argued that some form of downward mobility, against the favorable substrate gradient direction, is needed at least in models and possibly in actuality. PMID- 21240565 TI - Selenium, copper and zinc in seminal plasma of men with varicocele, relationship with seminal parameters. AB - Varicocele has been associated with decrease in seminal parameters. Selenium (Se), copper (Cu), and zinc (Zn) are trace elements essential for normal spermatogenesis of mammals and play a critical role as antioxidant defense system enzymes. Se, Cu, and Zn are associated with sperm quality in fertile and infertile men. However, there is little information about Se, Cu, and Zn concentrations in semen in patients with varicocele and its association with seminal parameters. The purpose of this study was to determine the concentrations of Se, Cu, and Zn in semen of patients with varicocele and the relationship with seminal parameters. Total Reflection X-Ray Fluorescence was used for the fist time in the seminal fluid analysis. The concentration of selenium in men with varicocele was smaller than the normozoospermic group, while no differences were observed for both concentrations of zinc and copper. A significant positive correlation between zinc and selenium concentration was observed. Selenium in seminal plasma correlates with a good spermatozoa concentrations, motility, and morphology. Additionally, a significant positive correlation was observed between zinc levels and sperm count. In conclusion, a decrease in selenium concentration was associated with detriment of seminal parameters. A study should be conducted to evaluate the benefits of both zinc and selenium supplementation to improve seminal parameters in patients with varicocele. PMID- 21240564 TI - Insulin stimulates lipogenesis and attenuates Beta-oxidation in white adipose tissue of fed rainbow trout. AB - As lipid deposition tissue in fish, the white adipose tissue (WAT) has important functions related to reproduction and the challenges of long-term fasting. In the study reported here, we infused fish fed a high-carbohydrate diet with two doses of insulin for 5 days in order to explore the effects of this hormone on lipogenesis and beta-oxidation-related enzymes. We demonstrated the presence of some of the main lipogenic enzymes at molecular, protein and activity levels (ATP citrate lyase and fatty acid synthase). However, while ATP-citrate lyase was unexpectedly down-regulated, fatty acid synthase was up-regulated (at protein and activity levels) in an insulin dose-dependent manner. The main enzymes acting as NADPH donors for lipogenesis were also characterized at biochemical and molecular levels, although there was no evidence of their regulation by insulin. On the other hand, lipid oxidation potential was found in this tissue through the measurement of gene expression of enzymes involved in beta-oxidation, highlighting two carnitine palmitoyltransferase isoforms, both down-regulated by insulin infusion. We found that insulin acts as an important regulator of trout WAT lipid metabolism, inducing the final stage of lipogenesis at molecular, protein and enzyme activity levels and suppressing beta-oxidation at least at a molecular level. These results suggest that WAT in fish may have a role that is important not only as a lipid deposition tissue but also as a lipogenic organ (with possible involvement in glucose homeostasis) that could also be able to utilize the lipids stored as a local energy source. PMID- 21240566 TI - Toxic effect of nickel (Ni) on growth and metabolism in germinating seeds of sunflower (Helianthus annuus L.). AB - To assess the toxic effect of nickel (Ni) on the growth and some key metabolic processes in sunflower, varying levels of Ni as Ni(NO(3))(2) up to 60 mg L(-1) were applied once to sunflower cultivars SF-187 and Hysun-33 at sowing time in sand culture. An increase in Ni in the growth medium adversely affected growth parameters, sugar concentration (both reducing and non-reducing), as well as the activities of alpha-amylase and protease. It also slowed down mobilization of stored proteins and amino acids in the germinating seeds. However, an increase in the activities of alpha-amylase and protease was observed over time from 24 to 120 h after sowing. Cultivar Hysun-33 showed better performance than SF-187 in the presence of excess Ni. Overall, Ni-induced reduction in germination of sunflower seed appeared to be due to disturbance in biochemical metabolism as the availability of sugars for the synthesis of metabolic energy as well as necessary amino acids for the synthesis of proteins and enzymes essential for the growing embryo are generally reduced due to suppression in alpha-amylase and protease activities. PMID- 21240567 TI - Effect of different levels of copper and molybdenum supplements on performance, nutrient digestibility, and follicle characteristics in cashmere goats. AB - A 2 * 3 factorial arrangement of treatments was used to investigate the effects of different levels of copper (Cu, 0, 19, and 38 mg/kg, dry matter (DM)) and molybdenum (Mo, 0 and 5 mg/kg, DM) supplements and an interaction of these two factors on growth performance, nutrient digestibility, and cashmere and follicle characteristics in cashmere goats. Thirty-six Liaoning cashmere goats (approximately 1.5 years of age; 27.53 +/- 1.38 kg of body weight) were assigned randomly to one of six treatments and fed with Chinese wildrye- and alfalfa hay based treatment diets (the basal diet contained 4.72 mg Cu/kg, 1.65 mg Mo/kg, and 0.21% S.). Body weight was measured on two consecutive days at the start and the end of the 70-day experimental period. On day 30, the metabolism trial was conducted to study the effects of dietary Cu and Mo on nutrient digestibility. The cashmere and skin samples were collected on day 70. Copper supplementation increased (P < 0.05) growth performance and fiber digestion, but there were no differences (P > 0.05) between Cu-supplemented groups. Addition of 19 mg Cu/kg DM increased (P < 0.05) cashmere growth length or growth rate by increasing the number of active secondary follicles. Molybdenum supplementation decreased (P < 0.05) growth, but did not affect (P > 0.05) nutrient digestion, cashmere, and follicle characteristics. There is a tendency or significant interaction effect of Cu and Mo on growth performance (P = 0.057), cashmere growth (P = 0.076), or diameter (P < 0.05) which might be accomplished by changing the number of secondary follicle and active secondary follicle, and secondary to primary follicle ratio. In conclusion, the optimal supplemental Cu level for Liaoning cashmere goats fed with the basal diet was 19 mg/kg DM (the total dietary Cu level of 23.72 mg/kg DM), while 38 mg Cu/kg DM supplementation was found to be needed when 5 mg Mo/kg was added in the basal diet during the cashmere growing period. PMID- 21240568 TI - Selenium-vitamin E combination and melatonin modulates diabetes-induced blood oxidative damage and fetal outcomes in pregnant rats. AB - Oxidative stress is considered to be the main cause of diabetic complications. In the current study, we investigated the effect of selenium-vitamin E combination and melatonin on lipid peroxidation (LPO) and scavenging enzyme activity in the blood of streptozocin (STZ)-induced diabetic pregnant rats. Forty female Wistar rats were randomly divided into five groups. The first and second groups were used as the non-pregnant control and pregnant control groups, respectively. The third group was the pregnant diabetic group. Vitamin E plus selenium and melatonin were administered to the diabetic pregnant rats consisting fourth and fifth groups, respectively. Diabetes was induced on day 0 of the study by STZ. Blood samples were taken from all animals on the 20th day of pregnancy. LPO level was higher in diabetic pregnant rats than in control, although superoxide dismutase, catalase, and glutathione peroxidase activities were lower in diabetic pregnant animals than in control. LPO levels were lower both in the two treatment groups than in the diabetic pregnant rats, whereas selenium-vitamin E combination and melatonin caused a significant increase in the activities of these antioxidant enzymes (p<0.01). In conclusion, vitamin E plus selenium seems to be a more potent antioxidant compared to melatonin in diabetic pregnant rats. Melatonin did not significantly affect the elevated glucose concentration of diabetic pregnant treated with melatonin group. Vitamin E plus selenium may play a role in preventing diabetes-related diseases of pregnant subjects. PMID- 21240569 TI - Effects of radiofrequency electromagnetic wave exposure from cellular phones on the reproductive pattern in male Wistar rats. AB - The present study investigates the effect of free radical formation due to mobile phone exposure and effect on fertility pattern in 70-day-old male Wistar rats (sham exposed and exposed). Exposure took place in Plexiglas cages for 2 h a day for 35 days to mobile phone frequency. The specific absorption rate was estimated to be 0.9 W/kg. An analysis of antioxidant enzymes glutathione peroxidase (P < 0.001) and superoxide dismutase (P < 0.007) showed a decrease, while an increase in catalase (P < 0.005) was observed. Malondialdehyde (P < 0.003) showed an increase and histone kinase (P = 0.006) showed a significant decrease in the exposed group. Micronuclei also show a significant decrease (P < 0.002) in the exposed group. A significant change in sperm cell cycle of G(0)-G(1) (P = 0.042) and G(2)/M (P = 0.022) were recorded. Generation of free radicals was recorded to be significantly increased (P = 0.035). Our findings on antioxidant, malondialdehyde, histone kinase, micronuclei, and sperm cell cycle are clear indications of an infertility pattern, initiated due to an overproduction of reactive oxygen species. It is concluded that radiofrequency electromagnetic wave from commercially available cell phones might affect the fertilizing potential of spermatozoa. PMID- 21240570 TI - Granular cell tumour of the thyroid gland: a case report and review of the literature. AB - Granular cell tumours of the thyroid gland are rare, with only six previously reported cases in the English literature. Current histological, immunohistochemical and electron microscopic evidence favours a neural/Schwannian relationship. A case of a granular cell tumour of the thyroid gland in a healthy 36-year-old woman is described. The tumour was found incidentally following a right thyroid lobectomy for symptoms from an asymmetric multinodular goitre. Macroscopically, the lesion resembled a papillary microcarcinoma. Microscopically, the tumour was composed of nests of epithelioid cells with abundant granular, eosinophilic cytoplasm. The nests were divided by fibrous septa and peripherally interdigitated with surrounding thyroid follicles. Immunohistochemistry helped to distinguish the lesion from other neoplasms such as Hurthle cell tumour, medullary carcinoma or metastasis, and also from a histiocytic reaction to previous fine needle aspiration. On the basis of this diagnosis, no further intervention was required, and the patient was discharged following post-operative review. PMID- 21240572 TI - Dynamic visual perception and reading development in Chinese school children. AB - The development of reading skills may depend to a certain extent on the development of basic visual perception. The magnocellular theory of developmental dyslexia assumes that deficits in the magnocellular pathway, indicated by less sensitivity in perceiving dynamic sensory stimuli, are responsible for a proportion of reading difficulties experienced by dyslexics. Using a task that measures coherent motion detection threshold, this study examined the relationship between dynamic visual perception and reading development in Chinese children. Experiment 1 compared the performance of 27 dyslexics and their age- and IQ-matched controls in the coherent motion detection task and in a static pattern perception task. Results showed that only in the former task did the dyslexics have a significantly higher threshold than the controls, suggesting that Chinese dyslexics, like some of their Western counterparts, may have deficits in magnocellular pathway. Experiment 2 examined whether dynamic visual processing affects specific cognitive processes in reading. One hundred fifth grade children were tested on visual perception and reading-related tasks. Regression analyses found that the motion detection threshold accounted for 11% and 12%, respectively, variance in the speed of orthographic similarity judgment and in the accuracy of picture naming after IQ and vocabulary size were controlled. The static pattern detection threshold could not account for any variance. It is concluded that reading development in Chinese depends to a certain extent on the development of dynamic visual perception and its underlying neural pathway and that the impact of visual development can be specifically related to orthographic processing in reading Chinese. PMID- 21240571 TI - Nutrition therapy and the management of obesity and diabetes: an update. AB - Diabetes and obesity have each become a national health crisis in recent years. The number of people who have diabetes and prediabetes continues to grow with a predicted number of 336 million people worldwide with type 2 diabetes by 2030. The prevalence of diabetes has risen in parallel with the increased prevalence of obesity. The optimal nutrition therapy for the treatment of both diabetes and obesity remains controversial. Health care practitioners are no longer solely prescribing the conventional low-fat, higher-carbohydrate diet approach that was used for over a decade. Lower-carbohydrate, higher-fat, or higher-protein diets are now being viewed as equally or sometimes more effective treatment plans for diabetes and obesity. In addition, there are other aspects of diet beyond macronutrient composition that are currently being investigated. This article will summarize research conducted over the past 2 years examining medical nutrition therapy for diabetes and obesity. It will also describe the unique challenges that come with treating this patient population. PMID- 21240573 TI - Synchronous squamous cell carcinoma of tongue and unicentric cervical Castleman's disease clinically mimicking a stage IV disease: a rare association or coincidence? AB - Malignancy in a setting of hyaline vascular type of Castleman's disease (HVCD) is an exceptional occurrence. Herein, we report an extremely rare case of synchronous unicentric cervical HVCD and squamous cell carcinoma (SCC) of tongue mimicking stage IV disease. A 32-year-old gentleman presented with an ulcerated mass on the right tongue border and ipsilateral cervical nodal mass. As the clinical stage was IVB (T(1)N(3)M(0)), an anterior two-third glossectomy with bilateral modified neck dissection was performed. On gross examination, an ulcerated mass on the right lateral border was identified. In addition, an 8 cm large nodal mass at right level III-V was seen. Microscopy from the ulcerated growth in the tongue revealed an invasive well differentiated squamous cell carcinoma. However, the right cervical nodal mass yielded surprise histology of Castleman's disease, hyaline-vascular type. Final tumor pathological staging was revised to pT1N0M0 . This case reveals that HVCD can rarely be associated with an epithelial malignancy wherein it can clinically mimic nodal metastasis. Whether such a phenomenon occurs due to underlying immune aberrations or is a rare co incidence remains unclear. PMID- 21240574 TI - Cyclodextrin-based nanosponges for delivery of resveratrol: in vitro characterisation, stability, cytotoxicity and permeation study. AB - The aim of this work was to increase the solubility, stability and permeation of resveratrol by complexation with cyclodextrin-based nanosponges (NS). Nanosponges are recently developed hyper-cross-linked cyclodextrin polymers nanostructured to form three-dimensional networks; they are obtained by reacting cyclodextrin with a cross-linker such as carbonyldiimidazole. They have been used to increase the solubility and stability of poorly soluble actives. This study aimed at formulating complexes of resveratrol with beta-cyclodextrin nanosponges in different weight ratios. DSC, FTIR and X-ray powder diffraction (XRPD) studies confirmed the interaction of resveratrol with NS. XRPD showed that the crystallinity of resveratrol decrease after encapsulation. The particle sizes of resveratrol-loaded NS are in between 400 to 500 nm with low polydispersity indices. Zeta potential is sufficiently high to obtain a stable colloidal nanosuspension. TEM measurement also revealed a particle size around 400 nm for NS complexes. The in vitro release and stability of resveratrol complex were increased compared with plain drug. Cytotoxic studies on HCPC-I cell showed that resveratrol formulations were more cytotoxic than plain resveratrol. The permeation study indicates that the resveratrol NS formulation showed good permeation in pigskin. The accumulation study in rabbit mucosa showed better accumulation of resveratrol NS formulation than plain drug. These results signify that resveratrol NS formulation can be used for buccal delivery and topical application. PMID- 21240575 TI - NIR spectroscopy applications in the development of a compacted multiparticulate system for modified release. AB - The purpose of this study was to utilize near-infrared spectroscopy and chemical imaging to characterize extrusion-spheronized drug beads, lipid-based placebo beads, and modified release tablets prepared from blends of these beads. The tablet drug load (10.5-19.5 mg) of theophylline (2.25 mg increments) and cimetidine (3 mg increments) could easily be differentiated using univariate analyses. To evaluate other tablet attributes (i.e., compression force, crushing force, content uniformity), multivariate analyses were used. Partial least squares (PLS) models were used for prediction and principal component analysis (PCA) was used for classification. The PLS prediction models (R (2) >0.98) for content uniformity of uncoated compacted theophylline and cimetidine beads produced the most robust models. Content uniformity data for tablets with drug content ranging between 10.5 and 19.5 mg showed standard error of calibration (SEC), standard error of cross-validation, and standard error of prediction (SEP) values as 0.31, 0.43, and 0.37 mg, and 0.47, 0.59, and 0.49 mg, for theophylline and cimetidine, respectively, with SEP/SEC ratios less than 1.3. PCA could detect blend segregation during tableting for preparations using different ratios of uncoated cimetidine beads to placebo beads (20:80, 50:50, and 80:20). Using NIR chemical imaging, the 80:20 formulations showed the most pronounced blend segregation during the tableting process. Furthermore, imaging was capable of quantitating the cimetidine bead content among the different blend ratios. Segregation testing (ASTM D6940-04 method) indicated that blends of coated cimetidine beads and placebo beads (50:50 ratio) also tended to segregate. PMID- 21240576 TI - 50 Years ago in CORR: A sterilizable container for special instruments and internal fixation apparatus for operating-room orthopaedic surgery procedures William Compere Basom MD CORR 1959;13:327-328. PMID- 21240577 TI - Propionibacterium acnes infection as an occult cause of postoperative shoulder pain: a case series. AB - BACKGROUND: Infections after shoulder surgery are potentially devastating complications. Propionibacterium acnes is recognized as a causal agent in shoulder infections. The clinical presentation is usually insidious and nonspecific, but a P. acnes infection could be an occult cause of postoperative shoulder pain. QUESTIONS/PURPOSES: What are the clinical and microbiologic characteristics of a postsurgical P. acnes shoulder infection and how should it be addressed? PATIENTS AND METHODS: Ten patients with an average age of 57 years presented with P. acnes postsurgical shoulder infection. Clinical infection signs and surgical history were assessed and joint aspirates and tissue biopsy specimens were obtained. Diagnosis was confirmed by microbiologic cultures. RESULTS: At the time of confirmation of the diagnosis, clinical signs of infection were absent. C-reactive protein and erythrocyte sedimentation rates were inconsistently elevated. Cultures took a mean 7 days to confirm organism growth. The average time from surgery to diagnosis of infection was 1.8 years (range, 0.07-8.0 years). All patients underwent irrigation and debridement and were treated with antibiotics for 6 weeks. CONCLUSIONS: P. acnes shoulder infections should be considered as a cause for persistent, unexplained shoulder pain. Shoulder aspirations and tissue samples should be obtained. Surgical debridement and intravenous antibiotics are necessary treatment modalities. LEVEL OF EVIDENCE: Level IV, Prognostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID- 21240578 TI - Clinical cartilage restoration: evolution and overview. AB - BACKGROUND: Clinical cartilage restoration is evolving, with established and emerging technologies. Randomized, prospective studies with adequate power comparing the myriad of surgical techniques used to treat chondral injuries are still lacking and it remains a challenge for the surgeon treating patients to make evidence-based decisions. QUESTIONS/PURPOSES: We reviewed the history of the major cartilage repair/restorative procedures, indications for currently available repair/restorative procedures, and postoperative management. METHODS: We performed searches using MEDLINE and cartilage-specific key words to identify all English-language literature. Articles were selected based on their contributions to our current understanding of the basic science and clinical treatment of articular cartilage lesions or historical importance. We then selected 77 articles, two of which are articles of historical importance. RESULTS: Current cartilage restorative techniques include debridement, microfracture, osteochondral fragment repair, osteochondral allograft, osteochondral autograft, and autologous chondrocyte transplantation. Pending techniques include two-staged cell-based therapies integrated into a variety of scaffolds, single-stage cell-based therapy, and augmentation of marrow stimulation, each with suggested indications including lesion size, location, and activity demands of the patient. The literature demonstrates variable improvements in pain and function contingent upon multiple variables including indications and application. CONCLUSIONS: For the patient with symptomatic chondral injury, numerous techniques are available to the surgeon to relieve pain and improve function. Until rigorous clinical trials (prospective, adequately powered, randomized control) are available, treatment decisions should be guided by expert extrapolation of the available literature based in historically sound principles. PMID- 21240579 TI - ADAM12 and ADAM17 gene expression in laser-capture microdissected and non microdissected breast tumors. AB - ADAM (a disintegrin and metalloprotease)12 and ADAM17 are multidomain transmembrane proteins involved in ectodomain shedding of cytokines, growth factors and adhesion molecules, with pivotal activities in the tumor microenvironment. The aim of this study was to confirm the up-regulation of ADAM17 and ADAM12 gene splicing variants in breast tumors and to delineate their expression between laser-capture microdissected (LCM) and non-microdissected breast tumors. The gene expression was analyzed by quantitative-reverse transcription-PCR in a total sample of 109 breast tumors paired with corresponding non-neoplastic breast tissues. ADAM12 and 17 proteins expression for corresponding tissue samples was confirmed by immunohistochemistry. ADAM12S, 12L and 17 genes were significantly up-regulated in either malign or benign LCM samples when compared to non-tumor controls. For non-LCM samples, it was obtained also an increased expression for ADAM12 and 17 genes in cancers, while in benign tumors only ADAM12 variants were significantly up-regulated compared to controls. When benign versus malignant tumors were compared, in LCM samples all investigated genes displayed a higher expression in cancers, whereas in non-LCM, ADAM12 variants were overexpressed in benign samples. The increased expression of ADAM12 protein in the tumor cells and stroma of benign breast diseases was immunohistochemically confirmed. These differences between LCM and non-LCM samples were explained by the contribution of the stroma to the expression of this marker. This study underlines the accuracy conferred by homogenous LCM samples on gene expression profiles and confers further evidence regarding the role of ADAM12 and 17 in the breast tumorigenesis and progression. PMID- 21240581 TI - Hantavirus pulmonary syndrome: encephalitis caused by virus Andes. AB - Hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome (HPS) are rodent-borne emerging diseases caused by members of the genus Hantavirus, family Bunyaviridae. Some species of hantavirus may cause encephalitis, but this is the first report in Andes virus associated to HPS. PMID- 21240582 TI - [In retrospect]. PMID- 21240580 TI - Topography of cerebellar deficits in humans. AB - The cerebellum is a key-piece for information processing and is involved in numerous motor and nonmotor activities, thanks to the anatomical characteristics of the circuitry, the enormous computational capabilities and the high connectivity to other brain areas. Despite its uniform cytoarchitecture, cerebellar circuitry is segregated into functional zones. This functional parcellation is driven by the connectivity and the anatomo-functional heterogeneity of the numerous extra-cerebellar structures linked to the cerebellum, principally brain cortices, precerebellar nuclei and spinal cord. Major insights into cerebellar functions have been gained with a detailed analysis of the cerebellar outputs, with the evidence that fundamental aspects of cerebrocerebellar operations are the closed-loop circuit and the predictions of future states. Cerebellar diseases result in disturbances of accuracy of movements and lack of coordination. The cerebellar syndrome includes combinations of oculomotor disturbances, dysarthria and other speech deficits, ataxia of limbs, ataxia of stance and gait, as well as often more subtle cognitive/behavioral impairments. Our understanding of the corresponding anatomo functional maps for the human cerebellum is continuously improving. We summarize the topography of the clinical deficits observed in cerebellar patients and the growing evidence of a regional subdivision into motor, sensory, sensorimotor, cognitive and affective domains. The recently described topographic dichotomy motor versus nonmotor cerebellum based upon anatomical, functional and neuropsychological studies is also discussed. PMID- 21240583 TI - ["Medizinische Klinik" - prospects]. PMID- 21240585 TI - [Aortic dissection - a not so rare disease]. AB - BACKGROUND AND PURPOSE: Acute aortic dissection is a life-threatening disease with a high rate of mortality. The dissection of the artery with a distal blood flow can explain the variable and changeable symptoms. Aortic dissections require immediate diagnosis and therapy. METHODS: In the Institute of Legal Medicine of the Hannover Medical School, 34 cases of aortic dissection were found during autopsy between 2006 and 2009. The cases were analysed retrospectively. RESULTS: In the majority of cases (55.9%) an antemortem medical consultation has taken place. In only one case an aortic dissection could be diagnosed at a later time. CONCLUSION: Key in the management of acute aortic dissection is to maintain a high clinical index of suspicion for this diagnosis. Etiologically hereditary diseases (Marfan syndrome, Ehlers-Danlos syndrome, Loeys-Dietz syndrome) should be taken into consideration as a possible cause. In all unexpected deaths of young adults an autopsy should be performed to detect the cause of death and for genetic testing to provide information for the relatives in case an aortic aneurysm can be found. PMID- 21240584 TI - [Impairment of cardiac autonomic nervous system and incidence of arrhythmias in severe hyperglycemia]. AB - BACKGROUND AND PURPOSE: Deterioration of cardiac autonomic nervous system in diabetics is associated with increased cardiac and arrhythmogenic mortality. Therefore, the present study engaged in the question how heart rate variability is acutely changed in diabetic ketoacidosis or hyperglycemic hyperosmolar syndrome. Moreover was evaluated how blood pressure, heart rate and incidence of arrhythmias can be explained by figures of heart rate variability. PATIENTS AND METHODS: In a prospective observation of time course we investigated in 4 years consecutively 12 intensive care patients with DKA and 2 with HHS (10 male, 4 female, 19-62 years, initial plasma glucose 404-1192 mg/dl). All patients received a standardized treatment to international current guidelines. In addition to hemodynamic and clinical-chemical monitoring HRV analysis was performed continuously for at least 48 hours. Simultaneously, we determined supraventricular and ventricular arrhythmic episodes. RESULTS: HRV was diminished over the whole spectrum in dependence on blood glucose concentration. Thus, sympathovagal balance (LF/HF ratio) was initially sympathetic predominated in blood glucose levels < 600 mg/dl (relatively prevailing LF power) and vagal predominated in blood glucose levels > 600 mg/dl (relatively prevailing HF power). In correlation analysis of HRV parameters with blood glucose rS coefficients from -0.934 to -0.821 were achieved (p < 0.001). Further, the initial mean blood pressure correlated with the LF/HF ratio in HRV minimum (rS = 0.711, p = 0.004). The initial heart rate in relation to assumed intrinsic frequency correlated with minimal found Total Power (rS = -0.656, p = 0.011). In the period of whole 48 hours, more arrhythmic events occurred in consequence to initial glucose levels (rS = 0.693, p = 0.006). But the maximum of arrhythmic episodes was usually later ascertained than the minimum of HRV (p < 0.001). At the time of each arrhythmic maximum the sympathovagal balance (LF/HF) showed no uniform figures. Only similar in all cases was that the LF/HF ratio was found either > 4 or < 1. CONCLUSION: Clinical complications in high glucose levels must be seen in the context of a nearly complete blockade of sympathetic and parasympathetic activity. Basically to extreme autonomic restriction, sympathetic and vagal predominance can change rapidly into each other. This retarded vulnerable predisposition may declare the arrhythmic potential. An important progress in the monitoring of patients could be achieved by implementation of a continuous HRV measurement because hereby the actual risk potential can be ascertained timely and reliably. PMID- 21240586 TI - [Influence of the demographic change on hospital admissions and costs in Germany]. AB - BACKGROUND: In the next years the population of most western countries will age rapidly. Beside socioeconomic and social problems sustainable consequences on the health care system are expected. Ageing of the population will place a corresponding growth in demand of health care services and relating expenditures. The following analysis assesses the impact of demographic factors on hospital admissions and related costs over the next 30 years. METHOD: German Federal Statistical Office 12th coordinated population projection, diagnosis statistics and cost of illness data were used to develop a projection of future hospital admissions and associated economic burden. The model considers age- and sex specific differences. RESULTS: Ageing will increase all-cause hospital admissions by 12% between 2010 and 2040. Diseases of the circulatory system will have one of the most tremendous increases with an expected rise of 34% until 2040. In contrast, hospital stays because of mental and behavioural disorders will decrease by 9%. As hospital admissions rise we expect a further increase in overall expenditures for hospitalisations. DISCUSSION: Ageing of the population will further increase the demand for inpatient hospital services during the coming years. Nevertheless, the increase of hospital admissions will differ concerning single illness groups. The development of new care strategies should take these aspects into consideration. PMID- 21240588 TI - [Drug treatment of cystic fibrosis - cost patterns and savings potential for outpatient treatment]. AB - BACKGROUND AND PURPOSE: Drug treatment of cystic fibrosis (CF) is associated with significant costs. To help ensure sustainable care, this study assesses the costs associated with outpatient treatment of adult CF patients in Germany. It identifies main cost drivers, evaluates the potential for cost savings from "aut idem" substitution and presents a projection of lifelong medication costs. METHODS: The analysis is based on a complete set of prescriptions for adult CF patients from the outpatient clinic of the university hospital of Frankfurt am Main during 2007 (n = 124 patients). Annual treatment costs were calculated on the basis of the "Rote Liste", while the potential for cost savings from "aut idem" drug substitution was obtained through ABDATA Pharma Data Service. RESULTS: The annual outpatient drug costs for an adult patient with CF averages ? 17,219 (n = 124), which increases to ? 21,782 if i.v. therapies are included. With an average life expectancy at birth of 39.7 years, total lifetime drug treatment costs amount to ? 824,159 (reference year 2007, inflation rate 2.7%, 3% discount rate). "Aut idem" substitution with cheaper drugs could reduce pharmaceutical expenditures by 4.1%. CONCLUSION: Our results confirm the costly nature of drug treatment for CF patients, both on an annual and in particular on a lifelong basis. At the same time, the potential for cost savings through "aut idem" substitution with cheaper drugs remains limited. The added transparency around a small set of costdriving drugs, which is offered in this study, represents a solid contribution to assess treatment choices and financing options to help secure adequate yet sustainable care for CF patients. PMID- 21240587 TI - Health care workers and pertussis: an underestimated issue. AB - PURPOSE: Communicable and vaccine-preventable airway infections are a major public and occupational health issue. The epidemiology of pertussis has changed, with unprotected adults being the main source of infections. Thus, the prevention of a transmission from health care workers (HCWs) to patients is an important strategy to control this communicable infection. The Standing Committee on Vaccination (STIKO) at the Robert Koch-Institute in Germany has explicitly recommended that HCWs ought to be vaccinated against pertussis. However, vaccination rates among HCWs remain low. This study was meant to evaluate the attitudes of HCWs towards the pertussis vaccination and to determine the correlation between the influenza and pertussis vaccination status of HCWs. METHODS: An anonymous questionnaire was distributed to HCWs at a German university hospital. RESULTS: Overall, we found a disturbingly low level of awareness concerning official recommendations as to immunizations (35.6%) and the personal risk assessment of acquiring a work-related pertussis infection (23.2%). In general, both aspects were frequently associated with a refusal to get immunized. A strong correlation between the immunization status of pertussis and influenza was found among physicians: overall, 93.1% of physicians who were vaccinated against pertussis were also vaccinated against influenza. Nurses showed significantly weaker correlation rates as well as lower vaccination rates (p<0.05). CONCLUSIONS: Misconceptions about pertussis and low vaccination rates were prevalent among HCWs, particularly nurses. Hospital-based pertussis vaccination campaigns should focus on the risk of nosocomial pertussis transmission and on the new recommendations for pertussis immunization among adults and HCWs. PMID- 21240589 TI - Significant association of female gender with lower degree of pathological 99mTc sestamibi scintigraphy results as well as higher cardiac-related deaths free survival in elderly patients. AB - BACKGROUND: The aim of the present study was to assess the impact of female gender on the extent of myocardial perfusion defects as revealed by (99m)Tc sestamibi myocardial perfusion scintigraphy (MPS) and on emerging cardiac events (CE) in patients aged >= 70 years. PATIENTS AND METHODS: 86 patients aged >= 70 years with known or suspected CAD undergoing MPS (74.4 +/- 3.2 years; women: n = 46; 53.5%) were included in this study. Semiquantitative analysis of MPS was performed and summed stress (SSS), summed difference (SDS), and summed rest scores (SRS) were calculated. Emerging CE comprised myocardial revascularization and -infarction and cardiac-related death. Multivariate regression analysis was performed to assess the independent prognostic impact of several patient related variables on MPS results. Kaplan-Meier- and log rank analyses were calculated for assessment of CE free survival as related to gender. RESULTS: Normal SSS (87.0% vs. 27.5%; p < 0.0001), SDS (80.4% vs. 27.5%; p < 0.0001), and SRS (97.8% vs. 82.5%; p = 0.023) were significantly more often found in women, whereas incidence of mildly and severely impaired SSS (6.5% vs. 35%; p = 0.001 and 2.2% vs. 25%; p = 0.002, respectively) and SDS (15.2% vs. 52.5%; p < 0.0001 and 2.2% vs. 17.5%; p = 0.023, respectively) were significantly higher in men. Multivariate logistic regression analysis revealed female gender as an independent predictor of normal SSS (odds ratio/OR: 17.6) and SDS (OR: 53.3). Female gender was associated with a significant higher cardiac-death free survival compared to male patients (p = 0.031). CONCLUSION: Female gender is independently associated with a significantly lower degree of pathological MPS results and a higher cardiac-death free survival in elderly patients. PMID- 21240590 TI - [Coffee and diabetes]. AB - Lack of physical activity and high caloric diet are main causes for increasing diabetes prevalence. Thus, it is possible to influence blood glucose levels by lifestyle modifications. Coffee is an important lifestyle factor in Germany with a mean consumption of about 150 litres per inhabitant. It is important to know that coffee cannot be equated with caffeine. Scientific investigations have shown that caffeine can temporarily have a negative impact on cardiovascular risk factors but does not promote development of cardiovascular events. On the other hand, several international prospective studies demonstrate a protective effect of coffee on the development of type 2 diabetes as coffee consumption can reduce glucose uptake. Coffee components, e.g. chlorogenic acid, play a central role, as they can inhibit oxidative stress and inflammation in addition. In the context of lifestyle tasks coffee consumption therefore is an additional option for modifying diabetes risk. PMID- 21240592 TI - [Memorandum III "methods for health services research", Part 1 [authors: H. Pfaff, G. Glaeske, E. A. M. Neugebauer, M. Schrappe] and Part 2 [authors: E. A. M. Neugebauer, A. Icks, M. Schrappe] of the Deutsches Netzwerk Versorgungsforschung e.V.: A summary]. AB - This article presents an overview of the recently published first two parts of the Memorandum III "Methods for Health Services Research" discussed and approved by the member societies of the German Network Health Services Research [Deutsches Netzwerk Versorgungsforschung e.V.]. Part one of this memorandum covers methodical principles and minimum standards for the subject areas of health services research "Epidemiological Methods for Health Services Research", "Methods for Organisational Health Services Research" and "Methods for Quality of Life Research", the second part the topics "Methods of Health Economic Evaluation" and "Registries for the Health Services Research". The Memorandum is addressed to health services researchers and to reviewers who are planning, conducting, publishing studies as well as evaluating research proposals and publications. Assurance of quality and increase of the health services research are the aims of the Memorandum III. According to the advanced knowledge in health services research the Memorandum needs regular updates. Therefore the Memorandum has to be understood as "work in progress". PMID- 21240591 TI - [Pulmonary affection in advanced liver disease - hepatepulonary syndrome and portopulmonary hypertension]. AB - Patients suffering from severe chronic liver disease, in particular cirrhosis, are at risk for pulmonary complications. The leading clinical symptom is shortness of breath, which can accompany the actual disease as indirect effect because of anemia, faint muscles or ascites. On the other hand, dyspnea can have multiple additive causes in case of accompanying cardial or pulmonary disease. The hepatopulmonary syndrome (HPS) and the portopulmonary hypertension (PoPH) belong to the most relevant pulmonary complications in liver cirrhosis. HPS appears to be more common than PoPH and the presence of either entity increases morbidity and mortality in patients with liver disease. The two diseases have to be strictly distinguished, as they have opposed histological and pathophysiological origin. While the HPS is a dilatative pulmonary- vascular disease, the PoPH is a constrictive or obliterative pulmonary-vascular disease in the context of a liver disease or a portal hypertension. Therefore, these diseases are separate entities also when it comes to diagnostics and therapy. PMID- 21240593 TI - [From the design of use study to the assessment of the benefit: with or without pharmaceutical industry?]. AB - The financing of clinical studies by the pharmaceutical industry is a controversial topic both internationally and in here in Germany. The well-known unacceptable shortcomings require no further confirmation. It is, however, indisputable that the pharmaceutical industry and medical science are co dependent. Neither the marketing of industrial products nor the research and education of clinical scientists could function without this cooperation. Therefore, all partners need suggestions concerning goal orientation and consensus. The aim of this discussion is to formulate just such suggestions. To structure this discussion, we have raised the following questions: Must we always be suspicious of the results of studies financed by the pharmaceutical industry? We have to keep in mind that in Germany all clinical trials leading to approval of a drug were supported by the industry. What, exactly, do we want to achieve with our explicit and often justified criticism of these studies? What should be done to achieve a higher validity of the published data if we avoid answering the decisive question of whether we accept the challenge of continuing to let research and teaching be financed by the pharmaceutical industry or reject this kind of cooperation and support altogether. PMID- 21240595 TI - [Resistant hypertension despite nine different antihypertensive drugs?]. AB - BACKGROUND: Treatment-resistant hypertension is a common problem in an outpatient setting and often results in hospital admission. Non-identified secondary hypertension, hypertensive nephrosclerosis and non-compliance are major reasons for treatment resistance. CASE REPORT: A 75-year old woman was admitted to the emergency room because of a hypertensive crisis with alleged treatment-resistant hypertension and progressive headache. Two months ago, renal artery stenosis had been ruled out and a diagnosis of hypertensive cardiomyopathy was established. On admission, the patient had a blood pressure of 210/100 mmHg despite an antihypertensive treatment with nine different drugs. Further investigations ruled out secondary hypertension due to an endocrine cause but were consistent with hypertensive nephrosclerosis. With a supervised drug intake the blood pressure was rather normal to hypotensive, resulting in the need for significant reduction of the antihypertensive medication. The apparent discrepancies were discussed in detail with the patient who finally admitted a previous inconsistent intake of the antihypertensive drugs. Following thorough training and education on the purpose of continued antihypertensive therapy, the patient could be discharged with a normotensive blood pressure profile. CONCLUSIONS: Therapy of treatment-resistant hypertension should always consider non-compliance and secondary hypertension as possible reason. PMID- 21240596 TI - [Mesenterial lymphangiolipoma - a rare finding in an asymptomatic patient]. AB - BACKGROUND: Lymphangioma is an uncommon tumor, an intraperitoneal lymphangiolipoma is exceedingly rare. These tumors are principally benign, but lead to complications due to their size and localization. CASE REPORT: A 46 year old male patient presented for a regular medical check up. Apart from a hearing loss 2006 and 2008 he reported no previous or chronic diseases. An extensive health examination had been performed two years ago and had been without pathological results. Abdominal ultrasound revealed a large polycystic lesion in the right middle and lower abdomen, approximately 12x10x7 cm in size. There was no vascularisation in the septae. In MRI, the tumor appeared cystic as well without communication to the intestinal wall. Laboratory values including echinococcus serology was without pathological results. An explorative laparotomy was done with right hemicolectomy and subsequent ileotransversostomy. Histologically, a lymphangiolipoma was diagnosed, as well as a chronic appendicitis and chronic lymphangitis of the ileocolic lymph nodes. Postoperatively, the patient recovered without any complications. CONCLUSION: Lymphangiomas, especially lymphangiolipomas, are an extremely rare differential diagnosis of intraabdominal cystic tumors. Potential complications included ileus, intussusception or an immuring growth. Abdominal ultrasound can reveal important pathological findings even in symptom- free patients. PMID- 21240597 TI - [75-year old female with progressive idiopathic lung fibrosis]. AB - CASE REPORT: A 75-year old female was admitted to the intensive care unit because of a respiratory insufficiency during a bronchoscopy. Extubation was done rapidly. Two months before, the patient suffering from breast cancer without metastases underwent a radical mastectomy. Thoracic x-ray presented a progressive shadow. Differential diagnoses took into consideration neoplastic, infectious or immunologic causes. The following day the patient suffered from dyspnea. A cardiopulmonary resuscitation was without success. Obduction revealed a honeycomb lung. Histology presented an idiopathic lung fibrosis. PMID- 21240598 TI - [Liver cysts - a distinct progressive form]. PMID- 21240602 TI - Influence of protecting groups on the reactivity and selectivity of glycosylation: chemistry of the 4,6-o-benzylidene protected mannopyranosyl donors and related species. AB - The genesis and development of the 4,6-O-benzylidene acetal method for the preparation of beta-mannopyranosides are reviewed. Particular emphasis is placed on the influence of the various protecting groups on stereoselectivity and these effects are interpreted in the framework of a general mechanistic scheme invoking a series of solvent-separated and contact ion pairs in dynamic equilibrium with a covalent alpha-glycosyl trifluoromethanesulfonate. PMID- 21240603 TI - The end of the fat dodo? A new mass estimate for Raphus cucullatus. AB - A new mass estimate for the dodo (Raphus cucullatus), based on the lengths of the femur, tibiotarsus and tarsometatarsus, is attempted. The obtained mean mass is 10.2 kg, which is less than previous estimates based on other methods, which ranged from 10.6 to 21.1 kg, and much lower than the 50 lbs reported by a seventeenth-century eyewitness. The new estimated mass, which is similar to that of a large wild turkey, seems more realistic than previous ones and supports the hypothesis that contemporary illustrations of extremely fat dodos were either exaggerations, or based on overfed specimens. Pictures of "fat" dodos may also have been based on individuals exhibiting a display behaviour with puffed out feathers. PMID- 21240604 TI - [Progressive multifocal leukoencephalopathy under natalizumab. Initial possibilities for risk stratification?]. AB - Natalizumab (Tysabri(r)) is the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS) but while treatment is highly efficient, it carries the risk of progressive multifocal leukoencephalopathy (PML). Based on reports of confirmed cases of PML, the risk of PML might increase beyond 24 months of treatment. Thus, attempts to stratify patients treated with natalizumab into those carrying higher or lower risk for developing PML are currently being undertaken. Among these strategies JC virus serology might potentially be the first tool available. As a large variety of methods have been published resulting in controversial results for JC virus seroprevalence, standardized testing will be mandatory when applying this method in clinical practice. In addition, risk management strategies for the seropositive majority of patients need to be redefined and optimized further. PMID- 21240605 TI - Slow oscillatory eye movement during visual fixation. AB - A slow oscillatory eye movement was discovered in a 20-min-long recording. The frequency of this slow oscillation was lower than any known eye movement. Fixational eye movements were recorded in seven healthy subjects with four different recording techniques and with different sampling frequencies. The frequency of the oscillation is 0.04-0.10 Hz, and the amplitude is less than 0.2 degrees . Right and left eyes oscillate conjugately in the vertical direction implying a neural control. We suggest the oscillation to be a fourth movement in the fixational eye movement system. The influence of the oscillation on visual function is not known nor the underlying mechanism controlling the eye movement. PMID- 21240606 TI - The efficacy of coblation nucleoplasty for protrusion of lumbar intervertebral disc at a two-year follow-up. AB - PURPOSE: The purpose of this study was to evaluate longer-term efficacy over a two-year follow-up of coblation nucleoplasty treatment for protruded lumbar intervertebral disc. METHODS: Forty-two cases of protruded lumbar intervertebral disc treated by coblation nucleoplasty followed-up for two years were analysed. Relief of low back pain, leg pain and numbness after the operation were assessed by visual analogue pain scale (VAS). Function of lower limb and daily living of patients were evaluated by the Oswestry Disability Index (ODI). RESULTS: Operations were performed successfully in all cases. Three patients had recurrence within a week of the procedure. Evaluation of the 42 patients demonstrated significant improvement rate of VAS: defined as 66.2% in back pain, 68.1% in leg pain, and 85.7% in numbness at one-week after the operation; 53.2%, 58.4%, 81.0% at one-year; and 45.5%, 50.7%, 75.0% at two-year follow-up. One week after the operation, obvious amelioration occurred in all the patients, but the tendency decreased. Before operation, the mean value of ODI was 68.2 +/- 10.9%. The value at one week was 28.6 +/- 8.2%; one-year at 35.8 +/- 6.5%; and two-years at 39.4 +/- 5.8%. CONCLUSION: Coblation nucleoplasty may have satisfactory clinical outcomes for treatment of protruded lumbar intervertebral disc for as long as two-year follow-up, but longer-term benefit still needs verification. PMID- 21240608 TI - The breast lesion excision system (BLES): a novel technique in the diagnostic and therapeutic management of small indeterminate breast lesions? AB - OBJECTIVE: To investigate whether the breast lesion excision system (BLES) could render formal surgery unnecessary in patients with small indeterminate breast lesions. METHODS: Following review board ethical permission and the consent of each patient, we aimed to perform a complete excision biopsy, with a margin, of small indeterminate breast lesions that measure less than 1 cm. 76 patients with small BIRADS type 3 breast lesions underwent a BLES biopsy. Mean radiological lesion size was 7.1 mm (range 2-10 mm). RESULTS: 61 lesions had a final benign diagnosis, 6 of which underwent subsequent surgery although only 1 showing residual lesion. 15 lesions were malignant but with residual tumour at re excision present in only 5 cases. CONCLUSION: The BLES biopsy is an efficacious technique at excising small indeterminate breast lesions with a complete margin without the need for follow-up diagnostic surgery in the majority. PMID- 21240607 TI - Toxicity of antiseptics against chondrocytes: what is best for the cartilage in septic joint surgery? AB - In septic joint surgery, the most frequently used antiseptics are polyhexanide, hydrogen peroxide and taurolidine. The aim of this study was to examine the effects of these antiseptics on viability of human chondrocytes. Our hypothesis was that antiseptics and supplemental irrigation with sodium chloride lavage are less toxic on human chondrocytes than treatment with antiseptics only. Primary human chondrocytes were isolated and cultured from six donated human knee joints. Polyhexanide, hydrogen peroxide or taurolidine were added to the cultures. Toxicity analysis was performed by visualisation of cell structure using light microscopy and LDH activity. The determination of vital cells and total cell numbers of chondrocytes treated with antiseptics partly followed by irrigation with sodium chloride solution was performed by using Casy Cell-Counter. Light microscopic data revealed a defect in cell structure after addition of antiseptics. We showed a significant increase of LDH enzyme activity after the treatment with polyhexanide or taurolidine. After treatment with antiseptics followed by sodium chloride solution a significant increase of vital and total cell numbers resulted in comparison with the chondrocytes that were only treated with antiseptics. The data show that treatment with polyhexanid, hydrogen peroxide or taurolidine induces cell death of human chondroctes in vitro. The application of sodium chloride solution after the treatment with polyhexanide and hydrogen peroxide possibly has a protective effect on chondrocyte viability. PMID- 21240609 TI - A technical innovation in paediatric chest wall reconstruction. AB - INTRODUCTION: Extensive paediatric chest wall resections and reconstructions are a surgical challenge. Chest wall reconstruction is well known to be associated with chest wall deformity, scoliosis and restrictive lung disease. MATERIALS AND METHODS: We describe, via illustrative cases, the technical innovation of paediatric chest wall reconstruction following tumour resection with titanium rib replacement. RESULTS: The results from this chest wall reconstruction technique have been cosmetically excellent. Both cases, following significant chest wall resections, did not require post-operative ventilation and have returned to normal function. CONCLUSIONS: This Novel Paediatric Chest wall reconstruction technique is ideally suitable after extensive chest wall resection. It has provided stability and protection of underlying viscera and may prevent scoliosis. PMID- 21240610 TI - The vacuum bell for conservative treatment of pectus excavatum: the Basle experience. AB - OBJECTIVE: Surgical repair of pectus excavatum (PE) in childhood is a well established procedure. Previously used operative techniques to correct PE were largely based on the Ravitch technique. Since about 10 years, the minimally invasive repair (MIRPE) by Nuss is well established. Conservative treatment with the vacuum bell to elevate the funnel in patients with PE represents a potential alternative to surgery in selected patients. METHODS: A suction cup is used to create a vacuum at the anterior chest wall. Three different sizes of vacuum bell exist which are selected according to the individual patients age. When creating the vacuum, the lift of the sternum is obvious and remains for a different time period. The device should be used for a minimum of 30 min (twice/day), and may be used up to a maximum of several hours daily. RESULTS: One hundred and thirty three patients (110 males, 23 females) aged from 3 to 61 years (median 16.21 years) used the vacuum bell for 1 to a maximum of 36 months. Computed tomographic scans showed that the device lifted the sternum and ribs immediately. In addition, this was confirmed thoracoscopically during the MIRPE procedure. One hundred and five patients showed a permanent lift of the sternum for more than 1 cm after 3 months of daily application. Thirteen patients stopped the application and underwent MIRPE. Relevant side effects were not noted. CONCLUSION: The vacuum bell has proved to be an alternative therapeutic option in selected patients suffering from PE. The initial results proved to be dramatic, but long-term results are so far lacking, and further evaluation and follow-up studies are necessary. PMID- 21240611 TI - Effects of neuromodulation with sacral magnetic stimulation for intractable bowel or bladder dysfunction in postoperative patients with anorectal malformation: a preliminary report. AB - BACKGROUND AND PURPOSE: The effects of neuromodulation with sacral magnetic stimulation (SMS) were examined in postoperative patients with bowel or bladder dysfunction. PATIENTS AND METHODS: SMS was performed at the S3 level using a MagPro(r) instrument (Medtronic Inc., USA) while the patients were under light sedation. One treatment course consisted of stimulation delivered at 15 Hz for 5 s, 10 times over an interval of 1 min. Three patients with bladder or bowel dysfunction refractory to conservative treatment were examined. RESULTS: Case 1 is a 7-year-old male with a rectourethral fistula. This patient developed a hyperdynamic bladder after a laparoscopic pull-through operation at the age of 7 months. The administration of an anticholinergic agent slightly improved the condition. SMS was started at the age of 4 years with one trial each year. A marked expansion of bladder volume from 20 ml before trial to 120 ml after the third trial was obtained. Case 2 (a 4-year old female with a recto-vaginal fistula) and Case 3 (a 8-year-old female with an ano-vestibular fistula) showed severe constipation after radical surgery during infancy. Case 2 needed appendicostomy. After SMS, bowel movements could become controllable with enemas. No adverse effects were observed for any of the three cases. CONCLUSIONS: These results suggest that SMS might be a useful modality to improve postoperative bowel or bladder dysfunction. PMID- 21240612 TI - Therapeutic strategy for persistent cloaca: the efficacy of antegrade continent enema as a salvage surgery. AB - PURPOSE: The aim of this study is to evaluate our therapeutic strategy for persistent cloaca from the viewpoint of long-term functional outcome. MATERIALS AND METHODS: This study covers 17 cases of persistent cloaca treated at our institution and followed for more than 3 years. As a definitive repair for anorectal and urogenital systems, simultaneous surgery with posterior sagittal approach or anorecto-urethrovagino-plasty (PSARUVP) was performed. The length of the common channel and the shape of the vagina determined the vaginoplasty methods. Fecal function was assessed with the scoring system of the Japan Study Group of Anorectal Anomalies. RESULTS: Anorectoplasty was performed with the posterior sagittal approach in 15 cases and with the perineal approach in two. Vaginoplasty was performed with total urogenital mobilization in nine cases, rectal interposition in four, vaginal flap in two and with other methods. Fecal function was classified as good in three cases, moderate in ten, and poor in four. In the poor cases, Malone's antegrade continence enema (MACE) was performed, which improved fecal function significantly. CONCLUSION: PSARUVP might be the optimal surgery for persistent cloaca at present; however, satisfactory fecal function could not be achieved in those cases with a longer common channel. MACE effectively compensated for the poor outcome and was especially successful at eliminating incontinence. PMID- 21240613 TI - Cough hypersensitivity syndrome: a distinct clinical entity. AB - We postulate that most patients with chronic cough have a single discrete clinical entity: cough hypersensitivity syndrome. We constructed a questionnaire that elicits the major components of the syndrome. Here we describe the validation of this questionnaire. Following iterative development, the Hull Airway Reflux Questionnaire (HARQ) was administered to patients and normal volunteers. It is self-administered and comprises 14 items with a maximum score of 70. Unselected patients were recruited sequentially from the Hull Cough Clinic. Preclinic questionnaires were compared with those obtained at the clinic. Responsiveness was assessed 2 months after the clinic visit. One hundred eighty five patients and 70 normal volunteers were included in this study. There was a marked difference in HARQ scores between patients with chronic cough and normal volunteers. The sensitivity (94%) and specificity (95%) of the HARQ was high, with an area under the ROC curve of 0.99. All items of the scale significantly correlated positively with others in the scale and with the total score. On repeatability testing using Cohen's kappa with quadratic weights, significant agreement was noted for all items. Good correlation was observed between the total scores (r = 0.78). The questionnaire was also responsive to treatment; the minimum clinically significant change was estimated to be 16 points. We have demonstrated the HARQ to have good construct and criterion validity. It is both reproducible and responsive to change. It can be used as a diagnostic instrument and demonstrates that chronic cough represents a single coherent entity: cough hypersensitivity syndrome. PMID- 21240614 TI - High corn oil and extra virgin olive oil diets and experimental mammary carcinogenesis: clinicopathological and immunohistochemical p21Ha-Ras expression study. AB - Dietary lipids have a role in the aetiology of breast cancer, acting at several cellular levels. We investigated the effects of a high corn oil and a high extra virgin olive oil diet on the clinical and histopathological characteristics of rat dimethylbenz(alpha)anthracene-induced mammary carcinogenesis and on the expression of p21Ha-Ras, detected by immunohistochemistry, in one experimental series including a low-fat corn oil diet (LFCO) and two high-fat diet groups: HFCO(P), rich in corn oil, and HFOO(P), rich in extra virgin olive oil. Whereas the high corn oil diet tended to reduce latency time, to raise tumour incidence and to increase total tumour yield, the high extra virgin olive oil diet led to a latency time similar to that of LFCO and to a lower tumour incidence than HFCO(P) and lower total tumour yield, even than LFCO. HFCO(P) tumours displayed a higher histological grade and profile than LFCO tumours, while adenocarcinomas in HFOO(P) were similar to LFCO ones. Although no significant differences in p21Ha Ras expression among dietary groups was found, we detected a significant p21Ha Ras decreasing expression as grade increased, in groups LFCO and HFCO(P). HFOO(P) tumours exhibited a higher staining in high-grade carcinomas compared to the similar malignant tumours of the two other dietary groups. These data suggest that dietary lipids influence the clinical behaviour and the morphological malignancy of the experimental mammary carcinogenesis, according to the type of fat, without altering p21Ha-Ras expression. Nevertheless, this expression could be affected by the malignancy of tumours, probably through a post-translational event. PMID- 21240615 TI - Body mass index and annual increase of body mass index in long-term childhood cancer survivors; relationship to treatment. AB - PURPOSE: Evaluation of body mass index (BMI) at final height (FH) and annual BMI increase in adult childhood cancer survivors (CCS) after treatment with anthracyclines, platinum, and/or radiotherapy. METHODS: BMI (weight/height2) was calculated retrospectively from diagnosis until FH. The prevalence of underweight (BMI < 18.5 kg/m(2)) and overweight (BMI >= 25 kg/m(2))/obesity (BMI >= 30 kg/m(2)) at FH was compared with age-matched controls. The association between underweight/overweight at FH and treatment was assessed by multivariate logistic regression. Annual BMI increase after treatment was assessed by multilevel analysis. Analyses were adjusted for age and underweight/overweight at diagnosis, and age at FH. RESULTS: At FH the prevalence of overweight had not increased, while CCS experienced more underweight as compared to controls (14% vs. 4%, P < 0.001). Overweight at FH was associated with cranial/craniospinal radiotherapy (CRT; OR, 2.23; 95% CI, 1.17-4.26) and underweight at FH with anthracyclines > 300 mg/m(2) (OR, 2.84; 95% CI, 1.33-6.06). Annual BMI increase was +0.47 (0.34 0.60) kg/m(2)/year. In CCS, the annual BMI increase was greater in those with CRT >= 30 Gy as compared with those with less or no CRT (+0.15 kg/m(2)/year [0.04 0.25 kg/m(2)/year], P = 0.008) and smaller in those with a higher cumulative anthracycline dose (-0.03 kg/m(2)/year [-0.05 to -0.0005 kg/m(2)/year] per 100 mg/m(2), P = 0.046). CONCLUSIONS: After treatment with anthracyclines, platinum, and/or radiotherapy, CRT-treated survivors have more overweight at FH, and a greater annual BMI increase, while anthracycline-treated survivors have more underweight at FH and a lower annual BMI increase. PMID- 21240616 TI - Study of short-pulse laser propagation in biological tissue by means of the boundary element method. AB - Propagation of short pulses of light through biological tissues can be studied by numerically solving the diffusion equation. The boundary integral method was used to convert the differential equation to integral form and the result was solved using the boundary element method. The effects of different optical parameters of the tissue, i.e. scattering, absorption coefficients and anisotropic factor, on temporal evolution of the diffusely reflected pulse were studied. The results were compared with those obtained using the finite difference time domain method and the boundary integral method was found to be more precise and faster than the last method. The method can be used to investigate reflected pulses in the study of cell morphology and tumours in different types of tissue. PMID- 21240617 TI - Successful treatment of acquired hemophilia A, complicated by chronic GVHD, with tocilizumab. AB - A 65-year-old woman who had suffered from chronic graft-versus-host disease (GVHD) presented with extensive purpura and was diagnosed with acquired hemophilia A. Because she was refractory to corticosteroids and her condition was complicated with diabetes mellitus, glaucoma, and hypoglobulinemia, she was treated with tocilizumab. Tocilizumab treatment increased the activity of factor VIII in a rapid and sustained manner, leading to a reduction of the prednisolone dose. Tocilizumab may thus be an optional treatment modality for acquired hemophilia A. PMID- 21240618 TI - In rheumatoid arthritis patients treated with tocilizumab, the rate of clinical disease activity index (CDAI) remission at 24 weeks is superior in those with higher titers of IgM-rheumatoid factor at baseline. AB - We aimed to evaluate the efficacy of tocilizumab in patients with rheumatoid arthritis (RA), using the clinical disease activity index (CDAI), and to determine the baseline variables associated with CDAI remission. Fifty-eight patients with active RA were enrolled. We tried to evaluate whether baseline variables were associated with CDAI remission at 24 weeks. Twenty-two of the 58 patients (37.9%) had received tumor necrosis factor (TNF) inhibitors. The continuation rate of tocilizumab at 24 weeks was 87.9%. The seropositivity rates of IgM-rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies at baseline were both 91.4%. The rate of CDAI remission at 24 weeks was 20.7%. We selected baseline variables including age, gender, duration of disease, concomitant use of glucocorticoids, concomitant use of methotrexate (MTX), previous anti-TNF therapy, titer of anti-CCP antibodies (high or low toward median), titer of IgM-RF (high or low toward median), and CDAI, and found that a high titer of IgM-RF was the only variable to be associated with CDAI remission, according to univariate and logistic regression analyses. This is a new finding, and may be specific to tocilizumab as compared with previous observations in anti-TNF therapy. PMID- 21240619 TI - Pneumatosis cystoides intestinalis in neuropsychiatric systemic lupus erythematosus with diabetes mellitus: case report and literature review. AB - We report a patient with neuropsychiatric systemic lupus erythematosus (NPSLE) complicated by diabetes mellitus (DM) who showed pneumatosis cystoides intestinalis (PCI) while being treated with prednisolone (PSL) and an alpha glucosidase inhibitor (alphaGI). The PCI was ameliorated with the cessation of the alphaGI and tapering of PSL in addition to transient fasting. Multiple factors, including NPSLE, DM, and medications, may have been involved in the pathogenesis of PCI in this patient. PMID- 21240620 TI - Efficacy and safety of intravenous cyclophosphamide pulse therapy with oral prednisolone in the treatment of interstitial lung disease with systemic sclerosis: 4-year follow-up. AB - Interstitial lung disease (ILD) is a noteworthy condition in the treatment of systemic sclerosis (SSc) because of its associated mortality and morbidity; however, the efficacy of various treatments for ILD has been controversial in previous reports. In this study, we examined the efficacy and safety of intravenous cyclophosphamide (IVCY) pulse therapy with prednisolone (PSL) for the treatment of ILD with SSc. A total of 121 patients with SSc were screened and evaluated for ILD, using high-resolution computed tomography of the chest, pulmonary function testing, and bronchoalveolar lavage. Thirteen patients with active ILD were enrolled in this study. The treatment protocol for ILD was 0.4 g/m(2) of body surface area of IVCY monthly plus 0.8 mg/kg of body weight of PSL daily. Two to six doses of IVCY were administered, depending on the remission of ILD. Initial PSL doses were maintained for a month and then gradually tapered to 10 mg daily. An activity index of ILD showed improvements in all patients in the 12 months after the initial intervention; however, four patients experienced recurrence of ILD after 24 months, and one additional patient had recurrence of ILD after 36 months. Seven patients reached the 48-month point with no recurrence of ILD. This long observational study for 48 months showed the efficacy of IVCY with PSL for active alveolitis in the first year. However, because five patients had recurrence of ILD more than 1 year after the treatment, it would be necessary to consider maintenance therapy for ILD beyond 1 year. PMID- 21240621 TI - Polymyositis associated with autoimmune hepatitis, primary biliary cirrhosis, and autoimmune thrombocytopenic purpura. AB - We describe a 40-year-old woman with polymyositis (PM) who developed autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and autoimmune thrombocytopenic purpura (AITP) concurrently. About 4 years earlier, she suffered from muscle weakness probably due to PM. When she visited our hospital, she had polyarthritis, myalgia, symmetrical proximal limb-muscle weakness, elevated muscle enzymes, and myogenic abnormalities on electromyogram. Pathological findings obtained by muscle biopsy showed histological findings consistent with PM. Her serum liver enzymes were also elevated. The histology obtained by liver biopsy revealed the mixture findings of chronic active hepatitis and biliary cirrhosis. As antibodies to mitochondria M2 and liver/kidney microsome type 1 (LKM-1) were present, we concluded her liver disease was due to an overlap of AIH and PBC. Furthermore, purpura on the legs with thrombocytopenia appeared in parallel with liver dysfunction. She was diagnosed as having AITP by clinical and laboratory findings. Her serum showed a speckled pattern in immunofluorescence antinuclear antibody testing, but the antigen specificities were distinct from those of the known myositis-related autoantigens. This is a first case report of PM accompanied by AIH, PBC, and AITP. It was notable that there was an overlap of disease-associated immunological findings and immunogenetic backgrounds. This case provides a possible insight into the mechanisms and interplay of autoimmune diseases. PMID- 21240622 TI - Applying forces to elastic network models of large biomolecules using a haptic feedback device. AB - Elastic network models of biomolecules have proved to be relatively good at predicting global conformational changes particularly in large systems. Software that facilitates rapid and intuitive exploration of conformational change in elastic network models of large biomolecules in response to externally applied forces would therefore be of considerable use, particularly if the forces mimic those that arise in the interaction with a functional ligand. We have developed software that enables a user to apply forces to individual atoms of an elastic network model of a biomolecule through a haptic feedback device or a mouse. With a haptic feedback device the user feels the response to the applied force whilst seeing the biomolecule deform on the screen. Prior to the interactive session normal mode analysis is performed, or pre-calculated normal mode eigenvalues and eigenvectors are loaded. For large molecules this allows the memory and number of calculations to be reduced by employing the idea of the important subspace, a relatively small space of the first M lowest frequency normal mode eigenvectors within which a large proportion of the total fluctuation occurs. Using this approach it was possible to study GroEL on a standard PC as even though only 2.3% of the total number of eigenvectors could be used, they accounted for 50% of the total fluctuation. User testing has shown that the haptic version allows for much more rapid and intuitive exploration of the molecule than the mouse version. PMID- 21240623 TI - Structural-dynamical investigation of the ZnuA histidine-rich loop: involvement in zinc management and transport. AB - Comparative homology modelling techniques have been used to model the protein ZnuA from Salmonella enterica serovar Typhimurium using the 3D structure of the homologous protein from Escherichia coli. These two-domain proteins bind one Zn(2+) atom, with high affinity, in the inter-domain cleft and possess a histidine-rich loop in the N-terminal domain. Alternative structures of the ZnuA histidine-rich loop, never resolved by the X-ray diffraction method, have been modelled. A model of the apo form, one with the histidine-rich loop deleted and two alternative structures with a second zinc ion bound to the histidine-rich loop, have been generated. In all the modelled proteins, investigated through molecular dynamics simulation, the histidine-rich loop is highly mobile and its fluctuations are correlated to the ligand stability observed in the zinc sites. Based on the plasticity of the histidine-rich loop and its significant effects on protein mobility a possible role in the capture and/or transfer of the zinc ions has been suggested. PMID- 21240624 TI - Spatial and temporal characterization of trace elements and nutrients in the Rawal Lake Reservoir, Pakistan using multivariate analysis techniques. AB - Rawal Lake Reservoir is renowned for its ecological significance and is the sole source of drinking water of the third largest city of Pakistan. However, fish kill in recent years and anthropogenic impacts from human-related activities in its catchment area have resulted in deterioration of its surface water quality. This study aims to characterize spatial and temporal variations in surface water quality, identify contaminant sources, and compare their levels with quality guidelines. Surface water samples were collected from 10 sites and analyzed for 27 physicochemical parameters for a period of 2 years on a seasonal basis. Concentration of metals in surface water in pre-monsoon were in the order: Fe > Mg > Ca > Mn > Zn > Ni > Cr > Cu > Co > Pb, whereas in post-monsoon, the order of elemental concentrations was: Ca > Mg > Na > Fe > K > Zn > Cr > Li > Pb > Co > Ni > Cu > Mn > Cd. Metals (Ni, Fe, Zn, and Ca), pH, electrical conductivity (EC), dissolved oxygen (DO), chemical oxygen demand (COD), and nutrients (PO (4) (3-) , NO(3)-N, and SO (4) (2-) ) were measured higher in pre-monsoon, whereas concentration of Cu, Mn, Cr, Co, Pb, Cd, K, Na, Mg, Li, Cl(-), and NH(4)-N were recorded higher in post-monsoon. Results highlighted serious metal pollution of surface water. Mean concentration of Zn, Cd, Ni, Cu, Fe, Cr, and Pb in both seasons and Mn in post-monsoon were well above the permissible level of surface water quality criteria. Results stress the dire need to reduce heavy-metal input into the lake basin and suggest that heavy-metal contamination should be considered as an integral part of future planning and management strategies for restoration of water quality of the lake reservoir. PMID- 21240626 TI - Photolumiscent properties of nanorods and nanoplates Y2O3:Eu3+. AB - Nanorods and nanoplates of Y(2)O(3):Eu(3+) powders were synthesized through the thermal decomposition of the Y(OH)(3) precursors using a microwave-hydrothermal method in a very short reaction time. These powders were analyzed by X-ray diffraction, field emission scanning electron microscopy, Fourrier transform Raman, as well as photoluminescence measurements. Based on these results, these materials presented nanoplates and nanorods morphologies. The broad emission band between 300 and 440 nm ascribed to the photoluminescence of Y(2)O(3) matrix shifts as the procedure used in the microwave-hydrothermal assisted method changes in the Y(2)O(3):Eu(3+) samples. The presence of Eu(3+) and the hydrothermal treatment time are responsible for the band shifts in Y(2)O(3):Eu(3+) powders, since in the pure Y(2)O(3) matrix this behavior was not observed. Y(2)O(3):Eu(3+) powders also show the characteristic Eu(3+) emission lines at 580, 591, 610, 651 and 695 nm, when excited at 393 nm. The most intense band at 610 nm is responsible for the Eu(3+) red emission in these materials, and the Eu(3+) lifetime for this transition presented a slight increase as the time used in the microwave-hydrothermal assisted method increases. PMID- 21240627 TI - Synthesis, physicochemical and optical characterization of novel fluorescing complex: o-phenylenediamine-benzoin. AB - The complex of o-phenylenediamine (o-PDA) and benzoin (BN) was synthesized adopting solid state reaction by mixing of their melt together followed by chilling. The phase diagram study shows the formation of a complex in 1:1 molar ratio with congruent melting point and two eutectics lying on either side of complex. The formation of complex was confirmed using the FTIR, NMR, mass spectroscopy, powder XRD and DSC studies. The optical properties of the parent component, their complex and few other compositions nearby the complex were studied using absorption and laser luminescence techniques. The significantly higher green/yellow emission was noted with newly synthesized complex as compared to that of their parents as well as other compositions of o- PDA and BN. PMID- 21240628 TI - Synthesis of highly selective indole-based sensors for mercuric ion. AB - Two indole-based fluorescent chemosensors 1 and 2 were prepared and investigated characteristic features with transition metal ions. Sensors 1 and 2 were selective for Hg(2+) ion, among a series of metal ions, in aqueous ethanol (H(2)O EtOH, 1:2, v/v) with association constants of 5.74 * 10(3) and 4.46 * 10(3) M(-1) and detection limits of 7.4 and 6.8 MUM, respectively. Computational results revealed that sensor 1 or 2 with Hg(2+) ion formed 1:1 complex with a central, sandwich-coordinated Hg(2+) ion. Computational calculations provided evidence that a sandwich-coordinated Hg(2+) ion center was formed and the polyoxyethylene spacer acted as a scaffold for bringing functional ligands into a suitable geometry. PMID- 21240629 TI - Improved survival of patients with primary distant metastatic breast cancer in the period of 1995-2008. A nationwide population-based study in the Netherlands. AB - In this study, changes in prognosis for more than 8,000 patients with primary distant metastatic breast cancer were analyzed, using nation-wide data of the Netherlands Cancer Registry. Besides the roll of systemic treatment, the effect of surgery of the primary tumor was evaluated. Between 1995 and 2008, 160,595 new patients were diagnosed with invasive breast cancer. Of these patients, 8,031 (5.0%) had distant metastases at diagnosis. Patients were divided into three periods, based on the year of diagnosis of their disease. The median survival was 1.42 years for patients diagnosed in the period 1995-1999, 1.61 years in the period 2000-2004 and 1.95 years in the period 2005-2008. The improvement of the median survival was most pronounced for patients younger than 50 years. Patients receiving systemic treatment, loco-regional radiotherapy or breast surgery had a significantly lower risk of death compared to patients not receiving these treatments. An improvement of 6 months is observed in the median survival of patients with primary distant metastatic breast cancer between 1995 and 2008. The increased efficacy of chemotherapy and the introduction of targeted treatments are the most likely explanations for this improvement, which was most marked for younger patients. PMID- 21240630 TI - Relationships among the lactulose breath test, intestinal gas volume, and gastrointestinal symptoms in patients with irritable bowel syndrome. AB - BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) patients frequently complain of gas-related symptoms, and the lactulose breath test (LBT) is a test that assesses the amount of fermented gas generated by bacteria in the bowel. We aimed to assess the relationship among intestinal gas volume, LBT result, and gastrointestinal symptom score in healthy control and functional bowel disorder (FBD) subjects. METHOD: In 84 IBS subjects, 24 FBD subjects other than IBS, and 25 healthy controls, a symptom questionnaire that enquired about seven main symptoms, plain abdominal radiography and a LBT were checked on the same day. The intestinal gas volume was calculated as the gas volume score (GVS) with a digitalized image of plain supine abdominal radiographs. RESULTS: The GVS was greater in the LBT (+) group compared to the LBT (-) group (P = 0.02). The GVS was greater in the FBD and IBS groups than in the control group (P < 0.01). The GVS showed low but positive correlations with the severity and frequency of bloating, flatulence, abdominal pain, constipation, and tenesmus (P < 0.05). The severity of flatulence (P = 0.02) and the frequency of bloating (P = 0.02) in the LBT (+) group were significantly higher than those in the LBT (-) group. CONCLUSIONS: Subjects with positive LBT had more gas-related symptoms and greater gas volume scores. Gas-related symptoms, positive LBT and increased GVS were significantly associated to each other. These findings can broaden the understanding of the pathophysiologic mechanisms of gas-related symptoms in IBS. PMID- 21240637 TI - Combined simulation and experimental study of large deformation of red blood cells in microfluidic systems. AB - We investigate the biophysical characteristics of healthy human red blood cells (RBCs) traversing microfluidic channels with cross-sectional areas as small as 2.7 * 3 MUm. We combine single RBC optical tweezers and flow experiments with corresponding simulations based on dissipative particle dynamics (DPD), and upon validation of the DPD model, predictive simulations and companion experiments are performed in order to quantify cell deformation and pressure-velocity relationships for different channel sizes and physiologically relevant temperatures. We discuss conditions associated with the shape transitions of RBCs along with the relative effects of membrane and cytosol viscosity, plasma environments, and geometry on flow through microfluidic systems at physiological temperatures. In particular, we identify a cross-sectional area threshold below which the RBC membrane properties begin to dominate its flow behavior at room temperature; at physiological temperatures this effect is less profound. PMID- 21240638 TI - A physiologically relevant, simple outflow boundary model for truncated vasculature. AB - A realistic outflow boundary condition model for pulsatile flow in a compliant vessel is studied by taking into account physiological effects: compliance, resistance, and wave reflection of the downstream vasculature. The new model extends the computational domain with an elastic tube terminated in a rigid contraction. The contraction ratio, the length, and elasticity of the terminal tube can be adjusted to represent effects of the truncated vasculature. Using the wave intensity analysis method, we apply the model to the test cases of a straight vessel and the aorta and find good agreement with the physiological characteristics of blood flow and pressure. The model is suitable for cardiac transient (non-periodic) events and easily employed using so-called black box software. PMID- 21240639 TI - Value of FDG PET/CT in patients with treated ovarian cancer and raised CA125 serum levels. AB - PURPOSE: Patients treated for ovarian cancer are usually referred for 2-deoxy-2 [18F]fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT) in case of increased Carcinoma Antigen 125 (CA125) but negative conventional imaging. However, there is not enough in the literature to support the value of FDG PET/CT in this context. This study aimed to assess role of FDG PET/CT in a cohort of patients with treated ovarian cancer and correlate the results with serum levels of CA125. PROCEDURES: We retrospectively studied 175 patients, mean age 65.2 years (range 24-88 years) who had radical treatment for ovarian cancer (chemotherapy, surgery or combination). The patients had a standard FDG PET/CT and measurement of serum CA125 within a month of the scan. PET/CT was considered positive if demonstrated areas of abnormally increased metabolic activity unrelated to physiological distribution, on the basis of a visual analysis. The results of PET/CT imaging were compared to the level of CA125, and receiver operating characteristic (ROC) curves were plotted and area under-the curve (AUC) statistics were computed. Cytologic or histologic data or clinical and imaging follow-up were taken as gold standard. RESULTS: Patients were divided into five groups based on CA125 values. The average level of CA125 was 107.7 (range 3-867, SD 166.1). PET/CT was positive in 125/175 cases (71.4%), mean value of CA125 132.2 (SD 182.9) and negative in 50/175 (28.6%), mean value of CA125 46.4 (SD 89.3). In descriptive ROC analyses, the discriminatory power of this marker was relatively high (AUC statistics 0.77, range = 0.703-0.8). The optimal cut-off point of CA125 after treatment to reflect active disease on PET/CT was 18 U/mL achieving a detection rate of 85.6%. There was no relation between PET/CT negativity and the histological type of the tumor. CONCLUSION: PET/CT was able to detect active disease at relatively low levels of CA125, thereby facilitating the early diagnosis of recurrence or residual disease. Also in patients with low CA125 levels (<30), PET/CT had a relatively high detection rate (53%). According to our preliminary results, the use of FDG PET/CT in this setting is justified even with low serum CA125 levels. PMID- 21240640 TI - Treatment of acute delayed visceral hemorrhage after pancreatic surgery from hepatic arteries with covered stents. AB - BACKGROUND: Delayed visceral hemorrhage following pancreatic surgery is a rare but life-threatening complication. Usually hemorrhage originates from pseudoaneurysms secondary to pancreatic or biliary fistula. Re-laparotomy is often associated with high morbidity and mortality. Endovascular occlusion with metallic coils can stop pseudoaneurysmatic bleeding, but hepatic artery occlusion can result in severe organ damage. Interventional treatment with covered stents is an alternative providing persistent organ perfusion. RESULTS: In our department endovascular stenting for visceral hemorrhage was introduced in November 2008. From November 2008 until October 2009, 303 patients underwent pancreatic surgery at our institution. Among those, four patients were successfully treated with covered stents for delayed visceral hemorrhage. In all four patients bleeding originated from hepatic arteries. Mean onset of hemorrhage was 24 days after surgery. Endovascular stenting was successful in all four patients. None of these patients required re-operation or died during the study. CONCLUSION: Treatment of delayed visceral hemorrhage from hepatic arteries after pancreatic surgery with covered stents is safe and effective. Endovascular stenting is associated with a lower morbidity than re-laparotomy or coil embolisation. Emergency angiography with endovascular stenting should be considered for all patients with delayed hemorrhage from hepatic arteries after pancreatic surgery. PMID- 21240641 TI - Fatty acid imaging of the heart. AB - Imaging metabolic processes in the human heart yields valuable insights into the mechanisms contributing to myocardial pathology and allows assessment of the efficacy of therapies designed to treat cardiac disease. Recent advances in fatty acid (FA) imaging using positron emission tomography (PET) include the development of a method to assess endogenous triglyceride metabolism and the design of new fluorine-18 labeled tracers. Studies of patients with diabetes have shown that the heart is resistant to insulin-mediated glucose uptake and that metabolism of nonesterified FA is upregulated. Cardiac PET imaging has also recently shown the increase in myocardial FA uptake seen in obese patients can be reversed with weight loss. And a pilot study of patients with chronic kidney disease demonstrated that PET imaging can reveal myocardial metabolic alterations that parallel the decline in estimated glomerular filtration rate. Recent advances in FA imaging using single photon emission computed tomography (SPECT) have been accomplished with the tracer beta-methyl-p-[(123)I]-iodophenyl pentadecanoic acid (BMIPP). Two meta-analyses showed this imaging technique has a diagnostic accuracy for the detection of obstructive coronary artery disease that compares favorably with SPECT myocardial perfusion imaging and that BMIPP imaging yields excellent prognostic data in patients across the spectrum of coronary artery disease. A recent multicenter study of patients presenting with acute coronary syndromes found BMIPP SPECT imaging has greater diagnostic sensitivity than, and enhances the negative predictive value of, clinical assessment alone. Because of their exquisite sensitivity, nuclear imaging techniques facilitate the study of physiologic processes that are the key to our understanding of cardiac metabolism in health and disease. PMID- 21240642 TI - The central nervous system and its role in bowel and bladder control. AB - Bowel and bladder issues have been noted to be coexistent in children, and treatment of bladder symptoms without concomitant targeting of bowel issues generally leads to failure. This article explores the potential roots for this persistent connection between bowel and bladder and the role that the central nervous system plays in affecting both. An ever-increasing pool of knowledge drawn from multiple medical disciplines has provided us with a wealth of functional imaging information that is allowing us to map the areas of the brain better with regards to bowel and bladder function. We explore these new findings and attempt to connect the dots between the central nervous system bladder and bowel dysfunction. PMID- 21240643 TI - Bioanalytical approaches to quantify "total" and "free" therapeutic antibodies and their targets: technical challenges and PK/PD applications over the course of drug development. AB - The predominant driver of bioanalysis in supporting drug development is the intended use of the data. Ligand-binding assays (LBA) are widely used for the analysis of protein biotherapeutics and target ligands (L) to support pharmacokinetics/pharmacodynamics (PK/PD) and safety assessments. For monoclonal antibody drugs (mAb), in particular, which non-covalently bind to L, multiple forms of mAb and L can exist in vivo, including free mAb, free L, and mono- and/or bivalent complexes of mAb and L. Given the complexity of the dynamic binding equilibrium occurring in the body after dosing and multiple sources of perturbation of the equilibrium during bioanalysis, it is clear that ex vivo quantification of the forms of interest (free, bound, or total mAb and L) may differ from the actual ones in vivo. LBA reagents and assay formats can be designed in principle to measure the total or free forms of mAb and L. However, confirmation of the forms being measured under the specified conditions can be technically challenging. The assay forms and issues must be clearly communicated and understood appropriately by all stakeholders as the program proceeds through the development process. This paper focuses on monoclonal antibody biotherapeutics and their circulatory L that are either secreted as soluble forms or shed from membrane receptors. It presents an investigation into the theoretical and practical considerations for total/free analyte assessment to increase awareness in the scientific community and offer bioanalytical approaches to provide appropriate PK/PD information required at specific phases of drug development. PMID- 21240644 TI - The relationship between aortic baroreceptor activity and arterial pressure is not monotonic. AB - Previous reports indicate that when aortic pressure (AP) falls below the threshold (P (th)) for baroreceptor sensitivity, activity in the aortic depressor nerve (ADN) may increase. To quantify and explain this anomalous behaviour, we analysed curves describing the relationship of baroreceptor fibre activity in rabbit left ADN to AP. Data were obtained in anaesthetised New Zealand White rabbits. Occlusion and release of cuffs around the inferior vena cava and descending aorta generated AP ramps (25-140 mmHg). Response curves were obtained for 173 fibres in 26 animals. Thirty percent of curves had a nadir (J-shaped curve), and in 40% activity was always present. In fibres showing activity below P (th), firing was predominantly diastolic, switching to systolic firing at P (th). The unusual behaviour of a substantial fraction of aortic baroreceptors below P (th) accounts for the J-shaped response curve of the whole ADN. We suggest that fibres that fire during diastole at pressures below P (th) may have sensory endings close to the origin of the left subclavian artery. As a consequence of this anatomical location, low pressures can impose strain on these receptors, which is then relieved by the systolic pulse. PMID- 21240646 TI - The mystery of the discolored flints. New molecules turn prehistoric lithic artifacts blue. AB - Prehistoric artifacts turning blue in the store rooms of the Natural History Museum in Verona, Italy recently raised serious issues for heritage materials conservation. Our analytical investigation showed that the unusual discoloration process of the flint tools is caused by the surface presence of at least three previously unknown pigmenting molecules of the triphenylmetane dyes class: 6 (bis(2,2,4-trimethyl-1,2-dihydroquinolin-6-yl)methylene)-2,2,4-trimethyl-2,6 dihydroquinolinium and its hydrogenated derivatives 2,2,4-trimethyl-6-((2,2,4 trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)(2,2,4-trimethyl-1,2-dihydroquinolin-6 yl)methylene)-2,6-dihydroquinolinium and 6-(bis(2,2,4-trimethyl-1,2,3,4 tetrahydroquinolin-6-yl)methylene)-2,2,4-trimethyl-2,6-dihydroquinolinium. The peculiar formation of the molecules is possibly catalyzed within the silica pore surface starting from a well-known rubber stabilizer 2,2,4-trimethyl-1,2 dihydroquinoline released by the plastic pads flooring the storing cabinets. The investigated reaction and its surprising blue product represent a case study of the application of modern materials science to conservation and a serious warning towards the unpredictable challenges faced in the preservation of our cultural heritage. PMID- 21240647 TI - Value of MRI and diffusion-weighted MRI for the diagnosis of locally recurrent rectal cancer. AB - OBJECTIVES: To evaluate the accuracy of standard MRI, diffusion-weighted MRI (DWI) and fusion images for the diagnosis of locally recurrent rectal cancer in patients with a clinical suspicion of recurrence. METHODS: Forty-two patients with a clinical suspicion of recurrence underwent 1.5-T MRI consisting of standard T2-weighted FSE (3 planes) and an axial DWI (b0,500,1000). Two readers (R1,R2) independently scored the likelihood of recurrence; [1] on standard MRI, [2] on standard MRI+DWI, and [3] on T2-weighted+DWI fusion images. RESULTS: 19/42 patients had a local recurrence. R1 achieved an area under the ROC-curve (AUC) of 0.99, sensitivity 100% and specificity 83% on standard MRI versus 0.98, 100% and 91% after addition of DWI (p = 0.78). For R2 these figures were 0.87, 84% and 74% on standard MRI and 0.91, 89% and 83% with DWI (p = 0.09). Fusion images did not significantly improve the performance. Interobserver agreement was kappa0.69 for standard MRI, kappa0.82 for standard MRI+DWI and kappa0.84 for the fusion images. CONCLUSIONS: MRI is accurate for the diagnosis of locally recurrent rectal cancer in patients with a clinical suspicion of recurrence. Addition of DWI does not significantly improve its performance. However, with DWI specificity and interobserver agreement increase. Fusion images do not improve accuracy. PMID- 21240648 TI - Tractography of lumbar nerve roots: initial results. AB - OBJECTIVES: The aims of this preliminary study were to demonstrate the feasibility of in vivo diffusion tensor imaging (DTI) and fibre tracking (FT) of the lumbar nerve roots, and to assess potential differences in the DTI parameters of the lumbar nerves between healthy volunteers and patients suffering from disc herniation. METHODS: Nineteen patients with unilateral sciatica related to posterolateral or foraminal disc herniation and 19 healthy volunteers were enrolled in this study. DTI with tractography of the L5 or S1 nerves was performed. Mean fractional anisotropy (FA) and mean diffusivity (MD) values were calculated from tractography images. RESULTS: FA and MD values could be obtained from DTI-FT images in all controls and patients. The mean FA value of the compressed lumbar nerve roots was significantly lower than the FA of the contralateral nerve roots (p = 0.0001) and of the nerve roots of volunteers (p = 0.0001). MD was significantly higher in compressed nerve roots than in the contralateral nerve root (p = 0.0002) and in the nerve roots of volunteers (p = 0.04). CONCLUSION: DTI with tractography of the lumbar nerves is possible. Significant changes in diffusion parameters were found in the compressed lumbar nerves. PMID- 21240650 TI - A technical solution to improving palliative and hospice care. AB - PURPOSE: This project sought to help palliative and hospice care practices improve patient care quality and operational efficiency by improving patient symptom status reporting and symptom management, reducing associated provider documentation workload, and enhancing patient-provider and provider-provider communication. We developed a user-friendly, electronic medical record compatible, software prototype that allows typical clinical data and patient reported outcomes (PRO) to be entered and stored. This data is immediately available during the clinical encounter with graphically depicted summaries for patient history and PRO assessments, a trending feature that links symptom behavior to interventions and the Edmonton Labeled Visual Information System. METHODS: A user-centered design approach allowed for iterative cycles of needs/usability feedback from providers and patients/caregivers to be incorporated into the development of our prototype's technical structure and features. To determine the needs and initial usability of the project's prototype, we interviewed eight providers and 18 patients/caregivers. Another usability test, consisting of patient/caregiver (n = 18) and provider (n = 9) interviews, assessed the functioning prototype's design, usability, and usefulness. RESULTS: Patients/caregivers (n = 18) reported that the prototype was usable (100%), it would facilitate patient-provider communication, shared decision making, and self-management (100%), and they would be willing to try the system and recommend it to their providers (100%). The providers (n = 9) felt that the prototype encouraged better use of patient assessments in decision making and patient care (100%) and improved identification of cause/temporal relationship between care events and outcomes (100%), monitoring of patient status (100%), communication in a multi-disciplinary team (100%), and operational efficiency and patient care quality (88.9%). CONCLUSIONS: Quality of patient care and operational efficiency can be improved with an effective assessment, evaluation, and communication tool. This project developed an electronic version of such a tool. Future efforts will hone its usability and integration across multiple hospice/palliative care settings. PMID- 21240649 TI - Body mass index and breast cancer treatment-related lymphedema. AB - PURPOSE: The main purpose was to examine longitudinally the influence of body mass index (BMI) and obesity on the development of breast cancer treatment related lymphedema. We asked, does elevated BMI increase lymphedema risk? METHODS: A secondary analysis was conducted on de-identified data collected from 138 newly diagnosed breast cancer survivors who had arm-volume measurements and symptom assessment at pre-treatment baseline and measurements up to 30 months post-surgery in a prospective longitudinal parent study. Arm volume and weight data, part of the information collected during each participant visit, were examined. RESULTS: Breast cancer survivors whose BMI was >=30 at the time of breast cancer treatment were approximately 3.6 times more likely to develop lymphedema at 6 months or greater after diagnosis than those with a BMI < 30 at the time of cancer treatment (95% confidence interval, C.I., for odds ratio, O.R., 1.42-9.04; p = 0.007). Those with a general BMI increase or a BMI rise to 30 or greater during their first 30 months of survivorship were not more likely to develop late-onset lymphedema than those who did not have similar changes in BMI. CONCLUSIONS: Pre-treatment BMI may be a risk factor for lymphedema. Weight gain post-treatment may not be. Further research is warranted. PMID- 21240651 TI - Clinical significance of nontuberculous mycobacteria isolates in elderly Taiwanese patients. AB - The aim of this study was to investigate the clinical significance of nontuberculous mycobacteria (NTM) isolates in elderly Taiwanese patients. From 2004 through 2008, patients >65 years old with NTM isolation were identified. The definitions of NTM disease followed the American Thoracic Society and Infectious Disease Society of America (ATS/IDSA) criteria. Among the 3,175 NTM isolates, Mycobacterium avium complex (MAC; n = 1,118, 35.2%) was the most prevalent species, followed by M. abscessus (n = 545, 17.2%). Among the 1,633 elderly patients with NTM isolates, the most prevalent NTM species were MAC (n = 592, 36.3%) and M. fortuitum complex (n = 311, 19.0%). NTM colonization was found in 1,339 (80.4%) patients and only 326 (19.6%) patients had NTM diseases. During the study period, the annual incidence rates (per 100,000 inpatients and outpatients) of NTM colonization and disease both increased significantly (p < 0.0001) from 10.5 to 15.8 and from 2.1 to 4.3, respectively. Isolated pulmonary NTM infections compromised 294 (90.2%) of the 326 elderly cases of NTM disease. In conclusion, this study found an increasing trend in the incidence of both NTM isolates and NTM diseases among elderly Taiwanese patients. MAC and M. abscessus were the most frequent species causing various types of NTM disease. PMID- 21240652 TI - Aluminum exposure alters behavioral parameters and increases acetylcholinesterase activity in zebrafish (Danio rerio) brain. AB - Aluminum is a metal that is known to impact fish species. The zebrafish has been used as an attractive model for toxicology and behavioral studies, being considered a model to study environmental exposures and human pathologies. In the present study, we have investigated the effect of aluminum exposure on brain acetylcholinesterase activity and behavioral parameters in zebrafish. In vivo exposure of zebrafish to 50 MUg/L AlCl(3) for 96 h at pH 5.8 significantly increased (36%) acetylthiocholine hydrolysis in zebrafish brain. There were no changes in acetylcholinesterase (AChE) activity when fish were exposed to the same concentration of AlCl(3) at pH 6.8. In vitro concentrations of AlCl(3) varying from 50 to 250 MUM increased AChE activity (28% to 33%, respectively). Moreover, we observed that animals exposed to AlCl(3) at pH 5.8 presented a significant decrease in locomotor activity, as evaluated by the number of line crossings (25%), distance traveled (14.1%), and maximum speed (24%) besides an increase in the absolute turn angle (12.7%). These results indicate that sublethal levels of aluminum might modify behavioral parameters and acetylcholinesterase activity in zebrafish brain. PMID- 21240653 TI - The effects of metabolizable energy intake on body fat depots of adult Pelibuey ewes fed roughage diets under tropical conditions. AB - The objective of this work was to evaluate the effect of metabolizable energy intake (MEI) on changes in fat depots of adult Pelibuey ewes fed roughage diets under tropical conditions. Eighteen 3-year-old Pelibuey ewes with similar body weight (BW) of 37.6 +/- 4.0 kg and body condition score (BCS) of 2.5 +/- 0.20 were randomly assigned to three groups of six ewes each in a completely randomized design. Ewes were housed in metabolic crates and fed three levels of MEI: low (L), medium (M), and high (H) for 65 days to achieve different BW and BCS. At the end of the experiment, the ewes were slaughtered. Data recorded at slaughter were: weights of viscera and carcass. Internal fat (IF, internal adipose tissue) was dissected, weighed, and grouped as pelvic (around kidneys and pelvic region), omental, and mesenteric regions. Carcass was split at the dorsal midline in two equal halves, weighed, and chilled at 6 degrees C during 24 h. After refrigeration, the left half of the carcass was completely dissected into subcutaneous and intermuscular fat (carcass fat). Dissected carcass fat (CF) of the left carcass was adjusted as whole carcass. At low levels of MEI, proportion of IF and CF was approximately 50%; however, as the MEI was increased, the proportion of IF was increased up to 57% and 60% for M and H, respectively. Omental and pelvic fat depots were those which increased in a larger proportion with respect to the mesenteric fat depot. Regression equations between the weight of each body fat depot and BW had a coefficient of determination (r (2)) that ranged between 0.37 for mesenteric fat and 0.87 for CF. The regression with BCS had a r (2) that ranged between 0.57 for mesenteric and 0.71 for TBF. BW was the best predictor for TBF, CF, omental fat, and pelvic fat; whereas, BCS was better than BW in predicting IF and mesenteric fat. Inclusion of both BW and BCS in multiple regressions improved the prediction for all fat depots, except for pelvic fat, which was best estimated by BCS alone. The greater slope of the regression for the pelvic fat depot equation, relative to TBF (1.40), EBW (4.02), and BCS (2.36), suggested that pelvic fat has a greater capacity to accumulate and mobilize fat. These results indicated that adult Pelibuey ewes seem to store a considerable proportion of absorbed energy in the IF depots rather than in the carcass. PMID- 21240654 TI - Effects of road type during transport on lamb welfare and meat quality in dry hot climates. AB - This study determined whether transporting lambs on paved (PR) or unpaved roads (UR) for 3 h had an effect on plasma stress indicators (cortisol, lactate, glucose, creatine kinase [CK], red blood cells, white blood cells, hematocrit, and neutrophil/lymphocyte [N/L] ratio) and instrumental meat quality (pH24, bruising score, water holding capacity [WHC], color, and texture). A total of 48 Rasa Aragonesa male lambs were used that were approximately 100 days old (12.5 kg +/- 1.64, carcass weight). The results suggest that transport on unpaved roads had a significant influence on physiological and hematological stress parameters. Road type had a significant effect on all variables, except for white and red blood cells, and hematocrit levels. The UR lambs had significantly higher (at least p <= 0.01) cortisol, lactate, glucose, and CK levels and a higher N/L ratio than PR lambs. Meat from UR lambs had some dark-cutting characteristics, with a darker color, higher ultimate pH, and higher tenderness values than PR. In conclusion, lambs transported on unpaved roads had a more intense stress response and poorer meat quality than lambs transported on paved roads. An effort to improve the logistics associated with route planning is necessary to prevent welfare problems during transport to slaughter. PMID- 21240655 TI - Anesthesiologist's knowledge and attitudes about obstructive sleep apnea: a survey study. AB - OBJECTIVE: The objectives of this study were to measure the anesthesiologists' knowledge and attitudes about OSA and assess the need for additional educational programs focusing on OSA. METHODS: The Obstructive Sleep Apnea Knowledge and Attitude Questionnaire (OSAKA) developed by Helena Metal was translated into Chinese and distributed to anesthesiologists from Shandong Province. Anesthesiologists completed the OSAKA questionnaire containing sections regarding knowledge (18 items) and attitudes about OSA (5 items). RESULTS: A total of 321 questionnaires were completed. The mean total knowledge score was 11.21, with the scores ranging from 2 to 17. The total correct score ratio was 62%. The knowledge score positively corrected with the participants' job titles and attitude scores. None of the dependent variables, such as sex, age, education, and working in a different hospital level, affected the score. CONCLUSION: The study shows that anesthesiologists lack adequate knowledge about OSA. The total correct score ratio was 62%; when they managed an OSA patient, the positive attitude score is mostly below 50%. They have low confidence about OSA patients. It is necessary to develop special training programs on OSA regularly for anesthesiologists after graduation. PMID- 21240657 TI - The potential for delivery of particulate matter through positive airway pressure devices (CPAP/BPAP). AB - BACKGROUND: Airborne particulate matter may induce health risk with inhalation. Special concerns exist for deployed military personnel with inhaled particulate matter in desert environments. Continuous positive airway pressure (CPAP) used in obstructive sleep apnea may facilitate inhalation of particulate matter. We evaluated the ability of commercial CPAP filter systems to eliminate inhalation of particulate matter. METHODS: An ultrasonic medical nebulizer (DeVilbliss Ultraneb, DeVilbliss, Somerset, PA) atomized liquid producing "respirable" aerosol. Technetium-99m diethylene triamine pentaacetic acid dissolved in water was also aerosolized to quantify aerosol inhalation. A high efficiency particulate air (HEPA) filter placed at the patient-hose connection port in the bilevel positive airway pressure (BPAP) device captured the aerosol inbound to the patient. The HEPA filter provided a means to quantify aerosol dose delivered to a simulated patient. Commercial foam and ultrafine filters were assessed with aerosol to determine the simulated patient exposure. RESULTS: Foam and ultrafine filters used together allowed 1.5% or less of aerosol volume to pass through the BPAP system. Foam filters alone allowed an average of 18.9% of aerosol delivered to pass through the BPAP system. CONCLUSIONS: Foam and ultrafine filters used together in BPAP systems provide excellent aerosol filtration in this laboratory simulation of BPAP use. PMID- 21240656 TI - Primary snoring in school children: prevalence and neurocognitive impairments. AB - PURPOSE: We aimed to investigate the prevalence of primary snoring (PS) and its association with neurocognitive impairments. METHODS: Data from a community-based study in 1,114 primary school children were used to identify children who never (N = 410) or habitually snored (N = 114). In order to separate children with PS from those with upper airway resistance syndrome (UARS) or obstructive sleep apnoea (OSA), home polysomnography was conducted in all habitually snoring children. Neurocognitive impairments and poor school performance were compared between children who never snored, PS, and UARS/OSA. RESULTS: Polysomnography was successfully conducted in 92 habitual snorers. Of these, 69 and 23 had PS and UARS/OSA, respectively. Prevalence [95% confidence interval (95% CI)] of PS was 6.1% (4.5-7.7). Compared to children who had never snored, children with PS had more hyperactive (39% vs. 20%) and inattentive behaviour (33% vs. 11%), as well as poor school performance in mathematics (29% vs. 16%), science (23% vs. 12%), and spelling (33% vs. 20%; all P values <0.05). PS was a significant risk factor (odds ratio; 95% CI) for hyperactive behaviour (2.8; 1.6-4.8), inattentive behaviour (4.4; 2.4-8.1), as well as daytime sleepiness (10.7; 4.0-28.4). PS was also an independent risk factor for poor school performance in mathematics (2.6; 1.2-5.8), science (3.3; 1.2-8.8), and spelling (2.5; 1.1-5.5). Odds ratios throughout were similar to the UARS/OSA group. CONCLUSIONS: Children with non hypoxic, non-apnoeic PS may exhibit significant neurocognitive impairments. Consequences may be similar to those associated with UARS or OSA. If confirmed, PS is not "benign" and may require treatment. PMID- 21240658 TI - Adiponectin downregulates hyperglycemia and reduces pancreatic islet apoptosis after roux-en-y gastric bypass surgery. AB - BACKGROUND: The resolution of type 2 diabetes mellitus is an additional outcome of Roux-en-Y gastric bypass (RYGB) surgery. The general objective was to explore whether RYGB could reduce beta cells apoptosis and what roles adiponectin played in downregulating hyperglycemia after RYGB. METHODS: Twenty Goto-Kakizaki (GK) rats were allocated in RYGB group (ten) and GK group (ten), and ten Wistar (WS) rats were allocated in WS group. RYGB was performed in RYGB group and sham operation in the GK and WS groups. Fasting plasma glucose, body weight, food intake per 100 g body weight, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), C peptide, and adiponectin were measured pre- and postoperatively. Terminal deoxynucleotidyl transferase 2'-deoxyuridine 5' triphosphate nick end-labeling and transmission electron microscopy were performed to detect apoptosis of pancreatic beta cells. Data were analyzed by analysis of variance, Student t test, and post hoc comparisons (Tukey's test). RESULTS: Animals in WS group had significant higher postprandial insulin, C peptide, and adiponectin concentrations compared to RYGB and GK groups preoperatively. Body weight and food intake in RYGB group significantly decreased compared to WS and GK groups postoperatively. Postprandial insulin, C peptide, and adiponectin concentrations significantly increased, while fasting plasma glucose and HOMA-IR values decreased in RYGB group compared to GK group postoperatively. More apoptotic beta cells were detected in GK group than RYGB and WS groups postoperatively. CONCLUSIONS: RYGB could increase postprandial insulin and reduce pancreatic islet apoptosis. Adiponectin played a key role in regulating plasma glucose and reducing pancreatic islet apoptosis after RYGB. PMID- 21240659 TI - Early and late abdominal bleeding after Roux-en-Y gastric bypass: sources and tailored therapeutic strategies. AB - Bleeding is a potentially serious complication after Roux-en-Y gastric bypass (RYGB). Preventive measures and therapeutic strategies have not been adequately defined. We reviewed data on 742 consecutive patients treated at the University of California San Francisco to identify cases of early and late bleeding (less or greater than 30 days after surgery) after RYGB. Bleeding was defined as symptoms or signs of bleeding, associated with blood transfusion. We recorded patient characteristics, details of the operative technique, diagnostic approach, therapeutic strategies, and outcomes. Twenty-six patients (3.5%) had postoperative bleeding, which mostly occurred in the first 30 days postoperatively (N=19). Hematocrit decreased significantly from preoperative values (-5.2 +/- 3.1 without bleeding vs. -14.8 +/- 4.7 with, p<0.01). Type 2 diabetes was more prevalent in patients who had bleeding (58% vs. 32%, p=0.03). No other patient characteristics or details of the operative technique were associated with different rates of bleeding. Therapeutic intervention other than transfusion was needed for seven patients with early bleeding (36.8%) and for all patients with late bleeding. Four patients with early bleeding required reoperation. Early bleeding source was intraluminal in four patients, intraperitoneal in five, and self-limited and of unknown location in ten. Late bleeding occurred on average at 62.6 months (range, 5 to 300 months) after index surgery, five patients required reoperation, and the source was always intraluminal. Bleeding after RYGB may be from various anatomic sites; details of the operative technique were not associated with different rates of bleeding, and therapy should be tailored to suspected location of bleeding. PMID- 21240660 TI - Hepatic expression of adiponectin receptors increases with non-alcoholic fatty liver disease progression in morbid obesity in correlation with glutathione peroxidase 1. AB - BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) in obesity is very high. The role of adiponectin receptors in NAFLD progression remains still unclear. We speculate that changes in the hepatic expression levels of the two adiponectin receptors may be associated with the expression of oxidative stress-related genes. METHODS: We studied 60 morbidly obese patients with NAFLD, who underwent liver biopsy at the time of bariatric surgery. We measured the hepatic messenger-RNA concentration of adiponectin receptors (ADIPOR1 and ADIPOR2), glutathione peroxidase 1 (GPx1), glutathione reductase (GRd) and inducible oxide nitric synthase. Additionally, biochemical parameters and oxidative stress markers were determined in blood samples. According to the Kleiner score, the patients were divided into two groups: group 1 (25 patients without steatohepatitis) and group 2 (25 patients with probable steatohepatitis and ten patients with steatohepatitis). RESULTS: The messenger-RNA concentration of all genes analysed in the study was higher among the patients in group 2. However, no differences in blood oxidative stress markers were observed. Strong correlations were found among the expression levels of ADIPOR1, ADIPOR2 and GPx1. The multivariate analysis showed that the only independent variable associated with NAFLD progression was the increase in GPx1 expression levels. CONCLUSIONS: NAFLD progression in morbid obesity is associated with increase in hepatic adiponectin receptor and oxidative stress-related genes. The linear correlations suggest that ADIPOR1, ADIPOR2 and GPx1 share key molecular factors in the regulation of the genetic expressions. PMID- 21240661 TI - Real-life safety and effectiveness of amlodipine/valsartan combination in the treatment of hypertension. AB - INTRODUCTION: The aim of our study was to evaluate the safety and effectiveness of the free combination of amlodipine/valsartan in patients with arterial hypertension in a real-life setting. METHODS: This was a multicenter, open-label, observational, noninterventional, postmarketing surveillance study conducted in 298 centers in China, Malaysia, Pakistan, Bangladesh, Egypt, and Russia. We evaluated changes in heart rate, systolic and diastolic office blood pressure (BP), as well as BP control rate (<140/90 mmHg) overall, and in clinically relevant subgroups of hypertensive patients (BP >140/90 mmHg) after 12 weeks of treatment with 5/10 mg amlodipine and 80/160 mg valsartan combination. RESULTS: Two thousand seven hundred and eighty-five patients with arterial hypertension were enrolled, 52 discontinued (eight due to adverse events), and four patients' data were missing. In total, 2729 patients completed the study: mean age 57.9 years, 54.5% men, 54.2% Asian, 44.6% Caucasian; 86.5% had prior hypertension treatment (which was discontinued), baseline BP was 163.1/96.2 mmHg. The significant reduction in BP (-33.2/-16.9 mmHg, P<0.0001) was achieved with amlodipine/valsartan treatment resulting in a final BP of 129.9/79.3 mmHg. A dose dependent effect was observed with the least BP reduction for 5/80 mg (-29.2/ 15.1 mmHg, P<0.0001) and the greatest for the 10/160 mg dose regimen (-43.6/-22.4 mmHg, P<0.0001). Treatment response increased with increasing initial severity of hypertension with the least BP reduction in patients with baseline grade 1 hypertension BP level (SBP 140-159 mmHg): -20.0/-13.4 mmHg, P<0.0001, and the greatest BP drops observed in grade 3 hypertensive patients with baseline systolic BP over 200 mmHg: -73.1/-26.3 mmHg, P<0.0001. Patients with isolated systolic hypertension had BP reductions of -24.2/-4.8 mmHg, P<0.0001. CONCLUSION: An optimal BP reduction was achieved for all hypertension grades as well as isolated systolic hypertension, providing evidence that most hypertensive patients may benefit from amlodipine/valsartan combination treatment. PMID- 21240662 TI - Single-point mutation in a conserved TPR domain of Hip disrupts enhancement of glucocorticoid receptor signaling. AB - The Hsp70-interacting protein Hip has been identified as a transient participant in the assembly of both glucocorticoid (GR) and progesterone receptor complexes. Although it has been difficult to identify a physiological role for Hip, it is believed to have intrinsic chaperoning properties and has been identified as a potential anti-apoptotic target of Granzyme B. In vitro assays have provided evidence that Hip may interact with GR complexes in an Hsp70 independent manner and can enhance the function of GR in hormone based reporter assays. In this study, a cDNA for human Hip was used in mutational analysis to map Hip function to critical structural elements. A single amino acid substitution (L211S) resulted in a loss of Hip function. This mutation also appears to disrupt the interaction of Hip with Hsp70 in vitro. Failure to recover Hip-L211S constructs in co-immunoprecipitation assays with an Hsp70 monoclonal antibody suggests that the mutation is unlikely to result in a misfolded substrate. PMID- 21240663 TI - Human papillomavirus in benign prostatic hyperplasia and prostatic adenocarcinoma patients. AB - The aim of this study was to determine the prevalence of human papillomavirus (HPV) types in tissue and HPV antibodies in prostatic disease. Prostate tissue samples were collected from 51 patients diagnosed with adenocarcinoma and 11 with benign prostatic hyperplasia (BPH). All tissue samples were confirmed by histology. Plasma samples were available for 52 prostate patients. We investigated HPV DNA prevalence by PCR, and PCR positive samples were HPV type determined by sequencing. Prevalence of antibodies against twenty-seven HPV proteins from fourteen different HPV types was assessed in the plasma samples. The HPV DNA prevalence in the tissue samples was 14% (7/51) for prostate cancer samples and 27% (3/11) for BPHs. HPV-18 was the only type detected in tissue samples (10/62). No significant difference in HPV prevalence between the prostate cancer and BPH samples was found. HPV-positive cells were identified in eight of our thirteen prostate tissue slides (3/3 BPH and 5/10 adenocarcinoma) by in situ hybridisation, and the positive cells were found in epithelial cells and peripheral blood cells. Serology data showed no significant increase in levels of antibodies against any of the HPV-18 proteins tested for in prostatic disease patients. Antibodies against HPV-1, HPV-4, HPV-6 and HPV-11 were significantly higher in the group of males with prostatic disease. Our study did not show an association between prostatic disease and either presence of HPV DNA in samples or previous exposure of high-risk HPV. PMID- 21240667 TI - Challenging reconstructive techniques for skull base defect following endoscopic endonasal approaches. AB - OBJECTIVE: We assessed the outcomes of various reconstructive methods for skull base defect after endoscopic endonasal approaches (EEA) depending on the degree of intraoperative cerebrospinal fluid (CSF) leaks. METHODS: Between Jan. 2008 and Sep. 2009, 122 consecutive patients underwent 124 EEA for sellar and extra-sellar lesions. Intraoperative CSF leaks were classified as grade 0, no intraoperative CSF leak; grade 1, low output; and grade 2, high-output based on the degree of CSF leakage and size of opening in the arachnoid membrane (<5 or >=5 mm). RESULTS: Postoperative CSF leaks or meningitis occurred in 13 of 124 cases (10.5%). In 77 patients with grade 0, there was no postoperative CSF leak. Among 20 patients with grade 1 CSF leaks, four patients developed meningitis or postoperative CSF leak. Postoperative CSF leaks occurred in nine of 26 patients (34.6%) with grade 2 leaks. Comparison of reconstructive methods revealed that gasket-seal method provided better control of CSF leaks than free-fat graft in patients with grade 2 leaks (11.8% vs. 66.7%, p = 0.028). However, in grades 0 and 1, we found no difference among the various reconstructive methods. CONCLUSION: The selection of reconstructive methods for skull base defects should be determined by the degree of CSF leaks. Although grade 0 or 1 leak requires relatively conservative management such as simple closure or free-tissue grafting, a more aggressive reconstructive technique is required to prevent postoperative complication in grade 2 CSF leak. PMID- 21240668 TI - Seizures and stupor during intravenous mannose therapy in a patient with CDG syndrome type 1b (MPI-CDG). AB - MPI-CDG (formally called CDG 1b), caused by phosphomannose isomerase (MPI) deficiency, leads to hypoglycaemia, protein losing enteropathy, hepatopathy, and thrombotic events, whereas neurologic development remains unaffected. Dietary supplementation of mannose can reverse clinical symptoms by entering the N glycosylation pathway downstream of MPI. When oral intake of mannose in patients with MPI-CDG is not possible, e.g. due to surgery, mannose has to be given intravenously. We report a patient with MPI-CDG on intravenous mannose therapy that showed severe depression of consciousness and seizures without apparent cause. EEG and cranial MRI findings were compatible with metabolic coma whereas extended laboratory examinations including repeated blood glucose measurements were normal. Importantly, an intravenous bolus of glucose immediately led to clinical recovery and EEG improvement. Mannose did not interfere with glucose measurement in our assay. We suggest that in patients with MPI-CDG, intravenous mannose infusion can lead to intracellular ATP deprivation due to several mechanisms: (1) in MPI deficiency, mannose 6-P cannot be isomerised to fructose 6 P and therefore is unavailable for glycolysis; (2) animal data has shown that accumulating intracellular mannose 6-P inhibits glycolysis; and (3) elevated intracellular mannose 6-P may induce an ATP wasting cycle of dephosphorylation and rephosphorylation ("honey bee effect"). The mannose-induced metabolic inhibition may be overcome by high-dose glucose treatment. We caution that, in patients with MPI-CDG, life-threatening central nervous system disturbances may occur with intravenous mannose treatment. These may be due to intracellular energy failure. Clinical symptoms of energy deficiency should be treated early and aggressively with intravenous glucose regardless of blood glucose levels. PMID- 21240669 TI - Cardiovascular risk in rheumatoid arthritis and systemic autoimmune rheumatic disorders: a suggested model of preventive strategy. AB - The pathogenesis of accelerated cardiovascular damage commonly characterizing patients affected by systemic chronic inflammatory and autoimmune rheumatic disorders is quite complex and still not fully clarified. However, it is well accepted that a strong relationship between multiple factors, including both traditional cardiovascular risk factors and disease-related inflammatory and autoimmune mechanisms, may in part explain the precocious atherosclerotic vessel damage and the increased incidence of cardiovascular events. Nevertheless, although several recent studies focused their attention on the investigation of these complex mechanisms, data regarding possible preventive strategies aimed to reduce long-term cardiovascular risk in these subjects are still lacking and not conclusive. In this setting, the early introduction of evidence-based preventive measures for the correct management of patients with systemic autoimmune disorders would be of extreme importance to reduce subclinical atherosclerosis incidence and possible major cardiovascular events. PMID- 21240670 TI - Academic aptitude as a predictor of headache proneness during college: could headache be an outcome of low test scores? AB - BACKGROUND: Academic work as well as compensated employment has been found adversely associated with frequent headache; headache remains a costly disorder to the person and to society. However, little is known of factors--other than prior headache complaints--that may predict headache frequency over extended periods of time. Based on previous research, effortful task engagement appears to be a contributing factor to headache onset. This suggests that relatively stable attributes that are likely to affect effort expenditure may predict headache frequency over long intervals. PURPOSE: The goal of this study was to evaluate the predictability of headache proneness in college-attending students by college aptitude tests administered in high school. METHODS: Five hundred undergraduate students enrolled in a large public, urban university completed a number of questionnaires. Official admissions records of the college aptitude tests ACT (an acronym for the original test name, the American College Testing), SAT (the Scholastic Aptitude Test), and GPA (grade point average) were obtained and compared to the report of headache frequency. RESULTS: The ACT test mathematics predicted headache proneness in the hypothesized direction, while the ACT English test provided conflicting data; some evidence of gender differences was suggested. CONCLUSION: While nearly all research on headache and work effectiveness has considered headache to be a cause of reduced efficiency or productivity, this study suggests that a factor which presumably affects the ease of work completion (e.g., scholastic aptitude) may predict headache, at least in some cases within the "work" environment of academia. PMID- 21240671 TI - Laser microperforated biodegradable microbial polyhydroxyalkanoate substrates for tissue repair strategies: an infrared microspectroscopy study. AB - Flexible and biodegradable film substrates prepared by solvent casting from poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBHV) solutions in chloroform were microperforated by ultraviolet laser ablation and subsequently characterized using infrared (IR) microspectroscopy and imaging techniques and scanning electron microscopy (SEM). Both transmission synchrotron IR microspectroscopy and attenuated total reflectance microspectroscopy measurements demonstrate variations in the polymer at the ablated pore rims, including evidence for changes in chemical structure and crystallinity. SEM results on microperforated PHBHV substrates after cell culture demonstrated that the physical and chemical changes observed in the biomaterial did not hinder cell migration through the pores. PMID- 21240672 TI - Is cellular senescence important in pediatric kidney disease? AB - Somatic cellular senescence (SCS) describes the limited ability of cells to divide. Normally, SCS is associated with physiological aging, but evidence suggests that it may play a role in disease progression, even in young patients. Stressors such as acute injury or chronic inflammation may induce SCS, which in turn exhausts organ regenerative potential. This review summarizes what is known about SCS in the kidney with aging and disease. As most patients with chronic kidney disease (CKD) also develop cardiovascular complications, a second focus of this review deals with the role of SCS in cardiovascular disease. Also, as SCS seems to accelerate CKD and cardiovascular disease progression, developing strategies for new treatment options that overcome SCS or protect a patient from it represents an exciting challenge. PMID- 21240673 TI - Diagnostic performance of an enzyme-linked immunospot assay for interferon-gamma in skeletal tuberculosis. AB - The aim of this study was to evaluate the diagnostic performance of an enzyme linked immunospot (ELISPOT) assay for interferon-gamma in patients with suspected skeletal tuberculosis (TB). From March 2007 to June 2010, a total of 36 patients with suspected skeletal TB in a tertiary care hospital in Taiwan were enrolled. Twelve patients (35.3%) had culture-confirmed TB, three (8.8%) patients had probable TB, and the remaining 21 (58.3%) patients did not have TB. Fourteen patients with mycobacterial infection had available biopsy or surgical specimens for histopathological examination and 12 (85.7%) specimens had pathological features consistent with mycobacterial infection. Among the 12 patients with positive findings indicating mycobacterial infection, all seven patients with spinal TB and three of five patients with TB arthritis had positive ELISPOT assays. All nine patients with spinal TB had positive ELISPOT assays, but only four of six patients with TB arthritis had positive ELISPOT assays. The sensitivity, specificity, positive predictive value, and negative predictive value for skeletal TB diagnosis by the ELISPOT assay were 86.7%, 61.9%, 61.9%, and 86.7%, respectively. In conclusion, the ELISPOT assay can provide useful support in diagnosing skeletal TB, and spinal TB can be excluded based on a negative ELISPOT assay. PMID- 21240674 TI - Cerebral gene expression in response to single or combined gestational exposure to methylmercury and selenium through the maternal diet. AB - Controversy remains regarding the safety of consuming certain types of seafood, particularly during pregnancy. While seafood is rich in vital nutrients, it may also be an important source of environmental contaminants such as methylmercury (MeHg). Selenium (Se) is one essential element present in seafood, hypothesised to ameliorate MeHg toxicity. The aim of the present study was to ascertain the impact of Se on MeHg-induced cerebral gene expression in a mammalian model. Microarray analysis was performed on brain tissue from 15-day-old mice that had been exposed to MeHg throughout development via the maternal diet. The results from the microarray analysis were validated using qPCR. The exposure groups included: MeHg alone (2.6 mg kg(-1)), Se alone (1.3 mg kg(-1)), and MeHg + Se. MeHg was presented in a cysteinate form, and Se as Se-methionine, one of the elemental species occurring naturally in seafood. Eight genes responded to Se exposure alone, five were specific to MeHg, and 63 were regulated under the concurrent exposure of MeHg and Se. Significantly enriched functional classes relating to the immune system and cell adhesion were identified, highlighting potential ameliorating mechanisms of Se on MeHg toxicity. Key developmental genes, such as Wnt3 and Sparcl1, were also identified as putative ameliorative targets. This study, utilising environmentally realistic forms of toxicants, delivered through the natural route of exposure, in association with the power of transcriptomics, highlights significant novel information regarding putative pathways of selenium and MeHg interaction in the mammalian brain. PMID- 21240675 TI - Genome shuffling of marine derived bacterium Nocardia sp. ALAA 2000 for improved ayamycin production. AB - Genome shuffling is a recent development in microbiology. The advantage of this technique is that genetic changes can be made in a microorganism without knowing its genetic background. Genome shuffling was applied to the marine derived bacterium Nocardia sp. ALAA 2000 to achieve rapid improvement of ayamycin production. The initial mutant population was generated by treatment with ethyl methane sulfonate (EMS) combined with UV irradiation of the spores, resulting in an improved population (AL/11, AL/136, AL/213 and AL/277) producing tenfold (150 MUg/ml) more ayamycin than the original strain. These mutants were used as the starting strains for three rounds of genome shuffling and after each round improved strains were screened and selected based on their ayamycin productivity. The population after three rounds of genome shuffling exhibited an improved ayamycin yield. Strain F3/22 yielded 285 MUg/ml of ayamycin, which was 19-fold higher than that of the initial strain and 1.9-fold higher than the mutants used as the starting point for genome shuffling. We evaluated the genetic effect of UV + EMS-mutagenesis and three rounds of genome shuffling on the nucleotide sequence by random amplified polymorphic DNA (RAPD) analysis. Many differences were noticed in mutant and recombinant strains compared to the wild type strain. These differences in RAPD profiles confirmed the presence of genetic variations in the Nocardia genome after mutagenesis and genome shuffling. PMID- 21240676 TI - The Immune system's moderating response to inflammation relieves autistic behavior: response to Peter Good. PMID- 21240677 TI - Red ginseng deregulates hypoxia-induced genes by dissociating the HIF-1 dimer. AB - Water extract of Korean red ginseng (KRGW) contains numerous bioactive ginsenosides and is very popular as a multi-purpose medicine for health improvement. KRGW has been in the limelight because of its clinical benefit in cancer control. A growing body of evidence suggests that hypoxia-inducible factor 1 (HIF-1) plays critical roles in tumor promotion under hypoxia and that it is a compelling target for cancer therapy. In this paper we investigated the effect of KRGW on HIF-1-mediated adaptation to hypoxia. In both Hep3B cancer and HEK293 immortalized normal cell lines, KRGW attenuated the expression of hypoxia-induced genes without apparent cytotoxicity. Mechanistically, KRGW did not affect the synthesis, degradation, and translocation of HIF-1 in hypoxia. Interestingly, KRGW was found to repress the transcriptional activity of HIF-1 by interfering with the dimerization between HIF-1alpha and aryl hydrocarbon receptor nuclear translocator. To identify the HIF-inhibiting ingredient(s), we examined the effects of major ginsenosides on HIF-1 activity, but all ginsenosides tested failed to inactivate HIF-1. Based on these results, we propose that HIF-1 inhibition underlies the anticancer effect of ginseng. It is also proposed that KRGW could be an anticancer drug targeting hypoxic tumors. PMID- 21240679 TI - Constituents of cultivated Agaricus blazei. AB - Two phenylhexane derivatives (1, 2), benzoylergostane (3), N-benzoyl-L-leucine methyl ester (4), two known ergostanes, and highly degraded incisterol were isolated from fruit bodies of Agaricus blazei. Compound 3 exhibited strong cytotoxicity toward HepG2 cells (IC(50) = 6.0 +/- 0.33 MUM). PMID- 21240678 TI - New phenolic compounds from Meehania urticifolia. AB - A new phenylethanoid glycoside, rashomoside A (1), a new phenolic glucoside, rashomoside B (2), and a new shikimic acid derivative (3) were isolated from Meehania urticifolia together with 12 known flavones (4-15), three known phenylethanoid glycosides (16-18), and 13 other compounds (19-31). The structure of each of these compounds was elucidated based on the results of spectroscopic analysis. PMID- 21240680 TI - Two case reports of inherited antithrombin deficiency: a novel frameshift mutation and a large deletion including all seven exons detected using two methods. AB - An inherited antithrombin deficiency is an autosomal dominant thrombotic disorder. We identified two pedigrees of inherited type I antithrombin deficiency and two responsible mutations in each. A novel 21-22delAA appeared to have caused a frameshift with a premature termination at amino acid +63 in one patient and a large deletion including all seven exons was identified by multiplex ligation dependent probe amplification in the other. Some asymptomatic relatives of the second patient had the same mutation. The present findings support the value of using more than one method of gene analysis and of studying the families of probands with inherited thrombotic disorders. PMID- 21240684 TI - Epidemiological study of primary intracranial tumors: a regional survey in Kumamoto prefecture in southern Japan--20-year study. AB - BACKGROUND: The increased use of neuro-imaging techniques, as well as various environmental factors, has been changing the incidence and the proportions of types of intracranial tumors. However, no accurate population-based epidemiological study of intracranial tumors in Japan has been reported. We evaluated recent trends in the occurrence of primary intracranial tumors among residents of Kumamoto prefecture, Japan. METHODS AND RESULTS: We surveyed 5,448 new cases of primary intracranial tumors that were diagnosed in Kumamoto prefecture between 1989 and 2008. The overall age-adjusted incidence rate was 14.09 (11.59 for males, 16.38 for females) per 100,000 population per year. The most common tumors were meningiomas (36.8%), followed by gliomas (19.5%), adenomas (17.8%), schwannomas (9.9%), and malignant lymphomas (3.6%). The number of cases of primary brain tumors, especially meningiomas and malignant gliomas, among the elderly has steadily increased and the incidence of asymptomatic intracranial tumors also increased. The number of asymptomatic meningiomas diagnosed per year was higher than that of symptomatic meningiomas in the years between 1997 and 2008. Furthermore, the incidence rate of brain lymphoma in Kumamoto prefecture is approaching that recorded in Western countries. On the other hand, the incidence rate of germ cell tumors is on the decline, approaching that recorded for children in Western countries. CONCLUSION: Even though we adjusted the population in Kumamoto prefecture based on the Japanese population, increasing rates of several types of intracranial tumors were observed. These incidence rates are approaching those in Western countries. PMID- 21240683 TI - Effects of intravenous zoledronic acid and oral ibandronate on early changes in markers of bone turnover in patients with bone metastases from non-small cell lung cancer. AB - BACKGROUND: The aim of this study was to assess the early effects of zoledronic acid (ZOL) and oral ibandronate (IBA) on the bone resorption marker s-CTX (serum C-telopeptide of collagen type I) and the bone formation marker B-ALP (bone alkaline phosphatase) in patients with bone metastases from non-small cell lung cancer (NSCLC). METHODS: Fifty-five patients with at least one site of bone metastasis secondary to NSCLC were randomly assigned to receive intravenous ZOL 4 mg every 4 weeks, or oral IBA 50 mg/day. RESULTS: At 1 month of treatment, s-CTX was reduced by 54.8% (95% CI 40.4-59.8%) in the ZOL group (26 evaluable patients) compared with 38.2% (95% CI 29.8-48.7%) in the oral IBA group (27 evaluable patients) (p = 0.03). At 3 months, s-CTX was reduced by 72.6% (95% CI 58.6-71.3%) in the ZOL group, compared with 66.4% (95% CI 54.3-79.5%) in the oral IBA group (p = 0.22). Both bisphosphonates similarly decreased the bone marker B-ALP at 1 month (ZOL 24.7%, 95% CI 3.6-39.5%, and IBA 24.2%, 95% CI 2.8-43.4%) and 3 months (ZOL 28.6%, 95% CI +2.8-43.3%, and IBA 24.2%, 95% CI 3.2-47.4%). Both bisphosphonates were well tolerated. CONCLUSION: Considering the changes in bone markers, ZOL and oral IBA show comparable efficacy in patients with NSCLC and bone metastases. PMID- 21240685 TI - Citric acid inhibits growth of Helicobacter pylori in vitro: a new strategy for eradication. AB - BACKGROUND: About 50% of the world population is infected with Helicobacter pylori. The association of peptic ulcer disease with Helicobacter pylori is well documented. Therefore eradication is obligatory. However, the high costs of multidrug therapy, the resistance of Helicobacter pylori to antibiotics as well as the sometimes present drug intolerance are limiting factors. METHODS: The inhibitory effect of 3% hydrogen peroxide, 8.4% sodium bicarbonate, 2% ascorbic acid, citric acid in combination with sodium citrate, 7% and 14% citric acid solutions, respectively, on nine Helicobacter pylori strains were tested in vitro. RESULTS: Citric acid showed a potent inhibitory activity on growth of Helicobacter pylori strains in vitro. This was observed not only when citric acid was applied alone but also if citric acid was given together with low concentration of sodium citrate. Two percent ascorbic acid inhibited three, sodium bicarbonate two and hydrogen peroxide one of the nine tested Helicobacter pylori strains, respectively. CONCLUSIONS: Citric acid is a cheap substance present in many fruits and produced by food industry, and it demonstrated powerful inhibitory effect on the growth of Helicobacter pylori strains. On the basis of our findings citric acid should be further evaluated for the eradication of Helicobacter pylori. PMID- 21240686 TI - Sorafenib in unresectable intrahepatic cholangiocellular carcinoma: a case report. AB - BACKGROUND: The oral multikinase inhibitor sorafenib is the new reference standard for the treatment of advanced hepatocellular carcinoma. Only few data are available on the use of sorafenib in cholangiocellular carcinoma (CCC). METHODS: A 70-year-old male patient with histologically confirmed unresectable intrahepatic cholangiocellular carcinoma not amenable to any other systemic chemotherapy was treated with sorafenib 400 mg bid. RESULTS: Sorafenib treatment led to a significant improvement of tumor symptoms, liver function parameters, and a decrease in tumor marker levels. The best radiologic tumor response according to RECIST and mRECIST was stable disease (SD) with a time to progression (TTP) of 5.7 months. Side effects of sorafenib (diarrhea, fatigue, and skin toxicity) were low-grade and manageable. Twenty-four months after sorafenib initiation the patient is still alive and presents in a well-preserved physical constitution, performance status 0. Gene analyses revealed that neither B-raf nor K-ras was mutated in our patient. CONCLUSIONS: Sorafenib was effective and well-tolerated in a patient with advanced cholangiocellular carcinoma. Prospective trials are warranted to evaluate the benefit of sorafenib in unresectable CCC. PMID- 21240687 TI - Influenza A(H1N1) infection and severe cardiac dysfunction in adults: A case series. AB - BACKGROUND: While viral myocarditis and heart failure are recognized and feared complications of seasonal influenza A infection, only limited information is available for 2009 influenza A(H1N1)-induced heart failure. METHODS AND MAIN FINDINGS: This case series summarizes the disease course of four patients with 2009 influenza A(H1N1) infection who were treated at our institution from November 2009 until September 2010. All patients presented with severe cardiac dysfunction (acute heart failure, cardiogenic shock or cardiac arrest due to ventricular fibrillation) as the leading symptom of influenza A(H1N1) infection. Two patients most likely had pre-existent cardiac pathologies, and three required catecholamine therapy to maintain hemodynamic function. Except for one patient who died before influenza A(H1N1) infection had been diagnosed, all patients received antiviral therapy with oseltamivir and supportive critical care. Acute respiratory distress syndrome due to influenza A(H1N1) infection developed in one patient. Heart function normalized in two of the three surviving patients but remained impaired in the other one at hospital discharge. CONCLUSIONS: Influenza A(H1N1) infection may be associated with severe cardiac dysfunction which can even be the leading clinical symptom at presentation. During an influenza pandemic, a thorough history may reveal flu-like symptoms and should indicate testing for H1N1 infection also in critically ill patients with acute heart failure. PMID- 21240688 TI - Functional electrical stimulation combined with botulinum toxin type A to improve hand function in children with spastic hemiparesis - a pilot study. AB - BACKGROUND: Children with spastic hemiparesis frequently present with impaired hand function due to paresis, spasticity, and disturbed motor control. The aim of this study was to examine the effectiveness of functional electrical stimulation in combination with botulinum toxin type A in these children. DESIGN: Randomized, controlled, observer-blinded pilot study. SUBJECTS: Children with impaired hand function. INTERVENTIONS: Either a combined treatment group (functional electrical stimulation and botulinum toxin type A) or a botulinum toxin type A group alone. Botulinum toxin type A was injected into arm muscles according to the patient's clinical requirements. Functional electrical stimulation of the wrist and finger extensor muscles was started after five to six days. Patients were given a stimulation device and asked to use it at home twice daily for 15 min, for a total period of three months. MAIN MEASURES: Active and passive range of motion, muscle tone, muscle strength, and functional tests for children. RESULTS: Six children aged between 7 and 17 years with spastic hemiparesis were enrolled. In both groups, active and passive range of motion, muscle tone, and muscle strength improved after three and six months compared to baseline data. The functional score was improved only in the group that received combined treatment. CONCLUSIONS: Combined treatment with functional electrical stimulation and botulinum toxin type A is a promising treatment option to improve upper limb function in children with spastic hemiparesis. PMID- 21240690 TI - Cognition and driving in older persons. AB - In Switzerland, approximately 350,000 people aged 70 years or older own a valid driving license. By law, these drivers are medically assessed every other year, most commonly by their general practitioner, to exclude that a medical condition is interfering with their driving skills. A prerequisite for driving is the integration of high-level cognitive functions with perception and motor function. Ageing, per se, does not necessarily impair driving or increase the crash risk. However, medical conditions, such as cognitive impairment and dementia, become more prevalent with advancing age and may contribute to poor driving and an increased crash risk. The extent to which driving skills are impaired depends on the cause of dementia, disease severity, other co-morbidities and individual compensation strategies. Dementia often remains undiagnosed and therefore general practitioners (GPs) can find themselves in the difficult situation to disclose a suspicion about cognitive impairment and queries about medical fitness to drive, at the same time. In addition, the literature suggests that cognitive screening tests, most commonly used by GPs, have a limited role in judging whether an older person remains fit to drive. Further specialist assessment, for example in a memory clinic or on the road testing (ORT), may be helpful when the diagnosis or its implication for driving remain unclear. Here, we review the literature about cognition and driving, for GPs who advise older drivers who wish to continue driving. PMID- 21240691 TI - Attachment processes in Early Head Start families. PMID- 21240693 TI - Does attachment style influence social support or the other way around? A longitudinal study of Early Head Start mothers. AB - Understanding the association between attachment style and social support is important for informing programs that seek to improve outcomes for families by intervening with either or both of these systems. The present study examines whether increasing levels of social support among 181 low-income, primarily African American mothers leads to changes in their self-reported attachment style, or whether attachment style influences the extent to which they perceive others as supportive. Results suggest that whereas scores on the avoidant attachment dimension were relatively stable and led to decreasing perceptions of social support over time, scores on the anxious dimension were more malleable, at least under conditions of low stress. For mothers who experienced fewer stressful life events, increasing social support led to decreased attachment anxiety over time. However, when life stress was high, social support had no such positive influence. Implications for the need to attend to mothers' attachment styles in providing appropriate and effective intervention are discussed. PMID- 21240692 TI - Early mother-child separation, parenting, and child well-being in Early Head Start families. AB - Drawing on theories of attachment and family instability, this study examined associations between early mother-child separation and subsequent maternal parenting behaviors and children's outcomes in a sample of 2080 families who participated in the Early Head Start Research and Evaluation Project, the vast majority of whom were poor. Multiple regression models revealed that, controlling for baseline family and maternal characteristics and indicators of family instability, the occurrence of a mother-child separation of a week or longer within the first two years of life was related to higher levels of child negativity (at age three) and aggression (at ages three and five). The effect of separation on child aggression at age five was mediated by aggression at age three, suggesting that the effects of separation on children's aggressive behavior are early and persistent. PMID- 21240694 TI - Testing maternal depression and attachment style as moderators of Early Head Start's effects on parenting. AB - This study examined maternal depression, attachment avoidance, and attachment anxiety as moderators of Early Head Start's effects on four parenting outcomes assessed at age three. Participants (N = 947) were drawn from six sites of the Early Head Start National Research and Evaluation Project, a multi-site randomized trial. Findings suggest more positive program effects for mothers with less initial attachment avoidance or attachment anxiety. First, baseline attachment avoidance moderated Early Head Start program effects on observed maternal supportiveness, such that program mothers with lower baseline attachment avoidance were rated as more supportive of their three-year-olds than program mothers with higher baseline attachment avoidance. Second, program effects on spanking varied depending on mothers' baseline attachment anxiety. PMID- 21240695 TI - Validity of the TAS-45 as a measure of toddler-parent attachment: preliminary evidence from Early Head Start families. AB - A new observational measure of attachment strategies in the home, the Toddler Attachment Sort-45 (TAS-45) was completed for 59 18- to 36-month-old recipients of EHS. Mothers completed the Brief Infant Toddler Social and Emotional Assessment (BITSEA); children were tested on the Preschool Language Scale (PLS 4); and a mother-child snack was videotaped and coded for dyadic mutuality. The TAS-45 Security score was associated with more dyadic mutuality, higher language and competence scores, and lower problem scores. Discriminant validity was evidenced by a lack of associations with the TAS-45 Dependence score. The TAS-45 Disorganized "hotspot" (cluster) score also showed expected associations with these outcomes. Results are discussed in terms of next steps for use of the TAS 45 in research and practice. PMID- 21240696 TI - Attachment relationships in Early Head Start families. AB - The remarkable papers in this Special Issue underscore the importance of applied research on families in poverty, the opportunities to developmental science of the Early Head Start National Research and Evaluation Project, and the mutual benefits from collaborations between research scientists and program practitioners. This commentary highlights the insights of these papers concerning the consequences of maternal attachment style and mother-child interaction, the challenges of assessing attachment in intervention research, and the program and policy implications of these findings. PMID- 21240697 TI - Attachment research and Early Head Start: from data to practice. AB - Early Head Start is the only federal program in the United States to support families from birth to three-years, a phase in which attachment is a central developmental task. The papers which make up this Special Issue represent formative work in using attachment theory and measures to frame research in Early Head Start. In this commentary, we offer some initial thoughts on how each of the studies presented might be used to foster program improvement and inspire research that will address pressing questions looking forward. PMID- 21240698 TI - Ecological behaviour of three serogroups of Legionella pneumophila within a model plumbing system. AB - Three Legionella pneumophila strains isolated from water samples and belonging to serogroups (sgs) 1, 6 and 9 were analysed for their capacity to colonise an experimental model simulating a domestic hot water distribution system. Ecological factors that could influence the persistence of the sgs such as intracellular life within protozoan hosts and bacterial interference by the production of antagonistic compounds were also studied. Viable counts of L. pneumophila increased both in the planktonic and in the sessile phases. Sg 6 showed a marked prevalence during the whole experiment and exhibited the highest host infection efficiency. Sg 1 was significantly less represented, but showed the highest capacity to reproduce in the protozoan hosts. Sg 9 was poorly represented and less adapted to intracellular life. Among the 14 bacteria constantly isolated in the system, five (35.7%) produced antagonistic substances against Legionella, with differences according to the bacterial strain and L. pneumophila sgs. PMID- 21240699 TI - Development of a quantitative lateral flow immunoassay for the detection of aflatoxins in maize. AB - An immunoassay-based lateral flow device for the quantitative determination of four major aflatoxins in maize has been developed. The one-step assay has performance comparably with that of other screening methods, as confirmed by the intra- and the inter-day precision of the data (RSD 10-22%), and can be completed in 10 min. Quantification was obtained by acquiring images of the strip and correlating intensities of the coloured lines with analyte concentration by means of a stored calibration curve carried out by diluting aflatoxins in the extract from a blank maize sample. Limit of detection (1 ug kg-1) and dynamic range (2-40 ug kg-1) allows the direct assessment of aflatoxin contamination in maize at all levels of regulatory relevance. All reagents are immobilized on the lateral flow device. In addition, very simple sample preparation, using an aqueous buffered solution, has been demonstrated to allow the quantitative extraction of aflatoxins. Twenty-five maize samples were extracted with the aqueous medium and analyzed by the developed assay. A good correlation was observed (y = 0.97x + 0.07, r2= 0.980) when data was compared with that obtained through an official method. The developed method is reliable, rapid and allows for application outside the laboratory as a point-of-use test for screening purposes. PMID- 21240700 TI - Simultaneous determination of bisphenol A and bisphenol B in beverages and powdered infant formula by dispersive liquid-liquid micro-extraction and heart cutting multidimensional gas chromatography-mass spectrometry. AB - The purpose of this study was to establish a reliable, cost-effective, fast and simple method to quantify simultaneously both bisphenol A (BPA) and bisphenol B (BPB) in liquid food matrixes such as canned beverages (soft drinks and beers) and powdered infant formula using dispersive liquid-liquid micro-extraction (DLLME) with in-situ derivatisation coupled with heart-cutting gas chromatography mass spectrometry (GC-MS). For the optimisation of the DLLME procedure different amounts of various extractive and dispersive solvents as well as different amounts of the derivative reagent were compared for their effects on extraction efficiency and yields. The optimised procedure consisted of the injection of a mixture containing tetrachloroethylene (extractant), acetonitrile (dispersant) and acetic anhydride (derivatising reagent) directly into an aliquot of beverage samples or into an aqueous extract of powdered milk samples obtained after a pretreatment of the samples. Given the compatibility of the solvents used, and the low volumes involved, the procedure was easily associated with GC-MS end point determination, which was accomplished by means of an accurate GC dual column (heart-cutting) technique. Careful optimisation of heart-cutting GC-MS conditions, namely pressure of front and auxiliary inlets, have resulted in a good analytical performance. The linearity of the matrix-matched calibration curves was acceptable, with coefficients of determination (r2) always higher than 0.99. Average recoveries of the BPA and BPB spiked at two concentration levels into beverages and powdered infant formula ranged from 68% to 114% and the relative standard deviation (RSD) was <15%. The limits of detection (LOD) in canned beverages were 5.0 and 2.0 ng l(-1) for BPA and BPB, respectively, whereas LOD in powdered infant formula were 60.0 and 30.0 ng l(-1), respectively. The limits of quantification (LOQ) in canned beverages were 10.0 and 7.0 ng l-1 for BPA and BPB, respectively, whereas LOQ in powdered infant formula were 200.0 and 100.0 ng l(-1), respectively. BPA was detected in 21 of 30 canned beverages (ranging from 0.03 to 4.70 ug l(-1)) and in two of seven powdered infant formula samples (0.23 and 0.40 ug l(-1)) collected in Portugal. BPB was only detected in canned beverages being positive in 15 of 30 samples analysed (ranging from 0.06 to 0.17 ug l(-1)). This is the first report about the presence of BPA and BPB in canned beverages and powdered infant formula in the Portuguese market. PMID- 21240701 TI - Teens' attention to crime and emergency programs on television as a predictor and mediator of increased risk perceptions regarding alcohol-related injuries. AB - This study examined the hypotheses that media exposure and attention would predict, and partially mediate, the effects of various individual-difference variables on alcohol-related risk perceptions among teen viewers of crime and emergency (e.g., medical drama) shows on television. Risk perceptions including perceived severity, perceived alcohol-attributable fraction of incidents involving alcohol, controllability, and concern regarding alcohol-related crime, assaults, and other injuries were the outcome measures. Attention to crime and emergency shows was predictive of increased concern and other risk perceptions regarding alcohol-related incidents. Attention also partially mediated the effects of demographic and other individual difference variables on adolescents' risk perceptions regarding alcohol-related injuries. The findings (a) suggest emergency and medical drama television narratives can at times have incidental positive impacts on health-related attitudes and (b) provide further evidence regarding the endogenous nature of media use variables in influencing such attitudes. PMID- 21240702 TI - Water and sediment quality in a tropical swamp used for agricultural and oil refining activities. AB - The Godineau Swamp in Trinidad receives anthropogenic input from agricultural and oil refining activities, sewage and domestic waste. This study was conducted in order to provide a comprehensive baseline dataset for the swamp, to assess water and sediment quality in the swamp, and to identify hotspots and possible sources of pollutants to the swamp. Ten sampling stations were established in the swamp during April/May and July 2002. Water quality parameters monitored included physicochemical measurements (pH, temperature, dissolved oxygen and salinity), total suspended solids, and nutrients (ammonia, nitrites, nitrates and total phosphorus). Sediments were analyzed for hydrocarbons, heavy metals and total organic carbon. Temperatures and pH of water in the swamp were ambient; dissolved oxygen was low in many instances (<3 mg/L). In the dry season, there was saltwater intrusion along the Oropuche River up to the most easterly station. Levels of ammonia and phosphorus concentrations were suggestive of periodic inputs of agricultural and domestic wastes. Hydrocarbons concentrations in sediment were above ambient levels and suggestive of contamination from industrial activities. Sediments from the Godineau River contained elevated nutrients, hydrocarbons, metals and TOC compared with other stations. The results of this study indicate some degree of pollution of the Godineau swamp, which prompts the need for the implementation of measures beneficial for wise use of the swamp. PMID- 21240703 TI - Classification and modeling of different fractions of aerosol monitoring data. AB - The present study deals with the application of self-organizing maps (SOM) of Kohonen and four-way Tucker method for the classification and modeling, respectively, of aerosol monitoring data sets from two sampling points (Arnoldstein and Unterloibach) located close to the border, between Austria and Slovenia. The goal of the chemometric data treatment was to find some specific patterns in the classification maps and in the four-way model of complexity [2422] for 5 different aerosol fractions collected in 4 different seasons of the year. The results indicated a distinct separation of the ultrafine particles (PM 0.01-PM 0.4) from the other fractions, which underlines their specific effect on human health. Seasonal separation (but only between summer and winter sampling) is also observed. PMID- 21240704 TI - In vitro assessment of molybdenum-induced secretory activity, proliferation and apoptosis of porcine ovarian granulosa cells. AB - Molybdenum (Mo) is an essential trace element and it plays an important role in cell functions. The mechanism of the action of molybdenum in connection with growth factor IGF-I, proliferation-related peptide cyclin B1 and apoptosis related peptide caspase-3 has not been examined previously in porcine ovarian granulosa cells. The general objective of this in vitro study was to examine the secretory activity of porcine ovarian granulosa cells after experimental Mo administration and to outline the potential intracellular mediators of its effects. Ovarian granulosa cells were incubated with ammonium molybdate for 18 hours: 1.0 mg/mL; 0.5 mg/mL; 0.33 mg/mL; 0.17 mg/mL and 0.09 mg/mL, while the control group received no Mo. The secretion of IGF-I was assessed by RIA and expression of cyclin B1 and caspase-3 by immunocytochemistry. IGF-I release was decreased by Mo addition at the doses 1.0 mg/mL and 0.5 mg/mL. The expression of cyclin B1 was stimulated by Mo addition at all doses ranging from 1.0-0.09 mg/mL. Caspase-3 expression was also stimulated after experimental Mo addition at the doses 1.0 and 0.5 mg/mL. These data contribute to new insights regarding the mechanism of action of Mo on porcine ovarian functions, secretory activity, proliferation and apoptosis of granulosa cells through hormonal and intracellular substances such as are cyclin B1 and caspase-3. PMID- 21240705 TI - Post-refining removal of organic nitrogen compounds from diesel fuels to improve environmental quality. AB - The purpose of this investigation was to remove the organic nitrogen compounds from petroleum-derived diesel fuels. These nitrogen compounds can cause environmental problems, as well as fuel instability problems that can degrade fuels and affect engine performance. Fuels were treated with two different filtering media, activated clay and silica tel. The methylene chloride extracts from both the activated clay and silica gel were subjected to GC/MS analysis. Close to 99% of the total organic nitrogen compounds were removed. About 60% of the nitrogen compounds identified consisted of pyridines, quinolines and tetra hydroquinolines made up 26%, while indoles and carbazoles about 10% of the total nitrogen compounds. Of the nitrogen heterocyclics identified, indoles and carbazoles were linked to fuel instability reactions. The proposed method was tested on diesels fuels from a variety of countries and found to remove between 97.8 and 99.9% of the N-compounds. The results of this study showed that both of these filtering materials were effective in removing the organic nitrogen compounds and resulted in fuels that exhibited excellent storage stability. These simple filtering methods can be independent of the refining process and do result in an environmentally cleaner burning fuel. PMID- 21240706 TI - Outdoor and indoor benzene evaluation by GC-FID and GC-MS/MS. AB - The evaluation of benzene in different environments such as indoor (with and without tobacco smoke), a city area, countryside, gas stations and near exhaust pipes from cars running on different types of fuels was performed. The samples were analyzed using gas chromatography (GC) with flame ionization detection (FID) and tandem mass spectrometric detection (MS/MS) (to confirm the identification of benzene in the air samples). Operating conditions for the GC-MS analysis were optimized as well as the sampling and sample preparation. The results obtained in this work indicate that i) the type of fuel directly influences the benzene concentration in the air. Gasoline with additives provided the highest amount of benzene followed by unleaded gasoline and diesel; ii) the benzene concentration in the gas station was always higher than the advisable limit established by law (5 MUg m-3) and during the unloading of gasoline the achieved concentration was 8371 MUg m-3; iii) the data from the countryside (Taliscas) and the urban city (Matosinhos) were below 5 MUg m-3 except 5 days after a fire on a petroleum refinery plant located near the city; iv) it was proven that in coffee shops where smoking is allowed the benzene concentration is higher (6 MUg m-3) than in coffee shops where this is forbidden (4 MUg m-3). This method may also be helpful for environmental analytical chemists who use GC-MS/MS for the confirmation or/and quantification of benzene. PMID- 21240707 TI - Effect of biomass open burning on particulate matter and polycyclic aromatic hydrocarbon concentration levels and PAH dry deposition in ambient air. AB - The objectives of the present study were to investigate particulate matter (PM) and polycyclic aromatic hydrocarbon (PAH) concentrations in ambient air during rice straw open burning and non-open burning periods. In the ambient air of a rice field, the mean PM concentration during and after an open burning event were 1828 and 102 MUg m-3, respectively, which demonstrates that during a rice field open burning event, the PM concentration in the ambient air of rice field is over 17 times higher than that of the non-open burning period. During an open burning event, the mean total PAH and total toxic equivalence (BaP(eq)) concentrations in the ambient air of a rice field were 7206 ng m-3 and 10.3 ng m-3, respectively, whereas after the open burning event, they were 376 ng m-3 and 1.50 ng m-3, respectively. Open burning thus increases total PAH and total BaP(eq) concentrations by 19-fold and 6.8-fold, respectively. During a rice straw open burning event, in the ambient air of a rice field, the mean dry deposition fluxes of total PAHs and total BaP(eq) were 1222 MUg m-2 day-1 and 4.80 MUg m-2 day-1, respectively, which are approximately 60- and 3-fold higher than those during the non-open burning period, respectively. During the non-open burning period, particle-bound PAHs contributed 79.2-84.2% of total dry deposition fluxes (gas + particle) of total PAHs. However, an open burning event increases the contribution to total PAH dry deposition by particle-bound PAHs by up to 85.9 95.5%. The results show that due to the increased amount of PM in the ambient air resulting from rice straw open burning, particle-bound PAHs contributed more to dry deposition fluxes of total PAHs than they do during non-open burning periods. The results show that biomass (rice straw) open burning is an important PAH emission source that significantly increases both PM and PAH concentration levels and PAH dry deposition in ambient air. PMID- 21240708 TI - Sensitivity enhancement at 594.8 nm atomic transition of Cl I for chloride detection in the reinforced concrete using LIBS. AB - A new atomic line at 594.8 nm of neutral chlorine (Cl I) has been used as a marker to quantify the amount of chloride present in the concrete sample using Laser Induced Breakdown Spectroscopy (LIBS). Although, the relative intensity of the 594.8 nm line is 1000-fold less than that of the most commonly used intense atomic line of Cl I at 837.5 nm reported in the literature, the limit of detection of chlorine achieved with our set-up in the concrete sample using the new line is comparable with the 837.5 nm. This clearly indicates that the sensitivity of the LIBS system for detection of chlorine in concrete sample using 594.8 nm is at least 1000-fold more than the one using 837.5 nm, which can be attributed to the characteristic less self absorption. LIBS data for different concentration of chloride content in concrete sample was also carried out and a calibration curve was drawn. The excitation scheme for 594.8 nm line is also proposed in this work. PMID- 21240709 TI - Characteristics of particulate emissions from a diesel generator fueled with varying blends of biodiesel and fossil diesel. AB - This study investigated the particulate matter (PM), particle-bound carbons, and polycyclic aromatic hydrocarbons (PAHs) emitted from a diesel-engine generator fuelled with blends of pure fossil diesel oil (D100) and varying percentages of waste-edible-oil biodiesel (W10, 10 vol %; W20, 20 vol %; W30, 30 vol %; and W50, 50 vol %) under generator loads of 0, 1.5, and 3 kW. On average, the PM emission factors of all blends was 30.5 % (range, 13.7-52.3 %) lower than that of D100 under the tested loads. Substituting pure fossil diesel oil with varying percentages of waste-edible-oil biodiesel reduced emissions of particle-bound total carbon (TC) and elemental carbon (EC). The W20 blend had the lowest particle-bound organic carbon (OC) emissions. Notably, W10, W20, and W30 also had lower Total-PAH emissions and lower total equivalent toxicity (Total-BaP(eq)) compared to D100. Additionally, the brake-specific fuel consumption of the generator correlated positively with the ratio of waste-edible-oil biodiesel to pure fossil diesel. However, generator energy efficiency correlated negatively with the ratio of waste-edible-oil biodiesel to pure fossil diesel. PMID- 21240710 TI - Antiradical activity of natural honeys and antifungal effect against Penicillium genera. AB - The purpose of the study was to examine the antiradical activity of 11 natural honeys and to evaluate the antifungal properties of honey. Honey samples (10) were collected from different locations of Slovak Republic. Honeys were native to different plant species of Robinia pseudoacaccia, Brassica napus subs. napus, Castanea sativa Mill. Thymus serpyllum vulgaris and the other samples had multifloral origin. The low antiradical activitity in honey samples was determined. The best results were found in thyme honey from Rhodos (11.84 %) and Castanea honey from Nitra (10.61 %). The lowest antiradical activity was found in Acacia honey and determined to be 7.62 %. Statistically significant differences (P< 0.001) were found among thyme/Rhodos and Castanea/Nitra. The antifungal activities of honey samples were tested by 10 %, 25 % and 50 % (by mass per volume) concentration against fungi Penicillium crustosum, P. expansum, P. griseofulvum, P. raistrickii and P. verrucosum and by the agar well diffusion method. The solutions containing 10 % (by mass per volume) of honey did not have any effect on the growth of fungi. The strongest antifungal effect was shown by 50 % honey concentration against P. raistrickii. PMID- 21240712 TI - Causality conundrums and advice to authors. PMID- 21240711 TI - Pilot biomonitoring of adults and children following use of chlorpyrifos shampoo and flea collars on dogs. AB - Pesticide handlers and pet owners who use products such as shampoos and dips and insecticide-impregnated collars to treat and control fleas on companion animals are exposed to a variety of active ingredients. Chlorpyrifos exposures of adults and children were measured using urine biomonitoring following use of over-the counter products on dogs. Age and gender-specific measurements of urinary 3, 5, 6 trichloro-2-pyridinol (TCPy) revealed modest elevations of biomarker excretion following shampoo/dips. Smaller TCPy increments were measured following application of impregnated dog collars. The extent of indoor activity and potential pet contact were important determinants of urine biomarker level. Children without direct pet contact excreted more TCPy following collar application. Pet collars may be a source of indoor surface contamination and human exposure. Children excreted up to 4 times more TCPy than adults when urine volumes were adjusted using age-specific creatinine excretion levels. Although chlorpyrifos is no longer used in the United States in pet care products, results of this research provide perspective on the extent of human exposure from similar pet care products. These pilot studies demonstrated that pet care products such as insecticidal shampoos and dips and impregnated collars may expose family members to low levels of insecticide relative to toxic levels of concern. PMID- 21240713 TI - The meaning of gender while aging with paralytic polio. AB - The purpose of this article is to report the influence of gender on aging with childhood onset paralytic polio. The hermeneutic phenomenological exploration of gender was done using multiple qualitative interviews with 25 women, age 55 to 75 years of age, who had polio since before 14 years of age. We noted three themes: (a) the movement of her body, (b) integrating body and gender, and (c) gender discrepancies. Findings are discussed in the context of gendered expectations and the women's bodies. PMID- 21240715 TI - Aging with a severe mental illness: challenges and treatments. AB - Severe mental illness (SMI) impacts many different facets of individuals' lives. As they age, those with SMI experience increased physical illnesses, functional impairment, cognitive deficits, and social disability. To promote more effective social work practice with this population, this article highlights the major biopsychosocial and family issues of aging with a psychiatric diagnosis. In addition, intervention approaches that have demonstrated efficacy are summarized along with ways to coordinate services across multiple service delivery sectors. Finally, future directions in practice and research are presented to develop additional methods of support for older adults with SMI and their families. PMID- 21240714 TI - Family perspectives on the hospice experience in adult family homes. AB - Growing numbers of terminally ill older adults receive hospice services in adult family homes (AFHs); however, little is known about the provision and receipt of end-of-life care in such environments. This article reports findings from a qualitative exploration of family members' perspectives of the hospice experience in AFHs. Analysis of data obtained during interviews of 15 residents' family members exposed significant challenges associated with transition to an AFH, highlighted the importance of AFH and hospice staff in family members' assessment of overall quality of care, and emphasized the critical nature of communication in AFH settings. PMID- 21240716 TI - Social work knowledge of community-based services for older adults: an educational model for social work students. AB - Social workers are often the key link between older adults, their families and community-based services. Thus, knowledge about older adults and community-based care is imperative for social work practice. Evaluation data are provided on a national multisite effort (N = 353) from 35 schools to assure graduate social work student's competency related to community services for older adults. Results suggest that the educational model as described in this article sets forth positive outcomes in the education of aging savvy social workers. Ongoing social work education is needed to meet the burgeoning needs of the geriatric population. PMID- 21240717 TI - Multilevel factors related to psychosocial care outcomes in Washington State skilled nursing facilities. AB - As the primary providers of psychosocial services in skilled nursing facilities, social services professionals report barriers interfering with their ability to meet residents' needs. This study utilizes a 3-category quality assessment framework and a cross-sectional survey design to assess factors impacting the provision of effective psychosocial services in Washington State facilities. Hierarchical linear regression results indicate that the 3-factor model explains 26.4% of the variance in psychosocial outcomes; 4 variables exert the most influence: ownership turnover, practitioner experience, practitioner role identity, and the importance of individualizing care. Findings have implications for developing necessary supports for quality psychosocial care delivery. PMID- 21240718 TI - Selection, optimization, and compensation: strategies to maintain, maximize, and generate resources in later life in the face of chronic illnesses. AB - This qualitative study of 45 older adults examines how they allocate their resources in the face of chronic health conditions. Participants were recruited from 2 senior centers and interviewed about their repertoire of activities, any changes in those activities in later life, and meanings they ascribed to those changes. The Selection, Optimization, and Compensation model guided our analysis and interpretation of participants' responses. The findings demonstrate the complexity of participants' responses to age-related changes, particularly in how they adapted and negotiated both their perception and life goals when faced with changing social landscapes. We discuss some implications and nuances of our findings. PMID- 21240720 TI - Assessing literacy in clinical and community settings: the patient perspective. AB - A common concern among patient advocates and practitioners is the potential to offend patients with literacy testing in clinical settings. Patients' perceptions of, and comfort level with, literacy testing have not been well established. The aim of this study was to assess patient attitudes about literacy assessments in a primary care clinic and a community-based wellness program and to explore whether patients preferred one assessment tool over another. Participant recruitment occurred at a general internal medicine clinic and two community settings (YMCAs) in the southeast. Two literacy measures (Rapid Estimate of Adult Literacy in Medicine and Test of Functional Health Literacy in Adults) and a questionnaire to assess opinions on the instruments were administered. Most participants were comfortable having their literacy assessed and indicated that it would be useful for practitioners to know the literacy levels of patients. A sizable minority (10%) were concerned that such testing in health care settings may be inappropriate. An additional finding was that self-reported reading skills of participants did not correspond to actual reading scores. Patients recognize the importance of literacy in their health care and most are comfortable with literacy assessments. An important minority, however, object to this practice. PMID- 21240721 TI - Effect of media campaigns and smoke-free ordinance on public awareness and secondhand smoke exposure in Taiwan. AB - This study evaluated the effect of Taiwan's smoke-free ordinance and media campaigns on public awareness and secondhand smoke exposure. The authors conducted 3 waves of research--in July 2008 (before media campaigns), in December 2008 (during media campaigns), and in March 2009 (3 months after implementation of the smoke-free law). National representative samples of 1074, 1084, and 1094 people, respectively, were interviewed successfully by telephone in the 3 surveys. The results showed that general awareness of smoke-free workplace legislation rose dramatically from 28.5% in July 2008 to 87.6% in December 2008 to 93.6% in March 2009. Exposure to secondhand smoke in the workplace fell from 28.5% in July 2008 to 24.9% in December 2008 to 7.3% in March 2009, and household secondhand smoke exposure decreased from 36.8% to 34.3% to 21.3%, respectively, during the same period. Multivariate analyses results indicated that media campaigns, smoke-free ordinance implementation, having higher education, and having higher income were associated with more awareness of the smoke-free workplace legislation. In addition, smoke-free ordinance implementation, being female, having higher education, and having higher income were associated with less likelihood of reporting secondhand smoke exposure in the workplace. In conclusion, smoke-free ordinance implementation and media campaigns were effective in raising public awareness of the new law and reducing secondhand smoke exposure in workplaces, in public places, and at home. PMID- 21240722 TI - Cancer recurrence worry, risk perception, and informational-coping styles among Appalachian cancer survivors. AB - Despite a growing literature on the psychosocial impact of the threat of cancer recurrence, underserved populations, such as those from the Appalachian region, have been understudied. To examine worry and perceived risk in cancer survivors, Appalachian and non-Appalachian cancer patients at an ambulatory oncology clinic in a university hospital were surveyed. Appalachians had significantly higher worry than non-Appalachians. Cancer type and lower need for cognition were associated with greater worry. Those with missing perceived risk data were generally older, less educated, and lower in monitoring, blunting, and health literacy. Additional resources are needed to assist Appalachians and those with cancers with poor prognoses (e.g., liver cancer, pancreatic cancer) to cope with worry associated with developing cancer again. More attention for cancer prevention is critical to improve quality of life in underserved populations where risk of cancer is greater. PMID- 21240723 TI - An exploratory model of the relationships between cancer-related trauma outcomes on quality of life in non-Hodgkin lymphoma survivors. AB - Given that more than one third of some cohorts of cancer survivors exhibit post traumatic stress disorder (PTSD) symptomatology, this study examines how trauma outcomes might relate to quality of life (QOL). Eight hundred thirty survivors of adult lymphoma were assessed for PTSD, post-traumatic growth (PTG) and QOL. Structural equation modeling revealed that QOL was best explained by the model in which stressors (e.g., co-morbidities) were mediated by PTSD and PTG. Trauma outcomes mediated the relationship between specific stressors and QOL. These findings support using PTSD and PTG as a diagnostic framework in understanding symptomatology in survivors. PMID- 21240724 TI - Clinical, demographic, and situational factors linked to distress associated with benign breast biopsy. AB - Benign breast biopsy (BBB) can be distressing for many women. Few studies have examined specific aspects of the BBB more or less distressing or risk factors for distress. Women (N = 51) who had a recent BBB reported the magnitude of distress associated with specific aspects of their experience. Clinical and demographic variables were also examined as risk factors for distress. All women reported some distress associated with the BBB with one third reporting their experience was "very stressful." Generally, biopsy-specific events were more distressing than follow-up mammography. Distress risk factors included younger age, less education, nonsurgical biopsy, and no family history of breast cancer. Clinical efforts to better manage biopsy-related distress are warranted. The authors identified clinical and demographic risk factors that furnish a simple, efficient, and potentially cost-effective means of stratifying risk for distress in the breast biopsy setting. PMID- 21240725 TI - Swedish mothers and fathers of children with cancer: perceptions of well-being, social life, and quality care. AB - The overall aim was to describe and compare well-being, social life, and quality care among parents of children with cancer with respect to mothers versus fathers and whether the children were on versus. off treatment. The Life Situation Scale for Parents (LSS-P) was answered by 320 parents, comprising 85 mothers and 71 fathers of children on treatment, and 93 mothers and 71 fathers of children off treatment. The results show that the well-being of parents of children with cancer is affected by their child's situation, and that they experience such things as economic strain and a sense of being dependent on the care provided, especially during the child's treatment phase. Mothers whose children are receiving treatment see their life situation as less satisfying, and report being sadder and having lower self-esteem. PMID- 21240726 TI - The return to the community after cancer treatment: from safety to reality check. AB - The survivorship of children diagnosed with cancer has risen during the last decade. After the end of treatment those children and their families return to the community where another period of crisis unfolds. In this article, the findings of a larger qualitative study in Puerto Rico related to the return to the community of these patients and their families are discussed, including financial difficulties, the burden of responsibility, and transition to school. These findings provide a rationale for the implementation of a bio-psycho-social model of health that emphasizes reciprocal interactions among the multiple systems in which these families are embedded. PMID- 21240727 TI - Initial Development of the Mental Health Assessment and Dynamic Referral for Oncology (MHADRO). AB - The Mental Health Assessment and Dynamic Referral for Oncology (MHADRO) is a program that conducts a computerized assessment of physical, psychological, and social functioning related to oncology treatment, prints personalized summary reports for both the patient and the provider, and for those who provide consent, faxes a referral and assessment summary report to a matched mental health treatment provider (i.e., dynamic referral). The functionality, feasibility, and end user satisfaction of the MHADRO were tested in a comprehensive care center. Of the 101 participants enrolled, 61 (60%) exhibited elevated distress on at least one of the mental health indices, and, of these, 12 (20%) chose a dynamic referral for mental health services. Patients and health care providers exhibited high levels of satisfaction with the program. The MHADRO has potential for assisting in meeting the psychosocial needs faced by individuals with cancer and should be tested further for its facilitation of mental health treatment initiation. PMID- 21240728 TI - Benefits from participation in the chemo club: psychosocial insights on an exercise program for cancer patients. AB - Recent research has established the important beneficial relationship between exercise and cancer rehabilitation and survivorship. However, the complexities of this interrelationship are as yet underexplored. This article presents the findings of a recent qualitative research study that examined the psychosocial benefits associated with involvement in an exercise club (the Chemo Club) specifically designed for cancer patients during or postchemotherapy from the perspectives of the patients. The findings validate the important benefits involvement in the Chemo Club provides its members and highlight the need for further initiates, hospital based and external, to establish such services for cancer patients. PMID- 21240729 TI - Determining when enhanced pause (Penh) is sensitive to changes in specific airway resistance. AB - Penh is a dimensionless index normally used to evaluate changes in the shape of the airflow pattern entering and leaving a whole-body flow plethysmograph as an animal breathes. The index is sensitive to changes in the distribution of area under the waveform during exhalation and increases in a nonlinear fashion as the normalized area increases near the beginning of the curve. Enhanced pause (Penh) has been used to evaluate changes in pulmonary function and as a method to evaluate airway reactivity. However, the use of Penh to assess pulmonary function has been challenged (Bates et al., 2004; Lundblad et al., 2002; Mitzner et al., 2003; Mitzner & Tankersley, 1998; Petak et al., 2001; Sly et al., 2005). The objective of this study was to show how Penh of the thorax and plethysmograph flow patterns are related. That relationship is used to describe the conditions under which whole-body plethysmograph Penh measurements can be used to detect changes in sRaw. PMID- 21240730 TI - Comparison of gene expression profiles induced by coarse, fine, and ultrafine particulate matter. AB - Coarse, fine, and ultrafine particulate matter (PM) fractions possess different physical properties and chemical compositions and may produce different adverse health effects. Studies were undertaken to determine whether or not gene expression patterns may be used to discriminate among the three size fractions. Airway epithelial cells obtained from 6 normal individuals were exposed to Chapel Hill coarse, fine or ultrafine PM (250 MUg/ml) for 6 and 24 h (n=3 different individuals each). RNA was isolated and hybridized to Affymetrix cDNA microarrays. Significant genes were identified and mapped to canonical pathways. Expression of selected genes was confirmed by reverse-transcription polymerase chain reaction (RT-PCR). The numbers of genes altered by coarse, fine, and ultrafine PM increased from 0, 6, and 17 at 6 h to 1281, 302, and 455 at 24 h, respectively. The NRF2-mediated oxidative stress response, cell cycle:G2/M DNA damage checkpoint regulation, and mitotic roles of polo-like kinase were the top three pathways altered by all three fractions. Fine and ultrafine PM displayed more similar gene expression patterns. One example was the increased expression of metallothionein isoforms, reflecting the higher zinc content associated with fine and ultrafine fractions. A set of 10 genes was identified that could discriminate fine and ultrafine PM from coarse PM. These results indicate that common properties shared by the three size fractions as well as size-specific factors, e.g., compositions, may determine the effects on gene expression. Genomic markers may be used to discriminate coarse from fine and ultrafine PM. PMID- 21240731 TI - Brevetoxin inhalation alters the pulmonary response to influenza A in the male F344 rat. AB - Epidemiological studies demonstrated that the number of emergency-room visits for respiratory indications increases during periods of Florida Red Tides. The purpose of this study was to examine whether or not repeated brevetoxin inhalation, as may occur during a Florida Red Tide, affects pulmonary responses to influenza A. Male F344 rats were divided into four groups: (1) sham aerosol/no influenza; (2) sham aerosol/influenza; (3) brevetoxin/no influenza; and (4) brevetoxin/influenza. Animals were exposed by nose-only inhalation to vehicle or 50 MUg brevetoxin-3/m3, 2 h/d for 12 d. On d 6 of aerosol exposure, groups 2 and 4 were administered 10,000 plaque-forming units of influenza A, strain HKX-31 (H3N2), by intratracheal instillation. Subgroups were euthanized at 2, 4, and 7 d post influenza treatment. Lungs were evaluated for viral load, cytokine content, and histopathologic changes. Influenza virus was cleared from the lungs over the 7-d period; however, there was significantly more virus remaining in the group 4 lungs compared to group 2. Influenza virus significantly increased interleukins 1alpha and -6 and monocyte chemotactic protein-1 in lung; brevetoxin exposure significantly enhanced the influenza-induced response. At 7 d, the severity of perivascular and peribronchiolar inflammatory cell infiltrates was greatest in group 4. Bronchiolitis persisted, with low incidence and severity, only in group 4 at d 7. These results suggest that repeated inhalation exposure to brevetoxin may delay virus particle clearance and recovery from influenza A infection in the rat lung. PMID- 21240732 TI - Experimental methods for determining permethrin dermal absorption. AB - The objectives of this study were to (1) determine the percutaneous absorption of radiolabeled permethrin and piperonyl butoxide (PBO) in vivo in rats and in vitro to permit a calculation of the ratio of in vitro to in vivo values, and (2) test a method of estimating in vivo human absorption. Carbon-14 labeled permethrin in ethanol solution was applied to the clipped skin of rats in vivo at doses of 2.25, 20, or 200 MUg/cm2. As a reference compound, 14C-labeled PBO in isopropanol solution was applied to rat skin in vivo at a dose of 100 MUg/cm2. All applications were washed at 24 h postapplication, and rats were sacrificed either at 24 h for permethrin or 5 d for both compounds. The radiolabel recovered from carcass, urine including cage wash, and feces was summed to determine percent absorption. For the 24-h time point, at doses of 2.25, 20, and 200 MUg/cm2 of permethrin, values of 22, 22, and 28%, respectively, were obtained for in vivo rat percutaneous absorption (n=6 per dose). For the 5-d time point, at doses of 2.25, 20, and 200 MUg/cm2 of permethrin, values of 38, 38, and 30%, respectively, were obtained for in vivo rat percutaneous absorption (n=6 per dose). The 5-d percutaneous absorption of 14C-PBO at 100 MUg/cm2 was determined to be 42% (n=6). Dose and test duration did not exert a statistically significant effect on percutaneous absorption of permethrin in the rat in vivo. For in vitro absorption determination, 14C-permethrin in ethanol solution was applied to freshly excised human skin in an in vitro test system predictive of skin absorption in humans. Twenty-four hours after application, the radiolabel recovered from dermis and receptor fluid was summed to determine percent absorption. At doses of approximately 2.25, 20, and 200 MUg/cm2 permethrin, values of 1, 3, and 2%, respectively, were obtained for percutaneous absorption (n=9 per dose). Excised human skin absorption of 14C-PBO at 100 MUg/cm2 was determined to be 7% (n=9). Excised rat skin absorptions of permethrin at 2.25, 20, and 200 MUg/cm2 were found to be 20, 18, and 24%, respectively (n=6 per dose), approximately 10-fold higher than human skin absorption. Excised rat skin absorption of PBO was also higher (35%) than the value obtained for human skin by a factor of about 5. PMID- 21240733 TI - Rising prevalence of gastroschisis in Washington State. AB - The aim of this study was to assess gastroschisis prevalence in Washington (WA) State in relation to putative risk factors. Gastroschisis prevalence was calculated from the WA State birth cohort during 1987-2006 using an administrative database with birth certificate data linked with hospital discharge records and the ICD-9 procedure code 54.71, which specifies gastroschisis repair. Poisson regression analysis was used to evaluate time trends while adjusting for risk factors. Birth year was included as a linear term. Maternal age, smoking, race, residence in urban versus rural area, geographic region (eastern versus western Washington), paternal age, and infant gender were included as categorical factors. Prevalence ratios were adjusted for birth year and all of the preceding factors. Two hundred and eighty-two infants with gastroschisis were identified. In the adjusted analysis, the prevalence ratio for gastroschisis was 1.1 per year (95% CI 1.08-1.13), indicating an average 10% increase per birth year. Teen mothers were at a higher risk compared to mothers>=25 yr old (adjusted rate ratio [aRR] 8.02; 95% CI 5.30-12.13), as were teen fathers (aRR 2.35; 95% CI 1.48-3.74) compared to fathers>=25 years old. Maternal smoking was associated with a higher risk compared to those who were nonsmokers (aRR 1.58; 95% CI 1.19-2.09). Black mothers had a lower risk compared with white mothers. There was no association with geographic classification of mother's residence. Gastroschisis prevalence has increased in WA, particularly in teen mothers and in smokers. This is not explained by a rise in teenage pregnancies or maternal smoking. Further investigation of factors specific to teenage lifestyle is warranted. PMID- 21240734 TI - The view from here: 50 years as a trauma psychotherapist. PMID- 21240735 TI - Are major dissociative disorders characterized by a qualitatively different kind of dissociation? AB - A total of 66 patients with a major dissociative disorder, 54 patients with nondissociative disorders, and 30 nonclinical controls were administered the Structured Clinical Interview for DSM-IV Dissociative Disorders-Revised, the Dissociative Experiences Scale, the Multidimensional Inventory of Dissociation, and the Symptom Checklist 90-Revised. Dissociative patients reported significantly more dissociative and nondissociative symptoms than did nondissociative patients and nonclinical controls. When general psychopathology was controlled, the dissociation scores of dissociative patients were still significantly higher than those of both other groups, whereas the dissociation scores of nondissociative patients and nonclinical controls no longer differed. These findings appear to be congruent with a typological model of dissociation that distinguishes between 2 qualitatively different kinds of dissociation. Specifically, the results of this study suggest that the dissociation that occurs in major dissociative disorders (i.e., dissociative identity disorder [DID] and dissociative disorder not otherwise specified, Type 1 [DDNOS-1]) is qualitatively different from the dissociation that occurs in persons who do not have a dissociative disorder. In contrast to previous research, the dissociation of persons who do not have a dissociative disorder is not limited to absorption; it covers a much wider range of phenomena. The authors hypothesize that different mechanisms produce the dissociation of persons with DID and DDNOS-1 as opposed to the dissociation of persons who do not have a dissociative disorder. PMID- 21240736 TI - Women at war: implications for mental health. AB - Few studies have investigated the impact of deployment stressors on the mental health outcomes of women deployed to Iraq in support of Operation Iraqi Freedom. This pilot study examined exposure to combat experiences and military sexual harassment in a sample of 54 active duty women and assessed the impact of these stressors on post-deployment posttraumatic stress disorder (PTSD) symptoms and depressive symptoms. Within 3 months of returning from deployment to Iraq, participants completed (a) the Combat Experiences Scale and the Sexual Harassment Scale of the Deployment Risk and Resilience Inventory, (b) the Primary Care PTSD Screen, and (c) an abbreviated version of the Center for Epidemiological Studies Depression scale. Approximately three quarters of the sample endorsed exposure to combat experiences, and more than half of the sample reported experiencing deployment-related sexual harassment, with nearly half of the sample endorsing both stressors. Approximately one third of the sample endorsed clinical or subclinical levels of PTSD symptoms, with 11% screening positive for PTSD and 9% to 14% of the sample endorsing depressive symptoms. Regression analyses revealed that combat experiences and sexual harassment jointly accounted for significant variance in post-deployment PTSD symptoms, whereas military sexual harassment was identified as the only unique significant predictor of these symptoms. Findings from the present study lend support to research demonstrating that military sexual trauma may be more highly associated with post-deployment PTSD symptoms than combat exposure among female service members and veterans. PMID- 21240737 TI - Exploring the relationships between dissociation, victimization, and juvenile sexual offending. AB - An etiological model of sexually abusive behavior including dissociation could have utility for researchers and treatment providers working with sexually abusive youth with trauma histories. This article explores relationships between dissociation, victimization, and juvenile sexual offending. Self-reported data on dissociation and 5 types of abuse were collected from 2 racially/ethnically diverse groups of sexually abusive and general delinquent male adolescents (n = 502). Bivariate analysis showed significant correlations between all types of child abuse and dissociation with the exception of emotional neglect. Hierarchical logistic regression analysis indicated that dissociation was significant in predicting sexual offender status. Moreover, dissociation, sexual victimization, and physical abuse showed significant effects in predicting membership in the sexual offender group. The results confirm the need for additional research in the areas of assessment and treatment of dissociation among sexually abusive youth. PMID- 21240738 TI - Memory for complex emotional material in dissociative identity disorder. AB - Eleven women with dissociative identity disorder (DID) participated in an experiment that included a variety of memory measures. DID participants were faster than a group of 13 female students at producing autobiographical memories in response to cue words. DID participants had difficulty answering detailed questions about a story containing fear compared with a neutral story; the student group did not. The DID group reported experiencing significantly more childhood trauma than did the student group. Effect sizes were moderate to high. This preliminary study uses a broad conceptualization of memory functioning, combining ecologically valid testing with experimental paradigms and addressing the impact of emotion on memory in trauma survivors. PMID- 21240739 TI - Predicting stabilizing treatment outcomes for complex posttraumatic stress disorder and dissociative identity disorder: an expertise-based prognostic model. AB - The purpose of this study was to develop an expertise-based prognostic model for the treatment of complex posttraumatic stress disorder (PTSD) and dissociative identity disorder (DID). We developed a survey in 2 rounds: In the first round we surveyed 42 experienced therapists (22 DID and 20 complex PTSD therapists), and in the second round we surveyed a subset of 22 of the 42 therapists (13 DID and 9 complex PTSD therapists). First, we drew on therapists' knowledge of prognostic factors for stabilization-oriented treatment of complex PTSD and DID. Second, therapists prioritized a list of prognostic factors by estimating the size of each variable's prognostic effect; we clustered these factors according to content and named the clusters. Next, concept mapping methodology and statistical analyses (including principal components analyses) were used to transform individual judgments into weighted group judgments for clusters of items. A prognostic model, based on consensually determined estimates of effect sizes, of 8 clusters containing 51 factors for both complex PTSD and DID was formed. It includes the clusters lack of motivation, lack of healthy relationships, lack of healthy therapeutic relationships, lack of other internal and external resources, serious Axis I comorbidity, serious Axis II comorbidity, poor attachment, and self-destruction. In addition, a set of 5 DID-specific items was constructed. The model is supportive of the current phase-oriented treatment model, emphasizing the strengthening of the therapeutic relationship and the patient's resources in the initial stabilization phase. Further research is needed to test the model's statistical and clinical validity. PMID- 21240740 TI - A preliminary qualitative investigation of voice hearing and its association with dissociation in chronic PTSD. AB - Following on from a quantitative study, this research used a qualitative methodology to investigate the lived experience of 3 men with chronic posttraumatic stress disorder associated with the conflict in Northern Ireland who reported auditory hallucinations. Data analysis used the Framework method. Results showed that beliefs about voices, dissociation of identity and body, and interpersonal impact were central superordinate themes associated with auditory hallucinations in posttraumatic stress disorder. Central subordinate themes included feeling a lack of controllability over voices, experiencing them as ego dystonic, and feeling an increased sense of isolation and shame because of their presence. Results provide an in-depth analysis of participants' lived experiences and enhance understanding of previous quantitative findings. PMID- 21240745 TI - Contributions of familiarity and recollection rejection to recognition: evidence from the time course of false recognition for semantic and conjunction lures. AB - It has been suggested that both familiarity and recollection contribute to the recognition decision process. In this paper we leverage the form of false alarm rate functions--in which false alarm rates describe an inverted U-shaped function as the time between study and test increases--to assess how these processes support retention of semantic and surface form information from previously studied words. We directly compare the maxima of these functions for lures that are semantically related and lures that are related by surface form to previously studied material. This analysis reveals a more rapid loss of access to surface form than to semantic information. To separate the contributions of item familiarity and reminding-induced recollection rejection to this effect, we use a simple multinomial process model; this analysis reveals that this loss of access reflects both a more rapid loss of familiarity and lower rates of recollection for surface form information. PMID- 21240746 TI - Objective and subjective measures indicate that orthographically similar words produce a blocking experience. AB - Memory blocks are a common experience characterised by inappropriate retrieval of information that impairs memory search processes. In five studies, memory blocks were induced via exposure to orthographically similar words (Smith & Tindell, 1997) while participants reported their subjective experiences to determine whether the memory block effect (MBE) paradigm produces a feeling of being blocked. Experiments 1 and 3 provided evidence that the MBE is associated with more blocked experiences. In Experiments 2 and 4 increased blocking experiences correlated with blocked fragments when the experimental manipulation was disguised, which demonstrates that ratings were not contaminated by demand characteristics. Experiment 5 demonstrated that blocking happens even when there is no study list. Collectively, the subjective retrieval ratings and the objective response data provide converging evidence that exposure to orthographically similar words induces a memory block characterised by an ineffective memory search that perseverates on interfering information. PMID- 21240747 TI - Impaired directed forgetting in abstinent heroin addicts. AB - Drug-related memories persist long into abstinence and are potent elicitors of drug craving and relapse. We report two experiments examining whether heroin dependent individuals are impaired in intentionally suppressing drug-related memories. Experiment 1 adopted the Item paradigm where addicts and healthy controls were presented with a list of words each followed by a remember or forget cue. Experiment 2 adopted the List paradigm where they studied one list of items and were then split into a remember group and a forget group. Both groups studied a second list, except that the forget group was told to forget the first list. Compared with controls, addicts showed a reduced directed forgetting effect in the Item method and a total absence of one measure of directed forgetting in the List method (List 2 benefits). Results indicate that heroin addicts are impaired in directed forgetting and that the deficits are likely associated with memory encoding as opposed to retrieval. Possible problems include reduced ability in actively suppressing/stopping encoding of irrelevant information into memory or inability in changing/resetting encoding strategies. In neither experiment did the addicts show any differential directed forgetting effects between drug-related words and neutral words, indicating the generic nature of their intentional forgetting deficits. PMID- 21240748 TI - To do or not to do? Prospective memory versus response inhibition in autism spectrum disorder and attention-deficit/hyperactivity disorder. AB - In the present research, event-based prospective memory and response inhibition (RI) abilities were investigated in children with ASD (Study 1), with ADHD (Study 2), and their matched neurotypical controls. Children engaged in a categorisation (ongoing) task and, concurrently, in either an event-based prospective memory (PM) or a Go/No-Go secondary task. Results showed that, as compared to their matched controls, ASD children's performance was more impaired in the PM task than in the Go/No-Go task, while the performance pattern of ADHD children was reversed. In the ongoing task, ASD children were as accurate as, but significantly slower than, controls, independently of conditions. ADHD children did not differ from controls in the presence of a concurrent PM task, while they were less accurate than controls in the presence of the go/no-go task. Overall, the two patterns of findings suggest important differences in the way ASD and ADHD children remember and realise intentions requiring opposite behaviours (acting vs stopping). PMID- 21240749 TI - Inter- and intra-individual variation in immediate free recall: an examination of serial position functions and recall initiation strategies. AB - Serial position functions in immediate free recall have been historically noted for their bowed shape, where items presented at the beginning (primacy) and end (recency) of a list are better remembered than those presented in the middle. While extensive work has examined these effects, researchers typically ignore the systematic differences among individuals that likely contribute, but are lost when using an aggregate function. In the current study, inter- and intra individual differences in serial position functions and differences in recall strategies were examined. Participants performed a free recall task on multiple lists. Three groups of participants were derived based on the relative profiles in their serial position functions. These groups differed in the extent that they output mainly primacy items, recency items, or both primacy and recency items. Performance on immediate free recall and on cognitive ability tasks was compared between these three groups. Systematic inter- and intra-individual variation in recall strategies led to differential profiles of performance in immediate free recall, which was also related to the additional cognitive ability measures. Performance on a task can be due to the utilisation of a variety of control processes that emphasise various components of that task over other components. PMID- 21240750 TI - Proactive interference and practice effects in visuospatial working memory span task performance. AB - In the current study the influence of proactive interference (PI) and practice on recall from a visuospatial working memory (WM) task was examined. Participants completed a visuospatial WM span task under either high-PI conditions (a traditional span task) or low-PI conditions (a span task with breaks between trials). Trials of each length (i.e., two to five to-be-remembered items) were equally distributed across three blocks in order to examine practice effects. Recall increased across blocks to a greater extent in the low-PI condition than in the high-PI condition, indicating that reducing PI increased recall from WM. Additionally, in the final block the correlation between fluid intelligence and WM recall was stronger for the high-PI condition than the low-PI condition, indicating that practice reduced the strength of the correlation between span task recall and fluid intelligence, but only in the low-PI condition. These results support current theories that propose that one source of variability in recall from WM span task is the build-up of PI, and that PI build-up is an important contributing factor to the relation between visuospatial WM span task recall and higher-level cognition. PMID- 21240751 TI - Presentation modality effect on false memories in younger and older adults: the use of an inference paradigm. AB - Classically, false memories are studied using the DRM paradigm (Deese, 1959; Roediger & McDermott, 1995), involving use of words lists. The words of each list are linked to a critical word not presented. Participants create a false memory in recognising and/or recalling this critical word. In most cases older adults have more false memories than younger adults in this paradigm. To use less strategy-dependent material, we compared predictive inferences activated during text reading in young and healthy older participants. For example, in the sentence "The fragile porcelain vase was thrown against the wall" the predictive inference was that the vase is broken. After reading or hearing the texts, the participants had false memories in recalling and/or recognising the predictive inferences. Older adults had more false recognitions than younger adults when they read or heard the text. However, the difference did not reach significance with the cued recalled task. It is concluded that, in more ecological situations such as text reading, abilities in older adults can be preserved. PMID- 21240752 TI - Travelling backwards and forwards in time: culture and gender in the episodic specificity of past and future events. AB - There is considerable evidence that, when recalling past events, Westerners exhibit greater episodic specificity than East Asians and women exhibit greater episodic specificity than men. Yet it is unknown whether the same cultural and gender differences are true for future events. In the present study 209 European American and Chinese young adults were asked to recall past personal events and imagine future personal events occurring in varied time periods (i.e., 1 week, 1 year, 10-15 years). Regardless of time period, European Americans consistently produced more specific details than Chinese for future events than they did for past events, and women produced more specific details than men for both past and future events. These findings provide additional support for the constructive episodic-simulation hypothesis, and shed new light on the influence of culture and gender on episodic thinking. PMID- 21240753 TI - The role of forget-cue salience in list-method directed forgetting. AB - Research suggests that manipulating the wording of the forget cue in list-method directed forgetting affects the magnitude of directed forgetting both in younger children (Aslan, Staudigl, Samenieh, & Bauml, in press) and in older adults (Sahakyan, Delaney, & Goodmon, 2008). This occurs when the forget cue overemphasises the importance of forgetting in the current context. The present experiment investigated whether de-emphasising forgetting affected the magnitude of list-method directed forgetting in college adults. Some participants received overt forget cues that explicitly instructed them to forget earlier studied items, whereas others received covert forget cues that implied forgetting by emphasising selective remembering (e.g., "you will only need to remember some of the items"). Results indicated equivalent directed forgetting for both types of cues. However, regardless of the type of cue received, participants who reported using specific forgetting strategies in response to the forget cue showed directed forgetting, whereas those that reported doing nothing did not show any effects. The results underscore that successful directed forgetting requires engagement of controlled processes. PMID- 21240754 TI - Isoswertisin flavones and other constituents from Peperomia obtusifolia. AB - A phytochemical investigation of the leaves and stems of Peperomia obtusifolia (Piperaceae) yielded a new flavone C-diglycoside isoswertisin-4'-methyl-ether 2''alpha-L-rhamnoside (1), along with four known compounds: isoswertisin-2''alpha L-rhamnoside (2), (+)-diayangambin (3), 2-episesalatin (4) and corchoionoside C (5). The structures of the two flavone C-diglycosides (1, 2) were elucidated on the basis of 1D and 2D NMR spectroscopy and MS spectrometric data. These flavones were evaluated by bioautographic assay against Cladosporium cladosporioides and C. sphaerospermum and showed weak antifungal activity. PMID- 21240755 TI - Lavandulifolioside B: a new phenylethanoid glycoside from the aerial parts of Stachys lavandulifolia Vahl. AB - Reversed-phase preparative HPLC analyses of the methanol extract of the aerial parts of Stachys lavandulifolia afforded a new phenylethanoid glycoside, 4,3',4' trimethoxy-lavandulifolioside A, named lavandulifolioside B, together with three other known phenylethanoid glycosides, lavandulifolioside A, verbascoside and leucosceptoside A, and an iridoid glycoside 5-O-beta-allopyranosyloxy-aucubin (5 O-beta-allopyranosyl-monomelittoside). While the structures of the known compounds, except the iridoid glycoside, were established by direct comparison of their spectroscopic data with respective literature data, lavandulifolioside B and 5-O-beta-allopyranosyloxy-aucubin were identified comprehensively by extensive 1D and 2D NMR analyses. The distribution of the isolated compounds within the genus Stachys has been discussed. PMID- 21240756 TI - A new HPTLC densitometric method for analysis of swertiamarin in Enicostemma littorale and commercial formulations. AB - A high-performance thin layer chromatographic densitometric method for the analysis of swertiamarin in 60% methanolic extract of Enicostemma littorale and commercial formulations has been developed and validated in this study. Swertiamarin was separated on aluminium-backed silica gel 60 F254 plates using ethyl acetate : methanol : water (77 : 15 : 8)% v/v as the mobile phase. This system was found to give a compact spot of swertiamarin at R(f) value 0.36 +/- 0.01. The limit of detection and limit of quantification were found to be 31.25 and 103.12 ng spot-1, respectively. The proposed method was employed with a high degree of precision and accuracy for the estimation of swertiamarin in methanolic extract of Enicostemma littorale and in commercial formulations. PMID- 21240757 TI - A new amide from the stems of Cinnamomum reticulatum Hay. AB - Cinnaretamine, a new amide, has been isolated from Cinnamomum reticulatum Hay (Lauraceae), together with six known compounds, N-trans-feruloylmethoxytyramine, N-cis-feruloylmethoxytyramine, (+)-syringaresinol, p-hydroxybenzoic acid, syringic acid and vanillic acid. The structure of cinnaretamine was determined on the basis of spectroscopic analysis. PMID- 21240758 TI - A new steroidal glycoside from the Ophiopogon japonicus Ker-Gawler (Liliaceae). AB - A new steroidal glycoside (1), (25R)-14alpha, 17alpha-hydroxyspirost-5-en-3beta yl 3-O-alpha-L-rhamnpyranosyl-(1 -> 2)-beta-D-glucopyranosyl-(1 -> 3)-beta-D glucopyranoside, together with three known steroidal glycosides, (25R)-3beta hydroxyspirost-5-en-1beta-yl-3-O-alpha-L-rhamnopyranosyl-(1 -> 2)-O-beta-D xylopyranosyl-(1 -> 3)-alpha-L-arabinopyranoside (2), Cixi-ophiopogon B (3) and Cixi-ophiopogon A (4), were obtained from the tuberous roots of Ophiopogon japonicus (Liliaceae). Compound 2 was isolated from the Ophiopogon genus for the first time. Their structures were identified on the basis of extensive mass and nuclear magnetic resonance spectroscopic analysis. PMID- 21240759 TI - Flavonoids from the aerial parts of Macrothelypteris torresiana. AB - Two new flavone derivatives (1 and 2) were isolated from the aerial parts of Macrothelypteris torresiana, along with four known flavonoids: protoapigenin, apigenin, kaempferol and quercetin. The structures were determined on the basis of spectroscopic data. Compound 1 showed weak cytotoxic activity against human tumour cell lines HepG2 , MCF7 and K562. PMID- 21240760 TI - Plantagiolide F, a minor withanolide from Tacca plantaginea. AB - A minor new withanolide, named plantagiolide F, was isolated from the whole plant of Tacca plantaginea (Hance). The structure of plantagiolide F was elucidated on the basis of spectroscopic methods including extensive 1- and 2-D NMR experiments. PMID- 21240761 TI - Cinnamyl alcohols and methyl esters of fatty acids from Wedelia prostrata callus cultures. AB - Two methyl esters of fatty acids, namely octadecanoic acid methyl ester (methyl stearate) and hexadecanoic acid methyl ester (methyl palmitate), in addition to four cinnamyl alcohol derivatives, sinapyl alcohol, coniferyl alcohol, p-coumaryl alcohol and coniferyl alcohol 4-O-glucoside (coniferin), were isolated from callus cultures of Wedelia prostrata. The structure of coniferin was established by spectroscopic and chemical methods, while the other compounds were identified by gas chromatography-mass spectrometry and thin layer chromatography in comparison with standards. PMID- 21240762 TI - Relationship between HPLC fingerprints and in vivo pharmacological effects of a traditional Chinese medicine: Radix Angelicae Dahuricae. AB - We report the fingerprint development of a traditional Chinese medicine Radix Angelicae Dahuricae root and the correlation of the fingerprint peaks with its in vivo pharmacological effects. The high-performance liquid chromatography (HPLC) methods with the computer aided similarity evaluation were validated and used in serial pharmacological studies in mice. The major constituents of R. Angelicae Dahuricae were successfully separated by the HPLC methods, and the effects of sedation and analgesia were mainly related to the chromatographic peaks of group II. The anti-inflammatory, anti-heat stroke and anti-endotoxemic effects were mainly related to the peaks in group III. These results indicated a correlation between the HPLC fingerprints in groups and the pharmacological effects of R. Angelicae Dahuricae. This simple and accurate method can be used for the identification of the active components of R. Angelicae Dahuricae and for the quality control of its pharmaceutical preparations. PMID- 21240763 TI - Two new phenylalkanoids from the rhizomes of Zingiber officinale. AB - Two new phenylalkanoids, 5-hydroxy-1-(4',5'-dihydroxy-3'-methoxy-phenyl)-decan-3 one and 1-(4',5'-dihydroxy-3'-methoxy-phenyl)-dec- 4-en-3-one, were isolated from the rhizomes of Chinese ginger (Zingiber officinale Roscoe (Zingiberaceae)). The structures of these new phenylalkanoids were elucidated by chemical and physical evidence. PMID- 21240764 TI - Phenylpropanoids from the stem bark of Jacaranda mimosaefolia. AB - Two new compounds: 2-(3',4'-dihydroxyphenyl) ethyl-3-O-alpha-L-rhamnopyranosyl-4 O-p-hydroxyphenylacetyl-6-O-caffeoyl-beta-D-glucopyranoside and 2-(3',4' dihydroxyphenyl) ethyl-3-O-alpha-L-rhamnopyranosyl-4-O-piperidine-3-carboxylic acid-6-O-caffeoyl-beta-D-glucopyranoside were isolated from the stem bark of Jacaranda mimosaefolia. In addition, the known compounds lupeol, betulinaldehyde, terminic acid, betulinic acid, maslinic acid, beta-sitosterol glucoside and isoacteoside were isolated and identified. PMID- 21240765 TI - Chemical composition of essential oils from leaves, stems, flower heads and roots of Conyza bonariensis L. from Tunisia. AB - The essential oils isolated at the flowering stage in spring, summer and autumn of the aerial and underground parts of Conyza bonariensis L. growing in Tunisia were analysed by GC and GC/MS; 143 constituents were identified, and among them 20 were major. The oils of C. bonariensis gathered in spring were rich in matricaria ester (1.2-67.3%), (Z)-nerolidol (0.3-19.9%) and caryophyllene oxide (0.8-14.3%). In the summer samples, the oils of C. bonariensis were rich in matricaria ester (1.6-76.4%), caryophyllene oxide (1.6-22.6%) and (E)-beta farnesene (1.1-22.7%). The main constituents in the autumn samples were matricaria ester (trace to 63.5%), geranyl acetone (0.0-25.3%), trans-alpha bergamotene (0.0-24.3%) and limonene (2.7-15.3%). The oils showed significant variation among the seasons. Remarkable differences were found between the constituent percentages of the different studied organs. The C. bonariensis sample from Tunisia was a matricaria ester chemotype and was quite different from the samples of other countries of origin. PMID- 21240766 TI - Sulforaphane absorption and excretion following ingestion of a semi-purified broccoli powder rich in glucoraphanin and broccoli sprouts in healthy men. AB - Sulforaphane (SF) is a chemopreventive isothiocyanate (ITC) derived from the myrosinase-catalyzed hydrolysis of glucoraphanin, a thioglucoside present in broccoli. Broccoli supplements often contain glucoraphanin but lack myrosinase, putting in question their ability to provide dietary SF. This study compared the relative absorption of SF from air-dried broccoli sprouts rich in myrosinase and a glucoraphanin-rich broccoli powder lacking myrosinase, individually and in combination. Subjects (n=4) each consumed 4 meals consisting of dry cereal and yogurt with 2 g sprouts, 2 g powder, both, or neither. Blood and urine were analyzed for SF metabolites. The 24 h urinary SF recovery was 74%, 49%, and 19% of the dose ingested from broccoli sprouts, combination, and broccoli powder meals, respectively. Urinary and plasma ITC appearance was delayed from the broccoli powder compared to the sprouts and combination. A liver function panel indicated no toxicity from any treatment at 24 h. These data indicate a delayed appearance in plasma and urine of SF from the broccoli powder relative to SF from myrosinase-rich sprouts. Combining broccoli sprouts with the broccoli powder enhanced SF absorption from broccoli powder, offering the potential for development of foods that modify the health impact of broccoli products. PMID- 21240767 TI - Preface to special issue: social work with the military: current practice challenges and approaches to care. PMID- 21240768 TI - The importance of understanding military culture. AB - Social workers can make a significant contribution to military service members and their families, but first it is essential that the worldview, the mindset, and the historical perspective of life in the military are understood. Unless we understand how the unique characteristics of the military impact the service members and their families, we cannot work effectively with them. In addition, unless we understand their language, their structure, why they join, their commitment to the mission, and the role of honor and sacrifice in military service, we will not be able to adequately intervene and offer care to these families. PMID- 21240769 TI - The battle within: understanding the physiology of war-zone stress exposure. AB - Faced with pervasive loss, life threat, and moral conflict in the field of battle, the human body and brain adapt to extraordinary circumstances in extraordinary ways. These adaptations come at a high price, and many men and women returning from Iraq and Afghanistan are paying that price every day. For the clinician who seeks to help, an understanding of the physiology of war-zone stress and resilience is an essential foundation, both for recovery from post traumatic stress disorder and other conditions, and for addressing the stigma and shame that keep many service members and veterans from seeking and accepting the help and support they need. This article explores ways in which the body and brain adapt to war-zone stress, resulting challenges, and implications for clinical services and ongoing recovery. PMID- 21240770 TI - Experiences of sexual harassment and sexual assault in the military among OEF/OIF veterans: implications for health care providers. AB - Given the frequent occurrence and significant health impact of sexual harassment and sexual assault in the military, it is important that for health care providers working with Veterans to have at least some basic knowledge in this area. Targeting providers addressing mental health and psychosocial issues, but also applicable to clinicians working with survivors in a variety of capacities, this article provides an overview of clinical care with survivors of sexual trauma in the military, particularly those who are OEF/OIF Veterans. We cover basic background information, focusing primarily on the impact of sexual trauma in the military, how survivor's reactions are shaped by various aspects of the military context, and general principles to assist clinicians in working effectively with survivors, whatever their role. PMID- 21240771 TI - A civilian social worker's guide to the treatment of war-induced PTSD. AB - Post-traumatic stress disorder has been designated as one of the signature wounds of the Iraq/Afghanistan war. Approximately 15% of returning service members have been diagnosed with PTSD and the numbers increase daily. As such, civilian social workers and other mental health professionals need to understand the diagnosis and how best to help those struggling with the disorder. This article will explore the etiology and treatment approaches used in management for those with PTSD. PMID- 21240772 TI - Considerations for the effects of military deployment on children and families. AB - Children of deployed military personnel represent a unique subculture in the United States. While many children exhibit high levels of resiliency, others will struggle with the impact of a parent who has gone to war. This article looks at some of the stressors of deployment as experienced by children and offers three case examples as well as clinical considerations for those who work with the children and families of the deployed. PMID- 21240773 TI - Practical considerations for addressing substance use disorders in veterans and service members. AB - Support and treatment for military veterans and active duty service members is a national priority. Furthermore, there is increased need for professionals with experience and interest in working with these brave individuals. Veterans and service members face significant challenges both during their service and after transitioning back to civilian settings. One such challenge for some veterans is substance use and its multidimensional effects on mental and physical health. The current article presents a brief but comprehensive overview of the prevalence and comorbidity of substance use disorders in veterans and service members. It also reviews practical information about assessment, treatment, and general clinical issues from the authors' clinical experience that is relevant to providers working with veterans and service members with substance use disorders. This information may be of particular interest to professionals with an interest in helping veterans, those who have limited experience working with veterans, or those who may work outside of standard military or Department of Veterans Affairs settings. Finally, future directions in this important area are discussed. PMID- 21240775 TI - The efficacy of a targeted remediation process for students who fail standardized patient examinations. AB - BACKGROUND: Current remediation strategies for students failing standardized patient examinations represent poorly targeted approaches since the specific nature of clinical performance weaknesses has not been defined. PURPOSE: The purpose is to determine the impact of a specifically targeted clinical performance course required of students who failed a clinical performance examination. METHODS: A month-long clinical performance course, targeted to treat specific types of clinical performance deficiencies, was designed to remediate students failing standardized patient examinations in 2007 (n=8) and 2008 (n=5). Participating students were assessed on pre- and postperformance measures, including multiple-choice tests that measured diagnostic pattern recognition and clinical data interpretation and clinical performance measures using standardized clinical encounters. Comparisons between average pre- and postintervention performance scores were computed using paired sample t tests. Results were adjusted for regression toward the mean. RESULTS: In both 2007 and 2008, the mean preintervention clinical data interpretation and standardized patient examination scores were below the criterion referenced passing standard set for the clinical competency exam. In both years the mean postintervention scores for the participants were above the passing standard for these two examinations. Pre- and postintervention differences were statistically significant in both cases. CONCLUSIONS: This study provides insight into the reasons that students fail clinical performance examinations and elucidates one method by which such students may be successfully remediated. PMID- 21240776 TI - How does a comprehensive clinical performance examination relate to ratings on the medical school student performance evaluation? AB - BACKGROUND: U.S. medical schools have long used the Medical Student Performance Evaluation (MSPE) to represent overall student performance while comprehensive clinical performance exams (CPX) are beginning to emerge as a new standard for determining student competence. PURPOSE: This study describes the association between the MSPE and CPX in their independent measures of student competence. METHODS: We examined the relationship between CPX scores and student MSPE rating at our institution, which was completed independently of the CPX. RESULTS: Students with higher CPX scores had better MSPE rating, but the associations are small ranging from rs=.13 for history-taking skills to rs=.31 for interpersonal skills. CONCLUSIONS: CPX results are not strongly related to MSPE rating and, thus, they may provide information on clinical competencies that should be included in the MSPE. PMID- 21240777 TI - Simulation-based teaching to improve cardiovascular exam skills performance among third-year medical students. AB - BACKGROUND: Evidence supports the need for improvement in cardiac physical examination skills training. PURPOSE: This study evaluates whether the addition of simulation offers added benefit over training utilizing standardized patients only. METHODS: All 124 third-year students who completed the required clerkship in one academic year received cardiac examination skills training utilizing a standardized patient and a cardiac simulator. The control group, comprising 281 students from 2 previous academic years, received training utilizing a standardized patient only. All students' physical exam skills were assessed in an objective structured clinical examination. RESULTS: Students trained with cardiac simulation performed significantly better than the control group in all 5 cardiac skills. The number of students who correctly performed all 5 cardiac exam skills increased significantly (p=.004). Pulmonary exam skills were unchanged. CONCLUSION: The use of simulation in addition to standardized patient teaching can improve students' performance of cardiac examination skills. PMID- 21240778 TI - Relying on others' reliability: challenges in clinical teaching assessment. AB - BACKGROUND: The quality of the data generated from internally created faculty teaching instruments often draws skepticism. Strategies aimed at improving the reliability and validity of faculty teaching assessments tend to revolve around literature searches for a replacement instrument(s). PURPOSE: The purpose was to test this "search-and-apply" method and discuss our experiences with it within the context of observational assessment practice. METHOD: In a naturalistic pilot test, two previously validated faculty assessment instruments were paired with a global question. The reliability of both metrics was estimated. RESULTS: Generalizability analyses indicated that for both pilot tested faculty teaching instruments, the global question was a more reliable measure of perceived clinical teaching effectiveness than a multiple-item inventory. Item analysis with Cronbach's coefficient alpha suggested redundant instrument content. Rater error accounted for the greatest proportion of the variance and straight-line responses occurred in approximately 28% of residents' appraisals. CONCLUSIONS: The results of the present study draw attention to one of the common fallacies surrounding instrument-based assessment in medical education; the solution to improving one's assessment practice primarily involves identifying a previously published instrument from the literature. Academic centers need to invest in ongoing quality control efforts including the pilot testing of any proposed instruments. PMID- 21240779 TI - A trial of team-based versus small-group learning for second-year medical students: does the size of the small group make a difference? AB - BACKGROUND: Team-based learning is a large-group instructional modality intended to provide active learning with modest faculty resources. PURPOSE: The goal is to determine if team-based learning could be substituted for small-group learning in case sessions without compromising test performance or satisfaction. METHODS: One hundred and sixty-seven students were assigned to team-based or small-group learning for 6 case discussion sessions. Examination scores and student satisfaction were compared. RESULTS: Instruction modality had no meaningful effect on examination score, 81.7% team based versus 79.7% small-group, p=.56 after multivariate adjustment. Student satisfaction was lower with team-based learning, 2.45 versus 3.74 on a 5-point scale, p<.001. Survey responses suggested that the very small size (8-10 students) of our small groups influenced the preference for small-group learning. CONCLUSIONS: Team-based learning does not adversely affect examination performance. However, student satisfaction may be inferior, especially if compared to instruction in very small groups of 10 or fewer students. PMID- 21240780 TI - A controlled trial of team-based learning in an ambulatory medicine clerkship for medical students. AB - BACKGROUND: Team-based learning (TBL) has been studied in several preclinical settings, but there is less evidence for its effectiveness in clinical curricula. PURPOSE: We compared the impact of TBL versus usual small group lecture (SGL) on knowledge objectives in a clinical clerkship. METHODS: We used an unblinded crossover design with 112 students rotating through the Ambulatory Medicine clerkship. In each rotation of the clerkship, 3 clinical topics were taught as SGL and 3 as TBL. We compared performance on the knowledge examination for those items taught with TBL and those with SGL. RESULTS: Performance by students taught by TBL was higher than those taught by SGL in each topic, except Hypertension. The average effect size of the six measures was 0.51. CONCLUSIONS: TBL appears to be a more effective method than the usual small group lecture in achievement of knowledge objectives for clinical clerkship students. PMID- 21240782 TI - Relationship of participation in an optional student-run clinic to medical school grades. AB - BACKGROUND: Medical school is arduous and participating in optional service learning activities may compete with the required curriculum. The student-run SHARING Clinics at the University of Nebraska are managed by a Board of students who commit to extensive voluntary participation. PURPOSE: The purpose of this study was to determine whether optional service-learning participation resulted in compromised medical school grades. METHODS: Of 908 students who matriculated between 1999 and 2006, 87 served on the SHARING Board. A 2*2 repeated measures ANOVA was used to compare the grade point averages of Board members and non members before and after participating on the Board. RESULTS: The grades for SHARING Board members and non-members were not statistically different. The study had sufficient statistical power to detect even a small effect size. CONCLUSIONS: Concern about compromised academic performance appears to be an invalid reason to avoid service-learning participation. The benefits of participation appear to outweigh the costs. PMID- 21240781 TI - Effects of varying inpatient attending physician rotation length on medical students' and attending physicians' perceptions of teaching quality. AB - BACKGROUND: Patient care needs and work hour restrictions have altered inpatient internal medicine educational experiences. PURPOSE: The goal is to compare different attending physician rotation lengths on medical students' and attending physicians' experiences. METHODS: We studied clerkship students' evaluations (N= 86) and internal medicine attending surveys (N=21). We divided attending experiences into 2-week and 4-week rotations. We assessed exam scores and evaluations with 5-point Likert questions (5=strongly agree). Means were compared with t tests, Wilcoxon Ranked Sums, and logistic regression. RESULTS: More than 90% of students and attending physicians responded. Students and attending physicians generally evaluated their 2- and 4-week experiences similarly. Attending physicians favored 4 weeks for evaluating students' performance (3.30 vs. 4.36, p<.01). Exam scores were similar in the 2- and 4-week student groups (M=78.2, SD=5.0 vs. 76.5, SD=8.5, p=.43). CONCLUSIONS: Shorter rotations do not negatively impact students' experiences. Obtaining quality evaluations may be difficult for shorter rotations. PMID- 21240783 TI - An investigation of alternating group dissections in medical gross anatomy. AB - BACKGROUND: Reduction in contact hours has led to the use of more efficient teaching approaches in medical education, yet the efficacy of such approaches is often not fully investigated. PURPOSE: This work provides a detailed analysis of alternating group dissections with peer-teaching in Medical Anatomy (MA). METHODS: MA I and II percentages of the alternating (ALT) and nonalternating (NALT) groups were compared, scores of ALT subgroups (A and B) were compared, and subgroup performance on practical exam questions was compared. RESULTS: MA I and MA II percentages indicated no significant difference in median scores (pMAI=0.581, pMAII=0.223) between ALT and NALT. Subgroup analysis and assessment of question types showed that student performance and ability to identify a structure were not dependent on dissection group assignment. CONCLUSION: Alternating dissections offered students more unscheduled time for independent learning activities, such as studying or shadowing preceptors, and reduced student-to-cadaver and student-to-faculty ratios by 50%. Alternating dissections with peer teaching were not detrimental to student performance. PMID- 21240784 TI - The effect of rural training experiences during residency on the selection of primary care careers: a retrospective cohort study from a single large internal medicine residency program. AB - BACKGROUND: Little is known about the factors during internal medicine residency that influence career choice. PURPOSE: To determine if rural training experiences were associated with primary care career choice. METHODS: We conducted a retrospective cohort study at a single, large, internal medicine residency program. We reviewed self-reported career plan at the time of graduation. Independent variables obtained from curricular data included track (categorical or primary care), gender, year of graduation, timing of clinic block, and having had a rural training experience. We studied 451 program graduates who completed all three years of training between the years 1996 and 2006. RESULTS: Factors associated with an intended primary care career at the time of graduation were: primary care track (OR 4.5, 95% CI 2.4-8.6) and a rural training experience (OR 2.1, 95% CI 1.3-3.4). CONCLUSIONS: These data suggest that provision of more rural training experiences might increase interest in primary care careers. PMID- 21240785 TI - The oral case presentation: what internal medicine clinician-teachers expect from clinical clerks. AB - BACKGROUND: The oral case presentation (OCP) is a fundamental communication skill that frequently is taught as part of internal medicine clerkships. However, little is known about the optimal content for an OCP. PURPOSE: We hypothesized that internal medicine clinician-teachers have common expectations regarding OCPs by 3rd-year medical students. METHODS: We administered a 42-item survey to 136 internal medicine faculty members at 5 U.S. medical schools who spent at least 8 weeks as "ward attending" in the 2005-6 academic year, or spent at least 4 weeks as a "ward attending" and had an administrative role in medical education. We asked about the relative importance of 14 potential attributes in a 3rd-year medical student OCP using a 6-point Likert scale. We also asked about their expectations for the length of a new patient presentation. Mean responses from the 5 schools were compared using chi-squared, analysis of variance (ANOVA), and t testing, as appropriate. RESULTS: We received 106 responses (78% response rate). Of our respondents, 45% were hospitalists and 80% self-identified as "clinician-educators." Some aspects of the OCP were rated as more important than others (p<.001) Six items, including aspects of the history of present illness, organization, and structuring the presentation to "make a case" were rated as important or very important by more than 70% of respondents. Fewer than 10% of respondents believed that inclusion of a complete review of systems or detailed family history were important. Few differences were seen between institutions. Faculty expected that OCPs should take 9.9+/-5.4 min, with faculty at one institution having significantly different expectations than all others (15.9+/ 6.4 min vs. 7.8+/-2.8, p<.001). CONCLUSIONS: Internal medicine clinician teachers from 5 U.S. medical schools share common expectations for OCPs. PMID- 21240786 TI - Trainee participation in an annual research day is associated with future publications. AB - BACKGROUND: Residency training programs seek to train future clinicians but also to stimulate scholarly interests and develop future academic physicians. PURPOSE: The goal was to determine if participation in an annual departmental research day is associated with future academic productivity among pediatrics trainees. METHODS: This retrospective cohort study enrolled all residents and fellows at our institution between 1985 and 2007. In 1985, our department began an annual Evening of Scholarship (EOS) at which both residents and fellows could voluntarily present submitted research and other scholarly work. We compared future academic productivity, measured by the number of future publications, between EOS participants and nonparticipants after controlling for confounding variables. RESULTS: There were 526 unique participants included (residents n=304 and fellows n=222). Participants in EOS (n=232) were more likely than nonparticipants to be male (53% vs. 30%, respectively, p<.001), be a fellow (63% vs. 27%, p<.001), and have published previously (31% vs. 15%, p<.001). Participants in EOS were more likely than nonparticipants to have publications after graduation (69% vs. 34%, p<.001), and this persisted in multivariate analysis (odds ratio [OR] for future publication in participants compared to nonparticipants equals 3.7, 95% CI=2.5-5.6) In addition, participants had significantly more publications after training (Mdn=2, interquartile range [IQR] 0-9.75, vs. 0, IQR 0-1, p<.001). The association was stronger for resident trainees (test of interaction, p=.01, ORresidents=4.7, 95% CI=2.7-8.3, ORfellows=1.6, 95% CI=0.82-3.0). CONCLUSIONS: An annual research day was significantly and strongly associated with future publications among resident trainees. PMID- 21240788 TI - The effectiveness of cognitive forcing strategies to decrease diagnostic error: an exploratory study. AB - BACKGROUND: Cognitive forcing strategies, a form of metacognition, have been advocated as a strategy to prevent diagnostic error. Increasingly, curricula are being implemented in medical training to address this error. Yet there is no experimental evidence that these curricula are effective. DESCRIPTION: This was an exploratory, prospective study using consecutive enrollment of 56 senior medical students during their emergency medicine rotation. Students received interactive, standardized cognitive forcing strategy training. EVALUATION: Using a cross-over design to assess transfer between similar (to instructional cases) and novel diagnostic cases, students were evaluated on 6 test cases. Forty-seven students were immediately tested and 9 were tested 2 weeks later. Data were analyzed using descriptive statistics and a McNemar chi-square test. CONCLUSIONS: This is the first study to explore the impact of cognitive forcing strategy training on diagnostic error. Our preliminary findings suggest that application and retention is poor. Further large studies are required to determine if transfer across diagnostic formats occurs. PMID- 21240787 TI - A web-based team-oriented medical error communication assessment tool: development, preliminary reliability, validity, and user ratings. AB - BACKGROUND: Multiple-choice exams are not well suited for assessing communication skills. Standardized patient assessments are costly and patient and peer assessments are often biased. Web-based assessment using video content offers the possibility of reliable, valid, and cost-efficient means for measuring complex communication skills, including interprofessional communication. DESCRIPTION: We report development of the Web-based Team-Oriented Medical Error Communication Assessment Tool, which uses videotaped cases for assessing skills in error disclosure and team communication. Steps in development included (a) defining communication behaviors, (b) creating scenarios, (c) developing scripts, (d) filming video with professional actors, and (e) writing assessment questions targeting team communication during planning and error disclosure. EVALUATION: Using valid data from 78 participants in the intervention group, coefficient alpha estimates of internal consistency were calculated based on the Likert-scale questions and ranged from alpha=.79 to alpha=.89 for each set of 7 Likert-type discussion/planning items and from alpha=.70 to alpha=.86 for each set of 8 Likert-type disclosure items. The preliminary test-retest Pearson correlation based on the scores of the intervention group was r=.59 for discussion/planning and r=.25 for error disclosure sections, respectively. Content validity was established through reliance on empirically driven published principles of effective disclosure as well as integration of expert views across all aspects of the development process. In addition, data from 122 medicine and surgical physicians and nurses showed high ratings for video quality (4.3 of 5.0), acting (4.3), and case content (4.5). CONCLUSIONS: Web assessment of communication skills appears promising. Physicians and nurses across specialties respond favorably to the tool. PMID- 21240789 TI - Learning social medicine in the Bronx: an orientation for primary care residents. AB - BACKGROUND: Primary care educators face the challenge of teaching the social context of health and disease to clinicians. DESCRIPTION: Since 1975, the Residency Program in Social Medicine has trained clinicians to practice in urban underserved communities. During Orientation Month, 1st-year residents are relieved of inpatient duties and participate in learning activities addressing social and cultural aspects of health. Learning objectives include understanding patients' social context, their community, and the role of physicians as professionals. Recent innovations include incorporating an overall theme, weekly case studies, "triple jump" exercises, community mapping projects, patient-led community tours, and theme-specific visits to community institutions (e.g., prisons). EVALUATION: Residents complete weekly formative evaluations, a summative evaluation, and narrative reflections. Faculty complete an evaluative questionnaire. CONCLUSIONS: Orientation is a highly rated and valued part of our curriculum. Its success derives from ongoing curricular innovation and evolution, a departmental commitment to social medicine, and positive community response to our learners' interest and energy. PMID- 21240793 TI - Beyond a pejorative understanding of conflict of interest. PMID- 21240794 TI - Response to open peer commentaries on "'Doctor, would you prescribe a pill to help me ... ?' a national survey of physicians on using medicine for human enhancement". PMID- 21240795 TI - "Doctor, would you prescribe a pill to help me ... ?" a national survey of physicians on using medicine for human enhancement. AB - Using medical advances to enhance human athletic, aesthetic, and cognitive performance, rather than to treat disease, has been controversial. Little is known about physicians' experiences, views, and attitudes in this regard. We surveyed a national sample of physicians to determine how often they prescribe enhancements, their views on using medicine for enhancement, and whether they would be willing to prescribe a series of potential interventions that might be considered enhancements. We find that many physicians occasionally prescribe enhancements, but doctors hold nuanced and ambiguous views of these issues. Most express concerns about the potential effects of enhancements on social equity, yet many also believe specific enhancements that are safe and effective should be available but not covered by insurance. These apparently contradictory views might reflect inherent tensions between the values of equity and liberty, which could make crafting coherent social policies on medical enhancements challenging. PMID- 21240796 TI - Responses to peer commentaries on "Clarifying conflict of interest". PMID- 21240797 TI - Begging important questions about cognitive enhancement, again. PMID- 21240798 TI - Considering the causes and implications of ambivalence in using medicine for enhancement. PMID- 21240799 TI - Physicians prescribing "medicine" for enhancement: Why we should not and cannot overlook safety concerns. PMID- 21240800 TI - The role of physician opinion in human enhancement. PMID- 21240801 TI - Medical and genetic enhancements: ethical issues that will not go away. PMID- 21240802 TI - Clarifying conflict of interest. AB - As the debate over how to manage or discourage physicians' financial conflicts of interest with the drug and medical device industries has become more heated, critics have questioned or dismissed the concept of "conflict of interest" itself. A satisfactory definition relates conflict of interest to concerns about maintaining social trust and distinguishes between breaches of ethical duty and temptations to breach duty. Numerous objections to such a definition have been offered, none of which prevails on further analysis. Those concerned about conflicts of interest have contributed to misunderstandings, however, by failing to demonstrate when social arrangements leading to temptations to breach duties are in themselves morally blameworthy. Clarifying "conflict of interest" is important if we are eventually going to develop productive modes of engagement between medicine and for-profit industry that avoid the serious ethical pitfalls now in evidence. PMID- 21240803 TI - Answering Brody's challenge from a pharmapologist perspective. PMID- 21240804 TI - It is time to move beyond a culture of unexamined assumptions, recrimination, and blame to one of systematic analysis and ethical dialogue. PMID- 21240805 TI - Taking a lesson from the lawyers: defining and addressing conflict of interest. PMID- 21240806 TI - More clarifications: on the goals of conflict of interest policies. PMID- 21240807 TI - How to evaluate conflict of interest policies. PMID- 21240808 TI - Pragmatic and proportional analysis of conflict of interest. PMID- 21240809 TI - Trustworthiness in conflict of interest. PMID- 21240810 TI - Managing nonfinancial conflict of interest: how the "New McCarthyism" could work. PMID- 21240811 TI - Shifting the focus: Conflict of interest and the food industry. PMID- 21240812 TI - Clarifying the dispute over academic-industry relationships. PMID- 21240813 TI - Another dip into the muddy waters of COI. PMID- 21240814 TI - Physicians and the pharmaceutical industry: working together on conflict of interest. PMID- 21240815 TI - Teachers' feeling of belonging, exhaustion, and job satisfaction: the role of school goal structure and value consonance. AB - In their daily teaching and classroom management, teachers inevitably communicate and represent values. The purpose of this study was to explore relations between teachers' perception of school level values represented by the goal structure of the school and value consonance (the degree to which they felt that they shared the prevailing norms and values at the school), teachers' feeling of belonging, emotional exhaustion, job satisfaction, and motivation to leave the teaching profession. The participants were 231 Norwegian teachers in elementary school and middle school. Data were analyzed by means of structural equation modeling (SEM). Teachers' perception of mastery goal structure was strongly and positively related to value consonance and negatively related to emotional exhaustion, whereas performance goal structure, in the SEM model, was not significantly related to these constructs. Furthermore, value consonance was positively related to teachers' feeling of belonging and job satisfaction, whereas emotional exhaustion was negatively associated with job satisfaction. Job satisfaction was the strongest predictor of motivation to leave the teaching profession. A practical implication of the study is that educational goals and values should be explicitly discussed and clarified, both by education authorities and at the school level. PMID- 21240816 TI - Remembering relationships: preserved emotion-based learning in Alzheimer's disease. AB - Research into Alzheimer's disease has long focused on cognitive impairments. Advocates of the person-centered approach argue that emotions and interpersonal responses may remain intact. The answer to this paradox may derive from the neuropsychology of emotion, demonstrating preserved ability on simple emotion learning tasks, though this may not capture the complex interpersonal interactions that some patients appear able to manage in everyday life. This study demonstrates, for the first time, preserved complex emotion-based learning capacity, despite profound episodic memory impairment in Alzheimer's disease. These findings offer a starting point for the development of a solid neuropsychological and neuroanatomical account for the person-centered approach. PMID- 21240817 TI - Age-related differences in learning incidental, environmental information. AB - Incidental task structure is consistent, potentially beneficial, information that is not necessary for successful task performance (i.e., is seemingly unrelated to the task). The authors investigated whether incidental task structure was differentially beneficial to younger and older adults. Across three experiments, 122 participants searched for targets among stimuli laid upon different patterns, such that certain patterns correlated with target location at varying degrees of consistency. An age-related difference was identified in the ability to learn an incidental structure under certain conditions and a strategy explanation for the difference was investigated. When older adults' were encouraged to orient at least some degree of attention toward the predictive information, learning occurred. Older adults are capable of learning incidental, environmental information but their learning was not identical to younger adults'. Younger adults showed performance benefits when provided with incidental task structure, but older adults may need to be made explicitly aware before it is useful. PMID- 21240818 TI - Changes in the limits of stability induced by weight-shifting training in elderly women. AB - This study examined the impact of visually guided weight-shifting training on elderly women's limits of stability during static leaning and dynamic swaying in different directions. Sixty-three elderly women were assigned into a group that practiced weight shifting (30-min sessions, 3 sessions/week, 4 weeks) either in the anterior/posterior or medio/lateral direction and a control group. Training resulted in a reduction of upper body rotation and an increase of shank rotation and center of pressure displacement. It is concluded that weight-shifting practice increases the limits of stability and enhances the inverted pendulum pivoting of the human body during leaning and dynamic swaying balance tasks. PMID- 21240819 TI - Age differences in the use of beneficial and misleading cues in recall: with a comment on the measurement of between-group differences in accuracy. AB - Young and old subjects were tested on their memory for paired-associate terms when cued with either facilitative or misleading word stems. After studying a long list of pairs of unrelated words (e.g., hair-turtle), recall of a particular target term was cued in a facilitative manner (hair-tu____) or a misleading manner (hair-ta____). The effects of these cues were assessed relative to a baseline condition in which levels of performance lay between the other two (hair t____). To interpret the age-related effects of the facilitative and misleading cues relative to baseline, the variance in differences between the baseline and the experimental conditions related to the overall baseline level was factored out, and age-related differences as a function of cue were assessed on the remaining variability. This analysis revealed that the two age groups differed both in their ability to overcome the adverse effects of the misleading cue and also to take advantage of the benefits afforded by the facilitative cue. This combination of results is consistent with the view that aging results in a loss of general strategic control, and not specifically inhibitory control, over the effects of retrieval cues. PMID- 21240820 TI - The influence of time of testing on interference, working memory, processing speed, and vocabulary: age differences in adulthood. AB - This research examines the effect of time of testing on adult age differences in resistance to interference, working memory, processing speed, and vocabulary. Results show that time of testing modulates age-related differences only in the ability to resist automatic and prepotent responses. Older adults tested in the afternoon were more susceptible to interference than young adults tested at the same time of the day, and than their peers tested in the morning. In contrast, age-related differences in working memory, processing speed, and vocabulary were not modulated by time of the day. Our findings suggest that age-related modulation of performance as a function of the time of the day is specific to resistance to interference. PMID- 21240821 TI - How arousal affects younger and older adults' memory binding. AB - A number of recent studies have shown that associative memory for within-item features is enhanced for emotionally arousing items, whereas arousal-enhanced binding is not seen for associations between distinct items (for a review, see Mather, 2007, Perspectives on Psychological Science, 2, 33-52). The costs and benefits of arousal in memory binding have been examined for younger adults but not for older adults. The present experiment examined whether arousal would enhance younger and older adults' within-item and between-item memory binding. The results revealed that arousal improved younger adults' within-item memory binding but not that of older adults. Arousal worsened both groups' between-item memory binding. PMID- 21240822 TI - In vitro inhibitory effect of tetrahydrocurcuminoids on Fusarium proliferatum growth and fumonisin B1 biosynthesis. AB - Many plant pathogens produce toxic metabolites when growing on food and feed. Some antioxidative components seem to prevent fungal growth and mycotoxin formation. Recently, we synthesized a new class of powerful antioxidative compounds, i.e. tetrahydrocurcuminoids, and its structure/antioxidant activity relationships have been established. The South West of France produces large amounts of corn, which can be infected by Fusarium species, particularly F. proliferatum. In this context, the efficiency of tetrahydrocurcuminoids, which can be obtained from natural curcuminoids, was investigated to control in vitro the growth of F. proliferatum and the production of its associated mycotoxin, fumonisin B1. The relation between structure and antifungal activity was studied. Tetrahydrocurcumin (THC1), with two guaiacyl phenolic subunits, showed the highest inhibitory activity (measured as radial growth on agar medium) against the F. proliferatum development (67% inhibition at a concentration of 13.6 umol ml-1). The efficiencies of THC2 (36% at a concentration of 11.5 umol ml-1), which contains syringyl phenolic units, and THC3 (30% at a concentration of 13.6 umol ml-1), which does not have any substituent on the aromatic rings, were relatively close. These results indicate that the simultaneous presence of guaiacyl phenols and the enolic function of the beta-diketone moiety play an important role in the inhibition mechanisms. The importance of this combination was confirmed using n propylguaiacol and acetylacetone as molecular models. Under the same conditions, ferulic acid and eugenol, other natural phenolic antioxidants, were less efficient in inhibiting fungal growth. THC1 also reduced fumonisin B1 production in liquid medium by approximately 35, 50 and 75% at concentrations of 0.8, 1.3, and 1.9 umol ml-1, respectively. These very low inhibitory concentrations show that tetrahydrocurcuminoids could be one of the most promising biobased molecules for the control of mycotoxinogen fungal strains. PMID- 21240823 TI - Review of sodium analysis proficiency test results. AB - Proficiency testing results for sodium analysis in foods raised concerns over the proportion of laboratories achieving satisfactory z-scores. Test materials for sodium analysis include fruit juice, canned meat meal, tomato sauce, cheese and pasta meal, and snack food. Fruit juice and tomato sauce data sets are the most problematic in deriving the assigned value with sufficiently low uncertainty to provide evaluative z-scores. The standard deviation for proficiency is derived from Horwitz, with a lack of collaborative trial data for these matrices to provide other guidance. The status of accreditation for the method/matrix does not appear to influence the observed variation in results. Microwave digestion is much less commonly used than simple acid digestion. The choice of determination method appears to be entirely matrix dependent (whether flame atomic absorption spectroscopy, flame photometry or inductively coupled plasma spectroscopy). Results for juice matrix may be overestimated if flame photometry is used, due to either potassium interference or careless reporting where potassium is also determined. PMID- 21240824 TI - Simultaneous determination of lincomycin and spectinomycin residues in animal tissues by gas chromatography-nitrogen phosphorus detection and gas chromatography-mass spectrometry with accelerated solvent extraction. AB - A new multi-dimensional analytical method using gas chromatography-nitrogen phosphorus detection (GC-NPD) and gas chromatography-mass spectrometry (GC-MS) was developed for qualitative and quantitative measurement of lincomycin and spectinomycin residues in food animal tissues. This method is based on a new extraction procedure using accelerated solvent extraction (ASE). The analytes were extracted by phosphate buffer with trichloroacetic acid deproteinization and clean-up by C18 solid-phase extraction (SPE) adding dodecanesulfonic acid sodium salt as an ion-pair reagent. The eluted fraction was evaporated and derivatised with N,O-bis(trimethylsilyl) trifluoroacetamide (BSTFA) for GC-NPD analysis and GC-MS confirmation. Parameters for extraction pressure, temperature and cycle of ASE, clean-up, derivatisation and analysis procedure were optimised. The method was validated in muscle, kidney and liver of swine, bovine with a low concentration (limit of quantification) of 16.4 and 21.4 ug kg-1 for these two analytes using GC-NPD. For GC-MS, the limits of quantification were 4.1 and 5.6 ug kg-1, respectively. Spiked recoveries from levels of 20 to 200 ug kg-1 were found to be between 73% and 99% with a relative standard deviation (RSD) of less than 17% in GC-NPD. For GC-MS, levels from 5 to 20 ug kg-1 had between 70% and 93% with an RSD of less than 21%. This rapid and reliable method can be used for the characterisation and quantification of residues of lincomycin and spectinomycin in animal tissues. PMID- 21240825 TI - Stability during cooking of anthelmintic veterinary drug residues in beef. AB - Anthelmintic drugs are widely used for treatment of parasitic worms in livestock, but little is known about the stability of their residues in food under conventional cooking conditions. As part of the European Commission-funded research project ProSafeBeef, cattle were medicated with commercially available anthelmintic preparations, comprising 11 active ingredients (corresponding to 21 marker residues). Incurred meat and liver were cooked by roasting (40 min at 190 degrees C) or shallow frying (muscle 8-12 min, liver 14-19 min) in a domestic kitchen. Raw and cooked tissues and expressed juices were analysed using a novel multi-residue dispersive solid-phase extraction method (QuEChERS) coupled with ultra-performance liquid chromatography-tandem mass spectrometry. After correction for sample weight changes during cooking, no major losses were observed for residues of oxyclozanide, clorsulon, closantel, ivermectin, albendazole, mebendazole or fenbendazole. However, significant losses were observed for nitroxynil (78% in fried muscle, 96% in roast muscle), levamisole (11% in fried muscle, 42% in fried liver), rafoxanide (17% in fried muscle, 18% in roast muscle) and triclabendazole (23% in fried liver, 47% in roast muscle). Migration of residues from muscle into expressed cooking juices varied between drugs, constituting 0% to 17% (levamisole) of total residues remaining after cooking. With the exception of nitroxynil, residues of anthelmintic drugs were generally resistant to degradation during roasting and shallow frying. Conventional cooking cannot, therefore, be considered a safeguard against ingestion of residues of anthelmintic veterinary drugs in beef. PMID- 21240826 TI - Inter-laboratory comparison of an analytical method for the determination of the feed additive semduramicin in poultry feed at authorised level by liquid chromatography single quadrupole mass spectrometry. AB - A collaborative study was carried out according to internationally recognised guidelines in order to establish the performance characteristics of an LC/MS method for the determination of the feed additive semduramicin (SEM) in poultry feed at the level (20-25 mg kg(-1)) authorised within the European Union. Fifteen laboratories participated in the validation study, and all reported results. The content of SEM in the tested materials, provided as blind duplicates, ranged from 11.5 mg kg(-1), which corresponds to half the mean authorised level, to 45.0 mg kg(-1), which corresponds to twice the mean authorised level. All the materials were analysed by the participating laboratories using two different quantification approaches: standard addition and external standard calibration. The relative standard deviation of reproducibility (RSD(R)) for both quantification approaches varied from 8% to 18%, corresponding to HORRAT values ranging from 0.8 to 1.5, which were therefore in all cases below the critical value of 2.0. Consequently, the proposed analytical method and both quantification approaches can be considered to be fully validated and transferable to the control laboratories and applied for the determination of SEM in poultry compound feed at authorised level within the frame of official control. Further steps in the administrative procedure aiming to adopt the method as part of an ISO/CEN standard are currently ongoing. PMID- 21240827 TI - Detection of endogenous steroid abuse in cattle: results from population studies in the UK. AB - The use of steroids as growth-promoting agents in food production is banned under European Union legislation. Detecting the abuse of testosterone, nandrolone, boldenone, oestradiol and progesterone is complicated by the fact that these steroids are known to be endogenous in certain situations. In this study, the concentrations of characteristic metabolites of each of these steroids were quantified in populations of untreated steers and heifers. Steroid concentration population data were then used by a statistical model (the Chebyshev inequality) to produce threshold concentrations for screening and confirming the abuse of these steroids in steer and non-pregnant heifer urine. In addition to thresholds based on testing one animal (a '1 out of 1' approach), new methods based on testing multiple animals from a herd (a 'y out of n' approach) allowed threshold concentrations to be significantly reduced and hence false compliances to be minimised. In the majority of cases, the suggested thresholds were found to be capable of confirming the abuse of endogenous steroids in steers and heifers. In the case of oestradiol abuse in the female, however, confirmation based on a threshold is not possible and alternative methods such as gas chromatography combustion-isotope ratio mass spectrometry are required. In addition to the steer and heifer populations, a small number of pregnant animals were also tested, yielding insights into the biosynthetic pathways of some of the steroids. PMID- 21240828 TI - Probabilistic risk assessment of dietary cadmium in the South Korean population. AB - Global interest in the adverse health effects of cadmium (Cd) has focused on dietary exposure as the principal source of Cd exposure to the general population. Common assumptions used in deterministic Cd assessment in global or regional diets have limitations when applied to specific national cases where local variation in food composition and consumption patterns are different than for global or regional norms. Stochastic dietary Cd exposure assessment was conducted for the general South Korean population to understand better Cd dietary intake. Because rice (Oryza sativa) is commonly and highly consumed by Koreans, it was the dominant contributor to Cd in the diet, representing on average 25% of the total dietary exposure for the general population. Hazard index (HI) values were below the level of concern for the 95th percentile of the general population. Sensitivity analyses demonstrated that variation in rice intake and Cd concentration had the greatest influence on the Cd risk estimate for the general population. Changes in food sources, such as the use of imported rice with higher Cd levels, would lead to increased Cd exposure in the diet, thus necessitating continued vigilance as to the status of Cd within the food supply. PMID- 21240829 TI - Dietary risk assessment of organophosphorus and dithiocarbamate pesticides in a total diet study at a Brazilian university restaurant. AB - In this study ready-to-eat food samples were collected in the production line of the university restaurant of the University of Brasilia, Brazil, which serves non vegetarian and vegetarian meals daily. Samples were analysed for the presence of ten organophosphorus insecticides (OPs) by GC/FPD, after extraction with ethyl acetate and anhydrous sodium sulfate (LOQ = 0.002 mg kg(-1)), and for dithiocarbamate fungicides, as CS(2), using the spectrophotometric method (LOQ = 0.05 mg kg(-1)). About 43% of the 175 samples analysed contained at least one OP compound at levels up to 1.83 mg kg(-1). Methamidophos was the compound most detected (37.7%), present in most of the soup, soybean and salad samples. No OP residues were found in fruit juice, beans and bran rice samples. The cumulative acute intake of OPs was estimated using methamidophos and acephate as index compounds (IC). The total cumulative intake represented 9.1% and 47.7% of the methamidophos ARfD for the non-vegetarian and vegetarian diets, respectively. When acephate was used as IC, the total intakes represented 20.7% and 116% of the ARfD for the non-vegetarian and vegetarian diets, respectively. Dithiocarbamates were detected in 70% of the 177 samples analysed, at levels up to 0.51 mg kg(-1) CS(2); all salad samples were positive and no residues were found in fruit juice. The chronic intake of dithiocarbamates represented 8.6 and 8.9% of the ADI (mancozeb) for the vegetarian and non vegetarian diets, respectively. PMID- 21240830 TI - Balancing the benefits and burdens of storytelling among vulnerable people. PMID- 21240831 TI - Tumor cell growth inhibition is correlated with levels of capsaicin present in hot peppers. AB - There are conflicting reports with regard to the value of hot peppers and their primary active component compound, capsaicin, as an anticancer agent. We tested extracts from a number of peppers and found them to induce significant growth arrest and apoptosis in human breast and leukemia cancer cell lines in vitro with no significant effect on normal breast epithelial cells. Further, cell growth inhibition and cell death induction were positively correlated with the capsaicin content (based on the Scoville scale) of the peppers, and the hydroxyl radical scavenger thiourea significantly inhibited the activity of pepper extracts, suggesting the involvement of free radicals in mediating the biological activity of the pepper extracts. These results suggest a potential use of pepper extracts as anticancer agents. PMID- 21240832 TI - Association of tea consumption and cutaneous squamous cell carcinoma. AB - Laboratory and epidemiologic studies suggest a protective effect of tea consumption on risk of cutaneous squamous cell carcinoma (SCC). We designed a case-control study to examine the association between putative protective exposures, including tea consumption, and SCC risk using a large health maintenance organization population. Cases (n=415) were defined as Kaiser Permanente Northern California (KPNC) members with a pathology-verified SCC in 2004 and controls (n=415) were age-, gender-, and race-matched members with no previous history of skin cancer. Tea consumption and SCC risk factors were ascertained by questionnaire. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression to estimate the association of SCC with regular use, as well as dose and duration of tea consumption. Risk factor adjusted models included education, smoking, hair and eye color, skin type, family history of skin cancer, and history of freckling, sunburns, sun exposure, and tanning bed use. Adjusted analyses showed no reduction in SCC risk with regular consumption of tea (OR=1.11, 95% CI: 0.81-1.54). Examining duration, dose, and combined duration and dose exposure variables did not alter findings. We found no evidence that tea consumption was associated with cutaneous SCC risk. PMID- 21240833 TI - Trends and geographic differentials in mortality under age 60 in India. AB - The study examines overall and region-specific mortality changes and regional mortality variation in India since the 1970s, using data from the Sample Registration System (SRS). An evaluation of the quality of SRS data confirms their reliability for children and adults under age 60. The results suggest the convergence of mortality across the regions of India with important inter-state differences in the pace of health improvements over time. After spectacular progress during the 1970s and the 1980s, many Indian states have witnessed slower mortality improvements in both young and adult age groups. India faces difficulties in making further reductions in infant mortality and in the burden of chronic and man-made diseases at adult ages. PMID- 21240834 TI - Expert reasoning in psychotherapy case formulation. AB - Therapist reasoning in case formulation construction was investigated. Sixty-five psychodynamic or cognitive-behavioral therapists classified as experts, experienced, or novices generated "think aloud" formulations based on six standardized vignettes. Formulations were reliably transcribed, segmented into idea units, and content coded. ANOVA and sequential analysis compared formulation content and reasoning processes. Expert formulations contained more descriptive, diagnostic, inferential, and treatment planning information. They focused more on given and inferred symptoms, on adult relationship history, on inferred psychological mechanisms, on the need for further evaluation, and on plans to focus on treatment expectations and symptoms. They exhibited more forward (inferential) than backward (deductive) reasoning and, compared with non-experts, they exhibited more forward and backward reasoning. Results are discussed in terms of cognitive science models for expert problem solving and on implications for psychotherapy training, practice, and research. PMID- 21240835 TI - [Fortschritte Neurologie Psychiatrie in 2010]. PMID- 21240836 TI - [Paraneoplastic neurological syndromes]. PMID- 21240837 TI - Endoscopic ultrasound-guided gastroenterostomy for palliative drainage of an obstructed hepaticojejunostomy loop. PMID- 21240838 TI - [67-year-old woman with painless nodule after arterial blood gas analysis]. PMID- 21240839 TI - Buruli ulcer: a review of in vitro tests to screen natural products for activity against Mycobacterium ulcerans. AB - Buruli ulcer (BU), caused by Mycobacterium ulcerans, has recently been recognized by the World Health Organization (WHO) as an important emerging disease. It is largely a problem of the poor in remote rural areas and has emerged as an important cause of human suffering. While antimycobacterial therapy is often effective for the earliest nodular or ulcerative lesions, for advanced ulcerated lesions, surgery is sometimes necessary. Antimycobacterial drugs may also prevent relapses or disseminated infections. Efficient alternatives different from surgery are presently explored because this treatment deals with huge restrictive factors such as the necessity of prolonged hospitalization, its high cost, and the scars after surgery. Traditional treatment remains the first option for poor populations of remote areas who may have problems of accessibility to synthetic products because of their high cost. The search for efficient natural products active on M. ulcerans should then be encouraged because they are part of the natural heritage of these populations; they are affordable financially and can be used at the earliest stage. This review provides a number of tests that will help to evaluate the antimycobacterial activity of natural products against M. ulcerans, which are adapted to its slow growing rate, and lists active extracts published up to now in Medline. PMID- 21240840 TI - Rhealba(r) oat plantlet extract: evidence of protein-free content and assessment of regulatory activity on immune inflammatory mediators. AB - Owing to their high content of flavonoids and saponins, plantlets of Avena sativa L. (Poaceae) are likely to possess anti-inflammatory and immunoregulatory properties of value in the treatment of atopic dermatitis (AD). With a view to its potential use in atopic subjects at risk of developing sensitisation to dietary proteins, we prepared a plantlet extract without proteins and isolated 2 flavonoids, isoorientin-2''- O-arabinoside (1) and isovitexin-2''- O-arabinoside (2), and two saponins, avenacosides A (3) and B (4). The absence of protein in this extract was evidenced by electrophoresis and Western immunoblotting. Furthermore, Western immunoblotting demonstrated the absence of cross-reaction between grain and plantlet proteins. We evaluated the anti-inflammatory activity of the plantlet extract and its compounds IN VITRO in a model of keratinocyte inflammation: 6-keto prostaglandin F1 alpha production was inhibited by the plantlet extract (- 35 % and - 57 % at 10 and 30 ug/mL, respectively; p < 0.001) and isoorientin-2''- O-arabinoside (- 31 %, - 51 %, and - 56 % at 3, 10, and 30 ug/mL, respectively; p < 0.001). Intracellular interleukin-2 production in activated T lymphocytes was also inhibited by 16 %, 27 %, and 31 % with 3, 10, and 30 ug/mL plantlet extract, respectively, and by 23 % and 32 % with 3 and 10 ug/mL avenacoside A, respectively, (p < 0.001), demonstrating their immunoregulatory activity IN VITRO. The plantlet extract was also effective on the phenotype and function of dendritic cells (DC) differentiated from monocytes. It decreased the expression of major histocompatibility complex class II molecules on DC and significantly impaired their stimulatory activity on autologous T-cell proliferation (-25 %, p < 0.05). In conclusion, this protein free oat plantlet extract exhibits anti-inflammatory and immunoregulatory activities in vitro. PMID- 21240841 TI - Dose-dependent effects of polyphenolic extracts from green tea, blue-berried honeysuckle, and chokeberry on rat caecal fermentation processes. AB - The physiological status of the colon or ceacum is known to be very important for the host organism. Therefore, the aim of this study was to estimate the influence of high doses of polyphenolic extracts from chokeberry (CH), blue-berried honeysuckle (H), and green tea (GT) on fermentation processes in the caecum and caecal parameters of rats fed casein diets. In a 4-week experiment, 35-day-old rats were fed diets containing 0.4, 0.8, and 1.2 % of pure polyphenols. The greatest weight of digesta was recorded in rats fed 1.2 % of GT extract, and these animals were also characterised by having the lowest content of dry matter. Supplementation of diets with the extracts of interest caused a reduction in pH values and ammonia concentrations in caecal digesta in comparison to control animals. The results of a two-way analysis of variance indicated dose-dependent (except for 0.4 % supplementation) inhibition of enzymatic activity compared to control animals. Introduction of CH and H extracts significantly reduced the activity of beta-glucuronidase compared to rats fed tea diets. Two-way analysis of variance showed a significant decrease in volatile fatty acids concentration in rats fed diets supplemented with H and CH extracts in comparison to control and tea-fed rats. The obtained results showed that the extracts tested can distinctly influence caecal parameters and metabolism. PMID- 21240842 TI - Chemical characterization of a commercial Commiphora wightii resin sample and chemical profiling to assess for authenticity. AB - The gum resin of Commiphora wightii [(Hook. ex Stocks) Engl.] is an ayurvedic medicine for the treatment of arthritis, inflammation, obesity, lipid disorders, and cardiovascular diseases and is known as guggul. Morphologically, it is not easy to distinguish guggul from closely related gum resins of other plants. Reliability of the commercially available guggul is critical due to the high risk of adulteration. To check authenticity, a commercial guggul sample was investigated for its chemical markers and 17 metabolites were identified, including three new, 20(S),21-epoxy-3-oxocholest-4-ene (1), 8 beta-hydroxy-3,20 dioxopregn-4,6-diene (2), and 5-(13' Z-nonadecenyl)resorcinol (17) from the ethyl acetate soluble part. During the current study, compounds 14- 17 were identified as constituents of Mangifera indica gum, as an adulterant in the commercial guggul sample. This discovery highlighted the common malpractices in the trade of medicinal raw material in the developing world. The structures of the compounds were deduced by the spectroscopic technique and chemical methods, as well as by comparison with the reported data. The structure of 20(S),21-epoxy-3-oxocholest-4 ene (1) was also unambiguously deduced by single-crystal X-ray diffraction technique. PMID- 21240843 TI - [Clinical trial endpoints in alpha-1-antitrypsin deficiency: interdisciplinary aspects]. AB - Patients with alpha-1-antitrypsin deficiency (AAD) represent a small subgroup of subjects with chronic obstructive pulmonary disease (COPD). Only about 800 patients are registered in the German AAD registry, so that about 90 % of the estimated 8000 afflicted individuals have not yet been diagnosed. Clinical trials to demonstrate the efficacy of alpha-1-antitrypsin augmentation therapy are difficult not only due to the small number of potential participants. As in recent COPD trials, FEV (1) and other standard respiratory function parameters have failed to demonstrate statistically significant differences between treatment groups. The present article reviews and discusses both established and potentially new study endpoints. Novel parameters emerge within the field of diagnostic imaging. IT-supported analysis of lung density allows to quantify the extent of emphysema. The EXACTLE trial has shown that CT densitometry is able to document the progression of emphysema over 2 to 3 years. Magnetic resonance imaging (MRI) can serve as an adjunct to assess lung perfusion, ventilation, and breathing dynamics. In the future, prospective multi-centre studies will rather use imaging endpoints than classical respiratory function measurements such as FEV (1). In addition, diffusion capacity and combined endpoints such as the BODE index, which correlates with mortality in COPD, should be considered. PMID- 21240844 TI - [Somatoform disorder or neurological syndrome? Complex mental and movement disorder and autonomic dysfunction in a 65-year-old patient - Case 1/2011]. AB - HISTORY AND ADMISSION FINDINGS: A 65-year-old female patient presented with increasing vertigo, tendency to fall, dry cough and, in addition, numerous psychic and somatic symptoms since 6 years. Former diagnostic attempts did not yield clarifying results. In part, the patient had not followed up on former recommendations for further diagnostic procedures. With a suspected somatization disorder the patient was admitted to the Department of Psychosomatic Medicine. INVESTIGATIONS: The neurological examination at admission revealed vertical oculomotor palsy and tendency to fall backwards indicating an affection of the brain stem. A magnetic resonance imaging of the head showed atrophy of the mesencephalon. DIAGNOSIS AND TREATMENT: In light of these findings the patient was diagnosed Steele-Richardson-Olszewksi syndrome. The therapy which comprises training measures and medication with a cholinesterase inhibitor aims to retain neuropsychological and motional abilities. Besides, psychotherapy is offered alongside to help the patient to cope with the disease. CONCLUSIONS: Treating patients with somatic and psychological symptoms calls for careful anamnestic exploration and clinical examination. Psychological alterations following neurological affection of the brain can imitate somatization disorder. PMID- 21240845 TI - In vitro calcified matrix deposition by human osteoblasts onto a zinc-containing bioactive glass. AB - Bioactive glasses synthesized by the sol-gel technique possess many of the qualities associated with an ideal scaffold material for a bone graft substitute. In view of the potential clinical applications, we performed a detailed in vitro study of the biological reactivity of synthesized 58S bioactive glass containing zinc, in terms of osteoblast morphology, proliferation, and deposition of a mineralized extracellular matrix (ECM). Human Sarcoma Osteoblast (SAOS-2) cells were used to i) assess cytotoxicity by lactate dehydrogenase (LDH) release and ii) evaluate the deposition of a calcified extracellular matrix by ELISA assay and quantitative RT-PCR (qRT-PCR). In comparison with pure silica and 58S, the 58S-Zn0.4 bioglass showed a significant increase in cellular proliferation and deposition of ECM components such as decorin, fibronectin, osteocalcin, osteonectin, osteopontin, type-I and -III collagens. Calcium deposition was significantly higher than on pure silica and 58S samples. Also Alkaline phosphatase (ALP) activity and its protein content was higher with respect to pure silica and 58S. qRT-PCR analysis revealed the up-regulation of type-I collagen, bone sialoprotein and osteopontin genes. All together these results demonstrate the cytocompatibility of 58S-Zn0.4 bioglass and its capability to promote osteoblast differentiation. PMID- 21240846 TI - Macrophage response to staphylococcal biofilms on crosslinked poly(ethylene) glycol polymer coatings and common biomaterials in vitro. AB - Biomaterial-associated-infections (BAI) are serious clinical complications that threaten the longevity of implanted devices and lead to high morbidity and mortality. Poly(ethylene)glycol (PEG) coatings have been studied as a strategy to reduce the incidence of BAI by reducing protein deposition that promotes pathogen adhesion and growth on device surfaces. Despite their effectiveness to reduce protein adsorption and a hundred-fold reduction in bacterial adhesion, PEG-based coatings still facilitate weak bacterial adhesion that can form an initial basis for biofilms. Here, we describe a methodology enabling direct, quantitative and detailed qualitative in situ observation of macrophage morphology, migration and phagocytosis of bacteria. In vitro interaction of macrophages with Staphylococcus epidermidis 3399 adhering to commercial, crosslinked PEG-based coatings (OptiChem(r)) was compared with fluorinated ethylene propylene, silicone rubber and glass. Adhesion, phagocytosis and migration were studied real-time in a parallel-plate-flow-chamber. Macrophages cultured on OptiChem(r) coatings showed enhanced migration and phagocytosis of bacteria compared to common biomaterials. Bacterial clearance per macrophage on both inert and reactive OptiChem(r) coatings were about three times higher than on the common biomaterials studied, corresponding with up to 70% reduction in bacterial numbers on OptiChem(r), whereas on the biomaterials less than 40% bacterial reduction was obtained. These findings show that bacterial clearance from cross-linked PEG-based coatings by macrophages is more effective than from common biomaterials, possibly resulting from weak adhesion of bacteria on Optichem(r). Moreover, macrophages exhibit higher mobility on Optichem(r) retaining an improved capability to clear bacteria from larger areas than from other common biomaterials, where they appear more immobilized. PMID- 21240847 TI - Characterisation of Listeria monocytogenes strains isolated from soft and semi soft cheeses sampled in a region of Italy. AB - A total of 47 Listeria monocytogenes strains isolated in a survey of cheeses sampled from retail outlets were characterised. Five cheeses (Gorgonzola, Taleggio, Asiago, Crescenza and Brie) were chosen from the most popular soft and semi-soft cheeses consumed in Italy and most commonly contaminated with L. monocytogenes. The serotype and antibiotic resistance pattern were determined for each strain and their macrorestriction profile was analysed with pulsed-field gel electrophoresis (PFGE). The main serotypes detected were 1/2a (76.6%) and 1/2c (21.3%). Serotype 1/2b was found in only one sample. A total of 97.9% of strains were resistant to oxacillin (OX), 80.9% to lincomycin (L) and 78.7% to clindamycin (CC). Of these strains, 17% were found to be resistant to two antibiotics (OX-CC or OX-L) while 70.2% were resistant to three antibiotics (OX CC-L). No strains were susceptible to all the compounds tested. A combined analysis of the macrorestriction profiles AscI and ApaI identified eleven pulsotypes divided into three clusters. Two pulsotypes predominated, accounting for 57.4% and 21.3% of the isolated strains. Analysis of the PFGE profiles did not reveal any correlation between pulsotype and type of cheese, producer or retail outlet. A temporal analysis revealed that one pulsotype was persistent throughout the study period, with the exception of August and September, in which time a different pulsotype was detected. This variability suggests the influence of factors affecting the dynamics of the contamination of these products. Large scale studies could help clarify this phenomenon. PMID- 21240848 TI - Assessment of critical parameters in blood processing for the bovine interferon gamma ELISPOT assay to detect Mycobacterium bovis infected cattle in India. AB - In vitro production of bovine interferon gamma (BoIFN-gamma) cytokine from bovine peripheral blood mononuclear cells (PBMCs) can be detected using the most sensitive enzyme-linked immunosorbent spot (ELISPOT) assay. ELISPOT assays are dependent on the quantity and quality of PBMC preparations and hence contribute significantly to the performance of this assay. In order to standardise the methods for isolation of PBMCs, we compared two methods for the processing of bovine blood which included aliquots of blood that were stored in a horizontal position without dilution or agitation and aliquots of blood that were immediately diluted 1:1 with complete Rosewell Park Memorial Institute (RPMI) 1640 medium and stored in a horizontal position with gentle agitation. PBMCs were isolated at 2, 4, 6, 8 and 24 h and at 4 degrees C and at 22 degrees C +/- 2 degrees C. They were stimulated using tuberculosis-specific antigens, after which the ELISPOT assay was performed. Quantities of spot-forming cells (SFC) created by the release of BoIFN-gamma in ELISPOT assays were significantly greater in the samples stored at 22 degrees C +/- 2 degrees C than those held +4 degrees C and the intensity of the signals dropped following processing after 6 h. A further drop in SFC was observed in those samples that had been stored undiluted and without agitation. These findings demonstrated that optimisation of PBMC isolation procedures can lead to increased sensitivity in the detection of BoIFN gamma using the ELISPOT assay, thus contributing to an enhanced diagnosis of bovine tuberculosis. PMID- 21240849 TI - Rift Valley fever: the Nigerian story. AB - Rift Valley fever (RVF) is an arthropod-borne zoonotic disease of livestock. It is characterised by fever, salivation, abdominal pain, diarrhoea, mucopurulent to bloody nasal discharge, abortion, rapid decrease in milk production and death in animals. Infected humans experience an influenza-like illness that is characterised by fever, malaise, headaches, nausea and epigastric pain followed by recovery, although mortality can occur. RVF was thought to be a disease of sub Saharan Africa but with the outbreaks in Egypt and the Arabian Peninsula, it may be extending its range further afield. Virological and serological evidence indicates that the virus exists in Nigeria and, with the warning signal sent by international organisations to countries in Africa about an impending outbreak, co-ordinated research between veterinarians and physicians in Nigeria is advocated. PMID- 21240850 TI - The use of pathological and histopathological techniques in the diagnosis of peste des petits ruminants in India. AB - The authors report on an outbreak of peste des petits ruminants (PPR) among sheep and goats in the Province of Gujarat, India. Clinical signs observed during outbreaks were typical of PPR. Predominant signs were severe diarrhoea, dyspnoea, mucopurulent discharge from the eyes and nose, erosive rhinitis, necrotic ulcers in the mouth, on the dental pad, tongue, upper and lower lips, fever and depression. Common post-mortem findings included congestion, red hepatisation, raised patches of emphysema in the lungs, haemorrhages and froth exudates in the trachea, severe enteritis and streaks of haemorrhages in the intestine, enlargement and petechial haemorrhages in the spleen and oedema and inflammatory lesions in the mesenteric lymph nodes. Spectacular histopathological changes were observed in the lungs, intestine, spleen, mesenteric lymph nodes, liver and kidneys. Clinical, gross and histopathological lesions and haematological changes were suggestive of PPR, which was further confirmed by detection of PPR viral antigen in clinical samples, as well as post-mortem tissues using the sandwich enzyme-linked immunosorbent assay (s-ELISA). PMID- 21240851 TI - Guidelines used in Japan to prevent the contamination of feed products with undesirable substances. AB - As Japan depends on imports for most ingredients used to manufacture feed products, close co-operation is indispensable between importers and manufacturers of feed and feed ingredients to effectively mitigate the risk associated with feed safety. Guidelines were issued by the Ministry of Agriculture, Forestry and Fisheries (MAFF) in March 2008 to prevent feed products from being contaminated with undesirable substances. These guidelines identify the responsibilities of feed ingredient importers, feed manufacturers and distributors, as well as the roles of the MAFF and the Food and Agricultural Materials Inspection Centre. PMID- 21240852 TI - Standardisation of an indirect enzyme-linked immunosorbent assay for the detection of Brucella antibodies in milk from water buffalo (Bubalus bubalis) in Italy. AB - An indirect enzyme-linked immunosorbent assay (ELISA) was evaluated for the detection of Brucella antibodies in milk from water buffalo (Bubalus bubalis Linnaeus, 1758). The test accuracy was evaluated on milk samples from the Campania Region in Italy. A total of 100 negative samples were collected from 10 officially brucellosis-free herds in Salerno Province, while 30 positive samples were collected from 3 herds in Caserta Province, where animals gave positive results to the official tests and it was here that Brucella abortus biovar 1 had been isolated. Test sensitivity was 100%, with a confidence interval (CI) of 90.8%-100%, while specificity was 98% (CI 93%-99.4%) on individual milk samples. To simulate bulk milk samples from herds infected at various levels of infection, dilutions from 1:10 to 1:100 of positive milk samples in negative milk were also used. The probability of detecting antibodies in positive milk samples was higher than 50% up to a dilution of 1:50 in negative milk. Considering the average national water buffalo herd size, the probability of identifying infection in a water buffalo herd by bulk milk testing is 50% (CI 33.1%-66.9%) in the worst case scenario of a single infected animal contributing to the bulk milk. PMID- 21240853 TI - Angiostrongylus vasorum in 20 dogs in the province of Chieti, Italy. AB - After a case of Angiostrongylus vasorum (canine lungworm) was diagnosed in the province of Chieti (Italy) in early 2008, parasitological research was conducted to investigate the presence of the parasite in dogs in the area. A total of 178 dogs, 56 carcasses and 122 stool samples were examined between January and September 2008. The carcasses were examined for the presence of adult parasites in the right ventricle and pulmonary artery, and larval forms in the internal organ and brain tissues. The faeces were inspected for larval form L1 using three diagnostic methods that are currently used to test for endoparasites and larvae of bronchopulmonary strongyles. A total of 20 cases of canine angiostrongylosis were diagnosed (8.9%), with adult parasites being identified in 5 dogs, and L1 larvae in another 15. The anatomo-pathological examination of the carcasses of the dogs infested with adult nematodes revealed pneumonia, pleurisy, reddish foam in the trachea, effusion of serohaemorrhagic fluid in the thoracic cavity and enlarged mediastinic and mesenteric lymph nodes. Histological examination of the tissues showed serious, similar syndromes with lesions caused by colonisation of the kidneys, lymph nodes and brain by the parasites. Given the large number of cases confirmed in relation to the period of study (9 months), it is essential to include angiostrongylosis among the differential diagnoses made in clinical and post-mortem examinations of dogs in the province of Chieti and in the neighbouring areas. PMID- 21240854 TI - Biochemical and pathological studies on the effects of levamisole and chlorambucil on Ehrlich ascites carcinoma-bearing mice. AB - Clinicopathological studies on the effects of combining immunostimulant drugs (levamisole) with anti-cancer drugs (chlorambucil) revealed the enhancement of the latter against Ehrlich ascites carcinoma-bearing mice and resulted in a reduction in the size of tumour. An evaluation of liver and kidney functions showed a significant increase of alanine transaminase (ALT), aspartate transaminase (AST) and creatinine in all groups. Histopathological studies of one group that received an intraperitoneal injection of Ehrlich ascites carcinoma cells (2.5 * 106) showed that hepatic parenchyma revealed degenerative changes. The portal area was oedematous and showed rounded cell aggregations. Cell death within hypertrophied Kupper cells was observed in some hepatic cells. The neoplastic emboli could be seen either inside blood vessels or hepatic sinusoids, while another group which had been treated orally with a combination of Leukeran(TM) (0.2 mg/kg body weight) and levamisole (5 mg/kg body weight) revealed that hepatic parenchyma revealed massive necrosis with proliferative bile duct epithelium. No neoplastic cells were observed without the hepatic parenchyma, while the renal cortex presented a large number of lymphocytes and plasma cells forming bands or aggregates, mainly around the blood vessels. It was concluded that the addition of levamisole to chlorambucil improved the anti cancer effect of chlorambucil against Ehrlich ascites carcinoma. However, it had adverse effects on the liver and kidneys as shown by liver and kidney function tests and confirmed by histopathology. PMID- 21240855 TI - The effect of vitamin C at varying times on physiological parameters in rabbits after xylazine anaesthesia. AB - The effects of vitamin C administration at varying time intervals on rectal temperature, respiratory rates, heart rates and sleeping time following xylazine anaesthesia was evaluated in rabbits. A total of 36 rabbits placed in six groups (A-F) with 6 animals per group each were used. Groups A and B were used as controls for vitamin C (120 mg/kg, oral) and xylazine (4 mg/kg, intramuscular) treatments, respectively, while groups C-F received vitamin C at four intervals prior to xylazine anaesthesia. The result of the study showed that vitamin C pre medication prior to xylazine anaesthesia induced depression in respiratory and heart rates and a slight increase in rectal temperature. It also significantly increased sleeping time in rabbits (p<0.05). The lengthiest duration of sleep was observed among rabbits that received vitamin C 60 min prior to xylazine anaesthesia. Vitamin C administration 10 min prior to xylazine anaesthesia in rabbits induced a sleeping time three times the value compared to those animals that had received xylazine anaesthesia alone. However, the study did not observe a significant difference (p>0.05) in temperature between groups either before or after xylazine administration. It was concluded that vitamin C alters the clinical parameters as well as the sleeping time in rabbits under xylazine anaesthesia. PMID- 21240856 TI - In memoriam: Jean Blancou, DVM, 1936-2010. World authority on rabies, historian and former Director General of the World Organisation for Animal Health (Office International des Epizooties: OIE). AB - Jean-Marie Blancou was born in Bangui on 28 August 1936 and passed away in Paris on 10 November 2010 at the age of 74. After studying at the Pierre de Fermat Lycee in Toulouse, Jean Blancou graduated from the Toulouse Veterinary School in 1960. He continued his studies in tropical veterinary medicine in Paris until 1963, extending his knowledge of immunology, microbiology, biochemistry and zoology, at the Institut Pasteur. He obtained his doctorate in biological sciences at the University of Nancy in 1982. Jean Blancou commenced his career as technical adviser to the Veterinary Services of Ethiopia where he directed a campaign against rinderpest in the south of the county. From 1965 to 1967 he was deputy director of the national veterinary laboratory in Niamey where he was responsible for the diagnosis of animal diseases and the production of veterinary vaccines. In 1967, he moved to the central livestock laboratory in Madagascar, where he commenced research on the diagnosis and control of dermatophilosis, bovine tuberculosis and other bacterial and parasitic diseases. In August 1968 he married Genevieve Orue. In 1975 he was appointed as head of the national veterinary laboratory in Senegal, where he remained until 1977. Initially deputy director, and then director of Research on rabies and wildlife diseases, at the World Health Organization collaborating centre in Nancy, he remained in this position until 1990. Jean Blancou was recognised as a world authority on rabies. He conducted research into the diagnosis, aetiology, epidemiology and control of rabies during his time in Nancy. Between 1988 and 1990, Dr Blancou also headed the animal health and protection department of the Centre national d'etudes veterinaires et animales (CNEVA) in Maisons-Alfort. On 1 January 1991, he was appointed director general of the World Organisation for Animal Health (Office International des Epizooties: OIE) and was re-elected in 1995 for a further five year term, until he retired in 2000. He attached great importance to the value of scientific publication and to the ethics involved in producing scientific literature. He had a very strong interest in the historical aspects of animal diseases and, in 2003, published a valuable book entitled History of the surveillance and control of transmissible animal diseases. He would always ensure that the most interesting and appropriate historic illustrations, irrespective of how difficult they were to obtain, were selected for the papers he published. Among some of the activities Jean Blancou undertook during his retirement was the mammoth task of co-editing Infectious and parasitic diseases of livestock in French and English. Dr Blancou authored over 370 scientific publications devoted to animal diseases, to the production and control of biologicals and, of course, many authoritative articles on rabies and vaccinology. He was always generous with the scientific knowledge he possessed and never missed an opportunity to assist colleagues in the preparation or correction of manuscripts that they wished to submit to peer-reviewed journals. He was gentle in nature and always softly spoken. As one of his colleagues wrote: 'we have lost a most gentle, thoughtful and kind man and the world has lost one of its stellar veterinarians'. Despite his busy and brilliant career, Jean Blancou was a family man and devoted to the education of his children. During his illness, he showed great courage. The Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise 'G. Caporale' has been privileged to benefit from the expert knowledge and experience that Dr Blancou so generously provided in his capacity as Member of the Scientific Advisory Board of Veterinaria Italiana. Jean Blancou is survived by his wife, Genevieve, his children and grandchildren. PMID- 21240857 TI - Regression of serous macular detachment due to peripheral exudative hemorrhagic chorioretinopathy following intravitreal bevacizumab. AB - PURPOSE: To describe a case of exudative macular detachment secondary to peripheral exudative chorioretinopathy with a favorable anatomic and visual outcome following treatment with intravitreal bevacizumab. METHODS: The medical records of a patient with peripheral exudative chorioretinopathy were reviewed. RESULTS: Macular reattachment was achieved with a corresponding visual acuity improvement that was maintained over an uncomplicated 17-month clinical course. CONCLUSIONS: Bevacizumab may be an effective treatment option for exudative macular detachment secondary to peripheral exudative hemorrhagic chorioretinopathy. PMID- 21240858 TI - Evaluation of the long-term effects of photorefractive keratectomy correction for myopia in China. AB - PURPOSE: To evaluate the long-term effects of photorefractive keratectomy (PRK) correction for myopia in China. METHODS: A comprehensive literature research was conducted in 2 Chinese databases and PubMed. Statistical analysis was performed using the RevMan 4.2 software. RESULTS: Seven prospective studies involving 2,796 eyes were included. The follow-up period was 5 to 11 years. Meta-analysis showed efficacies in low to moderate myopia that surpassed those in high myopia, and pooled odds ratios were 9.14 (95% confidence interval [CI] 4.37-19.11) in the proportion of eyes with uncorrected visual acuity (UCVA)=20/20 and 5.61 (95% CI 3.97-7.93) in the proportion of eyes with UCVA=20/40. More than 10 years post operation, 82.0% had 20/20 or better UCVA and 96.1% had 20/40 or better in the = 6.00 D myopia group. Among patients with >-6.00 D myopia, 31.7% had 20/20 or better UCVA and 80.4% had 20/40 or better. Moreover, 82.1% and 46.4% of the treated eyes were within +/-1.0 D of target refraction in the low to moderate myopia and high myopia group, respectively. About 1.4%-3.5% of eyes lost =2 lines of best spectacle-corrected visual acuity, and 0.6%-4.1% of eyes had grade 1 corneal haze. CONCLUSIONS: Photorefractive keratectomy for myopia is an effective and safe procedure for the long term in China. The efficacy and predictability of PRK in low to moderate myopia are better than in high myopia. PMID- 21240859 TI - Electronic prescribing and prescription design in ophthalmic practice. AB - PURPOSE: Prescription and drug errors are common causes of adverse clinical events, posing a significant risk to safe patient care. Although there has been a movement to increase the use of electronic prescribing, concerns over feasibility suggest that improving the design of written prescriptions to minimize missing information may still be worthwhile. This retrospective cross-sectional study examined the effect on prescription completeness of electronic prescriptions and adding information prompts to written prescriptions. We hypothesized that electronic prescription would be superior to written prescriptions on prescription completeness and the inclusion of information prompts in written prescriptions would result in increased recording of the prompted information. METHODS: Chi-square analysis was used to examine differences among 50 consecutive electronic discharge prescriptions, 100 consecutive outpatient prescriptions (with prompts for medicine duration but not form, frequency, or laterality), and 100 consecutive day surgery prescriptions (with prompts for form, frequency, and laterality) in the provision of 10 key pieces of information. RESULTS: Electronic prescriptions resulted in 100% complete information across all domains and more complete information on medicine duration than day surgery prescriptions. Written outpatient prescriptions (with duration prompts but not laterality prompts) were superior in recording duration and inferior in recording laterality than day surgery prescriptions (without duration prompts but with laterality prompts). CONCLUSIONS: Our results support the use of electronic prescribing. Where written prescribing must be used, our study highlights the importance of including information prompts to minimize missing information and improve patient safety. PMID- 21240860 TI - Late-onset Candida keratitis after Descemet stripping automated endothelial keratoplasty: clinical and confocal microscopic report. AB - PURPOSE: To report clinical and confocal microscopy features of late-onset Candida albicans keratitis after Descemet stripping automated keratoplasty (DSAEK). METHODS: We performed clinical and confocal scan on a patient who underwent DSAEK and phacoemulsification for Fuchs endothelial dystrophy and cataract. RESULTS: A 76-year-old woman who underwent uneventful DSAEK and phacoemulsification presented with white to cream deposits 3 months after DSAEK. Confocal microscopy showed a hyperintense deposit at the lenticule and interface. Confocal scan also disclosed intense haze and inflammation at the interface and clusters of hyperreflective round structures resembling epithelial cells within the interface area. No signs of hyphae-like structures were seen. Late-onset symptoms misled us into a bacterial chronic endophthalmitis diagnosis, and the patient was started on topical and systemic antibiotics. Despite intense antibiotic therapy, the patient developed severe endophthalmitis, so we performed anterior vitrectomy and the donor lenticule was removed. Microbiology results from the removed lenticule showed infection by C albicans. Antifungal therapy with systemic and topical voriconazole controlled the infection. CONCLUSIONS: Candida interface keratitis is possible after DSAEK. The posterior location of infected tissue poses diagnostic and therapeutic challenges. In our case, the late onset of the symptoms and not performing corneoscleral rim cultures delayed correct diagnosis. This is the first reported case of post-DSAEK Candida keratitis with confocal microscopy images. A hyperintense granular deposit was seen at the lenticule and interface with confocal microscopy. We also observed intense haze, granular round structures resembling epithelial cells, and hyperreflective needle-shaped material at the interface. No hyphae-like structures were seen with confocal imaging. PMID- 21240861 TI - A simple description of age-related changes in crystalline lens thickness. AB - PURPOSE: An increase in lens thickness is often described as a linear function of age. However, contradictory opinions exist about whether the lens thickness continues to increase after 50 years of age. Differences in slope exist between this increase in younger and older people, but these findings are inconsistent with the linear behavior of an increase in the lens thickness throughout life. We investigated among different functions, including slope variation, which would be the best to show the relation between lens thickness and age. An available model portraying lens growth could be advantageous in many practical applications. The possibility of differences between sexes in lens thickness growth is also analyzed. METHODS: We evaluated 102 eyes of patients aged between 15 and 84 years: 41 men, 61 women. The biometric measurements were performed with the aid of the OcuScan(r) (Alcon, USA). RESULTS: Both logarithmic and potential functions provide a good fit for the data (R2 = 0.905 and 0.906, respectively). The results do not show significant differences between men and women in any age range, nor when the data of the whole sample are considered (p = 0.29). CONCLUSIONS: The best fits for the data are both logarithmic and double logarithmic functions. According to this model, lens growth continues throughout life, but after 50 years, age-related thickness variations are lower than statistical variability. No differences were found between the sexes. PMID- 21240862 TI - High prevalence of pseudoexfoliation syndrome and its complications in Tarragona in northeast Spain. AB - PURPOSE: To determine the prevalence of pseudoexfoliation syndrome (PEX) in our health area, in 4 counties of Tarragona, and its involvement in the health status of the population. METHODS: This was a cross-sectional study of a sample of 2,342 inhabitants aged = 60 years, randomly selected from the population census. Subjects were classified in 3 groups according to age (group 1 = 60-69 years, group 2 = 70-79 years, group 3 = over 80 years). The diagnosis of PEX was made in all cases by the same ophthalmologist, using biomicroscopic and slit-lamp evaluation. Corneal endothelial study was made by specular microscope. RESULTS: The prevalence of PEX was 309/2,342 patients (13.19%), unilateral in 219/309 (70.87%). The prevalence of PEX in patients with open-angle glaucoma was 29.48%. Changes in corneal endothelium were higher in patients with PEX, with lower cell density and hexagonality percentage, with higher coefficient of variation, significant in age groups 2 and 3. The prevalence of cataract in patients with PEX was 80.58%, versus 54.64% in patients without PEX. Complications of cataract surgery were higher in patients with PEX and postoperative corneal edema was best correlated with a low hexagonality percentage. No systemic cardiovascular diseases were significant in patients with PEX. CONCLUSIONS: In our health district area, a high prevalence of PEX exists. A more extensive study of the causes of these differences is needed, including analysis of the genetic makeup of the population. PMID- 21240863 TI - Simulation training for vascular access interventions. AB - Training and learning in the field of access for dialysis, including peritoneal and hemodialysis and access for oncologic patients, is well suited for the use of simulators, simulated case learning, and root cause analysis of adverse outcomes and team training. Simulators range over a wide spectrum from simple suture learning devices, inexpensive systems for venous puncture simulation, such as a turkey breast or leg with a pressurized tunneled rubber or graft conduit, to sophisticated computer designed simulators to teach interventional procedures such as vascular access angiogram, balloon angioplasty and stent placing. Team training capitalizes on the principles used in aviation, known as Crew Resource Management (CRM) or Human Factor (HF). The objectives of team training are to improve communication and leadership skills, to use checklists to prevent errors, to promote a change in the attitudes towards vascular access from learning through mistakes in a non-punitive environment, to impacting positively the employee performance and to increase staff retention by making the workplace safer, more efficient and user-friendly. PMID- 21240864 TI - A case of bleeding access. PMID- 21240866 TI - In memoriam of Ali Bakran. PMID- 21240867 TI - Plasma B-type natriuretic peptide in dialyzed patients: marker of cardiovascular disease or link to plasma refilling. AB - BACKGROUND: B-type natriuretic peptide (BNP) is released in response to extracellular volume and blood pressure (BP) overload and is a risk factor for cardiovascular diseases (CVD). BNP is increased in dialyzed patients (HDpts). The aim of this study was to evaluate the relationships between BNP and renin, aldosterone and blood volume reduction rate (BV/WL), with the presence of CVD and mortality. METHODS: Fifty-one HDpts aged 70 +/- 14 years were enrolled. BP, BV/WL, BNP, aldosterone, renin, C-reactive protein (CRP), troponin I and routine biochemistry were measured. According to the predialytic plasma BNP levels, the patients were divided into group A with higher BNP and group B with lower BNP than the median value of 330 pg/mL. Follow-up was 1 year. RESULTS: After HD, plasma BNP (449.6 +/- 582.2 pg/mL vs. 264.1 +/- 269.8 pg/mL, p=0.0008) and aldosterone (421.8 +/- 573.4 pg/mL vs. 265.1 +/- 566.2 pg/mL, p=0.0003) decreased, but not rennin. BNP decreased more after hemodiafiltration than after standard HD (-55.1% +/- 28.5% vs. -26.5% +/- 19.5%, p=0.002). Patients in group A exhibited more diabetes (58% vs. 28%, p=0.03), ischemic heart disease (42% vs. 16%, p=0.04), left ventricular hypertrophy (88.8% vs. 33.3%, p<0.001), elevated levels of troponin I, CRP (50% vs. 24%, p=0.05), and low BV/BWL in a lower percentage (8% vs. 32%, p=0.03). After 11.2 +/- 3.5 months, 8 patients (33.3%) had died in group A and 2 (8%) in group B (p=0.02). CONCLUSION: This study demonstrates that BNP is high in HDpts and decreases after HD. It is correlated with a good capacity for plasma refilling, with diabetes, CVD and short-term mortality risk. PMID- 21240868 TI - Choroidopathy in patients with systemic lupus erythematosus with or without nephropathy. AB - BACKGROUND: The aim of this study was to evaluate indocyanine green angiographic findings in patients with systemic lupus erythematosus (SLE) with or without lupus nephritis. In particular, the presence of choroidal abnormalities at indocyanine green angiography (ICG-A) that could not be detected by fluorescein angiography (FAG) was investigated. METHODS: Sixteen patients with SLE underwent simultaneous ICG-A and FAG. Patients were divided into 2 groups based on whether renal disease was present (group A, n=9) or not (group B, n=7). RESULTS: Drusen like deposits were ophthalmoscopically evident in only 1 out of 9 group A patients (11.1%). While FAG disclosed the deposits in 4 out of 9 group A patients (44.4%), drusen-like deposits were otherwise found in all group A patients (100%) by ICG-A. FAG and ICG-A did not show choroidal alterations in group B patients. CONCLUSIONS: ICG-A can provide information that is not detectable by clinical or FAG examination in patients with lupus nephritis (group A). The findings of choroidopathy by ICG-A represent an indicator of ocular involvement and could be an indirect sign of renal involvement. Given that histological lesions may be present where there are no anomalies in urinary sediment and/or proteinuria, the positivity of ICG-A could help in deciding whether or not to carry out a renal biopsy. Therefore, ICG-A could be useful in the screening of patients with SLE, especially where there are no evident signs of renal involvement. PMID- 21240869 TI - Acute kidney injury in pregnancy: the thrombotic microangiopathies. AB - Acute kidney injury (AKI) is a rare but serious complication of pregnancy. Although prerenal and ischemic causes of AKI are most common, renal insufficiency can complicate several other pregnancy-specific conditions. In particular, severe preeclampsia/HELLP syndrome, acute fatty liver of pregnancy (AFLP) and thrombotic thrombocytopenic purpura (TTP) are all frequently complicated by AKI, and share several clinical features which pose diagnostic challenges to the clinician. In this article, we discuss the clinical and laboratory features, pathophysiology and treatment of these 3 conditions, with particular attention to renal manifestations. It is imperative to distinguish these conditions to make appropriate therapeutic decisions which can be lifesaving for the mother and fetus. Typically AFLP and HELLP improve after delivery of the fetus, whereas plasma exchange is the first-line treatment for TTP. PMID- 21240870 TI - Improvement of hypertension and LVH in maintenance hemodialysis patients treated with sustained-release isosorbide mononitrate. AB - BACKGROUND: Hypertension and left ventricular hypertrophy (LVH) are independent predictors of morbidity and mortality in maintenance hemodialysis (MHD) patients. The level of serum asymmetric dimethylarginine (ADMA) is increased in MHD patients, which is a kind of uremic toxin. It can competitively inhibit nitric oxide production from L-arginine, which can increase vascular resistance, then lead to endothelium dysfunction, hypertension, LVH and decrease of ejection fraction. A sustained-release preparation of isosorbide mononitrate can lead to vasodilatation by releasing nitrogen monoxide. But it remains unclear whether oral isosorbide mononitrate in MHD patients can control blood pressure (BP) and reverse LVH. The aim of the present study was to evaluate the safety and efficacy of oral sustained-release isosorbide mononitrate on hypertension and LVH in MHD patients. METHODS: One hundred and forty-four MHD patients with hypertension were enrolled in this perspective, randomized, controlled, single-center trial. All patients accepted antihypertensive drugs at baseline, including renin-angiotensin system inhibitor, calcium channel blocker, beta-receptor blocker or a-receptor blocker. Seventy-two patients (nitrate group) took isosorbide mononitrate 30 mg daily, titered to a maximal dosage of 120 mg daily for 24 weeks. The dosage was adjusted once a week according to BP. The remaining 72 patients (non-nitrate group) did not take nitrate drugs other than antihypertensive drugs. BP, left ventricular mass index (LVMI), heart rate, interdialytic weight gain (IDWG) and hemoglobin (Hb) were monitored. RESULTS: After 4, 8, 12 and 24 weeks of treatment, BP levels decreased in both nitrate and non-nitrate groups. BP in the nitrate group was significantly lower than in the non-nitrate group. But there was no statistical significance in the levels of response rate and control rate of BP between the 2 groups (response rate of BP: 91.4% vs. 86.1%, X2=1.004, p=0.316; control rate of BP: 60.0% vs. 47.2%, X2=2.230, p=0.127). BP before hemodialysis was maintained between 12 and 24 weeks in the nitrate group despite the decrease in total daily category and quantity of hypotensive drugs. At week 24 of treatment, LVMI in the nitrate group was significantly decreased from 65.3 +/- 14.2 g/m2.7 to 51.2 +/- 10.0 g/m2.7, and that in the non-nitrate group was also significantly decreased from 63.7 +/- 16.7 g/m2.7 to 56.1 +/- 13.8 g/m2.7. But LVMI in the nitrate group was significantly lower than that in the non nitrate group. The prevalence of LVH in the nitrate and non-nitrate groups decreased 17.2% and 9.8%, respectively. There was a significant difference in both groups at 24 weeks (X2=4.480, p=0.034). During 24 weeks of follow-up, the incidence of acute left heart failure in the nitrate group was 1.4% (1/70), which was significantly lower than in the non-nitrate group (11.1%, 8/72; X2=5.605, p=0.033). The incidence of adverse events was 1.4%. CONCLUSIONS: Sustained release isosorbide mononitrate, which is safe and well tolerated, can effectively control BP, decrease the category and quantity of hypotensive drugs, improve left ventricular hypertrophy and reduce the incidence of acute left heart failure in MHD patients. PMID- 21240871 TI - Low-grade albuminuria reduction with angiotensin II type 1 receptor blocker in renal transplant recipients. AB - BACKGROUND: Microalbuminuria, defined as urine albumin to urine creatinine ratio of 30 to <300 mg/g, is an established risk factor for cardiovascular morbidity and mortality in the general population. Low-grade albuminuria (<30 mg/g) is considered a marker for subclinical vascular damage that predisposes to future cardiovascular diseases and death. Lowering urinary albumin excretion reduces the risk of cardiovascular disease. Our study was designed to evaluate the influence of angiotensin II type 1 receptor blocker (ARB) in normotensive renal transplant recipients with low-grade albuminuria. PATIENTS AND METHODS: Our 6-month prospective observation study used a randomized control and open-label design as we examined the effects of an ARB (valsartan) on blood pressure, urinary albumin excretion, hematocrit, serum potassium and estimated glomerular filtration rate (eGFR) in normotensive recipients with allografts of more than 1 year. A total of 35 renal transplant recipients were enrolled in this study. Patients were randomly assigned to 2 groups: ARB group (n=18), receiving 40-80 mg valsartan daily for 6 months, and the control group (n=17). RESULTS: In the ARB group, urine albumin excretion was significantly reduced from 25.9 +/- 19.1 mg/g to 12.0 +/- 9.6 mg/g at 6 months after administration. eGFR decreased slightly at 6 months after administration. However, no patients undergoing treatment for adverse effects required discontinuation of ARB. CONCLUSIONS: This study reveals that ARB is safe and reduces low-grade albuminuria in normotensive renal transplant recipients. Thus, early treatment of ARB in recipients with low-grade albuminuria may prevent cardiovascular disease after renal transplantation. PMID- 21240872 TI - Distribution and complications of native arteriovenous fistulas in maintenance hemodialysis patients: a single-center study. AB - BACKGROUND: The aim of this study was to investigate the use of vascular access in maintenance hemodialysis (MHD) patients and the complications of native arteriovenous fistulas (NAVFs) in a Chinese single center. METHODS: Patients (n=376) were recruited in our descriptive cross-sectional study, 350 of them had wrist NAVFs (wrist group),and 18 of them had elbow NAVFs (elbow group). We evaluated the complications associated with NAVFs and the prevalence of high output cardiac failure between these 2 groups. All statistical analyses were performed with the use of the SPSS software package, version 17.0. Data were expressed as means +/- SD; a p value <0.05 was assumed to be statistically significant. RESULTS: We found 97.87% of patients had NAVFs, among them 93.09% (350/376) of patients had wrist NAVFs, followed by elbow NAVFs 4.79% (18/376), while 1.33% (5/376) had graft AVFs and only 0.80% (3/376) of patients depended on a cuff catheter. The most frequent complications seen in our patients were thrombosis (13.86%), followed by aneurysm (12.23%), anastomotic stenosis (2.17%); arterial steal syndrome (1.63%); infection (0.54%); and venous hypertension (0.27%). Aneurysm was more common in the elbow group (66.67%) than in the wrist group (9.43%) (p<0.01). There were no differences in other complications, patency rate during 1-3 years or Kt/V between the 2 groups. We did not find high-output cardiac failure related to NAVFs in our patients. CONCLUSION: The prevalence of complications of NAVFs is high, and greater attention should be paid to the prevention of these complications. Early diagnosis and management of complications related to AVFs is essential to prevent loss of the vascular access. We think the wrist radiocephalic NAVF is the first choice for MHD patients; an elbow NAVF is a reasonable alternative for MHD access when a radiocephalic NAVF is not possible. PMID- 21240873 TI - Good outcomes with cyclosporine very low exposure with everolimus high exposure in renal transplant patients. AB - INTRODUCTION: The aim of the study was to compare efficacy of cyclosporine (CsA) very low exposure with everolimus high exposure, with respect to CsA standard exposure with enteric-coated mycophenolate sodium (EC-MPS) therapy. METHODS: In a randomized, prospective, single-center, open-label study, patients were enrolled to receive either everolimus (C0 (trough level) 8-12 ng/mL) + CsA (C2 (CsA level 2 hours after drug administration) 250-300 ng/mL) + steroids, or EC-MPS (1,440 mg/day) + CsA (C2 500-700 ng/mL) + steroids. Fifty-six patients were enrolled in the everolimus group, 50 in the EC-MPS group. Efficacy was evaluated at 3 and 12 months. RESULTS: Characteristics of groups were similar. Biopsy-proven acute rejection (BPAR) rates were similar in both groups (everolimus 18.8% vs. EC-MPS 18.2%). Everolimus patients had a lower incidence of delayed graft function (DGF) than EC-MPS patients (22.6% vs. 40.9%; p<0.05; relative risk [RR] = 0.65). One year graft survival was 95% in the everolimus group and 88% in the EC-MPS group (p=NS). CsA dose at 1 year was lower in the everolimus group (1.52 +/- 0.67 vs. 2.55 +/- 0.79 mg/kg; p<0.0001). Estimated glomerular filtration rate (eGFR; Cockcroft-Gault) was higher in the everolimus group (81.64 +/- 32.67 vs. 62.62 +/ 22.81 ml/min; p<0.001). Systolic blood pressure was lower in the everolimus group (124.9 +/- 14.64 mm Hg vs. 131.1 +/- 13.23 mm Hg; p=0.03). Hemoglobin blood levels were slightly lower in the everolimus group (12.62 +/- 1.42 vs. 13.01 +/- 1.3 g/L; p=NS; for anemia, RR=1.302). Serum cholesterol was similar in both groups (everolimus 219.1 +/- 47.20 vs. EC-MPS 207.2 +/- 38.8 mg/dL; p=NS), but everolimus patients used more statins (RR=1.49). Twenty-four-hour proteinuria was higher in the everolimus group (519.7 +/- 77.31 vs. 296.7 +/- 33.42 mg/24 hours; p=0.01). CONCLUSIONS: Everolimus regimen compared with EC-MPS regimen is associated with lower incidence of DGF, slightly better 1-year graft survival rate, a significantly higher GFR and lower systolic blood pressure. PMID- 21240874 TI - Marked improvement by high-dose chemotherapy and autologous stem cell transplantation in a case of light chain deposition disease. AB - A 55-year-old woman presented with heavy proteinuria (6.2 g/day) in April 2007. Because monoclonal IgG-k was detected in serum and urine samples, bone marrow aspiration and renal biopsy were performed. She was diagnosed with plasma cell dyscrasia because a bone marrow aspiration specimen showed plasma cells at 6.1%. Renal tissues revealed the formation of nodular glomerulosclerosis which was negative for Congo-red staining. Renal immunohistochemistry showed positive staining for kappa light chains in the nodular lesions, proximal tubules and part of Bowman's capsules. Her renal involvement was diagnosed as light chain deposition disease. Proteinuria disappeared and renal function stabilized after high-dose chemotherapy and autologous stem cell transplantation. It appears that an early initiation of active therapy such as high-dose chemotherapy and autologous stem cell transplantation may be beneficial for patients with light chain deposition disease. PMID- 21240875 TI - Iron isomaltoside 1000: a new intravenous iron for treating iron deficiency in chronic kidney disease. AB - BACKGROUND: Patients with chronic kidney disease (CKD) often suffer from iron deficiency anemia necessitating treatment with intravenous iron. This study was designed to assess the safety of iron isomaltoside 1000 (Monofer) in CKD patients. The secondary objective was to assess its effect on iron deficiency anemia. METHODS: This open-label, noncomparative, multicenter trial assigned 182 patients with CKD (n=161 in dialysis and n=21 in predialysis) to iron isomaltoside 1000 either as 4 intravenous bolus injections of 100-200 mg iron per dose or as a fast high-dose infusion at baseline. Patients were generally undergoing erythropoiesis-stimulating agent (ESA) treatment (82%), and the dosage was to be kept constant during the trial. They were either switched from an existing parenteral maintenance therapy (n=144) or were not currently being treated with parenteral iron (n=38). Frequency of adverse events (AEs) and changes in markers of iron deficiency anemia were measured during 8 weeks from baseline. RESULTS: Nineteen treatment-related AEs occurred in 13 patients (7.1%) and after 584 treatments (3.3%). No anaphylactic or delayed allergic reactions were observed. There were no clinically significant changes in routine clinical laboratory tests or vital signs. Hemoglobin increased from 99.2 g/L (SD=9.0) at baseline to 111.2 g/L (SD=14.7) at week 8 in patients not currently treated with parenteral iron (p<0.001) and increased slightly or stabilized in patients in maintenance therapy. S-Ferritin, s-iron and transferrin saturation increased significantly at all visits. CONCLUSIONS: Iron isomaltoside 1000 was clinically well tolerated, safe and effective. This new intravenous iron may offer a further valuable choice in treating the anemia of CKD. PMID- 21240876 TI - A novel angiogenesis inhibitor, sunitinib malate, in encapsulating peritoneal sclerosis. AB - INTRODUCTION: Encapsulated peritoneal sclerosis (EPS) is characterized by neoangiogenesis and fibrosis. Increased inflammation is the leading cause of EPS. In turn, neoangiogenesis is both a consequence of and contributor to inflammation. The effects of sunitinib, a multitargeted receptor tyrosine kinase inhibitor, have been postulated in various antiangiogenesis, antiinflammatory and antifibrotic processes both in vitro and in vivo. This novel angiogenesis inhibitor, Sutent (sunitinib malate), was investigated in our rat EPS model. MATERIALS AND METHODS: Forty nonuremic Wistar albino rats were divided into 4 groups as follows: 2-mL isotonic saline intraperitoneally (i.p.) daily, for 3 weeks (control group); daily 2 ml/200 g injection i.p. of chlorhexidine gluconate (0.1%) and ethanol (15%) dissolved in saline, 3 weeks (CG group); CG + additional 3 weeks without any treatment, total 6 weeks (resting group); and CG + additional 3 weeks 1 mg/kg daily Sutent (SUT) in drinking water, total 6 weeks (SUT group). At the end of the study, 1-hour PET was performed. Functional parameters and morphological changes of peritoneum with dialysate cytokine levels were examined. RESULTS: SUT renewed ultrafiltration failure, D1/D0 glucose levels and dialysate protein loss. Peritoneal thickness, white blood cell count and inflammation of peritoneum were also decreased with SUT treatment. SUT significantly improved overexpression of dialysate transforming growth factor-beta1, monocyte chemoattractant protein-1 and vascular endothelial growth factor (VEGF) levels as compared with resting group. CONCLUSION: In conclusion, SUT might preserve membrane viability even at lower dosages. Although this is an experimental study, we believe that SUT after controlled trials may be a therapeutic agent for long term peritoneal dialysis patients. PMID- 21240877 TI - Homocysteine-dependent endothelial dysfunction induced by renal ischemia/reperfusion injury. AB - BACKGROUND: Elevation of serum homocysteine is considered to contribute to endothelial dysfunction, which is considered to be the initial event in vascular disease following renal transplantation. We sought to investigate whether an association existed between serum homocysteine levels and endothelial dysfunction after renal ischemia/reperfusion (I/R) injury. MATERIALS AND METHODS: Acetylcholine (Ach)-induced endothelium-dependent and sodium nitroprusside (SNP) induced endothelial-independent relaxation responses were determined in thoracic aortas from different I/R groups. A correlation analysis was performed between Ach responses and homocysteine levels. RESULTS: Long-term I/R injury decreased the responses to acetylcholine and the pD2 values of the concentration response curves compared with controls. While vascular responses to SNP were unchanged among all groups. Homocysteine levels correlated with the pD2 values of acetylcholine among control and I/R groups, indicating that the increase in homocysteine was associated with decreased sensitivity to acetylcholine. In short term I/R rats, no association was observed between these parameters. CONCLUSION: These data suggest a possible link between serum homocysteine and decreased vascular reactivity to endothelium-dependent relaxation in I/R aorta. PMID- 21240901 TI - Biochemical and metabolomic phenotyping in the identification of a vitamin D responsive metabotype for markers of the metabolic syndrome. AB - SCOPE: Metabolic phenotyping promises to be a useful tool in human intervention studies. This study examined whether metabolic phenotyping could identify responders to vitamin D supplementation in terms of the metabolic syndrome. METHODS AND RESULTS: In a double-blind, randomised placebo-controlled dietary intervention subjects were assigned to receive 15 MUg vitamin D(3) or placebo daily. Serum 25-hydroxyvitamin D (25(OH)D) and biochemical markers of the metabolic syndrome were measured at baseline and following the 4-wk intervention. k-means clustering and (1) H-NMR metabolomic analysis were used to explore responsive phenotypes. Vitamin D supplementation significantly increased serum 25(OH)D to an endpoint concentration of 78.1 +/- 20.0 nmol/L (p<0.001). There was no effect of supplementation on the measured markers of the metabolic syndrome. k means cluster analysis based on 13 biochemical markers of the metabolic syndrome and 25(OH)D concentrations revealed five discrete biomarker clusters. One of these clusters, characterised by lower serum 25(OH)D and higher levels of adipokines, showed significant responses in insulin (15% decrease), homestatic model assessment scores (19% decrease) and c-reactive protein (54% decrease). Metabolomic analysis revealed further changes and the extent of change in serum vitamin D correlated negatively with changes in glucose. CONCLUSION: Overall, metabolic phenotyping revealed a phenotype that was responsive to vitamin D supplementation. PMID- 21240902 TI - Antiglycative and neuroprotective activity of colon-derived polyphenol catabolites. AB - SCOPE: Dietary flavonoids and allied phenolic compounds are thought to be beneficial in the control of diabetes and its complications, because of their ability to inhibit oxidative stress, protein glycation and to act as neuroprotectants. Following ingestion by humans, polyphenolic compounds entering the large intestine undergo extensive metabolism by interaction with colonic microbiota and it is metabolites and catabolites of the parent compounds that enter the circulatory system. The aim of this study was to investigate the inhibitory activity of some colonic microbiota-derived polyphenol catabolites against advanced glycation endproducts formation in vitro and to determine their ability, at physiological concentrations, to counteract mild oxidative stress of cultured human neuron cells. METHODS AND RESULTS: This study demonstrated that ellagitannin-derived catabolites (urolithins and pyrogallol) are the most effective antiglycative agents, whereas chlorogenic acid-derived catabolites (dihydrocaffeic acid, dihydroferulic acid and feruloylglycine) were most effective in combination in protecting neuronal cells in a conservative in vitro experimental model. CONCLUSION: Some polyphenolic catabolites, generated in vivo in the colon, were able in vitro to counteract two key features of diabetic complications, i.e. protein glycation and neurodegeneration. These observations could lead to a better control of these events, which are usually correlated with hyperglycemia. PMID- 21240911 TI - Correlation between pre- and postnatal cerebral magnetic resonance imaging. AB - OBJECTIVES: To evaluate the diagnostic accuracy of fetal cerebral magnetic resonance imaging (MRI) on a large cohort and to compare pre- and postnatal MRI data. METHODS: This prospective study included all cases referred to our unit for fetal cerebral MRI examination between June 2006 and December 2009 and which underwent at least one postnatal MRI examination. Cases in which there was termination of pregnancy, fetal death or stillbirth were excluded. The pre- and postnatal diagnoses established by MRI were compared and divided into five subgroups: same diagnosis on pre- and postnatal MRI (Group 1); same diagnosis but different appearance related to the natural course of the disease (Group 2); different diagnosis (related to limitations of fetal MRI) (Group 3); same diagnosis but with additional findings discovered on postnatal MRI examination (Group 4); or same diagnosis but different appearance related to the natural course of the disease (as in Group 2) and associated with additional findings discovered on postnatal MRI examination (Group 5). The prognostic impact of a possible disagreement between pre- and postnatal findings was evaluated. RESULTS: One hundred fetuses were included. Fetal MRI was performed at a mean gestational age of 33 (range, 24-39) weeks and postnatal MRI at a mean age of 3.5 months. There were 53 cases classified as Group 1, 32 in Group 2, four in Group 3, 10 in Group 4 and one in Group 5. Thus, in 15 cases (Groups 3-5), there were discrepancies between pre- and postnatal findings (mostly related to corpus callosum anatomy, cortical and migration disorders). The discrepancy was judged to have a prognostic impact in 9/15 cases. Two postnatal MRI examinations were performed in eight cases, in one of which the second examination showed subependymal heterotopia which were not detectable on the first examination. CONCLUSION: Pre- and postnatal MRI data showed good agreement in 85% of cases. There was disagreement with a prognostic impact in 9% of cases. PMID- 21240915 TI - Maternal cardiac function in normal twin pregnancy: a longitudinal study. AB - OBJECTIVE: To investigate maternal cardiac function in a cohort of uncomplicated twin gestations assessed longitudinally. METHODS: Women with twin pregnancies were enrolled prospectively and underwent serial maternal echocardiography at 20 23 weeks, 26-29 weeks and 30-33 weeks of gestation. Patients were excluded if any of these complications occurred after recruitment: delivery < 34 weeks; pre eclampsia or gestational hypertension; small-for-gestational age neonates (birth weight of one or both twins < 5(th) centile for gestational age). Cardiac findings were compared with those obtained at the same gestational age periods in a group of singleton gestations. RESULTS: A group of 20 uncomplicated twin gestations was obtained for analysis and 10 singleton pregnancies were then selected as controls. At each visit, mean +/- SD cardiac output (CO) was significantly higher in twins than in singletons (6.55 +/- 0.82 vs 5.62 +/- 0.82 L/min, P = 0.007 at 20-23 weeks; 7.31 +/- 0.74 vs 6.39 +/- 0.74 L/min, P = 0.003 at 26-29 weeks; 7.50 +/- 0.89 vs 6.68 +/- 0.65 L/min, P = 0.015 at 30-33 weeks), whereas total vascular resistance (TVR) was lower (1005 +/- 137 vs 1179 +/- 199 dynes * s/cm(5) , P = 0.009 at 20-23 weeks; 924 +/- 100 vs 1070 +/- 138 dynes * s/cm(5), P = 0.003 at 26-29 weeks; 929 +/- 96 vs 1031 +/- 122 dynes * s/cm(5), P = 0.018 at 30-33 weeks). In both twins and singletons, CO showed a significant increase while TVR decreased significantly throughout the assessed pregnancy time period. CONCLUSION: In twin gestation, maternal cardiac function apparently undergoes more profound changes compared with in singleton gestation, as testified by higher CO and lower TVR values at each stage of pregnancy starting from the mid-trimester. PMID- 21240916 TI - Medial and lateral perforant path evoked potentials are selectively modulated by pairing with glutamatergic activation of locus coeruleus in the dentate gyrus of the anesthetized rat. AB - Norepinephrine (NE) in vitro produces long-lasting potentiation of medial perforant path input and depression of lateral perforant path input to dentate gyrus in the rat. Similar, but highly transient, effects have been reported in vivo using paragigantocellular stimulation to release NE. The present study uses alternate stimulation of the medial perforant path and lateral olfactory tract (eliciting a lateral perforant path-evoked potential) to examine the effects of glutamatergic activation of locus coeruleus (LC) on the two pathways for up to 3 h post-LC activation. In the first experiment, the expected potentiation of the medial perforant path population spike in dentate gyrus was observed, but without accompanying depression of the lateral perforant path-mediated evoked potential (lateral olfactory tract stimulation, 60 s ISI). In a second experiment, with more frequent pairing of input with NE release (10 s ISI), significant potentiation of lateral perforant path-mediated input to dentate gyrus occurred, but potentiation of medial perforant path input was not seen. A third experiment with a 30 s ISI again produced potentiation of lateral perforant path-mediated input without potentiation of the medial perforant path population spike. The size of effects with the 30 s ISI was intermediate between that seen with 10 s and 60 s ISI. Potentiation of lateral perforant path over medial perforant path input has previously been reported with acute nicotinic activation of the LC. This outcome also resembles heterosynaptic modulation previously reported with tetanic potentiation. The data argue for a competitive relationship between medial and lateral perforant path inputs to dentate gyrus and suggest pairing with increased NE produces a bias favoring one or the other pathway depending on parameters such as strength and frequency. NE potentiating effects on lateral perforant path input here may also have occurred in entorhinal cortex (EC) given the system-wide NE release with LC activation. PMID- 21240917 TI - Differential involvement of protein synthesis and actin rearrangement in the reacquisition of contextual fear conditioning. AB - Extinction learning is associated with a decline of the conditioned fear response (CR). However, re-exposure to the unconditioned stimulus (US, shock) is associated with the return of the fear response. This study aimed to study the role of protein synthesis and actin rearrangement in the CA1 hippocampal subregion and the basolateral amygdala (BLA) in acquisition and reacquisition of contextual fear conditioning. To that end, we trained rats on contextual fear conditioning and extinction, and on the last extinction training session we reconditioned the animals by re-exposure to the US. Immediately after, rats were microinfused with the protein synthesis inhibitor anisomycin or the actin rearrangement inhibitor cytochalasin D into either the BLA or the CA1. The results of this study show differential involvement of anisomycin and cytochalasin D in the acquisition and reacquisition of contextual fear conditioning. Specifically, while the microinfusion of anisomycin into the BLA or the CA1 immediately after reconditioning of fear did not inhibit the return of fear, the microinfusion of cytochalsin D into either the BLA or the CA1 attenuated fear responses. Interestingly, the initial acquisition of contextual fear memory is dependent on intra-BLA and CA1 protein synthesis and cytoskeletal rearrangement, since the microinfusion of these drugs blocked the formation of long-term fear memory. The results suggest that the two processes of acquisition and reacquisition of fear are not identical and they engage different mechanisms. PMID- 21240918 TI - Drebrin A expression is altered after pilocarpine-induced seizures: time course of changes is consistent for a role in the integrity and stability of dendritic spines of hippocampal granule cells. AB - We used a pathophysiological model of temporal lobe epilepsy induced by pilocarpine in adult rats in order to assess the in vivo role of drebrin A (DA), one of the major regulators of F-actin. This model displays a dynamic reorganization of the glutamatergic network including neo-spinogenesis, morphogenesis, and neo-synaptogenesis associated with an aberrant sprouting of granule cell axons in the dentate gyrus (DG). This reactive plasticity contributes in dentate granule-cell hyperexcitability that could lead to the emergence of recurrent spontaneous seizures. We investigated the hippocampal DA expression changes in pilocarpine animals using immunohistochemical, Western blot, and in situ hybridization analyses. We showed that DA immunoreactivity was decreased in the inner molecular layer (IML) and in the hilus (H) of the DG, at latent stage, when spinogenesis and morphogenesis occur. Western blot analysis confirmed these overall hippocampal decreases of DA protein expression. At chronic stage, when newly formed glutamatergic synapses are being established, the levels of immunolabeling for DA in the H and the IML were similar to control rats. This recovery is likely due to the increase of DA mRNA in perikarya of hilar and granule cells. Interestingly, our data showed that the changes pattern of labeling for Bassoon, a specific marker for presynaptic active zone, in the IML of pilocarpine-treated animals paralleled those found for DA at all time points examined. Furthermore, our double and triple immunofluorescence studies showed that the recovery in DA levels in the IML occurred within the dendritic spines involved in glutamatergic active synapses of presumed granule cells. Altogether, our results indicate that in vivo DA is not critical for spinogenesis and morphogenesis but instead is consistent with an involvement in synaptic structural integrity, stabilization, and function. Thus, DA appears as a novel modulator of reactive synaptic plasticity associated with epilepsy. PMID- 21240919 TI - Sprouty2 and -4 regulate axon outgrowth by hippocampal neurons. AB - Sprouty proteins act as negative feedback inhibitors of fibroblast growth factor (FGF) signaling. FGFs belong to the neurotrophic factors and are involved in axonal growth during development and repair. We investigated the expression of Sprouty isoforms in hippocampal neurons as well as the regulation of Sprouty2 and -4 during development and their role in axon growth. Sprouty2 and -4 were located in the nucleus, the cytoplasm, in dendrites, and axons of hippocampal neurons concentrated in growth cones. During development in vivo and differentiation in vitro, expression of Sprouty2 and -4 was gradually downregulated in hippocampal neurons. Between 5 and 24 days in culture expression of both Sprouty isoforms was reduced by 70%. In vivo expression of Sprouty2 was reduced by 79% and of Sprouty4 by 93% on postnatal day 14 compared to embryonic day 16.5. Downregulation of Sprouty2 and -4 by shRNAs strongly promoted elongative axon growth by cultured hippocampal neurons, which was further increased by FGF-2 treatment. In addition, FGF-2 reduced expression of Sprouty2 by 33% and of Sprouty4 by 44%. Together, our results imply that Sprouty2 and -4 are downregulated in the hippocampus during postnatal brain development and that they can act as regulators of developmental axon growth. PMID- 21240921 TI - Adult hippocampal glucocorticoid receptor expression and dentate synaptic plasticity correlate with maternal care received by individuals early in life. AB - Maternal care in mammals is the prevailing environmental influence during perinatal development. The adult rat offspring of mothers exhibiting increased levels of pup licking/grooming (LG; High LG mothers), compared to those reared by Low LG dams, show increased hippocampal glucocorticoid receptor expression, complex dendritic tree structure, and an enhanced capacity for synaptic potentiation. However, these data were derived from studies using the total amount of maternal care directed toward the entire litter, thus ignoring possible within-litter variation. We show that the amount of LG received by individual pups within a litter varies considerably. Therefore, we questioned if the amount of LG received by individual pups correlates with and thus putatively predicts later hippocampal structure and function. To this end, LG-scores were determined during the first postnatal week for all pups in 32 litters and correlated with neuroendocrine and hippocampal parameters in young-adulthood. Pup LG-score positively correlated with the glucocorticoid receptor mRNA expression in the adult hippocampus. Moreover, the ability to induce synaptic potentiation in the dentate gyrus in vitro was enhanced in animals with high LG-scores. Structural plasticity correlated less reliably with LG-scores early in life and differed between sexes. Male offspring with high LG-scores displayed fewer newborn neurons, higher brain derived neurotrophic factor expression and tended to have more complex granule cell dendritic trees. We conclude that even moderate variations in early life environment have a major impact on adult hippocampal function. This principle could provide a mechanistic basis for individual differences in susceptibility to psychopathology. PMID- 21240920 TI - Functional division of hippocampal area CA1 via modulatory gating of entorhinal cortical inputs. AB - The hippocampus receives two streams of information, spatial and nonspatial, via major afferent inputs from the medial (MEC) and lateral entorhinal cortexes (LEC). The MEC and LEC projections in the temporoammonic pathway are topographically organized along the transverse-axis of area CA1. The potential for functional segregation of area CA1, however, remains relatively unexplored. Here, we demonstrated differential novelty-induced c-Fos expression along the transverse-axis of area CA1 corresponding to topographic projections of MEC and LEC inputs. We found that, while novel place exposure induced a uniform c-Fos expression along the transverse-axis of area CA1, novel object exposure primarily activated the distal half of CA1 neurons. In hippocampal slices, we observed distinct presynaptic properties between LEC and MEC terminals, and application of either DA or NE produced a largely selective influence on one set of inputs (LEC). Finally, we demonstrated that differential c-Fos expression along the transverse axis of area CA1 was largely abolished by an antagonist of neuromodulatory receptors, clozapine. Our results suggest that neuromodulators can control topographic TA projections allowing the hippocampus to differentially encode new information along the transverse axis of area CA1. PMID- 21240922 TI - How to quantify protein diffusion in the bacterial membrane. AB - Lateral diffusion of proteins in the plane of a biological membrane is important for many vital processes, including energy conversion, signaling, chemotaxis, cell division, protein insertion, and secretion. In bacteria, all these functions are located in a single membrane. Therefore, quantitative measurements of protein diffusion in bacterial membranes can provide insight into many important processes. Diffusion of membrane proteins in eukaryotes has been studied in detail using various experimental techniques, including fluorescence correlation spectroscopy (FCS), fluorescence recovery after photobleaching (FRAP), and particle tracking using single-molecule fluorescence (SMF) microscopy. In case of bacteria, such experiments are intrinsically difficult due to the small size of the cells. Here, we review these experimental approaches to quantify diffusion in general and their strengths and weaknesses when applied to bacteria. In addition, we propose a method to extract multiple diffusion coefficients from trajectories obtained from SMF data, using cumulative probability distributions (CPDs). We demonstrate the power of this approach by quantifying the heterogeneous diffusion of the bacterial membrane protein TatA, which forms a pore for the translocation of folded proteins. Using computer simulations, we study the effect of cell dimensions and membrane curvature on measured CPDs. We find that at least two mobile populations with distinct diffusion coefficients (of 7 and 169 nm(2) ms( 1) , respectively) are necessary to explain the experimental data. The approach described here should be widely applicable for the quantification of membrane protein diffusion in living bacteria. PMID- 21240928 TI - Rotationally resolved electronic spectroscopy of 1,4-benzodioxan: the anomeric effect in the ground and electronically excited state. AB - We measured the rotationally resolved electronic spectra of the origin and of three vibronic bands of 1,4-benzodioxan. From comparison to various ab-initio calculated structures of 1,4-benzodioxan, the twisted C(2) symmetric 1,4 benzodioxan was shown to be responsible for all the observed spectral features. We analyzed the inertial defects in both electronic states as sensitive indicators of the non-planarity of the system. The molecule was found to be more planar in the electronic ground state than in the electronically excited singlet state. This effect can be traced back to an increased puckering of the dioxan ring, which also comprises the oxygen atoms, in the excited state. This observation is discussed in terms of natural bond orbitals. PMID- 21240947 TI - Issue editor's notes. New media and technology: youth as content creators. PMID- 21240949 TI - Beyond computer literacy: supporting youth's positive development through technology. AB - In a digital era in which technology plays a role in most aspects of a child's life, having the competence and confidence to use computers might be a necessary step, but not a goal in itself. Developing character traits that will serve children to use technology in a safe way to communicate and connect with others, and providing opportunities for children to make a better world through the use of their computational skills, is just as important. The Positive Technological Development framework (PTD), a natural extension of the computer literacy and the technological fluency movements that have influenced the world of educational technology, adds psychosocial, civic, and ethical components to the cognitive ones. PTD examines the developmental tasks of a child growing up in our digital era and provides a model for developing and evaluating technology-rich youth programs. The explicit goal of PTD programs is to support children in the positive uses of technology to lead more fulfilling lives and make the world a better place. This article introduces the concept of PTD and presents examples of the Zora virtual world program for young people that the author developed following this framework. PMID- 21240950 TI - Educational technology, reimagined. AB - "Educational technology" is often equated in the popular imagination with "computers in the schools." But technology is much more than merely computers, and education is much more than mere schooling. The landscape of child-accessible technologies is blossoming in all sorts of directions: tools for communication, for physical construction and fabrication, and for human-computer interaction. These new systems and artifacts allow educational designers to think much more creatively about when and where learning takes place in children's lives, both within and outside the classroom. PMID- 21240951 TI - Children as codesigners of new technologies: valuing the imagination to transform what is possible. AB - The technological complexity and richness of a child's environment today is far beyond what any adults today experienced when they were growing up. For example, no adult today knows what it is like to be a four-year-old using his or her first iPhone app or Webkinz account. Therefore, we seek ways to understand what children need in today's new technologies even without ourselves being children. Since 1999, young people ages seven to eleven have been the author's partners in codesigning new educational technologies at the University of Maryland's Human Computer Interaction Lab. This work has helped inform who children are--what matters to them, what technologies need to be changed, and what needs to be built for the future. This work uses cooperative inquiry, a set of codesign methods that can enable adults and children to share their ideas while minimizing the differences in age and communication styles. This article describes low-tech methods for brainstorming, offering feedback, and supporting creative change in technology prototype designs. Examples of technologies are discussed and insights from children shared. PMID- 21240952 TI - Content creation in virtual worlds to support adolescent identity development. AB - Virtual worlds are online graphical environments that are becoming an increasingly large part of the online experience of young people. Virtual worlds have the potential to become one additional environment, like school, home, and the playground, where youth can learn, play, and grow. The physical world is becoming interconnected with virtual worlds, and it is important for researchers to understand how this will affect children's development. Virtual worlds technologies provide a unique opportunity to allow youth to explore many types of content creation, including customizable avatars, media galleries, and virtual representations of personal spaces. This ability for youth to create content can be an important means by which to support and encourage adolescent identity development. PMID- 21240953 TI - Youth as content producers in a niche social network site. AB - Most U.S. teenagers participate in online social network sites, devoting hours to these networks, often at the expense of other leisure-time activities. This article describes young people's activities within one topic-focused niche network, outlining its unique features and the role of young people as content producers within and beyond the space. Links between youth's online contributions and their interest, self-expression, social connections, and civic involvement are discussed. PMID- 21240954 TI - YouTube as a participatory culture. AB - There is an explosion of youth subscriptions to original content-media-sharing Web sites such as YouTube. These Web sites combine media production and distribution with social networking features, making them an ideal place to create, connect, collaborate, and circulate. By encouraging youth to become media creators and social networkers, new media platforms such as YouTube offer a participatory culture in which youth can develop, interact, and learn. As youth development researchers, we must be cognizant of this context and critically examine what this platform offers that might be unique to (or redundant of) typical adolescent experiences in other developmental contexts. PMID- 21240955 TI - Making projects, making friends: online community as catalyst for interactive media creation. AB - To become full and active participants in today's technologically saturated society, young people need to become creators (and not just consumers) of interactive media. Developing the requisite abilities and capacities is not a wholly individual process; it is important for young people to have access to communities where they can collaborate and share ideas. This article uses the Scratch online community for exploring how different forms of participation and collaboration can support and shape the ways in which young people develop as creators of interactive media. We describe participation in this community in terms of a spectrum ranging from socializing to creating and present examples of three forms of collaboration within the community. We argue that the most exciting interactive media creation and valuable learning experiences are taking place in the middle space, where participants draw on the best of socializing and creating practices. PMID- 21240956 TI - Augmenting your own reality: student authoring of science-based augmented reality games. AB - Augmented Reality (AR) simulations superimpose a virtual overlay of data and interactions onto a real-world context. The simulation engine at the heart of this technology is built to afford elements of game play that support explorations and learning in students' natural context--their own community and surroundings. In one of the more recent games, TimeLab 2100, players role-play citizens of the early 22nd century when global climate change is out of control. Through AR, they see their community as it might be nearly one hundred years in the future. TimeLab and other similar AR games balance location specificity and portability--they are games that are tied to a location and games that are movable from place to place. Focusing students on developing their own AR games provides the best of both virtual and physical worlds: a more portable solution that deeply connects young people to their own surroundings. A series of initiatives has focused on technical and pedagogical solutions to supporting students authoring their own games. PMID- 21240957 TI - Developing technological initiatives for youth participation and local community engagement. AB - Recent advances in technology are transforming our lives, but in many cases they are also limiting the way children are exposed to local communities and physical spaces. Technology can help young people actively connect with their neighborhoods, but doing that requires different methods and tools from the ones typically available in schools, homes, and youth centers. This article introduces a theoretical framework describing the technical and nontechnical elements that must be considered in the implementation of technology initiatives for youth participation and local community engagement. The article then describes the application of the framework in two multiyear initiatives. PMID- 21240958 TI - "MXing it up": how African adolescents may affect social change through mobile phone use. AB - This chapter outlines mobile phone use among African (particularly South African) adolescents. With an estimated 350 million active mobile phone subscriptions, improving network infrastructure, low-cost Internet-ready handsets, innovative programs and applications, mobiles in Africa, and their increasingly younger, increasingly poorer, and increasingly savvy users have the potential to act as conduits for local and regional socially just change. This broad-based connectedness not only provides access to information, but also, and crucially, connects individuals and their social, intellectual, and financial capital. It may represent a powerful, transformative shift in a region where access to similar technologies was historically limited to a privileged few. In order to best leverage these developments and opportunities to promote socially just change, I argue that future mobile-based programs or initiatives in the region should be based in both contemporary developmental systems theory as well as current, popular mobile applications and services. PMID- 21240959 TI - El Silencio: a rural community of learners and media creators. AB - A one-to-one learning environment, where each participating student and the teacher use a laptop computer, provides an invaluable opportunity for rethinking learning and studying the ways in which children can program computers and learn to think about their own thinking styles and become epistemologists. This article presents a study done in a rural school in Costa Rica in which students used computers to create media. Three important components of the work are described: (1) student-owned technology that can accompany students as they interact at home and in the broader community, (2) activities that are designed with sufficient scope to encourage the appropriation of powerful ideas, and (3) teacher engagement in activity design with simultaneous support from a knowledge network of local and international colleagues and mentors. PMID- 21240962 TI - In memoriam. Professor Emeritus Jean Montreuil (1920-2010). A lifetime dedicated to the progress of science and education. PMID- 21240965 TI - Evaluation of balance and improvement of proprioception by repetitive muscle vibration in a 15-year-old girl with joint hypermobility syndrome. PMID- 21240966 TI - Pneumocystis jiroveci pneumonia in giant cell arteritis: A case series. AB - OBJECTIVE: To describe the clinical presentation, laboratory findings, and outcome of patients with Pneumocystis jiroveci pneumonia (PCP) and biopsy-proven giant cell arteritis (GCA) seen at a tertiary referral center. METHODS: Using International Classification of Diseases, Ninth Revision codes, all patients with GCA and PCP between January 1, 1976 and December 31, 2008 were identified. Medical records were reviewed. PCP was defined by the identification of Pneumocystis jiroveci organisms in the clinical setting of pneumonia. RESULTS: We identified 7 patients with GCA (5 women and 2 men) who developed PCP (the mean +/ SD age at diagnosis was 71.6 +/- 6.1 years). The median time from GCA diagnosis to PCP diagnosis was 3 months (range 1-18 months). All patients were taking prednisone (the median dosage 50 mg/day [range 30-80]) when diagnosed as having PCP. No patients were receiving PCP prophylaxis. PCP was diagnosed by positive smear on bronchoalveolar lavage fluid in 6 patients (86%) and by positive sputum polymerase chain reaction in 1 patient. All the patients were hospitalized (median duration 17 days [range 12-39 days]). Four patients (57%) were admitted to the intensive care unit. Three patients (43%) required mechanical ventilation. Two patients (29%) died; both were on mechanical ventilation. CONCLUSION: Although PCP is rare among patients with GCA, this preventable infection is associated with significant morbidity and mortality. PMID- 21240982 TI - Treatment and outcome of parosteal osteosarcoma: biological versus endoprosthetic reconstruction. AB - BACKGROUND AND OBJECTIVES: Due to its good prognosis despite local recurrence, more and less invasive methods for surgical treatment of parosteal osteosarcoma (POS) have been described. Aim of this retrospective single-center study was to investigate differences in outcome after biological and prosthetic reconstruction. METHODS: A total of 28 patients with POS, 14 females, 14 males, mean age of 27 years (median, 24 years; range 15-59 years), mean follow-up of 130 months (median, 104 months; range, 9-383 months), underwent wide tumor resection and prosthetic reconstruction (12 patients, 42.9%), less extensive resection and biological reconstruction (11 patients, 39.3%), rotationplasty (three patients, 10.7%), or amputation (two patients, 7.1%). RESULTS: There were two cases of local recurrence in patients with biological reconstruction and three cases of pulmonary metastases, leading to death of disease in two. Ten-year disease specific survival was 91.1%. There was no significant difference between prosthetic and biological reconstruction in terms of local recurrence, metastasis, or functional outcome (mean MSTS Score, 85%). There were significantly more revisions in prosthetic reconstructions. CONCLUSIONS: Given that the resection of the tumor has clear margins, both prosthetic and biological reconstruction show similar results; prostheses allow better local tumor control, however, require more revisions over time. PMID- 21240977 TI - Transdermal and oral dl-methylphenidate-ethanol interactions in C57BL/6J mice: transesterification to ethylphenidate and elevation of d-methylphenidate concentrations. AB - We tested the hypothesis that C57BL/6J mice will model human metabolic interactions between dl-methylphenidate (MPH) and ethanol, placing an emphasis on the MPH transdermal system (MTS). Specifically, we asked: (1) will ethanol increase d-MPH biological concentrations, (2) will MTS facilitate the systemic bioavailability of l-MPH, and (3) will l-MPH enantioselectively interact with ethanol to yield l-ethylphenidate (l-EPH)? Mice were dosed with MTS (1/4 of a 12.5 cm(2) patch on shaved skin) or a comparable oral dl-MPH dose (7.5 mg/kg), with or without ethanol (3.0 g/kg), and then placed in metabolic cages for 3 h. MPH and EPH isomer concentrations in blood, brain, and urine were analyzed by gas chromatographic-mass spectrometry monitoring of N-(S)-prolylpiperidyl fragments. As in humans, MTS greatly facilitated the absorption of l-MPH in this mouse strain. Similarly, ethanol led to the enantioselective formation of l-EPH and to an elevation in d-MPH concentrations with both MTS and oral MPH. Although only guarded comparisons between MTS and oral MPH can be made due to route-dependent drug absorption rate differences, MTS was associated with significant MPH-ethanol interactions. Ethanol-mediated increases in circulating concentrations of d-MPH carry toxicological and abuse liability implications should this animal model hold for ethanol-consuming attention-deficit hyperactivity disorder patients or coabusers. PMID- 21240983 TI - Is neoadjuvant chemotherapy prior to radio-chemotherapy beneficial in T4 anal carcinoma? AB - BACKGROUND: This study retrospectively describes the outcome of a series of 38 patients (pts) with T4 anal carcinoma exclusively treated by radio and chemotherapy. PATIENTS AND METHODS: From 1992 to 2007, 38 pts with UST4-N0-2-M0 anal carcinoma were treated with exclusive radiotherapy and chemotherapy. All patients received external beam radiotherapy (EBRT) (median dose 45 Gy) with a concomitant chemotherapy (5-fluorouracil-cisplatin). Eleven patients received neo adjuvant chemotherapy (5-fluorouracil-cisplatin). After 2-8 weeks, a 15-20 Gy boost was delivered either with EBRT (20 pts) or interstitial (192)Ir brachytherapy (18 pts). Mean follow-up was 66 months. RESULTS: After chemoradiation therapy (CRT), 13 pts (34%) had a complete response, 23 pts (60%) a response >50% (2 pts were not evaluated). The 5-year-disease-free survival was 79.2 +/- 6.5%, and the 5-year overall survival was 83.9 +/- 6%. Eight patients developed tumor progression (mean delay 8.8 months), six of them requiring a salvage surgery with definitive colostomy for local relapse. Late severe complication requiring colostomy was observed in 2 pts. The 5-year-colostomy-free survival was 78 +/- 6.9%. Patients who received primary chemotherapy had a statistically significant better 5-year colostomy-free survival (100% vs. 38 +/- 16.4%, P = 0.0006). CONCLUSION: T4 anal carcinoma can be treated with a curative intent using a sphincter-sparing approach of CRT, and neo-adjuvant chemotherapy should be considered prior to radiotherapy. PMID- 21240986 TI - Extra-gastrointestinal stromal tumor of the pancreas: clinical characteristics, diagnosis, treatment, and outcome. PMID- 21240987 TI - Monitoring response to neo-adjuvant chemotherapy with F-18 FDG PET/CT. PMID- 21240988 TI - Expression of nuclear receptor DAX-1 and androgen receptor in human breast cancer. AB - BACKGROUND: The functions of nuclear receptor DAX-1 and androgen receptor (AR) in breast cancer are unknown and have not been well-characterized in terms of their importance as a predictive or a prognostic factor. The study investigated the relationship between expression of AR, DAX-1, and clinicopathological factors in primary breast cancer patients. METHODS: The data of 476 breast cancer patients who were treated at Seoul St. Mary's hospital from January 2004 to March 2006 were reviewed. Among them, 169 cases (35.5%) were consecutively evaluated for AR and DAX-1 expression. RESULTS: DAX-1 expression was associated with smaller tumor size; earlier disease stage; and higher expression of estrogen receptor (ER), progesterone receptor (PgR) and AR. AR was significantly expressed in patients with smaller tumor size and higher expression of ER, PgR, and DAX-1. In the subgroup analysis of triple negative breast cancer patients, the expression rate of DAX-1 (4/12, 33.3%) was higher than AR (1/12, 8.3%). CONCLUSIONS: The present review revealed a very high expression rate of DAX-1 in human breast cancer (74%). DAX-1 might modify steroidogenic hormone systems like as AR, estrogen receptor, and progesterone receptor. DAX-1 might be a more effective target than AR for triple negative breast cancer. PMID- 21240989 TI - Goblet cell carcinoids at extraappendiceal locations of gastrointestinal tract: an underrecognized diagnostic pitfall. AB - BACKGROUND: Goblet cell carcinoid (GCC) is a clinicopathologically distinctive tumor that typically arises in appendix and metastasizes frequently. Although rare cases of ostensibly primary extraappendiceal GCC (EGCC) have been reported, the distinction from extraappendiceal metastasis of occult appendiceal primary may be problematic and has not been dealt with systematically in literature. METHODS: We reviewed our combined experience with EGCC at four North American hospitals and reevaluated all EGCC cases published in literature. RESULTS: We encountered 16 cases that were initially reported as EGCC. Five cases presented with disseminated abdominopelvic spread, nine cases with mass lesions in stomach, ileum, cecum, ascending colon, hepatic flexure, sigmoid, and rectum. One case was found incidentally in an ascending colon adenomatous polyp. A negative appendix was confirmed in 2 (12.5%) cases, whereas a primary appendiceal GCC was discovered in 4 (25%) cases at a later date, and appendix was not available for review in 10 cases (62.5%). Of 10 cases of EGCC found in literature, the tumor sites included stomach, duodenum, jejunum, ileum, cecum, splenic flexure, and rectum. Primary appendiceal tumor was excluded histologically in one (10%), grossly in three (30%), and not at all in six (60%). Nine of our cases were initially misdiagnosed as signet-ring cell adenocarcinomas. CONCLUSIONS: True EGCC is extremely rare. GCC found at locations other than appendix are most likely extraappendiceal presentations of appendiceal primary. A thorough review of the pathologic status of appendix should be a mandatory diagnostic criterion and should always be documented in the pathology reports. PMID- 21240990 TI - PML protein as a prognostic molecular marker for patients with esophageal squamous cell carcinomas receiving primary surgery. AB - BACKGROUND AND OBJECTIVES: We evaluated the clinicopathological associations and prognostic implications of promyelocytic leukemia gene (PML) expressions in patients with esophageal squamous cell carcinomas (ESCC) receiving primary surgery. METHODS: Expression patterns of PML and tumor protein 53 (TP53) of 132 cases of ESCC were evaluated by immunohistochemistry and correlated with clinicopathological parameters. The Cox proportional hazards model was used to determine the prognostic influence of clinicopathological factors on progression free survival (PFS) and overall survival (OS). RESULTS: Forty-two cases (31.82%) were classified as lost expression of PML, 25 (18.94%) as focally positive, and 65 (49.24%) as diffusely expressed. Sixty-three cases (47.73%) were classified as over-expression of TP53. High expression of TP53 and down-regulation of PML were often found in advanced disease; and, in together with high pathological staging, grading, and positive margin, were associated with poor survival. However, only tumor differentiation (P = 0.016), distant metastasis (P = 0.001), and PML expression (P = 0.001) could act as independent prognostic factors for PFS, and LN metastasis (P = 0.004), TP53 (P = 0.006), and PML expression (P = 0.029) were identified as independent prognostic factors for OS in multivariate analysis. CONCLUSIONS: Our study demonstrated PML protein as an independent prognostic marker for patients with ESCC receiving primary surgery. PMID- 21240991 TI - Usefulness of a modified inflammation-based prognostic system for predicting postoperative mortality of patients undergoing surgery for primary hepatocellular carcinoma. AB - OBJECTIVE: To assess and compare the predictive values of the hepatic Glasgow Prognostic Score (hGPS) and Cancer of the Liver Italian Program (CLIP) score in patients undergoing surgery for primary hepatocellular carcinoma (HCC). METHODS: The hGPS was calculated as follows: patients with an elevated level of C-reactive protein (CRP) (>0.3 mg/dl) were allocated a hGPS of 1 or 2 depending on the absence or presence of hypoalbuminemia (<3.5 g/dl), and patients without an elevation of the CRP level (<= 0.3 mg/dl) were allocated a hGPS of 0. RESULTS: Three hundred patients were evaluated. The hGPS divided patients into three independent groups, and that a hGPS of 2 predicted a higher mortality rate (P < 0.001) than a hGPS of 0 or 1. Univariate analysis demonstrated that hGPS (0, 1/2) (P = 0.010) was one of the factors predictive of postoperative mortality, along with the CLIP score (0, 1/>= 2) (P = 0.021). Comparative analysis using these two factors showed that the hGPS was predictively superior to the CLIP score (P = 0.033). CONCLUSIONS: The hGPS is able to divide patients undergoing surgery for primary HCC into three independent groups, and is considered to be an important factor predictive of postoperative mortality in such patients. PMID- 21240992 TI - Prevalence and prognostic influence of genomic changes of EGFR pathway markers in synovial sarcoma. AB - BACKGROUND: We aimed to study the prevalence and prognostic influence of epidermal growth factor receptor (EGFR) and its downstream effectors in synovial sarcoma (SS). OBJECTIVES AND METHODS: The tissue blocks from 30 patients were obtained. Expression of EGFR and phosphatase and tensin homolog (PTEN) were examined by immunohistochemistry, and mutation status of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2, V-raf murine sarcoma viral oncogene homolog B1 (BRAF) exon 15, phosphoinositide-3-kinase, catalytic, alpha polypeptide (PI3KCA) exons 9, 20, and PTEN exons 5-9 were analyzed by direct sequencing. RESULTS: EGFR overexpression and PTEN deletion were found in 63.3% and 46.7% of patients. Sequence analysis failed to demonstrate mutations of KRAS and BRAF. However, an E545A point mutation in exon 9 of PI3KCA was found in 2 of the 30 (6.7%) cases and 4 point mutations in exon 5 (E99K, D106N), intro 6 to exon 7 (AATA(G)), and exon 9 (A359T) of PTEN were found in 2 of the 30 (6.7%) cases. PTEN loss was significantly more frequent in cases of trunk tumors, and the overexpression of EGFR was significantly more prevalent in patients who were 35 or older. CONCLUSIONS: PTEN deletion was associated with poor survival. PMID- 21240993 TI - A new front in the debate over HPV vaccines for boys: studies hint at broader benefits fron Gardasil. PMID- 21240994 TI - Buying time in gastric cancer. PMID- 21240995 TI - Detection of EGFR and KRAS mutations in fine-needle aspirates stored on Whatman FTA cards: is this the tool for biobanking cytological samples in the molecular era? AB - BACKGROUND: The aims of this study were to compare the quality of DNA recovered from fine-needle aspirates (FNAs) stored on Whatman FTA cards with that retrieved from corresponding cell blocks and to determine whether the DNA extracted from the cards is suitable for multiple mutation analyses. METHODS: FNAs collected from 18 resected lung tumors and cell suspensions from 4 lung cancer cell lines were placed on FTA Indicating Micro Cards and further processed to produce paired formalin-fixed paraffin-embedded (FFPE) cell blocks. Fragment analysis was used for the detection of EGFR exon 19 deletion, and direct sequencing for detection of EGFR exon 21 L858R mutation and exon 2 deletion of KRAS. Corresponding FFPE tissue sections from 2 resection specimens were also tested. RESULTS: Analyses were successful with all FNAs and lung cancer-derived cell lines collected on cards. Polymerase chain reaction failed in 2 cell blocks. For FNAs collected on cards, 5 cases showed EGFR and 3 showed KRAS mutations. Eleven cases were wild type. With cell blocks, 4 cases were found to harbor KRAS and 4 harbored EGFR mutations. All lung cancer-derived cell lines tested positive for their respective mutations, and there was complete agreement between card and cell block FNA samples for EGFR exon 21. For EGFR exon 19, 1 of 18 cases showed discordant results between the card and cell block, and for KRAS 1 of 17. The two resection specimens tested gave concordant results with the FTA card. CONCLUSIONS: Storage of cytologic material on FTA cards can maximize and simplify sample procurement for multiple mutational analyses with results similar to those from cell blocks. PMID- 21240996 TI - Cytologic diagnosis and differential diagnosis of lung carcinoid tumors a retrospective study of 63 cases with histologic correlation. AB - BACKGROUND:: Neuroendocrine (NE) neoplasms of the lung are a spectrum of tumors including typical carcinoid (TC), atypical carcinoid tumor (ACT), small cell lung carcinoma (SCLC), and large cell NE carcinoma (LCNEC). Given the overlapping features within these tumors, misclassification is a known risk, with significant treatment consequences. METHODS:: A search of the pathology archives from The Johns Hopkins Hospital yielded 390 cases of TC diagnosed over 20 years. Sixty three cytology cases with corresponding surgical material were identified. The cytology specimens were comprised of 49 cases of lung fine-needle aspiriation specimens and 14 cases of lung brushings/washings. RESULTS:: Among 63 paired cases, 32 cases (51%) demonstrated concordant and 31 cases (49%) demonstrated discordant diagnoses. Among discordant cases, the most notable findings included overdiagnosis of TC as SCLC (4 cases; 6%), ACT (4 cases; 6%), and poorly differentiated carcinoma with NE features (5 cases; 8%) as well as misdiagnosis of other lesions as TC (4 cases; 6%) on cytology. CONCLUSIONS:: The significant morphologic factors for distinguishing low-grade TC from ACT, SCLC, or carcinoma remain the critical evaluation of nuclear features, chromatin patterns, and assessment of nucleoli. Nuclear molding and crowding are not discernible features because they may be found on smears with increased cellularity. Crush artifact can occur in both low-grade and high-grade NE neoplasms and may cause a misinterpretation of SCLC. Other artifacts resulting from delayed fixation or poor processing and sampling error are potential causes of incorrect interpretations. Ki-67 staining may be useful in difficult cases. Cancer (Cancer Cytopathol) 2010. (c) 2010 American Cancer Society. PMID- 21241008 TI - Visual outcome following chemotherapy for progressive optic pathway gliomas. AB - BACKGROUND: Optic pathway gliomas (OPG) are relatively indolent tumors that may occur sporadically or in association with neurofibromatosis 1. Treatment is initiated only when a clear clinical or radiological deterioration is documented. Chemotherapy is the standard first line of treatment. Due to the indolent nature of this tumor, the most important challenge in OPG treatment is vision preservation. METHODS: In this study we determined the visual outcome of 19 patients with progressive OPGs who received chemotherapy and correlated it with imaging. RESULTS: Mean neuro-ophthalmological follow-up is 4 years and 3 months. Indications for treatment were radiological tumor progression (6 patients), visual decline (6 patients), or both (7 patients). Fifteen patients (78%) had to change to 2nd line chemotherapy (7 due to allergies and 8 due to treatment failure). During the course of chemotherapy, 11 patients (57.8%) displayed radiological tumor progression, 4 (21.5%) demonstrated stable tumor, and 4 (21.5%) displayed tumor regression. During the follow-up period, 14 (73.6%) had an overall visual deterioration, 4 (21%) had stable vision, and 1 patient (5.2%) improved. Visual acuity was examined in 38 eyes. Seventeen eyes (47.2%) deteriorated, fourteen (38.8%) were stable, and five (13.8%) improved. Ten eyes (27.7%) deteriorated to legal blindness. There was no correlation between radiological tumor growth and visual deterioration. CONCLUSIONS: The majority of our patients, who received chemotherapy for progressive OPG, experienced a decline in their visual function. New, more effective treatments are needed in order to preserve vision in this group. PMID- 21241015 TI - The prognostic impact of the ratio of positive lymph nodes on survival of epithelial ovarian cancer patients. AB - BACKGROUND AND OBJECTIVES: To study the prognostic significance of ratio of positive to examined lymph nodes (LNR) on survival of patients with node positive epithelial ovarian cancer (NPEOC). METHODS: Data were obtained from Surveillance, Epidemiology, and End Results Program (SEER) from 1988 to 2006, and analyzed using Kaplan-Meier survival and Cox regression proportional hazard methods. Patients were divided into: stage IIIC group 1 (no macroscopic peritoneal disease), stage IIIC group 2 (macroscopic peritoneal disease), and stage IV. RESULTS: A total of 6,310 women were included. The 5-year survival for stage IIIC groups 1, 2, and stage IV was 55.4%, 35.5%, and 20.3%, respectively (P < 0.001). Increasing LNR (<10%, 10-50%, and >50%) was associated with decreased survival from 51.5% to 38.1% to 27.0%, respectively, (P < 0.001). On multivariate analysis, LNR was an independent prognostic factor for survival after adjusting for extent of peritoneal disease, stage, grade, race, age, extent of lymphadenectomy and absolute number of positive nodes. CONCLUSIONS: The impact of increasing LNR was strongly related to survival, especially in patients with no macroscopic peritoneal disease. Stratification of this subpopulation of node positive EOC based on nodal burden provides a significant prognostic value that may be considered in future staging and aid in management decisions. PMID- 21241016 TI - Protein and peptide fractionation, enrichment and depletion: tools for the complex proteome. AB - The identification, quantitation and global characterisation of all proteins within a given proteome are extremely challenging. This is due to the absolute detection limits of technology as well as the dynamic range in expression of proteins; and the extreme diversity and heterogeneity of the proteome. To overcome such issues, the use of separation technologies has played a critical role in reducing sample complexity. To date, a plethora of chromatographic and electrophoretic fractionation tools have evolved over the years assisting in simplifying complex protein and peptide mixtures. Here, we review a range of these technologies highlighting the challenges of protein and peptide analysis in the context of proteome research and some of the advantages and disadvantages of present techniques. PMID- 21241017 TI - Mapping of the secretome of primary isolates of mammalian cells, stem cells and derived cell lines. AB - Within a mammalian organism, the interaction among cells both at short and long distances is mediated by soluble factors released by cells into the extracellular environment. The secreted proteins may involve extracellular matrix proteins, proteinases, growth factors, protein hormones, immunoregulatory cytokines, chemokines or other bioactive molecules that have a direct impact on target cell phenotype. Stem cells of mesenchymal, adipose, neural and embryonic origin, fibroblast feeder cells as well as primary isolates of astrocytes, endothelial and muscle cells have recently become targets of intensive secretome profiling with the search for proteins regulating cell survival, proliferation, differentiation or inflammatory response. Recent advances and challenges of the stem cell and primary cell secretome analysis together with the most relevant results are discussed in this review. PMID- 21241018 TI - Discussion on common data analysis strategies used in MS-based proteomics. AB - Current proteomics technology is limited in resolving the proteome complexity of biological systems. The main issue at stake is to increase throughput and spectra quality so that spatiotemporal dimensions, population parameters and the complexity of protein modifications on a quantitative scale can be considered. MS based proteomics and protein arrays are the main players in large-scale proteome analysis and an integration of these two methodologies is powerful but presently not sufficient for detailed quantitative and spatiotemporal proteome characterization. Improvements of instrumentation for MS-based proteomics have been achieved recently resulting in data sets of approximately one million spectra which is a large step in the right direction. The corresponding raw data range from 50 to 100 Gb and are frequently made available. Multidimensional LC-MS data sets have been demonstrated to identify and quantitate 2000-8000 proteins from whole cell extracts. The analysis of the resulting data sets requires several steps from raw data processing, to database-dependent search, statistical evaluation of the search result, quantitative algorithms and statistical analysis of quantitative data. A large number of software tools have been proposed for the above-mentioned tasks. However, it is not the aim of this review to cover all software tools, but rather discuss common data analysis strategies used by various algorithms for each of the above-mentioned steps in a non-redundant approach and to argue that there are still some areas which need improvements. PMID- 21241019 TI - Energy matters: mitochondrial proteomics for biomedicine. AB - This review compiles results of medical relevance from mitochondrial proteomics, grouped either according to the type of disease - genetic or degenerative - or to the involved mechanism - oxidative stress or apoptosis. The findings are commented in the light of our current understanding of uniformity/variability in cell responses to different stimuli. Specificities in the conceptual and technical approaches to human mitochondrial proteomics are also outlined. PMID- 21241020 TI - Proteomics insights into plant signaling and development. AB - Mass spectrometry-based proteomics is used to gain insight into the abundance and subcellular localization of cellular signaling components, the composition of molecular complexes and the regulation of signaling pathways. Multicellular organisms have evolved signaling networks and fast responses to stimuli that can be discovered and monitored by the use of advanced proteomics techniques in combination with traditional functional analysis. Plants are multicellular organisms and products of tightly regulated developmental programmes that respond to environmental conditions and internal cues. Plant development is orchestrated by inter- and intracellular signaling molecules, receptors and transcriptional regulators, which act in a temporal and spatially coordinated manner. Here we review recent advances in proteomics applications used to understand complex cellular signaling processes in plants. PMID- 21241021 TI - Advances in membranous vesicle and exosome proteomics improving biological understanding and biomarker discovery. AB - Exosomes are membranous vesicles released by cells in extracellular fluids: they have been found and analyzed in blood, urine, amniotic fluid, breast milk, seminal fluid, saliva and malignant effusions, besides conditioned media from different cell lines. Several recent papers show that exosome proteomes of different origin include both a common set of membrane and cytosolic proteins, and specific subsets of proteins, likely correlated to cell-type associated functions. This is particularly interesting in relation to their possible involvement in human diseases. The knowledge of exosome proteomics can help not only in understanding their biological roles but also in supplying new biomarkers to be searched for in patients' fluids. This review offers an overview of technical and analytical issues in exosome proteomics, and it highlights the significance of proteomic studies in terms of biological and clinical usefulness. PMID- 21241022 TI - Glycan analysis by modern instrumental methods. AB - The oligosaccharides attached to proteins or lipids are among the most challenging analytical tasks due to their complexity and variety. Knowing the genes and enzymes responsible for their biosynthesis, a large but not unlimited number of different structures and isomers of such glycans can be imagined. Understanding of the biological role of structural variations requires the ability to unambiguously determine the identity and quantity of all glycan species. Here, we examine, which analytical strategies - with a certain high throughput potential - may come near this ideal. After an expose of the relevant techniques, we try to depict how analytical raw data are translated into structural assignments using retention times, mass and fragment spectra. A method's ability to discriminate between the many conceivable isomeric structures together with the time, effort and sample amount needed for that purpose is suggested as a criterion for the comparative assessment of approaches and their evolutionary stages. PMID- 21241024 TI - Notch1 is an independent prognostic factor for patients with glioma. AB - OBJECTIVES: Notch signaling plays a complex role in human malignancy. It can affect cell proliferation, differentiation, and apoptosis either positively or negatively, depending on cell type. METHODS: Clinical gliomas from 274 patients who had not received chemotherapy were collected, and the expression of Notch1 protein was assessed by immunochemistry assays. Staining evaluation results were analyzed statistically in relation to various clinicopathological characters. Kaplan-Meier and Cox proportional hazards regression methods were used to assess associations of Notch1 expression with glioma survival. RESULTS: We found that the levels of expression of Notch1 protein were higher in glioma than control normal brain tissue. Moreover, the expression of Notch1 was associated closely with glioma progression, since expression levels increased from grades I to IV glioma. The overall survival rate was significantly lower for patients with Notch1 positive than those with Notch1 negative tumors. Multivariate analysis showed that Notch1 was an independent prognostic factor for patients with glioma. CONCLUSIONS: These findings we confirm that Notch1 expression is up-regulated in glioma and related to tumor progression. Notch1 might also serve as a novel prognostic marker that is independent of, and additive to, the WHO grade. PMID- 21241026 TI - Micellar electrokinetic chromatographic analysis for in vitro accumulation of anthracyclines enhanced by inhibitors of cell membrane transporter-proteins in cancer cells. AB - Cell membrane transporter-proteins have been partly implicated in lowering the accumulation of drugs in cancer cells, leading to multidrug resistance (MDR). Two cancer cell lines, A549 and RDES, were continuously exposed to subclinical concentration (250 nM) of anthracyclines and micellar electrokinetic chromatography was used to investigate their in vitro accumulation after treatment with inhibitors of membrane transporter-proteins. The four anthracylines [doxorubicin (DOX), epirubicin (EPI), daunorubicin (DNR), and idarubicin (IDA)] were separated within a short analysis time of less than 15 min in borate buffer (80 mM, pH 9.22) containing sodium taurodeoxycholate (35 mM), 2 hydroxypropyl-gamma-cyclodextrin (3.5% wt/v), and sodium dodecylsulfate (20 mM). Laser-induced fluorescence was used for detection of the anthracyclines. Three inhibitors, verapamil, cyclosporine A and probenecid, were examined by adding each inhibitor independently or two inhibitors simultaneously to the culture medium. It was found that independent use of each inhibitor leads to more efficient accumulation than combined use of verapamil and probenecid. In addition, the results show that effect of inhibitors on the accumulation of anthracyclines depended on type of cell: in RDES, inhibitors enhanced accumulation of all four anthracyclines, while in A549, inhibitors showed different accumulation behavior for each anthracycline. Generally higher accumulation of anthracyclines was observed in RDES cells than A549, as evidenced by dead cells (7-16%) after 24 h of continuous exposure to subclinical concentration. PMID- 21241029 TI - Dutch children at family risk of dyslexia: precursors, reading development, and parental effects. AB - The study concerns reading development and its precursors in a transparent orthography. Dutch children differing in family risk for dyslexia were followed from kindergarten through fifth grade. In fifth grade, at-risk dyslexic (n = 22), at-risk non-dyslexic (n = 45), and control children (n = 12) were distinguished. In kindergarten, the at-risk non-dyslexics performed better than the at-risk dyslexics, but worse than the controls on letter-knowledge and rapid naming. The groups did not differ on phonological awareness. At-risk dyslexics read less fluently from first grade onwards than the other groups. At-risk non-dyslexics' reading fluency was at an intermediate position between the other groups at the start of reading. By fifth grade they had reached a similar level as the controls on word reading, but still lagged behind on pseudoword reading. Results further showed that the parents of the groups of at-risk children differed in educational level and reading skills. Overall, the groups of at-risk children differed on pre reading skills as well as on reading development. These differences do not seem to stem from differences in intellectual abilities or literacy environment. Instead, the better reading skills of parents of at-risk non-dyslexics suggest that these children might have a lower genetic liability. PMID- 21241030 TI - Acquisition of Malay word recognition skills: lessons from low-progress early readers. AB - Malay is a consistent alphabetic orthography with complex syllable structures. The focus of this research was to investigate word recognition performance in order to inform reading interventions for low-progress early readers. Forty-six Grade 1 students were sampled and 11 were identified as low-progress readers. The results indicated that both syllable awareness and phoneme blending were significant predictors of word recognition, suggesting that both syllable and phonemic grain-sizes are important in Malay word recognition. Item analysis revealed a hierarchical pattern of difficulty based on the syllable and the phonic structure of the words. Error analysis identified the sources of errors to be errors due to inefficient syllable segmentation, oversimplification of syllables, insufficient grapheme-phoneme knowledge and inefficient phonemic code assembly. Evidence also suggests that direct instruction in syllable segmentation, phonemic awareness and grapheme-phoneme correspondence is necessary for low-progress readers to acquire word recognition skills. Finally, a logical sequence to teach grapheme-phoneme decoding in Malay is suggested. PMID- 21241032 TI - The need for mentors in the odyssey of the academic hospitalist. PMID- 21241033 TI - Off-hours care: not so off. PMID- 21241034 TI - Survey of US academic hospitalist leaders about mentorship and academic activities in hospitalist groups. AB - BACKGROUND: Few data describe the structure, activities, and goals of academic hospital medicine groups. METHODS: We carried out a cross sectional email survey of academic hospitalist leaders. Our survey asked about group resources, services, recruitment and growth, as well as mentoring of faculty, future priorities, and general impressions of group stability. RESULTS: A total of 57 of 142 (40%) potential hospitalist leaders responded to our email survey. Hospitalist groups were generally young (<5 years old). Hospitalist group leaders worried about adequate mentorship and burnout while placing a high priority on avoiding physician turnover. However, most groups also placed a high priority on expanding nonclinical activities (teaching, research, etc.). Leaders felt financially and philosophically unsupported, a sentiment which seemed to stem from being viewed primarily as a clinical rather than an academic service. CONCLUSION: Academic hospital medicine groups have an acute need for mentoring and career development programs. These programs should target both individual hospitalists and their leaders while also helping to enhance scholarly work. PMID- 21241035 TI - The association between night or weekend admission and hospitalization-relevant patient outcomes. AB - INTRODUCTION: Nights and weekends represent a potentially high-risk time for hospitalized patients. Data regarding night or weekend admission and its impact on outcomes is limited. We studied the association between night or weekend admission and outcomes. METHODS: We reviewed 857 admissions to the general medicine services from the emergency department (ED) at our tertiary care hospital for demographic information, time and day of admission, and hospitalization-relevant outcomes (length of stay [LOS], hospital charges, intensive care unit [ICU] transfer during hospitalization, repeat ED visit within 30 days, readmission within 30 days, and poor outcome [ICU transfer, cardiac arrest, or death] within the first 24 hours of admission). Outcomes were compared between groups using univariate and multivariate modeling. RESULTS: Complete data for analysis were available for 824 patients. A total of 58% of patients were admitted at night and 22% were admitted during the weekend. Patients admitted at night as compared to those admitted during the day had similar a LOS (4.1 vs. 4.3, P = 0.38), hospital charges (25,200 vs. 27,500, P = 0.17), ICU transfer during hospitalization (3% vs. 6%, P = 0.06), 30 day repeat ED visit (22% vs. 20%, P = 0.42), 30 day readmission (20% vs. 17%, P = 0.23), and poor outcomes within 24 hours of admission (1% vs. 2%, P = 0.15). Patients admitted during the weekend as compared to those admitted during the week had lower hospital charges and lower likelihood of an ICU transfer but were otherwise similar. CONCLUSION: Night or weekend admission was not associated with worse hospitalization-relevant outcomes at our tertiary care hospital. PMID- 21241037 TI - Lessons learned from implementation of a computerized application for pending tests at hospital discharge. AB - BACKGROUND: Patients are often discharged from the hospital before test results are finalized. Awareness of these results is poor and therefore an important patient safety concern. Few computerized systems have been deployed at care transitions to address this problem. We describe an attempt to implement a computerized application to help inpatient physicians manage these test results. METHODS: We modified an ambulatory electronic medical record (EMR)-based results management application to track pending tests at hospital discharge (Hospitalist Results Manager, HRM). We trained inpatient physicians at 2 academic medical centers to track these tests using this application. We surveyed inpatient physicians regarding usage of and satisfaction with the application, barriers to use, and the characteristics of an ideal system to track pending tests at discharge. RESULTS: Of 29 survey respondents, 14 (48%) reported never using HRM, and 13 (45%) used it 1 to 2 times per week. A total of 23 (79%) reported barriers prohibiting use, including being inundated with clinically "irrelevant" results, not having sufficient time, and a lack of integration of post-discharge test result management into usual workflow. Twenty-one (72%) wanted to receive notification of abnormal and clinician-designated pending test results. Twenty seven physicians (93%) agreed that an ideally designed computerized application would be valuable for managing pending tests at discharge. CONCLUSIONS: Although inpatient physicians would highly value a computerized application to manage pending tests at discharge, the characteristics of an ideal system are unclear and there are important barriers prohibiting adoption and optimal usage of such systems. We outline suggestions for future electronic systems to manage pending tests at discharge. PMID- 21241038 TI - Audit and feedback: an intervention to improve discharge summary completion. AB - Discharge summaries (DS) communicate important clinical information from inpatient to outpatient settings. Previous studies noted increased adverse events and rehospitalization due to poor DS quality. We postulated that an audit and feedback intervention of DS completed by geriatric medicine fellows would improve the completeness of their summaries. We conducted a preintervention post intervention study. In phase 1 (AUDIT #1 and FEEDBACK) we scored all DS (n = 89) completed by first year fellows between July 2006 to December 2006 using a 21 item checklist. Individual performance scores were reviewed with each fellow in 30-minute feedback sessions. In phase 2 (AUDIT #2) we scored all DS (n = 79) completed after the first phase between February 2007 to July 2007 using the same checklist. Data were analyzed using generalized estimating equations. Fellows were more likely to complete all required DS data after feedback when compared with prior to feedback (91% vs. 71%, P < 0.001). Feedback was also associated with improved admission (93% vs. 70%, P < 0.001), duration of hospitalization (93% vs 78%, P < 0.001), discharge planning (93% vs. 18%, P < 0.02) and postdischarge care (83% vs. 57%., P < 0.001) section-specific information. In conclusion, audit and feedback sessions were associated with better DS completeness in areas of particular importance to geriatric care. PMID- 21241039 TI - Research in progress conference for hospitalists provides valuable peer mentoring. AB - BACKGROUND: Many academic hospitalist units lack senior mentors. In such groups, peer mentoring may be valuable. To formalize collaboration, we instituted a research-in-progress conference at our institution, and this article describes the format and evaluation data. METHODS: The research-in-progress sessions were held every 3 to 4 weeks and followed a specific format. Evaluation forms were completed after each of the 15 sessions during the 2009 academic year. Attendees and presenters completed surveys at the end of the sessions. The projects presented were tracked for successful academic outcomes, namely, publication in a peer-reviewed journal or presentation at a national meeting. RESULTS: A mean of 9.6 persons were present at each session and completed the evaluations. All 15 presenters rated the climate of the sessions as extremely supportive, and 86% believed they were helpful in advancing their project. A total of 143 evaluations were completed by the attendees, 86% and 96% of whom found the sessions to be intellectually stimulating and to have satisfactorily kept them abreast of their colleagues' scholarly pursuits, respectively. To date, 10 of the 15 projects have translated into successful academic outcomes: 6 peer-reviewed publications and 4 other presentations presented at national meetings. CONCLUSIONS: The research-in progress conference has been well received and has resulted in academic productivity within our hospitalist division. It is likely that such a conference will be most valuable for groups with limited access to senior mentors. PMID- 21241040 TI - Large gallstone ileus. PMID- 21241043 TI - The aging process in HIV-infected patients: a comorbidity that needs more research. PMID- 21241045 TI - Optimizing oral health in HIV patients with diabetes mellitus. PMID- 21241044 TI - Untreated depressive disorders have big impact on HIV. PMID- 21241046 TI - Impact of new same-sex hospital visitation memorandum. PMID- 21241047 TI - Challenges associated with HIV in transgendered patients. PMID- 21241048 TI - [Keypoints in harvesting a radial artery graft]. PMID- 21241049 TI - Absolute quantification of allergens from complex mixtures: a new sensitive tool for standardization of allergen extracts for specific immunotherapy. AB - Products for specific diagnosis and immunotherapy of IgE-mediated allergies are currently based on natural extracts. Quantification of major allergen content is an important aspect of standardization as important allergens particularly impact vaccine potency. The aim of the study was to develop a mass spectrometry (MS) based assay for absolute quantification of Timothy (Phleum pratense) pollen allergens Phl p 1 and Phl p 5 in P. pratense extract. High-resolution and accurate mass (HRAM) MS was selected for its ability to detect peptides with high selectivity and mass accuracy (<3 ppm). Isotope labeled heavy peptides were used for absolute quantification of specific isoallergens of Phl p 1 and Phl p 5 at low femtomole level in P. pratense extract. Robustness and linearity of the method was demonstrated with intra day precision <= 5% (n = 3). Phl p 1b was shown to be 5 times less abundant than its variant Phl p 1a and Phl p 5b was shown to be 9 times more abundant than the Phl p 5a. The present study shows that allergen, and/or isoallergen specific, surrogate signature peptides analyzed with HRAM MS is a sensitive and accurate tool for identification and quantification of allergens from complex allergen sources. PMID- 21241050 TI - Using ethidium to probe nonequilibrium states of DNA condensed for gene delivery. AB - Here we explore the use of ethidium to determine relative affinities of different gene delivery vectors for DNA and describe an improved method for studying the interaction. Specifically, we investigate the binding of poly(amidoamine) dendrimers and show that the DNA-dendrimer-ethidium system is far from thermodynamic equilibrium. Moreover, dendrimer surface modification through PEGylation appears to make the interaction with DNA more reversible, which is favorable from the perspective of vector unpacking. Probing the nonequilibrium state of DNA during condensation processes is thus important for developing novel vectors, and further, it could also be useful in the study of chromatin folding. PMID- 21241051 TI - Mechanism of mycolic acid cyclopropane synthase: a theoretical study. AB - The reaction mechanism of mycolic acid cyclopropane synthase is investigated using hybrid density functional theory. The direct methylation mechanism is examined with a large model of the active site constructed on the basis of the crystal structure of the native enzyme. The important active site residue Glu140 is modeled in both ionized and neutral forms. We demonstrate that the reaction starts via the transfer of a methyl to the substrate double bond, followed by the transfer of a proton from the methyl cation to the bicarbonate present in the active site. The first step is calculated to be rate-limiting, in agreement with experimental kinetic results. The protonation state of Glu140 has a rather weak influence on the reaction energetics. In addition to the natural reaction, a possible side reaction, namely a carbocation rearrangement, is also considered and is shown to have a low barrier. Finally, the energetics for the sulfur ylide proposal, which has already been ruled out, is also estimated, showing a large energetic penalty for ylide formation. PMID- 21241052 TI - Substrate specificity and catalysis by the editing active site of Alanyl-tRNA synthetase from Escherichia coli. AB - Aminoacyl-tRNA synthetases (ARSs) enhance the fidelity of protein synthesis through multiple mechanisms, including hydrolysis of the adenylate and cleavage of misacylated tRNA. Alanyl-tRNA synthetase (AlaRS) limits misacylation with glycine and serine by use of a dedicated editing domain, and a mutation in this activity has been genetically linked to a mouse model of a progressive neurodegenerative disease. Using the free-standing Pyrococcus horikoshii AlaX editing domain complexed with serine as a model and both Ser-tRNA(Ala) and Ala tRNA(Ala) as substrates, the deacylation activities of the wild type and five different Escherichia coli AlaRS editing site substitution mutants were characterized. The wild-type AlaRS editing domain deacylated Ser-tRNA(Ala) with a k(cat)/K(M) of 6.6 * 10(5) M(-1) s(-1), equivalent to a rate enhancement of 6000 over the rate of enzyme-independent deacylation but only 12.2-fold greater than the rate with Ala-tRNA(Ala). While the E664A and T567G substitutions only minimally decreased k(cat)/K(M,) Q584H, I667E, and C666A AlaRS were more compromised in activity, with decreases in k(cat)/K(M) in the range of 6-, 6.6-, and 15-fold. C666A AlaRS was 1.7-fold more active on Ala-tRNA(Ala) relative to Ser-tRNA(Ala), providing the only example of a true reversal of substrate specificity and highlighting a potential role of the coordinated zinc in editing substrate specificity. Along with the potentially serious physiological consequences of serine misincorporation, the relatively modest specificity of the AlaRS editing domain may provide a rationale for the widespread phylogenetic distribution of AlaX free-standing editing domains, thereby contributing a further mechanism to lower concentrations of misacylated tRNA(Ala). PMID- 21241054 TI - Influence of C-terminal amidation on the efficacy of modelin-5. AB - To gain insight into the effects of amidation on the mechanism of membrane interaction, we studied two peptides modelin-5-COOH and modelin-5-CONH(2) and found they exhibit high surface activities (23.2 and 27.1 mN/m, respectively). When they were tested against Escherichia coli, amidation was seen to increase efficacy approximately 10-fold. Our results demonstrated that both peptides adopted low levels of alpha-helix in solution (<20%); however, in the presence of E. coli lipid extract, modelin-5-CONH(2) had a greater propensity (69%) than modelin-5-COOH (32%) to generate alpha-helical structure. The binding coefficient for both peptides was ~10 MUM, and the Hill coefficient approximated 1, suggesting that for both peptides the interactions with E. coli membranes were monomeric and comparable in strength. The peptides showed a clear preference for anionic lipid, with monolayer data showing that enhanced levels of helicity were associated with a greater pressure change (~6 mN/m). Use of fluorescein phosphatidylethanolamine showed the amidated version was able to generate greater levels of membrane disruption, which was confirmed by thermodynamic analysis. The data would imply that both peptides are able to initially bind to bilayer structures, but upon binding, the amidation stabilizes helix formation. This would be expected to help overcome a key rate-limiting step and generate higher local concentrations of peptide at the bilayer interface, which in turn would be predicted to increase efficacy. PMID- 21241053 TI - Biochemical and structural characterization of WlbA from Bordetella pertussis and Chromobacterium violaceum: enzymes required for the biosynthesis of 2,3 diacetamido-2,3-dideoxy-D-mannuronic acid. AB - The unusual sugar 2,3-diacetamido-2,3-dideoxy-d-mannuronic acid, or ManNAc3NAcA, has been observed in the lipopolysaccharides of both pathogenic and nonpathogenic Gram-negative bacteria. It is added to the lipopolysaccharides of these organisms by glycosyltransferases that use as substrates UDP-ManNAc3NAcA. Five enzymes are ultimately required for the biosynthesis of UDP-ManNAc3NAcA starting from UDP-N acetylglucosamine. The second enzyme in the pathway, encoded by the wlba gene and referred to as WlbA, catalyzes the NAD-dependent oxidation of the C-3' hydroxyl group of the UDP-linked sugar. Here we describe a combined structural and functional investigation of the WlbA enzymes from Bordetella pertussis and Chromobacterium violaceum. For this investigation, ternary structures were determined in the presence of NAD(H) and substrate to 2.13 and 1.5 A resolution, respectively. Both of the enzymes display octameric quaternary structures with their active sites positioned far apart. The octamers can be envisioned as tetramers of dimers. Kinetic studies demonstrate that the reaction mechanisms for these enzymes are sequential and that they do not require alpha-ketoglutarate for activity. These results are in sharp contrast to those recently reported for the WlbA enzymes from Pseudomonas aeruginosa and Thermus thermophilus, which function via ping-pong mechanisms that involve alpha-ketoglutarate. Taken together, the results reported here demonstrate that there are two distinct families of WlbA enzymes, which differ with respect to amino acid sequences, quaternary structures, active site architectures, and kinetic mechanisms. PMID- 21241055 TI - Gap junction hemichannel interactions with zwitterionic lipid, anionic lipid, and cholesterol: molecular simulation studies. AB - Interactions with membrane lipids can exert dramatic functional consequences on gap junction proteins. Recent experimental work has highlighted the importance of anionic lipids and cholesterol in facilitating channel activity. In this work, we have employed a coarse-grained molecular model in conjunction with molecular dynamics (MD) simulations to study the interactions between a connexin 26 (Cx26) hemichannel and a number of lipid species, including palmitoyloleoylphosphatidylcholine (POPC), anionic palmitoyloleoylphosphatidic acid (POPA), and cholesterol, in order to identify sites at the protein interface which may exhibit preferential, specific binding to these lipids, as well as determine the characteristics of these interactions. We have also employed an atomistic model of Cx26 embedded in a mixed PA/PC bilayer as a comparison and to elucidate further lipid-protein interactions. Our simulation results suggest enrichment of interfacial PA at the intracellular leaflet at high bulk PA concentrations. PC can form tight binding interactions with the hemichannel, particularly at intersubunit crevices (classical nonannular sites). In mixed bilayers, however, POPA competes with POPC for these sites, displacing the latter in some cases. While the residues responsible for interactions with PC and PA are similar, the latter exhibits a unique property of being capable of forming stable hydrophilic contacts with multiple residues spanning two different adjacent subunits at both leaflets of the bilayer, as opposed to POPC which can only do so at the extracellular side. These results suggest that POPA may be essential to channel function by acting as an intersubunit lipid bridge. Additionally, we propose that the compositional enrichment of POPA at the Cx26 interface may serve important roles in voltage gating. Simulation of a mixed POPC:cholesterol bilayer suggests that the hemichannel enhances the transbilayer mobility of vicinal cholesterols, increasing the likelihood of site-hopping and interleaflet flip flop transitions. PMID- 21241056 TI - Screening multicomponent reactions for X-linked inhibitor of apoptosis baculoviral inhibitor of apoptosis protein repeats domain binder. AB - We report a second example of a general reaction screening approach to discover low molecular weight inhibitors of protein protein interactions. On the basis of the known pharmacophore model of SMAC mimetics, we predicted several inhibitors based on four different multicomponent reactions. The predicted inhibitors were subsequently synthesized, tested, and found to bind to the antiapoptotic protein X-linked inhibitor of apoptosis protein (XIAP) and showed cellular activity. Also the compounds are currently not highly potent. They could form a starting point for future medicinal chemistry optimization. PMID- 21241057 TI - Technical and biological variation in UPLC-MS-based untargeted metabolic profiling of liver extracts: application in an experimental toxicity study on galactosamine. AB - The relative importance of technical versus bio-logical variation in UPLC-MS liver metabolic profiling studies was assessed on liver samples collected as part of an in vivo hepatotoxicity study. Biological variability within and between two treatment groups (three rats treated with galactosamine and three with galactosamine+uridine) was compared with sampling/extraction variability (three portions extracted from each rat liver section) and UPLC-MS platform variability (triplicate injections of each extract) for aqueous and organic extracts. The impact of scaling on error measurement was investigated on replicate injections of a quality control sample, and consequently started log-transformation was used to stabilize the variance across the ion intensity range. For aqueous extracts, technical variability was two to four times lower than within group interanimal variability. Similar results were obtained for organic extracts for the galactosamine group, sampling/extraction variability being more elevated in the galactosamine+uridine group. For both extract types, differences between treatment groups were the principal source of observed variation, and triplicate injections clustered closely in PCA plots and in HCA dendrograms, indicating small instrument variability compared to observed biological variation. This protocol can be applied to investigate differences in liver metabolic profiles between animal groups in toxicology studies and clinical investigations of liver disease. PMID- 21241059 TI - Expedient route to the tigliane-daphnane skeleton via oxonium ylide [1,2]-shift. AB - A short, stereoselective approach to the fused tricyclic carbon skeleton found in the tigliane and daphnane classes of diterpene natural products is described. Convergent coupling of the A- and C-rings, followed by diastereoselective cerium enolate addition and formation of a double acetal set the stage for generation of an oxonium ylide via a transient metallocarbene. An efficient Stevens [1,2]-shift furnished the 7-membered B-ring, possessing the bridgehead oxygenation pattern found in the natural systems. PMID- 21241058 TI - Biostructural features of additional jasplakinolide (jaspamide) analogues. AB - The cyclodepsipeptide jasplakinolide (1) (aka jaspamide), isolated previously from the marine sponge Jaspis splendens, is a unique cytotoxin and molecular probe that operates through stabilization of filamentous actin (F-actin). We have recently disclosed that two analogues of 1, jasplakinolides B (3) and E, were referred to the National Cancer Institute's (NCI) Biological Evaluation Committee, and the objective of this study was to reinvestigate a Fijian collection of J. splendens in an effort to find jasplakinolide congeners with similar biological properties. The current efforts have afforded six known jasplakinolide analogues (4-7, 9, 10), two structures requiring revision (8 and 14), and four new congeners of 1 (11-13, 15) including open-chain derivatives and structures with modified beta-tyrosine residues. Compounds were evaluated for biological activity in the NCI's 60 cell line screen and in a microfilament disruption assay in both HCT-116 and HeLa cells. These two phenotypic screens provide evidence that each cytotoxic analogue, including jasplakinolide B (3), operates by modification of microfilaments. The new structure jasplakinolide V (13) has also been selected for study by the NCI's Biological Evaluation Committee. In addition, the results of a clonogenic dose-response study on jasplakinolide are presented. PMID- 21241060 TI - Electron correlation effects on the femtosecond dephasing dynamics of E22 excitons in (6,5) carbon nanotubes. AB - Highly nonlinear pump fluence dependence was observed in the ultrafast one-color pump-probe responses excited by 38 fs pulses resonant with the E(22) transition in a room-temperature solution of (6,5) carbon nanotubes. The differential probe transmission (DeltaT/T) at the peak of the pump-probe response (tau = 20 fs) was measured for pump fluences from ~10(13) to 10(17) photons/pulse cm(2). The onset of saturation is observed at ~2 * 10(15) photons/pulse cm(2) (~8 * 10(5) excitons/cm). At pump fluences >4 * 10(16) photons/pulse cm(2) (~1.6 * 10(6) excitons/cm), DeltaT/T decreases as the pump fluence increases. Analogous signal saturation behavior was observed for all measured probe delays. Despite the high exciton density at saturation, no change in the E(22) population decay rate was observed at short times (<300 fs). The pump probe signal was modeled by a third order perturbation theory treatment that includes the effects of inhomogeneous broadening. The observed DeltaT/T signal is well-fit by a pump-fluence-dependent dephasing rate linearly dependent on the number of excitons created by the pump pulse. Therefore, the observed nonlinear pump intensity dependence is attributed to the effects of quasi-elastic exciton-exciton interactions on the dephasing rates of single carbon nanotubes. The low fluence total dephasing time is 36 fs, corresponding to a homogeneous width of 36 meV (290 cm(-1)), and the derived E(22) inhomogeneous width is 68 meV (545 cm(-1)). These results are contrasted with photon-echo-derived parameters for the E(11) transition. PMID- 21241061 TI - Nanotopographic control of neuronal polarity. AB - We employ simple geometrical rules to design a set of nanotopographies able to interfere with focal adhesion establishment during neuronal differentiation. Exploiting nanoimprint lithography techniques on cyclic-olefin-copolymer films, we demonstrate that by varying a single topographical parameter the orientation and maturation of focal adhesions can be finely modulated yielding independent control over the final number and the outgrowth direction of neurites. Taken together, this report provides a novel and promising approach to the rational design of biocompatible textured substrates for tissue engineering applications. PMID- 21241062 TI - Selective depletion of mutant p53 by cancer chemopreventive isothiocyanates and their structure-activity relationships. AB - Isothiocyanates (ITCs) derived from cruciferous vegetables induce apoptosis in cancer cells. We demonstrate that certain naturally occurring ITCs selectively deplete mutant p53 but not the wild-type and do so via a transcription independent mechanism. Direct p53 binding followed by conformational changes appears to be a mechanism by which mutant p53 is depleted. Structure-activity relationship studies (SARs) using naturally occurring and synthetic ITCs show that depletion is influenced by the ITC side-chain moiety. Furthermore, we show that cells with p53 mutations are more sensitive to cytotoxicity induced by phenethyl isothiocyanate (PEITC) than those with the wild-type protein. 2,2 Diphenylethyl ITC, a synthetic ITC, is one of the most potent depletors of mutant p53 studies and induces apoptosis to the greatest extent in mutant p53 breast cancer cells. Collectively, this study shows that mutant p53 depletion may be an important novel target for cancer chemoprevention and therapy by natural and synthetic ITCs. PMID- 21241063 TI - Combined receptor and ligand-based approach to the universal pharmacophore model development for studies of drug blockade to the hERG1 pore domain. AB - Long QT syndrome, LQTS, results in serious cardiovascular disorders, such as tachyarrhythmia and sudden cardiac death. A promiscuous binding of different drugs to the intracavitary binding site in the pore domain (PD) of human ether-a go-go related gene (hERG) channels leads to a similar dysfunction, known as a drug-induced LQTS. Therefore, an assessment of the blocking ability for potent drugs is of great pragmatic value for molecular pharmacology and medicinal chemistry of hERGs. Thus, we attempted to create an in silico model aimed at blinded drug screening for their blocking ability to the hERG1 PD. Two distinct approaches to the drug blockage, ligand-based QSAR and receptor-based molecular docking methods, are combined for development of a universal pharmacophore model, which provides rapid assessment of drug blocking ability to the hERG1 channel. The best 3D-QSAR model (AAADR.7) from PHASE modeling was selected from a pool consisting of 44 initial candidates. The constructed model using 31 hERG blockers was validated with 9 test set compounds. The resulting model correctly predicted the pIC(50) values of test set compounds as true unknowns. To further evaluate the pharmacophore model, 14 hERG blockers with diverse hERG blocking potencies were selected from literature and they were used as additional external blind test sets. The resulting average deviation between in vitro and predicted pIC(50) values of external test set blockers is found as 0.29 suggesting that the model is able to accuretely predict the pIC(50) values as true unknowns. These pharmacophore models were merged with a previously developed atomistic receptor model for the hERG1 PD and exhibited a high consistency between ligand-based and receptor-based models. Therefore, the developed 3D-QSAR model provides a predictive tool for profiling candidate compounds before their synthesis. This model also indicated the key functional groups determining a high-affinity blockade of the hERG1 channel. To cross-validate consistency between the constructed hERG1 pore domain and the pharmacophore models, we performed docking studies using the homology model of hERG1. To understand how polar or nonpolar moieties of inhibitors stimulate channel inhibition, critical amino acid replacement (i.e., T623, S624, S649, Y652 and F656) at the hERG cavity was examined by in silico mutagenesis. The average docking score differences between wild type and mutated hERG channels was found to have the following order: F656A > Y652A > S624A > T623A > S649A. These results are in agreement with experimental data. PMID- 21241064 TI - Giant piezoelectric size effects in zinc oxide and gallium nitride nanowires. A first principles investigation. AB - Nanowires made of materials with noncentrosymmetric crystal structure are under investigation for their piezoelectric properties and suitability as building blocks for next-generation self-powered nanodevices. In this work, we investigate the size dependence of piezoelectric coefficients in nanowires of two such materials - zinc oxide and gallium nitride. Nanowires, oriented along their polar axis, ranging from 0.6 to 2.4 nm in diameter were modeled quantum mechanically. A giant piezoelectric size effect is identified for both GaN and ZnO nanowires. However, GaN exhibits a larger and more extended size dependence than ZnO. The observed size effect is discussed in the context of charge redistribution near the free surfaces leading to changes in local polarization. The study reveals that local changes in polarization and reduction of unit cell volume with respect to bulk values lead to the observed size effect. These results have strong implication in the field of energy harvesting, as piezoelectric voltage output scales with the piezoelectric coefficient. PMID- 21241065 TI - Stereoselective synthesis of unsymmetrical beta,beta-diarylacrylates by a Heck Matsuda reaction: versatile building blocks for asymmetric synthesis of beta,beta diphenylpropanoates, 3-aryl-indole, and 4-aryl-3,4-dihydro-quinolin-2-one and formal synthesis of (-)-indatraline. AB - beta,beta-Disubstituted alpha,beta-unsaturated esters may serve as valuable derivatives for the preparation of other highly functionalized systems found in many natural products and marketed drugs. The stereoselective synthesis of unsymmetrical beta,beta-diarylacrylate compounds possessing two similar aromatic groups remains a substantial challenge. A simple and convenient stereoselective protocol for the preparation of beta,beta-disubstituted acrylates via a Heck Matsuda reaction is reported. Good to high yields were accomplished by a "ligand free" Pd-catalyzed arylation reaction of cinnamate esters with arenediazonium tetrafluoroborates. Both electron-deficient and electron-rich arenediazonium salts could be employed as arylating reagents, and cinnamate esters were generally more reactive when substituted with an electron-donating group. The overall methodology is highly stereoselective, and this attribute was taken advantage of in the asymmetric Cu-catalyzed 1,4 reduction reaction to provide beta,beta-diarylpropanoates in high enantioselectivities. The synthesis of a 3 aryl indole and a chiral 4-aryl-2-quinolone from beta,beta-diarylacrylates was achieved by cyclization in the presence of a diphosphine ligated CuH catalyst. A convenient route for the asymmetric formal synthesis of the psychoactive compound (-)-Indatraline is also presented. PMID- 21241066 TI - Giant brainlike aggregates from new fluorocarbon/hydrocarbon hybrid cationic surfactants. AB - A rapid synthetic procedure in two steps from perfluoroalkylethyl iodide derivatives led to 18 novel ammonium type hybrid surfactants of the general formula: R(F)(CH(2))(2)S(CH(2))(2)N(+)(CH(3))(2)R(H)Br(-) (R(F) = C(4)F(9), C(6)F(13), C(8)F(17); R(H) = C(4)H(9), C(6)H(13), C(8)H(17), C(10)H(21), C(12)H(25), C(14)H(29)). These hybrid surfactants exhibited very low surface tension (from 16 to 25 mN/m) as well as low critical micellar concentration until 1.5 * 10(-5) mol/L. A special focus was made on aggregation phenomenon as giant multilamellar "brainlike" vesicles were observed via cryogenic scanning electron microscopy (cryoSEM) and transmission electron microscopy (TEM; with a contrast agent) suggesting a high encapsulation ability and a very important specific surface of these particular organizations. PMID- 21241067 TI - Biological evaluation of a novel doxorubicin-peptide conjugate for targeted delivery to EGF receptor-overexpressing tumor cells. AB - Epidermal growth factor receptor (EGFR) is overexpressed in a variety of epithelial malignancies and thus can be used for EGFR-targeted therapy to improve antitumor efficacy. Therefore we synthesized a novel conjugate of doxorubicin (DOX) with an EGFR-binding peptide (NH2-CMYIEALDKYAC-COOH; EBP) via an ester bond at position 14 of DOX through a glutarate spacer. To confirm that the DOX-EBP conjugate is capable of targeting tumor cells overexpressing EGFR, we compared the cellular accumulation, intracellular distribution and in vitro cytotoxicity of DOX-EBP and free DOX. After treating with equimolar concentration of DOX-EBP or free DOX, the conjugate accumulated at significantly higher levels in EGFR overexpressing cells than in non-EGFR-overexpressing cells, while the intracellular accumulation of free DOX was almost the same in all the cells. However, the intracellular accumulation of DOX-EBP was significantly reduced in EGFR-overexpressing cells preincubated with inhibitory anti-EGFR monoclonal antibody, demonstrating the involvement of EGFR pathway in the transport of the conjugate. Confocal fluorescence microscopy reveals that the conjugate was distributed in cytoplasmic and perinuclear areas during the first 30 min, whereas the free DOX was accumulated in both cytoplasm and nuclei. After 24 h, however, the DOX signal in the cells treated with DOX-EBP was also distributed in the nuclei, suggesting the release of DOX from the conjugate and entry into the nuclei. Biodistribution and in vivo antitumor experiments, together with in vitro cytotoxicity, indicate that the therapeutic competence of DOX-EBP was due to its increased accumulation in EGFR-expressing tumor cells. Furthermore, the survival of tumor-bearing mice treated with DOX-EBP was significantly higher than that with free DOX. These data demonstrate the enhanced anticancer efficacy and reduced systemic toxicity of DOX-EBP conjugate with targeting ability to EGFR overexpressing tumor cells. PMID- 21241068 TI - Identification and optimization of small molecules that restore E-cadherin expression and reduce invasion in colorectal carcinoma cells. AB - E-cadherin is a transmembrane protein that maintains intercellular contacts and cell polarity in epithelial tissue. The down-regulation of E-cadherin contributes to the induction of the epithelial-to-mesenchymal transition (EMT), resulting in an increased potential for cellular invasion of surrounding tissues and entry into the bloodstream. Loss of E-cadherin has been observed in a variety of human tumors as a result of somatic mutations, chromosomal deletions, silencing of the CDH1 gene promoter, and proteolytic cleavage. To date, no compounds directly targeting E-cadherin restoration have been developed. Here, we report the development and use of a novel high-throughput immunofluorescent screen to discover lead compounds that restore E-cadherin expression in the SW620 colon adenocarcinoma cell line. We confirmed restoration of E-cadherin using immunofluorescent microscopy and were able to determine the EC(50) for selected compounds using an optimized In-Cell Western assay. The profiled compounds were also shown to have a minimal effect on cell proliferation but did decrease cellular invasion. We have also conducted preliminary investigations to elucidate a discrete molecular target to account for the phenotypic behavior of these small molecules and have noted a modest increase in E-cadherin mRNA transcripts, and RNA-Seq analysis demonstrated that potent analogues elicited a 10-fold increase in CDH1 (E-cadherin) gene expression. PMID- 21241069 TI - Influence of efflux transporters on drug metabolism: theoretical approach for bioavailability and clearance prediction. AB - Cytochrome P450 enzymes and efflux transporters, expressed in the intestine and/or in the liver, play important roles in drug clearance and oral bioavailability. The relative contribution of transporters and enzymes in drug metabolism is still controversial. Some antiepileptic drugs, such as carbamazepine, phenytoin and phenobarbital (phenobarbitone), show time-dependent and dose-dependent pharmacokinetics due to their inductive effect on both efflux transporters and enzymes. However, steady-state plasma drug concentrations for each antiepileptic drug do not relate to oral daily dose in the same way, with decreased or increased apparent clearance according to the drug. A multicompartment pharmacokinetic model was developed in order to explain these different behaviours using a single mechanism of inductive action. The key for solving these apparent dissimilarities was to consider in the model the unique physiological connection that intestine, liver and bloodstream have. Efflux transporters not only enhance enzymatic competition in relation to first-order processes, but also change the predominance of some elimination routes. For instance, the carbamazepine-10,11-epoxide formation increases at the expense of other carbamazepine metabolites, enhancing both the systemic and presystemic elimination of parent drug. Conversely, the major hepatic metabolism of phenytoin diminishes in favour of its minor intestinal elimination, decreasing the total drug clearance. PMID- 21241070 TI - Clinical pharmacokinetics of metformin. AB - Metformin is widely used for the treatment of type 2 diabetes mellitus. It is a biguanide developed from galegine, a guanidine derivative found in Galega officinalis (French lilac). Chemically, it is a hydrophilic base which exists at physiological pH as the cationic species (>99.9%). Consequently, its passive diffusion through cell membranes should be very limited. The mean +/- SD fractional oral bioavailability (F) of metformin is 55 +/- 16%. It is absorbed predominately from the small intestine. Metformin is excreted unchanged in urine. The elimination half-life (t(½)) of metformin during multiple dosages in patients with good renal function is approximately 5 hours. From published data on the pharmacokinetics of metformin, the population mean of its clearances were calculated. The population mean renal clearance (CL(R)) and apparent total clearance after oral administration (CL/F) of metformin were estimated to be 510 +/- 130 mL/min and 1140 +/- 330 mL/min, respectively, in healthy subjects and diabetic patients with good renal function. Over a range of renal function, the population mean values of CL(R) and CL/F of metformin are 4.3 +/- 1.5 and 10.7 +/ 3.5 times as great, respectively, as the clearance of creatinine (CL(CR)). As the CL(R) and CL/F decrease approximately in proportion to CL(CR), the dosage of metformin should be reduced in patients with renal impairment in proportion to the reduced CL(CR). The oral absorption, hepatic uptake and renal excretion of metformin are mediated very largely by organic cation transporters (OCTs). An intron variant of OCT1 (single nucleotide polymorphism [SNP] rs622342) has been associated with a decreased effect on blood glucose in heterozygotes and a lack of effect of metformin on plasma glucose in homozygotes. An intron variant of multidrug and toxin extrusion transporter [MATE1] (G>A, SNP rs2289669) has also been associated with a small increase in antihyperglycaemic effect of metformin. Overall, the effect of structural variants of OCTs and other cation transporters on the pharmacokinetics of metformin appears small and the subsequent effects on clinical response are also limited. However, intersubject differences in the levels of expression of OCT1 and OCT3 in the liver are very large and may contribute more to the variations in the hepatic uptake and clinical effect of metformin. Lactic acidosis is the feared adverse effect of the biguanide drugs but its incidence is very low in patients treated with metformin. We suggest that the mean plasma concentrations of metformin over a dosage interval be maintained below 2.5 mg/L in order to minimize the development of this adverse effect. PMID- 21241071 TI - Pharmacokinetics of intravenous paracetamol in elderly patients. AB - BACKGROUND AND OBJECTIVES: Intravenous paracetamol (N-acetyl-paraminophenol, acetaminophen) is a widely used nonopioid analgesic which has become popular in the treatment of pain in many patient groups, including the elderly. Although intravenous paracetamol has been studied widely in clinical analgesia studies, there is little information on its pharmacokinetics in the elderly. We designed this study to determine the pharmacokinetics of intravenous paracetamol in very old patients and to compare them with that of younger patients. We also considered the effect of adenosine triphosphate-binding cassette G2 protein (ABCG2) genotype and renal function on paracetamol pharmacokinetics in these patients. METHODS: We compared the pharmacokinetics of intravenous paracetamol in four groups of ten patients, aged 20-40, 60-70, 70-80 and 80-90 years, undergoing orthopaedic surgery. Paracetamol 1000 mg was given by infusion over 15 minutes. Plasma concentrations of paracetamol and its glucuronide and sulphate conjugates were measured for 24 hours with a high-performance liquid chromatographic method and ABCG2 genotype was determined. Glomerular filtration rate (GFR) was estimated from age, sex and serum creatinine of the patient. RESULTS: In the group aged 80 90 years, the mean value of the area under the plasma concentration-time curve extrapolated to infinity (AUC(infinity)) of paracetamol was 54-68% higher than in the two youngest groups. Paracetamol clearance showed a statistically significant dependence on age group, whereas volume of distribution during elimination and elimination half-life were associated with age group and sex, respectively. Based on mean AUC(infinity) of paracetamol glucuronide and paracetamol sulphate, the oldest patients had 1.3- to 1.5-fold greater exposure to these metabolites than patients aged 20-40 years. ABCG2 genotype did not affect paracetamol pharmacokinetics. There was a linear correlation between the values of AUC(infinity) of paracetamol, its glucuronide and sulphate metabolites and GFR. CONCLUSION: Age and sex are important factors affecting the pharmacokinetics of paracetamol. The higher the age of the patient, the higher is the exposure to paracetamol. Female sex is associated with increased paracetamol concentrations but ABCG2 genotype does not seem to affect paracetamol pharmacokinetics. Trial registration number (EudraCT): 2006-001917-14. PMID- 21241072 TI - Quantitative prediction of human pharmacokinetics for monoclonal antibodies: retrospective analysis of monkey as a single species for first-in-human prediction. AB - BACKGROUND AND OBJECTIVES: Prediction of human pharmacokinetics for monoclonal antibodies (mAbs) plays an important role for first-in-human (FIH) dose selection. This retrospective analysis compares observed FIH pharmacokinetic data for 16 mAbs to those predicted in humans based on allometric scaling of Cynomolgus monkey pharmacokinetic data. METHODS: Ten mAbs exhibited linear pharmacokinetics in monkeys based on non-compartmental analysis. For these, simple allometric scaling based on bodyweight was applied to predict human clearance (CL) and volume of distribution (V(d)) from those obtained in monkeys. Six mAbs exhibited nonlinear pharmacokinetics in monkeys based on population modelling. For these, a population modelling approach using nonlinear mixed effects modelling software, NONMEM, was applied to describe monkey data by a two compartment pharmacokinetic model with parallel linear and nonlinear elimination from the central compartment. The pharmacokinetic parameters in monkeys were then scaled to humans based on simple allometry. Human concentration-time profiles of these mAbs were then simulated and compared with those observed in the FIH studies. RESULTS: Antibodies with linear elimination in monkeys also exhibited linear elimination in humans. For these, observed CL and V(d) were predicted within 2.3-fold by allometry. The predictability of human peak serum concentration (C(max)) and area under the serum concentration-time curve (AUC) for mAbs with nonlinear pharmacokinetics in monkeys was, however, concentration dependent. C(max) was consistently overestimated (up to 5.3-fold higher) when below the predicted Michaelis-Menten constant (Km; range 0.3-4 MUg/mL). The prediction of human C(max) was within 2.3-fold when concentrations greatly exceeded Km. Similarly, differences between predicted human AUCs and those observed in the FIH studies were much greater at low doses/concentrations. Consequently, predicted drug exposure in humans at low starting doses (range 0.01 0.3 mg/kg) in FIH studies was poorly estimated for three of six mAbs with nonlinear pharmacokinetics. CONCLUSIONS: Allometric prediction of human pharmacokinetics may be sufficient for mAbs that exhibit linear pharmacokinetics. For mAbs that exhibited nonlinear pharmacokinetics, the best predictive performance was obtained after doses that achieved target-saturating concentrations. PMID- 21241073 TI - Communication: A dramatic transition from nonferromagnet to ferromagnet in finite fused-azulene chain. AB - One-dimensional fused-azulene oligomers (n = 2-6) are studied with the effective valence bond as well as density functional theory methods. A nonferromagnetic (closed-shell singlet) to ferromagnetic (triplet) ground state transformation is witnessed with increasing length of oligomers. The computational results are interpreted in terms of spin coupling between the unpaired electrons of two nonbonding molecular orbitals localized, respectively, on the top and bottom chains of the oligomers. The present study provides a theoretical suggestion for understanding the ferromagnetic spin polarizations that has been observed very recently in graphene nanoribbons. PMID- 21241074 TI - The use of two-phase molecular dynamics simulations to determine the phase behavior and critical point of propane molecular models. AB - Molecular dynamics simulations were performed to determine two-phase configurations of model propane molecules below the critical point and in the near-critical, two-phase region. A postprocessor that uses a Monte Carlo method for determination of volumes attributable to each molecule was used to obtain density histograms of the particles from which the bulk coexisting equilibrium vapor and liquid densities were determined. This method of analyzing coexisting densities in a two-phase simulation is straightforward and can be easily implemented for complex, multisite models. Various degrees of internal flexibility in the propane models have little effect on the coexisting densities at temperatures 40 K or more below the critical point, but internal flexibility (angle bending and bond vibrations) does affect the saturated liquid densities in the near-critical region, changing the critical temperature by approximately 20 K. Shorter cutoffs were also found to affect the phase dome and the location of the critical point. PMID- 21241075 TI - Regarding the validity of the time-dependent Kohn-Sham approach for electron nuclear dynamics via trajectory surface hopping. AB - The implementation of fewest-switches surface-hopping (FSSH) within time dependent Kohn-Sham (TDKS) theory [Phys. Rev. Lett. 95, 163001 (2005)] has allowed us to study successfully excited state dynamics involving many electronic states in a variety of molecular and nanoscale systems, including chromophore semiconductor interfaces, semiconductor and metallic quantum dots, carbon nanotubes and graphene nanoribbons, etc. At the same time, a concern has been raised that the KS orbital basis used in the calculation provides only approximate potential energy surfaces [J. Chem. Phys. 125, 014110 (2006)]. While this approximation does exist in our method, we show here that FSSH-TDKS is a viable option for computationally efficient calculations in large systems with straightforward excited state dynamics. We demonstrate that the potential energy surfaces and nonadiabatic transition probabilities obtained within the TDKS and linear response (LR) time-dependent density functional theories (TDDFT) agree semiquantitatively for three different systems, including an organic chromophore ligating a transition metal, a quantum dot, and a small molecule. Further, in the latter case the FSSH-TDKS procedure generates results that are in line with FSSH implemented within LR-TDDFT. The FSSH-TDKS approach is successful for several reasons. First, single-particle KS excitations often give a good representation of LR excitations. In this regard, DFT compares favorably with the Hartree-Fock theory, for which LR excitations are typically combinations of multiple single particle excitations. Second, the majority of the FSSH-TDKS applications have been performed with large systems involving simple excitations types. Excitation of a single electron in such systems creates a relatively small perturbation to the total electron density summed over all electrons, and it has a small effect on the nuclear dynamics compared, for instance, with thermal nuclear fluctuations. In such cases an additional, classical-path approximation can be made. Third, typical observables measured in time-resolved experiments involve averaging over many initial conditions. Such averaging tends to cancel out random errors that may be encountered in individual simulated trajectories. Finally, if the flow of energy between electronic and nuclear subsystems is insignificant, the ad hoc FSSH procedure is not required, and a straightforward mean-field, Ehrenfest approach is sufficient. Then, the KS representation provides rigorously a convenient and efficient basis for numerically solving the TDDFT equations of motion. PMID- 21241076 TI - Vibrational transitions of the 7LiH+ ion calculated without the Born-Oppenheimer approximation and with leading relativistic corrections. AB - We recently presented very accurate calculations of the fundamental vibrational frequency of the (7)LiH(+) and (3)He(4)He(+) ions [Stanke et al. Phys. Rev. A 79, 060501(R) (2009)] performed without the Born-Oppenheimer approximation and included leading relativistic corrections. The accuracy of those calculations was estimated to be of the order of 0.06 cm(-1). In the present work we extend the calculations to the remaining pure vibrational states of (7)LiH(+) and similarly accurate results are generated. They may lead to the experimental search for still unidentified lines corresponding to those transitions. PMID- 21241077 TI - Visualizing electron correlation by means of ab initio scanning tunneling spectroscopy images of single molecules. AB - Scanning tunneling microscopy (STM) has been a fundamental tool to characterize many-body effects in condensed matter systems, from extended solids to quantum dots. STM of molecules decoupled from the supporting conductive substrate has the potential to extend STM characterization of many-body effects to the molecular world as well. In this paper, we describe a many-body tunneling theory for molecules decoupled from the STM substrate, and we report on the use of standard quantum chemical methods to calculate the quantities necessary to provide the "correlated" STM molecular image. The developed approach has been applied to 18 different molecules to explore the effects of their chemical nature and of their substituents, as well as to verify the possible contribution by transition metal centers. Whereas the bulk of calculations has been performed with the configuration interaction method with single and double excitations (CISD), because of the computational cost some tests have been also performed with the more accurate coupled cluster with single and double excitations (CCSD) method to quantify the importance of the computational level on many-body STM images. We have found that correlation induces a remarkable squeezing of the images, and that correlated images are not derived from Hartree-Fock HOMO or LUMO alone, but include contributions from other orbitals as well. Although correlation effects are too small to be resolved by present STM experiments for the studied molecules, our results provide hints for seeking out other species with larger, and possibly experimentally detectable, correlation effects. PMID- 21241078 TI - A new approach to decoherence and momentum rescaling in the surface hopping algorithm. AB - As originally proposed, the fewest switches surface hopping (FSSH) algorithm does not allow for decoherence between wavefunction amplitudes on different adiabatic surfaces. In this paper, we propose an inexpensive correction to standard FSSH dynamics wherein we explicitly model the decoherence of nuclear wave packets on distinct electronic surfaces. Our augmented fewest switches surface hopping approach is conceptually simple and, thus far, it has allowed us to capture several key features of the exact quantum results. Two points in particular merit attention. First, we obtain the correct branching ratios when a quantum particle passes through more than one region of nonadiabatic coupling. Second, our formalism provides a new and natural approach for rescaling nuclear momenta after a surface hop. Both of these features should become increasingly important as surface hopping schemes are applied to higher-dimensional problems. PMID- 21241079 TI - Autoionization widths by Stieltjes imaging applied to Lanczos pseudospectra. AB - Excited states of atoms and molecules lying above the ionization threshold can decay by electron emission in a process commonly known as autoionization. The autoionization widths can be calculated conveniently using Fano formalism and discretized atomic and molecular spectra by a standard procedure referred to as Stieltjes imaging. The Stieltjes imaging procedure requires the use of the full discretized spectrum of the final states of the autoionization, making its use for poly-atomic systems described by high-quality basis sets impractical. Following our previous work on photoionization cross-sections, here we show that also in the case of autoionization widths, the full diagonalization bottleneck can be overcome by the use of Lanczos pseudospectra. We test the proposed method by calculating the well-documented autoionization widths of inner-valence-excited neon and apply the new technique to autoionizing states of hydrofluoric acid and benzene. PMID- 21241080 TI - Potential curves for inner-shell states of CO calculated at multiconfigurational self-consistent field level. AB - A general strategy to calculate potential curves at multiconfigurational self consistent field (MCSCF) level for inner-shell states is reported in this paper. Convergence is commonly very tough for inner-shell states, especially at this level of calculation, due to the problem of variational collapse of the inner shell wave function to the ground or to a low-lying excited state. The present method allows to avoid this drawback by a sequence of constrained optimization in the orbital mixing step. The specific states studied are that resulting from transitions X (1)Sigma(+) -> (C 1s(-1) pi(*)) (1,3)Pi of CO. Accurate values are achieved for transition energies and vibrational splittings. A comparison is made with other approach, i.e., inner-shell CI based on a MCSCF wave function optimized for ground or low-lying excited states. This last approach is shown to fail in describing the whole potential curve. PMID- 21241081 TI - Performance of dynamically weighted multiconfiguration self-consistent field and spin-orbit coupling calculations of diatomic molecules of Group 14 elements. AB - The efficacy of several multiconfiguration self-consistent field (MCSCF) methods in the subsequent spin-orbit coupling calculations was studied. Three MCSCF schemes to generate molecular orbitals were analyzed: state-specific, state averaged, and dynamically weighted MCSCF. With Sn(2)(+) as the representative case, we show that the state-specific MCSCF orbitals lead to discontinuities in potential energy curves when avoided crossings of electronic states occur; this problem can be solved using the state-averaged or dynamically weighted MCSCF orbitals. The latter two schemes are found to give similar results when dynamic electron correlation is considered, which we calculated at the level of multiconfigurational quasidegenerate perturbation theory (MCQDPT). We employed the recently developed Douglas-Kroll spin-orbit adapted model core potential, ZFK3-DK3, and the dynamically weighted MCSCF scheme to calculate the spectroscopic constants of the mono-hydrides and compared them to the results obtained using the older set of potentials, MCP-TZP. We also showed that the MCQDPT tends to underestimate the dissociation energies of the hydrides and discussed to what extent coupled-cluster theory can be used to improve results. PMID- 21241082 TI - Simple and effective application of the Wang-Landau method for multicanonical molecular dynamics simulation. AB - We propose a novel application of the Wang-Landau method (WLM) for multicanonical molecular dynamics (McMD) simulations. Originally, WLM was developed for Monte Carlo (MC) simulations. Fundamentally, WLM remarkably reduces simulation efforts because it estimates the optimal multicanonical energy function automatically. When WLM is applied to McMD, not only the multicanonical energy but also energy gradient must be estimated adequately. However, because of the rugged multicanonical energy function at the early simulation stage, applications of WLM for MD simulations are difficult and require a smoothing procedure: simulation efforts such as cubic-spline extrapolation and gathering multiple preruns are utilized for smoothing. We propose a simple and effective smoothing method that requires only one additional equation and two time-dependent parameters. As a result, our method produced the correct multicanonical energy function and succeeded in the flat sampling of a small biomolecule with reduced simulation effort. PMID- 21241083 TI - Shape transformation of lipid vesicles induced by diffusing macromolecules. AB - The attachment of macromolecules to the surface of a lipid vesicle may cause its deformations such as budding or creation of cylindrical protrusions. Diffusion of the macromolecules in the membranes may cause its shape transformations. The process of shrinking the protrusions due to diffusion of the macromolecules is investigated. It is assumed that macromolecules modify locally the spontaneous curvature and bending rigidity of the lipid membrane. Both spontaneous curvature and bending rigidities depend on the concentration of membrane components. It has been shown that cylindrical protrusions are created when the macromolecules which induce large spontaneous curvature are accumulated at a piece of the vesicle surface. It has been observed that here the elastic constants influence very little the evolution of the vesicle shape caused by diffusing macromolecules and the most important is the value the spontaneous curvature imposed by the macromolecules. PMID- 21241084 TI - Estimating equilibrium ensemble averages using multiple time slices from driven nonequilibrium processes: theory and application to free energies, moments, and thermodynamic length in single-molecule pulling experiments. AB - Recently discovered identities in statistical mechanics have enabled the calculation of equilibrium ensemble averages from realizations of driven nonequilibrium processes, including single-molecule pulling experiments and analogous computer simulations. Challenges in collecting large data sets motivate the pursuit of efficient statistical estimators that maximize use of available information. Along these lines, Hummer and Szabo developed an estimator that combines data from multiple time slices along a driven nonequilibrium process to compute the potential of mean force. Here, we generalize their approach, pooling information from multiple time slices to estimate arbitrary equilibrium expectations. Our expression may be combined with estimators of path-ensemble averages, including existing optimal estimators that use data collected by unidirectional and bidirectional protocols. We demonstrate the estimator by calculating free energies, moments of the polymer extension, the thermodynamic metric tensor, and the thermodynamic length in a model single-molecule pulling experiment. Compared to estimators that only use individual time slices, our multiple time-slice estimators yield substantially smoother estimates and achieve lower variance for higher-order moments. PMID- 21241085 TI - A study of electron affinities using the initiator approach to full configuration interaction quantum Monte Carlo. AB - For the atoms with Z <= 11, energies obtained using the "initiator" extension to full configuration interaction quantum Monte Carlo (i-FCIQMC) come to within statistical errors of the FCIQMC results. As these FCIQMC values have been shown to converge onto FCI results, the i-FCIQMC method allows similar accuracy to be achieved while significantly reducing the scaling with the size of the Slater determinant space. The i-FCIQMC electron affinities of the Z <= 11 atoms in the aug-cc-pVXZ basis sets are presented here. In every case, values are obtained to well within chemical accuracy [the mean absolute deviation (MAD) from the relativistically corrected experimental values is 0.41 mE(h)], and significantly improve on coupled cluster with singles, doubles and perturbative triples [CCSD(T)] results. Since the only remaining source of error is basis set incompleteness, we have investigated using CCSD(T)-F12 contributions to correct the i-FCIQMC results. By doing so, much faster convergence with respect to basis set size may be achieved for both the electron affinities and the FCIQMC ionization potentials presented in a previous paper. With this F12 correction, the MAD can be further reduced to 0.13 mE(h) for the electron affinities and 0.31 mE(h) for the ionization potentials. PMID- 21241086 TI - Single center method: a computational tool for ionization and electronic excitation studies of molecules. AB - We discuss the recent progress in the development of the single center (SC) method for computation of highly-delocalized discrete and partial photoelectron wave continuous functions of molecules. Basic equations of the SC method are presented, and an efficient scheme for the numerical solution of a system of coupled Hartree-Fock equations for a photoelectron is described. Several illustrative applications of the method to photoionization and electronic excitation processes in diatomic molecules are considered. Thereby, we demonstrate its potential for theoretically studying angularly resolved molecular photoionization processes. PMID- 21241087 TI - Excitation energy calculation of conjugated hydrocarbons: a new Pariser-Parr Pople model parameterization approaching CASPT2 accuracy. AB - A new parameterization for the Pariser-Parr-Pople (PPP) model for conjugated hydrocarbons is proposed in this work. The distance-dependence of PPP parameters are obtained from CASPT2 ground state and low-lying excited state energies of ethylene and its cation at various C-C single bond lengths and are fitted to a set of carefully chosen mathematical functions. Our new PPP model is applied to the calculation of vertical singlet-triplet energy gaps and the excitation energies for low-lying pi->pi(*) valence excitations in various pi-conjugated molecules. Results with the new PPP model are consistently better than the standard PPP model in use. It often surpasses density functional theory and single-reference excited state methods such as configuration interaction singles or time-dependent density functional theory in terms of its accuracy and agrees reasonably well with high-level theories or experiments. PMID- 21241088 TI - Turning symmetric an asymmetric hydrogen bond with the inclusion of nuclear quantum effects: the case of the [CN...H...NC]- complex. AB - Nuclear quantum effects (NQE) on the geometry, energy, and electronic structure of the [CN.L.NC](-) complex (L = H, D, T) are investigated with the recently developed APMO/MP2 code. This code implements the nuclear molecular orbital approach (NMO) at the Hartree-Fock (HF) and MP2 levels of theory for electrons and quantum nuclei. In a first study, we examined the H/D/T isotope effects on the geometry and electronic structure of the CNH molecule at NMO/HF and NMO/MP2 levels of theory. We found that when increasing the hydrogen nuclear mass there is a reduction of the R(N-H) bond distance and an increase of the electronic population on the hydrogen atom. Our calculated bond distances are in good agreement with experimental and other theoretical results. In a second investigation, we explored the hydrogen NQE on the geometry of [CNHNC](-) complex at the NMO/HF and NMO/MP2 levels of theory. We discovered that while a NMO/HF calculation presented an asymmetric hydrogen bond, the NMO/MP2 calculation revealed a symmetric H-bond. We also examined the H/D/T isotope effects on the geometry and stabilization energy of the [CNHNC](-) complex. We noted that gradual increases in hydrogen mass led to reductions of the R(NN) distance and destabilization of the hydrogen bond (H-bond). A discussion of these results is given in terms of the hydrogen nuclear delocalization effects on the electronic structure and energy components. To the best of our knowledge, this is the first ab initio NMO study that reveals the importance of including nuclear quantum effects in conventional electronic structure calculations for an enhanced description of strong-low-barrier H-bonded systems. PMID- 21241089 TI - Improved hybrid functional for solids: the HSEsol functional. AB - We introduce the hybrid functional HSEsol. It is based on PBEsol, a revised Perdew-Burke-Ernzerhof functional, designed to yield accurate equilibrium properties for solids and their surfaces. We present lattice constants, bulk moduli, atomization energies, heats of formation, and band gaps for extended systems, as well as atomization energies for the molecular G2-1 test set. Compared to HSE, significant improvements are found for lattice constants and atomization energies of solids, but atomization energies of molecules are slightly worse than for HSE. Additionally, we present zero-point anharmonic expansion corrections to the lattice constants and bulk moduli, evaluated from ab initio phonon calculations. PMID- 21241090 TI - Broadband inversion for MAS NMR with single-sideband-selective adiabatic pulses. AB - We explain how and under which conditions it is possible to obtain an efficient inversion of an entire sideband family of several hundred kHz using low-power, sideband-selective adiabatic pulses, and we illustrate with some experimental results how this framework opens new avenues in solid-state NMR for manipulating spin systems with wide spinning-sideband (SSB) manifolds. This is achieved through the definition of the criteria of phase and amplitude modulation for designing an adiabatic inversion pulse for rotating solids. In turn, this is based on a framework for representing the Hamiltonian of the spin system in an NMR experiment under magic angle spinning (MAS). Following earlier ideas from Caravatti et al. [J. Magn. Reson. 55, 88 (1983)], the so-called "jolting frame" is used, which is the interaction frame of the anisotropic interaction giving rise to the SSB manifold. In the jolting frame, the shift modulation affecting the nuclear spin is removed, while the Hamiltonian corresponding to the RF field is frequency modulated and acquires a spinning-sideband pattern, specific for each crystallite orientation. PMID- 21241091 TI - Open-system electronic dynamics and thermalized electronic structure. AB - We propose and implement a novel computational method for simulating open-system electronic dynamics and obtaining thermalized electronic structures within an open quantum system framework. The system-bath interaction equation of motion is derived and modeled from the local harmonic oscillator description for electronic density change. The nonequilibrium electronic dynamics in a thermal bath is simulated using first-order kinetics. The resultant electronic densities are temperature-dependent and can take characteristics of the ground and excited states. We present results of calculations performed on H(2) and 1,3-butadiene performed at the Hartree-Fock level of theory using a minimal Slater-type orbital basis set. PMID- 21241092 TI - Monomer density profiles for polymer chains in confined geometries: massive field theory approach. AB - Taking into account the well known correspondence between the field theoretical phi(4) O(n)-vector model in the limit n -> 0 and the behavior of long flexible polymer chains in a good solvent, the universal density-force relation is analyzed and the corresponding universal amplitude ratio B(real) is obtained using the massive field theory approach in fixed space dimensions d < 4. The monomer density profiles of ideal chains and real polymer chains with excluded volume interaction in a good solvent between two parallel repulsive walls, one repulsive and one inert wall, are obtained in the framework of the massive field theory approach up to one-loop order. Besides, the monomer density profiles for the dilute polymer solution confined in semi-infinite space containing mesoscopic spherical particle of big radius are calculated. The obtained results are in qualitative agreement with previous theoretical investigations and with the results of Monte Carlo simulations. PMID- 21241093 TI - High-resolution electron spectroscopy, preferential metal-binding sites, and thermochemistry of lithium complexes of polycyclic aromatic hydrocarbons. AB - Polycyclic aromatic hydrocarbons are model systems for studying the mechanisms of lithium storage in carbonaceous materials. In this work, Li complexes of naphthalene, pyrene, perylene, and coronene were synthesized in a supersonic metal-cluster beam source and studied by zero-electron-kinetic-energy (ZEKE) electron spectroscopy and density functional theory calculations. The adiabatic ionization energies of the neutral complexes and frequencies of up to nine vibrational modes in the singly charged cations were determined from the ZEKE spectra. The metal-ligand bond energies of the neutral complexes were obtained from a thermodynamic cycle. Preferred Li/Li(+) binding sites with the aromatic molecules were determined by comparing the measured spectra with theoretical calculations. Li and Li(+) prefer the ring-over binding to the benzene ring with a higher pi-electron content and aromaticity. Although the ionization energies of the Li complexes show no clear correlation with the size of the aromatic molecules, the metal-ligand bond energies increase with the extension of the pi electron network up to perylene, then decrease from perylene to coronene. The trends in the ionization and metal-ligand bond dissociation energies of the complexes are discussed in terms of the orbital energies, local quadrupole moments, and polarizabilities of the free ligands and the charge transfer between the metal atom and aromatic molecules. PMID- 21241094 TI - Addition of one and two units of C2H to styrene: a theoretical study of the C10H9 and C12H9 systems and implications toward growth of polycyclic aromatic hydrocarbons at low temperatures. AB - Various mechanisms of the formation of naphthalene and its substituted derivatives have been investigated by ab initio G3(MP2,CC)/B3LYP/6-311G** calculations of potential energy surfaces for the reactions of one and two C(2)H additions to styrene combined with RRKM calculations of product branching ratios under single-collision conditions. The results show that for the C(2)H + styrene reaction, the dominant routes are H atom eliminations from the initial adducts; C(2)H addition to the vinyl side chain of styrene is predicted to produce trans or cis conformations of phenylvinylacetylene (t- and c-PVA), whereas C(2)H addition to the ortho carbon in the ring is expected to lead to the formation of o-ethynylstyrene. Although various reaction channels may lead to a second ring closure and the formation of naphthalene, they are not competitive with the direct H loss channels producing PVAs and ethynylstyrenes. However, c-PVA and o ethynylstyrene may undergo a second addition of the ethynyl radical to ultimately produce substituted naphthalene derivatives. alpha- and beta-additions of C(2)H to the side chain in c-PVA are calculated to form 2-ethynyl-naphthalene with branching ratios of about 30% and 96%, respectively; the major product in the case of alpha-addition would be cis-1-hexene-3,5-diynyl-benzene produced by an immediate H elimination from the initial adduct. C(2)H addition to the ethynyl side chain in o-ethynylstyrene is predicted to lead to the formation of 1-ethynyl naphthalene as the dominant product. The C(2)H + styrene -> t-PVA + H/c-PVA + H/ o-ethynylstyrene, C(2)H + c-PVA -> 2-ethynyl-naphthalene + H, and C(2)H + o ethynylstyrene -> 1-ethynyl-naphthalene + H reactions are calculated to occur without a barrier and with high exothermicity, with all intermediates, transition states, and products lying significantly lower in energy than the initial reactants, and hence to be fast even at very low temperature conditions prevailing in Titan's atmosphere or in the interstellar medium. If styrene and C(2)H are available and overlap, the sequence of two C(2)H additions can result in the closure of a second aromatic ring and thus provide a viable route to the formation of 1- or 2-ethynyl-naphthalene. The analogous mechanism can be extrapolated to the low-temperature growth of polycyclic aromatic hydrocarbons (PAH) in general, as a step from a vinyl-PAH to an ethynyl-substituted PAH with an extra aromatic ring. PMID- 21241095 TI - Ultrafast charge separation driven by differential particle and hole mobilities. AB - The process of a local excitation evolving into an intramolecular charge separated state is followed and compared for several systems by directly simulating the time propagation of the electronic wavefunction. The wavefunction and Hamiltonian are handled using the extended second-order algebraic diagrammatic construction (ADC(2)-x), which explicitly accounts for electron correlation in the dynamic many-particle state. The details of the charge separation can be manipulated according to the chemical composition of the system; atoms which dope the conjugated system with either particles or holes are shown to effect whether the particle or hole is more mobile. Initially, the charges oscillate between the ends of linear molecules (with different rates), separating periodically, but, at long times, both charges tend to spread over the whole molecule. Charge separation is also shown to occur for asymmetric systems, where it may eventually be experimentally feasible to excite a localized resonance (nonstationary state) on one end of the molecule preferentially and follow the ensuing dynamics. PMID- 21241096 TI - Role of higher excited electronic states on high harmonic generation in H2(+)--a time-independent Hermitian Floquet approach. AB - We have theoretically studied the role of high-lying molecular electronic states on the high harmonic generation (HHG) in H(2)(+) within the framework of a time independent Hermitian nonperturbative three-dimensional Floquet technique for continuous wave monochromatic lasers of intensities of 2.59 * 10(13), 4.0 * 10(13), and 5.6 * 10(13) W/cm(2), and wavelengths of 1064, 532, and 355 nm. To evaluate the HHG spectra, the resonance Floquet quasienergy and the Fourier components of the Floquet state corresponding to the initial vibrational rotational level v = 0, J = 0 have been computed by solving the time-independent close-coupled Schrodinger equation following the Floquet method. The calculations include seven molecular electronic states in the basis set expansion of the Floquet state. The electronic states considered, apart from the two lowest 1ssigma(g) and 2psigma(u) states, are 2ppi(u), 2ssigma(g), 3psigma(u), 3dsigma(g), and 4fsigma(u). All the concerned higher excited molecular electronic states asymptotically degenerate into the atomic state H(2 l) with l = 0, 1. The computations reveal signature of significant oscillations in the HHG spectra due to the interference effect of the higher molecular electronic states for all the considered laser intensities and wavelengths. We have attempted to explain, without invoking any ionization, the dynamics of HHG in H(2)(+) within the framework of electronic transitions due to the electric dipole moments and the nuclear motions on the field coupled ground, the first and the higher excited electronic states of this one-electron molecular ion. PMID- 21241097 TI - Calculations of fine-structure resolved collisional rate coefficients for the NH(X3Sigma-)-He system. AB - We present fine-structure-resolved collisional rate coefficients for the NH(X(3)Sigma(-))-He van der Waals complex. The calculations are based on the state-of-the-art potential energy surface [Cybulski et al., J. Chem. Phys. 122, 094307 (2005)]. Close-coupling calculations of the collisional excitation cross sections of the fine-structure levels of NH by He are calculated for total energies up to 3500 cm(-1), which yield, after thermal average, rate coefficients up to 350 K. The fine-structure splitting of rotational levels is taken into account rigorously. The propensity rules between fine-structure levels are reported, and it is found that F-conserving cross sections are much larger than F changing cross sections, as expected from theoretical considerations. The calculated rate coefficients are compared with available experimental measurements at room temperature and a fairly good agreement is found between experimental and theoretical data. The agreement confirms the relatively good quality of the scattering calculations and also the accuracy of the potential energy surface used in this work. The new set of thermal rate coefficients for this system may be used for improvements in astrophysical and atmospherical modeling. PMID- 21241098 TI - Interactions of M(z)-X complexes (M = Cu, Ag, and Au; X = He, Ne, and Ar; and z = +/-1). AB - The coupled cluster singles and doubles method with perturbative treatment of triple excitations is applied to calculate the potentials of M(z)-X complexes (M = Cu, Ag, and Au; X = He, Ne, and Ar; and z = +/-1). The bond functions and the basis set superposition errors are considered to obtain accurate interaction energies. The potential energy curves of all complexes are obtained. The vibrational energy levels and the spectroscopic parameters for these complexes are determined. The analytical potential energy functions are also fitted based on the potential energies. PMID- 21241099 TI - Quantum theory of time-resolved femtosecond stimulated Raman spectroscopy: direct versus cascade processes and application to CDCl3. AB - We present a quantum mechanical wave packet treatment of time-resolved femtosecond stimulated Raman spectroscopy (FSRS), or two-dimensional (2D) FSRS, where a vibrational coherence is initiated with an impulsive Raman pump which is subsequently probed by FSRS. It complements the recent classical treatment by Mehlenbacher et al. [J. Chem. Phys. 131, 244512 (2009)]. In this 2D-FSRS, two processes can occur concurrently but with different intensities: a direct fifth order process taking place on one molecule, and a cascade process comprising two third-order processes on two different molecules. The cascade process comprises a parallel and a sequential cascade. The theory is applied to the 2D-FSRS of CDCl(3) where calculations showed that: (a) the cascade process is stronger than the direct fifth-order process by one order of magnitude, (b) the sidebands assigned to C-Cl E and A(1) bends, observed on both sides of the Stokes C-D stretch frequency, are not due to anharmonic coupling between the C-D stretch and the C-Cl bends, but are instead due to the coherent anti-Stokes Raman spectroscopy (CARS) and coherent Stokes Raman spectroscopy (CSRS) fields produced in the first step of the cascade process, (c) for each delay time between the femtosecond impulsive pump and FSRS probe pulses, the line shape of the sidebands shows an inversion symmetry about the C-D stretch frequency, and this is due to the 180(?) phase difference between the CARS and CSRS fields that produced the left and right sidebands, and (d) for each sideband, the line shape changes from positive Lorentzian to dispersive to negative Lorentzian, then to negative dispersive and back to positive Lorentzian with the period of the bending vibration, and it is correlated with the momentum of the wave packet prepared on the ground-state surface by the impulsive pump along the sideband normal coordinate. PMID- 21241100 TI - Electron ionization of methane: the dissociation of the methane monocation and dication. AB - Time-of-flight mass spectrometry and two-dimensional coincidence techniques have been used to determine, for the first time, the relative precursor-specific partial ionization cross sections following electron-methane collisions. Precursor-specific partial ionization cross sections quantify the contribution of single, double, and higher levels of ionization to the partial ionization cross section for forming a specific ion (e.g. CH(+)) following electron ionization of methane. Cross sections are presented for the formation of H(+), H(2)(+), C(+), CH(+), CH(2)(+), and CH(3)(+), relative to CH(4)(+), at ionizing electron energies from 30 to 200 eV. We can also reduce our dataset to derive the relative partial ionization cross sections for the electron ionization of methane, for comparison with earlier measurements. These relative partial ionization cross sections are in good agreement with recent determinations. However, we find that there is significant disagreement between our partial ionization cross sections and those derived from earlier studies. Inspection of the values of our precursor specific partial ionization cross sections shows that this disagreement is due to the inefficient collection of energetic fragment ions in the earlier work. Our coincidence experiments also show that the lower energy electronic states of CH(4)(2+) populated by electron double ionization of CH(4) at 55 eV are the same (ground (3)T(1), first excited (1)E(1)) as those populated by 40.8 eV photoionization. The (3)T(1) state dissociating to form CH(3)(+) + H(+) and CH(2)(+) + H(2)(+) and the (1)E(1) to form CH(2)(+) + H(+) and CH(+) + H(+). At this electron energy, we also observe population of the first excited triplet state of CH(4)(2+) ((3)T(2)) which dissociates to both CH(2)(+) + H(+) + H and CH(+) + H(+) + H(2). PMID- 21241101 TI - State-to-state reactive scattering in six dimensions using reactant-product decoupling: OH + H2 -> H2O + H (J = 0). AB - We extend to full dimensionality a recently developed wave packet method [M. T. Cvitas and S. C. Althorpe, J. Phys. Chem. A 113, 4557 (2009)] for computing the state-to-state quantum dynamics of AB + CD -> ABC + D reactions and also increase the computational efficiency of the method. This is done by introducing a new set of product coordinates, by applying the Crank-Nicholson approximation to the angular kinetic energy part of the split-operator propagator and by using a symmetry-adapted basis-to-grid transformation to evaluate integrals over the potential energy surface. The newly extended method is tested on the benchmark OH + H(2) -> H(2)O + H reaction, where it allows us to obtain accurately converged state-to-state reaction probabilities (on the Wu-Schatz-Fang-Lendvay-Harding potential energy surface) with modest computational effort. These methodological advances will make possible efficient calculations of state-to-state differential cross sections on this system in the near future. PMID- 21241102 TI - Guided ion beam and theoretical study of the reactions of Au+ with H2, D2, and HD. AB - Reactions of the late third-row transition metal cation Au(+) with H(2), D(2), and HD are examined using guided ion beam tandem mass spectrometry. A flow tube ion source produces Au(+) in its (1)S (5d(10)) electronic ground state level. Corresponding state-specific reaction cross sections for forming AuH(+) and AuD(+) as a function of kinetic energy are obtained and analyzed to give a 0 K bond dissociation energy of D(0)(Au(+)-H) = 2.13 +/- 0.11 eV. Quantum chemical calculations at the B3LYP/HW+/6-311+G(3p) and B3LYP/Def2TZVPP levels performed here show good agreement with the experimental bond energy. Theory also provides the electronic structures of these species and the reactive potential energy surfaces. We also compare this third-row transition metal system with previous results for analogous reactions of the first-row and second-row congeners, Cu(+) and Ag(+). We find that Au(+) has a stronger M(+)-H bond, which can be explained by the lanthanide contraction and relativistic effects that alter the relative size of the valence s and d orbitals. Results from reactions with HD provide insight into the reaction mechanism and indicate that ground state Au(+) reacts largely via a direct mechanism, in concordance with the behavior of the lighter group 11 metal ions, but includes more statistical behavior than these metals as well. PMID- 21241103 TI - Structures and energetics of small lead cluster ions. AB - By a combination of gas phase ion mobility measurements and relativistic density functional theory calculations with inclusion of spin-orbit coupling, we assign structures of lead cluster cations and anions in the range between 4 and 15 atoms. We find a planar rhombus for the tetramer, a trigonal bipyramid for the pentamer, and a pentagonal bipyramid for the heptamer, independent of charge state. For the hexamer, the cation and anion structures differ: we find an octahedron for the anion while the cation consists of fused tetrahedra. For the octamer, we find in both cases structures based on the pentagonal bipyramid motif plus adatom. For the larger clusters investigated we always find different structures for cations and anions. For example, Pb(12)(-) is confirmed to be a hollow icosahedron while Pb(12)(+) is a truncated filled icosahedron. Pb(13)(+) is a filled icosahedron but Pb(13)(-) is a hollow icosahedron with the additional atom capping a face. In order to get experimental information on the relative stabilities, we investigated the collision induced dissociation mass spectra for the different cluster sizes and charge states, and observe a strong correlation with the calculated fragmentation energies. Up to n = 13 the main fragmentation channel is atom loss; for the larger cluster sizes we observe fission into two large fragments. This channel is dominant for larger anions, less pronounced but clearly present for the cations. PMID- 21241104 TI - SH...N and SH...P blue-shifting H-bonds and N...P interactions in complexes pairing HSN with amines and phosphines. AB - Quantum calculations at the MP2/aug-cc-pVDZ level examine complexes pairing HSN with aliphatic amines and phosphines. Complexes are cyclic and contain two attractive interactions. The first is a SH...N/P H-bond in which the S-H covalent bond contracts and shifts its stretching frequency to the blue, more so for amines than for phosphines. The second interaction is different for the amines and phosphines. The amines engage in a NH...N H-bond comparable in strength to the aforementioned SH...N interaction. In contrast, the second interaction in the phosphine complexes is a direct N...P attraction without an intervening H. This interaction is due in part to opposite partial charges on the N and P atoms, as well as covalent forces generated by charge transfer effects. PMID- 21241105 TI - Ultrafast photofragmentation dynamics of molecular iodine driven with timed XUV and near-infrared light pulses. AB - Photofragmentation dynamics of molecular iodine was studied as a response to the joint illumination with femtosecond 800 nm near-infrared and 13 nm extreme ultraviolet (XUV) pulses delivered by the free-electron laser facility FLASH. The interaction of the molecular target with two light pulses of different wavelengths but comparable pulse energy elucidates a complex intertwined electronic and nuclear dynamics. To follow distinct pathways out of a multitude of reaction channels, the recoil of created ionic fragments is analyzed. The delayed XUV pulse provides a way of following molecular photodissociation of I(2) with a characteristic time-constant of (55 +/- 10) fs after the laser-induced formation of antibonding states. A preceding XUV pulse, on the other hand, preferably creates a 4d(-1) inner-shell vacancy followed by the fast Auger cascade with a revealed characteristic time constant tau(A2)=(23+/-11) fs for the second Auger decay transition. Some fraction of molecular cationic states undergoes subsequent Coulomb explosion, and the evolution of the launched molecular wave packet on the repulsive Coulomb potential was accessed by the laser-induced postionization. A further unexpected photofragmentation channel, which relies on the collective action of XUV and laser fields, is attributed to a laser-promoted charge transfer transition in the exploding molecule. PMID- 21241106 TI - Photodissociation of protonated leucine-enkephalin in the VUV range of 8-40 eV. AB - Until now, photodissociation studies on free complex protonated peptides were limited to the UV wavelength range accessible by intense lasers. We have studied photodissociation of gas-phase protonated leucine-enkephalin cations for vacuum ultraviolet (VUV) photons energies ranging from 8 to 40 eV. We report time-of flight mass spectra of the photofragments and various photofragment-yields as a function of photon energy. For sub-ionization energies our results are in line with existing studies on UV photodissociation of leucine-enkephalin. For photon energies exceeding 10 eV we could identify a new dissociation scheme in which photoabsorption leads to a fast loss of the tyrosine side chain. This loss process leads to the formation of a residual peptide that is remarkably cold internally. PMID- 21241107 TI - Kinetic study on the H + SiH4 abstraction reaction using an ab initio potential energy surface. AB - Variational transition state theory calculations with the correction of multidimensional tunneling are performed on a 12-dimensional ab initio potential energy surface for the H + SiH(4) abstraction reaction. The surface is constructed using a dual-level strategy. For the temperature range 200-1600 K, thermal rate constants are calculated and kinetic isotope effects for various isotopic species of the title reaction are investigated. The results are in very good agreement with available experimental data. PMID- 21241108 TI - Electronically excited rubidium atom in helium clusters and films. II. Second excited state and absorption spectrum. AB - Following our work on the study of helium droplets and film doped with one electronically excited rubidium atom Rb(*) ((2)P) [M. Leino, A. Viel, and R. E. Zillich, J. Chem. Phys. 129, 184308 (2008)], we focus in this paper on the second excited state. We present theoretical studies of such droplets and films using quantum Monte Carlo approaches. Diffusion and path integral Monte Carlo algorithms combined with a diatomics-in-molecule scheme to model the nonpair additive potential energy surface are used to investigate the energetics and the structure of Rb(*)He(n) clusters. Helium films as a model for the limit of large clusters are also considered. As in our work on the first electronic excited state, our present calculations find stable Rb(*)He(n) clusters. The structures obtained are however different with a He-Rb(*)-He exciplex core to which more helium atoms are weakly attached, preferentially on one end of the core exciplex. The electronic absorption spectrum is also presented for increasing cluster sizes as well as for the film. PMID- 21241109 TI - Quantum reaction boundary to mediate reactions in laser fields. AB - Dynamics of passage over a saddle is investigated for a quantum system under the effect of time-dependent external field (laser pulse). We utilize the recently developed theories of nonlinear dynamics in the saddle region, and extend them to incorporate both time-dependence of the external field and quantum mechanical effects of the system. Anharmonic couplings and laser fields with any functional form of time dependence are explicitly taken into account. As the theory is based on the Weyl expression of quantum mechanics, interpretation is facilitated by the classical phase space picture, while no "classical approximation" is involved. We introduce a quantum reactivity operator to extract the reactive part of the system. In a model system with an optimally controlled laser field for the reaction, it is found that the boundary of the reaction in the phase space, extracted by the reactivity operator, is modulated with time by the effect of the laser field, to "catch" the system excited in the reactant region, and then to "release" it into the product region. This method provides new insights in understanding the origin of optimal control of chemical reactions by laser fields. PMID- 21241110 TI - Decomposition of excited electronic state s-tetrazine and its energetic derivatives. AB - Decomposition of excited electronic state s-tetrazine and its energetic derivatives, such as 3-amino-6-chloro-1,2,4,5-tetrazine-2,4-dioxide (ACTO), and 3,3(')-azobis (6-amino-1,2,4,5-tetrazine)-mixed N-oxides (DAATO(3.5)), is investigated through laser excitation and resonance enhanced multi photon ionization techniques. The N(2) molecule is detected as an initial product of the s-tetrazine decomposition reaction, through its two photon, resonance absorption transitions [a(") (1)Sigma(g)(+) (v(') = 0) <- X (1)Sigma(g)(+) (v(") = 0)]. The suggested mechanism for this reaction is a concerted triple dissociation yielding rotationally cold (~20 K) ground electronic state N(2) and 2 HCN molecules. The comparable decomposition of excited electronic state ACTO and DAATO(3.5) yields an NO product with a cold rotational (~20 K) but a hot vibrational (~1200 K) distribution. Thus, tetrazine and its substituted energetic materials ACTO and DAATO(3.5) evidence different decomposition mechanisms upon electronic excitation. N(2)O is excluded as a potential intermediate precursor of the NO product observed from these two s-tetrazine derivatives through direct determination of its decomposition behavior. Calculations at the CASMP2/CASSCF level of theory predict a concerted triple dissociation mechanism for generation of the N(2) product from s-tetrazine, and a ring contraction mechanism for the generation of the NO product from the energetic s-tetrazine derivatives. Relaxation from S(n) evolves through a series of conical intersections to S(0), upon which surface the dissociation occurs in both mechanisms. This work demonstrates that the substituents on the tetrazine ring change the characteristics of the potential energy surfaces of the derivatives, and lead to a completely different decomposition pathway from s-tetrazine itself. Moreover, the N(2) molecule can be excluded as an initial product from decomposition of these excited electronic state energetic materials. PMID- 21241111 TI - Quantum and classical study of surface characterization by three-dimensional helium atom scattering. AB - Exact time-dependent wavepacket calculations of helium atom scattering from model symmetric, chiral, and hexagonal surfaces are presented and compared with their classical counterparts. Analysis of the momentum distribution of the scattered wavepacket provides a convenient method to obtain the resulting energy and angle resolved scattering distributions. The classical distributions are characterized by standard rainbow scattering from corrugated surfaces. It is shown that the classical results are closely related to their quantum counterparts and capture the qualitative features appearing therein. Both the quantum and classical distributions are capable of distinguishing between the structures of the three surfaces. PMID- 21241112 TI - A new ab initio potential energy surface for the NeCO complex with the vibrational coordinate dependence. AB - A new high quality three-dimensional potential energy surface for the Ne-CO van der Waals complex is developed using the CCSD(T) method and avqz/avqz+33221 basis set. The ab initio calculation is performed in a total of 1365 configurations with supermolecule method. There is a single global minimum located in a nearly T shaped geometry. The global minimum energy is -49.4090 cm(-1) at R(e)=6.40a(0) and theta(e)=82.5(?) for V(00). Using the three-dimensional potential energy surface, we have calculated bound rovibrational energy levels up to J = 10 including the Coriolis coupling terms. Compared with the experimental transition frequencies, the theoretical results are in good agreement with the experimental results. PMID- 21241113 TI - The X 1Sigma+ state of LiRb studied by Fourier-transform spectroscopy. AB - We report on the first experimental observation of the ground electronic state of the LiRb molecule at high resolution. A large body of experimental data was collected which led to an accurate potential energy curve for this state. Transitions to the lowest triplet state were also observed, but these data are rather fragmentary and allow only a first attempt for the description of this state. Both potentials were used for evaluating published Feshbach resonances of this molecule. We compare the results of this study with those of the related LiK and LiCs molecules. PMID- 21241114 TI - Dominant folding pathways of a peptide chain from ab initio quantum-mechanical simulations. AB - Using the dominant reaction pathways method, we perform an ab initio quantum mechanical simulation of a conformational transition of a peptide chain. The method we propose makes it possible to investigate the out-of-equilibrium dynamics of these systems, without resorting to an empirical representation of the molecular force field. It also allows to study rare transitions involving rearrangements in the electronic structure. By comparing the results of the ab initio simulation with those obtained by employing a standard force field, we discuss its capability to describe the nonequilibrium dynamics of conformational transitions. PMID- 21241115 TI - Homogeneous nucleation in vapor-liquid phase transition of Lennard-Jones fluids: a density functional theory approach. AB - Density functional theory (DFT) with square gradient approximation for the free energy functional and a model density profile are used to obtain an analytical expression for the size-dependent free energy of formation of a liquid drop from the vapor through the process of homogeneous nucleation, without invoking the approximations used in classical nucleation theory (CNT). The density of the liquid drop in this work is not the same as the bulk liquid density but it corresponds to minimum free energy of formation of the liquid drop. The theory is applied to study the nucleation phenomena from supersaturated vapor of Lennard Jones fluid. The barrier height predicted by this theory is significantly lower than the same in CNT which is rather high. The density at the center of the small liquid drop as obtained through optimization is less than the bulk density which is in agreement with other earlier works. Also proposed is a sharp interface limit of the proposed DFT of nucleation, which is as simple as CNT but with a modified barrier height and this modified classical nucleation theory, as we call it, is shown to lead to improved results. PMID- 21241116 TI - Modeling the interactions of phthalocyanines in water: from the Cu(II) tetrasulphonate to the metal-free phthalocyanine. AB - A quantum and statistical study on the effects of the ions Cu(2+) and SO(3)(-) in the solvent structure around the metal-free phthalocyanine (H(2)Pc) is presented. We developed an ab initio interaction potential for the system CuPc-H(2)O based on quantum chemical calculations and studied its transferability to the H(2)Pc H(2)O and [CuPc(SO(3))(4)](4-)-H(2)O interactions. The use of the molecular dynamics technique allows the determination of energetic and structural properties of CuPc, H(2)Pc, and [CuPc(SO(3))(4)](4-) in water and the understanding of the keys for the different behaviors of the three phthalocyanine (Pc) derivatives in water. The inclusion of the Cu(2+) cation in the Pc structure reinforces the appearance of two axial water molecules and second-shell water molecules in the solvent structure, whereas the presence of SO(3)(-) anions implies a well defined hydration shell of about eight water molecules around them making the macrocycle soluble in water. Debye-Waller factors for axial water molecules have been obtained in order to examine the potential sensitivity of the extended x-ray absorption fine structure technique to detect the axial water molecules. PMID- 21241117 TI - Ultrafast optical multidimensional spectroscopy without interferometry. AB - We present here the details of a phase retrieval technique that provides access to multidimensional modalities that are not currently available using existing interferometric techniques. The development of multidimensional optical spectroscopy has facilitated significant insights into electronic processes in physics, chemistry, and biology. The versatility and number of available techniques are, however, significantly limited by the requirement that the detection be interferometric. Many of these techniques are closely related to the vast range of multidimensional NMR spectroscopies, which revolutionized analytical chemistry more than 30 years ago. We focus here on the specific case of two-color multidimensional spectroscopy (analogous to heteronuclear NMR) and discuss the details of an iterative algorithm that recovers the relative phase relationships required to perform the Fourier transformation and find the unique solution for the 2D spectrum. A detailed guide is provided that describes the practical implementation of such algorithms. The effectiveness and accuracy of the phase retrieval process are assessed for simulated one- and two-color experiments. It is also compared with one-color experimental data for which the target phase information has been obtained independently by interferometry. In all the cases, the present algorithm yields results that compare well with the solutions obtained by other means. There are, however, some limitations and potential pitfalls that are identified and discussed. We conclude with a discussion of the potential applications and further advances that may be possible by adopting iterative phase retrieval algorithms of the type discussed here. PMID- 21241118 TI - Long-range dynamic correlations in a compressible viscous fluid confined in a circular tube. AB - A set of simplified one-dimensional hydrodynamic equations proposed for the description of transient small amplitude flow of a compressible viscous fluid in a linear channel is tested by comparison with exact results for a circular tube obtained from the linearized Navier-Stokes equations. There is a qualitative agreement between the approximate and exact results, but for the simplified calculation the amplitude of the algebraic long-time tail is a factor of 2 too small. PMID- 21241119 TI - Demonstration and interpretation of significant asymmetry in the low-resolution and high-resolution Q(y) fluorescence and absorption spectra of bacteriochlorophyll a. AB - Low- and high-resolution absorption and fluorescence emission Q(y) spectra of bacteriochlorophyll a (BChl a) were recorded, along with homogeneous band line shapes, revealing significant asymmetry between the absorption and emission profiles that are interpreted using a priori spectral calculations. The spectra were recorded in a range of organic solvents facilitating both penta- and hexa coordination of Mg at ambient and cryogenic temperatures. Detailed vibrational structure in the ground electronic state, virtually independent of Mg coordination, was revealed at 4.5 K by a hole-burning fluorescence line-narrowing technique, complementing the high-resolution spectrum of the excited state measured previously by hole burning to provide the first complete description of the Q(y) absorption and fluorescence spectra of BChl a. Spectral asymmetry persists from 4.5 to 298 K. Time-dependent density-functional theory calculations of the gas-phase absorption and emission spectra obtained using the CAM-B3LYP density functional, curvilinear coordinates, and stretch-bend-torsion scaling factors fitted to data for free-base porphyrin quantitatively predict the observed frequencies of the most-significant vibrational modes as well as the observed absorption/emission asymmetry. Most other semi-empirical, density functional, and ab initio computational methods severely overestimate the electron-vibrational coupling and its asymmetry. It is shown that the asymmetry arises primarily through Duschinsky rotation. PMID- 21241120 TI - Dependence of the localized surface plasmon resonance of noble metal quasispherical nanoparticles on their crystallinity-related morphologies. AB - The absorption spectra of 5 nm noble metal nanoparticles (Ag, Au, and Cu) with typical morphologies of multiply twinned particles (MTPs) and single crystals are calculated by using the discrete dipole approximation method. Among the considered morphologies, it is found that icosahedral, cuboctahedral and truncated octahedral particles behave like quasispherical particles whereas the optical response of the decahedral particles significantly differs from the others. This result, which originates from the shape anisotropy of the decahedron, points out the capacity to discriminate decahedral MTPs from a population of particles with mixed crystallinities and related quasispherical shapes. PMID- 21241121 TI - Joint analysis of ESR lineshapes and 1H NMRD profiles of DOTA-Gd derivatives by means of the slow motion theory. AB - The "Swedish slow motion theory" [Nilsson and Kowalewski, J. Magn. Reson. 146, 345 (2000)] applied so far to Nuclear Magnetic Relaxation Dispersion (NMRD) profiles for solutions of transition metal ion complexes has been extended to ESR spectral analysis, including in addition g-tensor anisotropy effects. The extended theory has been applied to interpret in a consistent way (within one set of parameters) NMRD profiles and ESR spectra at 95 and 237 GHz for two Gd(III) complexes denoted as P760 and P792 (hydrophilic derivatives of DOTA-Gd, with molecular masses of 5.6 and 6.5 kDa, respectively). The goal is to verify the applicability of the commonly used pseudorotational model of the transient zero field splitting (ZFS). According to this model the transient ZFS is described by a tensor of a constant amplitude, defined in its own principal axes system, which changes its orientation with respect to the laboratory frame according to the isotropic diffusion equation with a characteristic time constant (correlation time) reflecting the time scale of the distortional motion. This unified interpretation of the ESR and NMRD leads to reasonable agreement with the experimental data, indicating that the pseudorotational model indeed captures the essential features of the electron spin dynamics. PMID- 21241122 TI - Molecular dynamics simulation of liquid methanol. I. Molecular modeling including C-H vibration and Fermi resonance. AB - A flexible and polarizable methanol model has been developed on the basis of charge response kernel (CRK) theory. The present CRK methanol model well reproduces bulk liquid and interfacial properties, including density, enthalpy of vaporization, diffusion coefficient, surface tension, and radial distribution functions. The modeling of intramolecular potential incorporates the anharmonic coupling effects pertinent to the Fermi resonance of stretching and bending overtones, with its effective quantum correction. Therefore, the present methanol model can describe the vibrational spectroscopic features of infrared, Raman, and sum frequency generation spectra of C-H or C-D stretching region of methanol or deuterated methanol on the same footing. This model allows for further detailed analysis of C-H vibrations of alkyl moieties by molecular dynamics simulation. PMID- 21241123 TI - Molecular dynamics simulation of liquid methanol. II. Unified assignment of infrared, Raman, and sum frequency generation vibrational spectra in methyl C-H stretching region. AB - Vibrational spectra of methyl C-H stretching region are notoriously complicated, and thus a theoretical method of systematic assignment is strongly called for in condensed phase. Here we develop a unified analysis method of the vibrational spectra, such as infrared (IR), polarized and depolarized Raman, and ssp polarized sum frequency generation (SFG), by flexible and polarizable molecular dynamics simulation. The molecular model for methanol has been developed by charge response kernel model to allow for analyzing the methyl C-H stretching vibrations. The complicated spectral structure by the Fermi resonance has been unraveled by empirically shifting potential parameters, which provides clear information on the coupling mechanism. The analysis confirmed that for the IR, polarized Raman, and SFG spectra, two-band structure at about 2830 and 2950 cm( 1) results from the Fermi resonance splitting of the methyl C-H symmetric stretching and bending overtones. In the IR spectrum, the latter, higher frequency band is overlapped with prominent asymmetric C-H stretching bands. In the depolarized Raman spectrum, the high frequency band at about 2980 cm(-1) is assigned to the asymmetric C-H stretching mode. In the SFG spectrum, the two bands of the splitted symmetric C-H stretching mode have negative amplitudes of imaginary nonlinear susceptibility chi(2), while the higher-frequency band is partly cancelled by positive imaginary components of asymmetric C-H stretching modes. PMID- 21241124 TI - Thermodynamic and dynamic anomalies in a one-dimensional lattice model of liquid water. AB - We investigate the occurrence of waterlike thermodynamic and dynamic anomalous behavior in a one dimensional lattice gas model. The system thermodynamics is obtained using the transfer matrix technique and anomalies on density and thermodynamic response functions are found. When the hydrogen bond (molecules separated by holes) is more attractive than the van der Waals interaction (molecules in contact) a transition between two fluid structures is found at null temperature and high pressure. This transition is analogous to a 'critical point' and intimately connects the anomalies in density and in thermodynamic response functions. Monte Carlo simulations were performed in the neighborhood of this transition and used to calculate the self diffusion constant, which increases with density as in liquid water. PMID- 21241125 TI - Enthalpy space analysis of the evolution of the primary relaxation time in ultraslowing systems. AB - For decades the Vogel-Fulcher-Tammann equation has dominated the description of dynamics of the non-Arrhenius behavior in glass forming systems. Recently, this dominance has been questioned. Hecksher et al. [Nat. Phys. 4, 737 (2008)], Elmatad et al. [J. Phys. Chem. B 113, 5563 (2009)], and Mauro et al. [Proc. Natl. Acad. Sci. U.S.A. 106, 19780 (2009)] indicated superiority of several equations showing no divergence at a finite (nonzero) temperature. This paper shows distortion-sensitive and derivative based empirical analysis of the validity of leading equations for portraying the previtreous evolution of primary relaxation time. PMID- 21241126 TI - Single molecules reveal the dynamics of heterogeneities in a polymer at the glass transition. AB - The notion of heterogeneous dynamics in glasses, that is, the spatial and temporal variations of structural relaxation rates, explains many of the puzzling features of glass dynamics. The nature and the dynamics of these heterogeneities, however, have been very controversial. Single rhodamine B molecules in poly(vinyl acetate) at the glass transition reorient through sudden jumps. With a statistical search for the most likely break points in the logarithm of the ratio of the two perpendicular fluorescence polarizations, we determine the times of these angular jumps. We interpret these jumps as an indication for individual glass rearrangements in the vicinity of the probe molecule. Time-series analysis of the resulting sequence of waiting times between jumps shows that dynamic heterogeneities in the matrix exist, but are short lived. From the correlation of the logarithm of the waiting time between subsequent jumps, we determine an upper limit for the lifetime of heterogeneities in the sample. The correlation time of tau(het) = 32 s is three times shorter than the orientational correlation time of the probe molecule, tau(orient) = 90 s, in the sample at this temperature, but 13 times longer than the structural relaxation time, tau(alpha) = 2.5 s, estimated for this sample from dielectric experiments. We present a model for glass dynamics in which each rearrangement in one region causes a random change in the barrier height for subsequent rearrangements in a neighboring region. This model, which equates the dynamics of the heterogeneities with the dynamics of the glass itself and thus implies a factor of one between heterogeneity lifetime and structural relaxation time, successfully reproduces the statistics of the experimentally observed waiting time sequences. PMID- 21241127 TI - Photodissociation of thioglycolic acid studied by femtosecond time-resolved transient absorption spectroscopy. AB - Steady-state and time-resolved spectroscopies were employed to study the photodissociation of both the neutral (HS-CH(2)-COOH) and doubly deprotonated (( )S-CH(2)-COO(-)) forms of thioglycolic acid (TGA), a common surface-passivating ligand used in the aqueous synthesis and organization of semiconducting nanostructures. Room temperature UV-Vis absorption spectroscopy indicated strong absorption by the S(1) and S(2) excited states at 250 nm and 185 nm, respectively. The spectrum also contained a weaker absorption band that extended to approximately 550 nm, which was assigned to the pi(CO) (*)<-n(O) transition. Femtosecond time-resolved transient absorption spectroscopy was performed on TGA using 400 nm excitation and a white-light continuum probe to provide the temporally and spectrally resolved data. Both forms of TGA underwent a photoinduced dissociation from the excited state to form an alpha-thiol substituted acyl radical (alpha-TAR, S-CH(2)-CO(?)). For the acidic form of TGA, radical formation occurred with an apparent time constant of 60 +/- 5 fs; subsequent unimolecular decay took 400 +/- 60 fs. Similar kinetics were observed for the deprotonated form of TGA (70 +/- 10 fs radical formation; 420 +/- 40 fs decay). The production of the alpha-TAR was corroborated by the observation of its characteristic optical absorption. Time-resolved data indicated that the photoinduced dissociation of TGA via cleavage of the C-OH bond occurred rapidly (<=100 fs). The prevalence of TGA in aqueous semiconducting nanoparticles makes its absorption in the visible spectral region and subsequent dissociation key to understanding the behavior of nanoscale systems. PMID- 21241128 TI - Structural study of low concentration LiCl aqueous solutions in the liquid, supercooled, and hyperquenched glassy states. AB - Neutron diffraction experiments on a solution of LiCl in water (R = 40) at ambient conditions and in the supercooled and hyperquenched states are reported and analyzed within the empirical potential structure refinement framework. Evidence for the modifications of the microscopic structure of the solvent in the presence of such a small amount of salt is found at all investigated thermodynamic states. On the other hand, it is evident that the structure of the hyperquenched salty sample is similar to that of pure low density amorphous water, although all the peaks of the radial distribution functions are broader in the present case. Changes upon supercooling or hyperquenching of the ion's hydration shells and contacts are of limited size and evidence for segregation phenomena at these states does not clearly show up, although the presence of water separated contacts between ion of the same sign is intriguing. PMID- 21241129 TI - Density, structure, and dynamics of water: the effect of van der Waals interactions. AB - It is known that ab initio molecular dynamics (AIMD) simulations of liquid water at ambient conditions, based on the generalized gradient approximation (GGA) to density functional theory (DFT), with commonly used functionals fail to produce structural and diffusive properties in reasonable agreement with experiment. This is true for canonical, constant temperature simulations where the density of the liquid is fixed to the experimental density. The equilibrium density, at ambient conditions, of DFT water has recently been shown by Schmidt et al. [J. Phys. Chem. B, 113, 11959 (2009)] to be underestimated by different GGA functionals for exchange and correlation, and corrected by the addition of interatomic pair potentials to describe van der Waals (vdW) interactions. In this contribution we present a DFT-AIMD study of liquid water using several GGA functionals as well as the van der Waals density functional (vdW-DF) of Dion et al. [Phys. Rev. Lett. 92, 246401 (2004)]. As expected, we find that the density of water is grossly underestimated by GGA functionals. When a vdW-DF is used, the density improves drastically and the experimental diffusivity is reproduced without the need of thermal corrections. We analyze the origin of the density differences between all the functionals. We show that the vdW-DF increases the population of non-H-bonded interstitial sites, at distances between the first and second coordination shells. However, it excessively weakens the H-bond network, collapsing the second coordination shell. This structural problem is partially associated to the choice of GGA exchange in the vdW-DF. We show that a different choice for the exchange functional is enough to achieve an overall improvement both in structure and diffusivity. PMID- 21241130 TI - Structural and dynamical properties of solid ammonia borane under high pressure. AB - The structural and dynamical properties of solid ammonia borane were investigated by means of extensive density functional theory calculation up to 60 GPa. Molecular dynamics simulations suggest that the Cmc2(1) phase found by recent room-temperature x-ray diffraction experiments can be obtained from the Pmn2(1) structure at high pressure and low temperature. Two new high-pressure phases were found on further compression at room temperature. We also found that all three high-pressure phases have proton-ordered structures, and the separation of the NH(3) and BH(3) rotation observed in the simulations can be explained by their distinct rotational energy barriers. The role of dihydrogen bonds in the high pressure phases is discussed. PMID- 21241131 TI - Quasielastic small-angle neutron scattering from heavy water solutions of cyclodextrins. AB - We present a model for quasielastic neutron scattering (QENS) by an aqueous solution of compact and inflexible molecules. This model accounts for time dependent spatial pair correlations between the atoms of the same as well as of distinct molecules and includes all coherent and incoherent neutron scattering contributions. The extension of the static theory of the excluded volume effect [A. K. Soper, J. Phys.: Condens. Matter 9, 2399 (1997)] to the time-dependent (dynamic) case allows us to obtain simplified model expressions for QENS spectra in the low Q region in the uniform fluid approximation. The resulting expressions describe the quasielastic small-angle neutron scattering (QESANS) spectra of D(2)O solutions of native and methylated cyclodextrins well, yielding in particular translational and rotational diffusion coefficients of these compounds in aqueous solution. Finally, we discuss the full potential of the QESANS analysis (that is, beyond the uniform fluid approximation), in particular, the information on solute-solvent interactions (e.g., hydration shell properties) that such an analysis can provide, in principle. PMID- 21241132 TI - A first principles molecular dynamics study of lithium atom solvation in binary liquid mixture of water and ammonia: structural, electronic, and dynamical properties. AB - The preferential solvation of solutes in mixed solvent systems is an interesting phenomenon that plays important roles in solubility and kinetics. In the present study, solvation of a lithium atom in aqueous ammonia solution has been investigated from first principles molecular dynamics simulations. Solvation of alkali metal atoms, like lithium, in aqueous and ammonia media is particularly interesting because the alkali metal atoms release their valence electrons in these media so as to produce solvated electrons and metal counterions. In the present work, first principles simulations are performed employing the Car Parrinello molecular dynamics method. Spontaneous ionization of the Li atom is found to occur in the mixed solvent system. From the radial distribution functions, it is found that the Li(+) ion is preferentially solvated by water and the coordination number is mostly four in its first solvation shell and exchange of water molecules between the first and second solvation shells is essentially negligible in the time scale of our simulations. The Li(+) ion and the unbound electron are well separated and screened by the polar solvent molecules. Also the unbound electron is primarily captured by the hydrogens of water molecules. The diffusion rates of Li(+) ion and water molecules in its first solvation shell are found to be rather slow. In the bulk phase, the diffusion of water is found to be slower than that of ammonia molecules because of strong ammonia-water hydrogen bonds that participate in solvating ammonia molecules in the mixture. The ratio of first and second rank orientational correlation functions deviate from 3, which suggests a deviation from the ideal Debye-type orientational diffusion. It is found that the hydrogen bond lifetimes of ammonia-ammonia pairs is very short. However, ammonia-water H-bonds are found to be quite strong when ammonia acts as an acceptor and these hydrogen bonds are found to live longer than even water water hydrogen bonds. PMID- 21241133 TI - Comparison of hydration reactions for "piano-stool" RAPTA-B and [Ru(eta6 arene)(en)Cl]+ complexes: density functional theory computational study. AB - The hydration process for two Ru(II) representative half-sandwich complexes: Ru(arene)(pta)Cl(2) (from the RAPTA family) and [Ru(arene)(en)Cl](+) (further labeled as Ru_en) were compared with analogous reaction of cisplatin. In the study, quantum chemical methods were employed. All the complexes were optimized at the B3LYP/6-31G(d) level using Conductor Polarizable Continuum Model (CPCM) solvent continuum model and single-point (SP) energy calculations and determination of electronic properties were performed at the B3LYP/6 311++G(2df,2pd)/CPCM level. It was found that the hydration model works fairly well for the replacement of the first chloride by water where an acceptable agreement for both Gibbs free energies and rate constants was obtained. However, in the second hydration step worse agreement of the experimental and calculated values was achieved. In agreement with experimental values, the rate constants for the first step can be ordered as RAPTA-B > Ru_en > cisplatin. The rate constants correlate well with binding energies (BEs) of the Pt/Ru-Cl bond in the reactant complexes. Substitution reactions on Ru_en and cisplatin complexes proceed only via pseudoassociative (associative interchange) mechanism. On the other hand in the case of RAPTA there is also possible a competitive dissociation mechanism with metastable pentacoordinated intermediate. The first hydration step is slightly endothermic for all three complexes by 3-5 kcal/mol. Estimated BEs confirm that the benzene ligand is relatively weakly bonded assuming the fact that it occupies three coordination positions of the Ru(II) cation. PMID- 21241134 TI - Ostwald ripening of binary alloy particles. AB - Classical Lifshitz-Slyozov-Wagner theory is generalized for Ostwald ripening of particles composed of random binary alloy. We show that the steady state ripening process is characterized by self-similar particle size and composition distributions. The shape of particle size distribution depends on whether the process is diffusion controlled (Lifshitz-Slyozov) or reaction controlled (Wagner) and is consistent with the predictions of classical theory for one component materials. The steady state composition distribution, in contrast, has the same functional form in both extreme cases featuring a universal dependence of the composition upon particle size. We also found that transients in particle's composition can be very quick resulting in a steady state distribution well before it is reached by particles sizes. These transients involve significant changes in particle sizes and open an opportunity for producing metastable particle size distributions of required shape. PMID- 21241135 TI - Theoretical realization of cluster-assembled hydrogen storage materials based on terminated carbon atomic chains. AB - The capacity of carbon atomic chains with different terminations for hydrogen storage is studied using first-principles density functional theory calculations. Unlike the physisorption of H(2) on the H-terminated chain, we show that two Li (Na) atoms each capping one end of the odd- or even-numbered carbon chain can hold ten H(2) molecules with optimal binding energies for room temperature storage. The hybridization of the Li 2p states with the H(2)sigma orbitals contributes to the H(2) adsorption. However, the binding mechanism of the H(2) molecules on Na arises only from the polarization interaction between the charged Na atom and the H(2). Interestingly, additional H(2) molecules can be bound to the carbon atoms at the chain ends due to the charge transfer between Li 2s2p (Na 3s) and C 2p states. More importantly, dimerization of these isolated metal capped chains does not affect the hydrogen binding energy significantly. In addition, a single chain can be stabilized effectively by the C(60) fullerenes termination. With a hydrogen uptake of ~10 wt.% on Li-coated C(60)-C(n)-C(60) (n = 5, 8), the Li(12)C(60)-C(n)-Li(12)C(60) complex, keeping the number of adsorbed H(2) molecules per Li and stabilizing the dispersion of individual Li atoms, can serve as better building blocks of polymers than the (Li(12)C(60))(2) dimer. These findings suggest a new route to design cluster-assembled hydrogen storage materials based on terminated sp carbon chains. PMID- 21241136 TI - From caging to Rouse dynamics in polymer melts with intramolecular barriers: a critical test of the mode coupling theory. AB - By means of computer simulations and solution of the equations of the mode coupling theory (MCT), we investigate the role of the intramolecular barriers on several dynamic aspects of nonentangled polymers. The investigated dynamic range extends from the caging regime characteristic of glass-formers to the relaxation of the chain Rouse modes. We review our recent work on this question, provide new results, and critically discuss the limitations of the theory. Solutions of the MCT for the structural relaxation reproduce qualitative trends of simulations for weak and moderate barriers. However, a progressive discrepancy is revealed as the limit of stiff chains is approached. This disagreement does not seem related with dynamic heterogeneities, which indeed are not enhanced by increasing barrier strength. It is not connected either with the breakdown of the convolution approximation for three-point static correlations, which retains its validity for stiff chains. These findings suggest the need of an improvement of the MCT equations for polymer melts. Concerning the relaxation of the chain degrees of freedom, MCT provides a microscopic basis for time scales from chain reorientation down to the caging regime. It rationalizes, from first principles, the observed deviations from the Rouse model on increasing the barrier strength. These include anomalous scaling of relaxation times, long-time plateaux, and nonmonotonous wavelength dependence of the mode correlators. PMID- 21241137 TI - Conductance switching in diarylethenes bridging carbon nanotubes. AB - The recently reported photoswitching of diarylethene derivative molecules bridging carbon nanotube (CNT) contacts is theoretically analyzed. The short lifetime of the lowest unoccupied molecular orbital (LUMO) indicates that neither the open nor closed form of the molecule can be photoexcited into a charge neutral excited state for any appreciable length of time preventing photochromic ring opening. Analysis of the highest occupied molecular orbital (HOMO) and LUMO lifetimes also suggests that photoexcitation results in oxidation of the molecules. This either reduces the quantum yield of photochromic ring closing, or it gives rise to the possibility of oxidative ring closing. Analysis of the resistance values and energy levels indicates that the HOMO energy levels of the closed isomers relevant for transport must lie within a few k(B)T of the CNT Fermi level. For armchair contacts, the change in resistance with isomer or substituent group is the result of shifts in the energy level of the molecular HOMO. The coupling of the molecular HOMO to the CNT contacts is insensitive to the isomer type or substituent group. For zigzag CNTs, the conductance is dominated by surface states at the Fermi level on the cut ends of the CNTs so that the conductance is relatively insensitive to the isomer type, and the conductance switching ratio is low. Multiple bridging molecules can interact coherently, resulting in energy splitting, shifting, and interference that cause a nonlinear change in conductance with increasing numbers of molecules. Instead of a factor of 3 increase in conductance expected for three independent channels, a factor of 10(3) increase in conductance is obtained for three bridging molecules. PMID- 21241138 TI - In vivo molecular labeling of halogenated volatile anesthetics via intrinsic molecular vibrations using nonlinear Raman spectroscopy. AB - Halogenated volatile anesthetics are frequently used for inhaled anesthesia in clinical practice. No appropriate biological method has been available for visualizing their localization in action. Therefore, despite their frequent use, the mechanism of action of these drugs has not been fully investigated. We measured coherent anti-Stokes Raman scattering (CARS) spectra of sevoflurane and isoflurane, two of the most representative volatile anesthetics, and determined the low-frequency vibrational modes without nonresonant background disturbance. Molecular dynamics calculations predict that these modes are associated with multiple halogen atoms. Because halogen atoms rarely appear in biological compounds, the entire spectral landscape of these modes is expected to be a good marker for investigating the spatial localization of these drugs within the intracellular environment. Using live squid giant axons, we could detect the unique CARS spectra of sevoflurane for the first time in a biological setting. PMID- 21241139 TI - Transient molecular dynamics simulations of liquid viscosity for nonpolar and polar fluids. AB - A transient molecular dynamics (TMD) method for obtaining fluid viscosity is extended to multisite, force-field models of both nonpolar and polar liquids. The method overlays a sinusoidal velocity profile over the peculiar particle velocities and then records the transient decay of the velocity profile. The viscosity is obtained by regression of the solution of the momentum equation with an appropriate constitutive equation and initial and boundary conditions corresponding to those used in the simulation. The transient velocity decays observed appeared to include both relaxation and retardation effects. The Jeffreys viscoelastic model was found to model accurately the transient responses obtained for multisite models for n-butane, isobutane, n-hexane, water, methanol, and 1-hexanol. TMD viscosities obtained for saturated liquids over a wide range of densities agreed well for the polar fluids, both with nonequilibrium molecular dynamics (NEMD) results using the same force-field models and with correlations based on experimental data. Viscosities obtained for the nonpolar fluids agreed well with the experimental and NEMD results at low to moderate densities, but underpredicted experimental values at higher densities where shear-thinning effects and viscous heating may impact the TMD simulations. PMID- 21241140 TI - Application of Brewster angle microscopy and fractal analysis in investigations of compressibility of Langmuir monolayers. AB - The aim of this study was to investigate the connection between the lipid/amphiphile monolayer structure at the interface and its macroscopic/rheological properties, in particular, to establish the link between the fractality of the monolayer structure and its compressibility modulus. To that purpose we have used fractal analysis of images obtained by Brewster angle microscopy to infer the fractal dimension of the monolayer structure and relate its change to the corresponding changes in compressibility derived from a simultaneously measured pi-A isotherm. The results of the study confirmed the starting assumption based on theoretical considerations that the fractal dimension of an amphiphilic monolayer and its compressibility should be correlated. We have shown that there exists a strong correlation between the fractal dimension and the corresponding compressibility modulus of different amphiphilic materials. Thus, confirming the link between the short ordered structure on the molecular level and the macroscopic property-compressibility of the monolayer. The established correlation between the fractal dynamics and compressibility modulus of the monolayer enabled identification of onset of percolation-a second-order phase transition that is otherwise not easy and unambiguously detectable. We have found that the signature of percolation in a monolayer, regardless of its composition, is the occurrence of a sharp increase (a jump) of compressibility modulus (at macroscopic level) at the characteristic value of the corresponding fractal dimension D = 1.89. This is the result of the abrupt establishment of a connected structure on the molecular level, consequently involving a change in the elastic properties of the monolayer on a macroscopic scale. The results of this investigation provide means for unambiguous identification of the onset of percolation in the Langmuir layer and should facilitate a more efficient application of the percolation theory in further study of processes and structures at the interface during the monolayer compression. PMID- 21241141 TI - Calibrated NEXAFS spectra of common conjugated polymers. AB - Near edge x-ray absorption fine structure (NEXAFS) spectroscopy has evolved into a powerful characterization tool for polymeric materials and is increasingly being used to elucidate composition and orientation in thin films of relevance to organic electronic devices. For accurate quantitative compositional analysis, insight into the electronic structure and the ability to assess molecular orientation, reliable reference spectra with known energy resolution and calibrated energy scale are required. We report a set of such NEXAFS spectra from 23 semiconducting polymers and some related materials that are frequently used in organic device research. PMID- 21241142 TI - Water clusters on Cu(110): chain versus cyclic structures. AB - Water clusters are assembled and imaged on Cu(110) by using a scanning tunneling microscope. Water molecules are arranged along the Cu row to form "ferroelectric" zigzag chains of trimer to hexamer. The trimer prefers the chain form to a cyclic one in spite of the reduced number of hydrogen bonds, highlighting the crucial role of the water-substrate interaction in the clustering of adsorbed water molecules. On the other hand, the cyclic form with maximal hydrogen bonds becomes more favorable for the tetramer, indicating the crossover from chain to cyclic configurations as the constituent number increases. PMID- 21241143 TI - Magnetism of substitutional Fe impurities in graphene nanoribbons. AB - Using the generalized gradient approximation to exchange and correlation, we perform density functional calculations on an Fe atom at a single vacancy of graphene nanoribbons. Our results show that, after relaxation, the Fe atom is magnetic, in contrast to the behavior recently found for Fe at a single vacancy of the graphene sheet. PMID- 21241144 TI - The water-amorphous silica interface: analysis of the Stern layer and surface conduction. AB - To explain why dynamical properties of an aqueous electrolyte near a charged surface seem to be governed by a surface charge less than the actual one, the canonical Stern model supposes an interfacial layer of ions and immobile fluid. However, large ion mobilities within the Stern layer are needed to reconcile the Stern model with surface conduction measurements. Modeling the aqueous electrolyte-amorphous silica interface at typical charge densities, a prototypical double layer system, the flow velocity does not vanish until right at the surface. The Stern model is a good effective model away from the surface, but cannot be taken literally near the surface. Indeed, simulations show no ion mobility where water is immobile, nor is such mobility necessary since the surface conductivity in the simulations is comparable to experimental values. PMID- 21241145 TI - Characterizing interfacial friction in bis(2-ethylhexyl) sodium sulfosuccinate reverse micelles from photoisomerization studies of carbocyanine derivatives. AB - Photoisomerization of two carbocyanine derivatives has been examined in bis(2 ethylhexyl) sodium sulfosuccinate (AOT) reverse micelles to understand the factors that govern this process in the interfacial region of organized assemblies. To this effect, fluorescence lifetimes and quantum yields of 3,3(') diethyloxadicarbocyanine iodide and merocyanine 540 have been measured in AOT/isooctane/water and AOT/cyclohexane/water reverse micellar systems as a function of the mole ratio of water to the surfactant, W. The nonradiative rate constants, which have been identified as the rates of photoisomerization for these solutes, were obtained from the experimentally measured parameters. The steady rise and subsequent saturation observed in the nonradiative rate constants upon increasing W has been rationalized in terms of micellar packing. An inverse correlation has been obtained between the nonradiative rate constants and the critical packing parameter, indicating that the interfacial friction experienced by the solute molecule is essentially described by this parameter. PMID- 21241146 TI - Quantum confinement effects on charge-transfer between PbS quantum dots and 4 mercaptopyridine. AB - We obtain the surface enhanced Raman spectra of 4-mercaptopyridine on lead sulfide (PbS) quantum dots as a function of nanoparticle size and excitation wavelength. The nanoparticle radii are selected to be less than the exciton Bohr radius of PbS, enabling the observation of quantum confinement effects on the spectrum. We utilize the variation of nontotally symmetric modes of both b(1) and b(2) symmetry as compared to the totally symmetric a(1) modes to measure the degree of charge-transfer between the molecule and quantum dot. We find both size dependent and wavelength dependent resonances in the range of these measurements, and attribute them to charge-transfer resonances which are responsible for the Raman enhancement. PMID- 21241147 TI - Temperature-ramping measurement of dye reorientation to probe molecular motion in polymer glasses. AB - A temperature-ramping anisotropy measurement is introduced as an efficient way to study molecular motion in polymer glasses. For these experiments, fluorescent molecules were dispersed in the polymer glass and the reorientation of these dyes was used as a probe of segmental dynamics. For thick samples of polystyrene, poly (4-tert-butyl styrene), and poly(2-vinyl pyridine), temperature-ramping anisotropy measurements have a shape similar to differential scanning calorimetry measurements and nearly the same transition temperature. We present results using different fluorescent molecules and different temperature-ramping rates; such experiments show potential for accessing slow molecular motions considerably below T(g). Temperature-ramping anisotropy measurements were performed on freestanding poly (4-tert-butyl styrene) films of varying thicknesses. The anisotropy decay of a 22 nm film was shifted about 12 K lower in temperature as compared to a bulk sample. PMID- 21241148 TI - Brownian dynamics simulation of insulin microsphere formation from break-up of a fractal network. AB - Motivated by a recent experiment on insulin microsphere formation where polyethylene glycol (PEG) is used as the precipitating agent, we have developed a simple theoretical model that can predict the formation of a fractal network of insulin monomers and the subsequent break-up of the fractal network into microsphere aggregates. In our approach the effect of PEG on insulin is modeled via a standard depletion attraction mechanism via the Asakura-Oosawa model. We show that even in the context of this simple model, it is possible to mimic important aspects of the insulin experiment in a brownian dynamics simulation. We simulate the effect of changing temperature in our model by changing the well depth of the Asakura-Oosawa potential. A fractal network is observed in a "deep quench" of the system, followed by a "heating" that results in a break-up of the network and subsequent formation of microspheres. PMID- 21241150 TI - Effects of ionic strength on SAXS data for proteins revealed by molecular dynamics simulations. AB - The combination of small-angle X-ray solution scattering (SAXS) experiments and molecular dynamics (MD) simulations is now becoming a powerful tool to study protein conformations in solution at an atomic resolution. In this study, we investigated effects of ionic strength on SAXS data theoretically by using MD simulations of hen egg white lysozyme at various NaCl concentrations from 0 to 1 M. The calculated SAXS excess intensities showed a significant dependence on ion concentration, which originates from the different solvent density distributions in the presence and absence of ions. The addition of ions induced a slow convergence of the SAXS data, and a ~20 ns simulation is required to obtain convergence of the SAXS data with the presence of ions whereas only a 0.2 ns simulation is sufficient in the absence of ions. To circumvent the problem of the slow convergence in the presence of ions, we developed a novel method that reproduces the SAXS excess intensities with the presence of ions from short MD trajectories in pure water. By applying this method to SAXS data for the open and closed forms of transferrin at 1 M ion concentration, the correct form could be identified by simply using short MD simulations of the protein in pure water for 0.2 ns. PMID- 21241149 TI - Effects of heme on the thermal stability of mesophilic and thermophilic cytochromes c: comparison between experimental and theoretical results. AB - We have recently proposed a measure of the thermal stability of a protein: the water-entropy gain at 25 degrees C upon folding normalized by the number of residues, which is calculated using a hybrid of the angle-dependent integral equation theory combined with the multipolar water model and the morphometric approach. A protein with a larger value of the measure is thermally more stable. Here we extend the study to analyses on the effects of heme on the thermal stability of four cytochromes c (PA c(551), PH c(552), HT c(552), and AA c(555)) whose denaturation temperatures are considerably different from one another despite that they share significantly high sequence homology and similar three dimensional folds. The major conclusions are as follows. For all the four cytochromes c, the thermal stability is largely enhanced by the heme binding in terms of the water entropy. For the holo states, the measure is the largest for AA c(555). However, AA c(555) has the lowest packing efficiency of heme and the apo polypeptide with hololike structure, which is unfavorable for the water entropy. The highest stability of AA c(555) is ascribed primarily to the highest efficiency of side-chain packing of the apo polypeptide itself. We argue for all the four cytochromes c that due to covalent heme linkages, the number of accessible conformations of the denatured state is decreased by the steric hindrance of heme, and the conformational-entropy loss upon folding becomes smaller, leading to an enhancement of the thermal stability. As for the apo state modeled as the native structure whose heme is removed, AA c(555) has a much larger value of the measure than the other three. Overall, the theoretical results are quite consistent with the experimental observations (e.g., at 25 degrees C the alpha-helix content of the apo state of AA c(555) is almost equal to that of the holo state while almost all helices are collapsed in the apo states of PA c(551), PH c(552), and HT c(552)). PMID- 21241151 TI - Kinetics of hydrogen bonds in aqueous solutions of cyclodextrin and its methyl substituted forms. AB - Molecular dynamics simulations of beta-cyclodextrin (BCD) and its two methyl substituted derivatives, namely, heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB) and heptakis(2,3,6-tri-O-methyl)-beta-cyclodextrin (TRIMEB) have been performed in aqueous solutions. Detailed analyses were carried out to investigate the effects of substitution on the kinetics of cyclodextrin-water and water-water hydrogen bonds formed by water present in the hydration layers around these macromolecules as well as those formed by water inside their cavities. It is observed that increased geometrical constraints due to substitution of the OH groups of the glucose rings of the BCD molecule result in rapid establishment of hydrogen bond breaking and reformation equilibria for DIMEB and TRIMEB. This has been found to be the microscopic origin of highly rigid arrangement of water around TRIMEB and inside its cavity, as against water in and around BCD and DIMEB. PMID- 21241152 TI - Relative stability of the open and closed conformations of the active site loop of streptavidin. AB - The eight-residue surface loop, 45-52 (Ser, Ala, Val, Gly, Asn, Ala, Glu, Ser), of the homotetrameric protein streptavidin has a "closed" conformation in the streptavidin-biotin complex, where the corresponding binding affinity is one of the strongest found in nature (DeltaG ~ -18 kcal/mol). However, in most of the crystal structures of apo (unbound) streptavidin, the loop conformation is "open" and typically exhibits partial disorder and high B-factors. Thus, it is plausible to assume that the loop structure is changed from open to closed upon binding of biotin, and the corresponding difference in free energy, DeltaF = F(open) - F(closed) in the unbound protein, should therefore be considered in the total absolute free energy of binding. DeltaF (which has generally been neglected) is calculated here using our "hypothetical scanning molecular-dynamics" (HSMD) method. We use a protein model in which only the atoms closest to the loop are considered (the "template") and they are fixed in the x-ray coordinates of the free protein; the x-ray conformation of the closed loop is attached to the same (unbound) template and both systems are capped with the same sphere of TIP3P water. Using the force field of the assisted model building with energy refinement (AMBER), we carry out two separate MD simulations (at temperature T = 300 K), starting from the open and closed conformations, where only the atoms of the loop and water are allowed to move (the template-water and template-loop interactions are considered). The absolute F(open) and F(closed) (of loop + water) are calculated from these trajectories, where the loop and water contributions are obtained by HSMD and a thermodynamic integration (TI) process, respectively. The combined HSMD-TI procedure leads to total (loop + water) DeltaF = -27.1 +/- 2.0 kcal/mol, where the entropy TDeltaS constitutes 34% of DeltaF, meaning that the effect of S is significant and should not be ignored. Also, DeltaS is positive, in accord with the high flexibility of the open loop observed in crystal structures, while the energy DeltaE is unexpectedly negative, thus also adding to the stability of the open loop. The loop and the 250 capped water molecules are the largest system studied thus far, which constitutes a test for the efficiency of HSMD-TI; this efficiency and technical issues related to the implementation of the method are also discussed. Finally, the result for DeltaF is a prediction that will be considered in the calculation of the absolute free energy of binding of biotin to streptavidin, which constitutes our next project. PMID- 21241153 TI - Langevin dynamics for the transport of flexible biological macromolecules in confined geometries. AB - The transport of flexible biological macromolecules in confined geometries is found in a variety of important biophysical systems including biomolecular movements through pores in cell walls, vesicle walls, and synthetic nanopores for sequencing methods. In this study, we extend our previous analysis of the Fokker Planck and Langevin dynamics for describing the coupled translational and rotational motions of single structured macromolecules near structured external surfaces or walls [M. H. Peters, J. Chem. Phys. 110, 528 (1999); 112, 5488 (2000)] to the problem of many interacting macromolecules in the presence of structured external surfaces representing the confining geometry. Overall macromolecular flexibility is modeled through specified interaction potentials between the structured Brownian subunits (B-particles), as already demonstrated for protein and DNA molecules briefly reviewed here. We derive the Fokker-Planck equation using a formal multiple time scale perturbation expansion of the Liouville equation for the entire system, i.e., solvent, macromolecules, and external surface. A configurational-orientational Langevin displacement equation is also obtained for use in Brownian dynamics applications. We demonstrate important effects of the external surface on implicit solvent forces through formal descriptions of the grand friction tensor and equilibrium average force of the solvent on the B-particles. The formal analysis provides both transparency of all terms of the Langevin displacement equation as well as a prescription for their determination. As an example, application of the methods developed, the real-time movement of an alpha-helix protein through a carbon nanotube is simulated. PMID- 21241155 TI - Dielectrophoretic tweezer for isolating and manipulating target cells. AB - The ability to isolate and accurately position single cells in three dimensions is becoming increasingly important in many areas of biological research. The authors describe the design, theoretical modelling and testing of a novel dielectrophoretic (DEP) tweezer for picking out and relocating single target cells. The device is constructed using facilities available in most electrophysiology laboratories, without the requirement of sophisticated and expensive microfabrication technology, and offers improved practical features over previously reported DEP tweezer designs. The DEP tweezer has been tested using transfected HEI-193 human schwannoma cells, with visual identification of the target cells being aided by labelling the incorporated gene product with a green fluorescent protein. PMID- 21241156 TI - Scanning tunneling microscopy of cauliflower-like DNA nanostructures synthesised by loop-mediated isothermal amplification. AB - DNA nanotechnology is a novel approach for synthesis of DNA-based nanostructures. Stem-loops, nanojunctions, sticky-ends and periodic lengths of DNA are the most essential nanostructures in DNA nanofabrications. Loop-mediated isothermal amplification (LAMP) is a powerful technology for repetitive synthesis of double stranded and cauliflower-like DNAs. The process leads to long and repetitive sequences of DNAs, which are fabricated via loop primers. The authors demonstrate here scanning tunneling micrographs of LAMP-synthesised DNAs deposited on highly ordered pyrolytic graphite. The scans are compared with natural DNAs. Scanning tunneling microscopy (STM) images indicated the creation of periodic long DNAs, stem-looped DNAs and three-way DNA nanojunctions. It is also suggested that such nanomaterials could be promising candidates for use in DNA-based nanodevices. PMID- 21241157 TI - Conjugation behaviours of CdTe quantum dots and antibody by a novel immunochromatographic method. AB - Three water-soluble CdTe quantum dots (QDs) (green-emitting, yellow-emitting and red-emitting) were synthesised for different refluxing time with 3 mercaptopropionic acid (MPA) as stabiliser. Then the red-emitting CdTe QDs and mouse immunoglobulin G (IgG) were taken as the representative to study the conjugation behaviour of QDs and antibody by a novel immunochromatographic method. After comparing with several methods, that is, direct conjugation, 1 ethyl-3(3-dimethylaminopropyl) carbodiimides hydrochloride (EDC)-mediated conjugation, N-hydroxysuccinimide (NHS)-mediated conjugation, EDC/NHS-mediated conjugation by immunochromatographic strips, EDC and NHS were selected together as coupling agents to conjugate QDs with antibody efficiently. Finally, the K562 leukaemia cells were incubated with the EDC/NHS-mediated conjugates to evaluate the performance in practical application, and the result from fluorescence images showed that it was successfully applied to label cells. The immunochromatographic strip was a superior method to study the conjugation of the fluorophore and antibody. PMID- 21241158 TI - Interaction of gold nanoparticles with Pfu DNA polymerase and effect on polymerase chain reaction. AB - The interaction of gold nanoparticles with Pfu DNA polymerase has been investigated by a number of biological, optical and electronic spectroscopic techniques. Polymerase chain reaction was performed to show gold nanoparticles' biological effect. Ultraviolet-visible and circular dichroism spectra analysis were applied to character the structure of Pfu DNA polymerase after conjugation with gold nanoparticles. X-ray photoelectron spectroscopy was used to investigate the bond properties of the polymerase-gold nanoparticles complex. The authors demonstrate that gold nanoparticles do not affect the amplification efficiency of polymerase chain reaction using Pfu DNA polymerase, and Pfu DNA polymerase displays no significant changes of the secondary structure upon interaction with gold nanoparticles. The adsorption of Pfu DNA polymerase to gold nanoparticles is mainly through Au-NH(2) bond and electrostatic interaction. These findings may have important implications regarding the safety issue as gold nanoparticles are widely used in biomedical applications. PMID- 21241159 TI - Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: a window of opportunity in the search for genetic modifiers. AB - Transgenic (Tg) mouse models of FALS containing mutant human SOD1 genes (G37R, G85R, D90A, or G93A missense mutations or truncated SOD1) exhibit progressive neurodegeneration of the motor system that bears a striking resemblance to ALS, both clinically and pathologically. The most utilized and best characterized Tg mice are the G93A mutant hSOD1 (Tg(hSOD1-G93A)1GUR mice), abbreviated G93A. In this review we highlight what is known about background-dependent differences in disease phenotype in transgenic mice that carry mutated human or mouse SOD1. Expression of G93A-hSOD1Tg in congenic lines with ALR, NOD.Rag1KO, SJL or C3H backgrounds show a more severe phenotype than in the mixed (B6xSJL) hSOD1Tg mice, whereas a milder phenotype is observed in B6, B10, BALB/c and DBA inbred lines. We hypothesize that the background differences are due to disease-modifying genes. Identification of modifier genes can highlight intracellular pathways already suspected to be involved in motor neuron degeneration; it may also point to new pathways and processes that have not yet been considered. Most importantly, identified modifier genes provide new targets for the development of therapies. PMID- 21241160 TI - Clinical and economic burden of chemotherapy-induced nausea and vomiting among patients with cancer in a hospital outpatient setting in the United States. AB - OBJECTIVE: This study evaluated the overall burden of illness of chemotherapy induced nausea and vomiting (CINV) and associated all-cause costs from a hospital's perspective (costs to the hospital) in patients with cancer treated with chemotherapy (CT) in the US hospital outpatient setting. METHODS: Patients with a cancer diagnosis aged >=18 years initiating CT in a hospital outpatient setting for the first time between April 1 2007 and March 31 2009 were extracted from the Premier Perspective Database. Patients were followed through eight CT cycles or 6 months post-index date, whichever occurred first. Within each CT cycle, the follow-up time for CINV event estimation was from day 1 (except rescue medication use that was identified from day 2) to cycle end. A multivariate regression model was developed to predict the CINV event rate per CT cycle in the study follow-up period. Associated total all-cause costs of managing CINV from a hospital's perspective were analyzed descriptively. Event rate and associated costs were estimated in the entire hospital setting (outpatient, inpatient, and emergency room). All-cause costs included inpatient, hospital outpatient, and ER visit costs (identified through a primary or secondary diagnosis code for nausea, vomiting, and/or volume depletion) and pharmacy cost (rescue medications for CINV treatment). All physician costs and non CINV-related treatment (pharmacy) costs were excluded from the analyses. RESULTS: Among 11,495 study patients, 8,806 patients (76.6%) received prophylaxis for all cycles in the follow-up period. The overall base population had an average age of 63.3 years, was 51.0% female, and 72.7% White. The distribution of emetogenicity for cycle 1 CT cycle was 26.0% HEC, 46.1% MEC, and 26.4% LEC/MinEC combined. In the follow-up period, a total of 47,988 CINV events with an associated total all-cause treatment cost of $89 million were observed. Average daily treatment cost for all care settings was $1854.7. The regression model predicted a 20% CINV event rate per CT cycle in the follow-up period. Study limitations include potential lack of generalizibility, absence of data on certain confounders including alcohol consumption and prior history of motion sickness, lack of a control analysis group to estimate incremental use of resource utilization and associated costs, and a potential for cost under-estimation. CONCLUSION: In the current study analysis, a 20% CINV event rate per CT cycle per patient was predicted with an associated all-cause average daily total cost of approximately $1850. Further studies on early and appropriate antiemetic prophylaxis on CINV rates and economic outcomes are warranted. PMID- 21241161 TI - Association between glycemic control and short-term healthcare costs among commercially insured diabetes patients in the United States. AB - Abstract Objectives: Glycemic control, measured by HbA(1c), is well known to be a risk marker for long-term costly diabetes-related complications. The relationship between HbA(1c) and short-term costs is unclear. This study investigates how HbA(1c) is correlated to short-term diabetes-related medical expenses. METHODS: Patients with diabetes with an HbA(1c) reading >=6% between April and September 2007 were identified from a large US managed-care organization. Healthcare utilization data was obtained during the subsequent 12-month period. Multivariate analyses were performed to estimate the correlation between HbA(1c) and diabetes related healthcare costs. RESULTS: In all, 34,469 and 1,837 patients with type 2 and type 1 diabetes, respectively, were identified with an HbA(1c) reading >=6% (mean HbA(1c): 7.4% and 7.9%). The majority of patients with type 1 diabetes were treated with insulin, while most patients with type 2 diabetes were treated with metformin. The multivariate analysis showed that several characteristics, including HbA(1c), significantly correlate with diabetes-related medical costs for both patients with type 1 and type 2 diabetes. A 1-percentage-point increase in HbA(1c) will, on average, lead to a 6.0% and 4.4% increase in diabetes-related medical costs for type 1 and type 2 diabetes, respectively. This corresponds to an annual cost increase of $445 and $250 for patients with type 1 and type 2 diabetes, respectively. LIMITATIONS: Retrospective data analyses inherently associated with selection bias which can only partly be adjusted by statistical techniques. Furthermore, the study population is not necessarily representative of the general population and there can be isolated coding or data errors in the dataset. CONCLUSIONS: These results suggest that tighter glycemic control is associated with short-term cost benefits for patients with diabetes. This supplements conventional wisdom that HbA(1c) affects risk of long-term complications and long-term costs. PMID- 21241162 TI - Evaluation of smoking cessation drug use and outcomes in the Netherlands. AB - OBJECTIVE: Several pharmacological therapies are available to help smokers quit. The aim was to investigate the utilisation and effectiveness of smoking cessation drugs in daily practice in the Netherlands. METHODS: Subjects aged >=18 years with a pharmacy prescription of varenicline, bupropion, nicotine replacement therapy (NRT) or nortriptyline between March 2007 and September 2008 were identified from the PHARMO data warehouse, which includes drug dispensing, hospitalisation and other data from approximately 2.5 million residents in the Netherlands. Using an encrypted methodology, corresponding non-person identifiable dispensing IDs were linked to a web-based system for patient reported data collection. Corresponding pharmacists asked the subjects to participate in the study and complete a web-based questionnaire on smoking history and cessation, including utilisation of (pharmaco) therapies. RESULTS: Of 2,684 invited subjects, 698 responded (26%), of whom 612 were included in the analyses. Bupropion was the most frequently used smoking cessation drug (35% of patients), followed by varenicline (28%), bupropion + NRT (12%) and varenicline + NRT (9%). Overall, 51% of patients also reported behavioural therapy. A total of 53% of bupropion users, 51% of varenicline users, 42% of NRT users and 20-40% of patients using multiple drugs reported to not smoke at the time of questionnaire. Median (interquartile range) number of days between time of questionnaire and start date of last quit attempt ranged from 271 (104-432) for varenicline + bupropion to 356 (205-518) for bupropion. Mean duration of drug use ranged from 42 to 53 days among quitters and from 19 to 42 days among relapsers. CONCLUSION: In this study up to 50% of patients who obtained smoking cessation drugs at the pharmacy stopped smoking. Better access to smoking cessation drugs as recommended in guidelines will help to further decrease smoking prevalence. PMID- 21241164 TI - Production of bovine hand-made cloned embryos by zygote-oocyte cytoplasmic hemi complementation. AB - The aim of this study was to evaluate the effect of the cytoplast type and activation process on development of cloned embryos. Bovine oocytes (MII) or zygotes at the one-cell stage (IVF) were manually bisected and segregated in MII or IVF hemi-cytoplasts or hemi-karyoplasts. Adult skin cells from a bovine female were used as nucleus donors (SC). Experimental groups were composed of IVF embryos; parthenogenetic embryos; hand-made cloned (HMC) embryos; and reconstructed HMC embryos using IVF hemi-cytoplast + MII hemi-cytoplast + SC (G I); IVF hemi-cytoplast + IVF hemi-cytoplast + SC (G-II); MII hemi-cytoplast + IVF hemi-karyoplast (G-III); and IVF hemi-cytoplast + IVF hemi-karyoplast (G-IV). Embryos from G-I to G-IV were allocated to subgroups as sperm-activated (SA) or were further chemically activated (SA + CA). Embryos from all groups and subgroups were in vitro cultured in the WOW system. Blastocyst development in subgroup G-I SA (28.2%) was similar to IVF (27.0%) and HMC (31.4%) controls, perhaps due to a to a more suitable activation process and/or better complementation of cytoplasmic reprogramming factors, with the other groups and subgroups having lower levels of development. No blastocyst development was observed when using IVF hemi-karyoplasts (G-III and G-IV), possibly due to the manipulation process during a sensitive biological period. In summary, the presence of cytoplasmic factors from MII hemi-oocytes and the sperm activation process from hemi-zygotes appear to be necessary for adequate in vitro development, as only the zygote-oocyte hemi-complementation was as efficient as controls for the generation of bovine cloned blastocysts. PMID- 21241165 TI - Telemedicine: the role of specialist second opinion for GPs in the care of hypertensive patients. AB - RATIONALE: To evaluate the feasibility of a second-opinion consultation in supporting general practitioners (GPs) during the daily diagnosis and therapeutic management of patients with essential hypertension. METHODS: Italian GPs were encouraged to follow-up their patients by the use of the Telemedicine Service. All known hypertensive patients with signs and symptoms (teleconsultation for symptoms) and all asymptomatic patients (teleconsultation for clinical control) undergoing a visit by their GPs were enrolled. During the first visit, the GP performed electrocardiography (ECG), measured blood pressure and required cardiological teleconsultation. RESULTS: 399 GPs examined 1719 consecutive patients (mean age 73+/-13 years, 38% male). During teleconsultation for a routine control, GPs identified 36% of new episodes of atrial fibrillation in the absence of any symptom and about 70% of patients with uncontrolled blood pressure. In about 50% of the cases, 10 min of teleconsultation helped GP to quicken the solution of the clinical problems, reducing time and number of specialist's visit. In 8% of cases, an emergency department admission was suggested. CONCLUSIONS: Telemedicine applied to hypertensive patients at high risk of cardiovascular problems offers to GPs an easy-to-use tool to control blood pressure by improving connection with second-opinion specialist consultations. PMID- 21241166 TI - The use of hot and cold high pressure homogenization to enhance the loading capacity and encapsulation efficiency of nanostructured lipid carriers for the hydrophilic antiretroviral drug, didanosine for potential administration to paediatric patients. AB - A major obstacle to the application of nanostructured lipid carriers (NLCs) as carriers for hydrophilic drugs is the limited loading capacity (LC) and encapsulation efficiency (EE) of NLCs for these molecules. The purpose of this research was to design and implement a strategy to enhance the LC and EE of NLCs for the hydrophilic drug, didanosine (DDI). DDI was dispersed in Transcutol((r)) HP and the particle size of DDI in the liquid lipid was reduced gradually using hot high pressure homogenization (HPH). The product obtained thereafter was added to Precirol((r)) ATO 5 and the hot mixture was immediately dried using liquid nitrogen. The dried materials were then ground and passed through a 200 MUm sieve and the solid lipid particles were dispersed in a surfactant solution and subsequently used to manufacture DDI-loaded NLCs using cold HPH. The LC and EE of NLCs for DDI manufactured using the new strategy were 3.39 +/- 0.63% and 51.58 +/ 1.31%, respectively, compared to 0.079 +/- 0.001% and 32.45 +/- 0.08%, respectively, obtained when DDI-loaded NLCs were produced using conventional hot HPH. The enhanced LC and EE for DDI make NLCs a potential technology for the oral administration of DDI to paediatric patients. PMID- 21241167 TI - Cutaneous and sensory effects of two types of sanitary pads with different surfaces in the Shanghai, Chinese population. AB - BACKGROUND: Regional differences in practices, ethnicity, and climate may influence the skin compatibility of sanitary pads. Although several clinical trials have been performed in North America, Mexico, Western Europe, Eastern Europe, and Africa, there is no clinical study reported for Asia. OBJECTIVE: The purpose of this study was to examine the skin compatibility of two types of modern sanitary pads in Chinese women along with a dermatological assessment and their satisfaction and preference. MATERIALS AND METHODS: The self-feeling and safety of a new sanitary pad with a non-woven top specially-shaped surface sheet was tested and compared with a conventional sanitary pad with a perforated film top sheet. The subjects studied were 22 Chinese women (age: 20-50 years) with a history of mild and occasional sanitary pad dermatitis residing in Shanghai. One subject wished to discontinue the trial for personal reasons, thus 21 subjects completed the trial. These subjects were randomly assigned to two types of sanitary pads, and used one type during their next menstrual period, and another type during their following menstrual period. After each menstrual period, a dermatologist examined the objective and subjective skin symptoms and determined a score. The subjects were asked to rate their level of satisfaction with respect to overall usability, softness, stickiness, dryness, and absorbency, and to choose which pad they had preferred. RESULTS: No adverse effect was observed for either type of pad. Edema, erythema, burning, and stinging were not obvious symptoms for either type of pad. For itching, 30-65% of the subjects scored slight or mild for both types of pads. A comprehensive evaluation showed that several symptoms were observed on both type of pads at slight and mild levels, but minimal and insignificant differences were found between them. The majority of subjects were highly satisfied with both types, but preferred the new sanitary pad with a non-woven specially-shaped surface top sheet for its softness and absorbency. CONCLUSION: Our results indicate that both types of sanitary pads were tolerated well by Chinese women, thereby providing an important extension of earlier studies. PMID- 21241168 TI - Metabolomic analysis of resveratrol-induced effects in the human breast cancer cell lines MCF-7 and MDA-MB-231. AB - Resveratrol is a naturally occurring anticancer compound present in grapes and wine with antiproliferative properties against breast cancer cells and xenografts. Our objective was to investigate the metabolic alterations that characterize the effects of resveratrol in the human breast cancer cell lines MCF 7 and MDA-MB-231 using high-throughput liquid chromatography-based mass spectrometry. In both cell lines, growth inhibition was dose dependent and accompanied by substantial metabolic changes. For all 21 amino acids analyzed levels increased more than 100-fold at a resveratrol dose of 100 MUM with far lower concentrations in MDA-MB-231 compared to MCF-7 cells. Among the biogenic amines and modified amino acids (n = 16) resveratrol increased the synthesis of serotonin, kynurenine, and spermindine in both cell lines up to 61-fold indicating that resveratrol strongly interacts with cellular biogenic amine metabolism. Among the eicosanoids and oxidized polyunsaturated fatty acids (n = 17) a pronounced increase in arachidonic acid and its metabolite 12S-HETE was observed in MDA-MB-231 and to a lesser extent in MCF-7 cells, indicating release from cell membrane phospholipids upon activation of phospholipase A2 and subsequent metabolism by 12-lipoxygenase. In conclusion, metabolomic analysis elucidated several small molecules as markers for the response of breast cancer cells to resveratrol. PMID- 21241169 TI - Structure and function of DsbA, a key bacterial oxidative folding catalyst. AB - Since its discovery in 1991, the bacterial periplasmic oxidative folding catalyst DsbA has been the focus of intense research. Early studies addressed why it is so oxidizing and how it is maintained in its less stable oxidized state. The crystal structure of Escherichia coli DsbA (EcDsbA) revealed that the oxidizing periplasmic enzyme is a distant evolutionary cousin of the reducing cytoplasmic enzyme thioredoxin. Recent significant developments have deepened our understanding of DsbA function, mechanism, and interactions: the structure of the partner membrane protein EcDsbB, including its complex with EcDsbA, proved a landmark in the field. Studies of DsbA machineries from bacteria other than E. coli K-12 have highlighted dramatic differences from the model organism, including a striking divergence in redox parameters and surface features. Several DsbA structures have provided the first clues to its interaction with substrates, and finally, evidence for a central role of DsbA in bacterial virulence has been demonstrated in a range of organisms. Here, we review current knowledge on DsbA, a bacterial periplasmic protein that introduces disulfide bonds into diverse substrate proteins and which may one day be the target of a new class of anti virulence drugs to treat bacterial infection. PMID- 21241170 TI - Long-term results evaluation in medical management programs. AB - The evaluation of multiyear programs in medical management becomes increasingly difficult as the program continues. As programs continue to run over a number of years, calculation of results becomes problematic as the comparison "baseline" recedes into the past and program impact reaches a steady state. Purchasers of services to begin to doubt program effectiveness, while methods for calculating economic impact seem increasingly unreliable. The economics of program impact across time requires insight into the drivers of savings and costs at the program level and how each changes with continued program activity. This article will review key concepts in the economic impact of medical management programs over time, and how some of these issues are addressed. PMID- 21241171 TI - Health care utilization and self-care behaviors of Medicare beneficiaries with diabetes: comparison of national and ethnically diverse underserved populations. AB - Caring for persons with diabetes is expensive, and this burden is increasing. Little is known about service use, behaviors, and self-care of older individuals with diabetes who live in underserved communities. Information about self-care, informal care, and service utilization in urban (largely Latino, n = 695) and rural (mostly white, n = 819) Medicare beneficiaries with diabetes living in federally designated medically underserved areas was collected using computer aided telephone interviews as part of the baseline assessment in the Informatics and Diabetes Education and Telemedicine (IDEATel) Project. Where items were comparable, service use was compared with that of a nationally representative group of Medicare beneficiaries with diabetes, using data from the Medical Expenditure Panel Survey. Compared to nationally representative groups, the underserved groups reported worse general health but similar health care service use, with the exception of home care. However, compared to the underserved rural group, the underserved, largely minority urban group, reported worse general health (P < 0.0001); more inpatient nights (P = 0.003), emergency room visits (P < 0.001), and home health care (P < 0.001); spent more time on self-care; and had more difficulty with housework, meal preparation, and personal care. Differences in service use between urban and rural groups within the underserved group substantially exceeded differences between the underserved and nationally representative groups. These findings address a gap in knowledge about older, ethnically diverse individuals with diabetes living in medically underserved areas. This profile of disparate service use and health care practices among urban minority and rural majority underserved adults with diabetes can assist in the planning of future interventions. PMID- 21241172 TI - Predictive modeling in practice: improving the participant identification process for care management programs using condition-specific cut points. AB - The objective of this study was to optimize predictive modeling in the participant selection process for care management (CM) programs by determining the ideal cut point selection method. Comparisons included: (a) an evidence-based "optimal" cut point versus an "arbitrary" threshold, and (b) condition-specific cut points versus a uniform screening method. Participants comprised adult Medicaid health plan members enrolled during the entire study period (January 2007-December 2008) who had at least 1 of the chronic conditions targeted by the CM programs (n = 6459). Adjusted Clinical Groups Predictive Modeling (ACG-PM) system risk scores in 2007 were used to predict those with the top 5% highest health care expenditures in 2008. Comparisons of model performance (ie, c statistic, sensitivity, specificity, positive predictive value) and identified population size were used to assess differences among 3 cut point selection approaches: (a) single arbitrary cut point, (b) single optimal cut point, and (c) condition-specific optimal cut points. The "optimal" cut points (ie, single and condition-specific) both outperformed the "arbitrary" selection process, yielding higher probabilities of correct prediction and sensitivities. The condition specific optimal cut point approach also exhibited better performance than applying a single optimal cut point uniformly across the entire population regardless of condition (ie, a higher c statistic, specificity, and positive predictive value, although sensitivity was lower), while identifying a more manageable number of members for CM program outreach. CM programs can optimize targeting algorithms by utilizing evidence-based cut points that incorporate condition-specific variations in risk. By efficiently targeting and intervening with future high-cost members, health care costs can be reduced. PMID- 21241173 TI - Impact of a comprehensive worksite wellness program on health risk, utilization, and health care costs. AB - In 2005, Blue Cross Blue Shield of Kansas City initiated a comprehensive worksite wellness program designed to impact employer culture and to assist healthy employees to stay at low risk and to reduce risk levels for those at moderate or high risk. Fifteen employer groups (9637 employees) participated in the A Healthier You (AHY) program for 3 consecutive years, 2006-2008. The results of health risk appraisals and biometric screening were used to evaluate program impact. Among the 4230 employees (44.0% of eligible employees) who completed health risk appraisals in all 3 years, 85.8% of individuals in the low-risk category in 2006 remained at low risk in 2008. There were also improvements in other risk categories, with 39.9% of those in the medium-risk category and 48.9% of those in the high-risk category in 2006 moving to a lower risk category in 2008. There were improvements in blood pressure control and total cholesterol, but no improvement in weight control. To assess financial and utilization outcomes, claims for the participating employer groups were compared to those for 7 employers (3800 employees) who did not participate in AHY in 2006-2008. Although none of the utilization measures was statistically different, the AHY groups had significantly smaller increases in both overall and emergency room costs per member per month. The AHY program now has over 180 employer groups, which will allow future evaluations to examine the impact of the program on a much larger population and to focus on the comparative effectiveness of different intervention strategies across implementations. PMID- 21241174 TI - Using motion interactive games to promote physical activity and enhance motor performance in children with cerebral palsy. AB - OBJECTIVE: To explore the feasibility of using low-cost motion interactive games as a home-based intervention for children with cerebral palsy (CP). METHODS: Fourteen children with CP, 6-16 years old, practiced with the EyeToy for PlayStation2(r) in their homes during 4 weeks. Outcome measures were physical activity monitors, Movement Assessment Battery for Children-2 (mABC-2), Bruininks Oseretsky Test of Motor Proficiency (sub-test 5 : 6), 1 Minute Walk Test and gaming diaries. RESULTS: Motivation for practice and compliance of training were high. The children's physical activity increased during the intervention and activity monitors were feasible to use, although data loss may be a concern. According to mABC-2 the children's motor performance improved, but there were both floor and ceiling effects. The two additional motor tests showed only non significant progress. CONCLUSION: It is highly feasible to use motion interactive games in home rehabilitation for children with CP. Specific motor effects need to be further explored. PMID- 21241175 TI - A comparison of parenting stress between mothers of children with spina bifida and able-bodied controls. AB - OBJECTIVES: To compare parenting stress between mothers of children with spina bifida (SB) and able bodied controls. METHODS: Sixty-six mothers of children with SB and controls (matched for age, sex and ethnicity) completed the Parenting Stress Index Short Form (PSI/SF) and General Health Questionnaire-12 (GHQ-12). Each child's adaptive skills was assessed using the Vineland Adaptive Behaviour Scales (VABS). RESULTS: Mothers of children with SB had significantly higher scores for GHQ-12 and the Parental Distress (PD), Parent-Child Dysfunctional Interaction (P-CDI) and Difficult Child (DC) sub-scales of the PSI/SF, even after adjusting for socioeconomic and caregiver status. Single parent status, having a child with SB and higher Life Stress scores were associated with higher PD and DC scores. Lower VABS scores were associated with higher P-CDI scores. CONCLUSION: Factors such as recent life change events, single parent status and the child's adaptive skills modify the impact of spina bifida on parenting stress. PMID- 21241176 TI - Self-management and supervisory feedback improves trainer implementation of communication rehabilitation programmes. AB - OBJECTIVE: This study investigated the differential effects of self-management and supervisory feedback on the acquisition and maintenance of accurate use of response prompts by five trainers who provided communication training to individuals with severe intellectual disability. METHODS: A counterbalanced design was used. For three trainers the self-management condition was first in effect followed by the supervisory feedback condition. For the two other trainers this order was reversed. RESULTS: Results revealed that for three trainers there was a statistically significant difference between the two conditions, favouring supervisory feedback. For the other two trainers, self-management and supervisory feedback were equally effective in establishing accurate use of response prompts. Acceptability ratings from trainers suggest a preference for self-management over supervisory feedback. CONCLUSION: For three out of five trainers supervisory feedback was more effective in improving implementation of the communication intervention (i.e. response prompting) than self-management. PMID- 21241177 TI - Stability of symptoms of autism spectrum disorders in toddlers: an examination using the Baby and Infant Screen for Children with aUtIsm Traits-Part 1 (BISCUIT). AB - OBJECTIVE: The diagnostic stability of Autism Spectrum Disorders (ASD) at very young ages continues to be debated, despite empirical evidence that ASDs can be reliably diagnosed in children under the age of 3 years. This topic is of the upmost importance given that early intervention increases long-term outcomes in this population. METHODS: The goal of the current study was to examine the stability of symptoms of ASD between two assessment times for 114 toddlers. The following was compared from the first to second assessment: diagnostic classification stability, correlations between scores and the impact of time between the first and second assessment. RESULTS: Significant correlations were found for toddlers as young as 18 months of age. In addition, even with up to a year between assessment intervals, symptoms of ASD were relatively stable prior to 3 years of age. CONCLUSIONS: Implications of the current findings are discussed. PMID- 21241178 TI - The relationship between autism spectrum disorders and symptoms of conduct problems: the moderating effect of communication. AB - OBJECTIVE: To examine the relationship between ASD diagnosis (i.e. Autism, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) and atypical developing control) and tantrum/conduct symptoms in infants and toddlers. Then examine the moderating role of communication. DESIGN: Analysis of Covariance was conducted for study 1 followed by hierarchical regression analyses for study 2. METHODS: The Baby and Infant Screen for Children with aUtIsm Traits, Part 2 was administered to the caregivers of 774 infants and toddlers. RESULTS: Those with autism exhibited the greatest tantrum/conduct symptoms followed by those with PDD NOS and then atypical controls, F(3, 771) =94.42, p=0.003. Communication was not a significant moderator. CONCLUSIONS: Those with Autistic Disorder exhibited greater symptoms of tantrum/conduct problems, which is consistent with previous research. It seems that the relationship with communication as a moderator may differ in young children as their language skills are still in the early stages of development. PMID- 21241179 TI - Microswitch-cluster technology to enhance adaptive engagement and head upright by a post-coma man with multiple disabilities. AB - OBJECTIVE: To evaluate microswitch-cluster technology to help a post-coma man with multiple disabilities increase adaptive responding and reduce head forward tilting. METHOD: The intervention programme initially focused on promoting a simple adaptive response (i.e. manipulating and moving a wobbling, ball-like device), which produced brief periods of preferred stimulation. Subsequently, this response produced the stimulation only if performed in the presence of head upright. Moreover, the stimulation lasted the scheduled time only if the head upright was maintained. RESULTS: Data showed that the programme was successful in increasing the frequency of adaptive responses and in reducing the unhealthy posture of head forward tilting. Toward the end of the programme, the participant performed virtually all responses with his head upright and kept this posture through nearly the entire length of the sessions. CONCLUSION: Microswitch-cluster technology might help post-coma persons with multiple disabilities improve adaptive engagement and head posture simultaneously. PMID- 21241181 TI - Tensile resistance of mineralized and demineralized rat bones in different regions (calvarial and femur). AB - The aim of this study was to evaluate the tensile resistance of mineralized and demineralized bones. Twelve mice were used. Specimens were collected and divided into groups 1 and 2, mineralized and demineralized calvarial bone, and groups 3 and 4, mineralized and demineralized femoral bone. There was not a statistically significant difference (analysis of variance) between the regions; however, when comparing the demineralized and mineralized groups, a statistically significant difference (Student test) for the mineralized group was noticed. PMID- 21241182 TI - Theory-based telehealth and patient empowerment. AB - Health care technology holds great potential to improve the quality of health care delivery. One effective technology is remote patient monitoring, whereby patient data, such as vital signs or symptom reports, are captured from home monitoring devices and transmitted to health care professionals for review. The use of remote patient monitoring, often referred to as telehealth, has been widely adopted by health care providers, particularly home care agencies. Most agencies have invested in telehealth to facilitate the early identification of disease exacerbation, particularly for patients with chronic diseases such as heart failure and diabetes. This technology has been successfully harnessed by agencies to reduce rehospitalization rates through remote data interpretation and the provision of timely interventions. We propose that the use of telehealth by home care agencies and other health care providers be expanded to empower patients and promote disease self-management with resultant improved health care outcomes. This article describes how remote monitoring, in combination with the application of salient adult learning and cognitive behavioral theories and applied to telehealth care delivery and practice, can promote improved patient self-efficacy with disease management. We present theories applicable for improving health-related behaviors and illustrate how theory-based practices can be implemented in the field of home care. Home care teams that deliver theory based telehealth function as valuable partners to physicians and hospitals in an integrated health care delivery system. PMID- 21241183 TI - The solution to ongoing health care challenges: creating integrated personal health ecosystems. PMID- 21241184 TI - The complexity of disease combinations in the Medicare population. AB - Developing systems of care that address the mortality, morbidity, and expenditures associated with Medicare beneficiaries with multiple diseases would benefit from a greater understanding of the complexity of disease combinations (DCs) found in the Medicare population. To develop estimates of the number of DCs, we performed an observational analysis on 32,220,634 beneficiaries in the Medicare Fee-for-Service claims database based on a set of records containing each beneficiary's Part A and B International Classification of Diseases, 9(th) Revision, Clinical Modification (ICD-9-CM) claims data for the year of 2008. We made 2 simplifying adjustments. First, we mapped the individual ICD-9-CM codes to the Centers for Medicare and Medicaid Services-Hierarchical Conditions Categories (HCC) model that was developed in 2004 to risk adjust capitation payments to private health care plans based on the health expenditure risk of their enrollees. Second, we aggregated beneficiaries with identical HCCs regardless of the temporal order of these findings within the 2008 claims year; thus the DC to which they are assigned represents the summation of their 2008 claims data. We defined 3 distinct populations at the HCC level. The first consisted of 35% of the beneficiaries who did not fall into any HCC category and accounted for 6% of expenditures. The second was represented by the 100 next most prevalent DCs that accounted for 33% of the beneficiaries and 15% of expenditures. The final population, accounting for 32% of the beneficiaries and 79% of expenses, was complex and consisted of over 2 million DCs. Our results indicate that the majority of expenditures are associated with a complex set of beneficiaries. PMID- 21241185 TI - Quality of life following participation in cardiac rehabilitation programs of longer or shorter than 6 months: does duration matter? AB - Cardiac rehabilitation (CR) participation results in significant health benefits. However, there is wide variation in program duration, and little is known about the optimal duration of CR for patient outcomes. The objective of this study was to compare quality of life (QoL) of patients who participated in CR programs of < or >=6 months duration versus patients who did not attend CR. A total of 1056 cardiac outpatients completed mailed surveys at baseline and 9 months later. Patients were categorized based on CR participation in one of 31 programs: a program of < or >=6 months duration, or nonattendance. Outcomes were body mass index, activity status, depressive symptoms, physical activity, QoL, posttraumatic growth inventory (PTGI), and percentage of CR sessions attended. Generalized estimating equations were used. A total of 148 (14%) patients participated in a program of < 6 months, and 183 (17.3%) participated in a program of >=6 months. Patients who participated in the former completed a greater percentage of CR sessions (P = 0.02). Activity status (P = 0.002), several domains of QoL (P > 0.0001), and PTGI (P = 0.007) were significantly greater regardless of CR duration when compared to those who did not attend CR. There were no significant differences in outcomes when comparing patients attending CR programs of < or >=6 months duration. Patients achieve greater activity status and QoL when compared to those who did not attend CR, regardless of program duration. This could be a result of greater program adherence among those who attend shorter programs. Future research is needed using a randomized design to assess effects of program duration on cardiac events and mortality. PMID- 21241186 TI - Disease management enrollment estimation. PMID- 21241187 TI - The RNA activator ds-p21 potentiates the cytotoxicity induced by fludarabine in Dohh2 cells. AB - Recently, it has been reported that, in several tumor cell lines, short double stranded RNAs tailored for promoter regions of specific genes are able to activate their transcription. Such molecules (named RNA activators) act opposite to other double-stranded RNA molecules (named RNA inhibitors) in that the overexpression instead of underexpression of a given gene is triggered. In Dohh2 non-Hodgkin lymphoma cells, the transcriptional repressor BCL6, which negatively controls both p53 and p21, is overexpressed, so that the cells can escape the check point governed by p53 and proliferate. The aim of this work was to investigate whether the RNA activator p21 can represent a tool to circumvent the transcriptional control of BCL6 and induce the blockage of cell proliferation in Dohh2 non-Hodgkin lymphoma cells. For that, Dohh2 cells were transfected with either a control RNA activator (ds-NC) or an RNA activator specific for human p21 promoter (ds-p21). At various time points after transfection, the cells were collected and p21 was measured. Dohh2 cells transfected with ds-p21 showed a slight but significant overexpression of p21 at both mRNA and protein levels. Nonetheless, cell proliferation, cell cycle, and apoptosis were not significantly modified. In contrast, the exposure of Dohh2 cells transfected with ds-p21 to fludarabine potentiates the cytotoxicity of the drug, suggesting the RNA activator p21 complements the fludarabine-dependent cell death pathways. PMID- 21241188 TI - Pluripotency maintenance in mouse somatic cell nuclear transfer embryos and its improvement by treatment with the histone deacetylase inhibitor TSA. AB - Reprogramming of somatic cells to pluripotency can be achieved by nuclear transfer into enucleated oocytes (SCNT). A key event of this process is the demethylation of the Oct4 gene and its temporally and spatially regulated expression. Different studies have shown that it occurs abnormally in some SCNT embryos. TSA is a histone deacetylase inhibitor known to increase the efficiency of development to term of SCNT embryos, but its impact on the developmental features of SCNT embryos is poorly understood. Here, we have followed the fate of the pluripotent cells within SCNT embryos, from the late blastocyst to the early epiblast prior to gastrulation. Our data show a delay in development correlated with a defect in forming and maintaining a correct number of Oct4 expressing ICM and epiblast cells in SCNT embryos. As a consequence, during the outgrowth phase of embryonic stem cell derivation as well as during diapause in vivo, part of the SCNT blastocysts completely lose their ICM cells. Meanwhile, the others display a correctly reprogrammed ICM compatible with the derivation of ES cells and development of the epiblast. Our data also indicate that TSA favors the establishment of pluripotency in SCNT embryos. PMID- 21241189 TI - Differentiation of embryonic stem cells using pancreatic bud-conditioned medium gives rise to neuroectoderm-derived insulin-secreting cells. AB - Human embryonic stem cells can be differentiated into insulin-secreting cells by emulating in vitro the key processes that occur during embryonic development. However, the resulting cells are generally immature; thus, further research must be performed to identify the necessary factors to complete the differentiation. To this end, we cultured mouse embryonic stem cells with pancreatic bud conditioned medium, based on a recent publication. Unlike in humans, mouse cells present two types of insulin, which can be used to identify different cell lineages. As a result, the cell product presented a neuroectodermal genetic expression pattern, with no expression of any definitive endodermal marker analyzed. Also, nonglucose-dependent insulin release was detected. Altogether, this previously published protocol results in neuroectoderm, and not definitive endoderm, derived insulin-positive cells. This further confirms the difficulty of obtaining true cell types of this germ layer. Finally, we identified a 16-kDa protein band that was present in pancreatic bud-conditioned medium. Sequencing this band revealed the presence of Reg proteins. The role of pancreatic bud conditioned medium remains to be tested in definitive endoderm committed cells. PMID- 21241190 TI - Improved production of genetically modified fetuses with homogeneous transgene expression after transgene integration site analysis and recloning in cattle. AB - Animal cloning by nuclear transfer (NT) has made the production of transgenic animals using genetically modified donor cells possible and ensures the presence of the gene construct in the offspring. The identification of transgene insertion sites in donor cells before cloning may avoid the production of animals that carry undesirable characteristics due to positional effects. This article compares blastocyst development and competence to establish pregnancies of bovine cloned embryos reconstructed with lentivirus-mediated transgenic fibroblasts containing either random integration of a transgene (random integration group) or nuclear transfer derived transgenic fibroblasts with known transgene insertion sites submitted to recloning (recloned group). In the random integration group, eGFP-expressing bovine fetal fibroblasts were selected by fluorescence activated cell sorting (FACS) and used as nuclei donor cells for NT. In the recloned group, a fibroblast cell line derived from a transgenic cloned fetus was characterized regarding transgene insertion and submitted to recloning. The recloned group had higher blastocyst production (25.38 vs. 14.42%) and higher percentage of 30-day pregnancies (14.29 vs. 2.56%) when compared to the random integration group. Relative eGFP expression analysis in fibroblasts derived from each cloned embryo revealed more homogeneous expression in the recloned group. In conclusion, the use of cell lines recovered from transgenic fetuses after identification of the transgene integration site allowed for the production of cells and fetuses with stable transgene expression, and recloning may improve transgenic animal yields. PMID- 21241191 TI - Generation of dorsal spinal cord GABAergic neurons from mouse embryonic stem cells. AB - Developmental signaling molecules involved in dorsal patterning of the spinal cord have been identified in vivo; however, studies have not produced specific functional dorsal spinal cord neurons in vitro. We present here differentiation of R1 embryonic stem (ES) cells into GABAergic dorsal spinal cord neurons by sequential treatment with developmental signaling molecules. We found that retinoic acid, Bmp4 altered the specification of neural progenitors and instructed neural fate when applied at distinct stages of development. High concentration of retinoic acid initiated caudal patterning during early differentiation; Bmp4 induced dorsal development. The combination of retinoic acid and different concentration Bmp4 controlled the differing regional progenitors of spinal cord. Low-concentration Bmp4 and high concentration of retinoic acid-treated embryoid bodies resulted in the differentiation of GABAergic neurons. In summary, we demonstrate this simple treatment paradigm produced simple dorsal spinal cord neurons, which could be utilized for developmental and preclinical studies. PMID- 21241192 TI - Pediatric robot-assisted pyeloplasty. AB - The emergence of robot-assisted surgical technology has permitted application of laparoscopic pyeloplasty to the pediatric age group to a much wider degree than previously possible. The challenging learning curve for conventional laparoscopic pyeloplasty, particularly in infants, has hindered its widespread application. Robot-assisted pyeloplasty in children has been clearly shown to provide an equally effective, safe, and reasonably efficient means to repair ureteropelvic junction obstruction with more rapid hospital discharge and less postoperative analgesic requirements. Precise port placement, adjusted to the child's anatomy and size, delicate anastomosis, and use of postoperative stent appear to be important elements for successful repair. The procedure has become reproducible and in some centers is exclusively used over open repair. The specific procedural steps are detailed and the potential limitations and complications are reviewed, as well as the limited available data in the literature. PMID- 21241193 TI - Transperitoneal robot-assisted laparoscopic pyeloplasty. AB - Minimally invasive pyeloplasty has achieved success that has approached open pyeloplasty. Key principles such as removal of fibrosis, extensive mobilization of the ureteropelvic junction and crossing vessels, and creation of a tension free, widely spatulated anastamosis are important in successful repair. In this review, we discuss the preparation and operative steps in performing a robotic pyeloplasty. Patient selection and diagnostic approach is discussed in the preoperative setting. Important surgical steps described include port placement, management of crossing vessels, division and spatulation of the ureter, and reanastamosis. Finally, management of more difficult cases is discussed. PMID- 21241194 TI - Writing abstracts and developing posters for national meetings. AB - Presenting posters at national meetings can help fellows and junior faculty members develop a national reputation. They often lead to interesting and fruitful networking and collaboration opportunities. They also help with promotion in academic medicine and can reveal new job opportunities. Practically, presenting posters can help justify funding to attend a meeting. Finally, this process can be invaluable in assisting with manuscript preparation. This article provides suggestions and words of wisdom for palliative care fellows and junior faculty members wanting to present a poster at a national meeting describing a case study or original research. It outlines how to pick a topic, decide on collaborators, and choose a meeting for the submission. It also describes how to write the abstract using examples that present a general format as well as writing tips for each section. It then describes how to prepare the poster and do the presentation. Sample poster formats are provided as are talking points to help the reader productively interact with those that visit the poster. Finally, tips are given regarding what to do after the meeting. The article seeks to not only describe the basic steps of this entire process, but also to highlight the hidden curriculum behind the successful abstracts and posters. These tricks of the trade can help the submission stand out and will make sure the reader gets the most out of the hard work that goes into a poster presentation at a national meeting. PMID- 21241195 TI - Laparoscopic partial nephrectomy: a decade of evolution. AB - The detection of renal tumors is increasing with the widespread use of ultrasonography and CT. Laparoscopic partial nephrectomy (LPN) offers less pain, smaller scars, and shorter convalescence. Expanded indications of LPN include larger and more complex tumors, including those in hilar or central locations, multiple tumors, solitary kidneys, and patients with previous renal surgery. This procedure is in constant evolution. We describe the technical nuances of LPN over the past decade of evolution. PMID- 21241196 TI - Dexmedetomidine as an adjuvant analgesic for intractable cancer pain. AB - Abstract Dexmedetomidine (Precedex(r)) is an alpha-2 adrenergic agonist that can produce sedation and analgesia without causing respiratory depression. Its use has been described in patients undergoing mechanical ventilation, sedation for surgical and nonsurgical procedures, and prevention of withdrawal. We describe its use as an adjuvant analgesic in a patient with cancer pain refractory to multiple treatment modalities. PMID- 21241197 TI - Cost-effectiveness analyses of elective orthopaedic surgical procedures in patients with inflammatory arthropathies. AB - OBJECTIVE: To examine the costs per quality-adjusted life year (QALY) gained for surgical interventions in patients with inflammatory arthropathies, and to compare the costs per QALY gained for replacement versus non-replacement surgical interventions. METHODS: In total, 248 patients [mean age 57 (SD 13) years, 77% female] with inflammatory arthropathies underwent orthopaedic surgical treatment and responded to mail surveys at baseline and during follow-up (3, 6, 9, and 12 months). Questionnaires included the quality-of-life EuroQol-5D (EQ-5D) and Short Form-6D (SF-6D) utility scores. The health benefit from surgery was subsequently translated into QALYs. The direct treatment costs in the first year were, for each patient, derived from the hospital's cost per patient accounting system (KOSPA). The costs per QALY were estimated and future costs and benefits were discounted at 4%. RESULTS: Improvement in utility at 1-year follow-up was 0.10 with EQ-5D and 0.03 with SF-6D (p < 0.05). The estimated 10-year cost per QALY gained was EUR 5000 for hip replacement surgery (EUR18 600 using SF-6D) and EUR 10 500 (EUR 48 500 using SF-6D) for all replacement procedures. The 5-year cost per QALY was EUR 17 800 for non-replacement surgical procedures measured by EQ-5D (SF-6D: EUR 67 500). CONCLUSIONS: Elective orthopaedic surgery in patients with inflammatory arthropathies was cost-effective when measured with EQ-5D, and some procedures were also cost-effective when SF-6D was used in the economic evaluations. Hip replacement surgery was most cost-effective, irrespective of the method of analysis. PMID- 21241198 TI - Drug and metabolite concentrations in tissues in relationship to tissue adverse findings: a review. AB - INTRODUCTION: Drug blood (or plasma) levels measured during safety preclinical investigations do not always correlate with toxicological findings. Concentrations in target tissues or, even better, at target receptors would probably be more relevant. In addition, toxicity may be caused by drug metabolites which, in turn, can be tissue specific. Tissue concentrations and tissue metabolism may be crucial for interpreting tissue toxicity. AREAS COVERED: This paper, starting from the authors' direct experience, focuses on distribution of the parent compound and metabolites in target toxicity tissues and presents a review of several examples where organ or tissue concentrations have been either useful or not relevant for interpreting safety findings. Regulatory aspects and technological progresses are also mentioned. EXPERT OPINION: The authors advocate directing more attention and efforts toward investigating tissue distribution: this approach might reduce late stage attrition. When unexpected tissue toxicity is found, measuring drug concentrations in the target tissue and characterising and measuring tissue metabolites could bring relevant information for interpreting the adverse finding. Evidence of slow accumulation of a long lasting metabolite in a tissue should be considered as an alert: this evidence can be obtained during short-term toxicity studies. PMID- 21241199 TI - Role of organic cation transporters in drug-induced toxicity. AB - INTRODUCTION: Membrane transporters are important determinants of in vivo drug disposition, therapeutic efficacy and adverse drug reactions. Many commonly used drugs are organic cations and substrates of organic cation transporters (OCTs). These transporters have a large binding site containing partially overlapping interaction domains for different substrates and are specifically distributed around the body. Consequently, drug interactions with these transporters can result in specific toxicity. AREAS COVERED: This review describes the general properties of OCT and illustrates their importance for the development of important drug toxicities using the examples of metformin and cisplatin. Additionally, this review discusses the role of OCT polymorphisms in the modulation of these toxic effects. EXPERT OPINION: Understanding how drugs interact with membrane transporters is pivotally important in explaining the mechanisms of specific toxicities and also in designing new drugs or new therapeutic protective protocols by specific competition at the transporter. Defining the pharmacogenomics of these transporters will be essential to personalized medicine, enabling physicians to choose drugs for patients based on efficacy, availability, cost, safety, tolerability and convenience. PMID- 21241201 TI - Dose-toxicity models in oncology. AB - INTRODUCTION: The first human exposure to a new medicine always carries a major risk. Assessment of the safety profile and determination of a therapeutic dose are formidable tasks, particularly in oncology where toxicity is seen as a surrogate for efficacy. Increasing evidence supports the adoption of innovative dose-toxicity models, as these are safer and more efficient in meeting the challenges of modern investigational oncology than traditional models used in Phase I clinical trials. AREAS COVERED: A literature review on dose-toxicity models in oncology was carried out. The objective of this study was to provide a non-mathematical, reader-friendly overview of current and innovative dose toxicity models in oncology with an emphasis on recent clinical advances, including the benefits of a Bayesian framework. EXPERT OPINION: Innovative dose toxicity models attempt to minimize clinical risk and maximize research performance. Of these, the Bayesian Continual Reassessment Method and the Escalation With Overdose Control are two successful contemporary designs that outperformed traditional models in clinical trials; they account for patient heterogeneity, combination therapy, and they appropriately assess molecularly targeted agents. Support by regulatory authorities is providing an additional incentive to the widespread use of innovative and efficient dose-toxicity designs: this will improve investigational oncology, and ultimately benefit patients and science alike. PMID- 21241202 TI - Placental volume and vascularization flow indices by 3D power Doppler US using VOCAL technique and correlation with IGF-1, free beta-hCG, PAPP-A, and uterine artery Doppler at 11-14 weeks of pregnancy. AB - AIMS: The purpose of this study was to investigate correlations between first trimester placental volume (PV) and blood flow indexes (FIs), bilateral uterine artery pulsatility indexes, notching, and biochemical parameters: pregnancy associated plasma protein-A (PAPP-A), free beta-human chorionic gonadotropin (f beta-hCG), and insulin-like growth factor-1 (IGF-1) to predict the high-risk pregnancies in the first trimester. METHODS: We prospectively examined 310 patients at 11-14 weeks of pregnancy using transabdominal 3D gray scale and power Doppler ultrasound for assessing PV, vascularization index, FI, and vascularization FI (VFI). The acquired volumes were analyzed using VOCALTM imaging software. The results were correlated with biochemical parameters. RESULTS: We found significant correlations between PV and biochemical parameters, and between placental blood flow studies and other parameters. Finally, PV/crown rump length so called the placental quotient is also related to both PAPP-A and VFI. CONCLUSIONS: Placental volumetry, uterine artery Doppler studies, blood flow calculations and biochemical parameters, such as f-beta-hCG, PAPP-A, and IGF-1 could be important in the early and rapid diagnosis of high-risk pregnancies. Thus, they may be useful in first trimester prediction of fetal growth restriction presenting with alterations in PV and vascularity. PMID- 21241203 TI - Normal fasting plasma glucose levels during pregnancy: a hospital-based study. AB - OBJECTIVE: Recently, the International Association of Diabetes and Pregnancy Study Groups have suggested new criteria for the diagnosis of gestational diabetes including a fasting glucose level of >=92 mg/dL. We determined reference levels for normal fasting plasma glucose levels throughout pregnancy and evaluated the new normal cut-off for fasting glucose level. METHODS: Charts of patients who delivered in our hospital between June 2001 and June 2006 were reviewed. Women with pregestational diabetes, fasting glucose level >105 mg/dL or delivery at <24 weeks were excluded. Fasting glucose levels were assessed in 11 time categories between three months prior and four months postpartum in 7946 women. RESULTS: Compared to preconception levels, fasting glucose levels decreased by a median of 3 mg/dL in the first trimester (81-78 mg/dL). During the third trimester a slight further glucose reduction was observed (median 76 mg/dL). After delivery fasting glucose levels increased sharply (84 mg/dL in the puerperium and 81 mg/dL by three months postpartum). Throughout pregnancy 5.2 9.0% of pregnant women had a fasting glucose level of >=92 mg/dL [compared to 8.2% in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study]. CONCLUSION: Fasting glucose levels decrease early in pregnancy with only slight further decrease later on. It seems that the same fasting glucose cut-off can be used throughout pregnancy for the diagnosis of gestational diabetes mellitus. PMID- 21241200 TI - Biomarkers of immunosuppressant organ toxicity after transplantation: status, concepts and misconceptions. AB - INTRODUCTION: A major challenge in transplantation is improving long-term organ transplant and patient survival. Immunosuppressants protect the transplant organ from alloimmune reactions, but sometimes also exhibit limiting side effects. The key to improving long-term outcome following transplantation is the selection of the correct immunosuppressive regimen for an individual patient for minimizing toxicity while maintaining immunosuppressive efficacy. AREAS COVERED: Proteomics and metabolomics have the potential to develop sensitive and specific diagnostic tools for monitoring early changes in cell signal transduction, regulation and biochemical pathways. Here, we review the steps required for the development of molecular markers from discovery, mechanistic and clinical qualification to regulatory approval, and present a critical discussion of the current status of molecular marker development as relevant for the management and individualization of immunosuppressive drug regimens. EXPERT OPINION: Although metabolomics and proteomics-based studies have yielded several candidate molecular markers, most published studies are poorly designed, statistically underpowered and/or often have not gone beyond the discovery stage. Most molecular marker candidates are still at an early stage. Due to the high complexity of and the resources required for diagnostic marker development, initiatives and consortia organized and supported by funding agencies and regulatory agencies will be critical. PMID- 21241204 TI - Syndrome of inappropriate antidiuretic hormone secretion after cesarean section complicated with hemorrhage. PMID- 21241205 TI - Longitudinal evaluation of health care utilization and costs during the first three years after a new diagnosis of fibromyalgia. AB - OBJECTIVE: To evaluate health care resource utilization and costs 1 year before and 3 years after a fibromyalgia (FM) diagnosis. METHODS: This retrospective cohort analysis used claims from Humana to identify newly diagnosed FM patients >=18 years of age based on >=2 medical claims for ICD-9 CM code 729.1 and 729.0 between June 1, 2002 and March 1, 2005. Prevalence of comorbidities, as well as utilization and costs of pharmacotherapy and health care services were examined for 12 months preceding (pre-diagnosis) and 36 months following (post-diagnosis) the date of first FM diagnosis. These periods were subdivided into 6-month blocks to better observe patterns of change. RESULTS: We identified 2613 FM patients who had a mean age at diagnosis of 58.5 +/- 15.3 years and a mean Charlson Comorbidity Index of 0.48 +/- 1.05. Of those, 73% were female. The use and costs of pain-related medications rose from pre-diagnosis and remained stable after the 6-month post-diagnosis period, while the use of non-pain-related medications steadily rose from pre-diagnosis to 3 years post-diagnosis. This increase was concomitant with an increase in the presence of conditions that may account for higher resource utilization. The use of recommended FM therapies (i.e., antidepressants and anticonvulsants) increased post-diagnosis but remained less common than other pain-related therapies. Total resource utilization and costs increased during the period up to 6 months after diagnosis. This increase was followed by a decline (7-12 months post-diagnosis), and plateau, with an increase during the final 6 months of the study period. Total mean per patient costs were $3481 for the 6-month post-diagnosis period, and $3588 for the final 6 months. Limitations include potential errors in coding and recording, and an inability of claims analyses to determine causality between resource utilization and the specific diagnosis of interest. CONCLUSIONS: An FM diagnosis was associated with increased utilization and pain-related medication cost up to the first 6 months post-diagnosis followed by stabilization over 3 years post-diagnosis. Less use of recommended therapies relative to other therapies suggests that further dissemination of treatment guidelines is needed. An increase in non-pain medications over the observation period accounted for the majority of pharmacy costs. These pharmacy costs may be related to an increasing prevalence of comorbid conditions. PMID- 21241206 TI - Factors associated with clopidogrel use, adherence, and persistence in patients with acute coronary syndromes undergoing percutaneous coronary intervention. AB - OBJECTIVE: Recent guidelines recommend use of aspirin and either clopidogrel or prasugrel for at least 12 months following use of drug-eluting or bare metal stents in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). This study evaluated factors associated with clopidogrel use and adherence in ACS patients following PCI. RESEARCH DESIGN AND METHODS: The US employer-based MarketScan commercial claims database was used to examine factors associated with clopidogrel use and adherence. Adherence was defined as a medication possession ratio of 80% or higher. Multivariate logistic regression analyses were conducted to identify factors associated with clopidogrel use and adherence and included patient demographics, comorbidities, and prior beta-blocker, statin, and angiotensin converting enzyme inhibitor (BSI) use as factors. RESULTS: A total of 10,465 patients aged 18-65 years who met inclusion criteria were hospitalized for ACS and underwent PCI between 01/01/2005 and 12/31/2006. Overall, the rate of clopidogrel use was 92.8% for ACS-PCI patients and 66.8% of the clopidogrel users were adherent. Receiving PCI without stenting (Odds Ratio [OR] = 3.28), comorbid hypertension (OR = 1.50), diabetes (OR = 1.49), and atrial fibrillation (OR = 1.91) were associated with decreased filled prescriptions for clopidogrel. Younger age (OR = 0.83) and prior use of clopidogrel (OR = 0.54) or other BSI medications (OR = 0.44) were associated with increased use of clopidogrel (all p values < 0.05). Factors significantly associated with non-adherence of clopidogrel were prior use of clopidogrel (OR = 1.40), prior hospitalization (OR = 1.34), chronic pulmonary disease (OR = 1.31), PCI without stenting (OR = 1.32), diabetes (OR = 1.17), and younger age (OR = 1.29). Prior use of BSI medications (OR = 0.82) increased adherence to clopidogrel. CONCLUSIONS: Prior use of clopidogrel, comorbid conditions such as diabetes and chronic pulmonary disease, prior hospitalization, PCI without stenting, and younger age had a negative impact on clopidogrel adherence. These findings may assist programs to improve thienopyridine compliance through a better understanding of patients' disease profiles and concomitant medication use. PMID- 21241209 TI - An analysis of clinical outcomes and costs of a long term acute care hospital. AB - OBJECTIVE: Compare clinical outcomes and costs in a study group of long-term acute care hospital (LTCH) patients with a control group of LTCH-eligible patients in an acute care hospital. LTCHs were created to provide post-acute care services not available at other post-acute settings. This is based on the premise that these patients would otherwise have stayed at acute care hospitals as high cost outliers. The LTCH hospital is intended to deliver care to patients more efficiently, however, there are little documented clinical and financial data regarding the comparative clinical outcomes and costs for patients. METHODS: Retrospective medical and billing record review of patients from the following groups: (1) LTCH study comprising patients admitted directly from an acute care hospital to the study LTCH and discharged from the LTCH from September 2004 through August 2006; (2) a control group of LTCH-eligible, medically complex patients treated and discharged from an acute care hospital in FY 2002. The control group was selected from approximately 500 patients who had at least one of the ten most common principle diagnosis DRGs of the study LTCH with >30-day length of stay at the referring hospital and met NALTH admitting guidelines. RESULTS: Discharge disposition is an important outcome measure of the quality of care of medically complex patients. The in-hospital mortality rate trended lower and home discharge was 3 times higher for the LTCH study group than for the control group. As a possible result, SNF discharge of LTCH patients was approximately half that of the control group. Both mean patient cost per day and mean total cost per patient were significantly higher in the control group than in the LTCH study group. CONCLUSIONS: The patients in the LTCH study group had both better clinical outcomes and lower cost of care than the control group. PMID- 21241207 TI - Safety and efficacy of maintenance infliximab therapy for moderate-to-severe Crohn's disease in children: REACH open-label extension. AB - OBJECTIVE: Assess long-term effects of maintenance infliximab therapy in children with moderately-to-severely active Crohn's disease. RESEARCH DESIGN AND METHODS: One hundred twelve patients with a Pediatric Crohn's Disease Activity Index (PCDAI) score >30 received infliximab 5 mg/kg at weeks 0, 2, and 6 in the REACH study. Patients considered responders at week 10 were randomized to infliximab 5 mg/kg every 8 (q8w) or 12 (q12w) weeks. Patients who completed treatment through week 46, and who the investigator believed would benefit from continued treatment, could enter the open-label extension (OLE) and receive up to three additional years of infliximab. No hypothesis testing was performed. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov, identifier: NCT0020767. RESULTS: Sixty children entered the OLE: 33, 12, and 15 patients were receiving infliximab 5 mg/kg q8w, 5 mg/kg q12w, and 10 mg/kg q8w, respectively, at extension entry. Patients receiving infliximab for up to 3 years during the OLE maintained clinical benefit, with approximately 80% of patients consistently having no to mild disease activity per the physician's global assessment and very good to fair health in the past 2 weeks per the patient and parent/guardian global assessments. Patients with >=1-year delay in bone age at baseline trended toward improvement in height during the OLE. Respiratory system disorders, most commonly upper respiratory infections, were the most prevalent adverse events reported; six (10%) patients had serious infections. CONCLUSIONS: Among children with moderately-to-severely active Crohn's disease who received infliximab for 46 weeks in REACH and then for up to 3 additional years in the REACH OLE, infliximab was effective in maintaining clinical benefit and was generally well-tolerated. PMID- 21241210 TI - Treating diabetic ulcers. AB - INTRODUCTION: Diabetic foot ulceration is a serious secondary complication of diabetes mellitus and the most common cause of hospitalization in diabetic patients. The etiology of diabetic foot ulcerations is complex due to their multifactorial nature. Thus, addressing all of the factors involved remains instrumental in wound healing. AREAS COVERED: The first part of this review focuses on the pathophysiology of diabetic foot ulceration and wound-healing impairment. The second part reviews the standard treatments, including advanced wound-care products and new therapeutic approaches currently under investigation. The reader will understand the most up-to-date research regarding the unique pathophysiology of diabetic foot ulceration along with the basic cornerstones of current recommended standard therapy. EXPERT OPINION: Diabetic foot ulceration is a serious complication that can lead--potentially--to devastating lower-extremity amputations. Proper adherence to standard treatment strategies can potentially prevent the need for amputation. PMID- 21241211 TI - Pharmacotherapy of social anxiety disorder. AB - INTRODUCTION: Social anxiety disorder (SAD) is one of the most common psychiatric disorders, with a lifetime prevalence of 5-12%. Fears of scrutiny and embarrassment in social and public situations are accompanied by anxiety symptoms, avoidance behavior, and impairment in social and work functioning. Several classes of medication, as well as cognitive-behavioral therapies, have evidence for efficacy in the treatment of SAD, but only a minority of individuals with the disorder receives treatment. AREAS COVERED: This review focuses on the evidence-based treatment of SAD with medications including serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, other antidepressants, benzodiazepines, alpha-delta calcium-channel agents, and beta-adrenergic blockers. It discusses clinical considerations in the selection and monitoring of treatments, including issues of safety, duration of treatment, comorbidity, and integration of medication with psychotherapeutic treatment. For this review, a PubMed literature search was conducted during July, 2010. EXPERT OPINION: Medications in several classes have been demonstrated efficacious in the treatment of SAD. Treatment selection and implementation require attention to clinical diagnosis, patient education, and appropriate monitoring. PMID- 21241212 TI - Novel small molecules for the treatment of infections caused by Candida albicans: a patent review (2002-2010). AB - INTRODUCTION: The fungal pathogen Candida albicans is one of the leading causes of infections affecting immunodeficient individuals, including those HIV-infected and patients undergoing cancer therapy. Emerging problems in terms of therapeutic efficacy and drug resistance have highlighted the need to consider new therapeutic approaches, based on the exploitation of virulence factors as alternatives to conventional drug targets. AREAS COVERED: Advances in the development of anti-Candida drugs are examined in this review, as reflected by the patent literature since 2002 along with selected peer-reviewed publications. Taking into account a total of 26 patents, the discussion encompasses several therapeutic approaches, including azoles as ergosterol biosynthesis inhibitors, glucan and chitin synthase inhibitors, and secreted aspartyl protease inhibitors. EXPERT OPINION: New analogs of existing drugs are being developed as broad spectrum antifungals to improve efficacy and circumvent drug resistance. Also, candidate drugs targeting new virulence factors are promising to overcome limitations due to poor efficacy and the rising of drug resistance observed for several available drugs. Efforts for the discovery and development of antifungal agents should be equivalent to other therapeutic areas, and advances in the generation of therapeutic agents with fungus-specific mechanisms of action are of highest priority. PMID- 21241213 TI - Abagovomab for ovarian cancer. AB - INTRODUCTION: Ovarian cancer (OC) is the fifth most common cancer in women. Unfortunately, more than 70% of cases are detected at an advanced stage with a risk of recurrence, after front line therapy, of over 75%. The need for new therapeutic strategies is extremely high. AREAS COVERED: The development status and the possible role of specific immunotherapy of abagovomab are discussed in the context of the possible therapeutic options for maintenance therapy in advanced OC. An overview of abagovomab, generation and mechanism of action, Phase I/II results and the status of the Phase II/III ongoing trial is given. EXPERT OPINION: Abagovomab stimulates the humoral immune response and the cell-mediated immune response in the studies conducted to date. In the proof of concept (POC) study abagovomab prolonged overall survival in those OC recurrent patients who showed an immune response. Abagovomab has an excellent safety and tolerability profile. These characteristics make abagovomab an optimal candidate for a maintenance treatment for OC patients after frontline therapy. The final results of the Phase II/III pivotal study evaluating abagovomab in this setting will be available in the first half of 2011. PMID- 21241215 TI - Academic health science centres in Australia: let's get competitive. PMID- 21241216 TI - Towards evidence-based dementia screening in Australia. PMID- 21241217 TI - Tackling inequities in men's health: a reflective lens on the National Male Health Policy. PMID- 21241218 TI - The impact of mandatory fortification of flour with folic acid on the blood folate levels of an Australian population. AB - OBJECTIVE: To determine the impact that mandatory fortification with folic acid of wheat flour used in breadmaking has had on the blood folate levels of an Australian population since it was introduced in September 2009. DESIGN, SETTING AND PATIENTS: A retrospective analysis of serum and red blood cell (RBC) folate levels of 20,592 blood samples collected between April 2007 and April 2010 from a wide variety of inpatients and outpatients and analysed in a large public hospital diagnostic pathology laboratory. MAIN OUTCOME MEASURES: Prevalences of low levels of serum and RBC folate and monthly mean levels before and after introduction of mandatory fortification. RESULTS: Between April 2009 and April 2010, there was a 77% reduction in the prevalence of low serum folate levels (from 9.3% to 2.1%) in all samples tested and an 85% reduction in the prevalence of low RBC folate levels (from 3.4% to 0.5%). In April 2010, the prevalence of low RBC folate levels for females of childbearing age was 0.16% for all samples. There was a 31% increase in mean serum folate level (from 17.7 nmol/L to 23.1 nmol/L; t = 9.3, P < 0.01), and a 22% increase in mean RBC folate level (from 881 nmol/L to 1071 nmol/L). The greatest increment in mean serum folate levels occurred in September 2009, the month that mandatory fortification was introduced, although there was evidence of a gradual change during the preceding months. CONCLUSION: The introduction of mandatory fortification with folic acid has significantly reduced the prevalence of folate deficiency in Australia, including in women of childbearing age. PMID- 21241219 TI - Incidence of pandemic (H1N1) 2009 influenza infection in children and pregnant women during the 2009 influenza season in Western Australia - a seroprevalence study. AB - OBJECTIVE: To determine antibody levels and estimate incidence of infection with pandemic (H1N1) 2009 influenza in children and pregnant women during the 2009 winter in Western Australia. DESIGN, SETTING AND PARTICIPANTS: Two cross sectional serosurveys using stored specimens collected for unrelated pathology testing, from before and after (3 August to 30 November 2009) circulation of the pandemic virus, and before commencement of the pandemic vaccination program. Specimens were from three groups: children aged 1-4 years, older children and teenagers aged 5-19 years, and pregnant women aged 21-45 years. The groups were geographically representative of the WA population. MAIN OUTCOME MEASURES: Reactivity against pandemic (H1N1) 2009 and seasonal A(H1N1) influenza viruses measured using haemagglutination inhibition (HI) assays. RESULTS: Antibody titres were determined for 648 individuals in the prepandemic period and 736 in the postpandemic period. In the prepandemic period, HI titres >= 40 against the pandemic virus were found in 0 (95% CI, 0.0%-1.6%) children aged 1-4 years, 8.3% (95% CI, 5.3%-12.7%) of older children and teenagers, and 4.5% (95% CI, 2.4% 8.3%) of pregnant women. In postpandemic specimens collected from 1 September 2009 (when influenza activity had declined to near-baseline levels), estimated infection rates (subtracting prepandemic levels) were 25.4% (95% CI for difference, 18.6%-33.4%) in 1-4-year-old children, 39.4% (95% CI, 29.8%-48.5%) in older children and teenagers, and 10.2% (95% CI, 4.1%-17.1%) in pregnant women. CONCLUSIONS: A quarter of preschool children and about 40% of school-aged children and older teenagers had serological evidence of pandemic influenza infection during winter 2009, indicating high levels of mild or asymptomatic infection. The infection rate in pregnant women was much lower. The high infection rates in children help explain the reduced impact of the pandemic virus during the 2010 winter. Augmented by vaccination, there should be sufficiently high levels of immunity in the Australian population to significantly reduce the impact of the virus in future influenza seasons. PMID- 21241220 TI - When do I know I am cured? Using conditional estimates to provide better information about cancer survival prospects. AB - OBJECTIVE: To report the latest conditional survival estimates for patients with cancer in Queensland, Australia. DESIGN, SETTING AND PARTICIPANTS: Descriptive study of state-wide population-based data from the Queensland Cancer Registry on patients aged 15-89 years who were diagnosed with invasive cancer between 1982 and 2007. MAIN OUTCOME MEASURE: Conditional 5-year relative survival for the 13 most common types of invasive cancer, and all cancers combined. RESULTS: The prognosis for patients with cancer generally improves with each additional year that they survive. A significant excess in mortality compared with the general population ceases to occur within 10 years after diagnosis for survivors of stomach, colorectal, cervical and thyroid cancer and melanoma, with these groups having a conditional 5-year relative survival of at least 95% after 10 years. For the remaining cancers we studied (pancreatic, lung, breast, prostate, kidney, and bladder cancer, non-Hodgkin lymphoma, and leukaemia), conditional 5-year relative survival estimates (at 10 years after diagnosis) ranged from 82% to 94%, suggesting that patients in these cohorts continue to have poorer survival compared with the age-matched general population. CONCLUSIONS: Estimates of conditional survival have the potential to provide useful information for cancer clinicians, patients and their carers as they are confronted by personal and surveillance-related decisions. This knowledge may be effective in building realistic hope and helping people manage uncertainty about the future. We suggest that measures of conditional survival be incorporated into routine statistical reporting in Australia. PMID- 21241221 TI - Consensus standards for the care of children and adolescents in Australian health services. AB - The medical and psychosocial needs of children and adolescents differ from those of adults, and this should be reflected in the care they receive in all areas of a health service. Children and adolescents must be accommodated separately to adults to ensure that their unique needs are met and risks of harm are minimised. The Standards for the care of children and adolescents in health services have been developed by a working group of clinicians, health service providers and consumer advocates based on a combination of available research evidence, published best practice guidelines and multidisciplinary expert consensus. Stakeholder input was obtained through invitations to comment, and pilot testing of the Standards was conducted in six metropolitan, regional and rural hospitals. The Standards provide detailed recommendations in the areas of recognising rights; the provision of child-, adolescent- and family-friendly health service facilities; the availability of child- and adolescent-specific equipment; and the importance of appropriately trained staff. To facilitate implementation and allow ongoing performance monitoring, the Standards have been developed for use alongside the Australian Council on Healthcare Standards Evaluation and Quality Improvement Program. The Standards provide a vehicle to ensure patient safety and to facilitate the provision of high-quality care for children and adolescents in Australian health services. PMID- 21241222 TI - The Trans-Pacific Partnership Agreement: challenges for Australian health and medicine policies. AB - Four formal rounds of Trans-Pacific Partnership Agreement (TPPA) negotiations took place in 2010. They involved over 200 officials from Australia, the United States, New Zealand, Chile, Singapore, Brunei, Peru, Vietnam and Malaysia. Future negotiations officially are set to include three issues with public health and medicines policy implications for Australia and our region: ways to approach regulatory coherence and transparency; how to benefit multinational and small medium enterprises; and multilateral investor-state dispute settlement. US-based multinational pharmaceutical companies are lobbying for TPPA provisions like those in the Australia-US Free Trade Agreement, which reduce government cost effectiveness regulatory control of pharmaceuticals, threatening equitable access to medicines. They also advocate increased TPPA intellectual monopoly privilege protection, which will further limit the development of Australian generic medicine enterprises and restrict patient access to cheap, bioequivalent prescription drugs. Of particular concern is that proposed TPPA multilateral investor-state dispute settlement procedures would allow US corporations (as well as those of other TPPA nations) to obtain damages against Australian governments through international arbitral proceedings if their investments are impeded by Australian public health and environment protection legislation. PMID- 21241223 TI - Doctors writing outside the square. AB - Publications written by doctors about subjects outside their professional activities are often widely read and may be more enduring than their technical publications. Dr Graeme Robertson, Sir Clive Fitts and Professor Richard Lovell were three doctors from Victoria who wrote with skill and artistry about subjects outside their professional work. Here I discuss these publications and the reasons these doctors came to write them, and offer some reasons for the enduring interest of these publications. PMID- 21241214 TI - Slower clearance of nevirapine resistant virus in infants failing extended nevirapine prophylaxis for prevention of mother-to-child HIV transmission. AB - Nevirapine resistance mutations arise commonly following single or extended-dose nevirapine (ED-NVP) prophylaxis to prevent mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV), but decay within 6-12 months of single dose exposure. Use of ED-NVP prophylaxis in infants is expected to rise, but data on decay of nevirapine resistance mutations in infants in whom ED-NVP failed remain limited. We assessed, in Ethiopian infants participating in the Six-Week Extended Nevirapine (SWEN) Trial, the prevalence and persistence of nevirapine resistance mutations at 6 and 12 months following single-dose or up to 6 weeks of ED-NVP, and correlated their presence with the timing of infection and the type of resistance mutations. Standard population genotyping followed by high throughput cloning were done on dried blood spot samples collected during the trial. More infants who received ED-NVP had nevirapine resistance detected by standard population genotyping (high frequencies) at age 6 months compared with those who received single-dose nevirapine (SD-NVP) (58% of 24 vs. 26% of 19, respectively; p = 0.06). Moreover, 56% of ED-NVP-exposed infants with nevirapine resistance at age 6 months still had nevirapine resistance mutations present at high frequencies at age 1 year. Infants infected before 6 weeks of age who received either SD- or ED-NVP were more likely to have Y181C or K103N; these mutations were also more likely to persist at high frequencies through 1 year of age. HIV-infected infants in whom ED-NVP prophylaxis fails are likely to experience delayed clearance of nevirapine-resistant virus in the first year of life, which in turn places them at risk for early selection of multidrug resistant HIV after initial therapy with nonnucleoside reverse transcriptase inhibitor-based regimens. PMID- 21241224 TI - Do we need a national electronic summary care record? AB - Electronic referrals and discharge summaries can improve the quality and timeliness of clinical communication. The electronic summary care record (SCR) extends the concept of digital health summaries to create a perpetually updated and centrally stored summary of care, extracting key data from local systems after each encounter. The only major SCR evaluation to date, in England, found that rates of usage were low, and any impact on care was difficult to quantify. The SCR is seen by some as a first step to building a national distributed shared electronic health record (SEHR). However, the SCR may be a problematic diversion, creating a need for centralised databases, while the SEHR can function by sharing locally stored records, letters and discharge summaries. Uncertainty about the quality and provenance of SCR data raises concerns about patient safety, as key data may be absent and old data may persist, partly because of a lack of ownership of the summary. A national e-health strategy should emphasise the true stepping stones to a distributed and shared electronic record, including encouraging the uptake and meaningful use of electronic clinical records, clinical messaging, electronic discharge summaries and letters, and services such as decision support and e-prescribing, all of which have good evidence to support them. PMID- 21241225 TI - Selection into specialist training programs: an approach from general practice. AB - Procedures to select medical specialist trainees aim to predict which junior doctors will become the best specialists. A 1998 review of Australian postgraduate selection processes recommended use of the principles of good assessment. Australia has expertise in national procedures used by medical schools to select students for undergraduate and graduate courses, but little experience in national specialist training program selection. A system for selection into postgraduate general practitioner training, based on a national "selection-centre" approach used in the United Kingdom, is being piloted in Australia. Initial evaluation shows the piloted system to be feasible but further evaluation is needed. Any selection-centre approach must be adapted to the Australian health care context and have the confidence of the trainees, the professional colleges, the training providers and the public. PMID- 21241226 TI - "The case for boosting infant male circumcision in the face of rising heterosexual transmission of HIV" ... and now the case against. Comment. PMID- 21241227 TI - Atypical femoral fractures: a complication of prolonged bisphosphonate therapy? PMID- 21241228 TI - Azithromycin treatment levels inadequate for recommended trachoma control guidelines. PMID- 21241229 TI - ESAC point prevalence methodology to assess antimicrobial consumption and quality of prescribing in an Australian setting. PMID- 21241230 TI - Melanoma: the radiotherapeutic point of view; review of the current literature. AB - Surgery remains the mainstay of melanoma therapy at all sites. Melanoma is widely believed to be a radioresistant tumor, a misconception that has historically led to the limited use of RT for its treatment. We searched pubmed from 1978 until 2010 by means of prospective randomized trials. The aim was to assess the potential impact of radiotherapy (RT) on local control, quality of life and overall survival. Radiotherapy should be considered in lentigo maligna, especially in elderly patients with extensive or unresectable disease in difficult areas on the face, with adequate tumor control with good cosmetic and functional results. In addition, radiation therapy provides effective palliation in patients with metastatic malignant melanoma. Doses up to 30 Gy or BED > 39.0Gy were found to be associated with prolonged palliation. These findings should be viewed with caution because the lack of data regarding performance status as well as other unknown confounding factors limits the applicability of retrospectives studies. We recommend that higher doses of RT be considered when using RT for the palliation of patients with metastatic melanoma and a performance status that could tolerate such therapy. In the future, the combination of radiation therapy with hyperthermia may be a reasonable therapeutic option. PMID- 21241231 TI - The role of lipoprotein-associated phospholipase A2 (Lp-PLA2) in cardiovascular disease. AB - Lipoprotein-associated Phospholipase A2 (Lp-PLA(2)) is an enzyme that belongs to the A2 Phospholipase superfamily and is produced by inflammatory cells that are involved in the process of atherogenesis. Even though there is controversy in current bibliography whether Lp-PLA(2) exerts proatherogenic or anti-atherogenic properties, the weight of evidence suggests a pro-atherogenic role for this protein. Lp-PLA(2) is detected in human atherosclerotic lesions and elevated Lp PLA(2) levels are associated with an increased risk of cardiovascular events and adverse events in patients with coronary artery disease independently of traditional risk factors and other markers of inflammation. It has been recently shown that direct pharmacological inhibition of Lp-PLA(2) activity exerts beneficiary effects on the atherosclerotic process. This finding is most interesting since it could offer a novel target for therapeutic intervention in patients suffering from cardiovascular disease. The purpose of this review article is to report on the role of Lp-PLA(2) in cardiovascular diseases and to enlighten the putative pathophysiologic mechanisms by which this protein exerts its effect on cardiovascular function. Additionally, the pharmacological interventions that influence Lp-PLA(2) activity and may offer a new approach for the treatment of atherosclerosis will be analyzed. PMID- 21241232 TI - Recent clinical evidence for the treatment of osteoarthritis: what we have learned. AB - Osteoarthritis (OA) is a chronic arthritis affecting growing numbers of the ageing population. Patients diagnosed with OA place a large burden on access to healthcare services, including primary care, prescription of analgesic drugs, physiotherapy and joint replacement surgery. Not all patients diagnosed with OA will require joint replacement surgery, and therefore avenues for non-surgical treatment for such patients need to be explored in many cases. In this review we discuss current concepts underlying the pathophysiology of OA. These form a basis to understanding the rationale for new and existing therapies based on recent evidence available from clinical studies and trials in OA. In particular, we discuss the evidence for use of pharmacological treatments, including NSAIDs (non steroidal anti-inflammatory drugs), chondroitin sulphate and glucosamine, hyaluronan, potential disease-modifying drugs and other interventions such as weight reduction and physiotherapy. Finally, we discuss new developments from clinical evidence for surgical options, including ACL repair surgery and joint replacement surgery. PMID- 21241233 TI - Design and endpoints of clinical and translational trials in advanced colorectal cancer. a proposal from GROUP Espanol Multidisciplinar en Cancer Digestivo (GEMCAD). AB - Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided. PMID- 21241234 TI - Current strategies to achieve further cardiac and renal protection through enhanced renin-angiotensin-aldosterone system inhibition. AB - An incomplete inhibition of the renin angiotensin aldosterone system (RAAS) may be responsible for the residual organ damage and event rate that still occur in spite of an apparent blood pressure control in patients with hypertension, diabetes, chronic kidney disease and heart failure treated with angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Additional antiproteinuric effect in diabetic and non diabetic chronic kidney disease, and reduction in hospitalizations in patients with heart failure already receiving a single RAAS antagonist, has been achieved by incremental inhibition of the RAAS with dual therapy or uptitration of an individual agent above conventional dosages. However, the synergistic increase in plasma renin activity (PRA) and the angiotensin II escape could reduce the expected benefit obtained with dual therapy. Results from ONTARGET showing a lack of additional outcome benefit over monotherapy, with a concomitant increase risk of hyperkalemia, renal impairment, and hypotension, discourage the use of the ACEI/ARB combination in patients at high risk of cardiovascular events. This occured despite a lower albumin excretion in dual versus single RAAS blockade, indicating that an incremental antiproteinuric effect is not automatically translated into clinical outcome benefits. The efficacy and safety of ACEI/ARB combination versus monotherapy in patients with overt proteinuria is currently evaluated by LIRICO and VA NEPHRON-D clinical trials. The long lasting direct renin inhibitor aliskiren, acting at the first and rate limiting step of the RAAS cascade, prevents the reactive increase in PRA when combined with ACEIs, ARBs or diuretics. The ASPIRE HIGHER programme, involving more than 35,000 patients with hypertension, heart failure, kidney disease and diabetes, is currently evaluating the efficacy and safety of aliskiren on top of standard therapy. The clinical benefit of adding mineralocorticoid receptor blockers (MRBs) in the control of resistant hypertension, proteinuric kidney diseases, and prevention of mortality in patients with heart failure on top of conventional treatment, evidences the pathogenic role of inadequately suppressed aldosterone as a cause of suboptimal response to conventional RAAS inhibition. The present review will focus on the pathophysiological ground, and the evidence provided by clinical trials assessing the efficacy and safety of recent strategies for the prevention of cardiovascular events and target organ damage progression via enhanced RAAS inhibition. PMID- 21241235 TI - Is there evidence to support the use of direct Factor Xa inhibitors in coronary artery disease? AB - As coronary artery disease (CAD) remains a leading cause of death in the world, the development of anti-coagulants to prevent CAD progressing to myocardial infarction and death is a high priority. A number of direct Factor Xa (FXa) inhibitors are being developed for use in CAD. Despite being developed to the stage of Phase II clinical trials, DX-9065a is no longer a priority with its developing company for further development, possibly because the Phase II trials did not show any major benefit of DX-9065a over heparin in subjects undergoing percutaneous coronary interventions (PCI) or with non-ST-elevation acute coronary syndromes (ACS). ZK-807834, otamixaban, apixaban, and rivaroxaban are all direct FXa inhibitors that have undergone preclinical and some clinical testing for use in CAD. In a large Phase II clinical trial of subjects with ACS, some doses of otamixaban had a better benefit/risk profile than the unfractionated heparin/eptifibatide combination. However, neither ZK-807834 nor otamixaban appear to be undergoing further clinical development at present. In ACS, placebo controlled large Phase II clinical trials with apixaban and rivaroxaban have not shown clear cut benefits. Nevertheless, apixaban and rivaroxaban are presently in placebo-controlled Phase III clinical trials for ACS. Presently, there is no compelling evidence to support the use of direct FXa inhibitors in ACS. PMID- 21241236 TI - Treatment options for cystic fibrosis: state of the art and future perspectives. AB - Cystic fibrosis (CF) is an autosomal recessive disorder characterized by chronic lung and sinus disease, impaired mucociliary clearance (leading to recurrent pulmonary infection), pancreatic insufficiency, elevated sweat chloride levels and male infertility. Cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel in the plasma membrane of epithelial cells lining the lung, pancreas, liver, intestines, sweat duct, and the epididymis. Genetic mutations in CFTR affect its synthesis, processing, and transport to the plasma membrane and/or impede its function as a chloride channel and conductance regulator. Research is proceeding on multiple fronts including inhalational agents, anti-inflammatory treatments, and pancreatic replacement therapies. Furthermore, improved understanding of the molecular mechanisms that lead to CFTR dysfunction has stimulated the design of therapeutic strategies aimed at restoration of CFTR function, or "protein repair therapy". Recent clinical trials have shown these interventions have the ability to restore some level of CFTR function in vivo. This review will provide an overview of recent clinical trials that investigate new therapeutic approaches in CF designed to treat chronic respiratory infection, reduce inflammation, and improve pancreatic enzyme supplementation as well as trials addressing the greatest therapeutic challenge- restoring the function of the CFTR protein. PMID- 21241237 TI - The current status of cryotherapy and high-intensity focused ultrasound in the treatment of low-grade prostate cancer. AB - As a result of widespread serum prostate-specific antigen (PSA) screening and prostate cancer awareness, the detection of low-grade prostate cancer has increased. At the moment, it is unclear how to treat patients in this population. Thus, we focused on reviewing therapies for patients in this low risk group. The purpose of this review paper is to present the status of emerging therapies of cryotherapy and high-intensity focused ultrasound (HIFU) in patients with low risk disease. Based on our review of the literature, there are several small scale studies of these two therapies that have revealed favorable outcomes, but with complications of urinary incontinence and impotence. With further research, these therapies may develop into good alternatives for patients in this expanding group. PMID- 21241238 TI - Neuroinflammation and ageing: current theories and an overview of the data. AB - The increase in the average lifespan and the consequent proportional growth of the elderly segment of society has furthered the interest in studying ageing processes. Ageing may be considered a multifactorial process derived from the interaction between genetic and environmental factors including lifestyle. There is ample evidence in many species that the maximum age attainable (maximum lifespan potential, MLSP) is genetically determined and several mitochondrial DNA polymorphisms are associated with longevity. This review will address the current understanding of the relationship between ageing and several factors both genetics and life style related. Firstly we focused on the most reliable and commonly shared theories which attempt to explain the phenomenon of ageing as the genetic, cellular, neuroendocrine, immunological and free-radicals related theories. Many studies have shown that most of the phenotypic characteristics observed in the aging process are the result of the occurrence, with age, of a low grade chronic pro-inflammatory status called "inflammaging", partially under genetic control. The term indicate that aging is accompanied by a low degree of chronic inflammatory, an up-regulation of inflammatory response and that inflammatory changes are common to many age-related diseases. In this review special attention was dedicated to diseases related to age as atherosclerosis, cancer and Alzheimer disease. Despite the fact that in recent years many theories about ageing have been developed, we are still far from a full understanding of the mechanisms underlying the ageing process. PMID- 21241239 TI - Excess exposure to insulin is the primary cause of insulin resistance and its associated atherosclerosis. AB - The main goal of this review is to provide more specific and effective targets for prevention and treatment of insulin resistance and associated atherosclerosis. Modern technologies and medicine have vastly improved human health and prolonged the average life span of humans primarily by eliminating various premature deaths and infectious diseases. The modern technologies have also provided us abundant food and convenient transportation tools such as cars. As a result, more people are becoming overfed and sedentary. People are generally ingesting more calories than their bodies' need, leading to the so-called "positive energy imbalance", which is inseparable from the development of insulin resistance and its associated atherosclerosis. A direct consequence of insulin resistance is hyperinsulinemia. The current general view is that insulin is not functional properly in the presence of insulin resistance. Thus, the role of insulin itself in the development of insulin resistance and associated atherosclerosis has not been recognized. We have recently observed that the basal level of insulin signaling is increased in the presence of insulin resistance and hyperinsulinemia. In this review, we will explain how the increased basal insulin signaling contributes to the development of insulin resistance and associated atherosclerosis. We will first explain how insulin causes insulin resistance through two arbitrary stages (before and after the presence of obvious insulin resistance), and, then, explain how the excess exposure to insulin and the relative insulin insufficiency contributes to the atherosclerotic diseases. We propose that blockade of the excess insulin signaling is a viable approach to prevent and/or reverse insulin resistance and its associated atherosclerosis. PMID- 21241240 TI - Adynamic ileus induced by varenicline. AB - Varenicline is a drug specifically developed for smoking cessation. Gastrointestinal symptoms are among the most common side effects (nausea, vomiting, and constipation). Here, we described the case of a 75 year-old man who suffered from functional adynamic ileus while taking varenicline. Adynamic ileus is a rare condition on treatment with varenicline. Clinicals should be aware of this side effect due to it could lead to varenicline withdrawal and reconsideration of patient smoking cessation strategy. PMID- 21241241 TI - Potential interaction between valproic acid and doripenem. AB - A potential interaction between valproate (VPA) and doripenem leading to decreased valproic acid concentrations in two patients is described. In the first patient case, a 54-year-old female presented to the emergency department following a seizure episode after stopping her medications a few days prior. She was given a 1500 mg (23 mg/kg) intravenous (IV) bolus dose of valproate and restarted on her home regimen of divalproex sodium 750 mg daily which quickly resulted in valproic acid blood concentrations within the reference range. The patient was later started on doripenem 500 mg IV every 8 hours and subsequent valproic acid concentrations decreased by 62%. The second patient was a 54-year old female transferred from an outlying facility following a motor vehicle accident. The patient was receiving valproate 1250 mg IV every 8 hours for seizure prophylaxis following a traumatic brain injury. She developed pneumonia and was started on doripenem 500mg IV every 8 hours. Valproic acid concentrations decreased by 69% within two days. This case report describes two patients receiving concomitant valproate and doripenem resulting in a 62% and 69% reduction in valproic acid concentration. PMID- 21241242 TI - Aripiprazole-induced pathological gambling: a report of 3 cases. AB - We report three cases of pathological gambling induced by aripiprazole, in patients with schizophrenia or schizoaffective disorder. All three patients had no history of pathological gambling, and they started gambling after initiation of treatment with Aripiprazole. The fact that pathological behaviour disappears quickly as medication was ended suggests that an elaborate behavioral manifestation could be related to dopaminergic tone in patients with schizophrenia. We recommend consideration with increased attention for the appearance of pathological gambling symptoms among patients on Aripiprazole. PMID- 21241243 TI - Off-label prescribing of drugs for children. AB - Under normal circumstances, children are excluded from clinical trials of new drug candidates. Yet, when the drug product is approved for marketing by the authorities, it is only a matter of time before physicians use that drug on pediatric patients. We do know that the practice of prescribing drugs for off label conditions is found in approximately 50% of all physician prescribing. We should not look at off-label pediatric drug use as always a bad or negative behavior. It may be that a manufacturer has conducted a successful clinical trial for a new pediatric condition and has submitted the documentation to the FDA staff to support that new indication, but the regulatory agency has not completed its review and formally awarded the new indication to the sponsor. Or it might be the case that over a dozen years of clinician experience informs all clinicians that an off-label use of a drug works most effectively and yet the manufacturer is reluctant to spend the money required for a supplemental investigation when it loses patent protection in under a year. As with many other situations where not all of the facts may be known, it seems that the wisest path is to approach the use of drugs for off-label conditions with great caution and with as much knowledge as may be gained before the prescribing decision is arrived at. PMID- 21241244 TI - BeMORE: a novel method for detection of adverse fetal effects induced by drugs. AB - We describe a unique new collaboration which allows linkage of administrative databases in Southern Israel, and hence ascertain risk/safety of prescription drugs in pregnancy. The advantages of this system include availability of rigorous data confounders, solid data on maternal conditions for which the drug is given, ability to capture all cases of elective abortions and not just live births, and ability to construct drug doses. PMID- 21241245 TI - Genetic transmission of cytochrome P450 2D6 (CYP2D6) ultrarapid metabolism: implications for breastfeeding women taking codeine. AB - The pro-drug codeine is commonly prescribed for postpartum pain relief in North America. The safety of codeine during breastfeeding is related in part to the extent of the active morphine metabolite catalyzed from codeine via the cytochrome P450 2D6 (CYP2D6) enzyme. In mothers who have greater than two functional copies of the CYP2D6 gene (CYP2D6 ultrarapid metabolism phenotype; UM) a substantially higher proportion of morphine is produced. Label changes on codeine-containing medications will highlight the risks associated with this genotype for breastfeeding mothers, but are not supported by translation strategies on how to incorporate this pharmacogenetic knowledge into clinical practice. To address the immediate issue of CYP2D6 UM inheritance in family members of a breastfed infant who succumbed to fatal opioid intoxication and whose codeine-prescribed mother was a CYP2D6 UM, we constructed a pedigree. While the pedigree approach is helpful to aid diagnosis, identify other at risk family members, and simplify pharmacogenetic analysis, its clinical usefulness is dependant on an institutional framework which is not available in most centers at this time. PMID- 21241246 TI - The effect of lamotrigine on valproic acid concentrations. AB - PURPOSE: To determine whether lamotrigine affects serum concentrations of valproic acid. METHODS: Pre-morning-dose serum valproic acid concentrations were measured in 76 subjects with epilepsy (48 M, 28 F, age range 6-20 years, mean age 14 years) in whom lamotrigine was added while the dose of valproate and other medication remained unchanged. In a comparison group, either acetazolamide or gabapentin was added to sodium valproate. RESULTS: Far more subjects (26/76 = 34%) had an increase of >25% in valproic acid concentration with lamotrigine than those who had a decrease of >25% (4/76 = 5.3%). The mean valproic acid concentration before starting lamotrigine was 61.0 mg/L and on lamotrigine was 67.1 mg/L; the difference in means was 6.1 mg/L (standard error 2.1, 95% confidence limits 2.0, 10.2, p=0.004, highly significant, paired sample t-test, two-tailed), a rise of 10%. The change in valproic acid concentration appeared to depend on the initial valproic acid concentration (Pearson r=-0.405, p<0.001). In 14.5% of the subjects the increase in valproate concentration was >50%, which could lead to toxicity, although the increase tended to occur with lower or intermediate initial valproic acid concentrations whereas a small overall decrease in valproic acid concentrations with lamotrigine was found with the higher initial valproic acid concentrations. One subject had abnormal bruising with the increased valproate level after lamotrigine was added, which resolved on decreasing the valproate dose. The changes in valproic acid concentrations in the comparison group were small (mean increase 2.6%) and were not statistically significant. CONCLUSIONS: Although there is a wide variation in the changes of valproic acid concentrations when lamotrigine is added, the concentrations tend to increase rather than decrease, especially with low or intermediate initial valproic acid concentrations. In some cases valproate toxicity, manifested by abnormal bruising, may result, although at higher initial valproic acid concentrations the valproic acid concentration usually tends to fall slightly with the addition of lamotrigine. PMID- 21241247 TI - Adverse effects of tacrolimus in renal transplant patients from living donors. AB - INTRODUCTION: The main objectives of this study were to estimate the prevalence of and the risk factors for the adverse effects of tacrolimus-based immunosuppression in patients who obtained renal transplant from living donors. METHODS: A multicenter cross-sectional observational study in 154 kidney transplant patients who received grafts from living donors. RESULTS: Large proportion of patients had hypertension (83%) and hyperlipidemia (53%); 27% had posttransplant diabetes mellitus. Patients had on average two chronic diseases. Tremor was present in 40%, neurologic toxicity in 45%, and anemia in 51.5% of patients. The average number of adverse effects was 3.52 +/- 1.57. In multivariate analysis some adverse effects were related to tacrolimus concentration, duration of treatment, number of medications or medical problems. In linear regression analysis correlation was found, among the others, between diastolic blood pressure and tacrolimus concentration, and inverse correlation between erythrocyte count and duration of treatment. CONCLUSION: There is a significant prevalence of tacrolimus adverse effects and supratherapeutic TAC blood concentrations in Jordanian renal transplant patients in spite of using low TAC doses and overall adequate renal function. PMID- 21241248 TI - In vitro investigation of renal epithelial injury suggests that primary cilium length is regulated by hypoxia-inducible mechanisms. AB - Primary cilia are non-motile sensory organelles that project from cells in many tissues. The role of renal primary cilium-based signalling in regulating epithelial cell proliferation and differentiation is highlighted by studies showing that defects of the cilium lead to epithelial de-differentiation, over proliferation and polycystic kidney disease. Recent studies show that renal primary cilia may also play a role in controlling epithelial differentiation during renal repair. After injury, renal cilium length increases dramatically and then undergoes a normalization that coincides with structural and functional repair in both human patients and mouse models of renal injury. These changes in cilium length are likely to modulate cilium-based signalling, but the injury related factors that influence renal primary cilium length have yet to be determined. Here, we investigated the effect of three factors commonly associated with renal injury on renal cilium length in an in vitro setting. MDCK (Madin Darby canine kidney) cell cultures bearing primary cilia were treated with BSA to simulate albuminuria, cobalt chloride to simulate hypoxia and the inflammation related cytokine tumour necrosis factor alpha. Primary cilium length was only increased in cultures treated with cobalt chloride. Our results suggest a role for hypoxia and the induction of HIF-1alpha (hypoxia-inducible factor 1alpha) in increasing renal primary cilium length following renal injury. PMID- 21241249 TI - A novel antioestrogen agent (3R,6R)-bassiatin inhibits cell proliferation and cell cycle progression by repressing cyclin D1 expression in 17beta-oestradiol treated MCF-7 cells. AB - Bassiatin [(3R,6R)-bassiatin] was isolated from the endogenous fungus Fusarium oxysporum J8-1-2. We found that oestrogen-dependent cell growth was inhibited by bassiatin in MCF-7 ERalpha (oestrogen receptor alpha)-positive breast cancer cells. In addition, the mRNA and protein levels of ERalpha and the oestrogen responsive gene cyclin D1 were down-regulated by bassiatin in the presence of 17beta-oestradiol. Co-treatment of 17beta-oestradiol and bassiatin increased phospho-cyclin D1 (Thr286), an indicator of cyclin D1 phosphorylation-dependent degradation. However, this effect was not obvious in the absence of 17beta oestradiol, suggesting that bassiatin may play a role in the metabolism of cyclin D1 by decreasing cyclin D1 protein expression in the presence of 17beta oestradiol. Cyclin D1, known as a key cell cycle regulator, regulates the transition of G1- and S-phase. Decreased cyclin D1 was found to be involved in bassiatin-induced MCF-7 cell cycle arrest. Collectively, our study showed that bassiatin induced cell cycle arrest and exerted an antioestrogen effect. It may prove to be a potential drug target for antioestrogen therapy in ERalpha-positive breast cancer. PMID- 21241250 TI - Effect of cobalt-60 (gamma radiation) on multidrug-resistant multiple myeloma cell lines. AB - Emergence of resistance to chemotherapy and radiotherapy is a major obstacle for the successful treatment of MM (multiple myeloma). Prednisone, vincristine and melphalan are commonly used chemotherapeutic agents for the treatment of MM. In the current study, we examined the presence of possible cross-resistance between these drugs and gamma (gamma) radiation. Prednisone, vincristine and melphalan resistant RPMI-8226 and U-266 MM cells were generated by stepwise increasing concentrations of the drugs. The sensitive and resistant cells were exposed to 200- and 800 cGy gamma radiation, and proliferation was examined by XTT {2,3 bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide} assay. The results showed that Prednisone- and melphalan-resistant RPMI-8226 cells were also cross-resistant to 200 and 800 cGy gamma radiation application, while vincristine-resistant cells did not show resistance. On the other hand, Prednisone-, vincristine- and melphalan-resistant U-266 cells showed cross-resistance to 200- and 800 cGy gamma radiation application. These results demonstrated that MM cells resistant to anticancer agents respond to radiation in different levels. These findings may be important in the clinical applications of radiation therapy in the treatment of vincristine resistant MM. PMID- 21241251 TI - The Arabidopsis class I TCP transcription factor AtTCP11 is a developmental regulator with distinct DNA-binding properties due to the presence of a threonine residue at position 15 of the TCP domain. AB - The TCP domain is a DNA-binding domain present in plant transcription factors that modulate different processes. In the present study, we show that Arabidopsis class I TCP proteins are able to interact with a dyad-symmetric sequence composed of two GTGGG half-sites. TCP20 establishes symmetric interactions with the 5' half of each strand, whereas TCP11 interacts mainly with the 3' half. SELEX (systematic evolution of ligands by exponential enrichment) experiments with TCP15 and TCP20 indicated that these proteins have similar, although not identical, DNA-binding preferences and are able to interact with non-palindromic binding sites of the type GTGGGNCCNN. TCP11 shows a different DNA-binding specificity, with a preference for the sequence GTGGGCCNNN. The distinct DNA binding properties of TCP11 are due to the presence of a threonine residue at position 15 of the TCP domain, a position that is occupied by an arginine residue in most TCP proteins. TCP11 also forms heterodimers with TCP15 that have increased DNA-binding efficiency. The expression in plants of a repressor form of TCP11 demonstrated that this protein is a developmental regulator that influences the growth of leaves, stems and petioles, and pollen development. The results suggest that changes in DNA-binding preferences may be one of the mechanisms through which class I TCP proteins achieve functional specificity. PMID- 21241252 TI - ER stress modulates cellular metabolism. AB - Changes in metabolic processes play a critical role in the survival or death of cells subjected to various stresses. In the present study, we have investigated the effects of ER (endoplasmic reticulum) stress on cellular metabolism. A major difficulty in studying metabolic responses to ER stress is that ER stress normally leads to apoptosis and metabolic changes observed in dying cells may be misleading. Therefore we have used IL-3 (interleukin 3)-dependent Bak-/-Bax-/- haemopoietic cells which do not die in the presence of the ER-stress-inducing drug tunicamycin. Tunicamycin-treated Bak-/-Bax-/- cells remain viable, but cease growth, arresting in G1-phase and undergoing autophagy in the absence of apoptosis. In these cells, we used NMR-based SIRM (stable isotope-resolved metabolomics) to determine the metabolic effects of tunicamycin. Glucose was found to be the major carbon source for energy production and anabolic metabolism. Following tunicamycin exposure, glucose uptake and lactate production are greatly reduced. Decreased 13C labelling in several cellular metabolites suggests that mitochondrial function in cells undergoing ER stress is compromised. Consistent with this, mitochondrial membrane potential, oxygen consumption and cellular ATP levels are much lower compared with untreated cells. Importantly, the effects of tunicamycin on cellular metabolic processes may be related to a reduction in cell-surface GLUT1 (glucose transporter 1) levels which, in turn, may reflect decreased Akt signalling. These results suggest that ER stress exerts profound effects on several central metabolic processes which may help to explain cell death arising from ER stress in normal cells. PMID- 21241253 TI - How the biotin-streptavidin interaction was made even stronger: investigation via crystallography and a chimaeric tetramer. AB - The interaction between SA (streptavidin) and biotin is one of the strongest non covalent interactions in Nature. SA is a widely used tool and a paradigm for protein-ligand interactions. We previously developed a SA mutant, termed Tr (traptavidin), possessing a 10-fold lower off-rate for biotin, with increased mechanical and thermal stability. In the present study, we determined the crystal structures of apo-Tr and biotin-Tr at 1.5 A resolution. In apo-SA the loop (L3/4), near biotin's valeryl tail, is typically disordered and open, but closes upon biotin binding. In contrast, L3/4 was shut in both apo-Tr and biotin-Tr. The reduced flexibility of L3/4 and decreased conformational change on biotin binding provide an explanation for Tr's reduced biotin off- and on-rates. L3/4 includes Ser45, which forms a hydrogen bond to biotin consistently in Tr, but erratically in SA. Reduced breakage of the biotin-Ser45 hydrogen bond in Tr is likely to inhibit the initiating event in biotin's dissociation pathway. We generated a Tr with a single biotin-binding site rather than four, which showed a simi-larly low off-rate, demonstrating that Tr's low off-rate was governed by intrasubunit effects. Understanding the structural features of this tenacious interaction may assist the design of even stronger affinity tags and inhibitors. PMID- 21241254 TI - Predictors for 5-year survival in a prospective cohort of elderly stroke patients. AB - OBJECTIVES: To examine predictors for 5-year survival in elderly stroke patients. MATERIALS AND METHODS: Prospective cohort study of 186 consecutive acute stroke patients aged >=65 years admitted to Bankstown-Lidcombe Hospital, Australia 03/2002 to 03/2003. All subjects were followed up in 2007/8, at 5 years post stroke, for outcome measures. Logistic regression analysis was performed to predict 5-year survival using covariables, including functional status, age, stroke type and severity and vascular risk factors. Patients lost to follow-up (n = 20) were excluded from the analyses. RESULTS: One hundred patients (60%) were dead at study end. Predictors for survival in final logistic regression model were as follows: Glasgow Coma Scale (GCS) on admission (OR 1.49, 95%CI 1.1-2.0, P = 0.01), preadmission functional independence measure (FIM) score (OR 1.04, 95%CI 1.0-1.1, P = 0.01), age (OR 0.93, 95%CI 0.87-0.98, P = 0.01) and atrial fibrillation (OR 0.43, 95% CI 0.19-0.95, P = 0.04). For 5-year survivors, mean Modified Rankin Scale was 3.1 +/- 1.5, total FIM score 85 +/- 32, mini-mental state examination (MMSE) 22 +/- 8 and Hospital Anxiety and Depression (HAD) scores 5.4 +/- 3.4 and 5.2 +/- 3.9, respectively. FIM cognition score was significantly lower at 5 years when compared to baseline (24 +/- 8 vs 29 +/- 8, P < 0.05) (all scores expressed as mean +/- SD). In contrast, MMSE, HAD and total FIM scores were not significantly different at 5 years when compared to baseline. CONCLUSIONS: The study identified lower GCS on admission, lower preadmission FIM score, age and atrial fibrillation as negative predictors for 5-year survival following stroke. PMID- 21241255 TI - A simple scoring system for outcome prediction of ischemic stroke. AB - OBJECTIVES: According to most existing models, a computer is usually needed for predicting stroke outcome. Our purpose was to construct a simple and reliable prognostic scale not requiring the use of a calculating machine. MATERIALS AND METHODS: The scale [the Bologna Outcome Algorithm for Stroke (BOAS)] was obtained in 221 patients with ischemic stroke not undergoing thrombolysis and was then validated in a test group of 100 different patients. Outcome was assessed at 9 months as the number of dependent or dead patients (modified Rankin scale - mRS > 2). RESULTS: By a preliminary systematic univariate analysis, 25 of 415 baseline variables were found to be associated with a mRS > 2 independently of stroke severity and age. Subsequent multivariable analyses led to a final model based on five dichotomous risk factors (RF): National Institutes of Health Stroke Scale score >=10, age >=78, need of urinary catheter, oxygen administration, and persistence of upper limb paralysis at discharge from stroke unit. The patients with two or more RF (53%) had a mRS > 2 in 91% of cases and were dead in 42% of cases. With 0-1 RF, the two percentages were 24% and 2%, respectively (overall accuracy of prediction 83.9%, area under ROC curve [AUC] 0.891). In the test group, the accuracy was 79.0% and the AUC was 0.839. CONCLUSIONS: The need of urinary catheter, oxygen administration, and persistence of upper limb paralysis, together with stroke severity and advanced age, allow a simple and accurate prediction of dependency or death after ischemic stroke. PMID- 21241256 TI - From fecundity to the traffic rules of medicine. PMID- 21241257 TI - Has fertility declined in recent decades? AB - OBJECTIVE: Increasing use of infertility treatment and a decline in demographic fertility in some countries have raised concern whether human fecundity is declining or has declined over time. A dramatic decline in semen quality over the past half-century has been proposed and widely discussed, but none of the existing studies provide data good enough for coming to any firm conclusion. RESULTS: Results from 19 articles published during the last 5 years on semen quality and fecundity, covering data from the Nordic countries since the year 2000, do not indicate an ongoing decline in fertility. CONCLUSION: We will probably never know, whether semen quality and fecundity has declined over time, but we may be able to monitor biological fecundity and semen quality over time from now on. There are both research initiatives and interest from official channels that could provide more funding for infertility research. PMID- 21241258 TI - Distribution of endometriotic lesions in endometriosis stage IV supports the menstrual reflux theory and requires specific preoperative assessment and therapy. AB - A detailed picture of the prevalence and distribution of abdomino-pelvic endometriosis in more that 1,500 cases of endometriosis stage IV is presented. A great prevalence of endometriotic localizations in the posterior pelvic compartment compared to the other quadrants with more frequently observed lesions on the left part of the pelvis supports the menstrual reflux theory. The extent of anatomical sites suggests the opportunity to plan a proper preoperative instrumental study for patients with clinical suspect of severe endometriosis possibly to set a multidisciplinary clinical or surgical management. PMID- 21241259 TI - Placental abruption: epidemiology, risk factors and consequences. AB - Placental abruption, classically defined as a premature separation of the placenta before delivery, is one of the leading causes of vaginal bleeding in the second half of pregnancy. Approximately 0.4-1% of pregnancies are complicated by placental abruption. The prevalence is lower in the Nordic countries (0.38-0.51%) compared with the USA (0.6-1.0%). Placental abruption is also one of the most important causes of maternal morbidity and perinatal mortality. Maternal risks include obstetric hemorrhage, need for blood transfusions, emergency hysterectomy, disseminated intravascular coagulopathy and renal failure. Maternal death is rare but seven times higher than the overall maternal mortality rate. Perinatal consequences include low birthweight, preterm delivery, asphyxia, stillbirth and perinatal death. In developed countries, approximately 10% of all preterm births and 10-20% of all perinatal deaths are caused by placental abruption. In many countries, the rate of placental abruption has been increasing. Although several risk factors are known, the etiopathogenesis of placental abruption is multifactorial and not well understood. PMID- 21241261 TI - Pregnancy-associated breast cancer. AB - Currently, it is estimated that approximately one in every 3,000 births are from women who have or are being treated for breast cancer. Although rare, the incidence of pregnancy-associated breast cancer (PABC) is increasing as women are delaying childbirth. Diagnostic and treatment recommendations have been mainly based on evidence from retrospective single institutional and collective series and expert consensus, as randomized trials on this entity are understandably lacking. PABC is often associated with a poor outcome, but this is mainly due to delay in diagnosis and initiation of treatment. For the most part, women with PABC should be managed like non-pregnant breast cancer patients and should expect a similar outcome, without causing harm to the unborn child. Increased awareness and knowledge of how to assess symptomatic breast problems in pregnancy and a specialized multidisciplinary team approach for established PABC is likely to improve outcomes. This review analyses the evidence on the diagnosis, treatment and prognosis of patients with PABC. PMID- 21241260 TI - Use of uterine electromyography to diagnose term and preterm labor. AB - Current methodologies to assess the process of labor, such as tocodynamometry or intrauterine pressure catheters, fetal fibronectin, cervical length measurement and digital cervical examination, have several major drawbacks. They only measure the onset of labor indirectly and do not detect cellular changes characteristic of true labor. Consequently, their predictive values for term or preterm delivery are poor. Uterine contractions are a result of the electrical activity within the myometrium. Measurement of uterine electromyography (EMG) has been shown to detect contractions as accurately as the currently used methods. In addition, changes in cell excitability and coupling required for effective contractions that lead to delivery are reflected in changes of several EMG parameters. Use of uterine EMG can help to identify patients in true labor better than any other method presently employed in the clinic. PMID- 21241262 TI - Human papillomavirus and predictors of cervical intraepithelial neoplasia among young mothers in a prospective follow-up study. AB - OBJECTIVE: To study the incidence times and rates for cervical intraepithelial neoplasia (CIN) and its predictors. MATERIAL AND METHODS: This is a prospective follow-up study at Turku University Hospital, Finland. The Finnish Family human papillomavirus (HPV) study comprised 329 pregnant women followed up for 3 years. In an extension of the follow-up period, 171 women participated in an additional 3 years follow-up. Cervical scrapings for HPV testing and cervical smears were collected at each follow-up visit (2, 12, 24 and 36 months and 6 years). Following two abnormal cervical smears, colposcopy with biopsies was done. The main outcome measures were actuarial and crude incidence times, incidence rates and predictors of incident CIN. RESULTS: During the follow-up period, 10 women (3.2%) developed biopsy-confirmed CIN, and four presented with incident atypical squamous cells suggesting high-grade squamous intraepithelial lesion cytology. The CIN/squamous intraepithelial lesion developed in 74.5 and 66.3 months, with crude incidence rates of 13.4/1,000 and 15.1/1,000 women months at risk, respectively. In multivariate Poisson regression, independent predictors of incident CIN were as follows: high-risk HPV positive at baseline (incidence rate ratio = 5.54; 95% confidence interval 1.02-30.14, p= 0.048); type-specific high risk HPV persistence during follow-up (incidence rate ratio = 5.84; 95% confidence interval 2.28-17.93, p= 0.0001); cervical smear cytologically diagnosed for atypical squamous cells of undetermined significance or worse at any follow-up visit (incidence rate ratio = 4.56; 95% confidence interval 2.37 8.78, p= 0.0001); and new sexual partner during follow-up (incidence rate ratio = 9.45; 95% confidence interval 1.90-46.97, p= 0.006). CONCLUSION: The results indicate that combined use of cervical smear and HPV testing, with prompt referral to colposcopy, enables accurate detection of incident CIN well before progression to invasive cancer. In addition to baseline and persistent high-risk HPV, abnormal cervical smear and new sexual partner are key predictors of incident CIN. PMID- 21241263 TI - Is oxytocin given during surgical termination of first trimester pregnancy useful? A randomized controlled trial. AB - OBJECTIVE: To compare the impact of 5 IU (international units) of oxytocin administered during surgical termination of first-trimester pregnancy compared to no oxytocin, on postoperative bleeding, pain and nausea. DESIGN: A randomized controlled single-blinded study. SETTING: A Norwegian community hospital with 1,064 consecutive legal abortions in the 20 months of study period. SAMPLE: A total of 378 women undergoing surgical termination of first-trimester pregnancy and willing to participate in the study. METHODS: Women were randomized into two groups: Group 1, receiving a standard procedure of 5 IU of oxytocin during the surgical procedure, or Group 2, receiving no oxytocic agent. All women had preoperative misoprostol. MAIN OUTCOME MEASURES: Vaginal bleeding, pain and nausea recorded by weighing pads immediately after the surgical procedure and counting pads during the three following days. RESULTS: No significant differences between the two groups could be demonstrated with regard to the recorded postoperative blood loss, pain and nausea. CONCLUSIONS: The standard routine of administering oxytocin during surgical termination of first-trimester pregnancy should be revised. PMID- 21241264 TI - Relative growth estimated from self-administered symphysis fundal measurements. AB - OBJECTIVE: To establish absolute- and relative-growth reference curves for the detection of intrauterine growth restriction from weekly self-administered symphysis-fundus (SF) measurements and to assess the influence of fetal sex, maternal obesity and parity. DESIGN: Prospective longitudinal study. SETTING: Pregnant women from six primary antenatal care centres. POPULATION: Three hundred women with singleton ultrasound dated pregnancies. METHODS: Weekly self administered SF measurements from gestational week 25 until delivery were obtained. A linear mixed longitudinal model was used to estimate the absolute SF growth using the natural logarithm (lnSF). Relative lnSF growth was calculated as the lnSF measurement in one gestational week subtracted by the lnSF measurement in the previous gestational week. The influence of fetal sex, maternal obesity and parity was assessed in regression models and by a graphical display. MAIN OUTCOME MEASURES: Absolute lnSF and relative lnSF growth curves and influence of fetal sex, maternal obesity and parity on these. RESULTS: SF measurements from 191 women were used to establish an SF-growth reference. The absolute lnSF growth was influenced by maternal obesity, and for fetal sex and parity, borderline significance was recorded; while there was no evidence that the relative lnSF growth could depend on these variables. CONCLUSIONS: Weekly self-administered SF measurements can be obtained and used to estimate SF growth. Relative growth of the lnSF height seems to be independent of fetal sex, maternal obesity and parity. PMID- 21241265 TI - Identification of barriers for good adherence to a guideline on recurrent miscarriage. AB - OBJECTIVE: Guidelines on recurrent miscarriage are poorly implemented in daily clinical practice. To ensure proper implementation, we identified existing barriers and facilitators for guideline adherence according to professionals and patients. DESIGN: Qualitative research. SETTING: Two different regions in the Netherlands. POPULATION: Forty-two professionals: gynecologists, residents in obstetrics and gynecology, fertility doctors and clinical geneticists. Ten patients with recurrent miscarriage. METHODS: Focus group interviews were performed with professionals and individual in-depth interviews with patients. Reports from the interviews were analyzed and barriers were identified. MAIN OUTCOME MEASURES: Identified barriers, categorized in four domains, including characteristics of: (I) the guideline, (II) professionals, (III) patients, (IV) organization. RESULTS: Ninety-six barriers, at all four domains, were identified among professionals. The most frequently mentioned barriers were: guideline being too complicated in the consultancy room and finding it difficult to refuse demands of insistent patients. Patients mentioned 40 barriers, of which lack of up-to-date patient information and lack of detailed knowledge about family history were most frequently mentioned. Potential facilitators, such as an electronic decision tool and patient questionnaires prior to their first visit, were mentioned by both professionals and patients. All participants agreed that complete adherence to the guideline was theoretically achievable. CONCLUSIONS: Both professionals and patients experienced barriers and facilitators for guideline adherence in recurrent miscarriage. Guideline implementation strategies should take these identified barriers into account. PMID- 21241266 TI - Recurrent massive hemoperitoneum due to ovulation as a clinical sign in congenital afibrinogenemia. AB - Massive hemoperitoneum due to ovulation is a rare but serious and life threatening complication for women with coagulation disorders, and may lead to surgical interventions and even oophorectomy. Congenital afibrinogenemia is an uncommon coagulation disorder usually discovered during childhood. Intraabdominal bleeding due to ovulation is very rare in these patients and only a few cases of corpus luteum rupture and hemoperitoneum in afibrinogenemic patients have been described. In all women, the diagnosis was known since childhood. We report on a 24-year-old woman with congenital afibrinogenemia with recurrent massive intraabdominal bleeding due to ovulation as the presenting clinical sign. Exploratory laparotomy and excision of the ruptured follicle was performed at the first bleeding episode; the second episode was managed with fresh frozen plasma and blood transfusions. Conservative management is crucial for these patients. If surgery cannot be avoided, a conservative surgical approach should be chosen to preserve ovarian function. PMID- 21241267 TI - Laparoendoscopic single-site surgery (LESS) - is it feasible in gynecological surgery? AB - Increases in technical expertise in gynecological surgery and advances in surgical instrumentation have led to the development of laparoendoscopic single site surgery (LESS). Between March and September 2009, 24 patients underwent adnexal surgery at our institution with laparoendoscopic single-site surgery. The LESS technique was performed using the TriPort through an umbilical incision of 10 mm and bent laparoscopic instruments. We furthermore compared the LESS technique with a control group of 24 patients operated consecutively in the same period and for the same procedures with conventional multiport laparoscopy. Comparing the two techniques we found differences between the operation time and mean hospital stay. The surgeon must master the use of novel bent instruments in close proximity to each another. The LESS technique for benign adnexal surgery is technically feasible and safe, representing a reproducible alternative to conventional multiport laparoscopy. PMID- 21241268 TI - Maternal height should be considered in the evaluation of macrosomia related risk of infant injuries at birth. PMID- 21241270 TI - Is a 6.7% cesarean section rate significantly different from 5% for low-risk women in the years 2001-2003? PMID- 21241272 TI - Pregnancy complicated by Werner syndrome. PMID- 21241273 TI - Structural equation modeling of gene-environment interactions in coronary heart disease. AB - Coronary heart disease (CHD) is a complex disease, which is influenced not only by genetic and environmental factors but also by gene-environment (GE) interactions in interconnected biological pathways or networks. The classical methods are inadequate for identifying GE interactions due to the complex relationships among risk factors, mediating risk factors (e.g., hypertension, blood lipids, and glucose), and CHD. Our aim was to develop a two-level structural equation model (SEM) to identify genes and GE interactions in the progress of CHD to take into account the causal structure among mediating risk factors and CHD (Level 1), and hierarchical family structure (Level 2). The method was applied to the Framingham Heart Study (FHS) Offspring Cohort data. Our approach has several advantages over classical methods: (1) it provides important insight into how genes and contributing factors affect CHD by investigating the direct, indirect, and total effects; and (2) it aids the development of biological models that more realistically reflect the complex biological pathways or networks. Using our method, we are able to detect GE interaction of SERPINE1 and body mass index (BMI) on CHD, which has not been reported. We conclude that SEM modeling of GE interaction can be applied in the analysis of complex epidemiological data sets. PMID- 21241274 TI - A flexible model for association analysis in sibships with missing genotype data. AB - A common design in family-based association studies consists of siblings without parents. Several methods have been proposed for analysis of sibship data, but they mostly do not allow for missing data, such as haplotype phase or untyped markers. On the other hand, general methods for nuclear families with missing data are computationally intensive when applied to sibships, since every family has missing parents that could have many possible genotypes. We propose a computationally efficient model for sibships by conditioning on the sets of alleles transmitted into the sibship by each parent. This means that the likelihood can be written only in terms of transmitted alleles and we do not have to sum over all possible untransmitted alleles when they cannot be deduced from the siblings. The model naturally accommodates missing data and admits standard theory of estimation, testing, and inclusion of covariates. Our model is quite robust to population stratification and can test for association in the presence of linkage. We show that our model has similar power to FBAT for single marker analysis and improved power for haplotype analysis. Compared to summing over all possible untransmitted alleles, we achieve similar power with considerable reductions in computation time. PMID- 21241275 TI - Procoagulant properties of microparticles released from red blood cells in paroxysmal nocturnal haemoglobinuria. AB - Thrombosis in paroxysmal nocturnal haemoglobinuria (PNH) has been suggested to be due to several pathophysiological states: a suppressed fibrinolytic system, increased leucocyte-derived tissue factor, complement (C')-mediated damage to platelets and endothelia, or increased platelet- and endothelium-derived microparticles (MPs). Because haemolytic attack is often accompanied by thrombosis in PNH, we studied the role of C'-induced release of MPs in the thrombogenesis of PNH. C' activation induced procoagulant alteration in PNH red blood cells (RBC), when assessed by thrombin generation in the presence of C' activated PNH RBC, which was abolished by their subsequent treatment with annexin V. Significant amounts of procoagulant MPs, measured by phosphatidylserine binding prothrombinase activity, were released from PNH RBC in association with the formation of C5b-9, but not significantly before C5b-8. Generation of procoagulant, annexin V-binding, MPs from C'-activated RBC was studied also by flow cytometry. While phorbol 12-myristate 13-acetate, an activator of protein kinase C (PKC), induced the release of MPs from normal RBC as well as PNH RBC, C' induced release of MPs from PNH RBC was Ca(2+) -independent and not associated with the activation of PKC, calpain or caspase. Procoagulant properties of MPs released from PNH RBC could contribute to the thrombogenesis of PNH. PMID- 21241276 TI - High dose chemotherapy with autologous stem cell support for patients with histologically transformed B-cell non-Hodgkin lymphomas. A Norwegian multi centre phase II study. AB - We present a prospective phase II study of patients with relapse after chemotherapy showing transformation of follicular lymphoma to diffuse large B cell lymphoma, performed before rituximab was included in standard treatment. Patients in complete (CR) or partial remission (PR) after salvage chemotherapy were eligible for high-dose chemotherapy with autologous stem cell support (HDT). Forty-seven patients from five Norwegian centres were included, of whom 30 (63%) received HDT. Eighteen (60%) achieved CR, seven (23%) PR and five (10%) had progressive disease following HDT. Median follow-up for the surviving patients was 75 months; median progression-free (PFS) and overall survival (OS) were 26 and 47 months, respectively. Median OS for all patients was 43 months, compared to only 10 months for patients not eligible for HDT. Patients receiving CD34(+) enriched/B-cell depleted grafts had inferior PFS and a trend for inferior OS compared to patients receiving non-purged grafts (Log Rank 0.025 and 0.151, respectively). In conclusion, two thirds of patients with transformation of follicular lymphoma were eligible for HDT. The majority of patients achieved CR and a considerable number had prolonged OS. The use of in vitro purged grafts did not result in a survival benefit compared to that of non-purged grafts. PMID- 21241277 TI - Interphase fluorescent in situ hybridization deletion analysis of the 9p21 region and prognosis in childhood acute lymphoblastic leukaemia (ALL): results from a prospective analysis of 519 Nordic patients treated according to the NOPHO-ALL 2000 protocol. AB - Interphase fluorescent in situ hybridization (FISH) was applied on diagnostic BM smears from 519 children with acute lymphoblastic leukaemia (ALL) in order to establish the frequency and prognostic importance of 9p21 deletion in children enrolled in the Nordic Society of Paediatric Haematology and Oncology (NOPHO) - 2000 treatment protocol. Among the patients, 452 were diagnosed with B-cell precursor (BCP)-ALL and 66 with T-ALL. A higher incidence of 9p21 deletions was found in T-ALL (38%) compared to BCP-ALL (15.7%). Homozygous deletions were found in 19.7% of T-ALL and 4.0% of BCP-ALL; hemizygous deletions were found in 18.2% and 11.7% respectively. In our series, 9p21 deletions were detected in all age groups with a steady rise in the frequency with age. There was no significant difference in outcome between cases with or without 9p21 deletion or between cases with hemi- or homozygous deletions of 9p21. In conclusion, in this large series of childhood ALL deletion of 9p21 was not associated with worse prognosis. However, interphase FISH deletion analysis of 9p21 could be used as a first step to detect unfavourable subtle cytogenetic aberrations such as the dic(9;20) rearrangement. PMID- 21241279 TI - Bortezomib and thalidomide, a steroid free regimen in newly diagnosed patients with multiple myeloma. AB - Despite their efficacy in myeloma, corticosteroids have acute and chronic toxicities. Newer agents with significant anti-myeloma activity permit the development of steroid-free regimens. We designed a Phase II clinical trial to study the toxicity and efficacy of a steroid-free combination of bortezomib and thalidomide as a first-line treatment in patients with symptomatic myeloma. Patients received bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 every 21 d and thalidomide 150 mg/d for a maximum of eight cycles. Amongst 27 evaluable patients, the overall response was 81.5% with 25.8% near complete response or greater. The response rate was comparable to most other two drug combinations for upfront therapy but lower than that obtained with the use of three drugs. The most common grade 3 toxicities were peripheral neuropathy (22%), pneumonia (15%), fatigue (7%) and anaemia (7%). Peripheral neuropathy completely resolved in 80% of the patients upon completion of therapy, but not in the remaining 20% of patients. No venous thromboembolic events were observed even in the absence of prophylactic anticoagulation. The median progression-free survival was 16.8 months (95% confidence interval 8.7-21.6 months). Median overall survival has not yet been reached at a median follow up of 39 months. The 3-year overall survival was 74%. This study demonstrates: (i) the efficacy of a steroid-free regimen; (ii) mostly reversible treatment-related peripheral neuropathy; and (iii) the absence of venous thrombotic events. PMID- 21241280 TI - Ernest Beutler: his life and contribution to medical science. AB - Ernest Beutler was one of the preeminent haematologists of the last half of the 20th and the early 21st century. In a career that spanned six decades, his research interests included such diverse areas as red cell metabolism, blood preservation, glycolipid storage diseases, leukaemias and iron metabolism. Indeed, he was quite different from most of his contemporaries in that his knowledge encompassed not only haematology and not only the medical sciences, but the biological sciences as a whole. He was among the first to describe X chromosome inactivation, and he established the critical link between glucose-6 phosphate dehydrogenase deficiency and drug-induced haemolysis. He was a skilled and innovative clinician, and an early advocate of bone marrow transplantation for the treatment of acute leukaemia. He was a prolific author, with over 800 publications; a long time member of the Editorial Board of Blood; founder of the journal Blood Cells Molecules and Diseases; and an editor of Williams Haematology from the time of its inception. He bequeathed $1 million to the American Society of Haematology to recognise and reward outstanding basic research and its clinical application: a pursuit to which he had committed his life. Indeed, he became an extraordinary exemplar of the bench-to-bedside ethos, which holds that even today, an MD researcher, working with limited means and independent of pharmaceutical companies, can have a great impact on the practice of medicine. PMID- 21241278 TI - Blockade of interleukin-6 signalling with siltuximab enhances melphalan cytotoxicity in preclinical models of multiple myeloma. AB - Signalling through the interleukin (IL)-6 pathway induces proliferation and drug resistance of multiple myeloma cells. We therefore sought to determine whether the IL-6-neutralizing monoclonal antibody siltuximab, formerly CNTO 328, could enhance the activity of melphalan, and to examine some of the mechanisms underlying this interaction. Siltuximab increased the cytotoxicity of melphalan in KAS-6/1, INA-6, ANBL-6, and RPMI 8226 human myeloma cell lines (HMCLs) in an additive-to-synergistic manner, and sensitized resistant RPMI 8226.LR5 cells to melphalan. These anti-proliferative effects were accompanied by enhanced activation of drug-specific apoptosis in HMCLs grown in suspension, and in HMCLs co-cultured with a human-derived stromal cell line. Siltuximab with melphalan enhanced activation of caspase-8, caspase-9, and the downstream effector caspase 3 compared with either of the single agents. This increased induction of cell death occurred in association with enhanced Bak activation. Neutralization of IL 6 also suppressed signalling through the phosphoinositide 3-kinase/Akt pathway, as evidenced by decreased phosphorylation of Akt, p70 S6 kinase and 4E-BP1. Importantly, the siltuximab/melphalan regimen demonstrated enhanced anti proliferative effects against primary plasma cells derived from patients with myeloma, monoclonal gammopathy of undetermined significance, and amyloidosis. These studies provide a rationale for translation of siltuximab into the clinic in combination with melphalan-based therapies. PMID- 21241281 TI - Treatment-related deaths in second complete remission in childhood acute myeloid leukaemia. AB - The frequency and causes of treatment-related deaths (TRD) in second complete remission (CR2) in acute myeloid leukaemia (AML) were investigated in a historical, prospective cohort study of 429 children included in the Nordic Society of Paediatric Haematology and Oncology (NOPHO)-AML-88 and -93 trials. Relapse occurred in 158 children (39%). Seventeen (18%) of the 96 patients entering CR2 suffered TRD. The main causes were infection (59%) and complications from graft-versus-host disease (22%). Fourteen (82%) of 17 TRDs occurred in children undergoing haematopoietic stem cell transplantations (HSCT). Optimal supportive care after HSCT is essential, and studies on risk factors for TRD are needed. PMID- 21241282 TI - From over-imitation to super-copying: adults imitate causally irrelevant aspects of tool use with higher fidelity than young children. AB - Recent research has revealed a striking tendency in young children to imitate even causally irrelevant actions, a phenomenon dubbed 'over-imitation'. To investigate whether children develop beyond this, we allowed both adults and children to witness either a child or adult model performing goal-relevant and goal-irrelevant actions to extract a reward from a transparent puzzle box. Surprisingly, copying of irrelevant actions increased with age, with the adults performing the task with less efficiency than the children. Participants of all ages were more likely to perform the irrelevant actions performed by an adult model, than by a child model. These results suggest that people may become more imitative as they mature, whilst selectively copying particular models with a high level of fidelity. We suggest that this combination of faithful copying and selectivity underwrites the powerful social learning necessary for the level of cultural transmission on which our species depends. PMID- 21241283 TI - Differential effects of grammatical gender and gender inflection in bare noun production. AB - In a new series of experiments with the picture-word interference paradigm, we replicated the grammatical gender interference effect in bare noun production in Italian: naming times are slower to picture-word noun pairs sharing the same gender. This effect is independent from the morphological transparency for gender, but responses are significantly slower when the distracters are transparent for gender. Overall, the pattern of results supports the assumption that in bare noun production grammatical gender is always selected, at least in languages like Italian. We assume that the differential effects of the nominal endings are due to the mechanisms involved in the recognition of grammatical gender of the distracter nouns which are sensitive to the morphological transparency for gender: lexical representation of transparent written words leads to a higher level of activation, thus resulting in stronger gender interference. PMID- 21241284 TI - Variation in perceptions of physical dominance and trustworthiness predicts individual differences in the effect of relationship context on women's preferences for masculine pitch in men's voices. AB - Several studies have found that women tend to demonstrate stronger preferences for masculine men as short-term partners than as long-term partners, though there is considerable variation among women in the magnitude of this effect. One possible source of this variation is individual differences in the extent to which women perceive masculine men to possess antisocial traits that are less costly in short-term relationships than in long-term relationships. Consistent with this proposal, here we show that the extent to which women report stronger preferences for men with low (i.e., masculine) voice pitch as short-term partners than as long-term partners is associated with the extent to which they attribute physical dominance and low trustworthiness to these masculine voices. Thus, our findings suggest that variation in the extent to which women attribute negative personality characteristics to masculine men predicts individual differences in the magnitude of the effect of relationship context on women's masculinity preferences, highlighting the importance of perceived personality attributions for individual differences in women's judgments of men's vocal attractiveness and, potentially, their mate preferences. PMID- 21241285 TI - Predicting beauty: fractal dimension and visual complexity in art. AB - Visual complexity has been known to be a significant predictor of preference for artistic works for some time. The first study reported here examines the extent to which perceived visual complexity in art can be successfully predicted using automated measures of complexity. Contrary to previous findings the most successful predictor of visual complexity was Gif compression. The second study examined the extent to which fractal dimension could account for judgments of perceived beauty. The fractal dimension measure accounts for more of the variance in judgments of perceived beauty in visual art than measures of visual complexity alone, particularly for abstract and natural images. Results also suggest that when colour is removed from an artistic image observers are unable to make meaningful judgments as to its beauty. PMID- 21241286 TI - Ganging up or sticking together? Group processes and children's responses to text message bullying. AB - Drawing on social identity theory and intergroup emotion theory (IET), we examined group processes underlying bullying behaviour. Children were randomly assigned to one of three groups: a perpetrator's group, a target's group, or a third party group. They then read a gender-consistent scenario in which the norm of the perpetrator's group (to be kind or unkind towards others) was manipulated, and an instance of cyberbullying between the perpetrator's group and a member of the target's group was described. It was found that group membership, group norms, and the proposed antecedents of the group-based emotions of pride, shame, and anger (but not guilt) influenced group-based emotions and action tendencies in ways predicted by social identity and IET. The results underline the importance of understanding group-level emotional reactions when it comes to tackling bullying, and show that being part of a group can be helpful in overcoming the negative effects of bullying. PMID- 21241287 TI - Constructive or cruel? Positive or patronizing? Reactions to expressions of positive and negative stereotypes of the mentally ill. AB - Previous research has shown that people respond with greater sensitivity to negative stereotypical comments about a group that are made from someone outside the group in question than from someone who belongs to the group. In this paper, we investigated if the same effect occurs in response to comments made about stigmatized groups. Specifically, we examined how people react to comments made about the mentally ill. The conditions under which people accept or reject stereotypes of the mentally ill may shed light on the conditions necessary for effective anti-discrimination campaigns. In the current study, participants responded to positive or negative stereotypes of the mentally ill voiced by either someone who has, or has not, suffered from a mental illness. Participants were more sensitive, agreed less, and evaluated the speaker less favourably when comments came from the out-group rather than the in-group source. The effects were strongest for negative comments, however contrary to previous research participants also responded less favourably to positive comments from the out group source. These reactions were mediated by the perceived constructiveness of the speaker's motives. Implications for the effectiveness of anti-discrimination campaigns are discussed. PMID- 21241288 TI - Why do we listen to music? A uses and gratifications analysis. AB - Four 'uses and gratifications' studies investigated peoples' reasons for listening to music (Study 1); and whether these reasons differ significantly from those associated with other leisure activities (Study 2). In Study 3, an open ended, qualitative research design was used to investigate why people listen to music. In Study 4, a cross-sectional design was used to investigate the possibility that people of different ages might listen to music for different reasons. Findings showed that there are a number of reasons why participants listen to music, comparison of which indicated that participants listen to music primarily to manage/regulate their moods. Comparison with other leisure activities indicated that for the most part, listening to music was rated better than other leisure activities at serving an individual's different needs. This versatility may explain why music is so important to people. Evidence was also found to suggest that the reasons for listening to music may change as people grow older. PMID- 21241290 TI - Magnesium improves the beta-cell function to compensate variation of insulin sensitivity: double-blind, randomized clinical trial. AB - BACKGROUND: Given that role of magnesium in insulin secretion is uncertain, our objective was to determine whether oral supplementation with magnesium chloride (MgCl(2)) improves the ability of beta-cells to compensate for variations in insulin sensitivity in non-diabetic individuals with significant hypomagnesaemia. MATERIALS AND METHODS: Eligible individuals were non-diabetic, normo-tensive men and non-diabetic, normo-tensive, non-pregnant women with serum magnesium levels <=0.70 mM/L; they were enrolled in a randomized double-blind clinical trial to receive either 50 mL of 5% MgCl(2) solution or 50 mL of inactive solution daily for 3 months. The primary trial end point was a change in the AUC of the hyperbolic model of beta-cell function (HMbCF) derived from the fasting state. Individuals, caregivers and personnel who assessed the outcomes were all blinded to the group assignments. RESULTS: A total of 54 and 52 individuals were assigned to the MgCl(2) and placebo groups, respectively; five individuals in the MgCl(2) group and four in the placebo group dropped out. There were no serious adverse events or side effects because of MgCl(2) or placebo. At the beginning of the study, the AUC of the HMbCF was similar in both groups (AUC = 7.591 and 7.895 cm(2)); at the end of follow-up, the curve of the MgCl(2) group showed a hyperbolic distribution (AUC = 18.855 cm(2)), whereas in the placebo group, there were no changes (AUC = 7.631 cm(2)). CONCLUSIONS: MgCl(2) 2.5 g daily improves the ability of beta-cells to compensate for variations in insulin sensitivity in non-diabetic individuals with significant hypomagnesaemia. PMID- 21241291 TI - On receiving what has gone astray, on finding what has got lost. AB - Disturbing emotions that act as bodily cryptograms waiting to be deciphered are currently understood as intra-psychic trauma. The author briefly discusses Fordham's concepts of deintegration and primitive identity, as well as early patterns of mother-infant attunement to describe how the empathic capacity of the analyst is dramatically challenged in helping patients to give birth to unbearable emotions that remain an undifferentiated entity. Referring to Ogden's understanding of the mechanism of projective identification, the author will explore how unconscious mental processes in the analyst and the patient can work at re-activating failures in the deintegrative process. Clinical material is presented to show how unconscious psychic events that affect the patient but cannot be known consciously can be born into mind by the analytic couple. PMID- 21241292 TI - Associative dreaming: reverie and active imagination. AB - The idea of countertransference has expanded beyond its original meaning of a neurotic reaction to include all reactions of the therapist: affective, bodily, and imaginal. Additionally, Jung's fundamental insight in 'The psychology of the transference' was that a 'third thing' is created in the analysis, but he failed to demonstrate how this third is experienced and utilized in analysis. This 'analytic third', as Ogden names it, is co-created by analyst and analysand in depth work and becomes the object of analysis. Reverie, as developed by Bion and clinically utilized by Ogden, provides a means of access to the unconscious nature of this third. Reverie will be placed on a continuum of contents of mind, ranging from indirect to direct associative forms described as associative dreaming. Active imagination, as developed by Jung, provides the paradigm for a mode of interaction with these contents within the analytic encounter itself. Whether the analyst speaks from or about these contents depends on the capacity of the patient to dream. Classical amplification can be understood as an instance of speaking about inner contents. As the ego of the analyst, the conscious component, relates to unconscious contents emerging from the analytic third, micro-activations of the transcendent function constellate creating an analytic compass. PMID- 21241293 TI - Psychosomatic disorders: the canalization of mind into matter. AB - Psychosomatic disorders represent a therapeutic conundrum. Despite compelling evidence to suggest the integrity of mind and body, humans are famously prone to experiencing them as separate. This paper explores the scientific challenges posed by psychosomatic disorders and how changing cultural notions contribute to their perplexing presentations. Excerpts of cases from patients with chronic pelvic pain, chronic fatigue, and a factitious disorder are presented as examples of the challenges that these patients pose in analysis. An explanatory model of mind/body interaction based on early maternal-infant interactions and the placebo response complex is proposed as the basis for how psychosomatic pathologies may develop. Finally, therapeutic approaches to the psychological treatment of patients with psychosomatic issues are considered. PMID- 21241294 TI - Winnicott on Jung: destruction, creativity and the unrepressed unconscious. AB - This paper considers Winnicott's critique of Jung, principally expressed in his review of Memories, Dreams, Reflections, which asserts that Jung's creative contribution to analysis was constrained by his failure to integrate his 'primitive destructive impulses', subsequent to inadequate early containment. It is argued that although Winnicott's diagnosis illuminates Jung's shadow, particularly his constraints vis-a-vis the repressed Freudian unconscious, it fails to appreciate the efficacy of the compensatory containment Jung found in the collective unconscious. This enigmatic relationship between destruction and creativity-so central to late Winnicott-is illuminated by Matte Blanco's bi logic, and further explored in relation to William Blake. Winnicott's personal resolution through his Jung-inspired 'splitting headache' dream of destruction previously considered in this Journal by Morey (2005) and Sedgwick (2008)-is given particular attention. PMID- 21241295 TI - An analysis with Bion: an interview with James Gooch. Interview by JoAnn Culbert Koehn. AB - In 1968 Wilfred Bion moved to Los Angeles, escaping the perils of fame in London. He lived in Los Angeles until a few months before his death in Oxford in 1979. He made a deep impact on psychoanalysis in Los Angeles through those he analysed and what he wrote. James Gooch, psychiatrist and founding president of the Psychoanalytic Center of California describes in detail the transformative experience of his analysis with Bion in an interview with JoAnn Culbert-Koehn, Jungian analyst. Dr. Gooch describes important differences between his analysis with Bion and his classical Freudian analysis during his analytic training. PMID- 21241296 TI - Entertaining the stranger. AB - This paper attempts to address the problematic of the other in analytical psychology. Despite the important contributions of Papadopoulos (1991, 2002) and Huskinson (2000, 2002) this question has not received the attention it warrants. Read in the light of Levinas' writings on otherness, Jung's tendency to characterize the self as unitary, autonomous and undivided may be seen as a defence against or even an erasure of otherness. However, a Derridean revisioning of this approach suggests that the ambiguities and paradoxes which Jung insisted were intrinsic to his intuitions about the self-concept have the potential to evoke a remarkably subtle vision of Selfhood manifesting within the very tensions generated between Same and Other. In conclusion, this experience of Selfhood is amplified in the light of some of the insights of contemporary German philosopher Waldenfels, with particular attention to the role of pathos in the encounter with alterity. PMID- 21241297 TI - Empirical study of Kanji as archetypal images: understanding the collective unconscious as part of the Japanese language. AB - Chinese characters originated as a semiotic system independent from spoken language and in the Japanese language they function non-phonetically with speakers exhibiting right-hemispheric advantage in their processing. We tested the hypothesis that Chinese characters are archetypal images and therefore part of our collective unconscious memory. Our study builds on the first empirical study of archetypal memory of Rosen et al. (1991) which demonstrated that archetypal symbols presented matched with their correct meaning were better learned and recalled. In a series of three experiments we used 40 Chinese characters instead of the archetypal symbols used by Rosen, et al. (1991). The results provided empirical evidence that Chinese characters matched with their correct meaning were significantly better recalled than the ones that were mismatched. Thus, we demonstrated that there appears to be unconscious knowledge of the meaning of the Chinese characters which was triggered as a result of priming when the characters were correctly matched with their meaning. On this basis, we suggest that Chinese characters exhibit the same cognitive qualities as archetypal symbols. Thus, in the Japanese language an archetypal image is integrated non-phonetically into the system of language and signifies the concept independent from the phonetic signifier and is equal to it. PMID- 21241301 TI - Identification of immunoreactive epitopes of the Porphyromonas gingivalis heat shock protein in periodontitis and atherosclerosis. AB - BACKGROUND AND OBJECTIVE: Heat shock protein 60 (HSP60) of Porphyromonas gingivalis, a major periodontal pathogen, might be a trigger molecule linking infectious periodontitis and autoimmune atherosclerosis. The aim of this study was to identify the peptide specificity of anti-P. gingivalis HSP60 monoclonal antibodies and their cross-reactivity with bacterial and human HSPs. Their specific immunoreactivity to periodontal or atherosclerotic lesions was also investigated. METHODS: Twenty patients with chronic periodontitis and 20 atherosclerosis patients who had undergone surgical intervention for atheromatous plaques with evidence of ongoing periodontal disease, were selected. Synthetic peptide 19 ((TLVVNRLRGSLKICAVKAPG)-specific T-cell lines were established from inflamed gingiva and atheromatous plaque and the phenotypes and cytokine profiles were characterized. RESULTS: Thirty per cent of periodontitis patients and 100% of atherosclerosis patients reacted positively to cross-reactive peptide 19 from both P. gingivalis and human HSP60. The peptide 19-specific T-cell lines demonstrated the phenotype characteristic of helper T cells (CD4(+)) but did not express CD25 or FOXP3. The interleukin-10 levels were elevated significantly in the peptide 19 T-cell line. CONCLUSION: Synthetic peptide 19 of P. gingivalis HSP60 is an immunoreactive epitope in the periodontitis-atherosclerosis axis. PMID- 21241302 TI - Therapeutic effect of a topical CCR2 antagonist on induced alveolar bone loss in mice. AB - BACKGROUND AND OBJECTIVE: Chemokines are known to regulate leukocyte trafficking, recruitment and infiltration in periodontal diseases. The study objective was to determine the effect of an experimental oral/topical chemokine (C-C motif) receptor 2 (CCR2)-antagonist treatment on alveolar bone loss in a mouse model of Porphyromonas gingivalis-induced periodontitis. MATERIAL AND METHODS: Balb/C mice (n = 41) were randomly assigned to four groups. Group 1 was infected by P. gingivalis applied orally/topically for 5 wk. Group 2 was also infected and then treated with vehicle (aqueous methylcellulose) for an additional 4 wk. Group 3 was infected and orally/topically treated with CCR2 antagonist (10 mg/kg). Group 4 served as a noninfected, nontreated control group. Mice received intraperitoneal injections of Alizarin (30 mg/kg) and calcein (20 mg/kg) three times from the last day of infection to determine mineral deposition, reflecting bone dynamics. Mandibles were analysed by morphometry and confocal fluorescence microscopy. RESULTS: Alveolar bone loss was compared among groups using Tukey's test, and bone formation was qualitatively observed. Infected mice showed significantly greater alveolar bone loss than noninfected control animals (group 1 vs. 4, p < 0.01). Vehicle-treated mice (group 2) showed the largest area of alveolar bone loss (p < 0.01), while mice treated with the CCR2 antagonist showed the smallest area of alveolar bone loss and were similar to the control group (group 3 vs. 4, p = 0.14). Qualitative analysis of fluorescent dye uptake indicated increased bone formation in CCR2-antagonist-treated mice, suggesting an improved bone repairing process. CONCLUSION: The results suggested that treatment with CCR2 antagonist inhibited alveolar bone loss and improved bone formation in this model. These data support further evaluation of CCR2 antagonist as a therapeutic target for the development of new treatment modalities on bacterially induced alveolar bone resorption. PMID- 21241303 TI - Dependability of personality, life satisfaction, and affect in short-term longitudinal data. AB - The consistency of individual differences across time has implications for theory building and clinical applications. Indeed, personality psychologists have long worked to place constructs on the continuum of consistency of more trait-like to more state-like constructs. Recently, Chmielewski and Watson () highlighted the importance of dependability coefficients for interpreting the results of stability studies. These coefficients provide an estimate of how strongly short term transient error affects retest correlations for a given measure. In this article, we use a modified version of Kenny and Zautra's (, ) STARTS model to estimate dependability of personality, life satisfaction, and affect in a 2-month longitudinal study of 8 waves. Results from 226 undergraduate students indicated that personality ratings were least influenced by transient state factors, whereas affect was most influenced. We discuss these findings in terms of their implications for the continuum of consistency and for the practical issue of selecting retest intervals for dependability analyses. PMID- 21241304 TI - Low trait self-control predicts self-handicapping. AB - Past research has shown that self-handicapping stems from uncertainty about one's ability and self-presentational concerns. The present studies suggest that low dispositional self-control is also associated with self-handicapping. In 3 studies (N = 289), the association between self-control and self-handicapping was tested. Self-control was operationalized as trait self-control, whereas self handicapping was operationalized as trait self-handicapping in Study 1 (N = 160), self-reported self-handicapping in Study 2 (N = 74), and behavioral self handicapping in Study 3 (N = 55). In all 3 studies, hierarchical regression analyses revealed that low self-control predicts self-handicapping, independent of self-esteem, self-doubt, social desirability, and gender. PMID- 21241305 TI - "... And how about now?": effects of item redundancy on contextualized self reports of personality. AB - A common method of studying cross-situational variation in personality involves asking people to describe their behavior in several different contexts. Although this approach is intuitively appealing, it introduces a great deal of redundancy into the measurement process and may affect the interpretation of contextualized self-reports. Specifically, when participants are asked the same questions repeatedly in a single questionnaire, they may be compelled to focus on how their behavior is different. We tested this hypothesis by experimentally manipulating the number of contexts that were included in a measure of role-related personality. In 2 experiments (Study 1 N=377, Study 2 N=524), we found that multiple-role questionnaires produced greater variation in trait levels across roles, larger differences between general and role-specific ratings, and weaker correlations between general and role-specific ratings than single-role questionnaires. These findings illustrate how the measurement process can have an effect on the variability of responses to contextualized self-reports. PMID- 21241306 TI - On the relationship between interoceptive awareness and alexithymia: is interoceptive awareness related to emotional awareness? AB - Interoceptive awareness (IA) is associated with emotional experience, the processing of emotional stimuli, and activation of brain structures that monitor the internal visceral and emotional state of the organism. Alexithymia is characterized by difficulties in identifying and describing one's emotions and externally oriented thinking (EOT) and reflects impairments in emotional awareness and the regulation of emotions. This study examined the relationship between alexithymia and IA in a healthy population of N=155 persons. A well validated heartbeat perception task to measure interoceptive awareness, the Toronto Alexithymia Scale (TAS-20) and a depression questionnaire (BDI-2) were administered to 88 women and 67 men. IA was inversely associated with all features of alexithymia in the whole sample. When considering sex differences, IA turned out to be a relevant negative predictor for the EOT subscale only in men. This large sample investigation in a nonclinical population indicates that IA represents a relevant negative predictor for alexithymia. PMID- 21241307 TI - An experiential thinking style: its facets and relations with objective and subjective criterion measures. AB - In Study 1, an experiential factor divided into the following 3 factors when 3 or more factors were extracted: intuition, emotionality, and imagination; whereas a rational factor retained its coherence. In Study 2, an experiential but not a rational thinking style was positively associated with performance measures of creativity, humor, aesthetic judgment, and intuition and with self-report measures of empathy and social popularity. A rational thinking style was associated with several measures of adjustment. Both thinking styles were positively related to personal growth. Support was provided from several sources for the discriminant validity of the experiential facets. In a third study, the independence of the 2 thinking styles and of gender differences in self-reported data were verified by observations by others of participants' thinking styles. The importance of identifying facets of an experiential thinking style and of discovering previously unrecognized favorable attributes of this thinking style was discussed. PMID- 21241308 TI - I'm outgoing and she's reserved: the reciprocal dynamics of personality in close friendships in young adulthood. AB - Close college-age friendships provide differential opportunities for reinforcing dispositional tendencies and fostering accommodation or change. This finding was obtained from a cross-sectional study of 66 pairs of same-sex college-age friends (58% female). Each pair of friends was extreme and either very similar or different with regard to extraversion-introversion. Interviews with each friend were analyzed for references to each other's role in various friendship domains, including the setting of the friendship and position with regard to chatting, disclosing, expressing opinions about peers, and energizing the friendship. Matched friends mutually reinforced each other's similar dispositional tendencies. Friends with contrasting personalities showed patterns of personality accommodation as well as complementary reinforcement. Implications are discussed for embedding reciprocal theories of personality development in close friendships. PMID- 21241309 TI - Uncovering the affective core of conscientiousness: the role of self-conscious emotions. AB - We conducted 3 studies to test the idea that guilt is a key affective component of Conscientiousness and that it can account for the relation between Conscientiousness and negative affect. Study 1 used meta-analysis to show that Conscientiousness was associated with specific emotions and overall negative affect but was most strongly associated with guilt. Conscientiousness was negatively related to guilt experience but positively related to guilt proneness. Also, guilt experience mediated the relation between Conscientiousness and negative affect. Study 2 (N = 142) examined the relation between facets of Conscientiousness and guilt. We replicated results from Study 1 and showed that the relation between Conscientiousness and guilt was not due to overlap with Extraversion and Neuroticism. Study 3 (n = 176) examined the interplay between Conscientiousness and guilt on grades in a short-term longitudinal study. These studies showed that Conscientiousness is primarily related to guilt and highlighted the importance of examining the emotional substrate of Conscientiousness. PMID- 21241310 TI - Profiling the "pro-environmental individual": a personality perspective. AB - There is considerable scientific interest in the psychological correlates of pro environmental behaviors. Much research has focused on demographic and social psychological characteristics of individuals who consistently perform such actions. Here, we report the results of 2 studies in which we explored relations between broad personality traits and pro-environmental actions. Using a wide variety of behavior and personality measures, we consistently found moderate positive relations between Openness to Experience and pro-environmental activities in both a community sample (Study 1: N = 778) and an undergraduate student sample (Study 2: N = 115). In Study 2, we showed that the effect of Openness on pro-environmental behaviors was fully mediated by individuals' environmental attitudes and connection to nature. Our findings suggest that high levels of aesthetic appreciation, creativity, and inquisitiveness, but not personality traits associated with altruism, may have motivated the performance of pro-environmental actions among our respondents. Implications for intervention development are discussed. PMID- 21241311 TI - Characterization of FLC, SOC1 and FT homologs in Eustoma grandiflorum: effects of vernalization and post-vernalization conditions on flowering and gene expression. AB - A rosette plant of Eustoma grandiflorum requires vernalization (exposure to a period of cold temperature) and long-day conditions to promote flowering, while prolonged cold or cool temperatures in post-vernalization periods delay flowering. This study aimed to investigate the effect of growth conditions on flowering regulation in Eustoma. In Arabidopsis, vernalization suppresses a floral repressor gene, FLOWERING LOCUS C (FLC) and upregulates floral promoter genes, such as SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1) and FLOWERING LOCUS T (FT). We identified and characterized the Eustoma homologs of these genes. In contrast to Arabidopsis FLC, Eustoma grandiflorum FLC-like (EgFLCL) expression was upregulated by cold temperature and downregulated by subsequent warm temperature exposure. The expression of Eustoma grandiflorum SOC1-like (EgSOC1L) and FT-like (EgFTL) genes was not significantly induced during vernalization, but their transcripts increased during a warm post-vernalization period in the long days. Vernalized plants grown under cool post-vernalization temperatures exhibited higher EgFLCL expression, lower EgSOC1L and EgFTL expression and flowered later than those grown under warm temperatures. Overexpression of EgFLCL cDNA repressed flowering in transgenic Arabidopsis, whereas overexpression of EgSOC1L or EgFTL cDNA promoted flowering. Our results suggest that flowering regulation by vernalization in Eustoma differs from the paradigm developed for Arabidopsis. EgFLCL is regulated by temperature and may be involved in floral repression during cold and cool seasons. Warm- and long-day conditions following vernalization are required to induce two putative floral promoters, EgSOC1L and EgFTL, effectively. PMID- 21241312 TI - Slow photosynthetic induction and low photosynthesis in Paphiopedilum armeniacum are related to its lack of guard cell chloroplast and peculiar stomatal anatomy. AB - Paphiopedilum and Cypripedium are close relatives in the subfamily Cypripedioideae. Cypripedium leaves contain guard cell chloroplasts, whereas Paphiopedilum do not. It is unclear whether the lack of guard cell chloroplasts affects photosynthetic induction, which is important for understory plants to utilize sunflecks. To understand the role of guard cell chloroplasts in photosynthetic induction of Paphiopedilum and Cypripedium, the stomatal anatomy and photosynthetic induction of Paphiopedilum armeniacum and Cypripedium flavum were investigated at different ratios of red to blue light. The highest stomatal opening and photosynthesis of intact leaves in P. armeniacum were induced by irradiance enriched with blue light. Its stomatal opening could be induced by red light 250 umol m-2 s-1, but the magnitude of stomatal opening was lower than those at the other light qualities. However, the stomatal opening and photosynthesis of C. flavum were highly induced by mixed blue and red light rather than pure blue or red light. The two orchid species did not differ in stomatal density, but P. armeniacum had smaller stomatal size than C. flavum. The stomata of P. armeniacum were slightly sunken into the leaf epidermis, while C. flavum protruded above the leaf surface. The slower photosynthetic induction and lower photosynthetic rate of P. armeniacum than C. flavum were linked to the lack of guard cell chloroplasts and specific stomatal structure, which reflected an adaptation of Paphiopedilum to periodic water deficiency in limestone habitats. These results provide evidence for the morphological and physiological evolution of stomata relation for water conservation under natural selection. PMID- 21241313 TI - Hormonal synchronization of the menstrual cycles of pigtail macaques to facilitate biomedical research including modeling HIV susceptibility. AB - BACKGROUND: Menstrual cycle synchronization of female pigtail macaques could prove an invaluable resource in studies of the reproductive tract, associated infections, and other potential research fields. We tested whether use of an oral progesterone and estradiol combination tablet could synchronize menstrual cycles following treatment discontinuation. METHODS: Daily desogestrel 0.075 mg and ethinyl estradiol 0.01 mg were administered orally to three pigtail macaques at visual onset of perineal sex swelling and were continued until all animals had received it for at least 45 days. The hormones were discontinued, and these three macaques and three controls were observed for menstruation and had blood progesterone and estrogen measured over an additional 2-month period. RESULTS: All treatment animals showed spontaneous menstrual cycle synchronization for 2 months after menstrual cycling resumed. CONCLUSION: Progesterone and estradiol combination therapy can be used in pigtail macaques to induce synchronized cycling that persists in the absence of on-going hormone treatments. PMID- 21241314 TI - IgE-sensitization to the cough suppressant pholcodine and the effects of its withdrawal from the Norwegian market. AB - BACKGROUND: IgE-mediated anaphylaxis to neuromuscular blocking agents (NMBA), frequent in Norway, was proposed to be caused by exposure to pholcodine (PHO) carrying the allergenic quarternary ammonium ion epitope. Consequently, the PHO containing drug was withdrawn from the market in March 2007. OBJECTIVE: Describe the effects of withdrawal of PHO on IgE, IgE-antibodies and reported frequencies of anaphylaxis to NMBAs. METHODS: Three hundred sera from supposedly allergic patients sampled yearly through 2006 to 2010 were analysed for IgE antibodies to PHO, suxamethonium (SUX) and morphine (MOR). Furthermore, IgE and preliminary reports from the Norwegian Network for Anaphylaxis under Anaesthesia (NARA) were monitored. RESULTS: PHO exposure was associated with IgE sensitization to PHO, MOR and SUX. However, after withdrawal, within 1 year, antibody prevalences to PHO and SUX fell significantly from 11.0% to 5.0% and from 3.7% to 0.7%, respectively. At 3 years, SUX had fallen to 0.3%, PHO to 2.7% and MOR to 1.3%. By 2 years, the prevalence of elevated IgE was significantly reduced. After 3 years, the incidence of reported suspected anaesthetic anaphylaxis fell significantly, both the total number, the reactions related to NMBAs and those with IgE antibodies to SUX. CONCLUSIONS: Withdrawing of PHO lowered significantly within 1 2 years levels of IgE and IgE antibodies to PHO, MOR and SUX, and, within 3 years, the frequency of NMBA suspected anaphylaxis. The results strengthen the PHO hypothesis considerably and equally the need to question the existence of cough depressants containing PHO. PMID- 21241315 TI - Tetraspanins CD9 and CD81 are molecular partners of trimeric FcERI on human antigen-presenting cells. AB - BACKGROUND: Most functions of tetraspanins are not related to cell-surface receptor ligand binding, but are mediated by direct interactions with their partner proteins. Functions of trimeric FcERI, expressed by antigen-presenting cells (APCs), range from amplification of allergic inflammatory reactions to their active suppression. Cell-type-specific protein-protein interactions might play a role in the regulation of these bidirectional tasks. Therefore, we intended to study the interactions of trimeric FcERI with tetraspanins. METHODS: The expression levels of tetraspanins CD9, CD37, CD53, CD63, CD81, CD82, and CD151 on skin dendritic cells of atopic dermatitis (AD) patients or healthy individuals were detected by flow cytometry. Tetraspanin expression on FcERI(pos) and FcERI(neg) monocyte subpopulations was evaluated. Flow cytometry, confocal microscopy, immunoprecipitation, and immunoblotting experiments were performed to observe the relationship between tetraspanins CD9 and CD81 and FcERI. Furthermore, plate stimulation experiments were performed, and cytokines in the supernatants were detected. RESULTS: We found that human FcERI(pos) APCs expressed high amounts of tetraspanins and that the tetraspanins CD9 and CD81 were associated with FcERI. Concomitant activation of FcERI and CD9 on human monocytes increased FcERI-mediated cytokine release. CONCLUSION: Taken together, we show for the first time that CD9 and CD81 act as molecular partners of trimeric FcERI on human APC, which might be of importance in allergic diseases such as AD. PMID- 21241316 TI - Therapeutic induction of tolerance by IL-10-differentiated dendritic cells in a mouse model of house dust mite-asthma. AB - BACKGROUND: It has been reported that retrovirally transduced IL-10-expressing dendritic cells can reverse the asthma phenotype in mice, but that i.v. delivery of dendritic cells differentiated with IL-10 alone (DC10) does not. We report herein DC10 can be highly effective therapeutically in experimental asthma. METHODS: BALB/c mice were sensitized by airway exposure to house dust mite (HDM) without use of adjuvants, then treated with 106 allergen-presenting DC10. We assessed the airway hyperresponsiveness (AHR) to methacholine, circulating levels of IgE and IgG1, and airway recall responses to HDM allergen, including eosinophilia and Th2 cytokines. We also asked whether the DC10 treatments induced tolerance through activation of pulmonary regulatory T cell activities. RESULTS: In vitro, cognate-, but not irrelevant-, allergen-presenting DC10 productively engaged pulmonary Th2-phenotype CD4(+) cells magnetically sorted from HDM asthmatic mice in Forster (or fluorescence) resonance energy transfer assays. In vivo, treatment of HDM-asthmatic mice with HDM, but not ovalbumin-presenting DC10 abrogated AHR within 4 weeks, and significantly reduced airway eosinophilia, IL 4, IL-5, and IL-13 responses, and circulating HDM-specific IgE and IgG1 levels (each, P <= 0.01 versus control mice). CD4(+) CD25(+) Foxp3(+) cells from the lungs of the DC10-treated mice, but not those from asthmatic animals, up regulated expression of the activated regulatory T cell markers CTLA4 and LAG3, and passive transfer of pulmonary CD4(+) T cells from these mice induced allergen tolerance in HDM-asthmatic recipients. CONCLUSIONS: These findings indicate that allergen-presenting DC10 treatments up-regulate T cell regulatory activities and thereby induce allergen-specific tolerance in a relevant model of human asthma. PMID- 21241317 TI - NOD-like receptors in the human upper airways: a potential role in nasal polyposis. AB - BACKGROUND: Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are newly discovered cytosolic receptors belonging to the pattern-recognition receptor family. They detect various pathogen-associated molecular patterns, triggering an immune response. The knowledge about these receptors, and their role in health and disease, is limited. The aim of the present study was to characterize the expression of NOD1, NOD2, and NALP3 in the human upper airways. METHODS: Surgical samples were obtained from patients with tonsillar disease (n = 151), hypertrophic adenoids (n = 9), and nasal polyposis (n = 24). Nasal biopsies were obtained from healthy volunteers (n = 10). The expression of NOD1, NOD2, and NALP3 was analyzed using real-time PCR and immunohistochemistry. RESULTS: Expression of NOD1, NOD2, and NALP3 mRNA and protein were seen in all tissue specimens. The NLR mRNA was found to be higher in nasal polyps than in normal nasal mucosa, and local steroid treatment reduced the NLR expression in polyps. In contrast, tonsillar infection with Streptococcus pyogenes or Haemophilus influenzae did not affect the NLR expression. CONCLUSIONS: The present study demonstrates the presence of NLRs in several upper airway tissues and highlights a potential role of NLRs in chronic rhinosinusitis with polyps. PMID- 21241318 TI - Grading quality of evidence and strength of recommendations in clinical practice guidelines part 3 of 3. The GRADE approach to developing recommendations. AB - This is the third and last article in the series about the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to grading the quality of evidence and the strength of recommendations in clinical practice guidelines and its application in the field of allergy. We describe the factors that influence the strength of recommendations about the use of diagnostic, preventive and therapeutic interventions: the balance of desirable and undesirable consequences, the quality of a body of evidence related to a decision, patients' values and preferences, and considerations of resource use. We provide examples from two recently developed guidelines in the field of allergy that applied the GRADE approach. The main advantages of this approach are the focus on patient important outcomes, explicit consideration of patients' values and preferences, the systematic approach to collecting the evidence, the clear separation of the concepts of quality of evidence and strength of recommendations, and transparent reporting of the decision process. The focus on transparency facilitates understanding and implementation and should empower patients, clinicians and other health care professionals to make informed choices. PMID- 21241319 TI - Restricted growth of U-type infectious haematopoietic necrosis virus (IHNV) in rainbow trout cells may be linked to casein kinase II activity. AB - Previously, we demonstrated that a representative M genogroup type strain of infectious haematopoietic necrosis virus (IHNV) from rainbow trout grows well in rainbow trout-derived RTG-2 cells, but a U genogroup type strain from sockeye salmon has restricted growth, associated with reduced genome replication and mRNA transcription. Here, we analysed further the mechanisms for this growth restriction of U-type IHNV in RTG-2 cells, using strategies that assessed differences in viral genes, host immune regulation and phosphorylation. To determine whether the viral glycoprotein (G) or non-virion (NV) protein was responsible for the growth restriction, four recombinant IHNV viruses were generated in which the G gene of an infectious IHNV clone was replaced by the G gene of U- or M-type IHNV and the NV gene was replaced by NV of U- or M-type IHNV. There was no significant difference in the growth of these recombinants in RTG-2 cells, indicating that G and NV proteins are not major factors responsible for the differential growth of the U- and M-type strains. Poly I:C pretreatment of RTG-2 cells suppressed the growth of both U- and M-type IHNV, although the M virus continued to replicate at a reduced level. Both viruses induced type 1 interferon (IFN1) and the IFN1 stimulated gene Mx1, but the expression levels in M-infected cells were significantly higher than in U-infected cells and an inhibitor of the IFN1-inducible protein kinase PKR, 2-aminopurine (2-AP), did not affect the growth of U- or M-type IHNV in RTG-2 cells. These data did not indicate a role for the IFN1 system in the restricted growth of U-type IHNV in RTG-2 cells. Prediction of kinase-specific phosphorylation sites in the viral phosphoprotein (P) using the NetPhosK program revealed differences between U- and M-type P genes at five phosphorylation sites. Pretreatment of RTG-2 cells with a PKC inhibitor or a p38MAPK inhibitor did not affect the growth of the U- and M type viruses. However, 100 MUm of the casein kinase II (CKII) inhibitor, 5,6 dichloro-1-beta-d-ribofuranosylbenzimidazole (DRB), reduced the titre of the U type 8.3-fold at 24 h post-infection. In contrast, 100 MUm of the CKII inhibitor reduced the titre of the M type only 1.3-fold at 48 h post-infection. Our data suggest that the different growth of U- and M-type IHNV in RTG-2 cells may be linked to a differential requirement for cellular protein kinases such as CKII for their growth. PMID- 21241320 TI - Studies on pathogenicity and prevalence of white spot syndrome virus in mud crab, Scylla serrata (Forskal), in Zhejiang Province, China. AB - Mud crab, Scylla serrata (Forskal), is the most commercially important marine crab species in China. In recent years, serious diseases have occurred in major mud crab culture regions in SE China. PCR detection of white spot syndrome virus (WSSV) in diseased mud crabs collected from Zhejiang Province during 2006-2008 showed a prevalence of 34.82%. To study the pathogenicity of WSSV to mud crab, healthy mud crabs were injected intramuscularly with serial 10-fold dilutions of a WSSV inoculum. The cumulative mortalities in groups challenged with 10-1, 10-2, 10-3 and 10-4 dilutions were 100%, 100%, 66.7% and 38.9% at 10 days post injection, respectively. All moribund and dead mud crabs except the control group were positive for WSSV by PCR. Based on the viral load of the WSSV inoculum by quantitative real-time PCR, the median lethal dose (LD50) of WSSV in S. serrata was calculated as 1.10 * 106 virus copies/crab, or 7.34 * 103 virus copies g-1 crab weight. The phenoloxidase, peroxidase and superoxide dismutase activities in haemolymph of WSSV-infected moribund crabs, were significantly lower than the control group, whereas alkaline phosphatase, glutamate-pyruvate transaminase and glutamic-oxaloacetic transaminase were higher than in the control group. WSSV was mainly distributed in gills, subcuticular epithelia, heart, intestine and stomach as shown by immunohistochemical analysis with Mabs against WSSV. The epithelial cells of infected gill showed hypertrophied nuclei with basophilic inclusions. Numerous bacilliform virus particles were observed in nuclei of infected gill cells by transmission electron microscopy. It is concluded that WSSV is a major pathogen of mud crab with high pathogenicity. PMID- 21241321 TI - The fate of Lernaeocera branchialis (L.) (Crustacea; Copepoda) in Atlantic cod, Gadus morhua L. AB - Lernaeocera branchialis, a copepod crustacean parasite of gadoids, represents a potential threat to both wild and farmed cod, Gadus morhua. The pathological changes associated with the early stages of experimental infection have previously been reported in detail, and this article describes the lesions associated with later chronic stages of experimental infection. Chronic infection is characterised by extravascular granuloma formation and proliferation of fibrovascular tissue around intact and fragmented, degenerate parasites within both the gill arch and cardiac region. The majority of parasite granulomas are located within connective tissues of the gill arch or pericardium; however, low numbers are present within the wall of large vessels. The intraluminal parasites and thrombi of early stage infection are largely absent in these later lesions. We propose that organisation and incorporation of the parasite thrombus into the vessel wall with subsequent granuloma formation and extrusion into the surrounding connective tissue leads to the elimination of the parasite from the vascular system. Thus, rather than being a negative consequence of infection thrombosis is protective, allowing the host to survive the substantial initial vascular insult. PMID- 21241322 TI - Lesions associated with plerocerci (Platyhelminthes: Cestoda: Trypanorhyncha) in the gastric wall of a cownose ray, Rhinoptera bonasus (Mitchill), (Myliobatiformes: Rhinopteridae) from the northern Gulf of Mexico. AB - We describe lesions associated with a seemingly intense infection of trypanorhynch plerocerci (Platyhelminthes: Cestoda: Trypanorhyncha) in the gastric wall of a female cownose ray, Rhinoptera bonasus (Myliobatiformes: Rhinopteridae) captured in the northern Gulf of Mexico. Grossly, the multitude of encapsulated, encysted plerocerci imparted a bumpy and cobbled appearance to the serosa of the stomach, and none was observed in any other tissue during routine parasitological necropsy. Histologically, the plerocerci were associated with severe intramural granulomatous gastritis, vascular ectasia and mesothelial polyposis with the exclusion of the mucosa. To our knowledge, this is the first published case study documenting platyhelminth-associated histopathological changes in the gastrointestinal tract of R. bonasus as well as that of the efficacy of immunocytochemical markers for smooth muscle actin, Factor VIII, S 100, and proliferating cell nuclear antigen in Myliobatiformes. It also may serve as a potential primer for much needed ecological investigations regarding the potential role of elasmobranchs as intermediate or 'paratenic' hosts in the life cycles of trypanorhynch cestodes. PMID- 21241323 TI - Investigation of ornamental fish entering the EU for the presence of ranaviruses. AB - A survey was performed on ornamental fish imported into the EU to detect viral agents belonging to the genus Ranavirus. The objective was to gain knowledge of the potential for these systemic iridoviruses to gain entry into the EU via international trade in ornamental fish. A total of 208 pooled samples, representing 753 individual fish, were tested. The samples included 13 orders and 37 families, originating from different countries and continents. Tissues from fish that died during or just after transport were collected and examined by standard virological techniques in epithelioma papulosum cyprini cells, by transmission electron microscopy and by PCR for the detection of the major capsid protein and DNA polymerase gene sequences of ranaviruses. Virus was isolated from nine fish species but ranavirus was not identified in those samples. The results suggest that ranaviruses are not highly prevalent in ornamental fish imported into the EU. PMID- 21241324 TI - Analysis and characterization of the complete genomic sequence of the Chinese strain of hirame rhabdovirus. PMID- 21241325 TI - The influence of modulation of P-glycoprotein and /or cytochrome P450 3A on the pharmacokinetics and pharmacodynamics of orally administered morphine in dogs. AB - The influence of pretreatment with ketoconazole [cytochrome P450 3A (CYP3A) + P glycoprotein (P-gp) inhibitor], elacridar (selective P-gp inhibitor) and rifampicin (CYP3A + P-gp inducer) on oral morphine pharmacokinetics and pharmacodynamics was investigated in experimental dogs. Seven beagles were used in a four-way crossover design. Morphine hydrochloride was administered orally (2.5 mg/kg) alone (control group CON) or after pretreatment with ketoconazole (group KETO), elacridar (group ELA) or rifampicin (group RIF). Morphine plasma concentrations were analysed by liquid chromatography-tandem mass spectrometry. Sedation scores (none, mild, moderate or severe) were evaluated subjectively. Dogs were significantly (P < 0.05) more sedated after ketoconazole pretreatment. There were no significant differences between group CON and the other pretreatment groups in pharmacokinetic parameters taking both sexes into account. Sex differences were apparent in some pharmacokinetic parameters of morphine. The area under the plasma concentration time curve (AUC(0-infinity) ) was significantly higher, and the total body clearance was significantly lower in male compared to female dogs in all treatment groups. Ketoconazole, rifampicin and elacridar pretreatment had no significant effects on morphine pharmacokinetics, although dogs in the ketoconazole group showed higher sedation scores. PMID- 21241326 TI - Gene expression analysis of wounding-induced root-to-shoot communication in Arabidopsis thaliana. AB - Root-to-shoot communication plays an important role in the adaptation to environmental stress. In this study, we established a model system for root-to shoot signalling to observe global gene expression in Arabidopsis thaliana. The roots of Arabidopsis seedlings were wounded and the expression in the shoots of 68 and 5 genes was up-regulated threefold at 30 min and 6 h post-injury, respectively. These genes were designated early and late Root-to-Shoot responsive (RtS) genes, respectively. Many of the early RtS genes were found to encode transcription factors such as AtERFs, whereas others were associated with jasmonic acid (JA) and ethylene (ET). Some of the late RtS genes were shown to be regulated by 12-oxo-phytodienoic acid (OPDA). In fact, elevated levels of JA and OPDA were detected in the shoots of seedlings 30 min and 6 h, respectively, after wounding of the roots. A mutant analysis revealed that JA and ET are involved in the expression of the early RtS genes. Thus, root-to-shoot communication for many RtS genes is associated with the systemic production of JA, OPDA and possibly ET. PMID- 21241327 TI - Effects of the hydraulic coupling between xylem and phloem on diurnal phloem diameter variation. AB - Measurements of diurnal diameter variations of the xylem and phloem are a promising tool for studying plant hydraulics and xylem-phloem interactions in field conditions. However, both the theoretical framework and the experimental verification needed to interpret phloem diameter data are incomplete. In this study, we analytically evaluate the effects of changing the radial conductance between the xylem and the phloem on phloem diameter variations and test the theory using simple manipulation experiments. Our results show that phloem diameter variations are mainly caused by changes in the radial flow rate of water between the xylem and the phloem. Reducing the hydraulic conductance between these tissues decreases the amplitude of phloem diameter variation and increases the time lag between xylem and phloem diameter variation in a predictable manner. Variation in the amplitude and timing of diameter variations that cannot be explained by changes in the hydraulic conductance, could be related to changes in the osmotic concentration in the phloem. PMID- 21241328 TI - Light exerts multiple levels of influence on the Arabidopsis wound response. AB - Light plays important roles in modulating plant responses to attack by pests and pathogens. Here, we test the hypothesis that darkness modifies the response to wounding, and examine possible mechanisms for such an effect. We investigated changes in the Arabidopsis transcriptome following a light-dark transition and the response to wounding either in the light or in the dark. The transcriptional response to the light-dark transition strongly resembles responses associated with carbon depletion. The dark shift and wound responses acted largely independently, but more complex interactions were identified at a number of levels. Darkness attenuates the overall transcriptional response to wounding, and we identified genes and physiological processes, such as anthocyanin accumulation, that exhibit light-dependent wound responses. Transcriptional activation of light-dependent wound-induced genes requires a chloroplast-derived signal originating from photosynthetic electron transport. We also present evidence of a role for the circadian clock in modifying wound responses. Our results show that darkness impacts on the wound response at a number of levels, which may imply differences in induced herbivore defences during the day and night. PMID- 21241329 TI - The effect of competition from neighbours on stomatal conductance in lettuce and tomato plants. AB - Competition decreased transpiration from young lettuce plants after 2 days, before any reductions in leaf area became apparent, and stomatal conductance (g(s) ) of lettuce and tomato plants was also reduced. Stomatal closure was not due to hydraulic signals or competition for nutrients, as soil water content, leaf water status and leaf nitrate concentrations were unaffected by neighbours. Competition-induced stomatal closure was absent in an abscisic acid (ABA) deficient tomato mutant, flacca, indicating a fundamental involvement of ABA. Although tomato xylem sap ABA concentrations were unaffected by the presence of neighbours, ABA/pH-based stomatal modulation is still likely to underlie the response to competition, as soil and xylem sap alkalization was observed in competing plants. Competition also modulated leaf ethylene production, and treatment of lettuce plants with an ethylene perception inhibitor (1 methylcyclopropene) diminished the difference in g(s) between single and competing plants grown in a controlled environment room, but increased it in plants grown in the greenhouse: ethylene altered the extent of the stomatal response to competition. Effects of competition on g(s) are discussed in terms of the detection of the absence of neighbours: increases in g(s) and carbon fixation may allow faster initial space occupancy within an emerging community/crop. PMID- 21241330 TI - The role of class A1 heat shock factors (HSFA1s) in response to heat and other stresses in Arabidopsis. AB - In Arabidopsis, there are four homologs of class A1 heat shock factor (HSFA1) genes, which likely encode the master regulators of heat shock response (HSR). However, previous studies with double knockout (KO) mutants were unable to confirm this point probably due to functional redundancy. Here, we generated a quadruple KO (QK) and four triple KO mutants to dissect their functions. Our data show that members of the HSFA1 group not only play a pivotal role in HSR but also are involved in growth and development. Alterations in morphology and retardation in growth were observed in the quadruple but not in triple KO mutants. The basal and acquired thermotolerance capacity was dramatically decreased in the QK mutant but varied in triple KO mutants at different developmental stages. The transcriptomics profiles suggested that more than 65% of the heat stress (HS)-up regulated genes were HSFA1 dependent. HSFA1s were also involved in the expression of several HS genes induced by H(2) O(2) , salt and mannitol, which is consistent with the increased sensitive phenotype of the QK mutant to the stress factors. In conclusion, the Arabidopsis HSFA1s function as the master regulators of HSR and participate as important components in other abiotic stress responses as well. PMID- 21241331 TI - Expression of a Brassica napus heme oxygenase confers plant tolerance to mercury toxicity. AB - Plant heme oxygenases (HOs) regulate biosynthesis of phytochrome which accounts for photo-acceptance and -morphogenesis. Recent studies have demonstrated that plant HOs also regulate many other physiological processes including response to environmental stimuli. To elucidate the mechanism by which HOs regulate plant adaptation to heavy metal exposure, three novel HOs genes were isolated from rapeseed (Brassica napus) and their expression patterns were analysed. Alignment of deduced protein sequences revealed that the three BnHOs share high identity with their corresponding orthologos (AtHO1-3) from Arabidopsis. To investigate whether the BnHO regulates plant tolerance to Hg toxicity, we constructed B. napus transgenic plants overexpressing BnHO-1. Under Hg stress, the transgenic plants had 1.41-1.59 folds higher biomass than the untransformants. However, overexpression of BnHO-1 resulted in less accumulation of Hg in some lines of transformants than in untransformants. The transgenic plants show lower abundance of reactive oxygen species and attenuated oxidative injury compared with the untransgenic plants. We cloned the promoter sequences of BnHO-1 from B. napus. Analysis revealed that the 1119 bp fragment contains a conserved Cd responsive element (CdRE) and others responding to multiple environmental stimuli. Transient expression in tobacco leaves showed differential responses to heavy metals (Zn, Cu, Pb, Hg and Cd). PMID- 21241332 TI - The rate-limiting step for CO(2) assimilation at different temperatures is influenced by the leaf nitrogen content in several C(3) crop species. AB - Effects of nitrogen (N) supply on the limiting step of CO(2) assimilation rate (A) at 380 umol mol(-1) CO(2) concentration (A(380) ) at several leaf temperatures were studied in several crops, since N nutrition alters N allocation between photosynthetic components. Contents of leaf N, ribulose 1.5-bisphosphate carboxylase/oxygenase (Rubisco) and cytochrome f (cyt f) increased with increasing N supply, but the cyt f/Rubisco ratio decreased. Large leaf N content was linked to a high stomatal (g(s) ) and mesophyll conductance (g(m) ), but resulted in a lower intercellular (C(i) ) and chloroplast CO(2) concentration (C(c) ) because the increase in g(s) and g(m) was insufficient to compensate for change in A(380) . The A-C(c) response was used to estimate the maximum rate of RuBP carboxylation (V(cmax) ) and chloroplast electron transport (J(max) ). The J(max) /V(cmax) ratio decreased with reductions in leaf N content, which was consistent with the results of the cyt f/Rubisco ratio. Analysis using the C(3) photosynthesis model indicated that A(380) tended to be limited by RuBP carboxylation in plants grown at low N concentration, whereas it was limited by RuBP regeneration in plants grown at high N concentration. We conclude that the limiting step of A(380) depends on leaf N content and is mainly determined by N partitioning between Rubisco and electron transport components. PMID- 21241333 TI - Class and lifestyle 'lock-in' among middle-aged and older men: a Multiple Correspondence Analysis of the British Regional Heart Study. AB - Health lifestyles are collective patterns of health risk behaviour that develop within a social habitus. An important area for research is the extent to which health lifestyles become more individualised over time and as people age, or whether health lifestyles remain socially structured. This article presents findings from a Multiple Correspondence Analysis of the British Regional Heart Study. Our findings suggest that smoking and alcohol use retain a strong class patterning as men age (suggesting some support for the long-term importance of social structures in old age). This indicates that, in later life, some forms of class-related health lifestyles become fixed or 'locked in'. In contrast there is evidence to suggest that, for exercise, class becomes less important as people age (suggesting either some support for growing individualisation and or important ageing effects). Further studies are required to examine different forms of health lifestyle in later life in relation to forms of cultural and economic capital. This study provides evidence in support of attempts to theorise health lifestyles in terms of collectivities. Furthermore, the concept of selective lifestyle 'lock-in' may be a useful way of understanding the relationship between class and health lifestyles in old age. PMID- 21241334 TI - Educating with the hands: working on the body/self in Alexander Technique. AB - Traditionally, forms of body work such as Alexander Technique have been excluded from mainstream biomedicine and healthcare, despite attempts by practitioners to have the work accepted within the medical community. Using data from a UK-based study of Alexander Technique which combined participant observation, interviews with 17 teachers and pupils, and analysis of historical texts, this article examines the relationship of the Alexander Technique to the field of healthcare, looking at its embodied practices, and contrasting these with the discourses in which it is framed. Applying Foucault's concept of 'techniques of the self', the article examines Alexander Technique's physical practices as a form of embodied knowledge, and goes on to look at its use of particular ideas about nature and evolution as guiding authorities, its emphasis on holism through its conception of the 'self', and how it has been positioned in relation to biomedical approaches. The article argues that while the embodied practice of Alexander Technique has much to offer to mainstream healthcare, the discourses and knowledge systems in which it is embedded make it unlikely to receive mainstream medical acceptance. PMID- 21241335 TI - Subjective social status and health in young people. AB - Health inequalities according to objective socioeconomic position (SEP), have been well-documented. Yet, in young people the associations are negligible. Recently, research on the association of subjective social status (SSS), and adult health has begun to accumulate. Studies on young people are rare and describe societies with large income inequalities. Here, we investigated the association between SSS and health, while controlling for own and familial SEP. The study population consisted of 15-year-olds (N = 2369) who have grown up in a context of low social inequalities. Data were derived from surveys carried out in 2004 in 29 secondary schools in Helsinki. The SSS was measured with an indicator specific to and validated for adolescents (a societal ladder). Outcome measures were self-rated health, health complaints, presence of limiting longstanding illness (LLI) and GHQ-12 caseness (indicating psychiatric morbidity). The SSS associated strongly with all health measures. Adjusting for objective socioeconomic measures attenuated the associations; although they all remained statistically significant apart from LLI among girls. The subjective assessment contributes to health inequalities in young people largely independent of objective SEP. Subjective ratings most probably capture aspects of social hierarchy that are more subtle and less well represented than in conventional measures. PMID- 21241336 TI - Treating women's sexual difficulties: the body work of sexual therapy. AB - This paper seeks to illuminate the interactions of medics and other healthcare practitioners with women's bodies by looking at intervention in the area of women's sexual problems or 'Female Sexual Dysfunction' (FSD). Drawing on data produced in the first empirical study to date of women's accounts of their experiences of seeking and receiving treatment for perceived sexual difficulties, we analyse two treatments for women's sexual difficulties involving direct touch of the body: sexual medicine and pelvic physiotherapy. We adopt the concept of 'body work' as a way of illuminating practitioners' focus on the bodies of patients and the complex, contradictory meanings of genital touch brought by these interactions. We conclude by considering the goals and methods of these sexual therapies, the challenges that practitioners face, and the implications of all the above for women, their bodies, and their capacity for sexual enjoyment. PMID- 21241337 TI - The co-marking of aged bodies and migrant bodies: migrant workers' contribution to geriatric medicine in the UK. AB - This article sits at the nexus between two bodies of work, gerontology and migration research, both of which have theorised the body as the locus of stigma. Gerontologists, while acknowledging the significance of perceptions of the ageing body for engagement and participation in society, have often evaded direct engagement with physical and medical understandings of older bodies. In parallel, research which focuses on migration, race and the body has focused on how the migrant body is stigmatised both because of its somatic markers and because of the status of the frail older people whom they tend. Drawing on oral history interviews with UK born and South Asian overseas-trained geriatricians, the article argues that the two bodies, which are usually seen in negative ways, came together in meaningful ways in the development of the specialty of geriatric medicine. Thinking of the body as an assemblage with many elements, some of which are stigmatised but which can nevertheless be recuperated, helps us to think beyond stigma in the context of body work. PMID- 21241338 TI - Innovation and evaluation: taming and unleashing telecare technology. AB - Telecare is advocated in most European countries with great, if not grandiose, promises: improving healthcare, lowering costs, solving workforce shortage. This paper does not so much question these specific promises, but rather the 'register of promising' as such, by comparing the promises with actual processes of incorporating technologies in healthcare practices. The case we study is the use of webcams in follow-up care from a Dutch rehabilitation clinic for people with severe chronic obstructive pulmonary disease (COPD). This process shows many changes and contingencies, and corresponding shifts in goals and aims. The conclusion is that when innovative technologies such as telecare are actually put to work, 'the same' technology will perform differently. In order to function at all, technology has to be tamed, it has to be tinkered with to fit the practices of the users. The technology, however, is not meekly put to use (tamed), but is unleashed as well, affecting care practices in unforeseen ways. The untenability of pre-given promises and the fluidity of locally evolving goals has important implications for the way in which innovations are promoted, as well as for the way innovative technologies may be evaluated. PMID- 21241339 TI - 'You can't ask for a Dubonnet and lemonade!': working class masculinity and men's health practices. AB - In recent years, much research concerning men's health has focused on men's health-related practices. While this body of research has often sought to contextualise men's health practice it has done so primarily in terms of gender not social class. The need remains therefore to link theories of masculinity and health to broader theories regarding social class and health which highlight the social and economic context of people's lives, in order to develop more complex understandings regarding the interactions between social class, gender and men's health practices. The aim of this article is to explore these interactions via a qualitative examination of the ways in which two groups of working class men living in two contrasting socio-economic areas construct masculinity and how this intertwines with their class position to impact on their health practices. This study highlights how men's conceptualisations of masculinity coupled with their class position informed their understanding of male roles and the expectations that flow from this. It shows how certain risky practices are firmly rooted in the material reality of men's lives, not simply in their gender, and how aspects of masculinity and class position intimately entwine to structure men's health seeking behaviour. PMID- 21241340 TI - Yeasts from Macrobrachium amazonicum: a focus on antifungal susceptibility and virulence factors of Candida spp. AB - In the present study, it was sought to compare yeast microbiota of wild and captive Macrobrachium amazonicum and evaluate the antifungal susceptibility and production of virulence factors by the recovered isolates of Candida spp. Additionally, cultivation water was monitored for the presence of fungi. Overall, 26 yeast isolates belonging to three genera and seven species were obtained, out of which 24 were Candida spp., with Candida famata as the most prevalent species for both wild and captive prawns. From cultivation water, 28 isolates of filamentous fungi were obtained, with Penicillium spp., Cladosporium spp. and Aspergillus spp. as the most frequent genera. Eight out of 24 Candida spp. isolates were resistant to azole derivatives, out of which four were recovered from wild-harvested prawns. As for production of virulence factors, three (12.5%) and eight (33.3%) isolates presented phospholipase and protease activity, respectively. This is the first comparative study between wild and captive prawns and the first report on yeast microbiota of M. amazonicum. The most relevant finding was the high percentage of resistant Candida spp., including from wild individuals, which suggests the occurrence of an environmental imbalance in the area where these prawns were captured. PMID- 21241342 TI - Development of a PCR-based assay for rapid detection of class IIa bacteriocin genes. AB - AIMS: We have developed a PCR-based assay using custom designed panel of primers which allows rapid detection of class IIa bacteriocin-coding genes. To demonstrate the applicability of the developed assay, the method was applied on 40 metagenomic DNA preparations isolated from native microbiota of Polish artisanal cheeses produced in the Tatra Mountains. METHODS AND RESULTS: The developed assay was designed on the basis of a large scale alignment of class IIa bacteriocin-coding genes. A panel of seven primer pairs with confirmed ability to detect class IIa bacteriocin-coding sequences was obtained. The following study has revealed a superb bacteriocinogenic potential of all forty analysed cheese samples. CONCLUSIONS: The majority of obtained sequences were lactic acid bacteria (LAB) related, although some sequences showed significant similarity to bacteriocin-coding sequences present in non-LAB bacteriocin producers. The results suggest that several potentially new bacteriocin-coding sequences were found. SIGNIFICANCE AND IMPACT OF THE STUDY: The developed assay can be extremely helpful in establishing whether isolates from the environment of interest have a potential of synthesizing antilisterial class IIa bacteriocins. Application of the approach may represent a useful tool contributing to ecological studies looking for valuable probiotic, bacteriocinogenic microbiota developing in foods. PMID- 21241343 TI - Ethics, ambiguity aversion, and the review of complex translational clinical trials. AB - Clinical trials of novel agents often present several layers of ethical challenge. Because time and resources for ethical and safety review are limited, how investigators, IRBs, and regulators allocate attention to a trial's various safety dimensions itself represents a critical ethical question. In what follows, I use the example of a Parkinson's disease gene transfer trial to show how risks involving unknown probabilities or outcomes (ambiguity), might sometimes draw attention away from risks that involve known probabilities or outcomes. This potentially undermines the goal of 'systematic and nonarbitrary analysis of risk' during ethical review. To counteract the possible effects of such attention biases, I propose that reviewers develop 'cognitive aids' like lists and, where appropriate, set aside time to discuss non-ambiguous risks. I also propose further research for addressing and understanding how attention allocation, emotion, and ambiguity influence ethical decision-making. PMID- 21241344 TI - Realizing benefit sharing - the case of post-study obligations. AB - In 2006, the Indonesian government decided to withhold avian flu samples from the World Health Organization. They argued that even though Indonesian samples were crucial to the development of vaccines, the results of vaccine research would be unaffordable for its citizens. Commentaries on the case varied from alleging blackmail to welcoming this strong stance against alleged exploitation. What is clear is that the concern expressed is related to benefit sharing. Benefit sharing requires resource users to return benefits to resource providers in order to achieve justice. One benefit sharing tool within health research is the duty to provide a health care intervention which has been proven to be beneficial (or alternative benefits) to research participants after a study has been concluded. This duty is generally known as a post-study obligation. It was enshrined in the Declaration of Helsinki in 2000 and re-emphasized in 2008. Yet, there are few, if any, examples of good practice. In this article, we analyse the obstacles to giving more bite to benefit sharing provisions in health research through ethical review. We conclude that the provision of post-study access to healthcare interventions is not a promising mechanism when monitored through research ethics committees. Alternative benefit provision is preferable if one focuses on achieving compliance. However, even the latter faces challenges, which we address in specific recommendations. PMID- 21241345 TI - Expertise, wisdom and moral philosophers: a response to Gesang. AB - In a recent issue of Bioethics, Bernard Gesang asks whether a moral philosopher possesses greater moral expertise than a non-philosopher, and his answer is a qualified yes, based not so much on his infallible access to the truth, but on the quality of his theoretically-informed moral justifications. I reject Gesang's claim that there is such a thing as moral expertise, although the moral philosopher may well make a valid contribution to the ethics committee as a concerned and educated citizen. I suggest that wisdom is a lot more interesting to examine than moral expertise. Again, however, moral philosophers have no monopoly on wisdom, and the study of philosophy may even impede its cultivation. PMID- 21241346 TI - Continuous deep sedation at the end of life and the 'natural death' hypothesis. AB - Surveys in different countries (e.g. the UK, Belgium and The Netherlands) show a marked recent increase in the incidence of continuous deep sedation at the end of life (CDS). Several hypotheses can be formulated to explain the increasing performance of this practice. In this paper we focus on what we call the 'natural death' hypothesis, i.e. the hypothesis that acceptance of CDS has spread rapidly because death after CDS can be perceived as a 'natural' death by medical practitioners, patients' relatives and patients. We attempt to show that the label 'natural' cannot be unproblematically applied to the nature of this end-of life practice. We argue that the labeling of death following CDS as 'natural' death is related to a complex set of mechanisms which facilitate the use of this practice. However, our criticism does not preclude the view that CDS may be clinically and ethically justified in many cases. PMID- 21241347 TI - Patients' perceptions of barriers for participation in nursing care. AB - BACKGROUND: In many Western countries as in Sweden, patients have legal right to participate in own care individually adjusted to each patient's wishes and abilities. There are still few empirical studies of patients' perceptions of barriers for participation. Accordingly, there is a need to identify what may prevent patients from playing an active role in own nursing care. Such knowledge is highly valuable for the nursing profession when it comes to implementation of individual patient participation. AIM AND OBJECTIVE: To explore barriers for patient participation in nursing care with a special focus on adult patients with experience of inpatient physical care. METHODOLOGICAL DESIGN AND JUSTIFICATION: Data were collected through 6 focus groups with 26 Swedish informants recruited from physical inpatient care as well as discharged patients from such a setting. A content analysis with qualitative approach of the tape-recorded interview material was made. ETHICAL ISSUES AND APPROVAL: The ethics of scientific work was adhered to. Each study participant gave informed consent after verbal and written information. The Ethics Committee of Goteborg University approved the study. RESULTS: The barriers for patient participation were identified as four categories: Facing own inability, meeting lack of empathy, meeting a paternalistic attitude and sensing structural barriers, and their 10 underlying subcategories. CONCLUSIONS: Our study contributes knowledge and understanding of patients' experiences of barriers for participation. The findings point to remaining structures and nurse attitudes that are of disadvantage for patients' participation. The findings may increase the understanding of patient participation and may serve as an incentive in practice and nursing education to meet and eliminate these barriers, in quality assurance of care, work organization and further research. PMID- 21241348 TI - Influence of oral health-related behaviours on income inequalities in oral health among adolescents. AB - OBJECTIVES: To determine income inequalities in both perceived oral health and oral health-related behaviours and the role oral health-related behaviours in explaining income inequalities in perceived oral health among Sri Lankan adolescents. METHODS: The sample included 1,218 fifteen-year-olds selected from 48 schools in the Colombo district using a stratified cluster sampling technique. Data were collected by means of questionnaires to both adolescents and their parents. Perceived oral health status was the oral health outcome considered while oral health-related behaviours included brushing frequency, use of dental services in the preceding year and consumption of sugary food/drinks and fruit/vegetables. RESULTS: Tooth brushing frequency, use of dental services in the preceding year and consumption of fruit/vegetables were associated with perceived oral health status. Also, the trends in perceived oral health and all oral health behaviours across ordered income groups were statistically significant. However, it was evident from the Poisson regression models that the effect of income on perceived oral health did not attenuate significantly following adjustment for oral health behaviours. CONCLUSIONS: This study demonstrated that oral health behaviours were associated with perceived oral health and also the existence of income gradients in perceived oral health and oral health behaviours. However, oral health behaviours were not accountable for the observed income gradients in perceived oral health. PMID- 21241349 TI - Gender-dependent associations between socioeconomic status and tooth loss in working age people in the Study of Health in Pomerania (SHIP), Germany. AB - OBJECTIVES: Individual impact and the effect magnitude of socioeconomic key indicators (income, education and occupation) and of gender on oral health are ambiguous. In primary analyses of cross-sectional data among participants of the Study of Health in Pomerania (north-east Germany), women with low school education and low income were at highest risk for missing teeth, whereas being single was a risk indicator for missing teeth in men. Using the 5-year follow-up of this study, we aimed at verifying these findings and at investigating the gender-dependent impact of key socioeconomic indicators on tooth loss. METHODS: The longitudinal data originate from 1971 subjects (1062 women) aged 25-59 enrolled from 1997 to 2001 and again from 2002 to 2006. The effects of marital status, household income, school education and occupational prestige for tooth loss were examined by gender using negative binomial regression analyses. RESULTS: Low education and low income were moderately [relative risks (RR) between 1.6 and 2.0] associated with tooth loss among both women and men, whereas occupational prestige was not. After multiple imputations of missing data, less educated women with lower income exhibited the highest risk of tooth loss [RR=3.1; 95% confidence interval (CI)=1.7-5.5 for <10 years of school education and the lowest income tertile] and tooth loss was more likely in single men (RR=1.5; 95% CI=1.0-2.2) than in single women (RR=0.9; 95% CI=0.6-1.3). CONCLUSIONS: The primary cross-sectional results were partly confirmed. Socioeconomic factors help to explain differences in tooth loss, although the causal pathways are speculative. To improve dental health, the policies should target not only the individual, e.g. oral health promotion, but also an entire population by better education and higher wage employment. PMID- 21241350 TI - Guidelines and recommendations for assessment of somatosensory function in oro facial pain conditions--a taskforce report. AB - The goals of an international taskforce on somatosensory testing established by the Special Interest Group of Oro-facial Pain (SIG-OFP) under the International Association for the Study of Pain (IASP) were to (i) review the literature concerning assessment of somatosensory function in the oro-facial region in terms of techniques and test performance, (ii) provide guidelines for comprehensive and screening examination procedures, and (iii) give recommendations for future development of somatosensory testing specifically in the oro-facial region. Numerous qualitative and quantitative psychophysical techniques have been proposed and used in the description of oro-facial somatosensory function. The selection of technique includes time considerations because the most reliable and accurate methods require multiple repetitions of stimuli. Multiple-stimulus modalities (mechanical, thermal, electrical, chemical) have been applied to study oro-facial somatosensory function. A battery of different test stimuli is needed to obtain comprehensive information about the functional integrity of the various types of afferent nerve fibres. Based on the available literature, the German Neuropathic Pain Network test battery appears suitable for the study of somatosensory function within the oro-facial area as it is based on a wide variety of both qualitative and quantitative assessments of all cutaneous somatosensory modalities. Furthermore, these protocols have been thoroughly described and tested on multiple sites including the facial skin and intra-oral mucosa. Standardisation of both comprehensive and screening examination techniques is likely to improve the diagnostic accuracy and facilitate the understanding of neural mechanisms and somatosensory changes in different oro facial pain conditions and may help to guide management. PMID- 21241351 TI - Assessment of mastication with implications for oral rehabilitation: a review. AB - During chewing, food is reduced in size, while saliva moistens the food and binds the masticated food into a bolus that can be easily swallowed. Characteristics of the oral system, like number of teeth, bite force and salivary flow, will influence the masticatory process. Masticatory function of healthy persons has been studied extensively the last decades. These results were used as a comparison for outcomes of various patient groups. In this review, findings from literature on masticatory function for both healthy persons and patient groups are presented. Masticatory function of patients with compromised dentition appeared to be significantly reduced when compared with the function of healthy controls. The influence of oral rehabilitation, e.g. dental restorations, implant treatment and temporomandibular disorder treatment, on masticatory function will be discussed. For instance, implant treatment was shown to have a significant positive effect on both bite force and masticatory performance. Also, patient satisfaction with an implant-retained prosthesis was high in comparison with the situation before implant treatment. The article also reviews the neuromuscular control of chewing. The jaw muscle activity needed to break solid food is largely reflexly induced. Immediate muscle response is necessary to maintain a constant chewing rhythm under varying food resistance conditions. Finally, the influence of food characteristics on the masticatory process is discussed. Dry and hard products require more chewing cycles before swallowing than moist and soft foods. More time is needed to break the food and to add enough saliva to form a cohesive bolus suitable for swallowing. PMID- 21241352 TI - A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects. AB - WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: * Therapy with topical non-steroidal anti-inflammatory drugs (NSAIDs) relies on the ability of the active drug to penetrate the skin in sufficiently high amounts to exert a clinical effect, which is linked to the specific galenic properties of the formulation. WHAT THIS STUDY ADDS: * This phase 1 study characterizes the transdermal penetration and plasma exposure of different dose levels with galenic differences of a novel topical diclofenac formulation under development and indicates greater diclofenac penetration through the skin when compared with a commercially available formulation. AIMS: To evaluate the relative plasma and tissue availability of diclofenac after repeated topical administration of a novel diclofenac acid-based delivery system under development (DCF100C). METHODS: This was a single-centre, open-label, three-period, crossover clinical trial of five discrete diclofenac formulations. Test preparations comprised two concentrations (1.0% and 2.5%) of DCF100C, with and without menthol and eucalyptus oil (total daily doses of 5 mg and 12.5 mg). Voltaren Emulgel gel (1.0%) was the commercially available comparator (total daily dose of 40 mg). Topical application was performed onto the thigh of 20 male healthy subjects for 3 days. Applying a Youden square design, each drug was evaluated in 12 subjects, with each subject receiving three test preparations. Blood sampling and in vivo microdialysis in subcutaneous adipose and skeletal muscle tissues were performed for 10 h after additional final doses on the morning of day 4. RESULTS: All four DCF100C formulations demonstrated a three- to fivefold, dose-dependent increase in systemic diclofenac availability compared with Voltaren Emulgel and were approximately 30-40 times more effective at facilitating diclofenac penetration through the skin, taking different dose levels into account. Tissue concentrations were low and highly variable. The 2.5% DCF100C formulation without sensory excipients reached the highest tissue concentrations. AUC(0,10 h) was 2.71 times greater than for Voltaren Emulgel (90% CI 99.27, 737.46%). Mild erythema at the application site was the most frequent adverse event associated with DCF100C. There were no local symptoms after treatment with the reference formulation. CONCLUSION: DCF100C formulations were safe and facilitated greater diclofenac penetration through the skin compared with the commercial comparator. DCF100C represents a promising alternative to oral and topical diclofenac treatments that warrants further development. PMID- 21241353 TI - Prescribing of medicines in the Danish paediatric population outwith the licensed age group: characteristics of adverse drug reactions. AB - AIM: To identify adverse drug reactions (ADRs) associated with off-label prescribing of medicines in a paediatric population. METHODS: We analysed spontaneous ADR reports for children from ages 0 to 17 years submitted to the Danish national ADR database from 1998 to 2007. We defined off-label prescribing as prescriptions outside the licensed age group. Off-label ADRs were categorized by therapeutic group, age of child, type and severity. The unit of analysis was one ADR. RESULTS: We analysed 4388 ADRs for children reported in the national database. Approximately 17% of reported ADRs were associated with off-label use, 60% of them serious. More than one half of off-label ADRs were reported in adolescents. Serious ADRs due to off-label prescribing are more likely to be reported for hormonal contraceptives (ATC group G), anti-acne preparations (ATC group D) and allergens (ATC group V). CONCLUSION: One-fifth of all ADRs reported over a decade in Danish children was associated with off-label prescribing, and serious ADRs due to off-label prescribing were primarily present in three therapeutic groups: sex hormones, dermatologicals and allergens. There is a need for more research into the prescribing of these medicines in the teenage population, as well as tighter reporting and monitoring of ADRs for medicines prescribed off-label in the paediatric population. PMID- 21241355 TI - Quality of life in people with venous leg ulcers: an integrative review. AB - OBJECTIVE: To explore the impact of venous leg ulcers on health-related quality of life and analyse the quality of life instruments that have been used for this topic. BACKGROUND: Venous leg ulcers represent more than 80% of all chronic leg ulcers. Several studies have demonstrated that health-related quality of life is affected in patients with such lesions. METHOD: An integrative review was conducted, together with an additional methodological review of quality of life instruments. Eight electronic databases were searched, and all studies published between 2003 and 2008 were considered in with both qualitative and quantitative approaches and in Spanish, English, French, German and Portuguese. Thus, no restrictions were applied as regards study design. RESULTS: Twenty-two studies were included; one used mixed methods, three employed qualitative methods and the remaining articles used a quantitative approach. Pain was the factor most frequently identified as affecting health-related quality of life. The generic instruments most commonly used were Short Form-36 and adaptations, the Nottingham Health Profile and EuroQol-5, whilst the disease-specific tools were Hyland, Cardiff Wound Impact Schedule and Charing Cross Venous Leg Ulcer Questionnaire. Two new instruments were also identified, venous leg ulcer quality of life and Sheffield Preference-based Venous Leg Ulcer 5D. CONCLUSIONS: The negative impact of venous leg ulcers on health-related quality of life is confirmed in this review. This impact has been measured using a variety of specific health-related quality of life instruments. However, the review findings suggest that the Charing Cross Venous Leg Ulcer Questionnaire is the most appropriate instrument due to its disease-specific psychometric characteristics. PMID- 21241354 TI - Direct thrombin inhibitors. AB - Heparins and vitamin K antagonists have been the primary agents used for anticoagulation in certain cardiovascular and thromboembolic diseases for over 50 years. However, they can be difficult to administer and are fraught with limitations. In response to the need for new anticoagulants, direct thrombin inhibitors (DTIs) have been developed and investigated for their utility in prophylaxis and treatment of venous thromboembolism (VTE), heparin-induced thrombocytopenia (HIT), acute coronary syndromes (ACS), secondary prevention of coronary events after ACS, and nonvalvular atrial fibrillation. Currently, four parenteral direct inhibitors of thrombin activity are FDA-approved in North America: lepirudin, desirudin, bivalirudin and argatroban. Of the new oral DTIs, dabigatran etexilate is the most studied and promising of these agents. This review discusses the clinical indications and efficacy of these direct thrombin inhibitors as well as future directions in anticoagulant therapy. PMID- 21241356 TI - prhKLM genes of Ralstonia solanacearum encode novel activators of hrp regulon and are required for pathogenesis in tomato. AB - The genes in the hrp regulon encode the proteins composing type III secretion system in Ralstonia solanacearum. The hrp regulon is positively controlled by HrpB, and hrpB expression is activated by both HrpG and PrhG. We have identified three genes, prhK, prhL, and prhM, which positively control the hrp regulon in strain OE1-1. These genes are likely to form an operon, and this operon is well conserved in the genera Ralstonia and Burkholderia. This indicates that the operon is not specific to the plant pathogens. Mutations in each of these three genes abolished hrpB and prhG expression. prhK, prhL, and prhM mutant strains lost pathogenicity toward tomato completely, and they were less virulent toward tobacco. PrhK and PrhL share sequence similarity with allophanate hydrolase and PrhM with LamB. This suggests that the three gene products are not transcriptional regulators in the strict sense, but regulate hrp regulon indirectly. This novel class of virulence-related genes will mark the beginning of new findings regarding the overall infection mode of R. solanacearum. PMID- 21241357 TI - Alkali-metal-cation influx and efflux systems in nonconventional yeast species. AB - To maintain optimal intracellular concentrations of alkali-metal-cations, yeast cells use a series of influx and efflux systems. Nonconventional yeast species have at least three different types of efficient transporters that ensure potassium uptake and accumulation in cells. Most of them have Trk uniporters and Hak K(+)-H(+) symporters and a few yeast species also have the rare K(+) (Na(+)) uptake ATPase Acu. To eliminate surplus potassium or toxic sodium cations, various yeast species use highly conserved Nha Na(+) (K(+))/H(+) antiporters and Na(+) (K(+))-efflux Ena ATPases. The potassium-specific yeast Tok1 channel is also highly conserved among various yeast species and its activity is important for the regulation of plasma membrane potential. PMID- 21241358 TI - Environmental mutagens may be implicated in the emergence of drug-resistant microorganisms. AB - The emergence of drug-resistant microorganisms is an important medical and social problem. Drug-resistant microorganisms are thought to grow selectively in the presence of antibiotics. Most clinically isolated drug-resistant microorganisms have mutations in the target genes for the drugs. While any of the many mutagens in the environment may cause such genetic mutations, no reports have yet described whether these mutagens can confer drug resistance to clinically important microorganisms. We investigated how environmental mutagens might be implicated in acquired resistance to antibiotics in clinically important microorganisms, which causes human diseases. We selected mutagens found in the environment, in cigarette smoke, or in drugs, and then exposed Pseudomonas aeruginosa to them. After exposure, the incidence of rifampicin- and ciprofloxacin-resistant P. aeruginosa strains markedly increased, and we found mutations in genes for the antibiotic-target molecule. These mutations were similar to those found in drug-resistant microorganisms isolated from clinical samples. Our findings show that environmental mutagens, and an anticancer drug, are capable of inducing drug-resistant P. aeruginosa similar to strains found in clinical settings. PMID- 21241359 TI - Biochemical properties of Candida parapsilosis ecto-5'-nucleotidase and the possible role of adenosine in macrophage interaction. AB - Candida parapsilosis is considered to be an emerging fungal pathogen because it is associated with an increasing range of infections. In this work, we biochemically characterized ecto-5'-nucleotidase activity on the surface of living, intact C. parapsilosis cells. At a pH of 4.5, intact cells were able to hydrolyze 5'-AMP at a rate of 52.44 +/- 7.01 nmol Pi h(-1) 10(-7) cells. 5'-AMP, 5'-IMP and 5'-UMP were hydrolyzed at similar rates, whereas 5'-GMP and 5'-CMP hydrolyzed at lower rates. Enzyme activity was increased by about 42% with addition of Mg(2+) or Ca(2+), and the optimum pH was in the acidic range. An inhibitor of phosphatase activities, sodium orthovanadate, showed no effect on AMP hydrolysis; however, as expected, ammonium molybdate, a classical nucleotidase inhibitor, inhibited the activity in a dose-dependent manner. The results indicated that the existence of an ecto-5'-nucleotidase could play a role in the control of extracellular nucleotide concentrations. PMID- 21241360 TI - SopB effector protein of Salmonella Typhimurium is translocated in mesenteric lymph nodes during murine salmonellosis. AB - Salmonella Typhimurium harbors two Salmonella pathogenicity islands (SPIs), each encoding a type three secretion system for virulence proteins. Although there is increasing evidence of postinvasion roles for SPI-1, it has been generally accepted that SPI-1 genes are downregulated following the invasion process. Here, we analyzed the expression and translocation of SopB in vitro, in cell culture and in vivo. To this end, a sopB-FLAG-tagged strain of Salmonella Typhimurium was obtained by epitope tagging. Tagged proteins were detected by sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunoblotting with anti-FLAG antibodies. SopB expression was observed in vitro under cultured conditions that mimic the intestinal niche and different intracellular environments. In agreement, bacteria isolated from infected monolayers expressed and translocated SopB for at least 24 h postinoculation. For in vivo experiments, BALB/c mice were inoculated intraperitoneally with the tagged strain of Salmonella Typhimurium. Infecting bacteria and infected cells were recovered from mesenteric lymph nodes. Our results showed that SopB continues to be synthesized in vivo during 5 days after inoculation. Interestingly, translocation of SopB was detected in the cytosol of cells isolated from lymph nodes 1 day after infection. Altogether, these findings indicate that the expression and translocation of SopB during Salmonella infection is not constrained to the initial host-bacteria encounter in the intestinal environment as defined previously. PMID- 21241361 TI - Characterization of a functional toxin-antitoxin module in the genome of the fish pathogen Piscirickettsia salmonis. AB - This is the first report of a functional toxin-antitoxin (TA) locus in Piscirickettsia salmonis. The P. salmonis TA operon (ps-Tox-Antox) is an autonomous genetic unit containing two genes, a regulatory promoter site and an overlapping putative operator region. The ORFs consist of a toxic ps-Tox gene (P. salmonis toxin) and its upstream partner ps-Antox (P. salmonis antitoxin). The regulatory promoter site contains two inverted repeat motifs between the -10 and 35 regions, which may represent an overlapping operator site, known to mediate transcriptional auto-repression in most TA complexes. The Ps-Tox protein contains a PIN domain, normally found in prokaryote TA operons, especially those of the VapBC and ChpK families. The expression in Escherichia coli of the ps-Tox gene results in growth inhibition of the bacterial host confirming its toxicity, which is neutralized by coexpression of the ps-Antox gene. Additionally, ps-Tox is an endoribonuclease whose activity is inhibited by the antitoxin. The bioinformatic modelling of the two putative novel proteins from P. salmonis matches with their predicted functional activity and confirms that the active site of the Ps-Tox PIN domain is conserved. PMID- 21241362 TI - Antiplatelet drugs in the elderly: prescriptions often inappropriate and reduced tolerance by associated diseases and drugs. AB - To assess the conditions of prescriptions and tolerance of antiplatelet drugs (APD) in the elderly and to detail the parameters that influence the tolerance of these drugs. Prospective survey in a Department of Geriatric Medicine. Two hundred nineteen patients 70 years and older treated with one or two APD prior to admission were included during 7 months in 2008. We recorded the type of APD, associated diseases, main associated or co-prescribed drugs which could interact with APD and the bleeding adverse events including cutaneous bleeding. The mean age of the 219 patients was 84.5 +/- 6.7 years (70-101 years), women 59.4%. Among patients 64.8% received aspirin (mainly 75 mg), 28.3% received clopidogrel and 6.8% received their combination; 16.9% of prescriptions were off-label; 51.6% of patients had an associated disease and/or an associated drug which could have increased risk of bleeding event. Among the patients who received a gastric protective drug, the prescription followed the recommendations of the French Health Authority in 38.9%. We recorded bleeding events in 24.2% of patients at admission and in 18.3% of patients during the hospitalization. Bleeding events were significantly more frequent in patients treated with aspirin than clopidogrel (40.8 vs. 24.2%, P < 0.05) and/or with an associated drug (OR = 2.36, 95% CI 1.34-4.14, P < 0.01) and/or an associated disease (OR = 1.22, 95% CI 1.01 3.42, P < 0.05). APD treatment was stopped in 28.8% of patients, mainly because lack of indication or bleeding adverse events. Off-label prescriptions of APD were not rare in the elderly, and adverse events are frequent. The results of this preliminary study evoke that medical situations at increased risk of bleeding are perhaps insufficiently evaluated, either in case of prescription of associated drugs with increased bleeding risk or during the follow-up of patients with associated diseases. Cutaneous bleeding events should be more taken into account in prospective studies. PMID- 21241363 TI - I(Kr) vs. I(Ks) blockade and arrhythmogenicity in normoxic rabbit Purkinje fibers: does it really make a difference? AB - The electrophysiological (standard intracellular microelectrode technique) and pro-arrhythmic (occurrence of early after-depolarization) effects of five class III agents acting on delayed rectifier current (I(K)), rapid (I(Kr)), and/or slow (I(Ks)) components have been studied in rabbit Purkinje fibers taken near the septum and submitted in vitro to reduced stimulation rate (from 1 to 0.5 Hz) in the absence or presence of epinephrine (10 nm) during normoxic conditions. There were two I(Kr) blockers (d-sotalol and dofetilide), two I(Ks) blockers (chromanol 293B and HMR 1556), and a non-selective I(K) blocker (azimilide). d-sotalol, dofetilide, and azimilide lengthened APD(60) and APD(90) in a concentration dependent manner. Both d-sotalol and dofetilide showed pro-arrhythmia at highest concentrations and in the presence of epinephrine and lower stimulation rate. Despite azimilide markedly lengthened APD(90), it was globally less pro arrhythmic than dofetilide. Thus, in normoxic rabbit Purkinje fibers, I(Kr) blockade prolonged action potential duration (APD) and increased the incidence of early after-depolarizations, particularly so in the presence of adrenergic stimulation and bradycardia, I(Ks) blockade did neither, and non-selective I(K) blockade (by azimilide) behaved principally as I(Kr) blockade. It is concluded that in normoxic rabbit Purkinje fibers, I(Ks) blockade was neutral, whereas I(Kr) blockade was pro-arrhythmic, which may make a difference worth exploration in more complex models. PMID- 21241365 TI - Expression of selected genes escaping from X inactivation in the 41, XX(Y)* mouse model for Klinefelter's syndrome. AB - AIM: We hypothesized that patients with Klinefelter's syndrome (KS) not only undergo X inactivation, but also that genes escape from inactivation. Their transcripts would constitute a significant difference, as male metabolism is not adapted to a 'female-like' gene dosage. We evaluated the expression of selected X linked genes in our 41, XX(Y)* male mice to determine whether these genes escape inactivation and whether tissue-specific differences occur. METHODS: Correct X inactivation was identified by Xist expression. Relative expression of X-linked genes was examined in liver, kidney and brain tissue by real-time PCR in adult XX(Y)* and XY* males and XX females. RESULTS: Expression of genes known to escape X inactivation was analysed. Relative mRNA levels of Pgk1 (control, X inactivated), and the genes Eif2s3x, Kdm5c, Ddx3x and Kdm6a escaping from X inactivation were quantified from liver, kidney and brain. Pgk1 mRNA expression showed no difference, confirming correct X inactivation. In kidney and liver, XX(Y)* males resembled the female expression pattern in all four candidate genes and were distinguishable from XY* males. Contrastingly, in brain tissue XX(Y)* males expressed all four genes higher than male and female controls. CONCLUSION: Altered expression of genes escaping X inactivation probably contributes directly to the XX(Y)* phenotype. PMID- 21241364 TI - Predictors of the risk of cognitive deficiency in very preterm infants: the EPIPAGE prospective cohort. AB - AIM: To assess cerebral lesions and other medical as well as social characteristics as predictors of risk of mild and severe cognitive deficiencies in very preterm infants. METHODS: As part of the EPIPAGE population-based prospective cohort study, perinatal data and cognitive outcome at 5 years of age were recorded for 1503 infants born before 33 weeks of gestation in nine regions of France in 1997. Mild cognitive deficiency was defined as a Mental Processing Composite score on the Kaufman Assessment Battery for Children test of between 70 and 84, and severe cognitive deficiency as a score of <70. RESULTS: After controlling for cerebral lesions and other medical as well as social factors, low parental socio-economic status and lack of breastfeeding were significant predictors of mild and severe cognitive deficiencies, whereas presence of cerebral lesions, being small for gestational age and having a large number of siblings were predictors of severe cognitive deficiency. CONCLUSION: Predictors of poor cognitive outcome in very preterm infants are low social status, lack of breastfeeding, presence of cerebral lesions on ultrasound scan, being born small for gestational age and having a high number of siblings. Social factors predicted both mild and severe cognitive deficiencies, whereas medical factors predicted mostly severe cognitive deficiencies. PMID- 21241366 TI - Breast cancer risk among patients with Klinefelter syndrome. AB - AIM: To evaluate male breast cancer (MBC) risk among patients with Klinefelter syndrome (KS) and relate this to possible biological explanations. METHODS: A literature review was conducted to identify case series and epidemiologic studies that have evaluated MBC risk among patients with KS. RESULTS: Case reports without expected values have often led to false impressions of risk. Problems include that a diagnosis of cancer can prompt a karyotypic evaluation and that many cases of KS are unrecognized, resulting in incomplete denominators. Few carefully conducted epidemiologic studies have been undertaken given that both KS and MBC are rare events. The largest study found 19.2- and 57.8-fold increases in incidence and mortality, respectively, with particularly high risks among 47,XXY mosaics. These risks were still approximately 70% lower than among females, contradicting case reports that patients with KS have breast cancer rates similar to females. Altered hormone levels (especially the ratio of oestrogens to androgens), administration of exogenous androgens, gynaecomastia and genetic factors have been offered as possible explanations for the high risks. CONCLUSIONS: Additional well-designed epidemiologic studies are needed to clarify which patients with KS are at a high risk of developing MBC and to distinguish between possible predisposing factors, including altered endogenous hormones. PMID- 21241367 TI - Modelling collagen fibre orientation in porcine skin based upon confocal laser scanning microscopy. AB - BACKGROUND: The mechanical properties of skin, and its ability to resist a wide range of deformations, are mainly determined by the collagen network within the dermis. AIMS: In order to quantify the structure-function relationship of skin, quantitative data on collagen orientation are acquired in this study. MATERIALS & METHODS: Saggital cryosections from the abdominal region of young pigs were stained with picrosirus red for collagen detection and images were acquired by confocal laser scanning microscopy (CLSM). Spatial distributions of collagen orientation were determined using a structure-tensor approach. Orientation data were fitted to a mixture of two von Mises distributions. RESULTS: It was observed that collagen is organised into large bundles in the reticular dermis that run obliquely between the epidermis to hypodermis along two predominant orientations. DISCUSSION: This distinct lattice structure was apparent in all sections, regardless of the sectioning orientation. Based on our observations from CLSM images,we propose a conceptual model expressed in terms of a density distribution function to describe collagen orientation. CONCLUSION: We demonstrate that two parameters of this distribution (the mean and spread parameter) may be directly determined using CLSM image analysis. An important advantage of this approach is that model parameters can be estimated directly from observable microstructural features. PMID- 21241368 TI - Intradermal tacrolimus prevent scar hypertrophy in a rabbit ear model: a clinical, histological and spectroscopical analysis. AB - BACKGROUND: Keloids and hypertrophic scars (HSc) affect 4.5-16% of the population. Thus far, the different approaches of keloid treatment are not very efficient, with a 50% relapse rate and many ongoing researches are looking for simple, safe and more efficient therapeutic methods. Tacrolimus is an immunomodulator that could be useful in treating keloid. OBJECTIVES: The objective of this study is to evaluate the effectiveness of Tacrolimus in inhibiting HSc formation on rabbits' ears model and to check optical skin spectroscopy in tissue characterization. METHODS: Our study was carried out on 20 New-Zealand female white rabbits. HSc were obtained by wounding rabbits' ear. These wounds were treated with intradermal injections of tacrolimus (0.2-0.5 mg/cm(2)) or a vehicule. The assessment of treatment efficacy was performed by clinical examinations, histological assay and skin spectrometry. RESULTS: Tacrolimus did not induce general or local side-effects. The scar elevation index in treated subjects was half less than that of the untreated ones. Furthermore, dermal thickness and inflammatory cellular density were both significantly smaller for treated scars than for the control ones. In vivo optical skin spectroscopy can characterize hypertrophic and normal skin with high sensibility and specificity. CONCLUSION: Intradermal injection of tacrolimus at 0.5 mg/cm(2) is an efficient way to prevent HSc in our experiment model and its tolerance is correct. Optical spectroscopy could be a good non-invasive tool to evaluate HSc treatment. These promising results might be proposed for patients suffering from keloid. PMID- 21241369 TI - Hair shaft abnormalities in alopecia areata evaluated by optical coherence tomography. AB - BACKGROUND/PURPOSE: Optical coherence tomography (OCT) is able to provide highly reproducible measurements of hair shaft thickness, including hair shaft diameter, cross-sectional surface area and hair shape, similar to histology but in vivo. Variations in the caliber of hair shafts have been described in patchy hair loss like alopecia areata (AA) using electron microscopy. The aim of this study was to evaluate whether OCT is useful for the evaluation of hair shaft abnormalities in AA. METHODS: The measurements were performed on patients with AA (n=9), aged 2-66 years. Fifty hairs from the border of an alopecic area and 50 hairs from an unaffected area without hair loss were examined using the OCT technique. The hair parameters were characterized by the cross-section (CS) and the form factor. The ratio of the maximal and minimal diameters of the hair at a fixed measuring distance from the scalp surface determined the form factor (d(max)/d(min)). RESULTS: In all cases, the CS of hairs from an AA patch was significantly lower compared with hairs of an unaffected area. However, the form factor did not indicate any disturbances in hair growth. CONCLUSIONS: The results demonstrate that structural abnormalities of hair shafts are found in active lesions of AA, but not in clinically unaffected hairs. The OCT technique is a promising method to gain more insight into the pathogenesis of AA in a non-invasive way. PMID- 21241370 TI - A modified in vitro stripping method to automate the calculation of geometry of corneocytes imaged with fluorescent microscopy: example of moisturizer treatment. AB - BACKGROUND/PURPOSE: To develop a modification of the stripping method allowing quick automated processing of corneocyte samples to study human skin conditions. Although the previous scrubbing technique and stripping method can provide sufficient information about human corneocytes, they are either subject to artifacts or involve time-consuming data processing. METHODS AND MATERIALS: In the first stage, an adhesive tape is used to collect corneocytes as in the regular stripping method. Then, a D-squame skin indicator is used to divide the collected corneocytes into a lesser populated sample, in which more individual corneocytes can be observed with the help of fluorescent microscopy after dye staining. The method was applied to study the change of corneocytes after moisturizer (glycerin) treatment. RESULTS: The modified stripping method described allows the automated processing of the geometrical characteristics of corneocytes. Data for several hundreds of corneocytes can easily be collected. The analysis of glycerin treatment demonstrated a high sensitivity for the method. An average increase of the corneocyte area of 5.1% was found after 9 days of treatment (the accuracy of the method was 0.5%). CONCLUSION: The method described is suitable for the automated data processing. It allows for the reliable detection of the expansion of the average area of corneocytes after 9 days of daily glycerin treatment. PMID- 21241372 TI - Factors related to pain during routine photodynamic therapy: a descriptive study of 301 patients. AB - BACKGROUND: Pain may be a limiting factor in the use of photodynamic therapy (PDT). The consequences of the pain i.e. the resources spent on pain-intervention during routine PDT therapy are poorly described. OBJECTIVES: To describe the consequences of pain during PDT by describing the use of pain-reducing interventions in routine use. We studied the frequency as well as level of pain reducing intervention. METHODS: Descriptive data from PDT treated patients. The level of pain-reducing intervention was graded 0, no intervention; +, cold water spray and ++, pause or nerve block. RESULTS: Data from 983 PDT treatments on 579 lesions distributed on 301 patients: 56% did not require pain-reducing intervention, 35% required spraying of cold water, while 9% required pause or nerve block. Ordinate logistic regression revealed an association between lesion size and pain-reducing intervention: the larger the lesion, the more frequent the intervention. Lesion size did not, however, appear associated with the level of intervention. Intervention was most frequently required when treating the scalp/forehead and the extremities. The scalp/forehead also required the highest level of intervention. No significant association between pain-reducing intervention and diagnosis, pre-treatment, gender or age was found. CONCLUSIONS: Pain-reducing intervention was required in 44% of the PDT treatments. Intervention was particularly required when treating lesions in areas suited for PDT therapy for cosmetic reasons such as the scalp/forehead or extremities. Treatment of large areas more frequently calls for pain intervention than treatment of small areas. PMID- 21241371 TI - Effective continuous systemic therapy of severe plaque-type psoriasis is accompanied by amelioration of biomarkers of cardiovascular risk: results of a prospective longitudinal observational study. AB - BACKGROUND: Severe psoriasis is associated with significant cardiovascular mortality. OBJECTIVES: We investigated the effects of continuous systemic therapy on the cardiovascular risk of patients with severe plaque-type psoriasis. METHODS: A total of 42 consecutive patients receiving systemic treatment for their severe plaque-type psoriasis were included. The clinical course was monitored over 24 weeks. Initially as well as after 12 and 24 weeks, oral glucose tolerance tests were performed along with comprehensive laboratory monitoring. RESULTS: Responding patients, defined as a Psoriasis Area and Severity Index (PASI)-50 response, showed correlations between the PASI and high-sensitive C reactive protein (r = 0.45, P = 0.03) as well as with vascular endothelial growth factor (r = 0.76, P = 0.007). The adipokine resistin was positively and the potentially cardio-protective adiponectin was negatively correlated with the PASI (r = 0.50, P = 0.02 and r = -0.56, P = 0.007, respectively). Oral glucose tolerance tests yielded a correlation between the PASI and plasma levels for C peptide (r = 0.73, P = 0.02) at t = 120 min in patients with a pathological Homeostasis Model Assessment (>2.5), indicating that the state of peripheral insulin resistance is driven at least in part by the severity of the psoriatic inflammation. Correlations between the change of adipokine levels and change in PASI were more pronounced among patients with better clinical improvement (PASI 75 vs. PASI-50). CONCLUSIONS: We document an amelioration of biomarkers of cardiovascular risk in patients with severe plaque-type psoriasis responding to continuous systemic therapy. The impact on the patients'metabolic state was found to be better if the psoriatic inflammation was controlled for longer. Future studies need to compare the cardioprotective effects of different treatment modalities, based on hard clinical endpoints. PMID- 21241373 TI - Psoriasis: is it the tip of the iceberg for the quality of life of patients and their families? AB - OBJECTIVE: To evaluate the impact of psoriasis on patients' and their relatives' quality of life (QoL). METHODS: Eighty patients with their accompanying family members were included in the study. For measuring health related QoL (HRQoL) of patients with psoriasis, two questionnaires were used: Short Form 36 Health Survey (SF-36) and EuroQol (EQ-5D). Disease-specific HRQoL was assessed by the Dermatology Life Quality Index. For measuring the quality of life of patients' relatives, a specific questionnaire for dermatological diseases was used (Family Dermatology Life Quality Index, FDLQI). RESULTS: Of our patients, 88.3% reported that their disease affects in many and different ways their QoL whereas only 11.2% reported that psoriasis does not influence at all their life. Regarding FDLQI, 90% of the participating family members, responded that their relative's psoriasis affected their own QoL. CONCLUSIONS: Psoriasis is a chronic disease that affects in a cumulative way the quality of life of both patients and their close relatives. PMID- 21241374 TI - Insulin-like growth factor-1 in psoriatic plaques treated with PUVA and methotrexate. AB - BACKGROUND: The pathogenesis of psoriasis is thought to depend on the activation of immune cells and their secreted cytokines, chemokines and growth factors like IGF-1 which may contribute to the epidermal hyperplasia of psoriasis. Treatment of psoriasis with PUVA and methotrexate are associated with clinical improvement and decrease in epidermal hyperplasia. OBJECTIVE: To examine the effects of PUVA and methotrexate therapy on IGF-1 expression in psoriatic plaques and whether this change correlates with clinical response. METHODS: For 24 psoriatic patients, the PASI score and levels of lesional IGF-1 and its mRNA were determined by RT-PCR before and after treatment with either methotrexate or PUVA. Skin biopsies from 12 healthy volunteers served as control for IGF-1 levels in normal skin. RESULTS: Lesional skin of psoriatic patients showed a statistically significant elevation in IGF-1 and its mRNA levels in comparison to control (P = 0.0001). Both methotrexate and PUVA treatment were associated with a significant decrease in both PASI scores and lesional IGF-1 after 10 month treatment. CONCLUSION: Both methotrexate and PUVA therapy for psoriasis are associated with a decrease in PASI score and IGF-1. The IGF-1 down-regulation may possibly be a consequence of the decrease in cytokines and inflammatory cellular infiltrate that occur following treatment with either modalities or due to their effect on local fibroblast activity and proliferation. PMID- 21241375 TI - Evaluation of sensitive scalp severity and symptomatology by using a new score. AB - BACKGROUND: Among localizations of sensitive skin, scalp is one of the less known. OBJECTIVES: We performed a study for a better understanding of sensitive scalp and proposed a new score: the 3S score. METHODS: An opinion poll was conducted on 2117 persons, which were representative of the French population. The total score was obtained by multiplying score severity of abnormal sensations by the number of these sensations. RESULTS: About one-third of the population declared to suffer from a sensitive scalp. It was increasingly frequent with age. The 3S questionnaire allowed discrimination among subjects with slightly sensitive, sensitive and very sensitive scalps. Itching and prickling were the most frequent symptoms. Sensitive scalp was sometimes associated with some scalp diseases. Dandruff cannot be considered as a symptom of sensitive scalp. CONCLUSIONS: This study is only the third reported study about sensitive scalp. The 3S questionnaire is a convenient and effective tool for investigating the severity and symptomatology of the sensitive scalp. PMID- 21241376 TI - Comparisons of clinical features of HLA-DRB1*07 positive and negative vitiligo patients in Chinese Han population. AB - BACKGROUND: Human leucocyte antigen (HLA)-II alleles have been found to be associated with vitiligo in different populations, and several studies also suggested that HLA class II alleles/haplotypes were associated with a different type vitiligo. Of HLA class II alleles, DRB1*07 has consistently shown a positive association with vitiligo in Chinese Han population. OBJECTIVE: To further explore the relationship between DRB1*07 and vitiligo and to evaluate the DRB1*07 effect on the clinical features of vitiligo in Chinese Han population. METHODS: This study investigated DRB1*07 allele distribution in 1178 unrelated Chinese vitiligo patients and 1743 healthy controls using polymerase chain reaction/sequence specific primer method and observed clinical differences between DRB1*07 positive and DRB1*07 negative patients. RESULTS: The analysis of the 1178 cases and 1743 controls revealed a highly association between DRB1*07 allele and vitiligo [odds ratio (OR) = 1.97, P = 2.13 * 10(-17) ]. DRB1*07 positive patients had early disease onset (OR = 1.49, P = 0.001), higher frequency of family history (OR = 1.44, P = 0.006) compared with DRB1*07 negative patients. CONCLUSIONS: The DRB1*07 showed significant association with vitiligo in the study population. This study confirmed that DRB1*07 positive patients had some obvious clinical differences from DRB1*07 negative patients in the Chinese Han population. PMID- 21241377 TI - Serum levels of acute phase proteins: SAA, Hp and progesterone (P4) in mares with early embryonic death. AB - The study involved 46 healthy purebred Arabian mares exhibiting regular oestrous cycles that underwent artificial insemination (AI). Pregnancy was detected ultrasonographically (US) in 40 mares. In 15 mares in foal, early embryonic death (EED) was observed during the pregnancy days 14-21. Blood for determinations of serum acute phase proteins (SAA and Hp) and progesterone (P4) was sampled 12-24 h before ovulation and the first insemination, at 12, 24, 72, 96 h and on day 7, 10, 14, 21, 35 and 55 after ovulation. The results revealed that in 25 mares without EED, the serum levels of P4, SAA and Hp were within physiological limits; in 15 mares with EED, the levels of SAA and Hp were significantly increased. In seven mares with EED, high levels of SAA and Hp were already found before ovulation and at 12, 24, 72, 96 h as well as on day 7 and 10 post-ovulation, whereas the level of P4 was normal for early pregnancy. In the remaining eight mares with EED, increased levels of SAA and Hp were found at 72 h after ovulation and maintained until day 55. In this group, the level of P4 decreased since 96 h after ovulation. Determinations of SAA, Hp and P4 in mares in early pregnancy (EP) are useful for monitoring normal development of pregnancy and for diagnosis of subclinical genital inflammations, which may lead to EED. PMID- 21241378 TI - The expression of interferon-stimulated gene 15 in equine endometrium. AB - Establishment of pregnancy is critically dependent upon a precisely orchestrated embryo-maternal interaction leading to a receptive uterine environment. The up regulation of the interferon-stimulated protein 15 kDa (ISG15) during pregnancy has been described in various species and has been hypothesized to be part of the molecular repertoire that makes the uterus receptive to conceptus development. In the current study, the expression of ISG15 and enzymes involved in ISG15ylation was examined at the mRNA and protein level in equine endometrium at Day 14 of the luteal phase and at Day 14 and 50 of pregnancy. ISG15 mRNA showed a 2.63-fold higher expression at Day 14 of pregnancy when compared to Day 14 of the cycle, while mRNA abundance at Day 50 of pregnancy was unchanged compared to Day 14 of the cycle. Upon Western blot analysis using anti-ISG15 antibody, several higher molecular weight bands could be observed, representing proteins conjugated to ISG15. No free ISG15 could be detected. The pattern of ISG15 reactive proteins differed from those observed in non-uterine samples. Upon immunohistochemistry, ISG15 reactive proteins located primarily to luminal and glandular epithelial cells, while stromal cells showed weaker staining. In conclusion, the expression of ISG15-conjugated proteins in equine endometrium did not differ between cyclic and pregnant 14 days after ovulation and Day 50 of pregnancy. It is hypothesized that the unique subset of ISG15ylated proteins expressed in endometrial tissue contributes to normal cellular function and that, unlike other species, the modification of ISG15-conjugated proteins is not an active contributor to conceptus-maternal interaction in the mare. PMID- 21241379 TI - Progesterone and insulin-like growth factor I levels in blood of Boer goats during puerperium out-of-season in a mild climate region. AB - The aims of this study were to compare insulin-like growth factor-I (IGF-I) and progesterone concentrations as indicators of cycle activity in the blood of Boer goats during puerperium out-of-season in mild climate conditions and to investigate the influence of parity and litter size on the concentration of IGF-I and progesterone in serum during the study period. Twenty Boer (8 primiparous and 12 pluriparous) goats were examined in this study. Blood samples were taken every 4 days starting on the 3rd day and up to the 40th day of puerperium. IGF-I and progesterone (P4) blood levels were determined using radio immune assay (RIA). Results indicated cyclic ovarian activity outside the breeding season in 18 of 20 Boer goats. IGF-I levels in blood sera followed oestrus and cyclic ovarian activity. IGF-I concentrations correlated significantly with P4 concentrations. The IGF-I peak preceded the P4 peak by approximately 8 days in cycling goats. IGF I and P4 blood levels were not influenced by parity or litter size. Changes in blood serum P4 and IGF-I concentrations levels during puerperal period can assist in the evaluation of reproductive status of goats. PMID- 21241380 TI - Impact of ovarian and uterine conditions on some diagnostic tests output of endometritis in postpartum high-yielding dairy cows. AB - The effect of ovarian predominating structures and uterine condition on the result of some diagnostic tools for the evaluation of endometritis was studied in postpartum (pp) Holstein-Friesian dairy cows (n = 58). Endometrial cytology (EC) and the evaluation of vaginal mucus by vaginoscopy or Metricheck were performed weekly from week 3 to 7 pp. The ovarian studies involved the predominating structures including cystic follicles with plasma progesterone (P(4) ; more or <1 ng/ml; >23 mm), corpus luteum (CL), pre-ovulatory follicles (10-23 mm) and small follicles (<10 mm). The uterine conditions comprised uterine involution, tonicity and fluid in uterus (FIU) regarding echogenicity extent. During week 5, the percentage of polymorphonuclear neutrophils (PMN%) was higher (p < 0.05) in animals with pre-ovulatory follicles (mean +/- SEM, 26.3 +/- 7.6%) than animals having CL (11.0 +/- 3.6%). In cystic ovaries, during week 5, PMN% was higher (p < 0.05) in follicular cysts with low progesterone (P(4) < 1 ng/ml; 9.3 +/- 2.6%) than those with high P(4) (P(4) >= 1 ng/ml; 1.5 +/- 1.1%). Moreover, PMN% was higher (p < 0.01) in animals with non-involuted uterus (11.5 +/- 7.4%) than those with involuted uterus (2.7 +/- 0.6%) during week 7 pp. The animals that had abnormal mucus determined by Metricheck was higher in animals with atonic uterus than those with tonic uterus during week 6 (82.6% vs 51.5%; p < 0.05) and 7 (71.4% vs 25.7%; p < 0.01) pp. In addition, by vaginoscopy, the prevalence of animals with abnormal discharge showing small follicles (100%, 5/5) during week 3 pp and pre-ovulatory follicles (40.0%, 8/20) during week 5 pp was higher (p < 0.05) when compared to those having CL during week 3 (33.3%; 1/3) and week 5 pp (7.7%; 2/26), respectively. In conclusion, endometrial cytology, Metricheck and vaginoscopy were influenced by the predominating various ovarian structures and uterine condition in early pp high-yielding dairy cows. PMID- 21241381 TI - Effects of heavy metals and pesticides on buffalo (Bubalus bubalis) spermatozoa functions in vitro. AB - Industrial toxic metals, pollutants and bio-accumulative pesticides interfere with the male reproductive functions in farm animals. Frozen-thawed semen samples were incubated with heavy metals (cadmium and lead) and pesticides (chlorpyrifos and endosulfan) of different concentrations (0, 0.005, 0.05, 0.02, 0.1, 0.5, 1.0, 2.0 and 4.0 MUg/ml) for 1 h, and various spermatozoa functional parameters and in vitro fertilization rates were assessed. Any significant effect was assessed by comparing the 1 h data between the control and treatment groups. Progressive forward motility was significantly (p < 0.05) reduced in spermatozoa exposed to lower concentrations (0.05-0.5 MUg/ml) of toxic substances. The straight-line velocity (MUm/s) and the average path velocity (MUm/s) were significantly (p < 0.05) reduced in spermatozoa exposed to 1.0 and 0.5 MUg/ml of cadmium (11.6 +/- 1.9 and 16.3 +/- 1.9) and chlorpyrifos (10.4 +/- 1.5 and 17.1 +/- 1.3), respectively, when compared to control (20.4 +/- 1.4 and 28.1 +/- 1.7). The acrosomal integrity was also significantly (p < 0.05) reduced at 0.05 MUg/ml of chlorpyrifos (33.3 +/- 1.9), 1.0 MUg/ml of cadmium (36.8 +/- 3.7), 1.0 MUg/ml of lead (39.4 +/- 2.8) and 0.5 MUg/ml of endosulfan (38.3 +/- 3.2), respectively. The spermatozoa chromatin decondensation was significantly (p < 0.05) affected at higher concentrations (>0.5 MUg/ml) of these chemicals. The mitochondrial membrane potential (%) was significantly (p < 0.05) reduced at 0.05 MUg/ml of cadmium (3.2 +/- 0.2) and chlorpyrifos (4.3 +/- 0.4), 0.1 MUg/ml of lead (3.8 +/- 0.3) and 0.5 MUg/ml of endosulfan (3.2 +/- 0.3) when compared to control (6.7 +/- 1.0). The in vitro fertilization capabilities (cleavage percentage) of spermatozoa were significantly reduced at 1.0 MUg/ml of cadmium (28.3 +/- 2.4) and 2.0 MUg/ml of lead (31.1 +/- 2.7), chlorpyrifos (29.4 +/- 2.2) and endosulfan (32.6 +/- 2.5) when compared to control (59.4 +/- 4.4). This study suggested that the mitochondrial membrane potential was primarily affected even with lowest doses of toxic chemicals. Cadmium when compared to lead and chlorpyrifos when compared to endosulfan were found to be more toxic to the spermatozoa. PMID- 21241382 TI - Fertility following CIDR based synchronization regimens in anoestrous Nili-Ravi buffaloes. AB - The objective of this study was to compare oestrus expression and fertility rate in used and new controlled internal drug releasing (CIDR) device treated anoestrous buffaloes. Furthermore, to determine the timing of ovulation, and fertility rate in estradiol benzoate (EB) and GnRH-administered CIDR-treated anoestrous Nili-Ravi buffaloes. In experiment 1, buffaloes received either a used CIDR (UCIDR, n = 35) or a new CIDR (NCIDR, n = 36) for 7 day and PGF2alpha on day 6. Oestrous expression was similar (p > 0.05) between UCIDR (88.5%) and NCIDR (96.6%) buffaloes. The pregnancy rate did not differ (p > 0.05) because of treatment (37.1% in UCIDR vs 36.6% in NCIDR). In experiment 2, buffaloes (n = 55) received CIDR device for 7 days and PGF2alpha, on day 6 and randomly assigned into three treatment groups: (i) CIDR-EB (n = 17) received EB on day 8, (ii) CIDR GnRH (n = 18) received GnRH on day 9 and (iii) control (n = 20) received no further treatment. Mean interval from CIDR removal to ovulation in CIDR-EB, CIDR GnRH and CIDR group were 61.3 +/- 0.8, 64.9 +/- 1.8 and 65.1 +/- 16.7 h, respectively. However, the buffaloes in the CIDR-EB and CIDR-GnRH group had lesser variability in the timing of ovulation compared to control. The pregnancy rate of both CIDR-EB group (58%) and CIDR-GnRH group (61%) were tended to be higher (p < 0.1) than control (30%). In conclusion, compared to NCIDR devices, previously UCIDR devices are equally effective to induce oestrus in anoestrous buffaloes resulting optimal pregnancy rate. Administration of EB and GnRH after CIDR removal results in tighter synchrony (less variability) and improved fertility in anoestrous buffaloes. CIDR based synchronization regimens have great potential in fertility improvement in anoestrous buffaloes. PMID- 21241383 TI - A role for accumbens neurons in exertion of effort and evaluating effort-related costs of instrumental actions (Commentary on Day et al.). PMID- 21241384 TI - Use of biological molecules in the treatment of inflammatory bowel disease. AB - The introduction of biological agents (i.e. antitumour necrosis factor-alpha and anti-integrin treatments) for the treatment of inflammatory bowel disease (IBD) [i.e. Crohn's disease (CD) and ulcerative colitis] has led to a substantial change in the treatment algorithms and guidelines, especially in CD. However, many questions still remain about the true efficacy and the best treatment regimens. Thus, a need for further treatment options still exists as up to 40% of IBD patients treated with the presently available biologicals do not have positive clinical responses. Better patient selection might maximize the clinical benefit for those in most need of an effective therapy to avoid disabling disease whilst also minimizing the complications associated with therapy. Further, the 'trough-level strategy' may help clinicians to optimize therapy and to avoid loss of response and/or immunogenicity. The idea behind this dosage regimen is that correct dosing must ensure that the patient's lowest level of drug concentration (i.e. the trough level) occurring just before the next drug administration is high enough for the full effect to be seen. Controversy continues regarding the appropriate use of biologicals; therefore, in this review, we focus on considerations that might lead to a more rational strategy for antitumour necrosis factor-alpha agents in IBD, emphasizing the situations in which the risks may outweigh the benefits. Finally, the need for an appropriate strategy for stopping biological treatment is discussed. PMID- 21241385 TI - Matrix-producing carcinoma of the breast: fine needle aspiration cytology findings of a rare subtype of metaplastic carcinoma. PMID- 21241386 TI - H blood-group deficiency has a high frequency in Lahu Chinese. PMID- 21241387 TI - Solanaceae XIPs are plasma membrane aquaporins that facilitate the transport of many uncharged substrates. AB - Major intrinsic proteins (MIPs) transport water and uncharged solutes across membranes in all kingdoms of life. Recently, an uncharacterized MIP subfamily was identified in the genomes of plants and fungi and named X Intrinsic Proteins (XIPs). Here, we describe the genetic features, localization, expression, and functions of a group of Solanaceae XIPs. XIP cDNA and gDNA were cloned from tobacco, potato, tomato, and morning glory. A conserved sequence motif in the first intron of Solanaceae XIPs initiates an RNA-processing mechanism that results in two splice variants (alpha and beta). When transiently or stably expressed in tobacco plants, yellow fluorescent protein-tagged NtXIP1;1alpha and NtXIP1;1beta were both localized in the plasma membrane. Transgenic tobacco lines expressing NtXIP1;1-promoter-GUS constructs and RT-PCR studies showed that NtXIP1;1 was expressed in all organs. The NtXIP1;1 promoter was mainly active in cell layers facing the environment in all above-ground tissues. Heterologous expression of Solanaceae XIPs in Xenopus laevis oocytes and various Saccharomyces cerevisiae mutants demonstrated that these isoforms facilitate the transport of bulky solutes, such as glycerol, urea, and boric acid. In contrast, permeability for water was undetectable. These data suggest that XIPs function in the transport of uncharged solutes across the cell plasma membrane in specific plant tissues, including at the interface between the environment and external cell layers. PMID- 21241388 TI - Building bridges: formin1 of Arabidopsis forms a connection between the cell wall and the actin cytoskeleton. AB - Actin microfilament (MF) organization and remodelling is critical to cell function. The formin family of actin binding proteins are involved in nucleating MFs in Arabidopsis thaliana. They all contain formin homology domains in the intracellular, C-terminal half of the protein that interacts with MFs. Formins in class I are usually targeted to the plasma membrane and this is true of Formin1 (AtFH1) of A. thaliana. In this study, we have investigated the extracellular domain of AtFH1 and we demonstrate that AtFH1 forms a bridge from the actin cytoskeleton, across the plasma membrane and is anchored within the cell wall. AtFH1 has a large, extracellular domain that is maintained by purifying selection and that contains four conserved regions, one of which is responsible for immobilising the protein. Protein anchoring within the cell wall is reduced in constructs that express truncations of the extracellular domain and in experiments in protoplasts without primary cell walls. The 18 amino acid proline rich extracellular domain that is responsible for AtFH1 anchoring has homology with cell-wall extensins. We also have shown that anchoring of AtFH1 in the cell wall promotes actin bundling within the cell and that overexpression of AtFH1 has an inhibitory effect on organelle actin-dependant dynamics. Thus, the AtFH1 bridge provides stable anchor points for the actin cytoskeleton and is probably a crucial component of the signalling response and actin-remodelling mechanisms. PMID- 21241389 TI - Sucrose transporter plays a role in phloem loading in CMV-infected melon plants that are defined as symplastic loaders. AB - Based on the high density of plasmodesmata interconnecting the intermediary cells and their neighboring phloem parenchyma or bundle-sheath cells, and based on the insensitivity to the sucrose transport inhibitor p-chloromercuribenzenesulfonic acid (PCMBS), cucurbits have been concluded to be symplastic loaders. In the present study, we identified and characterized the full-length sequence of sucrose transporter gene (CmSUT1) from melon (Cucumis melo L. cv. Hale's best jumbo). In vitro experiments confirmed that the identified gene product has sucrose transporter activity in baker's yeast. Healthy and cucumber mosaic virus (CMV)-infected melon plants were employed to examine sucrose transporter activity in planta. Pretreatment with PCMBS inhibited loading of newly fixed 14CO2 into minor veins of CMV-infected plants. Moreover, CMV infection caused significant increase in CmSUT1 transcripts expression, mainly in vascular bundles of minor veins, which was associated with elevated sucrose content in phloem sap collected from source-leaf petioles. We propose that cucurbit plants contain the machinery for apoplastic phloem loading and that CMV infection causes a quantitative shift in the mode by which photoassimilates are loaded into the sieve tube. PMID- 21241390 TI - Enhanced levels of vitamin B(6) increase aerial organ size and positively affect stress tolerance in Arabidopsis. AB - Vitamin B6 is an essential nutrient in the human diet derived primarily from plant sources. While it is well established as a cofactor for numerous metabolic enzymes, more recently, vitamin B6 has been implicated as a potent antioxidant. The de novo vitamin B6 biosynthesis pathway in plants has recently been unraveled and involves only two proteins, PDX1 and PDX2. To provide more insight into the effect of the compound on plant development and its role as an antioxidant, we have overexpressed the PDX proteins in Arabidopsis, generating lines with considerably higher levels of the vitamin in comparison with other recent attempts to achieve this goal. Interestingly, it was possible to increase the level of only one of the two catalytically active PDX1 proteins at the protein level, providing insight into the mechanism of vitamin B6 homeostasis in planta. Vitamin B6 enhanced lines have considerably larger vegetative and floral organs and although delayed in pre-reproductive development, do not have an altered overall morphology. The vitamin was observed to accumulate in seeds and the enhancement of its levels was correlated with an increase in their size and weight. This phenotype is predominantly a consequence of embryo enlargement as reflected by larger cells. Furthermore, plants that overaccumulate the vitamin have an increased tolerance to oxidative stress providing in vivo evidence for the antioxidant functionality of vitamin B6. In particular, the plants show an increased resistance to paraquat and photoinhibition, and they attenuate the cell death response observed in the conditional flu mutant. PMID- 21241391 TI - Genetic differentiation among North Atlantic killer whale populations. AB - Population genetic structure of North Atlantic killer whale samples was resolved from differences in allele frequencies of 17 microsatellite loci, mtDNA control region haplotype frequencies and for a subset of samples, using complete mitogenome sequences. Three significantly differentiated populations were identified. Differentiation based on microsatellite allele frequencies was greater between the two allopatric populations than between the two pairs of partially sympatric populations. Spatial clustering of individuals within each of these populations overlaps with the distribution of particular prey resources: herring, mackerel and tuna, which each population has been seen predating. Phylogenetic analyses using complete mitogenomes suggested two populations could have resulted from single founding events and subsequent matrilineal expansion. The third population, which was sampled at lower latitudes and lower density, consisted of maternal lineages from three highly divergent clades. Pairwise population differentiation was greater for estimates based on mtDNA control region haplotype frequencies than for estimates based on microsatellite allele frequencies, and there were no mitogenome haplotypes shared among populations. This suggests low or no female migration and that gene flow was primarily male mediated when populations spatially and temporally overlap. These results demonstrate that genetic differentiation can arise through resource specialization in the absence of physical barriers to gene flow. PMID- 21241395 TI - Intellectual disability and homelessness. AB - BACKGROUND: The association between poverty and intellectual disability (ID) has been well documented. However, little is known about persons with ID who face circumstances of extreme poverty, such as homelessness. This paper describes the situation of persons with ID who were or are homeless in Montreal and are currently receiving services from a team dedicated to homeless persons. AIMS: (1) To describe the characteristics, history and current situation of these persons; and (2) to report within-group differences as a function of gender and current residential status. METHODS: The data were collected from files using an anonymous chart summary. Descriptive statistics on the whole sample (n = 68) and inferential statistics on cross-tabulations by gender and residential status were performed. RESULTS: Persons with ID exhibited several related problems. Some of these persons, primarily women, experienced relatively short periods of homelessness and their situations stabilised once they were identified and followed up. Other persons with ID experienced chronic homelessness that appeared to parallel the number and severity of their other problems. When compared with a previous epidemiological study of the homeless in Montreal, the population of homeless persons with ID differed from the overall homeless population in a number of respects. CONCLUSION: The results suggest prevention and intervention targets. The need for epidemiological research appears particularly clear in light of the fact that below-average intellectual functioning has been identified as a risk factor for homelessness and a predisposing factor for vulnerability among street people. PMID- 21241394 TI - Parents' emotion expression as a predictor of child's social competence: children with or without intellectual disability. AB - BACKGROUND: Parents' expression of positive emotion towards children who are typically developing (TD) is generally associated with better social development. However, the association between parents' negative emotion expression and social development can be positive or negative depending upon a number of factors, including the child's emotion regulation abilities. Given the lower emotion regulation capabilities of children with intellectual disability (ID), we hypothesised that parents' negative emotion expression would be associated with lower social development in children with ID compared to those with TD. METHODS: Participants were 180 families of children with or without ID enrolled in a longitudinal study. Parents' positive and negative affect were coded live from naturalistic home interactions at child ages 5-8 years, and child's social skills were measured by using mother report at child ages 6-9 years. We examined mothers' and fathers' emotion expression as a time-varying predictor of social skills across ages 5-9 years. RESULTS: Mothers, but not fathers, expressed less positive affect and more negative affect with ID group children. Parents' positive affect expression was related to social skills only for TD children, with mothers' positive affect predicting higher social skills. Contrary to expectations, fathers' positive affect predicted lower social skills. Parents' negative affect predicted significantly lower social skills for children with ID than for children with TD. CONCLUSIONS: Findings support the theory that low to moderate levels of negative expression may be less beneficial or detrimental for children with ID compared to children with TD. Implications for further research and intervention are discussed. PMID- 21241396 TI - Comparison of community residential supports on measures of information & planning; access to & delivery of supports; choice & control; community connections; satisfaction; and, overall perception of outcomes. AB - BACKGROUND: This paper reports on some of the findings of a large-scale survey (n = 852) of family members and support staff of adults with intellectual disabilities receiving community living services in British Columbia, Canada, concentrating on comparison of outcomes across four types of community residential settings: group homes, family model homes, independent home or apartment, and family home. METHOD: Comparisons were conducted on six domains: information and planning; access to and delivery of supports; choice and control; community connections; satisfaction; and, overall perception of outcomes. Where applicable, further multivariate analyses were undertaken to determine the effect of the degree of help required by the residents and the respondent type. RESULTS: Findings indicate that on all measures other than choice and control, group homes and family model homes showed better outcomes than either independent settings or family homes. CONCLUSION: The findings may indicate that the move to more independent living settings is not being accompanied by appropriate supports. PMID- 21241397 TI - 'We've been through it all together': supports for parents with children with rare trisomy conditions. AB - BACKGROUND: Parenting a child with a developmental disability can be a positive experience. A salient part of this outcome is support at the time of diagnosis and in an ongoing manner from immediate and extended family members. Studies are sparse on this topic for parents with a child with a rare trisomy condition. METHOD: The present study examined the support needs of parents with a child or adult with a rare trisomy condition (n = 20). Participants were recruited from the Tracking Rare Incidence Syndromes (TRIS) project. The TRIS Family, Friends and Finances Protocol was the data collection instrument. The protocol included primarily open-ended items. Qualitative analyses were conducted to identify themes from the protocol and follow-up phone contacts. RESULTS: Support from immediate and extended family members varied from very positive to participants describing very negative interactions with specific individuals. Many in the sample reported affirming experiences with spouses and difficulties with grandparents and other extended family members. CONCLUSIONS: Results both confirmed the literature and reflected the unique circumstances of the participants. It is critical to raise awareness of the similar and disparate support needs of this unique population, as the affected children are living longer and their families require continuing support to meet their and their children's needs. PMID- 21241398 TI - Reappraisal of aquaporin-4 astrocytopathy in Asian neuromyelitis optica and multiple sclerosis patients. AB - Selective aquaporin-4 (AQP4) loss and vasculocentric complement and immunoglobulin deposition are characteristic of neuromyelitis optica (NMO). We recently reported extensive AQP4 loss in demyelinated and myelinated layers of Balo's lesions without perivascular immunoglobulin and complement deposition. We aimed to reappraise AQP4 expression patterns in NMO and multiple sclerosis (MS). We evaluated AQP4 expression relative to glial fibrillary acidic protein, extent of demyelination, lesion staging (CD68 staining for macrophages), and perivascular deposition of complement and immunoglobulin in 11 cases with NMO and NMO spectrum disorders (NMOSD), five with MS and 30 with other neurological diseases. The lesions were classified as actively demyelinating (n = 66), chronic active (n = 86), chronic inactive (n = 48) and unclassified (n = 12). Six NMO/NMOSD and two MS cases showed preferential AQP4 loss beyond the demyelinated areas, irrespective of lesion staging. Five NMO and three MS cases showed AQP4 preservation even in actively demyelinating lesions, despite grave tissue destruction. Vasculocentric deposition of complement and immunoglobulin was detected only in NMO/NMOSD patients, with less than 30% of actively demyelinating lesions showing AQP4 loss. Our present and previous findings suggest that antibody-independent AQP4 loss can occur in heterogeneous demyelinating conditions, including NMO, Balo's disease and MS. PMID- 21241399 TI - Mast cells and ethanol consumption: interactions in the prostate, epididymis and testis of UChB rats. AB - PROBLEM: Alcoholism has reached alarming proportions while fertility rates slowing in populations. The assessment of inflammatory effects with emphasis on the variation of the mast cells comparing ethanol chronic ingestion on reproductive organs deserves attention. METHOD OF STUDY: The mast cells were investigated with light microscopy using toluidine blue to locate and count total mast cells and immunohistochemistry to identify the connective tissue mast cells (CTMC). RESULTS: The increase in total mast cells in the prostate, total and degranulated mast cells in epididymis of UChB rats was accompanied by a greater proportion of mucosal mast cells (MMC) in these organs. In addition, a lower incidence of degranulated mast cells was observed in epididymis of control rats. CONCLUSIONS: Ethanol increases the number of total and degranulated mast cells in the prostate and epididymis, as well as associated with increasing MMC, and therefore, it could be leading to inflammation in these organs. PMID- 21241400 TI - Female infertility related to thyroid autoimmunity: the ovarian follicle hypothesis. AB - PROBLEM: The aim of this study was to verify whether anti-thyroid antibodies are present in the follicular milieu of euthyroid infertile women with thyroid autoimmunity undergoing in vitro fertilization (IVF) and whether IVF outcome is different in affected women with respect to negative controls. A secondary endpoint was to check whether there are changes in thyroid hormone levels during the IVF cycle. METHOD OF STUDY: Anti-thyroglobulin and anti-thyroperoxidase levels were measured in both follicular fluid and serum on the day of oocyte retrieval in women with thyroid autoimmunity. Serum TSH, FT3, and FT4 levels were measured in all patients before treatment initiation, on the day of oocyte retrieval and of pregnancy test. IVF outcome parameters were recorded in all women. RESULTS: Oocyte fertilization, grade A embryos, and pregnancy rates were lower in women with thyroid autoimmunity than in negative controls, while early miscarriage rate was higher. Anti-thyroid antibodies were measurable in follicular fluid in all affected women and were strongly correlated with serum levels. No significant changes in thyroid hormone levels were recorded in any women. CONCLUSION: The presence of anti-thyroid antibodies in ovarian follicles, as demonstrated for the first time in this study, may play a critical role in female infertility related to thyroid autoimmunity. PMID- 21241401 TI - Increased COX-2 expression in human vaginal epithelial cells exposed to nonoxynol 9, a vaginal contraceptive microbicide that failed to protect women from HIV-1 infection. AB - PROBLEM: Despite displaying virucidal activity in vitro, nonoxynol-9 (N-9), a vaginal contraceptive microbicide candidate, failed to reduce the rate of human immunodeficiency virus (HIV) transmission in clinical trials. With frequent use, it even increased the risk of HIV acquisition. Such outcome was postulated to be because of N-9-induced mucosal inflammation, which resulted in recruitment of HIV target immune cells to the sites of virus entry. Understanding the mechanism underlying the response of the vaginal epithelium to N-9 is critical to properly evaluate the safety of prospective vaginal microbicides and contraceptives. METHODS AND RESULTS: Using DNA microarray and quantitative RT-PCR techniques, we observed that N-9 initiated a strong transcriptional upregulation of cyclooxygenase-2 (COX-2) in immortalized human vaginal epithelial cells (VK2/E6E7 cell line). Increased COX-2 protein expression evaluated by immunoblotting was dose- and time-dependent. The level of prostaglandin E(2) (PGE(2) ) increased subsequently to COX-2 elevation. This upregulation was in part because of NF-kB activation. CONCLUSION: Expression of COX-2, a potent inflammation-related enzyme, as well as increased secretion of PGE(2) , an important local mediator of mucosal immunoinflammatory responses, by human vaginal epithelial cells exposed to vaginal microbicide and contraceptive candidates may be used as a biomarker of undesirable compound properties. PMID- 21241403 TI - Analysis of plasminogen activator inhibitor-1, integrin beta3, beta fibrinogen, and methylenetetrahydrofolate reductase polymorphisms in Iranian women with recurrent pregnancy loss. AB - PROBLEM: To identify the associations of the plasminogen activator inhibitor-1 (PAI-1) -675 4G/5G, beta fibrinogen (BF) -455G/A, integrin beta 3 (ITGB3) 1565T/C, and methylenetetrahydrofolate reductase (MTHFR) 677C/T and 1298A/C polymorphisms with recurrent pregnancy loss (RPL). METHOD OF STUDY: Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) were performed to assess the frequency of five candidate genetic risk factors for RPL, and the frequencies of the polymorphisms were calculated and compared between case and control groups. RESULTS: The BF -455G/A, MTHFR 677C/T, and 1298A/C polymorphisms were found to be positively, and ITGB3 1565T/C polymorphism negatively, associated with RPL. Homozygosity but not heterozygosity for PAI-1 675 4G/5G polymorphism was significantly higher in patients with RPL than in the control group. The presence of both mutations of MTHFR genes highly increased the risk of RPL. CONCLUSION: The data highlight the importance of thrombophilia screening in patients with RPL. PMID- 21241402 TI - Enhanced stimulation of anti-ovarian cancer CD8(+) T cells by dendritic cells loaded with nanoparticle encapsulated tumor antigen. AB - PROBLEM: Dendritic cell (DC)-based cancer therapies are favored approaches to stimulate anti-tumor T-cell responses. Unfortunately, tolerance to tumor antigens is difficult to overcome. Biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) are effective reagents in the delivery of drugs and tumor associated antigens (TAA). In this study, we assessed the capacity of a PLGA NP based delivery system to augment CD8 T-cell responses to ovarian cancer TAA. METHOD OF STUDY: Human DC were generated from blood monocytes by conventional in vitro differentiation and loaded with either soluble tumor lysate or NP/lysate conjugates (NPL). These antigen-loaded DC were then used to stimulate autologous CD8(+) T cells. Cytokine production and activation markers were evaluated in the CD8(+) T cells. RESULTS: DC loading with NPL increased cytokine production by stimulated CD8 T cells and induced T-cell expression of cell surface co stimulatory molecules, typical of anti-tumor immune responses. In contrast, delivery of naked tumor lysate antigens preferentially induced a T-cell profile characteristic of tolerization/exhaustion. CONCLUSION: These findings indicate that delivery of TAA in NP enables DC to efficiently activate anti-tumor CD8(+) T cells. PLGA NP encapsulation of tumor-derived lysate protein antigens is an encouraging new preparative methodology for DC-based vaccination meriting clinical testing. PMID- 21241404 TI - High mobility group box 1 (HMGB1) levels in the placenta and in serum in preeclampsia. AB - PROBLEM: Preeclampsia is a pregnancy disorder characterized by systemic inflammation. High mobility group box 1 (HMGB1) is a molecule known to act as a 'danger signal' by participating in various inflammatory processes, but data in regard to preeclampsia are sparse. The aim of this study was to analyze placental and serum HMGB1 levels in normal pregnancy and preeclampsia. METHOD OF STUDY: Sera were collected from women with preeclampsia soon after the manifestation of the disease and before commencing any medication. Placental samples were collected immediately after delivery. Expressed isoforms of HMGB1 (28- and 30 kDa) in the placenta were evaluated by Western blot analysis. Serum HMGB1 concentrations were measured using enzyme-linked immunosorbent assays (ELISA). RESULTS: Two isoforms of HMGB1 are expressed by the human placenta. The 28- and 30-kDa HMGB1 isoforms were expressed highly in preeclamptic placental tissue; however, compared with normotensive control tissue, differences in detected expression levels did not reach statistical significance. No significant difference was observed in serum HMGB1 levels between control and preeclampsia. CONCLUSION: Inflammation provoked by HMGB1 is likely to be involved in the proinflammatory process in preeclamptic placenta. Further studies are needed to elucidate the precise role of HMGB1 in preeclampsia. PMID- 21241406 TI - The role of interleukin-17 in the Helicobacter pylori induced infection and immunity. AB - BACKGROUND: Helicobacter pylori infection is regarded as the major cause of various gastric diseases and induces the production of several cytokines including interleukin-17 (IL-17) recently recognized as an important player in the mammalian immune system. OBJECTIVE: This review deals with the role of IL-17 on the H. pylori-induced infection and immunity in humans and experimental animals. RESULTS: H. pylori infection increases IL-17 in the gastric mucosa of humans and experimental animals. In humans, IL-17 induces the secretion of IL-8 by activating the ERK 1/2 MAP kinase pathway and the released IL-8 attracts neutrophils promoting inflammation. IL-23 is increased in patients with H. pylori related gastritis and regulates IL-17 secretion via STAT3 pathway. Studies in H. pylori-infected mice indicate that IL-17 is primarily associated with gastric inflammation. The early events in the immune response of immunized and challenged mice include the recruitment of T cells and the production of IL-17. Neutrophil attracting chemokines are released, and the bacterial load is considerably reduced. IL-17 plays a dual role in infection and vaccination. In infection, T regulatory cells (Tregs) suppress the inflammatory reaction driven by IL-17 thereby favoring bacterial persistence. Immunization produces Helicobacter specific memory T-helper cells that can possibly alter the ratio between T-helper 17 and Treg responses so that the IL-17-driven inflammatory reaction can overcome the Treg response leading to bacterial clearance. CONCLUSION: IL-17 plays an important role in H. pylori-related gastritis and in the reduction of Helicobacter infection in mice following immunization. PMID- 21241407 TI - Strain-dependent proliferation in response to human gastric mucin and adhesion properties of Helicobacter pylori are not affected by co-isolated Lactobacillus sp. AB - BACKGROUND: Helicobacter pylori colonize the mucus layer that covers the gastric epithelium and can cause gastritis, ulcers, and gastric cancer. Recently, Lactobacillus sp. have also been found to reside in this niche permanently. This study compares adhesive properties and proliferation of co-isolated lactobacilli and H. pylori in the presence of mucins and investigates possibilities for lactobacilli-mediated inhibition of H. pylori. MATERIALS AND METHODS: Binding and proliferation of four H. pylori and four Lactobacillus strains, simultaneously isolated after residing in the stomachs of four patients for >4 years, to human gastric mucins were investigated using microtiter-based methods. RESULTS: The H. pylori strains co-isolated with lactobacilli exhibited the same mucin binding properties as demonstrated for H. pylori strains previously. In contrast, no binding to mucins was detected with the Lactobacillus strains. Proliferation of mucin-binding H. pylori strains was stimulated by the presence of mucins, whereas proliferation of non-binding H. pylori and Lactobacillus strains was unaffected. Associative cultures of co-isolated H. pylori and Lactobacillus strains showed no inhibition of H. pylori proliferation because of the presence of whole bacteria or supernatant of lactobacilli. CONCLUSIONS: The presence of lactobacilli in the stomach did not select for different mucin binding properties of H. pylori, and Lactobacillus sp. did neither compete for binding sites nor inhibit the growth of co-isolated H. pylori. The effects of human gastric mucins on H. pylori proliferation vary between strains, and the host-bacteria interaction in the mucus niche thus depends on both the H. pylori strain and the microenvironment provided by the host mucins. PMID- 21241408 TI - Differences of urease activity and expression of associated genes according to gastric topography. AB - BACKGROUND: We hypothesize that pH difference between acid-secreting corpus and non-secreting antrum might influence the activity of H. pylori's urease and/or related genes. We therefore measured urease activity and the expression of amiE whose encoded protein that hydrolyzes short-chain amides to produce ammonia. MATERIALS AND METHODS: Fifty-four patients were recruited into this study. Each gastroscopic biopsy specimen collected from the antrum and body of each patient was immediately used to measure urease activity using serial changes of urease activity (ammonia levels) during 60 minutes. Probe specific for amiE was labeled with a biotin nick-translation kit and was used to detect expression of these genes (mRNA) in fresh-frozen gastroscopic biopsy specimens using fluorescent in situ hybridization (FISH). RESULTS: Urease activity at 60 minutes from the gastric antrum and body of all patients infected with H. pylori was 399.5 +/- 490.5 and 837.9 +/- 1038.9 MUg/dL, respectively (p = .004). Urease activity in the antrum was correlated with H. pylori density. Urease activity or H. pylori density in the antrum was significantly correlated with chronic active inflammation; in contrast, this correlation was not found in the gastric body. The expression level of amiE was 1.5 times higher (p < .05) in the gastric body compared with the antrum. CONCLUSION: Topographically, the urease activity in body was much higher than in antrum. The expression level of amiE was higher in the gastric body compared with the antrum. PMID- 21241409 TI - Pediatric Helicobacter pylori infection and circulating T-lymphocyte activation and differentiation. AB - BACKGROUND: In this study, H. pylori-infected and noninfected children with gastritis were compared to a control group with respect to circulating CD4(+) and CD8(+) T lymphocytes expressing activation and differentiation markers. Additionally, the lymphocyte phenotypes of children with gastritis were correlated with the gastric inflammation scores. MATERIALS AND METHODS: H. pylori infection status was assessed based on [13C]urea breath test, rapid urease test, and histology. Analysis of the lymphocyte surface molecule expression was carried out by triple-color flow cytometry. RESULTS: The group of H. pylori-infected children showed an elevated proportion of peripheral B cells with CD19(low) , along with a twofold increase in the percentage of memory (CD45RO(+)) CD4(+) and CD8(+) T-cell subsets (p < .05). Moreover, a positive correlation between the age and the percentage of these subsets was seen (r = .38, p = .04 and r = .56, p < .01, respectively). Children with gastritis but without infection had a slightly increased percentage of CD8(+) T cells and CD56(+) NK cells, CD3(high) T cells and CD45RO(high) CD4(+) T-cell subsets (p < .05). Both H. pylori-infected and noninfected children with gastritis were characterized by an increased percentage of memory/effector CD4(+) T cells, the presence of NK cells with CD56(high), memory T-cell subset with CD4(high), and naive, memory, memory/effector, and effector T-cell subsets with CD8(high) (p < .05). Gastric inflammation scores correlated positively with the percentage of CD4(+) T lymphocytes in H. pylori infected children (r = .42, p = .03). In noninfected children, gastric inflammation scores correlated positively with the percentage of B cells (r = .45, p = .04). CONCLUSION: In H. pylori-negative children, gastritis was associated with an increased percentage of activated NK and T cells, and intermediate-differentiated peripheral blood CD4(+) T cells, which was more pronounced in H. pylori-positive children who also showed an increased B-cell response. However, increased inflammation was only associated with the elevation of CD4(+) T-cell percentage in H. pylori-positive children as well as B-cell percentage in H. pylori-negative children with gastritis. PMID- 21241410 TI - The role of abdominal CT scan as follow-up after complete remission with successful Helicobacter pylori eradication in patients with H. pylori-positive stage I(E1) gastric MALT lymphoma. AB - BACKGROUND: Eradication of Helicobacter pylori with antibiotics is the established initial treatment of patients with localized gastric mucosa associated lymphoid tissue (MALT) lymphoma. However, there are few reports on follow-up modalities to identify sustained remission in patients who achieve complete remission (CR). We therefore investigated the role of abdominal computed tomography (CT) as follow-up after CR with H. pylori eradication. PATIENTS AND METHODS: We retrospectively analyzed 122 patients with H. pylori-positive stage I(E1) gastric MALT lymphoma who achieved CR with successful H. pylori eradication. RESULTS: The median follow-up after CR was 35 months (range 3-140 months). At a median of 17 months (range 12-21 months) after CR, 7 of 122 patients (5.7%) experienced lymphoma recurrence, all cases of which were confined to the gastric mucosa and were detectable only by endoscopy with multiple biopsies. At the time of recurrence, four of seven patients showed re-infection by H. pylori. Eradication therapy was successful in these patients, resulting in both bacterial eradication and tumor regression. Three patients who experienced histologic recurrence without H. pylori re-infection were observed by a watch and wait strategy and again achieved CR. CONCLUSIONS: None of the patients with H. pylori-positive stage I(E1) gastric MALT lymphoma who experienced tumor recurrence after CR with successful H. pylori eradication showed recurrence at extragastric sites, including lymph nodes without gastric mucosal lesion. These findings indicate that endoscopic biopsies without abdominal CT scans are sufficient to detect recurrence in these patients. PMID- 21241411 TI - Evaluation of a new antigen for diagnosis of Helicobacter pylori infection in stool of adult and children. AB - BACKGROUND: Nowadays, there is an increasing interest in noninvasive methods to diagnose Helicobacter pylori infection. Indeed, they can profitably replace endoscopy in predicting the diagnosis. The stool antigen test for H. pylori is a noninvasive immunoassay to diagnose active infection with this bacterium in human fecal samples. The aim of this study was detection of alkyl hydroperoxide reductase protein (AhpC) antigen by immunoblotting in stool samples for diagnosis of H. pylori. MATERIALS AND METHODS: Chromosomal DNA from H. pylori was isolated. AhpC gene was amplified by PCR, These amplicons were cloned into pTZ57R/T cloning vector then subcloned into pQE30 expression vector and overexpressed using isopropyl-beta-D-thiogalactopyranoside in E. coli M15. AhpC protein was purified by affinity chromatography. Rabbits were immunized with the purified AhpC protein for the production of antibodies. To determine the accuracy of the test for diagnosing H. pylori infection from stool, we evaluated 84 patients (6-81 years old) using Western blot analysis by rabbit anti-AhpC antibody. Positive rapid urease test on biopsy samples was considered as the gold standard. RESULTS: AhpC gene was overexpressed, and AhpC protein was purified. Rabbit anti-AhpC antibody produced after immunization with the purified AhpC protein. By immunoblotting, we detected AhpC protein in the positive stool samples. The test showed a 83.3% sensitivity (95% CI: 69.8-92.5%) and a 91.7% specificity (95% CI: 77.5-98.2). Among the children, the sensitivity was 88.2% (95% CI: 63.6-98.5) and the specificity was 100% (95% CI: 69.2-100); in adults, the sensitivity and specificity were 80.6% (95% CI: 62.5-92.5) and 88.5% (95% CI: 69.8-97.6), respectively. CONCLUSIONS: Using of AhpC antigen for diagnosis of H. pylori infection is a useful noninvasive method, accurate in adolescents and children, and can be used for the development of a stool antigen detection kit for H. pylori. PMID- 21241412 TI - Analysis of antibiotic susceptibility patterns of Helicobacter pylori isolates from Malaysia. AB - BACKGROUND: The prevalence of antibiotic resistance varies in geographic areas. The information on the antibiotic susceptibility patterns of Helicobacter pylori (H. pylori) in our local setting is therefore relevant as a guide for the treatment options. OBJECTIVE: This study was conducted to determine the primary resistance rates among H. pylori isolated from Malaysian patients. MATERIALS AND METHODS: Biopsy samples were obtained from the stomach antrum and corpus of 777 patients from September 2004 until 2007. H. pylori isolated from these patients were then subjected to minimum inhibitory concentration (MICs) determination using E-test method, against metronidazole, clarithromycin, levofloxacin, ciprofloxacin, amoxicillin, and tetracycline. RESULTS: From 777 patients, 119 were positive for H. pylori where a total of 187 strains were isolated. The resistance rates were noted to be 37.4% (metronidazole), 2.1% (clarithromycin), 1% (levofloxacin and ciprofloxacin), and 0% (amoxicillin and tetracycline). Different resistance profiles were observed among isolates from the antrum and corpus of 13 patients. Resistance to one type of antibiotic was observed in 36.4% of the strains where mono-resistance to metronidazole was the most common. Resistance to >=2 antibiotics was noted in 3.3% of isolates. High metronidazole MICs of >=256 MUg/mL were observed among the resistant strains. CONCLUSIONS: The resistance rates of the antibiotics used in primary treatment of H. pylori infections in Malaysia are low, and multi-antibiotic-resistant strains are uncommon. Infections with mixed populations of metronidazole-sensitive and resistant strains were also observed. However, the high metronidazole MIC values seen among the metronidazole-resistant strains are a cause for concern. PMID- 21241413 TI - Moxifloxacin-tetracycline-lansoprazole triple therapy for first-line treatment of Helicobacter pylori infection: a prospective study. AB - AIM: To document the efficacy and tolerability of 14-day moxifloxacine tetracycline-lansoprazole (MTL) regimens for Helicobacter pylori (Hp) eradication as a first-line therapy. METHOD: Fifty-six Hp-positive patients were enrolled. Patients were considered eligible for the study if they underwent upper gastrointestinal endoscopy, and Hp infection was diagnosed through histologic examination of antral and body bioptic samples. Primary end point of this study was to evaluate the eradication rate of 14-day MTL regimen therapies. Hp eradication was assessed using the 13C urea breath test performed. All patients were asked to fill in a validated questionnaire to report therapy-related side effects. Each symptom was graded from absent or present. RESULTS: Fifty-six patients (29 men and 27 women) were enrolled. The studied therapeutic regimens were completed by 96.4% patients. Two dropouts occurred in the MTL group because of side effects. The eradication rate in MTL regimens was 55.4%. The overall prevalence of side effects was high in the MTL group. CONCLUSION: The MTL regimen failed to achieve the recommended eradication rates and had higher adverse effect rate. Hence, MTL regimen does not seem to be a suitable choice as a first-line Hp eradication therapy. PMID- 21241414 TI - The effect of Helicobacter pylori and economic status on growth parameters and leptin, ghrelin, and insulin-like growth factor (IGF)-I concentrations in children. AB - BACKGROUND: It was suggested that gastric colonization with Helicobacter pylori (H. pylori) was associated with suboptimal nutrition and growth in childhood. Furthermore, several studies indicated a relationship between H. pylori colonization and alterations in the circulating levels of growth-related molecules (GRM). Accordingly, in this study, we investigate the effect of H. pylori infection on GRMs and on the growth of healthy school children, taking into consideration the effect of their economic status (ES) and anthropometric indices of their parents. METHODS: To acquire sociodemographic and anthropometric nutritional parameters and to detect H. pylori-specific serum IgG antibodies and growth-related molecules, we evaluated a total of 473 children attending four different primary and secondary schools in Istanbul. Subsequently, we assessed the effect of H. pylori on growth-related parameters (weight for age SDS, height for age SDS, BMI SDS, TSF, and waist-to-hip ratio) and on GRMs (leptin, ghrelin, and insulin-like growth factor-1 (IGF-1)), controlling for age, gender, family income, household crowding (HC), breastfeeding, maternal and paternal BMI SDS, and midparental height SDS with complex statistical models. RESULTS: Of the 473 children (275 F/198 M, age 6-15 years; mean: 10.3 +/- 0.1 years), 161 (34%) were H. pylori-positive. The prevalence of H. pylori was significantly higher in lower economic status (ES) groups, in children living in crowded houses, and in older age groups. Using simple statistical models, we did not find any significant associations between H. pylori infection and the growth parameters. However, in complex models for height for age SDS and for weight for age SDS, there was a significant interaction between H. pylori infection status and ES. Whereas in H. pylori-positive subjects, mid-income family children were both taller and heavier than the low-income group, there was no such an association in H. pylori-negative subjects. Among biochemical parameters, only ghrelin levels were associated with H. pylori infection in all models. Leptin levels were associated with HC in girls, whereas none of the parameters was significantly associated with leptin levels in boys. For IGF-1 levels, for boys, age and maternal BMI, and for girls, age and HC were significantly associated with IGF-1 levels. CONCLUSION: We suggest that H. pylori may impair growth significantly only in susceptible children where unfavorable socioeconomic conditions facilitate its action, probably through mechanisms, at least in part, involving growth-related molecules. PMID- 21241415 TI - Effect of Helicobacter pylori infection on Barrett's esophagus and esophageal adenocarcinoma formation in a rat model of chronic gastroesophageal reflux. AB - OBJECTIVES: To investigate the relationship between Helicobacter pylori infection and Barrett's esophagus (BE), a rat model of chronic gastroesophageal reflux with H. pylori infection was established and the degree of inflammation, incidence of BE and esophageal adenocarcinoma (EA) were evaluated. METHODS: Eight-week-old male specific-pathogen-free SD rats were divided into five groups randomly: pseudo-operation group; esophagojejunum anastomosis (EJA) group; EJA with H. pylori infection group; EJA with H. pylori infection and celecoxib-treated group; EJA with celecoxib-treated group. Rats were kept for 30 weeks after surgery. Esophageal lesion was evaluated grossly and microscopically. The expression of COX-2 and CDX2 was determined by RT-PCR and immunohistochemistry staining. The level of PGE2 was assessed by enzyme-linked immunosorbent assay. RESULTS: Esophageal mucosal injury in the group of EJA with H. pylori infection was decreased than that in EJA group (p < .05). The incidence of BE and EA in rats undergoing EJA with H. pylori infection was increased than in rats undergoing EJA with no statistical difference. Celecoxib treatment decreased the incidence of EA in rats undergoing EJA with H. pylori infection (p < .05). The expression of CDX2 mRNA was decreased in rats with H. pylori infection or treated with celecoxib than in the rats of pseudo-operation group (p < .05). When compared with those in rats of pseudo-operation group, the expression of COX-2 mRNA and the level of PGE2 were upregulated in rats undergoing EJA irrespective of H. pylori infection (p < .05) and downregulated in rats treated with celecoxib (p < .05). When H. pylori colonized in esophagus, the severity of inflammation and the incidence of BE and EA were increased significantly. Higher levels of COX-2 expression and PGE2 were detected in rats with esophageal H. pylori colonization. CONCLUSIONS: When H. pylori infect in stomach, it may reduce the severity of inflammation. However, when colonizes in esophagus, H. pylori increases the severity of esophageal inflammation and the incidence of BE and EA. Celecoxib administration attenuates the incidence of EA by inhibiting COX-2 expression. PMID- 21241416 TI - Ultrasound-guided bilateral paravertebral continuous nerve blocks for a mildly coagulopathic patient undergoing exploratory laparotomy for bowel resection. AB - Regional anesthesia techniques commonly utilized in post-operative pain management are often considered contraindicated in coagulopathic patients. We report on successful postoperative pain control utilizing peripheral nerve blockade after exploratory laparotomy with small bowel resection in a mildly coagulopathic patient. In our case, complicated by abnormal PT, PTT and INR, a thromboelastogram (TEG) was performed before the procedure and found to be normal. An ultrasound-guided bilateral paravertebral blockade with continuous paravertebral catheters was then performed in this pediatric patient without complications. The patient expressed satisfaction with his pain control. More studies are needed to evaluate the validity of TEG in the prediction of bleeding risk and the safety of this regional technique in a mildly coagulopathic patients. PMID- 21241417 TI - Epicatechin gallate and catechin gallate are superior to epigallocatechin gallate in growth suppression and anti-inflammatory activities in pancreatic tumor cells. AB - Green tea catechins are considered as possible cancer preventive agents for several cancer types but little is known regarding their effects on pancreatic cancer cells. The best studied catechin and the major polyphenol present in green tea is epigallocatechin gallate (EGCG). In the present study, we investigated the in vitro anti-tumoral properties of EGCG on human pancreatic ductal adenocarcinoma (PDAC) cells PancTu-I, Panc1, Panc89 and BxPC3 in comparison with the effects of two minor components of green tea catechins, catechin gallate (CG) and epicatechin gallate (ECG). We found that all three catechins inhibited proliferation of PDAC cells in a dose- and time-dependent manner. Interestingly, CG and ECG exerted much stronger anti-proliferative effects than EGCG. Western blot analyses performed with PancTu-I cells revealed catechin-mediated modulation of cell cycle regulatory proteins (cyclins, cyclin-dependent kinases [CDK], CDK inhibitors). Again, these effects were clearly more pronounced in CG or ECG than in EGCG-treated cells. Importantly, catechins, in particular ECG, inhibited TNFalpha-induced activation of NF-kappaB and consequently secretion of pro inflammatory and invasion promoting proteins like IL-8 and uPA. Overall, our data show that green tea catechins ECG and CG exhibit potent and much stronger anti proliferative and anti-inflammatory activities on PDAC cells than the most studied catechin EGCG. PMID- 21241420 TI - Use of bacteriophage endolysin EL188 and outer membrane permeabilizers against Pseudomonas aeruginosa. AB - AIMS: To select and evaluate an appropriate outer membrane (OM) permeabilizer to use in combination with the highly muralytic bacteriophage endolysin EL188 to inactivate (multi-resistant) Pseudomonas aeruginosa. METHODS AND RESULTS: We tested the combination of endolysin EL188 and several OM permeabilizing compounds on three selected Ps. aeruginosa strains with varying antibiotic resistance. We analysed OM permeabilization using the hydrophobic probe N-phenylnaphtylamine and a recombinant fusion protein of a peptidoglycan binding domain and green fluorescent protein on the one hand and cell lysis assays on the other hand. Antibacterial assays showed that incubation of 10(6) Ps. aeruginosa cells ml(-1) in presence of 10 mmol l(-1) ethylene diamine tetraacetic acid disodium salt dihydrate (EDTA) and 50 MUg ml(-1) endolysin EL188 led to a strain-dependent inactivation between 3.01 +/- 0.17 and 4.27 +/- 0.11 log units in 30 min. Increasing the EL188 concentration to 250 MUg ml(-1) further increased the inactivation of the most antibiotic resistant strain Br667 (4.07 +/- 0.09 log units). CONCLUSIONS: Ethylene diamine tetraacetic acid disodium salt dihydrate was selected as the most suitable component to combine with EL188 in order to reduce Ps. aeruginosa with up to 4 log units in a time interval of 30 min. SIGNIFICANCE AND IMPACT OF THE STUDY: This in vitro study demonstrates that the application range of bacteriophage encoded endolysins as 'enzybiotics' must not be limited to gram-positive pathogens. PMID- 21241418 TI - Apoptotic effect of tolfenamic acid in androgen receptor-independent prostate cancer cell and xenograft tumor through specificity protein 1. AB - Tolfenamic acid (Tol) is a non-steroidal anti-inflammatory drug that was reported to exhibit anticancer activity in pancreatic and colorectal cancer models. This study examined the role of Tol in the death regulation of PC-3 and DU145 human androgen-independent prostate cancer cells. The results showed that Tol inhibited cell growth and induced apoptosis, as evidenced by nuclear fragmentation and cleaved caspase 3 and poly(ADP-ribose) polymerase. Tol suppressed the specificity protein 1 (Sp1) protein in both PC-3 and DU145 cells. Tol also attenuated Sp1 mRNA and its promoter activity in DU145 cells, but did not alter them in PC-3 cells, indicating that Tol degrades Sp1 protein in these cells. Tol also downregulated protein levels, mRNA levels and promoter activities of survivin and myeloid cell leukemia-1, which are downstream targets of Sp1. The expressions of survivin and Mcl-1 and cancer cell growth were lower in the PC-3 cells treated with Sp1 interfering RNA and mithramycin A. Moreover, an oral injection of Tol decreased tumor growth and downregulated the Sp1 protein in athymic nude mice bearing DU145 cell xenografts without hepatotoxicity. Overall, Tol downregulates the Sp1 protein to inhibit growth and induce apoptosis in androgen-refractory prostate cancers, both in vitro and in vivo, that show resistance against many chemotherapeutic agents. PMID- 21241422 TI - Optimal culture conditions for keratinase production by a novel thermophilic Myceliophthora thermophila strain GZUIFR-H49-1. AB - AIMS: To investigate the effect of medium compositions and culture conditions on keratinase production by a novel thermophilic fungus Myceliophthora thermophila (Apinis) Oorschot strain GZUIFR-H49-1. METHODS AND RESULTS: The thermophilic strain GZUIFR-H49-1 with keratinolytic ability was characterized and identified as a strain of M. thermophila on the basis of its morphological characters and molecular analysis of ITS1-5.8S-ITS2 rDNA sequence. Among the medium compositions tested, the soluble starch (SS), urea, sodium thiosulfate and CaCl2 were the most effective C-source, N-source, S-source and mineral ion, respectively, by employing the single-factor experiment. The urea and pH value were the significant factors (P < 0.05) for the keratinase production in this experiment condition using Plackett-Burman factorial design. The conditions of keratinase production were further optimized by Box-Behnken design. Consequently, there was a 6.4-fold increase (5100 U l-1) in the keratinase activity than the initial value (800 U l-1) by this optimal process. CONCLUSIONS: This study indicated that the optimization design proved a useful and powerful tool for the development of optimal medium compositions and culture conditions. Myceliophthora thermophila strain GZUIFR-H49-1 was a promising fungus strain for keratinase production. PMID- 21241423 TI - Experimental and clinical evidence for modification of hepatic ischaemia reperfusion injury by N-acetylcysteine during major liver surgery. AB - BACKGROUND: Hepatic ischaemia-reperfusion (I/R) injury occurs in both liver resectional surgery and in transplantation. The biochemistry of I/R injury involves short-lived oxygen free radicals. N-acetylcysteine (NAC) is a thiol containing synthetic compound used in the treatment of acetaminophen toxicity. The present study is a detailed overview of the experimental and clinical evidence for the use of NAC as a pharmaco-protection agent in patients undergoing major liver surgery or transplantation. METHODS: A computerized search of the Medline, Embase and SCI databases for the period from 1st January 1988 to 31st December 2008 produced 40 reports. For clinical studies, the quality of reports was assessed according to the criteria reported by the Cochrane communication review group. RESULTS: Nineteen studies evaluated NAC in experimental liver I/R injury. NAC was administered before induction of ischaemia in 13. The most widely used concentration was 150 mg/kg by intravenous bolus. Fifteen studies report an improvement in outcome, predominantly a reduction in transaminase. Seven studies used an isolated perfused liver model with all showing improvement (predominantly an improvement in bile production after N-acetylcysteine). Two out of four transplantation models showed an improvement in hepatic function. Clinical studies in transplantation show a modest improvement in transaminase levels with no beneficial effect on either patient or graft survival. CONCLUSION: N acetylcysteine, given before induction of a liver I/R injury in an experimental model can ameliorate liver injury. Clinical outcome data are limited and there is currently little evidence to justify use either in liver transplantation or in liver resectional surgery. PMID- 21241425 TI - Hepatectomy after hepatic arterial therapy with either yttrium-90 or drug-eluting bead chemotherapy: is it safe? AB - BACKGROUND: The use of hepatic arterial therapy (HAT) with either yttrium-90 or drug-eluting bead therapy for initially unresectable hepatic malignancies has risen significantly. The safety of hepatic resection after hepatic arterial therapy (HAT) is not established. OBJECTIVE: The present study evaluates the safety profile for hepatic resection after HAT. METHODS: We identified 840 patients undergoing hepatectomy for primary or metastatic lesions. Forty patients underwent HAT before hepatectomy (pre-HAT). A 1:4 case-matched analysis compared three groups: (i) pre-HAT and pre-operative chemotherapy (n=40); (ii) pre operative chemotherapy (n=160); and (iii) no pre-operative therapy (n=640). Controls were matched for age, resection type, maximal tumour size and magnitude of resection. Morbidity and mortality among groups were compared using a graded complication scale. RESULTS: There were no differences in post-operative complications, grade of complication or liver-specific complications among the groups. A proportional hazards model for all patients did not demonstrate any association between increased complications and either pre-HAT or pre-operative chemotherapy when compared with patients without pre-operative therapy (P=0.7). CONCLUSIONS: Pre-HAT demonstrated similar morbidity, liver-specific morbidity and intra-operative complications when compared with patients undergoing pre operative chemotherapy alone or without pre-operative chemotherapy. These results suggest that pre-HAT is safe and should not preclude hepatectomy in carefully selected patients. PMID- 21241424 TI - Analytical review of diagnosis and treatment strategies for dominant bile duct strictures in patients with primary sclerosing cholangitis. AB - BACKGROUND: The diagnosis and treatment of indeterminate dominant strictures (DS) in patients with primary sclerosing cholangitis (PSC) is challenging and the literature on the subject is scarce. OBJECTIVES: This review aims to appraise and synthesize the evidence published in the English-language medical literature on this topic. METHODS: Scientific papers published from 1950 until week 4 of July 2010 were extracted from MEDLINE, Ovid Medline In-Process, the Cochrane Database of Systematic Reviews, the Database of Systematic Reviews, the Database of Abstracts of Reviews of Effects, EMBASE, PubMed and the National Library of Medicine Gateway. RESULTS: Strategies for the optimal management of DS in PSC patients are supported only by level II and III evidence. Intraductal endoscopic ultrasound appears to be the most sensitive (64%) and specific (95%) diagnostic test for the evaluation of DS in PSC. Endoscopic and percutaneous dilatations achieve 1- and 3-year palliation in 80% and 60% of patients, respectively. Although dilatation and stenting are the most common palliative interventions in DS, no randomized trials on the optimal duration of treatment have been conducted. CONCLUSIONS: In benign DS, endoscopic dilatation with short-term stenting seems to be effective and safe and does not increase the risks for malignant transformation or complications after liver transplantation. Surgical bile duct resection and/or bilioenteric bypass are indicated only in patients with preserved liver function. PMID- 21241426 TI - National trends in discharge disposition after hepatic resection for malignancy. AB - BACKGROUND: There is a paucity of data on the trends in discharge disposition for patients undergoing hepatic resection for malignancy. AIM: To analyse the national trends in discharge disposition after hepatic resection for malignancy. METHODS: The National Inpatient Sample (NIS) database was queried (1993 to 2005) to identify patients that underwent hepatic resection for malignancy and analyse the discharge status (home, home health or rehabilitation/skilled facility). RESULTS: A weighted total of 74,520 patients underwent hepatic resection of whom, 53,770 patients had a principal diagnosis of malignancy. The overall mortality improved from 6.3% to 3.4%. After excluding patients that died in the post operative period and those with incomplete discharge status, 45,583 patients were included. The proportion of patients that had acute care needs preventing them from being discharged home without assistance increased from 10.9% in 1993 to 19.5% in 2005. While there was an increase in the number of patients discharged to home health care during this time (8.9% to 13.8%), there was a larger increase in the proportion of patients that were discharged to a rehabilitation or skilled nursing facility (2% to 5.7%). Despite a decrease in the mortality rates, there was no improvement in rate of patients discharged home without assistance over the period of the study. CONCLUSIONS: The results of the present study demonstrate that after hepatic resection, a significant proportion of patients will need assistance upon discharge. This information needs to be included in patient counselling during pre-operative risk and benefit assessment. PMID- 21241427 TI - Liver resection in obese patients: results of a case-control study. AB - OBJECTIVES: Obesity has been associated with worse postoperative outcomes. No data are available regarding short-term results after liver resection (LR). The aim of this study was to analyse outcomes in obese patients (body mass index [BMI] > 30 kg/m(2) ) undergoing LR. METHODS: 85 consecutive obese patients undergoing LR between 1998 and 2008 were matched on a ratio of 1:2 with 170 non obese patients. Matching criteria were diagnosis, ASA score, METAVIR fibrosis score, extent of LR, and Child-Pugh score in patients with cirrhosis. RESULTS: Operative time, blood loss and blood transfusions were similar in the two groups. Mortality was 2.4% in both groups. Morbidity was significantly higher in the obese group (32.9% vs. 21.2%; P= 0.041). However, only grade II morbidity was increased in obese patients (14.1% vs. 1.8%; P < 0.001) and this was mainly related to abdominal wall complications (8.2% vs. 2.4%; P= 0.046). No differences were encountered in terms of grade III or IV morbidity. The same results were observed in major LR and cirrhotic patients. When patients were stratified by BMI (<20, 20-25, 25-30 and >30 kg/m(2) ), progressive increases in overall and infectious morbidity were observed (5.6%, 22.4%, 23.7%, 32.9%, and 5.6%, 11.8%, 14.5%, 18.8%, respectively). Rates of grade III and IV morbidity did not change. DISCUSSION: Obese patients have increased postoperative morbidity after LR in comparison with non-obese patients, but this is mainly related to minor abdominal wall complications. Severe morbidity rates and mortality are similar to those in non-obese patients, even in cirrhosis or after major LR. PMID- 21241428 TI - Endoscopic ultrasound may be unnecessary in the preoperative evaluation of intraductal papillary mucinous neoplasm. AB - OBJECTIVES: Several imaging modalities are commonly performed during work-up of intraductal papillary mucinous neoplasm (IPMN), but guidelines do not suggest any one technique. The aim of this study was to evaluate tumour and duct measurements by computed tomography (CT) and endoscopic ultrasound (EUS) and their ability to predict high-grade dysplasia (HGD) and cancer within pancreatic IPMN. METHODS: Patients with IPMN who underwent preoperative CT and EUS between 2001 and 2009 were selected. Data were gathered retrospectively from medical records. RESULTS: The study group was comprised of 52 patients, 33% (17/52) of whom had HGD or cancer. On fine needle aspirate (FNA), neither carcinoembryonic antigen (CEA) >200 nor cytological analysis correlated with malignancy. In multivariate analysis, duct size >= 1.0 cm (P= 0.034) was a significant predictor of HGD or cancer, and diameter on CT scan (P= 0.056) approached significance. Lesion diameter of >= 2.5 cm on CT scan identified malignancy in 71% (12/17) of patients (P= 0.037). When analysed, all patients with HGD or cancer had a lesion diameter >= 2.5 cm and/or a duct diameter >= 1.0 cm by CT scan. CONCLUSIONS: The use of radiographic criteria on CT including lesion size >= 2.5 cm and/or pancreatic duct diameter >= 1.0 cm appears to reliably identify patients with either HGD or invasive cancer. High-resolution CT scanning may obviate the need for EUS and FNA in patients with suspected IPMN. PMID- 21241429 TI - Population-based study to estimate prevalence and determine risk factors of gallbladder diseases in the rural Gangetic basin of North India. AB - BACKGROUND: A high prevalence of gallbladder diseases (GBD) in Northern India warranted a population survey into environmental risk factors. METHODS: In 60 villages of Uttar Pradesh and Bihar from 13 334 households, 22 861 persons aged >30 years were interviewed for symptoms of GBD, diet and environmental factors. Subsequently ultrasonography (US) was performed in 5100 and 1448 people with and without symptoms, respectively. Heavy metal and pesticide content in soil and water were estimated. RESULTS: US revealed a prevalence of GBD of 6.20%. GBD was more common in 5100 persons with symptoms (7.12%) compared with 1448 without (2.99%) (P < 0.05). Adjusted odds ratio (ORs) [95% confidence interval (CI)] revealed a significantly increased risk of GBD in females >50, 1.703 (CI 1.292 2.245); multiparity 1.862 (CI 1.306-2.655) and a genetic history 1.564 (CI 1.049 2.334). An increased risk noted in males with diabetes was 4.271 (CI 2.130 8.566), chickpea consumption 2.546 (CI 1.563-4.146) and drinking unsafe water 3.835 (CI 2.368-6.209). Prevalence of gallstones was 4.15%; more in females 5.59% than males 1.99% (P < 0.05). Cluster analysis identified a positive correlation of nickel, cadmium and chromium in water with a high prevalence of GBD in adjacent villages in Vaishali district, Bihar. CONCLUSION: A high risk of GBD was observed in older, multiparous women and men with diabetes, intake of chickpeas, unsafe water and villages with heavy metal water pollution. PMID- 21241430 TI - Side-branch intraductal papillary mucinous neoplasms of the pancreatic head/uncinate: resection or enucleation? AB - INTRODUCTION: Side-branch intraductal papillary mucinous neoplasms (IPMN) of the pancreatic head/uncinate are an increasingly common indication for pancreaticoduodenectomy (PD). However, enucleation (EN) may be an alternative to PD in selected patients to improve outcomes and preserve pancreatic parenchyma. AIM: To determine peri-operative outcomes in patients with side-branch IPMN of the pancreatic head/uncinate undergoing EN or PD compared with a cohort of patients with pancreatic adenocarcinoma (PA) undergoing PD. METHODS: Retrospective review of a prospectively collected, combined, academic institutional series from 2005 to 2008. Of 107 pancreatic head/uncinate IPMN, enucleation was performed in 7 (IPMN EN) and PD was performed in 100 (IPMN PD) with 17 of these radiographically amenable to EN (IPMN PD(en) ). During the same time period, 281 patients underwent PD for PA (Control PD). RESULTS: Operative time was shorter (p<0.05) and blood loss (p<0.05) was less in the IPMN EN group compared with all other groups. Peri-operative mortality and morbidity of all IPMN groups (IPMN EN, IPMN PD(en) ) were similar to the Control PD group. Overall pancreatic fistulae rate in the IPMN EN group was higher than in the IPMN PD(en) and Control PD groups; however, the rate of grade C pancreatic fistulae was the same in all groups. CONCLUSIONS: Pancreaticoduodenectomy for side-branch IPMNs can be performed safely. Compared with PD, enucleation for IPMN has less blood loss, shorter operative time and similar morbidity, mortality, hospital length of stay (LOS) and readmission rate. Enucleation should be considered more frequently as an option for patients with unifocal side-branch IPMN. PMID- 21241431 TI - Management of delayed major visceral arterial bleeding after pancreatic surgery. AB - OBJECTIVES: Postoperative bleeding represents a life-threatening complication after pancreatic surgery. Recent developments in interventional radiology have challenged the role of surgery in bleeding control. This study aimed to assess the management of major haemorrhagic complications after pancreatic surgery at a tertiary referral centre. METHODS: Between August 1998 and June 2009, 18 patients with major bleeding after pancreatic surgery were admitted to the University Hospital of Zurich, Zurich, Switzerland. We retrospectively analysed their medical charts, focusing on diagnosis, therapy and outcome. RESULTS: Major arterial bleeding occurred after a median postoperative interval of 21.5 days (range: 9-259 days). Seventeen patients demonstrated various symptoms, such as repeated upper gastrointestinal bleeding or haemorrhagic shock. Diagnosis was usually made by contrast-enhanced computed tomography (CT). Leakage of the pancreaticojejunostomy caused the formation of a pseudoaneurysm in 78% of patients. Haemostasis was achieved in 10 patients by interventional radiology. Two patients died of massive re-bleeding. Six patients underwent primary emergency surgery, which five did not survive. CONCLUSIONS: Delayed bleeding after pancreatic surgery is suspicious for a pseudoaneurysm. Contrast-enhanced CT followed by early angiography provides accurate diagnosis and treatment. Interventional radiological treatment should be preferred over primary surgery because it is currently the most life-saving approach. PMID- 21241432 TI - Post-operative morbidity results in decreased long-term survival after resection for hilar cholangiocarcinoma. AB - BACKGROUND: The purpose of the present study was to demonstrate that post operative morbidity (PM) associated with resections of hilar cholangiocarcinoma (HCCA) is associated with short- and long-term patient survival. METHODS: Between 1998 and 2008, 51 patients with a median age of 64 years underwent resection for HCCA at a single institution. Associations between survival and clinicopathologic factors, including peri- and post-operative variables, were studied using univariate and multivariate models. RESULTS: Seventy-six per cent of patients underwent major hepatectomy with resection of the extrahepatic bile ducts. The 30 and 90-day operative mortality was 10% and 12%. The overall incidence of PM was 69%, with 68% of all PM as major (Clavien grades III-V). No difference in operative blood loss or peri-operative transfusion rates was observed for patients with major vs. minor or no PM. Patients with major PM received adjuvant chemotherapy less frequently than patients with minor or no complications 29% vs. 52%, P= 0.15. The 1-, 3- and 5-year overall (OS) and disease-specific survival (DSS) rates for all patients were 65%, 36%, 29% and 77%, 46%, 35%, respectively. Using univariate and multivariate analysis, margin status (27% R1), nodal metastasis (35% N1) and major PM were associated with OS and DSS, P < 0.01. Major PM was an independent factor associated with decreased OS and DSS [hazard ratio (HR) = 3.6 and 2.8, respectively, P < 0.05]. The median DSS for patients with major PM was 14 months compared with 40 months for patients who experienced minor or no PM, P < 0.01. CONCLUSION: Extensive operations for HCCA can produce substantial post-operative morbidity. In addition to causing early mortality, major post-operative complications are associated with decreased long-term cancer specific survival after resection of HCCA. PMID- 21241435 TI - With great power comes great responsibility--what pediatricians referring babies and small children to radiological interventions should know. PMID- 21241434 TI - Design and usability of heuristic-based deliberation tools for women facing amniocentesis. AB - BACKGROUND: Evidence suggests that in decision contexts characterized by uncertainty and time constraints (e.g. health-care decisions), fast and frugal decision-making strategies (heuristics) may perform better than complex rules of reasoning. OBJECTIVE: To examine whether it is possible to design deliberation components in decision support interventions using simple models (fast and frugal heuristics). DESIGN: The 'Take The Best' heuristic (i.e. selection of a 'most important reason') and 'The Tallying' integration algorithm (i.e. unitary weighing of pros and cons) were used to develop two deliberation components embedded in a Web-based decision support intervention for women facing amniocentesis testing. Ten researchers (recruited from 15), nine health-care providers (recruited from 28) and ten pregnant women (recruited from 14) who had recently been offered amniocentesis testing appraised evolving versions of 'your most important reason' (Take The Best) and 'weighing it up' (Tallying). RESULTS: Most researchers found the tools useful in facilitating decision making although emphasized the need for simple instructions and clear layouts. Health-care providers however expressed concerns regarding the usability and clarity of the tools. By contrast, 7 out of 10 pregnant women found the tools useful in weighing up the pros and cons of each option, helpful in structuring and clarifying their thoughts and visualizing their decision efforts. Several pregnant women felt that 'weighing it up' and 'your most important reason' were not appropriate when facing such a difficult and emotional decision. CONCLUSION: Theoretical approaches based on fast and frugal heuristics can be used to develop deliberation tools that provide helpful support to patients facing real-world decisions about amniocentesis. PMID- 21241436 TI - Selection criteria for liver transplantation in paediatric acute liver failure: the saga continues. PMID- 21241437 TI - Hematopoietic stem cell transplant: does congenital heart disease matter? PMID- 21241438 TI - Portal vein obstruction after liver transplantation in children treated by simultaneous minilaparotomy and transhepatic approaches: initial experience. AB - Portal vein thrombosis is a complication that occurs anytime after liver transplantation and can compromise the patient and graft survival. We describe a combined technique for PV recanalization in cases of PV obstruction after liver transplantation. Four children (1%), of 367 subjected to liver transplantation from June 1991 to December 2008, underwent PV recanalization through a combined approach (transhepatic and minilaparotomy). All children received left lateral hepatic segments, developed Portal vein thrombosis (n=3) and stenosis (n=1), and presented with symptoms of portal hypertension after transplantation. PV recanalization was tried by transhepatic retrograde access, and a minilaparotomy was performed when percutaneous recanalization was unsuccessful. Three patients underwent a successful portal recanalization and stent placement with the combined technique. In one patient, the recanalization was unsuccessful because of an extensive portomesenteric thrombosis. The other three children had the portal flow reestablished and followed with Doppler US studies. They received oral anticoagulation for three consecutive months after the procedure and the clinical symptoms subsided. In case of PV obstruction, the combined approach is technically feasible with good clinical and hemodynamic results. It' is a minimally invasive procedure and can be tried to avoid or delay surgical treatment or retransplantation. PMID- 21241439 TI - Governance approval for multisite, non-interventional research: what can Harmonisation of Multi-Centre Ethical Review learn from the New South Wales experience? AB - BACKGROUND: In 2007, New South Wales Health mandated the separation of ethical and scientific review from research governance at all New South Wales public health sites based on their distinction in the National Health and Medical Research Council National Statement. This separation allowed for single-site ethical review of multicentre studies. AIMS: To investigate the time taken for governance approval of multicentre studies through the site-specific approval (SSA) process. METHODS: A retrospective audit of the SSA process for five non interventional studies proposed by a university cancer research unit. RESULTS: The median total governance approval time for all submissions (n= 28) was 12 weeks (range 2.5-64); median time from starting the SSA to submission was 8 weeks (range 1-48) and median time for governance approval was 5 weeks (range 0.3-40). Approval times were shorter for public compared to private institutions. Reasons for delays in finalising submissions for approval were the absence of institutional governance officers, lack of clarity regarding signatories, the need to identify a principal investigator employed by the institution, and lack of recognition of ethical approval by private institutions. The need to develop legal agreements between the university and hospital was the main reason for lengthy delays in obtaining approval. CONCLUSIONS: The advantages of a harmonised single ethical review process were undermined by the coexistence of a fragmented, complex and lengthy governance approval process. This experience has implications for the success of the national Harmonisation of Multi-Centre Ethical Review (HoMER) model. A harmonised and fully supported national approach to research governance should be developed contemporaneously with HoMER. PMID- 21241440 TI - Prevalence and management of HER2/neu-positive early breast cancer in a single institution following availability of adjuvant trastuzumab. AB - AIM: To ascertain the prevalence of HER2/neu-positive early breast cancer (EBC), utilisation of adjuvant trastuzumab and incidence of cardiac toxicity in a community private hospital setting. METHODS: Prospective data collected by breast oncologist and surgeons in all women diagnosed with EBC at the Mount Hospital (MH) were reviewed. Women with HER2/neu-positive disease diagnosed between 1 October 2006 and 31 March 2009 were included in this analysis. RESULTS: In total, 1128 women with invasive EBC were seen in the 30-month period. All tumours underwent HER2/neu testing by immunohistochemistry, with 61% being evaluated by in situ hybridisation. Time to definitive HER2/neu result improved over time from median of 17 to 14 days. The prevalence of HER2 positivity (by in situ hybridisation) in this cohort was 12%. Uptake of trastuzumab-based treatment was 100% in those patients receiving their treatment at the MH, compared to 52% of the 25 patients treated elsewhere. Ninety-eight per cent of MH patients completed the planned 12 months of therapy, with one patient developing recurrent disease and two patients experiencing significant cardiac toxicity. Chemotherapy relative dose intensity was 98% in HER2/neu-positive and negative patients. At a median of 25 months follow up, actuarial disease-free and overall survival in the HER2/neu positive cohort is 99% and 100% respectively. CONCLUSION: In a community private hospital setting, adjuvant trastuzumab and chemotherapy was delivered optimally, in line with national and international guidelines. Early efficacy and safety results in a non-clinical trial setting underscore the significant benefits achieved with this targeted therapy in HER2/neu-positive EBC. PMID- 21241441 TI - Attitudes and views of the general public towards research participation. AB - BACKGROUND: While the challenges of recruitment into clinical trials are well described, little is known about the public's perceptions towards research. AIMS: We sought to describe the attitudes, beliefs and knowledge of the public towards research and research participation, focusing on clinical trials, contrast these attributes among individuals with different relationships with the healthcare system and to identify predictors of willingness to participate. METHODS: We conducted a self-administered cross-sectional survey of patients and their significant others in two clinics and two intensive care unit waiting rooms and in three public venues. RESULTS: We analysed responses from 417 respondents (102 and 105 in dialysis and oncology clinics, and 106 in intensive care unit (ICU) waiting rooms, 104 in public locations). While most (68.3%) respondents favoured the use of humans in clinical trials, 53% felt that trial participants always or almost always receive the best quality of care, only 30.4% had participated in clinical research. Approximately 70% felt that subjects are always advised of the risks and benefits of participation, and 30% expressed ambiguity regarding whether participants are informed of their involvement. Oncology and dialysis respondents were the most and least informed regarding research methods and ethics. The perceived risks and benefits associated with clinical circumstances influence research participation decisions and vary with healthcare experiences. We identified six predictors of willingness to participate. CONCLUSION: Attitudes of the public towards research participation are beleaguered by misconceptions. Stakeholders in clinical research must educate the general public regarding research methods and ethics. PMID- 21241442 TI - A variant in microRNA-196a2 is not associated with susceptibility to and progression of colorectal cancer in Chinese. AB - BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs with regulatory functions as tumour suppressors and oncogenes. Although single nucleotide polymorphism (SNP) in miRNA regions have been reported to be rare and unlikely to be functionally important, recent evidence suggested that rs11614913 SNP in miR 196a2 was associated with the susceptibility of lung cancer, breast cancer, congenital heart disease and shortened survival time of non-small-cell lung cancer. AIMS: The aim of this study was to investigate the association between this genetic variant and the risk and/or progression of colorectal cancer (CRC). METHODS: A total of 126 CRC patients and 407 healthy controls was periodically enrolled. DNA was extracted from blood specimens, and miR-196a2 polymorphism was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). RESULTS: Although the frequency of CC homozygotes or miR-196a2C allele-containing genotypes (CT and CC) was lower in CRC patients than in the healthy controls, no significant association between miR-196a2 polymorphism and the risk of CRC was found. The frequency of the 'C' allele in CRC patients was also not significantly lower than in healthy controls. In a subsequent analysis of the association between this polymorphism and the progression of CRC, there was still no significant difference in both genotype and allelic frequency. CONCLUSIONS: Our results suggest that miR-196a2 polymorphism is not associated with both an increased risk and progression of CRC in Chinese. PMID- 21241443 TI - Assessment of chronic hepatitis B: the importance of hepatitis B virus DNA testing. AB - BACKGROUND: Chronic hepatitis B (CHB) has an estimated prevalence of 90 000 to 160 000 in Australia. Cirrhosis and hepatocellular carcinoma are important complications of CHB and appropriate evaluation of hepatitis B surface antigen (HBsAg)-positive individuals is vital to identify treatment candidates. METHODS: A review of the database of a tertiary hospital was performed and 348 HBsAg positive individuals with baseline demographic, virological, serological and biochemical variables were identified and evaluated cross-sectionally. A small subgroup of hepatitis B e antigen (HBeAg)-negative patients with normal alanine aminotransferase (ALT) at baseline were identified and followed longitudinally. RESULTS: 175/348 (50%) of patients were in the HBeAg-negative, chronic hepatitis phase of disease, 22% in the HBeAg-positive immune clearance and 6% in the immune tolerant phases. HBeAg-negative patients were older and more likely to be male than HBeAg-positive patients. The correlation between hepatitis B virus (HBV) DNA and ALT levels was examined. ALT and HBV DNA levels showed no correlation in HBeAg-positive CHB and only a weak correlation in HBeAg-negative patients. Furthermore, 35% of HBeAg-negative patients with detectable HBV DNA had a normal ALT. Conversely 38% of HBeAg-negative patients with no detectable HBV DNA had an elevated ALT. A persistently normal ALT over 24 months was seen in five of nine HBeAg-negative patients with normal initial ALT and detectable HBV DNA. CONCLUSION: Appropriate evaluation of HBeAg-negative CHB must include HBV DNA because the ALT is not a reliable guide to underlying viral replication. PMID- 21241444 TI - Comparison of the bacterial isolates and antibiotic resistance patterns of elderly nursing home and general community patients. AB - BACKGROUND: Nursing home-acquired infections may differ from general community acquired infections in bacteriology and antibiotic resistance. However, there are currently limited data on this topic in the Australian setting. AIMS: To compare bacterial isolates and antibiotic resistance patterns, from pathology specimens of nursing home and community patients, and to comment on the suitability of empiric antibiotic guidelines for nursing home-acquired infection. METHODS: This was a retrospective cohort study of patients, aged >= 65 years, who resided in either nursing homes or the general community. Patients with a hospital admission in the previous 28 days were excluded. Positive specimen cultures, collected between July 2003 and June 2008 in the Emergency Department and Outpatient Clinics of the Austin Hospital (Melbourne), were examined. The main outcome measures were the bacterial isolates, and their antibiotic resistance patterns, of patients from nursing homes and the general community. RESULTS: Specimens of blood (638), sputum (425), urine (4044) and wound cultures (785) were examined. The bacteriology of blood culture isolates did not differ between the two groups (P= 0.3). However, the bacteriology of sputum, urine and wound cultures differed significantly between the groups (P= 0.025, P < 0.001, P= 0.004 respectively). There were also higher proportions of antibiotic resistance among some bacteria in nursing home patients, especially methicillin resistance among Staphylococcus aureus isolates across all specimen types, and resistance to several empiric antibiotics among Enterobacteriaceae isolates in urine cultures. CONCLUSION: Empiric antibiotic guidelines appear adequate to treat nursing home-acquired septicaemia and pneumonia. However, guidelines for urinary tract infections and wound infections may need to be refined. PMID- 21241445 TI - Anhedonia in Japanese patients with Parkinson's disease. AB - AIM: Anhedonia has been proposed as a specific mood disorder related to the dopaminergic nerve dysfunction seen in Parkinson's disease (PD). This study examined hedonic tone in patients with PD using the Snaith-Hamilton Pleasure Scale (SHAPS) and investigated the associations with depressive mood by the Self Rating Questionnaire for Depression (SRQ-D). METHODS: This study examined 100 patients with PD and 111 age-matched controls (C2) recruited from 300 healthy subjects (C1) to compare the frequency of anhedonia and to clarify whether anhedonia in PD is associated with depression and anti-Parkinson medication. RESULTS: Forty-six percent of PD patients revealed possible/probable depression and 10 patients (10%) with PD showed anhedonia as compared to 3.3% in C1 and 2.7% in C2. The reduction in hedonic tone was related to depression in PD. Among 10 PD patients with anhedonia, seven were in anhedonia with depression and three were in anhedonia without depression. There was no sex difference in anhedonia and depression. No patients treated with pramipexole showed anhedonia but also the highest proportion of normal hedonic tone was found in patients treated with pramipexole among PD patients. In analysis of each SHAPS item, no significant difference was seen on social interaction scores in contrast to the significant reduction of interest/pastimes and sensory experience and food/drink scores between PD patients and C1/C2. CONCLUSION: Anhedonia may overlap depressive syndrome but some PD patients without depression presented anhedonia. Pramipexole could maintain hedonic tone. The PD patients could enjoy attracting attention and wish to do things helpful for others. PMID- 21241446 TI - Fear of falling and falls self-efficacy and their relationship to higher-level competence among community-dwelling senior men and women in Japan. AB - AIM: This cross-sectional study examined the relationships of fear of falling and falls self-efficacy with higher-level competence among community-dwelling senior citizens in Japan. METHODS: Of the 822 registered senior citizens, 731 (89%) community dwellers were requested to participate in the survey using a mailed self-accomplished questionnaire. Data from 648 respondents with duly accomplished questionnaires were analyzed using R(2) , the coefficient of determination, based on a multivariate regression analysis. RESULTS: Fear of falling, low falls self efficacy and higher-level functional disability were observed among respondents. Of the hypothesized relationships examined by sex, fear of falling was significantly associated with disability among male respondents and low falls self-efficacy among both sexes. Several confounding variables were strongly associated with competence. CONCLUSION: While the data underscore the strategic importance of promoting higher-level competence among the senior citizens, there is much to suggest that their competence is likely to be maintained if their fear of falling and falls self-efficacy were modified. Programs must also consider a wide array of intervening factors. PMID- 21241447 TI - Effects of laughter therapy on depression, cognition and sleep among the community-dwelling elderly. AB - AIM: To investigate the effects of laughter therapy on depression, cognitive function, quality of life, and sleep of the elderly in a community. METHODS: Between July and September 2007, the total study sample consisted of 109 subjects aged over 65 divided into two groups; 48 subjects in the laughter therapy group and 61 subjects in the control group. The subjects in the laughter therapy group underwent laughter therapy four times over 1 month. We compared Geriatric Depression Scale (GDS), Mini-Mental State Examination (MMSE), Short-Form Health Survey-36 (SF-36), Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Index (PSQI) between the two groups before and after laughter therapy. RESULTS: There were no significant differences in baseline characteristics between the two groups. Before laughter therapy, the GDS scores were 7.98 +/- 3.58 and 8.08 +/- 3.96; the MMSE scores were 23.81 +/- 3.90 and 22.74 +/- 4.00; total scores of SF 36 were 54.77 +/- 17.63 and 52.54 +/- 21.31; the ISI scores were 8.00 +/- 6.29 and 8.36 +/- 6.38; the PSQI scores were 6.98 +/- 3.41 and 7.38 +/- 3.70 in laughter therapy group and control groups, respectively. After laughter therapy, the GDS scores were 6.94 +/- 3.19 (P=0.027) and 8.43 +/- 3.44 (P=0.422); the MMSE scores were 24.63 +/- 3.53 (P=0.168) and 23.70 +/- 3.85 (P=0.068); total scores of SF-36 were 52.24 +/- 17.63 (P=0.347) and 50.32 +/- 19.66 (P=0.392); the ISI scores were 7.58 +/- 5.38 (P=0.327) and 9.31 +/- 6.35 (P=0.019); the PSQI scores were 6.04 +/- 2.35 (P=0.019) and 7.30 +/- 3.74 (P=0.847) in both groups, respectively. CONCLUSION: Laughter therapy is considered to be useful, cost effective and easily-accessible intervention that has positive effects on depression, insomnia, and sleep quality in the elderly. PMID- 21241448 TI - Serum high-density lipoprotein cholesterol levels, their relationship with baseline functional and cognitive status, and their utility in predicting mortality in nonagenarians. AB - AIM: Little is known about the role of high-density lipoprotein cholesterol (HDL C) in oldest-old subjects. The aim of this study is to evaluate the association between HDL-C levels and physical and cognitive performance indicators in nonagenarians, and also to determine the influence of HDL-C levels on the 3-year mortality risk. METHODS: The data analyzed were taken from the NonaSantfeliu Study. Functional status was determined by the Lawton-Brody Index (LI) for instrumental activities of daily living (IADL) and the Barthel Index (BI) for basic activities (BADL). Cognition was assessed using the Spanish version of the Mini-Mental State Examination (MEC). RESULTS: The sample consisted of 49 women (79%) and 13 men, aged 94.3 +/- 2.6 years. Mean HDL-C levels were 60 +/- 16 mg/dL, and 16 subjects (25.8%) had low HDL-C values. HDL-C levels did correlate with BI (r = 0.28, P = 0.02) and LI (r = 0.32, P = 0.01), but not with MEC (r = 0.18, P = 0.15). Normal HDL-C levels at baseline were significantly associated with higher BI scores (P < 0.006, odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01-1.05) and a lower number of prescription drugs used (P < 0.04, OR = 0.71, 95% CI = 0.49-0.99). Baseline HDL-C levels were significantly lower among the group of nonagenarians who died within the 3 years of follow up (P = 0.02). However, after adjusting for potential confounders, the association between HDL-C and mortality lost significance. CONCLUSION: Higher levels of HDL-C correlate with better functional status and less use of prescribed drugs in nonagenarians. However, the relationship between low HDL-C levels and long-term mortality in this population remains unclear. PMID- 21241449 TI - Nuclear Argonaute 2 regulates adipose tissue-derived stem cell survival through direct control of miR10b and selenoprotein N1 expression. AB - Argonaute 2 (Ago2) has a leading function in miRNA-induced RNA silencing, a conserved gene regulatory mechanism in cells and organisms. miRNAs are critical for stem cell self-renewal, development, and other functions. Here, we report that nuclear Ago2, by binding to a specific region of functional genes, directly controls adipose tissue-derived stem cell (ATSC) survival in response to a critical dose of reactive oxygen species (ROS)-mediated oxidative cell damage or senescence. The role of nuclear Ago2 has not been previously reported. Here, we show that human ATSCs in which Ago2 was downregulated underwent apoptosis. Silencing of Ago2 in ATSCs significantly induces upregulation of miR10b and miR23b expression. These miRNAs directly interfere with ROS-scavenging gene expression, such as TXNL1 and GPX3. Upregulation of miR10b and miR23b is sufficient to induce ATSC cell apoptosis via p38 MAPK phosphorylation and caspase 3 activation. In addition, Ago2 overexpression or interference by miR10b and miR23b expression in ATSCs partially rescued H(2) O(2) /ROS-mediated apoptotic cell death by upregulating the expression of TXNL2, JUNK, caspase-3, and cytochrome C. Nuclear Ago2-mediated miR10b and miR23b downregulation also allows cells to escape senescence, which results in telomerase reverse transcriptase, stemness overexpression, and improved self-renewal and differentiation through Wnt5a/beta-catenin activation. Argonaute 2 expression is critical for stem cells to escape senescence by downregulating miR10b and miR23b. The Ago2-binding gene selenoprotein N1 (SEPN1) was also effectively involved in ATSC survival and self renewal through ROS-mediated p38 MAPK inactivation. PMID- 21241450 TI - HIF-1 modulates longevity and healthspan in a temperature-dependent manner. AB - The hypoxia-inducible factor HIF-1 has recently been identified as an important modifier of longevity in the roundworm Caenorhabditis elegans. Studies have reported that HIF-1 can function as both a positive and negative regulator of life span, and several disparate models have been proposed for the role of HIF in aging. Here, we resolve many of the apparent discrepancies between these studies. We find that stabilization of HIF-1 increases life span robustly under all conditions tested; however, deletion of hif-1 increases life span in a temperature-dependent manner. Animals lacking HIF-1 are long lived at 25 degrees C but not at 15 degrees C. We further report that deletion or RNAi knockdown of hif-1 impairs healthspan at lower temperatures because of an age-dependent loss of vulval integrity. Deletion of hif-1 extends life span modestly at 20 degrees C when animals displaying the vulval integrity defect are censored from the experimental data, but fails to extend life span if these animals are included. Knockdown of hif-1 results in nuclear relocalization of the FOXO transcription factor DAF-16, and DAF-16 is required for life span extension from deletion of hif-1 at all temperatures regardless of censoring. PMID- 21241451 TI - E47 retroviral rescue of intrinsic B-cell defects in senescent mice. AB - In aging, immune responses are dramatically impaired, specifically the ability to produce protective antibodies. We previously showed that with age there is a B cell intrinsic decrease in class switch recombination (CSR) because of a decrease in activation-induced cytidine deaminase (AID). One mechanism we have demonstrated for decreased AID includes increased mRNA degradation of the transcription factor E47, critical for AID transcription. Here, we show by means of a retroviral construct containing the DsRED reporter and the 3'UTR of E47 that the 3'UTR lowers mRNA expression, and particularly in B cells from old mice. This is the first demonstration that the E47 3'UTR directly regulates its degradation. The AID mRNA was not differentially regulated by degradation in aging. Therefore, we have here further established critical components for decreased AID with age. The major aim of this study was to establish conditions for the rescue of the intrinsic defect of aged B cells with retroviral addition of the coding region of E47 in splenic B cells to restore their ability to produce optimal AID and class switch to IgG. In this study, we show that young and old primary B cells overexpressing a stable E47 mRNA up-regulate E47, AID, and CSR and improve B-cell immune responses in senescent murine B cells. Our results provide a proof of principle for the rescue of intrinsic B-cell defects and the humoral immune response in senescence. PMID- 21241453 TI - Postorgasmic Illness Syndrome (POIS) in 45 Dutch caucasian males: clinical characteristics and evidence for an immunogenic pathogenesis (Part 1). AB - INTRODUCTION: Postorgasmic illness syndrome (POIS) is a combination of local allergic symptoms and transient flu-like illness. In this study, the investigators propose five preliminary criteria to establish the diagnosis. AIM: To describe the clinical details in 45 males being suspected of having POIS and to test an immunogenic hypothesis as the underlying mechanism of their presentations. METHODS: Forty-five males were studied according to standardized protocol, including neuropsychiatric and medical sexological evaluations; their complaints were categorized using their own words, and their self-perceived intravaginal ejaculation latency time (IELT). Skin-prick testing with autologous diluted semen in 33 men were also performed. MAIN OUTCOME MEASURES: Clinical features of POIS including self-perceived IELTs and the results of skin-prick testing with autologous diluted seminal fluid. RESULTS: Of the 45 included men, 33 subjects consented with skin-prick testing. Of them, 29 (88%) men had a positive skin-prick test with their own (autologous) semen, and four had a negative test. In 87% of men, POIS symptoms started within 30 minutes after ejaculation. Complaints of POIS were categorized in seven clusters of symptoms, e.g., general, flu-like, head, eyes, nose, throat, and muscles. Local allergic reactions of eyes and nose were reported in 44% and 33% of subjects, a flu-like syndrome in 78% of subjects, exhaustion and concentration difficulties in 80% and 87% of subjects. Of all subjects, 58% had an atopic constitution. Lifelong premature ejaculation, defined as self-perceived IELT < 1 minute, was reported in 25 (56%) of subjects. CONCLUSIONS: The combination of allergic and systemic flu like reactions post-ejaculation together with a positive skin-prick test in the majority of males underscores the hypothesis of an "immunogenic" etiology of POIS, e.g., that POIS is caused by Type-1 and Type-IV allergy to the males' own semen, as soon it is triggered by ejaculation. PMID- 21241454 TI - Hyposensitization therapy with autologous semen in two Dutch caucasian males: beneficial effects in Postorgasmic Illness Syndrome (POIS; Part 2). AB - INTRODUCTION: Postorgasmic illness syndrome (POIS) is a post-ejaculatory complex of local and/or systemic symptoms that nearly always occurs within seconds, minutes, or hours post-masturbation, coitus, or spontaneous ejaculation. Recent data suggest an autoimmunogenic/allergic underlying mechanism. AIM: To treat males with POIS by hyposensitization with their own semen (autologous semen). METHODS: Two males suffering from POIS, of which one male with coincidental lifelong premature ejaculation (PE) were investigated. Based on their local and systemic symptoms including a positive dermatologic reaction after skin-prick testing with autologous semen, auto-allergy to semen was likely an underlying mechanism. A hyposensitization program was initiated, including multiple subcutaneous (SC) injections with autologous semen, initially at 2 weeks intervals in the first year and gradually at 4 weeks intervals in the second and third year. From initial semen dilutions of 1 on 40,000 and 1 on 20,000, the titers were gradually increased to 1 on 20 and 1 to 280, respectively. MAIN OUTCOME MEASURES: Evaluation with a dedicated questionnaire about severity of POIS symptoms and specialized interviews on self-perceived intravaginal ejaculation latency times (IELT) before and during the desensitization program. RESULTS: POIS was confirmed in both subjects, PE was confirmed in one male, and skin-prick tests with autologous semen in both subjects were positive. During the program, gradual reduction of complaints resulted in 60% and 90% amelioration of POIS complaints at 31 and 15 months, respectively, which coincided in one male with a delay of the IELT from 20 seconds at baseline to 10 minutes after 3 years of treatment. The cause of this association with IELT is unknown and remains to be elucidated. CONCLUSIONS: Two males with POIS were successfully treated by hyposensitization with autologous semen, which supports an immunogenic/allergic etiology and underscores the clinical implication for immunological sexual medicine. PMID- 21241452 TI - Accelerated hematopoietic stem cell aging in a mouse model of dyskeratosis congenita responds to antioxidant treatment. AB - Mutations in DKC1, encoding telomerase associated protein dyskerin, cause X linked dyskeratosis congenita (DC), a bone marrow (BM) failure, and cancer susceptibility syndrome. Decreased accumulation of telomerase RNA resulting in excessive telomere shortening and premature cellular senescence is thought to be the primary cause of disease in X-linked DC. Affected tissues are those that require constant renewal by stem cell activity. We previously showed that in Dkc1(Delta15) mice, which contain a mutation that is a copy of a human mutation causing DC, mutant cells have a telomerase-dependent proliferative defect and increased accumulation of DNA damage in the first generation before the telomeres are short. We now demonstrate the presence of the growth defect in Dkc1(Delta15) mouse embryonic fibroblasts in vitro and show that accumulation of DNA damage and levels of reactive oxygen species increase with increasing population doublings. Treatment with the antioxidant, N-acetyl cysteine (NAC), partially rescued the growth disadvantage of mutant cells in vitro and in vivo. Competitive BM repopulation experiments showed that the Dkc1(Delta15) mutation is associated with a functional stem cell defect that becomes more severe with increasing age, consistent with accelerated senescence, a hallmark of DC hematopoiesis. This stem cell phenotype was partially corrected by NAC treatment. These results suggest that a pathogenic Dkc1 mutation accelerates stem cell aging, that increased oxidative stress might play a role in the pathogenesis of X-linked DC, and that some manifestations of DC may be prevented or delayed by antioxidant treatment. PMID- 21241455 TI - In vitro antifungal and antibacterial activities of pentacycloundecane tetra amines. AB - The antifungal and antimicrobial activities of three pentacycloundecane (PCU) tetra-amine derivatives are reported herein. The in vitro activity of these PCU derivatives against yeasts (Candida albicans and non-albicans species) and filamentous fungi was evaluated using the Clinical and Laboratory Standards Institute (CLSI) M27-A2 and M38-A2 guidelines and the 2H-tetrazolium salt, (MTS) colorimetric method. The minimum inhibitory concentration against most of the tested clinical fungal strains for GKM8 and GKM9 derivatives ranges from 15.6 to 62.5 MUg/mL while GKM11 ranged from 3.9 to 7.8 MUg/mL. The GKM11 derivative was also active against fluconazole-resistant strains of fungi. The GKM11 derivative also exhibited promising activity against filamentous fungi in that it was 2.5 times more active than amphotericin B against Sporothrix schenckii. Antibacterial activity was determined using the broth microdilution method (BMM) and the iodonitrotetrazolium chloride (INT) colorimetric method. The GKM11 derivative was mainly active against Gram-positive bacteria with MIC ranging from 3.9 to 7.8 MUg/mL. Activity against Gram-negative bacteria tested was limited to Escherichia coli and Elizabethkingia meningoseptica (MIC of 31 MUg/mL). PMID- 21241456 TI - The combination of L-arginine and ischaemic post-conditioning at the onset of reperfusion limits myocardial injury in the pig. AB - AIM: To investigate whether ischaemic post-conditioning (IPoC) combined with i.v. infusion of the nitric oxide (NO) substrate L-arginine at the onset of reperfusion exerts cardioprotective effect that is superior to either treatment given separately. METHODS: Twenty-six anesthetized pigs were subjected to coronary artery (left anterior descending artery, LAD) ligation for 40 min followed by 4 h reperfusion. The pigs were randomized into five different groups receiving either i.v. vehicle, i.v. L-arginine, IPoC 4 * 60 s together with i.v. vehicle or IPoC together with i.v. L-arginine and a group with IPoC 8 * 30 s. All infusions were started 10 min before reperfusion. RESULTS: The infarct size of the vehicle group was 82 +/- 4% of the area at risk. L-Arginine alone (79 +/- 8%), IPoC 4 * 60 s vehicle (86 +/- 3%) or IPoC 8 * 30 s vehicle (94 +/- 7%) did not affect infarct size. l-Arginine together with IPoC significantly reduced infarct size to 59 +/- 4% (P < 0.01). Except for higher LAD flow during early reperfusion in the IPoC L-arginine group, haemodynamic parameters did not differ between the four main groups. Heart rate and rate pressure product were lower during ischaemia and reperfusion in the IPoC 8 * 30 s vehicle group. In comparison with the vehicle group, there were no changes in the expression of Akt, phosphorylated Akt Ser(473) , inducible NO synthase, endothelial NO synthase (eNOS) or phosphorylated eNOS Ser(1177) in the ischaemic/reperfused myocardium. CONCLUSION: L-Arginine given systemically at the onset of reperfusion protects the pig heart against ischaemia and reperfusion injury only when combined with IPoC. These results indicate that the combination of the two treatment strategies exerts cardioprotection. PMID- 21241457 TI - Caffeine activates preferentially alpha1-isoform of 5'AMP-activated protein kinase in rat skeletal muscle. AB - AIM: Caffeine activates 5'AMP-activated protein kinase (AMPK), a signalling intermediary implicated in the regulation of glucose, lipid and energy metabolism in skeletal muscle. Skeletal muscle expresses two catalytic alpha subunits of AMPK, alpha1 and alpha2, but the isoform specificity of caffeine-induced AMPK activation is unclear. The aim of this study was to determine which alpha isoform is preferentially activated by caffeine in vitro and in vivo using rat skeletal muscle. METHODS: Rat epitrochlearis muscle was isolated and incubated in vitro in the absence or presence of caffeine. In another experiment, the muscle was dissected after intravenous injection of caffeine. Isoform-specific AMPK activity, the phosphorylation status of AMPKalpha Thr(172) and acetyl-CoA carboxylase (ACC) Ser(79) , the concentrations of ATP, phosphocreatine (PCr) and glycogen, and 3-O-methyl-d-glucose (3MG) transport activity were estimated. RESULTS: Incubation of isolated epitrochlearis muscle with 1 mm of caffeine for 15 min increased AMPKalpha1 activity, but not AMPKalpha2 activity; concentrations of ATP, PCr and glycogen were not affected. Incubation with 3 mm of caffeine activated AMPKalpha2 and reduced PCr and glycogen concentrations. Incubation with 1 mm of caffeine increased the phosphorylation of AMPK and ACC and enhanced 3MG transport. Intravenous injection of caffeine (5 mg kg(-1) ) predominantly activated AMPKalpha1 and increased 3MG transport without affecting energy status. CONCLUSION: Our results suggest that of the two alpha isoforms of AMPK, AMPKalpha1 is predominantly activated by caffeine via an energy-independent mechanism and that the activation of AMPKalpha1 increases glucose transport and ACC phosphorylation in skeletal muscle. PMID- 21241458 TI - The next generation of review for cardiac cell therapies. PMID- 21241459 TI - From fibroblast cells to cardiomyocytes: direct lineage reprogramming. AB - Recent advances in stem cell biology have established the feasibility of reprogramming human and murine fibroblast cells into induced pluripotent stem cells. Three master regulators have been demonstrated to be sufficient in the management of cell status of 'pluripotent' versus 'differentiated'. The same strategy has been used to directly convert one somatic cell type into another cell type, such as the converting of exocrine pancreas cells into cells closely resembling beta cells and the reprogramming of fibroblast cells into functional neuron cells. Srivastava's group reported the first direct reprogramming of mouse fibroblast cells into mesoderm lineage cells (cardiomyocytes) with the enforced expression of three cardiac transcriptional factors: Gata4, Mef2c, and Tbx5. The induced cardiomyocytes exhibit a global gene expression profile and basic electrophysiological characteristics similar to those of postnatal cardiomyocytes. This study made significant advances in cardiovascular and stem cell fields and has important implications in understanding heart developmental biology as well as in potential therapies of human cardiovascular diseases. PMID- 21241460 TI - Essential fatty acids for premenstrual syndrome and their effect on prolactin and total cholesterol levels: a randomized, double blind, placebo-controlled study. AB - OBJECTIVE: To evaluate the effectiveness and safety of polyunsaturated fatty acids for the treatment of the premenstrual syndrome (PMS) using a graded symptom scale and to assess the effect of this treatment on basal plasma levels of prolactin and total cholesterol. METHODS: A randomized, double-blind, placebo controlled study was conducted with 120 women with PMS divided into three groups and treated with 1 or 2 grams of the medication or placebo. Symptoms were recorded over a 6-month period using the Prospective Record of the Impact and Severity of Menstruation (PRISM) calendar. Total cholesterol and prolactin levels were measured. Analysis of variance (ANOVA), Pearson's chi-square test, Wilcoxon's nonparametric signed-rank test for paired samples and the Mann-Whitney nonparametric test for independent samples were used in the statistical analysis. RESULTS: There were no differences in age, marital status, schooling or ethnicity between the groups. In the group treated with 1 gram of the medication, a significant reduction was found when the median PRISM score recorded in the luteal phase at baseline (99) was compared with the median score recorded in the 3rd month (58) and in the 6th month of evaluation (35). In the 2-gram group, these differences were even more significant (baseline score: 98; 3rd month: 48; 6th month: 28). In the placebo group, there was a significant reduction at the 3rd but not at the 6th month (baseline: 96.5; 3rd month: 63.5; 6th month: 62). The difference between the phases of the menstrual cycle was greater in the 2 gram group compared to the group treated with 1 gram of the medication. There were no statistically significant differences in prolactin or total cholesterol levels between baseline values and those recorded after six months of treatment. CONCLUSION: The difference between the groups using the medication and the placebo group with respect to the improvement in symptomatology appears to indicate the effectiveness of the drug. Improvement in symptoms was higher when the 2-gram dose was used. This medication was not associated with any changes in prolactin or total cholesterol levels in these women. PMID- 21241461 TI - Macrophage and Galleria mellonella infection models reflect the virulence of naturally occurring isolates of B. pseudomallei, B. thailandensis and B. oklahomensis. AB - BACKGROUND: Burkholderia pseudomallei is the causative agent of melioidosis, a tropical disease of humans with a variable and often fatal outcome. In murine models of infection, different strains exhibit varying degrees of virulence. In contrast, two related species, B. thailandensis and B. oklahomensis, are highly attenuated in mice. Our aim was to determine whether virulence in mice is reflected in macrophage or wax moth larvae (Galleria mellonella) infection models. RESULTS: B. pseudomallei strains 576 and K96243, which have low median lethal dose (MLD) values in mice, were able to replicate and induce cellular damage in macrophages and caused rapid death of G. mellonella. In contrast, B. pseudomallei strain 708a, which is attenuated in mice, showed reduced replication in macrophages, negligible cellular damage and was avirulent in G. mellonella larvae. B. thailandensis isolates were less virulent than B. pseudomallei in all of the models tested. However, we did record strain dependent differences. B. oklahomensis isolates were the least virulent isolates. They showed minimal ability to replicate in macrophages, were unable to evoke actin-based motility or to form multinucleated giant cells and were markedly attenuated in G. mellonella compared to B. thailandensis. CONCLUSIONS: We have shown that the alternative infection models tested here, namely macrophages and Galleria mellonella, are able to distinguish between strains of B. pseudomallei, B. thailandensis and B. oklahomensis and that these differences reflect the observed virulence in murine infection models. Our results indicate that B. oklahomensis is the least pathogenic of the species investigated. They also show a correlation between isolates of B. thailandensis associated with human infection and virulence in macrophage and Galleria infection models. PMID- 21241463 TI - Complete response for advanced liver cancer during sorafenib therapy: case report. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the fifth most common neoplasia in the world. In the past, treatment of advanced HCC with conventional antineoplastic drugs did not result in satisfactory outcomes: recently, in this patient population the oral multikinase inhibitor sorafenib has been able to induce a statistically significant improvement of overall survival. Similarly to other anti-angiogenic drugs employed in other tumour types, also sorafenib seldom induces the dimensional tumour shrinking usually observed with conventional cytotoxic drugs: data gathered from studies carried out with sorafenib and other competitors under development do not report any complete response in HCV-induced HCC. CASE PRESENTATION: An 84-year old man with a long-lasting history of chronic HCV hepatitis was referred to our Institution for an ultrasonography investigation of a focal hepatic lesion. To better characterize the liver disease and clearly define the diagnosis of the focal hepatic lesion, the patient was hospitalized in our department. Laboratory and instrumental investigations confirmed the clinical picture of HCV-related liver cirrhosis and identified a hepatic lesion of about 6 cm featuring infiltrating HCC with thrombosis of the portal trunk. Due to the advanced stage of the disease, therapy with sorafenib 400 mg bid was started. Right from one month after the treatment was started, a reduction of alpha-fetoprotein level was observed which, by the third month, turned down within the normal limits. In addition the CT scan showed 50% reduction of the neoplastic lesion along with canalization of the portal trunk. At the sixth month the normalization of the alpha-fetoprotein level at the lower limit of normality was confirmed and the MRI showed complete disappearance of the neoplasia. In addition a reduction of a metallo-proteinase serum level was observed. At the twelfth month a further MRI confirmed complete response had been maintained. At present the patient is in a follow-up program to evaluate the duration of the complete response. CONCLUSIONS: This case is worth mentioning since, to the best of our knowledge, it represents the first evidence of complete response to sorafenib in an elderly patient with advanced HCV-related HCC. PMID- 21241462 TI - The blockade of the transient receptor potential vanilloid type 1 and fatty acid amide hydrolase decreases symptoms and central sequelae in the medial prefrontal cortex of neuropathic rats. AB - BACKGROUND: Neuropathic pain is a chronic disease resulting from dysfunction within the "pain matrix". The basolateral amygdala (BLA) can modulate cortical functions and interactions between this structure and the medial prefrontal cortex (mPFC) are important for integrating emotionally salient information. In this study, we have investigated the involvement of the transient receptor potential vanilloid type 1 (TRPV1) and the catabolic enzyme fatty acid amide hydrolase (FAAH) in the morphofunctional changes occurring in the pre limbic/infra-limbic (PL/IL) cortex in neuropathic rats. RESULTS: The effect of N arachidonoyl-serotonin (AA-5-HT), a hybrid FAAH inhibitor and TPRV1 channel antagonist, was tested on nociceptive behaviour associated with neuropathic pain as well as on some phenotypic changes occurring on PL/IL cortex pyramidal neurons. Those neurons were identified as belonging to the BLA-mPFC pathway by electrical stimulation of the BLA followed by hind-paw pressoceptive stimulus application. Changes in their spontaneous and evoked activity were studied in sham or spared nerve injury (SNI) rats before or after repeated treatment with AA 5-HT. Consistently with the SNI-induced changes in PL/IL cortex neurons which underwent profound phenotypic reorganization, suggesting a profound imbalance between excitatory and inhibitory responses in the mPFC neurons, we found an increase in extracellular glutamate levels, as well as the up-regulation of FAAH and TRPV1 in the PL/IL cortex of SNI rats. Daily treatment with AA-5-HT restored cortical neuronal activity, normalizing the electrophysiological changes associated with the peripheral injury of the sciatic nerve. Finally, a single acute intra-PL/IL cortex microinjection of AA-5-HT transiently decreased allodynia more effectively than URB597 or I-RTX, a selective FAAH inhibitor or a TRPV1 blocker, respectively. CONCLUSION: These data suggest a possible involvement of endovanilloids in the cortical plastic changes associated with peripheral nerve injury and indicate that therapies able to normalize endovanilloid transmission may prove useful in ameliorating the symptoms and central sequelae associated with neuropathic pain. PMID- 21241464 TI - Systems biology of interstitial lung diseases: integration of mRNA and microRNA expression changes. AB - BACKGROUND: The molecular pathways involved in the interstitial lung diseases (ILDs) are poorly understood. Systems biology approaches, with global expression data sets, were used to identify perturbed gene networks, to gain some understanding of the underlying mechanisms, and to develop specific hypotheses relevant to these chronic lung diseases. METHODS: Lung tissue samples from patients with different types of ILD were obtained from the Lung Tissue Research Consortium and total cell RNA was isolated. Global mRNA and microRNA were profiled by hybridization and amplification-based methods. Differentially expressed genes were compiled and used to identify critical signaling pathways and potential biomarkers. Modules of genes were identified that formed a regulatory network, and studies were performed on cultured cells in vitro for comparison with the in vivo results. RESULTS: By profiling mRNA and microRNA (miRNA) expression levels, we found subsets of differentially expressed genes that distinguished patients with ILDs from controls and that correlated with different disease stages and subtypes of ILDs. Network analysis, based on pathway databases, revealed several disease-associated gene modules, involving genes from the TGF-beta, Wnt, focal adhesion, and smooth muscle actin pathways that are implicated in advancing fibrosis, a critical pathological process in ILDs. A more comprehensive approach was also adapted to construct a putative global gene regulatory network based on the perturbation of key regulatory elements, transcription factors and microRNAs. Our data underscores the importance of TGF beta signaling and the persistence of smooth muscle actin-containing fibroblasts in these diseases. We present evidence that, downstream of TGF-beta signaling, microRNAs of the miR-23a cluster and the transcription factor Zeb1 could have roles in mediating an epithelial to mesenchymal transition (EMT) and the resultant persistence of mesenchymal cells in these diseases. CONCLUSIONS: We present a comprehensive overview of the molecular networks perturbed in ILDs, discuss several potential key molecular regulatory circuits, and identify microRNA species that may play central roles in facilitating the progression of ILDs. These findings advance our understanding of these diseases at the molecular level, provide new molecular signatures in defining the specific characteristics of the diseases, suggest new hypotheses, and reveal new potential targets for therapeutic intervention. PMID- 21241465 TI - Impact of breakfast on daily energy intake--an analysis of absolute versus relative breakfast calories. AB - OBJECTIVE: The role of breakfast energy in total daily energy intake is a matter of debate. Acute feeding experiments demonstrated that high breakfast energy leads to greater overall intake supported by cross-sectional data of a free living population. On the other hand, a large intraindividual analysis has indicated that a high proportion of breakfast to overall intake is associated with lower daily energy intake. To evaluate these apparently contradictory results in greater detail both ways of analysis were applied to the same data set of dietary records. METHODS: On an intraindividual basis total daily energy intake was related to the absolute values of breakfast energy intake or to the ratio of breakfast to overall intake, respectively. Food intake of 280 obese and 100 normal weight subjects was analyzed who recorded over 10 (obese) or 14 (normal weight) consecutive days, respectively. RESULTS: Increasing breakfast energy was associated with greater overall intake in normal weight and obese subjects. The increasing ratio of breakfast to total daily energy intake was associated with a significant reduction of overall intake on days where post breakfast energy was significantly reduced. Correlational and multiple regression analysis support the concept that absolute breakfast calories have the strongest influence on daily energy intake. CONCLUSION: Reduced breakfast energy intake is associated with lower total daily intake. The influence of the ratio of breakfast to overall energy intake largely depends on the post-breakfast rather than breakfast intake pattern. Therefore, overweight and obese subjects should consider the reduction of breakfast calories as a simple option to improve their daily energy balance. PMID- 21241466 TI - Excess healthcare burden during 1918-1920 influenza pandemic in Taiwan: implications for post-pandemic preparedness. AB - BACKGROUND: It is speculated that the 2009 pandemic H1N1 influenza virus might fall into a seasonal pattern during the current post-pandemic period with more severe clinical presentation for high-risk groups identified during the 2009 pandemic. Hence the extent of likely excess healthcare needs during this period must be fully considered. We will make use of the historical healthcare record in Taiwan during and after the 1918 influenza pandemic to ascertain the scope of potential excess healthcare burden during the post-pandemic period. METHODS: To establish the healthcare needs after the initial wave in 1918, the yearly healthcare records (hospitalizations, outpatients, etc.) in Taiwan during 1918 1920 are compared with the corresponding data from the adjacent "baseline" years of 1916, 1917, 1921, and 1922 to estimate the excess healthcare burden during the initial outbreak in 1918 and in the years immediately after. RESULTS: In 1918 the number of public hospital outpatients exceeded the yearly average of the baseline years by 20.11% (95% CI: 16.43, 25.90), and the number of hospitalizations exceeded the corresponding yearly average of the baseline years by 12.20% (10.59, 14.38), while the excess number of patients treated by the public medics was statistically significant at 32.21% (28.48, 39.82) more than the yearly average of the baseline years. For 1920, only the excess number of hospitalizations was statistically significant at 19.83% (95% CI: 17.21, 23.38) more than the yearly average of the baseline years. CONCLUSIONS: Considerable extra burden with significant loss of lives was reported in 1918 by both the public medics system and the public hospitals. In comparison, only a substantial number of excess hospitalizations in the public hospitals was reported in 1920, indicating that the population was relatively unprepared for the first wave in 1918 and did not fully utilize the public hospitals. Moreover, comparatively low mortality was reported by the public hospitals and the public medics during the second wave in 1920 even though significantly more patients were hospitalized, suggesting that there had been substantially less fatal illnesses among the hospitalized patients during the second wave. Our results provide viable parameters for assessing healthcare needs for post-pandemic preparedness. PMID- 21241467 TI - Effects of diet-induced obesity and voluntary wheel running on the microstructure of the murine distal femur. AB - BACKGROUND: Obesity and osteoporosis, two possibly related conditions, are rapidly expanding health concerns in modern society. Both of them are associated with sedentary life style and nutrition. To investigate the effects of diet induced obesity and voluntary physical activity we used high resolution micro computed tomography (MUCT) together with peripheral quantitative computed tomography (pQCT) to examine the microstructure of the distal femoral metaphysis in mice. METHODS: Forty 7-week-old male C57BL/6J mice were assigned to 4 groups: control (C), control + running (CR), high-fat diet (HF), and high-fat diet + running (HFR). After a 21-week intervention, all the mice were sacrificed and the left femur dissected for pQCT and MUCT measurements. RESULTS: The mice fed the high-fat diet showed a significant weight gain (over 70% for HF and 60% for HFR), with increased epididymal fat pad mass and impaired insulin sensitivity. These obese mice had significantly higher trabecular connectivity density, volume, number, thickness, area and mass, and smaller trabecular separation. At the whole bone level, they had larger bone circumference and cross-sectional area and higher density-weighted maximal, minimal, and polar moments of inertia. Voluntary wheel running decreased all the cortical bone parameters, but increased the trabecular mineral density, and decreased the pattern factor and structure model index towards a more plate-like structure. CONCLUSIONS: The results suggest that in mice the femur adapts to obesity by improving bone strength both at the whole bone and micro-structural level. Adaptation to running exercise manifests itself in increased trabecular density and improved 3D structure, but in a limited overall bone growth. PMID- 21241468 TI - ISRCTN12125882 - Influence of topical anti-VEGF (Ranibizumab) on the outcome of filtration surgery for glaucoma - Study Protocol. AB - BACKGROUND: Excessive wound healing, with scarring of the episcleral tissue or encapsulation of the filtering bleb is the main reason for failure in trabeculectomy. Ranibizumab, an inhibitor of the Vascular Endothelial Growth Factor (VEGF), is seen as a promising candidate to prevent or treat extensive wound healing. We describe the design of a two phased study, i) assessing the local tolerability and safety of topical ranibizumab and ii) assessing the efficacy of topical ranibizumab against placebo in patients who underwent trabeculectomy with mitomycin C combined with phacoemulsification and intra ocular lens (IOL) implantation. METHODS/DESIGN: In the first phase five patients that had trabeculectomy with mitomycin C combined with phacoemulsification and IOL implantation will be treated with topical ranibizumab (Lucentis(r)) eye drops (2 mg/ml) four times daily for one month. The treatment will be started at the first postoperative day. Patients will be assessed for local and systemic side effects using a standardised schedule. In the second phase, after successful completion of phase 1, consenting eligible patients who underwent trabeculectomy with mitomycin C combined with phacoemulsification and IOL implantation will be randomised to either receive topical ranibizumab eye drops (2 mg/ml) four times daily for 1 month or placebo (BSS 4x/d for 1 month). Patients will be reviewed weekly for 4 weeks until conjunctival sutures are removed. Further follow up examinations are planned after 3 and six months. Assessment of differences in the intraocular eye pressure will be considered primary, and bleb appearance/vascularisation using a standardized photography and the Moorfields bleb grading system, postoperative intraocular pressure and conjunctival wound healing problems will be considered secondary outcome parameters. DISCUSSION: Anti-VEGF-antibodies might be more effective in preventing scaring and might have fewer toxic side effects than the currently used anti-metabolites and may replace them in the long term. PMID- 21241469 TI - Comparison of the McGrath(r) Series 5 and GlideScope(r) Ranger with the Macintosh laryngoscope by paramedics. AB - BACKGROUND: Out-of-hospital endotracheal intubation performed by paramedics using the Macintosh blade for direct laryngoscopy is associated with a high incidence of complications. The novel technique of video laryngoscopy has been shown to improve glottic view and intubation success in the operating room. The aim of this study was to compare glottic view, time of intubation and success rate of the McGrath(r) Series 5 and GlideScope(r) Ranger video laryngoscopes with the Macintosh laryngoscope by paramedics. METHODS: Thirty paramedics performed six intubations in a randomised order with all three laryngoscopes in an airway simulator with a normal airway. Subsequently, every participant performed one intubation attempt with each device in the same manikin with simulated cervical spine rigidity using a cervical collar. Glottic view, time until visualisation of the glottis and time until first ventilation were evaluated. RESULTS: Time until first ventilation was equivalent after three intubations in the first scenario. In the scenario with decreased cervical motion, the time until first ventilation was longer using the McGrath(r) compared to the GlideScope(r) and AMacintosh (p < 0.01). The success rate for endotracheal intubation was similar for all three devices. Glottic view was only improved using the McGrath(r) device (p < 0.001) compared to using the Macintosh blade. CONCLUSIONS: The learning curve for video laryngoscopy in paramedics was steep in this study. However, these data do not support prehospital use of the McGrath(r) and GlideScope(r) devices by paramedics. PMID- 21241470 TI - Bikeability and methodological issues using the active commuting route environment scale (ACRES) in a metropolitan setting. AB - BACKGROUND: Route environments can positively influence people's active commuting and thereby contribute to public health. The Active Commuting Route Environment Scale (ACRES) was developed to study active commuters' perceptions of their route environments. However, bicycle commuters represent a small portion of the population in many cities and thus are difficult to study using population-based material. Therefore, the aim of this study is to expand the state of knowledge concerning the criterion-related validity of the ACRES and the representativity using an advertisement-recruited sample. Furthermore, by comparing commuting route environment profiles of inner urban and suburban areas, we provide a novel basis for understanding the relationship between environment and bikeability. METHODS: Bicycle commuters from Greater Stockholm, Sweden, advertisement- (n = 1379) and street-recruited (n = 93), responded to the ACRES. Traffic planning and environmental experts from the Municipality of Stockholm (n = 24) responded to a modified version of the ACRES. The criterion-related validity assessments were based on whether or not differences between the inner urban and the suburban route environments, as indicated by the experts and by four existing objective measurements, were reflected by differences in perceptions of these environments. Comparisons of ratings between advertisement- and street-recruited participants were used for the assessments of representativity. Finally, ratings of inner urban and suburban route environments were used to evaluate commuting route environment profiles. RESULTS: Differences in ratings of the inner urban and suburban route environments by the advertisement-recruited participants were in accord with the existing objective measurements and corresponded reasonably well with those of the experts. Overall, there was a reasonably good correspondence between the advertisement- and street-recruited participants' ratings. Distinct differences in commuting route environment profiles were noted between the inner urban and suburban areas. Suburban route environments were rated as safer and more stimulating for bicycle-commuting than the inner urban ones. In general, the findings applied to both men and women. CONCLUSIONS: The overall results show: considerable criterion-related validity of the ACRES; ratings of advertisement recruited participants mirroring those of street-recruited participants; and a higher degree of bikeability in the suburban commuting route environments than in the inner urban ones. PMID- 21241471 TI - Retinoblastoma-independent antiproliferative activity of novel intracellular antibodies against the E7 oncoprotein in HPV 16-positive cells. AB - BACKGROUND: "High risk" human papillomavirus strains are the causative agents of the vast majority of carcinomas of the uterine cervix. In these tumors, the physical integration of the HPV genome is a frequent, though not invariable occurrence, but the constitutive expression of the E6 and E7 viral genes is always observed, suggesting key roles for the E6 and E7 oncoproteins in the process of malignant transformation. The "intracellular antibody" technology using recombinant antibodies in single-chain format offers the possibility of targeting a protein in its intracellular environment even at the level of definite domains thus representing a valuable strategy to "knock out" the function of specific proteins. METHODS: In this study, we investigate the in vitro activity of two single-chain antibody fragments directed against the "high risk" HPV 16 E7 oncoprotein, scFv 43M2 and scFv 51. These scFvs were expressed by retroviral system in different cell compartments of the HPV16-positive SiHa cells, and cell proliferation was analyzed by Colony Formation Assay and EZ4U assay. The binding of these scFvs to E7, and their possible interference with the interaction between E7 and its main target, the tumor suppressor pRb protein, were then investigated by immunoassays, PepSetTM technology and Surface Plasmon Resonance. RESULTS: The expression of the two scFvs in the nucleus and the endoplasmic reticulum of SiHa cells resulted in the selective growth inhibition of these cells. Analysis of binding showed that both scFvs bind E7 via distinct but overlapping epitopes not corresponding to the pRb binding site. Nevertheless, the binding of scFv 43M2 to E7 was inhibited by pRb in a non-competitive manner. CONCLUSIONS: Based on the overall results, the observed inhibition of HPV positive SiHa cells proliferation could be ascribed to an interaction between scFv and E7, involving non-pRb targets. The study paves the way for the employment of specific scFvs in immunotherapeutic approaches against the HPV associated lesions. PMID- 21241473 TI - Is computer aided detection (CAD) cost effective in screening mammography? A model based on the CADET II study. AB - BACKGROUND: Single reading with computer aided detection (CAD) is an alternative to double reading for detecting cancer in screening mammograms. The aim of this study is to investigate whether the use of a single reader with CAD is more cost effective than double reading. METHODS: Based on data from the CADET II study, the cost-effectiveness of single reading with CAD versus double reading was measured in terms of cost per cancer detected. Cost (Pound (L), year 2007/08) of single reading with CAD versus double reading was estimated assuming a health and social service perspective and a 7 year time horizon. As the equipment cost varies according to the unit size a separate analysis was conducted for high, average and low volume screening units. One-way sensitivity analyses were performed by varying the reading time, equipment and assessment cost, recall rate and reader qualification. RESULTS: CAD is cost increasing for all sizes of screening unit. The introduction of CAD is cost-increasing compared to double reading because the cost of CAD equipment, staff training and the higher assessment cost associated with CAD are greater than the saving in reading costs. The introduction of single reading with CAD, in place of double reading, would produce an additional cost of L227 and L253 per 1,000 women screened in high and average volume units respectively. In low volume screening units, the high cost of purchasing the equipment will results in an additional cost of L590 per 1,000 women screened.One-way sensitivity analysis showed that the factors having the greatest effect on the cost-effectiveness of CAD with single reading compared with double reading were the reading time and the reader's professional qualification (radiologist versus advanced practitioner). CONCLUSIONS: Without improvements in CAD effectiveness (e.g. a decrease in the recall rate) CAD is unlikely to be a cost effective alternative to double reading for mammography screening in UK. This study provides updated estimates of CAD costs in a full field digital system and assessment cost for women who are re-called after initial screening. However, the model is highly sensitive to various parameters e.g. reading time, reader qualification, and equipment cost. PMID- 21241472 TI - Carbohydrate-active enzymes from the zygomycete fungus Rhizopus oryzae: a highly specialized approach to carbohydrate degradation depicted at genome level. AB - BACKGROUND: Rhizopus oryzae is a zygomycete filamentous fungus, well-known as a saprobe ubiquitous in soil and as a pathogenic/spoilage fungus, causing Rhizopus rot and mucomycoses. RESULTS: Carbohydrate Active enzyme (CAZy) annotation of the R. oryzae identified, in contrast to other filamentous fungi, a low number of glycoside hydrolases (GHs) and a high number of glycosyl transferases (GTs) and carbohydrate esterases (CEs). A detailed analysis of CAZy families, supported by growth data, demonstrates highly specialized plant and fungal cell wall degrading abilities distinct from ascomycetes and basidiomycetes. The specific genomic and growth features for degradation of easily digestible plant cell wall mono- and polysaccharides (starch, galactomannan, unbranched pectin, hexose sugars), chitin, chitosan, beta-1,3-glucan and fungal cell wall fractions suggest specific adaptations of R. oryzae to its environment. CONCLUSIONS: CAZy analyses of the genome of the zygomycete fungus R. oryzae and comparison to ascomycetes and basidiomycete species revealed how evolution has shaped its genetic content with respect to carbohydrate degradation, after divergence from the Ascomycota and Basidiomycota. PMID- 21241474 TI - Low prevalence of fibrosis in thalassemia major assessed by late gadolinium enhancement cardiovascular magnetic resonance. AB - BACKGROUND: Heart failure remains a major cause of mortality in thalassaemia major. The possible role of cardiac fibrosis in thalassemia major in the genesis of heart failure is not clear. It is also unclear whether cardiac fibrosis might arise as a result of heart failure. METHODS: We studied 45 patients with thalassaemia major who had a wide range of current cardiac iron loading and included patients with prior and current heart failure. Myocardial iron was measured using T2* cardiovascular magnetic resonance (CMR), and following this, late gadolinium enhancement (LGE) was used to determine the presence of macroscopic myocardial fibrosis. RESULTS: The median myocardial T2* in all patients was 22.6 ms (range 5.3-58.8 ms). Fibrosis was detected in only one patient, whose myocardial T2* was 20.1 ms and left ventricular ejection fraction 57%. No fibrosis was identified in 5 patients with a history of heart failure with full recovery, in 3 patients with current left ventricular dysfunction undergoing treatment, or in 18 patients with myocardial iron loading with cardiacT2* < 20 ms at the time of scan. CONCLUSION: This study shows that macroscopic myocardial fibrosis is uncommon in thalassemia major across a broad spectrum of myocardial iron loading. Importantly, there was no macroscopic fibrosis in patients with current or prior heart failure, or in patients with myocardial iron loading without heart failure. Therefore if myocardial fibrosis indeed contributes to myocardial dysfunction in thalassemia, our data combined with the knowledge that the myocardial dysfunction of iron overload can be reversed, indicates that any such fibrosis would need to be both microscopic and reversible. PMID- 21241475 TI - Joint and tendon subclinical involvement suggestive of gouty arthritis in asymptomatic hyperuricemia: an ultrasound controlled study. AB - INTRODUCTION: In this study, we aimed to investigate ultrasonographic (US) changes suggestive of gouty arthritis in the hyaline cartilage, joints and tendons from asymptomatic individuals with hyperuricemia. METHODS: We conducted a cross-sectional, controlled study including US examinations of the knees and first metatarsal-phalangeal joints (first MTPJs), as well as of the tendons and enthesis of the lower limbs. Differences were estimated by chi2 or unpaired t tests as appropriate. Associations were calculated using the Spearman's correlation coefficient rank test. RESULTS: Fifty asymptomatic individuals with hyperuricemia and 52 normouricemic subjects were included. Hyperechoic enhancement of the superficial margin of the hyaline cartilage (double contour sign) was found in 25% of the first MTPJs from hyperuricemic individuals, in contrast to none in the control group (P < 0.0001). Similar results were found on the femoral cartilage (17% versus 0; P < 0.0001). Patellar enthesopathy (12% versus 2.9%; P = 0.01) and tophi (6% versus 0; P = 0.01) as well as Achilles enthesopathy (15% versus 1.9%; P = 0.0007) were more frequent in hyperuricemic than in normouricemic individuals. Intra-articular tophi were found in eight hyperuricemic individuals but in none of the normouricemic subjects (P = 0.003). CONCLUSIONS: These data demonstrate that morphostructural changes suggestive of gouty arthritis induced by chronic hyperuricemia frequently occur in both intra- and extra-articular structures of clinically asymptomatic individuals. PMID- 21241477 TI - Assessing the use of an essential health package in a sector wide approach in Malawi. AB - BACKGROUND: The sector wide approach (SWAp) used in many developing countries is difficult to assess. One way is to consider the essential health package (EHP) which is commonly the vehicle for a SWAp's policies and plans. It is not possible to measure the impact of an EHP by measuring health outcomes in countries such as Malawi. But it is possible to assess the choice of interventions and their delivery in terms of coverage. This paper describes an attempt to assess the Malawi SWAp through its EHP using these available measures of technical efficiency. METHODS: A burden of disease model was used to identify the priority diseases and their estimated incidence. Data from the health management information system (HMIS) were used to measure the coverage of these interventions. A review of the cost-effectiveness of the chosen and potential interventions was undertaken to assess the appropriateness of each intervention used in the EHP. Expenditure data were used to assess the level of funding of the EHP. RESULTS: 33 of the 55 EHP interventions were found to be potentially cost effective (<$150/DALY), 12 were not so cost-effective (>$150/DALY) and cost effective estimates were not available for ten. 15 potential interventions, which were cost-effective and tackling one of the top 20 ranked diseases, were identified.Provision had increased in nearly all EHP services over the period of the SWAp. The rates of out patient attendances and inpatient days per 1000 population had both increased from 929 attendances in 2002/3 to 1135 in 2007/08 and from 124 inpatient days in 2002/03 to 179 in 2007/08.However, by 2007/08 the mean gap between what was required and what was provided was 0.68 of the estimated need. Two services involving the treatment of malaria were overprovided, but the majority were underprovided, with some such as maternity care providing less than half of what was required.The EHP was under-funded throughout the period covering on average 57% of necessary costs. By 2007/08 the funding paid by SWAp partners including the government of Malawi to fund the EHP was at US$13.5 per capita per annum, which was almost half of the revised EHP estimated required expenditure per capita per annum. DISCUSSION: The SWAp had invested in some very cost-effective health interventions. In terms of numbers of patients treated, the EHP had delivered two thirds of the services required. This was despite serious under-funding of the EHP, an increase in the population and shortage of staff. CONCLUSIONS: The identification of interventions of proven effectiveness and good value for money and earmarked funding through a SWAp process can produce measurable improvement in health service delivery at extremely low cost. PMID- 21241476 TI - Hyperadiponectinemia enhances bone formation in mice. AB - BACKGROUND: There is growing evidence that adiponectin, a physiologically active polypeptide secreted by adipocytes, controls not only adipose tissue but also bone metabolism. However, a role for adiponectin in bone development remains controversial. METHODS: We therefore investigated the endocrine effects of adiponectin on bone metabolism using 12-week-old male transgenic (Ad-Tg) mice with significant hyperadiponectinemia overexpressing human full-length adiponectin in the liver. RESULTS: In Ad-Tg mice, the serum level of osteocalcin was significantly increased, but the levels of RANKL, osteoprotegerin, and TRAP5b were not. Bone mass was significantly greater in Ad-Tg mice with increased bone formation. In contrast, bone resorption parameters including the number of osteoclasts and eroded surface area did not differ between Ad-Tg and their littermates. CONCLUSIONS: These findings demonstrate that hyperadiponectinemia enhances bone formation in mice. PMID- 21241478 TI - Traumatic pericardial rupture with skeletonized phrenic nerve. AB - BACKGROUND: Traumatic pericardial rupture is a rare presentation. Pericardial rupture itself is asymptomatic unless complicated by either hemorrhage or herniation of the heart through the defect. Following diagnosis surgical repair of the pericardium is indicated because cardiac herniation may result in vascular collapse and sudden death. OBJECTIVES: Here we present a case of traumatic, non herniated pericardial rupture with complete skeletonization of the phrenic nerve. CASE REPORT: An 18-year-old healthy male suffered multi-trauma after falling 50 feet onto concrete. The patient could not be stabilized despite exploratory laparotomy with splenectomy, IR embolization and packing for a liver laceration. Right posterolateral thoracotomy revealed a ruptured pericardium with a completely skeletonized phrenic nerve. The pericardium was repaired with a Goretex(R) patch. CONCLUSION: A high level of suspicion for pericardial rupture is necessary in all patients with high-velocity thoracic injuries. PMID- 21241479 TI - Early life socioeconomic adversity is associated in adult life with chronic inflammation, carotid atherosclerosis, poorer lung function and decreased cognitive performance: a cross-sectional, population-based study. AB - BACKGROUND: Socioeconomic gradients in health persist despite public health campaigns and improvements in healthcare. The Psychosocial and Biological Determinants of Ill-health (pSoBid) study was designed to uncover novel biomarkers of chronic disease that may help explain pathways between socioeconomic adversity and poorer physical and mental health. METHODS: We examined links between indicators of early life adversity, possible intermediary phenotypes, and markers of ill health in adult subjects (n = 666) recruited from affluent and deprived areas. Classical and novel risk factors for chronic disease (lung function and atherosclerosis) and for cognitive performance were assessed, and associations sought with early life variables including conditions in the parental home, family size and leg length. RESULTS: Associations were observed between father's occupation, childhood home status (owner-occupier; overcrowding) and biomarkers of chronic inflammation and endothelial activation in adults (C reactive protein, interleukin 6, intercellular adhesion molecule; P < 0.0001) but not number of siblings and leg length. Lung function (forced expiratory volume in 1 second) and cognition (Choice Reaction Time, the Stroop test, Auditory Verbal Learning Test) were likewise related to early life conditions (P < 0.001). In multivariate models inclusion of inflammatory variables reduced the impact and independence of early life conditions on lung function and measures of cognitive ability. Including variables of adult socioeconomic status attenuated the early life associations with disease biomarkers. CONCLUSIONS: Adverse levels of biomarkers of ill health in adults appear to be influenced by father's occupation and childhood home conditions. Chronic inflammation and endothelial activation may in part act as intermediary phenotypes in this complex relationship. Reducing the 'health divide' requires that these life course determinants are taken into account. PMID- 21241481 TI - Effect of norepinephrine dosage and calibration frequency on accuracy of pulse contour-derived cardiac output. AB - INTRODUCTION: Continuous cardiac output monitoring is used for early detection of hemodynamic instability and guidance of therapy in critically ill patients. Recently, the accuracy of pulse contour-derived cardiac output (PCCO) has been questioned in different clinical situations. In this study, we examined agreement between PCCO and transcardiopulmonary thermodilution cardiac output (COTCP) in critically ill patients, with special emphasis on norepinephrine (NE) administration and the time interval between calibrations. METHODS: This prospective, observational study was performed with a sample of 73 patients (mean age, 63 +/- 13 years) requiring invasive hemodynamic monitoring on a non-cardiac surgery intensive care unit. PCCO was recorded immediately before calibration by COTCP. Bland-Altman analysis was performed on data subsets comparing agreement between PCCO and COTCP according to NE dosage and the time interval between calibrations up to 24 hours. Further, central artery stiffness was calculated on the basis of the pulse pressure to stroke volume relationship. RESULTS: A total of 330 data pairs were analyzed. For all data pairs, the mean COTCP (+/-SD) was 8.2 +/- 2.0 L/min. PCCO had a mean bias of 0.16 L/min with limits of agreement of -2.81 to 3.15 L/min (percentage error, 38%) when compared to COTCP. Whereas the bias between PCCO and COTCP was not significantly different between NE dosage categories or categories of time elapsed between calibrations, interchangeability (percentage error <30%) between methods was present only in the high NE dosage subgroup (>=0.1 MUg/kg/min), as the percentage errors were 40%, 47% and 28% in the no NE, NE < 0.1 and NE >= 0.1 MUg/kg/min subgroups, respectively. PCCO was not interchangeable with COTCP in subgroups of different calibration intervals. The high NE dosage group showed significantly increased central artery stiffness. CONCLUSIONS: This study shows that NE dosage, but not the time interval between calibrations, has an impact on the agreement between PCCO and COTCP. Only in the measurements with high NE dosage (representing the minority of measurements) was PCCO interchangeable with COTCP. PMID- 21241482 TI - Types of the cerebral arterial circle (circle of Willis) in a Sri Lankan population. AB - BACKGROUND: The variations of the circle of Willis (CW) are clinically important as patients with effective collateral circulations have a lower risk of transient ischemic attack and stroke than those with ineffective collaterals. The aim of the present cadaveric study was to investigate the anatomical variations of the CW and to compare the frequency of prevalence of the different variations with previous autopsy studies as variations in the anatomy of the CW as a whole have not been studied in the Indian subcontinent. METHODS: The external diameter of all the arteries forming the CW in 225 normal Sri Lankan adult cadaver brains was measured using a calibrated grid to determine the prevalence in the variation in CW. Chisquared tests and a correspondence analysis were performed to compare the relative frequencies of prevalence of anatomical variations in the CW across 6 studies of diverse ethnic populations. RESULTS: We report 15 types of variations of CW out of 22 types previously described and one additional type: hypoplastic precommunicating part of the anterior cerebral arteries (A1) and contralateral posterior communicating arteries (PcoA) 5(2%). Statistically significant differences (p < 0.0001) were found between most of the studies except for the Moroccan study. An especially notable difference was observed in the following 4 configurations: 1) hypoplastic precommunicating part of the posterior cerebral arteries (P1), and contralateral A1, 2) hypoplastic PcoA and contralateral P1, 3) hypoplastic PcoA, anterior communicating artery (AcoA) and contralateral P1, 4) bilateral hypoplastic P1s and AcoA in a Caucasian dominant study by Fisher versus the rest of the studies. CONCLUSION: The present study reveals that there are significant variations in the CW among intra and inter ethnic groups (Caucasian, African and Asian: Iran and Sri Lanka dominant populations), and warrants further studies keeping the methods of measurements, data assessment, and the definitions of hypoplasia the same. PMID- 21241480 TI - Stem cells in clinical practice: applications and warnings. AB - Stem cells are a relevant source of information about cellular differentiation, molecular processes and tissue homeostasis, but also one of the most putative biological tools to treat degenerative diseases. This review focuses on human stem cells clinical and experimental applications. Our aim is to take a correct view of the available stem cell subtypes and their rational use in the medical area, with a specific focus on their therapeutic benefits and side effects. We have reviewed the main clinical trials dividing them basing on their clinical applications, and taking into account the ethical issue associated with the stem cell therapy. METHODS: We have searched Pubmed/Medline for clinical trials, involving the use of human stem cells, using the key words "stem cells" combined with the key words "transplantation", "pathology", "guidelines", "properties" and "risks". All the relevant clinical trials have been included. The results have been divided into different categories, basing on the way stem cells have been employed in different pathological conditions. PMID- 21241484 TI - Medicinal plants of Otwal and Ngai Sub Counties in Oyam district, Northern Uganda. AB - BACKGROUND: An ethnobotanical study was carried out in four parishes in the Ngai and Otwal Sub Counties in Oyam district, Northern Uganda, where insurgency has been prevalent for the past 20 years. Documenting medicinal plant species used in treating various health conditions among the local people. METHODS: Information was obtained from mainly the local population, the traditional healers and other experienced persons through interviews, formal and informal discussions and field excursions. RESULTS: Seventy one plant species were reported for use in the treatment of various diseases in the study area. These plant species belongs to 41 families, with Asteraceae being the most represented. Roots were ranked the commonest plant part used. Oral administration was the most frequently used route of administration. A total of 41 different health conditions were reported to be treated by use of medicinal plant species. Thirty nine percent of the recorded plant species were reported for treating stomach related ailments. CONCLUSION: The use of medicinal plants in primary healthcare is still a common practice in Ngai and Otwal Sub Counties. The trust they have is built on the curative outcome properties claimed, poverty and armed conflict that lead to inadequate healthcare facilities. The generation gap caused by the over 20 years of insurgency in the area has brought about knowledge gap on the usage of medicinal plant species between the young and the older generation. PMID- 21241483 TI - A novel insight of sentinel lymph node concept based on 1-3 positive nodes in patients with pT1-2 gastric cancer. AB - BACKGROUND: Sentinel node (SN) biopsy has been practiced in gastric cancer in recent years, and many studies focused on the distribution of solitary lymph node metastasis (SLM) to assess the pattern of SN. In fact, there is usually more than one SN existing in gastric cancer. The distribution of SNs needs to be further re evaluated. METHODS: A total of 289 patients in pT1-2 stage with 1-3 positive nodes confined to same compartment were included in this study with informed consents. The primary lesion was solitary (<= 5.0 cm in diameter) and D2 or D3 lymph node dissection had been performed. The location of metastatic lymph nodes was analyzed retrospectively. RESULTS: Most positive nodes occurred in N1 compartment, with frequency of 79.6% to 85.7% based on site of tumor. In the lower third of stomach, no. 6 was the most common metastatic site and no. 3 was the second; the order was reversed for SLM. With increasing depth of tumor invasion, a progressively augmented nodal involvement was shown. Nearly a half appeared transverse metastasis when the tumor located at the lesser or greater curvature. Among skip metastasis, no. 7, 8a, 9 and 11p were the most common metastatic sites and the prognosis was as similar as that of patients with N1 involved only. CONCLUSIONS: The 1-3 positive nodes in the same compartment should be possible SNs, and most of which are restricted in N1 in pT1-2 gastric cancer. Transversal and 2 stations lymph node metastasis are common. PMID- 21241485 TI - Proliferation-associated POU4F2/Brn-3b transcription factor expression is regulated by oestrogen through ERalpha and growth factors via MAPK pathway. AB - INTRODUCTION: In cancer cells, elevated transcription factor-related Brn-3a regulator isolated from brain cDNA (Brn-3b) transcription factor enhances proliferation in vitro and increases tumour growth in vivo whilst conferring drug resistance and migratory potential, whereas reducing Brn-3b slows growth both in vitro and in vivo. Brn-3b regulates distinct groups of key target genes that control cell growth and behaviour. Brn-3b is elevated in >65% of breast cancer biopsies, but mechanisms controlling its expression in these cells are not known. METHODS: Bioinformatics analysis was used to identify the regulatory promoter region and map transcription start site as well as transcription factor binding sites. Polymerase chain reaction (PCR) cloning was used to generate promoter constructs for reporter assays. Chromatin immunoprecipitation and site-directed mutagenesis were used to confirm the transcription start site and autoregulation. MCF-7 and Cos-7 breast cancer cells were used. Cells grown in culture were transfected with Brn-3b promoter and treated with growth factors or estradiol to test for effects on promoter activity. Quantitative reverse transcriptase PCR assays and immunoblotting were used to confirm changes in gene and protein expression. RESULTS: We cloned the Brn-3b promoter, mapped the transcription start site and showed stimulation by estradiol and growth factors, nerve growth factor and epidermal growth factor, which are implicated in breast cancer initiation and/or progression. The effects of growth factors are mediated through the mitogen-activated protein kinase pathway, whereas hormone effects act via oestrogen receptor alpha (ERalpha). Brn-3b also autoregulates its expression and cooperates with ERalpha to further enhance levels. CONCLUSIONS: Key regulators of growth in cancer cells, for example, oestrogens and growth factors, can stimulate Brn-3b expression, and autoregulation also contributes to increasing Brn-3b in breast cancers. Since increasing Brn-3b profoundly enhances growth in these cells, understanding how Brn-3b is increased in breast cancers will help to identify strategies for reducing its expression and thus its effects on target genes, thereby reversing its effects in breast cancer cells. PMID- 21241486 TI - Fine mapping and replication of QTL in outbred chicken advanced intercross lines. AB - BACKGROUND: Linkage mapping is used to identify genomic regions affecting the expression of complex traits. However, when experimental crosses such as F(2) populations or backcrosses are used to map regions containing a Quantitative Trait Locus (QTL), the size of the regions identified remains quite large, i.e. 10 or more Mb. Thus, other experimental strategies are needed to refine the QTL locations. Advanced Intercross Lines (AIL) are produced by repeated intercrossing of F(2) animals and successive generations, which decrease linkage disequilibrium in a controlled manner. Although this approach is seen as promising, both to replicate QTL analyses and fine-map QTL, only a few AIL datasets, all originating from inbred founders, have been reported in the literature. METHODS: We have produced a nine-generation AIL pedigree (n = 1529) from two outbred chicken lines divergently selected for body weight at eight weeks of age. All animals were weighed at eight weeks of age and genotyped for SNP located in nine genomic regions where significant or suggestive QTL had previously been detected in the F(2) population. In parallel, we have developed a novel strategy to analyse the data that uses both genotype and pedigree information of all AIL individuals to replicate the detection of and fine-map QTL affecting juvenile body weight. RESULTS: Five of the nine QTL detected with the original F(2) population were confirmed and fine-mapped with the AIL, while for the remaining four, only suggestive evidence of their existence was obtained. All original QTL were confirmed as a single locus, except for one, which split into two linked QTL. CONCLUSIONS: Our results indicate that many of the QTL, which are genome-wide significant or suggestive in the analyses of large intercross populations, are true effects that can be replicated and fine-mapped using AIL. Key factors for success are the use of large populations and powerful statistical tools. Moreover, we believe that the statistical methods we have developed to efficiently study outbred AIL populations will increase the number of organisms for which in-depth complex traits can be analyzed. PMID- 21241487 TI - Gait stability and variability measures show effects of impaired cognition and dual tasking in frail people. AB - BACKGROUND: Falls in frail elderly are a common problem with a rising incidence. Gait and postural instability are major risk factors for falling, particularly in geriatric patients. As walking requires attention, cognitive impairments are likely to contribute to an increased fall risk. An objective quantification of gait and balance ability is required to identify persons with a high tendency to fall. Recent studies have shown that stride variability is increased in elderly and under dual task condition and might be more sensitive to detect fall risk than walking speed. In the present study we complemented stride related measures with measures that quantify trunk movement patterns as indicators of dynamic balance ability during walking. The aim of the study was to quantify the effect of impaired cognition and dual tasking on gait variability and stability in geriatric patients. METHODS: Thirteen elderly with dementia (mean age: 82.6 +/- 4.3 years) and thirteen without dementia (79.4 +/- 5.55) recruited from a geriatric day clinic, walked at self-selected speed with and without performing a verbal dual task. The Mini Mental State Examination and the Seven Minute Screen were administered. Trunk accelerations were measured with an accelerometer. In addition to walking speed, mean, and variability of stride times, gait stability was quantified using stochastic dynamical measures, namely regularity (sample entropy, long range correlations) and local stability exponents of trunk accelerations. RESULTS: Dual tasking significantly (p < 0.05) decreased walking speed, while stride time variability increased, and stability and regularity of lateral trunk accelerations decreased. Cognitively impaired elderly showed significantly (p < 0.05) more changes in gait variability than cognitive intact elderly. Differences in dynamic parameters between groups were more discerned under dual task conditions. CONCLUSIONS: The observed trunk adaptations were a consistent instability factor. These results support the concept that changes in cognitive functions contribute to changes in the variability and stability of the gait pattern. Walking under dual task conditions and quantifying gait using dynamical parameters can improve detecting walking disorders and might help to identify those elderly who are able to adapt walking ability and those who are not and thus are at greater risk for falling. PMID- 21241488 TI - Oncocytic carcinoma of the parotid gland with late cervical lymph node metastases: a case report. AB - INTRODUCTION: Oncocytic carcinoma is a rare proliferation of cytomorphologically malignant oncocytes mainly found in glandular tissue, accounting for 0.5% of all epithelial salivary gland malignancies and 0.18% of all epithelial salivary gland tumors. CASE PRESENTATION: We report a case of oncocytic carcinoma arising in the parotid gland of a 65-year-old Caucasian man. Our patient initially underwent left superficial parotidectomy, including the removal of the mass. A close follow up was made, and four years after first surgery cervical lymph node metastases were confirmed. Therefore, a complete parotidectomy and radical neck dissections were performed. There were no complications and no sign of recurrence after six months of follow-up. CONCLUSION: Oncocytic carcinoma is an extremely rare malignancy in the salivary glands. Prophylactic neck dissection may be indicated for tumors larger than 2 cm in diameter (our patient's tumor was 2.5 cm at its greatest diameter). The clinical course of our patient, with the appearance of cervical lymph node metastases after four years of follow-up, supports this approach. Further investigation of the prognosis and correct treatment of patients with oncocytic carcinoma are required as more cases are reported. PMID- 21241489 TI - Endogenous plasma activated protein C levels and the effect of enoxaparin and drotrecogin alfa (activated) on markers of coagulation activation and fibrinolysis in pulmonary embolism. AB - INTRODUCTION: There are no published data on the status of endogenous activated protein C (APC) in pulmonary embolism (PE), and no data on the effect of drotrecogin alfa (activated) (DAA) given in addition to therapeutic dose enoxaparin. METHODS: In this double-blind clinical trial, 47 patients with computed tomography (CT)-confirmed acute submassive PE treated with 1 mg/kg body weight of enoxaparin twice daily were randomized to groups receiving a 12-hour intravenous infusion of 6, 12, 18, or 24 MUg/kg/hour of DAA or a placebo. Blood samples were drawn before starting DAA infusion, after 4, 8 and 12 hours (at the end of the infusion period), and on treatment days 2, 3, 4, 5 and 6. RESULTS: Initial endogenous plasma activated protein C (APC) levels were 0.36 +/- 0.48 ng/ml (<0.10 to 1.72 ng/ml) and remained in the same range in the placebo group. APC levels in patients treated with DAA were 13.67 +/- 3.57 ng/ml, 32.71 +/- 8.76 ng/ml, 36.13 +/- 7.60 ng/ml, and 51.79 +/- 15.84 ng/ml in patients treated with 6, 12, 18, and 24 MUg/kg/hour DAA, respectively. In patients with a D-dimer level >4 mg/L indicating a high level of acute fibrin formation and dissolution, DAA infusion resulted in a more rapid drop in soluble fibrin, D-dimer, and fibrinogen/fibrin degradation products (FDP) levels, compared to enoxaparin alone. There was a parallel decline of soluble fibrin, D-dimer, FDP, and plasmin plasmin inhibitor complex (PPIC) in response to treatment with enoxaparin +/- DAA, with no evidence of a systemic profibrinolytic effect of the treatment. CONCLUSIONS: In patients with acute submassive PE endogenous APC levels are low. DAA infusion enhances the inhibition of fibrin formation. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00191724. PMID- 21241490 TI - Invasive ventilation modes in children: a systematic review and meta-analysis. AB - INTRODUCTION: The purpose of the present study was to critically review the existing body of evidence on ventilation modes for infants and children up to the age of 18 years. METHODS: The PubMed and EMBASE databases were searched using the search terms 'artificial respiration', 'instrumentation', 'device', 'devices', 'mode', and 'modes'. The review included only studies comparing two ventilation modes in a randomized controlled study and reporting one of the following outcome measures: length of ventilation (LOV), oxygenation, mortality, chronic lung disease and weaning. We quantitatively pooled the results of trials where suitable. RESULTS: Five trials met the inclusion criteria. They addressed six different ventilation modes in 421 children: high-frequency oscillation (HFO), pressure control (PC), pressure support (PS), volume support (VS), volume diffusive respirator (VDR) and biphasic positive airway pressure. Overall there were no significant differences in LOV and mortality or survival rate associated with the different ventilation modes. Two trials compared HFO versus conventional ventilation. In the pooled analysis, the mortality rate did not differ between these modes (odds ratio = 0.83, 95% confidence interval = 0.30 to 1.91). High frequency ventilation (HFO and VDR) was associated with a better oxygenation after 72 hours than was conventional ventilation. One study found a significantly higher PaO2/FiO2 ratio with the use of VDR versus PC ventilation in children with burns. Weaning was studied in 182 children assigned to either a PS protocol, a VS protocol or no protocol. Most children could be weaned within 2 days and the weaning time did not significantly differ between the groups. CONCLUSIONS: The literature provides scarce data for the best ventilation mode in critically ill children beyond the newborn period. There is no evidence, however, that high frequency ventilation reduced mortality and LOV. Longer-term outcome measures such as pulmonary function, neurocognitive development, and cost-effectiveness should be considered in future studies. PMID- 21241492 TI - Urethral metastasis from non-seminomatous germ cell tumor: a case report. AB - INTRODUCTION: We present a case of nonseminomatous germ cell tumor of the testes with acute urinary retention secondary to urethral metastasis. This presentation, and similar cases of urethral metastasis from this tumor, have not been reported previously. CASE PRESENTATION: A 35-year-old Caucasian man presented to hospital with a history of acute urinary retention. On examination he was found to have right testicular enlargement with raised beta-human chorionic gonadotrophin, serum alpha-fetoprotein and lactate dehydrogenase levels. He underwent radical left inguinal orchidectomy and histology confirmed a nonseminomatous germ cell tumor of the testes. Cystoscopy carried out due to urinary retention showed penile metastasis and the biopsy confirmed metastatic malignant undifferentiated teratoma. Staging computed tomography scan and magnetic resonance imaging of the pelvis showed pulmonary, pelvic nodal, ischial and penile metastasis. The diagnosis of the International Germ Cell Cancer Collaborative Group of poor prognosis metastatic nonseminomatous germ cell tumor was made, following which he received four cycles of bleomycin, etoposide and cisplatin chemotherapy with curative intent. He had a complete marker and an excellent radiological response. He is currently under follow up. CONCLUSION: The unusual presentation of lymphovascular spread in this case of nonseminomatous germ cell tumor highlights the need to include routine pelvic imaging in the assessment and follow up of testicular cancer. PMID- 21241493 TI - Eosinophilic pneumonia associated with daptomycin: a case report and a review of the literature. AB - INTRODUCTION: Although several studies did not demonstrate that daptomycin may cause significantly higher rates of pulmonary adverse effects when compared with vancomycin or penicillinase-resistant penicillins, there have been a few case reports of severe pulmonary complications associated with daptomycin administration. CASE PRESENTATION: A rare case of eosinophilic pneumonia occurring 10 days after daptomycin administration in a 78-year-old Caucasian man with possible infectious endocarditis is described. He developed new onset fever, up to 38.5 degrees C, with bilateral pulmonary crackles on physical examination and with no signs of severe respiratory failure. A chest computed tomography-scan showed bilateral nodular consolidations with air bronchograms and pleural effusions. Immediate discontinuation of daptomycin was followed by vigorous improvement of clinical signs and symptoms with progressive resolution of pulmonary consolidations a month later. CONCLUSION: Physicians should be aware of this rare but serious complication during daptomycin treatment, and prompt discontinuation of the offending agent, with or without additional supportive treatment, must occur immediately. PMID- 21241491 TI - (Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis. AB - INTRODUCTION: Both cardiovascular disease and osteoporosis are important causes of morbidity and mortality in the elderly. The co-occurrence of cardiovascular disease and osteoporosis prompted us to review the evidence of an association between cardiovascular (CV) disease and osteoporosis and potential shared common pathophysiological mechanisms. METHODS: A systematic literature search (Medline, Pubmed and Embase) was conducted to identify all clinical studies that investigated the association between cardiovascular disease and osteoporosis. Relevant studies were screened for quality according to guidelines as proposed by the Dutch Cochrane Centre and evidence was summarized. RESULTS: Seventy studies were included in this review. Due to a large heterogeneity in study population, design and outcome measures a formal meta-analysis was not possible. Six of the highest ranked studies (mean n = 2,000) showed that individuals with prevalent subclinical CV disease had higher risk for increased bone loss and fractures during follow-up compared to persons without CV disease (range of reported risk: hazard ratio (HR) 1.5; odds ratio (OR) 2.3 to 3.0). The largest study (n = 31,936) reported a more than four times higher risk in women and more than six times higher risk in men. There is moderate evidence that individuals with low bone mass had higher CV mortality rates and incident CV events than subjects with normal bone mass (risk rates 1.2 to 1.4). Although the shared common pathophysiological mechanisms are not fully elucidated, the most important factors that might explain this association appear to be, besides age, estrogen deficiency and inflammation. CONCLUSIONS: The current evidence indicates that individuals with prevalent subclinical CV disease are at increased risk for bone loss and subsequent fractures. Presently no firm conclusions can be drawn as to what extent low bone mineral density might be associated with increased cardiovascular risk. PMID- 21241494 TI - Expenditures for the care of HIV-infected patients in rural areas in China's antiretroviral therapy programs. AB - BACKGROUND: The Chinese government has provided health services to those infected by the human immunodeficiency virus (HIV) under the acquired immunodeficiency syndrome (AIDS) care policy since 2003. Detailed research on the actual expenditures and costs for providing care to patients with AIDS is needed for future financial planning of AIDS health care services and possible reform of HIV/AIDS-related policy. The purpose of the current study was to determine the actual expenditures and factors influencing costs for untreated AIDS patients in a rural area of China after initiating highly active antiretroviral therapy (HAART) under the national Free Care Program (China CARES). METHODS: A retrospective cohort study was conducted in Yunnan and Shanxi Provinces, where HAART and all medical care are provided free to HIV-positive patients. Health expenditures and costs in the first treatment year were collected from medical records and prescriptions at local hospitals between January and June 2007. Multivariate linear regression was used to determine the factors associated with the actual expenditures in the first antiretroviral (ARV) treatment year. RESULTS: Five ARV regimens are commonly used in China CARES: zidovudine (AZT) + lamivudine (3TC) + nevirapine (NVP), stavudine (D4T) + 3TC + efavirenz (EFV), D4T + 3TC + NVP, didanosine (DDI) + 3TC + NVP and combivir + EFV. The mean annual expenditure per person for ARV medications was US$2,242 (US$1 = 7 Chinese Yuan (CNY)) among 276 participants. The total costs for treating all adverse drug events (ADEs) and opportunistic infections (OIs) were US$29,703 and US$23,031, respectively. The expenses for treatment of peripheral neuritis and cytomegalovirus (CMV) infections were the highest among those patients with ADEs and OIs, respectively. On the basis of multivariate linear regression, CD4 cell counts (100-199 cells/MUL versus <100 cells/MUL, P = 0.02; and >=200 cells/MUL versus <100 cells/MUL, P < 0.004), residence in Mangshi County (P < 0.0001), ADEs (P = 0.04) and OIs (P = 0.02) were significantly associated with total expenditures in the first ARV treatment year. CONCLUSIONS: This is the first study to determine the actual costs of HIV treatment in rural areas of China. Costs for ARV drugs represented the major portion of HIV medical expenditures. Initiating HAART in patients with higher CD4 cell count levels is likely to reduce treatment expenses for ADEs and OIs in patients with AIDS. PMID- 21241495 TI - Global gene expression of Poncirus trifoliata, Citrus sunki and their hybrids under infection of Phytophthora parasitica. AB - BACKGROUND: Gummosis and root rot caused by Phytophthora are among the most economically important diseases in citrus. Four F1 resistant hybrids (Pool R), and four F1 susceptible hybrids (Pool S) to P. parasitica, were selected from a cross between susceptible Citrus sunki and resistant Poncirus trifoliata cv. Rubidoux. We investigated gene expression in pools of four resistant and four susceptible hybrids in comparison with their parents 48 hours after P. parasitica inoculation. We proposed that genes differentially expressed between resistant and susceptible parents and between their resistant and susceptible hybrids provide promising candidates for identifying transcripts involved in disease resistance. A microarray containing 62,876 UniGene transcripts selected from the CitEST database and prepared by NimbleGen Systems was used for analyzing global gene expression 48 hours after infection with P. parasitica. RESULTS: Three pairs of data comparisons (P. trifoliata/C. sunki, Pool R/C. sunki and Pool R/Pool S) were performed. With a filter of false-discovery rate less than 0.05 and fold change greater than 3.0, 21 UniGene transcripts common to the three pairwise comparative were found to be up-regulated, and 3 UniGene transcripts were down regulated. Among them, our results indicated that the selected transcripts were probably involved in the whole process of plant defense responses to pathogen attack, including transcriptional regulation, signaling, activation of defense genes participating in HR, single dominant genes (R gene) such as TIR-NBS-LRR and RPS4 and switch of defense-related metabolism pathway. Differentially expressed genes were validated by RT-qPCR in susceptible and resistant plants and between inoculated and uninoculated control plants CONCLUSIONS: Twenty four UniGene transcripts were identified as candidate genes for Citrus response to P. parasitica. UniGene transcripts were likely to be involved in disease resistance, such as genes potentially involved in secondary metabolite synthesis, intracellular osmotic adjustment, signal transduction pathways of cell death, oxidative burst and defense gene expression. Furthermore, our microarray data suggest another type of resistance in Citrus-Phytophthora interaction conferred by single dominant genes (R gene) since we encountered two previously reported R genes (TIR-NBS-LRR and RPS4) upregulated in the resistant genotypes relative to susceptible. We identified 7 transcripts with homology in other plants but yet unclear functional characterization which are an interesting pool for further analyses and 3 transcripts where no significant similarity was found. This is the first microarray study addressing an evaluation of transcriptional changes in response to P. parasitica in Citrus. PMID- 21241496 TI - Thin anterior uterine wall with incomplete uterine rupture in a primigravida detected by palpation and ultrasound: a case report. AB - INTRODUCTION: Uterine rupture is an obstetric complication associated with significant maternal and fetal morbidity and mortality. This disorder usually occurs with a scarred uterus, especially in a uterus with prior Cesarean section. Uterine sacculation or diverticulum may also lead to a thin uterine wall during pregnancy. CASE PRESENTATION: A 27-year-old Japanese primigravid woman was admitted to our hospital due to weak, irregular uterine contractions in her 38th week of gestation. She had no past history of uterine surgery or known diseases. A hard mass was palpable in her abdomen. An ultrasound revealed that the anterior uterine wall was thin and bulging, with a fetal minor part beneath it which corresponded to the palpated mass. A Cesarean section was performed which revealed a thin anterior uterine wall with incomplete uterine rupture. The woman and baby were healthy. CONCLUSIONS: Although extremely rare, an unscarred primigravid uterus can undergo incomplete rupture even without discernable risk factors or labor pains. Abdominal palpation and ultrasound may be useful in detecting this condition. PMID- 21241497 TI - Perceived barriers to integrated care in rheumatoid arthritis: views of recipients and providers of care in an inner-city setting. AB - BACKGROUND: A number of recent reports published in the UK have put the quality of care of adults with Rheumatoid Arthritis (RA) centre stage. These documents set high standards for health care professionals and commissioning bodies that need to be implemented into routine clinical practice. We therefore have obtained the views of recipients and providers of care in inner city settings as to what they perceive are the barriers to providing integrated care. METHODS: We conducted focus groups and face to face interviews between 2005-8 with 79 participants (patients, carers, specialist medical and nursing outpatient staff and general practitioners (GPs)) working in or attending three hospitals and three primary care trusts (PCT). RESULTS: Three barriers were identified that stood in the way of seamless integrated care in RA from the perspective of patients, carers, specialists and GPs: (i) early referral (e.g. 'gate keeper's role of GPs); (ii) limitations of ongoing care for established RA (e.g. lack of consultation time in secondary care) and (iii) management of acute flares (e.g. pressure on overbooked clinics). CONCLUSION: This timely study of the multi perspective views of recipients and providers of care was conducted during the time of publications of many important reports in the United Kingdom (UK) that highlighted key components in the provision of high quality care for adults with RA. To achieve seamless care across primary and secondary care requires organisational changes, greater personal and professional collaboration and GP education about RA. PMID- 21241498 TI - In utero exposure to butyl benzyl phthalate induces modifications in the morphology and the gene expression profile of the mammary gland: an experimental study in rats. AB - BACKGROUND: Environmental estrogens are exogenous estrogen-mimicking compounds that can interfere with endogenous endocrine systems. Several of these endocrine disruptors have been shown to alter normal development and influence tumorigenesis in experimental models. N-butyl benzyl phthalate (BBP), a widely used plasticizer, is a well-known endocrine disruptor. The aim of this study was to elucidate the effect of prenatal exposure to BBP on the morphology, proliferative index, and genomic signature of the rat mammary gland at different ages. METHODS: In utero exposure was performed by gavage of pregnant Sprague Dawley CD rats with 120mg or 500mg BBP/kg/day from day 10 post-conception to delivery. Female litters were euthanized at 21, 35, 50 and 100 days. The morphology and proliferative index of the mammary gland were studied from whole mount preparations and BrdU incorporation, respectively. Gene expression profile was assessed by microarrays. Several genes found differentially expressed and related to different functional categories were further validated by real time RT PCR. RESULTS: Prenatal exposure of BBP induced delayed vaginal opening and changes in the post-natal mammary gland long after the end of the treatment, mainly by 35 days of age. Exposure to the high dose resulted in modifications in architecture and proliferative index of the mammary gland, mostly affecting the undifferentiated terminal end buds. Moreover, the expression profiles of this gland in the exposed rats were modified in a dose-dependent fashion. Analysis of functional categories showed that modified genes were related to immune function, cell signaling, proliferation and differentiation, or metabolism. CONCLUSIONS: Our data suggest that in utero exposure to BBP induced a delayed pubertal onset and modified morphology of the mammary gland. These alterations were accompanied by modifications in gene expression previously associated with an increased susceptibility to carcinogenesis. PMID- 21241499 TI - Virological and serological surveillance for type A influenza in the black-legged kittiwake (Rissa tridactyla). AB - BACKGROUND: The epidemiology of avian influenza viruses (AIVs) in gulls is only partially known. The role of the world's most numerous gull species, the black legged kittiwake (Rissa tridactyla), as a potential AIV reservoir species has been unclear. The prevalence of AIV and humoral response against AIV were therefore studied in a colony of apparently healthy black-legged kittiwakes breeding in a nesting cliff in the South West Barents Region of Norway (70 degrees 22' N, 31 degrees 10' E), in 2008 and 2009. RESULTS: AIVs were detected from the oropharynx and cloaca in low amounts, with prevalences of 15% and 5%, in 2008 and 2009, respectively. Direct, partial sequencing of the hemagglutinin (HA) gene revealed that the H4 subtype was present. In 2009, antibodies to influenza A virus were detected in sera from 57 of 80 adult birds. In contrast, none of the three-week-old chicks (n = 18) tested seropositive. Hemagglutination inhibition (HI) assays demonstrated that the adult kittiwakes primarily had antibodies specific to the gull-associated H13 and H16 subtypes, with antibodies to H16 being most common. CONCLUSIONS: These results support that the highly pelagic black-legged kittiwake is a reservoir of AIV. The serological findings suggest that H16 might be the main AIV subtype in the black-legged kittiwake. Further studies are needed to understand the ecology of AIV in the black-legged kittiwake and in gulls in general. PMID- 21241500 TI - Lifetime body size and reproductive factors: comparisons of data recorded prospectively with self reports in middle age. AB - BACKGROUND: Data on lifetime exposures are often self-reported in epidemiologic studies, sometimes many years after the relevant age. Validity of self-reported data is usually inferred from their agreement with measured values, but few studies directly quantify the likely effects of reporting errors in body size and reproductive history variables on estimates of disease-exposure associations. METHODS: The MRC National Survey of Health and Development (NSHD) and the Million Women Study (MWS) are UK population-based prospective cohorts. The NSHD recruited participants at birth in 1946 and has followed them at regular intervals since then, whereas the MWS recruited women in middle age. For 541 women who were participants in both studies, we used statistical measures of association and agreement to compare self-reported MWS data on body size throughout life and reproductive history, obtained in middle age, to NSHD data measured or reported close to the relevant ages. Likely attenuation of estimates of linear disease exposure associations due to the combined effects of random and systematic errors was quantified using regression dilution ratios (RDRs). RESULTS: Data from the two studies were very strongly correlated for current height, weight and body mass index, and age at menopause (Pearson r = 0.91-0.95), strongly correlated for birth weight, parental heights, current waist and hip circumferences and waist-to height ratio (r = 0.67-0.80), and moderately correlated for age at menarche and waist-to-hip ratio (r = 0.52-0.57). Self-reported categorical body size and clothes size data for various ages were moderately to strongly associated with anthropometry collected at the relevant times (Spearman correlations 0.51-0.79). Overall agreement between the studies was also good for most quantitative variables, although all exhibited both random and systematic reporting error. RDRs ranged from 0.66 to 0.86 for most variables (slight to moderate attenuation), except weight and body mass index (1.02 and 1.04, respectively; little or no attenuation), and age at menarche, birth weight and waist-to-hip ratio (0.44, 0.59 and 0.50, respectively; substantial attenuation). CONCLUSIONS: This study provides some evidence that self-reported data on certain anthropometric and reproductive factors may be adequate for describing disease exposure associations in large epidemiological studies, provided that the effects of reporting errors are quantified and the results are interpreted with caution. PMID- 21241501 TI - WebGimm: An integrated web-based platform for cluster analysis, functional analysis, and interactive visualization of results. AB - Cluster analysis methods have been extensively researched, but the adoption of new methods is often hindered by technical barriers in their implementation and use. WebGimm is a free cluster analysis web-service, and an open source general purpose clustering web-server infrastructure designed to facilitate easy deployment of integrated cluster analysis servers based on clustering and functional annotation algorithms implemented in R. Integrated functional analyses and interactive browsing of both, clustering structure and functional annotations provides a complete analytical environment for cluster analysis and interpretation of results. The Java Web Start client-based interface is modeled after the familiar cluster/treeview packages making its use intuitive to a wide array of biomedical researchers. For biomedical researchers, WebGimm provides an avenue to access state of the art clustering procedures. For Bioinformatics methods developers, WebGimm offers a convenient avenue to deploy their newly developed clustering methods. WebGimm server, software and manuals can be freely accessed at http://ClusterAnalysis.org/. PMID- 21241502 TI - Expression of angiogenic basic fibroblast growth factor, platelet derived growth factor, thrombospondin-1 and their receptors at the porcine maternal-fetal interface. AB - BACKGROUND: Commercial swine breeds in North America undergo two waves of spontaneous fetal loss; one during peri-attachment and another during mid gestation. Although an exact mechanism for this loss is not known, deficits in vasculature at the attachment sites appear to be a major cause. We hypothesized that a balance between pro-angiogenic and anti-angiogenic factors is needed at the maternal-fetal interface for successful conceptus development. Six selected members of the pro-angiogenic fibroblast growth factor (FGF) and platelet derived growth factor (PDGF) families and anti-angiogenic factor thrombospondin-1 (TSP-1) and its receptor CD36 were quantified and localized at the porcine maternal-fetal interface at early and midgestation time points. METHODS: Mesometrial endometrium was collected from non-pregnant gilts (n = 8). Endometrial and chorioallantoic membrane samples were collected from healthy and arresting conceptus attachment sites at gestation day (gd) 20 (n = 8) and gd 50 (n = 8). At gd20 arresting conceptus attachment sites were distinguished by decreased vasculature of the placental membranes and decreased conceptus size. At gd50 arresting conceptuses attachment sites were identified by smaller conceptus length and weight measurements. Quantitative real time PCR was used to determine relative transcript levels of genes of interest, and cellular localization was determined by immunohistochemistry in paraffin embedded endometrial sections. RESULTS: At gd20, endometrial samples from arresting conceptuses had elevated transcripts for bFGF, and PDGF-bb than healthy sites (p < 0.05). At gd50, bFGF, FGFR2, and CD36 were more abundant at arresting than at healthy conceptus attachment sites (p < 0.05). Chorioallantoic membrane from arresting conceptus attachment sites at gd20 had elevated transcripts for bFGF, FGFR1, FGFR2 and CD36 compared with healthy sites (p < 0.05). FGFR2 transcripts were more abundant in chorioallantoic membrane from arresting conceptuses at gd 50 (p < 0.05). Immunohistochemical localization of selected pro- and anti-angiogenic factors and receptors revealed their abundance in the luminal epithelium, uterine glands and perivascular areas of endometrium at gd20 and gd50. CONCLUSIONS: We provide comprehensive analysis of pro and anti-angiogenic factors at the porcine maternal fetal interface during early and mid-pregnancy. At mRNA levels, the majority of pro-angiogenic factors investigated were elevated at the sites of fetal arrest. These observations contrast with our previous findings of decreased Vascular Endothelial Growth Factor (VEGF) family members at arresting sites, and suggest that the bFGF family functions as a compensatory survival mechanism when major angiogenic proteins are decreasing at the sites of fetal arrest. PMID- 21241503 TI - Strong functional patterns in the evolution of eukaryotic genomes revealed by the reconstruction of ancestral protein domain repertoires. AB - BACKGROUND: Genome size and complexity, as measured by the number of genes or protein domains, is remarkably similar in most extant eukaryotes and generally exhibits no correlation with their morphological complexity. Underlying trends in the evolution of the functional content and capabilities of different eukaryotic genomes might be hidden by simultaneous gains and losses of genes. RESULTS: We reconstructed the domain repertoires of putative ancestral species at major divergence points, including the last eukaryotic common ancestor (LECA). We show that, surprisingly, during eukaryotic evolution domain losses in general outnumber domain gains. Only at the base of the animal and the vertebrate sub trees do domain gains outnumber domain losses. The observed gain/loss balance has a distinct functional bias, most strikingly seen during animal evolution, where most of the gains represent domains involved in regulation and most of the losses represent domains with metabolic functions. This trend is so consistent that clustering of genomes according to their functional profiles results in an organization similar to the tree of life. Furthermore, our results indicate that metabolic functions lost during animal evolution are likely being replaced by the metabolic capabilities of symbiotic organisms such as gut microbes. CONCLUSIONS: While protein domain gains and losses are common throughout eukaryote evolution, losses oftentimes outweigh gains and lead to significant differences in functional profiles. Results presented here provide additional arguments for a complex last eukaryotic common ancestor, but also show a general trend of losses in metabolic capabilities and gain in regulatory complexity during the rise of animals. PMID- 21241504 TI - Classical homeopathy in the treatment of cancer patients--a prospective observational study of two independent cohorts. AB - BACKGROUND: Many cancer patients seek homeopathy as a complementary therapy. It has rarely been studied systematically, whether homeopathic care is of benefit for cancer patients. METHODS: We conducted a prospective observational study with cancer patients in two differently treated cohorts: one cohort with patients under complementary homeopathic treatment (HG; n = 259), and one cohort with conventionally treated cancer patients (CG; n = 380). For a direct comparison, matched pairs with patients of the same tumour entity and comparable prognosis were to be formed. Main outcome parameter: change of quality of life (FACT-G, FACIT-Sp) after 3 months. Secondary outcome parameters: change of quality of life (FACT-G, FACIT-Sp) after a year, as well as impairment by fatigue (MFI) and by anxiety and depression (HADS). RESULTS: HG: FACT-G, or FACIT-Sp, respectively improved statistically significantly in the first three months, from 75.6 (SD 14.6) to 81.1 (SD 16.9), or from 32.1 (SD 8.2) to 34.9 (SD 8.32), respectively. After 12 months, a further increase to 84.1 (SD 15.5) or 35.2 (SD 8.6) was found. Fatigue (MFI) decreased; anxiety and depression (HADS) did not change. CG: FACT-G remained constant in the first three months: 75.3 (SD 17.3) at t0, and 76.6 (SD 16.6) at t1. After 12 months, there was a slight increase to 78.9 (SD 18.1). FACIT-Sp scores improved significantly from t0 (31.0 - SD 8.9) to t1 (32.1 - SD 8.9) and declined again after a year (31.6 - SD 9.4). For fatigue, anxiety, and depression, no relevant changes were found. 120 patients of HG and 206 patients of CG met our criteria for matched-pairs selection. Due to large differences between the two patient populations, however, only 11 matched pairs could be formed. This is not sufficient for a comparative study. CONCLUSION: In our prospective study, we observed an improvement of quality of life as well as a tendency of fatigue symptoms to decrease in cancer patients under complementary homeopathic treatment. It would take considerably larger samples to find matched pairs suitable for comparison in order to establish a definite causal relation between these effects and homeopathic treatment. PMID- 21241505 TI - Raised temperatures over the Kericho tea estates: revisiting the climate in the East African highlands malaria debate. AB - BACKGROUND: Whether or not observed increases in malaria incidence in the Kenyan Highlands during the last thirty years are associated with co-varying changes in local temperature, possibly connected to global changes in climate, has been debated for over a decade. Studies, using differing data sets and methodologies, produced conflicting results regarding the occurrence of temperature trends and their likelihood of being responsible, at least in part, for the increases in malaria incidence in the highlands of western Kenya. A time series of quality controlled daily temperature and rainfall data from Kericho, in the Kenyan Highlands, may help resolve the controversy. If significant temperature trends over the last three decades have occurred then climate should be included (along with other factors such as land use change and drug resistance) as a potential driver of the observed increases in malaria in the region. METHODS: Over 30 years (1 January 1979 to 31 December 2009) of quality controlled daily observations ( > 97% complete) of maximum, minimum and mean temperature were used in the analysis of trends at Kericho meteorological station, sited in a tea growing area of Kenya's western highlands. Inhomogeneities in all the time series were identified and corrected. Linear trends were identified via a least-squares regression analysis with statistical significance assessed using a two-tailed t-test. These 'gold standard' meteorological observations were compared with spatially interpolated temperature datasets that have been developed for regional or global applications. The relationship of local climate processes with larger climate variations, including tropical sea surface temperatures (SST), and El Nino Southern Oscillation (ENSO) was also assessed. RESULTS: An upward trend of ~0.2 degrees C/decade was observed in all three temperature variables (P < 0.01). Mean temperature variations in Kericho were associated with large-scale climate variations including tropical SST (r = 0.50; p < 0.01). Local rainfall was found to have inverse effects on minimum and maximum temperature. Three versions of a spatially interpolated temperature data set showed markedly different trends when compared with each other and with the Kericho station observations. CONCLUSION: This study presents evidence of a warming trend in observed maximum, minimum and mean temperatures at Kericho during the period 1979 to 2009 using gold standard meteorological observations. Although local factors may be contributing to these trends, the findings are consistent with variability and trends that have occurred in correlated global climate processes. Climate should therefore not be dismissed as a potential driver of observed increases in malaria seen in the region during recent decades, however its relative importance compared to other factors needs further elaboration. Climate services, pertinent to the achievement of development targets such as the Millennium Development Goals and the analysis of infectious disease in the context of climate variability and change are being developed and should increase the availability of relevant quality controlled climate data for improving development decisions. The malaria community should seize this opportunity to make their needs heard. PMID- 21241506 TI - Race, gender, class, and sexual orientation: intersecting axes of inequality and self-rated health in Canada. AB - BACKGROUND: Intersectionality theory, a way of understanding social inequalities by race, gender, class, and sexuality that emphasizes their mutually constitutive natures, possesses potential to uncover and explicate previously unknown health inequalities. In this paper, the intersectionality principles of "directionality," "simultaneity," "multiplicativity," and "multiple jeopardy" are applied to inequalities in self-rated health by race, gender, class, and sexual orientation in a Canadian sample. METHODS: The Canadian Community Health Survey 2.1 (N = 90,310) provided nationally representative data that enabled binary logistic regression modeling on fair/poor self-rated health in two analytical stages. The additive stage involved regressing self-rated health on race, gender, class, and sexual orientation singly and then as a set. The intersectional stage involved consideration of two-way and three-way interaction terms between the inequality variables added to the full additive model created in the previous stage. RESULTS: From an additive perspective, poor self-rated health outcomes were reported by respondents claiming Aboriginal, Asian, or South Asian affiliations, lower class respondents, and bisexual respondents. However, each axis of inequality interacted significantly with at least one other: multiple jeopardy pertained to poor homosexuals and to South Asian women who were at unexpectedly high risks of fair/poor self-rated health and mitigating effects were experienced by poor women and by poor Asian Canadians who were less likely than expected to report fair/poor health. CONCLUSIONS: Although a variety of intersections between race, gender, class, and sexual orientation were associated with especially high risks of fair/poor self-rated health, they were not all consistent with the predictions of intersectionality theory. I conclude that an intersectionality theory well suited for explicating health inequalities in Canada should be capable of accommodating axis intersections of multiple kinds and qualities. PMID- 21241508 TI - Single-tube multiplex PCR using type-specific E6/E7 primers and capillary electrophoresis genotypes 21 human papillomaviruses in neoplasia. AB - BACKGROUND: Human papillomavirus (HPV) E6/E7 type-specific oncogenes are required for cervical carcinogenesis. Current PCR protocols for genotyping high-risk HPV in cervical screening are not standardized and usually use consensus primers targeting HPV capsid genes, which are often deleted in neoplasia. PCR fragments are detected using specialized equipment and extra steps, including probe hybridization or primer extension. In published papers, analytical sensitivity is typically compared with a different protocol on the same sample set.A single-tube multiplex PCR containing type-specific primers was developed to target the E6/E7 genes of two low-risk and 19 high-risk genotypes (HPV6, 11 and 16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 70, 73 and 82) and the resulting short fragments were directly genotyped by high-resolution fluorescence capillary electrophoresis. RESULTS: The method was validated using long oligonucleotide templates, plasmid clones and 207 clinical samples of DNA from liquid-based cytology, fresh and formalin-fixed specimens and FTA Microcards(r) imprinted with cut tumor surfaces, swabbed cervical cancers or ejected aspirates from nodal metastases of head and neck carcinomas. Between one and five long oligonucleotide targets per sample were detected without false calls. Each of the 21 genotypes was detected in the clinical sample set with up to five types simultaneously detected in individual specimens. All 101 significant cervical neoplasias (CIN 2 and above), except one adenocarcinoma, contained E6/E7 genes. The resulting genotype distribution accorded with the national pattern with HPV16 and 18 accounting for 69% of tumors. Rare HPV types 70 and 73 were present as the sole genotype in one carcinoma each. One cervical SCC contained DNA from HPV6 and 11 only. Six of twelve oropharyngeal cancer metastases and three neck metastases of unknown origin bore E6/E7 DNA; all but one were HPV16. One neck aspirate contained atypical squames with HPV26.Analytical sensitivity in dilute plasmid mixes was variable. CONCLUSIONS: A primer-rich PCR readily detects the E6/E7 oncogenes of 21 HPV types in cellular and fixed tissue specimens. The method is straightforward, robust and reproducible and avoids post-PCR enzymatic and hybridization steps while detecting HPV with high clinical sensitivity in significant HPV-related neoplasia regardless of specimen type. PMID- 21241507 TI - A combined approach for comparative exoproteome analysis of Corynebacterium pseudotuberculosis. AB - BACKGROUND: Bacterial exported proteins represent key components of the host pathogen interplay. Hence, we sought to implement a combined approach for characterizing the entire exoproteome of the pathogenic bacterium Corynebacterium pseudotuberculosis, the etiological agent of caseous lymphadenitis (CLA) in sheep and goats. RESULTS: An optimized protocol of three-phase partitioning (TPP) was used to obtain the C. pseudotuberculosis exoproteins, and a newly introduced method of data-independent MS acquisition (LC-MSE) was employed for protein identification and label-free quantification. Additionally, the recently developed tool SurfG+ was used for in silico prediction of sub-cellular localization of the identified proteins. In total, 93 different extracellular proteins of C. pseudotuberculosis were identified with high confidence by this strategy; 44 proteins were commonly identified in two different strains, isolated from distinct hosts, then composing a core C. pseudotuberculosis exoproteome. Analysis with the SurfG+ tool showed that more than 75% (70/93) of the identified proteins could be predicted as containing signals for active exportation. Moreover, evidence could be found for probable non-classical export of most of the remaining proteins. CONCLUSIONS: Comparative analyses of the exoproteomes of two C. pseudotuberculosis strains, in addition to comparison with other experimentally determined corynebacterial exoproteomes, were helpful to gain novel insights into the contribution of the exported proteins in the virulence of this bacterium. The results presented here compose the most comprehensive coverage of the exoproteome of a corynebacterial species so far. PMID- 21241509 TI - Unanswered questions in the use of blood component therapy in trauma. AB - Recent advances in our approach to blood component therapy in traumatic hemorrhage have resulted in a reassessment of many of the tenants of management which were considered standards of therapy for many years. Indeed, despite the use of damage control techniques, the mortality from trauma induced coagulopathy has not changed significantly over the past 30 years. More specifically, a resurgence of interest in postinjury hemostasis has generated controversies in three primary areas: 1) The pathogenesis of trauma induced coagulopathy 2) The optimal ratio of blood components administered via a pre-emptive schedule for patients at risk for this condition, ("damage control resuscitation"), and 3) The appropriate use of monitoring mechanisms of coagulation function during the phase of active management of trauma induced coaguopathy, which we have previously termed "goal directed therapy". Accordingly, recent experience from both military and civilian centers have begun to address these controversies, with certain management trends emerging which appear to significantly impact the way we approach these patients. PMID- 21241510 TI - Stable isotope shifted matrices enable the use of low mass ion precursor scanning for targeted metabolite identification. AB - We describe a method to identify metabolites of proteins that eliminates endogenous background by using stable isotope labeled matrices. This technique allows selective screening of the intact therapeutic molecule and all metabolites using a modified precursor ion scan that monitors low molecular weight fragment ions produced during MS/MS. This distinct set of low mass ions differs between isotopically labeled and natural isotope containing species allowing excellent discrimination between endogenous compounds and target analytes. All compounds containing amino acids that consist of naturally abundant isotopes can be selected using this scanning technique for further analysis, including metabolites of the parent molecule. The sensitivity and selectivity of this technique is discussed with specific examples of insulin metabolites identified within a complex matrix using a range of different validated low mass target ions. PMID- 21241511 TI - Staphylococcus aureus requires cardiolipin for survival under conditions of high salinity. AB - BACKGROUND: The ability of staphylococci to grow in a wide range of salt concentrations is well documented. In this study, we aimed to clarify the role of cardiolipin (CL) in the adaptation of Staphylococcus aureus to high salinity. RESULTS: Using an improved extraction method, the analysis of phospholipid composition suggested that CL levels increased slightly toward stationary phase, but that this was not induced by high salinity. Deletion of the two CL synthase genes, SA1155 (cls1) and SA1891 (cls2), abolished CL synthesis. The cls2 gene encoded the dominant CL synthase. In a cls2 deletion mutant, Cls1 functioned under stress conditions, including high salinity. Using these mutants, CL was shown to be unnecessary for growth in either basal or high-salt conditions, but it was critical for prolonged survival in high-salt conditions and for generation of the L-form. CONCLUSIONS: CL is not essential for S. aureus growth under conditions of high salinity, but is necessary for survival under prolonged high salt stress and for the generation of L-form variants. PMID- 21241512 TI - Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model. AB - BACKGROUND: Hedgehog signalling has been implicated in prostate tumorigenesis in human subjects and mouse models, but its effects on transforming normal basal/stem cells toward malignant cancer stem cells remain poorly understood. METHODS: We produced pCX-shh-IG mice that overexpress Hedgehog protein persistently in adult prostates, allowing for elucidation of the mechanism during prostate cancer initiation and progression. Various markers were used to characterize and confirm the transformation of normal prostate basal/stem cells into malignant cancer stem cells under the influence of Hedgehog overexpression. RESULTS: The pCX-shh-IG mice developed prostatic intraepithelial neoplasia (PIN) that led to invasive and metastatic prostate cancers within 90 days. The prostate cancer was initiated through activation of P63+ basal/stem cells along with simultaneous activation of Hedgehog signalling members, suggesting that P63+/Patch1+ and P63+/Smo+ cells may serve as cancer-initiating cells and progress into malignant prostate cancer stem cells (PCSCs). In the hyperplastic lesions and tumors, the progeny of PCSCs differentiated into cells of basal intermediate and intermediate-luminal characteristics, whereas rare ChgA+ neuroendocrine differentiation was seen. Furthermore, in the metastatic loci within lymph nodes, kidneys, and lungs, the P63+ PCSCs formed prostate-like glandular structures, characteristic of the primitive structures during early prostate development. Besides, androgen receptor (AR) expression was detected heterogeneously during tumor progression. The existence of P63+/AR-, CK14+/AR- and CD44+/AR- progeny indicates direct procurement of AR- malignant cancer trait. CONCLUSIONS: These data support a cancer stem cell scenario in which Hedgehog signalling plays important roles in transforming normal prostate basal/stem cells into PCSCs and in the progression of PCSCs into metastatic tumor cells. PMID- 21241513 TI - Oncolysis of malignant human melanoma tumors by Coxsackieviruses A13, A15 and A18. AB - Many RNA viruses are displaying great promise in the field of oncolytic virotherapy. Previously, we reported that the picornavirus Coxsackievirus A21 (CVA21) possessed potent oncolytic activity against cultured malignant melanoma cells and melanoma xenografts in mice. In the present study, we demonstrate that three additional Group A Coxsackieviruses; Coxsackievirus A13 (CVA13), Coxsackievirus A15 (CVA15) and Coxsackievirus A18 (CVA18), also have similar oncolytic activity against malignant melanoma. Each of the viruses grew quickly to high titers in cancer cells expressing ICAM-1 and intratumoral injection of preformed subcutaneous SK-Mel-28 xenografts in mice with CVA13, CVA15 and CVA18 resulted in significant tumor volume reduction.As preexisting immunity could potentially hinder oncolytic virotherapy, sera from stage IV melanoma patients and normal controls were tested for levels of protective antibody against the panel of oncolytic Coxsackieviruses. Serum neutralization assays revealed that 3 of 21 subjects possessed low levels of anti-CVA21 antibodies, while protective antibodies for CVA13, CVA15 and CVA18 were not detected in any sample. Serum from individuals who were seropositive for CVA21 failed to exhibit cross neutralization of CVA13, CVA15 and CVA18. From these studies it can be concluded that the administration of CVA13, CVA15 or CVA18 could be employed as a potential multivalent oncolytic therapy against malignant melanoma. PMID- 21241514 TI - Feasibility of a randomised trial of a continuing medical education program in shared decision-making on the use of antibiotics for acute respiratory infections in primary care: the DECISION+ pilot trial. AB - BACKGROUND: The misuse and limited effectiveness of antibiotics for acute respiratory infections (ARIs) are well documented, and current approaches targeting physicians or patients to improve appropriate use have had limited effect. Shared decision-making could be a promising strategy to improve appropriate antibiotic use for ARIs, but very little is known about its implementation processes and outcomes in clinical settings. In this matter, pilot studies have played a key role in health science research over the past years in providing information for the planning, justification, and/or refinement of larger studies. The objective of our study was to assess the feasibility and acceptability of the study design, procedures, and intervention of the DECISION+ program, a continuing medical education program in shared decision-making among family physicians and their patients on the optimal use of antibiotics for treating ARIs in primary care. METHODS: A pilot clustered randomised trial was conducted. Family medicine groups (FMGs) were randomly assigned, to either the DECISION+ program, which included three 3-hour workshops over a four- to six month period, or a control group that had a delayed exposure to the program. RESULTS: Among 21 FMGs contacted, 5 (24%) agreed to participate in the pilot study. A total of 39 family physicians (18 in the two experimental and 21 in the three control FMGs) and their 544 patients consulting for an ARI were recruited. The proportion of recruited family physicians who participated in all three workshops was 46% (50% for the experimental group and 43% for the control group), and the overall mean level of satisfaction regarding the workshops was 94%. CONCLUSIONS: This trial, while aiming to demonstrate the feasibility and acceptability of conducting a larger study, has identified important opportunities for improving the design of a definitive trial. This pilot trial is informative for researchers and clinicians interested in designing and/or conducting studies with FMGs regarding training of physicians in shared decision making. TRIAL REGISTRATION: Clinicaltrials.Gov NCT00354315. PMID- 21241515 TI - Adenovirus serotype 7 associated with a severe lower respiratory tract disease outbreak in infants in Shaanxi Province, China. AB - BACKGROUND: Pneumonia caused by adenovirus infection is usually severe especially with adenovirus serotype 7 commonly associated with lower respiratory tract disease outbreaks. We reported an outbreak of 70 cases of severe pneumonia with one death of infants in Shaanxi Province, China. Sampling showed adenovirus 7 (Ad7) as the primary pathogen with some co-infections. RESULTS: Two strains of adenovirus and two strains of enterovirus were isolated, the 21 pharynx swabs showed 14 positive amplifications for adenovirus; three co-infections with respiratory syncytial virus, two positive for rhinovirus, one positive for parainfluenza 3, and four negative. Adenovirus typing showed nine of the nine adenovirus positive samples were HAdV-7, three were HAdV-3 and two were too weak to perform sequencing. The entire hexon gene of adenovirus was sequenced and analyzed for the two adenovirus serotype 7 isolates, showing the nucleic acid homology was 99.8% between the two strains and 99.5% compared to the reference strain HAdV-7 (GenBank accession number AY769946). For the 21 acute phase serum samples from the 21 patients, six samples had positives results for ELISA detection of HAdV IgA, and the neutralization titers of the convalescent-phase samples were four times higher than those of the acute-phase samples in nine pairs. CONCLUSIONS: We concluded adenovirus was the viral pathogen, primarily HAdV-7, with some co-infections responsible for the outbreak. This is the first report of an infant pneumonia outbreak caused by adenovirus serotype 7 in Shaanxi Province, China. PMID- 21241516 TI - The effects of pre-pregnancy body mass index and gestational weight gain on perinatal outcomes in Korean women: a retrospective cohort study. AB - BACKGROUND: The purpose of the study was to evaluate the effects of maternal pre pregnancy body mass index (BMI) and gestational weight gain on perinatal outcomes in a population of Korean women. METHODS: We retrospectively reviewed the medical records of 2,454 women who had received antenatal care at Seoul St. Mary's Hospital from January 2007 to December 2009. We used World Health Organization definitions for Asian populations of underweight (BMI < 18.5), normal (BMI equal or higher 18.5 and < 23), overweight (BMI equal or higher 23 and < 25), and obese (BMI equal or higher 25). We analyzed perinatal outcomes according to the pre pregnancy BMI and weight gain during pregnancy, and calculated the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) from multiple logistic regression models by considering maternal age, parity, number of fetuses, length of gestation, and medical history. RESULTS: Among obese women, the adjusted ORs for gestational diabetes, hypertensive disorder, and incompetent internal os of cervix were 4.46, 2.53, and 3.70 (95% CI = 2.63-7.59, 1.26-5.07, and 1.50-9.12), respectively, and the adjusted ORs for neonatal complications such as macrosomia and low Apgar score were 2.08 and 1.98 (95% CI = 1.34-3.22 and 1.19-3.29), respectively, compared with normal weight women. However, there was no positive linear association between gestational weight gain and obstetric outcomes. In normal weight women, maternal and neonatal complications were significantly increased with inadequate weight gain during pregnancy (p < 0.0001 and = 0.0180, respectively), and we observed similar results in underweight women (p = 0.0136 and 0.0004, respectively). CONCLUSIONS: This study shows that pre-pregnancy overweight and obesity are more closely related to the adverse obstetric outcomes than excess weight gain during pregnancy. In addition, inadequate weight gain during pregnancy can result in significant complications. PMID- 21241517 TI - Rice black-streaked dwarf virus P6 self-interacts to form punctate, viroplasm like structures in the cytoplasm and recruits viroplasm-associated protein P9-1. AB - BACKGROUND: Rice black-streaked dwarf virus (RBSDV), a member of the genus Fijivirus within the family Reoviridae, can infect several graminaceous plant species including rice, maize and wheat, and is transmitted by planthoppers. Although several RBSDV proteins have been studied in detail, functions of the nonstructural protein P6 are still largely unknown. RESULTS: In the current study, we employed yeast two-hybrid assays, bimolecular fluorescence complementation and subcellular localization experiments to show that P6 can self interact to form punctate, cytoplasmic viroplasm-like structures (VLS) when expressed alone in plant cells. The region from residues 395 to 659 is necessary for P6 self-interaction, whereas two polypeptides (residues 580-620 and 615-655) are involved in the subcellular localization of P6. Furthermore, P6 strongly interacts with the viroplasm-associated protein P9-1 and recruits P9-1 to localize in VLS. The P6 395-659 region is also important for the P6-P9-1 interaction, and deleting any region of P9-1 abolishes this heterologous interaction. CONCLUSIONS: RBSDV P6 protein has an intrinsic ability to self interact and forms VLS without other RBSDV proteins or RNAs. P6 recruits P9-1 to VLS by direct protein-protein interaction. This is the first report on the functionality of RBSDV P6 protein. P6 may be involved in the process of viroplasm nucleation and virus morphogenesis. PMID- 21241518 TI - Combining blue native polyacrylamide gel electrophoresis with liquid chromatography tandem mass spectrometry as an effective strategy for analyzing potential membrane protein complexes of Mycobacterium bovis bacillus Calmette Guerin. AB - BACKGROUND: Tuberculosis is an infectious bacterial disease in humans caused primarily by Mycobacterium tuberculosis, and infects one-third of the world's total population. Mycobacterium bovis bacillus Calmette-Guerin (BCG) vaccine has been widely used to prevent tuberculosis worldwide since 1921. Membrane proteins play important roles in various cellular processes, and the protein-protein interactions involved in these processes may provide further information about molecular organization and cellular pathways. However, membrane proteins are notoriously under-represented by traditional two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and little is known about mycobacterial membrane and membrane-associated protein complexes. Here we investigated M. bovis BCG by an alternative proteomic strategy coupling blue native PAGE to liquid chromatography tandem mass spectrometry (LC-MS/MS) to characterize potential protein-protein interactions in membrane fractions. RESULTS: Using this approach, we analyzed native molecular composition of protein complexes in BCG membrane fractions. As a result, 40 proteins (including 12 integral membrane proteins), which were organized in 9 different gel bands, were unambiguous identified. The proteins identified have been experimentally confirmed using 2-D SDS PAGE. We identified MmpL8 and four neighboring proteins that were involved in lipid transport complexes, and all subunits of ATP synthase complex in their monomeric states. Two phenolpthiocerol synthases and three arabinosyltransferases belonging to individual operons were obtained in different gel bands. Furthermore, two giant multifunctional enzymes, Pks7 and Pks8, and four mycobacterial Hsp family members were determined. Additionally, seven ribosomal proteins involved in polyribosome complex and two subunits of the succinate dehydrogenase complex were also found. Notablely, some proteins with high hydrophobicity or multiple transmembrane helixes were identified well in our work. CONCLUSIONS: In this study, we utilized LC-MS/MS in combination with blue native PAGE to characterize modular components of multiprotein complexes in BCG membrane fractions. The results demonstrated that the proteomic strategy was a reliable and reproducible tool for analysis of BCG multiprotein complexes. The identification in our study may provide some evidence for further study of BCG protein interaction. PMID- 21241519 TI - Simvastatin reduces atherogenesis and promotes the expression of hepatic genes associated with reverse cholesterol transport in apoE-knockout mice fed high-fat diet. AB - BACKGROUND: Statins are first-line pharmacotherapeutic agents for hypercholesterolemia treatment in humans. However the effects of statins on atherosclerosis in mouse models are very paradoxical. In this work, we wanted to evaluate the effects of simvastatin on serum cholesterol, atherogenesis, and the expression of several factors playing important roles in reverse cholesterol transport (RCT) in apoE-/- mice fed a high-fat diet. RESULTS: The atherosclerotic lesion formation displayed by oil red O staining positive area was reduced significantly by 35% or 47% in either aortic root section or aortic arch en face in simvastatin administrated apoE-/- mice compared to the control. Plasma analysis by enzymatic method or ELISA showed that high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apoA-I) contents were remarkably increased by treatment with simvastatin. And plasma lecithin-cholesterol acyltransferase (LCAT) activity was markedly increased by simvastatin treatment. Real-time PCR detection disclosed that the expression of several transporters involved in reverse cholesterol transport, including macrophage scavenger receptor class B type I, hepatic ATP-binding cassette (ABC) transporters ABCG5, and ABCB4 were induced by simvastatin treatment, the expression of hepatic ABCA1 and apoA-I, which play roles in the maturation of HDL-C, were also elevated in simvastatin treated groups. CONCLUSIONS: We demonstrated the anti-atherogenesis effects of simvastatin in apoE-/- mice fed a high-fat diet. We confirmed here for the first time simvastatin increased the expression of hepatic ABCB4 and ABCG5, which involved in secretion of cholesterol and bile acids into the bile, besides upregulated ABCA1 and apoA-I. The elevated HDL-C level, increased LCAT activity and the stimulation of several transporters involved in RCT may all contribute to the anti-atherosclerotic effect of simvastatin. PMID- 21241520 TI - Airway inflammation and mannitol challenge test in COPD. AB - BACKGROUND: Eosinophilic airway inflammation has successfully been used to tailor anti-inflammatory therapy in chronic obstructive pulmonary disease (COPD). Airway hyperresponsiveness (AHR) by indirect challenges is associated with airway inflammation. We hypothesized that AHR to inhaled mannitol captures eosinophilia in induced sputum in COPD. METHODS: Twenty-eight patients (age 58 +/- 7.8 yr, packyears 40 +/- 15.5, post-bronchodilator FEV1 77 +/- 14.0%predicted, no inhaled steroids >=4 wks) with mild-moderate COPD (GOLD I-II) completed two randomized visits with hypertonic saline-induced sputum and mannitol challenge (including sputum collection). AHR to mannitol was expressed as response-dose-ratio (RDR) and related to cell counts, ECP, MPO and IL-8 levels in sputum. RESULTS: There was a positive correlation between RDR to mannitol and eosinophil numbers (r = 0.47, p = 0.03) and level of IL-8 (r = 0.46, p = 0.04) in hypertonic saline induced sputum. Furthermore, significant correlations were found between RDR and eosinophil numbers (r = 0.71, p = 0.001), level of ECP (r = 0.72, p = 0.001), IL 8 (r = 0.57, p = 0.015) and MPO (r = 0.64, p = 0.007) in sputum collected after mannitol challenge. ROC-curves showed 60% sensitivity and 100% specificity of RDR for >2.5% eosinophils in mannitol-induced sputum. CONCLUSIONS: In mild-moderate COPD mannitol hyperresponsiveness is associated with biomarkers of airway inflammation. The high specificity of mannitol challenge suggests that the test is particularly suitable to exclude eosinophilic airways inflammation, which may facilitate individualized treatment in COPD. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1283. PMID- 21241521 TI - Possible impact of rising sea levels on vector-borne infectious diseases. AB - BACKGROUND: Vector-borne infectious diseases are a significant cause of human and animal mortality and morbidity. Modeling studies predict that changes in climate that accompany global warming will alter the transmission risk of many vector borne infectious diseases in different parts of the world. Global warming will also raise sea levels, which will lead to an increase in saline and brackish water bodies in coastal areas. The potential impact of rising sea levels, as opposed to climate change, on the prevalence of vector-borne infectious diseases has hitherto been unrecognised. PRESENTATION OF THE HYPOTHESIS: Mosquito species possessing salinity-tolerant larvae and pupae, and capable of transmitting arboviruses and parasites are found in many parts of the world. An expansion of brackish and saline water bodies in coastal areas, associated with rising sea levels, can increase densities of salinity-tolerant vector mosquitoes and lead to the adaptation of freshwater vectors to breed in brackish and saline waters. The breeding of non-mosquito vectors may also be influenced by salinity changes in coastal habitats. Higher vector densities can increase transmission of vector borne infectious diseases in coastal localities, which can then spread to other areas. TESTING THE HYPOTHESIS: The demonstration of increases in vector populations and disease prevalence that is related to an expansion of brackish/saline water bodies in coastal areas will provide the necessary supportive evidence. However the implementation of specific vector and disease control measures to counter the threat will confound the expected findings. IMPLICATIONS OF THE HYPOTHESIS: Rising sea levels can act synergistically with climate change and then interact in a complex manner with other environmental and socio-economic factors to generate a greater potential for the transmission of vector-borne infectious diseases. The resulting health impacts are likely to be particularly significant in resource-poor countries in the tropics and semi tropics. Some measures to meet this threat are outlined. PMID- 21241522 TI - The Zea mays mutants opaque-2 and opaque-7 disclose extensive changes in endosperm metabolism as revealed by protein, amino acid, and transcriptome-wide analyses. AB - BACKGROUND: The changes in storage reserve accumulation during maize (Zea mays L.) grain maturation are well established. However, the key molecular determinants controlling carbon flux to the grain and the partitioning of carbon to starch and protein are more elusive. The Opaque-2 (O2) gene, one of the best characterized plant transcription factors, is a good example of the integration of carbohydrate, amino acid and storage protein metabolisms in maize endosperm development. Evidence also indicates that the Opaque-7 (O7) gene plays a role in affecting endosperm metabolism. The focus of this study was to assess the changes induced by the o2 and o7 mutations on maize endosperm metabolism by evaluating protein and amino acid composition and by transcriptome profiling, in order to investigate the functional interplay between these two genes in single and double mutants. RESULTS: We show that the overall amino acid composition of the mutants analyzed appeared similar. Each mutant had a high Lys and reduced Glx and Leu content with respect to wild type. Gene expression profiling, based on a unigene set composed of 7,250 ESTs, allowed us to identify a series of mutant-related down (17.1%) and up-regulated (3.2%) transcripts. Several differentially expressed ESTs homologous to genes encoding enzymes involved in amino acid synthesis, carbon metabolism (TCA cycle and glycolysis), in storage protein and starch metabolism, in gene transcription and translation processes, in signal transduction, and in protein, fatty acid, and lipid synthesis were identified. Our analyses demonstrate that the mutants investigated are pleiotropic and play a critical role in several endosperm-related metabolic processes. Pleiotropic effects were less evident in the o7 mutant, but severe in the o2 and o2o7 backgrounds, with large changes in gene expression patterns, affecting a broad range of kernel-expressed genes. CONCLUSION: Although, by necessity, this paper is descriptive and more work is required to define gene functions and dissect the complex regulation of gene expression, the genes isolated and characterized to date give us an intriguing insight into the mechanisms underlying endosperm metabolism. PMID- 21241524 TI - The similarity of gene expression between human and mouse tissues. AB - Meta-analysis of human and mouse microarray data reveals conservation of patterns of gene expression that will help to better characterize the evolution of gene expression. PMID- 21241523 TI - Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. AB - BACKGROUND: Metformin protection against cancer risk in Orientals is uncertain. We examined the possible metformin effect on total, esophageal, gastric, colorectal (CRC), hepatocellular (HCC) and pancreatic cancers in a Taiwanese cohort. METHODS: A representative sample of 800,000 was drawn from the Taiwanese National Health Insurance data of 2000. A cohort of 480,984 participants 20 years or older, diabetes-cancer-free on 1st January 2000 was formed and categorized as four groups by DM and metformin usage status. Eligible incident cancer events had to occur one year after the index date until the end of 2007. The Cox proportional-hazards model evaluated relative risk of cancer for treated DM patients with or without metformin. The covariates included age, gender, other oral anti-hyperglycemic medication, Charlson comorbidity index (CCI) score and metformin exposure dosage and duration. RESULTS: With diabetes but no anti hyperglycemic medication, cancer incidence density increased at least 2-fold for total, CRC and HCC. On metformin, total, CRC and HCC incidences decreased to near non-diabetic levels but to varying degrees depending on gender and cancer type (CRC in women, liver in men). Adjustment for other oral anti-hyperglycemic agents usage and CCI made the benefit of metformin more evident [hazard ratios (95% confidence intervals): total 0.12 (0.08-0.19), CRC 0.36 (0.13-0.98), liver 0.06 (0.02-0.16), pancreas 0.15 (0.03-0.79)]. There was a significant gender interaction with metformin in CRC which favored women. Metformin dosage for a significant decrease in cancer incidence was <= 500 mg/day. CONCLUSIONS: Metformin can reduce the incidences of several gastroenterological cancers in treated diabetes. PMID- 21241525 TI - Is cortisol the key to the pathogenesis of delirium after coronary artery bypass graft surgery? AB - Postoperative delirium is a serious complication of cardiac surgery. However, the pathophysiology of this mental syndrome is largely unknown. Recent findings suggest an association between elevated level of cortisol and postoperative delirium. Further studies should investigate the mechanisms responsible for excessive perioperative cortisol secretion. PMID- 21241526 TI - Exploiting the complexity of the genome and transcriptome using pharmacogenomics towards personalized medicine. AB - A report of the 8th annual Pharmacogenomics and Personalized Therapy meeting, Cold Spring Harbor Laboratory, USA, 17-21 November 2010. PMID- 21241527 TI - Getting ready for the marriage market? A comment. AB - This text comments on the article by Lundborg et al. 'Getting ready for the marriage market? The association between divorce risks and investments in attractive body mass among married Europeans' published in July 2007 in this journal. This commentary presents differing results from the original data using multilevel analysis for calculation. The results presented here suggest there is no significant relation between divorce risk and body mass index (BMI) among married individuals in European countries. Therefore, the primary finding of Lundborg et al. (2007) is questioned. PMID- 21241528 TI - Chronic pain conditions and depression in the Ibadan Study of Ageing. AB - BACKGROUND: Chronic pain is quite common in the elderly and is often associated with comorbid depression, limitation of functioning and reduced quality of life. The aim of this study was to ascertain whether there is a differential risk of depression among persons with pain in different anatomical sites and to determine which pain conditions are independent risk factors for depression. METHODS: Data are from the Ibadan Study of Ageing (ISA), a community-based longitudinal survey of persons aged 65 years and older from eight contiguous Yoruba-speaking states in Nigeria (n = 2152). Data were collected in face-to-face interviews; depression was assessed using the World Mental Health initiative version of the Composite International Diagnostic Interview (CIDI) while chronic pain was assessed by self report (response rate = 74%). RESULTS: Estimates of persistent pain (lasting more than six months), in different anatomical sites range from 1.3% to 12.8%, with the commonest being joint pains (12.8%), neck or back (spinal) pain (7.6%) and chest pain (3.0%). Significantly more pain conditions were reported by females and by respondents who were aged over 80 years. The risk for depression was higher in respondents with spinal, joint and chest pain. However, only chest pain was independently associated with depression after adjustments were made for pains at other sites and for functional disability. CONCLUSION: Our data suggests that, among elderly persons, there is a differential association of depression with chronic pain that is related to the anatomical site of the pain. PMID- 21241529 TI - Heterogeneity in symptom profiles among older adults diagnosed with major depression. AB - BACKGROUND: Late-life depression may be undiagnosed due to symptom expression. These analyses explore the structure of depressive symptoms in older patients diagnosed with major depression by identifying clusters of patients based on their symptom profiles. METHODS: The sample comprised 366 patients enrolled in a naturalistic treatment study. Symptom profiles were defined using responses to the Center for Epidemiologic Studies Depression Scale (CES-D), the Hamilton Rating Scale for Depression (HAM-D) and the depression section of the Diagnostic Interview Schedule (DIS) administered at enrollment. Latent class analysis (LCA) was used to place patients into homogeneous clusters. As a final step, we identified a risk profile from representative items across instruments selected through variable reduction techniques. RESULTS: A model with four discrete clusters provided the best fit to the data for the CES-D and the DIS depression module, while three clusters best fit the HAM-D. Using LCA to identify clusters of patients based on their endorsement of seventeen representative symptoms, we found three clusters of patients differing in ways other than severity. Age, sex, education, marital status, age of onset, functional limitations, level of perceived stress and subjective social support were differentially distributed across clusters. CONCLUSIONS: We found considerable heterogeneity in symptom profiles among older adults with an index episode of major depression. Clinical indicators such as depression history may play less of a role differentiating clusters of patients than variables such as stress, social support, and functional limitations. These findings can help conceptualize depression and potentially reduce misdiagnosis for this age group. PMID- 21241530 TI - Nonliteral language in Alzheimer dementia: a review. AB - The use of nonliteral language in clinical assessment, especially testing the patients' ability to interpret proverbs, has a long tradition in psychiatry. However, its diagnostic sensitivity and specificity in dementias is not yet clear. The aim of this review article is to examine the current evidence on nonliteral/figurative language (proverb, metaphor, metonymy, idiom, irony, sarcasm) comprehension in Alzheimer's disease and related disorders. A comprehensive literature search identified 25 studies (16 proverb, 3 metaphor, 0 metonymy, 5 idiom, 3 sarcasm) on nonliteral language comprehension in dementia. Studies predominantly indicate a deficit. Most studies investigated Alzheimer's dementia. Applied correctly, nonliteral language is a worthwhile diagnostic tool to evaluate language and abstract thinking in dementias. During assessment, familiarity testing (e.g., by asking "are you familiar with the proverb XY") is obligatory. Still, future research is needed in several areas: evidence on decline of nonliteral language over the course of the illness is limited. So far, almost no studies delineated proverb comprehension in high risk populations such as patients with mild cognitive impairment. Currently, there is a lack of studies addressing performance in direct comparison to relevant differential diagnosis like older-age depression, delirium, brain lesion, or other psychiatric conditions. PMID- 21241531 TI - Coping strategies as a predictor of post-concussive symptoms in children with mild traumatic brain injury versus mild orthopedic injury. AB - This study examined whether children's coping strategies are related to post concussive symptoms following mild traumatic brain injury (TBI) versus orthopedic injury (OI). Participants were 8- to 15-year-old children with mild TBI (n = 167) or OI (n = 84). They rated their current preferred coping strategies and post injury symptoms at 2 weeks (baseline) and 1, 3, and 12 months post-injury. Children's reported use of coping strategies did not vary significantly over time, so their baseline coping ratings were examined as predictors of post concussive symptoms across time. Self-ratings of symptoms were positively related to emotion-focused strategies and negatively related to problem-focused engagement after both mild TBI and OI. Higher problem-focused disengagement predicted larger group differences in children's ratings of symptoms, suggesting that problem-focused disengagement moderates the effects of mild TBI. Coping strategies collectively accounted for approximately 10-15% of the variance in children's post-concussive symptoms over time. The findings suggest that coping may play an important role in accounting for children's perceptions of post concussive symptoms after mild TBI. PMID- 21241532 TI - Nutrition labels on pre-packaged foods: a systematic review. AB - OBJECTIVE: To review research on consumer use and understanding of nutrition labels, as well as the impact of labelling on dietary habits. DESIGN: A systematic review was conducted by searching electronic databases. Relevant articles were screened by two reviewers and included if they met inclusion criteria, including eight methodological criteria. A total of 120 articles were included in the review, including cross-sectional surveys (n 96), experimental designs (n 17), 'natural experiments' (n 7) and longitudinal population-based surveys (n 2). SETTING: Articles covered seven jurisdictions: USA (n 88), Europe (n 12), Canada (n 9), Australia and New Zealand (n 4), Norway (n 2), Thailand (n 1) and Trinidad (n 1). SUBJECTS: Participants were from a wide range of age groups, socio-economic strata and geographical regions. RESULTS: Nutrition labels on pre-packaged foods are among the most prominent sources of nutrition information. Nutrition labels are perceived as a highly credible source of information and many consumers use nutrition labels to guide their selection of food products. Evidence also shows a consistent link between the use of nutrition labels and healthier diets. However, the use of labels varies considerably across subgroups, with lower use among children, adolescents and older adults who are obese. Research also highlights challenges in terms of consumer understanding and appropriate use of labelling information. CONCLUSIONS: Nutrition labels on pre packaged foods are a cost-effective population-level intervention with unparalleled reach. However, to capitalize on their potential, governments will need to explore new formats and different types of information content to ensure that nutrition information is accessible and understandable. PMID- 21241533 TI - The impact of a workplace catering initiative on dietary intakes of salt and other nutrients: a pilot study. AB - OBJECTIVE: Owing to modern lifestyles, individuals are dependent on out-of-home eating. The catering sector can have a pivotal role in influencing our food choices. The objective of the present study was to examine the impact of a structured catering initiative on food choices in a public sector workplace setting. DESIGN: A cross-sectional comparison study in two hospitals, one of which had implemented a catering initiative designed to provide nutritious food while reducing sugar, fat and salt intakes. SETTING: Two public sector hospitals in Cork, Ireland. SUBJECTS: A total of 100 random participants aged 18-64 years (fifty intervention, fifty non-intervention) who consumed at least one main meal in the hospital staff canteen daily. Each respondent was asked to complete one anonymous 24 h dietary recall and questionnaire. Food and nutrient analysis was conducted using WISP (Weighed Intake Software Program). RESULTS: Reported mean intakes of total sugars (P < 0.001), total fat (P < 0.000), saturated fat (P < 0.000) and salt (P < 0.046) were significantly lower in the intervention hospital when adjusted for age and gender. In the intervention hospital, 72 % of respondents, compared with 42 % in the non-intervention hospital, complied with the recommended under-3 daily servings of food high in fat and sugar (P < 0.005). In the intervention hospital, 43 % of respondents exceeded the recommended salt intake of 4-6 g/d, compared with 57 % in the non-intervention hospital. CONCLUSIONS: Structured catering initiatives in the workplace are a potentially important option in the promotion of healthy food choices. Targeted public health programmes and health policy changes are needed to motivate caterers in the public sector and other industries to develop interventions that promote a healthy diet. PMID- 21241534 TI - Changes in meal pattern among Norwegian children from 2001 to 2008. AB - OBJECTIVE: The present study aimed to analyse changes in meal pattern among Norwegian children from 2001 to 2008 in general; to analyse associations between meal pattern and gender, parental educational level and number of parents in the household; and to analyse the association between intake of unhealthy snacks, meal pattern and the mentioned variables. DESIGN: Within the Fruits and Vegetables Make the Marks (FVMM) project, two cross-sectional studies were conducted, one in 2001 and one in 2008, where participants from the same schools filled in a questionnaire on meals eaten the previous day. SUBJECTS: Participants were 6th and 7th grade pupils, n 1488 in 2001 and n 1339 in 2008. SETTING: Twenty seven elementary schools in two Norwegian counties. RESULTS: There were no significant changes in children's meal pattern from 2001 to 2008. For both years more than 90 % of the participants reported that they had breakfast yesterday, while 95 % had lunch, 94 % had dinner and 82 % had supper. More girls than boys reported that they had lunch yesterday (96 % v. 94 %, P = 0.03). More children with higher v. lower educated parents reported that they had breakfast yesterday (93 % v. 88 %, P < 0.001). More children living with two parents v. one parent had breakfast (93 % v. 88 %, P = 0.001) and lunch yesterday (97 % v. 93 %, P < 0.001). CONCLUSIONS: There were no changes in meal pattern from 2001 to 2008 among Norwegian children. Characteristics associated with skipping meals were living in a one-parent family and having lower educated parents. PMID- 21241535 TI - Factors associated with dietary patterns among low-income adults. AB - OBJECTIVE: To describe the association of socio-economic, demographic and lifestyle characteristics with three eating patterns identified among low-income adults living in the Rio de Janeiro metropolitan area, Brazil. DESIGN: Data were obtained in a population-based cross-sectional study. The analysed patterns were: (i) 'Mixed', in which diverse foods had similar factor loadings; (ii) 'Western', which included items with high energy density; and (iii) 'Traditional', which relied in rice and beans, traditional staple foods in Brazil. Hierarchical logistic analysis was performed to estimate the association between the independent variables and each one of the dietary patterns. The variables that presented statistical significance <0.20 in the univariate analysis (chi2 test) were included in the multivariate models. SETTING: Duque de Caxias, a low-income area in the Rio de Janeiro metropolitan region, Brazil. SUBJECTS: Adults (n 1009) aged 20 to 65 years (339 men and 670 women). RESULTS: The 'Mixed' pattern was positively associated with smoking (OR = 1.58, 95 % CI 1.00, 2.48 for current smoking v. those who never smoked). The 'Western' pattern was positively associated with family income (OR = 3.00, 95 % CI 1.81, 4.97 for those with monthly per capita family income >=1.0 v. <0.5 times the official Brazilian minimum wage) and inversely associated with family food insecurity (OR = 0.55, 95 % CI 0.36, 0.84). The 'Traditional' pattern was associated with family food insecurity (OR = 1.79, 95 % CI 1.27, 2.51). CONCLUSIONS: The results support previous findings relating improvement in economic conditions to reduced adherence to the traditional Brazilian food consumption pattern based on the combination of rice and beans. PMID- 21241536 TI - Evolutionary diversification of bruchine beetles: climate-dependent traits and development associated with pest status. AB - A number of insect species infest human households and stored foods and products, leading to their designation as pests. Until recently, little was known about the factors driving the evolution of pests that feed on stored dry foods. Here, I review the effects of changes in climate and species interactions on the evolution and ecology of beetles that feed on dried seeds/grains. My review focuses on evidence that the host utilization by part of the species in the subfamily Bruchinae (Chrysomelidae) is a preadaptation for utilizing stored dry seeds and grains, thus leading to their status as a pest. These and other stored product pest beetles retain a higher percentage of water in their body, relative to the water content of their diet, than beetles that feed on fresh crops. I review the studies that have documented adaptation, acclimation and polyphenetic response to high temperatures and desiccation and/or made direct comparisons between these traits between developmental stages, populations and among higher taxonomic groups. Finally, I review evidence for the effects of environmental change on insect host-parasitoid and competitor assemblages. PMID- 21241537 TI - Transmission of swine pathogens: different means, different needs. AB - There seems to be two main types of pathogens that cause diseases in swine: those that are mainly introduced through direct pig contacts, and those that are often, and in some situations mainly introduced by indirect transmission means. In this review, the mange mite (Sarcoptes scabiei), toxigenic Pasteurella multocida and Brachyspira hyodysenteriae will be used as examples of the first type, and foot and mouth disease virus, Mycoplasma hyopneumoniae and porcine reproductive and respiratory syndrome (PRRS) virus as examples of the second. It is now clear from various epidemiological studies as well as experimental and field data that aerosol transmission of some swine pathogens plays an important role in their epidemiology. As previous biosecurity programs did not take this factor into consideration, it can at least partially explain why many of these programs suffered frequent failures and why air filtration is now becoming increasingly popular in North America. Identifying and quantifying transmission means should be a priority for every important infectious disease for which it has not been done. PMID- 21241538 TI - Are Trauma Memories Disjointed from other Autobiographical Memories in Posttraumatic Stress Disorder? An Experimental Investigation. AB - This study tested the hypothesis that trauma memories are disjointed from other autobiographical material in posttraumatic stress disorder (PTSD). Assault survivors with (n = 25) and without PTSD (n = 49) completed an autobiographical memory retrieval task during script-driven imagery of (a) the assault and (b) an unrelated negative event. When listening to a taped imagery script of the worst moment of their assault, survivors with PTSD took longer to retrieve unrelated non-traumatic autobiographical information than those without PTSD, but not when listening to a taped script of the worst moment of another negative life event. The groups also did not differ in general retrieval latencies, neither at baseline nor after the imagery tasks. The findings are in line with suggestions that traumatic memories are less integrated with other autobiographical information in trauma survivors with PTSD than in those without PTSD. PMID- 21241539 TI - Maintenance of intrusive memories in posttraumatic stress disorder: a cognitive approach. AB - Intrusive recollections are very common immediately after traumatic events and are considered necessary aspects of emotional processing. However, if these intrusive recollections persist over a long time, they are linked to long-term psychiatric disorder, especially Posttraumatic Stress Disorder (PTSD). This paper discusses the need to investigate factors involved in the maintenance of intrusive traumatic recollections. It is suggested that the idiosyncratic meaning of the intrusive recollections predicts the distress caused by them, and the degree to which the individual engages in strategies to control the intrusions. These control strategies maintain the intrusive recollections by preventing a change in the meaning of the trauma and of the traumatic memories. It is further suggested that what is needed is a comprehensive assessment of the processes that prevent change in meaning, going beyond the assessment of avoidance. In particular, safety behaviours, dissociation and numbing, suppression of memories and thoughts about trauma, rumination, activation of other emotions such as anger and guilt and corresponding cognitions, and selective information processing (attentional and memory biases) may be involved in the maintenance of intrusive recollections. Preliminary data supporting these suggestions from studies of individuals involved in road traffic accidents and survivors of child sexual abuse are described. PMID- 21241540 TI - [More attention should be devoted to molecular target therapy of lung cancer in our country]. PMID- 21241541 TI - [Trend of molecular target therapy of non-small cell lung cancer]. PMID- 21241542 TI - A new horizon of targeted therapy in management of lung cancer. PMID- 21241543 TI - Targeted therapy in non-small cell lung cancer. PMID- 21241544 TI - [Experimental study of tissue-specific suicide gene therapy for lung adenocarcinoma]. AB - BACKGROUND: To study the effect and safety of tissue specific gene therapy of suicide gene for lung adenocarcinoma. METHODS: Retroviral vector of G1CEACDNa contained a carcinoembryonic antigen (CEA) promoter regulated cytosine deaminase expression cassete (CEA/CD). By means of infection of virus, tissue specific expressing vectors and non-specific expressing vectors were transfected into A549 cell, which was CEA-producing lung adenocarcinoma cell line and then xenografted in nude mice, and the anti-tumor effect was evaluated. Then the retrovirus was injected directly into the tumor mass on nude mice, and the sensitivity of the xenograft to G1CEACDNa/5-fluorocytosine (5-FC) and the side effects were observed. RESULTS: (1) After transfected and untransfected A549 cells were implanted into nude mice, there was no difference in tumor formation among all the groups. (2) After 5-FC administration, the tumor transfected with tissue specific gene displayed a higher sensitivity to the drug than those treated with non-specific in vitro gene-therapy. (3) The tumor-bearing nude mice were randomized in a blind manner based on comparable size to receive the supernatant of recombinant retrovirus G1CEACDNa followed by 5-FC, and significant growth suppression could be observed. (4) Comparing to the group with injection of 5 fluorouracil (5-FU) alone, tissue-specific suicide gene therapy showed lower suppression to bone marrow. CONCLUSIONS: The results suggest that tissue-specific suicide gene therapy may play an important role in individual treatment of lung cancer. PMID- 21241545 TI - [Targeting blockage of Wnt signal transduction pathway of nm23-H1 gene transfection in human high-metastatic large cell lung cancer cell line L9981]. AB - BACKGROUND: To explore the possibility of targeting blockage of Wnt signal transduction pathway of nm23-H1 gene transfection in human high-metastatic large cell lung cancer cell line L9981, and to provide evidence to elucidate the signal conductive mechanism of nm23-H1 mediated tumor metastasis suppression. METHODS: The expression of GSK-3beta and beta-catenin of Wnt signal pathway was detected in cytoplasm and nucleus in L9981 cell line with nm23-H1 deletion, L9981-pLXSN cell line transfected with vector and L9981-nm23-H1 cell line transfected with nm23-H1 gene by Western blot. RESULTS: (1)GSK-3beta expression in L9981-nm23-H1 cytoplasm (6 341+/-541) was significantly higher than those in L9981 (3 736+/ 298) and L9981-pLXSN (3 613+/-383) cell lines ( P < 0.001); (2)GSK-3beta expression in L9981-nm23-H1 nucleus (4 356+/-490) was significantly higher than those in L9981 (657+/-57) and L9981-pLXSN (705+/-75) cell lines ( P < 0.001); (3)beta-catenin expression in L9981-nm23-H1 cytoplasm (3 649+/-118) was significantly higher than those in L9981 (1 401+/-31) and L9981-pLXSN (1 350+/ 55) cell lines ( P < 0.001); (4)No statistical difference of the beta-catenin expression in nucleus was observed among L9981-nm23-H1 (2 945+/-68), L9981 (2 604+/-23) and L9981-pLXSN (2 652+/-53)( P > 0.05); (5)No significant difference of GSK-3beta or beta-catenin expression in cytoplasm and nucleus was observed between L9981 and L9981-pLXSN ( P > 0.05). CONCLUSIONS: (1)nm23-H1 gene can remarkably upregulate the expression of GSK-3beta in cytoplasm and nucleus, and beta-catenin expression in cytoplasm in L9981-nm23-H1 cell, but can not induce the nucleus accumulation of beta-catenin. (2)Regulation of GSK-3beta and beta catenin expression, and targeting blockage of Wnt signaling pathway may be one of molecular mechanisms that nm23-H1 contributes to play a vital role in the "Lung Cancer Metastasis Suppressive Cascade". PMID- 21241546 TI - [Gefitinib is active in patients with brain metastasis from non-small cell lung cancer]. AB - BACKGROUND: To explore the efficacy of gefitinib to non small cell lung cancer (NSCLC) patients irrespective of their performance status, number of prior treatment regimens and the presence of brain metastasis. METHODS: A total of 76 patients were enrolled. RESULTS: For all enrolled patients, the disease control rate was 63.2% (95% CI, 52.1%-74.3%) with a median progression-free survival of 5.0 months (95% CI, 3.5-6.6 months) and median overall survival of 9.9 months (95% CI, 4.9-14.8 months). Fifty seven patients had measurable lesions and the objective response rate was 33.3% (95% CI, 20.7%-46.0%). Twenty one patients had simultaneously assessable intracranial and extracranial lesions, 17 of them (81.0%) showed comparable tumor response. There was no survival difference between the patients with and without metastatic brain disease. Most drug-related adverse events were mild. Intolerable toxicities happened in 5 patients, 4 of them were interstitial pneumonia (5.8%) CONCLUSIONS: Gefitinib is active in patients with brain metastasis from NSCLC. It is feasible to conduct randomized trials to identify the role of gefitinib alone or in combination with other modality in the treatment of NSCLC patients who have metastatic brain lesion(s). PMID- 21241547 TI - [Iressa for refractory non-small cell lung cancer: A preliminary report]. AB - BACKGROUND: To summarize the preliminary experience on Iressa for refractory non small cell lung cancer (NSCLC). METHODS: Fifty-five patients with NSCLC, who failed after surgery, radiotherapy, chemotherapy or combination of the above modalities, were registered in this clinical trail. Prior to Iressa, 50 patients were in stage IV, and 5 in stage III. Iressa was administered orally at 250 mg, once a day until cancer progressed or severe toxicity occured, which made patients intolerable. The median time for administration of Iressa was 4 months. RESULTS: The toxicity of Iressa was tolerable with 47% of skin toxicity (rash) and 2%-7% of diarrhea, nausea, orally mucosal ulceration and alopecia. Overall response rate was 20%. Different sites of distant metastases responded to Iressa in different ways with higher response rate for pulmonary disseminations. One quarter of patients felt improvement of their symptoms over 2 weeks. Median survival time for entire group was 5 months (1-17 months). Median time to progression (TTP) was 3.6 months. Survival at 6 months was 67%. Prognostic predictor, which could imply the outcome, was skin toxicity with higher response rate and longer survival time ( P < 0.05), and no relationship with sex, histological types of NSCLC and distant metastasis had been found. CONCLUSIONS: Iressa could be tolerated by refractory NSCLC patients with acceptable side effects, and have palliative effects. PMID- 21241548 TI - [ZD1839 (Iressa) in the treatment of non-small cell lung cancer patients]. AB - BACKGROUND: To investigate the antitumor effects and toxicity of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor ZD1839 (Iressa) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: From December 2002 to August 2003, 39 patients with unresectable NSCLC were enrolled for 250 mg once daily oral treatment with ZD1839. Clinical data was analysed using chi-square test, t test and Kaplan-Meier survival analysis. Quality of Life (QoL) was analyzed using Chinese Version of European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 and lung cancer related questionnaire QLQ-LC13. RESULTS: Tumor response rate (complete response and partial response) was 28.2% . Disease control rate, which included both tumor responses and stable disease, was 59.0%. Objective tumor response was correlated with gender and pathological type. Time to progress was (6.6+/-1.6) months (95% CI, 3.4-9.7), and 1 year survival rate was 54.3%. Response rate of global, functional and lung cancer-related symptom scales were 34.8%, 65.2% and 73.9% respectively. The ZD1839 of 250 mg/d was well tolerated by patients. The majority of adverse events were grade I or grade II skin rash and diarrhea, which were manageable and reversible. CONCLUSIONS: ZD1839 offers a new treatment option providing meaningful tumor control and symptom relief for many patients with advanced NSCLC. PMID- 21241549 TI - [The salvage regimen for patients with advanced non-small cell lung cancer who failed prior chemotherapy: once-daily single oral agent Iressa]. AB - BACKGROUND: To summarize the effect of Iressa for refractory patients with advanced non small cell lung cancer (NSCLC) failed to prior chemotherapy. METHODS: Thirty-one patients, with unresectable stage IIIB or IV NSCLC who had disease progression or relapse after prior chemotherapy using platinum-based regimen for at least 2 cycles, were admitted to the Osaka Prefectural Hobikino Hospital. Iressa 250 mg was administered once a day until disease progression was noted. Weekly chest x-ray and monthly CT scan were performed for response assessment each month. RESULTS: Among the 31 patients, one complete response (CR) and 7 partial responses (PR) were observed. CR rate was 3.2% (95% confidence interval: 0-17%), PR rate 22.6% (95% confidence interval: 10%-41%), disease control rate including both tumor responses and stable disease was 80.6% (95% confidence interval: 52%-92%). The rate of symptoms relieves was 51.6% (95% confidence interval: 33%-70%), the most effective symptoms being cough and pain. The median time to improved symptoms was 14 days. The most common adverse events were grade I or II skin rash and diarrhea which were readily manageable and reversible. No patients were withdrawn due to the adverse events CONCLUSIONS: Monotherapy using Iressa is effective and tolerable for the patients with advanced NSCLC who failed prior chemotherapy. PMID- 21241550 TI - [Gefitinib molecular target therapy for Chinese patients with non-small cell lung cancer]. AB - BACKGROUND: To explore the experience of gefitinib molecular target therapy for Chinese patients with non-small cell lung cancer (NSCLC). METHODS: The unpublished data of gefitinib for advanced NSCLC in 7 hospitals were collected. The detailed data from Guangdong Provincial People's Hospital were analyzed. RESULTS: A total of 282 patients with advanced NSCLC was treated with gefitinib from July 2001 to December 2003. Response rate was 22.2%-47.7%, disease control rate 62.6%-81.8%. No severe side effects were surveyed. CONCLUSIONS: Gefitinib can be used safely and effectively in Chinese patients with advanced NSCLC. PMID- 21241551 TI - [Iressa for the non-small cell lung cancer patients who failed prior chemotherapy and radiotherapy]. AB - BACKGROUND: To summarize the clinical results of Iressa in the treatment of patients with non small cell lung cancer (NSCLC) who failed prior chemotherapy and radiotherapy. METHODS: Twenty-nine patients with NSCLC, who failed prior chemotherapy and radiotherapy, were registered in this open clinical trial. Prior to Iressa therapy, 26 patients were in stage IV, 3 patients in stage IIIB. Iressa was administered orally at 250 mg, once a day until cancer progressed or severe toxicity occured. The median time for administration of Iressa was 5 months. RESULTS: The main toxicity of Iressa was skin toxicity (rash). Twelve cases had rash with 41.4% of the whole group. Two cases had diarrhea, 1 case had bradycardia and 1 case had elevation of transaminase. Among the 29 patients, one patient got complete response (CR), 7 partial response (PR), 12 stable disease (SD) and 9 progression disease (PD). The response rate was 27.59% and disease control rate including both tumor response and stable disease was 68.97%. The median survival time was 5.5 months (1-19 months). Median time to progression (TTP) was 6.5 months. The 1-year survival rate was 44.83%. CONCLUSIONS: Iressa is effective and tolerable for the patients with NSCLC who failed prior chemotherapy and radiotherapy. It can remarkably improve symptoms and prolong survival time of NSCLC patients. PMID- 21241552 TI - [Phase II clinical trial of homemade human rh-endostatin in the treatment of patients with stage IIIB-IV non-small cell lung cancer]. AB - BACKGROUND: To evaluate the efficacy and safety of homemade human rh-endostatin (YH-16) combined with NP regimen (vinorelbine+cisplatin) for stage IIIB-IV non small cell lung cancer (NSCLC), and to compare with NP regimen alone. METHODS: Eighteen NSCLC patients were divided into two groups. Group A ( n =9) received YH 16 combined with NP plan. Group B ( n =9) received NP regimen. They were treated with 2 or 3 cycles of chemotherapy. The overall response, time to progression (TTP), quality of life (QOL) and safety were observed. RESULTS: The overall response was 22.2% in group A, and 0% in group B ( P > 0.05). The clinical benefit rate was 100% in group A, and 44.4% in group B ( P < 0.05). There was no significant relationship between response and clinical pathological characteristics of patients ( P > 0.05). The TTP was 178.8+/-70.8 days in group A and 85.4+/-48.2 days in group B ( P < 0.05). The main toxicities of the two groups were hematological toxicities, nausea and vomiting. No significant difference in incidence of toxicity was observed between the two groups ( P > 0.05). CONCLUSIONS: The rh-endostatin combined with NP regimen for NSCLC tends to show a better chemotherapeutic effect and less toxicity than NP regimen alone. It is worthy of extensive clinical trial. PMID- 21241553 TI - [Targeted Iressa therapy in patients with brain metastases from non-small cell lung cancer]. PMID- 21241554 TI - [Effect of exogenous p73 gene on chemosensitivity of wild-type p53 human lung adenocarcinoma cell A549]. AB - BACKGROUND: To assess the effects of exogenous p73 gene on chemosensitivity of wild-type p53 human lung adenocarcinoma cell A549 to cisplatin (DDP) and adriamycin (ADM). METHODS: Recombinant eukaryotic expression vector pcDNA3 containing full-length human wild-type p73alpha cDNA or p53 cDNA was transfected into A549 cells which had wtp53 by lipofectamine-mediated gene transfection. The chemosensitivity of tumor cells to DDP and ADM was observed before and after transfection. RESULTS: A549-p73alpha could stably express P73alpha protein. The P73alpha protein expression was significantly increased in A549-p73alpha than that in A549 and A549-pcDNA3. The growth and colony formation of A549-p73alpha were significantly inhibited compared with A549, A549-pcDNA3 and A549-wtp53. Flow cytometry and DNA fragmentation analysis showed apoptosis of A549-p73alpha cells was significantly increased. The IC50 values for DDP and ADM were reduced to approximate 1/6 and 1/70 in A549-p73alpha cells compared with A549 cells respectively.. CONCLUSIONS: Exogenous p73 gene is capable of enhancing the sensitivity of wild-type p53 human lung adenocarcinoma cell A549 to chemotherapeutic drugs. It is probably for p73 to be used in the treatment of p53 resistant tumors. PMID- 21241555 TI - [Relationship of cytokine level with cancer cachexia and therapeutic effects of indomethacin for cancer cachexia]. AB - BACKGROUND: To investigate the relationship between cytokine level and cancer cachexia on murine model, and to observe the effects of regular dose of indomethacin on cancer cachexia and survival of mice. METHODS: C57 mice bearing Lewis lung carcinoma were used to establish murine cancer cachexia model. The serum cytokine levels (IL-1, IL-6, TNF-alpha and IFN-gamma) and body weight of the mice were measured at different time points before and after treatment with daily intraperioneal injection of either indomethacin (1 mg/kg) or saline. RESULTS: The mice in cancer cachexia group had significantly higher serum levels of IL-1, IL-6 and TNF-alpha ( P < 0.05) and lower body weight ( P < 0.05) than those in healthy control group. Compared to saline treatment, indomethacin intervention apparently down regulated the levels of IL-1, IL-6 and TNF-alpha ( P < 0.05 ), and remarkably prolonged the survival of mice ( P < 0.05). No significant difference in IFN-gamma level was observed between cancer cachexia and healthy control groups ( P > 0.05), as well as between indomethacin and saline groups ( P > 0.05). CONCLUSIONS: The results suggest that serum IL-1, IL-6 and TNF-alpha are possibly associated with cancer cachexia, however, IFN-gamma seems to be irrelevant. Indomethacin may potentially ameliorate cancer cachexia through down-regulating levels of cytokines. PMID- 21241556 TI - [Different expressions of p53 gene family members and their clinical significance in human non-small cell lung cancer]. AB - BACKGROUND: To investigate the different expressions of p53 gene family members p53, p63 and p73, and their clinical significance in non small cell lung cancer (NSCLC). METHODS: p53, p63 and p73 protein expressions were detected in 60 NSCLC tissues and 7 normal lung tissues by immunohistochemistry. RESULTS: In NSCLC, positive rate of p53, p63 and p73 protein was 61.67%(37/60), 80.00%(48/60), 73.33% (44/60) respectively. There were significant differences in positive rate of three proteins as compared to normal lung tissue ( P < 0.05). p53 protein expression was closely associated with tumor cell differentiation degree ( P =0.023), but was not associated with histological classification, lymph node metastasis and clinical stages ( P > 0.05). Expression of p63 protein was closely related to lymph node metastasis ( P =0.028) and histological classification ( P =0.001), but not to cell differentiation degree and clinical stages ( P > 0.05). There was no significant relationship between p73 protein expression and clinical characteristics of NSCLC ( P > 0.05). A positive correlation was present between p63 and p73 protein expressions ( P =0.000 1). No statistical correlation was found between p53 and p73 ( P > 0.05). CONCLUSIONS: p53 gene family may be related to the oncogenesis and development of NSCLC. p63 and p73 proteins may have different biological function from p53 protein, and both might play oncogenic roles. PMID- 21241557 TI - [Expression of hypoxia inducible factor 1alpha and its clinical significance in non-small cell lung cancer]. AB - BACKGROUND: To explore the expression level and its clinical significance of hypoxia inducible factor 1alpha (HIF-1alpha) in non-small cell lung cancer. METHODS: The expression of HIF-1alpha was detected in 68 human non-small cell lung cancer samples by immunohistochemistry. RESULTS: Thirty-nine (57.35%) out of 68 human non-small cell lung cancer samples were positive for HIF-1alpha. The positive rate of HIF-1alpha in adenocarcinoma was 54.76% (23/42) and 61.54% (16/26) in squamous cell carcinoma ( P > 0.05) respectively. The positive rate of HIF-1alpha in moderate- to well-differentiated samples was 74.29%(26/35) and 39.39%(13/33) in low-differentiated samples respectively ( P < 0.05). The expression rate of HIF-1alpha in I-II stage ( 86.96%, 20/23) was significantly higher than that in III-IV stage (42.22%,19/45)( P < 0.05). The positive expression of HIF-1alpha was not related to sex and age of patients and lymph node status. CONCLUSIONS: High expression of HIF-1alpha exists in non-small cell lung cancer, and it may be related to cell differentiation and TNM stage of tumor. The results suggest that resistance to radiotherapy and chemotherapy induced by HIF-1alpha should be considered in the treatment of non-small cell lung cancer. PMID- 21241558 TI - [Thoracoscopy and thoracotomy for lung biopsy and wedge resection in solitary pulmonary nodule]. AB - BACKGROUND: Lung wedge resections and biopsies are frequently needed to diagnose and treat benign or malignant lung lesions. This study aims to compare thoracoscopy with thoracotomy for lung biopsy and wedge resection in solitary pulmonary nodule (SPN). METHODS: A controlled retrospective study was performed in this hospital. Patients with clinical diagnosis of SPN were undergone thoracoscopy or thoracotomy. Data of operation time, hours of stay in recover room, duration and volume of chest tube drainage, accuracy of biopsies, days of hospitalization and the whole cost of hospitalization were evaluated. RESULTS: All patients were received lung biopsies and wedge resections (thoracoscopy 26,thoracotomy 47), and they were diagnosed pathologically. The days of hospitalization were similar in the two groups. The minutes of operation had no significant difference (thoracoscopy: 103.9+/-29.4 minutes, thoracotomy: 94.7+/ 33.9 minutes). Both groups had equivalent duration of chest tube drainage (thoracoscopy: 60.3+/-25.0 hours, thoracotomy: 62.5+/-20.1 hours, P =0.687) . The total volume of chest tube drainage showed no difference in both groups. The hours of stay in recover room (thoracoscopy: 75.4+/-21.6 hours, thoracotomy: 80.4+/-17.7 hours, P =0.287) and days of hospitalization after operation (thoracoscopy: 11.3+/-3.4 days, thoracotomy: 10.6+/-2.4 days, P = 0.304 ) were not different significantly. The whole cost of thoracoscopy was 17 800.2+/-6 038.9 CNY and thoracotomy was 17 677.4+/-6 327.8 CNY ( P = 0.936 ). CONCLUSIONS: There is no significant difference in outcomes for thoracoscopy and thoracotomy approaches. Both thoracoscopy and thoracotomy are acceptable procedures for lung biopsy and wedge resection in solitary pulmonary nodules. PMID- 21241559 TI - [Sequential variation of pulmonary flow spectrum and its value on the evaluation of risk for pulmonary resection in perioperative patients with lung cancer]. AB - BACKGROUND: To explore the sequential variation of pulmonary flow spectrum and its value on evaluation of risk for pulmonary resection in perioperative patients with lung cancer. METHODS: Forty-nine patients with lung cancer who underwent pneumonectomy (12 cases) and lobectomy (37 cases) were observed for the values of Doppler pulmonary flow spectrum before operation, on the 3-5 days and 8-10 days postoperatively. Moreover the patients were divided into different groups according to the different operative procedures and with or without postoperative cardiac arrhythmia. RESULTS: Doppler pulmonary flow spectrum changed in all cases who underwent pneumonectomy and lobectomy from 3 to 5 days postoperatively. These changs included prolonged preejection period (PEP), shortened acceleration time (ACT), increased PEP/ACT ratio, increased pulmonary artery mean pressure (PAMP), and increased pulmonary vascular resistance (PVR). There were significant differences comparing with those before operation ( P < 0.01). The patients who underwent lobectomy recovered to the same level of pre operation on the 8th to 10th postoperative days. However, the changes of pulmonary flow spectrum continuously existed in the patients who underwent pneumonectomy on the 8th to 10th postoperative days. There were significant differences of pulmonary flow spectrum between patients with postoperative arrhythmia and without postoperative arrhythmia before operation. CONCLUSIONS: Pulmonary hemodynamic obviously changes after pulmonary resection in the patients with lung cancer and the changes last longer in pneumonectomy patients. Patients with postoperative cardiac arrhythmia have marked pulmonary hemodynamic changes before operation. Doppler pulmonary flow spectrum can not only be used to analyse the pulmonary hemodynamic changes for those cases undergoing pulmonary resection after operation, but also to evaluate the risk of pulmonary resection before operation. PMID- 21241560 TI - [Comparative study of sputum sediment paraffin section and sputum smear examinations for diagnosis of lung cancer]. AB - BACKGROUND: To explore a rapid and accurate method for examining cancer cell from the sputum in patients with lung cancer. METHODS: One hundred and twenty patients with lung cancer diagnosed by operation and pathologically confirmed were enrolled in this study. Sputum sediment section and sputum smear examinations were performed and compared for diagnosis of lung cancer. RESULTS: (1) The positive rate of lung cancer cell was 71.67% (86/120) by sputum sediment section examination, however, only 31.67% (38/120) by sputum smear examination ( P < 0.001). The diagnostic rate of combination of two methods for lung cancer was 90.83% (109/120), which was significantly higher than that of single sputum sediment section examination ( P < 0.001). (2) With routine HE staining, 55 patients (55/86,63.95%) could be histologically identified by sputum sediment section examination, but only 6 patients (6/38,15.79%) by sputum smear examination ( P < 0.001). (3) In 31 patients unidentified with routine HE staining, 29 were further histologically confirmed by sputum sediment section examination with immunohistochemistry. CONCLUSIONS: Compared to sputum smear examination, sputum sediment section examination can make use of more sputum materials, show a higher sensitivity for cancer cell, and accurately identify the histological classification of tumor. It is supposed to be a good examination for lung cancer and deserved to be extended in clinical application. PMID- 21241561 TI - [Long-term consecutive follow-up of high-dose chemotherapy supported by autologous peripheral blood stem cell transplantation (APBSCT) in the treatment of small cell lung cancer]. AB - BACKGROUND: To study the efficacy and long-term survival of high-dose chemotherapy supported by autologous peripheral blood stem cell transplantation (APBSCT) in the treatment of small cell lung cancer (SCLC).. METHODS: Seven patients with pathologically confirmed SCLC were enrolled into the study, including 6 patients who had achieved CR or PR after conventional chemotherapy, and 1 patient who underwent surgical treatment and 6 cycles of conventional postoperative chemotherapy. All patients received a high-dose chemotherapy regimen of cyclophosphamide 6 g/m2, etoposide 1.2 g/m2, carboplatin 1.2 g/m2 following APBSCT. Six of 7 patients received local radiotherapy after the procedure, however, another patient over 60 years did not receive local radiotherapy because of pneumonia complication. All patients were consecutively followed up and median follow-up duration was 27 (25-82) months. RESULTS: Survival of the 7 patients was longer than 2 years. Three patients were still alive for more than 5 years after treatment, and the longest one up to 82 months. Three patients died and their survival time was 26, 27 and 27 months respectively. CONCLUSIONS: High-dose chemotherapy supported by APBSCT combined with local radiotherapy may be helpful to prolong survival and improve prognosis for SCLC, especially to those patients with limited disease, relatively younger age and better performance status, and responding to conventional chemotherapy. PMID- 21241562 TI - [Clinical study on the metastatic patterns of lymph node in lung cancer]. AB - BACKGROUND: To investigate the relationship between the size of primary tumor, pathologic classification, cell differentiation or location of tumor and lymph node metastasis in lung cancer. METHODS: Three hundred and thirty-two patients with lung cancer underwent pulmonectomy plus extensive dissection of hilar and mediastinal nodes. The law of lymph node metastasis was analyzed. RESULTS: A total of 3 280 lymph nodes were removed. Metastatic rates of N1 and N2 were 29.9% and 22.4% respectively. The total lymph node metastatic rates of T1, T2, and T3 diseases were 8.5%, 27.4% and 61.2% respectively ( P < 0.005). No lymphatic metastasis was observed in well-differentiated squamous cell carcinoma, however, the lymph node metastatic rates in moderate- and poor-differentiated squamous cell carcinoma were 16.8% and 19.6% respectively. The lymph node metastatic rates were 27.5% and 71.6% in moderate- and poor-differentiated adenocarcinoma respectively ( P < 0.005). The total lymph node metastatic rates in central and peripheral squamous cell carcinoma were 19.6% and 11.7% respectively ( P < 0.005), while in adenocarcinoma, the rates were 57.9% and 24.0% respectively ( P < 0.005). The N2 metastatic rates in central and peripheral squamous cell carcinoma were 10.9% and 2.9% respectively ( P < 0.005), while in adenocarcinoma, the rates were 47.5% and 17.8% respectively ( P < 0.005 ). Under the same T status, cell differentiation or location of tumor, the metastatic rate of adenocarcinoma was much higher than that of squamous cell carcinoma ( P < 0.005 ). CONCLUSIONS: The frequency of lymph node metastasis significantly correlate with size of primary tumor, pathological classification, cell differentiation and location of tumor. PMID- 21241563 TI - [The lifelong contributions to workers' health and medical education - commemorating the 100th birth anniversary of professor Gu Xue-qi]. PMID- 21241564 TI - [Review of occupational hazard census and large-scale surveys in sixty years in China]. AB - OBJECTIVE: To compare and analyze the all previous censuses and large-scale surveys on occupational hazard in China, draw lessons from the past, and try to provide references for the development of census or surveys on the occupational hazard in the new period. METHODS: A literature retrieval had been performed mainly on the occupational hazard census and large-scale surveys since the founding of People's Republic of China. Only the survey items carried on a national scale were selected. Some keywords were drawn from these items such as survey time, survey scope, industries, occupational diseases and the rate of examination, organization and technical director, methods and so on. The outcomes and experiences were summarized. RESULTS: Since the founding of People's Republic of China, there were seven occupational hazard census and large-scale surveys carried in China, three of them were about silicosis or pneumoconiosis, two of them were about poison and carcinogens, one was about noise, another one was about the township industrial enterprises. CONCLUSION: Leadership attention was the fundamental guarantee of the success of the survey, sound occupational health management organizations were the base, collaborative relationship with each other was an import factor, and only the interdisciplinary team, scientific design, quality control and incentive mechanism could assure the quality of the survey. The survey should be designed and carried out according to industries. PMID- 21241565 TI - [Effects of ethylbenzene on oxidative damage, ultrastructure and expressions of apoptosis-related genes in rat brain tissues]. AB - OBJECTIVE: To investigate the influence of ethylbenzene on oxidative damage, ultrastructure and the expressions of apoptosis-related genes in the rat brain tissues. METHODS: Four groups of 10 males of Sprague-Dawley rats were allocated randomly, and inhaled daily with different doses of ethylbenzene: 0, 433.5 mg/m3, 4335.0 mg/m3, and 6500.0 mg/m3 6 h daily, 5 days per week for 13 weeks. The contents of glutathione (GSH) and malondialdehyde (MDA) and activity of acetylcholinesterase (AChE) were assayed, respectively. The ultrastructure of brain tissues was observed via electron microscope. The gene expression levels of Bax, Bcl-2, cytochrome C, caspase-9 and caspase-3 in brain tissues were measured by real-time polymerase chain reaction (PCR), respectively. RESULTS: The contents of MDA [(2.03 +/- 0.56), (4.17 +/- 1.31) nmol/mg pro] in the brain tissues of 4335.0 mg/m3 and 6500.0 mg/m3 ethylbenzene-treated groups were significantly higher than that [(1.08 +/- 0.26) nmol/mg pro] in the control group (P < 0.05), while AChE activities [(0.321 +/- 0.066), (0.276 +/- 0.031), (0.202 +/- 0.041) U/mg] and GSH contents [(35.19 +/- 15.08), (33.42 +/- 15.32), (27.99 +/- 7.53) mg/g pro] in all ethylbenzene-treated groups were remarkably depressed (P < 0.05, P < 0.05, respectively). After 6500.0 mg/m3 ethylbenzene inhalation, the nucleolus exhibit demilune with decreased mitochondria. Electrondense of myelin occurred in the injured nerve, ascribing to lipid peroxidationed membrane. The gene expression level of Bax in brain tissue of 4335.0 mg/m3 and 6500.0 mg/m3 ethylbenzene-treated group was significantly higher than that in the control group (P < 0.05). Compared with the control group, the gene expression levels of cytochrome C, caspase-9 and caspase-3 in all ethylbenzene-treated groups were enhanced (P < 0.05, P < 0.05, respectively), while bcl-2 gene expression levels in all ethylbenzene-treated groups were decreased (P < 0.05). CONCLUSION: Ethylbenzene can induce oxidative damage and apoptosis in brain tissues. The apoptotic mechanism might be involved with up-regulation of Bax, cytochrome C, caspase-9 and caspase-3, as well as restraint of Bcl-2. PMID- 21241566 TI - [Combined effects of typical natural estrogens with MCF-7 proliferation assay]. AB - OBJECTIVE: To study 17beta-estradiol (E2), ethinylestradiol (EE2), estriol (E3), estrone (E1) on MCF-7 proliferation effects, and compare the effects of independent action (IA) model with concentration addition (CA) model in assessing the combined effects of estrogen. METHODS: The combinations of E2 + EE2, E2 + E3 and E2 + E1 were chosen and the cellular proliferation effects were examined by MTT assay. RESULTS: The maximum proliferation effects at dose of 10-9 mol/L was 325.48% for E2, 330.34% for EE2, 255.22% for E3, and 199.61% for E1. In the E2 + EE2, E2 + E3, E2 + E1 groups, the results of IA model analysis were very close to the experimental results. The IA model tend to overestimated the experimental results, while the CA model often underestimated the experimental results. In the EC (E2, 30) + C (EE2, 70) group, the results exceed the maximum estrogen effects of E2, while in other groups, the results were lower. CONCLUSIONS: The estrogenic effects of the four tested substances from high to low efficiency were that: EE2 > E2 > E3 > E1. The effect of IA model in predicting the combined effects of binary mixture was better than CA model. A small proportion of binary mixture showed synergy. PMID- 21241567 TI - [Effect of p38MAPK on proliferation in human embryonic lung fibroblasts in vitro]. AB - OBJECTIVE: To study the proliferation effect of the AM supernatant incubated activation of p38 mitogen activated protein kinases (p38MAPK) signal transduction pathway in human embryonic lung fibroblasts, and to participate in the development of fibrosis in silicosis. METHODS: The silicotic alveolar macrophages were collected by bronchoalveolar lavage and incubated in vitro in the DMEM medium containing SiO2 (50 ug/ml) and DMEM medium without SiO2 for 18 h. Then the AM supernatant incubated for 18 h was collected. HELFs were isolated by organize paste block method, and incubated with AM supernatants. HELFs were divided into four groups: blank control groups, AM groups, SiO2 + AM groups, SB203580 + SiO2 + AM groups. The proliferation in the HELF was detected with MTT method and Flow cytometry. RESULTS: The proliferation in the HELF acted with the conditioned AM supernatant fluid were more than blank control groups, AM groups and SB203580 + SiO2 + AM groups [average optical density: (0.48 +/- 0.03) vs (0.29 +/- 0.01), (0.38 +/- 0.02), (0.33 +/- 0.03)], the values with MTT method were statistically different (P < 0.05); Proliferous index with flow cytometry in SiO2 + AM groups (18.12 +/- 0.82) was bigger than blank control groups (9.24 +/- 0.48), AM groups (14.76 +/- 0.43) and SB203580 + SiO2 + AM groups (11.71 +/- 0.70) and the values were statistically different(P < 0.05). CONCLUSIONS: The AM supernatant stimulated by silicon dioxide can accelerate the proliferation in the HELF by activation of p38MAPK signal transduction pathway. PMID- 21241568 TI - [Preliminary experimental research on glucocorticoid for treatment of nitrogen dioxide induced acute pulmonary edema in rats]. AB - OBJECTIVE: To investigate the therapeutic effect of glucocorticoids on the acute pulmonary edema in rats induced by nitrogen dioxide (NO2). METHODS: Thirty SD female rats were randomly equally divided into 5 groups: normal control group, NO2 exposed group, high-, middle- and low-dose of glucocorticoids treated group (6 rats per group). 6 rats in the normal control group were exposed to room air for 30 min, and the other rats to NO2. 18 rats in the glucocorticoids group were treated with different doses of dexamethasone (6.0, 3.0, 1.0 mg/kg), while the rats in the NO2 poisoning group were treated with normal saline (2.5 mg/kg). The lung wet/dry (W/D) weight ratio was calculated, and plasma atrial natriuretic peptide (ANP) levels, superoxide dismutase (SOD) activity from whole blood, plasma interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The lung W/D ratios were increased significantly in glucocorticoids treated group and NO2-exposed group compared with normal control group (P < 0.05), while they were significantly reduced in glucocorticoids treated group as compared with NO2-exposed group (P < 0.05). SOD activity in whole blood in glucocorticoids treated group and NO2-exposed group was significantly lower than that of normal control group (P < 0.05), while it was no significant difference between that of glucocorticoids treated group and NO2-exposed group (P > 0.05). Plasma ANP was significantly increased in NO2 exposed group compared with normal control group (P < 0.05), while it was significantly decreased in glucocorticoids treated group compared with NO2 exposed group (P > 0.05). Plasma TNF-alpha of high-, middle- and low-dose of glucocorticoids treated group [(27.04 +/- 8.19), (40.10 +/- 9.09), (39.76 +/- 9.60) pg/ml] was decreased significantly as compared with NO2-exposed group (68.55 +/- 27.84 pg/ml) (P < 0.05). Plasma IL-6 in high- and middle-dose of glucocorticoids treated group [(15.97 +/- 6.18), (19.69 +/- 5.52) pg/ml] was significantly decreased as compared to NO2-exposed group [(29.29 +/- 9.31) pg/ml] (P < 0.05). Plasma IL-10 in high-, middle- and low-dose of glucocorticoids treated group [(23.24 +/- 5.14), (27.78 +/- 8.17), (33.29 +/- 10.42) pg/ml] was significantly reduced compared with NO2-exposed group [(44.38 +/- 9.19) pg/ml] (P < 0.05). Plasma IFN-gamma in high- and middle-dose of glucocorticoids treated group [(7.21 +/- 4.55), (19.23 +/- 4.35) pg/ml] was reduced compared with NO2 exposed group [(30.83 +/- 6.82) pg/ml] (P < 0.05). CONCLUSION: High-, middle-, low-dose glucocorticoids all can improve the permeability of alveolar wall and capillary, and have nonspecific anti-inflammatory effects. The therapeutic effects on pulmonary edema are significant. High and middle dose of glucocorticoids treated group are more useful for decreased inflammatory factors. PMID- 21241569 TI - [Screening and identification of differential expression genes related to stress fracture by cDNA microarray assay]. AB - OBJECTIVE: To evaluate the differentially expressed genes between the Stress fracture (SF) cases and controls. METHODS: Total RNA was extracted and purified from peripheral blood sample of 3 SF cases and 3 controls who conducted a 1:1 matched case-control study, then used for Human Genome Array analysis. The hybridization data were analyzed using SAM software. Parts of these genes were analyzed and identified by real-time PCR. RESULTS: Upregulated and downregulated genes were 22 and 1, respectively. Thus the highest ratio and most significant cytokine was tumor necrosis factor receptor superfamily, member 10c (TNFRSF10C). The result of real-time PCR shows that TNFRSF10C was over-expressed in 3 cases and low-expressed in 1 case. CONCLUSION: Obvious difference exists in gene expression between SF cases and controls, showing there may be a lot of genes involving in the occurrence and development of SF. Meanwhile, the identification of the specific genes is helpful for biomechanics study, early diagnosis and screening of SF. PMID- 21241570 TI - [Investigation on occupational hazards of ultraviolet light, sunscreen awareness and behaviors in Wuhan city traffic police]. AB - OBJECTIVE: To understand the awareness of occupational hazards to ultraviolet (UV) and sunscreen awareness, protective measures in Wuhan City traffic police on duty outside. METHODS: The investigation included questionnaire survey in Wuhan City 367 traffic police on duty outside, talk with them face to face, fill in the questionnaires, and medical examine skin of exposed parts of body of them and 134 Wuhan City administration staffs. RESULTS: They understand UV harm to the human body and skin well (94.8% of them know that UV harm to skin), did not understand sun skin care and protective measures enough, and did not adopt enough sun skin care and protective measures (only 3.8% of them use sun skin care more than twice); but contrast to older persons, younger traffic police had better understanding of UV radiation damage on the human body and the skin, and sunscreen products and protective measures, paid more attention to sunscreen, and had less chance of sunburn (in the past 5 years, 18.3% of younger traffic police had sunburnt more than 3 times, but for older traffic police, the number is 30.3%). Traffic police had more skin problems than administration staffs in exposed parts of body (Traffic police face appears oily and large pores, facial pigmentation spots, face telangiectasia, deep wrinkles crude rates respectively were 73.7%, 40.4%, 36.5%, 10.4%, but for administration staffs, the numbers respectively were 26.1%, 15.7%, 15.7%, 1.5%). CONCLUSION: UV can induce skin problems in exposed parts of body. The traffic police should be enhanced the publicity and education on UV-related knowledge and occupational hazards, especially for older traffic police. PMID- 21241571 TI - [Analysis of outcomes of monitoring pneumoconiosis in Inner Mongolia Autonomous Region in last two years]. PMID- 21241572 TI - [Injury of dimethylacetamide on liver of exposed workers]. PMID- 21241573 TI - [Analysis of length of service with dust exposure in 56,546 patients with pneumoconiosis in Hunan province]. PMID- 21241574 TI - [Expression and significance of NF-kappaB p65 in ethanol induced acute liver cell damage in mice]. PMID- 21241575 TI - [Effect of silica on expression of interleukin-1beta of lung alveolus macrophages in patients with silicosis]. PMID- 21241576 TI - [Cases of benzene-related leukemia reported in periodicals in China and analysis of diagnosis]. PMID- 21241577 TI - [Change characteristics of blood lactic acid in patients with acute severe carbon monoxide poisoning and its effect on prognosis]. PMID- 21241578 TI - [Influence factors of coal worker's pneumoconiosis combined with chronic obstructive pulmonary disease]. PMID- 21241579 TI - [Lanthanum coated graphite tube - graphite furnace atomic absorption spectrometry for determination of trace barium in urine]. PMID- 21241580 TI - [Gas chromatography for determination of ethylene glycol in blood]. PMID- 21241582 TI - [High-performance liquid chromatography for determination of urea in air of work place]. PMID- 21241581 TI - [High-performance liquid chromatography for determination of paraquat in air of work place]. PMID- 21241583 TI - [Practice of promotion for basic occupational health service pilot project]. PMID- 21241584 TI - [Investigation on basic occupational health service practice in Rongxian county]. PMID- 21241585 TI - [Investigation on construction of basic occupational health service three-level network in Xinhui District of Guangdong province]. PMID- 21241586 TI - [Analysis for outcome of health promotion practice in an enterprise]. PMID- 21241587 TI - [Status quo and practice of occupational health monitoring in Suzhou Industrial Park]. PMID- 21241588 TI - [Noise hazards of steel structure coal washing plant and control]. PMID- 21241589 TI - [Bibliometrics analysis for research paper on occupational poisoning in China between 1999 and 2008]. PMID- 21241590 TI - [Four cases of acute hydrogen sulfide poisoning]. PMID- 21241591 TI - [Application of grey relational analysis in public health]. PMID- 21241592 TI - [Clinical progress in organ transplantation for treatment of physical and chemical diseases]. PMID- 21241593 TI - [Emergency treatment and nursing for acute trimethyltin chloride poisoning]. PMID- 21241594 TI - [Effect of carbon disulfide on expression of matrix metalloproteinase-2 and metalloproteinase-9 in embryo and uterus of pregnant mice]. AB - OBJECTIVE: To observe the effect of carbon disulfide (CS(2)) on the expression of matrix metalloproteinase (MMP)-2, MMP-9 in mouse embryo and uterus tissues and to explore the mechanism of embryo toxicity induced by CS(2). METHODS: At the phases of follicular development and embryonic implantation which was subdivided into early-implantation phase and late-implantation phase, mice were intraperitoneally exposed to CS(2) (the dosage was 631.4 mg/kg, and the volume was 0.1ml/10 g body weight) for 2 consecutive days. All indicators were got at the ninth day in gestation, and the expression of MMP-2 and MMP-9 in embryo and uterus tissues was analyzed by gelatin zymography. RESULTS: The number of implanted embryos significantly decreased after exposure at late-implantation phase (16.000 +/- 12.166) compared with those of the control (30.700 +/- 5.599, P < 0.05). Expression of MMP-2 and MMP-9 in embryos declined obviously at the three reproductive phases (P < 0.01), and the levels of MMP-2 and MMP-9 expression in embryos at the phases of late-implantation phase (0.6837 +/- 0.0929, 0.7309 +/- 0.0822) and follicular development (0.6222 +/- 0.0997, 0.7520 +/- 0.1068) were much lower than those of the control (1.0000 +/- 0.0710, 1.0000 +/- 0.0413, P < 0.01). Expression of MMP-2 and MMP-9 in uterus significantly increased at the phase of late-implantation (1.3153 +/- 0.3032, 5.0210 +/- 4.0307) compared with those of the control (1.0000 +/- 0.1771, 1.0000 +/- 0.0996, P < 0.01). CONCLUSION: Embryo toxicity of CS(2) is more obvious at the phase of late implantation. Exposure to CS(2) disturbs expression of MMP-2 and MMP-9 in embryo and uterus tissues, which might be one of the important factors contributed to embryo toxicity induced by CS(2). PMID- 21241595 TI - [Dynamic changes of hemorheology in rats after carbon monoxide poisoning]. AB - OBJECTIVE: To investigate the startup detail of circulation dysfunction and its role in the progress of delayed neuropsychologic sequelae (DNS) after carbon monoxide (CO) poisoning with comparison with the model of ischemia-reperfusion. METHODS: The ischemia-reperfusion rat model was established by Pulsinelli Brierley method, and the CO poisoning rats model by i.p. injected with CO repeatedly respectively, and the rats were identified with DNS following the experiment of pathology and the ethnology. RESULTS: The whole blood viscosity, plasma viscosity, hematocrit and fibrinogen increased significantly immediately after reperfusion, and recovered gradually with the ischemia-reperfusion rat model. The whole blood viscosity decreased significantly immediately after CO treated i.p. Especially at low shear rate, the hematocrit also declined remarkably in the early stage after CO treatment. But 1day later, these parameters turned to the trend of the ischemia-reperfusion rats. There was a prominent elevation of both indexes until the 14th day following CO injection i.p. CONCLUSION: There are significantly sustained hyper-coagulation and hyper viscosity with circulation in rats after CO poisoning compared with ischemia reperfusion model during the period of DNS, which might contribute to increase cerebral circulation resistance, blocked blood flow, and deteriorate hypoxemia in progression of DNS. PMID- 21241596 TI - [Effects of alpha-lipoic acid and vitamin C on oxidative stress in rat exposed to chronic arsenic toxicity]. AB - OBJECTIVE: To explore arsenic-induced oxidative stress and the protective efficacy of alpha-lipoic acid and vitamin c. METHODS: 50 male SD rats were randomly divided into 5 groups. Ten rats (the control group) were exposed to deionized water for 6 weeks, and the others were alone exposed to sodium arsenite (50 mg/L water) for 6 weeks, at the same time, three group rats were administered intragastrically (i.g.) with alpha-lipoic acid 10 mg*kg(-1)*d(-1) and vitamin C 25 mg*kg(-1)*d(-1) either alone or in combination. At the end of experiment, blood was drawn from abdominal aorta, and then the blood, brain and liver of rats were used for biochemical assays, including blood glutathione (GSH), delta aminolevulinic acid dehydratase (delta-ALAD ), reactive oxygen species (ROS) and oxidized glutathione (GSSG) level. At the same time, the super oxide dismutase (SOD) activity, glutathione peroxidase (GSH-Px) activity, catalase (CAT) activity, ATPase activity of brain and liver were determined. The caspase activity of brain were also determined. RESULTS: There were a significant increase in ROS level (P < 0.05), but a significant decrease in delta-ALAD activity (P < 0.01) in the chronic arsenic toxicity model group compared with the control group. These alterations were marginally restored by co-administration of vitamin C and alpha-lipoic acid individually, while significant recovery was observed in the animals supplemented with both the antioxidants together with arsenite in rat (P < 0.05). At the same time, there was a significant increase in the ROS and TBARS level of the brain and liver (P < 0.05), and caspase activity of the brain (P < 0.05), while there was a significant decrease in antioxidant enzymes and ATPase activity on arsenite exposure in rats (P < 0.05). These alterations were also marginally restored by co-administration of vitamin C and alpha-lipoic acid individually, while significant recovery was observed in the animals supplemented with both the antioxidants together with arsenite in rat (P < 0.05). CONCLUSIONS: Arsenite-induced oxidative stress can be significantly protected by co-administration of alpha-lipoic acid and vitamin C individually, but the best effects could be observed with combined administration of two antioxidants during arsenite exposure in animals. The dietary intervention of or supplementation with natural dietary nutrients is possible to prevent the effects of arsenic in populations of risk. PMID- 21241598 TI - [Oxidative stress of decabromodiphenylether in mice brain tissue]. AB - OBJECTIVE: To study the oxidative stress induced by decabromodiphenylether (PBDE 209) in the cerebral cortex, hippocampus, cerebellum and striatum of mice. METHODS: Twenty-eight male BALB/c mice were randomized divided into four groups with seven mice in each: solvent control, blank control, low (200 mg/kg) and high (500 mg/kg) dose groups. Test substances were administered by gavage and mice were sacrificed 6 weeks after treatment. Malonyldialdehyde (MDA), total superoxide dismutase (T-SOD) and glutathione (GSH) in cerebral cortex, hippocampus, cerebellum and striatum were examined. RESULTS: The content of MDA in cerebral cortex, cerebellum, striatum and hippocampus in high dose group was (92.25 +/- 36.64), (4.24 +/- 1.15), (12.92 +/- 4.30), (12.12 +/- 6.39) nmol/mg pro respectively, higher than that in blank group [(56.713 +/- 6.44), (2.42 +/- 1.41), (4.05 +/- 2.23), (4.91 +/- 1.60) nmol/mg pro] and the difference was statistically significant (P < 0.05); T-SOD activity in cerebral cortex, cerebellum and striatum in low dose group was (182.48 +/- 11.59), (6.67 +/- 1.56), (35.48 +/- 21.98) U/mg pro respectively, lower than that in blank group [(277.76 +/- 106.70), (18.02 +/- 16.40), (63.57 +/- 20.83) U/mg pro] and the difference was statistically significant (P < 0.05); in high dose group the T-SOD activity in hippocampus was(59.26 +/- 37.09) U/mg pro, lower than that in blank group [(93.28 +/- 21.75) U/mg pro] and the difference was statistically significant (P < 0.05); The content of GSH in cerebral cortex, cerebellum and striatum in high dose group was (40.98 +/- 13.19), (3.55 +/- 1.55), (24.46 +/- 11.30) mg/g pro respectively, lower than that in blank group [(75.79 +/- 26.51), (8.01 +/- 3.23), (44.52 +/- 13.15) mg/g pro and the difference was statistically significant (P < 0.05); while the content of GSH in hippocampus was not decreased significantly compared with the blank group (P > 0.05). CONCLUSION: PBDE-209 could induce oxidative stress in nervous tissue. The tissue oxidative damage might be one of the primary mechanisms of neurotoxicity of PBDE-209. PMID- 21241597 TI - [Expression of fragile histidine triad (FHIT) protein and Ki-67 in transformed epithelial cells induced by Yunnan tin mine dust]. AB - OBJECTIVE: To study the expression and significance of fragile histidine triad (FHIT) and Ki-67 in transformed epithelial cells induced by Yunnan tin mine dust. METHODS: Every second generation of immortalized human bronchial epithelial cells (BEAS-2B) and human embryo lung fibroblasts (WI-38) were exposed to 100 ug/ml Yunnan tin mine dust for 72 h, until the ninth generation. The cells were subsequently co-cultured from the 11th generation. Experimental setup: B group, B (W) group, B (W 100) group, B100 group, B100 (W) group, B100 (W100) group. The expressions of FHIT and Ki-67 in epithelial cells were determined by the method of immunocytochemistry at the 16th, 26th and 36th generation. The percentage of Ki-67 positive cells was calculated as proliferation index. RESULTS: The expression of FHIT was observed in BEAS-2B cells. The expression levels of FHIT among B group, B (W) group and B (W 100) group had not instinctive difference. At the 16th generation, the expression of FHIT in the B100 group was decreased compared with that in the B group and the expression of FHIT between B100 (W) group and B100 (W100) group was lower than that in the B100 group. At the 26th generation, the expression of FHIT was decreased compared with that at the 16th generation in the B100, B100 (W) and B100 (W100) groups. However, At the 36th generation, positive expression were observed again in the B100, B100 (W) and B100 (W100) groups and the expression levels were in incremental order. At the 16th, 26th and 36th generation, the proliferation indexes of B group, B (W) group and B (W 100) group were all < 3%. The proliferation indexes of B100, B100 (W) and B100 (W100) were increased step by step with the generation elongation. CONCLUSIONS: FHIT could be a target at which Yunnan tin mine dust induces transformation of BEAS-2B cells. The proliferation activation of BEAS-2B cells can be improved by Yunnan tin mine dust. PMID- 21241600 TI - [Effect of cadmium oxide in air of workplace on lens]. PMID- 21241599 TI - [Effects of occupational stress on serum tumor necrosis factor-alpha and interleukins]. AB - OBJECTIVE: To explore the effect of occupational stress on serum tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-2 and IL-4. METHODS: A cross sectional epidemiological study was conducted in 200 workers from the refrigerator assembly line in Henan province in China. Psychosocial work conditions were measured by using the job demand-control model, the effort-reward imbalance model questionnaires and occupational stress measurement scale. Serum TNF-alpha, IL-1beta, IL-2, and IL-4 concentrations were measured by radioimmunoassay or immunoradiometric assay method respectively. RESULTS: Serum TNF-alpha concentration was statistically significantly different between workers with higher affective balance level and control groups [(1.947 +/- 0.173) and (2.029 +/- 0.240) fmol/ml] (P < 0.05). Serum IL-1beta concentration was statistically significantly different between workers with higher effort level and control groups [(0.133 +/- 0.034) and (0.118 +/- 0.031) ng/ml] (P < 0.05). Serum IL-2 concentration was statistically significantly different between workers with higher role ambiguity level [(1.658 +/- 0.376) and (1.491 +/- 0.033) ng/ml] and control groups (P < 0.05), as well as between workers with higher role conflict level and control groups [(1.774 +/- 0.311) and (1.589 +/- 0.380) ng/ml] (P < 0.05), between workers with higher daily life stress level and control groups [(1.759 +/- 0.361) and (1.606 +/- 0.381) ng/ml] (P < 0.05). Serum IL-4 concentration was statistically significantly different between workers with higher reward level and control groups [(1.449 +/- 0.025) and (1.466 +/- 0.041) pg/ml] (P < 0.05). Stepwise regression analysis indicated that affective balance was the predictor of serum TNF-alpha (R(2) = 0.029). Effort and mental health were the predictors of serum IL-1beta (R(2) was 0.029 and 0.055, respectively). Role conflict, daily life stress and role ambiguity were the predictors of serum IL-2 (R(2) was 0.040, 0.078 and 0.104, respectively). Reward was the predictor of serum IL-4 (R(2) = 0.030). CONCLUSION: Unhealthy psychological stress factor might be induce a marked increase in the concentrations of serum TNF-alpha, IL 1beta, IL-2, as well as IL-4. PMID- 21241601 TI - [Effect of microwave irradiation on expression of heat shock proteins family in primary cultured rat hippocampal neurons]. AB - OBJECTIVE: To investigate the effects of microwave irradiation on the expression and regulation of heat shock proteins (HSPs) in primary cultured rat hippocampal neurons. METHODS: Neurons were exposed to 90 mW/cm(2) microwave irradiation for 10 minutes. Western blot was used to determine the expression of HSP27, HSP70, HSP90 and heat shock factor 1 (HSF1) at 0, 3, 6, 12 and 24 hour respectively. Real-time RT-PCR was used to determine the mRNA expression of HSF1. DNA-binding activity of HSF1 was measured by electrophoretic mobility shift assay (EMSA). RESULTS: The protein expression of HSP27 was significantly increased by 22%, 36%, 18% at 3, 6, 12 h, respectively (P < 0.05). The protein expression of HSP70 was significantly increased by 23%, 32%, 26% at 3, 6, 12 h, respectively (P < 0.05, P < 0.01). The protein expression of HSP90 was significantly increased by 27%, 33% at 6, 12 h, respectively (P < 0.05, P < 0.01). The DNA-binding activity of HSF1 was stimulated, however, no significant change of the expression of HSF1 was observed on both the mRNA and protein levels. CONCLUSION: The transcriptional activity of HSF1 is activated by microwave irradiation, which promotes the expression of HSPs. Heat shock response which contributes to establish a cytoprotective state is induced by microwave irradiation in primary cultured rat hippocampal neurons. PMID- 21241602 TI - [Genotoxicity of organic bentonite particles in vitro]. AB - OBJECTIVE: To study the genotoxicity induced by organic bentonite particles in vitro. METHODS: Human B lymphoblast cells (HMy2.CIR) were exposed to organic bentonite particles at the doses of 0, 1.88, 3.75, 7.50 and 15.00 ug/ml for 24, 48 and 72 h, calcium sulfate (30 ug/ml) and SiO2 (30 and 240 ug/ml) served as negative and positive controls, respectively. The genotoxicity of organic bentonite particles and soluble fraction was detected using comet assay and Cytokinesis-block micronucleus (CBMN) assay. RESULTS: The results of comet assay indicated that % tail DNA increased with the exposure doses and time in organic bentonite group, % tail DNA at the dose of 15.00 ug/ml for 24 h, 48 h and 72 h in organic bentonite group were 3.20 +/- 0.19, 4.63 +/- 0.88 and 9.49 +/- 1.31 respectively which were significantly higher than those in calcium sulfate group (1.40 +/- 0.11, 1.37 +/- 0.22 and 0.90 +/- 0.16) and those in 30 ug/ml SiO2 group (1.83 +/- 0.21, 1.41 +/- 0.27 and 2.48 +/- 0.25) (P < 0.01). The results of CBMN assay showed that micronucleus frequencies (MNF) in organic bentonite group (except for 1.88 ug/ml for 24 h) were significantly higher than those in 30 ug/ml calcium sulfate group (MNF for 24, 48 and 72 h were 1.330/00 +/- 0.580/00, 1.330/00 +/- 1.150/00 and 1.330/00 +/- 0.580/00) and those in 30 ug/ml SiO2 group (2.000/00 +/- 0.000/00, 1.680/00 +/- 0.580/00 and 2.330/00 +/- 0.580/00) (P < 0.01). The results of two assays demonstrated that the soluble fraction of organic bentonite did not induce the genotoxicity. CONCLUSION: The organic bentonite dusts can induce the genotoxicity in vitro, which may be from the particle fraction. PMID- 21241603 TI - [30 cases of electric ophthalmia induced by dysprosium lamp]. PMID- 21241604 TI - [Biomechanics analysis on lumbar force during manual handing tasks of push table saw's work place in wood processing industries]. PMID- 21241605 TI - [Investigation of personal protective equipment against occupational diseases used by welders in Qingdao municipality]. PMID- 21241606 TI - [Epidemiological investigation and analysis on acute poisoning in Huaian from 2007 to 2008]. PMID- 21241607 TI - [Analysis of results of brainstem auditory evoked potentials of patients with occupational noise deafness]. PMID- 21241608 TI - [Biomarkers of workers exposed to manganese]. PMID- 21241609 TI - [Clinical research on correlation between occupational acute arsine poisoning and thrombotic thrombocytopenic purpura]. PMID- 21241610 TI - [Analysis of acute occupational accidents in a province between 2005 and 2009]. PMID- 21241611 TI - [Clinical report on 58 cases of acute nickel carbonyl poisoning]. PMID- 21241612 TI - [Progress in research on effect of extremely low frequency magnetic fields on microfilaments]. PMID- 21241613 TI - [Progress in research on evaluation method of lifting equation of National Institute for Occupational Safety and Health of USA]. PMID- 21241614 TI - [Progress in research on paraquat determination method]. PMID- 21241615 TI - [Sleep deprivation model and its effect on body]. PMID- 21241616 TI - [A case of IgA nephropathy union protein in workers after getting rid of exposure to cadmium]. PMID- 21241617 TI - [One case of self-reinfusion of surfactant in whole lung lavage]. PMID- 21241618 TI - [Interpretation on diagnostic criteria of occupational high altitude disease 2008 edition]. PMID- 21241619 TI - [Practice and investigation of reformation of occupational hygiene technology service and organizations]. PMID- 21241620 TI - [Problems of primary occupational hygiene monitoring in Guangming New District, Shenzhen and strategy]. PMID- 21241621 TI - [Changes of high temperature working condition in 50 enterprises in Suzhou Industrial Park in three years]. PMID- 21241622 TI - [Announcement of conflict of interest in Ugeskrift for Laeger and Danish Medical Bulletin]. PMID- 21241623 TI - [Long live the life--also with dialysis?]. PMID- 21241624 TI - [Safe delivery of term breech presentation]. AB - It is well-documented from descriptive studies and a large randomized and controlled trial that planned vaginal delivery of term breech infants is associated with a risk of perinatal mortality and morbidity. However, in a modern setting with careful case selection and labour management, complication rates are low. When informed of the risks, the majority of women will choose Caesarean delivery. This paper provides the basis for informing women with term breech so that they may make an informed choice. Recommendations on selection criteria, intrapartum management parameters, and delivery techniques for a trial of vaginal breech birth are proposed. PMID- 21241625 TI - [Toxocariasis]. AB - The clinical presentation of toxocariasis, a zoonotic parasitosis transmitted from dogs and cats to humans, can be very diverse, which is one of the reasons why Toxocara-related disease may go unnoticed. This paper gives a brief summary of the various clinical presentations (covert/common toxocariasis, visceral larva migrans, ocular toxocariasis and neurotoxocariasis), diagnostic and differential diagnostic considerations as well as treatment and prevention. In brief, the diagnosis of human toxocariasis relies mainly on patient data, anamnestic information, symptoms, eosinophil count and total-IgE levels. PMID- 21241626 TI - [Another genetic cause of sudden cardiac death]. AB - Mutations in the Lamin A/C gene (LMNA) are a new part of the spectrum of genes responsible for sudden cardiac death (SCD). Relatives of SCD-cases should receive counselling, clinical assessment and perhaps molecular screening. The consequence of being an LMNA mutation carrier is discussed with regard to counselling and prophylactic measures. Device therapy may be relevant in LMNA-mutation carriers, although the proper time for implantation is uncertain. However, we recommend LMNA genetic screening in SCD cases with dilated cardiomyopathy as well as cases with unexplained SCD. PMID- 21241627 TI - [Chromosomal changes in congenital heart disease]. AB - Congenital heart disease (CHD) affects 1% of the population. The aetiology of CHD is complex and largely unknown, comprising both environmental and genetic components. Recent progress in molecular cytogenetics has led to the identification of rare genomic copy number variants (CNVs) in a significant proportion of CHD patients. These novel results imply new diagnostic possibilities and may aid in the identification of novel disease genes. PMID- 21241628 TI - [Hip arthroscopy]. AB - This review article describes the role of hip arthroscopy and the development of the technique over the past decade. The refinement of this technique has led to the discovery of ''new'' diseases of the hip joint. Recently, femoro-acetabular impingement (FAI) has been proposed as a source of soft tissue dysfunction, motion loss, and early osteoarthritis in the hip. Recognition of FAI is important, as failure to address this underlying pathology may lead to early onset osteoarthritis and subsequent hip replacement. The preliminary results after hip arthroscopy are described. PMID- 21241629 TI - [Promising web-based introductory course in research training]. AB - The Faculty of Health Sciences, University of Southern Denmark has developed a course in research training for residents, where traditional face-to-face teaching is mixed with computer-supported collaborative learning. The course focuses on the ability to ask research questions, retrieve information and appraise scientific papers. Initially, many course participants are reluctant to the course concept. Yet a majority of participants are very active online and give the course good evaluations. The course concept seems well-suited to "scaffold" participants' acquisition of research methodology competences. PMID- 21241630 TI - [Vena cava inferior agenesia as a retroperitoneal mass]. AB - This case-report presents a young man with a random finding of a retroperitoneal mass due to a vena cava inferior agenesia with an ectatic cavity. This probably caused a severe pulmonary embolism six years before in this previously healthy man. No other hereditary factors were found at the screening for thrombophilia. We describe the potential differential diagnostic difficulties of such cases. PMID- 21241631 TI - [Toxic hepatitis triggered by green tea]. AB - Green tea is associated with various beneficial health effects, but several cases of hepatotoxic side effects have been reported. We present the first Danish case of toxic hepatitis following the consumption of 4-6 cups of green tea per day for six months. Green tea's main chemical component is epigallocatechin gallate (EGCG). Animal studies have shown that EGCG accumulated in the liver is most toxic when consumed fasting and that it causes greater hepatotoxicity upon repeated administration. Green tea hepatotoxicity should be kept in mind and cases are notifiable to the food authorities. PMID- 21241632 TI - [Picture of the month: sialolithiasis]. PMID- 21241633 TI - Stable environmentally sensitive cationic hydrogels for controlled delivery applications. AB - New thermosensitive, cationic hydrogels were synthesized by the dispersion copolymerization of N-isopropylacrylamide (NIPAM) and (3 acrylamidopropyl)trimethylammonium chloride (AAPTAC). In the polymerization protocol, an amide-based comonomer, (3-acrylamidopropyl)trimethylammonium chloride, was reacted as a new alternative monomer for introducing positive charges into the thermosensitive hydrogel. The hydrogels were synthesized without making any pH adjustment in the aqueous medium. These hydrogel particles exhibited colloidal stability in the pH range of 1.5 to 11.0, while similar cationic hydrogels were reported to be unstable at pHs higher than 6. The stronger cationic character of the selected comonomer provided higher colloidal stability to the poly(NIPAM-co-AAPTAC) hydrogels. Furthermore, these hydrogels displayed sensitivity towards temperature, pH, and salt concentration. Interestingly, the particle size of hydrogels was found to be decreased significantly with an increase in temperature and salt concentration. In addition, using pyrene fluorescence spectroscopy, it was established that the hydrophobicity/hydrophilicity of the hydrogel particles was largely controlled by both pH and temperature. The thermosensitive hydrogels reported in this paper may be suitable for delivering different actives for cosmetic and medical applications. Although direct application of these hydrogel particles in cosmetics has not been shown at this stage, the methodology of making them and controlling their absorption and release properties as a function of temperature and pH has been demonstrated. Furthermore, these hydrogels may also have applications in scavenging organic and inorganic toxics. PMID- 21241634 TI - A statistical analysis of hair breakage. II. Repeated grooming experiments. AB - The objective of this work was to introduce the idea of analyzing data from repeated brushing and combing experiments on hair in accordance with standard fatigue testing approaches. In mechanical testing terms, the brushing and combing of hair represents a fatiguing process wherein individual strands experience repeated exposure to an external stimulus. Therefore, in accordance with fatiguing principles, one expects a gradual propagation of flaws within individual fibers until, ultimately, catastrophic failure (breakage) results. A previous paper in this series described the modeling of single-fiber fatigue data using the Weibull approach, and, in so doing, introduced the idea of treating fiber breakage as a statistical variable. Here, a grouped Weibull methodology was used to analyze breakage data from repeated brushing and combing experiments. At a top level, the generation of the two Weibull parameters provides a means of characterizing these experiments. However, the real strength of the approach involves the ability to generate survival probability plots that provide predictions as to the likelihood of fiber breakage under different conditions. Therefore, assuming laboratory experiments are a reasonable representation of real-life conditions, it becomes possible to predict breakage rates on actual heads as a function of different habits and practices. It is also shown how the two Weibull parameters, together with information about the number of fibers in the test tresses, allow for the modeling of repeated brushing and combing tests and allow anyone to re-create the experimental outcome for comparison to their own experiences. These principles have been demonstrated using experiments that compare breakage in virgin and chemically damaged hair, while also showing how conditioning treatments provide considerable retardation. PMID- 21241635 TI - A survey of phthalate esters in consumer cosmetic products. AB - Certain phthalate esters have been shown to cause reproductive toxicity in animal models. For this reason, the FDA has been monitoring the use of phthalate esters in cosmetics. In this study, the U.S. Food and Drug Administration (FDA) conducted a limited survey of 84 adult-use and baby-care cosmetic products for the presence of five phthalate esters: dimethyl phthalate (DMP), diethyl phthalate (DEP), benzylbutyl phthalate (BBP), dibutyl phthalate (DBP), and diethylhexyl phthalate (DEHP) (Figure 1). The analytes were extracted from a cosmetic product/Celite mixture with hexane, and the extract was then analyzed using reversed-phase high-performance chromatography (HPLC) on an instrument equipped with an ultraviolet radiation (UV) detector set at 230 nm. The analytes were separated on a Partisil octadecylsilane (ODS)-3 column (250 mm * 4.6 mm I.D., 5MUm). The mobile phase consisted of a mixture of 50% water, 34% acetonitrile, 13% 2-propanol, and 3% methanol that was changed linearly (35 minutes) to 15% water, 55% acetonitrile, 25% 2-propanol, and 5% methanol and held for an additional ten minutes. Spiked recoveries in antiperspirant and nail color ranged from 88% to 104%. Thirty-one of the 60 adult-use cosmetic products were found to contain at least one phthalate ester. Twenty products contained DEP and 11 nail products contained DBP. Concentrations of DBP ranged from 123 MUg/g to 62,607 MUg/g. Concentrations of DEP ranged from 80 MUg/g to 36,006 MUg/g. Five of the 24 baby-care products contained DEP at concentrations ranging from 10 MUg/g to 274 MUg/g. PMID- 21241636 TI - The thickness of 18-MEA on an ultra-high-sulfur protein surface by molecular modeling. AB - The use of computational chemistry techniques via molecular modeling software provides additional support to the hair surface model by Negri et al. (1) and refines the thickness of the 18-methyl eicosanoic acid (18-MEA) lipid layer attached by thioester linkages to an ultra-high-sulfur protein (UHSP) at 1.08 +/- 0.2 nm. This value compares favorably to the thickness of that same layer from X ray photoelectron spectroscopy (XPS) measurements by Ward et al. (2) at 1.00 +/- 0.5 nm on Soxhlet-extracted wool. The model clarifies that the results of Ward et al. via XPS are not an artifact of high vacuum (3), but due to relaxation of the 18-MEA structure onto the wool protein backbone as suggested by Zahn et al. (4). In this molecular model, 18-MEA is attached to beta sheets of an UHSP via thioester linkages as suggested by Negri et al. in their 1993 study (15) and by earlier work by Evans et al. (5). The beta sheets of this model provide an intersheet spacing of 0.7 nm and a beta sheet density of 1.42 g/cm(3) compared with Allworden membrane fractions that varied from 1.39 to 1.54 g/cm(3) (6). PMID- 21241642 TI - The ear-brain system: approaches to the study and treatment of hearing loss. PMID- 21241644 TI - Assessing binaural hearing: results using the speech, spatial and qualities of hearing scale. AB - BACKGROUND: Binaural hearing is important for hearing target signals against competing ones, and for spatial hearing. PURPOSE: Survey of results using the Speech, Spatial and Qualities of Hearing scale (SSQ), a measure emphasizing contexts that rely on binaural hearing ability. Results show that self-rating can identify binaural hearing influences and benefits. RESEARCH DESIGNS: Retrospective design compared fitting with one versus two hearing aids. Prospective design compared one versus two cochlear implants. Brief descriptions are made of studies using other comparative designs. STUDY SAMPLES: There were 69 new adult-age clients of an audiology clinic with unilateral hearing aid fittings, 34 with bilateral (and n = 63 in a pre-aided sample); there were 14 people with one cochlear implant (CI), 18 with two; in both CI groups, age ranged from 20 to 90 yr. DATA COLLECTION AND ANALYSIS: The data are scores on the 49 items comprising the SSQ, grouped into 10 "pragmatic" subscales, analyzed using t tests and ANOVA. RESULTS: Two aids offer advantage for challenging conditions (e.g., multistream signal monitoring), for dynamic spatial hearing, and in reducing listening effort. These outcomes are observable, though less distinctly, in one versus two implants. Overall advantage of two implants is very clear in a 20-59-yr-old cohort of patients. Recent application and development of the SSQ indicates sensitivity to subtle differences in abilities. CONCLUSIONS: Self report data are valuable in revealing the everyday listening domains in which improvement in binaural hearing function provides beneficial outcomes. PMID- 21241646 TI - Auditory training and challenges associated with participation and compliance. AB - BACKGROUND: When individuals have hearing loss, physiological changes in their brain interact with relearning of sound patterns. Some individuals utilize compensatory strategies that may result in successful hearing aid use. Others, however, are not so fortunate. Modern hearing aids can provide audibility but may not rectify spectral and temporal resolution, susceptibility to noise interference, or degradation of cognitive skills, such as declining auditory memory and slower speed of processing associated with aging. Frequently, these deficits are not identified during a typical "hearing aid evaluation." Aural rehabilitation has long been advocated to enhance communication but has not been considered time or cost-effective. Home-based, interactive adaptive computer therapy programs are available that are designed to engage the adult hearing impaired listener in the hearing aid fitting process, provide listening strategies, build confidence, and address cognitive changes. Despite the availability of these programs, many patients and professionals are reluctant to engage in and complete therapy. PURPOSE: The purposes of this article are to discuss the need for identifying auditory and nonauditory factors that may adversely affect the overall audiological rehabilitation process, to discuss important features that should be incorporated into training, and to examine reasons for the lack of compliance with therapeutic options. Possible solutions to maximizing compliance are explored. CONCLUSIONS: Only a small portion of audiologists (fewer than 10%) offer auditory training to patients with hearing impairment, even though auditory training appears to lower the rate of hearing aid returns for credit. Patients to whom auditory training programs are recommended often do not complete the training, however. Compliance for a cohort of home-based auditory therapy trainees was less than 30%. Activities to increase patient compliance to auditory training protocols are proposed. PMID- 21241645 TI - Sensory-cognitive interaction in the neural encoding of speech in noise: a review. AB - BACKGROUND: Speech-in-noise (SIN) perception is one of the most complex tasks faced by listeners on a daily basis. Although listening in noise presents challenges for all listeners, background noise inordinately affects speech perception in older adults and in children with learning disabilities. Hearing thresholds are an important factor in SIN perception, but they are not the only factor. For successful comprehension, the listener must perceive and attend to relevant speech features, such as the pitch, timing, and timbre of the target speaker's voice. Here, we review recent studies linking SIN and brainstem processing of speech sounds. PURPOSE: To review recent work that has examined the ability of the auditory brainstem response to complex sounds (cABR), which reflects the nervous system's transcription of pitch, timing, and timbre, to be used as an objective neural index for hearing-in-noise abilities. STUDY SAMPLE: We examined speech-evoked brainstem responses in a variety of populations, including children who are typically developing, children with language-based learning impairment, young adults, older adults, and auditory experts (i.e., musicians). DATA COLLECTION AND ANALYSIS: In a number of studies, we recorded brainstem responses in quiet and babble noise conditions to the speech syllable /da/ in all age groups, as well as in a variable condition in children in which /da/ was presented in the context of seven other speech sounds. We also measured speech-in-noise perception using the Hearing-in-Noise Test (HINT) and the Quick Speech-in-Noise Test (QuickSIN). RESULTS: Children and adults with poor SIN perception have deficits in the subcortical spectrotemporal representation of speech, including low-frequency spectral magnitudes and the timing of transient response peaks. Furthermore, auditory expertise, as engendered by musical training, provides both behavioral and neural advantages for processing speech in noise. CONCLUSIONS: These results have implications for future assessment and management strategies for young and old populations whose primary complaint is difficulty hearing in background noise. The cABR provides a clinically applicable metric for objective assessment of individuals with SIN deficits, for determination of the biologic nature of disorders affecting SIN perception, for evaluation of appropriate hearing aid algorithms, and for monitoring the efficacy of auditory remediation and training. PMID- 21241647 TI - Is there a hearing aid for the thinking person? AB - BACKGROUND: The history of auditory prosthesis has generally concentrated on bottom-up processing, that is, on audibility. However, a growing interest in top down processing has focused on correlations between success with a hearing aid and such higher order processing as the patient's intelligence, problem solving and language skills, and the perceived effort of day-to-day listening. PURPOSE: Examination of two cases of cognitive effects in hearing that illustrate less often-studied issues: (1) Individual subjects in a study use different listening strategies, a fact that, if not known to the experimenter, can lead to errors in interpretation; (2) A measure of shared attention can point to otherwise unknown functional effects of an algorithm used in hearing aids. RESEARCH DESIGN: In the two examples described above: (1) Patients with cochlear implants served in a study of the binaural precedence effect, that is, echo suppression. (2) Individuals identifying speech-in-noise benefit from noise reduction (NR) when the criterion was improved performance in simultaneous tests of verbal memory or visual reaction times. CONCLUSIONS: Studies of hearing impairment, either in the laboratory or in a fitting session, should include study of the complex stimuli that make up the natural environment, conditions where the thinking auditory brain adopts strategies for dealing with large amounts of input data. In addition to well-known factors that must be included in communication, such things as familiarity, syntax, and semantics, the work here shows that strategic listening can affect even how we deal with seemingly simpler requirements, localizing sounds in a reverberant auditory scene and listening for speech in noise when busy with other cognitive tasks. PMID- 21241648 TI - Adapting to changed hearing: the potential role of formal training. AB - Changed hearing occurs when sensorineural loss is acquired or increases, when hearing aids or cochlear implants are first acquired, when hearing aids are reprogrammed, and when cochlear implants are remapped. The changes affect speech perception-a process in which decisions about a talker's language output are made on the basis of sensory and contextual evidence, using knowledge and skill. The importance of spoken communication dictates speedy and optimal adaptation to changed hearing. Adaptation is a process in which the individual acquires new knowledge and modifies skill. Formal training provides the listener with the opportunity to enhance both knowledge and skill by spending time on speech perception tasks without the demands, constraints, uncertainties, and risks associated with everyday communication. Benefits of such training have been demonstrated in terms of improvement on trained tasks and talkers, generalization to untrained tasks and talkers, improvements in self-perceived competence, and reduction of self-perceived handicap. So far, however, we lack information on which aspects of training are responsible for benefit, which aspects of perception are changed, how individual differences interact with the foregoing, and whether these benefits translate into significantly increased participation and quality of life. PMID- 21241650 TI - Medicare safety issues. PMID- 21241651 TI - An enzymatic fluorescent assay for the quantification of phosphite in a microtiter plate format. AB - A sensitive fluorometric assay for the quantification of phosphite has been developed. The assay uses the enzymatic oxidation of phosphite to phosphate by a recombinant phosphite dehydrogenase with NAD(+) as cosubstrate to produce the highly fluorescent reaction product resorufin. The optimized assay can be carried out in a 96-well microtiter plate format for high-throughput screening purposes and has a detection limit of 0.25 nmol phosphite. We used the method to quantify phosphite levels in plant tissue extracts and to determine phosphite dehydrogenase activity in transgenic plants. The assay is suitable for other biological or environmental samples. Because phosphite is a widely used fungicide to protect plants from pathogenic oomycetes, the assay provides a cost-effective and easy-to-use method to monitor the fate of phosphite following application. PMID- 21241652 TI - Electrophoretic transfer protein zymography. AB - Zymography detects and characterizes proteolytic enzymes by electrophoresis of protease-containing samples into a nonreducing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gel containing a copolymerized protein substrate. The usefulness of zymography for molecular weight determination and proteomic analysis is hampered by the fact that some proteases exhibit slower migration through a gel that contains substrate protein. This article introduces electrophoretic transfer protein zymography as one solution to this problem. In this technique, samples containing proteolytic enzymes are first resolved in nonreducing SDS-PAGE on a gel without protein substrate. The proteins in the resolving gel are then electrophoretically transferred to a receiving gel previously prepared with a copolymerized protein substrate. The receiving gel is then developed as a zymogram to visualize clear or lightly stained bands in a dark background. Band intensities are linearly related to the amount of protease, extending the usefulness of the technique so long as conditions for transfer and development of the zymogram are kept constant. Conditions of transfer, such as the pore sizes of resolving and receiving gels and the transfer time relative to the molecular weight of the protease, are explored. PMID- 21241653 TI - Preventing arginine-to-proline conversion in a cell-line-independent manner during cell cultivation under stable isotope labeling by amino acids in cell culture (SILAC) conditions. AB - Quantitative proteomics has increasingly gained impact in life science research as a tool to describe changes in protein expression between different cellular states. Stable isotope labeling by amino acids in cell culture (SILAC) is a powerful technique for relative quantification of proteins. However, the accuracy of quantification is impaired by the metabolic conversion of arginine to proline resulting in additional heavy labeled proline peptide satellites. Here we reinvestigated the addition of unlabeled proline during cell cultivation under SILAC conditions considering several thousand peptides and demonstrated that the arginine-to-proline conversion is prevented independent of the cell line used. PMID- 21241654 TI - Explicit analytic approximations for time-dependent solutions of the generalized integrated Michaelis-Menten equation. AB - Various explicit reformulations of time-dependent solutions for the classical two step irreversible Michaelis-Menten enzyme reaction model have been described recently. In the current study, I present further improvements in terms of a generalized integrated form of the Michaelis-Menten equation for computation of substrate or product concentrations as functions of time for more real-world, enzyme-catalyzed reactions affected by the product. The explicit equations presented here can be considered as a simpler and useful alternative to the exact solution for the generalized integrated Michaelis-Menten equation when fitted to time course data using standard curve-fitting software. PMID- 21241655 TI - Temperature-dependent selective purification of plasmid DNA using magnetic nanoparticles in an RNase-free process. AB - Carboxyl group-functionalized magnetic nanoparticles were used to develop an RNase-free method for plasmid DNA (pDNA) purification directly from RNA containing crude Escherichia coli lysates. This method takes advantage of differing adsorption behaviors of pDNA and RNA onto magnetic nanoparticle surfaces at different temperatures. Pure pDNA can be isolated between 70 and 80 degrees C without sacrificing DNA quality and quantity, as evidenced by comparison with that obtained using organic solvents or commercial kits. This RNase-free method is rapid, simple, cost-effective, and environmentally friendly, and it can be easily scaled up for the production of pharmacological-grade pDNA. PMID- 21241656 TI - Characterization of a non-ribosomal peptide synthetase-associated diiron arylamine N-oxygenase from Pseudomonas syringae pv. phaseolicola. AB - The regiospecific oxidation of aromatic amines to aryl nitro compounds is critical to the synthesis of several natural products having pharmacological importance. The arylamine N-oxygenase (AAO) from Streptomyces thioluteus (AurF) selectively oxidizes p-aminobenzoic acid to p-nitrobenzoic acid and has been the subject of investigation for its unique chemistry and substrate preferences. Little, however, is known about the biochemistry and substrate specificities of AurF homologues, which are often associated with non-ribosomal peptide synthetases or polyketide synthases and have substrate binding pockets with substantially different amino acid compositions based on sequence alignments. An AAO homolog from Pseudomonas syringae pv. phaseolicola was expressed and purified to further explore the substrate specificity and biosynthetic utility of this enzyme class. PsAAO was most active on substituted o-aminophenols at pH 9 in buffer solutions containing 40% methanol. o-Aminophenols allow both the Pseudomonas and Streptomyces AAOs to act on para-substituted arylamines having methoxy, methyl, and nitro groups, which was previously unseen. A Hammett plot of k(cat,app) vs. sigma has a rho = -1.5, indicating substrate reactivity is dependent on the electron donating effects of substituents. The mechanistic data are consistent with an amine lone pair attacking an activated oxygen atom after formation of the hydroperoxy Fe(III/III) intermediate. PMID- 21241657 TI - Contributions of cation-pi interactions to the collagen triple helix stability. AB - Cation-pi interactions are found to be an important noncovalent force in proteins. Collagen is a right-handed triple helix composed of three left-handed PPII helices, in which (X-Y-Gly) repeats dominate in the sequence. Molecular modeling indicates that cation-pi interactions could be formed between the X and Y positions in adjacent collagen strands. Here, we used a host-guest peptide system: (Pro-Hyp-Gly)(3)-(Pro-Y-Gly-X-Hyp-Gly)-(Pro-Hyp-Gly)(3), where X is an aromatic residue and Y is a cationic residue, to study the cation-pi interaction in the collagen triple helix. Circular dichroism (CD) measurements and Tm data analysis show that the cation-pi interactions involving Arg have a larger contribution to the conformational stability than do those involving Lys, and Trp forms a weaker cation-pi interaction with cationic residues than expected as a result of steric effects. The results also show that the formation of cation-pi interactions between Arg and Phe depends on their relative positions in the strand. Moreover, the fluorinated and methylated Phe substitutions show that an electron-withdrawing or electron-donating substituent on the aromatic ring can modulate its pi-electron density and the cation-pi interaction in collagen. Our data demonstrate that the cation-pi interaction could play an important role in stabilizing the collagen triple helix. PMID- 21241658 TI - A new cytochrome P450 belonging to the 107L subfamily is responsible for the efficient hydroxylation of the drug terfenadine by Streptomyces platensis. AB - Fexofenadine, an antihistamine drug used in allergic rhinitis treatment, can be produced by oxidative biotransformation of terfenadine by Streptomyces platensis, which involves three consecutive oxidation reactions. We report here the purification and identification of the enzyme responsible for the first step, a cytochrome P450 (P450)-dependent monooxygenase. The corresponding P450, designated P450(terf), was found to catalyze the hydroxylation of the t-butyl group of terfenadine and exhibited UV-Vis characteristics of a P450. Its interaction with terfenadine led to a shift of its Soret peak from 418 to 390 nm, as expected for the formation of a P450-substrate complex. In combination with spinach ferredoxin:NADP(+) oxidoreductase and ferredoxin, and in the presence of NADPH, it catalyzed the hydroxylation of terfenadine and some of its analogues, such as terfenadone and ebastine, with k(m) values at the MUM level, and k(cat) values around 30min(-1). Sequencing of the p450(terf) gene led to a 1206 bp sequence, encoding for a 402 aminoacid polypeptide exhibiting 56-65% identity with the P450s from the 107L family. These results confirmed that P450s from Streptomyces species are interesting tools for the biotechnological production of secondary metabolites, such as antibiotics or antitumor compounds, and in the oxidative biotransformation of xenobiotics, such as drugs. PMID- 21241659 TI - Biased cellular locations of tandem repeat antigens in African trypanosomes. AB - Trypanosoma brucei subspecies cause African trypanosomiasis in humans and animals. These parasites possess genes encoding proteins with large tandem repeat (TR) domains as do the other trypanosomatid parasites. We have previously demonstrated that TR protein of Leishmania infantum and Trypanosoma cruzi are often targets of B-cell responses. However, African trypanosomes are susceptible to antibody-mediated immunity, and it may be detrimental for the parasites to have such B-cell antigens on the cell surface. Here we show TR proteins of T. brucei subspecies are also antigenic: recombinant TR proteins of these parasites detect antibodies in sera from mice infected with the parasites by ELISA. Analysis of amino acid sequences revealed that, different from TR proteins of Leishmania species or T. cruzi, the presence of predicted signal peptides, trans membrane domains and GPI anchor signals in T. brucei TR proteins are significantly lower than those of the whole proteome. Many of the T. brucei TR proteins are specific in the species or conserved only in the closely related species, as is the same case for Leishmania major and T. cruzi. These results suggest that, despite their sharing some common characteristics, such abundance in large TR domains and immunological dominance, TR genes have evolved independently among the trypanosomatid parasites. PMID- 21241660 TI - PANP is a novel O-glycosylated PILRalpha ligand expressed in neural tissues. AB - PILRalpha is an immune inhibitory receptor possessing an immunoreceptor tyrosine based inhibitory motif (ITIM) in its cytoplasmic domain enabling it to deliver inhibitory signals. Binding of PILRalpha to its ligand CD99 is involved in immune regulation; however, whether there are other PILRalpha ligands in addition to CD99 is not known. Here, we report that a novel molecule, PILR-associating neural protein (PANP), acts as an additional ligand for PILRalpha. Transcription of PANP was mainly observed in neural tissues. PILRalpha-Ig fusion protein bound cells transfected with PANP and the transfectants stimulated PILRalpha reporter cells. Specific O-glycan structures on PANP were found to be required for PILR recognition of this ligand. These results suggest that PANP is involved in immune regulation as a ligand of the PILRalpha. PMID- 21241661 TI - The characteristic region of arenicin-1 involved with a bacterial membrane targeting mechanism. AB - The antimicrobial peptide arenicin-1 consists of two antiparallel beta-sheets linked by a hydrophilic beta-turn. To determine the role of a specific region found in a particular beta-sheet structure of the peptide for antibacterial activity, two analogs with N-terminal deletions (RW) and substitutions of Arg to Ala in the beta-turn region were designed. In the minimum inhibitory concentration (MIC) test, the antibacterial activities of the analogs were reduced for both Gram-positive and Gram-negative bacteria, when compared to arenicin-1. The influence of the decrease in hydrophobicity on the antibacterial activity was confirmed by a hemolytic assay. Through flow cytometric analysis using propidium iodide (PI) and a 1,6-diphenyl-1,3,5-hexatriene (DPH) assay, it was confirmed that the analogs decreased the degree of plasma membrane permeability compared to arenicin-1. In particular, analog 2 showed a lower permeability in Gram-negative bacteria than in Gram-positive bacteria. The results indicate that a reduction in the net charge weakened the electrostatic interactions between the peptides and the negatively charged membranes. In liposomes, which mimic bacterial membranes, due to a reduced binding affinity to the membranes, the analogs could not deeply penetrate into the hydrocarbon region and induce enough fluorescein isothiocyanate-dextran (FD) leakage compared to that of arenicin-1. It is thought that the Arg residue in the hydrophilic beta turn region is more important to antibacterial activity than the Arg residue in the N-terminal region. This study suggests that the Arg and Trp residues in the N terminal region and the Arg residue in the beta-turn region of arenicin-1 play a key role in antibacterial activity. PMID- 21241662 TI - Critical role of the transient activation of p38 MAPK in the etiology of skeletal muscle insulin resistance induced by low-level in vitro oxidant stress. AB - Increased cellular exposure to oxidants may contribute to the development of insulin resistance and type 2 diabetes. Skeletal muscle is the primary site of insulin-dependent glucose disposal in the body; however, the effects of oxidative stress on insulin signaling and glucose transport activity in mammalian skeletal muscle are not well understood. We therefore studied the effects of a low-level in vitro oxidant stress (30-40 MUM H2O2) on basal and insulin-stimulated (5 mU/ml) glucose transport activity and insulin signaling at 2, 4, and 6 h in isolated rat soleus muscle. H2O2 increased basal glucose transport activity at 2 and 4 h, but not at 6 h. This low-level oxidant stress significantly impaired insulin-stimulated glucose transport activity at all time points, and was associated with inhibition of insulin-stimulated phosphorylation of Akt Ser473 and GSK-3beta Ser9. In the presence of insulin, H2O2 decreased total protein expression of IRS-1 at 6 h and IRS-2 at 4 and 6 h. Phosphorylation of p38 MAPK Thr180/Tyr182 was transiently increased by H2O2 in the presence and absence of insulin at 2 and 4 h, but not at 6 h. Selective inhibition of p38 MAPK with A304000 partially rescued the H2O2-induced reduction in insulin-stimulated glucose transport activity. These results indicate that direct in vitro exposure of isolated mammalian skeletal muscle to a low-level oxidant stress impairs distal insulin signaling and insulin-stimulated glucose transport activity, at least in part, due to a p38 MAPK-dependent mechanism. PMID- 21241663 TI - The role of palmitoylation in directing dopamine D1 receptor internalization through selective endocytic routes. AB - We previously determined that D1 receptors can endocytose through caveolae, a subset of lipid rafts, in addition to internalization via a clathrin-dependent pathway. In this report, we investigated the potential role that palmitoylation might have on directing D1 receptor internalization through either a clathrin or caveolar-dependent route. Through whole cell binding analysis and sucrose gradient fractionation studies, we demonstrated that although palmitoylation of the D1 receptor was not required for agonist-independent localization to caveolae, agonist induced internalization kinetics of a de-palmitoylated D1 receptor were accelerated ~8-fold in comparison to wild-type D1 receptor and were very similar to that observed for clathrin-dependent D1 receptor internalization. Additionally, inhibition of the clathrin mediated pathway led to significant attenuation in the extent of agonist induced internalization of the de palmitoylated D1 receptor, suggesting the de-palmitoylated D1 receptor was directed to a clathrin-dependent internalization pathway. Taken together, these data suggest that palmitoylation may be involved in directing agonist-dependent D1 receptor internalization through selective endocytic routes. PMID- 21241664 TI - ERK1/2 deactivation enhances cytoplasmic Nur77 expression level and improves the apoptotic effect of fenretinide in human liver cancer cells. AB - Fenretinide, a synthetic retinoid, is a promising anticancer agent based on many in vitro, animal, and chemoprevention clinical trial studies. However, cells such as HepG2 human liver cancer cells are resistant to the apoptotic effect of fenretinide. Previously, we have shown that fenretinide-induced apoptosis is Nur77 dependent, and the sensitivity of the cancer cells to fenretinide-induced apoptosis is positively associated with cytoplasmic enrichment of Nur77. The goal of current study was to identify means to modulate nuclear export of Nur77 in order to improve the efficacy of fenretinide. Fenretinide treatment deactivated ERK1/2 in Huh7 cells, but activated ERK1/2 in HepG2 cells, which was positively associated with the sensitivity of cells to the apoptotic effect of fenretinide. Neither fenretinide nor ERK1/2 inhibitor PD98059 alone could affect the survival of HepG2 cells, but the combination of both induced cell death and increased caspase 3/7 activity. In fenretinide sensitive Huh7 cells, activation of ERK1/2 by epidermal growth factor (EGF) prevented fenretinide-induced cell death and caspase 3/7 induction. In addition, modulation of ERK1/2 changed the intracellular localization of Nur77. Fenretinide/PD98059-induced cell death of HepG2 cell was positively associated with induction and cytoplasmic location as well as mitochondria enrichment of Nur77. The effect was specific for ERK1/2 because other mitogen activated protein kinases such as P38, Akt, and JNK did not have correlated changes in their phosphorylation levels. Taken together, the current study demonstrates that ERK1/2-modulated Nur77 intracellular location dictates the efficacy of fenretinide-induced apoptosis. PMID- 21241665 TI - Evaluating the role of Toll-like receptors in diseases of the central nervous system. AB - A key part of the innate immune system is a network of pattern recognition receptors (PRRs) and their associated intracellular signalling pathways. Toll like receptors (TLRs) are one such group of PRRs that detect pathogen associated molecular patterns (PAMPs). Activation of the TLRs with their respective agonists results in the activation of intracellular signalling pathways leading to the expression of proinflammatory mediators and anti-microbial effector molecules. Activation of the innate immune system through TLRs also triggers the adaptive immune response, resulting in a comprehensive immune program to eradicate invading pathogens. It is now known that immune surveillance and inflammatory responses occur in the central nervous system (CNS). Furthermore it is becoming increasingly clear that TLRs have a role in such CNS responses and are also implicated in the pathogenesis of a number of conditions in the CNS, such as Alzheimer's, stroke and multiple sclerosis. This is likely due to the generation of endogenous TLR agonists in these conditions which amplifies a detrimental neurotoxic inflammatory response. However TLRs in some situations can be neuroprotective, if triggered in a favourable context. This review aims to examine the recent literature on TLRs in the CNS thus demonstrating their importance in a range of infectious and non-infectious diseases of the brain. PMID- 21241666 TI - The dilated TRPA1 channel pore state is blocked by amiloride and analogues. AB - TRPA1 channels are a member of the transient receptor potential (TRP) superfamily. Several of its members, including TRPA1 can exist in at least two distinct open states: a restricted and a dilated state. The restricted state is a tetramer non-selective cation channel, whereas the dilated state allows influx of much larger molecules, e.g. Yo-Pro (Mw~630). The exact nature of the dilated channel is not well understood, however it was recently shown that the dilated state is regulated by extracellular divalent, especially calcium. Using open channel blockers as tool compounds and a combination of calcium imaging, fluorescence dye uptake and whole-cell patch clamp recordings I here demonstrate that amiloride and its analogue 5-(N,N-Dimethyl)amiloride (DMA) block the channels at low but not at high extracellular calcium. Hence, these data suggest that amiloride and other open channel blockers bind to sites revealed during the dilation process. Furthermore, the same series of compounds blocked the agonist induced Yo-Pro uptake in TRPA1 expressing cells. Thus, these results support the hypothesis that in low extracellular calcium the TRP channels are dilating, and as a consequence open channel blockers such as amiloride are allowed deeper into the pore providing a more efficient block. The TRP channel dilation mechanism may play important roles in many sensory processes, including pain and hearing. PMID- 21241667 TI - The effects of sevoflurane anesthesia on rat hippocampus: a genomic expression analysis. AB - Recent studies have shown that general anesthesia induces memory impairment. Sevoflurane, an inhalation anesthetic, is widely used in clinical practice, increasing pieces of evidence suggest that sevoflurane impairs memory processes due to changing gene expression in hippocampus. However, little is known about genome-widely analyzing the expression change induced by sevoflurane in hippocampus. In this study, we profiled the changes of hippocampal gene expression by microarray analysis. Six-week-old male Sprague-Dawley rats were anesthetized for 4h with 2.5% sevoflurane (n = 6) and were sacrificed 48 h later. RNA was extracted from the hippocampus for gene expression profile. Compared to control group, 417 genes, including up-regulated 67 and down-regulated 350, were significantly changed (> 2.0 or < -2.0 fold) (P < 0.05). Of these, there are 45 named genes, which are most involved in metabolism, development, biosynthesis, life material binding, location, signal transduction and communication, structural and vesicular processes. We randomly chose 6 differential genes to verify the microarray result. We also selected seven most differential genes, including 3 up-regulated genes (RMCP-1, Slc6a3, and Pitx2) and 4 down-regulated genes (VN7, AVP, IP10, and OT), to investigate whether there is a dose- or time dependent effect of sevoflurane on gene expression. The result indicated that the microarray profile is reliable; there is no obvious dose-dependent effect of sevoflurane on gene expression. These results suggested that sevoflurane induced long-term (at least 2 days) expression change of the numerous genes in hippocampus, which may be related to the memory impairment or the other neural disorders. PMID- 21241668 TI - Effect of tooth pulp and periaqueductal central gray stimulation on the expression of genes encoding the selected neuropeptides and opioid receptors in the mesencephalon, hypothalamus and thalamus in rats. AB - Nociceptive stimulation has been considered to affect the expression of genes encoding endogenous neuropeptides and their receptors. The effect of electric stimulation of the tooth pulp and/or periaqueductal gray (PAG) in rats on mRNA levels of the selected neuropeptides and opioid receptors (ORs) was investigated in comparison with control group, without stimulation. The levels of mRNA for the selected neuropeptides: galanin (GAL), vasopressin (AVP), oxytocin (OT), substance P (SP), somatostatin (SOM), vasoactive intestinal peptide (VIP), endomorphin-2 (EM-2), and opioid receptors: MOR, DOR and KOR in mesencephalic, hypothalamic and thalamic tissues were determined by real-time PCR. It was demonstrated that in the control group expression of the tested neuropeptides was at a very low level in the mesencephalon and thalamus, but at the higher level in the hypothalamus. The highest expression of ORs was observed in the mesencephalon. Nociceptive tooth pulp stimulation had the strongest effect in the hypothalamus, elevating mRNA levels of all tested neuropeptides except SOM. Electric stimulation of PAG either did not change or down-regulated mRNA levels of the neuropeptides in the cerebral structures. Simultaneous stimulation of PAG and tooth pulp either did not affect mRNA levels of the investigated neuropeptides or caused their slight decrease versus tooth pulp stimulation. The noxious stimulation of tooth pulp increased also the levels of OR mRNAs, while stimulation of PAG had the opposite effect. The above results demonstrated that tooth pulp stimulation significantly up-regulated the mRNA levels for a number of neuropeptides and all three types of ORs in the rat brain, which would result in more potent antinociception. In contrast, PAG stimulation down-regulated the mRNA levels of several neuropeptides and ORs in the cerebral tissues, which would cause decreased synthesis of ORs. The obtained results represent a new insight into the mechanism of orofacial pain. PMID- 21241669 TI - Morphological changes in the enteric nervous system of aging and APP23 transgenic mice. AB - Gastrointestinal motility disorders often pose a debilitating problem, especially in elderly patients. In addition, they are frequently occurring co-morbidities in dementia. Whereas a failing enteric nervous system has already been shown to be involved in gastrointestinal motility disorders and in Parkinson's disease, a relationship with the neurodegenerative process of Alzheimer's disease was not yet shown. Therefore, we sought to document quantitative changes in the distribution of betaIII-tubulin (general neuronal marker), Substance P, neuronal nitric oxide synthase (NOS), glial fibrillary acidic protein (GFAP) and S-100 immunoreactivity in addition to a qualitative assessment of the presence of amyloid in the small and large intestines of 6, 12 and 18-month-old wild type and transgenic Thy-1-APP23 mice. Amyloid deposits were seen in the vasculature, the mucosal and muscle layer of both heterozygous and wild type mice. Amyloidbeta1-42 could not be detected, pointing to a different amyloid composition than that found in senile plaques in the mice's brains. The finding of an increased density of betaIII-tubulin-, Substance P- and NOS-IR-nerve fibres in heterozygous mice could not undoubtedly be related to amyloid deposition or to an activation of glial cells. Therefore, the alterations at the level of the enteric nervous system and the deposition of amyloid seem not primarily involved in the pathogenesis of Alzheimer's disease. At most they are secondary related to the neurodegenerative process. Additionally, our data could not show extensive neuronal or glial cell loss associated with aging, in contrast to other reports. Instead an increase in S100-IR was observed in senescent mice. PMID- 21241670 TI - The pattern of retinoic acid receptor expression and subcellular, anatomic and functional area translocation during the postnatal development of the rat cerebral cortex and white matter. AB - Retinoic acid (RA), which is an important modulator of brain development, neural cell proliferation, neurite outgrowth, and synaptic plasticity, is regulated via changes in RA receptors. The pattern of RA receptor changes in the rat cerebral cortex and white matter during postnatal development has not been extensively studied. Therefore, we studied the mRNA expression patterns of 6 RA receptors in the postnatal rat cerebral cortex and white matter at 1, 3, 7, 10, 14, 21, 28, and 35days. We found that RARbeta, RXRalpha and RXRbeta mRNA levels gradually increased during postnatal development. RARalpha presented a nearly unimodal trend, but RARgamma and RXRgamma were generally bimodal. RARalpha, RARgamma, and RXRgamma mRNA levels peaked at postnatal day 21 (P21). The pattern of RARalpha expression was consistent with that of its mRNA levels. RARalpha and RXRgamma mRNA levels were the highest among those of all RA receptors during postnatal development. Interestingly, RARalpha expression was mainly located in the cytoplasm in the postnatal development apart from P3d. We further showed that RARalpha is expressed mainly in layers 2 and 3, partly in layers 1 and 4, and in a limited manner in layers 5 and 6 in the parietal cortex. Most RARalpha expression occurs in layers 2, 3, and 4 in the temporal lobe cortex. We realized that the M1 S2 region of RARalpha is highly expressed and that the position of RARalpha changes dynamically to meet the needs of different regions during development. These results support the idea that the RA receptor plays an important role in the cerebrum during postnatal development and implementation of these functions may be mainly dependent on the non-transcriptional or post- transcriptional regulation. PMID- 21241671 TI - Functional endothelin receptors are selectively expressed in isolectin B4 negative sensory neurons and are upregulated in isolectin B4-positive neurons by neurturin and glia-derived neurotropic factor. AB - Activation of endothelin receptors expressed in DRG neurons is functionally coupled to translocation of PKCepsilon from cytoplasm to the plasma membrane. Using immunocytochemistry we show that in DRG cultured neurons PKCepsilon translocation induced by endothelin-1 was prominently seen in a peptidergic subpopulation of cultured DRG neurons largely negative for isolectin B4 staining, indicating that in basal conditions functional expression of endothelin receptors does not occur in non-peptidergic, RET-expressing nociceptors. Translocation was blocked by the specific ETA-R antagonist BQ-123 while it was unaffected by the ETB-R antagonist BQ-788. No calcium response in response to endothelin-1 was observed in sensory neurons, while large and long-lasting responses were observed in the majority of non-neuronal cells present in DRG cultures, which are ensheathing Schwann cells and satellite cells, identified with the glial marker S 100. Calcium responses in non-neuronal cells were abolished by BQ-788. The fraction of peptidergic PKCepsilon-translocated neurons was significantly increased by nerve growth factor, while in the presence of neurturin or glia derived neurotropic factor (GDNF), an IB4-positive subpopulation of small- and medium-sized neurons showed PKCepsilon translocation induced by endothelin-1 which could be blocked by BQ-123 but not by BQ-788. Our in vitro results show that the level of expression of functional endothelin receptors coupled to PKCepsilon is different in peptidergic and non-peptidergic nociceptors and is modulated with different mechanisms in distinct neuronal subpopulations. PMID- 21241672 TI - Interleukin-18 promoter polymorphisms and risk of Parkinson's disease in a Han Chinese population. AB - The etiology of sporadic Parkinson's disease (PD) is not well established. Interleukin-18 (IL-18), a member of pro-inflammatory cytokines, might influence the risk of sporadic PD occurrence and development. In this study, two DNA polymorphisms at interleukin (IL)-18 promoter, -607C/A (rs1946518) and -137G/C (rs187238), were examined in sporadic PD patients in a Han Chinese population with 290 sporadic PD patients and 200 healthy controls. Direct sequencing was performed in 10% of the samples to validate the genotyping results. The results revealed that for -607C/A polymorphisms, there were significant differences in genotype distribution between PD and control in the total sample (P=0.017) and between LOPD and healthy-matched controls subgroup (P=0.011). For -137G/C polymorphisms, there were no significant differences in genotype distribution and gender and age-related differences between PD and control in the total sample (P=0.610). Results in this study revealed that the IL-18 607C/A polymorphism is a risk factor for sporadic LOPD in Han Chinese population, while IL-18 137G/C polymorphism is not a risk factor for sporadic PD in the Han Chinese population. PMID- 21241673 TI - Salidroside protects against MPP(+)-induced apoptosis in PC12 cells by inhibiting the NO pathway. AB - Oxidative stress plays an important role in Parkinson's disease and other neurodegenerative disorders. Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L., has potent antioxidant properties. In the present study, we investigated the protective activity of salidroside against 1-methyl-4 phenylpyridinium (MPP(+))-induced apoptosis in PC12 cells. We found that incubation of PC12 cells with salidroside prior to MPP(+) exposure significantly reduced cell apoptosis and attenuated collapse of the mitochondrial membrane potential (MMP). Furthermore, salidroside inhibited the MPP(+)-induced nitric oxide (NO) increase and overexpression of nNOS and iNOS and suppressed accumulation of reactive oxygen species (ROS) and intracellular free Ca(2+). Our results show that the protective effects of salidroside on PC12 cells are mediated, at least in part, by inhibition of the NO pathway. PMID- 21241674 TI - Isolation rearing in rats: effect on expression of synaptic, myelin and GABA related immunoreactivity and its utility for drug screening via the subchronic parenteral route. AB - Depriving weaned rats of social contact by rearing them in isolation brings about a spectrum of behavioural and neuropathological changes in adulthood which resemble some of the characteristics observed in schizophrenia. Hence, isolation rearing provides a non-pharmacological means to induce in an animal model certain aspects of schizophrenia with a neurodevelopmental origin. We compared the prepulse inhibition and locomotor activity behaviours in group-reared and isolation-reared rats in the context of determining the robustness of any behavioural changes following a subchronic parenteral drug administration protocol. The expression of synaptic, myelin and GABA-related proteins was also assessed in the brains of these rats using semi-quantitative fluorescence immunohistochemistry. Compared to their group-reared counterparts, isolation reared rats displayed disruption in prepulse inhibition which was lost after repeated testing and subchronic vehicle administration. However, isolation-reared rats showed open-field hyperlocomotion post-subchronic vehicle treatment compared to group-reared rats. Isolation rearing resulted in reduced expression of synaptophysin, synapsin I, myelin basic protein and GABA(B1) receptor proteins, along with an increase in 2',3'-cyclic nucleotide 3'-phosphodiesterase. Of the brain areas examined these observed changes were localised to the hippocampal regions and the substantia nigra. These results suggest an alteration in the synaptic, myelin and GABA-related functions in the brains of isolation-reared rats that displayed behavioural anomalies. Since dysfunction in these systems has also been implicated in schizophrenia, our findings provide additional evidence to support the use of isolation rearing for schizophrenia research; however, its use in the screening of putative antipsychotics following subchronic administration needs to be undertaken warily. PMID- 21241675 TI - Pristanic acid promotes oxidative stress in brain cortex of young rats: a possible pathophysiological mechanism for brain damage in peroxisomal disorders. AB - Pristanic acid (Prist) is accumulated in various peroxisomal disorders characterized by severe neurological dysfunction whose pathogenesis is poorly understood. Since oxidative damage has been demonstrated in brain of patients affected by neurodegenerative disorders, in the present work we investigated the in vitro effects of Prist on important parameters of oxidative stress in cerebral cortex from young rats. Prist significantly increased malondialdehyde levels, reflecting an increase of lipid peroxidation. This effect was totally prevented by the free radical scavenger melatonin, suggesting the involvement of reactive species. Prist also provoked protein oxidative damage, as determined by increased carbonyl formation and sulfhydryl oxidation. Otherwise, it did not alter nitric oxide production, indicating that nitrogen reactive species were not implicated in the lipid and oxidative damage provoked by Prist. Furthermore, the concentration of glutathione (GSH), the major brain non-enzymatic antioxidant defense, was significantly decreased by Prist and this decrease was fully prevented by melatonin and attenuated by alpha-tocopherol. It is therefore presumed that Prist elicits oxidative stress in the brain probably via reactive oxygen species formation and that this pathomechanism may possibly be involved in the brain damage found in patients affected by peroxisomal disorders where Prist accumulates. PMID- 21241676 TI - ERK pathway activation is required for amyloid-beta(1-40)(-)induced neurotoxicity of THP-1 human monocytes towards SK-N-SH neuroblastoma. AB - Alzheimer's disease (AD) is characterized by amyloid-beta peptide deposition, increased activated microglia, and progressive loss of neurons in the brain. Although Abeta1-40 can elicit inflammation in microglia, the intracellular signaling events mediating these effects are poorly defined. Here we show that cell-free supernatant from Abeta1-40-treated THP-1 monocytes induced cytotoxicity towards neuroblastoma SK-N-SH cells. Exposure of THP-1 monocytes to Abeta1-40 leads to increased tyrosine phosphorylation and extracellular signaling-regulated kinase (ERK) and increased levels of inflammatory cytokines (IL-1beta, IL-8, and TNF-alpha) in the supernatant of THP-1 monocytes. Pretreatment of THP-1 monocytes with either a protein tyrosine kinase (PTK) inhibitor or an ERK inhibitor protects SK-N-SH cells from the cytotoxic effect of conditional supernatant from Abeta1-40-treated THP-1 monocytes. Abeta1-40-treated THP-1 monocytes also lead to upregulation of cyclooxygenase-2 and iNOS expression and increased of nitric oxide production. These results suggest that Abeta1-40-induced activation of PTK/MEK/ERK pathway in THP-1 monocytes leads to the release of inflammatory factors that are toxic to SK-N-SH cells and might contribute to the onset of AD. PMID- 21241677 TI - Thrombin-induced activation of astrocytes in mixed rat hippocampal cultures is inhibited by soluble thrombomodulin. AB - Thrombin, a serine protease known for its role in coagulation, also induces a variety of protease activated receptor (PAR)-mediated responses in the central nervous system that contribute to many brain pathologies. Since the proteolytic specificity of thrombin is uniquely controlled by thrombomodulin (TM), we investigated the mechanisms by which thrombin and a recombinant soluble form of human TM (Solulin, INN: sothrombomodulin alpha; rhsTM) could influence rat hippocampal cultures. Treatment of hippocampal cultures with thrombin for up to 48h resulted in a significant morphological rearrangement with the formation of expansive cell-free areas (CFAs) and a reduction in cell viability; both effects were blocked by rhsTM. Treatment with the selective PAR-1 agonist, TRAP (SFLLRN) caused the formation of CFAs, suggesting that CFA formation involved PAR-1 signaling. Astrocytes prepared from PAR-1(-/-) mice also had an attenuated CFA response to thrombin. Thrombin-induced CFA formation was a consequence of cell movement and substantial changes in cell morphology, rather than due to cell detachment. Immunocytochemical and functional analyses revealed that the thrombin sensitive cells within these hippocampal cultures were astrocytes. The effects of thrombin on CFA development were mediated by astrocyte-specific release of intracellular calcium and signalling through ERK1/2. rhsTM was able to attenuate thrombin-induced ERK1/2 phosphorylation. Finally, astrocytes were shown to maintain thrombin-sensitivity following neuronal depletion with NMDA, a result which was confirmed with pure astrocyte cultures. Hence thrombin mediates PAR-1 induced activation of hippocampal astrocytes, but not neurons, in a process that can be modulated by rhsTM. PMID- 21241678 TI - Membrane estrogen receptors mediate calcium signaling and MAP kinase activation in individual hippocampal neurons. AB - Previously we demonstrated that 17beta-Estradiol (E2) induced rapid Ca(2+) influx via L-type calcium channel activation, which was required for activation of Src/ERK/CREB/Bcl2 signaling cascade and subsequent induction of neuroprotective and neurotrophic responses in rat hippocampal and cortical neurons (Wu et al., 2005; Zhao et al., 2005). The current study determined the presence and specificity of membrane E2 binding sites and the functional consequence of E2 binding to membrane receptors in individual neurons. Using E2-BSA-FITC (fluorescein isothiocyanate) macromolecular complex, membrane E2 binding sites were observed in hippocampal neurons. Punctate FITC signal was observed on plasma membrane of soma and neuronal processes in E2-BSA-FITC binding neurons. No membrane binding was observed with BSA-FITC. Specificity of binding was demonstrated by competition with excess un-conjugated E2. An ERa specific agonist, PPT, and an ERb agonist, DPN, partially competed for E2-BSA-FITC binding. Imaging of intracellular Ca(2+) ([Ca(2+)]i) in live neurons, revealed rapid Ca(2+) responses in E2-BSA-FITC binding neurons within minutes that culminated in a greater [Ca(2+)]i rise and [Ca(2+)]i spikes at >20 min. The same neurons in which E2-BSA-FITC induced a [Ca(2+)]i rise also exhibited activated pERK (extracellular signal-regulated kinase) that was translocated to the nucleus. Immunofluorescent analyses demonstrated that both excitatory and inhibitory neuronal markers labeled subpopulations of E2-BSA-FITC binding neurons. All E2-BSA-FITC binding neurons expressed L-type calcium channels. These results demonstrate, at a single cell level, that E2 membrane receptors mediate the rapid signaling cascades required for E2 neuroprotective and neurotrophic effects in hippocampal neurons. These results are discussed with respect to therapeutic targets of estrogen therapy in brain. PMID- 21241679 TI - GABA- and acetylcholine-related gene expression in blood correlate with tic severity and microarray evidence for alternative splicing in Tourette syndrome: a pilot study. AB - Tourette syndrome (TS) is a complex childhood neurodevelopmental disorder characterized by motor and vocal tics. Recently, altered numbers of GABAergic parvalbumin (PV) and cholinergic interneurons were observed in the basal ganglia of individuals with TS. Thus, we postulated that gamma-amino butyric acid (GABA)- and acetylcholine (ACh)-related genes might be associated with the pathophysiology of TS. Total RNA isolated from whole blood of 26 un-medicated TS subjects and 23 healthy controls (HC) was processed on Affymetrix Human Exon 1.0 ST arrays. Data were analyzed to identify genes whose expression correlated with tic severity in TS, and to identify genes differentially spliced in TS compared to HC subjects. Many genes (3627) correlated with tic severity in TS (p < 0.05) among which GABA- (p = 2.1 * 10-3) and ACh- (p = 4.25 * 10-8) related genes were significantly over-represented. Moreover, several GABA and ACh-related genes were predicted to be alternatively spliced in TS compared to HC including GABA receptors GABRA4 and GABRG1, the nicotinic ACh receptor CHRNA4 and cholinergic differentiation factor (CDF). This pilot study suggests that at least some of these GABA- and ACh-related genes observed in blood that correlate with tics or are alternatively spliced are involved in the pathophysiology of TS and tics. PMID- 21241680 TI - Alterations of steroid receptor coactivator-1 (SRC-1) immunoreactivities in specific brain regions of young and middle-aged female Sprague-Dawley rats. AB - Previous studies have shown that steroid receptor coactivator-1 (SRC-1) is involved in the regulation of Purkinje cell development and motor learning, neural stem cell differentiation and reproductive-related plasticity. It is widely distributed in the adult brain, but the aging-related changes in the brain remain unclear. In this study age-related alterations of SRC-1 expression in female brain were examined. The results showed that striking age-related decreases of SRC-1 were noticed in those regions related to central regulation of motor (substantia nigra, pontine nuclei, lateral reticular nucleus and Purkinje cells, etc.), learning and memory (olfactory bulb, hippocampus, Purkinje cells, etc.), and neural stem cell (olfactory, dentate gyrus, cerebral cortex, etc.). Surprisingly, although SRC-1 immunopositive materials were predominantly detected in the cell nuclei, they were also detected in the extra-nuclear components predominantly in these motor-regulation sub-regions. The above results showing age-related decrease of SRC-1 in specific motor, learning and memory nuclei suggested its potential roles in neurodegenerative disorders, which may be one of the underlying mechanisms of the vulnerability of the aged brain. PMID- 21241681 TI - Olivary climbing fiber alterations in PN40 rat cerebellum following postnatal ethanol exposure. AB - Developmental ethanol exposure in rats during postnatal days (PN) 4-6 is known to cause significant loss of the cerebellar Purkinje cells. It is not known what happens to the surviving neurons as they continue to develop. This study was designed to quantify the interactions between the olivary climbing fibers and the Purkinje cells when the cerebellar circuits have matured. Rat pups were treated with a daily dose of ethanol (4.5g/kg body weight) delivered by intragastric intubation on PN4, PN4-6, or PN7-9. The interactions between the climbing fibers and the Purkinje cells were examined on PN40 using confocal microscopy. Mid vermal cerebellar sections were stained with antibodies to calbindin-D28k (to visualize Purkinje cells) and vesicular glutamate transporter 2 (VGluT2, to visualize climbing fibers). Confocal z-stack images were obtained from Lobule 1 and analyzed with Imaris software to quantify the staining of the two antibodies. The VGluT2 immunostaining was significantly reduced and this was associated with alterations in the synaptic integrity, and synaptic number per Purkinje cell with only a single exposure on PN4 enough to cause the alterations. Previously, we demonstrated similar deficits in climbing fiber innervation when analyzed on PN14 (Pierce, Hayar, Williams, and Light, 2010). The present study confirms that these alterations are sustained and further identifies the decreased synaptic density as well as alterations to the general morphology of the molecular layer of the cerebellar cortex that are the result of the binge ethanol exposure. PMID- 21241682 TI - Inhibition of voltage-gated sodium channels by bisphenol A in mouse dorsal root ganglion neurons. AB - Bisphenol A (BPA), an estrogenic compound, is contained in cans, polycarbonate bottles, and some dental sealants. Exposure to BPA might have potential toxicological effects on the nervous system. Previous studies have demonstrated that BPA may affect ion channel function, but the effects of BPA on voltage-gated sodium channels are unknown. Herein, we report the effects of BPA on TTX sensitive (TTX-S) and TTX-resistant (TTX-R) Na+ currents, using a conventional whole-cell patch clamp technique from acutely isolated mouse dorsal root ganglion neurons. BPA inhibited TTX-S Na+ currents and TTX-R Na+ currents, the effects of BPA were rapid, reversible and in a concentration-dependent manner. Moreover, BPA could shift the voltage-gated activation curve for TTX-S Na+ channel in the hyperpolarizing direction without changing that for TTX-R Na+ channel; shift the steady-state inactivation curve for TTX-S Na+ channel in the depolarizing direction without changing that for TTX-R Na+ channel; and lengthen the time course of recovery from inactivation for both TTX-S Na+ current and TTX-R Na+ current. We also found that PKC inhibitor GO-6983 and PKA inhibitor H-89 blocked the BPA-induced inhibition of Na+ currents. Considering its complex modulatory effects on voltage-gated sodium channels, BPA might have potential toxicological effects on the nervous system and lead to a change in excitability of nociceptive afferent fibers. PMID- 21241683 TI - Hippocampal responsiveness to 17beta-estradiol and equol after long-term ovariectomy: implication for a therapeutic window of opportunity. AB - A 'critical window of opportunity' has been proposed for the efficacy of ovarian hormone intervention in peri- and post-menopausal women. We sought to address this hypothesis using a long-term ovariectomized non-human primate (NHP) model, the cynomolgus macaque (Macaca fascicularis). In these studies, we assessed the ability of 17beta-estradiol and equol to regulate markers of hippocampal bioenergetic capacity. Results indicated that 17beta-estradiol treatment significantly increased expression of mitochondrial respiratory chain proteins complex-I and -III in the hippocampus when compared to non-hormone-treated animals. Expression of the TCA cycle protein succinate dehydrogenase alpha was decreased in animals treated with equol compared to those treated with 17beta estradiol. There were no significant effects of either 17beta-estradiol or equol treatment on glycolytic protein expression in the hippocampus, nor were there significant effects of treatment on expression levels of antioxidant enzymes. Similarly, 17beta-estradiol and equol treatment had no effect on mitochondrial fission and fusion protein expression. In summary, findings indicate that while 17beta-estradiol induced a significant increase in several proteins, the overall profile of bioenergetic system proteins was neutral to slightly positively responsive. The profile of responses with the ERbeta-preferring molecule equol was consistent with overall nonresponsiveness. Collectively, the data indicate that long-term ovariectomy is associated with a decline in response to estrogens and estrogen-like compounds. By extension, the data are consistent with a primary tenet of the critical window hypothesis, i.e., that the brains of post-menopausal women ultimately lose their ability to respond positively to estrogenic stimulation. PMID- 21241684 TI - Spatial-temporal expression of NDRG2 in rat brain after focal cerebral ischemia and reperfusion. AB - N-myc downstream regulated gene 2 (NDRG2) was reported to be widely expressed in the nervous system. However, the expression and potential role of NDRG2 in focal cerebral ischemia brain remain unclear. Herein, we investigated spatial-temporal expression of NDRG2 in the rat brain following transient focal cerebral ischemia. Male Sprague-Dawley rats underwent a 120-min transient occlusion of middle cerebral artery. Rats were killed and brain samples were harvested at 4, 12, 24, and 72h after reperfusion. Expression of NDRG2 in the brain was determined by reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot analysis and immunohistochemical staining. Cellular apoptosis was assessed by TUNEL staining. The results showed that NDRG2 was expressed on cells with an astrocytes like morphology in ischemic penumbra. NDRG2 mRNA and protein expression began to increase at 4h after reperfusion and peaked at 24h in the ischemic penumbra. By using immunofluorescence, NDRG2 signals were co-localized with GFAP-positive astrocytes, and NDRG2 expression in astrocytes translocated from a cytoplasm to a nuclear localization at 24h after reperfusion. Double immunofluorescent staining for TUNEL and NDRG2 showed that some NDRG2 signals co-localized with TUNEL positive cells, and that the apoptotic cells increased with enhancement of NDRG2 positive signals. In conclusion, NDRG2 expression is up-regulated in ischemic penumbra following transient focal cerebral ischemia. NDRG2 expression in astrocytes may play important pathological roles in cell apoptosis after stroke. PMID- 21241685 TI - ROS-Ca(2+) is associated with mitochondria permeability transition pore involved in surfactin-induced MCF-7 cells apoptosis. AB - The surfactin can inhibit proliferation and induce apoptosis in cancer cells. Moreover, surfactin can induce cell death in human breast cancer MCF-7 cells through mitochondrial pathway. However, the molecular mechanism involved in this pathway remains to be elucidated. Here, the reactive oxygen species (ROS) and Ca(2+) on mitochondria permeability transition pore (MPTP) activity, and MCF-7 cell apoptosis which induced by surfactin were investigated. It is found that surfactin evoked mitochondrial ROS generation, and the surfactin-induced cell death was prevented by N-acetylcysteine (NAC, an inhibitor of ROS). An increasing cytoplasmic Ca(2+) concentration was detected in surfactin-induced MCF-7 apoptosis, which was inhibited by 1,2-bis (2-aminophenoxy) ethane-N,N,N',N' tetraacetic acid (BAPTA-AM, a chelator of calcium). In addition, the relationship between ROS generation and the increase of cytoplasm Ca(2+) was determined. The results showed that surfactin initially induced the ROS formation, leading to the MPTP opening accompanied with the collapse of mitochondrial membrane potential (DeltaPsi(m)). Then the cytoplasmic Ca(2+) concentration increased in virtue of the changes of mitochondrial permeability, which was prevented by BAPTA-AM. Besides, cytochrome c (cyt c) was released from mitochondria to cytoplasm through the MPTP and activated caspase-9, eventually induced apoptosis. In summary, surfactin has notable anti-tumor effect on MCF-7 cells, however, there was no obvious cytotoxicity on normal cells. PMID- 21241686 TI - Differentiation of human embryonic stem cells along a hepatic lineage. AB - The limited availability of hepatic tissue suitable for the treatment of liver disease and drug discovery research advances the generation of hepatic-like cells from alternative sources as a valuable approach. In this investigation we exploited a unique hepatic differentiation approach to generate hepatocyte-like cells from human embryonic stem cells (hESCs). hESCs were cultured for 10-20 days on collagen substrate in highly defined and serum free hepatocyte media. The resulting cell populations exhibited hepatic cell-like morphology and were characterized with a variety of biological endpoint analyses. Real-time PCR analysis demonstrated that mRNA expression of the 'stemness' marker genes NANOG and alkaline phosphatase in the differentiated cells was significantly reduced, findings that were functionally validated using alkaline phosphatase activity detection measures. Immunofluorescence studies revealed attenuated levels of the 'stemness' markers OCT4, SOX2, SSEA-3, TRA-1-60, and TRA-1-81 in the hepatic-like cell population. The hepatic character of the cells was evaluated additionally by real-time PCR analyses that demonstrated increased mRNA expression of the hepatic transcription factors FOXA1, C/EBPalpha, and HNF1alpha, the nuclear receptors CAR, RXRalpha, PPARalpha, and HNF4alpha, the liver-generated plasma proteins alpha-fetoprotein, transthyretin, transferrin, and albumin, the protease inhibitor alpha-1-antitrypsin, metabolic enzymes HMGCS2, PEPCK, and biotransformation enzymes CYP3A7, CYP3A4, CYP3A5, and CYP2E1. Indocyanine green uptake albumin secretion and glycogen storage capacity further confirmed acquisition of hepatic function. These studies define an expeditious methodology that facilitates the differentiation of hESCs along a hepatic lineage and provide a framework for their subsequent use in pharmacological and toxicological research applications requiring a renewable supply of human hepatocytes. PMID- 21241687 TI - Cryopreservation of buffy-coat-derived platelet concentrates in dimethyl sulfoxide and platelet additive solution. AB - Platelets prepared in plasma can be frozen in 6% dimethyl sulfoxide (Me(2)SO) and stored for extended periods at -80 degrees C. The aim of this study was to reduce the plasma present in the cryopreserved product, by substituting plasma with platelet additive solution (PAS; SSP+), whilst maintaining in vitro platelet quality. Buffy coat-derived pooled leukoreduced platelet concentrates were frozen in a mixture of SSP+, plasma and 6% Me(2)SO. The platelets were concentrated, to avoid post-thaw washing, and frozen at -80 degrees C. The cryopreserved platelet units (n=9) were rapidly thawed at 37 degrees C, reconstituted in 50% SSP+/plasma and stored at 22 degrees C. Platelet recovery and quality were examined 1 and 24h post-thaw and compared to the pre-freeze samples. Upon thawing, platelet recovery ranged from 60% to 80%. However, there were differences between frozen and liquid stored platelets, including a reduction in aggregation in response to ADP and collagen; increased CD62P expression; decreased viability; increased apoptosis and some loss of mitochondrial membrane integrity. Some recovery of these parameters was detected at 24h post-thaw, indicating an extended shelf-life may be possible. The data suggests that freezing platelets in 6% Me(2)SO and additive solution produces acceptable in vitro platelet quality. PMID- 21241688 TI - Apoptosis induced by a new flavonoid in human hepatoma HepG2 cells involves reactive oxygen species-mediated mitochondrial dysfunction and MAPK activation. AB - Earlier reports suggest that protoapigenone showed remarkable anticancer activities. In the present study, the cytotoxic effect of a new flavonoid, 2-(cis 1, 2-dihydroxy 4-oxo-cyclohex-5-enyl)-5, 7-dihydroxy-chromone (DEDC), which is a protoapigenone analog, was investigated in human hepatoma HepG2 cells. We found that hepatoma cells were highly susceptible to DEDC in contrast with normal cells. The sustainable and rapid generation of reactive oxygen species was observed in DEDC-induced cell death. Following oxidative stress, DEDC sequentially decreased mitochondrial membrane potential (DeltaPsim), reduced Bcl 2 expression, increased cytochrome c release, and activated caspase-3, -8, and 9. Phosphorylation of c-Jun N-terminal kinase (JNK) and p38 mitogen activated protein kinase (MAPK) was stimulated by treatment with DEDC. To further investigate the mechanisms of the DEDC-induced cell death, we examined the effects of reactive oxygen species scavenger N-acetyl-L-cysteine (NAC) and selective inhibitors for MAPK pathways on the cell death. The DEDC-induced cell death was significantly inhibited by both NAC and JNK inhibitor SP600125, but promoted by p38 MAPK inhibitor, SB203580. Together, DEDC may have antitumor effects in HepG2 cells through reactive oxygen species production as well as activation of MAPK signaling pathways. PMID- 21241689 TI - Evaluation of oxidative stress markers in pathogenesis of primary open-angle glaucoma. AB - Primary open-angle glaucoma (POAG) is the leading cause of blindness in the industrial countries. It is reported that oxidative stress might be an important risk factor in the pathogenesis of POAG. Forty subjects including 20 patients with open-angle glaucoma (9 men and 12 women, mean age 61.8+/-12.1yr) and 20 controls without glaucoma symptoms (9 men and 12 women, mean age 58.1+/-17.7yr) were enrolled in our study. The main aim of the work was to evaluate oxidative stress markers in the pathogenesis of open-angle glaucoma. In our work the activity of antioxidant enzymes: catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPX) as well as the total antioxidant status (TAS) was estimated. An alkaline comet assay was used to measure DNA damage of strand breaks (SB), oxidized purines as glicosylo-formamido-glicosylase (Fpg) sites, and oxidized pirmidines as endonuclease III (Nth) sites. We measured endogenous as well as exogenous DNA damage after 10MUM hydrogen peroxide treatment (H(2)O(2)). We did not observe any statistical changes of DNA strand break lesion in examined POAG patients according to healthy subjects (P>0.05). However, either endogenous (P<0.01) or exogenous (P<0.001) levels of oxidative DNA damage in POAG patients were found to be statistically higher than controls. A significant decrease of antioxidant enzymes: CAT (P<0.001), SOD (P<0.05), and GPX (P<0.001) and a non statistical decrease of TAS status (P>0.05) in glaucoma patients according to controls were also indicated. In conclusion our data revealed that oxidative stress had a pathogenic role in primary open-angle glaucoma. Therefore, we suggested that the modulation of a pro-oxidant/antioxidant status might be a relevant target for glaucoma prevention and therapy. PMID- 21241690 TI - Angiocidin inhibits breast cancer proliferation through activation of epidermal growth factor receptor and nuclear factor kappa (NF-KB). AB - Angiocidin, a tumor-associated peptide, has been previously shown to inhibit tumor progression by blocking angiogenesis. We now show that angiocidin has a direct inhibitory effect on tumor cell proliferation. MDA-MB-231 breast cancer cells were inhibited from proliferating in the presence of epidermal growth factor (EGF) and angiocidin. Angiocidin transfected breast cancer cells also displayed growth inhibition in vitro and failed to develop significant tumors in mice as compared to vector controls. The anti-proliferative effect of angiocidin was reversed by treating the cells with the epidermal growth factor receptor (EGFR) inhibitor 4557W, a potent tyrosine kinase inhibitor. Consistent with these results, we found that treatment of breast cancer cells with angiocidin induced a 2.3 fold increase in EGFR tyrosine 845 phosphorylation while no change in phosphorylation was observed in the remaining 16 phosphorylation sites of EGFR and those of its family members as measured by a human EGFR phosphorylation array. Treatment of breast cancer cells with angiocidin also resulted in the activation of nuclear factor KB (Nf-KB) and the de novo up-regulation of many down-stream genes transcribed by Nf-KB, including cytokines, inflammatory mediators and the cell cycle inhibitor p21(waf1). Therefore, angiocidin is a peptide that not only inhibits tumor angiogenesis but also directly induces inhibition of tumor growth progression through the activation of EGFR and down stream genes transcribed by Nf-KB. PMID- 21241691 TI - Chemokine research moves on. PMID- 21241692 TI - Sex differences in the manifestation of peripheral diabetic neuropathy in gonadectomized rats: a correlation with the levels of neuroactive steroids in the sciatic nerve. AB - Clinical observations suggest a sex-dimorphism in the incidence and symptomatology of diabetic neuropathy, but this possible gender effect has never been investigated in detail in a well-characterized experimental model such as streptozotocin (STZ)-induced diabetes. Therefore, in this study we have compared with a multimodal set of tests the impact of diabetes on the sciatic nerve in male and female rats. To assess whether sex-dimorphism in peripheral diabetic neuropathy is dependent on gonadal hormones we have also analyzed the effect of ovariectomy and orchidectomy on the sciatic nerve of STZ-diabetic rats. Nerve conduction velocity (NCV), Na(+),K(+)-ATPase activity, expression of myelin proteins, thermal sensitivity and reactive oxygen species production were similarly affected in male and female animals by STZ. However, ovariectomy, but not orchidectomy, significantly counteracted STZ-induced alterations on NCV, Na(+),K(+)-ATPase activity, and expression of myelin proteins. This effect of ovariactomy was associated to an increase in the levels of neuroactive steroids, such as dehydroepiandrosterone, testosterone and dihydrotestosterone, in the sciatic nerve of diabetic rats. These neuroactive steroids have been demonstrated to be protective agents in this experimental model of diabetic neuropathy. However, their efficacy has been so far tested only in male animals. Therefore, the present data might represent an important background to evaluate their efficacy also in female diabetic animals. PMID- 21241695 TI - De novo origin of new genes with introns in Plasmodium vivax. AB - The origin of new genes is critical for organisms adapting to new niches. Here, we present evidence for a recent de novo origin of at least 13 protein-coding genes in the genome of Plasmodium vivax. Although recently de novo originated genes have often been suggested to be initially intronless, five of the genes identified in our analysis contain introns in their coding regions. Further investigations revealed that these introns likely evolved from previously intergenic regions together with the coding sequences. We discuss the potential mechanisms for intron formation in these genes and propose that intronization be considered in the formation of de novo originated genes. PMID- 21241694 TI - Oesophagostomum dentatum: effect of glutathione S-transferase (GST) inhibitors on GST activity and larval development. AB - Sulphobromophthalein (SBP) inhibits isolated glutathione S-transferase of the porcine nodule worm Oesophagostomum dentatum (Od-GST) and reduces larval development in vitro. In this study possible inhibitory effects of various inhibitors were evaluated in an enzymatic (CDNB) assay with isolated Od-GST and in a larval development assay (LDA). Reversibility was tested in the LDA by removing the inhibitor from culture halfway through the cultivation period. SBP, indomethacin and ethacrynic acid inhibited both enzyme activity and larval development in a dose-dependent and reversible manner. HQL-79 also reduced larval development but had only a minor effect on the isolated enzyme. The phospholipase A(2) inhibitors dexamethasone and hydrocortisone had no major effect. High thermal stability of Od-GST was demonstrated with increasing activity between 4 and 50 degrees C. Differences between Od-GST and GST of other organisms indicate structural and possibly functional peculiarities and highlight the potential of such enzymes as targets of intervention. PMID- 21241693 TI - A brain slice culture model of viral encephalitis reveals an innate CNS cytokine response profile and the therapeutic potential of caspase inhibition. AB - Viral encephalitis is a significant cause of human morbidity and mortality in large part due to suboptimal diagnosis and treatment. Murine reovirus infection serves as a classic experimental model of viral encephalitis. Infection of neonatal mice with T3 reoviruses results in lethal encephalitis associated with neuronal infection, apoptosis, and CNS tissue injury. We have developed an ex vivo brain slice culture (BSC) system that recapitulates the basic pathological features and kinetics of viral replication seen in vivo. We utilize the BSC model to identify an innate, brain-tissue specific inflammatory cytokine response to reoviral infection, which is characterized by the release of IL6, CXCL10, RANTES, and murine IL8 analog (KC). Additionally, we demonstrate the potential utility of this system as a pharmaceutical screening platform by inhibiting reovirus-induced apoptosis and CNS tissue injury with the pan-caspase inhibitor, Q-VD-OPh. Cultured brain slices not only serve to model events occurring during viral encephalitis, but can also be utilized to investigate aspects of pathogenesis and therapy that are not experimentally accessible in vivo. PMID- 21241696 TI - LKB1 loss of function studied in vivo. AB - Recent developments have placed the serine/threonine kinase LKB1 on the crossroads linking energy metabolism, cell structure and cancer progression and that its deletion can affect tumorigenesis, metastasis, cell adhesion and polarity. LKB1 can regulate a host of different functions which all have potential to impact upon the initiation and progression of neoplastic disease. To understand the phenotypic consequences of LKB1 loss in a range of different settings, a number of animal models of loss of function have been generated and analyzed. In this review we summarize recent data generated from a range of these models, which reveal clear tissue specific differences in LKB1 function in vivo and in the consequences of its loss. PMID- 21241697 TI - Increase in CIP2A expression is associated with doxorubicin resistance. AB - The cancerous inhibitor of protein phosphatase 2A (CIP2A) increases the migration and metastasis of various cancer cells. Overexpression of CIP2A has been shown to increase the proliferation of MDA-MB-231 cells. We thus assessed whether CIP2A expression is associated with sensitivity to doxorubicin. MDA-MB-231 cells showed an increase in CIP2A expression after treatment with doxorubicin, while MCF-7 cells showed a decrease in CIP2A expression. The overexpression of CIP2A in MCF-7 cells overcame the inhibition of cell proliferation in response to doxorubicin treatment. CIP2A expression was not affected by wild-type or mutant p53. However, mutant p53 blocked doxorubicin-mediated CIP2A down-regulation in HCT116 cells. As a regulation mechanism of doxorubicin-mediated CIP2A expression, we showed that phosphorylated Akt was involved in the suppression of CIP2A expression. PMID- 21241702 TI - Neuropeptide evolution: neurohormones and neuropeptides predicted from the genomes of Capitella teleta and Helobdella robusta. AB - Genes encoding neurohormones and neuropeptide precursors were identified in the genomes of two annelids, the leech Helobdella robusta and the polychaete worm Capitella teleta. Although no neuropeptides have been identified from these two species and relatively few neuropeptides from annelids in general, 43 and 35 such genes were found in Capitella and Helobdella, respectively. The predicted peptidomes of these two species are similar to one another and also similar to those of mollusks, particular in the case of Capitella. Helobdella seems to have less neuropeptide genes than Capitella and it lacks the glycoprotein hormones bursicon and GPA2/GPB5; in both cases the genes coding the two subunits as well as the genes coding their receptors are absent from its genome. In Helobdella several neuropeptide genes are duplicated, thus it has five NPY genes, including one pseudogene, as well as four genes coding Wwamides (allatostatin B). Genes coding achatin, allatotropin, allatostatin C, conopressin, FFamide, FLamide, FMRFamide, GGRFamide, GnRH, myomodulin, NPY, pedal peptides, RGWamide (a likely APGWamide homolog), RXDLamide, VR(F/I)amide, WWamide were found in both species, while genes coding cerebrin, elevenin, GGNG, LFRWamide, LRFYamide, luqin, lymnokinin and tachykinin were only found in Capitella. PMID- 21241703 TI - Responses of Drosophila melanogaster to atypical oxygen atmospheres. AB - We examined physiological phenotypes of Drosophila melanogaster in hypoxic to hyperoxic atmospheres. We performed measurements on life span or behavioural function in 5, 21, 40, 60, and 80% O(2), and combined this with literature data for 2% and 100% O(2). O(2) incubation resulted in a concentration-dependent reduction of life span in both hypoxia and hyperoxia, though different measures of life span were affected differently. We also examined how behavioural and metabolic functions were affected by exposure to hyperoxia (up to 60% O(2)). Climbing behaviour was measured as a fast (4 s) and slow (55 s) response in a negative geotaxis assay. In normoxia, both measures of climbing response declined exponentially until disappearing completely. Interestingly, survivorship was very high until the loss of climbing ability, after which it dropped rapidly. This pattern appeared accelerated in 40% O(2). However, while flies in 60% O(2) also apparently lost their fast climbing ability immediately prior to the drop in survivorship, they maintained considerable climbing ability over the longer trial. Metabolism, measured by CO(2) release, did not change with age in normoxic flies, but was significantly lower in flies exposed to hyperoxia, particularly as the flies aged. There was, however, a slight increase in water loss rate with age in normoxia, while in hyperoxia, water loss was reduced. Uniquely, the water loss rates of flies in 60% O(2) doubled immediately prior to the end of their life span. Because ageing results in generally irreversible functional declines, we examined if functional declines in hyperoxia (60% O(2)) were also irreversible, or whether some functioning could recover after a return to normoxia. After 7 days of recovery, water loss rates decreased, CO(2) exhalation slightly increased, and climbing ability was partially recovered. Therefore, the effect of O(2) on D. melanogaster function is non-linear, may be reversible, and may include unique phenotypes that arise at some O(2) concentrations, and not others. PMID- 21241704 TI - The first record of entomopathogenic nematodes (Rhabiditiae: Steinernematidae and Heterorhabditidae) in natural ecosystems in Lebanon: A biogeographic approach in the Mediterranean region. AB - A survey of entomopathogenic nematodes in Lebanon was conducted for the first time during 2008-2009. Samples were collected on the coastal strip and in nine vegetation types extending from the coastal line to 3088m above sea level. Wooded and herbaceous ecosystems were considered for sampling purposes. A total of 570 samples were taken, out of which 1% were positive for entomopathogenic nematodes. Approximately, 15.8% out of the 19 sites sampled revealed entomopathogenic nematodes presence (representing three samples). Two entomopathogenic nematodes species Heterorhabditis bacteriophora and Steinernema feltiae were recovered, and identification of their symbiotic bacteria revealed the presence of a Xenorhabdus bovienii, Photorhabdus temperata subsp. thracensis, Photorhabdus luminescens subsp. kayaii and Photorhabdus luminescens subsp. Laumondii. PMID- 21241705 TI - Investigation of biota associated and natural infection by sporulated bacteria in Culicidae larvae from Sao Paulo state, Brazil. AB - The aim of this study was to investigate the naturally occurring bacteria from Culicidae larvae found in Sao Paulo state between 2006 and 2008 from the Tiete Ecological Park in the municipality of Caraguatatuba. Bacterial strains were obtained after surface sterilization of larvae followed by thermal treatment and incubation in bacteriological media under laboratory conditions. Identification was determined using cytomorphology, biochemical and physiological tests. Strains were characterized by qualitative evaluation of biological activity against Culicidae larvae, comparing protein profiles obtained by electrophoresis of crystal protoxins, electrophoresis of Lysinibacillus sphaericus isoenzymes, detection of the L(2) fraction of Hemolytic BL enterotoxin and amplification of DNA using Multiplex-PCR to detect HBL, NHE, CytK, BceT and EntFM enterotoxins. The results obtained in this study demonstrated that the endosymbiotic bacterial diversity belonging to Bacillus and related genera associated with Culicidae larvae is limited to a number of species that does not vary throughout the seasons. PMID- 21241706 TI - Mutational specificities of brominated DNA adducts catalyzed by human DNA polymerases. AB - Chronic inflammation is known to lead to an increased risk for the development of cancer. Under inflammatory condition, cellular DNA is damaged by hypobromous acid, which is generated by myeloperoxidase and eosinophil peroxidase. The reactive brominating species induced brominated DNA adducts such as 8-bromo-2' deoxyguanosine (8-Br-dG), 8-bromo-2'-deoxyadenosine (8-Br-dA), and 5-bromo-2' deoxycytidine (5-Br-dC). These DNA lesions may be implicated in carcinogenesis. In this study, we analyzed the miscoding properties of the brominated DNA adducts generated by human DNA polymerases (pols). Site-specifically modified oligodeoxynucleotides containing a single 8-Br-dG, 8-Br-dA, or 5-Br-dC were used as a template in primer extension reactions catalyzed by human pols alpha, kappa, and eta. When 8-Br-dG-modified template was used, pol alpha primarily incorporated dCMP, the correct base, opposite the lesion, along with a small amount of one-base deletion (4.8%). Pol kappa also promoted one-base deletion (14.2%), accompanied by misincorporation of dGMP (9.5%), dAMP (8.0%), and dTMP (6.1%) opposite the lesion. Pol eta, on the other hand, readily bypassed the 8-Br dG lesion in an error-free manner. As for 8-Br-dA and 5-Br-dC, all the pols bypassed the lesions and no miscoding events were observed. These results indicate that only 8-Br-dG, and not 5-Br-dC and 8-Br-dA, is a mutagenic lesion; the miscoding frequency and specificity vary depending on the DNA pol used. Thus, hypobromous acid-induced 8-Br-dG adduct may increase mutagenic potential at the site of inflammation. PMID- 21241707 TI - Recombinase-mediated cassette exchange (RMCE): traditional concepts and current challenges. AB - Traditional DNA transduction routes used for the modification of cellular genomes are subject to unpredictable alterations, as the cell-intrinsic repair machinery may affect both the integrity of the transgene and the recipient locus. These problems are overcome by recombinase-mediated cassette exchange (RMCE) approaches enabling predictable expression patterns by the nondisruptive insertion of a gene cassette at a pre-characterized genomic locus. The destination is marked by a "tag" consisting of two heterospecific recombination target sites (RTs) at the flanks of a selection marker. Provided on a circular donor vector, an analogous cassette encoding the gene of interest can cleanly replace the resident cassette under the influence of a site-specific recombinase. RMCE was first based on the yeast integrase Flp but had to give way to the originally more active phage derived Cre enzyme. To be effective, both Tyr-recombinases have to be applied at a considerable concentration, which, in the case of Cre, triggers endonucleolytic activities and therefore cellular toxicity. This review addresses the particularities of both recombination routes depending on the structure of the synaptic complex and on improved integrase and RT variants. While the performance of Flp-RMCE can now firmly rely on optimized Flp variants and multiple sets of functional target sites (FRTs), the Cre system suffers from the promiscuity of its RT mutants, which is explained in molecular terms. At present, RMCE enters applications in the stem cell field. Remarkable efforts are noted in the framework of various mouse mutagenesis programs, which, in their first phase, have targeted virtually all genes and now start to shift their emphasis from gene trapping to gene modification. PMID- 21241708 TI - The crystal structures of eukaryotic phosphofructokinases from baker's yeast and rabbit skeletal muscle. AB - Phosphofructokinase 1 (PFK) is a multisubunit allosteric enzyme that catalyzes the principal regulatory step in glycolysis-the phosphorylation of fructose 6 phosphate to fructose 1,6-bisphosphate by ATP. The activity of eukaryotic PFK is modulated by a number of effectors in response to the cell's needs for energy and building blocks for biosynthesis. The crystal structures of eukaryotic PFKs-from Saccharomyces cerevisiae and rabbit skeletal muscle-demonstrate how successive gene duplications and fusion are reflected in the protein structure and how they allowed the evolution of new functionalities. The basic framework inherited from prokaryotes is conserved, and additional levels of structural and functional complexity have evolved around it. Analysis of protein-ligand complexes has shown how PFK is activated by fructose 2,6-bisphosphate (a powerful PFK effector found only in eukaryotes) and reveals a novel nucleotide binding site. Crystallographic results have been used as the basis for structure-based effector design. PMID- 21241709 TI - Structure of the human protein kinase CK2 catalytic subunit CK2alpha' and interaction thermodynamics with the regulatory subunit CK2beta. AB - Protein kinase CK2 (formerly "casein kinase 2") is composed of a central dimer of noncatalytic subunits (CK2beta) binding two catalytic subunits. In humans, there are two isoforms of the catalytic subunit (and an additional splicing variant), one of which (CK2alpha) is well characterized. To supplement the limited biochemical knowledge about the second paralog (CK2alpha'), we developed a well soluble catalytically active full-length mutant of human CK2alpha', characterized it by Michaelis-Menten kinetics and isothermal titration calorimetry, and determined its crystal structure to a resolution of 2 A. The affinity of CK2alpha' for CK2beta is about 12 times lower than that of CK2alpha and is less driven by enthalpy. This result fits the observation that the beta4/beta5 loop, a key element of the CK2alpha/CK2beta interface, adopts an open conformation in CK2alpha', while in CK2alpha, it opens only after assembly with CK2beta. The open beta4/beta5 loop in CK2alpha' is stabilized by two elements that are absent in CK2alpha: (1) the extension of the N-terminal beta-sheet by an additional beta strand, and (2) the filling of a conserved hydrophobic cavity between the beta4/beta5 loop and helix alphaC by a tryptophan residue. Moreover, the interdomain hinge region of CK2alpha' adopts a fully functional conformation, while unbound CK2alpha is often found with a nonproductive hinge conformation that is overcome only by CK2beta binding. Taken together, CK2alpha' exhibits a significantly lower affinity for CK2beta than CK2alpha; moreover, in functionally critical regions, it is less dependent on CK2beta to obtain a fully functional conformation. PMID- 21241710 TI - Response of an actin filament network model under cyclic stretching through a coarse grained Monte Carlo approach. AB - Cells are complex, dynamic systems that actively adapt to various stimuli including mechanical alterations. Central to understanding cellular response to mechanical stimulation is the organization of the cytoskeleton and its actin filament network. In this manuscript, we present a minimalistic network Monte Carlo based approach to model actin filament organization under cyclic stretching. Utilizing a coarse-grained model, a filament network is prescribed within a two-dimensional circular space through nodal connections. When cyclically stretched, the model demonstrates that a perpendicular alignment of the filaments to the direction of stretch emerges in response to nodal repositioning to minimize net nodal forces from filament stress states. In addition, the filaments in the network rearrange and redistribute themselves to reduce the overall stress by decreasing their individual stresses. In parallel, we cyclically stretch NIH 3T3 fibroblasts and find a similar cytoskeletal response. With this work, we test the hypothesis that a first-principles mechanical model of filament assembly in a confined space is by itself capable of yielding the remodeling behavior observed experimentally. Identifying minimal mechanisms sufficient to reproduce mechanical influences on cellular structure has important implications in a diversity of fields, including biology, physics, medicine, computer science, and engineering. PMID- 21241711 TI - Spatial patterns and scaling behaviors of Steller sea lion (Eumetopias jubatus) distributions and their environment. AB - Fractal geometry and other multi-scale analyses have become popular tools for investigating spatial patterns of animal distributions in heterogeneous environments. In theory, changes in patterns of animal distributions with changes in scale reflect transitions between the controlling influences of one environmental factor or process over another. In an effort to find linkages between Steller sea lions (Eumetopias jubatus) and their environment, the objective of this study was to determine if the spatial distribution of Steller sea lions at sea displayed similar scaling properties to the variation of two environmental features, including bathymetry and sea surface temperature (SST). Additionally, distributions of Steller sea lion point patterns were examined with respect to measurements of bathymetric complexity. From February 2000 to May 2004, satellite transmitters were deployed on 10 groups of juvenile Steller sea lions (n=52) at eight different locations within the Aleutian Islands and Gulf of Alaska. Indices of fractal dimension were calculated for each group of sea lions using a unit square box-counting method, whereas indices of bathymetry and SST patchiness were derived by conducting a variance ratio analysis over the same scales. Distributions of Steller sea lions at sea displayed self-similar fractal patterns, suggesting that individuals were distributed in a continuous hierarchical set of clumps within clumps across scales, and foraging behavior was likely influenced by a scale invariant mechanism. Patterns of bathymetric variability also were self-similar, whereas patterns of SST variability were scale dependent and failed to retain self-similar spatial structure at larger scales. These results indicate that the distributions of Steller sea lions at sea were more influenced by bathymetry than SST at the scales examined, but scale dependent patterns in the distribution of Steller sea lions at sea or linkages with SST may have been apparent if analyses were conducted at finer spatial scales. PMID- 21241712 TI - Synchronized reproduction promotes species coexistence through reproductive facilitation. AB - Theories for species coexistence often emphasize niche differentiation and temporal segregation of recruitment to avoid competition. Recent work on mutualism suggested that plant species sharing pollinators provide mutual facilitation when exhibit synchronized reproduction. The facilitation on reproduction may enhance species persistence and coexistence. Theoretical ecologists paid little attention to such indirect mutualistic systems by far. We propose a new model for a two-species system using difference equations. The model focuses on adult plants and assumes no resource competition between these well-established individuals. Our formulas include demographic parameters, such as mortality and recruitment rates, and functions of reproductive facilitation. Both recruitment and facilitation effects reach saturation levels when flower production is at high levels. We conduct mathematical analyses to assess conditions of coexistence. We establish demographical conditions permitting species coexistence. Our analyses suggest a "rescue" effect from a "superior" species to a "weaker" species under strong recruitment enhancement effect when the later is not self-sustainable. The facilitation on rare species may help to overcome Allee effect. PMID- 21241713 TI - Fluid mechanics in the perivascular space. AB - Perivascular space (PVS) within the brain is an important pathway for interstitial fluid (ISF) and solute transport. Fluid flowing in the PVS can affect these transport processes and has significant impacts on physiology. In this paper, we carry out a theoretical analysis to investigate the fluid mechanics in the PVS. With certain assumptions and approximations, we are able to find an analytical solution to the problem. We discuss the physical meanings of the solution and particularly examine the consequences of the induced fluid flow in the context of convection-enhanced delivery (CED). We conclude that peristaltic motions of the blood vessel walls can facilitate fluid and solute transport in the PVS. PMID- 21241714 TI - Prevention of diabetic nephropathy in rats through enhanced renal antioxidative capacity by inhibition of the proteasome. AB - AIMS: Oxidative stress may play an important role in the pathogenesis of diabetic nephropathy (DN). Recent studies have shown that the ubiquitin-proteasome pathway (UPP) and oxidative stress have interaction. We aimed to investigate whether inhibiting the proteasome has a preventive effect on DN through suppression of renal oxidative stress. MAIN METHODS: Male Sprague-Dawley rats were randomly divided into three groups: a normal control (NC) group, a streptozotocin-induced DN model group, and a DN plus MG132 (10 MUg/kg) treatment group. KEY FINDINGS: Increased 24-h urinary protein excretion rate (UPER) and renal pathological changes were all improved after MG132 administration. Furthermore, enhanced renal 26S proteasome activity and concentration in DN rats were effectively reduced after MG132 administration. Increased p47phox and nitrotyrosine (NT) expressions in kidneys of DN rats were decreased after MG132 treatment. Renal mRNA and protein expressions of NF-E2 related factor 2 (Nrf2) were up-regulated by MG132 in comparison to DN alone. Decreased renal mRNA expression of superoxide dismutase 1 (SOD1), catalase (CAT) and glutathione peroxidase (GPx) in DN rats was heightened after MG132 intervention. Depressed activities of renal SOD, CAT and GPx in DN rats were also improved by MG132 treatment. Increased renal nuclear factor kappaB (NF-kappaB) activity was inhibited after MG132 administration in DN rats at the end of 12 weeks. SIGNIFICANCE: Our present data suggest that inhibition of the proteasome by low-dose MG132 has a preventive effect on DN development and progression in rats through the up-regulation of antioxidant genes. PMID- 21241715 TI - Heat shock enhances CMV-IE promoter-driven metabotropic glutamate receptor expression and toxicity in transfected cells. AB - In CHO-K1 cells, heat shock strongly activated reporter-gene expression driven by the cytomegalovirus immediate-early (CMV-IE) promoter from adenoviral and plasmid vectors. Heat shock treatment (2h at 42.5 degrees C) significantly enhanced the promoter DNA-binding activity in nuclear extracts. In CHO cells expressing mGluR1a and mGluR5a receptors under the control of the CMV promoter, heat shock increased receptor protein expression, mRNA levels and receptor function estimated by measurement of PI hydrolysis, intracellular Ca2+ and cAMP. Hyperthermia increased average amplitudes of Ca2+ responses, the number of responding cells, and revealed the toxic properties of mGluR1a receptor. Heat shock also effectively increased the expression of EGFP. Hence, heat shock effects on mGluR expression and function in CHO cells may be attributed to the activation of the CMV promoter. Moreover, this effect was not limited to CHO cells as heat shock also increased EGFP expression in PC-12 and HEK293 cells. Heat shock treatment may be a useful tool to study the function of proteins expressed in heterologous systems under control of the CMV promoter. It may be especially valuable for increasing protein expression in transient transfections, for enhancing receptor expression in drug screening applications and to control the expression of proteins endowed with toxic properties. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 21241716 TI - The space of affordances: a TMS study. AB - Previous studies have shown a motor recruitment during the observation of graspable objects. This recruitment has been considered crucial in encoding the observed objects in terms of one or more potential motor acts. However, an agent can actually act upon an object only when the latter is close enough to be reached. Thus, the question we deal with in this paper is whether the motor system is always activated whenever a graspable object comes into view or whether it requires the object to be located within the reachable space of the perceiver. The left primary motor cortex was magnetically stimulated and motor evoked potentials (MEPs) were recorded while participants observed graspable and non graspable objects located within or outside their own reachable space. We found higher MEPs during the observation of graspable objects falling within the reachable space compared to the observation of either a non graspable object or a graspable object falling outside the reachable space. Our results shed new light on the functional role of the motor system in encoding visually presented objects. Indeed, they clearly indicate that its recruitment is spatially constrained, as it depends on whether the object falls within the actual reaching space of the onlooker. PMID- 21241717 TI - The neural correlates of impaired inhibitory control in anxiety. AB - According to Attentional Control Theory (Eysenck et al., 2007) anxiety impairs the inhibition function of working memory by increasing the influence of stimulus driven processes over efficient top-down control. We investigated the neural correlates of impaired inhibitory control in anxiety using an antisaccade task. Low- and high-anxious participants performed anti- and prosaccade tasks and electrophysiological activity was recorded. Consistent with previous research high-anxious individuals had longer antisaccade latencies in response to the to be-inhibited target, compared with low-anxious individuals. Central to our predictions, high-anxious individuals showed lower ERP activity, at frontocentral and central recording sites, than low anxious individuals, in the period immediately prior to onset of the to-be-inhibited target on correct antisaccade trials. Our findings indicate that anxiety interferes with the efficient recruitment of top-down mechanisms required for the suppression of prepotent responses. Implications are discussed within current models of attentional control in anxiety (Bishop, 2009; Eysenck et al., 2007). PMID- 21241718 TI - Neural correlates of language comprehension in autism spectrum disorders: when language conflicts with world knowledge. AB - In individuals with ASD, difficulties with language comprehension are most evident when higher-level semantic-pragmatic language processing is required, for instance when context has to be used to interpret the meaning of an utterance. Until now, it is unclear at what level of processing and for what type of context these difficulties in language comprehension occur. Therefore, in the current fMRI study, we investigated the neural correlates of the integration of contextual information during auditory language comprehension in 24 adults with ASD and 24 matched control participants. Different levels of context processing were manipulated by using spoken sentences that were correct or contained either a semantic or world knowledge anomaly. Our findings demonstrated significant differences between the groups in inferior frontal cortex that were only present for sentences with a world knowledge anomaly. Relative to the ASD group, the control group showed significantly increased activation in left inferior frontal gyrus (LIFG) for sentences with a world knowledge anomaly compared to correct sentences. This effect possibly indicates reduced integrative capacities of the ASD group. Furthermore, world knowledge anomalies elicited significantly stronger activation in right inferior frontal gyrus (RIFG) in the control group compared to the ASD group. This additional RIFG activation probably reflects revision of the situation model after new, conflicting information. The lack of recruitment of RIFG is possibly related to difficulties with exception handling in the ASD group. PMID- 21241719 TI - Attentional modulation of external speech attribution in patients with hallucinations and delusions. AB - A range of psychological theories have been proposed to account for the experience of auditory hallucinations and delusions in schizophrenic patients. Most influential theories are those implicating the defective self-monitoring of inner speech. Some recent studies measured response bias independently of self monitoring and found the results inconsistent with the defective self-monitoring model, but explained by an externalizing response bias. We aimed to investigate the role of attentional bias in external misattribution of source by modulating participant's endogenous expectancies. Comparisons were made between patients with paranoid schizophrenia (N=23) and matched healthy controls (N=23) who participated in two different versions of an audio-visual task, which differed based upon level of the cue predictiveness. The acoustic characteristic of voice was altered in half of the trials by shifting the pitch (distortion). Participants passively listened to recordings of single adjectives spoken in their own and another person's voice (alien) preceded by their own or another person's (alien) face and made self/non self judgments about the source. The patients showed increased error rates comparing to controls, when listening to the distorted self spoken words, misidentifying their own speech as produced by others. Importantly, patients made significantly more errors across all the invalid cue conditions. This suggests not only the presence of pathological misattribution bias, but also an inadequate balance between top-down and bottom up attentional processes in the patients, which could be responsible for misattribution of the ambiguous sensory material. PMID- 21241720 TI - Tool use and action planning in apraxia. AB - Apraxia after left inferior parietal lesions has been widely interpreted as evidence of damage or impaired access to representations of tool-use, but most research has investigated pantomime of tool actions, not handling of actual tools. An alternative account is that inferior parietal damage does not affect tool-use representations but impairs cognitive processing about postural and hand tool spatial relationships which is necessary for planning and controlling any complex action. Four apraxic patients and 10 age-matched controls were asked to reach rapidly for tools or abstract objects of similar dimensions. Under conditions of time pressure and divided attention, the patients frequently failed to invert the hand to grasp inverted tools by the handle, whereas ability to invert the hand to avoid a barrier and grasp abstract objects was largely unimpaired. Frequency of errors in tool grasping correlated with severity of apraxia. When inverted tools were correctly grasped, rotation of the wrist occurred later during the reaching movement than when inverting the hand to grasp an abstract object. These data are consistent with the theory of degraded access to tool-use representations in apraxia, but this theory cannot account for co occurring deficits in imitating or matching meaningless hand or body postures. PMID- 21241721 TI - Functional connectivity during top-down modulation of visual short-term memory representations. AB - Recent evidence has revealed that short-lived internal representations held in visual short-term memory (VSTM) can be modulated by top-down control via retrospective attention which impacts subsequent behavioral performance. However, the functional inter-regional interactions underlying these top-down modulatory effects are not fully characterized. Here we used event-related functional magnetic imaging to investigate whether the strength of functional connectivity between the frontal cortex and posterior visual areas varies with the efficacy of top-down modulation of memory traces. Top-down modulation was manipulated by the timing of retro-cuing (early or late) in a VSTM task. Univariate analyses revealed that more effective top-down modulation (early cueing vs. late cueing) increased activity in early visual areas. Importantly, coherency analyses revealed that top-down modulation produced stronger functional connectivity between frontal and posterior occipital regions. Also, participants with stronger functional connectivity exhibit better memory performance. These results suggest that augmented functional connectivity between frontal and posterior visual areas strengthens the VSTM representations of importance to behavioral goals. PMID- 21241722 TI - When Pinocchio acts like a human, a wooden hand becomes embodied. Action co representation for non-biological agents. AB - Action observation automatically activates corresponding motor representations in the observer, which is essential in coordinating actions with others. It is assumed that this co-representation system is activated by biological agents only. However, we often identify with biological agents, whereas this is not the case for non-biological agents. The present study investigated whether action co representation depends on the perceived animacy of the non-biological interaction partner. Before performing a joint Simon task with either an animated image of a human or a wooden hand, participants either watched a video fragment of a biological agent, or of a non-biological agent, Pinocchio, to increase perceived animacy of this agent. Whereas participants who watched the 'biological' agent showed a Simon effect only when co-acting with a biological agent, participants who watched 'non-biological' agent (i.e. Pinocchio) showed a Simon effect only when co-acting with a non-biological agent. The present findings provide evidence for the assumption that motor simulation strongly depends on higher order processes. PMID- 21241724 TI - Involvement of the ventral tegmental area in the inhibitory avoidance memory in rats. AB - The ventral tegmental area (VTA) is a neural structure that sends strong efferent projections to the hippocampus. Output from the VTA can affect hippocampal dependent neural processes that are critical for learning and memory, including long term potentiation and theta activity. However, no study to date has elucidated what role the VTA plays in mediating the different stages of learning and memory. Therefore, the current study was designed to assess how reversible inactivation of the VTA may affect the acquisition, consolidation and retrieval of memory in rats using an inhibitory avoidance (IA) task. In this experiment, rats with chronically implanted cannulae aimed at the VTA were trained on an inhibitory avoidance task. They received intra-VTA infusions of lidocaine or saline immediately before training, after training or before a memory retention test. The results indicate that inactivation of the VTA prior to the first acquisition session increased the number of trials rats required to reach the acquisition criterion. Similarly, inactivation of the VTA after acquisition training decreased the step-through latency and increased the amount of time spent in the dark compartment relative to the saline-treated group. However, inactivation of the VTA immediately prior to the memory retention test failed to alter either step-through latency or the amount of time spent in the dark compartment. Overall, these results suggest the VTA facilitates the acquisition and consolidation of IA learning and memory. PMID- 21241725 TI - The impact of maternal cafeteria diet on anxiety-related behaviour and exploration in the offspring. AB - Contemporary trends in obesity mean that research into whether unbalanced diets could impact on behavioural traits became increasingly important. The timing of exposure to obesity is particularly important, as sensitive periods during development have been identified where dietary extremes play a critical role in determining adult risk of physiological dysfunction. To this end, female Wistar rats were fed on chow or cafeteria diet (CD) for 8 weeks from weaning until mating. Half of the mated animals within each group were crossed-over to the alternative diet. This generated four treatment groups, differing in their pre gestational and gestational diets. After birth, offspring of dams from each of the 4 pregnancy groups were further divided into groups, either being fed chow or CD throughout lactation. Anxiety-related behaviour and exploration in the offspring were tested in the Elevated Plus Maze (EMP) and the Open Field (OF) at 10 weeks of age. Maternal obesity significantly reduced the EPM locomotor activity in male and female offspring and grooming in males. Lactational CD had an anxiolytic effect in male offspring as shown in the EPM (increased entries into and more time on open arms) and the OF (shorter latency to enter the centre). In both sexes, lactational CD reduced grooming upon exposure to the EPM and the OF. Post mortem analysis revealed a stimulant effect of lactational CD on adipose tissue growth. The present study demonstrates that pre-gestational, gestational and lactational maternal CD programme behaviour in the offspring with lactational CD reducing anxiety in the male offspring. PMID- 21241723 TI - Consumption of a high-fat diet induces central insulin resistance independent of adiposity. AB - Plasma insulin enters the CNS where it interacts with insulin receptors in areas that are related to energy homeostasis and elicits a decrease of food intake and body weight. Here, we demonstrate that consumption of a high-fat (HF) diet impairs the central actions of insulin. Male Long-Evans rats were given chronic (70-day) or acute (3-day) ad libitum access to HF, low-fat (LF), or chow diets. Insulin administered into the 3rd-cerebral ventricle (i3vt) decreased food intake and body weight of LF and chow rats but had no effect on HF rats in either the chronic or the acute experiment. Rats chronically pair-fed the HF diet to match the caloric intake of LF rats, and with body weights and adiposity levels comparable to those of LF rats, were also unresponsive to i3vt insulin when returned to ad libitum food whereas rats pair-fed the LF diet had reduced food intake and body weight when administered i3vt insulin. Insulin's inability to reduce food intake in the presence of the high-fat diet was associated with a reduced ability of insulin to activate its signaling cascade, as measured by pAKT. Finally, i3vt administration of insulin increased hypothalamic expression of POMC mRNA in the LF- but not the HF-fed rats. We conclude that consumption of a HF diet leads to central insulin resistance following short exposure to the diet, and as demonstrated by reductions in insulin signaling and insulin-induced hypothalamic expression of POMC mRNA. PMID- 21241726 TI - Stress augments food 'wanting' and energy intake in visceral overweight subjects in the absence of hunger. AB - Stress may induce eating in the absence of hunger, possibly involving changes in food reward, i.e. 'liking' and 'wanting'. The objective of this study was to assess the effects of acute psychological stress on food reward, and on energy intake, in visceral overweight (VO) vs. normal weight (NW) subjects. Subjects (27 NW, age=26 +/- 9 yrs, BMI=22 +/- 2 kg/m2; 15 VO, age=36 +/- 12 yrs, BMI=28 +/- 1 kg/m2) came to the university twice, fasted, for either a rest or stress condition (randomized cross-over design). Per test-session 'liking' and 'wanting' for 72 items divided in six categories (bread, filling, drinks, dessert, snacks, and stationery (control)) were measured twice, each time followed by a wanted meal. Appetite profile (visual analogue scales, VAS), heart rate, mood state and level of anxiety (POMS/STAI questionnaires) were measured. High hunger and low satiety (64 +/- 19, 22 +/- 20 mmVAS) confirmed the fasted state. Elevated heart rate, anger and confusion scores (p <= 0.03) confirmed the stress vs. rest condition. Consumption of the first meal decreased hunger, increased satiety, and decreased ranking of 'liking' of bread vs. increased ranking of 'liking' of the control (p<0.001). 'Wanting' for dessert and snacks, energy intake, carbohydrate and fat intake for the second meal stress vs. rest relatively increased in VO vs. decreased in NW (p<0.02). During stress vs. rest VO showed a 6 +/- 9% increase in percentage of daily energy requirements consumed over the two meals (p=0.01). To conclude, visceral overweight subjects showed stress-induced food intake in the absence of hunger, resulting in an increased energy intake. PMID- 21241727 TI - The impact of partial manganese superoxide dismutase (SOD2)-deficiency on mitochondrial oxidant stress, DNA fragmentation and liver injury during acetaminophen hepatotoxicity. AB - Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure in many countries. The mechanism of cell death is initiated by formation of a reactive metabolite that binds to mitochondrial proteins and promotes mitochondrial dysfunction and oxidant stress. Manganese superoxide dismutase (SOD2) is a critical defense enzyme located in the mitochondrial matrix. The objective of this investigation was to evaluate the functional consequences of partial SOD2-deficiency (SOD2+/-) on intracellular signaling mechanisms of necrotic cell death after APAP overdose. Treatment of C57Bl/6J wild type animals with 200mg/kg APAP resulted in liver injury as indicated by elevated plasma alanine aminotransferase activities (2870+/-180U/L) and centrilobular necrosis at 6h. In addition, increased tissue glutathione disulfide (GSSG) levels and GSSG-to GSH ratios, delayed mitochondrial GSH recovery, and increased mitochondrial protein carbonyls and nitrotyrosine protein adducts indicated mitochondrial oxidant stress. In addition, nuclear DNA fragmentation (TUNEL assay) correlated with translocation of Bax to the mitochondria and release of apoptosis-inducing factor (AIF). Furthermore, activation of c-jun-N-terminal kinase (JNK) was documented by the mitochondrial translocation of phospho-JNK. SOD2+/- mice showed 4-fold higher ALT activities and necrosis, an enhancement of all parameters of the mitochondrial oxidant stress, more AIF release and more extensive DNA fragmentation and more prolonged JNK activation. CONCLUSIONS: the impaired defense against mitochondrial superoxide formation in SOD2+/- mice prolongs JNK activation after APAP overdose and consequently further enhances the mitochondrial oxidant stress leading to exaggerated mitochondrial dysfunction, release of intermembrane proteins with nuclear DNA fragmentation and more necrosis. PMID- 21241728 TI - Health behaviors and obesity among US children with attention deficit hyperactivity disorder by gender and medication use. AB - OBJECTIVE: We examined the levels of physical activity, sedentary behaviors, and obesity among children with attention deficit hyperactivity disorder (ADHD) by gender and medication use and estimated the associations between health behaviors and obesity. METHODS: Cross-sectional analysis of children 6-17 years-old enrolled in the National Survey of Children's Health 2003 (n=66,707). Odds ratios were adjusted for multistage-sampling and survey-design effects. RESULTS: ADHD prevalence was 8.6%. In general, children with ADHD engaged in less physical activity, organized sports, and reading than their counterparts. Children with ADHD had increased risk of obesity for boys [24.9% vs. 21.6%, OR(95% CI): 1.42(1.13-1.77)] and girls [21.9% vs. 16%, 1.85(1.26-2.73)], if not medicated. Only girls with ADHD and not on medication were more likely to have higher media time (52.7% vs. 42%) and this was associated with higher odds for obesity [27.7% vs. 19.5%, 2.51 (1.24-5.08)]. Children with ADHD on medication had higher prevalence of depression than those not taking medication [boys: 29.5% vs. 26.3%; girls: 30.9% vs. 23.6%] and the odds of being depressed remained significant after controlling for obesity [boys: 1.45 (1.09-1.94); girls: 2.27 (1.48-3.49)]. CONCLUSIONS: Health promotion and obesity prevention programs targeting children with ADHD should take gender and medication use into consideration. PMID- 21241729 TI - Sensing disease and danger: a survey of vertebrate PRRs and their origins. AB - A key facet of the innate immune response lays in its ability to recognize and respond to invading microorganisms and cellular disturbances. Through the use of germ-line encoded PRRs, the innate immune system is capable of detecting invariant pathogen motifs termed pathogen-associated molecular patterns (PAMPS) that are distinct from host encoded proteins or products released from dying cells, which are known as damage-associated molecular patterns (DAMPs). PAMPs and DAMPs include both protein and nucleic acids for the detection and response to pathogens and metabolic "danger" signals. This is by far one of the most active areas of research as recent studies have shown retinoic acid inducible gene 1 (RIG1)-like receptors (RLRs), the nucleotide-binding domain, leucine-rich repeat containing proteins (NLRs) and Toll-like receptors (TLRs) and the recently described AIM-like receptors (ALRs) are responsible for initiating interferon production or the assembly and activation of the inflammasome, ultimately resulting in the release of bioactive IL-1 family members. Overall, the vertebrate PRR recognition machinery consists of seven domains (e.g., Death, NACHT, CARD, TIR, LRR, PYD, helicase), most of which can be traced to the very origins of the deuterostomes. This review is intended to provide an overview of the basic components that are used by vertebrates to detect and respond to pathogens, with an emphasis on these receptors in fish as well as a brief note on their likely origins. PMID- 21241730 TI - Expression of perforin-granzyme pathway genes in the bursa of infectious bursal disease virus-infected chickens. AB - Infectious bursal disease (IBD) is an economically important immunosuppressive disease of chickens. The IBD virus (IBDV) actively replicates in B cells and causes severe bursal damage. Generally, T cells are refractory to infection with IBDV but are known to promote virus clearance. However, the mechanisms of T cell mediated viral clearance are not well understood. In this study, we evaluated the molecular mechanisms of cytotoxic T cell responses in the pathogenesis of IBD in chickens. Infection of chickens with IBDV was accompanied by the infiltration of CD4(+) and CD8(+) T cells in the bursa. There was an upregulation in the gene expression of important cytolytic molecules; perforin (PFN), granzyme-A (Gzm-A), DNA repair and apoptotic proteins; high mobility proteins group (HMG) and poly (ADP-ribose) polymerase (PARP) in the bursa of Fabricius (BF) whereas expression of NK (natural killer) lysin was downregulated. Importantly, PFN producing CD4(+) and CD8(+) T cells were also detected in the bursa of IBDV-infected chickens by immunohistochemistry. The Th1 cytokines, IL-2 and IFN-gamma expression was also strongly upregulated, suggesting the activation of T cells. The findings of this study highlight the mechanisms of IBD pathogenesis and the role of cytotoxic T cells in the clearance of virus-infected cells. PMID- 21241731 TI - HPV16/18 L1 VLP vaccine induces cross-neutralizing antibodies that may mediate cross-protection. AB - Human papillomavirus (HPV) L1 VLP-based vaccines are protective against HPV vaccine-related types; however, the correlates of protection have not been defined. We observed that vaccination with CervarixTM induced cross-neutralizing antibodies for HPV types for which evidence of vaccine efficacy has been demonstrated (HPV31/45) but not for other types (HPV52/58). In addition, HPV31/45 cross-neutralizing titers showed a significant increase with number of doses (HPV31, p<0.001; HPV45, p<0.001) and correlated with HPV16/18 neutralizing titers, respectively. These findings raise the possibility that cross neutralizing antibodies are effectors of cross-protection observed for the HPV16/18 vaccine. PMID- 21241732 TI - Preclinical evaluation of HIV-1 therapeutic ex vivo dendritic cell vaccines expressing consensus Gag antigens and conserved Gag epitopes. AB - BACKGROUND: Dendritic cell (DC) therapy is a promising technology for the treatment of HIV infected individuals. HIV-1 Gag- and Nef RNA-loaded DC have previously been shown to induce immune responses ex vivo following coculture with autologous lymphocytes. However, polyfunctionality and memory responses following coculture have not been evaluated. In addition, little is known regarding whether specific HIV-1 proteome components, such as highly conserved regions of the HIV 1, could enhance clinical responses following DC therapy. METHODOLOGY AND PRINCIPAL FINDINGS: To determine the breadth of the immune responses to antigen loaded DC, we analyzed polyfunctional T cell response ex vivo to Gag RNA loaded DC. Blood samples were used to generate monocyte derived DC, which were then matured and cocultured with autologous lymphocytes. We found that cytokine matured DC loaded with Gag RNA was able to induce Gag-specific IFN-gamma and IL-2 responses after a 12-day coculture. We characterized these responses by polyfunctional intracellular cytokine staining and evaluation of T cell memory phenotypes. Central memory CD8+ T cells were induced ex vivo after DC coculture from each of 3 patients, and the effector memory pool was increased by DC coculture from 2 patients. We also observed a decrease in the terminal effector and intermediate CD8+ T cell pool and an increase in the naive/other population. There was a reduction in terminal effector and intermediate CD4+ T cells, and a corresponding increase in naive/other CD4+ T cells. Finally, we evaluated conserved regions of Gag as a novel DC therapy immunogen and found that a conserved element (CE) p24 Gag antigen elicited IFN-gamma and IL-2 responses comparable to those induced by a full-length Gag antigen. CONCLUSIONS: We showed that RNA-loaded DC therapy induced a polyfunctional T cell response ex vivo, supporting the use of such DC-therapy for HIV infection. However, the central and effector memory phenotypes of T cells did not appear to be enhanced during coculture with Gag RNA-loaded DC. Furthermore, comparable antigen-specific responses were induced in HIV infected individuals using full-length Gag or only conserved elements of the Gag p24 protein. This indicates that immune responses can be focused onto the conserved elements of Gag in the absence of other Gag components. PMID- 21241733 TI - Projected health benefits and costs of pneumococcal and rotavirus vaccination in Uganda. AB - We determined impact and cost-effectiveness of pneumococcal and rotavirus vaccination programs among children<5 years of age in Uganda from the public health system perspective. Disease-specific models compared the disease burden and cost with and without a vaccination program. If introduced, pneumococcal and rotavirus vaccine programs will save 10,796 and 5265 lives, respectively, prevent 94,071 Streptococcus pneumoniae and 94,729 rotavirus cases in children<5 years, and save 3886 and 996 million Ugandan shillings ($2.3 and $0.6 million US dollars), respectively, in direct medical costs annually. At the GAVI price ($0.15/dose), pneumococcal vaccine will be cost-saving and rotavirus vaccine highly cost-effective. PMID- 21241734 TI - Cooperative serum bactericidal activity between human antibodies to meningococcal factor H binding protein and neisserial heparin binding antigen. AB - A meningococcal group B vaccine containing multiple protein antigens including factor H binding protein (fHbp) and Neisserial heparin binding antigen (NHba) is in clinical development. The ability of antibodies against individual antigens to interact and augment protective immunity is unknown. We assayed human complement mediated bactericidal activity (SBA) in stored sera from six immunized adults before and after depletion of antibodies to fHbp and/or NHba. All six subjects developed >= 4-fold increases in SBA titer against a test strain with fHbp in the variant 1 group with an amino acid sequence that matched the vaccine antigen (GMT <1:4 baseline, to 1:139 after 3 doses of vaccine). By adsorption 88 to >95% of the SBA was directed against fHbp. Four subjects developed >= 4-fold increases in SBA titer against a test strain with a heterologous fHbp variant 2 antigen and a homologous NHba amino acid sequence that matched the vaccine antigen (GMT <1:4 baseline, to 1:45). SBA was directed primarily against NHba in one subject, against fHbp in a second, while depletion of either anti-NHba or anti-fHbp antibody removed the majority of SBA in sera from two subjects. In all four subjects, depletion of both anti-fHbp and anti-NHba antibodies removed more SBA than depletion of either antibody individually. Mixing a mouse non-bactericidal anti-fHbp variant 1 antiserum with a mouse anti-NHba antiserum also augmented the anti-NHba SBA titer against this test strain. For meningococcal vaccines that target relatively sparsely exposed antigens such fHbp or NHba, non-bactericidal antibodies against individual antigens can cooperate and elicit SBA. PMID- 21241735 TI - HIV vaccine trial willingness among injection and non-injection drug users in two urban centres, Barcelona and San Francisco. AB - Being able to recruit high-risk volunteers who are also willing to consider future participation in vaccine trials are critical features of vaccine preparedness studies. We described data from two cohorts of injection- and non injection drug users in Barcelona, Spain [Red Cross centre] and in San Francisco, USA, [UFO-VAX study] at high risk of HIV/HCV infection to assess behaviour risk exposure and willingness to participate in future preventive HIV vaccine trials. We successfully identified drug-using populations that would be eligible for future HIV vaccine efficacy trials, based on reported levels of risk during screening and high levels of willingness to participate. In both groups, Red Cross and UFO-VAX respectively, HCV infection was highly prevalent at baseline (41% and 34%), HIV baseline seroprevalence was 4.2% and 1.5%, and high levels of willingness were seen (83% and 78%). PMID- 21241736 TI - Affective neuroscientific and neuropsychoanalytic approaches to two intractable psychiatric problems: why depression feels so bad and what addicts really want. AB - The affective foundations of depression and addictions are discussed from a cross species - animal to human - perspective of translational psychiatric research. Depression is hypothesized to arise from an evolutionarily conserved mechanism to terminate protracted activation of separation-distress (PANIC/GRIEF) systems of the brain, a shutdown mechanism which may be in part mediated by down-regulation of dopamine based reward-SEEKING resources. This shutdown of the brain's core motivational machinery is organized by shifts in multiple peptide systems, particularly increased dynorphin (kappa opioids). Addictions are conceived to be primarily mediated by obsessive behaviors sustained by reward-SEEKING circuits in the case of psychostimulant abuse, and also powerful consummatory-PLEASURE responses in the case of opioid abuse, which in turn capture SEEKING circuits. Both forms of addiction, as well as others, eventually deplete reward-SEEKING resources, leading to a state of dysphoria which can only temporarily be reversed by drugs of abuse, thereby promoting a negative affect that sustains addictive cycles. In other words, the opponent affective process - the dysphoria of diminished SEEKING resources - that can be aroused by sustained over-arousal of separation-distress (PANIC/GRIEF) as well as direct pharmacological over stimulation and depletion of SEEKING resources, may be a common denominator for the genesis of both depression and addiction. Envisioning the foundation of such psychiatric problems as being in imbalances of the basic mammalian emotional systems that engender prototype affective states may provide more robust translational research strategies, coordinated with, rather than simply focusing on, the underlying molecular dynamics. Emotional vocalizations might be one of the best ways to monitor the underlying affective dynamics in commonly used rodent models of psychiatric disorders. PMID- 21241737 TI - Mefloquine neurotoxicity is mediated by non-receptor tyrosine kinase. AB - Among several available antimalarial drugs, mefloquine has proven to be effective against drug-resistant Plasmodium falciparum and remains the drug of choice for both therapy and chemoprophylaxis. However, mefloquine is known to cause adverse neurological and/or psychiatric symptoms, which offset its therapeutic advantage. The exact mechanisms leading to the adverse neurological effects of mefloquine are poorly defined. Alterations in neurotransmitter release and calcium homeostasis, the inhibition of cholinesterases and the interaction with adenosine A(2A) receptors have been hypothesized to play prominent roles in mediating the deleterious effects of this drug. Our recent data have established that mefloquine can also trigger oxidative damage and subsequent neurodegeneration in rat cortical primary neurons. Furthermore, we have utilized a system biology centered approach and have constructed a pathway model of cellular responses to mefloquine, identifying non-receptor tyrosine kinase 2 (Pyk2) as a critical target in mediating mefloquine neurotoxicity. In this study, we sought to establish an experimental validation of Pyk2 using gene-silencing techniques (siRNA). We have examined whether the downregulation of Pyk2 in primary rat cortical neurons alters mefloquine neurotoxicity by evaluating cell viability, apoptosis and oxidative stress. Results from our study have confirmed that mefloquine neurotoxicity is associated with apoptotic response and oxidative injury, and we have demonstrated that mefloquine affects primary rat cortical neurons, at least in part, via Pyk2. The implication of these findings may prove beneficial in suppressing the neurological side effects of mefloquine and developing effective therapeutic modalities to offset its adverse effects. PMID- 21241738 TI - Dichlorvos-induced central apnea: effects of selective brainstem exposure in the rat. AB - The area of the brain responsible for organophosphate (OP)-induced central apnea is unknown. Automatic breathing is governed by circuits in the medulla and pons. Respiratory-related neurons in the brainstem are concentrated in a few areas, including ventral regions of the medulla, which contains a number of sites critical for respiratory rhythmogenesis, including the pre-Botzinger complex (preBotC). The preBotC contains cholinergic receptors, making it a candidate site of action for the apnea-inducing effect of OP. We analyzed respiratory output during a series of experiments using both intact and reduced Wistar rat preparations exposed to dichlorvos (2,2-dichlorovinyl dimethyl phosphate). Exposure of the brainstem using a working heart-brainstem preparation resulted in a central apnea similar to that seen in intact animal models. In contrast, microdialysis of locally toxic doses of dichlorvos to the ventral region of the medulla resulted in delayed and mild respiratory depression in most animals and apnea in only 29% of the animals. We conclude that exposure of the entire brainstem to OP is sufficient to induce central apnea. Our microdialysis experiments suggest that the neural substrate for OP-induced central apnea involves a specific brainstem site other than the ventral region of the medulla, or apnea might result from a distributed effect involving cholinergic toxicities of multiple brainstem sites. PMID- 21241739 TI - Effect of chloramine-T on long-term potentiation at synapses between perforant path and dentate gyrus in hippocampus of rats in vivo. AB - Reactive oxygen species (ROS), including superoxide, are generally considered as neurotoxic molecules whose effects can be alleviated by antioxidant enzymes. However, ROS also are known to be necessary components of the signal transduction cascades underlying normal synaptic plasticity. The oxidant chloramine-T (Ch-T), a specific oxidant to sulphur-containing residues, can oxidize methionine (Met) residues in proteins to alter protein function. To investigate the effect of Ch-T on the induction of hippocampal long-term potentiation (LTP) in dentate gyrus (DG), in vivo electrophysiological recording was employed. It was found that intracerebroventricular (ICV) injection of 0.1 MUM Ch-T in 5 MUL enhanced hippocampal LTP of rats slightly, whereas, 20 mM Ch-T in 5 MUL greatly attenuated LTP. These effects can be reversed by pretreatment with 0.1 mM dithiothretol (DTT), a special thiol reductant. In addition, 0.1 MUM Ch-T elevated LTP-induced increase in phosphorylation of Ca2+/calmodulin (CaM)-dependent protein kinase (CaMKII) and neurogranin (Ng), whereas 2 MUM and 20 mM Ch-T reduced LTP-induced increase in phosphorylation status of the two key proteins, especially for 20 mM Ch-T. Pretreatment with DTT significantly prevented these effects. Taken together, these findings demonstrated that Ch-T has concentration-dependent effects on the induction of hippocampal LTP in vivo. In brief, low concentration of Ch-T facilitated hippocampal LTP by enhancing LTP-induced increase in p-CaMKII and p-Ng compared to controls, whereas high concentration of Ch-T obviously attenuated LTP accompanied by a decrease in the phosphorylated proteins, and both of these effects can be prevented by DTT. These results indicate that Ch-T modulates hippocampal LTP through regulating phosphorylation status of CaMKII and Ng. PMID- 21241740 TI - Human leukocyte antigen class I and class II genes polymorphisms might be associated with interferon alpha therapy efficiency of chronic hepatitis B. AB - Certain host genetic polymorphisms in human leukocyte antigen (HLA) genes are reported to be associated with response to interferon alpha (IFNalpha) therapy. Two hundred and eighteen IFNalpha treatment-naive chronic hepatitis B (CHB) patients were enrolled in the present study. HLA-A, B, C and DQA1, DQB1, DRB1 gene alleles were detected by polymerase chain reaction-sequencing based typing (PCR-SBT) and PCR-sequence specific primer (PCR-SSP), respectively. Frequencies of HLA-DQB1*0303 and DRB1*08 in response group were clearly lower than those in nonresponse group (P=0.019, OR=1.81, 95%CI=1.07-3.15; P=0.031, OR=2.43, 95%CI=1.02-5.98, respectively). Frequencies of haplotype *1101-*4601-*0102 (HLA A, B, C) and haplotype *0302-*0303-*09 (HLA-DQA1, DQB1, DRB1) were clearly lower than those in nonresponse group (P=0.009, OR=4.84, 95%CI=1.29-19.48; P=0.031, OR=1.94, 95%CI=1.01-3.73, respectively). These results suggest that patients with HLA-DQB1*0303 or DRB1*08 alleles, and haplotype *1101-*4601-*0102 (HLA-A, B, C) or haplotype *0302-*0303-*09 (HLA-DQA1, DQB1, DRB1), might be less responsive to IFNalpha treatment. PMID- 21241741 TI - Rana catesbeiana ribonuclease inhibits Japanese encephalitis virus (JEV) replication and enhances apoptosis of JEV-infected BHK-21 cells. AB - Rana catesbeiana ribonuclease (RC-RNase) is a cytotoxic and antitumor RNase isolated from the oocyte yolk granules of the bullfrog R. catesbeiana. Our previous studies have shown that RC-RNase possesses antitumor activity by activating proapoptotic caspases. Here, we demonstrate that RC-RNase also possesses antiviral activity. By using cell viability and caspase activation assays, we show that RC-RNase largely enhances apoptosis of Japanese encephalitis virus (JEV)-infected BHK-21 cells by activating caspase-3, caspase-8, and caspase 9. In addition, immunoblotting experiments revealed that JEV infection enhances the internalization of RC-RNase by cells. In sum, these results indicate that RC RNase provides a beneficial effect on JEV-infected cells by enhancing apoptosis. PMID- 21241742 TI - Lithium chloride disrupts consolidation of morphine-induced conditioned place preference in male mice: the nitric oxide/cyclic GMP signaling pathway. AB - Lithium effects on brain functions such as cognition, attention, learning and memory are well-established for ages; however, the way it affects these functions and its precise mechanism of action remains unknown. The purpose of this study was to determine the effects of lithium on the consolidation of morphine associated conditioned place preference and the possible involvement of the NO/cGMP pathway. Using an unbiased conditioned place preference (CPP) model, the effects of lithium (1-100 mg/kg, i.p.), nitric oxide synthase inhibitor NG-nitro L-arginine methyl ester (L-NAME) (5-100 mg/kg, i.p.), nitric oxide precursor L arginine (50-150 mg/kg, i.p.) and phosphodiesterase inhibitor sildenafil (5-40 mg/kg, i.p.) on the consolidation of morphine-induced CPP were assessed. In addition, the possible interaction between lithium, L-arginine and sildenafil or subeffective doses of lithium and L-NAME on the consolidation of morphine-induced contextual memory was evaluated. NMRI mice were used in all studies. Lithium (5 30 mg/kg, i.p.), immediately after conditioning trials, significantly reduced the time spent by mice in the reward-paired compartment. Although post-training administration of L-arginine, sildenafil or L-NAME had no significant effect on the consolidation of CPP, concomitant administration of L-arginine (50-150 mg/kg) and sildenafil (5-10 mg/kg) with lithium (30 mg/kg) prevented the impairing effect of lithium. Also, co-administration of sub-effective doses of lithium (1 mg/kg) and L-NAME (5 mg/kg) disrupted consolidation of CPP. However, delayed administration of effective doses of lithium, which shows specific effect on memory consolidation, did not affect morphine-induced CPP. Lithium seems to inhibit consolidation of morphine-induced CPP and this impairing effect might be via nitric oxide/cyclic GMP pathway. PMID- 21241743 TI - Characterization of the DMAE-modified juvenile excretory-secretory protein Juv p120 of Litomosoides sigmodontis. AB - Juv-p120 is an excretory-secretory 160 kDa glycoprotein of juvenile female Litomosoides sigmodontis and exhibits features typical for mucins. 50% of its molecular mass is attributed to posttranslational modifications with the unusual substituent dimethylaminoethanol (DMAE). By that Juv-p120 corresponds to the surface proteins of the microfilarial sheath, Shp3 and Shp3a. The secreted protein consists of 697 amino acids, organized in two different domains of repeat elements separated by a stretch of polar residues. The N-terminal domain shows fourteen P/S/T/F-rich repeat elements highly modified with phospho-DMAE substituted O-glycans confering a negative charge to the protein. The C-terminal domain is extremely rich in glutamine (35%) and leucine (25%) in less organized repeats and may play a role in oligomerization of Juv-p120 monomers. A protein family with a similar Q/L-rich region and conserved core promoter region was identified in Brugia malayi by homology screening and in Wuchereria bancrofti and Loa loa by database similarity search. One of the Q/L-rich proteins in each genus has an extended S/T-rich region and due to this feature is supposed to be a putative Juv-p120 ortholog. The corresponding modification of Juv-p120 and the microfilarial sheath surface antigens Shp3/3a explains the appearance of anti sheath antibodies before the release of microfilariae. The function of Juv-p120 is unknown. PMID- 21241744 TI - An inverted method for culturing dissociated mouse hippocampal neurons. AB - Dissociated hippocampal neuron culture has long been the model system of choice for many neuroscientists. The ability to culture dissociated hippocampal neurons from genetically modified mice provides an invaluable tool for studying many neuronal processes. In this study, we established a novel method to culture dissociated hippocampal neurons from embryonic and neonatal mice. Dissociated neurons were cultured in a microchamber between the glass coverslip and the plastic cell container without the use of glial feeder cells. Our method significantly simplifies the preparation while produces healthy and long-lived neuronal cultures that are difficult to achieve without the use of feeder cells. PMID- 21241745 TI - A multi-channel near-infrared spectroscopy study of prefrontal cortex activation during working memory task in major depressive disorder. AB - Many neuropsychological studies demonstrate impairment of working memory in patients with major depressive disorder (MDD). However, there are not enough functional neuroimaging studies of MDD patients seeking for the underlying brain activity relevant to working memory function. The objective of this study is to evaluate prefrontal hemodynamic response related to working memory function in patients with MDD. Twenty-four subjects with MDD and 26 age- and gender-matched healthy subjects were recruited for the present study. We measured hemoglobin concentration changes in the prefrontal and superior temporal cortical surface areas during the execution of working memory task (WM; 2-back, letter version) using 52-channel near-infrared spectroscopy (NIRS), which enables real-time monitoring of task-related changes in cerebral blood volumes in the cortical surface areas. MDD patients showed a smaller increase in lateral prefrontal and superior temporal cortex activation during the 2-back task and associated poorer task performance than healthy controls. The results coincided with previous findings in terms of working memory deficits and prefrontal cortex dysfunction in MDD patients, but contradicted with some previous fMRI studies that suggested increased cortical activity during the working memory task in patients with depression. The contradiction may, in part, be explained by a relatively low level of cognitive demand imposed on the subjects in the present study. PMID- 21241746 TI - mRNA distribution of the thalidomide binding protein cereblon in adult mouse brain. AB - Cereblon is implicated in mild mental retardation and proved to bind to a teratogenic hypnotic, thalidomide. Here, we determined cereblon mRNA distributions in adult mouse brain. Almost all neurons expressed cereblon mRNA with various intensities whereas the signals in astrocytes and oligodendrocytes were modest or negligible. Intense mRNA signals were found in the hippocampus and cerebellum, especially in hippocampal pyramidal cells and Purkinje cells. Higher levels of cereblon mRNA were also detected in serotonergic and noradrenergic neurons in raphe nuclei and locus ceruleus, respectively. These observations indicate novel biological roles of cereblon in neuronal physiology and thalidomide pharmacology. PMID- 21241747 TI - Edaravone and carnosic acid synergistically enhance the expression of nerve growth factor in human astrocytes under hypoxia/reoxygenation. AB - Edaravone is a brain-penetrant free radical scavenger that is known to ameliorate postischemic neuronal dysfunction. The transcription factor Nrf2 plays an important role in the coordinated expression of stress-inducible genes. Here we examined the effects of edaravone and carnosic acid (CA), an Nrf2-inducer, on the expression of nerve growth factor (NGF) in human astrocytes exposed to hypoxia/reoxygenation. Cultured astrocytes were exposed to hypoxia for up to 4.5 h and then treated with edaravone and/or CA under normoxia (reoxygenation) for up to 72 h. Edaravone (~1 mM) and CA (~50 MUM) treatment synergistically enhanced NGF expression. Nrf2 knockdown by siRNA and the inhibition of JNK (c-Jun N terminal kinase) by SP600125 decreased both CA-induced NGF expression and Nrf2 nuclear accumulation and suppressed their synergistic effect on NGF expression. In contrast, the MEK (mitogen-activated protein kinase/extracellular signal regulated kinase kinase) inhibitor U0126 suppressed the synergism without inhibiting CA-induced NGF expression. These results suggest that the synergistic effects of CA and edaravone depend, at least partially, on JNK-dependent Nrf2 accumulation (induced by CA) and on MEK-dependent pathways (induced by edaravone). We conclude that the use of edaravone and CA in combination may have therapeutic potential in the treatment of brain damage, particularly ischemia/reperfusion injury. PMID- 21241748 TI - Molecular imaging in neuroscience research with small-animal PET in rodents. AB - Cognitive neuroscience, which studies the biological basis of mental processes, widely uses neuroimaging technologies like functional magnetic resonance imaging and positron emission tomography (PET) to study the human brain. Small laboratory animals, like rodents, are commonly used in brain research and provide abundant models of human brain diseases. The development of high-resolution small-animal PET and various radiotracers together with sophisticated methods for analyzing functional brain imaging data have accelerated research on brain function and neurotransmitter release during behavioral tasks in rodents. In this review, we first summarize advances in the methodology of cognitive research brought about by the development of sophisticated methods for whole-brain imaging analysis and improvements in neuroimaging protocols. Then, we discuss basic mechanisms related to metabolic changes and the expression of neurotransmitters in various brain areas during task-induced neural activity. In particular, we discuss glucose metabolism imaging and brain receptor imaging for various receptor systems. Finally, we discuss the current status and future perspectives. Mechanisms of neurotransmitter expression will probably become an increasingly important field of study in the future, leading to more collaboration between investigators in fields such as computational and theoretical neuroscience. PMID- 21241749 TI - A comprehensive study in triblock copolymer membrane interaction. AB - Poloxamers are triblock copolymers made of poly(ethylene glycol)-(poly(propylene glycol))-poly(ethylene glycol). They have been shown to enhance gene transfer in the muscle, and co-administration of polymers and DNA appeared to be crucial to obtain this effect. It is questionable then if some interaction occurs between polymers and DNA. Polymer interaction with membranes represents a second crucial point due to the central hydrophobic part of the triblock copolymers. Besides, the question of the polymer spanning or adsorbing to the surface has not been solved by now. We addressed these issues by means of sensitive techniques that allowed working in diluted conditions and gaining in comprehension of gene transfection. By means of simultaneous time-correlated single-photon counting and fluorescence correlation spectroscopy, we have shown that the diffusion time of a single DNA molecule and PicoGreen lifetime was not altered in the presence of the triblock copolymer L64. Polypropylene (glycol) interactions with dodecylphosphocholine micelles were shown to occur at a deep level by (1)H NMR using doxyl probes located at the head or the lipid extremity of the micelles. The polypropylene (glycol) also interacted with lipid bilayers in a manner dependent on the cholesterol content, as shown by differential scanning calorimetry using liposomes. This interaction destabilised the membrane and allowed the release of small molecules. Finally, molecular dynamic simulation of the copolymer L64 in the presence of dodecylphosphocholine showed that the hydrophobic core of the polymer formed an extremely tight cluster, whose dimensions excluded the possibility of polymer spanning across the lipidic micelles. The simulation positively correlated with the destabilising effect observed on the liposomal membrane models. PMID- 21241750 TI - Tuning core vs. shell dimensions to adjust the performance of nanoscopic containers for the loading and release of doxorubicin. AB - Detailed studies were performed to probe the effects of the core and shell dimensions of amphiphilic, shell crosslinked, knedel-like polymer nanoparticles (SCKs) on the loading and release of doxorubicin (DOX), a widely-used chemotherapy agent, in aqueous buffer, as a function of the solution pH. Effects of the nanoparticle composition were held constant, by employing SCKs constructed from a single type of amphiphilic diblock copolymer, poly(acrylic acid)-b polystyrene (PAA-b-PS). A series of four SCK nanoparticle samples, ranging in number-average hydrodynamic diameter from 14-30 nm, was prepared from four block copolymers having different relative block lengths and absolute degrees of polymerization. The ratios of acrylic acid to styrene block lengths ranged from 0.65 to 3.0, giving SCKs with ratios of shell to core volumes ranging from 0.44 to 2.1. Although the shell thicknesses were calculated to be similar (1.5-3.1 nm by transmission electron microscopy (TEM) calculations and 3.5-4.9 nm by small angle neutron scattering (SANS) analyses), two of the SCK nanoparticles had relatively large core diameters (19+/-2 and 20+/-2 nm by TEM; 17.4 and 15.3 nm by SANS), while two had similar, smaller core diameters (11+/-2 and 13+/-2 nm by TEM; 9.0 and 8.9 nm by SANS). The SCKs were capable of being loaded with 1500 9700 DOX molecules per each particle, with larger numbers of DOX molecules packaged within the larger core SCKs. Their shell-to-core volume ratio showed impact on the rates and extents of release of DOX, with the volume occupied by the poly(acrylic acid) shell relative to the volume occupied by the polystyrene core correlating inversely with the diffusion-based release of DOX. Given that the same amount of polymer was used to construct each SCK sample, SCKs having smaller cores and higher acrylic acid vs. styrene volume ratios were present at higher concentrations than were the larger core SCKs, and gave lower final extents of release., Higher final extents of release and faster rates of release were observed for all DOX-loaded particle samples at pH 5.0 vs. pH 7.4, respectively, ca. 60% vs. 40% at 60 h, suggesting promise for enhanced delivery within tumors and cells. By fitting the data to the Higuchi model, quantitative determination of the kinetics of release was made, giving rate constants ranging from 0.0431 to 0.0540 h-1/2 at pH 7.4 and 0.106 to 0.136 h-1/2 at pH 5.0. In comparison, the non-crosslinked polymer micelle analogs exhibited rate constants for release of DOX of 0.245 and 0.278 h-1/2 at pH 7.4 and 5.0, respectively. These studies point to future directions to craft sophisticated devices for controlled drug release. PMID- 21241751 TI - Mucoadhesive curcumin nanospheres: biological activity, adhesion to stomach mucosa and release of curcumin into the circulation. AB - Although mucoadhesive drug carriers for the gastro-intestinal tract (GIT) have been reported, the mucoadhesive property and drug release characteristics have never been evaluated separately, whilst the adherence of the carriers to the surface of GIT has not been directly visualized. Here, a monopolymeric carrier made from ethylcellulose (EC) and a dipolymeric carrier made from a blend of methylcellulose (MC) and EC (ECMC) were easily fabricated through a self assembling process and yielded the highest reported curcumin loading of ~48-49%. Both curcumin loaded ECMC (C-ECMC) and curcumin loaded EC (C-EC) particles showed an in vitro free radical scavenging activity and a dose-dependent in vitro cytotoxic effect towards MCF-7 human breast adenocarcinoma and HepG2 hepatoblastoma cells in tissue culture. The in vivo evaluation of their adherence to stomach mucosa and their ability to release curcumin into the circulation were carried out through quantification of curcumin levels in the stomach tissue and in blood of mice orally administered with the two spheres. Direct evidence of the adherence of the C-EC and C-ECMC particles along the mucosal epithelia of the stomach is also presented for the first time through SEM images. The mucoadhesive property of self-assembled C-EC nanoparticles is discussed. PMID- 21241752 TI - Development and characterization of Cyclosporine A loaded nanoparticles for ocular drug delivery: Cellular toxicity, uptake, and kinetic studies. AB - Dry eye syndrome is a common disorder of the tear film caused by decreased tear production or increased evaporation. The objective of this study was to evaluate the potential effectiveness of Cyclosporine A (CsA) nanoparticles (NPs) for the treatment of inflammation of the eye surface. Topical CsA is currently the only and safe pharmacologic treatment of severe dry eye symptoms. The NPs were prepared using either poly-lactide-co-glycolide (PLGA) or a mixture of PLGA with Eudragit(r)RL or were coated with Carbopol(r). The mean size of CsA loaded NPs was within the range from 148 to 219nm, except for the Carbopol(r) coated NPs (393nm). The drug entrapment efficiency was very high (from 83 to 95%) and production yield was found between 75 and 92% in all preparations. The zeta potential of the Eudragit(r) RL containing NPs was positive (19-25mV). The NPs formulations exhibited a biphasic drug release with initial burst followed by a very slow drug release and total cumulative release within 24h ranged from 75 to 90%. Kinetically, the release profiles of CsA from NPs appeared to fit best with the Weibull model. The viability of L929 cells was decreased by increasing the concentration of the various NPs examined as well as the incubation time. The amount of NPs uptake was related to the polymer type used. The highest degree of cellular uptake (52.2%), tear film concentration of the drug (366.3ng/g) and AUC(0->24) (972.6ngh/g) value were obtained from PLGA: Eudragit(r) RL (75:25)-CsA NPs formulations. The change of surface characteristics of NPs represents a useful approach for improvement of ocular retention and drug availability. PMID- 21241753 TI - Positron emission tomography imaging of the stability of Cu-64 labeled dipalmitoyl and distearoyl lipids in liposomes. AB - Changes in lipid acyl chain length can result in desorption of lipid from the liposomal anchorage and interaction with blood components. PET studies of the stability of such lipids have not been performed previously although such studies can map the pharmacokinetics of unstable lipids non-invasively in vivo. The purpose of this study was to characterize the in vivo clearance of (64)Cu-labeled distearoyl- and dipalmitoyl lipid included within long circulating liposomes. Distearoyl and dipalmitoyl maleimide lipids (1mol%) in liposomes were labeled with a (64)Cu-incorporated bifunctional chelator (TETA-PDP) after the activation of pyridine disulfide to thiol by TCEP. Long circulating liposomes containing HSPC:DSPE-PEG2k-OMe:cholesterol: x (55:5:39:1), where x was (64)Cu-DSPE or (64)Cu DPPE, or HSPC:DSPE-PEG2k-OMe:cholesterol:(64)Cu-DSPE:DPPC (54:5:39:1:1) were evaluated in serum (in vitro) and via intravenous injection to FVB mice. The time activity curves for the blood, liver, and kidney were measured from PET images and the biodistribution was performed at 48h. In vitro assays showed that (64)Cu DPPE transferred from liposomes to serum with a 7.9h half-life but (64)Cu-DSPE remained associated with the liposomes. The half clearance of radioactivity from the blood pool was 18 and 5h for (64)Cu-DSPE- and (64)Cu-DPPE liposome-injected mice, respectively. The clearance of radioactivity from the liver and kidney was significantly greater following the injection of (64)Cu-DPPE-labeled liposomes than (64)Cu-DSPE-labeled liposomes at 6, 18 and 28h. Forty eight hours after injection, the whole body radioactivity was 57 and 17% ID/cc for (64)Cu-DSPE and (64)Cu-DPPE, respectively. These findings suggest that the acyl chain length of the radiolabel should be considered for liposomal PET studies and that PET is an effective tool for evaluating the stability of nanoformulations in vivo. PMID- 21241754 TI - Viral hepatitis in solid organ transplantation other than liver. AB - Transplantation is the best treatment for end-stage organ failure. Hepatitis virus infections, mainly hepatitis B virus (HBV) and hepatitis C virus (HCV) infections still constitute a major problem because they are common in allograft recipients and are a significant cause of morbidity and mortality after transplantation. Recently, hepatitis E virus infection has been added as an emergent cause of chronic hepatitis in organ transplantation. The prevalence of HBV and HCV infections has markedly decreased in patients who are candidates for transplantation since the introduction of screening, hygiene and prevention measures, including systematic screening of blood and organ donations, use of erythropoietin, compliance with universal hygiene rules, segregation of HBV infected patients from non-infected patients and systematic vaccination against HBV. A liver biopsy is preferable to non-invasive biochemical and/or morphological tests of fibrosis to evaluate liver fibrosis before and even after transplantation. Treatment with entecavir or tenofovir is indicated in HBV infected dialyzed patients who have moderate or severe disease (>=A2 or F2 on the Metavir scale) in preparation for renal transplantation. Due to the risks of severe reactivation, fibrosing cholestatic hepatitis or histological deterioration after transplantation, systematic use of nucleoside or nucleotide analogues shortly before or at the time of transplantation is recommended (tenofovir or entecavir are preferable to lamivudine) in all patients, whatever the baseline histological evaluation. In HCV-infected dialyzed patients who are not candidates for renal transplantation, the indication for antiviral therapy is limited to significant fibrosis (fibrosis >=2 on the Metavir scale). Treatment must be proposed to all candidates for renal transplantation, whatever their baseline histopathology, and interferon-alpha should be used as monotherapy. After transplantation, interferon-alpha is contraindicated but may be used in patients for whom the benefits of antiviral treatment clearly outweigh the risks, especially that of allograft rejection. All cirrhotic patients, notably after solid organ transplantation, should be screened for hepatocellular carcinoma. Sustained suppression of necro-inflammation may result in regression of cirrhosis, which in turn may lead to decreased disease-related morbidity and improved survival. Finally, due to the high mortality after renal transplantation, active (namely without sustained viral suppression) cirrhosis should be considered a contraindication to kidney transplantation, but an indication to combined liver-kidney transplantation; on the contrary, inactive (namely with sustained viral suppression) compensated cirrhosis may permit renal transplantation alone. Organ transplantations other than kidney (cardiac or pulmonary transplantations) involve the same diagnosis and therapeutic issues. PMID- 21241755 TI - Positive regulation of hepatic miR-122 expression by HNF4alpha. AB - BACKGROUND & AIMS: miR-122 is the most abundant microRNA in the liver and regulates metabolic pathways including cholesterol biosynthesis, fatty acid synthesis, and oxidation. However, little is known about mechanisms that regulate the expression of miR-122 in the liver. The aim of this study was to identify key transcriptional regulators for miR-122 expression through intensively studying its primary transcript and promoter region. METHODS: Bioinformatics analysis, Northern blotting, RT-PCR, and 5'/3' RACE were performed to analyze miR-122 primary transcript structure, its promoter region, and potential transacting factor binding sites. Reporter gene assays integrated with truncation and site mutation in miR-122 promoter were performed to determine the trans-activation effect of HNF4alpha to miR-122-promoter in vitro. ChIP and EMSA assays were performed to determine HNF4alpha binding to miR-122 promoter. Finally, forced expression and RNAi were performed to verify the regulatory roles of HNF4 to miR 122 expression in vitro and in vivo. RESULTS: Here, we show that miR-122 is processed from a long spliced primary transcript directed by a distal upstream promoter region conserved across species. We dissected this promoter region and identified putative binding sites for liver-enriched transcriptional factors that contribute to the regulation of miR-122 expression, including a putative binding site for hepatocyte nuclear factor 4alpha (HNF4alpha). We demonstrate that HNF4alpha binds to the miR-122 promoter region through the conserved DR-I element. We observed the DR-1-element-dependent activation effect of HNF4alpha on the conserved miR-122 promoter and the activation could be further enhanced by the addition of PGC1alpha. Using overexpression and knockdown strategies, we show that HNF4alpha positively regulates miR122 expression in both Huh7 cells and the mouse liver. CONCLUSIONS: Our results suggest that HNF4alpha is a key regulator of miR-122 expression in the liver. PMID- 21241756 TI - Skin tissue engineering--in vivo and in vitro applications. AB - Significant progress has been made over the years in the development of in vitro engineered substitutes that mimic human skin, either to be used as grafts for the replacement of lost skin or for the establishment of human-based in vitro skin models. This review summarizes these advances in in vivo and in vitro applications of tissue-engineered skin. We further highlight novel efforts in the design of complex disease-in-a-dish models for studies ranging from disease etiology to drug development and screening. PMID- 21241757 TI - Regulatory systems for hypoxia-inducible gene expression in ischemic heart disease gene therapy. AB - Ischemic heart diseases are caused by narrowed coronary arteries that decrease the blood supply to the myocardium. In the ischemic myocardium, hypoxia responsive genes are up-regulated by hypoxia-inducible factor-1 (HIF-1). Gene therapy for ischemic heart diseases uses genes encoding angiogenic growth factors and anti-apoptotic proteins as therapeutic genes. These genes increase blood supply into the myocardium by angiogenesis and protect cardiomyocytes from cell death. However, non-specific expression of these genes in normal tissues may be harmful, since growth factors and anti-apoptotic proteins may induce tumor growth. Therefore, tight gene regulation is required to limit gene expression to ischemic tissues, to avoid unwanted side effects. For this purpose, various gene expression strategies have been developed for ischemic-specific gene expression. Transcriptional, post-transcriptional, and post-translational regulatory strategies have been developed and evaluated in ischemic heart disease animal models. The regulatory systems can limit therapeutic gene expression to ischemic tissues and increase the efficiency of gene therapy. In this review, recent progresses in ischemic-specific gene expression systems are presented, and their applications to ischemic heart diseases are discussed. PMID- 21241759 TI - Lessons from (patho)physiological tissue stiffness and their implications for drug screening, drug delivery and regenerative medicine. AB - Diseased tissues are noted for their compromised mechanical properties, which contribute to organ failure; regeneration entails restoration of tissue structure and thereby functions. Thus, the physical signature of a tissue is closely associated with its biological function. In this review, we consider a mechanics centric view of disease and regeneration by drawing parallels between in vivo tissue-level observations and corroborative cellular evidence in vitro to demonstrate the importance of the mechanical stiffness of the extracellular matrix in these processes. This is not intended to devalue the importance of biochemical signaling; in fact, as we discuss, many mechanical stiffness-driven processes not only require cooperation with biochemical cues, but they ultimately converge at common signaling cascades to influence cell and tissue function in an integrative manner. The study of how physical and biochemical signals collectively modulate cell function not only brings forth a more holistic understanding of cell (patho)biology, but it also creates opportunities to control material properties to improve culture platforms for research and drug screening and aid in the rationale design of biomaterials for molecular therapy and tissue engineering applications. PMID- 21241758 TI - miRNA and vascular cell movement. AB - miRNAs are a new class of endogenous small RNAs that negatively regulate gene expression at the posttranscriptional level. Accumulating experimental evidence shows that miRNAs regulate cellular apoptosis, proliferation, differentiation, and migration. Dysregulation of miRNA expression leads to various human diseases including cancer and cardiovascular disease. miRNA maturation is regulated at multiple steps by different mechanisms, including miRNA editing, hairpin loop binding, self-regulation, and cross-talk with other signaling pathways. Vascular cell movement plays a pivotal role in the development of various cancers and cardiovascular diseases. miRNAs have been found to regulate vascular cell movement. Presently the chemically synthesized antagomir and miRNA mimics have been widely used in investigating the biological functions of miRNA genes. The viral vectors, including adenoviral, lentiviral, and adeno-associated viral vectors, have been used to efficiently overexpress or knockdown miRNAs in vitro and in vivo. Therefore, targeting vascular cell movement using miRNA-based drug or gene therapy would provide a novel therapeutic approach in the treatment of cancers and vascular diseases. PMID- 21241760 TI - RNA interference therapy via functionalized scaffolds. AB - Tissue engineering aims to provide structural and biomolecular cues to compromised tissues through scaffolds. An emerging biomolecular cue is that of RNA interference by which the expression of genes can be silenced through a potent endogenous pathway. Recombinant viral-based approaches in RNAi delivery exist; however non-viral strategies offer many opportunities to exploit this mechanism of regulation in a safer way. Current RNAi therapies in clinical trials are without a vector (naked) or have slightly modified structures. Modification of these molecules with efficient backbone moieties for improved stability and potency, protecting and buffering them with delivery vehicles, and using scaffolds as reservoirs of delivery is at the frontier of current research. However, to enable an efficient sustained therapeutic effect scaffolds have a potentially significant role to play. This review presents non-viral delivery of RNAi that have been attempted via tissue engineered scaffolds. For RNAi to have a clinical impact, it is imperative to evaluate optimal delivery systems to ensure that the efficacy of this promising technology can be maximized. PMID- 21241761 TI - The association between home environmental variables and soft drink consumption among adolescents. Exploration of mediation by individual cognitions and habit strength. AB - Soft-drink consumption is one of the important target behaviours for the prevention of excessive weight gain among adolescents. To be able to modify these behaviours in obesity prevention interventions, further understanding of the underlying factors and mediational pathways is required. The present study aimed to explore associations between home environment variables and adolescent soft drink consumption and potential mediation of these associations by individual cognitions derived from the Theory of Planned Behaviour and habit strength. The ENDORSE study (N=1005) provided data on soft drink consumption and on home environment variables related to soft drink consumption (availability, accessibility, parental modelling, and parental rules), cognitive variables (intention, attitude, perceived behaviour control, and parental norm) and habit strength. Multiple mediation analyses were conducted using regression analyses according to the steps described by MacKinnon to assess the association between home environment variables and soft drink consumption and mediation of these associations by cognitive variables and habit strength. The bootstrapping method was used to calculate the confidence intervals. There were significant associations between the home environment variables and soft drink consumption. After inclusion of the mediators the strength of these associations was reduced. In the multiple mediator models, habit strength (39.4-62.6%) and intention (19.1 36.6%) were the strongest mediators. Intention and habit strength partly mediate the associations between home environment factors and soft drink consumption, suggesting that home environment variables influence soft drink consumption both indirectly and directly. PMID- 21241762 TI - Loganin protects against hydrogen peroxide-induced apoptosis by inhibiting phosphorylation of JNK, p38, and ERK 1/2 MAPKs in SH-SY5Y cells. AB - We investigated the mechanisms underlying the protective effects of loganin against hydrogen peroxide (H(2)O(2))-induced neuronal toxicity in SH-SY5Y cells. The neuroprotective effect of loganin was investigated by treating SH-SY5Y cells with H(2)O(2) and then measuring the reduction in H(2)O(2)-induced apoptosis using 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) release assays. Following H(2)O(2) exposure, Hoechst 33258 staining indicated nuclear condensation in a large proportion of SH-SY5Y cells, along with an increase in reactive oxygen species (ROS) production and an intracellular decrease in mitochondria membrane potential (MMP). Loganin was effective in attenuating all the above-stated phenotypes induced by H(2)O(2). Pretreatment with loganin significantly increased cell viability, reduced H(2)O(2)-induced LDH release and ROS production, and effectively increased intracellular MMP. Pretreatment with loganin also significantly decreased the nuclear condensation induced by H(2)O(2). Western blot data revealed that loganin inhibited the H(2)O(2)-induced up-regulation of cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspase-3, increased the H(2)O(2)-induced decrease in the Bcl-2/Bax ratio, and attenuated the H(2)O(2)-induced release of cytochrome c from mitochondria to the cytosol. Furthermore, pretreatment with loganin significantly attenuated the H(2)O(2)-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase 1/2 (ERK 1/2). These results suggest that the protective effects of loganin against H(2)O(2)-induced apoptosis may be due to a decrease in the Bcl-2/Bax ratio expression due to the inhibition of the phosphorylation of JNK, p38, and ERK 1/2 MAPKs. Loganin's neuroprotective properties indicate that this compound may be a potential therapeutic agent for the treatment of neurodegenerative diseases. PMID- 21241763 TI - Effects of dexmedetomidine on the release of glial cell line-derived neurotrophic factor from rat astrocyte cells. AB - Dexmedetomidine (DEX) has been found to improve neuronal survival after transient global or focal cerebral ischemia in rats. Astrocyte cells may possess beneficial properties that promote neuronal recovery by secreting neurotrophic factors, such as glial cell line-derived neurotrophic factor (GDNF). The purpose of this study was to investigate the effects of DEX on GDNF release from astrocytes and the possible mechanisms involved. Astrocyte cells were treated with DEX, and GDNF level in the conditioned media was determined by ELISA assay. The expression of CREB, p-CREB and PKCalpha was analyzed by Western blotting to explore the mechanisms involved in GDNF release. Our results showed that DEX stimulated GDNF release in a time- and dose-dependent manner; and this stimulation was blocked by the alpha2-adrenoreceptor antagonist yohimbine, but not by alpha1-adrenoreceptor antagonist prasozin, demonstrating that DEX induced GDNF release likely acts via activating the alpha2A adrenoreceptor. In addition, DEX-stimulated GDNF release was also blocked by the universal PKC inhibitor Ro-318220 and PKCalpha/beta inhibitor Go 6976, but not by PKCdelta inhibitor rottlerin and PKCbeta inhibitor LY333531. Interestingly, DEX also activated CREB phosphorylation, which was inhibited by Ro-318220, Go 697 and ERK kinase inhibitor PD98059. Silencing CREB by siRNA decreased the DEX-stimulated GDNF release. In addition, the membrane translocation of PKCalpha was enhanced following DEX treatment. Furthermore, we found that DEX stimulated GDNF release rescued neurons against OGD-induced neurotoxicity; this effect was partly abolished by GDNF antibody. Thus, through alpha2A adrenergic receptors, DEX may activate astrocytes, and promote GDNF release to protect neurons after stroke, and this signaling is possibly dependent on PKCalpha and CREB activation. PMID- 21241764 TI - Evaluation of genotoxicity of Yukmijihwang-tang, a herbal formula. AB - Yukmijihwang-tang (Liu wei di huang tang, Rokumigan; YMJ) has been used for body enrichment; however, little toxicological evaluation of YMJ has been performed to assure its safety for clinical treatment. To increase the safety information for YMJ, its genotoxicity was evaluated. There was no increase in the number of revertant colonies in four strains of Salmonella typhimurium or one strain of Escherichia coli at any concentration of YMJ studied, regardless of the including when dosed with YMJ metabolized with and S-9 microsomal fraction. YMJ significantly increased structural aberrations in Chinese hamster lung (CHL) cells at the high concentrations (2500 and 5000 MUg/ml) in the presence or absence of metabolic activation by the S-9 microsomal fraction. Oral administration of YMJ at doses up to 2000 mg/kg did not increase the incidence of micronucleated polychromatic erythrocytes in bone marrow. These results suggest that YMJ is not genotoxic at the proper dose. PMID- 21241765 TI - The influence of temporary cements on dental adhesive systems for luting cementation. AB - OBJECTIVE: This study tested the hypothesis that bond strength of total- and self etching adhesive systems to dentine is not affected by the presence of remnants from either eugenol-containing (EC) or eugenol-free (EF) temporary cements after standardized cleaning procedures. METHODS: Thirty non-carious human third molars were polished flat to expose dentine surfaces. Provisional acrylic plates were fabricated and cemented either with EC, EF or no temporary cements. All specimens were incubated for 7 days in water at 37 degrees C. The restorations were then taken out and the remnants of temporary cements were mechanically removed with a dental instrument. The dentine surfaces were cleaned with pumice and treated with either total-etching (TE) or self-etching (SE) dental adhesive systems. Atomic force microscopy was used to examine the presence of remnants of temporary cements before and after dentine cleaning procedures. Composite resin build-ups were fabricated and cemented to the bonded dentine surfaces with a resin luting cement. The specimens were then sectioned to obtain 0.9mm(2) beams for microtensile bond strength testing. Fractographic analysis was performed by optical and scanning electron microscopy. RESULTS: ANOVA showed lower mean microtensile bond strength in groups of specimens treated with EC temporary cement than in groups treated with either no cement or an EF cement (p<0.05). Mean microtensile bond strength was lower in groups employing the SE rather than the TE adhesive system (p<0.001). SE samples were also more likely to fail during initial processing of the samples. There was no evidence of interaction between cement and adhesive system effects on tensile strength. Fractographic analysis indicated different primary failure modes for SE and TE bonding systems, at the dentine-adhesive interface and at the resin cement-resin composite interface, respectively. CONCLUSION: The use of eugenol-containing temporary cements prior to indirect bonding restorations reduce, to a statistically similar extent, the bond strength of both total- and self-etching adhesive systems to dentine. PMID- 21241766 TI - Resin cement color stability and its influence on the final shade of all ceramics. AB - OBJECTIVES: Adhesive resin cements may go through internal discoloration, which may show-through and affect the appearance of translucent all-ceramic restorations. This in vitro study evaluated the amount of resin cement color change and its effect on the final shade of the all-ceramics. METHODS: Three different resin cements in both light and dual-cure forms were included in the study (Nexus-2/Kerr; Appeal/Ivoclar Vivadent; Calibra/Dentsply). All resin cements contained veneered (IPS Empress Esthetic, ETC1 shade, 20 mm * 1 mm ingot discs) and uncovered groups (n=10/group), all luted on white backgrounds (acetalpolyoxymethylene/Delrin((r))). Curing was performed according to ISO standards with a calibrated LED curing-light (Flashlite 1401). Samples were stored in 37 degrees C distilled water at dark. Spectrophotometric baseline color measurements (Color Eye 7000A) were performed from the samples' top surfaces at 24h (D65 illuminator). Samples were subjected to 65 h of accelerated ageing (Atlas Ci4000). Further color measurements from the same areas were recorded in CIEL*a*b* coordinates where a DeltaE data above 3 was accepted as visible discoloration (OptiviewLite-1.9software). Statistical analysis was performed using a nested random effects model and Tukey's post hoc analysis. RESULTS: Light cure groups showed better color stability in all three resins but only in Appeal resin cement, the dual-cure group discolored significantly more (p<0.001). More discoloration was recorded on uncovered cement groups that represented the exposed cement at the margins. There was no visible color change (DeltaE>3) through the ceramic surface on any veneered group. CONCLUSIONS: All resin cements showed varying degrees of discoloration after accelerated ageing however their actual color change was partially masked by the ceramic. Dual-cure resin cements may affect aesthetics on restoration margins if directly exposed. PMID- 21241767 TI - Differential tissue-regulation of myostatin genes in the teleost fish Lates calcarifer in response to fasting. Evidence for functional differentiation. AB - Gene or genome duplication is a fundamental evolutionary mechanism leading towards the origin of new genes, or gene functions. Myostatin (MSTN) is a negative regulator of muscle growth that in teleost fish, as a result of genome duplication, is present in double copy. This study provides evidence of differentiation of MSTN paralogs in fish by comparatively exploring their tissue regulation in the Asian sea bass (Lates calcarifer) when subjected to fasting stress. Results showed differential regulation as well as specific tissue responses in the muscle, liver, gill and brain of L. calcarifer after nutritional deprivation. In particular, the LcMstn-1 expression increased in liver (~4 fold) and muscle (~3 fold) and diminished in brain (~0.5 fold) and gill (~0.5 fold) while that of LcMstn-2 remained stable in brain and muscle and was up regulated in gill (~2.5 fold) and liver (~2 fold). Differential regulation of Mstn paralogs was supported by in silico analyses of regulatory motifs that revealed, at least in the immediate region upstream the genes, a differentiation between Mstn-1 and Mstn-2. The Mstn-1 in particular showed a significantly higher conservation of regulatory sites among teleost species compared to its paralog indicating that this gene might have a highly conserved function in the taxon. PMID- 21241768 TI - Phosphoinositide 3-kinase as a novel functional target for the regulation of the insulin signaling pathway by SIRT1. AB - The protein deacetylase SIRT1, and its activator resveratrol, exert beneficial effects on glucose metabolism. Different SIRT1 targets have been identified, including PTP1B, AMPK, FOXO, PGC-1alpha and IRS2. The latter may underscore a tight link between SIRT1 and insulin signaling components. However, whether SIRT1 has a direct effect on insulin resistance and whether resveratrol acts directly or indirectly in this context is still a matter of controversy and this question has not been addressed in muscle cells. Here, we show that SIRT1 protein expression is decreased in muscle biopsies and primary myotubes derived from type 2 diabetic patients, suggesting a contribution of diminished SIRT1 in the determination of muscle insulin resistance. To investigate the functional impact of SIRT1 on the insulin pathway, the activation of insulin downstream effector PKB was evaluated after SIRT1 inactivation by RNAi, SIRT1 overexpression, or resveratrol treatments. In muscle cells and HEK293 cells, downregulation of SIRT1 reduced, while overexpression increased, insulin-induced PKB activatory phosphorylation. Further molecular characterisation revealed that SIRT1 interacts in an insulin-independent manner with the PI3K adapter subunit p85. We then investigated whether resveratrol may improve insulin signaling in muscle cells via SIRT1, or alternative targets. Incubation of muscle cells with resveratrol reverted the insulin-resistant state induced by prolonged TNFalpha or insulin treatment. Resveratrol-dependent improvement of insulin-resistance occurred through inhibition of serine phosphorylation of IRS1/2, implicating resveratrol as a serine kinase inhibitor. Finally, a functional interaction between PI3K and SIRT1 was demonstrated in C. elegans, where constitutively active PI3K - mimicking increased IIS signaling - lead to shortened lifespan, while removal of sir-2.1 abolished PI3K-induced lifespan shortening. Our data identify SIRT1 as a positive modulator of insulin signaling in muscle cells through PI3K, and this mechanism appears to be conserved from C. elegans through humans. PMID- 21241769 TI - Ghrelin neutralization during fasting-refeeding cycle impairs the recuperation of body weight and alters hepatic energy metabolism. AB - Ghrelin, a hormone whose levels increase during food deprivation, plays a pivotal role in the regulation of food intake, energy metabolism and storage, as well as in insulin sensitivity. Here, we investigated the effects of acyl-ghrelin neutralization with the acyl-ghrelin-binding compound NOX-B11(2) during the fasting-refeeding cycle. Our data demonstrate that ghrelin neutralization with NOX-B11(2) impairs recuperation of lost body weight after food deprivation. Analysis of enzymes involved in glucose and lipid metabolism in liver of fed, fasted and refed rats revealed that neutralization of acyl-ghrelin resulted in minor decreases in the enzymes of glycolytic and lipogenic pathways during fasting. However, during refeeding these enzymes as well as glycogen levels recovered more slowly when acyl-ghrelin was blocked. The high levels of ghrelin in response to food deprivation may contribute to an adequate decrease in hepatic glycolytic and lipogenic enzymes and aid in the recovery of body weight and energetic reserves once food becomes available after the fasting period. PMID- 21241770 TI - Perfluorooctanoic acid-induced inhibition of placental prolactin-family hormone and fetal growth retardation in mice. AB - Perfluorooctanoic acid (PFOA) is a persistent pollutant worldwide and even found in human cord blood and breast milk. Some animal studies have reported that PFOA causes developmental toxicity such as fetal weight loss, but the mechanism is still unclear. This study focused on developmental toxicity of PFOA, particularly impacts of PFOA on placental endocrine function such as placental prolactin (PRL) family hormone gene expression and fetal growth in mouse. Time-mated CD-1 mice were dosed by gavage with 0, 2, 10 and 25 mg/kg B.W/day of PFOA (n-10) dissolved with de-ionized water from gestational day (GD) 11-16. During treatment, body weight of each pregnant mouse was measured daily. On day 16, caesarean sections were performed and developmental data were observed. Three placentas from three different pregnant mice were assigned to each of the following experiments. The mRNA levels of mouse placental lactogen (mPL)-II, prolactin like protein (mPLP) E, -F and Pit-1alpha and beta isotype mRNAs, a transacting factor of mPLs and mPLPs genes, were analyzed using northern blot, in situ hybridization and RT-PCR, respectively. Maternal body weight gain was significantly declined from GD 13 in the PFOA treated groups compared to control. Developmental data such as fetal and placental weights were significantly decreased in accordance with PFOA dosage. Number of dead fetuses and post-implantation losses were significantly increased in the PFOA-exposed groups. In addition, placental efficiency (fetal weight/placental weight) was significantly reduced in PFOA treated groups in accordance with PFOA dosage. Histopathologic changes were observed in placenta. Dose dependent necrotic changes were observed in both 10 mg and 25 mg PFOA treated groups. Cell frequency of glycogen trophoblast cell and parietal trophoblast giant cell were decreased dose dependently in the junctional zone. In the labyrinth zone, sinusoidal trophoblast giant cell frequency was decreased in the 25 mg PFOA treated group. Also, morphological change such as crushed nuclear (atrophy) of trophoblast cells was observed in 25 mg PFOA treated group. Finally, mRNA levels of the mPL-II, mPLP-E, -F and Pit-1alpha and beta were significantly reduced in the PFOA treated groups dose dependently. In addition, the changing pattern between mPL-II, mPLP-E, -F mRNA levels and fetal body weight showed positive relationship. In conclusion, the inhibitory effects of PFOA on the placental prolactin-family hormone genes expression may be secondary effects to insufficient trophoblast cell type differentiation and/or increased trophoblast cell necrosis. The impacts of PFOA on placental development and endocrine function reduced the placental efficiency and partly contributed to the fetal growth retardation in the mouse. PMID- 21241771 TI - Antinociceptive effects of intracerebroventricular injection of the galanin receptor 1 agonist M 617 in rats. AB - Previous studies in our laboratory demonstrated that galanin and its receptors play important roles in nociceptive modulation in the central nervous system. The present study was performed to explore the antinociceptive effects of the galanin receptor 1 agonist M 617 in the central nervous system of rats. Intracerebroventricular injection of 0.1nmol, 0.5nmol, 1nmol or 2nmol of M 617 induced dose-dependent increases in hindpaw withdrawal latencies (HWLs) to noxious thermal and mechanical stimulations in rats. Furthermore, both intracerebroventricular injection of M 617 and galanin induced significant increases in HWLs in rats. Interestingly, there were no significant differences between the antinociceptive effects induced by M 617 and galanin, indicating that galanin receptor 1 plays main roles in galanin-induced antinociceptive effects in the brain of rats. PMID- 21241772 TI - Ongoing pain in the MIA model of osteoarthritis. AB - Osteoarthritis (OA) is a chronic pain condition characterized by pain during joint use as well as pain at rest (i.e., ongoing pain). Although injection of monosodium iodoacetate (MIA) into the intra-articular space of the rodent knee is a well established model of OA pain that is characterized by changes in weight bearing and hypersensitivity to tactile and thermal stimuli, it is not known if this procedure elicits ongoing pain. Further, the time-course and possible underlying mechanisms of these components of pain remain poorly understood. In these studies, we demonstrated the presence of ongoing pain in addition to changes in weight bearing and evoked hypersensitivity. Twenty-eight days following MIA injection, spinal clonidine blocked changes in weight bearing and thermal hypersensitivity and produced place preference indicating that MIA induces ongoing and evoked pain. These findings demonstrate the presence of ongoing pain in this model that is present at a late-time point after MIA allowing for mechanistic investigation. PMID- 21241773 TI - Expression and significance of DSCAM in the cerebral cortex of APP transgenic mice. AB - Down syndrome cell adhesion molecule (DSCAM) plays important roles in the regulation of synaptogenesis, neurite outgrowth, axon guidance and synapse formation. Overexpression of DSCAM in Down syndrome (DS) may be involved in the pathogenesis of mental retardation through an inhibitory action on synaptogenesis/neurite outgrowth, and in the precocious dementia associated with an amyloid precursor protein (APP) dosage effect with enhanced plaque formation. In this report we examined the expression of DSCAM in the cerebral cortex of APP transgenic mice versus age-matched wild-type mice. We found that the level of DSCAM expression increased with increasing age in both groups of mice, up to a maximum at 3 months old. The level of DSCAM expression in APP transgenic mice was significantly higher than in the age-matched wild types. We propose that overexpression of DSCAM in the cerebral cortex might play an important role in the learning and memory defects of APP transgenic mice. PMID- 21241774 TI - Delayed sodium pyruvate treatment improves working memory following experimental traumatic brain injury. AB - Prior work indicates that cerebral glycolysis is impaired following traumatic brain injury (TBI) and that pyruvate treatment acutely after TBI can improve cerebral metabolism and is neuroprotective. Since extracellular levels of glucose decrease during periods of increased cognitive demand and exogenous glucose improves cognitive performance, we hypothesized that pyruvate treatment prior to testing could ameliorate cognitive deficits in rats with TBI. Based on pre surgical spatial alternation performance in a 4-arm plus-maze, adult male rats were randomized to receive either sham injury or unilateral (left) cortical contusion injury (CCI). On days 4, 9 and 14 after surgery animals received an intraperitoneal injection of either vehicle (Sham-Veh, n=6; CCI-Veh, n=7) or 1000 mg/kg of sodium pyruvate (CCI-SP, n=7). One hour after each injection rats were retested for spatial alternation performance. Animals in the CCI-SP group showed no significant working memory deficits in the spatial alternation task compared to Sham-Veh controls. The percent four/five alternation scores for CCI-Veh rats were significantly decreased from Sham-Veh scores on days 4 and 9 (p<0.01) and from CCI-SP scores on days 4, 9 and 14 (p<0.05). Measures of cortical contusion volume, regional cerebral metabolic rates of glucose and regional cytochrome oxidase activity at day 15 post-injury did not differ between CCI-SP and CCI-Veh groups. These results show that spatial alternation testing can reliably detect temporal deficits and recovery of working memory after TBI and that delayed pyruvate treatment can ameliorate TBI-induced cognitive impairments. PMID- 21241775 TI - Ergosta-4,6,8(14),22-tetraen-3-one induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. AB - BACKGROUND: Mushrooms have been used in Asia as traditional foods and medicines for a long time. Ergosta-4,6,8(14),22-tetraen-3-one (ergone) is one of the well known bioactive steroids, which exists widely in various medicinal fungi such as Polyporus umbellatus, Russula cyanoxantha, and Cordyceps sinensis. Ergone has been demonstrated to possess cytotoxic activity. However, the molecular mechanisms by which ergone exerts its cytotoxic activity are currently unknown. METHODS: In the present study, ergone possessed a remarkable anti-proliferative activity toward human hepatocellular carcinoma HepG2 cells. We assayed the cell cycle by flow cytometry using PI staining; investigated the exposure of phosphatidylserine at the outer layer of the cytoplasmic membrane by the FITC annexin V/PI staining; observed the nuclear fragmentation by Hoechst 33258 staining and studied the protein expression of Bax, Bcl-2, p-53, procaspase-3, 8, -9, PARP and cleaved PARP by Western blotting analysis. RESULTS: Cells treated with ergone showed typical markers of apoptosis: G2/M cell cycle arrest, chromatin condensation, nuclear fragmentation, and phosphatidylserine exposure. Furthermore, PARP-cleavage; activation of caspase-3, -8, -9; up-regulation of Bax and down-regulation of Bcl-2 were observed in HepG2 cells treated with ergone, which show that both the intrinsic and extrinsic apoptotic pathways are involved in ergone-induced apoptosis in HepG2 cells. Ergosta-4,6,8(14),22-tetraen-3-one induces G2/M cell cycle arrest and apoptosis in HepG2 cells in a caspase dependent manner. GENERAL SIGNIFICANCE: In this study, we reported for the first time that ergone-induced apoptosis through activating the caspase. These results would be useful for the further utilization of many medicinal fungi in cancer treatment. PMID- 21241776 TI - Phylogenetic diversity and functional efficacy of the C-terminally expressed heptapeptide unit in the opioid precursor polypeptide proenkephalin A. AB - The heptapeptide Met-enkephalin-Arg6-Phe7 (MERF) with the sequence of YGGFMRF is a potent endogenous opioid located at the C-terminus of proenkephalin-A (PENK), the common polypeptide precursor of Met- and Leu-enkephalin. Our systematic bioinformatic survey revealed considerable sequence polymorphism at the heptapeptide region of different PENK prepropeptides among 56 vertebrate animals. Four orthologous heptapeptides with single or double amino acid replacements were identified among 15 animals, such as YGGFMGY (zebrafish), YGGFMRY (newt), YGGFMKF (hedgehog tenrek) and YGGFMRI (mudpuppy). Each novel heptapeptide, together with the mammalian consensus MERF and Met-enkephalin, were chemically synthesized and subjected to functionality studies, using radioligand binding competition and G protein activation assays in rat brain membranes. Equilibrium binding affinities changed from good to modest as measured by receptor type selective [3H]opioid radioligands. The relative affinities of the heptapeptides reveal slight mu receptor (MOP) preference over the delta-receptors (DOP). [35S]GTPgammaS assay, which measures the agonist-mediated G-protein activation, has demonstrated that all the novel heptapeptides were also potent in stimulating the regulatory G proteins. All peptides were effective in promoting the agonist induced internalization of the green fluorescence protein-tagged human mu-opioid receptor (hMOP-EGFP) stably expressed in HEK293 cells. Thus, the C-terminally processed PENK heptapeptide orthologs exhibited satisfactory bioactivities, moreover they represent further members of the so-called "natural combinatorial neuropeptide library" emerged by evolution. PMID- 21241777 TI - Valproate reduces CHOP levels and preserves oligodendrocytes and axons after spinal cord injury. AB - Spinal cord injury (SCI) is a major cause of disability to which there are not yet effective treatments. We previously reported that degeneration of oligodendrocytes and neurons that occurs after SCI is associated with the development of endoplasmic reticulum (ER) stress and the progressive accumulation of the pro-apoptotic factor CHOP. Since following ER stress, the balance between the pro-survival chaperone BiP and CHOP drives the cell destiny, we aimed to find drugs that modulate this ratio in favour of the former. We found that valproate (VPA) induced a significant reduction of CHOP levels after ER stress in an organotypic-based culture of spinal cord in vitro. We then administered different doses of VPA to rats following spinal cord contusion, and found that the treatment caused a marked reduction of CHOP levels early after the lesion. In addition, VPA administration partially prevented cord tissue, myelin and axonal loss, and significantly increased the relative number of surviving oligodendrocytes in the damaged spinal cord. Besides, VPA-treated rats showed better recovery of the locomotor activity than vehicle-treated rats after SCI. Since VPA is a drug already in clinical use, these results open the avenue for its therapeutical use in SCI as well as in demyelinating disorders. PMID- 21241778 TI - Edaravone alleviates delayed neuronal death and long-dated cognitive dysfunction of hippocampus after transient focal ischemia in Wistar rat brains. AB - Edaravone is currently being used in acute ischemic stroke both in clinical and experimental research as a potent antioxidant. Here we explore the effects of edaravone on delayed neuronal death (DND) and long-dated cognitive dysfunction of hippocampus after cerebral ischemia-reperfusion (IR) injury and explain the underlying mechanisms and pathways. Our findings suggested that edaravone not only significantly alleviated delayed neuronal death and cognitive dysfunction of hippocampus after cerebral focal ischemia, but also markedly decreased malondialdehyde (MDA) levels. In addition, edaravone increased superoxide dismutase (SOD) levels and reduced the levels of inflammatory cytokines such as IL-1beta and TNF-alpha expression; edaravone, also suppressed glial fibrillary acidic protein (GFAP) proliferation at days 3, 7 and 30 after reperfusion. Overall, the consensus emerging from this body of data indicated that edaravone exerts a later neuroprotective effect to hippocampus through its ability to inhibit inflammation, suppression of astrocyte activation and scavenging free radicals in stroke events. PMID- 21241779 TI - Restorative effect of intracerebroventricular insulin-like growth factor-I gene therapy on motor performance in aging rats. AB - Insulin-like growth factor-I (IGF-I) is a powerful neuroprotective molecule in the brain and spinal cord. We have previously shown that intracerebroventricular (i.c.v.) IGF-I gene therapy is an effective strategy to increase IGF-I levels in the cerebrospinal fluid (CSF). Since aging in rats is associated with severe motor function deterioration, we implemented i.c.v. IGF-I gene therapy in very old rats (30-31 months) and assessed the beneficial impact on motor performance. We used recombinant adenovectors (RAds) expressing either green fluorescent protein (GFP) or rat IGF-I. Injection in the lateral or fourth ventricle led to high transgene expression in the ependymal cell layer in the brain and cervical spinal cord. RAd-IGF-I-injected rats but not RAd-GFP-injected controls, showed significantly increased levels of CSF IGF-I. Motor tests showed the expected age related decline in aged rats. Seventeen-day IGF-I gene therapy induced a significant improvement in motor performance in the aged but not in the young animals. These results show that IGF-I is an effective restorative molecule in the aging brain and spinal cord. The data also reveal that the ependymal route constitutes a promising approach for implementing protective IGF-I gene therapy in the aging CNS. PMID- 21241780 TI - Exercise preconditioning and brain ischemic tolerance. AB - It is well established that physical exercise can exert neuroprotection both in clinical settings and animal experiments. A series of studies have demonstrated that physical exercise may be a promising preconditioning method to induce brain ischemic tolerance through the promotion of angiogenesis, mediation of the inflammatory response, inhibition of glutamate over-activation, protection of the blood brain barrier (BBB) and inhibition of apoptosis. Through these mechanisms, exercise preconditioning may reduce the neural deficits associated with ischemia and the development of brain infarction and thus provide brain ischemic tolerance. An awareness of the benefits of exercise preconditioning may lead more patients to accept exercise therapy in cases of ischemic stroke. PMID- 21241781 TI - Gray matter alterations in parosmia. AB - Parosmia is a common olfactory disorder. In this condition, odors are perceived in a different quality than usual. This distorted olfactory percept is typically reported to be unpleasant. Little is known about the pathophysiology of this phenomenon. Previous studies demonstrated smaller volumes of the olfactory bulbs in patients with parosmia compared to subjects without parosmia. In order to investigate structural brain alterations in areas beyond the olfactory bulb, in the current study voxel-based morphometry was applied. A group of 22 parosmic patients was compared with control subjects matched for age- and sex, who exhibited a similar performance in olfactory tests. Performing a whole brain analysis, we found profound gray matter volume loss in the left anterior insula in parosmic patients. In an additional volume of interest analysis including primary and secondary olfactory areas, we also found volume loss in the right anterior insula, the anterior cingulate cortex, the hippocampus bilaterally, and the left medial orbitofrontal cortex. Many of these areas are critically involved in olfactory quality discrimination and odor memory. The present results indicate that reduced gray matter volume in brain regions supporting odor discrimination and memory is related to disturbed olfactory sensation in parosmia. PMID- 21241782 TI - The DYT1 carrier state increases energy demand in the olivocerebellar network. AB - DYT1 dystonia is caused by a GAG deletion in TOR1A, the gene which encodes torsinA. Gene expression studies in rodents and functional imaging studies in humans suggest that DYT1 dystonia may be a network disorder of neurodevelopmental origin. To generate high resolution metabolic maps of DYT1 dystonia and pinpoint dysregulated network elements, we performed 2-deoxyglucose autoradiography and cytochrome oxidase (CO) histochemistry in transgenic mice expressing human mutant (hMT1) torsinA and wild-type littermates. In comparison with controls, hMT1 mice showed increased glucose utilization (GU) in the inferior olive (IO) medial nucleus (IOM), IO dorsal accessory nucleus and substantia nigra compacta, and decreased GU in the medial globus pallidus (MGP) and lateral globus pallidus. The hMT1 mice showed increased CO activity in the IOM and Purkinje cell layer of cerebellar cortex, and decreased CO activity in the caudal caudate-putamen, substantia nigra reticulata and MGP. These findings suggest that (1) the DYT1 carrier state increases energy demand in the olivocerebellar network and (2) the IO may be a pivotal node for abnormal basal ganglia-cerebellar interactions in dystonia. PMID- 21241784 TI - The resurgence of Hormone-Sensitive Lipase (HSL) in mammalian lipolysis. AB - The ability to store energy in the form of energy-dense triacylglycerol and to mobilize these stores rapidly during periods of low carbohydrate availability or throughout the strong metabolic demand is a highly conserved process, absolutely essential for survival. In the industrialized world the regulation of this pathway is viewed as an important therapeutic target for disease prevention. Adipose tissue lipolysis is a catabolic process leading to the breakdown of triacylglycerols stored in fat cells, and release of fatty acids and glycerol. Mobilization of adipose tissue fat is mediated by the MGL, HSL and ATGL, similarly functioning enzymes. ATGL initiates lipolysis followed by the actions of HSL on diacylglycerol, and MGL on monoacylglycerol. HSL is regulated by reversible phosphorylation on five critical residues. Phosphorylation alone, however, is not enough to activate HSL. Probably, conformational alterations and a translocation from the cytoplasm to lipid droplets are also involved. In accordance, Perilipin functions as a master regulator of lipolysis, protecting or exposing the triacylglycerol core of a lipid droplet to lipases. The prototype processes of hormonal lipolytic control are the beta-adrenergic stimulation and suppression by insulin, both of which affect cytoplasmic cyclic AMP levels. Lipolysis in adipocytes is an important process in the management of body energy reserves. Its deregulation may contribute to the symptoms of type 2 diabetes mellitus and other pathological situations. We, herein, discuss the metabolic regulation and function of lipases mediating mammalian lipolysis with a focus on HSL, quoting newly identified members of the lipolytic proteome. PMID- 21241783 TI - Influence of central glia on spiral ganglion neuron neurite growth. AB - Spiral ganglion neurons (SGNs) extend processes that interact with Schwann cells (SCs) and with oligodendrocytes (OLs) and astrocytes (ACs). We investigated the ability of these glial cells to support SGN neurite growth. In the presence of cultured ACs, OLs and SCs, SGN neurites tended to follow SCs and OLs and cross over ACs. Most neurites initially followed the type of glial cell on which the neuronal cell body was found. To determine the influence of homogeneous populations of glia on neurite growth, SG explants were plated on cultured SCs, ACs or OLs. The number of neurites/explant extending onto SCs (463.89+/-16.25) was significantly greater than the number extending onto ACs (111.38+/-38.73) or OLs (6.75+/-2.21), indicating that populations of central glia inhibit SGN neurite growth. Treatment with cell-permeant cpt-cAMP or forskolin (FSK) each significantly increased the number of neurites on OLs (133.54+/-25.59 and 292.25+/-83.57, respectively). cpt-cAMP and FSK each also increased the number of neurites on ACs (213.19+/-36.06 and 208.64+/-59.25, respectively), however the difference was not significant compared with control. The neurites on ACs and OLs failed to grow radially in a well-fasciculated pattern as on SCs. In explants plated on the borders of cultured OL-SC or AC-SC groups, more neurites extended onto SCs compared with OLs and ACs. Conditioned media (CM) from OL or AC cultures did not reduce neurite length, implying that the inhibition of neurite growth by central glia is not due to soluble factors. Taken together, these results demonstrate that homogeneous populations of central glia inhibit SGN neurite growth. PMID- 21241785 TI - Species-specific 5'-genomic structure and multiple transcription start sites in the chicken Pax5 gene. AB - Master differentiation transcription factors (MDFs) play decisive roles in cell lineage commitment. Paired box 5 (Pax5) is one of MDFs essential for differentiation of pre-B cells into mature B cells. Here, we analyzed the 5' genomic structure and transcription of the chicken Pax5 (cPax5) gene in the chicken mature B cell line, DT40. We showed that the cPax5 gene has two first exons: exon 1A contains long AG repeats, while exon 1B has high GC contents. The exons 1A and 1B had one and three major transcription start sites, respectively. Semi-quantitative RT-PCR revealed that comparable amounts of mRNA are transcribed from the exons 1A and 1B. Interestingly, the transcription start site of the cPax5 exon 1A was chicken-specific. In addition, the cPax5 promoter upstream of the exon 1A had no homology with the human and mouse Pax5 promoters. Thus, the mechanisms regulating transcription of the Pax5 exon 1A might not be conserved among species. Furthermore, we determined the physical structure of the exons 1A, 1B, and 2 in the genome of DT40 cells. Our results will be useful for elucidating mechanisms that control cPax5 transcription and B cell lineage commitment, which is conserved or not conserved among different species. PMID- 21241786 TI - Molecular evolution of two duplicated CDPK genes CPK7 and CPK12 in grass species: a case study in wheat (Triticum aestivum L.). AB - Gene duplication contributes to the expansion of gene families and subsequent functional diversification. Calcium-dependent protein kinases (CDPKs) are members of an important calcium sensor family involved in abiotic and biotic stress signaling in plants. We report here the molecular evolution and expression analysis of a pair of duplicated CDPK genes CPK7 and CPK12 that arose in the common ancestor of grass species. With higher nonsynonymous/synonymous ratios (dN/dS, or omega), CPK12 genes appear to diverge more rapidly than CPK7s, suggesting relaxed selection constraints on CPK12s. Sliding window analysis revealed increased dN and omega values at N-terminal regions and the calcium binding EF hand loops. Likelihood analyses using various models in PAML 4.0 showed purifying selection on both CPK7 and CPK12 lineages. In addition to the divergence in cis-element combinations on their promoters, functional divergence of CPK7 and CPK12 genes was also observed in wheat where TaCPK7 was found to respond to drought (PEG), salt (NaCl), cold, and hydrogen peroxide (H(2)O(2)) while TaCPK12 responded only to the treatment of ABA, a feature that may complement or expand TaCPK7-mediated stress signaling networks of wheat. The contrasting expression patterns of CPK7 and CPK12 genes under stress conditions were also observed in rice, suggesting conservative functional evolution of these genes. Since no positive selection was detected between the two lineages, the divergence of CPK7 and CPK12 genes should be ascribed to subfunctionalization, rather than neofunctionalization. Thus, our work demonstrates another case of evolutionary employment of duplicated genes via subfunctionalization for better adaptation. PMID- 21241787 TI - Characterization of the complete chloroplast genome of Hevea brasiliensis reveals genome rearrangement, RNA editing sites and phylogenetic relationships. AB - Rubber tree (Hevea brasiliensis) is an economical plant and widely grown for natural rubber production. However, genomic research of rubber tree has lagged behind other species in the Euphorbiaceae family. We report the complete chloroplast genome sequence of rubber tree as being 161,191 bp in length including a pair of inverted repeats of 26,810 bp separated by a small single copy region of 18,362 bp and a large single copy region of 89,209 bp. The chloroplast genome contains 112 unique genes, 16 of which are duplicated in the inverted repeat. Of the 112 unique genes, 78 are predicted protein-coding genes, 4 are ribosomal RNA genes and 30 are tRNA genes. Relative to other plant chloroplast genomes, we observed a unique rearrangement in the rubber tree chloroplast genome: a 30-kb inversion between the trnE(UUC)-trnS(GCU) and the trnT(GGU)-trnR(UCU). A comparison between the rubber tree chloroplast genes and cDNA sequences revealed 51 RNA editing sites in which most (48 sites) were located in 26 protein coding genes and the other 3 sites were in introns. Phylogenetic analysis based on chloroplast genes demonstrated a close relationship between Hevea and Manihot in Euphorbiaceae and provided a strong support for a monophyletic group of the eurosid I. PMID- 21241788 TI - Gene editing activity on extrachromosomal arrays in C. elegans transgenics. AB - Gene editing by modified single-stranded oligonucleotides is a strategy aimed at inducing single base changes into the genome, generating a permanent genetic change. The work presented here explores gene editing capabilities in the model organism Caenorhabditis elegans. Current approaches to gene mutagenesis in C. elegans have been plagued by non-specificity and thus the ability to induce precise, directed alterations within the genome of C. elegans would offer a platform upon which structure/function analyses can be carried out. As such, several in vivo assay systems were developed to evaluate gene editing capabilities in C. elegans. Fluorescence was chosen as the selectable endpoint as fluorescence can be easily detected through the transparent worm body even from minimal expression. Two tissue specific fluorescent expression vectors containing either a GFP or mCherry transgene were mutagenized to create a single nonsense mutation within the open reading frame of each respective fluorescent gene. These served as the target site to evaluate the frequency of gene editing on extrachromosomal array transgenic lines. Extrachromosomal arrays can carry hundreds of copies of the transgene, therefore low frequency events (like those in the gene editing reaction) may be detected. Delivery of the oligonucleotide was accomplished by microinjection into the gonads of young adult worms in an effort to induce repair of the mutated fluorescent gene in the F1 progeny. Despite many microinjections on the transgenic strains with varying concentrations of ODNs, no gene editing events were detected. This result is consistent with the previous research, demonstrating the difficulties encountered in targeting embryonic stem cells and the pronuclei of single-celled embryos. PMID- 21241789 TI - Development and in vitro-in vivo relationship of controlled-release microparticles loaded with tramadol hydrochloride. AB - In conclusion, the controlled-release microparticles of TmH can be developed via phase separation method. The development and optimization of controlled-release microparticles of tramadol hydrochloride (TmH) for the oral delivery and their in vitro and in vivo correlation was prime objective of the present study. Four formulations of controlled-released microparticles were developed and optimized in terms of encapsulation efficiency, dissolution study and release kinetics. Among all formulated microparticles F-3 (ratio of TmH:EC 1:2) and F-4 (ratio of TmH:EC 1:3) presented the better characteristics in reference to entrapment efficiency, release kinetics and dissolution profile compared to other formulations (F-1, F-2). For in vivo analysis a new HPLC analytical method was developed and validated. The optimized formulations were subjected to in vivo studies to calculate various pharmacokinetic parameters, i.e., C(max), t(max), AUC(0-infinity) and MRT. The in vitro dissolution and in vivo absorption data was correlated with the help of Wagner-Nelson method. F-3 showed a good in vitro-in vivo correlation with a correlation determination of 0.9957. Moreover, lower T(max), t(1/2) and MRT, and higher values of C(max) and K(e) were observed for F 3. The control formulation (immediate-release) presented lowest values of t(1/2), MRT and T(max) but the highest values of C(max) and K(e). The controlled-release microparticles (F-3 and F-4) could sustain the drug release within therapeutic level up to 24 h and good IVIVC is expected from them. PMID- 21241790 TI - Polyamines: natural and engineered abiotic and biotic stress tolerance in plants. AB - Polyamines (PAs) are ubiquitous biogenic amines that have been implicated in diverse cellular functions in widely distributed organisms. In plants, mutant and transgenic plants with altered activity pointed to their involvement with different abiotic and biotic stresses. Furthermore, microarray, transcriptomic and proteomic approaches have elucidated key functions of different PAs in signaling networks in plants subjected to abiotic and biotic stresses, however the exact molecular mechanism remains enigmatic. Here, we argue that PAs should not be taken only as a protective molecule but rather like a double-faced molecule that likely serves as a major area for further research efforts. This review summarizes recent advances in plant polyamine research ranging from transgenic and mutant characterization to potential mechanisms of action during environmental stresses and diseases. PMID- 21241791 TI - Characterization of genes associated with internalization of enteroaggregative Escherichia coli. AB - On animal models enteroaggregative Escherichia coli (EAEC) can cause mild, but significant mucosal damage, suggesting the invasive capability of these strains. In the study we investigated the ability of typical, aggR-positive and atypical, aggR-negative EAEC isolates to enter intestinal epithelial Int407 cells in relation to the distribution of genes encoding the putative invasins described among pathogenic E. coli categories. The results demonstrated that regardless of origin and affiliation to typical and atypical EAEC, most isolates examined were internalized by the epithelial cells to different extent. Although as many as 50 (84.3%) EAEC demonstrated a variety of combinations of the aggB, afaD, ipaH and tia genes determined, there was no correlation between the invasion efficiency of these strains and the presence of any particular gene involved in invasion. Most of EAEC examined belonged to phylogenetic group B2 and D. PMID- 21241792 TI - Genomic analysis of bacteriophage phiAB1, a phiKMV-like virus infecting multidrug resistant Acinetobacter baumannii. AB - We present the complete genomic sequence of a lytic bacteriophage phiAB1 which can infect many clinical isolates of multidrug-resistant Acinetobacter baumannii. The recently isolated bacteriophage displays morphology resembling Podoviridae family. The phiAB1 genome is a linear double-stranded DNA of 41,526 bp containing 46 possible open reading frames (ORFs). The majority of the predicted structural proteins were identified as part of the phage particle by mass spectrometry analysis. According to the virion morphology, overall genomic structure, and the phylogenetic tree of RNA polymerase, we propose that phiAB1 is a new member of the phiKMV-like phages. Additionally, we identified four ORFs encoding putative HNH endonucleases, one of which is presumed to integrate and create a genes-in pieces DNA polymerase. Also, a potential lysis cassette was identified in the late genome. The lytic power of this bacteriophage combined with its specificity for A. baumannii makes phiAB1 an attractive agent for therapeutic or disinfection applications. PMID- 21241793 TI - Openness and conscientiousness predict 34-week patterns of Interleukin-6 in older persons. AB - Studies have indicated that personality may be associated with inflammatory markers such as Interleukin (IL)-6. One pathway between personality and IL-6 may be health behaviors and conditions resulting in inflammation, while an alternate pathway involves activation of stress-response systems. In a clinical trial sample of 200 older adults, we examined associations between personality traits at baseline and three measures of IL-6 spanning 34 weeks of follow-up. Results indicate that IL-6 remained very stable over time, and that higher Conscientiousness and Openness were associated with lower IL-6 across the entire 34 week period. Goal striving was the active subcomponent of Conscientiousness, while aesthetic interests was the active subcomponent of Openness in IL-6 associations. Common health behaviors and chronic illness accounted for only a portion of these effects, suggesting that other behavioral and/or physiological processes may also predispose some persons to inflammation. Personality phenotype may provide useful prognostic information for inflammation. Older adults lower in Conscientiousness and Openness constitute a target population for anti inflammatory interventions. Openness and Conscientiousness predicts 32-week patterns of Interleukin-6 in older persons. PMID- 21241794 TI - The role of the Golgi apparatus in oxidative stress: is this organelle less significant than mitochondria? AB - Reactive oxygen species (ROS)/reactive nitrogen species (RNS) and ROS/RNS mediated oxidative stress have well-established roles in many physiological and pathological processes and are associated with the pathogenesis of many diseases, such as hypertension, ischemia/reperfusion injury, diabetes mellitus, atherosclerosis, stroke, cancer, and neurodegenerative disorders. It is generally accepted that mitochondria play an essential role in oxidative stress because they are responsible for the primary generation of superoxide radicals. Little attention, however, has been paid to the importance of the Golgi apparatus (GA) in this process. The GA is a pivotal organelle in cell metabolism and participates in modifying, sorting, and packaging macromolecules for cell secretion or use within the cell. It is inevitably involved in the process of oxidative stress, which can cause modification and damage of lipids, proteins, DNA, and other structural constituents. Here we discuss the connections between the GA and oxidative stress and highlight the role of the GA in oxidative stress related Ca(2+)/Mn(2+) homeostasis, cell apoptosis, sphingolipid metabolism, signal transduction, and antioxidation. We also provide a novel perspective on the subcellular significance of oxidative stress and its pathological implications and present "GA stress" as a new concept to explain the GA-specific stress response. PMID- 21241796 TI - Prenatal exposure to diclofenac sodium changes the morphology of the male rat cervical spinal cord: a stereological and histopathological study. AB - Diclofenac sodium is one of the most commonly used non-steroidal anti inflammatory drugs. It may cause alteration in the nervous system during neuronal development. However, there is no investigation concerning its role in the cervical spinal cord. Pregnant rats were divided into two groups, namely drug treated and control (saline-injected) groups. To obtain the offspring of the drug treated group, a dose of 1mg/kg daily diclofenac sodium (Voltaren, 75 mg/3 ml ampoule, Novartis) was injected into the pregnant rats beginning from the 5th day after mating to the 20th day of the pregnancy. To obtain the control group of offspring, serum physiological at a 1 ml/kg daily dose was injected into the pregnant control rats during the same period. Male offspring were obtained after delivery and each group was divided into two subgroups: 4-week-old and 20-week old. The total neuron number in diclofenac sodium-treated rats was significantly lower than in the control group animals. The total volume of the cervical spinal cord segments (C1-C4) was also estimated. There was a significant difference between the volumes of the two groups, especially in the 20-week-old subgroup. This may suggest that development of neurons and volume of cervical spinal cord are affected in prenatal animals after administration of diclofenac sodium. PMID- 21241797 TI - Hypoxia followed by re-oxygenation induces oxidation of tyrosine phosphatases. AB - Hypoxia and hypoxia/reoxygenation (H/R) are components of tissue ischemia and reperfusion implicated in myocardial infarction, organ transplantation, and tumor perfusion. H/R enhances production of reactive oxygen species (ROS). Candidate molecular targets of ROS are the catalytic site cysteine of protein tyrosine phosphatases (PTPs), which are major regulators of tyrosine kinase signaling. This study aimed at analyzing potential effects of H/R on PTP-oxidation in cultured cells and in heart tissue. Exposure of mouse NIH3T3 fibroblasts to H/R increased the oxidation of the PTPs SHP-2- and DEP-1. The catalytic pan-PTP- and SHP-2-activity after H/R were also decreased in rat cardiomyoblasts. In vivo dephosphorylation of the Platelet-derived Growth Factor (PDGF)-receptor in NIH3T3 fibroblasts was delayed following H/R. Erk1/2 displayed an antioxidant-sensitive increase in H/R. Furthermore, increased PDGF-induced cytoskeleton re-arrangements were evident following H/R and could be prevented by antioxidant pretreatment. Finally, decreased pan-PTP- and SHP-2 activity was demonstrated in tissue extracts from an ex vivo Langendorff-model of rat heart ischemia-reperfusion. This study thus demonstrates PTP-oxidation as a previously unrecognized molecular component of the cellular response to H/R in cells and tissues. The study additionally provides the first demonstration of increased PTP-oxidation in tissues under patho-physiological settings. PMID- 21241795 TI - Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. AB - Previously our laboratory has shown that ketamine exposure (24h of clinically relevant anesthesia) causes significant increases in neuronal cell death in perinatal rhesus monkeys. Sensitivity to this ketamine-induced neurotoxicity was observed on gestational days 120-123 (in utero exposure via maternal anesthesia) and on postnatal days (PNDs) 5-6, but not on PNDs 35-37. In the present study, six monkeys were exposed on PND 5 or 6 to intravenous ketamine anesthesia to maintain a light surgical plane for 24h and six control animals were unexposed. At 7 months of age all animals were weaned and began training to perform a series of cognitive function tasks as part of the National Center for Toxicological Research (NCTR) Operant Test Battery (OTB). The OTB tasks used here included those for assessing aspects of learning, motivation, color discrimination, and short-term memory. Subjects responded for banana-flavored food pellets by pressing response levers and press-plates during daily (M-F) test sessions (50 min) and were assigned training scores based upon their individual performance. As reported earlier (Paule et al., 2009) beginning around 10 months of age, control animals significantly outperformed (had higher training scores than) ketamine-exposed animals for approximately the next 10 months. For animals now over 3 and one-half years of age, the cognitive impairments continue to manifest in the ketamine-exposed group as poorer performance in the OTB learning and color and position discrimination tasks, as deficits in accuracy of task performance, but also in response speed. There are also apparent differences in the motivation of these animals which may be impacting OTB performance. These observations demonstrate that a single 24-h episode of ketamine anesthesia, occurring during a sensitive period of brain development, results in very long-lasting deficits in brain function in primates and provide proof-of-concept that general anesthesia during critical periods of brain development can result in subsequent functional deficits. Supported by NICHD, CDER/FDA and NCTR/FDA. PMID- 21241798 TI - Apoptosis in polycystic kidney disease. AB - Apoptosis is the process of programmed cell death. It is a ubiquitous, controlled process consuming cellular energy and designed to avoid cytokine release despite activation of local immune cells, which clear the cell fragments. The process occurs during organ development and in maintenance of homeostasis. Abnormalities in any step of the apoptotic process are associated with autoimmune diseases and malignancies. Polycystic kidney disease (PKD) is the most common inherited kidney disease leading to end-stage renal disease (ESRD). Cyst formation requires multiple mechanisms and apoptosis is considered one of them. Abnormalities in apoptotic processes have been described in various murine and rodent models of PKD as well as in human PKD kidneys. The purpose of this review is to outline the role of apoptosis in progression of PKD as well as to describe the mechanisms involved. This article is part of a Special Issue entitled: Polycystic Kidney Disease. PMID- 21241799 TI - Biliverdin reductase--a protein levels and activity in the brains of subjects with Alzheimer disease and mild cognitive impairment. AB - Biliverdin reductase-A is a pleiotropic enzyme involved not only in the reduction of biliverdin-IX-alpha into bilirubin-IX-alpha, but also in the regulation of glucose metabolism and cell growth secondary to its serine/threonine/tyrosine kinase activity. Together with heme oxygenase, whose metabolic role is to degrade heme into biliverdin-IX-alpha, it forms a powerful system involved in the cell stress response during neurodegenerative disorders. In this paper, an up regulation of the biliverdin reductase-A protein levels was found in the hippocampus of the subjects with Alzheimer disease and arguably its earliest form, mild cognitive impairment. Moreover a significant reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A was found, and this was paralleled by a marked reduction in its reductase activity. Interestingly, the levels of both total and phosphorylated biliverdin reductase-A were unchanged as well as its enzymatic activity in the cerebella. These results demonstrated a dichotomy between biliverdin reductase-A protein levels and activity in the hippocampus of subjects affected by Alzheimer disease and mild cognitive impairment, and this effect likely is attributable to a reduction in the phosphorylation of serine, threonine and tyrosine residues of biliverdin reductase-A. Consequently, not just the increased levels of biliverdin reductase-A, but also its changed activity and phosphorylation state, should be taken into account when considering potential biomarkers for Alzheimer disease and mild cognitive impairment. PMID- 21241800 TI - Biophysical properties of mutant KCNQ1 S277L channels linked to hereditary long QT syndrome with phenotypic variability. AB - Hereditary long QT syndrome (LQTS) is associated with ventricular torsade de pointes tachyarrhythmias and sudden cardiac death. Mutations in a cardiac voltage gated potassium channel, KCNQ1, induce the most frequent variant of LQTS. We identified a KCNQ1 missense mutation, KCNQ1 S277L, in a patient presenting with recurrent syncope triggered by emotional stress (QTc=528ms). This mutation is located in the conserved S5 transmembrane region of the KCNQ1 channel. Using in vitro electrophysiological testing in the Xenopus oocyte expression system, the S277L mutation was found to be non-functional and to suppress wild type currents in dominant-negative fashion in the presence and in the absence of the regulatory beta-subunit, KCNE1. In addition, expression of S277L and wild type KCNQ1 with KCNE1 resulted in a shift of the voltage-dependence of activation by -8.7mV compared to wild type I(Ks), indicating co-assembly of mutant and wild type subunits. The electrophysiological phenotype corresponds well with the severe clinical phenotype of the index patient. However, investigation of family members revealed three patients that exhibit asymptomatic QT interval prolongation (QTc=493-518ms). In conclusion, this study emphasizes the value of biophysical testing to provide mechanistic evidence for pathogenicity of ion channel mutations identified in LQTS patients. The inconsistent association of the KCNQ1 S277L mutation with the clinical presentation suggests that additional genetic, epigenetic, or environmental factors play a role in defining the individual clinical LQTS phenotype. PMID- 21241801 TI - Amyloid beta impairs mitochondrial anterograde transport and degenerates synapses in Alzheimer's disease neurons. AB - Loss of synapses and synaptic damage are the best correlates of cognitive decline identified in patients with Alzheimer's disease (AD), and mitochondrial oxidative damage and synaptic pathology have been identified as early events in the progression of AD. The progressive accumulation of amyloid beta (Abeta) in synapses and synaptic mitochondria are hypothesized to cause synaptic degeneration and cognitive decline in patients with AD. However, the precise mechanistic link between Abeta and mitochondria is not well understood. The purpose of this study was to better understand the effects of Abeta on mitochondrial axonal transport and synaptic alterations in AD. Using mouse hippocampal neurons and Abeta(25-35) peptide, we studied axonal transport of mitochondria, including mitochondrial motility, mitochondrial length and size, mitochondrial index per neurite, and synaptic alterations of the hippocampal neurons. In the PBS-treated neurons, 36.4+/-4.7% of the observed mitochondria were motile, with 21.0+/-1.3% moving anterograde and 15.4+/-3.4% moving retrograde and the average speed of movement was 12.1+/-1.8MUm/min. In contrast, in the Abeta-treated neurons, the number of motile mitochondria were significantly less, at 20.4+/-2.6% (P<0.032), as were those moving anterograde (10.1+/-2.6%, P<0.016) relative to PBS-treated neurons, suggesting that the Abeta(25-35) peptide impairs axonal transport of mitochondria in AD neurons. In the Abeta-treated neurons, the average speed of motile mitochondria was also less, at 10.9+/-1.9MUm/min, and mitochondrial length was significantly decreased. Further, synaptic immunoreactivity was also significantly less in the Abeta treated neurons relative to the PBS-treated neurons, indicating that Abeta affects synaptic viability. These findings suggest that, in neurons affected by AD, Abeta is toxic, impairs mitochondrial movements, reduces mitochondrial length, and causes synaptic degeneration. PMID- 21241802 TI - Pharmaceutical acrylic beads obtained by suspension polymerization containing cellulose nanowhiskers as excipient for drug delivery. AB - Direct compression is one of the most popular techniques to prepare tablets but only a few commercial excipients are well adapted for this process into controlled release formulations. In the last years, the introduction of new materials for drug delivery matrix tablets has become more important. This paper evaluated the physicochemical and flow properties of new polymeric excipient of ethyl acrylate, methyl methacrylate and butyl metacrylate, synthesized by suspension polymerization using cellulose nanowhiskers as co-stabilizer, to be used as direct compression for modified release tablets. Infrared spectroscopy (FTIR) confirmed the success of the copolymerization reaction. Scanning electron microscopy (SEM) showed that excipient was obtained how spherical beads. Thermal properties of the beads were characterized by thermogravimetric (TG) analysis. Particle size analysis of the beads with cellulose nanowhiskers (CNWB) indicated that the presence of the nanowhiskers led to a reduction of particle size and to a narrower size distribution. In vitro test showed that the nanowhiskers and beads produced are nontoxic. Parameters such as Hausner ratio, Carr's index and cotangent of angle alpha were employed to characterize the flow properties of CNWB beads. Furthermore, the beads are used to produce tablets by direct compression contained propranolol hydrochloride as model drug. Dissolution tests performed suggested that beads could be used as excipient in matrix tablets with a potential use in drug controlled release. PMID- 21241803 TI - Inhibition of T-cell activation and proliferation by mycophenolic acid in patients awaiting liver transplantation: PK/PD relationships. AB - Mycophenolic acid (MPA) plasma concentrations were reported to be associated with a decrease in T-cell proliferation, and in both IL-2 alpha-chain (CD25) and transferin receptor (CD71) expression. The aim of this study was to confirm, quantify and model these PK/PD relationships. Full profiles of MPA plasma concentrations, T-cell proliferation, intracytoplasmic IL-2 and TNF-alpha expression, and both CD71 and CD25 expression were collected over the 12h after dosing in 10 patients on the waiting list for liver transplantation. Data were analyzed using NONMEM((r)). Both CD25 and CD71 expression and T cell proliferation clearly decreased (median of decrease from baseline 62%, 68% and 94%, respectively) with increasing MPA concentrations, in contrast to IL-2 and TNF-alpha expression. The CD25 and CD71 baseline expression (E(0)) and maximum effect (E(max)) were correlated with the E(0) and E(max) values of T-cell proliferation (r(2)=0.509 and r(2)=0.622, respectively). The CD25, CD71 expression and T-cell proliferation profiles were adequately fitted using a sigmoid inhibitory E(max) model. Low estimated values (<=2 mg/L) for 50% inhibitory MPA concentrations were obtained. This study confirmed a transient MPA concentration-dependent decrease in T-cells expressing CD25 and CD71 and a strong reduction of T-cell proliferation and showed that CD25 and CD71 expression was correlated with T-cell proliferation. PMID- 21241804 TI - Paediatric pharmacology: remember the excipients. AB - Excipients are largely used by pharmaceutical industry to guarantee preservation and stability and confer shape, volume and consistency to pharmaceutical preparations. They are particularly important in medicines intended for prescription in children since they often play a critical role in manufacturing of suitable paediatric formulations. It was generally believed that excipients were inert substances; on the contrary, it is actually well known that excipients are far from being inactive and much more interest is growing about safety issues associated with their extensive use by pharmaceutical industry in general, and for manufacturing of paediatric drugs in particular. PMID- 21241806 TI - Role of Neph2 in pontine nuclei formation in the developing hindbrain. AB - Nuclei are anatomical units of the central nervous system (CNS). Their formation sets the structural basis for the functional organization of the brain, a process known as nucleogenesis. In the present study, we investigated the role of the transmembrane immunoglobulin superfamily molecule Neph2 in the nucleogenesis of the pontine nucleus (PN). Neph2 expression is turned on in migrating PN neurons only after they enter the presumptive nuclear region. Neph2 knockdown disrupted the nuclear organization of PN presumably by changing the migratory behavior of PN neurons inside the nuclear region. Moreover, overexpression of the cytoplasmic region of Neph2, which can sequester intracellular signaling of endogenous Neph2, resulted in similar phenotypes. Overall, these results suggest Neph2 is involved in the nucleogenesis of the PN through the control of neuronal migration inside the nucleus. PMID- 21241805 TI - Cytokines inhibit norepinephrine transporter expression by decreasing Hand2. AB - Functional noradrenergic transmission requires the coordinate expression of enzymes involved in norepinephrine (NE) synthesis, as well as the norepinephrine transporter (NET) which removes NE from the synapse. Inflammatory cytokines acting through gp130 can suppress the noradrenergic phenotype in sympathetic neurons. This occurs in a subset of sympathetic neurons during development and also occurs in adult neurons after injury. For example, cytokines suppress noradrenergic function in sympathetic neurons after axotomy and during heart failure. The molecular basis for suppression of noradrenergic genes is not well understood, but previous studies implicated a reduction of Phox2a in cytokine suppression of dopamine beta hydroxylase. We used sympathetic neurons and neuroblastoma cells to investigate the role of Phox2a in cytokine suppression of NET transcription. Chromatin immunoprecipitation experiments revealed that Phox2a did not bind the NET promoter, and overexpression of Phox2a did not prevent cytokine suppression of NET transcription. Hand2 and Gata3 are transcription factors that induce noradrenergic genes during development and are present in mature sympathetic neurons. Both Hand2 and Gata3 were decreased by cytokines in sympathetic neurons and neuroblastoma cells. Overexpression of either Hand2 or Gata3 was sufficient to rescue NET transcription following suppression by cytokines. We examined expression of these genes following axotomy to determine if their expression was altered following nerve injury. NET and Hand2 mRNAs decreased significantly in sympathetic neurons 48 h after axotomy, but Gata3 mRNA was unchanged. These data suggest that cytokines can inhibit NET expression through downregulation of Hand2 or Gata3 in cultured sympathetic neurons, but axotomy in adult animals selectively suppresses Hand2 expression. PMID- 21241807 TI - Burkavidin: a novel secreted biotin-binding protein from the human pathogen Burkholderia pseudomallei. AB - The avidin-biotin technology has many applications, including molecular detection; immobilization; protein purification; construction of supramolecular assemblies and artificial metalloenzymes. Here we present the recombinant expression of novel biotin-binding proteins from bacteria and the purification and characterization of a secreted burkavidin from the human pathogen Burkholderia pseudomallei. Expression of the native burkavidin in Escherichia coli led to periplasmic secretion and formation of a biotin-binding, thermostable, tetrameric protein containing an intra-monomeric disulphide bond. Burkavidin showed one main species as measured by isoelectric focusing, with lower isoelectric point (pI) than streptavidin. To exemplify the potential use of burkavidin in biotechnology, an artificial metalloenzyme was generated using this novel protein-scaffold and shown to exhibit enantioselectivity in a rhodium catalysed hydrogenation reaction. PMID- 21241808 TI - Expression of Apostichopus japonicus lysozyme in the methylotrophic yeast Pichia pastoris. AB - Apostichopus japonicus (sea cucumber) is one of the economically important farmed echinoderm species in Northern China. As a crucial enzyme in innate immunity, lysozyme plays a key role in the overall defense against pathogens in A. japonicus. In the present study, a lysozyme gene from A. japonicus was cloned by PCR and expressed in Pichia pastoris using the expression vector pPIC9K. The expressed lysozyme had a molecular mass of ~14 kD, as shown by SDS-PAGE and Western-blotting. The expression condition was optimized, and the highest expression level was achieved by induction with 1% methanol at pH 5.0 for 120 h. The recombinant lysozyme was purified by affinity chromatography using a Ni-NTA column. The specific activity of the purified lysozyme was 34,000 U/mg using Micrococcus lysodeikticus as substrates. It exhibited antimicrobial activity toward M.lysodeikticus, as detected by growth inhibition on agar plate and turbidity assay, suggesting a potential application of A. japonicus lysozyme as an antimicrobial agent in A. japonicus aquaculture. PMID- 21241809 TI - Cortical thickness correlates of specific cognitive performance accounted for by the general factor of intelligence in healthy children aged 6 to 18. AB - Prevailing psychometric theories of intelligence posit that individual differences in cognitive performance are attributable to three main sources of variance: the general factor of intelligence (g), cognitive ability domains, and specific test requirements and idiosyncrasies. Cortical thickness has been previously associated with g. In the present study, we systematically analyzed associations between cortical thickness and cognitive performance with and without adjusting for the effects of g in a representative sample of children and adolescents (N=207, Mean age=11.8; SD=3.5; Range=6 to 18.3 years). Seven cognitive tests were included in a measurement model that identified three first order factors (representing cognitive ability domains) and one second-order factor representing g. Residuals of the cognitive ability domain scores were computed to represent g-independent variance for the three domains and seven tests. Cognitive domain and individual test scores as well as residualized scores were regressed against cortical thickness, adjusting for age, gender and a proxy measure of brain volume. g and cognitive domain scores were positively correlated with cortical thickness in very similar areas across the brain. Adjusting for the effects of g eliminated associations of domain and test scores with cortical thickness. Within a psychometric framework, cortical thickness correlates of cognitive performance on complex tasks are well captured by g in this demographically representative sample. PMID- 21241812 TI - Molecular phylogeny of the Neoplecostominae and Hypoptopomatinae (Siluriformes: Loricariidae) using multiple genes. AB - A phylogenetic analysis is provided for representatives of more than one hundred species of the catfish family Loricariidae, including nearly all genera of the subfamilies Neoplecostominae and Hypoptopomatinae. This analysis is based on fragments of the subunit 1 of the cytochrome c oxidase gene (COI), the recombination activating genes 1 (RAG1) and 2 (RAG2), and the F-Reticulon 4 gene. We obtained an alignment of 4678 contiguous nucleotides for 136 species of 50 loricariid genera from five loricariid subfamilies, and ten outgroup species from five loricarioid families. Our results from Maximum Parsimony, Maximum Likelihood, and Bayesian analyses show the following set of interrelationships ((((Hypoptopomatinae, Neoplecostominae) Hypostominae), Loricariinae) Delturinae). However, neither Hypoptopomatinae nor Neoplecostominae were recovered as monophyletic groups. A previously hypothesized monophyly of Hypoptopomatini and Otothyrini was refuted. Furthermore, the genera Pareiorhaphis, Pareiorhina, Hisonotus and Parotocinclus were recovered as polyphyletic. PMID- 21241811 TI - Analysis of the evolutionary forces shaping mitochondrial genomes of a Neotropical malaria vector complex. AB - Many vectors of human malaria belong to complexes of morphologically indistinguishable cryptic species. Here we report the analysis of the newly sequenced complete mitochondrial DNA molecules from six recognized or putative species of one such group, the Neotropical Anopheles albitarsis complex. The molecular evolution of these genomes had been driven by purifying selection, particularly strongly acting on the RNA genes. Directional mutation pressure associated with the strand-asynchronous asymmetric mtDNA replication mechanism may have shaped a pronounced DNA strand asymmetry in the nucleotide composition in these and other Anopheles species. The distribution of sequence polymorphism, coupled with the conflicting phylogenetic trees inferred from the mitochondrial DNA and from the published white gene fragment sequences, indicates that the evolution of the complex may have involved ancient mtDNA introgression. Six protein coding genes (nad5, nad4, cox3, atp6, cox1 and nad2) have high levels of sequence divergence and are likely informative for population genetics studies. Finally, the extent of the mitochondrial DNA variation within the complex supports the notion that the complex consists of a larger number of species than until recently believed. PMID- 21241813 TI - Identification of a novel helitron transposon in the genome of Antarctic fish. AB - Rolling-circle (RC) eukaryotic transposons, known as helitrons, are found in a wide range of organisms, from protist to mammals. Autonomous helitrons have a distinctive open reading frame (ORF) encoding a polypeptide that contains typical domains for RC replication (RCR): the Rep (RCR initiator) and the DNA helicase domains. These elements are believed to have an important role in the host genome evolution, owing to their frequent capture of host genes, some of which can evolve into novel genes or become essential for helitron transposition. We conducted a molecular analysis of the suborder Notothenioidei, a group of Perciformes that currently dominate the Antarctic waters by virtue of their remarkable cold-adaptation ability. A novel helitron from the genome of the icefish species Chionodraco hamatus, belonging to the Channichthyidae, the most derived Notothenioids family, was isolated, characterized and designated as HeliNoto (8.9 kb). Its ORF was compared to homologous sequences from different species in a comprehensive phylogenetic analysis. For the first time the putative functional domains of a helitron were subjected to a well accurate structural analysis including chromosomal localization. Finally, the distribution of HeliNoto among Notothenioids was investigated. PMID- 21241810 TI - Immunotherapeutic modulation of the suppressive liver and tumor microenvironments. AB - The liver is an immunologically unique organ, consisting of resident hematopoietic and parenchymal cells which often contribute to a relatively tolerant microenvironment. It is also becoming increasingly clear that tumor induced immunosuppression occurs via many of the same cellular mechanisms which contribute to the tolerogenic liver microenvironment. Myeloid cells, consisting of dendritic cells (DC), macrophages and myeloid derived suppressor cells (MDSC), have been implicated in providing a tolerogenic liver environment and immune dysfunction within the tumor microenvironment which can favor tumor progression. As we increase our understanding of the biological mechanisms involved for each phenotypic and/or functionally distinct leukocyte subset, immunotherapeutic strategies can be developed to overcome the inherent barriers to the development of improved strategies for the treatment of liver disease and tumors. In this review, we discuss the principal myeloid cell-based contributions to immunosuppression that are shared between the liver and tumor microenvironments. We further highlight immune-based strategies shown to modulate immunoregulatory cells within each microenvironment and enhance anti-tumor responses. PMID- 21241814 TI - Multilocus analysis of a taxonomically densely sampled dataset reveal extensive non-monophyly in the avian family Locustellidae. AB - The phylogeny of most of the species in the avian passerine family Locustellidae is inferred using a Bayesian species tree approach (Bayesian Estimation of Species Trees, BEST), as well as a traditional Bayesian gene tree method (MrBayes), based on a dataset comprising one mitochondrial and four nuclear loci. The trees inferred by the different methods agree fairly well in topology, although in a few cases there are marked differences. Some of these discrepancies might be due to convergence problems for BEST (despite up to 1*10(9) iterations). The phylogeny strongly disagrees with the current taxonomy at the generic level, and we propose a revised classification that recognizes four instead of seven genera. These results emphasize the well known but still often neglected problem of basing classifications on non-cladistic evaluations of morphological characters. An analysis of an extended mitochondrial dataset with multiple individuals from most species, including many subspecies, suggest that several taxa presently treated as subspecies or as monotypic species as well as a few taxa recognized as separate species are in need of further taxonomic work. PMID- 21241815 TI - Genetic and molecular characterization of a blue light photoreceptor MGWC-1 in Magnaporth oryzae. AB - Three key factors involved in successful plant disease development include the presence of a susceptible host, a virulent pathogen, and a disease-conducive environment. Our understanding of how environmental factors influence disease conducive or disease-suppressive conditions, and how a pathogen advantageously capitalizes on them, is quite limited. Utilizing the model pathosystem Magnaporthe oryzae-Oryza sativa, we found a significant light-dependent disease suppression. Our genetic data suggest that the blue-light receptor MGWC-1 in M. oryzae is involved in light-dependent disease suppression during the dark-phase (disease-conducive light condition) immediately after pathogen-host contact. Sensing "darkness" is accomplished by MGWC-1, a blue-light receptor in M. oryzae. To explore the potential molecular mechanisms of light-dependent disease suppression we performed a genome-wide microarray experiment and identified several groups of gene families that are differentially regulated during the light-to-dark transition. Our genetic and molecular data provide insights into how a fungal pathogen utilizes ambient light signals for successful disease development. PMID- 21241816 TI - From zero to hero--design-based systems metabolic engineering of Corynebacterium glutamicum for L-lysine production. AB - Here, we describe the development of a genetically defined strain of l-lysine hyperproducing Corynebacterium glutamicum by systems metabolic engineering of the wild type. Implementation of only 12 defined genome-based changes in genes encoding central metabolic enzymes redirected major carbon fluxes as desired towards the optimal pathway usage predicted by in silico modeling. The final engineered C. glutamicum strain was able to produce lysine with a high yield of 0.55 g per gram of glucose, a titer of 120 g L(-1) lysine and a productivity of 4.0 g L(-1) h(-1) in fed-batch culture. The specific glucose uptake rate of the wild type could be completely maintained during the engineering process, providing a highly viable producer. For these key criteria, the genetically defined strain created in this study lies at the maximum limit of classically derived producers developed over the last fifty years. This is the first report of a rationally derived lysine production strain that may be competitive with industrial applications. The design-based strategy for metabolic engineering reported here could serve as general concept for the rational development of microorganisms as efficient cellular factories for bio-production. PMID- 21241817 TI - Search for new naturally occurring strains of Pleurotus to improve yields: Pleurotus albidus as a novel proposed species for mushroom production. AB - BACKGROUND: The species of genus Pleurotus are worldwide cultivated. AIMS: To evaluate growth, yield production and morphological variations of fruiting bodies obtained from the cultivation of fourteen naturally occurring Pleurotus strains isolated from Argentina. METHODS: The strains growth was tested at different temperatures on Nobles' medium. Substrates assayed were: supplemented Salix sawdust, supplemented and non supplemented wheat straw. The species studied were Pleurotus albidus, Pleurotus cystidiosus, Pleurotus djamor, Pleurotus ostreatus and Pleurotus pulmonarius. RESULTS: The maximum rate growth was reached by strains of P. pulmonarius, P. albidus, and P. ostreatus. No relationship was found when optimal mycelium growth, incubation time and yields were compared. The highest yield was obtained with P. albidus on wheat straw (biological efficiency 171.3%) which overcame in 82% the yield obtained for the commercial strain in the same substrate. When morphological variations were analyzed for each species, significant differences were found among strains. It was also possible to find a naturally occurring strain of P. ostreatus with better biological efficiency than the commercial strain assayed. CONCLUSIONS: We propose the study of naturally occurring strains as a useful practice to improve yields of species of Pleurotus. Due to the high biological efficiency obtained we propose P. albidus as a new species for commercial production. PMID- 21241818 TI - Fungal bloodstream infections in tertiary care hospitals in Colombia. AB - BACKGROUND: Fungal infections have increased in critical care patients, causing high morbidity and mortality. AIMS: Describe the frequency and responsible fungal species involved in bloodstream fungal infection from 2001 to 2007 in tertiary care level hospitals belonging to a surveillance network in Colombian cities. METHODS: Data were collected from a microbiology surveillance network based on 27 hospital laboratories in five Colombian cities. Data were entered into a Whonet(r) version 5.4 database. Fungemia data were analyzed according to location (Intensive care unit -ICU- vs. non-ICU services). Frequency over time was also described. RESULTS: Fungal infections corresponded to 4.1% of all bloodstream infections. Candidemia represented 3.7% and 5.2% of all isolates in non-ICU and ICU services, respectively. Over 99% of the isolates were yeasts, and Candida albicans was the most frequently isolated organism in and out of the ICU, showing a decreasing trend in the last few years. In the adult ICU and non-ICU services, the second organism most frequently isolated was C. tropicalis, while C. parapsilopsis was the most frequent in the pediatric and neonatal ICU, also showing an overall decreasing trend. Cryptococcus neoformans was the fourth mycotic organism most frequently identified. CONCLUSIONS: In Colombia, epidemiology of fungal infections seems to be changing. C. albicans is the principal agent causing bloodstream fungal infection, but an increase of non albicans species has been observed as well as high frequency of C. neoformans. PMID- 21241819 TI - Promotion of phagocytosis of Streptococcus pyogenes in human blood by a fibrinogen-binding peptide. AB - The binding of fibrinogen to M-related protein (Mrp) is known to contribute to the ability of Streptococcus pyogenes to evade phagocytosis by preventing the deposition of complement on the streptococcal surface. The objectives of this investigation were to map the common fibrinogen-binding domain of Mrp and to determine if this domain has a therapeutic potential to enhance phagocytosis of S. pyogenes in human blood. Using a series of recombinant, truncated proteins of Mrp, two fibrinogen-binding domains (FBD) were mapped. FBD1 was contained within amino acid residues 1-55 of Mrp and FBD2 within residues 81-138. FBD2 is found in all Mrp sequenced to date whereas FBD1 is not. Both FBD1 and FBD2 peptides but not a control peptide blocked the binding of fibrinogen to S. pyogenes and promoted phagocytosis of the streptococci in human blood. The data support the hypothesis that the binding of fibrinogen by S. pyogenes is centrally involved in their resistance to phagocytosis in human blood and suggest that treatments that interfere with the binding of fibrinogen to S. pyogenes may help in fighting infections by these organisms. PMID- 21241820 TI - Enhancer of zeste homolog 2: A potential target for tumor therapy. AB - Enhancer of zeste homolog 2 (EZH2) is a subunit of the Polycomb-Repressive Complex 2 (PRC2), which catalyses the trimethylation of histone H3 on Lys 27 (H3K27) and involves in genes repression. EZH2 is amplified and overexpressed in a variety of cancers, including prostate and breast cancer. Overexpression of EZH2 has been associated with the invasion and progression of malignant cancers, especially with the progression of prostate cancer. Here, we review the structure and biological function of EZH2, especially focused on its activities in the tumorigenesis. PMID- 21241821 TI - Biomonitoring of a population of Portuguese workers exposed to lead. AB - Lead is a heavy metal that has been used for many centuries and it is still used for various industrial purposes thanks to its physical and chemical characteristics. Human exposure to lead can result in a wide range of biological effects depending upon the level and duration of exposure. Despite the fact that lead has been found capable of eliciting genotoxic responses in a wide range of tests, not all studies have been conclusive. Although several experimental studies have shown that lead may modulate immune responses, data in exposed humans are still preliminary. The purpose of our study was to evaluate the genotoxic and immunotoxic effects of lead exposure in a group of 70 male workers from two Portuguese factories. The control group comprised 38 healthy males. The exposed individuals showed significantly higher levels of lead in blood and zinc protoporphyrin, and significantly lower delta-aminolevulinic acid dehydratase activity than the controls, suggesting a relatively high lead exposure. Nevertheless, the limit of 70 MUg/dl for lead in blood established by the Portuguese regulation was never reached. Results of the comet assay were not modified by the exposure, but a significant increase in the mutation frequency in the exposed workers was obtained in the T-cell receptor mutation assay. Furthermore, data obtained in the analysis of the different lymphocyte subsets showed a significant decrease in %CD8+ cells and a significant increase in the %CD4+/%CD8+ ratio in exposed individuals with regard to the controls. No clear effect was observed for vitamin D receptor genetic polymorphism on the parameters evaluated. In view of our results showing mutagenic and immunotoxic effects related to lead exposure in occupational settings, it seems that the Portuguese biological exposure limit for lead needs to be revised in order to increase the safety of exposed workers. PMID- 21241822 TI - Ontologies for clinical and translational research: Introduction. PMID- 21241823 TI - An efficient statistical feature selection approach for classification of gene expression data. AB - Classification of gene expression data plays a significant role in prediction and diagnosis of diseases. Gene expression data has a special characteristic that there is a mismatch in gene dimension as opposed to sample dimension. All genes do not contribute for efficient classification of samples. A robust feature selection algorithm is required to identify the important genes which help in classifying the samples efficiently. In order to select informative genes (features) based on relevance and redundancy characteristics, many feature selection algorithms have been introduced in the past. Most of the earlier algorithms require computationally expensive search strategy to find an optimal feature subset. Existing feature selection methods are also sensitive to the evaluation measures. The paper introduces a novel and efficient feature selection approach based on statistically defined effective range of features for every class termed as ERGS (Effective Range based Gene Selection). The basic principle behind ERGS is that higher weight is given to the feature that discriminates the classes clearly. Experimental results on well-known gene expression datasets illustrate the effectiveness of the proposed approach. Two popular classifiers viz. Nave Bayes Classifier (NBC) and Support Vector Machine (SVM) have been used for classification. The proposed feature selection algorithm can be helpful in ranking the genes and also is capable of identifying the most relevant genes responsible for diseases like leukemia, colon tumor, lung cancer, diffuse large B cell lymphoma (DLBCL), prostate cancer. PMID- 21241824 TI - Point: M cells are present in the ventricular myocardium. PMID- 21241825 TI - Reversal of left bundle and His bundle potentials during wide complex tachycardia: what is the mechanism? PMID- 21241826 TI - Counterpoint: M cells do not have a functional role in the ventricular myocardium of the intact heart. PMID- 21241827 TI - How many measurements for time-averaged differences in repeated measurement studies? AB - In many studies, investigators have perceived the number of repeated measurements as a fixed design characteristic. However, the number of repeated measurements is a design choice that can be informed by statistical considerations. In this paper, we investigate how the number of repeated measurements affects the required sample size in longitudinal studies with scheduled assessment times and a fixed total duration. It is shown that the required sample size always decreases as the number of measurements per subject increases under the compound symmetry (CS) correlation. The magnitude of sample size reduction, however, quickly shrinks to less than 5% when the number of measurements per subject increases beyond 4. We then reveal a counterintuitive property of the AR(1) correlation structure, under which making additional measurements from each subject might increase the sample size requirement. This observation suggests that practitioners should be cautious about assuming the AR(1) model in repeated measurements studies, whether in experimental design or in data analysis. Finally, we show that by introducing measurement error into the AR(1) model, the counterintuitive behavior disappears. That is, additional measurements per subject result in reduced sample sizes. PMID- 21241828 TI - COACH trial: a randomized controlled trial of nurse practitioner/community health worker cardiovascular disease risk reduction in urban community health centers: rationale and design. AB - BACKGROUND: Despite well-publicized guidelines on the appropriate management of cardiovascular disease (CVD) and type 2 diabetes, implementation of risk-reducing practices remains poor. This paper describes the rationale and design of a randomized controlled clinical trial evaluating the effectiveness of a comprehensive program of CVD risk reduction delivered by nurse practitioner (NP)/community health worker (CHW) teams versus enhanced usual care in improving the proportion of patients in urban community health centers who achieve goal levels recommended by national guidelines for lipids, blood pressure, HbA1c and prescription of appropriate medications. METHODS: The COACH (Community Outreach and Cardiovascular Health) trial is a randomized controlled trial in which patients at federally-qualified community health centers were randomly assigned to one of two groups: comprehensive intensive management of CVD risk factors for one year by a NP/CHW team or an enhanced usual care control group. RESULTS: A total of 3899 patients were assessed for eligibility and 525 were randomized. Groups were comparable at baseline on sociodemographic and clinical characteristics with the exception of statistically significant differences in total cholesterol and hemoglobin A1c. CONCLUSIONS: This study is a novel amalgam of multilevel interdisciplinary strategies to translate highly efficacious therapies to low-income federally-funded health centers that care for patients who carry a disproportionate burden of CVD, type 2 diabetes and uncontrolled CVD risk factors. The impact of such a community clinic-based intervention is potentially enormous. PMID- 21241829 TI - Molecular epidemiology of Orientia tsutsugamushi in Cambodia and Central Vietnam reveals a broad region-wide genetic diversity. AB - Scrub typhus is an acute infectious disease caused by an obligate intracellular bacterium Orientia tsutsugamushi following the bite of infected trombiculid mites of the genus Leptotrombidium. This zoonotic disease is a major cause of febrile illness in the Asia-Pacific region, with a large spectrum of clinical manifestations from unapparent or mild disease to fatal disease. O. tsutsugamushi is characterized by a very high genomic plasticity and a large number of antigenic variants amongst strains. The 56-kDa type specific antigen (TSA) gene, encoding the major antigenic protein, was used as reference to investigate the genetic relationships between the strains and to genotype O. tsutsugamushi isolates. The open reading frame of the 56-kDa TSA gene of 41 sequences (28 Cambodian and 13 Vietnamese strains) from patient samples were sequenced and used for genotyping. The 28 Cambodian isolates clustered into 5 major groups, including Karp (43.5%), JG-v (25%), Kato/TA716 (21.5%), TA763 (3.5%) and Gilliam (3.5%). Karp (77%), TA763 (15.5%) and JG-v (7.5%) strains were identified amongst the 13 Vietnamese isolates. This is the first countrywide genotyping description in Cambodia and in Central Vietnam. These results demonstrate the considerable diversity of genotypes in co-circulation in both countries. The genotyping result might raise awareness amongst Cambodian and Vietnamese clinicians of the high genetic diversity of circulating O. tsutsugamushi strains and provides unique and beneficial data for serological and molecular diagnosis of scrub typhus infections as well as raw materials for future studies and vaccine development. PMID- 21241830 TI - Alpha-actinin: a multidisciplinary protein with important role in B-cell driven autoimmunity. AB - Alpha-actinin (alpha-actinin) is a ubiquitous cytoskeletal protein, which belongs to the superfamily of filamentous actin (F-actin) crosslinking proteins. It is present in multiple subcellular regions of both muscle and non-muscle cells, including cell-cell and cell-matrix contact sites, cellular protrusions and stress fiber dense regions and thus, it seems to bear multiple important roles in the cell by linking the cytoskeleton to many different transmembrane proteins in a variety of junctions. Four isoforms of human alpha-actinin have already been identified namely, the "muscles" alpha-actinin-2 and alpha-actinin-3 and the "non muscles" alpha-actinin-1 and alpha-actinin-4. The precise functions of alpha actinin isoforms as well as the precise role and significance of their binding to F-actin particularly in-vivo, have been elusive. They are generally believed to represent key structural components of large-scale F-actin cohesion in cells required for cell shape and motility. alpha-Actinin-2 has been implicated in myopathies such as nemalin body myopathy, hypertrophic and dilated cardiomyopathy and it may have at least an indirect pathogenetic role in diseases of the central nervous system (CNS) like schizophrenia, epilepsy, ischemic brain damage, CNS lupus and neurodegenerative disorders. The role of "non-muscle" alpha-actinins in the kidney seems to be crucial as an essential component of the glomerular filtration barrier. Therefore, they have been implicated in the pathogenesis of familial focal segmental glomerulosclerosis, nephrotic syndrome, IgA nephropathy, focal segmental glomerulosclerosis and minimal change disease. alpha-Actinin is also expressed on the membrane and cytosol of parenchymal and ductal cells of the liver and it seems that it interacts with hepatitis C virus in an essential way for the replication of the virus. Finally alpha-actinin, especially alpha-actinin 4, has been implicated in cancer cell progression and metastasis, as well as the migration of several cell types participating in the immune response. Based on these functions, the accumulating reported evidence of the importance of alpha actinin as a target autoantigen in the pathogenesis of autoimmune diseases, particularly systemic lupus erythematosus and autoimmune hepatitis, is also discussed along with the possible perspectives that are potentially emerging from the study of this peculiar molecule in health and disease. PMID- 21241831 TI - Chitosan microparticles incorporating gold as an enhanced contrast flow tracer in dynamic X-ray imaging. AB - In situ monitoring of a biofluid can provide important information on circulatory disorders and a basic understanding on the metabolic mechanisms of living organisms. X-ray imaging has significant advantages as one of the most popular diagnostic tools to seethrough various biological systems. Particle traced velocity field measurement is one of the most popular methods for quantitative analysis of dynamic flow motion. In this study we have developed chitosan microparticles incorporating gold nanoparticles (AuNP) as a new enhanced contrast flow tracer for dynamic X-ray imaging. Gold is a useful material possessing high X-ray absorption ability and also biocompatibility. We chose chitosan as an AuNP delivery system because it can effectively trap AuNPs at high yield. In particular, the unique gold ion reduction ability of and compatibility with surface-modified chitosans are effectively utilized. The physical properties of the Au-chitosan microparticles can be controlled by varying the molecular weight of the chitosan employed and the AuNP incorporation methodology. The environment of the particles and the type of applied X-ray essentially determine the imaging efficiency. The designed chitosan microparticles incorporating Au have been successfully applied to track the digestive mechanisms occurring in delicate insects such as live mosquitoes. PMID- 21241832 TI - Cell adhesion to borate glasses by colloidal probe microscopy. AB - The adhesion of osteoblast-like cells to silicate and borate glasses was measured in cell growth medium using colloidal probe microscopy. The probes consisted of silicate and borate glass spheres, 25-50 MUm in diameter, attached to atomic force microscope cantilevers. Variables of the study included glass composition and time of contact of the cell to the glasses. Increasing the time of contact from 15 to 900 s increased the force of adhesion. The data could be plotted linearly on a log-log plot of adhesive force versus time. Of the seven glasses tested, five had slopes close to 0.5, suggesting a square root dependence of the adhesive force on the contact time. Such behavior can be interpreted as a diffusion limited process occurring during the early stages of cell attachment. We suggest that the rate limiting step in the adhesion process is the diffusion of integrins resident in the cell membrane to the area of cell attachment. Data presented in this paper support the hypothesis of Hench et al. that strong adhesion depends on the formation of a calcium phosphate reaction layer on the surfaces of the glass. Glasses that did not form a calcium phosphate layer exhibited a weaker adhesive force relative to those glasses that did form a calcium phosphate layer. PMID- 21241833 TI - Biofabrication of discrete spherical gold nanoparticles using the metal-reducing bacterium Shewanella oneidensis. AB - Nanocrystallites have garnered substantial interest due to their various applications, including catalysis and medical research. Consequently important aspects of synthesis related to control of shape and size through economical and non-hazardous means are desirable. Highly efficient bioreduction-based fabrication approaches that utilize microbes and/or plant extracts are poised to meet these needs. Here we show that the gamma-proteobacterium Shewanella oneidensis can reduce tetrachloroaurate (III) ions to produce discrete extracellular spherical gold nanocrystallites. The particles were homogeneously shaped with multiple size distributions and produced under ambient conditions at high yield, 88% theoretical maximum. Further characterization revealed that the particles consist of spheres in the size range of ~2-50 nm, with an average size of 12+/-5 nm. The nanoparticles were hydrophilic and resisted aggregation even after several months. Based on our experiments, the particles are likely fabricated by the aid of reducing agents present in the bacterial cell membrane and are capped by a detachable protein/peptide coat. Ultraviolet-visible and Fourier transform infrared spectroscopy, X-ray diffraction, energy dispersive X ray spectra and transmission electron microscopy measurements confirmed the formation, surface characteristics and crystalline nature of the nanoparticles. The antibacterial activity of these gold nanoparticles was assessed using Gram negative (Escherichia coli and S. oneidensis) and Gram-positive (Bacillus subtilis) bacterial species. Toxicity assessments showed that the particles were neither toxic nor inhibitory to any of these bacteria. PMID- 21241834 TI - Preparation and characterization of a three-dimensional printed scaffold based on a functionalized polyester for bone tissue engineering applications. AB - At present there is a strong need for suitable scaffolds that meet the requirements for bone tissue engineering applications. The objective of this study was to investigate the suitability of porous scaffolds based on a hydroxyl functionalized polymer, poly(hydroxymethylglycolide-co-epsilon-caprolactone) (pHMGCL), for tissue engineering. In a recent study this polymer was shown to be a promising material for bone regeneration. The scaffolds consisting of pHMGCL or poly(epsilon-caprolactone) (PCL) were produced by means of a rapid prototyping technique (three-dimensional plotting) and were shown to have a high porosity and an interconnected pore structure. The thermal and mechanical properties of both scaffolds were investigated and human mesenchymal stem cells were seeded onto the scaffolds to evaluate the cell attachment properties, as well as cell viability and differentiation. It was shown that the cells filled the pores of the pHMGCL scaffold within 7 days and displayed increased metabolic activity when compared with cells cultured in PCL scaffolds. Importantly, pHMGCL scaffolds supported osteogenic differentiation. Therefore, scaffolds based on pHMGCL are promising templates for bone tissue engineering applications. PMID- 21241835 TI - Influence of different polymeric gels on the ectopic bone forming ability of an osteoinductive biphasic calcium phosphate ceramic. AB - To evaluate moldable osteoinductive putties for bone repair we combined microstructured biphasic calcium phosphate (BCP) particles with five different polymeric gels, carboxymethyl cellulose (CMC), Pluronic((r)) F-127 (PLU), polyvinyl alcohol (PVA), chitosan (CHI) and alginate (ALG). In vitro gel dissolution showed that CMC, PLU and ALG gels dissolved rapidly (within hours), while the CHI gel took several days and the PVA gel did not dissolve within 2 weeks. Implanting the putty formulations into sheep muscle for 12 weeks demonstrated ectopic bone formation in the control BCP group as well as the putties prepared with dissolving gels (CMC, PLU, ALG and CHI). Bone was not seen in the putty comprising PVA. Quantitative data showed that the CMC and PLU gels did not significantly affect the osteoinductivity of BCP granules, while the ALG and CHI gels showed a significant decrease in bone formation. These results suggest that the dissolvability and chemistry of the gels may be factors affecting the osteoinduction of the putties. PMID- 21241836 TI - Redox proteomics and drug development. AB - As alterations of the redox homeostasis lie at the root of many pathophysiological processes in human health, redox proteomics holds the promise to shed further light on fundamental biological processes. In this review, the mechanisms of reactive oxygen species (ROS) and reactive nitrogen species (RNS) production are reviewed, mainly addressing those chemical phenomena which have already been associated with pathological conditions (of the central nervous system, cardiovascular system, or simply related to aging and altered-cell cycle regulation). From Alzheimer's to Parkinson's and Hungtinton's disease, from ageing to cancer, oxidative stress (OS) appears to represent a common trait in so many relevant biological aspects of human health, that further investments in the field of redox proteomics ought to be mandatory. For the foreseeable future, redox proteomics will likely play a pivotal role in the quest for new therapeutical targets and their validation, in the process of determining OS triggered cellular alteration upon drug treatments and thus in the very heart of the design and testing of new drugs and their metabolites against those pathologies relying on altered redox homeostasis. PMID- 21241837 TI - deltaEF1 promotes osteolytic metastasis of MDA-MB-231 breast cancer cells by regulating MMP-1 expression. AB - Breast cancer metastasis is supposed to involve several stages in which epithelial-mesenchymal transition (EMT) is regarded as the mechanistic basis for the behavior of cancer cells. Our recent studies have implicated that deltaEF1, a member of the zinc finger-homeodomain transcription factor family, is required for governing both breast cancer EMT and bone remodeling, highlighting a potential role of deltaEF1 in modulating bone metastasis of breast cancer. In the present study, we further demonstrated that conditioned medium derived from deltaEF1-overexpressing MDA-MB-231 cells significantly induces osteoclast maturation and concurrently represses osteoblast differentiation and mineralization. On the contrary, conditioned medium derived from deltaEF1 interfered MDA-MB-231 cells exhibits an opposite effect, thus confirming the effect of deltaEF to mediate osteolytic metastasis of breast cancer. Furthermore, we found that, during this process, deltaEF1 remarkably up-regulates matrix metalloproteinase-1 (MMP-1) expression at both mRNA and protein levels in MDA-MB 231 cells. Importantly, the results of luciferase and CHIP assays indicated that deltaEF1 activates MMP-1 promoter activity through the AP-1 response element. Overexpression of deltaEF1 in MDA-MB-231 cells significantly increases the recruitment of the AP-1 components, c-Jun/c-Fos, to the endogenous MMP-1 promoter, which in effect could be mediated via the MAPK signaling pathway. In conclusion, these observations suggest a potent role of deltaEF1 to promote breast cancer metastasis to bone by regulating secretion of growth factors in the tumor microenvironment. PMID- 21241838 TI - Mitigation of bone loss with ultrasound induced dynamic mechanical signals in an OVX induced rat model of osteopenia. AB - This study tests the hypothesis that an ultrasound generated dynamic mechanical signal can attenuate bone loss in an estrogen deficient model of osteopenia. Eighty-four 16-week-old Sprague-Dawley rats were divided into six groups: baseline control, age-matched control, ovariectomy (OVX) control, OVX+5mW/cm(2) ultrasound (US), OVX+30mW/cm(2) US and OVX+100mW/cm(2) US. Low intensity pulsed ultrasound (LIPUS) was delivered transdermally at the L4/L5 vertebrae, using gel coupled plane wave US transducers. The signal, characterized by 200MUs pulses of 1.5MHz sine waves repeating at 1kHz with spatial-averaged temporal-averaged (SATA) intensities of 5, 30 or 100mW/cm(2), was applied 20 min/day, 5 days/week for 4 weeks. OVX treatment reduced bone volume fraction 40% and compromised microstructure at 4 weeks. LIPUS treatment, however, significantly increased BV/TV (+33%) compared to OVX controls for the 100mW/cm(2) treated group. SMI and Tb.N showed significant improvements compared with OVX for the 100mW/cm(2) treated group and Tb.Th was significantly improved in the 30 and 100mW/cm(2) treated groups. Improvements in bone's microstructural characteristics with 100mW/cm(2) US treatment translated into improved load bearing characteristics, including a significant 42% increase in apparent level elastic modulus compared to OVX controls. Significant improvement of trabecular mechanical strength was also observed in the treated animals, e.g., principal compressive stress (represent bone's ability to resist loads) was significantly higher compared to OVX controls. Histomorphometric analysis also showed that treatment with 100mW/cm(2) US resulted in a 76% improvement in MS/BS. In addition, measures of bone quantity and quality at the femoral metaphysis suggest that LIPUS is site specific. This study indicates that localized ultrasound treatment, delivered at specific intensities, has beneficial effects on intact bone and may represent a novel intervention for bone loss. PMID- 21241840 TI - A novel automated electrochemical ascorbic acid assay in the 24-well microtiter plate format. AB - Automatic ascorbic acid (AA) voltammetry was established in 24-well microtiter plates. The assay used a movable assembly of a pencil rod working, an Ag/AgCl reference and a Pt counter electrode with differential pulse voltammetry (DPV) for concentration-dependent current generation. A computer was in command of electrode (z) and microtiter plate (x, y) positioning and timed potentiostat operation. Synchronization of these actions supported sequential approach of all wells and subsequent execution of electrode treatment procedures or AA voltammetry at defined intervals in a measuring cycle. DPV in well solutions offered a linear current/concentration range between 0.1 and 8.0 mM, a sensitivity of about 1 MUA mM(-1) AA, and a detection limit of 50 MUM. When used with a calibration curve or standard addition, automated voltammetry of samples with added known amounts of AA demonstrated good recovery rates. Also, the assay achieved the accurate determination of the AA content of vitamin C tablets, a fruit juice and an herbal tea extract. Robotic AA voltammetry has the advantage of conveniently handling multiple samples in a single measuring run without the continuous attention of laboratory personnel. It is a good option when the goal is cost-effective AA screening of sample libraries and has potential for applications in health care and the food processing, cosmetic and pharmaceutical industries. PMID- 21241841 TI - Integrated electrochemical transistor as a fast recoverable gas sensor. AB - A new design of conductometric chemical sensors based on conducting polymers as chemosensitive elements was suggested. The sensor includes six electrodes. Four inner electrodes coated by chemosensitive polymer are used for simultaneous two- and four-point resistance measurements thus providing information on the bulk polymer resistance and on the resistance of the polymer/electrode contacts. Two outer electrodes wired to inner electrodes by polymeric electrolyte are used for electrical control of redox state of the chemosensitive polymer. The outer electrodes are connected to potentiostat as reference and counter electrodes. It allows us to control redox state of the inner (working) electrodes. This new measurement configuration, resembling chemosensitive electrochemical transistors, provides an internal test of the sensor integrity and an electrically driven sensor regeneration. It was tested as a sensor for the detection of nitrogen dioxide. Polythiophene or polyaniline was used as receptors. Cyclic voltammograms of these polymers on the sensor surface measured in air atmosphere were very similar to that measured in aqueous electrolyte. A control of conductivity of these chemosensitive polymers by electrical potential applied vs. incorporated reference electrode was demonstrated. This effect was used for the regeneration of the chemosensitive material after exposure to nitrogen dioxide: in comparison to usual chemiresistors displaying an irreversible behavior in such test even in the time scale of hours, a completely reversible sensor regeneration within few minutes was observed. PMID- 21241839 TI - Mechanical loads and cortical bone geometry in healthy children and young adults. AB - Muscle and bone form a functional unit. While muscle size is a useful surrogate of mechanical load on bone, the independent contributions to bone strength of muscle force, muscle size, gravitational load (body weight), and physical activity have not been assessed. Three hundred twenty-one healthy participants (32% black, 47% male), aged 5-35 years were assessed. Peak dorsiflexion muscle torque (ft-lbs) of the ankle was assessed using isometric dynamometry. Tibia peripheral quantitative computed tomography measures included polar section modulus (Zp; mm(3)), periosteal and endosteal circumference (mm), cortical area (mm(2)), and volumetric bone mineral density (vBMD; mg/cm(3)) at the 38% site, and muscle cross-sectional area (CSA; mm(2)), at the 66% site. Physical activity (average hours per week) was assessed by questionnaire. Log linear regression was used to assess determinants of muscle specific force (MSF; torque relative to muscle CSA) and Zp adjusted for age and tibia length. MSF was greater in blacks than whites (p<0.05) and lower in females than males (p<0.001). Zp was greater in blacks than whites (p=0.002) in Tanner stages 1-4, but the difference was attenuated in Tanner 5 (interaction, p=0.02); R(2)=0.87. Muscle CSA, muscle torque, body weight, and physical activity were added to the model and each load covariate was independently and significantly (all, p<0.02) associated with Zp (R(2)=0.92), periosteal circumference, and cortical area. Inclusion of these measures attenuated but did not eliminate the significant race differences. Only muscle CSA was positively associated with endosteal circumference, while none of the load covariates were associated with vBMD. In conclusion, bone geometry is associated with several factors that define the mechanical load on bone, independent of age, tibia length, maturation, race, and sex. Race differences in Zp were not explained by these measures of mechanical load. Given that inclusion of muscle torque, body weight, and physical activity resulted in a nominal increase in the R(2), muscle size is an adequate surrogate for the mechanical load on bone in healthy participants. PMID- 21241842 TI - Microfluidic DNA microarray analysis: a review. AB - Microarray DNA hybridization techniques have been used widely from basic to applied molecular biology research. Generally, in a DNA microarray, different probe DNA molecules are immobilized on a solid support in groups and form an array of microspots. Then, hybridization to the microarray can be performed by applying sample DNA solutions in either the bulk or the microfluidic manner. Because the immobilized probe DNA binds and retains its complementary target DNA, detection is achieved through the read-out of the tagged markers on the sample target molecules. The recent microfluidic hybridization method shows the advantages of less sample usage and reduced incubation time. Here, sample solutions are confined in microfabricated channels and flow through the probe microarray area. The high surface-to-volume ratio in microchannels of nanolitre volume greatly enhanced the sensitivity as obtained with the bulk solution method. To generate nanolitre flows, different techniques have been developed, and this including electrokinetic control, vacuum suction and syringe pumping. The latter two are pressure-driven methods which are more flexible without the need of considering the physicochemical properties of solutions. Recently, centrifugal force is employed to drive liquid movement in microchannels. This method utilizes the body force from the liquid itself and there are no additional solution interface contacts such as from electrodes or syringes and tubing. Centrifugal force driven flow also features the ease of parallel hybridizations. In this review, we will summarize the recent advances in microfluidic microarray hybridization and compare the applications of various flow methods. PMID- 21241843 TI - Biosensors and rapid diagnostic tests on the frontier between analytical and clinical chemistry for biomolecular diagnosis of dengue disease: a review. AB - The past decades have witnessed enormous technological improvements towards the development of simple, cost-effective and accurate rapid diagnostic tests for detection and identification of infectious pathogens. Among them is dengue virus, the etiologic agent of the mosquito-borne dengue disease, one of the most important emerging infectious pathologies of nowadays. Dengue fever may cause potentially deadly hemorrhagic symptoms and is endemic in the tropical and sub tropical world, being also a serious threat to temperate countries in the developed world. Effective diagnostics for dengue should be able to discriminate among the four antigenically related dengue serotypes and fulfill the requirements for successful decentralized (point-of-care) testing in the harsh environmental conditions found in most tropical regions. The accurate identification of circulating serotypes is crucial for the successful implementation of vector control programs based on reliable epidemiological predictions. This paper briefly summarizes the limitations of the main conventional techniques for biomolecular diagnosis of dengue disease and critically reviews some of the most relevant biosensors and rapid diagnostic tests developed, implemented and reported so far for point-of-care testing of dengue infections. The invaluable contributions of microfluidics and nanotechnology encompass the whole paper, while evaluation concerns of rapid diagnostic tests and foreseen technological improvements in this field are also overviewed for the diagnosis of dengue and other infectious and tropical diseases as well. PMID- 21241844 TI - Highly sensitive detection of silybin based on adsorptive stripping analysis at single-sided heated screen-printed carbon electrodes modified with multi-walled carbon nanotubes with direct current heating. AB - A new disposable multi-walled carbon nanotubes modified single-sided heated screen-printed carbon electrode (MWNT/ss-HSPCE) was fabricated. The electrochemical behavior of silybin was investigated by cyclic voltammetry and the probable electrode reaction mechanism was proposed. A simple and cheap direct current heating supplier was used to heating the electrode for adsorptive accumulation of silybin. The square wave voltammetric stripping peak current of silybin at MWNT/ss-HSPCE with an elevated electrode temperature of 50 degrees C only during accumulation step was dramatically improved compared with that at bare single-sided heated screen-printed carbon electrode (ss-HSPCE) without heating. This enhancement was mainly contributed to the combination of the advantages of multi-walled carbon nanotubes and electrically heated electrodes. Under optimum conditions, two detection linear ranges of silybin were from 1.0*10(-9) to 1.0*10(-7) M and 3.0*10(-7) to 1.0*10(-6) M. A detection limit of 5.0*10(-10) M could be obtained (S/N=3), which was more than two magnitudes lower than that at bare ss-HSPCE without heating. To the best of our knowledge, this was also at least two magnitudes lower than any others for electrochemical detection of silybin in the literature. Finally, the method was successfully applied to the determination of silybin in pharmaceutical tablets. PMID- 21241845 TI - Liquid-phase microextraction with in-drop derivatization combined with microvolume fluorospectrometry for free and hydrolyzed formaldehyde determination in textile samples. AB - A new miniaturized methodology based on the combination of headspace single drop microextraction and microvolume fluorospectrometry is proposed in this work for the determination of free and hydrolyzed formaldehyde in textile samples. The proposed method is based on the extraction and in-drop derivatization of free and hydrolyzed formaldehyde using the Hantzsch reaction. The effect of experimental variables affecting the performance of the proposed method, such as fluorescence parameters, nature of the extractant phase composition (including acetylacetone concentration, pH, ammonium acetate concentration and presence of an organic solvent), sample temperature, NaCl concentration and microextraction time was carefully investigated. Under optimized conditions, instrumental detection and quantification limits were 26 and 87 MUg L(-1), respectively, whereas procedural detection and quantification limits were 1.0 and 3.5 mg kg(-1), respectively. Repeatability, expressed as relative standard deviation, was 4.6% (n=9). The method was successfully applied to the determination of free and hydrolyzed formaldehyde in several textile samples, the found results being in good agreement with those obtained with the EN ISO 14184-1:1998 method. PMID- 21241846 TI - Application of porous membrane protected micro-solid-phase-extraction combined with gas chromatography-mass spectrometry for the determination of estrogens in ovarian cyst fluid samples. AB - A cost effective and environmentally friendly extraction technique using porous membrane protected micro-solid phase extraction (MU-SPE) is described for the extraction of estrogens in cyst fluid samples obtained from cancer patients. A sorbent (ethylsilane (C2) modified silica) (20 mg) was packed in a porous polypropylene envelope (2 cm*1.5 cm) whose edges were heat sealed to secure the contents. The MU-SPE device was conditioned with acetone and placed in a stirred (1:5) diluted cyst fluid sample solution (10 mL) to extract estrogens for 60 min. After extraction, the analytes were desorbed and simultaneously derivatized with a 5:1 mixture of acetone and N,O-bis(trimethylsilyl)-trifluoroacetamide. The extract (2 MUL) was analyzed by gas chromatography-mass spectrometry. Various extraction, desorption and derivatization conditions were optimized for MU-SPE. With this simple technique, low limits of detection of between 9 and 22 ng L(-1) and linear range from the detection limits up to 50 MUg L(-1) were achieved. The optimized method was used to extract estrogens from cyst fluid samples obtained from patients with malignant and benign ovarian tumors. PMID- 21241847 TI - Extraction mechanism of sulfamethoxazole in water samples using aqueous two-phase systems of poly(propylene glycol) and salt. AB - Based on the poly(propylene glycol)(400) (PPG(400))-salt aqueous two-phase system (ATPS), a green, economical and effective sample pretreatment technique coupled with high performance liquid chromatography was proposed for the separation and determination of sulfamethoxazole (SMX). The extraction yield of SMX in PPG(400) salt ATPS is influenced by various factors, including the salt species, the amount of salt, pH, and the temperature. Under the optimum conditions, most of SMX was partitioning into the polymer-rich phase with the average extraction efficiency of 99.2%, which may be attributed to the hydrophobic interaction and salting-out effect. This extraction technique has been successfully applied to the analysis of SMX in real water samples with the recoveries of 96.0-100.6%, the detection limits of 0.1 MUg L(-1), and the linear ranges of 2.5-250.0 MUg L(-1). PMID- 21241848 TI - Pros and cons of analytical methods to quantify surrogate contaminants from the challenge test in recycled polyethylene terephthalate. AB - Different analytical methods were optimized and applied to quantify certain surrogate contaminants (toluene, chlorobenzene, phenol, limonene and benzophenone) in samples of contaminated and recycled flakes and virgin pellets of polyethylene terephthalate (PET) coming from the industrial challenge test. A screening analysis of the PET samples was carried out by direct solid-phase microextraction (SPME) in headspace mode (HS). The methods developed and used for quantitative analysis were a) total dissolution of PET samples in dichloroacetic acid and analysis by HS-SPME coupled to gas chromatography-mass spectrometry (GC MS) and, b) dichloromethane extraction and analysis by GC-MS. The concentration of all surrogates in the contaminated PET flakes analyzed by HS-SPME method was lower than expected according to information provided by the supplier. Dichloroacetic acid interacted with the surrogates, resulting in a tremendous decrease of limonene concentration. The degradation compounds from limonene were identified. Dichloromethane extraction and GC-MS analysis evidenced the highest values of analytes in these PET samples. Based on the foregoing data, the efficiency of the recycling process was evaluated, whereby the removal of 99.9% of the surrogates proceeding from the contaminated flakes was confirmed. PMID- 21241849 TI - Quartz crystal microbalance as a sensing active element for rupture scanning within frequency band. AB - A new method based on the use of quartz crystal microbalance (QCM) as an active sensing element is developed, optimized and tested in a model system to measure the rupture force and deduce size distribution of nanoparticles. As suggested by model predictions, the QCM is shaped as a strip. The ratio of rupture signals at the second and the third harmonics versus the geometric position of a body on QCM surface is investigated theoretically. Recommendations concerning the use of the method for measuring the nanoparticle size distribution are presented. It is shown experimentally for an ensemble of test particles with a characteristic size within 20-30 nm that the proposed method allows one to determine particle size distribution. On the basis of the position and value of the measured rupture signal, a histogram of particle size distribution and percentage of each size fraction were determined. The main merits of the bond-rupture method are its rapid response, simplicity and the ability to discriminate between specific and non-specific interactions. The method is highly sensitive with respect to mass (the sensitivity is generally dependent on the chemical nature of receptor and analyte and may reach 8*10(-14) g mm(-2)) and applicable to measuring rupture forces either for weak bonds, for example hydrogen bonds, or for strong covalent bonds (10(-11)-10(-9) N). This procedure may become a good alternative for the existing methods, such as AFM or optical methods of determining biological objects, and win a broad range of applications both in laboratory research and in biosensing for various purposes. Possible applications include medicine, diagnostics, environmental or agricultural monitoring. PMID- 21241850 TI - Quantum dot-based "turn-on" fluorescent probe for detection of zinc and cadmium ions in aqueous media. AB - Health or environmental issue caused by abnormal level of metal ions like Zn(2+) or Cd(2+) is a worldwide concern. Developing an inexpensive and facile detection method for Zn(2+) and Cd(2+) is in urgent demand. Due to their super optical properties, fluorescent quantum dots (QDs) have been developed as a promising alternative for organic dyes in fluorescence analysis. In this study, a CdTe QDs based sensitive and selective probe for Zn(2+) and Cd(2+) in aqueous media was reported. The proposed probe worked in fluorescence "turn-on" mode. The initial bright fluorescence of CdTe QDs was effectively quenched by sulfur anions (S(2 )). The presence of Zn(2+) (or Cd(2+)) can "turn-on" the weak fluorescence of QDs quenched by S(2-) due to the formation of ZnS (or CdS) passivation shell. Under optimal conditions, a good linear relationship between the fluorescence response and concentration of Zn(2+) (or Cd(2+)) could be obtained in the range from 1.6 to 35 MUM (1.3-25 MUM for Cd(2+)). The limit of detection (LOD) for Zn(2+) and Cd(2+) were found to be 1.2 and 0.5 MUM, respectively. Furthermore, the present probe exhibited a high selectivity for Zn(2+) and Cd(2+) over other metal ions and was successfully used in the detection of Zn(2+) or Cd(2+) in real water samples. PMID- 21241852 TI - Transient clamp-induced mechanical block of pulmonary vein potentials. PMID- 21241851 TI - Label-free capacitive immunosensor based on quartz crystal Au electrode for rapid and sensitive detection of Escherichia coli O157:H7. AB - A label-free capacitive immunosensor based on quartz crystal Au electrode was developed for rapid and sensitive detection of Escherichia coli O157:H7. The immunosensor was fabricated by immobilizing affinity-purified anti-E. coli O157:H7 antibodies onto self-assembled monolayers (SAMs) of 3-mercaptopropionic acid (MPA) on the surface of a quartz crystal Au electrode. Bacteria suspended in solution became attached to the immobilized antibodies when the immunosensor was tested in liquid samples. The change in capacitance caused by the bacteria was directly measured by an electrochemical detector. An equivalent circuit was introduced to simulate the capacitive immunosensor. The immunosensor was evaluated for E. coli O157:H7 detection in pure culture and inoculated food samples. The experimental results indicated that the capacitance change was linearly correlated with the cell concentration of E. coli O157:H7. The immunosensor was able to discriminate between cellular concentrations of 10(2) 10(5) cfu mL(-1) and has applications in detecting pathogens in food samples. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were also employed to characterize the stepwise assembly of the immunosensor. PMID- 21241853 TI - Bigger. PMID- 21241854 TI - Joint Council on Thoracic Surgical Education: an investment in our future. PMID- 21241855 TI - Midterm results with thoracic endovascular aortic repair for chronic type B aortic dissection with associated aneurysm. AB - OBJECTIVE: Thoracic endovascular aortic repair for chronic type B aortic dissection with associated descending thoracic aneurysm remains controversial. Concerns include potential ischemic complications due to branch vessel origin from the chronic false lumen and continued retrograde false lumen/aneurysm sac pressurization via fenestrations distal to implanted endografts. The present study examines midterm results with thoracic endovascular aortic repair for chronic (>2 weeks) type B aortic dissection with associated aneurysm to better understand the potential role of thoracic endovascular aortic repair for this condition. METHODS: Between March 2005 and December 2009, 51 thoracic endovascular aortic repair procedures were performed at a single institution for management of chronic type B dissection. The indication for thoracic endovascular aortic repair was aneurysm in all cases. A subset of 7 patients (14%) underwent placement of the EndoSure wireless pressure measurement system (CardioMEMS, Inc, Atlanta, Ga) in the false lumen adjacent to the primary tear for monitoring aneurysm sac/false lumen pulse pressure after thoracic endovascular aortic repair. RESULTS: Mean patient age was 57+/-12 years (range, 30-82 years); 14 patients (28%) were female. Mean aortic diameter was 6.2+/-1.4 cm. There were no in-hospital/30-day deaths, strokes, or permanent paraplegia/paresis. There were no complications related to compromise of downstream branch vessels arising from the false lumen. Two patients (3.9%) who had preexisting ascending aortic dilation had retrograde acute type A aortic dissection; both were repaired successfully. Median postoperative length of stay was 4 days. Mean follow-up is 27.0+/-16.5 months (range, 2-60 months). Actuarial overall survival is 77.7% at 60 months with an actuarial aorta-specific survival of 98% over this same time period. Actuarial freedom from reintervention is 77.3% at 60 months. All patients with the EndoSure wireless pressure measurement system exhibited a decrease in aneurysm sac/false lumen pulse pressure indicating a depressurized false lumen. The aneurysm sac/false lumen pulse pressure ratio decreased from 52%+/-27% at the predischarge measurement to 14%+/-5% at the latest follow-up reading (P=.029). CONCLUSIONS: Thoracic endovascular aortic repair for chronic type B dissection with associated aneurysm is safe and effective at midterm follow-up. Aneurysm sac/false lumen pulse pressure measurements demonstrate a significant reduction in false lumen endotension, thus ruling out clinically significant persistent retrograde false lumen perfusion and provide proof of concept for a thoracic endovascular aortic repair-based approach. Longer-term follow-up is needed to determine the durability of thoracic endovascular aortic repair for this aortic pathology. PMID- 21241856 TI - Predictive value of surgical scoring systems in determining operative risk for octogenarians undergoing aortic valve replacement. PMID- 21241859 TI - Synchronized epiaortic two-dimensional and color Doppler echocardiographic guidance enables routine ascending aortic cannulation in type A acute aortic dissection. AB - OBJECTIVES: Preference for arterial inflow during surgery for type A acute aortic dissection remains controversial. Antegrade central perfusion prevents malperfusion and retrograde embolism, and the ascending aorta provides arterial access for rapid establishment of systemic perfusion, especially if there is hemodynamic instability. It has not been used routinely, however, because of the disruption caused to the aorta. We evaluated the safety and efficacy of routine cannulation of the dissected aorta for the repair of type A dissection. METHODS: Surgical results were analyzed for 83 consecutive patients with type A acute aortic dissection between 2002 and 2009. They were treated surgically by prosthetic graft replacement under hypothermic circulatory arrest. The ascending aorta was routinely cannulated using the Seldinger technique with epiaortic echocardiographic guidance; antegrade systemic perfusion was evaluated by color Doppler ultrasound. RESULTS: Systemic antegrade perfusion via the dissected ascending aorta was performed safely in all cases. There was no malperfusion or thromboembolism as a result of ascending aortic cannulation. Epiaortic 2 dimensional and color Doppler imaging provided real-time monitoring adequate for the placement and for proper systemic perfusion. There were 5 in-hospital deaths (5/83=6.0%) and 8 strokes (preoperative 6/83=7.2%, postoperative 2/83=2.4%). A total of 78 patients (78/83=94%) were discharged and have been followed up without major adverse cardiac events for a mean duration of 31.8 months. CONCLUSIONS: Ascending aortic cannulation is a simple and safe technique that provides a rapid and reliable route of antegrade central systemic perfusion in type A aortic dissection. PMID- 21241857 TI - Effects of different annuloplasty ring types on mitral leaflet tenting area during acute myocardial ischemia. AB - OBJECTIVE: The study objective was to quantify the effects of different annuloplasty rings on mitral leaflet septal-lateral tenting areas during acute myocardial ischemia. METHODS: Radiopaque markers were implanted along the central septal-lateral meridian of the mitral valve in 30 sheep: 1 each to the septal and lateral aspects of the mitral annulus and 4 and 2 along the anterior and posterior mitral leaflets, respectively. Ten true-sized Carpentier-Edwards Physio, Edwards IMR ETLogix, and GeoForm annuloplasty rings (Edwards Lifesciences, Irvine, Calif) were inserted in a releasable fashion. Marker coordinates were obtained using biplane videofluoroscopy with ring inserted at baseline (RING_BL) and after 90 seconds of left circumflex artery occlusion (RING_ISCH). After ring release, another dataset was acquired before (No_Ring_BL) and after left circumflex artery occlusion (No_Ring_ISCH). Anterior and posterior mitral leaflet tenting areas were computed at mid-systole from sums of marker triangles with the midpoint between the annular markers being the vertex for all triangles. RESULTS: Compared with No_Ring_BL, mitral regurgitation grades and all tenting areas significantly increased with No_Ring_ISCH. Compared with No_Ring_ISCH, (1) all rings significantly prevented mitral regurgitation and reduced all tenting areas; (2) Edwards IMR ETLogix and GeoForm rings reduced posterior mitral leaflet area, but not anterior mitral leaflet tenting area, to a significantly greater extent than the Carpentier-Edwards Physio ring; and (3) Edwards IMR ETLogix and GeoForm rings affected tenting areas similarly. CONCLUSIONS: In response to acute left ventricular ischemia, disease-specific functional/ischemic mitral regurgitation rings (Edwards IMR ETLogix, GeoForm) more effectively reduced posterior mitral leaflet area, but not anterior mitral leaflet tenting area, compared with true-sized physiologic rings (Carpentier Edwards Physio). Despite its radical 3-dimensional shape and greater amount of mitral annular septal-lateral downsizing, the GeoForm ring did not reduce tenting areas more than the Edwards IMR ETLogix ring, suggesting that further reduction in tenting areas in patients with FMR/IMR may not be effectively achieved on an annular level. PMID- 21241860 TI - Stage II palliation of hypoplastic left heart syndrome without cardiopulmonary bypass. AB - OBJECTIVES: Bidirectional cavopulmonary anastomosis has been performed without cardiopulmonary bypass for some single-ventricle heart defects. Limited data are available for the outcomes of off-pump bidirectional cavopulmonary anastomosis in infants with hypoplastic left heart syndrome. The purpose of this study is to determine the early outcomes for stage II palliation of hypoplastic left heart syndrome without cardiopulmonary bypass. METHODS: This is a retrospective review of infants having surgical palliation of hypoplastic left heart syndrome from April 2003 to March 2010 at a single institution. RESULTS: Seventy-five infants had a modified Norwood procedure, 65 with a right ventricle-pulmonary artery conduit, 10 with an aortopulmonary shunt, 2 with atrioventricular valve repair, and 3 with extracorporeal life support. Sixty-eight patients had hypoplastic left heart syndrome or one of its variants, and 7 had other single-ventricle lesions. There were 2 stage I deaths. Stage I survival was 97% (95% confidence interval, 88%-99%). Another 5 infants succumbed in the interstage period. Of the 68 stage I and interstage survivors, 61 had bidirectional cavopulmonary anastomoses, 20 without cardiopulmonary bypass. Median age was 6 months (range, 4-13 months), and median weight was 6.1 kg (range, 5.2-9.0 kg). There were no conversions to cardiopulmonary bypass when off-pump bidirectional cavopulmonary anastomosis was attempted. There were no hospital deaths. Median ventilation duration was 10 hours (range, 6-18 hours), and length of stay was 5 days (range, 4-9 days). Follow-up was available on all infants at a median duration of 17 months (range, 3-43 months), with no unplanned reinterventions. CONCLUSIONS: Bidirectional cavopulmonary anastomosis without the use of cardiopulmonary bypass can be performed safely and with low mortality for selected infants with hypoplastic left heart syndrome. Midterm to long-term outcomes remain to be determined. PMID- 21241861 TI - Stenotic aortic valves have dysfunctional mechanisms of anti-inflammation: implications for aortic stenosis. AB - OBJECTIVE: Aortic stenosis is an inflammatory disease, associated with increased tissue levels of interleukin-1 beta. We hypothesized that the antagonist of interleukin-1 beta, interleukin-1 receptor antagonist, is deficient in aortic valves and that its production by aortic valve interstitial cells is less in cells from stenotic valves than from controls. METHODS: Valve leaflets from stenotic aortic valves (n=6) and from valves from hearts explanted at the time of cardiac transplantation (n=6) were studied by immunostaining for interleukin-1 receptor antagonist. Aortic valve interstitial cells were isolated from valves, and receptor antagonist levels were determined from cell lysates (enzyme-linked immunosorbent assay). Osteogenic phenotype changes in valve cells stimulated by toll-like receptors 2 and 4 were determined by immunoblotting for bone morphogenetic protein-2 after treatment with and without interleukin-1 receptor antagonist (100 MUg/mL). Statistics were by analysis of variance. RESULTS: Interleukin-1 receptor antagonist was abundant in nonstenotic aortic valve leaflets and virtually absent in leaflets from stenotic valves. Aortic valve interstitial cells from grossly normal leaflets produced significantly more receptor antagonist at baseline and in response to toll-like receptor 2 and 4 stimulation, than did cells from diseased valves (P<0.05). Interleukin-1 receptor antagonist was able to significantly attenuate toll-like receptor 2, but not toll like receptor 4, stimulated bone morphogenetic protein-2 production in aortic valve interstitial cells (P<.05). CONCLUSIONS: Interleukin-1 receptor antagonist mediated mechanisms of anti-inflammation are dysfunctional in stenotic valves. We conclude that such impaired mechanisms of anti-inflammation may contribute to the pathogenesis of aortic stenosis. PMID- 21241862 TI - Eighteen-month outcome of pulmonary valve stent implantation by direct right ventricle puncture: an animal study. AB - OBJECTIVE: The purpose of this study was to investigate the feasibility and safety of pulmonary valve implantation via direct right ventricle puncture. METHODS: A standard thoracotomy and direct right ventricle puncture were performed in 8 healthy sheep to implant the pulmonary valve stents. Animals were followed up for 18 months. RESULTS: Three sheep died within the first 4 months after stent placement. The remaining 5 animals survived. After 18 months, examinations by color echocardiography, 64-slice computed tomography scan, and cardiac catheter showed an ideal position of each stent. The function of the pulmonary valves and hearts was not different compared with the preoperative conditions of the sheep. Anatomic examination revealed that the stent was covered by a layer of endothelial tissue with no stent fracture or valvular calcification. The histologic evaluation of the stent and surrounding tissue showed that the surface of the stent was smooth and covered by a complete layer of endothelial cells without obvious infiltration of inflammatory cells. The vascular wall was integrative without tear phenomenon in each layer of tissue. CONCLUSIONS: These results show that pulmonary valve stents can be implanted via direct right ventricle puncture. Further studies evaluating xenograft valve material and the effect of implantation in vivo are needed. PMID- 21241863 TI - Factors associated with in-hospital mortality in infants undergoing heart transplantation in the United States. AB - OBJECTIVE: Infants undergoing heart transplantation have the highest early posttransplant mortality of any age group. We sought to determine the pretransplantation factors associated with in-hospital mortality in transplanted infants in the current era. METHODS: All infants under 12 months of age who underwent primary heart transplantation during a recent 10-year period (1999 2009) in the United States were identified using the Organ Procurement and Transplant Network database. Multivariable logistic regression was used to identify independent pretransplantation factors associated with in-hospital mortality. RESULTS: Of 730 infants in the study (median age 3.8 months), 462 (63%) had congenital heart disease, 282 (39%) were supported by a ventilator, 94 (13%) with extracorporeal membrane oxygenation, and 22 (3%) with a ventricular assist device at the time of transplantation. Overall, 82 (11.2%) infants died before their initial hospital discharge. In adjusted analysis, in-hospital mortality was associated with repaired congenital heart disease (odds ratio [OR], 3.6; 95% confidence interval [CI], 1.8, 7.2), unrepaired congenital heart disease not on prostaglandin E (OR, 2.8; CI, 1.3, 6.1), extracorporeal membrane oxygenator support (OR, 6.1; CI, 2.8, 13.4), ventilator support (OR, 4.4; CI, 2.3, 8.3), creatinine clearance less than 40 mL.min(-1).1.73 m(-2) (OR, 3.1; CI, 1.7, 5.3), and dialysis (OR, 6.2; CI, 2.1, 18.3) at transplantation. CONCLUSIONS: One in 9 infants undergoing heart transplantation dies before hospital discharge. Pretranplantation factors associated with early mortality include congenital heart disease, extracorporeal membrane oxygenator support, mechanical ventilation, and renal failure. Risk stratification for early posttransplant mortality among infants listed for heart transplantation may improve decision making for transplant eligibility, organ allocation, and posttransplant interventions to reduce mortality. PMID- 21241864 TI - Veno-venous extracorporeal membrane oxygenation with interatrial shunting: a novel approach to lung transplantation for patients in right ventricular failure. AB - OBJECTIVE: This study evaluated the effectiveness of an atrial septostomy with veno-venous extracorporeal membrane oxygenation in alleviating high afterload right ventricular dysfunction while providing respiratory support. This technique could be applied as a bridge to lung transplantation. METHODS: Sheep (56+/-3 kg) underwent a clamshell thoracotomy and hemodynamic instrumentation, including right ventricular pressure and cardiac output. Sheep with and without tricuspid insufficiency (n=5 each) were examined. While sheep were on extracorporeal membrane oxygenation, right ventricular failure was established by banding the pulmonary artery until cardiac output was 40% to 60% of baseline. An extracardiac atrial shunt was created with modified vascular grafts to examine the effect of shunt flow on hemodynamics. Hemodynamic data were thus collected at baseline, during right ventricular failure, and for 1 hour at 100% (fully open), 70%, 50%, and 30% of baseline shunt flow. RESULTS: Cardiac output was returned to baseline values (tricuspid insufficiency: 5.2+/-0.2 L/min, without tricuspid insufficiency: 5.3+/-1.2 L/min) with 100% shunt flow (tricuspid insufficiency: 4.8+/-1.1 L/min, without tricuspid insufficiency: 4.8+/-1.0 L/min; P=.15) but remained significantly lower than baseline at 70% to 30% shunt flow. At 100% shunt flow, tricuspid insufficiency shunt flow was 1.4+/-0.8 L/min and without tricuspid insufficiency shunt flow was 1.7+/-0.2 L/min. Right ventricular pressure was significantly elevated over baseline values at all shunt flows (P<.001). In the group without tricuspid insufficiency, all sheep died beginning at the 70% shunt condition, whereas all animals with tricuspid insufficiency survived the entire experiment. Normal arterial blood gases were maintained under all conditions. CONCLUSIONS: An atrial septostomy accompanied by veno-venous extracorporeal membrane oxygenation is capable of eliminating right ventricular failure while maintaining normal arterial blood gases if sufficient shunt flows are achieved. The presence of tricuspid insufficiency improves the efficacy of the shunt. PMID- 21241865 TI - Intracavitary tumor spread of a metastatic testicular seminoma in the left atrium and ventricle. PMID- 21241866 TI - Coronary aneurysm with double right coronary artery and fistula. PMID- 21241868 TI - Bioprosthetic durability assessment: importance of complete data. PMID- 21241869 TI - Reply to difference in outcome in the transection of the pulmonary artery and vein. PMID- 21241870 TI - A risk factor for hyperlactatemia after surgical repair of secundum atrial septal defect in children: What is the problem? PMID- 21241871 TI - To fenestrate or not to fenestrate. PMID- 21241872 TI - Comment on editorial by Lapeyre and colleagues. Re: Prosthetic heart valves: difficult to make something simple. PMID- 21241873 TI - Pseudoaneurysm of ascending aorta combined with aortic valve infective endocarditis after cardiac operations for congenital ventricular septal defect. PMID- 21241874 TI - Acute kidney injury after coronary artery bypass grafting: does rhabdomyolysis play a role? PMID- 21241876 TI - Functional mitral stenosis after surgical annuloplasty for ischemic mitral regurgitation: importance of subvalvular tethering in the mechanism and dynamic deterioration during exertion. PMID- 21241878 TI - A self-introduced sharp metallic foreign body migrating transcutaneously to the interventricular septum, mistaken as an inhaled pin. PMID- 21241879 TI - An idea for construction of a new modification of thoracic endograft for treatment of delayed paraplegia. PMID- 21241883 TI - Structure determination and dynamics of protein-RNA complexes by NMR spectroscopy. PMID- 21241884 TI - Interpreting protein chemical shift data. PMID- 21241885 TI - Paramagnetic tagging for protein structure and dynamics analysis. PMID- 21241886 TI - Funding in 2011: East heats up as West cools down. PMID- 21241887 TI - Are polycomb group bodies gene silencing factories? AB - Polycomb group (PcG) proteins mediate long-range associations between Hox genes, which correlate with gene repression in vivo. Bantignies et al. (2011) identify a physiological role for the nuclear localization of Hox genes in PcG-mediated gene silencing, strengthening the evidence that nuclear positioning regulates gene expression. PMID- 21241888 TI - Rallying the exocyst as an autophagy scaffold. AB - Protein scaffolds coordinate the assembly of many multicomponent signaling complexes. Bodemann et al. (2011) now show that the exocyst, a protein complex involved in tethering transport vesicles to the plasma membrane, provides an assembly and activation platform for components of the autophagy machinery via a process requiring the GTPase RalB. PMID- 21241889 TI - High-resolution genome-wide mapping of the primary structure of chromatin. AB - The genomic organization of chromatin is increasingly recognized as a key regulator of cell behavior, but deciphering its regulation mechanisms requires detailed knowledge of chromatin's primary structure-the assembly of nucleosomes throughout the genome. This Primer explains the principles for mapping and analyzing the primary organization of chromatin on a genomic scale. After introducing chromatin organization and its impact on gene regulation and human health, we then describe methods that detect nucleosome positioning and occupancy levels using chromatin immunoprecipitation in combination with deep sequencing (ChIP-Seq), a strategy that is now straightforward and cost efficient. We then explore current strategies for converting the sequence information into knowledge about chromatin, an exciting challenge for biologists and bioinformaticians. PMID- 21241890 TI - Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase independent manner. AB - PTEN is a frequently mutated tumor suppressor gene that opposes the PI3K/AKT pathway through dephosphorylation of phosphoinositide-3,4,5-triphosphate. Recently, nuclear compartmentalization of PTEN was found as a key component of its tumor-suppressive activity; however its nuclear function remains poorly defined. Here we show that nuclear PTEN interacts with APC/C, promotes APC/C association with CDH1, and thereby enhances the tumor-suppressive activity of the APC-CDH1 complex. We find that nuclear exclusion but not phosphatase inactivation of PTEN impairs APC-CDH1. This nuclear function of PTEN provides a straightforward mechanistic explanation for the fail-safe cellular senescence response elicited by acute PTEN loss and the tumor-suppressive activity of catalytically inactive PTEN. Importantly, we demonstrate that PTEN mutant and PTEN null states are not synonymous as they are differentially sensitive to pharmacological inhibition of APC-CDH1 targets such as PLK1 and Aurora kinases. This finding identifies a strategy for cancer patient stratification and, thus, optimization of targeted therapies. PAPERCLIP: PMID- 21241892 TI - Polycomb-dependent regulatory contacts between distant Hox loci in Drosophila. AB - In Drosophila melanogaster, Hox genes are organized in an anterior and a posterior cluster, called Antennapedia complex and bithorax complex, located on the same chromosome arm and separated by 10 Mb of DNA. Both clusters are repressed by Polycomb group (PcG) proteins. Here, we show that genes of the two Hox complexes can interact within nuclear PcG bodies in tissues where they are corepressed. This colocalization increases during development and depends on PcG proteins. Hox gene contacts are conserved in the distantly related Drosophila virilis species and they are part of a large gene interaction network that includes other PcG target genes. Importantly, mutations on one of the loci weaken silencing of genes in the other locus, resulting in the exacerbation of homeotic phenotypes in sensitized genetic backgrounds. Thus, the three-dimensional organization of Polycomb target genes in the cell nucleus stabilizes the maintenance of epigenetic gene silencing. PMID- 21241891 TI - Global regulation of H2A.Z localization by the INO80 chromatin-remodeling enzyme is essential for genome integrity. AB - INO80 is an evolutionarily conserved, ATP-dependent chromatin-remodeling enzyme that plays roles in transcription, DNA repair, and replication. Here, we show that yeast INO80 facilitates these diverse processes at least in part by controlling genome-wide distribution of the histone variant H2A.Z. In the absence of INO80, H2A.Z nucleosomes are mislocalized, and H2A.Z levels at promoters show reduced responsiveness to transcriptional changes, suggesting that INO80 controls H2A.Z dynamics. Additionally, we demonstrate that INO80 has a histone-exchange activity in which the enzyme can replace nucleosomal H2A.Z/H2B with free H2A/H2B dimers. Genetic interactions between ino80 and htz1 support a model in which INO80 catalyzes the removal of unacetylated H2A.Z from chromatin as a mechanism to promote genome stability. PMID- 21241893 TI - Dual action of ATP hydrolysis couples lid closure to substrate release into the group II chaperonin chamber. AB - Group II chaperonins are ATP-dependent ring-shaped complexes that bind nonnative polypeptides and facilitate protein folding in archaea and eukaryotes. A built-in lid encapsulates substrate proteins within the central chaperonin chamber. Here, we describe the fate of the substrate during the nucleotide cycle of group II chaperonins. The chaperonin substrate-binding sites are exposed, and the lid is open in both the ATP-free and ATP-bound prehydrolysis states. ATP hydrolysis has a dual function in the folding cycle, triggering both lid closure and substrate release into the central chamber. Notably, substrate release can occur in the absence of a lid, and lid closure can occur without substrate release. However, productive folding requires both events, so that the polypeptide is released into the confined space of the closed chamber where it folds. Our results show that ATP hydrolysis coordinates the structural and functional determinants that trigger productive folding. PMID- 21241894 TI - RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. AB - The study of macroautophagy in mammalian cells has described induction, vesicle nucleation, and membrane elongation complexes as key signaling intermediates driving autophagosome biogenesis. How these components are recruited to nascent autophagosomes is poorly understood, and although much is known about signaling mechanisms that restrain autophagy, the nature of positive inductive signals that can promote autophagy remain cryptic. We find that the Ras-like small G protein, RalB, is localized to nascent autophagosomes and is activated on nutrient deprivation. RalB and its effector Exo84 are required for nutrient starvation induced autophagocytosis, and RalB activation is sufficient to promote autophagosome formation. Through direct binding to Exo84, RalB induces the assembly of catalytically active ULK1 and Beclin1-VPS34 complexes on the exocyst, which are required for isolation membrane formation and maturation. Thus, RalB signaling is a primary adaptive response to nutrient limitation that directly engages autophagocytosis through mobilization of the core vesicle nucleation machinery. PMID- 21241895 TI - RIM proteins tether Ca2+ channels to presynaptic active zones via a direct PDZ domain interaction. AB - At a synapse, fast synchronous neurotransmitter release requires localization of Ca(2+) channels to presynaptic active zones. How Ca(2+) channels are recruited to active zones, however, remains unknown. Using unbiased yeast two-hybrid screens, we here identify a direct interaction of the central PDZ domain of the active zone protein RIM with the C termini of presynaptic N- and P/Q-type Ca(2+) channels but not L-type Ca(2+) channels. To test the physiological significance of this interaction, we generated conditional knockout mice lacking all multidomain RIM isoforms. Deletion of RIM proteins ablated most neurotransmitter release by simultaneously impairing the priming of synaptic vesicles and by decreasing the presynaptic localization of Ca(2+) channels. Strikingly, rescue of the decreased Ca(2+)-channel localization required the RIM PDZ domain, whereas rescue of vesicle priming required the RIM N terminus. We propose that RIMs tether N- and P/Q-type Ca(2+) channels to presynaptic active zones via a direct PDZ-domain-mediated interaction, thereby enabling fast, synchronous triggering of neurotransmitter release at a synapse. PMID- 21241897 TI - SnapShot: Chromatin remodeling: SWI/SNF. PMID- 21241896 TI - Densely interconnected transcriptional circuits control cell states in human hematopoiesis. AB - Though many individual transcription factors are known to regulate hematopoietic differentiation, major aspects of the global architecture of hematopoiesis remain unknown. Here, we profiled gene expression in 38 distinct purified populations of human hematopoietic cells and used probabilistic models of gene expression and analysis of cis-elements in gene promoters to decipher the general organization of their regulatory circuitry. We identified modules of highly coexpressed genes, some of which are restricted to a single lineage but most of which are expressed at variable levels across multiple lineages. We found densely interconnected cis regulatory circuits and a large number of transcription factors that are differentially expressed across hematopoietic states. These findings suggest a more complex regulatory system for hematopoiesis than previously assumed. PMID- 21241898 TI - European Journal of Radiology. Editorial. PMID- 21241899 TI - When should we biopsy a solitary central cartilaginous tumor of long bones? Literature review and management proposal. AB - Differentiation between benign and low-grade malignant cartilaginous tumors is a radiological and pathological challenge. Based on a literature review, we propose the following guidelines for the management of a solitary central cartilaginous tumor of long bones distinguishing three situations: 1. The tumor is considered to be aggressive and requires surgery if one of the following criteria is present: cortical destruction, Moth-eaten or permeative osteolysis, spontaneous pathologic fracture, periosteal reaction, edema surrounding the tumor on MR images, and soft tissue mass. Tumor biopsy followed by complete intralesional treatment is indicated. 2. The tumor is classified as active if two of the following active criteria are present: pain related to the tumor, endosteal scalloping superior to two-thirds of the cortical thickness, extent of endosteal scalloping superior to two-thirds of the lesion length, cortical thickening and enlargement of the medullary cavity. Tumor biopsy or excision is indicated. 3. The tumor is classified as possibly active if one of the previous active criteria is present. In such cases, bone scintigraphy and dynamic-enhanced MR imaging should be obtained. Radionuclide uptake superior to the anterior iliac crest at bone scintigraphy and early and exponential enhancement at dynamic-enhanced MR are considered as two additional active criteria. After these two examinations, if only one criterion is still present, the lesion can be regarded as possibly quiescent, and the following monitoring is suggested: first follow-up at three to six months and then once a year. Otherwise, if two or more active criteria are present, biopsy is recommended. 4. The tumor is considered quiescent and does not require surgery if no active or aggressive criterion is present. A radiological follow-up can be proposed. PMID- 21241900 TI - Another year of progress. PMID- 21241901 TI - Pars plicata posterior continuous curvilinear capsulorhexis. AB - We describe a technique of pars plicata manual posterior capsulorhexis performed after implantation of an intraocular lens (IOL) in pediatric cataract surgery. The technique can be used to create a posterior capsulectomy of a desirable size in a controlled manner to avoid destabilization of the IOL. It can be applied selectively in cases of pediatric cataract surgery. PMID- 21241902 TI - Air-assisted Descemet-stripping automated endothelial keratoplasty with posterior chamber iris-fixation of aphakic iris-claw intraocular lens. AB - We report a combination of surgical techniques during Descemet-stripping automated endoithelial keratoplasty and intraocular lens (IOL) exchange in patients with pseudophakic bullous keratopathy and angle-supported anterior chamber IOLs. During this procedure, the anterior chamber IOL is exchanged for a posterior chamber iris-claw IOL enclavated to the posterior iris; the anterior chamber is kept filled with air using an air-fluid exchange machine during descemetorhexis and insertion of the donor endothelial disk. PMID- 21241903 TI - Combined phacoemulsification and removal of gas following macular hole surgery. AB - We describe a technique for combined fluid-gas exchange and phacoemulsification 2 weeks after macular hole surgery to achieve rapid visual rehabilitation. The procedure uses a standard cataract set and requires minimal vitreoretinal expertise. We encountered no significant complications and obtained long-term outcomes comparable to those with conventional management. PMID- 21241904 TI - Injectable 1-piece hydrophilic acrylic toric intraocular lens for cataract surgery: efficacy and stability. AB - PURPOSE: To evaluate the efficacy and rotational stability of an injectable 1 piece hydrophilic acrylic toric intraocular lens (IOL). SETTING: Department of Ophthalmology, Hillingdon Hospital, Uxbridge, Middlesex, United Kingdom. DESIGN: Cohort study. METHODS: This study enrolled consecutive patients who had 2.00 diopters (D) or more of preexisting corneal astigmatism. Patients had phacoemulsification with implantation of a T-flex 623T toric IOL through a 2.8 mm astigmatically neutral incision. Uncorrected (UDVA) and corrected (CDVA) distance visual acuities (logMAR), refraction, keratometry, and the cylinder axis of the toric IOL were measured. RESULTS: Thirty-three eyes of 25 patients were evaluated. The mean preoperative refractive astigmatism was 3.35 D +/- 1.20 (SD) and the mean keratometric astigmatism, 3.98 +/- 1.89 D, respectively. Four months postoperatively, the mean UDVA was 0.28 +/- 0.23 D logMAR, improving to 0.19 +/- 0.23 D logMAR CDVA. The mean refractive astigmatism was 0.95 D +/- 0.66 D; vector analysis using the Holladay-Cravy-Koch method showed that the mean reduction in refractive astigmatism was 2.94 +/- 0.89 D. The mean difference between the intended and the actual final IOL cylinder axis was 3.44 degrees (range 0 to 12). CONCLUSIONS: The toric IOL reduced visually significant keratometric astigmatism and increased spectacle independence after cataract surgery. There were no cases of significant IOL rotation in the capsular bag 4 months postoperatively. PMID- 21241905 TI - Visual outcomes and optical performance of a monofocal intraocular lens and a new generation multifocal intraocular lens. AB - PURPOSE: To compare visual acuity outcomes and ocular and intraocular optical quality in patients with a monofocal intraocular lens (IOL) or a multifocal IOL with rotational asymmetry. SETTING: Vissum Corporation, Alicante, Spain. DESIGN: Comparative case series. METHODS: Consecutive eyes of cataract patients were divided into 2 groups. One group received a Lentis Mplus LS-312 multifocal IOL and the other, an Acri.Smart 48S monofocal IOL. Distance and near visual acuities, contrast sensitivity, intraocular aberrations (global minus corneal aberrations), and defocus curves were evaluated preoperatively and postoperatively during a 3-month follow-up. RESULTS: The study evaluated 52 eyes of 29 patients (age range 36 to 87 years); 24 eyes were in multifocal IOL group and 28 eyes, in the monofocal IOL group. Both groups had a significant improvement in uncorrected and corrected distance visual acuities and in distance corrected near visual acuity (DCNVA) postoperatively (P <= .04). The multifocal IOL group had significantly better uncorrected near acuity and DCNVA (Jaeger [J] 5 versus J2) (both P < .01). The defocus curves showed significantly better visual acuities in the multifocal group at several levels of defocus. The multifocal group had significantly higher amounts of postoperative intraocular primary coma (P<.01), especially in eyes with significant IOL tilt, although there were no significant differences in contrast sensitivity between the 2 IOL groups (P >= .25). CONCLUSIONS: The new-generation multifocal IOL restored distance, intermediate, and near visual function after cataract surgery. The optical quality with this type of IOL was particularly affected by IOL tilt and decentration. PMID- 21241906 TI - Rotational stability and posterior capsule opacification of a plate-haptic and an open-loop-haptic intraocular lens. AB - PURPOSE: To compare the rotational stability and posterior capsule opacification (PCO) rate in eyes with a 1-piece or 3-piece acrylic intraocular lens (IOL). SETTING: Department of Ophthalmology, Medical University of Vienna, Vienna, Austria. DESIGN: Prospective randomized masked clinical trial. METHODS: Patients with age-related cataract received a plate-haptic acrylic IOL (Acri.Smart 46S) in 1 eye and a 3-piece loop-haptic acrylic IOL (Acri.Lyc 53N) in the other eye. Retroillumination images were taken 1 hour, 1 week, and 1, 6, and 12 months postoperatively. Intraocular lens rotation was measured using standard software (Adobe Photoshop). The amount of PCO was assessed subjectively at the slitlamp and objectively using an automated image-analysis software (AQUA). RESULTS: The study enrolled 80 eyes of 40 patients. The IOL rotation measurements showed excellent reproducibility, with a deviation of less than 0.8 degrees. Both IOLs had comparable and good rotational stability; rotation was less than 4 degrees in 71% of eyes 1 year postoperatively. The mean absolute rotation was 2.6 degrees +/ 1.9 (SD) in the plate-haptic IOL group and 3.1 +/- 2.4 degrees in the loop haptic IOL group. The mean AQUA PCO score (scale 0 to 10) was 0.4 in both IOL groups (P = .7). CONCLUSION: The 2 IOL models had comparable, excellent rotational stability and low PCO intensity 1 year postoperatively. Thus, the plate-haptic IOL may be a good platform for a toric model. PMID- 21241907 TI - Functional visual acuity after neodymium:YAG laser capsulotomy in patients with posterior capsule opacification and good visual acuity preoperatively. AB - PURPOSE: To evaluate the changes in functional visual acuity before and after neodymium:YAG (Nd:YAG) laser capsulotomy. SETTING: Keio University Hospital, Tokyo, Japan. DESIGN: Case series. METHODS: Eyes that had previous cataract surgery with a clinical diagnosis of central posterior capsule opacity requiring Nd:YAG laser capsulotomy were evaluated. All patients had refractive error and corrected distance visual acuity (CDVA) measurements; slitlamp microscopy examinations, including posterior capsule opacification evaluation; high-contrast visual acuity measured at 5 m using a Landolt chart; 10% low-contrast visual acuity (LCVA); functional visual acuity; wavefront examination; and a Schirmer test without anesthesia. RESULTS: The study enrolled 9 patients (4 women, 5 men; 10 eyes) with a mean age of 57.3 years +/- 7.0 (SD) (range 47 to 68 years). Although there was no significant difference in CDVA before and after Nd:YAG capsulotomy, there was a significant improvement in the mean functional visual acuity, from 0.18 +/- 0.11 logMAR (range -0.03 to 0.31 logMAR) to 0.08 +/- 0.07 logMAR (range -0.04 to 0.18 logMAR) (P < .05). The LCVA improved significantly after Nd:YAG laser capsulotomy (P = .003). Higher-order aberrations and the root mean square of the 4th-order coefficients decreased significantly after capsulotomy, and these aberrations were significantly correlated with functional visual acuity and LCVA. CONCLUSION: Results indicate that measurement of functional visual acuity is useful in assessing the quality of vision in patients who have Nd:YAG laser capsulotomy after cataract surgery. PMID- 21241908 TI - Evaluation of corneal biomechanical parameters after simultaneous phacoemulsification with intraocular lens implantation and limbal relaxing incisions. AB - PURPOSE: To determine whether alterations in architecture cause corneal biomechanical changes after simultaneous cataract surgery and limbal relaxing incisions (LRIs). SETTING: Department of Ophthalmology, Kitasato University, Kanagawa, Japan. DESIGN: Observational case series. METHODS: This study longitudinally assessed corneal hysteresis (CH) and the corneal resistance factor (CRF) using the Ocular Response Analyzer in eyes having cataract surgery with LRIs. The relationship between these biomechanical parameters and central corneal thickness (CCT), measured using an ultrasound pachymeter, was also assessed. RESULTS: The mean CH was 10.0 mm Hg +/- 1.2 (SD) preoperatively, 9.0 +/- 1.6 mm Hg 1 day postoperatively, 9.7 +/- 1.4 mm Hg at 1 week, 9.6 +/- 1.4 mm Hg at 1 month, and 10.2 +/- 1.3 mm Hg at 3 months. The mean CRF was 10.0 +/- 1.5 mm Hg, 8.9 +/- 1.6 mm Hg, 9.5 +/- 1.5 mm Hg, 9.5 +/- 1.4 mm Hg, and 9.5 +/- 1.4 mm Hg, respectively. There were significant differences between preoperative and 1-day postoperative measurements (P=.005, CH; P=.004, CRF). The CH and CRF were significantly correlated with CCT (r = 0.33, P=.04 and r = 0.40, P=.01, respectively) 3 months postoperatively. CONCLUSIONS: The CH and CRF values decreased 1 day after simultaneous cataract surgery with LRIs but soon recovered to preoperative levels, suggesting there were no significant changes in corneal biomechanical factors after 1 day. Corneal thickness may play a role in biomechanical factors even in such eyes. PMID- 21241909 TI - Ocular toxicity after intracameral injection of very high doses of cefuroxime during cataract surgery. AB - PURPOSE: To report cases of intraocular inflammation after intracameral injection of a very high dose of cefuroxime at the end of uneventful cataract surgery. SETTING: Department of Ophthalmology, Bordeaux University Hospital, Bordeaux, France. DESIGN: Case series. METHODS: Patients were followed on an outpatient basis and were examined postoperatively at 1 and 5 days and 6 weeks. Central macular thickness, angiography, central corneal thickness (CCT), endothelial cell density (ECD), and electroretinography (ERG) were analyzed to evaluate ocular toxicity. RESULTS: One day postoperatively, the mean corrected distance visual acuity (CDVA) was 0.95 logMAR +/- 0.40 (SD). All the cases had moderate anterior inflammation. Retinal optical coherence tomography scans systematically showed extensive macular edema (mean 843.2 +/- 212.7 MUm) associated with a large serous retinal detachment. Fluorescein angiograms showed diffuse leakage without abnormal retinal perfusion. At 5 days, the mean CDVA improved significantly to 0.52 +/- 0.29 logMAR (P < .005), as did the macular edema and serous retinal detachment (mean 339.4 +/- 138.3 MUm) (P = .005). At 6 weeks, the mean CDVA reached 0.09 +/- 0.06 logMAR. Modifications in CCT and ECD were similar to those observed after uneventful phacoemulsification. The macular thickness (mean 288.4 +/- 22.6 MUm) and profile returned to normal in all patients, although ERG recordings showed reduced rod photoreceptor cell function (P < .05). CONCLUSIONS: Intracameral injection of high doses of cefuroxime induced anterior and posterior inflammation. Without surgical intervention, the final visual outcome was satisfactory in all cases. Long-term retinal function, however, must be assessed through repeated ERG recordings. PMID- 21241910 TI - Effect of a fixed brimonidine-timolol combination on intraocular pressure after phacoemulsification. AB - PURPOSE: To evaluate the effect of a fixed combination of brimonidine-timolol on intraocular pressure (IOP) after phacoemulsification cataract surgery. SETTING: Department of Ophthalmology, Patras University Hospital, Patras, Greece. DESIGN: Prospective randomized comparative case series. METHODS: Patients scheduled for phacoemulsification were randomly assigned to 1 of 2 groups. The treatment group received 1 drop of brimonidine-timolol fixed combination immediately after surgery, and the control group received no treatment. The IOP was measured preoperatively and 6, 12, and 24 hours postoperatively. RESULTS: The treatment group comprised 28 eyes and the control group, 30 eyes. The mean IOP increased by 0.14 mm Hg +/- 3.88 (SD) (P = .88) in the treatment group and increased by 2.8 +/ 5.01 mm Hg (P = .007) in the control group. Twelve hours after surgery, the mean IOP decreased by -0.57 +/- 3.82 mm Hg (P = .49) in the treatment group and increased by 2.20 +/- 4.56 mm Hg (P = .009) in the control group. Twenty-four hours after surgery, the mean IOP decreased by -1.57 +/- 2.30 mm Hg (P=.012) in the treatment group and increased by 0.86 +/- 4.21 mm Hg (P = .175) in the control group. The mean IOP change between the 2 study groups 6, 12, and 24 hours postoperatively was statistically significantly different (P = .015, P = .006, and P = .003; respectively). CONCLUSION: The fixed brimonidine-timolol combination effectively reduced IOP 6, 12, and 24 hours after phacoemulsification cataract surgery. PMID- 21241911 TI - Higher-order aberrations after iris-fixated foldable phakic intraocular lens implantation and wavefront-guided photorefractive keratectomy for the correction of myopia. AB - PURPOSE: To compare higher-order aberrations (HOAs) after foldable phakic intraocular lens (pIOL) implantation and wavefront-guided photorefractive keratectomy (PRK) for the correction of myopia. SETTING: Department of Ophthalmology, Medisch Centrum Haaglanden, Den Haag, The Netherlands. DESIGN: Comparative case series. METHODS: This retrospective comparative case series comprised eyes that had implantation of an Artiflex foldable pIOL or wavefront guided PRK. Preoperative and postoperative refractive data, pupil diameter, endothelial cell density, and higher-order aberrations (HOAs) were measured and compared. RESULTS: The median follow-up was 13 months in the pIOL group and 10 months in the PRK group. The mean spherical equivalent (SE) in the pIOL group was -5.50 diopters (D) +/- 1.05 (SD) (range -3.25 to -7.13 D) preoperatively and 0.26 +/- 0.28 D (range -0.88 to 0.38 D) postoperatively and the mean in the PRK group, -5.72 +/- 0.88 D (range -4.25 to -7.50 D) and -0.03 +/- 0.42 D (range 0.75 to 1.00 D), respectively. The postoperative SE was within +/-0.50 D in 86.4% of eyes and 85.2% of eyes, respectively. Postoperatively, the significant changes in the pIOL group and the PRK group, respectively, were as follows: total HOAs, 0.03 MUm and 0.26 MUm (P = .001); trefoil-y, 0.09 MUm and -0.04 MUm (P = .004); spherical aberration, -0.05 MUm and 0.21 MUm (P = .002). CONCLUSIONS: Foldable pIOL implantation increased total HOAs and spherical aberration less than wavefront-guided PRK to correct low to moderate myopia, suggesting foldable pIOL implantation maintains the cornea's prolate shape better. PMID- 21241912 TI - Automated keratometry in routine cataract surgery: comparison of Scheimpflug and conventional values. AB - PURPOSE: To compare the mean keratometry (K) readings obtained with a conventional automated keratometer (IOLMaster) and a Scheimpflug keratometer (Pentacam) in eyes having preoperative assessment for routine cataract surgery. SETTING: Epsom and St. Helier University Hospitals, London, United Kingdom. DESIGN: Evaluation of diagnostic technology. METHODS: Mean K values were obtained with the conventional and Scheimpflug keratometers. The following Scheimpflug readings were evaluated: anterior K, true net power, and Holladay equivalent K measured at 1.0 to 7.0 mm corneal diameters. Mean readings for each type of keratometry were compared. Bland-Altman plots were used to determine the 95% limits of agreement (LoA) for the conventional and Scheimpflug keratometers. RESULTS: The mean conventional K was statistically significantly greater than the mean Scheimpflug K for true net power and equivalent K at 1.0 mm, 2.0 mm, 3.0 mm, and 4.0 mm corneal diameters. The mean conventional K was significantly less than the equivalent K at 5.0 mm, 6.0 mm, and 7.0 mm. The smallest mean difference was for equivalent K at 4.5 mm (0.02 diopters [D]). The smallest 95% LoA were -0.68 to 1.16 D (equivalent K at 5.0 mm) and -0.91 to 0.95 D (equivalent K at 4.5 mm). CONCLUSIONS: Overall, the equivalent K at 4.5 mm had the closest match with the conventional K values. The degree of interdevice variability with the conventional keratometer was lowest for the equivalent K at 4.5 mm and 5.0 mm, although this variability would be sufficient to influence intraocular lens power selection. PMID- 21241913 TI - Repeatability of automatic measurements performed by a dual Scheimpflug analyzer in unoperated and post-refractive surgery eyes. AB - PURPOSE: To assess the repeatability of the anterior segment measurements performed with a dual Scheimpflug analyzer (Galilei) in unoperated and post refractive surgery eyes. SETTING: Private practice. DESIGN: Evaluation of diagnostic test. METHODS: Three consecutive scans were acquired in unoperated eyes and in eyes that had excimer laser surgery for myopia. Unoperated eyes were enrolled from 3 subgroups: younger than 50 years, aged between 50 and 70 years, and older than 70 years. The following parameters were evaluated: simulated keratometry, posterior corneal power, total corneal power, anterior and posterior best-fit sphere radius, mean and thinnest central corneal thickness, anterior chamber depth and volume, horizontal and vertical corneal diameter, iridocorneal angle in the 4 quadrants, and corneal spherical aberration. Repeatability was assessed using analysis of variance (ANOVA), the coefficient of variation (COV), intraclass correlation (ICC), and test-retest variability. RESULTS: The study evaluated 45 unoperated eyes (n = 45) and 15 post-refractive surgery eyes (n = 15). Each age subgroup in the unoperated group comprised 15 eyes. The ANOVA did not detect significant differences between the 3 measurements for any parameter. The COV was less than 0.5% for corneal power measurements and less than 3.5% for all remaining parameters except spherical aberration (16.68%). The ICC was more than 0.99 for corneal power measurements and more than 0.94 for all remaining parameters. CONCLUSIONS: The anterior segment measurements provided by the dual Scheimpflug analyzer were highly repeatable. Repeatability did not change with age or after myopic photorefractive keratectomy or laser in situ keratomileusis. PMID- 21241914 TI - Pachymetric measurements with a new Scheimpflug photography-based system: intraobserver repeatability and agreement with optical coherence tomography pachymetry. AB - PURPOSE: To evaluate the intraobserver repeatability of pachymetric measurements obtained with a new Scheimpflug photography-based system and the agreement of the measurements with those obtained by optical coherence tomography (OCT). SETTING: Vissum Corporation, Alicante, Spain. DESIGN: Evaluation of diagnostic technology. METHODS: Corneal thickness was measured at different locations (center; 2.5 mm and 4.0 mm nasal, temporal, superior, and inferior) in 18 eyes of 18 patients with no ocular pathology or previous surgery with a Scheimpflug photography-based system (Sirius). Three consecutive measurements at each location were obtained with the system to evaluate intraobserver repeatability. Afterward, pachymetric measurements were obtained at the same locations with an OCT system (Visante) to evaluate the agreement between techniques using the Bland-Altman method. RESULTS: The intraclass correlation coefficient of repeated measures ranged from 0.990 to 0.997. The coefficient of variation was lower than 1% and the standard deviations of the repeated measurements (S(w)) were below 6 MUm at all corneal locations. Statistically significant differences were found between the coefficient of variation and S(w) values of the repeated measurements corresponding to the 2.5 mm and 4.0 mm locations (P <= .037). The agreement with OCT pachymetric measurements was poor, with ranges of agreement larger than 20 MUm at all corneal locations. Statistically significant differences were found between standard deviations of the differences between the 2 devices at the 2.5 mm and 4.0 mm locations (P <= .017). CONCLUSION: Scheimpflug photography-based technology provided repeatable pachymetric measurements that were not equivalent to those obtained with OCT. PMID- 21241915 TI - Combined correction of sphere and astigmatism using the light-adjustable intraocular lens in eyes with axial myopia. AB - PURPOSE: To determine the efficacy of light-adjustable intraocular lenses (IOL) in correcting residual spherical and cylindrical errors in patients with axial myopia. SETTING: Center for Vision Science, Ruhr University Eye Clinic, Bochum, Germany. DESIGN: Prospective cohort study. METHODS: Light-adjustable IOLs were implanted in eyes with axial myopia and treated with spatial irradiance profiles delivered by a digital light-delivery device to induce a target spherical and/or spherocylindrical refractive change. Once the desired correction was achieved, the power of the IOL was locked in (ie, photo locking). The manifest refraction, uncorrected distance visual acuity (UDVA), and corrected distance visual acuity (CDVA) were determined 1, 6, and 12 months after lock-in to determine the achieved refractive corrections and their stability. RESULTS: Twelve months postoperatively, 20 (96%) of the 21 eyes studied were within +/- 0.50 diopter (D) of the intended refractive outcome and 17 (81%) were within +/- 0.25 D. One eye had a 0.325 D change in mean refractive spherical equivalent (MRSE). The change in MRSE in the other 20 eyes was less than 0.250 D between 1 month after lock-in and the 3-, 6-, and 12-month postoperative visits. CONCLUSIONS: The light adjustable IOL reduced postoperative spherical and cylindrical errors of up to 2.00 D. Postoperative refractive errors were successfully corrected, and there was a significant improvement in UDVA with concomitant maintenance of CDVA. The achieved refractive change was stable after the adjustment and lock-in procedures. PMID- 21241916 TI - Corneal endothelial safety after ultraviolet light treatment of the light adjustable intraocular lens. AB - PURPOSE: To assess the safety to the corneal endothelium of ultraviolet (UV) light treatment to a light-adjustable intraocular lens (IOL). SETTING: Codet Vision Institute, Tijuana, Mexico. DESIGN: Cohort study. METHODS: The study evaluated consecutive patients scheduled for phacoemulsification cataract surgery with implantation of a light-adjustable IOL. Endothelial cell density (ECD), variation in the size of endothelial cells, and the percentage of hexagonal cells were determined centrally with a specular microscope preoperatively, 1 week postoperatively (before UV treatment), and 6 months postoperatively. Two adjustments and 2 lock-in procedures were performed with a light-delivery system between 2 weeks and 4 weeks postoperatively. RESULTS: The study enrolled 10 patients. Specular microscopy showed a mean ECD of 2344 cells/mm(2) preoperatively. The mean overall central ECD was 2047 cells/mm(2) 1 week postoperatively and 2130 cells/mm(2) at 6 months, representing an endothelial cell loss of 12.6% and 9.1%, respectively, from preoperative values. There was no statistically significant difference in the coefficient of variation or percentage of hexagonal cells at either postoperative evaluation. CONCLUSIONS: The endothelial cell loss at 6 months correlated well with previous reports of endothelial damage after phacoemulsification with IOL implantation. The light adjustable IOL irradiation protocol for adjustment and lock-in procedures did not seem to add to the endothelial damage caused by the cataract surgery, indicating the protocol is safe to the corneal endothelium. PMID- 21241917 TI - Monitoring and modernization to improve visual outcomes of cataract surgery in a community eyecare center in western India. AB - PURPOSE: To determine whether routine monitoring leads to better visual outcomes over time after cataract surgery. SETTING: Comprehensive community eyecare center in western India. DESIGN: Comparative case series. METHODS: Operative case sheets of all patients having cataract surgery were collected. Preoperative information, surgical details, and follow-up findings were included in the audit. The outcome measure was postoperative corrected distance visual acuity (CDVA), which was graded as good (>= 6/18), borderline, or poor (<6/60). If the outcome was poor, the causes were classified as follows: selection, surgery, spectacles, or sequelae. The surgeons were briefed about their performance twice a year. RESULTS: The audit included 16,382 cataract surgeries. The proportion of eyes having a CDVA of 6/18 or better 6 weeks postoperatively improved significantly, from 86.5% (95% confidence interval [CI], 84.8%-88.3%) in 2002 to 90.5% (95% CI, 89.3%-91.8%) in 2005, while CDVA worse than 6/60 declined from 5.9% in 2002 to 2.5% in 2005. Manual small-incision cataract surgery was more popular than conventional extracapsular cataract surgery in 2004 and 2005. The incidence of posterior capsule tear and vitreous loss declined in the later years, although the rate of striate keratitis remained the same. Younger patients, women, those without ocular comorbidity, and those with a preoperative CDVA of better than 6/60 had better visual acuity 8 weeks postoperatively. CONCLUSION: Routine monitoring and modernization of technique helped increase good visual outcomes and reduce poor visual outcomes after cataract surgery. PMID- 21241918 TI - Laser-assisted subepithelial keratectomy and photorefractive keratectomy for post penetrating keratoplasty myopia and astigmatism in adults. AB - PURPOSE: To evaluate whether laser-assisted subepithelial keratectomy (LASEK) and photorefractive keratectomy (PRK) achieve effective targeted correction and the extent of post-treatment corneal haze after corneal transplantation. SETTING: Nonhospital surgical facility, Calgary, Alberta, Canada. DESIGN: Evidence-based manuscript. METHODS: This study evaluated visual acuity, refractive error correction, and potential complications after LASEK or PRK to eliminate refractive error differences after penetrating keratoplasty in adults. A Nidek EC 5000 or Technolas 217 excimer laser was used in all treatments. RESULTS: At last follow-up (mean 20.50 months post laser), the mean spherical equivalent (SE) decreased from -2.71 diopters (D) +/- 4.17 (SD) to -0.54 +/- 3.28 D in the LASEK group and from -4.87 +/- 3.90 D to -1.82 +/- 3.34 D in the PRK group. The mean preoperative uncorrected distance visual acuity (UDVA) was 1.63 +/- 0.53 and 1.45 +/- 0.64, respectively, and the mean postoperative UDVA, 0.83 +/- 0.54 and 0.90 +/- 0.55, respectively. The improvement in SE and UDVA was statistically significant in both groups (P < .01). The mean haze (0 to 3 scale) at the last follow-up was 0.46 +/- 0.708 in the LASEK group and 0.58 +/- 0.776 in the PRK group. CONCLUSIONS: The UDVA improved and refractive errors were effectively reduced after LASEK or PRK in eyes with previous PKP. There was no significant difference in the change in SE, UDVA, or corrected distance visual acuity between LASEK and PRK. Some patients had evidence of corneal haze, although the difference between the groups was not significant. PMID- 21241919 TI - Comparison of anterior segment measurements with rotating Scheimpflug photography and partial coherence reflectometry. AB - PURPOSE: To compare central corneal thickness (CCT), anterior chamber depth (ACD), and keratometry (K) readings measured using optical low-coherence reflectometry (OLCR) biometry and high-resolution rotating Scheimpflug photography. SETTING: Eye Hospital of Wenzhou Medical College, Wenzhou, China. DESIGN: Comparative case series. METHODS: The CCT, ACD endothelium to lens, ACD epithelium to lens, and K (mean; in flattest meridian; in steepest meridian) were measured 5 times using the LenStar/Biograph OLCR biometer and 3 times with the Pentacam Scheimpflug system in eyes of healthy volunteers. Concordance was evaluated using paired t tests, the Pearson correlation, and Bland-Altman analyses. RESULTS: The CCT, ACD endothelium to lens, and ACD epithelium to lens measured with the Scheimpflug system were slightly, albeit significantly, higher than with the OLCR biometer (P<.05); the respective 95% limits of agreement (LoA) were -8.2 MUm to 15.7 MUm, -0.11 to 0.15 mm, and -0.13 to 0.17 mm. However, the Scheimpflug system gave significantly flatter readings for K in the flattest meridian (95% LoA, -0.54 to 0.32 diopters [D]), K in the steepest meridian (95% LoA, -0.63 to 0.45 D), and mean K (95% LoA, -0.53 to 0.33 D) (P<.001). The CCT, ACD, and K readings were all highly correlated between the 2 devices (r >0.95, P<.001). CONCLUSIONS: The CCT and ACD measurements with the OLCR biometer and Scheimpflug system can be used interchangeably in healthy young subjects. However, for K measurements, these devices have wide LoA so may not be interchangeable under certain clinical circumstances. PMID- 21241920 TI - Comparison of laser in situ keratomileusis flaps created by 3 femtosecond lasers and a microkeratome. AB - PURPOSE: To evaluate the thickness and side-cut angle of laser in situ keratomileusis (LASIK) flaps created by 1 of 3 femtosecond lasers or a microkeratome using Fourier-domain optical coherence tomography (OCT). SETTING: Department of Ophthalmology, Institute of Vision Research, Yonsei University College of Medicine, Seoul, Korea. DESIGN: Comparative case series. METHODS: Flap creation for bilateral LASIK was performed using an IntraLase (femtosecond group 1), VisuMax (femtosecond group 2), or Femto LDV (femtosecond group 3) femtosecond laser or an M2 microkeratome. Flap thickness was determined at 14 points. The side-cut angle was measured in 4 directions at the margin interface. Measurements were taken 2 months postoperatively using an RTVue Fourier-domain OCT device and integrated software. RESULTS: Femtosecond group 1 comprised 50 eyes; femtosecond group 2, 40 eyes; femtosecond group 3, 64 eyes; and the microkeratome group, 52 eyes. Eyes in femtosecond groups 1 and 2 had relatively even flap configuration. Flaps in femtosecond group 3 and the microkeratome group had a meniscus shape. Flaps in femtosecond group 1 had the least difference between the mean peripheral and the central flap thickness (P<.001). The greatest flap thickness predictability (measured versus intended thickness) was in femtosecond group 3 (P<.001). Flaps in femtosecond group 1 had a side-cut angle closest to 90 degrees (P<.001). CONCLUSIONS: Flap morphology differed according to the system used. The 3 femtosecond laser systems appeared to be superior to the microkeratome system generally. The 3 femtosecond laser systems also produced different flap configurations depending on their individual mechanisms. PMID- 21241921 TI - Laser-assisted subepithelial keratectomy retreatment surgery. AB - PURPOSE: To evaluate the outcomes of laser-assisted subepithelial keratectomy (LASEK) retreatment surgery after prior LASEK surgery. SETTING: Private practice, Ireland. DESIGN: Retrospective case series. METHODS: Laser-assisted subepithelial keratectomy retreatment surgery was performed in patients who had prior LASEK to correct residual refractive errors. All treatments were wavefront guided using the Visx S4 Star excimer laser. The main outcome measures were predictability, safety, efficacy, and stability. Mitomycin-C (MMC) was not used in the primary or retreatments. RESULTS: The mean age of the 16 patients (23 eyes) was 32 years (range 21 to 56 years). The mean preoperative spherical equivalent (SE) was -3.61 diopters (D) +/- 2.61 (SD) (range -8.25 to +3.63 D) and the mean SE before retreatment, -0.67 +/- 0.66 D (range -1.88 to +0.88 D). The mean time between procedures was 7.1 +/- 2.8 months (range 3 to 13 months). Six months after retreatment, the mean SE was +0.02 +/- 0.16 D (range -0.38 to 0.50 D) and the mean Snellen uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA) were 1.22 +/- 0.11 and 1.29 +/- 0.13, respectively. The UDVA was 6/6 or better in all eyes, and all were within +/- 0.50 D of SE. No eye lost lines of CDVA or developed corneal haze greater than grade 1. CONCLUSION: Laser assisted subepithelial keratectomy retreatment following prior LASEK, both without the use of MMC, provided good predictability, safety, efficacy, and stability outcomes. PMID- 21241922 TI - Oral gabapentin for photorefractive keratectomy pain. AB - PURPOSE: To compare the efficacy of oral gabapentin versus placebo for the control of severe pain after photorefractive keratectomy (PRK). SETTING: Center for Refractive Surgery, Walter Reed Army Medical Center, Washington, DC, USA. DESIGN: Randomized masked clinical trial. METHODS: This single-center clinical trial comprised active-duty United States Army soldiers aged 21 years or older having bilateral PRK for myopia with or without astigmatism. Patients received gabapentin 300 mg or placebo 3 times daily for 7 days beginning 2 days before and continuing for 4 days after surgery. Current and maximum pain levels were assessed using the Visual Analog Pain scale 2 hours after surgery and then daily on days 1 through 4. Repeated-measures analysis of variance (ANOVA) was used to compare the current and maximum pain scores over time between the gabapentin group and the placebo group. The Fisher exact test was used to determine whether there was a difference in severe pain (>7/10) between the 2 groups. RESULTS: Forty-two patients received gabapentin and 41 patients, placebo. The repeated measures ANOVA showed no significant difference between the 2 groups in current pain (P = .84) or in maximum pain over time (P = .35). Oxycodone-acetaminophen use in the gabapentin group was significantly higher than in the placebo group 1 day postoperatively (P = .034). CONCLUSION: When added to a standardized postoperative pain regimen, gabapentin use led to no additional improvement in PRK pain control compared with a placebo at the dose and the time intervals tested. PMID- 21241923 TI - Comparison of wavefront-guided photorefractive keratectomy and foldable iris fixated phakic intraocular lens implantation for low to moderate myopia. AB - PURPOSE: To compare and evaluate the visual and refractive outcomes of myopic wavefront-guided photorefractive keratectomy (PRK) and foldable phakic intraocular lens (pIOL) implantation for myopia. SETTING: Department of Ophthalmology, Haaglanden Medical Center, The Hague, The Netherlands. DESIGN: Comparative case series. METHODS: The differences in visual acuity and residual refractive outcomes after wavefront-guided PRK and Artiflex foldable pIOL implantation were compared in eyes with low to moderate myopia (spherical error 4.0 to -7.0 diopters [D]; maximum cylinder 2.25 D). One-year follow-up results are presented. RESULTS: At 1 year postoperatively, the mean decimal Snellen uncorrected distance visual acuity was 1.05 +/- 0.21 (SD) in the PRK group (60 eyes) and 1.04 +/- 0.21 in the pIOL group (33 eyes) and the mean corrected distance visual acuity (CDVA), 1.21 +/- 0.18 and 1.24 +/- 0.13, respectively. In the PRK group, 21.7% of eyes lost 1 to 3 lines of CDVA and 11.7% of eyes gained 1 or 2 lines. In the pIOL group, no eye lost lines of CDVA and 42% gained 1 or 2 lines. At 1 year, 80.0% of eyes in the PRK group and 90.9% of eyes in the pIOL group were within +/- 0.50 D of the spherical equivalent. CONCLUSION: There were no statistically significant differences in safety and efficacy between the pIOL group and the PRK group at 1 year. However, the percentage of eyes that gained lines of CDVA was significantly higher in the pIOL group. PMID- 21241924 TI - Accelerated 20-year sunlight exposure simulation of a photochromic foldable intraocular lens in a rabbit model. AB - PURPOSE: To assess the long-term biocompatibility and photochromic stability of a new photochromic hydrophobic acrylic intraocular lens (IOL) under extended ultraviolet (UV) light exposure. SETTING: John A. Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. DESIGN: Experimental study. METHODS: A Matrix Aurium photochromic IOL was implanted in right eyes and a Matrix Acrylic IOL without photochromic properties (n = 6) or a single-piece AcrySof Natural SN60AT IOL (n = 5) in left eyes of 11 New Zealand rabbits. The rabbits were exposed to a UV light source of 5 mW/cm(2) for 3 hours during every 8-hour period, equivalent to 9 hours a day, and followed for up to 12 months. The photochromic changes were evaluated during slitlamp examination by shining a penlight UV source in the right eye. After the rabbits were humanely killed and the eyes enucleated, study and control IOLs were explanted and evaluated in vitro on UV exposure and studied histopathologically. RESULTS: The photochromic IOL was as biocompatible as the control IOLs after 12 months under conditions simulating at least 20 years of UV exposure. In vitro evaluation confirmed the retained optical properties, with photochromic changes observed within 7 seconds of UV exposure. The rabbit eyes had clinical and histopathological changes expected in this model with a 12-month follow-up. CONCLUSIONS: The new photochromic IOL turned yellow only on exposure to UV light. The photochromic changes were reversible, reproducible, and stable over time. The IOL was biocompatible with up to 12 months of accelerated UV exposure simulation. PMID- 21241925 TI - Temperature increase in porcine cadaver iris during direct illumination by femtosecond laser pulses. AB - PURPOSE: To measure the temperature rise in porcine cadaver iris during direct illumination by the femtosecond laser as a model for laser exposure of the iris during femtosecond laser corneal surgery. SETTING: Department of Ophthalmology, University of California-Irvine, Irvine, California, USA. DESIGN: Experimental study. METHODS: The temperature increase induced by a 60 kHz commercial femtosecond laser in porcine cadaver iris was measured in situ using an infrared thermal imaging camera at pulse energy levels ranging from 1 to 2 MUJ (corresponding approximately to surgical energies of 2 to 4 MUJ per laser pulse). RESULTS: Temperature increases up to 2.3 degrees C (corresponding to 2 MUJ and 24-second illumination) were observed in the porcine cadaver iris with little variation in temperature profiles between specimens for the same laser energy illumination. CONCLUSIONS: The 60 kHz commercial femtosecond laser operating with pulse energies at approximately the lower limit of the range evaluated in this study would be expected to result in a 1.2 degrees C temperature increase and therefore does not present a safety hazard to the iris. PMID- 21241926 TI - Surface ablation techniques. AB - The ongoing quest for a safe, simple, effective, minimally invasive, and stable refractive surgical procedure to correct refractive errors has stimulated the development of surface ablation techniques and laser in situ keratomileusis. In this review, we describe the history, patient assessment, techniques, outcomes, and complications of surface ablation (photorefractive keratectomy, laser assisted sub-epithelial keratectomy, epithelial laser-assisted in situ keratomileusis) and compare the results of various surface techniques. Surface ablation procedures will continue to evolve, with potential improvements in outcomes accompanying future sophisticated ablation profiles and laser technology. PMID- 21241927 TI - Long-term pathological follow-up of 2-loop iridocapsular intraocular lens. AB - We analyzed an enucleated postmortem eye from an 86-year-old donor who had a 2 loop iridocapsular intraocular lens (IOL) that had been implanted at least 30 years earlier. High-frequency ultrasound showed a relatively well-centered iris supported optic in front of the pupil. Gross and light microscopic analyses of the eye and the IOL showed loop fixation outside the capsular bag remnants, a thickened cornea, mild attenuation of the corneal endothelium, multiple areas of iris trauma secondary to haptic abrasion, fragments of iris tissue attached to the haptics, as well as pigment dispersion within the eye with pigmented epithelial cells attached to the IOL haptics. Histopathological examination of the posterior segment was unremarkable. PMID- 21241928 TI - Alleviating debilitating photophobia and secondary exotropia caused by increased straylight by widening a small posterior capsulotomy. AB - In a patient with complaints of photophobia and an ocular deviation, straylight was found to be increased to 1.61 (log[s]), which is 5 times the normal value. The only relative clinical finding was the edge of a too small posterior capsulotomy. Visual acuity was normal. Six weeks after the posterior capsulotomy was widened to a diameter of 6.0 mm with a neodymium:YAG laser, the symptoms were resolved and the patient was satisfied. Straylight may manifest clinically as complaints of photophobia. Straylight increase, which can be related to slitlamp findings, may lead to an interventional decision. Our clinical decision-making was also guided by straylight measurements and proved to be crucial in resolving the patient's complaints. More study of clinical situations in which straylight measurement can be used is needed. PMID- 21241929 TI - Acute bilateral angle-closure glaucoma and choroidal effusion associated with acetazolamide administration after cataract surgery. AB - We present an interventional case report of a 76-year-old man who developed bilateral angle-closure glaucoma with extensive choroidal detachment following administration of oral acetazolamide immediately after routine cataract extraction and intraocular lens implantation. Rapid clinical improvement occurred after acetazolamide was stopped and high-dose intravenous steroid therapy was given. Although extremely rare, this adverse effect should be considered in patients who develop acute bilateral angle-closure glaucoma and choroidal effusion after cataract surgery. PMID- 21241930 TI - Diffuse lamellar keratitis 8 years after LASIK caused by corneal epithelial defect. PMID- 21241931 TI - Closed-globe intraocular lens fixation. PMID- 21241932 TI - Consultation section: Cataract surgical problem. PMID- 21241942 TI - Spontaneous partial dislocation of an aphakic capsular bag in high myopia. PMID- 21241943 TI - Capsulorhexis optic intraocular lens capture technique. PMID- 21241946 TI - How to classify? PMID- 21241947 TI - The devil you know: revealing racial/ethnic disparities in the treatment of adolescent depression. PMID- 21241948 TI - Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. AB - OBJECTIVE: The objective of this blinded, prospective, longitudinal study was to determine whether new group A beta hemolytic streptococcal (GABHS) infections are temporally associated with exacerbations of tic or obsessive-compulsive (OC) symptoms in children who met published criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). A group of children with Tourette syndrome and/or OC disorder without a PANDAS history served as the comparison (non-PANDAS) group. METHOD: Consecutive clinical ratings of tic and OC symptom severity were obtained for 31 PANDAS subjects and 53 non-PANDAS subjects. Clinical symptoms and laboratory values (throat cultures and streptococcal antibody titers) were evaluated at regular intervals during a 25-month period. Additional testing occurred at the time of any tic or OC symptom exacerbation. New GABHS infections were established by throat swab cultures and/or recent significant rise in streptococcal antibodies. Laboratory personnel were blinded to case or control status, clinical (exacerbation or not) condition, and clinical evaluators were blinded to the laboratory results. RESULTS: No group differences were observed in the number of clinical exacerbations or the number of newly diagnosed GABHS infections. On only six occasions of a total of 51 (12%), a newly diagnosed GABHS infection was followed, within 2 months, by an exacerbation of tic and/or OC symptoms. In every instance, this association occurred in the non-PANDAS group. CONCLUSIONS: This study provides no evidence for a temporal association between GABHS infections and tic/OC symptom exacerbations in children who meet the published PANDAS diagnostic criteria. PMID- 21241949 TI - Patterns and correlates of tic disorder diagnoses in privately and publicly insured youth. AB - OBJECTIVE: This study examined the prevalence and demographic and clinical correlates of children diagnosed with Tourette disorder, chronic motor or vocal tic disorder, and other tic disorders in public and private insurance plans over the course of a 1-year period. METHOD: Claims were reviewed of Medicaid (n = 10,247,827) and privately (n = 16,128,828) insured youth (4-18 years old) focusing on tic disorder diagnoses during a 1-year period. Rates are presented for children with each tic disorder diagnosis overall and stratified by demographic characteristics and co-identified mental disorders. Mental health service use, including medications prescribed, and co-existing psychiatric disorders were also examined. RESULTS: In Medicaid-insured children, rates of diagnosis per 1,000 were 0.53 (95% confidence interval [CI] 0.51-0.55) for Tourette disorder, 0.08 (95% CI 0.07-0.08) for chronic motor or vocal tic disorder, and 0.43 (95% CI 0.41-0.44) for other tic disorders. In privately insured children, comparable rates were 0.50 (95% CI 0.49-0.52), 0.10 (95% CI 0.10-0.11), and 0.59 (95% CI 0.58-0.61). In 1 year, children diagnosed with tic disorders also frequently received other psychiatric disorder diagnoses. Compared with privately insured youth, children under Medicaid diagnosed with Tourette disorder had higher rates of attention-deficit/hyperactivity disorder (50.2% versus 25.9%), other disruptive behavior (20.6% versus 5.6%), and depression (14.6% versus 9.8%) diagnoses and higher rates of antipsychotic medication use (53.6% versus 33.2%). CONCLUSIONS: Despite similarities in annual rates of tic disorder diagnoses in publicly and privately insured children, important differences exist in patient characteristics and service use of publicly and privately insured youth who are diagnosed with tic disorders. PMID- 21241950 TI - Age of menarche and psychosocial outcomes in a New Zealand birth cohort. AB - OBJECTIVE: This study examined associations between age of menarche and psychosocial outcomes in early adulthood, including sexual behavior, mental health, criminal behavior, and education/employment, to identify the possible causal role of earlier age of menarche in increasing risks of adverse outcomes. METHOD: Data were gathered from 497 female members of a New Zealand longitudinal birth cohort. Outcome measures (to age 18 years) were as follows: pregnancy; sexually transmitted infection (STI); DSM-IV major depression, anxiety disorder, alcohol dependence and conduct disorder/ASPD; self-reported crime; convictions; leaving school without qualifications; and unemployment. Associations between age of menarche and outcome measures were then adjusted for confounding factors spanning family background, family functioning, and individual factors. Additional analyses examined sexual behavior outcomes to age 21, and all other outcomes to age 30 years. RESULTS: Analyses showed that sexual behavior outcomes (pregnancy, STI) were significantly associated with age of menarche, even after controlling for confounding factors. Anxiety disorder was marginally (p < .10) associated with age of menarche. In addition, pregnancy during ages 18 to 21 years was significantly associated with age of menarche. There were no significant associations between age of menarche and outcomes at any other age (to age 30). CONCLUSIONS: The study showed that females reaching menarche at an earlier age were at increased risk of early pregnancy, and STI by age 18. The present study found little evidence to suggest that age of menarche was related to mental health, criminal behavior, or education/employment outcomes for this cohort. PMID- 21241951 TI - Do executive function deficits predict later substance use disorders among adolescents and young adults? AB - OBJECTIVE: There is increasing interest regarding the risk and overlap of executive function deficits (EFDs) in stable cigarette smoking and substance use disorders (SUD). Therefore, we examined whether earlier EFD was a risk factor for subsequent cigarette smoking and SUD and further explored the relationship between EFD and SUD. METHOD: We assessed 435 subjects at the 5-year follow-up (232 subjects with attention-deficit/hyperactivity disorder [ADHD], mean age +/- SD: 15.4 +/- 3.43 years; and 203 controls: 16.3 +/- 3.42 years) and again 4 to 5 years later as part of a prospective family study of youth with ADHD. Individuals were assessed by structured psychiatric interview for psychopathology and SUD. EFD was categorically defined in an individual who had abnormal results on at least two of six neuropsychological tests of executive functioning. RESULTS: At the final follow-up period, ADHD was found to be a significant predictor of stable cigarette smoking (p < .01) and SUD into late adolescence and young adult years (p < .01). However, EFDs were not associated with an increase in subsequent substance use outcomes. New-onset stable cigarette smoking, but not SUD, was associated with subsequent EFD (p < .01). CONCLUSIONS: Our results do not support the hypothesis that EFDs predicts later stable cigarette smoking or SUD in children with ADHD growing up. However, stable cigarette smoking is associated with subsequent EFD. PMID- 21241952 TI - Correlates of at-risk/problem internet gambling in adolescents. AB - OBJECTIVE: The Internet represents a new and widely available forum for gambling. However, relatively few studies have examined Internet gambling in adolescents. This study sought to investigate the correlates of at-risk or problem gambling in adolescents acknowledging or denying gambling on the Internet. METHOD: Survey data from 2,006 Connecticut high school student gamblers were analyzed using chi(2) and logistic regression analyses. RESULTS: At-risk/problem gambling was found more frequently in adolescent Internet gamblers than in non-Internet gamblers. Compared with at-risk/problem gambling in the non-Internet gambling group, at-risk/problem gambling in the Internet gambling group was more strongly associated with poor academic performance and substance use (particularly current heavy alcohol use; odds ratio 2.99; p = .03) and less strongly associated with gambling with friends (odds ratio 0.32; p = .0003). At-risk/problem gambling in the Internet and non-Internet gambling groups, respectively, was associated at p < .05, each with multiple adverse measurements including dysphoria/depression (odds ratios 1.76 and 1.96), getting into serious fights (odds ratios 2.50 and 1.93), carrying weapons (odds ratios 2.11 and 1.90), and use of tobacco (odds ratios 2.05 and 1.88 for regular use), marijuana (odds ratios 2.02 and 1.39), and other drugs (odds ratios 3.24 and 1.67). CONCLUSIONS: Clinically, it is important to assess for teenagers' involvement in Internet gambling, particularly because adolescent at-risk/problem Internet gambling appears specifically associated with non-peer involvement, heavy alcohol use, and poor academic functioning. PMID- 21241953 TI - Racial/ethnic differences in mental health service use among adolescents with major depression. AB - OBJECTIVE: Little is known about racial/ethnic differences in the receipt of treatment for major depression in adolescents. This study examined differences in mental health service use in non-Hispanic white, black, Hispanic, and Asian adolescents who experienced an episode of major depression. METHOD: Five years of data (2004-2008) were pooled from the National Survey on Drug Use and Health to derive a nationally representative sample of 7,704 adolescents (12-17 years old) diagnosed with major depression in the past year. Racial/ethnic differences were estimated with weighted probit regressions across several measurements of mental health service use controlling for demographics and health status. Additional models assessed whether family income and health insurance status accounted for these differences. RESULTS: The adjusted percentages of blacks (32%), Hispanics (31%), and Asians (19%) who received any treatment for major depression were significantly lower than those of non-Hispanic whites (40%; p < .001). Black, Hispanic, and Asian adolescents were also significantly less likely than non Hispanic whites to receive prescription medication for major depression, to receive treatment for major depression from a mental health specialist or medical provider, and to receive any mental health treatment in an outpatient setting (p < .01). These differences persisted after adjusting for family income and insurance status. CONCLUSION: Results indicated low rates of mental health treatment for major depression in all adolescents. Improving access to mental health care for adolescents will also require attention to racial/ethnic subgroups at highest risk for non-receipt of services. PMID- 21241954 TI - Clonidine extended-release tablets for pediatric patients with attention deficit/hyperactivity disorder. AB - OBJECTIVE: This study examined the efficacy and safety of clonidine hydrochloride extended-release tablets (CLON-XR) in children and adolescents with attention deficit/hyperactivity disorder (ADHD). METHOD: This 8-week, placebo-controlled, fixed-dose trial, including 3 weeks of dose escalation, of patients 6 to 17 years old with ADHD evaluated the efficacy and safety of CLON-XR 0.2 mg/day or CLON-XR 0.4 mg/day versus placebo in three separate treatment arms. Primary endpoint was mean change in ADHD Rating Scale-IV (ADHD-RS-IV) total score from baseline to week 5 versus placebo using a last observation carried forward method. Secondary endpoints were improvement in ADHD-RS-IV inattention and hyperactivity/impulsivity subscales, Conners Parent Rating Scale-Revised: Long Form, Clinical Global Impression of Severity, Clinical Global Impression of Improvement, and Parent Global Assessment from baseline to week 5. RESULTS: Patients (N = 236) were randomized to receive placebo (n = 78), CLON-XR 0.2 mg/day (n = 78), or CLON-XR 0.4 mg/day (n = 80). Improvement from baseline in ADHD-RS-IV total score was significantly greater in both CLON-XR groups versus placebo at week 5. A significant improvement in ADHD-RS-IV total score occurred between groups as soon as week 2 and was maintained throughout the treatment period. In addition, improvement in ADHD-RS-IV inattention and hyperactivity/impulsivity subscales, Conners Parent Rating Scale-Revised: Long Form, Clinical Global Impression of Improvement, Clinical Global Impression of Severity, and Parent Global Assessment, occurred in both treatment groups versus placebo. The most common treatment-emergent adverse event was mild-to-moderate somnolence. Changes on electrocardiogram were minor and reflected the known pharmacology of clonidine. CONCLUSIONS: Clonidine hydrochloride extended-release tablets were generally well tolerated by patients in the study and significantly improved ADHD symptoms in this pediatric population. PMID- 21241956 TI - Against le packing: a consensus statement. PMID- 21241957 TI - Asperger disorder in the DSM-V: sacrificing utility for validity. PMID- 21241955 TI - Emerging depression is associated with face memory deficits in adolescent girls. AB - OBJECTIVE: To examine the association between memory for previously encoded emotional faces and depression symptoms assessed over 4 years in adolescent girls. Investigating the interface between memory deficits and depression in adolescent girls may provide clues about depression pathophysiology. METHOD: Participants were 213 girls recruited from a longitudinal, community-based study; the majority were African American. Scores on depressive screening measures at age 8 were used to increase the base rate of depression. Depression symptoms and diagnoses were assessed annually for 4 years. In year 4, when the girls were 12 to 13 years old, a face emotion encoding task was administered during which ratings were generated in response to sad, fearful, angry, and happy faces. A surprise memory task followed whereby participants identified which of two faces, displaying neutral expressions, they had seen previously. RESULTS: Girls with higher depression symptom levels from ages 9 to 12 years evidenced lower accuracy in identifying previously encoded emotional faces. Controlling for IQ, higher depression symptom level was associated with a memory deficit specific to previously encoded sad and happy faces. These effects were not moderated by race. CONCLUSIONS: Individual differences in face memory deficits relate to individual differences in emerging, early adolescent depression, and may be vulnerability markers for depression. PMID- 21241959 TI - It's all change for the new editor--not another bioengineer. PMID- 21241960 TI - Soft lenses certainly have the dominant market share and have many advantages over other lens types. PMID- 21241961 TI - SCAI consensus document on occupational radiation exposure to the pregnant cardiologist and technical personnel. AB - Concerns regarding radiation exposure and its effects during pregnancy are often quoted as an important barrier preventing many women from pursuing a career in Interventional Cardiology. Finding the true risk of radiation exposure from performing cardiac catheterisation procedures can be challenging and guidelines for pregnancy exposure have been inadequate. The Women in Innovations group of Cardiologists with endorsement of the Society for Cardiovascular Angiography and Interventions aim to provide guidance in this publication by describing the risk of radiation exposure to pregnant physicians and cardiac catheterisation personnel, to educate on appropriate radiation monitoring and to encourage mechanisms to reduce radiation exposure. Current data do not suggest a significant increased risk to the foetus of pregnant women in the cardiac catheterisation laboratory and thus do not justify precluding pregnant physicians from performing procedures in the cardiac catheterisation laboratory. However, radiation exposure amongst pregnant physicians should be properly monitored and adequate radiation safety measures are still warranted. PMID- 21241964 TI - It is 2011, and Cardiovascular Revascularization Medicine (CRM) has expanded to 6 published issues per year. PMID- 21241965 TI - Effects of short-term anti-inflammatory therapy on endothelial function in patients with non-ST-segment elevation acute coronary syndrome. AB - The aim was to assess the impact of the short-term anti-inflammatory therapy on coronary endothelial function in non-ST-segment elevation acute coronary syndrome patients. In 30 patients, coronary endothelial function was assessed by acetylcholine test. Vessel response was calculated as a percent change of mean lumen diameter (MLD). Then patients were randomized into three groups: A (n = 11) placebo, B (n = 11) 80 mg atorvastatin, C (n = 8) 80 mg atorvastatin and 25 mg rofecoxib. After 7 days control test was performed. Recovery of coronary endothelial function was calculated as delta in percent changes of MLD between Days 1 and 7. On Day 1, percent change of MLD between baseline and maximum acetylcholine did not differentiate the groups: -20 +/- 3.5% in A, -25 +/- 3.9% in B and -26 +/- 3.7% in C, P = .20. On Day 7, percentage changes in MLD were as follows: -21 +/- 3.9% in A, -15 +/- 3.0% in B and -10 +/- 4.0% in C, P=.002. The delta in percentage change in MLD between Days 1 and 7 were as follows: -1% in A, + 10% in B and +16% in C, P = .02. In conclusion, short-term, anti-inflammatory therapy with high-dose atorvastatin and selective cyclooxygenase-2 inhibitor improves coronary endothelial function within 7 days in non-ST-segment elevation acute coronary syndrome patients. PMID- 21241966 TI - Deep calf veins arterialization for inferior limb preservation in diabetic patients with extended ischaemic wounds, unfit for direct arterial reconstruction: preliminary results according to an angiosome model of perfusion. AB - AIM OF THE STUDY: The study proposes to evaluate the limb salvage in diabetic ischemic limbs with foot wounds, where all types of common arterial reconstructions have previously failed or were impracticable, by using the "SAVES" technique (selective arterio-venous endoluminal switch) for deep calf veins arterialization upon an angiosomes model of distribution. MATERIALS AND METHODS: Since January 2001 until September 2009, a series of 26 limbs with threatening ischemic wounds in 25 diabetic patients at high risk for major amputation and no feasible conventional revascularizations, were treated by the hybrid (surgical and endovascular) SAVES technique and were retrospectively reviewed. The method consists in selective arterialization of the deep calf veins with synchronous endoluminal exclusion of the collaterals, guided by an angiosomes- model of vascularization. There were 12 limbs treated by preferential anterior tibial veins arterialization, 11 with revascularizations in the posterior tibial and three others targeting the peroneal-related territorial wound distribution. RESULTS: The initial technical success was achieved in 21 of 26 limbs (80%) with 0% 30-day perioperative mortality rate. The cumulative primary and secondary patency were: 66%, 60% and 48%, at 12, 24 and 36 months, respectively. Limb salvage revealed 73% at one year and steady 73% afterwards, while the clinical success was: 68%, 60% and 60% at identical time intervals. CONCLUSION: Selective deep calf venous arterialization oriented by an angiosome model for reperfusion may represent a complementary alternative for limb salvage in extreme situations, inoperable by direct arterial methods. Larger groups of study are needed to ascertain these preliminary observations. PMID- 21241967 TI - Platelet reactivity in diabetic patients subjected to acute exercise stress test. AB - BACKGROUND: Previous studies have reported ambiguous results regarding the effect of acute exercise on platelet reactivity in healthy and cardiac patients. OBJECTIVES: We aimed to assess platelet reactivity among diabetic patients before and immediately after an acute exercise stress test. METHODS: Patients (controls: mean age 53.1 +/- 12.1 years; four males; body mass index 27.0 +/- 5.7 kg/m(2); HbA(1c) 6.0 +/- 1.1%, n = 8) and diabetic patients (52.9 +/- 11.3; six males; body mass index 30.7 +/- 2.2 kg/m(2); HbA(1c) 7.8 +/- 1.7%, n = 8) referred for diagnostic nuclear exercise stress test were recruited. Blood samples obtained at rest and immediately post-exercise were stimulated with adenosine diphosphate (ADP), collagen and arachidonic acid. Expression of CD41 (pan-platelet marker) and CD62p (platelet stimulation marker) were measured by flow cytometry. Aspirin responsiveness was measured using VerifyNow. RESULTS: Although peak systolic blood pressure was significantly higher in the diabetics compared with nondiabetics (186.3 +/- 25.4 vs. 157.1 +/- 19.1, respectively, P = .028), peak exercise heart rate was similar (156.5 +/- 8.3 vs. 155.5 +/- 12.1 for diabetics and nondiabetics, respectively). No differences were observed between groups for aspirin resistance. Platelet stimulation with ADP exhibited significantly lower CD62p-positive cell population (%) in the diabetic patients both prior to and following the exercise stress test (P = .03). In addition, although not significant, platelet stimulation was higher post-exercise in the diabetic patients (6.3 +/- 4.7% vs. 12.0 +/- 5.6%, for pre- and post-exercise, respectively, P = .2) with no difference in controls (9.2 +/- 5.5% vs. 8.9 +/- 5.9%). CONCLUSION: Platelet stimulation in diabetic patients is blunted and might be explained by the prolonged exposure of platelets to multiple diabetic risk factors. PMID- 21241968 TI - Incidence, clinical characteristics, and 4-year follow-up of patients with isolated myocardial bridge: a retrospective, single-center, epidemiologic, coronary arteriographic follow-up study in southern Turkey. AB - INTRODUCTION: Myocardial bridge is a rare coronary anomaly that is generally considered to be benign. The true incidence and long-term prognosis are still under debate. Therefore, we investigated the prevalence and prognosis of patients with isolated myocardial bridge in our center. METHOD: This study is a retrospective, angiographic follow-up which includes 14,250 patients. Median follow-up was 4 years. The typical angiographic finding of myocardial bridging (MB) is systolic narrowing of an epicardial artery. Exclusion criterion was myocardial bridge with coronary artery disease (CAD). The primary end point was major cardiac events (death, myocardial infarction, and revascularization). RESULTS: Myocardial bridge was observed in 118 (0.83%) patients without CAD. The median age was 56.2. There were 30 (25.5%) male and 88 (74.5%) female patients. The arterial segment that was most frequently involved was the left anterior descending artery, as evident in 91 patients (77.2%). Most of the myocardial bridge produces a systolic narrowing between 30% and 50%. There was no major adverse cardiac event nor a need for any revascularization in the follow-up period with medical treatment. CONCLUSION: Isolated myocardial bridge is a benign and rare coronary anomaly. However, further studies are needed to detect long term prognosis. PMID- 21241969 TI - Combination stem cell therapy for the treatment of medically refractory coronary ischemia: a Phase I study. AB - PURPOSE: Infusion of a source of endothelial progenitor cells (EPC) into the ischemic myocardium is emerging as a promising therapy for coronary ischemia, probably mediated by the formation of new blood vessels. Studies have shown that while the procedure is safe and feasible, efficacy results are contentious. The investigators hypothesized that the infusion of a combination cell product consisting of a source of EPC and mesenchymal stem cells (MSC) is safe and promotes the formation of more stable and mature blood vessels resulting in improved clinical outcomes. METHODS: Ten patients with stable angina pectoris (class III to IV) on maximal medical therapy were included. All patients had >= 70% stenosis in at least one coronary artery, and none was considered a candidate for percutaneous coronary intervention or coronary artery bypass graft. End points were feasibility and safety of intracoronary infusion of the combination cell product and assessment of myocardial ischemia, left ventricular ejection fraction (LVEF), and quality of life at 6 months postinfusion. RESULTS: Six months after cell infusion there were no adverse clinical events. Functional cardiac evaluation during the same period showed significant improvements in LVEF (average increase: 11%, P = .02) and myocardial ischemia (average decrease: 1.8 fold, P = .02). Additionally, all patients described significant improvements in quality of life. CONCLUSIONS: Despite the inherent limitations associated with a Phase I clinical trial, this study demonstrates that the intracoronary infusion of the combination cell product is feasible and safe and also insinuates that this form of therapy may be beneficial. PMID- 21241971 TI - Would coronary collaterals to the infarct-related artery serve as a marker of viability in patients with prior myocardial infarction? A study with trimetazidine-(99m)Tc-sestamibi imaging. AB - BACKGROUND: Visualization of collateral circulation to the infarct-related artery on coronary angiography was suggested to predict viability in the infarct zone as demonstrated by dobutamine stress echocardiography. METHODS AND MATERIALS: We enrolled 30 consecutive patients referred from our catheterization labs with prior Q-wave myocardial infarction at least 6 months before study enrollment. Patients were classified according to the presence of collaterals to the infarct related artery into two groups: collateral group with Rentrop Grade 1-3 collaterals, and noncollateral group with Rentrop Grade 0 collaterals. Patients underwent resting (99m)Tc-sestamibi imaging study with the administration of trimetazidine, using the standard technique, within 4 days of coronary angiography. Viability in a specific territory was defined when at least 50% of its individual segments were classified as viable. RESULTS: The visualization of collaterals by coronary angiography was able to predict viability in the territory supplied by the infarct-related artery with a sensitivity of 88.2%; specificity of 53.8%; positive and negative predictive values of 71.4% and 77.8%, respectively; and a diagnostic accuracy of 73.3%. The presence of viability increased progressively, in a statistically significant manner, from Rentrop Grade 0 to Grade 1 and Grade 2 [2 (22.2%), 5 (50%), 10 (91%), respectively, P = .04]. CONCLUSIONS: Visualization of coronary collaterals to the infarct-related artery by coronary angiography may predict with a high sensitivity but a low specificity the presence of viability in the territory supplied by that artery. PMID- 21241970 TI - The universal classification is an independent predictor of long-term outcomes in acute myocardial infarction. AB - BACKGROUND: The long-term outcomes of patients with acute myocardial infarction (AMI) according to the universal classification (UC) are unknown. We investigated whether the outcome of these patients is better predicted by the UC than the ST segment classification (STC). METHODS: We conducted a retrospective study of 348 consecutive patients with AMI with mean follow-up of 30.6 months. The primary outcome was major adverse cardiovascular events (MACE) [composite of all causes of death and AMI]. RESULTS: The study included ST-segment elevation (STEMI) = 168 (48%), non-ST-segment elevation (NSTEMI) = 180 (52%), Type 1 = 278 (80%), Type 2 = 55 (15.8%), Type 3 = 5 (1.4%), Type 4a = 2 (0.6%), Type 4b = 5 (1.4%), and Type 5 = 3 (0.9%). During follow-up, 102 (29.3%) patients had MACE, 80 (23%) patients died, and 31 (8.9%) had an AMI. The adjusted risk of MACE was similar for NSTEMI and STEMI (HR 1.26, 95% CI 0.77-2.03, P = .35) but was significantly lower for patients with Type 2 AMI as compared to Type 1 (HR 0.44, 95% CI 0.21-0.90, P= .02). The UC, peak troponin levels, discharge glomerular filtration rate <60 ml/min per 1.73 m(2), and thrombolysis in myocardial infarction risk score were independent predictors of MACE (all, P<.05). CONCLUSIONS: The UC is an independent predictor of long-term outcomes in AMI patients compared to the STC. Type 2 AMI has less than half the risk of MACE as Type 1 AMI. Future studies should report outcomes of AMI patients according to the UC types. PMID- 21241972 TI - Prolonged clopidogrel application reduces tissue factor expression after percutaneous coronary intervention in the porcine model. AB - BACKGROUND: Late thrombotic events are important complications associated with intracoronary brachytherapy (ICBT) using ionizing radiation (IR) or with antiproliferative treatment modalities such as drug-eluting stents (DES). The mechanism mediating these thrombotic events is not well understood. This study assessed the effect of prolonged clopidogrel treatment on tissue factor (TF) expression in coronary arteries and on the circulating TF level after percutaneous transluminal coronary angioplasty /ICBT in a porcine coronary model. METHODS: Pigs were treated with aspirin plus a 300 mg loading dose of clopidogrel one day before percutaneous coronary intervention (PCI), followed by a daily dose of clopidogrel and aspirin. During PCI one of the two balloon-injured arteries was treated by brachytherapy. Animals were sacrificed at different time points. The pigs, which were sacrificed 3 months post-PCI, were divided into two groups (Group I: clopidogrel for 3 months; Group II: clopidogrel for 1 month). Plasma TF was measured by enzyme-linked immunosorbent assay in blood samples taken from all pigs before and immediately after intervention and before sacrifice. Morphometric analysis was performed on digitalized images employing the software LUCIA G for TF staining. Vascular TF expression levels were assessed by quantitative real time polymerase chain reaction. RESULTS: Prolonged clopidogrel application significantly reduced coronary TF at the protein (Group I vs. II, 8.975 +/- 3.947% vs. 26.44 +/- 5.375%, P = .007) and mRNA level [Group I vs. II, (0.3501 +/ 0.0519) * 10(-3) vs. (0.7073 +/- 0.0436) * 10(-3), P<.0005]. Circulating TF protein tended to be lower after 3 months than after 1 month clopidogrel treatment post-PCI (Group I vs. Group II, 488.3 +/- 35.37 pg/ml vs. 572.3 +/- 39.9 pg/ml, P = .130). CONCLUSIONS: Prolonged clopidogrel treatment reduced coronary TF expression and tended to reduce the blood TF level post-PCI, thus possibly modulating the risk of late thrombosis. PMID- 21241973 TI - Late stent thrombosis secondary to carbon monoxide poisoning. AB - Carbon monoxide poisoning has a variety of deleterious cardiac effects including arrhythmias, coronary spasm and myocardial infarction. The pro-thrombotic effect of carbon monoxide poisoning is one of the important postulated mechanisms of cardiac injury. There are multiple case reports of myocardial infarction secondary to carbon monoxide poisoning. However, there is no published case of carbon-monoxide-poisoning-induced stent thrombosis. We present a 50-year-old female with late stent thrombosis of a sirolimus-eluting stent secondary to acute carbon monoxide poisoning. PMID- 21241974 TI - Anteriorly displaced right coronary artery in acute myocardial infarction: what should every cardiologist know. AB - Anteriorly displaced right coronary artery (RCA) and anomalous origin RCAs occur in ~ 1% and 0.1% of adult patients, respectively, and are the leading cause of incomplete coronary angiography and prolonged procedure times. We present a case in which anteriorly displaced RCA occlusion resulted in an acute inferior posterior-right ventricular myocardial infarction complicated by complete atrioventricular block and hypotension. Failure to image the RCA resulted in considerable delay in reperfusion time with fibrinolysis. The authors discuss the most frequent anatomic locations of ectopic RCAs and suggest an algorithm to be employed when an ectopic RCA cannot be imaged with conventional diagnostic catheters. Contrary to popular belief, the search for an ectopic RCA has <90 degrees boundaries limited to the anterior third of the right sinus and anterior half of the left sinus. PMID- 21241975 TI - Single coronary artery but dual left anterior descending coronary artery anomaly. PMID- 21241977 TI - Embolic renal infarct, patent foramen ovale and coronary artery dissection: a strange case of cardio-renal connection. AB - A 50-year-old female with no cardiovascular risk factors presented to our service for urgent coronary angiography because of an acute coronary syndrome with electrocardiographic inferior ST elevation. The coronary angiography revealed the occlusion of a small distal branch of the posterior interventricular artery in the total absence of even mild coronary atherosclerosis with a concomitant regional akinesia of the distal inferior left ventricular wall. The patient was referred to medical therapy with double antiplatelet therapy with aspirin and clopidogrel. The patient being still hypertensive despite therapy with nitrates and symptomatic for angina, a computed tomographic scan was performed, revealing no aortic dissection but a small right cortical renal infarct. A rise in creatinine greater than 25% (0.3 mg/dl) from baseline documented a condition of acute kidney injury class "R." Two days after, on control coronary angiography the branch of the posterior interventricular coronary appeared as a dissection of a branch of moderate calibre. The echocardiogram confirmed a distal inferior left ventricular wall akinesia with a preserved left ventricular ejection fraction, but more interestingly, revealed a patent foramen ovale (PFO) with massive right to left shunt after Valsalva manoeuvre and a moderate atrial septal aneurysm. Based on reported findings we hypothesized that a paradoxical embolism trough the PFO caused the renal infarct and a subsequent high blood pressure-induced coronary artery dissection. PMID- 21241976 TI - Endovascular treatment of coronary steal. AB - Postoperative angina is generally caused by subclavian artery stenosis or flow diversion in anomalous or large unligated side branches of the left internal mammary artery. Previously, surgery was the treatment method for unligated side branches, but with the improvements of interventional techniques, it is shown that endovascular treatment is also effective in these patients. Herein, we present successful endovascular treatment of a large unligated intercostal side branch causing recurrent angina. PMID- 21241978 TI - Complex interventional procedures for the management of early postoperative left main coronary artery embolism after bioprosthetic aortic valve insertion. AB - The incidence of calcified debris coronary embolism after aortic valve replacement (AVR) with a bioprosthesis is a rare but potentially life-threatening condition. We sought to describe a case of immediate postoperative left main coronary artery embolism, resulting to severe acute coronary syndrome and cardiogenic shock, after aortic valve surgery due to severe aortic valve stenosis, with the use of bioprosthesis. Complex interventional procedures and possible diagnostic challenges are being described. PMID- 21241979 TI - Use of the GuideLiner catheter in facilitating coronary and graft intervention. AB - Visualization of distal vessel run-off following contrast injection in a coronary artery or bypass graft may be poor due to suboptimal 'seating' of the catheter or to competitive antegrade or retrograde flow from native vessels. In situations where percutaneous coronary intervention (PCI) is deemed necessary, such poor visualization may be compounded by poor guide catheter (GC) support, rendering intervention difficult or even impossible. These limitations may be overcome by deeply intubating the proximal or mid segment of the target vessel with a smaller GC through the outer GC. This double-coaxial catheter arrangement is often referred to as 'mother and child', with the outer GC being the 'mother' and the inner GC being the 'child'. Recently, several such catheters have become commercially available, including Terumo's Heartrail II catheter and Vascular Solutions' GuideLiner catheter. PMID- 21241980 TI - The use of excimer laser for complex coronary artery lesions. AB - Excimer laser coronary atherectomy (ELCA) has been used for coronary intervention for more than 20 years. Advances in delivery systems for laser energy using the xenon-chlorine pulsed laser catheter deliver higher energy density with lower heat production. The Spectranetics CVX-300 (Spectranetics, Colorado Springs, CO, USA) excimer laser catheter system has been used for the treatment of complex coronary lesions. We report our experience with the use of this advanced system for stenoses for which were unsuitable for standard percutaneous coronary intervention; for example, balloon-resistant lesions, chronic total occlusions, and for underexpanded stents in calcified lesions. ELCA may also be valuable for thrombus-containing lesion. We find ELCA to be indispensable in the catheterization laboratory for specific complex or calcified lesions. Its role should be explored in a large randomized trial of thrombus containing lesions and saphenous vein grafts. PMID- 21241981 TI - Effect of sodium fluoride on the virulence factors and composition of Streptococcus mutans biofilms. AB - OBJECTIVE: This study aimed to evaluate the influence of NaF (2, 10, 50 and 125 ppm F(-)) on the virulence factors and composition of Streptococcus mutans biofilms. METHODS: S. mutans UA159 biofilms were formed on saliva-coated hydroxyapatite discs. To assess the influence of NaF on the virulence factors of S. mutans biofilm cells, glycolytic pH drop, proton-permeability and F-ATPase activity assay were performed using 74 h old S. mutans biofilms. Glucosyltransferase (GTF) activity assay in suspension was also performed. To examine the influence of NaF on S. mutans biofilm composition, the biofilms were treated twice daily (5 min exposure/treatment) a total of five times during biofilm formation. After a total of 5 treatments, the biomass, colony forming unit (CFU) and polysaccharide composition of the treated 74h old S. mutans biofilms were analysed by microbiological and biochemical methods, and scanning electron microscopy. RESULTS: NaF showed inhibitory effects on the acid production and acid tolerance of S. mutans biofilm cells at 10, 50 and 125 ppm F( ), compared to the vehicle control (P<0.05) and the treatments at these concentrations also affected the biomass, water-insoluble extracellular polysaccharides and intracellular iodophilic polysaccharides of the biofilms, compared to the vehicle control (P<0.05). CONCLUSIONS: These results indicate that NaF (10, 50 and 125 ppm F(-)) has inhibitory effects on the virulence factors and composition of S. mutans biofilms, suggesting the potential use of these concentrations as an effective measure for controlling dental biofilms. PMID- 21241982 TI - A retrospective study of the association between shortening of the clavicle after fracture and the clinical outcome in 136 patients. AB - BACKGROUND AND PURPOSE: The purpose of this retrospective study was to examine the association between shortening of the clavicle after a united midshaft fracture and clinical outcome. Second, the purpose was to compare the results obtained by conservative treatment with either a figure-of-eight bandage or a simple sling. MATERIALS AND METHODS: This study included 136 patients with a united, conservatively treated, midshaft clavicle fracture. Mean age was 35 years (range 15-70 years); mean follow-up time was 55 months (range 24-83 months). The shortening of the clavicle was measured on a radiograph including one antero posterior view of both clavicles on a single film and defined as the difference between the injured and the contralateral clavicle. The clinical outcome was measured using the Constant-Murley Score. RESULTS: The mean difference in the Constant-Murley Score between the injured and the contralateral shoulder was 7.3, P<0.001 (95% confidence interval (CI) 5.6; 9.1). Mean shortening of the injured shoulder was 11.6mm, P<0.001 (95% CI 10.2; 13.0). A shortening of more than 20mm was not associated with a poorer clinical outcome. The results obtained by conservative treatment with either a figure-of-eight bandage or a simple sling showed no difference in shortening or in the Constant-Murley Score. CONCLUSIONS: We found that conservative treatment of midshaft clavicle fractures resulted in final shortening and mild reduction of shoulder function. A shortening of 20mm or more was not associated with a poorer clinical outcome. The figure-of-eight bandage and a simple sling were equal treatments of midshaft clavicle fractures. PMID- 21241983 TI - Measuring patient outcomes: a primer. AB - When designing a study, it is important to select appropriate instruments to measure health outcomes. An investigator must have a comprehensive understanding of the disease and its effects on patient health to inform instrument selection. We provide a brief introduction of different ways that health is defined and the properties of a good measurement tool (reliability, validity, sensitivity to change). We describe patient-reported outcomes (PROs) and methods to improve their interpretability, and we include strategies to reduce bias in health measurement and considerations that may improve the feasibility of measuring outcomes in a research study. PMID- 21241984 TI - Do educational interventions improve nurses' clinical decision making and judgement? A systematic review. AB - OBJECTIVES: Despite the growing popularity of decision making in nursing curricula, the effectiveness of educational interventions to improve nursing judgement and decision making is unknown. We sought to synthesise and summarise the comparative evidence for educational interventions to improve nursing judgements and clinical decisions. DESIGN: A systematic review. DATA SOURCES: Electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, CINAHL and PsycINFO, Social Sciences Citation Index, OpenSIGLE conference proceedings and hand searching nursing journals. REVIEW METHODS: Studies published since 1960, reporting any educational intervention that aimed to improve nurses' clinical judgements or decision making were included. Studies were assessed for relevance and quality. Data extracted included study design; educational setting; the nature of participants; whether the study was concerned with the clinical application of skills or the application of theory; the type of decision targeted by the intervention (e.g. diagnostic reasoning) and whether the evaluation of the intervention focused on efficacy or effectiveness. A narrative approach to study synthesis was used due to heterogeneity in interventions, study samples, outcomes and settings and incomplete reporting of effect sizes. RESULTS: From 5262 initial citations 24 studies were included in the review. A variety of educational approaches were reported. Study quality and content reporting was generally poor. Pedagogical theories were widely used but use of decision theory (with the exception of subjective expected utility theory implicit in decision analysis) was rare. The effectiveness and efficacy of interventions was mixed. CONCLUSIONS: Educational interventions to improve nurses' judgements and decisions are complex and the evidence from comparative studies does little to reduce the uncertainty about 'what works'. Nurse educators need to pay attention to decision, as well as pedagogical, theory in the design of interventions. Study design and reporting requires improvement to maximise the information contained in reports of educational interventions. PMID- 21241985 TI - Niacin results in reduced monocyte adhesion in patients with type 2 diabetes mellitus. AB - BACKGROUND AND AIM: Patients with type 2 diabetes have increased expression of cell adhesion molecules (CAMs). CAMs and monocyte adhesion mediate essential processes in atherogenesis. It remains unclear if monocytes from patients on niacin have reduced adhesion function. METHODS: We studied the variation of monocyte adhesion in patients with type 2 diabetes and low HDL-cholesterol, taking either extended release niacin (Niaspan(r), Abbott Laboratories) or controls not on niacin. Biochemical parameters including adiponectin, CAMs and fresh monocytes from whole blood for adhesion assays, were studied at baseline and 12-weeks. RESULTS: Niacin 1500 mg daily raised HDL-cholesterol from 0.8 mmol/l (95% CI: 0.7-0.9) to 0.9 mmol/l (95% CI: 0.8-1.1), p=0.10, and significantly reduced PECAM-1 by 24.9% (95% CI: 10.9-39.0; p<0.05), increased adiponectin by 30.5% (95% CI: 14.1-47.0; p<0.05), with monocyte adhesion reduced by 9.2% (95%CI: 0.7-17.7; p<0.05) in endothelial cells treated in basal conditions, and 7.8% (95% CI: 3.1-12.5; p<0.05) after TNF-alpha stimulation. CONCLUSIONS: Monocytes isolated from patients on niacin had reduced adhesion to endothelial cells. Our findings suggest niacin has broad range of effects apart from lipid-modification, and these could be important in cardiovascular risk reduction. PMID- 21241986 TI - Independent and additive effects of cytokine patterns and the metabolic syndrome on arterial aging in the SardiNIA Study. AB - OBJECTIVE: Metabolic syndrome (MetS) and its components accelerate age-associated increases in arterial stiffness and thickness. We investigated whether specific proinflammatory cytokines contribute to arterial aging, independent of age, sex, MetS, and other traditional CV risk factors. RESEARCH DESIGN AND METHODS: MetS components (ATP III criteria) and arterial properties were assessed in 6148 subjects, aged 14-102 in Sardinia, Italy. Common carotid artery (CCA) diameter, intima-media thickness (IMT), and aortic pulse wave velocity (PWV), adiponectin, leptin, high-sensitivity C reactive protein (hsCRP), monocyte chemoattractant protein 1 (MCP1), and interleukin 6 (IL6) were measured. RESULTS: While cytokine levels - except for MCP1 - were significantly higher (lower for adiponectin) in MetS than in control subjects, and the increased PWV and CCA IMT with aging were associated with MetS, this association was independent of cytokine levels (p<0.001 for both PWV and CCA IMT). Specific cytokines, however, were significantly associated with arterial stiffness (higher leptin, p<0.001, and higher hsCRP, p<0.001) or thickness (lower adiponectin, p<0.05, and higher IL6, p<0.001) - independent of age, sex, MetS and other traditional CV risk factors. The co-occurrence of both MetS and higher cytokines levels was associated with greater increases in arterial stiffness and thickness. CONCLUSION: While MetS and specific cytokine patterns associated with arterial aging, the increases in arterial stiffness and thickness are greater when both MetS and higher cytokine levels are present, suggesting a possible synergistic effect of MetS and inflammation on the arterial wall. PMID- 21241987 TI - Association between aldosterone induced by antihypertensive medication and arterial stiffness reduction: the J-CORE study. AB - OBJECTIVE: Excess aldosterone has a detrimental effect on large artery stiffness. We aimed to investigate the association of the change in plasma aldosterone concentration (PAC) by antihypertensive medication with the change in aortic pulse wave velocity (aPWV). METHODS: We conducted a prospective, randomized, open label, blinded end-point study in 207 hypertensive patients. Patients received olmesartan monotherapy for 12 weeks, followed by add-on use of hydrochlorothiazide (HCTZ; n=104) or azelnidipine (n=103) for 24 weeks after randomization. The aPWV, which was determined by measuring the carotid to femoral PWV, and laboratory data were assessed at baseline and 24 weeks later. RESULTS: PAC in the HCTZ group increased more than that in the azelnidipine group, while aPWV and mean arterial pressure in the azelnidipine group decreased more than those in the HCTZ group. In univariable analyses, the change in PAC was significantly and positively correlated with the change in aPWV in the total population (r=0.26, P<0.001) and the HCTZ group (r=0.28, P=0.004), but not in the azelnidipine group (r=0.17, P=0.09). In multivariable analyses, a positive association of the change in PAC with the change in aPWV was observed in the total population (standardized regression coefficient beta=0.18, P<0.001) and the HCTZ group (beta=0.23, P=0.004), independently of the changes in covariates, but not in the azelnidipine group (beta=0.13, P=0.06). CONCLUSION: The change in PAC was significantly and positively associated with the change in aPWV in patients treated with HCTZ. These findings may partly explain why thiazide diuretics have little effect on large artery stiffness. PMID- 21241988 TI - Multi-location peak parking method: an important new tool for the study of mass transfer kinetics in liquid chromatography. AB - The peak parking (PP) method probes the longitudinal diffusion coefficient of a compound at a single location along the chromatographic column. We extended to a so-called multi-location peak parking (MLPP) method, in which a large number of axial locations along the column are selected in order to check the validity of the conventional PP method and to reveal possible defaults in the structure of the packed bed or pitfalls of the PP and the MLPP methods. MLPP was applied to a series of HILIC columns, including a 5.0 MUm Venusil, a 3.0 MUm Luna-diol, three 2.7 MUm Halo, and a 1.7 MUm Kinetex columns. The results demonstrate that the MLPP method may reveal local heterogeneities in the axial diffusion of small retained low molecular weight compounds along the column. Most importantly, experiments show that the sample zone should not be parked in the entrance of the column (i.e., at <1/10 th of the column length). The abrupt drop in the flow rate considerably affects the peak shape and prevents scientists from using the conventional PP method. Practical solutions to cope with that problem are proposed and their success/failure are discussed. PMID- 21241989 TI - Gas chromatographic identification of chlorination products of aliphatic ketones. AB - Chlorinated derivatives of aliphatic ketones are a class of organic compounds poorly characterized by both mass spectra and chromatographic retention indices up to present. It is caused by objective difficulties of isolation of individual products from reaction mixtures formed in the result of non-selective chlorination of parent carbonyl compounds. Nevertheless the differences of GC retention indices for structurally analogous chlorination products of different ketones and initial substrates indicate the constancy depending on the number and position of chlorine atoms in the molecules. This feature permits us to use the simplest kind of additive schemes in identification of such chlorinated derivatives, including diastereomeric alpha,alpha'-dichloro-k-alkanones (k>2). Hence, the identification of chlorination products of aliphatic ketones becomes possible for any compounds of this class without using mass spectrometric data only in the result of accurate measurement of their GC retention indices. PMID- 21241990 TI - A microfabricated graphitic carbon column for high performance liquid chromatography. AB - We report the first development of a novel, planar, microfluidic, graphitic carbon separations column utilizing an array of graphitic micropillars of diamond cross-section as the chromatographic stationary phase. 795 nm femtosecond laser ablation was employed to subtractively machine fluidic architectures and a micropillared array in a planar, graphitic substrate as a monolithic structure. A sample injector was integrated on-chip, together with fluid-flow distribution architectures to minimize band-broadening and ensure sample equi-distribution across the micro-pillared column width. The separations chip was interfaced directly to the ESI probe of a Thermofisher Surveyor mass spectrometer, enabling the detection of test-mixture analytes following their differential retention on the micro-pillared graphitic column, thus demonstrating the exciting potential of this novel separations format. Importantly, unlike porous, graphitic microspheres, the temperature and pressure resilience of the microfluidic device potentially enables use in subcritical H(2)O chromatography. PMID- 21241991 TI - Two-step stacking in capillary zone electrophoresis featuring sweeping and micelle to solvent stacking: II. Organic anions. AB - Two-step stacking of organic anions by sweeping and micelle to solvent stacking (MSS) using cationic cetyltrimethylammonium micelles in co-electroosmotic flow (co-EOF) capillary zone electrophoresis (CZE) is described. The co-EOF condition where the direction of the EOF is the same as the test anions was satisfied by positive dynamic coating of a fused silica capillary with hexadimethrine bromide. The strategy was as follows. After conditioning the capillary with the background solution (BGS), a micellar solution (MS) was injected before the sample solution (S). The BGS, MS and S have similar conductivities. Voltage was applied at negative polarity. The analytes in the micelle-free S zone were swept by micelles from the MS. The swept analytes were brought by the micelles to the MSS boundary where the second stacking step was induced by the presence of organic solvent in the BGS. Finally was the separation of concentrated analytes by CZE. The effect of electrolyte concentration in the S, injection time of the MS and the S and surfactant concentration in the MS were studied. A 20-29, 17-33 and 18-21 times increase in peak height sensitivity was obtained for the test hypolipidaemic drugs (gemfibrozil, fluvastatin and atorvastatin), non-steroidal anti inflammatory drugs (diflunisal, naproxen, ketoprofen, indoprofen and indomethacin), and herbicides (mecoprop and fenoprop), respectively. The LODs (S/N=3) were from 0.05 to 0.55 MUg/mL. The intraday and interday repeatabilities (%RSD, n=12) in terms of retention time, corrected peak area, and peak heights was less than 3.6, 8.9, and 10.8%, respectively. The application of sweeping and MSS in co-EOF CZE together with a simple extraction procedure to a waste water sample spiked with the test herbicides was also demonstrated. PMID- 21241992 TI - Gas chromatography-atmospheric pressure chemical ionization-time of flight mass spectrometry for profiling of phenolic compounds in extra virgin olive oil. AB - A new analytical approach based on gas chromatography coupled to atmospheric pressure chemical ionization-time of flight mass spectrometry was evaluated for its applicability for the analysis of phenolic compounds from extra-virgin olive oil. Both chromatographic and MS parameters were optimized in order to improve the sensitivity and to maximize the number of phenolic compounds detected. We performed a complete analytical validation of the method with respect to its linearity, sensitivity, precision, accuracy and possible matrix effects. The LODs ranged from 0.13 to 1.05ppm for the different tested compounds depending on their properties. The RSDs for repeatability test did not exceed 6.07% and the accuracy ranged from 95.4% to 101.5%. To demonstrate the feasibility of our method for analysis of real samples, we analyzed the extracts of three different commercial extra-virgin olive oils. We have identified unequivocally a number of phenolic compounds and obtained quantitative information for 21 of them. In general, our results show that GC-APCI-TOF MS is a flexible platform which can be considered as an interesting tool for screening, structural assignment and quantitative determination of phenolic compounds from virgin olive oil. PMID- 21241993 TI - Sleep disorders and fatigue in multiple sclerosis: evidence for association and interaction. AB - Fatigue is highly prevalent in multiple sclerosis (MS). It appears to be multifactorial, with "primary" or disease-related factors involved, as well as "secondary" factors, including comorbidities. Sleep disturbances are frequent in MS as well, and often result from disease-related factors. Subjective sleep disturbances in MS have been extensively studied and have been associated with fatigue. Sleep disorders in the general population have been associated with fatigue as well. However, data on objectively diagnosed sleep disorders in MS are less conclusive. Studies of sleep in MS have often suffered from low numbers of study subjects and suboptimal methodology. We review the current knowledge on sleep disturbances in MS and the relationship to fatigue. Data from neuroimaging studies and studies of molecular consequences of sleep disorders in the general population, with particular attention to sleep-disordered breathing (SDB), are briefly reviewed. Potential biologic interactions with MS are discussed in this context. We conclude that further studies of sleep disorders in MS are needed, to objectively establish their significance in this disease, and also to document any impact of treatment of sleep disorders on biologic and clinical outcomes such as fatigue. PMID- 21241994 TI - Peripherin partially localizes in Bunina bodies in amyotrophic lateral sclerosis. AB - Peripherin is a type III intermediate filament protein expressed with low levels in spinal motor neurons. Amyotrophic lateral sclerosis (ALS) is characterized by the presence of Bunina bodies, skein-like inclusions, and Lewy body-like inclusions (LBLIs) in the remaining anterior horn cells, where the first and third structures are detected by Hematoxylin-Eosin (H & E) staining. We examined paraffin sections of lumbar spinal cords from six ALS patients, using H & E staining and immunostaining for human peripherin. The results demonstrated that there were a total of 73 anterior horn cells containing one or more Bunina bodies, and that twelve of these cells (approximately 16.4%) demonstrated peripherin-positive Bunina bodies. In fact, some part of chain-like Bunina bodies showed peripherin-positive reaction, although there were a much higher number of non-immunoreacitive Bunina bodies in each neuron. LBLIs were clearly immunostained for peripherin corresponding to the core, while some of them showed different types of immunoreactivities due to oblique cutting of inclusions. Our findings suggest that although the mechanisms underlying peripherin co localization in Bunina bodies are unknown, peripherin could be involved in forming these inclusions. Furthermore, following cystatin C and transferrin, peripherin is the third most prevalent protein that partially localizes in Bunina bodies. PMID- 21241995 TI - [Endothelial microparticles in preeclampsia and eclampsia]. AB - OBJECTIVE: To compare endothelial microparticles values in eclamptic, preeclamptic and normotensive pregnant women. MATERIALS AND METHODS: Patients were selected among those who assisted to Obstetrics Emergency at Hospital Central "Dr. Urquinaona", Maracaibo, Venezuela. There were included 30 patients with mild preeclampsia (group A), 30 patients with severe preeclampsia (group B) and 30 patients with eclampsia (group C). A control group was selected for having similar age and body mass index to studied groups and consisted in 35 healthy pregnant women (group D). There were included only nuliparous patients. Blood samples were collected in all patients before delivery and in studied groups immediately after diagnosis for endothelial microparticles determination. RESULTS: There were statistically significant differences in gestational age between groups B and C compared with controls (P<.05). Higher values of endothelial microparticles were observed in eclamptic patients together with severe preeclamptic patients. Lower values were found in mild preeclamptic patients. Studied groups presented significant higher values of endothelial microparticles compared with controls (P<.05). When linear regression was performed, factors that significantly affected endothelial microparticles values were: uric acid, 24-hour proteinuria, transaminases and platelet count (P<.05). CONCLUSIONS: The findings of this research showed that eclamptic and preeclamptic patients had higher endothelial microparticles values than normotensive pregnant women. PMID- 21241996 TI - Leishmania (Viannia) braziliensis identification by PCR in the state of Para, Brazil. AB - The incidence of cutaneous leishmaniasis (CL) is increasing and there is limited surveillance of Leishmania species throughout the world. We identified the species associated with CL in a region of Amazonia, an area recognized for its Leishmania species variability. Clinical findings were analyzed and correlated with the species identified in 93 patients. PCR assays were based on small subunit ribosomal DNA (SSU-rDNA) and G6PD, and were performed in a laboratory located 3,500km away. Leishmania (V.) braziliensis was identified in 53 patients (57%). The other 40 patients (43%) carried a different species (including six cases of L. (L.) amazonensis). Molecular methods can be employed, using special media, to allow transport to distant laboratories. L. (V.) braziliensis is the most common species in the area of Para. The location of ulcers can suggest CL species. PMID- 21241998 TI - What weight should be assigned to future environmental impacts? A probabilistic cost benefit analysis using recent advances on discounting. AB - Cost-benefit analysis is a standard methodological platform for public investment evaluation. In high environmental impact projects, with a long-term effect on future generations, the choice of discount rate and time horizon is of particular relevance, because it can lead to very different profitability assessments. This paper describes some recent approaches to environmental discounting and applies them, together with a number of classical procedures, to the economic evaluation of a plant for the desalination of irrigation return water from intensive farming, aimed at halting the degradation of an area of great ecological value, the Mar Menor, in South Eastern Spain. A Monte Carlo procedure is used in four CBA approaches and three time horizons to carry out a probabilistic sensitivity analysis designed to integrate the views of an international panel of experts in environmental discounting with the uncertainty affecting the market price of the project's main output, i.e., irrigation water for a water-deprived area. The results show which discounting scenarios most accurately estimate the socio environmental profitability of the project while also considering the risk associated with these two key parameters. The analysis also provides some methodological findings regarding ways of assessing financial and environmental profitability in decisions concerning public investment in the environment. PMID- 21241997 TI - The taking of the cytoskeleton one two three: how viruses utilize the cytoskeleton during egress. AB - The final assembly of nonlytic envelope viruses requires the coordinated transport of either subviral particles or fully formed virions to the plasma membrane for release from the cell. Recent research has delved into the mechanisms viruses employ to hijack the host cell's cytoskeletal system for active transport to the site of final assembly and release. This review will look at recent findings that relate to the transport of virions to the cell periphery and out of the cell. PMID- 21241999 TI - Voltage-dependent anion channel 2 modulates resting Ca2+ sparks, but not action potential-induced Ca2+ signaling in cardiac myocytes. AB - Voltage-dependent anion channels (VDACs) are pore forming proteins predominantly found in the outer mitochondrial membrane and are thought to transport Ca(2+). In this study, we have investigated the possible role of type 2 VDAC (VDAC2) in cardiac Ca(2+) signaling and Ca(2+) sparks using a lentiviral knock-down (KD) technique and two-dimensional confocal Ca(2+) imaging in immortalized autorhythmic adult atrial cells, HL-1. We confirmed high expression of VDAC2 protein in ventricular, atrial, and HL-1 cells using Western blot analysis. Infection of HL-1 cells with VDAC2-targeting lentivirus reduced the level of VDAC2 protein to ~10%. Comparisons of autorhythmic Ca(2+) transients between wild type (WT) and VDAC2 KD cells showed no significant change in the magnitude, decay, and beating rate of the Ca(2+) transients. Caffeine (10mM)-induced Ca(2+) release, which indicates sarcoplasmic reticulum (SR) Ca(2+) content, was not altered by VDAC2 KD. Interestingly, however, the intensity, width, and duration of the individual Ca(2+) sparks were significantly increased by VDAC2 KD in resting conditions, with no change in the frequency of sparks. VDAC2 KD significantly delayed mitochondrial Ca(2+) uptake during artificial Ca(2+) pulses in permeabilized HL-1 cells. These results suggest that VDAC2 may facilitate mitochondrial Ca(2+) uptake and restrict Ca(2+) spark expansion without regulating activations of sparks under resting conditions, thereby providing evidence on the functional role of VDAC2 in cardiac local Ca(2+) signaling. PMID- 21242000 TI - cAMP increases the sensitivity of exocytosis to Ca2+ primarily through protein kinase A in mouse pancreatic beta cells. AB - Cyclic AMP regulates the late step of Ca2+-dependent exocytosis in many secretory cells through two major mechanisms: a protein kinase A-dependent and a cAMP GEF/Epac-dependent pathway. We designed a protocol to characterize the role of these two cAMP-dependent pathways on the Ca2+ sensitivity and kinetics of regulated exocytosis in mouse pancreatic beta cells, using a whole-cell patch clamp based capacitance measurements. A train of depolarizing pulses or slow photo-release of caged Ca2+ were stimuli for the exocytotic activity. In controls, due to exocytosis after slow photo-release, the C(m) change had typically two phases. We observed that the Ca2+-dependency of the rate of the first C(m) change follows saturation kinetics with high cooperativity and half maximal rate at 2.9+/-0.2 MUM. The intracellular depletion of cAMP did not change amp1, while rate1 and amp2 were strongly reduced. This manipulation pushed the Ca2+-dependency of the exocytotic burst to significantly lower [Ca2+](i). To address the question of which of the cAMP-dependent mechanisms regulates the observed shifts in Ca2+ dependency we included regulators of PKA and Epac2 activity in the pipette solution. PKA activation with 100 MUM 6-Phe-cAMP or inhibition with 500 MUM Rp-cAMPs in beta cells significantly shifted the EC(50) in the opposite directions. Specific activation of Epac2 did not change Ca2+ sensitivity. Our findings suggest that cAMP modulates Ca2+-dependent exocytosis in mouse beta cells mainly through a PKA-dependent mechanism by sensitizing the insulin releasing machinery to [Ca2+](i); Epac2 may contribute to enhance the rates of secretory vesicle fusion. PMID- 21242001 TI - Differential effect of ill-being and chronic stress on cradling behavior of first and multi-time parents. AB - A preference for cradling infants on the left side has been demonstrated in women, as has a relation of reduced left-cradling and stress/negative affect. This relation has not yet been investigated in male participants. Due to less left-cradling in non-fathers compared to fathers it was suggested that fatherhood might have an influence on cradling behavior. The present study investigated the cradling preference of first- and multi-time parents before and after birth, and its relation to ill-being and stress. Results revealed that cradling behavior of first-time fathers was not different before and after the birth of the infant. Thus, fatherhood does not seem to have an acute influence on cradling behavior. Furthermore, cradling behavior of first- and multi-time parents was differentially influenced by ill-being and stress. These results present new information about the course of cradling preference from pregnancy to postpartum and indicate that the relation of cradling and ill-being/stress is more complex for parents than for non-parents. PMID- 21242002 TI - Increased risk of cancer subsequent to severe depression--a nationwide population based study. AB - BACKGROUND: Empirical findings on the association between a history of depression and subsequent cancer incidence are mixed and inconclusive. A link between depression and cancer would gain greater credence if it can be sustained across cultures. This nationwide, population-based study aimed to prospectively examine the relationship between a psychiatric diagnosis of depression in an inpatient setting and the risk of developing cancer in the following five years in Taiwan. METHOD: This study used data from the Taiwan National Health Insurance Research Database. A total of 778 patients hospitalized for depression from 1998 to 2003 were recruited, together with 3890 matched non-depressive enrollees as a comparison cohort. Each patient was tracked five years to identify the occurrence of any type of cancer. The Cox proportional hazards models were carried out to compute the risk of cancer between study and comparison cohorts, following adjustment for residence and socio-demographic characteristics. RESULTS: We found that during a five-year follow-up, 61 severely depressed patients (7.8%) and 212 patients in the non-depressed comparison cohort (5.5%) received cancer diagnoses. For adults age 18 and older, having been hospitalized with a diagnosis of depressive disorder was independently associated with a 1.62-fold (95% CI: 1.12, 2.34) overall increased risk of subsequent cancer during five years of follow-up, after adjusting for residence and socio-demographic characteristics. CONCLUSION: Our results suggest depression is significantly associated with increased risk of cancer in a rather short follow-up time. Our results call attention to the immediate health impacts of severe depression on patients. PMID- 21242003 TI - Transcriptional profiling of immune genes in bovine monocyte-derived macrophages exposed to bacterial antigens. AB - The involvement of Toll-like receptors (TLRs) and other immune signalling genes during challenge of bovine macrophages with bacterial products derived from disease-causing bacteria in cattle was investigated. An in vitro cell culture model of bovine monocyte derived macrophages (MDM) was established and these cells were exposed to purified protein derivative (PPD-b) derived from Mycobacterium bovis and to lipopolysaccharide (LPS) derived from Escherichia coli. Following 24h incubation, total RNA was extracted and expression of immune related genes was determined by real time quantitative reverse transcription PCR (qRT-PCR). Expression of a selection of genes spanning the TLR-2 and TLR-4 pathways, from the initial activation of the receptors to the production of pro inflammatory cytokines and chemokines was determined. Results from repeat experiments using MDM from seven different age-matched dairy cattle showed that PPD-b treatment caused significant up-regulation of the TLR2 and TLR4 genes and the expression profile of TLR adaptor molecules suggested that this signalling is MYD88-dependent. Conversely, LPS caused significant up-regulation of TLR4 via a MYD88-independent signalling pathway. Significant up-regulation of genes involved with NF-kappaB signalling was also detected in PPD-b- and LPS-treated samples accompanied by the expression of pro-inflammatory cytokine (TNF, IL1B, IL6) and chemokine genes (IL8, CCL5, CCL3). Overall, LPS challenge resulted in a more marked up-regulation of immune-related genes. Furthermore, the magnitude fold change difference in gene expression suggests, at least in part, that bovine macrophages produce IFN-gamma as a result of LPS challenge. PMID- 21242004 TI - Nasometry normative data for young Dutch children. AB - OBJECTIVE: Hypernasality is a common problem in cleft care. It should be treated before the age of six, because of the impact it can have on speech sound development in young children. An objective method of nasalance evaluation is nasometry. To decide whether a nasometer test result is normal or abnormal, normative data and cut off points are needed. Normative data for children are not available for every language and age. For Dutch children two sets of Dutch speech stimuli, the Van Zundert sentences or the Moolenaar-Bijl, sentences, are often used in the diagnostic process for hypernasality. Primary goal of this study is to determine normative data and cut off points for two sets of Dutch speech stimuli for Dutch children from four to six years of age. Secondary is to compare those two sets of oral sentences. METHOD: Children without clefts were recruited from schools. According to their teachers their speech was normal. They were tested with the nasometer with the two sets of speech stimuli. The set from Van Zundert has oral and oronasal sentences, the Moolenaar-Bijl set only has oral sentences. RESULTS: 118 children were recruited. Out of these children, 55 produced recording samples which were suitable for analysis. There were no significant differences between age groups or gender. The two different sets of speech stimuli used were significantly different, but the confidence intervals overlapped. CONCLUSIONS: Normal nasalance scores of the tested sentences are between 3 and 19% for oral sentences and between 17 and 37% for oronasal sentences. The Moolenaar-Bijl speech sentences are preferred to evaluate hypernasality in young Dutch children, because of the shortness and intelligibility. Normative nasalance scores are applicable to the whole group of children from four to six years of age. PMID- 21242005 TI - Pediatric laryngeal trauma: a case series at a tertiary children's hospital. AB - BACKGROUND: Pediatric blunt or sharp laryngotracheal injuries are infrequent because of the softer cartilages and the protection of the prominent mandible. These injuries usually occur secondary to striking furniture or via the "clothesline" injury. METHODS: We present five cases of pediatric laryngotracheal injury (thyroid cartilage, true vocal cords, cricoid cartilage, cricotracheal junction, and posterior tracheal wall). RESULTS: We examined the need for intubation, need for tracheostomy, length of intubation, length of hospital stay, interval until direct laryngoscopy, use of steroids, post-injury swallowing, and post-injury phonation. DISCUSSION: Three of the five patients were intubated either prior to arrival or upon arrival to the emergency department. Two of the patients underwent direct laryngoscopy on the day of arrival. Three patients received steroids. CT (computed tomography) was not helpful in diagnosis or decision regarding treatment. The patients with thyroid cartilage fracture, cricoid cartilage fracture, cricotracheal separation, and posterior tracheal wall tear required open repair. The tracheal wall injury, cricoid fracture, and cricotracheal separation were repaired with sutures and the thyroid cartilage fracture with a plate and screws. One tracheal stent was placed. Two open repairs were performed within 24h of injury. The patient with posterior tracheal wall injury experienced persistent dysphagia and dysphonia, which may have been secondary to intraoperative dissection. CONCLUSION: Dyspnea was not necessarily indicative of the severity of injury in our patients. CT added little information about the integrity of the larynx not already known by physical examination. Open repair was usually indicated for the blunt neck injuries in our series. Oral intubation proved less difficult than tracheostomy in our patient with cricoid cartilage fracture. PMID- 21242006 TI - A case of multiple abnormalities with eustachian tube obstruction by a protruded internal carotid artery. AB - We report a case of multiple abnormalities with eustachian tube obstruction by a protruded internal carotid artery. A 10-year-old male presented with multiple abnormalities including anomalous pinna, poor eyesight, facial palsy, moderate conductive deafness, and otitis media with effusion. Temporal bone computed tomography demonstrated obstruction of the right eustachian tube by a protruded internal carotid artery. Insertion of a tympanostomy tube did not improve his hearing, indicating a possible ossicular chain anomaly. Although tympanoplasty is necessary to improve the patients' hearing, the poor drainage function makes this difficult. Knowledge of this vascular anomaly is important when performing myringotomy or tympanoplasty. PMID- 21242008 TI - Edentulism risk indicators among Mexican elders 60-year-old and older. AB - The objective of this study was to determine the prevalence of edentulism in Mexican elders aged 60 years and older, and the associated risk indicators. A cross-sectional study was undertaken in 139 elders living in either of two long term care (LTC) facilities, or attending an adult day center (ADC) in Pachuca, Mexico. A subject was edentulous when natural teeth were completely absent, determined through a clinical examination. Risk indicators were collected using questionnaires. Analyses were performed using binary logistic regression in STATA 9.0. Mean age was 79.0+/-9.8 years. Many subjects were women (69.1%). The prevalence of edentulism was 36.7%. In multivariate analysis, after adjusting for age and sex, the variables that were inversely associated (p<0.05) with edentulism were living with a spouse (odds ratio=OR=0.31), and lacking health insurance (OR=0.70). Variables associated with higher risk of being edentate were lower educational attainment (OR=1.61), having received radiation therapy (OR=4.49), being a smoker (OR=4.82), and having diabetes (OR=2.94) or other chronic illnesses (OR=1.82) (with hypertension approaching significance, p=0.067). In this sample of Mexican elders, diverse variables were associated with edentulism, in particular smoking and past radiotherapy. Oral health programs within and outside LTC/ADC should take into account risk factors specific to the older population. PMID- 21242007 TI - Rho-associated coiled-coil-forming kinases (ROCKs): potential targets for the treatment of atherosclerosis and vascular disease. AB - ROCKs are important regulators of the actin cytoskeleton. Because changes in the actin cytoskeleton underlie vascular contractility and remodeling, inflammatory cell recruitment, and cell proliferation, it is likely that the Rho/ROCK pathway will play a central role in mediating vascular function. Indeed, increased ROCK activity is observed in cerebral and coronary vasospasm, hypertension, vascular inflammation, arteriosclerosis, and atherosclerosis. Recent experimental and clinical studies suggest that inhibition of ROCK could be a promising target for the treatment of cardiovascular disease. For example, inhibition of ROCK might be the underlying mechanism by which statins or HMG-CoA reductase inhibitors exert their therapeutic benefits beyond cholesterol reduction. In this review we summarize current understanding of the crucial role of RhoA/ROCK pathway in the regulation of vascular function and discuss its therapeutic potential in the treatment of atherosclerosis and vascular disease. PMID- 21242009 TI - Management of congestive heart failure in St. Elizabeth Catholic General Hospital Shisong, cardiac centre. PMID- 21242010 TI - Rare combination of congenital aplasia of the right pulmonary veins, left ventricular noncompaction, partial membranous obstruction of left-sided pulmonary veins and secundum atrial septal defect. PMID- 21242011 TI - Predictors, moderators and mediators for the effectiveness of pexelizumab treatment in patients undergoing primary coronary revascularization. PMID- 21242012 TI - Decreased intralymphocytic magnesium content is associated with diastolic heart dysfunction in patients with essential hypertension. PMID- 21242013 TI - Evaluation of the Finnish Diabetes Risk Score as a screening tool for impaired fasting glucose, impaired glucose tolerance and undetected diabetes. AB - AIM: To evaluate the performance of FINDRISC as a screening tool for prediabetes impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) and undetected diabetes (UDD) in subjects at risk of developing diabetes. SUBJECTS AND METHODS: 2169 subjects with at least one risk factor for diabetes completed the FINDRISC questionnaire and underwent an oral glucose tolerance test. FINDRISC performance was assessed using the area under the receiver operating characteristic curve (AUC-ROC). RESULTS: 56.6% of subjects demonstrated normal glucose tolerance (NGT), 14.5% - IFG, 11.4% - IGT and 17.5% - UDD. NGT group demonstrated mean FINDRISC 10.1+/-3.4, IFG group - 13.8+/-4.3 (p<0.0001 vs. NGT), IGT group - 14.4+/-5.4 (p<0.0001 vs. NGT) and UDD group - 15.5+/-4.8 (p<0.0001 vs. NGT and IFG, p<0.01 vs. IGT). The AUC-ROC was 0.70 (95% CI 0.67-0.73) for UDD and 0.71 (95% CI 0.69-0.73) for undetected prediabetes and diabetes. The FINDRISC cut-off value of 10 to identify both prediabetes and diabetes had sensitivity of 84% and specificity of 61%. CONCLUSIONS: FINDRISC is a feasible, non-invasive and useful tool for identifying subjects at risk for undetected diabetes and prediabetes. Laboratory screening should be performed in subjects with FINDRISC higher than 10. PMID- 21242014 TI - Type 2 diabetes risk in persons with dysglycemia: the Framingham Offspring Study. AB - AIMS: Detection of risk of type 2 diabetes mellitus (T2DM) among adults with dysglycemia. METHODS: We used a nested case-cohort prospective design to estimate risk of new diabetes (diabetes treatment or FPG >=7.0 mmol/L) among 1004 Framingham Heart Study Offspring with baseline dysglycemia [fasting plasma glucose (FPG) 5.4-6.9 mmol/L and/or 2-h post glucose load level 7.8-11.0 mmol/L]. Using clinical characteristics previously shown to predict incident T2DM, we used logistic regression to estimate odds ratios (OR), p-values for predictors, and assessment of model discrimination. RESULTS: At the end of 7 years follow-up there were 118 incident T2DM cases. In a model that included age, sex, elevated blood pressure or blood pressure treatment, lipid-lowering treatment and elevated triglycerides, we found the following additional characteristics to be independently associated with new T2DM: parental history of diabetes (OR 2.28, p=0.004); excess adiposity (BMI >=30 kg/m(2) or waist circumference >=101.6 cm) (OR 2.04, p=0.0005), and low HDL-C [<1.0 (men) or <1.3 mmol/L (women)] (OR 2.77, p<0.0001). The multivariable C-statistic for this model was 0.701, and with glycemic category information included, c=0.751. CONCLUSIONS: The key non glycemic traits that predicted later T2DM in adults with dysglycemia were parental history of diabetes, excess adiposity and low HDL-C. PMID- 21242015 TI - Structural insights into Met receptor activation. AB - The receptor tyrosine kinase Met plays a pivotal role in vertebrate development and tissue regeneration, its deregulation contributes to cancer. Met is also targeted during the infection by the facultative intracellular bacterium Listeria monocytogenes. The mechanistic basis for Met activation by its natural ligand hepatocyte growth factor/scatter factor (HGF/SF) is only beginning to be understood at a structural level. Crystal structures of Met in complex with L. monocytogenes InlB suggest that Met dimerization by this bacterial invasion protein is mediated by a dimer contact of the ligand. Here, I review the structural basis of Met activation by InlB and highlight parallels and differences to the physiological Met ligand HGF/SF and its splice variant NK1. PMID- 21242016 TI - The positional sterile (ps) mutation affects cuticular transpiration and wax biosynthesis of tomato fruits. AB - Cuticular waxes are known to play a pivotal role in limiting transpirational water loss across primary plant surfaces. The astomatous tomato fruit is an ideal model system that permits the functional characterization of intact cuticular membranes and therefore allows direct correlation of their permeance for water with their qualitative and quantitative composition. The recessive positional sterile (ps) mutation, which occurred spontaneously in tomato (Solanum lycopersicum L.), is characterized by floral organ fusion and positional sterility. Because of a striking phenotypical similarity with the lecer6 wax mutant of tomato, which is defective in very-long-chain fatty acid elongation, ps mutant fruits were analyzed for their cuticular wax and cutin composition. We also examined their cuticular permeance for water following the developmental course of fruit ripening. Wild type and ps mutant fruits showed considerable differences in their cuticular permeance for water, while exhibiting similar quantitative wax accumulation. The ps mutant fruits showed a five- to eightfold increase in water loss per unit time and surface area when compared to the corresponding wild type fruits. The cuticular waxes of ps mutant fruits were characterized by an almost complete absence of n-alkanes and aldehydes, with a concomitant increase in triterpenoids and sterol derivatives. We also noted the occurrence of alkyl esters not present in the wild type. Quantitative and qualitative cutin monomer composition remained largely unaffected. The significant differences in the cuticular wax composition of ps mutant fruits induced a distinct increase of cuticular water permeance. The fruit wax compositional phenotype indicates the ps mutation is responsible for effectively blocking the decarbonylation pathway of wax biosynthesis in epidermal cells of tomato fruits. PMID- 21242017 TI - [2011: a key year in Gastroenterologia y Hepatologia]. PMID- 21242018 TI - Antiphospholipid antibodies--we are not quite there yet. AB - The diagnosis of antiphospholipid syndrome is predominantly made in the laboratory and depends on the persistent presence of antiphospholipid antibodies in individuals with thrombosis or pregnancy morbidity. Correct diagnosis of the syndrome is imperative to prevent unnecessary long secondary thromboprophylaxis. Three antiphospholipid antibody subtypes are included in the classification criteria of the antiphospholipid syndrome: lupus anticoagulants, anticardiolipin antibodies and anti-beta2-glycoprotein I antibodies. Only lupus anticoagulants are undisputedly associated with thrombosis, which is why the serological criteria of the antiphospholipid syndrome are under debate. All of the assays used to detect antiphospholipid antibodies are in need of better standardization, although progress has been made in the detection of lupus anticoagulants. The inconsistent association between both anticardiolipin and anti-beta2-glycoprotein I antibodies and thrombosis is a cause for alarm. We are in need of better assays to detect those individuals at risk for thrombosis and population-based prospective studies to provide us with accurate risk assessments. PMID- 21242019 TI - Improvement in the hospital organisation of CPR training and outcome after cardiac arrest in Sweden during a 10-year period. AB - AIM: To describe (a) changes in the organisation of training in cardiopulmonary resuscitation (CPR) and the treatment of cardiac arrest in hospital in Sweden and (b) the clinical achievement, i.e. survival and cerebral function, among survivors after in-hospital cardiac arrest (IHCA) in Sweden. METHODS: Aspects of CPR training among health care providers (HCPs) and treatment of IHCA in Sweden were evaluated in 3 national surveys (1999, 2003 and 2008). Patients with IHCA are recorded in a National Register covering two thirds of Swedish hospitals. RESULTS: The proportion of hospitals with a CPR coordinator increased from 45% in 1999 to 93% in 2008. The majority of co-ordinators are nurses. The proportions of hospitals with local guidelines for acceptable delays from cardiac arrest to the start of CPR and defibrillation increased from 48% in 1999 to 88% in 2008. The proportion of hospitals using local defibrillation outside intensive care units prior to arrival of rescue team increased from 55% in 1999 to 86% in 2008. During the past 4 years in Sweden, survival to hospital discharge has been 29%. Among survivors, 93% have a cerebral performance category (CPC) score of I or II, indicating acceptable cerebral function. CONCLUSION: During the last 10 years, there was a marked improvement in CPR training and treatment of IHCA in Sweden. During the past 4 years, survival after IHCA is high and the majority of survivors have acceptable cerebral function. PMID- 21242020 TI - Clinical emergencies and outcomes in patients admitted to a surgical versus medical service. AB - BACKGROUND: The merit of rapid response systems (RRSs) remains controversial. A tailored approach to specific groups may increase the efficacy of these teams. The purpose of this study was to compare differences in triggers for RRS activation, interventions, and outcomes in patients on medical and surgical services. METHODS: A retrospective review RRS events was performed. The incidence of out of ICU cardiac arrests and hospital mortality were compared 2 years prior to and following RRS implementation. Call trigger, interventions, and disposition between medical and surgical patients were compared over a 15 month period. RESULTS: Out of ICU cardiac arrest was significantly more prevalent in the medical group both before and after implementation of RRS. The out of ICU cardiac arrest rate decreased 32% in the surgical group (p=0.05) but hospital mortality did not change. Out of ICU cardiac arrest decreased 40% in the medical group (p<0.001) and hospital mortality decreased 25% (p<0.001) following RRS implementation. There were 1082 RRS activations, 286 surgical and 796 medical. Surgical patients were more likely to have received sedation within 24 h of evaluation (14% vs. 4%, p<0.001). The majority of patients in both cohorts were discharged alive. CONCLUSION: Implementation of a RRS had greater impact on reduction of out of ICU cardiac arrest and mortality in medical inpatients. Triggers for activation and interventions were similar between groups; however, surgical patients demonstrated substantial risk for decompensation within the first 24 h following operation. More research is needed to evaluate the disproportionate benefit observed between cohorts. PMID- 21242021 TI - Rhabdomyolysis following therapeutic hypothermia after traumatic cardiac arrest. PMID- 21242022 TI - The beneficial effects of physical exercise on antioxidant status in asthmatic children. AB - BACKGROUND: The pathogenesis of asthma involves both airway inflammation and an oxidant/antioxidant imbalance. It is demonstrated in asthmatic adults that exercise programmes improve lung function, a mechanism yet to be elucidated. The purpose of this study was to investigate the possible beneficial effects of physical exercise on antioxidant status in asthmatic children which may lead to ameliorated lung function. METHODS: The study enrolled thirteen control and thirty asthmatic children. The asthmatic group was subdivided into two: the first group receiving only pharmacological treatment (n=15) and the second receiving pharmacological treatment with exercise programme (n=15) for 8 weeks. Blood samples were drawn from the subjects before and after treatment periods. As oxidant stress markers blood levels of malondialdehyde (MDA) and total nitric oxide (NO), and as antioxidant status, glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) enzyme activities were assessed. RESULTS: Before any treatment was initiated, MDA and NO levels in the asthmatic group were significantly higher than the controls (3.40+/-0.96 nmol/ml vs 2.46+/-0.58 nmol/ml, and 12.53+/-2.10 vs 9.40+/-1.39 micromol/L, respectively). Both SOD (p=0.0001) and GSH-Px (p=0.023) activities were significantly lower in the asthmatic group. Pharmacological treatment and exercise programme together significantly improved lung performance and decreased the levels of oxidant stress markers, in concordance with a significantly increase in antioxidant enzyme activity measures when compared to the pharmacological treatment. CONCLUSION: Structured exercise programme in asthmatic children resulted in better lung function, which may be attributed to its effect on antioxidant status. PMID- 21242023 TI - Effects of the gonadotropin-releasing hormone antagonist cetrorelix in the early postimplantation period on rat pregnancy. AB - OBJECTIVE: The effect of cetrorelix given in the early implantation period on rat pregnancy was investigated. STUDY DESIGN: Forty-nine virgin Sprague-Dawley rats were randomized into six groups. At the 4th or 8th days of sperm plug, groups received 15, 75, 150 MUg/kg cetrorelix or saline. Three subjects were randomly selected from each group and sacrificed at 11th gestational day for histomorphometric analysis. The remaining subjects were allowed to complete their pregnancy period. Volumes of total conceptus, labyrinth zone, transitional zone, giant cell zone, and exocoelomic cavity were calculated according to Cavalieri's principle. RESULTS: Subjects receiving cetrorelix at 15 or 150 MUg doses at the 4th day (D4) and those receiving cetrorelix at 150 MUg dose at the 8th day (D8) of pregnancy delivered later than the controls. On necropsy examination at the 11th day, mean embryo weights of the cetrorelix 15 D4, 150 D4, 15 D8 and 75 D8 groups were found to be significantly lower than that of the controls (p<0.05). On histomorphometric evaluation, volumes of the fetuses and the amniotic sacs were decreased by cetrorelix at all doses studied dose dependently. Gross congenital anomalies were observed in the pups of three rats of the cetrorelix 150 D4 and D8 groups. CONCLUSION: The results of this study suggest that cetrorelix in the early post-implantation period may lead to serious side effects in the rat. PMID- 21242025 TI - Preparation, characterization and activity evaluation of Ag2Mo4O13 photocatalyst. AB - Ag(2)Mo(4)O(13) photocatalyst was prepared by the hydrothermal method using AgNO(3) and (NH(4))(2)MoO(4) as raw materials in one step. The Ag(2)Mo(4)O(13) photocatalyst was characterized by X-ray powder diffraction (XRD), UV-Vis diffuse reflectance spectroscopy (DRS), scanning electron microscopy (SEM), Brunauer Emmett-Teller (BET) analysis, N(2) adsorption measurements, and terephthalic acid photoluminescence (TA-PL) probing technique. The photocatalytic activity of the photocatalyst was evaluated by photocatalytic oxidation of methyl orange and photocatalytic reduction of nitrobenzene. The results showed that, the optimum catalyst concentration is 3 g/L, and the optimum optical thickness is 49.4. When the reaction solution was illuminated for 60 min and 10 h, and the amount of photocatalyst was 2.0 g/L, the methyl orange conversion and aniline yield were 76.4% and 63.3%, respectively. The effect of different heat treatment conditions on the photocatalytic activity of the photocatalyst was also investigated. The best preparation condition is heat treatment at 500 degrees C for 10 h. Compared with those photocatalysts prepared at any other conditions, the photoabsorption wavelength range of the photocatalyst calcined at 500 degrees C for 10 h extends greatly towards visible light and it also improves the utilization of the total spectrum. The mechanisms of influence on the photocatalytic activity were also discussed. PMID- 21242026 TI - Identification and fate of halogenated PAHs formed during electrochemical treatment of saline aqueous solutions. AB - Halogenations of polycyclic aromatic hydrocarbons (PAHs) comprise a serious problem, when electrochemical oxidation (EO) is applied for treatment of chloride and bromide containing polluted sea water. In this study, the possible non-polar halogenated byproducts formed were identified in a series of chemical hypochlorination experiments using GC-MS, and the analytical information from these experiments was used in the primary EO treatment tests. An electrochemical cell equipped with a Ti/Pt(90)-Ir(10) anode was used in a batch recirculation setup with naphthalene, pyrene, and fluoranthene as the parent PAHs. Contrary to the chemical hypochlorination experiments, naphthalene as the most soluble compound was the only one to be halogenated in detectable amounts during EO. In a single sodium chloride electrolyte, up to 13% of the initial naphthalene was chlorinated at the peak concentration during treatment before it was subsequently removed. Even small concentrations of added bromide in a mixed electrolyte completely dominated the byproduct pattern with formation of primarily mono brominated naphthalene in peak concentrations up to 30-39% of the initial naphthalene. All of the considered byproducts were despite a more recalcitrant behavior degraded at prolonged treatment times, which need to be applied to ensure a safe discharge of the treated water. PMID- 21242027 TI - Arsenate adsorption and desorption kinetics on a Fe(III)-modified montmorillonite. AB - The adsorption-desorption kinetics of arsenate on a Fe(III)-modified montmorillonite (Fe-M) was studied at different arsenate concentrations, pH and stirring rates. The synthesized solid was a porous sample with Fe(III) present as a mix of monomeric and polymeric Fe(III) species in the interlayer and on the external surface. Adsorption took place in a two-step mechanism, with an initial fast binding of arsenate to Fe(III) species at the external surface (half-lives of 1 min or shorter) followed by a slower binding to less accessible Fe(III) species in pores and the interlayer (half-lives of around 1 h). Desorption kinetics also reflected the presence of externally and internally adsorbed arsenate. At pH 6 the maximum adsorbed arsenate was 52 MUmol/g, a value that is low as compared to adsorption on ferrihydrite (700 MUmol/g) and goethite (192-220 MUmol/g). However, since the Fe(III) content of Fe-M is much lower than that of ferrihydrite and goethite, Fe(III) species in Fe-M are more efficient in binding arsenate than in ferrihydrite or goethite (one As atom is attached every 8.95 iron atoms). This high binding efficiency indicates that Fe(III) species are well spread on montmorillonite, forming small oligomeric species or surface clusters containing just a few iron atoms. PMID- 21242028 TI - Photocatalytic degradation of gaseous toluene over ZnAl2O4 prepared by different methods: a comparative study. AB - The development of a "green" treatment process for typical indoor pollutants such as toluene is greatly desirable. In this study, ZnAl(2)O(4) nanoparticles were prepared via three different routes, i.e., solvothermal, citrate precursor and hydrothermal methods. Their structural properties were systematically investigated by X-ray powder diffraction (XRD), scanning electronic microscopy (SEM), energy-dispersive X-ray spectra (EDX), Brunauer-Emmett-Teller (BET), UV vis diffuse reflectance spectroscopy (DRS), and Fourier transform infrared spectroscopy (FT-IR) techniques. The photo-induced charge separation in the samples was demonstrated by surface photovoltage (SPV) measurement. The photocatalytic performances of the ZnAl(2)O(4) samples and nanostructured TiO(2) samples were comparatively studied by the degradation of gaseous toluene under UV lamp irradiation in in situ FTIR reactor. The results indicated that the sample synthesized by facile solvothermal method exhibited about 90% photocatalytic efficiency of toluene. The toluene was mineralized into carbon dioxide and water as the major species. The photocatalytic oxidation of gaseous pollutant over UV illuminated ZnAl(2)O(4) is a promising technique for air purification. PMID- 21242029 TI - Heavy metals in urban soils with various types of land use in Beijing, China. AB - Heavy metal concentrations of Cd, Cr, Cu, Ni, Pb and Zn were investigated for 127 urban soil samples collected from business area (BA), classical garden (CG), culture and education area (CEA), public green space (PGS), residential area (RA) and roadside area (RSA) in Beijing. The distribution of Cd, Cu, Pb and Zn was mainly affected by anthropogenic sources, with their mean concentrations much higher than the background values of Beijing, while Cr and Ni were from natural sources. Among the 6 types of land use, the concentrations of Cd, Cu, Pb and Zn in CG were significantly higher than those in the other 5 types of land use (p<0.05), which were due to their historical use such as pigments, wood preservation and brassware. For the other 5 types of land use except CG, the mean concentration of Cd in RSA was significantly higher than those in BA, CEA, PGS and RA (p<0.05), suggesting Cd was mainly from traffic sources. The distribution maps revealed that the concentrations of Cu, Pb and Zn showed decreasing trends from the center to the suburb of Beijing, they increased with the age of the urban area. PMID- 21242030 TI - Preparation of iminodiacetic acid functionalized multi-walled carbon nanotubes and its application as sorbent for separation and preconcentration of heavy metal ions. AB - In this paper, a novel material was prepared with functionalizing multi-walled carbon nanotubes (MWCNTs) using iminodiacetic acid (IDA) and characterized by FT IR. Isotherm and kinetics of adsorption were studied and the experimental data fitted the Langmuir model and pseudo-second-order equation very well. An on-line method for simultaneous determination of trace V (V), Cr (VI), Pb (II), Cd (II), Co (II), Cu (II) and As (III) in biological samples was developed using this material as sorbent coupled with inductively coupled plasma mass spectrometry (ICP-MS). A series of experimental parameters, including sample pH, sample flow rate and loading time, eluting solution and the effect of interfering ions have been investigated systematically. Under the optimum experimental conditions, the enrichment factors for above metal ions were ranged from 66 to 101. Detection limit (3 s) was achieved at 1.3, 1.2, 0.70, 0.40, 2.5, 3.4, 0.79 ng L(-1), respectively. At the 1.0 MUg L(-1) level, the precision (RSD, %) for 11 replicate measurements was from 1.0 to 4.0. In spiked biological samples, good recoveries (n=3) were obtained in the range of 90-110%. These results had proved that the proposed method was with good accuracy and could be applied to the analysis of trace metal ions in biological samples. PMID- 21242031 TI - Anodic titanium oxide as immobilized photocatalyst in UV or visible light devices. AB - Titanium anodizing can be a powerful technique to generate photoactive oxides, strongly adherent to the metallic substrate, and to modify their chemical composition by inducing doping effects. This work investigates the photocatalytic behavior of differently obtained anodic TiO(2) films under UV and visible light irradiation, so as to define the best treatment for wastewaters purifiers. Anodizing was performed in H(3)PO(4) and H(2)SO(4) mixtures or in fluoride containing electrolytes. Morphology, elemental composition and crystal structure of the anodic films were characterized by XDR, GDOES and SEM. When amorphous oxides were obtained, an annealing treatment was used to promote the formation of anatase crystals. Annealing was also performed in nitrogen atmosphere to induce nitrogen doping. The photocatalytic efficiency of anatase-enriched TiO(2) was investigated in rhodamine B photodegradation. Doping was induced not only by annealing but also directly by anodizing, and generated photoactivity in both the UV and Vis components of light. PMID- 21242032 TI - Molecular cloning and characterization of transgelin-like proteins mainly transcribed in newborn larvae of Trichinella spp. AB - A cDNA library was constructed from Trichinella pseudospiralis muscle larvae. One cDNA clone, designated Tp4, contained a cDNA transcript of 783 bp in length, with a single open reading frame that encoded 153 amino acids (16,793 Da as the estimated molecular mass). The predicted amino acid sequence of Tp4 showed that the clone had a calponin homology domain and was approximately 50% identical to the transgelin-like proteins (calponin-family members) present in Bombyx mori or Tribolium castaneum. A homologue of the Tp4 clone was also present in cDNA from Trichinella spiralis, and this clone was designated Ts4. A comparison of the amino acid sequence of the transgelin-like proteins from T. spiralis (Ts4 protein) with the Tp4 protein indicated that the two proteins are very similar (about 94% homology). Real time quantitative polymerase chain reaction results showed that the transcription level of the Tp4 and Ts4 genes was highest in newborn larvae. On Western blot, the recombinant Tp4 and Ts4 proteins migrated at 20 kDa when reacted to an antibody against the recombinant Tp4 and Ts4 proteins, respectively. An antibody against the recombinant Tp4 and Ts4 proteins strongly stained two bands migrating at approximately 9 and 8 kDa in the crude extracts from adult worms and newborn larvae, but only weakly stained proteins in muscle larvae. However, an immunocytochemical study showed that the Tp4 protein was present within the muscle of the muscle larvae of T. pseudospiralis. The antibody level against the recombinant Tp4 antigens in infected mice began to increase from 8 days post-infection, was highest in 13 days post-infection, and then slowly decreased. PMID- 21242033 TI - An optimized DNA extraction and multiplex PCR for the detection of Fasciola sp. in lymnaeid snails. AB - This study deals with the development and validation of an original PCR protocol to assess the presence of Fasciola hepatica in Galba truncatula its main intermediate host in Western Europe. In the present study two DNA extraction techniques are compared and a new multiplex PCR is described. The Chelex((r)) DNA extraction technique showed to be more appropriate than the classical Phenol/Chloroform/Proteinase K based method because of the absence of toxic organic solvent, shorter duration and lower cost, and a higher reproducibility regarding DNA concentrations and wavelength ratios. The multiplex PCR was set up to amplify the lymnaeid internal transcribed spacer 2 sequence (500-600 bp) that act as an internal control and a 124 bp Fasciola sp. sequence that is repeated more than 300,000 times in fluke whole genome. Ninety six snails were pooled and 6 snails (6.25%) found positive for Fasciola sp. The limit of detection is lower than the minimal biological infestation unit (one miracidium). DNA extracts from Paramphistomum daubneyi, Dicrocoelium lanceolatum, and Fascioloides magna did not cross react. PMID- 21242034 TI - Comparative evaluation of ectoparasiticide efficacy: non-inferiority and superiority assessment. AB - We present a statistical framework for the comparative evaluation of ectoparasiticide efficacy in controlled animal studies. Such a comparative evaluation can have one of two objectives: an assessment of non-inferiority of a test parasiticide to a reference parasiticide, or an assessment of superiority of one treatment over another. We show that the observed efficacy of an ectoparasiticide can be viewed as a point estimate of its conditional "kill" probability. Thus concepts used in the comparative evaluation of human antibiotics, which involve the comparison of cure probabilities, can be applied to the situation of comparing parasiticide efficacy. In particular, we define non inferiority of a test parasiticide to a reference parasiticide in terms of the "test - reference" difference of their efficacies. We outline the hypothesis testing framework and associated statistical decision rules for declaring either non-inferiority or superiority. Both non-inferiority and superiority can be evaluated statistically using confidence intervals. SAS and R code for data analysis is presented, and the methodology is applied to a data set from a controlled animal study. PMID- 21242035 TI - Quantitative comparison of different purification and detection methods for Cryptosporidium parvum oocysts. AB - Cryptosporidium parvum (C. parvum) is the causal agent of cryptosporidiosis in many animals, mainly cattle, and possesses a high zoonotic potential. It occurs worldwide and ubiquitously. Detection of C. parvum is mainly performed directly but purification of the oocysts is useful to increase sensitivity and to obtain oocyst material for further use. The study was designed to compare (a) three different direct diagnostic methods, namely modified Ziehl-Neelsen staining, carbol fuchsin staining and conventional PCR, and (b) three routine oocyst purification methods, in particular flotation with saturated sodium chloride solution, Sheather's sucrose solution and a Percoll((r)) gradient. During comparison of purification methods, special regard was paid to the ability to separate morphologically intact oocysts from the morphologically degenerated fraction or viable from non-viable oocysts, respectively. RESULTS: (a) DIAGNOSTIC METHODS: Most effective in C. parvum oocysts detection in calf faeces was PCR; carbol fuchsin and modified Ziehl-Neelsen stainings achieved comparable results. (b) Purification methods: Oocyst flotation using sodium chloride solution showed to be superior to Percoll((r)) gradient centrifugation and sugar flotation in terms of purification quality, recovery efficacy (yield) and reduction of the proportion of degenerated or non-viable oocysts. PMID- 21242036 TI - Comparative study on the stability of fish actomyosin and pork actomyosin. AB - Effects of temperature, pH and ionic strength on the stability of actomyosin (AM) from fish and pork were studied using UV spectra, solubility, turbidity, and sulfhydryl group content measurement for comparison. Pork AM exhibited higher stability to cold storage and heating than fish AM. The unfolding rate of AM increased with increasing temperature. Intense aggregation occurred over 30 degrees C for fish AM and 40 degrees C for pork AM. New disulfide bonds mainly formed over 40 degrees C for fish AM and 60 degrees C for pork AM. Pork AM exhibited the higher turbidity than fish AM in the range of 50-90 degrees C, suggesting the higher extent of aggregation of pork AM. Ionic strength mainly influenced solubility of AM, but there was no effect on cleavage and formation of disulfide bond. The lowest solubility of both AM was at pH 5.42. Additionally, fish AM was more sensitive to pH changes than pork AM. PMID- 21242037 TI - Heterocyclic amine content in commercial ready to eat meat products. AB - Heterocyclic amines (HCAs) are produced in meats cooked at high temperature, which are potent mutagens and a risk factor for human cancers. The aim of this study was to estimate the amount of HCAs in some commonly consumed ready-to-eat (RTE) meat products. The RTE products were purchased from a local grocery store, and HCA were analyzed using an analytical method based on solid-phase extraction followed by HPLC. The primary HCAs in these samples were PhIP (2-amino-1-methyl-6 phenylimidazo [4,5-b]pyridine) (not detected-7.9 ng/g) and MeIQx (2-amino-3,8 dimethylimidazo [4,5-f]quinoxaline) (not detected-3.6 ng/g). Products ranked in order of increasing total HCA content: pepperoni (0.05 ng/g)1.8 has a good sensitivity in identifying the association with cerebrovascular events. PMID- 21242045 TI - Application of adjusted subpixel method (ASM) in HRCT measurements of the bronchi in bronchial asthma patients and healthy individuals. AB - BACKGROUND: Recently, we described a model system which included corrections of high-resolution computed tomography (HRCT) bronchial measurements based on the adjusted subpixel method (ASM). OBJECTIVE: To verify the clinical application of ASM by comparing bronchial measurements obtained by means of the traditional eye driven method, subpixel method alone and ASM in a group comprised of bronchial asthma patients and healthy individuals. METHODS: The study included 30 bronchial asthma patients and the control group comprised of 20 volunteers with no symptoms of asthma. The lowest internal and external diameters of the bronchial cross sections (ID and ED) and their derivative parameters were determined in HRCT scans using: (1) traditional eye-driven method, (2) subpixel technique, and (3) ASM. RESULTS: In the case of the eye-driven method, lower ID values along with lower bronchial lumen area and its percentage ratio to total bronchial area were basic parameters that differed between asthma patients and healthy controls. In the case of the subpixel method and ASM, both groups were not significantly different in terms of ID. Significant differences were observed in values of ED and total bronchial area with both parameters being significantly higher in asthma patients. Compared to ASM, the eye-driven method overstated the values of ID and ED by about 30% and 10% respectively, while understating bronchial wall thickness by about 18%. CONCLUSIONS: Results obtained in this study suggest that the traditional eye-driven method of HRCT-based measurement of bronchial tree components probably overstates the degree of bronchial patency in asthma patients. PMID- 21242046 TI - Evaluation of matrix-assisted laser desorption ionization-time of flight whole cell profiles for assessing the cultivable diversity of aerobic and moderately halophilic prokaryotes thriving in solar saltern sediments. AB - The moderately halophilic, cultivable fraction of prokaryotes thriving in hypersaline sediments of a solar saltern in Mallorca, Spain, has been studied by means of different cultivation media. A set of 374 isolates retrieved with six different culture conditions was screened, using whole-cell MALDI-TOF MS analysis to classify them into 25 phenotypic clusters at 52% similarity. The phylogenetic inference, made from comparative sequence analyses of the 16S rRNA genes of selected strains, indicated that each phenotypic cluster was comprised of a genealogically homogeneous set of strains. DNA-DNA hybridization (DDH) results among selected strains confirmed that each MALDI-TOF cluster encompassed members of the same species. On the other hand, the intra-cluster diversity, measured by several RAPD (Random Amplified Polymorphic DNA) amplifications, indicated that the clusters corresponded to several populations of the same phylogenetic unit coexisting in the same environment. The results encourage the use of MALDI-TOF MS for further exhaustive studies of the cultivable diversity of hypersaline environments. PMID- 21242047 TI - Typing of nitrogen-fixing Frankia strains by matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry. AB - Matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) mass spectrometry (MS) was evaluated as a technique to characterize strains of the nitrogen-fixing actinomycete Frankia. MALDI-TOF MS reliably distinguished 37 isolates within the genus Frankia and assigned them to their respective host infection groups, i.e., the Alnus/Casuarina and the Elaeagnus host infection groups. The assignment of individual strains to sub-groups within the respective host infection groups was consistent with classification based on comparative sequence analysis of nifH gene fragments, confirming the usefulness of MALDI-TOF MS as a rapid and reliable tool for the characterization of Frankia strains. PMID- 21242048 TI - Qualitative research on health communication: what can it contribute? AB - OBJECTIVE: To contribute to the debate about the value of qualitative research in health care by discussing three key issues in relation to qualitative research on health communication. METHODS: As this paper does not report the results of a primary research study or a secondary analysis, no formal search strategy was employed to identify the cited papers; many other published papers would have made the same points just as well. RESULTS: The key issues are illustrated using a range of published studies drawn from the health care communication literature. The paper describes the range of outputs generated by qualitative research; illustrates different ways in which qualitative and quantitative methods can be combined; and shows the contribution of qualitative syntheses. CONCLUSIONS: Greater conceptual development and explanatory power may be achieved both by more ambitious primary studies and the conduct of more qualitative syntheses. The synthesis of qualitative research also offers the opportunity to build up a cumulative evidence base. PRACTICE IMPLICATIONS: The further development of methods of qualitative synthesis will be enhanced if qualitative researchers place greater emphasis on explanation rather than description; cite each other's work more often and conduct more syntheses; and continue to contribute to mixed methods studies. PMID- 21242049 TI - [Complete atrio-ventricular block: a rare complication of interferon alpha therapy]. PMID- 21242050 TI - [Slipping rib or Cyriax Syndrom]. PMID- 21242051 TI - [Pseudo-mesothelioma revealing an apparent primary pleural melanoma]. PMID- 21242052 TI - [Management of childhood epilepsy]. AB - Epilepsy in children is characterized by the occurring on a developing brain. There are many different types of epilepsy. Make an accurate diagnosis permits to explain the disease, to choose the treatment and to explain the prognosis. The side effects of antiepileptic drugs should be precisely monitored. It is important to take time to carefully evaluate the school performance. Neuropsychological evaluation may be necessary to propose adequate management. Behavior comorbidities should be assessed for an early management. An adapted information on the disease and on the management should be provided to the caregivers. PMID- 21242053 TI - [Paraganglioma as a cause of inflammation of unknown origin: usefulness of positon emission tomography]. PMID- 21242054 TI - [Varicella after Varivax(r) vaccine in a pregnant woman]. PMID- 21242055 TI - Content and correlates of checking related to symptoms of obsessive compulsive disorder and generalized anxiety disorder. AB - In addition to the central role of compulsive behaviors in obsessive compulsive disorder (OCD), recent data have documented the presence of compulsive behaviors in individuals with generalized anxiety disorder (GAD). However, there is a lack of information about potential similarities and differences with regard to the quality, or content, of checking associated with worry and obsessions. The two studies presented herein are an initial step towards gathering this information. Findings of Study 1, from a large unselected undergraduate sample, showed that symptoms of OCD and GAD were both significantly associated with checking behaviors. However, while OCD symptoms were associated with checking related to both objects and interpersonal situations, GAD symptoms were only significantly associated with interpersonal checking. Findings of Study 2, using a separate sample, suggest links between interpersonal checking and features characteristic of GAD, namely emotion regulation difficulties, and between object checking and a cognitive feature of OCD, namely thought-action fusion. In summary, the current studies add to a growing body of literature suggesting that checking may be important in numerous forms of psychopathology, while also suggesting that the nature and function of checking may differ for various symptom profiles. PMID- 21242056 TI - Emergent literacy activities, instructional adaptations and school absence of children with cerebral palsy in special education. AB - The goal of the present study was to get an overview of the emergent literacy activities, instructional adaptations and school absence of children with cerebral palsy (CP) compared to normally developing peers. The results showed that there were differences between the groups regarding the amount of emergent literacy instruction. While time dedicated to storybook reading and independent picture-book reading was comparable, the children with CP received fewer opportunities to work with educational software and more time was dedicated to rhyming games and singing. For the children with CP, the level of speech, intellectual, and physical impairments were all related to the amount of time in emergent literacy instruction. Additionally, the amount of time reading precursors is trained and the number of specific reading precursors that is trained is all related to skills of emergent literacy. PMID- 21242057 TI - Driving skills of young adults with developmental coordination disorder: regulating speed and coping with distraction. AB - In two experiments, we used an automatic car simulator to examine the steering control, speed regulation and response to hazards of young adults with developmental coordination disorder (DCD) and limited driving experience. In Experiment 1 participants either used the accelerator pedal to regulate their speed, or used the brake pedal when they needed to slow down from a pre-set speed. In Experiment 2, we introduced an auditory distraction condition that shared similarities with maintaining a conversation. Overall, the DCD group produced a larger variance in heading and needed more steering adjustments on straight roads, compared to age-matched controls. When turning bends, the DCD group showed greater difficulty in controlling steering while regulating their speed with the accelerator pedal but this was less problematic when using the brake. The DCD group also responded slower than the control group to pedestrians who walked towards their path. The auditory distraction in Experiment 2 had no visible effects on steering control but increased the reaction times to pedestrians in both groups. We discuss the results in terms of the visuomotor control in steering and the learning of optimal mappings between optic flow and vehicle control. PMID- 21242058 TI - Standardizing the use of whole slide images in digital pathology. AB - Whole slide imaging/images (WSI) offers promising new perspectives for digital pathology. We launched an initiative in the anatomic pathology (AP) domain of integrating the healthcare enterprise (IHE) to define standards-based informatics transactions for integrating AP information and WSI. The IHE integration and content profiles developed as a result of this initiative successfully support the basic image acquisition and reporting processes in AP laboratories and provide a standard solution for sharing or exchanging structured AP reports in which observations can be explicitly bound to WSI or to regions of interest (ROI) in images. PMID- 21242059 TI - Atypical presentation of acute coronary syndrome: a significant independent predictor of in-hospital mortality. AB - BACKGROUND: Patients with acute coronary syndrome (ACS) frequently present with typical chest pain; however a considerable proportion may present with atypical symptoms. OBJECTIVE: The purpose of this study was to evaluate the prognostic value of different presenting symptoms in ACS patients. METHODS: Over a 5-month period in 2007, 6704 consecutive patients presenting with ACS were enrolled and categorized into three groups according to their presenting symptom (typical chest pain, atypical chest pain, and dyspnea). Data were collected from a prospective, multicenter, multinational, observational study from 6 countries. The baseline characteristics, therapy, and in-hospital outcomes were analyzed and compared in the three groups. RESULTS: In comparison to typical chest pain, patients with atypical pain or dyspnea were older and had more cardiovascular risk factors. These two groups were significantly less likely to receive evidence based therapy and coronary angiography and suffered worse in-hospital outcomes. The mortality rates were 3%, 2.5%, and 6% in patients presenting with typical, atypical chest pain, and dyspnea, respectively. After adjustment for confounders, the absence of typical chest pain was associated with higher mortality rate (odds ratio 2.0, 95% confidence intervals 1.29-2.75). CONCLUSIONS: Across ACS, patients presenting without chest pain were frequently underestimated, less well treated with evidence-based therapy, and had worse in-hospital outcomes. Clinical presentation of ACS may provide additional prognostic impact particularly in high risk populations. PMID- 21242061 TI - Combination of free-flow electrophoresis and interactomics to analyze the dysregulated proteins of fibroblasts from atopic dermatitis patients. PMID- 21242060 TI - Cardiovascular risk in a first-episode psychosis sample: a 'critical period' for prevention? AB - OBJECTIVE: Studies in first episode psychosis samples about status of cardiovascular risk factors have shown discordant results. We aimed to determine the 10-year risk of developing coronary heart disease in a sample of first episode psychosis patients referred to an early intervention clinic and compared the same with age, gender, and race matched controls from the U.S. National Health and Nutrition Examination Survey (NHANES). METHOD: We conducted a cross sectional analysis of baseline data of 56 subjects enrolled in first episode psychosis clinic from April 2006 to January 2010. This sample was compared with age, gender, and race matched 145 individuals drawn from NHANES 2005-2006 database. Sociodemographic and clinical variables were collected. Physical examination including laboratory evaluation was used to screen for common medical illnesses. The 10-year risk of developing coronary heart disease was calculated by using a tool developed by the National Cholesterol Education Program (NCEP-ATP III). RESULTS: There were elevated rates of smoking (46%) and hypertension (11%) albeit statistically significant differences from the control could not be demonstrated for these measures or weight, body mass index, or total or HDL cholesterol, fasting plasma glucose, status of diabetes and impaired fasting plasma glucose, HbA1C level. The 10-year median (range) risk of developing coronary heart disease in patients and controls was 1 (0-5)% and 0 (0-9)% respectively. The difference was not statistically significant. CONCLUSIONS: First episode psychosis patients do not present with significantly higher cardiovascular risk than age and race-matched controls despite clinically significant prevalence of individual risk factors. This sample presents an opportunity for early intervention for the primary prevention of cardiovascular morbidity and mortality. PMID- 21242062 TI - Nationwide survey of antibacterial activity against clinical isolates from urinary tract infections in Japan (2008). AB - In this study, the causative bacteria and their sensitivity to various antimicrobial agents as well as risk factors for quinolone-resistant Escherichia coli were investigated in patients with acute uncomplicated cystitis or complicated cystitis by isolation and culture of bacteria from urine samples. In total, 1312 strains were isolated from 1009 patients with acute uncomplicated cystitis, including E. coli (63.3%), Enterococcus faecalis (12.8%) and Streptococcus agalactiae (4.6%). In addition, 994 strains were isolated from 725 patients with complicated cystitis, including E. coli (36.4%), E. faecalis (19.2%), Klebsiella pneumoniae (5.0%), S. agalactiae (4.7%) and Pseudomonas aeruginosa (4.5%). At least 90% of E. coli isolates from acute uncomplicated cystitis showed sensitivity to fluoroquinolones and cephems, whilst 70.4-88.4% of E. coli isolates from complicated cystitis were sensitive to fluoroquinolones and 85.4-89.5% were sensitive to cephems. Factors associated with quinolone-resistant E. coli included two or more episodes of cystitis within 1 year, failure of quinolone therapy, underlying urinary tract disease, prior quinolone treatment within 1 month and age >= 75 years. It is important to confirm the sensitivity of causative bacteria for optimal antimicrobial therapy, and empirical antimicrobial agents should be selected by considering patient characteristics and other factors. PMID- 21242063 TI - Novel cationic surfactant ion pair based solid phase microextraction fiber for nano-level analysis of BTEX. AB - Ion pair of cationic surfactant (cetytrimethylammonium bromide) and tungestosilicic acid incorporated in PVC matrix, was used for coating a piece of copper wire as a new high sensitive SPME fiber in extraction and determination of BTEX compounds from the headspace of water samples prior to GC/FID analysis. Under optimum extraction conditions, limits of detection for benzene, toluene, ethylbenzene, p-xylene, m-xylene and o-xylene were found to be 1.18, 5.61, 0.87, 0.29, 0.22 and 0.33 ng L(-1) respectively. Low detection limits, wide linear dynamic ranges, good reproducibility (RSD% 1.48-4.27), high fiber capacity and high mechanical durability are some of the most important advantages of the new fiber. PMID- 21242064 TI - The size of solid lipid nanoparticles: an interpretation from experimental design. AB - This study aimed to investigate the role of different factors affecting the size of solid lipid nanoparticles (SLN), prepared by the emulsification-solvent evaporation method. A double factorial design was conducted so as to cover a wide range of sizes, highlighting zones with different behaviour with respect to changes in the controlled variables: lipid concentration, solvent:lipid ratio and emulsifier concentration. The solvent:lipid ratio constituted the main factor influencing particle size. Increasing the amount of solvent induced a decrease in the size. This was a general trend, essentially independent from solvent and lipid type. The amount of emulsifier had a non-trivial impact on size, depending on whether systems were located below, above or close to the optimal surface coverage. The amount of lipid had a limited influence upon particle size, being more relevant for lower lipid concentrations. An optimal formulation was selected for intermediate levels of the three variables. Sonication reduced both particle size and polydispersity. These particles were also tested as drug carriers using simvastatin as a model of lipophilic drug. SLN were able to entrap a high amount of simvastatin, with little effect upon size and zeta potential, constituting a promising carrier for lipophilic drugs. PMID- 21242065 TI - Neuroprotective effect of preadministration with Ganoderma lucidum spore on rat hippocampus. AB - The aim of this study was to investigate if preadministration with Ganoderma lucidum spore (GLS) could (1) alleviate oxidative stress and mitochondrial dysfunction in rat hippocampus of intracerebroventricular (ICV) injection of streptozotocin (STZ), (2) protect neurons from apoptosis, and (3) improve cognitive dysfunction. Three groups of Sprague-Dawley rats were preadministrated with GLS at doses of 2.0, 4.0 and 8.0 g/kg, respectively, for 3 weeks before the ICV STZ injury. Thereafter the rats were operated with ICV STZ (1.5 mg/kg) bilaterally on days 1 and 3. The behavioral alterations, oxidative stress indexes, ATP, cytochrome oxidase (CytOx), and histopathology of hippocampal neurons were studied. The results showed that ICV STZ model rats exhibited a significant increase of malondialdehyde (MDA), a significant decrease of glutathione reductase (GR), reduced glutathione (GSH), ATP and CytOx, accompanied with marked impairments in spatial learning and memory, and severe damage of hippocampal neuron. In conclusion, preadministration with GLS at dose of 8.0 g/kg in ICV STZ rats significantly reversed these abnormalities. In conclusion, preadministration with GLS might protect hippocampus from oxidative impairment and energy metabolism disturbance of ICV STZ. This may also provide useful information for future research on the pathogenesis and prevention of Alzheimer's disease (AD). PMID- 21242066 TI - cDNA-AFLP analysis of differential gene expression related to cell chemotactic and encystment of Azospirillum brasilense. AB - Our previous study indicated org35 was involved in chemotaxis and interacted with nitrogen fixation transcriptional activator NifA via PAS domain. In order to reveal the role of org35 in nitrogen regulation, the downstream target genes of org35 were identified. We here report differentially expressed genes in org35 mutants comparing with wild type Sp7 by means of cDNA-AFLP. Four up-regulated transcript-derived fragments (TDFs) homologues of chemotaxis transduction proteins were found, including CheW, methyl-accepting chemotaxis protein and response regulator CheY-like receiver. Three distinct TDFs (AB46, AB58 and AB63) were similar to PHB de-polymerase C-terminus, cell shape-determining protein and flagellin domain protein. And 11 TDFs showed similarities with signal transduction proteins, including homologous protein of the nitrogen regulation protein NtrY and nitrate/nitrite response regulator protein NarL. These data suggested that the Azospirillum brasilense org35 was a multi-effecter and involved in chemotaxis, cyst development and regulation of nitrogen fixation. PMID- 21242067 TI - Dissimilatory perchlorate reduction: a review. AB - In the United States anthropogenic activities are mainly responsible for the wide spread perchlorate contamination of drinking water, surface water, groundwater, and soil. Even at microgram levels, perchlorate causes toxicity to flora and fauna and affects growth, metabolism and reproduction in humans and animals. Reports of antithyroid effects of perchlorate and its detection in common food items have raised serious public health concerns, leading to extensive decontamination efforts in recent years. Several physico-chemical removal and biological decontamination processes are being developed. Although promising, ion exchange is a non-selective and incomplete process as it merely transfers perchlorate from water to the resin. The perchlorate-laden spent resins (perchlorate 200-500 mg L(-1)) require regeneration resulting in production of concentrated brine (6-12% NaCl) or caustic waste streams. On the contrary, biological reduction completely degrades perchlorate into O(2) and innocuous Cl( ). High reduction potential of ClO(4)(-)/Cl(-) (E degrees =~ 1.28 V) and ClO(3)( )/Cl(-) pairs (E degrees =1.03 V) makes these contaminants thermodynamically ideal e(-) acceptors for microbial reduction. In recent years unique dissimilatory perchlorate reducing bacteria have been isolated and detailed studies pertaining to their microbiological, biochemical, genetics and phylogenetic aspects have been undertaken which is the subject of this review article while the various physico-chemical removal and biological reduction processes have been reviewed by others. PMID- 21242068 TI - 13C-metabolic enrichment of glutamate in glutamate dehydrogenase mutants of Saccharomyces cerevisiae. AB - Glutamate dehydrogenases (GDH) interconvert alpha-ketoglutarate and glutamate. In yeast, NADP-dependent enzymes, encoded by GDH1 and GDH3, are reported to synthesize glutamate from alpha-ketoglutarate, while an NAD-dependent enzyme, encoded by GDH2, catalyzes the reverse. Cells were grown in acetate/raffinose (YNAceRaf) to examine the role(s) of these enzymes during aerobic metabolism. In YNAceRaf the doubling time of wild type, gdh2Delta, and gdh3Delta cells was comparable at ~4 h. NADP-dependent GDH activity (Gdh1p+Gdh3p) in wild type, gdh2Delta, and gdh3Delta was decreased ~80% and NAD-dependent activity (Gdh2p) in wild type and gdh3Delta was increased ~20-fold in YNAceRaf as compared to glucose. Cells carrying the gdh1Delta allele did not divide in YNAceRaf, yet both the NADP-dependent (Gdh3p) and NAD-dependent (Gdh2p) GDH activity was ~3-fold higher than in glucose. Metabolism of [1,2-(13)C]-acetate and analysis of carbon NMR spectra were used to examine glutamate metabolism. Incorporation of (13)C into glutamate was nearly undetectable in gdh1Delta cells, reflecting a GDH activity at <15% of wild type. Analysis of (13)C-enrichment of glutamate carbons indicates a decreased rate of glutamate biosynthesis from acetate in gdh2Delta and gdh3Delta strains as compared to wild type. Further, the relative complexity of (13)C-isotopomers at early time points was noticeably greater in gdh3Delta as compared to wild type and gdh2Delta cells. These in vivo data show that Gdh1p is the primary GDH enzyme and Gdh2p and Gdh3p play evident roles during aerobic glutamate metabolism. PMID- 21242069 TI - Improvement of antibiotic productivity by knock-out of dauW in Streptomyces coeruleobidus. AB - Daunorubicin (DNR) is an important anthracycline antibiotic. Its biosynthesis pathway has been well understood, however, the regulation of DNR biosynthesis needs further investigations. An ORF cloned between drrB and dnrX from the genome of a DNR producer, Streptomyces coeruleobidus DM, was named dauW and designated as an orthologous gene with dnrW and drrD. Several plasmids were constructed for over-expression and/or disruption of dauW in DM. Complete disruption of dauW can significantly increase the yield of DNR. We also found that the transcription level of dnrI, a major regulatory protein in the biosynthesis of DNR, and the self-resistance level were improved in dauW knock-out mutant. These results suggested that dauW may be a down-regulatory gene for DNR biosynthesis. Antibiotics productivity in S. coeruleobidus could be improved via regulation of the transcription of dnrI, a SARP regulator. The production of DNR in a high producer and the yield of epi-DNR in an engineering strain were also increased by disruption of dauW. PMID- 21242070 TI - The oxalic acid biosynthetic activity of Burkholderia mallei is encoded by a single locus. AB - Although it is known that oxalic acid provides a selective advantage to the secreting microbe our understanding of how this acid is biosynthesized remains incomplete. This study reports the identification, cloning, and partial characterization of the oxalic acid biosynthetic enzyme from the animal bacterial pathogen, Burkholderia mallei. The discovered gene was named oxalate biosynthetic component (obc)1. Complementation of Burkholderia oxalate defective (Bod)1, a Burkholderia glumae mutant that lacks expression of a functional oxalic acid biosynthetic operon, revealed that the obc1 was able to rescue the no oxalate mutant phenotype. This single gene rescue is in contrast to the situation found in B. glumae which required the expression of two genes, obcA and obcB, to achieve complementation. Enzyme assays showed that even though the two Burkholderia species differed in the number of genes required to encode a functional enzyme, both catalyzed the same acyl-CoA dependent biosynthetic reaction. In addition, mutagenesis studies suggested a similar domain structure of the assembled oxalate biosynthetic enzymes whether encoded by one or two genes. PMID- 21242071 TI - Psychological and neuroendocrinological effects of odor of saffron (Crocus sativus). AB - AIM: The purpose of this study was to clarify the effects of saffron odor on symptoms unique to women, such as premenstrual syndrome (PMS), dysmenorrhea (menstrual pain) and irregular menstruation. MATERIALS AND METHODS: Thirty-five women with a normal sense of smell were exposed to saffron odor for 20 min. Saliva samples were then collected to measure levels of cortisol (C), testosterone (T) and 17-beta estradiol (E) by enzyme immunoassay, and the State Trait Anxiety Inventory (STAI) was administered as a psychological test. RESULTS: Saffron odor significantly decreased C levels after short-term stimulation (20 min) in both follicular and luteal phases. E level after exposure to saffron odor was increased in both the follicular- and luteal-phase groups. STAI score decreased in the follicular and luteal phases in the saffron group. CONCLUSIONS: The present findings support the existence of physiological and psychological effects of saffron odor in women. Our results indicate that saffron odor exert some effects in the treatment of PMS, dysmenorrhea and irregular menstruation. This is the first report to suggest that saffron odor may be effective in treating menstrual distress. PMID- 21242072 TI - Crataegus laevigata decreases neutrophil elastase and has hypolipidemic effect: a randomized, double-blind, placebo-controlled trial. AB - Crataegus laevigata is a medicinal plant most commonly used for the treatment of heart failure and psychosomatic disorders. Based on previous experimental findings, this double-blind placebo-controlled study was aimed at finding beneficial effects of C. laevigata on biomarkers of coronary heart disease (CHD). The study included 49 diabetic subjects with chronic CHD who were randomly assigned to the treatment for 6 months with either a micronized flower and leaf preparation of C. laevigata (400 mg three times a day) or a matching placebo. Blood cell count, lipid profile, C-reactive protein, neutrophil elastase (NE) and malondialdehyde were analyzed in plasma at baseline, at one month and six months. The main results were that NE decreased in the C. laevigata group compared to the placebo group. In the C. laevigata group, baseline figures (median and interquartile range) were 35.8 (4.5) and in the placebo group 31 (5.9). At the end of the study, values were 33.2 (4.7) ng/ml and 36.7 (2.2) ng/ml, respectively; p<0.0001. C. laevigata, added to statins, decreased LDL cholesterol (LDL-C) (mean+/-SD) from 105+/-28.5 mg/dl at baseline to 92.7+/-25.1 mg/dl at 6 months (p=0.03), and non-HDL cholesterol from 131+/-37.5 mg/dl to 119.6+/-33 mg/dl (p<0.001). Differences between groups did not reach statistical significance at 6 months. No significant changes were observed in the rest of parameters. In conclusion, C. laevigata decreased NE and showed a trend to lower LDL-C compared to placebo as add-on-treatment for diabetic subjects with chronic CHD. PMID- 21242073 TI - Assessment of reference ranges for blood Cu, Mn, Se and Zn in a selected Italian population. AB - The reference ranges for blood Cu, Mn, Se and Zn of 215 adult subjects non occupationally exposed and living in the Nuoro province (Sardinia, insular Italy) were assessed. Metals were determined by sector field inductively coupled plasma mass spectrometry after microwave-assisted acid digestion of blood. The blood reference ranges estimated as P5-P95 percentiles (geometric mean, GM) were 776 1495MUg/L (1036MUg/L) for Cu; 4.73-17.0MUg/L (8.91MUg/L) for Mn; 106-185MUg/L (140MUg/L) for Se and 4686-8585MUg/L (6418MUg/L) for Zn. These results were then stratified for sex, age, alcohol consumption, smoking habit and living area. The GM value of Cu was significantly higher in females (1127MUg/L) than in males (957MUg/L). Age, alcohol intake, smoking habit and residential area did not influence blood Cu. The GM of Mn was significantly higher in females (9.98MUg/L) respect to males (8.01MUg/L) and in drinkers (9.67MUg/L) compared to non-drinkers (8.38MUg/L). The other variables did not change the Mn data. Selenium concentrations did not differ significantly as a function of individuals factors. With reference to Zn, males had GM of 6804MUg/L and females of 6031MUg/L, and more blood Zn was found in subjects consuming alcohol (6618MUg/L) respect to abstainers (6155MUg/L). In addition, blood Zn was not affected by age, smoking habit and place of living. PMID- 21242074 TI - Trace elements in bipolar disorder. AB - INTRODUCTION: Trace elements may play an important role in bipolar disorders. The objective of this study is to determine serum copper and zinc, blood lead and cadmium and urine lead, cadmium and thallium concentrations in patients diagnosed with bipolar disorders and to compare these levels with those of a healthy control group. MATERIALS AND METHODS: A total of 25 patients diagnosed with bipolar disorder and 29 healthy subjects participated in this study. Serum copper and zinc concentrations were measured using flame atomic absorption spectrometry; the blood lead and cadmium concentrations were measured by electrothermal atomization atomic absorption spectrometry with Zeeman background correction; urine lead, cadmium and thallium concentrations were measured by inductively coupled plasma mass spectrometry. RESULTS: Median blood and urine lead and cadmium levels were significantly higher among the bipolar patients than among the control group: Blood lead (MUg/dL): patient median: 3.00 (IQR: 1.40-4.20); control median (MUg/dL): 2.20 (IQR: 0.90-3.00) p=0.040. Blood cadmium (MUg/L): patient median: 0.39 (IQR: 0.10-1.15); control median: 0.10 (IQR: 0.10-0.17) p<0.001. The median of cadmium (MUg/L) in patients who smoked (1.20 IQR: 0.44 2.30) was higher than that in non-smokers (0.12 IQR: 0.10-0.34) p<0.001. There was a statistically significant increase (p=0.001) in zinc levels among patients in the manic phase (mean 111.28, SD: 33.36 MUg/dL) with respect to the control group (mean 86.07, SD: 12.39 MUg/dL). CONCLUSIONS: The results suggest that there could be higher levels of some toxic trace elements in the group of patients with bipolar disorder than in the healthy control group. PMID- 21242075 TI - The biogenic methanobactin is an effective chelator for copper in a rat model for Wilson disease. AB - Copper is an essential redox-active metal ion which in excess becomes toxic due to the formation of reactive oxygen species. In Wilson disease the elevated copper level in liver leads to chronic oxidative stress and subsequent hepatitis. This study was designed to evaluate the copper chelating efficiency of the bacterial methanobactin (MB) in a rat model for Wilson disease. Methanobactin is a small peptide produced by the methanotrophic bacterium Methylosinus trichosporium OB3b and has an extremely high affinity for copper. Methanobactin treatment of the rats was started at high liver copper and serum aspartate aminotransferase (AST) levels. Two dosing schedules with either 6 or 13 intraperitoneal doses of 200mg methanobactin per kg body weight were applied. Methanobactin treatment led to a return of serum AST values to basal levels and a normalization of liver histopathology. Concomitantly, copper levels declined to 45% and 24% of untreated animals after 6 and 13 doses, respectively. Intravenous application of methanobactin led to a prompt release of copper from liver into bile and the copper was shown to be associated with methanobactin. In vitro experiments with liver cytosol high in copper metallothionein demonstrated that methanobactin removes copper from metallothionein confirming the potent copper chelating activity of methanobactin. PMID- 21242076 TI - Signaling in thymic selection. AB - T cell receptor signaling allows the developing thymocyte to undergo positive or negative selection, which is required for the formation of a useful mature T cell repertoire. Recent developments include the finding that much of the Lck kinase (required to initiate T cell signaling) is already in an active configuration before signaling. The analog strength of antigen binding to the T cell receptor binding may be translated into a digital signal by the amount of time the TCR is paired with a co-receptor carrying Lck. Downstream, the cellular localization of MAP kinase signaling is determined by the strength of the signal and in turn predicts positive or negative selection. A novel protein, Themis, is important in crossing the positive selection developmental checkpoint, but its mode of action is still uncertain. Commitment to the CD4 or CD8 lineage is influenced by the amount of ZAP-70 signaling and also by closely regulated responsiveness to intrathymic cytokines such as IL7. PMID- 21242077 TI - Multiple facets of nuclear periphery in gene expression control. AB - Nuclear pore complexes play a central role in controlling the traffic between the nucleus and the cytoplasm. Progress during the last decade has highlighted nuclear periphery components as novel players in chromatin organization, gene regulation, and genome stability. For instance, lamins associate with repressive chromatin while nuclear pores tend to associate with active chromatin. Interestingly, nucleoporins (Nups) act not only at the nuclear periphery but also in the nucleoplasm. Here we provide an overview of the latest findings and discuss the functional importance of nucleoporin association with specific genes, their role in transcriptional memory, the coupling of transcription and mRNA export, and genome integrity. PMID- 21242079 TI - Use of gelatine capsules for application of methamphetamine: a new harm reduction approach. AB - BACKGROUND: In order to reduce injecting drug use, low-threshold facilities in the Czech Republic have started to distribute empty gelatine capsules as an oral alternative of drug application for those injecting methamphetamine. This report reviews implementation of this intervention and its possible benefits and limitations. METHODS: Between December 2008 and January 2009, 109 low-threshold facilities were asked to complete a questionnaire about the capsule programmes. Two focus groups were conducted, one with professionals involved in distribution and one with peer outreach workers who were interviewed on their experience of using the capsules. RESULTS: A total of 50 facilities (46%) responded to the questionnaire; 16 (32%) distributed the capsules regularly and 19 (38%) were planning to introduce this practice. The main target groups were injecting users of methamphetamine whose veins had been damaged, and methamphetamine users wishing to reduce injecting. The advantages of capsules, as perceived by service staff and peer outreach workers, were their easy use and the satisfactory effect of the oral application; health risks related to the oral use of methamphetamine were considered drawbacks. CONCLUSION: Capsule distribution is a promising harm reduction approach for injectors of methamphetamine or other stimulants; nonetheless its benefits and limitations should be further analysed in an in depth longitudinal study. PMID- 21242078 TI - Modern fluorescent proteins and imaging technologies to study gene expression, nuclear localization, and dynamics. AB - Recent developments in reagent design can address problems in single cells that were not previously approachable. We have attempted to foresee what will become possible, and the sorts of biological problems that become tractable with these novel reagents. We have focused on the novel fluorescent proteins that allow convenient multiplexing, and provide for a time-dependent analysis of events in single cells. Methods for fluorescently labeling specific molecules, including endogenously expressed proteins and mRNA have progressed and are now commonly used in a variety of organisms. Finally, sensitive microscopic methods have become more routine practice. This article emphasizes that the time is right to coordinate these approaches for a new initiative on single cell imaging of biological molecules. PMID- 21242080 TI - BZP-party pills: a review of research on benzylpiperazine as a recreational drug. AB - BACKGROUND: BZP-party pills are yet another 'designer drug' which mimics the stimulant qualities of amphetamines and MDMA/Ecstasy. As legal markets for the substance have developed in the last decade (especially amongst young people) so has public and governmental concern. METHODS: This article provides a summary of the available international research on benzylpiperazine (BZP) and its popular use in the compound form known as 'party pills'. Through performing an analysis of the available medical and social scientific literature, the review outlines current knowledge on the compound, the prevalence of usage of BZP-party pills, as well as the associated harms, risks and rationales for use of the drug. RESULTS: Despite moves towards legislative control of BZP-party pills, the evidence presented suggests limited social and health harms associated with the drug, although research on long term effects is a significant gap in the literature. It also remains inconclusive as to whether BZP-party pills act as a 'gateway' to illegal drugs or, conversely, play a role in harm reduction with illegal drug users turning to legal alternatives; there is some evidence for both positions. CONCLUSION: With increasing controls of BZP-party pills, and with the increasing numbers of 'legal highs' and new designer drugs on the market, we conclude that new legal alternatives will continue to surface to replace the drug in the future. Considering a harm reduction approach to drug taking, it is suggested that policy makers consider the creation of a legal holding category which restricts and regulates the market in legal highs whilst the social and health harms associated with each drug can be thoroughly investigated. PMID- 21242081 TI - Avoidable alcohol-attributable criminality and its costs due to selected interventions in Canada. AB - BACKGROUND: Alcohol causes a considerable criminal burden on the Canadian society. The purpose of this study is to estimate the avoidable burden and avoidable costs of alcohol-attributable criminality in Canada for the year 2002. METHODS: The impact of the following six alcohol policy interventions relative to baseline costs obtained from the Second Canadian Cost Study (a cost-of-illness study) were modelled: taxation increases, lowering the blood alcohol concentration (BAC) legal limit from 0.08% to 0.05%, zero BAC restriction for all drivers under the age of 21, increasing the minimum legal drinking age (MLDA) from 19 to 21 years, a Safer Bars intervention, and brief interventions. In addition to the six interventions that reduce alcohol consumption, we also modelled one intervention that could increase alcohol consumption and alcohol attributable costs: the change from a government monopoly to privatized alcohol sales. The effect of these interventions was modelled for the Canadian population older than 15 years of age with the exception of BAC restriction and MLDA, which were modelled for the age group 19-21. RESULTS: Results revealed that the intervention which appears to be most effective in preventing drinking and driving incidents in Canada was lowering the BAC level. This intervention was estimated to reduce this type of alcohol-attributable crime compared with the baseline scenario by 19.1%. The Safer Bars programme was found to be the most effective measure to avoid homicide and other violent crimes (reductions of 3.4% were observed). Brief interventions were observed as the most effective measure to avoid other alcohol-attributable criminal activities, estimated at reducing them by 2.6%. The results also indicated that substantial increases in all types of criminality examined in this study could occur if all Canadian provinces were to privatize alcohol sales. CONCLUSION: This study demonstrates that the implementation of proven effective population-based interventions can reduce alcohol-attributable criminal burden and its costs to the Canadian society to a considerable degree. PMID- 21242082 TI - Experiences with mephedrone pre- and post-legislative controls: perceptions of safety and sources of supply. AB - BACKGROUND: Drug scenes within several countries have changed in recent years to incorporate a range of licit psychoactive products, collectively known as "legal highs." Hundreds of different legal high products have been described in the literature. Many of these products contain synthetic stimulants that allegedly "mirror" the effects of some illicit drugs. In 2009-2010, growing concern by the UK and Irish governments focused on mephedrone, a synthetic stimulant that had become embedded within several drug scenes in Britain and Ireland. In April 2010, mephedrone and related cathinone derivatives were banned under the UK's Misuse of Drugs Act 1971. Setting aside "worse case scenarios" that have been portrayed by UK and Irish media, little is known about mephedrone use from the consumer's perspective. The purpose of this paper was to (1) explore respondents' experiences with mephedrone, (2) examine users' perceptions about the safety of mephedrone, and primarily to (3) examine sources of mephedrone supply during the pre- and post-ban periods. METHODS: Semi-structured interviews were conducted with 23 adults who had used mephedrone during 2009-2010. Data collection occurred in May and June 2010, following the ban on mephedrone. A total of 20/23 respondents had used mephedrone during the post-ban period, and the vast majority had prior experience with ecstasy or cocaine. Respondents' ages ranged from 19 to 51, approximately half of the sample were female and the majority (19 of 23) were employed in full- or part-time work. RESULTS: Most respondents reported positive experiences with mephedrone, and for some, the substance emerged as a drug of choice. None of the respondents reported that the once-legal status of mephedrone implied that it was safe to use. Very few respondents reported purchasing mephedrone from street-based or on-line headshops during the pre-ban period, and these decisions were guided in part by respondents' attempts to avoid "drug user" identities. Most respondents purchased or obtained mephedrone from friends or dealers, and mephedrone was widely available during the 10-week period following the ban. Respondents reported a greater reliance on dealers and a change in mephedrone packaging following the criminalisation of mephedrone. CONCLUSION: The findings are discussed in the context of what appears to be a rapidly changing mephedrone market. We discuss the possible implications of criminalising mephedrone, including the potential displacement effects and the development of an illicit market. PMID- 21242083 TI - Beyond human rights and public health: citizenship issues in harm reduction. AB - There have been debates amongst harm reduction practitioners regarding the relationship of universal human rights vis-a-vis public health demands. The ideological debates around these two slippery concepts often obfuscate the important theme of citizenship. The author, therefore, argues for the perspective of citizenship as an alternative to comprehend harm reduction practises more thoroughly. An introduction of the concept of citizenship is followed by a case example of Taiwan's harm reduction policy-making, wherein injection drug users were subjected to various disciplinary actions and made into citizen addicts. It is hoped that more harm reduction researchers will have increased familiarity with the notion of citizenship as a useful tool to examine the power dynamics taking place in the name of harm reduction. PMID- 21242084 TI - Next generation challenges: an overview of Harm Reduction 2010, IHRA's 21st conference. PMID- 21242085 TI - Alcohol under the radar: do we have policy options regarding unrecorded alcohol? AB - BACKGROUND: According to the World Health Organization, the public health impact of illicit alcohol and informally produced alcohol should be reduced. This paper summarizes and evaluates the evidence base about policy and intervention options regarding unrecorded alcohol consumption. METHODS: A systematic review of the literature using electronic databases. RESULTS: The literature on unrecorded consumption was sparse with less than 30 articles about policy options, mostly based on observational studies. The most simplistic option to reduce unrecorded consumption would be to lower recorded alcohol prices to remove the economic incentive of buying unrecorded alcohol. However, this may increase the net total alcohol consumption, making it an unappealing public health policy option. Other policy options largely depend on the specific sub-group of unrecorded alcohol. The prohibition of toxic compounds used to denature alcohol (e.g. methanol) can improve health outcomes associated with surrogate alcohol consumption. Cross border shopping can be reduced by either narrowing the tax differences, or stricter control. Actions limiting illegal trade and counterfeiting include introduction of tax stamps and electronic surveillance systems of alcohol trade. Education campaigns might increase the awareness about the risks associated with illegal alcohol. The most problematic category appears to be the home and small scale artisanal production, for which the most promising option is to offer financial incentives to the producers for registration and quality control. CONCLUSION: Even though there are suggestions and theories on how to reduce unrecorded alcohol consumption, there is currently no clear evidence base on the effectiveness or cost effectiveness of available policy options. In addition, the differences in consumption levels, types of unrecorded alcohol, culture and tradition point to different measures in different parts of the world. Thus, the recommendation of a framework for moving forward in decision making currently seems premature. Instead, there is a need for systematic research. PMID- 21242086 TI - Sensitive and high-fidelity electrochemical immunoassay using carbon nanotubes coated with enzymes and magnetic nanoparticles. AB - We demonstrate a highly sensitive electrochemical immunosensor based on the combined use of substrate recycling and carbon nanotubes (CNTs) coated with tyrosinase (TYR) and magnetic nanoparticles (MNP). Both TYR and MNP were immobilized on the surface of CNTs by covalent attachment, followed by additional cross-linking via glutaraldehyde treatment to construct multi-layered cross linked TYR-MNP aggregates (M-EC-CNT). Magnetically capturable, highly active and stable M-EC-CNT were further conjugated with primary antibody against a target analyte of hIgG, and used for a sandwich-type immunoassay with a secondary antibody conjugated with alkaline phosphatase (ALP). In the presence of a target analyte, a sensing assembly of M-EC-CNT and ALP-conjugated antibody was attracted onto a gold electrode using a magnet. On an electrode, ALP-catalyzed hydrolysis of phenyl phosphate generated phenol, and successive TYR-catalyzed oxidation of phenol produced electrochemically measurable o-quinone that was converted to catechol in a scheme of substrate recycling. Combination of highly active M-EC CNT and substrate recycling for the detection of hIgG resulted in a sensitivity of 27.6 nA ng(-1) mL(-1) and a detection limit of 0.19 ng mL(-1) (1.2 pM), respectively, representing better performance than any other electrochemical immunosensors relying on the substrate recycling with the TYR-ALP combination. The present immunosensing system also displayed a long-term stability by showing a negligible loss of electrochemical detection signal even after reagents were stored in an aqueous buffer at 4 degrees C for more than 6 months. PMID- 21242087 TI - Mechanisms of excitatory synapse maturation by trans-synaptic organizing complexes. AB - Synapses are specialized cell-cell adhesion contacts that mediate communication within neural networks. During development, excitatory synapses are generated by step-wise recruitment of presynaptic and postsynaptic proteins to sites of contact. Several classes of synaptic organizing complexes have been identified that function during the initial stages of synapse formation. However, mechanisms underlying the later stages of synapse development are less well understood. In recent years, molecules have been discovered that appear to play a role in synapse maturation. In this review, we highlight recent findings that have provided key insights for understanding postsynaptic maturation of developing excitatory synapses with a focus on recruitment of AMPA receptors to developing synapses. PMID- 21242089 TI - Apical-access-related complications associated with trans-catheter aortic valve implantation. AB - OBJECTIVE: The left-ventricular trans-apical access has become well established for trans-catheter aortic valve implantation, especially for patients in whom a retrograde trans-arterial implantation is contraindicated. We report on the short and long-term implications of the apical-access-site-specific complications. METHODS: Between June 2007 and August 2010, 143 patients were scheduled for trans apical aortic valve implantation (mean age 80 +/- 6 years, n=116 females, mean logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) 21 +/- 13%). The patients are followed up at 30 days, 6 months, and then annually. RESULTS: Severe apical bleeding complications occurred in 10 patients (7%). In three of these patients, the procedure was terminated, and no valve was implanted. In the remaining, the bleeding was controlled with cardiopulmonary bypass support (n=3), via median sternotomy (n=1), or both (n=1) +/- later re exploration. Two additional patients required postprocedural re-exploration for apical bleeding. An apical pseudo-aneurysm developed in two patients (2%), one of whom was treated by surgical revision. Survival was significantly impaired when either apical bleeding, aneurysm, or re-exploration occurred (75% +/- 0.082 survival at 30 days and 59% +/- 0.122 at 1 year vs 94% +/- 0.023 and 80% +/- 0.043 in patients without apical complications, p=0.012). Twelve patients (8%) experienced secondary wound healing. An apical hypo- or akinesia was detected in 18/54 (33%) patients at 6 months' echocardiographic investigation, and in 11/30 (37%) 1 year after the procedure. CONCLUSIONS: The trans-apical access for trans catheter aortic valve implantation might be challenging in elderly patients with fragile tissue. Severe bleeding complications or aneurysm formation significantly impairs survival. The clinical impact of subsequent apical hypo- or akinesia has to be further followed up. PMID- 21242088 TI - Functional specialization of ribosomes? AB - Ribosomes are highly conserved macromolecular machines that are responsible for protein synthesis in all living organisms. Work published in the past year has shown that changes to the ribosome core can affect the mechanism of translation initiation that is favored in the cell, which potentially leads to specific changes in the relative efficiencies with which different proteins are made. Here, I examine recent data from expression and proteomic studies that suggest that cells make slightly different ribosomes under different growth conditions, and discuss genetic evidence that such differences are functional. In particular, I argue that eukaryotic cells probably produce ribosomes that lack one or more core ribosomal proteins (RPs) under some conditions, and that core RPs contribute differentially to translation of distinct subpopulations of mRNAs. PMID- 21242090 TI - How does hypothermia protect cardiomyocytes during cardioplegic ischemia? AB - OBJECTIVE: Insufficient myocardial protection is still a considerable cause for in-hospital mortality in children. The purpose of our study was to investigate underlying the basic mechanisms of cardioplegic cardioprotection during hypothermic and normothermic ischemia in a cardiomyocyte cell culture model. METHODS: We cooled cardiomyocytes to 20 degrees C for 20min; during this time, cardiac arrest was simulated by oxidative damage with 2mM H2O2 and cardioplegic solution, followed by rewarming to 37 degrees C. Later on, we analyzed cardiomyocyte cell morphology (phase-contrast-microscopy), viability (trypan blue staining), inflammation (cyclooxygenase-2 (Cox-2) and phosphorylated extracellular signal-regulated kinase (pERK) 1/2 expression in Western blot analysis), and expression of Akt survival protein (Western blot technique). RESULTS: Hypothermia increases cell survival of cardiomyocytes after cardioplegic ischemia, as demonstrated in significantly higher cell viability and less cell death in these cells compared with normothermic H2O2-damaged cardiomyocytes. As a possible underlying cellular mechanism, we found that, during cold cardioplegic ischemia, ERK 1/2 enzyme is less phosphorylated than under conditions of normothermic cardioplegic ischemia. This is in line with significantly diminished Cox-2 expression during cold cardioplegic ischemia. Moreover, hypothermic cardioplegia preserved cell survival by upregulation of Akt transcription factor in cardiomyocytes. CONCLUSION: In the present cell culture study, we clearly demonstrated that hypothermia exerts additional protection for cardiomyocytes during cardioplegic ischemia. The understanding of underlying basic mechanisms is evident to improve current techniques of myocardial protection. PMID- 21242091 TI - Imaging for trans-catheter pulmonary stent-valve implantation without angiography: role of intravascular ultrasound. AB - Patients with stenosed biologic pulmonary conduits require redo cardiac surgery to prevent severe right ventricular dysfunction. Following the latest trends, the trans-catheter pulmonary stent-valve implantation represents a new fascinating alternative carrying a lower operative risk, compared with the standard open heart re-intervention. Traditionally, the pulmonary stent valve is positioned off pump, under fluoroscopic control, and requires angiographies. However, alternative tools not requiring contrast injections for the intra-operative cardiac imaging have to be also considered strongly. The usefulness of intravascular ultrasound for the positioning of aortic endoprosthesis has already been proven in previous reports and, following the same principle, we have started to routinely implant balloon-expandable stent valves (Edwards SapienTM THV) in stenosed pulmonary valve conduits using intravascular ultrasound for the stent-valve positioning without angiography. We describe the intra-operative intravascular imaging technique with technical details. PMID- 21242092 TI - Anterior mediastinal lesion: giant aneurysms of saphenous vein graft to the right coronary artery compressing the right atrium. PMID- 21242093 TI - Giant fibrovascular esophageal polyp. PMID- 21242094 TI - Lymph node involvement in T1 non-small-cell lung cancer: could glucose uptake and maximal diameter be predictive criteria? AB - OBJECTIVE: The introduction of modern staging systems such as computed tomography (CT) and positron emission tomography/CT (PET/CT) with fluorodeoxyglucose ([(18)F]FDG) has increased the detection of small peripheral lung cancers at an early stage. We analyzed the behavior of pathological T1 non-small-cell lung cancer (NSCLC) to identify criteria predictive of nodal involvement, and the role of cancer size in lymph node metastases. METHODS: We retrospectively analyzed 219 patients with pathological T1 NSCLC. All patients were staged by high-resolution CT and PET as stage I, and underwent anatomical resection and radical lymphadenectomy. Our data were collected based on pathological nodule size (0-10 mm; 11-20 mm; and 21-30 mm); morphological features of lung nodule and FDG uptake of the tumor measured by standardized uptake value (SUV). RESULTS: A total of 190 patients (87%) were pN0, 14 (6%) pN1, and 15 (7%) pN2. No nodal involvement was observed in any of the 62 patients with nodule size less than 10 mm, in 20 out of 120 patients (17%) with nodule size 11-20 mm, and in nine out of 37 tumors (28%) 21-30 mm in size (p=0.0007). All 55 patients with nodule SUV<2.0 and all 26 non solid lesions were pN0 (respectively, p=0.0001 and p=0.03). All nodal metastases occurred among the group of 132 patients with size larger than 10 mm and SUV higher than 2.0 with a 22% rate of nodal involvement of (29 patients) (p<0.0001). CONCLUSIONS: The low probability of lymph node involvement in NSCLC <1 cm or showing glucose uptake <2 suggests lymphadenectomy could be avoided. A randomized trial should be performed to validate our data. PMID- 21242095 TI - Capnocytophaga canimorsis a cause of septicaemia following a dog bite: a case review. AB - Described in this study is the case of a 53-year-old woman who developed a life threatening infection caused by the bacterium Capnocytophaga canimorsus (C. canimorsus), subsequent to being bitten by a dog. The patient presented to an Emergency Department with a 24-h history of diarrhoea and vomiting with dehydration but within 36 h of presentation developed an overwhelming severe sepsis with septic shock, disseminated intravascular coagulation, acute renal failure, metabolic acidosis and threatened acute respiratory failure requiring urgent intensive care intervention. At subsequent questioning her husband volunteered that she had been bitten on the wrist by the family dog 24h prior to the onset of symptoms; this bite had been extremely minor, requiring no treatment at the time and leaving only a very superficial wound. The causative organism was finally identified two weeks later as C. canimorsus, a common commensal in the oral flora of dogs. C. canimorsus has been reported as a rare cause of severe infection in susceptible individuals; however this case is of particular interest as there were no apparent predisposing factors conferring risk of severe infection. This case also raised significant practice issues for the treating hospital. PMID- 21242096 TI - Measurement of the force-displacement response of in vivo human skin under a rich set of deformations. AB - The non-linear, anisotropic, and viscoelastic properties of human skin vary according to location on the body, age, and individual. The measurement of skin's mechanical properties is important in several fields including medicine, cosmetics, and forensics. In this study, a novel force-sensitive micro-robot applied a rich set of three-dimensional deformations to the skin surface of different areas of the arms of 20 volunteers. The force-displacement response of each area in different directions was measured. All tested areas exhibited a non linear, viscoelastic, and anisotropic force-displacement response. There was a wide quantitative variation in the stiffness of the response. For the right anterior forearm, the ratio of the maximum probe reaction force to maximum probe displacement ranged from 0.44 N mm(-1) to 1.45 N mm(-1). All volunteers exhibited similar qualitative anisotropic characteristics. For the anterior right forearm, the stiffest force-displacement response was when the probe displaced along the longitudinal axis of the forearm. The response of the anterior left forearm was stiffest in a direction 20 degrees to the longitudinal axis of the forearm. The posterior upper arm was stiffest in a direction 90 degrees to the longitudinal axis of the arm. The averaged posterior upper arm response was less stiff than the averaged anterior forearm response. The maximum probe force at 1.3mm probe displacement was 0.69N for the posterior upper arm and 1.1N for the right anterior forearm. The average energy loss during the loading-unloading cycle ranged from 11.9% to 34.2%. This data will be very useful for studying the non linear, anisotropic, and viscoelastic behaviour of skin and also for generating material parameters for appropriate constitutive models. PMID- 21242097 TI - Analysis of signal propagation in an elastic-tube flow model. AB - We combine linear and nonlinear signal analysis techniques to investigate the transmission of pressure signals along a one-dimensional model of fluid flow in an elastic tube. We derive a simple, generally applicable measure for the robustness of a simulated vessel against in vivo pressure fluctuations, based on quantifying the degree of synchronization between proximal and distal pressure pulses. The practical use of this measure will be in its application to simulated pulses generated in response to a stochastic forcing term mimicking biological variations of root pressure in arterial blood flow. PMID- 21242098 TI - Synthesis, growth and characterization of 4-bromo-4'chloro benzylidene aniline--a third order non linear optical material. AB - The organic nonlinear optical material of 4-bromo-4'chloro benzylidene aniline (BCBA) was synthesized and single crystal of BCBA was grown from acetone solution by solvent evaporation method at room temperature. Its three dimensional structure was elucidated from single crystal X-ray diffraction analysis at 173 K. Synthesized compound of BCBA was subjected to FTIR and (1)H and (13)C NMR spectral analyses. The range and percentage of optical transmission of BCBA was determined by UV-vis-NIR spectrum and its fluorescence spectrum was recorded using spectrofluorometer. The mechanical strength of the crystal was estimated using Vickers microhardness test on the (001) plane. Dielectric constant of the grown crystal was measured for various frequencies along (001) plane. The third order nonlinear optical properties of BCBA were investigated by Z-scan technique with He-Ne laser radiation of wavelength at 632.8 nm and the corresponding nonlinear refractive index, absorption coefficient and optical susceptibility were calculated. PMID- 21242099 TI - EPR study of gamma irradiated N-methyl taurine (C3H9NO3S) and sodium hydrogen sulphate monohydrate (NaHSO3.H2O) single crystals. AB - EPR study of gamma irradiated C(3)H(9)NO(3)S and NaHSO(3).H(2)O single crystals have been carried out at room temperature. There is one site for the radicals in C(3)H(9)NO(3)S and two magnetically distinct sites for the radicals in NaHSO(3). The observed lines in the EPR spectra have been attributed to the species of SO(3)(-) and RH radicals for N-methyl taurine, and to the SO(3)(-) and OH radicals for sodium hydrogen sulfate monohydrate single crystals. The principal values of the g for SO(3)(-), the hyperfine values of RH and OH proton splitting have been calculated and discussed. PMID- 21242100 TI - Single sensor for two metal ions: colorimetric recognition of Cu2+ and fluorescent recognition of Hg2+. AB - The first novel rhodamine B based sensor, rhodamine B hydrazide methyl 5-formyl 1H-pyrrole-2-carboxylate Schiff base (2) capable of detecting both Cu(2+) and Hg(2+) using two different detection modes has been designed and synthesized. The metal ion induced optical changes of 2 were investigated in MeOH:H(2)O (3:1) HEPES buffered solution at pH 7.4. Sensor 2 exhibits selective colorimetric recognition of Cu(2+) and fluorogenic recognition of Hg(2+) with UV-vis and fluorescence spectroscopy, respectively. Moreover, both of the Cu(2+) and Hg(2+) recognition processes are proven to be hardly influenced by other coexisting metal ions. PMID- 21242101 TI - Raman spectra of amino acids and their aqueous solutions. AB - Amino acids are the basic "building blocks" that combine to form proteins and play an important physiological role in all life-forms. Amino acids can be used as models for the examination of the importance of intermolecular bonding in life processes. Raman spectra serve to obtain information regarding molecular conformation, giving valuable insights into the topology of more complex molecules (peptides and proteins). In this paper, amino acids and their aqueous solution have been studied by Raman spectroscopy. Comparisons of certain values for these frequencies in amino acids and their aqueous solutions are given. Spectra of solids when compared to those of the solute in solution are invariably much more complex and almost always sharper. We present a collection of Raman spectra of 18 kinds of amino acids (L-alanine, L-arginine, L-aspartic acid, cystine, L-glutamic acid, L-glycine, L-histidine, L-isoluecine, L-leucine, L lysine, L-phenylalanine, L-methionone, L-proline, L-serine, L-threonine, L tryptophan, L-tyrosine, L-valine) and their aqueous solutions that can serve as references for the interpretation of Raman spectra of proteins and biological materials. PMID- 21242102 TI - Europium(III) complexed by HPSEC size-fractions of a vertisol humic acid: small differences evidenced by time-resolved luminescence spectroscopy. AB - The size fractionation of a humic acid (HA) by high performance size exclusion chromatography (HPSEC) was used as a proxy for the filtration effect during HA transport through a porous medium with minimum specific chemical interactions. The modification of the Eu(III)-HA complexes' formation with the different size fractions, as compared to the bulk HA, was studied in time-resolved luminescence spectroscopy (TRLS). Clear modifications in Eu(III)-HA complexes' structures were shown and related to the molecular characteristics of the separated size fractions. The properties of most of size-fractions did not induce a major alteration of the affinity towards Eu(III). Only the most hydrophilic fractions eluted in the tail of the chromatographic peak, representing about 11% of total fractions-weight, gave some significantly different parameters. Using a simplistic complexation model, it was found that the available complexation sites decreased with the size reduction of humic fractions. PMID- 21242103 TI - New method for comprehensive detection of chemical warfare agents using an electron-cyclotron-resonance ion-source mass spectrometer. AB - We developed a detection technology for vapor forms of chemical warfare agents (CWAs) with an element analysis system using an electron cyclotron resonance ion source. After the vapor sample was introduced directly into the ion source, the molecular material was decomposed into elements using electron cyclotron resonance plasma and ionized. The following CWAs and stimulants were examined: diisopropyl fluorophosphonate (DFP), 2-chloroethylethylsulfide (2CEES), cyanogen chloride (CNCl), and hydrogen cyanide (HCN). The type of chemical warfare agents, specifically, whether it was a nerve agent, blister agent, blood agent, or choking agent, could be determined by measuring the quantities of the monatomic ions or CN(+) using mass spectrometry. It was possible to detect gaseous CWAs that could not be detected by a conventional mass spectrometer. The distribution of electron temperature in the plasma could be closely controlled by adjusting the input power of the microwaves used to generate the electron cyclotron resonance plasma, and the target compounds could be detected as molecular ions or fragment ions, enabling identification of the target agents. PMID- 21242104 TI - The changes in caregivers' perceptions about the quality of information and benefits of nursing documentation associated with the introduction of an electronic documentation system in a nursing home. AB - PURPOSE: To date few studies have compared nursing home caregivers' perceptions about the quality of information and benefits of nursing documentation in paper and electronic formats. With the increased interest in the use of information technology in nursing homes, it is important to obtain information on the benefits of newer approaches to nursing documentation so as to inform investment, organisational and care service decisions in the aged care sector. This study aims to investigate caregivers' perceptions about the quality of information and benefits of nursing documentation before and after the introduction of an electronic documentation system in a nursing home. METHODS: A self-administered questionnaire survey was conducted three months before, and then six, 18 and 31 months after the introduction of an electronic documentation system. Further evidence was obtained through informal discussions with caregivers. RESULTS: Scores for questionnaire responses showed that the benefits of the electronic documentation system were perceived by the caregivers as provision of more accurate, legible and complete information, and reduction of repetition in data entry, with consequential managerial benefits. However, caregivers' perceptions of relevance and reliability of information, and of their communication and decision-making abilities were perceived to be similar either using an electronic or a paper-based documentation system. Improvement in some perceptions about the quality of information and benefits of nursing documentation was evident in the measurement conducted six months after the introduction of the electronic system, but were not maintained 18 or 31 months later. CONCLUSIONS: The electronic documentation system was perceived to perform better than the paper-based system in some aspects, with subsequent benefits to management of aged care services. In other areas, perceptions of additional benefits from the electronic documentation system were not maintained. In a number of attributes, there were similar perceptions on the two types of systems. PMID- 21242106 TI - Angiotensin and carotid body chemoreception in heart failure. AB - The carotid body (CB) plays an important role in the control of breathing and in autonomic control of cardiovascular function. CB chemoreceptor activity is enhanced in chronic heat failure (CHF) and contributes to the sympathetic hyperactivity that exacerbates the progression of the disease. Studies in the past few years have revealed that a local angiotensin (Ang) system exists in the CB and plays an important role in altering CB function in CHF as well as other conditions, such as chronic hypoxia. This brief review highlights recent revelations that Ang I metabolites exert effects within the CB, and focuses on the influence of Ang II and Ang-(1-7) on CB function in CHF. PMID- 21242105 TI - Vitamin D and the anti-viral state. AB - Vitamin D has long been recognized as essential to the skeletal system. Newer evidence suggests that it also plays a major role regulating the immune system, perhaps including immune responses to viral infection. Interventional and observational epidemiological studies provide evidence that vitamin D deficiency may confer increased risk of influenza and respiratory tract infection. Vitamin D deficiency is also prevalent among patients with HIV infection. Cell culture experiments support the thesis that vitamin D has direct anti-viral effects particularly against enveloped viruses. Though vitamin D's anti-viral mechanism has not been fully established, it may be linked to vitamin D's ability to up regulate the anti-microbial peptides LL-37 and human beta defensin 2. Additional studies are necessary to fully elucidate the efficacy and mechanism of vitamin D as an anti-viral agent. PMID- 21242107 TI - A review of the relationships between Landau-Kleffner syndrome, electrical status epilepticus during sleep, and continuous spike-waves during sleep. AB - The goal of this report is to review the relationships between Landau-Kleffner syndrome (LKS), electrical status epilepticus during sleep (ESES), and continuous spike-waves during sleep (CSWS). LKS is a clinical syndrome involving mainly acquired aphasia and sometimes seizures. Other clinical findings include cognitive impairments and global regression of behavior. The EEG may evolve from more benign conditions into ESES (or CSWS), seen in 50% of patients with LKS, or may also show focal findings. Seizures include atypical absence, generalized tonic-clonic, atonic, and partial motor attacks. Effective medications are discussed. The EEG patterns CSWS and ESES are likely equivalent terms. CSWS is used by some authors, and ESES by others. Patients with these patterns usually show mental retardation, seizures, and global regression. More benign EEG patterns, like focal discharges, may develop into these more severe generalized patterns, which are associated with atypical absences, negative myoclonus, and cognitive disturbances. Memory disorders are common, because the nearly continuous generalized discharges in sleep do not allow for the memory consolidation that also occurs during sleep. Medications and possible etiologies are discussed. PMID- 21242108 TI - Development and validation of a method for determination of corticosteroids in pig fat using liquid chromatography-tandem mass spectrometry. AB - A new method was developed to determine five corticosteroids (prednisolone, methylprednisone, flumethasone, dexamethasone, and methylprednisolone) in pig fat samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS) utilizing an optimized liquid-liquid extraction (LLE) and subsequent solid-phase extraction (SPE) for sample clean-up. In the sample preparation, a pig fat sample was dissolved in n-hexane and then extracted into the methanol-water (50/50, v/v) mixture that enabled extraction of only medium polar corticosteroids and not the non-polar components of matrices. This extract was cleaned-up and concentrated on polymeric Oasis HLB SPE cartridge. Separation involved isocratic solvent (methanol-acetate buffer, pH 5.4) and Ascentis Express Fused-Core type HLPC column; reduced the analysis time to 7.5 min, which is at least two times lower than time required for separation using conventional techniques. Other advantage of the developed method is the minimized ion suppression of LC-MS/MS analysis, which allowed detection of corticosteroids in sub MUg/kg. Method was validated according to European Union (EU) Commission Decision 2002/657/EC. Measured parameters such as selectivity, linearity, recovery, within-laboratory reproducibility, decision limit, and detection capability satisfied the EU Directive. Ranges of mean recoveries and within-laboratory reproducibility were 81-100% and 8.0-20.5%, respectively. Decision limits were calculated in the range from 4.5 to 11.9 MUg/kg for MRL compounds and varied from 0.1 to 0.2 MUg/kg for banned substances. Limit of detections (LODs), calculated as three time signal-to noise ratio, were in the range of 0.1-0.3 MUg/kg. PMID- 21242109 TI - UPLC methodology for identification and quantitation of naturally fluorescent crosslinks in proteins: a study of bone collagen. AB - Methods used to determine collagen crosslinks in different connective tissues require a relatively large amount of material and include a number of experimental steps. We addressed these issues by developing the first ultrahigh pressure liquid chromatography (UPLC) methodology for detection and quantification of naturally fluorescent enzymatic (pyridinoline, deoxypyridinoline) and senescent (pentosidine) crosslinks using nanogram amounts of acid-hydrolyzed bone and purified bone collagen. Not only the developed set of UPLC methods relies on a single column analysis of all three fluorescent crosslinks in one separation step, but under different separation conditions, the same column is also used to determine hydroxyproline concentration necessary to calculate collagen contents in the samples making this a unique feature of our methodology. The determined detection limit was 10 fmol for the pyridinium crosslinks and 1.5 fmol for pentosidine. The smallest pieces of human cortical bones were 224-240 ng in weight and this is approx. 10(6)-fold less as compared to some high-pressure LC (HPLC) methods that need a minimum of approx. 0.50-1 mg of a bone sample. In general, our UPLC methodology can be applied to analysis of similar crosslinks in various collagenous tissues as well as purified/recombinant proteins of different origin. Thus, in addition to biomedical and bone research, this work is of general importance to other fields including biology, forensic, anthropology and archaeology, where samples could truly be rare, minute and precious. PMID- 21242110 TI - A two-dimensional protein fragmentation-proteomic study of neuronal ceroid lipofuscinoses: identification and characterization of differentially expressed proteins. AB - The neuronal ceroid lipofuscinoses (NCLs) are a group of neuronal degenerative diseases that primarily affect children. Previously we hypothesized that the similarity of the phenotypes among the variant subtypes of NCL suggests that the NCLs share a common metabolic functional pathway. To test our hypothesis, we have studied several candidate proteins identified using a proteomic approach. We analyzed their differential expression and cataloged their functions and involved pathways. Forty protein peaks, differentially expressed in NCLs, were selected from two-dimensional protein fragmentation (PF2D) maps and twenty-four proteins were identified by MALDI-TOF-MS or LC-ESI-MS/MS. Six proteins were verified by further Western blotting. Our results showed that annexin A1, annexin A2, and vimentin were significantly down-regulated in NCL1, NCL2, NCL3, and NCL8 cells; galectin-1 was down-regulated in NCL1, NCL3, and NCL8 but up-regulated in NCL2 cells; and isoform 5 of caldesmon was up-regulated in all NCL cell types. The histone 2B was down-regulated in NCL3. Functional analysis showed that the differentially expressed proteins identified by PF2D could be grouped into categories of intermediate filaments, cell motility, apoptosis, cytoskeleton, membrane trafficking, calcium binding, nucleosome assembly, pigment granule and cell development. Immunocytochemistry revealed nuclear translocalization of annexin A1 in CLN2-deficient fibroblasts and abnormal distribution of L-caldesmon in cultured CLN1, CLN2, CLN3 and CLN8-deficient fibroblasts. Finding differentially expressed proteins in variant NCLs, which showed disturbances of cytoskeleton, RAGE-dependent cellular pathways and decreased glycolysis provides evidence supporting our hypothesis. These findings may contribute to the discovery of molecular biomarkers and may help further elucidate the pathogenic mechanisms underlying the NCLs. PMID- 21242111 TI - Amino acids analysis using a monolithic silica column after derivatization with 4 fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F). AB - A fast HPLC method using a monolithic silica column was developed for the measurement of amino acids. The amino acids were pre-column derivatized with 4 fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) and separated on a monolithic silica column (MonoClad C18-HS, 250 mm * 3 mm I.D.). The separation of 19 NBD-amino acids was achieved within 18 min, which was only one-fifth of the time taken by the methods using a conventional particle-packed column, with the gradient elution of a mobile phase at the flow rate of 1.4 mL/min. The sensitivity was good with a limit of detection for the individual amino acids ranging from 2.94 to 53.4 fmol. The calibration curves for all the amino acids were found to be linear in the range of 200 fmol to 20 pmol with correlation coefficients of 0.997 or better. The analytical method was successfully applied to determine the amino acids in a mouse plasma sample. PMID- 21242112 TI - A validated enantioselective assay for the simultaneous quantitation of (R)-, (S) fluoxetine and (R)-, (S)-norfluoxetine in ovine plasma using liquid chromatography with tandem mass spectrometry (LC/MS/MS). AB - A liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was developed and validated for the quantitation of (R)-, (S)-fluoxetine, and (R)-, (S) norfluoxetine in ovine plasma. The analytes were extracted from ovine plasma at a basic pH using a single-step liquid-liquid extraction with methyl-tert-butyl ether. Chromatographic separation of all enantiomers was achieved using an AGP chiral column with a run time of 10 min. (R)-, (S)-fluoxetine, and (R)-, (S) norfluoxetine were quantitated at the total ion current (TIC) of multiple reaction monitoring (MRM) transitions of m/z 310.2->44.1, m/z 310.2->147.7 for (R)-, (S)-fluoxetine, and m/z 296.2->30.3, m/z 296.2->133.9 for (R)-, (S) norfluoxetine. This method was validated for accuracy, precision, linearity, range, limit of quantitation (LOQ), selectivity, recovery, dilution integrity, matrix effect, and evaluation of carry-over. Observed accuracy ranges were as follows: (R)-fluoxetine -8.82 to 3.75%; (S)-fluoxetine -10.8 to 1.46%; (R) norfluoxetine -7.50 to 0.37% and (S)-norfluoxetine -8.77% to -1.33%. Observed precision ranges were as follows: (R)-fluoxetine 5.29-11.5%; (S)-fluoxetine 3.91 11.1%; (R)-norfluoxetine 4.32-7.67% and (S)-norfluoxetine -8.77% to -1.33%. The calibration curves were weighted (1/X(2), n=4) and observed to be linear for all analytes with the following r(2) values: (R)-fluoxetine >= 0.997; (S)-fluoxetine >= 0.996; (R)-norfluoxetine >= 0.989 and (S)-norfluoxetine >= 0.994. The analytical range of the method was 1-500 ng/ml with an LOQ of 1 ng/ml for all analytes, using a sample volume of 300 MUL. PMID- 21242113 TI - A rapid method for simultaneous determination of zearalenone, alpha-zearalenol, beta-zearalenol, zearalanone, alpha-zearalanol and beta-zearalanol in traditional Chinese medicines by ultra-high-performance liquid chromatography-tandem mass spectrometry. AB - A rapid and reliable ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous determination of zearalenone (ZEN), alpha-zearalenol (alpha-ZOL), beta-zearalenol (beta-ZOL), zearalanone (ZAN), alpha-zearalanol (alpha-ZAL) and beta-zearalanol (beta-ZAL) in traditional Chinese medicines (TCMs) was developed. The development of the method and investigations of the matrix influence were described in particular. After evaluation of the matrix effects of different TCMs, i.e., rhizomes and roots, seeds, flowers, grasses and leaves, by the post-extraction spiked method, a reliable sample clean-up method based on home-made clean-up cartridges, a suitable internal standard and the matrix calibration were combined using to minimize the matrix effects to ensure the accuracy of the method. The established method was further validated by determining the linearity (R(2)>=0.9990), sensitivity (limit of quantitation 0.11-0.99 ng mL(-1)), average recovery (86.6 113.5%) and precision (relative standard deviation <=13.5%). It was shown to be a suitable method for simultaneous determination of ZEN, alpha-ZOL, beta-ZOL, ZAN, alpha-ZAL and beta-ZAL in different TCMs. Finally, the established method was successfully applied to the determination of the six mycotoxins in various TCMs and the results were presented to provide relevant insights to researchers in TCM analysis. PMID- 21242114 TI - Certified reference materials (GBW09170 and 09171) of creatinine in human serum. AB - Creatinine is the most widely used clinical marker for assessing renal function. Concentrations of creatinine in human serum need to be carefully checked in order to ensure accurate diagnosis of renal function. Therefore, development of certified reference materials (CRMs) of creatinine in serum is of increasing importance. In this study, two new CRMs (Nos. GBW09170 and 09171) for creatinine in human serum have been developed. They were prepared with mixtures of several dozens of healthy people's and kidney disease patient's serum, respectively. The certified values of 8.10, 34.1 mg/kg for these two CRMs have been assigned by liquid chromatography-isotope dilution mass spectrometry (LC-IDMS) method which was validated by using standard reference material (SRM) of SRM909b (a reference material obtained from National Institute of Standards and Technology, NIST). The expanded uncertainties of certified values for low and high concentrations were estimated to be 1.2 and 1.1%, respectively. The certified values were further confirmed by an international intercomparison for the determination of creatinine in human serum (Consultative Committee for Amount of Substance, CCQM) of K80 (CCQM-K80). These new CRMs of creatinine in human serum pool are totally native without additional creatinine spiked for enrichment. These new CRMs are capable of validating routine clinical methods for ensuring accuracy, reliability and comparability of analytical results from different clinical laboratories. They can also be used for instrument validation, development of secondary reference materials, and evaluating the accuracy of high order clinical methods for the determination of creatinine in human serum. PMID- 21242115 TI - Schwannoma originating from the proper hepatic artery. PMID- 21242118 TI - Stathmin overexpression identifies high-risk patients and lymph node metastasis in endometrial cancer. AB - PURPOSE: Overexpression of the oncogen Stathmin has been linked to aggressive endometrial carcinoma and a potential for PI3Kinase inhibitors in this disease. We wanted to validate the prognostic value of Stathmin expression in a large prospective multicenter setting. As lymph node sampling is part of current surgical staging, we also aimed to test if Stathmin expression in endometrial curettage specimens could predict lymph node metastasis. EXPERIMENTAL DESIGN: A total of 1,076 endometrial cancer patients have been recruited from 10 centers to investigate the biological tumor marker Stathmin in relation to clinicopathologic variables, including lymph node status and survival. Stathmin immunohistochemical staining was carried out in 477 hysterectomy and 818 curettage specimens. RESULTS: Seventy-one percent of the patients (n = 763) were subjected to lymph node sampling, of which 12% had metastatic nodes (n = 94). Overexpression of Stathmin was detected in 37% (302 of 818) of the curettage and in 18% (84 of 477) of the hysterectomy specimens investigated. Stathmin overexpression in curettage and hysterectomy specimens were highly correlated and significantly associated with nonendometrioid histology, high grade, and aneuploidy. Stathmin analysis in preoperative curettage samples significantly correlated with, and was an independent predictor of, lymph node metastases. High Stathmin expression was associated with poor disease-specific survival (P <= 0.002) both in curettage and hysterectomy specimens. CONCLUSIONS: Stathmin immunohistochemical staining identifies endometrial carcinomas with lymph node metastases and poor survival. The value, as a predictive marker for response to PI3Kinase inhibition and as a tool to stratify patients for lymph node sampling in endometrial carcinomas, remains to be determined. PMID- 21242119 TI - Prediction of postoperative recurrence-free survival in non-small cell lung cancer by using an internationally validated gene expression model. AB - PURPOSE: This study was performed to discover prognostic genomic markers associated with postoperative outcome of stage I to III non-small cell lung cancer (NSCLC) that are reproducible between geographically distant and demographically distinct patient populations. EXPERIMENTAL DESIGN: American patients (n = 27) were stratified on the basis of recurrence and microarray profiling of their tumors was performed to derive a training set of 44 genes. A larger Korean patient validation cohort (n = 138) was also stratified by recurrence and screened for these genes. Four reproducible genes were identified and used to construct genomic and clinicogenomic Cox models for both cohorts. RESULTS: Four genomic markers, DBN1 (drebrin 1), CACNB3 (calcium channel beta 3), FLAD1 (PP591; flavin adenine dinucleotide synthetase), and CCND2 (cyclin D2), exhibited highly significant differential expression in recurrent tumors in the training set (P < 0.001). In the validation set, DBN1, FLAD1 (PP591), and CACNB3 were significant by Cox univariate analysis (P <= 0.035), whereas only DBN1 was significant by multivariate analysis. Genomic and clinicogenomic models for recurrence-free survival (RFS) were equally effective for risk stratification of stage I to II or I to III patients (all models P < 0.0001). For stage I to II or I to III patients, 5-year RFS of the low- and high-risk patients was approximately 70% versus 30% for both models. The genomic model for overall survival of stage I to III patients was improved by addition of pT and pN stage (P < 0.0013 vs. 0.010). CONCLUSION: A 4-gene prognostic model incorporating the multivariate marker DBN1 exhibits potential clinical utility for risk stratification of stage I to III NSCLC patients. PMID- 21242121 TI - Multiple genetic loci modulate lung adenocarcinoma clinical staging. AB - PURPOSE: The main prognostic factor of lung cancer patient outcome is clinical stage, a parameter of tumor aggressiveness. Our study was conducted to test whether germ line variations modulate individual differences in clinical stage. EXPERIMENTAL DESIGN: We conducted a case-only genome-wide association study (GWAS) using a 620,901 single-nucleotide polymorphism (SNP) array in a first series of 600 lung adenocarcinoma (ADCA) patients and in a replication series of 317 lung ADCA patients. RESULTS: GWAS identified 54 putatively associated SNPs, 3 of which were confirmed in the replication series. Joint analysis of the two series pointed to 22 statistically associated (P < 0.01) genetic variants that together explained about 20% of the phenotypic variation in clinical staging (P < 2 * 10(-16)) and showed a statistically significant difference in overall survival (P = 8.0 * 10(-8)). The strongest statistical association was observed at rs10278557 (P = 1.1 * 10(-5)), located in the mesenchyme homeobox 2 (MEOX2) gene. CONCLUSION: These data point to the role of germ line variations involving multiple loci in modulating clinical stage and, therefore, prognosis in lung ADCA patients. PMID- 21242120 TI - Smac modulates chemosensitivity in head and neck cancer cells through the mitochondrial apoptotic pathway. AB - PURPOSE: Overexpression of inhibitors of apoptosis proteins (IAP) contributes to therapeutic resistance. Second mitochondria-derived activator of caspase (Smac) promotes caspase activation by binding to IAPs upon release from the mitochondria. IAP antagonists, also called SMAC mimetics, are promising anticancer agents modeled after this mechanism. We investigated the role and mechanisms of Smac- and Smac mimetic-mediated chemosensitization in head and neck squamous cell carcinoma (HNSCC) cells. EXPERIMENTAL DESIGN: The effects of SMAC knockdown, SMAC overexpression, and a small molecule Smac mimetic on the chemosensitivities of HNSCC cells were determined. The mechanisms of Smac- and Smac mimetic-mediated chemosensitization were investigated by analyzing growth suppression, the mitochondrial apoptotic pathway, caspase activation, and IAP proteins. The therapeutic responses of HNSCC cells with different levels of Smac were compared in xenograft models. RESULTS: We found that Smac mediates apoptosis induced by several classes of therapeutic agents through the mitochondrial pathway. SMAC knockdown led to impaired caspase activation, mitochondrial membrane depolarization, and release of cytochrome c. A small molecule Smac mimetic, at nanomolar concentrations, significantly sensitized HNSCC cells to gemcitabine-induced apoptosis and restored gemcitabine sensitivity in SMAC knockdown cells, through caspase activation, X-linked IAP dissociation, and mitochondria-associated events, but not the TNF-alpha pathway. Furthermore, Smac levels modulated the therapeutic response of HNSCC cells to gemcitabine in xenograft models. CONCLUSIONS: Our results establish a critical role of Smac in mediating therapeutic responses of HNSCC cells and provide a strong rationale for combining Smac mimetics with other anticancer agents to treat HNSCC. PMID- 21242122 TI - Role and relevance of TrkB mutations and expression in non-small cell lung cancer. AB - PURPOSE: TrkB has been involved in poor cancer outcome. TrkB mutations have been reported in non-small cell lung cancer. In this study, we aimed at characterizing the role of three potentially sensitizing TrkB mutations previously reported in lung cancer. EXPERIMENTAL DESIGN: We characterized three activation loop mutants of TrkB (M713I, R715G, and R734C) in terms of pathway activation/phosphorylation, migration, anchorage-independent growth, and sensitivity to a Trk inhibitor, using NIH3T3 cells and Baf3 cells. We also sequenced the tyrosine kinase domain of TrkB in a large number of lung cancer samples of East-Asian origin and cell lines. RESULTS: None of the mutants were constitutively active in NIH3T3 transformation and migration assays. M713I and R734C mutants showed low levels of autophosphorylation in comparison with wild-type TrkB. Although R715G showed similar level of autophosphorylation to wild-type TrkB on brain-derived neurotrophic factor stimulation, the mutant was not as competent as wild-type TrkB in supporting interleukin-3-independent growth of Baf3 cells. In addition, the Trk inhibitor AZD6918 inhibited wild-type TrkB-induced cell migration and cell growth, whereas the mutants were relatively resistant to the Trk inhibitor compared with wild-type TrkB. We could not confirm the presence of nonsynonymous mutation in 78 lung cancer samples and 29 cell lines. CONCLUSIONS: Wild-type, but not mutant, TrkB enhances cell migration and transformation. Our study suggests that TrkB mutations should not be used for selection of patients with lung cancer treated with Trk inhibitors. High expression of wild-type TrkB might be beneficial for studies of Trk inhibitors. PMID- 21242123 TI - Utility of the APACHE IV, PPI, and combined APACHE IV with PPI for predicting overall and disease-specific ICU and ACU mortality. AB - BACKGROUND: The Acute Physiology and Chronic Health Evaluation (APACHE) IV and Palliative Performance Index (PPI) are scales commonly used to assess prognosis in intensive care units (ICUs) and acute care units (ACUs). OBJECTIVE: To compare the utility of APACHE IV, PPI, and combined APACHE IV with PPI for predicting overall and disease-specific mortality. DESIGN: This is a prospective cohort study using admission data during the first 24 hours. Chi-square contingency tables were used to analyze mortality data for each scale. SETTING: This study was conducted at a community hospital. PATIENTS: Participants were admitted between December 24, 2008 and April 2, 2010. RESULTS: The APACHE IV, PPI, and APACHE IV plus PPI (n = 599) were significant for predicting overall mortality (P < .0001 each). The APACHE IV was also significant in predicting mortality in patients with congestive heart failure (CHF), pulmonary edema (PULEDEM), stroke (cerebrovascular accident [CVA]), terminal or metastatic cancer (CA), and dementia. The PPI was significant for predicting mortality in PULEDEM, CA, and dementia but not CVA or CHF, while the APACHE IV with PPI was significant for all diseases but CVA. The APACHE IV was the most robust in predicting ICU/ACU mortality. The combined APACHE IV and PPI improved the specificity of the PPI to predict mortality but caused a decline in sensitivity. LIMITATIONS: Limitations are due to the subjective nature of the PPI and Glasgow Coma scale (GCS), differences in illness trajectories, and a lack of reliable follow-up of all participants. CONCLUSION: The benefits of combining scales were best exemplified in participants with dementia. Inconsistencies in the predictive value of specific participant populations are likely due to difference in the illness trajectories of disease processes. PMID- 21242124 TI - Positive effects of experience in terminal care on nursing home staff in Japan. AB - This study aimed to examine the psychological effects of terminal care experience on nursing home staff and analyze the differences between staff who are experienced and those who are inexperienced in providing terminal care. A mailed survey was conducted in 2007. A total of 37% (N = 72) of the participants had experience in terminal care in nursing homes. Analysis of variance (ANOVA) revealed that the professional efficacy (a subscale of the Maslach Burnout Inventory-General Survey [MBI-GS]) and tenure (duration of service) of the experienced staff were significantly higher than those of the inexperienced staff. The high professional efficacy noted among the experienced staff suggests that the provision of terminal care in nursing homes does not necessarily lead to burnout among caregivers and may in fact serve as an important motivational factor. PMID- 21242126 TI - The role of need for contraception in the evaluation of interventions to improve access to family-planning methods. AB - A nonrandomized experiment carried out in Jharkhand, India, shows how the effects of interventions designed to improve access to family-planning methods can be erroneously regarded as trivial when contraceptive use is utilized as dependent variable, ignoring women's need for contraception. Significant effects of the intervention were observed on met need (i.e., contraceptive use by women who need contraception) but not on contraceptive use (i.e., contraceptive use by women who may or may not need contraception). Met need captures the woman's success in overcoming barriers to access to family planning, whereas contraceptive use confounds this construct with risk of pregnancy and fertility desires. Exceptions to this rule are identified. PMID- 21242127 TI - New developments in understanding interfacial processes in turbulent flows. AB - Interfaces, across which fluid and flow properties change significantly, are a ubiquitous feature of most turbulent flows and are present within jets, plumes, homogeneous turbulence, oceans and planetary atmospheres. Even when the interfaces occupy a small volume fraction of the entire flow, they largely control processes such as entrainment and dissipation and can act as barriers to transport. This Theme Issue brings together some of the leading recent developments on interfaces in turbulence, drawing in many methodologies, such as experiments, direct number simulations, inverse methods and analytical modelling. PMID- 21242129 TI - Some characteristics of thin shear layers in homogeneous turbulent flow. AB - Tomographic particle image velocimetry measurements of homogeneous isotropic turbulence that have been made in a large mixing tank facility at Cambridge are analysed in order to characterize thin highly sheared regions that have been observed. The results indicate that such regions coincide with regions of high enstrophy, dissipation and stretching. Large velocity jumps are observed across the width of these regions. The thickness of the shear layers seems to scale with the Taylor microscale, as has been suggested previously. The results discussed here concentrate on examining individual realizations rather than statistics of these regions. PMID- 21242130 TI - Characteristics of the turbulent/non-turbulent interface of a non-isothermal jet. AB - The turbulent/non-turbulent interface of a jet is characterized by sharp jumps ('discontinuities') in the conditional flow statistics relative to the interface. Experiments were carried out to measure the conditional flow statistics for a non isothermal jet, i.e. a cooled jet. These experiments are complementary to previous experiments on an isothermal Re=2000 jet, where, in the present experiments on a non-isothermal jet, the thermal diffusivity is intermediate to the diffusivity of momentum and the diffusivity of mass. The experimental method is a combined laser-induced fluorescence/particle image velocimetry method, where a temperature-sensitive fluorescent dye (rhodamine 6G) is used to measure the instantaneous temperature fluctuations. The results show that the cooled jet can be considered to behave like a self-similar jet without any significant buoyancy effects. The detection of the interface is based on the instantaneous temperature, and provides a reliable means to detect the interface. Conditional flow statistics reveal the superlayer jump in the conditional vorticity and in the temperature. PMID- 21242131 TI - The role of coherent vortices near the turbulent/non-turbulent interface in a planar jet. AB - The role of coherent vortices near the turbulent/non-turbulent (T/NT) interface in a turbulent plane jet is analysed by a direct numerical simulation (DNS). The coherent vortices near the jet edge consist of large-scale vortical structures (LSVSs) maintained by the mean shear and intense vorticity structures (IVSs) created by the background fluctuating turbulence field. The radius of the LSVS is equal to the Taylor micro-scale R(lsvs)~lambda, while the radius of the IVS is of the order of the Kolmogorov micro-scale R(ivs)~eta. The LSVSs are responsible for the observed vorticity jump at the T/NT interface, being of the order of the Taylor micro-scale. The coherent vortices in the proximity of the T/NT interface are preferentially aligned with the tangent to the T/NT interface and are responsible for the viscous dissipation of kinetic energy near the T/NT interface and to the characteristic shape of the enstrophy viscous diffusion observed at that location. PMID- 21242132 TI - Jet sharpening by turbulent mixing. AB - Jets or localized strong currents in planetary atmospheres, as well as in the Earth's oceans, are often associated with sharp potential-vorticity gradients owing to the inherent balance exhibited by these flows. Here, we explore and quantify jet sharpening in a simple idealized single-layer quasi-geostrophic model on a mid-latitude beta-plane. The advantages of this idealization are that just two parameters control the flow development (the Rossby deformation length and the amplitude of the initial random flow perturbation), and that numerical experiments can comprehensively and accurately cover the parameter space. These experiments, carried out at unprecedented numerical resolution, reveal how an initially broad jet is sharpened, and the role played by coherent vortices in the vicinity of jets. PMID- 21242133 TI - Jupiter's zonal winds: are they bands of homogenized potential vorticity organized as a monotonic staircase? AB - The east-west striped pattern of clouds in Jupiter's weather layer is accompanied by a zonal flow containing 12 eastward-going jet streams alternating in latitude with westward-going jet streams. Based on theory, simulation and observations of the Earth's oceans and atmosphere, it is conjectured that Jupiter's weather layer is made of bands of constant potential vorticity (PV), where the interfaces between bands are at the latitudes of the maxima of the eastward-going jet streams. It is speculated that the mixing of PV on Jupiter is analogous to the mixing of salt in the ocean by the Phillips effect, which causes the salt density to form a monotonic 'staircase'. It is hypothesized that the PV in Jupiter's weather layer is also a staircase, decreasing from north to south. PV is a function of vorticity, as well as parameters with unknown values, e.g. the vertical stratification and the zonal flow beneath the observable weather layer. Therefore, these hypotheses cannot be tested directly. Using an atmospheric model that contains these unknown parameters, we solved the inverse problem and found values of the unknown parameters (and their uncertainties) that best fit Jovian observations. The unknown parameters influence how the zonal flow interacts with large vortices, e.g. the Great Red Spot (GRS; the largest and longest-lived Jovian vortex, centred at 23 degrees S) and the Oval BA (the second largest vortex, centred at 33 degrees S). Although we found that the PV distribution is approximately piecewise-constant and that the peaks of the eastward-going jet streams are at the latitudes of PV interfaces, there is also a PV interface at 20 degrees S, where there is a westward-going jet stream. We find that the zonal PV is not a monotonic staircase due to the 'backwards' interface at 20 degrees S. We show that this backwards interface is necessary to make the GRS nearly round, and that without that interface, the Red Spot would be highly elongated in the east-west direction and probably unstable. PMID- 21242134 TI - Long-range interactions in turbulence and the energy decay problem. AB - We discuss the long-range interactions that arise in homogeneous turbulence as a consequence of the Biot-Savart law. We note that, somewhat surprisingly, these long-range correlations are very weak in decaying, isotropic turbulence, and we argue that this should also be true for magnetohydrodynamic, rotating and stratified turbulence. If this is indeed the case, it is possible to make explicit predictions for the rate of decay of energy in these anisotropic systems, and it turns out that these predictions are consistent with the available numerical and experimental evidence. PMID- 21242135 TI - Interfaces and inhomogeneous turbulence. AB - A Euromech colloquium, on interfacial processes and inhomogeneous turbulence, was held in London on 28-30 June 2010. Papers were presented describing and analysing the influence of interfaces that separate turbulent/non-turbulent regions, between regions of contrasting fluid properties, or at the edge of boundaries. This paper describes a summary of the work presented, giving a snapshot of the current progress in this area, along with discussions about future research directions. PMID- 21242136 TI - Visual stability. AB - Our vision remains stable even though the movements of our eyes, head and bodies create a motion pattern on the retina. One of the most important, yet basic, feats of the visual system is to correctly determine whether this retinal motion is owing to real movement in the world or rather our own self-movement. This problem has occupied many great thinkers, such as Descartes and Helmholtz, at least since the time of Alhazen. This theme issue brings together leading researchers from animal neurophysiology, clinical neurology, psychophysics and cognitive neuroscience to summarize the state of the art in the study of visual stability. Recently, there has been significant progress in understanding the limits of visual stability in humans and in identifying many of the brain circuits involved in maintaining a stable percept of the world. Clinical studies and new experimental methods, such as transcranial magnetic stimulation, now make it possible to test the causal role of different brain regions in creating visual stability and also allow us to measure the consequences when the mechanisms of visual stability break down. PMID- 21242137 TI - Spatial constancy mechanisms in motor control. AB - The success of the human species in interacting with the environment depends on the ability to maintain spatial stability despite the continuous changes in sensory and motor inputs owing to movements of eyes, head and body. In this paper, I will review recent advances in the understanding of how the brain deals with the dynamic flow of sensory and motor information in order to maintain spatial constancy of movement goals. The first part summarizes studies in the saccadic system, showing that spatial constancy is governed by a dynamic feed forward process, by gaze-centred remapping of target representations in anticipation of and across eye movements. The subsequent sections relate to other oculomotor behaviour, such as eye-head gaze shifts, smooth pursuit and vergence eye movements, and their implications for feed-forward mechanisms for spatial constancy. Work that studied the geometric complexities in spatial constancy and saccadic guidance across head and body movements, distinguishing between self generated and passively induced motion, indicates that both feed-forward and sensory feedback processing play a role in spatial updating of movement goals. The paper ends with a discussion of the behavioural mechanisms of spatial constancy for arm motor control and their physiological implications for the brain. Taken together, the emerging picture is that the brain computes an evolving representation of three-dimensional action space, whose internal metric is updated in a nonlinear way, by optimally integrating noisy and ambiguous afferent and efferent signals. PMID- 21242138 TI - Neuronal mechanisms for visual stability: progress and problems. AB - How our vision remains stable in spite of the interruptions produced by saccadic eye movements has been a repeatedly revisited perceptual puzzle. The major hypothesis is that a corollary discharge (CD) or efference copy signal provides information that the eye has moved, and this information is used to compensate for the motion. There has been progress in the search for neuronal correlates of such a CD in the monkey brain, the best animal model of the human visual system. In this article, we briefly summarize the evidence for a CD pathway to frontal cortex, and then consider four questions on the relation of neuronal mechanisms in the monkey brain to stable visual perception. First, how can we determine whether the neuronal activity is related to stable visual perception? Second, is the activity a possible neuronal correlate of the proposed transsaccadic memory hypothesis of visual stability? Third, are the neuronal mechanisms modified by visual attention and does our perceived visual stability actually result from neuronal mechanisms related primarily to the central visual field? Fourth, does the pathway from superior colliculus through the pulvinar nucleus to visual cortex contribute to visual stability through suppression of the visual blur produced by saccades? PMID- 21242139 TI - Spatiotopic coding and remapping in humans. AB - How our perceptual experience of the world remains stable and continuous in the face of continuous rapid eye movements still remains a mystery. This review discusses some recent progress towards understanding the neural and psychophysical processes that accompany these eye movements. We firstly report recent evidence from imaging studies in humans showing that many brain regions are tuned in spatiotopic coordinates, but only for items that are actively attended. We then describe a series of experiments measuring the spatial and temporal phenomena that occur around the time of saccades, and discuss how these could be related to visual stability. Finally, we introduce the concept of the spatio-temporal receptive field to describe the local spatiotopicity exhibited by many neurons when the eyes move. PMID- 21242140 TI - Visual attention and stability. AB - In the present review, we address the relationship between attention and visual stability. Even though with each eye, head and body movement the retinal image changes dramatically, we perceive the world as stable and are able to perform visually guided actions. However, visual stability is not as complete as introspection would lead us to believe. We attend to only a few items at a time and stability is maintained only for those items. There appear to be two distinct mechanisms underlying visual stability. The first is a passive mechanism: the visual system assumes the world to be stable, unless there is a clear discrepancy between the pre- and post-saccadic image of the region surrounding the saccade target. This is related to the pre-saccadic shift of attention, which allows for an accurate preview of the saccade target. The second is an active mechanism: information about attended objects is remapped within retinotopic maps to compensate for eye movements. The locus of attention itself, which is also characterized by localized retinotopic activity, is remapped as well. We conclude that visual attention is crucial in our perception of a stable world. PMID- 21242141 TI - Remapping for visual stability. AB - Visual perception is based on both incoming sensory signals and information about ongoing actions. Recordings from single neurons have shown that corollary discharge signals can influence visual representations in parietal, frontal and extrastriate visual cortex, as well as the superior colliculus (SC). In each of these areas, visual representations are remapped in conjunction with eye movements. Remapping provides a mechanism for creating a stable, eye-centred map of salient locations. Temporal and spatial aspects of remapping are highly variable from cell to cell and area to area. Most neurons in the lateral intraparietal area remap stimulus traces, as do many neurons in closely allied areas such as the frontal eye fields the SC and extrastriate area V3A. Remapping is not purely a cortical phenomenon. Stimulus traces are remapped from one hemifield to the other even when direct cortico-cortical connections are removed. The neural circuitry that produces remapping is distinguished by significant plasticity, suggesting that updating of salient stimuli is fundamental for spatial stability and visuospatial behaviour. These findings provide new evidence that a unified and stable representation of visual space is constructed by redundant circuitry, comprising cortical and subcortical pathways, with a remarkable capacity for reorganization. PMID- 21242142 TI - Cortical mechanisms for trans-saccadic memory and integration of multiple object features. AB - Constructing an internal representation of the world from successive visual fixations, i.e. separated by saccadic eye movements, is known as trans-saccadic perception. Research on trans-saccadic perception (TSP) has been traditionally aimed at resolving the problems of memory capacity and visual integration across saccades. In this paper, we review this literature on TSP with a focus on research showing that egocentric measures of the saccadic eye movement can be used to integrate simple object features across saccades, and that the memory capacity for items retained across saccades, like visual working memory, is restricted to about three to four items. We also review recent transcranial magnetic stimulation experiments which suggest that the right parietal eye field and frontal eye fields play a key functional role in spatial updating of objects in TSP. We conclude by speculating on possible cortical mechanisms for governing egocentric spatial updating of multiple objects in TSP. PMID- 21242143 TI - Computational models of spatial updating in peri-saccadic perception. AB - Perceptual phenomena that occur around the time of a saccade, such as peri saccadic mislocalization or saccadic suppression of displacement, have often been linked to mechanisms of spatial stability. These phenomena are usually regarded as errors in processes of trans-saccadic spatial transformations and they provide important tools to study these processes. However, a true understanding of the underlying brain processes that participate in the preparation for a saccade and in the transfer of information across it requires a closer, more quantitative approach that links different perceptual phenomena with each other and with the functional requirements of ensuring spatial stability. We review a number of computational models of peri-saccadic spatial perception that provide steps in that direction. Although most models are concerned with only specific phenomena, some generalization and interconnection between them can be obtained from a comparison. Our analysis shows how different perceptual effects can coherently be brought together and linked back to neuronal mechanisms on the way to explaining vision across saccades. PMID- 21242144 TI - Right-hemispheric dominance for visual remapping in humans. AB - We review evidence showing a right-hemispheric dominance for visuo-spatial processing and representation in humans. Accordingly, visual disorganization symptoms (intuitively related to remapping impairments) are observed in both neglect and constructional apraxia. More specifically, we review findings from the intervening saccade paradigm in humans--and present additional original data- which suggest a specific role of the asymmetrical network at the temporo-parietal junction (TPJ) in the right hemisphere in visual remapping: following damage to the right dorsal posterior parietal cortex (PPC) as well as part of the corpus callosum connecting the PPC to the frontal lobes, patient OK in a double-step saccadic task exhibited an impairment when the second saccade had to be directed rightward. This singular and lateralized deficit cannot result solely from the patient's cortical lesion and, therefore, we propose that it is due to his callosal lesion that may specifically interrupt the interhemispheric transfer of information necessary to execute accurate rightward saccades towards a remapped target location. This suggests a specialized right-hemispheric network for visuo spatial remapping that subsequently transfers target location information to downstream planning regions, which are symmetrically organized. PMID- 21242145 TI - Position specificity of adaptation-related face aftereffects. AB - It has been shown that prolonged exposure to a human face leads to shape selective visual aftereffects. It seems that these face-specific aftereffects (FAEs) have multiple components, related to the adaptation of earlier and higher level processing of visual stimuli. The largest magnitude of FAE, using long-term adaptation periods, is usually observed at the retinotopic position of the preceding adaptor stimulus. However, FAE is also detected, to a smaller degree, at other retinal positions in a spatially invariant way and this component depends less on the adaptation duration. Several lines of evidences suggest that while the position-specific FAE involves lower level areas of the ventral processing stream, the position-invariant FAE depends on the activation of higher level face-processing areas and the fusiform gyrus in particular. In the present paper, we summarize the available behavioural, electrophysiological and neuroimaging results regarding the spatial selectivity of FAE and discuss their implications for the visual stability of object representations across saccadic eye movements. PMID- 21242146 TI - Vision and the representation of the surroundings in spatial memory. AB - One of the paradoxes of vision is that the world as it appears to us and the image on the retina at any moment are not much like each other. The visual world seems to be extensive and continuous across time. However, the manner in which we sample the visual environment is neither extensive nor continuous. How does the brain reconcile these differences? Here, we consider existing evidence from both static and dynamic viewing paradigms together with the logical requirements of any representational scheme that would be able to support active behaviour. While static scene viewing paradigms favour extensive, but perhaps abstracted, memory representations, dynamic settings suggest sparser and task-selective representation. We suggest that in dynamic settings where movement within extended environments is required to complete a task, the combination of visual input, egocentric and allocentric representations work together to allow efficient behaviour. The egocentric model serves as a coding scheme in which actions can be planned, but also offers a potential means of providing the perceptual stability that we experience. PMID- 21242147 TI - DHEA administration in poor responders. PMID- 21242148 TI - Acute increase in plasma D-dimer level in ovarian torsion: an experimental study. AB - BACKGROUND: Torsion of the ovary is a rare but serious cause of gynecologic surgical emergency. Specific laboratory markers that support the preoperative diagnosis of ovarian torsion are not currently available in the clinical routine. The aim of this study was to investigate the diagnostic value of plasma D-dimer level as an early indicator of ovarian torsion in an experimental rat ovarian torsion model. METHODS: Sixteen female adult Sprague-Dawley rats were used for this controlled experimental study. Eight rats in the sham operation group (Group I) underwent a surgical procedure similar to Group II but the ovary was not occluded. In Group II (eight rats), a torsion model was created by using atraumatic vascular clips just above and below the right ovary for a 2-h period of ischemia. Right ovaries were surgically removed at the end of the procedure in each group. Blood was sampled before and after operation to assess plasma D-dimer levels. The main outcome measure was ovarian histopathologic findings scores and plasma D-dimer levels. RESULTS: There was no significant difference in pre operative plasma D-dimer levels (0.5963 +/- 0.2047 mg/l in Group I, 0.6344 +/- 0.1348 mg/l in Group II, P = 0.815, Mann-Whitney U-test). However, mean plasma D dimer value for Group II was significantly higher than that in the control group (1.2267 +/- 0.3099 versus 0.6213 +/- 0.2346 mg/l, respectively, Mann-Whitney U test, P < 0.001), following 2 h of ovarian torsion. Ovarian tissue damage scores were also statistically significantly different among groups. CONCLUSIONS: If the observations made in a rat model are extended to humans, plasma D-dimer measurement may be a valuable parameter in the early diagnosis of ovarian torsion. PMID- 21242149 TI - Aberrant spindle structures responsible for recurrent human metaphase I oocyte arrest with attempts to induce meiosis artificially. AB - BACKGROUND In some couples, not all retrieved oocytes mature, even after prolonged in vitro culture. The underlying mechanisms are not known, although ionophore treatment may alleviate metaphase I (MI) arrest in some mouse strains. We attempted to induce first polar body (PB) extrusion and fertilization using assisted oocyte activation (AOA) after ICSI in maturation-resistant human MI oocytes. METHODS Four ICSI patients are described in this retrospective study. A pilot study tested the calcium ionophore ionomycin (10 uM) on donated MI oocytes from patients with a normal number of metaphase II (MII) oocytes. Subsequently, ionomycin was used to induce first PB extrusion in two patients showing maturation-resistant MI oocytes. AOA, by calcium injection and ionomycin exposure, was applied when mature oocytes were available. Oocytes were analysed by polarized microscopy and immunostaining. RESULTS Ionomycin induced the first PB extrusion in MI oocytes from patients with a normal number of retrieved MII oocytes, while extended in vitro culture failed to achieve the MII stage. Similarly, ionomycin induced first PB extrusion in one of two patients with recurrent maturation-resistant MI oocytes. Use of ICSI combined with AOA on MII oocytes matured in vitro or in vivo resulted in failed or abnormal fertilization with no further embryo cleavage potential. Highly abnormal spindle and chromosome configurations were observed in MI maturation-resistant oocytes, in contrast to control MI oocytes. CONCLUSIONS Ionophore induced first PB extrusion in MI oocytes from patients without maturation arrest but to a lower extent in maturation-resistant MI oocytes. Immunofluorescence staining and confocal analysis revealed, for the first time, highly abnormal spindle/chromosomal structures that may be responsible for this maturation arrest. PMID- 21242150 TI - Mood disorders in oocyte donor candidates: brief report and implications for future research. AB - BACKGROUND IVF, using donor oocytes, has become increasingly common. The donation procedure carries psychiatric risks, including depression, anxiety and rarely, psychosis, and this risk increases when there is a past history of psychiatric illness. We report on the psychiatric status, at intake assessment, of a group of candidate oocyte donors. METHODS The authors reviewed clinical records of 63 women continuously presenting to a University medical center for psychiatric evaluation as part of the screening process for oocyte donation. A board certified psychiatrist administered a structured clinical interview to candidate donors, and self-report measures were obtained from 28 women. RESULTS There was a significant discrepancy between psychiatric history of depression and current mood status, as measured by both clinical interview and psychometric self-report data. Nearly one-quarter of candidate donors (22%) reported a history of major depressive disorder; however, all candidate donors denied current mood disturbance on clinical interview, and mean Beck depression inventory and profile of mood states scores were lower than expected compared with psychometric norms (P < 0.0005), epidemiological data and the recurrent nature of depressive disorders. CONCLUSIONS Candidate donors may minimize psychiatric symptoms. Given the potential for ovarian stimulation protocols to induce or exacerbate mood symptoms, and the moderate heritability of mood disorders, careful evaluation of candidate donor affective disorder history is recommended. This evaluation should focus on sensitivity to mood destabilization during times of hormonal change. Measures that examine whether a candidate donor may have a tendency to present herself in an overly favorable manner, and/or a tendency to minimize symptoms, are recommended. PMID- 21242151 TI - Climate change and health in the urban environment: adaptation opportunities in Australian cities. AB - Urban populations are growing rapidly throughout the Asia-Pacific region. Cities are vulnerable to the health impacts of climate change because of their concentration of people and infrastructure, the physical (geographical, material, and structural) attributes of the built environment, and the ecological interdependence with the urban ecosystem. Australia is one of the most highly urbanized countries in the region and its already variable climate is set to become hotter and drier with climate change. Climate change in Australia is expected to increase morbidity and mortality from thermal stress, bacterial gastroenteritis, vector-borne disease, air pollution, flooding, and bushfires. The cost and availability of fresh water, food, and energy will also likely be affected. The more vulnerable urban populations, including the elderly, socioeconomically disadvantaged groups, and those with underlying chronic disease, will be most affected. Adaptation strategies need to address this underlying burden of disease and inequity as well as implement broad structural changes to building codes and urban design, and infrastructure capacity. In doing so, cities provide opportunities to realize "co-benefits" for health (eg, from increased levels of physical activity and improved air quality). With evidence that climate change is underway, the need for cities to be a focus in the development of climate adaptation strategies is becoming more urgent. PMID- 21242152 TI - Climate change, aeroallergens, natural particulates, and human health in Australia: state of the science and policy. AB - The objective of this article is to systematically review and assess what is known about the impacts of climate change on aeroallergens and other naturally derived particulates, and the associated human health impacts, and to examine responses to these in Australia, focusing on adaptation. Prior research was searched using several general and discipline-specific research databases. The review concludes that whereas there is little original research on the impacts of climate change on aeroallergens and other naturally derived particulates in Australia, or the human health consequences of these, research from overseas suggests that these impacts may be adverse and of considerable magnitude. More research is required to assess the impacts of climate change on these airborne particles and associated diseases in Australia and other parts of the Asia Pacific. There are important policy implications of this review. There is a need for enhanced monitoring of the atmospheric environment and associated health conditions in Australia. Education about climate change and human health in general, and air quality and related diseases specifically, is required for the community, health professionals, and others. Improvements are needed in the preparedness of infrastructure, such as health care facilities and early warning systems, particularly for aeroallergens, and all of these adaptive policy responses require further research. PMID- 21242153 TI - Climate change and Australian agriculture: a review of the threats facing rural communities and the health policy landscape. AB - Population health is a function of social and environmental health determinants. Climate change is predicted to bring significant alterations to ecological systems on which human health and livelihoods depend; the air, water, plant, and animal health. Agricultural systems are intrinsically linked with environmental conditions, which are already under threat in much of southern Australian because of rising heat and protracted drying. The direct impact of increasing heat waves on human physiology and survival has recently been well studied. More diffusely, increasing drought periods may challenge the viability of agriculture in some regions, and hence those communities that depend on primary production. A worst case scenario may herald the collapse of some communities. Human health impacts arising from such transition would be profound. This article summarizes existing rural health challenges and presents the current evidence plus future predictions of climate change impacts on Australian agriculture to argue the need for significant augmentation of public health and existing health policy frameworks. The article concludes by suggesting that adaptation to climate change requires planning for worst case scenario outcomes to avert catastrophic impacts on rural communities. This will involve national policy planning as much as regional-level leadership for rapid development of adaptive strategies in agriculture and other key areas of rural communities. PMID- 21242154 TI - Effectiveness of remote monitoring in the management of syncope and palpitations. AB - AIMS: Recently, the remote transmission of data detected by implantable loop recorders (ILRs) has become available. The aim of this study was to evaluate effectiveness and acceptance of remote monitoring in the clinical management of syncope and palpitations in patients with ILR. METHODS AND RESULTS: Consecutive patients implanted with ILR (Reveal DX/XT Medtronic, Inc.) and followed up by means of remote monitoring (CareLink((r))) were included. The patients were requested to transmit the data stored in the ILR every week, via the CareLink system, or more frequently during the first period. Patient acceptance of ILR was evaluated by means of a questionnaire concerning physical and mental components. Forty-seven patients (27 males, average age 64 +/- 19 years) were enrolled and followed up for 20 +/- 13 weeks. Thirty-two patients (68%) had at least one ECG recording of a true relevant event. The mean time from ILR implantation to the first true relevant ECG was 28 +/- 49 days, which was 71 +/- 17 days less than in the clinical practice of 3-monthly in-office follow-up examinations. Thirty-eight patients (81%) had at least one false arrhythmic event, mainly false asystole and false fast ventricular tachycardia. In the absence of Carelink transmission, at least one episode of memory saturation of ILR would have occurred in 21 patients (45%) that would have limited the diagnostic yield. Patient compliance was good even though one-fifth had some minor psychological concern regarding the ILR implant. CareLink was well accepted and judged easy to use. CONCLUSION: Remote monitoring enhances the diagnostic effectiveness of Reveal, limiting the risk of memory saturation due to the high number of false detections and reducing the time to diagnosis. Both ILR and CareLink were well accepted and well tolerated by the patients, as they were considered useful. PMID- 21242155 TI - Pacemaker lead laceration due to clavicular compression plate screw migration. AB - Laceration of pacemaker leads as a late complication after clavicular osteosynthesis is rare; however, the consequences can be fatal. We present the case of a 61-year-old gentleman with a history of right clavicular osteosynthesis using a compression plate, who 20 years later received a right pectoral dual chamber pacemaker. Twenty months after pacemaker implantation, a screw tip migration from the osteosynthesis caused laceration and dysfunction of the atrial lead. The osteosynthesis material was completely removed and atrial lead replaced. This case demonstrates that pacemaker systems in these rare patients should be placed on the contralateral side. PMID- 21242156 TI - Left ventricular lead implantation at a phrenic stimulation site is safe and effective. AB - AIMS: Phrenic stimulation (PS) is a major limiting factor for both left ventricular (LV) lead placement and cardiac resynchronization therapy (CRT) delivery. We have developed a protocol allowing for LV lead implantation at a PS site based on specific criteria regarding phrenic and LV acute capture thresholds. The present study examined long-term outcomes in patients treated using this protocol. METHODS AND RESULTS: A total of 211 consecutive patients underwent CRT device implantation. The procedure was successful in 201 patients. Leads were implanted at a PS site in 27 patients (PS patients) and a non-PS site in 174 patients (non-PS patients). Left ventricular leads were placed at a PS site only on the following conditions: no PS at <=3.5 V/0.5 ms, LV threshold <=1.5 V, and a PS/LV threshold ratio >4. The mean PS threshold decreased (5.1 +/- 1.6 vs. 2.8 +/- 1.6 V, P < 0.001) and the mean LV threshold remained stable (1.0 +/- 0.7 vs. 0.9 +/- 0.8 V, P = 0.6) in PS patients over the 16 +/- 9 month follow up. Only one PS patient experienced non-reprogrammable PS and required a re operation. Seven PS patients required very low LV channel output programming without the usual safety margin of twice the LV threshold amplitude or three times the pulse width. However, 100% LV capture was shown in those patients during daily activity. Non-reprogrammable PS occurred in 2 of the 174 non-PS patients. CONCLUSION: Our strategy for LV lead implantation at a PS site was found to result in long-term safe and effective outcomes. PMID- 21242157 TI - Quality of outpatient hospital care for children under 5 years in Afghanistan. AB - OBJECTIVE: To determine the quality of outpatient hospital care for children under 5 years in Afghanistan. DESIGN: Case management observations were conducted on 10-12 children under five selected by systematic random sampling in 31 outpatient hospital clinics across the country, followed by interviews with caretakers and providers. MAIN OUTCOME MEASURES: Quality of care defined as adherence to the clinical standards described in the Integrated Management of Childhood Illness. RESULTS: Overall quality of outpatient care for children was suboptimal based on patient examination and caretaker counseling (median score: 27.5 on a 100 point scale). Children receiving care from female providers had better care than those seen by male providers (OR: 6.6, 95% CI: 2.0-21.9, P = 0.002), and doctors provided better quality of care than other providers (OR: 2.7, 95% CI: 1.1-6.4, P = 0.02). The poor were more likely to receive better care in hospitals managed by non-governmental organizations than those managed by other mechanisms (OR: 15.2, 95% CI: 1.2-200.1, P = 0.04). CONCLUSIONS: Efforts to strengthen optimal care provision at peripheral health clinics must be complemented with investments at the referral and tertiary care facilities to ensure care continuity. The findings of improved care by female providers, doctors and NGO's for poor patients, warrant further empirical evidence on care determinants. Optimizing care quality at referral hospitals is one of the prerequisites to ensure service utilization and outcomes for the achievement of the Child health Millennium Development Goals for Afghanistan. PMID- 21242158 TI - Evidence-based practice: attitudes, knowledge and behaviour among allied health care professionals. AB - OBJECTIVE: To explore dieticians', occupational therapists' and physical therapists' attitudes, beliefs, knowledge and behaviour concerning evidence-based practice within a university hospital setting. DESIGN: Cross-sectional survey. SETTING: University hospital. PARTICIPANTS: All dieticians, occupational therapists and physical therapists employed at a Swedish university hospital (n = 306) of whom 227 (74%) responded. MAIN OUTCOME MEASURES: Attitudes towards, perceived benefits and limitations of evidence-based practice, use and understanding of clinical practice guidelines, availability of resources to access information and skills in using these resources. RESULTS: Findings showed positive attitudes towards evidence-based practice and the use of evidence to support clinical decision-making. It was seen as necessary. Literature and research findings were perceived as useful in clinical practice. The majority indicated having the necessary skills to be able to interpret and understand the evidence, and that clinical practice guidelines were available and used. Evidence based practice was not perceived as taking into account the patient preferences. Lack of time was perceived as the major barrier to evidence-based practice. CONCLUSIONS: The prerequisites for evidence-based practice were assessed as good, but ways to make evidence-based practice time efficient, easy to access and relevant to clinical practice need to be continuously supported at the management level, so that research evidence becomes linked to work-flow in a way that does not adversely affect productivity and the flow of patients. PMID- 21242159 TI - The Karen instruments for measuring quality of nursing care: construct validity and internal consistency. AB - BACKGROUND: Valid and reliable instruments for measuring the quality of care are needed for evaluation and improvement of nursing care. Previously developed and evaluated instruments, the Karen-patient and the Karen-personnel based on Donabedian's Structure-Process-Outcome triad (S-P-O triad) had promising content validity, discriminative power and internal consistency. OBJECTIVE: The objective of this study was to further develop the instruments with regard to construct validity and internal consistency. DESIGN AND SETTING: This prospective study was carried out in medical and surgical wards at a hospital in Sweden. A total of 95 patients and 120 personnel were included. METHODS: The instruments were tested for construct validity by performing factor analyses in two steps and for internal consistency using Cronbach's alpha coefficient. RESULTS: The first confirmatory factor analyses, with a pre-determined three-factor solution did not load well according to the S-P-O triad, but the second exploratory factor analysis with a six-factor solution appeared to be more coherent and the distribution of variables seemed to be logical. The reliability, i.e. internal consistency, was good in both factor analyses. CONCLUSIONS: The Karen-patient and the Karen-personnel instruments have achieved acceptable levels of construct validity. The internal consistency of the instruments is good. This indicates that the instruments may be suitable to use in clinical practice for measuring the quality of nursing care. PMID- 21242160 TI - Discrepant perceptions of communication, teamwork and situation awareness among surgical team members. AB - OBJECTIVE: To assess surgical team members' differences in perception of non technical skills. DESIGN: Questionnaire design. SETTING: Operating theatres (OTs) at one university hospital, three teaching hospitals and one general hospital in the Netherlands. PARTICIPANTS: Sixty-six surgeons, 97 OT nurses, 18 anaesthetists and 40 nurse anaesthetists. METHODS: All surgical team members, of five hospitals, were asked to complete a questionnaire and state their opinion on the current state of communication, teamwork and situation awareness at the OT. RESULTS: Ratings for 'communication' were significantly different, particularly between surgeons and all other team members (P <= 0.001). The ratings for 'teamwork' differed significantly between all team members (P <= 0.005). Within 'situation awareness' significant differences were mainly observed for 'gathering information' between surgeons and other team members (P < 0.001). Finally, 72-90% of anaesthetists, OT nurses and nurse anaesthetists rated routine team briefings and debriefings as inadequate. CONCLUSIONS: This study shows discrepancies on many aspects in perception between surgeons and other surgical team members concerning communication, teamwork and situation awareness. Future research needs to ascertain whether these discrepancies are linked to greater risk of adverse events or to process as well as systems failures. Establishing this link would support implementation and use of complex team interventions that intervene at multiple levels of the healthcare system. PMID- 21242161 TI - Is it enough to set national patient safety goals? An empirical evaluation in Taiwan. AB - OBJECTIVE: In 2004, the Taiwan Department of Health set the national patient safety goals. To date, however, there has been no evaluation of these goals. This study aimed to develop a method to evaluate the status of the national patient safety goals in Taiwan. DESIGN: A cross-sectional questionnaire surveys to measure achievements on Taiwan's national patient safety goals. This survey was also followed up with an onsite audit to ensure accuracy. SETTING: All hospitals in Taiwan. PARTICIPANTS: A total of 361 hospitals in Taiwan respond to questionnaire survey and 80 randomly selected hospitals for onsite audit. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Average scores on achievements of the national patient safety goals. RESULTS: Among the 516 hospitals to which the questionnaire was sent, 361 (70%) responded. A total of 80 hospitals were randomly selected according to geographic location and size for onsite audit. The results show that the longer the period of implementation, the higher the average scores on achievements of the goals. After stratified analysis by hospital size, the large hospitals were found to have a higher average score in every goal, especially in the new goals. Furthermore, in terms of the difference between self report results and the onsite audit, the score in the self-report was higher than the score given by experts upon onsite audit; however, they were similar. Most items were approximately the same in the self-report score and the onsite judgment, and those that differed were merely either one rank higher or lower. CONCLUSION: The self-report questionnaire combined with an onsite audit appears to be a promising approach for measuring scores on achievements of the national patient safety goals. The Department of Health could conduct this program annually to evaluate the progress and propose coping strategies. PMID- 21242162 TI - Preventable adverse drug events and their causes and contributing factors: the analysis of register data. AB - OBJECTIVE: To identify the causes and contributing factors of adverse drug events (ADEs) from the information management point of view. DESIGN: Retrospective study. Official register data were used to analyse preventable ADEs. The data were retrieved from the National Supervisory Authority for Welfare and Health and were analysed using qualitative content analysis, which was mainly based on the classification of ADEs. SETTING: National health care system. PARTICIPANTS: Patient complaints (n = 16) and official statements about causality of injuries or deaths (n = 41) in which ADEs were present from the years 2001-07. A total of 57 statements were reviewed, and the 67 ADEs that occurred in the statements were analysed. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Causes, contributing factors, types of errors. RESULTS: The majority of ADEs (81%) occurred in inpatients in general health care units (n = 26), in specialized health care units (n = 19) or in nursing homes (n = 10). ADEs occurring in the prescription, transcription (n = 23) and administration (n = 21) stages were the most frequent, and human factors were the leading class of underlying cause followed by the use of data. Error types relating to information management (n = 26) occurred in every phase of the medication use process. The majority of information management errors were related to documentation, copying data or contraindicated prescriptions, and they mainly occurred in the prescription and transcription (n = 11), and admission phases (n = 8). CONCLUSION: Information management processes need to be improved to improve medication safety. PMID- 21242163 TI - Prevention of venous thromboembolism and safe use of heparin in Spanish hospitals. AB - OBJECTIVE: To assess compliance with basic and actionable indicators in relation to prevention of venous thromboembolism (VTE) and safe use of heparin. DESIGN: We built, pilot tested and measured a set of evidence-based structure (existence of guidelines) and process (risk assessment for VTE, and dose adjustment to patient weight and renal function when prescribing heparin) indicators in a nation-wide random sample of 22 hospitals. Compliance with process indicators is estimated at national level and by groups of hospitals (stratified by size). At hospital level, compliance is assessed with Lot Quality Acceptance Sampling, for 85% compliance standard (alpha <= 0.05), 55% threshold (beta <= 0.10). Contents of existing guidelines are analyzed, and their influence on performance is assessed using logistic regression. SETTING: Acute care hospitals in Spain. INTERVENTIONS: None MAIN OUTCOME MEASURES: Problem identification through indicators assessment. RESULTS: Less than half of hospitals have guidelines and their contents are very variable and incomplete. No hospital complies with the standard for VTE prevention and only one for heparin dose adjustment. Nationally, VTE risk assessment is performed in 5.8% of patients (95% CI: 5.6-6.0), and heparin dose is explicitly adjusted in 17.5% (95% CI: 16.8-18.2). Performance is relatively higher in large hospitals and it is associated with the existence of guidelines for VTE prevention (OR: 8.3; 95% CI: 2.1-32.1). CONCLUSIONS: We have identified some actionable contributing factors to safety problems using evidence-based structure and process indicators. Explicit process design and key clinical interventions (risk assessment for VTE and heparin dose adjustment) should be addressed to improve the current situation. PMID- 21242164 TI - Ca(2+) wave probability is determined by the balance between SERCA2-dependent Ca(2+) reuptake and threshold SR Ca(2+) content. AB - AIMS: In this manuscript, we determined the roles of the sarcoendoplasmic reticulum Ca(2+) ATPase 2 (SERCA2) and the ryanodine receptor (RyR) in Ca(2+) wave development during beta-adrenergic stimulation. METHODS AND RESULTS: SERCA2 knockout mice (KO) were used 6 days after cardio-specific gene deletion, with left ventricular SERCA2a abundance reduced by 54 +/- 9% compared with SERCA2(flox/flox) controls (FF) (P < 0.05). Ca(2+) waves occurred in fewer KO than FF myocytes (40 vs. 68%, P < 0.05), whereas the addition of isoproterenol (ISO) induced waves in an equal percentage of myocytes (82 vs. 64%). SERCA2 dependent Ca(2+) reuptake was slower in KO (-ISO, KO vs. FF: 15.4 +/- 1.2 vs. 21.1 +/- 1.4 s(-1), P < 0.05), but equal during ISO (+ISO, KO vs. FF: 21.9 +/- 3.3 vs. 27.7 +/- 2.7 s(-1)). Threshold SR Ca(2+) content for wave development was lower in KO (-ISO, KO vs. FF: 126.6 +/- 10.3 vs. 159.3 +/- 7.1 umol/L, P < 0.05) and was increased by ISO only in FF (+ISO, KO vs. FF: 131.7 +/- 8.7 vs. 205.5 +/- 20.4 umol/L, P < 0.05). During ISO, Ca(2+)/calmodulin-dependent kinase II (CaMKII)-dependent phosphorylation of RyR in KO was 217 +/- 21% of FF (P < 0.05), and SR Ca(2+) leak indicated higher RyR open probability in KO. CaMKII inhibition decreased Ca(2+) spark frequency in KO by 44% (P < 0.05) but not in FF. Mathematical modelling predicted that increased Ca(2+) sensitivity of RyR in KO could account for increased Ca(2+) wave probability during ISO. CONCLUSIONS: In ventricular cardiomyocytes with reduced SERCA2 abundance, Ca(2+) wave development following beta-adrenergic stimulation is potentiated. We suggest that this is caused by a CaMKII-dependent shift in the balance between SERCA2-dependent Ca(2+) reuptake and threshold SR Ca(2+) content. PMID- 21242165 TI - Monte Carlo simulations of the electric field close to the body in realistic environments for application in personal radiofrequency dosimetry. AB - Personal dosemeters can play an important role in epidemiological studies and in radiofrequency safety programmes. In this study, a Monte Carlo approach is used in conjunction with the finite difference time domain method to obtain distributions of the electric field strength close to a human body model in simulated realistic environments. The field is a proxy for the response of an ideal body-worn electric field dosemeter. A set of eight environments were modelled based on the statistics of Rayleigh, Rice and log-normal fading to simulate outdoor and indoor multipath exposures at 450, 900 and 2100 MHz. Results indicate that a dosemeter mounted randomly within 10-50 mm of the adult or child body model (torso region) will on average underestimate the spatially averaged value of the incident electric field strength by a factor of 0.52 to 0.74 over the frequencies of 450, 900 and 2100 MHz. The uncertainty in results, assessed at the 95 % confidence level (between the 2.5th and 97.5th percentiles) was largest at 2100 MHz and smallest at 450 MHz. PMID- 21242166 TI - EURADOS self-sustained programme of intercomparisons for individual monitoring services. AB - Within EURADOS working group 2, a system for self-sustained intercomparisons for individual monitoring services for external radiation was developed. With the intercomparison results, the participants can show compliance within their quality management system, compare their results with those from other participants and develop plans for improvement of their system. The costs of the exercises are covered by the participants fees. In this programme, the first intercomparison exercise for whole-body dosemeters has been executed in 2008 with 62 participating dosimetry systems from participants across Europe. In general, film systems show the largest deviations, although the results of some participants indicate that it is possible to achieve results with a film system with similar quality as for thermoluminescence dosimetry (TLD) systems. A second intercomparison has been organised for extremity dosemeters in 2009. For 2010 it is planned to organise a second intercomparison for whole-body dosemeters. PMID- 21242167 TI - Monte Carlo determination of the conversion coefficients Hp(3)/Ka in a right cylinder phantom with 'PENELOPE' code. Comparison with 'MCNP' simulations. AB - This work has been performed within the frame of the European Union ORAMED project (Optimisation of RAdiation protection for MEDical staff). The main goal of the project is to improve standards of protection for medical staff for procedures resulting in potentially high exposures and to develop methodologies for better assessing and for reducing, exposures to medical staff. The Work Package WP2 is involved in the development of practical eye-lens dosimetry in interventional radiology. This study is complementary of the part of the ENEA report concerning the calculations with the MCNP-4C code of the conversion factors related to the operational quantity H(p)(3). In this study, a set of energy- and angular-dependent conversion coefficients (H(p)(3)/K(a)), in the newly proposed square cylindrical phantom made of ICRU tissue, have been calculated with the Monte-Carlo code PENELOPE and MCNP5. The H(p)(3) values have been determined in terms of absorbed dose, according to the definition of this quantity, and also with the kerma approximation as formerly reported in ICRU reports. At a low-photon energy (up to 1 MeV), the two results obtained with the two methods are consistent. Nevertheless, large differences are showed at a higher energy. This is mainly due to the lack of electronic equilibrium, especially for small angle incidences. The values of the conversion coefficients obtained with the MCNP-4C code published by ENEA quite agree with the kerma approximation calculations obtained with PENELOPE. We also performed the same calculations with the code MCNP5 with two types of tallies: F6 for kerma approximation and *F8 for estimating the absorbed dose that is, as known, due to secondary electrons. PENELOPE and MCNP5 results agree for the kerma approximation and for the absorbed dose calculation of H(p)(3) and prove that, for photon energies larger than 1 MeV, the transport of the secondary electrons has to be taken into account. PMID- 21242168 TI - Radon exposure assessment for underground workers: a case of Seoul Subway Police officers in Korea. AB - The objective of this study is the systematic and individual assessment of the annual effective dose due to inhaled radon for the Seoul Subway Police officers, Korea. The annual average radon concentrations were found to be in the range of 18.9-114 Bq.m(-3) in their workplaces. The total annual effective doses which may likely to be received on duty were assessed to be in the range of 0.41-1.64 mSv.y(-1). These were well below the recommended action level 10 mSv.y(-1) by ICRP. However, the effective doses were higher than subway station staff in Seoul, Korea. PMID- 21242169 TI - Nuclear interactions in heavy ion transport and event-based risk models. AB - The physical description of the passage of heavy ions in tissue and shielding materials is of interest in radiobiology, cancer therapy and space exploration, including a human mission to Mars. Galactic cosmic rays (GCRs) consist of a large number of ion types and energies. Energy loss processes occur continuously along the path of heavy ions and are well described by the linear energy transfer (LET), straggling and multiple scattering algorithms. Nuclear interactions lead to much larger energy deposition than atomic-molecular collisions and alter the composition of heavy ion beams while producing secondary nuclei often in high multiplicity events. The major nuclear interaction processes of importance for describing heavy ion beams was reviewed, including nuclear fragmentation, elastic scattering and knockout-cascade processes. The quantum multiple scattering fragmentation model is shown to be in excellent agreement with available experimental data for nuclear fragmentation cross sections and is studied for application to thick target experiments. A new computer model, which was developed for the description of biophysical events from heavy ion beams at the NASA Space Radiation Laboratory (NSRL), called the GCR Event Risk-Based Model (GERMcode) is described. PMID- 21242171 TI - Selenium status, thyroid volume, and multiple nodule formation in an area with mild iodine deficiency. AB - OBJECTIVE: The objective was to study the associations between serum selenium concentration and thyroid volume, as well as the association between serum selenium concentration and risk for an enlarged thyroid gland in an area with mild iodine deficiency before and after iodine fortification was introduced. Another objective was to examine the association between serum selenium concentration and prevalence of thyroid nodules. DESIGN: Cross-sectional study. METHODS: We studied participants of two similar cross-sectional studies carried out before (1997-1998, n=405) and after (2004-2005, n=400) introduction of iodine fortification. Serum selenium concentration and urinary iodine were measured, and the thyroid gland was examined by ultrasonography in the same subjects. Associations between serum selenium concentration and thyroid parameters were examined in multiple linear regression models or logistic regression models. RESULTS: Serum selenium concentration was found to be significantly, negatively associated with thyroid volume (P=0.006), and a low selenium status significantly increased the risk for thyroid enlargement (P=0.007). Furthermore, low serum selenium status had a tendency to increase the risk for development of multiple nodules (P=0.087). CONCLUSIONS: Low serum selenium concentration was associated with a larger thyroid volume and a higher prevalence of thyroid enlargement. PMID- 21242172 TI - Children, adolescents and their carers' expectations of child and adolescent mental health services (CAMHS). AB - BACKGROUND: The use of service users' views as performance indicators highlights the trend to make services more responsive to patients' needs. However, recent research indicates that there is a lack of clear understanding about specialist CAMHS and the outcomes that children, adolescents and their parents hope to achieve from treatment differ. AIMS: To explore children/young people's and parents/carers' expectations of CAMHS in Leicestershire, England. METHODS: Sixty children/young people and their parents/carers were asked to identify goals they want to achieve following contact with CAMHS. Qualitative thematic analysis in relation to Hoagwood's SFCES model (Symptoms, Functional, Consumer perspectives, Environment and Systems) was used. RESULTS: The question was answered by 46.7% of children and young people and 60% of carers. Overall, children, young people and parents/carers agreed that symptomatic modification and functional aspects were the most important goals. However, internalising items seemed more important for parents/carers than children and adolescents, who in contrast hoped for improvement in externalising factors. Goals outside the scope of CAMHS were also noted for both groups. CONCLUSION: Attention to children/young people and their parents/carers' expectations of services is needed to improve therapeutic relationships and engagement. Improvement in mental health literacy and practitioners' guidance is required to allow service users to set realistic and achievable treatment goals. PMID- 21242173 TI - Impact and costs of targeted recruitment of minorities to the National Lung Screening Trial. AB - BACKGROUND: To promote results in the National Lung Screening Trial (NLST) that are generalizable across the entire US population, a subset of NLST sites developed dedicated strategies for minority recruitment. PURPOSE: To report the effects of targeted strategies on the accrual of underrepresented groups, to describe participant characteristics, and to estimate the costs of targeted enrollment. METHODS: The 2002-2004 Tobacco Use Supplement was used to estimate eligible proportions of racial and ethnic categories. Strategic planning included meetings/conferences with key stakeholders and minority organizations. Potential institutions were selected based upon regional racial/ethnic diversity and proven success in recruitment of underrepresented groups. Seven institutions submitted targeted recruitment strategies with budgets. Accrual by racial/ethnic category was tracked for each institution. Cost estimates were based on itemized receipts for minority strategies relative to minority accrual. RESULTS: Of 18,842 participants enrolled, 1576 (8.4%) were minority participants. The seven institutions with targeted recruitment strategies accounted for 1223 (77.6%) of all minority participants enrolled. While there was a significant increase in the rate of minority accrual pre-implementation to post-implementation for the institutions with targeted recruitment (9.3% vs. 15.2%, p < 0.0001), there was no significant difference for the institutions without (3.5% vs. 3.8%, p = 0.46). Minority enrollees at the seven institutions tended to have less than a high school education, be economically disadvantaged, and were more often uninsured. These socio-demographic differences persisted at the seven institutions even after adjusting for race and ethnicity. The success of different strategies varied by institution, and no one strategy was successful across all institutions. Costs for implementation were also highly variable, ranging from $146 to $749 per minority enrollee. LIMITATIONS: Data on minority recruitment processes were not consistently kept at the individual institutions. In addition, participant responses via newspaper advertisements and the efforts of minority staff hired by the institutions could not be coded on Case Report Forms. CONCLUSIONS: Strategic efforts were associated with significant increases in minority enrollment. The greatest successes require that a priori goals be established based on eligible racial/ethnic proportions; the historical performance of sites in minority accrual should factor into the selection of sites; recruitment planning must begin well in advance of trial launch; and there must be endorsement by prominent representatives of the racial groups of interest. PMID- 21242174 TI - Diagnostics and epidemiology in ventilator-associated pneumonia. AB - Ventilator-associated pneumonia (VAP) represents a common nosocomial complication arising in the intensive care unit. Owing to concerns regarding the excess morbidity related to VAP, multiple interventions for preventing this syndrome exist. Despite controversy regarding the optimal diagnostic approach to VAP, clinicians now face many external pressures to try to reduce, if not eliminate, VAP. In fact, some organizations consider VAP an entirely preventable event. However, any dialog regarding the outcomes and burden of VAP must rest on an understanding and appreciation of both the diagnostic complexities surrounding VAP and the epidemiology of this condition. In addition, the issues of diagnostics and epidemiology are closely linked. The means employed for diagnosing VAP certainly affect the observed prevalence of VAP. Despite these concerns, several general themes emerge in the literature describing VAP epidemiology. First, VAP rates vary based on the diagnostic approach employed. Second, select cohorts of patients are at high risk for VAP, and patient case-mix clearly influences the epidemiology of VAP. Third, rates of VAP appear higher outside the US, irrespective of the diagnostic paradigm utilized. PMID- 21242175 TI - Electronic waste management cost: a scenario-based analysis for Greece. AB - Waste electrical and electronic equipment (WEEE) is recognized as a priority waste stream internationally, mostly due to their volume and hazardousness. This paper presents an analysis for the quantification of WEEE management cost for Greece, taking into consideration scenarios for reverse logistics network's development and WEEE volume scenarios. Transportation cost, which represents a major cost element for any reverse logistics network, is modelled with the use of mathematical programming, targeting towards the optimization of locations for the development of required intermediate storage infrastructures. Additionally, overall operational cost and recycling fees are estimated. PMID- 21242176 TI - Vinasses: characterization and treatments. AB - The final products of the ethanol industry are alcoholic beverages, industrial ethanol and biofuels. They are produced by the same production process, which includes fermentation and distillation of raw materials which come from plant biomass. At the end of the distillation process a waste effluent is obtained called vinasse or stillage. The direct disposal of stillages on land or in groundwater (rivers, streams or lakes), or even for the direct irrigation of crops, pollutes the environment due to their high organic contents, dissolved solids and many other compounds which are toxic or could be contaminants under certain environmental conditions. This work reviews the characterization of vinasses from different feedstock sources and the main treatments for conditioning the soluble solids of vinasses before their disposal. PMID- 21242177 TI - Hazardous medical waste generation in Greece: case studies from medical facilities in Attica and from a small insular hospital. AB - The accurate calculation of the unit generation rates and composition of medical waste generated from medical facilities is necessary in order to design medical waste treatment systems. In this work, the unit medical waste generation rates of 95 public and private medical facilities in the Attica region were calculated based on daily weight records from a central medical waste incineration facility. The calculated medical waste generation rates (in kg bed(-1) day( -1)) varied widely with average values at 0.27 +/- 113% and 0.24 +/- 121%, for public and private medical facilities, respectively. The hazardous medical waste generation was measured, at the source, in the 40 bed hospital of the island of Ikaria for a period of 42 days during a 6 month period. The average hazardous medical waste generation rate was 1.204 kg occupied bed(-1) day(-1) or 0.33 kg (official) bed( 1) day(-1). From the above amounts, 54% resulted from the patients' room (solid and liquid wastes combined), 24% from the emergency department (solid waste), 17% from the clinical pathology lab and 6% from the X-ray lab. In average, 17% of the total hazardous medical waste was solely infectious. Conclusively, no correlation among the number of beds and the unit medical waste generation rate could be established. Each hospital should be studied separately, since medical waste generation and composition depends on the number and type of departments/laboratories at each hospital, number of external patients and number of occupied beds. PMID- 21242178 TI - Community perceptions of human excreta as fertilizer in peri-urban agriculture in Ghana. AB - Although human excreta contain the necessary nutrients for plant growth, local authorities in Ghana spend huge sums of money to dispose them as waste. Reusing excreta for agricultural purposes saves expenditure for chemical fertilizers, improves soil fertility, reduces poverty and ensures food security. People's attitudes and perceptions about excreta vary between cultures and even within specific cultures. This study aimed to explore attitudes and perceptions among a peri-urban agricultural community towards sanitized human excreta and its use. The study adopted an exploratory design and collected data from 154 randomly selected households using questionnaires and focus group discussions. It was found that there is a general negative attitude to fresh excreta and the handling of it. However, the residents accept that excreta can be used as fertilizer, but they are not willing to use it on their own crops or consume crops fertilized with excreta. The study recommends open discussions in the community for a successful implementation of ecological sanitation. PMID- 21242179 TI - Appraisal of domestic solid waste generation, components, and the feasibility of recycling in Erbil, Iraq. AB - Solid waste collection and disposal are among the most vital services provided to about 700 770 residents of the city of Erbil in northern Iraq. As such, proper waste management systems that consider both the quantity and composition of domestic solid waste are strongly required to address the increasing amount of solid waste. Unfortunately, these essential data are not easily available. The present study sought to gather data on the quantity and composition of domestic solid waste collected from different quarters in Erbil, and the feasibility of recycling these wastes. The solid waste generation rate (GR), uncompacted density, and weight percentages of combustible and incombustible materials were determined based on the collected materials (i.e., food, plastic, paper, metal, glass and cloth). The results show that the average GR and uncompacted density were 0.654 kg capita(-1) day(-1) and 175.72 kg m(-3), respectively. The weight percentages of food, plastic, paper, metal, glass, and cloth as components of domestic solid waste were 79.34, 6.28, 5.9, 3.6, 3.42 and 1.45%, respectively. PMID- 21242180 TI - Solid waste management in tropical Asia: what can we learn from Bali? AB - Solid waste is a serious and growing problem thoughout tropical Asia. Waste management technologies and policies have not kept pace with the increase in waste production. The island of Bali in Indonesia is an atypical case in which both production and awareness of waste are relatively advanced. As such it is a useful case for exploring the wider problem and possible solutions. This article reviews the current state of solid waste management in Bali. It shows that there is a fundamental tension between large-scale industrial solutions and small-scale community-based ones, but that the most successful solutions to date are at intermediate scales. It argues that the reasons for this relative success are primarily social, cultural and political ones rather than technical or economic ones. PMID- 21242181 TI - Optimization of enzymatic hydrolysis for ethanol production by simultaneous saccharification and fermentation of wastepaper. AB - The present study investigated the development of high sugar production by optimization of an enzymatic hydrolysis process using both conventional and statistical methods, as well as the production of ethanol by the selected wastepaper source. Among four sources of pretreated wastepaper including office paper, newspaper, handbills and cardboard, office paper gave the highest values of cellulose (87.12%) and holocelluloses (89.07%). The effects of the amount of wastepaper, the pretreatment method and the type of enzyme on reducing sugar production from office paper were studied using conventional methods. The highest reducing sugar production (1851.28 ug L(-1); 37.03% conversion of glucose) was obtained from the optimal condition containing 40 mg of office paper, pretreated with stream explosion and hydrolysed with the combination of cellulase from Aspergillus niger and Trichoderma viride at the fixed loading rate of 20 FPU g( 1) sample. The effects of interaction of wastepaper amount and enzyme concentration as well as incubation time were studied by a statistical method using central composite design. The optimal medium composition consisted of 43.97 ug L(-1), 28.14 FPU g(-1) sample and 53.73 h of wastepaper, enzyme concentration and incubation time, respectively, and gave the highest amount of sugar production (2184.22 ug L(-1)) and percentage conversion of glucose (43.68%). The ethanol production from pretreated office paper using Saccharomyces cerevisiae in a simultaneous saccharification and fermentation process was 21.02 g L(-1) after 36 h of cultivation, corresponding to an ethanol volumetric production rate of 0.58 g ethanol L(-1) h(-1). PMID- 21242182 TI - Present and future status of gastric cancer surgery. AB - The type of surgery and the role of adjuvant therapies in the treatment of gastric cancer have changed in recent times. The treatment of gastric cancer with curative intent is moving away from standard D2 or more extensive surgery to a tailored approach depending on the stage of the disease. Data collected from extensive lymphadenectomy for all stages of gastric cancer have confirmed that some subsets of early gastric cancer are very low risk for nodal metastasis. This group of patients may benefit from resection by endoscopic or laparoscopic techniques and may also be suitable for function-preserving procedures. The extent of resection for gastric cancer has always excited debate. D2 gastrectomy was criticized for its higher mortality in the early European Phase III trials, but recent studies from Taiwan and Italy have shown that the procedure is safe when performed by experienced surgeons and has a survival benefit over D1 gastrectomy. The role of para-aortic lymph node dissection for nodes without apparent metastasis in advanced gastric cancer was assessed by a Phase III Japanese trial and showed no additional benefit over D2 resection. Radical gastric resections, involving resection of adjacent organs for direct tumor invasion result in higher rates of complications, and the role of multi-visceral resections has also been reevaluated. Effective adjuvant therapies for gastric cancer have been reported since the early part of 2000. Development of more effective adjuvant therapy combined with D2 resection should continue to improve survival in the future. PMID- 21242183 TI - Significance of primary tumor volume and T-stage on prognosis in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy. AB - OBJECTIVE: The aim of this study was to evaluate the effect of the primary tumor volume on prognosis in nasopharyngeal carcinoma treated with intensity-modulated radiation therapy. METHODS: Between August 2003 and April 2005, 112 patients with Stage I-IVB nasopharyngeal carcinoma treated by intensity-modulated radiation therapy were included. Measurement of the primary tumor volume was based on contrast-enhanced computed tomography scans before treatment. A receiver operating characteristics curve was used to determine the best cut-off point of the primary tumor volume. RESULTS: The mean primary tumor volume for 112 patients with nasopharyngeal carcinoma was 33.9 +/- 28.7 ml. Within the framework of UICC T-staging, all patients were divided into four groups according to the primary tumor volume. We call it the volume stage (V1 <15.65 ml, V2 = 15.65-24.25 ml, V3 = 24.25-50.55 ml and V4 >50.55 ml). The 5-year overall survival rates for V1, V2, V3 and V4 were 88.5, 83.3, 82.4 and 54.5% (P = 0.014), respectively. The cumulative survival curves for V1, V2 and V3 were very close, but clearly separated from V4. In addition, Cox proportional hazards regression model analysis showed that a primary tumor volume >50 ml was an independent risk factor for radiotherapy (risk ratio = 3.485, P = 0.025). CONCLUSIONS: This study demonstrated that the primary tumor volume had significantly impacted on the prognosis of patients with nasopharyngeal carcinoma. We proposed that the primary tumor volume should be considered as an additional stage indicator in the new revision of the clinical stage of nasopharyngeal carcinoma. PMID- 21242184 TI - Long-term survival in a patient with small-cell lung cancer undergoing hemodialysis who received multiple courses of chemotherapy. AB - The prognosis of small-cell lung cancer remains poor and it is speculated that small-cell lung cancer patients with end-stage renal failure undergoing hemodialysis have a poorer prognosis. In this article, we present a Japanese woman with extensive small-cell lung cancer with end-stage renal failure undergoing hemodialysis who received multiple courses of chemotherapy. Although she achieved long-term survival of more than 2 years, the last-line chemotherapy, consisting of irinotecan, induced grade 4 febrile neutropenia and her performance status deteriorated even with a reduced dose according to the analysis of UDP glucuronosyltransferase 1A1. We also conducted a pharmacokinetic analysis of irinotecan, the resulting values of which were much higher than in previous reports. Although further studies are needed, chemotherapy for small-cell lung cancer patients should not be withheld just because they are undergoing hemodialysis; however, chemotherapy should be performed more carefully because more severe toxicities can occur than expected. PMID- 21242186 TI - MicroRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia. AB - BACKGROUND: MicroRNA regulate the activity of protein-coding genes including those involved in hematopoietic cancers. The aim of the current study was to explore which microRNA are unique for seven different subtypes of pediatric acute lymphoblastic leukemia. DESIGN AND METHODS: Expression levels of 397 microRNA (including novel microRNA) were measured by quantitative real-time polymerase chain reaction in 81 cases of pediatric leukemia and 17 normal hematopoietic control cases. RESULTS: All major subtypes of acute lymphoblastic leukemia, i.e. T-cell, MLL-rearranged, TEL-AML1-positive, E2A-PBX1-positive and hyperdiploid acute lymphoblastic leukemia, with the exception of BCR-ABL-positive and 'B other' acute lymphoblastic leukemias (defined as precursor B-cell acute lymphoblastic leukemia not carrying the foregoing cytogenetic aberrations), were found to have unique microRNA-signatures that differed from each other and from those of healthy hematopoietic cells. Strikingly, the microRNA signature of TEL AML1-positive and hyperdiploid cases partly overlapped, which may suggest a common underlying biology. Moreover, aberrant down-regulation of let-7b (~70 fold) in MLL-rearranged acute lymphoblastic leukemia was linked to up-regulation of oncoprotein c-Myc (P(FDR)<0.0001). Resistance to vincristine and daunorubicin was characterized by an approximately 20-fold up-regulation of miR-125b, miR-99a and miR-100 (P(FDR)<=0.002). No discriminative microRNA were found for prednisolone response and only one microRNA was linked to resistance to L asparaginase. A combined expression profile based on 14 microRNA that were individually associated with prognosis, was highly predictive of clinical outcome in pediatric acute lymphoblastic leukemia (5-year disease-free survival of 89.4%+/-7% versus 60.8+/-12%, P=0.001). CONCLUSIONS: Genetic subtypes and drug resistant leukemic cells display characteristic microRNA signatures in pediatric acute lymphoblastic leukemia. Functional studies of discriminative and prognostically important microRNA may provide new insights into the biology of pediatric acute lymphoblastic leukemia. PMID- 21242187 TI - FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype. AB - BACKGROUND: Several genetic aberrations with prognostic impact in first-line therapy have been described in patients with acute myeloid leukemia and normal karyotype. However, little is known about the influence of these aberrations on outcome after relapse. This study aimed to identify clinical and molecular risk factors for patients with relapsed acute myeloid leukemia with normal karyotype. DESIGN AND METHODS: We analyzed 94 patients with acute myeloid leukemia and normal karyotype after first relapse for clinical and molecular risk factors for survival. All patients had received first-line treatment and follow-up within two prospective, multicenter trials. Leukemic blasts were analyzed at diagnosis for genetic aberrations in the FLT3, NPM1, CEBPA, WT1, IDH1 and IDH2 genes by polymerase chain reaction and/or direct sequencing. RESULTS: A second complete remission was achieved in 52% of patients who received re-induction therapy. The presence of an FLT3-internal tandem duplication, duration of first complete remission less than 6 months and age above the median of 47 years were associated with a significantly lower rate of second complete remission. The median survival after relapse was 11 months and the 6-year survival rate was 28%. In multivariate analysis, FLT3-internal tandem duplication and age above the median were the only independent negative prognostic factors for survival. The 6-year survival rate of patients with none of these factors was 56%, whereas it was significantly inferior in patients with one or both of these factors (15% and 6%, respectively). This was also true for patients who underwent allogeneic stem cell transplantation after relapse. CONCLUSIONS: FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with a normal karyotype. Patients with at least one of these risk factors have a dismal outcome and might be considered for investigational treatment approaches after relapse. (ClinicalTrials.gov Identifier: NCT00209833). PMID- 21242185 TI - The Ph-positive and Ph-negative myeloproliferative neoplasms: some topical pre clinical and clinical issues. AB - This review focuses on topical issues in the biology and treatment of the myeloproliferative neoplasms (MPNs). Studies in transgenic mice suggest that BCR ABL1 reduces the fraction of self-renewing 'leukemic' stem cells in the bone marrow but that some of these cells survive treatment with imatinib. This also seems to operate in humans. Data from models also strongly support the notion that JAK2(V617F) can initiate and sustain MPNs in mice; relevance to disease in humans is less clear. These data also support the hypothesis that level of JAK2(V617F) expression influences the MPN phenotype: higher levels favor erythrocytosis whereas lower levels favor thrombocytosis. Although TET2-mutations were thought to precede JAK2(V617F) in some persons with MPNs, it now appears that TET2 mutations may occur after JAK2(V617F). Further understanding of signal transduction pathways activated in chronic myeloid leukemia suggests various possible targets for new therapies including the WNT/beta catenin, notch and hedgehog pathways. Finally, the clinical role of the new JAK2- and BCR-ABL1 inhibitors is considered. Much further progress is likely in several of these areas soon. PMID- 21242188 TI - Membrane-bound IL-15 stimulation on peripheral blood natural kiler progenitors leads to the generation of an adherent subset co-expressing dendritic cells and natural kiler functional markers. AB - Human peripheral blood natural killer progenitors represent a flexible, heterogeneous population whose phenotype and function are controlled by their membrane-bound IL-15. Indeed, reciprocal membrane-bond IL-15 trans-presentation commits these cells into NK differentiation, while membrane-bound IL-15 stimulation with its soluble ligand (sIL-15Ralpha) triggers a reverse signal (pERK1/2 and pFAK) that modifies the developmental program of at least two subsets of PB-NKPs. This treatment generates: i) the expansion of an immature NK subset growing in suspension; ii) the appearance of an unprecedented adherent non proliferative subset with a dendritic morphology co-expressing marker, cytokines and functions typical of myeloid dendritic cells (CD1a(+)/BDCA1(+)/IL-12(+)) and NK cells (CD3-/NKp46(+)/ CD56(+)/IFNgamma(+)). The generation of these putative NK/DCs is associated to the rapid inhibition of negative regulators of myelopoiesis (the transcription factors STAT6 and GATA-3) followed by the transient upregulation of inducers of myeloid development, such as the transcription factors (PU.1, GATA-1) and the anti-apoptotic molecule (MCL-1). PMID- 21242189 TI - Polo-like kinase-1 as a novel target in neoplastic mast cells: demonstration of growth-inhibitory effects of small interfering RNA and the Polo-like kinase-1 targeting drug BI 2536. AB - BACKGROUND: In advanced systemic mastocytosis the response of neoplastic mast cells to conventional drugs is poor and the prognosis is bad. Current research is, therefore, attempting to identify novel drug targets in neoplastic mast cells. Polo-like kinase-1 is a serine/threonine kinase that plays an essential role in mitosis and has recently been introduced as a new target in myeloid leukemias and solid tumors. DESIGN AND METHODS: In the present study, we analyzed the expression and function of Polo-like kinase-1 in neoplastic mast cells in systemic mastocytosis. RESULTS: As determined by immunostaining, primary neoplastic mast cells as well as the human mast cell leukemia cell line HMC-1 displayed phosphorylated Polo-like kinase-1. In addition, neoplastic mast cells expressed Polo-like kinase-1 mRNA. Polo-like kinase-1-specific small interfering RNA induced apoptosis in neoplastic mast cells, whereas no effect was seen with a control small interfering RNA. BI 2536, a drug targeting Polo-like kinase-1, was found to inhibit proliferation in HMC-1 cells in a dose-dependent manner. BI 2536 also inhibited the growth of primary neoplastic mast cells and cells of the canine mastocytoma cell line C2. The growth-inhibitory effects of BI 2536 on neoplastic mast cells were found to be associated with mitotic arrest and subsequent apoptosis. Finally, BI 2536 was found to synergize with the KIT targeting kinase inhibitor midostaurin (PKC412) in inhibiting the growth of neoplastic mast cells. In control experiments, BI 2536 did not induce apoptosis in normal cultured mast cells. CONCLUSIONS: Collectively, our data show that Polo like kinase-1 is a potential therapeutic target in neoplastic mast cells. Targeting Polo-like kinase-1 may be an attractive pharmacological concept in the management of advanced systemic mastocytosis. PMID- 21242191 TI - Comparison of retrospective interviews and prospective diaries to facilitate fall reports among people with stroke. PMID- 21242192 TI - Vitamin E may affect the life expectancy of men, depending on dietary vitamin C intake and smoking. AB - BACKGROUND: antioxidants might protect against oxidative stress, which has been suggested as a cause of aging. METHODS: the Alpha-Tocopherol-Beta-Carotene (ATBC) Study recruited males aged 50-69 years who smoked at least five cigarettes per day at the baseline. The current study was restricted to participants who were followed up past the age of 65. Deaths were identified in the National Death Registry (1,445 deaths). We constructed Kaplan-Meier survival curves for all participants, and for four subgroups defined by dietary vitamin C intake and level of smoking. We also constructed Cox regression models allowing a different vitamin E effect for low and high age ranges. RESULTS: among all 10,837 participants, vitamin E had no effect on those who were 65-70 years old, but reduced mortality by 24% when participants were 71 or older. Among 2,284 men with dietary vitamin C intakes above the median who smoked less than a pack of cigarettes per day, vitamin E extended lifespan by 2 years at the upper limit of the follow-up age span. In this subgroup, the survival curves of vitamin E and no vitamin E participants diverged at 71 years. In the other three subgroups covering 80% of the participants, vitamin E did not affect mortality. CONCLUSIONS: this is the first study to strongly indicate that protection against oxidative stress can increase the life expectancy of some initially healthy population groups. Nevertheless, the lack of effect in 80% of this male cohort shows that vitamin E is no panacea for extending life expectancy. PMID- 21242193 TI - Beating-heart coronary artery bypass surgery with the help of mini extracorporeal circulation for very high-risk patients. AB - BACKGROUND: Left ventricle dysfunction and co-morbidities are responsible for a large number of complications after coronary artery bypass graft (CABG) surgery. The best strategy for these patients, including the use or not and type of extracorporeal circulation (ECC), the use of minimized ECC (MECC), or conventional ECC (CECC), remains unclear. The aim of the present study was to investigate the potential effect of on-pump beating-heart (OPBH) surgery with the help of MECC for CABG in patients with a high-risk EuroSCORE and to compare this strategy to three other different procedures, including OPCAB and MECC or CECC with cardiac arrest. METHODS: Patients were included if their EuroSCORE was strictly >" xbd="1427" xhg="1404" ybd="1477" yhg="1440"/>9. Four groups were retrospectively compared: an OPCAB, an OPBH, a MECC and a CECC group under cardiac arrest. RESULTS: 214 patients, mean age 74.26 +/- 8.5 years, 68.7% male, were operated. Mean EuroSCORE was 12.1 +/- 2.9, left ventricular (LV) function 37.4 +/- 12.3%, recent myocardial infarction (MI) 49.5%, renal failure 48.1%, chronic obstructive pulmonary disease (COPD) 42.2%, and peripheral vascular disease (PVD) 55.6%. Mean number of grafts per patient was 2.4 +/- 0.7. Our study showed that it was possible, in very high-risk patients, to carry out revascularisation with OPBH similar to that using MECC or CECC under cardiac arrest (p=NS). This technique reduces troponin release (3.23 vs 6.56, p<0.01), postoperative myocardial complications (2% vs 8%, p<0.01), cardiotonic drug prescription (15.7% vs 31.3%, p<0.01), ventilation time (4.57H vs 6.48H, p<0.01) and length of stay (LOS) in ICU (2.16 vs 2.53, p=0.02). CONCLUSION: The OPBH method seems to be safe, secure and effective in this population of very high risk patients, reducing early complications and multi-organ failure. OPBH surgery, combining MECC without aortic cross-clamping, makes it possible to perform complete revascularization and is an interesting alternative for CABG in high-risk patients. PMID- 21242190 TI - Chronic lymphocytic leukemia and autoimmunity: a systematic review. AB - Chronic lymphocytic leukemia is frequently associated with immune disturbances. The relationship between chronic lymphocytic leukemia and autoimmune cytopenias, particularly autoimmune hemolytic anemia and immune thrombocytopenia, is well established. The responsible mechanisms, particularly the role of leukemic cells in orchestrating the production of polyclonal autoantibodies, are increasingly well understood. Recent studies show that autoimmune cytopenia is not necessarily associated with poor prognosis. On the contrary, patients with anemia or thrombocytopenia due to immune mechanisms have a better outcome than those in whom these features are due to bone marrow infiltration by the disease. Moreover, fears about the risk of autoimmune hemolysis following single agent fludarabine may no longer be appropriate in the age of chemo-immunotherapy regimens. However, treatment of patients with active hemolysis may pose important problems needing an individualized and clinically sound approach. The concept that autoimmune cytopenia may precede the leukemia should be revisited in the light of recent data showing that autoimmune cytopenia may be observed in monoclonal B-cell lymphocytosis, a condition that can only be detected by using sensitive flow cytometry techniques. On the other hand, there is no evidence of an increased risk of non-hemic autoimmune disorders in chronic lymphocytic leukemia. Likewise, there is no epidemiological proof of an increased risk of chronic lymphocytic leukemia in patients with non-hemic autoimmunity. Finally, since immune disorders are an important part of chronic lymphocytic leukemia, studies aimed at revealing the mechanisms linking the neoplastic and the immune components of the disease should help our understanding of this form of leukemia. PMID- 21242194 TI - miR-20a targets BNIP2 and contributes chemotherapeutic resistance in colorectal adenocarcinoma SW480 and SW620 cell lines. AB - Chemotherapy is an important treatment for colorectal adenocarcinoma cancer; however, colorectal adenocarcinoma cells often develop resistance to chemotherapeutic drugs, leading to relapse and poor patient prognosis. The development of drug resistance is often a multifactor process, which involved several genes and cellular mechanisms. microRNAs are endogenous small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. In the present study, we investigated the possible role of microRNAs in regulating drug sensitivity of colorectal adenocarcinoma cells SW620 and SW480. Using microRNA expression arrays and quantitative reverse transcriptase (RT)-PCR, we found that SW620 cells exhibited elevated miR-20a expression compared with SW480 cells. In addition, these two cell lines displayed different sensitivities to the chemotherapeutic drugs fluorouracil, oxaliplatin, and teniposide. Modulation of miR-20a altered the sensitivity of SW620 and SW480 cells to these drugs; knockdown of miR-20a sensitized SW620 cells to chemotherapeutic agents, whereas overexpression of miR-20a in SW480 cells resulted in chemoresistance. Endogenous BNIP2 mRNA and BNIP2 protein levels were inversely related to miR-20a levels as detected by quantitative RT-PCR and western blot analysis. Fluorescence reporter assays showed a direct interaction between miR-20a and the BNIP2 3'UTR. Taken together, our findings suggested that miR-20a may play a role in colorectal adenocarcinoma cancer cell drug resistance and may be a therapeutic target against chemotherapy drug resistance in colorectal adenocarcinoma. PMID- 21242195 TI - Identification of novel SRY mutations and SF1 (NR5A1) changes in patients with pure gonadal dysgenesis and 46,XY karyotype. AB - Primary amenorrhea due to 46,XY disorders of sexual development (DSD) is complex with the involvement of several genes. Karyotyping of such patients is important as they may develop dysgerminoma and molecular analysis is important to identify the underlying mechanism and explore the cascade of events occurring during sexual development. The present study was undertaken for the genetic analysis in seven patients from five families presenting with primary amenorrhea and diagnosed with pure gonadal dysgenesis. Karyotyping was done and the patients were screened for underlying changes in SRY, desert hedgehog (DHH), DAX1 (NR0B1) and SF1 (NR5A1) genes, mutations in which are implicated in DSD. All the patients had 46,XY karyotype and two novel SRY mutations were found. In Family 1 (Patient S1.1) a missense mutation c.294G>A was seen, which results in a stop codon at the corresponding amino acid (Trp98X) and in Family 2 (Patients S2.1, S2.2 and S2.3), a missense mutation c.334G>A (Glu112Leu) was identified in all affected sisters. Both mutations were seen to occur in the conserved high mobility group box of SRY gene. One heterozygous change c.427G>A resulting in Glu143Lys in DHH gene in one patient and two heterozygous changes in the intronic region of SF1 (NR5A1) gene (c.244+80G>A+ c.1068-20C>T) in another patient were noted. One individual did not show changes in any of the genes analyzed. These results reiterate the importance of SRY and others, such as SF1 (NR5A1) and DHH, that are involved in the cascade of events leading to sex determination and also their role in sex reversal. PMID- 21242196 TI - Requirements for Vitamin D across the life span. AB - Adequate provision of vitamin D has been found, in ecological, cross-sectional, and observational studies, to be associated with reduction in the risk of many types of cancer, cardiovascular diseases (CVDs), autoimmune diseases, diabetes mellitus types 1 and 2, neurological disorders, several bacterial and viral infections, and adverse pregnancy outcomes in addition to the classical bone disorders of rickets and osteomalacia. Furthermore, investigators have found adequate repletion and increased intakes of vitamin D to be associated with reduced all-cause mortality rates. These findings have been supported by the limited number of properly conducted randomized controlled trials (RCTs) that used more than 400 IU/day of vitamin D. This review presents an overview of the role of vitamin D for the promotion of health for the more important vitamin D related diseases and conditions. Serum 25-hydroxyvitamin D concentrations of 30 60 ng/ml, corresponding to oral intake or skin production of 1,000-4,000 IU/day of vitamin D, appear necessary in adults for avoidance of hypovitaminosis D related ill health. People of all ages are encouraged to obtain more vitamin D from judicious exposure to sunshine (for ultraviolet B [UVB] irradiation) or from regular vitamin D supplements because dietary sources do not provide sufficient vitamin D to prevent any health risks other than those of rickets and osteomalacia. PMID- 21242197 TI - Predator satiation and recruitment in a mast fruiting monocarpic forest herb. AB - BACKGROUND AND AIMS: Cross-pollination and satiation of seed predators are often invoked to explain synchronous mast reproduction in long-lived plants. However, explanations for the synchronous death of parent plants are elusive. The roles of synchronous seeding and post-reproductive mortality were investigated in a perennial monocarpic herb (Isoglossa woodii) in coastal dune forest in South Africa. METHODS: Pre-dispersal seed predation and seed production were assessed by measuring fruit and seed set of inflorescences sprayed with insecticide or water and with no spray treatments. Seed predation was measured at different densities of I. woodii plants by monitoring removal rates of seed from the forest floor. The influence of adult plants on establishment of I. woodii seedlings was assessed by monitoring growth and survivorship of seedlings in caged and uncaged 1 * 1 m plots in understorey gaps and thickets. KEY RESULTS: Fruit and seed set were similar between spray treatments. An I. woodii stem produced 767.8 +/- 160.8 seeds (mean +/- s.e.) on dune crests and 1359.0 +/- 234.4 seeds on the foredune. Seed rain was greater on the foredune than in other topographic locations. Seed predation rates were 32 and 54 % on dune crests and in dune slacks, respectively, and decreased with seed abundance, number of inflorescences per stem and plant height. Seedling recruitment was greater beneath synchronously dying adult plants than in natural understorey gaps (no I. woodii). However, seedling growth rate beneath I. woodii mid-way through its life-cycle was less than in gaps, although survivorship was similar. CONCLUSIONS: The selective advantage of masting in I. woodii derives from satiation of both pre- and post-dispersal seed predators. In addition, post-seeding mortality of adult plants facilitates seedling establishment. Satiation of seed predators and the benefits of seedling establishment are strong drivers of the evolution of synchronous monocarpy in I. woodii. PMID- 21242198 TI - Comparison of changes in growth percentiles of US children on CDC 2000 growth charts with corresponding changes on WHO 2006 growth charts. AB - Longitudinal data with 37 964 length and weight measurements from 10 844 children who participated in the California Child Health and Development Study was used to compare the proportion of children aged <=24 months who crossed major percentile lines on the Centers for Disease Control and Prevention (CDC) 2000 growth charts with the percentage who crossed corresponding lines on the World Health Organization (WHO) 2006 growth charts. Percentage of children aged <=24 months who crossed at least 2 major percentile lines for length-for-age, weight-for-age, and weight-for-length according to CDC 2000 charts were compared with the percentage who did so according to WHO 2006 charts. The results from this analysis suggest that pediatricians who monitor children's growth on the basis of WHO 2006 growth charts may be more likely to refer children aged <6 months and less likely to refer those aged 6 to 12 months for further evaluation for failure to thrive. PMID- 21242199 TI - Pediatric adenovirus infection: relationship of clinical spectrum, seasonal distribution, and serotype. PMID- 21242200 TI - The prognostic value of obtaining a negative endoscopy in children with functional gastrointestinal disorders. AB - OBJECTIVES: Functional gastrointestinal disorders (FGIDs) are common. Diagnosis is based on the Rome criteria. It has been argued that performing endoscopies could help by providing reassurance and thus improve outcomes. This study was conducted to evaluate the impact of obtaining normal endoscopies in the outcome of children with FGIDs. METHODS: Medical records of patients diagnosed with abdominal pain related-FGIDs were reviewed. To assess the child's symptoms at follow-up, parents completed the Questionnaire on Pediatric Gastrointestinal Symptoms III (QPGS III). Primary outcome was presence of abdominal pain (AP) and secondary outcomes were AP severity. RESULTS: A total of 301 patients were diagnosed with abdominal pain-related FGIDs. Overall, 62.6% reported persistence of AP and 37.4% were asymptomatic at follow-up. Among patients with endoscopies, 61% reported AP. Among patients without endoscopies, 64% were symptomatic (P = .76). AP frequency, AP intensity, and child's disability were similar in those with and without endoscopies. CONCLUSION: The study does not suggest that a negative endoscopy improves the outcome of children with FGIDs. PMID- 21242201 TI - Newborn female with a midline perineal defect. PMID- 21242202 TI - Fluoride content of water used to reconstitute infant formula. AB - OBJECTIVE: To assess the fluoride content of water used to reconstitute infant formula by a Latino population living in the Indianapolis, Indiana, area. BACKGROUND: Negligible as well as excessive fluoride can be detrimental to oral health. Estimates of fluoride intake and exposure for individuals may aid in the determination of their risk for developing dental fluorosis or caries. METHODS: Interviews were conducted to determine brands of bottled water used to reconstitute infant formula. Identified brands were analyzed for fluoride concentration. RESULTS: Of the 458 samples tested (from 20 brands), fluoride concentration ranged from 0.006 to 0.740 MUg/mL. All brands but one had fluoride concentration less than 0.7 MUg/mL, with 16 brands having less than 0.22 MUg/mL. Most bottled waters analyzed in the study comply with the American Dental Association recommendation to prevent fluorosis. Comparisons made demonstrated that only waters targeted for infants and that are fluoridated do not comply with recent American Dental Association recommendations. PMID- 21242203 TI - Principal component analysis based methods in bioinformatics studies. AB - In analysis of bioinformatics data, a unique challenge arises from the high dimensionality of measurements. Without loss of generality, we use genomic study with gene expression measurements as a representative example but note that analysis techniques discussed in this article are also applicable to other types of bioinformatics studies. Principal component analysis (PCA) is a classic dimension reduction approach. It constructs linear combinations of gene expressions, called principal components (PCs). The PCs are orthogonal to each other, can effectively explain variation of gene expressions, and may have a much lower dimensionality. PCA is computationally simple and can be realized using many existing software packages. This article consists of the following parts. First, we review the standard PCA technique and their applications in bioinformatics data analysis. Second, we describe recent 'non-standard' applications of PCA, including accommodating interactions among genes, pathways and network modules and conducting PCA with estimating equations as opposed to gene expressions. Third, we introduce several recently proposed PCA-based techniques, including the supervised PCA, sparse PCA and functional PCA. The supervised PCA and sparse PCA have been shown to have better empirical performance than the standard PCA. The functional PCA can analyze time-course gene expression data. Last, we raise the awareness of several critical but unsolved problems related to PCA. The goal of this article is to make bioinformatics researchers aware of the PCA technique and more importantly its most recent development, so that this simple yet effective dimension reduction technique can be better employed in bioinformatics data analysis. PMID- 21242204 TI - Pharmacists state ambition to expand their role in community health. PMID- 21242208 TI - HFEA canvasses on whether to increase compensation to egg and sperm donors. PMID- 21242209 TI - Ethics and effectiveness: rationing healthcare by thresholds of minimum effectiveness. PMID- 21242210 TI - Community services for people who have had a stroke are "patchy," says watchdog. PMID- 21242211 TI - New cancer strategy for England focuses on earlier diagnosis. PMID- 21242212 TI - Cross-border healthcare in the European Union: clarifying patients' rights. PMID- 21242213 TI - Decline in US abortion rate has stalled, report says. PMID- 21242214 TI - Illinois assembly votes to abolish death penalty, but governor hesitates. PMID- 21242216 TI - Clustering of risk factors: a simple method of detecting cardiovascular disease in youth. AB - OBJECTIVE: Cardiovascular risk assessment is an accepted practice in adults and correlates with early changes in carotid structure and function. Its clinical use in pediatrics is less common. We sought to determine whether a simple method of clustering cardiovascular risks could detect early atherosclerotic changes in youth. In addition, we compared risk clustering with the accepted Patholobiological Determinants of Atherosclerosis in Youth score to assess its utility for predicting early vascular disease. PATIENTS AND METHODS: We collected demographic, anthropometric, laboratory, and vascular measures in a cross sectional study. The study population (n = 474; mean age: 18 years) was divided into low-risk (0-1) or high-risk (>= 2) groups on the basis of the number of cardiovascular risk factors present at evaluation. Group differences and vascular outcomes were compared. General linear models were used to compare clustering cardiovascular risks with the Patholobiological Determinants of Atherosclerosis in Youth score. RESULTS: The high-risk group had higher vascular thickness and stiffness compared with the low-risk group (P < .05). Regression models found that clustering cardiovascular risks is associated with abnormal vascular structure and function after adjustment for age, race, and gender. The Patholobiological Determinants of Atherosclerosis in Youth score also is associated with abnormal vascular structure and function but with lower R(2) values (P < .05). CONCLUSIONS: Cardiovascular risk clustering is a reliable tool for assessing abnormal vascular function. Its simplicity, compared with the Patholobiological Determinants of Atherosclerosis in Youth score, provides an advantageous tool for the practicing clinician to identify those youth who are at higher risk for early cardiovascular disease. PMID- 21242217 TI - Cigarette advertising and teen smoking initiation. AB - OBJECTIVE: To test the specificity of the association between cigarette advertising and adolescent smoking initiation. METHODS: A longitudinal survey of 2102 adolescents, aged 10 to 17 years at baseline, who never smoked was conducted by using masked images of 6 cigarette advertisements and 8 other commercial products with all brand information digitally removed. The exposure variable was a combination of contact frequency and cued recall of brands for cigarette and other advertisements. Multilevel mixed-effects Poisson regressions were used to assess smoking initiation 9 months after the baseline assessment as a function of cigarette-advertisement exposure, other advertisement exposure, and baseline covariates. RESULTS: Thirteen percent (n = 277) of students initiated smoking during the observation period. Although the incidence of trying smoking was associated with increased exposure to cigarette advertisements (10% in the low, 12% in the medium, and 19% in the high cigarette-advertisement exposure tertile initiated smoking), exposure to other advertisements did not predict smoking initiation. Compared with low exposure to cigarette advertisements, high exposure remained a significant predictor of adolescent smoking initiation after controlling for baseline covariates (adjusted relative risk: 1.46 [95% confidence interval: 1.08-1.97]; P < .05). CONCLUSIONS: Our results support the notion of a content-related effect of cigarette advertisements and underlines the specificity of the relationship between tobacco marketing and teen smoking; exposure to cigarette advertisements, but not other advertisements, is associated with smoking initiation. PMID- 21242218 TI - A U-shaped association between intensity of Internet use and adolescent health. AB - OBJECTIVE: To examine the relationship between different Internet-use intensities and adolescent mental and somatic health. METHODS: Data were drawn from the 2002 Swiss Multicenter Adolescent Survey on Health, a nationally representative survey of adolescents aged 16 to 20 years in post-mandatory school. From a self administered anonymous questionnaire, 3906 adolescent boys and 3305 girls were categorized into 4 groups according to their intensity of Internet use: heavy Internet users (HIUs; >2 hours/day), regular Internet users (RIUs; several days per week and <= 2 hours/day), occasional users (<= 1 hour/week), and non-Internet users (NIUs; no use in the previous month). Health factors examined were perceived health, depression, overweight, headaches and back pain, and insufficient sleep. RESULTS: In controlled multivariate analysis, using RIUs as a reference, HIUs of both genders were more likely to report higher depressive scores, whereas only male users were found at increased risk of overweight and female users at increased risk of insufficient sleep. Male NIUs and female NIUs and occasional users also were found at increased risk of higher depressive scores. Back-pain complaints were found predominantly among male NIUs. CONCLUSIONS: Our study provides evidence of a U-shaped relationship between intensity of Internet use and poorer mental health of adolescents. In addition, HIUs were confirmed at increased risk for somatic health problems. Thus, health professionals should be on the alert when caring for adolescents who report either heavy Internet use or very little/none. Also, they should consider regular Internet use as a normative behavior without major health consequence. PMID- 21242219 TI - Professionalism expectations seen through the eyes of resident physicians and patient families. AB - BACKGROUND: Resident physicians and patient families have not traditionally been involved in setting expectations for professional behavior by physicians. OBJECTIVE: To elicit and compare prioritized lists of attributes and behaviors of physician professionalism formulated by residents and patient families. METHODS/DESIGN: We used qualitative and quantitative methods to identify and compare prioritized perceptions of important attributes and behaviors of physician professionalism among residents and families of patients. We conducted 3 resident focus groups, 1 for residents in each resident-training year (postgraduate years 1, 2, and 3), and elicited attributes and behaviors the residents associated with physician professionalism by using free-listing and nominal-group techniques. Family perspectives of the attributes/behaviors of physician professionalism were elicited by using semistructured interviews of consecutive families with a child who was admitted to the hospital. All results were transcribed, and common themes were identified. RESULTS: Fifty-eight residents (78% of the total in the program) and 40 families participated. Similar themes arose from all 3 resident focus groups, which prioritized tactfulness, support of team members, respectfulness, good communication, and humanism. Residents also provided specific behavioral strategies to put these attributes into practice, such as avoiding jokes about patients and using patient names when addressing and discussing them. Patient families most frequently cited good communication, caring, knowledge, skill, honesty, and attitude. Communication and humanism were aspects consistently endorsed by both residents and patient families. CONCLUSIONS: There was important overlap in the attributes of professionalism generated and prioritized by resident physicians and patient families, although only residents identified ways that health care providers should interact with each other. This novel approach to identifying professionalism attributes provides opportunities for curriculum improvement. PMID- 21242220 TI - Risk stratification of children being evaluated for intussusception. AB - CONTEXT: Intussusception is the most common cause of intestinal obstruction in young children, and delayed diagnosis may lead to bowel perforation. OBJECTIVE: To determine predictive clinical criteria and develop a decision tree to risk stratify children with possible intussusception. DESIGN/METHODS: This is a prospective observational cohort study of children aged 1 month to 6 years who presented with possible intussusception. A data-collection form was completed before knowledge of any advanced imaging. Univariate analysis was performed, and decision trees were developed using recursive partitioning. RESULTS: In the study, 310 patients were enrolled, including 38 (12.3%) with intussusception. The median age was 21.1 months and 61% were male. Univariate predictors of intussusception included age older than 6 months (P = 0.04), male gender (P = .007), history of lethargy (P = .001), and abnormal plain x-ray (P = .0001). Multivariate analysis through recursive partitioning identified decision trees (with and without the result of a plain abdominal x-ray) and allowed identification of patients at low risk. The decision tree based on the results of an abdominal x-ray (negative or positive), age (<= 5 or >5 months), diarrhea (present or absent), and bilious emesis (present or absent) had the best test performance (sensitivity: 97% [95% confidence interval (CI): 86-100]; negative predictive value: 99% [95% CI: 93-100]; negative likelihood ratio: 0.08 [95% CI: 0.01-0.6]). CONCLUSIONS: Among children who were being evaluated for intussusception, we prospectively determined clinical criteria and developed a decision tree to risk-stratify children with possible intussusception. PMID- 21242221 TI - Pathological video game use among youths: a two-year longitudinal study. AB - OBJECTIVES: We aimed to measure the prevalence and length of the problem of pathological video gaming or Internet use, to identify risk and protective factors, to determine whether pathological gaming is a primary or secondary problem, and to identify outcomes for individuals who become or stop being pathological gamers. METHODS: A 2-year, longitudinal, panel study was performed with a general elementary and secondary school population in Singapore, including 3034 children in grades 3 (N = 743), 4 (N = 711), 7 (N = 916), and 8 (N = 664). Several hypothesized risk and protective factors for developing or overcoming pathological gaming were measured, including weekly amount of game play, impulsivity, social competence, depression, social phobia, anxiety, and school performance. RESULTS: The prevalence of pathological gaming was similar to that in other countries (~9%). Greater amounts of gaming, lower social competence, and greater impulsivity seemed to act as risk factors for becoming pathological gamers, whereas depression, anxiety, social phobias, and lower school performance seemed to act as outcomes of pathological gaming. CONCLUSION: This study adds important information to the discussion about whether video game "addiction" is similar to other addictive behaviors, demonstrating that it can last for years and is not solely a symptom of comorbid disorders. PMID- 21242222 TI - Getting beyond "Good job": how to give effective feedback. AB - This article is the fourth in a series by the Council on Medical Student Education in Pediatrics (COMSEP) reviewing the critical attributes and skills of superb clinical teachers. The previous article in this series reviewed the vital importance of direct observation of students.(1) The purpose of this article is to describe how to use the information gained from the direct observation, namely the role of feedback. Although too often used interchangeably, encouragement, evaluation, and feedback are quite distinct. Encouragement (eg, "good job!") is supportive but does nothing to improve the learner's skills. Evaluation is summative and is the final judgment of the learner's performance. Feedback, however, is designed to improve future performance. This article focuses on feedback-what it is, why it is important, some of the barriers to effective feedback, and how to give helpful feedback. PMID- 21242223 TI - Maternal resolution of grief after preterm birth: implications for infant attachment security. AB - OBJECTIVE: This study explored the association between mothers' unresolved grief regarding their infant's preterm birth and infant-mother attachment security. We hypothesized that mothers with unresolved grief would be more likely to have insecurely attached infants at 16 months and that this association would be partially mediated by maternal interaction quality. METHODS: This longitudinal study focused on 74 preterm infants (age of <36 weeks) and their mothers who were part of a larger study of high-risk infants. The present analysis included assessment of neonatal and socioeconomic risks at NICU discharge; maternal depression, Reaction to Preterm Birth Interview findings, and quality of parenting at a postterm age of 9 months; and infant-mother attachment at postterm age of 16 months. Associations among findings of grief resolution with the Reaction to Preterm Birth Interview, quality of parenting interactions, and attachment security were explored by using relative risk ratios and logistic and multivariate regression models. RESULTS: The relative risk of developing insecure attachment when mothers had unresolved grief was 1.59 (95% confidence interval: 1.03-2.44). Controlling for covariates (adjusted odds ratio: 2.94), maternal feelings of resolved grief regarding the preterm birth experience were associated with secure infant-mother attachment at 16 months. Maternal grief resolution and interaction quality were independent predictors of attachment security. CONCLUSION: Maternal grief resolution regarding the experience of preterm birth and the quality of maternal interactions have important implications for emerging attachment security for infants born prematurely. PMID- 21242224 TI - Impact of bisphosphonates on survival for patients with Duchenne muscular dystrophy. AB - OBJECTIVE: In this article we describe the association of bisphosphonate therapy on survival within a regional cohort of patients with Duchenne muscular dystrophy (DMD) who received steroid therapy and were managed in a single center. PATIENTS AND METHODS: The records of all patients with confirmed DMD who were born between 1963 and 2006 and who had received at least 1 year of steroid therapy were reviewed from birth until they reached the study end points (death, loss to follow-up, or the last follow-up was in 2009). A survival analysis was used to account for the variable follow-up duration within this cohort. RESULTS: Forty four boys from this cohort with DMD were exposed to continuous steroid use. Bisphosphonate therapy was initiated for 16 patients (36%) between 1997 and 2007 at a median age of 12.5 years (range: 7-23 years). At the time of the last follow up in 2009, 13 patients had died (30%) at a median age of 16 years (range: 14-27 years). Survival curves demonstrate that the prescription of bisphosphonates was associated with a significant improvement in survival rate (P = .005, log-rank test). Furthermore, a possible therapy-duration effect could be shown for bisphosphonate use (P = .007, log-rank test). CONCLUSIONS: The treatment of patients with DMD with steroids and bisphosphonates seems to be associated with significantly improved survival compared with treatment with steroids alone. PMID- 21242225 TI - Improving care for children with sickle cell disease/acute chest syndrome. AB - BACKGROUND: Acute chest syndrome (ACS) is a leading cause of hospitalization and death of children with sickle cell disease (SCD). An evidence-based ACS/SCD guideline was established to standardize care throughout the institution in February 2008. However, by the summer of 2009 use of the guideline was inconsistent, and did not seem to have an impact on length of stay. As a result, an implementation program was developed. OBJECTIVE: This quality-improvement project evaluated the influence of the development and implementation of a clinical practice guideline for children with SCD with ACS or at risk for ACS on clinical outcomes. METHODS: Clinical outcomes of 139 patients with SCD were evaluated before and after the development of the implementation program. Outcomes included average length of stay, number of exchange transfusions, average cost per SCD admission, and documentation of the clinical respiratory score and pulmonary interventions. RESULTS: Average length of stay decreased from 5.8 days before implementation of the guideline to 4.1 days after implementation (P = .033). No patients required an exchange transfusion. Average cost per SCD admission decreased from $30 359 before guideline implementation to $22 368. Documentation of the clinical respiratory score increased from 31.0% before implementation to 75.5%, which is an improvement of 44.5% (P < .001). Documentation of incentive spirometry and positive expiratory pressure increased from 23.3% before implementation to 50.4%, which is an improvement of 27.1% (P < .001). CONCLUSIONS: Implementation of a guideline for children with SCD with ACS or at risk for ACS improved outcomes for patients with SCD. PMID- 21242226 TI - Nonurgent emergency-department care: analysis of parent and primary physician perspectives. AB - OBJECTIVE: To better understand parental decisions to seek care for their children and physician perceptions of parents' decisions to seek nonurgent emergency-department care. PATIENTS AND METHODS: In-depth interviews of 26 parents of children and 20 primary care physicians of the same children presenting for nonurgent care at a children's hospital emergency department were completed. Parent accounts of events that preceded the emergency-department visit were coded and qualitatively analyzed for themes. Physician evaluations of the accounts of events and parental decisions were ascertained through interviews with primary care physicians, who also described their practice characteristics. The parent/physician analyses allowed for an investigation of all aspects of the child's care and were designed to reveal differences between parent and physician beliefs. RESULTS: Parents believed that they acted appropriately, and physicians approved of parents' decisions. Four main themes emerged: (1) immediate reassurance that their children are safe from harm is critical to parents' decisions; (2) primary care offices lack specific tests and treatments that parents and physicians believe may be necessary, regardless of whether they are actually needed; (3) discrepancies exist between physician and parent perceptions of adequate communication and access; and (4) nonurgent emergency-department visits are not perceived as a significant enough breach in continuity of care by physicians and parents to warrant any concern. CONCLUSIONS: When individual interviews were evaluated, neither parents nor primary care physicians saw nonurgent emergency-department visits as a significant enough problem to warrant any change in physician care practices or parent care-seeking behavior. PMID- 21242227 TI - Fulminant hepatitis after 10 days of acetaminophen treatment at recommended dosage in an infant. AB - Acetaminophen is considered a safe drug for children, although hepatotoxicity may develop after overdosing. Reports of liver failure after repeated therapeutic doses of the drug have been rare. Here we describe the case of an infant who developed acute liver failure after administration of acetaminophen for 10 days at a total dose of 720 mg/day (72 mg/kg per day). The patient had high levels of aspartate aminotransferase (11 735 U/L) and alanine aminotransferase (6611 U/L) accompanied by encephalopathy and an increased ammonium level (266 MUg/dL). Intravenous N-acetylcysteine therapy resulted in rapid improvement of the child's clinical condition and laboratory test results. Health care providers should be aware that multiple doses of acetaminophen in infants may lead to acute hepatic failure. N-acetylcysteine therapy should be initiated in cases of drug-induced acute liver failure. PMID- 21242228 TI - Effects of tobacco smoke exposure during lactation on nutritional and hormonal profiles in mothers and offspring. AB - Exposure to tobacco smoke is related to changes in energy balance regulation and several endocrine dysfunctions. Previously, we showed that maternal nicotine (the main addictive compound of tobacco) exposure exclusively during lactation affects biochemical profiles in mothers, milk, and pups. As the possible consequences for mothers and offspring of maternal smoking during lactation are still unknown, we evaluated the effects of tobacco smoke exposure on nutritional, biochemical, and hormonal parameters in dams and pups at weaning. After 72 h from birth, lactating rats were divided into two groups: smoke-exposed (S) in a cigarette-smoking machine, 4 * 1 h per day throughout the lactation period without pups; control (C), rats were treated the same as the experimental group but exposed to filtered air. Dams and pups were killed at weaning (21 days of lactation). Body weight and food intake were evaluated. Milk, blood, visceral fat, adrenal, and carcass were collected. S dams showed hyperprolactinemia (+50%), hypoinsulinemia (-40%), hypoleptinemia (-46%), as well as lower triglycerides (-53%) and very low-density lipoprotein cholesterol (-50%). Milk of S dams had higher lactose (+52%) and triglycerides (+78%). S pups presented higher body protein (+17%), lower total ( 24%) and subcutaneous fat contents (-25%), hypoglycemia (-11%), hyperinsulinemia (+28%), hypocorticosteronemia (-40%), lower adrenal catecholamine content (-40%), hypertriglyceridemia (+34%), higher high-density lipoprotein cholesterol (+16%), and lower low-density lipoprotein cholesterol (-45%). In conclusion, tobacco smoke exposure leads to changes in nutritional, biochemical, and hormonal parameters in dams and, passively through the milk, may promote several important metabolic disorders in the progeny. PMID- 21242229 TI - Effects of endogenous glucocorticoid secretion on the interleukin-6 response to bacterial endotoxin in pregnant and non-pregnant rats. AB - Glucocorticoids (GCs) are released in response to immune activation by the bacterial endotoxin, lipopolysaccharide (LPS). However, GC secretion in response to immune activation and other stressors is attenuated at term of pregnancy. GCs are important modulators of the immune response, and both pro- and anti inflammatory effects are described. Here, we examined whether GC secretion in response to LPS is maintained in earlier pregnancy before term, and investigated the role of endogenous GCs in modulating LPS-induced circulating cytokines, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), in pregnant compared to non-pregnant female rats. Plasma corticosterone (Cort) and ACTH responses to LPS were well maintained in pregnant rats at embryonic days 15/16 (E15/16) and E18/19 compared to non-pregnant rats. At E19, maternal LPS administration increased fetal plasma Cort and decreased testosterone in male fetuses. In non-pregnant animals, pretreatment with the GC synthesis inhibitor, metyrapone, inhibited the LPS-induced increase in IL-6, and the IL-6 response was restored by Cort replacement, indicating that LPS induction of IL-6 is Cort dependent. In E15 pregnant animals, metyrapone had no effect on LPS-induced IL-6 levels, indicating that LPS-induction of IL-6 is not dependent on Cort. These contrasting patterns of IL-6 induction in non-pregnant and pregnant animals were reflected in levels of hypothalamic Socs3 mRNA, an indicator of IL-6 signaling pathway activation. In both non-pregnant and pregnant rats, LPS-induced plasma TNF-alpha responses were inhibited by metyrapone but not re-instated by Cort replacement. It is suggested that altered GC regulation of IL-6 may be required to sustain specialized functions of IL-6 during pregnancy. PMID- 21242230 TI - Prevention of intellectual disability through screening for congenital hypothyroidism: how much and at what level? AB - OBJECTIVE: Congenital hypothyroidism (CHT) is a common cause of preventable mental retardation, and the quantification of intellectual disability due to CHT is needed to assess the public health benefit of newborn screening. DESIGN: Review of published studies conducted among children born prior to the introduction of newborn screening for CHT and reporting cognitive test scores. SETTING: Population-based studies. PATIENTS: Children with clinically diagnosed CHT. INTERVENTIONS: Thyroid hormone substitution. MAIN OUTCOME MEASURES: Intelligence quotient (IQ) (mean and distribution). RESULTS: The prevalence of recognised CHT rose from one in 6500 prior to screening to approximately one in 3000 with screening. In four population-based studies in high-income countries, among children with clinically diagnosed CHT 8-28% were classified as having intellectual disability (defined as an IQ <70) and the mean IQ was 85 (a leftward shift of 1 SD). Among children with subclinical CHT, the risk of overt intellectual disability was lower (zero in one study), but decreased intellectual potential and increased behavioural abnormalities were documented. CONCLUSIONS: Although the prevalence of overt disability among children with CHT in the absence of screening may be less than previously estimated, the preventable burden of intellectual disability due to CHT is substantial and justifies newborn screening. However, changes in existing newborn screening protocols to capture more cases are unlikely to prevent overt cases of disability and should therefore be justified instead by the documentation of other benefits of early detection. PMID- 21242231 TI - Healthcare use by children fatally or seriously harmed by child maltreatment: analysis of a national case series 2005-2007. AB - AIM: To determine antecedent patterns of healthcare use by children fatally or seriously harmed by maltreatment. METHODS: The authors analysed recorded healthcare use for children who were the subject of a serious case review (SCR) in England in 2005-2007. The SCRs were initiated when a child under 18 years old died or was seriously harmed, maltreatment (abuse or neglect) was a factor, and there were lessons for interagency working. The authors analysed a purposive sample (N=40), similar in key demographics to all 189 SCRs in England in 2005 2007. RESULTS: Children had extensive recorded contact with universal (N=34/40; 85%) and secondary (N=26/40; 65%) healthcare services and children's social care (N=21/40; 53%). Thirty-one children (78%) had recorded health visitor and/or school nurse contact. Fourteen children (35%) had missed appointments. Almost three-quarters (N=29) had complex family problems recorded (parental domestic violence, alcohol/drug and/or mental health problems). Data quality regarding healthcare use was poor, and the extent and type of 'missing data' varied by age. CONCLUSIONS: Complex paediatric and family problems and a high level of contact with services preceded serious adverse events. Universal health services are likely to be well placed for giving ongoing and family-orientated support to vulnerable families. The absence of standardised data collection and any control group limits how far the Biennial Analyses of SCRs can meet their stated objective of identifying national trends and patterns. Linking SCRs to healthcare databases would provide a control group, improve understanding of the population context and diminish demands for data from professionals delivering care. PMID- 21242232 TI - The infrapatellar fat pad of patients with osteoarthritis has an inflammatory phenotype. AB - OBJECTIVES: Obesity is a risk factor for the development of osteoarthritis (OA) in hands and knees. Adipose tissue can secrete different adipokines with powerful immunomodulatory effects. The infrapatellar fat pad (IFP) is an intra-articular organ in the vicinity of the synovium and cartilage. It is hypothesised that IFP derived soluble factors could contribute to pathological processes in the knee joint. A study was therefore undertaken to compare the release of inflammatory mediators in the IFP and subcutaneous adipose tissue (ScAT) and to characterise the adipocytes and immune cell infiltrate in these tissues. METHODS: Paired IFP and ScAT samples were obtained from 27 patients with primary OA. The stromal vascular cell fraction (SVF) was isolated and characterised by fluorescence activated cell sorting. Cytokine and adipokine release in fat- and adipocyte conditioned media was measured by luminex. RESULTS: IFP secreted higher levels of inflammatory mediators such as interleukin 6 (IL-6), adipsin, adiponectin and visfatin than ScAT. This could be due to differences in the phenotype of adipocytes and/or in the composition and phenotype of the SVF cells. IFP adipocyte-conditioned media showed a trend towards more IL-6 and adipsin than ScAT. Moreover, the SVF fraction of IFP contained more cells/g tissue, a lower percentage of T cells and a higher percentage of mast cells than ScAT. In addition, T cells had a predominantly pro-inflammatory phenotype while macrophages had a mixed pro- and anti-inflammatory phenotype in the IFP. CONCLUSION: There are profound differences in secreted inflammatory factors and immune cell composition between the IFP and ScAT. These data indicate that IFP derived soluble mediators could contribute to pathophysiological processes in the OA knee joint. PMID- 21242233 TI - High resolution mapping in the major histocompatibility complex region identifies multiple independent novel loci for psoriatic arthritis. AB - OBJECTIVE: Psoriatic arthritis (PsA) has a clear familial predisposition, the major histocompatibility complex (MHC) region being the strongest genetic locus. The study primary objective was to identify single nucleotide polymorphisms (SNPs) independent of known human leucocyte antigen (HLA) alleles within the MHC region that are associated with PsA using a high-density SNP map. METHOD: In all, 914 samples were assessed, including 427 PsA cases from 2 well established PsA cohorts and 487 controls from Canada. The genotype data consisted of 2521 SNPs from 2 Illumina Goldengate MHC panels, spanning 4.9 Mb of chromosome 6 with an average spacing of 2 kb. Classical HLA alleles were genotyped in all subjects using sequence-specific oligonucleotide probes or sequence-specific primers. A conditioning approach was used to distinguish between new associations and those in linkage disequilibrium (LD) with known HLA alleles. RESULTS: Unconditional association analysis revealed 43 markers with p<7.26*10(-5) (calculated experiment-wide significance threshold). In the conditional analysis, 10 SNPs showed statistically significant association at a threshold of p<7.26*10(-5). Seven SNPs were in strong LD in the study data (pairwise r(2) >0.77 in the controls) reflecting one association signal. These SNPs spanned a 1.6 Mb region. SNP rs1150735 is 1.5 kb upstream from ring finger protein 39 (RNF39). RNF39 SNPs have been associated with HIV1 disease progression and set point CD4 T cell count. CONCLUSION: Four new loci for either psoriasis or PsA in the MHC region that are independent of known HLA alleles have been identified. The effect size of these variants is modest. Replication of these variants in multiple larger populations is necessary. PMID- 21242234 TI - A model for the development and implementation of a national plan for the optimal management of early spondyloarthritis: the Esperanza Program. AB - OBJECTIVES: To evaluate the performance of a healthcare programme in early spondyloarthritis (SpA). METHODS: Based on previous analyses and expectations of a nominal group, the following were set: (1) minimum standards to create early SpA units; (2) standard operating procedures; and (3) eight performance indicators that can be measured in real time using a web-based platform. RESULTS: At the end of the evaluation of the programme the expected level of performance was achieved in three of the indicators: 'referral reliability' (standard (S) >50%, real value (RV) 92%), 'accessibility' (S >90%, RV=91%) and 'duration of first visit' (S >50%, RV=53%). The performance in the remaining indicators was inferior: 'success of referral criteria' (S >50%, RV=28%), 'clinical reports issued' (S >90%, RV=25%), 'feedback guarantee' (S >85%, RV=2%), 'missing data' (S <10%, RV=24%) and 'frequency of review' (S >90%, RV=84%). Explanations for the low performance are provided. CONCLUSIONS: It is possible to implement a large scale programme that is measurable. PMID- 21242235 TI - Disease activity score-driven therapy versus routine care in patients with recent onset active rheumatoid arthritis: data from the GUEPARD trial and ESPOIR cohort. AB - OBJECTIVES: To compare the efficacy of disease activity score in 28 joints (DAS28ESR)-driven therapy with anti-tumour necrosis factor (patients from the GUEPARD trial) and routine care in patients with recent-onset rheumatoid arthritis (patients of the ESPOIR cohort). RESULTS: After matching GUEPARD and ESPOIR patients on the basis of a propensity score and a 1:2 ratio, at baseline all patients had comparable demographic characteristics, rheumatoid factor, anticyclic citrullinated peptide antibody positivity and clinical disease activity parameters: erythrocyte sedimentation rate, C-reactive protein, mean DAS (6.26+/-0.87), Sharp/van der Heijde radiographic score (SHS), health assessment questionnaire (HAQ). Disease duration was longer in GUEPARD patients (5.6+/-4.6 vs 3.5+/-2.0 months, p<0.001). After 1 year, the percentage of patients in remission with an HAQ (<0.5) and an absence of radiological progression was higher in the tight control group (32.3% vs 10.2%, p=0.011) as well as the percentage of patients in low DAS with an HAQ (<0.5) and an absence of radiological progression (36.1% vs 18.9%, p=0.045). However, there was no difference in the decrease in DAS, nor in the percentage of EULAR (good and moderate), ACR20, ACR50 and ACR70 responses. More patients in the tight control group had an HAQ below 0.5 (70.2% vs 45.2%, p=0.005). Overall, pain, patient and physician assessment and fatigue decreased more in the tight control group. The mean SHS progression was similar in the two groups as was the percentage of patients without progression. CONCLUSIONS: In patients with recent onset active rheumatoid arthritis, a tight control of disease activity allows more patients to achieve remission without disability and radiographic progression. PMID- 21242236 TI - Should imaging be a component of rheumatoid arthritis remission criteria? A comparison between traditional and modified composite remission scores and imaging assessments. AB - OBJECTIVES: Patients can fulfil clinical criteria for remission, yet still have evidence of synovitis detectable clinically and by ultrasound, and this is associated with structural damage. Stricter remission criteria may more accurately reflect true remission (no synovitis). This hypothesis was examined by studying patients using more stringent thresholds for clinical remission and determining their levels of ultrasound synovitis. METHODS: Rheumatoid arthritis patients with a disease activity score in 28 joints (DAS28) <=2.6 for at least 6 months were classified using standard and more stringent DAS28 and simplified disease activity index (SDAI) remission thresholds and the corresponding clinical and ultrasound imaging measures of synovitis recorded. RESULTS: 128 patients (all DAS28 <2.6, median DAS28 1.70) receiving either disease-modifying antirheumatic drugs alone (n=66) or with a tumour necrosis factor blocker (n=62) were recruited. Of the 640 imaged joints, 5% had moderate or severe power Doppler (PD) activity, 8% were clinically swollen and 1% tender. In patients fulfilling DAS28, American College of Rheumatology or SDAI remission criteria, moderate or severe PD activity was present in 21%, 15% and 19%, respectively. More stringent DAS28 and SDAI criteria reduced the mean number of swollen and tender joints (p<0.001) but not the percentage of patients with PD activity: 32 patients had a DAS28 <1.17 but eight (25%) had significant PD activity. CONCLUSION: Using more stringent remission criteria resulted in reduced signs and symptoms of inflammation, but the percentage of joints with PD activity was not reduced, even in those without signs or symptoms. These data suggest that clinical criteria are sufficiently insensitive to detect low but clinically relevant levels of inflammation accurately. PMID- 21242237 TI - Cerebral ultrasound abnormalities in infants born to mothers with autoimmune disease. AB - OBJECTIVES: Cerebral abnormalities detected by cranial ultrasound (cUS) have been reported in infants born to mothers with autoimmune disease. However, the pathogenesis of the infants' brain injury remains unclear. The authors aimed to study the possible association between abnormalities on neonatal cUS and perinatal factors related to maternal autoimmune disease. METHODS: cUS evaluation was carried out at birth in 114 infants born to mothers with autoimmune disease, and repeated up to 8-9 months of life in those showing sonographic abnormalities at the first examination. The authors analysed the relationships among cerebral ultrasound abnormalities and antenatal exposure to maternal drug treatment, placental transfer of auto-antibodies and gestational complications. In addition, infants were investigated for neuromotor development from birth to 24 months of age. RESULTS: Cerebral ultrasound abnormalities, including subependymal pseudocyst, lenticulostriate vasculopathy and echogenic periventricular white matter, were detected in 41 of 114 infants (35.9%). No significant associations were found between abnormalities on cUS and the perinatal factors included in the study. No cases of persistent cerebral ultrasound abnormalities or neuromotor delay were observed during the follow-up period. CONCLUSIONS: A considerable number of cerebral ultrasound abnormalities were observed in a cohort of infants born to mothers with autoimmune disease. However, no perinatal factors were significantly associated with this finding, suggesting the fetal brain impairment had a multi-factorial aetiology. Although no case of neuromotor delay was observed, long term neurological assessment of these babies is recommended in view of the cognitive impairment reported in previous studies. PMID- 21242238 TI - Postnatal ultrasound reliability in cerebellar vermis assessment. AB - BACKGROUND: Cerebellar growth in late gestation is impeded by prematurity which may adversely affect neurocognitive development. Assessment of cerebellar growth should be easily attainable, reliable and reproducible. OBJECTIVE: To assess the reliability of linear sonographic cerebellar vermis measurement. METHOD: Cranial ultrasounds of 110 infants ranging from 24 to 41 weeks' gestation were retrospectively reviewed. Cerebellar vermian height, craniocaudal diameter and superior and inferior vermis widths were independently measured on the first midline sagittal image by three neonatal sonologists of varying experience. Interobserver and intraobserver reliability were calculated using the intraclass correlation coefficient (ICC) (2 way mixed model, SPSS V.15.0). RESULTS: 61 images were technically adequate. Interobserver ICCs (95% CI) were: cerebellar vermian height 0.88 (0.82 to 0.92); craniocaudal diameter 0.91 (0.86 to 0.94); superior vermis width 0.84 (0.77 to 0.89); inferior vermis width 0.92 (0.89 to 0.95). Intraobserver ICCs were similar. CONCLUSION: With adequate images, linear ultrasound measurements of cerebellar vermis are reliable. PMID- 21242239 TI - Propranolol treatment for subglottic haemangioma. PMID- 21242240 TI - Vitamin A provision for preterm infants: are we meeting current guidelines? AB - BACKGROUND: Preterm infants have reduced liver stores of vitamin A at birth compared to term born infants. Current guidelines recommend an intake of 700-1500 IU/kg/day vitamin A, and there is evidence to support higher doses for infants with significant lung disease. The importance of appropriate early nutrition for preterm infants is increasingly becoming apparent. OBJECTIVES: To examine whether preterm infants admitted to a UK neonatal unit received the currently recommended amounts of vitamin A during the first 4 weeks of life, and to identify the feeding patterns associated with optimal vitamin A intake. DESIGN: Retrospective case note review. SETTING: UK tertiary neonatal unit. POPULATION: 36 preterm infants with a median gestation of 30 weeks (range 26-33 weeks) and median birth weight of 1305 g (range 880-1800 g). MAIN OUTCOME MEASURE: Mean daily total intake of vitamin A in each of the first 4 weeks of life. RESULTS: Despite a policy of introducing intravenous lipid supplemented with fat soluble vitamins on day 2, only four infants (11%) consistently met the recommended daily intake of vitamin A during the first 2 weeks of life. Adequacy of vitamin A intake in the first 2 weeks of life was not predicted by gestation or pattern of feeding. CONCLUSION: Recommendations for intravenous vitamin A supplementation in parenterally fed preterm infants require revision. Intravenous lipid with added fat soluble vitamins should be started as soon as possible after birth, and consideration given to early oral vitamin A supplementation in those infants tolerant of enteral feeds. PMID- 21242241 TI - Height at 2 and 5 years of age in children born very preterm: the EPIPAGE study. AB - OBJECTIVES: To evaluate growth for children born very preterm with particular focus on those born small-for-gestational age (SGA) or with ex utero growth restraint (GR), and to identify risk factors for short stature at 5 years of age. STUDY DESIGN: Population-based study of children born at less than 33 completed weeks of gestation (Etude Epidemiologique sur les Petits Ages Gestationnels (EPIPAGE)). Short stature was defined as height <-2SD on WHO growth curves. Ex utero GR was considered to have occurred in children with appropriate size for gestational age at birth and with a height and/or weight below -2SD at 2 years of corrected age. Logistic regression models were used to test associations between risk factors and short stature. RESULTS: The authors measured height at 5 years of age for 1,597 of 2,193 children (73%), 5.6% (95% CI 4.6 to 6.9) of whom were diagnosed as having a short stature. Height was measured at 2 and 5 years of age in 1417 children. Among these, 24% of those born SGA and 36% of those with ex utero GR (p=0.002) had a short stature at 5 years. Predictors of short stature were SGA or birth length <-2SD, maternal height <= 160 cm, gestational age <29 weeks and systemic corticosteroids. Breastfeeding at discharge decreased the risk of short stature. CONCLUSIONS: Short stature at 5 years of age is common in children born preterm. The highest incidence was observed in the group with ex utero GR. Systemic steroids have a long-term impact on growth and should be used with caution. Breastfeeding at discharge appeared to be protective. PMID- 21242242 TI - Determinants of neonatal weight loss in term-infants: specific association with pre-pregnancy maternal body mass index and infant feeding mode. AB - OBJECTIVE: We aimed to study the determinants of neonatal weight loss measured on the third day of life in term-infants. DESIGN: The EDEN mother-child cohort is a prospective study that recruited 2002 pregnant women before 24 weeks of gestation in two French university hospitals. Neonates were weighed every day until discharge that occurred on average 4.5 days after birth. Altogether, 1557 healthy term neonates with data on weight at day 3 and feeding mode available were included. The outcome variable was weight loss at day 3 (D3WL), expressed as a percentage of birth weight lost in the first 3 days of life. Our main explanatory variables were maternal pre-pregnancy body mass index (BMI), gestational weight gain, gestational diabetes, birth weight, gestational age and feeding mode. RESULTS: Factors associated with greater D3WL, whatever the feeding mode, were: higher birth weight, gestational diabetes and caesarean section; higher gestational age was associated with a reduced D3WL. The association between maternal pre-pregnancy BMI and D3WL differed by feeding mode (interaction p value=0.0002). In breastfed babies, mean D3WL ranged from 4.9% for neonates of underweight mothers to 5.8% for neonates of obese mothers (p trend=0.0005). In formula-fed babies, D3WL was highest for neonates of underweight mothers (4.1%) and lowest for those of obese mothers (2.6%) (p trend=0.01). CONCLUSIONS: The lower D3WL in formula-fed neonates, especially in neonates of obese mothers, suggests a relative overfeeding in the early days compared with breastfed neonates, which may potentially have consequences on later health. Overweight and obese mothers may need extra support to prevent early breastfeeding discontinuation. PMID- 21242243 TI - Reference values for pulse oximetry recordings in healthy term neonates during their first 5 days of life. AB - OBJECTIVE: To determine reference values for pulse oximeter saturation (SpO(2)) variables and desaturation event indices in healthy term neonates during their first 5 days of life, and to compare two definitions for the identification of desaturation events. DESIGN: Observational study (case series). Setting Maternity ward, Department of Neonatology, University Children's Hospital, Tuebingen, Germany. PATIENTS: 209 healthy term neonates (50% boys), median (minimum-maximum) age 2 (0-5) days. MAIN OUTCOME MEASURES: SpO(2) variables (eg, median SpO(2)) and desaturation events obtained by motion-resistant pulse oximetry (VitaGuard 310; Getemed, incorporating Masimo SET). Desaturation events were identified based either on a good signal quality (SIQ) provided by the device or on the combination of a good SIQ and an undisturbed pulse waveform (SIQ+PW). Desaturation event indices were calculated as desaturation events divided by hour of artefact-free recording time. RESULTS: The mean (SD) of the obtained median SpO(2) was 97.3% (1.4%). There were 36 (17%) subjects with desaturation events to <80% SpO(2) based on SIQ, and 26 (12%) based on SIQ+PW. Median desaturation event rate to <80% SpO(2)/h (75th centile; 95th centile; maximum) was 0 (0; 0.6; 2.3) based on SIQ, and 0 (0; 0.4; 1.7) based on SIQ+PW. CONCLUSIONS: Desaturation events to <80% SpO(2) were rare in our sample of healthy term neonates during their first 5 days of life. Analysis of SIQ alone could be a quick and simple alternative to traditional analysis of PW. The presented reference values may be used for clinical decision making. PMID- 21242244 TI - Ice age: a case of cold panniculitis. PMID- 21242245 TI - Assessment of newborn resuscitation skills of physicians with a simulator manikin. AB - OBJECTIVE: Education of medical staff according to Neonatal Resuscitation Program guidelines improves outcome of delivery room resuscitation. Regular assessment of skills is important for reliable performance of neonatal resuscitation. We assessed the practical resuscitation skills of clinicians in a standard scenario in a newborn simulation. DESIGN: Observational cohort study. MAIN OUTCOME MEASURES: The resuscitation skills of 6 consultant neonatologists, 11 paediatricians and 11 anaesthesiologists were assessed in a simulation. The standard test scenario was a newborn infant with asphyxia. A 30-item checklist was used for scoring technical skills, while non-technical skills were scored using a nine-item checklist. The pass/fail score was 18.66 for technical skills. Scoring was carried out by a neonatologist/anaesthesiologist team in real time. RESULTS: Two paediatricians and two anaesthesiologists failed the test. The average score was 25 for neonatologists, 22 for paediatricians and 20 for anaesthesiologists. Technical scores were compiled into four clusters for assessment of items in the same category. The scores in the ventilation cluster were lower the later the participants started ventilation, the longer they maintained pauses in ventilation, the older the baby at the time of intubation and the longer the time they used for intubation. The time intervals were checked from the video recordings. The neonatologists had better non-technical skills than the other groups. Good group-working skills correlated with high technical scores. CONCLUSIONS: Many clinicians exhibited inadequate skills to resuscitate a newborn infant in a standard scenario. The neonatologists, as clinical experts, performed best in both technical and non-technical skills testing. PMID- 21242246 TI - Updating the 2003 European regulatory requirements for registering disease modifying drugs to be used in the treatment of rheumatoid arthritis. PMID- 21242247 TI - Developments in osteoarthritis. PMID- 21242250 TI - Impaired beta-adrenergic responsiveness accentuates dysfunctional excitation contraction coupling in an ovine model of tachypacing-induced heart failure. AB - Reduced inotropic responsiveness is characteristic of heart failure (HF). This study determined the cellular Ca2+ homeostatic and molecular mechanisms causing the blunted beta-adrenergic (beta-AR) response in HF.We induced HF by tachypacing in sheep; intracellular Ca2+ concentration was measured in voltage-clamped ventricular myocytes. In HF, Ca2+ transient amplitude and peak L-type Ca2+ current (ICa-L) were reduced (to 70 +/- 11% and 50 +/- 3.7% of control, respectively, P <0.05) whereas sarcoplasmic reticulum (SR) Ca2+ content was unchanged. beta-AR stimulation with isoprenaline (ISO) increased Ca2+ transient amplitude, ICa-L and SRCa2+ content in both cell types; however, the response of HF cells was markedly diminished (P <0.05).Western blotting revealed an increase in protein phosphatase levels (PP1, 158 +/- 17% and PP2A, 188 +/- 34% of control, P <0.05) and reduced phosphorylation of phospholamban in HF (Ser16, 30 +/- 10% and Thr17, 41 +/- 15% of control, P <0.05). The beta-AR receptor kinase GRK-2 was also increased in HF (173 +/- 38% of control, P <0.05). In HF, activation of adenylyl cyclase with forskolin rescued the Ca2+ transient, SR Ca2+ content and SR Ca2+ uptake rate to the same levels as control cells in ISO. In conclusion, the reduced responsiveness of the myocardium to beta-AR agonists in HF probably arises as a consequence of impaired phosphorylation of key intracellular proteins responsible for regulating the SR Ca2+ content and therefore failure of the systolic Ca2+ transient to increase appropriately during beta-AR stimulation. PMID- 21242252 TI - L-Dopa activates histaminergic neurons. AB - L-Dopa is the most effective treatment of early and advanced stages of Parkinson's disease (PD), but its chronic use leads to loss of efficiency and dyskinesia. This is delayed by lower dosage at early stages, made possible by additional treatment with histamine antagonists. We present here evidence that histaminergic tuberomamillary nucleus (TMN) neurons, involved in the control of wakefulness, are excited under L-Dopa (EC50 15 MUM), express Dopa decarboxylase and show dopamine immunoreactivity. Dopaergic excitation was investigated with patch-clamp recordings from brain slices combined with single-cell RT-PCR analysis of dopamine receptor expression. In addition to the excitatory dopamine 1 (D1)-like receptors, TMN neurons express D2-like receptors, which are coupled through phospholipase C (PLC) to transient receptor potential canonical (TRPC) channels and the Na+/Ca2+ exchanger. D2 receptor activation enhances firing frequency, histamine release in freely moving rats (microdialysis) and wakefulness (EEG recordings). In histamine deficient mice the wake-promoting action of the D2 receptor agonist quinpirole (1 mg kg-1, I.P.) is missing. Thus the histamine neurons can, subsequent to L-Dopa uptake, co-release dopamine and histamine from their widely projecting axons. Taking into consideration the high density of histaminergic fibres and the histamine H3 receptor heteromerization either with D1 or with D2 receptors in the striatum, this study predicts new avenues for PD therapy. PMID- 21242253 TI - Altered sympathetic reflexes and vascular reactivity in rats after exposure to chronic intermittent hypoxia. AB - Exposure to chronic intermittent hypoxia (CIH) yields persistent elevations in sympathetic nerve activity (SNA) and mean arterial pressure(MAP)with exaggerated sympathetic chemoreflexes. We examined the impact of CIH upon other sympathoexcitatory reflexes and a potential central mechanism underlying the altered regulation of SNA.Male Sprague-Dawley rats were exposed to CIH for 2 weeks (40 s at 6% O2 every 9 min, 8 h day-1). After exposure to CIH, urethane anaesthetized, vagotomized, ventilated, paralysed rats had significantly elevated MAP, splanchnic SNA, and rate of phrenic nerve discharge (PND; P<0.05). Elimination of SNA by ganglionic blockade produced a larger fall in MAP in rats exposed to CIH (P<0.05). Like acute hypoxia, stimulation of the sciatic nerve or the nasal mucosa evoked greater increases in SNA after exposure to CIH (P<0.05). In addition, acute hypoxia promoted exaggerated increases in PND amplitude after CIH (P<0.05). In contrast, the nasopharyngeal reflex evoked exaggerated increases in SNA during apnoea. These sympathoexcitatory reflexes are mediated by glutamatergic activation of the rostral ventrolateral medulla (RVLM), and accordingly, microinjections of glutamate into RVLM evoked larger increases in SNA after CIH (P<0.05). Paradoxically, none of these exaggerated acute rises in SNA was accompanied by enhanced pressor responses. Reduced adrenergic vascular reactivity may contribute to the blunted sympathetically mediated pressor responses, because bolus doses of phenylephrine evoked attenuated pressor responses after CIH (P<0.01).These data suggest exposure to CIH facilitates activation of SNA, potentially by changes within the RVLM. However, the exaggerated rises in SNA are not dependent upon stimulation of inspiratory drive. Although elevated SNA may contribute to CIH-induced hypertension, reduced adrenergic vascular reactivity buffers the cardiovascular impact of exaggerated acute rises in SNA. PMID- 21242254 TI - Spinal 5-HT7 receptor activation induces long-lasting phrenic motor facilitation. AB - Acute intermittent hypoxia elicits a form of serotonin-dependent respiratory plasticity known as phrenic long term facilitation (pLTF). Episodic spinal serotonin-2 (5-HT2) receptor activation on or near phrenic motor neurons is necessary for pLTF. A hallmark of pLTF is the requirement for serotonin-dependent synthesis of brain-derived neurotrophic factor (BDNF), and activation of its high affinity receptor, TrkB. Activation of spinal Gs protein-coupled adenosine 2A receptors (GsPCRs) elicits a unique form of long-lasting phrenic motor facilitation (PMF), but via unique mechanisms (BDNF independent TrkB trans activation).We hypothesized that other GsPCRs elicit PMF, specifically serotonin 7 (5-HT7) receptors, which are expressed in phrenic motor neurons. Cervical spinal (C4) injections of a selective 5-HT7 receptor agonist, AS-19 (10 MUM, 5 MUl; 3 * 5 min), in anaesthetized, vagotomized and ventilated male Sprague-Dawley rats elicited long-lasting PMF (>120 min), an effect prevented by pretreatment with a 5-HT7 receptor antagonist (SB 269970; 5mM, 7 MUl).GsPCR activation 'trans activates'TrkB by increasing synthesis of an immature TrkB isoform. Spinal injection of a TrkB inhibitor (k252a) and siRNAs that prevent TrkB (but not BDNF) mRNA translation both blocked 5-HT7 agonist-induced PMF, confirming a requirement for TrkB synthesis and activity. k252a affected late PMF (>= 90 min) only. Spinal inhibition of the PI3K/AKT pathway blocked 5-HT7 agonist-induced PMF, whereas MEK/ERK inhibition delayed, but did not block, PMF. An understanding of signalling mechanisms giving rise to PMF may guide development of novel therapeutic strategies to treat ventilatory control disorders associated with respiratory insufficiency, such as spinal injury and motor neuron disease. PMID- 21242255 TI - The microcirculation: physiology at the mesoscale. AB - The microcirculation exemplifies the mesoscale in physiological systems, bridging larger and smaller scale phenomena. Microcirculatory research represents an example of a 'middle-out,' rather than 'top-down' or 'bottom-up,' approach to the study of biological function. Computational and mathematical approaches can be used to analyse the functioning of the microcirculation and to establish quantitative relationships between microvascular processes and phenomena occurring on larger and smaller scales, leading to insights which could not be obtained solely by reductionist biological experiments. Given its integrative approach to processes occurring on disparate scales and its emphasis on theoretical as well as experimental approaches, microcirculatory research belongs within current definitions of systems biology. PMID- 21242256 TI - A dual action of saturated fatty acids on electrical activity in rat pancreatic beta-cells. Role of volume-regulated anion channel and KATP channel currents. AB - Free fatty acids (FFAs) exert complex actions on pancreatic beta-cells. Typically, an initial potentiation of insulin release is followed by a gradual impairment of beta-cell function, the latter effect being of possible relevance to hyperlipidaemia in type 2 diabetes mellitus. The molecular actions of FFAs are poorly understood. The present study investigated the acute effects of saturated FFAs on electrophysiological responses of rat pancreatic beta-cells. Membrane potential and KATP channel activity were recorded using the perforated patch technique. Volume-regulated anion channel (VRAC) activity was assessed from conventional whole-cell recordings. Cell volume regulation was measured using a video-imaging technique. Addition of octanoate caused a transient potentiation of glucose-induced electrical activity, followed by a gradual hyper-polarisation and a prolonged inhibition of electrical activity. Octanoate caused an initial increase in VRAC activity followed by a secondary inhibition coinciding with increased KATP channel activity. Similar effects were observed with palmitate and 2-bromopalmitate whereas butyrate was virtually ineffective. Octanoate and palmitate also exerted a dual effect on electrical activity evoked by tolbutamide. Octanoate significantly attenuated cell volume regulation in hypotonic solutions, consistent with VRAC inhibition. It is concluded that medium and long chain FFAs have a dual action on glucose-induced electrical activity in rat pancreatic beta-cells: an initial stimulatory effect followed by a secondary inhibition. These effects appear to be the result of reciprocal actions on VRAC and KATP channel currents, and could contribute towards the stimulatory and inhibitory actions of FFAs on pancreatic beta-cell function. PMID- 21242257 TI - Intracellular calcium transients evoked by pulsed infrared radiation in neonatal cardiomyocytes. AB - Neonatal rat ventricular cardiomyocytes were used to investigate mechanisms underlying transient changes in intracellular free Ca2+ concentration ([Ca2+]i) evoked by pulsed infrared radiation (IR, 1862 nm). Fluorescence confocal microscopy revealed IR-evoked [Ca2+]i events with each IR pulse (3-4 ms pulse-1, 9.1-11.6 J cm-2 pulse-1). IR-evoked [Ca2+]i events were distinct from the relatively large spontaneous [Ca2+]i transients, with IR-evoked events exhibiting smaller amplitudes (0.88 DeltaF/F0 vs. 1.99 DeltaF/F0) and shorter time constants (tau =0.64 s vs. 1.19 s, respectively). Both IR-evoked [Ca2+]i events and spontaneous [Ca2+]i transients could be entrained by the IR pulse (0.2-1 pulse s 1), provided the IR dose was sufficient and the radiation was applied directly to the cell. Examination of IR-evoked events during peak spontaneous [Ca2+]i periods revealed a rapid drop in [Ca2+]i, often restoring the baseline [Ca2+]i concentration, followed by a transient increase in [Ca2+]i.Cardiomyocytes were challenged with pharmacological agents to examine potential contributors to the IR-evoked [Ca2+]i events. Three compounds proved to be the most potent, reversible inhibitors: (1) CGP-37157 (20 MUM, n =12), an inhibitor of the mitochondrial Na+/Ca2+ exchanger (mNCX), (2) Ruthenium Red (40 MUM, n =13), an inhibitor of the mitochondrial Ca2+ uniporter (mCU), and (3) 2 aminoethoxydiphenylborane (10 MUM, n =6), an IP3 channel antagonist. Ryanodine blocked the spontaneous [Ca2+]i transients but did not alter the IR-evoked events in the same cells. This pharmacological array implicates mitochondria as the major intracellular store of Ca2+ involved in IR-evoked responses reported here. Results support the hypothesis that 1862 nm pulsed IR modulates mitochondrial Ca2+ transport primarily through actions on mCU and mNCX. PMID- 21242258 TI - Distribution of electrical activation to the external intercostal muscles during high frequency spinal cord stimulation in dogs. AB - In contrast to previous methods of electrical stimulation of the inspiratory muscles, high frequency spinal cord stimulation (HF-SCS) results in more physiological activation of these muscles. The spatial distribution of activation to the external intercostal muscles by this method is unknown. In anaesthetized dogs, multiunit and single motor unit (SMU) EMG activity was monitored in the dorsal portion of the 3rd, 5th and 7th interspaces and ventral portion of the 3rd interspace during spontaneous breathing and HF-SCS following C2 spinal section. Stimulus amplitude during HF-SCS was adjusted such that inspired volumes matched spontaneous breathing (Protocol 1). During HF-SCS, mean peak SMU firing frequency was highest in the 3rd interspace (dorsal) (18.8 +/- 0.3 Hz) and significantly lower in the 3rd interspace (ventral) (12.2 +/- 0.2 Hz) and 5th interspace (dorsal) (15.3 +/- 0.3 Hz) (P <0.05 for each comparison). Similar rostrocaudal and dorsoventral gradients of activity were observed during spontaneous breathing prior to C2 section. No significant activity was observed in the 7th interspace during either spontaneous breathing or HF-SCS. Since peak discharge frequencies of the SMUs were higher and rib cage movement greater during HF-SCS compared to spontaneous breathing, stimulus amplitude during HF-SCS was adjusted such that rib cage movement matched (Protocol 2). Under these conditions, mean peak SMU frequencies and rostrocaudal and dorsoventral gradients of activity during HF-SCS were not significantly different compared to spontaneous breathing. These results indicate that (a) the topographic pattern of electrical activation of the external intercostal muscles during HF-SCS is similar to that occurring during spontaneous breathing and (b) differential descending synaptic input from supraspinal centres is not a required component of the differential spatial distribution of external intercostal muscle activation. HF-SCS may provide a more physiological method of inspiratory muscle pacing. PMID- 21242259 TI - Infrared photostimulation of the crista ampullaris. AB - The present results show that the semicircular canal crista ampullaris of the toadfish, Opsanus tau, is sensitive to infrared radiation (IR) applied in vivo. IR pulse trains (~1862 nm, ~200 MUs pulse-1) delivered to the sensory epithelium by an optical fibre evoked profound changes in phasic and tonic discharge rates of postsynaptic afferent neurons. Phasic afferent responses to pulsed IR occurred with a latency of <8 ms while tonic responses developed with a time constant (tau) of 7 ms to 10 s following the onset or cessation of the radiation. Afferents responded to direct optical radiation of the sensory epithelium but did not respond to thermal stimuli that generated nearly equivalent temperature increases of the whole organ. A subset of afferent neurons fired an action potential in response to each IR pulse delivered to the sensory epithelium, at phase-locked rates up to 96 pulses per second. The latency between IR pulses and afferent nerve action potentials was much greater than synaptic delay and spike generation, demonstrating the presence of a signalling delay interposed between the IR pulse and the action potential. The same IR stimulus applied to afferent nerve axons failed to evoke responses of similar magnitude and failed to phase lock afferent nerve action potentials. The present data support the hypothesis that pulsed IR activates sensory hair cells, thus leading to modulation of synaptic transmission and afferent nerve discharge reported here. PMID- 21242260 TI - Common variant in 6q26-q27 is associated with distal colon cancer in an Asian population. AB - BACKGROUND AND AIM: Colorectal cancer (CRC) is a multifactorial disease with both environmental and genetic factors contributing to its development. The incidence of CRC is increasing year by year in Japan. Patients with CRC in advanced stages have a poor prognosis, but detection of CRC at earlier stages can improve clinical outcome. Therefore, identification of epidemiologial factors that influence development of CRC would facilitate the prevention or early detection of disease. METHODS: To identify loci associated with CRC risk, we performed a genome-wide association study (GWAS) for CRC and sub-analyses by tumour location using 1583 Japanese CRC cases and 1898 controls. Subsequently, we conducted replication analyses using a total of 4809 CRC cases and 2973 controls including 225 Korean subjects with distal colon cancer and 377 controls. RESULTS: We identified a novel locus on 6q26-q27 region (rs7758229 in SLC22A3, p = 7.92 * 10 9, OR of 1.28) that was significantly associated with distal colon cancer. We also replicated the association between CRC and SNPs on 8q24 (rs6983267 and rs7837328, p = 1.51 * 10-8 and 7.44 * 10-8, ORs of 1.18 and 1.17, respectively). Moreover, we found cumulative effects of three genetic factors (rs7758229, rs6983267, and rs4939827 in SMAD7) and one environmental factor (alcohol drinking) which appear to increase CRC risk approximately twofold. CONCLUSIONS: We found a novel susceptible locus in SLC22A3 that contributes to the risk of distal colon cancer in an Asian population. These findings would further extend our understanding of the role of common genetic variants in the aetiology of CRC. PMID- 21242261 TI - Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. AB - BACKGROUND & AIMS: Inflammatory bowel disease (IBD) is characterised by chronic intestinal inflammation, resulting from dysregulation of the mucosal immune system and compromised intestinal epithelial barrier function. The bile salt, nuclear farnesoid X receptor (FXR), was recently implicated in intestinal antibacterial defence and barrier function. The aim of this study was to investigate the therapeutic potential of FXR agonists in the treatment of intestinal inflammation in complementary in vivo and in vitro models. METHODS: Colitis was induced in wild-type (WT) and Fxr-null mice using dextran sodium sulfate, and in WT mice using trinitrobenzenesulfonic acid. Mice were treated with vehicle or the FXR agonist INT-747, and colitis symptoms were assessed daily. Epithelial permeability assays and cytokine expression analysis were conducted in mouse colon and enterocyte-like cells (Caco-2/HT29) treated with medium or INT-747. Inflammatory cytokine secretion was determined by ELISA in various human immune cell types. RESULTS: INT-747-treated WT mice are protected from DSS- and TNBS-induced colitis, as shown by significant reduction of body weight loss, epithelial permeability, rectal bleeding, colonic shortening, ulceration, inflammatory cell infiltration and goblet cell loss. Furthermore, Fxr activation in intestines of WT mice and differentiated enterocyte-like cells downregulates expression of key proinflammatory cytokines and preserves epithelial barrier function. INT-747 significantly decreases tumour necrosis factor alpha secretion in activated human peripheral blood mononuclear cells, purified CD14 monocytes and dendritic cells, as well as in lamina propria mononuclear cells from patients with IBD. CONCLUSIONS: FXR activation prevents chemically induced intestinal inflammation, with improvement of colitis symptoms, inhibition of epithelial permeability, and reduced goblet cell loss. Furthermore, FXR activation inhibits proinflammatory cytokine production in vivo in the mouse colonic mucosa, and ex vivo in different immune cell populations. The findings provide a rationale to explore FXR agonists as a novel therapeutic strategy for IBD. PMID- 21242262 TI - Prospective study of serum cysteine levels and oesophageal and gastric cancers in China. AB - BACKGROUND: Cancers of the upper gastrointestinal tract remain a significant cause of morbidity and mortality. Cysteine, known to be involved in a myriad of immuno-modulatory, anti-oxidant, and anti-carcinogenic pathways, has not been investigated in the aetiology of oesophageal or gastric cancers. To examine the relationship between serum cysteine concentration and risk of these cancers we conducted a nested case-cohort study within the General Population Nutrition Intervention Trial in Linxian, China. METHODS: 498 oesophageal squamous cell carcinomas (OSCCs) and 255 gastric cardia adenocarcinomas (GCAs) were matched by age and sex to 947 individuals from the wider cohort. We calculated HRs and 95% CIs using the case-cohort estimator for the Cox proportional hazards models, stratified on age and sex, with adjustment for potential confounders. RESULTS: Higher concentrations of serum cysteine were significantly associated with a lower risk of both OSCC and GCA. For those in the highest quartile of serum cysteine, compared to those in the lowest, the multivariate HRs were 0.70 for OSCC (95% CI 0.51 to 0.98) and 0.59 for GCA (95% CI 0.38 to 0.91). These associations were dose dependent (p for trend=0.006 and 0.008, respectively). These inverse associations were not significantly modified by other risk factors, with the exception of age, where a stronger association was noted among persons in the older age strata. CONCLUSION: Higher serum concentrations of cysteine were associated with a significantly reduced risk of OSCC and GCA. Cysteine should be further investigated for its potential as a chemopreventive agent for upper gastrointestinal cancers. PMID- 21242263 TI - Does being born big confer advantages? PMID- 21242264 TI - Seeing is Belizing. PMID- 21242266 TI - Osteopoikilosis in the pelvic region. PMID- 21242265 TI - Binge drinking: all too prevalent and hazardous. PMID- 21242267 TI - Experts call for national immunization registry, coordinated schedules. PMID- 21242268 TI - Free "Global University" launched. PMID- 21242269 TI - Osteopoikilosis in the knee. PMID- 21242270 TI - Benign spotted bones: a diagnostic dilemma. PMID- 21242272 TI - Rwanda struggles to treat its burden of blindness. PMID- 21242271 TI - Association of macrosomia with perinatal and postneonatal mortality among First Nations people in Quebec. AB - BACKGROUND: High prevalence of infant macrosomia (up to 36%, the highest in the world) has been reported in some First Nations communities in the Canadian province of Quebec and the eastern area of the province of Ontario. We aimed to assess whether infant macrosomia was associated with elevated risks of perinatal and postneonatal mortality among First Nations people in Quebec. METHODS: We calculated risk ratios (RRs) of perinatal and postneonatal mortality by birthweight for gestational age, comparing births to First Nations women (n = 5193) versus women whose mother tongue is French (n = 653 424, the majority reference group) in Quebec 1991-2000. RESULTS: The prevalence of infant macrosomia (birthweight for gestational age > 90th percentile) was 27.5% among births to First Nations women, which was 3.3 times (confidence interval [CI] 3.2 3.5) higher than the prevalence (8.3%) among births to women whose mother tongue is French. Risk ratios for perinatal mortality among births to First Nations women were 1.8 (95% CI 1.3-2.5) for births with weight appropriate for gestational age, 4.1 (95% CI 2.4-7.0) for small-for-gestational-age (< 10th percentile) births and < 1 (not significant) for macrosomic births compared to births among women whose mother tongue is French. The RRs for postneonatal mortality were 4.3 (95% CI 2.7-6.7) for infants with appropriate-for-gestational age birthweight and 8.3 (95% CI 4.0-17.0) for infants with macrosomia. INTERPRETATION: Macrosomia was associated with a generally protective effect against perinatal death, but substantially greater risks of postneonatal death among births to First Nations women in Quebec versus women whose mother tongue is French. PMID- 21242273 TI - Metastasis from renal cell carcinoma to the thyroid 12 years after nephrectomy. PMID- 21242274 TI - The risk of hypotension following co-prescription of macrolide antibiotics and calcium-channel blockers. AB - BACKGROUND: The macrolide antibiotics clarithromycin and erythromycin may potentiate calcium-channel blockers by inhibiting cytochrome P450 isoenzyme 3A4. However, this potential drug interaction is widely underappreciated and its clinical consequences have not been well characterized. We explored the risk of hypotension or shock requiring hospital admission following the simultaneous use of calcium-channel blockers and macrolide antibiotics. METHODS: We conducted a population-based, nested, case-crossover study involving people aged 66 years and older who had been prescribed a calcium-channel blocker between Apr. 1, 1994, and Mar. 31, 2009. Of these patients, we included those who had been admitted to hospital for the treatment of hypotension or shock. For each antibiotic, we estimated the risk of hypotension or shock associated with the use of a calcium blocker using a pair-matched analytic approach to contrast each patient's exposure to each macrolide antibiotic (erythromycin, clarithromycin or azithromycin) in a seven-day risk interval immediately before admission to hospital and in a seven-day control interval one month earlier. RESULTS: Of the 7100 patients admitted to hospital because of hypotension while receiving a calcium-channel blocker, 176 had been prescribed a macrolide antibiotic during either the risk or control intervals. Erythromycin (the strongest inhibitor of cytochrome P450 3A4) was most strongly associated with hypotension (odds ratio [OR] 5.8, 95% confidence interval [CI] 2.3-15.0), followed by clarithromycin (OR 3.7, 95% CI 2.3-6.1). Azithromycin, which does not inhibit cytochrome P450 3A4, was not associated with an increased risk of hypotension (OR 1.5, 95% CI 0.8 2.8). We found similar results in a stratified analysis of patients who received only dihydropyridine calcium-channel blockers. INTERPRETATION: In older patients receiving a calcium-channel blocker, use of erythromycin or clarithromycin was associated with an increased risk of hypotension or shock requiring admission to hospital. Preferential use of azithromycin should be considered when a macrolide antibiotic is required for patients already receiving a calcium-channel blocker. PMID- 21242275 TI - Curcumin modulates the immune response associated with LPS-induced periodontal disease in rats. AB - Curcumin is a plant-derived dietary spice ascribed various biological activities. Curcumin therapeutic applications have been studied in a variety of conditions, but not on periodontal disease. Periodontal disease is a chronic inflammatory condition initiated by an immune response to micro-organisms of the dental biofilm. Experimental periodontal disease was induced in rats by injecting LPS in the gingival tissues on the palatal aspect of upper first molars (30 ug LPS, 3 times/week for 2 weeks). Curcumin was administered to rats daily via oral gavage at 30 and 100 mg/kg body weight. Reverse transcriptase-qPCR and ELISA were used to determine the expression of IL-6, TNF-alpha and prostaglandin E(2) synthase on the gingival tissues. The inflammatory status was evaluated by stereometric and descriptive analysis on hematoxylin/eosin-stained sections, whereas modulation of p38 MAPK and NK-kappaB signaling was assessed by Western blot. Curcumin effectively inhibited cytokine gene expression at mRNA and protein levels, but NF kappaB was inhibited only with the lower dose of curcumin, whereas p38 MAPK activation was not affected. Curcumin produced a significant reduction on the inflammatory infiltrate and increased collagen content and fibroblastic cell numbers. Curcumin potently inhibits innate immune responses associated with periodontal disease, suggesting a therapeutic potential in this chronic inflammatory condition. PMID- 21242276 TI - Chinese herbal medicines, aristolochic acid and Balkan endemic nephropathy. PMID- 21242278 TI - Journal requirements to register observational studies: OEM's policy. PMID- 21242277 TI - Differences in the association between sickness absence and long-term sub-optimal health by occupational position: a 14-year follow-up in the GAZEL cohort. AB - OBJECTIVES: Although sickness absence is a strong predictor of health, whether this association varies by occupational position has rarely been examined. The aim of this study was to investigate overall and diagnosis-specific sickness absence as a predictor of future long-term sub-optimal health by occupational position. METHODS: This was a prospective occupational cohort study of 15 320 employees (73% men) aged 37-51. Sickness absences (1990-1992), included in 13 diagnostic categories, were examined by occupational position in relation to self rated health measured annually during 1993-2006. RESULTS: 60% of employees in higher occupational positions and 22% in lower positions had no sickness absence. Conversely, 9.5% of employees in higher positions and 40% in lower positions had over 30 sick-leave days. Repeated-measures logistic regression analyses adjusted for age, sex and chronic disease showed employees with over 30 days absence, compared to those with no absence, had approximately double the risk of sub optimal health over the 14-year follow-up in all occupational positions. 1-30 days sick-leave was associated with greater odds of sub-optimal health in the high (OR 1.48; 95% CI 1.27 to 1.72) and intermediate (1.29; 1.15 to 1.45) but not lower occupational positions (1.06; 0.82 to 1.38). Differences by occupational position in the association between sickness absence in 13 specific diagnostic categories and sub-optimal health over the ensuing 14 years were limited to stronger associations observed with cancer and mental disorders in the higher occupational positions. CONCLUSIONS: The association between sickness absence of more than 30 days over 3 years and future long-term self-rated health appears to differ little by occupational position. PMID- 21242281 TI - Parallel high-throughput RNA interference screens identify PINK1 as a potential therapeutic target for the treatment of DNA mismatch repair-deficient cancers. AB - Synthetic lethal approaches to cancer treatment have the potential to deliver relatively large therapeutic windows and therefore significant patient benefit. To identify potential therapeutic approaches for cancers deficient in DNA mismatch repair (MMR), we have carried out parallel high-throughput RNA interference screens using tumor cell models of MSH2- and MLH1-related MMR deficiency. We show that silencing of the PTEN-induced putative kinase 1 (PINK1), is synthetically lethal with MMR deficiency in cells with MSH2, MLH1, or MSH6 dysfunction. Inhibition of PINK1 in an MMR-deficient background results in an elevation of reactive oxygen species and the accumulation of both nuclear and mitochondrial oxidative DNA lesions, which likely limit cell viability. Therefore, PINK1 represents a potential therapeutic target for the treatment of cancers characterized by MMR deficiency caused by a range of different gene deficiencies. PMID- 21242282 TI - Multiplexed homogeneous proximity ligation assays for high-throughput protein biomarker research in serological material. AB - A high throughput protein biomarker discovery tool has been developed based on multiplexed proximity ligation assays in a homogeneous format in the sense of no washing steps. The platform consists of four 24-plex panels profiling 74 putative biomarkers with sub-pm sensitivity each consuming only 1 MUl of human plasma sample. The system uses either matched monoclonal antibody pairs or the more readily available single batches of affinity purified polyclonal antibodies to generate the target specific reagents by covalently linking with unique nucleic acid sequences. These paired sequences are united by DNA ligation upon simultaneous target binding forming a PCR amplicon. Multiplex proximity ligation assays thereby converts multiple target analytes into real-time PCR amplicons that are individually quantified using microfluidic high capacity qPCR in nano liter volumes. The assay shows excellent specificity, even in multiplex, by its dual recognition feature, its proximity requirement, and most importantly by using unique sequence specific reporter fragments on both antibody-based probes. To illustrate the potential of this protein detection technology, a pilot biomarker research project was performed using biobanked plasma samples for the detection of colorectal cancer using a multivariate signature. PMID- 21242283 TI - Embedded symptom validity tests and overall neuropsychological test performance. AB - A sample of 314 consecutive clinical and forensic referrals with mild traumatic brain injury was evaluated using the Meyers Neuropsychological Battery (MNB). A comparison was made of the test performance and performance on the embedded Symptom Validity Tests (SVTs) with a control for multicolinearity utilized. Using the nine embedded SVTs in the MNB, the incidence of poor effort fell at 26% of the total sample. Involvement in litigation was related to more failures on the individual SVTs. The correlation between failed effort measures and the Overall Test Battery Mean (OTBM) was consistently negative, regardless of litigation status, in that more failures were associated with lower OTBM scores. The correlation between the number of SVTs failed and the OTBM was -.77. Our results are similar to those presented by Green, Rohling, Lees-Haley, and Allen (2001); who reported a .73 correlation with the failure on the Word Memory Test and performance on the OTBM. The results of the current study also indicate that 50% of the variance in neuropsychological testing can be accounted by failures on internal SVTs. PMID- 21242285 TI - Utility of post-traumatic amnesia in predicting 1-year productivity following traumatic brain injury: comparison of the Russell and Mississippi PTA classification intervals. AB - BACKGROUND: Duration of post-traumatic amnesia (PTA) correlates with global outcomes and functional disability. Russell proposed the use of PTA duration intervals as an index for classification of traumatic brain injury (TBI) severity. Alternative duration-based schemata have been recently proposed as better predictors of outcome to the commonly cited Russell intervals. OBJECTIVE: Validate a TBI severity classification model (Mississippi intervals) of PTA duration anchored to late productivity outcome, and compare sensitivity against the Russell intervals. METHODS: Prospective observational data on TBI Model System participants (n=3846) with known or imputed PTA duration during acute hospitalisation. Productivity status at 1-year postinjury was used to compare predicted outcomes using the Mississippi and Russell classification intervals. Logistic regression model-generated curves were used to compare the performance of the classification intervals by assessing the area under the curve (AUC); the highest AUC represented the best-performing model. RESULTS: All severity variables evaluated were individually associated with return to productivity at 1 year (RTP1). Age was significantly associated with RTP1; however, younger patients had a different association than older patients. After adjustment for individually significant variables, the odds of RTP1 decrease by 14% with every additional week of PTA duration (95% CI 12% to 17%; p<0.0001). The AUC for the Russell intervals was significantly smaller than the Mississippi intervals. CONCLUSIONS: PTA duration is an important predictor of late productivity outcome after TBI. The Mississippi PTA interval classification model is a valid predictor of productivity at 1 year postinjury and provides a more sensitive categorisation of PTA values than the Russell intervals. PMID- 21242286 TI - 1H-magnetic resonance spectroscopy indicates damage to cerebral white matter in the subacute phase after CO poisoning. AB - OBJECTIVE: The authors examined whether (1)H-magnetic resonance spectroscopy (MRS) can identify damage to the centrum semiovale in the subacute phase after CO exposure. METHODS: Subjects comprised 29 adult patients who were treated with hyperbaric oxygenation within a range of 4-95 h (mean 18.7 h) after CO exposure. Subjects were classified into three groups according to clinical behaviours: Group A, patients with transit acute symptoms only; Group P, patients with persistent neurological symptoms; and Group D, patients with 'delayed neuropsychiatric sequelae' occurring after a lucid interval. MRS of bilateral centrum semiovale was performed 2 weeks after CO inhalation for all patients and 13 healthy volunteers. The mean ratios of choline-containing compounds/creatine ((mean)Cho/Cr) and N-acetylaspartate/Cr ((mean)NAA/Cr) for bilateral centrum semiovale were calculated and compared between the three CO groups and controls. Myelin basic protein (MBP) concentration in cerebrospinal fluid was examined at 2 weeks to evaluate the degree of demyelination in patients. RESULTS: MBP concentration was abnormal for almost all patients in Groups P and D, but was not abnormal for any Group A patients. The (mean)Cho/Cr ratios were significantly higher in Groups P and D than in Group A. No significant difference in (mean)NAA/Cr ratio was seen between the three pathological groups and controls. A significant correlation was identified between MBP and (mean)Cho/Cr ratio. CONCLUSIONS: These results suggest that the Cho/Cr ratio in the subacute phase after CO intoxication represents early demyelination in the centrum semiovale, and can predict chronic neurological symptoms. PMID- 21242287 TI - Visual extinction in relation to visuospatial neglect after right-hemispheric stroke: quantitative assessment and statistical lesion-symptom mapping. AB - BACKGROUND: Visual neglect and extinction are two common neurological syndromes in patients with right-hemispheric brain damage. Whether and how these two syndromes are associated or share common neural substrates is still a matter of debate. METHODS: To address these issues, the authors investigated 56 patients with right-hemispheric stroke with a novel diagnostic test to detect extinction and neglect. In this computerised task, subjects had to respond to target stimuli in uni- and bilateral stimulation conditions with detection probabilities being assessed. A cluster-analytical approach identified 18 patients with neglect and 13 patients with extinction. Statistical lesion-symptom mapping analyses with measures for extinction and neglect were performed. RESULTS: Extinction and neglect co-occurred in a subset of patients but were also observed independently from each other, thereby constituting a double dissociation. Lesions within the right inferior parietal cortex were significantly associated with the severity of visual extinction. Visuospatial neglect was related to damage of fronto-parietal brain regions, with parieto-occipital areas affecting line bisection and dorsal fronto-parietal areas affecting cancellation task performance, respectively. CONCLUSION: Quantifying lesion-induced symptoms with this novel paradigm shows that extinction and neglect are dissociable syndromes in patients with right hemispheric stroke. Furthermore, extinction and neglect can be related to differential neural substrates, with extinction being related to focal brain damage within the right inferior parietal cortex. PMID- 21242288 TI - Predictive ability of preinjury stressful life events and post-traumatic stress symptoms for outcomes following mild traumatic brain injury: analysis in a prospective emergency room sample. AB - BACKGROUND: A subset of persons with mild traumatic brain injury (mTBI) experience long-term difficulties. Preinjury stress has been hypothesised to play a role in long-term maintenance of symptoms. OBJECTIVE: To investigate the predictive ability of preinjury stressful life events and post-traumatic stress symptoms to health-related quality of life and emotional distress after mTBI. METHODS: Within 2 weeks of injury, 186 participants with mTBI who were admitted to an emergency centre completed an interview and questionnaires regarding preinjury functioning, including the Stressful Life Events Questionnaire and the Post-Traumatic Stress Disorder Checklist. Outcomes were assessed at 3 months after injury and included the depression and anxiety subscales of the Brief Symptom Inventory, and the physical and mental component scores of the 36-item Short-Form Health Survey (SF-36). The incidence and type of stressful life events were reported. Hierarchical regression analyses were used to determine the predictive utility of Stressful Life Events Questionnaire and Post-Traumatic Stress Disorder Checklist after controlling for age, injury severity (complicated versus uncomplicated mild) and preinjury depression. RESULTS: Several potentially life-altering stressful events were endorsed by at least 25% of participants as having been experienced prior to injury. The incidence of stressful life events was a significant predictor of all four outcome variables. History of post traumatic stress symptoms was predictive of scores on the SF-36 mental health component. CONCLUSIONS: A history of stressful events may predispose persons with mTBI to have poor outcomes. History of stress should be assessed during the early stages after mTBI to help identify those who could benefit from therapies to assist with adjustment and maximise recovery. PMID- 21242289 TI - The Drosophila blood brain barrier is maintained by GPCR-dependent dynamic actin structures. AB - The blood brain barrier (BBB) is essential for insulation of the nervous system from the surrounding environment. In Drosophila melanogaster, the BBB is maintained by septate junctions formed between subperineurial glia (SPG) and requires the Moody/G protein-coupled receptor (GPCR) signaling pathway. In this study, we describe novel specialized actin-rich structures (ARSs) that dynamically form along the lateral borders of the SPG cells. ARS formation and association with nonmuscle myosin is regulated by Moody/GPCR signaling and requires myosin activation. Consistently, an overlap between ARS localization, elevated Ca(2+) levels, and myosin light chain phosphorylation is detected. Disruption of the ARS by inhibition of the actin regulator Arp2/3 complex leads to abrogation of the BBB. Our results suggest a mechanism by which the Drosophila BBB is maintained by Moody/GPCR-dependent formation of ARSs, which is supported by myosin activation. The localization of the ARSs close to the septate junctions enables efficient sealing of membrane gaps formed during nerve cord growth. PMID- 21242290 TI - Neural integrity is maintained by dystrophin in C. elegans. AB - The dystrophin protein complex (DPC), composed of dystrophin and associated proteins, is essential for maintaining muscle membrane integrity. The link between mutations in dystrophin and the devastating muscle failure of Duchenne's muscular dystrophy (DMD) has been well established. Less well appreciated are the accompanying cognitive impairment and neuropsychiatric disorders also presented in many DMD patients, which suggest a wider role for dystrophin in membrane cytoskeleton function. This study provides genetic evidence of a novel role for DYS-1/dystrophin in maintaining neural organization in Caenorhabditis elegans. This neuronal function is distinct from the established role of DYS-1/dystrophin in maintaining muscle integrity and regulating locomotion. SAX-7, an L1 cell adhesion molecule (CAM) homologue, and STN-2/gamma-syntrophin also function to maintain neural integrity in C. elegans. This study provides biochemical data that show that SAX-7 associates with DYS-1 in an STN-2/gamma-syntrophin-dependent manner. These results reveal a recruitment of L1CAMs to the DPC to ensure neural integrity is maintained. PMID- 21242291 TI - RAD21L, a novel cohesin subunit implicated in linking homologous chromosomes in mammalian meiosis. AB - Cohesins are multi-subunit protein complexes that regulate sister chromatid cohesion during mitosis and meiosis. Here we identified a novel kleisin subunit of cohesins, RAD21L, which is conserved among vertebrates. In mice, RAD21L is expressed exclusively in early meiosis: it apparently replaces RAD21 in premeiotic S phase, becomes detectable on the axial elements in leptotene, and stays on the axial/lateral elements until mid pachytene. RAD21L then disappears, and is replaced with RAD21. This behavior of RAD21L is unique and distinct from that of REC8, another meiosis-specific kleisin subunit. Remarkably, the disappearance of RAD21L at mid pachytene correlates with the completion of DNA double-strand break repair and the formation of crossovers as judged by colabeling with molecular markers, gamma-H2AX, MSH4, and MLH1. RAD21L associates with SMC3, STAG3, and either SMC1alpha or SMC1beta. Our results suggest that cohesin complexes containing RAD21L may be involved in synapsis initiation and crossover recombination between homologous chromosomes. PMID- 21242292 TI - A single ubiquitin is sufficient for cargo protein entry into MVBs in the absence of ESCRT ubiquitination. AB - ESCRTs (endosomal sorting complexes required for transport) bind and sequester ubiquitinated membrane proteins and usher them into multivesicular bodies (MVBs). As Ubiquitin (Ub)-binding proteins, ESCRTs themselves become ubiquitinated. However, it is unclear whether this regulates a critical aspect of their function or is a nonspecific consequence of their association with the Ub system. We investigated whether ubiquitination of the ESCRTs was required for their ability to sort cargo into the MVB lumen. Although we found that Rsp5 was the main Ub ligase responsible for ubiquitination of ESCRT-0, elimination of Rsp5 or elimination of the ubiquitinatable lysines within ESCRT-0 did not affect MVB sorting. Moreover, by fusing the catalytic domain of deubiquitinating peptidases onto ESCRTs, we could block ESCRT ubiquitination and the sorting of proteins that undergo Rsp5-dependent ubiquitination. Yet, proteins fused to a single Ub moiety were efficiently delivered to the MVB lumen, which strongly indicates that a single Ub is sufficient in sorting MVBs in the absence of ESCRT ubiquitination. PMID- 21242293 TI - ATR-mediated phosphorylation of DNA polymerase eta is needed for efficient recovery from UV damage. AB - DNA polymerase eta (poleta) belongs to the Y-family of DNA polymerases and facilitates translesion synthesis past UV damage. We show that, after UV irradiation, poleta becomes phosphorylated at Ser601 by the ataxia-telangiectasia mutated and Rad3-related (ATR) kinase. DNA damage-induced phosphorylation of poleta depends on its physical interaction with Rad18 but is independent of PCNA monoubiquitination. It requires the ubiquitin-binding domain of poleta but not its PCNA-interacting motif. ATR-dependent phosphorylation of poleta is necessary to restore normal survival and postreplication repair after ultraviolet irradiation in xeroderma pigmentosum variant fibroblasts, and is involved in the checkpoint response to UV damage. Taken together, our results provide evidence for a link between DNA damage-induced checkpoint activation and translesion synthesis in mammalian cells. PMID- 21242294 TI - Dectin-1 diversifies Aspergillus fumigatus-specific T cell responses by inhibiting T helper type 1 CD4 T cell differentiation. AB - Pulmonary infection of mice with Aspergillus fumigatus induces concurrent T helper type 1 (Th1) and Th17 responses that depend on Toll-like receptor/MyD88 and Dectin-1, respectively. However, the mechanisms balancing Th1 and Th17 CD4 T cell populations during infection remain incompletely defined. In this study, we show that Dectin-1 deficiency disproportionally increases Th1 responses and decreases Th17 differentiation after A. fumigatus infection. Dectin-1 signaling in A. fumigatus-infected wild-type mice reduces IFN-gamma and IL-12p40 expression in the lung, thereby decreasing T-bet expression in responding CD4 T cells and enhancing Th17 responses. Absence of IFN-gamma or IL-12p35 in infected mice or T bet in responding CD4 T cells enhances Th17 differentiation, independent of Dectin-1 expression, in A. fumigatus-infected mice. Transient deletion of monocyte-derived dendritic cells also reduces Th1 and boosts Th17 differentiation of A. fumigatus-specific CD4 T cells. Our findings indicate that Dectin-1 mediated signals alter CD4 T cell responses to fungal infection by decreasing the production of IL-12 and IFN-gamma in innate cells, thereby decreasing T-bet expression in A. fumigatus-specific CD4 T cells and enabling Th17 differentiation. PMID- 21242295 TI - The human syndrome of dendritic cell, monocyte, B and NK lymphoid deficiency. AB - Congenital or acquired cellular deficiencies in humans have the potential to reveal much about normal hematopoiesis and immune function. We show that a recently described syndrome of monocytopenia, B and NK lymphoid deficiency additionally includes the near absence of dendritic cells. Four subjects showed severe depletion of the peripheral blood HLA-DR(+) lineage(-) compartment, with virtually no CD123(+) or CD11c(+) dendritic cells (DCs) and very few CD14(+) or CD16(+) monocytes. The only remaining HLA-DR(+) lineage(-) cells were circulating CD34(+) progenitor cells. Dermal CD14(+) and CD1a(+) DC were also absent, consistent with their dependence on blood-derived precursors. In contrast, epidermal Langerhans cells and tissue macrophages were largely preserved. Combined loss of peripheral DCs, monocytes, and B and NK lymphocytes was mirrored in the bone marrow by complete absence of multilymphoid progenitors and depletion of granulocyte-macrophage progenitors. Depletion of the HLA-DR(+) peripheral blood compartment was associated with elevated serum fms-like tyrosine kinase ligand and reduced circulating CD4(+)CD25(hi)FoxP3(+) T cells, supporting a role for DC in T reg cell homeostasis. PMID- 21242296 TI - Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme. AB - Proliferating embryonic and cancer cells preferentially use aerobic glycolysis to support growth, a metabolic alteration commonly referred to as the "Warburg effect." Here, we show that the glycolytic enzyme hexokinase 2 (HK2) is crucial for the Warburg effect in human glioblastoma multiforme (GBM), the most common malignant brain tumor. In contrast to normal brain and low-grade gliomas, which express predominantly HK1, GBMs show increased HK2 expression. HK2 expression correlates with worse overall survival of GBM patients. Depletion of HK2, but neither HK1 nor pyruvate kinase M2, in GBM cells restored oxidative glucose metabolism and increased sensitivity to cell death inducers such as radiation and temozolomide. Intracranial xenografts of HK2-depleted GBM cells showed decreased proliferation and angiogenesis, but increased invasion, as well as diminished expression of hypoxia inducible factor 1alpha and vascular endothelial growth factor. In contrast, exogenous HK2 expression in GBM cells led to increased proliferation, therapeutic resistance, and intracranial growth. Growth was dependent on both glucose phosphorylation and mitochondrial translocation mediated by AKT signaling, which is often aberrantly activated in GBMs. Collectively, these findings suggest that therapeutic strategies to modulate the Warburg effect, such as targeting of HK2, may interfere with growth and therapeutic sensitivity of some GBMs. PMID- 21242297 TI - Growth differentiation factor 15 deficiency protects against atherosclerosis by attenuating CCR2-mediated macrophage chemotaxis. AB - Growth differentiation factor (GDF) 15 is a member of the transforming growth factor beta (TGF-beta) superfamily, which operates in acute phase responses through a currently unknown receptor. Elevated GDF-15 serum levels were recently identified as a risk factor for acute coronary syndromes. We show that GDF-15 expression is up-regulated as disease progresses in murine atherosclerosis and primarily colocalizes with plaque macrophages. Hematopoietic GDF-15 deficiency in low density lipoprotein receptor(-/-) mice led to impaired initial lesion formation and increased collagen in later lesions. Although lesion burden in GDF 15(-/-) chimeras was unaltered, plaques had reduced macrophage infiltrates and decreased necrotic core formation, all features of improved plaque stability. In vitro studies pointed to a TGFbetaRII-dependent regulatory role of GDF-15 in cell death regulation. Importantly, GDF-15(-/-) macrophages displayed reduced CCR2 expression, whereas GDF-15 promoted macrophage chemotaxis in a strictly CCR2- and TGFbetaRII-dependent manner, a phenomenon which was not observed in G protein coupled receptor kinase 2(+/-) macrophages. In conclusion, GDF-15 deletion has a beneficial effect both in early and later atherosclerosis by inhibition of CCR2 mediated chemotaxis and by modulating cell death. Our study is the first to identify GDF-15 as an acute phase modifier of CCR2/TGFbetaRII-dependent inflammatory responses to vascular injury. PMID- 21242298 TI - Cells on the MEND: exploring the role of lipidic forces in membrane trafficking. PMID- 21242299 TI - Mechanistic analysis of massive endocytosis in relation to functionally defined surface membrane domains. AB - A large fraction of endocytosis in eukaryotic cells occurs without adaptors or dynamins. Here, we present evidence for the involvement of lipid domains in massive endocytosis (MEND) activated by both large Ca transients and amphipathic compounds in baby hamster kidney and HEK293 cells. First, we demonstrate functional coupling of the two MEND types. Ca transients can strongly facilitate detergent-activated MEND. Conversely, an amphipath with dual alkyl chains, ditridecylphthalate, is without effect in the absence of Ca transients but induces MEND to occur within seconds during Ca transients. Ca transients, like amphipaths, enhance the extraction of lipids from cells by beta-cyclodextrins. Second, we demonstrate that electrical and/or optical signals generated by selected membrane probes are nearly insensitive to MEND, suggesting that those probes segregate into membrane domains that are not taken up by MEND. Triphenylphosphoniums are increasingly excluded from domains that internalize as the carbon chain length increases from 4 to 12. The small cationic membrane dye, FM 4-64, binds well to domains that internalize, whereas a closely related dye with a larger hydrophobic moiety, di-4-ANEPPDHQ (ANEPPDHQ) is excluded. Multiple carrier-type ionophores and a small amphipathic anion, niflumic acid, are also excluded. Probes with modest MEND sensitivity include the hydrophobic anion, dipicrylamine, carbonyl cyanide m-chlorophenylhydrazone, and NBD phosphatidylethanolamine. Third, we demonstrate that large Ca transients can strongly enhance the extracellular binding of several membrane probes, monitored electrically or optically, consistent with a more disordered membrane with more amphipath-binding sites. Fluorescence shifts of ANEPPDHQ report increased disorder of the extracellular monolayer after large Ca transients, consistent with an increased propensity of the membrane to phase separate and vesiculate. Collectively, the results indicate that >50% of the outer monolayer is ordered and can be selectively internalized during MEND responses initiated by two very different cell perturbations. PMID- 21242300 TI - Massive endocytosis driven by lipidic forces originating in the outer plasmalemmal monolayer: a new approach to membrane recycling and lipid domains. AB - The roles that lipids play in endocytosis are the subject of debate. Using electrical and imaging methods, we describe massive endocytosis (MEND) in baby hamster kidney (BHK) and HEK293 cells when the outer plasma membrane monolayer is perturbed by the nonionic detergents, Triton X-100 (TX100) and NP-40. Some alkane detergents, the amphipathic drugs, edelfosine and tamoxifen, and the phospholipase inhibitor, U73122, are also effective. Uptake of the membrane tracer, FM 4-64, into vesicles and loss of reversible FM 4-64 binding confirm that 40-75% of the cell surface is internalized. Ongoing MEND stops in 2-4 s when amphipaths are removed, and amphipaths are without effect from the cytoplasmic side. Thus, expansion of the outer monolayer is critical. As found for Ca activated MEND, vesicles formed are <100 nm in diameter, membrane ruffles are lost, and beta-cyclodextrin treatments are inhibitory. However, amphipath activated MEND does not require Ca transients, adenosine triphosphate (ATP) hydrolysis, G protein cycling, dynamins, or actin cytoskeleton remodeling. With elevated cytoplasmic ATP (>5 mM), MEND can reverse completely and be repeated multiple times in BHK and HEK293 cells, but not cardiac myocytes. Reversal is blocked by N-ethylmaleimide and a nitric oxide donor, nitroprusside. Constitutively expressed Na/Ca exchangers internalize roughly in proportion to surface membrane, whereas Na/K pump activities decrease over-proportionally. Sodium dodecyl sulfate and dodecylglucoside do not cause MEND during their application, but MEND occurs rapidly when they are removed. As monitored capacitively, the binding of these detergents decreases with MEND, whereas TX100 binding does not decrease. In summary, nonionic detergents can fractionate the plasma membrane in vivo, and vesicles formed connect immediately to physiological membrane-trafficking mechanisms. We suggest that lateral and transbilayer inhomogeneities of the plasma membrane provide potential energies that, when unbridled by triggers, can drive endocytosis by lipidic forces. PMID- 21242301 TI - Life-course socioeconomic position and type 2 diabetes mellitus: The Framingham Offspring Study. AB - Evidence is lacking on whether the duration and timing of low socioeconomic position (SEP) across a person's life course may be associated with incidence of type 2 diabetes mellitus (T2D). The authors' objectives were to investigate associations between cumulative SEP and the incidence of T2D in the Framingham Offspring Study (n = 1,893; 52% women; mean baseline age = 34 years). Pooled logistic regression analyses demonstrated that age-adjusted cumulative SEP was associated with T2D in women (for low vs. high cumulative SEP, odds ratio (OR) = 1.92, 95% confidence interval (CI): 1.08, 3.42). Age-adjusted analyses for young adulthood SEP (7.85 for <=12 vs. >16 years of education, OR = 2.84, 95% CI: 1.03), active professional life SEP (for laborer vs. professional/executive/supervisory/technical occupations, OR = 2.40, 95% CI: 1.05, 5.47), and social-mobility frameworks (for declining life-course SEP, OR = 2.99, 95% CI: 1.39, 6.44; for stable low vs. stable high life-course SEP, OR = 1.85, 95% CI: 1.02, 3.35) all demonstrated associations between low SEP and T2D incidence in women. No association was observed between childhood SEP and T2D in women for father's education (some high school or less vs. any postsecondary education, OR = 1.26, 95% CI: 0.72, 2.22). In men, there was little evidence of associations between life-course SEP and T2D incidence. These findings suggest that cumulative SEP is inversely associated with incidence of T2D in women, and that this association may be primarily due to the women's educational levels and occupations. PMID- 21242302 TI - Alternative methods of accounting for underreporting and overreporting when measuring dietary intake-obesity relations. AB - Misreporting characterized by the reporting of implausible energy intakes may undermine the valid estimation of diet-disease relations, but the methods to best identify and account for misreporting are unknown. The present study compared how alternate approaches affected associations between selected dietary factors and body mass index (BMI) by using data from the European Prospective Investigation Into Cancer and Nutrition-Spain. A total of 24,332 women and 15,061 men 29-65 years of age recruited from 1992 to 1996 for whom measured height and weight and validated diet history data were available were included. Misreporters were identified on the basis of disparities between reported energy intakes and estimated requirements calculated using the original Goldberg method and 2 alternatives: one that substituted basal metabolic rate equations that are more valid at higher BMIs and another that used doubly labeled water-predicted total energy expenditure equations. Compared with results obtained using the original method, underreporting was considerably lower and overreporting higher with alternative methods, which were highly concordant. Accounting for misreporters with all methods yielded diet-BMI relations that were more consistent with expectations; alternative methods often strengthened associations. For example, among women, multivariable-adjusted differences in BMI for the highest versus lowest vegetable intake tertile (beta = 0.37 (standard error, 0.07)) were neutral after adjusting with the original method (beta = 0.01 (standard error, 07)) and negative using the predicted total energy expenditure method with stringent cutoffs (beta = -0.15 (standard error, 0.07)). Alternative methods may yield more valid associations between diet and obesity-related outcomes. PMID- 21242303 TI - Invited commentary: on population subgroups, mathematics, and interventions. AB - New sex-specific equations, each with race/ethnic-specific intercept, for predicted lung function illustrate a methodological point, that complex differences between groups may not imply interactions with other predictors, such as age and height. The new equations find that race/ethnic identity does not interact with either age or height in the prediction equations, although there are race/ethnic-specific offsets. Further study is warranted of the effect of possible small race/ethnic interactions on disease classification. Additional study of repeated measures of lung function is warranted, given that the new equations were developed in cross-sectional designs. Predicting lung function is more than a methodological exercise. Predicted values are important in disease diagnosis and monitoring. It is suggested that measurement and tracking of lung function throughout young adulthood could be used to provide an early warning of potential long-term lung function losses to encourage improvement of risky behaviors including smoking and failure to maintain normal body weight in the general population. PMID- 21242304 TI - Similar relation of age and height to lung function among Whites, African Americans, and Hispanics. AB - Current guidelines recommend separate spirometry reference equations for whites, African Americans, and Mexican Americans, but the justification for this recommendation is controversial. The authors examined the statistical justification for race/ethnic-specific reference equations in adults in the Third National Health and Nutrition Examination Survey (1988-1994) and the Multi-Ethnic Study of Atherosclerosis Lung Study (2000-2006). Spirometry was measured following American Thoracic Society guidelines. "Statistical justification" was defined as the presence of effect modification by race/ethnicity among never smoking participants without respiratory disease or symptoms and was tested with interaction terms for race/ethnicity (* age and height) in regression models. There was no evidence of effect modification by race/ethnicity for forced expiratory volume in 1 second, forced vital capacity, or the forced expiratory volume in 1 second/forced vital capacity ratio among white, African-American, and Mexican-American men or women on an additive scale or a log scale. Interaction terms for race/ethnicity explained less than 1% of variability in lung function. The mean lung function for a given age, gender, and height was the same for whites and Mexican Americans but was lower for African Americans. Findings were similar in the Multi-Ethnic Study of Atherosclerosis Lung Study. The associations of age and height with lung function are similar across the 3 major US race/ethnic groups. Multiethnic rather than race/ethnic-specific spirometry reference equations are applicable for the US population. PMID- 21242305 TI - SmgGDS is a guanine nucleotide exchange factor that specifically activates RhoA and RhoC. AB - SmgGDS is an atypical guanine nucleotide exchange factor (GEF) that promotes both cell proliferation and migration and is up-regulated in several types of cancer. SmgGDS has been previously shown to activate a wide variety of small GTPases, including the Ras family members Rap1a, Rap1b, and K-Ras, as well as the Rho family members Cdc42, Rac1, Rac2, RhoA, and RhoB. In contrast, here we show that SmgGDS exclusively activates RhoA and RhoC among a large panel of purified GTPases. Consistent with the well known properties of GEFs, this activation is catalytic, and SmgGDS preferentially binds to nucleotide-depleted RhoA relative to either GDP- or GTPgammaS-bound forms. However, mutational analyses indicate that SmgGDS utilizes a distinct exchange mechanism compared with canonical GEFs and in contrast to known GEFs requires RhoA to retain a polybasic region for activation. A homology model of SmgGDS highlights an electronegative surface patch and a highly conserved binding groove. Mutation of either area ablates the ability of SmgGDS to activate RhoA. Finally, the in vitro specificity of SmgGDS for RhoA and RhoC is retained in cells. Together, these results indicate that SmgGDS is a bona fide GEF that specifically activates RhoA and RhoC through a unique mechanism not used by other Rho family exchange factors. PMID- 21242306 TI - Reactive oxygen species regulate nucleostemin oligomerization and protein degradation. AB - Nucleostemin (NS) is a nucleolar-nucleoplasmic shuttle protein that regulates cell proliferation, binds p53 and Mdm2, and is highly expressed in tumor cells. We have identified NS as a target of oxidative regulation in transformed hematopoietic cells. NS oligomerization occurs in HL-60 leukemic cells and Raji B lymphoblasts that express high levels of c-Myc and have high intrinsic levels of reactive oxygen species (ROS); reducing agents dissociate NS into monomers and dimers. Exposure of U2OS osteosarcoma cells with low levels of intrinsic ROS to hydrogen peroxide (H(2)O(2)) induces thiol-reversible disulfide bond-mediated oligomerization of NS. Increased exposure to H(2)O(2) impairs NS degradation, immobilizes the protein within the nucleolus, and results in detergent-insoluble NS. The regulation of NS by ROS was validated in a murine lymphoma tumor model in which c-Myc is overexpressed and in CD34+ cells from patients with chronic myelogenous leukemia in blast crisis. In both instances, increased ROS levels were associated with markedly increased expression of NS protein and thiol reversible oligomerization. Site-directed mutagenesis of critical cysteine containing regions of nucleostemin altered both its intracellular localization and its stability. MG132, a potent proteasome inhibitor and activator of ROS, markedly decreased degradation and increased nucleolar retention of NS mutants, whereas N-acetyl-L-cysteine largely prevented the effects of MG132. These results indicate that NS is a highly redox-sensitive protein. Increased intracellular ROS levels, such as those that result from oncogenic transformation in hematopoietic malignancies, regulate the ability of NS to oligomerize, prevent its degradation, and may alter its ability to regulate cell proliferation. PMID- 21242307 TI - Clusterin (apolipoprotein J), a molecular chaperone that facilitates degradation of the copper-ATPases ATP7A and ATP7B. AB - The copper-transporting P(1B)-type ATPases (Cu-ATPases) ATP7A and ATP7B are key regulators of physiological copper levels. They function to maintain intracellular copper homeostasis by delivering copper to secretory compartments and by trafficking toward the cell periphery to export excess copper. Mutations in the genes encoding ATP7A and ATP7B lead to copper deficiency and toxicity disorders, Menkes and Wilson diseases, respectively. This report describes the interaction between the Cu-ATPases and clusterin and demonstrates a chaperone like role for clusterin in facilitating their degradation. Clusterin interacted with both ATP7A and ATP7B in mammalian cells. This interaction increased under conditions of oxidative stress and with mutations in ATP7B that led to its misfolding and mislocalization. A Wilson disease patient mutation (G85V) led to enhanced ATP7B turnover, which was further exacerbated when cells overexpressed clusterin. We demonstrated that clusterin-facilitated degradation of mutant ATP7B is likely to involve the lysosomal pathway. The knockdown and overexpression of clusterin increased and decreased, respectively, the Cu-ATPase-mediated copper export capacity of cells. These results highlight a new role for intracellular clusterin in mediating Cu-ATPase quality control and hence in the normal maintenance of copper homeostasis, and in promoting cell survival in the context of disease. Based on our findings, it is possible that variations in clusterin expression and function could contribute to the variable clinical expression of Menkes and Wilson diseases. PMID- 21242308 TI - Cytoplasmic mRNP granules at a glance. PMID- 21242310 TI - Post-transcriptional control of circadian rhythms. AB - Circadian rhythms exist in most living organisms. The general molecular mechanisms that are used to generate 24-hour rhythms are conserved among organisms, although the details vary. These core clocks consist of multiple regulatory feedback loops, and must be coordinated and orchestrated appropriately for the fine-tuning of the 24-hour period. Many levels of regulation are important for the proper functioning of the circadian clock, including transcriptional, post-transcriptional and post-translational mechanisms. In recent years, new information about post-transcriptional regulation in the circadian system has been discovered. Such regulation has been shown to alter the phase and amplitude of rhythmic mRNA and protein expression in many organisms. Therefore, this Commentary will provide an overview of current knowledge of post transcriptional regulation of the clock genes and clock-controlled genes in dinoflagellates, plants, fungi and animals. This article will also highlight how circadian gene expression is modulated by post-transcriptional mechanisms and how this is crucial for robust circadian rhythmicity. PMID- 21242309 TI - Intravital microscopy: new insights into metastasis of tumors. AB - Metastasis, the process by which cells spread from the primary tumor to a distant site to form secondary tumors, is still not fully understood. Although histological techniques have provided important information, they give only a static image and thus compromise interpretation of this dynamic process. New advances in intravital microscopy (IVM), such as two-photon microscopy, imaging chambers, and multicolor and fluorescent resonance energy transfer imaging, have recently been used to visualize the behavior of single metastasizing cells at subcellular resolution over several days, yielding new and unexpected insights into this process. For example, IVM studies showed that tumor cells can switch between multiple invasion strategies in response to various densities of extracellular matrix. Moreover, other IVM studies showed that tumor cell migration and blood entry take place not only at the invasive front, but also within the tumor mass at tumor-associated vessels that lack an intact basement membrane. In this Commentary, we will give an overview of the recent advances in high-resolution IVM techniques and discuss some of the latest insights in the metastasis field obtained with IVM. PMID- 21242312 TI - An association between NUAK2 and MRIP reveals a novel mechanism for regulation of actin stress fibers. AB - Actin stress fiber assembly and contractility in nonmuscle motile cells requires phosphorylation of myosin regulatory light chain (MLC). Dephosphorylation and disassembly are mediated by MLC phosphatase, which is targeted to actin fibers by the association of its regulatory subunit MYPT1 with myosin phosphatase Rho interacting protein (MRIP). In the present study, we identify the kinase NUAK2 as a second protein targeted by MRIP to actin fibers. Association of NUAK2 with MRIP increases MLC phosphorylation and promotes formation of stress fibers. This activity does not require the kinase activity of NUAK2 but is dependent on both MRIP and MYPT1, indicating that the NUAK2-MRIP association inhibits fiber disassembly and MYPT1-mediated MLC dephosphorylation. NUAK2 levels are strongly induced by stimuli increasing actomyosin fiber formation, and NUAK2 is required for fiber maintenance in exponentially growing cells, implicating NUAK2 in a positive-feedback loop regulating actin stress fibers independently of the MLC kinase Rho-associated protein kinase (ROCK). The identified MRIP-NUAK2 association reveals a novel mechanism for the maintenance of actin stress fibers through counteracting MYPT1 and, together with recent results, implicates the NUAK proteins as important regulators of the MLC phosphatase acting in both a kinase-dependent and kinase-independent manner. PMID- 21242311 TI - A reduction in ATP demand and mitochondrial activity with neural differentiation of human embryonic stem cells. AB - Here, we have investigated mitochondrial biology and energy metabolism in human embryonic stem cells (hESCs) and hESC-derived neural stem cells (NSCs). Although stem cells collectively in vivo might be expected to rely primarily on anaerobic glycolysis for ATP supply, to minimise production of reactive oxygen species, we show that in vitro this is not so: hESCs generate an estimated 77% of their ATP through oxidative phosphorylation. Upon differentiation of hESCs into NSCs, oxidative phosphorylation declines both in absolute rate and in importance relative to glycolysis. A bias towards ATP supply from oxidative phosphorylation in hESCs is consistent with the expression levels of the mitochondrial gene regulators peroxisome-proliferator-activated receptor gamma coactivator (PGC) 1alpha, PGC-1beta and receptor-interacting protein 140 (RIP140) in hESCs when compared with a panel of differentiated cell types. Analysis of the ATP demand showed that the slower ATP turnover in NSCs was associated with a slower rate of most energy-demanding processes but occurred without a reduction in the cellular growth rate. This mismatch is probably explained by a higher rate of macromolecule secretion in hESCs, on the basis of evidence from electron microscopy and an analysis of conditioned media. Taken together, our developmental model provides an understanding of the metabolic transition from hESCs to more quiescent somatic cell types, and supports important roles for mitochondria and secretion in hESC biology. PMID- 21242313 TI - The nuclear scaffold protein SAF-A is required for kinetochore-microtubule attachment and contributes to the targeting of Aurora-A to mitotic spindles. AB - Segregation of chromosomes during cell division requires correct formation of mitotic spindles. Here, we show that a scaffold attachment factor A (SAF-A), also known as heterogeneous nuclear ribonucleoprotein-U, contributes to the attachment of spindle microtubules (MTs) to kinetochores and spindle organization. During mitosis, SAF-A was localized at the spindles, spindle midzone and cytoplasmic bridge. Depletion of SAF-A by RNA interference induced mitotic delay and defects in chromosome alignment and spindle assembly. We found that SAF-A specifically co immunoprecipitated with the chromosome peripheral protein nucleolin and the spindle regulators Aurora-A and TPX2, indicating that SAF-A is associated with nucleolin and the Aurora-A-TPX2 complex. SAF-A was colocalized with TPX2 and Aurora-A in spindle poles and MTs. Elimination of TPX2 or Aurora-A from cells abolished the association of SAF-A with the mitotic spindle. Interestingly, SAF-A can bind to MTs and contributes to the targeting of Aurora-A to mitotic spindle MTs. Our finding indicates that SAF-A is a novel spindle regulator that plays an essential role in kinetochore-MT attachment and mitotic spindle organization. PMID- 21242314 TI - Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. AB - The transfer of antigens from oligodendrocytes to immune cells has been implicated in the pathogenesis of autoimmune diseases. Here, we show that oligodendrocytes secrete small membrane vesicles called exosomes, which are specifically and efficiently taken up by microglia both in vitro and in vivo. Internalisation of exosomes occurs by a macropinocytotic mechanism without inducing a concomitant inflammatory response. After stimulation of microglia with interferon-gamma, we observe an upregulation of MHC class II in a subpopulation of microglia. However, exosomes are preferentially internalised in microglia that do not seem to have antigen-presenting capacity. We propose that the constitutive macropinocytotic clearance of exosomes by a subset of microglia represents an important mechanism through which microglia participate in the degradation of oligodendroglial membrane in an immunologically 'silent' manner. By designating the capacity for macropinocytosis and antigen presentation to distinct cells, degradation and immune function might be assigned to different subtypes of microglia. PMID- 21242316 TI - Shared and unique G alpha proteins in the zebrafish versus mammalian senses of taste and smell. AB - Chemosensory systems in vertebrates employ G protein-coupled receptors as sensors. In mammals, several families of olfactory and gustatory receptors as well as specific G alpha proteins coupling to them have been identified, for example, gustducin for taste. Orthologous receptor families have been characterized in fish, but the corresponding G alpha genes have not been well investigated so far. We have performed a comprehensive search of several lower vertebrate genomes to establish the G alpha protein family in these taxa and to identify those genes that may be involved in chemosensory signal transduction in fish. We report that gustducin is absent from the genomes of all teleost and amphibian species analyzed, presumably due to independent gene losses in these lineages. However, 2 other G alpha genes, Gi1b and G14a, are expressed in zebrafish taste buds and 4 G proteins, Go1, Go2, Gi1b, and Golf2, were detected in the olfactory epithelium. Golf2, Gi1b, and G14a are expressed already shortly after hatching, consistent with the physiological and behavioral responses of larvae to odorants and tastants. Our results show general similarity to the mammalian situation but also clear-cut differences and as such are essential for using the zebrafish model system to study chemosensory perception. PMID- 21242315 TI - Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex. AB - Autophagy is a lysosome-dependent cellular catabolic mechanism that mediates the turnover of intracellular organelles and long-lived proteins. Reduced autophagic activity has been shown to lead to the accumulation of misfolded proteins in neurons and might be involved in chronic neurodegenerative diseases. Here, we uncover an essential role for the syntaxin-5 SNARE complex in autophagy. Using genetic knockdown, we show that the syntaxin-5 SNARE complex regulates the later stages of autophagy after the initial formation of autophagosomes. This SNARE complex acts on autophagy by regulating ER-to-Golgi transport through the secretory pathway, which is essential for the activity of lysosomal proteases such as cathepsins. Depletion of syntaxin-5 complex components results in the accumulation of autophagosomes as a result of lysosomal dysfunction, leading to decreased degradation of autophagic substrates. Our findings provide a novel link between a fundamental process such as intracellular trafficking and human diseases that might be affected by defective biogenesis and/or homeostasis of the autophagosome-lysosome degradation system. PMID- 21242317 TI - Partners in dementia care: a care coordination intervention for individuals with dementia and their family caregivers. AB - PURPOSE: This article provides a detailed description of a telephone-based care coordination intervention, Partners in Dementia Care (PDC), for veterans with dementia and their family caregivers. Essential features of PDC included (a) formal partnerships between Veterans Affairs (VA) medical centers and Alzheimer's Association Chapters; (b) a multidimensional assessment and treatment approach, (c) ongoing monitoring and long-term relationships with families, and (d) a computerized information system to guide service delivery and fidelity monitoring. DESIGN AND METHODS: Data illustrating the use of the intervention were displayed for 93 veterans and their caregivers after 12 months in PDC. Descriptive data were provided for each major component of the intervention protocol, including: initial assessment, goals, action steps, and on-going monitoring. Care coordinators completed a 12-item questionnaire ascertaining the acceptability and feasibility of implementing PDC. RESULTS: Data from the assessments and goals indicated areas of need were not limited to any one issue or subset of issues, but were widely distributed across a variety of domains. Findings for action steps suggested a primary focus on getting/giving information and action-oriented tasks to access services and programs. Most action steps were assigned and completed by veteran's spouses and the majority were successfully accomplished. On average, families had two contacts per month with care coordinators. Few barriers were indicated by care coordinators in implementing PDC, highlighting the acceptability and feasibility of the PDC protocol. IMPLICATIONS: PDC addressed the diverse needs of individuals with dementia and their caregivers, including important non-medical care issues, such as understanding VA benefits, accessing community resources, and addressing caregiver strain. PDC proved to be a feasible model that was complementary to the existing programs of the 2 partnering organizations. PMID- 21242318 TI - EFO1 and EFO2, encoding putative WD-domain proteins, have overlapping and distinct roles in the regulation of vegetative development and flowering of Arabidopsis. AB - From screening a population of Arabidopsis overexpression lines, two Arabidopsis genes were identified, EFO1 (early flowering by overexpression 1) and EFO2, that confer early flowering when overexpressed. The two genes encode putative WD domain proteins which share high sequence similarity and constitute a small subfamily. Interestingly, the efo2-1 loss-of-function mutant also flowered earlier in short days and slightly earlier in long days than the wild type, while no flowering-time or morphological differences were observed in efo1-1 relative to the wild type. In addition, the efo2-1 mutation perturbed hypocotyl elongation, leaf expansion and formation, and stem elongation. EFO1 and EFO2 are both regulated by the circadian clock. Expression and genetic analyses revealed that EFO2 suppresses flowering largely through the action of CONSTANS (CO) and flowering locus T (FT), suggesting that EFO2 is a negative regulator of photoperiodic flowering. The growth defects in efo2-1 were augmented in efo1 efo2, but the induction of FT in the double mutant was comparable to that in efo2 1. Thus, while EFO2 acts as a floral repressor, EFO1 may not be directly involved in flowering, but the two genes do have overlapping roles in regulating other developmental processes. EFO1 and EFO2 may function collectively to serve as one of the converging points where the signals of growth and flowering intersect. PMID- 21242319 TI - Focal and global brain measurements in siblings of patients with schizophrenia. AB - BACKGROUND: It remains unclear whether structural brain abnormalities in schizophrenia are caused by genetic and/or disease-related factors. Structural brain abnormalities have been found in nonpsychotic first-degree relatives of patients with schizophrenia, but results are inconclusive. This large magnetic resonance imaging study examined brain structures in patients with schizophrenia, their nonpsychotic siblings, and healthy control subjects using global and focal brain measurements. METHODS: From 155 patients with schizophrenia, their 186 nonpsychotic siblings, and 122 healthy controls (including 25 sibling pairs), whole-brain scans were obtained. Segmentations of total brain, gray matter (GM), and white matter of the cerebrum, lateral and third ventricle, and cerebellum volumes were obtained. For each subject, measures of cortical thickness and GM density maps were estimated. Group differences in volumes, cortical thickness, and GM density were analyzed using Structural Equation Modeling, hence controlling for familial dependency of the data. RESULTS: Patients with schizophrenia, but not their nonpsychotic siblings, showed volumetric differences, cortical thinning, and reduced GM density as compared with control subjects. CONCLUSIONS: This study did not reveal structural brain abnormalities in nonpsychotic siblings of patients with schizophrenia compared with healthy control subjects using multiple imaging methods. Therefore, the structural brain abnormalities observed in patients with schizophrenia are for the largest part explained by disease-related factors. PMID- 21242320 TI - The bHLH transcription factor MYC3 interacts with the Jasmonate ZIM-domain proteins to mediate jasmonate response in Arabidopsis. AB - The Arabidopsis Jasmonate ZIM-domain proteins (JAZs) act as substrates of SCF(COI1) complex to repress their downstream targets, which are essential for JA regulated plant development and defense. The bHLH transcription factor MYC2 was found to interact with JAZs and mediate JA responses including JA-inhibitory root growth. Here, we identified another bHLH transcription factor MYC3 which directly interacted with JAZs by virtue of its N-terminal region to regulate JA responses. The transgenic plants with overexpression of MYC3 exhibited hypersensitivity in JA-inhibitory root elongation and seedling development. The JAZ-interacting pattern and the JA-induced expression pattern of MYC3 were distinguishable from those of MYC2. We speculate that MYC3 and MYC2 may have redundant but also distinguishable functions in regulation of JA responses. PMID- 21242322 TI - hivstigma.com, an innovative web-supported stigma reduction intervention for gay and bisexual men. AB - An intervention to address stigma directed toward HIV-positive men and to enhance the sexual health of gay and bisexual men was developed through a community-based process involving HIV prevention workers, public health, government and researchers. The intervention aimed to diminish stigma, create greater support for HIV-positive men, make disclosure safer and easier, discourage reliance on disclosure to prevent transmission and encourage testing. The question, 'If you were rejected every time you disclosed, would you?' was widely disseminated in the gay community and supported by the Web site, hivstigma.com, to encourage participation in blog-based discussions. Eight bloggers moderated lively discussions over 5 months. There were 20 844 unique visitors to the site averaging more than 5 min each; 4384 visitors returned more than 10 times. About 1,942 men answered a pre-test survey on a popular gay dating site and 1791, a post-test evaluation. Results show a statistically significant shift among those aware of the intervention toward reduced stigma-related attitudes and behaviors and toward recognition that HIV-positive gay men face stigma in the gay community and that stigma reduces the likelihood of HIV disclosure. PMID- 21242321 TI - Proteomics analysis reveals post-translational mechanisms for cold-induced metabolic changes in Arabidopsis. AB - Cold-induced changes of gene expression and metabolism are critical for plants to survive freezing. Largely by changing gene expression, exposure to a period of non-freezing low temperatures increases plant tolerance to freezing-a phenomenon known as cold acclimation. Cold also induces rapid metabolic changes, which provide instant protection before temperature drops below freezing point. The molecular mechanisms for such rapid metabolic responses to cold remain largely unknown. Here, we use two-dimensional difference gel electrophoresis (2-D DIGE) analysis of sub-cellular fractions of Arabidopsis thaliana proteome coupled with spot identification by tandem mass spectrometry to identify early cold-responsive proteins in Arabidopsis. These proteins include four enzymes involved in starch degradation, three HSP100 proteins, several proteins in the tricarboxylic acid cycle, and sucrose metabolism. Upon cold treatment, the Disproportionating Enzyme 2 (DPE2), a cytosolic transglucosidase metabolizing maltose to glucose, increased rapidly in the centrifugation pellet fraction and decreased in the soluble fraction. Consistent with cold-induced inactivation of DPE2 enzymatic activity, the dpe2 mutant showed increased freezing tolerance without affecting the C repeat binding transcription factor (CBF) transcriptional pathway. These results support a model that cold-induced inactivation of DPE2 leads to rapid accumulation of maltose, which is a cold-induced compatible solute that protects cells from freezing damage. This study provides evidence for a key role of rapid post-translational regulation of carbohydrate metabolic enzymes in plant protection against sudden temperature drop. PMID- 21242323 TI - When do online sexual fantasies become reality? The contribution of erotic chatting via the Internet to sexual risk-taking in gay and other men who have sex with men. AB - Seeking sexual partners online is associated with sexual risk-taking among men who have sex with men (MSM), but it is not well understood how this use of the Internet is implicated in potential sexual risks. The present study explores whether fantasizing about unprotected anal intercourse (UAI) during online chatting is associated with UAI with partners met online. An online survey of 2058 MSM in France included assessments of UAI with partners met online, responses to erotic chatting about UAI, intentions to use condoms, attitudes regarding UAI, practicing UAI with casual partners, alcohol and drug use with sex and biographical characteristics. While intentions to use condoms with casual partners were high, one-third (32.1%) of respondents reported UAI with partners met online. Responding positively to online chatting about UAI was significantly associated with UAI with partners met online, controlling for intentions, attitudes, behavior and biographic characteristics. These findings suggest that, while MSM may not go online to seek UAI, some engage in online fantasizing about UAI that is associated with possible sexual risk-taking. This speaks critically to the assumption that online fantasizing has no behavioral implications, and underscores the importance of human immunodeficiency virus prevention that addresses the dynamics of online chatting. PMID- 21242324 TI - Long-term stability of anterior open bite closure corrected by surgical orthodontic treatment. AB - In adults, superior repositioning of posterior maxilla with or without mandibular surgery has become the treatment method of choice to close anterior open bite. Study aim was to examine the long-term stability of anterior open bite closure by superior repositioning of maxilla or by combining maxillary impaction with mandibular surgery. The sample comprised 24 patients who underwent anterior open bite closure by superior repositioning of maxilla (maxillary group, n = 12, mean age 29.3 years) or by maxillary impaction and mandibular osteotomy (bimaxillary group, n = 12, mean age 30.8 years). Lateral cephalograms were studied prior to surgery (T1), the first post-operative day (T2) and in the long term (T3, maxillary group mean 3.5 years; bimaxillary group mean 2.0 years). Paired and two sample t-tests were used to assess differences within and between the groups. The vertical incisal bite relations were -2.6 and -2.2 mm at T1; 1.23 and 0.98 mm at T2; and 1.85 and 0.73 mm at T3 in the maxillary and bimaxillary groups. At T3, all subjects had positive overbite in the maxillary group, but open bite recurred in three subjects with bimaxillary surgery. For both groups, the maxilla relapsed vertically. Significant changes in sagittal and vertical positions of the mandible occurred in both groups. In the bimaxillary group, the changes were larger and statistically significant. In general, the maxilla seems to relapse moderately vertically and the mandible both vertically and sagittally, particularly when both jaws were operated on. Overbite seems to be more stable when only the maxilla has been operated on. PMID- 21242325 TI - Conscientious objection, emergency contraception, and public policy. AB - Defenders of medical professionals' rights to conscientious objection (CO) regarding emergency contraception (EC) draw an analogy to CO in the military. Such professionals object to EC since it has the possibility of harming zygotic life, yet if we accept this analogy and utilize jurisprudence to frame the associated public policy, those who refuse to dispense EC would not have their objection honored. Legal precedent holds that one must consistently object to all forms of the relevant activity. In the case at hand, then, I argue that these professionals must also oppose morally innocuous practices that may prevent pregnancy after fertilization. These results reveal that such objectors cannot offer a plausible and consistent objection to harming zygotic life. Additionally, there are good reasons to reject the analogy itself. In either case, these findings call into question the case supporting refusals of EC based on scruples. PMID- 21242326 TI - Chikungunya fever in the United States: a fifteen year review of cases. AB - BACKGROUND: Chikungunya virus (CHIKV) represents a threat to the United States, because humans amplify CHIKV and vectors that transmit CHIKV are present. METHODS: We described the epidemiology of laboratory-confirmed chikungunya fever (CHIK) cases in the United States in 1995-2009 and compared states with CHIKV vectors with states with returning viremic CHIK cases. For 2006-2009, we evaluated reporting of CHIK cases to ArboNET, the arboviral surveillance system. RESULTS: In 1995-2009, 109 CHIK cases were identified in the United States; all adult travelers. Sixty-two subjects (57%) had recently visited India, and 13 (12%) had CHIKV viremia. Of the 26 jurisdictions with CHIK cases, 22 (85%) reported the presence of CHIKV vectors. Twelve viremic travelers returned to 6 states with CHIKV vectors. Of the 106 cases identified in 2006-2009, only 27 (25%) were reported to ArboNET, with a median of 122 days (range, 44-273 days) between illness onset and reporting. CONCLUSIONS: No locally acquired CHIK cases were identified. However, several viremic travelers returned to states with CHIKV vectors and presented a risk for local transmission. Incomplete and delayed reporting made ArboNET less useful. To minimize the risk of CHIKV spread in the United States, healthcare providers and public health officials should be educated about recognition, diagnosis, and reporting of CHIK cases. PMID- 21242327 TI - Effect of street connectivity and density on adult BMI: results from the Twin Cities Walking Study. AB - BACKGROUND: The prevalence of overweight and obesity in the US population has risen dramatically in recent years. To try to explain this, some studies have examined the association between the built environment and obesity (measured using the body mass index (BMI)). Most of these studies have not sought to identify causal effects, but rather correlations. METHODS: Data from the Twin Cities Walking Study were used to examine the effect of population density and block size on BMI. Although the Twin Cities Walking Study is a cross-sectional observational study, the matched-sampling design is novel in that it maximises environmental variance while minimising person variance to enhance exchangeability of subjects and more closely mimic an experimental study. RESULTS: Contrary to expectations, the hypothesised most walkable neighbourhood (high density, small block stratum) had the greatest mean and median BMI. After adjusting for demographic covariates, physical activity and clustering due to neighbourhood, no conclusive effect of population density by block size on BMI was found (beta=-1.024, 95% CI -2.408 to 0.359). CONCLUSION: There is no evidence of an effect of population density by block size on BMI. PMID- 21242328 TI - Mesenchymal stem cells in infantile haemangioma. AB - BACKGROUND: Fibro-fatty deposition commonly occurs during involution of infantile haemangioma (IH). Mesenchymal stem cells have been identified in this tumour and have been proposed to be recruited from the bone marrow and/or adjacent niches, and then give rise to the fibro-fatty tissue. The authors have recently demonstrated that the capillary endothelium of proliferating IH co-expresses primitive mesodermal, mesenchymal and neural crest markers and proposed that this same endothelium has the ability to give rise to cells of mesenchymal lineage that constitute the fibro-fatty deposition. METHODS: Immunohistochemistry and real-time RT-PCR were used to further characterise proliferating IHs and haemangioma explant-derived cells (HaemEDCs). RESULTS: The authors have further confirmed expression of the mesenchymal-associated proteins including preadipocyte factor-1, a mesenchymal differentiation inhibition-associated cytokine. The HaemEDCs could be differentiated into osteoblasts and adipocytes, indicating their functional potential for terminal differentiation. DISCUSSION: The collective expression of neural crest, mesenchymal and mesenchymal differentiation inhibition-associated proteins on the endothelium of proliferating IH suggests that the cells in the capillary endothelium within the lesion possess the ability to undergo terminal mesenchymal differentiation during the proliferating phase, but are inhibited from doing so. PMID- 21242329 TI - Changes of B and T lymphocytes and selected apopotosis markers in Hashimoto's thyroiditis. AB - The aim was to assess changes of B and T lymphocytes and selected apoptotic markers in Hashimoto thyroiditis (HT) cases on the basis of quantitative immunohistochemical studies (CD20, CD43, CD8, Bcl-2, caspase-3). The control group comprised colloid goitres without inflammatory infiltrate taken from 10 female patients. Thyroid specimens were obtained retrospectively from 40 patients. The immunohistochemical reactions were subject to quantitative evaluation performed using image-processing methods, including a spatial visualisation of the markers' expression. The percentage of Bcl-2 reactions in HT (mean 3.65%, SD 2.94%) was significantly lower than in the control group (mean 13.99%, SD 5.04%), while the thyroid follicles in HT samples exhibited a higher degree of staining for caspase-3 (mean 1.10%, SD 1.03%) in contrast to normal control tissues (mean 0.48%, SD 1.02%). The results from this study indicate that apoptosis plays a major role in the patogenesis of autoimmune thyroid diseases containing the main pathogenic events in the lesion of thyroid follicular cells in HT. Moreover, the reactivity of CD43 and CD20 was significantly higher in Hashimoto disease, while CD8 was not significantly different from the control group. PMID- 21242330 TI - A prospective assessment of racial/ethnic differences in future mammography behavior among women who had early mammography. AB - BACKGROUND: Twenty-nine percent of women, aged 30 to 39, report having had a mammogram, though sensitivity and specificity are low. We investigate racial/ethnic differences in future mammography behavior among women who had a baseline screening mammogram prior to age 40. METHODS: Using 1994-2008 data from the Breast Cancer Surveillance Consortium (BCSC), we identified 29,390 women aged 35 to 39 with a baseline screening mammogram. We followed this cohort for 2 outcomes: (i) future BCSC mammography between ages 40 and 45; and (2) among those, delay in screening mammography until ages 43 to 45 compared with ages 40 to 42. Using adjusted log-linear models, we estimated the relative risk (RR) of these outcomes by race/ethnicity, while also considering the impact of false positive/true-negative (FP/TN) baseline mammography results on these outcomes. RESULTS: Relative to non-Hispanic white women, Hispanic women had an increased risk of no future BCSC mammography (RR: 1.21, 95% CI: 1.13-1.30); Asian women had a decreased risk (RR: 0.67, 95% CI: 0.61-0.74). Women with a FP result, compared with a TN result, had a decreased risk of no future BCSC mammography (RR: 0.89, 95% CI: 0.85-0.95). Among those with future BCSC screening mammography, African American women were more likely to delay the timing (RR: 1.26, 95% CI: 1.09 1.45). The interaction between race/ethnicity and FP/TN baseline results was not significant. CONCLUSIONS: Race/ethnicity is differentially associated with future BCSC mammography and the timing of screening mammography after age 40. IMPACT: These findings introduce the need for research that examines disparities in lifetime mammography use patterns from the initiation of mammography screening. PMID- 21242331 TI - The effects of body mass index on changes in prostate-specific antigen levels and prostate volume over 15 years of follow-up: implications for prostate cancer detection. AB - OBJECTIVE: To investigate the association of body mass index (BMI) and BMI change with change in prostate-specific antigen (PSA) level and to assess the possible roles of PSA hemodilution and prostate volume in explaining the obesity and PSA association. METHODS: In 1990, a randomly selected cohort of Caucasian men, aged 40 to 79 years, from Olmsted County, Minnesota, completed questionnaires ascertaining demographic characteristics, current medical conditions, and medications biennially, with a subset undergoing blood draws and clinical examinations. Linear mixed models were used to predict annual changes and intercepts of individual changes in BMI, PSA, prostate volume, plasma volume, and PSA mass, adjusting for age in 545 men with at least 2 serial PSA, BMI, and prostate volume measurements. RESULTS: Baseline BMI was inversely associated with the annual percent change in PSA, adjusting for age, baseline PSA, and prostate volume and for the rates of change in BMI and prostate volume (beta=-0.003, 95% CI: -0.006 to -0.0003). Baseline obesity was positively associated with mean baseline levels and the rate of change in prostate volume (P=0.002) and plasma volume (both P<0.001) but was not associated with either the mean baseline values or the rate of change in PSA mass. CONCLUSIONS: Baseline obesity was associated with baseline PSA and prostate volume and with the rate of change in PSA over 15 years of follow-up. IMPACT: The inverse association of obesity with prostate cancer diagnosis may be at least partly due to detection bias, which is due to larger prostate volumes and PSA hemodilution in obese men. PMID- 21242332 TI - Complex genotype sarcomas display familial inheritance independent of known cancer predisposition syndromes. AB - BACKGROUND: The low incidence of sarcomas in the general population makes heritable contribution to disease risk difficult to discern beyond highly penetrant Mendelian syndromes. METHODS: The Utah Cancer Registry (UCR) and Utah Population Database were interrogated for sarcoma diagnostic codes grouped by genetic type, either complex genotype/karyotype sarcoma or balanced translocation associated sarcoma. The genealogic index of familiality (GIF) was calculated and relative risks (RR) of disease estimated for first-, second-, and third-degree relatives of sarcoma probands. Cancer patterns in pedigrees of sarcoma probands were examined to rule out known hereditary cancer syndromes. RESULTS: A total of 229 balanced translocation type and 1,161 complex genotype type sarcomas with at least three generations of ancestral genealogy data were identified in the UCR. There was no evidence for excess relatedness for the balanced translocation group by using the GIF test (P = 0.657) and no significantly elevated RRs. In the complex genotype group, we observed significantly elevated GIF (P = 0.03). Modest RRs corroborated the GIF analysis, in which excess relatedness existed in distant relationships. No recognized cancer syndromes were identified among high-risk pedigrees. DISCUSSION: We identified strong familiality among complex genotype sarcomas, independent from known cancer predisposition syndromes. In the absence of significantly elevated RRs for close relatives, the high GIF argues for a strong genetic-rather than environmental-component to complex genotype sarcoma risk. We observed no significant familial risk of developing balanced translocation-associated sarcomas, but the sample was small. IMPACT: There exists yet to be deciphered heritable risk for developing complex genotype sarcomas. PMID- 21242334 TI - Nanoimaging devices illuminate tumor margins during surgery. PMID- 21242335 TI - Getting around PLX4032: studies turn up unusual mechanisms of resistance to melanoma drug. PMID- 21242336 TI - Materials scientists join oncologists to explore nano- and microtherapeutics. PMID- 21242333 TI - Protein microarray analysis of mammary epithelial cells from obese and nonobese women at high risk for breast cancer: feasibility data. AB - BACKGROUND: Obesity is a well-established risk factor for cancer, accounting for up to 20% of cancer deaths in women. Studies of women with breast cancer have shown obesity to be associated with an increased risk of dying from breast cancer and increased risk of developing distant metastasis. While previous studies have focused on differences in circulating hormone levels as a cause for increased breast cancer incidence in postmenopausal women, few studies have focused on potential differences in the protein expression patterns of mammary epithelial cells obtained from obese versus nonobese women. METHODS: Protein expression was assessed by reverse-phase protein microarray in mammary epithelial cells from 31 random periareolar fine needle aspirations performed on 26 high-risk women. RESULTS: In this pilot and exploratory study, vimentin (unadjusted P=0.028) expression was significantly different between obese and nonobese women. CONCLUSIONS: Vimentin is integral both to adipocyte structure and function and to the epithelial-to-mesenchymal transition needed for cancer cell metastasis. Further research is needed to confirm this finding and determine the possible effects of the adipocyte microenvironment on the initiation and progression of breast cancer in high-risk women. IMPACT: Differential protein expression patterns obtained from a future expanded study may serve to elaborate the underlying pathology of breast cancer initiation and progression in obese women and identify potential biomarkers of response to preventative interventions such as dietary changes and exercise. PMID- 21242337 TI - StatBite: Melanoma incidence: 1992-2007. PMID- 21242338 TI - Abiraterone and MVD3100 take androgen deprivation to a new level. PMID- 21242339 TI - Acceptability and practicability of elastic compression stockings in the elderly: a randomized controlled evaluation. AB - BACKGROUND: Compression stockings are the cornerstone of the treatment of chronic venous disorders, but practical acceptability is an important limitation in the elderly. OBJECTIVE: To evaluate the practicability of compression stockings in elderly patients. METHODS: Twenty women aged 68-85 years without major disability were asked to put on, wear for three hours and take off Solegg(r) and Solegg(r) Fine compressive stockings (15-20 mmHg) in random order on different days, and to rate through questionnaires the difficulties and discomfort they experienced in comparison with their usual non-compressive stockings (controls). RESULTS: Foot and heel insertions of the compression stockings, as well as their removal, were found significantly more difficult, whereas comfort when they were on was higher. In the whole, the compression stockings were found to be more agreeable than the controls. CONCLUSION: Difficulties regarding putting on and removal of the compression stockings remain significant but are counterbalanced by a better comfort when they are on. PMID- 21242340 TI - Summaries for patients: Screening for osteoporosis: recommendations from the U.S. preventive services task force. PMID- 21242341 TI - Screening for osteoporosis: U.S. preventive services task force recommendation statement. AB - DESCRIPTION: Update of the 2002 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for osteoporosis. METHODS: The USPSTF evaluated evidence on the diagnostic accuracy of risk assessment instruments for osteoporosis and fractures, the performance of dual-energy x-ray absorptiometry and peripheral bone measurement tests in predicting fractures, the harms of screening for osteoporosis, and the benefits and harms of drug therapy for osteoporosis in women and men. RECOMMENDATIONS: The USPSTF recommends screening for osteoporosis in women aged 65 years or older and in younger women whose fracture risk is equal to or greater than that of a 65-year-old white woman who has no additional risk factors. (Grade B recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis in men. (I statement). PMID- 21242342 TI - Neurothrombectomy devices for the treatment of acute ischemic stroke: state of the evidence. AB - BACKGROUND: Acute ischemic strokes are associated with poor outcomes and high health care burden. Evidence exists evaluating the use of neurothrombectomy devices in patients receiving currently recommended treatments that may have limited efficacy. PURPOSE: To describe the state of the evidence supporting use of neurothrombectomy devices in the treatment of acute ischemic stroke. DATA SOURCES: MEDLINE, SCOPUS, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Web of Science were searched, without language restrictions, from their inception through May 2010. The MEDLINE and Cochrane Central Register of Controlled Trials searches were updated through November 2010. STUDY SELECTION: Two independent investigators screened citations for human studies of any design or case series or case reports of patients with an acute ischemic stroke that evaluated a neurothrombectomy device and reported at least 1 clinical effectiveness outcome or harm. DATA EXTRACTION: Using standardized protocols, 2 independent investigators extracted information about study characteristics and outcomes, and a third reviewer resolved disagreement. DATA SYNTHESIS: 87 articles met eligibility criteria, including 18 prospective single-group studies, 7 noncomparative retrospective studies, and 62 case series or case reports. Two U.S. Food and Drug Administration (FDA)-cleared devices, the MERCI Retriever (Concentric Medical, Mountain View, California) (40%) and the Penumbra System (Penumbra, Alameda, California) (9%), represented a large portion of the available data. All prospective and retrospective studies provided data on successful recanalization with widely varying rates (43% to 78% with the MERCI Retriever and 83% to 100% with the Penumbra System). Rates of harms, including symptomatic (16 studies; 0% to 10% with the MERCI Retriever and 0% to 11% with the Penumbra System) or asymptomatic (13 studies; 28% to 43% and 1% to 30%, respectively) intracranial hemorrhage and vessel perforation or dissection (11 studies; 0% to 7% and 0% to 5%, respectively), also varied by device. Predictors of harm included older age, history of stroke, and higher baseline stroke severity scores, whereas successful recanalization was the sole predictor of good outcomes. LIMITATIONS: Most available data are from single-group, noncomparative studies. In addition, the patient population most likely to benefit from these devices is undetermined. CONCLUSION: Currently available neurothrombectomy devices offer intriguing treatment options in patients with acute ischemic stroke. Future trials should use a randomized design, with adequate power to show equivalency or noninferiority between competing strategies or devices, and strive to identify populations that are most likely to benefit from use of neurothrombectomy devices. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 21242343 TI - Neurothrombectomy devices for acute ischemic stroke: a state of uncertainty. PMID- 21242345 TI - Cataracts in atopic dermatitis: a case presentation and review of the literature. AB - BACKGROUND: Atopic dermatitis (AD) is a common skin disorder of increasing prevalence. Many ophthalmologic conditions are associated with AD, including cataract formation. Posterior and anterior subcapsular cataracts have been described in AD. Topical and systemic corticosteroids have been implicated in the development of cataracts. The precise pathogenic mechanisms and risk factors for development of atopic cataract are not clear. OBSERVATION: We report a case of cataract development in a child with severe AD and performed an extensive review of the dermatologic and ophthalmologic literature pertaining to AD and cataract formation. The incidence, demographics, pathogenesis, and characteristics of atopic cataracts are evaluated. CONCLUSIONS: Atopic dermatitis alone is a risk factor to develop both posterior and anterior subcapsular cataracts. There is a slightly increased probability of posterior subcapsular cataracts. However, anterior subcapsular cataracts are more specific to AD. A positive correlation was found between atopic cataract development and a decreased inducibility of superoxide dismutase. This suggests that atopic cataract development is correlated with oxidative damage of the lens and related to chronic inflammation. PMID- 21242344 TI - Epidermodysplasia verruciformis in human immunodeficiency virus-infected patients: a marker of human papillomavirus-related disorders not affected by antiretroviral therapy. AB - BACKGROUND: Skin eruptions resembling epidermodysplasia verruciformis (EV) are rarely observed in immunocompromised patients. We focused on the epidemiologic, clinical, virologic, and immunologic features of EV in human immunodeficiency virus (HIV)-positive patients. OBSERVATIONS: We studied 11 HIV-positive patients (6 men and 5 women) with clinical and histological features of EV observed at our department. The median age at HIV diagnosis was 27 years. At the onset of eruption, the median age was 40 years and the median CD4 T-cell count was 170/MUL. Clinical presentation included flat warts (n = 11), pityriasis versicolor-like macules (n = 5), and lichenoid papules (n = 3) on sun-exposed skin. Detection and typing of cutaneous human papillomavirus (HPV) were carried out in 8 cases and always revealed beta-HPV infection, including oncogenic HPV-5 or 8 (n = 6). Mucosal HPV-related diseases were present in 7 cases. Histories of skin cancer and lymphoproliferative disorder were recorded in 3 and 4 patients, respectively, including 2 fatal cases. Skin eruption was never improved by highly active antiretroviral therapy (HAART). In 2 cases, EV was associated with an immune reconstitution syndrome. The present series is the largest with a complete characterization. A review of similar cases was carried out. CONCLUSION: Despite effective HAART, HIV-infected patients with EV require a prolonged and careful follow-up to detect mucosal HPV-related diseases, lymphoproliferative disorders, and skin cancers. PMID- 21242346 TI - Melanomas detected in a follow-up program compared with melanomas referred to a melanoma unit. AB - OBJECTIVE: To compare melanomas diagnosed in patients included in follow-up programs with melanomas diagnosed in patients referred to a melanoma unit. DESIGN: Retrospective analysis of 215 consecutive melanomas diagnosed between 2007 and 2008. SETTING: Melanoma Unit, Hospital Clinic of Barcelona, Barcelona, Spain. PATIENTS: The study included 201 patients (105 men and 96 women), 40 of whom were included in a follow-up program in our unit and 161 of whom were referred for evaluation. MAIN OUTCOME MEASURES: Clinical (ABCD algorithm), dermoscopic (ABCD rule of dermoscopy), and main histologic characteristics were evaluated in both groups. RESULTS: Most melanomas diagnosed in follow-up did not fulfill some of the ABCD criteria, and only 12.0% fulfilled all 4 ABCD criteria, in contrast with 63.6% of the melanomas referred for evaluation (P < .001). The total dermoscopy score was lower in melanomas diagnosed in follow-up (5.04 vs. 6.39, P < .01), and 36% were misclassified as benign in this group according to the total dermoscopy score. Seventy percent of melanomas diagnosed in follow-up were in situ; among invasive melanomas, the Breslow index was significantly lower in the group of melanomas diagnosed in follow-up, with a mean (range) of 0.55 (0.25-0.90) mm vs 1.72 (0.25-13.00) mm (P < .001). CONCLUSIONS: The inclusion of patients who are at high risk for melanoma in follow-up programs allows the detection of melanomas in early stages, with good prognosis, even in the absence of clinical and dermoscopic features of melanoma. In the general population without specific surveillance, melanoma continues to be diagnosed at more advanced stages. PMID- 21242347 TI - Geographic distribution of melanoma in Miami-Dade County, Florida: online first. PMID- 21242349 TI - Lack of UV-A protection in daily moisturizing creams. PMID- 21242350 TI - Summaries for patients: Using patient stories to improve blood pressure control. PMID- 21242351 TI - Summaries for patients: Screening for liver cancer in patients with hepatitis C virus infection and cirrhosis. PMID- 21242352 TI - ACP Journal Club. Review: Acamprosate increases abstinence in patients with alcohol dependence. PMID- 21242353 TI - ACP Journal Club. Review: Contrast-enhanced MRA is highly accurate for diagnosing steno-occlusions in peripheral arterial disease. PMID- 21242354 TI - ACP Journal Club. Review: Fecal calprotectin is accurate for screening for suspected IBD in adults but less so in children. PMID- 21242355 TI - ACP Journal Club. The Canadian C-Spine Rule, used by nurses, accurately identified cervical-spine injury in patients with trauma. PMID- 21242356 TI - ACP Journal Club. Review: Prostate cancer screening using PSA does not decrease mortality. PMID- 21242357 TI - ACP Journal Club. 48 hours of cisatracurium reduced 90-day mortality in patients with early, severe ARDS. PMID- 21242358 TI - ACP Journal Club. Weekly INR self-testing did not reduce stroke, major bleeding, or death more than monthly clinic testing. PMID- 21242359 TI - ACP Journal Club. Review: Positive D-dimer results predict recurrence after first unprovoked VTE regardless of test timing or cutpoint, or patient age. PMID- 21242360 TI - ACP Journal Club. Local INR control had some effect on the benefits of dabigatran over warfarin for major bleeding in atrial fibrillation. PMID- 21242361 TI - ACP Journal Club. Increased doses of clopidogrel or aspirin did not prevent cardiovascular events. PMID- 21242362 TI - ACP Journal Club. Carotid artery stenting increased short-term risk for stroke or death more than endarterectomy in symptomatic carotid stenosis. PMID- 21242363 TI - ACP Journal Club. Celecoxib reduced GI events more than diclofenac plus omeprazole in patients with osteoarthritis or rheumatoid arthritis. PMID- 21242364 TI - Culturally appropriate storytelling to improve blood pressure: a randomized trial. AB - BACKGROUND: Storytelling is emerging as a powerful tool for health promotion in vulnerable populations. However, these interventions remain largely untested in rigorous studies. OBJECTIVE: To test an interactive storytelling intervention involving DVDs. DESIGN: Randomized, controlled trial in which comparison patients received an attention control DVD. Separate random assignments were performed for patients with controlled or uncontrolled hypertension. (ClinicalTrials.gov registration number: NCT00875225) SETTING: An inner-city safety-net clinic in the southern United States. PATIENTS: 230 African Americans with hypertension. INTERVENTION: 3 DVDs that contained patient stories. Storytellers were drawn from the patient population. MEASUREMENTS: The outcomes were differential change in blood pressure for patients in the intervention versus the comparison group at baseline, 3 months, and 6 to 9 months. RESULTS: 299 African American patients were randomly assigned between December 2007 and May 2008 and 76.9% were retained throughout the study. Most patients (71.4%) were women, and the mean age was 53.7 years. Baseline mean systolic and diastolic pressures were similar in both groups. Among patients with baseline uncontrolled hypertension, reduction favored the intervention group at 3 months for both systolic (11.21 mm Hg [95% CI, 2.51 to 19.9 mm Hg]; P = 0.012) and diastolic (6.43 mm Hg [CI, 1.49 to 11.45 mm Hg]; P = 0.012) blood pressures. Patients with baseline controlled hypertension did not significantly differ over time between study groups. Blood pressure subsequently increased for both groups, but between-group differences remained relatively constant. LIMITATION: This was a single-site study with 23% loss to follow-up and only 6 months of follow-up. CONCLUSION: The storytelling intervention produced substantial and significant improvements in blood pressure for patients with baseline uncontrolled hypertension. PRIMARY FUNDING SOURCE: Finding Answers: Disparities Research for Change, a national program of the Robert Wood Johnson Foundation. PMID- 21242365 TI - Utilization of surveillance for hepatocellular carcinoma among hepatitis C virus infected veterans in the United States. AB - BACKGROUND: Surveillance for hepatocellular carcinoma (HCC) is recommended for patients with hepatitis C virus (HCV) infection and cirrhosis. However, whether surveillance is being done as recommended is unknown. OBJECTIVE: To examine the prevalence and determinants of HCC surveillance among HCV-infected patients with cirrhosis in Veterans Affairs (VA) health care facilities in the United States. DESIGN: Retrospective cohort study of HCV-infected patients using data obtained from the national VA Hepatitis C Clinical Case Registry. SETTING: 128 VA medical centers. PATIENTS: HCV-infected patients with cirrhosis diagnosed between fiscal years 1998 and 2005. MEASUREMENTS: Abdominal ultrasonography and measurement of alpha-fetoprotein for HCC surveillance were identified from administrative data by using a previously validated algorithm. Patients were categorized as having routine (tests done during at least 2 consecutive years in the 4 years after cirrhosis diagnosis), inconsistent (at least 1 test, but not routine), or no surveillance in the 4 years after cirrhosis diagnosis. Predictors of surveillance were identified by using hierarchical random-effects regression. RESULTS: 126 670 patients with HCV were identified; 13 002 (10.1%) had cirrhosis. Approximately 42.0% of patients with cirrhosis received 1 or more HCC surveillance tests within the first year after the cirrhosis index date; however, a decline in receipt of surveillance was observed in the following 2 to 4 years. Among patients with cirrhosis and at least 2 years of follow-up, routine surveillance occurred in 12.0%, inconsistent surveillance in 58.5%, and no surveillance in 29.5%. Lower medical and psychological comorbid conditions, presence of varices, and the absence of decompensated liver disease were associated with a higher likelihood of receiving routine surveillance. LIMITATIONS: Hepatocellular carcinoma surveillance tests were indirectly identified from registry data. Physician recommendations could not be captured. CONCLUSION: Few HCV-infected veterans with cirrhosis received routine HCC surveillance. New strategies are needed to improve the implementation of HCC surveillance in clinical practice. PRIMARY FUNDING SOURCE: Houston Veterans Affairs Health Services Research and Development Center of Excellence and the National Cancer Institute. PMID- 21242366 TI - The association between hospital volume and processes, outcomes, and costs of care for congestive heart failure. AB - BACKGROUND: Congestive heart failure (CHF) is common and costly, and outcomes remain suboptimal despite pharmacologic and technical advances. OBJECTIVE: To examine whether hospitals with more experience in caring for patients with CHF provide better, more efficient care. DESIGN: Retrospective cohort study. SETTING: 4095 hospitals in the United States. PATIENTS: Medicare fee-for-service patients with a primary discharge diagnosis of CHF. MEASUREMENTS: Hospital Quality Alliance CHF process measures; 30-day, risk-adjusted mortality rates; 30-day, risk-adjusted readmission rates; and costs per discharge. National Medicare claims data from 2006 to 2007 were used to examine the relationship between hospital case volume and quality, outcomes, and costs for patients with CHF. RESULTS: Hospitals in the low-volume group had lower performance on the process measures (80.2%) than did medium-volume (87.0%) or high-volume (89.1%) hospitals (P < 0.001). In the low-volume group, being admitted to a hospital with a higher case volume was associated with lower mortality, lower readmission, and higher costs. Similar, though smaller, relationships were found between case volume and both mortality and costs in the medium- and high-volume hospital groups. LIMITATIONS: Analysis was limited to Medicare patients 65 years or older. Risk adjustment was performed by using administrative data. CONCLUSION: Experience with managing CHF, as measured by an institution's volume, is associated with higher quality of care and better outcomes for patients but a higher cost. Understanding which practices employed by high-volume institutions account for these advantages can help improve quality of care and clinical outcomes for all patients with CHF. PRIMARY FUNDING SOURCE: American Heart Association. PMID- 21242367 TI - Addressing missing data in clinical trials. AB - The reliability and interpretability of results from clinical trials can be substantially reduced by missing data. Frequently used approaches to address these concerns, such as upward adjustments in sample sizes or simplistic methods for handling missing data, including last-observation-carried-forward, complete case, or worst-case analyses, are usually inadequate. Although rational imputation methods may be useful to treat missingness after it has occurred, these methods depend on untestable assumptions. Thus, the preferred and often only satisfactory approach to addressing missing data is to prevent it. Procedures should be in place to maximize the likelihood that outcome data will be obtained at scheduled times of evaluation for all surviving patients who have not withdrawn consent. To meaningfully reduce missing data, it is important to recognize and address many factors that commonly lead to higher levels of missingness. PMID- 21242368 TI - Lost in translation: the unintended consequences of advance directive law on clinical care. AB - BACKGROUND: Advance directive law may compromise the clinical effectiveness of advance directives. PURPOSE: To identify unintended legal consequences of advance directive law that may prevent patients from communicating end-of-life preferences. DATA SOURCES: Advance directive legal statutes for all 50 U.S. states and the District of Columbia and English-language searches of LexisNexis, Westlaw, and MEDLINE from 1966 to August 2010. STUDY SELECTION: Two independent reviewers selected 51 advance directive statutes and 20 articles. Three independent legal reviewers selected 105 legal proceedings. DATA EXTRACTION: Two reviewers independently assessed data sources and used critical content analysis to determine legal barriers to the clinical effectiveness of advance directives. Disagreements were resolved by consensus. DATA SYNTHESIS: Legal and content related barriers included poor readability (that is, laws in all states were written above a 12th-grade reading level), health care agent or surrogate restrictions (for example, 40 states did not include same-sex or domestic partners as default surrogates), and execution requirements needed to make forms legally valid (for example, 35 states did not allow oral advance directives, and 48 states required witness signatures, a notary public, or both). Vulnerable populations most likely to be affected by these barriers included patients with limited literacy, limited English proficiency, or both who cannot read or execute advance directives; same-sex or domestic partners who may be without legally valid and trusted surrogates; and unbefriended, institutionalized, or homeless patients who may be without witnesses and suitable surrogates. LIMITATION: Only appellate-level legal cases were available, which may have excluded relevant cases. CONCLUSION: Unintended negative consequences of advance directive legal restrictions may prevent all patients, and particularly vulnerable patients, from making and communicating their end-of-life wishes and having them honored. These restrictions have rendered advance directives less clinically useful. Recommendations include improving readability, allowing oral advance directives, and eliminating witness or notary requirements. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs and the Pfizer Foundation. PMID- 21242370 TI - Tripping on the HIPAA Hurdle. PMID- 21242369 TI - Storytelling: a novel intervention for hypertension. PMID- 21242371 TI - Moses. PMID- 21242372 TI - The effect of funding source on outcome reporting among drug trials. PMID- 21242373 TI - The effect of funding source on outcome reporting among drug trials. PMID- 21242374 TI - The effect of funding source on outcome reporting among drug trials. PMID- 21242375 TI - Comments on the Affordable Care Act and the future of clinical medicine. PMID- 21242376 TI - Comments on the Affordable Care Act and the future of clinical medicine. PMID- 21242377 TI - Comments on the Affordable Care Act and the future of clinical medicine. PMID- 21242378 TI - Comments on the Affordable Care Act and the future of clinical medicine. PMID- 21242379 TI - Comments on the Affordable Care Act and the future of clinical medicine. PMID- 21242380 TI - Comments on the Affordable Care Act and the future of clinical medicine. PMID- 21242381 TI - Comments on the affordable care act and the future of clinical medicine. PMID- 21242382 TI - Comments on the Affordable Care Act and the future of clinical medicine. PMID- 21242383 TI - Comments on the Affordable Care Act and the future of clinical medicine. PMID- 21242384 TI - Comments on the Affordable Care Act and the future of clinical medicine. PMID- 21242385 TI - Comments on the Affordable Care Act and the future of clinical medicine. PMID- 21242386 TI - Comments on the Affordable Care Act and the future of clinical medicine. PMID- 21242388 TI - Syphilis in greek poetry: a uniquely positive perspective. PMID- 21242389 TI - Development of a photographic scale for consistency and guidance in dermatologic assessment of forearm sun damage. AB - OBJECTIVES: To develop a photographic sun damage assessment scale for forearm skin and test its feasibility and utility for consistent classification of sun damage. DESIGN: For a blinded comparison, 96 standardized 8 * 10 digital photographs of participants' forearms were taken. Photographs were graded by an expert dermatologist using an existing 9-category dermatologic assessment scoring scale until all categories contained photographs representative of each of 4 clinical signs. Triplicate photographs were provided in identical image sets to 5 community dermatologists for blinded rating using the dermatologic assessment scoring scale. SETTING: Academic skin cancer prevention clinic with high-level experience in assessment of sun-damaged skin. PARTICIPANTS: Volunteer sample including participants from screenings, chemoprevention, and/or biomarker studies. MAIN OUTCOME MEASURES: Reproducibility and agreement of grading among dermatologists by Spearman correlation coefficient to assess the correlation of scores given for the same photograph, kappa statistics for ordinal data, and variability of scoring among dermatologists, using analysis of variance models with evaluating physician and photographs as main effects and interaction effect variables to account for the difference in scoring among dermatologists. RESULTS: Correlations (73% to >90%) between dermatologists were all statistically significant (P < .001). Scores showed good to substantial agreement but were significantly different (P < .001) for each of 4 clinical signs and the difference varied significantly (P < .001) among photographs. CONCLUSIONS: With good to substantial agreement, we found the development of a photographic forearm sun damage assessment scale highly feasible. In view of significantly different rating scores, a photographic reference for assessment of sun damage is also necessary. PMID- 21242391 TI - Need to improve skin cancer screening of high-risk patients: Comment on "Skin cancer screening by dermatologists, family practitioners, and internists". PMID- 21242390 TI - Skin cancer screening by dermatologists, family practitioners, and internists: barriers and facilitating factors. AB - OBJECTIVE: To determine barriers and facilitating factors to skin cancer screening practices among US primary care physicians and dermatologists. DESIGN: Survey. SETTING: Physicians randomly selected from the American Medical Association's Medical Marketing Services database from April 1 through November 30, 2005. PARTICIPANTS: A total of 2999 US dermatologists, family practitioners, and internists. MAIN OUTCOME MEASURES: Results based on 1669 surveys returned regarding practice characteristics, skin cancer screening behaviors, and barriers and facilitating factors to performing full-body skin examinations for patients. RESULTS: The overall response rate was 59.2%. More dermatologists (552 [81.3%]) reported performing full-body skin examinations on patients than did family practitioners (333 [59.6%]) (P < .05) or internists (243 [56.4%]) (P < .05). Among all physicians, time constraints, competing comorbidities, and patient embarrassment were reported as the top 3 barriers to performing full-body skin examinations, and these barriers were different among medical specialties. Among all physicians, having patients at high risk for skin cancer, patient demand for complete examination/mole check, and the influence of medical training were reported as facilitating factors to performing full-body skin examinations. CONCLUSION: Becoming more knowledgeable about physician barriers to skin cancer screening could help improve primary and secondary practices in both the primary care and dermatology settings. PMID- 21242392 TI - Dermoscopy of patients with multiple nevi: Improved management recommendations using a comparative diagnostic approach. AB - OBJECTIVE: To assess the outcome on management recommendations of a comparative approach vs a morphologic approach in evaluating dermoscopic images of lesions from a series of patients with multiple nevi. DESIGN: In a 2-step study, 6 experienced dermoscopists were asked to provide management recommendations (excision or follow-up) for a series of lesions from patients with multiple nevi based on dermoscopic images of the lesions. In the first step, participating dermoscopists evaluated individual images of lesions based only on morphologic structure (morphologic approach). In the second step, the same lesions were grouped by patient, allowing the participants to evaluate the lesions in the context of other nevi from the same patient (comparative approach). SETTING: Academic referral center. PATIENTS: Seventeen patients with 190 lesions (184 monitored nevi, 4 excised nevi, and 2 excised melanomas). MAIN OUTCOME MEASURE: Using pooled data from each step, excision recommendation rates for the comparative approach and the morphologic approach were calculated. RESULTS: Using the morphologic approach, 55.1% of overall recommendations favored excision; using the comparative approach, the rate decreased to 14.1%. The 2 melanomas included in the study were correctly judged to merit excision by all participants in step 1 and in step 2. Conclusion Among patients with multiple nevi, evaluation of equivocal lesions in the context of a patient's other nevi results in a lower rate of excision recommendations compared with evaluation of individual lesions based on morphologic structure alone. PMID- 21242393 TI - Failure to compare dermoscopy findings of pigmented lesions on your patient: Comment on "Dermoscopy of patients with multiple nevi". PMID- 21242394 TI - Dermoscopy in skin self-examination: A useful tool for select patients. AB - BACKGROUND: Education for patients on the technique of skin self-examination is important for improving the rate of early detection of melanoma. Strategies to improve skills in skin self-examination include the use of mnemonics to facilitate the recognition of melanoma features and photography to assist in the detection of change. OBSERVATION: We describe 2 patients who used dermoscopy on their own initiative to help identify suspicious pigmented lesions during skin self-examination. CONCLUSIONS: Dermoscopy has not yet been evaluated for patient use. We were intrigued by this concept and suggest that dermoscopy, with appropriate training, may improve the ability for early detection of melanoma in skin self-examination for select patients. PMID- 21242396 TI - Reflectance confocal microscopy of the yellow dot pattern in alopecia areata. AB - BACKGROUND: The presence of yellow dots is a characteristic dermoscopic finding in alopecia areata. The aim of this study was to investigate the yellow dot pattern observed at dermoscopy in alopecia areata with reflectance confocal microscopy (RCM) and correlate RCM findings with pathological features. OBSERVATIONS: Six patients affected by alopecia totalis entered the study. Patients were first submitted to scalp dermoscopy, which was followed by RCM examination of the same area. After RCM, a 5-mm punch biopsy specimen was also taken. Dermoscopic findings showed the yellow dot pattern in all patients, with round or polycyclic yellow-pink dots often containing miniaturized or broken hair shafts. At RCM, a Vivablock mosaic taken at the level of the spinous layer showed striking reduction of follicular adnexal structures and empty lumina containing highly refractile material corresponding to the yellow dots seen on dermoscopy. The pathological features showed that the yellow dots correspond to the dilated infundibula of the velluslike anagen and telogen follicles that characterize the chronic phase of alopecia areata. CONCLUSION: The RCM study of the yellow dot pattern showed a good correlation with the dermoscopic and pathological findings and confirms that the yellow dots correspond to inefficient follicular structures that often contain hair remnants. PMID- 21242397 TI - Paraneoplastic pemphigus herpetiformis with IgG antibodies to desmoglein 3 and without mucosal lesions. AB - BACKGROUND: Pemphigus herpetiformis (PH) is a rare clinical entity that combines the clinical features of dermatitis herpetiformis and the immunopathologic features of pemphigus. The target antigen is usually desmoglein 1, with exceptional cases manifesting autoantibodies against desmoglein 3. More recently, it has been found that many patients with PH also demonstrate autoantibodies against desmocollin. The association of PH with a malignant neoplasm is rare. OBSERVATIONS: We describe a patient with PH and a lung neoplasm. Immunologic studies demonstrated IgG antibodies to desmoglein 3 and to an unknown 178-kDa protein but no antibodies to desmocollin. CONCLUSIONS: The association of PH with a thoracic malignant neoplasm has been reported in only 4 previous cases, and the neoplasm could be responsible for the unusual immunologic profile in the patient described herein. To our knowledge, this is the first report of PH with an associated neoplasm in which only anti-desmoglein 3 antibody was detected. PMID- 21242398 TI - Etanercept: an overview of dermatologic adverse events. AB - OBJECTIVES: To provide a comprehensive overview of dermatologic adverse events of etanercept described in the literature (including all study types, case reports, and surveys) and to present information on the occurrence, severity, treatment, and course of these adverse events. DATA SOURCES: MEDLINE and EMBASE. STUDY SELECTION: All reports on individual patients who developed a dermatologic adverse event associated with systemic etanercept treatment for any indication in any type of original article were included. DATA EXTRACTION: All data were independently extracted by 2 reviewers. Disagreements were resolved by consensus. All articles included (except for case reports/case series) were assessed regarding level of evidence. DATA SYNTHESIS: In 126 included study reports, a total of 72 separate specific dermatologic adverse events of etanercept were mentioned. In 101 case reports/case series, 153 individual patients with approximately 65 different specific diagnoses (eg, not rash) were reported. CONCLUSIONS: Etanercept is associated with a wide variety of dermatologic adverse events, many of which were described in study reports, but case reports also described numerous exceptional cases. Although the adverse events are usually mild, some reactions are serious and even potentially life threatening. Therefore, all drug-associated cutaneous abnormalities should be carefully evaluated. Diagnostic steps do not deviate from the norm in these patients, but management of the dermatologic adverse events may need special attention. PMID- 21242399 TI - Effectiveness of oral ivermectin and malathion lotion for difficult-to-treat head lice. PMID- 21242400 TI - Is topical monotherapy effective for localized pyoderma gangrenosum? PMID- 21242401 TI - On reducing the need to excise nevi. PMID- 21242402 TI - Generalized annular bullous eruption--quiz case. Anti-laminin gamma1 pemphigoid with a linear IgA bullous dermatosis-like presentation. PMID- 21242403 TI - Necrotic papules on the thigh of a 76-year-old woman with prolonged fever--quiz case. Intravascular B-cell lymphoma (IBL). PMID- 21242404 TI - Tender papules and plaques adjacent to a scar--quiz case. Subcutaneous and cutaneous sarcoidosis. PMID- 21242405 TI - Pruritic indurated plaques on the legs of a 62-year-old woman--quiz case. Polycythemia vera (PCV). PMID- 21242406 TI - A pilot study of etanercept treatment for pemphigus vulgaris. PMID- 21242407 TI - Detection of human papillomavirus in multiple eccrine poromas in a patient with chronic graft-vs-host disease and immunosuppression. PMID- 21242408 TI - Botulinum toxin type A vs type B for axillary hyperhidrosis in a case series of patients observed for 6 months. PMID- 21242409 TI - Neurogenic rosacea: a distinct clinical subtype requiring a modified approach to treatment. PMID- 21242410 TI - Bullous amyloidosis complicated by cellulitis and sepsis: a case report. PMID- 21242411 TI - Clear cell papulosis of the skin: acquired hypomelanosis. PMID- 21242412 TI - A case of epithelioid angiosarcoma of the scalp treated with paclitaxel and radiotherapy. PMID- 21242413 TI - Acneiform follicular mucinosis responding to hydroxychloroquine. PMID- 21242414 TI - Effectiveness of infliximab for intralymphatic histiocytosis with rheumatoid arthritis. PMID- 21242415 TI - Invasive squamous cell carcinoma and sorafenib in a black patient. PMID- 21242417 TI - In vivo imaging of lichen nitidus with confocal laser scanning microscopy. PMID- 21242416 TI - Exudative, nonhealing scalp: a complication of systemic chemotherapy with capecitabine and bevacizumab. PMID- 21242418 TI - Evaluating revascularization and flap survival using vascular endothelial growth factor in an irradiated rat model. AB - OBJECTIVE: To evaluate the role of vascular endothelial growth factor (VEGF) plasmid DNA (pDNA) in improving flap revascularization in a previously developed rat model. Our hypothesis was that the uptake and expression of VEGF pDNA in the wound bed would improve revascularization and flap viability. DESIGN: Twenty eight male Sprague-Dawley rats received a total dose of 40 Gy electron beam radiation to the ventral abdominal wall. After a recovery period, they underwent a ventral fasciocutaneous flap procedure with a 2-hour ischemia period. Group 1 (n = 14) received topical VEGF pDNA, in vivo cationic polymer, and fibrin sealant. Group 2 (n = 14) received topical cationic polymer and fibrin sealant only. Seven of the rats from each group underwent pedicle ligation at 8 or 14 days. The primary outcome measure was percentage of flap revascularization 5 days after pedicle ligation. RESULTS: Rats receiving VEGF pDNA had a significantly higher rate of flap revascularization (90.8% vs 79.8%) after pedicle ligation at 14 days (P = .045). At 8 days, rats receiving VEGF pDNA (group 1) had an increased rate of flap revascularization (58.2% vs 42.8%) that approached significance (P = .11). CONCLUSION: This study demonstrates the potential of VEGF pDNA to improve revascularization and flap viability in previously irradiated tissue. PMID- 21242419 TI - Improving aesthetic outcomes in pediatric free tissue oromandibular reconstruction. AB - OBJECTIVE: To review our substantial favorable experience with oromandibular free tissue reconstruction in pediatric patients, emphasizing technical pearls, which seem to be associated with favorable long-term aesthetic and functional outcomes. METHODS: Retrospective review of a consecutive series of all free tissue transfers performed from 1997 to 2010 by the senior author (Y.D.) in patients younger than 18 years. Demographic data, techniques used, and complications were examined. RESULTS: A total of 51 patients were identified, and their data were available for collection. Twenty-eight were female, and 23 were male; the mean age was 10 years (range, 4-17 years). Flaps performed included 43 fibula free flaps and 8 radial forearm free flaps with successful transplantation in each case. Twenty-six patients had temporomandibular joint reconstruction as part of their initial repair. The reasons for reconstruction were trauma (in 18 cases) and oncologic (in 33 cases). Functional and aesthetic results were improved with minimal access, maximal exposure approaches as outlined. CONCLUSIONS: Pediatric free tissue oromandibular reconstruction is associated with excellent outcomes in most patients. Specific technical modifications allowing for minimal visible scarring and improved function, particularly at the level of the joint, allow for rewarding results in young patients. PMID- 21242420 TI - Mandibular distraction osteogenesis in infants younger than 3 months. AB - OBJECTIVES: To examine the long-term outcomes and complications in infants with upper airway obstruction and feeding difficulty who underwent bilateral mandibular distraction osteogenesis (MDO) within the first 3 months of life and to identify any preoperative characteristics that may predict the long-term outcome following early MDO intervention for airway obstruction. METHODS: An institutional, retrospective medical chart review was performed. Inclusion criteria were bilateral MDO performed at an age younger than 3 months, with a minimum follow-up of 3 years. A quantitative outcome measures scale was developed, and patients were scored based on long-term postoperative complications as well as airway and feeding goals. Factors such as need for an additional surgical procedure were also considered. RESULTS: Nineteen children were identified as having undergone MDO before 3 months of age and having more than 3 years of follow-up data. The mean age at distraction was 4.8 weeks (range, 5 days-12 weeks); the mean length of follow-up was 5.6 years (range, 37-122 months). Of these 19 patients, 14 had isolated Pierre Robin sequence (PRS) and 5 had syndromic PRS. All patients with isolated PRS had a good or intermediate long term result. Infants with comorbidities such as developmental delay, seizures, or arthrogryposis had the poorest outcomes. CONCLUSIONS: Bilateral MDO is a relatively safe and effective means of treating airway obstruction and feeding difficulty in infants with PRS. The effects of this procedure, which carries a relatively low morbidity, persist through early childhood in most patients. PMID- 21242421 TI - Factors associated with trauma center use for elderly patients with trauma: a statewide analysis, 1999-2008. AB - OBJECTIVES: To estimate the likelihood of trauma center admission for injured elderly patients with trauma, determine trends in trauma center admissions, and identify factors associated with trauma center use for elderly patients with trauma. DESIGN: Retrospective analysis. SETTING: Acute care hospitals in California. PATIENTS: All patients hospitalized for acute traumatic injuries during the period from January 1, 1999, to December 31, 2008 (n = 430,081). Patients who had scheduled admissions for nonacute or minor trauma were excluded. MAIN OUTCOME MEASURE: Likelihood of admission to level I or II trauma center was calculated according to age categories after adjusting for patient and system factors. RESULTS: Of 430,081 patients admitted to California acute care hospitals for trauma-related diagnoses, 27% were older than 65 years. After adjusting for demographic, clinical, and system factors, compared with trauma patients aged 18 25 years, the odds of admission to a trauma center decreased with increasing age; patients aged 26-45 years had lower odds (odds ratio [OR], 0.75; 95% confidence interval [CI], 0.71-0.80) of being admitted to a trauma center for their injuries than did patients 46-65 years of age (OR, 0.57; 95% CI, 0.54-0.60), patients 66 85 years of age (OR, 0.35; 95% CI, 0.30-0.41), and patients older than 85 years (OR, 0.30; 95% CI, 0.25-0.36). Similar patterns were found when stratifying the analysis by trauma type and severity. Living more than 50 miles away from a trauma center (OR, 0.03; 95% CI, 0.01-0.06) and lack of county trauma center (OR, 0.17; 95% CI, 0.09-0.35) were also predictors of not receiving trauma care. CONCLUSION: Age and likelihood of admission to a trauma center for injured patients were observed to be inversely proportional after controlling for other factors. System-level factors play a major role in determining which injured patients receive trauma care. PMID- 21242422 TI - Prevalence and implications of preinjury warfarin use: an analysis of the National Trauma Databank. AB - OBJECTIVES: To describe the prevalence of preinjury warfarin use in a large national sample of trauma patients and to define the relationship between preinjury warfarin use and mortality. DESIGN: Retrospective cohort study. SETTING: The National Trauma Databank (7.1). PATIENTS: All patients admitted to eligible trauma centers during the study period; 1,230,422 patients (36,270 warfarin users) from 402 centers were eligible for analysis. MAIN OUTCOME MEASURES: Prevalence of warfarin use and all-cause in-hospital mortality. Multivariate logistic regression was used to estimate the odds ratio (OR) for mortality associated with preinjury warfarin use. RESULTS: Warfarin use increased among all patients from 2.3% in 2002 to 4.0% in 2006 (P < .001), and in patients older than 65 years, use increased from 7.3% in 2002 to 12.8% in 2006 (P < .001). Among all patients, 9.3% of warfarin users died compared with only 4.8% of nonusers (OR, 2.02; 95% confidence interval [CI], 1.95-2.10; P < .001). After adjusting for important covariates, warfarin use was associated with increased mortality among all patients (OR, 1.72; 95% CI, 1.63-1.81; P < .001) and patients 65 years and older (OR, 1.38; 95% CI, 1.30-1.47; P < .001). CONCLUSIONS: Warfarin use is common among injured patients and its prevalence has increased each year since 2002. Its use is a powerful marker of mortality risk, and even after adjusting for confounding comorbidities, it is associated with a significant increase in death. PMID- 21242423 TI - Rural-urban differences in surgical procedures for Medicare beneficiaries. AB - OBJECTIVE: To determine whether Medicare beneficiaries in rural areas were less likely to undergo a variety of surgical procedures compared with their urban counterparts. DESIGN, SETTING, AND PATIENTS: Cross-sectional study of Medicare beneficiaries. MAIN OUTCOME MEASURE: Any incidence of the surgical procedures studied. RESULTS: Compared with urban Medicare beneficiaries, rural Medicare beneficiaries were more likely to undergo a broad array of surgical procedures: 35% more likely for carotid endarterectomy (odds ratio [OR] = 1.35; 95% confidence interval [CI], 1.33-1.38), 32% for lumbar spine fusion (OR = 1.32; 95% CI, 1.29-1.35), 30% for knee replacement surgery (OR = 1.30; 95% CI, 1.28-1.31), 28% for abdominal aortic aneurysm repair (OR = 1.28; 95% CI, 1.24-1.31), 22% for prostatectomy (OR = 1.22; 95% CI, 1.19-1.24), 19% for hip replacement surgery (OR = 1.19; 95% CI, 1.17-1.21), 18% for aortic valve replacement (OR = 1.18; 95% CI, 1.14-1.21), 16% for open reduction and internal fixation of the femur (OR = 1.16; 95% CI, 1.14-1.18), and 15% for appendectomy (OR = 1.15; 95% CI, 1.11-1.19). To determine whether these differences could be explained by known confounding variables, we then used logistic regression to adjust for age, sex, race/ethnicity, median household income, average house value, mean poverty ratio, and state of residence. Rural beneficiaries were still more likely to undergo all of these surgical procedures. CONCLUSIONS: Medicare beneficiaries living in rural areas were more likely to undergo a broad array of surgical procedures compared with those living in urban areas. While allaying some concern about rural access to surgical procedures, the uniformity of these results raises concern that people living in rural areas may have an overall poorer quality of health. PMID- 21242424 TI - Adherence to the enhanced recovery after surgery protocol and outcomes after colorectal cancer surgery. AB - OBJECTIVES: To study the impact of different adherence levels to the enhanced recovery after surgery (ERAS) protocol and the effect of various ERAS elements on outcomes following major surgery. DESIGN: Single-center prospective cohort study before and after reinforcement of an ERAS protocol. Comparisons were made both between and across periods using multivariate logistic regression. All clinical data (114 variables) were prospectively recorded. SETTING: Ersta Hospital, Stockholm, Sweden. PATIENTS: Nine hundred fifty-three consecutive patients with colorectal cancer: 464 patients treated in 2002 to 2004 and 489 in 2005 to 2007. MAIN OUTCOME MEASURES: The association between improved adherence to the ERAS protocol and the incidence of postoperative symptoms, complications, and length of stay following major colorectal cancer surgery was analyzed. RESULTS: Following an overall increase in preoperative and perioperative adherence to the ERAS protocol from 43.3% in 2002 to 2004 to 70.6% in 2005 to 2007, both postoperative complications (odds ratio, 0.73; 95% confidence interval, 0.55 0.98) and symptoms (odds ratio, 0.53; 95% confidence interval, 0.40-0.70) declined significantly. Restriction of intravenous fluid and use of a preoperative carbohydrate drink were major independent predictors. Across periods, the proportion of adverse postoperative outcomes (30-day morbidity, symptoms, and readmissions) was significantly reduced with increasing adherence to the ERAS protocol (>70%, >80%, and >90%) compared with low ERAS adherence (<50%). CONCLUSION: Improved adherence to the standardized multimodal ERAS protocol is significantly associated with improved clinical outcomes following major colorectal cancer surgery, indicating a dose-response relationship. PMID- 21242425 TI - Minimally invasive temporalis tendon transposition. AB - OBJECTIVE: To describe a minimally invasive approach of the temporalis tendon transposition technique for dynamic reanimation in patients with long-standing facial paralysis. METHODS: We report a case series of 17 consecutive patients with facial paralysis who underwent minimally invasive temporalis tendon transposition surgery for dynamic facial reanimation between January 1, 2006, and December 31, 2008. The minimally invasive technique is described. Preoperative and postoperative records, photographs, and videos were reviewed for feasibility of the technique, symmetry, oral competence, and dynamic oral commissure movement. RESULTS: All the patients tolerated the procedure well, and none developed procedure-related complications. All the patients achieved improved symmetry at rest and voluntary motion of the oral commissure. In all the patients, the temporalis tendon was transposed to the modiolus without the need for fascial extension or lengthening myoplasty. CONCLUSIONS: The temporalis tendon can be transposed for immediate dynamic reanimation of the paralyzed lower face using a minimally invasive approach. This procedure involves a single small incision and minimal dissection, with no major osteotomies. Acquisition of desired facial movement requires intensive physiotherapy and a motivated patient. PMID- 21242426 TI - Threshold of visual perception of facial asymmetry in a facial paralysis model. AB - OBJECTIVE: To determine the degree of facial asymmetry required to trigger conscious perception in the observer in a simulated model of facial paralysis. METHODS: A model of unilateral facial paralysis was created using the face of a participant without facial paralysis. Digital morphing software was used to create progressive asymmetry of the brow, oral commissure, and combined brow and oral commissure based on the typical sequelae seen in facial paralysis. Volunteers naive to the goals of the study repeatedly were shown a series of photographs of faces without facial paralysis, with the manipulated image interspersed within the series. RESULTS: At least 3 mm of facial asymmetry of the oral commissure, brow, or both was required before participants detected the asymmetry. With longer display intervals, participants tended to detect a smaller degree of asymmetry. CONCLUSIONS: To our knowledge, this is the first study directed at determining the amount of facial asymmetry required to trigger conscious perception of patients' facial paralysis in the naive observer. The pilot data and the discussion herein provide insight into the processes of visual perception of facial asymmetry and may be useful to surgeons for patient counseling and in setting surgical goals. PMID- 21242428 TI - Analysis of nasal ptosis correction using lower lateral to upper lateral cartilage suspension. AB - OBJECTIVE: To evaluate the durability of lower lateral to upper lateral cartilage suspension (LUCS) in the correction of nasal tip ptosis. METHODS: Patients with extreme nasal tip ptosis who subsequently underwent cosmetic rhinoplasty were eligible for this retrospective case study. Severe tip ptosis was defined as a nasolabial angle less than or equal to 80 degrees in men and 90 degrees in women. Of 34 patients identified who underwent LUCS in the past 18 years, 24 were found to have at least 1-year follow-up images and documented clinic visits. Thirteen of these patients were observed for at least 3 years and comprise the long-term cohort. Preoperative morphed or hand-drawn illustrations were obtained, and the nasolabial angles were measured and compared with those of the standard preoperative, 1-year postoperative, and long-term postoperative groups. RESULTS: The mean preoperative nasolabial angle for the entire group was 83.4 degrees . The mean preoperative morphed or illustrated angles measured 104.7 degrees . The mean 1-year and long-term follow-up angles measured 102.5 degrees and 101.5 degrees , respectively. The differences among the preoperative, 1-year postoperative, and long-term groups were significant at P < .001. The similarities between the morphed, 1-year postoperative, and long-term angles were also statistically significant. CONCLUSIONS: The LUCS is a durable technique in the correction of nasal tip ptosis. It has consistently proved to provide accurate and reproducible results. PMID- 21242427 TI - Modified back-to-back autogenous conchal cartilage graft for caudal septal reconstruction: the medial crural extension graft. AB - OBJECTIVE: To report our experience with the use of a modification of the back-to back autogenous conchal cartilage graft, used as a medial crural extension graft, for reconstruction of the caudal septum. METHODS: Retrospective review of all patients undergoing caudal septal reconstruction using a modification of the back to-back conchal cartilage graft from January 1, 2007, through June 1, 2009, at a tertiary referral center. Photodocumentation of all patients was obtained preoperatively and postoperatively. Patients were asked to subjectively rate their functional and cosmetic outcomes at each follow-up visit. RESULTS: Eight patients underwent caudal septal reconstruction with the modified back-to-back conchal cartilage graft during the time period studied. Six patients underwent caudal septal reconstruction via external septorhinoplasty while 2 patients underwent an endonasal approach. The median duration of follow-up was 12 months. At the last follow-up, patients rated their breathing as normal in 7 of 8 cases and improved, but not to normal, in 1 of 8 cases. Cosmesis was rated as excellent in 7 of 8 cases and good in 1 of 8 cases. There were no postoperative complications. CONCLUSIONS: Modification of the back-to-back autogenous conchal cartilage graft used as a medical crural extension graft should be considered for reconstruction of the caudal septum in the cartilage deficient nose. The technique produces reliable outcomes with minimal donor site morbidity. PMID- 21242429 TI - Minimally invasive bioabsorbable bone plates for rigid internal fixation of mandible fractures. AB - OBJECTIVES: To optimize design variables of a bioabsorbable bone plate using a finite element model of the mandible and to discover a minimally invasive bioabsorbable bone plate design that can provide the same mechanical stability as a titanium plate. METHODS: A finite element model of a mandible with a fracture in the body was subjected to bite loads. An analysis was run to determine the principal strain in the fracture callus and von Mises stress in a titanium plate. These values were then set as the limits within which the bioabsorbable bone plate must comply. The model then considered a bone plate made of the polymer poly(L-lactide-co-D,L-lactide) (P[L/DL]LA) 70/30. An optimization routine determined the smallest volume of bioabsorbable bone plate that can perform as well as a titanium bone plate when fixating mandibular fractures. RESULTS: A P(L/DL)LA plate volume of 315 mm(2) with a thickness of 1.5 mm provided as much mechanical stability as a commonly used titanium strut structure of 172 mm(2). The peak plate stress was well below the yield strength of the material. CONCLUSIONS: The P(L/DL)LA bioabsorbable bone plate design is as strong as a titanium plate when fixating fractures of the mandible body despite the polymer material having only 6% of the stiffness of the titanium. The P(L/DL)LA plate can be less than half the volume of its strut-style counterpart. PMID- 21242430 TI - Preoperative magnetic resonance angiography detection of septocutaneous perforators in fibula free flap transfer. AB - OBJECTIVE: To investigate whether preoperative magnetic resonance angiography (MRA) is predictive of surgical findings in fibula free flap surgery for head and neck reconstruction. METHODS: Retrospective review (April 2004 until September 2009) of 123 patients who underwent preoperative MRA as part of surgical planning for fibula free flap tissue transfer for head and neck reconstruction. Each MRA was reviewed by a board-certified radiologist masked to the intraoperative findings and to the number of septocutaneous perforators documented. Operative notes were reviewed and the number of septocutaneous perforators found during the operation was recorded. A kappa interrater agreement statistic was calculated to compare these values. RESULTS: Two vascular anomalies found during the operation were undetected by MRA. Analysis of the entire cohort demonstrated that agreement between the number of perforators documented on MRA and the number found intraoperatively approached zero (unweighted kappa = -0.088, P = .04). The agreement between the 2 values was 17.9% and the average percentage correctly classified was 10.9%. CONCLUSIONS: Contrary to previous reports, preoperative MRA does not accurately predict the presence and/or number of skin perforators found intraoperatively for a fibula free flap operation. The surgeon should not be dissuaded from planning a fibula free flap operation if skin perforators appear unfavorable on preoperative MRA because intraoperative observation is definitive. The surgeon should prepare for anomalous cases in which perforators may arise from the posterior tibial system. Further investigation is needed to achieve more accurate imaging modalities for evaluating septocutaneous perforators prior to free fibula flap transfer. PMID- 21242431 TI - Histologic evaluation of laser lipolysis comparing continuous wave vs pulsed lasers in an in vivo pig model. AB - OBJECTIVES: To evaluate acute and delayed laser effects of subdermal lipolysis and collagen deposition using an in vivo pig model and to compare histologic findings in fatty tissue after continuous wave diode (CW) vs pulsed laser treatment. METHODS: Three CW lasers (980, 1370, and 1470 nm) and 3 pulsed lasers (1064, 1320, and 1440 nm) were used to treat 4 Gottingen minipigs. Following administration of Klein tumescent solution, a laser cannula was inserted at the top of a 10 * 2.5-cm rectangle and was passed subdermally to create separate laser "tunnels." Temperatures at the surface and at intervals of 4-mm to 20-mm depths were recorded immediately after exposure and were correlated with skin injury. Full-thickness cutaneous biopsy specimens were obtained at 1 day, 1 week, and 1 month after exposure and were stained with hematoxylin-eosin and trichrome stain. Qualitative and semiquantitative histopathologic evaluations were performed with attention to vascular damage, lipolysis, and collagen deposition. RESULTS: Skin surface damage occurred at temperatures exceeding 46 degrees C. Histologic examination at 1 day after exposure showed hemorrhage, fibrous collagen fiber coagulation, and adipocyte damage. Adipocytes surrounded by histiocytes, a marker of lipolysis, were present at 1 week and 1 month after exposure. Collagen deposition in subdermal fatty tissue and in reticular dermis of some specimens was noted at 1 week and had increased at 1 month. Tissue treated with CW laser at 1470 nm demonstrated greater hemorrhage and more histiocytes at damage sites than tissue treated with pulsed laser at 1440 nm. There was a trend toward more collagen deposition with pulsed lasers than with CW lasers, but this was not statistically significant. Histopathologic comparison between results of CW laser at 980 nm vs pulsed laser at 1064 nm showed the same trend. Hemorrhage differences may result from pulse duration variations. A theoretical calculation estimating temperature rise in vessels supported this hypothesis. CONCLUSIONS: Pulsed lasers with higher peak powers provided better hemostatic effects than CW lasers. The degree of lipolysis depended on wavelength, laser power, and energy density. Subdermal laser irradiation can stimulate collagen deposition in subdermal tissue and reticular dermis. PMID- 21242432 TI - The relationship of the globe to the orbital rim. AB - OBJECTIVE: To present a novel method for accurately characterizing the position of the globe relative to the orbital rim. The appearance and function of the eyelids are dependent on the underlying orbital bony architecture and globe position; however, no comprehensive language to describe these complex 3 dimensional relationships exists. METHODS: Three-dimensional orbital reconstructions were generated from computed tomographic scans of 15 Occidental and 12 Oriental orbits without orbital pathologic disease. Globe and orbital rim anatomy were identified and outlined. Reference points were measured along 2 independent axes: (1) the distance between a plane defined by the corneal apex and the sagittal projection of the orbital rim and (2) the distance between the circumference of the globe and the coronal projection of the orbital rim. RESULTS: For Occidental orbits, the mean (SD) elevation of the sagittal projection of the orbital rim relative to the anterior projection of the globe was 4.6 (4.2) mm superiorly, 5.9 (3.0) mm nasally, 12.6 (3.7) mm inferiorly, and 20.6 (2.6) mm laterally. The mean (SD) radial distance between the coronal projection of the orbital rim and the circumference of the globe was 3.7 (2.1) mm superiorly, 7.6 (1.8) mm nasally, 6.6 (2.2) mm inferiorly, and 4.6 (2.3) mm laterally. For Oriental orbits, the mean (SD) elevation of the sagittal projection of the orbital rim relative to the anterior projection of the globe was 5.0 (4.5) mm superiorly, 6.8 (4.1) mm nasally, 11.1 (4.3) mm inferiorly, and 17.5 (3.3) mm laterally. The mean (SD) radial distance between the coronal projection of the orbital rim and the circumference of the globe was 2.1 (1.2) mm superiorly, 8.2 (2.0) mm nasally, 6.5 (1.9) mm inferiorly, and 4.5 (1.7) mm laterally. CONCLUSIONS: Comparison of Occidental and Oriental orbital rim and globe configurations revealed quantitative and qualitative differences. In addition to differences in soft-tissue anatomy, bony architectural variations may contribute substantially to racial differences in the surface anatomy of the periorbital area. Anatomic analysis, based on 3-dimensional orbital imaging, may provide a rational approach to surgical planning for aesthetic and reconstructive orbitofacial surgery. PMID- 21242433 TI - Ultrasonography for rapid detection of pneumothorax after costal cartilage harvest. AB - The rib is a generous source of donor cartilage. Thus, costal cartilage harvest is a frequently performed adjunctive procedure in facial plastic and reconstructive surgery. Pneumothorax is an uncommon complication of rib graft harvest but is potentially highly morbid. Although chest radiography is the current diagnostic study of choice to rule out air in the chest, there is growing evidence that ultrasonography is less expensive and more sensitive. Furthermore, the portability of the ultrasonographic unit allows for immediate evaluation and more rapid diagnosis. The use of ultrasonography also precludes exposing the patient to ionizing radiation. We present a case in which ultrasonography was used to rapidly confirm the absence of pneumothorax after costal cartilage harvest and review the literature associated with use of ultrasonography for detection of this uncommon but serious complication. PMID- 21242434 TI - Facial suspension with acellular human dermal allograft. PMID- 21242435 TI - Facial acne scarring: ten years of treatment with the carbon dioxide laser. PMID- 21242436 TI - What is beauty, and why do we care so much about it? PMID- 21242437 TI - La Marguerite by William Morris Hunt. PMID- 21242439 TI - Limitations in resident work hours: are we preaching to the choir? That is the question! PMID- 21242440 TI - More recurrences after hernia mesh fixation with short-term absorbable sutures: A registry study of 82 015 Lichtenstein repairs. AB - OBJECTIVE: To assess the effects of different mesh fixation suture materials on the risk of recurrence after Lichtenstein inguinal hernioplasty. DESIGN: Observational, population-based registry study. SETTING: Data from the nationwide Swedish Hernia Registry. PATIENTS: All 82 015 Lichtenstein inguinal hernioplasties with sutured mesh fixation in adolescents and adults (15 years or older) from January 1, 2002, to December 31, 2009, at surgical units enrolled in the Swedish Hernia Registry. INTERVENTIONS: Mesh fixation with nonabsorbable, long-term absorbable, or short-term absorbable sutures. Main Outcome Measure Relative risk (RR) for reoperation due to recurrence of a hernia in the same groin during the study period, based on cumulative reoperation rates adjusted for time and confounding variables. RESULTS: For each study group, RR was calculated with multiregression analysis. There was no significant difference in risk for reoperation after mesh fixation with standard nonabsorbable sutures (RR, 1) or with long-term absorbable sutures (RR, 1.12; 95% confidence interval, 0.81-1.55; P = .49). Short-term absorbable sutures, however, more than doubled that risk (RR, 2.23; 95% confidence interval, 1.67-2.99; P < .001). CONCLUSIONS: With regard to recurrence risk, long-term absorbable sutures are an excellent alternative to permanent sutures for mesh fixation in Lichtenstein inguinal hernioplasty. Short-term absorbable sutures entail an independent risk factor for recurrence and should therefore be avoided. PMID- 21242441 TI - Ten-year retrospective analysis of incisional herniorrhaphy following renal transplantation. AB - HYPOTHESIS: Repair of incisional hernias in renal transplant recipients is compromised because of immunosuppressive therapy. DESIGN: Retrospective review. SETTING: University tertiary care institution. PATIENTS: Forty-two recipients of renal transplants or combined renal-pancreas transplants who underwent incisional herniorrhaphy were included in our study. INTERVENTION: Incisional herniorrhaphy. MAIN OUTCOME MEASURES: Postoperative complications and recurrence of incisional hernia. RESULTS: Forty-two patients (mean age, 49.6 years) underwent incisional herniorrhaphy (mean area, 99.9 cm(2)) following renal transplantation (26 cadaveric donor renal, 12 combined renal-pancreas, and 4 living related donor renal) from January 1, 1995, to December 31, 2005. Using various techniques, hernia repairs were performed on average 36.4 months following transplantation. Diabetes mellitus was a frequent cause of end-stage renal disease (16 patients), followed by polycystic kidney disease (6 patients), focal segmental glomerular sclerosis (3 patients), hypertension (2 patients), Alport syndrome (2 patients), and IgA nephropathy (2 patients), with 11 patients having lupus or glomerulonephritis. Four patients developed cellulitis, 2 patients required mesh removal, and 1 patient was admitted for abscess drainage and intravenous antibiotics. Fourteen patients had recurrence of incisional hernias, with 3 patients experiencing 2 recurrences and 1 patient experiencing 4 recurrences. CONCLUSIONS: To our knowledge, this is the largest series of incisional herniorrhaphies performed among patients following renal transplantation. Although smoking history, the presence of diabetes, and immunosuppressive therapy were not associated with the initial development of an incisional hernia, they were associated with complications. Component separation performed by transplant and plastic and reconstructive surgeons should be considered in the setting of recurrent hernias and large defects. PMID- 21242442 TI - Evaluation of absolute serum alpha-fetoprotein levels in liver transplant for hepatocellular cancer. AB - HYPOTHESIS: An elevated serum alpha-fetoprotein (AFP) level before orthotopic liver transplant (OLT) is predictive of mortality after OLT for hepatocellular carcinoma (HCC). DESIGN: Retrospective analysis of a population-based cohort. SETTING: United Network for Organ Sharing registry (2003-2008). PATIENTS: We identified 2253 patients who underwent OLT for HCC with available pre-OLT serum AFP values. METHODS: Patients were stratified by AFP levels into low (<20 ng/mL), medium (20-399 ng/mL), or high (>=400 ng/mL) groups. Clinical and pathological characteristics were compared among groups. Survival curves were constructed by the Kaplan-Meier method, and univariate and multivariate Cox-regression analysis was performed. RESULTS: Of the 2253 patients, 1210 (53.7%), 805 (35.7%), and 238 (10.6%) were in the low, medium, and high AFP groups, respectively. On univariate analysis, the low AFP group demonstrated the best 4-year survival (76%) compared with the medium (65%; P = .001) and high (57%; P < .001) AFP groups. When AFP levels in patients with only stage II HCC underwent assessment, improved survival in the low AFP group was still observed (P < .001). On multivariate analysis, the medium and high AFP groups were associated with higher mortality (hazard ratios, 1.50 [95% confidence interval, 1.19-1.89; P = .001] and 2.11 [1.55-2.88; P < .001], respectively). CONCLUSIONS: Serum AFP level is an independent prognostic predictor of outcome after OLT for HCC. The association between serum AFP value and post-OLT survival warrants further investigation to potentially better allocate donor allografts for HCC. PMID- 21242443 TI - Implementing Liberia's poverty reduction strategy: An assessment of emergency and essential surgical care. AB - OBJECTIVE: To document infrastructure, personnel, procedures performed, and supplies and equipment available at all county hospitals in Liberia using the World Health Organization Tool for Situational Analysis of Emergency and Essential Surgical Care. DESIGN: Survey of county hospitals using the World Health Organization Tool for Situational Analysis of Emergency and Essential Surgical Care. SETTING: Sixteen county hospitals in Liberia. MAIN OUTCOME MEASURES: Infrastructure, personnel, procedures performed, and supplies and equipment available. RESULTS: Uniformly, gross deficiencies in infrastructure, personnel, and supplies and equipment were identified. CONCLUSIONS: The World Health Organization Tool for Situational Analysis of Emergency and Essential Surgical Care was useful in identifying baseline emergency and surgical conditions for evidenced-based planning. To achieve the Poverty Reduction Strategy and delivery of the Basic Package of Health and Social Welfare Services, additional resources and manpower are needed to improve surgical and anesthetic care. PMID- 21242444 TI - Provider response to a rare but highly publicized transmission of HIV through solid organ transplantation. AB - OBJECTIVE: On November 13, 2007, the first reported case in 20 years of HIV (human immunodeficiency virus) transmission from a Centers for Disease Control and Prevention high-risk donor (HRD) made national headlines. We sought to characterize change in the practice of transplant surgeons resulting from this rare event. DESIGN: We performed a survey between January 17, 2008, and April 15, 2008, assessing attitudes and practices of transplant surgeons regarding HRDs. Descriptions of changes in practice after the event were categorized, and associations between responses and regional-, center-, and physician-level factors were studied. SETTING: Transplant centers in the United States. PARTICIPANTS: Four hundred twenty-two transplant surgeons in current practice. MAIN OUTCOME MEASURE: Changing practice following the 2007 HIV transmission event. RESULTS: Among surgeons who responded to the survey, 31.6% changed their practice following the event. Also, 41.7% decreased use of HRDs, 34.5% increased emphasis on informed consent, 16.7% increased use of nucleic acid testing, and 6.0% implemented a formal policy. Ranking fear of being sued or hospital pressure as important disincentives to HRD use was associated with more than 2-fold higher odds of changing practice. Ranking medical risks of HIV as an important disincentive was associated with 8.29-fold higher odds of decreasing HRD use. CONCLUSION: The most common responses to this rare event were avoidance (decreased HRD use) and assurance (increased emphasis on informed consent) behaviors rather than patient safety measures (increased use of nucleic acid testing and implementation of formal policies), suggesting that fear of legal or regulatory consequences was the biggest driver of physician decision making and that the current litigious environment is failing to protect patient interests. PMID- 21242445 TI - Possible geographical barriers to trauma center access for vulnerable patients in the United States: an analysis of urban and rural communities. AB - OBJECTIVE: To study whether traditionally vulnerable populations have worse geographic access to trauma centers. DESIGN: A cross-sectional analysis using data from the American Hospital Association Annual Survey from 2005 linked with zip code-level data from the US Census. We used a multinomial logit model to examine the odds of having difficult as opposed to easy access to trauma centers for a given subgroup of vulnerable populations. SETTING AND PARTICIPANTS: Population in rural and urban communities as defined by zip codes in the United States. MAIN OUTCOME MEASURES: Each community's distance to the nearest trauma center (levels I-III). RESULTS: In urban areas, 67% of the population had easy access to trauma centers and 12% had difficult access compared with 24% and 31% in rural areas, respectively. Areas with higher shares of the following vulnerable population groups had higher risks (odds ratios) of facing difficult access to trauma center services in 2005: foreign born in urban areas (1.65 for a medium share and 2.18 for a high share [both P < .01]); African American in urban and rural areas (1.25 for a medium share and 1.35 for a high share, respectively [both P < .05]); and near-poor in urban and rural areas (1.52 [P < .05] and 1.69 [P < .01] for a high share, respectively). CONCLUSIONS: A significant segment of the US population (representing 38.4 million people) does not have access to trauma care within 1 hour of driving time. Moreover, certain vulnerable groups are at higher risk than others for worse access to trauma centers. Stakeholders and health care planners should consider these factors in the development of trauma systems because a mismatch of potential need and access could signal inefficiencies in the delivery of care. PMID- 21242446 TI - Special report: suicidal ideation among American surgeons. AB - BACKGROUND: Suicide is a disproportionate cause of death for US physicians. The prevalence of suicidal ideation (SI) among surgeons and their use of mental health resources are unknown. STUDY DESIGN: Members of the American College of Surgeons were sent an anonymous cross-sectional survey in June 2008. The survey included questions regarding SI and use of mental health resources, a validated depression screening tool, and standardized assessments of burnout and quality of life. RESULTS: Of 7905 participating surgeons (response rate, 31.7%), 501 (6.3%) reported SI during the previous 12 months. Among individuals 45 years and older, SI was 1.5 to 3.0 times more common among surgeons than the general population (P < .02). Only 130 surgeons (26.0%) with recent SI had sought psychiatric or psychologic help, while 301 (60.1%) were reluctant to seek help due to concern that it could affect their medical license. Recent SI had a large, statistically significant adverse relationship with all 3 domains of burnout (emotional exhaustion, depersonalization, and low personal accomplishment) and symptoms of depression. Burnout (odds ratio, 1.910; P < .001) and depression (odds ratio, 7.012; P < .001) were independently associated with SI after controlling for personal and professional characteristics. Other personal and professional characteristics also related to the prevalence of SI. CONCLUSIONS: Although 1 of 16 surgeons reported SI in the previous year, few sought psychiatric or psychologic help. Recent SI among surgeons was strongly related to symptoms of depression and a surgeon's degree of burnout. Studies are needed to determine how to reduce SI among surgeons and how to eliminate barriers to their use of mental health resources. PMID- 21242447 TI - Decreased use of computed tomography with a modified clinical scoring system in diagnosis of pediatric acute appendicitis. AB - HYPOTHESIS: Use of a modified clinical grading score improves accuracy in diagnosing acute appendicitis in the pediatric population while decreasing the use of computed tomography (CT). DESIGN: Retrospective medical records review after approval by the institutional review board. We determined the Alvarado score for each patient and correlated it with the pathological findings and imaging studies to evaluate the efficacy of CT and its attendant radiation exposure. SETTING: Community teaching hospital. PATIENTS: Sixty-one patients, aged 3 to 16 years, admitted with suspected acute appendicitis. MAIN OUTCOME MEASURES: Sensitivity, specificity, and accuracy of the modified Alvarado scoring system. RESULTS: The standard Alvarado score for acute appendicitis had a sensitivity of 92% and a specificity of 82%, with an accuracy of 92%. In the modified Alvarado scoring system, CT findings were substituted for Alvarado scores in the ranges of 5 or 6, 5 to 7, 5 to 8, and 5 to 9. The modification resulted in the greatest accuracy (98%) in diagnosing appendicitis in patients with scores in the range of 5 to 7. This modification theoretically would have decreased the use of CT by about 27% in this group of retrospectively studied patients. Furthermore, in patients with Alvarado scores of 1 to 4, another diagnosis should be considered; in patients with scores of 5 to 7, CT should be performed; and, in patients with scores of 8 to 10, an appendectomy should be performed promptly without further studies. CONCLUSIONS: The modified Alvarado score is useful as an aid in diagnosing acute appendicitis in the pediatric population. This scoring system eliminates unnecessary use of CT and the attendant potential cancer-inducing radiation in the pediatric population. PMID- 21242448 TI - Single-incision multiport laparoscopic cholecystectomy: things to overcome. AB - OBJECTIVES: To report on our initial experience with single-incision multiport laparoscopic cholecystectomy, together with its clinical outcomes. DESIGN: Nonrandomized prospective study. SETTING: University department of surgery. PATIENTS: Sixty-four patients with gallstones and gallbladder polyps were enrolled after providing informed consent. Based on our experience, we excluded patients with acute cholecystitis, concomitant choledocholithiasis, a history of previous upper abdominal surgery, and a suspicion of gallbladder cancer. MAIN OUTCOME MEASURES: We analyzed the outcomes and complications, based on our experience, according to the clinicopathologic and operative factors. We also compared patients who underwent single-incision multiport laparoscopic cholecystectomy with those who were converted to conventional laparoscopic cholecystectomy. RESULTS: There were 2 bile duct injuries and 4 surgical site infections. We had difficulties in visualizing the Calot triangle in 22 patients. Higher levels of inflammatory markers, longer operation times, and more frequent bile juice spillage were significantly observed in those patients. Ten patients were converted to conventional laparoscopic cholecystectomy. The mean age of patients who underwent conversion surgery was significantly older than that of the no-conversion group. The more the body mass index increased, the more the conversion rate increased. CONCLUSIONS: Experienced laparoscopic surgeons can safely perform cholecystectomy using conventional and curved laparoscopic instruments in selected patients. We recommend that you consider performing conventional laparoscopic cholecystectomy or that you use additional retraction devices for patients with a higher body mass index or acute cholecystitis. PMID- 21242449 TI - Single-port laparoscopic sphincter-saving mesorectal excision for rectal cancer: report of the first 4 human cases. AB - HYPOTHESIS: Single-port laparoscopic rectal surgery can be performed using the principles of oncologic surgery in institutes experienced in laparoscopy with the advantages of minimally invasive surgery. DESIGN: Sphincter-saving mesorectal excision in 4 human cases via a single laparoscopic port. SETTINGS: A university hospital and a private hospital. PATIENTS: A series of 4 patients who underwent single-port laparoscopic sphincter-saving rectal resection for rectal cancer. Two of them were total and 2 were partial mesorectal excisions. INTERVENTIONS: An umbilical incision was made to place the multichannel single port. The sigmoid colon was hung to the left lateral abdominal wall using an intracorporeal stitch passing through its appendices epiploicae to achieve medial dissection and vascular ligation. The mesorectum was sharply dissected down to the pelvic floor. Endoscopic linear roticulating staplers were used to divide the rectum and proximal colon. A specimen was retrieved using an extraction bag through the umbilicus. Anastomosis was performed using a circular stapler, or pull-through hand-sewn anastomosis was performed. MAIN OUTCOME MEASURES: Duration of the operation, length of hospital stay, surgical complications, wound size, and histopathologic data. RESULTS: There were no perioperative or postoperative complications. Mean operative time was 347 minutes (range, 240-480 minutes). Mean hospital stay was 4.25 days (range, 4-5 days). Mean wound size was 3.5 cm (range, 3-4 cm). Mean number of harvested lymph nodes was 15 (range, 8-28). CONCLUSIONS: With the help of sophisticated surgical technology and techniques, single-port laparoscopic surgery for rectal cancer will be feasible while also maintaining oncologic principles and patient safety. PMID- 21242450 TI - To divert or not to divert: A retrospective analysis of variables that influence ileostomy omission in ileal pouch surgery. AB - HYPOTHESIS: A model could be developed to identify patients who can safely undergo restorative proctocolectomy (RPC) without proximal diversion. DESIGN: Logistic regression analysis was used to identify independent factors favoring omission of ileostomy at the time of RPC. A propensity nomogram was developed and validated using measures of calibration, discrimination, and subgroup analysis. SETTING: Two tertiary referral centers. PATIENTS: A total of 4013 patients undergoing RPC between January 1977 and December 2005 were included in the study sample. MAIN OUTCOME MEASURE: The decision to omit loop ileostomy at the time of RPC. RESULTS: After study group exclusions, proximal diversion was performed in 3196 of 3733 patients (85.6%) undergoing RPC; 45.4% of 3733 patients were women. The mean (SD) age at surgery was 37.4 (12.8) years. Ulcerative colitis was the indication for RPC in 2304 patients (61.7%) and familial adenomatous polyposis in 364 patients (9.8%), and a J pouch was performed in 2657 patients (71.2%). The following were found to be associated with ileostomy omission: stapled anastomosis (odds ratio [OR], 6.4), no preoperative corticosteroid use (OR, 3.2), familial adenomatous polyposis diagnosis (OR, 2.6), cancer diagnosis (OR, 3.4), female sex (OR, 1.6), and age at surgery younger than 26 years (OR, 2.1) (P < .01 for all). The model discriminated well (area under the receiver operating characteristic curve, 74.9%), with no significant differences between observed and expected outcomes (P = .49). Omission of proximal diversion demonstrated no significant effect on postoperative adverse events, although it was associated with a 2-day increase in the median length of hospital stay (P < .01). CONCLUSION: Incorporation of a 5-point nomogram in the preoperative assessment of patients undergoing RPC may aid clinicians in identifying a select group of patients who may be candidates for ileostomy omission during RPC. PMID- 21242451 TI - Integration of a formalized handoff system into the surgical curriculum: resident perspectives and early results. AB - HYPOTHESIS: The Situation, Background, Assessment, and Recommendation model (SBAR) provides an excellent framework for communication in daily resident handoffs. OBJECTIVE: To evaluate implementation of SBAR into the surgical curriculum. DESIGN: A curriculum using video and role-play scenarios to augment a didactic lecture on SBAR was implemented for general surgery residents. Resident assessment was achieved via an anonymous survey administered after training. Outcome was evaluated by assessing sentinel events and resident order entry 30 days before and after training. Surgical subspecialty resident order entries were used as controls. Duplicated, cancelled, and wrong patient orders were attributed to failed communication. SETTING: Academic department of surgery. PARTICIPANTS: Forty-five general surgery residents at our institution. RESULTS: Survey response rate was 100%. Poor communication was identified as the leading cause of handoff failure, with nurse-to-resident handoffs considered the most problematic. Overall, the curriculum was well received. Outcomes analysis demonstrated no difference in sentinel events. A 2.3% decrease in pretraining and posttraining order entry errors (14.5% vs 12.2%; P = .003) was demonstrated. No difference was demonstrated in controls who did not undergo SBAR training (12.9% vs 13.6%; P = .47). CONCLUSIONS: Most of the residents indicate that the SBAR curriculum addressed frequently encountered communication issues and taught clinically beneficial communication skills. The identified specific communication deficiencies will direct future curriculum goals. The SBAR model is an effective and valuable tool to standardize communication. Early outcomes analysis demonstrates a decrease in order entry errors after training. Sentinel events are infrequent and will require long-term evaluation. PMID- 21242452 TI - Incisional hernias in temporary stoma wounds: a cohort study. AB - HYPOTHESIS: The prevalence of and risk factors for incisional hernias among temporary stoma wounds have implications for clinical practice. DESIGN: Retrospective cohort study. SETTING: University tertiary care hospital. PATIENTS: All adult patients with a stoma closed between January 1, 2000, and August 1, 2004. Of 150 living patients, 111 (74.0%) were included for analysis after follow up at the outpatient clinic. MAIN OUTCOME MEASURES: The main outcome was incisional hernia in a temporary stoma wound, defined as a defect within the musculature and fascia detected by ultrasonographic examination. Risk factors for incisional hernias and the diagnostic validity of clinical symptoms and palpation during the Valsalva maneuver were determined. RESULTS: After a median follow-up of 35 months (range, 5-77 months), hernia prevalence was 32.4%. Among patients with a body mass index (calculated as weight in kilograms divided by height in meters squared) of less than 30, hernia prevalence was 25.8%; among patients with a body mass index of 30 or higher, hernia prevalence was 59.1%. Palpation demonstrated the highest sensitivity (58.3%). One in 6 patients had discomfort at the temporary stoma site and no palpable defect but showed an incisional hernia on ultrasonographic examination. Obesity was the sole significant risk factor identified in this study (odds ratio, 5.53; 95% confidence interval, 1.72-17.80). The presence of a stoma in situ for less than 6 months showed a trend toward being a risk factor (odds ratio, 2.38; 95% confidence interval, 0.96-5.99). CONCLUSION: Incisional hernias occur in 1 of 3 temporary stoma wounds, and a body mass index of 30 or higher is a risk factor. PMID- 21242453 TI - Acute care surgery survey: opinions of surgeons about a new training paradigm. AB - HYPOTHESIS: The acute care surgery (ACS) 2-year training model, incorporating surgical critical care (SCC), trauma surgery, and emergency general surgery, was developed to improve resident interest in the field. We believed that analysis of survey responses about the new training paradigm before its implementation would yield valuable information on current practice patterns and on opinions about the ACS model. DESIGN: Two surveys. PARTICIPANTS: Members of the Surgery Section of the Society of Critical Care Medicine and SCC program directors. INTERVENTIONS: One survey was sent to SCC program directors to define the practice patterns of trauma and SCC surgeons at their institutions, and another survey was sent to all Surgery Section of the Society of Critical Care Medicine members to solicit opinions about the ACS model. MAIN OUTCOME MEASURES: Practice patterns of trauma and SCC surgeons and opinions about the ACS model. RESULTS: Fifty-seven of 87 SCC program directors responded. Almost all programs are associated with level I trauma centers with as many as 15 trauma surgeons. Most of these trauma surgeons cover SCC and emergency general surgery. Sixty-six percent of surgical intensive care units are semiclosed; 89.0% have surgeons as directors. Seventy percent of the staff in surgical intensive care units are surgeons. One hundred fifty-five of approximately 1100 Surgery Section of the Society of Critical Care Medicine members who responded to the other survey did not believe that the ACS model would compromise surgical intensive care unit and trauma care or trainee education yet would allow surgeons to maintain their surgical skills. Respondents were less likely to believe that the ACS fellowship would be important financially, increase resident interest, or improve patient care. CONCLUSIONS: In academic medical centers, surgical intensivists already practice the ACS model but depend on many nonsurgeons. Surgical intensivists believe that ACS will not compromise care or education and will help maintain the field, although the effect on resident interest is unclear. PMID- 21242454 TI - Emerging trends in the outsourcing of medical and surgical care. AB - As total health care expenditures are expected to constitute an increasing portion of the US gross domestic product during the coming years, the US health care system is anticipating a historic spike in the need for care. Outsourcing medical and surgical care to other nations has expanded rapidly, and several ethical, legal, and financial considerations require careful evaluation. Ultimately, the balance between cost savings, quality, and patient satisfaction will be the key determinant in the future of medical outsourcing. PMID- 21242455 TI - Image of the month--quiz case. Sporadic duodenal macrogastrinoma. PMID- 21242456 TI - Image of the month--quiz case. Colon cancer with splenic abscess. PMID- 21242457 TI - Timing of repair of bile duct injuries associated with laparoscopic cholecystectomy. PMID- 21242458 TI - GPR30, mineralocorticoid receptors, and the rapid vascular effects of aldosterone. PMID- 21242459 TI - Relationship between muscle sympathetic nerve activity and aortic wave reflection characteristics in young men and women. AB - Increased arterial stiffness is associated with higher levels of aortic wave reflection and aortic blood pressure. Recent evidence suggests a link between muscle sympathetic nerve activity and indices of arterial stiffness. Therefore, the aims of this study were to examine the relationship between resting muscle sympathetic nerve activity and characteristics of aortic pressure wave reflection and the influence of sex on these relationships. In 44 subjects (23 females and 21 males; 25 +/- 1 years of age), we measured muscle sympathetic nerve activity via peroneal microneurography. In addition, noninvasive aortic pressure waveforms were synthesized from radial pressure waveforms obtained from applanation tonometry. Aortic blood pressure, augmentation index, wave reflection amplitude, and wasted left ventricular energy were calculated. Resting sympathetic activity (bursts/100 heart beats) was not associated with any of the aortic pressure wave reflection characteristics for all patients. However, there was a positive relationship between sympathetic activity and augmentation index (r = 0.46; P = 0.05) in men. Further, sympathetic activity in men was related to wave reflection amplitude (r = 0.53; P<0.05) and wasted left ventricular energy (r = 0.57; P<0.01). In contrast to men, women demonstrated strong inverse relationships between sympathetic activity and augmentation index (r = -0.63), wave reflection amplitude ( r = -0.59), and wasted left ventricular energy (r = -0.58; P<0.01 for all). Our results suggest another possible mechanism by which young women are protected against the development of cardiovascular disease. PMID- 21242460 TI - GPR30 expression is required for the mineralocorticoid receptor-independent rapid vascular effects of aldosterone. AB - It has been increasingly appreciated that steroids elicit acute vascular effects through rapid, so-called nongenomic signaling pathways. Though aldosterone, for example, has been demonstrated to mediate rapid vascular effects via both mineralocorticoid receptor-dependent and -independent pathways, the mechanism(s) of this mineralocorticoid receptor-independent effect of aldosterone is yet to be determined. For estrogen, its rapid effects have been reported to be, at least in part, mediated via the 7-transmembrane-spanning, G protein-coupled receptor GPR30. Previous studies have demonstrated common response outcomes in response to both aldosterone and estrogen on GPR30 expression, ie, activation of phosphatidylinositol 3-kinase-dependent contraction and extracellular signal regulated kinase activation in vascular smooth muscle cells. The present studies were undertaken to test the hypothesis that the rapid response to aldosterone in smooth muscle is dependent on the availability of a GPR30-dependent signaling pathway. These findings not only reconcile differences in the literature for aldosterone response in freshly isolated versus cultured aortic smooth muscle cells but also suggest alternative therapeutic strategies for modulating aldosterone actions on the vasculature in vivo. PMID- 21242461 TI - Creation and characterization of a renin knockout rat. AB - The renin-angiotensin system plays an important role in the control of blood pressure (BP) and renal function. To illuminate the importance of renin in the context of a disease background in vivo, we used zinc-finger nucleases (ZFNs) designed to target the renin gene and create a renin knockout in the SS/JrHsdMcwi (SS) rat. ZFN against renin caused a 10-bp deletion in exon 5, resulting in a frameshift mutation. Plasma renin activity was undetectable in the Ren-/- rat, and renin protein was absent from the juxtaglomerular cells in the kidney. Body weight was lower in the Ren-/- rats (than in the Ren+/- or wild-type littermates), and conscious BP on low-salt diet (0.4% NaCl) was 58 +/- 2 mm Hg in the Ren-/- male rats versus 117 mm Hg in the Ren+/- littermates, a reduction of almost 50 mm Hg. Blood urea nitrogen (BUN) and plasma creatinine levels were elevated in the Ren-/- strain (BUN 112 +/- 7 versus 23 +/- 2 mg/dL and creatinine 0.53 +/- 0.02 versus 0.26 +/- 0.02 mg/dL), and kidney morphology was abnormal with a rudimentary inner renal medulla, cortical interstitial fibrosis, thickening of arterial walls, and abnormally shaped glomeruli. The development of the first rat knockout in the renin-angiotensin system demonstrates the efficacy of the ZFN technology for creating knockout rats for cardiovascular disease on any genetic background and emphasizes the role of renin in BP regulation and kidney function even in the low-renin SS rat. PMID- 21242462 TI - The effects of continuous positive airway pressure on prehypertension and masked hypertension in men with severe obstructive sleep apnea. AB - Obstructive sleep apnea and hypertension are common conditions that frequently coexist. Continuous positive airway pressure (CPAP) reduces blood pressure in patients with obstructive sleep apnea and sustained hypertension. However, the impact of CPAP on patients with obstructive sleep apnea and prehypertension and masked hypertension, conditions associated with increased cardiovascular risk, is unknown. Thirty-six male patients (age, 43 +/- 7 years; body mass index, 28.8 +/- 3.0 kg/m(2)) with untreated severe obstructive sleep apnea (apnea-hypopnea index, 56 +/- 22 events/hr on polysomnography) with diagnostic criteria for prehypertension and/or masked hypertension, based on office and 24-hour ambulatory blood pressure monitoring, respectively, were studied. The patients randomized to no treatment (control; n=18) or CPAP (n=18) for 3 months had similar frequency of prehypertension and masked hypertension at study entry. There were no significant changes in blood pressure in patients randomized to the control group. In contrast, patients randomized to CPAP presented significant reduction in office systolic (from 126 +/- 5 to 121 +/- 7 mm Hg; P=0.001) and a trend for diastolic blood pressure (from 75 +/-7 to 73 +/- 8 mm Hg; P=0.08) as well as a significant decrease in daytime and nighttime systolic and diastolic blood pressure (P<0.05 for each comparison). There was a significant reduction in the frequency of prehypertension (from 94% to 55%; P=0.02) and masked hypertension (from 39% to 5%; P=0.04) only in the CPAP group. In conclusion, effective CPAP therapy promotes significant reduction in the frequency of prehypertension and masked hypertension by promoting significant blood pressure reductions in patients with severe obstructive sleep apnea. PMID- 21242464 TI - Acute phase reactants predict the risk of amputation in diabetic foot infection. AB - BACKGROUND: prediction of amputation would aid clinicians in the management of diabetic foot infections. We aimed to assess the predictive value of baseline and post-treatment levels of acute phase reactants in the outcome of patients with diabetic foot infections. METHODS: we collected data prospectively during minimum follow-up of 6 months in patients with infected diabetic foot ulcers hospitalized in Dokuz Eylul University Hospital between January 1, 2003, and January 1, 2008. After excluding patients who did not attend the hospital for follow-up visits regularly (n = 36), we analyzed data from 165 foot ulcer episodes. RESULTS: limb ischemia and osteomyelitis were much more frequent in patients who underwent amputation. Wagner grade, which assesses ulcer depth and the presence of osteomyelitis or gangrene, was higher in patients who needed amputation. Ulcer size was slightly larger in the amputation group. Baseline and post-treatment C reactive protein levels, erythrocyte sedimentation rates, white blood cell counts, and platelet counts were significantly elevated in patients who underwent amputation. Albumin levels were significantly suppressed in the amputation group. Univariate analysis showed that a 1-SD increase in baseline and post-treatment C reactive protein levels, erythrocyte sedimentation rates, and white blood cell counts and a 1-SD decrease in post-treatment albumin levels were significantly associated with increased risk of amputation. Post-treatment C-reactive protein level was strongly associated with amputation risk. CONCLUSIONS: circulating levels of acute phase reactants were associated with amputation risk in diabetic foot infections. PMID- 21242465 TI - Effect of foot orthoses contour on pain perception in individuals with patellofemoral pain. AB - BACKGROUND: foot orthoses have been described as a possible intervention for individuals with patellofemoral joint pain. No study has attempted to quantify the perceived comfort and support of foot orthoses when used as an intervention for patellofemoral joint pain. METHODS: a randomized case-control trial with crossover between contoured and flat orthoses was conducted on ten individuals with patellofemoral pain and ten healthy participants. All of the participants completed a comfort-support assessment and had in-shoe plantar pressure data collected before and after 3 weeks of wear. A 1-week washout period was used to minimize any continued treatment effect between orthotics testing. The patellofemoral pain group also completed a numeric rating scale to assess pain reduction after using each orthosis. RESULTS: all of the participants perceived that greater support was provided by the contoured orthoses in the heel and arch regions. Even with a 30% difference in material hardness between the two orthoses, all of the participants rated cushioning as equivalent. Six individuals in the patellofemoral pain group reported a clinically significant reduction in knee pain as a result of wearing foot orthoses. CONCLUSIONS: a key factor in the selection of contoured foot orthoses versus flat inserts is the amount of support that an individual perceives in the arch and heel regions. In addition, clinicians using foot orthoses as an intervention for patellofemoral pain should expect an individualistic, nonsystematic response. PMID- 21242463 TI - Angiotensin II type 1A receptors in vascular smooth muscle cells do not influence aortic remodeling in hypertension. AB - Vascular injury and remodeling are common pathological sequelae of hypertension. Previous studies have suggested that the renin-angiotensin system acting through the type 1 angiotensin II (AT(1)) receptor promotes vascular pathology in hypertension. To study the role of AT(1) receptors in this process, we generated mice with cell-specific deletion of AT(1) receptors in vascular smooth muscle cells using Cre/Loxp technology. We crossed the SM22alpha-Cre transgenic mouse line expressing Cre recombinase in smooth muscle cells with a mouse line bearing a conditional allele of the Agtr1a gene (Agtr1a (flox)), encoding the major murine AT(1) receptor isoform (AT(1A)). In SM22alpha-Cre(+)Agtr1a (flox/flox) (SMKO) mice, AT(1A) receptors were efficiently deleted from vascular smooth muscle cells in larger vessels but not from resistance vessels such as preglomerular arterioles. Thus, vasoconstrictor responses to angiotensin II were preserved in SMKO mice. To induce hypertensive vascular remodeling, mice were continuously infused with angiotensin II for 4 weeks. During infusion of angiotensin II, blood pressures increased significantly and to a similar extent in SMKO and control mice. In control mice, there was evidence of vascular oxidative stress indicated by enhanced nitrated tyrosine residues in segments of aorta; this was significantly attenuated in SMKO mice. Despite these differences in oxidative stress, the extent of aortic medial expansion induced by angiotensin II infusion was virtually identical in both groups. Thus, vascular AT(1A) receptors promote oxidative stress in the aortic wall but are not required for remodeling in angiotensin II-dependent hypertension. PMID- 21242466 TI - Plantar pressures in children with and without sever's disease. AB - BACKGROUND: a case-control study was conducted to compare static plantar pressures and distribution of body weight across the two lower limbs, as well as the prevalence of gastrocnemius soleus equinus, in children with and without calcaneal apophysitis (Sever's disease). METHODS: the participants were 54 boys enrolled in a soccer academy, of which eight were lost to follow-up. Twenty-two boys with unilateral Sever's disease comprised the Sever's disease group and 24 healthy boys constituted a control group. Plantar pressure data were collected using pedobarography, and gastrocnemius soleus equinus was assessed. RESULTS: peak pressure and percentage of body weight supported were significantly higher in the symptomatic feet of the Sever's disease group than in the asymptomatic feet of the Sever's disease group and the control group. Every child in the Sever's disease group had bilateral gastrocnemius equinus, while nearly all children in the control group had no equinus. CONCLUSIONS: high plantar foot pressures are associated with Sever's disease, although it is unclear whether they are a predisposing factor or a result of the condition. Gastrocnemius equinus may be a predisposing factor for Sever's disease. Further research is needed to identify other factors involved in the disease and to better understand the factors that contribute to abnormal distribution of body weight in the lower limbs. PMID- 21242467 TI - Soft-tissue movement at the foot during the stance phase of walking. AB - BACKGROUND: soft-tissue movement has challenged the use of noninvasive skin-based markers that are assumed to be rigidly attached to the underlying bony landmarks. We assessed soft-tissue movement in multiple foot segments by calculating the relative changes in the intermarker distances of the hindfoot, midfoot, and forefoot segments during the early, middle, and late stances of walking compared with the intermarker distances measured while participants remained still during standing. METHODS: seven healthy young adults with no previous lower-limb injury were tested while walking barefoot at a comfortable pace. Skin-based markers were placed on three foot regions (hindfoot-calcaneus, midfoot-navicular, and forefoot first to fifth metatarsals). A motion system sampled at 120 Hz was used to capture the foot markers during the stance phase of walking. RESULTS: soft-tissue movement was found in the forefoot region characterized by shortened distances, specifically during early (breaking) stance and late (propulsion) stance. In the hindfoot region, soft-tissue movement was characterized by shortened and elongated distances during the early and late stance periods, respectively. All of the foot regions showed the least intermarker distance changes during midstance. CONCLUSIONS: the dynamics of soft-tissue movement in multiple foot segments were characterized by the greatest changes in the intermarker distances in the forefoot and hindfoot during the early and late stance phases and the least changes in the foot segments during midstance. The results provide a feasible and accessible measurement for assessing soft-tissue movement in the foot when skin-based motion markers are used. PMID- 21242468 TI - Prevalence of plantar verrucae in patients with human immunodeficiency virus infection during the post-highly active antiretroviral therapy era. AB - BACKGROUND: since the implementation of highly active antiretroviral therapy (HAART), the life expectancy of patients with human immunodeficiency virus (HIV) has significantly increased. This is likely to cause changes in podiatric medical manifestations, such as plantar verrucae, in this population. METHODS: attendees at a San Francisco street fair in 2008 provided information about HIV status and the presence of verrucae via a survey. A total of 504 surveys were analyzed and compared with 1995 data, before HAART implementation. We examined if there was a statistically significant change in the increased likelihood of plantar verrucae in HIV-positive patients from 1995 to 2008. Then we examined the likelihood of HIV-positive patients (compared to HIV-negative patients) presenting with plantar verrucae in 2008, by using logistic regression, and controlling for age, sex, and race/ethnicity. RESULTS: patients with HIV infection were 5.2 times more likely to present with plantar verrucae compared to patients without HIV infection in 2008 (95% confidence interval, 2.5-11.0, P < .0001) and 10.0 times more likely in 1995 (95% confidence interval, 3.4-29.0, P < .0001). This decrease in likelihood over time was not statistically significantly different (P = .33). Logistic regression analysis controlling for the covariates of age, race, and sex showed that patients with HIV in 2008 were 4.5 times more likely to present with verrucae compared to patients without HIV (95% confidence interval, 2.1-9.9, P = .0002). CONCLUSIONS: patients with HIV infection in 2008 are still significantly more likely to present with plantar verrucae after controlling for age, race, and sex. This increased likelihood has not changed significantly across time. Because HAART has increased the life expectancy of patients with HIV, this group of patients with plantar verrucae will continue to represent a significant population in the practice of podiatric medicine. PMID- 21242469 TI - Distally based adipofascial sural flap for foot and ankle reconstruction. AB - BACKGROUND: this retrospective study of a case series analyzed the results from the application of a distally based adipofascial sural flap for nonweightbearing defects of the foot and ankle. METHODS: twenty-eight patients with post-traumatic ankle and foot defects (ten women and 18 men; age range, 17-63 years) underwent surgery between November 1, 2003, and November 30, 2008. Distally based adipofascial sural flaps were used in ten open fractures, 14 soft-tissue post traumatic defects, and four deep burns. Defects were on the dorsal side of the foot (eight cases), the lateral malleolus (four cases), the medial malleolus and inframalleolar region (four cases), the Achilles tendon region (eight cases), and the anterior surface of the ankle (four cases). Surgical procedures were performed by a single surgeon (A.M.). RESULTS: all of the flaps healed uneventfully. There was no partial or total flap loss. All 28 patients walked normally at the time of follow-up. Three delayed healings occurred at the donor site. CONCLUSIONS: this is a homogeneous series of lower-limb reconstructions with the distally based adipofascial sural flap, which permits better analysis of the results. This flap has a constant and reliable blood supply. It can be used for the reconstruction of nonweightbearing foot and ankle regions to avoid the bulky volume of the fasciocutaneous flap in this area and to minimize the donor site scar. PMID- 21242470 TI - Prevalence of toenail onychomycosis in patients with type 2 diabetes mellitus and evaluation of risk factors. AB - BACKGROUND: we sought to determine the frequency of toenail onychomycosis in diabetic patients, to identify the causative agents, and to evaluate the epidemiologic risk factors. METHODS: data regarding patients' diabetic characteristics were recorded by the attending internal medicine clinician. Clinical examinations of patients' toenails were performed by a dermatologist, and specimens were collected from the nails to establish the onycomycotic abnormality. All of the specimens were analyzed by direct microscopy and culture. RESULTS: of 321 patients with type 2 diabetes mellitus, clinical onychomycosis was diagnosed in 162; 41 of those diagnoses were confirmed mycologically. Of the isolated fungi, 23 were yeasts and 18 were dermatophytes. Significant correlations were found between the frequency of onychomycosis and retinopathy, neuropathy, obesity, family history, and duration of diabetes. However, no correlation was found with sex, age, educational level, occupation, area of residence, levels of hemoglobin A(1c) and fasting blood glucose, and nephropathy. The most frequently isolated agents from clinical specimens were yeasts. CONCLUSIONS: long-term control of glycemia to prevent chronic complications and obesity and to promote education about the importance of foot and nail care should be essential components in preventing onychomycosis and its potential complications, such as secondary foot lesions, in patients with diabetes mellitus. PMID- 21242471 TI - Autologous skin fibroblast and keratinocyte grafts in the treatment of chronic foot ulcers in aging type 2 diabetic patients. AB - BACKGROUND: we assessed the tolerability and efficacy of autologous skin cell grafts in older type 2 diabetic patients with chronic foot ulcers. METHODS: treatment with Hyalograft 3D and Laserskin Autograft was proposed to a consecutive series of type 2 diabetic patients older than 65 years affected by long-standing (>6 months) foot ulcers with an area greater than 15 cm(2). Ulcer healing rates and measurements of ulcer area were determined monthly for 12 months. RESULTS: seven patients with 12 ulcers, nine of which received the described treatment, were enrolled. During 12-month follow-up, all of the ulcers healed except one. In the remaining eight ulcers, the median healing time was 21 weeks (interquartile range, 4-29 weeks). CONCLUSIONS: autologous skin cell grafts are feasible, well tolerated, and apparently effective in the treatment of diabetic ulcers of the lower limbs in advanced age. Age did not seem to moderate healing times. PMID- 21242472 TI - Clinical assessment of ankle joint dorsiflexion: a review of measurement techniques. AB - Ankle dorsiflexion measurement is important for clinical and research use. With so much evidence on the unreliability of goniometric measurements, a systematic review was performed to investigate various alternative techniques for measuring ankle dorsiflexion in the nonneurologic patient. All of the major databases were queried electronically to identify studies that used any method of ankle dorsiflexion measurement in the nonneurologic subject. Keywords included ankle dorsiflexion NOT cerebral palsy NOT stroke, the latter to exclude neurologic conditions. In 755 studies that used some form of ankle joint dorsiflexion measurement, ten different techniques were identified that included various apparatuses designed specifically for this purpose. Reliability testing of these techniques involved test-retest trials with small student populations as subjects, which returned high intraclass correlation coefficient scores. However, their methodological quality would have benefitted from the use of an actual patient population and comparison with a reference standard. When validating ankle dorsiflexion measurement techniques, actual patient populations should be used, otherwise papers would score poorly on methodological quality assessment. Standardizing patient position, foot posture, amount of moment applied, and reference landmarks will ensure that various trial results can be compared directly. PMID- 21242473 TI - Extra-abdominal desmoid fibromatosis in the foot: a case study. AB - Extra-abdominal desmoid tumors account for 0.03% of all neoplasms and rarely present in the foot. They are benign but locally aggressive, and wide local surgical excision is the treatment of choice owing to the high rate of recurrence in the lower extremities. Invasiveness into the surrounding soft-tissue structures often makes wide excision difficult without compromise of function. We describe a 34-year-old woman with a large, pedal, extra-abdominal desmoid fibroma treated by wide local surgical excision with minimal complications postoperatively and no clinical evidence of recurrence at 28 months. PMID- 21242474 TI - Foot care recommendations: an excerpt from diabetes care. PMID- 21242475 TI - Motivational interviewing by podiatric physicians: a method for improving patient self-care of the diabetic foot. AB - Foot ulceration and lower-extremity amputation are devastating end-stage complications of diabetes. Despite agreement that diabetic foot self-care is a key factor in prevention of ulcers and amputation, there has only been limited success in influencing these behaviors among patients with diabetes. While most efforts have focused on increasing patient knowledge, knowledge and behavior are poorly correlated. Knowledge is necessary but rarely sufficient for behavior change. A key determinant to adherence to self-care behavior is clinician counseling style. Podiatrists are the ideal providers to engage in a brief behavioral intervention with a patient. Motivational interviewing is a well accepted, evidence-based teachable approach that enhances self-efficacy and increases intrinsic motivation for change and adherence to treatment. This article summarizes some key strategies that can be employed by podiatrists to improve foot self-care. PMID- 21242477 TI - Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography. AB - BACKGROUND: Acute kidney injury (AKI) is associated with early mortality after percutaneous coronary revascularization procedures, but its prognostic relevance to long-term clinical outcomes remains controversial. METHODS AND RESULTS: We conducted a retrospective study of 14782 adults who received coronary angiography in the province of Alberta, Canada, between 2004 and 2006. AKI was identified on the basis of changes in serum creatinine concentration within 7 days of the procedure according to AKI Network criteria. The associations between AKI and long-term outcomes, including mortality, end-stage renal disease, and cardiovascular and renal hospitalizations, were studied with the use of Cox regression of multiple failure times. The adjusted risk of death increased with increasing severity of AKI; compared with no AKI, the adjusted hazard ratio for death was 2.00 (95% confidence interval, 1.69 to 2.36) with stage 1 AKI and 3.72 (95% confidence interval, 2.92 to 4.76) with stage 2 or 3 AKI. The adjusted risk of end-stage renal disease requiring renal replacement therapy also increased according to the severity of AKI (hazard ratio, 4.15 [95% confidence interval, 2.32 to 7.42] and 11.74 [95% confidence interval, 6.38 to 21.59], respectively), as did the risks of subsequent hospitalizations for heart failure and acute renal failure. CONCLUSIONS: These findings inform the controversy surrounding AKI after angiography, demonstrating that it is a significant risk factor for long-term mortality, end-stage renal disease, and hospitalization for cardiovascular and renal events after coronary angiography. PMID- 21242478 TI - Longevity of Sprint Fidelis implantable cardioverter-defibrillator leads and risk factors for failure: implications for patient management. AB - BACKGROUND: Sprint Fidelis (Fidelis) implantable cardioverter-defibrillator leads are prone to fractures that have caused adverse events, primarily inappropriate shocks, and a few reported deaths. More than 100 000 patients have Fidelis leads. No independent multicenter long-term performance information exists for this lead, and single-center studies suggest that certain patients are at increased risk for Fidelis failure. Our aim was to assess the longevity of Fidelis leads and to evaluate clinical variables and adverse events associated with Fidelis failure. The results were compared with like data for Quattro Secure (Quattro) implantable cardioverter-defibrillator leads implanted at our centers. METHODS AND RESULTS: This 3-center study included adults >=18 years of age who received Fidelis or Quattro leads for the prevention of sudden cardiac death. From November 2001 to January 2009,1023 Fidelis and 1668 Quattro leads were implanted and followed up. The failure rate for Fidelis leads was 2.81%/y compared with 0.43%/y for Quattro leads (P<0.0001). No deaths or injuries occurred as a result of lead failure, but 42% of fractures caused inappropriate shocks. The survival of Fidelis leads at 4 years was 87.0% (95% confidence interval, 83.6 to 90.1) compared with 98.7% (95% confidence interval, 97.9 to 99.4) for Quattro leads (P<0.0001). Multivariate predictors of Fidelis failure were younger age (hazard ratio, 0.98; 95% confidence interval, 0.96 to 0.99), female gender (hazard ratio, 0.61; 95% confidence interval, 0.40 to 1.00), and cardiac disease (P=0.041). CONCLUSIONS: Compared with Quattro leads, the survival of Fidelis leads continues to decline, and Fidelis failure is notably higher in younger patients, women, individuals with hypertrophic cardiomyopathy, and patients with arrhythmogenic right ventricular dysplasia or channelopathies. These findings have significant implications for the management of patients who have Fidelis leads, and they demonstrate the importance of weighing clinical variables in assessments of implantable cardioverter-defibrillator lead performance. PMID- 21242479 TI - Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction. AB - BACKGROUND: Mineralocorticoid receptor (MR) blockade improves morbidity and mortality among patients with heart failure; however, the underlying mechanisms are still under investigation. We studied left ventricular remodeling after myocardial infarction in mice with cardiomyocyte-specific inactivation of the MR gene (MR(MLCCre)) that were generated with a conditional MR allele (MR(flox)) in combination with a transgene expressing Cre recombinase under control of the myosin light-chain (MLC2a) gene promoter. METHODS AND RESULTS: Control (MR(flox/flox), MR(flox/wt)) and MR(MLCCre) mice underwent coronary artery ligation. MR ablation had no detectable baseline effect on cardiac morphology and function. The progressive left ventricular chamber enlargement and functional deterioration in infarcted control mice, detected by echocardiography and conductance catheter analysis during the 8-week observation period, were substantially attenuated in MR(MLCCre) mice. Chronically infarcted MR(MLCCre) mice displayed attenuated pulmonary edema, reduced cardiac hypertrophy, increased capillary density, and reduced accumulation of extracellular matrix proteins in the surviving left ventricular myocardium. Moreover, cardiomyocyte-specific MR ablation prevented the increases in myocardial and mitochondrial O(2)(.-) production and upregulation of the NADPH oxidase subunits Nox2 and Nox4. At 7 days, MR(MLCCre) mice exhibited enhanced infarct neovessel formation and collagen structural organization associated with reduced infarct expansion. Mechanistically, cardiomyocytes lacking MR displayed accelerated stress-induced activation and subsequent suppression of nuclear factor-kappaB and reduced apoptosis early after myocardial infarction. CONCLUSION: Cardiomyocyte-specific MR deficiency improved infarct healing and prevented progressive adverse cardiac remodeling, contractile dysfunction, and molecular alterations in ischemic heart failure, highlighting the importance of cardiomyocyte MR for heart failure development and progression. PMID- 21242480 TI - Overview of the 2010 Food and Drug Administration Cardiovascular and Renal Drugs Advisory Committee meeting regarding ticagrelor. PMID- 21242482 TI - Distinct effects of leukocyte and cardiac phosphoinositide 3-kinase gamma activity in pressure overload-induced cardiac failure. AB - BACKGROUND: Signaling from phosphoinositide 3-kinase gamma (PI3Kgamma) is crucial for leukocyte recruitment and inflammation but also contributes to cardiac maladaptive remodeling. To better understand the translational potential of these findings, this study investigates the role of PI3Kgamma activity in pressure overload-induced heart failure, addressing the distinct contributions of bone marrow-derived and cardiac cells. METHODS AND RESULTS: After transverse aortic constriction, mice knock-in for a catalytically inactive PI3Kgamma (PI3Kgamma KD) showed reduced fibrosis and normalized cardiac function up to 16 weeks. Accordingly, treatment with a selective PI3Kgamma inhibitor prevented transverse aortic constriction-induced fibrosis. To define the cell types involved in this protection, bone marrow chimeras, lacking kinase activity in the immune system or the heart, were studied after transverse aortic constriction. Bone marrow-derived cells from PI3Kgamma KD mice were not recruited to wild-type hearts, thus preventing fibrosis and preserving diastolic function. After prolonged pressure overload, chimeras with PI3Kgamma KD bone marrow-derived cells showed slower development of left ventricular dilation and higher fractional shortening than controls. Conversely, in the presence of a wild-type immune system, KD hearts displayed bone marrow-derived cell infiltration and fibrosis at early stages but reduced left ventricular dilation and preserved contractile function at later time points. CONCLUSIONS: Together, these data demonstrate that, in response to transverse aortic constriction, PI3Kgamma contributes to maladaptive remodeling at multiple levels by modulating both cardiac and immune cell functions. PMID- 21242481 TI - Genetic risk score and risk of myocardial infarction in Hispanics. AB - BACKGROUND: Genome-wide association studies have identified loci associated with coronary heart disease in whites of European ancestry. This study evaluated whether genetic markers previously identified in whites are associated with nonfatal acute myocardial infarction (MI) in Hispanics. METHODS AND RESULTS: Cases (n=1989) with a first nonfatal acute MI and population-based controls (n=2096) living in Costa Rica were studied. Fourteen single-nucleotide polymorphisms were genotyped. Seven single-nucleotide polymorphisms at 3 independent loci showed significant associations with MI. The odds ratios for the loci with the strongest associations were 1.16 (95 confidence interval [CI], 1.05 to 1.27) for rs4977574 (CDKN2A/2B), 1.15 (95 CI, 1.03 to 1.29) for rs646776 (CELSR2-PSRC1-SORT1), and 1.22 (95 CI, 1.08 to 1.38) for rs501120 (CXCL12); the corresponding PARs were 6.8, 10.5, and 15.2; respectively. We developed a genetic risk score by summing the number of the top 3 associated risk alleles. The OR for MI per genetic risk score unit was 1.18 (95 CI, 1.11 to 1.25; P=4.83 * 10(-8)). Discrimination of MI was significantly improved (P=0.02) when the genetic risk score was added to a model including clinical predictors. However, the increase in the area under the receiver-operating characteristic curve after the genetic risk score was added was moderate, from 0.67 (95 CI, 0.65 to 0.69) to 0.68 (95 CI, 0.66 to 0.70). CONCLUSIONS: These results indicate both the consistency and disparity of genetic effects on risk of MI between Hispanic and white populations. The improvement in the identified genetic markers on discrimination of MI in Hispanics was modest. PMID- 21242483 TI - How much scrutiny and stress can the Fidelis lead withstand? PMID- 21242484 TI - Safety of percutaneous left atrial appendage closure: results from the Watchman Left Atrial Appendage System for Embolic Protection in Patients with AF (PROTECT AF) clinical trial and the Continued Access Registry. AB - BACKGROUND: The Watchman Left Atrial Appendage System for Embolic Protection in Patients With AF (PROTECT AF) randomized trial compared left atrial appendage closure against warfarin in atrial fibrillation (AF) patients with CHADS2 >=1. Although the study met the primary efficacy end point of being noninferior to warfarin therapy for the prevention of stroke/systemic embolism/cardiovascular death, there was a significantly higher risk of complications, predominantly pericardial effusion and procedural stroke related to air embolism. Here, we report the influence of experience on the safety of percutaneous left atrial appendage closure. METHODS AND RESULTS: The study cohort for this analysis included patients in the PROTECT AF trial who underwent attempted device left atrial appendage closure (n=542 patients) and those from a subsequent nonrandomized registry of patients undergoing Watchman implantation (Continued Access Protocol [CAP] Registry; n=460 patients). The safety end point included bleeding- and procedure-related events (pericardial effusion, stroke, device embolization). There was a significant decline in the rate of procedure- or device-related safety events within 7 days of the procedure across the 2 studies, with 7.7% and 3.7% of patients, respectively, experiencing events (P=0.007), and between the first and second halves of PROTECT AF and CAP, with 10.0%, 5.5%, and 3.7% of patients, respectively, experiencing events (P=0.006). The rate of serious pericardial effusion within 7 days of implantation, which had made up >50% of the safety events in PROTECT AF, was lower in the CAP Registry (5.0% versus 2.2%, respectively; P=0.019). There was a similar experience-related improvement in procedure-related stroke (0.9% versus 0%, respectively; P=0.039). Finally, the functional impact of these safety events, as defined by significant disability or death, was statistically superior in the Watchman group compared with the warfarin group in PROTECT AF. This remained true whether significance was defined as a change in the modified Rankin score of >=1, >=2, or >=3 (1.8 versus 4.3 events per 100 patient-years; relative risk, 0.43; 95% confidence interval, 0.24 to 0.82; 1.5 versus 3.7 events per 100 patient-years; relative risk, 0.41; 95% confidence interval, 0.22 to 0.82; and 1.4 versus 3.3 events per 100 patient-years; relative risk, 0.43; 95% confidence interval, 0.22 to 0.88, respectively). CONCLUSION: As with all interventional procedures, there is a significant improvement in the safety of Watchman left atrial appendage closure with increased operator experience. Clinical Trial Registration- URL: http://clinicaltrials.gov. Unique identifier: NCT00129545. PMID- 21242485 TI - Characterization and functionality of cardiac progenitor cells in congenital heart patients. AB - BACKGROUND: Human cardiac progenitor cells (hCPCs) may promote myocardial regeneration in adult ischemic myocardium. The regenerative capacity of hCPCs in young patients with nonischemic congenital heart defects for potential use in congenital heart defect repair warrants exploration. METHODS AND RESULTS: Human right atrial specimens were obtained during routine congenital cardiac surgery across 3 groups: neonates (age, <30 days), infants (age, 1 month to 2 years), and children (age, >2 to <=13 years). C-kit(+) hCPCs were 3-fold higher in neonates than in children >2 years of age. hCPC proliferation was greatest during the neonatal period as evidenced by c-kit(+) Ki67(+) expression but decreased with age. hCPC differentiation capacity was also greatest in neonatal right atrium as evidenced by c-kit(+), NKX2-5(+), NOTCH1(+), and NUMB(+) expression. Despite the age-dependent decline in resident hCPCs, we isolated and expanded right atrium derived CPCs from all patients (n=103) across all ages and diagnoses using the cardiosphere method. Intact cardiospheres contained a mix of heart-derived cell subpopulations that included cardiac progenitor cells expressing c-kit(+), Islet 1, and supporting cells. The number of c-kit(+)-expressing cells was highest in human cardiosphere-derived cells (hCDCs) grown from neonatal and infant right atrium. Furthermore, hCDCs could differentiate into diverse cardiovascular lineages by in vitro differentiation assays. Transplanted hCDCs promoted greater myocardial regeneration and functional improvement in infarcted myocardium than transplanted cardiac fibroblasts. CONCLUSIONS: Resident hCPCs are most abundant in the neonatal period and rapidly decrease over time. hCDCs can be reproducibly isolated and expanded from young human myocardial samples regardless of age or diagnosis. hCPCs are functional and have potential in congenital cardiac repair. PMID- 21242486 TI - Cardiac recovery during continuous-flow left ventricular assist device support: some good news from across the Atlantic. PMID- 21242487 TI - Reversal of severe heart failure with a continuous-flow left ventricular assist device and pharmacological therapy: a prospective study. AB - BACKGROUND: We have previously shown that a specific combination of drug therapy and left ventricular assist device unloading results in significant myocardial recovery, sufficient to allow pump removal, in two thirds of patients with dilated cardiomyopathy receiving a Heartmate I pulsatile device. However, this protocol has not been used with nonpulsatile devices. METHODS AND RESULTS: We report the results of a prospective study of 20 patients who received a combination of angiotensin-converting enzymes, beta-blockers, angiotensin II inhibitors, and aldosterone antagonists followed by the beta2-agonist clenbuterol and were regularly tested (echocardiograms, exercise tests, catheterizations) with the pump at low speed. Before left ventricular assist device insertion, patient age was 35.2 +/- 12.6 years (16 male patients), patients were on 2.0 +/- 0.9 inotropes, 7 (35) had an intra-aortic balloon pump, 2 were hemofiltered, 2 were ventilated, 3 had a prior Levitronix device, and 1 had extracorporeal membrane oxygenation. Cardiac index was 1.39 +/- 0.43 L . min-1 . m-2, pulmonary capillary wedge pressure was 31.5 +/- 5.7 mm Hg, and heart failure history was 3.4 +/- 3.5 years. One patient was lost to follow-up and died after 240 days of support. Of the remaining 19 patients, 12 (63.2) were explanted after 286 +/- 97 days. Eight had symptomatic heart failure for <=6 months and 4 for >6 months (48 to 132 months). Before explantation, at low flow for 15 minutes, ejection fraction was 70 +/- 7, left ventricular end-diastolic diameter was 48.6 +/- 5.7 mm, left ventricular end-systolic diameter was 32.3 +/- 5.7 mm, mV(O2) was 21.6 +/- 4 mL . kg-1 . min-1, pulmonary capillary wedge pressure was 5.9 +/- 4.6 mm Hg, and cardiac index was 3.6 +/- 0.6 L . min-1 . m-2. Estimated survival without heart failure recurrence was 83.3 at 1 and 3 years. After a 430.7 +/- 337.1-day follow-up, surviving explants had an ejection fraction of 58.1 +/- 13.8, left ventricular end-diastolic diameter of 59.0 +/- 9.3 mm, left ventricular end systolic diameter of 42.0 +/- 10.7 mm, and mV(O2) of 22.6 +/- 5.3 mL . kg-1 . min 1. CONCLUSIONS: Reversal of end-stage heart failure secondary to nonischemic cardiomyopathy can be achieved in a substantial proportion of patients with nonpulsatile flow through the use of a combination of mechanical and pharmacological therapy. PMID- 21242488 TI - Pearls & oy-sters: clues for spinal dural arteriovenous fistulae. PMID- 21242489 TI - Teaching NeuroImages: CT scan of congenital cytomegalovirus infection. PMID- 21242490 TI - Oculopharyngodistal myopathy is a distinct entity: clinical and genetic features of 47 patients. AB - BACKGROUND: Oculopharyngodistal myopathy (OPDM) has been reported as a rare, adult-onset hereditary muscle disease with putative autosomal dominant and autosomal recessive inheritance. Patients with OPDM present with progressive ocular, pharyngeal, and distal limb muscle involvement. The genetic defect causing OPDM has not been elucidated. METHODS: Clinical and genetic findings of 47 patients from 9 unrelated Turkish families diagnosed with OPDM at the Department of Neurology, Istanbul Faculty of Medicine, between 1982 and 2009 were evaluated. RESULTS: The mean age at onset was around 22 years. Both autosomal dominant and autosomal recessive traits were observed, without any clear difference in clinical phenotype or severity. The most common initial symptom was ptosis, followed by oropharyngeal symptoms and distal weakness, which started after the fifth disease year. Intrafamilial variability of disease phenotype and severity was notable in the largest autosomal dominant family. Atypical presentations, such as absence of limb weakness in long-term follow-up in 9, proximal predominant weakness in 4, and asymmetric ptosis in 3 patients, were observed. Swallowing difficulty was due to oropharyngeal dysphagia with myopathic origin. Serum creatine kinase levels were slightly increased and EMG revealed myopathic pattern with occasional myotonic discharges. Myopathologic findings included rimmed and autophagic vacuoles and chronic myopathic changes. Importantly, a considerable proportion of patients developed respiratory muscle weakness while still ambulant. Linkage to the genetic loci for all known muscular dystrophies, and for distal and myofibrillar myopathies, was excluded in the largest autosomal dominant and autosomal recessive OPDM families. CONCLUSIONS: We suggest that OPDM is a clinically and genetically distinct myopathy. PMID- 21242491 TI - Neuromuscular junction toxicity with tandutinib induces a myasthenic-like syndrome. AB - BACKGROUND: Tandutinib (MLN 518, Millennium Pharmaceuticals, Cambridge, MA) is an orally active multitargeted tyrosine kinase inhibitor that is currently under evaluation for the treatment of glioblastoma and has been used in the treatment of leukemia. In prior clinical and animal studies, a dose-dependent muscular weakness has been observed with this drug, though the etiology of the weakness has not been defined. METHODS: Standard neurophysiologic techniques, including repetitive nerve stimulation, needle EMG, and single-fiber EMG, were used to evaluate patients who developed weakness while being treated with tandutinib and bevacizumab (Avastin, Genentech, South San Francisco, CA) for glioblastoma (NCT00667394). RESULTS: Six patients were observed to develop a reversible weakness that correlated with the administration of the tandutinib. The onset of weakness after starting tandutinib occurred within 3 to 112 days and in less than 15 days in 3 patients. Electrophysiologic studies showed that all patients developed abnormal repetitive nerve stimulation studies. Four patients had short duration motor unit potentials. Two of these patients also had abnormal single fiber EMG, as did a third patient who did not have standard needle EMG. The clinical and electrophysiologic abnormalities improved with the termination or reduction in the dose of tandutinib. CONCLUSION: These observations suggest that tandutinib is toxic to the neuromuscular junction, possibly by reversibly binding to a molecule on the postsynaptic acetylcholine receptor complex. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that tandutinib 500 mg twice daily induces reversible muscle weakness and electrophysiologic changes consistent with neuromuscular junction dysfunction. PMID- 21242492 TI - Coated-platelet levels and progression from mild cognitive impairment to Alzheimer disease. AB - OBJECTIVES: Coated-platelets are a subset of platelets produced by dual-agonist activation with collagen and thrombin. These platelets retain full-length amyloid precursor protein on their surface, are elevated in patients with amnestic as compared to nonamnestic mild cognitive impairment (MCI), and correlate with disease progression in Alzheimer disease (AD). Prompted by these findings, we investigated the association between coated-platelet production in amnestic MCI and rate of progression to AD. METHODS: Coated-platelet levels were assayed in 74 patients with amnestic MCI who were subsequently followed longitudinally for up to 36 months in an outpatient dementia clinic. Levels are reported as percent of cells converted into coated-platelets. Subjects were categorized into tertiles of coated-platelet levels. The distributions of time to progression to AD were estimated for each tertile using cumulative incidence curves and compared statistically using a log-rank test. Cox proportional hazards regression was used to adjust for potential confounders. RESULTS: The 24-month cumulative incidence of progression to AD was different among tertiles: 4% for the first tertile (lowest coated-platelet levels), 13% for the second tertile, and 37% for the third tertile (overall log-rank test, p = 0.02). The hazard rate of progression to AD for patients in the highest coated-platelet tertile was 5.1 times that for patients in the lowest tertile (p = 0.04), whereas the hazard rate for the middle tertile was similar to that for the lowest tertile (hazard rate ratio = 1.5, p = 0.7). CONCLUSIONS: Elevated coated-platelet levels in patients with amnestic MCI are associated with increased risk for progression to AD. PMID- 21242493 TI - Clinical phenotypes in autopsy-confirmed Pick disease. AB - BACKGROUND: Neuropathology of frontotemporal lobar degeneration is variable and relationship between the pathology and the clinical presentation remains uncertain. Abnormal deposits of hyperphosphorylated and ubiquitinated tau protein are present in 30% of cases, which include the classic presentation of Pick disease with argyrophilic, intraneuronal inclusions known as Pick bodies. This study aimed to improve sensitivity of clinicopathologic relations in cases with neuropathologically confirmed Pick disease and to identify clinical symptoms and signs predictive of disease progression. METHODS: This was a retrospective analysis of 21 cases with a pathologic diagnosis of Pick disease and sufficient clinical information to establish early presenting clinical features from 2 specialist centers, representing 70% of all cases of Pick disease identified between 1998 and 2007 in these centers. RESULTS: At presentation, 13/21 cases (62%) were clinically diagnosed with behavioral variant frontotemporal dementia (bvFTD) and 8/21 (38%) with language variant frontotemporal dementia (lvFTD) including 2 with mixed syndromes. Patients with bvFTD died on average 5 years earlier than those with lvFTD (7 years vs 12 years after disease onset). Pathologically, fewer Pick bodies were present in the frontal and inferior temporal cortices of bvFTD than lvFTD cases. In contrast, both groups showed decreased neuronal density in the dentate gyrus with increasing disease duration. CONCLUSIONS: The pathologic course of the disease in FTLD cases with Pick bodies is not uniform and disease duration can be estimated based on early clinical features. These findings have relevance as treatment options, which are likely to be pathology specific, are developed. PMID- 21242494 TI - A novel DCC mutation and genetic heterogeneity in congenital mirror movements. AB - OBJECTIVE: DCC is the receptor for netrin, a protein that guides axon migration of developing neurons across the body's midline. Mutations in the DCC gene were recently identified in 2 families with congenital mirror movements (MM). The objective was to study clinical and genetic characteristics of 3 European families with MM and to test whether this disorder is genetically homogeneous. METHODS: We studied 3 MM families with a total of 13 affected subjects. Each patient had a standardized interview and neurologic examination, focusing on the phenomenology and course of the MM. The severity of MM was also assessed. Molecular analysis of DCC was performed in the index cases. In addition, linkage analysis of the DCC locus was performed in a large French family. RESULTS: The clinical expression and course of MM were very similar in all the affected subjects, regardless of DCC mutational status. However, slight intersubject variability in the severity of MM was noted within each family. Onset always occurred in infancy or early childhood, and MM did not deteriorate over time. Motor disability due to MM was mild and restricted to activities that require independent movements of the 2 hands. We found a novel mutation in the DCC gene in an Italian family with MM associated with abnormal ipsilateral corticospinal projection. The DCC locus was excluded in the French family. CONCLUSION: DCC has a crucial role in the development of corticospinal tracts in humans. Congenital MM is genetically heterogeneous, despite its clinical homogeneity. PMID- 21242495 TI - Phase I trial of pegylated interferon-alpha-2b in young patients with plexiform neurofibromas. AB - OBJECTIVE: Interferon has antiproliferative and antiangiogenic properties. We sought to evaluate preliminary efficacy and determine the recommended phase II dose (RP2D) for pegylated interferon-alpha-2b (PI) in patients with unresectable progressive or symptomatic plexiform neurofibromas (PN). METHODS: PI was administered weekly in cohorts of 3-6 patients during the dose-finding phase and continued for up to 2 years. Twelve patients were treated at the RP2D to further evaluate toxicity and activity. RESULTS: Thirty patients (median age 9.3 years, range 1.9-34.7 years) were enrolled. No dose-limiting toxicity (DLT) was seen in patients treated at the 3 MUg/kg dose level (DL) during the first 4 weeks. All 5 patients treated at the 4.5 MUg/kg DL came off study or required dose reductions for behavioral toxicity or fatigue. Similar DLT on the 3 MUg/kg DL became apparent over time. There was 1 DLT (myoclonus) in 12 patients enrolled at the 1.0 MUg/kg DL. Eleven of 16 patients with pain showed improvement and 13 of 14 patients with a palpable mass had a decrease in size. Five of 17 patients (29%) who underwent volumetric analysis had a 15%-22% decrease in volume. Three of 4 patients with documented radiographic progression prior to enrollment showed stabilization or shrinkage. CONCLUSIONS: The RP2D of PI for pediatric patients with PN is 1 MUg/kg/wk. Clinical and radiographic improvement and cessation of growth can occur. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that pegylated interferon-alpha-2b in patients with unresectable, progressive, symptomatic, or life-threatening PNs results in radiographic reduction or stabilization of PN size. PMID- 21242496 TI - Adverse antiepileptic drug effects in new-onset seizures: a case-control study. AB - OBJECTIVE: Adverse effects (AEs) are a major concern when starting antiepileptic drug (AED) treatment. This study quantified the extent to which AE reporting in people with new-onset seizures started on AEDs is attributable to the medication per se, and investigated variables contributing to AE reporting. METHODS: We pooled data from 2 large prospective studies, the Multicenter Study of Early Epilepsy and Single Seizures and the Northern Manhattan Study of incident unprovoked seizures, and compared adverse event profile (AEP) total and factor scores between adult cases prescribed AEDs for new-onset seizures and untreated controls, adjusting for several demographic and clinical variables. Differences in AEP scores were also tested across different AED monotherapies and controls, and between cases and controls grouped by number of seizures. RESULTS: A total of 212 cases and 206 controls were identified. Most cases (94.2%) were taking low AED doses. AEP scores did not differ significantly between the 2 groups. Depression, female gender, symptomatic etiology, younger seizure onset age, >=2 seizures, and history of febrile seizures were associated with higher AEP scores. There were no significant differences in AEP scores across different monotherapies and controls. AEP scores increased in both cases and controls with increasing number of seizures, the increment being more pronounced in cases. CONCLUSIONS: When AED treatment is started at low doses following new-onset seizures, AE reporting does not differ from untreated individuals. Targeting specific factors affecting AE reporting could lead to improved tolerability of epilepsy treatment. PMID- 21242497 TI - Na+, K+-ATPase: functions in the nervous system and involvement in neurologic disease. PMID- 21242498 TI - Evidence-based guideline update: Plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. AB - OBJECTIVE: To reassess the role of plasmapheresis in the treatment of neurologic disorders. METHODS: We evaluated the available evidence based on a structured literature review for relevant articles from 1995 through September 2009. In addition, due to revision of the definitions of classification of evidence since the publication of the previous American Academy of Neurology assessment in 1996, the evidence cited in that manuscript was reviewed and reclassified. RESULTS AND RECOMMENDATIONS: Plasmapheresis is established as effective and should be offered in severe acute inflammatory demyelinating polyneuropathy (AIDP)/Guillain-Barre syndrome (GBS) and in the short-term management of chronic inflammatory demyelinating polyneuropathy (Class I studies, Level A). Plasmapheresis is established as ineffective and should not be offered for chronic or secondary progressive multiple sclerosis (MS) (Class I studies, Level A). Plasmapheresis is probably effective and should be considered for mild AIDP/GBS, as second-line treatment of steroid-resistant exacerbations in relapsing forms of MS, and for neuropathy associated with immunoglobulin A or immunoglobulin G gammopathy, based on at least one Class I or 2 Class II studies (Level B). Plasmapheresis is probably not effective and should not be considered for neuropathy associated with immunoglobulin M gammopathy, based on one Class I study (Level B). Plasmapheresis is possibly effective and may be considered for acute fulminant demyelinating CNS disease (Level C). There is insufficient evidence to support or refute the use of plasmapheresis for myasthenia gravis, pediatric autoimmune neuropsychiatric disorders associated with streptococcus infection, and Sydenham chorea (Class III evidence, Level U). PMID- 21242499 TI - Mutations in the glucocerebrosidase gene confer a risk for Parkinson disease in North Africa. PMID- 21242500 TI - Progressive encephalomyelitis with rigidity and myoclonus: resolution after thymectomy. PMID- 21242501 TI - Stroke while squeezing a pimple: traumatic rupture of a vulnerable carotid artery plaque. PMID- 21242502 TI - Evidence-based guideline update: Determining brain death in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology. PMID- 21242503 TI - Multidetector computerized tomography can guide and document alcohol septal ablation in hypertrophic obstructive cardiomyopathy. PMID- 21242504 TI - Letter by Baruteau et al regarding article, "Peripartum cardiomyopathy as a part of familial dilated cardiomyopathy". PMID- 21242505 TI - Cardiac resynchronization therapy for mild heart failure: the time has come. PMID- 21242506 TI - Cardiac resynchronization therapy in patients with class I-II heart failure and a wide QRS: a cautionary note. PMID- 21242507 TI - Device-based antihypertensive therapy: therapeutic modulation of the autonomic nervous system. PMID- 21242508 TI - Exercise testing in nonatherosclerotic heart disease: hypertrophic cardiomyopathy, valvular heart disease, and arrhythmias. PMID- 21242509 TI - Acute myocarditis mimicking reverse Takotsubo cardiomyopathy. PMID- 21242510 TI - A review of the British Thoracic Society scientific meeting 1-3 December 2010. AB - This review presents the inaugural report of the British Thoracic Society Winter Scientific Meeting held from 1(st)-3(rd) December 2010. Although a wide spectrum of respiratory research was presented at the meeting the content of the review focuses specifically on three key themes of inflammation and lung injury, airways disease and respiratory infection. Advances in both clinical and translational respiratory research presented within the major symposia and spoken sessions related to these themes are summarised. PMID- 21242511 TI - An initial characterization of N-terminal-proatrial natriuretic peptide in serum of Sprague Dawley rats. AB - In the clinical setting, natriuretic peptides (NPs) have proven to be reliable noninvasive markers for diagnostic, prognostic, and therapeutic monitoring of heart failure. Given their proven utility in humans, NPs are potential candidates for translational biomarkers during drug development to detect drug-induced hemodynamic stress resulting in cardiac hypertrophy in preclinical species. We evaluated the intra- and interassay precision and the stability of serum N terminal-proatrial natriuretic peptide (NT-proANP) using a commercially available enzyme-linked immunoassay (EIA). We then measured NT-proANP concentrations in 532 serum samples from 337 male Crl:CD(SD) rats with or without pressure-induced cardiac hypertrophy. Additionally, we established a reference range using samples from control animals across multiple studies. The data demonstrate that the NT proANP EIA is a robust and reproducible assay for the measurement of NT-proANP. The noninvasive translational utility, minimal sample volume requirement, and the lack of existing hypertrophic biomarkers in the male rat make NT-proANP an excellent candidate for further interrogation as a biomarker of cardiac hypertrophy in preclinical toxicology investigations. PMID- 21242512 TI - IL-3 attenuates collagen-induced arthritis by modulating the development of Foxp3+ regulatory T cells. AB - IL-3, a cytokine secreted by Th cells, functions as a link between the immune and the hematopoietic system. We previously demonstrated the potent inhibitory role of IL-3 on osteoclastogenesis, pathological bone resorption, and inflammatory arthritis. In this study, we investigated the novel role of IL-3 in development of regulatory T (Treg) cells. We found that IL-3 in a dose-dependent manner increases the percentage of Foxp3(+) Treg cells indirectly through secretion of IL-2 by non-Treg cells. These IL-3-expanded Treg cells are competent in suppressing effector T cell proliferation. Interestingly, IL-3 treatment significantly reduces the severity of arthritis and restores the loss of Foxp3(+) Treg cells in thymus, lymph nodes, and spleen in collagen-induced arthritis mice. Most significantly, we show that IL-3 decreases the production of proinflammatory cytokines IL-6, IL-17A, TNF-alpha, and IL-1 and increases the production of anti inflammatory cytokines IFN-gamma and IL-10 in collagen-induced arthritis mice. Thus, to our knowledge, we provide the first evidence that IL-3 play an important role in modulation of Treg cell development in both in vitro and in vivo conditions, and we suggest its therapeutic potential in the treatment of rheumatoid arthritis and other autoimmune diseases. PMID- 21242513 TI - A2B adenosine receptor blockade enhances macrophage-mediated bacterial phagocytosis and improves polymicrobial sepsis survival in mice. AB - Antimicrobial treatment strategies must improve to reduce the high mortality rates in septic patients. In noninfectious models of acute inflammation, activation of A2B adenosine receptors (A2BR) in extracellular adenosine-rich microenvironments causes immunosuppression. We examined A2BR in antibacterial responses in the cecal ligation and puncture (CLP) model of sepsis. Antagonism of A2BR significantly increased survival, enhanced bacterial phagocytosis, and decreased IL-6 and MIP-2 (a CXC chemokine) levels after CLP in outbred (ICR/CD-1) mice. During the CLP-induced septic response in A2BR knockout mice, hemodynamic parameters were improved compared with wild-type mice in addition to better survival and decreased plasma IL-6 levels. A2BR deficiency resulted in a dramatic 4-log reduction in peritoneal bacteria. The mechanism of these improvements was due to enhanced macrophage phagocytic activity without augmenting neutrophil phagocytosis of bacteria. Following ex vivo LPS stimulation, septic macrophages from A2BR knockout mice had increased IL-6 and TNF-alpha secretion compared with wild-type mice. A therapeutic intervention with A2BR blockade was studied by using a plasma biomarker to direct therapy to those mice predicted to die. Pharmacological blockade of A2BR even 32 h after the onset of sepsis increased survival by 65% in those mice predicted to die. Thus, even the late treatment with an A2BR antagonist significantly improved survival of mice (ICR/CD-1) that were otherwise determined to die according to plasma IL-6 levels. Our findings of enhanced bacterial clearance and host survival suggest that antagonism of A2BRs offers a therapeutic target to improve macrophage function in a late treatment protocol that improves sepsis survival. PMID- 21242514 TI - A combination of Flt3 ligand cDNA and CpG oligodeoxynucleotide as nasal adjuvant elicits protective secretory-IgA immunity to Streptococcus pneumoniae in aged mice. AB - Our previous study showed that a combination of a plasmid-expressing Flt3 ligand (pFL) and CpG oligodeoxynucleotides (CpG ODN) as a combined nasal adjuvant elicited mucosal immune responses in aged (2-y-old) mice. In this study, we investigated whether a combination of pFL and CpG ODN as a nasal adjuvant for a pneumococcal surface protein A (PspA) would enhance PspA-specific secretory-IgA Ab responses, which could provide protective mucosal immunity against Streptococcus pneumoniae infection in aged mice. Nasal immunization with PspA plus a combination of pFL and CpG ODN elicited elevated levels of PspA-specific secretory-IgA Ab responses in external secretions and plasma in both young adult and aged mice. Significant levels of PspA-specific CD4(+) T cell proliferative and PspA-induced Th1- and Th2- type cytokine responses were noted in nasopharyngeal-associated lymphoreticular tissue, cervical lymph nodes, and spleen of aged mice, which were equivalent to those in young adult mice. Additionally, increased numbers of mature-type CD8, CD11b-expressing dendritic cells were detected in mucosal inductive and effector lymphoid tissues of aged mice. Importantly, aged mice given PspA plus a combination of pFL and CpG ODN showed protective immunity against nasal S. pneumoniae colonization. These results demonstrate that nasal delivery of a combined DNA adjuvant offers an attractive possibility for protection against S. pneumoniae in the elderly. PMID- 21242515 TI - IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression. AB - IL-1F6, IL-1F8, and IL-1F9 and the IL-1R6(RP2) receptor antagonist IL-1F5 constitute a novel IL-1 signaling system that is poorly characterized in skin. To further characterize these cytokines in healthy and inflamed skin, we studied their expression in healthy control, uninvolved psoriasis, and psoriasis plaque skin using quantitative RT-PCR and immunohistochemistry. Expression of IL-1F5, 1F6, -1F8, and -1F9 were increased 2 to 3 orders of magnitude in psoriasis plaque versus uninvolved psoriasis skin, which was supported immunohistologically. Moreover, treatment of psoriasis with etanercept led to significantly decreased IL-1F5, -1F6, -1F8, and -1F9 mRNAs, concomitant with clinical improvement. Similarly increased expression of IL-1F5, -1F6, -1F8, and -1F9 was seen in the involved skin of two mouse models of psoriasis. Suggestive of their importance in inflamed epithelia, IL-1alpha and TNF-alpha induced IL-1F5, -1F6, -1F8, and -1F9 transcript expression by normal human keratinocytes. Microarray analysis revealed that these cytokines induce the expression of antimicrobial peptides and matrix metalloproteinases by reconstituted human epidermis. In particular, IL-1F8 increased mRNA expression of human beta-defensin (HBD)-2, HBD-3, and CAMP and protein secretion of HBD-2 and HBD-3. Collectively, our data suggest important roles for these novel cytokines in inflammatory skin diseases and identify these peptides as potential targets for antipsoriatic therapies. PMID- 21242516 TI - Thymic stromal lymphopoietin interferes with airway tolerance by suppressing the generation of antigen-specific regulatory T cells. AB - Thymic stromal lymphopoietin (TSLP) is an essential cytokine for the initiation and development of allergic inflammation. In this study, we have investigated the role of TSLP in the breakdown of immune tolerance and generation of inducible regulatory T cells (iTregs). Our results demonstrated that TSLP diverted airway tolerance against OVA to Th2 sensitization and inhibited the generation of OVA specific iTregs. TSLP exerted a direct inhibitory effect on both human and mouse iTreg development in vitro. Low doses of TSLP were capable of inhibiting iTreg induction without significantly promoting Th2 development, indicating that these two functions of TSLP are separable. Moreover, the TSLP-mediated inhibition of iTreg generation was only partially dependent on IL-4 and Stat6, and was effective when TSLP was present for the first 24 h of T cell activation. These results define a novel role for TSLP in regulating the balance of airway tolerance and allergic inflammation. PMID- 21242517 TI - Cutting Edge: Coding single nucleotide polymorphisms of endoplasmic reticulum aminopeptidase 1 can affect antigenic peptide generation in vitro by influencing basic enzymatic properties of the enzyme. AB - ER aminopeptidase 1 (ERAP1) customizes antigenic peptide precursors for MHC class I presentation and edits the antigenic peptide repertoire. Coding single nucleotide polymorphisms (SNPs) in ERAP1 were recently linked with predisposition to autoimmune disease, suggesting a link between pathogenesis of autoimmunity and ERAP1-mediated Ag processing. To investigate this possibility, we analyzed the effect that disease-linked SNPs have on Ag processing by ERAP1 in vitro. Michaelis-Menten analysis revealed that the presence of SNPs affects the Michaelis constant and turnover number of the enzyme. Strikingly, specific ERAP1 allele-substrate combinations deviate from standard Michaelis-Menten behavior, demonstrating substrate-inhibition kinetics; to our knowledge, this phenomenon has not been described for this enzyme. Cell-based Ag-presentation analysis was consistent with changes in the substrate inhibition constant K(i), further supporting that ERAP1 allelic composition may affect Ag processing in vivo. We propose that these phenomena should be taken into account when evaluating the possible link between Ag processing and autoimmunity. PMID- 21242518 TI - Presentation of acquired peptide-MHC class II ligands by CD4+ regulatory T cells or helper cells differentially regulates antigen-specific CD4+ T cell response. AB - Activated T cells can acquire membrane molecules from APCs through a process termed trogocytosis. The functional consequence of this event has been a subject of debate. Focusing on transfer of peptide-MHC class II (MHC-II) complexes from APCs to CD4(+) T cells after activation, in this study we investigated the molecule acquisition potential of naturally occurring regulatory T cells (Tregs) and CD4(+) Th cells. We show that acquisition of membrane molecules from APCs is an inherent feature of CD4(+) T cell activation. Triggering of the TCR enables CD4(+) T cells to acquire their agonist ligands as well as other irrelevant membrane molecules from the interacting APCs or bystander cells in a contact dependent manner. Notably, trogocytosis is a continuous process during cell cycle progression, and Th cells and Tregs have comparable capacity for trogocytosis both in vitro and in vivo. The captured peptide-MHC-II molecules, residing in sequestered foci on the host cell surface, endow the host cells with Ag presenting capability. Presentation of acquired peptide-MHC-II ligands by Th cells or Tregs has either stimulatory or regulatory effect on naive CD4(+) T cells, respectively. Furthermore, Th cells with captured peptide-MHC-II molecules become effector cells that manifest better recall responses, and Tregs with captured ligands exhibit enhanced suppression activity. These findings implicate trogocytosis in different subsets of CD4(+) T cells as an intrinsic mechanism for the fine tuning of Ag-specific CD4(+) T cell response. PMID- 21242519 TI - Polypyrimidine tract-binding protein is critical for the turnover and subcellular distribution of CD40 ligand mRNA in CD4+ T cells. AB - CD40L (CD154) is regulated at the posttranscriptional level by an activation induced process that results in a highly stable transcript at extended times of T cell activation. Transcript stability is mediated by polypyrimidine tract-binding protein (PTB)-containing complexes (complex I and II) that bind to three adjacent CU-rich sequences within the 3' untranslated region. To assess the role of PTB in the expression and distribution of CD40L mRNA, PTB was targeted using short hairpin RNA in both primary T cells and a T cell line that recapitulates the stability phase of regulated CD40L mRNA decay. PTB knockdown resulted in a marked decrease in the mRNA stability that resulted in lowered CD40L surface expression. PTB was also critical for appropriate distribution of CD40L mRNA between the nucleus and cytoplasm and in the cytoplasm between the cytosol and the translating polysomes. The activation-induced formation of PTB-specific ribonucleoprotein complexes was observed only with cytoplasmic and not nuclear PTB indicating functional differences in the protein defined by cellular localization. Finally, we observed that cytoplasmic and nuclear PTB isoforms were differentially modified relative to each other and that the changes in cytoplasmic PTB were consistent with activation-induced phosphorylation. Together this work suggests that differentially modified PTB regulates CD40L expression at multiple steps by 1) retaining CD40L mRNA in the nucleus, 2) directly regulating mRNA stability at late times of activation, and 3) forming a ribonuclear complex that preferentially associates with translating ribosomes thus leading to an enhanced level of CD40L protein. PMID- 21242520 TI - Regulatory T cell properties of chicken CD4+CD25+ cells. AB - Chicken CD4(+)CD25(+) cells were characterized for mammalian regulatory T cells' suppressive and cytokine production properties. Anti-chicken CD25 mAb was produced in mice and conjugated with a fluorescent tag. The specificity of the Ab against chicken CD25 was confirmed by evaluating Con A-induced CD25 upregulation in thymocytes and by quantifying the CD25 mRNA content of positive and negative cells identified by anti-chicken CD25 Ab. The percentage of CD4(+)CD25(+) cells, expressed as a percentage of CD4(+) cells, in thymus and blood was ~3-7%, in spleen was 10%, and in cecal tonsil, lung, and bone marrow was ~15%. Bursa had no detectable CD4(+)CD25(+) cells. CD25(+) cells were mostly CD4(+) in the thymus, whereas in every other organ studied, CD25(+) cells were distributed between CD4(+) and CD4(-) cells. Chicken thymic CD4(+)CD25(+) cells did not proliferate in vitro in the absence of recombinant chicken IL-2 (rCIL-2). In the presence of rCIL-2, PMA plus ionomycin or Con A stimulated CD4(+)CD25(+) cell proliferation, whereas anti-CD3 plus CD28 did not stimulate CD4(+)CD25(+) cell proliferation. Naive CD4(+)CD25(+) cells had 29-fold more IL-10 mRNA and 15-fold more TGF-beta mRNA than the naive CD4(+)CD25(-) cells. Naive CD4(+)CD25(+) had no detectable IL 2 mRNA. Both naive and PMA plus ionomycin-stimulated thymic CD4(+)CD25(+) cells suppressed naive T cell proliferation. The suppressive properties were partially contact dependent. Supplementing CD4(+)CD25(+) cell coculture with rCIL-2 reversed the suppressive properties of CD4(+)CD25(+) cells. Chicken CD4(+)CD25(+) cells have suppressive properties similar to that of mammalian regulatory T cells. PMID- 21242521 TI - Proper regrafting of Ig-like transcript 2 after trogocytosis allows a functional cell-cell transfer of sensitivity. AB - The acquisition by T cells of exogenous ligands originally expressed by APC has been already described. However, reports essentially focused on the outward signaling of acquired ligands and their effects on surroundings cells. We investigated the function of transferred receptors (not ligands) on the T cells that acquired them (not on cells they interact with). We show that inhibitory Ig like transcript 2 receptors efficiently transfer from monocytes to autologous T cells by trogocytosis and integrate within the plasma membrane of the acquirer T cells. Furthermore, the acquired receptors can access compatible signaling machinery within acquirer T cells and use it to signal and alter the functions of their new host cells. These data are a formal demonstration that a transferred molecule may send signals to its new host cell. We also provide evidence that sensitivity to modulatory molecules can be acquired from other cells and introduce the notion of intercellular transfer of sensitivities. PMID- 21242522 TI - Regulatory T cells more effectively suppress Th1-induced airway inflammation compared with Th2. AB - Asthma is a syndrome with different inflammatory phenotypes. Animal models have shown that, after sensitization and allergen challenge, Th2 and Th1 cells contribute to the development of allergic airway disease. We have previously demonstrated that naturally occurring regulatory T cells (nTregs) can only marginally suppress Th2-induced airway inflammation and airway hyperresponsiveness. In this study, we investigated nTreg-mediated suppression of Th2-induced and Th1-induced acute allergic airway disease. We demonstrate in vivo that nTregs exert their suppressive potency via cAMP transfer on Th2- and Th1 induced airway disease. A comparison of both phenotypes revealed that, despite similar cAMP transfers, Th1-driven airway hyperresponsiveness and inflammation are more susceptible to nTreg-dependent suppression, suggesting that potential nTreg-based therapeutic strategies might be more effective in patients with predominantly neutrophilic airway inflammation based on deregulated Th1 response. PMID- 21242523 TI - STAT6 expression in multiple cell types mediates the cooperative development of allergic airway disease. AB - Th2 cells induce asthma through the secretion of cytokines. Two such cytokines, IL-4 and IL-13, are critical mediators of many features of this disease. They both share a common receptor subunit, IL-4Ralpha, and signal through the STAT6 pathway. STAT6(-/-) mice have impaired Th2 differentiation and reduced airway response to allergen. Transferred Th2 cells were not able to elicit eosinophilia in response to OVA in STAT6(-/-) mice. To clarify the role of STAT6 in allergic airway inflammation, we generated mouse bone marrow (BM) chimeras. We observed little to no eosinophilia in OVA-treated STAT6(-/-) mice even when STAT6(+/+) BM or Th2 cells were provided. However, when Th2 cells were transferred to STAT6*Rag2(-/-) mice, we observed an eosinophilic response to OVA. Nevertheless, the expression of STAT6 on either BM-derived cells or lung resident cells enhanced the severity of OVA-induced eosinophilia. Moreover, when both the BM donor and recipient lacked lymphocytes, transferred Th2 cells were sufficient to induce the level of eosinophilia comparable with that of wild-type (WT) mice. The expression of STAT6 in BM-derived cells was more critical for the enhanced eosinophilic response. Furthermore, we found a significantly higher number of CD4(+)CD25(+)Foxp3(+) T cells (regulatory T cells [Tregs]) in PBS- and OVA treated STAT6(-/-) mouse lungs compared with that in WT animals suggesting that STAT6 limits both naturally occurring and Ag-induced Tregs. Tregs obtained from either WT or STAT6(-/-) mice were equally efficient in suppressing CD4(+) T cell proliferation in vitro. Taken together, our studies demonstrate multiple STAT6 dependent and -independent features of allergic inflammation, which may impact treatments targeting STAT6. PMID- 21242524 TI - Mismatch repair proteins MSH2, MLH1, and EXO1 are important for class-switch recombination events occurring in B cells that lack nonhomologous end joining. AB - In the absence of core nonhomologous end-joining (NHEJ) factors, Ab gene class switch recombination (CSR) uses an alternative end-joining (A-EJ) pathway to recombine switch (S) region DNA breaks. Previous reports showing decreased S junction microhomologies in MSH2-deficient mice and an exonuclease 1 (EXO1) role in yeast microhomology-mediated end joining suggest that mismatch repair (MMR) proteins might influence A-EJ-mediated CSR. We have directly investigated whether MMR proteins collectively or differentially influence the A-EJ mechanism of CSR by analyzing CSR in mice deficient in both XRCC4 and individual MMR proteins. We find CSR is reduced and that Igh locus chromosome breaks are reduced in the MMR/XRCC4 double-deficient B cells compared with B cells deficient in XRCC4 alone, suggesting MMR proteins function upstream of double-strand break formation to influence CSR efficiency in these cells. Our results show that MLH1, EXO1, and MSH2 are all important for efficient A-EJ-mediated CSR, and we propose that MMR proteins convert DNA nicks and point mutations into dsDNA breaks for both C-NHEJ and A-EJ pathways of CSR. We also find Mlh1-XRCC4(-) B cells have an increased frequency of direct S junctions, suggesting that MLH1 proteins may have additional functions that influence A-EJ-mediated CSR. PMID- 21242525 TI - TLR3-specific double-stranded RNA oligonucleotide adjuvants induce dendritic cell cross-presentation, CTL responses, and antiviral protection. AB - Maturation of dendritic cells (DC) to competent APC is essential for the generation of acquired immunity and is a major function of adjuvants. dsRNA, a molecular signature of viral infection, drives DC maturation by activating TLR3, but the size of dsRNA required to activate DC and the expression patterns of TLR3 protein in DC subsets have not been established. In this article, we show that cross-priming CD8alpha(+) and CD103(+) DC subsets express much greater levels of TLR3 than other DC. In resting DC, TLR3 is located in early endosomes and other intracellular compartments but migrates to LAMP1(+) endosomes on stimulation with a TLR3 ligand. Using homogeneous dsRNA oligonucleotides (ONs) ranging in length from 25 to 540 bp, we observed that a minimum length of ~90 bp was sufficient to induce CD86, IL-12p40, IFN-beta, TNF-alpha, and IL-6 expression, and to mature DC into APC that cross-presented exogenous Ags to CD8(+) T cells. TLR3 was essential for activation of DC by dsRNA ONs, and the potency of activation increased with dsRNA length and varied between DC subsets. In vivo, dsRNA ONs, in a size dependent manner, served as adjuvants for the generation of Ag-specific CTL and for inducing protection against lethal challenge with influenza virus when given with influenza nucleoprotein as an immunogen. These results provide the basis for the development of TLR3-specific adjuvants capable of inducing immune responses tailored for viral pathogens. PMID- 21242526 TI - Chemokine-containing exosomes are released from heat-stressed tumor cells via lipid raft-dependent pathway and act as efficient tumor vaccine. AB - Exosomes derived from dendritic cells or tumor cells are a population of nanometer-sized membrane vesicles that can induce specific antitumor immunity. During investigation of the effects of hyperthermia on antitumor immune response, we found that exosomes derived from heat-stressed tumor cells (HS-TEX) could chemoattract and activate dendritic cells (DC) and T cells more potently than that by conventional tumor-derived exosomes. We show that HS-TEX contain chemokines, such as CCL2, CCL3, CCL4, CCL5, and CCL20, and the chemokine containing HS-TEX are functionally competent in chemoattracting CD11c(+) DC and CD4(+)/CD8(+) T cells both in vitro and in vivo. Moreover, the production of chemokine-containing HS-TEX could be inhibited by ATP inhibitor, calcium chelator, and cholesterol scavenger, indicating that the mobilization of chemokines into exosomes was ATP- and calcium-dependent and via a lipid raft dependent pathway. We consistently found that the intracellular chemokines could be enriched in lipid rafts after heat stress. Accordingly, intratumoral injection of HS-TEX could induce specific antitumor immune response more efficiently than that by tumor-derived exosomes, thus inhibiting tumor growth and prolonging survival of tumor-bearing mice more significantly. Therefore, our results demonstrate that exosomes derived from HS-TEX represent a kind of efficient tumor vaccine and can chemoattract and activate DC and T cells, inducing more potent antitumor immune response. Release of chemokines through exosomes via lipid raft dependent pathway may be a new method of chemokine exocytosis. PMID- 21242527 TI - Description of the development and validation of the Canadian Paediatric Trigger Tool. AB - OBJECTIVE: To describe the process of developing and validating the Canadian Association of Paediatric Health Centres Trigger Tool (CPTT). METHODS: Five existing trigger tools were consolidated with duplicate triggers eliminated. After a risk analysis and modified Delphi process, the tool was reduced from 94 to 47 triggers. Feasibility of use was tested, reviewing 40 charts in three hospitals. For validation, charts were randomly selected across four age groups, half medical/half surgical diagnoses, from six paediatric academic health sciences centres. 591 charts were reviewed by six nurses (for triggers and adverse events (AEs)) and three physicians (for AEs only). The incidence of trigger- and AE-positive charts was documented, and the sensitivity and specificity of the tool to identify charts with AEs were determined. Identification of AEs by nurses and physicians was compared. The positive predictive value (PPV) of each trigger was calculated and the ratio of false- to true-positive AE predictors analysed for each trigger. RESULTS: Nurses rated the CPTT easy to use and identified triggers in 61.1% (361/591; 95% CI 57.2 to 65.0) of patient charts; physicians identified AEs in 15.1% (89/ 591, 95% CI 0.23 to 0.43). Over a third of patients with AEs were neonates. The sensitivity and specificity were 0.88 and 0.44, respectively. Nurse and physician AE assessments correlated poorly. The PPV for each trigger ranged from 0 to 88.3%. Triggers with a false/true-positive ratio of >0.7 were eliminated, resulting in the final 35 trigger CPTT. CONCLUSIONS: The CPTT is the first validated, comprehensive trigger tool available to detect AEs in children hospitalised in acute care facilities. PMID- 21242528 TI - Improving patient safety: the comparative views of patient-safety specialists, workforce staff and managers. AB - INTRODUCTION: Methods for improving patient safety are predicated on cooperation between healthcare groups, but are the views of health professionals involved in promoting safety shared by other healthcare workforce staff and managers? AIM: To compare patient-safety suggestions from health workforce managerial and staff groups with those of patient-safety specialists. METHOD: Samples of managers (424) and staff (1214) in the South Australian state health system and 131 Australian patient-safety specialists were asked to write suggestions for improving patient safety. Group responses were content analysed and compared. RESULTS: Patient-safety specialists (83.2%) were more likely to make suggestions than were workforce managers (57.8%) or staff (44.1%). Workforce members from clinical professions were more likely than non-clinicians to tender suggestions. No relationship existed between the importance specialists and managers (rho = 0.062, p = 0.880) and specialists and staff (rho = -0.046, p = 0.912) attached to nine categories of suggestions. There was a high correlation between the importance that managers and non-managers attached to safety strategies (rho = 0.817, p = 0.011). Among those who made suggestions, specialists were more likely to suggest implementing reviews and guidelines, and incident reporting. Workforce groups were more likely to recommend increased and improved staffing and staffing conditions, and better equipment and infrastructure. There were no significant differences in the proportions of group members recommending: improving management and leadership; increasing staff safety education and supervision; communication and teamwork; improved patient focus; or tackling specific safety projects. IMPLICATIONS: Differences between safety specialists' and workforce groups' beliefs about how to improve patient safety may impede the successful implementation of patient-safety programmes. PMID- 21242530 TI - Penetrating globe injury during infraorbital nerve block. PMID- 21242529 TI - Evolution of modern birds revealed by mitogenomics: timing the radiation and origin of major orders. AB - Mitochondrial (mt) genes and genomes are among the major sources of data for evolutionary studies in birds. This places mitogenomic studies in birds at the core of intense debates in avian evolutionary biology. Indeed, complete mt genomes are actively been used to unveil the phylogenetic relationships among major orders, whereas single genes (e.g., cytochrome c oxidase I [COX1]) are considered standard for species identification and defining species boundaries (DNA barcoding). In this investigation, we study the time of origin and evolutionary relationships among Neoaves orders using complete mt genomes. First, we were able to solve polytomies previously observed at the deep nodes of the Neoaves phylogeny by analyzing 80 mt genomes, including 17 new sequences reported in this investigation. As an example, we found evidence indicating that columbiforms and charadriforms are sister groups. Overall, our analyses indicate that by improving the taxonomic sampling, complete mt genomes can solve the evolutionary relationships among major bird groups. Second, we used our phylogenetic hypotheses to estimate the time of origin of major avian orders as a way to test if their diversification took place prior to the Cretaceous/Tertiary (K/T) boundary. Such timetrees were estimated using several molecular dating approaches and conservative calibration points. Whereas we found time estimates slightly younger than those reported by others, most of the major orders originated prior to the K/T boundary. Finally, we used our timetrees to estimate the rate of evolution of each mt gene. We found great variation on the mutation rates among mt genes and within different bird groups. COX1 was the gene with less variation among Neoaves orders and the one with the least amount of rate heterogeneity across lineages. Such findings support the choice of COX 1 among mt genes as target for developing DNA barcoding approaches in birds. PMID- 21242531 TI - How airway venous malformations differ from airway infantile hemangiomas. AB - OBJECTIVE: To compare airway infantile hemangiomas (IHs) and venous malformations (VMs) clinically, radiographically, endoscopically, and histologically. DESIGN: Retrospective cohort study. SETTING: Tertiary care pediatric hospital. PATIENTS: The study included patients seen in the Vascular Anomaly Clinic, Seattle Children's Hospital, Seattle, Washington, between 2001 and 2008. METHODS: All patients with airway vascular anomalies were identified by searching the Vascular Anomaly Quality Improvement Database and hospital discharge data. The data, which were analyzed with descriptive statistics and the Fisher exact test, included presenting age, sex, presenting signs, lesion site, and radiographic, endoscopic, and histologic findings.. RESULTS: Seventeen patients with airway lesions were identified, 6 with VMs and 11 with IHs. Patients with VMs presented at a mean (SD) age of 11.3 (13.7) months (age range, 3-39 months), while those with IHs presented at 3 (1.8) months of age (age range, 1-6 months) (P = .03). The patients with IHs were predominantly female (9 of 11 [81%]), while no sex difference was noted among the patients with VMs (3 of 6 [50%]). All patients with IHs presented with stridor and cutaneous lesions, whereas patients with VMs more often presented with hemoptysis or dysphagia (P = .001). Computed tomographic angiograms demonstrated enhancing endolaryngeal lesions in all IHs, while VMs enhanced poorly. Endoscopically, IHs were transglottic, while VMs were postcricoid or epiglottic (P < .001). Histologically, immunostained lesions showed submucosal lobules of capillaries lined by GLUT-1 (glucose transporter isoform 1)-positive endothelium in IHs, whereas VMs consisted of loosely organized venous channels that lacked GLUT-1 staining. CONCLUSION: Patients with airway IHs and VMs differ in presenting age and signs, sex, airway lesion location, enhancement on computed tomographic angiograms, and histologic appearance. PMID- 21242532 TI - Sialoendoscopy: prognostic factors for endoscopic removal of salivary stones. AB - OBJECTIVE: To detect prognostic factors for successful sialoendoscopic removal of salivary stones. DESIGN: Retrospective case series. SETTING: Tertiary referral hospital. PATIENTS: Forty-nine consecutive patients who underwent sialoendoscopy for sialolithiasis between January 1, 2008, and January 1, 2010, at University Hospital of Cologne, Cologne, Germany. INTERVENTIONS: Diagnostic and interventional sialoendoscopy using local anesthesia. MAIN OUTCOME MEASURES: Stone removal rate, size, mobility, shape, and location, as well as clinical follow-up data. RESULTS: Sixty-one percent (39 of 64) of all salivary stones were removed endoscopically. The cutoff point for endoscopic removal was between 5 and 6 mm in stone diameter. Small size, good mobility, round or oval, and distal location of a salivary stone were positive prognostic factors for sialoendoscopic removal, with sialolith mobility having the greatest effect in multivariate analysis. CONCLUSION: Small size, good mobility, round or oval, and distal location of a salivary stone in the main duct predict significantly greater probability of endoscopic removal and consequently are positive prognostic factors. PMID- 21242533 TI - Botulinum toxin A for treatment of sialorrhea in children: an effective, minimally invasive approach. AB - OBJECTIVES: To report (1) our experience with botulinum toxin A injections into the salivary glands of pediatric patients with sialorrhea, (2) the clinical outcomes of these interventions, and (3) the associated complication rates. DESIGN: Retrospective cohort study. SETTING: Urban pediatric hospital and pediatric rehabilitation center. PATIENTS: Forty-five neurologically impaired children. INTERVENTIONS: Patients received botulinum toxin A intrasalivary injections between January 2004 and May 2008 at the Hospital for Sick Children in Toronto, Ontario, Canada. All patients received sedation or general anesthesia for their botulinum toxin A injections, which were performed using ultrasonographic guidance. MAIN OUTCOME MEASURES: Posttreatment assessments included the duration of effect, patient complications, saliva consistency, caregiver willingness to repeat the treatment, caregiver satisfaction with the treatment, and caregiver overall assessment of the child's posttreatment quality of life. RESULTS: Forty-five subjects received a total of 91 botulinum toxin A treatments. The mean (SD) duration of effect was 4.6 (5.2) months. Duration of effect (log transformed) was significantly negatively associated with saliva quantity (P = .02), and there was a positive association with both increasing age and female sex, although neither reached statistical significance (P = .08 for each). Seven of the 24 documented complications were major, according to the Society of Interventional Radiology Classification System for Complications by Outcome scale. Thirty-six of the caregivers reported that this treatment improved the child's quality of life (80%). CONCLUSION: Ultrasonographically guided botulinum toxin A injections into the salivary glands are safe and efficacious in the management of sialorrhea in children with neurologic disorders. PMID- 21242534 TI - Cryptic evolution: does environmental deterioration have a genetic basis? AB - Cryptic evolution has been defined as adaptive evolutionary change being masked by concurrent environmental change. Empirical studies of cryptic evolution have usually invoked a changing climate and/or increasing population density as the form of detrimental environmental change experienced by a population undergoing cryptic evolution. However, Fisher (1958) emphasized that evolutionary change in itself is likely to be an important component of "environmental deterioration," a point restated by Cooke et al. (1990) in the context of intraspecific competition. In this form, environmental deterioration arises because a winning lineage has to compete against more winners in successive generations as the population evolves. This "evolutionary environmental deterioration" has different implications for the selection and evolution of traits influenced by resource competition than general environmental change. We reformulate Cooke's model as a quantitative genetic model to show that it is identical in form to more recent developments proposed by quantitative geneticists. This provides a statistical framework for discriminating between the alternative hypotheses of environmental change and environmental deterioration caused by evolutionary change. We also demonstrate that in systems where no phenotypic change has occurred, there are many reasonable biological processes that will generate patterns in predicted breeding values that are consistent with what has been interpreted as cryptic evolution, and care needs to be taken when interpreting these patterns. These processes include mutation, sib competition, and invisible fractions. PMID- 21242536 TI - A Bayesian framework for inference of the genotype-phenotype map for segregating populations. AB - Complex genetic interactions lie at the foundation of many diseases. Understanding the nature of these interactions is critical to developing rational intervention strategies. In mammalian systems hypothesis testing in vivo is expensive, time consuming, and often restricted to a few physiological endpoints. Thus, computational methods that generate causal hypotheses can help to prioritize targets for experimental intervention. We propose a Bayesian statistical method to infer networks of causal relationships among genotypes and phenotypes using expression quantitative trait loci (eQTL) data from genetically randomized populations. Causal relationships between network variables are described with hierarchical regression models. Prior distributions on the network structure enforce graph sparsity and have the potential to encode prior biological knowledge about the network. An efficient Monte Carlo method is used to search across the model space and sample highly probable networks. The result is an ensemble of networks that provide a measure of confidence in the estimated network topology. These networks can be used to make predictions of system-wide response to perturbations. We applied our method to kidney gene expression data from an MRL/MpJ * SM/J intercross population and predicted a previously uncharacterized feedback loop in the local renin-angiotensin system. PMID- 21242535 TI - Targeted introgression of a wheat stem rust resistance gene by DNA marker assisted chromosome engineering. AB - Chromosome engineering is a useful strategy for transfer of alien genes from wild relatives into modern crops. However, this strategy has not been extensively used for alien gene introgression in most crops due to low efficiency of conventional cytogenetic techniques. Here, we report an improved scheme of chromosome engineering for efficient elimination of a large amount of goatgrass (Aegilops speltoides) chromatin surrounding Sr39, a gene that provides resistance to multiple stem rust races, including Ug99 (TTKSK) in wheat. The wheat ph1b mutation, which promotes meiotic pairing between homoeologous chromosomes, was employed to induce recombination between wheat chromosome 2B and goatgrass 2S chromatin using a backcross scheme favorable for inducing and detecting the homoeologous recombinants with small goatgrass chromosome segments. Forty recombinants with Sr39 with reduced surrounding goatgrass chromatin were quickly identified from 1048 backcross progenies through disease screening and molecular marker analysis. Four of the recombinants carrying Sr39 with a minimal amount of goatgrass chromatin (2.87-9.15% of the translocated chromosomes) were verified using genomic in situ hybridization. Approximately 97% of the goatgrass chromatin was eliminated in one of the recombinants, in which a tiny goatgrass chromosome segment containing Sr39 was retained in the wheat genome. Localization of the goatgrass chromatin in the recombinants led to rapid development of three molecular markers tightly linked to Sr39. The new wheat lines and markers provide useful resources for the ongoing global effort to combat Ug99. This study has demonstrated great potential of chromosome engineering in genome manipulation for plant improvement. PMID- 21242537 TI - Diversity in copy number and structure of a silkworm morphogenetic gene as a result of domestication. AB - The carotenoid-binding protein (CBP) of the domesticated silkworm, Bombyx mori, a major determinant of cocoon color, is likely to have been substantially influenced by domestication of this species. We analyzed the structure of the CBP gene in multiple strains of B. mori, in multiple individuals of the wild silkworm, B. mandarina (the putative wild ancestor of B. mori), and in a number of other lepidopterans. We found the CBP gene copy number in genomic DNA to vary widely among B. mori strains, ranging from 1 to 20. The copies of CBP are of several types, based on the presence of a retrotransposon or partial deletion of the coding sequence. In contrast to B. mori, B. mandarina was found to possess a single copy of CBP without the retrotransposon insertion, regardless of habitat. Several other lepidopterans were found to contain sequences homologous to CBP, revealing that this gene is evolutionarily conserved in the lepidopteran lineage. Thus, domestication can generate significant diversity of gene copy number and structure over a relatively short evolutionary time. PMID- 21242538 TI - Ploidy dictates repair pathway choice under DNA replication stress. AB - This study reports an unusual ploidy-specific response to replication stress presented by a defective minichromosome maintenance (MCM) helicase allele in yeast. The corresponding mouse allele, Mcm4(Chaos3), predisposes mice to mammary gland tumors. While mcm4(Chaos3) causes replication stress in both haploid and diploid yeast, only diploid mutants exhibit G2/M delay, severe genetic instability (GIN), and reduced viability. These different outcomes are associated with distinct repair pathways adopted in haploid and diploid mutants. Haploid mutants use the Rad6-dependent pathways that resume stalled forks, whereas the diploid mutants use the Rad52- and MRX-dependent pathways that repair double strand breaks. The repair pathway choice is irreversible and not regulated by the availability of repair enzymes. This ploidy effect is independent of mating type heterozygosity and not further enhanced by increasing ploidy. In summary, a defective MCM helicase causes GIN only in particular cell types. In response to replication stress, early events associated with ploidy dictate the repair pathway choice. This study uncovers a fundamental difference between haplophase and diplophase in the maintenance of genome integrity. PMID- 21242539 TI - Temporomandibular joint dysfunction after mandibular fracture in children: a 10 year review. AB - OBJECTIVES: To collect demographic and clinical data on pediatric mandibular fractures and to assess temporomandibular joint (TMJ) dysfunction in patients with condylar and subcondylar (C/SC) fractures. DESIGN: Retrospective case series of pediatric mandibular fractures (1999-2009) with follow-up telephone questionnaire of patients with C/SC fractures. Collected data included age, gender, unilateral vs bilateral C/SC fracture, presence of concomitant fracture, velocity of injury, and treatment modality. SETTING: Tertiary care children's hospital. PATIENTS: Of 164 patients with mandibular fractures, 83 (50.6%) had C/SC fractures, of which 45 (54.2%) completed the questionnaire. MAIN OUTCOME MEASURES: Helkimo Anamnestic Dysfunction Index (A(i)) quantification of TMJ dysfunction after C/SC fracture and treatment modality of C/SC fractures. RESULTS: Of the 164 patients, 122 (74.4%) were male (median age, 10.4 years; age range, 0.6-19.0 years). Of the 83 patients with C/SC fractures, 61 (73.5%) were male (median age, 9.1 years; age range, 1.1-18.7 years); 66 (79.5%) had unilateral fractures and 17 (20.5%) had bilateral fractures. The A(i) distribution of the 45 patients who completed the questionnaire was as follows: 15 (33.3%) none, 6 (13.3%) mild, and 24 (53.3%) severe. Females have more severe dysfunction than do males (95% confidence interval, 1.6-140.0; P = .02). No other significant predictors of treatment modality or TMJ dysfunction were identified. Patients with bilateral fracture are 8.1 times (95% confidence interval, 1.0-66.1 times; P = .05) more likely to have closed reduction than are those with unilateral fracture. CONCLUSIONS: This is one of the largest series of pediatric C/SC fractures reported in the recent literature. Findings are significant for increased severity of TMJ dysfunction in females and higher incidence of closed reduction in patients with bilateral C/SC fracture. PMID- 21242540 TI - Polysomnographic variables predictive of adverse respiratory events after pediatric adenotonsillectomy. AB - OBJECTIVE: To determine polysomnographic (PSG) variables that may potentially predict adverse respiratory events after pediatric adenotonsillectomy. DESIGN: Retrospective, case-control study. SETTING: Free-standing academic tertiary-care pediatric hospital. PATIENTS: The study included 1131 patients undergoing adenotonsillectomy by 2 attending surgeons. There were no exclusion criteria. MAIN OUTCOME MEASURES: Variables from preoperative PSGs were analyzed to determine predictors of postoperative respiratory complications. Logistic regression analysis was performed. RESULTS: A total of 151 patients (13.4%) underwent preoperative PSG. Twenty-three of these patients (15.2%) had adverse respiratory events. The primary adverse event was desaturation requiring supplemental oxygen therapy, with 1 case of postobstructive pulmonary edema. Patients with adverse events had a significantly higher apnea-hypopnea index) (31.8 vs 14.1; P = .001), higher hypopnea index (22.6 vs 8.9; P = .004), higher body mass index (z score, 1.43 vs 0.70; P = .02), and lower nadir oxygen saturation (72% vs 84%; P <.001). Patients with adverse events had a prolonged hospital course (odds ratio, 32.1; 95% confidence interval, 7.8-131.4). There were no differences in age or other PSG variables. There were no intubations or mortalities. CONCLUSIONS: Polysomnography may be used to predict which patients are at higher risk for adverse respiratory events after adenotonsillectomy. Such knowledge is valuable for planning optimal postoperative management and intraoperative anesthesia. Predictors of increased respiratory complications include apnea-hypopnea index, hypopnea index, body mass index, and nadir oxygen saturation. PMID- 21242541 TI - Biofilm formation on silicone tympanostomy tubes with polyvinylpyrrolidone coating. AB - OBJECTIVE: To determine whether biofilm formation on silicone tympanostomy tubes (TTs) is prevented by polyvinylpyrrolidone (PVP) coating. DESIGN: In vitro microbiologic study. SUBJECTS: Silicone TTs with and without a PVP coating. INTERVENTION: The TTs were exposed to blood or phosphate-buffered saline and cultured with Pseudomonas aeruginosa or Staphylococcus aureus. After 4 days, antibiotics were added to kill planktonic bacteria. Biofilm formation was assessed by quantitative bacterial counts and scanning electron microscopy. RESULTS: Human blood enhanced S aureus biofilm formation on TTs with and without PVP (P < .001). Staphylococcus aureus biofilm formation was similar on TTs with and without PVP coating. Pseudomonas aeruginosa biofilm formation was less on TTs with PVP coating after exposure to phosphate-buffered saline (P = .04), but this difference was not significant after blood exposure (P = .19). CONCLUSIONS: Polyvinylpyrrolidone coating of TTs imparts resistance to P aeruginosa biofilm formation. The clinical impact of PVP on TTs may be attenuated by exposure to blood, but this will require study in clinical trials. PMID- 21242542 TI - Cartilage shield tympanoplasty in children: review of 268 consecutive cases. AB - OBJECTIVE: To assess the efficacy of partial ossicular chain reconstruction using autologous cartilage. DESIGN: Prospective study (April 1, 1997, through January 1, 2008). SETTING: Tertiary academic children's hospital. PATIENTS: Two hundred forty-eight children (268 ears) underwent partial ossicular chain reconstruction using a shaped block of tragal cartilage interposed between the head of the stapes and an underlay tympanic membrane reconstruction along with tragal cartilage and its perichondrium. MAIN OUTCOME MEASURES: Anatomical and audiologic results were evaluated according to the American Academy of Otolaryngology-Head and Neck Surgery guidelines. chi2 Tests and multivariate analysis were used for statistical evaluation. RESULTS: Mean age at surgery was 10.9 years. Single-stage surgery was performed in 124 ears (46.3%) (62.9% for cholesteatomas and 32.3% for retraction pockets). Second-look patients (53.7%) included 93.8% of staged surgery. Audiometric results were available for 222 ears at 1 year and for 78 ears at 5 years. Closure of the average air-bone gap (ABG) to within 20 dB was achieved in 62.2% of ears at 1 year. The mean (SD) preoperative and 1-year postoperative ABGs were 25 (11.8) dB and 18.9 (10.3) dB, respectively. Anatomical results were satisfactory in 87.3%. No cases of extrusion, resorption, or displacement of the cartilage were encountered. No statistically significant difference was found between audiometric results at 1 and 5 years. Multivariate analysis showed a significant negative correlation between preoperative and postoperative ABGs and between postoperative otitis media with effusion and postoperative ABG (P < .05). CONCLUSIONS: Cartilage ossiculoplasty is a reliable technique for partial ossicular replacement. Long-term hearing outcomes remain stable and satisfactory. Preoperative ABG and postoperative otitis media are the predictive factors of the hearing outcome. PMID- 21242543 TI - Automated cuff pressure modulation: a novel device to reduce endotracheal tube injury. AB - OBJECTIVE: To assess whether dynamically modulating endotracheal tube (ETT) cuff pressure, by decreasing it during each ventilatory cycle instead of maintaining a constant level, would reduce the extent of intubation-related laryngotracheal injury. DESIGN: Single-blind, randomized controlled animal study using a previously validated live porcine model of accelerated intubation-related tracheal injury. SETTING: Animal research facility. PATIENTS: Ten piglets (weight, 16-20 kg each) were anesthetized and underwent intubation using a cuffed ETT. INTERVENTIONS: The animals were randomized into the following 2 groups: 5 pigs had a novel device to modulate their cuff pressure from 25 cm H2O during inspiration to 7 cm H2O during expiration, and 5 pigs had a constant cuff pressure of 25 cm H2O. Both groups underwent ventilation under hypoxic conditions for 4 hours. MAIN OUTCOME MEASURE: Laryngotracheal mucosal injury after blinded histopathological assessment. RESULTS: The modulated-pressure group showed significantly less overall laryngotracheal damage than the constant-pressure group (mean grades, 1.2 vs 2.1; P < .001). Subglottic damage and tracheal damage were significantly less severe in the modulated-pressure group (mean grades, 1.0 vs 2.2; P < .001, and 1.9 vs 3.2; P < .001, respectively). There was no significant difference in glottic or supraglottic damage between the groups (P = .06 and .27, respectively). CONCLUSIONS: This novel device reduces the risk of subglottic and tracheal injury by modulating ETT cuff pressure in synchronization with the ventilatory cycle. This finding could have far-reaching implications for reducing the risk of airway injury in patients undergoing long-term intubation. Further clinical study of this device is warranted. PMID- 21242544 TI - A prospective study of the effect of gastroesophageal reflux disease treatment on children with otitis media. AB - OBJECTIVES: To demonstrate improvements in validated quality-of-life measures for otitis media and gastroesophageal reflux disease (GERD) and an objective score for pediatric reflux obtained by fiberoptic laryngoscopy after treatment with antireflux precautions and therapy in children diagnosed as having either recurrent acute otitis media or otitis media with effusion and GERD. DESIGN: Prospective, before-and-after intervention study. SETTING: Hospital-based pediatric otolaryngology practice. PARTICIPANTS: Population-based sample of 47 patients (mean age, 19.5 months). INTERVENTION: Standard antireflux therapy for 2 consecutive 12-week periods. MAIN OUTCOME MEASURES: Otitis Media 6-Item quality of-life survey, Infant GERD Questionnaire-Revised, GERD Symptom Questionnaire for Young Children, Pediatric Reflux Finding Score, and speech awareness threshold. RESULTS: Follow-up data were available for 37 patients. Mean (SD) change scores for Otitis Media 6-Item quality-of-life survey were 1.6 (1.1) at visit 2 and 1.5 (1.1) at visit 3 (P < .001 and P = .004, respectively). Change scores were significantly improved for Infant GERD Questionnaire-Revised and GERD Symptom Questionnaire for Young Children at visit 2 and for Infant GERD Questionnaire Revised at visit 3. Mean (SD) change scores for the Pediatric Reflux Finding Score were 6.4 (4.9) at visit 2 and 8.0 (7.2) at visit 3 (P < .001 and P = .03, respectively). Hearing loss was significantly improved following therapy, as were laryngeal findings of reflux on fiberoptic laryngoscopy. Otitis media was considered by the examining physician to be clinically improved in 28 of 37 children (76%; 95% confidence interval, 60%-87%) at visit 2 and in 6 of 10 children (60%; 95% confidence interval, 31%-83%) at visit 3. Nine children (19.1%) required myringotomy tube placement. CONCLUSIONS: Children with otitis media with effusion or recurrent acute otitis media and GERD have improved quality of life following treatment with antireflux therapy. Control of gastroesophageal reflux may play a role in the management of otitis media and avoidance of tympanostomy. PMID- 21242545 TI - Use of laryngeal mask airway in pediatric adenotonsillectomy. AB - OBJECTIVE: To compare the use of flexible laryngeal mask airway (LMA) and endotracheal tube (ETT) in pediatric adenotonsillectomy. DESIGN: Prospective randomized trial. SETTING: Tertiary care hospital. PATIENTS: One hundred thirty one children (aged 2-12 years). Exclusion criteria were body mass index (calculated as the weight in kilograms divided by the height in meters squared) greater than 35 and craniofacial anomalies. Obstructive sleep apnea was the most common indication for surgery. INTERVENTION: Children undergoing adenotonsillectomy were randomized to use of an LMA or ETT. A standardized anesthesia protocol was used. MAIN OUTCOME MEASURES: Primary outcome measure was laryngospasm. Secondary measures included anesthesia, operative, and recovery times. RESULTS: Sixty children were randomized to the LMA group and 71 to the ETT group. There was no difference between groups with regard to age (P = .76), ethnicity (P = .75), body mass index (P = .99), or American Society of Anesthesiologists grade (P = .46). Incidence of postoperative laryngospasm between LMA (12.5%) and ETT (9.6%) was similar (P = .77). In 10 patients, the LMA was changed to ETT intraoperatively owing to tube kinking or difficulty with visualization. Mean (SD) surgical times for LMA and ETT groups were 33.35 (13.39) and 37.76 (18.26) minutes, respectively (P = .15). Time from surgery end to extubation was significantly shorter in patients who used LMA (P = .01) by 4.06 minutes. There were no differences (P = .49) in postanesthesia care unit recovery times. CONCLUSIONS: An LMA is an efficient alternative to ETT in pediatric adenotonsillectomy. When comparing LMA and ETT, there is no difference in rates of laryngospasm. Time to extubation is significantly shorter in patients using LMA. Before adopting the routine use of LMA in pediatric adenotonsillectomy, further study is needed to address visualization and kinking issues associated with this device. PMID- 21242546 TI - Congenital cytomegalovirus infection in pediatric hearing loss. AB - OBJECTIVES: To compare the prevalence of congenital cytomegalovirus (CMV) infection in Washington State in children with hearing loss (HL) and the general population and to compare the characteristics of HL in children with and without congenital CMV infection. DESIGN: Matched case-control; case cohort. SETTING: Regional pediatric hospital, Washington State Department of Health (WSDOH). PATIENTS: Cases were children 4 years and older with HL born in Washington State. Control individuals matched for demographic characteristics were identified at random through the WSDOH. MAIN OUTCOME MEASURES: Congenital CMV status determined using quantitative polymerase chain reaction testing on newborn heel stick blood spots archived by the WSDOH. Audiologic data were used to characterize HL. RESULTS: Congenital CMV testing was performed for 222 matched cases and controls. Congenital CMV infection was detected in 1.4% of controls and in 9.9% of cases (odds ratio, 10.5; 95% confidence interval, 2.6-92.4). An estimated 8.9% of HL in children in Washington can be attributed to CMV infection. After inclusion of an additional 132 children with HL (for a total of 354 cases in the case cohort), we observed that children with congenital CMV had more severe HL (P < .001) and higher proportions of progressive (P = .02) and unilateral (P = .002) HL compared with children without congenital CMV infection. In the 35 children with congenital CMV infection, there was no relationship between neonatal CMV load and severity of HL. CONCLUSIONS: In Washington State, children with HL had a far higher prevalence of congenital CMV viremia than did the general pediatric population, and CMV infection seems to be responsible for an appreciable fraction of pediatric HL in Washington State. PMID- 21242547 TI - Autosomal dominant progressive sensorineural hearing loss due to a novel mutation in the KCNQ4 gene. AB - OBJECTIVE: To identify the genetic etiology in a family with autosomal dominant progressive sensorineural hearing loss. DESIGN: Prospective molecular genetic research study. SETTING: Academic genetic research laboratory. PARTICIPANTS: Seventeen members of a family with dominant progressive nonsyndromic sensorineural hearing loss: 9 affected, 6 unaffected, and 2 spouses. INTERVENTIONS: Clinical data from questionnaires, interviews, serial audiograms, and medical records; genetic data from genome-wide linkage analysis and candidate gene mutation analysis. MAIN OUTCOME MEASURES: Symptoms, age at onset, serial audiometric data, and the presence or absence of a deafness-associated mutation. RESULTS: Affected individuals in this family presented with autosomal dominant nonsyndromic high-frequency progressive sensorineural hearing loss, with age at onset ranging from 1 to 21 years. Genome-wide linkage analysis of single nucleotide polymorphisms yielded evidence of linkage to an 18.9-Mb region on chromosome 1p34-p36, with a multipoint logarithm of odds score of 3.6. This interval contains a known deafness gene, KCNQ4, which underlies DNFA2 deafness. Sequencing of the 14 coding exons and intron-exon junctions of KCNQ4 revealed a novel heterozygous missense mutation, c.859G>C, p.Gly287Arg. The mutation disrupts the highly conserved GYG motif (glycine-tyrosine-glycine) of the phosphate-binding loop, hypothesized to be critical in maintaining pore structure and function. All 274 controls were negative for the mutation. CONCLUSIONS: Autosomal dominant high-frequency hearing loss is genetically heterogeneous, and linkage analysis is an efficient means of identifying the etiology in larger families. Deafness in this family is caused by a novel mutation in KCNQ4. PMID- 21242548 TI - Hypopharyngeal pharyngoplasty in the treatment of severe aspiration following skull base tumor removal: experience in pediatric patients. AB - OBJECTIVE: To report the surgical treatment of severe swallowing disorders associated with skull base surgery resulting in unilateral pharyngolaryngeal paralysis in pediatric patients. DESIGN: Retrospective case review. SETTING: Tertiary referral center for pediatric otolaryngology. PATIENTS: Five infants undergoing swallowing rehabilitation surgery for severe dysphagia and aspiration resulting from skull base or brainstem surgery. INTERVENTION: A hypopharyngeal pharyngoplasty, consisting of the partial resection of the inferior constrictor and cricopharyngeal muscles, was performed for the treatment of severe swallowing disorders. A thyroplasty was also performed if clinically significant glottic incompetence was present. MAIN OUTCOME MEASURES: Functional outcomes after surgery were evaluated with a videoendoscopic swallowing study and videofluoroscopy. Postoperative clinical evaluation included respiratory, swallowing, and nutritional outcomes. RESULTS: A hypopharyngeal pharyngoplasty was performed following a mean period of 6 weeks (range, 1-10 weeks) after skull base surgery. In 3 patients a thyroplasty and a temporary tracheotomy were performed. Oral feeding was reintroduced after a mean period of 6 days (range, 4 20 days). Complete oral feeding autonomy was obtained after 13 days (range, 7-25 days). Postoperative swallowing assessment revealed the disappearance of pharyngeal stasis and aspiration in all patients. Three infants died because of tumor recurrence. Neither dysphagia or bronchopulmonary infections were observed after a mean follow-up period of 33 months (range, 6-61 months). CONCLUSIONS: Pharyngolaryngeal paralysis represents a severe consequence of skull base and brainstem surgery. This condition leads to high morbidity, particularly in the pediatric population. The hypopharyngeal pharyngoplasty, with a possible thyroplasty, may be considered to treat patients with severe pharyngolaryngeal paralysis after skull base or brainstem surgery. PMID- 21242549 TI - Characteristics of children diagnosed as having coagulopathies following posttonsillectomy bleeding. AB - OBJECTIVE: To determine the prevalence of coagulopathy among children presenting with posttonsillectomy bleeding (PTB) and describe risk factors that could indicate the presence of occult coagulopathy. DESIGN: Retrospective medical chart review. SETTING: Tertiary-care pediatric hospital. PATIENTS: The study population comprised 182 patients presenting with PTB from January to December 2007. MAIN OUTCOME MEASURES: Demographics, laboratory studies, type of intervention, transfusion status, need for hematology consultation, type of coagulopathy, and disposition were recorded. RESULTS: There were 216 emergency department (ED) encounters for PTB. The mean age of the patients was 8.4 years, and 56% were male and 79% were white. Patients presented on mean postoperative day 5.9. Of the 182 children, 34 (19%) presented with abnormally elevated prothrombin time, activated partial thromboplastin time, or platelet function assays (PFAs) for both adenosine diphosphate and epinephrine. Eight patients (4%) ultimately were diagnosed as having a coagulopathy. Differences in mean age (P = .23), sex (P = .47), race (P = .76), number of days posttonsillectomy (P = .34), and higher ED visit frequency (P = .06) between the coagulopathic and noncoagulopathic children were not statistically significant. Coagulopathic children had significantly higher mean activated partial thromboplastin time (P < .001), PFA for adenosine diphosphate (P < .001), and PFA for epinephrine (P = .001). Of the 8 coagulopathic children, 3 (38%) presented with a history of oral bleeding and a normal physical examination. CONCLUSIONS: In children presenting with PTB, activated partial thromboplastin time and PFA studies and hematology consultations are helpful in identifying occult coagulopathies. The definition of PTB should be broadened to include children with any history of oral bleeding, regardless of examination findings. PMID- 21242550 TI - Variation in surgical time-out and site marking within pediatric otolaryngology. AB - OBJECTIVE: To determine variation in surgical time-out and site-marking within pediatric otolaryngology. DESIGN: Survey e-mailed via the American Society of Pediatric Otolaryngology (ASPO). PARTICIPANTS: A total of 167 Children's Hospital Corp of America (CHCA) operating room (OR) directors and ASPO members were asked about perioperative preparation of their patients. RESULTS: Most respondents who operate at children's hospitals report policies that do not require site marking for bilateral placement of ventilation tubes, adenotonsillar surgery, airway endoscopy, or nasal surgery. Policies allowing assistants to perform site marking were identified by 45.0% of respondents from children's hospitals. Community hospitals were 3.68 times (range, 1.31-10.31 times) more likely than other facilities to permit only the attending to perform site marking. Most respondents operating at children's hospitals (84.4%) were satisfied with their hospital's site-marking policy and with their hospital's surgical checklist policy for pediatric otolaryngology procedures (87.1%). There seems to be a relationship between ear tube insertion marking policy and surgeon's age (chi2 = 12.9; P = .045), area of country (chi2 = 29.1; P = .004), and ambulatory centers for children (chi2 = 8.1; P = .02). Twenty-one percent of survey respondents reported involvement in a wrong-site surgery at some point in their career. CONCLUSIONS: This survey of ASPO members and CHCA OR directors reveals substantial variation in the time-out and site-marking procedures. There is a dynamic tension between universal, national mandates, and allowing local variation to encourage hospitals to tailor policies to unique needs. Further study is needed to determine if the observed variations are beneficial or harmful. PMID- 21242551 TI - Prevalence of hoarseness in the cleft palate population. AB - OBJECTIVE: To determine the prevalence of hoarseness in the cleft palate population. DESIGN: Retrospective chart review from a tertiary pediatric hospital's craniofacial clinic. PATIENTS: Nonsyndromic patients with cleft palate who had undergone cleft palate repair were eligible for inclusion. Patients were excluded if they had previously undergone a tracheostomy or if they had significant hearing loss. A total of 487 patients met the inclusion criteria. MAIN OUTCOME MEASURES: Medical records were reviewed for demographic data, presence of hoarseness, velopharyngeal insufficiency, symptoms of gastroesophageal reflux disease, and laryngoscopic findings. RESULTS: Of the 487 patients, 27 (5.5%) had complaints of hoarseness: 13 boys and 14 girls. The average age at initial complaint was 4.6 years, with slight differences according to sex: 4.2 years for boys and 5.0 years for girls. Of those with hoarseness, 19 (70%) had velopharyngeal insufficiency, and 8 (30%) had concomitant symptoms of possible gastroesophageal reflux disease. Eleven patients underwent either direct or flexible laryngoscopy: 9 (33%) had vocal fold nodules, and 2 (7%) had edema and/or mucosal thickening of the vocal folds. CONCLUSIONS: The 5.5% prevalence of hoarseness in this study is similar to the reported prevalence of 6% to 34% in the normal pediatric population. These results suggest that there is no difference in the cleft palate population and that hoarseness is either underrecognized and/or underreported. More studies are needed to fully elucidate the true prevalence of hoarseness in the cleft palate population and any correlation of hoarseness with velopharyngeal insufficiency and/or gastroesophageal reflux disease. PMID- 21242552 TI - Induction chemotherapy for advanced squamous cell carcinoma of the paranasal sinuses. AB - OBJECTIVE: To review the oncologic outcomes in patients with advanced (stage III IV) squamous cell carcinoma of the paranasal sinuses treated with induction chemotherapy prior to definitive local therapy. METHODS: The medical records of 46 consecutive patients with previously untreated, biopsy-proved squamous cell carcinoma of the paranasal sinuses who received induction chemotherapy during the course of their treatment were reviewed for demographics, tumor types and stages, treatment details, and oncologic outcomes. RESULTS: Of the 46 patients (median age, 59 years), the tumor epicenter was in the maxillary sinus in 31 (67%), ethmoid sinus in 9 (20%), nasal cavity in 4 (9%), and sphenoid sinus in 2 (4%). All patients had T3 or T4 tumors, and 12 (26%) patients had clinical evidence of nodal metastasis, with an overall stage of III (20%) or IV (80%). Induction chemotherapy regimens consisted of a combination of a taxane and platinum in 80% of patients, by themselves (14 patients) or in combination with a third agent, such as ifosfamide (14 patients) or 5-fluorouracil (9 patients). The combination of a taxane and 5-fluorouracil was used in the remaining 9 patients. More than two-thirds (67%) of the patients achieved at least a partial response to induction chemotherapy, 24% had progressive disease, and 9% had stable disease. Subsequent treatment after induction chemotherapy consisted of surgery, usually followed by radiation or chemoradiation or by definitive radiation or chemoradiation with surgical salvage of any residual disease. Overall, surgical resection was performed in only 24 of 46 patients (52%) treated with induction chemotherapy. The 2-year survival for patients with at least a partial response or stable disease after induction chemotherapy was 77% in contrast to only 36% for patients with progressive disease. CONCLUSIONS: Tumor response to induction chemotherapy in patients with advanced squamous cell carcinoma of the paranasal sinuses may be predictive of treatment outcome and prognosis. Favorable response to induction chemotherapy is associated with better survival and a reasonable chance of organ preservation. PMID- 21242553 TI - Submental island pedicled flap vs radial forearm free flap for oral reconstruction: comparison of outcomes. AB - OBJECTIVE: To compare intraoperative, postoperative, and functional results of submental island pedicled flap (SIPF) against radial forearm free flap (RFFF) reconstruction for tongue and floor-of-mouth reconstruction. DESIGN: Multi institutional retrospective review. SETTING: Academic tertiary referral center. PATIENTS: Consecutive patients from February 2003 to December 2009 undergoing resection of oral tongue or floor of mouth followed by reconstruction with SIPF or RFFF. INTERVENTION: Two groups: SIPF vs RFFF. MAIN OUTCOME MEASURES: Duration of operation, hospital stay, surgical complications, and speech and swallowing function. RESULTS: The study included 60 patients, 27 with SIPF reconstruction and 33 with RFFF reconstruction. Sex, age, and TNM stage were similar for both groups. Mean flap size was smaller for SIPF (36 cm2) than for RFFF (50 cm2) (P < .001). Patients undergoing SIPF reconstruction had shorter operations (mean, 8 hours 44 minutes vs 13 hours 00 minutes; P < .001) and shorter hospitalization (mean, 10.6 days vs 14.0 days; P < .008) compared with patients who underwent RFFF. Donor site, flap-related, and other surgical complications were comparable between groups, as was speech and swallowing function. CONCLUSIONS: Reconstruction of oral cavity defects with the SIPF results in shorter operative time and hospitalization without compromising functional outcomes. The SIPF may be a preferable option in reconstruction of oral cavity defects less than 40 cm2. PMID- 21242554 TI - A classification system for the reconstruction of vertical hemipharyngolaryngectomy for hypopharyngeal squamous cell carcinoma. AB - OBJECTIVE: To evaluate microvascular reconstruction of a vertical hemipharyngolaryngectomy (VHPL) defect for hypopharyngeal squamous cell carcinoma. DESIGN: Retrospective analysis of medical records. SETTING: Tertiary care referral center. PATIENTS: Thirty-two patients who underwent a VHPL. MAIN OUTCOME MEASURES: Assess the surgical technique and safety of VHPL and review the functional parameters of swallowing and decannulation. RESULTS: The classification was composed of 3 types of VHPL according to the extent of resection: limited VHPL (type I), resection at the lateral border of the conus elasticus to preserve both vocal cords (n = 10); total VHPL (type II), removal of a vertical section of the thyroid cartilage through the anterior commissure to the upper border of the cricoid cartilage with preservation of 1 vocal cord (n = 12); and extended VHPL (type III), inclusion of a supraglottic laryngectomy (type IIIa) (n = 6) or partial cricoid cartilage resection (type IIIb) (n = 4). A radial forearm free flap that included the palmaris longus tendon was used for reconstruction in 31 patients, and an anterolateral thigh flap was used in 1 patient. There was no perioperative mortality, and there was 100% free flap survival. Oral realimentation and tracheotomy weaning were achieved a mean of 33 and 32 days postoperatively, respectively. In 25 patients observed for longer than 6 months, the recurrence rate was 28% (7 of 25), and 5-year disease-specific survival was 64%. CONCLUSION: Microvascular reconstruction of VHPL offers a wider resection with promising functional results for hypopharyngeal carcinoma. PMID- 21242555 TI - Effect of preventive messages tailored to family history on health behaviors: the Family Healthware Impact Trial. AB - PURPOSE: We wanted to determine the impact of automated family history assessment and tailored messages for coronary heart disease, stroke, diabetes, colorectal, breast, and ovarian cancer on preventive behaviors compared with a standard preventive message. METHODS: The study was a cluster-randomized clinical trial that included 41 primary care practices, the majority in the Midwest, using Family Healthware, a self-administered, Web-based tool that assesses familial risk for the diseases and provides personalized risk-tailored messages. Patients in the control group received an age- and sex-specific health message related to lifestyle and screening. Smoking cessation, fruit and vegetable intake, physical activity, aspirin use, blood pressure, and cholesterol and blood glucose screening were assessed at baseline and 6 months after the intervention. RESULTS: Of 4,248 participants, 3,344 (78%) completed the study. Participants were white (91%), female (70%), and insured (97%), and had a mean age of 50.6 years (range 35-65 years). Intervention participants were more likely to increase daily fruit and vegetable consumption from 5 or fewer servings a day to 5 or more servings a day (OR = 1.29; 95% confidence interval [CI], 1.05-1.58) and to increase physical activity (OR = 1.47; 95% CI, 1.08-1.98) to 5 to 6 times a week for 30 minutes or more a week. The absolute differences in proportion were 3% and 4%, respectively. Intervention participants were less likely to move from not having cholesterol screening in the last 5 years to having their cholesterol measured within 5 years (OR = 0.34; 95% CI, 0.17-0.67), with an absolute difference of 15%. CONCLUSIONS: Messages tailored to an individual's familial risk for 6 common diseases modestly increased self-reported physical activity and fruit and vegetable intake but reduced the likelihood of receiving cholesterol screening. PMID- 21242556 TI - Impact of electronic health record clinical decision support on diabetes care: a randomized trial. AB - PURPOSE: We wanted to assess the impact of an electronic health record-based diabetes clinical decision support system on control of hemoglobin A(1c) (glycated hemoglobin), blood pressure, and low-density lipoprotein (LDL) cholesterol levels in adults with diabetes. METHODS: We conducted a clinic randomized trial conducted from October 2006 to May 2007 in Minnesota. Included were 11 clinics with 41 consenting primary care physicians and the physicians' 2,556 patients with diabetes. Patients were randomized either to receive or not to receive an electronic health record (EHR)-based clinical decision support system designed to improve care for those patients whose hemoglobin A(1c), blood pressure, or LDL cholesterol levels were higher than goal at any office visit. Analysis used general and generalized linear mixed models with repeated time measurements to accommodate the nested data structure. RESULTS: The intervention group physicians used the EHR-based decision support system at 62.6% of all office visits made by adults with diabetes. The intervention group diabetes patients had significantly better hemoglobin A(1c) (intervention effect -0.26%; 95% confidence interval, -0.06% to -0.47%; P=.01), and better maintenance of systolic blood pressure control (80.2% vs 75.1%, P=.03) and borderline better maintenance of diastolic blood pressure control (85.6% vs 81.7%, P =.07), but not improved low-density lipoprotein cholesterol levels (P = .62) than patients of physicians randomized to the control arm of the study. Among intervention group physicians, 94% were satisfied or very satisfied with the intervention, and moderate use of the support system persisted for more than 1 year after feedback and incentives to encourage its use were discontinued. CONCLUSIONS: EHR-based diabetes clinical decision support significantly improved glucose control and some aspects of blood pressure control in adults with type 2 diabetes. PMID- 21242557 TI - Impact of EHR-based clinical decision support on adherence to guidelines for patients on NSAIDs: a randomized controlled trial. AB - PURPOSE: Electronic health records (EHRs) with clinical decision support hold promise for improving quality of care, but their impact on management of chronic conditions has been mixed. This study examined the impact of EHR-based clinical decision support on adherence to guidelines for reducing gastrointestinal complications in primary care patients on nonsteroidal anti-inflammatory drugs (NSAIDs). METHODS: This randomized controlled trial was conducted in a national network of primary care offices using an EHR and focused on patients taking traditional NSAIDs who had factors associated with a high risk for gastrointestinal complications (a history of peptic ulcer disease; concomitant use of anticoagulants, anti-platelet medications [including aspirin], or corticosteroids; or an age of 75 years or older). The offices were randomized to receive EHR-based guidelines and alerts for high-risk patients on NSAIDs, or usual care. The primary outcome was the proportion of patients who received guideline-concordant care during the 1-year study period (June 2007-June 2008), defined as having their traditional NSAID discontinued (including a switch to a lower-risk medication), having a gastroprotective medication coprescribed, or both. RESULTS: Participants included 27 offices with 119 clinicians and 5,234 high-risk patients. Intervention patients were more likely than usual care patients to receive guideline-concordant care (25.4% vs 22.4%, adjusted odds ratio = 1.19; 95% confidence interval, 1.01-1.42). For individual high-risk groups, patients on low-dose aspirin were more likely to receive guideline concordant care with the intervention vs usual care (25.0% vs 20.8%, adjusted odds ratio = 1.30; 95% confidence interval, 1.04-1.62), but there was no significant difference for patients in other high-risk groups. CONCLUSIONS: This study showed only a small impact of EHR-based clinical decision support for high risk patients on NSAIDs in primary care offices. These results add to the growing literature about the complexity of EHR-based clinical decision support for improving quality of care. PMID- 21242558 TI - Comparing the diagnostic performance of 2 clinical decision rules to rule out deep vein thrombosis in primary care patients. AB - PURPOSE: The Wells rule is widely used for clinical assessment of patients with suspected deep vein thrombosis (DVT), especially in the secondary care setting. Recently a new clinical decision rule for primary care patients (the primary care rule) has been proposed, because the Wells rule is not sufficient to rule out DVT in this setting. The objective was to compare the ability of both rules to safely rule out DVT and to efficiently reduce the number of referrals for leg ultrasound investigation that would result in a negative finding. METHODS: Family physicians collected data on 1,086 patients to calculate the scores for both decision rules before leg ultrasonography was performed. In all patients D-dimer (dimerized plasmin fragment D) testing was performed using a rapid point-of-care assay. Patients were stratified into risk categories defined by each rule and the D dimer result. Outcomes were DVT (diagnosed by ultrasonography) and venous thromboembolic complications or death caused by a possible thromboembolic event during a 90-day follow-up period. We calculated the differences between the 2 rules in the number of missed diagnoses and the proportions of patients that needed ultrasound testing. RESULTS: Data from 1,002 eligible patients were used for this analysis. A venous thromboembolic event occurred during follow-up in 7 patients with a low score and negative D-dimer finding, both with the Wells rule (7 of 447; 1.6%; 95% confidence interval [CI], 0.7%-3.3% ) and the primary care rule (7 of 495; 1.4%; 95% CI, 0.6%-3.0%). Using the Wells rule, 447 patients (45%) would not need referral for further testing compared with 495 patients (49%) when using the primary care rule (McNemar P <.001). CONCLUSIONS: In primary care, suspected DVT can safely be ruled out using either of the 2 rules in combination with a point-of-care D-dimer test. Both rules can reduce unnecessary referrals for compression ultrasonography by about 50%, though the primary care rule reduces it slightly more. PMID- 21242559 TI - Challenges of providing confidential care to adolescents in urban primary care: clinician perspectives. AB - PURPOSE: Clinician time alone with an adolescent has a major impact on disclosure of risk behavior. This study sought to describe primary care clinicians' patterns of delivering time alone, decision making about introducing time alone to adolescents and their parents, and experiences delivering confidential services. METHODS: We undertook qualitative interviews with 18 primary care clinicians in urban health centers staffed by specialists in pediatrics, family medicine, and adolescent medicine. RESULTS: The annual preventive care visit is the primary context for provision of time alone with adolescents; clinicians consider the parent-child dynamic and the nature of the chief complaint for including time alone during visits for other than preventive care. Time constraints are a major barrier to offering time alone more frequently. Clinicians perceive that parental discomfort with time alone is rare. Many clinicians wrestle with internal conflict about providing confidential services to adolescents with serious health threats and regard their role as facilitating adolescent-parent communication. Health systems factors can interfere with delivery of confidential services, such as inconsistent procedures for determining whether unaccompanied youth would be seen. CONCLUSION: Despite competing time demands, clinicians report commitment to offering time alone during preventive care visits and infrequently offer it at other times. Experienced clinicians can gain skills in the art of managing complex relationships between adolescents and their parents. Office systems should be developed that enhance the consistency of delivery of confidential services. PMID- 21242560 TI - Comparison between US Preventive Services Task Force recommendations and Medicare coverage. AB - PURPOSE: The US Preventive Services Task Force (USPSTF) is authorized by the US government to review and disseminate the scientific evidence for clinical preventive services. The purpose of this study was to evaluate the alignment of Medicare preventive services coverage with the recommendations of the USPSTF before implementation of health reform. METHODS: We recorded all Medicare coverage for preventive services as listed in the Medicare preventive services guide of 2007 (including the 2009 update) for all recommended (A-or B-rated) USPSTF and not recommended (D-rated) guidelines for preventive screening and counseling in adults aged 65 years and older. We analyzed 2 components of preventive care: preventive coordination (risk assessment, patient motivation, and arranging of preventive service) and the preventive service itself. The main outcome measure was the percentage of agreement between USPSTF recommendations and Medicare coverage. RESULTS: The USPSTF recommended 15 preventive interventions for adults aged 65 years and older. Although Medicare partially reimbursed 93% of recommended services, full reimbursement for the preventive coordination, as well as the service, was available for only 7% of these services. This partial coverage is available mostly as part of the Welcome to Medicare Visit. Further, the USPSTF recommended against 16 preventive services; Medicare reimbursed clinicians for 44% of these services. CONCLUSIONS: Medicare coverage for preventive services needs to be reassessed, with special focus on preventive coordination. Continuing previous practices will likely promote both inadequate and excessive delivery of preventive services. The new health care reform law has the potential to improve the provision of preventive services to Medicare beneficiaries. PMID- 21242561 TI - Knowledge and use of ethnomedical treatments for asthma among Puerto Ricans in an urban community. AB - PURPOSE: Puerto Ricans have higher lifetime and current asthma prevalence than other racial and ethnic groups in the United States. A great many Hispanics use ethnomedical therapies for asthma. This study elicited participant knowledge of ethnomedical therapies, developed a typology of the therapies, and considered whether some types are used or deemed efficacious based, in part, on information source. METHODS: Eligible participants were randomly selected from the medical records of an inner-city primary care clinic serving a predominantly Hispanic community in Buffalo, New York. Thirty adult Puerto Ricans who had asthma or were care-givers of children with asthma were interviewed in person using a semistructured instrument. Qualitative data analysis followed a content-driven immersion-crystallization approach. Outcome measures were ethnomedical treatments for asthma known to participants, whether these treatments were used or perceived effective, and the participant's information source about the treatment. RESULTS: Participants identified 75 ethnomedical treatments for asthma. Behavioral strategies were significantly more likely to be used or perceived effective compared with ingested and topical remedies (P <.001). Among information sources for ingested and topical remedies, those recommended by community members were significantly less likely to be used or perceived effective (P <.001) compared with other sources. CONCLUSIONS: This sample of Puerto Ricans with a regular source of medical care was significantly more likely to use or perceive as effective behavioral strategies compared with ingested and topical remedies. Allopathic clinicians should ask Puerto Rican patients about their use of ethnomedical therapies for asthma to better understand their health beliefs and to integrate ethnomedical therapies with allopathic medicine. PMID- 21242562 TI - Methods to achieve high interrater reliability in data collection from primary care medical records. AB - PURPOSE: We assessed interrater reliability (IRR) of chart abstractors within a randomized trial of cardiovascular care in primary care. We report our findings, and outline issues and provide recommendations related to determining sample size, frequency of verification, and minimum thresholds for 2 measures of IRR: the kappa statistic and percent agreement. METHODS: We designed a data quality monitoring procedure having 4 parts: use of standardized protocols and forms, extensive training, continuous monitoring of IRR, and a quality improvement feedback mechanism. Four abstractors checked a 5% sample of charts at 3 time points for a predefined set of indicators of the quality of care. We set our quality threshold for IRR at a kappa of 0.75, a percent agreement of 95%, or both. RESULTS: Abstractors reabstracted a sample of charts in 16 of 27 primary care practices, checking a total of 132 charts with 38 indicators per chart. The overall kappa across all items was 0.91 (95% confidence interval, 0.90-0.92) and the overall percent agreement was 94.3%, signifying excellent agreement between abstractors. We gave feedback to the abstractors to highlight items that had a kappa of less than 0.70 or a percent agreement less than 95%. No practice had to have its charts abstracted again because of poor quality. CONCLUSIONS: A 5% sampling of charts for quality control using IRR analysis yielded kappa and agreement levels that met or exceeded our quality thresholds. Using 3 time points during the chart audit phase allows for early quality control as well as ongoing quality monitoring. Our results can be used as a guide and benchmark for other medical chart review studies in primary care. PMID- 21242563 TI - Card studies for observational research in practice. AB - PURPOSE: Observational studies that collect patient-level survey data at the point-of-care are often called card studies. Card studies have been used to describe clinical problems, management, and outcomes in primary care for more than 30 years. In this article we describe 2 types of card studies and the methods for conducting them. METHODS: We undertook a descriptive review of card studies conducted in 3 Colorado practice-based research networks and several other networks throughout the United States. We summarized experiences of the State Networks of Colorado Ambulatory Practices and Partners (SNOCAP). RESULTS: Card studies can be designed to study specific conditions or care (clinicians complete a card when they encounter patients who meet inclusion criteria) and to determine trends and prevalence of conditions (clinicians complete a card on all patients seen during a period). Data can be collected from clinicians and patients and can be linked. CONCLUSIONS: Card studies provide cross-sectional descriptive data about clinical care, knowledge and behavior, perception of care, and prevalence of conditions. Card studies remain a robust method for describing primary care. PMID- 21242564 TI - A systematic review of clinical decision rules for the diagnosis of influenza. AB - PURPOSE: In this study, we assessed whether multivariate models and clinical decision rules can be used to reliably diagnose influenza. METHODS: We conducted a systematic review of MEDLINE, bibliographies of relevant studies, and previous meta-analyses. We searched the literature (1962-2010) for articles evaluating the accuracy of multivariate models, clinical decision rules, or simple heuristics for the diagnosis of influenza. Each author independently reviewed and abstracted data from each article; discrepancies were resolved by consensus discussion. Where possible, we calculated sensitivity, specificity, predictive value, likelihood ratios, and areas under the receiver operating characteristic curve. RESULTS: A total of 12 studies met our inclusion criteria. No study prospectively validated a multivariate model or clinical decision rule, and no study performed a split-sample or bootstrap validation of such a model. Simple heuristics such as the so-called fever and cough rule and the fever, cough, and acute onset rule were each evaluated by several studies in populations of adults and children. The areas under the receiver operating characteristic curves were 0.70 and 0.79, respectively. We could not calculate a single summary estimate, however, as the diagnostic threshold varied among studies. CONCLUSIONS: The fever and cough, and the fever, cough, and acute onset heuristics have modest accuracy, but summary estimates could not be calculated. Further research is needed to develop and prospectively validate clinical decision rules to identify patients requiring testing, empiric treatment, or neither. PMID- 21242565 TI - Health care reform and equity: promise, pitfalls, and prescriptions. AB - The United States has made little progress during the past decade in addressing health care disparities. Recent health care reforms offer an historic opportunity to create a more equitable health care system. Key elements of health care reform relevant to promoting equity include access, support for primary care, enhanced health information technology, new payment models, a national quality strategy informed by research, and federal requirements for health care disparity monitoring. With effective implementation, improved alignment of resources with patient needs, and most importantly, revitalization of primary care, these reforms could measurably improve equity. PMID- 21242567 TI - AAFP and other primary care associations release joint principles for accountable care organizations. PMID- 21242568 TI - Family medicine clerkship curriculum--next steps. PMID- 21242570 TI - Academic health centers: will they survive? PMID- 21242571 TI - You get what you pay for, and it's time to stop paying for what we've been getting. PMID- 21242572 TI - Reverse crossed cerebellar diaschisis following refractory status epilepticus. PMID- 21242573 TI - The smaller bowel: imaging the small bowel in paediatric Crohn's disease. AB - Crohn's disease begins in childhood in 20% of cases. Imaging of the small bowel is needed for diagnosis and management and also to inform the clinician of the location, extent, and activity of disease. There are several modalities available to image the small bowel and the combined use of these is often required to optimise benefit. Methods available for imaging the small bowel include barium studies, sonography, CT, wireless capsule endoscopy, nuclear medicine studies, and MRI. Patient comfort is paramount in imaging paediatric patients. Therefore, non-invasive techniques are most likely to be successful. Furthermore, as children are at greatest risk of radiation induced malignancy, modalities which do not carry a radiation burden are preferable. This article discusses the methods available for imaging the small bowel in paediatric Crohn's disease and the relative merits of each modality. PMID- 21242574 TI - Gas patterns on plain abdominal radiographs: a pictorial review. AB - Abdominal radiographs are one of the most commonly performed radiological examinations and have an established role in the assessment of the acute abdomen. The main indication is for suspected bowel obstruction and in conjunction with an erect chest x-ray for suspected visceral perforation. Often, the pattern of gas points to a particular pathology, and accurate interpretation is important for prompt diagnosis. The diagnosis in most cases will be confirmed by further imaging studies such as ultrasound, contrast studies or, most commonly in contemporary practice, CT. This pictorial review summarises the various types of intraluminal and extraluminal gas patterns, illustrates some of the common clinical diagnoses made from plain films, describes some commonly encountered clinical problems with radiographs, and discusses the role of advanced imaging techniques. PMID- 21242575 TI - Acute severe ulcerative colitis: timing is everything. AB - The idiopathic inflammatory bowel diseases comprise mainly two types of intestinal disorder, Crohn disease and ulcerative colitis. The clinical course is marked by exacerbations and remissions that occur spontaneously in response to treatment or intercurrent illness. The disease affects approximately 240,000 patients in the UK. Acute severe ulcerative colitis is a medical emergency; prompt effective treatment at the point of admission can avoid significant morbidity and be potentially life-saving. Although such patients need specialist management, it is imperative that emergency care physicians are aware of the important principles of management of this condition to achieve successful outcomes. Corticosteroids remain the cornerstone of initial therapy, but a third of patients will fail to respond, and further management involves critical and timely decisions on whether to use rescue therapy in the form of ciclosporin or infliximab without compromising the health or safety of the patient or to offer timely surgery. The evidence base for the choices for optimal management of this condition is presented. PMID- 21242576 TI - Biomarkers to guide perioperative management. AB - Stratifying preoperative risk and guiding perioperative therapy objectively has acquired critical importance, given robust data demonstrating that morbidity following non-cardiac surgery confers substantially increased risk of death, even beyond hospital discharge. The development of useful perioperative biomarkers depends fundamentally on both prospective morbidity data that enable the identification of higher risk patients as well as the translational understanding of pathophysiological mechanisms underlying postoperative organ dysfunction, the development of which may be specific to the perioperative environment. The emergence of cardiac insufficiency, rather than cardiac ischaemia, as the dominant factor associated with excess risk of prolonged postoperative morbidity has promoted the application of biomarkers used commonly in cardiovascular medicine. Several novel, organ specific biomarkers offer potential perioperative application. Nevertheless, common tests/biomarkers that are widely available do provide valuable, objective information that is perhaps under-utilised perioperatively. Despite significant challenges, perioperative medicine presents exciting-arguably unique-opportunities for novel biomarker development. PMID- 21242577 TI - Four cases of bilateral acute retinal necrosis with a long interval after the initial onset. AB - AIMS: To report the clinical features and causative virus of bilateral acute retinal necrosis (BARN) with a long interval after the initial onset. METHODS: The causative virus and clinical features were retrospectively investigated in four patients with delayed-onset BARN with an interval of more than 3 years after the onset of the disease in the initially affected eye. RESULTS: The intervals between the initially affected eye and the latter affected eye of the four cases were 8 years 7 months, 19 years 3 months, 9 years 7 months and 3 years 6 months. The fourth patient developed a second recurrence in the latter affected eye 17 years 6 months after the initial inflammation in the fellow eye. In all four cases, the same virus species, either varicella-zoster virus or herpes simplex virus, was detected in both eyes by PCR or antibody detection. In all cases, the final best-corrected visual acuity of the latter affected eye (20/20, 18/20, 20/20 and 12/20, respectively) was better than that of the initially affected eye (20 cm hand motion, light perception-negative, light perception-negative and light perception-positive, respectively). CONCLUSION: The present findings indicate that delayed-onset BARN in the fellow eye was caused by the same herpes virus species that induced the disease in the first affected eye. PMID- 21242578 TI - Changing the status quo bias. PMID- 21242579 TI - Surgical treatment of sphenoorbital meningiomas. AB - AIM: To evaluate the outcome of surgery and radiotherapy in the treatment of sphenoorbital meningioma (SOM). METHOD: A retrospective study of 66 consecutive cases treated with surgery for SOM with a minimum follow-up of 4 years. Clinical and radiological information were compared before and after the following surgical approaches: frontotemporal craniotomy, frontotemporal craniotomy combined with orbitozygomatic resection and extended lateral orbitotomy alone. RESULTS: The median age at presentation was 46 years (range, 26-68 years) and the median follow-up after surgery was 102 months (range, 48-288 months). In total, 48 (73%) patients showed preoperative visual deterioration, with visual field defects. All patients had proptosis at presentation (mean +/- SD=6.4 +/- 3.0 mm). Surgery for patients with SOM arrested visual deterioration in 61% and improved vision in 30% of cases. Furthermore, a substantial reduction of proptosis was achieved in 85% of patients. The proptosis in this group was reduced by 2.6 +/- 2.6 mm. There was no correlation between surgical approach and proptosis reduction (p = 0.125). The recurrence rate was 17%. Only 1 out of 15 patients who underwent radiotherapy showed signs of recurrence. CONCLUSIONS: The surgical aims in the treatment of SOM should be the restoration of visual acuity and reduction of proptosis, rather than complete tumour removal. The surgical approach can be tailored to individual cases. The authors recommend radiotherapy in cases of subtotally removed SOM. PMID- 21242580 TI - Endoscope assisted enhanced internal search for iatrogenic retinal breaks in 20 gauge macular surgery. PMID- 21242581 TI - Survey of childhood blindness and visual impairment in Botswana. AB - BACKGROUND/AIMS: In terms of blind-person years, the worldwide burden of childhood blindness is second only to cataracts. In many developing countries, 30 72% of childhood blindness is avoidable. The authors conducted this study to determine the causes of childhood blindness and visual impairment (VI) in Botswana, a middle-income country with limited access to ophthalmic care. METHODS: This study was conducted over 4 weeks in eight cities and villages in Botswana. Children were recruited through a radio advertisement and local outreach programmes. Those <= 15 years of age with visual acuity <6/18 in either eye were enrolled. The WHO/Prevention of Blindness Eye Examination Record for Children with Blindness and Low Vision was used to record data. RESULTS: The authors enrolled 241 children, 79 with unilateral and 162 with bilateral VI. Of unilateral cases, 89% were avoidable: 23% preventable (83% trauma-related) and 66% treatable (40% refractive error and 31% amblyopia). Of bilateral cases, 63% were avoidable: 5% preventable and 58% treatable (33% refractive error and 31% congenital cataracts). CONCLUSION: Refractive error, which is easily correctable with glasses, is the most common cause of bilateral VI, with cataracts a close second. A nationwide intervention is currently being planned to reduce the burden of avoidable childhood VI in Botswana. PMID- 21242582 TI - Single versus sequential testing with scanning peripheral anterior chamber depth analyser, IOLMaster and anterior segment optical coherence tomography for the detection of narrow angles. AB - BACKGROUND: Scanning peripheral anterior chamber depth analyser (SPAC), IOLMaster and anterior segment optical coherence tomography (AS-OCT) are devices that can screen non-invasively for narrow angles (NAs) and may reduce the need for gonioscopy, especially where the availability of ophthalmologists is limited. When used individually to detect NAs, neither SPAC, AS-OCT nor IOLMaster were able to achieve both high sensitivity and specificity when using gonioscopy as a gold standard. AIMS: To assess whether sequential testing improves discrimination of NAs over single testing. METHODS: In a prospective community-based cross sectional study in Singapore, 2047 phakic right eyes underwent SPAC, IOLMaster and AS-OCT. NA eyes were defined as present when Shaffer scores were 0 or 1 in >= 2 quadrants on gonioscopy. Sensitivities and specificities of single and sequential testing were compared. RESULTS: At a fixed specificity of 95%, sensitivities in detecting NA eyes were 57.8% (95% CI 52.7% to 62.7%) for SPAC, 43.3% (95% CI 38.3% to 48.3%) for IOLMaster and 52.1% (95% CI 46.4% to 57.7%) for AS-OCT. After sequential testing using SPAC followed by AS-OCT, the sensitivity rose to 70.3% (95% CI 65.5% to 74.8%) while specificity remained at 94.3% (95% CI 93.1% to 95.4%), with sensitivity significantly higher than single testing alone (p<0.001). CONCLUSION: Sequential testing significantly improves the accuracy of detecting NAs and may be useful in screening settings. PMID- 21242583 TI - Influence of atypical retardation pattern on the peripapillary retinal nerve fibre distribution assessed by scanning laser polarimetry and optical coherence tomography. AB - AIM: To investigate the influence of atypical retardation pattern (ARP) on the distribution of peripapillary retinal nerve fibre layer (RNFL) thickness measured with scanning laser polarimetry in healthy individuals and to compare these results with RNFL thickness from spectral domain optical coherence tomography (OCT) in the same subjects. METHODS: 120 healthy subjects were investigated in this study. All volunteers received detailed ophthalmological examination, GDx variable corneal compensation (VCC) and Spectralis-OCT. The subjects were divided into four subgroups according to their typical scan score (TSS): very typical with TSS=100, typical with 99 >= TSS >= 91, less typical with 90 >= TSS >= 81 and atypical with TSS <= 80. Deviations from very typical normal values were calculated for 32 sectors for each group. RESULTS: There was a systematic variation of the RNFL thickness deviation around the optic nerve head in the atypical group for the GDxVCC results. The highest percentage deviation of about 96% appeared temporal with decreasing deviation towards the superior and inferior sectors, and nasal sectors exhibited a deviation of 30%. Percentage deviations from very typical RNFL values decreased with increasing TSS. No systematic variation could be found if the RNFL thickness deviation between different TSS groups was compared with the OCT results. CONCLUSIONS: The ARP has a major impact on the peripapillary RNFL distribution assessed by GDx VCC; thus, the TSS should be included in the standard printout. PMID- 21242584 TI - Comparison of imiquimod 5% cream versus radiotherapy as treatment for eyelid basal cell carcinoma. AB - BACKGROUND: To compare the efficacy, cosmesis and tolerance of two non-surgical treatments-imiquimod (IMQ) 5% cream and radiotherapy (RT)-to combat periocular nodular basal cell carcinoma (BCC). METHODS: Twenty-seven patients with clinical and histopathological diagnosis of nodular BCC on the eyelid were included and randomly selected: 15 patients were treated with IMQ 5% cream once daily, 5 days/week for 6 weeks, and 12 patients were treated with RT. RESULTS: All tumours showed histopathological remission within 3 months of the treatment, and sustained clinical remission was documented in each patient after 24 months' follow-up. Treatment tolerability was rated as moderate with IMQ and good with RT. Functional results were better in patients treated with IMQ. Loss of eyelashes was reported for most of the patients treated with RT. CONCLUSIONS: IMQ and RT therapies are effective for treating eyelid nodular BCCs. Cosmesis and functional results were better with IMQ, while tolerability was higher with RT. PMID- 21242585 TI - Primary extremity soft tissue sarcomas: outcome improvement over time at a single institution. AB - BACKGROUND: To assess changes in survival over time of extremity soft tissue sarcoma (ESTS) patients treated at a single reference institution. PATIENTS AND METHODS: Patients with primary localized adult-type ESTS surgically treated at our institution between 1987 and 2007 were retrospectively reviewed. Patients were categorized into four 5-year groups according to the timing of their first operation. Crude cumulative incidence (CCI) of sarcoma-specific mortality (SSM), local recurrence (LR), and distant metastases (DMs) were calculated for each time period. RESULTS: A total of 1094 patients were identified. Median follow-up was 81 months. CCI of SSM and LR were significantly better in period 4 in comparison to periods 1-3 (P < 0.001 for both end points), dropping, respectively, from 15% to 6% and from 23% to 9%. An overall improvement of DMs-free survival at 5 years could be detected in the latter period, as well as a better postmetastasis survival. CONCLUSIONS: Reference institutions for sarcomas may have improved their outcome in the last years. Although biases of retrospective analyses as well as the effect of institutional learning curves need to be discounted, it is possible that optimal exploitation of a series of subtle improvements in sarcoma treatment may make a difference in results currently achievable. PMID- 21242586 TI - The safety and efficacy of sunitinib before planned nephrectomy in metastatic clear cell renal cancer. AB - BACKGROUND: The safety and efficacy of upfront sunitinib, before nephrectomy in metastatic clear cell renal cancer (mCRC), has not been prospectively evaluated. METHODS: Two prospective single-arm phase II studies investigated either two cycles (study A: n = 19) or three cycles (study B: n = 33) of sunitinib before nephrectomy in mCRC. RESULTS: Overall, 38 of 52 (73%) of patients obtained clinical benefit (by RECIST) before surgery. The partial response rate of the primary tumour was 6% [median reduction in longest diameter of 12% (range 8% 35%)]. No patients became ineligible due to local progression of disease. A nephrectomy was carried out in 37 (71%) of patients. Necrosis (>50%) was a prominent feature at nephrectomy in 49%. Surgical complications (Clavien-Dindo classification) occurred in 10 (27%) patients, including one death (3%). The median blood loss and surgical time were 725 (90-4200) ml and 189 (70-420) min, respectively. The median progression-free survival was 8 months (95% confidence interval 6-15 months). A comparison of two versus three pre-surgery cycles showed no significant difference in terms of surgical complications or efficacy. CONCLUSIONS: Nephrectomy after upfront sunitinib can be carried out safely. It obtains control of disease. Randomised studies are required to address if this approach is beneficial. PMID- 21242587 TI - Clinical relevance of TNM staging system according to breast cancer subtypes. AB - BACKGROUND: There has been reported that the association between nodal spread and tumor size was disrupted in triple-negative breast cancer (TNBC) and it showed characteristically early relapse. The TNM (tumor-node-metastasis) staging system might not be equally effective as a prognostic indicator for all subtypes. The aim of our study was to evaluate the usefulness of the staging according to subtypes. PATIENTS AND METHODS: We conducted a retrospective analysis of invasive breast cancer patients who received curative surgery at Samsung Medical Center from 2000 to 2004. Relapse-free survivals (RFS) by stage were analyzed. RESULTS: Thousand eight hundred and seventy-nine patients who were available clinicopathologic data were included. These patients were divided into three subtypes: hormone receptor (HR)+, human epidermal growth factor receptor 2+, and triple negative groups. As the stage became more advanced, the slope of each stage of the RFS curves of patients with HR+ and HER2+ steadily increased. In contrast, RFS curves intermingled and showed overlap from stage 1 to 3A in TNBC patients. There was only wide separation of RFS curves between stage 1-3A and 3B 3C in TNBC. CONCLUSIONS: The current TNM staging system might not be enough for encompassing the tumor biology and for predicting outcomes to make therapeutic decisions for all BCs, especially for TNBC patients. PMID- 21242588 TI - Pregnancy-associated breast cancer is as chemosensitive as non-pregnancy associated breast cancer in the neoadjuvant setting. AB - BACKGROUND: The aim of this study was to determine the chemosensitivity of pregnancy-associated breast cancer (PABC) in the neoadjuvant setting by comparing the observed pathological complete response (pCR) rate with the rate predicted by a validated nomogram. METHODS: Data from 48 PABC patients who received neoadjuvant chemotherapy (NACT) were collected. To predict the response rate to chemotherapy, we used well-calibrated logistic regression-based nomograms to calculate individual probability of pCR. RESULTS: Observed rates of pCR were concordant with predictions in the whole sample and in the analyzed subgroups. For the whole sample, the area under the receiver-operated curve (AUC) was 0.77 (95% CI 0.66-0.87). The calibration of predicted and observed probabilities was excellent. In the subgroup analyses (NACT initiated during pregnancy or postpartum, NACT with only anthracycline or both anthracycline and taxanes), discriminations assessed by AUC were significantly above 0.5, except for patients treated with anthracycline only. The interpretation was limited by a lack of power. CONCLUSION: Through the use of nomograms, our study demonstrates that PABC is as chemosensitive as non-PABC and suggests that taxanes should be part of the NACT regimen for PABC. Further studies are warranted to increase the power of the presented data. PMID- 21242589 TI - Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect. AB - BACKGROUND: The purpose of this study was to confirm sunitinib activity in alveolar soft part sarcoma (ASPS) and to report on new insights into the molecular bases thereof. PATIENTS AND METHODS: From July 2007, nine patients with progressive metastatic ASPS received sunitinib 37.5 mg/day, within a named use program. Cryopreserved material was available for five naive patients, among whom three received sunitinib. Immunofluorescence (IF)/confocal microscopy, biochemical, and molecular/cytogenetic analyses were carried out, complemented by antiproliferative and activation assays in a short-term culture derived from one case. RESULTS: All patients were eligible for response. Best RECIST response was partial response in five cases, stable disease in three, and progression in one. The median progression-free survival was 17 months. Positron emission tomography results were consistent. Two cases of interval progressions were recorded. Antiproliferative assays and biochemistry on short-term culture showed that sunitinib is able to markedly impair ASPS cells growth and switch-off PDGFRB. IF/confocal microscopy demonstrated coexpression and physical association between PDGFRB/vascular endothelial growth factor receptor 2 (VEGFR2) and RET/VEGFR2 in ASPS cells, which was validated by biochemistry. PDGFRB, RET, and MET ligand dependent activation was confirmed. CONCLUSIONS: We confirm the clinical efficacy of sunitinib in ASPS, mediated by PDGFRB, VEGFR2, and RET, which are all expressed in tumor cells. A direct antitumor effect was shown in a short-term cell culture. PMID- 21242590 TI - Long-chain acyl-CoA synthetase 4 modulates prostaglandin E2 release from human arterial smooth muscle cells. AB - Long-chain acyl-CoA synthetases (ACSLs) catalyze the thioesterification of long chain FAs into their acyl-CoA derivatives. Purified ACSL4 is an arachidonic acid (20:4)-preferring ACSL isoform, and ACSL4 is therefore a probable regulator of lipid mediator production in intact cells. Eicosanoids play important roles in vascular homeostasis and disease, yet the role of ACSL4 in vascular cells is largely unknown. In the present study, the ACSL4 splice variant expressed in human arterial smooth muscle cells (SMCs) was identified as variant 1. To investigate the function of ACSL4 in SMCs, ACSL4 variant 1 was overexpressed, knocked-down by small interfering RNA, or its enzymatic activity acutely inhibited in these cells. Overexpression of ACSL4 resulted in a markedly increased synthesis of arachidonoyl-CoA, increased 20:4 incorporation into phosphatidylethanolamine, phosphatidylinositol, and triacylglycerol, and reduced cellular levels of unesterified 20:4. Accordingly, secretion of prostaglandin E2 (PGE2) was blunted in ACSL4-overexpressing SMCs compared with controls. Conversely, acute pharmacological inhibition of ACSL4 activity resulted in increased release of PGE2. However, long-term downregulation of ACSL4 resulted in markedly reduced PGE2 secretion. Thus, ACSL4 modulates PGE2 release from human SMCs. ACSL4 may regulate a number of processes dependent on the release of arachidonic acid-derived lipid mediators in the arterial wall. PMID- 21242591 TI - The acetaminophen enigma in asthma. PMID- 21242592 TI - Chronic obstructive pulmonary disease Th1 cells display impaired response to endotoxin. PMID- 21242593 TI - Targeting CCR2: a novel therapeutic strategy for septic shock? PMID- 21242595 TI - The positive predictive value of T-spot.TB and tuberculin skin test in patients with silicosis. PMID- 21242594 TI - HIF and the lung: role of hypoxia-inducible factors in pulmonary development and disease. PMID- 21242596 TI - Streptomycin susceptibility and MDR-TB: can we refine the definition of XDR-TB? PMID- 21242597 TI - Diagnostic strategy for hematology and oncology patients with acute respiratory failure. PMID- 21242598 TI - Activated protein C nebulization in severe late acute respiratory distress syndrome. PMID- 21242600 TI - Is the relationship between sprinting and maximal aerobic speeds in young soccer players affected by maturation? AB - The purpose of this study was to investigate the relationship between maximal sprinting (MSS) and aerobic (MAS) speeds in a cohort of highly-trained young male soccer players with the influence of body mass controlled for using allometric scaling. MSS and MAS were obtained in 14 pre-age at peak height velocity (APHV) players (12.3 +/- 0.7 years), 21 circum-APHV players (14.3 +/- 0.9 year) and 26 post-APHV players (16.9 +/- 0.7 years). The three groups showed similar positive correlations between MSS and MAS (r = 0.73 to 0.52; p < .01). In conclusion, our results suggest that the relationship between MSS and MAS is not affected by maturation. PMID- 21242601 TI - Effects of a school-based physical activity program on physical and psychosocial quality of life in elementary school children: a cluster-randomized trial. AB - The present study tested the effect of a school-based physical activity (PA) program on quality of life (QoL) in 540 elementary school children. First and fifth graders were randomly assigned to a PA program or a no-PA control condition during one academic year. QoL was assessed by the Child Health Questionnaire at baseline and postintervention. Based on mixed linear model analyses, physical QoL in first graders and physical and psychosocial QoL in fifth graders were not affected by the intervention. In first graders, the PA intervention had a positive impact on psychosocial QoL (effect size [d], 0.32; p < .05). Subpopulation analyses revealed that this effect was caused by an effect in urban (effect size [d], 0.38; p < .05) and overweight first graders (effect size [d], 0.45; p < .05). In conclusion, a school-based PA intervention had little effect on QoL in elementary school children. PMID- 21242599 TI - The Y238X stop codon polymorphism in the human beta-glucan receptor dectin-1 and susceptibility to invasive aspergillosis. AB - BACKGROUND: Dectin-1 is the major receptor for fungal beta-glucans on myeloid cells. We investigated whether defective Dectin-1 receptor function, because of the early stop codon polymorphism Y238X, enhances susceptibility to invasive aspergillosis (IA) in at-risk patients. METHODS: Association of Dectin-1 Y238X polymorphism with occurrence and clinical course of IA was evaluated in 71 patients who developed IA post hematopoietic stem cell transplantation (HSCT) and in another 21 non-HSCT patients with IA. The control group consisted of 108 patients who underwent HSCT. Functional studies were performed to investigate consequences of the Y238X Dectin-1 polymorphism. RESULTS: The Y238X allele frequency was higher in non-HSCT patients with IA (19.0% vs 6.9%-7.7%; P < .05). Heterozygosity for Y238X polymorphism in HSCT recipients showed a trend toward IA susceptibility (odds ratio, 1.79; 95% CI, .77-4.19; P = .17) but did not influence clinical course of IA. Functional assays revealed that although peripheral blood mononuclear cells with defective Dectin-1 function due to Y238X responded less efficiently to Aspergillus, corresponding macrophages showed adequate response to Aspergillus. CONCLUSIONS: Dectin-1 Y238X heterozygosity has a limited influence on susceptibility to IA and may be important in susceptible non-HSCT patients. This is partly attributable to redundancy inherent in the innate immune system. Larger studies are needed to confirm these findings. PMID- 21242602 TI - Difference between self-reported and accelerometer measured moderate-to-vigorous physical activity in youth. AB - We examined differences between objective (accelerometer) and subjective (selfreport) measures of moderate-to-vigorous physical activity (MVPA) in youth. Participants included 2761 youth aged 12-19 years. Within each sex and race group, objective and self-reported measures of MVPA were poorly correlated (R2 = .01-.10). Self-reported MVPA values were higher than objective values (median: 42.4 vs. 15.0 min/d). 65.4% of participants over-reported their MVPA by 35 min/d. The difference between self-reported and objective measures was not influenced by sex, age, or race. There was, however, a systematic difference such that inactive participants over-reported their MVPA to the greatest extent. PMID- 21242603 TI - The effect of active video gaming on children's physical activity, behavior preferences and body composition. AB - Active video game interventions typically provide children a single game that may become unappealing. A peripheral device (jOG) encourages step-powered gaming on multiple games. This trial evaluated the effect of jOG on children's objectively measured PA, body fat and self-reported behaviors. 42 of 58 eligible children (8 10 y) randomly assigned to an intervention (jOG) or control (CON) completed the trial. Intervention children received two jOG devices for home use. Analyses of covariance compared the intervention effect at 6 and 12 weeks from baseline. No differences were found between groups for counts per minute (CPM; primary outcome) at 6 and 12 weeks (p > .05). Active video gaming increased (adjusted change 0.95 (95% CI 0.25, 1.65) h.d-1, p <.01) and sedentary video gaming decreased (-0.34 (-1.24, 0.56) h.d-1, p > .05) at 6 weeks relative to CON. No body fat changes were observed between groups. Targeted changes in video game use did not positively affect PA. Larger trials are needed to verify the impact of active video games on children's PA and health. PMID- 21242604 TI - Plyometric training does not affect central and peripheral muscle fatigue differently in prepubertal girls and boys. AB - The aim of the study was to evaluate the effect of plyometric training (PT) on central and peripheral (muscle) fatigue in prepubertal girls and boys. The boys (n = 13, age 10.3 +/- 0.3 years) and girls (n = 13, age, 10.2 +/- 0.3 years) performed continuous 2-min maximal voluntary contractions (MVCs) before and after 16 high-intensity PT sessions. PT comprised two training sessions per week of 30 jumps in each session with 20 s between jumps. The greatest effect of PT was on excitation-contraction coupling, (twitch force increased by 323% in boys and 21% in girls) and height of a counter-movement jump (increased by 37% in boys and 38% in girls). In contrast, the quadriceps voluntary activation index, central activation ratio, and MVC did not change significantly after PT. The thickness of the quadriceps muscle increased by 9% in boys and 14% in girls after PT. In conclusion, boys and girls demonstrated similar changes in indicators of central fatigue (50-60% decrease) and peripheral fatigue (45-55% decrease) after MVC before and after PT. PMID- 21242605 TI - Lower relative bone mineral content in obese adolescents: role of non-weight bearing exercise. AB - We assessed relative bone mineral content (BMC) in normal-weight (BMI < 85th percentile), overweight (BMI >= 85th---< 95th percentile), and obese (BMI >= 95th percentile) adolescents and evaluated the impact of nonweight bearing stationary cycle exercise training in a subset of obese participants. Obese and overweight adolescents had higher (p = .001) BMC than normal-weight counterparts, but after adjusting for total body mass the overweight and obese adolescents had a significantly lower (p < .001) BMC than normal-weight subjects. Although aerobic training such as cycling would seem optimal for caloric expenditure in obese adolescents, this study showed that eight weeks of cycle training did not improve BMC in obese adolescents. Weight-bearing aerobic exercise would be a better option for optimizing bone health in this population. PMID- 21242606 TI - Energy expenditure and perceived effort during brisk walking and running in 8- to 10-year-old children. AB - There are no previous reports of energy expenditure and perceived effort during brisk-walking and running at speeds self-selected by young children. Fifty four participants (age 8-11 years old) performed 1500 m of brisk-walking and running in a marked school playground, and were given simple instructions to either 'walk quickly' or to 'jog'. During the running the children achieved higher mean speeds and a greater total energy expenditure (p < .001). However, there was no difference in the perceived effort between the two activities (p > .05). These findings suggest that under certain conditions children find it just as easy to run as they do to walk briskly, even though the speed and energy expenditure is significantly higher. PMID- 21242607 TI - Measurement of walking activity throughout childhood: influence of leg length. AB - The aim of this study was to describe walking (stride) activity frequency and intensity in 428 children ages 2-15 years with a single accelerometer-based device. With comparison with published pedometer-determined data, the influence of leg length was examined. Decline in stride frequency and intensity throughout childhood increased with adjustment for leg length. The accelerometer-based device documented higher stride counts than published pedometer-based data with the greatest discrepancy in 4-5 year olds. Recommended walking levels for optimal weight throughout childhood should be examined with knowledge of the device measurement differences and the natural history of walking activity changes with age. PMID- 21242608 TI - Size and maturity mismatch in youth soccer players 11- to 14-years-old. AB - The purpose of the study was to compare the anthropometric, functional and sport specific skill characteristics and goal orientations of male youth soccer players at the extremes of height and skeletal maturity in two competitive age groups, 11 12 and 13-14 years. The shortest and tallest players, and least and most skeletally mature players (n = 8 per group) within each age group were compared on chronological age; skeletal age (Fels method); pubertal status (pubic hair); size, proportions and adiposity; four functional capacities; four soccer-specific skills; and task and ego orientation. The tallest players were older chronologically, advanced in maturity (skeletal, pubertal) and heavier, and had relatively longer legs than the shortest players in each age group. At 11-12 years, the most mature players were chronologically younger but advanced in pubertal status, taller and heavier with more adiposity. At 13-14 years, the most mature players were taller, heavier and advanced in pubertal status but did not differ in chronological age compared with the least mature players. Players at the extremes of height and skeletal maturity differed in speed and power (tallest > shortest; most mature > least mature), but did not differ consistently in aerobic endurance and in soccer-specific skills. Results suggested that size and strength discrepancies among youth players were not a major advantage or disadvantage to performance. By inference, coaches and sport administrators may need to provide opportunities for or perhaps protect smaller, skilled players during the adolescent years. PMID- 21242609 TI - Time-of-day effects on short-term exercise performances in 10- to 11-year-old boys. AB - The purpose of this study was to examine the time-of-day effects on short-term performances in boys. In a balanced and randomized study design, 20 boys performed four anaerobic tests of strength and power (grip strength, Squat-Jump, Five-jump and cycle Wingate tests) at 08:00, 14:00 and 18:00 hr on separate days. The results showed a time-of-day effect on oral temperature. Analysis of variance revealed a significant time-of-day effect for short-term performances for strength, cycle, and jump tests. The post hoc analysis revealed that performances improved significantly from morning to afternoon but no significant differences were noticed between 14:00 and 18:00 hr. The differences between the morning and the afternoon (the highest value measured either at 14:00 or at 18:00 hr) reached 5.9% for grip strength, 3.5% for the squat jump test, 5% for the five jump test, and 5.5% for P(peak) and 6% for P(mean) during the Wingate test. A significant positive correlation was found between temperature and short-term performances. In conclusion, a time-of-day effect in the child's maximal short-term exercise performances exists in relation with core temperature. Such variations would have pronounced effects when expressed in training programs and competitions. PMID- 21242610 TI - Prediction of peak oxygen uptake from a maximal treadmill test in 12- to 18-year old active male adolescents. AB - The aims were to develop and validate a VO(2peak) prediction equation from a treadmill running test in active male adolescents. Eighty-eight athletes (12-18 yrs.) performed a maximal exercise test on a treadmill to assess the actual VO2peak and a 20m Shuttle-Run-Test (20mST). A step-wise linear regression analysis was used and the following equation for estimation of VO(2peak) (mL.kg 1.min-1) = 35.477 + 1.832 * duration in min - 0.010 * duration * body mass in kg was developed. The cross-validation statistics were: R = .54, CE = 0.1 mL.kg-1min 1, SEE = 2.5 mL.kg-1.min-1 (4.6%), and TE = 2.6 mL.kg-1.min-1 (4.9%). The cross validation values (CE, SEE, and TE) were lower compared with those of previously published equations in adolescents that estimated VO(2peak) using anthropometric data, performance in 20mST, and energy cost at submaximal speeds. PMID- 21242611 TI - Examining influences on boy's and girls' physical activity patterns: the A-CLASS project. AB - Understanding children's physical activity (PA) patterns and the factors that may influence PA are important for developing interventions within this population. One hundred and ten children aged 9-10 years from 8 schools had their PA patterns assessed over 7 days. Physiological and self-report data were also collected. Multilevel analyses revealed that cardiorespiratory fitness was a consistent, significant and positive predictor of weekday and weekend PA, while the availability of home sedentary activities was a significant but negative predictor of PA. Since a range of variables were associated with PA levels, intervention developers should be cognizant of variables that may influence children's activity. PMID- 21242612 TI - Tunneling magnetoresistance modulation in a magnetic tunnel junction with a ferroelectric barrier. AB - A simple model is developed to investigate the potential profile changes due to mechanical stress at the ferromagnetic/ferroelectric interfaces of ferromagnetic ferroelectric-ferromagnetic tunnel junctions with an ultrathin ferroelectric barrier. The potential changes associated with the polarization variation have significant effects on the tunneling conductance of the junctions. The discovered effect is illustrated by the example of a multiferroic tunnel junction in which approximately four orders of changes of the tunneling conductance and several fold changes of the tunneling magnetoresistance (TMR) are observed due to the spin-flip induced nanomechanical stress. The TMR modulation effect is essential for realization of novel spintronics nano-devices as well as being useful for investigating fundamental aspects of the spin transfer. PMID- 21242613 TI - Tunable plasmonic coupling between silver nano-cubes and silver nano-hole arrays. AB - A quasi-three-dimensional (quasi-3D) system composed of Ag nano-cubes and Ag nano hole arrays was fabricated through a low cost chemical process. The coupling of localized surface plasmons (LSPs) in the cube-hole array system has been investigated through surface-enhanced Raman scattering (SERS) from Rhodamine 6G (R6G) molecules. A SERS enhancement factor as large as 1.1 * 10(8) can be achieved due to this plasmonic coupling effect, and is highly sensitive to geometrical parameters, such as cube-hole array distance, hole diameter, inter hole spacing and Ag film thickness. PMID- 21242614 TI - Simulation of lattice strain due to a CNT-metal interface. AB - We report an atomistic molecular statics study of strains in single wall carbon nanotubes (SWCNTs) interfaced with a planar nickel surface. We calculate axial and radial strain distributions along the SWCNT axis. We demonstrate axial strains of up to 2% extending over a distance of ~ 10 nm away from the interface along the CNT axis. In addition to the effect of strains on the thermal and mechanical properties of a CNT-metal contact, our results suggest a significant contribution to the contact electrical resistance via local strain-induced modification in the SWCNT electron energy band structure. PMID- 21242615 TI - Silicide-induced multi-wall carbon nanotube growth on silicon nanowires. AB - A novel multi-walled carbon nanotube (MWNT) growth process is reported based on carbon incorporation in a nickel catalyst layer deposited via plasma-enhanced atomic layer deposition (PEALD) on silicon nanowires and silicon wafer substrates. As-deposited PEALD Ni films containing relatively high amounts of carbon (>18 at.%) were observed to promote the growth of MWNTs upon post deposition rapid thermal annealing. For these films the carbon originated from the ALD precursor ligand and MWNT growth occurred in the absence of a vapor-phase carbon feedstock. MWNT growth relied on the formation of nickel silicide at the PEALD Ni/Si interface which increased the local carbon concentration in the Ni film sufficiently to promote carbon saturation/precipitation at Ni catalyst grains and nucleate MWNT growth. Similar MWNT growth from annealed PEALD Ni films was not observed on SiO(2)-coated Si wafer substrates, consistent with the role of silicidation in the observed Ni-catalyzed MWNT growth on Si. This MWNT growth mode requires neither the catalytic decomposition of a gaseous hydrocarbon source nor the high-temperature pyrolysis of metallocene materials and purposely avoids a catalyst diffusion barrier at the Si substrate, commonly used in MWNT growth processes on Si. PMID- 21242616 TI - Understanding frictional duality and bi-duality: Sb-nanoparticles on HOPG. AB - Antimony nanoparticles deposited under UHV conditions on HOPG are found to exhibit an intriguing frictional behavior characterized by a distinct clearly separated double dual behavior of dependence of the frictional force on contact area. We present the first realistic simulations, density functional modeling adapted to accommodate van der Waals interactions, of the (double) dual frictional behavior. The simulations provide insights into the physics/chemistry of all the frictional branches in terms of incommensurable interfaces, mobile spacer molecules as well as a novel concept of mobile oxidized multi nanoasperities. PMID- 21242617 TI - Optical properties of heavily doped GaAs nanowires and electroluminescent nanowire structures. AB - We present GaAs electroluminescent nanowire structures fabricated by metal organic vapor phase epitaxy. Electroluminescent structures were realized in both axial pn-junctions in single GaAs nanowires and free-standing nanowire arrays with a pn-junction formed between nanowires and substrate, respectively. The electroluminescence emission peak from single nanowire pn-junctions at 10 K was registered at an energy of around 1.32 eV and shifted to 1.4 eV with an increasing current. The line is attributed to the recombination in the compensated region present in the nanowire due to the memory effect of the vapor liquid-solid growth mechanism. Arrayed nanowire electroluminescent structures with a pn-junction formed between nanowires and substrate demonstrated at 5 K a strong electroluminescence peak at 1.488 eV and two shoulder peaks at 1.455 and 1.519 eV. The main emission line was attributed to the recombination in the p doped GaAs. The other two lines correspond to the tunneling-assisted photon emission and band-edge recombination in the abrupt junction, respectively. Electroluminescence spectra are compared with the micro-photoluminescence spectra taken along the single p-, n- and single nanowire pn-junctions to find the origin of the electroluminescence peaks, the distribution of doping species and the sharpness of the junctions. PMID- 21242618 TI - Multiplexed sensing based on Brownian relaxation of magnetic nanoparticles using a compact AC susceptometer. AB - A novel multiplexed sensing scheme based on the measurement of the magnetic susceptibility of the affinity captured target molecules on magnetic nanoparticles in liquid suspension is proposed. The AC magnetic susceptibility provides a measurement of Brownian relaxation behavior of biomolecules bound to magnetic nanoparticles (MNPs) that is related to its hydrodynamic size. A room temperature, compact AC susceptometer is designed and developed to measure complex AC magnetic susceptibility of such magnetic nanoparticles. The AC susceptometer exhibits high sensitivity in magnetic fields as low as 10 uT for 1 mg ml(-1) concentration and 5 ul volume, and is fully software programmable. The capability of biological sensing using the proposed scheme has been demonstrated in proof of principle using the binding of biotinylated horseradish peroxidase (HRP) to streptavidin-coated MNPs. The proposed technique and instrument are readily compatible with lab-on-chip applications for point-of-care medical applications. PMID- 21242619 TI - Electron-beam-induced deposition and post-treatment processes to locally generate clean titanium oxide nanostructures on Si(100). AB - We have investigated the lithographic generation of TiO(x) nanostructures on Si(100) via electron-beam-induced deposition (EBID) of titanium tetraisopropoxide (TTIP) in ultra-high vacuum (UHV) by scanning electron microscopy (SEM) and local Auger electron spectroscopy (AES). In addition, the fabricated nanostructures were also characterized ex situ via atomic force microscopy (AFM) under ambient conditions. In EBID, a highly focused electron beam is used to locally decompose precursor molecules and thereby to generate a deposit. A drawback of this nanofabrication technique is the unintended deposition of material in the vicinity of the impact position of the primary electron beam due to so-called proximity effects. Herein, we present a post-treatment procedure to deplete the unintended deposits by moderate sputtering after the deposition process. Moreover, we were able to observe the formation of pure titanium oxide nanocrystals (<100 nm) in situ upon heating the sample in a well-defined oxygen atmosphere. While the nanocrystal growth for the as-deposited structures also occurs in the surroundings of the irradiated area due to proximity effects, it is limited to the pre-defined regions, if the sample was sputtered before heating the sample under oxygen atmosphere. The described two-step post-treatment procedure after EBID presents a new pathway for the fabrication of clean localized nanostructures. PMID- 21242620 TI - Silver nanoparticles on titanate nanobelts via the self-assembly of weak polyelectrolytes: synthesis and photocatalytic properties. AB - A weak-polyelectrolyte multilayer on a surface of titanate nanobelts (Ti-NBs) was utilized as a template for in situ Ag nanoparticle formation in the fabrication of Ag-loaded Ti-NBs nanocomposites. The polyelectrolyte multilayer (PEM) was fabricated using layer-by-layer self-assembly of poly(acrylic acid) (PAA) and poly(allylamine hydrochloride) (PAH) on the surface of high-surface-area titanate nanobelts (Ti-NBs) synthesized using a hydrothermal procedure. The concentration of Ag nanoparticles in the PEM was controlled by repeating the ion loading/reduction cycle. The subsequent annealing of the Ag/Ti-NBs-PEM nanocomposites yielded nanostructured crystalline Ag/Ti-NBs. Transmission electron microscopy (TEM) techniques (HRTEM, SAED) and x-ray powder diffraction (XRD) were employed to evaluate the morphological, structural and growth characteristics of the silver nanocrystallites in the Ag/Ti-NBs nanocomposites. The UV-vis photoactivity of the as-fabricated nanocomposites was monitored by the degradation of the cationic dye methylene blue (MB). An enhanced UV photo efficiency was observed for the Ag/Ti-NBs nanocomposites compared with pure Ti NBs. As-fabricated Ag(x)/Ti-NBs nanocomposites also exhibited visible photoactivity assisted by the near-field amplitudes of the localized surface plasmon resonance (LSPR) of the silver nanoparticles in the 1D nanocomposite. PMID- 21242621 TI - Electrically controlled drug release from nanostructured polypyrrole coated on titanium. AB - Previous studies have demonstrated that multi-walled carbon nanotubes grown out of anodized nanotubular titanium (MWNT-Ti) can be used as a sensing electrode for various biomedical applications; such sensors detected the redox reactions of certain molecules, specifically proteins deposited by osteoblasts during extracellular matrix bone formation. Since it is known that polypyrrole (PPy) can release drugs upon electrical stimulation, in this study antibiotics (penicillin/streptomycin, P/S) or an anti-inflammatory drug (dexamethasone, Dex), termed PPy[P/S] or PPy[Dex], respectively, were electrodeposited in PPy on titanium. The objective of the present study was to determine if such drugs can be released from PPy on demand and (by applying a voltage) control cellular behavior important for orthopedic applications. Results showed that PPy films possessed nanometer-scale roughness as analyzed by atomic force microscopy. X-ray photoelectron spectroscopy confirmed the presence of P/S and Dex encapsulated within the PPy films. Results from cyclic voltammetry showed that 80% of the drugs were released on demand when sweep voltages were applied for five cycles at a scan rate of 0.1 V s(-1). Furthermore, osteoblast (bone-forming cells) and fibroblast (fibrous tissue-forming cells) adhesion were determined on the PPy films. Results showed that PPy[Dex] enhanced osteoblast adhesion after 4 h of culture compared to plain Ti. PPy-Ti (with or without anionic drug doping) inhibited fibroblast adhesion compared to plain Ti. These in vitro results confirmed that electrodeposited PPy[P/S] and PPy[Dex] can release drugs on demand to potentially fight bacterial infection, reduce inflammation, promote bone growth or reduce fibroblast functions, further implicating the use of such materials as implant sensors. PMID- 21242622 TI - Growth of GaN nanotubes by halide vapor phase epitaxy. AB - We have investigated low temperature growth of GaN nanostructures using halide vapor phase epitaxy on c-oriented Al(2)O(3) and Au coated Al(2)O(3) substrates. Depending on the III/V ratio and the growth temperature, the shape and density of the structures could be controlled. By increasing the GaCl partial pressure, the structure changed from dot-like to nanotubes. The nanotubes, which could be open or closed, were about 1 um long with a diameter of typically 200 nm. In addition, it was observed that the nanostructures were spontaneously nucleated at droplets of Ga or, when using Au coated Al(2)O(3), on droplets of Au/Ga alloy. By varying the growth temperature, the inner diameter of the nanotubes could be controlled. The experimental results suggest that this approach with pre-patterned Au coated Al(2)O(3)substrates has the potential for fabrication of well-organized nanotubes with a high density. PMID- 21242623 TI - Measuring the electrical resistivity and contact resistance of vertical carbon nanotube bundles for application as interconnects. AB - Carbon nanotubes (CNT) are known to be materials with potential for manufacturing sub-20 nm high aspect ratio vertical interconnects in future microchips. In order to be successful with respect to contending against established tungsten or copper based interconnects, though, CNT must fulfil their promise of also providing low electrical resistance in integrated structures using scalable integration processes fully compatible with silicon technology. Hence, carefully engineered growth and integration solutions are required before we can fully exploit their potentialities. This work tackles the problem of optimizing a CNT integration process from the electrical perspective. The technique of measuring the CNT resistance as a function of the CNT length is here extended to CNT integrated in vertical contacts. This allows extracting the linear resistivity and the contact resistance of the CNT, two parameters to our knowledge never reported separately for vertical CNT contacts and which are of utmost importance, as they respectively measure the quality of the CNT and that of their metal contacts. The technique proposed allows electrically distinguishing the impact of each processing step individually on the CNT resistivity and the CNT contact resistance. Hence it constitutes a powerful technique for optimizing the process and developing CNT contacts of superior quality. This can be of relevant technological importance not only for interconnects but also for all those applications that rely on the electrical properties of CNT grown with a catalytic chemical vapor deposition method at low temperature. PMID- 21242624 TI - High-temperature thermal stability and axial compressive properties of a coaxial carbon nanotube inside a boron nitride nanotube. AB - The structural performance of double-walled C(5, 5)@BN(10, 10) and C(5, 5)@C(10, 10) nanotubes subject to high temperatures is investigated through molecular dynamics simulations. It is found that the inner tube C(5, 5) in the C(5, 5)@BN(10, 10) exhibits less distortion than that in the C(5, 5)@C(10, 10) at annealing temperatures of 3500 and 4000 K. The C(5, 5)@BN(10, 10) and C(5, 5)@C(10, 10) models with different axial compressive strains are optimized using the universal force field (UFF) method. It is found that the critical buckling strains of the inner tubes in the C(5, 5)@BN(10, 10) and C(5, 5)@C(10, 10) are 12.74% and 9.1%, respectively. The critical buckling strain of the former is larger than that of the latter; although the former exhibits greater deformation and energy loss after buckling than does the latter. These phenomena are also analyzed on the basis of the radial distribution function (RDF) and system energy. The results of this study indicate that the outer tube boron nitride nanotube (BNNT) has a better protective effect on the inner tube than does the outer tube carbon nanotube (CNT) under both high-temperature and lower compressive strain conditions. In these cases, the thermal stability and compressive resistance properties of the C(5, 5)@BN(10, 10) are superior to those of the C(5, 5)@C(10, 10). PMID- 21242625 TI - Control of domain wall pinning in ferromagnetic nanowires by magnetic stray fields. AB - We have found that the depinning field of domain walls (DWs) in permalloy (Ni(81)Fe(19)) nanowires can be experimentally controlled by interactions between magnetic stray fields and artificial constrictions. A pinning geometry that consists of a notch and a nanobar is considered, where a DW traveling in the nanowire is pinned by the notch with a nanobar vertical to it. We have found that the direction of magnetization of the nanobar affects the shape and local energy minimum of the potential landscape experienced by the DW; therefore, the pinning strength strongly depends on the interaction of the magnetic stray field from the nanobar with the external pinning force of the notch. The mechanism of this pinning behavior is applied for the instant and flexible control of the pinning strength with respect to various DW motions in DW-mediated magnetic memory devices. PMID- 21242626 TI - Synthesis of few-layered graphene by ion implantation of carbon in nickel thin films. AB - The synthesis of few-layered graphene is performed by ion implantation of carbon species in thin nickel films, followed by high temperature annealing and quenching. Although ion implantation enables a precise control of the carbon content and of the uniformity of the in-plane carbon concentration in the Ni films before annealing, we observe thickness non-uniformities in the synthesized graphene layers after high temperature annealing. These non-uniformities are probably induced by the heterogeneous distribution/topography of the graphene nucleation sites on the Ni surface. Taken altogether, our results indicate that the number of graphene layers on top of Ni films is controlled by the nucleation process on the Ni surface rather than by the carbon content in the Ni film. PMID- 21242627 TI - A simulation study of irregular respiratory motion and its dosimetric impact on lung tumors. AB - This study is aimed at providing a dosimetric evaluation of the irregular motion of lung tumors due to variations in patients' respiration. Twenty-three lung cancer patients are retrospectively enrolled in this study. The motion of the patient clinical target volume is simulated and two types of irregularities are defined: characteristic and uncharacteristic motions. Characteristic irregularities are representative of random fluctuations in the observed target motion. Uncharacteristic irregular motion is classified as systematic errors in determination of the target motion during the planning session. Respiratory traces from measurement of patient abdominal motion are also used for the target motion simulations. Characteristic irregular motion was observed to cause minimal changes in target dosimetry with the largest effect of 2.5% +/- 0.9% (1sigma) reduction in the minimum target dose (D(min)) observed for targets that move 2 cm on average and exhibiting 50% amplitude variations within a session. However, uncharacteristic irregular motion introduced more drastic changes in the clinical target volume (CTV) dose; 4.1% +/- 1.7% reduction for 1 cm motion and 9.6% +/- 1.7% drop for 2 cm. In simulations with patients' abdominal motion, corresponding changes in target dosimetry were observed to be negligible (<0.1%). Only uncharacteristic irregular motion was identified as a clinically significant source of dosimetric uncertainty. PMID- 21242628 TI - Monte Carlo simulation of small electron fields collimated by the integrated photon MLC. AB - In this study, a Monte Carlo (MC)-based beam model for an ELEKTA linear accelerator was established. The beam model is based on the EGSnrc Monte Carlo code, whereby electron beams with nominal energies of 10, 12 and 15 MeV were considered. For collimation of the electron beam, only the integrated photon multi-leaf-collimators (MLCs) were used. No additional secondary or tertiary add ons like applicators, cutouts or dedicated electron MLCs were included. The source parameters of the initial electron beam were derived semi-automatically from measurements of depth-dose curves and lateral profiles in a water phantom. A routine to determine the initial electron energy spectra was developed which fits a Gaussian spectrum to the most prominent features of depth-dose curves. The comparisons of calculated and measured depth-dose curves demonstrated agreement within 1%/1 mm. The source divergence angle of initial electrons was fitted to lateral dose profiles beyond the range of electrons, where the imparted dose is mainly due to bremsstrahlung produced in the scattering foils. For accurate modelling of narrow beam segments, the influence of air density on dose calculation was studied. The air density for simulations was adjusted to local values (433 m above sea level) and compared with the standard air supplied by the ICRU data set. The results indicate that the air density is an influential parameter for dose calculations. Furthermore, the default value of the BEAMnrc parameter 'skin depth' for the boundary crossing algorithm was found to be inadequate for the modelling of small electron fields. A higher value for this parameter eliminated discrepancies in too broad dose profiles and an increased dose along the central axis. The beam model was validated with measurements, whereby an agreement mostly within 3%/3 mm was found. PMID- 21242629 TI - In vivo quantification of lead in bone with a portable x-ray fluorescence system- methodology and feasibility. AB - This study was conducted to investigate the methodology and feasibility of developing a portable x-ray fluorescence (XRF) technology to quantify lead (Pb) in bone in vivo. A portable XRF device was set up and optimal settings of voltage, current, and filter combination for bone lead quantification were selected to achieve the lowest detection limit. The minimum radiation dose delivered to the subject was calculated by Monte Carlo simulations. An ultrasound device was used to measure soft tissue thickness to account for signal attenuation, and an alternative method to obtain soft tissue thickness from the XRF spectrum was developed and shown to be equivalent to the ultrasound measurements (intraclass correlation coefficient, ICC = 0.82). We tested the correlation of in vivo bone lead concentrations between the standard KXRF technology and the portable XRF technology. There was a significant correlation between the bone lead concentrations obtained from the standard KXRF technology and those obtained from the portable XRF technology (ICC = 0.65). The detection limit for the portable XRF device was about 8.4 ppm with 2 mm soft tissue thickness. The entrance skin dose delivered to the human subject was about 13 mSv and the total body effective dose was about 1.5 uSv and should pose minimal radiation risk. In conclusion, portable XRF technology can be used for in vivo bone lead measurement with sensitivity comparable to the KXRF technology and good correlation with KXRF measurements. PMID- 21242630 TI - Development of a platform for co-registered ultrasound and MR contrast imaging in vivo. AB - Imaging of the microvasculature is often performed using contrast agents in combination with either ultrasound (US) or magnetic resonance (MR) imaging. Contrast agents are used to enhance medical imaging by highlighting microvascular properties and function. Dynamic signal changes arising from the passage of contrast agents through the microvasculature can be used to characterize different pathologies; however, comparisons across modalities are difficult due to differences in the interactions of contrast agents with the microvasculature. Better knowledge of the relationship of contrast enhancement patterns with both modalities could enable better characterization of tissue microvasculature. We developed a co-registration platform for multi-modal US and MR imaging using clinical imaging systems in order to study the relationship between US and MR contrast enhancement. A preliminary validation study was performed in phantoms to determine the registration accuracy of the platform. In phantoms, the in-plane registration accuracy was measured to be 0.2 +/- 0.2 and 0.3 +/- 0.2 mm, in the lateral and axial directions, respectively. The out-of-plane registration accuracy was estimated to be 0.5 mm +/-0.1. Co-registered US and MR imaging was performed in a rabbit model to evaluate contrast kinetics in different tissue types after bolus injections of US and MR contrast agents. The arrival time of the contrast agent in the plane of imaging was relatively similar for both modalities. We studied three different tissue types: muscle, large vessels and fat. In US, the temporal kinetics of signal enhancement were not strongly dependent on tissue type. In MR, however, due to the different amounts of agent extravasation in each tissue type, tissue-specific contrast kinetics were observed. This study demonstrates the feasibility of performing in vivo co registered contrast US and MR imaging to study the relationships of the enhancement patterns with each modality. PMID- 21242631 TI - Effects of increased collagen-matrix density on the mechanical properties and in vivo absorbability of hydroxyapatite-collagen composites as artificial bone materials. AB - The aim of this study was to evaluate the effects of increased collagen-matrix density on the mechanical properties and in vivo absorbability of porous hydroxyapatite (HAp)-collagen composites as artificial bone materials. Seven types of porous HAp-collagen composites were prepared from HAp nanocrystals and dense collagen fibrils. Their densities and HAp/collagen weight ratios ranged from 122 to 331 mg cm-3 and from 20/80 to 80/20, respectively. The flexural modulus and strength increased with an increase in density, reaching 2.46 +/- 0.48 and 0.651 +/- 0.103 MPa, respectively. The porous composites with a higher collagen-matrix density exhibited much higher mechanical properties at the same densities, suggesting that increasing the collagen-matrix density is an effective way of improving the mechanical properties. It was also suggested that other structural factors in addition to collagen-matrix density are required to achieve bone-like mechanical properties. The in vivo absorbability of the composites was investigated in bone defects of rabbit femurs, demonstrating that the absorption rate decreased with increases in the composite density. An exhaustive increase in density is probably limited by decreases in absorbability as artificial bones. PMID- 21242632 TI - Surfactant-controlled morphology and magnetic property of manganese ferrite nanocrystal contrast agent. AB - MnFe(2)O(4) nanocrystals (NCs) coated with three different surfactants (oleic acid, oleylamine or 1,2-hexadecanediol) and their mixtures, with sizes in range 6 12 nm, were synthesized by high-temperature decomposition of organometallic precursors. The effects of morphology and surface chemistry of MnFe(2)O(4) NCs on the magnetic properties were systematically investigated by comparing their saturation magnetization values and their capability to improve the negative contrast for magnetic resonance imaging (MRI) after converting the hydrophobic NCs to hydrophilic ones by a ligand exchange protocol. An important finding is that the magnetization values and proton relaxivity rates of MnFe(2)O(4) NCs are strongly dependent on the size and surface state of the particles that covalently bonded with different hydrophobic ligands before ligand exchange. In particular, monodisperse cubic MnFe(2)O(4) NCs could be obtained when oleylamine and 1,2 hexadecanediol were used as mixed stabilizers, and showed excellent morphology and magnetic properties. Furthermore, the low cytotoxicity and good cell uptake MR imaging of the dopamine capped MnFe(2)O(4) NCs make them promising candidates for use as bio-imaging probes. PMID- 21242633 TI - Highly sensitive hydrogen detection of catalyst-free ZnO nanorod networks suspended by lithography-assisted growth. AB - We have successfully demonstrated a ZnO nanorod-based 3D nanostructure to show a high sensitivity and very fast response/recovery to hydrogen gas. ZnO nanorods have been synthesized selectively over the pre-defined area at relatively low temperature using a simple self-catalytic solution process assisted by a lithographic method. The conductance of the ZnO nanorod device varies significantly as the concentration of the hydrogen is changed without any additive metal catalyst, revealing a high sensitivity to hydrogen gas. Its superior performance can be explained by the porous structure of its three dimensional network and the enhanced surface reaction of the hydrogen molecules with the oxygen defects resulting from a high surface-to-volume ratio. It was found that the change of conductance follows a power law depending on the hydrogen concentration. A Langmuir isotherm following an ideal power law and a cross-over behavior of the activation energy with respect to hydrogen concentration were observed. This is a very novel and intriguing phenomenon on nanostructured materials, which suggests competitive surface reactions in ZnO nanorod gas sensors. PMID- 21242634 TI - Metal ion (silver, cadmium and zinc ions) modified CdS quantum dots for ultrasensitive copper ion sensing. AB - Metal ion (Ag(+), Cd(2+), Zn(2+)) modified CdS quantum dots (QDs) were synthesized and used for Cu(2+) sensing. Modification by these metal ions could enhance the PL intensity of CdS QDs with the extent of the PL enhancement being related to the concentration of the metal ions. Different metal ion (Ag(+), Cd(2+), Zn(2+)) modified CdS QDs also showed different analytical characteristics for Cu(2+) sensing. In particular, Ag( + ) modified CdS QDs showed greatly enhanced sensitivity for Cu(2+) determination than did the unmodified CdS QDs. A limit of detection (LOD) of 2.0 * 10(-10) M was obtained for Ag(+) modified CdS QDs, which is the lowest LOD obtained using QDs as fluorescence probes for Cu(2+) sensing. This study demonstrates the important role of surface state of QDs in fluorescence sensing. PMID- 21242635 TI - Indium tin oxide nanopillar electrodes in polymer/fullerene solar cells. AB - Using high surface area nanostructured electrodes in organic photovoltaic (OPV) devices is a route to enhanced power conversion efficiency. In this paper, indium tin oxide (ITO) and hybrid ITO/SiO(2) nanopillars are employed as three dimensional high surface area transparent electrodes in OPVs. The nanopillar arrays are fabricated via glancing angle deposition (GLAD) and electrochemically modified with nanofibrous PEDOT:PSS (poly(3,4-ethylenedioxythiophene):poly(p styrenesulfonate)). The structures are found to have increased surface area as characterized by porosimetry. When applied as anodes in polymer/fullerene OPVs (architecture: commercial ITO/GLAD ITO/PEDOT:PSS/P3HT:PCBM/Al, where P3HT is 2,5 diyl-poly(3-hexylthiophene) and PCBM is [6,6]-phenyl-C(61)-butyric acid methyl ester), the air-processed solar cells incorporating high surface area, PEDOT:PSS modified ITO nanoelectrode arrays operate with improved performance relative to devices processed identically on unstructured, commercial ITO substrates. The resulting power conversion efficiency is 2.2% which is a third greater than for devices prepared on commercial ITO. To further refine the structure, insulating SiO(2) caps are added above the GLAD ITO nanopillars to produce a hybrid ITO/SiO(2) nanoelectrode. OPV devices based on this system show reduced electrical shorting and series resistance, and as a consequence, a further improved power conversion efficiency of 2.5% is recorded. PMID- 21242636 TI - Combating torture with medical evidence: the use of medical evidence and expert opinions in international and regional human rights tribunals. PMID- 21242638 TI - Epithelioid sarcoma of the orbit. AB - Epithelioid sarcoma is an aggressive and rare malignancy first recognized by Enzinger in 1970. It is known most commonly to affect the distal upper extremities in young adults. The classical "distal" form has a male predominance and can also involve other less frequent sites including lower extremities, proximal upper extremities, and the trunk. The "proximal" variant of this tumor is deep seated, tends to occur in older patients and predominantly develops in the pelvis, perineum, and genital tract. In the orbit, only a single report of two cases, which had a typical histopathologic appearance, has been previously published. We present the third case of orbital primary epithelioid sarcoma. PMID- 21242637 TI - Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young. AB - The term "maturity onset diabetes of the young" (MODY) describes a heterogeneous group of monogenic diabetes of which hepatic nuclear factor-1 alpha (HNF-1alpha) MODY is the most common. Patients with HNF-1alpha mutations typically present after puberty, and oral sulfonylureas (SU) have been shown to be effective in adults with this condition. A 7-year-old boy presented with asymptomatic hyperglycemia ranging between 6.2 and 10.1 mmol/L and glycosuria for nearly a year. The child's initial HbA 1c was 6.9% and the pancreatic Islet cell autoantibodies were negative. His response to the oral glucose tolerance test (OGTT) showed a large increment of glucose from basal level of 7.7 to 21.1 mmol/L in 120 min. The mild presentation, family history, and negative autoantibodies were suggestive of HNF-1alpha MODY, which was confirmed by mutation analysis. Initial management with diet alone was not sufficient, but he responded well to 20 mg oral gliclazide once a day with an improvement of HbA 1C from 7.2% to 6.5% within 3 months of treatment. The case is an illustration of the clinical utility of molecular genetic tests in the management of childhood diabetes. PMID- 21242639 TI - Paget disease of the bone: does it exist in Saudi Arabia? AB - Paget disease of the bone is a chronic disease characterized by accelerated bone turnover with abnormal repair leading to expansion, pain and deformities. The disease is common in the West, but little if any information is available on its existence in the Arab world, including Saudi Arabia. We present four cases of Saudi patients with Paget disease with variable presentations. The first case, a 63-year-old woman with a history of papillary thyroid cancer, presented with bone, shoulder and chest wall pain and foci of uptake in the ribs and skull that were thought to be metastases, indicating the possibility of diagnostic difficulty in a patient with history of malignancy. Bone biopsy confirmed the diagnosis of Paget disease. The second case was a 47-year-old asymptomatic woman with an elevated alkaline phosphatase of 427 U/L, a common presentation but at an unusual age. Plain x-rays and bone scan confirmed the diagnosis. The third case was a 43-year-old man who presented with hearing impairment and right knee osteoarthritis, unusual presentations at a young age leading to a delay in diagnosis. The fourth case was a 45-year-old man who presented with sacroiliac pain and normal biochemical values, including a normal alkaline phosphatase. Bone biopsy unexpectedly revealed features of Paget disease, which evolved over time into a classical form. A common feature in all except the first case was the relatively young age. Paget disease does exist in Saudi Arabia, and it should be considered in the differential diagnosis of similar cases. PMID- 21242640 TI - Chronic spontaneous cervicothoracic epidural hematoma in an 8-month-old infant. AB - Spontaneous spinal epidural hematoma is an uncommon cause of cord compression in children, especially in infants. An 8-month-old infant was admitted to our hospital for a 40-day history of paraparesis in the lower extremities. This rapidly progressed to paraparesis with an inability to move the lower extremities. MRI of the cervicothoracic spine revealed an epidural mass with compression of the spinal cord. The infant underwent C7-T3 total laminectomies. The pathology and postoperative MRI confirmed spinal epidural hematoma from a vascular malformation. We present the case to highlight the significance of recognizing this chronic spontaneous spinal epidural hematoma and discuss the diagnosis, treatment options and prognosis. PMID- 21242641 TI - Soft tissue mass of the chest wall as the sole manifestation of brucellosis in a 7-year-old boy. AB - We report the case of a child who presented with a subcutaneous mass on the left side of the chest wall of one month's duration. The mass was painful and increasing in size over time. He had a history of weight loss and a decrease in appetite, but no history of fever or trauma. He had ingested raw camel milk, but had no history of contact with animals. He was diagnosed by the standard tube agglutination titer and tissue culture for brucellosis, treated with surgery and three months of antibrucella antibiotics. The report includes a brief review of the current pediatric literature to familiarize pediatricians with this uncommon presentation. PMID- 21242642 TI - Synergistic effect of combined HMG-CoA reductase inhibitor and angiotensin-II receptor blocker therapy in patients with chronic heart failure: the HF-COSTAR trial. AB - BACKGROUND: It is known that HMG-CoA reductase inhibitors (statins) may have a therapeutic benefit in patients with heart failure (HF). However, no studies have yet evaluated the possible interaction of statins and angiotensin-II receptor blockers (ARBs) on left ventricular (LV) function in patients with HF. We hypothesized that statins might alter the effect of ARBs on cardiac function in patients with HF. METHODS AND RESULTS: We prospectively randomized patients with chronic HF who received the ARB, losartan (LOS group), or the statin, simvastatin (SIM), in combination with LOS (SIM+LOS group) at our hospitals and assessed before and after treatment for 6 months. Although no significant improvement of HF symptoms as evaluated by the New York Heart Association (NYHA) classification was observed in the LOS group, HF symptoms in the SIM+LOS group significantly improved. The percent increase of LV ejection fraction after treatment in the SIM+LOS group was significantly larger than in the LOS group. Furthermore, the plasma brain natriuretic peptide level was significantly lower after treatment in the SIM+LOS group than in the LOS group. CONCLUSIONS: Combined statin and ARB therapy significantly improves both symptoms and LV function over time in patients with HF. Thus, the combination of an ARB with a statin may be a useful therapeutic strategy for HF. PMID- 21242643 TI - Anatomical variants of coronary venous system on cardiac computed tomography. AB - BACKGROUND: In a few studies, huge anatomical variability of coronary venous system (CVS) has been documented without analysis of its variants. The aim of the present study was to evaluate anatomical variants of CVS in multislice computed tomography (MSCT). METHODS AND RESULTS: In 199 patients (114 males, age 56.6+/ 11.5 years), a 64-slice computed tomography (Aquilion 64) was performed due to coronary artery disease suspicion. A scan with electrocardiogram-gating was performed using a slice thickness of 0.5mm during a breath-hold. In each case, 3D volume rendering and 2D multi-planar reformatting reconstructions of CVS were created (Vitrea 2). As target veins for cardiac resynchronization therapy (CRT), the posterolateral, lateral and anterolateral veins were recognized. Coronary sinus was well visualized in all cases. A total of 27 anatomical variants of CVS were identified, 9 of them are most common (in 148/199 cases; 74.4%). In 4 out of these 9 variants, a single coronary vein in the target area for CRT appeared, 2 target veins in 3 variants and 3 veins in 2 variants occurred. In 6 cases (2 seldom variants-3.0%) no veins in the target area were identified. CONCLUSIONS: In the majority of the examined patients, at least one vein in the target area for CRT was observed. Anatomical variability of CVS strengthen the potential role of MSCT in CVS visualization before CRT implantation. PMID- 21242644 TI - The impact of hyperuricemia on in-hospital mortality and incidence of acute kidney injury in patients undergoing percutaneous coronary intervention. AB - BACKGROUND: There is very little information about the relationship between hyperuricemia, acute kidney injury (AKI) and in-hospital mortality. METHODS AND RESULTS: With a retrospective analysis of the medical records, 1,247 patients who had percutaneous coronary intervention (PCI) were investigated. AKI was defined as an increase in serum creatinine of >=0.5mg/dl or >=50% over baseline within 7 days of PCI. The association of AKI with clinical, biochemical and procedural variables were examined. In addition, the association of hyperuricemia with in hospital mortality was also examined. Of the 1,247 patients in the study population, 51 (4.1%) experienced AKI after PCI, 15 of whom required hemodialysis. In-hospital mortality occurred in 1.6% (20 of 1,247) in 19.6% (10 of 51) of AKI individuals, and 0.8% (10 of 1,186) of the non-AKI participants (odd ratios, 28.927; 95% confidence intervals, 11.411-73.328; P<0.001). In our study, the most powerful predictors of these variables were acute myocardial infarction, baseline estimated glomerular filtration rate (eGFR) <60 ml.min( 1).1.73 m(-2), diabetics mellitus, anemia and hyperuricemia. Notably, the incidence of AKI after PCI markedly increased in diabetic or hyperuricemic patients with a baseline eGFR of <60 ml.min(-1).1.73 m(-2). CONCLUSIONS: It is clear that AKI develops due to multiple risk factors. Our results indicate that hyperuricemia is independently associated with an increased risk of in-hospital mortality and AKI in patients treated with PCI. PMID- 21242645 TI - What can the volume of distribution of a macromolecular drugs indicate? PMID- 21242646 TI - GATA3 abnormalities in six patients with HDR syndrome. AB - GATA3 mutations cause HDR (hypoparathyroidism, sensorineural deafness, and renal dysplasia) syndrome and, consistent with the presence of the second DiGeorge syndrome locus (DGS2) proximal to GATA3, distal 10p deletions often leads to HDR and DiGeorge syndromes. Here, we report on six Japanese patients with GATA3 abnormalities. Cases 1-5 had a normal karyotype, and case 6 had a 46,XX,del(10)(p15) karyotype. Cases 1-6 had two or three of the HDR triad features. Case 6 had no DiGeorge syndrome phenotype except for hypoparathyroidism common to HDR and DiGeorge syndromes. Mutation analysis showed heterozygous GATA3 mutations in cases 1-5, i.e., c.404-405insC (p.P135fsX303) in case 1, c.700T>C & c.708-709insC (p.F234L & p.S237fsX303) on the same allele in case 2, c.737 738insG (p.G246fsX303) in case 3, c.824G>T (p.W275L) in case 4, and IVS5+1G>C (splice error) in case 5. Deletion analysis of chromosome 10p revealed loss of GATA3 and preservation of D10S547 in case 6. The results are consistent with the previous finding that GATA3 mutations are usually identified in patients with two or three of the HDR triad features, and provide supportive data for the mapping of DGS2 in the region proximal to D10S547. PMID- 21242647 TI - Matrix metalloproteinase inhibition impairs murine adipose tissue development independently of leptin. AB - Administration of Tolylsam, a MMP inhibitor with relative specificity for gelatinases, at a dose of 100 mg/kg/day to leptin-deficient (ob/ob) mice kept on high fat diet for 15 weeks, was associated with significantly reduced weight gain as compared to controls (p < 0.0005), resulting in lower body weight (p < 0.0005) at the end of the experiments. Food intake, physical activity and body temperature were not affected. Subcutaneous (SC) (2.9 +/- 0.1g vs. 3.4 +/- 0.2g in controls; p < 0.05) and gonadal (GON) (3.4 +/- 0.1g vs. 3.7 +/- 0.1g in controls; p = NS) fat mass were reduced by Tolylsam treatment. Reduced MMP-2 (gelatinase A) activity in adipose tissue extracts was confirmed by zymography. Mild adipocyte hypotrophy was observed in treated SC and GON adipose tissues. Blood vessel density was significantly reduced in Tolylsam treated SC (p < 0.05) and GON (p < 0.005) adipose tissues. Sirius red staining revealed comparable collagen content in both SC and GON fat of treated mice, whereas collagen disorganization (ratio thick/thin fibers) was also similar. Thus, gelatinase inhibition in mice with leptin deficiency resulted in lower body and fat pad weights, associated with mild adipocyte hypotrophy. This indicates that MMP inhibition may impair adipose tissue development independently of leptin. PMID- 21242648 TI - Association between bone mineral density and metabolic syndrome in pre- and postmenopausal women. AB - Metabolic syndrome (MS) has 2 conflicting factors: obesity known to be protective against osteoporosis and an inflammation that activates bone resorption. The aim of this study was to evaluate the difference of bone mineral density(BMD) in women with or without MS according to menopausal state. This is a cross-sectional study of 2,265 women(1,234-premenopausal, 931-postmenopausal) aged over 20 years who visited the Health Promotion Center from January 2006 to December 2009. We measured BMD at the lumbar spine and femoral neck. MS was defined according to the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) criteria. The prevalence of MS was 5.5% in the premenopausal group and 13.5% in the postmenopausal group. In the postmenopausal group, C-reactive protein (CRP) was significantly higher in subjects with MS than those without MS, but it was not in the premenopausal group. In the postmenopausal group, women with MS had a lower BMD at the lumbar spine and femoral neck before or after adjustment. In the premenopausal group, women with MS had a lower BMD at the lumbar spine, but not at the femoral neck. In stepwise linear regression analysis, predictive variables for BMD of the lumbar spine were systolic blood pressure in the premenopausal group and HDL-cholesterol and diastolic blood pressure (DBP) in the postmenopausal group. The predictive variables for BMD of the femoral neck were DBP and waist circumference in the premenopausal group and CRP and DBP in the postmenopausal group. Inflammation might have a more important role in BMD than obesity in the postmenopausal women. PMID- 21242649 TI - Williams syndrome is an epigenome-regulator disease. AB - A human multi-protein complex (WINAC), composed of SWI/SNF components and DNA replication-related factors, that directly interacts with the vitamin D receptor (VDR) through the Williams syndrome transcription factor (WSTF), was identified with an ATP-dependent chromatin remodeling activity. This novel ATP-dependent chromatin remodeling complex facilitates VDR-mediated transrepression as well as transactivation with its ATP-dependent chromatin remodeling activity and promoter targeting property for the activator to access to the DNA. It also suggested that in this complex, WSTF serves as a signaling sensor to receive intra-cellular singalings to switch the activity of WINAC as well as WICH, another ATP-dependent chromatin remodeling complex containing hSNF2h. By making WSTF-deficient mice, some of the heart defects as well as abnormal calcium metabolism observed in Williams syndrome are attributed to the abnormal chromatin remodeling activity caused by WSTF deficiency. Thus, we would propose to designate Williams syndrome as an epigenome-regulator disease. PMID- 21242650 TI - Identification of chromosome 15q26 terminal deletion with telomere sequences and its bearing on genotype-phenotype analysis. AB - We report a de novo heterozygous 5,013,940 bp terminal deletion of chromosome 15q26 in a 13 9/12 -year-old Japanese girl with short stature (-3.9 SD), mild mental retardation, and ventricular septal defect (VSD). This terminal deletion involved IGF1R but not NR2F2, and was associated with an addition of telomere repeat sequences (TTAGGG) at the end of the truncated chromosome. The results provide further support for the notion that terminal deletions are healed by de novo addition of telomere sequences essential for chromosome stability and DNA replication. Furthermore, while growth failure and mental retardation are primarily explained by loss of IGF1R, the occurrence of VSD might suggest the existence of a cardiac anomaly gene, other than the candidate cardiac anomaly gene NR2F2, in the deleted region. PMID- 21242651 TI - Marked regression of aortic plaque by intensive cholesterol-lowering therapy. AB - A 65-year-old man with rheumatic combined valvular heart disease showed a persistent fever after cardiac catheterization. He was diagnosed with cholesterol embolism due to multiple mobile plaques in the descending thoracic aorta by transesophageal echocardiography (TEE) along with persistent eosinophilia, deteriorating renal function, and blue toe sign. He was treated with intensive cholesterol-lowering therapy for 3 years, resulting in marked regression of the aortic plaque on TEE. PMID- 21242652 TI - Attenuation of meal-induced inflammatory and thrombotic responses in overweight men and women after 6-week daily strawberry (Fragaria) intake. A randomized placebo-controlled trial. AB - AIM: A pro-thrombotic, pro-inflammatory diet can play a causative role in atherosclerotic-cardiovascular diseases. Dietary intervention studies provide insight into their pathophysiological manifestations and opportunities for prevention and management. We previously showed in an acute-meal setting that a beverage containing polyphenolic- and antioxidant-rich strawberry (Fragaria) vs placebo attenuated postprandial (fed-state) increases in biomarkers of oxidative and inflammatory stress, and insulin concentrations, induced by a high carbohydrate/fat (HCF) meal. In the present study, we aimed to extend our findings and investigate hypotheses related to the effects of chronic/6-week (wk) strawberry consumption on HCF meal-induced increases in glucose, insulin, and indicators of inflammation and hemostasis. METHODS: In a crossover design, 14 women and 10 men (mean age, BMI: 50.9+/-15 years, 29.2+/-2.3 kg/m(2), respectively), were randomized to a 6-wk strawberry or placebo beverage followed by an HCF meal with assessments for 6-hours (h) postprandially. RESULTS: HCF meal responses after 6-wk strawberry beverage showed significantly attenuated postprandial PAI-1 concentrations compared to the placebo (p =0.002); the difference was most notable at 6 h. The IL-1 beta response was attenuated with strawberry compared to the placebo (p =0.05). IL-6 attenuation was apparent but non-significant; IL-6 rose significantly from baseline to 6 h after the HCF meal following a placebo (p <=0.01), although it remained relatively flat following the strawberry beverage from fasting to 6 h. No significant treatment-related differences were apparent for platelet aggregation, hsCRP, TNF-alpha, insulin, or glucose. CONCLUSION: These data are the first to suggest that regular consumption of strawberry, a polyphenolic- and antioxidant-rich fruit, may provide protection from HCF meal-induced increases in fibrinolytic and inflammatory factors in at risk men and women. PMID- 21242653 TI - Cloned porcine embryos can maintain developmental ability after cryopreservation at the morula stage. AB - The aim of the present study was to clarify the overall efficiency of porcine somatic cell nuclear transfer (SCNT) by incorporating cryopreservation of the cloned embryos before transfer. The SCNT embryos reconstructed with preadipocytes and in vitro-matured (IVM) oocytes were cultured to harvest morula stage embryos; they were then subjected to delipation (removal of cytoplasmic lipid droplets) and vitrification. After warming and culture, the embryos developing to blastocysts were transferred to recipients to obtain cloned piglets. From 372 reconstructed embryos, 188 (50.5%) reached the morula stage and 117 (31.5%) developed to blastocysts after vitrification. Transfer of 98 (26.3%) morphologically normal blastocysts gave rise to 6 (1.6%) piglets, including 1 stillborn. The efficiency of the cloned piglet production was comparable with that obtained using SCNT embryos without cryopreservation (2.7%, 17/635). Here, we demonstrate that porcine somatic cell cloning can be performed without a significant reduction in efficiency even when the SCNT embryos are cryopreserved before transfer. PMID- 21242654 TI - Effects of estrogen on growth hormone pulsatility in peripheral blood and neuropeptide profiles in the cerebrospinal fluid of goats. AB - We previously reported that growth hormone (GH) pulses were negatively associated with neuropeptide Y (NPY) profiles in cerebrospinal fluid (CSF) of the third ventricle of Shiba goats. In addition, while most GH pulses were coincident with GH-releasing hormone (GHRH) pulses, there was no correlation between GH and somatostatin (SRIF) levels. The present study was performed to elucidate the relationship between GH pulses and these neuropeptide levels in CSF when estradiol (1.0 mg/head) was subcutaneously administered to ovariectomized goats. CSF and plasma samples were collected every 15 min for 18 h (from 6 h before to 12 h after injection). GH levels in peripheral blood and GHRH, SRIF and NPY levels in CSF were measured by radioimmunoassay. Pulse/trough characteristics and correlations were assessed by the ULTRA algorithm and cross-correlation analysis. Before estradiol was injected, significant coincidence was found between GHRH pulses and GH pulses, and negative coincidence was found between NPY troughs and GH pulses. Six to 12 h after estradiol injection, the amplitude and area under the curve (AUC) of the GH pulses were markedly increased. The duration and AUC of the GHRH pulses in the CSF were also increased, and stronger synchrony of GHRH with GH was observed. In contrast, the baseline of NPY was significantly decreased, and the negative correlation between the GH pulses and NPY troughs disappeared. The parameters of SRIF troughs were not clearly changed. These observations suggest that estrogen enhances the pattern of secretion of GH in the goat via enhancement of GHRH pulses and decrease of NPY levels. PMID- 21242655 TI - Comparison of plasma concentrations of estradiol-17beta and progesterone, and conception in dairy cows with cystic ovarian diseases between Ovsynch and Ovsynch plus CIDR timed AI protocols. AB - The objectives of this study were 1) to determine the effects of adding a CIDR to the Ovsynch protocol on plasma concentrations of estradiol-17beta and progesterone and conception in dairy cows with cystic ovarian diseases and 2) to examine associations among the estradiol-17beta and progesterone concentrations and conception. Cows were diagnosed as having cystic ovarian diseases if they were found to have a cystic follicle (diameter >=25 mm) without a corpus luteum by two palpations per rectum with an interval for 7 to 14 days. They were treated with either the Ovsynch (GnRH on Day 0, PGF(2alpha) on Day 7 and GnRH on Day 9, with AI on Day 10; n=15) or Ovsynch+CIDR protocol (Ovsynch protocol plus a CIDR from Day 0 to Day 7; n=23). Plasma estradiol-17beta concentrations were determined on Days 0, 7 and 9, and plasma progesterone concentrations were determined on Days 0, 7, 9 and 17. The plasma estradiol-17beta and progesterone concentrations at all of the days examined and conception rates did not differ significantly between the two timed AI protocols. The progesterone concentrations on Day 17 and conception rates were lower (P<0.05) for cows with low concentrations of estradiol-17beta (<2 pg/ml) on Day 9 than for cows with high concentrations of estradiol-17beta (>=2 pg/ml). The present study suggests that, in dairy cows with cystic ovarian diseases, addition of a CIDR to the Ovsynch protocol had no remarkable effects on plasma estradiol-17beta and progesterone concentrations during and after the treatments or on conception after timed AI. This study indicates that the low plasma estradiol-17beta concentration at the second administration of GnRH in the protocols can be a predictor for impaired luteal formation and lower likelihood of pregnancy in dairy cows with cystic ovarian diseases. PMID- 21242656 TI - Fecal progestagens to detect and monitor pregnancy in captive female cheetahs (Acinonyx jubatus). AB - The purposes of the present study were to establish a noninvasive monitoring assay of fecal progestagen measurement to detect pregnancy and to identify the components of fecal progestagens in early, middle and late pregnancy in cheetahs. Feces were collected from 7 female cheetahs and analyzed from 30 days before the last copulation to parturition in 9 pregnancies. Blood was collected from one cheetah. Fecal progestagen and serum progesterone concentrations were determined by enzyme immunoassay (EIA). The profiles of the fecal progestagen concentrations were similar to the serum progesterone profile. Fecal progestagen and serum progesterone concentrations remained at the baseline until copulation. In the mean fecal progestagen profile during pregnancy (92.8 +/- 0.4 days; from the last copulation to parturition), the concentrations increased 3-4 days after the last copulation and remained high until parturition. To investigate changes in the components of progestagen metabolites in the tripartite periods of gestation, fecal progestagens were analyzed by HPLC-EIA. Marked immunoreactive peaks consistent with 5alpha-pregnan-3alpha/beta-ol-20-one and 5alpha-pregnan-3,20 dione and small peaks consistent with 5beta-pregnan-3alpha/beta-ol-20-one were detected. There were no distinct difference in the components of progestagens among the first, second and third trimesters of pregnancy. The hormone assay, as an indicator of fecal 5alpha-reduced pregnanes, is useful for detecting pregnancy and monitoring pregnant luteal activity in cheetahs. PMID- 21242657 TI - Destabilization of coxsackievirus b3 genome integrated with enhanced green fluorescent protein gene. AB - AIMS: To evaluate the stability of coxsackievirus B (CVB) genome integrated with the enhanced green fluorescent protein gene (egfp) and provide valuable information for the use of the recombinant CVB variant. METHODS: A CVB3 variant expressing eGFP was constructed by insertion of the egfp open-reading frame (ORF) at the 5' end of CVB3 ORF. The recombinant virus CVB3-eGFP was serially passaged in HeLa cells. The deletions in the CVB3-eGFP genome around egfp were examined by reverse transcription polymerase chain reaction and sequencing. RESULTS: Genomic deletions of CVB3-eGFP could be observed as early as the 2nd passage. Sequencing showed that the genomic deletions caused either viral ORF shifts or partial deletions of the viral VP4 coding sequence. The 6th passage of CVB3-eGFP was checked by plaque assay for eGFP expression. All plaque-like foci showed eGFP expression. eGFP expression was also viewed in HeLa cells infected with plaque forming viruses. CONCLUSIONS: The insertion of egfp destabilized the CVB3 genome. The genomic deletions led to lethal mutations because of the termination of viral protein synthesis due to viral ORF shift and loss of partial viral gene. These findings imply that experimental data based on CVB integrated with the reporter gene should be interpreted with caution. PMID- 21242658 TI - Replicative activity of hepatitis B virus is negatively associated with methylation of covalently closed circular DNA in advanced hepatitis B virus infection. AB - OBJECTIVES: The aim of this study was to examine the methylation status of intrahepatic hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) and to elucidate the possible relationship between the cccDNA methylation and viral replicative activity in patients with HBV-related liver cirrhosis (HBV-LC). METHODS: The methylation status of HBV cccDNA was investigated by bisulfite sequencing in nonneoplastic tissues from 12 patients with HBV-LC who underwent surgical resection for combined hepatocellular carcinoma. Clinical, biochemical and virologic factors were evaluated with respect to the degrees of cccDNA methylation. We also examined the effect of methylation of cccDNA on viral transcription by an in vitro transcription assay. RESULTS: Variable degrees of CpG methylation were present in the HBV cccDNA from patients with HBV-LC. Old age, low serum HBV DNA levels and low virion productivity were significantly associated with elevated cccDNA methylation. Virion productivity of cccDNA was also lower in HepAD38 cells with a higher degree of cccDNA methylation. In vitro transcription assays showed that the transcriptional activity of HBV cccDNA was suppressed by increased methylation of cccDNA. CONCLUSIONS: Increased CpG methylation of cccDNA is associated with old age, low serum HBV DNA levels and suppressed replicative activity in HBV-LC. PMID- 21242659 TI - Interferon alone or combined with ribavirin for acute prolonged infection with hepatitis C virus in chimpanzees. AB - Infection with hepatitis C virus (HCV) persisted for longer than 29 weeks in 2 chimpanzees after they had been inoculated with it experimentally. One of them (C 210) received short-term subcutaneous interferon-alpha (IFN-alpha) 6 million units (MU) daily for 7 days at week 29. He cleared HCV RNA from the serum and remained negative for it during 25 weeks after the withdrawal of IFN. The other (C-224) did not respond to 2 courses of a short-term IFN monotherapy at weeks 20 and 23. Twelve weeks thereafter, he received IFN-alpha 3 MU daily for 2 weeks and then 3 times a week for 14 weeks combined with oral ribavirin 600 mg daily during 16 weeks. HCV RNA disappeared from the serum and stayed negative until the last follow-up 24 weeks after the completion of combination therapy. PMID- 21242660 TI - Numerical diagnoses of superinfection in chronic hepatitis B viral dynamics. AB - OBJECTIVES: Fluctuation profile has been observed in chronic hepatitis B patients who are untreated or interrupt therapy. A mathematical model and its parameters could be used to diagnose the assumption of superinfection of hepatocytes and to understand the causes for the spontaneous fluctuation pattern of HBV DNA loads in chronically infected patients. METHODS: We propose a new conceptual model in terms of chemical kinetics, which is based on the assumption that hepatocytes can be superinfected with hepatitis B virus (HBV). Minimizing the sum of squares of the deviations, we fitted the model to the HBV DNA trajectories from clinical data and obtained the model parameters. RESULTS: The model with the fitted parameters can capture the tendency of HBV DNA trajectories. The mean value of the fitted number of virions that enter a single hepatocyte at the beginning stage of an invasion is 2.10 +/- 0.18. The dynamics patterns may correlate with the clinical phenotypes of patients and the value of clinical parameters, such as alpha-fetoprotein, hepatitis B e-antigen, hepatitis B e-antibody, total bilirubin and alanine transaminase. CONCLUSIONS: The superinfection scenario is possible in HBV infection and it may induce HBV DNA fluctuation in the host. PMID- 21242661 TI - Development of an indirect ELISA with artificially synthesized N protein of PPR virus. AB - The full-length gene encoding the nucleocapsid (N) protein of the virus (PPRV) responsible for an outbreak of peste des petits ruminants in Tibet in 2007 was synthesized in two stages using overlapping PCR without the need for viral genomic cDNA as template. The full-length N gene was successfully expressed in Escherichia coli, and the purified gene product bound to monoclonal antibody raised against PPRV N protein. Furthermore, it was able to replace recombinant B N antigen as the coating antigen in a commercial ELISA kit prepared with another PPRV strain. Recombinant protein was employed as the coating antigen to develop an indirect ELISA for PPRV antibody detection in the sera of infected small ruminants. Antibody detection was optimal at a 1:200 serum dilution and an antigen concentration of 3.2 MUg/ml, and the positive threshold (cutoff) value of the assay was 2.18. Analysis of 697 serum samples revealed the sensitivity and specificity of the indirect ELISA to be 96.7 and 96.1%, respectively, compared with a commercially available ELISA test. PMID- 21242662 TI - Comparative proteome analysis of silkworm in its susceptibility and resistance responses to Bombyx mori densonucleosis virus. AB - Bombyx mori densonucleosis virus (BmDNV) is one of the most disastrous viruses in cocoon production. Silkworm resistance to BmDNV has been examined previously using a number of traditional biochemical and molecular techniques. In this study, a near isogenic line, BC(6), was constructed to eliminate the difference in inherited background, which has 99.9% identity with the susceptible strain but carries a resistant gene. We utilized a proteomic approach involving two dimensional differential gel electrophoresis and mass spectrometry to examine changes in the midgut proteins from the susceptible and resistant silkworm larvae infected with BmDNV. The protein profiles were compared and 9 differentially expressed proteins were identified by mass spectrometry. In the resistant strains, the heat-shock 70-kDa protein cognate, cytochrome P450, vacuolar ATP synthase subunit B, arginine kinase, vacuolar ATP synthase subunit D and glutathione S-transferase sigma were strongly upregulated and alpha-tubulin was downregulated. Our results imply that these upregulated genes and the downregulated genes might be involved in B. mori immune responses against BmDNV-Z infection. PMID- 21242663 TI - Occurrence of human cytomegalovirus glycoprotein B genotypes in immunocompetent and immunosuppressed Taiwanese patients. AB - OBJECTIVES: To investigate the differences of genotypic distributions among isolates between immunosuppressed and immunocompetent patients in a Taiwanese population. METHODS: Human cytomegalovirus (HCMV) isolates from 76 patients with adequate chart data were analyzed. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to define gB genotypes which include gB1 to gB4. The clinical data of the 76 patients were retrospectively collected by chart review and classified into an immunosuppressed (n = 32) or immunocompetent (n = 44) group. RESULTS: Among the 32 immunosuppressed patients, the most commonly identified HCMV genotypes were gB1 (27/32, 84.3%) and gB3 (4/32, 12.5%). 59.1% (26/44) of the immunocompetent patients were infected by gB1 while 38.6% (17/44) of them were infected by gB3. The frequency of gB1 infection in the immunosuppressed group was significantly higher than that in the immunocompetent group (p = 0.025). However, there was no statistically significant difference between gB1 and gB3 distributions by clinical diagnosis within each group. CONCLUSIONS: Only gB1 and gB3 genotypes were identified in this Taiwanese population. Although there is no significant difference between clinical diagnosis and gB genotyping, gB1 infection is significantly more predominant in immunosuppressed patients. PMID- 21242664 TI - A comparison of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and surface plasmon resonance for genotyping of high-risk human papillomaviruses. AB - BACKGROUND: Human papillomavirus (HPV) testing coupled with appropriate clinical management is associated with a significant decline in the rate of advanced cervical cancer and associated death. METHODS: In this present study, we evaluated the performance of 2 new HPV genotyping methods, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) and surface plasmon resonance (SPR) in 30 kinds of HPV control materials and in 129 cases of cervical smears including 79 HPV-positive samples screened from 1,600 abnormal clinical samples and 50 cervical cytology samples. RESULTS: The HPV genotyping accuracy of both MALDI-TOFMS and SPR was 100% for the HPV genotyping of control materials. In the analysis of the 79 HPV-positive samples by MALDI-TOFMS, HPV positivity was 88.6% (70/79). Nine samples were non-high-risk HPV (non-HR-HPV), which were not targets of MALDI-TOFMS. In the analysis of the 50 cervical samples, the agreement of both tests was 84% with a kappa value of 0.660. By using consensus results that mean agreement between 2 of 3 methods, the HR-HPV genotyping accuracy was 100% (77/77) by MALDI-TOFMS and 94.8% (73/77) by SPR in the 129 cervical samples. The sensitivity (88.2%; 82/93) and specificity (88.9%; 32/36) of MALDI-TOFMS were similar to those of SPR. CONCLUSION: These results support that MALDI-TOFMS is a sensitive, specific and feasible method for HR-HPV detection in clinical application, compared with the SPR method. PMID- 21242665 TI - The applicability of a predictive index for second- and third-line treatment of unselected non-small-cell lung cancer patients. AB - BACKGROUND: Tyrosine kinase inhibitors of EGFR (TKI-EGFR) induced response in only 10% of Caucasian non-small-cell lung cancer patients in second- or third line treatment. Independent predictive factors for qualification to TKI-EGFR treatment have not been assessed. In 2008, a prognostic index was reported for patients treated with erlotinib in the BR.21 trial, but its application for real, unselected patients is limited. OBJECTIVES: Based on clinical and molecular factors of patients treated with erlotinib, we tried to create a predictive index which could be applied in real treatment practice. METHODS: In a Cox regression model, we established 6 factors which affected overall survival for erlotinib treatment: performance status, erlotinib-induced rash, time from diagnosis to treatment, gender, weight loss and LDH level. We analyzed the risk factors of early progression and survival shorter than 6 months. In addition we included: time from first-line chemotherapy to erlotinib treatment, smoking status, mutation status in EGFR and anemia. RESULTS: Our model consisted of 10 factors that were assigned points according to HR or chi2 and p value. The score was used to separate patients into 4 risk categories of unfavorable disease course based on 10th, 50th and 90th percentiles: low risk (I), intermediate low risk (II), intermediate high risk (III) and high risk (IV). Survival probability was significantly higher for group I, intermediate for groups II and III, and significantly lower for group IV (chi2 = 49.5, p < 0.0001). Based on the previously reported index we could not qualify our patients for the low risk group. CONCLUSIONS: Our model could be useful for qualification for erlotinib treatment of patients with numerous adverse factors and limited access to genetic examination. PMID- 21242666 TI - Polymorphisms of hypoxia-related genes in subjects susceptible to acute mountain sickness. AB - BACKGROUND: The occurrence of acute mountain sickness (AMS), which develops in some individuals who ascend to altitudes above 2,500 m, may be associated with 4 hypoxia-related genes (HIF-1, VEGFA, HSP-70 and eNOS). OBJECTIVES: The aim of our study was to investigate the potential role of the 4 hypoxia-related genes in AMS pathogenesis. We therefore evaluated single-nucleotide polymorphisms (SNPs) of the genes in an association study using a case-control design. METHODS: At an altitude of 4,600 m, 64 male Chinese patients with AMS, defined according to the Lake Louise consensus criteria, were compared to 64 Chinese men free of symptoms of AMS. Clinical data, such as age, history of diseases, oxygen saturation (SpO(2)) and heart rate, were obtained. Genotypes of selected SNPs of these genes in patients were compared with those in controls. RESULTS: The mean SpO(2) and heart rate of the AMS and control groups were similar before ascent to high altitude (p = 0.79, p = 0.62) but, 24 h after ascent, the mean SpO(2) of the AMS group was significantly lower than that of the control group (p = 0.001), and the mean heart rate of the AMS group was significantly higher than that of the control group (p = 0.001). Twenty-eight of the 48 SNPs investigated were successfully genotyped, and SNP allele frequencies were obtained. The rs3025039 SNP and the haplotype (rs1413711, rs833070 and rs3025000) in the VEGFA gene were significantly associated with AMS (p = 0.0435 and 0.024, respectively). CONCLUSIONS: Our study demonstrates a possible association between the VEGFA gene and AMS. We conclude that VEGFA may have an important role in the AMS process. PMID- 21242667 TI - Treatment of growth hormone-deficient infants with recombinant human growth hormone to near-adult height: patterns of growth. AB - BACKGROUND/AIMS: To determine adult statures and linear growth patterns of children with growth hormone deficiency (GHD) who began treatment with recombinant human growth hormone (rhGH) in infancy. METHODS: Forty-seven patients with GHD in whom administration of rhGH was initiated at or before 2 years of age and who had achieved near-adult heights (NAH) were identified in the database of the Genentech National Cooperative Growth Study. RESULTS: After beginning treatment at a mean age of 0.9 years and height of -2.3 SD, these subjects achieved mean statures of -0.6, -0.3, and -0.4 SD at 5 and 10 years of age and at NAH, respectively. In 23 patients whose parental heights were known, mean NAH was comparable to the target height. Patients with uncomplicated courses whose heights were normal or tall when spontaneous puberty occurred or was induced realized the tallest NAHs. Patients with severe prenatal or perinatal, congenital and acquired neurologic insults, sexual precocity, or associated illnesses achieved less optimal NAHs. CONCLUSION: A normal pattern of linear growth during childhood and adolescence and satisfactory NAHs can be achieved in the majority of patients when treatment of the GHD subject is begun during infancy. PMID- 21242669 TI - Validation of a transcutaneous CO(2) monitor in adult patients with chronic respiratory failure. AB - BACKGROUND: Home mechanical ventilation is usually started in hospital as arterial blood gas sampling is deemed necessary to monitor CO(2) and O(2) adequately during institution of ventilatory support. A non-invasive device to reliably measure CO(2) transcutaneously would alleviate the need for high care settings for measurement and open the possibility for home registration. OBJECTIVES: In this study we investigated whether the TOSCA(r) transcutaneous CO(2) (PtcCO(2)) measurements, performed continuously during the night, reliably reflect arterial CO(2) (PaCO(2)) measurements in adults with chronic respiratory failure. METHODS: Paired measurements were taken in 15 patients hospitalised to evaluate their blood gas exchange. Outcomes were compared 30 min, 2, 4, 6 and 8 h after attaching the sensor to the earlobe. A maximum difference of 1.0 kPa and 95% limits of agreement (LOA) of 1 kPa between CO(2) pressure measurements, following the analysis by Bland and Altman, were determined as acceptable. RESULTS: Mean PtcCO(2) was 0.4 kPa higher (LOA -0.48 to 1.27 kPa) than mean PaCO(2) after 30 min. These figures were 0.6 kPa higher (LOA -0.60 to 1.80 kPa) after 4 h, with a maximum of 0.72 kPa (LOA 0.35 to 1.79 kPa) after 8 h. The corresponding values for changes in PtcCO(2) versus PaCO(2) were not significant (ANOVA). CONCLUSIONS: PtcCO(2) measurement, using TOSCA, is a valid method showing an acceptable agreement with PaCO(2) during 8 h of continuous measurement. Therefore, this device can be used to monitor CO(2) adequately during chronic ventilatory support. PMID- 21242668 TI - Coexistent autoimmunity in familial type 1 diabetes: increased susceptibility in sib-pairs? AB - BACKGROUND: Type 1 diabetes (T1D) patients are at risk for additional autoimmune diseases (AID). OBJECTIVE: To compare the characteristics of associated autoimmunity among familial (parent-offspring and sib-pair) subgroups and sporadic T1D patients. PATIENTS AND METHODS: Data regarding AID in T1D patients and their nuclear family members were extracted from medical files of 121 multiplex T1D families (58 parent-offspring, 63 sib-pairs) and 226 sporadic controls followed between 1979 and 2008. RESULTS: The prevalence of associated autoimmunity was similar in familial and sporadic cases (33.6 vs. 32.7%). The frequency of additional AID and percentage of patients with two or more coexistent AID were significantly higher among sib-pairs than parent-offspring (p = 0.05 and p = 0.04, respectively). The median time elapsed between diagnosis of T1D and occurrence of additional autoimmunity tended to be shorter in the sib pairs. Only in familial cases did a positive autoimmune family background predict the development of coexistent autoimmunity (OR = 2.11, CI [1.0, 4.49] p = 0.05). CONCLUSIONS: Among sib-pairs with T1D, the higher prevalence of additional AID, the increased number of diseases per person, and the relatively earlier appearance of associated AID suggest an increased susceptibility for coexistent autoimmunity in this subgroup. Positive family history for autoimmunity in multiplex T1D families increased their risk for co-occurrence of AID. PMID- 21242670 TI - Brain-derived neurotrophic factor promotes central nervous system myelination via a direct effect upon oligodendrocytes. AB - The extracellular factors that are responsible for inducing myelination in the central nervous system (CNS) remain elusive. We investigated whether brain derived neurotrophic factor (BDNF) is implicated, by first confirming that BDNF heterozygous mice exhibit delayed CNS myelination during early postnatal development. We next established that the influence of BDNF upon myelination was direct, by acting on oligodendrocytes, using co-cultures of dorsal root ganglia neurons and oligodendrocyte precursor cells. Importantly, we found that BDNF retains its capacity to enhance myelination of neurons or by oligodendrocytes derived from p75NTR knockout mice, indicating the expression of p75NTR is not necessary for BDNF-induced myelination. Conversely, we observed that phosphorylation of TrkB correlated with myelination, and that inhibiting TrkB signalling also inhibited the promyelinating effect of BDNF, suggesting that BDNF enhances CNS myelination via activating oligodendroglial TrkB-FL receptors. Together, our data reveal a previously unknown role for BDNF in potentiating the normal development of CNS myelination, via signalling within oligodendrocytes. PMID- 21242671 TI - The effect of bacterial, viral and fungal infection on mast cell reactivity in the allergic setting. AB - Mast cells are well known for their role in allergic inflammation where, upon aggregation of the high-affinity immunoglobulin E receptor, they release mediators such as histamine that cause classical allergic symptoms. Mast cells are located in almost all tissues and are especially numerous in organs that interface with the environment. Given this strategic location and the more recent notion that they are endowed with receptors that recognize endogenous and exogenous danger signals such as pathogens, it is not surprising that they function as important cells in immune surveillance. When mast cells are activated by pathogens they modulate innate and adaptive immune responses. In allergy, infections might cause exacerbation of the allergic reaction by affecting the reactivity of mast cells. With new developments within the field of mast cell biology, we will better understand how mast cells execute their effector functions. This knowledge will also help to improve the management of allergic diseases. PMID- 21242672 TI - Chronic kidney disease in cancer patients: an independent predictor of cancer specific mortality. AB - BACKGROUND/AIMS: The effects of chronic kidney disease (CKD) on the risk of death for patients with malignant disease are uncertain. The aim of this study was to determine the association between the presence of CKD and mortality in cancer patients. METHOD: We retrospectively reviewed the cases of 8,223 cancer patients with one or more serum creatinine measurements from January 1, 2000 to December 31, 2004. The key outcome was cancer-specific mortality within the follow-up period. The cumulative incidence rate for death from cancer was estimated using methods of competing risks survival analysis. Cox proportional-hazards regression with the use of Fine and Gray's proportional-hazards model were evaluated in multiple analyses. RESULTS: CKD was associated with an increased risk of death in cancer patients. The adjusted hazard ratios were 1.12 for patients with an estimated glomerular filtration rate (eGFR) of 30-59 ml/min/1.73 m(2) (95% confidence interval 1.01-1.26, p = 0.04) and 1.75 for patients with an eGFR <30 ml/min/1.73 m(2) (95% confidence interval 1.32-2.32, p < 0.001). CONCLUSIONS: CKD should be considered a risk factor for survival among patients with cancer. PMID- 21242673 TI - Effects of sodium thiosulfate on vascular calcification in end-stage renal disease: a pilot study of feasibility, safety and efficacy. AB - BACKGROUND AND OBJECTIVES: Vascular calcification is a major contributor to morbidity and mortality in hemodialysis. The objective of this pilot study was to determine the feasibility, safety and efficacy of sodium thiosulfate (STS) in the progression of vascular calcification in hemodialysis patients. METHODS: Chronic hemodialysis patients underwent a battery of cardiovascular tests. Those with coronary artery calcium (Agatston scores >50) received intravenous STS after each dialysis for 5 months (n = 22) and the tests were repeated. Changes in MDCT determined calcification were assessed as the mean annualized rate of change in 3 vascular beds (coronary, thoracic and carotid arteries) and in L1-L2 vertebral bone density. RESULTS: Although individual analyses showed coronary artery calcification progression in 14/22 subjects, there was no progression in the mean annualized rate of change of vascular calcification in the entire group. The L1 L2 vertebral bone density showed no changes. There were no correlations between rates of progression of vascular calcification and phosphorus, fetuin or C reactive protein levels. Changes in coronary artery calcification scores correlated with those of the thoracic aorta. CONCLUSION: STS treatment is feasible, appears safe and may decrease the rate of progression of vascular calcification in hemodialysis patients. A large, randomized, controlled trial is warranted. PMID- 21242674 TI - Vitamin D receptor activation and left ventricular hypertrophy in advanced kidney disease. AB - BACKGROUND: In chronic kidney disease (CKD), left ventricular hypertrophy (LVH) is prevalent and is associated with increased cardiovascular morbidity and mortality. Vitamin D receptor (VDR) activation attenuates LVH progression in animal models. METHODS: PRIMO is a multinational, randomized, double-blinded trial with oral paricalcitol in subjects with stages 3-4 CKD, mild-to-moderate LVH and an LV ejection fraction >50%. The primary endpoint is change in the left ventricular mass index (LVMI) compared with placebo after 48 weeks of treatment. The main secondary endpoints are changes in diastolic function parameters. In this paper, we report baseline characteristics from this study. RESULTS: LVMI was 33.0 +/- 7.5 g/m(2.7) for males and 30.8 +/- 7.2 g/m(2.7) for females (p = 0.04). LVMI correlated with systolic blood pressure (r = 0.24), urine albumin creatinine ratio (r = 0.39), troponin T (r = 0.29), high-sensitivity C-reactive protein (r = 0.25) and plasma levels of B-type brain natriuretic peptide (r = 0.22); all p < 0.01. In multiple linear regression, each remained independently associated with LVMI. The early diastolic velocity of the lateral mitral annulus (E') was 8.1 +/- 2.4 cm/s. E' was inversely correlated with age in univariate (r = -0.14, p = 0.04) and multivariable (p = 0.02) analysis. CONCLUSION: Among 227 multinational subjects with stages 3-4 CKD, baseline LVMI correlates with baseline blood pressure, urine albumin creatinine ratio and cardiac biomarkers, and baseline diastolic function correlates with age. This research was funded by Abbott Laboratories; ClinicalTrials.gov No. NCT00497146. PMID- 21242675 TI - Enhancement of solute removal in a hollow-fiber hemodialyzer by mechanical vibration. AB - Better solute clearance, particularly of middle-molecular-weight solutes, has been associated with improved patient outcomes. However, blood-membrane interaction during dialysis results in the development of secondary mass transfer resistances on the dialyzer membrane surface. We discuss the potential effects of mechanical vibration on the diffusion, convection and adsorption of uremic solutes during dialysis. For sinusoidal and triangular vibratory motions, we conceptualized the hemodynamic changes inside the membrane and consequent effects on membrane morphology. Longitudinal vibration generates reverse flow by relative membrane motion, and transverse vibration generates a symmetric swirling flow inside the hollow fiber, which enhances wall shear stress and flow mixing. Moreover, the impulse induced by triangle wave vibration could provide higher absorption capacity to middle-molecular-weight solutes. Mechanical vibration could enhance solute removal by minimizing membrane morphology changes resulting from blood-membrane interaction during hemodialysis. These effects of mechanical vibration can be helpful in extracorporeal blood purification therapies including continuous, portable and wearable systems. PMID- 21242676 TI - Hemodiafiltration with endogenous reinfusion with and without acetate-free dialysis solutions: effect on ESA requirement. AB - BACKGROUND: Hemofiltrate reinfusion (HFR) is a form of hemodiafiltration (HDF) in which replacement fluid is constituted by ultrafiltrate from the patient 'regenerated' through a cartridge containing hydrophobic styrene resin. Bicarbonate-based dialysis solutions (DS) used in routine hemodialysis and HDF contain small quantities of acetate (3-5 mM) as a stabilizing agent, one of the major causes of intradialytic hypotension. Acetate-free (AF) DS have recently been made available, substituting acetate with hydrochloric acid. The impact of AF DS during HFR on Hb levels and erythropoietic-stimulating agent (ESA) requirement in chronic dialysis patients was assessed. PATIENTS AND METHODS: After obtaining informed consent, 30 uremic patients treated by standard bicarbonate dialysis (BHD, DS with acetate) were randomized to treatment in 3 month cycles: first AF HFR, followed by HFR with acetate, and again AF HFR. At the beginning and end of each period, Hb and ESA requirements were evaluated. RESULTS: A significant increase in the Hb level was observed throughout all periods of HFR versus BHD (from 11.1 to 11.86 g/dl; p = 0.04), with a significant decrease of ESA requirements from 29,500 to 25,033 IU/month (p = 0.04). CONCLUSION: Regardless of the presence or absence of acetate in DS, HFR per se allows a significant lowering of ESA dosage versus BHD, while at the same time increasing Hb levels. Taking for granted the clinical impact produced, HFR seems to provide a relevant decrease in end-stage renal disease patient costs. PMID- 21242677 TI - The impact of residual renal function on hospitalization and mortality in incident hemodialysis patients. AB - BACKGROUND/AIMS: Few data are available on the impact of residual renal function (RRF) on mortality and hospitalization in hemodialysis (HD) patients. The objective of our study was to compare clinical outcomes for HD patients with and without RRF. METHODS: In a cohort of 118 incident HD patients with RRF (n = 51) and without RRF (n = 67) who started dialysis in a single center, we recorded demographics, laboratory data, medication, hospitalizations and mortality. RESULTS: Patients without RRF were older (p = 0.007), had lower baseline serum albumin levels (p = 0.002) and spent 18.6 more days in hospital per year than those with RRF (p = 0.055). Mean survival time was significantly lower in patients without RRF (p = 0.027). In a Cox proportional hazards model, only RRF remained as a significant independent predictor. CONCLUSIONS: RRF is associated with significantly reduced mortality and hospital days, but does not decrease the hospitalization rate and time to first hospitalization. PMID- 21242678 TI - Tamoxifen downregulates connective tissue growth factor to ameliorate peritoneal fibrosis. AB - Peritoneal fibrosis (PF), including simple sclerosis and encapsulating peritoneal sclerosis (EPS), is a serious complication in patients on long-term peritoneal dialysis. Tamoxifen has successfully been used in treating EPS; however, the mechanism of tamoxifen in treating EPS fibrosis disorders remains unclear. This study demonstrates a possible antifibrotic mechanism of tamoxifen. A bleach induced PF rat model was applied as the in vivo treatment target. Tamoxifen was intraperitoneally injected daily to treat PF. The PF scores and thickness of the submesothelial zone over the liver surface were measured as indicators for the severity of PF. Human peritoneal mesothelial cells (HPMC) were used as an in vitro model to test the antifibrotic effect of tamoxifen. Gene expressions of transforming growth factors-beta (TGF-beta), connective tissue growth factor (CTGF) and collagen were investigated using quantitative polymerase chain reactions. In HPMC, tamoxifen showed paradoxical effects between collagen I and TGF-beta. Tamoxifen also inhibited TGF-beta-induced collagen and CTGF. The possible antifibrotic effect of tamoxifen is through inhibiting CTGF to block collagen synthesis, although it enhances TGF-beta which increases fibrosis. These results provide a possible molecular mechanism for tamoxifen. PMID- 21242679 TI - Evaluation of a new online hemodiafiltration mode with automated pressure control of convection. AB - BACKGROUND: Postdilution hemodiafiltration (HDF) still remains the gold standard for solute removal, but with high hemoglobin levels transmembrane pressure (TMP) may reach high levels, reducing filter performance. We compared three online postdilution HDF treatments without TMP alarms for convective volume and plasma changes following treatment. METHODS: Twelve patients were enrolled in a trial with three online postdilution HDF treatments. In the volume-controlled mode (VOLc), we set the exchanged volume to obtain a filtration fraction close to 25% without TMP alarms. In the pressure-controlled mode (TMPc), we set the TMP at 100 mm Hg. In the ULTRAc mode (TMP scan combined with TMPc), the dialysis machine automatically selects the TMP with a scan. All treatments were performed with an AK200 ULTRA-S system. RESULTS: Even with hemoglobin levels >12 g/dl, we found a 57% rise in ultrafiltration rate in TMPc versus VOLc and a 92% rise in ULTRAc versus VOLc. Phosphates and myoglobin levels were significantly affected by treatment type. CONCLUSIONS: ULTRAc may be a useful tool to achieve an excellent purification performance without the constraints associated with the risk of hemoconcentration. PMID- 21242680 TI - Assessment of inflow of endotoxin and its fragments in patients on maintenance hemodialysis. AB - BACKGROUND: We estimated the flow of endotoxins (ET) from dialysates into the blood of patients on hemodialysis (HD) using limulus amebocyte lysate (LAL) assays and endotoxin activity (EA) determined by neutrophil respiratory burst activity. METHODS: A cross-sectional study compared groups given ultrapure bicarbonate (n = 15; group A), acetate-free bicarbonate dialysates (n = 20; group B) and conventional bicarbonate dialysate (n = 23; group C). A prospective study of group C examined the effect of changing the purity of the dialysate. Biomarkers of inflammation and oxidative stress were measured and ET in blood was assessed by LAL assays and EA. RESULTS: Serum ET levels did not differ among the groups, whereas EA and the biomarkers were significantly increased in group C compared with those in groups A and B. HD using conventional dialysate was independently associated with an increase in EA. Purifying the dialysate significantly decreased EA in group C. CONCLUSION: Measuring EA is useful to assess the influence of dialysate contamination in HD patients. PMID- 21242681 TI - Malnutrition and inflammation determine prognosis of patients with CRS type 4. AB - BACKGROUND/AIMS: A significant number of uremic patients develop ischemic heart disease before hemodialysis (HD) is initiated. Recently, chronic cardiorenal syndrome among predialysis patients has been recognized. However, little is known about prognostic factors in this subgroup of incident HD patients. METHODS: A total of 87 incident HD patients, who were classified into cardiorenal syndrome type 4 (chronic cardiorenal syndrome), were identified at Mitsui Memorial Hospital between 1984 and 2003. The survival and risk factors for mortality were examined. RESULTS: 25 patients died and the 5-year survival rate amounted to approximately 75%. Both all-cause mortality and the adjusted mortality for age and sex were higher in patients with a lower serum albumin level (p = 0.03) or higher serum C-reactive protein level (p = 0.02). CONCLUSION: The poor survival rate of incident HD patients with a medical history of ischemic heart disease was predicted by malnutrition and inflammation at the start of HD. PMID- 21242682 TI - Microinflammation in hemodialysis patients is associated with increased CD14CD16(+) pro-inflammatory monocytes: possible modification by on-line hemodiafiltration. AB - BACKGROUND: An increased percentage of pro-inflammatory CD14(+)CD16(+) monocytes might contribute to inflammation in hemodialysis (HD) patients. The purpose of the study was to evaluate the possible contribution of pro-inflammatory monocytes to inflammation in HD patients and also to evaluate the effect of on-line hemodiafiltration (HDF). METHODS: Flow cytometric detection of monocytes in patients undergoing HD, on-line HDF and healthy controls as well as plasma cytokines and cytokine mRNA measurement were performed. RESULTS: Percent pro inflammatory monocytes, plasma cytokines and cytokine mRNA significantly increased in HD patients. Intracellular cytokine staining showed pro-inflammatory monocytes were the predominant source of tumor necrosis factor-alpha. Percent pro inflammatory monocytes positively correlated with plasma inflammatory cytokines. Percent pro-inflammatory monocytes, plasma cytokines and cytokine mRNA significantly decreased in on-line HDF patients. CONCLUSION: Increased pro inflammatory monocytes are likely to contribute to inflammation in HD patients, and beneficial effect of on-line HDF might be partially mediated by modulating the inflammatory response. PMID- 21242683 TI - What is the upper limitation of volume in Chinese peritoneal dialysis patients? AB - BACKGROUND: Overhydration (OH) is a well-recognized problem in peritoneal dialysis (PD) patients and is an independent risk factor of mortality in this patient population. Achieving normohydration remains an important issue in dialysis therapy. The present study tries to compare clinical signs and find the optimal range for PD patients in China. METHODS: A new bioimpedance spectroscopy device [body composition monitor (BCM)], which allows quantitative determination of how much the hydration status deviates from normal ranges (DeltaHS), was selected. Blood pressure and DeltaHS were analyzed in 92 PD patients from 1 dialysis center and compared with a matched healthy population (n = 45). Statistical analysis was performed using SPSS software, version 16.0 (SPSS Inc., Chicago, Ill., USA). RESULTS: We took different OH values as cutoff thresholds; predictive accuracy was evaluated with sensitivity and specificity, and a receiver-operating characteristics curve and Youden's index were adopted. CONCLUSION: Our data suggest that 2.0 liters is a reasonable cutoff value for DeltaHS. This represents an important step towards a more objective choice of strategies for the optimal treatment of hypertension and fluid overload. PMID- 21242684 TI - Volume control in peritoneal dialysis patients guided by bioimpedance spectroscopy assessment. AB - BACKGROUND: Volume overload is a common problem in peritoneal dialysis patients and may contribute to the high cardiac mortality in this patient population. Controlling volume status is difficult due to the lack of appropriate and accurate assessment of dry weight. This randomized, controlled study was conducted to test if the recent use of overhydration value (OH) provided by bioimpedance spectroscopy and patients' education would help to control overhydration. METHODS: 160 continuous ambulatory peritoneal patients were included in this study. All the patients were randomly allocated to 2 groups: in Group 1 the patients and their primary nurses were informed of the OH values provided by bioimpedance spectroscopy whereas in Group 2 the values were not revealed and patients' volume was measured by the standard methods. Fluid status was evaluated by means of repeated bioimpedance analysis and clinical assessment. Urine volume, blood pressure and use of antihypertensive medications were recorded. RESULTS: There were no differences in gender, age, diabetes, height, weight and clinical hydration status between the 2 groups at the baseline. In Group 1, OH (p < 0.05), extracellular volume and the extracellular volume to intracellular volume ratio decreased steadily during the 3-month follow-up. On the contrary, all 3 parameters increased significantly in Group 2. SBP decreased significantly in Group 1 but increased significantly in Group 2. CONCLUSION: Our study shows that the use of OH as determined by bioimpedance spectroscopy may facilitate volume control in peritoneal dialysis patients. PMID- 21242685 TI - Circuit start during continuous renal replacement therapy in vasopressor dependent patients: the impact of a slow blood flow protocol. AB - BACKGROUND AND AIMS: In vasopressor-dependent patients, we evaluated the impact of a slow blood flow protocol on hypotension when starting continuous renal replacement therapy (CRRT). METHODS: Retrospective observational study in tertiary ICU of a slow blood flow protocol at the start of CRRT circuits. RESULTS: 205 circuits in 52 patients were studied. No significant changes in mean arterial pressure (MAP) and norepinephrine dose were found. Only 16 circuit starts in 13 patients were associated with a decrease in MAP >20%. In 23 filters and 11 patients, norepinephrine dose was >50 MUg/min at baseline and also did not change significantly. There were no cardiac arrests or ventricular arrhythmias and CRRT was not discontinued because of hypotension. CONCLUSIONS: Implementation of a CRRT slow blood flow protocol in vasopressor-dependent patients enabled the initiation of CRRT circuits with limited hemodynamic consequences and no cardiac arrest or ventricular arrhythmia. PMID- 21242687 TI - Reappraisal of functional importance of coronary collateral circulation. AB - Coronary collateral circulation (CCC) is defined as an alternative blood conveying circuit to the ischemic myocardium supplied by a jeopardized coronary artery. Accumulating evidence on CCC and its functional role has been derived from basic and clinical studies over several decades. Progress in molecular biology and genetic engineering has enabled us to elucidate the mechanisms of collateral growth on the basis of the development of new experimental models and methods for accurate assessment of CCC. These achievements in basic research have been promptly translated into the clinical setting. Interaction between basic and clinical sciences in the fascinating field of CCC will contribute to the establishment of innovative collateral-promoting therapy for severe coronary artery disease. PMID- 21242686 TI - A vitamin E-coated polysulfone membrane reduces serum levels of inflammatory markers and resistance to erythropoietin-stimulating agents in hemodialysis patients: results of a randomized cross-over multicenter trial. AB - BACKGROUND: Oxidative stress is prevalent in dialysis patients and has been implicated in the pathogenesis of cardiovascular disease and anemia. Vitamin E is a fat-soluble antioxidant that plays a central role in reducing lipid peroxidation and inhibiting the generation of reactive oxygen species. The aim of this cross-over randomized study was to compare the effects of a vitamin E-coated polysulfone (Vit E PS) membrane and a non-vitamin E-coated polysulfone (PS) membrane on inflammatory markers and resistance to erythropoietin-stimulating agents (ESAs). METHODS: After a 1-month run-in period of standard bicarbonate dialysis with a synthetic membrane, 62 patients of both genders, and older than 18 years, dialysis vintage 48 +/- 27 months, BMI 22 +/- 3 (from 13 different dialysis units) were randomized (A-B or B-A) in a cross-over design to Vit E PS (treatment A) and to PS (treatment B) both for 6 months. C-reactive protein (CRP) and interleukin-6 (IL-6) concentrations were determined by a sandwich enzyme immunoassay at baseline and every 2 months; red blood cell count, ESA dose and ESA resistance index (ERI) were assessed monthly. RESULTS: Hemoglobin (Hb) levels significantly increased in the Vit E PS group from 11.1 +/- 0.6 g/dl at baseline to 11.5 +/- 0.7 at 6 months (p < 0.001) and remained unchanged in the PS group. Although ESA dosage remained stable during the observation periods in both groups, ERI was significantly reduced in the Vit E PS group from 10.3 +/- 2.2 IU dl/kg/g Hb week at baseline to 9.2 +/- 1.7 at 6 months (p < 0.001). No significant variation of ERI was observed in the PS group. A significant reduction in plasma CRP and IL-6 levels was observed in the Vit E PS group: CRP from 6.7 +/- 4.8 to 4.8 +/- 2.2 mg/l (p < 0.001) and IL-6 from 12.1 +/- 1.4 to 7.5 +/- 0.4 pg/ml (p < 0.05). In the PS group, CRP varied from 6.2 +/- 4.0 to 6.4 +/- 3.7, and IL-6 from 10.6 +/- 2.1 to 9.6 +/- 3.5 (p = n.s.). CONCLUSIONS: Treatment with Vit E PS membranes seems to lead to a reduction in ESA dosage in HD patients; in addition, a low chronic inflammatory response may contribute to a sparing effect on exogenous ESA requirements. PMID- 21242688 TI - A review of transcranial magnetic stimulation in vascular dementia. AB - Vascular dementia (VaD) is a clinical syndrome that encompasses a wide spectrum of cognitive disorders caused by cerebrovascular disease. The subcortical ischemic form of VaD is clinically homogeneous and a major cause of cognitive impairment in the elderly. Vascular lesions contribute to cognitive decline in neurodegenerative dementias, and VaD and Alzheimer's disease often coexist and share clinical features and multiple neurotransmission involvement. These similarities have led several investigators to use transcranial magnetic stimulation (TMS) to enucleate a neurophysiological profile of VaD. TMS studies have identified a pattern of cortical hyperexcitability probably related to the disruption of the integrity of white matter lesions due to cerebrovascular disease. The present review provides a perspective of these TMS techniques by further understanding the role of different neurotransmission pathways and plastic remodeling of neuronal networks in the pathogenesis of VaD. PMID- 21242689 TI - Malperformance in verbal fluency and delayed recall as cognitive risk factors for impairment in instrumental activities of daily living. AB - BACKGROUND: Maintaining independence in instrumental activities of daily living (IADL) is crucial for older adults. This study explored the association between cognitive and functional performance in general and in single IADL domains. Also, risk factors for developing IADL impairment were assessed. METHODS: Here, 3,215 patients aged 75-98 years were included. Data were collected during home visits. RESULTS: Cognitive functioning was associated with IADL both cross-sectionally and longitudinally. Regarding the single IADL domains cross-sectionally, executive functioning was especially associated with shopping, while episodic memory was associated with responsibility for own medication. CONCLUSION: Reduced performance in neuropsychological tests is associated with a greater risk of current and subsequent functional impairment. PMID- 21242690 TI - Does the clock drawing test predict dementia? Results of the Leipzig longitudinal study of the aged (LEILA 75+). AB - BACKGROUND/AIMS: Conversion rates to dementia are known to be high for patients with mild cognitive impairment (MCI), but the diagnosis of MCI is very time consuming. Since the Clock Drawing Test (CDT) is quick to administer, it will be of interest to compare the predictive validity of the CDT and of an MCI diagnosis for the diagnosis of dementia. METHODS: In a sample of 384 individuals, CDT scores and the presence of MCI were assessed at baseline and then compared between individuals with an incident dementia diagnosis at follow-up and those without. Multivariate analyses, receiver operating characteristic analyses and values of sensitivity and specificity of the CDT were performed. RESULTS: Individuals with incident dementia had significantly higher CDT scores at baseline than those without dementia. CDT was a significant predictor of incident dementia after adjusting for other factors. CDT reached a sensitivity of 68% and specificity of 65%. The area under the receiver operating characteristic curve of CDT was 0.70 and therefore slightly lower than for MCI diagnosis (0.78). CONCLUSIONS: Because of the only slightly lower predictive value of the CDT, its quick application and scoring compared to the MCI concept applied, it will be worthwhile to improve the CDT scoring system in order to increase the predictive validity in dementia. PMID- 21242691 TI - Longitudinal changes in cognition in Parkinson's disease with and without dementia. AB - BACKGROUND: The longitudinal cognitive course in Parkinson's disease (PD) with and without dementia remains undefined. We compared cross-sectional models of cognition in PD (both with and without dementia), Alzheimer's disease (AD), and nondemented aging and followed the participants over time. METHOD: Previously validated models of cognitive performance in AD and nondemented aging were extended to individuals with PD (with dementia, n = 71; without dementia, n = 47). Confirmatory factor analysis and piecewise regression were used to compare the longitudinal course of participants with PD with 191 cognitively healthy subjects and 115 individuals with autopsy-confirmed AD. RESULTS: A factor analytic model with one general factor and three specific factors (verbal memory, visuospatial memory, working memory) fit demented and nondemented PD. Longitudinal change indicated that individuals with PD with dementia declined significantly more rapidly on visuospatial and verbal memory tasks than AD alone. Cognitive declines across all factors in AD and PD dementia accelerated several years prior to clinical dementia diagnosis. CONCLUSION: Both specific and global cognitive changes are witnessed in PD and AD. Longitudinal profiles of cognitive decline in PD and AD differed. PD with or without dementia has a core feature of longitudinal decline in visuospatial abilities. PMID- 21242692 TI - Did goethe describe attention deficit hyperactivity disorder? AB - As early as 1846, the typical symptoms of attention deficit hyperactivity disorder (ADHD) were described by Heinrich Hoffmann (1809-1894). However, in Goethe's masterpiece Faust (1832), the character of Euphorion strongly suggests ADHD diagnosis. PMID- 21242693 TI - Simultaneous blockade of costimulatory signals CD28-CD80 and CD40-CD154 combined with monoclonal antibody against CD25 induced a stable chimerism and tolerance without graft-versus-host disease in rat. AB - BACKGROUND: The conditioning regimen to induce chimerism for immune tolerance is usually accompanied by high toxicity and graft-versus-host disease (GVHD). Our aim was to explore a nontoxic strategy for the induction of mixed chimerism by pretreatment with anti-CD25 monoclonal antibody (mAb), cytotoxic T-lymphocyte associated antigen 4 immunoglobulin (CTLA4Ig) and anti-CD154 mAb. METHODS: A total of 30 Lewis recipient rats (RT1l) were randomly divided into control (A and B) and treated (C, D and E) groups. Recipients serving as controls were without any pretreatment (group A) or pretreated with anti-CD25 mAb, CTLA4Ig and anti CD154 mAb on days 0, 2, 4, 6 and 8 without bone marrow transplantation (BMT; group B). In the treated groups, the recipients were pretreated with anti-CD25 mAb and CTLA4Ig (group C), with anti-CD25 mAb and anti-CD154 mAb (group D) or with anti-CD25 mAb, CTLA4Ig and anti-CD154 mAb (group E) on days 0, 2, 4, 6 and 8 plus BMT [2 * 10(8) unmodified whole bone marrow cells from Brown Norway donor rats (RT1n)] on day 0. Full-thickness skin grafts from donor-specific Brown Norway rats were grafted to the dorsal thoracic wall of Lewis recipients on day 8. GVHD was assessed after BMT, and chimerism and T cell apoptosis on days 7, 21, 35 and 49 were detected by flow cytometry. RESULTS: GVHD was not observed in any groups. On days 7, 21 and 35, hematopoietic chimerism was present and maintained in the recipients of the 3 treated groups (groups C, D and E), and thereafter disappeared on day 49. The rate of chimerism in group E was significantly higher compared to that in group C on day 7 and that in group C or D on day 21, but there was no significant difference on day 35 among the 3 groups. The rate of T cell apoptosis in group C, D or E was significantly higher than in group A or B on days 14, 21 and 35. The grafted skin survival in group C, D or E was longer than in group A or B, and survival was significantly longer in group E than in group C or D. CONCLUSION: Preconditioning with anti-CD25 mAb, CTLA4Ig and anti CD154 mAb could effectively induce chimerism and immune tolerance without GVHD in a major histocompatibility complex-disparate rat model. This strategy may be attractive for induction of transplantation tolerance. T cell apoptosis is one of the important considerations in tolerance induction. PMID- 21242694 TI - Satisfaction and quality of life in laryngectomees after voice prosthesis rehabilitation. AB - OBJECTIVE/HYPOTHESIS: The purpose of the study was to assess the satisfaction and quality of life in laryngectomees after vocal rehabilitation using voice prostheses. We evaluated the impact on quality of life between laryngectomees with voice prostheses, laryngectomees without them and healthy controls. METHODS: This was a prospective study on a sample of laryngectomees in an Italian university hospital. Our study population was composed of 42 patients who had previously undergone a total laryngectomy; in 24 of them, voice rehabilitation was obtained with a voice prosthesis device (group A), while 18 of them learned oesophageal voice (group B). The results were compared with a group of 25 healthy controls (group C). In order to investigate the quality of life, we administered the Short Form 36-Item Health Survey (SF-36) to the 3 groups. Moreover, self satisfaction of the subjects in group A was assessed by single questions regarding their use of the voice prosthesis. RESULTS: A statistical difference in the SF-36 was detected for social functioning (SF) between groups A and B. Role physical, SF and role emotional were significantly better in group C than in group A. Group A stated they were very satisfied with voice quality while there were still some problems regarding prosthesis lifetime and communication at the telephone or in noisy environments. CONCLUSIONS: Voice prosthesis implantation in laryngectomees showed positive effects on patients' quality of life; however, there are still some negative aspects. At present, an early diagnosis of larynx cancer with a partial laryngectomy in order to preserve phonatory function is the gold standard. PMID- 21242695 TI - An exploratory study on the combined effects of external and internal morphology on load dissipation in primate capitates: its potential for an understanding of the positional and locomotor repertoire of early hominins. AB - This pilot study explored whether the redirection of stress through trabeculae within morphologically constrained capitates provides information about habitual/positional behaviours unavailable from the study of external morphology alone. To assess this possibility, an experimental finite element approach was taken, whereby no attempt was made to reconstruct the actual magnitudes and loading conditions experienced by the capitates in vivo. Rather, this work addressed fundamental biological questions relating to bone plasticity, i.e. internal versus external bone morphology. The capitates of 7 species with different and - in the case of fossils - inferred locomotor behaviours were selected. Virtual models of capitates were created, scaled to the same size and subjected to the same theoretical load. In the first set of analyses, models were assigned the material properties of bone throughout, whereas in the second set, models were assigned 11 different material properties representing the trabecular architecture derived from high-resolution CT. Species with arboreal behaviours consistently redirected loads towards the ulnar aspect of the capitate when trabeculae were introduced, while terrestrial species, and the bipedal Homo, redirected stress towards the radial side. From these preliminary analyses, it is tentatively concluded that Australopithecus anamensis habitually engaged in arboreal behaviours, whereas Australopithecus afarensis did not. PMID- 21242696 TI - A population estimate of blue-eyed black lemurs in Ankarafa Forest, Sahamalaza Iles Radama National Park, Madagascar. AB - The critically endangered blue-eyed black lemur (Eulemur flavifrons) has one of the smallest distributions of any lemur, occurring only in the north-western forests of Madagascar. We report the results of a population estimate of this taxon in part of the Ankarafa Forest, Sahamalaza-Iles Radama National Park, a dry deciduous forest. We collected data between September 2007 and February 2008 using a total count method with marked individuals and known groups. In all, 228 individuals comprising 29 groups were counted. Group sizes ranged from 4 to 11 individuals with a mean of 8 +/- 1.8. We estimated population density to be 1.0 individual/ha or 97.3 individuals/km(2) for our study area, which is higher than previous estimates reported for Ankarafa and other sites within the Sahamalaza Peninsula. Our mean group size, however, was similar to those determined in previous studies. Both group size and density of the blue-eyed black lemur were higher within the National Park than in previous studies outside the Park. PMID- 21242697 TI - Range expansion as a response to increasing group size in the Yunnan snub-nosed monkey. AB - The Yunnan snub-nosed monkey (Rhinopithecus bieti) is characterized by a larger home range and group size than other colobine species. We investigated variations in home range size of a free-ranging group of R. bieti from 1998 to 2007 in the Baimaxueshan National Nature Reserve in Yunnan, China. Group size increased from 160 to 450 over the 10 years. Results also showed a home range shift and yearly home range expansion, although this expansion was very limited. The study group covered a 33.78-km(2) area during the 10-year period, with some areas abandoned and others used repeatedly. The yearly home range increase stopped in 2004 and decreased thereafter. Despite increasing group size usually being coupled with larger yearly home range (>30 km(2)), the group confined itself within a relatively small and stable area (<18 km(2)) during 2005-2007, with a significant portion of their accessible home range discarded. Consequently, the study group showed the highest recorded population density among extant groups of R. bieti. Reasons why the group settled into a substantially smaller home range area remain unclear. PMID- 21242698 TI - Controversies in the management of infective complications of peritoneal dialysis. AB - Peritoneal dialysis is an effective form of renal replacement therapy. Despite improvements in connection technology, peritoneal infection is still the most important preventable cause of patient morbidity and mortality. There has been a shift in focus from treatment to prevention of infection, but wide variation in peritonitis incidence across and within peritoneal dialysis populations remains. This minireview aims to highlight current best practice, whilst discussing controversies in the diagnosis, prediction, prevention and management of peritonitis. Exit-site infection will not be discussed per se but only as it relates to peritonitis. PMID- 21242699 TI - p38/MAPK inhibitor modulates the expression of dorsal horn GABA(B) receptors in the spinal nerve ligation model of neuropathic pain. AB - BACKGROUND: Neuropathic pain is one of the most challenging clinical problems due to a lack of understanding the mechanisms. Recent studies have suggested that activated microglia in spinal cord may play a vital role in nerve injury-induced neuropathic pain, but the exact mechanisms have not been fully determined. METHODS: First, we investigated the changes of dorsal horn GABA(B) receptor 1 (R1) expression in spinal nerve ligation rats. Second, we explored whether activated microglia contributed to such neuron changes by intrathecal administration of the p38 inhibitor, SB203580. RESULTS: In this study, we found a dynamic change of GABA(B)R1a protein expression after spinal nerve ligation, and the peripheral nerve injury-induced downregulation of GABA(B)R1a expression in the spinal dorsal horn could be prevented by intrathecal administration of a p38/MAPK inhibitor SB203580. CONCLUSIONS: Our results provide valuable information for a better understanding of neuropathic pain and may contribute to developing effective treatments in future studies. PMID- 21242700 TI - Glucocorticoid receptor expression on human B cells in response to acute heavy resistance exercise. AB - OBJECTIVE: To examine glucocorticoid receptor (GCR) expression on B lymphocytes in response to an acute bout of resistance exercise. METHODS: Using a within subject design, resistance-trained women (n = 7; age: 22.13 +/- 3.09 years; height: 1.69 +/- 0.084 m; body weight: 65.60 +/- 10.01 kg; body mass index: 22.63 +/- 2.03 kg/m2; means +/- SD) and men (n = 8; age: 23.28 +/- 4.26 years; height: 1.73 +/- 0.086 m; body weight: 73.93 +/- 12.71 kg; body mass index: 24.51 +/- 2.61 kg/m2; means +/- SD) performed an acute resistance exercise protocol (6 sets of 5 repetition maximum heavy squats) and a control test in a balanced, randomized order. Blood samples were obtained before, during, and immediately after exercise, and after 1, 6, and 24 h of recovery. GCR expression on circulating B lymphocytes was evaluated with flow cytometry, and circulating cortisol was assayed. RESULTS: Resting GCR expression on B lymphocytes was similar between men and women. GCR expression was elevated in anticipation of exercise (p = 0.047), decreased during exercise (p = 0.049), and increased during recovery (p = 0.05 and p = 0.03 after 1 and 6 h of recovery, respectively). Trends for gender differences were apparent before and during exercise, and after 6 h of recovery. Men had significantly higher cortisol responses during (p = 0.002) and after exercise (p = 0.094) compared to before exercise. In women, however, circulating cortisol concentrations did not significantly increase in response to the squat exercise protocol. CONCLUSIONS: GCR expression on B lymphocytes decreased during resistance exercise and increased during recovery. Circulating cortisol increased during exercise in men only. Responses were attenuated in women compared to men. Our data provide insights into the temporal interactions between the endocrine and immune systems in response to acute heavy resistance exercise in men and women. PMID- 21242701 TI - Inhibitory effect of canstatin in alkali burn-induced corneal neovascularization. AB - OBJECTIVE: To examine the effect of recombinant canstatin protein on the corneal neovascularization (CorNV) in an alkaline burn-induced CorNV model. METHODS: This study involved 50 C57BL/6 mice. CorNV was induced by an alkaline burn of the corneas with 1 N NaOH under general anesthesia. Beginning 24 h after CorNV induction, recombinant canstatin protein was administered intraperitoneally at 5 or 10 mg/kg body weight once a day for up to 14 days. CorNV was evaluated by slit lamp microscopy. Growth factors and cytokines relating to neovascularization and inflammation in the corneas were evaluated by real-time polymerase chain reaction (RT-PCR), Western blotting, immunohistochemistry or ELISA. RESULTS: Recombinant canstatin protein significantly inhibited CorNV. Compared to the untreated or PBS treated CorNV group, expression of vascular endothelial growth factor (VEGF) markedly decreased in the canstatin-treated group as detected by various methods. Western blotting and RT-PCR showed that the canstatin treatment inhibited the expression of hypoxia-inducible factor and VEGF. Day 7 revealed the greatest changes: ELISA assay showed that TNF-alpha also significantly decreased in canstatin-treated corneas. CONCLUSIONS: Recombinant canstatin protein suppressed experimental CorNV, suggesting that canstatin may serve as a useful angiogenic inhibitor for the treatment of neovascularization-related corneal diseases. PMID- 21242702 TI - Increased uric acid and glucose concentrations in vitreous and serum of patients with diabetic macular oedema. AB - BACKGROUND: Diabetic retinopathy (DR) is characterized by blood-retina barrier breakdown induced by local changes in the retina and systemic factors. We investigated vitreous and serum levels of glucose and uric acid (UA) in patients with DR and aimed to describe their correlation with the grade of DR. METHODS: Prospective study of 81 patients with DR and 48 non-diabetic controls. Biochemical analysis of vitreous and serum samples was performed. RESULTS: UA and glucose concentrations in vitreous and serum were significantly higher in diabetic patients than in controls. Absolute ratios (vitreous level/serum level) of UA and glucose were higher in proliferative compared with non-proliferative DR. CONCLUSIONS: The results suggest that, apart from glucose, increased levels of UA in diabetic patients may also be involved in the pathogenesis and progression of DR. PMID- 21242703 TI - 'Maintain focus and aim high'. An interview with Dr. Chung Owyang, H. Marvin Pollard Collegiate Professor, Department of Internal Medicine, University of Michigan, Ann Arbor, mMch., USA. Interviewed by Martin E Fernandez-Zapico. AB - Dr. Owyang is an academic leader well known for his work in pancreatic physiology and pathophysiology. He has made considerable contributions to our understanding of the neurohormonal control of digestive functions. His identification of the novel 'CCK releasing peptide' changed our understanding of hormone secretion during feeding and provides the mechanism responsible for feedback regulation of pancreatic secretion. Over the years, Dr. Owyang has trained numerous researchers, many of whom have gone on to become leaders in gastroenterology. Answering Martin Fernandez-Zapico's questions, he emphasizes the importance of good mentorship for the development of a new investigator and gives us a glimpse of his life and work. and IAP. PMID- 21242704 TI - Primers on molecular pathways: bicarbonate transport by the pancreas. AB - The pancreas has both endocrine and exocrine functions. As an endocrine organ, stimulation of the pancreatic beta-cells results in insulin secretion to control systemic glucose levels. The exocrine function of the pancreas and the need for alkaline pancreatic secretion (pH 8.0-8.5) have been appreciated for more than 40 years. Yet, our knowledge of the cellular mechanisms (signaling, transporters and channels) which accomplish these critical functions has evolved greatly. In the mid-1990s, basolateral Na-bicarbonate (HCO(3)(-)) uptake by NBCe1 (Slc4a4) was shown to be critical for the generation of approximately 75% of stimulated HCO(3)(-) secretion. In the last 10 years, several new HCO(3)(-) transporters in the Slc26 family and their interaction with the cystic fibrosis transmembrane conductance regulator-chloride channel have elucidated the HCO(3)(-) exit step at the ductal lumen. Most recently, both IRBIT (inositol 1,4,5-trisphosphate receptor-binding protein) and WNK [with no lysine (K)] kinase have been implicated as additional HCO(3)(-) secretory controllers. and IAP. PMID- 21242705 TI - Histopathologic and clinical subtypes of autoimmune pancreatitis: the honolulu consensus document. AB - Autoimmune pancreatitis (AIP) has been extensively reported from Japan, Europe and the USA. While the descriptions of AIP from Japan have predominantly been based on the presence of a distinct clinical phenotype, reports from Europe and the USA describe at least 2 histopathologic patterns in patients diagnosed with AIP, namely lymphoplasmacytic sclerosing pancreatitis (LPSP) and idiopathic duct centric pancreatitis (IDCP) or granulocytic epithelial lesion- positive pancreatitis. While the 2 entities share common histopathologic features (periductal lymphoplasmacytic infiltration and peculiar periductal fibrosis), expert pathologists can accurately distinguish them on the basis of other unique histopathologic features. Clinically, the 2 entities have a similar presentation (obstructive jaundice/pancreatic mass and a dramatic response to steroids), but they differ significantly in their demography, serology, involvement of other organs and disease relapse rate. While LPSP is associated with elevation of titers of nonspecific autoantibodies and serum IgG4 levels, IDCP does not have definitive serologic autoimmune markers. All experts agreed that the clinical phenotypes associated with LPSP and IDCP should be nosologically distinguished; however, their terminology was controversial. While most experts agreed that the entities should be referred to as type 1 and type 2 AIP, respectively, others had concerns regarding use of the term 'autoimmune' to describe IDCP. and IAP. PMID- 21242706 TI - Pancreatic cancer: the role of pancreatic stellate cells in tumor progression. AB - Pancreatic ductal adenocarcinoma is an aggressive and highly lethal disease frequently characterized by a dense stromal or desmoplastic response. Accumulating evidence exists that tumor desmoplasia plays a central role in disease progression and that e.g. activated pancreatic stellate cells (PSCs) are responsible for the excess matrix production. The mechanisms underlying the tumor versus stroma interplay are complex. Pancreatic cancer cells release mitogenic and fibrogenic stimulants, such as transforming growth factor beta(1), platelet derived growth factor (PDGF), sonic hedgehog, galectin 3, endothelin 1 and serine protease inhibitor nexin 2, all of which may promote the activated PSC phenotype. Stellate cells in turn secrete various factors, including PDGF, stromal-derived factor 1, epidermal growth factor, insulin-like growth factor 1, fibroblast growth factor, secreted protein acidic and rich in cysteine, matrix metalloproteinases, small leucine-rich proteoglycans, periostin and collagen type I that mediate effects on tumor growth, invasion, metastasis and resistance to chemotherapy. This review intends to shed light on the mechanisms by which PSCs in the stroma influence pancreatic cancer development. The increased understanding of this interaction will be of potential value in designing new modalities of targeted therapy. and IAP. PMID- 21242707 TI - Galanin receptor antagonist m35 but not m40 or c7 ameliorates cerulein-induced acute pancreatitis in mice. AB - BACKGROUND/AIMS: We compared the galanin antagonists C7, M35, M40 and galantide, for their ability to ameliorate acute pancreatitis (AP). METHODS: Galanin antagonists were co-administered with 7 hourly cerulein injections used to induce AP. Plasma amylase and lipase activities were measured as indices of AP, and pancreata were harvested at 12 h for histological examination and estimation of myeloperoxidase (MPO) activity. RESULTS: Treatment with galantide, M35 and C7 ameliorated the AP-induced plasma hyperenzymemia by 40-75%. Administration of M40 did not significantly alter plasma hyperenzymemia. Galantide, M35 and M40 significantly reduced the pancreatic MPO activity by 65-80%, whereas C7 increased MPO activity. Galantide and M35 but not C7 or M40 treatment significantly reduced the AP-induced necrosis score by 30-50% compared to the AP alone group. C7 alone increased plasma lipase activity and the pancreatic necrosis score compared with saline treatment alone, whereas the other antagonists were without effect. CONCLUSION: Galantide and M35 ameliorated the severity of AP, but M40 and C7 had mixed effects. Complex galanin pathways may be involved in cerulein-induced AP. M35 and galantide are potential therapeutic peptides for the treatment of AP and further evaluation should be considered. and IAP. PMID- 21242708 TI - Clinical value of serum neopterin, tissue polypeptide-specific antigen and CA19-9 levels in differential diagnosis between pancreatic cancer and chronic pancreatitis. AB - BACKGROUND: Neopterin and tissue polypeptide-specific antigen (TPS) have been suggested to be useful in differential diagnosis between pancreatic adenocarcinoma (PA) and chronic pancreatitis (CP). The aim of our study was to compare the clinical usefulness of CA19-9, neopterin and TPS serum levels in patients with PA and CP. METHODS: The study included 85 patients with PA, 72 with CP and 50 healthy controls. The serum concentrations of neopterin, TPS and CA19-9 were measured (DRG International, USA). The associations of the analyzed markers and clinical data at diagnosis have been evaluated. RESULTS: Serum levels of neopterin, TPS and CA19-9 were higher in PA patients compared to CP (p < 0.001). TPS and CA19-9 levels were also elevated in patients with CP compared to the control group (p < 0.001). In contrast, there was no difference between neopterin serum levels in CP patients and the control group (p > 0.05). Neopterin showed the best sensitivity and specificity (91.8 and 87.5%) in PA diagnosis compared to CA19-9 (respectively 83.5 and 75%) and TPS (75.3 and 65.3%). CONCLUSION: Our results indicate that neopterin may be potentially useful in differential diagnosis between PA and CP. Assessment of TPS probably adds no significant information to that obtained with CA19-9 and neopterin. and IAP. PMID- 21242709 TI - Clinical features and natural history of serous cystic neoplasm of the pancreas. AB - AIMS: To clarify the clinical features and the natural history of serous cystic neoplasm (SCN) of the pancreas. METHODS: We retrospectively analyzed data from 30 patients affected by SCN. SCNs were classified as (1) microcystic type, (2) micro and macrocystic type, and (3) macrocystic type according to the modified WHO classification. Eighteen patients who underwent serial radiographic imaging were identified, and tumor growth rate in these patients was evaluated. RESULTS: The median age was 62 years, and the female:male ratio was 2:1. Twenty-five patients (83%) were asymptomatic and 5 (17%) were symptomatic. The median tumor size was 2.6 cm. Fifteen cases (50%) had the microcystic type, 7 (23%) the micro- and macrocystic type, and 8 (27%) the macrocystic type. Age, gender, symptoms, location or tumor size did not differ significantly among the three subtypes. Eighteen patients were followed up for a median of 58 months. Morphological changes were observed in 3 patients (17%) and enlargement of tumor size in 9 patients (50%) during the follow-up. The growth rate was 0.29 cm per year and doubling time was 3.5 years; these rates did not differ among morphological subtypes or size of tumors. CONCLUSIONS: In asymptomatic patients with a clear imaging diagnosis of SCN, nonoperative management with a careful follow-up should be recommended. Surgery should be suggested in only symptomatic patients, those with giant tumors (>10 cm), rapid growing or when the presence of a potentially malignant tumor cannot be excluded. and IAP. PMID- 21242710 TI - Prognostic value of endoscopic ultrasound in acute pancreatitis. AB - BACKGROUND/AIMS: Endoscopic ultrasonography (EUS) is a useful modality to diagnose causes of pancreatitis. The role of EUS for prediction of pancreatitis severity has not been studied. The aim of this study was to identify the utility of EUS in determining the severity of acute pancreatitis (AP). METHODS: All patients diagnosed with pancreatitis consecutively underwent EUS on the 2nd day of their admission. Atlanta criteria were used as the severity index of pancreatitis. RESULTS: During the study period, 114 patients (74 females, 40 males; mean age of 53.03 +/- 17.7 years) were enrolled in the study. The most common cause of AP was gallstone (78.9%). According to the Atlanta criteria, pancreatitis was mild in 72 (63.2%) and severe in 42 (36.8%) patients. In univariate analysis, the presence of peripancreatic edema, pancreas inhomogeneity, common bile duct dilation and ascites were associated with severe pancreatitis. In multivariate analysis, only the presence of peripancreatic edema in EUS correlated with the severity of AP according to the Atlanta criteria (sensitivity, specificity and accuracy: 65.8, 75.7 and 72.2%, respectively). CONCLUSION: EUS may be a new useful imaging modality for prediction of severity of AP and may have prognostic significance in the early phase of AP. and IAP. PMID- 21242711 TI - A history of acute pancreatitis in intraductal papillary mucinous neoplasms of the pancreas is a potential predictive factor for malignant papillary subtype. AB - BACKGROUND/AIMS: There are several reports regarding intraductal papillary mucinous neoplasms (IPMNs) detected after the occurrence of acute pancreatitis. Although the presence of symptoms is regarded as a factor for predicting malignant IPMNs, there have been few reports demonstrating whether a history of acute pancreatitis is a predictor of malignancy. The aim of this study was to evaluate the relationship between a history of acute pancreatitis and clinicopathological features of IPMNs including the papillary subtype. METHODS: The data of 150 IPMNs resected between 1990 and 2009 were retrospectively reviewed. They were classified into IPMNs with or without history of acute pancreatitis, and then the clinicopathological features were compared between the 2 groups. RESULTS: Nineteen (13%) of the 150 patients had a history of acute pancreatitis. Nine of them had repeated episodes of pancreatitis; however, severe pancreatitis was uncommon. The diameter of the main pancreatic duct of the pancreatitis group was significantly larger than that of the nonpancreatitis group (p = 0.04). The pancreatitis group had a significantly higher frequency of carcinoma derived from IPMNs than the nonpancreatitis group (p = 0.03). The incidence of intestinal-type IPMNs in the pancreatitis group was significantly higher than that in the nonpancreatitis group (p < 0.001). CONCLUSION: Acute pancreatitis associated with IPMNs could predict malignant intestinal-type tumor. and IAP. PMID- 21242712 TI - Smoking is underrecognized as a risk factor for chronic pancreatitis. AB - BACKGROUND/AIMS: Smoking is an established risk factor for chronic pancreatitis (CP). We sought to identify how often and in which CP patients physicians consider smoking to be a risk factor. METHODS: We analyzed data on CP patients and controls prospectively enrolled from 19 US centers in the North American Pancreatitis Study-2. We noted each subject's self-reported smoking status and quantified the amount and duration of smoking. We noted whether the enrolling physician (gastroenterologist with specific interest in pancreatology) classified alcohol as the etiology for CP and selected smoking as a risk factor. RESULTS: Among 382/535 (71.4%) CP patients who were self-reported ever smokers, physicians cited smoking as a risk factor in only 173/382 (45.3%). Physicians cited smoking as a risk factor more often among current smokers, when classifying alcohol as CP etiology, and with higher amount and duration of smoking. We observed a wide variability in physician decision to cite smoking as a risk factor. Multivariable regression analysis however confirmed that the association of CP with smoking was independent of physician decision to cite smoking as a risk factor. CONCLUSIONS: Physicians often underrecognize smoking as a CP risk factor. Efforts are needed to raise awareness of the association between smoking and CP. and IAP. PMID- 21242713 TI - Factors in intraductal papillary mucinous neoplasms of the pancreas predictive of lymph node metastasis. AB - BACKGROUND: Little is known about the frequency of lymph node metastasis (LNM) in intraductal papillary mucinous neoplasms (IPMNs), and we have not been able to determine how much lymph node dissection is necessary in individual cases. The aim of this study was to investigate the predictive factors for the LNM in IPMNs. METHODS: Medical records of 120 patients pathologically diagnosed as having IPMN were reviewed, and 16 possible predictive factors regarding the LNM were analyzed. RESULTS: LNM was observed in 7 patients (6%), all of whom were diagnosed as having mural nodules preoperatively. Sensitivity, specificity, and accuracy of preoperative imaging for detecting mural nodules of IPMNs in this study were 84, 97, and 90%, respectively. Univariate analysis using 61 patients having mural nodules preoperatively revealed that the size of mural nodules >=10 mm and positive imaging findings for invasive tumor and possible LNM were significant predictive factors for the LNM. Multivariate analysis demonstrated that only an imaging finding for invasive tumor was an independent significant predictive factor. Positive and negative predictive values of the imaging finding of invasive IPMNs for LNM were 50 and 98%, respectively. CONCLUSIONS: Standard lymph node dissection would be recommended in patients with IPMNs with mural nodules demonstrating preoperative imaging findings for invasive carcinomas. and IAP. PMID- 21242714 TI - Severe acute pancreatitis requiring drainage therapy: findings on computed tomography as predictor of patient outcome. AB - BACKGROUND/AIMS: To evaluate whether morphologic features on computed tomography (CT) correlate with outcome of patients with severe acute pancreatitis (SAP). METHODS: 80 patients with SAP requiring percutaneous drainage therapy were retrospectively analyzed. Twelve CT features beyond the CT severity index (CTSI) were studied. Endpoints for patient outcome were patient death, length of hospital and ICU stay. The twelve features and the CTSI score were correlated with mortality using Kaplan-Meier estimator and correlated with length of hospital and ICU stay using the chi(2) test. A p value <=0.05 was considered statistically significant. RESULTS: Two CT features exhibited a significant correlation with mortality: (1) the number of parts of pancreas (head, corpus, tail) that exhibited areas of necrosis and (2) the presence of distant fluid collections (posterior pararenal space and/or paracolic gutter). Mortality was 42% (21 of 50 patients) and 20% (6 of 30 patients) if two/all three parts or none/one part of the pancreas exhibited necrosis, respectively. Mortality was 46% (18 of 39 patients) and 22% (9 of 41 patients) if distant fluid collections were present or absent, respectively. All other imaging features including the CTSI showed no significant correlation with patient outcome. CONCLUSION: We identified two morphologic features on CT that might be helpful to predict prognosis of patients suffering from SAP. and IAP. PMID- 21242715 TI - SKF 38393 and SCH 23390 inhibit reuptake of serotonin by rat hypothalamic synaptosomes. AB - BACKGROUND/AIMS: Both the dopamine receptor D(1) agonist SKF 38393 and the antagonist SCH 23390 are benzazepine derivatives that have been widely used as pharmacological tools and radioligands. Evidence suggests that behavioral effects of both compounds do not always correspond to their established receptor subtype selectivity. Here, we assessed the effects of SKF 38393 and SCH 23390 on the synaptosomal uptake of tritiated serotonin. METHODS: Uptake experiments were performed by using [(3)H]serotonin and synaptosomal fractions prepared from the hypothalamus of rat brain. RESULTS: Both SKF 38393 and SCH 23390 inhibited synaptosomal uptake of [(3)H]serotonin, with IC(50) values of 910 +/- 60 nmol/l and 1,400 +/- 80 nmol/l, respectively. Clomipramine, a known inhibitor of serotonin uptake, and (+)-amphetamine, a weak inhibitor, had IC(50) values of 14 +/- 1 nmol/l and more than 10,000 nmol/l, respectively, under the same experimental conditions. The IC(50) values for SKF 38393 and SCH 23390 fall within the broad range of corresponding values for antidepressants that have been shown to inhibit the uptake of serotonin. This finding indicates that SKF 38393 and SCH 23390 can enhance the activity of the serotonergic system in the brain, a mechanism that may be responsible for some of the effects of these drugs. CONCLUSION: SKF 38393 and SCH 23390 are useful tools to differentiate D(1) from D(2) receptors, but their indirect effects on serotonergic mechanisms have to be considered. PMID- 21242716 TI - Safety and reliability of the drug tolerance test: our experience in 739 patients. AB - BACKGROUND: Drug tolerance tests (DTTs) are commonly used to find a safe therapeutic alternative for patients with previous type B adverse drug reactions (ADRs), but few studies on safety and reliability are available. METHODS: We retrospectively studied 739 subjects with previous ADRs who underwent DTTs; 12 months after the test, use of the tested drug(s) and occurrence of ADRs were investigated in 260 of them. RESULTS: ADRs to antibiotics and nonsteroidal anti inflammatory drugs were the main reasons for which DTTs were requested. 925 DTTs were performed in the 739 patients, with 97 ADRs. Twelve months after the test, 125/260 patients interviewed had used the tested drug(s): 118 of them experienced no ADR, 4 experienced 'true' ADRs, and 3 reported predictable/unclear reactions. CONCLUSION: Our data show that DTTs are safe and reliable at 1 year, but patients and general practitioners do not trust them. It is strongly advisable to have better information on methods, benefits, risks and reliability of DTTs. PMID- 21242718 TI - Antioxidant therapies for wound healing: a clinical guide to currently commercially available products. AB - Many facets of wound healing under redox control require a delicate balance between oxidative stress and antioxidants. While the normal physiology of wound healing depends on low levels of reactive oxygen species and oxidative stress, an overexposure to oxidative stress leads to impaired wound healing. Antioxidants are postulated to help control wound oxidative stress and thereby accelerate wound healing. Many antioxidants are available over the counter or by prescription, but only one, Medihoney(r), has been specifically FDA approved for wound healing. Here we review the existing evidence for the use of antioxidants for wound healing, with a review of the pertinent animal and clinical studies. Natural products and naturally derived antioxidants are becoming more popular, and we specifically review the evidence for the use of naturally derived antioxidants in wound healing. Antioxidant therapy for wound healing is promising, but only few animal studies and even fewer clinical studies are available. Because only few products have undergone FDA approval, the consumer is advised to scrutinize them for purity and contaminants prior to use, and this may require direct contact with the companies that sell them. As a field of science, the use of antioxidants for wound healing is in its infancy, and future studies will better elucidate the role of antioxidants in wound healing. PMID- 21242719 TI - The 3 prime paradigm of the miR-200 family and other microRNAs. AB - The number of predicted human microRNAs in Sanger miRBase currently stands at over a thousand, with each of these in turn predicted to target numerous mRNAs. However, those microRNAs for which mRNA targets have been evaluated, verified and reported in the literature are still in the minority and the bulk of microRNA/mRNA interactions are yet to be confirmed. Confirmation of microRNA interaction with predicted mRNA targets represents a considerable undertaking, made more complex by potential synergistic effects of multiple microRNAs and the three possible outcomes (translational repression, degradation or a mixture of both). In addition, contrasting results obtained when either stably expressing or transiently transfecting members of the miR-200 family illustrate limitations in the verification methods currently in use. In this article we suggest that instead of allowing computational predictions to drive investigation, it would be desirable, when possible, to systematically evaluate microRNA targets using inducible, stable, ectopic expression. The advantage of stable lines ectopically expressing microRNA(s) is that they allow an analysis of changes to both the proteome and the transcriptome. This would allow verification of targets, improve the design of prediction algorithms and greatly increase our understanding of the outcome of microRNA/mRNA interaction. PMID- 21242720 TI - Genome-wide analysis of thioredoxin fold superfamily peroxiredoxins in Arabidopsis and rice. AB - A broad range of peroxides generated in subcellular compartments, including chloroplasts, are detoxified with peroxidases which are called as peroxiredoxins (Prx). The Prx are ubiquitously distributed in all organisms including bacteria, fungi, animals, and also in cyanobacteria and plants. Recently, the Prx have emerged as new molecules in antioxidant defense in plants. Here, the members which belong to Prx gene family in Arabidopsis and rice are been identified. Overall, the Prx members constitute a small family with 10 and 11 genes in Arabidopsis and rice respectively. The prx genes of rice are assigned to their functional groups based on homology search against Arabidopsis protein database. Deciphering the Prx functions in rice will add novel information to the mechanism of antioxidant defense in plants. Further, the Prx also forms the part of redox signaling cascade. Here, the Prx family has been described for rice. PMID- 21242721 TI - Fos-related antigen-1 (Fra-1) is a regulator of glioma cell malignant phenotype. PMID- 21242722 TI - Autophagy: a novel guardian of HCV against innate immune response. AB - Autophagy is an evolutionarily conserved process that catabolizes intracellular components and maintains cellular homeostasis. Autophagy involves the sequestration of cytoplasmic content within a double-membraned autophagosome, and the fusion of the autophagosome with a lysosome to form an autolysosome for subsequent degradation (Fig. 1A). Autophagy plays a pivotal role in various aspects of cellular responses to stresses, such as nutrient deprivation, damaged organelles, aggregated proteins, exposure to endoplasmic reticulum (ER) stress and pathogen infections. Virus infection often leads to ER stress and induction of the unfolded protein response (UPR). Recent studies reveal that virus-induced UPR may activate autophagy to support the virus life cycle. However, the exact roles of the UPR and autophagy in host cell-virus interactions are still enigmatic. PMID- 21242723 TI - New paradigm in ethylene signaling: EIN2, the central regulator of the signaling pathway, interacts directly with the upstream receptors. AB - The membrane protein ETHYLENE INSENSITIVE2 (EIN2), which is supposed to act between the soluble serine/threonine kinase CTR1 and the EIN3/EIL family of transcription factors, is a central and most critical element of the ethylene signaling pathway in Arabidopsis. In a recent study, we have identified that EIN2 interacts tightly with all members of the Arabidopsis ethylene receptor family - proteins that mark the starting point of the signaling pathway. Our studies show consistently that the kinase domain of the receptors is essential for the formation of the EIN2-receptor complex. Furthermore, mutational analysis demonstrates that phosphorylation is a key mechanism in controlling the interaction of EIN2 and the ethylene receptors. Interaction studies in the presence of the ethylene agonist cyanide revealed a causal link between hormone binding and complex formation. In the presence of the plant hormone agonist the auto-kinase activity of the receptors is inhibited and the non-phosphorylated kinase domain of the receptors binds tightly to the carboxyl-terminal domain of EIN2. In the absence of cyanide inhibition of the auto-kinase activity is relieved and complex formation with the phosphorylated kinase domain of the receptors is reduced. Our data suggest a novel model on the integration of EIN2 in the ethylene signaling pathway. PMID- 21242724 TI - Zinc homeostasis is involved in unfolded protein response under salt stress. AB - Accumulation of unfolded protein or misfolded protein causes endoplasmic reticulum (ER) stress. Increased salt concentration activates a stress response pathway in the ER in Arabidopsis thaliana to induce the expression of several salt stress response genes, leading to a more optimal protein folding environment in the ER. In addition, some salt stress-regulated proteins require zinc for their activity, including some zinc-dependent DNA binding proteins and zinc finger proteins. In a recent study, we reported that ZTP29, a putative zinc transporter at the ER membrane, is involved in the response to salt stress through regulation of zinc level in the ER to induce the UPR pathway. In this addendum, we propose a testable hypothesis for the role of ZTP29 in the response to salt stress via the regulation of zinc levels in the ER. PMID- 21242725 TI - Farnesyl transferase inhibitors, autophagy, and proteasome inhibition: synergy for all the right reasons. AB - The increasing appreciation of the importance of autophagy as consequence of cancer therapy or underlying disease biology is illustrated by the large number of papers that are evaluating autophagy as a cancer target. While autophagy is often linked to the generation of metabolic precursors, it is also important in diseases where protein production is a hallmark of the disease itself, such as pancreatic cancer and multiple myeloma. Multiple myeloma is characterized by ongoing autophagy as a consequence of constitutive immunoglobulin production, which creates the need for efficient transfer and disposal of misfolded or unfolded proteins. In order to survive this cellular stress, plasma cells depend on proteasomal degradation of the large volume of misfolded proteins as well as the autophagy pathway. It has previously been suggested that the excess proteins not targeted to the proteasome, or that accumulate when the proteasome is inhibited through the use of chemically active agents such as bortezomib, are linked to impaired cell survival, and that their packaging in the form of an aggresome somehow minimizes their 'proteotoxicity' allowing these toxic proteins to be sequestered away from normal cellular machinery. PMID- 21242726 TI - Regulatory and policy issues for T1DM immunotherapy. AB - The development of immunotherapies for T1DM has lagged the development T2DM drugs, but with more clarity around regulatory requirements, large pharmaceutical companies have recently entered the field to support late stage programs. This clarity around regulatory expectations has emerged because of the convergence among regulators and clinical experts in how efficacy of these therapies should be assessed. The key agreement is that the primary efficacy endpoint for treatments directed at the underlying autoimmune cause of T1DM should be endogenous insulin secretion as reflected by standardized C-peptide measurements. Important secondary endpoints include glycemic control, total daily insulin dose, and hypoglycemia rates. Most T1DM therapeutic development efforts are directed at new onset disease, which represents a small proportion of the entire T1DM population. A new frontier in T1DM therapeutic development is emerging around combination treatment of established T1DM, a population that far outnumbers those with new onset T1DM. Fully effective therapies of new onset or established T1DM will almost certainly require a combination of two or more therapies. A T1DM prevention vaccine will not be feasible until after extensive experience with the agent as a treatment of new onset and/or established T1DM. PMID- 21242727 TI - Who will bell the cat? A call for a new approach for validating blood pressure measuring devices. PMID- 21242733 TI - Did you implement the 2011 HCPCS code changes? PMID- 21242734 TI - Suprathel-antiseptic matrix: in vitro model for local antiseptic treatment? AB - Acetic acid is a traditional antiseptic agent that has been used for more than 6000 years. The main goal of this study was to demonstrate the suitability of Suprathel (PolyMedics Innovations GmbH, Denkendorf, Germany) in combination with various antiseptic agents to create an "antiseptic-matrix" especially designed for problematic microorganisms such as Proteus vulgaris, Acinetobacter baumannii, or Pseudomonas aeruginosa, which are frequently associated with burns. The study was designed to test the in vitro antimicrobial effect of a "Suprathel-antiseptic matrix" (Suprathel combined with acetic acid 3%, povidone-iodine 11% [Betaisodona], polyhexanide 0.04% [Lavasept], phenoxyethanol 2%/octenidine dihydrochloride 0.1% [Octenisept], mafenide acetate 5%, and chlorhexidine gluconate 1.5%/cetrimid 15% [Hibicet]). As a means to assess the typical bacterial spectrum of a burn unit, the following Gram-negative and Gram-positive bacteria strains were tested: Escherichia coli, P vulgaris, P aeruginosa, A baumannii, Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus aureus, methicillin-resistant S aureus, and beta-hemolytic streptococcus groups A and B. The tests showed a positive bactericidal effect of the Suprathel antiseptic matrix, particularly with problematic Gram-negative bacteria such as P vulgaris, P aeruginosa, and A baumannii, except for the combination of Suprathel and mafenide acetate. It can be concluded that Suprathel-antiseptic matrix appears to be suitable as a local antiseptic agent, but clinical studies need to be performed to confirm these in vitro observations. The authors' previous studies have shown that acetic acid demonstrates a wide antiseptic spectrum for microorganisms typically found in burn patients. The combination of Suprathel and acetic acid worked well in this study and appears to be promising for future clinical application. PMID- 21242735 TI - Leading wound care technology: The ARANZ medical silhouette. AB - Despite major advances in medical technology and wound care, wound assessment and documentation still rely mainly on rudimentary measures. Many practitioners continue to estimate wound size using maximal length, width, and depth measurements with rulers and probes. Others use acetate tracings or equivalent measures to outline the wound onto a grid to estimate surface area and document wound border changes. Even fewer practitioners seem to routinely photograph wounds with an included scale for more visual records. This article presents a recently developed device that is changing clinical documentation, assessment, auditing, and interservice communication-the ARANZ Medical Silhouette (ARANZ Medical Limited, Christchurch, New Zealand). PMID- 21242736 TI - Risk factors for pressure ulceration in an older community-dwelling population. AB - BACKGROUND: Older adults frequently experience pressure ulcers (PrUs) and suffer the risks of the ulceration. Risk factors for PrUs remain unclear in a community population. OBJECTIVE: The objective of this study was to determine the risk factors for future pressure ulceration in a community sample. DESIGN: This was a retrospective cohort study. PATIENTS: All patients older than 60 years in a primary care panel in Olmsted County, Minnesota, on January 1, 2005, were enrolled (n = 12,650). METHODS AND OUTCOMES: The primary outcome was a new diagnosis of pressure ulceration within 40 months of index date. The predictor risk variables included demographic and comorbid health risk factors. The data were analyzed using univariable and multivariable logistic regression. The authors created a final model based on multivariable risk factors. MAIN RESULTS: Of 12,650 patients, 366 patients developed an incident PrU (2.9%). In the final model, age, male sex, and long-term-care facility admission were significant factors. Prior pressure ulceration with an odds ratio of 5.60 (95% confidence interval, 3.86-8.14) was the largest risk factor. Diabetes, falls, cataracts, renal insufficiency, and peripheral vascular disease were also associated with PrU development. CONCLUSION: PrU development involves important risk factors of prior PrU development and long-term-care facility placement as the 2 largest risk factors. Both factors are easily determined by history. Increasing age and comorbid medical conditions also impact PrU development as important risk factors for PrU development. PMID- 21242739 TI - Venous dermatitis checklist. PMID- 21242737 TI - Reduction of bacterial burden and pain in chronic wounds using a new polyhexamethylene biguanide antimicrobial foam dressing-clinical trial results. AB - OBJECTIVE: A randomized controlled trial to evaluate the effectiveness of a polyhexamethylene biguanide (PHMB) foam dressing compared with a similar non antimicrobial foam for the treatment of superficial bacterial burden, wound associated pain, and reduction in wound size. SETTING AND PARTICIPANTS: This study was conducted in 2 wound healing clinics-a university hospital-based clinic and a community-based clinic. Forty-five chronic wound subjects, stratified to either foot or leg ulcers, were followed for 5 weeks. METHODS: A multicenter, prospective, double-blind, pilot, randomized controlled clinical trial with 3 study visits (Weeks 0, 2, 4) documented pain and local wound characteristics using NERDS and STONEES clinical criteria to determine superficial bacterial damage or deep/surrounding infection. RESULTS: The use of PHMB foam dressing was a significant predictor of reduced wound superficial bacterial burden (P = .016) at week 4 as compared with the foam alone. Pain reduction was also statistically significant at week 2 (P = .0006) and at week 4 (P = .02) in favor of the PHMB foam dressings. Polymicrobial organisms were recovered at week 4 in 5.3% in the PHMB foam dressing group versus 33% in the control group (P = .04). Subjects randomized to the PHMB foam dressing had a 35% median reduction in wound size by week 4, compared with 28% in the control group. CONCLUSIONS: PHMB foam dressing successfully reduced chronic wound pain and bacterial burden. PMID- 21242740 TI - Treatment of psychogenic polydipsia with acetazolamide: a report of 5 cases. AB - OBJECTIVE: Psychogenic polydipsia occurs frequently in patients with chronic psychiatric illness and is often unmanageable. We herein report 5 patients in whom acetazolamide was trialed for this symptom. METHODS: We encountered a case in which polydipsia improved with incidental administration of acetazolamide. We then used this treatment for 4 additional cases of treatment-resistant psychogenic polydipsia, some of which were accompanied by hyponatremia. RESULTS: Acetazolamide improved polydipsia and/or hyponatremia in 4 of the 5 cases. This treatment was well tolerated and allowed 3 of the patients to permanently leave isolation. CONCLUSION: Acetazolamide appears to have a beneficial effect in psychogenic polydipsia. PMID- 21242741 TI - A 52-week study of gabapentin enacarbil in restless legs syndrome. AB - OBJECTIVES: This open-label, multicenter, 52-week extension study (NCT00333359) assessed the long-term safety and efficacy of gabapentin enacarbil in subjects with moderate-to-severe primary restless legs syndrome (RLS). METHODS: Subjects had completed one of 4 randomized, double-blind parent studies (XP052/XP053/XP081/XP083). Gabapentin enacarbil 1200 mg was administered once daily at 5 pm; dose adjustments to 600 or 1800 mg were permitted based on investigator judgment. Safety assessments included adverse events (AEs), vital signs, clinical laboratory tests, and electrocardiograms. Efficacy evaluations included the International Restless Legs Scale total score and the investigator rated Clinical Global Impression-Improvement scale, at week 52 last observation carried forward. RESULTS: The safety population comprised 573 subjects; 386 (67.4%) completed the study. Treatment-emergent AEs were reported by 80.1% of subjects and led to withdrawal in 10.3% of subjects; most (67.7%) were mild or moderate in intensity. The most common AEs were somnolence and dizziness (19.7% and 11.5% of subjects). Twenty subjects (3.5%) reported serious AEs; one subject died (fall, 25 days after stopping gabapentin enacarbil, judged not treatment related). No serious AE occurred in more than 1 subject. No clinically relevant changes were reported in vital signs, laboratory parameters, or electrocardiograms. At week 52 last observation carried forward, the mean (SD) change from parent study baseline in International Restless Legs Scale total score was -15.2 (8.85 [parent study baseline score, 23.2 (5.03)]), and 84.8% of subjects were Clinical Global Impression-Improvement responders ("much improved" or "very much improved"). CONCLUSIONS: Gabapentin enacarbil was generally safe and well tolerated and improved RLS symptoms in subjects with moderate-to-severe primary RLS for up to 64 weeks of treatment. PMID- 21242742 TI - Cladribine: mode of action and implications for treatment of multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system. The inflammation is driven significantly by autoreactive lymphocytes, which recruit cells of the innate immune system such as macrophages that contribute to subsequent tissue damage, ultimately resulting in demyelination and axonal damage that are characteristic in MS lesions. Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic chlorinated deoxyadenosine analog that is biologically active in selected cell types and provides targeted and sustained reduction of circulating T and B lymphocytes implicated in the pathogenesis of MS. The biologic activity of cladribine depends on the preferential accumulation of cladribine phosphates in cell types with a high intracellular ratio of deoxycytidine kinase to 5'-nucleotidases. Cladribine phosphates interfere with DNA synthesis and repair through incorporation into DNA and through inhibition of enzymes involved in DNA metabolism, including DNA polymerase and ribonucleotide reductase. This in turn leads to DNA strand breaks and ultimately cell death. This review explores the mechanism of action of cladribine further, in the context of recent clinical data, after completion of the phase III, 96-week, placebo-controlled CLARITY study. In this study, cladribine tablets demonstrated significant efficacy on clinical and neuroimaging outcomes in relapsing-remitting MS. PMID- 21242743 TI - Treatment of irritable bowel syndrome with comorbid anxiety symptoms with mirtazapine. AB - Irritable bowel syndrome (IBS) is a functional gastrointestinal tract disorder characterized by recurrent abdominal pain or discomfort, where the onset is associated with either a change in form of stool or its frequency and is often improved with defecation. Alosetron, a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, was an effective drug in treating women with diarrhea-predominant IBS. However, the drug was removed from the United States market because of its association with ischemic colitis and serious complications related to severe constipation. Presented here is a case report of a 66-year-old woman with a history of panic disorder and major depression and a 1-year history of IBS-mixed type, which she reported to be "worsened by panic attacks." On the basis that mirtazapine is a potent 5-HT3 receptor antagonist and has demonstrated pain relief from somatic symptoms, we treated our patient with mirtazapine, which seems to have decreased her diarrhea and constipation symptoms, and her psychopathological symptoms. PMID- 21242745 TI - Dropped head associated with amantadine in Parkinson disease. AB - The antiviral agent amantadine has been used to manage Parkinson's disease or levodopa-induced dyskinesias for nearly 5 decades. Amantadine is often associated with hallucinations as an adverse effect, but a long-term study reported no serious motor complications. We describe an unusual patient who had Parkinson's disease with dropped head syndrome (DHS) caused by amantadine. When the patient, who had DHS while receiving only 2 kinds of antiparkinsonian drugs, was rechallenged with amantadine, DHS developed, accompanied by increased muscle tone in the neck muscles on surface electromyogram. The DHS resolved after the withdrawal of amantadine. Moreover, an intravenous infusion of levodopa did not alter the DHS. These findings collectively suggest that the DHS in our patient was most likely caused directly by amantadine. Our findings suggest that amantadine may carry the risk of augmenting dystonic syndrome in humans. PMID- 21242744 TI - Safety and tolerability of lamotrigine: results from 12 placebo-controlled clinical trials and clinical implications. AB - The mechanism of action of lamotrigine depends on voltage-sensitive sodium channels by which the neuronal membrane is stabilized and the release of excitatory neurotransmitters, such as glutamate and aspartate, is inhibited. Lamotrigine is indicated for maintenance treatment of bipolar I disorder to delay the time to the occurrence of mood episodes for those treated for acute mood episodes with standard therapy. There are significant gaps between clinical practices and research settings; data from controlled clinical trials of lamotrigine provide essential information about safety in bipolar populations because they result from large samples of patients with a specific disease and include comparisons with placebo or other comparators with randomized designs. In addition, lamotrigine's safety and tolerability data differ slightly in relation to disease entities, age ranges of the patients taking lamotrigine, and treatment conditions. For example, the incidence of serious rashes, including Stevens Johnson syndrome, is approximately 0.8% (8/1000) in pediatric patients (2-16 years of age) receiving lamotrigine as adjunctive therapy for epilepsy and 0.3% (3/1000) in adults on adjunctive therapy for epilepsy. In clinical trials of bipolar and other mood disorders, the rate of serious rash was 0.08% (0.8/1000) in adult patients receiving lamotrigine as initial monotherapy and 0.13% (1.3/1000) in adult patients receiving lamotrigine as adjunctive therapy. Hence, in this study, we focus on the data regarding the safety and tolerability of lamotrigine in the treatment of bipolar disorder gathered from 12 placebo controlled trials, regardless of publication status, that were sponsored by GlaxoSmithKline. We also inform clinicians of practical issues in safety and tolerability in the use of lamotrigine in the treatment of bipolar disorders. PMID- 21242746 TI - WGO Training Center update. PMID- 21242747 TI - Long-term durability of infliximab treatment in Crohn's disease and efficacy of dose "escalation" in patients losing response. AB - BACKGROUND: The efficacy of infliximab therapy in patients with Crohn's disease (CD) is unknown beyond 12 months. For patients who lose their initial response, consideration can be given to dose "escalation" to regain therapeutic benefit. AIM: Our primary goal was to evaluate the long-term durability of maintenance infliximab treatment. The secondary goals were to identify potential predictors of loss of infliximab efficacy, to evaluate the response to infliximab escalation, and the safety of the treatment with infliximab with and without escalation of dose. METHODS: CD patients treated with infliximab with response to an induction regimen were evaluated. Maintenance of long-term response was estimated using Kaplan-Meier analysis. The effect of specific variables was calculated using logistic regression analysis. Efficacy of dose escalation in patients who lose response to infliximab was analyzed. RESULTS: Three hundred and nine CD patients were included. The mean follow-up time with infliximab treatment was 41 months, and the majority (95%) were on concomitant immunosuppressive therapy. The annual risk of loss of response to infliximab was 12% per patient year of treatment. After loss of response, 41% of patients were managed with infliximab therapy escalation. After the first intensified dose, 56% of patients achieved remission and 40% partial response. Concurrent immunomodulators enhanced and smoking decreased the proportion of patients who maintained response (P<0.05). CONCLUSIONS: A relevant proportion of CD patients on long-term infliximab treatment loss response. After loss of response, a high proportion of these patients initially respond to infliximab dose escalation. Concurrent immunomodulators may increase and smoking may decrease maintenance of response. PMID- 21242749 TI - The pediatric infectious disease journal(r) newsletter: february 2011. PMID- 21242750 TI - B cell immunology for the clinician. PMID- 21242751 TI - Recurrent Fever, arthritis, lymphadenopathy, and hepatosplenomegaly. PMID- 21242753 TI - Pneumococcal pneumonia in preschool children: viral coinfection does not worsen clinical outcome. PMID- 21242754 TI - Rapid diagnosis of smear-negative tuberculous osteoarthritis by real-time polymerase chain reaction on bone tissue. PMID- 21242755 TI - Extensive hyperpigmented plaques in a chinese singaporean woman: a case of cutaneous plasmacytosis. AB - Cutaneous plasmacytosis is a rare disease entity presenting with multiple extensive red-brown plaques, histopathology showing marked hyperplasia of mature polyclonal plasma cells, and polyclonal hypergammaglobulinemia on serum protein electrophoresis, in the absence of an underlying secondary cause. We report in this article the first case of cutaneous plasmacytosis from Singapore. A 33-year old Chinese woman presented with mildly pruritic reddish brown papules and plaques over her trunk and arms for 2 years. Physical examination, laboratory investigations, and radiographic examination were negative for systemic involvement and lymphadenopathy. Serum immunoelectrophoresis showed polyclonal hypergammaglobulinemia with immunoglobulin G and immunoglobulin A. Two sets of skin biopsies performed 2 years apart essentially showed similar histopathological findings of a superficial and deep perivascular infiltrate with numerous mature plasma cells and small typical lymphocytes. There were lymphoid follicles with well-formed germinal centers and mantle zones, surrounded by mature lymphocytes. No light chain restriction was present on immunohistochemistry, and polymerase chain reaction for heavy chain gene rearrangement was negative for monoclonality. Despite potent topical corticosteroids and 8 months of phototherapy with narrow band ultraviolet light, there was no improvement. Intralesional triamcinolone injections to a few lesions afforded temporary relief of itch and flattening of lesions. PMID- 21242756 TI - Ichthyosis follicularis, alopecia, and photophobia syndrome: a case report and a pathological insight into pilosebaceous anomaly. AB - Ichthyosis follicularis, alopecia, and photophobia (IFAP) syndrome (OMIM 308205) is an extremely rare X-linked oculocutaneous genetic disorder characterized by follicular keratotic papules, total to subtotal alopecia, and photophobia. Previous reports depicted the histopathological features of affected skin lesions, represented by marked follicular plugging and hypoplastic pilosebaceous structures. However, past studies provided limited pathological information of pilosebaceous unit anomaly. Here, we report a 3-year-old boy's case with this uncommon condition. In this case, scalp biopsy samples were processed by both vertical and transverse sectioning techniques, which enabled a more detailed and quantitative pathological analysis of pilosebaceous structures. In vertical slices, miniaturized anagen hair follicles with characteristic follicular plugs were observed. A transverse section identified abortive sebaceous glands in hair follicles, a finding rarely observed in vertical sections. In addition, a transverse slice demonstrated that the number of total hair follicles was not significantly decreased compared with the average hair follicle density in Asians, suggesting that the pilosebaceous hypoplasia might arise from impaired maturation, not from initiation defect, during hair follicle morphogenesis. This study provides a more comprehensive pathological insight into pilosebaceous anomaly in IFAP syndrome and substantiats the usefulness of the combination of vertical and transverse sectioning approaches in the pathological examination of congenital hypotrichosis, including IFAP syndrome. PMID- 21242757 TI - Granuloma annulare of the penis: a uncommon location for an usual disease. AB - The subcutaneous clinical variant of granuloma annulare (GA) is rare and tends to present more frequently in children, in locations unusual for conventional GA. Involvement of the penis is exceptional and has been rarely reported. Most cases are located in the shaft of the penis and tend to persist without spontaneous remission. Diagnosis is done only after biopsy, and surgical resection of the lesions is not unusual. We report a new case of subcutaneous GA of the penis in a 13-year-old boy with lesions persistent for the past year. Surgical excision of one of them allowed the correct diagnosis. No further treatment was done, and the condition has not remitted 1 year later. We stress the importance of clinical recognition of unusual presentations of GA to avoid overtreatment of lesions that do not need an aggressive approach. PMID- 21242758 TI - Contaminant Treponema-positive bacteria in cutaneous biopsies with an infiltrate rich in plasma cells. PMID- 21242759 TI - Extraosseous calcification in chronic renal failure. PMID- 21242760 TI - Oral lichenoid reaction, dental amalgam, and tin allergy. PMID- 21242761 TI - Leukemia cutis in association With Grover's disease. AB - Grover's disease (GD), or transient acantholytic dermatosis, is a persistent recurrent dermatosis that usually occurs in men older than 50 years. Rare cases of GD and hematologic malignancy in the same cutaneous biopsy specimen have been reported. We report a case of GD in association with leukemia cutis. A 72-year old man with a history of myelodysplastic syndrome presented with numerous pruritic papules on the torso, which were clinically diagnosed as GD. A skin biopsy revealed foci of suprabasal acantholysis and dyskeratosis consistent with GD and dense aggregates of mononuclear atypical cells in the superficial dermis consistent with leukemia cutis. Direct immunofluorescence was negative. This case illustrates the need to consider a diagnostic skin biopsy in any patient who presents with classic clinical findings of GD if there is any indication that the patient may be at higher risk for a hematologic malignancy. PMID- 21242763 TI - Life after cancer: living with risk. AB - BACKGROUND: Recent research shows that cancer survivors are at greater risk of developing cancer than the general population. Although recommended, many cancer survivors receive no regular cancer screening. Cancer survivors' perceptions of their second cancer risk are, in part, suspected to influence their participation in cancer screening. OBJECTIVE: This study was conducted to explore how cancer survivors define and interpret second cancer risk. METHODS: An interpretive descriptive approach was taken whereby semistructured interviews were conducted with 22 cancer survivors (16 women and 6 men) drawn from a provincial cancer registry. The sample ranged in age from 19 to 87 years. The cancer history of the participants varied. Data were analyzed using the constant comparative method of data analysis. RESULTS: The overall theme, "life after cancer-living with risk," described cancer survivors' sense that risk is now a part of their everyday lives. Two themes emerged from the data that speak to how cancer survivors lived with second cancer risk: (1) thinking about second risk and (2) living with risk: a family affair. CONCLUSIONS: Effective risk communication to support the decisions made by cancer survivors with respect to cancer screening is warranted. IMPLICATIONS FOR PRACTICE: Study results provide foundational knowledge about the nature of second cancer risk that may be used to develop and refine standards for survivorship care including how second cancer risk can be best managed. PMID- 21242762 TI - Informal caregivers of hematopoietic cell transplant patients: a review and recommendations for interventions and research. AB - BACKGROUND: Informal caregivers (ICs) for medically fragile hematopoietic cell transplantation (HCT) patients are a vital unrecognized population supporting the transplant patient along the illness continuum. The long transplant recovery period shifts a greater burden of care to the patient's IC. Assessment of HCT caregivers' quality of life (QOL) and health status is critical to implementation of timely intervention and support. METHODS: A literature search using several search strategies covering 1980 to 2010 identified studies on ICs of HCT patients. These studies were summarized within the caregiver concepts of QOL, role, and resources. Findings of this review were used to create recommended interventions and identify implications for further research. RESULTS: Although limited, research on ICs of hematopoietic call transplant patients provides beginning evidence for clinical interventions to support this caregiver population. Interventions created focus on education, psychosocial support, and self-care. CONCLUSIONS: Although limited randomized trials of interventions have been reported, descriptive studies provide evidence for creating intervention content that addresses the needs of ICs of HCT patients. Testing of these interventions and additional areas of research are identified. IMPLICATIONS FOR PRACTICE: Beginning descriptive evidence provides the basis for interventions for ICs of HCT patients. These interventions support caregiver QOL and role implementation, depending on individual caregivers' resources and needs. Further evaluation and clinical research are needed. PMID- 21242764 TI - Difficulties of nursing staff involved in phase 1 oncology trials in Japan. AB - BACKGROUND: Nurses, such as clinical research coordinators (CRCs) and nursing staff, are playing a greater role in clinical trials. Prior studies show that CRCs face various challenges, yet information on the problems nursing staff encounter in phase 1 oncology trials is limited. OBJECTIVE: The purpose of the present study was to explore using a qualitative and descriptive approach the difficulties that nursing staff experience in their work with phase 1 oncology trials. METHODS: Twenty-one nurses from 2 hospital wards in Japan with phase 1 oncology trials completed semistructured interviews. The data were analyzed qualitatively and descriptively. RESULTS: The results show that nursing staff were expected to take on broader roles as specialists in clinical trial nursing. These expectations led to 3 categories of difficulties: caring for patients, conducting accurate and reliable clinical trials, and collaborating with the clinical trial team. In some cases, these had a negative effect on nurses' attitudes toward clinical trials. CONCLUSIONS: Nursing staff face unique difficulties, including a lack of clearly defined responsibilities and recognition from the clinical trial team. These differ from difficulties in ordinary oncology nursing and are similar to those encountered by CRCs. IMPLICATIONS FOR PRACTICE: The clinical trial team should reinforce the need for a collaborative approach, provide education and support for nursing staff, and recognize the critical role nurses play as specialists. These steps are important for the well-being of patients and the conduct of high-quality clinical trials. PMID- 21242765 TI - "I had already made up my mind": patients and caregivers' perspectives on making the decision to participate in research at a US cancer referral center. AB - BACKGROUND: Hematopoietic cell transplants (HCTs) are associated with high morbidity and mortality, which complicate the decision-making process for people considering HCT clinical trials. There is a lack of research examining longitudinally how patients make clinical trial participation decisions in US cancer referral centers. OBJECTIVE: A qualitative study was conducted to examine how patients and their family caregivers decide to participate in HCT research at a US cancer referral center. METHODS: Semistructured interviews were conducted with 25 patients enrolled in early-stage phase 2 HCT research studies and with 20 family caregivers. Interviews were conducted before HCT and approximately days 80 and 365 after HCT. RESULTS: Most patients (92%) and their caregivers (75%) decided to participate in research well before consent conferences at the cancer referral center. Patients' reasons for deciding to participate included having "no other option," seeking a cure, and following their home oncologists' recommendations. CONCLUSION: Currently, US researchers are primarily guided by Federal regulations that view the decision-making process as a cognitive one. Findings confirmed cognition was a part of consent; however, most patients made the decision to participate in high-risk clinical trials long before they had been apprised of the specific information about the study and before the consent conference. IMPLICATIONS FOR PRACTICE: The high risk of death from the disease and/or the HCT underscored the emotional component of decision making and affirmed that researchers need to acknowledge this emotional component to meet the ethical imperative of providing "informed consent." PMID- 21242766 TI - Treatment decision regret and related factors following radical prostatectomy. AB - BACKGROUND: Issues such as physical and psychological distress impact the quality of life of patients after a radical prostatectomy (RP). It is important to understand the regret that patients often report following a RP and the factors that influence their regret. OBJECTIVE: The objective of the present study was to understand the regret that patients report following a RP and the influencing factors for their regret. METHODS: Patients who had a diagnosis of prostate cancer and who underwent a RP between 2004 and 2010 were recruited for this study. The data gathered included a regret scale; the University of California, Los Angeles, Prostate Cancer Index; and demographic and disease-related information. RESULTS: A total of 100 patients participated in our study. Of those who participated, 31% regretted that they had received an RP. Stepwise regression showed that the following 5 variables were predictors of patient regret after an RP: whether the patient would choose to have an RP again, understanding the treatment and complications, bothersome adverse sexual effects, age, and bothersome adverse bowel effects. CONCLUSION: We found that 31% of the participants reported experiencing regret after receiving an RP. Our data suggest that urologists and nurses should carefully portray the risks and benefits of RPs during preoperative counseling to minimize patient regret and maximize patient satisfaction. IMPLICATIONS FOR PRACTICE: Patient regret after an RP is common. Urological nurses should therefore counsel patients regarding the impacts of complications associated with RPs and seek appropriate nursing interventions to reduce patient regret following an RP. PMID- 21242768 TI - Assessing cancer-related learning needs of Texas nurses. AB - BACKGROUND: Given the growing number of cancer survivors, all nurses must have current knowledge and skills to provide competent cancer care. Accordingly, access to evidence-based educational opportunities designed to promote ongoing competency must be ensured. Program offerings and services should be based on a systematic and periodic approach to provide appropriate programming that meets learners' self-identified needs, priorities, and self-reported gaps in existing knowledge and practice. OBJECTIVE: The purpose of this article was to report the process and findings of a statewide needs assessment of cancer-related needs of nurses across all practice settings. METHODS: A convenience sample of licensed nurses was recruited from throughout Texas to complete a learning needs assessment instrument. RESULTS: Five hundred twenty-one nurses completed the survey. Results revealed several priority areas for educational programming, including clinical care topics, survivorship issues, tobacco cessation strategies, and clinical trials. Although results varied somewhat between oncology and nononcology nurses, both groups cited time constraints as the biggest barrier to integrating cancer-related knowledge and skills into their practice. CONCLUSION: Findings from the survey can be used to direct program priorities and approaches for ongoing educational services that promote delivery of competent cancer care. IMPLICATIONS FOR PRACTICE: This approach to a cancer focused needs assessment serves as an exemplar for nursing education leaders who are charged with developing and delivering cancer-specific programming for nurses. PMID- 21242767 TI - Comparison of the prevalence of malnutrition diagnosis in head and neck, gastrointestinal, and lung cancer patients by 3 classification methods. AB - BACKGROUND: Malnutrition is prevalent among patients within certain cancer types. There is lack of universal standard of care for nutrition screening and a lack of agreement on an operational definition and on validity of malnutrition indicators. OBJECTIVE: In a secondary data analysis, we investigated prevalence of malnutrition diagnosis with 3 classification methods using data from medical records of a National Cancer Institute-designated comprehensive cancer center. METHODS: Records of 227 patients hospitalized during 1998 with head and neck, gastrointestinal, or lung cancer were reviewed for malnutrition based on 3 methods: (1) physician-diagnosed malnutrition-related International Classification of Diseases, Ninth Revision codes; (2) in-hospital nutritional assessment summaries conducted by registered dietitians; and (3) body mass indexes (BMIs). For patients with multiple admissions, only data from the first hospitalization were included. RESULTS: Prevalence of malnutrition diagnosis ranged from 8.8% based on BMI to approximately 26% of all cases based on dietitian assessment. kappa coefficients between any methods indicated a weak (kappa = 0.23, BMI and dietitians; and kappa = 0.28, dietitians and physicians) to-fair strength of agreement (kappa = 0.38, BMI and physicians). CONCLUSIONS: Available methods to identify patients with malnutrition in a National Cancer Institute-designated comprehensive cancer center resulted in varied prevalence of malnutrition diagnosis. A universal standard of care for nutrition screening that uses validated tools is needed. IMPLICATIONS FOR PRACTICE: The Joint Commission on the Accreditation of Healthcare Organizations requires nutritional screening of patients within 24 hours of admission. For this purpose, implementation of a validated tool that can be used by various healthcare practitioners, including nurses, needs to be considered. PMID- 21242769 TI - Comparison of differences and determinants between presence and absence of sleep disturbance in hepatocellular carcinoma patients. AB - BACKGROUND: Hepatocellular carcinoma patients often experience sleep disturbance after undergoing transcatheter arterial chemoembolization (TACE). OBJECTIVE: The objectives of this study were to (1) examine and compare symptom distress, depression, and sleep quality in hepatocellular carcinoma patients undergoing TACE with sleep disturbance versus without sleep disturbance and (2) examine the determinants of sleep disturbance in these patients. METHODS: Hepatocellular carcinoma patients undergoing TACE were recruited. The patients were evaluated 1 week (T1) and 1 month (T2) after receiving TACE in terms of performance status, symptom distress, depression (T1), and sleep disturbance (T2). Logistic regression was used to determine the predictive factors of sleep disturbance. RESULTS: Patients with sleep disturbance reported significantly higher overall symptom distress and depression and lower sleep quality than patients without sleep disturbance. The 5 leading causes of symptom distress in both groups were fatigue, pain, poor appetite, chest tightness, and fever. Older age, greater symptom distress, and higher levels of depression were significantly associated with sleep disturbance. CONCLUSIONS: The results of this study show significant associations among symptom distress, depression at baseline, and sleep problems 1 month after undergoing TACE. Clinicians should be aware of the possibility of lasting sleep disturbance in hepatocellular carcinoma patients undergoing TACE. IMPLICATIONS FOR PRACTICE: In clinical care, symptom management, psychological consultation, and relaxation training may promote sleep quality. PMID- 21242770 TI - Cognitive intervention for breast cancer patients undergoing adjuvant chemotherapy: a needs analysis. AB - BACKGROUND: Evidence suggests women with breast cancer who had received chemotherapy experienced cognitive problems. Although these are largely subtle deficits, they can negatively impact a patient's quality of life, ability to work, and subsequent employment decisions. OBJECTIVE: The present study explored what healthcare information and support are available to help women understand the effects of chemotherapy on daily functioning at home and at work. It also explored what information and support they would find useful as interventions. METHODS: Qualitative interviews were carried out with 31 patients attending a breast cancer clinic 4 months after treatment completion (phase 1) and with 5 oncology health professionals (phase 2). Fifteen women who took part in the interviews completed a short questionnaire on suitable interventions (phase 3). RESULTS: Participants reported problems with fatigue, low mood, memory, and attention. Problems with remembering tasks at work were most common. Participants requested more information and support on cognitive difficulties. Oncology health professionals discussed the need for information and support for patients on managing cognitive problems. From the findings, 4 interventions and delivery modes were identified and validated. These were information and activities on cognitive strategies, help with emotional distress associated with cognitive difficulties, and advice for families and employers. CONCLUSION: Despite mixed evidence for cognitive problems associated with chemotherapy, there is a need for an intervention, and this may be related to managing emotional distress associated with perceived cognitive problems. IMPLICATIONS FOR PRACTICE: Nurses should include potential cognitive problems when providing information to patients. PMID- 21242771 TI - Correlates of death anxiety among Taiwanese cancer patients. AB - BACKGROUND: Patients with cancer experience the approaching of death, which increases their fear of dying and the intensity of suffering. OBJECTIVE: This study examined relationships among cancer patients' demographic characteristics, sense of purpose in life, and death anxiety. METHODS: The study used a cross sectional correlational design. Data were collected using a demographic questionnaire, a sense-of-purpose-in-life scale, and a death anxiety scale. The stepwise multiple regression analysis was conducted to identify the factors that influenced the degree of death anxiety. RESULTS: Two hundred nineteen cancer patients who met the criteria for participation in the study completed the questionnaires. Results demonstrated that only 33.8% of participants had a sense of purpose in life, whereas 38.4% were uncertain about sense of purpose in life, and 27.8% indicated that they had no sense of purpose in life. Sense of purpose in life, level of fear of disease relapse, and sex were significant predictors, accounting for 32% of all variance in levels of death anxiety among cancer patients. CONCLUSIONS: Sense of purpose in life, level of fear of disease relapse, and sex had detrimental effects on levels of death anxiety among cancer patients. IMPLICATIONS FOR PRACTICE: The research results may provide clinicians with an understanding of death anxiety among cancer patients and facilitate improvements in sense of purpose in life among patients, which may reduce death anxiety among such patients. PMID- 21242772 TI - Characterizing burden, caregiving benefits, and psychological distress of husbands of breast cancer patients during treatment and beyond. AB - BACKGROUND: Husbands, as the primary providers of support for women with breast cancer, can experience significant burden and role strain, but also perceive positive aspects to the caregiving. Little is known about the specific caregiving tasks husbands perform, for how long, or how burden and positive aspects relate to later psychological distress. OBJECTIVE: Our primary aim was to better characterize the caregiving responsibilities and role strains of husbands during active cancer treatment and 1 year later. We also evaluated positive aspects during active treatment. Our second aim was to determine which of these predicted psychological distress 1 year later. METHODS: Husbands of women undergoing chemotherapy for breast cancer completed a battery of surveys during the time of wives' treatment and again 1 year later. RESULTS: Husbands performed a variety of caregiving tasks for wives during and after breast cancer treatment and also reported benefits associated with caregiving. Breast cancer-related worries were high at both time points. At 1 year after treatment, role strains improved in the social domain but worsened in the domestic domain. Domestic strains during active treatment were the strongest predictor of 1-year distress. CONCLUSIONS: Husbands who report persistent domestic role strain are at high risk for continued psychological distress following their wives' breast cancer treatment. IMPLICATIONS FOR PRACTICE: Health care providers should monitor husbands' caregiver burden regularly. Providing couples with resources to reduce domestic role strain (such as social support and communication training) may prevent or alleviate psychological distress in these husbands. PMID- 21242773 TI - Development and psychometric evaluation of the chemotherapy-induced peripheral neuropathy assessment tool. AB - BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) can be a debilitating and dose-limiting adverse effect of chemotherapy. Comprehensive self report tools for CIPN are needed for research and clinical practice. OBJECTIVE: The purpose of this psychometric study was to describe the development and evaluate the reliability and validity of a new self-report tool designed to measure CIPN, the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (CIPNAT). METHODS: One hundred sixty-seven patients receiving outpatient chemotherapy with paclitaxel, docetaxel, cisplatin, or oxaliplatin completed the CIPNAT. Content validity, convergent validity, discriminant validity, test-retest reliability, and internal consistency reliability were assessed. RESULTS: Content validity index was very acceptable at 0.95. Convergent validity data were provided by correlation with a measure of the same concept (r = 0.83, P < .001), and differences between contrasting groups (t = 7.66, P < .001) provided evidence of discriminant validity. High test-retest correlations (r = 0.92, P < .001), Cronbach alpha (alpha = .95), and significant item-to-total correlations ranging from 0.38 to 0.70 provided evidence of reliability. CONCLUSIONS: Results provide evidence of the validity and reliability of the CIPNAT, which can be used for comprehensive assessment of CIPN. IMPLICATIONS FOR PRACTICE: Use of the CIPNAT in research may lead to a better understanding of CIPN and guide nurses in developing and testing of interventions to relieve suffering and enhance quality of life for patients with CIPN. PMID- 21242774 TI - Effects of nurse navigators on health outcomes of cancer patients. AB - BACKGROUND: Care coordination has received increased attention in recent years because it critically affects patient safety and care quality across services and settings. OBJECTIVE: The effectiveness of systematically developed nurse navigator interventions for newly diagnosed cancer patients was evaluated. METHODS: Seventy-eight patients participated in a nonequivalent control group pretest-posttest design study. The study design spanned a 3-month period for all participants. Patient outcome measures included quality of life, satisfaction with care, and length of hospital stay. RESULTS: Participants in the experimental program reported significant increases in several components of quality of life and with satisfaction with care and experienced fewer hospital stay days compared with the control group. CONCLUSION: This study provides evidence that standardized nurse navigator programs can improve patient outcomes in cancer care. IMPLICATIONS FOR PRACTICE: Positive outcomes of the reduced length of stay and improved quality of life and patient satisfaction may help transform the cancer care delivery model toward more nurse-initiated cost-effective model. PMID- 21242775 TI - Differences between inpatient hospice care and in-hospital nonhospice care for cancer patients. AB - BACKGROUND: Decisions for the type of palliative care are affected by multiple factors. Currently, most patients die without palliative care, and hospice patients receive only a brief period of services before death. OBJECTIVE: This study aimed to compare palliative terminal cancer care in inpatient hospice and nonhospice care units in Taiwan for type of cancer, cost, stay, and selected demographic and clinical characteristics. METHODS: A retrospective study of terminally ill cancer patients hospitalized in a hospice unit (410 patients) or a general cancer ward (3005 patients) in a hospital in Taiwan was conducted. Patient demographic information, length of stay, cost of treatments, interventions and diagnostic testing, and types of cancer were analyzed. The factors associated with hospice care were revealed by multivariate stepwise regression. RESULTS: In the hospice group, the total cost was lower; there were more female, and more head, neck, and lung tumor patients. The most tumors in nonhospice group are hepatomas. The patients in hospice group received fewer interventions and had a long hospital stay (>14 days) before death; however, most of them were discharged from the hospital due to death. CONCLUSIONS: Utilization of hospice care varies by sex and type of cancer. Compared with the nonhospice service, hospice care needs a lower total cost and fewer interventions. IMPLICATIONS FOR PRACTICE: Hospice care in Taiwan should provide more services and facilities specific for sex (female) and tumors (head and neck). PMID- 21242776 TI - Secondary corneal amyloidosis in keratoconus. AB - We describe the case of a 37-year-old caucasian man with a history of keratoconus and long-term hard contact lens wear. Histological analysis of the corneal button after penetrating keratoplasty revealed staining with Congo red and apple green birefringence detected using polarized light. In the absence of other systemic or ocular pathology, the authors infer this amyloid deposition to be secondary to keratoconus and endeavor to discuss the possible etiopathogenesis of the disease. PMID- 21242777 TI - Chemical burns to the eye: paradigm shifts in treatment. PMID- 21242778 TI - Demographic study of expulsive hemorrhages in 3 patients with infectious keratitis. AB - PURPOSE: To investigate the demography, causative bacteria, and clinical findings in 3 patients with expulsive hemorrhage. METHODS: The clinical records of 3 patients (3 eyes), who developed expulsive hemorrhage because of infectious keratitis and were treated at our hospital between December 2006 and January 2008, were investigated retrospectively. RESULTS: Three women, older than 70 years, with physical and mental disabilities because of senile dementia were studied. Two were residents at a nursing home. Basic corneal disorders included bullous keratopathy, cicatricial syphilitic keratitis, and traumatic keratitis because of a foreign body. All patients developed expulsive hemorrhage. Two patients underwent enucleation, and 1 underwent bulbar exenteration with sclerocorneal patch for expulsive hemorrhage. Bacterial culture in these cases isolated either Capnocytophaga sp. and penicillin-intermediate resistant Streptococcus pneumoniae or methicillin-resistant Staphylococcus aureus. CONCLUSIONS: This is the first recorded case of Capnocytophaga keratitis in Japan. Patients with dementia may develop severe ocular complications after infectious keratitis because of their inability to communicate. PMID- 21242779 TI - OCT-documented incision features and natural history of clear corneal incisions used for bimanual microincision cataract surgery. AB - PURPOSE: Use of anterior segment OCT to identify features and natural history of bimanual incisions used only for phacoemulsification and a main incision used only for intraocular lens insertion. METHODS: Prospective study of 25 subjects who had uncomplicated bimanual phacoemulsification. The Zeiss Visante OCT identified incisions at 1 day, 1 week, and 1 month postoperatively. The absence or presence of features, endothelial gaping, detachment of the Descemet membrane, endothelial misalignment, epithelial gaping, and/or loss of coaptation, was recorded. Main incision data were compared with bimanual incision data. The difference for each feature, between the main incision and the bimanual incision, at each time point and over time were calculated. RESULTS: The most common findings at 1 day, 1 week, and 1 month were main incision endothelial misalignment (52%) and bimanual incision endothelial gape (24%), main incision endothelial misalignment (60%) and bimanual incision endothelial gape (22%), and main incision endothelial misalignment (35%) and bimanual incision endothelial misalignment (14%), respectively. Only at 1 day and 1 week was endothelial misalignment significantly more common in the main incision (P = 0.0352 and 0.0005, respectively). The only other incision feature that differed significantly was endothelial gape, which was more frequent in the bimanual incision at 1 week (P = 0.0391). For each incision feature combined over all time periods, only endothelial misalignment was significantly more prevalent in the main incision (P = 0.0004), whereas endothelial gape was more common in the bimanual incision (P = 0.0352). CONCLUSIONS: Using OCT, bimanual phacoemulsification did not adversely affect the anatomic incision integrity and healing. PMID- 21242780 TI - Comparison of Oculus Pentacam and Stratus optical coherence tomography for measurement of central corneal thickness. AB - PURPOSE: Measurement of central corneal thickness (CCT) plays an essential role in the diagnosis and treatment of many ocular diseases. In this study, we aimed to compare the CCT measurements obtained using the Scheimpflug system (Pentacam; Oculus, Inc) with a retinal optical coherence tomography device (Stratus OCT; Carl Zeiss Meditec, Inc) to examine healthy corneas. METHODS: CCT measurements of 80 eyes belonging to 40 male patients (mean age: 24.48 +/- 6.01 years) were evaluated with the Pentacam and the Stratus OCT. The relationship between the CCT values obtained with these 2 devices was examined with a Pearson correlation analysis, a paired t test, and a Bland-Altman analysis. RESULTS: The average CCT value obtained with Pentacam was 546.11 +/- 34.15 MUm and that obtained with Stratus OCT was 567.76 +/- 35.02 MUm. Although the average difference between the devices was 21.65 +/- 8.59 MUm (P < 0.0001), the measurements obtained with both devices were significantly correlated (r = 0.969, P < 0.0001). In Bland-Altman analysis, there was a high consistency between measurements obtained with either Pentacam or Stratus OCT devices. CONCLUSIONS: Corneal thickness measurements differ depending on the device used. Corneal thicknesses that have been calculated with Pentacam were lower than the values obtained with Stratus OCT. Both devices used for CCT measurement are easily applied, noninvasive, and effective. However, the devices are not interchangeable. Stratus OCT is not optimal for CCT measurement because of the important limitations of using manual measurements, but it can be used if other measurement devices designed for the purpose are not available. PMID- 21242781 TI - Novel CHST6 gene mutations in 2 unrelated cases of macular corneal dystrophy. AB - PURPOSE: To investigate the possible mutations in the carbohydrate sulfotransferase 6 (CHST6) gene of 2 unrelated cases of macular corneal dystrophy (MCD) and to report atypical stromal deposits in one of them. METHODS: Corneal tissues were stained with antisulfated keratan sulfate (KS), antitransforming growth factor beta 1-induced protein (TGFBIp), thioflavin-T, alcian blue, and Masson trichrome. Sequencing was performed to identify potential mutations in the CHST6 gene and the fourth and twelfth exons of the TGFBI gene. RESULTS: Alcian blue staining revealed the presence of multiple subepithelial and intrastromal mucopolysaccharide deposits, confirming the diagnosis of MCD in both cases. Immunofluorescence staining in case 1 revealed the presence of sulfated KS only in the keratocytes and select endothelial cells, consistent with MCD type IA. Preferential expression of sulfated KS was observed in keratocytes and extracellular stromal matrix in case 2, consistent with MCD type II. Atypical subepithelial and superficial stromal deposits were observed in case 1, which stained positively with alcian blue, eosin, Masson trichrome, and thioflavin-T indicating the presence of hyaline and amyloid materials. CHST6 gene sequencing revealed 2 heterozygous mutations in case 1 (a p.Arg211Gln and a novel mutation of p.Arg177Gly) and a novel homozygous mutation of p.Pro186Arg in case 2. No mutations were found in exons 4 or 12 of the TGFBI gene in case 1. CONCLUSIONS: Secondary hyalinosis and amyloidosis occur in a case of MCD type IA with a novel p.Arg177Gly mutation in CHST6. A novel p.Pro186Arg mutation in CHST6 is associated with MCD type II in an African American. PMID- 21242782 TI - Exaggerated subepithelial fibrosis after anterior stromal puncture presenting as a membrane. AB - PURPOSE: The aim of the study was to describe the clinical features, histopathological findings, and management of eyes presenting with a thick membrane after anterior stromal puncture (ASP) for bullous keratopathy. STUDY DESIGN: Retrospective interventional case series. METHODS: Retrospective chart analysis of 3 eyes presenting with a thick membrane between 12-30 months after ASP was done. Patients presented with complaints of recurrent symptoms of pain, watering, and irritation. The membrane was peeled off from the corneal surface in the operation room and sent for histopathological evaluation. A cryopreserved amniotic membrane was secured on the corneal surface using 10-0 nylon interrupted sutures. RESULTS: Patients reported alleviation of symptoms after the procedure and remained asymptomatic at the final follow-up (range 6-12 months). Histopathological evaluation of the excised membrane revealed the presence of a hyperplastic epithelium with loose fibrocollagenous tissue suggestive of subepithelial fibrosis. CONCLUSIONS: Subepithelial fibrosis after ASP, although a known entity, may rarely present as a thick membrane because of exaggerated response resulting in the recurrence of symptoms. This can be successfully managed by superficial keratectomy and amniotic membrane transplant. PMID- 21242783 TI - Delayed massive suprachoroidal hemorrhage after descemet stripping automated endothelial keratoplasty. AB - PURPOSE: To report the development of a delayed massive suprachoroidal hemorrhage after Descemet stripping automated endothelial keratoplasty (DSAEK). DESIGN: Retrospective case report. RESULTS: A 70-year-old woman with a failed graft for keratoconus underwent DSAEK in the setting of continued systemic anticoagulation. On the first postoperative day, she experienced a massive suprachoroidal hemorrhage. Despite surgical drainage, the donor graft subsequently failed, and vision declined to light perception. CONCLUSIONS: Massive suprachoroidal hemorrhage may occur as a rare complication of DSAEK. PMID- 21242784 TI - Mitomycin C-assisted photorefractive keratectomy in high myopia: a long-term safety study. AB - PURPOSE: To evaluate the long-term corneal safety of topical mitomycin C (MMC) used during photorefractive keratectomy to prevent haze formation in highly myopic eyes. METHODS: Twenty-eight patients with bilateral high myopia underwent photorefractive keratectomy. One eye was randomly assigned to intraoperative 0.02% MMC and the fellow eye to conventional treatment. Each eye was checked at baseline and at 5 years after surgery using in vivo corneal confocal microscopy. RESULTS: At baseline, the endothelial cell density was 2970 +/- 295 cells per square millimeter in the MMC-treated eyes and 2839 +/- 323 cells per square millimeter in the control eyes. At 5 years, it was 2803 +/- 307 and 2780 +/- 264 cells per square millimeter, respectively (P = 0.27). The number of corneal nerve fibers was 3.9 +/- 1.6 in the MMC-treated eyes and 4.4 +/- 1.3 in the control eyes. At 5 years, it was 3.0 +/- 1.6 and 2.7 +/- 1.3, respectively (P = 0.15). The density of corneal nerves was 9600 +/- 2915 MUm/mm(2) in the MMC-treated eyes and 11,352 +/- 3898 MUm/mm(2) in the control eyes. At 5 years, the density was higher in the MMC-treated eyes (6790 +/- 2447 MUm/mm(2)) than in the control eyes (6024 +/- 2977 MUm/mm(2)) (P = 0.003). The number of nerve beadings at baseline was 12.9 +/- 1.7/100 MUm in the MMC-treated eyes and 12.3 +/- 2.0/100 MUm in the control eyes. At 5 years, it was 9.9 +/- 2.6/100 and 9.4 +/- 2.9/100 MUm, respectively (P = 1.00). At 5 years, corneal nerve branching and tortuosity were similar in the 2 groups (P = 0.88 and 0.54, respectively). Epithelium thickness remained statistically unchanged (P = 0.69). CONCLUSIONS: Intraoperative use of topical 0.02% MMC compared with standard treatment does not induce significant long-term corneal changes, as assessed by in vivo corneal confocal microscopy. PMID- 21242785 TI - Analysis of corneal stroma organization with wavefront optimized nonlinear microscopy. AB - PURPOSE: To investigate the organization of stromal collagen in healthy ex vivo corneas of different species from second harmonic generation (SHG) microscopy images. METHODS: A custom backscattered nonlinear microscope has been used to study the corneal structure of different species: porcine, bovine, rabbit, rat, chicken, and humans. The instrument uses a femtosecond laser for illumination, a scanning unit, and a photon-counting detection device. It also includes a wavefront aberration control module. SHG signals produced by collagen within the cornea were acquired. A motorized stage allowed optical sectioning across the entire corneal thickness. Samples were neither fixed nor stained, and they were fully scanned. RESULTS: SHG images revealed the microscopic organization of the lamellae of collagen fibers. Despite absorption, for all corneal depths, images could be analyzed. The anterior stroma was similar in all samples, showing interwoven short bands of collagen randomly distributed. The lamellae at the central and posterior stroma were densely packed and often presented longer bundles lying predominantly parallel to the corneal surface with characteristic spatial distributions for each species. In particular, collagen bundles in bovine and porcine corneas were interweaved. In the chick cornea, the stromal arrangement had an orientation changing regularly with depth. In human corneas, lamellae were longer and had similar orientation than their neighbors. CONCLUSIONS: Using a unique wavefront aberration-controlled backscattered nonlinear microscope, changes in corneal morphology as a function of depth were characterized for different species (including humans). This allowed a direct comparison among species, which might help to establish the basis of collagen distribution in animal models or to understand diseased corneas. PMID- 21242786 TI - Analysis of deposit depth and morphology in granular corneal dystrophy type 2 using fourier domain optical coherence tomography. AB - PURPOSE: Granular corneal dystrophy type 2 (GCD2) causes the formation of corneal deposits having 3 different morphological types. We used Fourier domain optical coherence tomography to assess the depths of each type according to the morphology. METHODS: A prospective study was performed in 54 eyes of 54 heterozygous patients with GCD2. Corneal deposits of 54 patients with GCD2 were classified into 3 morphological types: type 1, diffuse haze; type 2, granular shape (2 subgroups: type 2a, round granulated and type 2b, round spiculated); and type 3, linear shape (2 subgroups: type 3a, short side branched and type 3b, long side branched). Using Fourier domain optical coherence tomography, we measured the distances from the Bowman layer to the upper surface of the deposits (USBL), to the lower surface of the deposits (LSBL), and the thickness of the deposits (TD). The deposits formed along the flap interface were also examined among 19 patients who had LASIK. RESULTS: Types 1 and 2 deposits were always adjacent to the Bowman layer; thus the USBLs for each were 0.0 +/- 0.0 MUm, whereas that of type 3 deposits was 65.4 +/- 48.0 MUm (P < 0.0001). The LSBL and TD of linear deposits with long side branches (type 3) (313.3 +/- 71.4 and 246.2 +/- 71.9 MUm) were greater than those of type 1 (47.7 +/- 10.2 and 47.7 +/- 10.2 MUm) and type 2 (91.3 +/- 39.5 and 91.3 +/- 39.5 MUm) (P < 0.0001). There were no differences in the measurements between the subgroups type 2a and type 2b or between types 3a and 3b. USBL of the laser in situ keratomileusis group was 54.5 +/- 29.8 MUm. CONCLUSIONS: The depths of corneal deposits in patients with GCD2 were associated with the morphology of the deposits. The linear deposits were located most deeply in the cornea, followed by granular deposits and diffuse haze moving anteriorly. Several deposits have distinct depths according to the morphological types. PMID- 21242787 TI - Management of endothelial decompensation because of glaucoma shunt tube touch by Descemet membrane endothelial keratoplasty and tube revision. AB - PURPOSE: To describe the trimming of a glaucoma shunt tube with Descemet membrane endothelial keratoplasty (DMEK) for the treatment of endothelial decompensation caused by tube-endothelium touch. METHODS: An 84-year-old man with pseudoexfoliative glaucoma OU had endothelial decompensation because of the touch of the tube of an Ahmed glaucoma valve at the corneal endothelium OS. The best corrected visual acuity decreased from 20/60 to counting fingers at 3 feet. The patient underwent uncomplicated trimming of the shunt tube and DMEK. RESULTS: After surgery, the cornea became clear, and the best-corrected visual acuity improved to 20/60. The intraocular pressure remained normal (8-12 mm Hg) without antiglaucoma medications, and endothelial cell count remained stable in a follow up of 12 months. No complications were encountered. CONCLUSIONS: Glaucoma shunt tube trimming with DMEK may be considered in cases of endothelial decompensation because of tube-endothelium touch and may replace penetrating keratoplasty and other posterior lamellar procedures for such cases. PMID- 21242788 TI - Randomized trial of initial trophic versus full-energy enteral nutrition in mechanically ventilated patients with acute respiratory failure. AB - OBJECTIVE: Enteral nutrition is provided to mechanically ventilated patients who cannot eat normally, yet the amount of support needed is unknown. We conducted this randomized, open-label study to test the hypothesis that initial low-volume (i.e., trophic) enteral nutrition would decrease episodes of gastrointestinal intolerance/complications and improve outcomes as compared to initial full-energy enteral nutrition in patients with acute respiratory failure. DESIGN: Randomized, open-label study. PATIENTS: A total of 200 patients with acute respiratory failure expected to require mechanical ventilation for at least 72 hrs. INTERVENTIONS: Patients were randomized to receive either initial trophic (10 mL/hr) or full-energy enteral nutrition for the initial 6 days of ventilation. MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was ventilator-free days to day 28. Baseline characteristics were similar between the 98 patients randomized to trophic and the 102 patients randomized to full-energy nutrition. At enrollment, patients had a mean Acute Physiology and Chronic Health Evaluation II score of 26.9 and a PaO2/FiO2 ratio of 182 and 38% were in shock. Both groups received similar durations of enteral nutrition (5.5 vs. 5.1 days; p = .51). The trophic group received an average of 15.8% +/- 11% of goal calories daily through day 6 compared to 74.8% +/- 38.5% (p < .001) for the full-energy group. Both groups had a median of 23.0 ventilator-free days (p = .90) and a median of 21.0 intensive-care-unit-free days (p = .64). Mortality to hospital discharge was 22.4% for the trophic group vs. 19.6% for the full-energy group (p = .62). In the first 6 days, the trophic group had trends for less diarrhea (19% vs. 24% of feeding days; p = .08) and significantly fewer episodes of elevated gastric residual volumes (2% vs. 8% of feeding days; p < .001). CONCLUSION: Initial trophic enteral nutrition resulted in clinical outcomes in mechanically ventilated patients with acute respiratory failure similar to those of early full energy enteral nutrition but with fewer episodes of gastrointestinal intolerance. PMID- 21242789 TI - Relationship of catheter-associated urinary tract infection to mortality and length of stay in critically ill patients: a systematic review and meta-analysis of observational studies. AB - OBJECTIVE: To determine whether catheter-associated urinary tract infections are associated with increased morbidity and mortality in critically ill patients. DATA SOURCES: MEDLINE, HealthStar, EMBASE, and CINAHL databases from inception to June 2010 and bibliographies of included studies without language restriction. STUDY SELECTION: Studies reporting mortality or morbidity in adult intensive care unit patients with and without catheter-associated urinary tract infections. DATA EXTRACTION: Two authors independently selected studies and extracted data on study methodology, quality, and patient outcomes using a standardized form. Meta analyses were performed using random-effects models. DATA SYNTHESIS: Of 720 citations, 11 studies enrolling 2,745 patients with and 60,719 patients without catheter-associated urinary tract infections met inclusion criteria. Catheter associated urinary tract infection was associated with a significant increase in mortality (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.72-2.31; p < .00001; I2 = 54%; eight studies; 62,063 patients) and length of stay in the intensive care unit (weighted mean difference of + 12 days; 95% CI, 9-15; p < .00001; I2 = 96%; seven studies; 13,011 patients) and hospital (mean difference + 21 days; 95% CI, 11-32; p < .0001; I2 = 98%; five studies; 10,183 patients). Restricting the analysis only to the two studies that adjusted for other outcome predictors, catheter-associated urinary tract infections were not associated with an increase in mortality (OR, 0.97; 95% CI, 0.82-1.16; p = .77; I2 = 0%; two studies; 5,626 patients). Although both studies individually demonstrated significantly increased intensive care unit length of stay after adjustment, pooled data showed that catheter-associated urinary tract infections were associated with a significant increase in intensive care unit length of stay using only a fixed effects model (mean difference + 2.6 days; 95% CI, 2.3-3.0; p < .00001) and not a random effects model (mean difference + 8 days; 95% CI, -13 to +28 days; p = .46) due to the high degree of heterogeneity for this outcome between the two studies (I2 = 99.6%) which results in a larger CI. CONCLUSIONS: Catheter-associated urinary tract infection is associated with significantly increased mortality and length of stay in unmatched studies. Increased mortality and possibly increased length of stay appear to be consequences of confounding by unmeasured variables. These findings highlight the importance of evaluating risks and benefits of commonly used treatments such as antibiotics to manage catheter associated urinary tract infection. PMID- 21242790 TI - Hypertonic saline versus mannitol for the treatment of elevated intracranial pressure: a meta-analysis of randomized clinical trials. AB - OBJECTIVES: Randomized trials have suggested that hypertonic saline solutions may be superior to mannitol for the treatment of elevated intracranial pressure, but their impact on clinical practice has been limited, partly by their small size. We therefore combined their findings in a meta-analysis. DATA SOURCES: We searched for relevant studies in MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and ISI Web of Knowledge. STUDY SELECTION: Randomized trials were included if they directly compared equiosmolar doses of hypertonic sodium solutions to mannitol for the treatment of elevated intracranial pressure in human subjects undergoing quantitative intracranial pressure measurement. DATA EXTRACTION: Two investigators independently reviewed potentially eligible trials and extracted data using a preformed data collection sheet. Disagreements were resolved by consensus or by a third investigator if needed. We collected data on patient demographics, type of intracranial pathology, baseline intracranial pressure, osms per treatment dose, quantitative change in intracranial pressure, and prespecified adverse events. Our primary outcome was the proportion of successfully treated episodes of elevated intracranial pressure. DATA SYNTHESIS: Five trials comprising 112 patients with 184 episodes of elevated intracranial pressure met our inclusion criteria. In random-effects models, the relative risk of intracranial pressure control was 1.16 (95% confidence interval, 1.00-1.33), and the difference in mean intracranial pressure reduction was 2.0 mm Hg (95% confidence interval, -1.6 to 5.7), with both favoring hypertonic saline over mannitol. A mild degree of heterogeneity was present among the included trials. There were no significant adverse events reported. CONCLUSIONS: We found that hypertonic saline is more effective than mannitol for the treatment of elevated intracranial pressure. Our meta-analysis is limited by the small number and size of eligible trials, but our findings suggest that hypertonic saline may be superior to the current standard of care and argue for a large, multicenter, randomized trial to definitively establish the first-line medical therapy for intracranial hypertension. PMID- 21242791 TI - N-Acetylcysteine protects the rat diaphragm from the decreased contractility associated with controlled mechanical ventilation. AB - OBJECTIVE: Controlled mechanical ventilation results in diaphragmatic dysfunction, and oxidative stress has been shown to be an important contributor to ventilator-induced diaphragm dysfunction. We hypothesized that the administration of an antioxidant, N-acetylcysteine, would restore the redox balance in the diaphragm and prevent against the deleterious effects of controlled mechanical ventilation. DESIGN: Randomized, controlled experiment. SETTINGS: Basic science animal laboratory. SUBJECTS: Male Wistar rats, 14 wks old. INTERVENTIONS: Anesthetized rats were submitted for 24 hrs to either spontaneous breathing receiving 150 mg/kg N-acetylcysteine (SBNAC) or saline (SBSAL) or to controlled mechanical ventilation receiving 150 mg/kg N acetylcysteine (MVNAC) or saline (MVSAL). MEASUREMENTS AND MAIN RESULTS: After 24 hrs of controlled mechanical ventilation, diaphragmatic force production was significantly lower in MVSAL compared with all groups. Importantly, administration of N-acetylcysteine completely abolished this controlled mechanical ventilation-induced diaphragmatic contractile dysfunction. Diaphragmatic protein oxidation was significantly increased after 24 hrs of controlled mechanical ventilation (+53%, p < .01) in MVSAL animals, whereas administration of N-acetylcysteine prevented this controlled mechanical ventilation-induced oxidative stress. Diaphragmatic 20S proteasome activity was increased in MVSAL (+62%, p < .05). Further, compared with SBSAL, diaphragm caspase-3 activity was significantly increased in MVSAL (+279%, p < .001), and N acetylcysteine treatment provided partial protection against caspase-3 activation. Diaphragmatic calpain activity was significantly increased after controlled mechanical ventilation (+137%, p < .001) in MVSAL animals, but N acetylcysteine treatment protected against this event. Finally, significant negative correlations existed between calpain activity and diaphragm force production (r from -0.56 to -0.49, p < .05). CONCLUSIONS: These data show that the administration of N-acetylcysteine protects the diaphragm from the deleterious effects of controlled mechanical ventilation. Specifically, N acetylcysteine prevents against controlled mechanical ventilation-induced diaphragmatic oxidative stress and proteolysis and abolishes controlled mechanical ventilation-induced diaphragmatic contractile dysfunction. PMID- 21242792 TI - Acute liver failure after recommended doses of acetaminophen in patients with myopathies. AB - OBJECTIVE: To determine the likelihood that recommended doses of acetaminophen are associated with acute liver failure in patients with myopathies. DESIGN: Retrospective analysis. SETTING: Level III pediatric intensive care unit. PATIENTS: Two pediatric patients with myopathies and acute liver failure. CLINICAL INVESTIGATIONS: We determined acetaminophen protein adduct levels, in combination with a literature review and systematic evaluation of the cases, using the Roussel Uclaf Causality Assessment Method for drug-induced liver injury to assess causality between recommended acetaminophen dosing and acute liver failure in two children with myopathies. MAIN RESULTS: The serum adduct levels were consistent with the values previously reported in children with acute liver injury following acetaminophen overdose. We found four similar cases of acute liver failure in pediatric and adult patients with myopathies following recommended acetaminophen doses in the literature (n = 3) and personal communication (n = 1). The Roussel Uclaf Causality Assessment Method suggested a probable relationship between acetaminophen use at recommended doses and acute liver failure in our myopathy patients. CONCLUSION: Our data suggest that some patients with myopathies who are receiving recommended doses of acetaminophen may be at increased risk for the development of toxicity resulting in acute liver failure. More studies are needed to corroborate these findings. In the meantime, we would advise physicians to be alert in these patients while taking acetaminophen, especially when critically ill or postoperative. PMID- 21242793 TI - The impact of enhanced cleaning within the intensive care unit on contamination of the near-patient environment with hospital pathogens: a randomized crossover study in critical care units in two hospitals. AB - OBJECTIVES: To determine the effect of enhanced cleaning of the near-patient environment on the isolation of hospital pathogens from the bed area and staff hands. DESIGN: Prospective randomized crossover study over the course of 1 yr. SETTING: Intensive care units at two teaching hospitals. PATIENTS: There were 1252 patients staying during enhanced cleaning and 1331 staying during standard cleaning. INTERVENTIONS: In each of six 2-month periods, one unit was randomly selected for additional twice-daily enhanced cleaning of hand contact surfaces. MEASUREMENTS AND MAIN RESULTS: Agar contact samples were taken at five sites around randomly selected bed areas, from staff hands, and from communal sites three times daily for 12 bed days per week. Patients admitted in the year commencing April 2007 were analyzed for hospital-acquired colonization and infection. Over the course of 1152 bed days, 20,736 samples were collected. Detection of environmental methicillin-resistant Staphylococcus aureus per bed area day was reduced during enhanced cleaning phases from 82 of 561 (14.6%) to 51 of 559 (9.1%) (adjusted odds ratio, 0.59; 95% confidence interval, 0.40-0.86; p = .006). Other targeted pathogens (Acinetobacter baumannii, extended-spectrum beta lactamase-producing Gram-negative bacteria, vancomycin-resistant enterococci, and Clostridium difficile) were rarely detected. Subgroup analyses showed reduced methicillin-resistant Staphylococcus aureus contamination on doctors' hands during enhanced cleaning (3 of 425; 0.7% vs. 11 of 423; 2.6%; adjusted odds ratio, 0.26; 95% confidence interval, 0.07-0.95; p = .025) and a trend to reduction on nurses' hands (16 of 1647; 1.0% vs. 28 of 1694; 1.7%; adjusted odds ratio 0.56; 95% confidence interval, 0.29-1.08; p = .077). All 1252 critical care patients staying during enhanced and 1,331 during standard cleaning were included, but no significant effect on patient methicillin-resistant Staphylococcus aureus acquisition was observed (adjusted odds ratio, 0.98; 95% confidence interval, 0.58-1.65; p = .93). CONCLUSIONS: Enhanced cleaning reduced environmental contamination and hand carriage, but no significant effect was observed on patient acquisition of methicillin-resistant Staphylococcus aureus. TRIAL REGISTRY: ISRCTN. Identifier: 06298448. http://www.controlled trials.com/isrctn/. PMID- 21242794 TI - Endotoxin tolerance of adrenal gland: attenuation of corticosterone production in response to lipopolysaccharide and adrenocorticotropic hormone. AB - OBJECTIVES: Reversible adrenal insufficiency frequently has been diagnosed in critically ill patients with sepsis who have either low basal cortisol levels or low cortisol responses to adrenocorticotropic hormone (ACTH) stimulation. It is generally accepted that a phenomenon called "endotoxin tolerance" contributes to immunosuppression during sepsis. The present study was to investigate whether endotoxin tolerance occurs in the adrenal gland, leading to hyporesponsiveness of adrenal gland during sepsis. DESIGN: Controlled laboratory experiment. SETTING: University research laboratory. SUBJECTS: Sprague-Dawley male rats 200-250 g and primary isolated adrenal fasciculata-reticularis cells. INTERVENTIONS: Rats received intra-arterial injection of purified lipopolysaccharide (0.5 mg/kg) through indwelling femoral arterial catheters, and 24 hrs later the adrenocortical sensitivity to exogenous ACTH (10 ng/kg) was detected. Primary fasciculata-reticularis cells were pretreated with lipopolysaccharide at 0.1-100 ng/mL or with ACTH at 0.01-10 ng/mL and then challenged, in fresh media, with 1 MUg/mL lipopolysaccharide or 10 ng/mL ACTH. MEASUREMENTS AND MAIN RESULTS: Toll like receptor 4 was expressed in adrenal gland and primary fasciculata reticularis cells. Plasma corticosterone response to ACTH was decreased in rats receiving preinjection of lipopolysaccharide. Lipopolysaccharide pretreatment caused a significant decrease in corticosterone production in response to subsequent ACTH and lipopolysaccharide stimulation in primary fasciculata reticularis cells. Lipopolysaccharide pretreatment inhibited ACTH- and lipopolysaccharide-induced expression of steroid metabolizing enzymes. Lipopolysaccharide significantly decreased Toll-like receptor 4 and ACTH receptor expression. CONCLUSIONS: Pre-exposure to lipopolysaccharide resulted in hyporesponsiveness to ACTH stimulation in rats. In vitro, lipopolysaccharide pretreatment impaired corticosterone production of fasciculata-reticularis cells in response to ACTH and lipopolysaccharide, which was associated with decreased expression of synthetic enzymes required for corticosterone production. Our results indicate that endotoxin tolerance of adrenal gland is one of the mechanisms for adrenocortical insufficiency during sepsis. PMID- 21242795 TI - Angiopoietin-1 and angiopoietin-2 as clinically informative prognostic biomarkers of morbidity and mortality in severe sepsis. AB - OBJECTIVE: To determine the utility of angiopoietin-1 and angiopoietin-2 as potentially novel biomarkers of morbidity and mortality in patients with severe sepsis. DESIGN: Multicenter longitudinal cohort study. SETTING: Three tertiary hospital intensive care units in Hamilton, Ontario, Canada. PATIENTS: A total of 70 patients with severe sepsis were enrolled within 24 hrs of meeting the inclusion criteria for severe sepsis and followed until day 28, hospital discharge, or death. INTERVENTIONS: Clinical data and plasma samples were obtained at intensive care unit admission for all 70 patients and then daily for 1 wk and weekly thereafter for a subset of 43 patients. Levels of angiopoietin-1 and angiopoietin-2 in stored plasma samples were measured and compared with clinical characteristics, including the primary outcomes of 28-day mortality and morbidity measured by the Multiple Organ Dysfunction score. MEASUREMENTS AND MAIN RESULTS: Lower angiopoietin-1 plasma levels (<= 5.5 ng/mL) at admission were associated with increased likelihood of death (relative risk 0.49 [95% confidence interval of 0.25-0.98], p = .046). Lower angiopoietin-1 levels remained a significant predictor of 28-day mortality in a multiple logistic regression model (adjusted odds ratio of 0.282 [95% confidence interval of 0.086-0.93], p = .037). Analysis of serial data using linear mixed models confirmed that sepsis survivors had higher levels of angiopoietin-1 (p = .012) and lower daily levels of angiopoietin-2 (p = .022) than nonsurvivors. Furthermore, survivors had higher peak angiopoietin-1 levels (median 13 vs. 10 ng/mL, p = .019) and lower nadir angiopoietin-2 levels (median 2.8 vs. 6.2 ng/mL, p = .013) than nonsurvivors. A score incorporating angiopoietin-1 and angiopoietin-2 and three other markers of endothelial activation discriminated with high accuracy between fatal and nonfatal cases (c-index of 0.80 [95% confidence interval of 0.69-0.90], p < .001). Plasma levels of angiopoietin-2 correlated with clinical markers of organ dysfunction and molecular markers of endothelial cell activation. CONCLUSIONS: Angiopoietin-1 levels at admission and both angiopoietin-1 and angiopoietin-2 levels measured serially correlated with 28-day mortality in severe sepsis. Angiopoietin-2 levels also correlated with organ dysfunction/injury and a validated clinical sepsis score. These results suggest the use of angiopoietins as clinically informative biomarkers of disease severity and patient outcome in severe sepsis. PMID- 21242796 TI - Improvements of cardiac electrophysiologic stability and ventricular fibrillation threshold in rats with myocardial infarction treated with cardiac stem cells. AB - OBJECTIVES: Arrhythmia is of concern after cardiac stem cell transplantation in repairing infarcted myocardium. However, whether transplantation improved the ventricular fibrillation threshold and whether severe malignant ventricular arrhythmia is induced in the myocardial infarction model are still unclear. We sought to investigate the electrophysiologic characteristics and ventricular fibrillation threshold in rats with myocardial infarction by treatment with allogeneic cardiac stem cells. DESIGN: Prospective, randomized, controlled study. SETTING: University-affiliated hospital. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Myocardial infarction was induced in 20 male Sprague-Dawley rats. Two weeks later, animals were randomized to receive 5 * 10(6) cardiac stem cells labeled with PKH26 in phosphate buffer solution or a phosphate buffer solution alone injection into the infarcted anterior ventricular-free wall. MEASUREMENTS AND MAIN RESULTS: Six weeks after the cardiac stem cell or phosphate buffer solution injection, electrophysiologic characteristics and ventricular fibrillation threshold were measured at the infarct area, infarct marginal zone, and noninfarct zone. Labeled cardiac stem cells were observed in 5-MUm cryostat sections from each harvested heart. The unipolar electrogram activation recovery time dispersions were shorter in the cardiac stem cell group compared with those at the phosphate buffer solution group (15.5 +/- 4.4 vs. 38.6 +/- 14.9 msecs, p = .000177). Malignant ventricular arrhythmias were significantly (p = .00108) less inducible in the cardiac stem cell group (one of ten) than the phosphate buffer solution group (nine of ten). The ventricular fibrillation thresholds were greatly improved in the cardiac stem cell group compared with the phosphate buffer solution group. Labeled cardiac stem cells were identified in the infarct zone and infarct marginal zone and expressed Connexin-43, von Willebrand factor, alpha-smooth muscle actin, and alpha-sarcomeric actin. CONCLUSIONS: Cardiac stem cells may modulate the electrophysiologic abnormality and improve the ventricular fibrillation threshold in rats with myocardial infarction treated with allogeneic cardiac stem cells and cardiac stem cell express markers that suggest muscle, endothelium, and vascular smooth muscle phenotypes in vivo. PMID- 21242797 TI - Does modulation of organic cation transporters improve pralidoxime activity in an animal model of organophosphate poisoning? AB - OBJECTIVES: Pralidoxime is an organic cation used as an antidote in addition to atropine to treat organophosphate poisoning. Pralidoxime is rapidly eliminated by the renal route and thus has limited action. The objectives of this work were as follows. 1) Study the role of organic cation transporters in the renal secretion of pralidoxime using organic cation transporter substrates (tetraethylammonium) and knockout mice (Oct1/2-/-; Oct3-/-). 2) Assess whether sustained high plasma concentrations increase pralidoxime antidotal activity toward paraoxon-induced respiratory toxicity. SETTING: INSERM U705, Faculte de Pharmacie, Universite Paris Descartes, 4 Avenue de l'Observatoire, 75006 Paris, France. SUBJECTS: Rodents: Knockout mice (Oct1/2-/-; Oct3-/-) and Sprague-Dawley rats. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In rats, the renal clearance of pralidoxime was 3.6-fold higher than the creatinine clearance. Pretreatment with tetraethylammonium (75 mg/kg) in rats or deficiencies in organic cation transporters 1 and 2 in mice (Oct1/2-/-) resulted in a significant increase in plasma pralidoxime concentrations. Lack of Oct3 did not alter plasma pralidoxime concentrations. The antidotal activity of pralidoxime (50 mg/kg intramuscularly) was longer and with greater effect, resulting in a return to normal values when administered to rats pretreated with tetraethylammonium. CONCLUSIONS: Pralidoxime is secreted in rats and mice by renal Oct1 and/or Oct2 but not by Oct3. Modulation of organic cation transporter activity increased the plasma pralidoxime concentrations and the antidotal effect of pralidoxime with sustained return within the normal range of respiratory variables in paraoxon-poisoned rats. These results suggest a promising approach in an animal model toward the increase in efficiency of pralidoxime. However, further studies are needed before these results are extended to human poisoning. PMID- 21242798 TI - Epidemiology and risk factors of sepsis after multiple trauma: an analysis of 29,829 patients from the Trauma Registry of the German Society for Trauma Surgery. AB - OBJECTIVES: The objectives of this study were 1) to assess potential changes in the incidence and outcome of sepsis after multiple trauma in Germany between 1993 and 2008 and 2) to evaluate independent risk factors for posttraumatic sepsis. DESIGN: Retrospective analysis of a nationwide, population-based prospective database, the Trauma Registry of the German Society for Trauma Surgery. SETTING: A total of 166 voluntarily participating trauma centers (levels I-III). PATIENTS: Patients registered in the Trauma Registry of the German Society for Trauma Surgery between 1993 and 2008 with complete data sets who presented with a relevant trauma load (Injury Severity Score of >= 9) and were admitted to an intensive care unit (n = 29,829). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Over the 16-yr study period, 10.2% (3,042 of 29,829) of multiply injured patients developed sepsis during their hospital course. Annual data were summarized into four subperiods: 1993-1996, 1997-2000, 2001-2004, and 2005-2008. The incidences of sepsis for the four subperiods were 14.8%, 12.5%, 9.4%, and 9.7% (p < .0001), respectively. In-hospital mortality for all trauma patients decreased for the respective subperiods (16.9%, 16.0%, 13.7%, and 11.9%; p < .0001). For the subgroup of patients with sepsis, the mortality rates were 16.2%, 21.5%, 22.0%, and 18.2% (p = .054), respectively. The following independent risk factors for posttraumatic sepsis were calculated from a multivariate logistic regression analysis: male gender, age, preexisting medical condition, Glasgow Coma Scale score of <= 8 at scene, Injury Severity Score, Abbreviated Injury ScaleTHORAX score of >= 3, number of injuries, number of red blood cell units transfused, number of operative procedures, and laparotomy. CONCLUSIONS: The incidence of sepsis decreased significantly over the study period; however, in this decade the incidence remained unchanged. Although overall mortality from multiple trauma has declined significantly since 1993, there has been no significant decrease of mortality in the subgroup of septic trauma patients. Thus, sepsis has remained a challenging complication after trauma during the past 2 decades. Recognition of the identified risk factors may guide early diagnostic workup and help to reduce septic complications after multiple trauma. PMID- 21242799 TI - Bilateral adrenal hemorrhage: the unrecognized cause of hemodynamic collapse associated with heparin-induced thrombocytopenia. AB - OBJECTIVE: Heparin-induced thrombocytopenia is a common adverse effect of treatment with heparin resulting in paradoxical thromboses. An immunoglobulin G class "heparin-induced thrombocytopenia antibody" attaches to a heparin-platelet factor 4 protein complex. The antibody then binds to the FcgammaIIa receptor on the surface of a platelet, resulting in activation, consumption, and thrombocytopenia in the clinical syndrome of heparin-induced thrombocytopenia. In contradistinction to other drug-induced thrombocytopenias that lead to a risk of hemorrhage, the state of thrombocytopenia in heparin-induced thrombocytopenia leads to an acquired hypercoagulability syndrome. Bilateral adrenal hemorrhage associated with heparin-induced thrombocytopenia has become an increasingly documented association. The adrenal gland has a vascular construction that lends itself to venous thrombus in the setting of heparin-induced thrombocytopenia and subsequent arterial hemorrhage. A literature search revealed 17 reported cases of bilateral adrenal hemorrhage in the setting of heparin-induced thrombocytopenia uniformly presenting with complete hemodynamic collapse. DATA SOURCES: An Ovid MEDLINE search of the English-language medical literature was conducted, identifying articles describing cases of bilateral adrenal hemorrhage in the setting of heparin-induced thrombocytopenia. STUDY SELECTION: All cases with this association were included in the review. DATA EXTRACTION AND DATA SYNTHESIS: A total of 14 articles were identified, describing 17 individual case reports of bilateral adrenal hemorrhage associated with heparin-induced thrombocytopenia. All cases confirmed known characteristics of heparin-induced thrombocytopenia and uniformly revealed hypotension due to adrenal insufficiency. There were five deaths, resulting in an overall mortality rate of 27.8%, and 100% mortality in the three cases where adrenal insufficiency went unrecognized. CONCLUSIONS: The secondary complication of adrenal vein thrombosis leading to bilateral adrenal hemorrhage remains insufficiently recognized and undertreated. The nonspecific presentation of adrenal hemorrhage and insufficiency as a complication of heparin induced thrombocytopenia, coupled with the catastrophic clinical course of untreated adrenal collapse, requires a high index of suspicion to achieve rapid diagnosis and provide life-saving therapy. PMID- 21242800 TI - Association of low serum 25-hydroxyvitamin D levels and mortality in the critically ill. AB - OBJECTIVE: We hypothesized that deficiency in 25-hydroxyvitamin D before hospital admission would be associated with all-cause mortality in the critically ill. DESIGN: Multicenter observational study of patients treated in medical and surgical intensive care units. SETTING: A total of 209 medical and surgical intensive care beds in two teaching hospitals in Boston, MA. PATIENTS: A total of 2399 patients, age >= 18 yrs, in whom 25-hydroxyvitamin D was measured before hospitalization between 1998 and 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Preadmission 25-hydroxyvitamin D was categorized as deficiency in 25 hydroxyvitamin D (<= 15 ng/mL), insufficiency (16-29 ng/mL), and sufficiency (>= 30 ng/mL). Logistic regression examined death by days 30, 90, and 365 post intensive care unit admission, in-hospital mortality, and blood culture positivity. Adjusted odds ratios were estimated by multivariable logistic regression models. Preadmission 25-hydroxyvitamin D deficiency is predictive for short-term and long-term mortality. At 30 days following intensive care unit admission, patients with 25-hydroxyvitamin D deficiency have an odds ratio for mortality of 1.69 (95% confidence interval of 1.28-2.23, p < .0001) relative to patients with 25-hydroxyvitamin D sufficiency. 25-Hydroxyvitamin D deficiency remains a significant predictor of mortality at 30 days following intensive care unit admission following multivariable adjustment (adjusted odds ratio of 1.69, 95% confidence interval of 1.26-2.26, p < .0001). At 30 days following intensive care unit admission, patients with 25-hydroxyvitamin D insufficiency have an odds ratio of 1.32 (95% confidence interval of 1.02-1.72, p = .036) and an adjusted odds ratio of 1.36 (95% confidence interval of 1.03-1.79, p = .029) relative to patients with 25-hydroxyvitamin D sufficiency. Results were similar at 90 and 365 days following intensive care unit admission and for in-hospital mortality. In a subgroup analysis of patients who had blood cultures drawn (n = 1160), 25 hydroxyvitamin D deficiency was associated with increased risk of blood culture positivity. Patients with 25-hydroxyvitamin D insufficiency have an odds ratio for blood culture positivity of 1.64 (95% confidence interval of 1.05-2.55, p = .03) relative to patients with 25-hydroxyvitamin D sufficiency, which remains significant following multivariable adjustment (odds ratio of 1.58, 95% confidence interval of 1.01-2.49, p = .048). CONCLUSION: Deficiency of 25 hydroxyvitamin D before hospital admission is a significant predictor of short- and long-term all-cause patient mortality and blood culture positivity in a critically ill patient population. PMID- 21242801 TI - Outcomes of patients with Killip class III acute myocardial infarction after primary percutaneous coronary intervention. AB - OBJECTIVES: Little is known about the outcomes of patients with Killip class III acute ST-segment elevation myocardial infarction in the reperfusion era. This study investigated the short- and long-term outcomes of these patients who underwent primary percutaneous coronary intervention. METHODS: Between January 2002 and November 2009, a total of 1,278 consecutive patients with acute ST segment elevation myocardial infarction underwent primary percutaneous coronary intervention. Of these patients, 230 (17.0%) with Killip III, 216 (16.9%) with Killip II, and 832 (65.1%) with Killip I upon presentation were prospectively recruited. RESULTS: Angiographic study showed significantly lower final thrombolysis in myocardial infarction 3 flow in patients with Killip III compared with those with Killip II and I (83.5% vs. 94.9% vs. 95.7%, p<.0001). The incidence of multiple vessel disease was also notably higher in Killip III than in Killip II and I (65.7% vs. 13.9% vs. 53.8%, p<.001). Besides, the incidence of advanced congestive heart failure (defined as greater than or equal to New York Heart Association functional class 3) during hospitalization was remarkably higher in Killip III compared to Killip II and I (71.3% vs. 13.9% vs. 6.6%, p<.001). Furthermore, the 30-day mortality and 1-yr cumulative mortality were notably higher in Killip III than in Killip II and I (20.0% vs. 4.2% vs. 1.7%, p<.001 and 31.7% vs. 7.9% vs. 4%, p<.001, respectively). Multivariate analysis showed that Killip III was independently predictive of 30-day and 1-yr mortality (all p < .04). CONCLUSION: Killip III remains strongly and independently predictive of 30-day and 1-yr mortality in ST-segment elevation myocardial infarction patients even undergoing primary percutaneous coronary intervention. PMID- 21242802 TI - Impaired endothelium-dependent vasodilatation is a novel predictor of mortality in intensive care. AB - OBJECTIVE: Endothelial function may be impaired in critical illness. We hypothesized that impaired endothelium-dependent vasodilatation is a predictor of mortality in critically ill patients. DESIGN: Prospective observational cohort study. SETTING: Seventeen-bed adult intensive care unit in a tertiary referral university teaching hospital. PATIENTS: Patients were recruited within 24 hrs of admission to the intensive care unit. INTERVENTIONS: The SphygmoCor Mx system was used to derive the aortic augmentation index from radial artery pulse pressure waveforms. Endothelium-dependent vasodilatation was calculated as the change in augmentation index in response to an endothelium-dependent vasodilator (salbutamol). MEASUREMENTS AND MAIN RESULTS: Demographics, severity of illness scores, and physiological parameters were collected. Statistically significant predictors of mortality identified using single regressor analysis were entered into a multiple logistic regression model. Receiver operator characteristic curves were generated. Ninety-four patients completed the study. There were 80 survivors and 14 nonsurvivors. The Simplified Acute Physiology Score II, the Sequential Organ Failure Assessment score, leukocyte count, and endothelium dependent vasodilatation conferred an increased risk of mortality. In logistic regression analysis, endothelium-dependent vasodilatation was the only predictor of mortality with an adjusted odds ratio of 26.1 (95% confidence interval [CI], 4.3-159.5). An endothelium-dependent vasodilatation value of 0.5% or less predicted intensive care unit mortality with a sensitivity of 79% (CI, 59-88%) and specificity of 98% (CI, 94-99%). CONCLUSIONS: In vivo bedside assessment of endothelium-dependent vasodilatation is an independent predictor of mortality in the critically ill. We have shown it to be superior to other validated severity of illness scores with high sensitivity and specificity. PMID- 21242803 TI - Modeling Legionnaires' disease outbreaks: estimating the timing of an aerosolized release using symptom-onset dates. AB - BACKGROUND: Over the last 30 years, there have been a number of reported Legionnaires' disease outbreaks resulting from the release of causative organisms from aerosol-producing devices. METHODS: We model a Legionnaires' disease epidemic curve as the convolution of an infection-time distribution (representing the aerosolized release) and an incubation-period distribution. The model is fitted to symptom-onset data from specific outbreaks to estimate the start and end dates of the release. We also develop this retrospective "back-calculation" model into a prospective "real-time" model that can estimate the final size of an ongoing outbreak, in addition to the timing of its release. RESULTS: In the retrospective analysis, the estimated release end dates were generally earlier than reported end dates. This suggests that, in many outbreaks, the release might have already ended by the time the source was reportedly cleaned or closed. Prospective analysis showed that valid estimates of the release start date could be achieved early in the outbreak, the total number of cases could be reasonably determined shortly after the release had ended, and estimates of the release end date could be satisfactorily achieved in the latter stages of the outbreak. CONCLUSIONS: This model could be used in the course of a Legionnaires' disease outbreak to provide early estimates of the total number of cases, thus helping to inform public-health planning. Toward the end of the outbreak, estimates of the release end date could help corroborate standard epidemiologic, environmental, and microbiologic investigations that seek to identify the source. PMID- 21242804 TI - The metabolic cost of locomotion; muscle by muscle. PMID- 21242805 TI - Burn of silicon-injected penis treated with dartos musculocutaneous flap. AB - A dartos musculocutaneous flap was used to cover a defect of a silicone-treated granulomatous penis after a burn. A 45-year-old man presented with a 4 * 5 cm skin defect on the ventral surface of the penis. A dartos musculocutaneous tubed flap was prepared from the testicle and transferred to the defect of the penis. The donor site was closed directly. On postoperative day 11, a delay procedure was started (from 1 N to 2.3 N under 85-90% oxygen saturation). On postoperative day 19, the flap was divided completely. The defect of the penis was satisfactorily covered by a local testicle flap. A dartos musculocutaneous flap can be used to cover a defect of the penis. PMID- 21242806 TI - Nicotinic acid has anti-atherogenic and anti-inflammatory properties on advanced atherosclerotic lesions independent of its lipid-modifying capabilities. AB - Inflammation contributes to atherosclerotic plaque initiation and progression. Recent studies suggest that nicotinic acid has anti-inflammatory effects independent of its lipid-modifying capabilities. We assessed the hypothesis that administration of nicotinic acid to older apolipoprotein E (apoE)-deficient mice with established lesions will reduce lesion size and plaque inflammation independent of its lipid-modifying effects. Therefore nicotinic acid was administered to 27-week-old apo E-deficient mice exhibiting advanced atherosclerotic lesions within the innominate artery. After 27 weeks of treatment both animal groups had no significant changes in plasma lipid levels. Mice treated with nicotinic acid (n = 22) demonstrated a 30% reduction in total lesion area compared with controls (n = 20). Furthermore, they revealed a more stable plaque composition with an increase in fibrous cap thickness and a reduction in the size of the necrotic core. Immunohistochemistry demonstrated a reduced accumulation of macrophages and a reduced expression of vascular cell adhesion molecule-1 and tissue factor. Additionally, administration of nicotinic acid significantly reduced tumor necrosis factor alpha expression in the thoracic aorta as demonstrated by real-time PCR. In conclusion, these data suggest that long-term administration of nicotinic acid has anti-atherogenic and anti inflammatory properties on advanced atherosclerotic lesions, which are independent of its lipid-modifying actions. PMID- 21242807 TI - Differential modulation of immunostimulant-triggered NO production by endoplasmic reticulum stress inducers in vascular smooth muscle cells. AB - We investigated the effects of endoplasmic reticulum (ER) stress inducers thapsigargin (TG) and tunicamycin (Tm) on immunostimulant lipopolysaccharide/interferon (LPS/IFN)-induced expression of isoform of nitric oxide synthase (iNOS) and nitric oxide (NO) production in vascular smooth muscle cells. LPS/IFN-induced iNOS mRNA expression was markedly enhanced by TG, whereas iNOS mRNA expression was strongly attenuated by Tm. Similarly, production of iNOS protein was markedly upregulated by TG but virtually eliminated by Tm. LPS/IFN induced guanosine triphosphate cyclohydrolase I mRNA expression was slightly reduced by TG and markedly inhibited by Tm. Similarly, LPS/IFN-mediated induction of cellular biopterin was modestly reduced by TG and markedly inhibited by Tm. TG modestly enhanced LPS/IFN-induced activation of NF-kappaB, whereas Tm had no effect on it. Cellular respiration was reduced by TG and Tm in a concentration dependent manner, which was confirmed by apoptosis assay. Thus, TG and Tm-induced ER stress and differently modulated NO production through alterations in iNOS expression and activity independently of NF-kappaB activation and caused a similar degree of ER stress-induced apoptosis. PMID- 21242809 TI - Pediatric cardiovascular drug trials, lessons learned. AB - Few drugs have been labeled for pediatric cardiovascular indications, and many children with cardiac disease are prescribed drugs off-label. Recent initiatives have narrowed this gap, and as a result, there are an increasing number of cardiology trials in the pediatric population. Many studies, however, have either failed to show a dose response in children or have not shown efficacy in children when they have established efficacy in adults. Clinical trials are challenging in children; many factors such as lack of development of a liquid formulation, failure to fully incorporate pharmacokinetic information into trial design, poor dose selection, the lack of clinical equipoise, and the use of difficult surrogate and composite primary endpoints have led to the difficulties and failures observed in several pediatric cardiovascular trials. These lessons learned may help to inform future pediatric clinical trial development. PMID- 21242808 TI - Recombinant human erythropoietin suppresses endothelial cell apoptosis and reduces the ratio of Bax to Bcl-2 proteins in the aortas of apolipoprotein E deficient mice. AB - Recent clinical trials have raised concern that therapy with recombinant human erythropoietin (EPO) may increase cardiovascular disease risk, event rate, and mortality. Endothelial cell apoptosis has been implicated in both atherogenesis and in the destabilization and rupture of atheromatous plaques. In the current study, we observed that EPO and the EPO-mimetic peptide EMP-1 markedly suppressed lipopolysaccharide-induced apoptosis in endothelial cell monolayers. Therapeutic concentrations of EPO upregulated Bcl-2 expression and concurrently diminished expression of Bax, resulting in a net decrease in the ratio of Bax to Bcl-2 protein concentrations. In vivo studies demonstrated that EPO receptor is abundantly expressed in murine aorta and that EPO treatment for 10 weeks markedly decreased the ratio of Bax to Bcl-2 protein in the aortas of apolipoprotein E deficient mice fed a high-fat diet. To our knowledge, these data are the first to reveal a modulation of regulators of the apoptotic pathway in murine aorta by chronic EPO treatment. These observations imply that long-term administration of EPO may have the potential to affect plaque stability. PMID- 21242810 TI - Management of hypertension in the young: role of antihypertensive medications. AB - Traditionally, antihypertensive medications were used in few children or adolescents, usually just those with underlying renal or other organ system disease. However, with recent data suggesting that the incidence of primary hypertension may be increasing in the young, it is possible that more children and adolescents will be prescribed antihypertensive agents. This article will review currently available pediatric data on the use of calcium channel blockers, agents affecting the renin-angiotensin-aldosterone system and other classes of antihypertensive medications in children, highlighting appropriate indications and safety considerations. Guidelines for use of antihypertensive medications, including choice of initial agent and how to prescribe appropriately, will be presented. PMID- 21242812 TI - Treatment of leg ischemia with biodegradable gelatin hydrogel microspheres incorporating granulocyte colony-stimulating factor. AB - Granulocyte colony-stimulating factor (G-CSF) is a potent angiogenic factor. We hypothesized that G-CSF-immersed gelatin hydrogel microspheres (G-CSF-GHMs) injected into the ischemic legs might continuously release a small amount of G CSF to locally stimulate angiogenesis without unfavorable systemic effects. Just after ligation of the right femoral artery of BALB/c mice, recombinant human G CSF (100-MUg/kg)-immersed GHM was injected into the right hindlimb muscles; the controls included a saline-injected group, an intramuscularly injected G-CSF group, a subcutaneously injected G-CSG group, and an empty GHM-injected group. Eight weeks later, improvement of blood perfusion to the ischemic limb was significantly augmented in the G-CSF-GHM group compared with any of the control groups. Despite there being no increase in the serum concentration of G-CSF, in peripheral granulocytes, or in circulating endothelial progenitor cells, not only capillary but also arteriolar density was significantly increased in this group. Next, we started treatment with G-CSF-GHM 4 weeks after ligation to examine whether the treatment is effective if performed during the chronic stage of ischemia. The late treatment was also found to effectively improve blood flow in the ischemic leg. In conclusion, G-CSF-GHM administration is suggested to be a promising and readily usable approach to treating peripheral artery disease, applicable even during the chronic stage. PMID- 21242811 TI - The cardiac fibroblast: functional and electrophysiological considerations in healthy and diseased hearts. AB - Cardiac fibrosis occurs in a number of cardiovascular diseases associated with a high incidence of arrhythmias. A critical event in the development of fibrosis is the transformation of fibroblasts into an active phenotype or myofibroblast. This transformation results in functional changes including increased proliferation and changes in the release of signaling molecules and extracellular matrix deposition. Traditionally, fibroblasts have been considered to affect cardiac electrophysiology indirectly by physically isolating myocytes and creating conduction barriers. There is now increasing evidence that cardiac fibroblasts may play a direct role in modulating the electrophysiological substrate in diseased hearts. The purpose of this review is to summarize the functional changes associated with fibroblast activation, the membrane currents that have been identified in adult cardiac fibroblasts, and describe recent studies of fibroblast-myocyte electrical interactions with emphasis on the changes that occur with cardiac injury. Further analysis of fibroblast membrane electrophysiology and their interactions with myocytes will lead to a more complete understanding of the arrhythmic substrate. These studies have the potential to generate new therapeutic approaches for the prevention of arrhythmias associated with cardiac fibrosis. PMID- 21242814 TI - Cortisol, hot flashes, and cardiovascular risk. PMID- 21242815 TI - An ocean between: the Archer-Stute mentor-mentee pair in The North American Menopause Society Mentorship Program. PMID- 21242813 TI - Microvesicles at the crossroads between infection and cardiovascular diseases. AB - Observational and experimental studies continue to support the association of infection and infection-stimulated inflammation with development of cardiovascular disease (CVD) including atherosclerosis and thrombosis. Microvesicles (MV) are heterogeneous populations of sealed membrane-derived vesicles shed into circulation by activated mammalian cells and/or pathogenic microbes that may represent an interface between bacterial/microbial infection and increased risk of CVD. This review evaluates how MV act to modulate and intersect immunological and inflammatory responses to infection with particular attention to progression of CVD. Although infection-related stimuli provoke release of MV from blood and vascular cells, MV express phosphatidylserine and other procoagulant factors on their surface, which initiate and amplify blood coagulation. In addition, MV mediate cell-cell adhesion, which may stimulate production of pro-inflammatory cytokines in vascular cells, which in turn aggravate progression of CVD and propagate atherothrombosis. MV transfer membrane receptors, RNA and proteins among cells, and present auto-antigens from their cells of origin to proximal or remote target cells. Because MV harbor cell surface proteins and contain cytoplasmic components of the parent cell, they mediate biological messages and play a pivotal role in the crossroad between infection-stimulated inflammation and CVDs. PMID- 21242816 TI - Ability to follow anti-reabsorptive drug treatment in postmenopausal women with reduced bone mass. AB - OBJECTIVE: Studies show that adherence to osteoporosis treatment and prevention is low, which could interfere with therapeutic response. The aim of this study was to evaluate the ability of women to follow a treatment for osteoporosis with different anti-reabsorptives in relation to the prescribed regimen, dose, indications, and mode of ingestion. METHODS: A cross-sectional study that included postmenopausal women all undergoing medicated treatment because of densitometric diagnosis of osteopenia or osteoporosis was carried out by means of the MedTake questionnaire. A total of 227 women at a menopause clinic were studied. The following were evaluated: sociodemographic characteristics, other illnesses, use of concomitant medication, use of medication for osteoporosis, length of use, and ability to follow the treatment in relation to the prescribed regimen, dose, indication, and mode of ingestion. RESULTS: The ability to follow the treatment as evaluated by the MedTake was below 80% for most of the women. No significant difference was found between the daily or weekly bisphosphonate users and those taking raloxifene. The factors associated with inadequate treatment were the following: being 70 years or older (odds ratio [OR], 5.62; 95% CI, 1.23 25.64), being illiterate (OR, 10.14; 95% CI, 2.14-48.12), use of other medications (OR, 0.33; 95% CI, 0.15-0.76), and shorter length of use of medication for osteoporosis (OR, 5.67; 95% CI, 2.27-14.16). CONCLUSION: The ability to follow a treatment involving different anti-reabsorptive medications for osteoporosis is high relative to mode of ingestion, coingestion, and indication and low in relation to knowledge of the correct dose. Low ability is associated with advanced age, being illiterate, not using other medications, and shorter treatment time. PMID- 21242817 TI - High-order maternity may be a more significant determinant of quality of midlife than some of the climacteric symptoms. AB - OBJECTIVE: The aim of this study was to assess the impact of menopause, age, and women's symptoms and characteristics on quality of midlife. METHODS: This was a cross-sectional study of 151 healthy women aged 45 to 55 years attending university-affiliated menopause clinics. To obtain the data, a questionnaire designed by the investigators and based on the Greene Climacteric Scale and the Utian Menopause-Specific Quality of Life scale was self-completed by the participants. RESULTS: A significant gradual increase in the total Greene Climacteric Scale score was observed from premenopausal to perimenopausal and postmenopausal women (P = 0.02), specifically in the vasomotor and sexual subscores (P < 0.0001 and P = 0.001, respectively). In contrast, the total quality-of-life score remained stable in every specific aspect (occupation, health, emotion, and sex) throughout the menopausal transition (P = 0.8). A significant correlation was found between the psychological, somatic, and sexual Greene Climacteric Scale subscores and the Utian quality-of-life score (r = 0.46, P < 0.001; r = -0.29, P < 0.05; r = -0.28, P < 0.05, respectively), whereas the vasomotor subscore had no impact on midlife quality. The number of children was the only demographic factor that had a significant impact on the Utian score (P < 0.05) and to a higher extent than the climacteric syndrome. Hormone therapy equalizes the climacteric symptom profile of users to that of nonusers, yet both users and nonusers reported similar scores of midlife quality. CONCLUSIONS: Menopause-specific quality of life may be affected by both demographic and climacteric parameters. Menopausal symptoms, but not vasomotor symptoms, have a negative impact on midlife quality, yet to a lesser degree than does the number of children. PMID- 21242818 TI - Hippocampal volume in postmenopausal cynomolgus macaques with behavioral depression. AB - OBJECTIVE: Magnetic resonance imaging (MRI) studies report hippocampal (HC) volume reductions in depression. Despite observations of functional heterogeneity and ovarian steroid influence in the hippocampus, few studies report regional volume alterations or control for menstrual cycle phase. Using in vitro methods, we recently observed reduced anterior HC volume in antidepressant-naive, ovarian intact, behaviorally depressed adult female monkeys. The purpose of this study was to confirm these findings in vivo and examine whether lack of ovarian steroids affects the relationship between depression and HC volume. METHODS: MRI was used to measure whole, anterior, and posterior HC volumes in a matched sample of antidepressant-naive, surgically postmenopausal adult female cynomolgus macaques characterized for behavioral depression (six depressed, six nondepressed). High-resolution structural MRIs were acquired, and HC regions of interest were manually segmented. HC volumes were normalized to whole brain volumes before analysis. RESULTS: Similar to the previous in vitro study, HC volume measured in vivo was associated with depression. In contrast to the previous study of ovarian-intact female monkeys, whole, anterior, and posterior volumes of both the left and right hippocampi were significantly smaller in depressed compared with nondepressed surgically postmenopausal female monkeys. CONCLUSIONS: These findings confirm and extend previous observations of smaller HC volumes in behaviorally depressed female monkeys and suggest a possible role for ovarian steroids in HC protection in depression. Further studies of the potential modulating effects of ovarian function on the relationship between depression and HC volume are warranted. PMID- 21242819 TI - Involvement of G-463A MPO gene polymorphism in the response of postmenopausal women to hormone therapy. AB - OBJECTIVE: The aims of this work were to determine (1) the effects of estrogen plus progestogen therapy (EPT) and raloxifene on oxidative stress and cardiovascular risk biomarkers in postmenopausal women and (2) the involvement of the functional G-463A polymorphism of the myeloperoxidase (MPO) gene in the therapy responses. METHODS: Postmenopausal women (45-55 y old) were assigned to three groups receiving (1) EPT (continuous 50 MUg transdermal estradiol daily and 200 mg/d micronized progesterone orally the first 14 d of each month; n = 21), (2) raloxifene (60 mg daily; n = 17), and (3) no treatment (control; n = 21). Blood and urine samples were taken before and after 6 months of therapy. Measurements were serum lipid profile, C-reactive intercellular adhesion molecule 1 (ICAM-1), alpha-tocopherol, gamma-tocopherol, uric acid, total antioxidant activity (TAA), malondialdehyde, and urinary 1,4-dihydroxynonane-mercapturic acid (the major urinary 4-hydroxynonenal metabolite). The G-463A MPO polymorphism was analyzed by polymerase chain reaction and restriction fragment length polymorphism. RESULTS: EPT significantly decreased TAA and the levels of ICAM-1, not modifying other cardiovascular risk or oxidative stress markers. The raloxifene and control groups experienced no modifications in oxidative stress or endothelial dysfunction markers. The MPO genotype specifically influenced the outcomes in the EPT group. Thus, TAA decreased significantly in GG (high expression genotype) homozygotes, whereas ICAM-1 levels were reduced in A allele carriers. CONCLUSIONS: EPT exerted a negative action on the serum oxidant/antioxidant balance in the MPO GG homozygotes and a positive effect on the ICAM-1 endothelial dysfunction marker in carriers of the low-expression A allele. This observation provides evidence of the importance of this polymorphism in the response to EPT. PMID- 21242821 TI - Depression in postmenopause: a study on a subsample of the Acupuncture on Hot Flushes Among Menopausal Women (ACUFLASH) study. AB - OBJECTIVE: The current study was conducted on a subsample of postmenopausal women with a high frequency of hot flashes who participated in the Norwegian Acupuncture on Hot Flushes Among Menopausal Women study. The purpose of this study was to examine the prevalence of depressive symptoms, as measured by the Beck Depression Inventory; the effect of acupuncture therapy for menopausal hot flashes on depressive symptoms; and the associations between depressive symptoms and hot flashes, sleep disturbances, and self-reported health. METHODS: The Acupuncture on Hot Flushes Among Menopausal Women study was a multicenter, pragmatic, randomized controlled trial. The present subsample consisted of 72 women who were randomized to two groups: self-care only and acupuncture in addition to self-care for a period of 12 weeks. RESULTS: The prevalence of depressive symptoms was 30.6% at baseline, decreased similarly in both study groups during the study period, and was 14.1% at the end of the intervention. Depressive symptoms were significantly associated with sleep disturbances and self-reported health, but not with frequency of hot flashes. CONCLUSIONS: Postmenopausal women experiencing a high frequency of hot flashes reported a high prevalence of depressive symptoms compared with the general female population. Study results lend support to previous findings of an increased risk for depression during menopause, at least in women with severe hot flashes. Results further indicate that symptoms of depression in postmenopausal women may be alleviated with limited resources. PMID- 21242820 TI - Hot flashes and carotid intima media thickness among midlife women. AB - OBJECTIVE: Emerging evidence suggests associations between menopausal hot flashes and cardiovascular risk. However, whether hot flashes are associated with intima media thickness (IMT) or IMT changes over time is unknown. We hypothesized that reported hot flashes would be associated with greater IMT cross-sectionally and with greater IMT progression over 2 years. METHODS: Participants were 432 women aged 45 to 58 years at baseline participating in the Study of Women's Health Across the Nation (SWAN) Heart, an ancillary study to the SWAN. Measures at the SWAN Heart baseline and follow-up visit 2 years later included a carotid artery ultrasound, reported hot flashes (past 2 weeks: none, 1-5 d, >=6 d), and a blood sample for measurement of estradiol. RESULTS: Women reporting hot flashes for 6 days or more in the prior 2 weeks had significantly higher IMT than did women without hot flashes at the baseline (mean [SE] difference, 0.02 [0.01] mm; P=0.03) and follow-up (mean [SE] difference, 0.02 [0.01] mm; P=0.04) visits, controlling for demographic factors and cardiovascular risk factors. Reporting hot flashes at both study visits was associated with higher follow-up IMT relative to reporting hot flashes at neither visit (mean [SE] difference, 0.03 [0.01] mm; P=0.03). Associations between hot flashes and IMT largely remained after adjusting for estradiol. An interaction between hot flashes and obesity status was observed (P=0.05) such that relations between hot flashes and IMT were observed principally among overweight/obese women. Hot flashes were not associated with IMT progression. CONCLUSIONS: These findings provide some indication that women reporting hot flashes for 6 days or more in the prior 2 weeks may have higher IMT than do women without hot flashes, particularly for women who are overweight or obese. Further work should determine whether hot flashes mark adverse underlying vascular changes. PMID- 21242822 TI - Can a self-expanding aneurysm stent be clipped? Emergency proximal control options for the vascular neurosurgeon. AB - BACKGROUND: If a self-expanding stent has been placed during endovascular treatment of an aneurysm and subsequently an open aneurysm surgery becomes necessary in the same or an adjacent area, is it possible and safe to obtain proximal control by placing a temporary clip on the artery at a point where it contains the stent? OBJECTIVE: To evaluate the effect of temporary clip application to 3 separate stent systems in an in vitro flow model with the stated hypothesis that clip application to these stents will result in permanent stent deformation. METHODS: This is an in vitro flow model study using an accepted synthetic blood vessel substitute. The Neuroform(3) (Boston Scientific), Enterprise (Cordis/Codman), and Pipeline (ev3) stents were deployed within the flow model; temporary clips were applied; and angiographic measurements subsequently made. RESULTS: Two 4 * 30-mm Neuroform(3) stents, two 4.5 * 28-mm Enterprise stents, and two 3.75 * 20-mm Pipeline stents were successfully deployed and clipped repeatedly (4 iterations). Two- and 3-dimensional angiograms were obtained. After repeated clip occlusion, the Neuroform(3) and Enterprise stents returned to their original configuration and diameter. Clip application to both also resulted in immediate flow arrest. In contrast, initial clip application to the Pipeline stents did not result in flow arrest, but the second single clip application did. The Pipeline stents were also irreversibly deformed after the experimental protocol, with an average luminal diameter reduction of 26.85% (P < .05). CONCLUSION: The Neuroform(3) and Enterprise stents responded favorably to temporary clip application, returning to their original diameter after clip removal and showing no sign of permanent structural modification. The Pipeline flow-diverting stent, however, was irreversibly deformed by clip application. These data indicate that temporary clip application to certain stents is possible. Further in vivo study is required. PMID- 21242823 TI - A comparison of mesenchymal precursor cells and amnion epithelial cells for enhancing cervical interbody fusion in an ovine model. AB - BACKGROUND: Rapid, reliable fusion is the goal in anterior cervical diskectomy and fusion. Iliac crest autograft has a high rate of donor-site morbidity. Alternatives such as bone graft substitutes lack osteoinductivity, and recombinant bone morphogenetic proteins risk life-threatening complications. Both allogeneic mesenchymal precursor cells (MPCs) and amnion derived epithelial cells (AECs) have osteogenic potential. OBJECTIVE: To compare for the first time the capacity of MPCs and AECs to promote osteogenesis in an ovine model. METHODS: Five groups of 2-year-old ewes were subjected to C3-4 anterior cervical diskectomy and fusion with a Fidji interbody cage packed with iliac crest autograft alone (group A; n = 6), hydroxyapatite-tricalcium phosphate Mastergraft granules (HA/TCP) alone (group B; n = 6), HA/TCP containing 5 million MPCs (group C; n = 6), or HA/TCP containing 5 million AECs (group D; n = 5); group E was made up of age-matched nonoperative controls (n = 6). At 3 months, animals were euthanized and quantitative multislice computed tomography, functional radiography, biomechanics, histology, and histomorphometry were performed. RESULTS: No procedure- or cell-related adverse events were observed. There was significantly more fusion in the MPC group (C) than in group A, B, or D. Computed tomography scan at 3 months revealed that 5 of 6 MPC-treated animals (83%) had continuous bony bridging compared with 0 of 5 AEC-treated and only 1 of 6 autograft- and 2 of 6 HA/TCP-treated animals (P = .01). CONCLUSION: Implantation of allogeneic MPCs in combination with HA/TCP within an interbody spacer facilitates interbody fusion after diskectomy. The earlier, more robust fusion observed with MPCs relative to autograft and HA/TCP bone substitute indicates that this approach may offer a therapeutic benefit. PMID- 21242824 TI - Clear-cell chondrosarcoma of the lumbar spine: case report and review of the literature. AB - BACKGROUND AND IMPORTANCE: Clear-cell chondrosarcoma is a rare subtype of chondrosarcoma. These osseous tumors are most commonly found in the end of long bones. We report a rare case of clear-cell chondrosarcoma of the osseous spine. CLINICAL PRESENTATION: A 52-year-old man presented to another institution with a pathologic L1 compression fracture. Intraoperatively, this fracture was discovered to be secondary to a chondrosarcoma involving T12, L1, and L2. He was then referred to our institution for further evaluation and treatment. A 2-stage operation was performed with successful en bloc resection of residual chondrosarcoma with negative margins. The first stage using a posterior approach resulted in placement of pedicle screws from T9 to L4, laminectomies from T12 to L2, and placement of Tomita saws between the thecal sac and the vertebral body at both the T11-12 and L2-3 disc levels. The second stage of the procedure involved a transthoracic, retroperitoneal approach to the thoracolumbar spine. Osteotomies between T11-12 and L2-3 were completed, and the vertebral bodies of T12, L1, and L2 were delivered as an en bloc specimen. The final pathology of the specimen was clear-cell chondrosarcoma with negative margins. CONCLUSION: This report discusses a rare occurrence of clear-cell chondrosarcoma in the osseous spine. Aggressive surgical intervention with the goal of en bloc resection of tumor is recommended to promote tumor-free survival. PMID- 21242825 TI - Three-dimensional in vivo modeling of vestibular schwannomas and surrounding cranial nerves with diffusion imaging tractography. AB - BACKGROUND: Preservation of cranial nerves (CNs) is of paramount concern in the treatment of vestibular schwannomas, particularly in large tumors with thinned and distorted CN fibers. However, imaging of the CN fibers surrounding vestibular schwannomas has been limited with 2-dimensional imaging alone. OBJECTIVE: To assess whether tractography of the CN combined with anatomic magnetic resonance imaging of the tumor can provide superior 3-dimensional (3D) visualization of tumor/CN complexes. METHODS: Magnetic resonance imaging at 3 T, including diffusion tensor imaging and anatomic images, were analyzed in 3 subjects with vestibular schwannomas using 3D Slicer software. The diffusion tensor images were used to track the courses of trigeminal, abducens, facial, and vestibulocochlear nerves. The anatomic images were used to model the 3D volume reconstruction of the tumor. The 2 sets of images were then superimposed through the use of linear registration. RESULTS: Combined 3D tumor modeling and CN tractography can effectively and consistently reconstruct the 3D spatial relationship of CN/tumor complexes and allows superior visualization compared with 2-dimensional imaging. Lateral and superior distortion of the trigeminal nerve was observed in all cases. The position of the facial nerve was primarily anteriorly and inferiorly. The gasserian ganglion and early postganglionic branches could also be visualized. CONCLUSION: Tractography and anatomic imaging were successfully combined to demonstrate the precise location of surrounding CN fibers. This technique can be useful in both neuronavigation and radiosurgical planning. Because knowledge of the course of these fibers is of important clinical interest, implementation of this technique may help decrease injury to CNs during treatment of these lesions. PMID- 21242827 TI - Evaluating endoscopic treatment of arachnoid cysts. PMID- 21242828 TI - Over-aggressive treatment of grade V SAH patients. PMID- 21242829 TI - Peripheral nerve palsy by torsional nerve injury. AB - BACKGROUND: Peripheral nerve palsy caused by torsional nerve injury is rare. Only a few patients have been reported in the literature. The etiology of this type of nerve lesion is poorly understood. OBJECTIVE: To report on 5 patients presenting with peripheral nerve palsy caused by a torsional nerve injury. METHODS: Five patients presented with 6 upper peripheral nerve palsy involving the axillary nerve (n = 2), musculocutaneous nerve (n = 2), radial nerve (n = 1), and suprascapular nerve (n = 1). There was no history of trauma in 3 patients, but in the other 2 patients, nerve palsy occurred after a traumatic event. Because of a lack of spontaneous recovery, surgical exploration was performed. Torsion of the whole nerve (n = 5) or only 1 fascicle (n = 1) was found. Epifascicular epineurectomy and detorsion, as well as resection of the torsion site with subsequent primary nerve suture, were performed in 3 lesions. RESULTS: Good to excellent recovery of motor function was achieved in all 5 patients. In the last patient who presented with 2 nerve torsions, the follow-up period after the last surgery is too short to allow evaluation. CONCLUSION: Although not a frequent event, torsional nerve injury should be taken into consideration when dealing with peripheral nerve injuries. Surgical exploration with detorsion or suture results in good recovery. PMID- 21242830 TI - Effect of early surgery, material, and method of flap preservation on cranioplasty infections: a systematic review. AB - BACKGROUND: Infection is a significant cause of morbidity with cranioplasty procedures. However, few studies have investigated the effect of specific surgical practices on cranioplasty infection. OBJECTIVE: To analyze the literature on the effect of early surgery (within 3 months of craniectomy), implant material, and method of flap preservation on cranioplasty infections, and to perform a subanalysis of the effect of early surgery on overall complications associated with cranioplasty. METHODS: A systematic search of the PubMed, Cochrane, SCOPUS, and CINAHL databases was conducted. Comparative studies that reported on timing of surgery, implant material (autograft vs allograft), or method of flap preservation (subcutaneous vs extracorporeal), and infection or complication rates were selected for detailed analysis. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each analysis. RESULTS: Eighteen articles (2254 data points) met criteria for inclusion. There was no difference in infection rates (OR, 1.35; 95% CI, 0.53-3.41; P = .53) or overall complication rates (OR, 0.57; 95% CI, 0.29-1.11; P = .10) between early or later surgery. Fourteen studies (n = 1582) compared infection rates between autograft and allograft materials; there was no difference in infection rates between the two (OR, 0.81; 95% CI, 0.40-1.66; P = .57). There was no significant difference in infection rates between subcutaneous or extracorporeal preservation (OR, 0.35; 95% CI, 0.09-1.35; P = .13). CONCLUSION: Analysis of the best current evidence suggests that early surgery, implant material, and method of flap preservation have no effect on the rate of cranioplasty infections. PMID- 21242831 TI - Individual fiber anatomy of the subthalamic region revealed with diffusion tensor imaging: a concept to identify the deep brain stimulation target for tremor suppression. AB - BACKGROUND: Deep brain stimulation (DBS) has been proven to alleviate tremor of various origins. Distinct regions have been targeted. One explanation for good clinical tremor control might be the involvement of the dentatorubrothalamic tract (DRT) as has been suggested in superficial (thalamic) and inferior (posterior subthalamic) target regions. Beyond a correlation with atlas data and the postmortem evaluation of patients treated with lesion surgery, proof for the involvement of DRT in tremor reduction in the living, the scope of this work, is elusive. OBJECTIVE: To report a case of unilateral refractory tremor in tremor dominant Parkinson disease treated with thalamic DBS. METHODS: Preoperative diffusion tensor imaging (DTI) was performed. Correlation with individual DBS electrode contact locations was obtained through postoperative fusion of helical computed tomography (CT) data with DTI fiber tracking. RESULTS: Tremor was alleviated effectively. An evaluation of the active electrode contact position revealed clear involvement of the DRT in tremor control. A closer evaluation of clinical effects and side effects revealed a highly detailed individual fiber map of the subthalamic region with DTI fiber tracking. CONCLUSION: This is the first time the involvement of the DRT in tremor reduction through DBS has been shown in the living. The combination of DTI with postoperative CT and the evaluation of the electrophysiological environment of distinct electrode contacts led to an individual detailed fiber map and might be extrapolated to refined DTI-based targeting strategies in the future. Data acquisition for a larger study group is the topic of our ongoing research. PMID- 21242833 TI - Disseminated intravascular coagulation during resection of a meningioma: case report. AB - BACKGROUND AND IMPORTANCE: Disseminated intravascular coagulation is a relatively common complication in patients with trauma, sepsis, obstetric calamities, and certain malignancies. We report a rare case of DIC after embolization and surgery for a large meningioma. We also review the literature on coagulopathy during brain tumor surgery as well as the diagnosis and treatment of this complication. CLINICAL PRESENTATION: A 62-year-old woman presented with a 3-week history of aphasia, difficulty with handwriting, personality change, and right-sided weakness. Magnetic resonance imaging demonstrated a 6.3 * 5.4-cm multilobe and avidly enhancing mass within the left frontal region. The patient underwent preoperative transcatheter Onyx embolization of the tumor, followed immediately by craniotomy for resection of the tumor. Surgery was complicated by coagulopathy leading to substantial blood loss. The diagnosis of disseminated intravascular coagulation was established by intraoperative thromboelastography, after which the patient was treated with replacement therapy, Amicar, and modest hypotension. One year after surgery, the patient had fully recovered and had no focal neurological deficit. CONCLUSION: This case report adds to the few reported cases of disseminated intravascular coagulation as a complication of brain tumor surgery. This patient's successful outcome may be attributed to timely recognition of the condition and effective, prompt treatment. PMID- 21242834 TI - Ependymoma and choroid plexus papilloma as synchronous multiple neuroepithelial tumors in the same patient: a case report and review of literature. AB - BACKGROUND AND IMPORTANCE: We report the case of a patient with multiple neuroepithelial tumors of different histological cell types. In this patient, synchronous appearance of tumors of the central nervous system, ie, cervical ependymoma and a fourth ventricle choroid plexus papilloma, was noted. CLINICAL PRESENTATION: A 36-year-old man presented with sensory disturbance of the bilateral upper extremities. Magnetic resonance imaging revealed a heterogeneously enhanced mass with syringomyelia in the upper cervical cord and a well-enhanced mass in the fourth ventricle. The patient underwent bilateral suboccipital craniotomy and laminectomy from the level of C1 to C3 for both lesions. The lesions were grossly resected. Histological and immunohistochemical examinations revealed that the cervical tumor was an ependymoma, and the fourth ventricle tumor was a choroid plexus papilloma. CONCLUSION: The appearance of synchronous multiple neuroepithelial tumors of different histological cell types is extremely rare, and this is the first known case of ependymoma occurring synchronously with choroid plexus papilloma, both tumors having different histological cell types. Displacement and maldifferentiation of primitive, multipotent neuroepithelial cells may be a causative factor for this unique presentation. PMID- 21242836 TI - Recurring intracranial malignant peripheral nerve sheath tumor: case report and systematic review of the literature. AB - BACKGROUND AND IMPORTANCE: To report the clinical presentation and management of an intracranial frontoparietal malignant peripheral nerve sheath tumor (MPNST) and its recurrence in a 6-year-old girl, along with a systematic review of the literature. CLINICAL PRESENTATION: A previously healthy 6-year-old girl presented with severe signs of increased intracranial pressure. Magnetic resonance imaging (MRI) revealed a large heterogeneously enhancing mass at the right frontoparietal convexity. The tumor was completely removed, the histological diagnosis was MPNST, and the patient underwent adjuvant radio- and chemotherapy. Fifteen months later, MRI revealed a small local recurrence. After upfront chemotherapy, the recurrence was removed in a radical, ie, true oncological, neuronavigationally guided, en bloc resection, including approximately 1 cm surrounding gray and white matter and overlying dura mater. Neuropathological examination revealed tumor-free margins. The patient again received adjuvant chemotherapy. Four years after diagnosis and 20 months after cessation of adjuvant therapy, there are no signs of tumor recurrence. The literature search resulted in 17 cases of intracranial MPNSTs not associated with cranial nerves. Despite macroscopically complete resection in many cases and adjuvant radio- and chemotherapy, overall survival was poor, with only 5 patients still alive upon publication (including the current patient). CONCLUSION: Intracranial MPNSTs not associated with cranial nerves are extremely rare and highly malignant tumors with poor overall survival, probably because of infiltrating growth into surrounding brain tissue. We therefore advocate consideration of nonconventional true oncological en bloc resection when approaching this rare tumor or its recurrence. PMID- 21242837 TI - Solitary fibrous tumor with multiple intracranial and spinal lesions: case report. AB - BACKGROUND AND IMPORTANCE: Solitary fibrous tumor (SFT) has been previously reported for its wide variety of presentations and atypical sites. We report a case of recurrent SFT with multiple intracranial and spinal lesions. CLINICAL PRESENTATION: A 45-year-old female with recurrent right frontoparietal SFT was found to have multiple intracranial and spinal lesions. Most of the lesions are asymptomatic. Each of the intracranial and spinal lesions has been confirmed histologically. In 1999 the patient was found to have a single right temporal SFT and had a gross total resection of the lesion. In 2005 the patient underwent a second gross total resection for the recurrence of the right temporal-parietal lesion, followed by radiation therapy. In 2009 she underwent a third and fourth gross total resection of the right frontoparietal lesion, and the L4-5 mass, as well as a cervical laminectomy for an extramedullary spinal lesion causing spinal compression. CONCLUSION: This is the first case report of recurrent SFT with multiple intracranial and spinal lesions. This case illustrates the nature of recurrence and multiplicity of SFT and raises the importance of a thorough investigation, especially in the entire neuroaxis, in patients with the diagnosis of SFT. This case also questions the justification of the name that was given to this tumor. PMID- 21242838 TI - Contribution of bradykinin receptors to the development of secondary brain damage after experimental subarachnoid hemorrhage. AB - BACKGROUND: Subarachnoid hemorrhage (SAH) is the stroke subtype with the highest mortality and morbidity. Which molecular events mediate brain damage after SAH is not well understood. OBJECTIVE: To investigate the role of proinflammatory bradykinin B(1) and B(2) receptors for the pathophysiology of SAH. METHODS: B(1) and B(2) receptor knockout or wild-type mice were subjected to SAH by endovascular puncture. Intracranial pressure, regional cerebral blood flow, and mean arterial blood pressure were continuously monitored up to 60 minutes after SAH. Brain water content was quantified 24 hours after SAH; mortality, neurological function, and body weight were assessed daily for 7 days after hemorrhage. RESULTS: Intracranial pressure, regional cerebral blood flow, and mean arterial blood pressure did not differ between groups. Mortality was 60% in wild-type mice and 82% in B(1)R mice but only 20% in B(2)R animals (P < .05). B(2)R mice also exhibited less severe neurological deficits (P < .05), a less pronounced loss of body weight (P < .05), and significantly less brain edema formation (P < .05) compared with wild-type mice. CONCLUSION: Signaling mediated by bradykinin B(2) receptors contributes to mortality and secondary brain damage after SAH in mice. Thus, B(2) receptors may represent novel targets for the treatment of SAH. PMID- 21242839 TI - Endovascular stenting of extracranial carotid and vertebral artery dissections: a systematic review of the literature. AB - BACKGROUND: Carotid and vertebral artery dissections are a leading cause of stroke in young individuals. OBJECTIVE: To examine the published safety and efficacy of endovascular stenting for extracranial artery dissection. METHODS: We conducted a systematic review of the literature to identify all cases of endovascular management of extracranial carotid and vertebral artery dissections. RESULTS: For carotid dissections, our review yielded 31 published reports including 140 patients (153 vessels). Reported etiologies were traumatic (48%, n = 64), spontaneous (37%, n = 49), and iatrogenic (16%, n = 21). The technical success rate of stenting was 99%, and the procedural complication rate was 1.3%. Mean angiographic follow-up was 12.8 months (range, 2-72 months) and revealed in stent stenosis or occlusion in 2% of patients. Mean clinical follow-up was 17.7 months (range, 1-72 months), and neurological events were seen in 1.4% of patients. For vertebral artery dissections, our review revealed 8 reports including 10 patients (12 vessels). Etiologies were traumatic (60%, n = 6), spontaneous (20%, n = 2), and iatrogenic (20%, n = 2). There was a 100% technical success rate. The mean angiographic follow-up period was 7.5 months (range, 2-12 months). No new neurological events were reported during a mean clinical follow up period of 26.4 months (range, 3-55 months). CONCLUSION: Endovascular management of extracranial arterial dissection continues to evolve. Current experience shows that this treatment option is safe and technically feasible. Prospective randomized trials compared with medical management are needed to further elucidate the role of stenting. PMID- 21242840 TI - Emergency neurosurgical care solutions: acute care surgery, regionalization, and the neurosurgeon: results of the 2008 CNS consensus session. AB - OBJECTIVE: Organized general surgery has recently proposed creation of a new acute care surgery subspecialty to include emergency care of basic neurosurgical and orthopedic surgical problems. Little is known about neurosurgical attitudes toward this proposal and alternative methods of improving access to emergency neurosurgical care. METHODS: During a consensus session at the 2008 Annual Meeting of the Congress of Neurological Surgeons (CNS), electronic data were collected regarding neurosurgeons' attitudes toward acute care surgery, emergency neurosurgical care regionalization, and other regulatory options. RESULTS: Ninety nine attendees participated in polling, broadly representing private (45%) and academic (34%) practices from all regions of the United States. Eighty-nine percent reported taking emergency calls (75% at least twice per week), with the majority (57%) not receiving a stipend. Only 9% responded that routine emergency cases are frequently transferred from their hospital. The majority (60%) either agreed or strongly agreed that there are problems with neurosurgery emergency coverage in their region. Before the session, 89% were opposed to the acute care surgery initiative as a solution for neurosurgery emergency coverage and 85% favored regionalization of emergency care. Opinions did not change significantly following expert presentations and discussion. CONCLUSION: Neurosurgeons polled during a 2008 CNS consensus session opposed creation of an acute care surgery specialty within general surgery that covers neurosurgical emergencies, but they favored neurosurgical emergency care regionalization. The CNS consensus sessions provide a forum for discussing socioeconomic and professional issues important to neurological surgery and for formulating preliminary information and strategies of use to regulatory stakeholders in addressing these issues. PMID- 21242841 TI - Classification and analysis of the errors in neuronavigation. AB - There are many different types of errors in neuronavigation, and the reasons and results of these errors are complex. For a neurosurgeon using the neuronavigation system, it is important to have a clear understanding of when an error may occur, what the magnitude of it is, and how to avoid it or reduce its influence on the final application accuracy. In this article, we classify all the errors into 2 groups according to the working principle of neuronavigation systems. The first group contains the errors caused by the differences between the anatomic structures in the images and that of the real patient, and the second group contains the errors occurring in transforming the position of surgical tools from the patient space to the image space. Each group is further divided into 2 subgroups. We discuss 16 types of errors and classify each of them into one of the subgroups. The classification and analysis of these errors should help neurosurgeons understand the power and limits of neuronavigation systems and use them more properly. PMID- 21242842 TI - Postoperative fever discharge guidelines increase hospital charges associated with spine surgery. AB - BACKGROUND: Postoperative fever is a common sequel of spine surgery. In the presence of rigid nationally mandated clinical guidelines, fever management may consume more health care resources than is reasonably appropriate. OBJECTIVE: To study the relationship between postoperative fever, infection rate, and hospital charges in a cohort of spine surgery patients. METHODS: We retrospectively reviewed 578 spine surgery patients (lumbar microdiskectomy [LMD], anterior cervical decompression and fusion [ACDF], and lumbar decompression and fusion [LDF]). Differences in length of stay and hospital charges as well as risk factors and correlation with infection and readmission rates were studied. RESULTS: Postoperative fever occurred in 41.7% of all spine surgery patients and more often in LDF patients (77.2%). Type of surgery was the most important variable affecting the prevalence of postoperative fever. Significant differences in length of stay were elicited between patients with and without postoperative fever in the ACDF and LMD groups and in hospital cost in the LMD group. The average length of stay was 2.41 vs 4.47 (P < .01) in the LMD group, 1.67 vs 2.80 (P < .05) in the ACDF group, and 5.03 vs 5.65 (P > .05) in the LDF group. The average hospital charges were $16 261 vs $22 166 (P < .01) in the LMD group, $26 021 vs $29 125 (P > .05) in the ACDF group, and $53 627 vs $53 210 (P > .05) in the LDF group. Obesity, female sex, and >=102 degrees F postoperative temperature were the most significant predictors of infection. Delayed discharge referable to postoperative fever did not seem to influence the infection readmission rate. CONCLUSION: Postoperative fever in spine surgery patients is associated with a delay in patient discharge and increases in hospital charges. Postoperative fever discharge guidelines should be regularly and publicly subjected to appropriate cost-benefit analysis. PMID- 21242843 TI - The accumbofrontal fasciculus in the human brain: a microsurgical anatomical study. AB - BACKGROUND: The fiber-dissection technique provides unique 3-dimensional anatomic knowledge of the white matter. OBJECTIVE: To better identify the frontostriatal pathways in the human brain, we used a fiber-dissection technique to reconstruct neural connections between the frontal cortex and the nucleus accumbens (NAcc), which is the most ventral extent of the striatum. METHODS: Thirty previously frozen, formalin-fixed human brains were dissected under the operating microscope using a modified fiber-dissection technique, primarily reported by Klingler. RESULTS: Our serial dissections of 30 human brain specimens clearly demonstrated that projection fibers form a connection between the NAcc and the frontal lobe. We evidenced this newly described subcortical tract as an accumbofrontal fasciculus. This focal projection was concentrated at the level of the ventromedial part of the NAcc and characterized by an elective and specific projection from the orbitomedial prefrontal cortex, particularly the gyrus rectus and the medial orbital gyrus situated between the H-shaped and the medial orbital sulcus. CONCLUSION: The accumbofrontal fasciculus is an elective and specific projection from the orbitoprefrontal cortex. This fasciculus is part of a corticostriatothalamocortical loop and a putative target for deep-brain stimulation in the treatment of obsessive-compulsive disorder and major depression. The analysis of in vivo diffusion tractography, used today as a standard in the investigation of many brain disorders, could potentially take advantage of complementary anatomic correlations and functional extrapolations, as described in this study. PMID- 21242844 TI - Frame-based vs frameless placement of intrahippocampal depth electrodes in patients with refractory epilepsy: a comparative in vivo (application) study. AB - BACKGROUND: Despite progress in imaging technologies, documentation of unifocal electrical excitability is pivotal in patient selection for epilepsy surgery. OBJECTIVE: To compare the application accuracy of the Vogele-Bale-Hohner system (VBH), a maxillary fixation system with an external fiducial frame permitting frameless stereotactic guidance, with that of conventional frame-based stereotaxy for placement of intrahippocampal depth electrodes (DEs) in patients with refractory epilepsy. METHODS: Retrospective study. Comparison of two patient cohorts with DEs implanted along the occipitotemporal axis (group A, VBH; group B, frame-based stereotaxy). In vivo accuracy (lateral target localization error [TLE]), determined postoperatively by measuring the normal distance between virtual target and real electrode position at the tip and at 4cm from the tip, number of electrode contacts within the target structure, and diagnostic quality of electroencephalogram recordings were compared. RESULTS: Seventeen DEs (A, 6 electrodes, 60 contacts; B, 11 electrodes, 90 contacts) were placed. electroencephalogram recordings via DEs supported further treatment decisions in all patients. TLE was 2.433 +/- 0.977 mm (SD) (95% confidence interval [CI], 1.715-3.214 mm) (A) and 1.803 +/- 0.392 mm (SD) (95% CI,1.511-2.195 mm) (B) (P = .185). Maximal error was 4 mm (A) and 3.2 mm (B). TLE 4 cm from the tip was 2.166 +/- 2.188 mm (SD) (95% CI,0.438-3.916 mm) (A) and 1.372 +/- 0.548 mm (SD) (95% CI,1.049-1.695 mm) (B) (P = .39). Maximal error 4 cm from the tip was 6.4 mm (A) and 2.14 mm (B). On average, 7 (A) and 5 (B) electrode contacts were placed in the target region. CONCLUSION: The VBH and frame-based systems offer similar in vivo accuracy for intrahippocampal DE placement. With frame-based methods, accuracy is higher but the number of contacts per side is lower. This does not translate to clinically important differences. PMID- 21242845 TI - 14-3-3zeta positive expression is associated with a poor prognosis in patients with glioblastoma. AB - BACKGROUND: When identifying clinical markers predicting clinical outcome, disease recurrence and resistance to therapies often determine the diagnosis and therapy of some cancer types. OBJECTIVE: To investigate whether 14-3-3zeta positive expression is an indicator of prognosis in patients with glioblastoma. METHODS: Forty-seven patients treated with surgery, radiotherapy, and adjuvant chemotherapy between 2005 and 2007 were divided into 2 groups according to 14-3 3zeta expression in an immunohistochemical study: the 14-3-3zeta negative group (n = 12 patients) and the 14-3-3zeta positive group (n = 35 patients). The clinicopathologic features and survival data for patients in the 14-3-3zeta positive group were compared with data from the patients in the 14-3-3zeta negative group. Kaplan-Meier survival analysis and univariate and multivariate analyses were performed to determine the prognostic factors that influenced patient survival. RESULTS: 14-3-3zeta positive expression was observed in approximately 74.5% of patients with glioblastoma. Patients in the 14-3-3zeta positive group had lower overall survival rates and median survival time than those in the 14-3-3zeta negative group (overall 2-year actuarial survival rates, 8.6% for the 14-3-3zeta positive group vs 16.7% for the 14-3-3zeta negative group; overall 2-year median survival time, 12.9 months for the 14-3-3zeta positive group vs 17.9 months for the 14-3-3zeta negative group, P = .019). 14-3 3zeta positive expression in tumor cells also was correlated with a shorter interval to tumor recurrence (median interval to recurrence, 5.9 months in the 14 3-3zeta positive group vs 8.3 months in the 14-3-3zeta negative group, P = .002). Univariate and multivariate analyses showed that 14-3-3zeta positive expression was an independent prognostic factor. CONCLUSION: 14-3-3zeta positive expression can be used as a potential molecular risk factor in patients with glioblastoma. PMID- 21242846 TI - Orbital lymphoma in the setting of idiopathic CD4+ lymphocytopenia (HIV-negative AIDS). AB - A 43-year-old Asian man with idiopathic CD4+ lymphocytopenia (human immunodeficiency virus [HIV]-negative acquired immunodeficiency syndrome [AIDS]) noted blurred vision OD. Visual acuity was 20/30 OD and 20/15 OS. The right eye showed features of axial proptosis (2 mm), blepharoptosis, upgaze restriction, conjunctival chemosis, color desaturation, and choroidal folds. The OS was unremarkable. There was no lymphadenopathy. Orbital MRI showed a well circumscribed mass indenting the globe. Excision revealed diffuse large-B-cell lymphoma. Systemic evaluation was negative and adjuvant external beam radiotherapy to the right orbit was performed. Idiopathic CD4+ lymphocytopenia is a rare hematologic condition characterized by depletion of CD4+ T cells in HIV negative patients. This condition closely resembles AIDS but HIV serology is negative. Similar to AIDS, patients are at risk for opportunistic infections and neoplasia, including systemic lymphoma. This is the first case, to the authors' knowledge, of orbital lymphoma with idiopathic CD4+ lymphocytopenia. PMID- 21242847 TI - A case of bilateral silent sinus syndrome presenting with chronic ocular surface disease. AB - The silent sinus syndrome is characterized by atelectasis of the maxillary sinus in the setting of subclinical maxillary sinusitis and obstruction of the osteomeatal unit. The resultant expansion of orbital volume causes enophthalmos and hypoglobus. A review of the literature reveals only unilateral cases. The authors present a case of bilateral silent sinus syndrome presenting with chronic ocular surface disease. A 56-year-old man was referred for tarsorrhaphy to treat a chronic recurrent corneal ulcer. Exam revealed an area of corneal thinning in the left eye. The patient appeared cachectic and there was enophthalmos, hypoglobus, and lagophthalmos on both sides, left worse than right. Due to the patient's appearance and a history of sinonasal malignancy, recurrent malignancy was suspected. A systemic workup was unrevealing, and radiographic studies showed the features of silent sinus syndrome bilaterally. The patient underwent sinus surgery and placement of a left orbital floor implant. PMID- 21242848 TI - Trochlear calcification mimicking an orbital foreign body. AB - A 39-year-old man presented with diplopia 1 day following left orbit trauma. CT scan and ultrasound showed a left trochlear hyperintensity that was interpreted by both the radiologist and echographer as a metallic foreign body. Surgical exploration failed to identify a foreign body. The patient presumably had preexisting trochlear calcification with a post-traumatic nonconcomitant small angle vertical deviation and diplopia. Calcification should be considered in the differential diagnosis of trochlear hyperintensity noted on imaging studies. PMID- 21242850 TI - Orbital floor abscess secondary to sinusitis in an immunocompromised patient. AB - A 65-year-old man with a history of renal transplantation presented with facial pain, purulent nasal discharge, and periorbital swelling. Signs of optic nerve compromise developed and persisted despite medial orbital wall decompression. Further imaging revealed an orbital floor abscess secondary to direct communication of a maxillary pseudomonal sinusitis. Full recovery was achieved after further surgical drainage via an endoscopic endonasal approach. Failure to improve after surgical decompression is an indication for repeat imaging. Immunocompromised patients can present atypically. Orbital floor abscess secondary to sinusitis without an underlying odontogenic or traumatic cause has not previously been reported. The authors highlight the importance of clinical vigilance, serial imaging, microbiological investigations, and early surgical intervention in high-risk patients. PMID- 21242849 TI - Ophthalmic complications following treatment of paranasal sinus rhabdomyosarcoma in comparison to orbital disease. AB - PURPOSE: To identify the type and frequency of ocular and orbital complications observed following treatment for primary rhabdomyosarcoma of the paranasal sinuses or the orbit. METHODS: An institutional review board-approved, Health Insurance Portability and Accountability Act-compliant retrospective chart review was conducted to identify all patients treated at one institution from 1966 to 2005 with biopsy-proven primary paranasal sinus or orbital rhabdomyosarcoma. Pretreatment, treatment, and follow-up data were collected. RESULTS: Forty-four patients (25 male) of a median age of 7.8 years (range 1.0-18.0 years) with primary paranasal sinus (17) or orbital (27) rhabdomyosarcoma were treated and followed for a median period of 5.3 years (range 0.6-32.0 years). The three most frequently observed ophthalmic complications were persistent eyelid erythema or cellulitis (12), epithelial keratitis (7), and conjunctival injection (6) in the paranasal sinus and epithelial keratitis (18), conjunctival injection (11), and cataract (10) in the orbit. Overall survival after treatment trended higher for the orbital rhabdomyosarcoma group (23 of 27) than the paranasal sinus group (9 of 17). CONCLUSIONS: The most frequently observed treatment-induced ophthalmic complications in the paranasal sinus group were manageable with minimal patient morbidity, as in the patients with orbital disease. Vision-threatening complications were infrequently encountered. Despite maximal therapy, the mortality rate was higher in the paranasal sinus rhabdomyosarcoma group than in the orbital rhabdomyosarcoma group. PMID- 21242851 TI - Ocular surface squamous neoplasia (squamous cell carcinoma) of the socket: management of extensive tumors with interferon. AB - PURPOSE: To describe the clinical features and management of extensive ocular surface squamous neoplasia (OSSN) (squamous cell carcinoma) of the socket. METHODS: Retrospective interventional case series. Interferon alpha 2b (IFNa2b) eye drops (1 million units/cc) 4 times daily and IFNa2b sublesional injection (5 million units/0.5cc to 8 million units/0.8 cc) were delivered for tumor control. Participants were 3 patients with ocular prosthesis who developed extensive socket OSSN. Tumor control was graded as complete regression, partial regression, or no regression. RESULTS: OSSN was detected in the socket at age 60, 43, and 20 years in patients who had worn ophthalmic prostheses for 54, 26, and 13 years, respectively. The patients had chronic discharge and irritation (n = 3) managed with intermittent topical corticosteroids (n = 2). There were no predisposing factors of cigarette exposure, radiation exposure, eczema, systemic immune suppression, or organ transplantation. The prosthesis fit well with nonirritative edges. At presentation, OSSN was subtle (n = 3), vascular (n = 3), and multifocal (n = 3), with largest lesions or confluence of lesions measuring 20, 25, and 20 mm, respectively. The tumors involved the tarsal (n = 3), bulbar (n = 2), and forniceal (n = 2) surfaces. All patients were treated with topical and injection IFNa2b, with complete regression achieved in 2 cases (at 1 months and 20 months) and partial regression in one case (at 9 months). All patients continue on chronic maintenance IFNa2b topically. There were no recurrences, and IFNa2b injection side effects of nausea and chills were minor, lasting 1 day. No patient required surgical removal of tumors from the socket and no patient required exenteration. CONCLUSIONS: Patients wearing ophthalmic prosthesis over a socket should be monitored for the development of OSSN. Combined topical and injection IFNa2b could represent a potentially effective therapy for this condition. PMID- 21242852 TI - Tuberculosis of the nasolacrimal duct. AB - Nasolacrimal tuberculosis is rare. The authors present a young Peruvian-born female with subacute onset of right eye epiphora, isolated right inferior turbinate enlargement, and ipsilateral cervical lymphadenopathy. Turbinate and neck mass incisional biopsies demonstrated histopathological findings consistent with tuberculosis. QuantiFERON-TB Gold-In-Tube testing was positive. Complete resolution of symptoms occurred after dacryocystorhinostomy and 9 months of standard 4-drug antituberculosis therapy. Tuberculosis of the nasolacrimal duct is highly unusual but should be considered in patients with tuberculosis risk factors who present with nasolacrimal obstruction from an inferior turbinate mass. PMID- 21242853 TI - Preoperative radiation therapy in the management of recurrent orbital hemangiopericytoma. AB - A 77-year-old man presented for evaluation of a recurrent right orbital hemangiopericytoma. It had been excised twice over the past 6 years. After the second resection, the tumor rapidly recurred and was insensitive to systemic chemotherapy, and the patient was thus referred to the authors' institution. The patient had proptosis, restricted ocular movement, and binocular diplopia on presentation. Orbital imaging confirmed a well-circumscribed right extraconal mass in the medial orbit. Preoperative radiation therapy was given, which reduced the tumor volume considerably and allowed a successful complete surgical excision of the mass. PMID- 21242854 TI - Drug-induced graves disease from CTLA-4 receptor suppression. AB - Monoclonal antibody, ipilimumab, useful for treatment of metastatic melanoma, blocks CTLA-4 mediated T-cell suppression and can also cause a Graves ophthalmopathy like syndrome. Epidemiologic study has linked variant polymorphisms of CTLA-4 receptor gene to the presence of thyroid eye disease. The combination of these observations suggests CTLA-4 mediated T-cell functions are important to the pathogenesis of thyroid-associated eye disease. PMID- 21242855 TI - Densities of orbital fat and extraocular muscles in graves orbitopathy patients and controls. AB - PURPOSE: To investigate CT densities of orbital soft tissue volumes in patients with Graves orbitopathy (GO) and to compare these with the densities of controls. METHODS: Observational case series. Of 95 patients with GO and 150 controls, soft tissue volumes, mean densities, and ratios of fat volume to orbital volume and muscle volume to orbital volume were calculated with software. The 95% confidence intervals of the controls were used as reference values. The densities were plotted against age and volume ratios. For statistical analysis SPSS 16.00.2 was used. p values were calculated with the following tests: analysis of variance, Pearson correlation, Kruskal-Wallis, Mann-Whitney, and linear regression. RESULTS: The main outcome measurements were differences in orbital soft tissue densities. In GO patients the mean orbital fat density was significantly higher than in controls (p <= 0.001) and independent of age (p = 0.23). The mean extraocular muscle density of GO patients was within the range of controls and did not decrease with age (p = 0.16) as it did in controls (p <= 0.001). Mean fat density increased with decreasing fat volume (p = 0.001). Mean extraocular muscle density increased slightly with increasing muscle volume (p = 0.09). Muscle density correlated with fat density in both controls and GO patients. CONCLUSIONS: Orbital fat density in GO patients is significantly higher than in controls and negatively correlated to fat volume but positively correlated to muscle volume and muscle density. PMID- 21242856 TI - Intracranial pressure and cerebral perfusion pressure responses to head elevation changes in pediatric traumatic brain injury. AB - OBJECTIVES: To determine the effect of and dynamic interaction between head elevation on intracranial pressure and cerebral perfusion pressure in severe pediatric traumatic head injury. DESIGN: Prospective, randomized, interventional cohort study. SETTING: Two tertiary pediatric critical care referral units. PATIENTS: Ten children admitted with severe traumatic brain injury defined as Glasgow Coma Score <= 8 necessitating intracranial pressure monitoring (10 yrs +/ 5 SD; range 2-16 yrs). INTERVENTIONS: Head elevation was randomly increased or decreased between 0 and 40 degrees from baseline level (30 degrees) in increments or decrements of 10 degrees. MEASUREMENTS AND MAIN RESULTS: Intracranial pressure and arterial blood pressure were continuously recorded in combination with time stamped clinical notations. Data were available for analysis in eight subjects (seven males and one female; mean age, 10 yrs +/- SD 5; range, 2-16 yrs) during 18 protocol sessions. This resulted in a total of 66 head-of-the-bed challenges. To compare results for a given change in head-of-the-bed elevation across age, we transformed head-of-the-bed angle to change in height (cm) at the level of Monro's foramen. An increase in head elevation of 10 cm resulted in an average change in intracranial pressure of -3.9 mm Hg (SD +/- 3.2 mm Hg; p < .001), whereas cerebral perfusion pressure remained unchanged (0.1 +/- 5.6 mm Hg; p = .957). Individual subjects showed marked variability in intracranial pressure change (range, -8.4 to +1.9 mm Hg/10 cm). The overall regression analysis for intracranial pressure response was change in intracranial pressure = -0.39/cm Deltah, r2 = 0.42, and p < .001, where Deltah is the change in vertical height at the level of foramen of Monro attributable to a change in the head of the bed. CONCLUSIONS: In severe pediatric traumatic brain injury, the relationship between change in head of the bed and change in intracranial pressure was negative and linear. The lowest intracranial pressure was usually, but not always, achieved at highest head-of-the-bed angles. The effect size of a head-of-the-bed angle change depended, in part, on the subject's height. In contrast, cerebral perfusion pressure was mostly unaffected by head-of-the-bed changes. PMID- 21242857 TI - Postmortem studies in the contemporary pediatric intensive care unit. AB - OBJECTIVES: To describe the implementation of an educational program that achieved high compliance with autopsy requests and consents in a pediatric intensive care unit. To evaluate the concordance between clinical diagnoses and autopsy findings and to identify patient characteristics in which postmortem diagnosis elucidated the primary disease process. DESIGN: Retrospective, observational study. SETTING: A pediatric intensive care unit in a tertiary care teaching hospital. PATIENTS: All pediatric intensive care unit patients with autopsy reports from 2000 to 2005. INTERVENTIONS: An educational program and protocol were initiated in 1995-1996 to raise awareness and formalize the process for autopsy request. From 2000 to 2005, data were collected from medical records and pathology department autopsy reports. Premortem and postmortem diagnoses were compared utilizing the modified Goldman's classification. The associations of Goldman's classification with age of patients and length of stay were explored. MEASUREMENTS AND MAIN RESULTS: After the educational program was instituted, an autopsy rate of >50% was attained compared to 20%-30% in previous years (p < .05). From 2000 to 2005, 139 autopsies were performed. In 111 patients (79.8%), complete concordance of premortem and postmortem diagnoses was found; in 22 cases (16%), there was no concordance and in six cases the postmortem studies failed to explain the mechanism of death. Autopsies provided new and pertinent findings in 47.5% of all studies, with histologic information accounting for 58% of them. A relationship between short length of stay and the presence of autopsy findings elucidating the main disease process was found (p < .05). CONCLUSIONS: It is feasible to produce a sustainable increase in the rate of postmortem studies within an organization. Autopsy results added new information to almost half of the patients, particularly those who died soon after admission. A pediatric intensive care unit strategy to increase and maintain compliance with autopsy requests is an important practice with favorable clinical and educational repercussions. PMID- 21242858 TI - Preferential hyperacuity perimeter in best vitelliform macular dystrophy. AB - PURPOSE: To determine the visual field patterns obtained by the preferential hyperacuity perimetry (PHP) in patients with Best vitelliform macular dystrophy with mutations in the BEST1 gene. METHODS: Consecutive patients with Best vitelliform macular dystrophy underwent a complete ophthalmologic examination, including functional assessment by best-corrected visual acuity and Foresee PHP and morphologic assessment by fundus biomicroscopy, fundus autofluorescence, and spectral-domain optical coherence tomography. The functional "PHP visual field defect index" (which is the max peak value of the metamorphopsia [maximal distortion value at the visual field] + the max peak value of the scotoma [maximal scotoma value at the visual field]) and best-corrected visual acuity were analyzed about the disease stage. RESULTS: Thirty eyes of 15 consecutive patients (8 men and 7 women; mean age 39 +/- 24 years) were included for analysis. Based on fundus biomicroscopy, fundus autofluorescence, and spectral domain optical coherence tomography, the macular lesions could be counted as follows: previtelliform lesions in 5 eyes of 3 patients (Stage 1), vitelliform lesions in 2 eyes of 2 patients (Stage 2), pseudohypopyon lesions in 6 eyes of 5 patients (Stage 3), vitelliruptive lesions in 4 eyes of 3 patients (Stage 4), atrophic lesions in 7 eyes of 5 patients (Stage 5), and fibrotic lesions in 6 eyes of 4 patients (Stage 6). Best-corrected visual acuity and PHP visual field defect index were averaged for each stage. Best-corrected visual acuity showed a good correlation (P = 0.01) with the morphologic severity (stage) of the disease (Pearson correlation = -0.88). Similarly, the PHP visual field defect index showed a good correlation (P = 0.03) with the morphologic severity (stage) of the disease (Pearson correlation = 0.78). Finally, best-corrected visual acuity showed a good correlation (P = 0.02) with the functional PHP visual field defect index (Pearson correlation = -0.83) about the morphologic stage of the disease. CONCLUSION: Preferential hyperacuity perimetry could be considered an adjunctive useful tool in the evaluation of functional impairment and disease progression in patients with Best vitelliform macular dystrophy. PMID- 21242859 TI - Trends in primary retinal detachment surgery: results of a Bicenter study. AB - PURPOSE: To assess trends and outcomes in retinal detachment (RD) surgery based on a retrospective, interventional, bicenter study. METHODS: Baseline demographic data, surgical procedures, and outcomes from 230 patients with a diagnosis of primary rhegmatogenous RD, who underwent surgery between January 2007 and December 2008 at the Rudolf Foundation Clinic, Vienna (Center 1) and the Weill Cornell Medical College, New York, (Center 2) were analyzed using a regression model. RESULTS: Besides the baseline parameters, lens status (P = 0.01), refraction (P = 0.01), retinal tears (P < 0.02), proliferative vitreoretinopathy (P = 0.02), and previous treatment (P < 0.02), the primary RD procedure (P < 0.0001) was significantly different between the 2 centers. In Center 1, scleral buckling was the most common primary RD procedure (66.19%) compared with vitrectomy (82.42%) in Center 2. Primary retinal reattachment (88.49% Center 1 vs. 84.62% Center 2, P = 0.43) and best-corrected visual acuity at the final follow-up (best-corrected visual acuity >= 0.3 logarithm of minimum angle of resolution 48.92% Center 1 vs. 47.25% Center 2, P = 0.78) were not significantly different between the 2 centers. CONCLUSION: Although there is a trend toward primary vitrectomy, scleral buckling was preferred in the center in Vienna and primary vitrectomy in the center in New York. Despite the different primary RD procedures, anatomical and visual outcomes were comparable. PMID- 21242860 TI - Different dosing of intravitreal bevacizumab for choroidal neovascularization because of pathologic myopia. AB - PURPOSE: To compare the visual outcomes and retreatment rate of single injection of intravitreal bevacizumab followed by pro re nata (PRN) treatment and three monthly injections of intravitreal bevacizumab followed by PRN treatment for myopic choroidal neovascularization. METHODS: Thirty-one consecutive eyes of 31 patients with myopic choroidal neovascularization were retrospectively evaluated. Nineteen eyes were treated with a single injection + PRN and 12 eyes with 3 monthly injections + PRN. The best-corrected visual acuity 12 months after the initial injection, logarithm of the minimum angle of resolution gain from baseline, recurrence rate, and number of injections were statistically compared. RESULTS: Baseline best-corrected visual acuity (logarithm of the minimal angle of resolution) was 0.42 +/- 0.31 in the single injection + PRN group and 0.47 +/- 0.29 in the 3 monthly injections + PRN group (P = 0.64). The best-corrected visual acuity improved significantly at 3, 6, and 12 months in both groups (P < 0.05 at each time point). Mean logarithm of the minimal angle of resolution gain at 3, 6, and 12 months did not differ significantly between groups. The single injection + PRN group required significantly fewer intravitreal bevacizumab treatments (P = 0.005). The rate of recurrence and choroidal neovascularization persistence did not differ significantly between groups. CONCLUSION: Compared with 3 monthly injections followed by PRN, single injection followed by PRN for myopic choroidal neovascularization required fewer injections and produced a similar visual outcome over 12 months. PMID- 21242861 TI - Macular thickness measurements in central retinal artery occlusion by optical coherence tomography. AB - PURPOSE: To evaluate the structural features of central retinal artery occlusion by means of optical coherence tomography. METHODS: Eleven consecutive patients with acute central retinal artery occlusion and at least 3-month follow-up were enrolled prospectively in this study. The main outcome measures included best corrected visual acuity, foveal thickness (FT), and total macular volume by optical coherence tomography. RESULTS: Five male and six female patients with central retinal artery occlusion were examined. The mean age was 71.2 +/- 8.7 years (range, 59-83 years). Mean FT and total macular volume were 195 +/- 26 MUm and 6.41 +/- 0.33 mm, respectively, in normal fellow eyes, increased to 299 +/- 76 MUm and 7.90 +/- 0.93 mm, respectively, at initial examination and declined to 167 +/- 30 MUm and 4.85 +/- 0.68 mm, respectively, at 3-month follow-up. Mean reduction in FT was 181 +/- 61 MUm (range, 120-270 MUm) in eyes with poor visual outcome and 43 +/- 25 MUm (range, 15-74 MUm) in eyes with fair visual outcome. Statistical analysis revealed that the relationships among visual prognosis and initial FT and initial total macular volume were not significant. CONCLUSION: Optical coherence tomography provides special information about central retinal artery occlusion. There were marked and variable changes in FT and total macular volume. Limited reduction in macular thickness might indicate a fair visual outcome. PMID- 21242862 TI - Effect of intravitreal gas tamponade for sutureless vitrectomy wounds: three dimensional corneal and anterior segment optical coherence tomography study. AB - PURPOSE: To investigate the effect of gas tamponade on wound closure and postoperative hypotony by comparing fluid-filled and gas-filled eyes after 25 gauge sutureless vitrectomy using three-dimensional corneal and anterior segment optical coherence tomography. METHODS: Twenty-four eyes of 24 patients who underwent a 25-gauge transconjunctival sutureless vitrectomy were included in this prospective study. A total of 72 scleral wounds were observed using three dimensional corneal and anterior segment optical coherence tomography at 3 hours and at 1, 3, 7, and 14 days postoperatively. Scleral wound closure was defined as the absence of a scleral gap at the sclerotomy site, as observed using three dimensional corneal and anterior segment optical coherence tomography. The rate of wound closure, intraocular pressure, and the incidence of complications were compared between the fluid- and gas-filled eyes. RESULTS: The rates of scleral wound closure at 3 hours and at 1, 3, 7, and 14 days were 26.2%, 28.6%, 35.7%, 52.4%, and 85.7% in fluid-filled eyes and 53.3%, 73.3%, 76.7%, 83.3%, and 93.3% in gas-filled eyes; these rates were significantly higher for the gas-filled eyes. The intraocular pressure was significantly higher in the gas-filled eyes than in the fluid-filled eyes on postoperative Day 1 but did not differ significantly between the 2 groups on postoperative Day 3 and thereafter. CONCLUSION: Three-dimensional corneal and anterior segment optical coherence tomography provided clear images of 25-gauge sutureless vitrectomy wounds and revealed that the sclerotomies closed faster in gas-filled eyes than in fluid filled eyes. Thus, gas tamponade might be effective for the closure of sutureless vitrectomy wounds. PMID- 21242863 TI - Surgical outcomes of degenerative spondylolisthesis with L5-S1 disc degeneration: comparison between lumbar floating fusion and lumbosacral fusion at a minimum 5 year follow-up. AB - STUDY DESIGN: A retrospective clinical and radiographic study was performed. OBJECTIVE: The purpose of this study was to compare outcomes of patients with degenerative spondylolisthesis and a preexisting degenerative L5-S1 disc treated with a lumbar floating fusion (LFF) versus lumbosacral fusion (LSF). SUMMARY OF BACKGROUND DATA: Fusion for treatment of degenerative spondylolisthesis often ends at the L5 level. These patients usually had a preexisting L5-S1 disc degeneration; however, no literature mentions the role of prophylactic LSF in degenerative spondylolisthesis associated with L5-S1 disc degeneration. METHODS: A total of 107 patients with a minimum 5-year follow-up who had lumbosacral or LFF with pedicle instrumentation for degenerative spondylolisthesis were included. UCLA (University of California, Los Angeles) classification was used to evaluate the radiographic results of the L5-S1 segment. The Oswestry Disability Index (ODI) and modified Brodsky's criteria were used to evaluate patients' clinical results. The incidence of adjacent segment disease (ASD) (includes radiographic and clinical ASD) of both ends was recorded. RESULTS: There were no statistically significant differences in sex, age distribution, or amount of follow-up between the LFF and LSF groups. The LSF group had a higher percentage of patients that underwent total L5 laminectomy with loss of L5-S1 posterior ligament integrity (LSF = 92% vs. LFF = 67%, P = 0.019). The higher incidence of cephalic ASD in the LSF group was statistically significant (LSF = 25% vs. LFF = 9.7%, P = 0.049). Although no patient in the LSF group developed L5-S1 ASD, need for L5-S1 segment revision surgery was not prevented with LSF. Clinical outcomes on the basis of the success rate (LFF = 85.5% vs.LSF = 70.8%, P = 0.103) and ODI difference (LFF = 28.97 +/- 15.82 vs. LSF = 23.04 +/- 10.97, P = 0.109), there were no statistically significant difference between these two groups. CONCLUSION: Posterior instrumentation with posterolateral LFF for the treatment of degenerative spondylolisthesis with concomitant L5-S1 disc degeneration results in a high percentage of satisfactory clinical results. Extended fusion to the sacrum did not provide a better clinical result. LSF could not reduce the incidence of revision surgery at the L5-S1 segment and involved greater incidence of cephalic ASD. PMID- 21242864 TI - Unilateral versus bilateral balloon kyphoplasty for multilevel osteoporotic vertebral compression fractures: a prospective study. AB - STUDY DESIGN: A prospective study of patients who underwent multilevel balloon kyphoplasty at a single institute. OBJECTIVE: To examine and compare the safety and long-term radiographic and clinical effects of unilateral or bilateral balloon kyphoplasty to treat multilevel symptomatic vertebral compression fractures. SUMMARY OF BACKGROUND DATA: Typically, balloon kyphoplasty involves placement of inflatable bone tamp via a bilateral transpedicular or extrapedicular approach. Recently, several articles reported unilateral kyphoplasty with comparable outcomes. However, few prospective randomized study comparing the radiographic and clinical outcomes using unilateral and bilateral approaches was reported. METHODS.: Forty-nine patients with 114 Osteoporotic vertebral compression fractures were randomly allocated into two groups adopting unilateral or bilateral balloon kyphoplasty. Preoperative and postoperative pain scores, back disability, and 36-Item Short Form Health Survey scores were compared with at least a 2-year follow-up. Vertebral body height and vertebral body kyphotic angle from this cohort were analyzed before surgery, after surgery, and at final follow-up. RESULTS: Both unilateral and bilateral balloon kyphoplasty resulted in significant pain reduction and back dysfunction improvement and remained unchanged at final follow-up. Quality of life assessment using 36-Item Short Form Health Survey recorded marked and significant improvements in all mean subscale scores except general health and social function. Regarding the pain reduction, back dysfunction, and 36-Item Short Form Health Survey scores, no significant difference existed between two groups. Significant increases of anterior and middle vertebral heights were recorded for both groups after surgery and maintained for the period of follow-up. The mean correction of vertebral body kyphotic angle was about 7 degrees in both groups. Asymptomatic cement extravasation occurred in six of 49 of patients, and three patients developed additional fractures at untreated levels during the period of follow-up. CONCLUSIONS: Both unilateral and bilateral kyphoplasty markedly improve symptom-related clinical effects of multilevel vertebral compression fractures and result in significant vertebral height restoration and kyphosis correction that remains stable for at least 2 years after treatment. PMID- 21242865 TI - External spinal skeletal fixation combination with percutaneous injury vertebra bone grafting in the treatment of thoracolumbar fractures. AB - STUDY DESIGN: A technical report of thoracolumbar fractures managed by percutaneous external pedicular fixation and intracorporeal bone grafting. OBJECTIVE: To develop a new technique by combining simplified percutaneous external pedicular fixator with intracorporeal bone grafting to treat thoracolumbar fractures and assess its technical safety and clinical efficacy. SUMMARY OF BACKGROUND DATA: For surgical treatment of thoracolumbar fractures, the classical techniques are beneficial in decompression, restoration, fixation, and graft fusion, but they are also hugely invasive procedures. The earlier external spinal fixation procedures are good at indirect restoration, decompression, and elastic fixation of spinal fracture. However, they are limited by remains of a large external frame and inability of vertebral reconstruct. Therefore, the minimally invasive techniques combining simplified percutaneous external pedicular fixation and intracorporeal bone grafting might be a useful alternative. METHODS: There were 50 consecutive patients who had thoracolumbar fractures with or without associated incomplete neurologic deficit. They underwent percutaneous external pedicle fixation and intracorporeal bone grafting surgery within 7 days of admission, had their implants removed after 3 months, and were prospectively followed for at least 12 months. American Spine Injury Association grading, spinal canal encroachment, spinal Cobb angle, and vertebral body height were calculated before and after surgery to assess clinical outcome. RESULTS: A minimum of 12-month follow-up was achieved in 50 patients. The average operative time was 90 minutes (range, 50-160 minutes). The mean bone graft volume was 4.8 cm (range, 3.2-10.6 cm). The intraoperative mean blood loss was 100 mL (range, 50-180 mL). Forty-two patients all had at least one American Spine Injury Association grade neurologic improvement on final follow-up observation; there were no surgery-related complications. The mean anterior height of vertebral body was 53.2% (range 25%-78%) before surgery, 93.6% (range 78%-104%) after surgery, and 94% (range 79%-103%) at final follow-up. The preoperative Cobb angle of the primary curve averaged 30.7 degrees (range 8 degrees -67 degrees ), and corrected to 4.5 degrees (range 0 degrees -12.0 degrees ) immediately after surgery, There were statistically significant (P < 0.01) among them before and after operation. There was no instrumentation failure or measurable loss of sagittal curve and vertebral height correction in any cases. CONCLUSION: The new technique by combination of percutaneous external transpedicular fixation and transpedicular bone grafting is a feasible, safe, useful, efficient, and minimally invasive method to treat thoracolumbar fractures. It is a reasonable alternative method to other minimally invasive techniques of surgical management of the thoracolumbar fractures. PMID- 21242866 TI - The risk assessment of a fall in patients with lumbar spinal stenosis. AB - STUDY DESIGN: A prospective case control study. OBJECTIVES: To investigate the risk of a fall by using functional mobility tests in patients with lumbar spinal stenosis (LSS) via a comparison with patients with knee osteoarthritis (KOA). SUMMARY OF BACKGROUND DATA: LSS is a degenerative arthritic disease in the spine that results in decreasing function, impaired balance, and gait deficit, with increased levels of leg and back pain. This physical impairment may result in an increased risk of fall later in the disease process, as shown in KOA. However, there has been no study regarding the association between the risk of a fall and LSS. METHODS: The study was an age- and weight-matched case control study consisting of two groups: one group consisting of 40 patients with LSS who were scheduled to undergo spine surgery (LSS group) and the other group consisting of 40 patients with advanced osteoarthritis in both knees, scheduled to undergo TKA on both knees (KOA group). For both groups, four functional mobility tests, such as a Six-Meter-Walk Test (SMT), Sit-to-Stand test (STS), Alternative-Step Test (AST), and Timed Up and Go Test (TUGT), were performed. RESULTS: There was no difference in demographic data between both groups except for body mass index. For the SMT and STS, the patients in the LSS group spent significantly more time performing these tests than the patients in the KOA. For the AST, however, patients in the KOA group presented a statistically worse performance in functional mobility, compared with the LSS group. The mean TUGT time was not statistically different between the two groups. CONCLUSIONS: The current study highlights that patients with symptomatic LSS have a risk of a fall comparable with the patients who had degenerative KOA based on the results of functional mobility tests (SMT, STS, AST, and TUGT). PMID- 21242867 TI - Esophageal rupture in a child after vertical expandable prosthetic titanium rib expansion thoracoplasty: first report of a rare complication. AB - STUDY DESIGN: Case report and clinical discussion. OBJECTIVE: To illustrate the significance of esophageal rupture as a rare complication after expansion thoracoplasty with implementation of a vertical expandable prosthetic titanium rib (VEPTR). SUMMARY OF BACKGROUND DATA: Chest wall deformities and secondary scoliosis are rare complications after a repair operation for esophageal atresia. The new technique of VEPTR expansion thoracoplasty directly treats the chest wall deformity and indirectly corrects the scoliosis. We describe a patient with an esophageal rupture after VEPTR expansion thoracoplasty. METHODS: We report the case of an 11-year-old boy who developed a progressive scoliosis caused by fused ribs after multiple reoperations for esophageal atresia. The patient was treated operatively by an expansion thoracoplasty via an opening wedge thoracostomy with implementation of two VEPTRs. RESULTS: After surgery, the patient developed a respiratory insufficiency because of rupture of the esophagus. The complication was treated conservatively. A second operation was needed to remove an infected VEPTR. The patient fully recovered after this severe complication. CONCLUSION: To our knowledge, this is the first report of esophageal rupture after VEPTR expansion thoracoplasty. This promising new technique treats scoliosis in patients with severe chest wall deformities. When a patient presents with fused ribs and there is a history of esophageal atresia, we should keep in mind that the esophagus is at risk of rupturing during the scoliosis correcting procedure. PMID- 21242868 TI - Lumbosacral stabilization using iliac wings: a new surgical technique. AB - STUDY DESIGN: Case reports. OBJECTIVE: A novel spinopelvic instrumentation system is introduced. SUMMARY OF BACKGROUND DATA: Spinopelvic stabilization is a problematic area of the spine. A mobile segment (spine) is fixed onto a stabile construction (pelvis). Another problem is the spinal anatomy because L5 vertebrae are affected by shear forces due to lomber lordosis so that stabilization needs extra power and 360 degrees fusion of L5-S1 level. Long instrumentation is preferred to decrease the stress on the screws and the rods. We designed iliac plates to support lumbopelvic instrumentation laterally. Four cases of spinopelvic pathology were treated in this way manner. The short-term results are good. METHODS: Four adult cases that had spinopelvic instability were treated with a novel spinopelvic instrument. All cases were evaluated with visual analog scale (VAS), Oswestry and radiologic studies pre- and postsurgery at 6 and 12 months. RESULTS: All the patients benefited from the stabilization. Preoperative mean VAS scores of all patients decreased from 7.75 to 1.75 and preoperative Oswestry disability index scores decreased from 83.50 to 24.50 at the 12 months postoperative evaluation. CONCLUSION: In this study, we define four cases and report that iliac wings can be used to augment stabilization. We review the literature and discuss our knowledge and experiences in these cases. PMID- 21242869 TI - Postoperative cervical myelopathy and cord compression associated with the use of recombinant bone morphogenetic protein-2 in posterior cervical decompression, instrumentation, and arthrodesis: a report of two cases. AB - STUDY DESIGN: Case report. OBJECTIVE: Two cases are presented in which the use of recombinant bone morphogenetic protein-2 (rh-BMP-2) in a posterior cervical decompression and instrumented arthrodesis may have contributed to seroma formation and cord compression. SUMMARY OF BACKGROUND DATA: The use of rh-BMP-2 has been proven effective in promoting bone formation in anterior lumbar spine arthrodesis. Whether rh-BMP-2 is safe and/or effective in the cervical spine has not been determined. Adverse effects when it is used for anterior cervical fusion procedures have been reported but its role in posterior cervical decompression and instrumented fusions has yet to be determined. METHODS: We report on two cases. The first is a 68-year-old man presenting with a substantial decline in his neurologic status approximately 2 weeks after surgery. The second is a 44 year-old man presenting with a substantial decline in his neurologic status approximately 5 days after surgery. Both complications occurred after a posterior cervical laminectomy and instrumented arthrodesis when rh-BMP-2 was used as a bone graft substitute. RESULTS: Both patients were found to have a moderate-to large seroma causing severe compression on the spinal cord and were urgently taken to an operating room for evacuation of the seromas. Both showed improvement of their neurologic status immediately after surgery. As rh-BMP-2 is known to occasionally cause seroma formation it is postulated that it may have been the cause of the seromas. CONCLUSION: Caution should be exercised with rh-BMP-2 use in posterior cervical applications when a laminectomy has been performed. The safe and effective dose and technique for application have yet to be determined. Seroma formation is possible, which can cause acute stenosis with cord compression and neurologic compromise. PMID- 21242870 TI - Functional morphology of the thoracolumbar transversospinal muscles. AB - STUDY DESIGN. A qualitative and semiquantitative study of the morphology of the human thoracolumbar transversospinal (TSP) muscles. OBJECTIVE. To further define the functional morphology of the thoracolumbar TSP muscles. SUMMARY OF BACKGROUND DATA. The TSP muscle group plays an important role in vertebral function but few studies have rigorously investigated their morphology throughout the thoracolumbar region and details on the location of motor endplates (MEPs) and fiber types are sparse. METHODS. Thoracolumbar TSP muscles were examined by microdissection in five cadavers (seven sides). MEPs were identified using acetylcholinesterase histochemistry in muscles between T5 and S4 unilaterally in two cadavers. The relative proportions of type I and type II skeletal muscle fibers were determined using immunohistochemistry on whole cross sections of every TSP muscle from one side of one cadaver (T5-S4). RESULTS.TSP morphology was homogeneous and consistent throughout the thoracolumbar region. Notable differences to standard descriptions included: (1) consistent attachments between muscles; (2) no discrete cleavage planes between muscles; and (3) attachment sites over the sacrum and to lumbar zygapophysial joints. Previously undescribed small muscles were found attaching to the medial sacrum. All TSP muscles were multipennate, with fibers arranged in parallel having one MEP per muscle fiber. Muscles were highly aerobic (mean proportion of type I fibers 89%), with the proportion of type I fibers decreasing caudally. A significantly greater proportion of type I fibers were found in the midthoracic compared to the low lumbar regions. CONCLUSION. The complex morphology of the TSP muscles indicates that they would be better classified as spinotransverse muscles. They are multipennate, highly aerobic, with fibers organized in parallel, an arrangement lending itself to "fine-tuning" of vertebral movements. Understanding their morphology has implications for investigation, treatment, motor control, and biomechanics. PMID- 21242871 TI - Transoral atlantoaxial reduction plate internal fixation with transoral transpedicular or articular mass screw of c2 for the treatment of irreducible atlantoaxial dislocation: two case reports. AB - STUDY DESIGN: Retrospective report of two surgical cases and review of the literature. OBJECTIVE: To report the clinical application of transoral atlantoaxial reduction plate (TARP) internal fixation with a novel technique of transoral transpedicular or articular mass screw of C2 in the treatment of irreducible atlantoaxial dislocation and basilar invagination with ventral spinal cord compression. SUMMARY OF BACKGROUND DATA: Current surgical treatments for IAAD have various disadvantages, such as posterior decompression followed by atlantoaxial or occipitocervical fusion with unsatisfactory decompression, transoral decompression, and one-stage posterior instrumentation needing two approaches although with satisfactory decompression, resection of dens and/or clivus with potential risk of spinal cord injury and CSF leakeage. METHODS: TARP system with a novel technique of transoral transpedicular screw or articular mass screw of C2 was designed and employed for two patients with irreducible atlantoaxial dislocation, during which one case was with basilar invagination. The histories of the cases and the novel technique of transoral articular mass screw and transpedicular screw insertion of C2 were reported in detail. RESULTS: The two case examples demonstrate the efficacy of this one-stage single transoral approach to the surgical treatment of irreducible anterior atlantoaxial dislocation with spinal cord compression especially in the case of basilar invagination. The role of the TARP in affecting and maintaining the reduction while promoting successful fusion is illustrated. CONCLUSION: The authors' one stage anterior procedure employing the TARP for the surgical treatment of irreducible anterior atlantoaxial dislocation and basilar invagination was effective in these two cases. This method was able to avoid the need for dens and clivus resection and/or a posterior instrumentation and fusion procedure. The technique of transoral articular mass screw and transpedicular screw insertion of C2 was valuable for transoral atlantoaxial plate internal fixation. PMID- 21242872 TI - The incidence of noncontiguous spinal fractures and other traumatic injuries associated with cervical spine fractures: a 10-year experience at an academic medical center. AB - STUDY DESIGN: Retrospective medical record review. OBJECTIVE: The purpose of this study was to describe the incidence of other injuries that commonly occur in conjunction with cervical spine fractures and dislocations. SUMMARY OF BACKGROUND DATA: Cervical spine fractures are often associated with other significant traumatic conditions, which may also require prompt diagnosis and management. However, the relative incidences of the injuries that occur in conjunction with various cervical spine fractures have not been well documented. METHODS: The radiographic reports of all patients who underwent CT scans of the cervical spine at a single level 1 trauma center over a 10-year period were reviewed. The medical records of individuals with acute, nonpenetrating fractures of the cervical spine were further assessed for any associated traumatic pathology including noncontiguous spine injuries and those affecting other organ systems (i.e., head and neck, intrathoracic, intra-abdominal/pelvic, and nonspinal orthopedic disorders). RESULTS: A total of 13,896 CT scans of the cervical spine were performed during this 10-year period of which 492 revealed acute fractures and/or dislocations. Of these subjects, 60% had sustained at least one additional injury. Overall, 57% were noted to have extraspinal injuries (34% head and neck, 17% intrathoracic, 10% intra-abdominal/pelvic, and 30% nonspinal orthopedic conditions) and noncontiguous spinal trauma was present in 19% of these cases (8% cervical injuries, 8% thoracic, and 6% lumbar). In general, the rates of associated injuries observed with occipital condyle and C7 fractures were significantly higher than those recorded for other cervical segments. CONCLUSION: For patients with a known history of cervical spine trauma, the frequencies of associated injuries were similar across all levels of the cervical spine with the exception of the injuries to the craniocervical junctions. In practice, this means that injuries to the cervical spine can likely be grouped together when considering other possible associated injuries. Further elucidation of these injury patterns will likely be useful for facilitating the expedient evaluation and proper management of these individuals. PMID- 21242873 TI - Anthropometry and body composition profile of girls with nonsurgically treated adolescent idiopathic scoliosis. AB - STUDY DESIGN: Cross-sectional study with level III of evidence. OBJECTIVE: To describe different anthropometric and body composition parameters of adolescent girls with adolescent idiopathic scoliosis (AIS), comparing them with the standards of a healthy age-matched population. SUMMARY OF BACKGROUND DATA: Body growth and development of adolescent girls with AIS seems to differ from the healthy subjects, especially at perpubertal stages. Young scoliotic adults have been found to be taller, lighter, and thinner than age-matched healthy population. Body composition profile taken from measurements of skin-fold thickness, bony diameters at different levels, and arm and legs perimeters has not been previously reported in AIS patients. METHODS: A nonconsecutive series of 52 AIS girls (mean age: 13.9 years) with an average scoliotic curve of 27 degrees Cobb (range: 20-58) underwent an anthropometric study. None of the AIS girls had been treated previously with spinal surgery. The control group consisted of 92 girls without spine deformity, matched in age (mean: 13.8 years). Weight, height, and skin-fold thickness in millimeters at six levels were measured. Body mass index (BMI), Ponderal index, percentage of body fat, percentage of muscular tissue, fat mass, lean body mass, muscular weight, bony weight, and residual weight were calculated using standard rules to estimate body composition. The somatotype components (endomorphy, mesomorphy, and ectomorphy) were calculated according to the Carter equations. RESULTS.: Compared with the control population, scoliotic girls had a significantly lower mean weight (51.4 +/- 10.2 kg vs. 54.7 +/- 8.1 kg; P < 0,05), a lower BMI (20.1 +/- 3.4 vs. 21.4 +/- 2.4; P < 0.001), and a higher Ponderal index (43.2 +/- 2.4 vs. 42.2 +/- 1.6; P < 0.01). Girls with AIS showed a progressive decrease of the BMI as the age increased. The percentage of body fat was also lower in scoliotic girls, without significant statistical differences (14.1 +/- 3.8 vs. 15 +/- 3.6). Out of the 52 AIS girls, 11 (21.2%) showed a BMI below 17.5, which has been considered the limit for anorexia. In the control group, only 3 of 92 girls (3.3%) had BMI below that level. The somatotype differed also between scoliotics and controls: higher in the ectomorphic component (3.29 +/- 1.68 vs. 2.40 +/- 1.11; P < 0.001), and lower in the mesomorphic component (2.86 +/- 0.82 vs. 3.70 +/- 1.11; P < 0.01) in AIS patients. CONCLUSION: The differences in some anthropometric parameters (weight, IMC, IP) and in the somatotype suggest that the idiopathic scoliosis not only disturbs normal spine growth but also seems to have implications on the whole corporal development. Whether these changes could be related to abnormal spinal growth or subsequent to nutritional changes in AIS still remains uncertain. Presumably, some endocrine factors affecting body composition and growth might be involved in the etiology of idiopathic scoliosis. PMID- 21242874 TI - Radiographic features of the Lenke 1A curves to help to determine the optimum distal fusion level selection. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: Investigate the radiographic features of the subtypes of Lenke 1A curves to help to determine the optimum distal fusion level selection. SUMMARY OF BACKGROUND DATA: The Lenke 1A was the most frequently evaluated curve type in adolescent idiopathic curves. Miyanji et al suggested that the lumbar modifier type A does not accurately define the behavior of the compensatory lumbar curve in Lenke 1A. The tilt of L3 and L4 in the coronal plane may have a significant role in determining distal fusion level. METHODS: Thirty-six patients with Lenke type 1A idiopathic scoliosis treated by segmental posterior instrumentation with an average of 52.1-month follow-up were retrospectively analyzed. Four different curve types depending on L3-L4 vertebral tilt were described. The radiographic measurements including proximal and distal junctional kyphosis was obtained at latest follow-up. RESULTS.: Preoperative mean major curve Cobb angle of 47.6 degrees was corrected to 12.9 degrees showing a correction rate of 72.8% and maintained at 14.2 degrees . Loss of correction at final follow-up was 2.7%. The mean compensatory curve Cobb angle of 24.4 degrees was corrected to 8.2 degrees . All patients balanced after surgery although seven had more than -5 degrees clavicle angle before surgery. The mean preoperative and postoperative sagittal T5-T12 angles were 30.6 degrees and 26.2 degrees , respectively, and 29.1 degrees at latest follow-up. The mean preoperative, postoperative, and latest follow-up T10-L2 sagittal Cobb angles were -0.2 degrees , 2.0 degrees , and 4.2 degrees . Three patients diagnosed as distal junctional kyphosis at latest follow-up. CONCLUSION: Distal fusion level should be extended to at least lower end vertebra (LEV) -1 in type 1A-A and type 1A-D curves, while it might be necessary to go down to LEV in the type 1A-B and 1A-C. It seems that LEV might be a reliable guide to select ideal distal fusion level in Lenke type 1A curves. PMID- 21242875 TI - Multilevel magnetic resonance imaging analysis of multifidus-longissimus cleavage planes in the lumbar spine and potential clinical applications to Wiltse's paraspinal approach. AB - STUDY DESIGN: Retrospective magnetic resonance imaging (MRI)-based study. OBJECTIVE: Our goal was to develop Wiltse's paraspinal surgical approach by determining the precise anatomic locations of the intermuscular cleavage planes formed by the multifidus and longissimus muscles. The primary objective was to measure the distances between the midline and the intermuscular planes, bilaterally, on MRI scans at each of the five disc levels between L1 and S1. Secondary objectives included identifying the existence of any correlations between patient demographics and the measured outcomes. SUMMARY OF BACKGROUND DATA: In 1968, Wiltse described an approach to the spine using the natural cleavage plane of the multifidus and longissimus muscles as an entry to the posterior spinal elements. The small direct incisions lessened bleeding, tissue violation, and muscle retraction, which popularized Wiltse's approach among surgeons. A detailed description of the locations of the intermuscular cleavage planes at each lumbar disc level, however, is not available. METHODS: MRI scans of 200 patients taken during routine care (2007-2009) were retrospectively reviewed to gather measurements of the distances from the intermuscular cleavage planes to the midline, bilaterally, at each disc level from L1 to S1. Age, sex, and BMI (body mass index) were obtained to determine correlations. RESULTS: Mean measurements significantly differed between all disc levels. At L5-S1, the mean distance was 37.8 mm; at L4-L5, 28.4 mm; at L3-L4, 16.2 mm; at L2-L3, 10.4 mm; and at L1-L2, 7.9 mm. The mean female distances were significantly greater than males (2 mm) on both sides of L5-S1 only. No correlation was discovered between BMI, age, height (N = 50), or weight (N = 50) with respect to measured distances. CONCLUSION: In the absence of any significant clinical correlation between patient demographics and the entry site in Wiltse's approach, the spine surgeon may use distances described in this paper to apply to a broad base of spine patients regardless of BMI, sex, or age. PMID- 21242876 TI - Distal adding-on phenomenon in Lenke 1A scoliosis: risk factor identification and treatment strategy comparison. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To identify risk factors for the presence of distal adding-on in Lenke 1A scoliosis and compare different treatment strategies. SUMMARY OF BACKGROUND DATA: Distal adding-on is often accompanied by unsatisfactory clinical outcome and high risk of reoperation. However, very few studies have focused on distal adding-on and its attendant risk factors and optimal treatment strategies remain controversial. METHODS: All surgically treated patients with adolescent idiopathic scoliosis were retrieved from a single institutional database. Inclusion criteria included: (1) Lenke 1A scoliosis patients treated with posterior pedicle screw-only constructs, (2) minimum 1-year radiographic follow-up. Distal adding-on was defined as a progressive increase in the number of vertebrae included distally within the primary curve combined with either an increase of more than 5 mm in deviation of the first vertebra below instrumentation from the center sacral vertical line (CSVL), or an increase of more than 5 degrees in the angulation of the first disc below the instrumentation at 1 year follow-up. Wilcoxon rank sum test, Fisher exact test, and Spearman correlation test were used to identify the risk factors for adding-on. A multiple logistic regression model was built to identify independent predictive factor(s). Risk factors included: (1) age at surgery; (2) preoperative Cobb angle; (3) correction rate; (4) the gap difference of stable vertebra-lowest instrumented vertebra (SV-LIV), neutral vertebra-lowest instrumented vertebra (NV-LIV), and end vertebra-lowest instrumented vertebra (EV LIV). Gap difference means, for example, if SV is at L2 and LIV is at Th12, then the difference of SV-LIV is 2; (5) the preoperative deviation of LIV+1 (the first vertebra below the instrumentation) from the CSVL (the vertical line that bisects proximal sacrum). Five methods for determining LIV were compared in both the adding-on group and no adding-on group. RESULTS: Out of the 278 patients reviewed, 45 met the inclusion criteria; 23 of these met the definition for distal adding-on, and were included in the adding-on group. The remaining 22 patients were included in the no adding-on group. The average follow-up was 3.6 years. Age, SV-LIV difference, EV-LIV difference, and LIV+1 deviation from CSVL were significantly different (P<0.05) between the two groups, and were also found to be significantly correlated with the presence of adding-on (P<0.05). Preoperative Cobb angle, correction rate, and NV-LIV difference were not found to be affiliated with the presence of adding-on. Multiple logistic regression results indicated that preoperative LIV+1 deviation from CSVL was an independent predictive factor. Among the five methods, choosing EV as LIV was nearly unable to prevent distal adding-on; choosing EV+1 as LIV resulted in fusing many more segments than necessary; only choosing DV as LIV showed satisfactory outcome from both perspectives. CONCLUSION: In Lenke 1A type scoliosis, the selection of LIV is highly correlated with the presence of adding-on; incidence increases dramatically when the preoperative LIV+1 deviation from CSVL is more than 10 mm. Choosing DV (the first vertebra in cephalad direction from sacrum with deviation from CSVL of more than 10 mm) as LIV may provide the best outcome as it not only prevents adding-on but also conserves more lumbar motion. PMID- 21242877 TI - Effect of sagittal alignment on kinematic changes and degree of disc degeneration in the lumbar spine: an analysis using positional MRI. AB - STUDY DESIGN: Retrospective analysis using positional MRI. OBJECTIVE: To determine the effects of total sagittal lordosis on spinal kinematics and degree of disc degeneration in the lumbar spine. SUMMARY OF BACKGROUND DATA: Changes in sagittal lordosis alter the load on the spine and may affect spinal mobility. There is increasing recognition of the clinical impact that sagittal alignment has on back pain, especially its possible role in accelerating adjacent segment degeneration after spinal fusion. However, its relationship to segmental mobility and degeneration of the lumbar spine has yet to be determined. METHODS: Four hundred and thirty patients who had low back pain with or without leg pain (241 males and 189 females) with a mean age of 42.98 years (range, 16-85 years) were included. Total sagittal lordosis (T12-S1) was divided into three groups; Group A: Straight or Kyphosis (<20 degrees , n = 84), Group B: Normal lordosis (20-50 degrees , n = 294), and Group C: Hyperlordosis (>50 degrees , n = 52). The degree of disc degeneration was graded using midsagittal T2-weighted MR images. Segmental mobility, including translational motion and angular variation, was measured using positional MRI. Their relationship with total segmental lordosis was identified. RESULTS: When compared with group B, the segmental motion in group C tended to be lower at the border of lordosis and higher at the apex of lordosis, with a significant difference in angular motion at L2-L3. The contrary finding was identified in group A, which had a higher segmental motion at border segments and lower motion at apical segments of lordosis, with significant difference of translational motion at L3-L4 and angular motion at L1-L2. Apical segments contributed more, whereas border segments contributed less to the total angular mobility in more lordotic spines. The opposite was seen in more kyphotic spines. Disc degeneration tended to be greater at all levels in group C, and at L1-L2 and L5-S1 in group A. CONCLUSION: Changes in sagittal alignment may lead to kinematic changes in the lumbar spine. This may subsequently influence load bearing and the distribution of disc degeneration at each level. Sagittal alignment, disc degeneration, and segmental mobility likely have a reciprocal influence on one another. PMID- 21242878 TI - Acellular dermal matrix in the treatment and prevention of exposed vertical expandable prosthetic titanium ribs. AB - STUDY DESIGN: Case series. OBJECTIVE: To illustrate the use of acellular dermal matrix (ADM) in treatment and prevention of exposed vertical expandable prosthetic titanium rib (VEPTR) implants. SUMMARY OF BACKGROUND DATA: In the pediatric population with severe kyphoscoliosis, VEPTR is an effective tool during growth for the correction of ribcage deformity. Prolonged VEPTR therapy can result in wound breakdown, implant exposure, and infection. Treatment includes the use of prolonged antibiotics, muscle flaps, and, when salvage fails, removal of the VEPTR. The use of ADM in the treatment and prevention of VEPTR exposure has not been previously described. METHODS: Between January 2002 and January 2010, eight patients who underwent placement of ADM for the treatment and prevention of exposed VEPTR devices were identified. Their records were reviewed for diagnosis, sex, age of patient at initial VEPTR placement, position of VEPTR placement, number of VEPTR expansions, wound complications, ADM use, adjunct procedures, and length of wound follow-up. RESULTS: ADM was used in eight patients. In five patients ADM was used for compromised soft tissue overlying the VEPTR and threatened exposure of the hardware. In these cases, subsequent expansions occurred without incident and the wound remained stable with an average follow-up of 7.6 months. In three patients, ADM was used for exposed VEPTR hardware secondary to wound breakdown. Average follow-up was 3.3 months. In two of the three cases of exposed and contaminated hardware, stable soft tissue coverage was achieved and continued VEPTR therapy was achieved. One of the three cases of exposure involved infected and prominent hardware with purulence. This patient failed to clear the infection and required complete device removal. CONCLUSION: ADM can treat and prevent exposed VEPTR, allowing subsequent VEPTR expansions and minimizing the need for muscle flap coverage and/or implant removal and replacement. PMID- 21242879 TI - Inflammatory characteristics of rhBMP-2 in vitro and in an in vivo rodent model. AB - STUDY DESIGN: In vivo and in vitro model. OBJECTIVE: Investigate soft-tissue inflammation caused by rhBMP-2. SUMMARY OF BACKGROUND DATA: Although rhBMP-2 produces excellent rates of fusion in the spine, dysphagia and respiratory compromise have occurred when used in the neck. The mechanism of the swelling and inflammatory response has yet to be fully elucidated. METHODS: ELISA kits (IL-6, IL-10, TNF-alpha) were used to measure cytokine levels at different concentrations of rhBMP-2. Absorbable collagen sponges were implanted with or without different concentrations of rhBMP-2 into the backs of rats subcutaneously (SC) and intramuscularly (IM). Magnetic resonance imaging was used to measure inflammation at 3 hours and 2, 4, and 7 days. The inflammatory volumes were measured and compared using MIPAV software. Rats were killed after 7 days and studied. RESULTS: IL-6, IL-10, and TNF-alpha release was dose-dependent. Soft tissue edema after rhBMP-2 implantation was also dose-dependent, peaking at 3 hours SC, after SC and IM implantations, and on day 2 IM after IM implantation. All formed a granuloma-type mass after SC insertion. The mass was much larger in the 10 and 20 MUg/10 MUL (high-concentration) groups. The inflammatory response did not diffuse across physiologic barriers (subcutaneous fascia). Both high-dose groups were associated with encapsulated hematomas and a significant increase in the inflammatory zone. CONCLUSION: Swelling and inflammation after rhBMP-2 use are dose-dependent. Swelling may be due to direct contact as well as spread in the plane of access. The causes are a robust inflammatory reaction as well as sterile seroma and encapsulated hematoma formation. PMID- 21242880 TI - Risk indicators for severe upper or mid back pain in men. PMID- 21242881 TI - Inadvertent injection of a cervical radicular artery using an atraumatic pencil point needle. AB - STUDY DESIGN: Case report and review of the literature. OBJECTIVE: To report the first case of inadvertent injection of a cervical radicular artery using an atraumatic pencil-point needle. SUMMARY OF BACKGROUND DATA: Rare complications from cervical transforaminal epidural corticosteroid injection have resulted in infarction of the spinal cord and brain. The most often-hypothesized mechanism is inadvertent intra-arterial injection of particulate corticosteroids with a resulting embolus and infarction. METHODS: Retrospective review of a patient's history and fluoroscopic imaging. RESULTS: A 30-year-old man with a diagnosed cervical radiculopathy underwent a right C6-C7 transforaminal epidural corticosteroid injection, using a 25-gauge 3.5-inch Whitacre spinal needle. Simultaneous epidural and radicular artery spread were observed under live fluoroscopy. The patient suffered no complications from the procedure. CONCLUSION: This case demonstrates that the use of pencil-point (Whitacre) needles does not eliminate the risk of inadvertent arterial injection during cervical transforaminal epidurals. Further investigation is required to determine whether the incidence of inadvertent vascular injection is reduced with pencil point needles compared with sharp-beveled needles. PMID- 21242882 TI - Quality control of reconstructed sagittal balance for sagittal imbalance. AB - STUDY DESIGN: Prospective radiographic study. OBJECTIVE: To investigate the feasibility of controlling quality of reconstructed sagittal balance for sagittal imbalance. SUMMARY OF BACKGROUND DATA: Patients with sagittal imbalance cannot walk or stand erect without overwork of musculature because of compromised biomechanical advantage. The result is muscle fatigue and activity-related pain. During reconstructive surgery, restoration of optimal sagittal balance is crucial for obtaining satisfactory clinical results. However, there is no way to control quality of reconstructed sagittal balance before or during surgery. METHODS: A method was developed to determine the lumbosacral curve in a way that theoretically would bring sagittal balance to an ideal state by calculation and simulation for each patient before surgery and then template rods of the curve and a blueprint were made accordingly for operative procedures. Ninety-four consecutive patients with sagittal imbalance due to lumbar kyphosis were treated for intractable pain and then followed up for a mean of 4.3 years. Radiographs were analyzed before surgery, 2 months after surgery, and at most recent follow up. RESULTS: The mean estimated values of L1-S1 lordosis, sacral inclination angle, sacrofemoral distance, and distribution of L1-S1 lordosis at the closing opening wedge osteotomy site and L4-S1 segments were 30.8 degrees , 24.6 degrees , 0 mm, 16.1% (-5 degrees ), and 62% (-19 degrees ), respectively. The mean reconstructed values were 41.1 degrees , 23.3 degrees , 3.9 mm, 41% (-17 degrees ), and 46% (-19 degrees ), respectively. There were significant differences between estimated and reconstructed values of L1-S1 lordosis and the percentage of distributions; however, there was no significant difference between the estimated and reconstructed magnitude of L4-S1 lordosis, sacral inclination angle, and sacrofemoral distance. A properly oriented pelvis can be brought nearly directly above the hip axis. The mean sagittal global balance, represented by the distance between the vertical line through the hip axis and sacral promontory, improved from 61.4 mm before surgery to 3.9 mm 2 months after surgery, and 1.3 mm at final follow-up. Normal sagittal global balance was reconstructed and maintained. The mean sagittal spinal balance measured as the horizontal distance between the C7 sagittal plumb line and the posterior superior corner of S1 improved from 97.4 mm before surgery to 11 mm 2 months after surgery. However, there was significant loss of sagittal spinal balance to 25.4 mm at the fi nal visit. Normal sagittal spinal balance was reconstructed and appeared to be maintained. The magnitude of T1-T12 kyphosis compensated from 13 degrees before surgery to 25.2 degrees 2 months after surgery and 34.5 degrees at fi nal follow-up. CONCLUSIONS: Quality control of the reconstructed sagittal balance for sagittal imbalance is possible. Correctly orienting the pelvis, reconstructed by the restoration of enough L1-S1 lordosis with adequate distribution at L4-S1 segments, is a matter of critical importance for optimizing reconstructed sagittal balance. The correctly oriented pelvis can be determined before surgery. Preventing junctional fracture and persistent rehabilitation of surgically injured lumbar extensor musculature are crucial for maintaining the reconstructed sagittal balance. PMID- 21242883 TI - Gene expression changes are associated with loss of kidney graft function and interstitial fibrosis and tubular atrophy: diagnosis versus prediction. AB - BACKGROUND: Loss of kidney graft function due to interstitial fibrosis (IF) and tubular atrophy (TA) is the most common cause of kidney allograft loss. METHODS: One hundred one allograft tissues (26 samples with IF/TA, 17 normal allografts, and an independent biopsy group collected at 3 month [n=34] posttransplantation) underwent microarray analysis to identify early detection/diagnostic biomarkers of IF/TA. Profiling of 24 allograft biopsies collected at or after 9-month posttransplantation (range 9-18 months) was used for validation. Three-month posttransplantation biopsies were classified as IF/TA nonprogressors (group 1) or progressors (group 2) using graft function and histology at 9-month posttransplantation. RESULTS: We identified 2223 differentially expressed probe sets between IF/TA and normal allograft biopsies using a Bonferroni correction. Genes up-regulated in IF/TA were primarily involved in pathways related to T-cell activation, natural killer cell-mediated cytotoxicity, and programmed cell death. A least absolute shrinkage and selection operator model was derived from the differentially expressed probe sets, resulting in a final model that included 10 probe sets and had 100% training set accuracy. The N-fold crossvalidated error was 2.4% (sensitivity 95.8% and specificity 100%). When 3-month biopsies were tested using the model, all the samples were classified as normal. However, evaluating gene expression of the 3-month biopsies and fitting a new penalized model, 100% sensitivity was observed in classifying the samples as group1 or 2. This model was evaluated in the sample set collected at or after 9-month posttransplantation. CONCLUSIONS: An IF/TA gene expression signature was identified, and it was useful for diagnosis but not prediction. However, gene expression profiles at 3 months might predict IF/TA progression. PMID- 21242884 TI - Tissue specificity of cross-reactive allogeneic responses by EBV EBNA3A-specific memory T cells. AB - BACKGROUND: The crossreactivity of Epstein-Barr virus (EBV Epstein-Barr virus nuclear antigen 3A [EBNA3A])-specific CD8 T cells against allogeneic human leukocyte antigen (HLA)-B*44:02 has been shown to be dependent on presentation of self-peptide EEYLQAFTY by the target antigen. In this study, we report that allogeneic HLA-B*44:02 proximal tubular epithelial cells (PTECs) and human umbilical vein endothelial cells (HUVECs) are poor targets for EBV EBNA3A specific T cells. METHODS: The EEY peptide was exogenously loaded onto HLA B*44:02 and HLA-B*44:03-expressing PTECs and HUVECs. EEY-peptide-loaded, and unloaded, PTECs and HUVECs were then incubated with serial dilutions of our EBNA3A T-cell clone, in a cytotoxicity assay. RESULTS: Although HLA-B*44:02 expressing PTECs were specifically lysed in proportion to the effector/target ratio by the EBNA3A T-cell clone, without peptide loading, lysis was greatly increased by exogenous EEY peptide loading (15% vs. 75%; P<0.0001). HLA-B*44:02 expressing HUVECs were only lysed when loaded with exogenous EEY peptide (0% vs. 64%; P<0.0001). Lack of HLA expression and lack of ABCD3 gene expression were excluded as a cause for these results. PTECs and HUVECs were specifically targeted by another alloreactive T-cell clone without exogenous peptide loading, suggesting that the lack of recognition of HLA-B*44:02 epithelial and endothelial cells by the EBV EBNA3A T-cell clone was due to lack of EEYLQAFTY peptide presentation. CONCLUSIONS: Tissue-specific (peptide dependent) alloreactivity may have important implications for transplantation monitoring and rejection. PMID- 21242885 TI - New-onset diabetes mellitus in kidney transplant recipients discharged on steroid free immunosuppression. AB - BACKGROUND: New-onset diabetes after transplant (NODAT) is a serious complication after kidney transplantation. We studied the relationship between steroid-free maintenance regimens and NODAT in a national cohort of adult kidney transplant patients. METHODS: A total of 25,837 previously nondiabetic kidney transplant patients, engrafted between January 1, 2004, and December 31, 2006, were included in the study. Logistic regression analysis was used to compare the risk of developing NODAT within 3 years after transplant for patients discharged with and without steroid-containing maintenance immunosuppression regimens. The effect of transplant program-level practice regarding steroid-free regimens on the risk of NODAT was studied as well. RESULTS: The cumulative incidence of NODAT within 3 years of transplant was 16.2% overall; 17.7% with maintenance steroids and 12.3% without (P<0.001). Patients discharged with steroids had 42% greater odds of developing NODAT compared with those without steroids (adjusted odds ratio [AOR]=1.42, 95% confidence interval [CI]=1.27-1.58, P<0.001). The maintenance regimen of tacrolimus and mycophenolate mofetil or mycophenolate sodium was associated with 25% greater odds of developing NODAT (AOR=1.25, 95% CI=1.08-1.45, P=0.003) than the regimen of cyclosporine and mycophenolate mofetil or mycophenolate sodium. Several induction therapies also were associated with lower odds of NODAT compared with no induction. Patients from programs that used steroid-free regimens for a majority of their patients had reduced odds of NODAT compared with patients from programs discharging almost all of their patients on steroid-containing regimens. CONCLUSION: The adoption of steroid-free maintenance immunosuppression at discharge from kidney transplantation in selected patients was associated with reduced odds of developing NODAT within 3 years. PMID- 21242886 TI - Introduction: challenges to finding a cure for HIV infection. AB - PURPOSE OF REVIEW: Renewed interest has emerged to address the latent reservoir of HIV to achieve a cure. RECENT FINDINGS: The integrated proviral genome is a fundamental component of the retroviral replication cycle. The establishment of latently infected CD4+ lymphocytes, and perhaps other as yet poorly characterized cells, represents a reservoir of HIV infection that is not appreciably affected by effective antiretroviral chemotherapy. Effective management of HIV infection, thus, will require lifelong treatment unless an approach to purging this reservoir is identified. Although substantial insights about the latent reservoir have been made, our understanding about the details of the reservoirs, the mechanisms of latency and potential targets to eliminate latently infected cells is too primitive to achieve a cure without a great deal of basic research to elucidate some of these areas. SUMMARY: A resurgence of interest in latent infection and its treatment promises progress in addressing the challenge of a cure, although, realistically, this will require a prolonged period of investigation in many areas. PMID- 21242887 TI - The molecular biology of HIV latency: breaking and restoring the Tat-dependent transcriptional circuit. AB - PURPOSE OF REVIEW: Despite the remarkable success of intensive antiretroviral drug therapy in blocking the HIV replication, the virus persists in a small number of cells in which HIV has been transcriptionally silenced. This review will focus on recent insights into the HIV transcriptional control mechanisms that provide the biochemical basis for understanding latency. RECENT FINDINGS: Latency arises when the regulatory feedback mechanism driven by HIV Tat expression is disrupted. Small changes in transcriptional initiation, induced by epigenetic silencing, can lead to restrictions in Tat levels and entry of proviruses into latency. In resting memory T-cells, which carry the bulk of the latent viral pool, additional restrictions limiting cellular levels of the essential Tat cofactor P-TEFb and the transcription initiation factors nuclear factor kappa B and nuclear factor of activated T cells ensure that the provirus remains silenced unless the host cell is activated. SUMMARY: Strategies to purge the latent proviral pool require nontoxic activator molecules. The multiple restrictions imposed on latent proviruses that need to be overcome suggest that proviral reactivation will not be achieved when only a single reactivation step is targeted but will require both removal of epigenetic blocks and the activation of P-TEFb. Alternatively, new inhibitors that block proviral reactivation could be developed. PMID- 21242888 TI - NF-kappaB/Rel: agonist and antagonist roles in HIV-1 latency. AB - PURPOSE OF REVIEW: To discuss recent advances in our understanding of the diverse roles of NF-kappaB/Rel family members in HIV-1 latency. RECENT FINDINGS: Various NF-kappaB/Rel family members can reinforce maintenance of HIV-1 latency. For example, p50 recruits histone deacetylase 1 to the HIV-1 long terminal repeat promoting chromatin condensation and reduced RNA Pol II recruitment. Low-level NF kappaB activation during homeostatic proliferation of memory CD4 T cells induced by IL-7 and TCR signaling or OX40 action promotes expression of antiapoptotic gene targets such as BCL2 and BCLXL. Additionally, the IkappaB kinase phosphorylates FOXO3a transcription factor, blocking its induction of proapoptotic genes. These combined effects promote memory CD4 T-cell survival, thus maintaining the latent reservoir. Conversely, when the nontumorigenic phorbol ester prostratin is combined with histone deacetylase inhibitors, potent synergistic activation of latent HIV-1 occurs involving nuclear expression of NF kappaB. SUMMARY: These recent findings highlight both the antagonistic and agonistic effects of the NF-kappaB signaling pathway on HIV-1 latency. Synergistic inducers might be useful for flushing of latent virus from reservoirs in infected patients. The ultimate, albeit lofty, goal is to achieve full viral eradication. However, a more reasonable goal might be a functional cure where patients experience a drug-free remission. PMID- 21242889 TI - Epigenetic regulation of HIV latency. AB - PURPOSE OF REVIEW: A reservoir of latently infected cells remains in HIV-infected patients treated with highly active antiretroviral therapy treatment. Persistence of HIV in this latent reservoir has prevented full viral eradication. In order to understand and develop rational therapeutics to flush out HIV latency, the molecular mechanisms governing the phenomena of HIV latency need to be understood. Several mechanisms have been proposed to explain HIV latency. RECENT FINDINGS: Epigenetic regulation of the HIV promoter in the 5' long terminal repeat of HIV-1 via histone protein modifications and the presence of inhibitory nucleosomes play a critical role in the establishment, maintenance, and reactivation of HIV latency. Recent reports have shed further light on how HIV latency might be epigenetically regulated. In this review, we discuss how these recent reports broaden our understanding of how HIV latency is regulated. Here, we review how histone modifications and chromatin remodeling affect the transcriptional activity of the HIV promoter in the context of HIV latency. SUMMARY: These new epigenetic regulators of HIV latency pose as potential interesting candidates for therapeutics against HIV latency. PMID- 21242890 TI - Histone deacetylase inhibitors and HIV latency. AB - PURPOSE OF REVIEW: Interest has re-emerged in approaches to eradicate HIV infection. A series of modifications of nucleosomal histones within chromatin are a key mechanism of HIV gene regulation that alters the recruitment of transcription factors to viral DNA. The balance of these histone modifications in the vicinity of the HIV LTR plays an important role in the maintenance of proviral quiescence in rare latently infected cells, and presents a target for therapies aimed at purging this reservoir of persistent HIV infection. RECENT FINDINGS: Altering the balance of acetylase and deacetylase activity within CD4+ lymphocytes using histone deacetylase (HDAC) inhibitors, or other epigenetic drugs, has recently emerged as a promising approach to purge the reservoir of persistent infection. Multiple molecular mechanisms appear to underlie the establishment and maintenance of persistent, latent HIV infection, most frequently in the resting central memory CD4+ T cell. HDAC inhibitors perturb this balance, induce expression of integrated provirus, and may allow attack of this primary form of persistent HIV infection. SUMMARY: Although HDAC inhibitors are a promising approach, a better understanding of relevant mechanisms of latency in vivo, and better tools to translate this knowledge into therapies are needed. PMID- 21242891 TI - Maintenance of CD4+ T-cell memory and HIV persistence: keeping memory, keeping HIV. AB - PURPOSE OF REVIEW: The present review summarizes the current challenges for the design of new therapeutic strategies toward HIV eradication in individuals receiving suppressive highly active antiretroviral therapy (HAART). We will focus on the experimental evidence suggesting that immunological mechanisms involved in the generation and maintenance of memory CD4+ T cells are also responsible for the establishment and persistence of a stable reservoir for HIV. RECENT FINDINGS: Recent studies performed on clinical samples obtained from virally suppressed HIV infected individuals indicate that T-cell survival and homeostatic proliferation, two major mechanisms involved in the maintenance of immunological memory, contribute to the persistence of latently infected memory CD4+ T cells. Thus, the long lifespan characteristic of the HIV reservoir is likely a consequence of the capacity of the immune system to generate and maintain memory CD4+ T cells for a long period. SUMMARY: These findings suggest that strategies aimed at reducing the pool of latently infected cells should interfere with the survival pathways responsible for the long-term maintenance of memory CD4+ T cells. Because memory CD4+ T cells are critical for appropriate immune defense, targeted approaches are needed to interfere only with the long-term survival of discrete fractions of memory T cells carrying proviral DNA. PMID- 21242892 TI - A simian immunodeficiency virus macaque model of highly active antiretroviral treatment: viral latency in the periphery and the central nervous system. AB - PURPOSE OF REVIEW: Here, simian immunodeficiency virus (SIV) macaque models are examined for their strengths in identifying in-vivo sites of HIV latency and persistent virus replication during highly active antiretroviral treatment (HAART). The best characterized HIV reservoir in HAART-treated persons is resting CD4 T cells in blood, although residual virus also comes from other reservoirs. Nonhuman primate/SIV models of HAART have been developed to characterize potential HIV reservoirs, particularly the central nervous system (CNS) and stem cells in bone marrow, known and potential reservoirs of latent virus that are difficult to study in humans. RECENT FINDINGS: Few SIV macaque models of HAART have examined plasma and cerebrospinal fluid virus decay, the number of resting CD4 T cells harboring replication-competent latent SIV, HAART-treatment effect on the CNS, or residual viral replication or viral DNA levels in that tissue. Using a consistent, accelerated SIV macaque model, we characterized peripheral viral reservoirs, including those in the CNS, among HAART-treated macaques. The SIV model reproduces latency in memory CD4 T cells throughout the body and indicates that the CNS contains a stable SIV DNA reservoir. SUMMARY: An SIV macaque model of HAART recapitulating viral latency, particularly in the CNS, is required to study therapeutic approaches for a functional HIV cure. PMID- 21242894 TI - Simian immunodeficiency virus macaque models of HIV latency. AB - PURPOSE OF REVIEW: This review will focus on recent developments in several nonhuman primate models of AIDS. These models are being used to address viral latency and persistence during antiretroviral therapy in studies that are not feasible in humans. RECENT FINDINGS: Further characterization of the various macaque models of AIDS has demonstrated that several aspects of viral persistence during antiretroviral therapy model HIV-1 infection in humans, including viral decay kinetics. Widespread distribution of viral RNA and viral DNA has been detected in many tissue organs. In addition, the brain has been identified as a site of persistent viral DNA. SUMMARY: The macaque models of AIDS are well suited for addressing viral persistence during antiretroviral therapy, including viral latency, residual replication, and tissue organ distribution. PMID- 21242893 TI - Hematopoietic stem/precursor cells as HIV reservoirs. AB - PURPOSE OF REVIEW: Although latent HIV-1 infection in CD4+ T cells contributes to HIV persistence, there is mounting evidence that other viral reservoirs exist. Here, we review recent data suggesting that the infection of hematopoietic progenitor cells creates additional reservoirs for HIV in vivo. RECENT FINDINGS: New studies suggest that some types of hematopoietic progenitor cells have the potential to generate reservoirs for HIV. This review focuses on two types that can be infected by HIV in vitro and in vivo: multipotent hematopoietic progenitor cells in the bone marrow and circulating mast cell progenitors. Of these two types, only CD34+ bone marrow cells have been shown to harbor latent provirus in HIV-positive individuals with undetectable viral loads on highly active antiretroviral therapy (HAART). Latent infection of these long-lived cell types may create a significant barrier to HIV eradication; the infection of hematopoietic stem cells in particular could lead to an HIV reservoir that does not appreciably decay over the lifespan of the host. SUMMARY: To eradicate HIV infection, it will be necessary to purge all viral reservoirs in the host. The findings highlighted here suggest that multipotent hematopoietic progenitor cells and possibly tissue mast cells may constitute significant reservoirs for HIV that must be addressed in order to eliminate HIV infection. Future studies are needed to determine which types of CD34+ cells are infected in vivo and whether infected CD34+ cells contribute to residual viremia in people with undetectable viral loads on HAART. PMID- 21242895 TI - Primary cell models of HIV latency. AB - PURPOSE OF REVIEW: To provide updated points of view regarding the recent development and application of in-vitro primary cell models of HIV latency and their potential application in future studies of HIV eradication. RECENT FINDINGS: It has been challenging to develop a primary cell model of HIV latency that can authentically recapitulate the quiescent features of resting CD4+ T cells. Recently, several articles have described different approaches that can generate latently HIV-infected resting CD4+ T cells in vitro. Some of them further demonstrated that the primary cell models of HIV latency are suitable for biochemical studies and drug screening. SUMMARY: Recent progress in primary cell models of HIV latency has facilitated research on the mechanisms of HIV latency. These models also serve as a platform for the discovery of drugs that can purge the latent reservoir for HIV in resting CD4+ T cells. These studies will allow deeper insight to the mechanisms governing HIV latency and may help identify some candidate compounds for use in therapeutic strategies for the eradication of latent HIV. PMID- 21242896 TI - Stem cell-based approaches to treating HIV infection. AB - PURPOSE OF REVIEW: Stem cell-based strategies for treating HIV-infected individuals represent a novel approach toward reconstituting the ravaged immune system with the ultimate aim of clearing the virus from the body. Genetic modification of human hematopoietic stem cells to produce cells that are either resistant to infection, cells that produce lower amounts of infectious virus, or cells that specifically target the immune response against the virus are currently the dominant strategies under development. This review focuses on the understanding of stem cell-based approaches that are under investigation and the rationale behind such approaches. RECENT FINDINGS: Significant progress has recently been made utilizing stem cell-based approaches to treat HIV infection. Ideally, a successful strategy would result in immune clearance of the virus from the body as well long-term restoration of overall immune responses to successfully combat everyday environmental antigens. Two recent clinical trails illustrate how new advances in stem cell-based approaches may propel this field forward to clinical reality: one that demonstrates that large-scale gene therapy trials can be performed in a conventional, reproducible manner; and one that demonstrates the utilization of a multipronged approach using lentiviral-based gene therapy vectors. These clinical trails serve as the foundation for the development of other technologies, discussed here, that are currently in preclinical development. SUMMARY: Recent advances using stem cell-based approaches to treat HIV infection have provided the impetus for a renewed and expanded interest in the development of new cell-based strategies to treat HIV infection as well as a variety of other diseases. PMID- 21242898 TI - Targeted cytotoxic therapy: adapting a rapidly progressing anticancer paradigm for depletion of persistent HIV-infected cell reservoirs. AB - PURPOSE OF REVIEW: HIV-infected cells persisting in the face of highly active antiretroviral therapy are arguably the greatest hurdle to eradication of the virus from the body. Complementary strategies aimed at selective killing of infected cells are described. RECENT FINDINGS: Pioneered by research in the cancer field, various approaches are under development for selective killing of HIV-infected cells. These include targeted cytotoxic proteins, adoptive cell therapy, cytocidal virotherapy, and targeted nonbiological drug carriers. SUMMARY: These developmental efforts may provide a critical complement to antiretroviral therapy in efforts to achieve HIV eradication, or a 'functional cure' whereby therapy can be stopped without viral rebound. PMID- 21242897 TI - Chemokine receptor 5 knockout strategies. AB - PURPOSE OF REVIEW: Individuals homozygous for a deletion in the chemokine receptor 5 (CCR5) gene (CCR5Delta32) are almost completely resistant to HIV-1 infection. A recent report that transplantation of hematopoietic stem or progenitor cells (HSCs) from a CCR5Delta32 homozygous donor effectively cured an HIV patient has increased interest in the development of strategies that could be used to recreate this phenotype using a patient's own cells. This review will focus on recent developments to disrupt CCR5 expression in both autologous T cells and HSCs. RECENT FINDINGS: CCR5 expression in HIV-1 target cells can be suppressed by RNA-based gene suppression technologies such as RNA interference, or completely eliminated by zinc finger nuclease (ZFN)-mediated gene disruption. ZFNs bind specifically to a DNA sequence and generate a double-stranded DNA break, whose subsequent repair by the cell's error-prone nonhomologous end joining pathway can lead to permanent disruption of the gene's open reading frame. Recent developments in humanized mouse models have facilitated preclinical studies that have demonstrated the ability of CCR5-targeted ZFNs to suppress HIV 1 in vivo, when used to modify human T cells or HSCs. The same CCR5 ZFNs are now being evaluated in a phase I clinical trial of ex vivo expanded autologous T cells. SUMMARY: CCR5 gene knockout in T cells or HSCs by ZFNs effectively suppresses the replication of CCR5-tropic strains of HIV-1 in animal models. ZFNs are currently being evaluated in a phase I clinical trials using ex vivo expanded T cells and HSCs targeted therapies are under development. PMID- 21242899 TI - [A special issue]. PMID- 21242900 TI - [CT colonography: current indications in France]. PMID- 21242901 TI - [Virtual colonoscopy meta-analysis of diagnostic accuracy, indications and conditions of use. Short text of technological evaluation report]. PMID- 21242902 TI - [Splenic abscess secondary to a colosplenic fistula as the presenting manifestation of colon cancer]. PMID- 21242903 TI - [Band occlusion of a Roux-en-Y anastomosis following Whipple procedure: a rare cause of cholangitis]. PMID- 21242904 TI - [Rare complications from laparoscopic cholecystectomy]. PMID- 21242905 TI - [Mechanical gastric distension: a rare cause of portal venous gas]. PMID- 21242906 TI - [Sacral Ewing sarcoma: report of two cases]. PMID- 21242907 TI - [Accessory soleus muscle: a report of two cases and review of the literature]. PMID- 21242908 TI - [Ultrasound diagnosis of plantaris tendon tear]. PMID- 21242909 TI - [Diabetic myonecrosis: a case report]. PMID- 21242910 TI - [Ewing sarcoma of the anterior mediastinum: a rare tumor localization]. PMID- 21242911 TI - [Partial aplasia of the posterior arch of C1: review of one case, classification and management]. PMID- 21242912 TI - [Hydatid cyst of the psoas: a report of two cases]. PMID- 21242913 TI - [Giant dumbbell shaped pleuropericardial cyst]. PMID- 21242914 TI - [A rare rumor: pulmonary blastoma with pleural involvement]. PMID- 21242915 TI - [A rare cause of solitary pulmonary nodule: sarcoidosis]. PMID- 21242916 TI - [Embolization of a ruptured postpartum ovarian artery aneurysm]. PMID- 21242917 TI - [Fibrosarcoma of the uterine cervix]. PMID- 21242918 TI - [Value of diffusion-weighted imaging for the diagnosis of unilateral adrenal lymphoma]. PMID- 21242919 TI - [Hemoptysis and spontaneous rupture of a primary renal angiosarcoma: a case report]. PMID- 21242920 TI - [Frontoparietal paraganglioma: a case report]. PMID- 21242921 TI - [Migraine associated with reversible and irreversible vascular lesions]. PMID- 21242922 TI - [Atypical MR imaging features of an unidentified bright object in neurofibromatosis: a case report]. PMID- 21242923 TI - [Congenital nasopalatine glioma with left nasal obstruction: a case report]. PMID- 21242924 TI - [Answer to November e-quid. Disseminated splenosis]. PMID- 21242933 TI - [Presentation of a handicap, impairment and disability: the example of cerebral palsy]. AB - This article, co-authored by a functional therapist and a neuroradiologist, proposes a definition as well as a general overview of epidemiological, legal and clinical concerns related to the handicap followed by a more in-depth study of subjects with cerebral palsy or other brain motor handicap. This patient population contains an increasing number of adults. The effects of aging and the increased incidence of letal malignancies in this population will be reviewed.The role of imaging in the management of these patients, its key features and related pitfalls are discussed. Finally, the role of MR imaging of the brain in patients with cerebral palsy is discussed with emphasis on the relation between lesion type and impairment, imaging characteristics and injury mechanism. PMID- 21242934 TI - [Scoliosis and disability]. AB - Upright standing radiographs of the entire spine, at times completed by supine radiographs, allow diagnosis and follow-up of scolioses to detect progression over time and enable timely intervention to avoid painful, esthetic, respiratory and cutaneous complications. Motor difficulties that may accompany severe scolioses may confine affected individuals to bed. Cross-sectional imaging with tridimensional reconstructions combined with myelographic MR imaging sequences allow complete evaluation of the disease and have alleviated the need for conventional myelography. Evaluation of the imaging data allows comprehensive patient management that may include therapy, image-guided spinal injections or surgery with the help of new titanium hardware enabling follow-up MRI. PMID- 21242935 TI - [Imaging features of neurologic and orthopedic complications from severe trauma]. AB - Cranial and spinal trauma are a frequent cause of disability in the general population. Post-traumatic paraplegia or quadriplegia or hemiplegia from vascular injury (CVA) can lead to early complications (respiratory, cardiovascular, urinary, cutaneous, infectious...) that may have an impact on the immediate prognosis. Neurologic and orthopedic complications occur later and further impair the quality of life of patients. Orthopedic complications include: neurogenic paraosteoarthropathy (NPOA) or neurogenic osteoma or myositis ossificans (NMO). The nomenclature currently in use is NMO; Osseous complications: osteoporosis and secondary insufficiency fractures; Joint complications: degenerative arthropathy and stiffness; Overuse mechanical complications; Muscular complications; Infectious complications: arthritis and myositis complicating skin ulcers and bed sores. The purpose of this paper is to describe these neuro-orthopedic complications and review their imaging features. PMID- 21242936 TI - [Spasticity: clinical and imaging features]. AB - Spasticity, a component of the pyramidal syndrome, characterized by increased tonic stretch reflexes and hyperactive deep tendon reflexes, occurs in patients with central nervous system lesions (stroke, brain or cord injury, multiple sclerosis, cerebral motor impairment). The implementation of standard procedures (patient positioning, increased examination time, turning off certain devices before MR imaging) allows the acquisition of high quality examinations in spastic patients. Worsening spasticity in a handicaped patients is due to an irritative process (deep seated infection, fracture, syrinx...) usually detectable with imaging. Ultrasound or CT guided injections of botulinum agents provides radiologists with the opportunity to further participate in the management of spastic patients. PMID- 21242937 TI - [Disability and epilepsy]. AB - The purpose of this article is to familiarize radiologists with the different aspects of severe drug resistant epilepsy. These result in three levels of disability: the disease itself (seizures and their impact, underlying cause), social impact (restrictions, safety and precautions, education, activities of daily life) and issues related to the medical treatment (long term medication intake, side effects, complications). First, clinical and EEG diagnosis will be reviewed to move on to MRI with attention to technical and protocol considerations followed by the imaging features of specific entities causing severe drug resistant epilepsy: migration and gyration disorders, Rasmussen's encephalitis, Sturge Weber disease and post-ischemic sequelae. Finally, current data and the imaging features of hemispherotomy, a radical treatment for epilepsy, will be presented. PMID- 21242938 TI - [Imaging features of post-traumatic spine and cord lesions]. AB - The imaging evaluation of post-traumatic spine and cord injuries is part of the global management of chronically handicapped patients. Diagnosis and follow-up MR imaging of cord lesions allows differentiation of static lesions from progressive lesions that could require surgical intervention. Follow-up CT imaging is helpful in the evaluation of spine lesions to distinguish between late complications (deformity, malunion, pseudoarthrosis, complications related to surgical hardware) and lesions secondary to the handicap (neurogenic spinal arthropathy). PMID- 21242939 TI - [Neuromuscular diseases: imaging of thoracic, digestive and urinary complications]. AB - Neuromuscular diseases have different characteristics. Respiratory and cardiovascular manifestations are frequent and severe. Respiratory difficulties secondary to muscle involvement and bronchial secretions worsen complications related to a frequent scoliosis. CT is a useful complement to standard radiographs in the setting of acute symptomatic deterioration and for presurgical evaluation of a scoliosis. Echocardiography is performed to determine the presence of cardiomyopathy. Gastrointestinal motility disorders are assessed with standard barium studies or CT in the acute setting. Urinary tract involvement also is possible in these patients given the increased survival and follow-up imaging may be helpful for palliative management. The imaging features of frequent manifestations will be discussed along with the imaging appearance of a few specific entities. PMID- 21242940 TI - Transition metal catalyzed synthesis of aryl sulfides. AB - The presence of aryl sulfides in biologically active compounds has resulted in the development of new methods to form carbon-sulfur bonds. The synthesis of aryl sulfides via metal catalysis has significantly increased in recent years. Historically, thiolates and sulfides have been thought to plague catalyst activity in the presence of transition metals. Indeed, strong coordination of thiolates and thioethers to transition metals can often hinder catalytic activity; however, various catalysts are able to withstand catalyst deactivation and form aryl carbon-sulfur bonds in high-yielding transformations. This review discusses the metal-catalyzed arylation of thiols and the use of disulfides as metal-thiolate precursors for the formation of C-S bonds. PMID- 21242941 TI - Chemistry of the enaminone of 1-acetylnaphthalene under microwave irradiation using chitosan as a green catalyst. AB - Enaminone 1 was reacted with hydrazonoyl halides 2a-d to yield 3,4-disubstituted pyrazoles 6a-d. Coupling with arenediazonium chlorides afforded the 2 (arylhydrazono)-3-(1-naphthalenyl)-3-oxopropionaldehydes 13a-c. Compounds 13 could be utilized for the synthesis of a variety of arylpyrazoles, arylazolopyrimidines, and pyridazinones via reaction with hydrazines, aminoazoles, and active methylene derivatives, respectively. A comparative study of aforementioned reactions was carried out with chitosan as a basic ecofriendly catalyst under conventional heating as well as under pressurized microwave irradiation conditions. PMID- 21242942 TI - Carotenoids in fruits of different persimmon cultivars. AB - Carotenoids in the peel and the flesh of persimmon fruit were identified, and the contents of carotenoids in the fleshes of 46 different persimmon cultivars were analyzed. The results indicated that 31 specific carotenoids were detected in both cultivars of persimmons, among which nine specific carotenoids were characterized. beta-cryptoxanthin was the most abundant carotenoid among all individual components in both the peel and the flesh, accounting for about 20-30% of the total carotenoids in both cultivars. The contents of total carotenoids in the fleshes of different persimmon cultivars were between 194.61 ug/100g FW and 1,566.30 ug/100g FW. Zeaxanthin was also the most abundant in all persimmon fleshes besides beta-cryptoxanthin, and the total amount of these two components accounted for 37.84-85.11% of the total carotenoids. The RE values in the fleshes of different cultivars also differed greatly. Besides, the stage of maturation was also important factor which could influence the carotenoid content and RE value in the fleshes. PMID- 21242943 TI - Synthesis, inhibitory effects on nitric oxide and structure-activity relationships of a glycosphingolipid from the marine sponge Aplysinella rhax and its analogues. AB - The novel glycosphingolipid, beta-D-GalNAcp(1-->4)[alpha-D-Fucp(1-->3)]-beta-D GlcNAcp(1-->)Cer (A), isolated from the marine sponge Aplysinella rhax has a unique structure, with D-fucose and N-acetyl-D-galactosamine moieties attached to a reducing-end N-acetyl-D-glucosamine through an alpha1-->3 and beta1-->4 linkage, respectively. We synthesized glycolipid 1 and some non-natural di- and trisaccharide analogues 2-6 containing a D-fucose residue. Among these compounds, the natural type showed the most potent nitric oxide (NO) production inhibitory activity against LPS-induced J774.1 cells. Our results indicate that both the presence of a D-Fucalpha1-3GlcNAc-linkage and the ceramide aglycon portion are crucial for optimal NO inhibition. PMID- 21242944 TI - Monosaccharide-NAIM derivatives for D-, L-configurational analysis. AB - The D-, L-enantiomeric pairs of common monosaccharides (xylose, ribose, rhamnose, arabinose, fucose, glucose, mannose, galactose, N-acetylgalactosamine, glucuronic acid and galacturonic acid) were derivatized with 2,3-naphthalenediamine to form the corresponding D-, L-aldo-NAIM derivatives. A simple and facile capillary electrophoretic method was established for sugar composition analysis by simultaneously determining the migration times of these aldo-NAIMs using borate buffer at high pH (100 mM, pH 9.0). The methodology is also applicable to sialic acid (ketose monosaccharides). The quantitation level of the proposed method was in the 10~500 ppm range and the LOD was 1 ppm. The enantioseparation of D, L pairs of aldo-NAIMs were also achieved by using modified sulfated-alpha cyclodextrin as the chiral selector in phosphate buffer (300 mM, pH 3.0). In addition, the combination by reductive amination of amino-aldo-NAIM agent and D-, L-enantiomeric pairs of monosaccharides formed a diastereomeric pair for saccharide configuration analysis. Aldo-NAIM derivatives are thus shown to be rapid and efficient agents for analyzing saccharide compositions and configurations with good linearity and short analysis times via capillary electrophoresis. PMID- 21242945 TI - Bioassay-guided isolation of an anti-ulcer compound, tagitinin C, from Tithonia diversifolia: role of nitric oxide, prostaglandins and sulfhydryls. AB - Tithonia diversifolia is a medicinal plant from the Municipality of Suchiapa, Chiapas, Mexico, that according to local folk medicine is considered useful in the treatment of gastric ulcers. The aim of the present study was to investigate the gastroprotective activity of T. diversifolia by using an ethanol-induced gastric ulcer experimental model in male Wistar rats. The results showed that T. diversifolia had gastroprotective activity, and that the dichloromethane extract had the highest protective activity (close to 90% when using doses between 10 to 100 mg/kg), and that further the compound tagitinin C isolated from this extract was the main active gastroprotective agent. Rats treated with tagitinin C suspended in Tween 80 at 1, 3, 10 and 30 mg/kg showed 37.7, 70.1, 100, and 100% gastroprotection, respectively. The effect elicited by tagitinin C (30 mg/kg) was not attenuated by pretreatment with either N(G)-nitro-L-arginine methyl ester (70 mg/kg, i.p.), a nitric oxide (NO) synthase inhibitor, N-ethylmaleimide (10 mg/kg, s.c.), a blocker of sulfhydryl groups, or indomethacin (10 mg/kg, s.c.), a blocker of prostaglandin synthesis, which suggests that the gastroprotective mechanism of action of this sesquiterpene lactone does not involve NO, sulfhydryl groups or prostaglandins. PMID- 21242946 TI - The role of adenosine receptor agonists in regulation of hematopoiesis. AB - The review summarizes data evaluating the role of adenosine receptor signaling in murine hematopoietic functions. The studies carried out utilized either non selective activation of adenosine receptors induced by elevation of extracellular adenosine or by administration of synthetic adenosine analogs having various proportions of selectivity for a particular receptor. Numerous studies have described stimulatory effects of non-selective activation of adenosine receptors, manifested as enhancement of proliferation of cells at various levels of the hematopoietic hierarchy. Subsequent experimental approaches, considering the hematopoiesis-modulating action of adenosine receptor agonists with a high level of selectivity to individual adenosine receptor subtypes, have revealed differential effects of various adenosine analogs. Whereas selective activation of A1 receptors has resulted in suppression of proliferation of hematopoietic progenitor and precursor cells, that of A3 receptors has led to stimulated cell proliferation in these cell compartments. Thus, A1 and A3 receptors have been found to play a homeostatic role in suppressed and regenerating hematopoiesis. Selective activation of adenosine A3 receptors has been found to act curatively under conditions of drug- and radiation-induced myelosuppression. The findings in these and further research areas will be summarized and mechanisms of hematopoiesis-modulating action of adenosine receptor agonists will be discussed. PMID- 21242947 TI - Imaging the inflammatory activity of sarcoidosis: sensitivity and inter observer agreement of (67)Ga imaging and (18)F-FDG PET. AB - AIM: The aim of this study was to investigate sensitivity of 67Ga imaging and 18F FDG PET for sarcoidosis activity and their inter observer variability. METHODS: Thirty-four newly diagnosed, histologically proven sarcoidosis patients were analyzed prospectively. (67)Ga imaging and (18)F-FDG PET were performed, the presence of pulmonary and extra pulmonary lesions was evaluated and inter observer variability of both techniques was assessed. RESULTS: Overall sensitivity to detect active sarcoidosis was 88% for (67)Ga imaging and 97% for (18)F-FDG PET. Although these results were not significantly different, 18F-FDG PET detected more lesions in the mediastinum (P<0.05), hila (P<0.05), lymph nodes (P<0.001) and extra pulmonary regions in general (P<0.001). Inter observer agreement was poor to moderate for (67)Ga imaging (kappa 0.19-0.59) and good to very good for (18)F-FDG PET (kappa 0.65-1.00). CONCLUSION: (18)F-FDG PET is more sensitive than (67)Ga imaging in the assessment of sarcoidosis activity with regard to the mediastinum, hila, lymph nodes and extra pulmonary lesions in general. Furthermore, (18)F-FDG PET demonstrates a very good inter observer agreement in contrast with (67)Ga imaging and (18)F-FDG PET is therefore the nuclear imaging technique of choice in sarcoidosis assessment. PMID- 21242948 TI - An analytical model for improving absorbed dose calculation accuracy in non spherical autonomous functioning thyroid nodule. AB - AIM: Patients candidate to radioiodine treatment of autonomous functioning thyroid nodule (AFTN) are characterized by a wide range of nodule volumes with different shapes. To optimize the treatment, pretherapeutic dosimetry should account also for the dependence of deposited energy on the nodule geometry. METHODS: We developed a Monte Carlo code in Geant4 to simulate the interaction of beta and gamma radiations emitted by Na-131I into ellipsoidal volumes of soft tissue homogeneously uptaking the radionuclide, surrounded by a simplified antropomorphic phantom. We simulated 9 volumes between 0.1 and 50 cm3, each one with 8 different ellipsoidal shapes. We considered the data of 10 patients affected by AFTN, whose nodule volumes were in the range 1-40 cm3, who underwent radioiodine therapy following the traditional dosimetric approach. The patients underwent ultrasonographic (US) study, in order to determine the nodule volume, and radioiodine thyroid uptake measurements between 3 and 168 hours after radioiodine tracer dose administration. RESULTS: We found an analytical relationship between the average deposited energy and the ellipsoid's semiaxes and we included it in the formula for the calculation of activity to be administered, A0. For the 10 patients studied, A0 calculated with our approach ranges from +9% to -2% with respect to the one calculated with the traditional formula. CONCLUSION: The proposed model, accounting for the dependence of beta and gamma absorbed fractions from nodule volume and shape, can lead to a more accurate estimation of A0 during AFTN therapy. Since the measurement of nodule axes is routinely obtained from pretherapeutic US, our approach can be introduced in the clinical practice without changing the diagnostic pre-therapeutic protocol. PMID- 21242949 TI - Cardiovascular outcome in asymptomatic hemodialysis patients submitted to aggressive medical therapy: results of a four-year follow-up. AB - AIM: Cardiovascular disease is a leading cause of morbidity and mortality in end stage renal disease (ESRD) patients on maintenance hemodialysis (HD). Neither traditional nor emerging risk factors for cardiovascular disease can explain completely this excess of morbidity and mortality and the role and timing of primary prevention strategies in this population has not been clarified. The aim of this study was to assess if an aggressive pharmacological preventive treatment may reduce the myocardial ischemic burden and then improve the cardiovascular outcome In ESRD patients. METHODS: Forty-three asymptomatic ESRD patients on maintenance HD were evaluated. Asymptomatic patients with neither history nor clinical evidence of cardiovascular disease were considered. A total of 31 ESRD patients were enrolled into the study and were submitted to Tc-99m SESTAMIBI myocardial gated- single-photon emission computed tomography (SPECT) stress test. All patients then received an aggressive medical regimen with statins, antiplatelet drugs, ACE inhibitors (ACE-I) and/or Angiotensin II Receptor Blockers (ARB) and other hypotensive, glucose-lowering medications, sevelamer, calcium carbonate and calcitriol if required. RESULTS: A significant reduction of coronary functional reserve was found in more than 50% of otherwise asymptomatic HD patients and may often be reverted by prolonged aggressive medical therapy. After a four-year follow-up under aggressive medical therapy no significant difference was observed neither in the incidence of conventional and emerging cardiovascular risk factors nor in cardiovascular outcome of patients with or without silent myocardial ischemia (SMI). CONCLUSION: As cardiovascular disease (CVD) is by far the first cause of death in ESRD, an aggressive medical management may be highly advisable for the primary prevention of major adverse cardiac events in all HD patients despite the stress test evidence of inducible myocardial ischemia . PMID- 21242950 TI - Assessment of insulin resistance, dyslipidemia and inflammatory response in North Indian male patients with angiographically proven coronary artery disease. AB - AIM: Coronary artery disease (CAD) is a leading cause of morbidity and mortality in the developed world and is rapidly assuming epidemic proportions in developing countries, including India. Extensive research has proven the role of multiple etiologies such as dyslipidemia, inflammation, endothelial dysfunction and insulin resistance in the pathogenesis of CAD. The following study was undertaken to determine a possible inter-relationship between insulin resistance, inflammation and dyslipidemia, which are important risk factors for CAD in the atherosclerosis-prone north Indian male population. METHODS: The present study was conducted in 100 patients of myocardial infarction diagnosed on electrocardiographic and biochemical criteria, who subsequently underwent coronary angiography and 100 age matched healthy controls. The parameters that were evaluated include lipid profile, hsCRP, apolipoprotein B, insulin levels and HOMA-IR. RESULTS: Significantly higher serum levels of cholesterol, triglycerides, LDL and apolipoprotein B was observed in the patients as compared to the controls. On further classification, the dyslipidemia was marked in the patients with triple vessel disease as compared to single and double vessel disease. Similar pattern was observed for insulin resistance and CRP. Upon plotting the ROC curves, hsCRP emerged as the strongest predictor for CAD followed by apolipoprotein B. A significantly positive correlation was discerned between apolipoprotein B, CRP and HOMA-IR. CONCLUSION: The present study illustrates interplay between insulin resistance, inflammation and dyslipidemia in the CAD prone north Indian population. It also highlights the superiority of hs CRP in risk stratification of patients with angiographically proven CAD. PMID- 21242951 TI - Unexpected effects on arterial oxygenation during reduction in oxygen flow via a pumpless lung assist system. AB - The authors describe the effect of marked increase in PaO2 in a patient with acute respiratory distress syndrome and treatment by a pumpless extracorporeal lung assist following reduction in oxygen sweep flow. PMID- 21242952 TI - Community-acquired pneumonia. AB - Despite the remarkable advances in antibiotic therapies, diagnostic tools, prevention campaigns and intensive care, community-acquired pneumonia (CAP) is still among the primary causes of death worldwide, and there have been no significant changes in mortality in the last decades. The clinical and economic burden of CAP makes it a major public health problem, particularly for children and the elderly. This issue provides a clinical overview of CAP, focusing on epidemiology, economic burden, diagnosis, risk stratification, treatment, clinical management, and prevention. Particular attention is given to some aspects related to the clinical management of CAP, such as the microbial etiology and the available tools to achieve it, the usefulness of new and old biomarkers, and antimicrobial and other non-antibiotic adjunctive therapies. Possible scenarios in which pneumonia does not respond to treatment are also analyzed to improve clinical outcomes of CAP. PMID- 21242953 TI - The low therapeutic efficacy of postoperative chest radiographs for surgical intensive care unit patients. AB - BACKGROUND: The clinical value of postoperative chest radiographs (CXRs) for surgical intensive care unit (ICU) patients is largely unknown. In the present study, we determined the diagnostic and therapeutic efficacy of postoperative CXRs for different surgical subgroups and related their efficacy to the time after ICU admission. METHODS: A prospective, observational study of consecutive postoperative surgical ICU patients was performed during a 10 month period. We restricted our analysis to CXRs obtained within six hours after admission to the ICU. Diagnostic efficacy was defined by the presence of predefined major abnormalities; therapeutic efficacy was defined by predefined actions taken because of any abnormality found on postoperative CXRs. RESULTS: Of 857 surgical ICU patients, 670 (78%) had a postoperative CXR after admission to the ICU. Of these CXRs, 80 were performed for clinical reasons, and 590 were routinely obtained (i.e., these CXRs were made without a reason other than admission to the ICU itself). The diagnostic efficacy of clinically indicated and routinely obtained CXRs was 18% (14/80) and 13% (79/590), respectively. Of all predefined abnormalities found on CXRs, 60% involved the malposition of invasive devices, such as endotracheal tubes or central venous lines. The therapeutic efficacy of clinically indicated and routinely obtained CXRs was 4% (3/80) and 4% (26/590), respectively. While the diagnostic and therapeutic efficacy of routinely obtained CXRs were not dependent on timing of admission, the diagnostic and therapeutic efficacy of clinically indicated CXRs was higher for CXRs taken closer to the time of ICU admission. CONCLUSION: Although the diagnostic efficacy of clinically indicated and routinely obtained postoperative CXRs in surgical ICU patients appears to be significant, their therapeutic efficacy is low. PMID- 21242954 TI - Assessment of left ventricular systolic function during acute myocardial ischemia: a comparison of transpulmonary thermodilution and transesophageal echocardiography. AB - BACKGROUND: The PiCCO system provides different variables of cardiac function: the cardiac function index (CFI), the global ejection fraction (GEF) and the maximal pressure developed by the left ventricle (dP/dtMax). The purpose of this study was to investigate the ability of these variables to predict impaired left ventricular ejection fraction (LVEF) derived by transesophageal echocardiography during acute myocardial ischemia. METHODS: In this prospective experimental study, fifteen pigs (28-34 kg) were anesthetized, mechanically ventilated and subjected to left anterior descending (LAD) coronary artery occlusion. PiCCO derived variables and LVEF were obtained 5, 10, 15, and 20 minutes after LAD occlusion. Receiver operating characteristics analysis was performed to assess the ability of PiCCO-derived parameters to estimate LVEF <=40% and <=50%. RESULTS: LAD occlusion induced a decrease in PiCCO-derived variables and LVEF (P<0.001 for each). Significant correlations were found between LVEF and CFI (r=0.59, P<0.001), GEF (r=0.64, P<0.001), dP/dtMax (r=0.36, P<0.001), and cardiac output (r=0.25, P=0.028). The area under the receiver operating characteristics curve for the estimation of LVEF <=40% and <=50% was 0.80 and 0.79 for CFI (P=0.009, P<0.001), 0.86 and 0.78 for GEF (P=0.002, P<0.001), 0.76 and 0.68 for dP/dtMax (P=0.033, P=0.012), and 0.57 and 0.58 for cardiac output (P=0.554, P=0.259). CONCLUSION: Cardiac function indices permit the bedside quantification of left ventricular systolic function during acute myocardial ischemia in pigs. Therefore, the PiCCO system may represent a valuable technique for cardiovascular monitoring, particularly for detecting acute left ventricular systolic dysfunction due to myocardial ischemia. PMID- 21242955 TI - Hyperlipidemic acute pancreatitis: a possible role of antiretroviral therapy with entecavir. AB - In most cases clinical profile of acute hyperlipidemic pancreatitis is a preexisting lipoprotein abnormality associated to second risk factors such as alcohol abuse, diabetes mellitus or medications that can induce hypertrygliceridemia. We report a case of a young male affected by chronic hepatitis B virus infection admitted to Emergency Department due to acute abdominal pain, vomiting and fever. The patient was in antiretroviral treatment with entecavir; moreover he was affected by diabetes mellitus and he presented a past history of alcohol abuse. Laboratory tests demonstrated hyperglycemia, severe metabolic acidosis and hypertriglyceridemia, whereas abdominal computed tomography scan revealed peripancreatic edema: hyperlipidemic pancreatitits was supposed and the patient was admitted to the intensive care unit. Considering its possible role in the pathogenesis of pancreatitis, entecavir was interrupted and total of 3 sections of plasmapheresis were performed, allowing clinical resolution and prevention of pancreatic damage. The possible pathogenetic role of entecavir is discussed. PMID- 21242956 TI - Rapid detection of low-abundance K-ras mutation in stools of colorectal cancer patients using chip-based temperature gradient capillary electrophoresis. AB - Mutant K-ras provides an independent negative predictive marker for epidermal growth factor receptor (EGFR)-targeted therapy in colorectal cancers (CRCs). Rapid, sensitive, and cost-effective screening for K-ras status will overarch rational personalized medicine. Stool-based DNA testing offers unique advantages for CRC screening such as noninvasiveness, high specificity, and patient compliance, whereas complicated procedures and the low sensitivity of the present approaches have hampered its application on a wide scale. In this study, a chip based temperature gradient capillary electrophoresis (TGCE) technique was applied to detect low-abundance K-ras mutations under a pooled experiment and analyze K ras mutations in 30 paired stool samples and cancer tissues of CRC patients and 15 stool samples of healthy volunteers. The chip-based TGCE results showed that the successful analysis of K-ras status could be achieved within 6 min with an extremely low sample consumption of 14 nl. Detection is sensitive enough to reliably report 0.2% mutant CRC cells in a wild-type background, and 0.5 ng of template DNA was sufficient for chip-based TGCE. Of the 30 stool samples of CRC patients analyzed, 17 (57%) harbored K-ras mutations, and the lowest percentage of the detectable mutant K-ras in stool samples was 2%. The coincidence rate for K-ras mutations between stools and tissues obtained by the chip-based method reached 97% (29/30). One of the 15 stool samples of normal controls carried K-ras mutations, producing a specificity of 93%. Clone sequencing data entirely confirmed the results obtained by chip-based TGCE. The study demonstrates that chip-based TGCE is capable of rapidly screening low-abundance K-ras mutations with high sensitivity, reproducibility, simplicity, and significant savings of time and sample. Application of this method to genotype the K-ras gene in stools would provide a potential means for predicting the effectiveness of EGFR-targeted therapy in CRC patients using noninvasive approaches. PMID- 21242957 TI - Vhl is required for normal pancreatic beta cell function and the maintenance of beta cell mass with age in mice. AB - Type 2 diabetes is hallmarked by insulin resistance and insufficient beta-cell function. Islets of type 2 diabetes patients have been shown to have decreased hypoxia-inducible factor (HIF)-1alpha/beta expression. Target genes of the HIF pathway are involved in angiogenesis, survival, proliferation, and energy metabolism, and von Hippel-Lindau protein (VHL) is a negative regulator of this pathway. We hypothesized that increased HIF-mediated gene transcription by VHL deletion in the beta-cells would increase beta-cell mass and function. We generated beta-cell-specific VHL-knockout mice using the Cre-loxP recombination system driven by the rat insulin promoter to assess the role of VHL in glucose homeostasis and beta-cell function. VHL deletion in the pancreatic beta-cells led to impaired glucose tolerance due to defects in glucose-stimulated insulin secretion and beta-cell mass with age. VHL-knockout islets had decreased GLUT2, but increased glucose transporter 1 and vascular endothelial growth factor expression. Furthermore, there were significant aberrations in islet morphology in the VHL-knockout mice, likely due to increased islet vasculature. Given that erythropoietin (EPO) is a target gene of the HIF pathway, which is not expressed in islets, we tested whether activating EPO signaling by systemic administration with recombinant human EPO (rHuEPO) can overcome the beta-cell defects that occurred with VHL loss. We observed improved glucose tolerance and restoration of GLUT2 expression in VHL-deficient beta-cells in response to rHuEPO. Contrary to our hypothesis, loss of VHL and increased transcription of HIF-target genes resulted in impaired beta-cell function and mass, which can be overcome with exogenous EPO. Our results indicate a critical role for VHL in beta-cell function and mass, and that EPO administration improved beta-cell function making it a potential strategy for diabetes treatment. PMID- 21242958 TI - Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells. AB - Host cell and bacterial factors determine severity and duration of infections. To allow for bacteria pathogenicity and persistence, bacteria have developed mechanisms that modify expression of host genes involved in cell cycle progression, apoptosis, differentiation and the immune response. Recently, Helicobacter pylori infection of the stomach has been correlated with epigenetic changes in the host genome. To identify epigenetic changes during Escherichia coli induced urinary tract infection (UTI), we developed an in vitro model of persistent infection of human uroepithelial cells with uropathogenic E. coli (UPEC), resulting in intracellular bacteria colonies. Cells inoculated with FimH negative E. coli (N-UPEC) that are not internalized and non-inoculated cells were used as controls. UPEC infection significantly induced de novo methyltransferase (DNMT) activity (12.5-fold P=0.002 UPEC vs non-inoculated and 250-fold P=0.001 UPEC vs N-UPEC inoculated cells) and Dnmt1 RNA expression (6-fold P=0.04 UPEC vs non-inoculated cells) compared with controls. DNMT1 protein levels were significantly increased in three uroepithelial cell lines (5637, J82, HT-1197) in response to UPEC infection as demonstrated by confocal analysis. Real-time PCR analysis of candidate genes previously associated with bacteria infection and/or innate immunity, revealed UPEC-induced downregulation of the tumor suppressor gene CDKN2A (3.3-fold P=0.007 UPEC vs non-inoculated and 3.3-fold P=0.001 UPEC vs N-UPEC) and the DNA repair gene MGMT (9-fold P=0.03 UPEC vs non-inoculated). Expression of CDH1, MLH1, DAPK1 and TLR4 was not affected. Pyrosequencing of CDKN2A and MGMT CpG islands revealed increased methylation in CDKN2A exon 1 (3.8 fold P=0.04 UPEC vs N-UPEC and UPEC vs non-inoculated). Methylation of MGMT was not affected. UPEC-induced methylation of CDKN2A exon 1 may increase bladder cancer and presage UTI risk, and be useful as a biological marker for UTI susceptibility or recurrence. PMID- 21242959 TI - The role of CD44 in the acute and resolution phase of the host response during pneumococcal pneumonia. AB - Streptococcus pneumoniae is the most prevalent pathogen causing community acquired pneumonia. CD44 is a transmembrane adhesion molecule, expressed by a wide variety of cell types, that has several functions in innate and adaptive immune responses. In this study, we tested the hypothesis that CD44 is involved in the host response during pneumococcal pneumonia. On intranasal infection with a lethal dose of S. pneumoniae CD44-knockout (KO) mice showed a prolonged survival when compared with wild-type mice, which was accompanied by a diminished pulmonary bacterial growth and reduced dissemination to distant body sites. Whereas, proinflammatory cytokine responses and lung pathology were not affected, CD44 deficiency resulted in increased early neutrophil influx into the lung. In separate experiments, we confirmed a detrimental role of CD44 in host defense against pneumococci during sublethal pneumonia, as demonstrated by an improved capacity of CD44 KO mice to clear a low infectious dose. In addition, CD44 appeared important for the resolution of lung inflammation during sublethal pneumonia, as shown by histopathology of lung tissue slides. In conclusion, we show here that CD44 facilitates bacterial outgrowth and dissemination during pneumococcal pneumonia, which in lethal infection results in a prolonged survival of CD44 KO mice. Moreover, during sublethal pneumonia CD44 contributes to the resolution of the inflammatory response. PMID- 21242960 TI - Myc/miR-378/TOB2/cyclin D1 functional module regulates oncogenic transformation. AB - The c-Myc transcription factor activates a cascade of downstream targets to form a complex transcriptional program that ultimately leads to cellular transformation. Although a large number of protein-encoding genes as well as non coding RNAs were identified as Myc targets, only a few have been validated to be functionally important for c-Myc-driven transformation. Here, we identify a microRNA (miRNA), miR-378, as a novel target of the c-Myc oncoprotein that is able to cooperate with activated Ras or HER2 to promote cellular transformation. Mechanistically, miR-378 achieves this oncogenic effect, at least in part, by targeting and inhibiting the anti-proliferative BTG family member, TOB2, which is further elucidated as a candidate tumor suppressor to transcriptionally repress proto-oncogene cyclin D1. Therefore, our study identifies miR-378-TOB2-cyclin D1 as a functional module to mediate the cross talk between Myc and Ras signaling in cellular transformation. PMID- 21242961 TI - hSSB1 binds and protects p21 from ubiquitin-mediated degradation and positively correlates with p21 in human hepatocellular carcinomas. AB - Downregulation of hSSB1, a single-stranded DNA-binding protein, causes increased radiosensitivity, defective checkpoint activation and genomic instability. However, the mechanisms of hSSB1 function in these responses remain to be uncovered. Here, we present evidence that hSSB1 directly binds p21 and this interaction may prevent p21 from ubiquitin-mediated degradation. Furthermore, both promotion of the G1/S transition and abrogation of the G2/M checkpoints induced by hSSB1 knockdown are partially dependent on p21. Most importantly, hSSB1 and p21 levels are positively correlated in human hepatocellular carcinomas (HCC), as determined by immunostaining. Therefore, hSSB1 may positively modulate p21 to regulate cell cycle progression and DNA damage response, implicating hSSB1 as a novel, promising therapeutic target for cancers such as HCC. PMID- 21242962 TI - Human papillomavirus type 16 E6 induces cervical cancer cell migration through the p53/microRNA-23b/urokinase-type plasminogen activator pathway. AB - Deregulation of microRNA (miRNA or miR) expression in human cervical cancer is associated frequently with human papillomavirus (HPV) integration. miR-23b is often downregulated in HPV-associated cervical cancer. Interestingly, urokinase type plasminogen activator (uPA), the miR-23b target, is detected in cervical cancer, but not in normal cervical tissues. Thus, the importance of miR-23b and uPA in HPV-associated cervical cancer development is investigated. In this study, the high-risk subtype HPV-16 E6 oncoprotein was found to decrease the expression of miR-23b, increase the expression of uPA, and thus induce the migration of human cervical carcinoma SiHa and CaSki cells. uPA is the target gene for miR-23b as the miR repressed uPA expression and interacted with the 3'-untranslated region of uPA mRNA. The tumor suppressor p53 is known to be inactivated by HPV-16 E6. A consensus p53 binding site is detected in the promoter region of miR-23b, whereas p53 trans-activated and also interacted with the miR's promoter. Therefore, p53 is believed to mediate the HPV-16 E6 downregulation of miR-23b. From the above, miR-23b/uPA are confirmed to be involved in HPV-16 E6-associated cervical cancer development. PMID- 21242963 TI - Identification of a progenitor cell of origin capable of generating diverse meningioma histological subtypes. AB - Meningiomas are among the most common primary central nervous system tumours in adults. Studies focused on the molecular basis for meningioma development are hampered by a lack of information with regard to the cell of origin for these brain tumours. Herein, we identify a prostaglandin D synthase-positive meningeal precursor as the cell of origin for murine meningioma, and show that neurofibromatosis type 2 (Nf2) inactivation in prostaglandin D2 synthase (PGDS) (+) primordial meningeal cells, before the formation of the three meningeal layers, accounts for the heterogeneity of meningioma histological subtypes. Using a unique PGDSCre strain, we define a critical embryonic and early postnatal developmental window in which biallelic Nf2 inactivation in PGDS (+) progenitor cells results in meningioma formation. Moreover, we identify differentially expressed markers that characterize the two major histological meningioma subtypes both in human and mouse tumours. Collectively, these findings establish the cell of origin for these common brain tumours as well as a susceptible developmental period in which signature genetic mutations culminate in meningioma formation. PMID- 21242964 TI - Cdc25B is negatively regulated by p53 through Sp1 and NF-Y transcription factors. AB - Cdc25B phosphatases function as key players in G2/M cell cycle progression by activating the CDK1-cyclinB1 complexes. They also have an essential role in recovery from the G2/M checkpoint activated in response to DNA damage. Overexpression of Cdc25B results in bypass of the G2/M checkpoint and illegitimate entry into mitosis, and also causes replicative stress, leading to genomic instability. Thus, fine-tuning of Cdc25B expression level is critical for correct cell cycle progression and G2 checkpoint recovery. However, the transcriptional regulation of Cdc25B remains largely unknown. Earlier studies have shown that the tumor suppressor p53 overexpression transcriptionally represses Cdc25B; however, the molecular mechanism of this repression has not yet been elucidated, although it was suggested to occur through the induction of p21. Here we show that Cdc25B is downregulated by the basal level of p53 in multiple cell types. This downregulation also occurs in p21-/- cell lines, indicating that p21 is not required for p53-mediated regulation of Cdc25B. Deletion and mutation analyses of the Cdc25B promoter revealed that downregulation by p53 is dependent on the presence of functional Sp1/Sp3 and NF-Y binding sites. Furthermore, chromatin immunoprecipitation analyses show that p53 binds to the Cdc25B promoter and mediates transcriptional attenuation through the Sp1 and NF-Y transcription factors. Our results suggest that the inability to downregulate Cdc25B after loss of p53 might contribute to tumorigenesis. PMID- 21242965 TI - hTID-1 defines a novel regulator of c-Met Receptor signaling in renal cell carcinomas. AB - The c-Met receptor tyrosine kinase (MetR) is frequently overexpressed and constitutively phosphorylated in a number of human malignancies. Activation of the receptor by its ligand, hepatocyte growth factor (HGF), leads to increased cell proliferation, motility, survival and disruption of adherens junctions. In this study, we show that hTid-1, a DNAJ/Hsp40 chaperone, represents a novel modulator of the MetR signaling pathway. hTid-1 is a co-chaperone of the Hsp70 family of proteins, and has been shown to regulate a number of cellular signaling proteins including several involved in tumorigenic and apoptotic pathways. In this study we demonstrate that hTid-1 binds to unphosphorylated MetR and becomes dissociated from the receptor upon HGF stimulation. Overexpression of the short form of hTid-1 (hTid-1(S)) in 786-0 renal clear cell carcinomas (RCCs) enhances MetR kinase activity leading to an increase in HGF-mediated cell migration with no discernible effect on cell proliferation. By contrast, knockdown of hTid-1 markedly impairs both the onset and amplitude of MetR phosphorylation in response to HGF without altering receptor protein levels. hTid-1-depleted cells display defective migratory properties, coincident with inhibition of ERK/MAP kinase and STAT3 pathways. Taken together, our findings denote hTid-1(S) as an essential regulatory component of MetR signaling. We propose that the binding of hTid-1(S) to MetR may stabilize the receptor in a ligand-competent state and this stabilizing function may influence conformational changes that take place during the catalytic cycle that promote kinase activation. Given the prevalence of HGF/MetR pathway activation in human cancers, targeted inhibition of hTid-1 may be a useful therapeutic in the management of MetR-dependent malignancies. PMID- 21242966 TI - Phosphorylation-dependent regulation of SCF(Fbx4) dimerization and activity involves a novel component, 14-3-3E. AB - Fbx4 is an F-box constituent of Skp-Cullin-F-box (SCF) ubiquitin ligases that directs ubiquitylation of cyclin D1. Ubiquitylation of cyclin D1 requires phosphorylation of both cyclin D1 and Fbx4 by GSK3beta. GSK3beta-mediated phosphorylation of Fbx4 Ser12 during the G1/S transition regulates Fbx4 dimerization, which in turn governs Fbx4-driven E3 ligase activity. In esophageal carcinomas that overexpress cyclin D1, Fbx4 is subject to inactivating mutations that specifically disrupt dimerization, highlighting the biological significance of this regulatory mechanism. In an effort to elucidate the mechanisms that regulate dimerization, we sought to identify proteins that differentially bind to wild-type Fbx4 versus a cancer-derived dimerization-deficient mutant. We provide evidence that phosphorylation of Ser12 generates a docking site for 14-3-3E. 14-3 3E binds to endogenous Fbx4 and this association is impaired by mutations that target either Ser8 or Ser12 in Fbx4, suggesting that this N-terminal motif in Fbx4 directs its interaction with 14-3-3E. Knockdown of 14-3-3E inhibited Fbx4 dimerization, reduced SCF(Fbx4) E3 ligase activity and stabilized cyclin D1. Collectively, the current results suggest a model wherein 14-3-3E binds to Ser12 phosphorylated Fbx4 to mediate dimerization and function. PMID- 21242967 TI - The constitutive activity of the ALK mutated at positions F1174 or R1275 impairs receptor trafficking. AB - Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK), which is transiently expressed during development of the central and peripheral nervous system. ALK has been recently identified as a major neuroblastoma predisposition gene and activating mutations have also been identified in a subset of sporadic neuroblastoma tumors. Two hot spots of ALK mutations have been observed at positions F1174 and R1275. Here, we studied stably transfected cell lines expressing wild-type or F1174L- or R1275Q-mutated ALK in parallel with a neuroblastoma cell line (CLB-GE) in which the allele mutated at position F1174 is amplified. We observed that the mutated ALK variants were essentially intracellular and were largely retained in the reticulum/Golgi compartments. This localization was corroborated by a defect of N-linked glycosylation. Although the mutated receptors exhibited a constitutive activation, the minor pool of receptor addressed to the plasma membrane was much more tyrosine phosphorylated than the intracellular pool. The use of antagonist monoclonal antibodies suggested that the constitutive activity of the mutated receptors did not require the dimerization of the receptor, whereas adequate dimerization triggered by agonist monoclonal antibodies increased this activity. Finally, kinase inactivation of the mutated receptors restored maturation and cell-surface localization. Our results show that constitutive activation of ALK results in its impaired maturation and intracellular retention. Furthermore, they provide a rationale for the potential use of kinase inhibitors and antibodies in ALK-dependent tumors. PMID- 21242968 TI - c-Cbl inhibits angiogenesis and tumor growth by suppressing activation of PLCgamma1. AB - Angiogenesis is regulated by highly coordinated function of various proteins with pro- and anti-angiogenic functions. Among the many cytoplasmic signaling proteins that are activated by VEGFR-2, activation of PLCgamma1 is considered to have a pivotal role in angiogenic signaling. In previous study we have identified c-Cbl as a negative regulator of PLCgamma1 in endothelial cells, the biochemical and biological significance of c-Cbl, however, in angiogenesis in vivo and molecular mechanisms involved were remained elusive. In this study, we report that genetic inactivation of c-Cbl in mice results in enhanced tumor angiogenesis and retinal neovascularization. Endothelial cells derived from c-Cbl null mice displayed elevated cell proliferation and tube formation in response to VEGF stimulation. Loss of c-Cbl also resulted in robust activation of PLCgamma1 and increased intracellular calcium release. c-Cbl-dependent ubiquitination selectively inhibited tyrosine phosphorylation of PLCgamma1 and mostly refrained from ubiquitin-mediated degradation. Hence, we propose c-Cbl as an angiogenic suppressor protein where upon activation it uniquely modulates PLCgamma1 activation by ubiquitination and subsequently inhibits VEGF-driven angiogenesis. PMID- 21242969 TI - P2X(7) receptor activation enhances SK3 channels- and cystein cathepsin-dependent cancer cells invasiveness. AB - ATP-gated P2X(7) receptors (P2X(7)R) are unusual plasma membrane ion channels that have been extensively studied in immune cells. More recently, P2X(7)R have been described as potential cancer cell biomarkers. However, mechanistic links between P2X(7)R and cancer cell processes are unknown. Here, we show, in the highly aggressive human breast cancer cell line MDA-MB-435s, that P2X(7) receptor is highly expressed and fully functional. Its activation is responsible for the extension of neurite-like cellular prolongations, of the increase in cell migration by 35% and in cell invasion through extracellular matrix by 150%. The change in cancer cell morphology and the increased migration appeared to be due to the activation of Ca(2+)-activated SK3 potassium channels. The enhanced invasion through the extracellular matrix was related to the increase of mature forms of cysteine cathepsins in the extracellular medium, which was independent of SK3 channel activity and not associated with cell death. Pharmacological targeting of P2X(7)R in vivo was crucial for cell invasiveness in a zebrafish model of metastases. Our results demonstrate a novel mechanistic link between P2X(7)R functionality in cancer cells and invasiveness, a key parameter in tumour growth and in the development of metastases. They also suggest a potential therapeutic role for the newly developed P2X(7)R antagonists. PMID- 21242970 TI - Targeting the Akt/mTOR pathway in Brca1-deficient cancers. AB - The breast cancer susceptibility gene 1 (Brca1) has a key role in both hereditary and sporadic mammary tumorigenesis. However, the reasons why Brca1-deficiency leads to the development of cancer are not clearly understood. Activation of Akt kinase is one of the most common molecular alterations associated with human malignancy. Increased Akt kinase activity has been reported in most breast cancers. We previously found that downregulation of Brca1 expression or mutations of the Brca1 gene activate the Akt oncogenic pathway. To further investigate the role of Brca1/Akt in tumorigenesis, we analyzed Brca1/Akt expression in human breast cancer samples and found that reduced expression of Brca1 was highly correlated with increased phosphorylation of Akt. Consistent with the clinical data, knockdown of Akt1 by short-hairpin RNA inhibited cellular proliferation of Brca1 mutant cells. Importantly, depletion of Akt1 significantly reduced tumor formation induced by Brca1-deficiency in mice. The third generation inhibitor of mammalian target of rapamycin (mTOR), Palomid 529, significantly suppressed Brca1 deficient tumor growth in mice through inhibition of both Akt and mTOR signaling. Our results indicate that activation of Akt is involved in Brca1-deficiency mediated tumorigenesis and that the mTOR pathway can be used as a novel target for treatment of Brca1-deficient cancers. PMID- 21242971 TI - Kruppel-like factor 4 (KLF4) is required for maintenance of breast cancer stem cells and for cell migration and invasion. AB - Kruppel-like factor 4 (KLF4) is highly expressed in more than 70% of breast cancers and functions as an oncogene. However, an exact mechanism by which KLF4 enhances tumorigenesis of breast cancer remains unknown. In this study, we show that KLF4 was highly expressed in cancer stem cell (CSC)-enriched populations in mouse primary mammary tumor and breast cancer cell lines. Knockdown of KLF4 in breast cancer cells (MCF-7 and MDA-MB-231) decreased the proportion of stem/progenitor cells as demonstrated by expression of stem cell surface markers such as aldehyde dehydrogenase 1, side population and by in vitro mammosphere assay. Consistently KLF4 overexpression led to an increase of the cancer stem cell population. KLF4 knockdown also suppressed cell migration and invasion in MCF-7 and MDA-MB-231 cells. Furthermore, knockdown of KLF4 reduced colony formation in vitro and inhibited tumorigenesis in immunocompromised non-obese diabetic/severe combined immunodeficiency mice, supporting an oncogenic role for KLF4 in breast cancer development. Further mechanistic studies revealed that the Notch signaling pathway was required for KLF4-mediated cell migration and invasion, but not for CSC maintenance. Taken together, our study provides evidence that KLF4 has a potent oncogenic role in mammary tumorigenesis likely by maintaining stem cell-like features and by promoting cell migration and invasion. Thus, targeting KLF4 may provide an effective therapeutic approach to suppress tumorigenicity in breast cancer. PMID- 21242972 TI - Activated ROCK II by-passes the requirement of the CDK2 activity for centrosome duplication and amplification. AB - Initiation of centrosome duplication and DNA replication is coupled, which is primarily achieved by the late G1 phase-specific activation of cyclin-dependent kinase 2 (CDK2)-cyclin E, which triggers both centrosome duplication and DNA replication. Uncoupling of these two events contributes to overduplication of centrosomes, resulting in the presence of more than two centrosomes (centrosome amplification). Centrosome amplification, which is frequently observed in cancers, contributes to tumor development through destabilizing genomes. Nucleophosmin (NPM/B23) is one of the phosphorylation targets of CDK2-cyclin E for the initiation of centrosome duplication. It has been found that NPM/B23 phosphorylated on Thr199 by CDK2-cyclin E acquires a high binding affinity to ROCK II kinase. The Thr199-phosphorylated NPM/B23 physically interacts with and super-activates the centrosomally localized ROCK II, which is a critical event for centrosomes to initiate duplication. Here, we provide direct evidence for the activation of ROCK II as a primary and sufficient downstream event of CDK2-cyclin E for the initiation of centrosome duplication and for the induction of centrosome amplification. PMID- 21242973 TI - Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG. AB - E26 transforming sequence-related gene (ERG) is a transcription factor involved in normal hematopoiesis and is dysregulated in leukemia. ERG mRNA overexpression was associated with poor prognosis in a subset of patients with T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Herein, a genome wide screen of ERG target genes was conducted by chromatin immunoprecipitation-on chip (ChIP-chip) in Jurkat cells. In this screen, 342 significant annotated genes were derived from this global approach. Notably, ERG-enriched targets included WNT signaling genes: WNT11, WNT2, WNT9A, CCND1 and FZD7. Furthermore, chromatin immunoprecipitation (ChIP) of normal and primary leukemia bone marrow material also confirmed WNT11 as a target of ERG in six of seven patient samples. A larger sampling of patient diagnostic material revealed that ERG and WNT11 mRNA were co expressed in 80% of AML (n=30) and 40% in T-ALL (n=30) bone marrow samples. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. Conversely, in a tet-on ERG-inducible assay, WNT11 transcripts were co-stimulated. A WNT pathway agonist, 6-bromoindirubin-3-oxime (BIO), was used to determine the effect of cell growth on the ERG-inducible cells. The addition of BIO resulted in an ERG-dependent proliferative growth advantage over ERG-uninduced cells. Finally, ERG induction prompted morphological transformation whereby round unpolarized K562 cells developed elongated protrusions and became polarized. This morphological transformation could effectively be inhibited with BIO and with siRNA knockdown of WNT11. In conclusion, ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Potent ERG induction promoted morphological transformation through WNT11 signals. The findings in this study unravel new ERG directed molecular signals that may contribute to the resistance of current therapies in acute leukemia patients with poor prognosis characterized by high ERG mRNA expression. PMID- 21242974 TI - Methylation by protein arginine methyltransferase 1 increases stability of Axin, a negative regulator of Wnt signaling. AB - Axin, a negative regulator of Wnt signaling, is a key scaffold protein for the beta-catenin destruction complex. It has been previously shown that multiple post translational modification enzymes regulate the level of Axin. Here, we provide evidence that protein arginine methyltransferase 1 (PRMT1) directly interacts with and methylates the 378th arginine residue of Axin both in vitro and in vivo. We found that the transient expression of PRMT1 led to an increased level of Axin and that knockdown of endogenous PRMT1 by short hairpin RNA reduced the level of Axin. These results suggest that methylation by PRMT1 enhanced the stability of Axin. Methylation of Axin by PRMT1 also seemingly enhanced the interaction between Axin and glycogen synthase kinase 3beta, leading to decreased ubiquitination of Axin. Consistent with the role of PRMT1 in the regulation of Axin, knockdown of PRMT1 enhanced the level of cytoplasmic beta-catenin as well as beta-catenin-dependent transcription activity. In summary, we show that the methylation of Axin occurred in vivo and controlled the stability of Axin. Therefore, methylation of Axin by PRMT1 may serve as a finely tuned regulation mechanism for Wnt/beta-catenin signaling. PMID- 21242975 TI - Cyclin D1 interacts and collaborates with Ral GTPases enhancing cell detachment and motility. AB - Alterations in the levels of adhesion and motility of cells are critical events in the development of metastasis. Cyclin D1 (CycD1) is one of the most frequently amplified oncogenes in many types of cancers and it is also associated with the development of metastasis. Despite this, we still do not know which are all the relevant pathways by which CycD1 induces oncogenic processes. CycD1 functions can be either dependent or independent of the cyclin-dependent kinase Cdk4, and they affect several cellular aspects such as proliferation, cell attachment and migration. In this work, we reveal a novel function of CycD1 that fosters our understanding of the oncogenic potential of CycD1. We show that CycD1 binds to the small GTPases Ral A and B, which are involved, through exocyst regulation, in the progression of metastatic cancers, inducing anchorage-independent growth and cell survival of transformed cells. We show that CycD1 binds active Ral complexes and the exocyst protein Sec6, and co-localizes with Ral GTPases in trans-Golgi and exocyst-rich regions. We have also observed that CycD1-Cdk4 phosphorylates the Ral GEF Rgl2 'in vitro' and that CycD1-Cdk4 activity stimulates accumulation of the Ral GTP active forms. In accordance with this, our data suggest that CycD1 Cdk4 enhances cell detachment and motility in collaboration with Ral GTPases. This new function may help explain the contribution of CycD1 to tumor spreading. PMID- 21242976 TI - Activation of nuclear factor-kappa B signalling promotes cellular senescence. AB - Cellular senescence is a programme of irreversible cell cycle arrest that normal cells undergo in response to progressive shortening of telomeres, changes in telomeric structure, oncogene activation or oxidative stress. The underlying signalling pathways, of major clinicopathological relevance, are unknown. We combined genome-wide expression profiling with genetic complementation to identify genes that are differentially expressed when conditionally immortalised human fibroblasts undergo senescence upon activation of the p16-pRB and p53-p21 tumour suppressor pathways. This identified 816 up and 961 downregulated genes whose expression was reversed when senescence was bypassed. Overlay of this data set with the meta-signatures of genes upregulated in cancer showed that nearly 50% of them were downregulated upon senescence showing that even though overcoming senescence may only be one of the events required for malignant transformation, nearly half of the genes upregulated in cancer are related to it. Moreover 65 of the up and 26 of the downregulated genes are known downstream targets of nuclear factor (NF)-kappaB suggesting that senescence was associated with activation of the NF-kappaB pathway. Direct perturbation of this pathway bypasses growth arrest indicating that activation of NF-kappaB signalling has a causal role in promoting senescence. PMID- 21242977 TI - The H3K27me3 demethylase, KDM6B, is induced by Epstein-Barr virus and over expressed in Hodgkin's Lymphoma. AB - There is now evidence for both increased and decreased activity of the enzymes controlling the methylation of lysine 27 on histone 3 (H3K27) in cancer. One of these enzymes, KDM6B formally known as JMJD3, a histone demethylase, which removes the trimethyl mark from H3K27, is required for the lineage commitment and terminal differentiation of neural stem cells and of keratinocytes. Our results suggest that KDM6B may also have a role in antigen-driven B-cell differentiation. KDM6B expression increases in B-cell subsets with increasing stage of differentiation, and gene expression profiling shows that KDM6B transcriptional targets in germinal centre B (GC B) cells are significantly enriched for those differentially expressed during memory and plasma cell differentiation. Our results also suggest that aberrant expression of KDM6B may contribute to the pathogenesis of Hodgkin's Lymphoma (HL), an Epstein-Barr virus (EBV) associated malignancy. KDM6B is over-expressed in primary HL and induced by the EBV oncogene, latent membrane protein (LMP1) in GC B cells, the presumptive progenitors of HL. Consistent with these observations, we found that KDM6B transcriptional targets in GC B cells are enriched for genes differentially expressed in HL, and that KDM6B depletion can restore the tri-methylation of H3K27 on these genes. PMID- 21242978 TI - Oncogenic Ras/Src cooperativity in pancreatic neoplasia. AB - Pancreas cancer is one of the most lethal malignancies and is characterized by activating mutations of Kras, present in 95% of patients. More than 60% of pancreatic cancers also display increased c-Src activity, which is associated with poor prognosis. Although loss of tumor suppressor function (for example, p16, p53, Smad4) combined with oncogenic Kras signaling has been shown to accelerate pancreatic duct carcinogenesis, it is unclear whether elevated Src activity contributes to Kras-dependent tumorigenesis or is simply a biomarker of disease progression. Here, we demonstrate that in the context of oncogenic Kras, activation of c-Src through deletion of C-terminal Src kinase (CSK) results in the development of invasive pancreatic ductal adenocarcinoma (PDA) by 5-8 weeks. In contrast, deletion of CSK alone fails to induce neoplasia, while oncogenic Kras expression yields PDA at low frequency after a latency of 12 months. Analysis of cell lines derived from Ras/Src-induced PDA's indicates that oncogenic Ras/Src cooperativity may lead to genomic instability, yet Ras/Src driven tumor cells remain dependent on Src signaling and as such, Src inhibition suppresses growth of Ras/Src-driven tumors. These findings demonstrate that oncogenic Ras/Src cooperate to accelerate PDA onset and support further studies of Src-directed therapies in pancreatic cancer. PMID- 21242979 TI - Akt1 deletion prevents lung tumorigenesis by mutant K-ras. AB - K-ras mutations are associated with smoking-induced lung cancer and poor clinical outcomes. In mice, K-ras mutations are sufficient to induce lung tumors, which require phosphoinoside-3-kinase (PI3K) and further downstream, mammalian target of rapamycin (mTOR) activation. However, the roles of individual Akt isoforms that link PI3K and mTOR are unknown. Here, we show that deletion of Akt1 but not Akt2 or Akt3 prevents lung tumorigenesis in a tobacco carcinogen-induced model and a genetic model. Akt1 deletion prevented tumor initiation as well as tumor progression, coincident with decreased Akt signaling in tumor tissues. In contrast, deletion of Akt3 increased tumor multiplicity in the carcinogen model and increased tumor size in the genetic model. Fibroblasts lacking Akt1 are resistant to transformation by mutant K-ras and stimulation by epidermal growth factor. Human lung cancer cells with mutant K-ras and diminished Akt1 levels fail to grow in vivo. These data suggest that Akt1 is the primary Akt isoform activated by mutant K-ras in lung tumors, and that Akt3 may oppose Akt1 in lung tumorigenesis and lung tumor progression. Given that Akt inhibitors in clinical development as cancer therapeutics are not isoform selective, these studies support specific targeting of Akt1 to mitigate the effects of mutant K-ras in lung cancer. PMID- 21242980 TI - Inhibition of androgen receptor activity by histone deacetylase 4 through receptor SUMOylation. AB - The transcriptional activity of the androgen receptor (AR) is regulated by both ligand binding and post-translational modifications, including acetylation and small ubiquitin-like modifier (SUMO)ylation. Histone deacetylases (HDACs) are known to catalyze the removal of acetyl groups from both histones and non-histone proteins. In this study, we report that HDAC4 binds to and inhibits the activity of the AR. This inhibition was found to depend on the SUMOylation, instead of deacetylation, of the AR. Consistently, HDAC4 increases the level of AR SUMOylation in both whole-cell and cell-free assay systems, raising the possibility that the deacetylase may act as an E3 ligase for AR SUMOylation. Knock down of HDAC4 increases the activity of endogenous AR and androgen induction of prostate-specific antigen expression and prostate cancer cell growth, which is associated with decreased SUMOylation of the receptor. Overall, the studies identify HDAC4 as a positive regulator for AR SUMOylation, revealing a deacetylase-independent mechanism of HDAC action in prostate cancer cells. PMID- 21242984 TI - Ocular loiasis in London 2008-2009: a case series. AB - PURPOSE: To report three cases of Loa loa infestation presenting over the course of 12 months to ophthalmology departments in the South West Thames region around London. METHODS: Case series (three case histories are described) and literature review. RESULTS: All three patients had a history of travel to West Africa. All had worms surgically removed and were referred to an infectious diseases hospital, where these were confirmed as adult Loa loa nematodes and treatment was initiated. CONCLUSIONS: Although ocular loiasis is endemic in West Africa, European ophthalmologists in areas of diverse ethnicity should be aware that it is presenting increasingly frequently, that there is often no history of recent travel abroad, and that loiasis is a differential diagnosis for any 'at-risk' patient with an unexplained foreign body sensation. PMID- 21242985 TI - Anterior chamber angle imaging with optical coherence tomography. AB - The technology of optical coherence tomography (OCT) has evolved rapidly from time-domain to spectral-domain and swept-source OCT over the recent years. OCT has become an important tool for assessment of the anterior chamber angle and detection of angle closure. Improvement in image resolution and scan speed of OCT has facilitated a more detailed and comprehensive analysis of the anterior chamber angle. It is now possible to examine Schwalbe's line and Schlemm's canal along with the scleral spur. High-speed imaging allows evaluation of the angle in 360 degrees . With three-dimensional reconstruction, visualization of the iris profiles and the angle configurations is enhanced. This article summarizes the development and application of OCT for anterior chamber angle measurement, detection of angle closure, and investigation of the pathophysiology of primary angle closure. PMID- 21242986 TI - Lacrimal sac pigmentation due to mascara. PMID- 21242988 TI - A possible genetic answer to a recently reported novel phenotype. PMID- 21242989 TI - Ultrasound biomicroscopy in the management of retinoblastoma. AB - PURPOSE: To determine the role of ultrasound biomicroscopy (UBM) in the management of children affected with retinoblastoma. METHODS: A review of clinical records of children with the diagnosis of retinoblastoma at the Hospital for Sick Children from January 1995 to December 2007, for whom UBM was used to determine the extent of intraocular tumor. Clinical characteristics were compared with UBM. Pathological correlation was performed for enucleated eyes. RESULTS: In total, 101 eyes of 75 patients were included in the final analysis. Only 11 eyes were diagnosed on UBM to have extension of the tumor anterior to the ora serrata, and were enucleated. Histopathological examination confirmed the anterior extension in all the 11 eyes. In total, 50 eyes were enucleated because of various reasons, such as poor visual prognosis (12 eyes), unilateral group D or E (23 eyes), recurrences (8 eyes), and treatment failure (7 eyes). None of those patients were found to have anterior extension of the disease on histopathological examination. UBM did not yield any false negative (0/50) or any false positives (0/11). CONCLUSIONS: The UBM provided a sensitive and reproducible visualization of the anterior retina, ciliary region, and anterior segment allowing a better staging of the advanced disease process. Primary assessment of the true extent of retinoblastoma is critical for the selection of an optimal management approach. PMID- 21242990 TI - Perceived threat predicts the neural sequelae of combat stress. AB - Exposure to severe stressors increases the risk for psychiatric disorders in vulnerable individuals, but can lead to positive outcomes for others. However, it remains unknown how severe stress affects neural functioning in humans and what factors mediate individual differences in the neural sequelae of stress. The amygdala is a key brain region involved in threat detection and fear regulation, and previous animal studies have suggested that stress sensitizes amygdala responsivity and reduces its regulation by the prefrontal cortex. In this study, we used a prospective design to investigate the consequences of severe stress in soldiers before and after deployment to a combat zone. We found that combat stress increased amygdala and insula reactivity to biologically salient stimuli across the group of combat-exposed individuals. In contrast, its influence on amygdala coupling with the insula and dorsal anterior cingulate cortex was dependent on perceived threat, rather than actual exposure, suggesting that threat appraisal affects interoceptive awareness and amygdala regulation. Our results demonstrate that combat stress has sustained consequences on neural responsivity, and suggest a key role for the appraisal of threat on an amygdala centered neural network in the aftermath of severe stress. PMID- 21242991 TI - Emotional memory impairments in a genetic rat model of depression: involvement of 5-HT/MEK/Arc signaling in restoration. AB - Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT(1A) receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT(1A)R/MEK/Arc or stimulation of 5-HT4R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies. PMID- 21242993 TI - Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase. AB - Human multipotent mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential, support hematopoiesis, and inhibit proliferation and effector function of various immune cells. On the basis of these properties, MSC are currently under clinical investigation in a range of therapeutic applications including tissue repair and immune-mediated disorders such as graft-versus-host disease refractory to pharmacological immunosuppression. Although initial clinical results appear promising, there are significant concerns that application of MSC might inadvertently suppress antimicrobial immunity with an increased risk of infection. We demonstrate here that on stimulation with inflammatory cytokines human MSC exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses. Moreover, we identify the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as the underlying molecular mechanism. We furthermore delineate significant differences between human and murine MSC in that murine MSC fail to express IDO and inhibit bacterial growth. Conversely, only murine but not human MSC express inducible nitric oxide synthase on cytokine stimulation thus challenging the validity of murine in vivo models for the preclinical evaluation of human MSC. Collectively, our data identify human MSC as a cellular immunosuppressant that concurrently exhibits potent antimicrobial effector function thus encouraging their further evaluation in clinical trials. PMID- 21242992 TI - Resting leukocyte telomerase activity is elevated in major depression and predicts treatment response. AB - Telomeres are DNA-protein complexes that cap linear DNA strands, protecting DNA from damage. When telomeres critically shorten, cells become susceptible to senescence and apoptosis. Telomerase, a cellular ribonucleoprotein enzyme, rebuilds the length of telomeres and promotes cellular viability. Leukocyte telomeres are reportedly shortened in major depression, but telomerase activity in depression has not been previously reported. Further, there are no published reports of the effects of antidepressants on telomerase activity or on the relationship between telomerase activity and antidepressant response. Peripheral blood mononuclear cell (PBMC) telomerase activity was assessed in 20 medication free depressed individuals and 18 controls. In total, 16 of the depressed individuals were then treated with sertraline in an open-label manner for 8 weeks, and PBMC telomerase activity was reassessed in 15 of these individuals after treatment. Pre- and post-treatment symptom severity was rated with the Hamilton Depression Rating Scale. All analyses were corrected for age and sex. Pre-treatment telomerase activity was significantly elevated in the depressed individuals compared with the controls (P=0.007) and was directly correlated with depression ratings (P<0.05) across all subjects. In the depressed group, individuals with relatively lower pre-treatment telomerase activity and with relatively greater increase in telomerase activity during treatment, showed superior antidepressant responses (P<0.05 and P<0.005, respectively). This is the first report characterizing telomerase activity in depressed individuals. PBMC telomerase activity might reflect a novel aspect of depressive pathophysiology and might represent a novel biomarker of antidepressant responsiveness. PMID- 21242995 TI - Non-malignant B cells and chronic lymphocytic leukemia cells induce a pro survival phenotype in CD14+ cells from peripheral blood. PMID- 21242994 TI - LBH589, a deacetylase inhibitor, induces apoptosis in adult T-cell leukemia/lymphoma cells via activation of a novel RAIDD-caspase-2 pathway. AB - Adult T-cell leukemia/lymphoma (ATLL), an aggressive neoplasm etiologically associated with human T-lymphotropic virus type-1 (HTLV-1), is resistant to treatment. In this study, we examined the effects of a new inhibitor of deacetylase enzymes, LBH589, on ATLL cells. LBH589 effectively induced apoptosis in ATLL-related cell lines and primary ATLL cells and reduced the size of tumors inoculated in SCID mice. Analyses, including with a DNA microarray, revealed that neither death receptors nor p53 pathways contributed to the apoptosis. Instead, LBH589 activated an intrinsic pathway through the activation of caspase-2. Furthermore, small interfering RNA experiments targeting caspase-2, caspase-9, RAIDD, p53-induced protein with a death domain (PIDD) and RIPK1 (RIP) indicated that activation of RAIDD is crucial and an event initiating this pathway. In addition, LBH589 caused a marked decrease in levels of factors involved in ATLL cell proliferation and invasion such as CCR4, IL-2R and HTLV-1 HBZ-SI, a spliced form of the HTLV-1 basic zipper factor HBZ. In conclusion, we showed that LBH589 is a strong inducer of apoptosis in ATLL cells and uncovered a novel apoptotic pathway initiated by activation of RAIDD. PMID- 21242996 TI - The frequency and prognostic impact of dic(9;20)(p13.2;q11.2) in childhood B-cell precursor acute lymphoblastic leukemia: results from the NOPHO ALL-2000 trial. AB - The dic(9;20)(p13.2;q11.2) is reported to be present in ~2% of childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL). However, it easily escapes detection by G-banding analysis and its true prevalence is hence unknown. We performed interphase fluorescence in situ hybridization analyses-in a three-step manner-using probes for: (i) CDKN2A at 9p21, (ii) 20p and 20q subtelomeres and (iii) cen9 and cen20. Out of 1033 BCP ALLs diagnosed from 2001 to 2006, 533 were analyzed; 16% (84/533) displayed 9p21 deletions, of which 30% (25/84) had dic(9;20). Thus, dic(9;20)-positivity was found in 4.7% (25/533), making it the third most common genetic subgroup after high hyperdiploidy and t(12;21)(p13;q22). The dic(9;20) was associated with a female predominance and an age peak at 3 years; 18/25 (72%) were allocated to non-standard risk treatment at diagnosis. Including cases detected by G-banding alone, 29 dic(9;20)-positive cases were treated according to the NOPHO ALL 2000 protocol. Relapses occurred in 24% (7/29) resulting in a 5-year event-free survival of 0.69, which was significantly worse than for t(12;21) (0.87; P=0.002) and high hyperdiploidy (0.82; P=0.04). We conclude that dic(9;20) is twice as common as previously surmised, with many cases going undetected by G-banding analysis, and that dic(9;20) should be considered a non-standard risk abnormality. PMID- 21242997 TI - Measuring the effect of incremental angles of wheelchair tilt on interface pressure among individuals with spinal cord injury. AB - STUDY DESIGN: This study was a repeated measures study. OBJECTIVES: The objective was to systematically measure the relative reduction in interface pressure (IP) at the ischial tuberosities (IT) and sacrum through 10 degrees increments of tilt in a manual wheelchair among individuals with motor complete spinal cord injury (SCI). SETTING: This study was carried out in Manitoba, Canada. METHODS: A total of 18 adults with ASIA A or B level of injury were recruited through an out patient SCI clinic. Using a standardized protocol, participants were tilted in 10 degrees increments between 0 degrees and 50 degrees , and IP readings were obtained at the IT and sacrum using pressure mapping technology. Relative pressure reduction from baseline was calculated and compared between tilt angles. RESULTS: Tilt angle had a highly significant effect on pressure reduction at the IT (P=0.000) and the cosine relationship between these variables was expressed as quadratic. Reduction in sacral pressure did not occur until 30 degrees tilt, with increased loading at smaller tilt angles. Pressure reduction at the IT and sacrum was not significantly different for tetraplegic and paraplegic participants. CONCLUSION: Small tilt angles are more suitable for postural control than pressure management. A minimum tilt of 30 degrees is required to initiate unloading the sacrum and to achieve a clinically important reduction in pressure at the IT. Larger tilt angles resulted in more substantial pressure reduction than previously reported. Tilt-in-space appears to have similar benefits for individuals with paraplegia and tetraplegia. PMID- 21242998 TI - Exercise therapy and recovery after SCI: evidence that shows early intervention improves recovery of function. AB - STUDY DESIGN: This was designed as an experimental study. OBJECTIVES: Locomotor training is one of the most effective strategies currently available for facilitating recovery of function after an incomplete spinal cord injury (SCI). However, there is still controversy regarding the timing of treatment initiation for maximal recovery benefits. To address this issue, the present study compares the effects of exercise initiated in the acute and secondary phase of SCI. SETTING: Texas A&M University, College Station, TX, USA. METHODS: Rats received a moderate spinal contusion injury and began an exercise program 1 (D1-EX) or 8 days (D8-EX) later. They were individually placed into transparent exercise balls for 60 min per day, for 14 consecutive days. Control rats were placed in exercise balls that were rendered immobile. Motor and sensory recovery was assessed for 28 days after injury. RESULTS: The D1-EX rats recovered significantly more locomotor function (BBB scale) than controls and D8-EX rats. Moreover, analyses revealed that rats in the D8-EX group had significantly lower tactile reactivity thresholds compared with control and D1-EX rats, and symptoms of allodynia were not reversed by exercise. Rats in the D8-EX group also had significantly larger areas of damage across spinal sections caudal to the injury center compared with the D1-EX group. CONCLUSION: These results indicate that implementing an exercise regimen in the acute phase of SCI maximizes the potential for recovery of function. PMID- 21242999 TI - Predictive factors of long-term mortality of persons with tetraplegic spinal cord injury: an 11-year French prospective study. AB - STUDY DESIGN: Longitudinal study with mortality follow-up. OBJECTIVE: Identify predictive factors for long-term mortality following tetraplegic spinal cord injury (TSCI). SETTING: The Tetrafigap survey is a multi-centre epidemiological survey on the long-term outcome of persons with TSCI, initiated in France in 1995 with the participation of 35 rehabilitation centres. METHODS: The mortality follow-up involves 1241 persons with TSCI who were admitted to one of the study rehabilitation units at the initial phase and who completed the initial self administered questionnaire. There were 226 observed deaths (18.2%) during an 11 year period. Logistic regression methods, with estimates of odds ratios (ORs), incorporating clinical, functional and social participation data were used to determine the factors related to mortality. This was followed by multivariate analysis to determine the best predictive factors for long-term mortality. RESULTS: Risk of death increases significantly with age but not with the time elapsed since the accident. The risk of death is higher in men. Interestingly, clinical variables are not the best predictors of long-term mortality. Instead, the significant effect of poor social participation (being single, infrequent contact with friends) and functional limitations (full assistance required with dressing or eating) persists after adjustment for other variables. CONCLUSION: Once the medical situation becomes more stable, factors related to the long-term mortality of persons with TSCI are not exactly identical to those observed in the short acute-phase and during the first year after the accident. Social participation has a significant effect on mortality. PMID- 21243000 TI - Therapeutic effects of detrusor botulinum toxin A injection on neurogenic detrusor overactivity in patients with different levels of spinal cord injury and types of detrusor sphincter dyssynergia. AB - STUDY DESIGN: The study was designed as a single-arm clinical trial. OBJECTIVES: To investigate the therapeutic effects of detrusor botulinum toxin A (BoNT-A) treatment in patients with different levels of spinal cord injury (SCI) and types of detrusor sphincter dyssynergia (DSD). SETTING: Patients with chronic suprasacral SCI and neurogenic detrusor overactivity (NDO) were treated with 200 U BoNT-A detrusor injection in a tertiary university hospital in Taiwan. METHODS: Outcome assessment of urodynamic parameters and therapeutic satisfaction were performed at 3 and 6 months among patients with different demographics, SCI levels and types of DSD. The treatment outcomes were assessed by changes in Urogenital Distress Inventory 6-item short form (UDI-6), quality of life (QoL) index and detrusor pressure at maximum flow rate (Pdet.Qmax). RESULTS: A total of 38 patients with a mean age of 40.1+/-12.4 years and median duration of SCI of 10.3 years were enrolled. Satisfactory response was reported in 23 (60%) patients. Significant improvements in the UDI-6 and QoL were reported and significant increases of cystometric bladder capacity and post-void residual were noted in overall patients after treatment. Patients with different clinical demographics and urodynamic parameters had similar treatment outcomes and UDI-6 scores. In 11 patients receiving repeat injections of 300 U of BoNT-A after failure of a previous 200 U injection, the treatment outcomes were not significantly different, except that the PdetQmax at 6 months were higher in the group that received 200 U of BoNT-A. CONCLUSION: Patients with different SCI levels or DSD types had similar treatment outcomes after detrusor 200 U BoNT-A injections for NDO. PMID- 21243001 TI - The effect of polytrauma as a possible confounder in the outcome of monotraumatic vs polytraumatic paraplegic patients: a clinical cohort study. AB - STUDY DESIGN: Clinical cohort study. OBJECTIVE: To evaluate if the impact of the severity of the trauma as a possible confounding factor influences the neurological and functional recovery in paraplegia during the course of a 6-month follow-up period after injury. SETTING: Spinal Cord Injury Center, Heidelberg University Hospital, Germany. METHODS: A retrospective monocentric analysis, from 2002 to 2008, of the Heidelberg European Multicenter Study about spinal cord injury database was performed. We included 31 paraplegic patients (neurological level T1-T12) who were assigned either to a monotrauma (polytraumaschluessel (PTS) 1) or to a polytrauma (PTS>=2) group. The American Spinal Injury Association Impairment Scale, lower extremity motor score, pin prick, light touch and the spinal cord independence measure (SCIM) were obtained at five distinct time points after trauma. Data were analyzed using Mann-Whitney U-test (alpha<0.05). RESULTS: The changes in lower extremity motor score, pin prick and light touch showed no significant differences in both groups over the whole evaluation period. Polytraumatic paraplegics showed a significantly delayed increase of SCIM between 2 and 6 weeks compared with monotraumatic patients, followed by a quantitative increase in the subitems bladder management, bowel management, use of toilet and prevention of pressure sores between 3 and 6 months (P=0.031). The mean length of primary rehabilitation in the polytrauma group was 5.5 vs 3.6 months in monotrauma. CONCLUSIONS: The prognosis of polytraumatic paraplegics in terms of neurological recovery is not inferior to those with monotrauma. Multiple-injured patients need a prolonged hospital stay to reach the functional outcome of monotraumatic patients. PMID- 21243002 TI - Conservative treatment with hyperbaric oxygen therapy for cervical spondylotic amyotrophy. AB - STUDY DESIGN: Small case series of patients with cervical spondylotic amyotrophy (CSA) managed by conservative treatment with hyperbaric oxygen (HBO) therapy. OBJECTIVE: To study the effects of conservative treatment with HBO therapy of CSA patients. SETTING: Department of Orthopaedic Surgery, Imakiire General Hospital, Kagoshima, Japan. METHODS: This study included 10 patients with CSA who underwent rehabilitation, including cervical traction and muscle exercise, for some period of time but did not respond well to it, and were then managed by additional HBO therapy for rehabilitation. Information was obtained on the duration of symptoms and strength of the most atrophic muscle, intramedullary high-signal-intensity changes on T2-weighted magnetic resonance imaging, presence of 'snake-eyes' appearance and the number of stenotic canal levels. RESULTS: The mean duration of symptoms before HBO treatment was 3.1 months. The axial T2-weighted magnetic resonance images of all 10 patients showed a 'snake-eyes' appearance. The mean number of stenotic canal levels was 0.3. There was marked improvement on manual muscle testing from a mean of 1.9 pretreatment to a mean of 4.4 at the last follow-up after HBO therapy. The outcomes of all 10 patients, whose results were classified as excellent or good, were considered clinically satisfactory. CONCLUSION: To our knowledge, conservative treatment with HBO therapy for CSA patients has not previously been described. It appears that HBO therapy might improve ischemic injury of the anterior horns in CSA patients with short duration of symptoms. PMID- 21243003 TI - Procalcitonin as an early predictor of postoperative infectious complications in patients with acute traumatic spinal cord injury. AB - STUDY DESIGN: Prospective, nonrandomized, observational cohort study. OBJECTIVES: To analyze procalcitonin (PCT) level in acute traumatic spinal cord injury patients with and without postoperative infectious complications, and to determine whether PCT is a prognostic parameter of infectious complications in the early postoperative period compared with other inflammatory markers. SETTING: Spine center of Chongqing, China; Trauma center of Chinese People's Liberation Army, China. METHODS: A total of 339 consecutive patients with acute spinal cord injury undergone surgery were evaluated. All patients underwent measurement of leukocyte count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and serum PCT preoperatively and 24-48 h postoperatively. RESULTS: In all, 26 (7.7%) of 339 participants experienced postoperative infectious complication. Patients with infection exhibited significantly higher PCT and CRP levels compared with noninfection (both P<0.01). Multivariate logistic regression analysis showed that PCT and CRP levels were independent predicators for postoperative infection. The area under the receiver operating characteristics curve of PCT and CRP were 0.82 (95% confidence intervals (CI) 0.74-0.91) and 0.68 (95%CI, 0.57-0.78), respectively. A PCT cutoff of 0.1 ng ml(-1) had a reasonable sensitivity of 92% to exclude an infection and antibiotics can be initially withheld. However, in patients with PCT level above 0.5 ng ml(-1), a rapid initiation of antibiotics may be warranted. CONCLUSIONS: Serum PCT is a more reliable biologic marker for the early prediction of postoperative infectious complications in patients with acute traumatic spinal cord injury compared with CRP. PCT can early identify postoperative infections for establishing effective antibiotic therapy. PMID- 21243004 TI - The Eph/ephrinB signal balance determines the pattern of T-cell maturation in the thymus. AB - In order to carry out an in-depth study of the roles of EphB receptors in T-cell development and to determine the specific relevance of forward and reverse signals in the process, we established severe combined immunodeficient (SCID) mice chimeras with wild-type (WT) or EphB-deficient bone marrow cells. The obtained results demonstrate that EphB2 contributes more significantly than EphB3 in the control of CD4(-)CD8(-) (DN)-CD4(+)CD8(+) (DP) progression, and that reverse signals generated in SCID mice receiving EphB2LacZ precursors, which express the EphB2 extracellular domain, partially rescue the blockade of DN cell maturation observed in EphB2-null chimeras. In addition, increased apoptotic DP thymocytes occurring in EphB2 and/or EphB3 SCID chimeras also contribute to the reduced proportions of DP cells. However, EphB2LacZ chimeras do not show any changes in the proportions of apoptotic DP cells, thus suggesting that there is a role for ephrinB reverse signaling in thymocyte survival. The maturation of DP to CD4(+)CD8(-) or CD4(-)CD8(+) seems to need EphB2 forward signaling and EphB3; a fact that was confirmed in reaggregates formed with either EphB2- or EphB3 deficient DP thymocytes and WT thymic epithelial cells (TECs). The DP thymocyte TEC conjugate formation was also affected by the absence of EphB receptors. Finally, EphB-deficient SCID chimeras show profoundly altered thymic epithelial organization that confirms a significant role for EphB2 and EphB3 receptors in the thymocyte-TEC crosstalk. PMID- 21243005 TI - Neonatal exposure to UVR alters skin immune system development, and suppresses immunity in adulthood. AB - Neonates have a developing immune response, with a predisposition towards induction of tolerance. As the immune system develops, immunity rather than tolerance is induced, with this development of immunity occurring in response to external factors such as the environment. As ultraviolet radiation (UVR) suppresses immunity, it is likely that the effect of UVR on the neonatal immune system would be augmentation of the suppressive response. In support, childhood exposure to UVR has been linked with an increased incidence of melanoma; consistent with an increase in suppression. To address this, phenotypic and functional immune system studies were undertaken at 8 weeks after one single exposure of solar-simulated UVR to mice, when mice had reached adulthood. Subtle changes were observed in cell populations resident in the skin-draining lymph nodes (LNs) and there also appeared to be a subtle, but not statistically significant, increase in the production of interleukin-10 and interferon-gamma. Importantly, these changes also corresponded with significant suppression of the contact hypersensitivity response in irradiated mice compared with their control counterparts. This suppression was apparent when antigen sensitisation occurred during the neonatal or adult period, and thus did not appear to be analogous to UVR-induced suppression in adults. Although the percentage of T regulatory cells was increased in the skin-draining LNs, they were induced in a different manner to those induced following adult UVR exposure, with no increase in function on a per-cell basis. It therefore appears that one single neonatal exposure to UVR alters development of the immune system, leading to long-term implications for induction of immunity. PMID- 21243006 TI - Differential effect of the rs4149056 variant in SLCO1B1 on myopathy associated with simvastatin and atorvastatin. AB - Statins reduce cardiovascular morbidity and mortality in appropriately selected patients. However, statin-associated myopathy is a significant risk associated with these agents. Recently, variation in the SLCO1B1 gene was reported to predict simvastatin-associated myopathy. The aim of this study was to replicate association of the rs4149056 variant in SLCO1B1 with severe statin-associated myopathy in a cohort of patients using a variety of statin medications and to investigate the association with specific statin types. We identified 25 cases of severe statin-associated myopathy and 84 controls matched for age, gender, statin type and dose. The rs4149056 variant in SLCO1B1 was not significantly associated with myopathy in this group as a whole. However, when subjects were stratified by statin type, the SLCO1B1 rs4149056 genotype was significantly associated with myopathy in patients who received simvastatin, but not in patients who received atorvastatin. Our findings provide further support for a role for SLCO1B1 genotype in simvastatin-associated myopathy, and suggest that this association may be stronger for simvastatin compared with atorvastatin. PMID- 21243007 TI - Prostate cancer screening and informed decision-making: provider and patient perspectives. AB - The objective was to determine the extent of informed decision making for prostate cancer screening in a defined population. A state-wide population based survey of men aged 50 and above (Behavioral Risk Factor Surveillance System, 2004, Washington state) and a simple random sample of primary care physicians, were conducted in the same geographic area. We examined prostate cancer screening rates among the men (defined as either PSA or digital rectal examination within the past year) and prostate cancer screening practices among the physicians. Screening rates were 56% at ages 50-64, 68% at ages 65-79 and 64% among men age 80 and older. Adjusted analyses indicated that age, income, marital status, possessing health insurance and a personal health care provider, and talking with a provider about prostate cancer screening tests were all positively associated with screening status. In the physician survey, most physicians recommend screening to their average-risk male patients. Three-fourths (74%) of physicians discussed benefits and risks of PSA testing with their patients; but few used educational tools. Only 35% discussed the side effects of prostate cancer treatment with their patients. The rates of screening reported by men were relatively high, given that current recommendations promote informed decision making rather than universal screening. The majority of physicians recommend prostate cancer screening to their patients, with few decision-making tools used. All relevant information may not be provided in the discussion. These results point to the need for increasing informed decision making about prostate cancer screening. PMID- 21243008 TI - Glutathione S-transferase gene polymorphisms (GSTM1, GSTT1, GSTP1) and prostate cancer: a case-control study in Tehran, Iran. AB - We evaluated the relationship between polymorphisms in the glutathione S transferases (GSTs) GSTM1, GSTT1 and GSTP1 genes and prostate cancer (PCa). PCR restriction fragment length polymorphism assay was used to genotype the GSTM1, GSTT1, and GSTP1 polymorphisms in 168 PCa cases and 336 frequency matched controls. The GSTM1 null, and GSTT1 null genotypes were associated with an increased odds ratio (OR) for PCa (OR=3.28, 95% confidence interval (CI): 2.47 5.64; P=0.005, and OR=3.21, 95% CI: 2.52-5.64; P=0.005, respectively) (Pcorrected=0.0062). The frequency of GSTP1 Val/Val genotype was 14.3% in cases compared with 2.4% in controls, this polymorphism thus being associated with a significantly increased risk of PCa (OR=3.72, 95% CI: 1.67-5.65; P=0.002). The risk associated with the concurrent absence of both of the genes (OR=4.8, 95% CI: 2.34-6.78) was greater than the product of risk in men with either null (OR=1.52, 95% CI: 0.82-2.31) genotype combinations (P=0.001, Pcorrected=0.0045). The combination of GSTP1 Ile/Val or Val/Val polymorphism with the GSTT1 null and GSTM1 null type resulted in an OR of 6.21 (95% CI: 4.83-16.87) (P=0.0001, Pcorrected=0.0062). A higher frequency of the GSTM1 null genotype and GSTT1 null genotype was observed in patients with Gleason score >7, with an OR for GSTM1 null 4.67 (95% CI: 3.64-7.62; P=0.001) and with an OR for GSTT1 null 3.62 (95% CI: 2.31-5.74; P=0.004). The results obtained demonstrated that simultaneous presence of three potentially risk alleles (GSTM1 null, GSTT1 null and GSTP1 Val) lead to a significant OR increase for PCa. PMID- 21243010 TI - Surgery for asymptomatic degenerative aortic and mitral valve disease. AB - Degenerative valvular heart disease, the most common form of valve disease in the Western world, can lead to aortic stenosis (AS) or mitral regurgitation (MR). In current guidelines for the management of patients with degenerative valvular disease, surgical intervention is recommended at the onset of symptoms or in the presence of left ventricular systolic impairment. Whether surgery is appropriate for asymptomatic patients remains a controversial issue. We argue the case for early pre-emptive intervention in selected, asymptomatic individuals with AS or MR, drawing on contemporary perioperative data, predictors of disease progression, and studies of the natural history of degenerative valvular heart disease. PMID- 21243009 TI - Novel HDL-directed pharmacotherapeutic strategies. AB - The burden of atherothrombotic cardiovascular disease remains high despite currently available optimum medical therapy. To address this substantial residual risk, the development of novel therapies that attempt to harness the atheroprotective functions of HDL is a major goal. These functions include the critical role of HDL in reverse cholesterol transport, and its anti-inflammatory, antithrombotic, and antioxidant activities. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights have fueled the development of HDL-targeted drugs, which can be classified among four different therapeutic approaches: directly augmenting apolipoprotein A-I (apo A-I) levels, such as with apo A-I infusions and upregulators of endogenous apo A-I production; indirectly augmenting apo A-I and HDL-cholesterol levels, such as through inhibition of cholesteryl ester transfer protein or endothelial lipase, or through activation of the high-affinity niacin receptor GPR109A; mimicking the functionality of apo A-I with apo A-I mimetic peptides; and enhancing steps in the reverse cholesterol transport pathway, such as via activation of the liver X receptor or of lecithin-cholesterol acyltransferase. PMID- 21243011 TI - From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer. AB - Adult stem cells of the mammary gland (MaSCs) are a highly dynamic population of cells that are responsible for the generation of the gland during puberty and its expansion during pregnancy. In recent years significant advances have been made in understanding how these cells are regulated during these developmentally important processes both in humans and in mice. Understanding how MaSCs are regulated is becoming a particularly important area of research, given that they may be particularly susceptible targets for transformation in breast cancer. Here, we summarize the identification of MaSCs, how they are regulated and the evidence for their serving as the origins of breast cancer. In particular, we focus on how changes in MaSC populations may explain both the increased risk of developing aggressive ER/PR(-) breast cancer shortly after pregnancy and the long term decreased risk of developing ER/PR(+) tumors. PMID- 21243013 TI - Efficient human iPS cell derivation by a non-integrating plasmid from blood cells with unique epigenetic and gene expression signatures. AB - To identify accessible and permissive human cell types for efficient derivation of induced pluripotent stem cells (iPSCs), we investigated epigenetic and gene expression signatures of multiple postnatal cell types such as fibroblasts and blood cells. Our analysis suggested that newborn cord blood (CB) and adult peripheral blood (PB) mononuclear cells (MNCs) display unique signatures that are closer to iPSCs and human embryonic stem cells (ESCs) than age-matched fibroblasts to iPSCs/ESCs, thus making blood MNCs an attractive cell choice for the generation of integration-free iPSCs. Using an improved EBNA1/OriP plasmid expressing 5 reprogramming factors, we demonstrated highly efficient reprogramming of briefly cultured blood MNCs. Within 14 days of one-time transfection by one plasmid, up to 1000 iPSC-like colonies per 2 million transfected CB MNCs were generated. The efficiency of deriving iPSCs from adult PB MNCs was approximately 50-fold lower, but could be enhanced by inclusion of a second EBNA1/OriP plasmid for transient expression of additional genes such as SV40 T antigen. The duration of obtaining bona fide iPSC colonies from adult PB MNCs was reduced to half (~14 days) as compared to adult fibroblastic cells (28 30 days). More than 9 human iPSC lines derived from PB or CB blood cells are extensively characterized, including those from PB MNCs of an adult patient with sickle cell disease. They lack V(D)J DNA rearrangements and vector DNA after expansion for 10-12 passages. This facile method of generating integration-free human iPSCs from blood MNCs will accelerate their use in both research and future clinical applications. PMID- 21243012 TI - NF-kappaB in immunobiology. AB - NF-kappaB was first discovered and characterized 25 years ago as a key regulator of inducible gene expression in the immune system. Thus, it is not surprising that the clearest biological role of NF-kappaB is in the development and function of the immune system. Both innate and adaptive immune responses as well as the development and maintenance of the cells and tissues that comprise the immune system are, at multiple steps, under the control of the NF-kappaB family of transcription factors. Although this is a well-studied area of NF-kappaB research, new and significant findings continue to accumulate. This review will focus on these areas of recent progress while also providing a broad overview of the roles of NF-kappaB in mammalian immunobiology. PMID- 21243014 TI - Cancer: do aspirin and other NSAIDs protect against colorectal cancer? PMID- 21243015 TI - Neuroplasticity in the context of motor rehabilitation after stroke. AB - Approximately one-third of patients with stroke exhibit persistent disability after the initial cerebrovascular episode, with motor impairments accounting for most poststroke disability. Exercise and training have long been used to restore motor function after stroke. Better training strategies and therapies to enhance the effects of these rehabilitative protocols are currently being developed for poststroke disability. The advancement of our understanding of the neuroplastic changes associated with poststroke motor impairment and the innate mechanisms of repair is crucial to this endeavor. Pharmaceutical, biological and electrophysiological treatments that augment neuroplasticity are being explored to further extend the boundaries of poststroke rehabilitation. Potential motor rehabilitation therapies, such as stem cell therapy, exogenous tissue engineering and brain-computer interface technologies, could be integral in helping patients with stroke regain motor control. As the methods for providing motor rehabilitation change, the primary goals of poststroke rehabilitation will be driven by the activity and quality of life needs of individual patients. This Review aims to provide a focused overview of neuroplasticity associated with poststroke motor impairment, and the latest experimental interventions being developed to manipulate neuroplasticity to enhance motor rehabilitation. PMID- 21243016 TI - Advances in MRI for 'cryptogenic' epilepsies. AB - Nearly one-third of patients with focal epilepsy experience disabling seizures that are refractory to pharmacotherapy. Drug-resistant focal epilepsy is, however, potentially curable by surgery. Although lesions associated with the epileptic focus can often be accurately detected by MRI, in many patients conventional imaging based on visual evaluation is unable to pinpoint the surgical target. Patients with so-called cryptogenic epilepsy represent one of the greatest clinical challenges in many tertiary epilepsy centers. In recent years, it has become increasingly clear that epilepsies that are considered cryptogenic are not necessarily nonlesional, the primary histopathological substrate being subtle cortical dysplasia. This Review considers the application of new advances in brain imaging, such as MRI morphometry, computational modeling and diffusion tensor imaging. By revealing dysplastic lesions that previously eluded visual assessments, quantitative structural MRI methods such as these have clearly demonstrated an increased diagnostic yield of epileptic lesions, and have provided successful surgical options to an increasing number of patients with 'cryptogenic' epilepsy. PMID- 21243017 TI - Contemporary concepts in the evaluation and management of male infertility. AB - Infertility in men is a common condition. At the core of the medical evaluation of the male partner in a couple who are unable to conceive is the history and physical examination. Special attention should be directed to the patient's developmental history and any use of testosterone products. The physical examination focuses on the genitals, and includes assessments of the size and consistency of the testicles, epididymis, vas deferens, and presence of varicoceles. Although many sophisticated tests are available, semen analysis is still the most important diagnostic tool used to assess fertility, and includes parameters such as sperm count, motility and viability. Treatment of male factor infertility can involve targeted agents, in the case of specific conditions such as hypogonadotropic hypogonadism, or it can be empirical-using medical therapy or assisted conception techniques-for patients in whom no underlying cause has been identified. Although an all-encompassing treatment for male factor infertility has not yet been developed, the field offers many promising avenues of research. PMID- 21243018 TI - The DABBEC phenotyping system: towards a mechanistic understanding of CP/CPPS. AB - There is an urgent need to elucidate the mechanistic basis of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), as the current methods of symptom-based diagnosis and treatment have failed. Here, we propose a phenotyping system that bridges the gap between the symptom-based diagnosis and treatment of the present and the mechanistic approach of the future. Our phenotyping system uses the Chronic Prostatitis Collaborative Research Network (CPCRN)-recommended algorithm in combination with the NIH Chronic Prostatitis Symptom Index (NIH CPSI) as a basis for diagnosis, while incorporating novel domains for quantitative assessment and stratification of CP/CPPS patients. We believe this novel system will serve to help advance our understanding of the roles of the patient's genome and proteome in the etiology of CP/CPPS. We predict that, as we begin to understand the mechanistic basis of CP/CPPS pathology and progression, we will develop specific treatments that will aim to cure the disease, rather than merely quell the symptoms. PMID- 21243020 TI - Prostate cancer: treatment triggers for patients on active surveillance. PMID- 21243019 TI - Blockade of testicular and adrenal androgens in prostate cancer treatment. AB - Prostate cancer is the most hormone sensitive of all cancers. However, any hormonal therapeutic strategy must take into account the fact that two almost equivalent sources of androgens act in the prostate, namely testosterone of testicular origin, and the locally produced androgens testosterone and dihydrotestosterone (DHT) derived from dehydroepiandrosterone of adrenal origin. Combined androgen blockade--medical or surgical castration plus a pure antiandrogen--would, therefore, be the logical first-line treatment for prostate cancer, although castration or an antiandrogen alone is still chosen in the majority of cases. Although long-term control, or even cure, is possible when combined androgen blockade is used when the tumor is localized, resistance to treatment invariably develops in patients when start of treatment is delayed until the disease has become metastatic. This observation can be explained either by elevated levels of the androgen receptor, which can increase the response to low levels of androgens and also modify the response to antiandrogens; or by local biosynthesis of androgens. Research to identify new and more potent antiandrogens, as well as blockers of peripheral and adrenal androgen biosynthesis--such as abiraterone--could be of great importance. PMID- 21243021 TI - Infections with the 2009 H1N1 influenza virus among hematopoietic SCT recipients: a single center experience. AB - We retrospectively reviewed medical records of 39 hematopoietic SCT (HSCT) recipients who presented at our hospital between 1 October 2009 and 31 January 2010 with the 2009 H1N1 influenza infection. The median age at presentation was 13.8 years (range: 3.3-56.9), infections developed at a median of 585 days (range: 0-2316) post transplant, the majority (n=27, 69%) occurred in allogeneic HSCT recipients, 12 (31%) patients were on immunosuppressive therapy and 12 (31%) had GVHD. Lower airway disease was present in 8 patients (21%). In total, 15 patients (39%) were hospitalized with a median duration of 4.5 days (range: 3-27 days) and 3 (8%) required mechanical ventilation; 2 of whom died. PMID- 21243022 TI - Immune recovery after autologous PBSC transplantation without in vitro graft manipulation for refractory systemic lupus erythematosus. AB - Autologous hematopoietic SCT (ASCT) has been investigated as salvage therapy for refractory systemic lupus erythematosus (SLE). Although immune recovery after ASCT with in vitro purging of lymphocytes has been extensively studied, little information is available about immune recovery after ASCT without in vitro purging. Therefore, we analyzed the immune recovery of a patient who successfully underwent ASCT without in vitro purging for refractory SLE. In addition to the numbers of PBL subsets, T-cell receptor rearrangement excision circles (TRECs) and the T-cell receptor repertoire diversity of both CD4+ and CD8+ T cells were sequentially analyzed. All SLE-related symptoms disappeared within 3 months after ASCT and the serum anti-dsDNA Ab became undetectable. The number of CD4+CD45RO+ memory T cells remained lower than that in healthy adult controls, but the number of CD4+CD45RA+ naive T cells showed a rapid increase after ASCT. TRECs of both CD4+ and CD8+ T cells were strongly suppressed before ASCT, but consistently increased after ASCT. The T-cell receptor repertoire of CD8+ T cells was skewed before ASCT, but the diversity recovered after ASCT. ASCT with the reinfusion of a large number of autologous T cells did not impair the recovery of naive T cells or resetting of the immune system. PMID- 21243023 TI - Successful hematopoietic SCT from non-identical twins to two sisters with beta thalassemia major by using preimplantation genetic diagnosis and HLA typing. PMID- 21243024 TI - Antiviral treatment of influenza A (H1N1-09) guided by molecular resistance testing in aplasia after allo-SCT. PMID- 21243025 TI - Low-dose trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT. PMID- 21243026 TI - Vitamin D status among long-term survivors of hematopoietic cell transplantation. AB - Little is known about serum vitamin D levels following hematopoietic cell transplantation (HCT). Patients are instructed to avoid sun exposure because of an increased risk of skin cancers. Altered gastrointestinal absorptive capacity as a result of GVHD, bile acid or pancreatic enzyme insufficiency or bacterial overgrowth may lead to difficulty in absorbing the fat-soluble vitamin D. This study was undertaken to determine the prevalence of serum 25-hydroxyvitamin D (25(OH)D) deficiency, and factors associated with 25(OH)D deficiency, among children and adults who were at least 1 year following HCT. A total of 95 participants (54 males and 41 females) completed a questionnaire on usual diet and lifestyle, and provided a blood sample for 25(OH)D determinations between November 2008 and July 2009. The majority of participants had serum 25(OH)D levels >=75 nmol/L (n=62, 65%), 23 had insufficient levels (50-75 nmol/L) and 10 participants were deficient (<50 nmol/L). The majority of participants reported regular use of vitamin D supplements (n=58, 61%). Prednisone use was significantly inversely associated with serum 25(OH)D concentrations. Total vitamin D intake was the strongest single predictor of 25(OH)D concentrations. These findings suggest that 400-600 IU vitamin D per day appears to be required to achieve optimal serum 25(OH)D concentrations following HCT. PMID- 21243028 TI - Inherent problems of comparing second and third remission in patients with acute lymphoblastic leukemia. PMID- 21243027 TI - High-dose chemotherapy and auto-SCT in elderly patients with Hodgkin's lymphoma. AB - Our purpose was to assess efficacy and toxicity of high-dose chemotherapy (HDCT) and ASCT in patients with relapsed and refractory Hodgkin's lymphoma (HL) aged 60 years and older and compare the results with a group of younger HL patients treated in a similar manner. We identified 15 consecutive patients, with HL aged 60 years and older who underwent HDCT (etoposide 60 mg/kg+ melphalan 160 mg/m(2)) and ASCT at our institution from May 2001 to March 2008. The results were compared with a cohort of 157 younger HL patients treated in a similar manner from January 1999 to December 2006. After a median follow-up of 2.5 years, PFS at 3 years after ASCT was 73% (95% confidence interval (CI) 37-90) for the older group and 56% (95% CI 46-64) for the younger group (P=0.45); OS after ASCT was 88% (95% CI 39-98) for the older group and 84% (95% CI 75-90) for the younger group (P=0.80). No transplant-related deaths were seen. Our study suggests that ASCT is feasible for selected elderly patients with HL, giving similar results to younger patients in terms of survival and toxicity. PMID- 21243030 TI - Reconstitution of CMV pp65 and IE-1-specific IFN-gamma CD8(+) and CD4(+) T-cell responses affording protection from CMV DNAemia following allogeneic hematopoietic SCT. AB - Threshold levels of CMV-specific T-cell populations presumably affording protection from active CMV infection in allo-SCT recipients have been proposed, but lack extensive validation. We quantified CMV pp65 and immediate-early 1 specific IFN-gamma CD8(+) and CD4(+) T cell responses at days +30, +60 and +90 after transplantation in 133 patients, and established cutoff cell levels protecting from CMV DNAemia within the first 120 days after transplantation. No patients showing IFN-gamma CD8(+) or IFN-gamma CD4(+) T-cell counts >1.0 and >1.2 cells/MUL, respectively, developed a subsequent episode of CMV DNAemia. Initial or recurrent episodes of CMV DNAemia occurred in the face of IFN-gamma T-cell levels below defined thresholds. Negative predictive values at day +30 for the IFN-gamma CD8(+) and CD4(+) T-cell markers were 68.1 and 61.8%, respectively. Recipients of grafts from CMV seropositive, related or HLA-matched donors, or receiving non-myeloablative conditioning had nonsignificant tendencies to reach more frequently protective levels of both T-cell subsets at early and late (day +365) times after transplantation. The use of anti-thymocyte globulin and umbilical cord blood transplantation were associated with impaired CMV-specific T cell reconstitution. CMV-specific IFN-gamma CD8(+) and CD4(+) T-cell recovery occurred irrespective of detectable CMV DNAemia. PMID- 21243031 TI - Expression of CD64 (FcgammaRI) in skin of patients with acute GVHD. AB - GVHD remains a major problem in allo-SCT. We explored the presence of APC in skin biopsies of GVHD patients, using the IgG receptor CD64 expression as a hallmark for activated APC. By immunohistochemistry we demonstrated CD64 to be upregulated on host APC in skin biopsies of patients with acute GVHD and, less prominently, in chronic GVHD. Double staining for CD32 polymorphism revealed CD64-positive cells to be mainly of host origin. The majority of CD64-positive cells coexpressed CD68, indicating a macrophage phenotype. Given its very restricted cellular distribution, CD64 may represent an excellent target for APC-directed therapies in GVHD. PMID- 21243032 TI - CD49d blockade by natalizumab therapy in patients with multiple sclerosis increases immature B-lymphocytes. PMID- 21243033 TI - Effect of vitamin D treatment in chronic GVHD. PMID- 21243034 TI - Phase-selective image reconstruction of the lungs in small animals using Micro CT. AB - Gating in small animal imaging can compensate for artifacts due to physiological motion. This paper presents a strategy for sampling and image reconstruction in the rodent lung using micro-CT. The approach involves rapid sampling of free breathing mice without any additional hardware to detect respiratory motion. The projection images are analyzed post-acquisition to derive a respiratory signal, which is used to provide weighting factors for each projection that favor a selected phase of the respiration (e.g. end-inspiration or end-expiration) for the reconstruction. Since the sampling cycle and the respiratory cycle are uncorrelated, the sets of projections corresponding to any of the selected respiratory phases do not have a regular angular distribution. This drastically affects the image quality of reconstructions based on simple filtered backprojection. To address this problem, we use an iterative reconstruction algorithm that combines the Simultaneous Algebraic Reconstruction Technique with Total Variation minimization (SART-TV). At each SART-TV iteration, backprojection is performed with a set of weighting factors that favor the desired respiratory phase. To reduce reconstruction time, the algorithm is implemented on a graphics processing unit. The performance of the proposed approach was investigated in simulations and in vivo scans of mice with primary lung cancers imaged with our in-house developed dual tube/detector micro-CT system. We note that if the ECG signal is acquired during sampling, the same approach could be used for phase selective cardiac imaging. PMID- 21243035 TI - Rearing Difficult Children: Parents' Personality and Children's Proneness to Anger as Predictors of Future Parenting. AB - OBJECTIVE: This multi-method study of 102 mothers, fathers, and children examined children's difficult temperament as a moderator of the links between parental personality and future parenting. METHODS: Parents described themselves on the Big Five traits and Optimism. Children's difficult temperament was observed at 25 and 38 months in paradigms that assessed proneness to anger. Each parent's responsive, affectively positive parenting was observed in lengthy naturalistic interactions at 67 months. RESULTS: Regardless of child temperament, for mothers, low Neuroticism, and for fathers, high Extraversion predicted more positive parenting. For difficult, anger-prone children, mothers' low and high Optimism and fathers' low and high Openness were associated, respectively, with less or more positive parenting. CONCLUSIONS: Challenges due to children's difficult temperaments appear to amplify links between parental personality traits and parenting. PMID- 21243036 TI - Epigenetics: Tools and Technologies. AB - Epigenetics refers to heritable changes that control how the genome is accessed in different cell-types and during development and differentiation. Even though each cell contains essentially the same genetic code, epigenetic mechanisms permit specialization of function between cells. The state of chromatin, the complex of histone proteins, RNA and DNA that efficiently package the genome, is largely regulated by specific modifications to histone proteins and DNA, and the recognition of these marks by other proteins and protein complexes. The enzymes that produce these modifications (the 'writers'), the proteins that recognize them (the 'readers'), and the enzymes that remove them (the 'erasers') are critical targets for manipulation in order to further understand the histone code and its role in biology and human disease. PMID- 21243037 TI - Progress in the Development of a new Angiography Suite including the High Resolution Micro-Angiographic Fluoroscope (MAF), a Control, Acquisition, Processing, and Image Display System (CAPIDS), and a New Detector Changer Integrated into a Commercial C-Arm Angiography Unit to Enable Clinical Use. AB - Due to the high-resolution needs of angiographic and interventional vascular imaging, a Micro-Angiographic Fluoroscope (MAF) detector with a Control, Acquisition, Processing, and Image Display System (CAPIDS) was installed on a detector changer which was attached to the C-arm of a clinical angiographic unit. The MAF detector provides high-resolution, high-sensitivity, and real-time imaging capabilities and consists of a 300 MUm-thick CsI phosphor, a dual stage micro-channel plate light image intensifier (LII) coupled to a fiber optic taper (FOT), and a scientific grade frame-transfer CCD camera, providing an image matrix of 1024*1024 35 MUm square pixels with 12 bit depth. The Solid-State X-Ray Image Intensifier (SSXII) is an EMCCD (Electron Multiplying charge-coupled device) based detector which provides an image matrix of 1k*1k 32 MUm square pixels with 12 bit depth. The changer allows the MAF or a SSXII region-of interest (ROI) detector to be inserted in front of the standard flat-panel detector (FPD) when higher resolution is needed during angiographic or interventional vascular imaging procedures. The CAPIDS was developed and implemented using LabVIEW software and provides a user-friendly interface that enables control of several clinical radiographic imaging modes of the MAF or SSXII including: fluoroscopy, roadmapping, radiography, and digital-subtraction angiography (DSA). The total system has been used for image guidance during endovascular image-guided interventions (EIGI) using prototype self-expanding asymmetric vascular stents (SAVS) in over 10 rabbit aneurysm creation and treatment experiments which have demonstrated the system's potential benefits for future clinical use. PMID- 21243038 TI - Generalized two-dimensional (2D) linear system analysis metrics (GMTF, GDQE) for digital radiography systems including the effect of focal spot, magnification, scatter, and detector characteristics. AB - The MTF, NNPS, and DQE are standard linear system metrics used to characterize intrinsic detector performance. To evaluate total system performance for actual clinical conditions, generalized linear system metrics (GMTF, GNNPS and GDQE) that include the effect of the focal spot distribution, scattered radiation, and geometric unsharpness are more meaningful and appropriate. In this study, a two dimensional (2D) generalized linear system analysis was carried out for a standard flat panel detector (FPD) (194-micron pixel pitch and 600-micron thick CsI) and a newly-developed, high-resolution, micro-angiographic fluoroscope (MAF) (35-micron pixel pitch and 300-micron thick CsI). Realistic clinical parameters and x-ray spectra were used. The 2D detector MTFs were calculated using the new Noise Response method and slanted edge method and 2D focal spot distribution measurements were done using a pin-hole assembly. The scatter fraction, generated for a uniform head equivalent phantom, was measured and the scatter MTF was simulated with a theoretical model. Different magnifications and scatter fractions were used to estimate the 2D GMTF, GNNPS and GDQE for both detectors. Results show spatial non-isotropy for the 2D generalized metrics which provide a quantitative description of the performance of the complete imaging system for both detectors. This generalized analysis demonstrated that the MAF and FPD have similar capabilities at lower spatial frequencies, but that the MAF has superior performance over the FPD at higher frequencies even when considering focal spot blurring and scatter. This 2D generalized performance analysis is a valuable tool to evaluate total system capabilities and to enable optimized design for specific imaging tasks. PMID- 21243039 TI - Identification of Purine-Scaffold Small-Molecule Inhibitors of Stat3 Activation by QSAR Studies. AB - To facilitate the discovery of clinically useful Stat3 inhibitors, computational analysis of the binding to Stat3 of the existing Stat3 dimerization disruptors and quantitative structure-activity relationships (QSAR) were pursued, by which a pharmacophore model was derived for predicting optimized Stat3 dimerization inhibitors. The 2,6,9-trisubstituted-purine scaffold was functionalized in order to access the three subpockets of the Stat3 SH2 domain surface and to derive potent Stat3-binding inhibitors. Select purine scaffolds showed good affinities (K(D), 0.8-12 MUM) for purified, nonphosphorylated Stat3 and inhibited Stat3 DNA binding activity in vitro and intracellular phosphorylation at 20-60 MUM. Furthermore, agents selectively suppressed viability of human prostate, breast and pancreatic cancer cells, and v-Src-transformed mouse fibroblasts that harbor aberrant Stat3 activity. Studies herein identified novel small-molecule trisubstituted purines as effective inhibitors of constitutively active Stat3 and of the viability of Stat3-dependent tumor cells, and are the first to validate the use of purine bases as templates for building novel Stat3 inhibitors. PMID- 21243040 TI - A New Route to Substituted Pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones and Facile Extension to 5,7(6H,8H) Isomers. AB - A new route to substituted pyrimido[5,4-e]-1,2,4-triazine-5,7(1H,6H)-diones is outlined. The synthesis proceeds via pre-formed hydrazone intermediates, which are then condensed with an activated chlorouracil to build up the entire molecular framework, followed by a reductive ring closure to provide the parent series. The route has been extended to the isomeric pyrimido[5,4-e]-1,2,4 triazine-5,7(6H,8H)-dione class via the use of methylhydrazine as hydrazine surrogate, followed by regiospecific alkylation of the N(8)-H pyrimidotriazinediones with a range of alkyl and alkaryl substituents. This new methodology permits the generation of a wide range of compounds with variable substitution at the N(1), C(3), and N(8) positions for a heterocyclic scaffold with demonstrated pharmacological activity. PMID- 21243041 TI - Prevalence of Overweight and At Risk of Overweight in Fourth-Grade Children across Five School-Based Studies Conducted during Four School Years. AB - PURPOSE/OBJECTIVES: This article discusses differences by ethnicity (Black, White), gender, and time (season/year) in body mass index (BMI)-for-age percentiles, and prevalence of overweight and at risk of overweight, in fourth grade children across five studies conducted during four school years. These five studies concerned either the accuracy of children's dietary recalls or children's social desirability, so weight and height measurements were secondary rather than primary aims. METHODS: Across five studies, 1,696 fourth-grade children (54% Black, 46% White; 51% girls) from a total of 14 public elementary schools in one school district were measured. Each child's BMI-for-age percentile was determined using the Centers for Disease Control and Prevention's gender-specific BMI-for age growth charts. RESULTS: Across all five studies, 20 children (1.2%) were underweight (<5(th) percentile), 989 children (58.3%) were at a healthy weight (>=5(th) and <85(th) percentiles), 281 children (16.6%) were at risk of overweight (>=85(th) and <95(th) percentiles), and 406 children (23.9%) were overweight (>=95(th) percentile). The mean gender-specific BMI-for-age percentile across all children was high (70.1%) and greater for Black children (72.0%) than White children (67.8%) (p=0.02; analysis of covariance). A higher percentage of Black children (26.5%) compared to White children (21.0%) were overweight (p=0.01; chi-square). No differences were found by gender or time in the prevalence of children who were overweight; likewise, no differences were found by ethnicity, gender, or time in the prevalence of children who were at risk of overweight. APPLICATIONS TO CHILD NUTRITION PROFESSIONALS: Schools provide an excellent venue for measuring children's weight and height annually to determine BMI-for-age percentiles. This information can be used to track changes over time, and linked to computerized administrative records of children's daily participation in school meals from one school year to the next to increase knowledge of a relationship between childhood obesity and daily participation in school meals. PMID- 21243042 TI - PUBLIC HEALTH NURSING IN MISSISSIPPI: CHANGES IN CONTEXT AND PRACTICE. AB - Current standards and competencies guiding public health nursing (PHN) practice promote population-focused practice, but few studies have examined the extent to which change toward this type of practice has occurred. A cross-sectional, mail back survey was conducted among public health nurses in Mississippi to examine recent changes in their practice, contextual factors related to population focused practice, and recommendations for improving practice and educational preparation for practice. The survey response rate was 54% (n=150 [of 277]). Participants were predominantly female (95%), White (85%), 46 years or older (62%) and held an associate degree in nursing (69%). Most experienced nurses (n=106, 70%) reported perceived practice changes compared to five years prior, but did not consistently report changes toward greater population-focused practice. Participants reported funding decreases and negative effects on practice stemming from the nursing shortage. Recommendations for improving practice conditions included increasing resources, improving workplace environment and management practices, changing the focus of services, and promoting awareness of public health and PHN. Recommendations for improving education included providing more clinical experiences in public health settings and increasing financial supports and distance learning options. Additional research is needed to determine the nature and characteristics of population focused PHN as practiced in Mississippi and elsewhere. PMID- 21243043 TI - Universal Patterns of Equilibrium Cluster Growth in Aqueous Sugars Observed by Dynamic Light Scattering. AB - Dynamic light scattering performed on aqueous solutions of three sugars (glucose, maltose and sucrose) reveal a common pattern of sugar cluster formation with a narrow cluster size distribution. In each case, equilibrium clusters form whose size increases with increasing sugar content in an identical power law manner in advance of a common, critical-like, percolation threshold near 83 wt% sugar. The critical exponent of the power law divergence of the cluster size varies with temperature, increasing with decreasing temperature, due to changes in the strength of the intermolecular hydrogen bond and appears to vanish for temperatures in excess of 90 degrees C. Detailed analysis of the cluster growth process suggests a two-stage process: an initial cluster phase formed at low volume fractions, phi, consisting of non-interacting, monodisperse sugar clusters whose size increases phi(1/3) followed by an aggregation stage, active at concentrations above about phi = 40%, where cluster-cluster contact first occurs. PMID- 21243044 TI - A Tunneling Model for Afterglow Suppression in CsI:Tl,Sm Scintillation Materials. PMID- 21243047 TI - Health information literacy meets evidence-based practice. PMID- 21243048 TI - Previous research shows Medical Library Association award winner publication rate. PMID- 21243049 TI - Introduction: librarians recovering our professional memory: enriching the past, present, and future. PMID- 21243050 TI - The lost history of American veterinary medicine: the need for preservation. AB - OBJECTIVE: The objective of this study was to survey holdings of ephemeral veterinary literature. METHODS: World Cat OCLC catalog, the Library of Congress online catalog, the US National Agricultural Library online catalog, and the Dictionary Catalog of the National Agricultural Library, 1862-1965, were used to determine current library holdings of materials published by veterinary schools that are no longer in existence and veterinary associations that are defunct, veterinary supply catalogs, veterinary house organs, patent medicine publications, and veterinary advertisements. Individual library catalogs were also consulted. In addition, the practice of removing advertisements from bound volumes was examined. RESULTS: There are many gaps in the cataloged library holdings of primary source materials relating to the history of the education of veterinarians in the United States. CONCLUSIONS: A proactive action plan needs to be designed and activated to locate, catalog, and preserve this primary source material of veterinary medicine for posterity. PMID- 21243045 TI - Towards understanding the epigenetics of transcription by chromatin structure and the nuclear matrix. AB - The eukaryotic nucleus houses a significant amount of information that is carefully ordered to ensure that genes can be transcribed as needed throughout development and differentiation. The genome is partitioned into regions containing functional transcription units, providing the means for the cell to selectively activate some, while keeping other regions of the genome silent. Over the last quarter of a century the structure of chromatin and how it is influenced by epigenetics has come into the forefront of modern biology. However, it has thus far failed to identify the mechanism by which individual genes or domains are selected for expression. Through covalent and structural modification of the DNA and chromatin proteins, epigenetics maintains both active and silent chromatin states. This is the "other" genetic code, often superseding that dictated by the nucleotide sequence. The nuclear matrix is rich in many of the factors that govern nuclear processes. It includes a host of unknown factors that may provide our first insight into the structural mechanism responsible for the genetic selectivity of a differentiating cell. This review will consider the nuclear matrix as an integral component of the epigenetic mechanism. PMID- 21243051 TI - Balancing between two goods: Health Insurance Portability and Accountability Act and ethical compliancy considerations for privacy-sensitive materials in health sciences archival and historical special collections. AB - OBJECTIVE: The investigation provides recommendations for establishing institutional collection guidelines and policies that protect the integrity of the historical record, while upholding the privacy and confidentiality of those who are protected by Health Insurance Portability and Accountability Act (HIPAA) or professional ethical standards. METHODS: The authors completed a systematic historical investigation of the concepts of collection integrity, privacy, and confidentiality in the formal and informal legal and professional ethics literature and applied these standards to create best practices for institutional policies in these areas. RESULTS: Through an in-depth examination of the historical concepts of privacy and confidentiality in the legal and professional ethics literature, the authors were able to create recommendations that would allow institutions to provide access to important, yet sensitive, materials, while complying with the standards set by HIPAA regulations and professional ethical expectations. CONCLUSION: With thoughtful planning, it is possible to balance the integrity of and access to the historical record of sensitive documents, while supporting the privacy protections of HIPAA and professional ethical standards. Although it is theorized that collection development policies of institutions have changed due to HIPAA legislation, additional research is suggested to see how various legal interpretations have affected the integrity of the historical record in actuality. PMID- 21243052 TI - Influence of the Casserius Tables on fetal anatomy illustration and how we envision the unborn. AB - OBJECTIVE: The paper demonstrates how visual representation of the fetus in early anatomy texts influenced the reader's perception of the unborn child as an autonomous being. DATA SOURCES: The health, art, and history literatures were used as sources. Original texts and illustrations, with particular attention paid to the Casserius Tables, published by Andreas Spigelius in 1627, are discussed. STUDY SELECTION: A review of the literature was conducted to identify and analyze published renderings, reproductions, and discussion of images of the unborn child. Original anatomy atlases were consulted. MAIN RESULTS: Artists' renderings of a particularly vulnerable state of human life influenced early perceptions of the status of the unborn child. The images show fetuses as highly independent, providing a visual cue that life is fully formed in utero. CONCLUSION: The legacy of the Casserius Tables is that they are still able to capture our attention because they portray the idea of a fetus and newborn even more clearly than our modern representations of this charged topic. The use of deceptive realism provides the viewer with an accessible visual representation of the unborn child. These early anatomy illustrations continue to influence modern-day perception of the unborn child as a separate being, completely autonomous from the mother. PMID- 21243053 TI - The library of the Royal Society of Physicians in Budapest becomes today's Semmelweis Medical History Library. AB - OBJECTIVES: The 170-year history of the library of the Royal Society of Medicine in Budapest illustrates both that political and cultural context matter and that "medical" libraries, if they survive, in due course become primarily "medical history" libraries. METHODS: Two of the authors are on the staff of the Semmelweis Medical History Library; the third is a US scholar who makes frequent use of the library. Together, they avail themselves of archival and published materials-and personal experience with the collection-to establish the context that produced the original library, trace its evolution, and describe its present day incarnation. RESULTS: A tale of transformation emerges that reflects how collections are likely to change. The authors present events and individuals in the life of the Royal Society's library and paint a picture of the value of today's Semmelweis Medical History Library. Unique treasures in the collection are described. CONCLUSION: The story told here is of how a particular nineteenth century library became a twenty-first-century institution. The authors establish its peculiarly Hungarian context and potential value to librarians and historians from outside Hungary. The overall message is that general medical libraries everywhere are perforce likely to become medical historical libraries over time. PMID- 21243054 TI - The Bellevue Classification System: nursing's voice upon the library shelves. AB - This article examines the inspiration, construction, and meaning of the Bellevue Classification System (BCS), created during the 1930s for use in the Bellevue School of Nursing Library. Nursing instructor Ann Doyle, with assistance from librarian Mary Casamajor, designed the BCS after consulting with library leaders and examining leading contemporary classification systems, including the Dewey Decimal Classification and Library of Congress, Ballard, and National Health Library classification systems. A close textual reading of the classes, subclasses, and subdivisions of these classification systems against those of the resulting BCS, reveals Doyle's belief that the BCS was created not only to organize the literature, but also to promote the burgeoning intellectualism and professionalism of early twentieth-century American nursing. PMID- 21243055 TI - From Hahnemann's hand to your computer screen: building a digital homeopathy collection. AB - The University of California, San Francisco (UCSF), Library holds the unique manuscript of the sixth edition of Samuel Hahnemann's Organon der Heilkunst, the primary text of homeopathy. The manuscript volume is Hahnemann's own copy of the fifth edition of the Organon with his notes for the sixth edition, handwritten throughout the volume. There is a high level of interest in the Organon manuscript, particularly among homeopaths. This led to the decision to present a digital surrogate on the web to make it accessible to a wider audience. Digitizing Hahnemann's manuscript and determining the best method of presentation on the web posed several challenges. Lessons learned in the course of this project will inform future digital projects. This article discusses the historical significance of the sixth edition of Hahnemann's Organon, its context in UCSF's homeopathy collections, and the specifics of developing the online homeopathy collection. PMID- 21243056 TI - Archives, accessibility, and advocacy: a case study of strategies for creating and maintaining relevance. AB - QUESTION/OBJECTIVE: How can a special collection maintain or increase its profile in its parent institution, when that parent institution emphasizes scientific and clinical learning? SETTING/CONTEXT: The Waring Historical Library, Medical University of South Carolina (MUSC), preserves and promotes the history of health sciences at MUSC and in South Carolina. As a state entity, MUSC has suffered significant budget cuts for the past several years. In this climate, the Waring had to find ways to maintain relevance in the MUSC community. METHODS: The Waring partnered with the MUSC College of Nursing to explore new ways to build institutional allies. By combining traditional archival administration with innovative uses of digital collections aimed at institutional promotion and outreach, the Waring's digital library became an advocacy tool that led to the Waring's enhanced value to its parent institution. OUTCOMES: The Waring Library is a resource for MUSC development and alumni relations. Tangible outcomes include additional funding from grants, increased staff, no loss of institutional funding, increased access to collections, increased accessions, cultivation of institutional allies for long-term support of the Waring, and development of a template for future partnerships. PMID- 21243057 TI - Miles to go before we sleep: education, technology, and the changing paradigms in health information. AB - PURPOSE: This lecture discusses a philosophy of educating health information professionals in a rapidly changing health care and information environment. DISCUSSION: Education for health information professionals must be based upon a solid foundation of the changing paradigms and trends in health care and health information, as well as technological advances, to produce a well-prepared information workforce to meet the demands of health-related environments. Educational programs should begin with the core principles of library and information sciences and expand in interdisciplinary collaborations. A model of the health care environment is presented to serve as a framework for developing educational programs for health information professionals. CONCLUSION: Interdisciplinary and collaborative relationships-which merge health care, library and information sciences, and other information-related disciplines should form the basis of education for health information professionals. PMID- 21243058 TI - Using information prescriptions to refer patients with metabolic conditions to the Genetics Home Reference website. AB - OBJECTIVES: The objectives of this study were to assess the reactions of adult patients and parents of children with metabolic conditions to receipt of an "information prescription" (IP) to visit Genetics Home Reference (GHR), a National Institutes of Health/National Library of Medicine online resource, and evaluate the perceived utility of information found on the site. METHODS: Patients seen at the University of Utah Metabolic Service Clinic were invited to participate in the study and asked to complete an initial survey to gather demographic data and an online survey six weeks later to obtain information about user experience. RESULTS: Fifty-three of 82 individuals completed both surveys, for an overall response rate of 64.6%. Most respondents (88.7%) agreed that receiving the IP was a "good idea," and nearly all used the IP to visit GHR. More than three-quarters (79.6%) agreed that information on GHR supplemented a physician's advice; 60.4% reported an improved understanding of a health condition; and 41.5% either looked for or would consider looking for additional information. Eighty-six percent of respondents were satisfied with the information found on GHR, and 80% would recommend the site. CONCLUSIONS: Use of an IP to direct patients to GHR was well received, and retrieved information was perceived as useful in key areas. The high level of satisfaction with GHR argues for expanded use of the IP approach in this patient population. PMID- 21243059 TI - A validated search assessment tool: assessing practice-based learning and improvement in a residency program. AB - OBJECTIVE: The objective of this study was to validate an assessment instrument for MEDLINE search strategies at an academic medical center. METHOD: Two approaches were used to investigate if the search assessment tool could capture performance differences in search strategy construction. First, data from an evaluation of MEDLINE searches from a pediatric resident's longitudinal assessment were investigated. Second, a cross-section of search strategies from residents in one incoming class was compared with strategies of residents graduating a year later. MEDLINE search strategies formulated by faculty who had been identified as having search expertise were used as a gold standard comparison. Participants were presented with a clinical scenario and asked to identify the search question and conduct a MEDLINE search. Two librarians rated the blinded search strategies. RESULTS: Search strategy scores were significantly higher for residents who received training than the comparison group with no training. There was no significant difference in search strategy scores between senior residents who received training and faculty experts. CONCLUSION: The results provide evidence for the validity of the instrument to evaluate MEDLINE search strategies. This assessment tool can measure improvements in information seeking skills and provide data to fulfill Accreditation Council for Graduate Medical Education competencies. PMID- 21243060 TI - Special report: symposium on transformational change in health sciences libraries: space, collections, and roles. PMID- 21243061 TI - Physicians and their use of information: a survey comparison between the United States, Canada, and the United Kingdom. PMID- 21243062 TI - Upward evaluation at the Arizona Health Sciences Library. PMID- 21243063 TI - Using LibGuides to offer library service to undergraduate medical students based on the case-oriented problem solving curriculum model. PMID- 21243064 TI - National Institutes of Health public access policy and the University of Michigan Libraries' role in assisting with depositing to PubMed Central. PMID- 21243065 TI - The Kernel Energy Method: Construction of 3 & 4 tuple Kernels from a List of Double Kernel Interactions. AB - The Kernel Energy Method (KEM) provides a way to calculate the ab-initio energy of very large biological molecules. The results are accurate, and the computational time reduced. However, by use of a list of double kernel interactions a significant additional reduction of computational effort may be achieved, still retaining ab-initio accuracy. A numerical comparison of the indices that name the known double interactions in question, allow one to list higher order interactions having the property of topological continuity within the full molecule of interest. When, that list of interactions is unpacked, as a kernel expansion, which weights the relative importance of each kernel in an expression for the total molecular energy, high accuracy, and a further significant reduction in computational effort results. A KEM molecular energy calculation based upon the HF/STO3G chemical model, is applied to the protein insulin, as an illustration. PMID- 21243066 TI - Course of Antisocial Behavior during Emerging Adulthood: Developmental Differences in Personality. AB - Despite similar normative changes in antisocial behavior (AB) and traits of disinhibition and negative emotionality during "emerging adulthood," few studies have tested if there are developmental differences in personality over this period for distinct courses of AB. In a college cohort assessed at ages 18 and 25, we examined if mean-level changes on traits from the Tridimensional Personality Questionnaire varied by course of AB. Compared to persisters, those who desisted in AB from 18 to 25 exhibited a larger decrease on novelty seeking and larger increase on reward dependence. A significant mean-level decline was observed for harm avoidance, but was unrelated to AB course. Findings support theories of the co-development of personality and AB during emerging adulthood. PMID- 21243067 TI - EMERGING THERAPIES AND NOVEL APPROACHES TO VISCERAL PAIN. PMID- 21243068 TI - Spatial variation in disease resistance: from molecules to metapopulations. AB - Variation in disease resistance is a widespread phenomenon in wild plant-pathogen associations. Here, we review current literature on natural plant-pathogen associations to determine how diversity in disease resistance is distributed at different hierarchical levels - within host individuals, within host populations, among host populations at the metapopulation scale and at larger regional scales.We find diversity in resistance across all spatial scales examined. Furthermore, variability seems to be the best counter-defence of plants against their rapidly evolving pathogens. We find that higher diversity of resistance phenotypes also results in higher levels of resistance at the population level.Overall, we find that wild plant populations are more likely to be susceptible than resistant to their pathogens. However, the degree of resistance differs strikingly depending on the origin of the pathogen strains used in experimental inoculation studies. Plant populations are on average 16% more resistant to allopatric pathogen strains than they are to strains that occur within the same population (48 % vs. 32 % respectively).Pathogen dispersal mode affects levels of resistance in natural plant populations with lowest levels detected for hosts of airborne pathogens and highest for waterborne pathogens.Detailed analysis of two model systems, Linum marginale infected by Melampsora lini, and Plantago lanceolata infected by Podosphaera plantaginis, show that the amount of variation in disease resistance declines towards higher spatial scales as we move from individual hosts to metapopulations, but evaluation of multiple spatial scales is needed to fully capture the structure of disease resistance.Synthesis: Variation in disease resistance is ubiquitous in wild plant-pathogen associations. While the debate over whether the resistance structure of plant populations is determined by pathogen-imposed selection versus non-adaptive processes remains unresolved, we do report examples of pathogen imposed selection on host resistance. Here we highlight the importance of measuring resistance across multiple spatial scales, and of using sympatric strains when looking for signs of coevolution in wild plant-pathogen interactions. PMID- 21243070 TI - A case report of the symptom-relieving action of an anterior flat plane bite plate for temporomandibular disorder. AB - Splint therapy is a widely used modality for temporomandibular disorders (TMDs). However, questions remain regarding the mechanism of symptom relief. Recently, a relation between TMD and a discrepancy between the habitual occlusal position (HOP) and the anterior flat plane bite plate-induced occlusal position (BPOP) has been reported. Therefore, to understand the mechanism of the symptom relief associated with the use of a bite plate, the changes in both the HOP and BPOP values were observed during anterior bite plate treatment in a patient with TMD. CASE PRESENTATION: Anterior bite plate treatment was started in a patient complaining of arthralgia. A discrepancy between the HOP and BPOP values was recorded three days after the first visit; this discrepancy disappeared on day 6, and the disappearance was maintained between days 6 and 12. The disappearance was associated with a decrease in the severity of the patient's symptoms; however, the discrepancy reappeared after 15 days, coinciding with the complete disappearance of the patient's symptoms. Therefore, the effect of the bite plate on the resolution of the discrepancy between the HOP and BPOP values was interpreted as being unsustainable and occlusal equilibration for the BPOP was performed at 17 days. Thereafter, neither a discrepancy in the HOP and BPOP values nor any symptoms of TMD (right temporomandibular joint pain or limited jaw opening) reoccurred during a two-year follow-up period. CONCLUSION: Within the limitations of the present study, the symptom-relieving action of an anterior flat plane bite plate on the resolution of occlusal discrepancy appeared to be temporary. This outcome supports previously reported conclusions that the effectiveness of stabilization splint therapy for reducing symptoms in patients with pain dysfunction syndrome does not differ significantly from that of other conservative therapies or of no treatment at all. PMID- 21243069 TI - Therapeutics for Circadian Rhythm Sleep Disorders. AB - The sleep-wake cycle is regulated by the interaction of endogenous circadian and homeostatic processes. The circadian system provides timing information for most physiological rhythms, including the sleep and wake cycle. In addition, the central circadian clock located in the suprachiasmatic nucleus of the hypothalamus has been shown to promote alertness during the day. Circadian rhythm sleep disorders arise when there is a misalignment between the timing of the endogenous circadian rhythms and the external environment or when there is dysfunction of the circadian clock or its entrainment pathways. The primary synchronizing agents of the circadian system are light and melatonin. Light is the strongest entraining agent of circadian rhythms and timed exposure to bright light is often used in the treatment of circadian rhythm sleep disorders. In addition, timed administration of melatonin, either alone or in combination with light therapy has been shown to be useful in the treatment of the following circadian rhythm sleep disorders: delayed sleep phase, advanced sleep phase, free running, irregular sleep wake, jet lag and shift work. PMID- 21243071 TI - Fibroblastic variant of osteosarcoma: a challenge in diagnosis & management. AB - Osteosarcoma of the jaws is a relative rare malignant bone tumor. Like, its counterpart in the long bones, osteosarcoma affecting the head and neck region shows distinct yet diverse clinical, histologic and prognostic characteristics. Its diagnosis is a challenge to histopathologists and is especially important in early stages to improve its prognosis. In the initial phase, it may present as nondescript swelling with an indolent growth rate, only to become overtly aggressive and malignant towards the later phase of the disease. This article reports on a case of an advanced osteosarcoma of the maxilla in a 42 year old woman who came for the evaluation of a swelling. The case was submitted for surgical intervention and was followed by one recurrence till the time of reporting. This case illustrates that immunohistochemical staining of Vimentin, S 100 and CD 68 markers are useful to confirm the histologic diagnosis of osteosarcoma, along with radiographic evaluation using CT scan and 3D imaging. PMID- 21243072 TI - NOMA: A Preventable "Scourge" of African Children. AB - Noma is a serious orofacial gangrene originating intraorally in the gingival-oral mucosa complex before spreading extraorally to produce a visibly destructive ulcer. Although cases of noma are now rarely reported in the developed countries, it is still prevalent among children in third world countries, notably in sub Sahara Africa, where poverty, ignorance, malnutrition, and preventable childhood infections are still common. This review summarizes historical, epidemiological, management, and research updates on noma with suggestions for its prevention and ultimate global eradication. The global annual incidence remains high at about 140,000 cases, with a mortality rate exceeding 90% for untreated diseases. Where the patients survive, noma defects result in unsightly facial disfigurement, intense scarring, trismus, oral incompetence, and social alienation. Although the etiology has long been held to be infectious, a definitive causal role between microorganisms cited, and noma has been difficult to establish. The management of noma with active disease requires antibiotics followed by reconstructive surgery. Current research efforts are focused towards a comprehensive understanding of the epidemiology, and further elucidation of the microbiology and pathogenesis of noma.Although a formidable public health challenge, noma can be prevented with a potential for subsequent global eradication. To achieve both desirable goals, detection of early disease is crucial because these early lesions respond to conventional antibiotic treatments when instituted side by side with nutritional rehabilitation, and obviates the necessity for extensive surgical reconstruction often indicated in late stage disease. The eradication of noma in the developed world in the mid 20(th) century bears out the notion of a similar outcome following effective preventive strategies in Africa. A fundamental and necessary step towards attaining this goal is for the international community to adopt a perception of noma as an urgent global public health challenge. Research effort toward deciphering the microbiology, molecular events, and pathogenesis of noma also should intensify. PMID- 21243073 TI - Soft drink, software and softening of teeth - a case report of tooth wear in the mixed dentition due to a combination of dental erosion and attrition. AB - This case report describes a 9-year-old boy with severe tooth wear as a result of drinking a single glass of soft drink per day. This soft drink was consumed over a period of one to two hours, while he was gaming intensively on his computer. As a result, a deep bite, enamel cupping, sensitivity of primary teeth and loss of fillings occurred. Therefore, dentists should be aware that in patients who are gaming intensively, the erosive potential of soft drinks can be potentiated by mechanical forces leading to excessive tooth wear. PMID- 21243074 TI - Informant Discrepancies in Assessing Child Dysfunction Relate to Dysfunction Within Mother-Child Interactions. AB - Examined whether mother-child discrepancies in perceived child behavior problems relate to dysfunctional interactions between mother and child and stress in the mother. Participants included 239 children (6-16 years old; 58 girls, 181 boys) referred for oppositional, aggressive, and antisocial behavior, and their mothers. Mother-child discrepancies in perceived child behavior problems were related to mother-child conflict. Moreover, maternal stress mediated this relationship. The findings suggest that discrepancies among mother and child evaluations of child functioning are not merely reflections of different perspectives or artifacts of the assessment process, but can form components of conceptual models that can be developed and tested to examine the interrelations among critical domains of child, parent, and family functioning. PMID- 21243075 TI - Exact calculations of average power for the Benjamini-Hochberg procedure. AB - Exact analytic expressions are developed for the average power of the Benjamini and Hochberg false discovery control procedure. The result is based on explicit computation of the joint probability distribution of the total number of rejections and the number of false rejections, and expressed in terms of the cumulative distribution functions of the p-values of the hypotheses. An example of analytic evaluation of the average power is given. The result is confirmed by numerical experiments and applied to a meta-analysis of three clinical studies in mammography. PMID- 21243076 TI - A Qualitative Study of Providers' Perception of Adherence of Women Living with HIV/AIDS in Puerto Rico. AB - This study examines healthcare providers' perceptions regarding experiences and factors that contribute to adherent and non-adherent behaviors to HIV treatment among women living with HIV infection in Puerto Rico and describes strategies implemented to improve adherence. Providers' accounts revealed that women with HIV infection are living "beyond their strengths" attempting to reconcile the burden of the illness and keep adherent. Factors putting women beyond their strengths and influencing non-adherence behavior were: gender-related demands, fear of disclosure, and treatment complexity. Strategies to improve adherence included: ongoing assessment, education, collaborative work, support groups, networking, disguising pills, readiness, and seeking medications outside their towns. Provider-patient interactions are critical for women's success and must assess all these factors in developing and providing health services. PMID- 21243077 TI - Social regulation of human gene expression. AB - Relationships between genes and social behavior have historically been construed as a one-way street, with genes in control. Recent analyses have challenged this view by discovering broad alterations in the expression of human genes as a function of differing socio-environmental conditions. The emerging field of social genomics has begun to identity the types of genes subject to social regulation, the biological signaling pathways mediating those effects, and the genetic polymorphisms that moderate socio-environmental influences on human gene expression. PMID- 21243078 TI - Landscape of finite-temperature equilibrium behaviour of curvature-inducing proteins on a bilayer membrane explored using a linearized elastic free energy model. AB - Using a recently developed multiscale simulation methodology, we describe the equilibrium behaviour of bilayer membranes under the influence of curvature inducing proteins using a linearized elastic free energy model. In particular, we describe how the cooperativity associated with a multitude of protein-membrane interactions and protein diffusion on a membrane-mediated energy landscape elicits emergent behaviour in the membrane phase. Based on our model simulations, we predict that, depending on the density of membrane-bound proteins and the degree to which a single protein molecule can induce intrinsic mean curvature in the membrane, a range of membrane phase behaviour can be observed including two different modes of vesicle-bud nucleation and repressed membrane undulations. A state diagram as a function of experimentally tunable parameters to classify the underlying states is proposed. PMID- 21243079 TI - Estimating the Influence of Cochlear Implantation on Language Development in Children. AB - Research studies reviewed here have identified a wide variety of factors that may influence a child's auditory, speech and language development following cochlear implantation. Intrinsic characteristics of the implanted child, including gender, family socio-economic status, age at onset of hearing loss and pre-implant residual hearing may predispose a child to greater or lesser post-implant benefit. Intervention characteristics that may influence outcome include age of the child when deafness is identified and amplification and habilitation is initiated, the communication mode used with the child and the type of classroom/therapy employed. Characteristics of the implant itself include generation of technology used, the age of the child when implant stimulation is initiated, and the amount of time the child has used the implant. These factors interact in unpredictable ways, so that isolated correlations between predictor variables and outcome scores may be difficult to interpret. Results for two independent samples of orally-educated children tested by different laboratories were compared using multiple regression analysis to illustrate interactions among predictor variables. Four predictor variables accounted for a similar proportion of variance (23% and 24%) in receptive vocabulary (PPVT) outcome scores in each sample. A unique predictor was then added to each analysis. The addition of pre implant aided threshold not only increased the total variance accounted for to almost 40%, but also increased the effect of implant age as a predictor variable. A different result was observed in the other sample, were the added predictor variable was nonverbal IQ, where the estimated contribution of implant age was reduced. The current analysis suggests that future analyses minimally control for independent contributions of implant age, nonverbal IQ, and pre-implant aided thresholds when examining expected outcomes. Children in both samples who received a cochlear implant sometime between their first and second birthday achieved age-appropriate oral receptive vocabulary levels during preschool. PMID- 21243080 TI - Embodied, Embedded Language Use. AB - Language use has a public face that is as important to study as the private faces under intensive psycholinguistic study. In the domain of phonology, public use of speech must meet an interpersonal "parity" constraint if it is to serve to communicate. That is, spoken language forms must reliably be identified by listeners. To that end, language forms are embodied, at the lowest level of description, as phonetic gestures of the vocal tract that lawfully structure informational media such as air and light. Over time, under the parity constraint, sound inventories emerge over communicative exchanges that have the property of sufficient identifiability.Communicative activities involve more than vocal tract actions. Talkers gesture and use facial expressions and eye gaze to communicate. Listeners embody their language understandings, exhibiting dispositions to behave in ways related to language understanding. Moreover, linguistic interchanges are embedded in the larger context of language use. Talkers recruit the environment in their communicative activities, for example, in using deictic points. Moreover, in using language as a "coordination device," interlocutors mutually entrain. PMID- 21243081 TI - How have developments in molecular imaging techniques furthered schizophrenia research? AB - Molecular imaging techniques have led to significant advances in understanding the pathophysiology of schizophrenia and contributed to knowledge regarding potential mechanisms of action of the drugs used to treat this illness. The aim of this article is to provide a review of the major findings related to the application of molecular imaging techniques that have furthered schizophrenia research. This article focuses specifically on neuroreceptor imaging studies with PET and SPECT. After providing a brief overview of neuroreceptor imaging methodology, we consider relevant findings from studies of receptor availability, and dopamine synthesis and release. Results are discussed in the context of current hypotheses regarding neurochemical alterations in the illness. We then selectively review pharmacological occupancy studies and the role of neuroreceptor imaging in drug development for schizophrenia. PMID- 21243084 TI - Probabilities for separating sets of order statistics. AB - Consider a set of order statistics that arise from sorting samples from two different populations, each with their own, possibly different distribution functions. The probability that these order statistics fall in disjoint, ordered intervals and that of the smallest statistics, a certain number come from the first populations is given in terms of the two distribution functions. The result is applied to computing the joint probability of the number of rejections and the number of false rejections for the Benjamini-Hochberg false discovery rate procedure. PMID- 21243083 TI - Host-Toxin Interactions Involving EspC and Pet, Two Serine Protease Autotransporters of the Enterobacteriaceae. AB - EspC and Pet are toxins secreted by the diarrheagenic enteropathogenic and enteroaggregative Escherichia coli pathotypes, respectively. Both toxins have a molecular mass around 110 kDa and belong to the same protein family called Serine Protease Autotransporters of the Enterobacteriaceae (SPATE). Furthermore, both toxins act within the cytosol of intoxicated epithelial cells to disrupt the architecture of the actin cytoskeleton. This cytopathic and enterotoxic effect results from toxin cleavage of the actin-binding protein fodrin, although the two toxins recognize different cleavage sites on fodrin. EspC and Pet also have dramatically different mechanisms of entering the target cell which appear dependent upon the E. coli pathotype. In this review, we compare/contrast EspC and Pet in regards to their mode of delivery into the target cell, their effects on fodrin and the actin cytoskeleton, and their possible effects on the physiology of the intestinal epithelial cell. PMID- 21243085 TI - Internal Dynamics of a Coarse-Grained Protein Using Analytical Harmonic Representation. AB - An analytical coarse-grained model (ACG) is introduced to represent individual macromolecules for simulation of dynamic processes in cells. In the ACG model, a macromolecular structure is treated as a fully coarse-grained entity with a uniform mass density without the explicit atomic details. The excluded volume and surface of the ACG macromolecular species are explicitly treated by a spherical harmonic representation in the present study (although ellipsoidal, solid, and radial augmented functions can be used), which can provide any desired accuracy and detail depending on the problem of interest. The present paper focuses on the description of the internal fluctuations of a single ACG macromolecule, modeled by the superposition of low frequency quasiharmonic modes from explicit molecular dynamics simulation. A procedure for estimating the amplitudes, time scales of the quasiharmonic motions and the corresponding phases is presented and used to synthesize the complex motion. The analytical description and numerical algorithm can provide an adequate representation of the internal protein fluctuations revealed from the corresponding atomistic simulations, although the internal motions of ACG macromolecules do not explore motions not exhibited in the dynamic simulations. PMID- 21243086 TI - A beta-glucosidase from Oenococcus oeni ATCC BAA-1163 with potential for aroma release in wine: Cloning and expression in E. coli. AB - Lactic acid bacteria (LAB) are responsible for olfactory changes in wine during malolactic fermentation (MLF). A side characteristic of MLF is the release of grape derived aroma compounds from their glycosylated precursors by beta glycosidase activities of these bacteria. Apart from Oenococcus oeni, which is regarded as the most promising species for MLF, glycosidic activities have also been observed in wine related members of the genera Lactobacillus and Pediococcus. Nevertheless, information on the involved enzymes including their potential use in winemaking is limited. In this study we report that beta glucosidases with similar protein sequences can be identified in the genomes of Lactobacillus brevis, O. oeni and Leuconostoc mesenteroides. TTG serves as start codon for the glucosidase gene of O. oeni. The beta-glucosidase of O. oeni ATCC BAA-1163 was expressed in E. coli and partially characterized. The enzyme displayed characteristics similar to beta-glucosidases isolated from L. brevis and L. mesenteroides. A pH optimum between 5.0 and 5.5, and a K(m) of 0.17 mmol L(-1 )pNP-beta-D-glucopyranoside were determined. A glycosyltransferase activity was observed in the presence of ethanol. The enzyme from O. oeni was capable to hydrolyze glycosides extracted from Muskat wine. This study also contains a report on glycosidase activities of several LAB species including Oenococcus kitaharae. PMID- 21243087 TI - When the Evidence Says, "Yes, No, and Maybe So": Attending to and Interpreting Inconsistent Findings Among Evidence-Based Interventions. AB - An international, multi-disciplinary effort aims to identify evidence-based treatments (EBTs) or interventions. The goal of this effort is to identify specific techniques or programs that successfully target and change specific behaviors. In clinical psychology, EBTs are identified based on the outcomes of randomized controlled trials examining whether treatments outperform control or alternative treatment conditions. Treatment outcomes are measured in multiple ways. Consistently, different ways of gauging outcomes yield inconsistent conclusions. Historically, EBT research has not accounted for these inconsistencies. This paper highlights the implications of inconsistencies, describes a framework for redressing inconsistent findings, and illustrates how the framework guides future work examining how to administer and combine treatments to maximize treatment effects, and study treatments meta-analytically. PMID- 21243088 TI - Continuous-Wave Operation of a Frequency-Tunable 460-GHz Second-Harmonic Gyrotron for Enhanced Nuclear Magnetic Resonance. AB - The design, operation, and characterization of a continuous-wave (CW) tunable second-harmonic 460-GHz gyrotron are reported. The gyrotron is intended to be used as a submillimeter-wave source for 700-MHz nuclear magnetic resonance experiments with sensitivity enhanced by dynamic nuclear polarization. The gyrotron operates in the whispering-gallery mode TE(11,2) and has generated 16 W of output power with a 13-kV 100-mA electron beam. The start oscillation current measured over a range of magnetic field values is in good agreement with theoretical start currents obtained from linear theory for successive high-order axial modes TE(11,2,q). The minimum start current is 27 mA. Power and frequency tuning measurements as a function of the electron cyclotron frequency have also been carried out. A smooth frequency tuning range of 1 GHz was obtained for the operating second-harmonic mode either by magnetic field tuning or beam voltage tuning. Long-term CW operation was evaluated during an uninterrupted period of 48 h, where the gyrotron output power and frequency were kept stable to within +/ 0.7% and +/-6 ppm, respectively, by a computerized control system. Proper operation of an internal quasi-optical mode converter implemented to transform the operating whispering-gallery mode to a Gaussian-like beam was also verified. Based on the images of the gyrotron output beam taken with a pyroelectric camera, the Gaussian-like mode content of the output beam was computed to be 92% with an ellipticity of 12%. PMID- 21243082 TI - Comparison of the Mechanisms of Drug Resistance among HIV, Hepatitis B, and Hepatitis C. AB - Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are the most prevalent deadly chronic viral diseases. HIV is treated by small molecule inhibitors. HBV is treated by immunomodulation and small molecule inhibitors. HCV is currently treated primarily by immunomodulation but many small molecules are in clinical development. Although HIV is a retrovirus, HBV is a double-stranded DNA virus, and HCV is a single-stranded RNA virus, antiviral drug resistance complicates the development of drugs and the successful treatment of each of these viruses. Although their replication cycles, therapeutic targets, and evolutionary mechanisms are different, the fundamental approaches to identifying and characterizing HIV, HBV, and HCV drug resistance are similar. This review describes the evolution of HIV, HBV, and HCV within individuals and populations and the genetic mechanisms associated with drug resistance to each of the antiviral drug classes used for their treatment. PMID- 21243089 TI - Tumor necrosis factor alpha inhibits olfactory regeneration in a transgenic model of chronic rhinosinusitis-associated olfactory loss. AB - BACKGROUND: Olfactory loss is a debilitating symptom of chronic rhinosinusitis (CRS). Although olfactory sensory neurons (OSNs) are normally regenerated constantly in the olfactory epithelium (OE), a transgenic model of CRS-associated olfactory loss (inducible olfactory inflammation [IOI] mouse) shows that inflammation causes widespread OSN loss without progenitor cell proliferation. In this study, we further examine whether the inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) inhibits olfactory regeneration. METHODS: IOI mice underwent either unilateral bulbectomy or sham surgery and then were induced to express TNF-alpha in the OE for 1 week. After death, the mice were assessed histologically and with bromodeoxyuridine staining to determine the effect of TNF alpha on olfactory regeneration. RESULTS: In the absence of TNF-alpha, bulbectomy was associated with death of OSNs, followed by robust proliferation of neural progenitors and regrowth of the OE. At 12 days postbulbectomy, OE thickness on the operated side had recovered to >80% of the unoperated side. In mice in which TNF-alpha expression was induced, significantly reduced proliferation was observed, associated with failure of normal reconstitution of OE thickness. CONCLUSION: The mechanism of olfactory dysfunction in CRS remains incompletely understood. Previous studies with a transgenic mouse model suggested that inflammation inhibits progenitor cell proliferation and olfactory regeneration. Here, the role of the CRS-associated cytokine TNF-alpha was investigated using surgical ablation of the olfactory bulb to stimulate synchronous OSN turnover. We find that TNF-alpha expression prevents normal OE recovery, supporting the role of suppressed olfactory regeneration in the pathophysiology of CRS-associated olfactory loss. PMID- 21243090 TI - Comparison of Current BLAST Software on Nucleotide Sequences. AB - The computational power needed for searching exponentially growing databases, such as GenBank, has increased dramatically. Three different implementations of the most widely used sequence alignment tool, known as BLAST (Basic Local Alignment Search Tool), are studied for their efficiency on nucleotide-nucleotide comparisons. The performance of these implementations are evaluated using target databases and query sequences of varying lengths and number of entries constructed from human genomic and EST sequences. In general, WU BLAST was found to be most efficient when the database and query composition are unknown. NCBI BLAST appears to work best when the database contains a small number of sequences, while mpiBLAST shows the power of database distribution when the number of bases per target database is large. The optimal number of compute nodes in mpiBLAST varies depending upon the database, yet in the cases studied, remains surprisingly low. PMID- 21243091 TI - CFS: A Review of Epidemiology and Natural History Studies. AB - Almost all studies with samples of patients who have chronic fatigue syndrome (CFS) have relied on referrals from physicians or health facilities. Under-served minorities, who not only tend to manifest higher levels of chronic illness, but are also less likely to seek and receive adequate medical care, have not been represented in these studies (1). This may have contributed to an under estimation of CFS among minority groups (2). Few studies have derived their samples from socioeconomically and ethnically diverse community-based populations. A technical report issued by the Agency for Healthcare Research and Quality (3) concluded that estimating rates of recovery/improvement or relapse from CFS are not possible because there are so few natural history studies and those that are available have involved selected referral populations. This paper provides a review of epidemiologic studies of CFS followed by a discussion of diagnostic issues and risk factors for the illness. Findings from Jason et al.'s (4) epidemiologic study in a multi-ethnic, economically diverse urban area are highlighted as this research group is now examining the natural course of CFS over the past 10 years with this community-based sample. The current study will add to current epidemiologic and risk factors research by assessing the course, progression, and risk factors of CFS among a demographically diverse sample of participants who are unbiased by illness, help-seeking behaviors, or differential access to the health care system. PMID- 21243092 TI - Sleep Disturbances in Cancer. PMID- 21243093 TI - Assessment of contrast flow modification in aneurysms treated with closed-cell self-deploying asymmetric vascular stents (SAVS). AB - The Asymmetric Vascular Stent (AVS) for intracranial aneurysm (IA) treatment is an experimental device, specially designed for intra-aneurysmal blood flow diversion and thrombosis promotion. The stent has a low-porous patch to cover only the aneurysm neck while the rest of the stent is very porous to avoid blockage of adjacent branches. The latest AVS design is similar to state-of-art, closed-cell, self-expanding, neurovascular stent. The stents were used to treat sixteen rabbit-elastase aneurysm models. The treatment effect was analyzed using normalized-time-density-curves (NTDC) measured by pixel-value integration over a region-of-interest containing the aneurysm. Normalization constant was the total bolus injection determined angiographically. Based on NTDC measurement, five quantities were derived to describe the contrast flow. Two are related to the amount of contrast entering the aneurysm: NTDC peak and NTDC input slope. The other three are related to contrast presence in the aneurysmal dome: time-to-peak (TTP), wash-out-time (WOT) and mean-transit-time (MTT). Flow modification descriptions using the contrast related quantities were expressed as a pre-/post stented NTDC parameter ratio, while the time related quantities were expressed as a post-/pre-stented ratio, so that ratios smaller than one indicate a desired effect. Thirteen aneurysms were treated successfully and achieved significant aneurysm occlusion. For these cases, the resulting average parameters were: peak ratio=0.17+/-0.21; input-slope-ratio=0.19+/-0.24, TTP-ratio=0.17+/-0.21, WOT ratio=0.58+/-0.73 and MTT-ratio=0.65+/-0.97). All the quantities revealed decreased aneurysmal flow due to blood flow diversion using the new self expanding asymmetrical vascular stent (SAVS). Treatment outcome results and angiographic analysis indicate that the new self-deploying stent design has great potential for clinical implementation. PMID- 21243094 TI - The Solid State X-ray Image Intensifier (SSXII) in Single Photon Counting (SPC) mode. AB - The new Solid State X-Ray Image Intensifier (SSXII) has the unique ability to operate in single photon counting (SPC) mode, with improved resolution, as well as in traditional energy integrating (EI) mode. The SSXII utilizes an electron multiplying CCD (EMCCD), with an effective pixel size of 32MUm, which enables variable signal amplification (up to a factor of 2000) prior to digital readout, providing very high-sensitivity capabilities. The presampled MTF was measured in both imaging modes using the standard angulated-slit method. A measured detector entrance exposure of 24MUR per frame was used to provide approximately 0.8 interaction events per pixel in the 10MUm-wide slit area. For demonstration purposes, a simple thresholding technique was used to localize events in SPC mode and a number of such frames were summed to provide an image with the same total exposure used for acquiring the EI image. The MTF for SPC mode, using a threshold level of 15% of the maximum 12-bit signal and 95% of the expected events, and for EI mode (in parentheses) was 0.67 (0.20), 0.37 (0.07), 0.20 (0.03), and 0.11 (0.01) at 2.5, 5, 7.5, and 10 cycles/mm, respectively. Increasing the threshold level resulted in a corresponding increase in the measured SPC MTF and a lower number of detected events, indicating a tradeoff between resolution and count efficiency is required. The SSXII in SPC mode was shown to provide substantial improvements in resolution relative to traditional EI mode, which should benefit applications that have demanding spatial resolution requirements, such as mammography. PMID- 21243095 TI - CHARACTERIZATION OF PARTICULATE MATTER EMISSION FROM OPEN BURNING OF RICE STRAW. AB - Emission from field burning of crop residue, a common practice in many parts of the world today, has potential effects on air quality, atmosphere and climate. This study provides a comprehensive size and compositional characterization of particulate matter (PM) emission from rice straw (RS) burning using both in situ experiments (11 spread field burning) and laboratory hood experiments (3 pile and 6 spread burning) that were conducted during 2003-2006 in Thailand. The carbon balance and emission ratio method was used to determine PM emission factors (EF) in the field experiments. The obtained EFs varied from field to hood experiments reflecting multiple factors affecting combustion and emission. In the hood experiments, EFs were found to be depending on the burning types (spread or pile), moisture content and the combustion efficiency. In addition, in the field experiments, burning rate and EF were also influenced by weather conditions, i.e. wind. Hood pile burning produced significantly higher EF (20+/-8 g kg(-1) RS) than hood spread burning (4.7+/-2.2 g kg(-1) RS). The majority of PM emitted from the field burning was PM(2.5) with EF of 5.1+/-0.7 g m(-2) or 8.3+/-2.7 g kg(-1) RS burned. The coarse PM fraction (PM(10-2.5)) was mainly generated by fire attention activities and was relatively small, hence the resulting EF of PM(10) (9.4+/-3.5 g kg(-1) RS) was not significantly higher than PM(2.5). PM size distribution was measured across 8 size ranges (from <0.4 MUm to >9.0 MUm). The largest fractions of PM, EC and OC were associated with PM(1.1). The most significant components in PM(2.5) and PM(10) include OC, water soluble ions and levoglucosan. Relative abundance of some methoxyphenols (e.g., acetylsyringone), PAHs (e.g., fluoranthene and pyrene), organochlorine pesticides and PCBs may also serve as additional signatures for the PM emission. Presence of these toxic compounds in PM of burning smoke increases the potential toxic effects of the emission. For illustration, an estimation of the annual RS field burning in Thailand was made using the obtained in situ field burning EFs and preliminary burning activity data. PMID- 21243096 TI - Hydrophilization of Magnetic Nanoparticles with Modified Alternating Copolymers. Part 2: Behavior in solution. AB - Aqueous solutions of iron oxide nanoparticles (NPs) stabilized by poly(maleic acid-alt-1-octadecene) (PMAcOD) modified with the 5,000 Da poly(ethylene glycol) (PEG) or the short ethylene glycol (EG) tails were analyzed by small-angle X-ray scattering (SAXS). Advanced SAXS data analysis methods were employed to systematically characterize the structure and interactions between the NPs. Depending on the type of the grafted tail and the grafting density all NPs can be separated into three groups. All the samples contain mixtures of individual nanoparticles, their dynamic clusters and aggregates, and the fractions of these species are different in the different groups. The first group consists of NPs coated with PMAcOD modified with the long PEG tails with the maximal grafting density, and the content of dynamic clusters and aggregates in the samples of this group does not exceed 4%. The samples from the second group with less dense coatings demonstrate a larger amount (5-7%) of the aggregates and dynamic clusters. The samples from the third group consisting of the NPs protected by EG modified PMAcOD contain mostly individual NPs and some amount of dumbbell dimers without noticeable aggregation. Importantly, the solution behavior of the NPs is independent on the iron oxide core size. Our results therefore provide means of predicting stabilization and avoiding aggregation of NPs based on the type of a protective shell. PMID- 21243097 TI - Overview of type 2 diabetes in Hispanic Americans. AB - Diabetes mellitus continues to be a heavy burden on health and health resources throughout the world. In the USA the burden is borne disproportionately by ethnic minorities such as Hispanics. Therefore health education for Hispanics is important and it can help reduce the incidence of diabetes among Hispanics in the USA. PMID- 21243098 TI - [Lu]-DOTA-Tyr-octreotate: A Potential Targeted Radiotherapeutic for the Treatment of Medulloblastoma. AB - Medulloblastoma, the most common pediatric brain tumor, is difficult to treat because conventional therapeutic approaches result in significant toxicity to normal central nervous system tissues, compromising quality of life. Given the fact that medulloblastomas express the somatostatin subtype 2 receptor, [(177)Lu DOTA(0),Tyr(3)]octreotate ([(177)Lu]DOTA-TATE) could be a potentially useful targeted radiotherapeutic for the treatment of this malignancy. The current study was undertaken to evaluate this possibility in preclinical models of D341 MED human medulloblastoma by comparing the properties of [(177)Lu]DOTA-TATE to those of glucose-[(125)I-Tyr(3)]-octreotate ([(125)I]Gluc-TOCA), a radiopeptide previously shown to target this cell line. In vitro assays indicated that both labeled peptides exhibited similar cell-associated and internalized radioactivity after a 30-min incubation at 37 degrees C; however, at the end of the 4 h incubation period, the internalized radioactivity for [(177)Lu]DOTA-TATE (6.22 " 0.75%) was nearly twice that for [(125)I]Gluc-TOCA (3.16 " 0.27%), with similar differences seen in total cell-associated radioactivity levels. Consistent with the results from the internalization assays, results from paired-label tissue distribution studies in athymic mice with subcutaneous D341 MED medulloblastoma xenografts showed a similar degree of tumor accumulation for [(177)Lu]DOTA-TATE and [(125)I]Gluc-TOCA at early time points but by 24 h, a more than 5-fold advantage was observed for the (177)Lu-labeled peptide. Tumor-to-normal tissue ratios generally were more favorable for [(177)Lu]DOTA-TATE at all time points, due in part to its lower accumulation in normal tissues except kidneys. Taken together, these results suggest that [(177)Lu]DOTA-TATE warrants further investigation as a targeted radiotherapeutic for medulloblastoma treatment. PMID- 21243099 TI - Fabrication of Polyvalent Therapeutic RNA Nanoparticles for Specific Delivery of siRNA, Ribozyme and Drugs to Targeted Cells for Cancer Therapy. AB - Bacteriophage phi29 DNA packaging motor is geared by a six-pRNA ring. pRNA is able to form a multimeric complex and patterned superstructures via the interaction of two reengineered interlocking loops. This unique feature makes it an ideal polyvalent vehicle for nanomachine fabrication, pathogen detection, and the delivery of therapeutics. This report describes novel approaches for the fabrication of polyvalent therapeutic pRNA nanoparticles, especially tetramers for specific siRNA delivery to cancer cells and for the silencing of targeted genes. RNA 3-D design, circular permutation, folding energy alteration, and nucleotide modification were applied to generate stable RNA nanoparticles with low toxicity. Animal trials demonstrated the high efficiency of the polyvalent RNA nanoparticles in the prevention and treatment of cancer. Using such protein free nanoparticles as therapeutic reagents would allow for long-term administration to avoid the induction of antibody due to repeated treatment for chronic diseases. PMID- 21243101 TI - Color Image Segmentation in a Quaternion Framework. AB - In this paper, we present a feature/detail preserving color image segmentation framework using Hamiltonian quaternions. First, we introduce a novel Quaternionic Gabor Filter (QGF) which can combine the color channels and the orientations in the image plane. Using the QGFs, we extract the local orientation information in the color images. Second, in order to model this derived orientation information, we propose a continuous mixture of appropriate hypercomplex exponential basis functions. We derive a closed form solution for this continuous mixture model. This analytic solution is in the form of a spatially varying kernel which, when convolved with the signed distance function of an evolving contour (placed in the color image), yields a detail preserving segmentation. PMID- 21243100 TI - Extraribosomal functions associated with the C terminus of the 37/67 kDa laminin receptor are required for maintaining cell viability. AB - The 37/67 kDa laminin receptor (LAMR) is a multifunctional protein, acting as an extracellular receptor, localizing to the nucleus, and playing roles in rRNA processing and ribosome assembly. LAMR is important for cell viability; however, it is unclear which of its functions are essential. We developed a silent mutant LAMR construct, resistant to siRNA, to rescue the phenotypic effects of knocking down endogenous LAMR, which include inhibition of protein synthesis, cell cycle arrest, and apoptosis. In addition, we generated a C-terminal-truncated silent mutant LAMR construct structurally homologous to the Archaeoglobus fulgidus S2 ribosomal protein and missing the C-terminal 75 residues of LAMR, which displays more sequence divergence. We found that HT1080 cells stably expressing either silent mutant LAMR construct still undergo arrest in the G1 phase of the cell cycle when treated with siRNA. However, the expression of full-length silent mutant LAMR rescues cell viability, whereas the expression of the C-terminal truncated LAMR does not. Interestingly, we also found that both silent mutant constructs restore protein translation and localize to the nucleus. Our findings indicate that the ability of LAMR to regulate viability is associated with its C terminal 75 residues. Furthermore, this function is distinct from its role in cell proliferation, independent of its ribosomal functions, and may be regulated by a nonnuclear localization. PMID- 21243102 TI - Summarizing Documents by Measuring the Importance of a Subset of Vertices within a Graph. AB - This paper presents a novel method of generating extractive summaries for multiple documents. Given a cluster of documents, we firstly construct a graph where each vertex represents a sentence and edges are created according to the asymmetric relationship between sentences. Then we develop a method to measure the importance of a subset of vertices by adding a super-vertex into the original graph. The importance of such a super-vertex is quantified as super-centrality, a quantitative measure for the importance of a subset of vertices within the whole graph. Finally, we propose a heuristic algorithm to find the best summary. Our method is evaluated with extensive experiments. The comparative results show that the proposed method outperforms other methods on several datasets. PMID- 21243103 TI - Application of Metamorphic Testing to Supervised Classifiers. AB - Many applications in the field of scientific computing - such as computational biology, computational linguistics, and others - depend on Machine Learning algorithms to provide important core functionality to support solutions in the particular problem domains. However, it is difficult to test such applications because often there is no "test oracle" to indicate what the correct output should be for arbitrary input. To help address the quality of such software, in this paper we present a technique for testing the implementations of supervised machine learning classification algorithms on which such scientific computing software depends. Our technique is based on an approach called "metamorphic testing", which has been shown to be effective in such cases. More importantly, we demonstrate that our technique not only serves the purpose of verification, but also can be applied in validation. In addition to presenting our technique, we describe a case study we performed on a real-world machine learning application framework, and discuss how programmers implementing machine learning algorithms can avoid the common pitfalls discovered in our study. We also discuss how our findings can be of use to other areas outside scientific computing, as well. PMID- 21243104 TI - Evaluation of Diarylureas for Activity Against Plasmodium falciparum. AB - A library of diarylurea IGFR inhibitors was screened for activity against chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. The 4-aminoquinaldine-derived diarylureas displayed promising antimalarial potency. Further exploration of the B ring of 4-aminoquinaldinyl ureas allowed identification of several quinaldin-4-yl ureas 4{13, 39} and 4{13, 58} sufficiently potent against both 3D7 and K1 strains to qualify as bone fide leads. PMID- 21243105 TI - Using Basic Science to Develop an Innovative Program in Complementary and Alternative Medicine. AB - The growing interest in Complementary and Alternative Medicine (CAM) and the increasing incorporation of its modalities in the United States' healthcare system have exposed a number of problems in the field. These include a shortage of qualified CAM providers, scarcity of evidence-based research, lack of trained scientists in the field, and the ubiquitous marketing of frequently uncontrolled CAM products. Thus, the development of a comprehensive and scientifically sound educational infrastructure has become a crucial initial step in redirecting these adverse trends.With support from the NIH-sponsored curricular CAM initiative, faculty from the department of physiology and biophysics at Georgetown University developed a M.S. program in CAM in 2003. This unique, first of its kind, science based graduate program offers a master's degree (MS) in physiology with an emphasis on CAM. The CAM-MS degree in physiology is designed to enable students to critically assess various CAM modalities, apply scientific rigor, and carry out evidence-based CAM research. The curriculum includes core science courses and CAM-related classes. Additionally, in order to emphasize the application of academic knowledge and further strengthen problem-solving skills, the students complete an eight-week summer practicum in a professional CAM-related environment.Here, we report on our innovative and interdisciplinary CAM graduate program where creative teaching is implemented by basic scientists and enhanced by the application of their disciplines in tandem with the clinical expertise of CAM practitioners in the community. Thus, the faculty in the Department of Physiology & Biophysics is developing emerging cross disciplinary areas of study and interest in order to prepare new generations of future physicians, health professionals, educators, and researchers capable of objectively assessing the safety and efficacy of various CAM modalities, and introducing scientific rigor to much needed research into the various aspects of CAM therapies. PMID- 21243106 TI - A 4-channel 3 Tesla phased array receive coil for awake rhesus monkey fMRI and diffusion MRI experiments. AB - Awake monkey fMRI and diffusion MRI combined with conventional neuroscience techniques has the potential to study the structural and functional neural network. The majority of monkey fMRI and diffusion MRI experiments are performed with single coils which suffer from severe EPI distortions which limit resolution. By constructing phased array coils for monkey MRI studies, gains in SNR and anatomical accuracy (i.e., reduction of EPI distortions) can be achieved using parallel imaging. The major challenges associated with constructing phased array coils for monkeys are the variation in head size and space constraints. Here, we apply phased array technology to a 4-channel phased array coil capable of improving the resolution and image quality of full brain awake monkey fMRI and diffusion MRI experiments. The phased array coil is that can adapt to different rhesus monkey head sizes (ages 4-8) and fits in the limited space provided by monkey stereotactic equipment and provides SNR gains in primary visual cortex and anatomical accuracy in conjunction with parallel imaging and improves resolution in fMRI experiments by a factor of 2 (1.25 mm to 1.0 mm isotropic) and diffusion MRI experiments by a factor of 4 (1.5 mm to 0.9 mm isotropic). PMID- 21243107 TI - Cascading Policies Provide Fault Tolerance for Pervasive Clinical Communications. AB - We implemented an end-to-end notification system that pushed urgent clinical laboratory results to Blackberry 7510 devices over the Nextel cellular network. We designed our system to use user roles and notification policies to abstract and execute clinical notification procedures. We anticipated some problems with dropped and non-delivered messages when the device was out-of-network, however, we did not expect the same problems in other situations like device reconnection to the network. We addressed these problems by creating cascading "fault tolerance" policies to drive notification escalation when messages timed-out or delivery failed. This paper describes our experience in providing an adaptable, fault tolerant pervasive notification system for delivering secure, critical, time-sensitive patient laboratory results. PMID- 21243108 TI - Applications of a new In vivo tumor spheroid based shell-less chorioallantoic membrane 3-D model in bioengineering research. AB - The chicken chorioallantoic membrane (CAM) is a classical in vivo biological model in studies of angiogenesis. Combined with the right tumor system and experimental configuration this classical model can offer new approaches to investigating tumor processes. The increase in development of biotechnological devices for cancer diagnosis and treatment, calls for more sophisticated tumor models that can easily adapt to the technology, and provide a more accurate, stable and consistent platform for rapid quantitative and qualitative analysis. As we discuss a variety of applications of this novel in vivo tumor spheroid based shell-less CAM model in biomedical engineering research, we will show that it is extremely versatile and easily adaptable to an array of biomedical applications. The model is particularly useful in quantitative studies of the progression of avascular tumors into vascularized tumors in the CAM. Its environment is more stable, flat and has a large working area and wider field of view excellent for imaging and longitudinal studies. Finally, rapid data acquisition, screening and validation of biomedical devices and therapeutics are possible with the short experimental window. PMID- 21243109 TI - Hard Braking Events Among Novice Teenage Drivers By Passenger Characteristics. AB - In a naturalistic study of teenage drivers (N = 42) hard braking events of <= 0.45 g were assessed over the first 6 months of licensure. A total of 1,721 hard braking events were recorded. The video footage of a sample (816) of these events was examined to evaluate validity and reasons for hard braking. Of these, 788 (96.6%) were estimated valid, of which 79.1% were due to driver misjudgment, 10.8% to risky driving behavior, 5.3% to legitimate evasive maneuvers, and 4.8% to distraction. Hard braking events per 10 trips and per 100 miles were compared across passenger characteristics. Hard braking rates per 10 trips among newly licensed teenagers during the first 6 months of licensure were significantly higher when driving with teen passengers and lower with adult passengers than driving alone; rates per 100 miles were lower with adult passengers than with no passengers. Further examination of the results indicates that rates of hard braking with teenage passengers were significantly higher compared with no passengers: 1) for male drivers; 2) during the first month of licensure. The data suggest that that novice teenage driving performance may not be as good or safe when driving alone or with teenage passengers than with adult passengers and provide support for the hypothesis that teenage passengers increase driving risks, particularly during the first month of licensure. PMID- 21243110 TI - Developmental Psychopathology and the Diagnosis of Mental Health Problems among Youth. AB - Recent years have evidenced a tremendous increase in research using a developmental psychopathology framework to examine clinical diagnoses among youth. Despite this increase, a relative dearth of literature systematically examines the development of co-occurring conditions among youth. In this introduction to the Special Issue on comorbidity among youth, we suggest that a developmental psychopathology perspective can provide an important foundation for the diagnosis of mental health problems among youth. As a potential framework for future investigations, we consider several developmental psychopathology principles that can inform assessment and diagnosis among youth psychological disorders. We use these principles as a foundation for considering co-occurring psychological disorders and provide potential explanations for comorbidity that can be addressed in future research that uses a developmental psychopathology perspective. PMID- 21243111 TI - The Future of Indirect Evidence. AB - Familiar statistical tests and estimates are obtained by the direct observation of cases of interest: a clinical trial of a new drug, for instance, will compare the drug's effects on a relevant set of patients and controls. Sometimes, though, indirect evidence may be temptingly available, perhaps the results of previous trials on closely related drugs. Very roughly speaking, the difference between direct and indirect statistical evidence marks the boundary between frequentist and Bayesian thinking. Twentieth-century statistical practice focused heavily on direct evidence, on the grounds of superior objectivity. Now, however, new scientific devices such as microarrays routinely produce enormous data sets involving thousands of related situations, where indirect evidence seems too important to ignore. Empirical Bayes methodology offers an attractive direct/indirect compromise. There is already some evidence of a shift toward a less rigid standard of statistical objectivity that allows better use of indirect evidence. This article is basically the text of a recent talk featuring some examples from current practice, with a little bit of futuristic speculation. PMID- 21243112 TI - What Does Teaching Declaratives Tell Us About the Criteria by Which we Can Judge the Developmental Importance of Treatment Outcomes? AB - This paper uses examples of treatment research on declaratives to illustrate criteria for determining whether a taught behavior is a "skill", not just a context-bound behavior and whether the taught skill has associations with other theoretically linked skills as one type of validation evidence. The paper uses data from three treatment studies to illustrate the issues and proposed criteria. The paper concludes with a call to consumers and producers of treatment research to use the criteria to judge the developmental importance of treatment outcomes. PMID- 21243113 TI - Conformational Statistics of Semi-Flexible Macromolecular Chains with Internal Joints. AB - Fluctuations in the bending angles at internal irregularities of DNA and RNA (such as symmetric loops, bulges, and nicks/gaps) have been observed from various experiments. However, little effort has been made to computationally predict and explain the statistical behavior of semi-flexible chains with internal defects. In this paper, we describe the general structure of these macromolecular chains as inextensible elastic chains with one or more internal joints which have limited ranges of rotation, and propose a method to compute the probability density functions of the end-to-end pose of these macromolecular chains. Our method takes advantage of the operational properties of the non-commutative Fourier transform for the group of rigid-body motions in three-dimensional space, SE(3). Two representative types of joints, the hinge for planar rotation and the ball joint for spatial rotation, are discussed in detail. The proposed method applies to various stiffness models of semi-flexible chain-like macromolecules. Examples are calculated using the Kratky-Porod model with specified stiffness, angular fluctuation, and joint locations. Entropic effects associated with internal angular fluctuations of semi-flexible macromolecular chains with internal joints can be computed using this formulation. Our method also provides a potential tool to detect the existence of internal irregularities. PMID- 21243114 TI - Bringing the Field into Focus: User-centered Design of a Patient Expertise Locator. AB - Managing personal aspects of health is challenging for many patients, particularly those facing a serious condition such as cancer. Finding experienced patients, who can share their knowledge from managing a similar health situation, is of tremendous value. Users of health-related social software form a large base of such knowledge, yet these tools often lack features needed to locate peers with expertise. Informed directly by our field work with breast cancer patients, we designed a patient expertise locator for users of online health communities. Using feedback from two focus groups with breast cancer survivors, we took our design through two iterations. Focus groups concluded that expertise locating features proved useful for extending social software. They guided design enhancements by suggesting granular user control through (1) multiple mechanisms to identify expertise, (2) detailed user profiles to select expertise, and (3) varied collaboration levels. Our user-centered approach links field work to design through close collaboration with patients. By illustrating trade-offs made when sharing sensitive health information, our findings inform the incorporation of expertise locating features into social software for patients. PMID- 21243115 TI - Foster Care Placement, Poor Parenting, and Negative Outcomes Among Homeless Young Adults. AB - Although homeless youth with and without foster care histories both face adverse life circumstances, little is known about how these two groups compare in terms of their early histories and whether they face similar outcomes. As such, we compared those with and without a history of foster care placement to determine if the associations between a history of poor parenting and negative outcomes including depression, delinquency, physical and sexual victimization, and substance use, are similar for these two groups. The sample consisted of 172 homeless young adults from the Midwestern United States. Multivariate results revealed that among those previously in foster care, a history of physical abuse and neglect were positively associated with more depressive symptoms whereas sexual abuse and neglect were related to delinquency and physical victimization. Additionally, lower caretaker monitoring was linked to greater delinquent participation. Among those without a history of foster care, physical abuse was related to more depressive symptoms whereas sexual abuse was positively correlated with delinquency, sexual victimization, and substance use. Furthermore, lower monitoring was related to more substance use. Our findings are discussed in terms of a social stress framework and we review the implications of foster care placement for homeless young adults. PMID- 21243116 TI - Expanded Highly Active Antiretroviral Therapy Coverage - A Powerful Strategy to Curb Progression to AIDS, Death and New Infections. AB - Sustained combination of HIV prevention strategies is essential to curb the spread of the HIV/AIDS epidemic. The use of highly active antiretroviral therapy (HAART) decreases morbidity and mortality, as well as HIV transmission, among treated individuals. The concept of 'treatment as prevention' is dependent on HAART's ability to sustain HIV-1 RNA virological suppression at the individual and population levels, and has been demonstrated in studies evaluating transmission in mother-to-child, sero-discordant couples and large treated populations. The worldwide expansion of maximally effective antiretroviral drug regimens has been coupled with concerns regarding the magnitude of the financial investment required. However, HAART's compounding effect on reduced morbidity, mortality and transmission makes the expansion of HAART coverage highly cost averting. Building on a mathematical model that evaluated the impact of expanded HAART access on viral load in a Canadian setting, we demonstrate that an investment of CA$249 million over the lifetime of treated individuals would result in a net gain of CA$2.1 billion over 30 years. This provides a powerful economic incentive to rapidly scale up HAART access worldwide. PMID- 21243117 TI - Uneven Profiles: Language Minority Learners' Word Reading, Vocabulary, and Reading Comprehension Skills. AB - English reading comprehension skill development was examined in a group of 87 native Spanish-speakers developing English literacy skills, followed from fourth through fifth grade. Specifically, the effects of Spanish (L1) and English (L2) oral language and word reading skills on reading comprehension were investigated. The participants showed average word reading skills and below average comprehension skills, influenced by low oral language skills. Structural equation modeling confirmed that L2 oral language skills had a large, significant effect on L2 reading comprehension, whereas students' word-level reading skills, whether in L1 or L2, were not significantly related to English reading comprehension in three of four models fitted. The results converge with findings from studies with monolinguals demonstrating the influence of oral language on reading comprehension outcomes, and extend these findings by showing that, for language minority learners, L2 oral language exerts a stronger influence than word reading in models of L2 reading. PMID- 21243118 TI - Use of the Simple and Extended Grunwald-Winstein Equations in the Correlation of the Rates of Solvolysis of Highly Hindered Tertiary Alkyl Derivatives. AB - The original Grunwald-Winstein equation (1948) involved the development of a scale of solvent ionizing power (Y). Subsequent work has refined this scale and involved the development of scales of solvent nucleophilicity (N) and a term to correct for deviations when aromatic rings are present, governed by the aromatic ring parameter (I). These three scales, and the sensitivities towards each, can be related to specific rates of solvolysis through linear free energy relationships (LFERs).One important area of application of LFERs has been to the solvolyses of tert-alkyl halides. It has been proposed that the solvolysis of tert-butyl chloride involves a nucleophilic component, although other workers have suggested that the effects observed are related to electrophilic not nucleophilic influences. Takeuchi (1997) studied a compound with two of the methyl groups of tert-butyl chloride replaced by neopentyl groups. For this highly-hindered substrate there was no evidence for nucleophilic participation. Liu (1998) and Takeuchi (2001) have reported concerning the solvolyses of additional significantly-hindered tertiary alkyl chlorides. Liu (2009) has presented a parallel study of bromides. Martins (2008) has considered hindered tertiary alkyl halides, mainly with carbon-carbon multiple bonds as substituents. It was proposed that the hI term was of importance, with the sensitivities (h) sometimes positive and sometimes negative. To explain negative values, it was suggested that the I scale might contain a nucleophilicity component. In this review, we bring together, with analysis and commentary, the work of Takeuchi, Liu, Martins and others concerning the solvolyses of tertiary alkyl halides, with emphasis on the relevance of the three scales that have been developed for use in Grunwald-Winstein correlations. PMID- 21243119 TI - A Two-Magnet System to Push Therapeutic Nanoparticles. AB - Magnetic fields can be used to direct magnetically susceptible nanoparticles to disease locations: to infections, blood clots, or tumors. Any single magnet always attracts (pulls) ferro- or para-magnetic particles towards it. External magnets have been used to pull therapeutics into tumors near the skin in animals and human clinical trials. Implanting magnetic materials into patients (a feasible approach in some cases) has been envisioned as a means of reaching deeper targets. Yet there are a number of clinical needs, ranging from treatments of the inner ear, to antibiotic-resistant skin infections and cardiac arrhythmias, which would benefit from an ability to magnetically "inject", or push in, nanomedicines. We develop, analyze, and experimentally demonstrate a novel, simple, and effective arrangement of just two permanent magnets that can magnetically push particles. Such a system might treat diseases of the inner ear; diseases which intravenously injected or orally administered treatments cannot reach due to the blood-brain barrier. PMID- 21243120 TI - The role of the marrow microenvironment in hematopoietic stem cell transplantation. AB - The success of hematopoietic stem cell transplantation depends on the engraftment of pluripotent hematopoietic stem cells and the regulated proliferation and maturation of committed progenitor cells. It is generally agreed that these processes cannot occur without an appropriate milieu provided by a competent marrow microenvironment (ME). The ME is composed of both non-hematopoietic and hematopoietic stem cell derived cells and consequently is chimeric following allogeneic stem cell transplantation, containing recipient stromal cells and donor macrophages. PMID- 21243121 TI - Assessing Local Model Adequacy in Bayesian Hierarchical Models Using the Partitioned Deviance Information Criterion. AB - Many diagnostic tools and goodness-of-fit measures, such as the Akaike information criterion (AIC) and the Bayesian deviance information criterion (DIC), are available to evaluate the overall adequacy of linear regression models. In addition, visually assessing adequacy in models has become an essential part of any regression analysis. In this paper, we focus on a spatial consideration of the local DIC measure for model selection and goodness-of-fit evaluation. We use a partitioning of the DIC into the local DIC, leverage, and deviance residuals to assess local model fit and influence for both individual observations and groups of observations in a Bayesian framework. We use visualization of the local DIC and differences in local DIC between models to assist in model selection and to visualize the global and local impacts of adding covariates or model parameters. We demonstrate the utility of the local DIC in assessing model adequacy using HIV prevalence data from pregnant women in the Butare province of Rwanda during 1989-1993 using a range of linear model specifications, from global effects only to spatially varying coefficient models, and a set of covariates related to sexual behavior. Results of applying the diagnostic visualization approach include more refined model selection and greater understanding of the models as applied to the data. PMID- 21243122 TI - It Is Developmental Me, Not Generation Me: Developmental Changes Are More Important Than Generational Changes in Narcissism-Commentary on Trzesniewski & Donnellan (2010). AB - In this article, we make two points about the ongoing debate concerning the purported increase in narcissistic tendencies in college students over the last 30 years. First, we show that when new data on narcissism are folded into preexisting meta-analytic data, there is no increase in narcissism in college students over the last few decades. Second, we show, in contrast, that age changes in narcissism are both replicable and comparatively large in comparison to generational changes in narcissism. This leads to the conclusion that every generation is Generation Me, as every generation of younger people are more narcissistic than their elders. PMID- 21243123 TI - A Path Analysis on the Nourishment Directed Haemoglobin Status and Resulting Endurance Capacity of Adolescent Indian Rural Girls. AB - A significant positive correlation of blood hemoglobin status and the endurance capacity as the function of nutritional status of a cross-sectional population of adolescent rural girls (13-15 years) of Thrissur district, Kerala State, India has been reported. Anthropometric measurements revealed that mean body weight and height of adolescent girls were low compared to Indian standards and BMI indicated a high prevalence (44 per cent) of chronic energy deficiency-Grade III. Very high portion (88.7 per cent) of the rural population of adolescent girls had energy intakes below normal standards. The prevalence of major deficiency diseases like dental caries, pigmented skins, glossitis and anaemia were also studied as functional responses. More than half of the population was suffering from either or more of the deficiencies and among the clinically identified symptoms, iron deficiency anaemia was most prevalent (30.0 per cent). Only 40 per cent had acceptable levels of haemoglobin (> 12g/dl). Though none of the adolescent girls had excellent or even good endurance capacity, two-way frequency analysis revealed a consistent increase in the same with acceptable levels of haemoglobin (Y = 3.33X + 26.11) and the nutritional status. The alarming status of malnutrition and its implications on rural girls is detailed hereunder. PMID- 21243125 TI - Highly hydrophobic polyfluorinated azo dyes grafted on surfaces. AB - Artificial hydrophobic surfaces have a great potential in a wide range of industrial applications owing to their self-cleaning, anti-fogging and anti biofouling properties. A family of polyfluorinated reactive azo dyes has been prepared and some of them easily modified and grafted on cotton fabric and glass surfaces obtaining new coloured hydrophobic materials. PMID- 21243126 TI - Photo-induced magnetic bistability in a controlled assembly of anisotropic coordination nanoparticles. AB - Anisotropic coordination nanoparticles of the photomagnetic network Cs(I)(2)Cu(II)(7)[Mo(IV)(CN)(8)](4) are obtained through a surfactant-free high yield synthetic procedure in water. These particles are organised as Langmuir Blodgett films with a preferential orientation of the nano-objects within the film that exhibit a magnetic bistability below 20 K with a very large coercivity due to an efficient photo-transformation. PMID- 21243124 TI - THE ROLE OF INTRACELLULAR SODIUM (Na) IN THE REGULATION OF CALCIUM (Ca)-MEDIATED SIGNALING AND TOXICITY. AB - It is known that activated N-methyl-D-aspartate receptors (NMDARs) are a major route of excessive calcium ion (Ca(2+)) entry in central neurons, which may activate degradative processes and thereby cause cell death. Therefore, NMDARs are now recognized to play a key role in the development of many diseases associated with injuries to the central nervous system (CNS). However, it remains a mystery how NMDAR activity is recruited in the cellular processes leading to excitotoxicity and how NMDAR activity can be controlled at a physiological level. The sodium ion (Na(+)) is the major cation in extracellular space. With its entry into the cell, Na(+) can act as a critical intracellular second messenger that regulates many cellular functions. Recent data have shown that intracellular Na(+) can be an important signaling factor underlying the up-regulation of NMDARs. While Ca(2+) influx during the activation of NMDARs down-regulates NMDAR activity, Na(+) influx provides an essential positive feedback mechanism to overcome Ca(2+)-induced inhibition and thereby potentiate both NMDAR activity and inward Ca(2+) flow. Extensive investigations have been conducted to clarify mechanisms underlying Ca(2+)-mediated signaling. This review focuses on the roles of Na(+) in the regulation of Ca(2+)-mediated NMDAR signaling and toxicity. PMID- 21243127 TI - Formaldehyde gas sensing chip based on single-walled carbon nanotubes and thin water layer. AB - We report a unique gaseous formaldehyde sensing chip based on a combination between patterned single-walled carbon nanotube field effect transistors and a precisely controlled aqueous layer with photopolymerized polyelectrolytic gels. The proposed system reliably detects 0.1 ppb level formaldehyde gas, suggesting a new type of indoor air quality monitoring device. PMID- 21243128 TI - Highly sensitive detection of saccharides under physiological conditions with click synthesized boronic acid-oligomer fluorophores. AB - Two phenylboronic acid based saccharide sensors bearing conjugated oligomer fluorophores with linear and cruciform pi-frameworks were synthesized in a modular approach utilizing a Cu-catalyzed alkyne azide cycloaddition (click) reaction. The cruciform fluorophore showed excellent saccharide sensing function under physiological conditions in the mM range, whereas the linear fluorophore gave very limited sensing functions. The different fluorescent sensing behaviours highlight the important role of oligomer fluorophore in the development of effective saccharide sensors. PMID- 21243129 TI - A straightforward and efficient synthetic access to biologically active marine sesterterpenoids, sesterstatins 4 and 5. AB - A straightforward and efficient synthesis of sesterstatins 4 and 5 is reported, in which the reductive Heck cyclisation was employed as the key step for constructing the D ring. PMID- 21243130 TI - Linking heterometallic rings for quantum information processing and amusement. AB - Linking polymetallic cages can be a method for creating new structures and new properties. In this tutorial review we use heterometallic anti-ferromagnetically coupled rings (AF-rings) as exemplars for three approaches that can be used to link cage compounds. The first of three routes involves an ion-pair interaction supported by hydrogen-bonding interactions, which allows the synthesis of hybrid rotaxanes among other materials. The second route involves functionalising the exterior of the AF-ring so that it will act as a Lewis base; complexes involving coordination of pyridine to bridging monometallic and dimetallic fragments are discussed. The third route involves creating a vacancy on one site of the AF ring, and then using the ring as a Lewis acid. Di-imine ligands can then be used to link the AF-rings into dimers. A brief discussion of the physical properties of these systems is also included. PMID- 21243131 TI - A new strategy to prepare surface-enhanced Raman scattering-active substrates by electrochemical pulse deposition of gold nanoparticles. AB - In this communication, we develop a simple pathway to prepare SERS-active substrates with Au nanoparticles (NPs) by an electrochemical strategy of deposition-dissolution cycles (DDCs). The prepared SERS-active substrates demonstrate large Raman scattering enhancement for Rhodamine 6G (R6G) with a detection limit of 2 * 10(-12) M and an enhancement factor of 5.8 * 10(7). PMID- 21243132 TI - Samarium diiodide induced ketyl-(het)arene cyclisations towards novel N heterocycles. AB - In this tutorial review we discuss recent advances in the field of ketyl (het)arene cyclisations promoted by samarium diiodide and related processes. Couplings of samarium ketyls with carbon-carbon multiple bonds are perhaps the most useful reactions to create carbocycles and heterocycles of various ring sizes. They have also successfully been exploited for the synthesis of biologically active compounds or natural products. In this article we intend to summarise our diversity orientated approaches towards nitrogen heterocycles and emphasize other approaches with SmI(2) as well as electrochemical cyclisation methods providing similar N-heterocycles. We also briefly discuss our recently published formal total synthesis of strychnine employing a new samarium diiodide induced cascade reaction as key step. All these examples demonstrate the high synthetic potential of samarium ketyl-(het)arene cyclisations for the preparation of various types of important heterocyclic compounds. PMID- 21243133 TI - Profiling biological samples using ultra performance liquid chromatography inductively coupled plasma-mass spectrometry (UPLC-ICP-MS) for the determination of phosphorus and sulfur-containing metabolites. AB - In this preliminary study UPLC-ICP-MS has been utilized to profile a range of different bio-fluids and tissue extracts for sulfur and phosphorus-containing metabolites. Particular attention has been given to the livers, plasma and urine from lean and obese Zucker rats, with a view to differentiating between them based solely on their respective sulfur or phosphorus profiles and/or their total sulfur and phosphorus content. In addition, bile and tumour extracts have been analysed to observe the nature of their profiles. To the best of our knowledge this is the first time ICP-MS has been used in a non-targeted metabonomic study. Results have shown lower limits of quantification for sulfur and phosphorus methods of 0.25 and 0.15 ng on column with CVs of 14.7% and 10.9% respectively. Total phosphorus analysis of the Zucker rat aqueous liver extracts, plasma and urine has shown the pattern of phosphorus concentrations to be statistically significantly different in the lean and obese Zucker rats. Chromatographic separation of the Zucker rat organic liver extracts and plasma allowed further differentiation between the lean and obese rats using their phosphorus profiles alone. In conclusion, this preliminary study has shown the potential of UPLC-ICP MS to quantitatively discriminate between different species biofluids, fluids and tissues based solely on their phosphorus or sulfur concentrations and/or metabolomes. PMID- 21243134 TI - A PDMS viscometer for assaying endoglucanase activity. AB - A poly(dimethylsiloxane) (PDMS) viscometer was developed to analyze the activity of endo-beta-1,4-glucanases (EC3.2.1.4) on hydrolyzing sodium carboxymethylcellulose (NaCMC). In the viscometer, a PDMS pump was used as the vacuum source to drive the fluid flow in the PDMS microchannel. The numerical simulation by COMSOL suggested that the vacuum level of the PDMS pump increased during the viscosity measurement. The increasing vacuum level of the PDMS pump allowed more stable fluid flow than the constant vacuum of the conventional vacuum pump. By monitoring the fluids traveling in the microchannel, the viscosity of the endoglucanase-NaCMC solution was derived at different reaction times. The non-Newtonian behavior of the NaCMC solution was studied to ensure that the viscosity measurement was performed in the Newtonian range. A protocol was established to convert the viscometric activity to the activity of standard international units with Almin's method. The PDMS viscometer required only 20 MUL sample for the endoglucanase assay and the results were in good agreement with the results from Ubbelohde viscometers. PMID- 21243135 TI - Synthesis and X-ray crystal structures of imido and ureato derivatives of titanium(IV) phthalocyanine and their application in the catalytic formation of carbodiimides by metathesis from isocyanates. AB - The imido titanium phthalocyanine complex [PcTi(NDip)] (Dip = 2,6 diisopropylphenyl) 2a was synthesized from [PcTiO] 1 and one eq. of DipNCO. Due to the steric demand of the Dip group, addition of another isocyanate molecule to the Ti = N functionality of 2a does not occur even at high molar ratios of DipNCO. However, 1 reacts with 2 eq. of arylisocyanates containing sterically less demanding aryl groups producing N,N'-diarylureatotitanium(iv)phthalocyanines [PcTi{kappa(2)-(NR)C(O)(N'R)}] (R = p-tolyl (Tol) 3a or mesityl (Mes) 3b). The N,N' coordination (III) of the ureato ligand in 3a and 3b was proven by a single set of resonances for the aryl groups in their (1)H-NMR spectra. An N,O coordination (IV) can therefore be excluded. This is also confirmed by the X-ray crystal structure of 3a. Upon heating [PcTiO] and an excess of aryl isocyanates for 6 days, a steady evolution of CO(2) was observed and a white precipitate, identified as the corresponding diarylcarbodiimides (V), could be isolated. Therefore this reaction was applied in the metathetic conversion of two isocyanate molecules into diarylcarbodiimides (V) and CO(2). Additionally, imido titanium Pc's 2b (R = tBu) and 2c (R = Mes) were prepared by a more general synthetic strategy, reacting the potassium salt of the ligand PcK(2) with appropriate imido titanium precursors. PMID- 21243136 TI - Isolation of four new CoII/CoIII and NiII complexes with a pentadentate Schiff base ligand: syntheses, structural descriptions and magnetic studies. AB - In this paper we report the temperature and pH dependent syntheses and systematic characterization of four new Co(II)/Co(III) and Ni(II) complexes with a pentadentate Schiff base ligand H(3)L obtained by condensing 1,3,-diaminopropan-2 ol with 2-hydroxyacetophenone in 1:2 molar ratio. The room temperature syntheses involving Co(II) and Ni(II) nitrates and the ligand H(3)L lead to the isolation of the dinuclear species [Co(2)L(2)(H(2)O)] (1), and the mononuclear complex [Ni(LH)] (3), respectively, whereas refluxing at basic pH leads to the tetranuclear complexes, [Co(II)(2)Co(III)(2)L(2)(MU(3) OMe)(2)(NO(3))(H(2)O)(2)]NO(3).2(H(2)O) (2), and [Ni(4)L(2)(MU(3) OMe)(2)(H(2)O)(2)].2H(2)O (4). 1 is found to be a simple mono alkoxo-bridged Co(III) dinuclear species, whereas 2 and 4 are both rhomb-like tetrameric complexes with double oxo bridges and MU(3)-methoxo bridges, derived from the methanol solvent, in an open dicubane arrangement. Moreover 2 shows six coordinate ordered Co(II) and Co(III) ions and 4 has both six- and five coordinate Ni(II) centers. Compound 3 is assigned a tentative mononuclear structure based on IR, UV-Vis spectroscopic, (1)H-NMR and ESI mass study results and is supposed to have one Ni(II) center coordinated with a ligand fragment in square planar geometry. The variable temperature magnetic susceptibility study for 2 and 4 is performed which indicate for both 2 and 4 the presence of intracluster dominant ferromagnetic interactions. PMID- 21243137 TI - Fluorescence-based detection of nitric oxide in aqueous and methanol media using a copper(II) complex. AB - The quenched fluorescent intensity of a copper(II) complex, 1, of a fluorescent ligand, in degassed methanol or aqueous (buffered at pH 7.2) solution, was found to reappear on exposure to nitric oxide. Thus, it can function as a fluorescence based nitric oxide sensor. It has been found that the present complex can be used to sense nanomolar quantities of nitric oxide in both methanol and pH 7.2 buffered-water medium. PMID- 21243138 TI - KCN sensor: unique chromogenic and 'turn-on' fluorescent chemodosimeter: rapid response and high selectivity. AB - An indole conjugated coumarin 1 for KCN chemodosimeter has been prepared and displayed considerable dual changes in both absorption (blue-shift) and emission (turn-on) bands exclusively for KCN. DFT/TDDFT calculations support that the fluorescence enhancement of 1-KCN is mainly due to blocking of the ICT process. PMID- 21243139 TI - A "by-productless" cellulose foaming agent for use in imidazolium ionic liquids. AB - Cellulose foams, or sponges, are produced from solutions in ionic liquids by the aqueous acid mediated decomposition of 1-alkyl-3-methylimidazolium-2 carboxylates, where the alkyl group and acid may be selected such that the by product is the ionic liquid solvent: a by-productless foaming. PMID- 21243140 TI - Facile synthesis of metal N-heterocyclic carbene complexes. AB - A novel electrochemical procedure for the preparation of metal complexes of N heterocyclic carbenes using imidazolium salts or corresponding silver-NHC complexes as carbene sources and electrolytes, and metal plates as the sacrificial anodes is described. The procedure is simple and good yielding without the use of expensive or air-sensitive reagents. PMID- 21243141 TI - A facile noncatalytic pathway for the nitrene transfer process: expeditious access to aziridines. AB - A fast and efficient method has been developed for generation of sulfonyl nitrene from N,N-dibromo-p-toluenesulfonamide (TsNBr(2)) in the presence of a base without any catalyst. This method was applied to produce aziridines from different kinds of olefins within a short time in high yields. PMID- 21243142 TI - Vesicle growth and deformation in a surfactant solution below the Krafft temperature. AB - We have studied vesicle growth and deformation in aqueous solutions of nonionic surfactant C(16)E(7) below the Krafft temperature by means of an optical microscope. It has been found that vesicles become larger by fusing together, and that the growth rate is slower than that of the unilamellar vesicle or emulsion systems due to the multilamellar structures of shells in a vesicle. The deformation of the vesicles depends on the temperature quench depth, and we found the transformation from spherical vesicles to string-like domains at a certain quench-temperature. From the small angle X-ray scattering and confocal microscope experiments, it can be deduced that the deformation of vesicles would be induced by osmotic pressure due to the micellar concentration difference between inside and outside of vesicles. PMID- 21243143 TI - Experimental and DFT studies of gold nanoparticles supported on MgO(111) nano sheets and their catalytic activity. AB - A wet chemical preparation of MgO with the (111) facet as the primary surface has recently been reported and with alternating layers of oxygen anions and magnesium cations, this material shows unique chemical and physical properties. The potential to utilize the MgO(111) surface for the immobilization of metal particles is intriguing because the surface itself offers a very different environment for the metal particle with an all oxygen interface, as opposed to the typical (100) facet that possesses alternating oxygen anion and magnesium cation sites on the surface. Gold nanoparticles have demonstrated a broad range of interesting catalytic properties, but are often susceptible to aggregation at high temperatures and are very sensitive to substrate effects. Here, we investigate gold-supported on MgO(111) nanosheets as a catalyst system for the aerobic oxidation of benzyl alcohol. Gold nanoparticles deposited on MgO(111) show an increased level of activity in the solvent-free benzyl alcohol aerobic oxidation as compared to gold nanoparticles deposited on a typical MgO aerogel. TEM studies reveal that the gold nanoparticles have a hemispherical shape while sitting on the main surface of MgO(111) nanosheets, with a large Au-MgO interface. Given that the gold nanoparticles deposited on the two types of MgO have similar size, and that the two types of unmodified MgO show almost the same activities in the blank reaction, we infer that the high activity of Au/MgO(111) is due to the properties of the (111) support and/or those of the gold-support interface. To understand the binding of Au on low-index MgO surfaces and the charge distribution at the surface of the support, we have performed density functional theory (DFT) calculations on all low-index MgO substrates (with and without gold), using a model Au(10) cluster. Due to similar lattice constants of Au(111) and MgO(111) planes, the Au cluster retains its structural integrity and binds strongly on MgO(111) with either oxygen or magnesium termination. Furthermore, we have found that for the (001) and (110) substrates the charges of the ions in the top surface layer have similar values as in bulk MgO, but that on (111) surfaces these charges are significantly different. This difference in surface charge determines the direction of the electronic transfer upon adsorption of gold, such transfer occurring so as to restore the bulk MgO charge values. Using the results from theoretical calculations, we provide an explanation of our observations of increased catalytic activity in the case of the Au/MgO(111) system. PMID- 21243144 TI - Non-reactive scattering of N2 from the W(110) surface studied with different exchange-correlation functionals. AB - The non-reactive scattering of N(2) from the W(110) surface is studied with six dimensional (6D) classical dynamics and two distinct potential energy surfaces (PES). Here, we use the PESs calculated with density functional theory and two different exchange-correlation functionals, the PW91 [J. E. Perdew et al., Phys. Rev. B, 1992, 46, 6671] and the RPBE [B. Hammer et al., Phys. Rev. B, 1999, 59, 7413]. By analyzing the final rotational state and angular distributions, we extract information on the characteristics of the two PESs in the 6D configurational space. Comparison of the theoretical results with the available experimental data provides detailed information on the validity of each functional. In general, the PW91 PES is more corrugated than the RPBE one in all the configurational space, meaning that there is a stronger dependence of the potential energy on the molecular orientation and position over the surface unit cell. Furthermore, we find that the larger corrugation and the less repulsive character exhibited by the PW91 PES seems to be realistic at distances above the chemisorption well. In contrast, the less corrugated RPBE PES performs better in the region below the chemisorption well. PMID- 21243145 TI - Oxygen reduction and fuel oxidation in alkaline solution. AB - This paper reviews work carried out over a number of years to try to elucidate the mechanism of oxygen reduction and methanol oxidation in alkaline solution. We have sought to achieve this by combining electrochemical, spectroscopic and solid state chemical approaches, bringing together as wide a variety of techniques as possible both to shed light on the mechanisms and to point the way to more effective and efficient fuel cells. This work has become considerably more topical in recent years with the development of anion-exchange electrolyte membranes that can operate in alkaline environments, an important advance since it permits both the use of non-noble-metal catalysts and organic fuels at the anode, the latter precluded in aqueous alkaline electrolyte due to precipitation of inorganic carbonates at the electrode surface. PMID- 21243146 TI - Photodissociation dynamics of ClOOCl at 248.4 and 308.4 nm. AB - The dynamics of ClOOCl photodissociation at 248.4 and 308.4 nm was studied with photofragment translational spectroscopy. At 248.4 nm photoexcitation, the observed products are Cl, O(2), ClO and O. Product translational energy distributions P(E) and anisotropy parameters beta were deduced from the measured time-of-flight spectra of the Cl, O(2), and ClO photoproducts. The photodissociation mechanisms have been discussed and compared with available theoretical results. Synchronous and fast sequential breaking of the two Cl-O bonds may both contribute to the dissociation. The relative product yields for [ClO]: [Cl] was measured to be 0.15 +/- 0.04:1. The relative amounts of [O]:[O(2)] products were estimated to be 0.12:1. The branching ratios among the Cl + O(2) + Cl:ClO + ClO:ClO + Cl + O product channels were estimated to be 0.82:0.08:0.10. At 308.4 nm excitation, time-of-flight spectra of the O(2) and ClO photoproducts were recorded while there was interference from Cl(2) impurity in detecting the Cl product. Nonetheless, the observed ClO yield relative to the O(2) yield at 308.4 nm is 1.5 times that at 248.4 nm. The branching ratio between the Cl + O(2) + Cl:ClO + ClO product channels was estimated to be 0.81:0.19 at 308.4 nm. This result suggests that the ClO product may contribute a noticeable yield in the photolysis of ClOOCl at the atmospherically important wavelengths above 300 nm. PMID- 21243147 TI - Zn2+-triggered excited-state intramolecular proton transfer: a sensitive probe with near-infrared emission from bis(benzoxazole) derivative. AB - Near-infrared (NIR) emission can offer distinct advantages for biological applications. A fluorescent sensor, Zinhbo-1, based on bis(benzoxazole) ligand with 2,2'-dipicolylamine (DPA) as receptor, was synthesized. In aqueous solution, Zinhbo-1 demonstrates high sensitivity and selectivity for sensing Zn(2+) with about 10-fold enhancement and nanomolar sensitivity (K(d) = 0.29 nM). Moreover, sensor Zinhbo-1 can detect Zn(2+) in near-infrared region (over 700 nm) with large Stokes shift (ca. 230 nm) attributing to the Zn(2+)-induced excited state intramolecular proton transfer (ESIPT). PMID- 21243148 TI - Si-H activation of hydrosilanes leading to hydrido silyl and bis(silyl) nickel complexes. AB - A general route for the synthesis of novel NHC stabilized nickel bis(silyl) and nickel hydrido silyl complexes is presented. The reaction of [Ni(2)((i)Pr(2)Im)(4)(COD)] 1 ((i)Pr(2)Im = 1,3-di-isopropyl-imidazolin-2 ylidene) with hydrosilanes H(n)SiR(4-n) leads to complexes of the type [Ni((i)Pr(2)Im)(2)(SiH(n-1)R(4-n))(H)] or [Ni((i)Pr(2)Im)(2)(SiH(n-1)R(4-n))(2)]. PMID- 21243149 TI - Evaluation of electrochemical processes for the removal of several target aromatic hydrocarbons from petroleum contaminated water. AB - Ground and surface water contamination resulting from the leakage of crude oil and refined petroleum products is a serious and growing environmental problem throughout the world. Consequently, a study of the use of electrochemical treatment in the clean-up was undertaken with the aim of reducing the water contamination by aromatic pollutants to more acceptable levels. In the experiments described, water contamination by refined petroleum products was simulated under laboratory conditions. Electrochemical treatment, using aluminium electrodes, has been optimised by full factorial design and surface response analysis in term of BTEX and PAHs removal and energy consumption. The optimal conditions of pH, current density, electrolysis time, electrolyte type, and electrolyte concentration have then been applied in the treatment of real water samples which were monitored as petroleum contaminated samples. Treatment results have shown that electrochemical methods could achieve the concentration of these pollutants to undetectable levels in particular groundwater and surface water, hence, they can be highly effective in the remediation of water contaminated by aromatic hydrocarbons, and the use of these processes is therefore recommended. PMID- 21243150 TI - Lensless CCD-based fluorometer using a micromachined optical Soller collimator. AB - In this paper, we describe a simple charge-coupled device (CCD) based lensless fluorometer with sensitivity in the range of current ELISA plate readers. In our lensfree fluorometer, a multi-wavelength LED light source was used for fluorophore excitation. To collimate the light, we developed a simple optical Soller collimator based on a "stack of pinholes" (a stack of black PMMA with array of pinholes machined with laser) enabling the light to be collimated from the LED through the filters and the assay's microfluidics directly onto the CCD without a lens. The elimination of the lens that is used in almost all other current CCD based detection systems has four major advantages: (1) It simplifies the device design and fabrication while reducing cost. (2) It reduces the distance between the sample and the measuring device (without a lens the distance needed to focus the image on the CCD is reduced and the fluorometer can be more compact). (3) It couples the CCD and the detected surface by using an optical Soller Collimator which allows the use of filters for fluorescence detection. (4) It also uncouples the CCD and the microfluidics to enable the use of interchangeable fluidics while protecting the delicate CCD. The lensless CCD based fluorometer is capable of detecting 16 samples simultaneously, and was used for in vitro detection of botulinum neurotoxin serotype A (BoNT-A) activity with a FRET assay that measures cleavage of a fluorophore-tagged peptide substrate specific for BoNT-A (SNAP-25) by the toxin light chain (LcA). The limit of detection (LOD) of our lensless fluorometer is 1.25 nM, which is similar to the LOD of a modern ELISA plate reader. Combined with microfluidics, this simple low cost point-of-care (POC) medical diagnostic system may be useful for the performance of many other complex medical diagnostic assays without a laboratory and thus potentially enhancing the accessibility and the quality of health care delivery in underserved populations. PMID- 21243151 TI - Synthesis and NLO properties of new trans 2-(thiophen-2-yl)vinyl heteroaromatic iodides. AB - The synthesis and characterisation of new trans 2-(thiophen-2-yl)vinyl pyridinium, imidazolium and quinoilinium iodides is reported together with their solvatochromic shifts and EFISH characterization. 2-{(E)-2-[5'-(dibutylamino) 2,2'-bithien-5-yl]vinyl}-1-methyl pyridinium and quinolinium iodides display high MU.beta(vec) values up to 1200 * 10(-48) esu. The promising non-linear optical (NLO) properties of this new family of chromophores, which can be further improved by the design of highly efficient systems exploiting the donor and acceptor properties of both heteroaromatic rings and substituents, make them suitable candidates for second harmonic generation imaging with interesting biological applications. PMID- 21243152 TI - Analysis of chorismate mutase catalysis by QM/MM modelling of enzyme-catalysed and uncatalysed reactions. AB - Chorismate mutase is at the centre of current controversy about fundamental features of biological catalysts. Some recent studies have proposed that catalysis in this enzyme does not involve transition state (TS) stabilization but instead is due largely to the formation of a reactive conformation of the substrate. To understand the origins of catalysis, it is necessary to compare equivalent reactions in different environments. The pericyclic conversion of chorismate to prephenate catalysed by chorismate mutase also occurs (much more slowly) in aqueous solution. In this study we analyse the origins of catalysis by comparison of multiple quantum mechanics/molecular mechanics (QM/MM) reaction pathways at a reliable, well tested level of theory (B3LYP/6-31G(d)/CHARMM27) for the reaction (i) in Bacillus subtilis chorismate mutase (BsCM) and (ii) in aqueous solvent. The average calculated reaction (potential energy) barriers are 11.3 kcal mol(-1) in the enzyme and 17.4 kcal mol(-1) in water, both of which are in good agreement with experiment. Comparison of the two sets of reaction pathways shows that the reaction follows a slightly different reaction pathway in the enzyme than in it does in solution, because of a destabilization, or strain, of the substrate in the enzyme. The substrate strain energy within the enzyme remains constant throughout the reaction. There is no unique reactive conformation of the substrate common to both environments, and the transition state structures are also different in the enzyme and in water. Analysis of the barrier heights in each environment shows a clear correlation between TS stabilization and the barrier height. The average differential TS stabilization is 7.3 kcal mol(-1) in the enzyme. This is significantly higher than the small amount of TS stabilization in water (on average only 1.0 kcal mol(-1) relative to the substrate). The TS is stabilized mainly by electrostatic interactions with active site residues in the enzyme, with Arg90, Arg7 and Glu78 generally the most important. Conformational effects (e.g. strain of the substrate in the enzyme) do not contribute significantly to the lower barrier observed in the enzyme. The results show that catalysis is mainly due to better TS stabilization by the enzyme. PMID- 21243153 TI - Product formation in rhodopsin by fast hydrogen motions. AB - The photochemical cis-trans isomerization of retinal in rhodopsin is investigated by structure sampling and excited state QM/MM trajectories with surface hopping. The calculations uncover the motions responsible for photoproduct formation and elucidate the reasons behind the efficient photoisomerization in the primary event of visual transduction. PMID- 21243154 TI - Studying protein-protein interactions using peptide arrays. AB - Screening of arrays and libraries of compounds is well-established as a high throughput method for detecting and analyzing interactions in both biological and chemical systems. Arrays and libraries can be composed from various types of molecules, ranging from small organic compounds to DNA, proteins and peptides. The applications of libraries for detecting and characterizing biological interactions are wide and diverse, including for example epitope mapping, carbohydrate arrays, enzyme binding and protein-protein interactions. Here, we will focus on the use of peptide arrays to study protein-protein interactions. Characterization of protein-protein interactions is crucial for understanding cell functionality. Using peptides, it is possible to map the precise binding sites in such complexes. Peptide array libraries usually contain partly overlapping peptides derived from the sequence of one protein from the complex of interest. The peptides are attached to a solid support using various techniques such as SPOT-synthesis and photolithography. Then, the array is incubated with the partner protein from the complex of interest. Finally, the detection of the protein-bound peptides is carried out by using immunodetection assays. Peptide array screening is semi-quantitative, and quantitative studies with selected peptides in solution are required to validate and complement the screening results. These studies can improve our fundamental understanding of cellular processes by characterizing amino acid patterns of protein-protein interactions, which may even develop into prediction algorithms. The binding peptides can then serve as a basis for the design of drugs that inhibit or activate the target protein-protein interactions. In the current review, we will introduce the recent work on this subject performed in our and in other laboratories. We will discuss the applications, advantages and disadvantages of using peptide arrays as a tool to study protein-protein interactions. PMID- 21243155 TI - Synthesis of star-shaped monodisperse oligo(9,9-di-n-octylfluorene-2,7-vinylene)s functionalized truxenes with two-photon absorption properties. AB - A series of new star-shaped monodisperse conjugated truxene derivatives bearing oligo(fluorene-vinylene) arms (Tr-OFVn, n = 1, 2, 3, 4) have been synthesized. It is found that the conjugation of the oligomers can be extended with prolonging the arms. Notably, the branched oligomers Tr-OFVn without strong donor and acceptor units exhibit two-photon absorption properties, and the two-photon absorption cross sections (delta(max)) increase with increasing the number of fluorene-vinylene units in the arms. The maximum value of delta(max) reaches 8073 GM for compound Tr-OFV4, which made it one of the most competitive compounds with enhanced TPA cross section. It provides a new platform for exploiting strong TPA compounds, in which the extended pi-conjugated systems are involved in the absence of strong donor and acceptor units. PMID- 21243156 TI - Hypericin incorporation and localization in fixed HeLa cells for various conditions of fixation and incubation. AB - Hypericin is a photosensitizer expressing high affinity for cancerous cells in vivo. Diagnosis of cancer based on hypericin fluorescence imaging has been successfully assessed in several clinical trials. Our final objective will be to evaluate the potential of hypericin fluorescence imaging to improve the efficacy of cervical cancer diagnosis performed on fixed cell smears obtained from liquid based cytology. For this purpose, the mechanism of hypericin incorporation and localization in fixed HeLa cells using different incubation media and fixation conditions was investigated. Since the duration of fixation may play an important role, the influence of fixation time on hypericin incorporation in fixed HeLa cells was studied. The uptake and distribution of hypericin in fixed HeLa cells were found to be strongly dependent on the hypericin incubation medium: for a polar organic solvent such as the alcohol-based fixative, the localization was essentially perinuclear and nuclear; for cell culture medium supplemented with serum, the localization was cytoplasmic and non-specific; the highest incorporation was observed for the serum-free culture medium but mainly as non fluorescent aggregates. The hypericin aggregation in the incubation medium, the passive diffusion and the partitioning between the cells and hypericin carriers seemed to be the major factors accounting for these results. The localization was found to be weakly dependent on fixation time, whereas fluctuations of hypericin fluorescence at short fixation time and stabilization after two days of fixation were observed. These results suggest that the fixed cells reached a steady state after two days of fixation. PMID- 21243157 TI - Supramolecular cations of the m-fluoroanilinium(dibenzo[18]crown-6) in ferromagnetic salt. AB - A supramolecular cation of (m-FAni(+))(DB[18]crown-6), where m-FAni(+) and DB[18]crown-6 denote m-fluoroanilinium(+) and dibenzo[18]crown-6, respectively, which is the polar unit rotating in the ferroelectric crystal of (m FAni(+))(DB[18]crown-6)[Ni(dmit)(2)](-), was introduced into a ferromagnetic [MnCr(oxalate)(3)](-) salt as the counter cation. The crystal structure of (m FAni(+))(DB[18]crown-6)[MnCr(oxalate)(3)](-)(CH(3)OH)(CH(3)CN) (1) is constructed from alternating layers of a two-dimensional honeycomb layer of [MnCr(oxalate)(3)](-) and (m-FAni(+))(DB[18]crown-6) supramolecular cations. The anionic layer is composed of Mn(II) and Cr(III) ions with S = 5/2 and S = 3/2 spins, respectively, bridged by the oxalate anions, which show ferromagnetic ordering at 5.5 K. The supramolecular structure is formed through the formation of hydrogen bonds between the ammonium hydrogen atoms of the m-FAni(+) cations and the oxygen atoms of the DB[18]crown-6 cavity. No orientational disorder of the fluorine atoms was observed in our X-ray structural analysis, suggesting that a two-fold flip-flop motion of the m-FAni(+) cations does not occur in the salt. The rotational freedom of the m-FAni(+) cations in the salt is restricted by the steric hindrance from neighbouring DB[18]crown-6 molecules. A design strategy for the rotation in a salt is discussed, based on the volume that the supramolecular cations occupy in the unit cell. PMID- 21243158 TI - Nanomanipulation using near field photonics. AB - In this article we review the use of near-field photonics for trapping, transport and handling of nanomaterials. While the advantages of traditional optical tweezing are well known at the microscale, direct application of these techniques to the handling of nanoscale materials has proven difficult due to unfavourable scaling of the fundamental physics. Recently a number of research groups have demonstrated how the evanescent fields surrounding photonic structures like photonic waveguides, optical resonators, and plasmonic nanoparticles can be used to greatly enhance optical forces. Here, we introduce some of the most common implementations of these techniques, focusing on those which have relevance to microfluidic or optofluidic applications. Since the field is still relatively nascent, we spend much of the article laying out the fundamental and practical advantages that near field optical manipulation offers over both traditional optical tweezing and other particle handling techniques. In addition we highlight three application areas where these techniques namely could be of interest to the lab-on-a-chip community, namely: single molecule analysis, nanoassembly, and optical chromatography. PMID- 21243159 TI - Microfluidic paper-based chemiluminescence biosensor for simultaneous determination of glucose and uric acid. AB - In this study, a novel microfluidic paper-based chemiluminescence analytical device (MUPCAD) with a simultaneous, rapid, sensitive and quantitative response for glucose and uric acid was designed. This novel lab-on-paper biosensor is based on oxidase enzyme reactions (glucose oxidase and urate oxidase, respectively) and the chemiluminescence reaction between a rhodanine derivative and generated hydrogen peroxide in an acid medium. The possible chemiluminescence assay principle of this MUPCAD is explained. We found that the simultaneous determination of glucose and uric acid could be achieved by differing the distances that the glucose and uric acid samples traveled. This lab-on-paper biosensor could provide reproducible results upon storage at 4 degrees C for at least 10 weeks. The application test of our MUPCAD was then successfully performed with the simultaneous determination of glucose and uric acid in artificial urine. This study shows the successful integration of the MUPCAD and the chemiluminescence method will be an easy-to-use, inexpensive, and portable alternative for point-of-care monitoring. PMID- 21243160 TI - Molecular dynamics simulations on [FePAH]+ pi-complexes of astrophysical interest: anharmonic infrared spectroscopy. AB - In this article, classical Born-Oppenheimer molecular dynamics (MD) simulations in the microcanonical ensemble are performed on neutral and cationic polycyclic aromatic hydrocarbon (PAH) species, focusing on [FePAH](+)pi-complexes. Their anharmonic mid-infrared (mid-IR) spectra in the classical approximation are derived. This approach allows us to describe the influence of the energy of a system on its IR spectrum in terms of band-shifts and broadenings. The MD simulations are performed on a potential energy surface (PES) described at the self-consistent-charge density functional tight-binding level of theory. The PES is benchmarked on DFT calculations, showing the validity of the approach for complexes of Fe(+) with PAHs larger than coronene (C(24)H(12)) that are of astrophysical interest. MD simulations at high temperature show the occurrence of the diffusion of the Fe cation on the surface of the PAH. It proceeds through the edge of the carbon skeleton which is the lowest energy pathway presenting barriers smaller than 1 eV. Although only qualitative information on the band broadenings can be obtained, we show that the dependence of the computed positions of the main bands of [C(24)H(12)](0/+)and [FeC(24)H(12)](+)pi-complexes on temperature can be fit by linear laws. The spectral trends determined for [FeC(24)H(12)](+) are compared to those of N-substituted [C(23)NH(12)](+)and [SiC(24)H(12)](+)pi-complexes of astrophysical interest. PMID- 21243161 TI - The selective addition of water to C=C bonds; enzymes are the best chemists. AB - Water is the liquid of life. Nature has therefore evolved countless enzymes that catalyse the addition of water to C=C bonds, isolated or conjugated. These reactions are regio- and enantioselective, they are part of primary metabolism as well as the secondary metabolism. The enzymes that catalyse these reactions (hydratases or hydro-lyases) are applied industrially in selected cases. However, they are not generally used in the laboratory although they outperform all currently available catalytic chemical methodologies. This feature article highlights the potential that hydratases have for chemistry compared to the acid catalysed addition of water. PMID- 21243162 TI - Electrochemical formation of transparent nanostructured TiO2 film as an effective bifunctional layer for dye-sensitized solar cells. AB - A bifunctional TiO(2) layer having an inner compact layer and an outer anchoring layer coated on fluorine-doped tin oxide (FTO) glass could reduce the charge recombination and interfacial contact resistance between FTO and the main TiO(2) layer; photoelectron conversion efficiency of cell was increased from 7.31 to 8.04% by incorporating the bifunctional layer. PMID- 21243163 TI - PET imaging of nobiletin based on a practical total synthesis. AB - A practical synthesis of nobiletin, a polymethoxylated citrus flavone, was accomplished by utilizing our novel flavone synthesis. Synthetic nobiletin was labelled by selective demethylation and rapid incorporation of (11)C atom. Positron emission tomography images successfully visualized the brain distribution, which may provide therapeutic benefits in the treatment of Alzheimer's disease. PMID- 21243164 TI - Towards energetically viable asymmetric deprotonations: selectivity at more elevated temperatures with C2-symmetric magnesium bisamides. AB - A novel chiral magnesium bisamide has enabled the development of effective asymmetric deprotonation protocols at substantially more elevated temperatures. This new, structurally simple, C(2)-symmetric magnesium complex displays excellent levels of asymmetric efficiency and energy reduction in the synthesis of enantioenriched enol silanes. PMID- 21243165 TI - Catalytic dehydrocoupling of Me2NHBH3 with Al(NMe2)3. AB - The catalytic dehydrocoupling reaction of Me(2)NHBH(3) with Al(NMe(2))(3) gives the dimer [Me(2)NBH(2)](2) and the chain [(Me(2)N)(2)BH], involving the thermally stable Al(III) hydride catalyst [{(Me(2)N)(2)BH(2)}(2)AlH]. PMID- 21243166 TI - Efficient and stable panchromatic squaraine dyes for dye-sensitized solar cells. AB - A new series of stable, unsymmetrical squaraine near-IR sensitizers (JK-216 and JK-217), which are assembled using both thiophenyl pyrrolyl and indolium groups, exhibit a panchromatic light harvesting up to 780 nm. The JK-216 based cell exhibited a record efficiency of 6.29% for near-IR DSSCs. In addition, the JK-217 device showed an excellent stability under a light soaking test at 60 degrees C for 1000 h. PMID- 21243167 TI - Surface segregation of poly(2-methoxyethyl acrylate) in a mixture with poly(methyl methacrylate). AB - Poly(2-methoxyethyl acrylate) (PMEA) exhibits excellent blood compatibility. To understand why such a surface functionality exists, the surface of PMEA should be characterized in detail, structurally and dynamically, under not only ambient conditions, but also in water. However, a thin film of PMEA supported on a solid substrate can be easily broken, namely it is dewetted. Our strategy to overcome this difficulty is to mix PMEA with poly(methyl methacrylate) (PMMA). Differential scanning calorimetry and cloud point measurements revealed that the PMEA/PMMA blend has a phase diagram with a lower critical solution temperature. The blend surface was also characterized by X-ray photoelectron spectroscopy in conjunction with microscopic observations. Although PMEA is preferentially segregated over PMMA at the blend surface due to its lower surface free energy, the extent of segregation in the as-prepared films was not sufficient to cover the surface. Annealing the blend film at an appropriate temperature, higher than the glass transition temperature and lower than the phase-separation temperature of the blend, enabled us to prepare a stable and flat surface that was perfectly covered with PMEA. PMID- 21243168 TI - Carrier protein substrates in cytochrome P450-catalysed oxidation. AB - Enzymes of the cytochrome P450 superfamily can catalyse many types of oxidative transformations of a diverse substrate range. This review summarises recent work on an subset of P450s that accept their substrates in carrier protein-bound form. These examples show how the oxidative power and precision that P450s bring to natural products biosynthesis can be coupled with the advantages of using a carrier protein as a scaffold for oxidation. PMID- 21243169 TI - Improvement of the prediction ability of multivariate calibration by a method based on the combination of data fusion and least squares support vector machines. AB - This paper suggests a novel method named DF-LS-SVM, which is based on least squares support vector machines (LS-SVM) regression combined with data fusion (DF) to enhance the ability to extract characteristic information and improve the quality of the regression. Simultaneous multicomponent determination of Fe(III), Co(II) and Cu(II) was conducted for the first time by using the proposed method. Data fusion is a technique that integrates information from disparate sources to produce a single model or decision. The LS-SVM technique allows for learning a high-dimensional feature with fewer training data, and reduces the computational complexity by only requiring the solution of a set of linear equations instead of a quadratic programming problem. Experimental results showed that the DF-LS-SVM method was successful for simultaneous multicomponent determination even when severe overlap of spectra existed. The DF-LS-SVM method is an attractive and promising hybrid approach that combines the best properties of the two techniques. The results obtained from an additional test case, simultaneous differential pulse voltammetric determination of o-nitrophenol, m-nitrophenol and p-nitrophenol, also demonstrated that the DF-LS-SVM method performed somewhat better than LS-SVM and PLS methods. PMID- 21243171 TI - Sulfate encapsulation in a metal-assisted capsule based on a mono-pyridylurea ligand. AB - A sulfate-encapsulating complex, [Cu(1)L(6)].3[Cu(2)L(2)(DMF)(4)](SO(4))(4) (1, L = N-(1-naphthyl)-N'-(3-pyridyl)urea) is synthesized in which two C(3)-clefts of the octahedral complexes interdigitate to form a cavity to encapsulate the sulfate ion by six urea groups. PMID- 21243170 TI - Ultrasensitive scanometric strategy for detection of matrix metalloproteinases using a histidine tagged peptide-Au nanoparticle probe. AB - A simple scanometric strategy was developed for ultrasensitive assay of matrix metalloproteinases based on their discriminatory and proteolytic activity by integrating a newly designed peptide-gold nanoparticle probe, a nitrilotriacetic acid modified chip and silver signal amplification. PMID- 21243172 TI - Haematogenous osteomyelitis: clinical presentation and outcome in three dogs. AB - Haematogenous osteomyelitis is a rare form of bone infection in adult dogs. Most commonly the infection is iatrogenic or traumatic in origin. The authors report three different presentations of haematogenous osteomyelitis: a focal pelvic localisation in a growing dog, a vertebral lesion in an adult dog with associated neurological signs and a multifocal affection in another adult dog with concomitant pathological fractures. Clinical signs included pyrexia of undetermined origin, focal pain and lameness. Diagnostic investigation included radiographic imaging, bone scintigraphy, magnetic resonance imaging, surgical biopsy, and bacteriological culture with sensitivity testing of biopsy specimens as well as of peripheral blood samples. Treatment consisted of long-term antimicrobial therapy and surgical debridement with curettage of the pelvic abscess of the young dog and decompressive hemilaminectomy of the second dog, with excellent recovery. The dog affected by polyostotic bone involvement and suffering pathological fractures was euthanatized. Haematogenous osteomyelitis may be a diagnostic and therapeutic challenge and may present as a devastating skeletal condition, even in adult dogs, and should be considered amongst the differential diagnoses early on to allow effective treatment. PMID- 21243173 TI - Kinematics of stair ascent in healthy dogs. AB - OBJECTIVE: The purpose of the study was to evaluate the kinematic characteristics of pelvic limb joints in orthopaedically normal dogs during stair ascent. DESIGN: Prospective study. PROCEDURE: Eight hound-type dogs were fitted with reflective spheres at palpable landmarks, including the tuber ischium, greater trochanter, cranial dorsal iliac spine, lateral epicondyle of the femur, lateral malleolus, and the base of the fifth metatarsal bone. Each dog was walked up a set of custom made stairs consisting of four steps and then trotted across a level test space. Data were recorded for the right and left pelvic limbs during ascent. Maximum and minimum joint angles and total joint motion were calculated for all joints and evaluated statistically. RESULTS: Pelvic limb joints had a greater total joint excursion during stair ascent. There was greater extension of the coxofemoral and tibiotarsal joints during ascent, whereas the stifle joint had less extension. Maximum flexion of the stifle and tarsal joints was significantly greater in stair ascent. There was not any significant difference between the right and left limbs. CONCLUSIONS: All joints of the pelvic limb undergo a greater joint motion to ascend stairs. PMID- 21243174 TI - Treatment of unilateral congenital flexural and torsional limb deformities with circular external skeletal fixation system in two calves. AB - CASE DESCRIPTION: Two calves with unilateral congenital flexural and torsional limb deformities below the hock joint of the left hindlimb were presented to Veterinary Teaching Hospital of the Ondokuz Mayis University. According to clinical, goniometric and radiological examinations, flexural (130 degrees -40 degrees ) and torsional (90 degrees -180 degrees ) deformities were diagnosed. Except for the limb deformities, both animals were otherwise completely healthy. TREATMENT AND OUTCOME: In case 1, hock joint arthrodesis was performed using a circular external skeletal fixation system with four full rings 160 mm in diameter. In case 2, the deformity was corrected by fixation after transverse osteotomy at the level of the proximal metatarsals with four full rings 150 mm in diameter, and arthrodesis of the fetlock joint with three full rings 100 mm in diameter. According to clinical examinations and follow-up telephone interviews performed 15 and 24 weeks after discharge, functional use with slight lameness in case 1 and full functional use in case 2 had been achieved. CLINICAL RELEVANCE: None of the previously reported cases of flexural deformity had radiographic signs similar to those of the calves in our report, and the deformities were not as severe as those reported here. To our knowledge, this is the first report of treatment of unilateral congenital flexural and torsional deformities in calves with a circular external skeletal fixation system. PMID- 21243175 TI - Effect of dog breed and body conformation on vertical ground reaction forces, impulses, and stance times. AB - OBJECTIVES: To assess whether fully normalised vertical ground reaction forces and stance times obtained at a trot depend on dog breed or body conformations. METHODS: Peak vertical forces (PVF), vertical impulses (VI), stance times (ST), and ratio of forelimb impulse to total impulse (RVI) of 54 dogs of seven different breeds were normalised to body weight and body size according to the theory of dynamic similarity, and were tested for differences between breeds. Breeds were Borzoi, Bernese Mountain dog, Great Dane, Labrador Retriever, Landseer, Rhodesian Ridgeback, and Rottweiler. Body length ratio (BLR) and body mass index (BMI) were also compared between breeds. RESULTS: Significant differences between breeds were found for the normalised forelimb PVF, VI and ST, and hindlimb PVF. Looking at individual breeds, it was most evident that Borzois had a lower forelimb VI, and a higher hindlimb PVF than the other breeds. This resulted in Borzois having a lower RVI compared to other dogs, indicating a more caudally located centre of gravity. Only a few differences in gait parameters were found between other dog breeds. The BMI was significantly lower in Borzois than in other breeds, but was otherwise not associated with gait parameters. CLINICAL SIGNIFICANCE: Force plate data of dogs of different breeds are not necessarily comparable, even after full normalisation to body weight and body size. Group comparisons should only be made when the groups consist of breeds with similar body conformations. PMID- 21243176 TI - Update on the aetiopathogenesis of canine cranial cruciate ligament disease. AB - Cranial cruciate ligament disease (CCLD) is the most common cause of hindlimb lameness in the dog, being associated with and eventually leading to stifle osteoarthritis. Canine cranial cruciate ligament disease is a gradual degeneration of the ligament extracellular matrix (ECM) leading to ligament rupture. The aetiopathogenesis of this condition is still poorly understood but several risk factors have been identified such as breed, bodyweight, gender and conformation. Recent developments in this area include the role of genetics, stifle joint conformation, ligament ECM metabolism, and inflammation associated with immune-mediated disease within the stifle joint. A genetic mode of inheritance has been demonstrated in the Newfoundland which is predisposed to CCLD. Increased cellular metabolism within the cranial cruciate ligament has been directly associated with increased craniocaudal stifle joint laxity in dog breeds at high risk of CCLD. Conformation abnormalities, such as a narrowed distal femoral intercondylar notch, in high risk breeds have been shown to be associated with alterations in cranial cruciate ligament ultrastructure. Increased production of inflammatory cytokines, such as cathepsins and interleukins, by the stifle synovial cells may occur secondary to or may be an inciting cause of ligament degeneration. Future research endeavours will focus on the association between immune-mediated response and fibrocartilaginous metaplasia and matrix degradation within the cranial cruciate ligament, and whether this can be altered in all susceptible dogs or only certain breeds. PMID- 21243177 TI - Computed tomographic findings and treatment of an unusual fracture of the proximal ulna in a mature dog. AB - This report describes the diagnosis and treatment of an unusual fracture of the proximal ulna in a four-year-old male neutered Labrador Retriever dog, the orientation of which has not been reported in the veterinary literature. Computed tomography allowed fracture visualisation and aided surgical planning. Fixation was achieved using a lag screw and an anti-rotational Kirschner wire. Six month follow-up indicated satisfactory outcome with complete return to normal function. PMID- 21243178 TI - Fixation of pelvic floor fractures in cats. AB - OBJECTIVES: To retrospectively evaluate the outcome of internal fixation of trauma- related pelvic floor fractures using a ventral abdominal approach in cats. METHODS: Clinical examination and radiographic findings at presentation, after surgery, and at follow-up were assessed. Information gathered included concurrent injuries, surgical technique used, lameness and pain scores, and radiographic signs of implant stability. RESULTS: Ten European shorthair cats were included in the study. Pelvic floor fractures were stabilised using locking plates in nine cats, and symphyseal separation was fixated using hemicerclage wire in one cat. Additional procedures included reduction of sacroiliac luxation in nine cats with positional screws placed in six cats, and plate stabilization of sacral fractures in one cat. All cats were able to walk within five days of surgery. No orthopaedic or neurological deficits were observed in seven cats at follow-up. Neurological deficits were observed in one cat. Signs of pain at implant sites due to inadequate surgical technique were noted in two cats. Anatomical reduction of the pelvic floor was achieved in eight cats. CLINICAL SIGNIFICANCE: Stabilization of the pelvic floor and repair of sacroiliac luxation and other injuries by a ventral abdominal approach in cats led to an overall successful outcome. Fixation of the pelvic floor in cats with intact acetabular and ilial bones should be considered in patients with multiple pelvic fractures in combination with sacroiliac joint luxation or sacral fracture, pelvic canal narrowing, traumatic abdominal hernia, and other abdominal injuries. PMID- 21243179 TI - Stifle synovial cyst in a Labrador Retriever with concurrent cranial cruciate ligament deficiency. AB - A seven-year-old Labrador Retriever dog was presented with the complaint of chronic left hindlimb lameness. A diagnosis of partial rupture of the left cranial cruciate ligament with concurrent cranio-medial synovial cyst formation was made. This cystic structure was assumed to be communicating with the stifle joint. There was no evidence of a meniscal tear, but superficial fibrillation of the axial border was present. Surgical excision of the cyst with concurrent treatment of the cranial cruciate ligament deficiency by tibial tuberosity advancement was performed with a successful outcome. Whilst commonly encountered in humans, synovial cysts are uncommon in dogs. To the authors' knowledge this is the first reported case of synovial cyst formation in the stifle of a dog. PMID- 21243180 TI - Pneumonia mortality in Brazilian children aged 4 years and younger. AB - OBJECTIVE: To evaluate the trend of pneumonia mortality in Brazilian children aged 4 years and younger from 1991 to 2007. METHODS: We conducted a retrospective study based on the database of the IT Department of the Brazilian Unified Health System (DATASUS), from which we obtained the number of deaths from pneumonia and the population aged 4 years and younger living in the five Brazilian regions and in the whole country. Mortality rate was calculated according to the number of deaths from pneumonia divided by the population, multiplied by 1,000 for the age group under 1 year old and by 10,000 in the age group from 1 to 4 years. The linear regression test was used to evaluate the time trend of mortality. RESULTS: There was a significant decrease in pneumonia mortality rates during the study period in both age groups and all regions of the country. In Brazil, the mean annual reduction in mortality rates in the population under 1 year old and between 1 and 4 years was 0.12 and 0.07, respectively. The South and Southeast regions showed the greatest reductions (-0.14 and -0.18 for < 1 year and -0.07 and -0.09 for 1 to 4 years). The smallest decreases were in the North and Northeast regions (-0.04 and -0.07) in children younger than 1 year, and in the North and Central West (-0.03 and -0.04) in the age group between 1 and 4 years. CONCLUSIONS: There was a significant reduction in pneumonia mortality in children aged 4 years and younger across the country from 1991 to 2007; however, a discrepancy between the different regions remains evident. PMID- 21243181 TI - [Adult smoking trends in Mexico between 1988 and 2008]. AB - OBJECTIVE: To describe the changes in several smoking indicators occurred in Mexico over the past two decades and to explore if the tobacco control policies implemented in Mexico, since 2004, show a favorable impact on tobacco consumption by 2008. MATERIALS AND METHODS: We analyze trends in comparable data on the prevalence of never and daily smokers, using the five National Addiction Surveys conducted between 1988 and 2008. The analysis is restricted to persons aged 18 through 65 years. Data are adjusted for age, sex and marginality index. RESULTS: Between 2002 and 2008 the percentage of never smokers has increased by 19.6% and the percentage of daily smokers has decreased by 24.8%. These changes were more important in men, but in women the average number of cigarettes consumed decreased by 21.1% over the compared period and there was also a 13.9% rise in the percentage of women attempting to quit. Daily smokers prevalence has declined more rapidly since 2005, coincidently with an increase in cigarette taxation. CONCLUSIONS: Over the past two decades there has been in Mexico an increase in the percentage of never smokers and a decline in the percentage of daily smokers. A positive impact is observed, few years after the implementation of more effective tobacco control policies in Mexico, notably higher taxation of tobacco products. PMID- 21243182 TI - [Anxiety and depression in Mexican smokers, and their relationship with the severity of addiction]. AB - OBJECTIVE: To determine the relationship between the degree of addiction (DA) and pattern of tobacco consumption (PTC) with anxiety and depression in smokers who want to quit smoking. MATERIAL AND METHODS: At admission to a smoking cessation program 495 smokers were surveyed to determine anxiety (IDARE Test), depression (Beck Inventory Test), DA (Fagerstrom Test) and PTC (pack-years). RESULTS: DA >= 6 points was associated with high anxiety levels RM=1.94, (IC95%1.02-3.72), p<0.04]; and with symptoms of severe depression; [RM=2.24, (IC95%1.00-4.99), p<0.04)]. The PCT equal or greater than 21 pack-year, was associated with moderate anxiety; [RM=3.19 (IC95%1.94-5.25), p<.00]; high anxiety; [RM=3.36 (IC95% 1.66-6-80), p<.00]; with moderate depressive symptoms; [RM=3.14, (IC95% 1.75-5-62), p<.00] and severe depressive symptoms; [RM=9.85, (IC95% 3.30-29.37), p<.00)]. CONCLUSION: A significant association exists in smokers having high GA and PCT, with moderate and high anxiety and depressive symptoms that should be considered during interventions to quit. PMID- 21243183 TI - [Social marketing and public policies for health: campaign to promote smoke-free spaces in Mexico]. AB - "Porque todos respiramos lo mismo" is a mass media campaign to promote smoke-free places (SFP). The development stages were: strategic planning; formative research; message development; media plan; and impact evaluation. Development involved formation of a coalition of key actors in various sectors. The target population was smokers and nonsmokers, with the aim of changing social norms around SFP. Nonsmokers were targeted because they comprised the majority and were most likely to appreciate the benefits of SFPs. Campaign materials were aired on television, radio, print and on billboards. One key limitation was the lack of evidence for previous campaigns, which increased the importance of formative research and of including a rigorous evaluation for this one. The campaign evaluation indicates a significant impact, which suggests that future campaigns use similar strategies in their development. PMID- 21243184 TI - Promoting smoke-free environments in Latin America: a comparison of methods to assess secondhand smoke exposure. AB - Secondhand smoke (SHS) contains toxicants and carcinogens that are known to cause premature death and disease. Objectively measuring SHS exposure can support and evaluate smoke-free legislation. In Latin America, the most commonly used methods to measure SHS exposure are airborne nicotine and respirable suspended particles (PM2.5). Here we present results from studies conducted in public places and homes across Latin American countries. Airborne nicotine was detected in most locations between 2002-2006, before the implementation of 100% smoke-free legislation in Uruguay, Panama, Guatemala and other large cities within Latin America. Between 2006 and 2008, PM2.5 levels were found to be five times higher in places where smoking was present at the time of sampling compared to those without smoking. Measuring SHS exposure across Latin America has increased our understanding of the magnitude of exposure in this region and results have been used to effectively promote smoke-free legislation. PMID- 21243185 TI - [Perception over smoke-free policies amongst bar and restaurant representatives in central Mexico]. AB - OBJECTIVE: To analyze the perceptions and appreciations over smoke-free environments of restaurant and bar managers from four cities in central Mexico. MATERIAL AND METHODS: Managers from 219 restaurants and bars from Mexico City, Colima, Cuernavaca and Toluca were surveyed about smoke-free environments opinions and implementation. Simultaneously, environmental nicotine was monitored. RESULTS: The majority of surveyed managers considered public places should be smoke-free, although more than half were concerned with potential economic loses. Implementation of smoke-free environments was more frequent in Mexico City (85.4%) than in the other cities (15.3% overall), with consequently lower environmental nicotine concentrations. CONCLUSION: Managers acknowledge the need to create smoke-free environments. Concerns over economic negative effects derived from the prohibition could explain, at least partially, the rejection of this sector towards the implementation of this type of policy. PMID- 21243186 TI - Informing effective smokefree policies in Argentina: air quality monitoring study in 15 cities (2007-2009). AB - OBJECTIVE: To evaluate indoor air pollution in hospitality venues in Argentina. MATERIAL AND METHODS: PM2.5 levels were measured in a convenience sample of venues in 15 cities with different legislative contexts following a protocol developed by Roswell Park Cancer Institute. RESULTS: 554 samples were collected. Across all 5 smoke free cities the mean PM2.5 level was lower during daytime vs. evening hours, 24 vs. 98 PM2.5 respectively (p=.012). In the three cities evaluated before and after legislation, PM2.5 levels decreased dramatically (p<0.001 each). Overall, PM2.5 levels were 5 times higher in cities with no legislation vs. smoke free cities (p<0.001). In cities with designated smoking areas, PM2.5 levels were not statistically different between smoking and non smoking areas (p=0.272). Non-smoking areas had significantly higher PM2.5 levels compared to 100% smoke free venues in the same city (twofold higher) (p=0.017). CONCLUSIONS: Most of the participating cities in this study had significantly lower PM2.5 levels after the implementation of 100% smoke free legislation. Hence, it represents a useful tool to promote 100% smoke free policies in Argentina. PMID- 21243187 TI - [Tobacco smoke exposure in public places in Mexico City, Guadalajara and Monterrey]. AB - OBJECTIVE: To quantify environmental tobacco smoke exposure in public places in Mexico to promote policies of 100% smoke-free environments. MATERIALS AND METHODS: In hospitals, schools and public offices of Monterrey, Guadalajara and Mexico City 20% of inner areas were monitored. Median nicotine concentrations were estimated by city, type of public space and type of inner area. RESULTS: Median concentration in areas where nicotine was detected was 0.06 ug/m3 (P25=0.03, P75=0.12 ug/m3). Higher concentrations were found in Mexico City and in public offices. Nicotine was not detected in 75% of monitored areas. CONCLUSIONS: Monitoring environmental nicotine is a useful tool to evaluate compliance of public places with the smoke-free environments legislation, and could constitute an important source of information to strengthen implementation efforts. PMID- 21243188 TI - [Taxation and tobacco control: the cases of Brazil and Mexico]. AB - This study analyzes the achievements, obstacles and challenges related to cigarette taxes in Brazil and Mexico. Both countries have increased cigarette taxes in recent years and have included a specific tax, which allows maximizing the impact of tax increases on prices. However, it seems they have not taken full advantage of these measures. Three recommendations follow from these experiences: 1) specific taxes must represent a significant percentage of final prices; 2) specific taxes must be regularly adjusted to keep pace with cumulative inflation; and 3) specific taxes must be adjusted to compensate increases in personal income. It is also important to consider that taxes on legal substitutes of cigarettes must be similar to cigarette taxes. As for illegal substitutes, the issue is to reduce the incentives for illicit trade and to make illegal transactions more difficult. Modifications to national legislation and international cooperation constitute key elements to achieve this. PMID- 21243189 TI - [Fiscal policy, affordability and cross effects in the demand for tobacco products: the case of Uruguay]. AB - Uruguay, a country with a solid tobacco control policy since 2005 shows, contrary to expectations, an insignificant decrease in total tobacco products' sales in the last five years. The hypothesis is that on one side, changes in household income and the income elasticity of the demand for cigarettes were important countervailing factors in the demand of both products. The period 2005-2009 shows a large increase of 36% in household real income in Uruguay due to fast economic recovery after the 2002 crisis. The second factor is the interchangeability of roll your own and cigarettes and the impact on the demand of each product as a reaction to tax and price changes. The tax and price of roll your own tobacco remains substantially lower than that of cigarettes. This fact, and the increased substitution of roll your own for cigarettes seems to be the main reasons for the low impact of the policy of tobacco tax and price increases. This paper then consists of a revision of a 2004 study to estimate separate demands for both main tobacco products and obtain estimates for own price, cross price and income elasticities. Then, a simulation study was performed using the elasticities found and two scenarios of increases in household income: moderate (2.5% per year) and high (5% per year) confirming that countries where income is growing fast and with a potential for substitution towards cheaper products require substantial cigarette tax and price increases for a fiscal tobacco control policy to become effective. PMID- 21243190 TI - [The effect of tobacco prices on consumption: a time series data analysis for Mexico]. AB - OBJECTIVE: To estimate the price elasticity of the demand for cigarettes in Mexico based on data sources and a methodology different from the ones used in previous studies on the topic. MATERIAL AND METHODS: Quarterly time series of consumption, income and price for the time period 1994 to 2005 were used. A long run demand model was estimated using Ordinary Least Squares (OLS) and the existence of a cointegration relationship was investigated. Also, a model using Dinamic Ordinary Least Squares (DOLS) was estimated to correct for potential endogeneity of independent variables and autocorrelation of the residuals. RESULTS: DOLS estimates showed that a 10% increase in cigarette prices could reduce consumption in 2.5% (p<0.05) and increase government revenue in 16.11%. CONCLUSIONS: The results confirmed the effectiveness of taxes as an instrument for tobacco control in Mexico. An increase in taxes can be used to increase cigarette prices and therefore to reduce consumption and increase government revenue. PMID- 21243191 TI - Assessing the impact of cigarette package health warning labels: a cross-country comparison in Brazil, Uruguay and Mexico. AB - OBJECTIVE: To assess the impact of different health warning labels (HWL). MATERIAL AND METHODS: Data from the International Tobacco Control Survey (ITC Survey) were analyzed from adult smokers in Brazil, Uruguay and Mexico, each of which used a different HWL strategy (pictures of human suffering and diseased organs; abstract pictorial representations of risk; and text-only messages, respectively). Main outcomes were HWL salience and cognitive impact. RESULTS: HWLs in Uruguay (which was the only country with a HWL on the front of the package) had higher salience than either Brazilian or Mexican packs. People at higher levels of educational attainment in Mexico were more likely to read the text-only HWLs whereas education was unassociated with salience in Brazil or Uruguay. Brazilian HWLs had greater cognitive impacts than HWLs in either Uruguay or Mexico. HWLs in Uruguay generated lower cognitive impacts than the text-only HWLs in Mexico. In Brazil, cognitive impacts were strongest among smokers with low educational attainment. CONCLUSIONS: This study suggests that HWLs have the most impact when they are prominent (i.e., front and back of the package) and include emotionally engaging imagery that illustrates negative bodily impacts or human suffering due to smoking. PMID- 21243192 TI - Smoke-free Sao Paulo: a campaign evaluation and the case for sustained mass media investment. AB - Although evidence from high-income countries suggests that mass media campaigns can increase knowledge of tobacco harms and encourage smoking cessation, there is little evidence of this from developing countries, particularly related to campaigns that seek to increase support for smoke-free places and laws. Two campaigns that ran in Sao Paulo, Brazil during implementation of a smoke-free law in Sao Paulo were evaluated to assess their effectiveness in changing attitudes and creating support for the law. The campaigns were evaluated through street intercept surveys conducted in early July and late August in Sao Paulo (Ns= 603; 615). Findings reveal that mass communications can generate support for smoke free laws and underscore the importance of running campaigns that are both well funded and that use harder-hitting, more graphic messages. PMID- 21243193 TI - "Plain packaging" regulations for tobacco products: the impact of standardizing the color and design of cigarette packs. AB - Tobacco packaging and labeling policies have emerged as prominent and cost effective tobacco control measures. Although packaging policies have primarily focused on health warnings, there is growing recognition of the importance of packaging as a marketing tool for the tobacco industry. The current paper reviews evidence on the potential impact of standardizing the color and design of tobacco packages -so called "plain" packaging. The evidence indicates three primary benefits of plain packaging: increasing the effectiveness of health warnings, reducing false health beliefs about cigarettes, and reducing brand appeal especially among youth and young adults. Overall, the research to date suggests that "plain" packaging regulations would be an effective tobacco control measure, particularly in jurisdictions with comprehensive restrictions on other forms of marketing. PMID- 21243194 TI - Cigarette labeling policies in Latin America and the Caribbean: progress and obstacles. AB - OBJECTIVE: To describe cigarette labeling policies in Latin America and the Caribbean as of August 2010. MATERIAL AND METHODS: Review of tobacco control legislation of all 33 countries of the region; analysis of British American Tobacco (BAT)'s corporate social reports; analysis of information from cigarette packages collected in 27 countries. RESULTS: In 2002, Brazil became the first country in the region to implement pictorial health warning labels on cigarette packages. Since then, six more countries adopted pictorial labels. The message content and the picture style vary across countries. Thirteen countries have banned brand descriptors and nine require a qualitative label with information on constituents and emissions. Tobacco companies are using strategies commonly used around the world to block the effective implementation of WHO Framework Convention on Tobacco Control (FCTC)'s Article 11. CONCLUSIONS: Since 2002, important progress has been achieved in the region. However, countries that have ratified the FCTC have not yet implemented all the recommendations of Article 11 Guidelines. PMID- 21243196 TI - [Monitoring strategy for control of tobacco in Mexico: advertising, promotion and sponsorship, packaging and labeling]. AB - OBJECTIVE: To describe strategies used in the publicity, marketing, and sale, of tobacco products in 12 cities in Mexico. MATERIAL AND METHODS: Tobacco products points of sale (POS) were identified within a 500 m radius of Global Youth Tobacco Survey (2005-2006) schools. We used observational surveys and an online Geographic Information System (GIS). RESULTS: In the 257 schools visited, we found, on average, 8.3 stores and 5 street vendors around each of them. Forty four percent of the stores had interior tobacco publicity, 8.3% had tobacco products at children's eye level, 6.5% had some promotion, 33.6% had a no selling to minors sign, and 44.4% of stores and 58.8% of street vendors sold single cigarettes. CONCLUSIONS: Tobacco products are largely publicized and marketed around schools. There is no compliance of tobacco control legislation in regards to selling to minors and single cigarettes. It is necessary to implement a surveillance system to monitor strategies for tobacco control and the tobacco industry. PMID- 21243195 TI - Differential impact of local and federal smoke-free legislation in Mexico: a longitudinal study among adult smokers. AB - OBJECTIVE: To assess the impact of Mexico City and federal smoke-free legislation on secondhand tobacco smoke (SHS) exposure and support for smoke-free laws. MATERIAL AND METHODS: Pre- and post-law data were analyzed from a cohort of adult smokers who participated in the International Tobacco Control (ITC) Policy Evaluation Suvey in four Mexican cities. For each indicator, we estimated prevalence, changes in prevalence, and between-city differences in rates of change. RESULTS: Self-reported exposure to smoke-free media campaigns generally increased more dramatically in Mexico City. Support for prohibiting smoking in regulated venues increased overall, but at a greater rate in Mexico City than in other cities. In bars and restaurants/cafes, self-reported SHS exposure had significantly greater decreases in Mexico City than in other cities; however, workplace exposure decreased in Tijuana and Guadalajara, but not in Mexico City or Ciudad Juarez. CONCLUSIONS: Although federal smoke-free legislation was associated with important changes smoke-free policy impact, the comprehensive smoke-free law in Mexico City was generally accompanied by a greater rate of change. PMID- 21243197 TI - [Let's talk about smoking today]. PMID- 21243198 TI - [Status of the implementation of the Framework Convention on Tobacco Control in the region of the Americas]. AB - OBJECTIVE: To assess the status of implementing the following Framework Convention on Tobacco Control (FTCT) mandates in the Americas: (1) Price and tax measures, (2) Protection from exposure to tobacco smoke, (3) Packaging and labeling, (4) Advertising, promotion and sponsorship, (5) Cessation, (6) Surveillance. MATERIAL AND METHODS: Progress is assessed based on the data published in the WHO Reports on the Global Tobacco Epidemic. The WHO Reports are based on national legislation collected at country level, analyzed by WHO and validated by corresponding national authorities. RESULTS: The essay concludes that FCTC implementation has been uneven throughout the Americas. CONCLUSION: A very small group of countries have been able to implement effective policies for at least two out of the six measures assessed, but the vast majority of countries, while having some existing legislation, have yet to meet the requirements laid out in the FCTC or be consistent with international best practices. PMID- 21243199 TI - [Scientific and technical evaluation of Mexico's General Law for Tobacco Control]. AB - The General Law for Tobacco Control, signed in February 2008, aims to protect the Mexican population against the negative effects associated with tobacco consumption and to guarantee the non-smoker's rights to live and relate in 100% smoke-free environments. The Law supports the development of smoke-free areas, but it also allows for indoor smoking areas. The present essay examines the Law and its Rule of Procedure, article by article, evaluating its capability to assure the protection of the population against the effects of environmental tobacco smoke. The analysis reveals conceptual and operative important imprecision, but mainly, discusses in detail the reasons why indoor smoking areas represent a health risk for the population. It concludes that the Law must be reformed, eliminating the provision of indoor smoking areas, any kind of roof in outdoor smoking areas and establishing a minimum distance between these areas and the 100% smoke-free environments. PMID- 21243200 TI - [Reflections on smoking intervention opportunities in Latin America]. AB - The tobacco epidemic is a huge public health problem affecting all Latin American countries. These countries have the characteristic of a wide base of the pyramidal population structure, with many young people who have been natural targets for the tobacco industry. Therefore in this region there is an urgent need to establish prevention and treatment strategies capable to reduce incidence and prevalence of tobacco smoking in the population and as a consequence modify the health effects of tobacco consumption. Treating nicotine addiction requires intervention strategies really effective to reduce the number of current smokers as well as giving them tools to avoid relapse and maintain abstinence. Currently poor and vulnerable groups, which represent 44% of the total population in Latin America, are the most susceptible to suffer the health consequences of smoking since they show the highest prevalence rates and have little or no access to health services. The Framework Convention on Tobacco Control (FCTC) and MPOWER, both strategies proposed by the World Health Organization against tobacco, define clear goals to achieve their purposes, nevertheless they are limited by the economic and human resources assigned by each country. The scientific community involved in the fight against tobacco must think about new ways to place this issue in the political agenda so there will be more opportunities to increase the resources and therefore to reduce tobacco consumption in all the groups of the population. In the fight against tobacco, this is the right time to consider primarily issues related to equity and social justice. PMID- 21243201 TI - Human rights as a tool for tobacco control in Latin America. PMID- 21243202 TI - [Development of capacities for tobacco control in Latin America]. AB - The Framework Convention for Tobacco Control is the first global public health treaty. It was approved unanimously by the 192 Member States of the World Health Organisation. It is a landmark of public health promotion and it includes a new legal dimension for international cooperation between countries. The multidisciplinarity of the topics and the actors involved require building the capacity in areas such as: management, leadership, human and financial resources. This involves the reinforcement of the existing technical and financial capacity at national level, so the activities at that level can be successful and sustainable, gathering the political will and the financial resources needed for that. PMID- 21243203 TI - [Global gender policies in prevention and tobacco control]. AB - Later stages of the smoking epidemic show that social and gender inequalities increase tobacco use among women and more deprived social groups. Given that smoking prevalence among women is increasing adding gender perspective in the design of prevention and tobacco control policies is a priority. After a brief description of the overall frame of tobacco control, different policies including minimum strategies that should incorporate gender specific aspects are described. Among them, empowerment measures addressed to reduce gender inequities are included; legislative measures; health care measures; and lastly measures related to research and evaluation aiming to add gender perspective in tobacco policy implementation and analysis. PMID- 21243204 TI - [Tobacco control strategies from a gender perspective in Latin America]. AB - In the Latin America region, the tobacco epidemic among women is a fact. This is related to the change in social and economic status among women and the efforts of the tobacco industry to capture their market share. The FCTC has the potential to be an important treaty for women if its articles include a gender perspective. Women's rights treaties, also represent an important tool to stop the epidemic. Women's participation is key in this process. PMID- 21243205 TI - [Progress and pending issues in the Latin American agenda for tobacco control]. AB - Projections based on the most recent report on the Global Burden of Disease show that the observed increase in smoking prevalence in middle and low income countries will contribute to the increase of the number of deaths due to cardiovascular diseases, chronic obstructive pulmonary diseases, and some cancers. The World Health Organization (WHO) Framework Convention on Tobacco Control recommends a group of actions to curb the tobacco epidemic. This is a review paper based on the most recent MPOWER report and also included in this review are some of the most recent tobacco control measures implemented during 2009 and 2010. We conclude that most Latin American countries have achieved significant progress in tobacco control in recent years. However, when comparing the current situation against the WHO recommendations we realized that for most countries there is still work to be done. If current smoking prevalence among teenagers remains unchanged, there will be a significant increase in the number of premature deaths attributable to tobacco consumption in future decades. PMID- 21243206 TI - The role of organized civil society in tobacco control in Latin America and the Caribbean. AB - Civil society has been the engine that has permitted many of the accomplishments seen in tobacco control in Latin America and the Caribbean. However, the role of civil society is not clearly understood. Civil society plays five main roles: advocate, coalition builder, provider of evidence-based information, watchdog and service provider. Some of these roles are played weakly by civil society in the region and should be encouraged to support beneficial societal change. Civil society working in tobacco control has evolved over the years to now become more professionalized. The WHO Framework Convention on Tobacco Control and the Bloomberg Initiative to Reduce Tobacco Use have brought about significant change with positive and negative consequences. Strengthening civil society not only supports the tobacco control movement but it provides competencies that may be used in many ways to promote change in democratic societies. PMID- 21243207 TI - Capacity building and human resource development for tobacco control in Latin America. AB - OBJECTIVE: To assess capacity and human resources in Latin America countries and compare with other countries. MATERIAL AND METHODS: Data were gathered through needs assessments that were conducted at the 2009 World Conference on Tobacco or Health, and the 2nd Society for Research on Nicotine and Tobacco-International American Heart Foundation, Latin America Tobacco Control Conference held in Mexico City in 2009. RESULTS: In comparing Latin America respondents to respondents from other countries, we found that the average number of years in tobacco control was higher and the majority of respondents reported higher levels of educational attainment. Respondents reported lack of funding and other resources as their number one challenge, as well as, tobacco industry interference and lack of political will to implement tobacco control policies. CONCLUSIONS: In Latin America there are some countries that have made significant progress in building their capacity and human resources to address their tobacco epidemics, but much still needs to be done. PMID- 21243208 TI - Implementation of smoke free workplaces: challenges in Latin America. AB - Latin America is at the forefront of global progress in smoke free workplaces. Comprehensive smoke free laws have been implemented in four countries, and in many cities, states and provinces. More than 130 million people in Latin America are now protected from secondhand tobacco smoke. Nevertheless, a survey of tobacco control advocates and governments in Latin America found several challenges to progress in smoke free workplaces: the need for voluntary workplace programs where there is no smoke free legislation; weak legislation or lack of comprehensive national smoke free laws; tobacco industry attempts to undermine progress with smoke free laws or overturn existing laws via litigation; lack of compliance with laws; the need for monitoring and evaluation of smoke free laws; the need to make better use of mass media campaigns; and strengthening civil society. However, much progress has already been achieved to address these challenges, in particular through collaborations and the exchange of experience and expertise across Latin America. PMID- 21243209 TI - [Proposal of Latin-American guidelines for smoking cessation]. AB - OBJECTIVE: Although prevalence of tobacco smoking is different in the Latin American regions, the consequences on health are similar. MATERIAL AND METHODS: Therefore, guidelines on treatment are needed and ideally speaking must be useful in the different countries. In order to make quick recommendations useful in the region we made a search in PubMed from the last 5 years with the titles "Smoking cessation guidelines" and "Smoking cessation treatment meta-analysis" to know the content of different guidelines and with the titles of "Nicotine replacement therapy", "Nicotine chewing gum", "Nicotine patches", "Nicotine inhaler", "Bupropion therapy", "Varenicline therapy" and "Individual and group behavioural counselling for smoking cessation" to determine the efficacy of each intervention. RESULTS AND CONCLUSION: Our recommendation based on the availability of pharmacotherapy and human resources is that medical advice and behavioural group counseling must be primary interventions either adding, or not, first line drugs for smoking cessation. PMID- 21243210 TI - The urgent need to change the current medical approach on tobacco cessation in Latin America. AB - Despite of the accumulation of scientific evidence confirming the health consequences of smoking and the new paradigm of smoking as a disease where nicotine is the drug that modifies the functional and morphological characteristics of the brain in dependent smokers, tobacco smoking continues as an important public health problem in many Latin American countries. In contrast with big advances in the tobacco control area, as an example the Framework Convention on Tobacco Control signed by 168 countries, the role of health professional in the fight against tobacco is still less than ideal. In many Latin American schools of medicine, deficiencies in medical education has led to insecure physicians when they have to motivate their patients to stop smoking or to prevent young people to begin tobacco consumption. If each general practitioner or specialist during their daily medical assistance could talk to their smoker patients about the big benefits of stop smoking and support them to get free of tobacco, we would be winning a battle against smoking. Also if we could achieve generations of young non smoking doctors, who could be a real example for patients, this could also impact the prevalence of smokers. In this article we analyze the neurobiological bases of nicotine addiction, which we think are missing in the medical curriculum and could help doctors to understand tobacco smoking as a disease rather than a risk factor, and discuss the main reasons supporting an urgent change in the medical approach of tobacco cessation in Latin America as well as the need to actualize the medical curriculum in order to give physicians the skills needed to intervene successfully with their smoker patients and to be themselves non smokers. PMID- 21243211 TI - [Carlos Rodriguez Ajenjo (1949-2010)]. PMID- 21243212 TI - [To Carlos Rodriguez Ajenjo: tireless fighter against addictions]. PMID- 21243213 TI - Latin America: a laboratory for tobacco control research. PMID- 21243214 TI - [Smoking epidemics and its control in Latin America]. PMID- 21243215 TI - [Presentation. The control of the epidemic of smoking in Latin America]. PMID- 21243216 TI - Estimating the burden of smoking: premature mortality, morbidity, and costs. AB - Estimation of the burden of disease attributable to smoking has now become standard in documenting the impact of the tobacco epidemic and in motivating tobacco control. This paper addresses the methods used to estimate the attributable burden of mortality and the related estimation of morbidity and economic costs. Estimates of attributable mortality and morbidity for the Americas range widely, reflecting the maturity of the tobacco epidemic. The estimates are highest for the United States, and lower for Mexico and other countries of the Americas. PMID- 21243217 TI - Ten years of information on health services access and use. PMID- 21243219 TI - [Recognizing Flexner: an inquiry into the production of myths in medical education in contemporary Brazil]. AB - In Brazil, there appears to be no doubt concerning the evils caused by Abraham Flexner, his Report, and the Flexnerian Biomedical Model (FBM), conceived and promoted by private foundations and linked to the U.S. health-industrial complex. In this article, I submit the above proposition to a rigorous critical inquiry. I begin with an overview of Flexner's life and work. I then review various representations of the Flexnerian model in the Brazilian literature on health education, after which I identify inconsistencies, contradictions, and omissions by comparing the original Report to elements referring to the FBM. Finally, contrasting historical sources and imaginary representations, I analyze possibilities for interpreting the FBM as an intriguing and peculiar political mythology. PMID- 21243218 TI - Tobacco use among the elderly: a systematic review and meta-analysis. AB - The aim of this study was to combine the results of identified surveys on the prevalence of tobacco use in old age to estimate world prevalence of tobacco use and possible factors related to such behavior among the elderly. The literature search included electronic databases such as MEDLINE, LILACS, and Biological Abstracts, hand-searching of specialist journals and cited reference searches. The combined global prevalence was estimated using the random effects model. The total number of elderly subjects included in all surveys was 140,058, with data available from all the continents. Overall prevalence of tobacco use was 13% in both genders (22% male and 8% female). The prevalence rates were heterogeneous among surveys and were associated with smoking definition, questionnaire application, and country economic status. Few epidemiological studies assessed tobacco use among the elderly. A higher prevalence rate of tobacco use in males who live in higher income countries could be found, although additional evidence regarding elderly samples is still required. PMID- 21243220 TI - Structural equation modeling in epidemiology. AB - Structural equation modeling (SEM) is an important statistical tool for evaluating complex relations in several research areas. In epidemiology, the use and discussion of SEM have been limited thus far. This article presents basic principles and concepts in SEM, including an application using epidemiological data analysis from a study on the determinants of cognitive development in young children, considering constructs related to organization of the child's home environment, parenting style, and the child's health status. The relations between the constructs and cognitive development were measured. The results showed a positive association between psychosocial stimulus at home and cognitive development in young children. The article presents the contributions by SEM to epidemiology, highlighting the need for an a priori theoretical model for improving the study of epidemiological questions from a new perspective. PMID- 21243222 TI - Meta-evaluation of baseline studies of the Brazilian Family Health Strategy Expansion Project: a participatory and formative approach. AB - A participatory, formative meta-evaluation of baseline studies in Brazil is presented. International standards recommended by associations of evaluators were used, along with "specificity" criteria built up using the terms of reference for proposals for the selection of studies. The methodological approach combined a "peer review" of baseline study reports, with a participatory (self) assessment for "primary" evaluators, the average of which provided the final score. Results revealed a classification of "good" and "very good" for the set of standards. The differences between the attribution of scores further highlight the importance of taking into account multiple points of view. Given the lack of pre-existing standards for the reports, the absence of standards and the incipient nature of evaluation focusing on utility, this meta-evaluation does not adequately reflect the quality or potential utility of the baseline studies, however, it will certainly contribute to overcoming these limitations and improving future impact studies of the Brazilian Family Health Strategy Expansion Project (PROESF). PMID- 21243221 TI - First reported outbreak of green tobacco sickness in Brazil. AB - Dermal absorption of nicotine by people harvesting tobacco may cause an acute intoxication called green tobacco sickness. Although Brazil is the second largest producer of tobacco in the world, green tobacco sickness had not been reported in the country to date. We conducted a 1:1 matched case-control study among persons involved in tobacco farming to determine the occurrence of green tobacco sickness in the northeast region of Brazil and to identify the risk factors involved. A case-patient was a person who received a diagnosis by health professional of acute intoxication during the study period and had a cotinine level over 10 ng/mL detected by High Performance Liquid Chromatography. We identified 107 case patients. The main signs and symptoms observed were dizziness, weakness, vomit, nausea and headache. Independent risk factors identified were being male, a non smoker and having worked in the harvest of tobacco leaves. Case-patients had higher median urinary cotinine levels than controls (p < 0.05). Epidemiological and laboratory data indicate for the first time the occurrence of green tobacco sickness in Brazil. PMID- 21243223 TI - [Health workers' community practices in primary health care models in South and Northeast Brazil]. AB - In order to verify the prevalence of health workers' participation in health practices in the community, a cross-sectional study was conducted with 3,743 primary care health workers in 41 municipalities with more than 100 thousand inhabitants each in South and Northeast Brazil. Overall prevalence of participation in the community was 62.7%, and was significantly higher in the Northeast and in the Family Health Program (FHP). The most common practice was health education on special holidays, in talks, and in groups. There was a positive association between participation and: female gender, training in the management of chronic diseases, use of protocols, satisfaction with community meetings, and academic health services. Differences in the prevalence of participation by region and health care model reaffirmed the inherent expectations in the historical context of reorganization of primary care. The results indicate that it is necessary to expand participation by health workers in the community, considering that primary care is the level of care that provides the best possibilities for promoting health practices with equity. PMID- 21243224 TI - [Development of a quantitative food frequency questionnaire for pregnant women attending primary care in Ribeirao Preto, Sao Paulo State, Brazil]. AB - The aim of this study was to design a food frequency questionnaire for pregnant women attending primary care under the Unified National Health System in Ribeirao Preto, Sao Paulo State, Brazil. A 24-hour food recall was obtained from 150 pregnant women, 50 in each trimester of pregnancy (age 18-35 years). A second food recall was obtained from 90 women, 30 in each trimester of pregnancy, from 7 to 15 days after the first dietary assessment. An 85-item questionnaire was developed with stepwise multiple linear regression models, based on the contribution of each food to inter-individual variation of energy and 28 target nutrients, which accounted for 74.2 to 98.8% of the selected nutrients. Portion sizes were determined according to percentiles 25, 50, 75, and 100 for each food item intake. To our knowledge, this is the first food frequency questionnaire designed for Brazilian pregnant women. PMID- 21243225 TI - [Intra-urban differences in vulnerability among the elderly population]. AB - This study examined the adequacy of a health vulnerability index (HVI) for identifying intra-urban differences in vulnerability in the elderly population. Study participants (n = 1,055) were selected by probabilistic sampling of residents in the city of Belo Horizonte, Minas Gerais State, Brazil, aged 60 years or older (mean = 70.1 years). The HVI was constructed with indicators of socioeconomic conditions and premature mortality at the census tract level. Based on its location and HVI value, each participant's household was classified as low, medium, or high-risk. Results of multivariate ordinal logistic regression models showed graded and statistically significant associations between the household's risk level and the social and physical environment, health conditions and behaviors, and health service needs (adjusted prevalence ratios ranging from 1.17; 95% CI: 1.02-1.34 to 1.65; 95% CI: 1.45-1.88). The HVI appears to be a useful instrument for identifying health and social service needs among the elderly. PMID- 21243226 TI - [Reception of children in primary health care: a study on attitudes by family health team members]. AB - This was a descriptive cross-sectional study with parents and guardians (n = 384) of children enrolled under six family health teams, using the Primary Care Assessment Tool (PCATool). Characteristics of the children were: 52.9% girls; 55.5% < 3 years of age; and 71.6% living with both parents. For 77.6%, the reference service for health care was the family health facility. In relation to reception and attitudes, 74.2% of parents reported that the health professional understood their complaints and questions, and 79.2% reported that the health professional responded in such a way that parents could understand. A total of 77.2% of the parents/guardians stated that they were always able to talk to the health professional when needed, and 73.8% felt comfortable about this dialogue. These results indicate that the family health team's reception of children and their attitudes in these services have allowed satisfactory user-provider interaction, an indispensable factor for quality health care. PMID- 21243227 TI - Calibration of the dietary data obtained from the Brazilian center of the Natural History of HPV Infection in Men study: the HIM Study. AB - The objective of this study was to estimate the regressions calibration for the dietary data that were measured using the quantitative food frequency questionnaire (QFFQ) in the Natural History of HPV Infection in Men: the HIM Study in Brazil. A sample of 98 individuals from the HIM study answered one QFFQ and three 24-hour recalls (24HR) at interviews. The calibration was performed using linear regression analysis in which the 24HR was the dependent variable and the QFFQ was the independent variable. Age, body mass index, physical activity, income and schooling were used as adjustment variables in the models. The geometric means between the 24HR and the calibration-corrected QFFQ were statistically equal. The dispersion graphs between the instruments demonstrate increased correlation after making the correction, although there is greater dispersion of the points with worse explanatory power of the models. Identification of the regressions calibration for the dietary data of the HIM study will make it possible to estimate the effect of the diet on HPV infection, corrected for the measurement error of the QFFQ. PMID- 21243228 TI - [Analysis of individual spending on smoking based on the Brazilian Family Budget Survey, 2002-2003]. AB - In order to discuss new parameters for assessing personal spending on smoking in Brazil, this study aimed to describe the population's socio-demographic characteristics and the proportions of spending on smoking. The sample included individuals that spend money on smoking, according to the Brazilian Family Budget Survey for 2002-2003, conducted by the Brazilian Institute of Geography and Statistics. In the lowest income bracket, the proportion of spending on smoking for expenses greater than the median varied negatively by as much as 10% as compared to the proportion of spending on smoking for income greater than the median. For intermediate income brackets, the two proportions were similar, and in the higher income brackets there was a reversal, with a positive difference of up to 15%. The percentage of spending on smoking doubled for all the groups with low schooling. As income and schooling increased, there was a proportional reduction in spending on smoking. PMID- 21243229 TI - [Factors associated with exclusive breastfeeding: the role of primary health care]. AB - The aim of this study was to assess the association between promotion, protection, and support for breastfeeding in primary health care services and prevalence of exclusive breastfeeding in the first six months of life. A cross sectional study was conducted in a representative sample of 1,029 mothers of infants younger than six months treated at primary health care facilities in the city of Rio de Janeiro, in southeastern Brazil. Prevalence ratios (PR) were estimated by Poisson regression. Prevalence of exclusive breastfeeding was 58.1%. Factors associated with increased prevalence of exclusive breastfeeding were: white skin color (PR = 1.20; 95% CI: 1.05-1.36); schooling (PR = 1.19; 95% CI: 1.05-1.35); marital status (married or in common-law marriage) (PR = 1.72; 95% IC:1.02-2.90); previous breastfeeding (PR = 1.27; 95% CI: 1.08-1,49); exclusive breastfeeding at the time of hospital discharge (PR = 2.01; 95% CI: 1.20-3.36); group support for the mother (PR = 1.14; 95% CI: 1.01-1.28); and orientation on breastfeeding (PR = 1.20; 95% CI: 1.08-1.33). Prevalence of exclusive breastfeeding decreased 17% per month in the infant's life. Support groups and orientation by primary health care for breastfeeding were associated with increased exclusive breastfeeding prevalence. PMID- 21243230 TI - [The AIDS epidemic in Brazil and differences according to geographic region and health services supply]. AB - The aim of this study was to identify different profiles in the AIDS epidemic in Brazil by relating them to the health sector's organization, situations involving increased risk of infection, and the degree of implementation of the response by health services. The Brazilian municipalities (counties) were grouped according to the magnitude of the epidemic and its trends from 2002 and 2006, and were then studied using indicators obtained from secondary databases. Municipalities with large epidemics (39%) displayed more situations associated with risk of infection, and those with an upward trend in incidence (11.5%) showed a lower degree of response. Cities with large epidemics but with downward or stable trends had 68.6% of all the anonymous testing centers and 75.8% of the outpatient clinics, and performed 81.4% of all the HIV antibody tests in the health system. Preventive measures in schools and primary health services showed low coverage rates. Differences were observed between geographic regions. Inequalities in the degree of implementation of the response to HIV may contribute to different profiles in the epidemic around the country. PMID- 21243231 TI - Neighborhood sociodemographic and environmental contexts and self-rated health among Brazilian adults: a multilevel study. AB - The aim of this study was to investigate the association between sociodemographic and environmental contexts on self-rated health. A population-based cross sectional study with a random sample of 38 neighborhoods (census tracts) and 1,100 adults was carried out. Data analysis used multilevel logistic regression. Data from the Brazilian Census of 2000, mean income, years of study of the head of household and mean number of residents per tract were R$955 (SD = 586), 8 years (SD = 3), and 746 residents (SD = 358) respectively. Higher prevalences of fair/poor self-rated health were found in neighborhoods with greater populations and lower income/schooling levels. After control for individual variables, the odds for fair/poor self-rated health was twice as high in more populous (OR = 2.04; 95%CI: 1.15-3.61) and lower-income neighborhoods (OR = 2.29; 95%CI: 1.16 4.50) compared to less populous, higher-income ones. Self-rated health depends on individual characteristics and the sociodemographic context of neighborhoods. PMID- 21243232 TI - [Validation of food and beverage indicators obtained by telephone survey in Belem, Para State, Brazil]. AB - The aim of this study was to evaluate the relative validity of indicators of food and beverage intake obtained from the telephone interview surveillance system (VIGITEL). A random sample (n = 100) was evaluated from the total sample of approximately two thousand adults studied by the system in 2009 in Belem, Para State, Brazil. The indicators were protective factors (adequate consumption of fruit, vegetables, and leafy vegetables) and risk factors (consumption of saturated fat, soft drinks, and alcoholic beverages) for chronic non-communicable diseases. The telephone interview results were compared with those of three 24 hour recalls (reference standard). The reference standard showed underestimation in the indicators' frequency, except for soft drinks and alcoholic beverages. The mean consumption frequencies were generally higher in the exposed group interviewed by the VIGITEL system. We cannot conclude that the VIGITEL system is not a good indicator of consumption, since the reference standard also shows limitations. Nevertheless, its use as a surveillance tool in Brazil is justifiable. PMID- 21243233 TI - [Risk factors associated with non-adherence to anti-hypertensive medication among patients treated in family health care facilities]. AB - In order to estimate the prevalence of treatment non-adherence and associated factors among individuals with systemic arterial hypertension treated at family health care facilities, a cross-sectional study was performed with 595 patients. The dependent variable non-adherence was measured with a Medication Adherence Questionnaire (MAQ). A hierarchical logistic regression model was used to analyze socioeconomic, health care-related, personal, and treatment-related variables. Prevalence of non-adherence was 53%. Variables associated with non-adherence were: (1) socioeconomic--belonging to economic classes C, D, or E; work market participation in unskilled labor; (2) health care--out-of-pocket payment for medication; more than six months since last physician consultation; and (3) personal and treatment characteristics--previous interruption of treatment; being on treatment for less than three years; and presence of a common mental disorder. The study of determinants of non-adherence articulated in a hierarchical model suggests that social inequalities are either directly associated with non adherence or mediated by personal and health services factors. PMID- 21243234 TI - Cervical cancer mortality trends in Brazil, 1981-2006. AB - The aim of this study was to describe cervical cancer mortality trends in Brazil for the period 1981-2006. Cervical cancer mortality was corrected on the basis of proportional redistribution of the deaths from "malignant neoplasm of uterus, part unspecified". Time trends were evaluated by means of simple linear regression. After correction, cervical cancer ranked second among the leading causes of death from cancer in the female population up to 2005, with a downward trend for the country as a whole, a decline in the State capitals, and a stable trend in the municipalities in the interior. A downward trend was confirmed in the State capitals in all geographic regions of the country. In the municipalities in the interior, there was an increase in the North and Northeast regions, a decline in the Southeast and South, and a stable trend in the Central West. Although uneven, the decline began to take consistent shape in the country. Even better results could be achieved by investing in the expansion of screening coverage, especially among the populations at greatest risk. PMID- 21243235 TI - [Molecular analysis of natural infection of Lutzomyia longipalpis in an endemic area for visceral leishmaniasis in Brazil]. AB - The main purpose of this study was to investigate natural infection by Leishmania chagasi in female sand flies in a visceral leishmaniasis (VL) focus on Sao Luis Island, Maranhao State, Brazil. Molecular analysis by polymerase chain reaction (PCR) was applied to determine the rate of natural infection of Lutzomyia longipalpis by L. chagasi in areas of old and recent human settlement on Sao Luis Island. Based on a sample of 800 female specimens captured from March to August 2005, the natural infection rate was 1.25% in an area of old settlement and 0.25% in two recently settled areas. Infection of L. longipalpis was detected in both areas, regardless of the number of reported human VL cases, indicating that other factors modulating infection in the wild need to be investigated. The results confirm PCR as a specific technique and an important tool for epidemiological surveillance. PMID- 21243236 TI - Lutzomyia longipalpis naturally infected by Leishmania (L.) chagasi in Varzea Grande, Mato Grosso State, Brazil, an area of intense transmission of visceral leishmaniasis. AB - The American visceral leishmaniasis (AVL) is caused by parasites belonging to the genus Leishmania (Trypanosomatidae) and is transmitted to humans through the bite of certain species of infected phlebotomine sand flies. In this study, we investigated the natural infection ratio of Lutzomyia longipalpis, the main vector species of AVL in Brazil, in Varzea Grande, Mato Grosso State. Between July 2004 and June 2006, phlebotomine sand flies were captured in peridomestic areas using CDC light-traps. Four hundred and twenty (420) specimens of Lu. longipalpis were captured. 42 pools, containing 10 specimens of Lu. longipalpis each, were used for genomic DNA extraction and PCR (polymerase chain reaction) amplification. Leishmania spp. DNA was detected in three out of the 42 pools tested, resulting in a minimal infection ratio of 0.71%. Restriction fragment length polymorphism (RFLP) analysis indicated that Leishmania (L.) chagasi was the infective agent in the positive pools. PMID- 21243237 TI - Sudden unexpected death in epilepsy and the song of science. PMID- 21243238 TI - Amyotrophic lateral sclerosis: considerations on diagnostic criteria. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder, compromising the motor neuron, characterized by progressive muscle weakness, with reserved prognosis. The diagnosis is based on inclusion and exclusion clinical criteria, since there is no specific confirmation test. The objective of this research is to critically examine the main diagnosis instrument - El Escorial revisited, from the World Federation of Neurology (1998). Of the 540 patients with initial ALS diagnosis, either probable or definite, seen at UNIFESP-EPM, 190 underwent thorough investigation, following regular clinical and therapeutic treatment for over two years. Thirty patients (15.78%) had their diagnosis completely changed. The false-positive diagnoses were related to: early age, clinical presentation of symmetry, weakness greater than atrophy, symptomatic exacerbation. In addition, three patients with myasthenia gravis developed framework for ALS, suggesting the post-synaptic disability as a sign of early disease. PMID- 21243239 TI - Myasthenia gravis in Ceara, Brazil: clinical and epidemiological aspects. AB - A retrospective chart review was performed on patients diagnosed as having myasthenia gravis in Ceara State, Brazil and who were followed from October 1981 to June 2009. Clinical and epidemiologic aspects were evaluated. In this work, 122 patients were studied, of whom 85 (69.7%) were females and 37 (30.3%) were males. The disease duration ranged from five months to 50 years (8.9+/-8.1 years). Age at the first symptoms varied from 0 to 74 years (31.9+/-14.4 years). The first main symptoms and signs were ptosis, diplopia and limb weakness. Generalized myasthenia was the most common clinical presentation, but 5.1% (n=6) persisted as ocular myasthenia. Thymectomy was performed in 42.6% (n=52) of myasthenic patients. A thymoma was present in 10 patients. Serum acetylcholine receptor (AChR) antibodies were present in 80% (n=20) of specimens tested. The data presented are similar to those of studies performed in other countries. PMID- 21243240 TI - Non-paraneoplastic Lambert-Eaton myasthenic syndrome: a brief review of 10 cases. AB - Lambert-Eaton myasthenic syndrome (LEMS) is an immune-mediated disorder of the presynaptic neuromuscular transmission, which more frequently occurs as the remote effect of a neoplasm, in the paraneoplastic form (P-LEMS), or in a non paraneoplastic form (NP-LEMS); but few studies describe the clinical features of NP-LEMS. We analyzed the clinical manifestations, laboratory findings, electrophysiological studies, and treatment responses in ten Brazilian patients suffering from NP-LEMS. The mean age was 41.5 years. More often neurological findings were hyporeflexia or areflexia with a post-exercise improvement. Treatment response occurred with pyridostigmine, guanidine, prednisone, azathioprine, and cyclosporine; but not response was observed after intravenous immunoglobulin and plasma exchange. Age at onset, clinical manifestations, and electrophysiological abnormalities can help more in the diagnosis than serum antibodies; the symptomatic treatment with pyridostigmine was effective; and the immunosuppressive treatment with prednisone, azathioprine, or cyclosporine was more beneficial than plasma exchange or intravenous immunoglobulin treatment. PMID- 21243241 TI - Swallowing in moderate and severe phases of Alzheimer's disease. AB - OBJECTIVE: To characterize the problems of feeding and swallowing in individuals with moderate and severe Alzheimer's disease (AD) and to correlate these with functional aspects. METHOD: Fifty patients with AD and their caregivers participated in this study. The instruments used were: Clinical Dementia Rating (CDR), Mini-Mental State Examination, Index of Activities of Daily Living, Assessment of Feeding and Swallowing Difficulties in Dementia, Functional Outcome Questionnaire for Aphasia, and Swallowing Rating Scale. RESULTS: Problems with passivity, distraction and refusal to eat were encountered in the CDR2 group. Distraction, passivity and inappropriate feeding velocity were predominant in the CDR3 group. The problems were correlated with communication, swallowing severity of AD individuals and caregiver schooling. CONCLUSION: Given the inexorable functional alterations during the course of the disease, it is vital to observe these in patients with a compromised feeding and swallowing mechanism. The present study supplies the instruments to orient caregivers and professionals. PMID- 21243242 TI - Cognitive deficits in patients with mild to moderate traumatic brain injury. AB - Traumatic brain injury (TBI) is one of the most frequent causes of brain damage. Cognitive deficits reported in the literature after moderate to severe TBI include memory, language, executive functions, attention and information processing speed impairments. However, systematic studies on patients with mild TBI are scarce although neuropsychological changes are present. OBJECTIVE: To investigate the cognitive functioning of patients with mild to moderate TBI. METHOD: We evaluated 12 patients with mild to moderate TBI using a comprehensive protocol (PN01) of neuropsychological tests. RESULTS: There were significant deficits of episodic memory including immediate and delayed verbal memory recall, verbal recognition, immediate and delayed visual memory recall, naming, verbal fluency and information processing speed. CONCLUSION: These results emphasize the importance of comprehensive neuropsychological assessments even in cases of mild TBI in order to identify impaired and preserved functions providing adequate managing including rehabilitation programs for each case. PMID- 21243243 TI - Restless legs syndrome in Parkinson's disease: clinical characteristics and biochemical correlations. AB - Restless legs syndrome (RLS) is a neurological disorder that responds to dopaminergic drugs, indicating a common pathophysiology with Parkinson's disease (PD). The prevalence of RLS was estimated in a group of PD patients and its clinical and biochemical characteristics were analysed. Forty-eight patients with PD were evaluated into two groups, with and without RLS. Clinical characteristics assessed in both groups were age, gender, duration of PD, Hoehn and Yahr, and Schwab and England scales. Laboratory variables such as hemoglobin, s-iron, s ferritin and creatinine were obtained. The prevalence of RLS was 18.75%. No significant differences regarding clinical variables and biochemical parameters were observed. The high prevalence of RLS found in PD patients suggests the concept of a common etiological link and it seems that secondary causes did not play a central role in the pathophysiology of RLS in this group of parkinsonian patients. PMID- 21243244 TI - Prevalence and impact of headache in undergraduate students in Southern Brazil. AB - OBJECTIVE: To determine the prevalence, characteristics and impact of headache among university students. METHOD: The criteria established by the International Headache Society were used to define the primary headache subtypes and the Migraine Disability Assessment Questionnaire (MIDAS), to assess the disability. The students were then grouped into six categories: [1] migraine; [2] probable migraine; [3] tension-type headache; [4] probable tension-type headache; [5] non classifiable headache; [6] no headache. RESULTS: Of all undergraduate students interviewed, 74.5% had at least one headache episode in the last three months. Regarding disability, there was a significant difference between the headache types (p<0.0001). In the post-hoc analysis, migraine was the headache type with most reported disability. CONCLUSION: Headache is a highly prevalent condition among the students at the University of Caxias do Sul. This disease may have a major impact on the students' lives and in some cases, ultimately lead to educational failure. PMID- 21243245 TI - Relative frequency of headache types: a longitudinal study in the tertiary care. AB - In order to properly assess patients with primary headache, one needs to follow the cases up longitudinally. In Brazil, there were no studies using this methodology published after the publication of the latest issue of the International Classification of Headaches in 2004 - ICHD-2. This is especially important when we consider that it was only after such publication that we had the criteria used to classify some types of headaches which evolve with daily, or almost daily, spells, and which are very common in tertiary health care centers. OBJECTIVE: To assess the frequency of headache types in a tertiary health care center, in a longitudinal fashion. METHOD: We assessed 95 consecutive patients. These patients were diagnosed and classified according to the ICDH-2. The subjects were followed up for 18 months, they were treated and reassessed. RESULTS: Most of the individuals had more than one type of headache. Among those with episodic migraine in 2007, 6 developed chronic migraine in 2008, producing an incidence rate of 7.2%. Among those with chronic migraine in 2007, 9 remitted, producing a remission rate of 75%. In 2007, 24 individuals abused analgesic agents and 17 no longer showed abuse criteria in 2008 - when 7 new cases were found. CONCLUSION: The diagnosis of migraine remained stable. On the other hand, treatment brought about a reduction in the frequency of headaches caused by excessive use of analgesic, although the frequency of daily chronic headache was almost unaltered. PMID- 21243246 TI - Neonatal meningitis according to the microbiological diagnosis: a decade of experience in a tertiary center. AB - The aim of this study was to evaluate the incidence of and mortality due to meningitis and compare data according to microbiological diagnosis. This was a ten-year retrospective study conducted at a neonatal intensive care unit (NICU). Newborns with meningitis confirmed by positive CSF culture were included; those with congenital infection or malformations that made lumbar puncture impossible were excluded. The variables investigated were birth weight, gestational and postnatal age, procedures, hematological and CSF parameters, and complications. Parametric and non-parametric tests were used (statistical value p<0.05). The incidence of meningitis was 0.6% and mortality was 27%. Of the 22 cases, 59% involved Gram-negative bacteria; 36% Gram-positive and 5% fungi. The groups did not differ in relation to birth weight, gestational and postnatal age, procedures or hematological and CSF parameters. Sepsis, convulsions and deaths were frequent in both groups, without statistical difference. Gram-negative cases showed abscesses and higher frequency of ventriculitis and hydrocephaly. Meningitis was infrequent, but presented high mortality and frequent complications. PMID- 21243247 TI - Management of supratentorial epidural hematoma in children: report on 49 patients. AB - Traumatic head injury is a common cause of mortality and acquired neurological impairment in children. However, pediatric epidural hematomas (EDHs) are not common and few series have studied the evolution of these patients. In this study, we present the results from a sample of patients with EDH with long-term follow-up. METHOD: Between January 2006 and December 2008, 49 patients with traumatic EDH were treated at our unit. Clinical course, radiological findings and outcomes were evaluated. Neurological status was assessed using the Glasgow Coma Scale (GCS). The patients' ages ranged from one day to 16 years. The mean follow-up was six months. RESULTS: On admission, most of the patients presented mild trauma and 57% had a GCS of 13-15. The most common symptom was irritability. The most frequent mechanisms of injury were: falling from a height in 29 cases and motor vehicle accidents in 16 cases. Three of these patients presented GCS 3, but only one died. We found a late neurological deficit in nine patients. CONCLUSION: These lesions may occur following mild head trauma and in alert children with nonfocal neurological examinations. However, in children presenting irritability with subgaleal hematomas and a history of loss of consciousness, skull computed tomography must be performed. PMID- 21243248 TI - The neurological examination of non-complicated preterm newborns using the Saint Anne Dargassies Scale from birth to term. AB - OBJECTIVE: To describe the maturational development of 20 (aged 32-36 weeks) premature newborns (PNBs) without clinical or neurological complications from birth until term. METHOD: The Saint-Anne Dargassies Scale was applied every two weeks until the age of 37 weeks. RESULTS: The PNBs showed normal Apgar and the growth in head circumference was adequate for postmentrual age. The Friedman ANOVA test found a significant difference only for the heel-to-ear angles from birth until term. The Saint-Anne Dargassies Scale detected changes in 11 PNBs and the most altered reflexes were: cardinal points, Moro, cross extension reflexe and automatic walking. These changes were found in the first 48 hours of life and in subsequent weeks until term. CONCLUSION: This finding alone justifies the neurological examination of PNBs, even if they show no clinical/neurological complications in the perinatal period and the importance of neuromotor assessment in preterm infants, as it enables detection and appropriate intervention. PMID- 21243249 TI - Incidence of SUDEP in a cohort of patients with refractory epilepsy: the role of surgery and lesion localization. AB - OBJECTIVE: The aim of this study was to verify incidence and characteristics of sudden unexpected death in patients (SUDEP) with refractory epilepsy and its relation to previous surgery and lesion localization. METHOD: A cross sectional study was carried out in a cohort of 550 patients with refractory epilepsy followed up by the Epilepsy Surgery Program of the University Hospital of PUCRS, Porto Alegre, Brazil, between January, 1992 and July, 2002. Patients were allocated in two groups (operated and non operated). Seizure type, distribution of interictal spikes and MRI findings were correlated with the SUDEP outcome. RESULTS: The estimated incidence of probable SUDEP amounted to 29:1000 individuals. Probable SUDEP occurred in 1.2% of the 166 patients of the non operated group and in 3.7% of the 384 patients who were operated (OR=3.02, 95% CI 0.69-13.16) (p=0.11). Comparing patients who died to patients alive in the operated group a significant difference was observed concerning the following variables: SUDEP patients had a predominance of generalized seizures (p=0.002), extratemporal lesion on MRI (p<0.001) and epileptiform activity over extratemporal regions (p=0.001). CONCLUSION: In surgically treated patients with refractory epilepsy, an extratemporal location of the lesion and of the epileptiform discharges significantly correlated to SUDEP. Thus it is possible that in those patients; the underlying disease may play a role in the pathogenesis of SUDEP. PMID- 21243250 TI - Sleep disorders in high school and pre-university students. AB - Adolescence is a period in which youngsters have to make choices such as applying for university. The selection process is competitive, and it brings distress and anxiety, risk factors for the appearance of sleep disorders. OBJECTIVE: To verify the occurrence of sleep disorders in third-year high school and pre-university students. METHOD: This cross-sectional descriptive study comprised a sample of 529 students (M=241, F=288) from three public schools, four private schools and two pre-university courses - a middle-class neighborhood in the city of Sao Paulo - aged between 16 and 19 years old. We used the Pittsburgh Sleep Quality Index (PSQI) - a standardized questionnaire. RESULTS: The participants (52.9%) took about 30 minutes to fall asleep, with an average of 306.4 minutes asleep, moderate daytime sleepiness (n=243, 45.9%) and indisposition (n=402, 75.9%) to develop the activities. The scores (M and F) were similar regarding problems that affect sleep. CONCLUSION: The investigated population showed sleep disorders and poor sleep quality. PMID- 21243251 TI - Use of hippotherapy in gait training for hemiparetic post-stroke. AB - OBJECTIVE: To evaluate the hippotherapy influence on gait training in post-stroke hemiparetic individuals. METHOD: The study was constituted of 20 individuals divided into two groups. Group A performed the conventional treatment while group B the conventional treatment along with hippotherapy during 16 weeks. The patients were evaluated by using the Functional Ambulation Category Scale, Fugl Meyer Scale, only the lower limbs and balance sub items, Berg Balance Scale, and functional assessment of gait (cadence) in the beginning and end of the treatment. RESULTS: Significant improvements were observed in the experimental group including motor impairment in lower limbs (p=0.004), balance, over time (p=0.007) but a significant trend between groups (p=0.056). The gait independence, cadence and speed were not significantly in both groups (p=0.93, 0.69 and 0.44). CONCLUSION: Hippotherapy associated with conventional physical therapy demonstrates a positive influence in gait training, besides bringing the patients' gait standard closer to normality than the control group. PMID- 21243252 TI - The effect of multiple sclerosis on the professional life of a group of Brazilian patients. AB - OBJECTIVE: To assess the impact of multiple sclerosis (MS) on the professional life of Brazilian patients. METHOD: One hundred MS patients were randomly selected from the database of the Brazilian Multiple Sclerosis Association (ABEM). An individual interview was carried out by telephone by a member of ABEM, who collected data on the patients' clinical status, educational level and professional lives. RESULTS: Complete data were obtained from 96 patients (27 males and 69 females) aged 55.0+/-14.1 years, with average disease duration of 4.6+/-4.0 years). Eighty percent had eleven or more years of schooling. Among the whole group, 66% did not present limitations on walking. The longer the disease duration and the older the patient were, the higher the chances were that the patient was retired or receiving workers' compensation benefits. However, even among patients with MS for less than five years, the rate of non-participation in the workforce was 47.7%. Fatigue, paresthesia, cognitive dysfunction and pain were often cited as the motives for not working. CONCLUSION: MS patients presented high levels of unemployment, retirement and receipt of workers' compensation benefits, despite their high schooling levels. Age, disease duration and disability influenced these results for the whole group. However, even among younger patients with shorter disease duration and low disability, this finding remained. PMID- 21243253 TI - Effect of N-acetylcysteine on vasospasm in subarachnoid hemorrhage. AB - Vasospasm remains an extremely serious complication that affects patients presenting with subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms. The current therapeutic armamentarium is still insufficient in many cases, and the search for new therapies is necessary. In this study, we evaluated the effect of N-acetylcysteine (NAC) on cerebral arterial vasospasm using an experimental model. Twenty-four wistar rats were divided into 4 groups: [1] Control, [2] SAH, [3] SAH+NAC and [4] SAH+Placebo. The experimental model employed double subarachnoid injections of autologous blood. The proposed dose of NAC was 250 mg/kg intraperitoneally per day. We analyzed the inner area of the basilar artery to assess the action of NAC. The experimental model proved to be very adequate, with a mortality rate of 4%. The inner area of the basilar artery in the SAH group showed significant difference to the control group (p=0.009). The use of NAC significantly reduced vasospasm as compared to the untreated group (p=0.048) and established no significant difference to the control group (p=0.098). There was no significant improvement with the administration of placebo (p=0.97). The model of the dual hemorrhage proved to be very useful for vasospasm simulation, with overall low mortality. The administration of NAC significantly reduced vasospasm resulting from SAH, and may represent a new therapeutic alternative. PMID- 21243254 TI - Motor cortex electric stimulation for the treatment of neuropathic pain. AB - OBJECTIVE: Motor cortex stimulation (MCS) is considered to be an effective treatment for chronic neuropathic pain. The aim of the present study was to assess the efficacy of MCS for treating neuropathic pain. METHOD: 27 patients with chronic neuropathic pain were operated. Electrodes were implanted with the use of an stereotactic frame. Electrophysiological evaluations (motor stimulation and somatosensory evoked potentials) were performed, with guidance by means of three-dimensional reconstruction of magnetic resonance images of the brain. 10 patients (37%) presented central neuropathic pain (post-stroke pain) and 17 others (63%) presented peripheral neuropathic pain (brachial plexus avulsion, phantom limb pain or trigeminal pain). RESULTS: In 15 patients (57.7%) the pain relief was 50% or more; while in ten patients (38.5%), more than 60% of the original pain was relieved. No differences were found in relation to central and peripheral neuropathic pain (p=0.90), pain location (p=0.81), presence of motor deficit (p=0.28) and pain duration (p=0.72). No major complications were observed. CONCLUSION: MCS was efficient for treating patients presenting chronic central or peripheral neuropathic pain. PMID- 21243255 TI - Coma scales: a historical review. AB - OBJECTIVE: To describe the most important coma scales developed in the last fifty years. METHOD: A review of the literature between 1969 and 2009 in the Medline and Scielo databases was carried out using the following keywords: coma scales, coma, disorders of consciousness, coma score and levels of coma. RESULTS: Five main scales were found in chronological order: the Jouvet coma scale, the Moscow coma scale, the Glasgow coma scale (GCS), the Bozza-Marrubini scale and the FOUR score (Full Outline of UnResponsiveness), as well as other scales that have had less impact and are rarely used outside their country of origin. DISCUSSION: Of the five main scales, the GCS is by far the most widely used. It is easy to apply and very suitable for cases of traumatic brain injury (TBI). However, it has shortcomings, such as the fact that the speech component in intubated patients cannot be tested. While the Jouvet scale is quite sensitive, particularly for levels of consciousness closer to normal levels, it is difficult to use. The Moscow scale has good predictive value but is little used by the medical community. The FOUR score is easy to apply and provides more neurological details than the Glasgow scale. PMID- 21243256 TI - Progressive supranuclear palsy: new concepts. AB - Progressive supranuclear palsy (PSP) is a distinctive form of neurodegenerative disease which affects the brainstem and basal ganglia. Patients present supranuclear ophthalmoplegia, postural instability and mild dementia. PSP is defined neuropathologically by the accumulation of neurofibrillary tangles in the subthalamic nucleus, pallidum, red nucleus, substantia nigra, striatum, pontine tegmentum, oculomotor nucleus, medulla and dentate nucleus. Over the last decade many lines of investigations have helped refine PSP in many aspects and it is the purpose of this review to help neurologists identify PSP, to better understand its pathophysiology and to provide a more focused, symptom-based treatment approach. PMID- 21243257 TI - Aberrant signaling pathways in medulloblastomas: a stem cell connection. AB - Medulloblastoma is a highly malignant primary tumor of the central nervous system. It represents the most frequent type of solid tumor and the leading cause of death related to cancer in early childhood. Current treatment includes surgery, chemotherapy and radiotherapy which may lead to severe cognitive impairment and secondary brain tumors. New perspectives for therapeutic development have emerged with the identification of stem-like cells displaying high tumorigenic potential and increased radio- and chemo-resistance in gliomas. Under the cancer stem cell hypothesis, transformation of neural stem cells and/or granular neuron progenitors of the cerebellum are though to be involved in medulloblastoma development. Dissecting the genetic and molecular alterations associated with this process should significantly impact both basic and applied cancer research. Based on cumulative evidences in the fields of genetics and molecular biology of medulloblastomas, we discuss the possible involvement of developmental signaling pathways as critical biochemical switches determining normal neurogenesis or tumorigenesis. From the clinical viewpoint, modulation of signaling pathways such as TGFbeta, regulating neural stem cell proliferation and tumor development, might be attempted as an alternative strategy for future drug development aiming at more efficient therapies and improved clinical outcome of patients with pediatric brain cancers. PMID- 21243258 TI - Alpha-fetoprotein as a biomarker for recessive ataxias. PMID- 21243259 TI - Isolation of neurosphere-like bodies from an adult patient with refractory temporal lobe epilepsy. PMID- 21243260 TI - Sphincter abnormality in polytransfused patient due to paroxysmal nocturnal hemoglobinuria (PNH): initial manifestation of tropical spastic paraparesis/HTLV 1 associated myelopathy (TSP/HAM). PMID- 21243261 TI - Polymyositis in childhood as clinical manifestation associated with HTLV-1. PMID- 21243262 TI - Semantic aphasia as a sole manifestation of acute stroke. PMID- 21243263 TI - Acute encephalitis caused by Schistosoma mansoni. PMID- 21243264 TI - Glial microtumor with 17-year of postoperative follow up. PMID- 21243265 TI - Guillain-Barre syndrome associated with H1N1 vaccination. PMID- 21243269 TI - Amyotrophic lateral sclerosis and herpes virus: a casual or causal association? Twelve years after. PMID- 21243270 TI - Valsalva maneuver in detection of right-to-left shunt by transcranial Doppler. PMID- 21243273 TI - The effects of iron deficiency anemia on p wave duration and dispersion. AB - OBJECTIVES: The association between P wave dispersion and iron deficiency anemia has not been documented in the literature. In this study, we evaluated P wave dispersion in patients with iron deficiency anemia and the possible relationships between P wave dispersion and other echocardiographic parameters. INTRODUCTION: The iron status of an individual may play an important role in cardiovascular health. Anemia is an independent risk factor for adverse cardiovascular outcomes. P wave dispersion is a simple electrocardiographic marker that has a predictive value for the development of atrial fibrillation. Apart from cardiovascular diseases, several conditions, such as seasonal variation, alcohol intake and caffeine ingestion, have been demonstrated to affect P wave dispersion. METHODS: The study included 97 patients who had iron deficiency anemia and 50 healthy subjects. The cases were evaluated with a clinical examination and diagnostic tests that included 12-lead electrocardiography and transthoracic echocardiography. RESULTS: Compared to the control group, patients with iron deficiency anemia showed significantly longer maximum P wave duration (Pmax) (91.1 +/- 18.0 vs. 85.8 +/- 6.7 msec, p = 0.054), P wave dispersion (PWD) (48.1 +/- 7.7 vs. 40.9 +/- 5.6 msec, p < 0.001), mitral inflow deceleration time (DT) (197.5 +/- 27.9 vs. 178.8 +/- 8.9 msec, p < 0.001) and isovolumetric relaxation time (IVRT) (93.3 +/- 9.2 vs. 77.4 +/- 8.2 msec, p < 0.001); they also showed increased heart rate (85.7 +/- 16.1 vs. 69.0 +/- 4.4, p < 0.001) and frequency of diastolic dysfunction (7 (7.2%) vs. 0). Correlation analysis revealed that PWD was significantly correlated with IVRT, DT, heart rate, the presence of anemia and hemoglobin level. CONCLUSIONS: Iron deficiency anemia may be associated with prolonged P wave duration and dispersion and impaired diastolic left ventricular filling. PMID- 21243275 TI - The association between estimated average glucose levels and fasting plasma glucose levels. AB - OBJECTIVE: The level of hemoglobin A1c (HbA1c), also known as glycated hemoglobin, determines how well a patient's blood glucose level has been controlled over the previous 8-12 weeks. HbA1c levels help patients and doctors understand whether a particular diabetes treatment is working and whether adjustments need to be made to the treatment. Because the HbA1c level is a marker of blood glucose for the previous 120 days, average blood glucose levels can be estimated using HbA1c levels. Our aim in the present study was to investigate the relationship between estimated average glucose levels, as calculated by HbA1c levels, and fasting plasma glucose levels. METHODS: The fasting plasma glucose levels of 3891 diabetic patient samples (1497 male, 2394 female) were obtained from the laboratory information system used for HbA1c testing by the Department of Internal Medicine at the Izmir Bozyaka Training and Research Hospital in Turkey. These samples were selected from patient samples that had hemoglobin levels between 12 and 16 g/dL. The estimated glucose levels were calculated using the following formula: 28.7 x HbA1c - 46.7. Glucose and HbA1c levels were determined using hexokinase and high performance liquid chromatography (HPLC) methods, respectively. RESULTS: A strong positive correlation between fasting plasma glucose levels and estimated average blood glucose levels (r=0.757, p<0.05) was observed. The difference was statistically significant. CONCLUSION: Reporting the estimated average glucose level together with the HbA1c level is believed to assist patients and doctors determine the effectiveness of blood glucose control measures. PMID- 21243274 TI - The progins progesterone receptor gene polymorphism is not related to endometriosis-associated infertility or to idiopathic infertility. AB - OBJECTIVE: This study aimed to determine the frequency of the PROGINS polymorphism in women with endometriosis-associated infertility, in infertile women without endometriosis and in controls. INTRODUCTION: The human progesterone receptor gene has two isoforms that modulate the biological action of progesterone: isoform A, which is capable of inhibiting the activation of the estrogen receptors, and isoform B, which has the capacity to activate the estrogen receptors. Several polymorphisms have been described for this gene, among which one stands out: a polymorphism named PROGINS, which has been speculated to be related to the genesis of endometriosis by several studies with conflicting results. METHODS: This was a prospective study that included 148 patients with endometriosis-associated infertility, 50 idiopathic infertile patients and 179 fertile women as controls. The PROGINS polymorphism was studied by PCR. RESULTS: Genotypes P1P1, P1P2 and P2P2 (P2 representing the PROGINS polymorphism) of the progesterone receptor gene presented frequencies of 93.9%, 5.4% and 0.7%, respectively, in the women with endometriosis-associated infertility (p=0.2101, OR=0.51, 95% CI=0.24-1.09); 94.4%, 4.2% and 1.4%, respectively, in the patients with minimal/mild endometriosis (p=0.2725, OR=0.53, 95% CI=0.20-1.43); 93.5%, 6.5% and 0%, respectively, among the patients with moderate/severe endometriosis (p=0.3679, OR=0.49, 95% CI=0.18-1.31); 86.0%, 14.0% and 0%, respectively, in idiopathic infertile women (p=0.8146, OR=1.10, 95% CI=0.46-2.63); and 88.3%, 10.6% and 1.1%, respectively, in the control group. CONCLUSION: The data suggest that PROGINS is not related either to endometriosis associated infertility or to idiopathic infertility in the population studied. PMID- 21243276 TI - Oseltamivir compounding in the hospital pharmacy during the (H1N1) influenza pandemic. AB - AIMS: Pandemics impose large demands on the health care system. The supply of appropriate chemotherapeutic agents, namely oseltamivir solution, presented a serious challenge in the recent influenza pandemic. This study reports on the rational series of pharmacotechnical steps that were followed to appropriately handle bulk oseltamivir powder to meet the increased demand. METHODS: During a six-week period in August and September of 2009, a task force was created in the Central Pharmacy of Hospital das Clinicas to convert imported oseltamivir phosphate into ready-to-use solution for utilization by physicians and public health authorities. The protocol included dissolution, physico-chemical tests and the bottling of a liquid microdose formulation for emergency room and outpatient dispensing with adequate quality control during all phases. RESULTS: The successful production routine was based on a specially designed flowchart according to which a batch of 33210 g of oseltamivir powder was converted into 32175 solution units during the aforementioned period with a net loss of only 2.6%. The end products were bottles containing 50 ml of 15 mg/mL oseltamivir solution. The measured concentration was stable and accurate (97.5% - 102.0% of the nominal value). The drug was prescribed as both a prophylactic and therapeutic agent. DISCUSSION: Hospital pharmacies are conventionally engaged in the manipulation of medical prescriptions and specialty drugs. They are generally responsible for only small-scale equipment used for manufacturing and quality control procedures. The compounding of oseltamivir was a unique effort dictated by exceptional circumstances. CONCLUSION: The shortage of oseltamivir solution for clinical use was solved by emergency operationalization of a semi-industrial process in which bulk powder was converted into practical vials for prompt delivery. PMID- 21243277 TI - Application of the pediatric risk of mortality (PRISM) score and determination of mortality risk factors in a tertiary pediatric intensive care unit. AB - INTRODUCTION: To establish disease severity at admission can be performed by way of the mortality prognostic. Nowadays the prognostic scores make part of quality control and research. The Pediatric Risk of Mortality is one of the scores used in the pediatric intensive care units. OBJECTIVES: The purpose of this study is the utilization of the pediatric risk of mortality to determine mortality risk factors in a tertiary pediatric intensive care units. METHODS: Retrospective cohort study, in a period of one year, at a general tertiary pediatric intensive care unit. The pediatric risk of mortality scores corresponding to the first 24 hours of hospitalization were recorded; additional data were collected to characterize the study population. RESULTS: 359 patients were included; the variables that were found to be risk factors for death were multiple organ dysfunction syndrome, mechanical ventilation, use of vasoactive drugs, hospital acquired infection, parenteral nutrition and duration of hospitalization (p < 0,0001). Fifty-four patients (15%) died; median pediatric risk of mortality score was significantly lower in patients who survived (p=0,0001). The ROC curve yielded a value of 0.76 (CI 95% 0,69-0,83) and the calibration was shown to be adequate. DISCUSSION: It is imperative for pediatric intensive care units to implement strict quality controls to identify groups at risk of death and to ensure the adequacy of treatment. Although some authors have shown that the PRISM score overestimates mortality and that it is not appropriate in specific pediatric populations, in this study pediatric risk of mortality showed satisfactory discriminatory performance in differentiating between survivors and non-survivors. CONCLUSIONS: The pediatric risk of mortality score showed adequate discriminatory capacity and thus constitutes a useful tool for the assessment of prognosis for pediatric patients admitted to a tertiary pediatric intensive care units. PMID- 21243278 TI - Intraobserver and interobserver reliability of radial torsion angle measurements by a new and alternative method with computed tomography. AB - OBJECTIVE: To evaluate the intraobserver and interobserver reliability of radial torsion angle measurement using computed tomography. METHODS: Twelve pairs of cadaver radii and 116 forearms from 58 healthy volunteers were evaluated using axial computed tomography sections measured at the level of the bicipital tuberosity and the subchondral region of the radius. During digital imaging, the angle was formed by two lines, one diametrically perpendicular to the radial tubercle and the other tangential to the volar rim of the distal joint surface. Measurements were performed twice each by three observers. RESULTS: In cadaveric bones, the mean radial torsion angle was 1.48o (-6o - 9o) on the right and 1.62o (-6 o - 8o) on the left, with a mean difference between the right and left sides of 1.61o (0o - 8o). In volunteers, the mean radial torsion angle was 3.00 degrees (-17 degrees - 17 degrees ) on the right and 2.91 degrees (-16 degrees - 15 degrees ) on the left, with a mean difference between the sides of 1.58o (0o - 7o). There was no significant difference between each side. The interobserver correlation coefficient for the cadaver radii measurements was 0.88 (0.72 - 0.96) and 0.81 (0.58 - 0.93) for the right and left radius, respectively, while for the volunteers, the difference was 0.84 (0.77 - 0.90) and 0.83 (0.75 - 0.89), respectively. Intraobserver reliability was high. CONCLUSION: The described method is reproducible and applicable even when the radial tubercle has a rounded contour. PMID- 21243279 TI - Does minor histocompatibility antigen HA-1 disparity affect the occurrence of graft-versus-host disease in tunisian recipients of hematopoietic stem cells? AB - INTRODUCTION: Minor histocompatibility antigen HA-1 (MiHAg-HA-1) disparity between a patient and his or her human leukocyte antigen (HLA) genoidentical donor has been widely associated with an increased risk of graft-versus-host disease following allogeneic hematopoietic stem cell transplantation. OBJECTIVE: To examine the effect of HA-1 disparity on the incidence of both acute and chronic graft-versus-host disease in Tunisian recipients of hematopoietic stem cells. METHODS: A total of 60 patients and their 60 respective sibling hematopoietic stem cell donors were enrolled in this study. All patients prophylactically received cyclosporine A and/or methotrexate for graft-versus host disease. An HA-1 genotyping assay was performed with the SSP-PCR method, and HLA-A*0201- and/or HLA-A*0206-positive samples were identified using the Luminex HLA typing method. RESULTS: The Luminex HLA typing assay showed that 54 patients were positive for either the HLA-A*0201 or HLA-A*0206 alleles. Among these cases, six pairs were mismatched for MiHAg-HA-1. Both acute and chronic graft-versus host disease occurred in four mismatched patients (Fisher's p-values were 0.044 and 0.170, respectively). A univariate logistic regression model analysis showed that only acute graft-versus-host disease may be affected by recipient MiHAg-HA-1 disparity (p: 0.041, OR: 6.727), while chronic graft-versus-host disease correlates with both age and recipient/donor sex mismatch (p: 0.014, OR: 8.556 and p: 0.033, OR: 8.664, respectively). CONCLUSION: Our findings support previously reported data suggesting a significant association between HA-1 disparity and the risk of acute graft-versus-host disease following hematopoietic stem cell transplantation. PMID- 21243280 TI - Effects of massage therapy on sleep quality after coronary artery bypass graft surgery. AB - INTRODUCTION: Having poor sleep quality is common among patients following cardiopulmonary artery bypass graft surgery. Pain, stress, anxiety and poor sleep quality may be improved by massage therapy. OBJECTIVE: This study evaluated whether massage therapy is an effective technique for improving sleep quality in patients following cardiopulmonary artery bypass graft surgery. METHOD: Participants included cardiopulmonary artery bypass graft surgery patients who were randomized into a control group and a massage therapy group following discharge from the intensive care unit (Day 0), during the postoperative period. The control group and the massage therapy group comprised participants who were subjected to three nights without massage and three nights with massage therapy, respectively. The patients were evaluated on the following mornings (i.e., Day 1 to Day 3) using a visual analogue scale for pain in the chest, back and shoulders, in addition to fatigue and sleep. Participants kept a sleep diary during the study period. RESULTS: Fifty-seven cardiopulmonary artery bypass graft surgery patients were enrolled in the study during the preoperative period, 17 of whom were excluded due to postoperative complications. The remaining 40 participants (male: 67.5%, age: 61.9 years +/- 8.9 years, body mass index: 27.2 kg/m2 +/- 3.7 kg/m2) were randomized into control (n = 20) and massage therapy (n = 20) groups. Pain in the chest, shoulders, and back decreased significantly in both groups from Day 1 to Day 3. The participants in the massage therapy group had fewer complaints of fatigue on Day 1 (p=0.006) and Day 2 (p=0.028) in addition, they reported a more effective sleep during all three days (p=0.019) when compared with the participants in the control group. CONCLUSION: Massage therapy is an effective technique for improving patient recovery from cardiopulmonary artery bypass graft surgery because it reduces fatigue and improves sleep. PMID- 21243281 TI - A comparative study of "plasmacup" and "porous-coated" acetabular components: survival after 10 to 12 years of follow-up. AB - OBJECTIVES: Our primary aim was to compare the long-term survivorship rates and the rates of successful osseointegration between two different types of uncemented acetabular components. INTRODUCTION: Two types of alloys have primarily been used for the manufacture of the uncemented acetabular components: titanium-based and cobalt-based alloys. A titanium-based alloy appears to be more effective with regard to interface stress transfer to the host bone because of its lower elastic modulus relative to a cobalt-based alloy. This supposed mechanical advantage of a titanium-based alloy component motivated this comparative study. METHODS: Two uncemented acetabular components, a porous-coated acetabulum and a Plasmacup(r), were compared with a focus on long-term prosthesis survivorship and the development of acetabular osseointegration. Five radiographic signs of osseointegration were evaluated at the last follow-up appointment: (1) absence of radiolucent lines, (2) presence of a superolateral buttress, (3) medial stress-shielding, (4) radial trabeculae, and (5) an inferomedial buttress. We considered the presence of any three of these radiographic signs, in the absence of acetabular dislocation or symptoms, to be indicative of successful acetabular osseointegration. RESULTS: Among 70 patients implanted with the porous-coated acetabulum, 80% achieved osseointegration over a mean follow-up time of 11.9 years versus 75.3% of the 73 patients who received a Plasmacup insert over a mean of 10.7 years. Prosthesis survivorship rates were not different between the two groups. Revision surgery due to mild or severe acetabular osteolysis, polyethylene wear, and aseptic loosening occurred in eight patients (11.4%) with a PCA versus nine (12.3%) with a Plasmacup. CONCLUSIONS: We conclude that, during the first ten years after surgery, there is no significant difference between these two types of uncemented cups with regard to either prosthesis survivorship or successful osseointegration. PMID- 21243282 TI - Frequency of the mdr-1 C>T gene polymorphism in patients with COPD. AB - BACKGROUND AND AIM: The multi-drug resistant-1 (MDR-1) gene is located on human chromosome 7 and encodes a glycosylated membrane protein that is a member of the ATP-binding cassette transporters superfamily. The aim of the study was to reveal the role of the C3435T MDR-1 gene polymorphism in chronic obstructive pulmonary disease. METHOD: DNA samples from 41 patients with chronic obstructive pulmonary disease and 50 healthy control participants were used to compare MDR-1 gene profiles. Genotyping assays were performed using the StripAssay technique that is based on reverse-hybridization. RESULTS: The T allele polymorphism in the MDR-1 gene located at position 3435 in exon 26 was shown to correlate with chronic obstructive pulmonary disease. CONCLUSION: These preliminary results suggest that the T allele polymorphism of the MDR-1 gene is associated with chronic obstructive pulmonary disease. PMID- 21243283 TI - Natural coagulation inhibitors and active protein c resistance in preeclampsia. AB - INTRODUCTION: The etiology of preeclampsia is not fully established. A few studies have shown a relationship between natural coagulation inhibitors and preeclampsia. OBJECTIVES: The purpose of this study was to investigate the status of natural coagulation inhibitors and active protein C resistance (APC-R) in preeclampsia. PATIENTS AND METHODS: We studied 70 women with preeclampsia recruited consecutively and 70 healthy pregnant and 70 nonpregnant women as controls. Plasma protein C (PC), free protein S (fPS), antithrombin III (ATIII) and APC-R were evaluated. RESULTS: ATIII values were found to be significantly lower in preeclamptic patients than in the control groups (p< 0.001). Nevertheless, there was no significant difference between the healthy pregnant and nonpregnant women groups (p=0.141). The fPS values of the preeclamptic and healthy pregnant groups were lower than that of the nonpregnant group (p< 0.001), and the fPS value of the preeclamptic pregnant women was lower than that of healthy pregnant women (p<0.001). The PC value of the preeclamptic pregnant women was lower than that of the control groups (p< 0.001). The PC value of the healthy pregnant women was lower than that of the nonpregnant women (p< 0.001). The mean APC activity values were lower in the preeclamptic patients than that of the control groups (p< 0.001, p< 0.001). The APC-R positivity rates of the preeclamptic groups were higher than that of the control groups (p<0.001). CONCLUSIONS: This study demonstrated that ATIII, fPS, PC values and APC resistance were lower and APC-R positivity was higher in preeclamptic women than in normal pregnant and nonpregnant women. PMID- 21243284 TI - Acute strength exercise and the involvement of small or large muscle mass on plasma brain-derived neurotrophic factor levels. AB - OBJECTIVE: Blood neurotrophins, such as the brain-derived neurotrophic factor, are considered to be of great importance in mediating the benefits of physical exercise. In this study, the effect of acute strength exercise and the involvement of small versus large muscle mass on the levels of plasma brain derived neurotrophic factor were evaluated in healthy individuals. METHODS: The concentric strengths of knee (large) and elbow (small) flexor and extensor muscles were measured on two separate days. Venous blood samples were obtained from 16 healthy subjects before and after exercise. RESULTS: The levels of brain derived neurotrophic factor in the plasma did not significantly increase after both arm and leg exercise. There was no significant difference in the plasma levels of the brain-derived neurotrophic factor in the arms and legs. CONCLUSION: The present results demonstrate that acute strength exercise does not induce significant alterations in the levels of brain-derived neurotrophic factor plasma concentrations in healthy individuals. Considering that its levels may be affected by various factors, such as exercise, these findings suggest that the type of exercise program may be a decisive factor in altering peripheral brain derived neurotrophic factor. PMID- 21243285 TI - Depression during pregnancy in women with a medical disorder: risk factors and perinatal outcomes. AB - BACKGROUND: Approximately one-fifth of women present depression during pregnancy and puerperium, and almost 13% of pregnant women experience a major depressive disorder. OBJECTIVE: The aim of this study was to identify risk factors for depression among pregnant women with a medical disorder and to evaluate the influence of depression on perinatal outcomes. METHODS: Three hundred and twenty six pregnant women with a medical disorder were interviewed. A semistructured interview was conducted for each participant using a questionnaire that had been developed previously. Major depression was diagnosed using the Portuguese version of the Primary Care Evaluation of Mental Disorders (PRIME-MD). The medical records of the participants were thoroughly reviewed to evaluate the perinatal results. RESULTS: Major depressive disorder was diagnosed in 29 cases (9.0%). The prevalence of major depression was as follows: 7.1% for preeclampsia or chronic hypertension, 12.1% for cardiac disorder, 7.1% for diabetes mellitus, 6.3% for maternal anemia, 8.3% for collagenosis and 12.5% for a high risk of premature delivery. An univariate analysis showed a significant positive correlation between an average household income below minimum wage and a PRIME-MD diagnosis of major depression. A multiple regression analysis identified unplanned pregnancy as an independent predictor of major depression (86.2% in the group with a diagnosis of major depression by PRIME-MD vs. 68.4% in the group without major depression). A comparison between women who presented major depression and those who did not revealed no significant differences in the perinatal results (i.e., preterm delivery, birth weight and low Apgar scores). CONCLUSION: In the present study, unplanned pregnancy in women with a medical disorder was identified as a risk factor for major depression during gestation. Major depression during pregnancy in women with a medical disorder should be routinely investigated using specific methods. PMID- 21243286 TI - High rate of viral identification and coinfections in infants with acute bronchiolitis. AB - OBJECTIVES: To determine the viruses and risk factors associated with hospital and intensive care unit (ICU) admissions in infants with acute bronchiolitis. INTRODUCTION: Bronchiolitis is a major cause of morbidity in infants. Widespread use of molecular-based methods has yielded new insights about its etiology, but the impact of viral etiologies on early outcomes is still unclear. METHODS: Seventy-seven infants with bronchiolitis who were under two years of age and visited an emergency unit were included. Using molecular-based methods, samples were tested for 12 different respiratory viruses. Logistic regression models were used to identify clinical and virological variables associated with the main endpoints: hospital admission and ICU admission. RESULTS: We identified at least one virus in 93.5% of patients, and coinfections were found in nearly 40% of patients. RSV was the most common pathogen (63.6%), followed by rhinovirus (39%). Identification of RSV was only associated with an increased risk of hospital admission in the univariate model. Younger age and enterovirus infection were associated with an increased risk of hospital admission, while atopy of a first degree relative showed a protective effect. Prematurity was associated with an increased risk of admission to the ICU. Coinfections were not associated with worse outcomes. CONCLUSIONS: Molecular-based methods resulted in high rates of viral identification but did not change the significant role of RSV in acute bronchiolitis. Younger age and enterovirus infection were risk factors for hospital admission, while prematurity appeared to be a significant risk factor for admission to the ICU in acute viral bronchiolitis. PMID- 21243287 TI - Insulin therapy does not interfere with venous endothelial function evaluation in patients with type 2 diabetes mellitus. AB - INTRODUCTION: Endothelium-dependent dilation is improved in insulin-treated diabetic patients, but this effect is probably due to improved glycemic control. The objective of the present study was to compare endothelium-dependent dilation in patients with well-controlled type 2 diabetes who are or are not using insulin as part of their therapy. METHODS: We studied 27 patients with type 2 diabetes (11 women, 60.3 years +/- 6 years, with HbA1c < 7% and no nephropathy), including 16 patients treated with anti-diabetic agents (No-Ins, 8 women) and 11 patients treated with insulin alone or in combination with anti-diabetic agents (Ins, 3 women). Endothelial function was evaluated by the dorsal hand vein technique, which measures changes in vein diameter in response to phenylephrine, acetylcholine (endothelium-dependent vasodilation) and sodium nitroprusside (endothelium-independent vasodilation). RESULTS: Age, systolic blood pressure (No Ins: 129.4 mmHg +/- 11.8 mmHg, Ins: 134.8 mmHg +/- 12.0 mmHg; P= 0.257), HbA1c, lipids and urinary albumin excretion rate [No-Ins: 9 mg/24 h (0-14.1 mg/24 h) vs. Ins: 10.6 mg/24 h (7.5-14.4 mg/24 h), P=0.398] were similar between groups. There was no difference between endothelium-dependent vasodilation of the No-Ins group (59.3% +/- 26.5%) vs. the Ins group (54.0% +/- 16.3%; P=0.526). Endothelium independent vasodilation was also similar between the No-Ins (113.7% +/- 35.3%) and Ins groups (111.9% +/- 28.5%; P=0.888). CONCLUSIONS: Subcutaneous insulin therapy does not interfere with venous endothelial function in type 2 diabetes when glycemic and blood pressure control are stable. PMID- 21243288 TI - Trends in ischemic heart disease and stroke death ratios in brazilian women and men. AB - OBJECTIVE: Cardiovascular diseases are the main cause of death in women and men in Brazil, but the trends for the death ratios for ischemic heart disease and stroke in women and men remain unknown. METHOD: In this study, the trends for the death ratios among women and men who were over 30 years of age were analyzed from 1980 to 2005. Data were collected for both the Brazilian population and the metropolitan area of Sao Paulo. Estimates of the population size and data for mortality were then obtained from the Brazilian Institute of Geography and Statistics and the Ministry of Health. The risk for death was adjusted using a direct method. RESULTS: Death rates due to cardiovascular disease, ischemic heart disease, and stroke have declined in both Brazil and the metropolitan region of Sao Paulo. A linear regression analysis revealed a similar trend for ischemic heart disease and demonstrated a male/female ratio of 1.653 +/- 0.001 (r=0.228; p=0.262) in Brazil and 1.763 +/- 0.008 (r=0.863; p<0.001) in Sao Paulo. Comparisons between the slopes of the linear regressions showed an increased ischemic heart disease ratio in men/women in Sao Paulo in comparison to those in Brazil (p<0.0001). The linear regression showed an increasing trend for the male/female stroke ratio of 1.252 +/- 0.004 (r=0.776; p<0.0001) in Brazil and 1.331 +/- 0.006 (r=0.580; p=0.002) in Sao Paulo. Comparisons between the regressions for the stroke ratio were similar for men/women in Sao Paulo compared to Brazil (p=0.244). CONCLUSION: We observed an increased trend in the ratio for ischemic heart disease death in men compared to women. Improvements in the control of risk factors and treatments for both men and women are mandatory to reduce the number of ischemic heart disease-related deaths in Brazil. PMID- 21243289 TI - Metabolic disorders prevalence in sudden deafness. AB - OBJECTIVES: The aim of the present study was to establish the frequency of metabolic disorders among patients with sudden deafness and to compare this frequency with data from population surveys. INTRODUCTION: No consensus has been reached regarding the prevalence of metabolic disorders among sudden deafness patients or their influence as associated risk factors. METHODS: This cross sectional study enrolled all sudden deafness patients treated in the Otolaryngology Department of the University of Sao Paulo between January 1996 and December 2006. Patients were subjected to laboratory exams including glucose and cholesterol levels, low-density lipoprotein cholesterol fraction, triglycerides, free T4 and TSH. RESULTS: The sample comprised 166 patients. We observed normal glucose levels in 101 (81.5%) patients and hyperglycemia in 23 (18.5%) patients, which is significantly different (p < 0.0001) compared to the diabetes mellitus prevalence (7.6%) in the Brazilian population. Cholesterol levels were normal in 78 patients (49.7%) and abnormal in 79 (50.3%) patients, which is significantly different compared to the Brazilian population (p = 0.0093). However, no differences were observed in low-density lipoprotein cholesterol fraction (p = 0.1087) or triglyceride levels (p = 0.1474) between sudden hearing loss patients and the Brazilian population. Normal levels of thyroid hormones were observed in 116 patients (78.4%), and abnormal levels were observed in 32 (21.6%) patients. Compared with the prevalence of thyroid disorders in the general population (10%), statistical analysis revealed a significant difference (p = 0.0132) between these two groups. DISCUSSION: Among sudden deafness patients, we observed frequencies of hyperglycemia and thyroid disorders that were more than twice those of the general population. CONCLUSIONS: Hyperglycemia and thyroid disorders are much more frequent in patients with sudden deafness than in the general population and should be considered as important associated risk factors. PMID- 21243290 TI - Clinical and haemodynamic evaluation of chronic thromboembolic pulmonary hypertension patients scheduled for pulmonary thromboendarterectomy: Is schistosomiasis hypertension an important confounding factor? AB - INTRODUCTION: Chronic thromboembolic pulmonary hypertension is a disease affecting approximately 4,000 people per year in the United States. The incidence rate in Brazil, however, is unknown. The estimated survival for patients with chronic thromboembolic pulmonary hypertension without treatment is approximately three years. Pulmonary thromboendarterectomy for select patients is a potentially curative procedure when correctly applied. In Brazil, the clinical and hemodynamic profiles of chronic thromboembolic pulmonary hypertension patients have yet to be described. OBJECTIVES: To evaluate the clinical and hemodynamic characteristics of chronic thromboembolic pulmonary hypertension patients scheduled for pulmonary thromboendarterectomy in a referral center for chronic thromboembolic pulmonary hypertension treatment in Brazil. METHODS: From December 2006 to November 2009, patients were evaluated and scheduled for pulmonary thromboendarterectomy. The subjects were classified according to gender, age and functional class and were tested for thrombofilia and brain natriuretic peptide levels. RESULTS: Thirty-five consecutive chronic thromboembolic pulmonary hypertension patients were evaluated. Two patients tested positive for schistosomiasis, and 31 were enrolled in the study (19 female, 12 male). The majority of patients were categorized in functional classes III and IV. Hemodynamic data showed a mean pulmonary vascular resistance (PVR) of 970.8 +/- 494.36 dynas.s.cm-5 and a low cardiac output of 3.378 +/- 1.13 L/min. Linear regression revealed a direct relation between cardiac output and pulmonary vascular resistance. Paradoxical septal movement was strongly correlated with pulmonary vascular resistance and cardiac output (p=0.001). Brain natriuretic peptide serum levels were elevated in 19 of 27 patients. CONCLUSIONS: In a referral center for pulmonary hypertension in Brazil, chronic thromboembolic pulmonary hypertension patients evaluated for pulmonary thromboendarterectomy had a hemodynamically severe status and had elevated brain natriuretic peptide serum levels. There was a predominance of females in our cohort, and the prevalence of hematological disorders and schistosomiasis was low (less than 10%). PMID- 21243291 TI - Absence of the predisposing factors and signs and symptoms usually associated with overreaching and overtraining in physical fitness centers. AB - OBJECTIVE: The aim of this study was to evaluate the occurrence of the well-known predisposing factors and signs and symptoms usually associated with either overreaching or overtraining syndrome in physical fitness centers in Sao Paulo City, Brazil. METHOD: A questionnaire consisting of 13 question groups pertaining to either predisposing factors (1-7) or signs and symptoms (8-13) was given to 413 subjects. The general training schedule of the volunteers was characterized by workout sessions of 2.18 +/- 0.04 h for a total of 11.0 +/- 0.3 h/week for 33 +/- 2 months independent of the type of exercise performed (walking, running, spinning, bodybuilding and stretching). A mean score was calculated ranging from 1 (completely absent) to 5 (severe) for each question group. A low occurrence was considered to be a question group score lower than 4, which was observed in all 13 question groups. RESULTS: The psychological evaluation by POMS Mood State Questionnaire indicated a normal non-inverted iceberg. The hematological parameters, creatine kinase activity, cortisol, total testosterone and free testosterone concentrations were within the normal ranges for the majority of the volunteers selected for this analysis (n = 60). CONCLUSION: According to the questionnaire score analysis, no predisposing factors or signs and symptoms usually associated with either overreaching or overtraining were detected among the members of physical fitness centers in Sao Paulo City, Brazil. This observation was corroborated by the absence of any significant hematological or stress hormone level alterations in blood analyses of the majority of the selected volunteers (n = 60). PMID- 21243292 TI - Phagocytic responses of peritoneal macrophages and neutrophils are different in rats following prolonged exercise. AB - OBJECTIVE: To analyze the effects of exhausting long-duration physical exercise (swimming) sessions of different durations and intensities on the number and phagocytic capacity of macrophages and neutrophils in sedentary rats. INTRODUCTION: Exercise intensity, duration and frequency are important factors in determining immune response to physical effort. Thus, the effects of exhausting long-duration exercise are unclear. METHODS: Wistar rats were divided into two groups: an untreated group (macrophage study) and oyster glycogen-treated rats (neutrophil study). In each group, the animals were subdivided into five groups (10 rats per group): unexercised controls, an unadapted low-intensity exercise group, an unadapted moderate-intensity exercise group, a preadapted low-intensity exercise group and a preadapted moderate-intensity exercise group. All exercises were performed to exhaustion, and preadaptation consisted of 5, 15, 30 and 45 min sessions. RESULTS: Macrophage study: the number of peritoneal macrophages significantly decreased (9.22 +/- 1.78 x 10(6)) after unadapted exercise but increased (21.50 +/- 0.63 x 10(6)) after preadapted low-intensity exercise, with no changes in the moderate-intensity exercise group. Phagocytic capacity, however, increased by more than 80% in all exercise groups (low/moderate, unadapted/preadapted). Neutrophil study: the number of peritoneal neutrophils significantly decreased after unadapted (29.20 +/- 3.34 x 10(6)) and preadapted (50.00 +/- 3.53 x 10(6)) low-intensity exercise but increased after unadapted (127.60 +/- 5.14 x 10(6)) and preadapted (221.80 +/- 14.85 x 10(6)) moderate exercise. Neutrophil phagocytic capacity decreased by 63% after unadapted moderate exercise but increased by 90% after corresponding preadapted sessions, with no changes in the low-intensity exercise groups. CONCLUSION: Neutrophils and macrophages of sedentary rats respond differently to exercise-induced stress. Adaptation sessions reduce exercise-induced stress on the immune system. PMID- 21243294 TI - The role of central mechanisms in the anti-inflammatory effect of amitriptyline on carrageenan-induced paw edema in rats. AB - OBJECTIVE: The present study was designed to further investigate the effect of amitriptyline, a classical tricyclic antidepressant, on carrageenan-induced paw edema in rats. METHODS: First, amitriptyline was administered intraperitoneally (i.p.) at doses of 20, 40 and 80 mg kg-1, 30 min before subplantar injection of carrageenan. Second, amitriptyline was given intracerebroventriculary or intrathecally at doses of 25, 50 and 100 MUg/rat, 30 min prior to carrageenan challenge. Third, the effect of adrenergic receptor antagonists such as propranolol (10 mg kg-1, i.p.), prazosin (4 mg kg-1, i.p.) and yohimbine (10 mg kg-1, i.p.) and an opioid receptor antagonist (naloxone, 4 mg kg-1, i.p.) on the anti-inflammatory effect of amitriptyline (40 mg kg-1, i.p.) was investigated. RESULTS: Our data confirm that intraperitoneally administered amitriptyline exhibits a marked anti-inflammatory effect on carrageenan-induced paw edema in rats 4 h postcarrageenan challenge (P < 0.001). Intracerebroventricular (i.c.v.) administration of amitriptyline also reduced the development of paw edema at 4 h postcarrageenan (P < 0.001), but intrathecal (i.t.) application of amitriptyline failed to alter the degree of paw swelling. Furthermore, the applied antagonists did not modify the anti-inflammatory effect of amitriptyline. CONCLUSION: These results support the view that amitriptyline has a considerable anti-inflammatory effect on carrageenan-induced paw edema in rats and suggest that at least a part of this property could be mediated through supraspinal sites. Moreover, it seems unlikely that the investigated adrenergic and opioid receptors have a significant role in this effect of amitriptyline. PMID- 21243293 TI - Nitric oxide contributes to learning and memory deficits observed in hypothyroid rats during neonatal and juvenile growth. AB - INTRODUCTION: Severe cognitive impairment follows thyroid hormone deficiency during the neonatal period. The role of nitric oxide (NO) in learning and memory has been widely investigated. METHODS: This study aimed to investigate the effect of hypothyroidism during neonatal and juvenile periods on NO metabolites in the hippocampi of rats and on learning and memory. Animals were divided into two groups and treated for 60 days from the first day of lactation. The control group received regular water, whereas animals in a separate group were given water supplemented with 0.03% methimazole to induce hypothyroidism. Male offspring were selected and tested in the Morris water maze. Samples of blood were collected to measure the metabolites of NO, NO2, NO3 and thyroxine. The animals were then sacrificed, and their hippocampi were removed to measure the tissue concentrations of NO2 and NO3. DISCUSSION: Compared to the control group's offspring, serum thyroxine levels in the methimazole group's offspring were significantly lower (P<0.01). In addition, the swim distance and time latency were significantly higher in the methimazole group (P<0.001), and the time spent by this group in the target quadrant (Q1) during the probe trial was significantly lower (P<0.001). There was no significant difference in the plasma levels of NO metabolites between the two groups; however, significantly higher NO metabolite levels in the hippocampi of the methimazole group were observed compared to controls (P<0.05). CONCLUSION: These results suggest that the increased NO level in the hippocampus may play a role in the learning and memory deficits observed in childhood hypothyroidism; however, the precise underlying mechanism(s) remains to be elucidated. PMID- 21243295 TI - Influence of asymptomatic pneumonia on the response to hemorrhage and resuscitation in swine. AB - INTRODUCTION: Investigation of resuscitation fluids in our swine hemorrhage model revealed moderate to severe chronic pneumonia in five swine at necropsy. Our veterinary staff suggested that we perform a retrospective analysis of prospectively collected data from these animals. We compared the data to that of ten healthy swine to determine the physiologic consequences of the added stress on our hemorrhage/resuscitation model. METHODS: Anesthetized, immature female swine (40 +/- 5 kg) were instrumented for determining arterial and venous pressures, cardiac output and urine production. A controlled hemorrhage of 20 ml/kg over 4 min 40 sec was followed at 30 min by a second hemorrhage of 8 ml/kg and resuscitation with 1.5 ml/kg/min of LR solutions to achieve and maintain systolic blood pressure at 80 +/- 5 mmHg for 3.5 hrs. Chemistries and arterial and venous blood gasses were determined from periodic blood samples along with hemodynamic variables. RESULTS: There were significant decreases in survival, urine output, cardiac output and oxygen delivery at 60 min and O2 consumption at 120 min in the pneumonia group compared to the non-pneumonia group. There were no differences in other metabolic or hemodynamic data between the groups. CONCLUSION: Although pneumonia had little influence on pulmonary gas exchange, it influenced cardiac output, urine output and survival compared to healthy swine, suggesting a decrease in the physiologic reserve. These data may be relevant to patients with subclinical infection who are stressed by hemorrhage and may explain in part why some similarly injured patients require more resuscitation efforts than others. PMID- 21243297 TI - Genitourinary paracoccidioidomycosis complicated with urinary outflow obstruction a report of two cases and a review of the literature. PMID- 21243296 TI - Glucocorticoid-induced osteoporosis in rheumatic diseases. AB - The aim of this article is to review rheumatological diseases that are associated with glucocorticoid-induced osteoporosis or fractures and to perform a critical analysis of the current guidelines and treatment regimens. The electronic database MEDLINE was searched using the date range of July 1986 to June 2009 and the following search terms: osteoporosis, bone mineral density, fractures, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, vasculitis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis and juvenile dermatomyositis. Osteopenia and osteoporosis respectively account for 1.4 to 68.7% and 5.0 to 61.9% of adult rheumatological diseases. Among juvenile rheumatological disorders, the frequency of low bone mass ranges from 38.7 to 70%. In general, fracture rates vary from 0 to 25%. Although glucocorticoid induced osteoporosis has a high rate of prevalence among rheumatic diseases, a relatively low number of patients on continuous glucocorticoid treatment receive adequate diagnostic evaluation or preventive therapy. This deficit in patient care may result from a lack of clear understanding of the attributed risks by the patients and physicians, the high complexity of the treatment guidelines and poor patient compliance. PMID- 21243298 TI - Prone position ventilation, recruitment maneuver and intravenous zanamivir in severe refractory hypoxemia caused by influenza A (H1N1). PMID- 21243299 TI - Anomalous origin of left coronary artery diagnosed by magnetic resonance imaging. PMID- 21243300 TI - Cerebrotendinous xanthomatosis: a treatable hereditary neuro-metabolic disease. PMID- 21243303 TI - Association between environmental quality, stress and APOE gene variation in fibromyalgia susceptibility determination. AB - INTRODUCTION: Fibromyalgia is a multifactorial disease, of which etiology is based on interaction between genetic susceptibility and environment. However, few studies attempted to identify the risk factors. OBJECTIVE: To investigate the genetic influence and its interaction with environmental quality and stress, as possible risk factors for fibromyalgia development. PATIENTS AND METHODS: This cross-sectional study investigated two groups of women, of which 47 had a clinical diagnosis of fibromyalgia, and 41 women comprising thre control group, all from the town of Novo Hamburgo, RS. The apolipoprotein E (APOE) gene polymorphism was analyzed in DNA extracted from total blood, in both samples. Environmental factors were studied through Lipp's Inventory of Stress Symptoms for Adults and by applying the WHOQOL-100 domain V. RESULTS: Among the patients, more women had high stress levels when compared to the control sample (P < 0.001); moreover, the average scores of the WHOQOL-100 domain V, which analyze environment quality, were lower in this group (P < 0.001). APOE genotypic and allelic frequencies were similar between the two groups. Multivariate analysis showed that low WHOQOL-100 scores increase the chance of disease development by 57.7 times (P < 0.001), and that high stress levels were related with the disease (OR = 197.2; P < 0.001). This approach pointed out an interaction between stress and presence of E*2 allele (P = 0.028). Fibromyalgia was much more frequent in patients with high stress levels that were E*2 non-carriers (estimated OR = 265.1), when compared to patients with the same stress level, but E*2 carriers (estimated OR = 1.06). CONCLUSION: E*2 allele presence could have a protective action regarding the association between fibromyalgia and stress. PMID- 21243304 TI - Assessment of nutritional status and physical activity in systemic lupus erythematosus patients. AB - INTRODUCTION: Patients with systemic lupus erythematosus (SLE) may present nutritional changes triggered by disease or treatment, and these conditions may interfere with prognosis. OBJECTIVE: Assess the nutritional status, physical activity and associated factors in patients with SLE under treatment at the Service of Rheumatology of Hospital das Clinicas/Universidade Federal de Minas Gerais. METHODS: A cross-sectional study evaluating the nutritional status, clinical laboratory findings, sociodemographic, and treatment characteristics of 170 SLE female patients. RESULTS: Patients aged between 18 and 60 years were included. The mean (SD) age of patients and duration of SLE was 39.1 (10.0) and 9.9 (6.2) years, respectively. Two (1.2%) patients were classified as grade I underweight, 59 (34.7%) eutrophic, 61 (35.9%) as overweight, 37 (21.8%) as grade I obesity, seven (4,1%) as grade II obesity, and four (2,4%) as grade III obesity. Overweight and obesity were significantly associated with older age, lower education, higher SLE damage index, higher serum concentration of complement, higher incidence of hypertension and diabetes mellitus, presence of ovarian failure, and less frequent use of antimalarials Regarding physical activity, 39 patients (22.9%) were classified as inactive, 100 (58.8%) insufficiently active, and 31 (18.2%) active. Of the latter, 13 (43.3%) were in the eutrophic group. CONCLUSION: Excess weight was high in this population and associated with some traditional risk factors for cardiovascular disease and SLE poor prognosis. Therefore, encouraging weight control must be part of the main goals in treating SLE patients. PMID- 21243305 TI - Occurrence of fibromyalgia in patients with ankylosing spondylitis. AB - INTRODUCTION: Ankylosing spondylitis (AS) is a chronic inflammatory disease that affects the axial skeletal system, causing pain and functional incapacity. To measure the impact of AS on patient's life, questionnaires are used to assess disease activity (BASDAI); functional incapacity (BASFI); and quality of life (ASQoL). Fibromyalgia (FM) is one of the most common causes of generalized pain and can coexist with other diseases; it can be assessed by the Fibromyalgia Impact Questionnaire (FIQ). Few studies have demonstrated correlations between FM and AS. The present study obtained data regarding the epidemiologic profile of patients with AS and FM and evaluated the prevalence of FM in patients with AS. The FM influence on BASDAI, BASFI and ASQoL test scores was assessed. PATIENTS AND METHOD: A total of 71 patients with AS, diagnosed according to the modified New York criteria, were studied. Clinical and functional assessment was performed and BASDAI, BASFI and ASQoL tests were applied. Patients with a diagnosis of FM were evaluated through the FIQ. RESULTS: Eleven patients met the criteria for FM; thus a FM prevalence of 15% was observed among the patients with AS. FM was more prevalent among women (3.8:1). Age at disease onset (AS) was 27.5 years. The HLA B27 antigen was positive in most of them (80.4%). When comparing BASDAI, BASFI and ASQoL test means, it was observed that values are significantly higher (P < 0.01) among patients with FM. We concluded that the coexistence of FM can worsen AS activity aspects, as well as functional incapacity and quality of life. PMID- 21243306 TI - Clinical relevance and frequency of cytoplasmic and nuclear dense fine speckled patterns observed in ANA-HEp-2. AB - OBJECTIVES: This study aimed to determine the frequency and antibody titers of nuclear dense fine and cytoplasmic patterns with possible clinical correlation. METHODS: From 2007 to 2009, the results of 2,788 autoantibody serological tests were assessed by indirect immunofluorescence (IIF) at LAC-HUSM/UFSM, using as substrate HEp-2. RESULTS: Among the analyzed samples, 1,998 of them were negative for autoantibodies. Among the positive samples (n = 790), we found 57 (7.2%) showing reactivity pattern described as dense fine speckled (DFS) (3.8%), or cytoplasmic (Cit) fluorescence (3.4%). In samples with standard DFS (n = 29), nine had titers of 1/160, and only one patient had autoimmune disease (AID). Among patients with titers > 1/160, only one patient did not have AID. Among samples with standard Cit (n = 27), 20 had titers of 1/160, and only eight were not associated with AID. The other seven patients with titers > 1/160 reported AID. CONCLUSION: The results confirm the value of 1/160 as the best cut-off point for defining AID presence, for any of the fluorescence assessed patterns. However, attention should be given to lower titers, especially for Cit IIF, since only 40% did not report the presence of AID. PMID- 21243307 TI - Immune system: part III. The delicate balance of the immune system between tolerance and autoimmunity. AB - The immune system consists of an intricate network of organs, cells, and molecules responsible for maintaining the body's homeostasis and responding to aggression in general. Innate immunity operates in conjunction with adaptive immunity and is characterized by rapid response to aggression, regardless of previous stimulus, being the organism first line of defense. Its mechanisms include physical, chemical and biological barriers, cellular components, as well as soluble molecules. The organism first line of defense against tissue damage involves several steps closely integrated and constituted by different components of this system. The aim of this review is to restore the foundations of this response, which has high complexity and consists of several components that converge to articulate the development of adaptive immune response. We selected some of the following steps to review: perception and molecular recognition of aggressive agents; activation of intracellular pathways, which result in vascular and tissue changes; production of a myriad of mediators with local and systemic effects on cell activation and proliferation, synthesis of new products involved in the chemoattraction and migration of cells specialized in destruction and removal of offending agent; and finally, tissue recovery with restoration of functional tissue or organ. PMID- 21243308 TI - RNA interference: a new alternative for rheumatic diseases therapy. AB - RNA interference (RNAi) is a post-transcriptional gene silencing mechanism preserved during evolution. This mechanism, recently described, is mediated by small double-stranded RNAs (dsRNAs) that can specifically recognize a target mRNA sequence and mediate its cleavage or translational repression. The use of RNAi as a tool for gene therapy has been extensively studied, especially in viral infections, cancer, inherited genetic disorders, cardiovascular and rheumatic diseases. Together with data from human genome, the knowledge of gene silencing mediated by RNAi could allow a functional determination of virtually any cell expressed gene and its involvement in cellular functioning and homeostasis. Several in vitro and in vivo therapeutic studies with autoimmune disease animal models have been carried out with promising results. The pathways of tolerance breakage and inflammation are potential targets for RNAi therapy in inflammatory autoimmune diseases. This review will present the basic principles of RNAi and discuss several aspects of RNAi-based therapeutic approaches, from in vitro tool design and target identification to in vivo pre-clinical drug delivery, and tests of autoimmune diseases in human cells and animal models. Finally, this review will present some recent clinical experience with RNAi-based therapy. PMID- 21243309 TI - Felty's syndrome and Kala-azar: a challenge for the rheumatologist. AB - Case report of a patient with rheumatoid arthritis who developed severe neutropenia, splenomegaly and was diagnosed with Felty's syndrome. The patient later developed Kala-azar. Both diseases have similar clinical and laboratory presentation, making the differential diagnosis difficult. The present case report aims at drawing attention to the identification of visceral Leishmaniasis infection in patients with rheumatic diseases, as well as possibility of a patient with Kala-azar mimicking a set of symptoms of systemic rheumatic disease. PMID- 21243310 TI - Libman-Sacks endocarditis, antiphospholipid antibodies and arterial thrombosis in systemic lupus erythematosus: case report. AB - Case report of a 38-year-old female patient with systemic lupus erythematosus (SLE) who presented an acute arterial thromboembolic event in the right lower limb. Investigation showed the presence of antiphospholipid antibodies and sterile vegetation in the mitral valve, Libman-Sacks endocarditis (LSE). Possible causes of thromboembolic events in SLE are discussed, with emphasis on current recommendations for diagnosis and treatment of LSE. PMID- 21243311 TI - Infliximab use and sequential occurrence of autoantibodies and neoplasia in a patient with spondyloarthritis. AB - The development of antinuclear antibodies after long-term use of anti-TNF therapy has been reported by several authors. The occurrence of lymphoproliferative neoplasms and, less commonly, solid tumors has also been reported. We present a case of simultaneous development of antinuclear antibodies and solid tumor in a patient with spondyloarthritis while on infliximab therapy. The implications and possible correlations with a solid tumor occurrence are reviewed and discussed. PMID- 21243312 TI - Correlation between diastolic function and maximal exercise capacity on exercise test. AB - BACKGROUND: Increased pulmonary capillary pressure (PCP) is one of the mechanisms of exercise intolerance. Assessment of the diastolic function by echocardiography (ECHO) enables estimation of PCP. OBJECTIVE: To identify variables that determine the exercise capacity in patients undergoing routine exercise test (ET), conventional ECHO, and tissue Doppler imaging (TD). METHODS: A total of 640 patients undergoing ET, ECHO, and TD were retrospectively studied. Patients with ejection fraction < 55% were excluded. Mitral annulus velocities by conventional Doppler imaging were obtained in early diastole (E) and late diastole (A), and TD of the mitral annulus measured early diastole (e') and late diastole (a') velocities. E/e'> 10 was considered an estimate of increased PCP. Maximal exercise capacity was analyzed by the number of metabolic equivalents (MET). The patients were divided into two groups for analysis: MET<7 (n=48) and MET>7 (n=572). Morise score showed a population at low risk (60%) for coronary artery disease (CAD). RESULTS: The number of patients with E/e' > 10 was significantly higher in the MET < 7 group in relation to the MET > 7 group (41.7% vs 9.4%, p=0.001), and so was the presence of any degree of diastolic dysfunction (76.6% vs 34.1% p=0.001). Using logistic regression analysis, age, female gender and A velocity (late diastole) were the independent variables related to a low exercise capacity (MET < 7). CONCLUSION: Diastolic dysfunction as determined by ECHO, female gender, and age are associated with a lower exercise capacity in a population at low risk for CAD. PMID- 21243313 TI - Prediction of metabolic syndrome in children through anthropometric indicators. AB - BACKGROUND: Because of the need to measure anthropometric, biochemical and hemodynamic variables for the diagnosis of metabolic syndrome, we realize how difficult it is to analyze large populations, especially children, due to the poor accessibility and the invasive character. There is an urgent need to develop easy-to-use, accurate and low-cost diagnostic tools in order to predict metabolic syndrome at early ages. OBJECTIVE: To verify the prevalence of metabolic syndrome in children and to test predictive anthropometric indicators. METHODS: Cross sectional study conducted among 109 children aged 7 to 11 years. The age-adjusted National Cholesterol Education Program definition was used for the diagnosis of metabolic syndrome. The following parameters were tested as possible predictors: body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), conicity index (C index), and body fat percentage. RESULTS: The prevalence of metabolic syndrome was 13.3% and 36% for boys and girls, respectively. The main anthropometric indicators were: BMI = 0.81 (0.69 - 0.94), WC = 0.79 (0.64 - 0.94), body fat = 0.79 (0.66 - 0.92) and WHR = 0.37 (0.21 - 0.54). CONCLUSION: WC higher than 78 cm, body fat higher than 41%, and BMI higher than 24.5 kg/m2 were considered predictors of metabolic syndrome. The C index and WHR were not considered predictors. PMID- 21243314 TI - Evasion of immune responses by Trypanosoma cruzi, the etiological agent of Chagas disease. AB - Infection with the protozoan parasite Trypanosoma cruzi leads to Chagas disease, which affects millions of people in Latin America. Infection with T. cruzi cannot be eliminated by the immune system. A better understanding of immune evasion mechanisms is required in order to develop more effective vaccines. During the acute phase, parasites replicate extensively and release immunomodulatory molecules that delay parasite-specific responses mediated by T cells. This immune evasion allows the parasite to spread in the host. In the chronic phase, parasite evasion relies on its replication strategy of hijacking the TGF-beta signaling pathway involved in inflammation and tissue regeneration. In this article, the mechanisms of immune evasion described for T. cruzi are reviewed. PMID- 21243315 TI - Construction of a recombinant adenovirus co-expressing truncated human prostate specific membrane antigen and mouse 4-1BBL genes and its effect on dendritic cells. AB - Our aim was to construct a recombinant adenovirus co-expressing truncated human prostate-specific membrane antigen (tPSMA) and mouse 4-1BBL genes and to determine its effect on dendritic cells (DCs) generated from bone marrow suspensions harvested from C57BL/6 mice for which the effect of 4-1BBL on DCs is not clear, especially during DCs processing tumor-associated antigen. Replication deficient adenovirus AdMaxTM Expression System was used to construct recombinant adenovirus Ad-tPSMA-internal ribosome entry site-mouse 4-1BBL (Ad-tPSMA-IRES-m4 1BBL) and Ad-enhanced green fluorescent protein. Day 7 proliferating DC aggregates generated from C57BL/6 mice were collected as immature DCs and further mature DCs were obtained by lipopolysaccharide activated immature DCs. After DCs were exposed to the recombinant adenovirus with 250 multiplicity of infection, the expression of tPSMA and m4-1BBL proteins were detected by Western blot, and the apoptosis and phenotype of DCs were analyzed by flow cytometry. Cytokines (IL 6 and IL-12) in the supernatant were detected by enzyme-linked immunosorbent assay (ELISA). Proliferation of T cells was detected by allogeneic mixed lymphocyte reactions. The tPSMA and m4-1BBL proteins were expressed correctly. The apoptosis rate of DCs transfected with Ad-tPSMA-IRES-m4-1BBL was 14.6%, lower than that of control DCs. The expression of co-stimulatory molecules [CD80 (81.6 +/- 5.4%) and CD86 (80.13 +/- 2.81%)] up-regulated in Ad-tPSMA-IRES-m4-1BBL pulsed DCs, and the level of IL-6 (3960.2 +/- 50.54 pg/mL) and IL-12 (249.57 +/- 12.51 pg/mL) production in Ad-tPSMA-IRES-m4-1BBL-transduced DCs were significantly higher (P < 0.05) than those in control DCs. Ad-tPSMA-IRES-m4-1BBL induced higher T-cell proliferation (OD(450) = 0.614 +/- 0.018), indicating that this recombinant adenovirus can effectively enhance the activity of DCs. PMID- 21243317 TI - Evidence for the endophytic colonization of Phaseolus vulgaris (common bean) roots by the diazotroph Herbaspirillum seropedicae. AB - Herbaspirillum seropedicae is an endophytic diazotrophic bacterium, which associates with important agricultural plants. In the present study, we have investigated the attachment to and internal colonization of Phaseolus vulgaris roots by the H. seropedicae wild-type strain SMR1 and by a strain of H. seropedicae expressing a red fluorescent protein (DsRed) to track the bacterium in the plant tissues. Two-day-old P. vulgaris roots were incubated at 30 degrees C for 15 min with 6 x 10(8) CFU/mL H. seropedicae SMR1 or RAM4. Three days after inoculation, 4 x 10(4) cells of endophytic H. seropedicae SMR1 were recovered per gram of fresh root, and 9 days after inoculation the number of endophytes increased to 4 x 10(6) CFU/g. The identity of the recovered bacteria was confirmed by amplification and sequencing of the 16SrRNA gene. Furthermore, confocal microscopy of P. vulgaris roots inoculated with H. seropedicae RAM4 showed that the bacterial cells were attached to the root surface 15 min after inoculation; fluorescent bacteria were visible in the internal tissues after 24 h and were found in the central cylinder after 72 h, showing that H. seropedicae RAM4 is capable of colonizing the roots of the dicotyledon P. vulgaris. Determination of dry weight of common bean inoculated with H. seropedicae SMR1 suggested that this bacterium has a negative effect on the growth of P. vulgaris. PMID- 21243316 TI - In vivo and in vitro anti-inflammatory and anti-nociceptive activities of lovastatin in rodents. AB - Statins are among the most prescribed drugs in recent clinical practice. They are also known for their pleiotropic actions, which are independent of their lipid lowering properties. The effect of lovastatin was investigated against carrageenan-induced paw edema in male Wistar rats (200-250 g) and on leukocyte migration, as measured by carrageenan-induced peritonitis in male Swiss mice (20 25 g), which are models of acute inflammation. Lovastatin (administered 1 h prior to carrageenan), at oral doses of 2, 5, and 10 mg/kg, markedly attenuated paw edema formation in rats at the 4th hour after carrageenan injection (25, 43, and 37% inhibition, respectively). Inhibitions of 20, 45 and 80% were observed in the leukocyte migration, as evaluated by carrageenan-induced peritonitis in mice with lovastatin doses of 0.5, 1 and 5 mg/kg, as compared to controls. Furthermore, lovastatin (administered 1 h before initiation) reduced the nociceptive effect of the formalin test in mice, at both phases, at doses of 2, 5, and 10 mg/kg: first phase (51, 65, and 70%, respectively) and second phase (73, 57, and 66% inhibition of licking time, respectively). The anti-nociceptive activity of lovastatin was inhibited by naloxone (3 mg/kg, sc). Lovastatin (0.01, 0.1, and 1 ug/mL) inhibited by 23, 79, and 86%, respectively, the release of myeloperoxidase from human neutrophils. Leukocyte (predominantly neutrophils) infiltration was almost completely reduced by lovastatin treatment, as observed in the model of acute paw edema with hematoxylin and eosin staining. In addition, lovastatin decreased the number of cells expressing tumor necrosis factor-alpha (TNF-alpha) and the inducible form of nitric oxide synthase (iNOS) activity. Therefore, the alterations in leukocyte activity and cytokine release could contribute to the anti-inflammatory activity of lovastatin. PMID- 21243318 TI - Randomized clinical trial comparing the efficacy of the vaginal use of metronidazole with a Brazilian pepper tree (Schinus) extract for the treatment of bacterial vaginosis. AB - A 7.4% vaginal extract of the Brazilian pepper tree (Schinus terebinthifolius Raddi) was compared with 0.75% vaginal metronidazole, both manufactured by the Hebron Laboratory, for the treatment of bacterial vaginosis, used at bedtime for 7 nights. The condition was diagnosed using the combined criteria of Amsel and Nugent in two groups of 140 and 137 women, aged between 18 and 40 years. Intention-to-treat analysis was performed. Women were excluded from the study if they presented delayed menstruation, were pregnant, were using or had used any topical or systemic medication, presented any other vaginal infections, presented hymen integrity, or if they reported any history suggestive of acute pelvic inflammatory disease. According to Amsel's criteria separately, 29 patients (21.2%) treated with the extract and 87 (62.1%) treated with metronidazole were considered to be cured (P < 0.001). According to Nugent's score separately, 19 women (13.9%) treated with the extract and 79 (56.4%) treated with metronidazole were considered to be cured (P < 0.001). Using the two criteria together, the so called total cure was observed in 17 women (12.4%) treated with the extract and in 79 women (56.4%) treated with metronidazole (P < 0.001). In conclusion, the cure rate for bacterial vaginosis using a vaginal gel from a pepper tree extract was lower than the rate obtained with metronidazole gel, while side effects were infrequent and non-severe in both groups. PMID- 21243319 TI - The effects of shift work on body weight change - a systematic review of longitudinal studies. AB - OBJECTIVE: This systematic review aims to summarize the available evidence to elucidate the effects of shift work, which includes night work, on body weight change. METHODS: A systematic search strategy using longitudinal studies was performed. Articles were included based on strict inclusion criteria; methodological quality was assessed by a standardized quality checklist. The results were summarized using a levels of evidence synthesis. RESULTS: The search strategy resulted in eight articles that met the inclusion criteria. Five of them were considered to be high- and three of them low-quality studies. Seven studies presented crude results for an association between shift work exposure and change in body weight: five high- and two low-quality studies. There was strong evidence for a crude relationship between shift work and body weight increase. Five studies presented weight-related outcomes adjusted for potentially relevant confounders (age, gender, bodyweight at baseline, and physical activity). Two studies found a significant difference between groups in the same direction. Consequently, the evidence for a confounders-adjusted relationship between shift work exposure and body weight was considered to be insufficient. CONCLUSIONS: Strong evidence for a crude association between shift work exposure and body weight increase was found. In order to further clarify the underlying mechanisms, more and better high quality studies about this subject are necessary. PMID- 21243320 TI - Organised angular cheilitis as the initial sign of Crohn's disease in two children. PMID- 21243321 TI - Strontium ranelate-induced DRESS syndrome with persistent autoimmune hepatitis. PMID- 21243322 TI - Thermal angiooedema induced by hot water. PMID- 21243323 TI - Febrile exanthema revealing toxocariasis: a case report. PMID- 21243324 TI - High EGFR mRNA expression is a prognostic factor for reduced survival in pancreatic cancer after gemcitabine-based adjuvant chemotherapy. AB - Pancreatic ductal adenocarcinoma (PDAC) still presents a major therapeutic challenge and a phase III clinical trial has revealed that the combination of gemcitabine and a human epidermal growth factor receptor type I (HER1/EGFR) targeting agent presented a significant benefit compared to treatment with gemcitabine alone. The aim of this study was to investigate EGFR mRNA expression in resected PDAC tissues and its correlation with patient prognosis. We obtained formalin-fixed paraffin-embedded (FFPE) tissue samples from 88 patients with PDAC who underwent pancreatectomy, and measured EGFR mRNA levels by quantitative real time reverse transcription-polymerase chain reaction. The high-level EGFR group had significantly shorter disease-free-survival (p=0.029) and overall-survival (p=0.014) as shown by univariate analyses, although these did not reach statistical significance, as shown by multivariate analyses. However, we found that high EGFR expression was an independent prognostic factor in patients receiving gemcitabine-based adjuvant chemotherapy (p=0.023). Furthermore, we measured EGFR mRNA levels in 20 endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) cytological specimens. Altered EGFR levels were distinguishable in microdissected neoplastic cells from EUS-FNA cytological specimens compared to those in whole cell pellets. In conclusion, quantitative analysis of EGFR mRNA expression using FFPE tissue samples and microdissected neoplastic cells from EUS-FNA cytological specimens could be useful in predicting prognosis and sensitivity to gemcitabine in PDAC patients. PMID- 21243325 TI - Hydroxyflutamide enhances cellular sensitivity to 5-fluorouracil by suppressing thymidylate synthase expression in bicalutamide-resistant human prostate cancer cells. AB - We investigated the antitumor effects of combination therapy with anti-androgens and 5-fluorouracil (5-FU), and examined the underlying mechanism of the treatment. Initially, we established the bicalutamide-resistant subline CDX25R from the androgen receptor (AR)-positive human prostate cancer cell line LNCaP through continuous exposure to bicalutamide. CDX25R cells lost the ability to respond to androgens, but still expressed AR. They showed significant resistance to bicalutamide, but had high sensitivity to hydroxyflutamide (OH-flutamide) compared with LNCaP cells. The CDX25R subline was thus considered to be a suitable model for prostate cancer that has developed resistance to first-line hormonal therapy but shows sensitivity to an alternative approach. Combined treatment with 5-FU and OH-flutamide had a synergistic effect on CDX25R cells. OH flutamide decreased expression of the transcription factor E2F1, and subsequently of thymidylate synthase (TS), in CDX25R cells but not in AR-negative DU145 cells. This suggested that OH-flutamide enhanced the growth-inhibitory activity of 5-FU in CDX25R cells by reducing TS expression through the AR pathway. Combined therapy with 5-FU and OH-flutamide may, therefore, be appropriate for patients with prostate cancer that has acquired resistance to initial hormone therapy including bicalutamide. PMID- 21243326 TI - [Original scientific articles: conception, accomplishment and publication]. PMID- 21243327 TI - [Surgery of traumatic tracheal and tracheobronchial injuries]. AB - Tracheal injuries are altogether rare events and can be divided into three broad categories: tracheobronchial injuries caused by external violence, iatrogenic ruptures of the trachea and inhalation trauma. Successful management of tracheobronchial injuries requires a fast and straightforward diagnostic evaluation. In all severely injured patients with cervicothoracic involvement an injury of the tracheobronchial system should be actively excluded. Although it is commonly agreed that posttraumatic injuries require surgical intervention the management of iatrogenic injuries is presently shifting towards a more conservative treatment. PMID- 21243328 TI - [Tracheal surgery - an interdisciplinary task]. PMID- 21243329 TI - [Xeroderma pigmentosum (XP) : A genetic disease sheds light on UV-induced skin cancer]. AB - The recessively inherited nucleotide excision repair (NER) defect syndrome xeroderma pigmentosum (XP) serves as a model disease for UV-induced skin cancer. XP is characterized by sun-sensitivity, freckling, and poikilodermic skin changes in sun-exposed areas, and a more than 1000-fold increased risk of skin cancer including melanoma as well as basal and squamous cell carcinomas. Seven XP complementation groups (XP-A to XP-G) are known to date representing the defective genes in XP patients. An additional "variant" form (XPV) which is clinically indistinguishable from the complementation groups exhibits defective translesional synthesis. An enhanced understanding of skin cancer development in general can help to identify individuals at an increased risk who should take special precautions, for example to avoid occupational exposures. The position of skin cancer induced by UV-light as an occupational disease in the ordinance on industrial diseases (BKV) is currently a topic of research and discussion in Germany. PMID- 21243330 TI - High-throughput genotyping of hop (Humulus lupulus L.) utilising diversity arrays technology (DArT). AB - Implementation of molecular methods in hop (Humulus lupulus L.) breeding is dependent on the availability of sizeable numbers of polymorphic markers and a comprehensive understanding of genetic variation. However, use of molecular marker technology is limited due to expense, time inefficiency, laborious methodology and dependence on DNA sequence information. Diversity arrays technology (DArT) is a high-throughput cost-effective method for the discovery of large numbers of quality polymorphic markers without reliance on DNA sequence information. This study is the first to utilise DArT for hop genotyping, identifying 730 polymorphic markers from 92 hop accessions. The marker quality was high and similar to the quality of DArT markers previously generated for other species; although percentage polymorphism and polymorphism information content (PIC) were lower than in previous studies deploying other marker systems in hop. Genetic relationships in hop illustrated by DArT in this study coincide with knowledge generated using alternate methods. Several statistical analyses separated the hop accessions into genetically differentiated North American and European groupings, with hybrids between the two groups clearly distinguishable. Levels of genetic diversity were similar in the North American and European groups, but higher in the hybrid group. The markers produced from this time and cost-efficient genotyping tool will be a valuable resource for numerous applications in hop breeding and genetics studies, such as mapping, marker assisted selection, genetic identity testing, guidance in the maintenance of genetic diversity and the directed breeding of superior cultivars. PMID- 21243331 TI - Molecular basis of seed lipoxygenase null traits in soybean line OX948. AB - The poor stability and off-flavors of soybean oil and protein products can be reduced by eliminating lipoxygenases from soybean seed. Mature seeds of OX948, a lipoxygenase triple null mutant line, do not contain lipoxygenase proteins. The objective of this study was to determine the molecular basis of the seed lipoxygenase null traits in OX948. Comparisons of the sequences for lipoxygenase 1 (Lx1) and lipoxygenase 2 (Lx2) genes in the mutant (OX948) with those in a line with normal lipoxygenase levels (RG10) showed that the mutations in these genes affected a highly conserved group of six histidines necessary for enzymatic activity. The OX948 mutation in Lx1 is a 74 bp deletion in exon 8, which introduces a stop codon that prematurely terminates translation. A single T-A substitution in Lx2 changes histidine H532 (one of the iron-binding ligands essential for L-2 activity) to glutamine. The mutation in the lipoxygenase 3 (Lx3) gene in OX948 is in the promoter region and represents two single base substitutions in a cis-acting AAATAC paired box. All three mutations would result in the loss of lipoxygenase activity in mature seed. The seed lipoxygenase gene mutation-based molecular markers could be used to accelerate and simplify breeding efforts for soybean cultivars with improved flavor. PMID- 21243332 TI - Codominant PCR-based markers and candidate genes for powdery mildew resistance in melon (Cucumis melo L.). AB - Powdery mildew caused by Podosphaera xanthii is a major disease in melon crops, and races 1, 2, and 5 of this fungus are those that occur most frequently in southern Europe. The genotype TGR-1551 bears a dominant gene that provides resistance to these three races of P. xanthii. By combining bulked segregant analysis and amplified fragment length polymorphisms (AFLP), we identified eight markers linked to this dominant gene. Cloning and sequencing of the selected AFLP fragments allowed the development of six codominant PCR-based markers which mapped on the linkage group (LG) V. Sequence analysis of these markers led to the identification of two resistance-like genes, MRGH5 and MRGH63, belonging to the nucleotide binding site (NBS)-leucine-rich repeat (LRR) gene family. Quantitative trait loci (QTL) analysis detected two QTLs, Pm-R1-2 and Pm-R5, the former significantly associated with the resistance to races 1 and 2 (LOD score of 26.5 and 33.3; 53.6 and 61.9% of phenotypic variation, respectively), and the latter with resistance to race 5 (LOD score of 36.8; 65.5% of phenotypic variation), which have been found to be colocalized with the MRGH5 and MRGH63 genes, respectively. The results suggest that the cluster of NBS-LRR genes identified in LG V harbours candidate genes for resistance to races 1, 2, and 5 of P. xanthii. The evaluation of other resistant germplasm showed that the codominant markers here reported are also linked to the Pm-w resistance gene carried by the accession 'WMR-29' proving their usefulness as genotyping tools in melon breeding programmes. PMID- 21243333 TI - Stressed hearts in children with obesity and diabetes: a cause for concern? AB - Obesity in young people is an emerging public health problem, particularly because of its association with type 2 diabetes. Since obesity and diabetes contribute to the development of cardiovascular disease in adults, the question arises as to whether or not these conditions may be associated with cardiovascular abnormalities in children and adolescents. In this issue of Diabetologia, Shah et al. report the results of a cross-sectional study of heart structure and function in 612 adolescents and young adults (aged 10-24 years) subdivided into three groups: (1) those with obesity and type 2 diabetes; (2) those with type 2 diabetes but without obesity; and (3) lean healthy controls. Their results revealed that left ventricular mass (indexed to body surface area) was greater in the obese individuals than in lean controls. Left ventricular systolic function was more dynamic in obese participants and obese participants with type 2 diabetes compared with lean controls, whereas systolic function was comparable in obese patients with or without type 2 diabetes. Furthermore, compared with the healthy lean control participants, diastolic function was impaired in the obese group and further impaired in the obese individuals with diabetes. These results, and those of a few other similar studies, lend support to the notion that obesity and diabetes in children cause subtle abnormalities in cardiovascular structure and function. The present commentary discusses potential mechanisms and possible clinical ramifications for such findings. PMID- 21243334 TI - Low-dose steroids for septic shock and severe sepsis: the use of Bayesian statistics to resolve clinical trial controversies. AB - PURPOSE: Low-dose steroids have shown contradictory results in trials and three recent meta-analyses. We aimed to assess the efficacy and safety of low-dose steroids for severe sepsis and septic shock by Bayesian methodology. METHODS: Randomized trials from three published meta-analyses were reviewed and entered in both classic and Bayesian databases to estimate relative risk reduction (RRR) for 28-day mortality, and relative risk increase (RRI) for shock reversal and side effects. RESULTS: In septic shock trials only (Marik meta-analysis; N = 965), the probability that low-dose steroids decrease mortality by more than 15% (i.e., RRR > 15%) was 0.41 (0.24 for RRR > 20% and 0.14 for RRR > 25%). For severe sepsis and septic shock trials combined, the results were as follows: (1) for the Annane meta-analysis (N = 1,228), the probabilities were 0.57 (RRR > 15%), 0.32 (RRR > 20%), and 0.13 (RRR > 25%); (2) for the Minneci meta-analysis (N = 1,171), the probability was 0.57 to achieve mortality RRR > 15%, 0.32 (RRR > 20%), and 0.14 (RRR > 25%). The removal of the Sprung trial from each analysis did not change the overall results. The probability of achieving shock reversal ranged from 65 to 92%. The probability of developing steroid-induced side effects was as follows: for gastrointestinal bleeding (N = 924), there was a 0.73 probability of steroids causing an RRI > 1%, 0.70 for RRI > 2%, and 0.67 for RRI > 5%; for superinfections (N = 964), probabilities were 0.81 (RRI > 1%), 0.76 (RRI > 2%), and 0.70 (RRI > 5%); and for hyperglycemia (N = 540), 0.99 (RRI > 1%), 0.97 (RRI > 2%), and 0.94 (RRI > 5%). CONCLUSIONS: Based on clinically meaningful thresholds (RRR > 15-25%) for mortality reduction in severe sepsis or septic shock, the Bayesian approach to all three meta-analyses consistently showed that low-dose steroids were not associated with survival benefits. The probabilities of developing steroid-induced side effects (superinfections, bleeding, and hyperglycemia) were high for all analyses. PMID- 21243335 TI - Accuracy of waste blood measurement in critically ill patients. PMID- 21243336 TI - Relationships of percent body fat and percent trunk fat with bone mineral density among Chinese, black, and white subjects. AB - We examined ethnic difference in the association of body fat and trunk fat with bone mineral density (BMD) among Chinese, white, and black subjects. We found that, with greater body and trunk fat, both white and black subjects were more likely to have a low BMD than Chinese subjects. INTRODUCTION: Ethnic differences in body fat, abdominal fat distribution, and BMD have been found in previous studies between Chinese and white subjects. However, the associations of body fat and abdominal fat distribution with BMD have not been studied, and whether the ethnic differences have an effect on these associations is unclear. METHODS: We evaluated 1,147 subjects aged >= 18 years (805 Chinese, 193 whites, and 149 blacks). Percent body fat (%BF), percent trunk fat (%TF), and total and regional BMD including that of head, arm, leg, trunk, rib, spine, and pelvis were measured by dual-energy X-ray absorptiometry. Linear regression models were developed to test the association of ethnicity, %BF, and interaction between ethnicity and %BF with BMD. The models were repeated again, replacing %BF with %TF. RESULTS: Chinese subjects showed lower BMD in total and most regions compared with black and white subjects; however, these differences were eliminated between Chinese and whites within both sexes and between Chinese and black men when age, weight, height, and %BF were added. %BF and %TF were negatively associated with most regional body BMD. The interactions between %BF, %TF, and ethnicity were found in most regional body BMD among Chinese, white, and black subjects for both men and women. CONCLUSION: Both %BF and %TF have negative associations with BMD. With greater accumulation of %BF and %TF, both white and black subjects may experience a higher risk of low BMD than Chinese subjects. PMID- 21243337 TI - Severe postpartum osteoporosis with increased PTHrP during lactation in a patient after total thyroidectomy and parathyroidectomy. AB - We present a 27-year-old woman with hypoparathyroidism following total thyroidectomy for papillary carcinoma, who presented postpartum during lactation with several vertebral osteoporotic fractures, increase in bone turnover markers, and measurable parathyroid hormone-related protein (PTHrP) levels. Cessations of lactation led to gradual decrease in bone turnover markers and PTHrP and improvement in bone mineral density. Pregnancy- and postpartum-associated osteoporosis is an uncommon condition characterized by the occurrence of fractures during late pregnancy or the puerperium. The patient presented postpartum with severe back pain and multiple vertebral fractures. Metabolic evaluation performed at presentation revealed hypercalcemia, hypercalciuria, increased alkaline phosphatase, vitamin D insufficiency, normal serum protein immunoelectrophoresis, and a detectable level of PTHrP. Serum levels of bone turnover markers were markedly increased. Bone mineral density at the lumbar spine was severely reduced. After cessation of lactation, the PTHrP level became undetectable. Bone turnover markers gradually decreased to normal and bone mineral density improved. Several factors contributed to the reduced bone mass in this patient, including amenorrhea treated with oral contraceptives, suppressive levothyroxine treatment, and lactation of twins with increased PTHrP. Patients with severely reduced bone mass need surveillance during pregnancy and lactation and should possibly consider avoiding breastfeeding. Patients with hypoparathyroidism should temporarily reduce their alphacalcidiol dose while lactating. PMID- 21243338 TI - A CtrA homolog affects swarming motility and encystment in Rhodospirillum centenum. AB - The alpha-proteobacterium, Rhodospirillum centenum, has a complex life cycle that allows adaptation to different environments. Transitions between vegetative swim cell and swarmer cell types depend on whether the organism is growing in liquid surroundings or on a solid substrate. Moreover, starvation can induce vegetative cells to differentiate into quiescent cysts. This paper describes the results of our investigation into the role of a putative DNA-binding response regulator that is homologous to CtrA, the cell cycle regulator from Caulobacter crescentus. Deletion of ctrA from the R. centenum genome resulted in a viable strain with impaired swarming motility coupled with an increased tendency to form cysts. Conversely, overexpression of wild type CtrA or a phosphomimetic allele, CtrAD51E, suppressed cyst cell formation, whereas overexpression of a CtrAD51A allele failed to suppress encystment but did prevent swarming motility. Thus, we propose that CtrA participates within a two-component signal transduction pathway that promotes swarming motility while contributing to the suppression of cyst cell formation. PMID- 21243339 TI - Study of non-covalent interactions of luotonin A derivatives and the DNA minor groove as a first step in the study of their analytical potential as DNA probes. AB - The interaction between DNA and several newly synthesized derivatives of the natural anticancer compound luotonin A has been studied. The results from our work reveal an effective and selective alkaloid/double-stranded DNA (ds-DNA) interaction. In the presence of increasing amounts of ds-DNA, a noticeable fluorescence quenching of the luotonin A derivatives under study was observed. However, this effect did not take place when single-stranded DNA (ss-DNA) was employed. The association constant alkaloids/ds-DNA was calculated by quantitation of such a quenching effect. The influence of other quenchers, namely Co(2+) and Br(-) on the native fluorescence of luotonin A and derivatives was also studied, and a remarkable quenching effect was observed for both ions. We have also investigated how by binding DNA the alkaloids could get protected from the external Co(2+) and Br(-) quenchers. The Stern-Volmer constants (K (SV)) for Co(2+) and Br(-) quenching effect on the studied alkaloids were considerably reduced (10-50%) after incubation of the compounds in the presence of DNA with regard to the K (SV) values in absence of DNA. An increase in the fluorescence anisotropy values of luotonins was also produced only in the presence of ds-DNA but not in the case of ss-DNA. To better characterize the nature of that interaction, viscosimetry assays and ethidium bromide displacement studies were conducted. With regard to DNA reference solutions, the viscosity of solutions containing DNA and luotonin A derivatives was reduced or not significantly increased. It was also observed that the studied compounds were unable to displace the intercalating agent ethidium bromide. All of these results, together with the obtained association constants values (K (ass) = 2.2 * 10(2) - 1.3 * 10(3)), support that neither covalent nor intercalating interactions luotonin A derivatives/ds-DNA are produced, leading to the conclusion that these alkaloids bind ds-DNA through the minor groove. The specific changes in the fluorescence behavior of luotonin A and derivatives distinguishing between ss-DNA and ds-DNA binding, lead us to propose these compounds as attractive turn-off probes to detect DNA hybridization. PMID- 21243340 TI - Fluorescent quantification of amino groups on silica nanoparticle surfaces. AB - Functionalization of the surfaces of silica particles is often the first step in their various applications. An improved heterogeneous Fmoc-Cl fluorescent assay using an aqueous solution was developed to detect the number of amino groups on solid-phase supports. The fluorescent Fmoc-Cl method is 50-fold more sensitive than the current UV assay using an organic solvent. This method, together with the homogeneous fluorescamine and OPA assays, is used to detect amino groups on the silica particle surface. The accuracy and effect factors of these methods were examined and the assays were optimized. The results showed that the amine groups on silica particles can produce stronger fluorescence than small amine molecules in solution, because the porous structure of the particle surface is a more hydrophobic environment. The number of active amino groups that can be conjugated with biomolecules is much less than the total number of amino groups on the silica particle. Compared with physical methods, chemical assays involving direct reaction with amino groups would furnish the closest result to the number of active amino groups on the particle surface. PMID- 21243341 TI - Letter to the Editor: Crossing the ecological threshold--of scientific analysis, natural chemicals and global trade. PMID- 21243342 TI - Tramadol-induced adrenal insufficiency. PMID- 21243343 TI - Risk of high-grade bleeding in patients with cancer treated with bevacizumab: a meta-analysis of randomized controlled trials. AB - PURPOSE: High-grade bleeding is a serious adverse event associated with bevacizumab, a humanized monoclonal antibody targeting vascular endothelial growth factor and widely used in the current cancer treatments. The aim of this study was to gain a better understanding of the overall incidence and risk of high-grade bleeding in cancer patients who receive bevacizumab therapy. METHODS: We performed a meta-analysis of relevant randomized controlled trials (RCTs) identified in PubMed, Cochrane library, Embase, and American Society of Clinical Oncology conferences. Overall relative risks (RRs), incidence rates, and 95% confidence intervals (CIs) were calculated using a random-effects model. The primary clinical endpoint was high-grade bleeding (grade 3 or above). RESULTS: A total of 14,277 patients with a variety of solid tumors from 22 RCTs were included in the present analysis. The addition of bevacizumab to cancer chemotherapy significantly increased the risk of high-grade bleeding (RR 1.60, 95% CI 1.19-2.15), with RRs of high-grade bleeding among patients receiving bevacizumab at 2.5 and 5 mg/kg per week of 1.27 (95% CI 0.95-1.71) and 3.02 (95% CI 1.85-4.95), respectively. The overall incidence of high-grade bleeding among patients receiving bevacizumab was 2.8% (95% CI 2.1-3.8). Higher risks were observed in patients with non-small-cell lung cancer (RR 3.41, 95% CI 1.68-6.91), renal cell carcinoma (RR 6.37, 95% CI 1.43-28.33), and colorectal cancer (RR 9.11, 95% CI 1.70-48.79) who were receiving bevacizumab at 5 mg/kg per week. CONCLUSIONS: Among the patients included in the trials analyzed in this meta analysis, the addition of bevacizumab to cancer chemotherapy significantly increased the risk of high-grade bleeding. The risk may be dose-dependent and may vary with tumor type. PMID- 21243344 TI - Suspected adverse reactions associated with herbal products used for weight loss: a case series reported to the Italian National Institute of Health. AB - PURPOSE: The aim of this study was to describe suspected adverse reactions (ARs) associated with herbal products used for weight control in Italy. METHODS: Spontaneous reports of suspected ARs associated with herbal products used for weight control were collected by the Italian National Institute of Health (April 2002 to June 2010), and the causality assessment was performed. RESULTS: Forty six of the suspected ARs were associated with herbal products used for weight control. Women were involved in 85% of the reports. The reactions affected mainly the cardiovascular system, the skin, the digestive system, the central nervous system, and the liver. A large proportion of ARs were serious. In more than half of the suspected ARs, the use of other therapies (herbs and/or drugs) was reported, while concomitant conditions were present in 22% of the reports. CONCLUSIONS: The use of herbal dietary supplements for weight loss is associated with several ARs. Considering the risk/benefit ratio, consumers should pay attention when using these products. PMID- 21243345 TI - Healthcare professional experiences and attitudes on unlicensed/off-label paediatric prescribing and paediatric clinical trials. AB - OBJECTIVES: To investigate the knowledge and views of a range of healthcare professionals (consultant paediatricians, general practitioners (GPs), community pharmacists and paediatric nurses) regarding the use of unlicensed/off-label medicines in children and the participation of children in clinical trials. METHODS: A regional study in which a survey instrument with 39 items was issued to 500 randomly selected GPs, all community pharmacists (n = 512), 50 hospital consultants and 150 paediatric nurses in Northern Ireland. RESULTS: Approximately half (46.5%) of the 1,212 healthcare professionals approached responded to the questionnaire. The majority of respondents indicated their familiarity with the term unlicensed (82.9%) or off-label (58.6%) prescribing with the most frequently quoted reason for such prescribing being younger age (33.6%). Apart from community pharmacists, most respondents reported having gained their knowledge through personal experience. Even though a large percentage of respondents expressed concerns about the safety (77.8%) or efficacy (87.9%) of unlicensed/off label prescribing in children, only 30.7% reported informing parents/guardians of these concerns on the use of such medicines in children. In addition, only 56% of respondents believed that unlicensed/off-label medicines should undergo clinical trials in children. Overall, 28.4% of respondents (20.1% of GPs, 41.4% of community pharmacists, 27.7% of paediatric nurses and 94% of consultant paediatricians) indicated their willingness to be actively involved in, and recruit their patients for paediatric clinical research. CONCLUSION: The use of unlicensed and off-label medicines remains a major issue in paediatric medicine. Until such times as more licensed medicines are available for children, clear guidance should be developed to allow consistency in practice across the spectrum of healthcare professionals who are involved with such medicines in their routine practice. PMID- 21243347 TI - Accuracy of CT-guided percutaneous core needle biopsy for assessment of pediatric musculoskeletal lesions. AB - BACKGROUND: CT-guided percutaneous core needle biopsy has been shown in adults to be an effective diagnostic tool for a large number of musculoskeletal malignancies. OBJECTIVE: To characterize our experience with CT-guided percutaneous core needle biopsy of pediatric bone lesions and determine its utility in diagnosing pediatric osseous lesions, in a population where such lesions are commonly benign. MATERIALS AND METHODS: From 2000 to 2009, 61 children underwent 63 CT-guided percutaneous biopsies. Radiological, pathological and clinical records were reviewed. RESULTS: Fourteen biopsies (22%) were performed on malignant lesions, while 49 biopsies (78%) were performed on benign lesions. Forty-nine of the 63 biopsies (78%) were adequate; these children underwent no further tissue sampling. Fourteen of the 63 biopsies (22%) were inadequate or non-conclusive. Of these patients, 12 underwent open biopsy. Retrospective analysis of percutaneous biopsies in these patients demonstrates that 9/12 provided clinically relevant information, and 4/12 patients received final diagnoses that confirmed initial core biopsy findings. No malignancies were diagnosed as benign on percutaneous biopsy. Overall, percutaneous core needle biopsy provided accurate diagnostic information in 84% (53/63) of biopsies. CONCLUSION: Our results demonstrate that CT-guided percutaneous biopsy is safe and beneficial in children. This study supports the use of CT-guided percutaneous core needle biopsy for primary diagnosis of pediatric bone lesions. PMID- 21243346 TI - Rigid 3D-3D registration of TOF MRA integrating vessel segmentation for quantification of recurrence volumes after coiling cerebral aneurysm. AB - INTRODUCTION: A fast and reproducible quantification of the recurrence volume of coiled aneurysms is required to enable a more timely evaluation of new coils. This paper presents two registration schemes for the semi-automatic quantification of aneurysm recurrence volumes based on baseline and follow-up 3D MRA TOF datasets. METHODS: The quantification of shape changes requires a previous definition of corresponding structures in both datasets. For this, two different rigid registration methods have been developed and evaluated. Besides a state-of-the-art rigid registration method, a second approach integrating vessel segmentations is presented. After registration, the aneurysm recurrence volume can be calculated based on the difference image. The computed volumes were compared to manually extracted volumes. RESULTS: An evaluation based on 20 TOF MRA datasets (baseline and follow-up) of ten patients showed that both registration schemes are generally capable of providing sufficient registration results. Regarding the quantification of aneurysm recurrence volumes, the results suggest that the second segmentation-based registration method yields better results, while a reduction of the computation and interaction time is achieved at the same time. CONCLUSION: The proposed registration scheme incorporating vessel segmentation enables an improved quantification of recurrence volumes of coiled aneurysms with reduced computation and interaction time. PMID- 21243348 TI - Stump entrapment of the anterior cruciate ligament in late childhood and adolescence. AB - Displacement of a portion of the torn anterior cruciate ligament (ACL) into the intercondylar notch can cause a focal fibrotic reaction similar to that seen following ACL reconstruction. This displacement, which can result in locking or limitation of knee extension, is termed stump entrapment and is described in adult MR imaging literature. We present a pictorial essay of the etiology and appearance of stump entrapment on MR imaging of the knee in an older child and adolescents and review the significance of this finding. PMID- 21243349 TI - Volumetric fat-water separated T2-weighted MRI. AB - BACKGROUND: Pediatric body MRI exams often cover multiple body parts, making the development of broadly applicable protocols and obtaining uniform fat suppression a challenge. Volumetric T2 imaging with Dixon-type fat-water separation might address this challenge, but it is a lengthy process. OBJECTIVE: We develop and evaluate a faster two-echo approach to volumetric T2 imaging with fat-water separation. MATERIALS AND METHODS: A volumetric spin-echo sequence was modified to include a second shifted echo so two image sets are acquired. A region-growing reconstruction approach was developed to decompose separate water and fat images. Twenty-six children were recruited with IRB approval and informed consent. Fat suppression quality was graded by two pediatric radiologists and compared against conventional fat-suppressed fast spin-echo T2-W images. Additionally, the value of in- and opposed-phase images was evaluated. RESULTS: Fat suppression on volumetric images had high quality in 96% of cases (95% confidence interval of 80 100%) and were preferred over or considered equivalent to conventional two dimensional fat-suppressed FSE T2 imaging in 96% of cases (95% confidence interval of 78-100%). In- and opposed-phase images had definite value in 12% of cases. CONCLUSION: Volumetric fat-water separated T2-weighted MRI is feasible and is likely to yield improved fat suppression over conventional fat-suppressed T2 weighted imaging. PMID- 21243350 TI - Interloop fluid in intussusception: what is its significance? AB - BACKGROUND: Sonography has been used to predict pneumatic reduction outcome in children with intussusception. OBJECTIVE: To assess the prognostic significance of fluid between the intussusceptum and intussuscepiens with respect to reduction outcome, lead point or necrosis. MATERIALS AND METHODS: Sonograms of children with a discharge diagnosis of intussusception from four institutions were reviewed for interloop fluid and correlated with results of pneumatic reduction and surgical/pathological findings when available. Maximal dimension of interloop fluid on a transverse image and fluid complexity were evaluated. RESULTS: Of 166 cases, 36 (21.7%) had interloop fluid. Pneumatic reduction was successful in 21 (58.3%) with fluid and 113 (87.6%) without. The average largest fluid dimension was 8.7 mm (range 5 mm-19 mm, median 8 mm) in cases with successful reduction and 12.8 mm (range 4 mm-26 mm, median 12.5 mm) in unsuccessful reduction (p < 0.05). Fluid dimension equal to or greater than 9 mm correlated with failed reduction (p < 0.0001;odds ratio 13:1). In 36 cases with interloop fluid that required surgery, there were four lead points and three necrosis. In cases without fluid with surgical reduction, there was one lead point and one necrosis. Interloop fluid correlated with lead point (p < 0.04) or necrosis (p < 0.03). Its significance increased with larger amounts of fluid (p < 0.0001). Patient age/fluid complexity did not correlate with reduction outcome (p = 0.9). CONCLUSION: Interloop fluid was associated with increased failure of pneumatic reduction and increased likelihood of lead point or necrosis, particularly when the maximum dimension exceeded 9 mm. PMID- 21243351 TI - Bacterial diversity in Solenopsis invicta and Solenopsis geminata ant colonies characterized by 16S amplicon 454 pyrosequencing. AB - Social insects harbor diverse assemblages of bacterial microbes, which may play a crucial role in the success or failure of biological invasions. The invasive fire ant Solenopsis invicta (Formicidae, Hymenoptera) is a model system for understanding the dynamics of invasive social insects and their biological control. However, little is known about microbes as biotic factors influencing the success or failure of ant invasions. This pilot study is the first attempt to characterize and compare microbial communities associated with the introduced S. invicta and the native Solenopsis geminata in the USA. Using 16S amplicon 454 pyrosequencing, bacterial communities of workers, brood, and soil from nest walls were compared between neighboring S. invicta and S. geminata colonies at Brackenridge Field Laboratory, Austin, Texas, with the aim of identifying potential pathogenic, commensal, or mutualistic microbial associates. Two samples of S. geminata workers showed high counts of Spiroplasma bacteria, a known pathogen or mutualist of other insects. A subsequent analysis using PCR and sequencing confirmed the presence of Spiroplasma in additional colonies of both Solenopsis species. Wolbachia was found in one alate sample of S. geminata, while one brood sample of S. invicta had a high count of Lactococcus. As expected, ant samples from both species showed much lower microbial diversity than the surrounding soil. Both ant species had similar overall bacterial diversities, although little overlap in specific microbes. To properly characterize a single bacterial community associated with a Solenopsis ant sample, rarefaction analyses indicate that it is necessary to obtain 5,000-10,000 sequences. Overall, 16S amplicon 454 pyrosequencing appears to be a cost-effective approach to screen whole microbial diversity associated with invasive ant species. PMID- 21243352 TI - The effect of trehalose on the fermentation performance of aged cells of Saccharomyces cerevisiae. AB - The fermentation process offers a wide variety of stressors for yeast, such as temperature, aging, and ethanol. To evaluate a possible beneficial effect of trehalose on ethanol production, we used mutant strains of Saccharomyces cerevisiae possessing different deficiencies in the metabolism of this disaccharide: in synthesis, tps1; in transport, agt1; and in degradation, ath1 and nth1. According to our results, the tps1 mutant, the only strain tested unable to synthesize trehalose, showed the lowest fermentation yield, indicating that this sugar is important to improve ethanol production. At the end of the first fermentation cycle, only the strains deficient in transport and degradation maintained a significant level of the initial trehalose. The agt1, ath1, and nth1 strains showed the highest survival rates and the highest proportions of non petites. Accumulation of petites during fermentation has been correlated to low ethanol production. When recycled back for a subsequent fermentation, those mutant strains produced the highest ethanol yields, suggesting that trehalose is required for improving fermentative capacity and longevity of yeasts, as well as their ability to withstand stressful industrial conditions. Finally, according to our results, the mechanism by which trehalose improves ethanol production seems to involve mainly protection against protein oxidation. PMID- 21243353 TI - The construction of a library of synthetic promoters revealed some specific features of strong Streptomyces promoters. AB - Streptomyces are bacteria of industrial interest whose genome contains more than 73% of bases GC. In order to define, in these GC-rich bacteria, specific sequence features of strong promoters, a library of synthetic promoters of various sequence composition was constructed in Streptomyces. To do so, the sequences located upstream, between and downstream of the -35 and -10 consensus promoter sequences were completely randomized and some variability was introduced in the 35 (position 6) and -10 (positions 3, 4 and 5) hexamers recognized by the major vegetative sigma factor HrdB. The synthetic promoters were cloned into the promoter-probe plasmid pIJ487 just upstream of the promoter-less aphII gene that confers resistance to neomycin. This synthetic promoter library was transformed into Streptomyces lividans, and the resulting transformants were screened for their ability to grow in the presence of different concentrations of neomycin (20, 50, and 100 MUgml(-1)). Promoter strengths varied up to 12-fold, in small increments of activity increase, as determined by reverse transcriptase-PCR. This collection of promoters of various strengths can be useful for the fine-tuning of gene expression in genetic engineering projects. Thirty-eight promoters were sequenced, and the sequences of the 14 weakest and 14 strongest promoters were compared using the WebLogo software with small sample correction. This comparison revealed that the -10 box, the -10 extended motif as well as the spacer of the strong Streptomyces promoters are more G rich than those of the weak promoters. PMID- 21243354 TI - Association of the presence of bone bars on radiographs and low bone mineral density. AB - OBJECTIVE: Bone bars (BB) are struts of normal trabecular bone that cross the medullary portions of the metaphysis and diaphysis at right angles to the long axis of the shaft. The purpose of this investigation was to determine whether the presence of bone bars (BB) identified on radiographs of the proximal femurs and tibia, predict lower bone mineral density (BMD) as evaluated with dual-energy x ray absorptiometry (DXA) in the lumbar spine, total hip, or femoral neck. MATERIALS AND METHODS: A total of 134 sequential DXA patients underwent radiography of the pelvis, hips, and both knees. The radiographs were evaluated for the presence of BB by two musculoskeletal radiologists who were blinded to DXA results. A t test was used to evaluate the relationship of BB to BMD and a Chi-square test was used to determine if BB were equally distributed among the categories of normal BMD, low bone mass (osteopenia), and osteoporosis. RESULTS: BB were associated with lower BMD at all measured sites. BB at the intertrochanteric and proximal tibial sites were the most predictive of low BMD while supraacetabular and distal femur BB were less predictive. Osteoporosis or osteopenia is seen in 60-91% of those with BB depending on the side and reader. It is only seen in about 40% of those without BB. CONCLUSIONS: We conclude that the presence of BB suggest decreased BMD and when correlated with other clinical information, might support further evaluation of BMD. PMID- 21243355 TI - One should not just read what one believes: the nearly irresolvable issue of producing truly objective, evidence-based guidelines for the management of differentiated thyroid cancer. PMID- 21243356 TI - Total Hip Arthroplasty, state of the art for the 21st century. PMID- 21243357 TI - Correlation of dynamic impact testing, histopathology and visual macroscopic assessment in human osteoarthritic cartilage. AB - OBJECTIVE: Improved staging of cartilage degeneration is required, particularly during the early stages. We correlated mechanical properties with histological and macroscopic findings. METHODS: One hundred and twenty cartilage samples were obtained during total knee arthroplasty. Two adjacent plugs were harvested--one for histological classification and one for macroscopic and biomechanical purposes. Dynamic impact testing was performed; normal stress, dissipated energy (?E), tangent modulus and stiffness were evaluated. RESULTS: Samples were classified according to six categories of the ICRS histological scale. Mechanical characteristics revealing significant differences between the groups (p < 0.01) were specific damping and related absolute ?E. A significant correlation was found between the macroscopic score and specific damping, as well as absolute and relative ?E (p < 0.01). A strong relation was revealed between relative ?E and cartilage thickness (p < 0.001; R (2) = 0.69). CONCLUSIONS: Only ?E correlated with the condition of the cartilage--the value increased with decreasing quality and is the most suitable characteristic. This change appears substantial in initial stages of cartilage deterioration. PMID- 21243358 TI - Reamer-irrigator-aspirator indications and clinical results: a systematic review. AB - BACKGROUND: The 'reamer-irrigator-aspirator' (RIA) is an innovation developed to reduce fat embolism (FE) and thermal necrosis (TN) that can occur during reaming/nailing of long-bone fractures. Since its inception its indications have expanded to include the treatment of long-bone osteomyelitis and as a harvester of bone graft/mesenchymal stem cells (MSCs). METHODS: This study involved a systematic review, via Pubmed(r) and Google Scholar(r), of English language sources (nine non-clinical studies, seven clinical studies and seven case reports) using the keywords: 'reamer', 'irrigator', 'aspirator' (1st May 2010). Sources were reviewed with reference to the RIAs efficacy in (1) preventing FE/TN, (2) treating long-bone osteomyelitis, (3) harvesting bone graft/MSCs, and (4) operating safely. Experimental data supports the use of the RIA in preventing FE and TN, however, there is a paucity of clinical data. CONCLUSIONS: The RIA is a reliable method in achieving high volumes of bone graft/MSCs, and high union rates are reported when using RIA bone-fragments to treat non-unions. Evidence suggests possible effectiveness in treating long-bone osteomyelitis. The RIA appears relatively safe, with a low rate of morbidity provided a meticulous technique is used. When complications occur they respond well to conventional techniques. The RIA demands further investigation especially with respect to the optimal application of MSCs for bone repair strategies. PMID- 21243359 TI - An exact stochastic hybrid model of excitable membranes including spatio-temporal evolution. AB - In this paper, we present a mathematical description for excitable biological membranes, in particular neuronal membranes. We aim to model the (spatio-) temporal dynamics, e.g., the travelling of an action potential along the axon, subject to noise, such as ion channel noise. Using the framework of Piecewise Deterministic Processes (PDPs) we provide an exact mathematical description-in contrast to pseudo-exact algorithms considered in the literature-of the stochastic process one obtains coupling a continuous time Markov chain model with a deterministic dynamic model of a macroscopic variable, that is coupling Markovian channel dynamics to the time-evolution of the transmembrane potential. We extend the existing framework of PDPs in finite dimensional state space to include infinite-dimensional evolution equations and thus obtain a stochastic hybrid model suitable for modelling spatio-temporal dynamics. We derive analytic results for the infinite-dimensional process, such as existence, the strong Markov property and its extended generator. Further, we exemplify modelling of spatially extended excitable membranes with PDPs by a stochastic hybrid version of the Hodgkin-Huxley model of the squid giant axon. Finally, we discuss the advantages of the PDP formulation in view of analytical and numerical investigations as well as the application of PDPs to structurally more complex models of excitable membranes. PMID- 21243360 TI - Vascular-specific activity of the Arabidopsis carotenoid cleavage dioxygenase 7 gene promoter. AB - Carotenoid cleavage dioxygenases (CCDs) are involved in the production of diverse apocarotenoids including phytohormones, the visual molecules and the aromatic volatile compounds derived from carotenoids. Here, we examined the spatial expression of four of the CCD genes (AtCcd1, 4, 7 and 8) among the nine members of this family in Arabidopsis by RT-PCR. We found that the AtCcd7 gene showed strong expression in seeds. However, the promoter activity of the 1,867-bp 5' upstream region of this gene exhibited a vascular specificity at all developmental stages throughout the transgenic Arabidopsis plants tested. The strength of the AtCcd7 promoter was also found to be lower than that of the 35S promoter by about 60%. The whole body expression of the beta-glucuronidase (GUS) reporter gene driven by the AtCcd7 promoter in Arabidopsis plants was confirmed in different organs by RT-PCR and GUS enzymatic assays. Histochemical GUS staining further revealed that the AtCcd7 promoter has utility in limiting the expression of target genes to the vascular tissues in all plant organs such as the leaf, stem, root, flower and seed. PMID- 21243361 TI - Effects of 2-aminoindan-2-phosphonic acid treatment on the accumulation of salidroside and four phenylethanoid glycosides in suspension cell culture of Cistanche deserticola. AB - 2-Aminoindan-2-phosphonic acid (AIP), a specific competitive phenylalanine ammonia lyase (PAL) inhibitor was applied to a suspension cell culture of Cistanche deserticola. The effects of AIP treatment on cell growth, PAL activity, contents and yields of total phenolic compound, salidroside and four phenylethanoid glycosides (PheGs) are investigated. The results demonstrated that, 0.5 and 2.0 MUM AIP treatments had similar effects on the measurements investigated in this study. AIP treatment resulted in significant decreases in PAL activity, total phenolic compounds content, and PheGs content. Linear regression analysis showed that PAL activity had a high correlation coefficient with the total phenolic compound content and the four PheGs contents. Total PAL activity-time area under curve (AUC) had a high correlation coefficient with the total phenolic compound yield and the yields of five tested compounds in untreated cell samples. In AIP-treated cells, total PAL activity-time AUC retained a high correlation with the total phenolic compound yield and the yields of three tested compounds, echinacoside, acteoside, and tubuloside A, but not salidroside and cistanoside A. The difference could be caused by the different biosynthetic origins of each of the tested compounds. These results demonstrate the important role of PAL in the biosynthesis of PheGs in the suspension cell culture of C. deserticola. PMID- 21243362 TI - Plant-made vaccines in support of the Millennium Development Goals. AB - Vaccines are one of the most successful public health achievements of the last century. Systematic immunisation programs have reduced the burden of infectious diseases on a global scale. However, there are limitations to the current technology, which often requires costly infrastructure and long lead times for production. Furthermore, the requirement to keep vaccines within the cold-chain throughout manufacture, transport and storage is often impractical and prohibitively expensive in developing countries-the very regions where vaccines are most needed. In contrast, plant-made vaccines (PMVs) can be produced at a lower cost using basic greenhouse agricultural methods, and do not need to be kept within such narrow temperature ranges. This increases the feasibility of developing countries producing vaccines locally at a small-scale to target the specific needs of the region. Additionally, the ability of plant-production technologies to rapidly produce large quantities of strain-specific vaccine demonstrates their potential use in combating pandemics. PMVs are a proven technology that has the potential to play an important role in increasing global health, both in the context of the 2015 Millennium Development Goals and beyond. PMID- 21243363 TI - Paediatric lumbar disc herniation in the very young: a case-based update. AB - BACKGROUND: A lumbar disc prolapse is commonly seen in the adult population and as a result, the signs and symptoms are well recognised and easily treated. A disc prolapse, in the adolescent and particularly the paediatric age group, is very rare indeed. The signs and symptoms are atypical in this age group, and there is often difficulty in recognising the pathology. This can lead to delays in the diagnosis and treatment of a very painful condition. DISCUSSION: Lumbar disc herniation in very young children can be hard to diagnose. There is limited information currently available in the literature on the topic of lumbar disc herniation in very young children. Overall, the surgical option in these children appears to have a favourable outcome. ILLUSTRATIVE CASE: This case highlights an 18-month-old child who was not able to walk, following a fall. The child had a normal neurological examination and normal bladder and bowel function. A magnetic resonance imaging (MRI) scan of her lumbar sacral spine indicated a large right paracentral L4/5 disc prolapse indenting the right anterolateral margin of the thecal sac and abutting the right L5 nerve root. She subsequently underwent a laminoplasty and excision of a sub-ligamentous L4/5 disc prolapse under an operating microscope. CONCLUSIONS: This case report highlights the problems in diagnosing an acute lumbar disc prolapse in an 18-month-old child and reviews the current literature dealing with an acute disc prolapse in very young children. PMID- 21243364 TI - Correlation of splenic volume with hematological parameters, splenic vein diameter, portal pressure and grade of varices in extrahepatic portal vein obstruction in children. AB - PURPOSE: To study the correlation between the volume of the spleen and hematological parameters, splenic vein diameter, portal pressure before shunt, portal pressure after shunt, reduction of portal pressure and grade of esophageal varices in patients with extrahepatic portal vein obstruction (EHPVO). METHODS: Twenty-four patients with EHPVO who underwent splenectomy with leino-renal shunt during a period of 2 years were prospectively analyzed. Splenic volumes were measured from CT scans using appropriate volumetry software. In order to standardize the difference in the size of the patients, the splenic volume was expressed as a ratio, the splenic volume index, between the actual volume as measured on the CT scan and the surface area of the body. The splenic vein diameter was measured on the CT portogram and confirmed during surgery using a caliper. The grade of esophageal varices was determined during esophageal endoscopy using the Japanese Research Society for Portal Hypertension classification. The portal pressure was measured by cannulating a venous tributary of the gastro-epiploic arcade and using a pressure transducer. RESULTS: The splenic volume, expressed as splenic volume index, ranged from 362.15 to 1,849.51 ml/m2 (mean 929.23 +/- 409.02). Larger splenic volumes were associated with lower hemoglobin and platelet counts and significantly lower total leukocyte counts (p = 0.0003). The portal pressures reduced remarkably following the splenectomy and leino-renal shunt; mean post-shunt pressure 20 +/- 6.63 mmHg from mean pre-shunt pressure of 34.33 +/- 6.21 mmHg (mean percentage reduction 43.37 +/- 16.02%). There was no statistically significant correlation between splenic volume and any of the hemodynamic parameters except a weak correlation with splenic vein diameter. There was no correlation between the splenic vein diameter and the pre-shunt portal pressure; however, there was a statistically significant correlation between the splenic vein diameter and the percentage of post-shunt portal pressure reduction (p = 0.0494). CONCLUSION: Splenic volume has a weak correlation with splenic vein diameter, but does not correlate with portal pressure or the grade of varix. Splenic vein diameter has a statistically significant correlation with the percentage of portal pressure reduction following a leino-renal shunt. There is a statistically significant negative correlation between the splenic volume and the total leukocyte count. PMID- 21243365 TI - Ileocaecal valve: how important is it? AB - PURPOSE: Our aim was to investigate the importance of the ileocaecal valve and its reconstruction in patients that are not suffering from short bowel syndrome and Crohn's disease. METHODS: Casenotes of 99 children with hemicolectomy and 24 children with terminal ileal resection were reviewed and sorted into three groups. Group 1: ileocaecal valve resection (limited hemicolectomy), Group 2: hemicolectomy, Group 3: terminal ileal resection between 10 and 25 cm. Patients with Crohn's, short bowel syndrome and incomplete follow-up were excluded. RESULTS: Chronic diarrhoea was documented in 7/26 cases (27%) in Group 1, 6/23 patients (26%) in Group 2, and none of the 13 patients had diarrhoea in Group 3. Pearson Chi-square test showed significant difference between Group 1 and Group 3 (p = 0.038) and between Group 2 and Group 3 (p = 0.043). But there was no significant difference between Group 1 and Group 2 (p = 0.947). CONCLUSION: Chronic diarrhoea is a significant complication after limited hemicolectomy not only in Crohn's disease and short bowel syndrome. This is likely to originate from the loss of the ileocaecal valve itself rather than the loss of the ileal or colonic segment. Our results justify attempts to reconstruct the ileocaecal valve. PMID- 21243366 TI - Thymectomy for inducing remission in juvenile myasthenia gravis. AB - PURPOSE: The aim of this study was to determine the efficacy of thymectomy to induce remission in juvenile myasthenia gravis. METHODS: A retrospective review of all patients undergoing a thymectomy for the treatment of juvenile myasthenia gravis was performed at a single tertiary referral centre between 1997 and 2009 (N = 8). All cases were moderate to severe cases (Osserman stage >= 2a). All operations were open. Median follow-up was 18 months (range 1-77). Postoperative progress was assessed using the De Filippi classification of remission. MAIN RESULTS: Only two minor complications were reported. Mean operative time was 120 min (range 80-290 min). Mean postoperative stay was 17 days (range 3-52 days). Remission was observed in 5 of 8 patients (62%) at last known follow up. CONCLUSIONS: Spontaneous remission rates for myasthenia gravis are quoted to be between 20 and 29% while remission rates following thymectomy are 29-68% at 3 years. Although not all of our patients have had 3 years of follow up-the remission rate of 62% demonstrated by this study is encouraging. If reproducible over a larger series this provides evidence of the efficacy of thymectomy for treating juvenile myasthenia gravis in selected patients. PMID- 21243367 TI - Pediatric surgery telehealth: patient and clinician satisfaction. AB - PURPOSE: The Stollery Children's Hospital serves a very large geographic region of over at least 650,000 km2 with patients from outside of Edmonton accounting for approximately 50% of the service population. The aim of this study is to document the experience and opinion of the patient and clinician satisfaction with telehealth encounter for various pediatric surgical consultations and follow up as a way to bridge the distance gap. METHODS: We observe our experience with recent telehealth implementation from 2008 to 2009. Qualitative data were collected through questionnaires aimed at patients and clinicians. RESULTS: There were 259 pediatric surgical telehealth encounters, of which 37% were from outside the province. There were 42 antenatal multidisciplinary, 13 chronic pain, 103 general surgery, 2 orthopedic, 63 urology, 33 head and shape nurse practioner clinic, and 3 neurosurgery consults. 83 patient and 12 clinician questionnaires were completed. 97% of patients and 73% of clinicians reported satisfaction with having a telehealth session. 97% of the patients reside more than 200 km from the city and 77% live more than 400 km away. 48% reported a cost saving >$500-$700. CONCLUSION: Telehealth for pediatric surgical services is an alternative as an acceptable, effective, and appropriate way to consult and follow-up pediatric patients who live in significantly remote areas with great clinician and patient satisfaction. PMID- 21243368 TI - Deficiency in TIMP-3 increases cardiac rupture and mortality post-myocardial infarction via EGFR signaling: beneficial effects of cetuximab. AB - Cardiac rupture is a fatal complication of myocardial infarction (MI); however, its underlying molecular mechanisms are not fully understood. This study investigated the role of tissue inhibitor of metalloproteinase-3 (TIMP-3)/matrix metalloproteinase (MMP)/epidermal growth factor (EGF)/transforming growth factor (TGF)-beta1 pathway in infarct healing and effects of cetuximab on cardiac rupture after MI. Induction of MI was achieved by left coronary artery ligation in wild-type (WT) and TIMP-3(-/-) mice. TIMP-3 deficiency resulted in a fourfold increase in cardiac rupture and 50% decrease in survival after MI. Hydroxyproline content, collagen synthesis and myofibroblast cell number in the infarct region, and the force required to induce rupture of the infarct scar were significantly decreased, while MMP activity was increased in TIMP-3(-/-) mice. EGF proteins were increased by threefold in TIMP-3(-/-) mice following MI, while TGF-beta1 mRNA levels were decreased by 68%. Cell proliferation of cultured adult cardiac myofibroblasts was significantly decreased in TIMP-3(-/-) compared to WT myofibroblasts. EGF treatment significantly decreased collagen synthesis and TGF beta1 expression. Conversely, TGF-beta1 treatment increased collagen synthesis in cardiac myofibroblasts. Treatment with cetuximab significantly decreased the incidence of cardiac rupture and improved survival post-MI in TIMP-3(-/-) mice. We conclude that deficiency in TIMP-3 increases cardiac rupture post-MI via EGF/epidermal growth factor receptor (EGFR) signaling which downregulates TGF beta1 expression and collagen synthesis. Inhibition of EGFR by cetuximab protects against cardiac rupture and improves survival post-MI. PMID- 21243369 TI - Granular expression of prolyl-peptidyl isomerase PIN1 is a constant and specific feature of Alzheimer's disease pathology and is independent of tau, Abeta and TDP 43 pathology. AB - Alzheimer's disease (AD) manifests with progressive memory loss and decline of spatial awareness and motor skills. Neurofibrillary tangles (NFTs) represent one of the pathological hallmarks of AD. Previous studies suggest that the enzyme prolyl-peptidyl cis-trans isomerase PIN1 [protein interacting with NIMA (never in mitosis A)-1] recognizes hyperphosphorylated tau (in NFTs) and facilitates its dephosphorylation, thereby recovering its function. This study aims to determine the frequency, severity and distribution of PIN1 immunoreactivity and its relationship to NFTs and other neuropathological markers of neurodegeneration such as amyloid-beta (Abeta) plaques and transcription-responsive DNA-binding protein of M(r) 43 kDa (TDP-43). Immunohistochemical analysis of 194 patients (46 with AD, 43 with Parkinson's disease/dementia with Lewy bodies, 12 with progressive supranuclear palsy/corticobasal degeneration, 36 with frontotemporal lobar degeneration, 21 with motor neuron disease and 34 non-demented (ND) individuals) revealed an increased frequency and severity of PIN1 immunoreactive inclusions in AD as compared to all diagnostic groups (P < 0.001). The hippocampal and cortical distribution of PIN1 granules was distinct from that of NFTs, Abeta and TDP-43 pathologies, though the frequency of neurons with PIN1 immunoreactivity increased with increasing NFT pathology. There was a progressive increase in PIN1 changes in ND individuals as the degree of AD-type pathological changes increased. Present findings indicate that PIN1 changes are a constant feature of AD pathology and could serve as a biomarker of the onset or spread of AD neuropathology independent of tau or Abeta. PMID- 21243370 TI - Pars plana vitrectomy for diabetic macular edema. Internal limiting membrane delamination vs posterior hyaloid removal. A prospective randomized trial. AB - BACKGROUND: Diabetes mellitus, as well as subsequent ocular complications such as cystoid macular edema (CME), are of fundametal socio-economic relevance. Therefore, we evaluated the influence of internal limiting membrane (ILM) removal on longterm morphological and functional outcome in patients with diabetes mellitus (DM) type 2 and chronic CME without evident vitreomacular traction. METHOD: Forty eyes with attached posterior hyaloid were included in this prospective trial and randomized intraoperatively. Prior focal (n = 31) or panretinal (n = 25) laser coagulation was permitted. Group I (n = 19 patients) underwent surgical induction of posterior vitreous detachment (PVD), group II (n = 20 patients) PVD and removal of the ILM. Eleven patients with detached posterior hyaloid (group III) were not randomized, and ILM removal was performed. One eye had to be excluded from further analysis. Examinations included ETDRS best-corrected visual acuity (BCVA), fluorescein angiography (FLA) and OCT at baseline, 3 and 6 months postoperatively. Main outcome measure was BCVA at 6 months, secondary was foveal thickness. RESULTS: Mean BCVA over 6 months remained unchanged in 85% of patients of group II, and decreased in 53% of patients of group I. Results were not statistically significant different [group I: mean decrease log MAR 95% CI (0.06; 0.32), group II: (-0.02; 0.11)]. OCT revealed a significantly greater reduction of foveal thickness following PVD with ILM removal [group I: mean change: 95% CI (-208.95 MUm; -78.05 MUm), group II: ( 80.90 MUm: +59.17 MUm)]. CONCLUSION: Vitrectomy, PVD with or without ILM removal does not improve vision in patients with DM type 2 and cystoid diabetic macular edema without evident vitreoretinal traction. ILM delamination shows improved morphological results, and appears to be beneficial in eyes with preexisting PVD. PMID- 21243371 TI - Uniocular and binocular fields of rotation measures: Octopus versus Goldmann. AB - PURPOSE: To compare the range of ocular rotations measured by Octopus versus Goldmann perimetry. METHODS: Forty subjects (20 controls and 20 patients with impaired ocular movements) were prospectively recruited, age range 21-83 years. Range of uniocular rotations was measured in six vectors corresponding to extraocular muscle actions: 0 degrees , 67 degrees , 141 degrees , 180 degrees , 216 degrees , 293 degrees . Fields of binocular single vision were assessed at 30 degrees intervals. Vector measurements were utilised to calculate an area score for the field of uniocular rotations or binocular field of single vision. Two test speeds were used for Octopus testing: 3 degrees / and 10 degrees /second. RESULTS: Test duration was two thirds quicker for Octopus 10 degrees /second than for 3 degrees /second stimulus speed, and slightly quicker for Goldmann. Mean area for control subjects for uniocular field was 7910.45 degrees(2) for Goldmann, 7032.14 for Octopus 3 degrees /second and 7840.66 for Octopus 10 degrees /second. Mean area for patient subjects of right uniocular field was 8567.21 degrees(2) for Goldmann, 5906.72 for Octopus 3 degrees /second and 8806.44 for Octopus 10 degrees /second. Mean area for left uniocular field was 8137.49 degrees(2) for Goldmann, 8127.9 for Octopus 3 degrees /second and 8950.54 for Octopus 10 degrees /second. Range of measured rotation was significantly larger for Octopus 10 degrees /second speed. CONCLUSIONS: Our results suggest that the Octopus perimeter is an acceptable alternative method of assessment for uniocular ductions and binocular field of single vision. Speed of stimulus significantly alters test duration for Octopus perimetry. Comparisons of results from both perimeters show that quantitative measurements differ, although qualitatively the results are similar. Differences per mean vectors were less than 5 degrees (within clinically accepted variances) for both controls and patients when comparing Goldmann to Octopus 10 degrees /second speed. However, differences were almost 10 degrees for the patient group when comparing Goldmann to Octopus 3 degrees /second speed. Thus, speed of stimulus must be considered if wishing to use these perimeters interchangeably. PMID- 21243372 TI - "Seeing but not identifying": pure alexia coincident with prosopagnosia in occipital arteriovenous malformation. AB - BACKGROUND: Pure alexia and prosopagnosia are two separate and uncommon disorders of visual recognition in neuro-ophthalmology. We report an extremely rare case of pure alexia coincident with prosopagnosia secondary to occipital arteriovenous malformation. The manifestations of these two visual recognition disorders are also described. METHODS: A 35-year-old, left-handed women had suffered from severe blurred vision when recognizing her family's faces and was unable to read or associate separate parts of a word into a whole word. Her visual field revealed slight right homonymous hemianopia. Computed tomography scans and magnetic resonance images were arranged and vertebral angiography confirmed the diagnosis of left occipital arteriovenous malformation. RESULTS: Gamma-knife stereoscopic radiotherapy was performed. Two months after the treatment, the ability to recognize faces and read improved and the visual field recovered. CONCLUSIONS: Ophthalmologists should keep in mind that usual complaints of "blurred vision" might correlate with unusual visual recognition disorders. Pure alexia and prosopagnosia have not been reported to occur together and the left handed- dominance in our case leads to this scarce concurrence. PMID- 21243373 TI - Retinal straylight and light distortion phenomena in normal and post-LASIK eyes. AB - PURPOSE: To assess the relationship between measures of light distortion and retinal straylight in normal and post-LASIK subjects. DESIGN: Cross-sectional, non-randomized, masked observational case series SETTING: Clinica Oftalmologica Novovision, Madrid, Spain. METHODS: Thirty eyes from 30 healthy subjects (mean age 33.9 +/- 8.3 years old; mean spherical equivalent (MSE) -2.06 +/- 1.40 D) and thirty six eyes from thirty six refractive surgery patients (mean age 36.1 +/- 7.7 years old; mean preop MSE -3.43 +/- 2.23 D) were examined with the Starlights and the C-Quant straylightmeter in a case-control study. RESULTS: The age of both treated and control groups was not statistically different (p > 0.05). Statistically significant differences between controls and post-LASIK eyes were found for luminous distortion index (LDI), but not for retinal straylight. Correlation analysis yielded significant correlation between retinal straylight Log(s) values and BCVA measures (r = 0.379, p = 0.002). Control subjects showed significant correlation between MSE and retinal straylight Log(s) values (r = 0.650, p < 0.001), while post-LASIK eyes showed a significant correlation between LDI and Log(s) values (r = 0.338, p = 0.044) and between Log(s) values and BCVA (r = 0.460, p = 0.005). Correlation between measures obtained by both methods was higher after LASIK than in control eyes, although values were quite scattered in any case. CONCLUSION: Light distortion phenomena and retinal straylight measures are correlated in both normal and postsurgical eyes. Both parameters are increased in LASIK subjects compared to control non-operated subjects. PMID- 21243374 TI - Mucoepidermoid carcinoma: a five-decade journey. AB - Several decades after a comprehensive description of mucoepidermoid carcinoma (MEC), there is no uniformly accepted grading system. The most recent debate regarding the histologic grading of MECs, centers on the wide range of reported prevalence of cyclic AMP response element-binding protein (CREB)-regulated transcription coactivator (CRTC1-MAML2) rearrangement in high-grade (HG) MECs. We hypothesize that difficulties in morphologic classification may partially explain problems in grading MECs. We believe that HG MECs, as diagnosed over the last several decades, represent a blend of true MECs with unrelated clinicopathologic entities. To examine the historic aspects of this problem, and to identify neoplasms that most commonly mimic "high-grade" MEC, we reviewed 46 cases of alleged MEC diagnosed in our department from 1956 to 1974. The diagnosis of MEC was confirmed in 22 cases and was changed in 24 cases. Compared to cases of confirmed MEC, cases with changed diagnoses had higher incidence of lymph node metastases, perineural invasion, and shorter overall survival. Adenosquamous carcinoma, squamous cell carcinoma, and salivary duct carcinoma emerged as the most common mimics of HG MEC. The single most common diagnostic issue in these cases is the level of keratinization acceptable for MEC. Twenty cases of confirmed MEC were tested for CRTC1-MAML2 rearrangement and 5 low-grade MECs, 7 intermediate grade MECs, and 2 cases of HG MEC were translocation-positive. PMID- 21243375 TI - Identification and functional response of interstitial Cajal-like cells from rat mesenteric artery. AB - Cells with irregular shapes, numerous long thin filaments, and morphological similarities to the gastrointestinal interstitial cells of Cajal (ICCs) have been observed in the wall of some blood vessels. These ICC-like cells (ICC-LCs) do not correspond to the other cell types present in the arterial wall: smooth muscle cells (SMCs), endothelial cells, fibroblasts, inflammatory cells, or pericytes. However, no clear physiological role has as yet been determined for ICC-LCs in the vascular wall. The aim of this study has been to identify and characterize the functional response of ICC-LCs in rat mesenteric arteries. We have observed ICC-LCs and identified them morphologically and histologically in three different environments: isolated artery, freshly dispersed cells, and primary-cultured cells from the arterial wall. Like ICCs but unlike SMCs, ICC-LCs are positively stained by methylene blue. Cells morphologically resembling methylene-blue positive cells are also positive for the ICC and ICC-LC markers alpha-smooth muscle actin and desmin. Furthermore, the higher expression of vimentin in ICC LCs compared with SMCs allows a clear discrimination between these two cell types. At the functional level, the differences observed in the variations of cytosolic free calcium concentration of freshly dispersed SMCs and ICC-LCs in response to a panel of vasoactive molecules show that ICC-LCs, unlike SMCs, do not respond to exogenous ATP and [Arginine](8)-vasopressin. PMID- 21243376 TI - Existence and distribution of gonadotropin-releasing hormone-like peptides in the central nervous system and ovary of the Pacific white shrimp, Litopenaeus vannamei. AB - We used antibodies against octopus gonadotropin-releasing hormone (octGnRH) and tunicate GnRH (tGnRH-I) in order to investigate the existence and distribution of GnRH-like peptides in the central nervous system (CNS) and in the ovary during various stages of the ovarian cycle of the white shrimp, Litopenaeus vannamei. OctGnRH-immunoreactive and tGnRH-I-immunoreactive neurons and fibers were present in several regions of the supraesophageal ganglion (brain), subesophageal ganglion (SEG), thoracic ganglia, and abdominal ganglia. In the brain, both octGnRH immunoreactivity (ir) and tGnRH-I-ir were detected in neurons of clusters 6, 11, 17, and associated fibers, and the anterior medial protocerebral, posterior medial protocerebral, olfactory, and tegumentary neuropils. In the SEG and thoracic ganglia, octGnRH-immunoreactive and tGnRH-I-immunoreactive neurons and fibers were present in dorsolateral and ventromedial cell clusters and in surrounding fibers. Only immunoreactive fibers were detected in the abdominal ganglia. In the ovary, both octGnRH and tGnRH-I were detected at medium intensity in the cytoplasm of early step oocytes (Oc2) and, at high intensity, in Oc3. Furthermore, octGnRH-ir and tGnRH-I-ir were intense in follicular cells surrounding Oc2 and Oc3. The presence of GnRH-ir in the CNS and ovary indicates that GnRH-like peptides occur in the white shrimp, and that GnRHs are involved in the reproductive process, especially ovarian maturation and the differentiation of oocytes, as reported in other species. PMID- 21243377 TI - The Beck Depression Inventory (BDI-II) and a single screening question as screening tools for depressive disorder in Dutch advanced cancer patients. AB - PURPOSE: Depression is highly prevalent in advanced cancer patients, but the diagnosis of depressive disorder in patients with advanced cancer is difficult. Screening instruments could facilitate diagnosing depressive disorder in patients with advanced cancer. The aim of this study was to determine the validity of the Beck Depression Inventory (BDI-II) and a single screening question as screening tools for depressive disorder in advanced cancer patients. METHODS: Patients with advanced metastatic disease, visiting the outpatient palliative care department, were asked to fill out a self-questionnaire containing the Beck Depression Inventory (BDI-II) and a single screening question "Are you feeling depressed?" The mood section of the PRIME-MD was used as a gold standard. RESULTS: Sixty-one patients with advanced metastatic disease were eligible to be included in the study. Complete data were obtained from 46 patients. The area under the curve of the receiver operating characteristics analysis of the BDI-II was 0.82. The optimal cut-off point of the BDI-II was 16 with a sensitivity of 90% and a specificity of 69%. The single screening question showed a sensitivity of 50% and a specificity of 94%. CONCLUSIONS: The BDI-II seems an adequate screening tool for a depressive disorder in advanced cancer patients. The sensitivity of a single screening question is poor. PMID- 21243378 TI - Arbuscular mycorrhizal fungi associated with Artemisia umbelliformis Lam, an endangered aromatic species in Southern French Alps, influence plant P and essential oil contents. AB - Root colonization by arbuscular mycorrhizal (AM) fungi of Artemisia umbelliformis, investigated in natural and cultivated sites in the Southern Alps of France, showed typical structures (arbuscules, vesicles, hyphae) as well as spores and mycelia in its rhizosphere. Several native AM fungi belonging to different Glomeromycota genera were identified as colonizers of A. umbelliformis roots, including Glomus tenue, Glomus intraradices, G. claroideum/etunicatum and a new Acaulospora species. The use of the highly mycorrhizal species Trifolium pratense as a companion plant impacted positively on mycorrhizal colonization of A. umbelliformis under greenhouse conditions. The symbiotic performance of an alpine microbial community including native AM fungi used as inoculum on A. umbelliformis was evaluated in greenhouse conditions by comparison with mycorrhizal responses of two other alpine Artemisia species, Artemisia glacialis and Artemisia genipi Weber. Contrary to A. genipi Weber, both A. umbelliformis and A. glacialis showed a significant increase of P concentration in shoots. Volatile components were analyzed by GC-MS in shoots of A. umbelliformis 6 months after inoculation. The alpine microbial inoculum increased significantly the percentage of E-beta-ocimene and reduced those of E-2-decenal and (E,E)-2-4 decadienal indicating an influence of alpine microbial inoculum on essential oil production. This work provides practical indications for the use of native AM fungi for A. umbelliformis field culture. PMID- 21243379 TI - Stereotactic versus endoscopic surgery in periventricular lesions. AB - OBJECT: Endoscopic and stereotactic surgery have gained widespread acceptance as minimally invasive tools for the diagnosis of intracerebral pathologies. We investigated the specific advantages and disadvantages of each technique in the assessment of periventricular lesions. METHOD: This study included a retrospective series of 70 patients with periventricular lesions. Endoscopic surgery was performed in 17 patients (mean age, 37 years; range, 4 months-78 years) and stereotactic biopsy in 55 patients (mean age, 63 years; range, 23-80 years), including two patients who underwent both procedures. RESULTS: Hydrocephalus was present in 13/17 patients in the endoscopic group (77%) and in 11/55 patients in the stereotactic group (20%). Diagnosis was achieved in all patients in the endoscopic group and in all but one patient in the stereotactic group, in whom histological diagnosis was obtained by endoscopic biopsy during a second operation. In the endoscopic group, additional procedures performed included ventriculostomy (2/17), cyst fenestration (3/17), endoscopic shunt revision (3/17) and placement of Rickham reservoirs or external cerebrospinal fluid drains (6/17). Adverse events occurred in one patient after endoscopy (chronic subdural hematoma) and in two patients after stereotactic surgery (one mild hemiparesis and one transitory paresis of the contralateral leg). CONCLUSIONS: Endoscopic and stereotactic surgery have distinct advantages and disadvantages in approaching periventricular lesions. The advantages of endoscopy encompass the possibility to perform additional surgical procedures during the same session (e.g. tumour reduction, third ventriculostomy, fenestration of a cyst). The visual control reduces the hazard of injury to anatomical structures and allows for a better control of bleeding although there is a considerable blind-out in such situations. The advantages of stereotactic surgery include a smaller approach and precise planning of the trajectory. It is usually performed under local anaesthesia. Both methods provide a safe and efficient therapeutic option in periventricular lesions with low surgical-related morbidity. PMID- 21243380 TI - Complete nucleotide sequence and genome organisation of grapevine Bulgarian latent virus. AB - The complete genome sequence of grapevine Bulgarian latent virus (GBLV) has been determined. RNA-1 (7,452 nt in length) contains a single ORF of 6,285 nt, encoding a polyprotein with conserved motifs characteristic of the viral protease cofactor (Prot-cofact), the NTP-binding protein (NTP), the cysteine-like protease (Cyst-Prot) and the RNA-dependent RNA polymerase (RdRp) of members of the order Picornavirales and show high aa sequence identity with blackcurrant reversion virus (BRV, 64%). RNA-2 (5,821 nt) contains a single ORF of 4,500 nt, encoding a polyprotein in which the conserved motifs of the movement protein (MP) and coat protein (CP) have been identified. The GBLV CP aa sequence shows highest homology with that of blueberry leaf mottle virus (BLMoV, 68%). Both RNAs have a poly(A) tail and a NCR at the 3' and 5' termini, respectively. The results of this study confirm the classification of GBLV as a member of a distinct species in subgroup C of the genus Nepovirus. PMID- 21243381 TI - Oxidative stress and cytotoxicity generated by dental composites in human pulp cells. AB - Dental composites are a source of residual monomers that are released into the oral environment. Since monomers act on cultured cells through reactive oxygen species (ROS), we hypothesized that composites generate ROS associated with cytotoxicity. Human pulp-derived cells were exposed to extracts of methacrylate based materials including triethylene glycol dimethacrylate and 2-hydroxyethyl methacrylate-free composites (Tetric Ceram, Tetric EvoCeram, els, els flow, Solitaire 2) and a silorane-based composite (Hermes III). The materials were polymerized in the presence and absence of a polyester film and then extracted in culture medium. The generation of ROS was measured by flow cytometry, and cytotoxicity was determined as well. Methacrylate-based composites reduced cell survival but varied in efficiency. Undiluted extracts of Solitaire 2 specimens prepared in the absence of a polyester film reduced cell survival to 26% compared with untreated cultures. Cytotoxicity was reduced when specimens were covered with a polyester film during preparation. Cytotoxicity of the composites was ranked as follows: Solitaire 2 >> els flow > Tetric Ceram = Tetric EvoCeram = els > Hermes III. The generation of ROS followed the same pattern as detected with cytotoxic effects. A positive correlation was found between ROS production and cell survival caused by extracts made from materials not covered with a polyester film. These findings suggest that components released from composites affect cellular signaling networks through ROS formation. Regenerative and reparative capacities of the dentine-pulp complex may be impaired by biologically active resin monomers released from composite restorations. PMID- 21243382 TI - Time-related hemolysis in stored shed mediastinal blood after cardiopulmonary bypass. AB - Reinfusion of mediastinal shed blood during cardiopulmonary bypass reportedly reduces the need for homologous blood transfusion. Although the fragility of blood components is thought to be amplified by shear stress during cardiopulmonary bypass and processing, the time-related deterioration of red blood cells (RBCs) in stored shed blood has not been studied extensively. In this study, we examined time-related hemolysis in shed blood stored at different temperatures. We examined processed shed blood collected from 15 patients (11 men and 4 women; mean age +/- standard deviation, 71 +/- 9 years) during cardiopulmonary bypass. The shed blood was collected and stored at 20 degrees C (group A) or 4 degrees C (group B). Stored blood collected by venipuncture at the end of the surgery was used as a control. Damage was assessed by measuring its free hemoglobin (Hb) levels, using a photometric assay. The free Hb levels in blood samples from each group were tested at 0, 3, 6, 12, 24, 36, and 48 h after surgery. The free Hb levels (g/dl) at 0, 12, and 24 h were 0.03 +/- 0.01, 0.05 +/ 0.02*, and 0.06 +/- 0.02* in group A; 0.03 +/- 0.02, 0.04 +/- 0.03, and 0.05 +/- 0.02* in group B; and 0.01 +/- 0.01, 0.01 +/- 0.01, and 0.01 +/- 0.01 in the control group (*p < 0.05 vs. 0 h after surgery). The free Hb levels in stored shed blood significantly increased after 12 h in group A (20 degrees C) and increased after 24 h in group B (4 degrees C), whereas in drawn blood, they did not significantly increase over the first 24 h. Compared to storage at 20 degrees C, storage at 4 degrees C suppresses the increase in the free Hb levels. PMID- 21243383 TI - A novel counterpulse drive mode of continuous-flow left ventricular assist devices can minimize intracircuit backward flow during pump weaning. AB - Recent developments in adjunct therapeutic options for end-stage heart failure have enabled us to remove implanted left ventricular assist devices (LVADs) from more patients than before. However, a safe and proper protocol for pump-off trials is yet to be established, because diastolic backward flow in a pump circuit turns up when it is driven at low-flow conditions. We have developed a novel drive mode of centrifugal pumps that can change its rotational speed in synchronization with the cardiac cycle of the native heart. The purpose of this study was to test-drive this novel system of a centrifugal pump in a mock circulation and to evaluate the effect of the counterpulse mode, which increases pump speed just in diastole, on the amount of this nonphysiological intracircuit retrograde flow. A rotary pump (EVAHEART, Sun Medical Technology Research Corporation) was connected to the mock circulation by left ventricular uptake and ascending aortic return. We drove it in the following four conditions: (A) continuous mode at 1500 rpm, (B) counterpulse mode (systolic 1500 rpm, diastolic 2500 rpm), (C) continuous mode at 2000 rpm, and (D) counterpulse mode (systolic 2000 rpm, diastolic 2500 rpm). Data concerning the rotation speed, pump flow, left ventricular pressure, aortic pressure, and pressure head (i.e., aortic pressure-left ventricular pressure) in each condition were collected. After data collection, we analyzed pump flow, and calculated its forward and backward flow. Counterpulse mode decreased the amounts of pump backward flow compared with the continuous mode [mean backward flow, -4, -1, -0.5, 0 l/min, in (A), (B), (C), and (D) conditions, respectively]. The actual amounts of mean backward flow can be different from those in clinical situations; however, this novel drive mode for rotary pumps can relatively decrease pump backward flow during pump weaning and can be beneficial for safe and proper pump-off trials. Further investigations in in vivo settings are currently ongoing. PMID- 21243384 TI - What is the ideal off-test trial for continuous-flow ventricular-assist-device explantation? Intracircuit back-flow analysis in a mock circulation model. AB - Bridge to recovery has become a major goal after left-ventricular-assist-device (LVAD) implantation thanks to recent development in adjunctive therapies. Precise assessment of native heart function under minimum LVAD support is the key for successful LVAD explantation. However, weaning of centrifugal LVADs normally generates diastolic intracircuit backward flow. This retrograde flow may become excessive load for the native heart during off-pump test. The flow itself is an inevitable characteristic of centrifugal pumps. Therefore, evaluating this retrograde flow in vitro is of considerable significance, even if its amount is different from that in clinical settings. The purpose of this study was to assess diastolic backflow of continuous-flow centrifugal LVADs in a mock circulation model. A centrifugal LVAD (EVAHEART, Sun Medical Technology) was installed in a mock circulation model by the left ventricle uptake and the ascending aortic return. Pump flow was measured at the pump rotational speed of 1000, 1500, 2000, and 2500 rpm, and pulse rate of the virtual native heart was varied to 60, 90, and 120 beats/min. After data collection, pump flow was integrated, and forward and backward intracircuit flow were calculated. As a result, nonphysiological reverse flow of approximately 2.0 L/min exists at the rotational speed, providing 0 L/min mean pump flow. An ideal off-test trial condition should be realizing both +/- 0 L/min pump flow and no intracircuit backward flow at the same time. We are developing a novel EVAHEART drive mode that can change its rotational speed in synchronization with cardiac cycle with the aim of controlling this retrograde flow with the new drive mode and creating an ideal off-test condition. PMID- 21243385 TI - Vitamin D and autoimmune rheumatic diseases. PMID- 21243386 TI - Hemiarthroplasty in a patient with severe systemic sclerosis. AB - Systemic sclerosis (scleroderma) is a connective tissue disorder of unknown etiology. This rare, chronic, multisystem disorder encompasses a number of variations leading to focal and systemic classifications, which includes features such as skin thickening. The changes within the skin microstructure have led to numerous surgical complications. In a review of the orthopedic literature, we found no reports describing surgical outcomes or the success of skin closures in procedures related to the hip for patients with scleroderma. We present a case of a 74-year-old man with a history of scleroderma who underwent a bipolar hemiarthroplasty to repair a right transcervical femoral neck fracture. The risk factors associated with wound healing and effects of skin contractures in systemic sclerosis patients are reviewed. PMID- 21243387 TI - Tennis leg--a new variant of an old syndrome. AB - This syndrome, while common, is not well recognised in the rheumatology literature. We describe two cases, one classical and one unusual with ultrasound illustrations. The literature, from the original description in 1883, is reviewed with a focus on both the clinical and anatomical variants. PMID- 21243389 TI - Relapsing polychondritis and familial Mediterranean fever--an association. AB - Relapsing polychondritis (RP) and familial Mediterranean fever (FMF) are systemic inflammatory disorders with seemingly distinct genetic and pathophysiologic mechanisms. An association between these disorders has been described based on a single case report with few clinical details available. We recently encountered a patient with biopsy-proven RP and genetically confirmed FMF. Following identification of this individual, we conducted a retrospective review of all cases of RP in our institution from 2000-2009 and identified one additional patient with RP who is also a genetic heterozygote for FMF. These cases highlight the previously reported but sparsely documented relationship between these seemingly separate disorders. PMID- 21243388 TI - Demographic, clinical, and serological features of Turkish patients with rheumatoid arthritis: evaluation of 165 patients. AB - The study was designed to describe demographic, clinical, serological, and radiological characteristics of patients with rheumatoid arthritis (RA) followed up by a single institution. One hundred sixty-five patients, diagnosed as RA using ACR classification criteria, and followed-up in the rheumatology clinic between December 2005 and January 2010, were enrolled in the study. Of the patients, 125 were female, and 40 were male. Mean age of the patients was 52.5 years, and mean duration of the disease was 10.5 years. The most frequently involved joints were the wrist (95.2%), MCP (90.9%), and the PIP (92.6%). The knee and hip joint involvement rates were 44.8% and 23.6%, respectively. Patients (50.9%) were detected to have tenosynovitis. Involvement of the elbow joint was shown in 10.9% of the patients. The most common extra-articular manifestations were sicca symptom (40.6%) and carpal tunnel syndrome (35.7%), followed by pulmonary involvement (6.6%), vasculitis (3.6%), and Raynaud's phenomenon (1.2%). Rheumatoid nodules were detected in six patients (3.6%). One patient had Felty syndrome, and another patient had secondary amyloidosis. Patients (90.3%) had positive rheumatoid factor (RF), and 124 patients had positive anti-CCP antibody (75.2%). A more severe clinical course and a higher incidence of erosion, tenosynovitis, and deformities were detected in patients with anti-CCP antibody and positive RF (p = 0.03, p = 0.04, p = 0.01, p = 0.04, respectively). The wrist was the most frequently involved joint in our patients, and the most frequently seen extra-articular manifestation was sicca symptom. Presence of RF and anti-CCP antibody was associated with more severe disease including erosive and destructive arthropathy. Extra-articular involvement and presence of accompanying diseases increase the mortality. PMID- 21243390 TI - Needs and preferences regarding health care delivery as perceived by patients with systemic sclerosis. AB - This study aims to examine the needs and preferences regarding the delivery of health care services and information provision and their determinants in patients with systemic sclerosis (SSc). A questionnaire was sent to 77 SSc outpatients, comprising 27 items on health care needs within the domains physical, psychological, social support, employment/daily activities, or other health problems and 13 items on information needs. Moreover, the patients' preferences regarding the provision of health care services and information were listed. Additional assessments included sociodemographic characteristics, physical functioning (SSc Health Assessment Questionnaire), and quality of life (SF-36). Sixty-four patients (83%) returned the questionnaire. Twenty-six patients (41%) reported one or more unmet health care needs, with the highest proportions of patients with unmet needs seen in the physical (28%) and psychological (20%) domain. The highest percentages of patients with information needs were observed for medical subjects (20-28%). A lower mental component summary scale score and younger age were associated with the presence of at least one health care need in the psychological domain. Worse physical functioning, a diagnosis of diffuse SSc and having a partner were associated with higher information need score. A yearly, standardized multidisciplinary assessment program was most frequently mentioned as a preferred, but not yet existing health care model (59%) and the rheumatologist as a preferred source of information supply (75%). Unmet health care and information needs are common among SSc patients. To improve SSc health care, more attention should be paid to health care services for specific physical and psychological problems and medical information supply by the rheumatologist. In addition, the development of new models of care, such as a yearly, standardized multidisciplinary diagnostic program seems warranted. PMID- 21243391 TI - An autolytic process for recovery of antioxidant activity rich carotenoprotein from shrimp heads. AB - Studies were carried out to utilize in situ proteases of shrimp heads to recover carotenoproteins possessing antioxidant activity. Highest protease activity of the buffer extract was found at pH 8.0 (9.85 +/- 0.61 units). The protease activity increased with temperature up to 50 degrees C and reduced thereafter with highest activity being 19.32 +/- 2.0 units. Thus, the autolysis of shrimp heads for recovery of carotenoprotein was carried out at pH 8.0 and at 50 degrees C. Waste to buffer ratio had a significant (p < 0.05) effect on recovery of carotenoids in carotenoprotein filtrate with a maximum of 58.5 +/- 6.4% recovery with a waste to buffer ratio of 1:2.5 (w:v). The carotenoid recovery increased significantly to 63.4% +/- 3.6% at the end of a 4-h autolysis. The studies on combined effect of waste to buffer ratio and autolysis time indicated increase in protein recovery with increase in waste to buffer ratio but not with autolysis time. DPPH scavenging activity of the carotenoprotein isolate increased with autolysis time up to 100 min, and thereafter, reduced above 160 min of autolysis time. With increase in waste to buffer ratio, the scavenging activity increased, reaching more than 12.5 mg TBHQ equivalent/mg protein at waste to buffer ratio of 1:5. The optimum autolysis condition for obtaining antioxidant activity rich carotenoprotein from shrimp heads was found to be waste to buffer (pH 8.0) ratio of 1:5 and an autolysis time of 2 h at 50 degrees C. The isolated carotenoprotein was found to have antioxidant activity with respect to singlet oxygen quenching, reducing power and metal chelating activity. PMID- 21243392 TI - Transient leukoencephalopathy after intrathecal methotrexate mimicking stroke. AB - Methotrexate (MTX) is an indispensable antimetabolite for the treatment of oncological and immunological disorders in all age groups. It can be administrated intravenously as well as intrathecally and may be used alone or in combination with other drugs. Chronic leukoencephalopathy is a well-known side effect of MTX, especially in conjunction with intrathecal administration. However, acute neurotoxicity with confusion, disorientation, seizures, and focal deficits may also be seen. This can clinically mimic stroke with restricted diffusion on MRI. However, unlike stroke, there is resolution of clinical and imaging findings within 1-4 weeks. We report two cases of transient leukoencephalopathy following intrathecal methotrexate, with complete clinical and radiological resolutions on follow-up. PMID- 21243393 TI - Weekly administration of temsirolimus for heavily pretreated patients with clear cell carcinoma of the ovary: a report of six cases. AB - Clear cell carcinoma (CCC) of the ovary is well-known to be chemotherapy resistant compared with other histologic subtypes. An inhibitor against the mammalian target of rapamycin, temsirolimus (TEM) has been reported to be effective in renal CCC. Therefore, we investigated the effects of TEM in patients with CCC of the ovary. Six patients with CCC of the ovary who had been heavily pretreated by more than 4 regimens were given TEM: the cycle consisted of weekly TEM (10 mg/m(2)) for 3 weeks followed by 1 week off. The treatment was continued until development of either progressive disease, or unmanageable adverse effects. Response evaluation was based upon the Response Evaluation Criteria in Solid Tumors version 1.0. Adverse effects were analyzed according to Common Terminology Criteria for Adverse Events version 3.0. The median cycle of weekly TEM was 3 (range 2-14). Among five cases in which responses could be evaluated, partial response was observed in one case (20%) and stabilized disease was seen in another case (20%). There were no toxicities greater than grade 3, and no case developed severe toxicity requiring discontinuation of weekly TEM. The patient who showed a partial response obtained a progression-free period of 14 months. In conclusion, weekly TEM shows a potential therapeutic benefit for patients with CCC of the ovary. Further studies including a translational approach are needed to select candidates for whom TEM therapy would be beneficial. PMID- 21243394 TI - Splenomegaly in FOLFOX-naive stage IV or recurrent colorectal cancer patients due to chemotherapy-associated hepatotoxicity can be predicted by the aspartate aminotransferase to platelet ratio before chemotherapy. AB - BACKGROUND: Chemotherapy-associated hepatotoxicity is a common cause of postoperative complications after major hepatectomy. Splenomegaly may indicate portal hypertension due to chemotherapy. To identify chemotherapy-naive patients with liver damage, the splenic volume (SV) and aspartate aminotransferase to platelet ratio (APR) were investigated. METHODS: Seventy-one patients receiving FOLFIRI, FOLFOX, or FOLFOX plus bevacizumab as first-line chemotherapy were included in this study. The SV measurement was performed by helical computed tomography volumetry, and the SV index (SVI) was calculated during 6 cycles of chemotherapy. The APR was used as an indicator of liver injury and the APR index (APRI) was calculated. RESULTS: The SVI and APRI were significantly higher in the FOLFOX group than in the FOLFIRI group. In the FOLFOX group, the maximum APR during FOLFOX administration was significantly higher in the subjects with SVI >= +30% than in those with SVI < +30% (p < 0.01). The incidences of grade 3 or 4 adverse events and grade 2 or greater histopathological sinusoidal injury were significantly higher in the SVI >= +30% than in the SVI < +30% group. Interestingly, the SVI was significantly higher in the group with APR >= 0.17 before FOLFOX than in the subjects with an APR < 0.17 before FOLFOX (p < 0.05). CONCLUSION: Splenomegaly due to FOLFOX-associated hepatotoxicity can be predicted if the APR before FOLFOX is 0.17 or higher. PMID- 21243395 TI - High-dose dexamethasone plus antihistamine prevents colorectal cancer patients treated with modified FOLFOX6 from hypersensitivity reactions induced by oxaliplatin. AB - BACKGROUND: Oxaliplatin is a third-generation platinum compound and a key agent for the management of colorectal cancer. Patients treated with oxaliplatin are at risk for hypersensitivity reactions. We designed a modified premedication regimen to prevent oxaliplatin-related hypersensitivity reactions and assessed if this approach is effective. METHODS: A retrospective cohort study of patients with advanced colorectal cancer who received modified FOLFOX6 (mFOLFOX6) was performed. Patients received routine premedication with dexamethasone 8 mg and granisetron 3 mg for the first five cycles of mFOLFOX6. From the sixth cycle onward, cohort 1 received the same premedication, and cohort 2 received modified premedication (diphenhydramine 50 mg orally, followed by dexamethasone 20 mg, granisetron 3 mg, and famotidine 20 mg). We compared the incidence of hypersensitivity reactions, duration of treatment, and reasons for treatment withdrawal between the two cohorts. RESULTS: A total of 181 patients were studied (cohort 1, 81; cohort 2, 100). Hypersensitivity reactions developed in 16 patients (20%) in cohort 1 and 7 (7.0%) in cohort 2 (P = 0.0153). The median number of cycles increased from 9 in cohort 1 to 12 in cohort 2. Apart from progressive disease, neurotoxicity was the reason for discontinuing treatment in 20% of the patients in cohort 1, as compared with 53% in cohort 2. CONCLUSION: Increased doses of dexamethasone and antihistamine significantly reduced oxaliplatin-related hypersensitivity reactions. This effective approach should be considered for all patients who receive FOLFOX, allowing treatment to be completed as planned. PMID- 21243396 TI - A case with fistula formation between a perinephric retroperitoneal abscess and the duodenum: successful outcome after conservative management. AB - A 67-year-old woman diagnosed with pyonephrosis and perinephric abscess because of an impacted urinary stone in the pelvicoureteric junction was admitted to the hospital with a high-grade fever. Although construction of a right nephrostomy for drainage of the abscess improved her general condition, she had a fever again 2 weeks after the initial treatment. Computed tomography revealed a persistent perinephric retroperitoneal abscess and a second drainage procedure was performed. Then, imaging examination revealed fistula formation between the cavity of the perinephric retroperitoneal abscess and the duodenum. The patient received conservative management including percutaneous drainage, discontinuation of oral intake, and antimicrobial chemotherapy. Three days after the second drainage and discontinuation of oral intake, imaging examination revealed complete closure of the fistula. Fistula formation between a perinephric abscess and the duodenum is very rare but a favorable outcome was obtained by our conservative management. PMID- 21243397 TI - Organizing pneumonia pattern in the follow-up CT of Legionella-infected patients. AB - The main aim of this study was to describe the appearance of the CT pattern of organizing pneumonia in Legionella-infected patients. Serial CT scans obtained from five sporadic cases of Legionella pneumophila pneumonia were retrospectively reviewed. The mean time of follow-up was 14 days. Chest CT was analyzed with regard to frequency and appearance of CT patterns of pulmonary abnormalities. Consolidation and ground-glass opacities, with or without an air bronchogram, were the most common abnormalities detected in CT scans during follow-up patients with L. pneumophila pneumonia. Two patterns were observed: subpleural and peribronchovascular. The subpleural pattern was seen in four patients and the peribronchovascular pattern in one. Interlobular septal thickening was seen in one patient. Pleural effusion was seen in one patient. The CT pattern of organizing pneumonia, a subpleural pattern, was frequently observed after treatment of L. pneumophila pneumonia. PMID- 21243398 TI - Development of new antituberculous drugs based on bacterial virulence factors interfering with host cytokine networks. AB - The worldwide increase in the prevalence of tuberculosis (TB), especially multidrug-resistant TB and extensively drug-resistant TB, is an important global health concern, and new effective drugs are urgently needed. Information on the genome of Mycobacterium tuberculosis (MTB) and various mycobacterial virulence genes is leading to the identification of genes that code for new drug targets. Mycobacterium tuberculosis (MTB) is resistant to the antimicrobial mechanisms of host macrophages and can survive and replicate in macrophages for long periods, resulting in a persistent infection. Mycobacterial virulence factors suppress macrophage bactericidal functions partly via their downregulatory effects on the host antimicrobial cytokine networks, consisting of proinflammatory, immunopotentiating, and Th1-inducing cytokines. Thus, for the development of unique drugs that exhibit antimycobacterial action through novel mechanisms, it is reasonable to search for targets among bacterial genes encoding virulence factors which interfere with the host cytokine responses protective to mycobacterial pathogens. In this review, we discuss the profiles of cytokine networks related to host resistance to mycobacteria, including the mechanisms of downregulation of host antimycobacterial immunity due to immunosuppressive cytokines, which are occasionally induced in the advanced stages of TB. We also highlight the development of antituberculous drugs based on bacterial virulence factors interfering with the host antimycobacterial cytokine network. PMID- 21243399 TI - A case of IgG4-related disease with features of Mikulicz's disease, and retroperitoneal fibrosis and lymphadenopathy mimicking Castleman's disease. AB - A 51-year-old man developed painless enlargement of the bilateral submandibular and lacrimal glands without xerostomia or xerophthalmia in the absence of autoantibodies to SS-A (Ro) and SS-B (La). In a few years, he developed generalized lymphadenopathy, with markedly elevated serum IgG4, and a computed tomography scan revealed soft-tissue-density lesions around the abdominal aorta, a finding consistent with retroperitoneal fibrosis. Biopsy of the cervical lymph node showed an expansion of the interfollicular area by heavily infiltrating plasma cells, consistent with multicentric Castleman's disease. Immunohistochemical analysis revealed that the IgG4-positive/IgG-positive plasma cell ratio was 80%, leading us to a single diagnosis of IgG4-related disease. High-dose corticosteroid treatment resulted in prompt resolution of the physical, serological, and imaging abnormalities. Although IgG4-related disease can mimic multicentric Castleman's disease, as in our patient, the two diseases have effective but distinct treatments, and thus measurement of serum IgG4 levels and specific immunohistochemical analysis for determining the IgG4-positive/IgG positive plasma cell ratio are recommended if IgG4-related disease is suspected. PMID- 21243400 TI - Infliximab and brucellosis: not the usual suspects, this time. AB - Tumor necrosis factor (TNF) plays an important role in the host defense mechanism, and anti-TNF antibody therapies may increase the risk of serious infections. We herein report a case of 57-year-old male with rheumatoid arthritis who developed brucellosis during treatment with infliximab in combination with methotrexate and a low-dose steroid. Brucellosis should be kept in mind, particularly in endemic areas, in patients receiving anti-TNF therapy. Clinicians should be aware of brucellosis symptoms and ways of contamination and should warn their patients. Early diagnosis and rapid treatment may prevent a possible poor course of the disease in immunocompromised patients. PMID- 21243401 TI - T2-T4 sympathectomy versus T3-T4 sympathicotomy for palmar and axillary hyperhidrosis. AB - OBJECTIVE: To evaluate and compare the immediate and long-term outcomes of videothoracoscopic T2-T4 sympathectomy and T3-T4 sympathicotomy for the treatment of palmar and axillary hyperhidrosis. METHODS: Between October 1993 and September 2007, we treated a total of 88 patients affected by palmar and axillary hyperhidrosis. Twenty-four patients underwent T2-T4 sympathectomy with 5-10 mm trocars (Group A), 43 T2-T4 sympathectomy with 2-5 mm trocars (Group B), 15 T3-T4 sympathicotomy with 5-10 mm trocars and 6 T3-T4 ganglion block with 2-5 mm trocars (Group C). The mean operative time, for each side, was 15 min for sympathicotomy and 28 min for sympathectomy. In September 2008, we recontacted 98% of patients (total 86), by telephone, to establish long-term results (follow up range 1-15 years). RESULTS: In this series, we did not find any significant difference between T2-T4 sympathectomy and T3-T4 sympathicotomy in terms of postsurgical palmar anhidrosis or onset of compensatory hyperhidrosis, while both methods show high efficacy for remission of palmar hyperhidrosis. The slightly higher recurrence rate in our early experience (Group A) can be attributed to the learning curve. Using smaller trocars (2-5 mm), we reduced postsurgical intercostal pain and obtained better aesthetic results and a higher grade of patient's satisfaction. INTERPRETATION: Thoracoscopic approach to hyperhidrosis has evolved in the last few decades with a consequent decrease in side effects. In this series, all patients experienced an improvement in quality of life even in case of recurrence or onset of compensatory hyperhidrosis. Due to these results, the shorter operative time and easier performance of sympathicotomy, we prefer this method. PMID- 21243402 TI - Synthesis and cytotoxic activities of some 2-arylnaphtho[2,3-d]oxazole-4,9-dione derivatives on androgen-dependent (LNCaP) and androgen-independent (PC3) human prostate cancer cell lines. AB - The synthesis of five 2-arylnaphtho[2,3-d]oxazole-4,9-dione derivatives was accomplished by refluxing 2-amino-3-bromo-1,4-naphthoquinone with appropriate benzoyl chloride analogs at elevated temperatures. In vitro anticancer evaluation of these compounds was performed on androgen-dependent, LNCaP, and androgen independent, PC3, human prostate cancer cell lines. In general, these compounds displayed slightly stronger cytotoxicity on the androgen-dependent LNCaP than on the androgen-independent PC3 prostate cancer cell lines. The meta-substituted 2 (3-Chloro-phenyl)-naphtho[2,3-d]oxazole-4,9-dione (10) appear to display the best cytotoxicity on both cell lines with an IC(50) of 0.03 MUM on LNCaP and 0.08 MUM on PC3 after 5 days of exposure. PMID- 21243403 TI - The relationship between stimulus intensity and response amplitude for the photopic negative response of the flash electroretinogram. AB - The aim of this study was to investigate the relationship between stimulus intensity and response amplitude for the photopic negative response (PhNR) of the flash ERG. Specific aims were (i) to determine whether a generalized Naka-Rushton function provided a good fit to the intensity-response data and (ii) to determine the variability of the parameters of the best-fitting Naka-Rushton models. Electroretinograms were recorded in 18 participants, on two occasions, using both DTL fibre and skin active electrodes, in response to Ganzfeld red stimuli (Lee filter "terry red") ranging in stimulus strength from -1.30 to 0.53 log cd.s.m( 2) (0.28-2.11 log phot td.s) presented over a steady blue background (Schott glass filter BG28; 3.9 log scot td). PhNR amplitude was measured from b-wave peak and from pre-stimulus baseline. The Naka-Rushton function was fitted to all intensity-response data, and parameters, 'n', 'Vmax' and 'K' were obtained. Coefficients of variation (CoV), and inter-ocular and inter-session limits of agreement (LoA) were calculated for both Naka-Rushton parameters. A generalized Naka-Rushton function was found to provide a good fit to the intensity-response data, except at the highest stimulus intensity, where a reduction in amplitude occurred in many individuals. The 'Vmax' parameter was less variable than 'K' for all intensity-response data. Variability was lower for DTL than skin electrodes, and for peak-to-trough PhNR measurements, compared to baseline-to-trough. This study has demonstrated for the first time that the Naka-Rushton model provides a useful means of quantifying the intensity-response relationship of the PhNR. PMID- 21243404 TI - Interactive effect of arsenic and fluoride on cardio-respiratory disorders in male rats: possible role of reactive oxygen species. AB - Epidemiological evidence demonstrates positive correlation between environmental and occupational arsenic or fluoride exposure and risk to various cardio respiratory disorders. Arsenic-exposure has been associated with atherosclerosis, hypertension, cerebrovascular diseases, ischemic heart disease, and peripheral vascular disorders, whereas Fluoride-exposure manifests cardiac irregularities and low blood pressure (BP). Present study aims to study the combined effects of these toxicants on various cardio-respiratory variables in male rats. Single intravenous (i.v.) dose of arsenic (1, 5, 10 mg/kg) or fluoride (5, 10, 20, 36.5 mg/kg) either alone or in combination were administered. Individual exposure to arsenic or fluoride led to a significant depletion of mean arterial pressure, heart rate (HR), respiration rate and neuromuscular (NM) transmission in a dose dependent manner. These changes were accompanied by increased levels of blood reactive oxygen species (ROS) and decreased glutathione (GSH) concentrations. An increase in the blood acetyl cholinesterase (AChE) activity was observed in both arsenic or fluoride exposed rats. These changes were significantly more pronounced in arsenic-exposed animals than in fluoride. During combined exposure to arsenic (5 mg/kg) + fluoride (20 mg/kg) or arsenic (10 mg/kg) + fluoride (36.5 mg/kg) the toxic effects were more pronounced compared to individual toxicities of arsenic or fluoride alone. However, combined exposure to arsenic (5 mg/kg) + fluoride (36.5 mg/kg) resulted in antagonistic effects on variables suggestive of altered cardio-respiratory function and oxidative stress. The results from the present study suggest that arsenic or fluoride individually demonstrate cardio respiratory failure at all doses whereas during combination exposure these toxins show variable toxicities; both synergistic and antagonistic effects depending upon the dose. Moreover, it may be concluded that arsenic and/or fluoride cardio respiratory toxicity may be mediated via oxidative stress. However, these results are new in the discipline thus requires further exploration. PMID- 21243405 TI - Reductive dechlorination of tetrachloroethene by a stepwise catalysis of different organohalide respiring bacteria and reductive dehalogenases. AB - The enrichment culture SL2 dechlorinating tetrachloroethene (PCE) to ethene with strong trichloroethene (TCE) accumulation prior to cis-1,2-dichloroethene (cis DCE) formation was analyzed for the presence of organohalide respiring bacteria and reductive dehalogenase genes (rdhA). Sulfurospirillum-affiliated bacteria were identified to be involved in PCE dechlorination to cis-DCE whereas "Dehalococcoides"-affiliated bacteria mainly dechlorinated cis-DCE to ethene. Two rdhA genes highly similar to tetrachloroethene reductive dehalogenase genes (pceA) of S. multivorans and S. halorespirans were present as well as an rdhA gene very similar to the trichloroethene reductive dehalogenase gene (tceA) of "Dehalococcoides ethenogenes" strain 195. A single strand conformation polymorphism (SSCP) method was developed allowing the simultaneous detection of the three rdhA genes and the estimation of their abundance. SSCP analysis of different SL2 cultures showed that one pceA gene was expressed during PCE dechlorination whereas the second was expressed during TCE dechlorination. The tceA gene was involved in cis-DCE dechlorination to ethene. Analysis of the internal transcribed spacer region between the 16S and 23S rRNA genes revealed two distinct sequences originating from Sulfurospirillum suggesting that two Sulfurospirillum populations were present in SL2. Whether each Sulfurospirillum population was catalyzing a different dechlorination step could however not be elucidated. PMID- 21243406 TI - A proteomic investigation into adriamycin chemo-resistance of human leukemia K562 cells. AB - This study aimed to explore the mechanism of adriamycin resistance in human chronic myelogenous leukemia cells. Proteomic approach was utilized to compare and identify differentially expressed proteins between human chronic myelogenous leukemia K562 cells and their adriamycin-resistant counterparts. The differentially expressed proteins were analyzed by 2-DE (two-dimensional gel electrophoresis), and protein identification were performed on ESI-Q-TOF MS/MS instrument. Out of the 35 differentially expressed proteins between the two cell lines, 29 were identified and grouped into 10 functional classes. Most of identified proteins were related to the categories of metabolism (24%), proteolysis (13%), signal transduction (21%) and calcium ion binding (6%), suggesting that alterations of those biological processes might be involved in adriamycin resistance of K562 cells. We believe this study may provide some clues to a better understanding of the molecular mechanisms underlying adriamycin resistance. PMID- 21243407 TI - Synergy between fipronil and amitraz in a Rhipicephalus sanguineus tick residual contact test. AB - Amitraz, a formamidine acaricide, has been reported to act as a synergist of contact insecticides and acaricides in both agriculture and animal health. A laboratory contact test was therefore conducted to determine whether amitraz at 12.5 ppm could improve the contact potency of fipronil on ticks. A controlled glass vial bioassay was used to assess the efficacy of fipronil alone, amitraz alone, and fipronil plus amitraz on unfed adult Rhipicephalus sanguineus. Assessments of lethality were made at 6, 24, and 48 h after the introduction of the ticks to the vials. No significant mortality was observed in the control treatment or in the amitraz alone treatment. Concentration and time dependent mortality rates were observed in ticks exposed to fipronil alone or fipronil plus amitraz, with higher mortality observed in the latter group. Results from this study gave synergistic EC50 ratios between fipronil alone and fipronil plus amitraz of >7.3, 137 and 97 at 6, 24, and 48 h, respectively. A similar response was seen at the EC90 level. These results indicate that fipronil was synergized by amitraz in this adult tick residual contact study. The addition of amitraz to fipronil also provided a significant improvement in the speed of kill. PMID- 21243408 TI - The absolute configuration of the sex pheromone of the citrophilous mealybug, Pseudococcus calceolariae. AB - The absolute configuration of the sex pheromone of the citrophilous mealybug, Pseudococcus calceolariae, was determined to be (1R,3R)-[2,2-dimethyl-3-(2 methylprop-1-enyl)cyclopropyl]methyl (R)-2-acetoxy-3-methylbutanoate. NMR, derivatization reactions, chiral gas chromatography-mass spectrometry, and comparison with synthetic chiral reference compounds, were used to determine the absolute configuration of this compound. This activity of this compound was further confirmed by testing synthetic stereoisomers of the compound as lures in traps for adult male mealybugs. Traps baited with 1,000 MUg of the pheromone compound caught 36 times more males than traps baited with virgin females. A mixture of stereoisomers of the pheromone compound can be used for field trapping without adverse effects on trap catch. A comparison with the structures of other sex pheromones of mealybugs is presented. PMID- 21243409 TI - Progressive visualization of losslessly compressed DICOM files over the Internet. AB - Presented in this paper is a method for progressive transfer and visualization of losslessly compressed DICOM files. The files from the same study are considered as a volumetric object, which is progressively compressed using a quadtree-based method. The textual information of the DICOM file is compressed using a predicting scheme. Decompression and visualization are implemented with Java applet technology. Users can display and interact with the object even during the data transfer. Tests have shown that an object can be recognized up to 70% faster than with the classical approaches. PMID- 21243410 TI - TAP.NET: a windows messaging service for nursing staff. AB - Nurses are the foundation of any healthcare system. It is essential to alert nurses on time so that they can offer care and comfort without any delay. Pager messages (short messages) represent an important part of the overall hospital communication network. These short messages are sent through data paging systems to direct nurses to patients. Telocator Alphanumeric Protocol (TAP) is used for submitting short messages to these data paging systems. In this paper, a windows messaging service (TAP.NET) is designed to connect to a data paging system using the TAP protocol. A Web application is also proposed that uses remote technology to transmit page requests to this messaging service. With this overall design, pager messages can be sent from any computer that has an Internet connection on the hospital network. A logging scheme is also introduced to assess the performance of the TAP.NET. PMID- 21243411 TI - Symptomatic vs. asymptomatic plaque classification in carotid ultrasound. AB - Quantitative characterization of carotid atherosclerosis and classification into symptomatic or asymptomatic type is crucial in both diagnosis and treatment planning. This paper describes a computer-aided diagnosis (CAD) system which analyzes ultrasound images and classifies them into symptomatic and asymptomatic based on the textural features. The proposed CAD system consists of three modules. The first module is preprocessing, which conditions the images for the subsequent feature extraction. The feature extraction stage uses image texture analysis to calculate Standard deviation, Entropy, Symmetry, and Run Percentage. Finally, classification is performed using AdaBoost and Support Vector Machine for automated decision making. For Adaboost, we compared the performance of five distinct configurations (Least Squares, Maximum- Likelihood, Normal Density Discriminant Function, Pocket, and Stumps) of this algorithm. For Support Vector Machine, we compared the performance using five different configurations (linear kernel, polynomial kernel configurations of different orders and radial basis function kernels). SVM with radial basis function kernel for support vector machine presented the best classification result: classification accuracy of 82.4%, sensitivity of 82.9%, and specificity of 82.1%. We feel that texture features coupled with the Support Vector Machine classifier can be used to identify the plaque tissue type. An Integrated Index, called symptomatic asymptomatic carotid index (SACI), is proposed using texture features to discriminate symptomatic and asymptomatic carotid ultrasound images using just one index or number. We hope this SACI can be used as an adjunct tool by the vascular surgeons for daily screening. PMID- 21243412 TI - Comparative effects of alcohols (methanol, glycerol) and polyethylene glycol (PEG 300) on acid denatured state of goat liver cystatin. AB - This report summarizes the effect of methanol, glycerol and polyol (PEG) on the acid induced state of goat liver cystatin by various spectroscopic techniques. Native goat liver cystatin (LC) has a fluorescence maximum at 340 nm, whereas the acid induced state shows a red shift of 15 nm with enhanced fluorescence intensity. Addition of 80% (V/V) methanol and glycerol both were found to stabilise the acid induced state of goat liver cystatin. However, glycerol was found to be a better stabilising agent than methanol. The unfolded state of liver cystatin obtained at pH 2 underwent a series of conformational changes when exposed to PEG-300 at varying concentrations. Tertiary structure was stabilized only at low concentrations of PEG-300 but higher concentrations resulted in the loss of tertiary structure. PMID- 21243413 TI - On the photophysics of 3,5,6-Trichlorosalicylic acid: spectroscopic study combined with Hartree-Fock and Density Functional Theory calculations. AB - The present contribution reports a detailed photophysical study of a simple salicylic acid derivative viz., 3,5,6-Trichlorosalicylic acid (TCSA) based on steady state absorption, emission and time-resolved emission spectroscopy. Anomalous "dual" emission coupled with a large Stokes shift and negligible solvent polarity dependence marks the spectroscopic signature for Excited State Intramolecular Proton Transfer (ESIPT) reaction. Variation of medium polarity and pH of the medium have been implemented as fruitful tools to decipher the photophysics of TCSA. Quantum chemical calculation by ab initio Hartree-Fock and Density Functional Theory methods yields consistent results to follow experimental findings with distinct illustration of the inoperativeness of GSIPT reaction as well as occurrence of ESIPT process. A rigorous comparison of our experimental and theoretical measurements of TCSA with the parent compound salicylic acid, 5-chlorosalicylic acid and 3,5-dichlorosalicylic acid reveals the impact of chlorine substitution on the photophysics of the studied molecular systems with simultaneous exploration of the complexities induced in TCSA with respect to salicylic acid. PMID- 21243414 TI - Two-photon fluorescence lysosomal bioimaging with a micelle-encapsulated fluorescent probe. AB - We report two-photon fluorescence microscopy (2PFM) imaging and in vitro cell viability of a new, efficient, lysosome-selective system based on a two-photon absorbing (2PA) fluorescent probe (I) encapsulated in Pluronic(r) F-127 micelles. Preparation of dye I was accomplished via microwave-assisted synthesis, resulting in improved yields and reduced reaction times. Photophysical characterization revealed notable 2PA efficiency of this probe. PMID- 21243415 TI - People with AIDS (PWA) since highly active antiretroviral therapy, 1996. AB - Although clarity about HIV transmission biology and effective therapy should mean that an AIDS diagnosis is more socially acceptable today, for some groups the cultural stigma of HIV infection has changed little in the last 30 years. This paper will examine why representations of HIV-positive gay men suggest they pose a special civic risk and how these conceptualizations have harnessed cultural anxieties about racial and sexual minorities to shape public policy and behavior since the advent of Highly Active Antiretroviral Therapy (HAART) in 1996. PMID- 21243416 TI - "Screw health": representations of sex as a health-promoting activity in medical and popular literature. AB - Recently, scientific and popular press articles have begun to represent sex as a health-promoting activity. A number of scientific studies have identified possible health benefits of sexual activity, including increased lifespan and decreased risk of certain types of cancers. These scientific findings have been widely reported on in the popular press. This "sex for health" discourse claims that sexual activity leads to quantifiable physical and mental health benefits in areas not directly related to sexuality. Analyzing this discourse provides an opportunity to better understand both broader health promotion discourses and current norms and anxieties about sexuality. In this article, I place this "sex for health" discourse within the context of broader health promotion discourses and within the context of a number of historical and contemporary discourses connecting health and sexuality. I argue that although the "sex for health" discourse may serve to de-stigmatize sexual activity for some, it may also increase pressure on others to be sexually active and may further pathologize sexual "dysfunction." In addition, these representations often serve to further privilege a normative form of sexual behavior - coitus in the context of a monogamous heterosexual partnership - at the expense of non-normative sexual desires, identities, and practices. PMID- 21243417 TI - Additive effect of dextrans on the stability of horseradish peroxidase. AB - The influence of various concentration (10, 20, and 30% w/v) of different molar weighted dextrans as additives on the stability of HRP has been studied in aqueous medium. Native HRP preparations were formulated with different additives for storage stabilization and better performance at high temperature and pH. The results obtained show a stabilizing effect in the presence of an additive (75 kDa dextran). The enzyme with 75 kDa dextran (in concentration 10% w/v) showed the highest thermal resistance and the best performance for long-term storage at pH 5.0. In the presence of the 75 kDa dextran, the enzyme activity was increased threefold at 25 degrees C and lost only 15% activity in 2 h at 50 degrees C in comparison to the native enzyme which lost all its activity. In addition, dextran protected HRP against inactivation by air bubbles. PMID- 21243418 TI - Invisible civic engagement among older adults: valuing the contributions of informal volunteering. AB - There is a growing call for civic engagement, largely in the form of formal volunteering, among older adults in America. This call is a response to the aging of the baby boom population, believed to be the healthiest and wealthiest cohort of older adults to date. It also coincides with the devolution of welfare programs. We argue that current discussions of civic engagement are too narrow and may exclude important informal contributions that older adults make to civic society, and put undue stress on, and devalue those who may not contribute to society due to poor health, poverty or other barriers. We draw on data collected from older adults of lower socio-economic status and diverse ethnic backgrounds in Baltimore City using focus groups to explore their definitions of volunteering and barriers which they face. Through a discussion of existing barriers and motivators for engagement, we critically assess the use of these terms and advance discussions on how to facilitate and value contributions of all older adults. We conclude that civic engagement includes more than formal volunteering and that significant barriers need to be removed to facilitate greater participation of all elders in both formal and informal activities. PMID- 21243419 TI - The use of automated parameter searches to improve ion channel kinetics for neural modeling. AB - The voltage and time dependence of ion channels can be regulated, notably by phosphorylation, interaction with phospholipids, and binding to auxiliary subunits. Many parameter variation studies have set conductance densities free while leaving kinetic channel properties fixed as the experimental constraints on the latter are usually better than on the former. Because individual cells can tightly regulate their ion channel properties, we suggest that kinetic parameters may be profitably set free during model optimization in order to both improve matches to data and refine kinetic parameters. To this end, we analyzed the parameter optimization of reduced models of three electrophysiologically characterized and morphologically reconstructed globus pallidus neurons. We performed two automated searches with different types of free parameters. First, conductance density parameters were set free. Even the best resulting models exhibited unavoidable problems which were due to limitations in our channel kinetics. We next set channel kinetics free for the optimized density matches and obtained significantly improved model performance. Some kinetic parameters consistently shifted to similar new values in multiple runs across three models, suggesting the possibility for tailored improvements to channel models. These results suggest that optimized channel kinetics can improve model matches to experimental voltage traces, particularly for channels characterized under different experimental conditions than recorded data to be matched by a model. The resulting shifts in channel kinetics from the original template provide valuable guidance for future experimental efforts to determine the detailed kinetics of channel isoforms and possible modulated states in particular types of neurons. PMID- 21243421 TI - Conservation of structural and functional elements of TSC1 and TSC2: a bioinformatic comparison across animal models. AB - The tuberous sclerosis complex 1/2-mammalian target of rapamycin (TSC1/2-mTOR) proteins act as integrators of a range of intracellular signalling pathways. Various genetic disorders associated with learning and behavioural deficits, including TSC, Fragile X, Neurofibromatosis Type 1, Noonan and Leopard syndromes, are associated with abnormalities in TSC-mTOR signalling. Based on the assumption that signalling proteins and their structural and functional components are widely conserved, a number of animal models are used to study aspects of the physical and behavioural phenotypes of these human disorders. Model organisms include rat (Rattus norvegicus), mouse (Mus musculus), zebrafish (Danio rerio), fruitfly (Drosophila melanogaster) and fission yeast (Schizosaccharomyces pombe). Here we used a bioinformatic approach to examine the presence of structural and functional elements of TSC1 and TSC2 across these organisms, together with Strongylocentrotus purpuratus and Dictyostelium discoideum. Results suggest that while Rattus norvegicus and Mus musculus TSC1 and TSC2 showed very high similarity to the human sequences, this was not the case for Danio rerio, Drosophila melanogaster, Strongylocentrotus purpuratus, Schizosaccharomyces pombe or Disctyostelium discoideum. Findings indicate that caution should be exercised in detailed interpretation of results from some model organisms. PMID- 21243420 TI - In search of the perfect phenotype: an analysis of linkage and association studies of reading and reading-related processes. AB - Reading ability and specific reading disability (SRD) are complex traits involving several cognitive processes and are shaped by a complex interplay of genetic and environmental forces. Linkage studies of these traits have identified several susceptibility loci. Association studies have gone further in detecting candidate genes that might underlie these signals. These results have been obtained in samples of mainly European ancestry, which vary in their languages, inclusion criteria, and phenotype assessments. Such phenotypic heterogeneity across samples makes understanding the relationship between reading (dis)ability and reading-related processes and the genetic factors difficult; in addition, it may negatively influence attempts at replication. In moving forward, the identification of preferable phenotypes for future sample collection may improve the replicability of findings. This review of all published linkage and association results from the past 15 years was conducted to determine if certain phenotypes produce more replicable and consistent results than others. PMID- 21243422 TI - Developmental competence of antral follicles and their oocytes after gonadotrophin treatment of sows with gene polymorphisms for leptin and melanocortin receptors (Iberian pig). AB - PURPOSE: To evaluate possible differences in follicle and oocyte developmental competence after gonadotrophin treatment in sows of obese and lean genotypes. METHODS: Follicle dynamics, ovulation rate and oocyte developmental competence to embryo were compared between females, of obese (n = 7) and lean genotypes (n = 10), treated with 1,250 I.U. of eCG and 500 I.U. of hCG. RESULTS: The obese genotype showed lower numbers of follicles growing to preovulatory stages (12.4 +/- 1.8 vs 18.6 +/- 1.0, P < 0.05), of corpora lutea (16.0 +/- 0.9 vs 23.5 +/- 0.9, P < 0.05), and of recovered oocytes/embryos (8.0 +/- 1.3 vs 12.9 +/- 0.9, P < 0.05). Thereafter, embryo viability rates also decreased when compared to lean genotypes (62.5 vs 77.6%, P < 0.05). DISCUSSION: To our knowledge, this is the first study analyzing the effect of obese genotypes on the ovarian response to exogenous gonadotrophins in a non-rodent animal model, the pig. A lower efficiency of gonadotrophin treatments for stimulation of follicle development and induction of ovulation was observed. PMID- 21243423 TI - Atmospheric BTEX concentrations in the vicinity of the crude oil refinery of the Baltic region. AB - Among chemical industries, petroleum refineries have been identified as large emitters of a wide variety of pollutants. Benzene, toluene, ethylbenzene, and xylene (BTEX) form an important group of aromatic volatile organic compounds (VOCs) because of their role in the troposphere chemistry and the risk posed to human health. A very large crude oil refinery of the Baltic States (200,000 bbl/day) is situated in the northern, rural part of Lithuania, 10 km from the town of Mazeikiai (Lithuania). The objectives of this study were: (1) to determine of atmospheric levels of BTEX in the region rural and urban parts at the vicinity of the crude oil refinery; and (2) to investigate the effect of meteorological parameters (wind speed, wind direction, temperature, pressure, humidity) on the concentrations measured. The averaged concentration of benzene varied from 2.12 ppbv in the rural areas to 2.75 ppbv in the urban areas where the traffic was determined to be a dominant source of BTEX emissions. Our study showed that concentration of benzene, as strictly regulated air pollutant by EU Directive 2008/50/EC, did not exceed the limit of 5 ppbv in the region in the vicinity of the crude oil refinery during the investigated period. No significant change in air quality in the vicinity of the oil refinery was discovered, however, an impact of the industry on the background air quality was detected. The T/B ratio (0.50-0.81) that was much lower than 2.0, identified other sources of pollution than traffic. PMID- 21243424 TI - Remote sensing as a tool for monitoring water quality parameters for Mediterranean Lakes of European Union water framework directive (WFD) and as a system of surveillance of cyanobacterial harmful algae blooms (SCyanoHABs). AB - Remote sensing has been used from the 1980s to study inland water quality. However, it was not until the beginning of the twenty-first century that CHRIS (an experimental multi-angle sensor with good spectral and spatial resolutions) and MERIS (with good temporal and spectral resolutions) started to acquire imagery with very good resolutions, which allowed to develop a reliable imagery acquisition system so as to consider remote sensing as an inland water management tool. This paper presents the methodology developed, from the field data acquisition with which to build a freshwater spectral library and the study of different atmospheric correction systems for CHRIS mode 2 and MERIS images, to the development of algorithms to determine chlorophyll-a and phycocyanin concentrations and bloom sites. All these algorithms allow determining water eutrophic and ecological states, apart from generating surveillance maps of toxic cyanobacteria with the main objective of Assessment of the Water Quality as it was used for Monitoring Ecological Water Quality in smallest Mediterranean Reservoirs integrated in the Intercalibration Exercise of European Union Water Framework Directive (WFD). We keep on using it to monitor the Ecological Quality Ratio (EQR) in Spain inland water. PMID- 21243425 TI - Cognitive engagement in the problem-based learning classroom. AB - The objective of the present study was to examine to what extent autonomy in problem-based learning (PBL) results in cognitive engagement with the topic at hand. To that end, a short self-report instrument was devised and validated. Moreover, it was examined how cognitive engagement develops as a function of the learning process and the extent to which cognitive engagement determines subsequent levels of cognitive engagement during a one-day PBL event. Data were analyzed by means of confirmatory factor analysis, repeated measures ANOVA, and path analysis. The results showed that the new measure of situational cognitive engagement is valid and reliable. Furthermore, the results revealed that students' cognitive engagement significantly increased as a function of the learning event. Implications of these findings for PBL are discussed. PMID- 21243426 TI - Cytostatic effect of the hypothalamic cytokine PRP-1 is mediated by mTOR and cMyc inhibition in high grade chondrosarcoma. AB - This study aimed to further elucidate the molecular mechanisms of antiproliferative action of proline rich polypeptide 1 (PRP-1) cytokine, produced by neurosecretory cells of the hypothalamus to be considered as alternative adjuvant therapy for metastatic chondrosarcoma, which does not respond to chemotherapy or radiation and currently without any effective treatment. Rapid cell proliferation assay of human primary cultures from high grade chondrosarcoma patients biopsies and human chondrosarcoma JJ012 cell line indicated 50 and 80% inhibition in PRP-1 treated samples correspondingly. Videomicroscopy detected that despite the treatment there are still dividing cells, meaning that cells are not in the state of dormancy, rather PRP-1 repressed the cell cycle progression, exhibited cytostatic effect. The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase that has a crucial role in a nutrient sensitive signaling pathway that regulates cell growth. Experiments with mTOR pathway after PRP-1 (10 MUg/ml) treatment indicated statistically significant 30% inhibition of mTOR activity and its 56% inhibition in immunoprecipitates with PRP-1 concentrations effective for cell proliferation inhibition. Treatment with PRP- caused inhibition of mTOR and downstream target cMyc oncogenic transcription factor sufficient to trigger the cytostatic effect in high grade, but not in low grade chondrosarcomas. The fact that lower concentrations than 10 MUg/ml peptide with cytostatic effect did not inhibit mTOR, but inhibited cMyc prompted us to assume that PRP-1 binds to two different receptors facilitating the antiproliferative effect. PMID- 21243427 TI - Fuzhisan, a Chinese herbal medicine, inhibits beta-amyloid-induced neurotoxicity and tau phosphorylation through calpain/Cdk5 pathway in cultured cortical neurons. AB - It has been shown that beta-amyloid (Abeta) induced hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease (AD), and deregulation of cyclin-dependent kinase 5 (Cdk5) activity is involved in the abnormal tau phosphorylation. The cleavage of neuron-specific Cdk5 activator, p35, to p25, mediated by calpain and calcium, deregulates Cdk5 activity and promotes neurodegeneration. Fuzhisan (FZS), a Chinese herbal complex prescription that has been used for the treatment of AD for over 15 years, is known to enhance the cognitive ability in AD patients. In this study, we investigated the neuroprotective effects and potential molecular mechanisms of FZS against Abeta(25-35)-induced toxicity in cultured cortical neurons. We revealed that FZS attenuated Abeta(25-35)-induced neurotoxicity in a dose-dependent manner. FZS inhibited Abeta(25-35)-induced activation of Cdk5 and decreased tau hyperphosphorylation although it did not directly inhibit Cdk5. In addition, FZS also blocked Abeta(25-35)-induced calcium influx, calpain activation and decreased cleavage of p35 to p25. PMID- 21243428 TI - Effect of HFE variants on sphingolipid expression by SH-SY5Y human neuroblastoma cells. AB - C282Y and H63D are two common variants of the hemochromatosis protein HFE. SH SY5Y human neuroblastoma cells stably transfected to express either wild type HFE (WT-HFE), or the C282Y or H63D allele were analyzed for effect of expression of the mutant proteins on transcription of 14 enzymes involved in sphingolipid metabolism. Cells expressing the C282Y variant showed significant increases (>2 fold) in transcription of five genes and decreases in two compared to that seen for cells expressing WT-HFE, while cells expressing the H63D variant showed an elevation in transcription of one gene and a decrease in two. These changes were seen as alterations in ganglioside composition, cell surface binding by the binding subunit of cholera toxin, expression of sphingosine-kinase-1 and synthesis of sphingosine-1-phosphate. These changes may explain why C282Y-HFE is a risk factor for colon and breast cancer and possibly protective against Alzheimer's disease while H63D-HFE is a risk factor for neurodegenerative diseases. PMID- 21243429 TI - Human umbilical cord-derived Schwann-like cell transplantation combined with neurotrophin-3 administration in dyskinesia of rats with spinal cord injury. AB - Mesenchymal stem cells are capable of differentiating into Schwann-like cells. In this study, we induced human umbilical-cord mesenchymal stem cells (HUMSCs) in vitro into neurospheres constituted by neural stem-like cells, and further into cells bearing strong morphological, phenotypic and functional resemblances with Schwann-like cells. These HUMSC-derived Schwann-like cells, after grafting into the injured area of the rats' spinal cord injury (SCI), showed a partial therapeutic effect in terms of improving the motor function. Neurotrophin-3 (NT 3) was reported to improve the local microenvironment of the grafted cells, and we, therefore, further tested the effect of Schwann-like cell grafting combined with NT-3 administration at the site of cell transplantation. The results showed that NT-3 administration significantly promoted the survival of the grafted cells in the host-injured area. Significant improvement in rats treated by Schwann-like cell grafting combined with NT-3 administration was demonstrated in the behavioral test as compared with that in animal models received the cell grafting only. These results suggest that transplantation of the Schwann-like cells combined with NT-3 administration may represent a new strategy of stem cell therapy for spinal cord injury. PMID- 21243430 TI - Systematizing and cloning of genes involved in the cerebellar cortex circuit development. AB - The cerebellar cortical circuit of mammals develops via a series of magnificent cellular events in the postnatal stage of development to accomplish the formation of functional circuit architectures. The contribution of genetic factors is thought to be crucial to cerebellar development. Therefore, it is essential to analyze the underlying transcriptome during development to understand the genetic blueprint of the cerebellar cortical circuit. In this review, we introduce the profiling of large numbers of spatiotemporal gene expression data obtained by developmental time-series microarray analyses and in situ hybridization cellular mRNA mapping, and the creation of a neuroinformatics database called the Cerebellar Development Transcriptome Database. Using this database, we have identified thousands of genes that are classified into various functional categories and are expressed coincidently with related cellular developmental stages. We have also suggested the molecular mechanisms of cerebellar development by functional characterization of several identified genes (Cupidin, p130Cas, very-KIND, CAPS2) responsible for distinct cellular events of developing cerebellar granule cells. Taken together, the gene expression profiling during the cerebellar development demonstrates that the development of cerebellar cortical circuit is attributed to the complex but orchestrated transcriptome. PMID- 21243431 TI - Spiritual well-being of people with psychiatric disabilities: the role of religious attendance, social network size and sense of control. AB - The influence of psychiatric symptoms, religious attendance, social network size, and sense of control on spiritual well-being were investigated in a cross sectional study using the Spirituality Index of Well-being. Forty-seven participants with psychiatric disabilities from six consumer-run organizations participated. A factor analysis result revealed two domains of spiritual well being for people with psychiatric disabilities: self-perceptions regarding making sense of life (developing life purpose) and self-efficacy in obtaining life goals. Based on our regression analyses, religious attendance, expanding social network size, and having a sense of control over important areas of life may enhance spiritual well-being in spite of severity of psychiatric symptoms. Supporting mental health consumers who hope to be fully integrated into social and spiritual communities is important. Given the increased attention to consumers' internal spiritual experiences in a recovery process, this study adds to knowledge about spirituality in the mental health field. PMID- 21243432 TI - Child welfare involvement of mothers with mental health issues. AB - Many mothers with mental health issues are caught up in the child protection system and face the prospect of having their children removed from their care. The aim of this study was to determine prevalence and outcomes for mothers with mental health issues and their children in child maltreatment cases opened for investigation in Canada. The method was secondary analysis of the Canadian Incidence Study of Reported Child Abuse and Neglect (CIS-2003) core data. This CIS-2003 contains process and outcome data on a nationally representative sample of 11,652 child maltreatment investigations. Maternal mental health issues were noted in 2,272 (19.7%) cases opened for investigation. The most common child protection concerns were neglect, emotional maltreatment and exposure to domestic violence. A significant association was found between maternal mental health issues and child maltreatment investigation outcomes, with many potentially confounding variables held constant. Broad spectrum, multi-disciplinary services are needed to support mothers with mental health issues. Effective mental health care is vital but insufficient. Addressing trauma, strengthening social relationships and alleviating poverty are also key. Systemic advocacy is needed to ensure that mothers with mental health issues can access broad spectrum supports. PMID- 21243433 TI - Polymorphisms in interleukin-1B (IL-1B) and interleukin 1 receptor antagonist (IL 1RN) genes associate with gastric cancer risk in the Chinese population. AB - BACKGROUND: Gastric cancer is one of the most common malignancies afflicting the Chinese population. Polymorphisms in interleukin-1B (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) genes have been associated with increased gastric cancer risk. AIMS: A case-control study enrolled 392 gastric cancer patients and 508 healthy were carried out to investigate the association between polymorphisms in IL-1B and IL-1RN and gastric cancer risk. METHODS: Polymerase chain reaction (PCR)-restriction fragment length polymorphism was used for detection of two potentially functional polymorphisms (IL-1B-31 and IL-1B-511) in the IL-1B gene promoter and PCR was used for detection of the variable tandem repeat in the second intron of IL-1RN. RESULTS: The data showed that the IL-1B-31CC genotype increased gastric cancer risk to an adjusted odd of 2.27 (95% CI, 1.49-3.46), IL 1B-31CT to 1.48 (95% CI, 1.01-2.16) and IL-1B-31CT/CC to 1.68 (95% CI, 1.17 2.40), while IL-1B-51TT genotype associated with increased gastric cancer risk to an adjusted odd of 2.53 (95% CI, 1.67-3.84), IL-1B-511TC to 1.45 (95% CI, 1.02 2.06), and IL-1B-511TC TT/TC to 1.72 (95% CI, 1.23, 2.39). Furthermore, IL-1RN heterogeneity genotype (IL-1RN2L) was associated with gastric cancer risk to an adjusted odd of 1.70 (95% CI, 1.05-2.74) compared to the wild-type homozygote (IL 1RNLL). In addition, H. pylori infection enhanced gastric cancer risk through these SNPs. CONCLUSIONS: The data from the current study demonstrated that the genotype CC or CT of IL-1B-31, TT or CT of IL-1B-511, and 2L of IL-1RN increased risk of gastric cancer in this Chinese population and the risk was further enhanced by H. pylori. PMID- 21243434 TI - Non-Jewish Israeli IBD patients have significantly higher glutathione S transferase GSTT1-null frequency. AB - BACKGROUND: The involvement of oxidant/antioxidant imbalance in the development of inflammatory bowel disease (IBD) is well documented. Two members of the glutathione S-transferase (GST) family of enzymes, GSTM1 and GSTT1, known to take part in cellular protection against electrophiles, demonstrate common deletion variants (termed null) associated with impaired enzyme function. AIM: To evaluate the effect of GSTM1/GSTT1 genotype on IBD susceptibility in a Israeli cohort and to study the correlation between GSTM1/GSTT1 genotype, smoking status, and a variety of clinical characteristics of IBD. METHODS: A cohort of 606 Israeli IBD patients (453 with Crohn's disease [CD] and 153 with ulcerative colitis [UC]) and 528 ethnically matched healthy controls were genotyped for the null variants of GSTM1 and GSTT1. In patients, phenotype-genotype correlations were examined. RESULTS: Ethnic stratification of healthy controls revealed a higher frequency of GSTT1-null in Jewish and Arab Moslem individuals compared to Druze individuals (P < 0.0005), but no difference in GSTM1-null was found. Comparing IBD patients (both CD and UC) to healthy controls revealed a pattern of lower GSTM1-null and higher GSTT1-null frequencies, which reached significance in Arab Moslem patients. No association was found between NOD2/CARD15 mutation carriage and GSTM1/GSTT1 genotype. No statistically significant association was found between GSTT1-null or GSTM1-null, smoking status, and other phenotypes of CD/UC. CONCLUSIONS: GSTT1-null appears to be associated with IBD, while GSTM1-null appears to be conversely associated with IBD. No association was found between GSTT1-null or GSTM1-null and specific IBD phenotypes. PMID- 21243435 TI - Non-extractable procyanidins and lignin are important factors in the bile acid binding and radical scavenging properties of cell wall material in some fruits. AB - The cell wall components and the food functions of alcohol-insoluble solids (AIS) of Chinese quince, quince, hawthorn, apple, pear and blueberry fruits were analyzed. Chinese quince contained characteristically high contents of cellulose, lignin, and non-extractable procyanidins (NEPCs). On the other hand, the quince AIS contained the highest proportion of NEPCs, the highest mean degree of polymerization (mDP), the strongest radical scavenging activity, and strong bile acid binding activity. In fruit AIS, the lignin and NEPC contents both showed positive correlations with the bile acid binding and radical scavenging activities. The value for mDP * NEPC content was a good index for the radical scavenging activity. The results suggest that highly polymerized NEPCs and lignin are important factors of cell wall components of fruits to having a high functionality, and Chinese quince and quince are interesting fruits from this view point. PMID- 21243436 TI - Phenolic compounds as cultivar- and variety-distinguishing factors in some plant products. AB - The aim of the study was to determine whether phenolic compounds in some varieties of buckwheat, winter and spring barley and peas can be used as factors which distinguish selected cultivars and varieties of plant material. It was observed that the content of total phenolics might be useful as a cultivar distinguishing factor for all the plant materials analyzed, but it was a distinguishing factor for only some varieties. Individual cultivars and varieties were best distinguished by the content of syringic acid. The levels of syringic and vanillic acids were in reverse proportion to the total amount of phenolics soluble in methanol and a positive correlation between syringic and ferulic acid was observed. Moreover, the protein content of plant material was analyzed and a significant (p <= 0.05) correlation between this component and ferulic and vanillic acids was noted. PMID- 21243437 TI - An automated microfluidic sample preparation system for laser scanning cytometry. AB - Laser scanning cytometry (LSC) is emerging as a clinical tool. In one application a "Clatch" slide, named after the inventor, is used in conjunction with LSC for cell surface marker immunophenotyping of patient samples. The slide requires time consuming and laborious pipetting steps, making a test tedious and prone to handling errors. The Clatch slide also uses a significant number of cells, limiting the number of analyses on paucicellular samples. This paper presents an automated microfluidic system consisting of a control circuit, a microfluidic system, and an aluminum frame, capable of performing immunophenotyping procedures. This prototype system reduces 36 pipetting steps to 1, reduces the amount of cell sample from 180 MUL to 56 MUL, and shortens the time used by technicians. PMID- 21243438 TI - A plant cocktail amenable for PCR-based genetic analysis in Arabidopsis thaliana. AB - Extraction of plant genomic DNA for subsequent genetic studies is often lengthy and difficult. In addition, it requires the use of toxic reagents that remove secondary plant products, which otherwise interfere with the polymerase chain reaction steps. Here we describe a simple cost-efficient one-step protocol for PCR-based analysis in Arabidopsis thaliana. This protocol is quick, performed at room temperature without the need for DNA extraction. Potential applications in higher plants are here discussed. PMID- 21243439 TI - Epworth Sleepiness Scale may be an indicator for blood pressure profile and prevalence of coronary artery disease and cerebrovascular disease in patients with obstructive sleep apnea. AB - OBJECTIVE: This study seeks to determine whether scores of a short questionnaire assessing subjective daytime sleepiness (Epworth Sleepiness Scale [ESS]) are associated with blood pressure (BP) level, BP profile, and prevalence of related coronary artery disease (CAD) and cerebrovascular disease (CVD) in obstructive sleep apnea (OSA) patients diagnosed by polysomnography (PSG). METHODS: Twenty university hospital sleep centers in China mainland were organized by the Chinese Medical Association to participate in this study. Between January 2004 and April 2006, 2,297 consecutive patients (aged 18-85 years; 1,981 males and 316 females) referred to these centers were recruited. BP assessments were evaluated at four time points (daytime, evening, nighttime, and morning) under standardized conditions. Anthropometric measurements, medical history of hypertension, CAD, and CVD were collected. ESS score was calculated for each participant and at the night of BP assessment, nocturnal PSG was performed and subjects were classified into four groups based on the apnea-hypopnea index (AHI) from PSG as follows: control group (control, n = 213) with AHI < 5; mild sleep apnea (mild, n = 420) with AHI >= 5 and <15; moderate sleep apnea (moderate, n = 460) with AHI >= 15 and <30; and severe sleep apnea (severe, n = 1,204) with AHI >= 30. SPSS 11.5 software package was used for the relationships between ESS and BP profile and prevalence of CAD and CVD. RESULTS: ESS is correlated positively with average daytime, nighttime, evening, and morning BP before and even after controlling for confounding effects of age, sex, BMI, AHI, and nadir nocturnal oxygen saturation (before--r = 0.182, 0.326, 0.245, and 0.329, respectively, all P values < 0.001; after--r = 0.069, 0.212, 0.137, and 0.208, respectively, all P values < 0.001). In the severe group, nighttime, evening, morning average BPs (ABPs), the ratio of nighttime/daytime average BP (ratio of nighttime average BP to daytime average BP), and prevalence of hypertension, drug-resistant hypertension (R-HTN), isolated nighttime hypertension (IN-HTN), CAD, and CVD in excessive daytime sleepiness (EDS, ESS >= 11) subjects are higher than those in non-EDS (ESS 0-10; t/chi(2) = -8.388, -6.207, -8.607, -5.901, 12.742, 38.980, 16.343, 59.113, and 67.113, respectively; all P values < 0.05). For EDS subjects in the moderate group but not in the control and mild group, nighttime ABP and the ratio of nighttime/daytime average BP are higher (t = -2.086 and -3.815, respectively, all P values < 0.05). Linear fitting with ESS and the ratio of nighttime/daytime average BP shows a positive correlation (r(2) = 0.049, P < 0.001). CONCLUSIONS: In severe OSA patients with comparable AHI, EDS may identify a subset of individuals with OSA at higher risk of hypertension, R-HTN, IN-HTN, CAD, and CVD. Overall, nighttime ABP seems to be more sensitive to be influenced by EDS than other ABP parameters. Future studies should investigate the potential dose-effect relationship between EDS and hypertension and the possibility that diagnosis and treatment of EDS could aid in BP reduction and ultimately in decreased morbidity and mortality from cardiovascular and cerebrovascular complications (TMUIRB20010002 at www.clinicaltrials.gov ). PMID- 21243441 TI - Evaluation of the acute oral toxicity class of trinuclear chromium(III) glycinate complex in rat. AB - Chromium(III) is considered as an essential element playing a role in carbohydrate and lipid metabolism, and various chemical forms of this element are widely used in dietary supplements. A new trinuclear chromium(III) glycinate complex [Cr(3)O(NH(2)CH(2)CO(2))(6)(H(2)O)(3)](+)NO(3)(-) (CrGly), an analogue of Cr3 (trinuclear Cr(III) propionate complex) has been synthesized as a potential source of supplementary Cr. In this study, we evaluated the acute toxicity class of CrGly in Wistar rats applying the OECD 423 procedure. Male and female Wistar rats (n = 12, 6 ? and 6 ?) were given by gavage either a single dose of CrGly 2,000 mg/kg body mass (equals to 300 mg Cr(III)/kg body mass; in aqueous solution) or equivalent volumes of distilled water and fed ad libitum commercial Labofeed B diet, and observed carefully for 14 days, then sacrificed to collect blood and internal organs for biochemical and histologic examination. No death cases were detected. No abnormalities in animal behavior, body mass gains, gross organ histology, or blood morphology and biochemistry were observed. The results demonstrate that LD(50) of CrGly is greater than 2,000 mg/kg when administrated orally to rat; thus, this compound appears to belong to the fifth category in the GHS system or the fourth class ("unclassified") in the EU classification system. PMID- 21243442 TI - Study on blood biochemical diagnostic indices for hepatic function biomarkers in endemic skeletal fluorosis. AB - The aim of the study was to determine the relationship of fluoride in drinking water to liver function in individuals living in normal and seven endemic fluorosis areas of Punjab, India. The concentration of fluoride in drinking water of different areas varied from 5.9 to 24.5 mg/L. Study group consisted of 705 patients in the age group between 20 and 60 years (mean age of 39.35+/-11.27) affected with osteodental fluorosis were compared with 300 age- and sex-matched controls (with mean age of 35.28+/-8.25 years). Biochemical data was analyzed by one-way analysis of variance (ANOVA) with post hoc Tukey-Kramer and Bonferroni multiple comparison tests. The relationship between hepatic enzymes was calculated by Pearson's correlation and linear regression. The results revealed significantly (P<0.001) higher concentration of serum fluoride in patients when compared to control. The mean activities of cyclic adenosine monophosphate (AMP), alkaline phosphatase (ALKP), acid phosphatase (ACP), aspartate aminotransaminase (AST), and alanine aminotransaminase (ALT) were significantly (P<0.05-0.001) elevated in patients from all fluoride areas. ANOVA with post hoc Turkey-Kramer and Bonferroni multiple comparison test demonstrated a significant (P<0.0001) variance in the activities of cAMP, ALKP, ACP, AST, and ALT in fluorotic patients, with elevation in water fluoride levels. Maximum elevation of 196.14% (ACP), 99.31% (cyclic adenosine monophosphate; cAMP), 72.08% (ALT), 60.14% (AST), and least 21.35% (ALKP) was recorded in patients exposed to 24.5 mg/L fluoride in drinking water. There was positive correlation between water fluoride, serum fluoride and AST (r=0.77, 0.91), ALT (r=0.82, 0.90), ALKP (r=0.88, 0.97), and ACP (r=0.74, 0.85). Pearson's correlation demonstrated highly significant (P<0.05) positive relationship between water fluoride and cAMP (regression equation: Y=0.9807*+22:081, =0.84; r=0.92, P<0.05). The increased levels of transaminases in fluorotic patients suggest alteration in liver functions. The level of alkaline and acid phosphatase was increased during fluoride intoxication which is also an early marker of hepatic cell damage because of its specificity and catalytic activity. The elevated levels of enzymes are reflective of bone disorders, which are characterized by increased osteoblastic activity. There levels increased several times if cellular damage occurs in the liver. The results suggest that fluoride exposure intensifies the activities of hepatic function enzymes in osteofluorosis. PMID- 21243443 TI - Gene cloning, heterologous expression, and characterization of a high maltose producing alpha-amylase of Rhizopus oryzae. AB - A putative alpha-amylase gene, designated as RoAmy, was cloned from Rhizopus oryzae. The deduced amino acid sequence showed the highest (42.8%) similarity to the alpha-amylase from Trichoderma viride. The RoAmy gene was successfully expressed in Pichia pastoris GS115 under the induction of methanol. The molecular weight of the purified RoAmy determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis was approximately 48 kDa. The optimal pH and temperature were 4-6 and 60 degrees C, respectively. The enzyme was stable at pH ranges of 4.5 6.5 and temperatures below 50 degrees C. Purified RoAmy had a K(m) and V(max) of 0.27 mg/ml and 0.068 mg/min, respectively, with a specific activity of 1,123 U/mg on soluble starch. Amylase activity was strongly inhibited by 5 mM Cu(2+) and 5 mM Fe(2+), whereas 5 mM Ca(2+) showed no significant effect. The RoAmy hydrolytic activity was the highest on wheat starch but showed only 55% activity on amylopectin relative to soluble corn starch, while the pullulanase activity was negligible. The main end products of the polysaccharides tested were glucose and maltose. Maltose reached a concentration of 74% (w/w) with potato starch as the substrate. The enzyme had an extremely high affinity (K(m) = 0.22 mM) to maltotriose. A high ratio of glucose/maltose of 1:4 was obtained when maltotriose was used at an initial concentration of 40 mM. PMID- 21243444 TI - Abstracts of the Israel Society for Neuroscience 19th Annual Meeting. Eilat, Israel. December 12-14, 2010. PMID- 21243446 TI - Disparity between tissue and serum calcitonin and carcinoembryonic antigen in a patient with medullary thyroid carcinoma. AB - Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of parafollicular or C-cells of thyroid that comprises 5-10% of all thyroid cancers [1, 2]. The neoplastic cells secrete calcitonin, carcinoembryonic antigen (CEA), and chromogranin A. Typically, increased serum levels of these tumor markers permit them to be used for initial diagnosis and long-term disease status surveillance. This article reports a case of sporadic MTC (pT2N0M0) in a young patient with normal serum tumor markers. A 16-year-old woman presented with MTC without evidence for this to be a familial case due to the absence of germline mutations in the RET proto-oncogene and negative family history. Surprisingly, there were normal preoperative serum levels of calcitonin, CEA, and chromogranin A, despite the immunohistochemistry showing strong and diffuse positive staining for these markers. This disparity between serum levels and tumor expression of calcitonin and CEA in MTC is quite rare. The relevant features of this case are discussed in consideration of the published experiences. This case may represent an unique subgroup of MTC with abnormal secretory capacity that requires reliance upon radiological evaluation for evidence of recurrent or disseminated disease, without the diagnostic benefit of serum tumor markers. PMID- 21243447 TI - Migraine chronification. AB - Migraine is a disorder with variable natural history. In some sufferers, migraine evolves over time into a state of headaches on more days than not. This process of migraine chronification is poorly understood, but risk factors have been clearly identified. Herein, we first discuss the role of heritability and of genetic risk factors on migraine chronification. We follow with a discussion of the role of comorbid conditions and environmental exposures. We suggest that clinicians consider risk factor modification as part of migraine management, aspiring to not just relieve current pain and disability, but to avoid migraine progression. Reducing attack frequency, avoiding medication overuse, appropriately using preventive drugs and behavioral therapies, and encouraging weight loss should be part of migraine therapy to improve current pain and disability and also to avoid future pain and disability by preventing chronification. PMID- 21243445 TI - Cutting-edge issues in primary biliary cirrhosis. AB - Several crucial issues remain open in our understanding of primary biliary cirrhosis (PBC), an autoimmune liver disease targeting the small- and medium sized intrahepatic bile ducts. These issues include the high tissue specificity of the autoimmune injury despite the nontraditional autoantigens found in all mitochondria recognized by PBC-associated autoantibodies, the causes of the commonly observed pruritus, and the disease etiology per se. In all these fields, there has been recent interest secondary to the use of large-scale efforts (such as genome-wide association studies) that were previously considered poorly feasible in a rare disease such as PBC as well as other intuitions. Accordingly, there are now fascinating theories to explain the onset and severity of pruritus due to elevated autotaxin levels, the peculiar apoptotic features of bile duct cells to explain the tissue specificity, and genomic and epigenetic associations contributing to disease susceptibility. We have arbitrarily chosen these four aspects as the most promising in the PBC recent literature and will provide herein a discussion of the recent data and their potential implications. PMID- 21243448 TI - Are sulfonylureas less desirable than DPP-4 inhibitors as add-on to metformin in the treatment of type 2 diabetes? AB - Sulfonylureas (SUs) are commonly used as add-on to metformin in treatment of type 2 diabetes in patients who are insufficiently controlled by metformin alone. They have good efficacy and have been shown to prevent microvascular complications. However, treatment with SUs is also associated with a high frequency of hypoglycemia, increased body weight, and a high risk of secondary failure. During recent years, dipeptidyl peptidase-4 (DPP-4) inhibitors have emerged as alternatives to SUs. They show similar efficacy as SUs but with lower risk of hypoglycemia, and reduction or no change in body weight, and if confirmed in humans, they may preserve islet function and thereby minimize the risk for secondary failure. Their limitation at present is the lack of long-term (>5 years) experience on durability and safety. Overall, therefore, the conclusion emerges that SUs are less desirable than DPP-4 inhibitors in management of hyperglycemia in type 2 diabetes. PMID- 21243449 TI - Approach to venous thromboembolism in the cancer patient. AB - OPINION STATEMENT: Venous thromboembolism (VTE) is frequently encountered in cancer patients, acts as an important cause of morbidity and mortality, and may be a predictor of worse prognosis. In cancer patient who have a poor life expectancy, preventing death from pulmonary embolism is the mainstay of treatment. Patients who present with severe hypotension or other clinical manifestations suggestive of critical pulmonary embolism and do not have contraindications to thrombolysis should promptly be administered thrombolytic drugs. Except for selected cases requiring aggressive therapy, treatment of VTE in patients with cancer should not differ from that of patients without malignancy; the initial treatment should be conducted with adjusted dose of unfractionated heparin (UH), fixed dose of low-molecular-weight heparins (LMWH), or fondaparinux. LMWHs and fondaparinux have the potential to greatly simplify the initial treatment of VTE, making the management of the pathology feasible in an outpatient setting for selected patients. Traditionally, in cancer as well as in non-cancer patients, UH or LMWH or fondaparinux are overlapped by oral anticoagulation, targeted to reach an International Normalized Ratio (INR) between 2.0 and 3.0, and then followed by oral anticoagulants. However, during oral anticoagulant therapy, cancer patients exhibit a two- to fourfold higher risk of recurrent VTE and major bleeding complications when compared to non cancer patients. Studies performed during the current decade have demonstrated that LMWHs offer several advantages in terms of efficacy in preventing VTE recurrences without increasing the bleeding risk. According to International Guidelines, the long-term administration of LMWH should be considered an alternative to anti-vitamin K drugs in patients with advanced disease and in those with conditions limiting the use of oral anticoagulants. The targeted policy is to administer LMWH at full therapeutic doses for the first month of treatment and then 75% of the initial dose for at least the following 5 months of therapy. Prolongation of anticoagulation should be considered for as long as the malignant disorder is active. In patients with acute deep venous thrombosis and contraindications to anticoagulation, vena cava filters should be considered. If anticoagulation is temporarily contraindicated, retrievable filters should be considered. Only patients who are actively bleeding or who are at extremely high risk for bleeding should receive a filter without anticoagulation coverage. PMID- 21243450 TI - Vascular arterial compression syndromes. AB - OPINION STATEMENT: Vascular arterial compression syndromes are uncommon disorders due to dynamic anatomic compression of an artery resulting in significant ischemia in the supplied territories with ensuing symptoms. The diagnosis of these disorders requires heightened awareness and a high index of suspicion by the clinician. These diagnoses should be particularly suspected in young patients with typical symptoms but without underlying cardiovascular risk factors. Physical examination may be unremarkable, although the clinical symptoms or signs may be elicited with provocative maneuvers. The diagnostic work-up may include noninvasive tests such as Doppler waveforms, duplex ultrasonography, computed tomographic angiography, and MRI/angiography, but may require conventional angiogram for confirmation or treatment planning. Although provocative maneuvers may indicate arterial compression in symptomatic patients, it is important to note that these maneuvers may also be positive in normal asymptomatic subjects. These disorders are typically treated surgically with procedures leading to decompression, but anticoagulation, thrombolytic therapy, and even surgical bypass operations may be needed for arterial occlusions. PMID- 21243451 TI - Recent advances in the epidemiology of alcoholic pancreatitis. AB - Clinical observation has defined the medical profile of alcoholic pancreatitis, but its low incidence and prevalence has limited characterizing the disease at a population level, the contribution of environmental exposures, and a clear picture of its natural history. Recent studies have defined the impact of alcohol use and smoking on disease risk, and a threshold for alcohol consumption has been identified. Recurrent attacks of acute pancreatitis have been linked with continued alcohol consumption, and aggressive alcohol intervention has been shown to decrease recurrence. Progression from alcoholic acute pancreatitis to chronic pancreatitis is now believed to occur infrequently, and factors associated with progression have been identified. Alcoholic pancreatitis reduces lifespan in these patients, and the economic impact of pancreatitis is substantial. Efforts are needed to increase awareness of the impact of alcohol consumption and smoking on risk for pancreatitis and the benefits of cessation for primary and secondary prevention. PMID- 21243452 TI - Early management of severe acute pancreatitis. AB - Significant literature on the management of acute severe acute pancreatitis has emerged in recent years. The new information ranges from data on newer single or multiparameter severity assessment tools and classification systems to therapeutic modalities. However, a few basic issues-the ideal severity assessment modality, volume of intravenous fluids required in the first 48 to 72 h, and the role of prophylactic antibiotics-are still not clear and are subject to controversy. The International Working Group has devised the Revised Atlanta Classification, which will be published soon. This new classification is eagerly awaited worldwide, and hopefully clarifies many of the problems of the original Atlanta Classification. In this article, we discuss the developments that have arisen in the past 2 to 3 years concerning the classification, prognostication, and early management of severe acute pancreatitis. PMID- 21243453 TI - Gene therapy for allergic airway diseases. AB - Airway diseases such as allergic asthma and rhinitis are characterized by a T helper type 2 (Th2) response. Treatment of allergic airway diseases is currently limited to drugs that relieve disease symptoms and inflammation. In the search for new therapeutics, efforts have been made to treat allergic airway disease with gene therapy, and many preclinical studies have demonstrated its impressive potential. Most strategies focus on blocking the expression of proinflammatory proteins or transcription factors involved in the disease pathogenesis using antisense oligonucleotides, DNAzymes, small interfering RNA, or blocking of microRNAs using antagomirs. Changing the Th1/Th2 balance by overexpressing Th1 stimulating factors is another treatment option. Although the proof of concept is convincing in animal models, progress in humans remains limited. In this review, we focus on preclinical models to describe the recent developments and major breakthroughs for treating allergic airway diseases with gene therapy. PMID- 21243454 TI - Omalizumab: Anti-IgE therapy in allergy. AB - Omalizumab is a humanized, monoclonal anti-IgE antibody that binds specifically to circulating IgE molecules, thus interrupting the allergic cascade. Omalizumab has been shown to be highly effective in treating children and adults with moderate to severe allergic asthma. Beyond this indication, the mode of action itself suggests that omalizumab is not only an antiasthmatic drug but also a promising therapeutic option for various allergic conditions, including allergic rhinitis, food allergy, urticaria, allergic bronchopulmonary aspergillosis, insect hypersensitivity, and atopic dermatitis. However, data from double-blind, placebo-controlled clinical trials are only available for allergic rhinitis and moderate to severe bronchial asthma. The aim of this review is to discuss the current clinical data as well as possible further indications of omalizumab treatment. PMID- 21243455 TI - Surgical simulation in pediatric urologic education. AB - The drive to achieve improved patient outcomes and patient safety has led to innovation in surgical education. The century-old teaching paradigms of "see one, do one, teach one" and training by opportunity are inappropriate in a surgical world of rapidly introduced advanced technologies. The need for improved surgical education methods is no more critical than in pediatric surgery, where the complexity of patient diseases and the physical size of the patients tend to challenge the limitations of existing surgical technology and skill. Surgical simulation offers extraordinary opportunities to teach multiple clinical scenarios in a safe, nonhuman patient environment where performance feedback is immediate and objective. Although minimally invasive surgical techniques (laparoscopic and robotic) are ideally suited for computer-assisted or virtual reality training, medical decision-making simulation for minimally invasive surgery and open surgery is in its infancy and, arguably, the most important aspect of effective surgical practice. PMID- 21243456 TI - Feminizing surgery for disorders of sex development: evolution, complications, and outcomes. AB - Since the first part of the 20th century, when physicians and surgeons were struggling to understand disorders of sex development (DSD) and the variety of associated anomalies they produced, there have been great strides in feminizing surgery for patients with DSD. Surgical techniques were devised and concepts about how best to manage these complicated patients were developed. In this article, the evolution of these concepts and refinements of technique for feminizing genitoplasty that have taken place over the past three quarters of a century are presented, and the surgical outcomes and complications of feminizing genitoplasty are critically reviewed. PMID- 21243457 TI - Role of melanocortin receptors in the regulation of gouty inflammation. AB - Gouty arthritis is a form of acute joint inflammation provoked by joint deposition of urate crystals. Although this acute pathology resolves after a few days, the marked degree of inflammation in the joint and--possibly more important to the patient--the excruciating pain it causes require proper therapeutic management. Often deemed a "poor sibling" of chronic joint pathologies such as rheumatoid arthritis and psoriatic arthritis, the increasing incidence of gout makes it a more palatable disease for novel drug discovery programs. This fact, associated with novel insights into the molecular mechanisms activated by the urate crystal deposition, is at the basis of new therapeutics under clinical development for gout, a valid example being the effective targeting of the proinflammatory cytokine interleukin-1. Here we briefly review the current status of antigout drug development and propose another target; our focus is on melanocortin receptor agonists as novel therapeutics for gout and inflammatory arthritides, a prototype of which, the adrenocorticotropic hormone, is already used in clinical settings. PMID- 21243458 TI - [Socio-economic impact at the household level of the health consequences of toxic waste discharge in Abidjan in 2006]. AB - In August 2006, toxic wastes were discharged in the district of Abidjan, causing important health consequences in many households in the area. In order to appreciate the socio-economic impact of the consequences of toxic waste discharge on the households and of the measures taken by the authorities to deal with this catastrophe, and to appreciate the spatial extent of the pollution, we undertook a multidisciplinary transversal investigation at the sites of discharge of oxic waste, from October the 19th to December the 8th, 2006, using a transect sampling methodology. This paper presents the results related to the socio-economic aspects of the survey while the environmental and epidemiological results are presented in two other published papers. The socioeconomics investigation, conducted using a questionnaire, concerned 809 households across the various sites of discharge of toxic waste. More than 62% of households had at least one person who had been affected by toxic waste (affected households). 62.47% of these households were in Cocody district (with 2 sites and 4 points of discharge), 30.14% in Abobo district (with 2 sites and 3 points) and 7.39% in Koumassi district (with 1 site and 1 point). To escape the bad smell and the nuisance, 22.75% of the 501 "affected" households had left their houses. To face the health consequences generated by the toxic waste, 30.54% of the "affected" households engaged expenses. Those were on average of 92 450 FCFA (?141), with a minimum of 1 000 FCFA (?1.5) and a maximum of 1500000 FCFA (?2.287), in spite of the advertisement of the exemption from payment treatment fees made by the government. The decision of destroying cultures and farms near the points of discharge of the toxic products in a radius of 200 meters, taken by the authorities, touched 2.22% of the households. For these households, it did nothing but worsen their state of poverty, since the zone of influence of the toxic waste went well beyond the 200 meters prescribed by the authorities as the limit of the operations of destruction. PMID- 21243459 TI - [Seroprevalence of rubella virus, varicella zoster virus, cytomegalovirus and parvovirus B19 among pregnant women in the Sousse region, Tunisia]. AB - The aim of the study is to evaluate seroprevalence of rubella virus (RV), cytomegalovirus (CMV), varicella zoster virus (VZV), and parvovirus B19 (PB19) in 404 Tunisian pregnant women, and to determine reliability of maternal past history of eruption. Sociodemographic characteristics, risk factors, and past history of eruption were collected through a questionnaire. Serologic tests were performed using enzyme immunoassays. Risk factors were analyzed using univariate and multivariate logistic regression models. Seroprevalences were 79.7% for rubella, 96.3% for CMV, 80.9% for VZV, and 76.2% for PB19. In multivariate analysis, the number of persons per room (> 2) in the house during childhood was associated with CMV infection (P = 0.004), irregular professional husband's activity was correlated with VZV infection (P = 0.04), and an age of more than 30 years was associated with PB19 infection (P = 0.02). History of rubella, varicella, and PB19 infection was unknown for, respectively, 55.8%, 20%, and 100% of women. False history of rubella and varicella were found for 7.4% and 15% of women, respectively. The positive and negative predictive values (PPV and NPV) of rubella history were, respectively, 92.6% and 17.2%, and were, respectively, 84.9% and 20.9% for varicella history. Susceptibility to RV, VZV, and PB19 infection remains high in pregnancy in our population. Preventive strategies against congenital rubella must be reinforced. Vaccination against VZV should be considered in seronegative women. Systemic CMV screening is not warranted in our country where high immunity is acquired probably in childhood. Since maternal history of eruption is not reliable, we recommend serologic testing to determine immune status of women. PMID- 21243460 TI - [Poisoning by Atractylis gummifera L. Morocco poison control center data]. AB - To assess the extent and severity of poisoning by Atractylis gummifera L. in Morocco, a descriptive retrospective study was conducted on all the poisoning cases listed between 1981 and 2004 to the Morocco Poison Control Center. During this period, 240 people were hospitalized for glue thistle poisoning, 72% of which are children under 16 years. The severity of the poisoning has been affirmed by significant intrahospital lethality. Indeed, among the 182 patients for whom the outcomes were known, 98 died (54%). PMID- 21243461 TI - [MRI for therapy planning in patients with atrial septum defects]. AB - PURPOSE: The aim of this study was to determine the value of a combined magnetic resonance imaging (MRI) protocol including steady-state free precession (SSFP) imaging, phase-contrast measurements and contrast-enhanced MR angiography (CE MRA) for presurgical or preinterventional diagnostic imaging in patients with suspected atrial septum defects. MATERIAL AND METHODS: Out of 65 MRI studies of patients with suspected atrial septum defects, 56 patients were included in the study. The atrial septum defects were identified on cine images. Velocity encoded flow measurements were used to determine shunt volumes, which were compared with invasive oxymetry in 24 patients. Contrast-enhanced MRI was used to assess the thoracic vessels in order to detect vascular anomalies. The findings were compared with the intraoperative results. RESULTS: A total of 24 patients with high shunt volumes were treated either surgically (16 patients) or interventionally (8 patients) and 32 patients with low shunt volumes did not require surgical or interventional treatment. The vascular anomaly, which in all cases was anomalous pulmonary venous return, was confirmed by the intraoperative findings. The type and location of atrial septal defects which required treatment, were confirmed intraoperatively or during the intervention. The results of shunt quantification by MRI showed a good correlation with the results of invasive oximetry (r=0.91, p <0.0001). CONCLUSION: A combined MRI protocol including cine SSFP images, velocity-encoded flow measurements and CE-MRA is an accurate method for preoperative and preinterventional evaluation of atrial septum defects. PMID- 21243462 TI - [MRI for therapy control in patients with tetralogy of Fallot]. AB - With prevalences ranging from 0.26 to 0.80/00 of all live births tetralogy of Fallot (TOF) is the most common congenital heart disease with primary cyanosis. Due to improvements in surgical techniques, nearly all patients can nowadays expect to reach adulthood. After surgical repair, pulmonary regurgitation (PR) occurs in almost every child and is an important contributing factor in long-term morbidity and mortality. Cardiac magnetic resonance imaging is well established for functional assessment and flow measurements and is an ideal tool for serial post-surgical follow-up examinations, as it is non-invasive and does not expose patients to ionizing radiation. The timing of pulmonary valve replacement is crucial as right ventricular (RV) volumes have only proven to normalize when preoperative end-diastolic volumes are <170 ml/m(2) and end-systolic volumes are <85 ml/m(2). After surgical repair up to 15% of patients have residual or recurrent pulmonary artery stenosis. Distal pulmonary branch stenosis can aggravate PR and lead to right heart failure due to combined pressure and volume overload. Therefore, it has to be diagnosed in time and treated by angioplasty with or without stenting. PMID- 21243463 TI - [ The ABC's of medical statistics. Reading and understanding clinical trials ]. PMID- 21243466 TI - First-principles-based multiscale, multiparadigm molecular mechanics and dynamics methods for describing complex chemical processes. AB - We expect that systematic and seamless computational upscaling and downscaling for modeling, predicting, or optimizing material and system properties and behavior with atomistic resolution will eventually be sufficiently accurate and practical that it will transform the mode of development in the materials, chemical, catalysis, and Pharma industries. However, despite truly dramatic progress in methods, software, and hardware, this goal remains elusive, particularly for systems that exhibit inherently complex chemistry under normal or extreme conditions of temperature, pressure, radiation, and others. We describe here some of the significant progress towards solving these problems via a general multiscale, multiparadigm strategy based on first-principles quantum mechanics (QM), and the development of breakthrough methods for treating reaction processes, excited electronic states, and weak bonding effects on the conformational dynamics of large-scale molecular systems. These methods have resulted directly from filling in the physical and chemical gaps in existing theoretical and computational models, within the multiscale, multiparadigm strategy. To illustrate the procedure we demonstrate the application and transferability of such methods on an ample set of challenging problems that span multiple fields, system length- and timescales, and that lay beyond the realm of existing computational or, in some case, experimental approaches, including understanding the solvation effects on the reactivity of organic and organometallic structures, predicting transmembrane protein structures, understanding carbon nanotube nucleation and growth, understanding the effects of electronic excitations in materials subjected to extreme conditions of temperature and pressure, following the dynamics and energetics of long-term conformational evolution of DNA macromolecules, and predicting the long-term mechanisms involved in enhancing the mechanical response of polymer-based hydrogels. PMID- 21243467 TI - Personality and temperament. AB - The assessment of personality and temperament in the context of eating disorders (EDs) poses unique challenges because of the physiological symptoms and sequelae of these illnesses. Four models of the relationship between personality and EDs are presented, along with a discussion of the different methodological designs which can evaluate these models. Current data support the likelihood that neuroticism and perfectionism are risk factors for EDs. Perfectionism and the related obsessive-compulsive personality disorder may also share a common cause with anorexia nervosa. High harm avoidance and low self-directedness also characterize all EDs, though more data are needed to confirm their role as risk factors; importantly however, this combination of traits may diminish one's ability to cope with stressful life events. At the other end of the spectrum, considering impulsivity multidimensionally may be important to understanding the role of this personality trait in EDs, though existing data do not yet allow for conclusions regarding its role as a risk factor versus a consequence of the ED. All of the identified traits that may be risk factors are also exacerbated as a consequence of having, or having had, an ED. Finally, the role of personality disorders in influencing the course and outcome of EDs is still unclear. A fruitful avenue for future research in this area is to utilize personality and temperament to classify individuals in a way that allows for the best chance of identifying genetic loci that confer increased risk for EDs. PMID- 21243468 TI - Cognitions and emotions in eating disorders. AB - The cognitive model of eating disorders (EDs) states that the processing of external and internal stimuli might be biased in mental disorders. These biases, or cognitive errors, systematically distort the individual's experiences and, in that way, maintains the eating disorder. This chapter presents an updated literature review of experimental studies investigating these cognitive biases. Results indicate that ED patients show biases in attention, interpretation, and memory when it comes to the processing of food-, weight-, and body shape-related cues. Some recent studies show that they also demonstrate errors in general cognitive abilities such as set shifting, central coherence, and decision making. A future challenge is whether cognitive biases and processes can be manipulated. Few preliminary studies suggest that an attention retraining and training in the cognitive modulation of food reward processing might be effective strategies to change body satisfaction, food cravings, and eating behavior. PMID- 21243471 TI - Dopamine-based reward circuitry responsivity, genetics, and overeating. AB - Data suggest that low levels of dopamine D2 receptors and attenuated responsivity of dopamine-target regions to food intake is associated with increased eating and elevated weight. There is also growing (although mixed) evidence that genotypes that appear to lead to reduced dopamine signaling (e.g., DRD2, DRD4, and DAT) and certain appetite-related hormones and peptides (e.g., ghrelin, orexin A, leptin) moderate the relation between dopamine signaling, overeating, and obesity. This chapter reviews findings from studies that have investigated the relation between dopamine functioning and food intake and how certain genotypes and appetite related hormones and peptides affect this relation. PMID- 21243469 TI - Neurocircuity of eating disorders. AB - OBJECTIVES: This chapter reviews brain imaging findings in anorexia and bulimia nervosa which characterize brain circuitry that may contribute to the pathophysiology of eating disorders (EDs). SUMMARY OF RECENT FINDINGS: Recent imaging studies provide evidence of disturbed gustatory processing in EDs which involve the anterior insula as well as striatal regions. These results raise the possibility that individuals with anorexia nervosa have altered appetitive mechanism that may involve sensory, interoceptive, or reward processes. Furthermore, evidence of altered reward mechanisms is supported by studies that suggest that individuals with anorexia nervosa and bulimia nervosa share a trait toward similar anterior ventral striatal pathway dysregulation. This shared trait disturbance of the modulation of reward and emotionality may create a vulnerability for dysregulated appetitive behaviors. However, those with anorexia nervosa may be able to inhibit appetite and have extraordinary self-control because of exaggerated dorsal cognitive circuit function, whereas individuals with bulimia nervosa are vulnerable to overeating when they get hungry, because they have less ability to control their impulses. FUTURE DIRECTIONS: Current therapeutic interventions have modest success. Better understanding of neurocircuits that may be related to altered appetite, mood, impulse control, and other symptoms underlying the pathophysiology of EDs might improve psychotherapeutic and drug treatment strategies. PMID- 21243470 TI - Serotonin: imaging findings in eating disorders. AB - Anorexia nervosa (AN) and bulimia nervosa (BN) are disorders characterized by aberrant patterns of feeding behavior, weight regulation, and disturbances in attitudes and perceptions toward body weight and shape. Several lines of evidence nominate disturbances of serotonin (5-HT) pathways as playing a role in the pathogenesis and pathophysiology of AN and BN. For example, 5-HT pathways are known to contribute to the modulation of a range of behaviors commonly seen in individuals with AN and BN. New technology using brain imaging with radioligands offers the potential for understanding previously inaccessible brain 5-HT neurotransmitter function and its dynamic relationship with human behaviors. Recent studies using positron emission tomography and single photon emission computed tomography with 5-HT-specific radioligands have consistently shown 5 HT(1A) and 5-HT(2A) receptor and 5-HT transporter alterations in AN and BN in cortical and limbic structures, which may be related to anxiety, behavioral inhibition, and body image distortions. These disturbances are present when subjects are ill and persist after recovery, suggesting that these may be traits that are independent of the state of the illness. Effective treatments for AN and BN have been elusive. A better understanding of neurobiology is likely to be important for developing specific and more powerful therapies for these often chronic and deadly disorders. PMID- 21243472 TI - Reward and neurocomputational processes. AB - The neurobiology of eating disorders (EDs) is largely unknown. However, brain imaging studies over the past decade have identified neurotransmitter alterations that could be part of dysfunctional behavior characteristics of EDs. In this chapter we focus on a specific behavioral construct, the brain reward system, and demonstrate a functional brain imaging approach toward identifying dopamine function in anorexia nervosa (AN). We demonstrate how human brain reward activation can be used in a translational approach to test whether computer models, based on basic science research, can predict expected in vivo reward system activation, and how such an approach can identify specific biologic alterations in a psychiatric population. PMID- 21243473 TI - Cognitive-behavioral flexibility in anorexia nervosa. AB - Anorexia nervosa (AN) patients are characterized by perfectionism and obsessional personality traits. This anorectic personality type is associated with an exaggerated cognitive control and impaired cognitive-behavioral flexibility. Neuropsychological studies addressing flexibility have supported an impaired cognitive set-shifting (i.e., concrete and rigid behaviors to changing rules) as well as an impaired behavioral response shifting (i.e., stereotyped or perseverative behaviors) in AN patients independent of nutritional status and body weight. Furthermore, impaired set-shifting was found in healthy sisters of AN patients suggesting that cognitive inflexibility is a trait marker in AN patients. Brain imaging studies have provided new insights in striatocortical circuit dysfunctions that may underlie both the clinical symptoms of obsessive compulsive personality traits and the neuropsychological observations of impaired cognitive-behavioral flexibility. The conceptualization of AN as a neurodevelopmental striatocortical disorder may help to develop new promising treatment approaches for this severe disorder. PMID- 21243475 TI - The genetics of eating disorders. AB - The eating disorders anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder and allied diagnoses such as eating disorder not otherwise specified are common, complex psychiatric disorders with a significant genetic component. Aetiology is unknown, but both phenotypic characteristics and genetic factors appear to be shared across these disorders, and indeed patients often change between diagnostic categories. Molecular studies have attempted to define genetic risk factors for these disorders, including case-control and family-based candidate gene association studies and linkage analysis of multiply affected nuclear families. These have used both clinical diagnoses and eating disorder related intermediate phenotypes such as drive-for-thinness or body dissatisfaction. Candidate gene studies have focussed on neurotransmitter and neurodevelopmental systems [e.g. serotonergic, opioid, cannabinoid and dopaminergic receptors, and brain-derived neurotrophic factor (BDNF)], appetite regulatory peptides and their receptors [leptin, ghrelin, agouti-related protein (AgRP), melanocortin receptors, neuropeptide Y], energy balance systems (e.g. uncoupling proteins), genes implicated in obesity (e.g. FTO) and sex hormone systems (e.g. oestrogen receptors), either identified on the basis of their function alone or as positional candidates from linkage analysis. Of these studies, linkage analysis implicates 1p33-36 for AN, 1q31.3 for quantitative behavioural traits related to anorexia and 10p14 for BN, as well as other behavioural phenotypes across both disorders. Candidate gene association has implicated BDNF, delta 1 opioid receptor (OPDR1) and AgRP. More recently, with the advent of genome-wide association studies (GWAS), analysis with microsatellite markers has implicated novel candidate loci for AN at 1q41 and 11q22, and further GWAS results are expected in the near future. PMID- 21243474 TI - The heritability of eating disorders: methods and current findings. AB - Family, twin, and adoption studies of anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), and the proposed purging disorder presentation (PD) have consistently demonstrated that genetic factors contribute to the variance in liability to eating disorders. In addition, endophenotypes and component phenotypes of eating disorders have been evaluated and provide further insight regarding genetic factors influencing eating disorders and eating disorder diagnostic criteria. Many of these phenotypes have demonstrated substantial heritability. This chapter reviews biometrical genetic methods and current findings from family and twin studies that investigate the role of genes and environment in the etiology of eating disorders. We review the methodology used to estimate heritability, the results of these studies, and discuss the implications of this research for the basic conceptualization of eating disorders and the future value of twin modeling in the molecular genetic era. PMID- 21243476 TI - The influence of gender and puberty on the heritability of disordered eating symptoms. AB - Eating disorders and disordered eating symptoms are clearly heritable, but recent research has suggested that genetic and environmental influences on disordered eating symptoms vary as a function of gender and development. Data are limited, but evidence suggests that gender may moderate the type of genetic risk, rather than the magnitude of genetic effects, on disordered eating symptoms. Only a moderate proportion of the genetic influences on disordered eating symptoms are shared between males and females. In females, at least some of the unique genetic risk may be related to puberty and ovarian hormone regulation. The heritability of disordered eating symptoms in females increases with both pubertal development and increasing levels of estradiol. Although much more research is needed to elucidate specific mechanisms, gonadal hormones may be promising candidates for understanding sex and developmental effects and the ways in which genes exert their influence on disordered eating. PMID- 21243477 TI - New frontiers in endocrinology of eating disorders. AB - Alterations of both central and peripheral feeding regulatory substances occur in the acute phases of anorexia nervosa (AN) and bulimia nervosa (BN) and, generally, reverse after recovery. Some of these alterations are believed not only to sustain the altered eating behavior but also to contribute to certain psychopathological aspects and/or etiopathogenetic processes of eating disorders (EDs). It has been suggested that EDs are clinical conditions linked to reward related mechanisms leading to a kind of addiction to self-starvation and/or overeating. Most of the feeding regulatory substances, which are dysregulated in EDs, are also implicated in the modulation of reward, emotional, and cognitive functions, thus representing possible links between altered nutritional regulation, motivated behaviors and reward processes. In this chapter, the ED literature dealing with ghrelin, brain-derived neurotrophic factor, opioid peptides, and endocannabinoids, which have prominent effects on eating behavior, body weight, reward, emotional, and cognitive functions, is reviewed in view of the above suggested links. Moreover, the potential therapeutics of new medications developed on the basis of neuroendocrine aberrations found in EDs is also presented. PMID- 21243478 TI - Animal models of eating disorder traits. AB - Eating disorders, such as anorexia and bulimia nervosa, are psychiatric disorders that are likely determined by a complex interaction between genetic variations, developmental processes, and certain life events. Cross-species analysis of traits related to eating disorders may provide a way to functionally and systematically study neurobiological mechanisms underlying these disorders. Interspecies trait genetics may offer opportunities to identify common neurobiological mechanisms underlying eating disorder characteristics relevant to the initiation, progression, and/or maintenance of the disease, such as cognitive rigidity, increased anxiety levels, and behavioral hyperactivity. These can subsequently be tested directly by studying allelic variation in mice and human subjects and by applying methods that can modify gene expression levels in rodent models. Increasing our knowledge about these traits and their underlying neurobiological mechanisms will be relevant to develop new therapies for patients within the heterogeneous eating disorder populations. Novel mouse genetic and phenotyping tools offer a way to study these neurobehavioral traits under controlled environmental and genetic background conditions. PMID- 21243479 TI - Neurobiology driving hyperactivity in activity-based anorexia. AB - Hyperactivity in anorexia nervosa is difficult to control and negatively impacts outcome. Hyperactivity is a key driving force to starvation in an animal model named activity-based anorexia (ABA). Recent research has started unraveling what mechanisms underlie this hyperactivity. Besides a general increase in locomotor activity that may be an expression of foraging behavior and involves frontal brain regions, the increased locomotor activity expressed before food is presented (food anticipatory behavior or FAA) involves hypothalamic neural circuits. Ghrelin plays a role in FAA, whereas decreased leptin signaling is involved in both aspects of increased locomotor activity. We hypothesize that increased ghrelin and decreased leptin signaling drive the activity of dopamine neurons in the ventral tegmental area. In anorexia nervosa patients, this altered activity of the dopamine system may be involved not only in hyperactivity but also in aberrant cognitive processing related to food. PMID- 21243480 TI - Translating experimental neuroscience into treatment of eating disorders: two examples. AB - Anorexia nervosa (AN) is a serious mental disorder with impaired functioning including not only the cognitive and socio-emotional but also physical domains. Improved treatments, especially for adults with AN, are urgently needed. The insights gained from basic research in experimental animal models and the advent of cognitive neuroscience have produced major advances in our understanding of the condition, but translating these into clinical research or practice remains a challenge. We describe here what the eating disorders field can gain from schizophrenia research in this area. We use the example of socio-emotional impairments in AN to describe the iterative process between basic research and intervention development for neurobiologically informed and based treatments for this condition and briefly touch on some other examples that stem from translational science. PMID- 21243481 TI - Cognitive remediation therapy for eating disorders: development, refinement and future directions. AB - In this chapter, we aim to address some basic conceptual and practical questions about cognitive remediation therapy (CRT) for eating disorders. We begin by providing an overall historical, conceptual, and theoretical framework for CRT. Next, we discuss the specific indications for how and why CRT might be useful for eating disorders based on existing neuropsychological research evidence. We also provide an overview of the types of tasks and stimuli used in CRT and a general protocol for a manualized version of CRT. In addition, modifications of the adult CRT manual for use with adolescents as well as preliminary acceptability of the approach with this younger age group are described. We also propose various ways to integrate CRT in a variety of inpatient and outpatient programmes. Finally, a discussion of potential future directions in research using the tools of neurocognitive assessment, imaging and treatment research is provided. PMID- 21243482 TI - Incorporating dispositional traits into the treatment of anorexia nervosa. AB - We provide a general framework to guide the development of interventions that aim to address persistent features in eating disorders that may preclude effective treatment. Using perfectionism as an exemplar, we draw from research in cognitive neuroscience regarding attention and reinforcement learning, from learning theory and social psychology regarding vicarious learning and implications for the role modeling of significant others, and from clinical psychology on the importance of verbal narratives as barriers that may influence expectations and shape reinforcement schedules. PMID- 21243483 TI - [Reconstruction after spinal fractures in the thoracolumbar region]. AB - The morbidity of anterior approaches has significantly influenced the development of therapeutic concepts for the treatment of thoracolumbar spine fractures. Minimally-invasive techniques such as mini-open and endoscopic have enlarged the numbers of anterior reconstruction after spinal fractures in the thoracolumbar region. These minimally-invasive approaches have been facilitated by the development of special implants adapted to the new technique and to the local anatomical requirements.Two multi center studies in Germany (MCSI and II) showed the trend towards minimal invasive procedures and anterior approaches in the German speaking spine centers. Since the first report on thoracoscopic anterior procedures in Germany in 1997 a growing number of spine centers established this method. There is still no evidence based high level literature to substantiate a significant benefit for the patients by anatomical reduction and reconstruction of the anterior spinal column. However, there are some reports on better short outcomes in radiological parameters as well as better clinical results in 5 to 8 year follow-ups.The minimal invasive anterior approach seems to be advantageous for the patients by reducing significantly additive operation morbidity. It has become more important over the last two decades for anterior reconstruction after trauma and posttraumatic malalignment of the thoracolumbar spine. PMID- 21243484 TI - Injury of the corona mortis during vaginal tape insertion (TVT-SecurTM using the U-Approach). AB - INTRODUCTION AND HYPOTHESIS: We report a serious bleeding complication due to injury of the corona mortis following insertion of a transvaginal tape, TVT SecurTM (Ethicon Women's Health, Sommerville, NJ, USA). METHODS: The TVT-SecurTM was inserted using the U-Approach: the tape was pushed along the periost behind the arc of the pubic bone at an angle of 45 degrees . RESULTS: Surgery was unproblematic. Four hours after surgery, the patient showed shock signs; a CT scan revealed a 13.5 * 9.5-cm-sized retrosymphysic haematoma. Instant laparotomy with removal of the large haematoma, ligation of the bleeding corona mortis and administration of erythrocyte concentrates were necessary. CONCLUSION: The corona mortis is an anastomosis between the arteria obturatoria and the external iliac vessels or its branches that passes over the superior pubic ramus. Its prevalence and anatomical relation to the pubic bone are important to bear in mind when applying new surgical techniques. PMID- 21243485 TI - Interaction between non-psychotropic cannabinoids in marihuana: effect of cannabigerol (CBG) on the anti-nausea or anti-emetic effects of cannabidiol (CBD) in rats and shrews. AB - RATIONALE: The interaction between two non-psychotropic cannabinoids, cannabidiol (CBD) and cannabigerol (CBG), which have been reported to act as a 5 hydroxytryptamine 1A (5-HT(1A)) agonist and antagonist, respectively, was evaluated. OBJECTIVE: To evaluate the potential of CBG to reverse the anti nausea, anti-emetic effects of CBD. MATERIALS AND METHODS: In experiment 1, rats were pre-treated with CBG (0.0, 1, 5, and 10 mg/kg, ip), 15 min prior to being treated with CBD (experiment 1a: VEH or 5 mg/kg, ip) or 8-OH-DPAT (experiment 1b: VEH or 0.01 mg/kg, ip). Thirty minutes later, all rats received a pairing of 0.1% saccharin solution and LiCl (20 ml/kg of 0.15 M, ip). Seventy-two hours later, the rats received a drug-free taste reactivity test with saccharin to evaluate the effects of the treatments on the establishment of conditioned gaping reactions (a model of nausea). As well, conditioned saccharin avoidance was measured. In experiment 2, Suncus murinus were injected with CBG (5 mg/kg, ip) or VEH 15 min prior to CBD (5 mg/kg) or VEH and 30 min later were injected with LiCl (60 ml/kg of 0.15 M, i.p.), and the number of vomiting episodes were measured. RESULTS: CBD (5 mg/kg) suppressed conditioned gaping in rats and vomiting in shrews, which were reversed by pre-treatment with all doses of CBG. CBG also prevented the anti-nausea effects of 8-OH-DPAT. CONCLUSIONS: Interactions between moderate doses of CBG and CBD may oppose one another at the 5-HT(1A) receptor in the regulation of nausea and vomiting. PMID- 21243486 TI - Direction and magnitude of nicotine effects on the fMRI BOLD response are related to nicotine effects on behavioral performance. AB - Considerable variability across individuals has been reported in both the behavioral and fMRI blood oxygen level-dependent (BOLD) response to nicotine. We aimed to investigate (1) whether there is a heterogeneous effect of nicotine on behavioral and BOLD responses across participants and (2) if heterogeneous BOLD responses are associated with behavioral performance measures. In this double blind, placebo-controlled, cross-over study, 41 healthy participants (19 smokers) -drawn from a larger population-based sample--performed a visual oddball task after acute challenge with 1 mg nasal nicotine. fMRI data and reaction time were recorded during performance of the task. Across the entire group of subjects, we found increased activation in the anterior cingulate cortex, middle frontal gyrus, superior temporal gyrus, post-central gyrus, planum temporal and frontal pole in the nicotine condition compared with the placebo condition. However, follow-up analyses of this difference in activation between the placebo and nicotine conditions revealed that some participants showed an increase in activation while others showed a decrease in BOLD activation from the placebo to the nicotine condition. A reduction of BOLD activation from placebo to nicotine was associated with a decrease in reaction time and reaction time variability and vice versa, suggesting that it is the direction of BOLD response to nicotine which is related to task performance. We conclude that the BOLD response to nicotine is heterogeneous and that the direction of response to nicotine should be taken into account in future pharmaco-fMRI research on the central action of nicotine. PMID- 21243487 TI - Cardioprotective microRNAs. AB - MicroRNAs (miRNAs) are involved in almost every aspect of a mammalian cell's functionality, from stem cell differentiation to aging and pathogenesis; however, their role in immediate cell signaling is less defined. This has been recently demonstrated by the rapid increase or decrease of miR-21's abundance within minutes of activation or inhibition of the v-akt murine thymoma viral oncogene homolog 1 (AKT) pathway, respectively, which mediates its regulation of Fas ligand and phosphatase and tensin homologue deleted on chromosome 10 expression, among other targets. Conversely, AKT induces rapid downregulation of miR-199a-5p to effect upregulation of hypoxia-inducible factor 1alpha and sirtuin 1. This suggests that posttranscriptional mechanisms regulate miRNAs' processing and/or stability to induce the rapid fluctuation in their levels. In support, a growing number of studies are showing specific posttranscriptional regulation of miRNAs. The data potentially explain how AKT, and plausibly other signaling pathways, can specifically and promptly modulate a gene's translation while circumventing the need for transcription during transient signaling events. PMID- 21243489 TI - Interaction between the skeletal and immune systems in cancer: mechanisms and clinical implications. AB - The skeletal and immune systems have a complex relationship. Both systems are intimately coupled, with osteoclastogenesis and hematopoiesis occurring in the bone marrow. Bone and immune cells also share common hematopoietic precursors. Furthermore, the skeletal and immune systems share various cytokines, receptors, and transcription factors that regulate signal transduction pathways involved in osteoclastogenesis and immune system activation, including the receptor activator of nuclear factor-kappaBeta ligand/receptor activator of nuclear factor kappaBeta/osteoprotegerin (RANKL-RANK-OPG) pathway. Cancer cells can disrupt both the skeletal and immune systems. Interaction between cancer and bone cells results in a vicious cycle of bone destruction and cancer growth. Bone remodeling generates a growth-factor-rich environment that attracts cancer cells and promotes their proliferation. In turn, cancer cells stimulate osteoclast formation and activity, resulting in additional bone resorption that further stimulates cancer cell growth. Currently available bone-targeted therapies may also modulate the immune system. Bisphosphonates such as zoledronic acid exert stimulating effects on the immune system, resulting in possible anticancer activity against malignant cells. Denosumab, an anti-RANKL monoclonal antibody with proven antiosteoclast activity, may suppress immune responses. This may result in the reported association with an increased risk of neoplasms, as well as serious skin and other infections as reported in some studies, mainly in the postmenopausal setting. When assessing bone-targeted therapies, it is important to consider the shared signaling pathways between bone and the immune system, as well as the clinical risk:benefit ratio. PMID- 21243488 TI - Complexity of transcriptional regulation within the Rag locus: identification of a second Nwc promoter region within the Rag2 intron. AB - Nwc represents a mysterious third evolutionarily conserved gene within the Rag locus. Here, we analyzed the phenotype of Nwc(tmpro1) mice, in which the Rag2 intragenic region containing the previously identified promoter responsible for initiating transcription of Nwc in all cells except lymphocytes was deleted by homologous recombination. Despite strong nonlymphocyte-specific inhibition of Nwc transcription which runs through the regulatory region of Rag genes, their expression remained suppressed, and no developmental, morphological, anatomical, functional, physiological, or cellular defects in Nwc(tmpro1) mice could be observed. However, careful analysis of the Rag2 intergenic region uncovered a second evolutionarily conserved Nwc promoter region from which a previously unknown Nwc transcript can be generated in nonlymphocytes of Nwc(tmpro1) and normal mice. The above results reveal an unexpected additional complexity of transcriptional regulation within the Rag/Nwc locus and show that strong inhibition of Nwc transcription in nonlymphoid cells is well tolerated. Complete inactivation of Nwc is necessary to get insight into its function at transcriptional and posttranscriptional levels. PMID- 21243490 TI - Different genetic effect of PXK on systemic lupus erythematosus in the Korean population. AB - PXK was identified as a novel candidate gene for systemic lupus erythematosus (SLE) from genome-wide association studies (GWAS) in Caucasians. But a recent replication study in Hong Kong Chinese reported that PXK was not associated with SLE. The aim of this study was to determine whether PXK is associated with SLE in Koreans. We genotyped single nucleotide polymorphism (SNP) rs6445975 of PXK using the TaqMan assay in 527 Korean patients with SLE and 517 healthy Korean control subjects. Genotypic associations were assessed using multiple logistic regression models. Additional analyses were also performed by subphenotype stratification. No association was detected between PXK rs6445975 and SLE (odds ratio (OR) = 1.06, P = 0.57). PXK rs6445975 showed positive associations with photosensitivity (P = 0.02) and the production of anti-Sm Ab (P = 0.04) among SLE patients. Thus, the association of PXK rs6445975 with SLE that was previously observed in Caucasians was not replicated in Koreans or in Hong Kong Chinese. It is possible that PXK has different genetic contribution on SLE between Caucasians and Asians and that the gene is associated with disease subphenotypes rather than with overall susceptibility. PMID- 21243491 TI - Leflunomide use in a cytomegalovirus infection of a patient with dermatomyositis. AB - Human cytomegalovirus (CMV) is responsible for significant morbidity and mortality in immunocompromised populations, such as those suffering from dermatomyositis (DM). We present here a case study of a DM patient undergoing methotrexate treatment who presents with weakness, myalgia, elevated levels of hepatic transaminases and serological markers of CMV primo-infection. The antiviral activity of leflunomide against CMV was described recently. The use of leflunomide as an immunomodulator may have contributed to the satisfactory evolution of the treatment for a symptomatic CMV infection in an immunocompromised patient, since the typical treatment outcome is more prolonged and with additional complications. PMID- 21243492 TI - Elevated Th17 cells are accompanied by FoxP3+ Treg cells decrease in patients with lupus nephritis. AB - To investigate the variations of T-helper 17 (Th17) and regulatory T (Treg) cells in patients with lupus nephritis (LN), a total of 60 systemic lupus erythematosus patients and 28 healthy controls (HCs) were enrolled. The frequency of Th17 cells and Treg cells in peripheral blood mononuclear cells (PBMCs) was evaluated by flow cytometric analysis. The serum concentrations of interleukin-17 (IL-17) and transforming growth factor-beta 1 (TGF-beta1) were measured by enzyme-linked immunosorbent assay (ELISA). The results demonstrated in LN patients a significant decrease in the frequency of CD4+CD25(high) and CD4+CD25+FoxP3+ T cells and a significant increase in the frequency of Th17 cells in peripheral blood, and the ratio of Th17 to Treg cell frequency was significantly increased along with increased SLEDAI scores. LN patients had a lower percentage and expression of FoxP3 in CD4+CD25(high) T cells than SLE patients without nephritis. The concentration of TGF-beta1 was found decreased in SLE patients compared with that from healthy controls, though no significant difference was found between LN patients and SLE patients without nephritis. The expression of IL-17 levels in LN patients exhibited a significant increase compared with patients without nephritis and healthy controls. Based on our results, the significantly elevated Th17 cells are accompanied by FoxP3+ Treg cells decrease in lupus nephritis, suggesting that Th17/Treg functional imbalance may be involved in the pathogenesis of renal damage in SLE patients. PMID- 21243493 TI - Long-term follow-up of adalimumab monotherapy for rheumatoid arthritis in Japanese patients: a report of six cases. AB - We present six cases of patients with Japanese rheumatoid arthritis (RA) treated with a tumor necrosis factor (TNF)-alpha blocking agent, adalimumab as monotherapy for 220 weeks. All six patients were women, and the median age was 54.0 +/- 7.07 years old. The median duration of the disease was 7.43 +/- 11.1 years, and the median disease activity score (DAS28-CRP) was 5.35 +/- 0.69. Three of six patients were able to continue to receive this treatment for 220 weeks successfully, and the DAS28-CRP decreased to 1.89 +/- 0.75. Two patients withdrew because of lack of efficacy, and one patient withdrew because of adverse events (non-Hodgkin lymphoma). Adalimumab resulted in a sustained clinical response in RA patients during 220-week follow-up. PMID- 21243494 TI - The association between dermatomyositis and papillary thyroid cancer: a case report. AB - We report the case of a 66-year-old woman who developed progressive proximal muscle weakness and papillary thyroid cancer. After a thyroidectomy, she was treated with intravenous methylprednisolone pulse therapy and oral prednisolone followed by tacrolimus therapy. However, her clinical symptoms and laboratory data did not improve sufficiently. Therefore, we administered intravenous immunoglobulin. As a result, she regained substantial muscle strength along with complete normalization of serum muscle enzymes and showed no evidence of recurrence of papillary thyroid cancer or exacerbation of dermatomyositis (DM). Although there is controversy as to whether papillary thyroid cancer is involved in DM, the results of this study support a connection between these two conditions. PMID- 21243495 TI - The impact of HSV for inflammatory arthropathy patients. AB - Herpes simplex virus type 1 (HSV-1), also known as herpes labialis, is the etiologic agent of vesicular lesions of the oral mucosa commonly referred to as "cold sores". HSV-1 can also cause clinical disease in a wide variety of other anatomic locations including the genitalia, liver, lung, eye, and central nervous system. These infections can be severe, particularly in the setting of immunosuppression, such as inflammatory arthropathy patients on Methotrexate +/- biological therapies. Here, we highlight the importance of physician awareness of HSV due to its potential impact for rheumatology patients. PMID- 21243496 TI - Thrombocytosis in rheumatoid arthritis: JAK2V617F-positive essential thrombocythemia. AB - Thrombocytosis is an important laboratory finding in rheumatoid arthritis (RA) and it has a correlation with disease activity. Janus kinase 2 valin 617 phenylalanine (JAK2V617F) mutation has gained importance in the diagnosis of myeloproliferative diseases recently. There is no published report in literature on the association between RA and JAK2V617F-positive essential thrombocythemia (ET). In this report, we present a JAK2V617F-positive ET case that had RA. A 57 year-old male patient was diagnosed with RA according to the criteria of American College of Rheumatology (ACR), whose complaint was of pain in the hands and morning stiffness lasting for about 2 h. The patient was evaluated for thrombocytosis because he was in remission and suffering persistent thrombocytosis under treatment. After excluding the causes of secondary thrombocytosis, bone marrow aspiration and biopsy was performed. On peripheral blood and bone marrow PCR examination, the patient was detected to be JAK2V617F positive heterozygously and diagnosed with ET. As a conclusion, mild-moderate thrombocytosis is frequent in RA; however, ET can be diagnosed by JAK2V617F evaluation in peripheral blood in thrombocytosis, especially when platelet count is more than 1 million/ml and when persisting thrombocytosis is detected in RA remission. PMID- 21243497 TI - Polymyositis and dermatomyositis in Sarawak: a profile of patients treated in the Sarawak General Hospital. AB - We performed a cross-sectional study of the demography, clinical and laboratory features of patients with polymyositis and dermatomyositis followed up in our centre from 2006 to 2009. There were 12 cases, with the majority of them (58.3%) being woman. They have a mean age of 57.8 years and mean disease duration of 11.83 (SD 9.92) months. Our patients comprised of multi-ethnic groups with predominantly Chinese (83.3%), Sarawak natives (8.3%) and Malays (8.3%). They have a mean lag time to diagnosis of 3.67 (SD 4.27) months. Nine (75%) patients had dermatomyositis and 3(25%) had polymyositis. The common clinical manifestations found in our patients were proximal myopathy (100%), neck weakness (33.3%), dysphagia (33.3%) and interstitial lung disease (33.3%). For the nine patients with dermatomyositis, the most common dermatological manifestations were shawl sign (88.9%) and V sign (88.9%). Muscle enzymes were raised in 91.7% of patients. Electromyographies were carried out in four patients, and only one of our patients had muscle biopsy. Only 41.7% of our patients have positive ANA. The majority received prednisolone (100%) and hydroxychloroquine (58.3%). Malignancy occurred in five (three nasopharyngeal carcinomas, one sigmoid colon cancer and one lung cancer) out of the nine dermatomyositis patients but none in the polymyositis group. The mortality rate in our group was 4(33.3%) over the 4-year period. This study demonstrated the rarity of PM/DM in our centre with considerable lag time to diagnosis in our patients. Despite lack of muscle biopsy in our centre, our centre achieved appropriate diagnosis and management of PM/DM. PMID- 21243498 TI - The prevalence of vertebral fractures and health-related quality of life in postmenopausal women. AB - Vertebral fractures are the hallmark of osteoporosis, responsible for increased back pain, impairment of mobility and functional limitations. These factors have an impact on patients' health-related quality of life (QOL). The aim of this study was to evaluate the prevalence of vertebral fractures in Moroccan postmenopausal women and to assess their QOL, using an Arabic validated version of QUALEFFO. The study recruited 347 postmenopausal women in obvious good health. We excluded women who had used a drug or who had chronic diseases affecting bone metabolism. All patients had density measurements and spinal radiography. Each vertebral body (T4-L5) was graded using the semiquantitative method of Genant. The mean age was 60 years. Forty-six percent of patients had at least one vertebral fracture. The prevalence ranged from 31% in patients 50-55 years to 69% in patients 65 years and older. Patients with vertebral fractures were older (61.6 +/- 8 vs 57 +/- 7 years, P < 0.001), had more frequent history of nonvertebral fractures, and had spine and hip BMD values significantly lower (P < 0.001) than patients without vertebral fractures. In multivariate analysis, older age and a history of nonvertebral fractures were the two independent clinical factors of vertebral fractures. The number of fractures was a determinant of a low QOL, as indicated by an increased score in physical function, social function, mental function, and general health [for all (P < 0.05)]. Patients with higher grades of vertebral deformities, i.e., more severe fractures, had low QOL in these four domains. Patient with thoracolumbar fractures had a worse general health than patients with thoracic or lumbar fractures. We found a high prevalence of vertebral fractures probably explained by socioeconomic factors in Morocco. QOL, assessed by an osteoporosis-specific instrument, is decreased in postmenopausal women as a function of both the number and the severity of the vertebral fractures. Treating women with prevalent fractures may avoid a further decrease in their quality of life. PMID- 21243499 TI - Health-related quality of life and utility in patients receiving biological and non-biological treatments in rheumatoid arthritis. AB - Biological treatments earn increasing significance in the treatment of rheumatoid arthritis (RA) but are associated with high incremental cost-effectiveness ratio compared to conventional antirheumatic treatments such as disease-modifying antirheumatic drugs. As the most important objective of medical technologies should be to increase life years and/or patients' health-related quality of life (HRQoL), measuring QoL and utility in RA patients treated with biological therapies is crucial. The objective of this study is to compare the utility and QoL of patients treated with biological (n = 85) and non-biological (n = 168) antirheumatic drugs in Hungary in a cross-sectional non-interventional study. A measure of impairment (Disease Activity Score (DAS)-28), QoL measure (EuroQol five Dimension (EQ-5D) Visual Analogue Scale (VAS), Rheumatoid Arthritis Quality of Life (RAQoL)) and utility measures (indirect: EQ-5D index, direct: time trade off (TTO)) were applied using an interview method. The Pearson correlation was used to assess the strength of the relationship of different measures in the total study group (n = 253). The EQ-5D index (biological treatment: 0.608, non biological treatment: 0.483; P = 0.012) and DAS-28 (biological treatment: 3.8, non-biological treatment: 4.5; P = 0.003) showed statistically significant difference between the two subcohorts after adjusting data by age, gender and disease duration. Our results indicate that patients on biological treatment have lower disease activity and higher utility; however, it was not statistically significant in all cases. According to our knowledge, TTO was not used previously in Hungarian RA patients. Utility data concerning biological treatments are essential for cost-utility models in health technology assessment reports for public reimbursement. PMID- 21243501 TI - Pneumosalpynx caused by colosalpingeal fistula secondary to acute colonic diverticulitis. PMID- 21243500 TI - Effects of intervention with sulindac and inulin/VSL#3 on mucosal and luminal factors in the pouch of patients with familial adenomatous polyposis. AB - BACKGROUND/AIM: In order to define future chemoprevention strategies for adenomas or carcinomas in the pouch of patients with familial adenomatous polyposis (FAP), a 4-weeks intervention with (1) sulindac, (2) inulin/VSL#3, and (3) sulindac/inulin/VSL#3 was performed on 17 patients with FAP in a single center intervention study. Primary endpoints were the risk parameters cell proliferation and glutathione S-transferase (GST) detoxification capacity in the pouch mucosa; secondary endpoints were the short chain fatty acid (SCFA) contents, pH, and cytotoxicity of fecal water. METHODS: Before the start and at the end of each 4 week intervention period, six biopsies of the pouch were taken and feces was collected during 24 h. Cell proliferation and GST enzyme activity was assessed in the biopsies and pH, SCFA contents, and cytotoxicity were assessed in the fecal water fraction. The three interventions (sulindac, inulin/VSL#3, sulindac/inulin/VSL#3) were compared with the Mann-Whitney U test. RESULTS: Cell proliferation was lower after sulindac or VSL#3/inulin, the combination treatment with sulindac/inulin/VSL#3 showed the opposite. GST enzyme activity was increased after sulindac or VSL#3/inulin, the combination treatment showed the opposite effect. However, no significance was reached in all these measures. Cytotoxicity, pH, and SCFA content of fecal water showed no differences at all among the three treatment groups. CONCLUSION: Our study revealed non-significant decreased cell proliferation and increased detoxification capacity after treatment with sulindac or VSL#3/inulin; however, combining both regimens did not show an additional effect. PMID- 21243502 TI - Ovarian morphology and endocrine function in polycystic ovary syndrome. AB - PURPOSE: To assess the relationship between ovarian morphology, hormonal levels and anthropometrical characteristics in a group of patients with polycystic ovary syndrome (PCOS). METHODS: This prospective, cross-sectional study included 82 patients with diagnosis of PCOS and 21 women with regular menstrual cycles without hyperandrogenism. They were submitted to endovaginal pelvic ultrasound. Anthropometric measures and hormonal levels of LH, FSH, insulin, total testosterone (T), free T, dehydroepiandrosterone and dehydroepiandrosterone sulfate were evaluated. The morphology of polycystic ovary (PCO) was considered when 12 or more follicles, less than 10 mm in diameter, in one or both ovaries, were observed. PCOS patients were divided into two groups: with PCO (n = 51) and without PCO (n = 31). RESULTS: In 51 out of 82 (62%) patients with PCOS, an image of PCO was observed. PCOS Patients with PCO showed a significantly greater body mass index and hip perimeter than PCOS patients without PCO. Higher levels of total T and free T were found in PCOS patients with PCO compared to those without PCO. CONCLUSION: PCOS patients with PCO on ultrasound present greater hyperandrogenism and obesity than PCOS patients without PCO. The presence of PCO appears to indicate a major clinical alteration of PCOS. PMID- 21243503 TI - The psychosis continuum: diagnosis and other phenotypes. PMID- 21243504 TI - Increasing the in vitro proliferation rate of Perkinsus mediterraneus, a parasite of the European flat oyster Ostrea edulis. AB - Perkinsus mediterraneus is an alveolate parasite first described in Ostrea edulis from the Balearic Islands (Mediterranean Sea, Spain), and little is known about its biology or the disease it causes. Continuous in vitro cultures of P. mediterraneus have recently been established in the protein-deficient culture medium JL-ODRP-2F to facilitate its study. Parasite proliferation rate in vitro however was low, with densities increasing 2- to 6-fold between subcultures at 6 week intervals. To increase the proliferation rate of P. mediterraneus cultures to rates similar to other Perkinsus species, various culture conditions (temperature, osmolality, pH, O(2), and CO(2) concentrations), culture procedures (seeding density and frequency of medium changes), concentrations of medium components, and addition of medium supplements (oyster tissue lysate, oyster plasma, animal sera, growth factors, and hormones) were tested. All treatments were evaluated by measuring parasite densities after 2 weeks of culture. The greatest increase in parasite densities, a 35-fold increase over the cell seeding density and 18 times that of the control (cells without supplementation), occurred in medium supplemented with 1,000 MUg/mL of O. edulis tissue lysate. P. mediterraneus proliferation was also significantly increased by oyster tissue lysate concentration as low as 125 MUg/mL. PMID- 21243505 TI - Fine structure of Longicollum pagrosomi (Acanthocephala: Pomphorhynchidae) and intestinal histopathology of the red sea bream, Pagrus major, infected with acanthocephalans. AB - The results described the structure of Longicollum pagrosomi and histopathological characters of the intestine of the red sea bream, Pagrus major, infected with acanthocephalans, using the light and electron microscopes. Among the six samples of P. major, L. pagrosomi was identified in the posterior intestine of five fish samples. Adult L. pagrosomi (total length, 8-27 mm) is divided into the presoma (proboscis, anterior neck, and posterior neck) and metasoma (trunk). The proboscis had vertically arranged hooks (40 MUm in length), with ten hooks per row, and the septum was observed between the posterior neck and trunk. The tegument thickness of the proboscis was approximately 15 MUm, and it was composed of thin, circular muscle fibers. The outer fibrous membrane was approximately 1 MUm, and the connective tissue layer was approximately 35 MUm in thickness in the anterior neck. The tegument of the posterior neck enclosed the cephalic ganglion and had longitudinal and vertical muscle fibers, and the tegument thickness was approximately 45 MUm. The tegument of the body, which was approximately 1 mm in thickness, was composed primarily of muscle and collagen fibers, and the structure of the tegument was different, depending on the body region. The acanthocephalans had ovaries and oval-shaped eggs with an eggshell (77.5 * 17.1 MUm), floating within the body cavity of the trunk. In the infected posterior intestine of P. major, the presoma and the anterior part of the metasoma of L. pagrosomi passed through the intestinal wall and infected the intestinal tissue, perforating the loose connective tissue. In the inflammatory connective tissue, collagen and muscle fibers were fragmented and revealed partial necrosis. Lipid drops and eosinophilic granular cells aggregated in the connective tissue of the tissue capsule. In the vicinity of the acanthocephalan, the mucosal epithelia contained hypertrophied nuclei, and the epithelial layer was collapsed. In an extreme case, the mucosal fold was degenerated because of pressure from the acanthocephalan. PMID- 21243506 TI - Anti-leishmanial and anti-trypanosomal potential of polygodial isolated from stem barks of Drimys brasiliensis Miers (Winteraceae). AB - Parasitic protozoan diseases affect the poorest population in developing countries. Leishmaniasis and Chagas disease have been included among the most important threats for public health in Central and South American continent, with few therapeutic alternatives and highly toxic drugs. In the course of selection of novel drug candidates, we studied the anti-protozoal potential of Drimys brasiliensis. Thus, the crude hexane extract from stem bark as well as its main derivative, the sesquiterpene polygodial, were tested using in vitro assays. The crude hexane extract and polygodial showed activity against Leishmania spp. in the range between 22 and 62 MUg/mL, but polygodial demonstrated high parasite selectivity towards Trypanosoma cruzi trypomastigotes (2 MUg/mL), with a selectivity index of 19. Finally, polygodial showed a leishmanicidal effect, inducing intense ultrastructural damages in Leishmania in short-time incubation. The obtained results suggested that polygodial could be used as a tool for drug design studies against protozoan diseases and as a candidate molecule for further in vivo studies against T. cruzi. PMID- 21243507 TI - Prevalence and risk factors for giardiasis and soil-transmitted helminthiasis in three municipalities of Southeastern Minas Gerais State, Brazil: risk factors for giardiasis and soil-transmitted helminthiasis. AB - Giardiasis and soil-transmitted helminthiasis (STH) are parasitic diseases that are among the major health concerns observed in economically disadvantaged populations of developing countries, and have clear social and environmental bases. In Brazil, there is a lack of epidemiologic data concerning these infections in the study area, whose inhabitants have plenty of access to health care services, including good dwelling and adequate sanitary conditions. In this survey we investigated the risk factors for giardiasis and STH in three municipalities with good sanitation, situated in Minas Gerais state, Brazil. A cross-sectional survey was conducted in the municipalities of Piau, Coronel Pacheco and Goiana, in both urban and rural areas. The fieldwork consisted of a questionnaire and the examination of 2,367 stool samples using the Hoffmann, Pons and Janer method. Of all individuals from the population sample, 6.1% were found infected with the parasitic diseases included in this work. Hookworm infection was the most prevalent disease, followed by giardiasis, trichuriasis and ascariasis. Infection was more prevalent in males (8.1%, p < 0.001; odds ratio [OR] = 1.975) and in individuals living in rural areas (8.6%, p = 0.003; OR = 1.693). Multivariate analysis showed that variables such as inadequate sewage discharge (p < 0.001), drinking of unsafe water (p < 0.001), lack of sanitary infrastructure (p = 0.015), and host sex (p < 0.001) were the risk factors more strongly associated with infection status (95% confidence interval [CI]). In this study we demonstrate that giardiasis and STH still persist, infecting people who have good housing conditions and free access to public health care and education. PMID- 21243508 TI - Letter to the Chief Editor: Outcome of thoracolumbar burst fractures treated with indirect reduction and fixation without fusion. Huilin Yang, Jin-hui Shi, Molly Ebraheim, Xiaochen Liu, Joseph Konrad, Ibrahim Husain, Tian-si Tang, Jiayong Liu Eur Spine J. Published online 8 August 2010. PMID- 21243509 TI - Towards the analysis of protein species: an overview about strategies and methods. AB - The deciphering of the relationship between function and exact chemical composition of a defined protein species in the context of the proteome is one of the major challenges in proteomics and molecular cell physiology. In the Special Issue of Amino Acids about the analysis of protein species current approaches are reviewed and new methods described focusing on the investigation of protein species. On the basis of the articles in this Special Issue it can be summarized that first important and promising steps towards the comprehensive analysis of protein species have been done. It is already possible to obtain full (100%) sequence coverage of proteins by mass spectrometry, if the amount of proteins available for their analysis allows their proteolytic degradation by more than one protease and the subsequent mass spectrometric analysis of the resulting peptides. Employing affinity chromatography helps to analyse proteins with defined post-translational modifications thus opening a targeted view on e.g. the phosphoproteome. In the future the aim to identify the exact chemical composition including not one but every posttranslational modification and complete sequence coverage on the protein species level should be achievable with further progress in sample preparation techniques, especially concerning separation techniques on the protein level, mass spectrometry and algorithms for mass spectrometric data processing. For determining the function of defined protein species a closer cooperation between cell biologists and proteomics experts is desirable. PMID- 21243510 TI - Porcelain conditioning with Nd:YAG and Er:YAG laser for bracket bonding in orthodontics. AB - In this study, shear bond strength (SBS) of metal orthodontic brackets to porcelain following conditioning by Er:YAG (erbium-doped yttrium aluminum garnet) and Nd:YAG (neodymium-doped yttrium aluminum garnet) laser in comparison to conventional methods was evaluated. One hundred glazed porcelain discs with an upper central shape were prepared and randomly assigned to five equal groups of 20. In the first group, samples were only deglazed and roughened by diamond burs. In the second group, after roughening and deglazing of porcelain samples, the samples were etched by 9.6% hydrofluoric acid for 4 min. Groups, 3, 4, and 5 were prepared by 0.8-W Nd:YAG laser, 2-W Er:YAG laser, 3-W Er:YAG laser for 10 s, respectively. Then, metal, mesh-based brackets were bonded to porcelain samples, and after being stored in distilled water for 24 h, debonding was carried out by a Zwick testing machine. ANOVA and Tukey tests were used to compare SBS in five groups. Mean SBS in groups 1 to 5 were 3.3 +/- 1.6, 7.0 +/- 2.1, 6.9 +/- 2.7, 2.3 +/- 1.1, and 3.7 +/- 2.3 MPa, respectively. ANOVA test revealed a significant difference between five groups (p < 0.05). Although Tukey's test showed SBS in groups 2 and 3 were significantly higher than the other groups, they did not differ with each other significantly (p > 0.05). The results revealed that SBS of 9.6% hydroflouric acid and Nd:YAG Laser was in an acceptable range for orthodontic treatment. Nd:YAG laser was shown to be an acceptable substitute for hydrofluoric acid while Er:YAG laser with the mentioned power and duration was not a suitable option. PMID- 21243511 TI - Combined validity of DIAGNOdentTM and visual examination for in vitro detection of occlusal caries in primary molars. AB - The purpose of this in vitro investigation was to compare in primary molars, the validity of DIAGNOdentTM 2095 on occlusal caries diagnosis used either separately or in combination with direct and/or indirect visual examinations, based on histological examination as the reference method. In 24 extracted primary molars, 111 occlusal pits were examined for caries by one trained operator (intra examiner reliability k > 0.80), using the following examination methods: direct visual (DV), indirect visual (IDV), radiographic (XR), and fluorescence (DD) with the DIAGNOdentTM. The extent of caries was then determined histologically. Sensitivity, specificity, accuracy, and the area under the ROC curve (AUC) were calculated for each method separately as well as for the combination of DD with DV and/or IDV. The DD accuracy was found both for lesions into enamel and into dentin to be 0.70 while the accuracy of the DD combination with DV and IDV was found to be 0.89. The DD AUC for lesions into enamel and into dentin, 0.68, were not statistically significant different from the other methods (p > 0.5), however the AUC of the combination of DD with DV and IDV, found to be 0.82, was higher than all the other methods, and this was statistically significant for enamel lesions. The validity of DIAGNOdentTM for occlusal caries diagnosis in primary molars was much higher when the DD was used in combination with direct and indirect visual examination, than when used by itself. PMID- 21243512 TI - Comparison between a 1.92-MUm fiber laser and a standard HF-dissection device for nephron-sparing kidney resection in a porcine in vivo study. AB - Nephron-sparing surgery was performed in a porcine model with a 1.92-MUm fiber laser dissection device in comparison to a standard high-frequency dissection device. In nine pigs, general anesthesia and a median laparotomy were performed to expose both kidneys. On six kidneys (three HF and three laser) a partial renal parenchyma resection of the lower pole without opening of the renal pelvis was performed (group A). On 12 kidneys (four HF and eight laser), a hemi nephrectomy with opening of the renal pelvis was performed (group B). Total resection time including hemostasis of the remaining tissue was 501 +/- 394 s in group "A-laser " vs. 176 +/- 139 s in group "A-HF". For the group "B", the total resection time was 1174 +/- 501 s (B laser) vs. 960 +/- 407 s (B-HF). Blood loss was 28 +/- 22 ml in group "A laser " vs. 15 +/- 15 ml in group "A-HF". In group "B", the blood loss was 98 +/- 73 ml (B laser) vs. 137 +/- 118 ml (B-HF). No ischemic time for the kidneys was needed in group "A" for both dissection devices. In group "B", ischemia of the kidneys was performed three times during the eight laser procedures (420 +/- 60 s) and only once at the four HF procedures (1,260 s). Healing process was observed over 4-6 weeks, survival rate was 100%, and no renal fistulas were found after the survival period. In conclusion, no significant differences were found between the compared dissection devices. However, the laser system with the flexible transmission fiber may have an advantage for a laparoscopic approach by steerable instruments. PMID- 21243513 TI - A nonsense mutation in a putative sulphate transporter gene results in low phytic acid in barley. AB - Low phytic acid grains can provide a solution to dietary micronutrient deficiency and environmental pollution. A low phytic acid 1-1 (lpa1-1) barley mutant was identified using forward genetics and the mutant gene was mapped to chromosome 2HL. Comparative genomic analysis revealed that the lpa1-1 gene was located in the syntenic region of the rice Os-lpa-MH86-1 gene on chromosome 4. The gene ortholog of rice Os-lpa-MH86-1 (designated as HvST) was isolated from barley using polymerase chain reaction and mapped to chromosome 2HL in a doubled haploid population of Clipper*Sahara. The results demonstrate the collinearity between the rice Os-lpa-MH86-1 gene and the barley lpa1-1 region. Sequence analysis of HvST revealed a single base pair substitution (C->T transition) in the last exon of the gene in lpa1-1 (M422), which resulted in a nonsense mutation. These results will facilitate our understanding of the molecular mechanisms controlling the low phytic acid phenotype and assist in the development of a diagnostic marker for the selection of the lpa1-1 gene in barley. PMID- 21243514 TI - Treating pneumonia in critical care in the United Kingdom following failure of initial antibiotic: a cost-utility analysis comparing meropenem with piperacillin/tazobactam. AB - BACKGROUND: Treating patients admitted to critical care with severe pneumonia requires timely intervention with an effective antibiotic. This reduces the risk of dying of pneumonia and minimises complications associated with a prolonged stay in critical care. OBJECTIVE: To compare the cost-effectiveness of meropenem 1 g/8 h with piperacillin/tazobactam 4.5 g/8 h for treating pneumonia in UK critical care. METHODS: A Markov model was built to estimate lifetime costs and quality-adjusted life years (QALYs) of using meropenem versus piperacillin/tazobactam to treat severe pneumonia. Estimates of effectiveness, utility weights and costs were obtained from published sources. Probabilistic sensitivity analysis was conducted to address uncertainty in the model results. RESULTS: Cost of treating a patient with severe pneumonia was estimated as L19,026 with meropenem and L19,978 with piperacillin/tazobactam, respectively. QALYs gained were 4.768 with meropenem and 4.654 with piperacillin/tazobactam. Probabilistic sensitivity analysis showed meropenem to be consistently less costly and more effective than piperacillin/tazobactam. CONCLUSION: The additional efficacy of meropenem translates into more patients surviving critical care and leaving this high-cost service more quickly than if they had been treated with piperacillin/tazobactam. As meropenem is more effective and less expensive than piperacillin/tazobactam at treating patients with severe pneumonia, it is the dominant treatment option. PMID- 21243515 TI - Direct targets of the transcription factors ABA-Insensitive(ABI)4 and ABI5 reveal synergistic action by ABI4 and several bZIP ABA response factors. AB - The plant hormone abscisic acid (ABA) is a key regulator of seed development. In addition to promoting seed maturation, ABA inhibits seed germination and seedling growth. Many components involved in ABA response have been identified, including the transcription factors ABA insensitive (ABI)4 and ABI5. The genes encoding these factors are expressed predominantly in developing and mature seeds, and are positive regulators of ABA mediated inhibition of seed germination and growth. The direct effects of ABI4 and ABI5 in ABA response remain largely undefined. To address this question, plants over-expressing ABI4 or ABI5 were used to allow identification of direct transcriptional targets. Ectopically expressed ABI4 and ABI5 conferred ABA-dependent induction of slightly over 100 genes in 11 day old plants. In addition to effector genes involved in seed maturation and reserve storage, several signaling proteins and transcription factors were identified as targets of ABI4 and/or ABI5. Although only 12% of the ABA- and ABI-dependent transcriptional targets were induced by both ABI factors in 11 day old plants, 40% of those normally expressed in seeds had reduced transcript levels in both abi4 and abi5 mutants. Surprisingly, many of the ABI4 transcriptional targets do not contain the previously characterized ABI4 binding motifs, the CE1 or S box, in their promoters, but some of these interact with ABI4 in electrophoretic mobility shift assays, suggesting that sequence recognition by ABI4 may be more flexible than known canonical sequences. Yeast one-hybrid assays demonstrated synergistic action of ABI4 with ABI5 or related bZIP factors in regulating these promoters, and mutant analyses showed that ABI4 and these bZIPs share some functions in plants. PMID- 21243516 TI - In vitro adhesion of staphylococci to diamond-like carbon polymer hybrids under dynamic flow conditions. AB - This study compares the ability of selected materials to inhibit adhesion of two bacterial strains commonly implicated in implant-related infections. These two strains are Staphylococcus aureus (S-15981) and Staphylococcus epidermidis (ATCC 35984). In experiments we tested six different materials, three conventional implant metals: titanium, tantalum and chromium, and three diamond-like carbon (DLC) coatings: DLC, DLC-polydimethylsiloxane hybrid (DLC-PDMS-h) and DLC polytetrafluoroethylene hybrid (DLC-PTFE-h) coatings. DLC coating represents extremely hard material whereas DLC hybrids represent novel nanocomposite coatings. The two DLC polymer hybrid films were chosen for testing due to their hardness, corrosion resistance and extremely good non-stick (hydrophobic and oleophobic) properties. Bacterial adhesion assay tests were performed under dynamic flow conditions by using parallel plate flow chambers (PPFC). The results show that adhesion of S. aureus to DLC-PTFE-h and to tantalum was significantly (P < 0.05) lower than to DLC-PDMS-h (0.671 +/- 0.001 * 10(7)/cm(2) and 0.751 +/- 0.002 * 10(7)/cm(2) vs. 1.055 +/- 0.002 * 10(7)/cm(2), respectively). No significant differences were detected between other tested materials. Hence DLC PTFE-h coating showed as low susceptibility to S. aureus adhesion as all the tested conventional implant metals. The adherence of S. epidermidis to biomaterials was not significantly (P < 0.05) different between the materials tested. This suggests that DLC-PTFE-h films could be used as a biomaterial coating without increasing the risk of implant-related infections. PMID- 21243517 TI - Electrohydrodynamic deposition of nanotitanium doped hydroxyapatite coating for medical and dental applications. AB - Nano-sized titanium containing hydroxyaptite has been prepared, the particle size of nanoTiHA was shown to be 12-20 nm in width and 30-40 nm in length, smaller than that of nanoHA. X-ray diffraction analysis revealed the phase purity of nanoTiHA produced. Antimicrobical assays demonstrated that nanoTiHA has excellent growth inhibitory properties, and is able to inhibit the growth of all bacterial strains tested, both Gram-negative and Gram-positive species, including multi antibiotic resistant EMRSA 15 and EMRSA 16 'superbugs'. Biocidal activity against all four Staphylococcus spp was also shown at the concentration tested. Nanostuctured TiHA coating was successfully deposited onto Ti surfaces using EHDA spraying under optimized processing conditions with the thickness of the coating being further controlled by the spraying time. All of the nanoTiHA coated Ti surfaces were able to support human osteoblast (HOB) cell attachment and growth. The coating thickness did not significantly influence the proliferation of HOB cells on nanoTiHA coatings, while the ability of nanoTiHA coating to support HOB cell differentiation was demonstrated from the alkaline phosphatase activity. Our study showed that nanoTiHA has excellent anti-bacterial properties and the thin nanoTiHA coating was also able to support the attachment, growth and differentiation of HOB cells. Therefore, nanoTiHA coating could pave the way for the development of the next generation of dental and orthopedic implants by offering anti-infection potential in addition to osteoconductivity. PMID- 21243518 TI - Volatility, house edge and prize structure of gambling games. AB - This study used simulations to examine the effect of prize structure on the outcome volatility and the number of winners of various game configurations. The two most common prize structures found in gambling games are even money payoff games (bet $1; win $2) found on most table games and multilevel prizes structures found in gambling machine games. Simulations were set up to examine the effect of prize structure on the long-term outcomes of these games. Eight different prize structures were compared in terms of the number of winners and volatility. It was found that the standard table game and commercial gambling machines produced fairly high numbers of short term winners (1 h), but few long term winners (50 h). It was found that the typical even money game set up produced the lowest level of volatility. Of the multilevel prize structures examined, the three simulations based on commercial gambling machines were the least volatile. The results are examined in terms of the pragmatics of game design. PMID- 21243519 TI - Leptin activates human B cells to secrete TNF-alpha, IL-6, and IL-10 via JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathway. AB - Leptin, one of the adipokines, functions as a hormone and a cytokine. In this investigation, we show for the first time that leptin, in a concentration dependent manner, activates human peripheral blood B cells to induce secretion of IL-6, IL-10, and TNF-alpha. Leptin increased B cells expressing CD25 and HLA-DR. Leptin induces phosphorylation of Janus activation kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), p38 mitogen-activated protein kinase (p38MAPK), and extracellular signal-regulated kinase (ERK1/2). Furthermore, leptin-induced cytokine secretion by B cells was blocked by inhibitors of JAK2, STAT3, p38MAPK, and ERK1/2. These data demonstrate that leptin activates human B cells to secrete cytokines via activation of JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathways, which may contribute to its inflammatory and immunoregulatory properties. PMID- 21243520 TI - Gain and loss of T cell subsets in old age--age-related reshaping of the T cell repertoire. AB - The immune system is affected by the aging process and undergoes significant age related changes, termed immunosenescence. Different T cell subsets are affected by this process. Alterations within the bone marrow and thymus lead to a shift in the composition of the T cell repertoire from naive to antigen-experienced T cells, thereby compromising the diversity of the T cell pool. Additional infection with latent pathogens such as cytomegalovirus aggravates this process. In this review, we focus on the major age-related changes that occur in the naive and the antigen-experienced T cell population. We discuss the mechanisms responsible for the generation and maintenance of these subsets and how age related changes can be delayed or prevented by clinical interventions. PMID- 21243521 TI - Distribution and clinical features of primary immunodeficiency diseases in Chinese children (2004-2009). AB - Two hundred and one patients have been diagnosed with primary immunodeficiency diseases (PIDs) in our center from January 2004 to December 2009. The male-to female ratio was 5.29:1. Spectrums of PIDs were as follows: predominantly antibody deficiency disease was the most common category (94 patients, 48.2%), followed by other well-defined immunodeficiency syndromes (40 patients, 20.5%), combined T and B cell immunodeficiencies (33 patients, 16.9%), congenital defects of phagocyte number and/or function (21 patients, 10.8%), and diseases of immune dysregulation (six patients, 3.1%). Agammaglobulinemia was the most frequent disease type. The median of diagnosis lag was 18.0 months. Pneumonia was the most common manifestation of PID patients. Some manifestations were prone to concentrate in certain diseases. As for therapy, 99 patients (50.8%) received intravenous immunoglobulin replacement therapy; 13 patients received hematopoietic stem cell transplantation and nine of them were still alive. In this study, we sought to describe and analyze the distribution, clinical features, and therapy methods of PIDs among children diagnosed in our country and to compare with reports from other countries and regions. PMID- 21243522 TI - beta-Arrestin 1 modulates functions of autoimmune T cells from primary biliary cirrhosis patients. AB - OBJECTIVES: Primary biliary cirrhosis (PBC) is an autoimmune disease, characterized by antimitochondrial antibodies and autoreactive T cells causing destruction of the primary bile ducts. The molecular mechanisms regulating the autoreactive T cells remain elusive. beta-Arrestins (betaarr) are multifunctional signaling molecules that are crucial to T cell survival. We hypothesized that betaarr plays a critical regulatory function in the autoreactive T cells of PBC patients. METHODS: Patients with hepatic biliary cirrhosis (n=60) were evaluated. Cytokine expression, T cell proliferation, and transcription factors were evaluated to assess regulatory functions in autoreactive T cells from the patient. RESULTS: Our studies showed that expression of betaarr1 was elevated significantly in T lymphocytes from patients with PBC. Moreover, the level of betaarr1 mRNA positively correlated with Mayo risk score in PBC patients. Based on modulation of betaarr in autoreactive T cell lines, overexpression of betaarr1 increased T cell proliferation, augmented interferon production, downregulated activities of nuclear factor kappaB and AP-1, promoted acetylation of histone H4 in the promoter regions of CD40L, LIGHT, IL-17 and interferon-gamma, while downregulating acetylation of histone H4 in the promoter regions of TRAIL, Apo2, and HDAC7A, thereby regulating expression of these genes. CONCLUSIONS: Our findings suggest that betaarr1 contributes to the pathogenesis of PBC, having significant implications for novel therapy strategy, further providing information for investigating the mechanisms of autoimmune disease. PMID- 21243523 TI - Chloral hydrate decreases gap junction communication in rat liver epithelial cells. AB - Gap junction communication (GJC) is involved in controlling cell proliferation and differentiation. Alterations in GJC are associated with carcinogenesis, but the mechanisms involved are unknown. Chloral hydrate (CH), a by-product of chlorine disinfection of water, is carcinogenic in mice, and we demonstrated that CH reduced GJC in a rat liver epithelial cell line (Clone 9). To examine the mechanism(s) by which CH inhibits GJC, Clone 9 cells treated with CH were examined using Western blot, real-time polymerase chain reaction, immunocytochemical, and dye-communication techniques. Treatment with CH (0.1-5 mM for 24 h) resulted in a dose-dependent inhibition of GJC as measured by Lucifer yellow dye transfer. Western blot analysis demonstrated expression of connexin (Cx) 43 and 26 in control cells and reduced expression of Cx 43 but not Cx 26 protein from 0.1 to 1 mM CH. CH treatment from 2.5 to 5 mM caused an apparent increase in expression of both connexins that was concomitant with a reduction in mRNA expression for both connexins. Similarly, with immunocytochemistry, a dose dependent decrease in Cx 43 staining at sites of cell-cell contact was apparent in CH (0.5-5 mM)-treated cultures, whereas no Cx 26 staining was observed. Thus, Clone 9 cells contain two types of connexins but only one type of plasma membrane channel. Understanding of the regulation of connexin may shed light on mechanisms responsible for inhibition of GJC by chemical carcinogens. PMID- 21243524 TI - Oppositional defiant disorder-gender differences in co-occurring symptoms of mental health problems in a general population of children. AB - Informant- and gender-specific characteristics of Oppositional Defiant Disorder (ODD) and how these might relate to patterns of comorbidity need to be further clarified. We collected data from 7,007 children (aged 7-9) who participated in the Bergen Child Study (BCS), an ongoing population-based study of children's development and mental health. A questionnaire containing the DSM-IV behavioral descriptions of ODD was distributed to parents and teachers. Co-occurring symptoms of mental health problems were measured by the Strengths and Difficulties Questionnaire (SDQ). The boys (n = 122) and girls (n = 41) with symptomatic ODD had an increased risk of co-occurring emotional symptoms, hyperactivity or inattention and peer problems, as compared to their peers without symptomatic ODD. The impact of symptomatic ODD was higher for boys than girls in teacher reported SDQ ratings, except for emotional symptoms. There were no significant interaction effects of gender in parent SDQ ratings. Our results are contrary to the gender paradox hypothesis, which states that co-occurring symptoms of mental health problems are more frequent among girls with ODD as compared to boys with ODD. PMID- 21243525 TI - Performance and long-term stability of the barley hordothionin gene in multiple transgenic apple lines. AB - Introduction of sustainable scab resistance in elite apple cultivars is of high importance for apple cultivation when aiming at reducing the use of chemical crop protectants. Genetic modification (GM) allows the rapid introduction of resistance genes directly into high quality apple cultivars. Resistance genes can be derived from apple itself but genetic modification also opens up the possibility to use other, non-host resistance genes. A prerequisite for application is the long-term performance and stability of the gene annex trait in the field. For this study, we produced and selected a series of transgenic apple lines of two cultivars, i.e. 'Elstar' and 'Gala' in which the barley hordothionin gene (hth) was introduced. After multiplication, the GM hth-lines, non-GM susceptible and resistant controls and GM non-hth controls were planted in a random block design in a field trial in 40 replicates. Scab resistance was monitored after artificial inoculation (first year) and after natural infection (subsequent years). After the trial period, the level of expression of the hth gene was checked by quantitative RT-PCR. Four of the six GM hth apple lines proved to be significantly less susceptible to apple scab and this trait was found to be stable for the entire 4-year period. Hth expression at the mRNA level was also stable. PMID- 21243526 TI - Regulation of the expression of H43/Fea1 by multi-signals. AB - The composition of extracellular proteins is known to be drastically changed in the unicellular green alga Chlamydomonas reinhardtii when the cells are transferred from ambient CO(2) to elevated CO(2) conditions. We previously observed very high production of the H43/Fea1 protein under high-CO(2) (0.3-3% in air) conditions. In addition, H43/Fea1 gene expression was reported to be induced under iron-deficient and cadmium-excess conditions, but it remains unclear how gene expression is regulated by multiple signals. To elucidate the regulatory mechanism of H43/Fea1 expression, this study intended to identify a high-CO(2) responsive cis-element in a wall-deficient strain C. reinhardtti CC-400. Cells incubated in the presence of acetate in the dark, namely heterotrophically generated high-CO(2) conditions, were used for inducing H43/Fea1 gene expression following our previous study (Hanawa et al., Plant Cell Physiol 48:299-309, 2007) in Fe-sufficient and Cd-deficient medium to prevent the generation of other signals. First, we constructed a reporter assay system using transformants constructed by introducing genes with series of 5'-deleted upstream sequences of H43/Fea1 that were fused to a coding sequence of the Ars for arylsulfatase2 reporter gene. Consequently, the high-CO(2)-responsive cis-element (HCRE) was found to be located at a -537/-370 upstream region from the transcriptional initiation site of H43/Fea1. However, it still remains possible that a -724/-537 upstream region may also have a significant role in activating gene expression regulated by high-CO(2). Remarkably, a -925/-370 upstream region could successfully activate the Ars reporter gene under heterotrophically generated high-CO(2) conditions even when the sequence containing two Fe-deficiency responsive elements was completely deleted. These results clearly showed that H43/Fea1 expression is regulated by high-CO(2) signal independently via the HCRE that is located distantly from Fe-deficient-signal responsive element, indicating that H43/Fea1 is a multi-signal-regulated gene. PMID- 21243527 TI - The relationships between quality of life and anxiety symptoms and the moderating effects of socio-demographic characteristics in Taiwanese adolescents. AB - PURPOSE: To examine the associations of the seven domains of quality of life (QOL) on the Taiwanese Quality of Life Questionnaire for Adolescents (TQOLQA) with the severity of anxiety symptoms on the total Multidimensional Anxiety Scale for Children (MASC-T) and the moderating effects of socio-demographic characteristics on the association between QOL and anxiety symptoms among Taiwanese adolescents in the community. METHODS: A total of 5,322 adolescents completed the TQOLQA, MASC-T, and the questionnaire for socio-demographic characteristics without omission. The associations of the QOL on the TQOLQA with the severity of anxiety symptoms on the total MASC-T and socio-demographic characteristics were examined using multiple regression analysis. The moderating effects of socio-demographic characteristics on the association between QOL and anxiety symptoms were also examined. RESULTS: After controlling for the effects of socio-demographic characteristics, more severe anxiety symptoms on the total MASC-T were significantly associated with poorer QOL in all seven domains of QOL on the TQOLQA. Meanwhile, socio-demographic characteristics had moderating effects on the associations between some domains of QOL and anxiety symptoms. CONCLUSIONS: Anxiety symptoms require intervention when developing strategies to improve the QOL of adolescents. Meanwhile, clinicians should take socio demographic characteristics into consideration when working on QOL issues and anxiety symptoms in adolescents. PMID- 21243528 TI - The development and validation of a general measure of well-being: the BBC well being scale. AB - PURPOSE: The concept of maximising well-being, as opposed to merely treating mental disorder, is a powerful current theme in the area of mental health. Clearly this emphasises the need for appropriate valid and reliable measures of general well-being. This paper examines the appropriateness of a number of measures in this area and concludes that existing assessment tools fail to address the full range of aspects of personal well-being. This paper therefore presents the psychometric properties, validity and reliability of a new measure of well-being-the BBC Well-being Scale. METHODS: A total of 1,940 participants completed the new measure, the Goldberg scales of anxiety and depression, the 'List of Threatening Experiences' life events scale, a modified version of the Response Styles Questionnaire and a modified version of the Internal, Personal and Situational Attributions Questionnaire presented via the internet. RESULTS: Exploratory factor-analysis suggested a three-factor solution including themes of psychological well-being, physical health and well-being and relationships. The total 24-item scale had good internal consistency (alpha = .935) and correlated significantly with key demographic variables and measures of concurrent validity. CONCLUSIONS: The new measure--the BBC Well-being Scale-is recommended for research and clinical purposes. PMID- 21243529 TI - The CASP-19 as a measure of quality of life in old age: evaluation of its use in a retirement community. AB - PURPOSE: The CASP-19 is a quality-of-life measure comprising four domains ('control', 'autonomy', 'pleasure' and 'self-realization'), developed initially in a population aged 65-75 years. This study tested the scale for use in a population whose demographic profile and residential status differed markedly from the original population. METHODS: CASP-19 data were gathered from 120 residents of a U.K. retirement community. Distribution of scores, factor structure, internal consistency and construct validity were examined. RESULTS: Scores were negatively skewed, especially on the pleasure domain. Attempts to confirm the factor structure of the scale were equivocal. Coefficients for composite reliability ranged from 0.52 to 0.84 across domains. Some items, particularly in the control and autonomy domains, showed low correlations with their domains. The CASP-19 correlated with the Diener Satisfaction with Life Scale (r = 0.66), and the physical (r = 0.53) and mental (r = 0.49) component summaries of the SF-12, supporting its construct validity. A recently proposed 12 item version of the scale appears to have superior dimensionality. CONCLUSION: Although in some respects the CASP-19 exhibited good psychometric properties, the internal consistency and dimensionality of the control and autonomy domains are suspect. Further modification of the scale may be fruitful from a psychometric point of view. PMID- 21243530 TI - The case for the case report: refine to save. AB - INTRODUCTION: The case report is the cornerstone of both medical teaching and writing. However, during recent years the value of the case report has been questioned, so much so that it has been abandoned by many journals. The aim of this study was to assess case reports published by the Irish Journal of Medical Science (IJMS) and to examine ways to preserve this type of article. METHODS: A review of all single-patient case reports published in the IJMS in 2008 and 2009. RESULTS: Forty-eight cases were published from nine countries. The range of authors was 2-11, length 525-1,787 words and number of references 4-24. All cases contained abstracts. CONCLUSION: Stricter guidelines with regards to a shorter more focused article should help to preserve this form of publication. PMID- 21243531 TI - Prospective phase I study of capecitabine and oxaliplatin concurrent with radiation therapy for the treatment of locally advanced pancreatic adenocarcinoma, and retrospective comparison to concurrent 5 fluorouracil/radiation and gemcitabine/radiation. AB - PURPOSE: The aims of this study is to determine the maximum tolerated dose of capecitabine and oxaliplatin (CAPOX) delivered concurrent with radiation therapy (RT) in the treatment of locally advanced pancreatic adenocarcinoma and to retrospectively compare outcomes with this regimen to concurrent 5-fluorouracil or capecitabine with RT (5FU-RT) or concurrent gemcitabine-based chemotherapy with RT (GEM-RT). MATERIALS AND METHODS: Twelve patients were enrolled in a phase I study using 50.4 Gy RT concurrent with capecitabine chemotherapy (twice daily, 7 days per week) and oxaliplatin (once weekly during weeks 1, 2, 4, and 5). Capecitabine and oxaliplatin doses were 400 mg/m(2) and 50 mg/m(2), respectively, at dose level 1; 600 mg/m(2) and 50 mg/m(2) at level 2; and 600 mg/m(2) and 60 mg/m(2) at level 3. A standard dose of gemcitabine was recommended following RT or following surgery (if done). The outcomes of patients treated with this regimen were retrospectively compared to 20 patients treated with 5FU-RT and 30 patients treated with GEM-RT. RESULTS: Dose level 3 was tolerated with acceptable toxicity. Survival in patients receiving CAPOX-RT did not differ from GEM-RT or 5FU-RT. Response of the primary tumor was observed in 38% of patients treated with CAPOX-RT, 31% of patients treated with 5FU-RT, and 66% of patients treated with GEM-RT (p = 0.03 GEM-RT versus 5FU-RT). CONCLUSIONS: CAPOX-RT has acceptable toxicity. A retrospective comparison shows higher response rate with GEM-RT versus 5FU-RT, but this difference did not translate into improvement in overall survival. PMID- 21243532 TI - Capecitabine-induced, nonneutropenic enterocolitis. PMID- 21243533 TI - Growth and nutritional status at corrected term gestational age in very low birth weight infants. AB - OBJECTIVE: To evaluate the growth and nutritional status at term (39-41 weeks) corrected gestational age in VLBW infants and to study the predictors of malnutrition. METHODS: This Cross-sectional study was conducted in a tertiary care perinatal centre with level III NICU. All Inborn VLBW infants who were discharged alive from the hospital during the study period from January 2008 through June 2009 were included in this study. Relevant perinatal, clinical and anthropometry data were collected at birth, at hospital discharge and at term gestation. Primary outcome was considered as Z scores of weight, occipitofrontal circumference, length and predictors of postnatal malnutrition (z-score for weight <=2SD) at term gestation. RESULTS: The mean gestational age and the mean birth weight of study subjects were 31.03 +/- 2.18 weeks and 1195.28 +/- 191.25 g respectively. Twenty-six (15%) infants had birth weight less than 1,000 g and 65 (37.4%) infants were of gestation less than 31 weeks. The mean weight, the mean length and mean occipitofrontal circumference (OFC) at term gestation were 2367.32 +/- 521 g, 43.72 +/- 3.3 cm and 32.65 +/- 1.6 cm respectively. The mean z scores for weight, length and OFC at term gestation was -1.66 +/- 1.2, -1.98 +/- 1.3 and -0.48 +/- 0.7 respectively. Forty three percent (n = 75) infants were malnourished. Birth weight (p = 0.005), gestational age (p = 0.001), z-score at birth (p = 0.001), female sex (p = 0.004), duration of oxygen (p = 0.008), duration of hospitalization (p = 0.005) and average post discharge weight gain per day (p < 0.001) predicted malnutrition. CONCLUSIONS: There is a high prevalence of postnatal malnutrition in VLBW infants. Poor intrauterine growth, female sex, lower birth weight, lower gestation, infant sickness and poor post discharge weight gain contribute significantly to postnatal malnutrition. PMID- 21243534 TI - Necrotizing enterocolitis in a term neonate following intravenous immunoglobulin therapy. AB - A term baby with severe BO isoimmunization was treated with intravenous immunoglobulin. Shortly after the completion of the infusion, the baby developed clinical and radiological signs of necrotizing enterocolitis, with intestinal perforation and massive hemorrhagic ascites, resulting in the death of the baby. PMID- 21243535 TI - Cerebellar atrophy in a child with valproate toxicity. AB - In the treatment of epilepsy, selecting an appropriate antiepileptic drug for each individual patient requires matching the patient's clinical needs with the agent's specific pharmacological attributes. In many situations, the final choice of an antiepileptic drug may need a change due to the agent's side-effect profile. The authors report a ten-year-old child with Lennox Gastaut syndrome who developed recurrence of seizures, hyperammonemic encephalopathy and cerebellar atrophy on valproate therapy. Valproate was discontinued and lamotrigine was added followed by good control of seizures. Cerebellar atrophy as a serious adverse side effect of valproate therapy, has been infrequently reported. PMID- 21243536 TI - Clinical and radiological features of pediatric cerebellar anaplastic oligodendrogliomas. AB - Oligodendrogliomas constitute 4-7% of primary intracranial gliomas in adult and 1% of primary central nervous system tumours in children. The authors report two unusual pediatric cases of anaplastic oligodendroglioma occurring in the cerebellum. The patient with a well-circumscribed lesion with 1p/19q co-deletion had a favorable outcome in comparison with the patient with a diffuse lesion and intact 1p/19q. The discussion elucidates the surgical outcome of such pediatric cerebellar anaplastic oligodendrogliomas in relation to their radiological findings. PMID- 21243537 TI - Abiraterone acetate, a novel adrenal inhibitor in metastatic castration-resistant prostate cancer. AB - The androgen receptor remains the key player in patients with castration resistant prostate cancer (CRPC). Available agents capable of blocking early adrenal androgen production have limited activity and can lead to significant toxicities. Abiraterone acetate, a pregnenolone analog, is a small molecule that irreversibly inhibits CYP17, a rate-limiting enzyme in androgen biosynthesis. Several clinical trials have demonstrated the safety and efficacy of this compound in men with metastatic CRPC. Recently, a randomized phase 3 trial evaluating abiraterone acetate in docetaxel-refractory CRPC patients demonstrated a survival improvement over placebo-treated patients (14.8 vs 10.9 months; HR 0.646; P < 0.0001). A similar trial in the pre-chemotherapy setting has completed accrual and is undergoing analysis. Here we review the rationale and clinical development of abiraterone acetate in men with CRPC. PMID- 21243538 TI - Sipuleucel-T: Prototype for development of anti-tumor vaccines. AB - Prostate cancer immunotherapy officially debuted with the recent FDA approval of Sipuleucel-T. The novel trend of cancer immunotherapy relies on the identification of particular tumor-associated antigens, like prostatic acid phosphatase (PAP). Sipuleucel-T consists of autologous dendritic cells activated in vitro with recombinant fusion protein PA2024, PAP-linked to granulocyte macrophage colony-stimulating factor. Sipuleucel-T represents a prototype for the development of cancer vaccines. Preclinical and clinical data as well as landmark studies for the existing narrow chemotherapy alternatives and early immunotherapy trials will be discussed. The pivotal trial demonstrated a 4.1-month difference of median survival, but with no effect on time to progression in asymptomatic or minimally symptomatic metastatic castrate-resistant patients. Several immunologic effects were observed in the treated population, including antibody and T cell specific activity to P2024 and PAP. With all new therapies the extent of clinical and objective benefits versus encountered limitations should be evaluated. This review highlights the events and decisions in the process of the development of Sipuleucel-T. We discuss how this successful immunotherapy outcome challenges us to use it as a starting point for variations to or try to amplify practical anticancer progress within the antitumor vaccine paradigm. PMID- 21243539 TI - Endoscopic resection of sinonasal malignancies. AB - Malignant tumors of the sinonasal tract are rare, accounting for only 1% of all malignancies. Although they are associated with substantial histological heterogeneity, surgery plays a key role in their management. This review addresses the evolution of current treatments in view of the introduction of endoscopic resection techniques. The absence of facial incisions and osteotomies, decreased hospitalization time, better control of bleeding, improved visualization of tumor borders, and reduced morbidity and mortality rate are the major advantages of endoscopic techniques in comparison to traditional external approaches. The major criticisms focus on oncologic results in view of the short/intermediate follow-up of large series, which have commonly grouped together several histologies that may be associated with different prognoses. Since prospective studies contrasting the results of endoscopic and craniofacial resections are difficult to carry out given the rarity of the disease together with ethical issues, the creation of a large database would favor the analysis of several variables related to the patient, tumor, and treatment on survival performed on a large number of patients. PMID- 21243540 TI - Esophageal transit study using a sliding sum image: application to patients with probable and definite systemic sclerosis. AB - PURPOSE: Esophageal complication is common in systemic sclerosis (SSc), but scintigraphic transit patterns based on each subtype have not been understood well. The aim of this study was to develop a new algorithm for integrating a dynamic esophageal transit study and to apply the method to patients with SSc. METHODS: A total of 40 patients suspected of having SSc were examined by a dynamic esophageal transit study. The subtypes included 32 with definite SSc (15 limited cutaneous type and 17 diffuse cutaneous type) and 8 with probable SSc. The serial esophageal images were shifted and summed to a functional image (sliding sum image) and compared to a conventional condensed image analysis. Esophageal retention fraction at 90 s (R (90)) and half-time (T (1/2)) of transit were also measured. RESULTS: The four patterns of the sliding sum image and condensed image agreed in all patients. Abnormal retention patterns were observed in none of the 8 (0%) patients with the probable SSc and in 15 of 32 (47%) patients with definite SSc (p = 0.014). The severity of scleroderma assessed by modified Rodnan skin thickness score correlated with that of esophageal retention R (90) (p = 0.04). CONCLUSION: The sliding sum image is a simple and effective method for integrating esophageal transit. Patients with definite SSc and severe scleroderma had significantly higher retention patterns, while probable SSc patients showed no esophageal dysmotility. PMID- 21243541 TI - Inflammatory demyelinating neuropathies. AB - OPINION STATEMENT: The primary goal of therapy in patients with the Guillain Barre syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is improved strength and functional ability. Improvement in pain, sensory loss, gait disorder, and autonomic instability are other goals of therapy. Patients with very mild symptoms that do not interfere with activities of daily living can be observed for deterioration without treatment. For GBS, standard care includes plasma exchange (PE) or human immune globulin (HIG), both of which have similar efficacy. Supportive care in the intensive care unit may be needed for those patients with severe bulbar or respiratory weakness. We treat most patients with PE, usually performing an exchange every other day for a total of five exchanges. We use HIG in children, if there are antiglycolipid antibodies (eg, anti-GM1 or anti-GQ1b) or if there is a contraindication to PE, such as hemodynamic instability; severe renal, hepatic, or cardiac disease; or poor venous access. For CIDP, there are no guidelines concerning the initial choice of therapy. Corticosteroids, HIG, and PE have all been shown to be effective in prospective, randomized controlled trials, and comparison trials have shown equal efficacy among these three immunomodulating therapies. The choice of therapy depends on several factors including disease severity, concomitant illnesses, side-effect profile, potential drug interactions, venous access, age-related risks, and cost of treatment. In patients with moderate to severe symptoms, treatment with corticosteroids or HIG should be used. We usually use high-dose, intermittent methylprednisolone as the initial drug of choice. We believe intermittent corticosteroids are better than HIG because of their good safety profile, low cost, ease of administration (can be given intravenously or by mouth), and proven efficacy. If there is a major contraindication to corticosteroids, then HIG is offered. PE is less well tolerated and is primarily used as a third choice and only for a few weeks to months to induce initial improvement. Once symptoms are improving, the dose of corticosteroids or HIG should be tapered with the goal of eventual discontinuation depending on patient response. Patients who do not respond to initial therapy, experience adverse effects from the initial immunomodulating agent, or require chronic treatment can be treated with another first-line agent or one of several second-line agents. PMID- 21243544 TI - Prevalence and morphology of supernumerary teeth in the population of a Swiss community. Short communication. AB - The objective of the study was to determine the current prevalence of supernumerary teeth (PST) in the population of a Swiss community. 3,004 orthopantomograms (OPTs) routinely produced during the annual school dental examinations in the Winterthur municipality from 1990 to 2005 served as the study basis (average age 9.45 years, 1391 girls, 1613 boys, age range 6-15 years). The study found 44 supernumerary teeth, which yields a prevalence of 1.5%. The prevalence among boys was higher than among girls, with 1.1% and 0.4%, respectively. The greatest proportion of supernumerary teeth was found in the maxillary anterior region (38 of 44 teeth, 86%). Based on their position, 33 of these were classified as mesiodens. Five supernumerary teeth had the same shape as a maxillary lateral incisor. In the mandibular anterior region, five supernumerary teeth were shaped the same as the permanent mandibular incisors. 70% of the supernumerary teeth were conical. The prevalence of supernumerary teeth is low (1.5%) and comparable to similar studies in the literature. The majority (86%) of supernumerary teeth are located in the maxillary anterior region. Thus, in the case of retention or delayed eruption, dentists should bear in mind that supernumerary teeth may be the cause. PMID- 21243545 TI - Composite materials: composition, properties and clinical applications. A literature review. AB - Various composite materials are available today for direct restorative techniques. The most well-known materials are the hybrid composites. This technology, based on methacrylates and different types of filler coupled with silanes, has been continuously improved. Disadvantages such as polymerisation shrinkage, bacterial adhesion and side effects due to monomer release still remain. The aim of material development is to eliminate or at least reduce these negative factors by adapting the individual components of the material. With ormocers, the methacrylate has been partially replaced by an inorganic network. According to recent studies, the biocompatibility was not improved in all cases. The development of compomer was an attempt to combine the positive properties of glassionomers with composite technology. This has only partially succeeded, because the fluoride release is low. In an in-situ study, a caries protective effect could be shown at least in the first days following filling placement with concurrent extra-oral demineralisation. By replacing the chain-monomers in the composite matrix by ring-shaped molecules, a new approach to reduce polymerisation shrinkage was investigated. A new group of materials, the siloranes, has been developed. Siloranes are hydrophobic and need to be bonded to the dental hard tissue using a special adhesive system. Long-term clinical studies are still needed to prove the superiority of this new group of materials over modern hybrid composites. PMID- 21243546 TI - Changes in dental caries in Zurich school-children over a period of 45 years. AB - In 16 rural communities of the Canton of Zurich, school-children of all age groups participated in dental examinations conducted at intervals of 4 years since 1963/64. The same standardised method was used throughout the entire period. This study documents the caries experience over a period of 45 years. From 1964 to 2009, the DM*FT per 14-year-old child fell from 12.50 to 1.31, corresponding to a caries reduction of 90%. The caries experience in 8-, 10- and 12-year-olds decreased by 90% to 92%. From 1964 to 2009, the "Significant Caries Index" (the mean DM*FT in the third of 12-year-olds with the highest DM*FT values) fell from 13.09 to 2.20, corresponding to a caries reduction of 83%. The observed caries decline was unexpectedly high. The effect of fluorides may explain a caries reduction of roughly 50%. A large part of the decline, however, remains unexplained. Possible causes are discussed in this paper. PMID- 21243547 TI - Rapid induction of remission in large vessel vasculitis by IL-6 blockade. A case series. AB - OBJECTIVE: To evaluate the effect of IL-6 blockade using tocilizumab in inducing remission of arterial large vessel vasculitides (LVV). METHODS: Five consecutive patients with giant-cell arteritis (GCA) and two with Takayasu's arteritis (TA) were treated by tocilizumab infusions (8 mg/kg). Tocilizumab was given every other week for the first month and once monthly thereafter. Clinical symptoms of disease activity, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level and glucocorticoid (GC) dosage necessary to maintain remission were prospectively assessed. MR angiography was performed to monitor local inflammation. RESULTS: Of the seven patients three were newly diagnosed and four showed GC resistance, i.e. GC could not be lowered to less than 7.5 mg/day. The mean follow-up time was 4.3 months (range 3-7 months). All patients achieved a rapid and complete clinical response and normalisation of the acute phase proteins. Remarkably, prednisone dosage could be reduced within 12 weeks to a mean of 2.5 mg/day (range 0-10 mg/day). No relapse and no drug-related side effects were noted. CONCLUSION: Collectively the data suggest that IL-6 blockade using tocilizumab qualifies as a therapeutic option to induce rapid remission in large vessel vasculitides. PMID- 21243548 TI - [Case Report: Failed epidural puncture for insertion of a catheter]. AB - We report on a failed epidural puncture for insertion of a catheter during chest wall correction by the minimally invasive procedure according to Nuss in a 16 year-old boy. After insertion of the catheter without any problem and establishment of a symmetrical thoracic analgesia and initiation of general anaesthesia, the catheter was surprisingly observed in the thoracic cavity upon insertion of the endoscopic camera. The catheter was then withdrawn under vision and the operation continued without any further incidents. PMID- 21243549 TI - [Acute renale failure in burns - causes, consequences and avoidance strategies]. AB - Acute renal failure (ARF) is a common and dangerous complication in intensive care medicine. Especially critical ill patients, who are suffering from major burns, have a high risk to develop ARF as a consequence of their trauma. Many factors, including the trauma itself, the damage of soft tissue and consecutive rhabdomyolysis, the development of the burn illness and therapeutic interventions play also a major role in this context. These circumstances have a major impact on the morbidity and mortality of severely burned patients. The aim of this manuscript is to review the reasons for the development of an ARF in burn patients as well as its consequences; moreover it highlights potential strategies to avoid ARF in critically ill burned patients. PMID- 21243550 TI - [Psychotropic drugs - The special importance of anticonvulsants and neuroleptics in treatment of patients with chronic pain]. AB - Therapy by psychotropic drugs is bound to limited indications, which are partially changing. By an extent literary research in pubmed and Cochrane especially corresponding articles of the past 10 years were proofed. So antidepressants were continually seldom given to nociceptor pain. While on the other side anticonvulsants are to be given in the case of neuropathic pain of defined quality, it will be looked for new applications for these drugs. Particularly hitherto existing difficult indications as fibromyalgia were investigated as possible indication for anticonvulsants. At least neuroleptics can be used for very difficult, resistant and bizarre pains such as cenesthesias. PMID- 21243551 TI - [Anesthesia incidents - treatment and risk of iatrogenic damage]. PMID- 21243552 TI - [Anaesthetic incidents - Airway management and injuries in anaesthesia - closed claims of the North German Arbitration Board]. AB - Injuries related to the airway management belong to the most often observed anaesthesia-related complications. Injuries of the trachea and the oesophagus possibly require surgical treatment. The most severe injuries caused by the airway management are the hypoxic brain damage and the patient's death. Tracheal injuries happen foremost as a result of tracheal intubation. Symptoms like subcutaneous emphysema and dyspnea are likely a sign of a tracheal lesion and need to be examined by Thorax-CT and endoscopy of the airways. In order to avoid injuries, medical treatment has to be applied with the appropriate care and strict adherence to the manufacturer's requirements regarding the use of the assisting devices necessary for the tracheal intubation. While some of he cases presented have to be assessed as of fateful origin, others are clearly the results of medical errors. PMID- 21243553 TI - [Anaesthics incidents - Injuries caused by regional anaesthesia - closed claims of the North German Arbitration Board]. AB - Injuries caused by regional anaesthesia are the second most common reason for a patient to apply to the North German Arbitration Board. Part of the reported injuries are mild and transient, while others are severe and permanent, e.g. a paraplegia after regional anaesthesia. In the majority of the reported cases, the Arbitration Board did not find a medical error as cause of the injury. Nevertheless, every possible effort needs to be made to reduce the number and the severity of the injuries due to regional anaesthesia. In order to reach that goal, medical treatment has to be applied with the appropriate care, including the strict adherence to the height of puncture for epidural and spinal anaesthesia below the Conus medullaris and the use of assisting devices like nerve stimulator and ultrasound-guided puncture. Using these measures, the frequency of injuries caused by regional anaesthesia will be reduced. PMID- 21243554 TI - [Incidents in anaesthesia - Legal evaluation of incidents in anaesthesia/Legal management of incidents in anaesthesia]. PMID- 21243555 TI - [Human resource management - Motivation of medical staff in intensive care medicine]. AB - Recently, human resource development concepts have become more important in intensive care medicine. Motivationally oriented leadership is an essential part of this strategy. Of particular significance, leadership first of all means not to demotivate the personnel. Furthermore, a motivationally oriented leadership concept creates a framework in which the physicians' own motivation may thrive. Intensive care supervisory staff today should be familiar with mechanisms and potential of established motivational concepts and should be able to transfer them consequently into clinical practice. PMID- 21243560 TI - [Joint statement of the German Respiratory Society and the German Roentgenological Society on the early detection of lung cancer by low-dose CT]. PMID- 21243561 TI - [A miniature "magic mountain" in the toy museum Davos]. PMID- 21243562 TI - [Oxygen in medicine]. PMID- 21243563 TI - The Thoracic and Cardiovascular Surgeon. Letter from the editor. PMID- 21243565 TI - Surgical correction of pectus excavatum. How did we get here? Where are we going? AB - The currently applied techniques recommended for the repair of pectus excavatum anomalies are discussed, set against a historical review of early clinical studies and surgical interventions. The issues of the future direction pectus excavatum surgery may take are analyzed in detail, with the reviewer expressing reservations in connection with the recent trend to closed repair and concern over the potential for serious complications associated with the application of this technique. PMID- 21243566 TI - In search of a standardized treatment for poststernotomy mediastinitis. AB - Poststernotomy mediastinitis following median sternotomy procedures such as open heart surgery is a rare complication which nevertheless has a mortality rate of up to 50 %. Several treatment options are currently available; however, none of them are standardized. Based on the experience gained from open heart surgery performed at the MediClin Heart Institute Lahr/Baden, a therapeutic algorithm was developed. The treatment steps consist of repeated radical surgical debridement, sternal restabilization, vacuum-assisted closure therapy (VAC) as well as a surgical reconstruction via M. pectoralis plasty (MPP). This approach had a 30 day mortality of 0 % and a hospital mortality of 10.4 %. The approach proved to be safe and advantageous for specific patient groups operated on at the MediClin Heart Institute Lahr/Baden. PMID- 21243567 TI - Transposition of greater omentum in deep sternal wound infection caused by methicillin-resistant Staphylococci, with differing clinical course for MRSA and MRSE. AB - BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis (MRSE) are an increasing problem in deep sternal wound infections (DSWI) after cardiac surgery. METHODS: Between 2005 and 2009, recalcitrant methicillin-resistant Staphylococcus was found in 21 patients with complicated DSWI, and a transposition of the greater omentum (TGO) was finally performed. A positive microbial culture at the time of procedure was present in all patients. The hospital course was reviewed discretely for MRSA and MRSE. RESULTS: Median patient age was 72.3 years (range 60.8-79.7); 76 % of patients were male. Time from the first sternal revision until consecutive open wound therapy due to re infection and total hospital stay was longer for MRSA compared to MRSE (38 vs. 14 days, P = 0.003, and 141 vs. 91 days, P = 0.007, respectively). The period from cardiac surgery to TGO was likewise prolonged for MRSA (78 vs. 55 days, P = 0.045), whereas in-hospital mortality and one-year mortality rate did not differ. CONCLUSION: TGO remains a good treatment option for DSWI type IV. Microbial findings determine the clinical course; nevertheless in-hospital mortality remains low for both MRSA and MRSE infection. PMID- 21243568 TI - Vacuum-assisted wound closure is superior to primary rewiring in patients with deep sternal wound infection. AB - OBJECTIVE: Deep sternal wound infections are serious complications after cardiac surgery. The aim of the present study is to compare the outcome after vacuum assisted wound closure to that after primary rewiring with disinfectant irrigation. The study additionally focuses on defining predictors for the failure of primary rewiring and its impact on postoperative outcome. METHODS: Retrospective analysis was performed in 5232 patients who underwent cardiac surgery with a median sternotomy. 192 patients postoperatively developed deep sternal wound infections and were distributed into 2 therapy groups: a vacuum assisted wound closure (= VAC) group and a primary rewiring (= RW) group, which was subdivided into healing after rewiring (= RW-h) and failure of rewiring (= RW f). These groups were compared statistically to reveal coincidental pre-, intra- and postoperative parameters. RESULTS: Compared to the VAC group, the RW group showed a poorer outcome, although RW baseline characteristics were apparently beneficial. Primary rewiring failed in 45.8 % of all cases, which led to even worse outcomes. Important predictors for failure of primary rewiring were morbid obesity, diabetes mellitus type II, chronic obstructive pulmonary disease, preoperatively impaired left ventricular function, postoperatively positive blood and wound cultures, bilateral harvesting of internal thoracic arteries and the need for surgical reexploration. CONCLUSIONS: In spite of patients being in a worse condition, vacuum-assisted wound closure therapy resulted in improved outcomes and thus should be preferred to primary rewiring. Moreover we report on predictors which may indicate whether there is a high risk of rewiring failure. PMID- 21243569 TI - Sternal plate closure: indications, surgical procedure and follow-up. AB - OBJECTIVES: Titanium plate osteosynthesis (Synthes) is an alternative option for sternal closure. The indications and time point of application are still debated. This study investigated the application and feasibility of this technique after median sternotomy. METHODS: Forty-one patients (29 M/12F, mean age 63 +/- 17 years) received the plate system for complicated sternal conditions. Indications, intraoperative course and postoperative follow-up were assessed. RESULTS: Sternal deformity was present in 5 % (2/41), sternal fractures in 17 % (7/41), bone defect in 12 % (5/41), wire loosening in 39 % (16/41) and pseudoarthrosis in 27 % (11/41). 54 % (22/41) of patients showed concomitant sternal infection. Two intraoperative complications were noted: mammary artery injury (1 patient), pleural injury (1 patient). At discharge the patients reported no pain (90 %, 37/41) or only occasional discomfort (10 %, 4/41). Postoperative complications were subcutaneous hematoma in 12 % (5/41), seroma in 12 % (5/41) and sternal reinfection in 7 % (3/41). 12 % (5/41) showed occasional discomfort and 7 % (3/41) had persistent pain leading to plate removal. CONCLUSION: The Titanium Sternal Fixation System is comfortable and easy to use. It can be used to treat a wide spectrum of indications, especially for pseudoarthrosis, an entity which has not yet received sufficient attention. PMID- 21243570 TI - Anatomical study of the thorax for the safe performance of the Nuss procedure for pectus excavatum. AB - BACKGROUND: To perform a minimally invasive repair for pectus excavatum safely, accurate knowledge of the anatomy of the retrosternal region is crucial. This study was carried out to provide more information on this region. METHODS: 1. Using 32 human cadavers, the vascular structure in the retrosternal region was studied. 2. The pleura, transverse thoracic ligament, pericardium, and diaphragm were taken from 10 fresh cadavers, and their thicknesses and breaking strengths were measured. RESULTS: Thick vessels connecting the internal mammary vessels and anterosuperior phrenic vessels were present in a certain number of cadavers. This presence of a vascular communication was observed in 44 % of left thoracic cavities and 12.5 % of right thoracic cavities. The breaking strengths of the pericardium and diaphragm were found to be nearly ten times greater than that of the pleura. CONCLUSIONS: Care should be taken not to injure vessels connecting the internal mammary vessels and anterosuperior phrenic vessels when performing retrosternal undermining of the xiphoid region. Since the pericardium is much thicker than the pleura, injury of the pericardium can be avoided by careful undermining. PMID- 21243571 TI - Biological materials for diaphragmatic repair: initial experiences with the PeriGuard Repair Patch(r). AB - BACKGROUND: We sought to analyze the efficacy of a bovine pericardial patch (PeriGuard(r)) for diaphragmatic repair. METHODS: Seven consecutive patients (6 males, median age 56 years) scheduled for diaphragmatic resection and/or repair were enrolled in this study. In all cases diaphragmatic repair was performed with a PeriGuard Repair Patch(r) (Synovis, St. Paul, MN, USA). At follow-up (median: 12 months; range: 6-18 months), quality of life, signs of reherniation and incorporation of mesh were assessed through clinical examination, blood samples and CT or MRT scan. RESULTS: Diagnosis on admission included sarcoma (n = 2), mesothelioma (n = 1), squamous cell carcinoma (n = 1), parachordoma (n = 1) and large congenital or posttraumatic herniation (n = 2). At follow-up successful diaphragmatic repair with no signs of reherniation, graft dehiscence or seroma formation was confirmed for all patients. Recorded inflammatory markers [C reactive protein (CRP), white blood cell count (WBC) and procalcitonin (PCT)] reached their peak values between postoperative day (POD) 4 and POD 7. Values ranged from 122-282 mg/L for CRP, 0.4-4.6 ug/L for PCT and 6.2-15.6 Tsd/uL for WBC. Overall oncological results were good and 5 out of 6 survivors reported a fully reestablished quality of life. CONCLUSION: We consider the PeriGuard Repair Patch(r) a viable alternative to synthetic materials for diaphragm replacement. Moreover, we advise carrying out cautious follow-up in patients undergoing extensive oncological resection to learn more about the biological behavior of the bovine PeriGuard Repair Patch(r) after diaphragmatic repair. PMID- 21243572 TI - Factors affecting morbidity and mortality in flail chest: comparison of anterior and lateral location. AB - OBJECTIVE: Flail chest is most often accompanied by significant underlying pulmonary parenchymal injuries and may constitute a life-threatening thoracic injury. In this study we evaluated the treatment modalities for flail chest depending on the effect of trauma localization on mortality and morbidity. METHODS: Between 2003 and 2008, 23 patients (20 males/3 females) were treated for flail chest. Location of the trauma in the chest wall, mechanical ventilation support, prognosis and injury severity score (ISS) were recorded for all patients. Mechanical ventilation support was given in 14 patients (60.8 %), and 12 of these 14 patients required subsequent tracheostomy. Internal fixation was used in 3 patients. RESULTS: The major cause of flail chest was a car crash in 18 of 23 patients (76 %). Median ISS was 62.8 for all patients. The patients with flail chest who had bilateral costochondral separation (anterior chest location) (group I, n = 10) had a significantly higher ISS than those with single-side posterolateral flail chest (group II, n = 13; ISS: 70/55; P = 0.02). The need for mechanical ventilation support was also higher in the group with bilateral costochondral separation. Morbidity was higher in group I than in group II ( P = 0.198), and mortality was also significantly higher in group I ( P = 0.08). Patients with a cranial trauma and flail chest had a higher mortality (19 %) than patients with only flail chest (no mortality). The mean ISS was 75 for patients with cranial trauma and flail chest and 55.7 ( P = 0.001) for patients with only flail chest. Sepsis and subarachnoid bleeding were the major causes of mortality. The mean ISS was 54.5 for patients under the age of 55 (n = 14) whereas it was 69.4 in those aged 55 and over (n = 9; P = 0.034). Mortality in the older group was also higher (33 % versus 7 %; P = 0.02). CONCLUSION: Early intubation and mechanical ventilation is of paramount importance in patients with flail chest. However, prolonged mechanical ventilation is associated with a poor outcome. Tracheotomy and frequent flexible bronchoscopy are an effective pulmonary toilet. Advanced age was a major risk factor for flail chest trauma mortality, together with the severity of the injury. When cranial trauma was accompanied by flail chest, mortality and morbidity rates increased. Bilateral costochondral separation also increased the risk of morbidity and the need for mechanical ventilation in patients with flail chest. PMID- 21243573 TI - Repair of sternal dehiscence with titanium mesh plates: the sandwich technique. AB - Sternal dehiscence after cardiac surgery occurs infrequently and can lead to mediastinitis and prolonged hospital stay and may even result in death. The most common treatment for mechanical sternal instability is rewiring with wound debridement. We present a case in which a modified titanium mesh plate fixation technique was used. A safe and easy to perform technique, this method can be an alternative option to wire closure in a sternum with fractures, instability or poor bone quality. PMID- 21243574 TI - Aorta-to-right ventricular fistula due to pectus bar migration. AB - A 23-year-old man, operated on for pectus excavatum with a modified Ravitch procedure, was admitted to our emergency department suffering from severe dyspnea. Massive pericardial effusion, rupture of the sinus of Valsalva, and aortic-to-right ventricular fistula were present on echocardiography. Cardiac penetration of the metal bar was detected on chest CT scan. The defect at the right sinus of Valsalva was closed with a PTFE patch, and the right aortic and ventricular ruptures were repaired primarily. PMID- 21243575 TI - Revision surgery in pectus excavatum after failure of Nuss technique. AB - A 17-year-old female had undergone two failed pectus excavatum repairs using the Nuss technique. Each time the bar had shifted, one time displacing the heart. Revision surgery was carried out using the Erlangen technique, which proved to be a safe and successful method to remove the displaced bar and correct the pectus excavatum. PMID- 21243576 TI - Should the pectus bar be removed before pregnancy? Two case reports. AB - The Nuss procedure is a minimally invasive repair for pectus excavatum in children and adults. However, it is unclear whether or not the stainless steel bar should be removed before pregnancy. We report on two adult females who had undergone a Nuss repair for pectus excavatum and successfully delivered prior to removal of the pectus bar. PMID- 21243577 TI - Lateral thoracic expansion in a preterm baby with asphyxiating thoracic dystrophy. AB - Lateral thoracic expansion is a surgical technique which consists of increasing the diameter of the thoracic rib cage by the division of ribs and underlying tissue in a staggered fashion. To our knowledge, this procedure has not yet been described in preterm babies. We report a case of a 32-week preterm baby who was initially treated sequentially with resection of the costal cartilages and sternal spreading with the interposition of cartilage grafts, followed by left and right lateral thoracic expansion. The patient survived for 4 months after birth, showing that this procedure can be performed at any age after delivery. PMID- 21243578 TI - Chest wall reconstruction in a patient with sternal fibrous dysplasia. AB - A patient with sternal fibrous dysplasia was treated via subtotal sternectomy using a sandwich titanium micromesh and polypropylene mesh to repair the chest wall defect. Pectoralis muscle flaps were created to cover the prosthesis. The patient had a normal postoperative course with good stability and postoperative cosmesis. PMID- 21243579 TI - Combined spontaneous contralateral pneumothorax and post-pneumonectomy mediastinal shift-associated dextrocardia. AB - We report here on an unusual late postoperative presentation of extreme post pneumonectomy dextrocardia and spontaneous contralateral pneumothorax presenting as late complications occurring approximately 2 years after right-sided pneumonectomy. Computed tomography is the diagnostic modality of choice to obtain information on anatomical changes within the post-pneumonectomy space. Knowledge of the spectrum of cardiopulmonary, pleural, and other complications after lung resection is important to properly manage complications in post-pneumonectomy patients. PMID- 21243580 TI - Regarding neurogenic malignant tumors in the mediastinum. AB - This letter reports on the rare presentation of a malignant neurogenic tumor in the phrenic nerve. PMID- 21243581 TI - [76-year-old man after creation of a Cimino shunt]. PMID- 21243582 TI - Current approaches to discover marine antileishmanial natural products. AB - Leishmaniasis is a neglected infectious disease caused by kinetoplastid protozoans. An urgent need for novel chemotherapeutics exists. The current approaches to discover new antileishmanial compounds present many drawbacks, including high-cost and time-consuming bioassays. Thus, advances in leishmaniasis treatment are limited, and the development of screening assays is hindered. The combination of multidisciplinary approaches using standardised methods and synchronous projects could be an alternative to develop novel drugs for leishmaniasis treatment. In this review, we discuss the current status of leishmaniasis occurrence and treatment. In addition, we address the advantages and limitations of in vitro leishmaniasis bioassays and discuss the findings of drug discovery research using natural products. Finally, we comprehensively review the marine natural products that are active against Leishmania spp., including their natural sources and bioactivity profile. PMID- 21243583 TI - Inhibition of AMPK-associated autophagy enhances caffeic acid phenethyl ester induced cell death in C6 glioma cells. AB - An increasing number of studies show that AMP-activated protein kinase (AMPK) activation can inhibit apoptosis. To clarify the antitumor mechanism of caffeic acid phenethyl ester (CAPE) and achieve increased therapeutic efficiency, we investigated the potential roles of AMPK and autophagy in CAPE treatment against C6 glioma cells. The roles of AMPK and autophagy inhibition in CAPE's cytotoxic action were investigated. Phosphorylation of AMPK and mitogen-activated protein kinases (MAPKs) were observed in tumor cells following CAPE treatment. A combination of CAPE and the AMPK inhibitor, compound C, resulted in augmented cell death. Similar effects of compound C were observed in response to changes in the mitochondrial membrane potential ( DeltaPsi(m)). Small interfering RNA mediated AMPK downregulation increased CAPE-induced cell death. The results suggest that AMPK activation plays a role in diminishing apoptosis. CAPE treatment induced an increase in LC3 conversion as represented by the LC3-II/LC3 I ratio. Enlarged lysosomes and autophagosomes were present according to electron microscopy. The autophagy inhibitor, 3-MA, caused increased CAPE cytotoxicity, which suggests that autophagy induction protected glioma cells from CAPE. The combination of CAPE with autophagy and AMPK inhibitors markedly enhanced the cytotoxicity toward C6 glioma cells. Accordingly, CAPE-triggered activation of AMPK and the autophagic response protected tumor cells from apoptotic death. This provides new insights for combined therapy to enhance the therapeutic potential of cancer treatments. PMID- 21243584 TI - Cytotoxic triterpenoids and steroids from the bark of Melia azedarach. AB - Two new triterpenoids (1, 2) and two new steroids (3, 4) along with twelve related known compounds (5-16) were isolated from the bark of Melia azedarach. The new structures were elucidated by means of spectroscopic methods and molecular modeling studies and found to be 21,24-cycloeupha-7-ene-3 beta,16 beta,21 alpha,25-tetrol (1), 3 beta-acetoxy-12 beta-hydroxy-eupha-7,24-dien-21,16 beta-olide (2), 29-hydroperoxy-stigmasta-7,24(28) E-dien-3 beta-ol (3), and 24 xi hydroperoxy-24-vinyl-lathosterol (4). All isolated compounds were tested for their cytotoxic activity against three human cancer cell lines (A549, H460, HGC27) using the CellTiter GloTM luminescent cell viability assay. Among them, compounds 2- 4, 24 xi-hydroperoxy-24-vinyl-cholesterol (6), kulinone (7), meliastatin 3 ( 8), 3-oxo-olean-12-en-28-oic acid (10), and (22 E,24 S)-5 alpha,8 alpha-epidioxy-24-methyl-cholesta-6,22-dien-3 beta-ol (12) were found to have cytotoxic effects, with IC50 values of 5.6-21.2 ug/mL. PMID- 21243585 TI - Antimycobacterial activity and alkaloid prospection of Psychotria species (Rubiaceae) from the Brazilian Atlantic Rainforest. AB - Ten Psychotria species were collected in two fragments of Atlantic Forest in Rio de Janeiro: Psychotria pubigera (P1A and B), P. ruelliifolia (P2), P. suterela (P3), P. stachyoides (P4), P. capitata (P5), P. glaziovii (P6), P. leiocarpa (P7), P. nuda (P8), P. racemosa (P9) and P. vellosiana (P10). Ethanol extracts of these species were evaluated for their antimycobacterial activity, in an attempt to find new antituberculosis agents. Psychotria pubigera (P1A), P. ruelliifolia (P2) and P. stachyoides (P4) were the most active against Mycobacterium. The anti inflammatory potential of these extracts was also evaluated in vitro to learn if they inhibit nitric oxide (NO) production in macrophages and if they have free radical scavenging properties, because inflammation is a severe problem caused by tuberculosis, especially when the infection is from M. bovis or M. tuberculosis. Psychotria suterela (P3), P. stachyoides (P4) and P. capitata (P5) were the most active in inhibiting macrophage NO production but they were not the most antioxidant species. This suggests that NO inhibitory activity is not due to the scavenging of NO generated but due to a specific inhibition of iNOS activity or expression. In addition, cytotoxicity was tested in the macrophages (the host cells of the Mycobacterium) and it was verified that the extracts selectively killed the bacteria and not the host cells. When analyzing antimycobacterial, cytotoxicity and NO inhibitory activities in combination, P. stachyoides (P4) was the most promising anti-TB extract tested. Further, indol alkaloids were detected in P. suterela and P. nuda, and 5,6-dihydro-beta-carboline alkaloids in all of the species studied, with the highest amounts found in P. capitata and P. racemosa. PMID- 21243586 TI - O-prenylated acridone alkaloids from the stems of Balsamocitrus paniculata (Rutaceae). AB - Two new O-prenylated acridone alkaloids, balsacridone A (1) and B (2), together with eighteen known compounds were isolated from the methanol extract from the stems of Balsamocitrus paniculata, a Cameroonian medicinal plant. The structures of all compounds were determined by comprehensive analyses of their 1D and 2D NMR, mass spectral (EI and ESI) data, and chemical reactions. N-methyl-6 methoxybenzoxazolinone (16) was isolated for the first time from a natural source while compounds 13, 14, and 15 for the first time from this genus. Pure compounds were tested for their activity against bacteria, fungi, and plant pathogen oomycetes, using the paper disk agar diffusion assay. The agar diffusion test delivered low to missing antimicrobial activities, corresponding to MICs > 1 mg/mL. However, compounds 1-15 exhibited a strong suppressive effect on phagocytosis response upon activation with serum opsonized zymosan in the range of IC50 = 0.5-7.2 MUM, and the acridone alkaloids (1-5), N-trans-p coumaroyltyramine (13), and N-trans-pcoumaroyloctopamine (14) displayed weak cytotoxic activity against the human Caucasian prostate adenocarcinoma cell line PC-3, with IC50 values ranging from 69.8 to 99.0 MUM. PMID- 21243587 TI - Cytotoxic steroidal saponins from Agave sisalana. AB - Two new steroidal saponins, 8 and 10, along with 7 known steroidal sapogenins and saponins (1-7) and a furostanol saponin (9) were isolated from Agave sisalana Perrine ex Engelm. The structures of these two new compounds were identified and characterized by 1D and 2D NMR spectroscopy and mass spectrometry. In addition, acid hydrolysis and GC-FID were used to confirm the sugar moieties of 8 and 10. The cytotoxic effects of 1-10 on MCF-7, NCI-H460, and SF-268 cancer cells were evaluated, and among them, compound 10 proved to be the most cytotoxic with IC50 values of 1.2, 3.8, and 1.5 uM, respectively. PMID- 21243588 TI - Lignans and other constituents from the roots of the Vietnamese medicinal plant Pseuderanthemum palatiferum. AB - Two new lignans, palatiferin A (1) and palatiferin B (2), were isolated from the roots of Pseuderanthemum palatiferum, together with five known triterpenes, epifriedelanol (3), lupeol (4), lupenone (5), betulin (6), pomolic acid (7), and a dipeptide asperglaucide (8). Their structures were established from 2D NMR and mass spectroscopy. The absolute configuration of 1 and 2 was proposed based on the comparison of their optical rotation activities with those of compounds with similar structures such as wodeshiol and paulownin. The new lignans, palatiferin A (1) and palatiferin B (2) exhibited a moderate cytotoxicity against KB and HepG2 cell lines. However, betulin and lupeol, two abundant compounds from the roots of P. palatiferum, showed cytotoxic and antimicrobial activities. PMID- 21243589 TI - New sesquiterpene lactones from Glechoma hederacea L. and their cytotoxic effects on human cancer cell lines. AB - Three new sesquiterpene lactones, 1 alpha,10 beta-epoxy-4-hydroxy-glechoma-5-en olide (1), 1 beta,10 alpha-epoxy-4,8-dihydroxy-glechoma-5-en-olide (2), and 1 beta,10 alpha;4 alpha,5 beta-diepoxy-8-methoxy-glechoman-8 alpha,12-olide (3), were isolated from the whole plant of Glechoma hederacea, together with four known sesquiterpene lactones. The structures of the three new sesquiterpene lactones were determined by spectroscopic evidence. Cytotoxic effects of the isolated compounds were examined against MDA-MB-231 (breast), HCT116 (colon), SW620 (colon), and DU145 (prostate) human cancer cell lines. PMID- 21243590 TI - [The internet: an Orthopedist's boon or bane?]. AB - AIM: The Internet provides additional and nearly endless health-related information material for the patient. On the other hand, previous studies reported on the lack of quality for health-related websites, especially for message boards. A direct analysis of treatment recommendations from message board members and spine experts has not yet been published in the medical literature. The aim of this study is to evaluate the quality of information regarding treatment of scoliosis one can receive from message board members compared to experts in this field. METHOD: All members of one of Germany's biggest scoliosis related message boards were invited to fill out an online questionnaire. This questionnaire included questions regarding demographic data, questions commenting on the influence of the Internet regarding their own decision finding, and six imaginary cases with four answer options each. The attendees were asked to provide the best treatment option. The answers of experts in the treatment of spinal disorders who commented on the same cases were used as control. RESULTS: 31 complete questionnaires from Internet patients were included in the analysis and compared to 36 answers from spine experts. In four of six cases an excellent agreement could be found. There was a good agreement in one case and a poor agreement in another. The disagreement would unlikely have led to harm for the patient. One third of the patients claimed that information received from the Internet has had a major impact on their own decision finding. CONCLUSION: The data show that treatment recommendations from members of a scoliosis-related message board have good to excellent agreement with treatment recommendations from experts in the majority of cases. The use of a message board can potentially be helpful in the care of scoliosis patients. Additional studies will evaluate whether or not the results of our study are representative for other message boards as well. PMID- 21243591 TI - [The prevalence of radiological osteoarthritis in relation to age, gender, birth year cohort, and ethnic origins]. AB - AIM: This metaanalysis was performed to evaluate the prevalence of the radiological assessed knee osteoarthritis in the whole community. MATERIALS AND METHODS: Medical databases (Medline, EMBASE, Cochrane) were searched for the strategy: ["Osteoarthritis" and "Knee" and "Prevalence"]. The deadline for the search was 31.12.2009. Two investigators (first and senior author) independently made the selection from 17 studies (from a total of 1428) according to the inclusion criteria: a cross-sectional study of the whole community, radiological investigation and definition of knee ROA by an established radiological score. Only studies in English or German language were evaluated. Effect sizes (event rate, odds ratio [OR] and confidence interval [CI]) were calculated by the software "Comprehensive Metaanalysis V2". Study heterogeneity (I2) was determined accordingly to Higgins. RESULTS: The kappa index for interobserver validity was k = 0.948. All studies judged the grade of osteoarthritis according to the Kellgren Lawrence (KL) score. For calculation of knee ROA KL grades 2+ were estimated only. The total prevalence of knee ROA was 24.3 % (CI 23.4-25.2 %). The whole prevalence in male patients was 24.3 % (CI 23.4-25.2 %); I2 = 59.4 (p = 0.002) and in female patients 32.6 % (CI 31.8-33.4 %); I2 = 49,1 (p < 0.001). Younger male patients (age 50-) had a prevalence of 5.6 (CI 4.5-6.8). In older patients (80+) the male prevalence was 44.5 % (CI 39.6-49.5 %). In this age group female patients had a prevalence of 71.6 % (CI 67.6-75.3 %). The higher prevalence of knee ROA in female patients was significant (OR = 1.8 [1.7-1.9]; I2 = 46.0 [p < 0.001]). The prevalence of knee ROA was higher in male Asians compared with male Caucasians (OR = 1.1, CI 0.9-1.2; p = 0.080) in tendency. This difference was significant in female patients (OR = 2.2; CI 2.0-2.4; p < 0.001). Furthermore another trend was evaluated. Female patients (70-79 years) from the birth-year cohort 1920- had a prevalence of 37.8 % (CI 35.9-39.7)%. In contrast female patients from the birth-year cohort 1920 had a prevalence of 62.8 % (CI 60.8-64.8 %) at 70-79 years. This difference was significant (OR = 2.8; CI 2.5-3.1; p < 0.001). CONCLUSIONS: This investigation confirms the high prevalence of knee ROA. The evaluated data may serve as a reference for medical or scientific investigations in the future. PMID- 21243592 TI - [Evaluation of results after total hip replacement using a minimally invasive and a conventional approach. Clinical scores and gait analysis]. AB - AIM: In a prospective study the results of total hip replacement of patients with coxarthrosis and minimally invasive anterolateral (MIS; n = 48) vs. conventional transgluteal approach (KONV; n = 10) were investigated by means of clinical and functional outcomes. Different clinical scores and gait parameters were compared with each other preoperatively and on average 5 weeks and 6 months postoperatively as well as to a control group (VG; n = 58) of healthy age-matched probands. MATERIAL AND METHOD: For clinical examination the range of hip motion was determined and the Harris hip score (HHS), the score according to Merle d'Aubigne (MD), the intensity of pain (visual analogue scale - VAS), the SF-36 and the WOMAC arthrosis index have been used. Furthermore, the subjective gait pattern was interpreted and the Trendelenburg sign was analysed. The influence of the implantation on the biomechanics of the joint was estimated with a biomechanical score by analysing the pelvic radiographs. Objective measurement data of the gait were obtained by using a three-dimensional motion analysis system with six infrared cameras and three force plates. RESULTS: Both groups of patients had good clinical results at five weeks after surgery, especially shown in the significantly better results of the used pain scores. Despite visually inconspicuous gait in both operated groups, the sensitive parameters of the gait analysis showed persistent large deficits. A significant improvement was appreciated six months after surgery, but the level of the healthy probands was not attained at this time. There were no significant differences of any gait parameter between the groups MIS and KONV at any time of examination. CONCLUSION: Advantages of minimally invasive approaches in total hip replacement which can be found a short time after surgery (like less blood loss, less pain after operation, quicker beginning of mobilisation) were not found in this study 5 weeks later regarding functional outcomes. Persistence of functional deficits, caused by damage to the arthromuscular complex, which occur during the process of the development of the arthrosis, need much more time to recover after surgery, independent of the used approach. PMID- 21243593 TI - [Importance of computer-assisted navigation in total knee arthroplasty - results of a nationwide survey in Germany]. AB - AIM: Total knee arthroplasty is one of the standard procedures in severe osteoarthritis of the knee. Computer-assisted navigation systems became more popular in the last decade. Navigation systems improve the component positioning and the alignment in total knee arthroplasties. The aim of this survey was to capture the actual trend in computer-assisted total knee arthroplasties in Germany and to discuss the results in comparison to the current literature. METHODS: A questionnaire form was sent to 506 orthopaedic and trauma surgery departments in Germany. The first part of the survey included general questions about the department and total knee arthroplasties. The surgeons were asked about their application behaviour and their rating of computer-assisted navigation in total knee arthroplasty in the second part. Questions concerning total knee arthroplasties, unicondylar knee arthroplasties and revision total knee arthroplasties were included in the form. RESULTS: 194 of the departments returned the questionnaire. A total of 39 941 knee arthroplasty surgeries were performed in these departments. 35 624 of these surgeries were primary knee arthroplasties including 32 789 total knee arthroplasties and 2835 unicondylar knee arthroplasties. In addition, 4317 revision total knee arthroplasties were performed by the respondents. 60 % of the departments used a computer-assisted navigation system. In synopsis 29 % of the primary total knee arthroplasties, 4 % of the unicondylar knee arthroplasties and 7 % of the revision knee arthroplasties were performed with a computer-assisted navigation system. Minimal invasive surgery was performed in 31 % of the departments and 36 % of these surgeries were done with navigation-assistance. The "ligament-balanced" procedure was the most common used technique to determine the femur rotation in navigated total knee arthroplasties. In 75 % of navigated total knee arthroplasties cemented components were implanted. Overall 65 % of respondents approved of navigation-assisted surgeries and 77 % saw an improved precision by this technique. The number of computer-assisted navigation uses in surgeries is increasing in 34 % of the departments and decreasing in 13 %. CONCLUSION: The computer-assisted navigation in total knee arthroplasties is a frequently used technique. The most respondents support the application of navigation-assisted knee arthroplasties and indicate an improved outcome measured by the postoperative alignment. Nevertheless, long-term results are needed for a final evaluation of navigation-assisted surgery. PMID- 21243594 TI - [Radial MRI of the hip joint for evaluation of degenerative changes in the young adult: a comparison of different sequences]. AB - AIM: Femoroacetabular impingement has been shown to be an important cause for the development of osteoarthritis of the hip joint. Radial MRI of the hip has proven to be the diagnostic procedure of choice to differentiate which patient to operate. While examinations after instillation of contrast agents have been described, new papers have shown high accuracy without contrast medium. Since instillation of contrast medium is considered painful and poses the risk of infection, it is not performed for MRI evaluation of the hip at our institution. However, the question as to which sequence to use has not been settled yet. Therefore, four frequently used sequences using the same resolution were compared. MATERIALS AND METHODS: A retrospective analysis of T (1)-weighted (T (1)), T (2)-weighted (T (2)) and proton density sequences (the latter with and without fat saturation [PDfs and PD]) of 50 hips in 48 patients with femoro acetabular impingement and developmental dysplasia of the hip was performed by two raters blinded to the clinical information. The different sequences were rated separately. Evaluated criteria were subjective imaging quality, power to differentiate acetabular from femoral cartilage as well as the labrum from the joint capsule, and localisation and characterisation of pathological changes in joint cartilage, the labrum and at the femoral head-neck junction. RESULTS: Subjective imaging quality was assessed to be similar for T (1), PDfs and PD, whereas it was significantly worse for T (2). In discriminating specific intraarticular structures, however, only PDfs and PD were superior. The differentiation of acetabular from femoral cartilage was possible in only 44% and 40% of T (1) and T (2) images, but in 79% and 76% of PDfs and PD images. Similar results were found for the differentiation of the acetabular labrum from its vicinity, especially the joint capsule (36%, 35%, 77% and 74%, respectively). Intralabral pathology was seen in a comparable extent in all sequences. An intramedullary oedema at the head-neck junction, however, was significantly more frequent in PDfs only (67% vs. 0%, 17% and 10% for PDfs vs. T (1), T (2) and PD). CONCLUSION: Despite their good subjective quality, T (1)- and T (2-)weighted sequences could not depict the acetabular labrum as efficiently as PD-weighted sequences. Concluding from our data, a PDfs sequence (possibly combined with a conventional PD sequence) is advantageous over T (1) and T (2) sequences. Intraarticular administration of contrast medium seems to be superfluous. PMID- 21243595 TI - [New treatment option for women with chronic constipation - prucalopride stimulates the disturbed gut motility again]. PMID- 21243596 TI - [M&M Conferences - how to learn from mistakes]. PMID- 21243597 TI - [Antibiotic resistance and biofilm formation in Staphylococcus aureus strains isolated from urine]. AB - BACKGROUND: The aim of this study was to evaluate antibiotic resistance and biofilm formation of Staphylococcus aureus strains, isolated from urine samples of patients with urinary tract infection. The samples were collected in the period of 2005-2009 and originated from patients of St. Anne's Teaching Hospital in Brno. MATERIAL AND METHODS: A total of 128 S. aureus strains from 128 patients with the diagnosis of urinary tract infection were examined. In addition to testing the antibiotic resistance to doxycycline, vankomycin, nitrofurantoin, oxacillin, amoxicillin/clavulanate, cefoxitin and sulfamethoxazol/trimethoprim, biofilm was also detected in 112 strains by the modified Christensen method. RESULTS: No S. aureus strain resistant to vankomycin and nitrofrantoin was found, 12 strains were resistant to oxacillin (9.4 %), 6 to doxycyklin (4.7 %), 9 to amoxicillin/clavulanate (7.0 %) as well as to cefoxitine, and 2 to sulfamethoxazol/trimethoprim (1.6 %). Out of 20,375 positive urine samples examined in our laboratory between 2005 and 2009, S. aureus was detected as a causative agent of urinary tract infection in 0.6 %, being more frequent in males. Biofilm was produced by 14 (12.5 %) out of 112 S. aureus strains. CONCLUSIONS: The biofilm formation of urinary S. aureus strains was low. The strains showed higher resistance to beta-lactams, in other cases resistance was low. S. aureus was found to be more frequent in urine of older patients, males and after previous interventions using instrumental. PMID- 21243598 TI - [Current perspective of the resistance of Helicobacter pylori strains to antimicrobial drugs]. AB - A significant increase in H. pylori resistance to clarithromycin and metronidazole has been proven in both children and adults. Clarithromycin with resistance over 20 % and metronidazole with resistance over 40 % are not recommended for treating H. pylori infection. Preferred treatment regimens were designed to reflect the current situation. The classical regimen PPI + AMO + CLA (MET) can be used in cases where the resistance against CLA and MET is lower than stated above. In the opposite case, a combination of PPI + AMO + levofloxacin (or rifabutin, or furazolidone) must be used. In many countries, this regimen is already the first-choice treatment. The 4-combination with bismuth is suitable in case of 3-combination treatment failure, or in patients allergic to penicillin. PMID- 21243599 TI - [The evidence of Helicobacter pylori in gastric biopsy and stool samples]. AB - In the diagnosis of Helicobacter pylori infection, it is possible to use either invasive methods when it is essential to take biopsy samples from endoscopic examination or non-invasive methods which do not require endoscopy. The invasive tests include histological examination, culture, rapid urease test and molecular methods. The non-invasive methods are serological tests, stool antigen detection (HpsAg) and respiratory tests. The article compares biopsy culture with stool antigen detection in a group of 300 patients in whom stool samples were collected simultaneously with endoscopic examination. PMID- 21243600 TI - [Incidence and characteristics of Clostridium difficile infection in patients with diarrhea in a Prague teaching hospital]. AB - AIM OF THE STUDY: Description of basic epidemiological and clinical data of patients suffering from Clostridium difficile infection (CDI). Recognizing important predisposing factors and detecting complications of the disease. MATERIALS AND METHODS: A retrospective study of clinical and laboratory parameters in patients with confirmed CDI who were admitted in our department between 1 January, 2008 and 30 June 2010. Etiology of the disease was identified using the enzyme-linked flourescent assay (ELFA). RESULTS: Clostridial etiology of post-antibiotic diarrhea was found in 82 patients. Those were 44 women and 38 men, aged 5-88 years (median of 66 years). Fifty-two patients (76 %) were older than 60 years. Seventy-seven patients (92 %) were given antibiotics before the onset of the disease, three patients received cytostatic therapy. In most cases, the disease began after treatment with aminopenicillins, third-generation cephalosporins or fluoroquinolones. Fifty-three patients (65 %) reported previous hospitalization. In 17 patients (21 %), the disease recurred; two patients developed ileus. Eleven patients died; with the death being caused by CDI in four of them. CONCLUSIONS: CDI is a live-threatening disease mainly affecting elderly hospitalized patients with comorbidities. The most important predisposing factor is the administration of broadspectrum antibiotics. Early diagnosis and treatment may improve the prognosis of serious cases. PMID- 21243601 TI - [Listeriosis in pregnant women and newborns in Czech Republic]. AB - Listeria monocytogenes is ubiquitous in nature, being commonly present in faecal flora of otherwise healthy human population or animals. Clinical manifestation of listeria infection may vary widely from mild to invasive, life-threatening disease. In an immunocompromised host, a rather serious course should be expected. Due to cell-mediated immune insufficiency associated with pregnancy even a short bacteraemia in pregnant women can result in transplacental infection. Most listeria infections are sporadic but outbreaks may occur. An outbreak of listeriosis in the Czech Republic in the autumn of 2006 and winter of 2007 was associated with an increased incidence of perinatal listeriosis. More information on listeriosis prevention in pregnancy should be given and each febrile episode during pregnancy should be carefully examined. Early treatment of listeriosis reduces the risk of vertical transmission. PMID- 21243602 TI - [Principles of macrophage resistance to intracellular parasites]. AB - Intracellular parasitism is a phenomenon present in nature for more than one billion years. Its keystone is the intriguing ability of viruses and some bacteria to survive and multiply inside eukaryotic host cells and to parasitize on their metabolic machinery. According to the classical definition, germs are classified as intracellular parasites only if they are able to survive inside macrophages. However, the ability of germs to survive inside eukaryotic cells is much more common than it was expected earlier. Reaction of macrophages to invading microbes is the key point in the complex immunological resistance of the host. The outcome of the host is substantially linked to macrophage reactivity. For example, if an evading microbe with a replication time of 20 minutes survived inside a host for 24 hours without reaction of innate immunity, there would be more than 2 x 1021 microbes at the end of this period. It would be fatal for the host, indeed. The key activities of macrophages in the sense of protection against intracellular parasites are reviewed. Some mechanisms of microbial defence and some new approaches to clinical diagnosis of the functional status of cells of innate immunity are also discussed. PMID- 21243603 TI - [Evidence-based treatment of depression: what does the new S3- and national healthcare guideline Unipolar Depression really recommend?]. AB - The paper reflects central recommendations and methodological issues of the new German guidelines for the treatment of depression, as discussed in the article New German Guidelines for the Treatment of Depression - The Central Role of Psychotherapy (Schauenburg et al. 2009). Members of the steering group for these guidelines disagree with the authors' description in several points, especially with reference to the efficacy of pharmacotherapy with antidepressants and psychotherapy, as well as the relationship between both strategies of therapy and their combination in diverse phases of treatment (acute/maintenance). Furthermore, we try to clarify some misunderstandings in matters of the guideline's methodology which arose in the paper cited. PMID- 21243604 TI - [Work in progress--why evidence-based guidelines do not mean the end of controversial discussions]. AB - Harter et al.s (2010) statement points to differences in the interpretation of the German National Guidelines for the treatment of depression and adds some of the recommendations missing in the original paper. The response again stresses the general consensus and relates to controversies that did not find entry into the recommendations, although they are important for establishing a transparency in the discussion process. Not all clinically relevant questions can be answered based on evidence (e.g. differential indication as to treatment duration). Also, the issue of external validity has to be discussed again and again to ensure reception and implementation of clinical guidelines. Finally, the very cooperative process of the guideline development is pointed out. PMID- 21243605 TI - [Psychotherapy by medical doctors in primary care: an empirical investigation in South Baden, Germany]. AB - OBJECTIVES: The present study investigates the kind and frequency of medical psychotherapy carried out in GPs' offices in South Baden, Germany. METHODS: Established GPs and other primary-care physicians from South Baden (n = 64) who had successfully completed additional training in psychotherapy were queried about their current psychotherapeutical services using a questionnaire. The data were evaluated by applying descriptive and correlative statistical procedures. RESULTS: The response rate was 93.8 % (n = 60). Standard psychotherapy short-term psychotherapies with up to 25 hours and long-term psychotherapies with up to 50 hours) had been supplied, with an average of 8.3 patients per doctor and quarter. Services rendered outside standard psychotherapy regimen including the approved services for basic psychosomatic care, especially short-term psychotherapeutic interventions of up to ten sessions, were performed with an average of 108.9 patients per doctor. As predictors for the performance of these services we found (1) patients with a high educational level (p = 0.002), (2) the cooperation with other psychosocial professional groups (p = 0.008), and (3) the participation in quality-assurance measurements (p = 0.009). CONCLUSIONS: Physicians with additional training in psychotherapy offered a great amount of psychotherapeutical services not covered by the the standard psychotherapy guidelines of the national health services. These offers, borne primarily by idealism, should be acknowledged by new reward models in the future. PMID- 21243606 TI - [Meaning in life and mental health: personal meaning systems of psychotherapists and psychotherapy patients]. AB - OBJECTIVES: This study investigated differences in the personal meaning systems of psychotherapists and psychotherapy patients as well as correlations between meaning in life and mental health. METHODS: We qualitatively assessed the content and structure of the personal meaning systems of 41 psychotherapists and 77 psychotherapy patients. In addition, the participants completed questionnaires measuring meaning in life (LRI-r-d), sense of coherence (SOC-9L), self-esteem (RSES), satisfaction with life (SWLS), self-efficacy (SWK), and depression (BDI). RESULTS: The personal meaning systems of psychotherapists were more complex and coherent compared to psychotherapy patients. In the group of psychotherapy patients, a more elaborate structure of the personal meaning system correlated with the subjective sense of meaning. We were able to confirm correlations between meaning in life and mental health for most of the instances. CONCLUSIONS: Psychotherapists had more elaborate and coherent meaning systems than psychotherapy patients. Especially for psychotherapy patients elaborate and coherent meaning systems turned out to be important for mental health. PMID- 21243607 TI - [Abrupt transient deteriorations in the experienced interaction and their relationship to the experience of other important persons--operationalisation of transference aspects in therapeutic processes]. AB - OBJECTIVES: Abrupt transient deterioration in the experienced therapeutic interaction is regarded as a sign of the emergence of negative transference aspects. How can these sessions be characterized in terms of similarity to the experience of other important relationships and in relation to the process? METHODS: The interaction-experience in six therapy courses was measured continuously (Intrex). Abrupt deterioration was statistically determined. The correlation between the experienced therapeutic interaction and nontherapeutic interaction patterns was determined. RESULTS: The transference aspects measured were instable over time. There were significant correlations with the experience of previous and current significant others, and parental interaction. The strongest correlations existed nearly consistently to the interaction with the most important person during the best times. CONCLUSION: The method allows measuring change and transference aspects in an economic way. After validation, it could be used for clinical diagnostics. Sessions thus selected could be analyzed more precisely with other procedures. PMID- 21243608 TI - [Evaluation of the clinical course Psychosomatics and Psychotherapy employing standardized patients]. AB - OBJECTIVE: Since the Winter Term 2008/2009 the Medical School of the University of Muenster, Germany, has used standardized patients in the clinical course Psychosomatic Medicine and Psychotherapy with fourth-year undergraduate students performing bio-psycho-social anamnesis on these standardized patients. We wanted to evaluate the influence of the course on the empathy of the students. METHODS: A total of 107 students participated in the standardized patient program during the Winter Term 2009/2010, with 90 (84.1 %) completing the Jefferson Scale of Physician Empathy before and after the course. In addition, we conducted a standard evaluation of the medical faculty. RESULTS: The pre-post comparison revealed a significant increase in empathy (d = 0.331, p = .001). The standard evaluation yielded a high satisfaction among the course participants, though several students did assess the course critically. CONCLUSION: The implementation of a standardized patient program in psychosomatics and psychotherapy proved to be of value, since it increased empathy of the students and received a positive evaluation. To prevent the students from being humiliated, it is of particular importance to implement a gentle and tactful feedback. PMID- 21243609 TI - [Predictors of treatment duration for inpatients with mental disorders--a systematic literature review]. AB - OBJECTIVES: In a systematic literature review we examined patient-related predictors of inpatient treatment duration for mental disorders. METHODS: The databases Medline, Embase, Psyndex, PsycINFO and EBMR were systematically reviewed for studies in the years 1990-2009 regarding treatment duration of inpatients with ICD-10 diagnoses F3-F6. Also, their methodological quality was evaluated. RESULTS: Twenty-one studies examining 28 predictors (sociodemographic, clinical) were included. Longer treatment durations were found for patients living alone and with higher levels of initial symptom severity, duration of mental disorder, number of previous treatments, work absenteeism, and comorbidity. Obsessive-compulsive, eating and personality disorders were treated longer than depressive, anxiety, somatoform, and adjustment disorders. Results for age, gender, education, and profession were inconsistent. CONCLUSIONS: The studies included heterogeneous analyses, treatments, and patients. Despite their sufficient methodical quality, these results are only tentative. PMID- 21243610 TI - [Autoaggressive donation motives in the context of living kidney donation]. AB - BACKGROUND: Which psychodiagnostic criteria indicate artificial donation motives at work in living organ donation? METHODOLOGY: Using a casuistic we investigated self-harmful behaviour with regard to peculiarities in transference as well as countertransference. RESULTS: Diagnostically of great important is the discrepancy between the difficulty of the examiner to understand the donation request in its psychosocial context and the vehemence with which the donor insists on going through with the transplantation. At the same time, one may notice a lack of reflective ability impeding an ambivalent attitude toward the donation. The doctor/patient relationship is restricted by aggressive affects, and the body of the donor is reduced to an object with exchangeable organs. DISCUSSION: When evaluating donor-recipient pairs who belong into the group of pairs with particular emotional investment according to Article 8.1 of the German Organ Transplantation Law, one should consider the possibility of autoaggressive motives as a background to a living organ donation. Also, when discussing the extension of anonymous and predominantly altruistically motivated living organ donation one should consider the exclusion of autoaggressive motives. PMID- 21243617 TI - Integration profile of retroviral vector in gene therapy treated patients is cell specific according to gene expression and chromatin conformation of target cell. AB - The analysis of genomic distribution of retroviral vectors is a powerful tool to monitor 'vector-on-host' effects in gene therapy (GT) trials but also provides crucial information about 'host-on-vector' influences based on the target cell genetic and epigenetic state. We had the unique occasion to compare the insertional profile of the same therapeutic moloney murine leukemia virus (MLV) vector in the context of the adenosine deaminase-severe combined immunodeficiency (ADA-SCID) genetic background in two GT trials based on infusions of transduced mature lymphocytes (peripheral blood lymphocytes, PBL) or a single infusion of haematopoietic stem/progenitor cells (HSC). We found that vector insertions are cell-specific according to the differential expression profile of target cells, favouring, in PBL-GT, genes involved in immune system and T-cell functions/pathways as well as T-cell DNase hypersensitive sites, differently from HSC-GT. Chromatin conformations and histone modifications influenced integration preferences but we discovered that only H3K27me3 was cell-specifically disfavoured, thus representing a key epigenetic determinant of cell-type dependent insertion distribution. Our study shows that MLV vector insertional profile is cell-specific according to the genetic/chromatin state of the target cell both in vitro and in vivo in patients several years after GT. PMID- 21243634 TI - Polymer/bacteria composite nanofiber non-wovens by electrospinning of living bacteria protected by hydrogel microparticles. AB - Physically crosslinked PVA-hydrogel microparticles are utilized for encapsulation of E. coli and M. luteus. The bacteria survive dry storage or treatment with bacteria-hostile organic solvents significantly better than unprotected bacteria as proven by culture-test experiments. The bacteria-protecting PVA microparticles are available for standard polymer-solution-processing techniques, as exemplarily shown by co-electrospinning of living bacteria encapsulated in dry PVA-hydrogel microparticles together with PVB-, PLLA-, and PCL-form organic solvents. PMID- 21243637 TI - Less label, more free: approaches in label-free quantitative mass spectrometry. AB - In this review we examine techniques, software, and statistical analyses used in label-free quantitative proteomics studies for area under the curve and spectral counting approaches. Recent advances in the field are discussed in an order that reflects a logical workflow design. Examples of studies that follow this design are presented to highlight the requirement for statistical assessment and further experiments to validate results from label-free quantitation. Limitations of label-free approaches are considered, label-free approaches are compared with labelling techniques, and forward-looking applications for label-free quantitative data are presented. We conclude that label-free quantitative proteomics is a reliable, versatile, and cost-effective alternative to labelled quantitation. PMID- 21243638 TI - Induction of transplantation tolerance converts potential effector T cells into graft-protective regulatory T cells. AB - Naturally occurring FOXP3(+) CD4(+) Treg have a crucial role in self-tolerance. The ability to generate similar populations against alloantigens offers the possibility of preventing transplant rejection without indefinite global immunosuppression. Exposure of mice to donor alloantigens combined with anti-CD4 antibody induces operational tolerance to cardiac allografts, and generates Treg that prevent skin and islet allograft rejection in adoptive transfer models. If protocols that generate Treg in vivo are to be developed in the clinical setting it will be important to know the origin of the Treg population and the mechanisms responsible for their generation. In this study, we demonstrate that graft protective Treg arise in vivo both from naturally occurring FOXP3(+) CD4(+) Treg and from non-regulatory FOXP3(-) CD4(+) cells. Importantly, tolerance induction also inhibits CD4(+) effector cell priming and T cells from tolerant mice have impaired effector function in vitro. Thus, adaptive tolerance induction shapes the immune response to alloantigen by converting potential effector cells into graft-protective Treg and by expanding alloreactive naturally occurring Treg. In relation to clinical tolerance induction, the data indicate that while the generation of alloreactive Treg may be critical for long-term allograft survival without chronic immunosuppression, successful protocols will also require strategies that target potential effector cells. PMID- 21243650 TI - Image printing on the surface of anti-biofouling zwitterionic polymer brushes by ion beam irradiation. AB - A CMB monomer was polymerized on a glass plate with a surface-confined ATRP initiator containing a 2-bromoisobutyryl group. The glass plate modified with a PCMB brush was highly hydrophilic and showed a strong resistance against non specific adsorption of proteins and cell adhesion. Upon ion beam irradiation, furthermore, the PCMB brush was ablated and a hollow space with a designed shape could be made to which HEK293 cells (from human embryonic kidney) and Hep G2 (from human hepatoma) cells non-specifically adhered, while no adhesion of these cells to the non-treated area on the brush was observed. The present results clearly indicate the usefulness of ion beam-printed patterns of anti-biofouling zwitterionic polymer brushes in the biomedical field. PMID- 21243654 TI - Format, style, and precision. PMID- 21243656 TI - Maternal role attainment with medically fragile infants: Part 1. measurement and correlates during the first year of life. AB - The purpose of this study was to extend scholarship on maternal role attainment (MRA). We used a triangulation of behavioral and self-report variables to measure MRA-identity, presence, and competence-with mothers of medically fragile infants (n = 81), and explored characteristics that influenced MRA longitudinally. Competence and presence were best measured using both self-report and observational methods, whereas identity was best measured with a questionnaire. Mothers with less worry reported higher levels of identity. Presence was higher with less alert infants, whereas competence was higher with more alert infants, lower parental role stress, higher education, and being married. Mothers with more illness-related distress and less alert infants, and unmarried and less educated mothers may need interventions to enhance MRA. PMID- 21243655 TI - Can modifications to the bedroom environment improve the sleep of new parents? Two randomized controlled trials. AB - Postpartum sleep disruption is common among new parents. In this randomized controlled trial we evaluated a modified sleep hygiene intervention for new parents (infant proximity, noise masking, and dim lighting) in anticipation of night-time infant care. Two samples of new mothers (n = 118 and 122) were randomized to the experimental intervention or attention control, and sleep was assessed in late pregnancy and first 3 months postpartum using actigraphy and the General Sleep Disturbance Scale. The sleep hygiene strategies evaluated did not benefit the more socioeconomically advantaged women or their partners in Sample 1, but did improve postpartum sleep among the less advantaged women of Sample 2. Simple changes to the bedroom environment can improve sleep for new mothers with few resources. PMID- 21243657 TI - Maternal role attainment with medically fragile infants: Part 2. relationship to the quality of parenting. AB - We examined which components of maternal role attainment (identity, presence, competence) influenced quality of parenting for 72 medically fragile infants, controlling for maternal education and infant illness severity. Maternal competence was related to responsiveness. Maternal presence and technology dependence were inversely related to participation. Greater competence and maternal education were associated with better normal caregiving. Presence was negatively related although competence was positively related to illness-related caregiving. Mothers with lower competence and more technology dependent children perceived their children as more vulnerable and child cues as more difficult to read. Maternal role attainment influenced parenting quality for these infants more than did child illness severity; thus interventions are needed to help mothers develop their maternal role during hospitalization and after discharge. (c) 2010 Wiley Periodicals, Inc. Res Nurs Health 34:35-48, 2011. PMID- 21243658 TI - Development and psychometric testing of the Register - Connectedness Scale for Older Adults. AB - Connectedness, maintaining active engagement with life, is crucial to successful aging. Yet, no instruments were found to measure connectedness. The purpose of this study was to develop and test a connectedness scale for older adults. A 72 item instrument was administered to 428 community-dwelling older adults. The sample was largely female, White widows/widowers, with a mean age of 76 (SD 6.95) years. The instrument was reduced to 45 items representing five factors with loadings ranging from .40 to .86. The factor labels and their reliability estimates were: (a) self-regulating (.86), (b) facing aging (.85), (c) being part of a family (.87), (d) having friends (.87), and (e) being spiritual (.88). This promising instrument may advance the science of successful aging. PMID- 21243659 TI - Development of the Fogg Intent-to-Screen for HIV (ITS HIV) questionnaire. AB - In this paper, we describe the development and psychometric properties of the Fogg Intent-to-Screen for HIV questionnaire (ITS HIV), which measures peoples' beliefs and intentions toward HIV screening. The ITS HIV was developed using the Theory of Planned Behavior as the framework for a developmental process that included qualitative interviews, a validation phase, two pilot tests, and a field test of the final 55-item questionnaire. The field test involved 312 homeless persons from five New England states. Cronbach alphas of the direct measures scales ranged from .72 to .90. Findings from a path analysis verified the construct validity. The psychometric estimates from these analyses suggest the ITS HIV questionnaire is appropriate for use in clinical practice or to evaluate the effectiveness of interventions. PMID- 21243667 TI - Prose and principle: getting your message across: more than detailed cataloguing of research findings, emphasis of principles within a narrative engages the readers of reviews. PMID- 21243671 TI - Mesoporous 2-line ferrihydrite by a solution-phase cooperative assembly process for removal of organic contaminants in air. PMID- 21243670 TI - Optical imaging with dynamic contrast agents. AB - Biological imaging applications often employ molecular probes or nanoparticles for enhanced contrast. However, resolution and detection are still often limited by the intrinsic heterogeneity of the sample, which can produce high levels of background that obscure the signals of interest. Herein, we describe approaches to overcome this obstacle based on the concept of dynamic contrast: a strategy for elucidating signals by the suppression or removal of background noise. Dynamic contrast mechanisms can greatly reduce the loading requirement of contrast agents, and may be especially useful for single-probe imaging. Dynamic contrast modalities are also platform-independent, and can enhance the performance of sophisticated biomedical imaging systems or simple optical microscopes alike. Dynamic contrast is performed in two stages: 1) a signal modulation scheme to introduce time-dependent changes in amplitude or phase, and 2) a demodulation step for signal recovery. Optical signals can be coupled with magnetic nanoparticles, photoswitchable probes, or plasmon-resonant nanostructures for modulation by magnetomotive, photonic, or photothermal mechanisms, respectively. With respect to image demodulation, many of the strategies developed for signal processing in electronics and communication technologies can also be applied toward the editing of digital images. The image processing step can be as simple as differential imaging, or may involve multiple reference points for deconvolution by using cross-correlation algorithms. Periodic signals are particularly amenable to image demodulation strategies based on Fourier transform; the contrast of the demodulated signal increases with acquisition time, and modulation frequencies in the kHz range are possible. Dynamic contrast is an emerging topic with considerable room for development, both with respect to molecular or nanoscale probes for signal modulation, and also to methods for more efficient image processing and editing. PMID- 21243672 TI - Low-temperature synthesis of visible-light active fluorine/sulfur co-doped mesoporous TiO2 microspheres. PMID- 21243673 TI - Discrimination of trace heavy-metal ions by filtration on sol-gel membrane arrays. PMID- 21243674 TI - Direct arylation of benzothiazoles and benzoxazoles with aryl boronic acids. PMID- 21243675 TI - Asymmetric hydrogenation of N-alkyl ketimines with phosphine-free, chiral, cationic Ru-MsDPEN catalysts. PMID- 21243676 TI - Highly enantioselective Henry reactions in water catalyzed by a copper tertiary amine complex and applied in the synthesis of (S)-N-trans-feruloyl octopamine. PMID- 21243677 TI - Highly enantioselective conjugate addition of cyclic diketones to beta,gamma unsaturated alpha-ketoesters catalyzed by an N,N'-dioxide-Cu(OTf)2 complex. PMID- 21243678 TI - Blue/red linear dichroic emission from a highly anisotropic crystal of triarylmethane dye conjugated with phenoxo-zinc complexes. AB - We have developed a novel triphenylmethane-based hexanuclear zinc complex that exhibits peculiar photochemical and photophysical properties. Upon UV irradiation, the compound turned from colorless to reddish purple, while the color of emission turned from blue to red. The color change was attributed to an oxidation of the ligand part. It was suggested that an intramolecular energy transfer mechanism operates to give rise to the red emission. The UV treatment of a single crystal results in simultaneous emission of orthogonally polarized blue and red light. This color switching, namely linear dichroic emission was so distinct that one can recognize with by sight through optical microscope. The columnar arrangement of molecules in the crystal clearly accounts for the observed polarization of the emission. PMID- 21243679 TI - Highly strained 2,3-bridged 2H-azirines at the borderline of closed-shell molecules. AB - Substituted 1-azidocyclopentenes and 1-azidocyclohexenes were photolyzed to generate 2,3-bridged 2H-azirines. In the case of bridgehead azirines with a six membered carbocycle, detection by NMR spectroscopic analysis was possible, whereas even kinetically stabilized bridgehead azirines with a five-membered ring could not be characterized by low-temperature NMR spectroscopic analysis. Thus, a recent report on the latter heterocycles was corrected. Depending on the substitution pattern, irradiation of 1-azidocyclopentenes either led to products that can be explained on the basis of short-lived 2,3-bridged 2H-azirines, or gave secondary products generated from triplet nitrenes. The diverse photoreactivity of 2,3-bridged 2H-azirines was also studied by quantum chemical methods (DFT, CCSD(T), CASSCF(6,6)) with respect to the singlet and triplet energy surfaces. The ring-opening processes leading to the corresponding vinyl nitrenes were identified as key steps for the observed reactivity. PMID- 21243680 TI - Desilication mechanism revisited: highly mesoporous all-silica zeolites enabled through pore-directing agents. AB - The role of pore-directing agents (PDAs) in the introduction of hierarchical porosity in silicalite-1 in alkaline medium was investigated. By incorporation of various PDAs in aqueous NaOH, homogenously distributed mesopores were introduced in 2.5 MUm silicalite-1 crystals. It was proven for the first time that framework aluminum is not a prerequisite for the introduction of intracrystalline mesoporosity by desilication. The pore-directing role is not directly exerted by framework trivalent cations metals, but by species on the external surface of the zeolite. The inclusion of metal complexes (Al(OH)(4)(-), Ga(OH)(4)(-)) and tetraalkyl ammonium cations (tetramethyl ammonium (TMA(+)), tetrapropyl ammonium (TPA(+))) in the alkaline solution led to distinct mesopore surface areas (up to 286 m(2) g(-1)) and pore sizes centered in the range of 5-20 nm. In the case alkaline treatment was performed in the presence of Al(OH)(4)(-), all aluminum partially integrated in the zeolite giving rise to both Lewis and Bronsted acidity. Apart from the concentration and location, the affinity of the PDA to the zeolite surface plays a crucial role in the pore formation process. If the PDA is attracted too strongly (e.g., TMA(+)), the dissolution is reduced dramatically. When the pore-directing agent is not attracted to the zeolite's external surface, excessive dissolution occurs (standard alkaline treatment). TPA(+) proved to be the most effective PDA as its presence led to high mesopore surface areas (>200 m(2) g(-1)) over a broad range of PDA concentrations (0.003 0.1 M). Importantly, our results enable to extend the suitability of desilication for controlled mesopore formation to all-silica zeolites. PMID- 21243681 TI - Platinum(II)-based hydrogen-evolving catalysts linked to multipendant viologen acceptors: experimental and DFT indications for bimolecular pathways. AB - Three new [PtCl(2)(bpy)] derivatives tethered to 2, 4, and 6 dicationic viologen moieties, [PtCl(2)(MV2)](4+) (1), [PtCl(2)(MV4)](8+) (2), and [PtCl(2)(MV6)](12+) (3), have been synthesized (MV2(4+)=5-ethoxycarbamoyl-5'-(N-R(1)-carbamoyl)-2,2' bipyridine, MV4(8+)=5,5'-bis(N-R(1)-carbamoyl)-2,2'-bipyridine, and MV6(12+)=5,5' bis(N-R(2)-carbamoyl)-2,2'-bipyridine, in which R(1)=Asp(NH-VG)-NH-VG, R(2)=Asp(NH-VG)-Asp(NH-VG)-NH-VG, and VG=-(CH(2))(2)-(+)NC(5)H(4)-C(5)H(4)N(+) CH(3)). In spite of the higher charge storage capacity of 2 and 3 due to the higher number of acceptor groups (VG groups), compound 1 with the lowest number of VG tethers has turned out to exhibit an outstanding catalytic performance towards the hydrogen evolution from water. Quantitative analysis of UV/Vis-NIR absorption spectral changes during the photolysis for 2 and 3 reveal that approximately 2 electrons per molecule are stored over the acceptor groups during the photolysis, and the storage events saturate after 20 min. As for 1, the total number of electrons stored per molecule increases once during the initial 10 min and then abruptly decreases down to around 0.1 electrons per molecule at 20 min, during which the storage is maximized at 10-20 min with 0.6-0.7 electrons stored per molecule, thereby indicating that the rates of radical formation and consumption are balanced during the photochemical hydrogen evolution reaction. The electrical conductivity measurements reveal that ion-pair adducts (adducts with PF(6)(-) ions in solution) are formed by 2 and 3 but are not given by 1 under the catalysis conditions. These, together with the results of molecular mechanics calculations, reveal that stack of two [PtCl(2)(bpy)] units becomes unfavorable as the number of sterically bulky and highly charged VG units per molecule increases. We have therefore concluded that dimerization that leads to the formation of a Pt-Pt association is a key step in the effective catalytic enhancement with [PtCl(2)(bpy)]-type catalysts. PMID- 21243682 TI - Induction-driven stabilization of the anion-pi interaction in electron-rich aromatics as the key to fluoride inclusion in imidazolium-cage receptors. AB - Intermolecular interactions that involve aromatic rings are key processes in both chemical and biological recognition. It is common knowledge that the existence of anion-pi interactions between anions and electron-deficient (pi-acidic) aromatics indicates that electron-rich (pi-basic) aromatics are expected to be repulsive to anions due to their electron-donating character. Here we report the first concrete theoretical and experimental evidence of the anion-pi interaction between electron-rich alkylbenzene rings and a fluoride ion in CH(3)CN. The cyclophane cavity bridged with three naphthoimidazolium groups selectively complexes a fluoride ion by means of a combination of anion-pi interactions and (C-H)(+)...F(-)-type ionic hydrogen bonds. (1)H NMR, (19)F NMR, and fluorescence spectra of 1 and 2 with fluoride ions are examined to show that only 2 can host a fluoride ion in the cavity between two alkylbenzene rings to form a sandwich complex. In addition, the cage compounds can serve as highly selective and ratiometric fluorescent sensors for a fluoride ion. With the addition of 1 equiv of F(-), a strongly increased fluorescence emission centered at 385 nm appears at the expense of the fluorescence emission of 2 centered at 474 nm. Finally, isothermal titration calorimetry (ITC) experiments were performed to obtain the binding constants of the compounds 1 and 2 with F(-) as well as Gibbs free energy. The 2-F(-) complex is more stable than the 1-F(-) complex by 1.87 kcal mol(-1), which is attributable to the stronger anion-pi interaction between F(-) and triethylbenzene. PMID- 21243683 TI - Vapor- and mechanical-grinding-triggered color and luminescence switches for bis(sigma-fluorophenylacetylide) platinum(II) complexes. AB - Square-planar bis(sigma-fluorophenylacetylide) platinum(II) complexes [Pt(Me(3)SiC=CbpyC=C-SiMe(3))(C=CC(6)H(4)F)(2)] (C=CC(6)H(4)F-2 for 2, C=CC(6)H(4)F-3 for 3, and C=CC(6)H(4)F-4 for 4; Me(3)SiC=CbpyC=CSiMe(3)=5,5' bis(trimethylsilylethynyl)-2,2'-bipyridine) were prepared and were characterized by spectroscopic and luminescence studies, and X-ray crystallography. The color and luminescence of crystalline complex 3 is specifically sensitive to CHCl(3) vapor to afford 140-180 nm of luminescence vapochromic redshift, which is useful for specific detection of CHCl(3) vapor. Complex 4 displays selective luminescence vapochromic properties to CH(2)Cl(2) and CHCl(3) vapors with a luminescence vapochromic shift response of ca. 150-200 nm. Interestingly, complexes 2-4 exhibit reversible, and naked-eye perceivable, mechanical stimuli responsive color and luminescence changes. When solid species 2-4 are crushed gently or ground, the crystalline state is converted to an amorphous phase. Meanwhile, bright yellow-orange luminescence in the crystalline species is converted to dark red under UV light irradiation with 100-160 nm of mechanochromic shift response. A vapochromic or mechanochromic cycle was monitored by dynamic variations in emission spectra and X-ray diffraction (XRD) patterns. The halohydrocarbon vapor- or mechanical-grinding-triggered color and luminescence switches are most likely correlated to a shorted intermolecular Pt Pt distance as that revealed in vapochromic species 4.0.5 CH(2)Cl(2) by X-ray crystallography, thus leading to an increased contribution from intermolecular Pt Pt interaction as demonstrated by DTF computational studies. PMID- 21243684 TI - Encapsulation of dye molecules and nanoparticles in hollow organogel fibers of a nonchiral polyurethane model compound. AB - We present the case of a nonchiral organogelator that forms hollow fibers and encapsulates silver nanoparticles (SNP) and a dye molecule. The biscarbamate molecule (a model compound for polyurethanes), which has two hydrogen-bonding motifs symmetrically attached to n-dodecyl side chains (C(12)), gels benzonitrile with hollow fibrillar morphology. The C(12) molecules form sheets that eventually wrap into hollow fibers to form the gel network. Herein, two-component gels were prepared with C(12) as one component and SNP, phthalocyanine (Pc), or perylene (Pe) as the other. Microscopic analysis and partial melting experiments confirmed the inclusion of the silver nanoparticles and phthalocyanine into the hollow fibers. On the other hand, Pe molecules tend to form crystals at the outer surface of the C(12) fibers, which results in a significant increase in the width of the gel fibers. This difference in the behavior of Pc and Pe molecules were accounted for by their crystal geometry and significantly different crystal growth rate compared with that of C(12) fiber formation in the gels. Pc crystallizes in a needle shape that facilitates occlusion in the gel fibers, whereas Pe forms large platelets. X-ray diffraction and spectroscopic analysis of the two-component gels along with their neat components confirmed that there was no change in the packing behavior of the Pc and Pe molecules in the gels. Therefore, these are examples of two-component physical gels in which the Pc crystals are occluded within the hollow fibers of C(12) by physical mixing of the components without the aid of any inter-molecular interactions between the different components. We have thus shown that lumen-loaded gel fibers with nanoparticles and dye molecules can be prepared by the two-component gel route, provided that the above growth rate, shape, and size conditions are satisfied. PMID- 21243685 TI - A pentiptycene-derived molecular brake: photochemical E->Z and electrochemical Z >E switching of an enone module. AB - The synthesis and brakelike performance of a new molecular system (1) consisting of a pentiptycene rotor and a 2-methyleneindanone brake are reported. The rotation kinetics of the rotor was probed by both variable-temperature (1)H and (13)C NMR spectroscopy and DFT calculations, and the switching between the brake on and brake-off states was conducted by a combination of photochemical and electrochemical isomerization. Because of the greater steric hindrance between the rotor and the brake units in the Z form ((Z)-1) than in the E form ((E)-1), rotation of the rotor is slowed down 500-fold at room temperature (298 K) on going from (E)-1 to (Z)-1, corresponding to the brake-off and brake-on states, respectively. The (E)-1->(Z)-1 photoisomerization in acetonitrile is efficient and reaches an (E)-1/(Z)-1 ratio of 11:89 in the photostationary state upon excitation at 290 nm, attributable to a much larger isomerization quantum efficiency for (E)-1 versus (Z)-1. An efficient (Z)-1->(E)-1 isomerization (96%) was also achieved by electrochemical treatment through the radical anionic intermediates. Consequently, the reversibility of the E-Z switching of 1 is as high as 85%. The repeated E-Z switching of 1 with alternating photochemical and electrochemical treatments is also demonstrated. PMID- 21243686 TI - Interfacial impregnation chemistry in the synthesis of nickel catalysts supported on titania. AB - The interfacial chemistry of the impregnation step involved in the preparation of nickel catalysts supported on titania is presented. Several methodologies based on deposition data, pH measurements, potentiometric mass titrations, and microelectrophoresis have been used in conjunction with diffuse reflectance UV/Vis/NIR spectroscopy, simulations, and semiempirical quantum chemical calculations. Three mononuclear inner-sphere complexes were formed at the compact layer of the "titania/electrolyte solution" interface: A monosubstituted, dihydrolyzed complex above a terminal oxo group, a disubstituted, dihydrolyzed complex above two terminal adjacent oxo groups, and a disubstituted, nonhydrolyzed complex above one terminal and one bridging adjacent oxo groups. The monosubstituted, dihydrolyzed complex predominates. The contribution of the disubstituted configurations is also important at very low Ni(II) surface concentration, but it decreases as the Ni(II) surface concentration increases. In addition, bi- and trinuclear inner-sphere complexes were formed. The receptor site involves one bridging and two terminal oxo groups in the first case and two bridging and three terminal oxo groups in the second case. The relative surface concentrations of these configurations increase initially with Ni(II) surface concentration and then remain practically constant. The understanding of these interfacial processes at a molecular level is very important to shift the catalytic synthesis from an art to a science as well as to obtain strict control of the impregnation step and, to some extent, of the whole preparative sequence. This study is very relevant to the synthesis of submonolayer/monolayer nickel catalysts supported on TiO(2) following equilibrium deposition filtration (otherwise called equilibrium adsorption). PMID- 21243687 TI - Graphene-based multifunctional iron oxide nanosheets with tunable properties. AB - We report the synthesis of graphenes with tunable properties due to the growth of needlelike iron oxide (IO) nanoparticles on their surfaces. The electrical conductivity, flexibility, and magnetic properties of graphene nanosheets (GNSs) could be tuned on demand by fine controlling both the surface coverage and the length of the IO nanoneedles. The degree of coverage of the IO nanoparticles on the surface of the GNSs made it possible to control the resulting properties of the IO/GNSs on demand. As examples of their utility, paperlike materials were generated by simple filtration, and the resulting IO/GNS nanocomposites showed extraordinary removal capacity and fast adsorption rates for As(V) and Cr(VI) ions in water. Another possible application is the preparation of multifunctional films equipped with conductivity, flexibility, and magnetic properties. The fabrication process is easy to scale up at a low cost. In addition, both the colloidal solution and film forms of the resulting IO/GNSs were effective for removal of heavy metal ions, meaning this material could be utilized for actual industrial applications. PMID- 21243688 TI - Regioisomeric control induced by DABCO coordination to rotatable self-assembled bis- and tetraporphyrin alpha,gamma-cyclic octapeptide dimers. AB - The design and synthesis of two alpha,gamma-cyclic octapeptides decorated with one and two Zn-porphyrin units in their periphery is described. In nonpolar organic solvents the alpha,gamma-cyclic octapeptides quantitatively self-assemble into Zn-bis- or -tetraporphyrin architectures that could act as molecular tweezers. The self-assembly process, however, is not regioselective and affords a mixture of different regioisomers that are involved in chemical exchange processes. The regioisomers with the Zn-porphyrin units positioned in register with respect to each other are proposed to be the less abundant species in the solution mixture. It has been demonstrated that the coordination of 1,4 diazabicyclo[2.2.2]octane (DABCO) to the supramolecular bis- or tetraporphyrin tweezers is an effective way to achieve regioisomeric control of the self assembled mixture of dimers. Thus, DABCO functions as an external molecular trigger and, when used under strict stoichiometric control with respect to the Zn porphyrin units, provokes the exclusive formation of self-assembled dimers with a cofacial arrangement of Zn-porphyrin units through the formation of sandwich-type complexes. The use of excess DABCO fragments the sandwich complexes and affords open dimers of high stoichiometry with DABCO molecules axially monocoordinated to the Zn-porphyrin units, probably as a regioisomeric mixture. In the case of Zn tetraporphyrin tweezers, the ditopic coordination of DABCO at the two binding sites shows a moderate positive cooperativity factor, alphaP=5. These assemblies have potential applications as light-induced energy and electron-transfer switches regulated by DABCO coordination; such applications would require the introduction of additional chromophores in the cyclic peptide scaffold. PMID- 21243689 TI - Dynamics effects on an E2/E1cb borderline mechanism: unimolecular elimination of 2-aryl-3-chloro-2-R-propanols. AB - The mechanistic dichotomy between concerted E2 and stepwise E1cb of the base promoted elimination of 2-aryl-3-chloro-2-R-propanols was examined computationally at the HF, M05-2X, and MP2 levels of theory. Optimizations of transition states (TSs) and reaction intermediates, and intrinsic reaction coordinates (IRC) calculations showed that there was a single reaction route for each substrate, and that the mechanism could be changed from E2 to E1cb by making a carbanion intermediate more stable through the introduction of electron withdrawing substituents. Molecular dynamics simulations revealed that trajectories started at a single TS led directly to two product regions; the carbanion intermediate region in the E1cb mechanism, and the alkene product region in the E2 mechanism, through path bifurcation after the TS. The present system is a new example of bifurcation in reactions of closed-shell molecules. The overall reaction mechanism changes dynamically from E2 to E1cb by a gradual change in the ratio of E2 and E1cb trajectories, rather than a path switch in concurrent pathways. PMID- 21243690 TI - [{Au(IPr)}2(MU-OH)]X complexes: synthetic, structural and catalytic studies. AB - The synthesis of a series of dinuclear gold hydroxide complexes has been achieved. These complexes of type [{Au(IPr)}(2)(MU-OH)]X (X=BF(4), NTf(2), OTf, FABA, SbF(6); IPr=2,6-bis(disopropylphenyl)imidazol-2-ylidene; NTf(2)=bis(trifluoromethanesulfonyl)imidate; OTf=trifluoromethanesulfonate; FABA=tetrakis(pentafluorophenyl)borate) are easily formed in the presence of water and prove highly efficient in the catalytic hydration of nitriles. Their facile formation in aqueous media suggests they are of relevance in gold catalyzed reactions involving water. Additionally, a series of [Au(IPr)(NCR)][BF(4)] (R=alkyl, aryl) complexes was synthesized as they possibly occur as intermediates in the catalytic reaction mechanism. (1)H and (13)C NMR data as well as key bond lengths obtained by X-ray diffraction studies are compared and reveal an interesting structure-activity relationship. The collected data indicate a negligible effect of the nature of the nitrile on the reactivity of [Au(L)(NCR)][X] complexes in catalysis. PMID- 21243691 TI - Hydrotalcite-supported gold catalyst for the oxidant-free dehydrogenation of benzyl alcohol: studies on support and gold size effects. AB - Gold nanoparticles with uniform mean sizes (~3 nm) loaded onto various supports have been prepared and studied for the oxidant-free dehydrogenation of benzyl alcohol to benzaldehyde and hydrogen. The use of hydrotalcite (HT), which possesses both strong acidity and strong basicity, provides the best catalytic performance. Au/HT catalysts with various mean Au particle sizes (2.1-21 nm) have been successfully prepared by a deposition-precipitation method under controlled conditions. Detailed catalytic reaction studies with these catalysts demonstrate that the Au-catalyzed dehydrogenation of benzyl alcohol is a structure-sensitive reaction. The turnover frequency (TOF) increases with decreasing Au mean particle size (from 12 to 2.1 nm). A steep rise in TOF occurs when the mean Au particle size becomes smaller than 4 nm. Our present work suggests that the acid-base properties of the support and the size of Au nanoparticles are two key factors controlling the alcohol dehydrogenation catalysis. A reaction mechanism is proposed to rationalize these results. It is assumed that the activation of the beta-C-H bond of alcohol, which requires the coordinatively unsaturated Au atoms, is the rate-determining step. PMID- 21243692 TI - The synthesis of (Z)-trisubstituted allylic alcohols by the selective 1,4 hydrogenation of dienol esters: improved synthesis of (-)-beta-santalol. AB - (E)-Trisubstituted allylic alcohols are commonly prepared from the corresponding (E)-enals, themselves readily accessible by a simple aldol condensation reaction. We demonstrate that these very same (E)-enals can be converted into (Z) trisubstituted allylic acetates (and thus alcohols) by a ruthenium-catalyzed 1,4 hydrogenation of the corresponding dienol acetates. This simple solution to a long-lasting problem was applied to an industrially feasible synthesis of (-) beta-santalol. PMID- 21243693 TI - Heterogeneously catalyzed efficient hydration of alkynes to ketones by tin tungsten mixed oxides. AB - The Sn-W mixed oxide prepared by calcination of the Sn-W mixed hydroxide precursor with a Sn/W molar ratio of 2:1 at 800 degrees C (SnW2-800) acts as an efficient heterogeneous catalyst for the hydration of alkynes. Structurally diverse terminal and internal alkynes, including aromatic, aliphatic, and double bond-containing ones, can be converted into the corresponding ketones in moderate to high yields. The catalytic activity of SnW2-800 is much higher than those of previously reported heterogeneous catalysts and commonly utilized acid catalysts. The observed catalysis was truly heterogeneous, and the retrieved catalyst can be reused at least three times with retention of its high catalytic performance. The reaction rate for the SnW2-800-catalyzed hydration was decreased by addition of 2,6-lutidine and the hydration hardly proceeded in the presence of an equimolar amount of this compound with respect to that of the Bronsted acid sites in SnW2 800. Therefore, the present hydration is mainly promoted by the Bronsted acid sites in SnW2-800. PMID- 21243694 TI - Three-component reactions of isochromenylium tetrafluoroborates via non-classical [4+2]-intermediates: mild one-step metal-free synthesis of functionalized dihydronaphthalenes and tetrahydronaphthalenes. AB - Two novel types of elegant three-component reactions of stable isochromenylium tetrafluoroborates (ICTBs) have been developed under mild metal-free conditions in this work. Mechanistically, these reactions are commonly initiated by a [4+2] cycloaddition between the non-classical isochromenylium diene and the aldehyde enol, and terminated by the following addition of weak nucleophiles, including nitriles or the second equivalent of aldehydes, in a one-pot fashion. The developed methodologies exhibit excellent chemoselectivity, regioselectivity, and diastereoselectivity, and provide a new convenient access to functionalized dihydronaphthalenes and tetrahydronaphthalenes. PMID- 21243695 TI - Crystal facet dependence of water oxidation on BiVO4 sheets under visible light irradiation. AB - Monoclinic BiVO(4) crystals with preferentially exposed (040) facets were hydrothermally synthesized by using a trace amount of TiCl(3) as the directing agent; this function was confirmed by X-ray diffraction patterns (XRD) and high resolution transmission electron microscopy (HRTEM). The effects of the directing agent TiCl(3) and the pH values applied during synthesis have been studied, and the optimized BiVO(4) sample with highly exposed (040) facet could be obtained by using 1.2 at.% of TiCl(3) as the directing agent at a pH value of 2. Some complementary techniques were also applied to exclude the effects of the structural and physical property changes, such as surface area and hydrophilicity. The photocatalytic activity of oxygen evolution on BiVO(4) is found to be proportionally correlated with the exposed surfaces of the (040) facet. It is assumed that the active sites with a BiV(4) structure on the exposed (040) facet is assigned to be responsible for the high activity of O(2) evolution. PMID- 21243697 TI - Bulky guanidinato nickel(I) complexes: synthesis, characterization, isomerization, and reactivity studies. AB - Reactions of lithium complexes of the bulky guanidinates [{(Dip)N}(2)CNR(2)](-) (Dip=C(6)H(3)iPr(2)-2,6; R=C(6)H(11) (Giso(-)) or iPr (Priso(-)), with NiBr(2) have afforded the nickel(II) complexes [{Ni(L)(MU-Br)}(2)] (L=Giso(-) or Priso( )), the latter of which was crystallographically characterized. Reduction of [{Ni(Priso)(MU-Br)}(2)] with elemental potassium in benzene or toluene afforded the diamagnetic species [{Ni(Priso)}(2)(MU-C(6)H(5)R)] (R=H or Me), which were shown, by X-ray crystallographic studies, to possess nonplanar bridging arene ligands that are partially reduced. A similar reduction of [{Ni(Priso)(MU Br)}(2)] in cyclohexane yielded a mixture of the isomeric complexes [{Ni(MU kappa(1)-N-,eta(2)-Dip-Priso)}(2)] and [{Ni(MU-kappa(2)-N,N'-Priso)}(2)], both of which were structurally characterized. These complexes were also formed through arene elimination processes if [{Ni(Priso)}(2)(MU-C(6)H(5)R)] (R=H or Me) were dissolved in hexane. In that solvent, diamagnetic [{Ni(MU-kappa(1)-N-,eta(2)-Dip Priso)}(2)] was found to slowly convert to paramagnetic [{Ni(MU-kappa(2)-N,N' Priso)}(2)], suggesting that the latter is the thermodynamic isomer. Computational analysis of a model of [{Ni(MU-kappa(2)-N,N'-Priso)}(2)] showed it to have a Ni-Ni bond that has a multiconfigurational electronic structure. An analogous copper(I) complex [{Cu(MU-kappa(2)-N,N'-Giso)}(2)] was prepared, structurally authenticated, and found, by a theoretical study, to have a negligible Cu...Cu bonding interaction. The reactivity of [{Ni(Priso)}(2)(MU C(6)H(5)Me)] and [{Ni(MU-kappa(2)-N,N'-Priso)}(2)] towards a range of small molecules was examined and this gave rise to diamagnetic complexes [{Ni(Priso)(MU CO)}(2)] and [{Ni(Priso)(MU-N(3))}(2)]. Taken as a whole, this study highlights similarities between bulky guanidinate ligands and the beta-diketiminate ligand class, but shows the former to have greater coordinative flexibility. PMID- 21243696 TI - The effect of sulfoxides on the stereoselective construction of tetrahydrofurans: total synthesis of (+)-goniothalesdiol. AB - Good to excellent stereoselectivities were achieved in the reductive cyclization (with Et(3)SiH/trimethylsilyl trifluoromethanesulfonate (TMSOTf)) of enantiopure hydroxy sulfinyl ketones en route to 2,5-cis-disubstituted tetrahydrofuran skeletons. Electrostatic effects of the exocyclic sulfoxide, which stabilized the reactive intermediate oxocarbenium conformations, were responsible for the observed stereocontrol. A model is proposed to explain the results. The use of this reaction and the asymmetric beta-ketosulfoxide reduction as key steps facilitated the total enantioselective synthesis of the natural beta-C-aryl glycoside (+)-goniothalesdiol. PMID- 21243698 TI - Polymorph-tuned synthesis of alpha- and beta-Bi2O3 nanowires and determination of their growth direction from polarized Raman single nanowire microscopy. AB - We report polymorph-tuned synthesis of alpha- and beta-Bi(2)O(3) nanowires and their single nanowire micro-Raman study. The single crystalline Bi(2)O(3) nanowires in different phases (alpha and beta) were selectively synthesized by adjusting the heating temperature of Bi precursor in a vapor transport process. No catalyst was employed. Furthermore, at an identical precursor evaporation temperature, alpha- and beta- phase Bi(2)O(3) nanowires were simultaneously synthesized along the temperature gradient at a substrate. The growth direction of alpha-Bi(2)O(3) nanowires was revealed by polarized Raman single nanowire spectra. For thin beta-Bi(2)O(3) nanowires with a very small diameter, the polarized Raman single nanowire spectrum was strongly influenced by the shape effect. PMID- 21243699 TI - A family of four-coordinate iron(II) complexes bearing the sterically hindered tris(pyrazolyl)borato ligand Tp(tBu,Me). AB - A new family of 14-electron, four-coordinate iron(II) complexes of the general formula [Tp(tBu,Me)FeX] (Tp(tBu,Me) is the sterically hindered hydrotris(3-tert butyl-5-methyl-pyrazolyl) borate ligand and X=Cl (1), Br, I) were synthesized by salt metathesis of FeX(2) with Tp(tBu,Me)K. The related fluoride complex was prepared by reaction of 1 with AgBF(4). Chloride 1 proved to be a good precursor for ligand substitution reactions, generating a series of four-coordinate iron(II) complexes with carbon, oxygen, and sulphur ligands. All of these complexes were fully characterized by conventional spectroscopic methods and most were characterized by single-crystal X-ray crystallographic analysis. Magnetic measurements for all complexes agreed with a high-spin (d(6), S=2) electronic configuration. The halide series enabled the estimation of the covalent radius of iron in these complexes as 1.24 A. PMID- 21243700 TI - Aspergiolides C and D: spirocyclic aromatic polyketides with potent protein kinase c-Met inhibitory effects. AB - Variation of the cultivation conditions for Aspergillus glaucus led to the discovery of two novel spirocyclic aromatic polyketides, aspergiolides C (3) and D (4). Their constitutions were elucidated by a combination of spectroscopic methods and isotope-labeling experiments. Aspergiolides C (3) and D (4) occur as racemic mixtures, the resolution of which was succeeded by HPLC on a chiral phase. The absolute configurations of their enantiomers were assigned online, from the peaks in the chromatogram, by a combination of HPLC-CD and quantum chemical CD calculations. Both compounds were found to inhibit the kinase activities of the receptor tyrosine kinases (RTKs) c-Met, Ron, and c-Src with low micromolar IC(50)s. The enantiomers of 3 were resolved by HPLC on a chiral phase. Both enantiomers showed a comparable inhibition of the HGF-induced autophosphorylation of c-Met and of subsequent cell migration. PMID- 21243701 TI - A quantitative, real-time assessment of binding of peptides and proteins to gold surfaces. AB - Interactions of peptides and proteins with inorganic surfaces are important to both natural and artificial systems; however, a detailed understanding of such interactions is lacking. In this study, we applied new approaches to quantitatively measure the binding of amino acids and proteins to gold surfaces. Real-time surface plasmon resonance (SPR) measurements showed that TEM1-beta lactamase inhibitor protein (BLIP) interacts only weakly with Au nanoparticles (NPs). However, fusion of three histidine residues to BLIP (3H-BLIP) resulted in a significant increase in the binding to the Au NPs, which further increased when the histidine tail was extended to six histidines (6H-BLIP). Further increasing the number of His residues had no effect on the binding. A parallel study using continuous (111)-textured Au surfaces and single-crystalline, (111)-oriented, Au islands by ellipsometry, FTIR, and localized surface plasmon resonance (LSPR) spectroscopy further confirmed the results, validating the broad applicability of Au NPs as model surfaces. Evaluating the binding of all other natural amino acid homotripeptides fused to BLIP (except Cys and Pro) showed that aromatic and positively-charged residues bind preferentially to Au with respect to small aliphatic and negatively charged residues, and that the rate of association is related to the potency of binding. The binding of all fusions was irreversible. These findings were substantiated by SPR measurements of synthesized, free, soluble tripeptides using Au-NP-modified SPR chips. Here, however, the binding was reversible allowing for determination of binding affinities that correlate with the binding potencies of the related BLIP fusions. Competition assays performed between 3H-BLIP and the histidine tripeptide (3 His) suggest that Au binding residues promote the adsorption of proteins on the surface, and by this facilitate the irreversible interaction of the polypeptide chain with Au. The binding of amino acids to Au was simulated by using a continuum solvent model, showing agreement with the experimental values. These results, together with the observed binding potencies and kinetics of the BLIP fusions and free peptides, suggest a binding mechanism that is markedly different from biological protein protein interactions. PMID- 21243702 TI - Chiral and extended pi-conjugated bis(2-pyridyl)phospholes as assembling N,P,N pincers for coordination-driven synthesis of supramolecular [2,2]paracyclophane analogues. AB - Chiral, pi-conjugated 3,4-butano-1-phenyl-2,5-bis(2-pyridyl)phosphole derivatives 1a(2,2') and 1a(3) with chiral trans-1,2-diol moieties and fused pinene derivatives, respectively, were prepared from the corresponding chiral diynes by using the Fagan-Nugent method. Their UV/Vis absorption and chiroptical properties (optical rotation and circular dichroism) were studied. Their behavior as N,P,N chelates towards coordination of Cu(I) and formation of chiral supramolecular assemblies with pi-conjugated ditopic dicyano ligands was investigated. Chiral C(2)-symmetric rectangles that are [2,2]paracyclophane analogues were obtained, as demonstrated by X-ray crystallography. During the course of this study, the first stable water-soluble phosphole derivative (1a(2).2 HCl) was prepared. Furthermore, achiral 3,4-butano-1-phenyl-2,5-bis(aza[4]helicene)phosphole 1a(4) was synthesized and displays extended pi conjugation. A supramolecular rectangle was obtained by coordination to Cu(I) and assembly with a dicyano stilbene. This coordination-driven supramolecular assembly contains a total of four aza[4]helicene moieties and displays two types of pi-pi stacking interactions in the solid state, that is, between two helicene moieties and between one helicene and a bridging dicyano ligand. All the supramolecular arrangements are discussed by comparing them with previous work on the parent 3,4-butano-1-phenyl-2,5-bis(2 pyridyl)phosphole. PMID- 21243703 TI - Hydrothermal fabrication of quasi-one-dimensional single-crystalline anatase TiO2 nanostructures on FTO glass and their applications in dye-sensitized solar cells. AB - One-dimensional and quasi-one-dimensional semiconductor nanostructures are desirable for dye-sensitized solar cells (DSSCs), since they can provide direct pathways for the rapid collection of photogenerated electrons, which could improve the photovoltaic performance of the device. Quasi-1D single-crystalline anatase TiO(2) nanostructures have been successfully prepared on transparent, conductive fluorine-doped tin oxide (FTO) glass with a growth direction of [101] through a facile hydrothermal approach. The influences of the initial titanium n butoxide (TBT) concentration, hydrothermal reaction temperature, and time on the length of quasi-1D anatase TiO(2) nanostructures and on the photovoltaic performance of DSSCs have been investigated in detail. A power conversion efficiency of 5.81% has been obtained based on the prepared TiO(2) nanostructure photoelectrode 6.7 MUm thick and commercial N719 dye, with a short-circuit current density of 13.3 mA cm(-2) , an open-circuit voltage of 810 mV, and a fill factor of 0.54. PMID- 21243704 TI - Pyrolytic carbon from an aromatic precursor and its application as a counter electrode in dye-sensitized solar cells. AB - Pyrolytic carbon thin films were deposited on quartz plates through a chemical vapor deposition process, by using a biphenyl precursor, 4,4'-bis(chloromethyl 1,1'-biphenyl). The pyrolytic carbons were microporous and catalytic toward reduction of tri-iodide, and the films thus obtained possessed a metallic appearance with good mirror reflections, hydrophilic surfaces, and low sheet resistances. The pyrolytic carbon-coated quartz plates were used, in place of the commonly used Pt-coated fluorine-doped tin oxide glass, as the counter electrode for dye-sensitized solar cells (DSSCs). The light to electricity conversion efficiency of the cell thus obtained was reasonably high, achieving 78% of that obtained by using the conventional but much more expensive Pt counter electrode. From the electrochemical impedance spectroscopic analysis, one found that the minor reduction in the conversion efficiency came from the relatively higher resistance and lower catalytic activity of the pyrolytic carbon. This work demonstrates that the newly developed pyrolytic carbon films may be a promising alternative to Pt as the counter electrode material for DSSCs. PMID- 21243706 TI - Basic emotion profiles in healthy, chronic pain, depressed and PTSD individuals. AB - OBJECTIVES: To compare self-reports of five basic emotions across four samples: healthy, chronic pain, depressed and post-traumatic stress disorder (PTSD), and to investigate the extent to which basic emotion reports discriminate between individuals in healthy or clinical groups. METHODS: In total, 439 participants took part in this study: healthy (n = 131), chronic pain (n = 220), depressed (n = 24) and PTSD (n = 64). The participants completed the trait version of the Basic Emotion Scale. Basic emotion profiles were compared both within each group and between the healthy group and each of the three other groups. Discriminant analysis was used to assess the extent to which basic emotions can be used to classify the participants as belonging to the healthy group or one of the clinical groups. RESULTS: In the healthy group, happiness was experienced more than any other basic emotion. This was not found in the clinical groups. In comparison to the healthy participants, the chronic pain group experienced more fear, anger and sadness, the depressed group reported more sadness and the PTSD group experienced all of the negative emotions more frequently. Discriminant analysis revealed that happiness was the most important variable in determining whether an individual belonged to the healthy group or one of the clinical groups. Anger was found to further discriminate between depressed and chronic pain individuals. CONCLUSION: The findings demonstrate that basic emotion profile analysis can provide a useful foundation for the exploration of emotional experience both within and between healthy and clinical groups. PMID- 21243707 TI - Molecular epigenetics: connecting human biology and disease with little marks. PMID- 21243710 TI - Structure and function of mammalian DNA methyltransferases. AB - DNA methylation plays an important role in epigenetic signalling, having an impact on gene regulation, chromatin structure, development and disease. Here, we review the structures and functions of the mammalian DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b, including their domain structures, catalytic mechanisms, localisation, regulation, post-translational modifications and interaction with chromatin and other proteins, summarising data obtained in genetic, cell biology and enzymatic studies. We focus on the question of how the molecular and enzymatic properties of these enzymes are connected to the dynamics of DNA methylation patterns and to the roles the enzymes play in the processes of de novo and maintenance DNA methylation. Recent enzymatic and genome-wide methylome data have led to a new model of genomic DNA methylation patterns based on the preservation of average levels of DNA methylation in certain regions, rather than the methylation states of individual CG sites. PMID- 21243709 TI - Mechanism(s) of SWI/SNF-induced nucleosome mobilization. AB - Impediments to DNA access due to assembly of the eukaryotic genome into chromatin are in part overcome by the activity of ATP-dependent chromatin-remodeling complexes. These complexes employ energy derived from ATP hydrolysis to destabilize histone-DNA interactions and alter nucleosome positions, thereby increasing the accessibility of DNA-binding factors to their targets. However, the mechanism by which theses complexes accomplish this task remains unresolved. We review aspects of nucleosome alteration by the SWI/SNF complex, the archetypal remodeling enzyme. We focus on experiments that provide insights into how SWI/SNF induces nucleosome movement along DNA. Numerous biochemical activities have been characterized for this complex, all likely providing clues as to the molecular mechanism of translocation. PMID- 21243711 TI - Quantitative proteomics for epigenetics. AB - Mass spectrometry has made many contributions to the chromatin field through the mapping of histone modifications and the identification of protein complexes involved in gene regulation. MS-based proteomics has now evolved from the identification of single protein spots in gels to the identification and quantification of thousands of proteins in complex mixtures. Quantitative approaches also allow comparative and time-resolved analysis of post translational modifications. An important emerging field is the unbiased interaction analysis of proteins with other proteins, defined protein modifications, specific DNA and RNA sequences, and small molecules. Quantitative proteomics can also accurately monitor whole proteome changes in response to perturbation of the gene expression machinery. We provide an up-to-date review of modern quantitative proteomic technology and its applications in the field of epigenetics. PMID- 21243713 TI - Structure and function of histone H3 lysine 9 methyltransferases and demethylases. AB - Histone lysine methylation is a dynamic chromatin modification that plays key regulatory roles in gene expression and other genomic functions. Methylation of Lys9 in histone H3 (H3K9) is a prominent modification that has been implicated in diverse processes, including transcriptional silencing, heterochromatin formation, and DNA methylation. In this review, we summarize recent advances in understanding the structure and substrate specificity of the H3K9-specific methyltransferases G9A and GLP and explore current efforts to develop inhibitors of these enzymes. In addition, we discuss the structure and specificity of the recently discovered PHF8 family of histone demethylases that target H3K9 as well as other methylation sites in histones H3 and H4. Finally, we conclude by comparing the H3K9 binding modes displayed by these enzymes and examine the relevance of these studies to their biological functions and to structure-based inhibitor design. PMID- 21243714 TI - Spreading chromatin into chemical biology. AB - Epigenetics, broadly defined as the inheritance of non-Mendelian phenotypic traits, can be more narrowly defined as heritable alterations in states of gene expression ("on" versus "off") that are not linked to changes in DNA sequence. Moreover, these alterations can persist in the absence of the signals that initiate them, thus suggesting some kind of "memory" to epigenetic forms of regulation. How, for example, during early female mammalian development, is one X chromosome selected to be kept in an active state, while the genetically identical sister X chromosome is "marked" to be inactive, even though they reside in the same nucleus, exposed to the same collection of shared trans-factors? Once X inactivation occurs, how are these contrasting chromatin states maintained and inherited faithfully through subsequent cell divisions? Chromatin states, whether active (euchromatic) or silent (heterochromatic) are established, maintained, and propagated with remarkable precision during normal development and differentiation. However, mistakes made in establishing and maintaining these chromatin states, often executed by a variety of chromatin-remodeling activities, can lead to mis-expression or mis-silencing of critical downstream gene targets with far-reaching implications for human biology and disease, notably cancer. Though chromatin biologists have identified many of the "inputs" that are important for controlling chromatin states, the detailed mechanisms by which these processes work remain largely opaque, in part due to the staggering complexity of the chromatin polymer, the physiologically relevant form of our genome. The primary objective of this article is to serve as a "call to arms" for chemists to contribute to the development of the precision tools needed to answer pressing molecular problems in this rapidly moving field. PMID- 21243712 TI - Histone tails: ideal motifs for probing epigenetics through chemical biology approaches. AB - Post-translational modifications (PTMs) on histone proteins have emerged as a central theme in the regulation of gene expression and other chromatin-associated processes. The discovery that certain protein domains can recognize acetylated and methylated lysine residues of histones has spurred efforts to uncover and characterize histone PTM-binding proteins. In this task, chromatin biology has strongly benefited from synthetic approaches stemming from chemical biology. Peptide-based techniques have been instrumental in identifying histone mark binding proteins and analyzing their binding specificities. To explore how histone PTMs carry out their function in the context of chromatin, reconstituted systems based on recombinant histones carrying defined modifications are increasingly being used. They constitute promising tools to analyze mechanistic aspects of histone PTMs, including their role in transcription and their transmission in replication. In this review, we present strategies that have been used successfully to investigate the role of histone modifications, concepts that have emerged from their application, and their potential to contribute to current developments in the field. PMID- 21243715 TI - Catalysis and mechanistic insights into sirtuin activation. AB - SIRT1 is a member of the Sir2 family of NAD(+)-dependent protein deacetylases. The central role of SIRT1 in multiple metabolic and age-related pathways has pushed SIRT1 to the forefront to discover small-molecule activators. Promising compounds, including resveratrol and SRT1720 have been reported, however, whether these compounds are direct activators and the mechanism by which they activate remains poorly defined. This review examines the current debate surrounding purported activators, and will focus on the assays used in screening compounds, sirtuin catalysis, and the mechanistic basis for their actions. We discuss the potential pathways of SIRT1 activation that could be exploited for the development of novel therapeutics for treating type II diabetes, neurodegeneration, and diseases associated with aging. PMID- 21243716 TI - KAT(ching) metabolism by the tail: insight into the links between lysine acetyltransferases and metabolism. AB - Post-translational modifications of histones elicit structural and functional changes within chromatin that regulate various epigenetic processes. Epigenetic mechanisms rely on enzymes whose activities are driven by coenzymes and metabolites from intermediary metabolism. Lysine acetyltransferases (KATs) catalyze the transfer of acetyl groups from acetyl-CoA to epsilon amino groups. Utilization of this critical metabolite suggests these enzymes are modulated by the metabolic status of the cell. This review highlights studies linking KATs to metabolism. We cover newly identified acyl modifications (propionylation and butyrylation), discuss the control of KAT activity by cellular acetyl-CoA levels, and provide insights into how acetylation regulates metabolic proteins. We conclude with a discussion of the current approaches to identifying novel KATs and their metabolic substrates. PMID- 21243718 TI - A modified epigenetics toolbox to study histone modifications on the nucleosome core. AB - In the eukaryotic cell nucleus, the DNA is packaged in a structure called chromatin. The fundamental building block of chromatin is the nucleosome, which is composed of DNA wrapped around an octamer of four distinct histone proteins. Post-translational modifications (PTMs) of histone proteins can affect chromatin structure and function and thereby play critical roles in regulating gene expression. Most histone PTMs are found in unstructured histone tails that protrude from the nucleosome core. As a consequence, (synthetic) peptide truncations of these tails provide convenient substrates for the analysis of histone binding proteins and modifying enzymes. Modifications located on residues that reside in the nucleosome core are more difficult to study because short peptides do not recapitulate this defined structured state well. Methylation of histone H3 on Lys79 (H3K79), mediated by the Dot1 enzyme, is an example of such a core PTM. This modification, which is highly conserved, is linked to human leukemia, and pharmacological modulation of Dot1 activity could be a strategy to treat leukemia. Here we review the available and emerging genetic, biochemical, and chemical methods that together are starting to reveal the function and regulation of this and other histone modifications on the nucleosome core. PMID- 21243717 TI - Dynamic interplay between histone H3 modifications and protein interpreters: emerging evidence for a "histone language". AB - Histone proteins organize DNA into dynamic chromatin structures and regulate processes such as transcription, repair, and replication. Control of chromatin function and structure is mediated in part by reversible post-translational modifications (PTMs) on histones. The most N-terminal region of histone H3 contains a high density of modifiable residues. Here we focus on the dynamic interplay between histone modification states on the H3 N terminus and the binding modules that recognize these states. Specifically, we discuss the effect of auxiliary modifications to H3K4unmod/me3 binding modules (specifically H3R2 methylation, H3T3 phosphorylation, and H3T6 phosphorylation). Emerging evidence suggests that histone PTMs behave less like a strict "code", but more like a "language", which better illustrates the importance of context. Using androgen receptor-mediated gene activation as an example, we propose a model of how the combinatorial natures of PTMs on the H3 N terminus and the complexes that recognize these epigenetic modifications control gene expression. PMID- 21243719 TI - Chemical approaches for the detection and synthesis of acetylated proteins. PMID- 21243720 TI - Xenoestrogens regulate the activity of arginine methyltransferases. AB - Arginine methylation is a common post-translational modification that has been strongly implicated in transcriptional regulation. The arginine methyltransferases (PRMTs) were first reported as transcriptional coactivators for the estrogen and androgen receptors. Compounds that inhibit these enzymes will provide us with valuable tools for dissecting the roles of these enzymes in cells, and will possibly also have therapeutic applications. In order to identify such inhibitors of the PRMTs, we have previously performed a high-throughput screen using a small molecule library. These compounds were named arginine methyltransferase inhibitors (AMIs). The majority of these inhibitors were polyphenols, and one in particular (AMI-18) shared additional features with a group of known xenoestrogens. We, thus, tested a panel of xenoestrogens and found that a number of them possess the ability to inhibit PRMT activity, in vitro. These inhibitors primarily target CARM1, and include licochalcone A, kepone, benzyl 4-hydroxybenzoate, and tamoxifen. We developed a cell-based reporter system for CARM1 activity, and showed that tamoxifen (IC(50) =30 MUM) inhibits this PRMT. The ability of these compounds to regulate the activity of transcriptional coactivators may be an unappreciated mechanism of action for xenoestrogens, and might also explain the efficacy of high-dose tamoxifen treatment on estrogen receptor negative cancers. PMID- 21243724 TI - A CW-EPR, ENDOR and special TRIPLE resonance study of a novel magnesium ketyl radical. AB - In this paper, the paramagnetic properties of a novel magnesium ketyl radical (compound 1), formed by reduction of benzophenone with a dimeric Mg(I) complex in the presence of dimethylaminopyridine, are described. Using CW EPR, ENDOR and special TRIPLE resonance, the spin distribution in the radical has been explored at variable temperatures (200-298 K). At 298 K, most of the unpaired spin is found to be confined to the (OCPh(2)(*)) fragment based on the hyperfine couplings (hfc's) of o-H = 8.30, m-H = 3.00 and p-H = 9.95 MHz. Smaller hfc's to (25)Mg (5.54 MHz) and (14)N(DMAP) (0.90 MHz) were also evidenced in the 298 K EPR spectrum, indicating some spin delocalisation onto the Mg(Nacnac)(DMAP) fragment. At lower temperatures, restricted rotations of the diphenyl rings create an inequivalent spin distribution in the two rings, with o(1)-H = 8.80, o(2)-H = 7.85, m-H = 3.00 and p-H = 10.00 MHz. PMID- 21243721 TI - A chemical method for labeling lysine methyltransferase substrates. AB - Several protein lysine methyltransferases (PKMTs) modify histones to regulate chromatin-dependent cellular processes, such as transcription, DNA replication and DNA damage repair. PKMTs are likely to have many additional substrates in addition to histones, but relatively few nonhistone substrates have been characterized, and the substrate specificity for many PKMTs has yet to be defined. Thus, new unbiased methods are needed to find PKMT substrates. Here, we describe a chemical biology approach for unbiased, proteome-wide identification of novel PKMT substrates. Our strategy makes use of an alkyne-bearing S adenosylmethionine (SAM) analogue, which is accepted by the PKMT, SETDB1, as a cofactor, resulting in the enzymatic attachment of a terminal alkyne to its substrate. Such labeled proteins can then be treated with azide-functionalized probes to ligate affinity handles or fluorophores to the PKMT substrates. As a proof-of-concept, we have used SETDB1 to transfer the alkyne moiety from the SAM analogue onto a recombinant histone H3 substrate. We anticipate that this chemical method will find broad use in epigenetics to enable unbiased searches for new PKMT substrates by using recombinant enzymes and unnatural SAM cofactors to label and purify many substrates simultaneously from complex organelle or cell extracts. PMID- 21243727 TI - Space partitioning strategies for indoor WLAN positioning with cascade-connected ANN structures. AB - Position information in indoor environments can be procured using diverse approaches. Due to the ubiquitous presence of WLAN networks, positioning techniques in these environments are the scope of intense research. This paper explores two strategies for space partitioning when utilizing cascade-connected Artificial Neural Networks (ANNs) structures for indoor WLAN positioning. A set of cascade-connected ANN structures with different space partitioning strategies are compared mutually and to the single ANN structure. The benefits of using cascade-connected ANNs structures are shown and discussed in terms of the size of the environment, number of subspaces and partitioning strategy. The optimal cascade-connected ANN structures with space partitioning show up to 50% decrease in median error and up to 12% decrease in the average error with respect to the single ANN model. Finally, the single ANN and the optimal cascade-connected ANN model are compared against other well-known positioning techniques. PMID- 21243728 TI - Semi-supervised analysis of human brain tumours from partially labeled MRS information, using manifold learning models. AB - Medical diagnosis can often be understood as a classification problem. In oncology, this typically involves differentiating between tumour types and grades, or some type of discrete outcome prediction. From the viewpoint of computer-based medical decision support, this classification requires the availability of accurate diagnoses of past cases as training target examples. The availability of such labeled databases is scarce in most areas of oncology, and especially so in neuro-oncology. In such context, semi-supervised learning oriented towards classification can be a sensible data modeling choice. In this study, semi-supervised variants of Generative Topographic Mapping, a model of the manifold learning family, are applied to two neuro-oncology problems: the diagnostic discrimination between different brain tumour pathologies, and the prediction of outcomes for a specific type of aggressive brain tumours. Their performance compared favorably with those of the alternative Laplacian Eigenmaps and Semi-Supervised SVM for Manifold Learning models in most of the experiments. PMID- 21243729 TI - An evaluation of multiple feed-forward networks on GPUs. AB - The Graphics Processing Unit (GPU) originally designed for rendering graphics and which is difficult to program for other tasks, has since evolved into a device suitable for general-purpose computations. As a result graphics hardware has become progressively more attractive yielding unprecedented performance at a relatively low cost. Thus, it is the ideal candidate to accelerate a wide variety of data parallel tasks in many fields such as in Machine Learning (ML). As problems become more and more demanding, parallel implementations of learning algorithms are crucial for a useful application. In particular, the implementation of Neural Networks (NNs) in GPUs can significantly reduce the long training times during the learning process. In this paper we present a GPU parallel implementation of the Back-Propagation (BP) and Multiple Back Propagation (MBP) algorithms, and describe the GPU kernels needed for this task. The results obtained on well-known benchmarks show faster training times and improved performances as compared to the implementation in traditional hardware, due to maximized floating-point throughput and memory bandwidth. Moreover, a preliminary GPU based Autonomous Training System (ATS) is developed which aims at automatically finding high-quality NNs-based solutions for a given problem. PMID- 21243730 TI - Information quantification of empirical mode decomposition and applications to field potentials. AB - The empirical mode decomposition (EMD) method can adaptively decompose a non stationary time series into a number of amplitude or frequency modulated functions known as intrinsic mode functions. This paper combines the EMD method with information analysis and presents a framework of information-preserving EMD. The enhanced EMD method has been exploited in the analysis of neural recordings. It decomposes a signal and extracts only the most informative oscillations contained in the non-stationary signal. Information analysis has shown that the extracted components retain the information content of the signal. More importantly, a limited number of components reveal the main oscillations presented in the signal and their instantaneous frequencies, which are not often obvious from the original signal. This information-coupled EMD method has been tested on several field potential datasets for the analysis of stimulus coding in visual cortex, from single and multiple channels, and for finding information connectivity among channels. The results demonstrate the usefulness of the method in extracting relevant responses from the recorded signals. An investigation is also conducted on utilizing the Hilbert phase for cases where phase information can further improve information analysis and stimulus discrimination. The components of the proposed method have been integrated into a toolbox and the initial implementation is also described. PMID- 21243731 TI - Recurrence-based estimation of time-distortion functions for ERP waveform reconstruction. AB - We introduce an approach to compensate for temporal distortions of repeated measurements in event-related potential research. The algorithm uses a combination of methods from nonlinear time-series analysis and is based on the construction of pairwise registration functions from cross-recurrence plots of the phase-space representations of ERP signals. The globally optimal multiple alignment path is approximated by hierarchical cluster analysis, i.e. by iteratively combining pairs of trials according to similarity. By the inclusion of context information in form of externally acquired time markers (e.g. reaction time) into a regularization scheme, the extracted warping functions can be guided near paths that are implied by the experimental procedure. All parameters occurring in the algorithm can be optimized based on the properties of the data and there is a broad regime of parameter configurations where the algorithm produces good results. Simulations on artificial data and the analysis of ERPs from a psychophysical study demonstrate the robustness and applicability of the algorithm. PMID- 21243732 TI - XCSc: a novel approach to clustering with extended classifier system. AB - In this paper, we propose a novel approach to clustering noisy and complex data sets based on the eXtend Classifier Systems (XCS). The proposed approach, termed XCSc, has three main processes: (a) a learning process to evolve the rule population, (b) a rule compacting process to remove redundant rules after the learning process, and (c) a rule merging process to deal with the overlapping rules that commonly occur between the clusters. In the first process, we have modified the clustering mechanisms of the current available XCS and developed a new accelerate learning method to improve the quality of the evolved rule population. In the second process, an effective rule compacting algorithm is utilized. The rule merging process is based on our newly proposed agglomerative hierarchical rule merging algorithm, which comprises the following steps: (i) all the generated rules are modeled by a graph, with each rule representing a node; (ii) the vertices in the graph are merged to form a number of sub-graphs (i.e. rule clusters) under some pre-defined criteria, which generates the final rule set to represent the clusters; (iii) each data is re-checked and assigned to a cluster that it belongs to, guided by the final rule set. In our experiments, we compared the proposed XCSc with CHAMELEON, a benchmark algorithm well known for its excellent performance, on a number of challenging data sets. The results show that the proposed approach outperforms CHAMELEON in the successful rate, and also demonstrates good stability. PMID- 21243733 TI - Recursive discriminant regression analysis to find homogeneous groups. AB - The main motivation of this paper is to propose a method to extract the output structure and find the input data manifold that best represents that output structure in a multivariate regression problem. A graph similarity viewpoint is used to develop an algorithm based on LDA, and to find out different output models which are learned as an input subspace. The main novelty of the algorithm is related with finding different structured groups and apply different models to fit better those structures. Finally, the proposed method is applied to a real remote sensing retrieval problem where we want to recover the physical parameters from a spectrum of energy. PMID- 21243734 TI - Cytologic diagnosis and differential diagnosis of lung carcinoid tumors a retrospective study of 63 Cases with histologic correlation. AB - BACKGROUND: Neuroendocrine (NE) neoplasms of the lung are a spectrum of tumors including typicalcarcinoid (TC), atypical carcinoid tumor (ACT), small cell lung carcinoma (SCLC), and large cell NEcarcinoma (LCNEC). Given the overlapping features within these tumors, misclassification is a known risk, with significant treatment consequences. METHODS: A search of the pathology archives from The Johns Hopkins Hospital yielded 390 cases of TC diagnosed over 20 years. Sixty three cytology cases with corresponding surgical material were identified. The cytology specimens were comprised of 49 cases of lung fine-needle aspiriation specimens and 14 cases of lung brushings/washings. RESULTS: Among 63 paired cases, 32 cases (51%) demonstrated concordant and 31 cases (49%) demonstrated discordant diagnoses. Among discordant cases, the most notable findings included overdiagnosis of TC as SCLC (4 cases; 6%), ACT (4 cases; 6%), and poorly differentiated carcinoma with NE features (5 cases; 8%) as well as misdiagnosis of other lesions as TC (4 cases; 6%) on cytology. CONCLUSIONS: The significant morphologic factors for distinguishing low-grade TC from ACT, SCLC, or carcinoma remain the critical evaluation of nuclear features, chromatin patterns, and assessment of nucleoli. Nuclear molding and crowding are not discernible features because they may be found on smears with increased cellularity. Crush artifact can occur in both low-grade and high-grade NE neoplasms and may cause a misinterpretation of SCLC. Other artifacts resulting from delayed fixation or poor processing and sampling error are potential causes of incorrect interpretations. Ki-67 staining may be useful in difficult cases. PMID- 21243735 TI - Menopausal symptoms and fertility concerns in premenopausal breast cancer survivors: a comparison to age- and gravidity-matched controls. AB - OBJECTIVE: Many young breast cancer survivors experience menopausal symptoms and feel concerned about infertility due to oncologic treatment. However, there has been little research to date comparing young survivors' concerns and symptoms with those of young women of the same age and gravidity in the general population. METHODS: We surveyed breast cancer survivors with regular menses after adjuvant chemotherapy and compared them with age-matched, gravidity-matched controls as part of a study to evaluate the effects of chemotherapy on ovarian reserve. All survivors were 1 year or more from diagnosis of early-stage breast cancer, without evidence of recurrence. The survey assessed menopausal symptoms and infertility concerns. RESULTS: The study was stopped after a planned interim analysis of the first 20 matched pairs revealed significantly diminished measures of ovarian reserve in survivors compared with controls. Mean age was 37 years for both groups(range, 31-43 y). Eighty percent of survivors and 25% of controls expressed some concern regarding fertility at the time of the survey (P = 0.001). Survivors were more likely to report bothersome menopausal symptoms than were controls (P = 0.05). An exploratory analysis revealed that menopausal symptoms were greatest in the survivor staking tamoxifen. CONCLUSIONS: Young women who remained premenopausal after breast cancer chemotherapy expressed greater concern about fertility and reported more menopausal symptoms than did age- and gravidity matched controls. This may have been due to cancer diagnosis or treatment, or it may reflect other differences between the survivors and controls in this study. Additional research is warranted to determine how to most effectively address fertility concerns and reduce symptom burden in this population. PMID- 21243737 TI - Subjective sleep disturbance increases the nocturnal blood pressure level and attenuates the correlation with target-organ damage. AB - OBJECTIVE: We aimed to investigate whether subjective sleep disturbance during overnight blood pressure (BP) monitoring results in higher night-time BP levels, and whether this affects the correlation between nocturnal BP and hypertensive target-organ damage. METHODS: In 203 untreated hypertensive patients (104 men) without a history of cardiovascular disease, with a mean age of 52.1 +/- 12.5 years, and with office BP levels of 170 +/- 23/104 +/- 12 mmHg, we performed duplicate ambulatory BP monitoring (ABPM), assessed subjective sleep quality using the Groningen Sleep Quality Scale, and obtained information on hypertension related cardiac damage by echocardiography. RESULTS: Overnight BP monitoring disturbed sleep significantly, but habituation to nocturnal measurements occurred on the second ABPM. Participants whose subjective sleep quality was less than usual on either ABPM did not have higher nocturnal BP levels than those who slept similar to usual (P > 0.05). When comparing the nocturnal BP levels between the first and second ABPM, we found that participants whose subjective sleep quality was less on the second ABPM had significantly higher pressure levels and a smaller BP dip than participants with a similar sleep quality for both ABPMs (P < 0.05). Accordingly, the correlations between the nocturnal BP and cardiac damage tended to be weaker based on the ABPM with the lowest sleep quality. CONCLUSIONS: Subjectively assessed sleep disturbance during overnight BP monitoring increases the nocturnal BP level and potentially attenuates the correlation with hypertension-related cardiac damage, even though habituation to overnight BP monitoring occurs. PMID- 21243739 TI - Screening for postmenopausal osteoporosis after 70 years of age: dual-energy x ray absorptiometry, radiography, both, or none? PMID- 21243736 TI - Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial. AB - OBJECTIVES: To address whether nondihydropyridine calcium-channel blocker added on angiotensin-converting-enzyme inhibitor therapy ameliorates albuminuria and cardiovascular outcomes in type 2 diabetes patients. DESIGN: The Bergamo Nephrologic Diabetes Complications Trial-B was a multicentre, prospective, double blind, parallel-group trial comparing renal and cardiovascular outcomes in 281 hypertensive type 2 diabetes patients with microalbuminuria randomized to at least 2-year VeraTran (verapamil/trandolapril 180 mg/2 mg daily) or trandolapril (2 mg daily, identical image) treatment. Main outcome was persistent macroalbuminuria (albuminuria >200 ug/min in two consecutive visits). Treatment targets were SBP/DBP less than 120/80 mmHg and HbA1C less than 7%. RESULTS: Over a median follow-up of 4.5 years, 18 patients (13%) on VeraTran vs. 15 (10.5%) on trandolapril [unadjusted hazard ratio (95% confidence interval [CI]) 1.07 (0.54 2.12), P = 0.852] progressed to macroalbuminuria, respectively; 62 (44.9%) vs. 71 (49.7%) [0.80 (0.57-1.12), P = 0.198] regressed to normoalbuminuria (urinary albumin excretion <20 ug/min), and 20 (14.5%) vs. 21 (14.7%) [hazard ratio 0.93 (0.50-1.72), P = 0.816] had major cardiovascular events. BP and metabolic control were similar between groups. Patients with cardiovascular events were significantly less [13 (9.8%) vs. 28 (18.9%), hazard ratio: 0.37 (0.19-0.71), P = 0.003] among those regressing to normoalbuminuria than those without regression. Difference was independent of treatment allocation and was significant also after adjusting for baseline characteristics [0.40 (0.20-0.79), P = 0.009], follow-up SBP [0.40 (0.20-0.80), P = 0.010] or DBP [0.36 (0.18-0.73), P = 0.004] BP or HbA1C [0.43 (0.21-0.88), P = 0.021]. CONCLUSION: In hypertensive type 2 diabetes patients with microalbuminuria, verapamil added-on trandolapril did not improve renal or cardiovascular outcomes. Independent of verapamil, trandolapril normalized albuminuria in half of patients and this translated into significant cardioprotection. PMID- 21243738 TI - Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats. AB - OBJECTIVES: Aldosterone is well recognized as the selective physiological ligand for mineralocorticoid receptor in epithelia. However, in-vitro studies have demonstrated that the affinity of aldosterone and glucocorticoids for mineralocorticoid receptor is similar. We hypothesized that glucocorticoids are involved in the development of renal injury through an mineralocorticoid receptor dependent mechanism. METHODS AND RESULTS: Uninephrectomized (UNX) rats were treated with 1% NaCl and divided into three groups: vehicle, bilateral adrenalectomy (ADX) + hydrocortisone (HYDRO; 5 mg/kg/day, s.c.), ADX + HYDRO + eplerenone (0.125% in chow). HYDRO-treated UNX-ADX rats showed increased blood pressure and urinary albumin-to-creatinine ratio with an increase in the expression of the mineralocorticoid receptor target genes, serum and glucocorticoid-regulated kinases-1 and Na+/H+ exchanger isoform-1, in renal tissues. HYDRO treatment induced morphological changes in the kidney, including glomerulosclerosis and podocyte injury. Treatment with eplerenone markedly decreased the gene expression and reduced the albuminuria and renal morphological changes. In contrast, dexamethasone (0.2 mg/kg per day, s.c.) + UNX + ADX induced hypertension and albuminuria in different groups of rats. Eplerenone failed to ameliorate these changes. CONCLUSIONS: Our findings indicate that chronic glucocorticoid excess could activate mineralocorticoid receptor and, in turn, induce the development of renal injury. PMID- 21243741 TI - When your HIV-infected patient doesn't speak English. PMID- 21243740 TI - Increased expression of vascular endothelial growth factor protein in dorsal root ganglion exposed to nucleus pulposus on the nerve root in rats. AB - STUDY DESIGN: An experimental rat study. OBJECTIVE: To assess pain-related behavior and vascular endothelial growth factor (VEGF) expression induced by nucleus pulposus (NP) applied to nerve roots in rats. SUMMARY OF BACKGROUND DATA: Radiculopathy from disc herniation is caused by nerve compression and chemical inflammation. In experimental studies, a decrease in mechanical withdrawal threshold, blood flow, and nerve root dysfunction was reported when the NP was applied to nerve roots. However, neuron reproduction and changes in nerve root blood vessels have not been clearly understood. METHODS: NP harvested from the tail was applied to the left L5 dorsal root ganglion (NP group; n = 77). As a control, sham-operated animals were used (n = 77). Behavioral testing with von Frey hairs was performed for 35 days. Immunoreactivity (IR) for VEGF, activating transcription factor-3, growth-associated protein-43 (GAP-43), factor VIII, and hypoxia-inducible factor-1[alpha] (HIF-1 a) were studied by immunohistochemistry. Western blot analyses of VEGF and GAP-43 were also performed. RESULTS: The mechanical withdrawal threshold significantly decreased from 7 to 28 days in the NP group versus the sham group (P < 0.05). In the NP group, activating transcription factor-3-IR cells increased from 3 to 14 days (P < 0.05), hypoxia inducible factor-1[alpha]-IR cells increased at 14 days (P < 0.05), and blood vessels with Factor VII-IR cells increased at 28 days (P < 0.05) compared with the sham group. The expression levels of VEGF and GAP-43 in the NP group significantly increased at 14 and 28 days (P < 0.05). CONCLUSION: Neuron damage induced by NP applied to the nerve root at the early stage, and axon extension occurred from 14 days. VEGF increased at 14 and 28 days, and the numbers of blood vessels increased 28 days after surgery. The mechanical withdrawal threshold improved at 35 days. Regeneration and vascularization by VEGF might be associated with pain-related behavior. PMID- 21243742 TI - "Parachute" shows promise for alleviating symptoms of heart failure. Device implanted in the heart improves pumping function. PMID- 21243743 TI - Research shows memory problems may affect more men that women. However, women are still more likely to develop Alzheimer's disease. PMID- 21243744 TI - New ovarian cancer gene variations discovered. Findings may help target at-risk women for ovarian cancer screening and earlier treatment. PMID- 21243745 TI - Healthy lifestyle combo will measurably reduce mortality. No matter what your age or level of health, adopting healthy lifestyle factors can still improve your life. PMID- 21243746 TI - Is there such a thing as a "light" form of weightlifting? PMID- 21243747 TI - [WHO Laboratory Manual for the Examination and Processing of Human Semen: its applicability to andrology laboratories in China]. AB - The 5th edition of WHO Laboratory Manual for the Examination and Processing of Human Semen (2010) represents a comprehensive revision. This article aims to explore the applicability of this manual to andrology laboratories in China mainland in view of sperm count analysis, sperm motility analysis, sperm morphology analysis, sperm function analysis, anti-sperm antibody and seminal plasma biochemical marker analysis, and quality assurance and quality control of semen analysis. The authors deem that its recommendation to the analysis method and lower reference limit of sperm concentration may be a little arbitrary and lack of evidence-based support, that the revised grading sperm motility, the strict criteria and the very low cut-off value of 4% morphologically normal spermatozoa for the evaluation of sperm morphology are not applicable to andrology laboratories in China mainland, that the sperm function markers need to be supplemented, and that the determination methods of anti-sperm antibody and seminal plasma biochemical markers are incompatible with the status of Chinese andrology laboratories. However, its recommended methods for quality assurance and quality control of semen analysis have a significant directive role in China mainland. It is worth to point out that the WHO manual ignored the data obtained from Chinese which accounts for approximate 20% of the world population. Thus, given the importance of the WHO manual, its general applicability should be evaluated in China. PMID- 21243748 TI - [Implantation brachytherapy with 32P-chromic phosphate-poly (L-lactide) delayed release particles for prostate cancer in nude mice]. AB - OBJECTIVE: To study the effects of implantation brachytherapy with delayed release particles of 32P-chromic phosphate-poly (L-lactide) (32P-CP-PLLA) on prostate cancer (PCa) in nude mice. METHODS: We established a subcutaneous transplantable PCa model in nude mice, and randomly divided them into six groups, Groups A, B and C implanted intratumorally with 32P-CP-PLLA delayed-release particles at 3.7, 7.4 and 14.8 MBq, Groups D, E and F with 125I particles at the same doses as the former three, and another six nude mice were included in Group G as the blank control. Then we killed the mice at 21 days after the treatment, observed the effects of the particles on the morphology of the tumor and their inhibition of tumor growth, counted WBCs and platelets (PLTs) in the peripheral blood, and detected the toxic reaction of the blood. RESULTS: At 21 days after the treatment, the solid tumor tissues exhibited bleeding and necrotic changes, and the rates of tumor inhibition were positively correlated with the doses of administration. Groups A, B and C showed statistically significant differences from Groups D, E, F and G in the rate of tumor inhibition ([ 65.72 +/- 6.95]%, [77.58 +/- 4.32]% and [82.64 +/- 4.03]% versus [35.61 +/- 5.61]%, [43.30 +/- 6.94]% and [69.01 +/- 4.98]%), WBC count ([1.72 +/- 0.37] x 10(9)/L, [1.23 +/- 0.27] x 10(9)/L and [0.86 +/- 0.25] x 10(9)/L versus [1.45 +/- 0.40] x 10(9)/L, [0.51 +/- 0.24] x 10(9)/L, [0.37 +/- 0.26] x 10(9)/L and [3.96 +/- 0.26] x 10(9)/L), PLT count ([1.18 +/- 0.11] x 10(11)/L, [0.97 +/- 0.10] x 10(11)/L and [0.72 +/- 0.11] x 10(11)/L versus [0.97 +/- 0.15] x 10(11)/L, [0.76 +/- 0.16] x 10(11)/L, [0.64 +/- 0.12] x 10(11)/L and [2.89 +/- 0.21] x 10(11)/L) and body weight ([18.60 +/- 0.66] g, [17.60 +/- 0.39] g and [16.90 +/- 0.68] g versus [17.86 +/- 0.60] g, [15.56 +/- 0.39] g, [14.61 +/- 0.65] g and [19.95 +/- 0.73] g) (P < 0.01). CONCLUSION: Intratumoral implantation of 32P-CP-PL-LA is a safe, simple and effective radionuclide interventional therapy for prostate cancer. PMID- 21243749 TI - [Proteomic analysis of the testis and differential expression of Annexin A3 in hypospadiac rats]. AB - OBJECTIVE: To investigate the effect of in utero exposure to di-n-butyl phthalate (DBP) on the protein expression in the penile tissue of hypospadiac rats, isolate and identify differentially expressed proteins, and determine the role of the differential expression of Annexin A3 in the development of hypospadia in the rat offspring after maternal exposure to DBP. METHODS: Twenty pregnant SD rats were randomly assigned to an experimental group, intragastrically administered DBP at 800 mg/kg, and a control group, given soybean oil at 5 ml/kg, both for 5 days. Three days after birth, the penises of the newborn rats were removed, and the total protein extracted for 2D-electrophoretic separation and image analysis. Differentially expressed protein spots were screened and identified by mass spectrometry, and the changes in the expression of Annexin A3 detected by Western blotting and immunohistochemistry. RESULTS: Thirty-one differentially expressed protein spots were screened, of which 17 were identified by mass spectrometry and the SwissProt database, including pyruvate kinase M2, alpha-enolase, and Annexin A3. Western blot showed that Annexin A3 was mainly located in the urethral epithelia and had a lower expression in the hypospadiac rats (1.851 +/- 0.014, n = 10) than in the controls (2.603 +/- 0.012, n = 10) (P < 0.05). CONCLUSION: A pedigree of differentially expressed proteins in the penises of DBP-induced hypospadia and normal rats was established by the proteomic method. The differential expression of Annexin A3 may play an important role in the development of hypospadia. PMID- 21243750 TI - [Expression of human testis development related gene 1 in testicular cancer detected by tissue microarray]. AB - OBJECTIVE: To investigate the protein expression of human testis development related gene 1 (TDRG1) in human testicular cancer and its pathological significance. METHODS: The expression levels of TDRG1 were detected in the testis tissues of testicular cancer patients and normal men by tissue microarray and immunohistochemistry, and the results were analyzed. RESULTS: Immunohistochemistry exhibited positive expression of the TDRG1 protein in the testis of 73.3% (11/15) of the normal men, 83.3% (10/12) of the patients with embryonal carcinoma, 80.0% (8/10) of those with yolk sac tumor, 26.9% (7/26) of those with seminoma, and 57.1% (4/7) of those with teratoma. The expression levels of TDRG1 in the testis tissues of the seminoma and teratoma groups were shown to be significantly lower than that of the normal control (P < 0.01 and P < 0.05), but those of the embryonal carcinoma and yolk sac tumor groups exhibited no significant differences from that of the latter (P > 0.05). CONCLUSION: The significantly reduced expression of the TDRG1 protein in patients with seminoma or teratoma indicates that TDRG1 may be a candidate cancer suppressor gene. PMID- 21243751 TI - [Identification of differential proteins in the seminal plasma of healthy fertile and non-obstructive azoospermia men by shotgun proteomic strategy]. AB - OBJECTIVE: To identify differential proteins in the seminal plasma of healthy fertile men and non-obstructive azoospermia patients by the shotgun proteomic strategy. METHODS: Six seminal plasma samples from 3 healthy fertile and 3 non obstructive azoospermia volunteers were collected by Percoll isolation, balanced mixed, and followed by separation of the mixture by SDS-PAGE. The proteins were subjected to in-gel enzymolysis and isolation of peptide fragments, and then identified by the shotgun proteomic strategy. Then comparative analyses were made between the two groups on the identified proteins with the unique peptide count > or = 2 and = 1 but with the peptide count > or = 4. RESULTS: A total of 213 differential proteins were identified, 133 in the non-obstructive azoospermia patients and 80 in the healthy fertile men. According to the molecular function, these differential proteins mainly fell into the types of signal transduction, cytoskeleton and catalytic activity, especially oxidoreductase activity in the latter type. Eighteen of the differential proteins were found to be of particular significance, including dynein heavy chain, fatty acid synthase, and tubulin alpha-6 chain. CONCLUSION: The differential proteins identified in this study were many in number and various in function, which not only demonstrated the value of the shotgun proteomic strategy in protein identification, but also suggested the complicated pathogenesis and varied types of non-obstructive azoospermia. The samples must be selected strictly based on their gene and histological types. Non-obstructive azoospermia was shown to be related with the M phase of the mitotic cell cycle at the protein level, but its specific mechanism remains unknown. PMID- 21243752 TI - [Influence of sperm morphology on the outcomes and neonatal status in IVF-ET]. AB - OBJECTIVE: To determine the influence of sperm morphology on the outcomes and status of the neonates in in vitro fertilization and embryo transfer (IVF-ET). METHODS: Strictly based on the WHO criteria, we divided semen samples into a moderately abnormal group (sperm of normal morphology 5% - 10%), a mildly abnormal group (10% < sperm of normal morphology < 15%) and a normal group (sperm of normal morphology > or = 15%) , and compared the rates of fertilization, cleavage, quality embryos, implantation, clinical pregnancy and live births among the three groups. RESULTS: There were not significant differences in the patients' age among the three groups (P > 0.05). The fertilization rate was markedly lower in the moderately abnormal than in the mildly abnormal group (63.70% vs 73.74%, P < 0.05), but not significantly different from the normal group (63.70% vs 68.05%, P > 0.05). The rate of quality embryos of the normal group was the highest, significantly higher than that of the moderately abnormal group (44.83% vs 35.75%, P < 0.05), but no statistically significant differences were observed in the rates of cleavage, implantation and clinical pregnancy among the three groups (P > 0.05). A total of 125 babies were born from the 280 ET cycles, including 73 singletons and 26 twins, of whom none showed any congenital birth defects. No statistically significant differences were found in the rates of abortion, ectopic pregnancy and premature delivery, nor in the mean gestational period and average body weight of the neonates among the three groups (P > 0.05). CONCLUSION: Moderately abnormal sperm morphology did not affect the fertility rate of IVF, but significantly decreased the quality of embryos; mildly abnormal sperm morphology had no obvious influence on the rates of fertilization, cleavage, quality embryos, implantation, clinical pregnancy and live births; while normal sperm morphology played a limited role in predicting the outcomes and status of the neonates in IVF-ET. PMID- 21243753 TI - [Determination of GATA-4 in the testis of the mouse]. AB - OBJECTIVE: To explore the characteristics and distribution of GATA-4 in the testis of male mice. METHODS: Paraffin sections were obtained from the testes of 24 male B6SJLF1/J mice, aged 0 day (n = 6), 2 weeks (n = 6), 4 weeks (n = 6) and 6 weeks (n = 6), and the expressions of GATA-4 in the testis were observed by the immunohistochemical ABC method and DAB visualization at different times. RESULTS: Positive expressions of GATA4 were found in the Sertoli cells and Leydig cells of all the mice, but significantly higher in the 4- and 6-week-old than in the 0-day and 2-week-old groups (P < 0.01). And they were also observed in the germ cells of the 4- and 6-week-old mice, significantly higher in the latter than in the former (P < 0.01). CONCLUSION: GATA-4 exists in the testis of male mice, which has provided a morphological base for sex determination and differentiation and hormone regulation in the testis. PMID- 21243754 TI - [Effects of intraprostatic injection of botulinum toxin A (BTX-A) on benign prostate hyperplasia]. AB - OBJECTIVE: To investigate the effects of intraprostatic injection of botulinum toxin A (BTX-A) on benign prostate hyperplasia (BPH) in rats. METHODS: Models of BPH were established in adult male Sprague-Dawley rats by injection of testosterone propionate, and then divided into three BTX-A groups, injected with BTX-A into the ventral prostate at the doses of 5 U, 10 U and 20 U, a negative control group, injected with saline only, and a sham operation group, with 12 in each. The prostates of the animals were harvested at 2 or 4 weeks after the injection, their volumes and weights measured, histological changes examined by HE staining, and glandular and interstitial areas semi-quantified by the image analysis system. RESULTS: Two rats died in the 20 U group within 3 days after BTX A injection. Compared with the saline group, the 5 U, 10 U and 20 U BTX-A groups showed significant decreases in prostatic volume (P < 0.01, 0.01 and 0.05), weight, and glandular and interstitial areas as well as atrophic epithelia in the glandular tube at 2 weeks. These changes were lessened at 4 weeks, especially in the 5 U group. CONCLUSION: Intraprostatic injection of BTX-A induces obvious atrophy and histological changes of the prostate, but meanwhile may potentially result in death at a large dose. PMID- 21243755 TI - [Expression of carbonic anhydrase II in human testes and spermatozoa and its clinical significance]. AB - OBJECTIVE: To investigate the expression of carbonic anhydrase II (CA2) in human testes and spermatozoa, and to compare the expressions of CA2 in ejaculated spermatozoa between normozoospermic and asthenozoospermic men. METHODS: The localization of CA2 in human testes was observed by immunohistochemistry, and that in human sperm by immunofluorescence. Western blot was used to detect the expression of CA2 in the semen samples obtained from 16 normozoospermic and 16 asthenozoospermic volunteers. RESULTS: The CA2 protein was shown to be localized in the tail of elongating spermatids by immunohistochemistry and in the flagellum of human sperm by immunofluorescence. Western blot revealed an obviously increased expression of CA2 in the spermatozoa of asthenozoospermic patients, with statistically significant difference from the normozoospermic group (1.84 +/ 0.32 vs 1.41 +/- 0.26, P < 0.05). CONCLUSION: The CA2 protein is expressed in the spermatogenic stage of elongating spermatids in human testes and localized in the sperm tail. The expression of CA2 is significantly increased in the spermatozoa of asthenozoospermic men, which might be responsible for low sperm motility. PMID- 21243756 TI - [Correlation of aging with psychological and organic ED: nocturnal electrobioimpedance volumetric assessment of 83 cases]. AB - OBJECTIVE: The ratio of psychological to organic ED changes with aging. This study aimed to analyze the results of nocturnal electrobioimpedance volumetric assessment (NEVA) for ED patients of different age groups and their significance in the diagnosis of ED. METHODS: A total of 83 ED patients were divided into 4 age groups (< or = 29 yr, 30 -39 yr, 40 -49 yr and > or = 50 yr) and detected for nocturnal penile tumescence (NPT) by NEVA. RESULTS: Thirty-four of the cases were diagnosed as organic ED, and the other 49 as psychological ED. With the increase of age, the former was increased from 30.3% in the < or = 29 yr group to 60.0% in the > or = 50 yr group, while the latter decreased from 69.7% to 40.0%. CONCLUSION: The percentage of organic ED tends to grow with the increase of age, while that of psychological ED is just the opposite. PMID- 21243757 TI - [Use of L-carnitine before percutaneous epididymal sperm aspiration intracytoplasmic sperm injection for obstructive azoospermia]. AB - OBJECTIVE: To explore the use of L-carnitine before percutaneous epididymal sperm aspiration-intracytoplasmic sperm injection (PESA-ICSI) in the treatment of obstructive azoospermia. METHODS: Seventy-nine cases of obstructive azoospermia treated in our center from Sep 2008 to Aug 2009 were divided into an L-carnitine (n = 43) and a control group (n = 36), the former given oral L-carnitine at 1 g bid for 3 months before PESA-ICSI, while the latter left untreated. Comparisons were made between the two groups in the number of retrieved oocytes and fertilized oocytes as well as the number and rate of good embryos. RESULTS: There were no significant differences between the two groups in the number of retrieved oocytes and fertilized oocytes. But the number and rate of good embryos were significantly higher in the L-carnitine than in the control group (P < 0.05). CONCLUSION: Three-month oral medication of L-carnitine before PESA-ICSI can raise the number and rate of good embryos in obstructive azoospermia patients and therefore benefit the therapeutic outcome. PMID- 21243758 TI - [Intracytoplasmic sperm injection for obstructive azoospermia]. AB - OBJECTIVE: To sum up the experience in the treatment of obstructive azoospermia by intracytoplasmic sperm injection (ICSI). METHODS: We retrospectively analyzed 107 cases of obstructive azoospermia treated by ICSI in our center from Jan. 2006 to Dec. 2008, and compared the rates of fertilization, cleavage and pregnancy between the patients with congenital bilateral absence of vas deferens (CBAVD) and those with non-CBAVD. RESULTS: A total of 949 oocytes were injected for the 107 patients undergoing ICSI, of which 678 (71.4%) were fertilized and 605 (89.2%) cleaved, with 44 pregnancies (41.4%). Of the 442 oocytes injected for the 49 patients with CBAVD, 308 (69.6%) were fertilized and 279 (90.6%) cleaved, with 27 pregnancies (55.1%), and of the 507 oocytes injected for the 58 cases induced by inflammation or surgery, 370 (72.9%) were fertilized and 326 (88.1%) cleaved, with 17 pregnancies (29.3%). The rate of pregnancy was significantly higher in the CBAVD than in the non-CBAVD group (P < 0.01), but there were no significant differences in the rates of fertilization and cleavage between the two groups (P > 0.05). CONCLUSION: PESA or TESE combined with ICSI is an effective approach to the treatment of male infertility induced by obstructive azoospermia, which may achieve a higher rate of pregnancy in patients with CBAVD than in those with non CBAVD. Inflammation or surgery may not only cause the obstruction of the deferent duct, but also affect sperm quality, and consequently reduce the potentiality of embryonic development. PMID- 21243759 TI - [Testicular mixed nonseminomatous germ cell cancer: a case report and review of the literature]. AB - OBJECTIVE: Testicular mixed nonseminomatous germ cell cancer (TMNGCC) is rarely reported. This study aimed to explore the clinical symptoms, pathological characteristics and treatment methods of TMNGCC. METHODS: We analyzed the clinical data of 1 case of TMNGCC, observed its pathological characteristics under the light microscope by histology, cytochemistry, immunohistochemistry and immune marking, and investigated the clinical features of such tumors by reviewing the relevant literature. RESULTS: The patient presented with a chief complaint of painless testicular swelling for 3 years. Histopathological examinations revealed a tumor of papillary, fissural or adenoid structure, with large polygonal or columnar cells with one or more irregular vesicular nuclei, the nuclear membrane clear, the cytoplasm eosinophilic or basophilic, and the interstitium infiltrated by a few lymphocytes. Here are the immunohistochemical results: CD117 -, CK8-18 + +, CD30 + +, CK + + +, vimentin -, PLAP +/-, P53 +, AFP + and EMA + +. The tumor was pathologically diagnosed as teratogenic embryonic testicular cancer, and treated by radical surgery, followed by adjuvant chemotherapy according to the treatment of TMNGCC. One-year follow-up found the patient to be alive. CONCLUSION: TMNGCC is a rare malignant tumor, mostly with unobvious clinical symptoms. Its diagnosis primarily depends on physical examination, ultrasonography, CT, and measurement of serum tumor markers; its confirmation necessitates pathological examination, and its first-choice treatment is surgical resection. PMID- 21243760 TI - [Recent development in ectopic reconstitution of seminiferous tubules]. AB - The testicular development and spermatogenesis of mammalians involve complex processes of cell migration, proliferation and differentiation and cell-cell interaction. In spite of extensive researches, many relevant aspects remain unclear. One of the impediments in the studies of testicular development and spermatogenesis of mammalians is the lack of a suitable model. In the last few years, two valuable models were developed for the study of mammalian spermatogenesis: testis tissue from immature animals transplanted ectopically into immunodeficient mice that could survive and produce functional spermatids, and isolated testis cells able to organize and rearrange into seminiferous cords that subsequently undergo complete spermatogenesis. This article presents an update and the applications and prospects of these two methods. PMID- 21243761 TI - [Jinleng undershorts palliates varicocele]. AB - OBJECTIVE: To investigate the effect of Jinleng undershorts on the elevated scrotal temperature induced by varicocele as well as on other clinical symptoms of the disease. METHODS: Fifty-one varicocele patients received the treatment of wearing Jinleng undershorts for 30 min twice a day for a course of 90 days. Comparisons were made between the scrotal temperatures and other clinical symptoms of varicocele before and after the treatment. RESULTS: After 90 days of treatment with Jinleng undershorts, the left scrotal temperature of the varicocele patients was significantly reduced from (32.16 +/- 0.79) degrees C to (31.53 +/- 0.77) degrees C (P < 0.01), and the right scrotal temperature decreased from (31.91 +/- 0.73) degrees C to (31.81 +/- 0.63) degrees C (P > 0.05). Compared with pretreatment, significant improvement was found in such symptoms as wetness, fever and swelling of the scrotum, backache, headache, dizziness, fatigue and anxiety (P < 0.05), as well as in testicular pain (P < 0.01) and IIEF-5 score, which was increased from 15.89 +/- 6.13 to 20.04 +/- 3.87 (P < 0.01). CONCLUSION: Jinleng undershorts can be used for the treatment of mild and moderate varicocele. PMID- 21243762 TI - [Nocturnal penile tumescence and the effect of tadalafil on erectile dysfunction]. AB - OBJECTIVE: To explore the correlation between the results of the nocturnal penile tumescence (NPT) test and the efficacy of tadalafil in the treatment of ED. METHODS: A total of 188 ED patients were divided into a normal NPT group (n = 136) and an abnormal NPT group (n = 52) according to the results of the NPT test. All of them were treated with tadalafil at 20 mg 3 times a week. The IIEF-5 score, SEP2, SEP3 and GAQ score were compared between the two groups before and 1 month after the treatment. RESULTS: Tadalafil treatment significantly improved IIEF-5 score, SEP2 and SEP3 of both groups of the patients (P < 0.01). Compared with the abnormal NPT group, the normal NPT group showed a remarkable increase in the IIEF-5 score, SEP2, SEP3 (P < 0.05) and GAQ score (P < 0.01). CONCLUSION: After 1 month of tadalafil treatment, the normal NPT group achieved a more significant improvement of erectile function and sexual satisfaction than the abnormal NPT group, suggesting that tadalafil has a better therapeutic effect for ED patients with normal NPT. PMID- 21243763 TI - [Clone and construction of plant expression vector of AeSS gene in Aralia elata]. AB - OBJECTIVE: To clone Aralia elata squalene synthase gene (designated as AeSS) and construct plant expression vector for transgenic research. METHODS: Isolated squalene synthase from Aralia elata with specific primers by RT-PCR and inserted AeSS gene into the plant expression vector pBI121. RESULTS: The full-length cDNA of AeSS (Genebank accession Number: GU354313) was 1 261 bp and contained a 1 245 bp open reading frame (ORF) encoding a polypeptide of 414 amino acids. The plant expression vector pAeSS was constructed by inserted AeSS gene into the downstream of 35 S promoter of plant expression vector pBI121. CONCLUSION: AeSS gene was cloned and plant expression vector was constructed for future research. PMID- 21243764 TI - [Study on standard of Ferula sinkinangensis seed quality classification]. AB - OBJECTIVE: Study on the standard of Ferula sinkinangensis seed quality classification. METHOD: Chose 30 samples of Ferula sinkiangensis seed. Weight per 1000 seeds, seed germination percentage, seed viability, seed purity, and content of water were mensurated. According to the data, standard of the seed quality classification was set up. RESULT: Seed germination percentage and weight per 1000 seeds are described as major standard of seed quality classification and others as reference. The first grading seed were described as that, seed viability percentage more than 85.9% and weight per 1000 seeds more than 25.7 g. The second grading seed were described as that, seed viability percentage more than 59.1% and weight per 1000 seeds more than 22.1 g. CONCLUSION: Set up standard of Ferula sinkinangensis seed quality classification. PMID- 21243765 TI - [Molecular identification for the asexual stage of Taishan cordyceps]. AB - OBJECTIVE: From gene lever identified the asexual stage of Taishan cordyceps. METHODS: Using rDNA ITS regions as molecular targets, PCR amplification, sequencing, and comparing with the other ITS region sequences of known. RESULTS: Through the Blast search of GenBank, the ITS sequence is same as the sequence of Paecilomyces tenuipes (100% ). CONCLUSION: The asexual stage of Taishan cordyceps was proved through molecular biology method for the first time. The results showed that the asexual stage of Taishan cordyceps. should be Isariafarinosa, not be Hirsutella sinensis. PMID- 21243766 TI - [Determination of geniposide and croein-1 in different breed of fructus gardeniae]. AB - OBJECTIVE: To determinate geniposide and croein-1 in Fructus Gardeniae from different breeds. METHODS: RP-HPLC method was adopted. The chromatographic separation was performed on an Eclipse XDB-C18 column (250 mm x 4.6 mm, 5 microm, Agilent). The mobile phase was a mixture of acetonitrile-0.1% phosphoric acid aqueous solution in gradient elution. The wavelength of 238 nm and 440 nm was selected to determinate geniposide and crocins simultaneously. RESULT: The contents of geniposide and croein-1 in different breeds of Fructus Gardeniae are different. CONCLUSION: This method is simple and repeatable, and could be used for the quality control of Fructus Gardeniae. PMID- 21243767 TI - [Study on the content of curcumin by HPLC and the anti-tumor effect in vivo from different processed products of Curuma kwangsiensis]. AB - OBJECTIVE: To determine curcumin content by HPLC and observe the antitumor effects in vivo from different processed products of Curuma kwangsiensis. METHODS: We determined the content of curcumin by HPLC from different processed products of Curuma kwangsiensis and studied the anti-tumor effects in vivo by establishing S180 transplanted tumors model in mice. RESULTS: The content of curcumin in different processed products of Curuma kwangsiensis as follows: primitive > vinegar-fried > vinegar-cooked. Different processed products had anti tumor effects in the tumor-bearing mice. The vinegar-fried group and vinegar cooked group showed obvious effect of inhibiting tumor growth than the primitive group. CONCLUSIONS: Different processed methods may have some affection to the quality of Curuma kwangsiensis. PMID- 21243768 TI - [Study on the chemical constituents of Antipathes dichotoma]. AB - OBJECTIVE: To investigate the chemical constituents of Antipathes dichotoma. METHODS: The compounds were isolated and purified by column chromatography on silica gel and their structures were identified by spectral analyses and comparison with literatures. RESULTS: Nine compounds were obtained from A. dichotam and characterized as cholesterol (I), ergosta-5-ene-3-ol (II), 4-methyl ergostatrien-3-ol (III), p-hydroxybenzoate (IV), 3,4-dihydroxybenzaldehyde (V), vanillin (VI), caffeic acid (VII), batyl alcohol (VIII), and theymine (IX). CONCLUSION: Compounds II - VII are obtained from Antipathes dichotoma for the first time. PMID- 21243769 TI - [Study on the chemical constituents from fresh roots of Euphorbia fischeriana]. AB - OBJECTIVE: To study the chemical constituents in ethyl acetate fraction from the Euphorbia fischeriana. METHODS: The compounds were isolated by silica gel column chromatography and HPLC, and their structures were elucidated by means of spectral analyses. RESULTS: Fourteen compounds were identified as 2,4-dihydroxy-6 methoxy-3-methylacetophenone (1), 12-deoxyphorbol-13-hexadecanoate (2), ethylgallate (3), esculetin (4), 2,4-dihydroxy-6-methoxy-acetophenone (5), 12 deoxyphorbol-13-acetate (6), 12-deoxyphorbol-13,20-diacetete (7), jolkinolide B (8), 17-hydroxyjolkinolide B (9), 17-hydroxy-jolkinolide A (10), langduin C (11), 3-methylp-hydroxybenzoic acid (12), methyl gallate (13), 3, 3'-diacetyl-pyridine 4,4'-dimethoxy-2, 2', 6, 6'-tetrahydroxydiphenylmethane (14). CONCLUSION: Compounds 3, 5, 12, 13 are isolated from this plant for the first time. PMID- 21243770 TI - [Study on lignans of Polygonum capitatum]. AB - OBJECTIVE: To study the lignan of Polygonum capitatum. METHODS: The compounds were isolated and purified by using of SiO2, Sephadex LH-20 column chromatography and pre-HPLC. The structures of the compounds were determined on the basis of their physical properties and the spectral data. RESULTS: Four compounds were isolated and identified as schizandriside (1), (-)-isolariciresinol-2a-O-beta-D xylopyranoside (2), (-) -5 '-methoxyisolariciresinol-2a-O-beta-D-xylopyranoside (3) and nudiposide (4). CONCLUSION: Compounds 1 - 4 are isolated from the genus for the first time. PMID- 21243771 TI - [Study on the purification and scavenging free radical activity of water soluble polysaccharide from Ligularia hodgsonii]. AB - OBJECTIVE: The study was to provided the reference for further development and utilization of Ligularia hodgsonii. METHODS: The crude polysaccharide LW was extracted from Lugularia hodgsonii with hot water, and prectated by ethanol. The crude polysaccharide has been fractionted and purified, so LW21 was got. Its homogeneity was confirmed by chromatography on Sepharose CL-4B, paper chromatography and cellulous actate electrophoresis. The scavenging effets of the polysacehardes on * OH and O2-* were determined by fluorescence method. RESULTS: Antioxidative experiment shows that LW and LW21 were effective in scavenging superoxide radical and hydroxyl radical. The scavenging capacity for superoxide radical and hydroxyl radical of LW21 had higher than that of LW. CONCLUSION: The polysaceharide from Ligularia hodgsonii had stronger antioxidant actioxdant activities, and their antioxidant activities had certain dose-relationship. PMID- 21243772 TI - [Analysis of volatile oil from different parts of Litsea cubeba]. AB - OBJECTIVE: To analyze and compare the compounds of the essential oil from the fruits and leaves and roots of Litsea cubeba. METHODS: With steam distillation extraction method, Litsea cubeba essential oil was extracted from the fruits and leaves and roots. The qualitative and quantitative analysis of Litsea cubeba essential oil were carried out with GC-MS. RESULTS: 18 compounds were identified from the fruits (93.57% of the total essential oil) and 17 compounds were identified from the roots (98.01% of the total essential oil) and 28 compounds were identified from the leaves (95.33% of the total essential oil). The main constituents of the fruits essential oil were Citral, Limonene, and so on; The main constituents of the roots essential oil were Citral, 6-Octenal, 3,7-dimethyl , 2-Octen-1-ol, 3,7-dimethyl-, and so on; The main constituents of the leaves essential oil were Citral, Eucalyptol, Citronellol, 6-Octenal, 3,7-dimethyl-, and so on. CONCLUSION: The constituents of volatile oil extracted from the different parts of Litsea cubeba were different, so they should be utilized differently in clinical application and study in great depth. PMID- 21243773 TI - [In vivo studies on metabolic network compatibility of herba houttuyniae injection and sodium neohouttuynin injection in rats]. AB - OBJECTIVE: To study metabolic rule in rats for heartleaf houttuynia herb injection and Sodium New Houttuyfonate injection. METHODS: The GC-MS was used to determine metabolites in plasma and urine of rats after intravenous and oral administration of heartleaf houttuynia herb injection as multi-component and Sodium New Houttuyfonate injection as single component. RESULTS: For rats 8 common metabolites were determined in plasma after intravenous administration of heartleaf houttuynia herb injection and Sodium New Houttuyfonate injection, meanwhile 39 in urine. The 16 common metabolites were determined in plasma after oral administration, and 12 in urine. The 9 and 11 of same metabolites were determined in plasma and urine respectively after intravenous and oral administration of heartleaf houttuynia herb injection, 8 and 17 common metabolites for Sodium New Houttuyfonate injection. CONCLUSION: The metabolites of heartleaf houttuynia herb and Sodium New Houttuyfonate injection in rats are the same or similar after intravenous and oral administration, and there are the same structure types between metabolites and original constituents of preparations. The metabolic pathways of the two preparations in rats are the same. There is metabolic Network Compatibility in organism between multi components, single components and different administration forms for traditional Chinese medicine. PMID- 21243774 TI - [Anti-HIV activities of extracts from Chinese medicinal fromula Liangcha]. AB - OBJECTIVE: To screen and evaluate the anti-HIV activities of extracts from Chinese medicinal formula Liangcha. METHODS: The anti-HIV-1 activities of extracts from Chinese medicinal formula Liangcha were evaluated by cytotoxicity assay,syncytium reduction assay, protection for HIV-1 induced lytic assay, and ELISA assay for HIV-1 p24 antigen expression. The primary mechanisms were investigated by fusion inhibition assay, inhibition of viral replication in HIV-1 chronically infected H9 cell and inhibition assay of HIV-1 RT activity. RESULTS: The extracts from Chinese medicinal formula Liangcha exhibited potent and broad spectrum anti-HIV-1 activity on different HIV-1 strains with EC50 range 12.74 116.87 microg/mL, but weakly inhibited HIV-2 replication. Meantime, it was not significantly cytotoxic in several T lymphocytes cell lines with CC50 range 564.79 - 1699.22 microg/mL. The activity of recombinant HIV-1 reverse transcriptase was inhibited by extracts from Chinese medicinal formula Liangcha, inhibition rate more than 50% at the concentration of 5.3 microg/mL. It also weakly inhibited the cell-to-cell fusion in co-culture with EC50 of 101.94 microg/mL. CONCLUSION: The extracts from Chinese medicinal formula Liangcha exhibited potent and broad-spectrum anti-HIV-1 activity on different HIV-1 strains in vitro. Its anti-HIV-1 mechanism might be inhibiting HIV-1 reverse transcriptase and cell entry. PMID- 21243775 TI - [Optimization of PNS/TGCO components effect on experimental Qi stagnation and blood stasis type of coronary heart disease with increase-decrease baseline geometric proportion design method]. AB - OBJECTIVE: Preliminary exploration of Panax notoginseng saponins (PNS) and total saponins from Cornus officinalis (TGCO) components treatment and characteristics of Qi stagnation and blood stasis type of coronary heart disease. METHODS: With increase-decrease baseline geometric proportion design method to Optimization of PNS/TGCO components, through observing different proportions effective components effect on mice with pituitrin-induced acute myocardial ischemia and the time of hypoxia tolerance. RESULTS: Prescriptions 1, 2, 3 and Xuesaitong groups had a certain degree of improvement the role of myocardial ischemia and prescriptions 4, 5, 6, compared with the control group with no significant changes; Prescriptions 3, 4, 5, 6 had a certain role in anti-anoxia in mice, prescriptions 1, 2 and Xuesaitong group, together with the control group with no significant changes. CONCLUSION: Prescription 3 has some effect on improving the role of myocardial ischemia and has a certain role in anti-anoxia. It's the best ratio of PNS/TGCO components for the treatment of Qi stagnation and blood stasis type of coronary heart disease. PMID- 21243776 TI - [Effect of decoction method on pharmacokinetics of puerarin in dogs]. AB - OBJECTIVE: To investigate the effect of decoction method on pharmacokinetics of Puerarin by determining Puerarin concentration of serum after administration of Gegenqinlian in single (D) and mixed decoction (H) to dogs. METHODS: HPLC method was established to determine serum concentration of Puerarin and pharmacokinetic parameters were calculated. RESULTS: The parameters in dogs after administration of H and D were as follows: C(max) was (5.164 +/- 0.637) and (5.383 +/- 0.818) microg/mL, t(max) was (1.10 +/- 0.374) and (1.25 +/- 0.274) h, AUC(0-t) was (25.76 +/- 5.48) and (27.97 +/- 7.16) microg/(h x mL), respectively. CONCLUSION: Decoction method has significant effect on pharmacokinetic parameters of puerarin in dogs. PMID- 21243777 TI - [The estrogenic effect of formononetin and its effect on the expression of rats' atrium estrogen receptors]. AB - OBJECTIVE: To observe the estrogenic effect of formononetin and its effect on the expressions of atrial estrogen receptor subtypes alpha and beta (ERalpha and ERbeta). METHODS: 50 femal rats were randomly divided into five groups: sham group, model group, nilestriol group, formononetin groups of low and high dose. Rats in sham group were cut a piece of fat before closing the abdomen, the others were ovariectomized. Vaginal exfoliated cell were observed from the fifth day to the tenth after operation to test if the model is successful. The sham and model group were given nomal saline in 10 mL/kg by gavage, the remaining three groups were given nilestriol 2.5 mg/(kg x w), low [20 mg/(kg x d) land high dose [100 mg/(kg x d)) of formononetin by gavage respectively. In the 8th week, vaginal exfoliated cell were observed, then decapitated the rats, removed the uterus, weighed and take wright staining microscopy. The relative expressions of ERalpha and ERbeta of right atrium were detected by RT-PCR. RESULTS: The vaginal cells exhibit a change of estrus after had been fed with high dose of formononetin after 8 weeks. Formononetin increase the uterus coefficient and the expression of atrial ERbeta (P < 0.01), but it dose not have any effect on the expression of ERalpha (P > 0.05). CONCLUSION: Formononetin have estrogenic effect in ovariectomized rats, and it can markedly upregulate the expression of rats' atrial ERbeta. PMID- 21243778 TI - [Inhibitory effect of TBN on platelet aggregation in rabbit]. AB - OBJECTIVE: To investigate the inhibitory effect of TBN on rabbit platelet aggregation in vitro and in vivo, and compare with tetramethylpyrazine (TMP). METHODS: To seek out the maximum of platelet aggregation (expressed in percentage) within 5 minutes which was induced by ADP, PAF and AA according to the Born turbidimetric method with a Platelet-Aggregometer. RESULTS: TBN significantly inhibited platelet aggregation induced by ADP, PAF and AA both in vitro and in vivo. TBN was more active than TMP. CONCLUSION: TBN has significant activity inhibiting platelet aggregation induced by ADP, PAF and AA in vitro and in vivo. PMID- 21243779 TI - [Study on the enrichment and purification of total flavonoids in Schizonepeta tenuifolia by macroporous adsorption resin]. AB - OBJECTIVE: To establish an optimum enrichment and purification process of total flavonoids in Schizonepeta tenuifolia by macroporous resins. METHODS: 9 kinds of resins were compared and the best one was chosen. Then the technique condition for separating and purifying total flavonoids from Schizonepeta tenuifolia was studied. RESULTS: HP-20 was selected for its excellent adsorption and desorption properties, 80% ethanol was found to be the best elution solution. The best result was based on the follows: pH value-6.0, feeding rate-2 BV/h,sample concentration-0.4 g/mL, the ratio of total flavonoids to HP-20 macroporous resin 133. 76 mg/g, elution flowing rate-4 BV/h, eluting agent amount-3 BV. Then the purity reached 74. 31% and the yield was 97.13%. CONCLUSION: The total flavonoids of Schizonepeta tenuifolia can be effectively purificated and separated by HP-20 macroporous resin. PMID- 21243780 TI - [Study on extraction of shikimic acid from pine needles of Pinus elliottii by decompressing inner ebullition]. AB - We studied the extracting process of shikimic acid from pine needles of Pinus elliottii Engelm, using pine needles of Pinus elliottii Engelm as raw materials, a high concentration of alcohol as the desorption and a low concentration of alcohol as the hot-extraction, and the decompressing inner ebullition method. Through the single factor test and orthogonal test, the best processing of the decompressing inner ebullition was as follows: when the concentration of alcohol was 70 percent with 18 minutes' desorption, the temperature of hot-extraction was 65 degrees C with 4 minutes' hot-extraction, solid-liquid ratio was 1:1.6 with 260 mL of hot-extraction, with a concentration of 30%. The extracting effect was the best when extracted twice. The extracting proportion of shikimic acid from dry pine needles of Pinus elliottii was 1.51%. PMID- 21243781 TI - [Extraction and antioxidant activity of flavonoids from Aralia cordata]. AB - In this study, microwave-assisted extraction techniques of flavonoids fom Aralia cordata were studied by the single factor analysis and orthogonal test, then the property antioxidant activities of flavonoids extracts were evaluated by two antioxidant assays, for 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals scavenging and reducing power. The results showed that the optimum conditions were as follows: twice extracting Aralia cordata with 75 times volume (V/W) of 30% ethanol at 140W of microwave for 60 min at 80 degrees C. Under these conditions, the extraction yield was 1.35%. The flavonoids extracts could significantly scavenge DPPH and superoxide anion free radicals in dose-dependent manner, meanwhile a linear correlation between its concentration and reducing power was also observed (R2 = 0.9855). PMID- 21243782 TI - [Studies on separation and purification of phenylethanoid glycosides from leaves of Forsythia suspensa by macroporous adsorption resin]. AB - OBJECTIVE: To study the technology for separation and purification of phenylethanoid glycosides from leaves of Forsythia suspensa by macroporous adsorption resin. METHODS: The absorption and separation abilities of 10 kinds of adsorption resin were studied and the separation and purification technological process of phenylethanoid glycosides from leaves of Forsythia suspensa was investigated by HPLC with the content of Forsythoside A as an index. RESULTS: The optimal conditions were as follows: taking AB-8 resin column as adsorbent, the resin was washed by 20BV distilled water to remove impurity and 8BV 30% ethanol to elute phenylethanoid glycosides, the eluting velocity was 2BV/h, the content of Forsythoside A in the extract was 34.8%. CONCLUSION: The process with AB-8 resin is an effective method to separate and purify phenylethanoid glycosides. PMID- 21243783 TI - [Lost humanity in an indifferent society]. PMID- 21243784 TI - [Helicobacter pylori--friend or foe?]. AB - Helicobacter pylori (H. pylori) is the bacterium that causes the most common infection in the world. Epidemiological studies show that over 50% of the population is infected, there are areas where virtually the entire population present the infection since childhood. Although the stomach seems to be a "hostile" environment for the development of microorganisms due to the acid pH not fit for life, it may be infected; the first spiral organisms were described at this level as early as 1874. These microorganisms were isolated by Waren and Marshall in 1982 and named Campylobacter pyloridis. In 1989 Goodwin renamed the bacterium Helicobacter pylori. Helicobacter pylori is thus a bacterium which "manages" to survive in gastric acid environment producing an infection which, untreated, is likely to persist the entire life. This feature explains the high rate in the spread of the infection. The infection manifests itself in different ways, depending on the pathogenic strain and the host response, the majority of those infected being asymptomatic or paucysymptomatic. The great achievement of Warren and Marshall,who were rewarded with a Nobel prize in 2005, was to demonstrate that H. pylori can lead to gastric cancer, the bacteria being categorized as an oncogene agent. The anti H. pylori "campaign" was only a step away... and yet, the bacterium has been living in the stomach for centuries. We will try to list the pros and cons of H. pylori infection, when and how the infection should be treated, clearly indicating groups of patients in which eradication is absolutely mandatory. Key words: PMID- 21243785 TI - [Hepato-pulmonary syndrome]. AB - The hepato-pulmonary syndrome (HPS) is a rare complication of liver cirrhosis, with poor outcome; the term includes liver disease, increased alveolo-arterial gradient and intrapulmonary vascular dilations, described by Fluckiger, Kennedy and Knudson. HPS impairs survival in cirrhotic patients and the posttransplant outcome is altered in correlation with severity of HPS. Combined determination of SaO2 in clino- and orthostatic position by a pulsoximeter is a simple test for HPS identification in patients with chronic liver disease or non-cirrhotic portal hypertension. PMID- 21243786 TI - [Allergic comorbidities in bronchial asthma, in children]. AB - Bronchial asthma is the most frequent chronic disease of childhood. The association of this disease with allergic rhinitis increases the prevalence and severity of bronchial asthma to 60% compared with 2% in subjects without allergic rhinitis. Food allergy can be expressed in a variety of respiratory symptoms, especially when IgE mediated immune responses are involved. In children, the prevalence of bronchial asthma associated with food induced atopic eczema is 2-8% and respiratory clinical picture can be a component of the multisystem anaphylactic reaction or of chronic respiratory disease like bronchial asthma, serous otitis. The association of other allergic comorbidities, like sinusitis, ocular allergies, lymphoid hypertrophy, sleep obstructive apnoea, leads to the conclusion that allergic bronchial asthma (extrinsic) is a systemic disease, with onset at any age, and the dominant clinical feature depends on the child's genetic pattern. PMID- 21243787 TI - [Clinical and epidemiologic study of cardiovascular complications in patients with metabolic syndrome]. AB - Our study aims to identify correlations between the metabolic syndrome and cardiovascular diseases determinism. MATERIAL AND METHODS: A retrospective study was carried out on a sample of 1463 patients of which 734 patients met the diagnostic criteria of cardiometabolic syndrome, admitted in the Clinic of Cardiovascular Rehabilitation, Rehabilitation Hospital, Iasi, between 01.01.2009 31.12.2009. RESULTS: The incidence of cardiometabolic syndrome has a soft predominance on the group 40-59 years (61.66%). The high level of hypertension was found in the patients group 48-69 years (53.70%) and lowest in the patients group 25-38 years (11.35%) (p = 0.001). The coronary heart diseases showed a significant difference between age groups: 48-69 years (41.80%), compared to 25 38 years (7.55%) (p = 0.003). Heart failure is part of the same age distribution curve (45%, 6.8%) (p = 0.02). CONCLUSIONS: The metabolic syndrome is a predictor of the occurrence and development cardiovascular disease. PMID- 21243788 TI - [Home control of high blood pressure]. AB - Control of blood pressure is far from satisfactory, reaching approximately 13% in Romania according the SEPHAR study. AIM: Assessment of blood pressure control in elderly by blood pressure monitoring at home. MATERIAL AND METHOD: 64 hypertensive patients (36 women and 28 men) with mean age of 76.3 years which blood pressure has been normalized by admitting in hospital were followed for a period of three months, by self-measuring blood pressure at home (twice a week). RESULTS: In the first week after hospital discharge the mean systolic pressure was 158 +/- 17.06 and after adjustment of treatment was 136.76 +/- 11.36 mmHg. To the end of the study blood pressure was controlled at a rate of 81.25%. CONCLUSIONS: To increase the percentage of therapeutic control of blood pressure at home, small changes in drug dosage are needed. PMID- 21243789 TI - [Diagnosis and therapeutic aspects of isolated systolic hypertension]. AB - The isolated systolic hypertension is a distinct entity concerning evolving, pathological, diagnosis and treatment particularities. The present study analyzed the behavior of the blood pressure by continuous ambulatory monitoring of a group of patients diagnosed with isolated systolic hypertension by office measurement. MATERIAL AND METHOD: One hundred and twenty nine patients with isolated systolic hypertension at office were included. They were subjected to continuous ambulatory monitoring of blood pressure, then the treatment was started. After six months the patients were reassessed. RESULTS: Continuous ambulatory monitoring better indicates the increase of systolic tension and the reduction of the diastolic tension by aging. The pulse pressure is significantly higher at the over sixty-five group. The systolic tension is directly correlated with the pulse pressure and indirectly with the diurnal index. (r = 0.36). After six months of treatment the reevaluation shows a statistically significant reduction of the pathological parameters although without achieving tensional control. CONCLUSIONS: The ambulatory monitoring better highlights the values of hypertension and assesses the LOAD and Day Index values. Achieving the therapeutic goal regarding systolic hypertension proves difficult. PMID- 21243790 TI - [Cardiovascular risk of haloperidol vs. atypical anti-psychotic drugs in schizophrenia treatment]. AB - The present study examined the safety of the atypical antipsychotic drugs sertindol, olanzapine and quetiapine used in the treatment of schizophrenia. Haloperidol, a typical antipsychotic drug, was used for comparison. These data may account for the different therapeutic effects and side-effect profiles (cardiovascular risk) of typical and atypical antipsychotic drugs in schizophrenia. PMID- 21243791 TI - [Clinical and biological correlations of esophageal varices in patients with compensated hepatic cirrhosis]. AB - MATERIAL AND METHODS: The retrospective study included 126 patients with hepatic cirrhosis (HC) CHILD A class, assisted in Botosani Hospital, during 2007 and 2008. Patients were clinic, biochemical, hematological, etiological, ultrasonographic, endoscopical examined. Statistical analysis carried out with EXCEL soft and SPSS 16.0 soft, calculating chi2, p, ROC curve, SPRI and ASPRI values. RESULTS: We assessed the sample characteristics using the univariate analysis: age, the presence/absence of esophageal varices, SPRI score (limit value > or = 15.5), ASPRI score (limit value > or = 19.3). CONCLUSIONS: Non invasive prediction cannot exclude the endoscopic exam in patients with compensated HC, caused especially by the virus C and alcohol consumption. Thrombocytopenia and splenomegaly and Fibroscan exam were the best noninvasive indicators to predict the esophageal varices. PMID- 21243792 TI - [Metabolic profile of patients with cholesterol gallstone disease]. AB - Metabolic syndrome is a clustering of cardiovascular risk factors as well as associated co morbidities, including cholesterol gallstones disease.The aim of our study is to prove the association between metabolic syndrome and cholesterol gallstones, to identify the main risk factors for this association and to trace the particularities of the metabolic syndrome in such patients. MATERIAL AND METHOD: Our cohort study enrolled 449 subjects, 312 patients diagnosed with metabolic syndrome and gallstones or cholecystectomy (group 1) and 137 patients diagnosed only with metabolic syndrome (group 2), hospitalized in the Respiratory Rehabilitation Medical Clinic between 2007-2009. RESULTS: 85.25% of the patients with metabolic syndrome and cholesterol gallstones and 79.92% of the patients with metabolic syndrome alone had a body mass index (BMI) > or = 25 Kg/m2. Univariate and multivariate logistic regression were used to calculate the risk of gallstone disease associated with different metabolic syndrome variables. Waist circumference, BMI, fasting glycemia, insulinemia and insulin resistance index (HOMA-IR) registered statistical significant differences between the two study groups and were significantly associated with a higher risk of cholesterol gallstone as well as were blood pressure values > or = 130/85 mmHg. The presence of 4 or 5 components of the metabolic syndrome increased the risk of gallstone disease by 3 times (OR = 3.3, p < 0.001) compared to a 2 times higher risk (OR = 2.1, p = 0.02) in case of increased insulin resistance; there was no statistical significance for any of the lipid parameters. CONCLUSION: In our study, cholesterol gallstones appeared strongly associated with anthropometric measurements, fasting glycemia and insulin resistance index, as well as with the presence of metabolic syndrome as defined by the new clinical definition, despite the negative results for the lipidic components. These findings are consistent with the hypothesis that insulin resistance plays an important role in the pathogenesis and that cholesterol gallstone disease belong to metabolic syndrome. PMID- 21243794 TI - [Obstructive sleep apnea (OSA) syndrome and traffic accidents]. AB - For many years traffic accidents represent an important concern in the world and was proven that excessive sleepiness, decreased vigilance of falling asleep in traffic are involved in many car accidents. AIM: To asses the correlation between obstructive sleep apnea (OSA) syndrome severity, the length of nocturnal arterial oxygen desaturation period and the patients' answers to the Epworth Sleepiness Scale Questionnaire (ESS) and Berlin Questionnaire (BQ). MATERIAL AND METHOD: We used the records of patients admitted in Iasi Pneumology Clinical Hospital with obstructive sleep apnea syndrome between 2007-2008, including only those patients which drive the car daily and excluding those patients with comorbidities which could increase the nocturnal arterial oxygen desaturation. The study group (33 patients) have been assessed through polysomnography and some specific questions from ESS and BQ. We identified those patients involved in traffic accidents due to sleepiness. The correlation between obstructive sleep apnea syndrome severity (reflected by Apnea-Hipopnea Index--AHI), the length of the nocturnal arterial oxygen desaturation period (< 90%) and the answers the answers to ESS and BQ were assessed. RESULTS: Two patients presented mild severity sleep apnea syndrome, 15 presented moderate severity and 16 high severity sleep apnea syndrome. The correlation of AHI with ESS (r = 0.59, p < 0.001) and BQ (r = 0.47, p < 0.05) were significant while the correlation with nocturnal arterial oxygen desaturation period had no significance (r = 0.29, p < 0.05). CONCLUSION: Patients with moderate or severe OSA present a high degree of diurnal sleepiness which could affect the driving capacity. PMID- 21243793 TI - [p-ANCA prevalence in ulcerative colitis patients and first-degree relatives]. AB - Perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) are more common in patients with ulcerative colitis (UC) than in patients with Crohn's disease (CD), but its prevalence depends on the population being studied and the method employed for its detection. AIM: To determinate the prevalence of p-ANCA in ulcerative colitis (UC) patients and their first degree in NE Romania area. MATERIAL AND METHOD: In this study, we investigated the prevalence of p-ANCA as detected by ELISA, in the serum of 44 patients with UC and 22 first degree relatives. We also correlated the presence of this antibody with disease activity and extent, extraintestinal complications and therapy. 26 healthy individuals comprised the control group. RESULTS: p-ANCA was detected in 11% of the patients with UC. Of the 5 p-ANCA positive UC patients, 1 case were found to have proctosigmoiditis, 1 cases had left-sided colitis and 3 cases had pancolitis. There was no correlation between the presence of this antibody and any of the studied clinical variables (extend disease, complication, family disease, surgery). No person of the first degree and control group presented positive test. CONCLUSIONS: The prevalence of p-ANCA in NE Romania patients with UC (11%) is lower than that in the Western population. The negativity of p-ANCA in all first degree relatives of NE Romania UC patients should be further elucidated. PMID- 21243795 TI - [Epidemiologic and forensic medical assessment of suicide incidence and other causes of violent death in Romania and Iasi, between 1997 and 2006]. AB - The study included information collected in the reports of Forensic Medicine Institutes, at the national level, processed and interpreted using epidemiological and biostatistical methods. RESULTS: In Romania, at the national level, the annual values of suicide incidence increased from 18 to 30% and in 70 80% of cases, other causes led to violent death (intoxication, precipitation, submersion, burning, cut wounds, shooting a.s.o.). In lasi County, the annual values of suicide incidence varied between 1.1 and 2 per thousand inhabitants, and the main cause was hanging registered in 60.2% of cases in 31-60 age groups, with male predominance. CONCLUSION: Results are useful for the orientation of educational prevention programs. PMID- 21243796 TI - [Prevalence of overweight and obesity in a rural population]. AB - The main objective of this study is to estimate the prevalence of overweight and obesity in a rural population, from the north-east part of Romania. MATERIAL AND METHOD: The study population included 3248 adult subjects (1341 men, 1907 women), aged 18 or over, registered with their general practitioner. Anthropometric parameters were assessed by medical staff and obesity and overweight were defined according to World Health Organization's (WHO) criteria. Abdominal obesity was described according to International Diabetes Federation's (IDF) criteria. RESULTS: The prevalence of overweight and obesity is 33.9% and 12.2% in men and respectively 35% and 21.3% in women. The majority of overweight and obese subjects had an increased waist circumference. There can be observed the predominance of the women in the overweight and obese group, as well as the increase of the obesity prevalence with age. CONCLUSION: Our results show that the weight excess could become a public health problem in Romania, therefore national screening programs are needed along with public information campaigns regarding effectual prevention and treatment possibilities. PMID- 21243797 TI - [Clinical and epidemiologic aspects of overweight and nutritional habits of schoolchildren and teenagers]. AB - Obesity is a complex, pluricausal disease that develops through the interaction of social,'behavioural, cultural, physiological, metabolic and genetical causes. MATERIAL AND METHODS: The study was conducted on 1764 school age children from Iasi city. Data was collected by measuring their weight, height and arterial pressure. 283 children were diagnosed with weight excess and have been questioned about their nutritional habits and life quality. RESULTS: It has been concluded that 50.17% of the children were breastfed in the first months of life. The weight excess was frequently correlated with: irregular meal schedule (57.59%), roast meal cooking (69.61%), eating white bread (77.38%), predilection for fat meat (66.78%), processed cheese and butter (69.25%), french fries (68.19%), everyday dessert (62.89%), highly concentrated sweets (cookies, chocolate) (63.95%), biscuits, snacks, chips (73.85%) and sweet juices (66.42%). Inactivity was also an important factor, often associated with weight excess, considering that 60.42% of the children spend their spare time watching TV or playing computer games and only 32.86% of the children practice sport during their spare time. CONCLUSIONS: Obesity and overweight are pathologies with increasing incidence in our country and they are caused by a combination between genetical factors and, more important, nutritional habits and the amount of time dedicated to physical exercise. PMID- 21243798 TI - [Nutrition in cholestasis and long-term impact on trasnplant]. AB - AIM: Plurietiological hepatic cholestasis involves an increased risk of protein caloric malnutrition and specifical nutritional deficiencies. Biological investigations to determine deficiencies in fat-soluble vitamins are essential for specific nutritional therapy . Although malnutrition is not an absolute contraindication for liver transplantation, its gravity has complex consequences in relation to this intervention. MATERIAL AND METHOD: The authors present a study conducted over a period of 5 years following the analysis of 293 children diagnosed with intra- or extrahepatic abnormalities that caused varying degrees of cholestasis. RESULTS: In the study group, the percentage of infants with cholestasis was 45.39% (133 cases) and among them 62.12% had malnutrition (82 children). Clinical evaluation of fat-soluble vitamins deficiency, in particular, but also of the soluble and minerals was performed in all patients. Liver transplantation was successfully performed in three cases. CONCLUSIONS: Most important factors affecting growth after transplantation were age at the time of the liver transplant and primary diagnosis that required transplant. The role of nutritional support prior to liver transplantation is of great importance. Quality nutritional support change impact that malnutrition has on survival after liver transplantation. PMID- 21243799 TI - [Trends in epidemiological evolution of viral hepatitis B and C , in children , Romania and Iasi county between 1990-2009]. AB - Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the frequent causes of acute and chronic hepatitis worldwide and the leading causes for hepatic cirrhosis and liver cancer. There is a distinct geographical variation in VHB and VHC incidence in adult and child. AIM: To assess the evolution trend of VHB and VHC incidence in child, in Romania and Iasi County, during the last two decades. MATERIAL AND METHODS: Data were obtained using information from the Reporting National System for acute viral hepatitis A, B, and C, from various geographical areas of Romania. Some systematical errors of information were identified, without significant influence of results and conclusions. RESULTS: Results highlighted an incidence peak of VHB in Romania, in 1989, and in Iasi county, in 1991 (43.1, respectively 41.2 per thousand inhabitants). The VHB incidence trend decreased after the implementation of vaccination programme, especially in children < 4 years old. CONCLUSIONS: The study remarked the necessity of viral hepatitis surveillance programme continuity in Romania and the importance of prevention measures including, for VHB, an optimal vaccination. PMID- 21243800 TI - [Chronic hepatitis B--still a problem in children]. AB - Vaccination of the newborns and adolescents had impact on the incidence of acute and chronic infection with hepatitis B virus (HBV) in children. After a decade of this national program application, authors proposed to study the epidemiologic dynamics of chronic infection with HBV in this interval, compared with the previous period, prior to vaccination. PMID- 21243801 TI - [Clinical aspects of tuberculous meningitis in children]. AB - The aim of the study was to investigate the particularities of the clinical manifestation and evolution of tuberculous meningitis at children. MATERIAL AND METHOD: The study was made between January 2000 and December 2008 in Clinic of Infectious Diseases IaSi and Emergency County Hospital ,,Sf. Ioan cel Nou" Suceava on a group of 169 children with tuberculous meningitis. RESULTS: The majority (78.1%) of patients had poor socio-economic conditions and 22.4$ had a family TB contact. The onset of the symptoms was atypical in infants and small children with fever associated with digestive, neurological or pulmonary manifestations. The admission in hospital was delayed in 56.8% of patients and 39.05% had a severe general status with coma. The positive diagnosis was based on cytological and biochemical features of CSF, results of QuantilFERON. TB Gold, pulmonary images, family TB contact and evolution under anti-tuberculous therapy. We observed a high rate of complications represented by hydrocephaly (28.9%). 18 patients died (4 infants), the cause of dead being meningeal coma or complications. CONCLUSION: The diagnosis of tuberculous meningitis at children remains a problem because of the atypical clinical manifestation, the delay of initiating the therapy causing high mortality and frequent complications. PMID- 21243802 TI - [Clinical and radiologic correlations in cerebral palsy]. AB - The aim of this study was to determine clinico-radiologic correlations, using cranial magnetic resonance imaging (IRM)/computed tomographic exam (CT), in cerebral palsy (CP). MATERIAL AND METHOD: We studied 129 children (86 males, 43 females; aged 2-18 years) diagnosed with different types of CP. Computed tomographic examinations was performed in 100 (77.52%) of children and IRM in 29 (22.48%). RESULTS: In 19 (14.72%) children the neuroimaging exam was normal. At 110 (85.28%) patients the IRM/CT showed different types of abnormalities. The most common neuroimaging findings was ventriculomegaly (38 cases), followed by focal infarct (28 cases), periventricular leukomalacia (17 cases), cortical and cortical/subcortical atrophy (13 cases), basal ganglia lesions (12 cases) and cortical migration and organization problems (12 cases). The CT/IRM abnormalities was associated in 65.45% of cases with mental retardation and 44.54% presented epileptic seizures. In CP neuroimaging findings are common, but variable and IRM/CT change correlates with neurological assessment. CONCLUSION: Patients with CP and mental retardation or/and epilepsy were more likely to have obvious CT/IRM changes. PMID- 21243803 TI - [Kostmann disease in children]. AB - Kostmann's disease (KD) is a severe congenital neutropenia, a rare autosomal recessive disorder of neutrophil number. Complete blood count with differential reveals an ANC less than 500/mm3 as seen in classic cases, monocytosis and eosinophilia. Bone marrow aspiration or biopsy reveals an arrest of neutrophil precursor maturation at the promielocyte or myelocyte level. KD results in an increased susceptibility to frequent bacterial infections. In the absence of medical intervention with granulocyte colony-stimulating factor (G-CSF), bone marrow transplantation, the mortality rate is 70% within the first year of life. We present three cases to illustrate this rare entity, the difficulty of diagnosis, but also to underline the importance of correct treatment. PMID- 21243804 TI - [Posterior fossa meningiomas--topographic and anatomopathologic aspects]. AB - Meningiomas are the most frequent met intracranial tumors. Many authors tried to order them according to location, origin and histopathologic type. MATERIAL AND METHOD: Our study is focused on posterior fosa meningiomas, initially classified according to their origin based on IRM and surgical findings in order to identify correlations between demographic data, topographic tumor origin and anatomopathologic characteristics for each subgroup. 35 posterior fosa meningioma patients that have been subject to neurosurgery in Iasi "Prof.Dr. N. Oblu" Hospital Neurosurgery Clinic between January 1st 2005 and December 1st 2009 were assessed. RESULTS: In our study group the majority of patients were females, with an average age in their early 60's. Benign meningiomas (1st degree) represented the unique subtype in tumors located in cerebellum convexity and foramen magnum. Other locations have different characteristic subtypes (fibrous vs. angiomatous meningioma). PMID- 21243805 TI - [Amyand hernia--a rare anatomic and clinical entity diagnosed intraoperatively]. AB - The Amyand hernia is an uncommon variant of the inguinal hernia, rarely recognised before the surgical treatment because of the confusion with a strangled hernia. In spite of this, the clinical presentation seems to follow a well determined pathway, so it is possible to state that the uncorrect diagnosis is to be attributed to the ignorance of this variant of hernia. We present two consecutive case reports of acute appendicitis founded in an inguinal hernia sac. The clinical presentation depended on the inflammation extension inside the hernia sac and the presence or not of peritoneal contamination. The patients were admitted for a painful pseudotumor in the inguinal region with irreducibility, mimicking strangled inguinal hernia with acute inflammatory syndrome. Intraoperatively we have found a hernia sac with a phlegmonous/gangrenous appendix inside. Appendectomy was performed, followed by hernioplasty (retrofunicular technique) without prosthetic material). The operation followings were favorable. We conclude that amyand hernia must be considered as differential diagnosis of apparently strangled inguinal hernias. Technical precautions and antibioprophylaxy applied during surgery may prevent septic complications after hernioplasty. The hernia repair must be performed without prosthetic material and using exclusively resorbable sutures. PMID- 21243806 TI - [PSA as a marker for prostate cancer progression]. AB - Monitoring the evolution of prostate cancer has crucial importance since this tip of neoplasia has a variable biology, ranging from latent cancers to extremely aggressive tumors. At the moment, PSA (prostate specific antigen) values point out to either successful or unsuccessful prostate cancer therapy. Depending on therapeutic strategies, biochemical recurrence (BCR) is differently defined. After radical prostatectomy, the PSA declines to undetectable levels in 3-4 weeks; BCR: PSA = 0.2-0.5 ng/mL for a single measurement or two consecutive values which surpass 0,2-0,4 ng/mL. PSADT < 10 months is a predictor for the progression of the disease. After external beam therapy, PSA is slowly decreasing reaching up the nadir of 0.2-0.5 ng/mL in months or years; BCR: PSA = nadir + 2 ng/mL. In the case of brachytherapy, the nadir is reached in 2-4 years; BCR: nadir + 2 ng/mL. After hormonal therapy, PSA declines in 3-6 months, maintains low values for 18-24 months, then increases, settling for hormone independency. After chemotherapy, PSA is considered normal at values < 2 ng/mL; the response of PSA represents a confirmed decreasing from the second test at 4 or more weeks after the initial decline; the length of the response is the period between first decline with 50 % of PSA to 50 % increase from nadir; the progression of PSA is shown in the increase with 25 % in comparison to the basic level. In the case of active monitoring, a PSADT < 2 years is an indication for radical prostatectomy, but there are cancers which can evoluate despite a stable PSA. The "PSA bounce" phenomenon and the "PSA surge postchimiotherapie" syndrome can complicate the assessment of biochemical recurrence. PMID- 21243807 TI - [Omega-3 fatty acids and acetylcysteine diet supplementation effects on learning performance]. AB - Omega-3 fatty acids are essential for human health, are crucial for the brain, body development and also in prevention of cardiovascular diseases. MATERIAL AND METHOD: We used 60 male Wistar fats, weight 180 +/- 20 grams, divided into two study groups: normal control animals (M) and test animals (T) divided in groups I (N3-PUFA), II (ACC) and III (N3-PUFA and ACC). Administration of the substances was made for 36 weeks (nine months), after which the animals were evaluated and subsequently sacrificed for further biochemical analysis. As an evaluation method has been used multiple T maze labyrinth. RESULTS: Group I recorded a time maze percentage decrease from -4.26% to -33.88%. In group II we recorded a decrease time maze percentage from -5.37% to -34.28%. During the experiment, group III recorded a decrease time maze percentage from -5.1% to -32.33% at the end of the experiment. The control group evolution for the maze recorded a decrease in time maze percentage, reaching 17-18% at the end of the experiment. CONCLUSION: By improving the diet with polyunsaturated fatty acids increased exponentially cognitive performance compared with normal diet, low in these acids. PMID- 21243808 TI - [Histopathologic and immunohistochemic changes in Helicobacter pylori colonised gastric mucosa]. AB - Helicobacter pylori (H. pylori) colonize gastric mucosa causing both inflammatory changes, premalignant lesions and malignant tumors, including gastric lymphoma and carcinoma. In this study, our propose was to evaluate the histopathological changes corellated with immunohistochemical results demonstrating the types of cellular infiltration and proliferative activity of gastric mucosa infected with H. pylori. MATERIAL AND METHOD: Gastric endoscopic examinations was performed in 468 patients with anti-H. pylori antibodies and dispeptic phenomena. Snippets harvested endobiopsic stomach were fixed in formalin and processed by paraffine inclusion. Histological sections were stained with hematoxylin-eosine and Giemsa. In 65 cases of endobiopsic fragments (36 deep chronic gastritis with intestinal metaplasia, glandular atrophy and intraepithelial neoplasia and 29 carcinomas) immunohistochemical reactions were performed by applying reagents for evidence of H. pylori colonies, of T lymphocytes (CD3) and macrophages (CD68) and Ki-67 reagent for proliferating nuclear antigen labelling. RESULTS: Endobiopsic specimen found in all H. pylori or by Giemsa staining or by anti-H. pylori antibodies when they were in small numbers. Histologically, were diagnosed : 463 superficial and deep chronic gastritis associated with premalignant lesions, 29 carcinomas, 2 non-Hodgkin's lymphoma and an adematous polyp. Immunohistochemically, inflammatory infiltrate consisted of numerous T lymphocytes, macrophages and lymphoid follicles. Foveolar cell nuclei, in areas of intraepithelial neoplasia and carcinomatous cells were intensely stained with Ki-67, demonstrating increased proliferation. CONCLUSIONS: In gastric infection with H. pylori, inflammatory infiltrat is composed of abundant macrophages and T lymphocytes. Ki-67 was absent or minimal in chronic gastritis, while in areas of intraepithelial neoplasia was positive in both foveolar and coating epithelium. Anti-H. pylori antibodies in human serum remains one of the simplest methods to detect H. pylori, therefore it plays an important role in practice. Medical eradication of bacteria may cancel inflammatory changes, metaplasia and proliferation of gastric mucosa and thus it prevents the cascade of carcinogenesis. PMID- 21243809 TI - [Immunohistochemic staining for CK5/6 and P63 significance in prostate premalignant lesions and adenocarcinoma]. AB - The morphologic information from usual hematoxiline-eosine staining are sometimes insufficient in certifying or excluding the adenocarcinoma of the prostate, cases who must be study by immunohistochemistry. AIM: The investigation of staining for CK5/6 and P63 in cases diagnosed with prostate adenocarcinoma associated with high grade prostatic intraepithelial neoplasia. MATERIAL AND METHODS: The study was realized on 56 cases analyzed in Pathology Laboratory of Focsani Emergency Hospital. RESULTS: We registered a positive correct diagnosis for atypical adenomatous hyperplasia in 86% of cases and for prostate adenocarcinoma grade 1 in 14% of cases. CONCLUSIONS: CK5/6 and P63 are useful markers for elucidating a positive false diagnosis for prostate adenocarcinoma grade 1. PMID- 21243810 TI - [Evaluation of p16INK4a and Ki-67 proteins expression in cervical intraepithelial neoplasia and their correlation with HPV-HR infection]. AB - OBJECTIVE: The aim of our study was to evaluate the expression of p16INK4A and Ki 67 in cervical intraepithelial neoplasia (CIN) and to correlate the high-risk human papillomavirus (HPV) infection with these two biomarkers. MATERIAL AND METHOD: Sixty patients were included in our study. All of the patient underwent colposcopy-guided biopsy to asses the grade of CIN. For the immunohistochemistry exam we used p161NK4A and Ki-67 antibody and their expression was semiquantitatively classified in 4 classes: 0, 1, 2 and 3. HPV genotyping was used to detect high-risk HPV. RESULTS: 7 of our cases were benign (11.66%); 18 cases presented CIN1 (30%), 14 cases CIN2 (23.33%), 16 cases CIN3 (26.66%) and 5 cases invasive squamous cell carcinoma (8.33%). We observed that the expression of p16INK4A and Ki-67 were positively associated with CIN grade, p161NK4A expressions increased significantly with high-risk HPV infection. We observed a positive correlation between the expression of the p16INK4A and Ki-67. CONCLUSION: In our study, the expression of p16 and Ki-67 were positively related to the CIN grade. p16INK4A expressions of high-risk HPV specimens significantly increased more than Ki-67. Therefore, in the diagnosis of CIN and high-risk HPV infection, p16INK4A can be a useful biomarker. PMID- 21243811 TI - [Research on the incidence and prevalence of congenital abnormalities in Iasi district and Iasi city, from 2001 to 2008]. AB - Congenital abnormalities (CA) are deviations from the normal embryonic development that appear antenatal and they are characterized by the alteration of the morphology and function of an organ, system of organs or even of the entire body. MATERIAL AND METHOD: The study, on a period of eight years, included 1685 children with CA, from which 58% were males and 50% were from the country-side. RESULTS: It has been observed that 36% of the CA cases were premature births and 64% were normal term births. Also, 21% of the children with CA weighed less than 2700 grams at birth and 79% weighed more than 2700 grams at birth. The birth's APGAR score has been less than 7 in 30% of the cases and higher than 7 in 70% of the cases. 72% of the cases were natural births and 28% were caesarian births. 88% of the CA cases were singular congenital abnormalities and 12% were multiple congenital abnormalities. 24% of the CA were cardiac abnormalities and 21% were skeletal abnormalities. 3% of the subjects of the study have died, of which 69% died from cardiac abnormalities, 22% from hydrocephalus abnormalities, 7% from diaphragmatic hernia and 2% from renal congenital abnormalities. PMID- 21243812 TI - [Family income--nutrition correlation in a group of Negresti Vaslui preschool children]. AB - Growth and development are influenced by genetic and environmental factors. From the environmental factors, nutrition plays a key role and is income dependent. OBJECTIVES: Assessing food intake according to family financial status. MATERIAL AND METHOD: A study was conducted on 134 preschool children (ages from 3 to 7 years of age) from a Negresti kindergarten. Questionnaires were filled by parents for weekly food intake and family financial situation. Statistical analysis used Pearson test. RESULTS: According to income the group is structured in: very low income (32.8%), low income (28.3%), average income (26.8%) and above average income (12.1%). The majority of the families provides milk to their children (58.9%), varying from 54.5% (very low income) to 63.1% (low income). Poultry is present in the diet mainly for 2-3 times per week (45.5%) going from 36.8% in low income families to 55.5% in average income families. Daily fruit intake is present in 59.7% of families, varying from 45.4% (very low income) to 68.7% (above average income). Recorded differences have no statistic significance. CONCLUSION: Families income is different but the nutrition provided to children is similar, being strongly influenced by traditional nutritional habits. PMID- 21243813 TI - [Some correlations between nourishment and physical growth. Observation on a group of teenagers from the Campulung Moldovenesc region, Romania]. AB - The raise and growth of children and youth are processes influenced by the action of internal (inheritance) and external factors (environmental). Among the external factors, nourishment plays an essential role. MATERIAL AND METHOD: The study was made on 369 high school students. There has been made an appreciation of height and weight of these students. There has also been made a nutritional survey on groups of food. RESULTS: Height is prevalent high (40.4%) and very high (29.8%) Weight is especially at average (53.8%) and high values (23.1%). The nutritional survey on groups of food shows a raising input of milk, meat (over 100%) at males and females of 11-14 years old, and also of eggs. On the other hand, fish scores a constant shortcoming (-50%). Corny and dried vegetables products are in high quantities whereas the input of fruit is insufficient (over 20%). CONCLUSION: These studies let us know the peculiarities of youth's nourishment, which allow a correct orientation of prevention programs. PMID- 21243814 TI - [Prevalence of tuberculosis in Mures County, Romania, 2006-2008]. AB - The aim of this study is analysis of tuberculosis prevalence in Mures county for a period of three years (2006-2008). MATERIAL AND METHOD: We monitored the prevalence of tuberculosis cases in the Mures area recorded at Tg. Mures TB Dispensary, the new cases and readmitted cases, chronic or abandonment, separately for children and adults, evolving for 2006-2008, data compared with national registration. RESULTS: From 2006 to 2008, frequency of TB illness in our area decreased instead of the share of patients with positive results (BK+) which have increased, associated with an amplified risk. In our study the assessment during the three years showed a decrease of the total number of TB cases, instead of increased frequency of new cases of acute than those of chronic, increased cases of adults against children and cases of failed healing. Number of new cases of TB in Mures urban areas, by years, showed the same decreasing trend for cities monitored, except Tg. Mures where the number of new cases recorded in 2008 was higher than in 2006. CONCLUSION: TB control programs in order to be effective, must be conducted throughout the all country, to be permanent, to the satisfaction of the population and to integrated structure of community health. PMID- 21243815 TI - [Considerations on death by domestic violence in Neamt County, between 1997 2008]. AB - MATERIAL AND METHODS: The study include a series of 132 cases of domestic violence (DV) accounting for 58% of the 228 homicides recorded between 1997 and 2008 in the Neamt county. Data were processed and interpreted based on epidemiological, statistic and mathematical computer-based methods. RESULTS: In 1998, in the Neamt county, 0.69 per thousand homicides were recorded as compared to 2.56 at country level. In 2000, the rate of homicides by DV had significantly increased, reaching 12.3 per thousand, compared to 4.5 per thousand at the national level. The prevalence of homicides by DV, according to environment, gender, age groups and other features is presented. CONCLUSIONS: Domestic violence is hard to control, this phenomenon being uncommon to Romanian society, but represents a major social and public health problem. PMID- 21243816 TI - [Some aspects regarding occupational health in small and middle enterprises]. AB - The objective of the study was to assess occupational health services in small and medium enterprises (SME's) in Bacau, between 2007 and 2008, in order to increase the quality of services' management. MATERIAL AND METHOD: Five hundred seventy nine SME's with 21,815 employees have been studied, with a number of employees varying from ten to 250 per enterprise. About 4478 employees, out of which 587 with different occupational exposures, have no occupational health services provided on a contract basis. RESULTS: The high number of occupational diseases and work related accidents in SME's show a low level of concern for occupational health and safety matters, compared to big enterprises. The employees' opinions showed that the role of occupational health is not known, there is no concern for the medical adaptation of new employees or old employees rehired after a long break, the employees do not consult occupational health services on their own accord. The occupational services do not fully satisfy the need. The study offers useful data to physicians and SME's management in order to improve the occupational health management. PMID- 21243817 TI - [Early childhood caries. Epidemiological considerations]. AB - AIM: To asses the current demographic tendencies of the carioactivity, in Iasi area, especially ECC and S-ECC. MATERIAL AND METHODS: Study group included 500 subjects (276 girls and 224 boys), 3-6 years of age, 70% urban and 30% rural. The oro-dental evaluation was achieved through clinical investigation, based on criteria and markers recommended by WHO, the estimation of the indices of the caries prevalence: caod, cao, SIC, ICDAS, psychological assessment and sociological investigation using interviews and questionnaires. Recorded data were used for statistical analysis in SPSS 17 trial, in visual FOX-PRO9. RESULTS: The hole assessment showed a low caries risk (83.3%), compared to the values of the medium caries risk (9.2%), and of the high caries risk (7.5%). In term of clinic variability, the normal carial pattern is frequent, followed by atypical carial patterns, ECC and S-ECC, with differences between genders (boys - 1.91, girls - 1.99). In relation to the socio-economic level of the family, the cao index varies: cao-1--high socio-economic level, cao-1.46--medium socio-economic level, cao2.87--low socio-economic level. CONCLUSIONS: The values of the epidemiologic indices, showed a variability of the carioactivity of the temporary dentition, with growth of the atipical carial patterns, ECC and SECC. The above mentioned aspects require to reconsider the view points on temporary dentition and the promotion of an educational and prevention programme. PMID- 21243818 TI - [Clinical study on the distribution of tooth wear of the adult population]. AB - Tooth wear is becoming increasingly significant in the developed societies, because the etiological factors are frequently present in the daily life. The aim of this study was to assess the distribution of the tooth wear of the adult population in a private practice of dentistry. MATERIAL AND METHOD: The group of study had 614 patients, structured on the following subgroups of age: 18- 30 years, 31-40, 41-50, 51-65 and more than 65 years old. Each patient had a clinical exam and a questionnaire for the diet and the lifestyle, spotlighting the etiology of tooth wear. RESULTS: attrition was the most frequent (55.7%), followed by abrasion (32.7%), erosion affected 7.5% of the patients and abfractions are the least frequent (4.1%). Erosions (9.7%) and attritions (59.9%) are more frequent at the feminine gender, and abrasions (40.4%) at the masculine gender. More than half of the abfractions (56%) were found at the youth patients (18-30 years old). Erosions were found in the 31-40 years subgroup at almost 40% of the patients; in the 41-50 years subgroup, abrasion and erosion were found in equal proportions. Abrasion prevails at the 51-65 years subgroup (30.8%). 72% of the consumers of acidic fruits had dental erosions. CONCLUSION: Tooth wear is under the influence of the diet and the age factor. PMID- 21243819 TI - [Clinical evaluation of the possibilities of restoring the dental and periodontal esthetics using veneers vs. metal ceramic crowns]. AB - Achiving the esthetic balance is one of the most important aims of the restorations used for the anterior area of the dental arches. AIM: To evaluate the possibilities of veneers and metal ceramic crowns to restore dental and periodontal esthetics. MATERIAL AND METHOD: We have evaluated 90 restorations, 40 veneers and 50 metal ceramic crowns, analysing the following parametres: gingival index, bleeding index, plaque index, also restorations margins index, presence/absence of secondary decays, marginal integrity index and the aspect of the restorations surfaces. The study also evaluates patient satisfaction using questionares. RESULTS: Even the veneers seem to be more indicated to restore dental and periodontal esthetics, the esthetic outcome depends mainly on the way the clinician evaluates and manages the tissues and less on the technique used (all ceramic or metal ceramic). PMID- 21243820 TI - [Ozone therapy efficiency and gerovital H3 as an additional way to the complex treatment of periodontal disease]. AB - The authors present the methodology of the ozone use and a method of chemical stimulation with Gerovital H3, applied within a complex therapy of the periodontal disease. Its efficiency is argued by the clinical images taken from the oral cavity and radiographic images of the patients with periodontal disease in various evolution stages. RESULTS: The images reveal the possibility of stopping the progressive disease and the improvement of the clinical aspect of the marginal periodontium. The X-ray images reveal the possibility of re mineralization of the alveolar bone and healing processes in certain areas, at different periods of time. CONCLUSIONS: Favorable results are associated firstly with compliant patients that benefit of treatment planning elaborated after a correct evaluation of the clinical situation. The results prove the strong oxidant and antibacterial effects of ozone as well as the regenerative and biotrophic action of Gerovital H3 in periodontal tissues for patients with early and advanced periodontal disease. PMID- 21243821 TI - [Research regarding extended-spectrum beta-lactamases produced by enterobacteria strains]. AB - AIM: To evaluate the susceptiblity of extended spectrum beta-lactamase (ESBL) producing organisms among Escherichia coli and Klebsiella pneumoniae, isolated between January-October 2009 from hospital and community. MATERIALS AND METHODS: From 611 enterobacteria strains, for 112 strains (E. coli, n = 84 and K. pneumoniae, n = 28), the ESBL phenotypic confirmation was performed with double disk test (DDT) and the replacement disk method. The minimum inhibitory concentrations (MICs) for next antimicrobial agents tested: ceftazidime, cefotaxime, ceftriaxone, cefepime, cefpirome, imipenem, meropenem, ertapenem, moxifloxacin, gatifloxacin, levofloxacin, ofloxacin were performed by agar dilution method. Resistance rates were reported using the Clinical Laboratory Standard Institute (CLSI) breakpoints for the fully susceptible category; moderately susceptible isolates were classified as resistant. K. pneumoniae ATCC 700603 and E. coli ATCC 25922 were used for quality control. RESULTS: Resistance rates for ceftazidime, cefotaxime, ceftriaxone and aztreonam among tested strains were very high: 84.5%, 100%, 100% and 96.4% for E. coli and 98.8%, 98.8%, 97.6% and 89.2% for K. pneumoniae, with the MIC90 values > 256 mg/L for either antimicrobial tested agent. The MICs for fourth generation cephalosporins ranges from 4 mg/L to 512 mg/L. The MICs for tested quinolones were > 2 mg/L for 89.2% strains. Using breakpoint for susceptibility, all isolates were sensitive to ertapenem, imipenem and meropenem. CONCLUSIONS: We noticed a high resistance rate for ceftazidime, cefotaxime, ceftriaxone and aztreonam. In this study, carbapenems demonstrated the highest degree of activity. PMID- 21243822 TI - [Construction and characterization of a selective membrane electrode for tenoxicam determination]. AB - This paper describes the construction and characterization of a selective membrane electrode which can be used for determination of tenoxicam. MATERIAL AND METHOD: The electroactive compound is a precipitate obtained in 2 N hydrocloric acid solution containing tenoxicam in which a solution of iodine is added. The membrane is made by mixing the electroactive compound with polyethylene using tetrahydrofurane as solvent. The solution is evaporated in order to obtain a thick membrane, which is attached at one end of a PVC tube and is fixed with the same polymeric solution. In this tube an internal Ag/AgCl reference electrode is inserted. The assembly is filled with an internal solution containing tenoxicam. The electrode was characterized (electrode slope, selectivity, optimal pH range, response time, life time). The developed method was validated. RESULTS: The method showed a good liniarity in the range of 10(-6)-10(-1) M (the correlation coefficient r = 0.9999). The detection limit (LD) was 7.347 x 10(-7) M and the quantification limit (LQ) was 1.017 x 10(-6) M. There were established the precision (RSD = 1.79%) and the accuracy (mean recovery is 100.17%) CONCLUSIONS: The experimental results demonstrated a good sensibility. PMID- 21243823 TI - [Selective separation of vitamin C and 2-ketogluconic acid by facilitated pertraction]. AB - The removal of vitamin C from a mixture with 2-ketogluconic acid by using a bulk liquid membrane (BLM) has been investigated. The studies on facilitated pertraction of vitamin C with Amberlite LA-2 indicated the major parameters that affect the separation efficiency: pH gradient between the two aqueous phases, carrier concentration in the liquid membrane and phase mixing intensity. The overall results obtained in this work showed that liquid membrane system can effectively be used to selectively separate vitamin C from its mixture with the fermentation by-product, 2-ketogluconic acid. PMID- 21243824 TI - [Study of bioelectrical properties of acupuncture areas]. AB - The research has as a goal the investigation of the bioelectrical behaviour of the acupunctural areas in order to obtain a scientific substantiation of the correspondence between the extreme--eastern medical tradition and the academical medicine. It is obvious that the Chinese traditional medicine knows a certain mechanism of ensurance of homeostasis of the organisms, a mechanism represented, according to the Chinese medical tradition, by the net of acupuncture points and meridians. The experimental data presented in this paper lead to the discovery of the fact that this net works as the fourth system of integration, the electrical- regulator one. The maintenance of the internal homeostasis of the superior organisms and their adaptation to the environment is ensured by the neuro endocrine and circulatory systems through a mechanism described by Selye under the name of the Uncertain General Syndrome of Adaptation represented by the hypothalamo-hypophyso-corticoadrenal axis. The evolution of these systems and of their mechanisms can be supervised on the basis of the cortisole concentration. The research emphasized the direct proportionality between the cortisone levels and the variation of the electrical values of the acupuncture points, a fact that demonstrates the involvement of the net of acupuncture points and meridians in the maintenance processes of the homeostasis, control, adjustment and adaptation of the living organisms. Additionally, the analysis of the bioelectrical behavior of the acupuncture areas led to the conclusion that the morpho-functional substrate of this net is the conjunctive tissue. The physical-chemical properties of the interstitial connective tissue assures its working as an electro-regulator system on one side and as a harmonization agent of the neuro-endocrine and circulatory systems on the other side, this aspect being to be developed in a future paper. PMID- 21243825 TI - [The body as source of significance. Interdisciplinary perspectives]. AB - This paper concerns a general theoretical aspect, followed by different examples which discusses the thesis in relation to major connected domains of research: psychology and philosophy. The thesis which we are arguing for is that the body represents a source of significance in the definitions of he self used as theoretical background in moral problems (philosophical aspect) and the explanations of the way the image of the self is constituted (psychological aspect). The philosophical "conclusion" is that the body, in its materiality, cannot be judged by the metaphysical dualism scheme, which assigns it a secondary role in the hierarchy of categories. From a psychological point of view, this paper tends to show that the body does not represent an accident of personality or a "prison of the soul" as Plato refers to it, but rather an element through which personality is built on and develops and similarly, the mental and personality structures are those which allow the forming of corporeality and then the person's reference to it. PMID- 21243826 TI - [Excision of thymoma and the thymus, combined removal of the left brachiocephalic vain, excision and reconstruction of the pericardium and removal of the left upper lobe in a patient with infiltrative thymoma combined with cardiac tamponade]. PMID- 21243828 TI - Alienation, authenticity and the self. AB - While many commentators have held that the concept "alienation" is of crucial importance when attempting to understand human existence, others have held that it is an inherently empty concept that we should abandon. In this article, I refute the latters' charge by showing that each conception of "alienation" is underpinned by a normative ontological conception of the preferable, or authentic, self and show that the concept "alienation" has ethical, existential and socio-political uses. From this I conclude that, when properly understood, the concept "alienation" can provide us with vital insights into human existence. PMID- 21243827 TI - WHO external quality assessment for detecting influenza A virus using polymerase chain reaction - summary, 2010. PMID- 21243829 TI - Birth of a brain disease: science, the state and addiction neuropolitics. AB - This article critically interrogates contemporary forms of addiction medicine that are portrayed by policy-makers as providing a "rational" or politically neutral approach to dealing with drug use and related social problems. In particular, it examines the historical origins of the biological facts that are today understood to provide a foundation for contemporary understandings of addiction as a "disease of the brain." Drawing upon classic and contemporary work on "styles of thought," it documents how, in the period between the mid-1960s and the mid 1970s, such facts emerged in relation to new neurobiological styles of explaining and managing social problems associated with drug abuse, and an alliance between a relatively marginal group of researchers and American policy makers who were launching the "War on Drugs." Beyond illustrating the political and material conditions necessary for the rise of addiction neuroscience, the article highlights the productivity of neurobiological thought styles, by focusing on the new biological objects, treatments and hopes that have emerged within the field of addiction studies over the last several decades. PMID- 21243830 TI - [Imaging diagnosis Q & A. Bone aneurysmal bone cyst originating in the rib or thoracic wall tumor originating from the rib, costal cartilage or the surrounding soft tissue]. PMID- 21243831 TI - Bone Workshops Davos 2006. Abstracts from the workshops: Frontiers of Skeletal Biology and What is New in Bisphosphonates?; the Eleventh and Valedictory Workshop on Cell Biology of Bone and Cartilage in Health and Disease; and the Eighth and Valedictory Workshop on Bisphosphonates -From the Laboratory to the Patient. Davos, Switzerland. March 2006. PMID- 21243832 TI - Evidence-based clinical recommendations regarding fluoride intake from reconstituted infant formula and enamel fluorosis: a report of the American Dental Association Council on Scientific Affairs. AB - BACKGROUND: This article presents evidence-based clinical recommendations regarding the intake of fluoride from reconstituted infant formula and its potential association with enamel fluorosis. The recommendations were developed by an expert panel convened by the American Dental Association (ADA) Council on Scientific Affairs (CSA). The panel addressed the following question: Is consumption of infant formula reconstituted with water that contains various concentrations of fluoride by infants from birth to age 12 months associated with an increased risk of developing enamel fluorosis in the permanent dentition? TYPES OF STUDIES REVIEWED: A panel of experts convened by the ADA CSA, in collaboration with staff of the ADA Center for Evidence-based Dentistry (CEBD), conducted a MEDLINE search to identify systematic reviews and clinical studies published since the systematic reviews were conducted that addressed the review question. RESULTS: CEBD staff identified one systematic review and two clinical studies. The panel reviewed this evidence to develop recommendations. CLINICAL IMPLICATIONS: The panel suggested that when dentists advise parents and caregivers of infants who consume powdered or liquid concentrate infant formula as the main source of nutrition, they can suggest the continued use of powdered or liquid concentrate infant formulas reconstituted with optimally fluoridated drinking water while being cognizant of the potential risks of enamel fluorosis development. These recommendations are presented as a resource to be considered in the clinical decision-making process. As part of the evidence-based approach to care, these clinical recommendations should be integrated with the practitioner's professional judgment and the patient's needs and preferences. PMID- 21243833 TI - Alzheimer's disease: future treatments. PMID- 21243834 TI - Rehabilitation. PMID- 21243835 TI - Glycemic targets for elderly diabetic patients need reappraisal. PMID- 21243836 TI - Collaborative and supervisory relationships between attending physicians and advanced practice nurses in long-term care facilities. AB - Recent years have seen an increased interest and use of advanced practice nurses in long-term care. Models of best practices of supervision and collaboration have been promulgated by many organizations, but none have specifically addressed how these interactions should occur in the nursing home setting. To better define the role of the attending physician and advanced practice nurses to provide optimal resident care, the American Medical Directors Association formed a work group to address collaborative and supervisory relationships in long-term care facilities. PMID- 21243838 TI - [On reading "the number of public health clinics and their activities based on the reports on the management of these clinics, regional public health and the activities in geriatric health services"]. PMID- 21243837 TI - Freethought, free love and feminism: secularist debates on marriage and sexual morality, England c. 1850-1885. AB - This article examines the previously unexplored current of Freethinking feminism in the second half of the nineteenth century. Active in the women's movement of this period, Freethinking feminists were nonetheless viewed as a liability-an attitude that contributed to their exclusion from much of the subsequent historiography. Such marginalisation was due not only to their vocal opposition to all forms of religion, but also their openness to discussing new ways of organising heterosexual relationships. This article focuses on Freethinking feminist critiques of marriage and support for free unions. It demonstrates that these issues continued to be debated in the Secularist movement at a time when many other radical organisations-including much of the women's movement-kept silent on such topics. In this way, Freethinking feminists kept alive the more radical and libertarian critiques of traditional sexual morality developed by Owenite feminists in the 1830s and 40s. The author argues that the ideology of Freethought propelled its adherents to readdress questions of sex within a new 'Secularist' ethical framework. Fierce debate ensued, yet commitment to freedom of discussion ensured that 'unrespectable', libertarian voices were never entirely silenced. Freethinking feminism might, then, be viewed as the 'missing link' between early nineteenth-century feminist visions of greater sexual freedom and the more radical discussions of sexuality and free love that began to emerge at the fin de sicle. PMID- 21243839 TI - [Overview of the study of public health nursing as basis for the training leading to the national licensure]. PMID- 21243841 TI - [A committee report on public health nursing: a satellite symposium.(5) Public health nurses facing new objectives of the society]. PMID- 21243840 TI - [Socially deciding factor of health (7). Cancer and socioeconomic positions]. PMID- 21243842 TI - [Diagnostic procedures such as those using DSM-IV that are available even to judges]. PMID- 21243843 TI - [The future of psychiatric societies. Discussion. Part 2]. PMID- 21243844 TI - [The frontier of biological understanding of mood disorders]. PMID- 21243845 TI - [Mechanism for new treatment of depressive diseases with a focus on glia cells- from a glia hypothesis of mood disorders to drug designing]. PMID- 21243846 TI - Preserving human potential as freedom: a framework for regulating epigenetic harms. AB - Epigenetics is a rapidly evolving scientific field of inquiry examining how a wide range of environmental, social, and nutritional exposures can dramatically control how genes are expressed without changing the underlying DNA. Research has demonstrated that epigenetics plays a large role in human development and in disease causation. In a sense, epigenetics blurs the distinction between "nature" and "nurture" as experiences (nurture) become a part of intrinsic biology (nature). Remarkably, some epigenetic modifications are durable across generations, meaning that exposures from our grandparents' generation might affect our health now, even if we have not experienced the same exposures. In the same vein, current exposures could affect the health of not only individuals currently living but also future generations. Given the relative novelty of epigenetics research and the multifactorial nature of human development and disease causation, it is unlikely that conclusive proof can be established showing that particular exposures lead to epigenetic risks that manifest into specific conditions. Using the Capabilities Approach ("CA") developed by Amartya Sen and Martha Nussbaum, this article argues that epigenetic risk is not merely a medical issue, but that it more generally implicates the underlying fairness and justice of our social contract. For instance, how we develop mentally or physically has a tremendous impact upon our inherent capabilities and our set of life options. The CA prompts us to ask questions such as: (1) what impact do particular epigenetic risks have on our ability to exercise free choices; (2) are these risks avoidable; and (3) how are these risks distributed across society? Due to the complex nature of epigenetic risk, tort law is predictably incapable of addressing this harm. Further, while regulatory agencies possess the statutory authority to begin addressing epigenetic harms, currently these agencies are not attuned to measure or to respond to this type of harm. This article argues that it is imperative to initiate a regulatory framework to address epigenetic risk from specific substances even if conclusive proof of disease causation cannot be established. Shifting the burden of generating epigenetic risk data to producers of suspected harmful substances serves as a start. As information concerning epigenetic risks accrues, the regulatory response should evolve concurrently. As part of a dynamic policy-making approach our goals need to encompass the following: (i) promotion of knowledge in the scientific, legal, and public domains; (ii) assessment and modification of current regulations to address preventable risk; and (iii) an overarching commitment to protect human capabilities in an equitable manner. PMID- 21243847 TI - Enabling responsible public genomics. AB - As scientific understandings of genetics advance, researchers require increasingly rich datasets that combine genomic data from large numbers of individuals with medical and other personal information. Linking individuals' genetic data and personal information precludes anonymity and produces medically significant information--a result not contemplated by the established legal and ethical conventions governing human genomic research. To pursue the next generation of human genomic research and commerce in a responsible fashion, scientists, lawyers, and regulators must address substantial new issues, including researchers' duties with respect to clinically significant data, the challenges to privacy presented by genomic data, the boundary between genomic research and commerce, and the practice of medicine. This Article presents a new model for understanding and addressing these new challenges--a "public genomics" premised on the idea that ethically, legally, and socially responsible genomics research requires openness, not privacy, as its organizing principle. Responsible public genomics combines the data contributed by informed and fully consenting information altruists and the research potential of rich datasets in a genomic commons that is freely and globally available. This Article examines the risks and benefits of this public genomics model in the context of an ambitious genetic research project currently under way--the Personal Genome Project. This Article also (i) demonstrates that large-scale genomic projects are desirable, (ii) evaluates the risks and challenges presented by public genomics research, and (iii) determines that the current legal and regulatory regimes restrict beneficial and responsible scientific inquiry while failing to adequately protect participants. The Article concludes by proposing a modified normative and legal framework that embraces and enables a future of responsible public genomics. PMID- 21243848 TI - Confidentiality of alcohol and other drug abuse treatment information for emergency department and trauma center patients. PMID- 21243849 TI - My health policy nightmare. AB - Imagine that the United States did not have universal public education. What would the politics of extending access to education look like? It might have a nightmarish cast but also look rather familiar. Thinking about that yields some disturbing implications about the politics of health reform and, in particular, the politics of universal coverage within the broader policy discussion about "health reform." PMID- 21243850 TI - Never say never: "never events" in Medicare. PMID- 21243851 TI - Minute medicine: examining retail clinic legal issues and legislative challenges. PMID- 21243852 TI - Clinico-pathological review of malignant gastric tumours in Lagos, Nigeria. AB - BACKGROUND: Gastric cancer is one of the most common cancers and the 2d most common cause of cancer deaths worldwide. Contrary to earlier reports from Africa, prevalence of this cancer has been found to be comparable to that of other parts of the world. OBJECTIVE: To describe the clinico-pathological features of gastric cancer diagnosed in Lagos and determine the prevalence of H. pylori infection in gastric adenocarcinoma. METHODS: This was a retrospective histopathological study of all gastric cancer seen between 1995 and 2007 in the Morbid Anatomy Department of Lagos University Teaching Hospital as well as two other private histopathology laboratories in Lagos (2002-2007). The blocks and slides of gastric cancer tissue were the materials used for the study. The patients' bio data and relevant clinical details were extracted from the demographic records. RESULTS: There were 105 cases of gastric cancer (M:F = 2:1, mean age-55.3 years), 81% of which occurred above 45 yrs. There were 95 cases (90%) of adenocarcinomas, 8 (7.6%) mesenchymal tumours with one case each of small cell non-Hodgkin's lymphoma and carcinoid tumour. H. pylori was detected in 15.5% of 45 cases of adenocarcinoma with 36% showing evidence of chronic gastritis in adjacent non cancerous gastric tissue. All patients with clinical data had one or more alarm features; most recurring being abdominal fullness, recurrent vomiting, anorexia and weight loss. CONCLUSION: This study suggests that gastric malignancies are not uncommon in Lagos and often manifest with alarm features which should raise a suspicion particularly in our setting with poor diagnostic endoscopic facilities. PMID- 21243853 TI - Biologic, anatomic and clinical considerations in the management of the classic intraosseous ameloblastoma of the jaws. AB - This paper reviews the types of surgical and nonsurgical treatment modalities that have been used to treat the classic intraosseous ameloblastoma of the jaws. The clinical, anatomic and biologic factors that may influence the clinicians' selection of a particular treatment modality were highlighted. Surgeons should be aware of these different modalities if they are to formulate a surgical treatment plan that is individualised to fit different clinical situations. PMID- 21243854 TI - Irrational prescribing of calcium channel blockers for the elderly in health facilities: a qualitative study in four hospitals in Benin City, Nigeria. AB - BACKGROUND: Calcium channel blockers (CCBs) can further depress a failing heart and are not recommended for elderly patients with systolic heart failure (HF). OBJECTIVE: This study conducted in four hospitals in Benin City was undertaken to evaluate rational prescribing of CCBs in hypertensive elderly outpatients. METHODS: Self-administered questionnaire was administered to 161 medical doctors to detect the proportion of physicians who prescribe CCBs to elderly outpatients with systolic HF with or without evaluating the heart status and/or counseling them on the possibility of recognizing the dangerous effect on heart while taking the CCBs. The association between inappropriate prescription of CCBs and sociodemographic variables was determined using logistic regression analysis. RESULTS: Majority (98.7%) of the 150 respondents reported ever treating hypertension in 48.5 +/- 42.3 (range: 2-250) elderly outpatients per month with most evaluating the patients' heart status. CCBs (nifedipine and amlodipine) were often prescribed for systolic HF for the elderly by 34.3% of participants but only 4.7% of them properly counseled the patients. Area of specialization (odds ratio = 1.076), hospital where the doctors worked (OD = 1.080) and status of the doctors were good predictors of CCBs prescription in systolic HF. CONCLUSION: It is concluded that irrational prescribing of CCBs for elderly outpatients is common in the four hospitals studied. This calls for appropriate educational intervention that will improve the knowledge of physicians in Benin City in rational prescribing of drugs for the elderly. PMID- 21243855 TI - Effects of herbal remedies (Agyanom mixture, Bolex bitters and Remedia mixture) on hepatic and renal functions in male rats. AB - BACKGROUND: Many people use herbal remedies for the treatment of a wide range of diseases due to the claims of their efficacies by the manufacturers. However, there is little insight as to the mode of action and possible toxic effects of these popular herbal formulations on organs such as, liver and kidney. OBJECTIVE: Hepatological, histological and renal function tests of Sprague-Dawley albino rats were investigated in order to determine the possible effects on rat kidney and liver following exposure of the physiological system to the processed herbal remedies through oral administration. METHODS: Thirty male Sprague-Dawley rats (120-170g) and divided into 7 groups were employed for this study. Six groups of 4 rats each were orally administered high dose (1.0 ml) and low dose (0.5 ml) of 'Agyanom mixture', 'Bolex bitters' and 'Remedia mixture' respectively for 15 days. The control group consisted of 6 rats given water only after acclimatization for 28 days, with food and water freely available to both groups. The rats were sacrificed, the blood samples were collected through the orbital sinus and cardiac puncture. The liver and kidney tissues for each group were also harvested. Liver and renal function test parameters were analysed. The liver and kidney from the rats were fixed in 10% formol saline and after 72 hours, dehydrated in graded alcohol, cleaned in xylene, and embedded in paraffin. The resulting blocks were sectioned. The sections were randomized and selected sections were stained in haemotoxylin and eosin. The slides were then examined at magnification of x400. RESULTS: There were significant (p < 0.05) differences in the concentrations of serum electrolytes in all the experimental groups compared with control. Na+, K+, HCO3(2-) urea and creatinin levels increased significantly in the experimental groups. Serum alanine amino transferase (ALT), aspartate amino transferase (AST), alkaline phosphatase (ALP), gamma glutamyl transpeptidase activities and bilirubin level were not significantly different (p > or = 0.05) in all the experimental groups compared with control. Histological features of mild to severe tubular necrosis were evident in the kidney tissues of all the experimental groups compared to the control, unlike in the liver tissues. CONCLUSION: Data of the present study indicate that herbal remedies such as 'agyanom mixture', 'bolex bitters' and 'remedia mixture' have adverse effects on the kidney and they might not be safe for human consumption. PMID- 21243857 TI - A two-year audit of thyroid disorders in an urban hospital in Nigeria. AB - BACKGROUND: Thyroid disorders are the second commonly encountered disorders in endocrine clinics and are significant causes of medical morbidity and mortality. It is pertinent to note that in the Nigerian setting, there are challenges of sub optimal investigative and therapeutic facilities especially as concerning thyroid disorders hence there is underreporting of this important group of endocrine disorders from our part of the world. OBJECTIVE: The objective of this audit is to describe the pattern of presentation, investigation, management and outcome of thyroid disorders in patients attending the Lagos State University Teaching Hospital (LASUTH) Endocrine Center. SUBJECTS AND METHODS: This was a retrospective medical record review of patients with thyroid disorders who presented to the out patient department, the Medical and Emergency wards of LASUTH between June 2007-June 2009. The clinical, biochemical, serological and histological parameters were used to characterize the patients. Investigations done, treatment type, complications of thyroid disorders, hospitalization records and outcome of management were all documented. RESULTS: One hundred and seventy patients with thyroid disorders aged between 11 and 70 years were seen during the period under review. The male: female ratio was 1:7. Patients presenting with thyrotoxicosis were 128 in number thus giving an incidence rate per year of 64. Therapeutic options were essentially thionamides, betablockers, steroids, surgery, radioactive iodine (RAI) and thyroxine. The mean (SEM) duration of medication usage was 24.5 and the median medication duration was 24 months. RAI usage was low as its use was documented in 7% of the subjects with thyroid dysfunction. The rate of occurrence of variable glucose intolerance was 28% with frank diabetes mellitus diagnosed in 9% of the cases of hyperthyroidism. Thyroid storm, psychiatric manifestations, thyrocardiac disease and cerebrovascular diseases were indications for hospitalizations. Two deaths were documented and these were due to thyrocardiac disease and thyroid storm. CONCLUSION: RAI usage is underutilized and the thionamides are the main stay of treatment for people presenting with thyrotoxicosis. Given the peculiarities of presentation of thyroid disorders in our practice and the challenges of poor accessibility to diagnostic and therapeutic facilities, it is imperative that management guidelines that take into consideration our resource poor background be set up. PMID- 21243856 TI - Eligibility of Nigerians with type 2 diabetes mellitus for inhaled insulin. AB - BACKGROUND: Parenteral delivery of insulin has been shown to reduce acceptance of insulin as a treatment option in type 2 diabetes mellitus (DM) patients. The advent of inhaled insulin is aimed at circumventing this problem; however inhaled insulin is a treatment option only for DM patients with normal lung function. OBJECTIVE: The study set out to evaluate the forced expiratory volume in the first second in Liters (FEV1) of Nigerians with type 2 DM and thus determine the proportion potentially eligible for inhaled insulin. METHODS: FEV1 was measured in 101 subjects with type 2 DM and 104 age, gender and body mass index matched controls without DM. All subjects were 'never smokers' without any physical condition that could compromise lung function. We then determined the proportion of subjects with FEV1, more than 70% of normal, which defines eligibility for inhaled insulin. RESULTS: On the basis of the mean FEV1 in Liters of matched controls in this study being 2.58+ 0.62, the cot off for minimium FEV1 to qualify for inhaled insulin therapy was determined as 1.80 liters (i.e 70% of 2.58). A total of 83 (84%) of the 101 subjects with type 2 DM had FEV1 >1.8 liters indicative of eligibility for inhaled insulin. Male sex, shorter duration of DM, normal body mass index (BMI) and younger age were associated with eligibility. CONCLUSION: A high proportion of Nigerians with type 2 DM attending tertiary care are eligible for inhaled insulin therapy making it a treatment option. The feasibility of this treatment option in terms of acceptability, affordability, side effect profile and efficacy in blood glucose control in Nigerians is an important research focus. PMID- 21243858 TI - Integrating maternal health services into a health insurance scheme: effect on healthcare delivery. AB - BACKGROUND: Healthcare delivery is a foremost important basic social services. OBJECTIVE: This study reviews the influence of the integration of maternal health services into the Anambra State of Nigeria government-community health care financing scheme on health service delivery at primary health care level in Igboukwu, Aguata Local Government Area of Anambra State, Nigeria. METHODS: A descriptive, cross-sectional study with an intervention component, conducted amongst 120 women of reproductive age group at Obiuno health centre, Igboukwu. RESULTS: Mean age of respondents was 30.5 +/- 6.0 years with majority, 44 (36.7%), in the age range of 26-30 years. Almost half, forty eight (40%), of the participants are of post secondary educational status; 60 (50%) are civil servants. Utilization of maternal health services % antenatal and delivery services, were significantly better at the late intervention period when compared to the early intervention period. Quality of service from clients' perspective also showed significant improvement at the late intervention period. There was an overall greater availability of maternal health service equipments, drugs and consumables, and medical records in the health facility later during the scheme. CONCLUSION: Community based health insurance schemes that focus on maternal health services ensure the provision of adequate funds for maternal health services that cover a great proportion of the rural communities. PMID- 21243859 TI - Knowledge of prostate cancer screening among native African urban population in Nigeria. AB - BACKGROUND: Cancer of the prostate a worldwide public health concern. It is the most commonly diagnosed cancer in men and ranked second as the cause of cancer related deaths. OBJECTIVE: To evaluate the awareness and attitude of the populace to screening for cancer of the prostate. METHODS: It is a cross-sectional study involving 156 respondents. A structured questionnaire detailing the biodata, the knowledge of cancer of prostate, the practice of screening by prostate specific antigen (PSA) estimation and the readiness to undergo screening by the respondent was used to obtain the set-out objectives. RESULTS: A total of 156 respondents completed the questionnaire and forms the basis of further analysis. The mean age of the respondents is 44.15 (+/- 11.9) years. Majority of the respondents were civil servant (51.9%) followed closely by politicians. About 23.1% of them have no formal education while 53.8% have acquired tertiary education. The result shows that 78.8% have never heard any information on cancer of the prostate and only 5.8% have heard about PSA. None of the respondents have ever had PSA test done, even once. Eighty four per cent of the respondents are ready to pay for prostate cancer screening test by PSA assay. CONCLUSION: We conclude that there was remarkable lack of awareness of prostate cancer among the Nigerian native African urban populace. Prostate cancer screening and serum PSA test for screening is globally unknown among them. PMID- 21243860 TI - Earlobe keloids: emerging cosmetic complication of ear-piercing. AB - BACKGROUND: Keloid is not a homogeneous biological entity. The exact pathologic mechanism of the lesion continues to be an enigma for physicians and researchers alike and no specific gene or sets of genes have been identified. The art of body piercing is ancient to people in the developed countries but over years it has rejuvenated to part of their fashion process. Ear-piercing or extra ear-piercing is becoming more rampant among youths in this part of the world, this however have been shown to cause hypertrophic scaring, keloids and its attendant cosmetic problems. OBJECTIVES: The objective of the study was to retrospectively review the number of keloids that were managed by the Division of Plastic and Reconstructive Surgery of University of Ilorin Teaching Hospital, Ilorin, Nigeria, between the period of September 2006 and April 2007. METHODS: We reviewed the number of keloids that were managed in our unit for the period of 8 months. Twenty six (26) patients had enough information for analysis. RESULTS: Fourteen patients (53.9%) had ear-lobe keloids and 11 (42.3%) of the patients developed the keloid from ear-piercing. Majority of the patients had surgical excision with post-operative intralesional triamcenelone as treatment modalities. CONCLUSION: Keloids are more likely to develop when ears are pierced in the susceptible age group. Keloids of the ear are a challenging problem with many treatment modalities advocated. Given the difficulty and cost of treating keloids and other infective complications that may arise from ear-piercing, preventive remains the best approach. PMID- 21243861 TI - Management of priapism: a case report. AB - Priapism is a pathologic condition of persistent penile erection in absence of sexual excitation, is a true erectile disorder. Although it is not common, it carries a major significance as possible complications of the disorder include penile fibrosis and permanent erectile dysfunction. All health care professionals should appreciate the importance of priapism and follow current principles of treatment to avert the complications of priapism PMID- 21243862 TI - Geographic and epidemiologic analysis of the cutaneous Leishmaniasis outbreak in northern Israel, 2000-2003. AB - BACKGROUND: The incidence of cutaneous leishmaniasis in northern Israel began to rise in 2000, peaking at 41.0 per 100,000 in the Kinneret subdistrict during the first half of 2003. OBJECTIVES: To examine the morbidity rates of CL in northern Israel during the period 1999-2003, which would indicate whether new endemic areas were emerging in this district, and to identify suspicious hosts. METHODS: The demographic and epidemiologic data for the reported cases (n=93) were analyzed using the GIS and SPSS software, including mapping habitats of suspicious hosts and localizing sites of infected sand flies. RESULTS: The maximal incidence rate in the district was found in the city Tiberias in 2003: 62.5/100,000 compared to 0-1.5/100,000 in other towns. The cases in Tiberias were concentrated on the peripheral line of two neighborhoods, close to the habitats of the rock hyraxes. Sand flies infected with Leishmania tropica were captured around the residence of those affected. Results of polymerase chain reaction were positive for Leishmania tropica in 14 of 15 tested patients. CONCLUSIONS: A new endemic CL area has emerged in Tiberias. The most suspicious reservoir of the disease is the rock hyrax. PMID- 21243863 TI - Breastfeeding patterns among Ethiopian immigrant mothers, Israel, 2005-2006. AB - BACKGROUND: The rate and duration of breastfeeding in Ethiopia is very high. Factors that could affect breastfeeding among women emigrating to Israel include the desire to adopt "modern" behaviors, the availability of infant formulas, and the greater awareness of AIDS and fear of transmission via breast milk. OBJECTIVES: To examine the rate and duration of breastfeeding among recent Ethiopian immigrants to Israel. METHODS: Using a structured questionnaire we interviewed 93 Ethiopian born mothers of children aged 2 months to 5 years living in northern Israel. RESULTS: Ninety-two percent of the children born in Ethiopia were exclusively breastfed as compared to 76.3% of the Israeli born children, in whom the rate of mixed feeding was 18.3%. Although the duration of breastfeeding of the youngest child was significantly shorter than that of the firstborn (20.1 vs. 24.8 months), it remains much longer than the average duration for native Israeli mothers. No association was seen between breastfeeding rate or duration and the years since immigration, work outside the home or exposure to formula. The women's attitude towards breastfeeding was positive despite the lack of specific knowledge concerning breast milk and infant formulas. CONCLUSIONS: Breastfeeding patterns among Ethiopian women have changed since their immigration to Israel. These changes probably reflect the cultural and societal pressures to acculturate to the mores of the adopted society. Reinforcing traditional family and peer support for these women is important to preserve breastfeeding in this population. This should be done within the context of changes that support breastfeeding in Israeli society. PMID- 21243864 TI - Step-and-Shoot: a new low radiation coronary computed tomography angiography technology: our initial experience with 125 consecutive asymptomatic patients. AB - BACKGROUND: Coronary CTangiography is an accurate imaging modality; however, its main drawback is the radiation dose. A new technology, the "step and shoot," which reduces the radiation up to one-eighth, is now available. OBJECTIVES: To assess our initial experience using the "step-and-shoot" technology for various vascular pathologies. METHODS: During a 10 month period 125 consecutive asymptomatic patients (111 men and 14 women aged 25-82, average age 54.9 years) with various clinical indications that were appropriate for step-and-shoot CCTA (regular heart rate < 65 beats/minute and body weight < 115 kg) were scanned with a 64-slice multidetector computed tomography Brilliance scanner (Philips, USA). The preparation protocol for the scan was the same as for regular coronary CTA. All examinations were interpreted by at least one experienced radiologist and one experienced interventional cardiologist. The quality of the examinations was graded from 1 (excellent imaging quality of all coronary segments) to 4 (poor quality, not diagnostic). There were 99 patients without a history of coronary intervention, 13 after coronary stent deployment (19 stents) and 3 after coronary artery bypass graft. RESULTS: Coronary interpretation was obtained in 122 examinations (97.6%). The imaging quality obtained was as follows: 103 patients scored 1 (82.4%), 15 scored 2 (12%), 4 scored 3 (3.2%) and 3 scored 4 (2.4%). The grades were unrelated to cardiac history or type of previous examinations. Poor image quality occurred because of sudden heart rate acceleration during the scan (one patient), movement and respiration (one patient), and arrhythmia and poor scan timing (in one). Two patients were referred to percutaneous coronary intervention based on the CCTA findings, which correlated perfectly. CONCLUSIONS: Step-and-shoot CCTA is a reliable technique and CCTA algorithm comparable to regular CCTA. This technique requires the lowest radiation dose, as compared to other coronary imaging modalities, that can be used for all CCTA indications based on the inclusion criteria of low (> 65 bpm) and stable heart rate. PMID- 21243865 TI - Clinical and electrophysiologic outcomes of patients undergoing percutaneous endocardial ablation of scar-related ventricular tachycardia: a single-center experience. AB - BACKGROUND: For patients with ventricular tachyarrhythmias, implantable cardioverter defibrillators are a mainstay of therapy to prevent sudden death. However, ICD shocks are painful, can result in clinical depression, and do not offer complete protection against death from arrhythmia. Radiofrequency catheter ablation of ventricular tachycardia in the setting of ischemic cardiomyopathy has emerged recently as a useful adjunctive therapy to ICD. OBJECTIVES: To assess the feasibility, safety and efficacy of our initial experience in ablation of scar related VT. METHODS: Eleven patients (all males, mean age 71 +/- 8 years) with drug-refractory ischemic VT were referred to our center for scar mapping and ablation procedures using the CARTO navigation system. RESULTS: Eleven clinical VTs (mean cycle length 436 +/- 93 ms) were induced in all patients. An endocardial circuit, identified by activation, entrainment and/or pace mapping, was found in eight patients with stable VT. These patients were mapped and ablated during VT. Three patients had predominantly unstable VT and linear ablation lesions were performed during sinus rhythm. Acute success, defined as termination of VT and/or non-inducibility during programmed electrical stimulation, was found in 9 patients (82%). During followup, a significant reduction in tachyarrythmia burden was observed in all patients who had successful initial ablation, except for one who had recurrence of VT 2 days after the procedure and died 2 weeks later. CONCLUSIONS: Ablation of ischemic VT using electroanatomic scar mapping is feasible, has an acceptable success rate and should be offered for ischemic patients with recurrent uncontrolled VT. PMID- 21243866 TI - Ischemic stroke due to acute basilar artery occlusion: proportion and outcomes. AB - BACKGROUND: Multiple case series, mostly highly selected, have demonstrated a very high mortality following acute basilar artery occlusion. The more widespread availability and use of non-invasive vascular imaging over recent years has increased the rate of ABAO diagnosis. OBJECTIVES: To estimate the proportion of diagnosed ABAO among all-cause ischemic stroke in an era of increasing use of non invasive vascular imaging and to compare the characteristics and outcomes between these two groups. METHODS: We compared 27 consecutive cases of ABAO identified in a university hospital between 2003 and 2007 with 311 unselected cases of ischemic stroke from two 4 month surveys. RESULTS: ABAO diagnosis increased from 0.3% of all-cause ischemic stroke (2003-2004) to 1.1% (2007), reflecting the increased use of non-invasive vascular imaging. In comparison to all-cause ischemic stroke, ABAO patients were younger (mean age 60 vs. 71 years), were more likely to be male (89% vs. 60%), had less atrial fibrillation (7% vs. 26%), more severe strokes (baseline NIHSS over 20: 52% vs. 12%), higher admission white cell count (12,000 vs. 9000 cells/ mm3), lower admission systolic blood pressure (140 +/- 24 vs. 153 +/- 27 mmHg), higher in-hospital mortality rates (30% vs. 8%) and worse functional outcome (modified Rankin scale < or = 3, 22% vs. 56%) (P< 0.05 for all). Rates of reperfusion therapy for ABAO increased from 0 in 2003-2004 to 60% in 2007. CONCLUSIONS: In this study, ABAO patients represented approximately 1% of all-cause ischemic stroke and were about a decade younger than patients with all-cause ischemic stroke. We report a lower ABAO mortality compared to previous more selected case series; however, most survivors had a poor functional outcome. Given the marked clinical heterogeneity of ABAO, a low threshold for non-invasive vascular imaging with a view to definitive reperfusion treatment is needed. PMID- 21243867 TI - Retrospective cohort study of a new infant formula during the first 6 months of life: reflections on growth curves, human milk and formula feeding. AB - BACKGROUND: Optimil is an infant formula, manufactured in Israel and introduced to the market in May 2008. OBJECTIVES: To assess the effect of this formula on infant growth. METHOD: The study group comprised 52 infants who for the first 6 months of life consumed Optimil, which constituted at least 25% of their total daily intake. Anthropometric data were collected from the records of the well baby clinics. Weight, length and head circumference at baseline and 3 months thereafter were converted to gender and age-matched standard deviation Z-scores. As an exploratory uncontrolled analysis, questionnaires were sent to the caregivers to assess satisfaction with the formula and to note the rate of constipation, irritability and vomiting as well as apparent palatability. RESULTS: The baseline Z-scores of all three parameters were below zero but increased significantly after 3 months (-0.2 +/- 0.88 to 0.12 +/- 0.88, P= 0.013 for weight; -0.44 +/- 0.87 to 0.10 +/- 0.72, P< 0.001 for length; and -0.58 +/- 0.78 to -0.1 +/- 0.76, P< 0.001 for head circumference). There was a significant dose-response effect of the formula with weight gain. The formula was generally well accepted, with 8% constipation, 8% vomiting and 6% significant irritability. CONCLUSIONS: This study provides the first evidence that infants consuming Optimil under age 6 months have adequate growth. Nonetheless, breastfeeding during this period should be preferred in almost all cases. PMID- 21243868 TI - A retrospective study of the eligibility for tonsillectomy. AB - BACKGROUND: The criteria for tonsillectomy for recurrent tonsillitis were established by prospective studies in the pediatric population and are applied to adults as well. No studies have been conducted to assess whether these guidelines are followed. OBJECTIVES: To examine the eligibility for tonsillectomy of tonsillectomized patients who were referred because of recurrent acute tonsillitis. METHODS: A retrospective case series in an ambulatory military otolaryngology clinic was conducted, and the medical records of 44 tonsillectomized patients who suffered from throat infections during the year before surgery were analyzed. The number of tonsillar infections that met the referral criteria was counted. RESULTS: The average number of throat infections that met the referral criteria was 1.89 per year. The average number of visits to the clinic due to upper respiratory tract infection was 12.92 (range 2-36) per year. The average number of visits for any cause was 45.13 (range 6-64) per year. One patient with eight documented throat infections met the criterion of more than six infections in the last year. CONCLUSION: Although the referral criteria were not strictly met, we speculate that surgery was probably beneficial. This study shows that the indications for tonsillectomy referral are not strictly followed, and that new criteria for referral of adults for tonsillectomy need to be established. PMID- 21243869 TI - Soy allergy following early soy feeding in neonates. AB - B ACKGROUND:Feeding neonates with humanized milk formula in maternity hospitals may increase the prevalence of milk allergy in infants. However, prospective studies of the possible allergenic effect of very early soy-based formula feeding are lacking. OBJECTIVES: To assess the prevalence of soy allergy in infants fed soy-based formula in the first 3 days of life. METHODS: The study group included 982 healthy full-term infants born within a 7 month period at a hospital that routinely uses soy-based formula to supplement breastfeeding. In-hospital feeding was recorded and the parents were interviewed once monthly over the next 6 months regarding feeding practices and clinical symptoms suggesting soy allergy in the infant. RESULTS: Ninety-nine percent of the infants received soy-based formula supplement in hospital, and 33%-42% at home. No cases of immediate allergic reaction to soy or soy-induced enterocolitis were reported. CONCLUSIONS: The use of soy-based formula in the early neonatal period does not apparently increase the prevalence of soy allergy in infants followed for the next 6 months. PMID- 21243870 TI - Transjugular intrahepatic portosystemic shunt: current indications, patient selection and results. AB - BACKGROUND: Inserting a transjugular intrahepatic portosystemic shunt by means of interventional radiology has become the procedure of choice for decompression of portal hypertension. The indications and criteria for patient selection have been expanded and refined accordingly. OBJECTIVES: To review our experience with TIPS and analyze the results with emphasis on patient selection and indication (conventional vs. atypical). METHODS: In this retrospective analysis in a single center all cases were managed by a multidisciplinary team (comprising liver surgery and transplantation, hepatology, imaging, interventional radiology and intensive care). RESULTS: Between August 2003 and December 2009, 34 patients (mean age 51, range 27-76 years) were treated with TIPS. The cause of portal hypertension was cirrhosis (23 cases), hypercoagulability complicated by Budd Chiari syndrome (n=6), and acute portal vein thrombosis (n=5). Clinical indications for TIPS included treatment or secondary prevention of variceal bleeding (10 cases), refractory ascites (n=18), mesenteric ischemia due to acute portal vein thrombosis (n=5), and acute liver failure (n=1). TIPS was urgent in 18 cases (53%) and elective in 16. Three deaths occurred following urgent TIPS. The overall related complication rate was 32%: trasient encephalopathy (6 cases), ischemic hepatitis (n=2), acute renal failure (n=2) and bleeding (n=1). Long-term results of TIPS were defined as good in 25 cases (73%), fair in 4 (12%) and failure in 5 (15%). In three of five patients with mesenteric ischemia following acute portal vein thrombosis, surgery was obviated. Revision of TIPS due to stenosis or thrombosis was needed in 7 cases (20%). CONCLUSIONS: TIPS is safe and effective. While its benefit for patients with portal hypertension is clear, the role of TIPS in treatment of portal-mesenteric venous thrombosis needs further evaluation. Patient selection, establishing the indication and performing TIPS should be done by a multidisciplinary dedicated team. PMID- 21243871 TI - Comparative efficacy analysis of an aspiration device before primary angioplasty in patients with acute myocardial infarction: a single-center experience. AB - BACKGROUND: ST-elevation myocardial infarction is caused by occlusive coronary thrombosis where antecedent plaque disruption occurs. When treating STEMI the main goal is to achieve prompt reperfusion of the infarction area. Several studies have demonstrated the efficacy of an aspiration device before percutaneous coronary intervention in patients with acute myocardial infarction. OBJECTIVES: To determine the added value of thrombus aspiration prior to primary PCI by comparing AMI patients with totally occluded infarct-related artery treated with routine primary PCI to those treated with extraction device prior to primary PCI. METHODS: The study group comprised 122 consecutive patients with AMI and a totally occluded infarct artery (TIMI flow 0) who underwent primary PCI. The patients were divided into two groups: 68 who underwent primary PCI only (control group) and 54 who underwent primary thrombus extraction with an extraction device before PCI (extraction group). Baseline clinical and lesion characteristics were similar in both groups. Final TIMI grade flow and myocardial blush as well as 1 year mortality, target lesion revascularization, recurrent myocardial infarction, unstable angina and stroke were compared between the two groups. RESULTS: Primary angiographic results were better for the extraction group versus the control group: final grade 3 TIMI flow was 100% vs. 95.6% (P= 0.03) and final grade 3 myocardial blush grade 50% vs. 41.18% (although Pwas not significant). Long-term follow-up total MACE showed a nonsignificant positive trend in the extraction group (12.96% vs. 24.71%, P= 0.26). CONCLUSIONS: The use of extraction devices for intracoronary thrombectomy during primary PCI in patients with totally occluded infarct artery significantly improved epicardial reperfusion in the infarct-related vessel and showed a trend for more favorable long-term outcome. PMID- 21243872 TI - Factors affecting rise in the incidence of infiltrating lobular carcinoma of the breast. AB - BACKGROUND: Infiltrating ductal carcinoma and infiltrating lobular carcinoma account for more than 90% of all invrasive breast cancer histological types. The rate of lLC is reported to be increasing steadily in the United States and Europe. OBJECTIVES: To describe the trend in the incidence of ILC in a large cohort of patients who underwent surgery in a single institution over an 18 year period. METHODS Our comprehensive database of 2175 consecutive patients with invasive breast cancer diagnosed during the period 1992-2009 served for the analysis. Several potential factors associated with lobular carcinoma as compared with ductal carcinoma were evaluated. RESULTS: During this period, a 2.4-fold increase in the incidence of pure ILC was noted, from 4.6% in theyears 1992-1994 to 10.9% in 2004-2006, followed by a modest decrease to 8.7% in 2007-2009. A significant association of lobular malignancies with external hormonal use was noted, including hormone replacement therapy exposure in patients diagnosed at age 50-64, and ovarian overstimulation during in vitro fertilization in those diagnosed at age 50 or less CONCLUSIONS: Better diagnostic tools - such as the liberal use of ultrasound and magnetic resonance imaging- and more accurate pathological definition for ILC type appear to influence the changes in the incidence of ILC in the subgroups of invasive breast cancer. PMID- 21243873 TI - The mystery of asymptomatic Wolff-Parkinson-White syndrome. PMID- 21243874 TI - Concepts and controversies in the management of cerebral developmental venous anomalies. PMID- 21243875 TI - Electrophysiological testing and ablation in an asymptomatic child with Wolff Parkinson-White syndrome. PMID- 21243876 TI - Multiple myeloma unveiled by multiple hyperkeratotic spicules. PMID- 21243877 TI - Percutaneous transluminal angioplasty with stenting for renal artery stenosis. PMID- 21243878 TI - Hurray for Obamacare! now comes the hard part. PMID- 21243879 TI - Politics as usual in the Washington debate over healthcare reform? PMID- 21243880 TI - Billing: the lifeblood of your business--does yours measure up? A roadmap to assess your billing performance and audit your billing practices. AB - Billing represents one of the most critical aspects of a medical practice, impacting your revenue, cash flow, and overall financial results. Yet many physicians do not have a clear understanding of their billing performance and, more importantly, how it affects the bottom line. This article examines key areas of medical billing, including steps to analyze your practice's performance against industry benchmarks. It also includes a real-world case study that highlights one practice's billing performance and opportunity for improvement. PMID- 21243881 TI - Medicare's ZPIC audits: the auditors' new stomping ground. AB - This article describes Medicare's recent Integrity Program effort, the Zone Program Integrity Contractors (ZPICs). The ZPICs are replacing the existing Program Safeguard Contractors and are part of Medicare's effort to enhance its auditing capabilities through centralization of audits and identification of potentially noncompliant activities. The ZPICs are currently active in three of the eventual seven zones, and through their active pursuit of fraudulent activities have already demonstrated their zealous intent to investigate potential fraud. ZPICs in all seven zones are scheduled to open by year end. PMID- 21243882 TI - Hey, coach. PMID- 21243883 TI - The citizen physician: governance principles make the difference. AB - Until recently, medicine was one of the few areas in which an individual could practice a profession as a citizen member of the organization. However, in the last 15 years as dramatic reductions have occurred in outpatient reimbursement, physicians have moved from self-governing organizations with the rights of citizen participation to autocratic, centrally controlled organizations with little offered to physicians other than to provide high-quality manual labor. The principles of prosperity and choice espoused in The Federalist Papers are governance principles that can reestablish citizenship in medical groups no matter who owns them. PMID- 21243884 TI - Deconstructing medical practice marketing. AB - The healthcare marketing game has radically changed. Medical practices must rely on strategies instead of tactics to better separate themselves from the competition. The Internet has become a disruptive force in marketing, tipping the balance and control of the reputations of medical practices to the patient. Done right, medical practices can harness this new energy to attract new patients and keep current patients loyal. PMID- 21243885 TI - Social media networking: Facebook and Twitter. AB - The new wave of marketing and practice promotion will include social media networking. This article will discuss Facebook and Twitter. After reading this article you, will have an understanding of these two important aspects of social media and how you might use Facebook and Twitter in your practice to enhance your communication with your existing patients and attract new patients. PMID- 21243886 TI - Defusing the angry patient: 25 tips. AB - Just about every member of the medical practice team will be, at one time or another, on the receiving end of a patient's anger. That's because even the calmest and gentlest patients can reach their boiling point when illness or injury threatens their health, mobility, independence, finances, self-esteem, dreams, and plans. Tempers are also likely to flair whenever anyone is frightened, not feeling well, and/or feeling out of control. Unfortunately, the quick pace of today's medical practice doesn't help much, as time for active listening and individual attention may be in less supply than we'd ideally like. This article offers 25 strategies the medical practice employee can use to defuse the angry patient. Among these are eight focus and mindset strategies to use before taking action, five strategies to use to take immediate control, seven early intervention strategies, and five resolution and closure strategies. This article also includes guidance about choosing an appropriate and safe venue within the medical practice for discussions with angry patients. It also describes why, specifically, it is in every medical practice's self-interest to welcome complaints from its patients, even those who lash out in anger. PMID- 21243887 TI - Healthcare reform: regulations issued on early compliance requirements. PMID- 21243888 TI - Fostering a culture of service excellence. AB - Patients' level of satisfaction with healthcare providers can have profound implications for operational and clinical outcomes. Are your organizational leaders fostering a practice culture of "service excellence"? Has your organization defined what "service excellence" means? Do your employees have a clear understanding of your expectations for service delivery? Medical practice leaders can improve patients' level of satisfaction by adopting and fostering a culture of service excellence in their practice. Strengthening the practice patient relationship through patient-service initiatives can lead to improved patient perception of care quality and overall satisfaction with their healthcare providers. When patients feel wanted and well cared for by their healthcare providers, they are less likely to be noncompliant and more likely to achieve positive clinical outcomes. Operationally, service-excellence initiatives will have a profound impact on patient retention and new referrals, and possibly a reduction of litigious risks. PMID- 21243889 TI - Physicians' emotional intelligence as a predictor of malpractice litigation: a conceptual review. AB - Several research studies have looked at the relationship between static personality traits and patient satisfaction but few studies have looked at the dynamic building blocks of emotional intelligence as they relate to patient satisfaction. Only a few previous research studies have preliminarily evaluated this relationship and determined that certain subsections of emotional intelligence were both negatively and positively correlated to patient satisfaction scores. This article evaluates the methodology under which these studies were conducted. The framework was found to be flawed due to limited sample size, the invalidity of satisfaction surveys, and the evolving contextual relationship between physicians and patients. PMID- 21243890 TI - Pensions, investments, and taxation. AB - Having for retirement has become increasingly challenging with retirement plan rules changing along with taxes and investment choices. The only certainty is that everyone needs to save money in order to be able to stop working. The best plan for a small business can be complex and confusing but rewarding if designed properly. There are a number of options available and many factors to consider in choosing the most appropriate plan. PMID- 21243891 TI - The patient-centered medical home: how to advance patient care through technology. AB - The process of applying for National Committee for Quality Assurance recognition as a Physician Practice Connections--Patient-Centered Medical Home (PPC-PCMH) can enrich even those practices already solidly committed to providing patient centric care based on evidence-based medical guidelines. The goal is to leverage information technology to transform both operational and patient care procedures. But even with robust technology, PCMH certification requires team commitment and an unremitting big-picture focus. This article provides an in-depth case study that shows how one groundbreaking Arizona practice used technology to reach the pinnacle of PCMH certification--and continues to use it to improve the quality of patient care. PMID- 21243892 TI - Improving influenza vaccine distribution in preparation for an H1N1 influenza pandemic: lessons from the field. AB - Vaccine distribution is an essential component of any healthcare organization's pandemic influenza plan. Variables surrounding distribution in these circumstances are often difficult to anticipate and require careful consideration. The 2009 H1N1 influenza pandemic provided organizations with an opportunity to test current models and overall organizational readiness for the next influenza pandemic. This article describes the experiences at a large, midwestern, multispecialty medical system in responding to the unique circumstances surrounding distribution of the 2009 H1N1 influenza vaccine. We discuss challenges, variables to consider when choosing a vaccine distribution model, institutional response, and lessons learned. PMID- 21243893 TI - Physicians with MBA degrees: change agents for healthcare improvement. AB - Increasingly, physicians gravitating toward the fields of quality improvement and healthcare management are seeking MBA degrees to supplement their medical training. Approximately half of all U.S. medical schools offer combined MD-MBA degrees, and numerous executive MBA programs exist for physicians in practice. Physicians who enter management are considered change agents for healthcare improvement, yet they receive little support and encouragement from their medical teachers and practicing colleagues. This situation can be rectified by placing greater value on the role of business-trained physicians and subsidizing their tuition for business school. PMID- 21243894 TI - Computer briefs: M-health: modern and mobile. PMID- 21243895 TI - Modification in the soil and traffic-related sources of particle matter between 1998 and 2007 in Santiago de Chile. AB - Santiago de Chile is one of the most polluted South American cities, concentrating its pollution episodes during winter. Daily PM2.5 (particulate matter [PM] < or = 2.5 microm in aerodynamic diameter) concentrations over 80 microg/m3 have been reached frequently since 1998. Despite several regulations introduced over the past 20 yr to improve the air quality, PM concentration levels remain high. In this work, sampling in downtown Santiago was conducted from April 1998 to August 2007 for PM2.5 and from October 2003 to March 2006 for PM10-2.5 (PM between 2.5 and 10 microm in aerodynamic diameter) with dichotomous samplers. Elemental analysis was performed on the samples with X-ray fluorescence. The resuming series of 859 samples and 216 elements identified were divided into semiannual periods and analyzed with factor analysis. Five factors are clearly discerned: soil, motor vehicles, residual oil, marine aerosols, and secondary sulfates. The soil factor in the fine fraction shows a clear increase from 2002 to 2006, whereas the coarse fraction of this factor shows a stable trend. The most probable cause for this trend is the growth in the number of vehicles in Santiago (6.5%/yr), which increases the resuspension of particles from the ground. Another cause for the increase is the growth in the construction activity (4.2%/yr). The motor vehicle factor in the fine fraction shows a decrease between 1998 and 2006. The decrease in the apportionment of this factor can be explained by the improvement in the vehicle fleet. In Santiago, the number of noncatalytic vehicles has been reduced from 389,000 in 2001 to 275,000 in 2006. The residual oil factor also shows a decrease between 1998 and 2006. The decrease could be attributed to the adoption of cleaner technologies and norms regarding gasoline and diesels. PMID- 21243896 TI - Road dust emissions from paved roads measured using different mobile systems. AB - Very few real-world measurements of road dust suspension have been performed to date. This study compares two different techniques (referred to as Sniffer and Emma) to measure road dust emissions. The main differences between the systems are the construction of the inlet, different instruments for recording particulate matter (PM) levels, and different loads on the wheel axes (the weight of Sniffer was much higher than that of Emma). Both systems showed substantial small-scale variations of emission levels along the road, likely depending on road surface conditions. The variations observed correlated quite well, and the discrepancies are likely a result of variations in dust load on the road surface perpendicular to the driving direction that cause variations in the measurements depending on slightly different paths driven by the two vehicles. Both systems showed a substantial influence on the emission levels depending on the type of tire used. The summer tire showed much lower suspension than the winter tires (one nonstudded and one studded). However, the relative importance of the nonstudded versus studded tire was rather different. For the ratio of studded/nonstudded, Emma shows higher values on all road sections compared with Sniffer. Both techniques showed increased emission levels with increasing vehicle speed. When the speed increased from 50 to 80 km hr(-1), the relative concentrations increased by 30-170% depending on the tire type and dust load. However, for road sections that were very dirty, Sniffer showed a much higher relative increase in the emission level with the nonstudded tire. Sniffer's absolute concentrations were mostly higher than Emma's. Possible reasons for the differences are discussed in the paper. Both systems can be used for studying relative road dust emissions and for designing air quality management strategies. PMID- 21243897 TI - Performance evaluation of an in situ nitrous acid measurement system and continuous measurement of nitrous acid in an indoor environment. AB - Nitrous acid (HONO) may cause adverse effects to mucous membranes and lung function when people are exposed to higher HONO concentrations than those present in typical indoor residential environments. Therefore, determination of HONO concentration in indoor environments is required to investigate occurrences of high HONO levels. In this work, a high-time-resolution measurement system was utilized to better understand the levels and dynamic behavior of HONO in an indoor environment. The performance of the in situ HONO analyzer applied to this work was evaluated using a 12-hr integrated annular denuder technique under ambient conditions. Both methods for the measurements of HONO were in good agreement, with a regression slope of 0.84, an intercept of 0.09, and correlation coefficient (r2) of 0.67. Indoor HONO and nitrogen oxide concentrations were also observed for approximately 5 days in winter in the living room of an apartment that had a gas range for cooking in the kitchen. Investigation of the relationships among nitric oxide (NO), nitrite (NO2), and HONO concentrations suggests that HONO production during combustion could be the result of direct emission, whereas the heterogeneous NO2 chemistry during the background period and after combustion was the possible pathway of HONO production. Controlled combustion experiments, performed at a burning rate of 50% valve setting, show peak HONO concentrations during the unvented combustion to be approximately 8-10 times higher than background levels depending on the time of day. At a burning rate setting of 50%, the peak concentration of HONO during unvented combustion was found to be 33-37% higher than those from "weak" (airflow = 340 m3/hr) and "strong" (airflow = 540 m3/hr) vented combustions. The decay rate of the HONO concentrations for the unvented combustion conditions was approximately 2-fold higher in the daytime than in the nighttime and significantly less than those of NO and NO2. PMID- 21243898 TI - In situ experimental study of carbon monoxide generation by gasoline-powered electric generator in an enclosed space. AB - On the basis of currently available data, approximately 97% of generator-related carbon monoxide (CO) fatalities are caused by operating currently marketed, carbureted spark-ignited gasoline-powered generators (not equipped with emission controls) in enclosed spaces. To better understand and to reduce the occurrence of these fatalities, research is needed to quantify CO generation rates, develop and test CO emission control devices, and evaluate CO transport and exposure when operating a generator in an enclosed space. As a first step in these efforts, this paper presents measured CO generation rates from a generator without any emission control devices operating in an enclosed space under real weather conditions. This study expands on previously published information from the U.S. Consumer Product Safety Commission. Thirteen separate tests were conducted under different weather conditions at half and full generator load settings. It was found that the CO level in the shed reached a maximum value of 29,300 +/- 580 mg/m3, whereas the oxygen (O2) was depleted to a minimum level of 16.2 +/- 0.02% by volume. For the test conditions of real weather and generator operation, the CO generation and the O2 consumption could be expressed as time-averaged generation/consumption rates. It was also found that the CO generation and O2 consumption rates can be correlated to the O2 levels in the space and the actual load output from the generator. These correlations are shown to agree well with the measurements. PMID- 21243899 TI - Improvements to lawn and garden equipment emissions estimates for Baltimore, Maryland. AB - Lawn and garden equipment are a significant source of emissions of volatile organic compounds (VOCs) and other pollutants in suburban and urban areas. Emission estimates for this source category are typically prepared using default equipment populations and activity data contained in emissions models such as the U.S. Environmental Protection Agency's (EPA) NONROAD model or the California Air Resources Board's (CARB) OFFROAD model. Although such default data may represent national or state averages, these data are unlikely to reflect regional or local differences in equipment usage patterns because of variations in climate, lot sizes, and other variables. To assess potential errors in lawn and garden equipment emission estimates produced by the NONROAD model and to demonstrate methods that can be used by local planning agencies to improve those emission estimates, this study used bottom-up data collection techniques in the Baltimore metropolitan area to develop local equipment population, activity, and temporal data for lawn and garden equipment in the area. Results of this study show that emission estimates of VOCs, particulate matter (PM), carbon monoxide (CO), carbon dioxide (CO2), and nitrogen oxides (NO(x)) for the Baltimore area that are based on local data collected through surveys of residential and commercial lawn and garden equipment users are 24-56% lower than estimates produced using NONROAD default data, largely because of a difference in equipment populations for high usage commercial applications. Survey-derived emission estimates of PM and VOCs are 24 and 26% lower than NONROAD default estimates, respectively, whereas survey derived emission estimates for CO, CO2, and NO(x) are more than 40% lower than NONROAD default estimates. In addition, study results show that the temporal allocation factors applied to residential lawn and garden equipment in the NONROAD model underestimated weekend activity levels by 30% compared with survey derived temporal profiles. PMID- 21243900 TI - Developing a high-resolution vehicular emission inventory by integrating an emission model and a traffic model: Part 1--Modeling fuel consumption and emissions based on speed and vehicle-specific power. AB - To improve the accuracy and applicability of vehicular emission models, this study proposes a speed and vehicle-specific power (VSP) modeling method to estimate vehicular emissions and fuel consumption using data gathered by a portable emissions monitoring system (PEMS). The PEMS data were categorized into discrete speed-VSP bins on the basis of the characteristics of vehicle driving conditions and emissions in Chinese cities. Speed-VSP modal average rates of emissions (or fuel consumption) and the time spent in the corresponding speed-VSP bins were then used to calculate the total trip emissions (or fuel consumption) and emission factors (or fuel economy) under specific average link speeds. The model approach was validated by comparing it against measured data with prediction errors within 20% for trip emissions and link-speed-based emission factors. This analysis is based on the data of light-duty gasoline vehicles in China; however, this research approach could be generalized to other vehicle fleets in other countries. This modeling method could also be coupled with traffic demand models to establish high-resolution emissions inventories and evaluate the impacts of traffic-related emission control measures. PMID- 21243901 TI - Developing a high-resolution vehicular emission inventory by integrating an emission model and a traffic model: Part 2--A case study in Beijing. AB - A grid-based, bottom-up method has been proposed by combining a vehicle emission model and a travel demand model to develop a high-resolution vehicular emission inventory for Chinese cities. Beijing is used as a case study in which the focus is on fuel consumption and emissions from hot-stabilized activities of light-duty gasoline vehicles (LGVs) in 2005. The total quantity of emissions, emission intensity, and spatial distribution of emissions at 1- by 1-km resolution are presented and compared with results from other inventory methods commonly used in China. The results show that the total daily fuel consumption and vehicular emissions of carbon dioxide, carbon monoxide, hydrocarbons, and oxides of nitrogen from LGVs in the Beijing urban area in 2005 were 1.95 x 10(7) L, 4.28 x 10(4) t, 1.97 x 10(3) t, 0.28 x 10(3) t, and 0.14 x 10(3) t, respectively. Vehicular fuel consumption and emissions show spatial variations that are consistent with the traffic characteristics. The grid-based inventory developed in this study reflects the influence of traffic conditions on vehicle emissions at the microscale and may be applied to evaluate the effectiveness of traffic related measures on emission control in China. PMID- 21243902 TI - Low-wind/high particulate matter episodes in the Calexico/Mexicali region. AB - The U.S. Environmental Protection Agency (EPA) currently classifies Imperial County, CA, as a nonattainment area for PM10 (particulate matter [PM] < or = 10 microm in diameter), and this region suffers from high rates of chronic bronchitis and childhood asthma. Although high annual and daily average PM levels can have negative health and economic effects, recent studies have identified an association between adverse health effects and short-term PM spikes of tens of micrograms per cubic meter. This study identified PM episodes in Calexico/Mexicali that involve PM concentration spikes with concentrations up to 10 times greater than those reported to cause adverse health effects. These episodes appear to be relatively common during the winter months, are associated with wind speeds below 2 m/sec and stable boundary level heights below 500 m, and can comprise a large portion of the 24-hr PM levels. The organic composition of the PM10 samples collected during the low-wind/ high-PM episodes differed from that collected at other times. However, a preliminary source attribution identified only one significant difference between the source classes: agricultural burning accounted for 6.7% of organic-fraction PM10 for low wind/high-PM episodes versus 0.25% at other times. This preliminary source attribution also revealed that motor vehicles were the most important relative contributor to organic PM10. PMID- 21243903 TI - Emission characteristics of granulated fuel produced from sewage sludge and coal slime. AB - The neutralization of wastewater treatment residues is an issue for many countries. The European Union (EU) legal regulations have limited the use of the residues in agriculture and implemented a ban for their disposal. Therefore, urgent action should be taken to find solutions for the safe disposal of sewage sludge. The problem refers in particular to the new EU member countries, including Poland, where one can now observe an intensive development of sewage system networks and new sewage treatment plants. At the same time, these countries have few installations for thermal sewage sludge utilization (e.g., there is only one installation of that type in Poland). Simultaneously, there are many coal-fired mechanical stoker-fired boilers in some of these countries. This paper presents suggestions for the production of granulated fuel from sewage sludge and coal slime. Additionally, among others, lime was added to the fuel to decrease the sulfur compounds emission. Results are presented of research on fuel with two average grain diameters (approximately 15 and 35 mm). The fuel with such diameters is adapted to the requirements of the combustion process taking place in a stoker-fired boiler. The research was aimed at identifying the behavior of the burning fuel, with special attention paid to its emission properties (e.g., to the emissions of oxides of nitrogen [NO(x)], sulfur dioxide [SO2], and carbon monoxide [CO], among others). The concentration and emission values were compared with similar results obtained while burning hard coal. The combustion process was carried out in a laboratory stand where realization of the large-scale tests is possible. The laboratory stand used made simulation possible for a wide range of burning processes in mechanical stoker-fired boilers. PMID- 21243904 TI - External manual defibrillators. Which models are ready to meet your needs? PMID- 21243906 TI - Hazard report. Connector damage while attaching Philips MMS modules to monitors can impede monitoring. PMID- 21243905 TI - Top 10 technology hazards. High-priority risks and what to do about them. PMID- 21243907 TI - Hazard report. Insecure connection between Zoll M Series defibrillator paddles and cables could delay therapy. PMID- 21243908 TI - Safety note. CT overdoses at Cedars-Sinai--perspectives from FDA and ECRI Institute. PMID- 21243910 TI - Large-volume infusion pumps. The evolution continues. PMID- 21243909 TI - Straight from the heart. Understanding cardiac output monitoring techniques. PMID- 21243911 TI - Hazard report. Hospitals should begin removing certain Electri-Cord power cords from service. AB - Some power cords manufactured by Electri-Cord Manufacturing may be susceptible to failure in the healthcare setting, posing a risk of shocks, burns, fires, or device failures. We believe hospitals should remove these cords-which are supplied with equipment from a variety of medical device manufacturers-from service. The removal process should not be done all at once but should be carried out over time, making sure that the process does not impede patient care. PMID- 21243912 TI - Hazard report. Defective oxygen supply tubing may delay use of some Allied EPV100 emergency portable ventilators. AB - Some of the diameter index safety system (DISS) connectors on the disposable oxygen (O2) supply tubing provided with Allied Healthcare Products EPV100 emergency portable ventilators were installed backwards during manufacturing. This problem may temporarily prevent connection of the ventilator to an O2 supply source. Facilities should inspect the tubing supplied with the EPV100 for reversed connectors and, if necessary, contact Allied Healthcare Products for replacement tubing. PMID- 21243913 TI - Hazard report. Using patient-supplied respiratory care equipment in hospitals requires careful assessment. AB - Patients may want to use their own ventilators or continuous positive airway pressure (CPAP) units when admitted to the hospital; however, doing so presents many risks. While ECRI Institute generally recommends against allowing patients to use their own ventilators or CPAP units in the hospital, exceptions can be justified in some circumstances, and your facility should have a process in place to assess the risks on a case-by-case basis. PMID- 21243914 TI - Attaining MDG 5 in northern Nigeria: need to focus on skilled birth attendance. PMID- 21243915 TI - Effects of maternal micronutrient supplementation on fetal loss and under-2-years child mortality: long-term follow-up of a randomised controlled trial from Guinea Bissau. AB - A number of trials on maternal multi-micronutrient supplementation (MMS) have found a benefical effect on birth weight, but few have demonstrated a beneficial effect on infant survival. We examined the effect of two different preparations of antenatal MMS on fetal loss and under-2-years child mortality, as compared with iron-folic acid supplementation among 2,100 pregnant women in Guinea-Bissau. Women receiving a 1xRDA MMS preparation (consisting of 14 vitamins and minerals) had a marginally reduced risk of fetal loss (Relative risk (RR) 0.65, 95% CI 0.40; 1.05), and women receiving a 2xRDA MMS preparation had a similar effect (RR 0.67, 95% CI 0.42; 1.08), the pooled effect being 0.66 (95% CI 0.44; 0.99). None of the supplements reduced under-2-years mortality or the combination of fetal loss and under-2-years mortality. There was a marginally negative effect of both the 1xRDA (RR 2.10, 95% CI 0.99; 4.46) and the 2xRDA (RR 2.02, 95% CI 0.95; 4.32) MMS preparation on mortality specifically between 92-365 days of age. PMID- 21243916 TI - Fertility desires and condom use among HIV-positive women at an antiretroviral roll-out program in Zimbabwe. AB - As access to anti-retroviral therapy (ART) increases in sub-Saharan Africa, fertility and contraception patterns are likely to change. Two hundred HIV positive women at an ART roll-out site in Zimbabwe responded to a questionnaire on fertility desires and condom use. Ten women (5%) reported planning a pregnancy in the next year, comprising 0% of women not yet eligible for ART, 8.22% of women on the waitlist for ART, and 4.17% of women on ART. Younger age, fewer living children, and higher quality of life were individually associated with intended pregnancy in the next year; however in multivariate analysis only the association with higher quality of life remained significant. Reported ever use of condoms was relatively low (46.5%) and condom use varied by neither ART status nor by fertility desires. In conclusion, our data demonstrates fertility desires among HIV-positive women in Zimbabwe correlate with higher perceived quality of life. PMID- 21243917 TI - Utilization of non-skilled birth attendants in northern Nigeria: a rough terrain to the health-related MDGs. AB - Non-skilled birth attendants (NSBAs) are likely to deliver low quality maternity care compared with skilled health workers. A total of 6,809 women (15-49 years) were interviewed in a survey of which 5,091 had delivery information. Among women with a last live birth delivered anytime within the five years prior to the survey, 89% had been assisted by NSBAs. Compared to older women (35+), middle aged women (20-34 years) were 21% more likely to be assisted by NSBAs. For women < or =20 years, the odds of being assisted by NSBAs more than doubled (AOR=2.14) when compared with older women. Residents of Yobe State were 42% more likely to be assisted by NSBA compared with residents of Katsina State. Key interventions should focus on strengthening health services delivery, radio messages and other communication channels to encourage supervised deliveries and intensifying provision of formal education to enable women better understand information given. PMID- 21243918 TI - Age at sexual debut: a determinant of multiple partnership among South African youth. AB - Age at sexual debut is an important determinant of HIV infection. The paper investigates the effects of age at sexual debut on sexual behaviour among South African youth. Among 2 875 respondents who ever had sexual intercourse, 39% had early sexual debut (sexual debut at age 16 years and below). Males (44.6%) were significantly more likely than females (35.1%) to report early sexual debut (odds ratio (OR) = 1.45, p-value < 0.001). Multiple sexual partners are significantly more common among those that had early sexual debut (10.4% vs. 4.8%) than those who had late sexual debut, (OR = 2.29, p-value < 0.001). Those aged 15 to 19 years were 1.4 times more likely to report multiple partners compared to those aged 20 to 24 years. Delaying sexual debut is a strategy many national programmes are promoting. The results of this study provide additional arguments to support such initiatives and show the need to strengthen intervention targeting youth. PMID- 21243919 TI - Audit of cases with uterine rupture: a process indicator of quality of obstetric care in Angola. AB - Audit of uterine rupture (UR) used as a process indicator, can identify factors considered avoidable to improve future quality of obstetric care. Records of UR cases at a referral maternity in Luanda were studied retrospectively (n=43) and prospectively (n=67) including basic obstetric information, maternal and foetal outcome, duration of labour, time interval between diagnosis and intervention, drugs used, type of delivery and intervention, surgical procedures and complications. A clinical estimation of avoidability was based on this information. Prevalence of UR was 4.9%. Maternal case fatality rate was 14% and early perinatal mortality 71%. Women with previous Caesarean Section (CS) constituted 28%, grand multiparous women 44% and primiparous women 6%. Uterotonic treatment was given in 36%. Avoidability was estimated to 65%. Regular morbidity oriented audits with analysis of clinical management reveal weaknesses in obstetric care and may serve as an instrument for future improvement. PMID- 21243920 TI - Application of health belief model for promoting behaviour change among Nigerian single youth. AB - The study analyzes the factors influencing conduct of HIV test and risky behavour change using the health belief model. The data were obtained from the Nigeria's 2004 NLSS data and analyzed with descriptive statistics and Probit regression. Results show that 87.79% of the single youths were aware of HIV/AIDS, 3.34% conducted HIV test and 71.73% desisted from risky behaviour by having sex with one partner (24.35%), not starting sex (16.90%) and using condom (14.29%). Also, probability of conducting HIV test and changing risky behaviours significantly increases (p<0.10) with age, access to radio, television and per capita expenditure, while it significantly decreases with no formal education. Residence in urban area significantly increases probability of conducting HIV test, but significantly reduces probability of changing risky behaviours. The study recommends integration of health studies into Nigerian elementary school curriculums, provision of adequate facilities for free HIV test in rural areas, among others. PMID- 21243921 TI - Determinants of referral practices of clients by traditional birth attendants in Ilorin, Nigeria. AB - A sizeable number of deliveries still take place with the assistance of Traditional Birth Attendants in Nigeria. This study aims to determine the factors that determine the referral practices of the TBAs in Ilorin of high risk and complicated pregnancies. This descriptive study was conducted among all the 162 registered TBAs in Ilorin that were traceable using pre-tested semi-structured interviewer-administered questionnaire. About 90%, whose source of skill acquisition was by inheritance did not refer their clients appropriately compared with 48% of those whose source of skill acquisition was through formal training (p<0.05). The more the numbers of trainings, the more appropriate the referral (p<0.05). Having supervisory visit by qualified personnel is associated with appropriate referral practices (p<0.05). Regular training and re-training of TBAs with routine monitoring and supportive supervision will promote prompt referral of high risk and complicated pregnancies and deliveries. PMID- 21243923 TI - Assessment of the protective effect of male circumcision from HIV infection and sexually transmitted diseases: evidence from 18 demographic and health surveys in sub-Saharan Africa. AB - A cross-sectional study based on the secondary data of 18 Demographic Health Surveys carried out in Sub-Saharan Africa was conducted to assess the protective effect of male circumcision from HIV infection and STDs. Information on 70,554 males aged 15-59 years was extracted. The association between circumcision and HIV infection and STD symptoms (Genital discharge or ulcer/sore) was assessed using logistic regression. Un-circumcision was significantly associated with risk of HIV with odds ratio of 4.12 (95%CI: 3.85-4.42). The association was even more significant, 4.95 (95%CI: 4.57-5.36), after adjustment was made for number lifetime sexual partners and socio-demographic variables. The risk associated with un-circumcision is significantly lower among younger men aged 15-29 years than older age categories. However, circumcision found to have no association with the symptoms of STDs. The study concluded that male circumcision can be considered as a way of reducing the spread of HIV infection. PMID- 21243922 TI - Cost-effectiveness analysis of unsafe abortion and alternative first-trimester pregnancy termination strategies in Nigeria and Ghana. AB - To explore the policy implications of increasing access to safe abortion in Nigeria and Ghana, we developed a computer-based decision analytic model which simulates induced abortion and its potential complications in a cohort of women, and comparatively assessed the cost-effectiveness of unsafe abortion and three first-trimester abortion modalities: hospital-based dilatation and curettage, hospital- and clinic-based manual vacuum aspiration (MVA), and medical abortion using misoprostol (MA). Assuming all modalities are equally available, clinic based MVA is the most cost-effective option in Nigeria. If clinic-based MVA is not available, MA is the next best strategy. Conversely, in Ghana, MA is the most cost-effective strategy, followed by clinic-based MVA if MA is not available. From a real world policy perspective, increasing access to safe abortion in favor over unsafe abortion is the single most important factor in saving lives and societal costs, and is more influential than the actual choice of safe abortion modality. PMID- 21243924 TI - Cultural and ethical challenges of assisted reproductive technologies in the management of infertility among the Yoruba of southwestern Nigeria. AB - This paper discusses the cultural and ethical issues arising from the use of Assisted Reproductive Health Technologies. Twenty-five In-depth interviews were conducted with 5 couples of reproductive age who have never conceived or brought pregnancy to term after one year of unprotected intercourse, 4 adult males, 4 adult females, a gyneacologist, a nurse, a herbalist and 2 religious leaders in Ibadan, Nigeria. Content analysis was used for data analysis. Legitimacy of children born through ART, religious obligation, patriarchy, polygamy and value of children are cultural issues surrounding ARTs while decision making about it, discrimination against children born through ART, psychological problems and loss of self esteem, side effects of the technologies and the cost of accessing them are the ethical challenges. The findings have methodological implications for conducting infertility research in non-western societies. PMID- 21243925 TI - Skilled attendance: the key challenges to progress in achieving MDG-5 in north central Nigeria. AB - The importance of skilled attendance at delivery, as reflected in the MDG 5, is being promoted in developing countries to address the high maternal/perinatal morbidity and mortality. Evaluation of personnel skills and availability of material resources are central to elimination of barriers to delivery of basic Emergency Obstetric Care (EOC) to the community. We designed a semi-structured, interviewee-administered questionnaire for 54 certified Nurse-Midwives working in Primary Health Care (PHC) clinics in Nasarawa State, central Nigeria, and examined their knowledge and competencies in the five major areas responsible for maternal mortality in sub-Saharan Africa, including power supply, referral linkages and motivation to work. Majority 51 (94.4%) of PHCs neither used the Partograph nor performed manual vacuum aspiration. Referral systems and feedback mechanisms were practically non-existent, 38 (70.4%) of facilities were >5 km from the nearest referral centre, with 14 (29.5%) connected to the national grid. Majority (68.5%) of respondents would want to work abroad. The quality of skilled attendance is low and basic EOC facilities are lacking, a situation further threatened by potential emigration to greener pastures. Governments and development partners need to address facility and skilled manpower shortages in developing countries to make a modest attempt at meeting the MDG on maternal health. PMID- 21243926 TI - The Society of Gynaecology and Obstetrics of Nigeria (SOGON) plan for sustainable reduction in maternal mortality: a review. AB - In the year 2000, SOGON formulated a strategic plan on women's health based on the reproductive health approach with the aim of reducing maternal mortality by 50% by the year 2010. In 2005, the Nigerian Road Map for accelerating the attainment of Millennium Development Goals 4 and 5 was launched. One of the key guiding principles of the Road Map was promoting partnerships and joint programming among stakeholders including professional associations. In response, SOGON decided to align her strategic plan with the Road Map by refocusing the plan to the key objectives of the Road Map. The new SOGON Plan involves interventions with a focal objective of reducing the case-fatality of emergency obstetric conditions. The plan is anchored on interventions where SOGON has comparative advantage such as providing human resources and promoting capacity building for emergency obstetric care and skilled attendance at delivery, and advocacy and information dissemination on maternal health. PMID- 21243927 TI - Anaesthetic challenges associated with achondroplasia: a case report. AB - We report the anaesthetic management of two achondroplastic patients who presented for emergency cesarean section. Regional anaesthesia could not be done in both cases as a result of technical difficulties and general anaesthesia was performed. Airway management was done with two different techniques following airway assessment. The perioperative periods were uneventful. We discuss the anaesthetic implications and problems associated with regional and general anaesthesia in achondroplastic parturients. The controversies in the anesthetic management of these patients are also highlighted. PMID- 21243928 TI - In vivo and in vitro immunological changes induced by a short course of grass allergy immunotherapy tablets. AB - BACKGROUND: The fast-dissolving grass allergy immunotherapy tablet (grass AIT), Grazax, has proven effective in grass pollen-induced rhinoconjunctivitis. OBJECTIVE: To investigate the immunological and cutaneous changes induced after a short course with grass AIT. METHODS: We performed a randomized, double-blind placebo-controlled trial with 78 patients randomly assigned to receive either grass AIT or placebo in a 2:1 ratio. Treatment lasted at least 8 weeks before the grass pollen season (GPS), and continued until the season finished. Specific immunoglobulin (Ig) G4, IgE, and IgE-blocking factor to Phleum pratense were measured at the beginning of the trial and at different intervals during treatment. Immediate and delayed skin tests with P pratense were also performed. Safety endpoints were defined in terms of adverse events reported. RESULTS: A total of 75 patients completed the trial (50 active and 25 placebo). P pratense IgG4, IgE, and IgE-blocking factor in actively treated patients increased significantly from baseline to the start of the GPS compared to placebo (P > .001, P = .017, and P = .005, respectively). The immediate cutaneous response was reduced during therapy in actively treated subjects, whereas placebo-treated subjects showed a decrease only after the start of the GPS. The delayed response to the intradermal test in grass AIT-treated subjects diminished, although not in a significantly different way from the placebo-treated subjects. CONCLUSION: Treatment with grass AIT for grass pollen allergic rhinoconjunctivitis induces immunological changes after only 1 month of treatment. PMID- 21243929 TI - Inhibitory effects of Schefflera leucantha extract on production of allergic mediators by Langerhans cells and mast cells. AB - BACKGROUND: Schefflera leucantha Viguier is used as a traditional medicine in Thailand and China to relieve chronic cough and asthma. However, little is known about its anti-allergic effects. OBJECTIVE: This study was designed to investigate the effects of S leucantha ethanol extract (SLEE) on chemokine production by epidermal Langerhans cells (LCs) stimulated with peptidoglycan (PEG) from Staphylococcus aureus and histamine release from mast cells. METHODS: LCs were purified from murine epidermal cells using the panning method with anti IA(d) monoclonal antibody. Chemokine production by LCs was investigated by reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). Mast cells for histamine release assay were induced by long-term culture of mouse spleen cells. Histamine release from these mast cells was measured by a competitive ELISA. RESULTS: Production of the eosinophil chemoattractant CCL5 and the type 2 T helper (TH2)-associated chemokine CCL17 from PEG-stimulated LCs was significantly inhibited by SLEE. Furthermore, SLEE significantly decreased the release of histamine from mast cells by IgE-mediated degranulation. CONCLUSION: These results suggest that S leucantha may offer a new therapeutic approach for the control of atopic dermatitis associated with S aureus colonization through inhibition of the production of allergic mediators. PMID- 21243930 TI - Diet and prevalence of atopic eczema in 6 to 7-year-old schoolchildren in Spain: ISAAC phase III. AB - BACKGROUND: The prevalence of atopic dermatitis (AD), a chronic skin disease, has increased substantially in recent decades, and different factors have been implicated in its etiology. Although dietary habits are being investigated, few conclusive findings have been reported. Nevertheless, increased consumption of polyunsaturated fatty acids (PUFA) and a diet poor in antioxidants have been related to AD. OBJECTIVES: The objectives of this study were to investigate the association between AD, the intake of different foods, and the effect of a Mediterranean diet among Spanish schoolchildren aged 6 to 7. METHODS: We performed a cross-sectional study with 20 106 schoolchildren aged 6-7 years from 10 different areas of Spain. The participation rate was 76.50%. The prevalence of AD was assessed using the International Study of Asthma and Allergies in Childhood questionnaire and the criteria of the Spanish Academy of Dermatology. To calculate the Mediterranean diet score, we classified food into 2 groups: Mediterranean food, including fruit, seafood, vegetables, pulses, cereals, pasta, rice, and potatoes; and non-Mediterranean food, including meat, milk, and fast food. RESULTS: Milk was negatively associated with AD. Butter and nuts also were negatively associated, although statistical significance was only reached when these foods were consumed 3 or more times a week. CONCLUSIONS: We found no association between the Mediterranean diet score and AD and a positive association between AD and obesity. PMID- 21243931 TI - Leukocyte phenotype changes induced by specific immunotherapy in patients with birch allergy. AB - BACKGROUND: The underlying mechanisms of allergen-specific immunotherapy (SIT) are not fully understood. OBJECTIVES: The present study aimed to investigate how leukocyte phenotypes are affected by SIT. METHODS: Blood samples were taken from 10 patients with birch pollen--induced allergic rhinitis before, during, and immediately after SIT. Further samples were obtained after 1 year and 3 years. All samples were analyzed by flow cytometry and leukocyte differentiation. RESULTS: SIT caused a decrease in cell-bound immunoglobulin (Ig) E on granulocytes, along with a corresponding increase in the high-affinity IgG receptor. Accordingly, a lower level of allergen-specific IgE was found after 3 years. The treatment induced a decrease in neutrophil CD1 1b levels, a shift in monocyte subsets, and an increase in the number of activated T lymphocytes, manifested as an upregulation of CD69 and CD98, and an expansion of the CD4+CD25+ T-cell pool. CONCLUSION: The present study shows that the clinical effects of SIT are mirrored by systemic changes in cellular events and in antibodies, and offers new targets for immunomodulation. PMID- 21243933 TI - Guidelines on ambient intramural airborne fungal spores. AB - OBJECTIVES: To generate baseline data for indoor airborne fungal spores in noncomplaint residential properties (with no moisture/mold-related problems) and to identify home characteristics indicative of elevated fungal levels. METHODS: Air samples were collected onto petroleum jelly-coated slides from living rooms of 100 residential properties in Leicestershire, United Kingdom, using a Burkard continuous recording air sampler. The slides were examined by microscopy to determine fungal spore concentrations (spores/m3 air/day). RESULTS: Total indoor fungal spore concentrations were approximately 16% of outdoor concentrations. Abundant indoor fungal genera include Cladosporium, Sporobolomyces, Tilletiopsis, and Didymella, all of which followed seasonal patterns of release and detection. No clear association was shown between outdoor-predominant fungi and home characteristics. In contrast, Aspergillus/Penicillium-type (Asp/ Pen-type) spores were common indoors and exceeded outdoor levels, with the highest concentrations detected in properties over 90 years old (P = .006) and terraced properties (P = .003). CONCLUSION: Asp/Pen-type spores are found in noncomplaint UK residential properties and mostly in old terraced houses. This study provides guidelines on acceptable levels of Asp/Pen-type spores and other abundant indoor fungal taxa that can be comparatively used in clinical evaluations of fungal exposure-related disease. PMID- 21243932 TI - Double (honeybee and wasp) immunoglobulin E reactivity in patients allergic to Hymenoptera venom: the role of cross-reactive carbohydrates and alcohol consumption. AB - BACKGROUND: Immunoglobulin (Ig) E-mediated sensitization to N-glycans (cross reactive carbohydrate determinants, CCDs) may induce double IgE reactivity to honeybee venom (HBV) and yellow jacket venom (YJV) in patients who are monosensitized to either of these venoms. Alcohol consumption is associated with increased IgE levels and possibly with sensitization to CCDs in the general population. OBJECTIVES: This study investigated the factors associated with double (HBV and YJV) IgE reactivity in patients who are allergic to Hymenoptera venom, and in particular, alcohol consumption. METHODS: Ninety-one patients with Hymenoptera allergy (68 to HBV, 19 to YJV, and 4 to both venoms) were studied. Determinations included a multiallergen IgE test and IgE to HBV, YJV, natural (glycosylated) HBV phospholipase-A2 (nPLA2), recombinant (nonglycosylated) HBV phospholipase-A2 (rPLA2), MUXF (the N-glycan from bromelain), natural (glycosylated) rubber latex, total IgE. Double reactivity was defined as an IgE level > 0.35 kU(A)/L to HBV and YJV. RESULTS: Double reactivity was observed in 28/87 (32%) clinically monosensitized patients. Double reactivity was associated with high levels of total IgE, MUXF-specific IgE, nPLA2-specific IgE, latex specific IgE, and false-positive results in the multiallergen IgE test, but not with rPLA2-specific IgE. Alcohol consumption was associated with double reactivity and with high levels of IgE to glycosylated allergens after adjusting for confounders in the multivariate analysis. CONCLUSIONS: Sensitization to CCDs and clinically irrelevant double (honeybee and wasp) IgE reactivity are common among Hymenoptera venom-allergic patients who drink alcohol. A simple questionnaire about alcohol consumption could be useful when interpreting levels of specific IgE in these patients. PMID- 21243934 TI - Estimating allergenicity of latex gloves using Hev b 1 and hevamine. AB - BACKGROUND: Latex allergy continues to be an increasingly serious occupational health problem in Taiwan, where it affects approximately 6.8% to 12% of health care workers. Contrasting with reports from western countries, Hev b 1 and hevamine, and not Hev b 3, 5 or 6.02, are the major latex allergens among health care workers in Taiwan. This study aimed at evaluating the allergenicity of 30 brands of commercially available medical latex gloves in Taiwan in 2007. METHODS: Residual Hev b 1 and hevamine from the gloves were measured by inhibition enzyme linked immunosorbent assay using polyclonal antibodies against purified recombinant Hev b 1 and hevamine. The results were compared to those achieved with quantification of residual total extractable proteins and skin prick testing. RESULTS: The residual extractable protein levels in 30 medical gloves all conformed to United States Food and Drug Administration regulations. All the gloves except one yielded strong skin prick reactions in latex-allergic individuals. The only brand of gloves that consistently produced no skin prick reactions in latex-allergic individuals contained the lowest residual levels of Hev b 1 (0.60 microg/g) and hevamine (0.07 microg/g). CONCLUSIONS: Our results suggest that the measurement of residual extractable total proteins is not sufficient to assess the allergenicity of latex gloves and that Hev b 1 and hevamine may be used as indicator allergens in areas where they are major latex allergens, such as Taiwan. PMID- 21243935 TI - Follow-up of venom immunotherapy (VIT) based on conventional techniques and monitoring of immunoglobulin E to individual venom allergens. AB - OBJECTIVES: To assess the efficacy of venom immunotherapy (VIT) and monitor changes in in vivo and in vitro test results after 5 years of treatment and subsequent follow-up. To study the profile of immunoglobulin (Ig) E to individual allergens prior to treatment and 1 year afterwards. METHODS: We studied 562 patients with hymenoptera venom allergy (438 to bee, 124 to wasp), all of whom underwent immunotherapy with Apis or Vespula extract. The patients were followed up using conventional in vivo and in vitro tests, and in 51 cases, specific IgE against the main hymenoptera allergens was measured before starting and after 1 year of treatment. RESULTS: Of the 387 patients who completed VLT, 130 sensitized to Apis and 68 to Vespula suffered spontaneous re-stings during treatment. Of these, 123 (94.6%) did not suffer any reaction and 64 (94.1%) suffered only a local reaction. Sixty-two patients sensitized to Apis and 14 sensitized to Vespula suffered spontaneous re-stings after stopping treatment. Only 3 patients suffered a systemic reaction (grade I Muller). At the end of treatment, the results of skin tests and specific IgE to whole extract improved significantly. Reductions in IgE to the main allergens were observed after 1 year of treatment (median differences in Ves v 5, -238.0, P = .0425; and in Api m 1, -183.0, P = .0024). CONCLUSION: The high rate of spontaneous re-stings shows that efficacy is maintained for years after completing treatment in a real-world setting. Determination of IgE to individual venom allergens may offer new perspectives in the diagnosis and follow-up of these patients. PMID- 21243936 TI - Sublingual immunotherapy in peach allergy: monitoring molecular sensitizations and reactivity to apple fruit and Platanus pollen. AB - BACKGROUND: Peach allergy is prevalent, persistent, and potentially severe and as such is a target for immunotherapy. Our aims were to evaluate the profile of sensitization to Rosaceae allergens and the effects of sublingual peach immunotherapy on immunoglobulin (Ig) E levels to these allergens, to monitor for neosensitizations, and to check if this treatment modified other Rosaceae fruit and pollen-related sensitizations. METHODS: A double-blind placebo-controlled trial was conducted on 56 peach-allergic patients who received, sublingually, a standardized peach extract quantified in mass units of Pru p 3, or placebo for 6 months. IgE to recombinant (r) Mal d 1, rMal d 4, rPru p 3, and natural (n) Art v 3 and skin prick test (SPT) reactivity to Platanus pollen and apple extracts evaluated before treatment (T0), after 1 month (T1) and after and 6 months (T6) were recorded. RESULTS: In total, 18.5% of patients recognized rMal d 1, 83.3%, rPru p 3, 24.1%, rMal d 4, and 25.9% nArt v 3. IgE to Pru p 3 rose from T0 to T1 in both the active group (P = .003) and the placebo group (P = .022), and remained elevated at T6 in the active group (P = .001). IgE to other purified allergens did not change significantly and no relevant neosensitizations were detected. SPT reactions to peach decreased from T0 to T6 in the active group (P < 0.05). Reactivity to peach (T1 and T6) and apple (T6) was lower in the active group than in the control group. CONCLUSIONS: The main allergen was Pru p 3. Changes in rPru p 3 IgE levels and in peach and apple extract SPT were induced by sublingual immunotherapy. PMID- 21243937 TI - Allergy workup in immediate-type local reactions to glatiramer acetate. AB - Local reactions to glatiramer acetate are common, but few cases of hypersensitivity reaction have been reported. We present 3 patients with multiple sclerosis who suffered immediate-type local reactions after subcutaneous injection of glatiramer acetate. Skin prick test (SPT), intradermal test (IDT), and determination of immunoglobulin (Ig) E to glatiramer acetate were performed in patients and controls (enzyme-linked immunosorbent assay). The results of SPT were all negative. Those of IDT in controls were negative at concentrations below 200 microg/mL, but positive for patients 1, 2, and 3 at 2, 20, and 200 microg/mL, respectively. Serum IgE to glatiramer acetate in patient 1 was 2.1 times higher than in the controls, whereas no differences were found between controls and patients 2 and 3. Glatiramer acetate was safely reintroduced in patients 2 and 3. The results obtained for patient 1 suggest that an IgE-mediated mechanism was probably involved. In conclusion, IDT and serum IgE determination to glatiramer acetate seem useful for identifying allergic reactions among the common local reactions induced by this drug. PMID- 21243938 TI - Induction of oral tolerance to peanut: a successful home-based protocol. AB - In Spain, peanut allergy is increasingly prevalent. Successful protocols for the induction of oral tolerance (LOT) with several foods have been reported. We aimed to induce clinical tolerance to peanut in a child with severe peanut allergy (age 4 years, facial urticaria and lip angioedema upon licking a peanut; peanut skin prick test, 13 x 10 mm; specific immunoglobulin (Ig) E > 100 kUA/L). At age 6, the threshold oral challenge dose was 62.5 mg. Several peanut solutions were prepared and sequentially administered at the patient's home. Over 138 days, the dose was increased from 0.625 to 5500 mg. There were 43 mild-to-moderate reactions (28% of the doses administered). Pre-LOT and post-LOT peanut IgE and IgG4 values were 265 vs 487 kUA/L, and 6.11 vs 14.8 mg/L. This is the first report of successful LOT to peanut in Spain. This home-based regimen is safe under permanent and close medical supervision by an allergist. PMID- 21243939 TI - Systemic corticosteroid hypersensitivity in children. AB - We describe 5 cases of immediate-type reactions to systemic corticosteroids observed during the last 2 decades in boys aged 2, 4, 8, 9, and 10 years. Symptoms ranged from generalized urticaria and angioedema to anaphylactic shock immediately after administration. Oral betamethasone was implicated in 2 cases, oral prednisolone in 2 cases, and intravenous prednisolone in 1 case. The parents of patient 5 refused the skin tests. The remaining patients underwent skin prick tests with the following undiluted corticosteroids: parenteral prednisolone, oral prednisolone, parenteral methylprednisolone, parenteral dexamethasone, parenteral hydrocortisone, and oral betamethasone. If the results were negative, intradermal tests were performed with the same drugs at increasing concentrations. Skin test results were positive for all suspect corticosteroids, thus indicating an immunoglobulin E-mediated mechanism. Two patients had positive skin test results to other corticosteroids, suggesting cross-reactivity. An oral challenge test was performed with deflazacort in 4 cases and with betamethasone in 1 case; the results were negative. PMID- 21243940 TI - Peripheral dendritic cells in asthma. PMID- 21243941 TI - Comparison of basophil activation test results in blood preserved in acid citrate dextrose and EDTA. PMID- 21243942 TI - Basophil activation test in a case of systemic hypersensitivity reaction to infliximab with good tolerance to another anti-TNF-alpha agent (adalimumab). PMID- 21243943 TI - Efficacy of the slow dose-up method for specific oral tolerance induction in children with cow's milk allergy: comparison with reported protocols. PMID- 21243944 TI - Metrorrhagia as an uncommon symptom of anaphylaxis. PMID- 21243945 TI - Why big is beautiful. PMID- 21243946 TI - 'Thermography windows' article misinformed. PMID- 21243947 TI - Green upgrades save some green. PMID- 21243948 TI - The many faces of fire hazards in industrial settings. PMID- 21243949 TI - AED mandates continue to rise. PMID- 21243950 TI - Combustible dust and the flash fire hazard. PMID- 21243951 TI - Use good practices throughout your facility. PMID- 21243952 TI - Here's your sign to make changes. PMID- 21243953 TI - Anchoring skills into daily actions. PMID- 21243954 TI - Not 'part of the job'. Nurses seek an end to workplace violence. PMID- 21243955 TI - A new health care horizon: nursing care reform. PMID- 21243956 TI - On the way to safety. PMID- 21243957 TI - ANA group uses expertise to examine and shape staffing, other policy. PMID- 21243959 TI - Nurses at center of health reform discussion with first lady. PMID- 21243958 TI - IOM report contains recommendations to facilitate advanced practice. PMID- 21243960 TI - IOM report calls for more nurse leaders throughout health care. PMID- 21243961 TI - ANF scholar's groundbreaking work on pain. PMID- 21243962 TI - Current perspectives on the biological study of play: signs of progress. AB - There has been a recent resurgence of interest in the study of play behavior, marked by much empirical research and theoretical review. These efforts suggest that play may be of greater biological significance than most scientists realize. Here we present a brief synopsis of current play research covering issues of adaptive function, phylogeny, causal mechanisms, and development. Our goal is to selectively highlight contemporary areas of research in which the underlying processes and consequences of play should not be ignored. We elucidate some of the new and burgeoning areas of play research and interpret them from an integrative biological theoretical perspective that highlights areas in need of further experimental, comparative, and field research. PMID- 21243963 TI - Experimental evolution, loss-of-function mutations, and "the first rule of adaptive evolution". AB - Adaptive evolution can cause a species to gain, lose, or modify a function; therefore, it is of basic interest to determine whether any of these modes dominates the evolutionary process under particular circumstances. Because mutation occurs at the molecular level, it is necessary to examine the molecular changes produced by the underlying mutation in order to assess whether a given adaptation is best considered as a gain, loss, or modification of function. Although that was once impossible, the advance of molecular biology in the past half century has made it feasible. In this paper, I review molecular changes underlying some adaptations, with a particular emphasis on evolutionary experiments with microbes conducted over the past four decades. I show that by far the most common adaptive changes seen in those examples are due to the loss or modification of a pre-existing molecular function, and I discuss the possible reasons for the prominence of such mutations. PMID- 21243964 TI - What is an individual organism? A multilevel selection perspective. AB - Most biologists implicitly define an individual organism as "one genome in one body." This definition is based on physiological and genetic criteria, but it is problematic for colonial organisms. We propose a definition based instead on the evolutionary criteria of alignment of fitness, export of fitness by germ-soma specialization, and adaptive functional organization. We consider how these concepts apply to various putative individual organisms. We conclude that complex multicellular organisms and colonies of eusocial insects satisfy these three criteria, but that, in most cases (with at least one notable exception), colonies of modular organisms and genetic chimeras do not. While species do not meet these criteria, they may meet the criteria for a broader concept--that of an evolutionary individual--and sexual reproduction may be a species-level exaptation for enhancing evolvability. We also review the costs and benefits of internal genetic heterogeneity within putative individuals, demonstrating that high relatedness is neither a necessary nor a sufficient condition for individuality, and that, in some cases, genetic variability may have adaptive benefits at the level of the whole. PMID- 21243965 TI - Irreducible incoherence and intelligent design: a look into the conceptual toolbox of a pseudoscience. AB - The concept of Irreducible Complexity (IC) has played a pivotal role in the resurgence of the creationist movement over the past two decades. Evolutionary biologists and philosophers have unambiguously rejected the purported demonstration of "intelligent design" in nature, but there have been several, apparently contradictory, lines of criticism. We argue that this is in fact due to Michael Behe's own incoherent definition and use of IC. This paper offers an analysis of several equivocations inherent in the concept of Irreducible Complexity and discusses the way in which advocates of the Intelligent Design Creationism (IDC) have conveniently turned IC into a moving target. An analysis of these rhetorical strategies helps us to understand why IC has gained such prominence in the IDC movement, and why, despite its complete lack of scientific merits, it has even convinced some knowledgeable persons of the impending demise of evolutionary theory. PMID- 21243966 TI - The impact of changes in gait speed and step frequency on the extent of the center of mass displacements. AB - Center of mass (COM) trajectory plays a crucial role in the analysis of human body movements. This research aimed at studying vertical and transverse COM displacements during gait on a treadmill at a given velocity and step frequency. Locomotion study was accomplished using: Vicon 250, Cardionics Treadmill 3113 and metronome Korg Ma-30. The data achieved for 12 women and 15 men aged 21-22 revealed similarity in vertical COM oscillations in both groups. Lateral COM displacements (L(COM)) were slightly higher in men than in women and they showed tendency to decrease as gait velocity increased. During natural locomotion there was an increasing trend as walking speed increased. At a given velocity of locomotion L(COM) were decreasing as step frequency increased. The only astonishing thing was that the biggest changes of vertical COM oscillations (V(COM)) were noticed at the fastest walking speed (6 km/h). It seems that so large decrease in V(COM) during walking with high velocity and increased step cadency is a consequence of considerable shortening of the movement cycles and performing time of one step. PMID- 21243967 TI - EMG frequency during isometric, submaximal activity: a statistical model for biceps brachii. AB - The purpose of this study was to develop a statistical model to describe the electromyography (EMG) signal frequency changes during a submaximal isometric contraction. Thirty subjects performed a 30-second isometric contraction of the biceps brachii muscle at 80% of the maximal voluntary isometric force. Surface EMG electrodes recorded electrical activity of the biceps brachii. Zero-Crossing Rate was calculated to identify EMG frequency shifts. The mean frequencies for every one-second period were used to calculate a linear relationship between frequency and time. A significant relationship (p<0.05) between slope and initial frequency value was identified. The model described EMG frequency changes during submaximal effort of biceps brachii up to 15 seconds. The prediction error was 9.8%. Modifying this equation to initial values of frequency of each participant decreased prediction error to 7.2%. These results demonstrate that despite individual differences between subjects it is possible to derive single equation that describes EMG alterations during submaximal, isometric contractions across a homogeneous group of people. PMID- 21243968 TI - Modelling dynamics and aerodynamic tests of a sport parachute jumper during flight in sitfly position. AB - Based on a model of a parachute jumper, for various body configurations in a sitting position, tests were carried out in an aerodynamic tunnel. Aerodynamic characteristics and dimensionless aerodynamic forces' coefficients were calculated. The tests were carried out for various configurations of the jumper's body. A universal mathematical model of a parachute jumper's body was prepared, thus enabling the analysis of the jumper's movement with a closed parachute in any position. In order to build the model, a digitized model of a jumper allowing changing the body configuration, making appropriate changes of the moment of inertia, distribution of the center of mass and the aerodynamic characteristics was adopted. Dynamic movement equations were derived for a jumper in a relative reference system. The mathematical model was formulated for a jumper with a variable body configuration during the flight, which can be realized through a change of the position and the speed of the parachute jumper's limbs. The model allows analyzing the motion of the jumper with a closed parachute. It is an important jump phase during an assault with delayed parachute opening in sports type jumping, e.g., Skydiving and in emergency jumps from higher altitudes for the parachute's opening to be safe. PMID- 21243969 TI - Magnetic resonance imaging (MRI) for assessment of differences in geometrical parameters in muscles stabilizing vertebral column in young and older persons. Case study. AB - Today non-traumatic low back pain (LBP) is a social disease being attributed to weakening the function of abdominal and back muscles. Condition of deep muscles, inaccessible to non-invasive examinations, can be assessed by means of magnetic resonance imaging (MRI). The method allows for the assessment of cross-sections, muscle girths, as well as their intensity (brightness). The aim of the investigations was to determine the opportunities to employ MRI technique for assessing the geometry of muscles which stabilize spinal column. The study covered 4 women without LBP symptoms. The cross-sectional area, thickness and brightness of abdominal and back muscles were measured at the level of L3-L4. Measurement of geometrical parameters in the positions studied was aimed at setting such measurement conditions that would force higher isometric contraction in the muscles examined. As a result of measurements it can be inferred that other conditions of the experiment affect neither an increase in cross-sectional surface area nor the thickness of the muscles examined. The differences observed in geometrical parameters of the muscles testify to different coordination of muscle activation in the positions studied, both in young and older subjects, and to the purposefulness of continuing this type of measurements. PMID- 21243970 TI - Assessment of the impact of orthotic gait training on balance in children with cerebral palsy. AB - The cerebral palsy symptoms are, among others, balance and gait disorders. The goal of this study was to assess balance capabilities in children with spastic diplegic cerebral palsy rehabilitated using Lokomat active orthosis. The experimental group included children with cerebral palsy, aged 6-14 years, independent standing, level II-III according to GMFCS classification. The cohort was randomly divided into two groups. The balance was assessed on a stabilometric platform. The experimental group was administered a rehabilitation program with the use of Lokomat active orthosis. Statistically significant improvement of balance was found in the experimental group; however, in the control group the improvement was also visible, but not on the statistically significant level. While comparing the results of both groups, significantly bigger improvement was achieved by the children from the experimental group. Lokomat active orthosis is one of the newest devices applied in the rehabilitation. The study shows that training with active orthosis can have positive influence on the balance improvement in children with CP and that further analysis of the impact of such training on locomotive functions is needed. PMID- 21243971 TI - The initial bearing capacities of subchondral bone replacements considerably contributing to chondrogenesis. AB - The degeneration of articular cartilage results from osteoarthritis and many other forms of severe arthritis. Current treatments for cartilage repair are less than satisfactory, and rarely restore a full function or return the tissue to its natural state. The leading strategies in the treatment are aimed at the transplantation of cells and/or the use of various biological grafts, bioactive agents, or biologically compatible implant matrices. The insertion of a crushed autologous bone graft has been reported as a possible therapy. However, the regenerative quality of the tissue was less than 70% of healthy cartilage for fragments and controls. The implantation of cycloolefin-blend 3D-cylinders with hydrogel scaffolds on their proximal parts and with the applications of type I collagen films is one of several surgical therapies. The replacement and continuous biomechanical properties of the subchondral bone play an important role in the morphology and the quality of chondrogenesis. The initial biomechanical stability of COC-blend polymer replacements in the subchondral bone contributes to the formation of a new cartilage tissue. The initial bearing capacities of the implanted tissue/replacements and vertical positions of the replacements have a principal influence upon both the quality and the quantity of new articular cartilage. PMID- 21243972 TI - Meta-analysis of clinical outcomes comparing surface ablation for correction of myopia with and without 0.02% mitomycin C. AB - PURPOSE: To evaluate the current clinical evidence of safety and efficacy of intraoperative topical application of 0.02% mitomycin C (MMC) used for up to 2 minutes after surface ablation for correction of myopia. METHODS: A comprehensive literature search was conducted of Cochrane Library, MEDLINE, and EMBASE to identify relevant trials comparing surface ablation for correction of myopia with and without MMC. A meta-analysis was performed on the results of the reports and statistical analysis was performed. RESULTS: Eleven clinical trials were identified with MMC used in 534 eyes and no MMC in 726 eyes. Surface ablations with MMC led to significantly less corneal haze in photorefractive keratectomy, whereas the results were comparable in laser epithelial keratomileusis (LASEK) and epithelial laser in situ keratomileusis (epi-LASIK). Although proportionately more eyes in the MMC group achieved uncorrected distance visual acuity 20/25 or better and less frequently lost >= 2 lines of corrected distance visual acuity, the difference was not statistically significant. CONCLUSIONS: Our meta-analysis suggests that the topical intraoperative application of 0.02% MMC may reduce haze and improve visual acuity after surface ablation for correction of myopia. However, the advantage of using MMC in LASEK and epi-LASIK is unclear. PMID- 21243973 TI - Corneal biomechanics following epi-LASIK. AB - PURPOSE: To evaluate corneal biomechanical changes following epi-LASIK. METHODS: In this prospective study of 51 patients, corneal hysteresis (CH), corneal resistance factor (CRF), and intraocular pressure (IOP) were assessed using the Ocular Response Analyzer (ORA, Reichert Technologies) preoperatively and at 1, 3, 6, and 12 months after epi-LASIK. Repeated measures analysis of variance (ANOVA) was used to compare changes over time (alpha=.05). Intraocular pressure was also measured by Goldmann applanation tonometry. RESULTS: Corneal hysteresis decreased from 10.22+/-1.65 mmHg preoperatively to 8.17+/-1.25 mmHg at 1 month, 8.46+/-1.44 mmHg at 3 months, 8.63+/-1.31 mmHg at 6 months, and 8.53+/-1.49 mmHg at 12 months. Corneal resistance factor decreased from 10.01+/-1.80 mmHg preoperatively to 7.82+/-1.68, 8.03+/-1.85, 7.77+/-1.50, and 7.80+/-1.66 mmHg at 1, 3, 6, and 12 months, respectively. Repeated measures ANOVA showed a significant change over time for both CH and CRF (P<.0005). All measures of IOP changed significantly over time (P<.0005). CONCLUSIONS: Epi-LASIK resulted in a significant change in CH and CRF postoperatively. Although some recovery occurred over time, CH, CRF, and IOP did not revert to preoperative levels. PMID- 21243974 TI - Phakic intraocular lens implantation in United States military warfighters: a retrospective analysis of early clinical outcomes of the Visian ICL. AB - PURPOSE: To assess short-term clinical outcomes after implantation of phakic intraocular lenses (Visian ICL, STAAR Surgical Co) in US military warfighters who are not good candidates for laser vision correction. METHODS: A retrospective interventional consecutive case series analysis of all eyes that underwent ICL surgery during a 14-month time period was performed. Main outcome measures included indications for surgery, efficacy, predictability, and early adverse events. RESULTS: Three-month postoperative visual data were available for 135 eyes of 69 patients who underwent ICL implantation during the study period. Indications included abnormal corneal topography (37%), thin predicted residual bed following LASIK (32%), history of dry eye (13%), thin corneal thickness (11%), or other (7%). Mean patient age was 30.9 +/- 6.6 years. Mean preoperative spherical equivalent refraction was -6.00 +/- 1.92 diopters (D) (range: -2.63 to 11.50 D). Three months postoperative, uncorrected distance visual acuity of 20/20 or better was found in 129/135 (96%) eyes and 91/135 (67%) were 20/15 or better. Manifest refraction and corrected distance visual acuity (CDVA) data were available for 128 eyes. Forty-two (33%) eyes had improvement of one or more lines of CDVA. One hundred fifteen eyes (90%) were within +/- 0.50 D of emmetropia, and predictability within +/- 0.75 D was found in 127/128 (99%) eyes. No significant intra- or postoperative complications were observed. CONCLUSIONS: This retrospective analysis of 3-month outcomes suggests that Visian ICL implantation in myopic warfighters provides excellent refractive and visual results. Further study is needed to evaluate long-term results. PMID- 21243975 TI - Bioptics in sutureless intrascleral multifocal posterior chamber intraocular lens fixation. AB - PURPOSE: To present a technique for sutureless fixation of a three-piece, multifocal, posterior chamber intraocular lens (IOL) in the ciliary sulcus. METHODS: A 24-year-old woman presented with bilateral subluxation of the crystalline lens. Two straight sclerotomies were prepared with a 24-gauge cannula 2.0 mm from the limbus 180 degrees apart from each other. The cannula was used to create a 2.0- to 3.0-mm tunnel parallel to the limbus starting from the sclerotomies. The leading haptic of the multifocal IOL was grasped at its tip with end-gripping, 25-gauge forceps and pulled through the sclerotomy. The forceps was used to introduce the IOL haptic into the scleral tunnel parallel to the limbus. RESULTS: Multifocal posterior chamber IOLs were stable and well centered. No postoperative complications occurred in the 16-month follow-up period. Preoperative astigmatism was corrected after IOL implantation with corneal wavefront-guided laser epithelial keratomileusis. CONCLUSIONS: Sutureless fixation of multifocal posterior chamber IOL haptics in a scleral tunnel parallel to the limbus can be successful, resulting in long-term centration and three dimensional axial stability for optimal refractive results. If necessary, postoperative wavefront-guided refractive correction can be performed to optimize final refraction. PMID- 21243976 TI - Detection of biomechanical changes after corneal cross-linking using Ocular Response Analyzer software. AB - PURPOSE: To investigate biomechanical changes after corneal cross-linking (CXL) with riboflavin/ultraviolet-A (UVA) in keratoconus using the recently developed Ocular Response Analyzer (ORA, Reichert Technologies) software. METHODS: Through use of the new ORA software (version 2.04), 37 new parameters derived from the best measurement signal with the highest wavescore of 4 measurements from 50 eyes of 46 patients with keratoconus were obtained before and 1 year after CXL. The parameters of 96 eyes from 96 age-matched, healthy individuals with a spherical equivalent refraction <3.00 diopters served as controls. RESULTS: Corneal hysteresis (CH) and corneal resistance factor (CRF) before CXL were 7.38+/-1.42 mmHg and 6.16+/-1.42 mmHg, respectively, compared to 7.37+/-1.26 mmHg (P=.971) and 6.16+/-1.50 mmHg after CXL (P=.997), respectively. Based on these 37 new parameters, the area under peak 2 (p2area) showed a statistically significant increase from 1262.3+/-623.1 before CXL to 1704.3+/-732.3 1 year after CXL (35%; P=.001). The related value for the p2area of the healthy control group was 3374.9+/-1099.9. A significant negative correlation was observed between the p2area and the difference in CH-CRF values (r=-0.29, P=.001). CONCLUSIONS: The area under peak 2 appears to be a more sensitive parameter to detect biomechanical changes after CXL than CH or CRF alone. After CXL, keratoconic corneas display altered biomechanical properties, which remain different to those observed in healthy corneas. PMID- 21243977 TI - Correction of astigmatism after cataract surgery using the light adjustable lens: a 1-year follow-up pilot study. AB - PURPOSE: The management of preoperative and residual astigmatism is critical to obtain optimized uncorrected visual acuity. The aim of this study was to determine whether residual astigmatism could be precisely corrected postoperatively using the Light Adjustable Lens (LAL, Calhoun Vision Inc) and to determine the stability of the adjusted refraction. METHODS: Ten eyes of 10 patients with cataract and corneal astigmatism between 1.00 and 2.00 diopters (D) were included. After standard phacoemulsification and implantation of the LAL, adjustment and lock-in procedures were completed. Before adjustment and 2 weeks, 6 months, and 1 year after lock-in, a full ophthalmic examination including uncorrected distance acuity (UDVA) and corrected distance visual acuity (CDVA), autorefraction, and manifest refraction was performed. RESULTS: All surgeries, adjustments, and lock-in procedures were performed with no complications. All eyes achieved +/-0.50 D of the targeted cylindrical adjustment. Mean spherical equivalent refraction was 0.03+/-0.84 D before adjustment and -0.06+/-0.25 D at final follow-up. The cylinder axis remained the same in 60% of eyes and all eyes were stable within 10 degrees rotation at 12-month follow-up. Seven of 10 eyes achieved UDVA of 20/25 or better whereas all eyes achieved UDVA of 20/32 or better. Corrected distance visual acuity remained stable in all eyes. CONCLUSIONS: In this pilot study, the LAL proved to be an efficient, predictable, and stable method of managing astigmatism in cataract patients. PMID- 21243978 TI - Congenital 4th nerve palsy. PMID- 21243979 TI - What's your diagnosis? Infantile primary congenital glaucoma with trisomy 21 (Down syndrome) associated with Brushfield spots. PMID- 21243980 TI - Binocular function in pseudophakic children. PMID- 21243982 TI - Diffuse choroidal atrophy in a boy with Klinefelter syndrome. PMID- 21243983 TI - Claiming cancer research in gerontological nursing. PMID- 21243984 TI - Patients eat food, not food categories or constituents. PMID- 21243986 TI - Increasing patient access to VBAC: New NIH and ACOG recommendations. PMID- 21243988 TI - Respiratory syncytial virus infection in children. AB - Respiratory syncytial virus (RSV) is an RNA virus that causes respiratory tract infections in children. In the North- ern Hemisphere, the peak infection season is November through April. By two years of age, most children will have had an RSV infection. Bronchiolitis, a lower respiratory tract infection, is often caused by RSV. An RSV infection is diagnosed based on patient history and physical examination. Children typically present with cough, coryza, and wheezing. Laboratory testing and chest radiography are not necessary to make the diagnosis. Serious concur- rent bacterial infections are rare. Treatment of an RSV infection is supportive, with particular attention to maintaining hydration and oxygenation. Children younger than 60 days and those with severe symptoms may require hospitalization. Neither antibiotics nor corticosteroids are helpful for bronchiolitis. A bronchodilator trial is appropriate for children with wheezing, but should not be continued unless there is a prompt favorable response. Frequent hand washing and contact isolation may prevent the spread of RSV infections. Children younger than two years at high risk of severe illness, including those born before 35 weeks of gestation and those with chronic lung or cardiac problems, may be candidates for palivizumab prophylaxis for RSV infection during the peak infection season. Most children recover uneventfully with supportive care. PMID- 21243989 TI - Respiratory syncytial virus infection. PMID- 21243990 TI - Cat-scratch Disease. AB - Cat-scratch disease is a common infection that usually presents as tender lymphadenopathy. It should be included in the differential diagnosis of fever of unknown origin and any lymphadenopathy syndrome. Asymptomatic, bacteremic cats with Bartonella henselae in their saliva serve as vectors by biting and clawing the skin. Cat fleas are responsible for horizontal transmission of the disease from cat to cat, and on occasion, arthropod vectors (fleas or ticks) may transmit the disease to humans. Cat-scratch disease is commonly diagnosed in children, but adults can present with it as well. The causative microorganism, B. henselae, is difficult to culture. Diagnosis is most often arrived at by obtaining a history of exposure to cats and a serologic test with high titers (greater than 1:256) of immunoglobulin G antibody to B. henselae. Most cases of cat-scratch disease are self-limited and do not require antibiotic treatment. If an antibiotic is chosen, azithromycin has been shown in one small study to speed recovery. Infrequently, cat-scratch disease may present in a more disseminated form with hepatosplenomegaly or meningoencephalitis, or with bacillary angiomatosis in patients with AIDS. PMID- 21243991 TI - Evaluation and management of intestinal obstruction. AB - Acute intestinal obstruction occurs when there is an interruption in the forward flow of intestinal contents. This interruption can occur at any point along the length of the gastrointestinal tract, and clinical symptoms often vary based on the level of obstruction. Intestinal obstruction is most commonly caused by intra abdominal adhesions, malignancy, or intestinal herniation. The clinical presentation generally includes nausea and emesis, colicky abdominal pain, and a failure to pass flatus or bowel movements. The classic physical examination findings of abdominal distension, tympany to percussion, and high-pitched bowel sounds suggest the diagnosis. Radiologic imaging can confirm the diagnosis, and can also serve as useful adjunctive investigations when the diagnosis is less certain. Although radiography is often the initial study, non-contrast computed tomography is recommended if the index of suspicion is high or if suspicion persists despite negative radiography. Management of uncomplicated obstructions includes fluid resuscitation with correction of metabolic derangements, intestinal decompression, and bowel rest. Evidence of vascular compromise or perforation, or failure to resolve with adequate bowel decompression is an indication for surgical intervention. PMID- 21243992 TI - Intestinal obstruction. PMID- 21243993 TI - Specialized nutrition support. AB - Specialized nutrition support should be offered to patients who are malnourished or at risk of becoming malnourished when it would benefit patient outcomes or quality of life. Improving the nutritional value of ingested food and tailoring intake to the patient's preferences, abilities, and schedule should be the first measures in addressing nutritional needs. When these interventions alone are insufficient to meet nutritional requirements, oral nutritional supplements should be considered. Nutritional status should be evaluated in patients before specialized nutrition sup- port is considered. Enteral nutrition is used when patients have a functional gastrointestinal tract but are unable to safely swallow. Although a variety of enteral formulas are available, evidence for choosing a specific formula is often lacking. Parenteral nutrition should be used only when enteral nutrition is not feasible. There are no known benefits of parenteral nutrition over the enteral route, and the risk of serious complications is much greater with parenteral nutrition. Even when the parenteral route is necessary, some enteral nutrition is beneficial when possible. Specialized nutrition support can provide an effective bridge until patients are able to return to normal food and, in rare cases, may be continued as long-term home enteral or parenteral nutrition. Specialized nutrition support is not obligatory and can be harmful in cases of futile care and at the end of life. PMID- 21243995 TI - Screening for impaired visual acuity in older adults. PMID- 21243996 TI - Acute foot rash in a healthy child during travel. Acute dermatitis. PMID- 21243997 TI - FPIN's clinical inquiries: Reducing ACL injuries in female athletes. PMID- 21243999 TI - Oleyl-chitosan nanoparticles based on a dual probe for optical/MR imaging in vivo. AB - Oleic acid-conjugated chitosan (oleyl-chitosan) is a powerful platform for encapsulating oleic acid-decorated iron oxide nanoparticles (ION), resulting in a good magnetic resonance imaging (MRI) probe. Oleyl-chitosan could self-assemble into core-shell structures in aqueous solution and provide the effective core compartment for loading ION. ION-loaded oleyl-chitosan nanoparticles showed good enhanced MRI sensitivity in a MR scanner. Cy5.5 dye was accessed to the oleyl chitosan conjugate for near-infrared (NIR) in vivo optical imaging. After intravenous injection of ION-loaded Cy5.5-conjugated oleyl-chitosan (ION-Cy5.5 oleyl-chitosan) nanoparticles in tumor-bearing mice, both NIRF and MR imaging showed the detectable signal intensity and enhancement in tumor tissues via enhanced permeability and retention (EPR) effect. Tumor accumulation of the nanoparticles was confirmed through ex vivo fluorescence images and Prussian blue staining images in tumor tissues. It is concluded that ION-Cy5.5-oleyl-chitosan nanoparticle is highly an effective imaging probe for detecting tumor in vivo. PMID- 21244000 TI - Zeta potential mediated reaction monitoring on nano and microparticles. AB - Nano and microparticles are widely used across the life science interface, with applications ranging from chemical probes of biological function to fluorescent particles for flow cytometry and cellular tracking. Increasingly, particles are modified with a variety of chemistries to boost their functionality and broaden their biological applicability. However, although particle modification has become standard laboratory practice, the ability to determine the extent and efficiency of chemical modification is often very limited and empirical in nature. Herein, we report the use of zeta potential analysis as a simple and rapid "direct-on-particle" approach allowing levels of bead modification and derivatization to be evaluated. As a proof-of-concept, aminomethyl-functionalized nano and microparticles were derivatized to display a variety of surface functionalities and their zeta potentials measured, allowing verification of the applicability of the approach for particle analysis. We demonstrate that zeta potential measurement is a convenient approach which allows multistep reaction sequences to be followed, and show that this method can be used to verify and validate successful particle modification. PMID- 21244002 TI - Bronsted acid-catalyzed decarboxylative redox amination: formation of N alkylindoles from azomethine ylides by isomerization. AB - A Bronsted acid-catalyzed decarboxylative redox amination involving aldehydes with 2-carboxyindoline for the synthesis of N-alkylindoles is described. The decarboxylative condensations of aldehydes with 2-carboxyindoline produce azomethine ylides in situ, which then transform into N-alkylindoles by isomerization. PMID- 21244003 TI - Synthesis of tetrahydrofurans by cyclization of homoallylic alcohols with iodine/iodine(III). AB - Tetrahydrofuran derivatives can be obtained by cyclofunctionalization of homoallylic alcohols bearing a terminal double bound by using [hydroxy(tosyloxy)iodo]benzene (HTIB, Koser's reagent) in the presence of a catalytic amount of I(2) (20 mol %) in MeOH under mild conditions. This transformation is an overall 5-endo-trig cyclization, which occurs by two different pathways. The first is a 4-exo-trig cyclization followed by ring expansion, whereas the second is an electrophilic addition followed by a 5-endo tet cyclization. PMID- 21244001 TI - Phenol nitration induced by an {Fe(NO)2}(10) dinitrosyl iron complex. AB - Cellular dinitrosyl iron complexes (DNICs) have long been considered NO carriers. Although other physiological roles of DNICs have been postulated, their chemical functionality outside of NO transfer has not been demonstrated thus far. Here we report the unprecedented dioxygen reactivity of a N-bound {Fe(NO)(2)}(10) DNIC, [Fe(TMEDA)(NO)(2)] (1). In the presence of O(2), 1 becomes a nitrating agent that converts 2,4,-di-tert-butylphenol to 2,4-di-tert-butyl-6-nitrophenol via formation of a putative iron-peroxynitrite [Fe(TMEDA)(NO)(ONOO)] (2) that is stable below -80 degrees C. Iron K-edge X-ray absorption spectroscopy on 2 supports a five-coordinated metal center with a bound peroxynitrite in a cyclic bidentate fashion. The peroxynitrite ligand of 2 readily decays at increased temperature or under illumination. These results suggest that DNICs could have multiple physiological or deleterious roles, including that of cellular nitrating agents. PMID- 21244004 TI - Gold-catalyzed stereoselective synthesis of azacyclic compounds through a redox/[2 + 2 + 1] cycloaddition cascade of nitroalkyne substrates. AB - We report a new redox/cycloaddition cascade on readily available 1-alkynyl-2 nitrobenzenes that produces complex azacyclic compounds stereoselectively. The core structures of the resulting products are constructed through a formal [2 + 2 + 1] cycloaddition among alpha-carbonyl carbenoids, nitroso species, and external alkenes. PMID- 21244005 TI - Protein detection using arrayed microsensor chips: tuning sensor footprint to achieve ultrasensitive readout of CA-125 in serum and whole blood. AB - Multiplexed assays that can measure protein biomarkers and internal standards are highly desirable given the potential to reduce false positives and negatives. We report here the use of a chip-based platform that achieves multiplexed immunosensing of the ovarian cancer biomarker CA-125 without the need for covalent labeling or sandwich complexes. The sensor chips allow the straightforward comparison of detectors of different sizes, and we used this feature to scan the microscale size regime for the best sensor size and optimize the limit of detection exhibited down to 0.1 U/mL. The assay has a straightforward design, with readout being performed in a single step involving the introduction of a noncovalently attached redox reporter group. The detection system reported exhibits excellent specificity, with analysis of a specific cancer biomarker, CA-125, performed in human serum and whole blood. The multiplexing of the system allows the analysis of the biomarker to be performed in parallel with an abundant serum protein for internal calibration. PMID- 21244006 TI - Three Streptococcus pneumoniae sialidases: three different products. AB - Streptococcus penumoniae is a major human pathogen responsible for respiratory tract infections, septicemia, and meningitis and continues to produce numerous cases of disease with relatively high mortalities. S. pneumoniae encodes up to three sialidases, NanA, NanB, and NanC, that have been implicated in pathogenesis and are potential drug targets. NanA has been shown to be a promiscuous sialidase, hydrolyzing the removal of Neu5Ac from a variety of glycoconjugates with retention of configuration at the anomeric center, as we confirm by NMR. NanB is an intramolecular trans-sialidase producing 2,7-anhydro-Neu5Ac selectively from alpha2,3-sialosides. Here, we show that the first product of NanC is 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (Neu5Ac2en) that can be slowly hydrated by the enzyme to Neu5Ac. We propose that the three pneumococcal sialidases share a common catalytic mechanism up to the final product formation step, and speculate on the roles of the enzymes in the lifecycle of the bacterium. PMID- 21244007 TI - Organocatalytic direct asymmetric vinylogous Michael reaction of an alpha,beta unsaturated gamma-butyrolactam with enones. AB - An organocatalytic asymmetric direct vinylogous Michael addition of alpha,beta unsaturated gamma-butyrolactam to enones has been achieved with a simple bifunctional thiourea-tertiary amine catalyst, affording the gamma-substituted butyrolactam products with high diastereo- and enantioselectivity (up to >40:1 dr and 94-99% ee). PMID- 21244008 TI - Double isocyanide cyclization: a synthetic strategy for two-carbon-tethered pyrrole/oxazole pairs. AB - A new strategy for the construction of the compounds with two different heterocycles, linked by a C(2)-tether via a domino process involving [5 + 1] annulation, ring-opening, and subsequent double isocyanide cyclization, from the reaction of ethyl isocyanoacetate with divinyl ketones (DVKs) has been developed. The chemoselective fragmentation of the cyclohexanone intermediate is the key for the formation of not only the C(2)-tether but also the two different heterocycles. PMID- 21244009 TI - Quercetin and isorhamnetin glycosides in onion (Allium cepa L.): varietal comparison, physical distribution, coproduct evaluation, and long-term storage stability. AB - During onion processing, the outer dried protective layer (outer paper layer) and first two fleshy leaf layers are removed. This coproduct material is a potential commercial source of flavonoids especially quercetin. In the following study, the flavonoid composition was determined in coproduct materials and the press cake (material generated after juice extraction) in several commercially important onion varieties grown in California. Flavonoids were characterized and quantified using LC-(ESI)MS/MS and HPLC. The long-term stability of quercetin glycosides was assessed in dried coproduct materials stored at 4 and 22 degrees C over a 12 month period. In all varieties, the predominant forms of quercetin were the quercetin 3,4'-O-glucoside and 4'-O-glucoside. The first layer had significantly higher levels of flavonoids than the outer paper, second, and inner flesh layers on a DW basis (p < 0.05). Allium cepa "Milestone" contained the highest levels (p < 0.05) of flavonoids (1703 mg/100 g on a dry weight basis (DW). Onion press cake had significantly higher levels of total quercetin as compared with fresh onions (p < 0.05). The levels of 4'-O-glucoside significantly decreased during the first month of storage and remained stable for 12 months of storage at either 4 or 22 degrees C (p < 0.05). PMID- 21244010 TI - Synthesis, structure, and optical properties of LiEu(PO3)4 nanoparticles. AB - A wet chemical approach was employed for the preparation of LiEu(PO(3))(4) nanoparticles. XRD, Raman spectroscopy, TEM, SAED, and IR measurements were used in order to determine the crystal structure and morphology of the obtained product. Complete optical studies including absorption, excitation, emission, and kinetic measurements were performed. At least two components of the (5)D(0) -> (7)F(0) transition were found, indicating the existence of more than one crystallographic position of the Eu(3+) ions. Asymmetry parameter R as well as the covalence of the Eu-O bond were found to decrease with the grain growth. PMID- 21244011 TI - Observation of hole accumulation in Ge/Si core/shell nanowires using off-axis electron holography. AB - Hole accumulation in Ge/Si core/shell nanowires (NWs) has been observed and quantified using off-axis electron holography and other electron microscopy techniques. The epitaxial [110]-oriented Ge/Si core/shell NWs were grown on Si (111) substrates by chemical vapor deposition through the vapor-liquid-solid growth mechanism. High-angle annular-dark-field scanning transmission electron microscopy images and off-axis electron holograms were obtained from specific NWs. The excess phase shifts measured by electron holography across the NWs indicated the presence of holes inside the Ge cores. Calculations based on a simplified coaxial cylindrical model gave hole densities of (0.4 +/- 0.2) /nm(3) in the core regions. PMID- 21244012 TI - Gold nanorod-photosensitizer complex for near-infrared fluorescence imaging and photodynamic/photothermal therapy in vivo. AB - A gold nanorod (GNR)-photosensitizer complex was developed for noninvasive near infrared fluorescence imaging and cancer therapy. We showed that (a) fluorescence emission and singlet oxygen generation by AlPcS(4) were quenched after complex formation with GNRs; (b) 4-fold greater intracellular uptake and better in vitro phototoxicity were observed in GNR-AlPcS(4)-treated cells than in free AlPcS(4) treated cells; and (c) after intravenous injection of the GNR-AlPcS(4) complex, tumor sites were clearly identified on near-infrared fluorescence images as early as 1 h after injection. The tumor-to-background ratio increased over time and was 3.7 at 24 h; tumor growth reduced by 79% with photodynamic therapy (PDT) alone and by 95% with dual photothermal therapy (PTT) and PDT. This novel multifunctional nanomedicine may be useful for near-infrared fluorescence imaging and PTT/PDT in various cancers. PMID- 21244013 TI - Linear correlation between 1H and 13C chemical shifts of ferriheme proteins and model ferrihemes. AB - The (1)H{(13)C} HMQC experiment at natural-abundance (13)C provides a very useful way of determining not only (1)H but also (13)C chemical shifts of most heme substituents, without isotopic labeling of the hemin. This is true both in model low-spin ferriheme complexes and in low-spin ferriheme proteins, even when the proton resonances are buried in the protein diamagnetic region, because the carbon shifts are much larger than the proton shifts. In addition, in many cases, the protohemin methyl cross peaks are fairly linearly related to each other, with the slope of the correlation, delta(C)/delta(H), being approximately -2.0 for most low-spin ferriheme proteins. The reasons why this should be the case, and when it is not, are discussed. PMID- 21244014 TI - Selective excitation of individual plasmonic hotspots at the tips of single gold nanostars. AB - Plasmonic hotspots in single gold nanostars are located at the tips and can be excited selectively by laser light as evidenced by photoelectron emission microscopy. Selectivity is achieved through wavelength and polarization of the excitation light. Comparing photoelectron emission intensity and dark-field scattering spectra of the same individual nanostars reveals differences in terms of observable plasmon resonance wavelengths and field enhancements. Differences are explained with the underlying near- and far-field processes of the two techniques. PMID- 21244015 TI - Supramolecular tetrads containing Sn(IV) porphyrin, Ru(II) porphyrin, and expanded porphyrins assembled using complementary metal-ligand interactions. AB - Two examples of supramolecular tetrads containing Sn(IV) porphyrin, expanded thiaporphyrins such as sapphyrin and rubyrin, and Ru(II) porphyrin assembled using non-interfering cooperative tin(IV)-oxygen and ruthenium(II)-nitrogen coordination properties are described. These are the first examples in which the expanded porphyrins are used as axial ligands. The tetrads were prepared by adopting one step as well as stepwise approaches. In a one pot approach, the mono meso-pyridyl dihydroxy Sn(IV) porphyrin, meso-hydroxyphenyl expanded thiaporphyrin, and Ru(II) porphyrin were reacted in benzene under refluxing conditions followed by column chromatographic purification on alumina to afford tetrads. In a stepwise approach, the axial bonding type of triads containing Sn(IV)porphyrin as central unit and expanded thiaporphyrins as axial ligands were synthesized first by reacting meso-pyridyl dihydroxy Sn(IV) porphyrin with meso hydroxyphenyl expanded thiaporphyrin in benzene at refluxing temperature. In the next step, the triads were reacted with Ru(II) porphyrin under mild reaction conditions to afford tetrads in decent yields. Both methods worked efficiently and produced stable, soluble tetrads in decent yields. One-dimensional (1D) and two-dimensional (2D) NMR techniques were used to confirm the identity of these novel tetrads. Absorption and electrochemical studies indicated that the components in tetrads interact weakly and retain their individual characteristic features. The steady state photophysical studies revealed that the quantum yield of Sn(IV) porphyrin in tetrads was reduced significantly because of non-radiative decay pathways operating in these systems. PMID- 21244016 TI - Cationic alkylaluminum-complexed zirconocene hydrides: NMR-spectroscopic identification, crystallographic structure determination, and interconversion with other zirconocene cations. AB - The ansa-zirconocene complex rac-Me(2)Si(1-indenyl)(2)ZrCl(2) ((SBI)ZrCl(2)) reacts with diisobutylaluminum hydride and trityl tetrakis(perfluorophenyl)borate in hydrocarbon solutions to give the cation [(SBI)Zr(MU-H)(3)(Al(i)Bu(2))(2)](+), the identity of which is derived from NMR data and supported by a crystallographic structure determination. Analogous reactions proceed with many other zirconocene dichloride complexes. [(SBI)Zr(MU-H)(3)(Al(i)Bu(2))(2)](+) reacts reversibly with ClAl(i)Bu(2) to give the dichloro-bridged cation [(SBI)Zr(MU-Cl)(2)Al(i)Bu(2)](+). Reaction with AlMe(3) first leads to mixed alkyl species [(SBI)Zr(MU-H)(3)(AlMe(x)(i)Bu(2-x))(2)](+) by exchange of alkyl groups between aluminum centers. At higher AlMe(3)/Zr ratios, [(SBI)Zr(MU Me)(2)AlMe(2)](+), a constituent of methylalumoxane-activated catalyst systems, is formed in an equilibrium, in which the hydride cation [(SBI)Zr(MU H)(3)(AlR(2))(2)](+) strongly predominates at comparable HAl(i)Bu(2) and AlMe(3) concentrations, thus implicating the presence of this hydride cation in olefin polymerization catalyst systems. PMID- 21244017 TI - Monitoring a reaction at submillisecond resolution in picoliter volumes. AB - Well-established rapid mixing techniques such as stopped-flow have been used to push the dead time for kinetic experiments down to a few milliseconds. However, very fast reactions are difficult to resolve below this limit. We now outline an approach that provides access to ultrafast kinetics but does not rely on active mixing at all. Here, the reagents are compartmentalized into water-in-oil emulsion microdroplets (diameter ~50 MUm) that are statically arrayed in pairs, resting side-by-side in a well feature of a poly(dimethylsiloxane) (PDMS) device. A reaction between the contents of two droplets arrayed in such a holding trap is initiated by droplet fusion that is brought about by electrocoalescence and known to occur on a time scale of about 100 MUs. A reaction between the reactants (Fe(3+) and SCN(-)) is monitored by image analysis measuring the product formation in the newly merged drop in both space and time, by use of a fast camera. A comparison of the concentration field of the reaction product with the output of a reaction-diffusion system of equations yields a rate constant k ~ 3 * 10(4) M(-3).s(-1). Since reaction and diffusion are formally included in the mathematical model, measurements can proceed immediately after the drop fusion, removing the need to allow time for mixing. This approach is different from existing methodologies, for example, experiments in a conventional stopped-flow apparatus but also electrofusion of moving droplets where contents are mixed by chaotic advection before a reaction is monitored. Our analysis makes kinetics accessible that are several times faster than techniques that have to allow time for mixing. PMID- 21244018 TI - Resistive-switching behavior in polycrystalline CaCu(3)Ti(4)O(12) nanorods. AB - Highly aligned CaCu(3)Ti(4)O(12) nanorod arrays were grown on Si/SiO(2)/Ti/Pt substrates by radio-frequency sputtering at a low deposition temperature of 300 degrees C and room temperature. Structural and morphological studies have shown that the nanostructures have a polycrystalline nature and are oriented perpendicular to the substrate. The high density of grain boundaries in the nanorods is responsible for the nonlinear current behavior observed in these arrays. The current-voltage (I-V) characteristics observed in nanorods were attributed to the resistive memory phenomenon. The electrical resistance of microcapacitors composed of CaCu(3)Ti(4)O(12) nanorods could be reversibly switched between two stable resistance states by varying the applied electric field. In order to explain this switching mechanism, a model based on the increase/decrease of electrical conduction controlled by grain boundary polarization has been proposed. PMID- 21244020 TI - Unveiling the formation pathway of single crystalline porous silicon nanowires. AB - Porous silicon nanowire is emerging as an interesting material system due to its unique combination of structural, chemical, electronic, and optical properties. To fully understand their formation mechanism is of great importance for controlling the fundamental physical properties and enabling potential applications. Here we present a systematic study to elucidate the mechanism responsible for the formation of porous silicon nanowires in a two-step silver assisted electroless chemical etching method. It is shown that silicon nanowire arrays with various porosities can be prepared by varying multiple experimental parameters such as the resistivity of the starting silicon wafer, the concentration of oxidant (H(2)O(2)) and the amount of silver catalyst. Our study shows a consistent trend that the porosity increases with the increasing wafer conductivity (dopant concentration) and oxidant (H(2)O(2)) concentration. We further demonstrate that silver ions, formed by the oxidation of silver, can diffuse upwards and renucleate on the sidewalls of nanowires to initiate new etching pathways to produce a porous structure. The elucidation of this fundamental formation mechanism opens a rational pathway to the production of wafer-scale single crystalline porous silicon nanowires with tunable surface areas ranging from 370 to 30 m(2) g(-1) and can enable exciting opportunities in catalysis, energy harvesting, conversion, storage, as well as biomedical imaging and therapy. PMID- 21244019 TI - Mechanistic studies of 1-aminocyclopropane-1-carboxylate deaminase: characterization of an unusual pyridoxal 5'-phosphate-dependent reaction. AB - 1-Aminocyclopropane-1-carboxylic acid (ACC) deaminase (ACCD) is a pyridoxal 5' phosphate (PLP)-dependent enzyme that cleaves the cyclopropane ring of ACC, to give alpha-ketobutyric acid and ammonia as products. The cleavage of the C(alpha) C(beta) bond of an amino acid substrate is a rare event in PLP-dependent enzyme catalysis. Potential chemical mechanisms involving nucleophile- or acid-catalyzed cyclopropane ring opening have been proposed for the unusual transformation catalyzed by ACCD, but the actual mode of cyclopropane ring cleavage remains obscure. In this report, we aim to elucidate the mechanistic features of ACCD catalysis by investigating the kinetic properties of ACCD from Pseudomonas sp. ACP and several of its mutant enzymes. Our studies suggest that the pK(a) of the conserved active site residue, Tyr294, is lowered by a hydrogen bonding interaction with a second conserved residue, Tyr268. This allows Tyr294 to deprotonate the incoming amino group of ACC to initiate the aldimine exchange reaction between ACC and the PLP coenzyme and also likely helps to activate Tyr294 for a role as a nucleophile to attack and cleave the cyclopropane ring of the substrate. In addition, solvent kinetic isotope effect (KIE), proton inventory, and (13)C KIE studies of the wild type enzyme suggest that the C(alpha)-C(beta) bond cleavage step in the chemical mechanism is at least partially rate-limiting under k(cat)/K(m) conditions and is likely preceded in the mechanism by a partially rate-limiting step involving the conversion of a stable gem-diamine intermediate into a reactive external aldimine intermediate that is poised for cyclopropane ring cleavage. When viewed within the context of previous mechanistic and structural studies of ACCD enzymes, our studies are most consistent with a mode of cyclopropane ring cleavage involving nucleophilic catalysis by Tyr294. PMID- 21244021 TI - Diversonol and blennolide derivatives from the endophytic fungus Microdiplodia sp.: absolute configuration of diversonol. AB - Chemical investigation of the fungal strain Microdiplodia sp. isolated from the shrub Lycium intricatum led to the isolation of four new compounds: a hexahydroxanthone (2), a 2,3-dihydrochroman-4-one (3), a 7-oxoxanthone derivative (4), and a 1,4-oxazepan-7-one (5). The relative configurations of the new compounds were determined by intensive NMR investigations, notably NOESY experiments at different temperatures. The absolute configurations of the well known fungal metabolite diversonol (1) and of other xanthone derivatives (3, 4) were established by means of TDDFT ECD calculations. Most of the metabolites were biologically active, with antibacterial activity against Legionella pneumophila and/or antifungal activity against Microbotryum violaceum. PMID- 21244022 TI - Characterization of the terminal activation step catalyzed by oxygenase CmmOIV of the chromomycin biosynthetic pathway from Streptomyces griseus. AB - Inactivation and initial interrogation of key oxygenase CmmOIV of the biosynthetic pathway of chromomycin A(3) in Streptomyces griseus ssp. griseus revealed that a completely methylated and acetylated prechromomycin is the preferred substrate of this enzyme. This suggests that the three sugar decoration reactions, two O-acetylations and an O-methylation, which were previously believed to occur as the final steps of chromomycin A(3) biosynthesis, indeed take place prior to the CmmOIV reaction. Upon inactivation of CmmOIV, four new compounds accumulated; the fully decorated prechromomycin and its incompletely acetylated precursor along with a diketoprechromomycin-type compound were fully characterized and assayed with CmmOIV. PMID- 21244023 TI - Unraveling the mechanism of nanotube formation by chiral self-assembly of amphiphiles. AB - The self-assembly of nanotubes from chiral amphiphiles and peptide mimics is still poorly understood. Here, we present the first complete path to nanotubes by chiral self-assembly studied with C(12)-beta(12) (N-alpha-lauryl-lysyl aminolauryl-lysyl-amide), a molecule designed to have unique hybrid architecture. Using the technique of direct-imaging cryo-transmission electron microscopy (cryo TEM), we show the time-evolution from micelles of C(12)-beta(12) to closed nanotubes, passing through several types of one-dimensional (1-D) intermediates such as elongated fibrils, twisted ribbons, and coiled helical ribbons. Scattering and diffraction techniques confirm that the fundamental unit is a monolayer lamella of C(12)-beta(12), with the hydrophobic tails in the gel state and beta-sheet arrangement. The lamellae are held together by a combination of hydrophobic interactions, and two sets of hydrogen-bonding networks, supporting C(12)-beta(12) monomers assembly into fibrils and associating fibrils into ribbons. We further show that neither the "growing width" model nor the "closing pitch" model accurately describe the process of nanotube formation, and both ribbon width and pitch grow with maturation. Additionally, our data exclusively indicate that twisted ribbons are the precursors for coiled ribbons, and the latter structures give rise to nanotubes, and we show chirality is a key requirement for nanotube formation. PMID- 21244024 TI - Low-temperature approach to high-yield and reproducible syntheses of high-quality small-sized PbSe colloidal nanocrystals for photovoltaic applications. AB - Small-sized PbSe nanocrystals (NCs) were synthesized at low temperature such as 50-80 degrees C with high reaction yield (up to 100%), high quality, and high synthetic reproducibility, via a noninjection-based one-pot approach. These small sized PbSe NCs with their first excitonic absorption in wavelength shorter than 1200 nm (corresponding to size < ~3.7 nm) were developed for photovoltaic applications requiring a large quantity of materials. These colloidal PbSe NCs, also called quantum dots, are high-quality, in terms of narrow size distribution with a typical standard deviation of ~7-9%, excellent optical properties with high quantum yield of ~50-90% and small full width at half-maximum of ~130-150 nm of their band-gap photoemission peaks, and high storage stability. Our synthetic design aimed at promotion of the formation of PbSe monomers for fast and sizable nucleation with the presence of a large number of nuclei at low temperature. For formation of the PbSe monomer, our low-temperature approach suggests the existence of two pathways of Pb-Se (route a) and Pb-P (route b) complexes. Either pathway may dominate, depending on the method used and its experimental conditions. Experimentally, a reducing/nucleation agent, diphenylphosphine, was added to enhance route b. The present study addresses two challenging issues in the NC community, the monomer formation mechanism and the reproducible syntheses of small-sized NCs with high yield and high quality and large-scale capability, bringing insight to the fundamental understanding of optimization of the NC yield and quality via control of the precursor complex reactivity and thus nucleation/growth. Such advances in colloidal science should, in turn, promote the development of next-generation low-cost and high-efficiency solar cells. Schottky-type solar cells using our PbSe NCs as the active material have achieved the highest power conversion efficiency of 2.82%, in comparison with the same type of solar cells using other PbSe NCs, under Air Mass 1.5 global (AM 1.5G) irradiation of 100 mW/cm(2). PMID- 21244025 TI - Theoretical molecular descriptors relevant to the uptake of persistent organic pollutants from soil by zucchini. A QSAR study. AB - The uptake of persistent organic pollutants (POPs) from soil by plants allows the development of phytoremediation protocols to rehabilitate contaminated areas. The use of diverse theoretical descriptors has been reported in the literature for developing quantitative structure-activity relationship (QSAR) models for predicting the bioconcentration factors (BCFs) of POPs in different plants. In this paper an evaluation is given on the molecular properties of POPs in terms of theoretical molecular descriptors that are relevant to the uptake and accumulation of these persistent pollutants from soil by two zucchini varieties. Statistically significant and predictive linear regression models have been developed for the BCF values of 20 polychlorinated dibenzo-p dioxins/dibenzofurans and 14 polyhalogenated biphenyls in two zucchini varieties based on retrospective data. The relevant parameters have been selected from a set of 1660 DRAGON, 150 VolSurf, and 11 quantum chemical descriptors. The two most significant regression models, containing VolSurf, DRAGON GETAWAY, and quantum chemical descriptors, displayed the following statistical parameters: (eq 3) n = 27, R(2) = 0.940, q(2) = 0.922, SE = 0.155, F = 392.1; (eq 4) n = 27, R(2) = 0.921, q(2) = 0.898, SE = 0.161, F = 140.4. Predictive capabilities of the equations have been validated by using external validation sets. The QSAR models proposed might contribute to the development of viable soil remediation strategies. PMID- 21244026 TI - Fluorescence sensing of zinc(II) using ordered mesoporous silica material (MCM 41) functionalized with N-(quinolin-8-yl)-2-[3 (triethoxysilyl)propylamino]acetamide. AB - A novel fluorescent zinc sensor was designed and synthesized on ordered mesoporous silica material, MCM-41, with N-(quinolin-8-yl)-2-[3 (triethoxysilyl)propylamino]acetamide (QTEPA; 3) using a simple one-step molecular self-assembly of the silane. The solution and solid samples were characterized using solid-state nuclear magnetic resonance, transmission electron microscopy, diffuse-reflectance infrared Fourier transform, and thermogravimetric analysis techniques. The QTEPA-modified MCM-41 (4) shows 3-fold fluorescence emission enhancement and about a 55 nm red shift upon addition of 1 MUM Zn(II) ions in a Tris-HCl (pH 7.22) aqueous buffer solution. The UV-vis absorption maximum is at 330 +/- 5 nm, and the fluorescence emission maximum wavelength is at 468 nm, with an increase in quantum yield from 0.032 to 0.106 under the same conditions. The presence of other metal ions has no observable effect on the sensitivity and selectivity of 4. This system selectively detects Zn(II) ions with submicromolar detection to a limit of 0.1 MUM. The MCM-41-based systems have the advantage that they can be employed in aqueous solutions without any aggregation. PMID- 21244027 TI - Slow conformational dynamics in the cystoviral RNA-directed RNA polymerase P2: influence of substrate nucleotides and template RNA. AB - The RNA-directed RNA polymerase P2 from cystovirus phi6 catalyzes the de novo synthesis of positive and negative strands of the viral double-stranded RNA genome. P2 is mobile on the slow, microsecond to millisecond time scale with various motional modes, putatively assisting in RNA translocation and catalysis. Here we investigate the influence of the extreme 3'-end sequence of the single stranded RNA templates and the nature of the substrate nucleotide triphosphates on these motional modes using multiple-quantum NMR spectroscopy. We find that P2, in the presence of templates bearing the proper genomic 3'-ends or the preferred initiation nucleotide, displays unique dynamic signatures that are different from those in the presence of nonphysiological templates or substrates. This suggests that dynamics may play a role in the fidelity of recognition of the correct substrates and template sequences to initiate RNA polymerization. PMID- 21244028 TI - Highly polar carbohydrates stack onto DNA duplexes via CH/pi interactions. AB - Carbohydrate-nucleic acid contacts are known to be a fundamental part of some drug-DNA recognition processes. Most of these interactions occur through the minor groove of DNA, such as in the calicheamicin or anthracycline families, or through both minor and major groove binders such as in the pluramycins. Here, we demonstrate that carbohydrate-DNA interactions are also possible through sugar capping of a DNA double helix. Highly polar mono- and disaccharides are capable of CH/pi stacking onto the terminal DNA base pair of a duplex as shown by NMR spectroscopy. The energetics of the carbohydrate-DNA interactions vary depending on the stereochemistry, polarity, and contact surface of the sugar involved and also on the terminal base pair. These results reveal carbohydrate-DNA base stacking as a potential recognition motif to be used in drug design, supramolecular chemistry, or biobased nanomaterials. PMID- 21244029 TI - Tuning the cavity of cyclodextrins: altered sugar adaptors in protein pores. AB - Cyclodextrins (CDs) have been widely used in host-guest molecular recognition because of their chiral and hydrophobic cavities. For example, beta-cyclodextrin (betaCD) lodged as a molecular adaptor in protein pores such as alpha-hemolysin (alphaHL) is used for stochastic sensing. Here, we have tuned the cavity and overall size of betaCD by replacing a single oxygen atom in its ring skeleton by a disulfide unit in two different configurations to both expand our ability to detect analytes and understand the interactions of betaCD with protein pores. The three-dimensional structures of the two stereoisomeric CDs have been determined by the combined application of NMR spectroscopy and molecular simulation and show distorted conformations as compared to natural betaCD. The interactions of these synthetic betaCD analogues with mutant alphaHL protein pores and guest molecules were studied by single-channel electrical recording. The dissociation rate constants for both disulfide CDs from the mutant pores show ~1000-fold increase as compared to those of unaltered betaCD, but are ~10-fold lower than the dissociation rate constants for betaCD from wild-type alphaHL. Both of the skeleton-modified CDs show altered selectivity toward guest molecules. Our approach expands the breadth in sensitivity and diversity of sensing with protein pores and suggests structural parameters useful for CD design, particularly in the creation of asymmetric cavities. PMID- 21244030 TI - Divided-evolution-based pulse scheme for quantifying exchange processes in proteins: powerful complement to relaxation dispersion experiments. AB - A method for quantifying millisecond time scale exchange in proteins is presented based on scaling the rate of chemical exchange using a 2D (15)N, (1)H(N) experiment in which (15)N dwell times are separated by short spin-echo pulse trains. Unlike the popular Carr-Purcell-Meiboom-Gill (CPMG) experiment where the effects of a radio frequency field on measured transverse relaxation rates are quantified, the new approach measures peak positions in spectra that shift as the effective exchange time regime is varied. The utility of the method is established through an analysis of data recorded on an exchanging protein-ligand system for which the exchange parameters have been accurately determined using alternative approaches. Computations establish that a combined analysis of CPMG and peak shift profiles extends the time scale that can be studied to include exchanging systems with highly skewed populations and exchange rates as slow as 20 s(-1). PMID- 21244031 TI - Xanthene-modified and hangman iron corroles. AB - Iron corroles modified with a xanthene scaffold are delivered from easily available starting materials in abbreviated reaction times. These new iron corroles have been spectroscopically examined with particular emphasis on defining the oxidation state of the metal center. Investigation of their electronic structure using (57)Fe Mossbauer spectroscopy in conjunction with density functional theory (DFT) calculations reveals the non-innocence of the corrole ligand. Although these iron corroles contain a formal Fe(IV) center, the deprotonated corrole macrocycle ligand is one electron oxidized. The electronic ground state of these complexes is best described as an intermediate spin S = 3/2 Fe(III) site strongly antiferromagnetically coupled to the S = 1/2 of the monoradical dianion corrole [Fe(III)Cl-corrole(+*)]. We show here that iron corroles as well as xanthene-modified and hangman xanthene iron corroles are redox active and catalyze the disproportionation of hydrogen peroxide via the catalase reaction, and that this activity scales with the oxidation potential. The meso position of corrole macrocycle is susceptible toward nucleophilic attack during catalase turnover. The reactivity of peroxide within the hangman cleft reported here adds to the emerging theme that corroles are good at catalyzing two electron activation of the oxygen-oxygen bond in a variety of substrates. PMID- 21244032 TI - Synthesis and luminescent properties of cis bis-N-heterocyclic carbene platinum(II) bis-arylacetylide complexes. AB - A series of luminescent N-heterocyclic carbene platinum(II) complexes, [(pmim)Pt(C=C-R)(2)] (R = C(6)H(5) (2), C(6)H(4)OMe (3), C(6)H(2)(OMe)(3) (4), C(6)H(4)NMe(2) (5), C(4)H(3)S (6), C(6)H(4)C=CC(6)H(5) (7), 1-pyrenyl (8), and C(6)H(4)F (9)), were successfully synthesized using the precursor (pmim)PtI(2), 1 (pmim = 1,1'-dipentyl-3,3'-methylene-diimidazoline-2,2'-diylidene). The X-ray crystal structures of 1, 4, 5, and 7 have been determined. These complexes showed long-lived emission in solution at room temperature. The emission origin of the complexes is tentatively assigned to be from triplet states of predominantly intraligand (IL) character with some mixing of metal-to-ligand charge-transfer (MLCT) character. TD-DFT and DFT calculations have been performed on most of the complexes to ascertain the nature of the excited state. Changes in the alkynyl ligands lead to a change in the absorption and emission maxima seen for these complexes in a potentially predictable way. PMID- 21244033 TI - Co3O4@graphene composites as anode materials for high-performance lithium ion batteries. AB - This paper reports on the synthesis of Co(3)O(4)@graphene composites (CGC) and their applications as anode materials in lithium ion batteries (LIBs). Through a chemical deposition method, Co(3)O(4) nanoparticles (NPs) with sizes in the range of 10-30 nm were homogeneously dispersed onto graphene sheets. Due to their high electrical conductivity, the graphene sheets in the CGC improved the electrical conductivity and the structure stability of CGC. CGC displayed a superior performance in LIBs with a large reversible capacity value of 941 mA hg(-1) in the initial cycle with a large current density and an excellent cyclic performance of 740 mA hg(-1) after 60 cycles, corresponding to 88.3% of the theoretical value of CGC, owing to the interactions between graphene sheets and Co(3)O(4) NPs anchored on the graphene sheets. This synthesis approach may find its application in the design and synthesis of novel electrode materials used in LIBs. PMID- 21244034 TI - Molecule-ion interaction and its effect on electrostatic interaction in the system of copper chloride and beta-cyclodextrin. AB - The present work was devoted to an experimental investigation of the molecule-ion interaction between copper chloride (CuCl(2)) and beta-cyclodextrin (CD) and its effect on the electrostatic interaction between Cu(2+) and Cl(-) ions. Our results gave an explicit description of the mutual effect between the interactions. First, the molecular arrangement and surface feature of beta-CD experienced a fundamental structural change after interaction with Cu(2+) and Cl( ) ions, which was ascribed to a good separation of Cu(2+) from Cl(-) ions in beta CD matrix. Second, arguments based on electronic structural analysis provided a direct indication of the change in charge density distributions of Cu(2+) and Cl( ) ions in the presence of beta-CD. Third, the actual occurrence of a second signal in the course of water release at a higher temperature suggested that the Cu(2+) ions were trapped in the form of hydrates in the crystal interstice of beta-CD molecules. Fourth, comparison of the mass spectra indicated that the thermal decomposition of beta-CD in the presence of CuCl(2) produced a series of interesting molecular ions: C(3)H(2)OH(+), C(4)H(3)OH(+), C(5)H(4)OH(+), and C(7)H(6)OH(+). We consider that this study is helpful in providing a new approach to the evaluation of the extent of the mutual effect between an inorganic salt and an organic molecule. PMID- 21244035 TI - Isomeric complexes of [RuII(trpy)(L)Cl] (trpy=2,2':6',2''-terpyridine and HL=quinaldic acid): preference of isomeric structural form in catalytic chemoselective epoxidation process. AB - The present work deals with the isomeric complexes of the molecular composition [Ru(II)(trpy)(L)Cl] in 1 and 2 (trpy = 2,2':6',2''-terpyridine, L = deprotonated form of quinaldic acid, HL). Isomeric identities of 1 and 2 have been established by their single-crystal X-ray structures, which reveal that under the meridional configuration of trpy, O(-) and N donors of the unsymmetrical L are in trans, cis and cis, trans configurations, respectively, with respect to the Ru-Cl bond. Compounds 1 and 2 exhibit appreciable differences in bond distances involving Ru Cl and Ru-O1/Ru-N1 associated with L on the basis of their isomeric structural features. In relation to isomer 2, the isomeric complex 1 exhibits a slightly lower Ru(II)-Ru(III) oxidation potential [0.35 (1), 0.38 (2) V versus SCE in CH(3)CN] as well as lower energy MLCT transitions [559 nm and 417 nm (1) and 533 nm and 378 nm (2)]. This has also been reflected in the DFT calculation where a lower HOMO-LUMO gap of 2.59 eV in 1 compared to 2.71 eV in 2 is found. The isomeric structural effect in 1 and 2 has also been prominent in their (1)H NMR spectral profiles. The relatively longer Ru-Cl bond in 1 (2.408(2) A) as compared to 2 (2.3813(9) A) due to the trans effect of the anionic O(-) of coordinated L makes it labile, which in turn facilitates the transformation of [Ru(II)(trpy)(L)(Cl)] (1) to the solvate species, [Ru(II)(trpy)(L)(CH(3)CN)](Cl) (1a) while crystallizing 1 from the coordinating CH(3)CN solvent. The formation of 1a has been authenticated by its single-crystal X-ray structure. However, no such exchange of "Cl(-)" by the solvent molecule occurs in 2 during the crystallization process from the coordinating CH(3)CN solvent. The labile Ru-Cl bond in 1 makes it a much superior precatalyst for the epoxidation of alkene functionalities. Compound 1 is found to function as an excellent precatalyst for the epoxidation of a wide variety of alkene functionalities under environmentally benign conditions using H(2)O(2) as an oxidant and EtOH as a solvent, while isomer 2 remains almost ineffective under identical reaction conditions. The remarkable differences in catalytic performances of 1 and 2 based on their isomeric structural aspects have been addressed. PMID- 21244037 TI - Statistical integration of 1H NMR and MRS data from different biofluids and tissues enhances recovery of biological information from individuals with HIV-1 infection. AB - Nuclear magnetic resonance (NMR) spectroscopy is widely used in metabonomics studies, but optimal recovery of latent biological information requires increasingly sophisticated statistical methods to identify quantitative relationships within these often highly complex data sets. Statistical heterospectroscopy (SHY) extracts latent relationships between NMR and mass spectrometry (MS) data from the same samples. Here we extend this concept to identify novel metabolic correlations between different biofluids and tissues from the same individuals. We acquired NMR data from blood plasma and cerebrospinal fluid (CSF) (N = 19) from HIV-1-infected individuals, who are known to be susceptible to neuropsychological dysfunction. We compared two computational approaches to SHY, namely the Pearson's product moment correlation and the Spearman's rank correlation. High correlations were observed for glutamine, valine, and polyethylene glycol, a drug delivery vehicle. Orthogonal projections to latent structures (OPLS) identified metabolites in blood plasma spectra that predicted the amounts of key CSF metabolites such as lactate, glutamine, and myo-inositol. Finally, brain metabolic data from magnetic resonance spectroscopy (MRS) measurements in vivo were integrated with CSF data to identify an association between 3-hydroxyvalerate and frontal white matter N acetyl aspartate levels. The results underscore the utility of tools such as SHY and OPLS for coanalysis of high dimensional data sets to recover biological information unobtainable when such data are analyzed in isolation. PMID- 21244036 TI - Chemistry of nitrosyliron complexes supported by a beta-diketiminate ligand. AB - Several nitrosyl complexes of Fe and Co have been prepared using the sterically hindered Ar-nacnac ligand (Ar-nacnac = anion of [(2,6 diisopropylphenyl)NC(Me)](2)CH). The dinitrosyliron complexes [Fe(NO)(2)(Ar nacnac)] (1) and (Bu(4)N)[Fe(NO)(2)(Ar-nacnac)] (2) react with [Fe(III)(TPP)Cl] (TPP = tetraphenylporphine dianion) to generate [Fe(II)(NO)(TPP)] and the corresponding mononitrosyliron complexes. The factors governing NO transfer with dinitrosyliron complexes (DNICs) 1 and 2 are evaluated, together with the chemistry of the related mononitrosyliron complex, [Fe(NO)Br(Ar-nacnac)] (4). The synthesis and properties of the related cobalt dinitrosyl [Co(NO)(2)(Ar-nacnac)] (3) is also discussed for comparison to DNICs 1 and 2. The solid-state structures of several of these compounds as determined by X-ray crystallography are reported. PMID- 21244038 TI - Simultaneous intracellular beta-D-glucosidase and phosphodiesterase I activities measurements based on a triple-signaling fluorescent probe. AB - Despite that considerable efforts have been devoted to the design of various fluorogenic enzyme substrates, they are single-enzyme assay approaches that cannot afford detection of multienzyme activity. In this study, we set out our first attempt to design a new probe that could measure intracellular beta-D glucosidase and phosphodiesterase I activities. Unlike the commonly used fluorogenic enzyme substrates that contain one recognition site and signaling reporter, the new probe molecule possesses two cleavage sites, specificly corresponding to beta-D-glucosidase and phosphodiesterase I, and three fluorescent reporters, 7-beta-D-glucopyranosyloxycoumarin, 7-hydroxycoumarin, and meso-tetraphenylporphyrin. On the basis of intramolecular photoinduced electron transfer and fluorescence resonance energy transfer mechanisms, interaction of the probe with the two enzymes, whether only one or both, produces different signal readouts with high sensitivity. Remarkably, the probe is chemically stable in complex biological fluids. Fluorescence outputs are not significantly affected by biologically related metal ions, anions, amino acids, and proteins. Furthermore, fluorescence microscopy confirmed that the probe is an excellent candidate for intracellular delivery and can be accumulated intensively in cells. We demonstrated the applicability for the simultaneous images of intracellular beta-D-glucosidase and phosphodiesterase I activities using the different optical imaging modes. PMID- 21244039 TI - Biological stability evaluation of the alpha2beta1 receptor imaging agents: diamsar and DOTA conjugated DGEA peptide. AB - Robust chelating stability under biological condi-tions is critical for the design of copper-based radiopharmaceuticals. In this study, the stabilities of (64)Cu-DOTA and diamsar (two bifunctional Cu-64 chelators (BFCs)) conjugated DGEA peptides were evaluated. The in vitro stabilities of (64)Cu-DOTA-DGEA, (64)Cu DOTA-Ahx-DGEA, and (64)Cu-Z-E(diamsar)-Ahx-DGEA were evaluated in PBS. A carboxyl protected DOTA-DGEA was also synthesized to study the potential inter- and intramolecular interactions between DOTA and the carboxylate groups of DGEA peptide. microPET imaging of (64)Cu-DOTA-DGEA and (64)Cu-Z-E(diamsar)-Ahx-DGEA were performed in PC-3 prostate tumor model to further investigate the in vivo behavior of the tracers. DOTA-DGEA, DOTA-Ahx-DGEA, Z-E(diamsar)-Ahx-DGEA, and protected DOTA-DGEA peptides were readily obtained, and their identities were confirmed by MS. (64)Cu(2+) labeling was performed with high radiochemical yields (>98%) for all tracers after 1 h incubation. Stability experiments revealed that (64)Cu-DOTA-DGEA had unexpectedly high (64)Cu(2+) dissociation when incubated in PBS (>55% free (64)Cu(2+) was observed at 48 h time point). The (64)Cu(2+) dissociation was significantly reduced in the carboxyl-protected (64)Cu-DOTA-DGEA complex but not in the (64)Cu-DOTA-Ahx-DGEA complex, which suggests the presence of competitive binding for (64)Cu(2+) between DOTA and the carboxyl groups of the DGEA peptide. In contrast, no significant (64)Cu(2+) dissociation was observed for (64)Cu-Z-E(diamsar)-Ahx-DGEA in PBS. For microPET imaging, the PC-3 tumors were clearly visualized with both (64)Cu-DOTA-DGEA and (64)Cu-Z-E(diamsar)-Ahx DGEA tracers. However, (64)Cu-DOTA-DGEA demonstrated 5* higher liver uptake than (64)Cu-Z-E(diamsar)-Ahx-DGEA. This biodistribution variance could be attributed to the chelating stability difference between these two tracers, which correlated well with the PBS stability experiments. In summary, the in vitro and in vivo evaluations of (64)Cu-Z-E(diamsar)-Ahx-DGEA and (64)Cu-DOTA-DGEA have demonstrated the significantly superior Cu-chelation stability for the diamsar derivative compared with the established DOTA chelator. The results also suggest that diamsar may be preferred for Cu chelation especially when multiple carboxylic acid groups are present. Free carboxyl groups may naturally compete with DOTA for (64)Cu(2+) binding and therefore reduce the complex stability. PMID- 21244041 TI - Controlled morphogenesis of organic polyhedral nanocrystals from cubes, cubooctahedrons, to octahedrons by manipulating the growth kinetics. AB - Morphological control of organic nanocrystals (ONCs) is important in the fields ranging from specialty chemicals to molecular semiconductors. Although the thermodynamic shape can be readily predicted, most growth morphologies of ONCs are actually determined by kinetic factors and remain poorly understood. On the basis of the reduction of zinc tetraphenylporphyrin perchlorate (ZnTPP(+)ClO(4)( )) with sodium nitrite (Na(+)NO(2)(-)), we synthesized two series of ONCs of aquozinc tetraphenylporphyrin (ZnTPP.H(2)O), in the presence of either cetyltrimethylammonium bromide (CTAB) or poly(vinyl pyrrolidone) (PVP) as the capping ligands. As the cationic precursors of ZnTPP(+) are separated in the solution phase, smoothly controlled release of ZnTPP.H(2)O building blocks via the reduction reaction facilitates the separation between the nucleation and growth stages during the formation of ONCs and provides a high and tunable supersaturation unavailable by employing conventional crystallization techniques. We found that CTAB mainly serve as the colloidal stabilizer, while selective adhesion of PVP on the {020}s facet alters the crystal habits significantly. In both cases, manipulation of the growth kinetics had been achieved by adjusting the concentration of ZnTPP.H(2)O growth units, and consequently, the supersaturation for the crystallization, thus yielding ONCs with well-controlled sizes and shapes. Remarkably, thermodynamically stable octahedrons have been obtained at high supersaturation in both CTAB and PVP cases. PMID- 21244042 TI - Influence of subsurface layers on the adsorption of large organic molecules on close-packed metal surfaces. AB - The asymmetric molecule 4-[trans-2-(pyrid-4-yl-vinyl)] benzoic acid (PVBA) adsorbed on Cu(111) is characterized by scanning tunneling microscopy (STM) and density functional theory (DFT) to determine the influence of subsurface atomic layers on the adsorption. In contrast to the 6-fold symmetry of the first atomic layer of close-packed surfaces, we find that the arrangement of the isolated molecules follows predominantly a 3-fold symmetry. This reduction in symmetry, where the molecule selects a specific orientation along the ?-211? axes, reveals the contribution of lower-lying Cu layers to the molecular arrangement. Our calculations rationalize the interaction of the substrate with the molecule in terms of electrostatic screening and local relaxation phenomena. PMID- 21244040 TI - Substitution of active site tyrosines with tryptophan alters the free energy for nucleotide flipping by human alkyladenine DNA glycosylase. AB - Human alkyladenine DNA glycosylase (AAG) locates and excises a wide variety of structurally diverse alkylated and oxidized purine lesions from DNA to initiate the base excision repair pathway. Recognition of a base lesion requires flipping of the damaged nucleotide into a relatively open active site pocket between two conserved tyrosine residues, Y127 and Y159. We have mutated each of these amino acids to tryptophan and measured the kinetic effects on the nucleotide flipping and base excision steps. The Y127W and Y159W mutant proteins have robust glycosylase activity toward DNA containing 1,N(6)-ethenoadenine (epsilonA), within 4-fold of that of the wild-type enzyme, raising the possibility that tryptophan fluorescence could be used to probe the DNA binding and nucleotide flipping steps. Stopped-flow fluorescence was used to compare the time-dependent changes in tryptophan fluorescence and epsilonA fluorescence. For both mutants, the tryptophan fluorescence exhibited two-step binding with essentially identical rate constants as were observed for the epsilonA fluorescence changes. These results provide evidence that AAG forms an initial recognition complex in which the active site pocket is perturbed and the stacking of the damaged base is disrupted. Upon complete nucleotide flipping, there is further quenching of the tryptophan fluorescence with coincident quenching of the epsilonA fluorescence. Although these mutations do not have large effects on the rate constant for excision of epsilonA, there are dramatic effects on the rate constants for nucleotide flipping that result in 40-100-fold decreases in the flipping equilibrium relative to wild-type. Most of this effect is due to an increased rate of unflipping, but surprisingly the Y159W mutation causes a 5-fold increase in the rate constant for flipping. The large effect on the equilibrium for nucleotide flipping explains the greater deleterious effects that these mutations have on the glycosylase activity toward base lesions that are in more stable base pairs. PMID- 21244043 TI - Highly regio- and stereoselective one-pot synthesis of carbohydrate-based butyrolactones. AB - The use of manganese(III) acetate allows the direct synthesis of diverse arrays of [4.3.0] bicyclic carbohydrate-based gamma-lactone building blocks from glycals. A mechanism to explain the high regio- and stereoselectivity is proposed. The new reaction has the potential to generate libraries for biological screening. PMID- 21244044 TI - On the chlorenium source in the asymmetric chlorolactonization reaction. AB - N-Acylated N-chlorohydantoins are shown to be competent chlorenium sources in the (DHQD)(2)PHAL-mediated asymmetric chlorolactonization. The derivatives demonstrate the exact role of the N1 and N3 chlorine atoms in the parent dichlorohydantoins with the N1 chlorine serving as an inductive activator and the N3 chlorine being delivered to the substrate. The putative associated catalyst/chlorine source complex was experimentally demonstrated through a series of matched/mismatched experiments employing chiral N-chlorinated hydantoins. PMID- 21244045 TI - A short and highly efficient synthesis of L-ristosamine and L-epi-daunosamine glycosides. AB - A highly efficient synthesis of L-ristosamine and L-epi-daunosamine glycosides via BF(3).OEt(2) promoted tandem hydroamination/glycosylation of 3,4-di-O-acetyl 6-deoxy-L-glucal and L-galactal has been developed. The new method proceeds in a completely stereocontrolled manner within a short reaction time. Preparation of a library of L-ristosamine and L-epi-daunosamine glycosides with potential biochemical applications, by varying each component, exemplified the generality of the reaction. PMID- 21244046 TI - One-pot azidochlorination of glycals. AB - A simple one-pot azidochlorination for the preparation of nitrogen-containing Koenigs-Knorr glycosyl donors proceeds upon reaction of protected glycals with sodium azide, ferric chloride, and hydrogen peroxide. Different mono- and disaccharide galactals and glucals are converted in a highly alpha-selective manner to the 2-azido glycosyl chlorides. Starting from disaccharide galactals, building blocks for the synthesis of the T-antigen are obtained in a straightforward manner. The simplicity of the reaction conditions allows for an efficient and scalable alpha-selective synthesis of 2-azido substituted glycosyl chlorides. PMID- 21244047 TI - Access to functionalized steroid side chains via modified Julia olefination. AB - Various functionalized steroidal side chains were conveniently accessed by a modified Julia olefination strategy using a common sulfone donor and an appropriate alpha-branched aldehyde acceptor. For the coupling of these hindered classes of reaction partners (and in contrast to typically observed trends), the benzothiazolyl(BT)-sulfone anion gave superior outcomes compared to the phenyltetrazolyl(PT)-sulfone anion. PMID- 21244048 TI - 2,2-Difunctionalization of alkenes via Pd(II)-catalyzed aza-Wacker reactions. AB - N-Ts and N-Boc derivatives of 1,2-diamines and 1,2-amino alcohols are shown to undergo efficient Pd(II)-catalyzed aza-Wacker reactions with a large range of electron-deficient alkenes. The resulting enamine intermediate generally undergoes cyclization with the second heteroatom to form 1,3-heterocycles. The sequence facilitates the rapid synthesis of saturated oxazolidines, imidazolidines, and their derivatives. Use of N-L-valinol derivatives results in highly diastereoselective reactions, where the net stereochemical outcome diverges between N-Ts and N-Boc. PMID- 21244049 TI - An approach to alpha-keto vinyl carbinols. AB - Adducts from the radical addition of xanthates to ethyl vinyl sulfide readily undergo elimination of the xanthate group upon thermolysis to give vinylic and/or allylic sulfides, depending on the structure. In the case of alpha-xanthyl ketones, the adducts are converted into alpha-keto vinyl carbinols by rearrangement of the sulfoxides derived from the vinylic and allylic sulfides. PMID- 21244050 TI - Contemporaneous dual catalysis by coupling highly transient nucleophilic and electrophilic intermediates generated in situ. AB - We report herein a new process, which we call contemporaneous dual catalysis, that selectively couples two highly reactive catalytic intermediates while overcoming competing trapping by stoichiometric reactive species also present in the reaction. The reaction proceeds via the convergence of a vanadium-catalyzed propargylic rearrangement and a palladium-catalyzed allylic alkylation. It generates a variety of alpha-allylated alpha,beta-unsaturated ketones, which are not readily accessible by other means. Notably, this dual catalysis is achieved using low catalyst loadings (1.0 mol % [Pd], 1.5 mol % [V]) and gives good to excellent yields (up to 98%) of the desired products. PMID- 21244051 TI - Ni-catalyzed intramolecular cycloaddition of methylenecyclopropanes to alkynes. AB - Ni-catalyzed intramolecular cycloaddition of methylenecyclopropanes (MCPs) to arkylalkynes via proximal bond cleavage is reported. The reaction provides a facile route for the preparation of cyclopenta[a]indene derivatives. PMID- 21244052 TI - NdhP and NdhQ: two novel small subunits of the cyanobacterial NDH-1 complex. AB - The subunit composition of the NAD(P)H dehydrogenase complex of Thermosynechococcus elongatus was analyzed by different types of mass spectrometry. All 15 known subunits (NdhA-NdhO) were identified in the purified NDH-1L complex. Moreover, two additional intact mass tags of 4902.7 and 4710.5 Da could be assigned after reannotation of the T. elongatus genome. NdhP and NdhQ are predicted to contain a single transmembrane helix each, and homologues are apparent in other cyanobacteria. Additionally, ndhP is present in some cyanophages in a cluster of PSI genes and exhibits partial similarity to NDF6, a subunit of the plant NDH-1 complex. PMID- 21244053 TI - Ruthenium-catalyzed oxidative vinylation of heteroarene carboxylic acids with alkenes via regioselective C-H bond cleavage. AB - The ruthenium-catalyzed oxidative vinylation of thiophene-2-carboxylic acids with alkenes efficiently proceeds through directed C-H bond cleavage to give the corresponding 3-vinylated products. Similarly, benzothiophene-, benzofuran-, pyrrole-, and indolecarboxylic acids also undergo regioselective vinylation. PMID- 21244054 TI - Enhancing the radiative rate in III-V semiconductor plasmonic core-shell nanowire resonators. AB - We investigate the radiative properties of plasmonic core-shell nanowire resonators and, using boundary element method calculations, demonstrate enhanced radiative decay rate by up to 3500 times in nanoscale compound semiconductor/metal cavities. Calculation of the local density of optical states enables identification of new types of modes in cavities with mode volumes on the order of 10(-4)(lambda/n)(3). These modes dramatically enhance the radiative decay rate and significantly modify the polarization of far-field emission. PMID- 21244056 TI - Comment on "New generalization of supersymmetric quantum mechanics to arbitrary dimensionality or number of distinguishable particles". PMID- 21244057 TI - General food semiochemicals attract omnivorous German cockroaches, Blattella germanica. AB - Stale beer and peanut butter are effective baits for the German cockroach (GCRs), Blattella germanica (L.) (Dictyoptera: Blattellidae). In still-air arena olfactometer experiments it was previously shown that headspace volatile extracts of peanut butter and solvent extract of beer attract male GCRs. The objective of this study was to identify the semiochemicals that mediate attraction of GCRs to these sources. Coupled gas chromatographic-electroantennographic detection (GC EAD) and GC-mass spectrometric (MS) analyses of these attractive extracts, or fractions thereof, and of synthetic standards revealed many candidate semiochemicals. Elaborate olfactometer experiments determined that 1-hexanol from peanut butter, and ethanol and 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one (DDMP) from beer, are the key semiochemicals of these food sources. 1-Hexanol is a well-known headspace volatile of decomposing lipids, ethanol conveys food fermentation, and DDMP with a caramel-type flavor has been found in several types of food. By responding to these rather general food-derived compounds, the omnivorous GCRs appear to exploit semiochemicals that indicate the presence of various food components, such as lipids and carbohydrates. Synthetic equivalents of these semiochemicals may be formulated as baits or be added to, and thus enhance the attractiveness of, natural food sources as trap or insecticidal baits. PMID- 21244058 TI - Identification of antioxidative flavonols and anthocyanins in Sicana odorifera fruit peel. AB - Ten flavonols and three anthocyanins were identified in the fruit peel of melon de olor (Sicana odorifera), and their structures were established by spectrometric and spectroscopic (ESI-MS and NMR) techniques. One of the identified flavonols, quercetin 3-O-(6''-O-malonyl)-beta-D-glucopyranoside 4'-O beta-D-glucopyranoside, has not been reported before in the plant kingdom. Although quercetin-3-O-alpha-L-rhamnopyranosyl-(1->6)-beta-d-glucopyranoside-4'-O beta-D-glucopyranoside had been reported before in literature and structure elucidation was done by comparison of NMR data with published data, to the best of our knowledge complete 1D and 2D NMR data have not been not delineated so far. Moreover, the antioxidant activity of pure compounds was measured by ABTS assay. It was established that quercetin 3-O-alpha-L-rhamnopyranosyl-(1->6)-beta-D glucopyranoside, quercetin-3-O-(6''-malonyl)-glucopyranoside, quercetin-3-O-beta D-glucopyranoside, and quercetin-3-O-alpha-L-rhamnopyranosyl-(1->6)-beta-D glucopyranoside-4'-O-beta-D-glucopyranoside contribute significantly to the antioxidant activity exhibited by the fruit peel methanolic extract. PMID- 21244059 TI - Unimolecular reactions in the CF3CH2Cl <-> CF2ClCH2F system: isomerization by interchange of Cl and F atoms. AB - The recombination of CF(2)Cl and CH(2)F radicals was used to prepare CF(2)ClCH(2)F* molecules with 93 +/- 2 kcal mol(-1) of vibrational energy in a room temperature bath gas. The observed unimolecular reactions in order of relative importance were: (1) 1,2-ClH elimination to give CF(2)?CHF, (2) isomerization to CF(3)CH(2)Cl by the interchange of F and Cl atoms and (3) 1,2-FH elimination to give E- and Z-CFCl?CHF. Since the isomerization reaction is 12 kcal mol(-1) exothermic, the CF(3)CH(2)Cl* molecules have 105 kcal mol(-1) of internal energy and they can eliminate HF to give CF(2)?CHCl, decompose by rupture of the C-Cl bond, or isomerize back to CF(2)ClCH(2)F. These data, which provide experimental rate constants, are combined with previously published results for chemically activated CF(3)CH(2)Cl* formed by the recombination of CF(3) and CH(2)Cl radicals to provide a comprehensive view of the CF(3)CH(2)Cl* < > CF(2)ClCH(2)F* unimolecular reaction system. The experimental rate constants are matched to calculated statistical rate constants to assign threshold energies for the observed reactions. The models for the molecules and transition states needed for the rate constant calculations were obtained from electronic structures calculated from density functional theory. The previously proposed explanation for the formation of CF(2)?CHF in thermal and infrared multiphoton excitation studies of CF(3)CH(2)Cl, which was 2,2-HCl elimination from CF(3)CH(2)Cl followed by migration of the F atom in CF(3)CH, should be replaced by the Cl/F interchange reaction followed by a conventional 1,2-ClH elimination from CF(2)ClCH(2)F. The unimolecular reactions are augmented by free-radical chemistry initiated by reactions of Cl and F atoms in the thermal decomposition of CF(3)CH(2)Cl and CF(2)ClCH(2)F. PMID- 21244060 TI - Translational and rotational diffusion of glycerol by means of field cycling 1H NMR relaxometry. AB - Field cycling (FC) (1)H NMR relaxometry has been applied to study translational and rotational dynamics of nondeuterated (-h(8)) and partially deuterated (-h(3) and -h(5)) glycerol in a broad temperature range. We demonstrate that a low frequency excess intensity observed in the relaxation dispersion stems from intermolecular dipole-dipole interactions mediated by translational dynamics, whereas the main relaxation is attributed to rotational dynamics. A theoretical description of the relaxation processes is formulated accounting for (1)H-(1)H as well as (1)H-(2)H relaxation channels for the partially deuterated systems. While the intermolecular spectral density is derived from the force-free-hard-sphere model (Fick diffusion with appropriate boundary conditions) of translational motion, the intramolecular relaxation contribution is described by a Cole Davidson spectral density. This ansatz reproduces very well the dispersion profiles obtained from FC (1)H NMR. Moreover, the approach allows extracting the diffusion coefficient D, which is in good agreement with results from gradient (1)H NMR. Thus, (1)H NMR relaxometry has the potential to become an alternative method for measuring the diffusion coefficient in viscous liquids. PMID- 21244061 TI - The use of co-crystals for the determination of absolute stereochemistry: an alternative to salt formation. AB - Absolute stereochemistry of oils and viscous liquids can be difficult to determine. Co-crystallization involves generating a crystalline material consisting of more than one neutral compound. The combination of co crystallization with both X-ray diffraction and chiral HPLC was particularly powerful in overcoming these difficulties for a series of chiral 3-arylbutanoic acids. Co-crystallization offers advantages over salt formation because co crystals dissociate in solution, meaning identical HPLC conditions can be used for both the materials of interest and their co-crystals. PMID- 21244062 TI - Selective synthesis of alpha-fluoro-beta-keto- and alpha-fluoro-beta aminophosphonates via electrophilic fluorination by selectfluor. AB - A series of alpha-mono- and alpha,alpha-difluoro-beta-ketophosphonates were synthesized in moderate to good yields with excellent selectivities via electrophilic fluorination by Selectfluor. Subsequently, synthetic potential of the obtained alpha-monofluoro-beta-ketophosphonates was demonstrated by their application in synthesis of alpha-monofluoro-beta-aminophosphonates, useful building blocks in the preparation of phosphapeptides. PMID- 21244063 TI - Synthesis of 2,4-diiodoquinolines via the photochemical cyclization of o alkynylaryl isocyanides with iodine. AB - Upon photoirradiation of o-alkynylaryl isocyanides in the presence of iodine, the intramolecular cyclization of o-alkynylaryl isocyanides proceeds to afford the corresponding 2,4-diiodoquinolines in good yields. 2,4-Diiodoquinolines can be employed in transition metal-catalyzed cross-coupling reactions. PMID- 21244064 TI - Dynamics and couplings of N-H stretching excitations of guanosine-cytidine base pairs in solution. AB - N-H stretching vibrations of hydrogen-bonded guanosine-cytidine (G.C) base pairs in chloroform solution are studied with linear and ultrafast nonlinear infrared (IR) spectroscopy. Assignment of the IR-active bands in the linear spectrum is made possible by combining structural information on the hydrogen bonds in G.C base pairs with literature results of density functional theory calculations, and empirical relations connecting frequency shifts and intensity of the IR-active vibrations. A local mode representation of N-H stretching vibrations is adopted, consisting of nu(G)(NH(2))(f) and nu(C)(NH(2))(f) modes for free NH groups of G and C, and of nu(G)(NH(2))(b), nu(G)(NH), and nu(C)(NH(2))(b) modes associated with N-H stretching motions of hydrogen-bonded NH groups. The couplings and relaxation dynamics of the N-H stretching excitations are studied with femtosecond mid-infrared two-dimensional (2D) and pump-probe spectroscopy. The N H stretching vibrations of the free NH groups of G and C have an average population lifetime of 2.4 ps. Besides a vibrational population lifetime shortening to subpicosecond values observed for the hydrogen-bonded N-H stretching vibrations, the 2D spectra reveal vibrational excitation transfer from the nu(G)(NH(2))(b) mode to the nu(G)(NH) and/or nu(C)(NH(2))(b) modes. The underlying intermode vibrational couplings are on the order of 10 cm(-1). PMID- 21244065 TI - Water-soluble substrates of the peptidoglycan-modifying enzyme O acetylpeptidoglycan esterase (Ape1) from Neisseria gonorrheae. AB - Peptidoglycan is the component of the bacterial cell wall that is essential for maintaining the shape and rigidity of the cell. As such, its polymeric structure, consisting of alternating units of N-acetylglucosamine (GlcNAc) and N acetylmuramic acid (MurNAc), is also a target for the action of host defense enzymes, such as lysozymes. Many bacteria have developed methods of masking their cell wall from these environmental dangers through the addition of aglycon moieties that prevent recognition or sterically hinder the degradative action of exogenous enzymes that would otherwise prove detrimental to the cell. Peptidoglycan acetyl-transferases (Pat's) and O-acetylpeptidoglycan esterases (Ape's) are the enzymes responsible for the controlled addition and removal of acetate onto the C-6 hydroxyl group of MurNAc residues in peptidoglycan. Studies on Ape1, an O-acetylpeptidoglycan esterase found in Neisseria gonorrheae, have suggested that this enzyme is essential for bacterial viability and thus presents an attractive target for antibacterial design. Previous studies on Ape1 have been hindered by the fact that Ape1's natural substrate is an insoluble polymer. In this paper we outline the design, synthesis, and testing of the water-soluble di- and monosaccharide substrate analogues 1 and 2. Both 1 and 2 serve as substrates of Ape1 with k(cat)/K(M) values of (5.1 +/- 1.7) * 10(3) M(-1) s(-1) and (3.1 +/- 0.8) * 10(3) M(-1) s(-1), respectively. It was determined that the substitution of the GlcNAc residue in compound 1 with an O-benzyl group in compound 2 did not significantly decrease the enzyme's affinity for the monosaccharide. These findings are important as they demonstrate that the catalytic prowess of Ape1 is not dependent on its binding to a polymeric substrate. This ensures that small molecule transition state/intermediate analogues can also capture the transition state binding energy of Ape1 and potentially serve as potent inhibitors. The synthetic route to compounds 1 and 2 could readily be modified to allow for the installation of a wide variety of functional groups at the MurNAc C-6 position in both the mono- and disaccharide scaffolds. This will serve as a general method for the construction of Ape1 substrates and inhibitors. PMID- 21244066 TI - Single-hole hollow nanospheres from enantioselective self-assembly of chiral AIE carboxylic acid and amine. AB - Phenylacrylonitrile tartaric acids have been found to enantioselectively self assemble with an enantiomer of a chiral amine to form either nanofibers or nanospheres that exhibit aggregation-induced emission (AIE). The nanofibers exhibited stronger emission intensity and longer wavelengths of absorption and emission than the nanospheres because of increased pi-pi conjugation, an effect previously unseen in AIE. When the solvent consists of a mixture of water and THF rather than water and ethanol, the resultant nanospheres have holes. The holes are the result of the dissolution of defects and a decrease in the bending energy. This is in contrast to hole formation from solvents flowing out of the nanospheres, as previously seen. Through control of the water/THF ratio, the size of the holes in the nanospheres can be tuned. Nanospheres with a single hole displayed both higher uptake capacity and larger release speed of the drug naproxen than closed nanospheres. The ability to adjust fluorescent properties of AIE molecules through the preparation of organic single-hole hollow nanospheres has also been investigated along with the implications of the AIE mechanism. PMID- 21244067 TI - Capillary filling in nanostructured porous silicon. AB - An experimental study on the capillary filling of nanoporous silicon with different fluids is presented. Thin nanoporous membranes were obtained by electrochemical anodization, and the filling dynamics was measured by laser interferometry, taking advantage of the optical properties of the system, related with the small pore radius in comparison to light wavelength. This optical technique is relatively simple to implement and yields highly reproducible data. A fluid dynamic model for the filling process is also proposed including the main characteristics of the porous matrix (tortuosity, average hydraulic radius). The model was tested for different ambient pressures, porous layer morphology, and fluid properties. It was found that the model reproduces well the experimental data according to the different conditions. The predicted pore radii quantitatively agree with the image information from scanning electron microscopy. This technique can be readily used as nanofluidic sensor to determine fluid properties such as viscosity and surface tension of a small sample of liquid. Besides, the whole method can be suitable to characterize a porous matrix. PMID- 21244068 TI - Dicyano and pyridine derivatives of beta-carotene: synthesis and vibronic, electronic, and photophysical properties. AB - Density functional theory and time-dependent density functional theory calculations provide pictures of the molecular orbitals involved in the ground and excited states of two cyano derivatives of 8'-apo-beta-caroten-8'-al synthesized via an acid-base-catalyzed Knoevenagel condensation reaction. Population analysis shows that the symmetry-allowed transition, S(0) ((1)A(g)) -> S(2) ((1)B(u)) based on the C(2h) symmetry is a HOMO (highest occupied molecular orbital) to LUMO (lowest unoccupied molecular orbital) pi -> pi* transition with electron densities located mostly on the polyene chain. Calculated and actual steady-state absorption spectra show similar features with low-energy peak maxima between 550 and 600 nm. PMID- 21244069 TI - Direct electrochemistry and electrocatalysis of myoglobin immobilized on L cysteine self-assembled gold electrode. AB - Myoglobin (Mb) has been successfully immobilized on a self-assembled monolayer (SAM) of L-cysteine (Cys) on a gold electrode, Au/Cys. The presence of a pair of well-defined and nearly reversible waves centered at ca. 0.086 V vs Ag/AgCl (pH 6.5) suggests that the native character of Mb heme Fe(III/II) redox couple has been obtained. The formal potential of Mb on Cys SAM exhibited pH-dependent variation in the pH range of 5-9 with a slope of 55 mV/pH, indicating that the electron transfer is accompanied by a single proton exchange. Thermodynamic and kinetic aspects of Mb adsorption processes on Au/Cys were studied by using voltammetric and quartz-crystal microbalance methods. The Au/Cys electrode with immobilized Mb exhibited electrocatalytic activity toward ascorbic acid (AA) oxidation with an overpotential decrease of over 400 mV and a linear dependence of current on the AA concentration from 0.5 to 5.0 mmol L(-1). PMID- 21244070 TI - Chiral recognition at one-dimensional metal-organic coordination networks initiates the ordering of prochiral catalytic reagent methylacetoacetate on Au{111}. AB - A scanning tunnelling microscopy investigation is reported of the adsorption of methylacetoacetate on Au{111} surfaces templated by the growth of 1-D chains of nickel pyroglutamate. The symmetry of the Au{111}-herringbone reconstruction and the chirality of the pyroglutamate species influence the preferred growth directions of pyroglutamate chains. The interaction of methylacetoacetate with the various chain types reveals details of the symmetry and conformation of the chains. In addition, the docking of methylacetoacetate initiates the growth of ordered domains of methylacetoacetate not observed on either Au{111} or Ni/Au{111} surfaces. The possibilities to utilize such chiral recognition and amplification effects in the design of enantioselective heterogeneous catalysts are discussed. PMID- 21244071 TI - Rheo-SANS studies on shear-thickening/thinning in aqueous rodlike micellar solutions. AB - Shear-induced thickening/thinning phenomena of aqueous rodlike micellar solutions of cetyltrimethylammonium bromide (CTAB) and sodium p-toluene sulfonate (NapTS) were investigated by means of simultaneous measurements of rheology and small angle neutron scattering (SANS), the so-called Rheo-SANS. The aqueous CTAB/NapTS solutions were classified into five different categories dependent on their flow behavior and micellar structure. By increasing salt concentration and/or shear rates, the micelles underwent morphological transition from (i) spherical or short rodlike micelles to (ii) long rodlike micelles without entanglements, followed by (iii) those with entanglements. These transitions were recognized as changes in flow behavior from Newtonian to shear-thickening and shear-thinning flow, respectively. In the latter two cases, anisotropic SANS patterns appeared around these critical shear rates. The physical meaning of the anisotropic SANS patterns accompanied by shear-thickening flow behavior is discussed in conjunction with other shear-thickening systems. PMID- 21244072 TI - Tuning the permeability of polymer hydrogel capsules: an investigation of cross linking density, membrane thickness, and cross-linkers. AB - Nanoengineered poly(methacrylic acid) hydrogel capsules (PMA HCs) are promising candidate carriers for biomedical applications, especially in the areas of drug delivery, encapsulated catalysis, and cell mimicry. The assembly, stability, and degradation of these carriers, as well as their use for the encapsulation of therapeutics, have received considerable attention. However, tailoring the permeability properties of PMA HCs to various types of cargo remains largely unexplored. Herein, we investigate fundamental parameters that govern the structural integrity and the capability of PMA HCs to encapsulate macromolecular cargo. The thiol content of the constituent polymers and the number of deposited polymer layers are shown to be key factors in controlling cargo retention within the PMA HCs. We further introduce a new strategy to achieve disulfide cross linking for PMA HCs via a thiol-disulfide exchange in order to obtain capsules with superior cargo retention characteristics. Finally, we provide evidence for the semipermeable nature of PMA HCs based on the charge of the solutes and demonstrate that rational design of these systems can yield capsules with specific cargo retention properties. This work contributes toward the development of multilayered polymer capsules and PMA HCs and associated applications in biomedicine. PMID- 21244073 TI - Immobilized beta-cyclodextrin on surface-modified carbon-coated cobalt nanomagnets: reversible organic contaminant adsorption and enrichment from water. AB - Surface-modified magnetic nanoparticles can be used in extraction processes as they readily disperse in common solvents and combine high saturation magnetization with excellent accessibility. Reversible and recyclable adsorption and desorption through solvent changes and magnetic separation provide technically attractive alternatives to classical solvent extraction. Thin polymer layered carbon-coated cobalt nanoparticles were tagged with beta-cyclodextrin. The resulting material reversibly adsorbed organic contaminants in water within minutes. Isolation of the immobilized inclusion complex was easily carried out within seconds by magnetic separation due to the strong magnetization of the nanomagnets (metal core instead of hitherto used iron oxide). The trapped molecules were fully and rapidly recovered by filling the cyclodextrin cavity with a microbiologically well accepted substitute, e.g., benzyl alcohol. Phenolphthalein was used as a model compound for organic contaminants such as polychlorinated dibenzodioxins (PCDDs) or bisphenol A (BPA). Fast regeneration of nanomagnets (compared to similar cyclodextrin-based systems) under mild conditions resulted in 16 repetitive cycles (adsorption/desorption) at full efficiency. The high removal and regeneration efficiency was examined by UV-vis measurements at chemical equilibrium conditions and under rapid cycling (5 min). Experiments at ultralow concentrations (160 ppb) underline the high potential of cyclodextrin modified nanomagnets as a fast, recyclable extraction method for organic contaminants in large water streams or as an enrichment tool for analytics. PMID- 21244074 TI - SERS detection of streptavidin/biotin monolayer assemblies. AB - A two-dimensional array of gold nanotriangles inscribed onto glass coverslips were optimized for the surface-enhanced Raman detection of streptavidin/biotin monolayer assemblies. The nanostructures were fabricated by electron beam lithography, and its optical parameters were optimized to be probed under a Raman microscope with a linearly polarized He-Ne laser with an excitation wavelength of lambda = 632.8 nm. The platforms were first tested against a monolayer of biotinylated alkanethiols (BAT) functionalized over the gold nanostructure, showing that good-quality spectra could be acquired with a short acquisition time. The supramolecular interaction of streptavidin (strep) with BAT showed subsequent modification of the Raman spectrum that implies a change in the secondary structure of the host biomolecule (streptavidin). Compared to gold surfaces without nanoscale structures, the local enhancement that results from our nanostructured surfaces allows one to detect the vibrational signal of monolayers within a time on the order of seconds and under modest laser intensity, further demonstrating the utility of using plasmonic metallic nanostructures for molecular recognition. PMID- 21244076 TI - Micellization and phase separation for triblock copolymer 17R4 in H2O and in D2O. AB - The reverse Pluronic triblock copolymer 17R4 is formed from poly(propylene oxide) (PPO) and poly(ethylene oxide) (PEO): PPO(14)-PEO(24)-PPO(14), where the subscripts denote the number of monomers in each block. In water, 17R4 shows both a transition to aggregated micellar species at lower temperatures and a separation into copolymer-rich and copolymer-poor liquid phases at higher temperatures. For 17R4 in H(2)O and in D(2)O, we have determined (1) the phase boundaries corresponding to the micellization line, (2) the cloud point curves marking the onset of phase separation at various compositions, and (3) the coexistence curves for the phase separation (the compositions of coexisting phases). In both H(2)O and in D(2)O, 17R4 exhibits coexistence curves with lower consolute temperatures and compositions that differ from the minima in the cloud point curves; we take this as an indication of the polydispersity of the micellar species. The coexistence curves for compositions near the critical composition are described well by an Ising model. For 17R4 in both H(2)O and D(2)O, the critical composition is 0.22 +/- 0.01 in volume fraction. The critical temperatures differ: 44.8 degrees C in H(2)O and 43.6 degrees C in D(2)O. The cloud point curve for the 17R4/D(2)O is as much as 9 degrees C lower than in H(2)O. PMID- 21244075 TI - Total syntheses of the histone deacetylase inhibitors largazole and 2-epi largazole: application of N-heterocyclic carbene mediated acylations in complex molecule synthesis. AB - Details of the evolution of strategies toward convergent assembly of the histone deacetylase inhibiting natural product largazole exploiting gamma,delta unsaturated-alpha,beta-epoxy-aldehydes and a thiazole-thiazoline containing omega amino-acid are described. The initial N-heterocyclic carbene mediated redox amidation exploying these two types of building blocks representing largazole's structural domains of distinct biosynthetic origin directly afforded the seco acid of largazole. This was accomplished without any protecting groups resident upon either thioester bearing epoxy-aldehyde or the tetrapeptide. However, the ineffective production of largazole via the final macrolactonization led to an alternative intramolecular esterification/macrolactamization strategy employing the established two building blocks. This provided largazole along with its C2 epimer via an unexpected inversion of the alpha-stereocenter at the valine residue. The biological evaluation demonstrated that both largazole and 2-epi largazole led to dose-dependent increases of acetylation of histone H3, indicating their potencies as class I histone deacetylase selective inhibitiors. Enhanced p21 expression was also induced by largazole and its C2 epimer. In addition, 2-epi-largazole displayed more potent activity than largazole in cell viability assays against PC-3 and LNCaP prostate cancer cell lines. PMID- 21244077 TI - Highly substituted Bodipy dyes with spectroscopic features sensitive to the environment. AB - A general method for the synthesis of butterfly-shaped difluoroboradiaza-s indacenes with different substituents has been developed. The mixed AB dye was produced in two successive Knoevenagel reactions involving first 4 dimethylaminobenzaldehyde and second 4-hydroxybenzaldehyde. Two pathways to A(2)B(2) and ABCD derivatives were investigated starting from a tetramethyl substituted Bodipy. The pivotal compound is a bis-styryl phenol derivative also produced by a Knoevenagel reaction without the need to protect the phenol functions. Methylation of the phenol functions provides mono- and bis-derivatives which have been used to construct tetrastyryl A(2)B(2) and ABCD derivatives, respectively. Stepwise alkylation of the monomethoxyphenol dye provided a mixed dye that was converted to a tris-substituted compound, isolated as a mixture of regioisomers. The fourth styryl function was introduced by using 4 dimethylaminobenzaldehyde and forcing conditions. These highly colored dyes display outstanding optical properties with absorption wavelengths spanning from 573 to 718 nm and emission wavelengths from 585 to 800 nm. The high quantum yields, nanosecond excited state lifetimes, and weak Stokes shifts are typical of singlet emitters. The presence of both dimethylamino and phenol residues in some of these dyes makes them sensitive to acids and bases, allowing the tuning of the optical properties over a large wavelength range as a function of pH. A unique three-color ratiometric pH sensor based on both absorption and fluorescence has been characterized and studied in detail. The tris- and tetra-substitution of the methyl groups by vinyl residues induces a weaker bathochromic shift than that due to mono- and disubstitution. Consequently, replacing an alkoxy function by a dimethylamino moiety in the tetra-substituted derivatives has little effect on the spectroscopic features. PMID- 21244078 TI - Influence of the structure of polyfluorinated alcohols on Bronsted acidity/hydrogen-bond donor ability and consequences on the promoter effect. AB - The influence of substituents on the properties of tri- and hexafluorinated alcohols derived from 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2 propanol (HFIP) was examined. Measurements of specific solvent-solute interactions revealed that H-bond donation (HBD) of fluorinated alcohols is sensitive to the steric hindrance of the OH group, whereas their Bronsted acidity is dependent only on the number of fluorine atoms. For hexafluorinated alcohols (HFAs), their association with amines characterized by X-ray diffraction showed that the balance between HBD and acidity is influenced by their structure. Moreover, the ability of HFAs to donate H-bonds is exerted in synclinal (sc), synperiplanar (sp), and also antiperiplanar (ap) conformations along the C-O bond. Comparison of the effects of fluorinated alcohols as promoting solvents in three reactions is reported. The positive correlation between rate constants and H-bonding donation ability for sulfide oxidation and imino Diels-Alder reaction brings to light the role of this property, while acidity might have a minor influence. In the third reaction, epoxide opening by piperidine, none of these properties can clearly be put forward at this stage. PMID- 21244079 TI - Preoxidation of CO on Os-modified Pt(111): a comparison with Ru-modified Pt(111). AB - The variation in CO adsorption structures during the preoxidation of CO on Os modified Pt(111) (Pt(111)/Os) was investigated using cyclic voltammetry and electrochemical scanning tunneling microscopy. The spontaneous deposition of Os on Pt(111) resulted in randomly scattered islands with a coverage range of 0.13 0.54. During preoxidation on Pt(111)/Os, a phase transition from (2 * 2)-alpha to (?19 * ?19) via the transient structures of (2 * 2)-beta and (1 * 1) took place as on unmodified Pt(111). As the amount of Os increased, however, the transient structures of (2 * 2)-beta and (1 * 1) appeared at lower potentials with higher populations. When the population of the transient structures was greater than 50%, an oxidative CO stripping process took place to the structure of (?19 * ?19), completing the preoxidation. These observations strongly support the idea that the presence of Os increases the mobility of adsorbed CO by electronic modification of the Pt(111) surface (electronic effect). In addition, the results obtained with Pt(111)/Os were compared with those of Pt(111)/Ru. PMID- 21244080 TI - A stripe-to-droplet transition driven by conformational transitions in a binary lipid-lipopolymer mixture at the air-water interface. AB - We report the observation of an unusual stripe-droplet transition in precompressed Langmuir monolayers consisting of mixtures of poly(ethylene) glycol (PEG) amphiphiles and phospholipids. This highly reproducible and fully reversible transition occurs at approximately zero surface pressure during expansion (or compression) of the monolayer following initial compression into a two-dimensional solid phase. It is characterized by spontaneous emergence of an extended, disordered stripe-like morphology from an optically homogeneous phase during gradual expansion. These stripe patterns appear as a transient feature and continuously progress, involving gradual coarsening and ultimate transformation into a droplet morphology upon further expansion. Furthermore, varying relative concentrations of the two amphiphiles and utilizing amphiphiles with considerably longer ethylene glycol headgroups reveal that this pattern evolution occurs in narrow concentration regimes, values of which depend on ethylene oxide headgroup size. These morphological transitions are reminiscent of those seen during a passage through a critical point by variations in thermodynamic parameters (e.g., temperature or pressure) as well as those involving spinodal decomposition. While the precise mechanism cannot be ascertained using present experiments alone, our observations can be reconciled in terms of modulations in competing interactions prompted by the pancake-mushroom-brush conformational transitions of the ethylene glycol headgroup. This in turn suggests that the conformational degree of freedom represents an independent order parameter, or a switch, which can induce large scale structural reorganization in amphiphilic monolayers. Because molecular conformational changes are pervasive in biological membranes, we speculate that such conformational transition-induced pattern evolution might provide a physical mechanism by which membrane processes are amplified. PMID- 21244081 TI - Photochemical control of molecular assembly formation in a catanionic surfactant system. AB - Photochemical control of vesicle disintegration and reformation in aqueous solution was examined using a mixture of 4-butylazobenzene-4' (oxyethyl)trimethylammonium bromide (AZTMA) as the photoresponsive cationic surfactant and sodium dodecylbenzenesulfonate (SDBS) as the anionic surfactant. Spontaneous vesicle formation was found in a wide-ranging composition of the trans-AZTMA/SDBS system. AZTMA molecules constituting vesicles underwent reversible trans-cis photoisomerization when irradiated with ultraviolet and visible light. Transmission electron microscopy observations using the freeze fracture technique (FF-TEM) showed that UV light irradiation caused the vesicles to disintegrate into coarse aggregates and visible light irradiation stimulated the reformation of vesicles (normal control). A detailed investigation of the phase state and the effects of UV and visible light irradiation on the AZTMA/SDBS system with the use of electroconductivity, dynamic/static light scattering, and surface tension measurements and FF-TEM observations revealed that in the AZTMA rich composition (AZTMA/SDBS 9:1) a micellar solution before light irradiation became a vesicular solution after UV light irradiation and visible light irradiation allowed the return to a micellar solution (reverse control). Thus, we could photochemically control the disintegration (normal control) and reformation (reverse control) of vesicles in the same system. PMID- 21244083 TI - Self-assembled graphene/azo polyelectrolyte multilayer film and its application in electrochemical energy storage device. AB - Graphene/azo polyelectrolyte multilayer films were fabricated through electrostatic layer-by-layer (LbL) self-assembly, and their performance as electrochemical capacitor electrode was investigated. Cationic azo polyelectrolyte (QP4VP-co-PCN) was synthesized through radical polymerization, postpolymerization azo coupling reaction, and quaternization. Negatively charged graphene nanosheets were prepared by a chemically modified method. The LbL films were obtained by alternately dipping a piece of the pretreated substrates in the QP4VP-co-PCN and nanosheet solutions. The processes were repeated until the films with required numbers of bilayers were obtained. The self-assembly and multilayer surface morphology were characterized by UV-vis spectroscopy, AFM, SEM, and TEM. The performance of the LbL films as electrochemical capacitor electrode was estimated using cyclic voltammetry. Results show that the graphene nanosheets are densely packed in the multilayers and form random graphene network. The azo polyelectrolyte cohesively interacts with the nanosheets in the multilayer structure, which prevents agglomeration of graphene nanosheets. The sheet resistance of the LbL films decreases with the increase of the layer numbers and reaches the stationary value of 1.0 * 10(6) Omega/square for the film with 15 bilayers. At a scanning rate of 50 mV/s, the LbL film with 9 bilayers shows a gravimetric specific capacitance of 49 F/g in 1.0 M Na(2)SO(4) solution. The LbL films developed in this work could be a promising type of the electrode materials for electric energy storage devices. PMID- 21244082 TI - Silica-coated gold nanorods as photoacoustic signal nanoamplifiers. AB - Photoacoustic signal generation by metal nanoparticles relies on the efficient conversion of light to heat, its transfer to the environment, and the production of pressure transients. In this study we demonstrate that a dielectric shell has a strong influence on the amplitude of the generated photoacoustic signal and that silica-coated gold nanorods of the same optical density are capable of producing about 3-fold higher photoacoustic signals than nanorods without silica coating. Spectrophotometry measurements and finite difference time domain (FDTD) analysis of gold nanorods before and after silica coating showed only an insignificant change of the extinction and absorption cross sections, hence indicating that the enhancement is not attributable to changes in absorption cross section resulting from the silica coating. Several factors including the silica thickness, the gold/silica interface, and the surrounding solvent were varied to investigate their effect on the photoacoustic signal produced from silica-coated gold nanorods. The results suggest that the enhancement is caused by the reduction of the gold interfacial thermal resistance with the solvent due to the silica coating. The strong contrast enhancement in photoacoustic imaging, demonstrated using phantoms with silica-coated nanorods, shows that these hybrid particles acting as "photoacoustic nanoamplifiers" are high efficiency contrast agents for photoacoustic imaging or photoacoustic image-guided therapy. PMID- 21244084 TI - Stability of DNA containing a structural water mimic in an A-T rich sequence. AB - We describe here the synthesis and properties of A-T rich DNA containing covalently bound water mimics located in the DNA minor groove. PMID- 21244085 TI - Mild transition-metal-free amination of fluoroarenes catalyzed by fluoride ions. AB - Trimethylsilyl-protected heterocycles undergo N-C bond formation with a variety of electron-deficient fluoroarenes catalyzed by fluoride ions. This reaction avoids stoichiometric amounts of base and thus makes N-arylheterocycles accessible in a very mild and transition-metal-free way. PMID- 21244086 TI - Selectivity control in alkylidene carbene-mediated C-H insertion and allene formation. AB - Regioselectivity of alkylidene carbene-mediated C-H insertion was explored utilizing electronic, conformational, steric, and stereoelectronic effects. Relying on these factors, highly regio- and chemoselective carbene insertion reaction of C-H bonds in different environments could be obtained. The observed selectivity clearly indicates that an electronic effect plays a more important role than steric effect. In general, C-H bonds in conformationally rigid cyclic environments are less reactive than those in acyclic systems toward carbene insertion, and in this situation, a competing intermolecular reaction between alkylidene carbene and trimethylsilyldiazomethane led to the formation of allenylsilanes. The formation of allenylsilane becomes more favorable as the concentration of reaction becomes higher, as well as the C-H bonds undergoing insertion becomes electronically and conformationally deactivated. PMID- 21244087 TI - The Pt(111)/electrolyte interface under oxygen reduction reaction conditions: an electrochemical impedance spectroscopy study. AB - The Pt(111)/electrolyte interface has been characterized during the oxygen reduction reaction (ORR) in 0.1 M HClO(4) using electrochemical impedance spectroscopy. The surface was studied within the potential region where adsorption of OH* and O* species occur without significant place exchange between the adsorbate and Pt surface atoms (0.45-1.15 V vs RHE). An equivalent electric circuit is proposed to model the Pt(111)/electrolyte interface under ORR conditions within the selected potential window. This equivalent circuit reflects three processes with different time constants, which occur simultaneously during the ORR at Pt(111). Density functional theory (DFT) calculations were used to correlate and interpret the results of the measurements. The calculations indicate that the coadsorption of ClO(4)* and Cl* with OH* is unlikely. Our analysis suggests that the two-dimensional (2D) structures formed in O(2)-free solution are also formed under ORR conditions. PMID- 21244088 TI - Binary matrix for MALDI imaging mass spectrometry of phospholipids in both ion modes. AB - Phospholipids (PLs) are the major building block molecules of cellular membranes. Their composition varies depending on cell types and cellular compartments. Thus, the information regarding PL distribution in tissue has important physiological and pathological significance. Recent developments in imaging mass spectrometry (IMS) have allowed complete mapping of the PL species on tissue. The IMS technique can detect different classes of PLs as well as their location information directly from tissue sections. PL head groups carry either positive and/or negative charges; therefore, IMS experiments must be conducted in both positive- and negative-ion mode to detect all types of phospholipids. Several conventional matrixes were applied on tissue for better identification. This study was conducted to enable appropriate matrix selection and optimized matrix preparation for IMS experiments in both ion modes that maximize PL identification from a single brain tissue section. The optimized matrix 2,5-dihydroxybenzoic acid (DHB) and alpha-cyano-4-hydroxycinnamic acid (CHCA) with a mixture of trifluoroacetic acid (TFA) and piperidine as ion pairing agents showed improved stability and consistency during both ion mode experiments and successfully identified >100 peaks of PLs determined by parent ion m/z value. Further tandem mass spectrometric analysis (MS/MS) was performed to those PLs that are anatomically important according to their distribution on rat brain tissue section. PMID- 21244089 TI - Synthesis of ligand-free colloidally stable water dispersible brightly luminescent lanthanide-doped upconverting nanoparticles. AB - The synthesis using the thermal decomposition of metal trifluoroacetates is being widely used to prepare oleate-capped lanthanide-doped upconverting NaYF(4):Er(3+)/Yb(3+) nanoparticles (Ln-UCNPs). These nanoparticles have no inherent aqueous dispersibility and inconvenient postsynthesis treatments are required to render them water dispersible. Here, we have developed a novel and facile approach to obtain water-dispersible, ligand-free, brightly upconverting Ln-UCNPs. We show that the upconversion luminescence is affected by the local environment of the lanthanide ions at the surface of the Ln-UCNPs. We observe a dramatic difference of the integrated upconverted red:green emission ratio for Ln UCNPs dispersed in toluene compared to Ln-UCNPs dispersed in water. We can enhance or deactivate the upconversion luminescence by pH and H/D isotope vibronic control over the competitive radiative and nonradiative relaxation pathways for the red and green excited states. Direct biofunctionalization of the ligand-free, water-dispersible Ln-UCNPs will enable myriad new opportunities in targeting and drug delivery applications. PMID- 21244090 TI - Evidence for sex differences in mercury dynamics in double-crested cormorants. AB - Aquatic fish-eating birds can demethylate methylmercury in their livers. In this study, we determined whether a previously documented male bias in mercury concentration in double-crested cormorants ( Phalacrocorax auritus ) was due entirely to the depuration of mercury into eggs or might also in part be related to sex differences in methylmercury demethylation or biliary excretion capability in the liver. We found egg depuration accounted for less than a fifth of the mercury concentration difference between males and females, hence not entirely explaining the sex difference. Females had a significantly steeper slope for the negative relationship between percent methylmercury (i.e., percentage of total mercury that is methylmercury) and total mercury concentration than did males. This suggests that females have a greater capacity to demethylate methylmercury, which might be reducing the amount of methylmercury available for depuration to eggs. We also found a significant negative relationship between methylmercury concentration and liver mass for females only; thus females might also have a greater capability to excrete methylmercury compared to males. Therefore, we conclude that the male bias in mercury concentration might also result from females having a greater capability to excrete mercury compared to males. PMID- 21244092 TI - Five-substrate cocktail as a sensor array for measuring enzyme activity fingerprints of lipases and esterases. AB - Substrate arrays for measuring enzyme activity fingerprints can be conveniently formulated as cocktails designed such that the reaction products can be separated and quantified by analytical high-performance liquid chromatography (HPLC). Fingerprinting of lipases and esterases, an important class of microbial enzymes, is reported with a cocktail of only five substrates as a practical fingerprinting reagent. An unusually strong C4-esterase activity was thus revealed in a recently discovered microbial esterase. PMID- 21244091 TI - Feeding rats dietary resistant starch reduces both the binding of ChREBP and the acetylation of histones on the Thrsp gene in the jejunum. AB - We have previously reported that the thyroid hormone-responsive spot 14 protein (Thrsp) gene is expressed in rat jejunum. In this study, we found that jejunal mRNA and protein expressions of Thrsp were markedly reduced in rats fed a diet containing a high amount of resistant starch (RS), which is an indigestible starch, for 7 days, compared with those fed a regular starch diet. Furthermore, we found that the binding of carbohydrate response element binding protein (ChREBP), which is a key transcription factor for the Thrsp gene, and the acetylation of histones H3 and H4, which is one of the histone modifications for transactivation, on the Thrsp gene were reduced by feeding the RS diet. These results suggest that the reduction of jejunal Thrsp gene expression by feeding a diet rich in less-digestible starch is associated with decreases in the binding of ChREBP and the acetylation of histones on the gene. PMID- 21244093 TI - Development of ultrabright semiconducting polymer dots for ratiometric pH sensing. AB - Semiconducting polymer-based nanoparticles (Pdots) have recently emerged as a new class of ultrabright probes for biological detection and imaging. This paper describes the development of poly(2,5-di(3',7'-dimethyloctyl)phenylene-1,4 ethynylene) (PPE) Pdots as a platform for designing Forster resonance energy transfer (FRET)-based ratiometric pH nanoprobes. We describe and compare three routes for coupling the pH-sensitive dye, fluorescein, to PPE Pdots, which is a pH-insensitive semiconducting polymer. This approach offers a rapid and robust sensor for pH determination using the ratiometric methodology where excitation at a single wavelength results in two emission peaks, one that is pH sensitive and the other one that is pH insensitive for use as an internal reference. The linear range for pH sensing of the fluorescein-coupled Pdots is between pH 5.0 and 8.0, which is suitable for most cellular studies. The pH-sensitive Pdots show excellent reversibility and stability in pH measurements. In this paper, we use them to measure the intracellular pH in HeLa cells following their uptake by endocytosis, thus demonstrating their utility for use in cellular and imaging experiments. PMID- 21244094 TI - Temporal trends and pattern of polyfluoroalkyl compounds in Tawny Owl (Strix aluco) eggs from Norway, 1986-2009. AB - Temporal trends of polyfluoroalkyl compounds (PFCs) were examined in tawny owl (Strix aluco) eggs collected in Central Norway over a period of 24 years (1986 2009). Concentrations of 12 PFCs, including C(6)-C(8), C(10) perfluoroalkyl sulfonates (PFSAs), perfluorooctane sulfonamide (PFOSA), and C(8)-C(14) perfluoroalkyl carboxylates (PFCAs), were measured, whereas saturated and unsaturated fluorotelomer carboxylates and shorter chain PFSAs and PFCAs were not detected. Perfluorooctane sulfonate (PFOS) was the predominant compound (geometric mean 10.1 ng/g wet weight (ww)), followed by perfluorotridecanoate (PFTriDA) (0.36 ng/g ww) and perfluoroundecanoate (PFUnDA) (0.19 ng/g ww). Significant decreasing concentrations were found for PFOS with an annual decrease of 1.6% (1986-2009), while, conversely, the C(10)-C(13) PFCA concentrations increase significantly with an annual increase of 4.2-12% (1986-2009). Consequently, the contribution of PFOS to the ?PFCs decreased, whereas the contribution of the ?PFCAs increased over the time. Toxicological implications for tawny owls are limited, but the maximal PFOS concentration found in this stu0dy is about 20 times lower than the predicted avian no effect concentration (PNEC) which suggest adverse effects caused by PFOS are unlikely. However, tawny owls are exposed to a mixture of various PFCs, and PFCA concentrations still increase. PMID- 21244095 TI - A new organic-inorganic hybrid layered molybdenum(V) cobalt phosphate constructed from [H24(Mo16O32)Co16(PO4)24(OH)4(C5H4N)2(H2O)6](4-) wheels and 4,4'-bipyridine linkers. AB - A new layered molybdenum cobalt phosphate, Na(2)[Co(H(2)O)(6)][(Mo(16)O(32))Co(16)(PO(4))(4) (HPO(4))(16)(H(2)PO(4))(4)(OH)(4)(C(10)H(8)N(2))(4)(C(5)H(4)N)(2)(H(2)O)(6)].4H(2 O (1), has been hydrothermally synthesized and structurally characterized. 1 crystallizes in the monoclinic space group P2(1)/n with a = 15.6825(18) A, b = 39.503(4) A, c = 17.2763(17) A, beta = 93.791(2) degrees , V = 10679.4(18) A(3), and Z = 2. A polyoxoanion of 1 exhibits an unusual organic-inorganic hybrid wheel type cluster, in which two pyridine ligands link to the surface Co(II) atoms of a [H(24)(Mo(16)O(32))Co(16)(PO(4))(24)(OH)(4)(H(2)O)(6)] (namely, {Mo(16)Co(16)P(24)}) wheel via the Co-N bonds. Furthermore, each {Mo(16)Co(16)P(24)} wheel is connected to four adjacent wheels by four pairs of 4,4'-bipyridine linkers, forming a 2D layered network. The susceptibility measurement shows the existence of dominant antiferromagnetic interactions in 1. PMID- 21244097 TI - Reversed-phase TLC and HPLC retention data in correlation studies with in silico molecular descriptors and druglikeness properties of newly synthesized anticonvulsant succinimide derivatives. AB - The properties relevant to pharmacokinetics of two series of newly synthesized succinimide derivatives have been studied. The properties under consideration have been either determined empirically, by reversed-phase liquid chromatography (TLC and HPLC technique), or calculated with the use of established theoretical medicinal chemistry/drug design software. Chromatographic techniques allowed determination of the retention constants R(M)0 and log k(w), which characterize lipophilicity of compounds. Considering potential pharmaceutical importance of succinimide derivatives, we (i) examined the retention behavior in the reversed phase liquid chromatographic (RP LC) systems, in both planar and column LC, and (ii) determined the relationships between chromatographic data and selected structural features of analytes that are believed to markedly affect their processes of absorption, distribution, metabolism, excretion and toxicity (ADMETox). Significant relationships were found between the retention constants, R(M)0 and log k(w), and the in silico calculated bioactivity descriptors, in particular HIA (human intestinal absorption) and PPB (plasma protein binding) parameters. The R(M)0 and log k(w) values of the investigated compounds have been recommended for description of their lipophilicity and evaluating pharmacokinetic properties. In view of results of this study the newly synthesized succinimide agents meet pharmacokinetic criteria of preselection of drug candidates and hence qualify for pharmacodynamic phase of antiepileptic drug development. Best compromising human intestinal absorption and plasma protein binding features appear to be compounds A4, A5, A10 and A11. PMID- 21244096 TI - Methemoglobinemia caused by 8-aminoquinoline drugs: DFT calculations suggest an analogy to H4B's role in nitric oxide synthase. AB - We suggest a possible mechanism of how 8-aminoquinolines (8-AQ's) cause hemotoxicity by oxidizing hemoglobin to methemoglobin. In our DFT calculations, we found that 5-hydroxyprimaquine is able to donate an electron to O(2) to facilitate its conversion to H(2)O(2). Meanwhile, Fe(II) is oxidized to Fe(III) and methemoglobin is formed. In this mechanism, the 8-AQ drug plays a similar role as that of H(4)B in nitric oxide synthase. Furthermore, our study offers an approach to inform the design of less toxic antimalarial drugs. PMID- 21244098 TI - Thermodynamic analysis of interactions between cofactor and neuronal nitric oxide synthase. AB - The thermodynamics of cofactor binding to the isolated reductase domain (Red) of nNOS and its mutants have been studied by isothermal titration calorimetry. The NADP(+) and 2',5'-ADP binding stoichiometry to Red were both 1:1, consistent with a one-site kinetic model instead of a two-site model. The binding constant (K(D) = 71 nM) and the large heat capacity change (DeltaC(p) = -440 cal mol(-1) K(-1)) for 2',5'-ADP were remarkably different from those for NADP(+) (1.7 MUM and -140 cal mol(-1) K(-1), respectively). These results indicate that the nicotinamide moiety as well as the adenosine moiety has an important role in binding to nNOS. They also suggest that the thermodynamics of the conformational change in Red caused by cofactor binding are significantly different from the conformational changes that occur in cytochrome c reductase, in which the nicotinamide moiety of the cofactor is not essential for binding. Analysis of the deletion mutant of the autoinhibitory helix (RedDelta40) revealed that the deletion resulted in a decrease in the binding affinity of 2',5'-ADP with more unfavorable enthalpy gain. In the case of RedCaM, which contains a calmodulin (CaM) binding site, the presence of Ca(2+)/CaM caused a 6.7-fold increase in the binding affinity for 2',5'-ADP that was mostly due to the favorable entropy change. These results are consistent with a model in which Ca(2+)/CaM induces a conformational change in NOS to a flexible "open" form from a "closed" form that locked by cofactor binding, and this change facilitates the electron transfer required for catalysis. PMID- 21244099 TI - Cell viability measurement using 2',7'-bis-(2-carboxyethyl)-5-(and-6) carboxyfluorescein acetoxymethyl ester and a cantilever sensor. AB - Detection of viable pathogenic bacteria has widespread application in food safety and human health. Antibody-based methods require a growth step which limits time to-results performance. In this study, we use a mass-change sensitive cantilever biosensor and a probe, 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM), that accumulates only in live cells inducing a mass-change response to determine the cell viability in a short time. A poly-L lysine coated sensor immobilized with live Escherichia coli JM101 (a surrogate for a pathogenic target) at various concentrations was exposed to BCECF-AM in a flow arrangement. A larger resonant frequency decrease in response to 100 MUL of 60 MUM BCECF-AM was observed when the sensor surface cell concentration was increased from 1 090 +/- 580 to 3 960 +/- 370 cells/mm(2) (n = 5). A log-linear relationship between the sensor surface cell concentration and frequency response was obtained in the range of 1 000-4 000 cells/mm(2) and as low as ~2 000 viable E. coli cells were rapidly detected (<1 h). PMID- 21244100 TI - Protein array based interactome analysis of amyloid-beta indicates an inhibition of protein translation. AB - Oligomeric amyloid-beta is currently of interest in amyloid-beta mediated toxicity and the pathogenesis of Alzheimer's disease. Mapping the amyloid-beta interaction partners could help to discover novel pathways in disease pathogenesis. To discover the amyloid-beta interaction partners, we applied a protein array with more than 8100 unique recombinantly expressed human proteins. We identified 324 proteins as potential interactors of oligomeric amyloid-beta. The Gene Ontology functional analysis of these proteins showed that oligomeric amyloid-beta bound to multiple proteins with diverse functions both from extra and intracellular localizations. This undiscriminating binding phenotype indicates that multiple protein interactions mediate the toxicity of the oligomeric amyloid-beta. The most highly impacted cellular system was the protein translation machinery. Oligomeric amyloid-beta could bind to altogether 24 proteins involved in translation initiation and elongation. The binding of amyloid-beta to purified rat hippocampal ribosomes validated the protein array results. More importantly, in vitro translation assays showed that the oligomeric amyloid-beta had a concentration dependent inhibitory activity on translation. Our results indicate that the inhibited protein synthesis is one of the pathways that can be involved in the amyloid-beta induced neurotoxicity. PMID- 21244101 TI - A model to transfer trial-based pharmacoeconomic analyses to clinical practice. AB - This article deals with the question of how to handle costs to enhance medication adherence in trial-based pharmacoeconomic analyses. It argues that resources to improve patient adherence have a clearly distinguishable impact on costs and utility and thus are relatively easy to exclude when transferring trial-based pharmacoeconomic analyses to clinical practice. It proposes a model that adjusts trial-based incremental costs and effectiveness for lower medication adherence in clinical practice. It shows that, contrary to conventional wisdom, drug cost effectiveness in clinical practice can be better than in clinical trials. This may have implications for policy recommendations, depending on how close trial based cost effectiveness is to the maximum willingness to pay. In many situations, the adjustment may not result in a change in policy recommendations. PMID- 21244102 TI - Cost effectiveness of treatments for wet age-related macular degeneration. AB - Age-related macular degeneration (AMD) is a leading cause of blindness in people aged >=50 years. Wet AMD in particular has a major impact on patient quality of life and imposes substantial burdens on healthcare systems. This systematic review examined the cost-effectiveness data for current therapeutic options for wet AMD. PubMed and EMBASE databases were searched for all articles reporting original cost-effectiveness analyses of wet AMD treatments. The Centre for Reviews and Dissemination and Cochrane Library databases were searched for all wet AMD health technology assessments (HTAs). Overall, 44 publications were evaluated in full and included in this review. A broad range of cost effectiveness analyses were identified for the most commonly used therapies for wet AMD (pegaptanib, ranibizumab and photodynamic therapy [PDT] with verteporfin). Three studies evaluated the cost effectiveness of bevacizumab in wet AMD. A small number of analyses of other treatments, such as laser photocoagulation and antioxidant vitamins, were also found. Ranibizumab was consistently shown to be cost effective for wet AMD in comparison with all the approved wet AMD therapies (four of the five studies identified showed ranibizumab was cost effective vs usual care, PDT or pegaptanib); however, there was considerable variation in the methodology for cost-effectiveness modelling between studies. Findings from the HTAs supported those from the PubMed and EMBASE searches; of the seven HTAs that included ranibizumab, six (including HTAs for Australia, Canada and the UK) concluded that ranibizumab was cost effective for the treatment of wet AMD; most compared ranibizumab with PDT and/or pegaptanib. By contrast, HTAs at best generally recommended pegaptanib or PDT for restricted use in subsets of patients with wet AMD. In the literature analyses, pegaptanib was found to be cost effective versus usual/best supportive care (including PDT) or no treatment in one of five studies; the other four studies found pegaptanib was of borderline cost effectiveness depending on the stage of disease and time horizon. PDT was shown to be cost effective versus usual/best supportive care or no treatment in five of nine studies; two studies showed that PDT was of borderline cost effectiveness depending on baseline visual acuity, and two showed that PDT was not cost effective. We identified no robust studies that properly evaluated the cost effectiveness of bevacizumab in wet AMD. PMID- 21244105 TI - Developing maximal neuromuscular power: part 2 - training considerations for improving maximal power production. AB - This series of reviews focuses on the most important neuromuscular function in many sport performances: the ability to generate maximal muscular power. Part 1, published in an earlier issue of Sports Medicine, focused on the factors that affect maximal power production while part 2 explores the practical application of these findings by reviewing the scientific literature relevant to the development of training programmes that most effectively enhance maximal power production. The ability to generate maximal power during complex motor skills is of paramount importance to successful athletic performance across many sports. A crucial issue faced by scientists and coaches is the development of effective and efficient training programmes that improve maximal power production in dynamic, multi-joint movements. Such training is referred to as 'power training' for the purposes of this review. Although further research is required in order to gain a deeper understanding of the optimal training techniques for maximizing power in complex, sports-specific movements and the precise mechanisms underlying adaptation, several key conclusions can be drawn from this review. First, a fundamental relationship exists between strength and power, which dictates that an individual cannot possess a high level of power without first being relatively strong. Thus, enhancing and maintaining maximal strength is essential when considering the long-term development of power. Second, consideration of movement pattern, load and velocity specificity is essential when designing power training programmes. Ballistic, plyometric and weightlifting exercises can be used effectively as primary exercises within a power training programme that enhances maximal power. The loads applied to these exercises will depend on the specific requirements of each particular sport and the type of movement being trained. The use of ballistic exercises with loads ranging from 0% to 50% of one-repetition maximum (1RM) and/or weightlifting exercises performed with loads ranging from 50% to 90% of 1RM appears to be the most potent loading stimulus for improving maximal power in complex movements. Furthermore, plyometric exercises should involve stretch rates as well as stretch loads that are similar to those encountered in each specific sport and involve little to no external resistance. These loading conditions allow for superior transfer to performance because they require similar movement velocities to those typically encountered in sport. Third, it is vital to consider the individual athlete's window of adaptation (i.e. the magnitude of potential for improvement) for each neuromuscular factor contributing to maximal power production when developing an effective and efficient power training programme. A training programme that focuses on the least developed factor contributing to maximal power will prompt the greatest neuromuscular adaptations and therefore result in superior performance improvements for that individual. Finally, a key consideration for the long-term development of an athlete's maximal power production capacity is the need for an integration of numerous power training techniques. This integration allows for variation within power meso-/micro-cycles while still maintaining specificity, which is theorized to lead to the greatest long-term improvement in maximal power. PMID- 21244107 TI - Should performance-enhancing drugs in sport be legalized under medical supervision? AB - This review examines the question of whether performance-enhancing drugs should be permitted in sport under the control of physicians, and evaluates the expected outcomes of such a scenario. Such a change in regulation would need to be tightly controlled because of the risks involved. The results of legalizing performance enhancing drugs in competitive sport would be either unhelpful or negative, and the unwanted aspects of doping control would not disappear. Athletes, including children and adolescents who wanted to pursue competitive sports, would be forced to take additional, avoidable health risks. The 'natural lottery' of athletic talents would be compensated for only partially by use of performance-enhancing agents. It would also be complemented by another 'natural lottery' of variable responses to doping measures, combined with the inventiveness of doping doctors. There would be no gain in 'justice' (i.e. fairer results that reflected efforts made) for athletes as a result of legalizing doping. Legalization would not reduce restrictions on athletes' freedom; the control effort would remain the same, if not increased. Extremely complicated international regulations would have to be adopted. The game of the 'tortoise and the hare' between doping athletes and inspectors would remain because prohibited but not identifiable practices could still provide additional benefits from use of permissible drugs. Audience mistrust, particularly toward athletes who achieved outstanding feats, would remain because it would still be possible that these athletes were reliant on illegal doping practices. Doping entails exposing the athletes to avoidable risks that do not need to be taken to increase the appeal of a sport. Most importantly, the function of sport as a role model would definitely be damaged. It is not necessary to clarify the question of what constitutes the 'spirit of sport' and whether this may be changed. From a practical point of view, a legalization of performance-enhancing drugs in sport should not be considered for the simple reason that it has no advantages but many disadvantages. PMID- 21244106 TI - Physiological profiles of elite judo athletes. AB - To be successful in international competitions, judo athletes must achieve an excellent level of physical fitness and physical condition during training. This article reviews the physiological profiles of elite judo athletes from different sex, age and weight categories. Body fat is generally low for these athletes, except for the heavyweight competitors. In general, elite judo athletes presented higher upper body anaerobic power and capacity than non-elite athletes. Lower body dynamic strength seems to provide a distinction between elite and recreational judo players, but not high-level judo players competing for a spot on national teams. Even maximal isometric strength is not a discriminant variable among judo players. However, more studies focusing on isometric strength endurance are warranted. Although aerobic power and capacity are considered relevant to judo performance, the available data do not present differences among judo athletes from different competitive levels. Typical maximal oxygen uptake values are around 50-55 mL/kg/min for male and 40-45 mL/kg/min for female judo athletes. As for other variables, heavyweight competitors presented lower aerobic power values. The typical differences commonly observed between males and females in the general population are also seen in judo athletes when analysing anaerobic power and capacity, aerobic power, and maximal strength and power. However, further research is needed concerning the differences among the seven weight categories in which judo athletes compete. PMID- 21244108 TI - Biomedical methods for preventing the sexual transmission of HIV. PMID- 21244104 TI - Two emerging concepts for elite athletes: the short-term effects of testosterone and cortisol on the neuromuscular system and the dose-response training role of these endogenous hormones. AB - The aim of this review is to highlight two emerging concepts for the elite athlete using the resistance-training model: (i) the short-term effects of testosterone (T) and cortisol (C) on the neuromuscular system; and (ii) the dose response training role of these endogenous hormones. Exogenous evidence confirms that T and C can regulate long-term changes in muscle growth and performance, especially with resistance training. This evidence also confirms that changes in T or C concentrations can moderate or support neuromuscular performance through various short-term mechanisms (e.g. second messengers, lipid/protein pathways, neuronal activity, behaviour, cognition, motor-system function, muscle properties and energy metabolism). The possibility of dual T and C effects on the neuromuscular system offers a new paradigm for understanding resistance-training performance and adaptations. Endogenous evidence supports the short-term T and C effects on human performance. Several factors (e.g. workout design, nutrition, genetics, training status and type) can acutely modify T and/or C concentrations and thereby potentially influence resistance-training performance and the adaptive outcomes. This novel short-term pathway appears to be more prominent in athletes (vs non-athletes), possibly due to the training of the neuromuscular and endocrine systems. However, the exact contribution of these endogenous hormones to the training process is still unclear. Research also confirms a dose-response training role for basal changes in endogenous T and C, again, especially for elite athletes. Although full proof within the physiological range is lacking, this athlete model reconciles a proposed permissive role for endogenous hormones in untrained individuals. It is also clear that the steroid receptors (cell bound) mediate target tissue effects by adapting to exercise and training, but the response patterns of the membrane-bound receptors remain highly speculative. This information provides a new perspective for examining, interpreting and utilizing T and C within the elite sporting environment. For example, individual hormonal data may be used to better prescribe resistance exercise and training programmes or to assess the trainability of elite athletes. Possible strategies for acutely modifying the hormonal milieu and, thereafter, the performance/training outcomes were also identified (see above). The limitations and challenges associated with the analysis and interpretation of hormonal research in sport (e.g. procedural issues, analytical methods, research design) were another discussion point. Finally, this review highlights the need for more experimental research on humans, in particular athletes, to specifically address the concept of dual steroid effects on the neuromuscular system. PMID- 21244110 TI - HIV exceptionalism as a prescription for health care reform. PMID- 21244109 TI - Risk compensation in the age of biomedical prevention. PMID- 21244111 TI - Planning and articulation in incremental word production: syllable-frequency effects in English. AB - We investigated the role of syllables during speech planning in English by measuring syllable-frequency effects. So far, syllable-frequency effects in English have not been reported. English has poorly defined syllable boundaries, and thus the syllable might not function as a prominent unit in English speech production. Speakers produced either monosyllabic (Experiment 1) or disyllabic (Experiment 2-4) pseudowords as quickly as possible in response to symbolic cues. Monosyllabic targets consisted of either high- or low-frequency syllables, whereas disyllabic items contained either a 1st or 2nd syllable that was frequency-manipulated. Significant syllable-frequency effects were found in all experiments. Whereas previous findings for disyllables in Dutch and Spanish languages with relatively clear syllable boundaries-showed effects of a frequency manipulation on 1st but not 2nd syllables, in our study English speakers were sensitive to the frequency of both syllables. We interpret this sensitivity as an indication that the production of English has more extensive planning scopes at the interface of phonetic encoding and articulation. (PsycINFO Database Record (c) 2010 APA, all rights reserved). PMID- 21244112 TI - Error biases in inner and overt speech: evidence from tongue twisters. AB - To compare the properties of inner and overt speech, Oppenheim and Dell (2008) counted participants' self-reported speech errors when reciting tongue twisters either overtly or silently and found a bias toward substituting phonemes that resulted in words in both conditions, but a bias toward substituting similar phonemes only when speech was overt. Here, we report 3 experiments revisiting their conclusion that inner speech remains underspecified at the subphonemic level, which they simulated within an activation-feedback framework. In 2 experiments, participants recited tongue twisters that could result in the errorful substitutions of similar or dissimilar phonemes to form real words or nonwords. Both experiments included an auditory masking condition, to gauge the possible impact of loss of auditory feedback on the accuracy of self-reporting of speech errors. In Experiment 1, the stimuli were composed entirely from real words, whereas, in Experiment 2, half the tokens used were nonwords. Although masking did not have any effects, participants were more likely to report substitutions of similar phonemes in both experiments, in inner as well as overt speech. This pattern of results was confirmed in a 3rd experiment using the real word materials from Oppenheim and Dell (in press). In addition to these findings, a lexical bias effect found in Experiments 1 and 3 disappeared in Experiment 2. Our findings support a view in which plans for inner speech are indeed specified at the feature level, even when there is no intention to articulate words overtly, and in which editing of the plan for errors is implicated. (PsycINFO Database Record (c) 2010 APA, all rights reserved). PMID- 21244113 TI - Making sense of surprise: an investigation of the factors influencing surprise judgments. AB - Surprise is often defined in terms of disconfirmed expectations, whereby the surprisingness of an event is thought to be dependent on the degree to which it contrasts with a more likely, or expected, outcome. The authors investigated the alternative hypothesis that surprise is more accurately modeled as a manifestation of an ongoing sense-making process. In a series of experiments, participants were given a number of scenarios and rated surprise and probability for various hypothetical outcomes that either confirmed or disconfirmed an expectation. Experiment 1 demonstrated that representational specificity influences the relationship that holds between surprise and probability ratings. Experiment 2 demonstrated that the inclusion of an enabling event lowers surprise ratings for disconfirming outcomes. Experiment 3 explored the reason for this effect, revealing that enabling events lower surprise by reducing uncertainty, thus enhancing ease of integration. Experiment 4 evaluated the contrast hypothesis directly, showing that differences in contrast are not correlated with differences in surprise. These results provide converging support for the view that the level of surprise experienced for an event is related to the difficulty of integrating that event with an existing representation. (PsycINFO Database Record (c) 2010 APA, all rights reserved). PMID- 21244114 TI - Adaptive memory: determining the proximate mechanisms responsible for the memorial advantages of survival processing. AB - J. S. Nairne, S. R. Thompson, and J. N. S. Pandeirada (2007) suggested that our memory systems may have evolved to help us remember fitness-relevant information and showed that retention of words rated for their relevance to survival is superior to that of words encoded under other deep processing conditions. The authors present 4 experiments that uncover the proximate mechanisms likely responsible. The authors obtained a recall advantage for survival processing compared with conditions that promoted only item-specific processing or only relational processing. This effect was eliminated when control conditions encouraged both item-specific and relational processing. Data from separate measures of item-specific and relational processing generally were consistent with the view that the memorial advantage for survival processing results from the encoding of both types of processing. Although the present study suggests the proximate mechanisms for the effect, the authors argue that survival processing may be fundamentally different from other memory phenomena for which item specific and relational processing differences have been implicated. (PsycINFO Database Record (c) 2010 APA, all rights reserved). PMID- 21244115 TI - Synesthesia and memory: color congruency, von Restorff, and false memory effects. AB - In the current study, we explored the influence of synesthesia on memory for word lists. We tested 10 grapheme-color synesthetes who reported an experience of color when reading letters or words. We replicated a previous finding that memory is compromised when synesthetic color is incongruent with perceptual color. Beyond this, we found that, although their memory for word lists was superior overall, synesthetes did not exhibit typical color- or semantic-defined von Restorff isolation effects (von Restorff, 1933) compared with control participants. Moreover, our synesthetes exhibited a reduced Deese-Roediger McDermott false memory effect (Deese, 1959; Roediger & McDermott, 1995). Taken as a whole, these findings are consistent with the idea that color-grapheme synesthesia can lead people to place a greater emphasis on item-specific processing and surface form characteristics of words in a list (e.g., the letters that make them up) relative to relational processing and more meaning-based processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved). PMID- 21244116 TI - Readers' reliance on source credibility in the service of comprehension. AB - The current project examined the impact of knowledge about the credibility of sources on readers' processing of texts. Participants read texts in which information about characters was provided by either a credible or a noncredible source; this information suggested that the character potentially possessed a particular trait. A subsequent text episode offered the opportunity for participants to apply any inferred trait to their understanding of unfolding story events. In Experiment 1, participants' moment-by-moment reading times indicated strong expectations for characters to behave in trait-consistent ways, with little effect of credibility on those expectations. Experiments 2 and 3 provided participants with additional encouragement to attend to credibility during reading, but these experiments also revealed little influence of credibility. In Experiment 4, in addition to being given added encouragement, participants were explicitly asked to evaluate the likelihood of future text events; under these conditions, expectations for story outcomes were influenced by the credibility of information sources. This influence was mediated by the degree to which participants self-reported relying on credibility during the task. These findings have implications for contemporary accounts of text comprehension, persuasion, and individual differences in credibility assessment. (PsycINFO Database Record (c) 2010 APA, all rights reserved). PMID- 21244117 TI - New rule use drives the relation between working memory capacity and Raven's Advanced Progressive Matrices. AB - The correlation between individual differences in working memory capacity and performance on the Raven's Advanced Progressive Matrices (RAPM) is well documented yet poorly understood. The present work proposes a new explanation: that the need to use a new combination of rules on RAPM problems drives the relation between performance and working memory capacity scores. Evidence for this account is supported by an item-based analysis of performance during standard administration of the RAPM and an experiment that manipulates the need to use new rule combinations across 2 subsets of RAPM items. (PsycINFO Database Record (c) 2010 APA, all rights reserved). PMID- 21244118 TI - Tip-of-the-tongue states reveal age differences in the syllable frequency effect. AB - Syllable frequency has been shown to facilitate production in some languages but has yielded inconsistent results in English and has never been examined in older adults. Tip-of-the-tongue (TOT) states represent a unique type of production failure where the phonology of a word is unable to be retrieved, suggesting that the frequency of phonological forms, like syllables, may influence the occurrence of TOT states. In the current study, we investigated the role of first-syllable frequency on TOT incidence and resolution in young (18-26 years of age), young old (60-74 years of age), and old-old (75-89 years of age) adults. Data from 3 published studies were compiled, where TOTs were elicited by presenting definition-like questions and asking participants to respond with "Know," "Don't Know," or "TOT." Young-old and old-old adults, but not young adults, experienced more TOTs for words beginning with low-frequency first syllables relative to high frequency first syllables. Furthermore, age differences in TOT incidence occurred only for words with low-frequency first syllables. In contrast, when a prime word with the same first syllable as the target was presented during TOT states, all age groups resolved more TOTs for words beginning with low-frequency syllables. These findings support speech production models that allow for bidirectional activation between conceptual, lexical, and phonological forms of words. Furthermore, the age-specific effects of syllable frequency provide insight into the progression of age-linked changes to phonological processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved). PMID- 21244120 TI - Gambling among Minnesota public school students from 1992 to 2007: declines in youth gambling. AB - The specific aims of this study are twofold. First, measure 2007 rates of gambling and underage gambling among public school students. Second, compare rates of gambling, frequent gambling, and underage gambling from 1992 to 2007. The 2007 sample includes 40,605 male and 42,655 female Minnesota public school students enrolled in the 9th and 12th grades and similar sample sizes from 1992, 1995, 1998, 2001, and 2004. Students were administered the Minnesota Student Survey, a 126-item, anonymous, self-administered, paper-and-pencil questionnaire that inquires about multiple health-related content domains, including gambling behavior. In 2007, most students gambled at least once during the past year, however, most did not gamble frequently. Gambling participation has shown a gradual and consistent decline from 1992 to 2007 for both boys and girls. Underage gambling has also shown declines over time. Conversely, rates of frequent gambling (weekly or more often) have remained fairly stable over time. There have been two fluctuations of note, a peak in lottery play in 1998 and a peak in card playing in 2004 with subsequent declines in both. PMID- 21244119 TI - Accuracy and bias in adolescents' perceptions of friends' substance use. AB - This study tested competing hypotheses related to the false consensus effect and pluralistic ignorance by examining the accuracy and bias of adolescents' perceptions of peer substance use and the effects of their own substance use, gender, and age on perceptions of peer behavior. Two samples (ns = 163 and 2,194) that collected data on peer nominations, perceptions of peer substance use, and self-reports of substance use were used in analyses. Results from both samples provided evidence supporting the false consensus effect, that is, adolescents' reports of their friends' substance use were biased in the direction of their own use. Users and nonusers did not differ in accuracy of perceptions; however, across all substances and samples, they differed significantly in bias. Substance users displayed nearly perfect liberal bias, assuming their friends also used substances. Nonusers displayed an opposite, conservative bias, assuming their friends did not use substances. Gender and age differences in bias also were observed, with older adolescents and girls having more liberal biases than younger adolescents and boys. Results suggest the importance of differentiating the effects of actual and perceived peer substance use. PMID- 21244121 TI - Hazardous alcohol use among active duty Air Force personnel: identifying unique risk and promotive factors. AB - Hazardous drinking is a significant public health concern and an important target for prevention efforts within both military and civilian populations. For such efforts to be maximally effective, comprehensive information regarding factors that increase or decrease risk for hazardous drinking is necessary. This is the first study to investigate risk and promotive factors across individual, family, community, and organizational levels in a representative sample of Air Force personnel (N = 52,780). Unique predictors of men's and women's hazardous drinking were identified both within and across ecological levels. Predictors that accounted for the most variance in predicting hazardous versus non-hazardous drinkers included family income, number of children, depressive symptoms, religious involvement, and perceived financial stress for men and women; and years in the military for men. Among hazardous drinkers, a different set of predictors best explained variance in severity of drinking problems. Results of the current study help identify key targets for prevention efforts operating at different levels (e.g., individual therapy, community-wide programs). PMID- 21244122 TI - Age of onset of first alcohol intoxication and subsequent alcohol use among urban American Indian adolescents. AB - The objective was to assess the effect of early onset intoxication on subsequent alcohol involvement among urban American Indian youth. The data come from the American Indian Research (AIR) project, a panel study of urban Indian youth residing in King County, Washington. Data were collected annually from the adolescent and his/her primary caregiver from the 1988-89 school year to the 1996 97 school year, providing a total of nine waves of data. Early intoxication (by age 14) was related to delinquency, family history of alcohol abuse or dependence, poverty, broken family structure, less family cohesiveness, and more family conflict. The effects of these characteristics were, therefore, partialed out in testing effects of early intoxication on later alcohol involvement. Two part latent growth models of alcohol use and alcohol problems were specified. Effects of early onset intoxication on these trajectories, as well as lifetime alcohol abuse or dependence by the transition to young adulthood, were examined. Findings indicate that adolescents who experienced their first intoxication early (by age 14), used alcohol more heavily from the ages of 16 to 18, experienced more problems related to the alcohol's use from the ages of 16 to 18, and were more likely to have a diagnosed alcohol disorder by the final wave of data collection. Congruent with similar studies in the general population, early intoxication appears to be associated with a deleterious course of alcohol involvement during adolescence and into the transition to young adulthood among urban American Indian youth. Implications for prevention are discussed. PMID- 21244123 TI - Predicting early gambling in children. AB - This large population-based study (N = 1,125) examined whether low inhibition (i.e., low anxiety) predicted early gambling, above and beyond disinhibition (i.e., impulsivity) and whether the two personal dispositions operated independently or interactively. It also examined whether the predictive role of these personal dispositions towards early gambling depended on parent gambling. Children's personal dispositions were assessed at ages 6, 7, and 8 years through teacher ratings. Parent gambling participation and gambling problems were assessed when the children were 8 years old. Finally, children's early gambling was measured through self-reports when the children were 10 years old. Results showed that teacher-rated impulsivity predicted early gambling for both genders. In addition, low anxiety predicted early gambling behavior, above and beyond impulsivity and control variables, albeit only in boys. Impulsivity and anxiety did not interact with each other, nor did they interact with parent gambling in predicting early gambling. However, parent gambling participation, but not problems, additively predicted early gambling for boys and for girls. The theoretical and practical implications of these findings are discussed. PMID- 21244124 TI - Lifestyle and mental health. AB - Mental health professionals have significantly underestimated the importance of lifestyle factors (a) as contributors to and treatments for multiple psychopathologies, (b) for fostering individual and social well-being, and (c) for preserving and optimizing cognitive function. Consequently, therapeutic lifestyle changes (TLCs) are underutilized despite considerable evidence of their effectiveness in both clinical and normal populations. TLCs are sometimes as effective as either psychotherapy or pharmacotherapy and can offer significant therapeutic advantages. Important TLCs include exercise, nutrition and diet, time in nature, relationships, recreation, relaxation and stress management, religious or spiritual involvement, and service to others. This article reviews research on their effects and effectiveness; the principles, advantages, and challenges involved in implementing them; and the forces (economic, institutional, and professional) hindering their use. Where possible, therapeutic recommendations are distilled into easily communicable principles, because such ease of communication strongly influences whether therapists recommend and patients adopt interventions. Finally, the article explores the many implications of contemporary lifestyles and TLCs for individuals, society, and health professionals. In the 21st century, therapeutic lifestyles may need to be a central focus of mental, medical, and public health. PMID- 21244125 TI - Time is tight: how higher economic value of time increases feelings of time pressure. AB - The common heuristic association between scarcity and value implies that more valuable things appear scarcer (King, Hicks, & Abdelkhalik, 2009), an effect we show applies to time as well. In a series of studies, we found that both income and wealth, which affect the economic value of time, influence perceived time pressure. Study 1 found that changes in income were associated with changes in perceived time pressure. Studies 2-4 showed that experimentally manipulating time's perceived economic value caused greater feelings of time pressure and less patient behavior. Finally, Study 5 demonstrated that the relationship between income and time pressure was strengthened when participants were randomly assigned to think about the precise economic value of their time. PMID- 21244126 TI - Does human capital matter? A meta-analysis of the relationship between human capital and firm performance. AB - Theory at both the micro and macro level predicts that investments in superior human capital generate better firm-level performance. However, human capital takes time and money to develop or acquire, which potentially offsets its positive benefits. Indeed, extant tests appear equivocal regarding its impact. To clarify what is known, we meta-analyzed effects drawn from 66 studies of the human capital-firm performance relationship and investigated 3 moderators suggested by resource-based theory. We found that human capital relates strongly to performance, especially when the human capital in question is not readily tradable in labor markets and when researchers use operational performance measures that are not subject to profit appropriation. Our results suggest that managers should invest in programs that increase and retain firm-specific human capital. PMID- 21244127 TI - Organizational culture and organizational effectiveness: a meta-analytic investigation of the competing values framework's theoretical suppositions. AB - We apply Quinn and Rohrbaugh's (1983) competing values framework (CVF) as an organizing taxonomy to meta-analytically test hypotheses about the relationship between 3 culture types and 3 major indices of organizational effectiveness (employee attitudes, operational performance [i.e., innovation and product and service quality], and financial performance). The paper also tests theoretical suppositions undergirding the CVF by investigating the framework's nomological validity and proposed internal structure (i.e., interrelationships among culture types). Results based on data from 84 empirical studies with 94 independent samples indicate that clan, adhocracy, and market cultures are differentially and positively associated with the effectiveness criteria, though not always as hypothesized. The findings provide mixed support for the CVF's nomological validity and fail to support aspects of the CVF's proposed internal structure. We propose an alternative theoretical approach to the CVF and delineate directions for future research. PMID- 21244128 TI - Relationships of role stressors with organizational citizenship behavior: a meta analysis. AB - Several quantitative reviews have documented the negative relationships that role stressors have with task performance. Surprisingly, much less attention has been directed at the impact of role stressors on other aspects of job performance, such as organizational citizenship behavior (OCB). The goal of this study was to therefore estimate the overall relationships of role stressors (i.e., role ambiguity, conflict, and overload) with OCB. A meta-analysis of 42 existing studies indicated that role ambiguity and role conflict were negatively related to OCB and that these relationships were moderated by the target of OCB, type of organization, OCB rating source, and publication status. As expected, role conflict had a stronger negative relationship with OCB than it did with task performance. Finally, we found support for a path model in which job satisfaction mediated relationships of role stressors with OCB and for a positive direct relationship between role overload and OCB. PMID- 21244129 TI - The dread factor: how hazards and safety training influence learning and performance. AB - On the basis of hypotheses derived from social and experiential learning theories, we meta-analytically investigated how safety training and workplace hazards impact the development of safety knowledge and safety performance. The results were consistent with an expected interaction between the level of engagement of safety training and hazardous event/exposure severity in the promotion of safety knowledge and performance. For safety knowledge and safety performance, highly engaging training was considerably more effective than less engaging training when hazardous event/exposure severity was high, whereas highly and less engaging training had comparable levels of effectiveness when hazardous event/exposure severity was low. Implications of these findings for theory testing and incorporating information on objective risk into workplace safety research and practice are discussed. PMID- 21244131 TI - Too much information: the perils of nondiagnostic information in negotiations. AB - Two studies showed that possessing information about a negotiation counterpart that is irrelevant to the negotiation task can impair negotiators' effectiveness because such knowledge impedes effective information exchange. In Study 1, negotiators who possessed diagnostic and nondiagnostic forms of information were each less likely to exchange information about their preferences within the negotiation. However, only those negotiators who possessed nondiagnostic information achieved inferior negotiation outcomes as a result. In Study 2, negotiators possessing nondiagnostic information about their counterparts in electronically mediated negotiations were more likely to terminate the search for mutually beneficial outcomes prematurely and declare impasses. They were also less able to use diagnostic forms of information to make mutually beneficial trade-offs. As a result, negotiators in these dyads achieved inferior outcomes. PMID- 21244132 TI - Curiosity adapted the cat: the role of trait curiosity in newcomer adaptation. AB - Using longitudinal data from 123 newcomers across 12 telemarketing organizations, we examined the role of 2 forms of trait curiosity (specific and diversive) as antecedents of proximal adaptation behaviors (information seeking and positive framing) and more distal, in-role and extra-role behaviors (job performance and taking charge). Results suggest that specific curiosity predicts information seeking behaviors, whereas diversive curiosity promotes positive framing. Results also support the relationship between positive framing and performance and the extra-role behavior of taking charge. Overall, the study validates the role of curiosity as a multifaceted individual difference that serves as an antecedent to newcomer adaptation. PMID- 21244133 TI - Are memory self-efficacy and memory performance related? A meta-analysis. AB - The association between memory self-efficacy (MSE) and memory performance is highly documented in the literature. However, previous studies have produced inconsistent results, and there is no consensus on the existence of a significant link between these two variables. In order to evaluate whether or not the effect size of the MSE-memory performance relationship in healthy adults is significant and to test several theory-driven moderators, we conducted a meta-analysis of published and unpublished studies. A random-effects model analysis of data from 107 relevant studies (673 effect sizes) indicated a low but significant weighted mean correlation between MSE and memory performance, r = .15, 95% CI [.13, .17]. In addition, the mean effect size was significantly moderated by the way MSE was assessed. Memory performance was more strongly related to concurrent MSE (perceived current ability to perform a given task) than it was to global MSE (perceived usual memory ability in general). Furthermore, we found marginally larger MSE-memory performance correlations when the memory situations used to assess MSE involved familiar stimuli. No effect of the method used to assess global MSE or domain MSE (memory rating vs. performance predictions) was found. The results also show that the resource demands of the memory tasks have a moderator effect, as the MSE-performance correlation is larger with free-recall and cued-recall tasks than it is with recognition tasks. Limitations (generalization issues, moderators not considered) and implications for future research are discussed. PMID- 21244134 TI - Development in children's sensitivity to the role of derivations in spelling. AB - The English orthography represents the units of meaning (morphemes) as well as the units of sound in words. This experiment focused on 6- to 10-year-old children's sensitivity to the role that an understudied group of morphemes, derivations, plays in spelling. We asked children to circle the correct ending out of 3 phonologically plausible options for 2-morpheme words ending in derivations (e.g., lucky) and for 1-morpheme words with the same word-final letter sequence (e.g., study). The older children (approximately 9 years of age) were more likely to complete the endings correctly for derived words than for 1 morpheme words. This effect did not emerge for the younger children (approximately 7 years). These results help to specify the developmental trajectory of children's sensitivity to the role of morphemes in spelling. PMID- 21244135 TI - Persistent effect of incubation temperature on stress-induced behavior in the Yucatan banded gecko (Coleonyx elegans). AB - Although variability in behavioral traits within animal populations is well documented, the mechanisms maintaining that variability are still insufficiently known. In this study, we examined whether differences in thermal environment during egg incubation can permanently organize nonsocial behavior across different contexts and situations in a lizard species. We incubated eggs of the Yucatan banded gecko, Coleonyx elegans (Squamata: Gekkota: Eublepharidae) at 3 constant temperatures (26, 28, and 30 degrees C) and raised juveniles separately under the same conditions until adulthood. We then subjected them to 3 behavioral tests within 2 different contexts: an open-field test and a test of antipredator behavior (stressful context) as well as a test of feeding behavior (nonstressful context). Individuals of both sexes incubated at 30 degrees C were consistently less active and showed lower frequencies of several stereotypic behaviors in the stressful contexts than did individuals incubated at 26 and 28 degrees C. The test of feeding behavior revealed no significant effect of incubation temperature on geckos' behavior. Thus, our study demonstrates that developmental plasticity may play an important role in producing variability in stress-induced behavior in lizards. PMID- 21244136 TI - Reverse-reward learning in squirrel monkeys (Saimiri sciureus): retesting after 5 years, and assessment on qualitative transfer. AB - Seven squirrel monkeys (Saimiri sciureus) previously trained on reverse-reward tasks were presented with the original "1-versus-4" task after a 5-year interval without reverse-reward experience (Experiment 1). None of them reliably selected the smaller food array; however, at around chance level, their performance was superior to when they were first exposed to the task almost 6 years previously, suggesting some long-term memory retention. One naive monkey consistently selected the larger array, as expected. In Experiment 2, trials consisting of 1 versus 1 piece of two qualitatively different types of food were interspersed among familiar 1-versus-4 trials. None of five monkeys tested reliably selected the less-preferred food to get the more preferred food as the reward, and one monkey scored below chance. However, when one piece of low-preference food was paired with four pieces of high-preference food (Experiment 3), all four monkeys tested avoided reaching for the latter and thereby obtained it as the reward; two monkeys obtained perfect scores on these trials. These two monkeys were trained on a specific qualitative reverse-reward pairing and then again tested on new pairings (Experiment 4), but transfer was incomplete. Compound trials that pit quantity against quality in novel ways appear taxing for squirrel monkeys, despite competence in reverse-reward on both dimensions separately. PMID- 21244137 TI - Playing with the face: playful facial "chattering" and signal modulation in a monkey species (Theropithecus gelada). AB - Darwin (1872), in The expression of emotions in man and animals, underlined that human facial expressions represent a shared heritage of our species with nonhuman primates. Play is a fertile field to examine the role of facial expressions that we share with our common ancestors because the primate play face is homologous to human laughter. Here, we focus on the use of two playful expression variants (PF: play face, mouth opened with only the lower teeth exposed; FPF: full play face, lower/upper teeth and gums exposed via the actively retraction of the upper lip) in Theropithecus gelada. During ontogeny PF was replaced by FPF; in older subjects PF was virtually absent. The ontogenetic transition appears to reflect the phylogenetic sequence of the two playful displays with FPF considered a derived form of PF. This age-trend bias of facial displays is probably due to their different roles in communication. The correspondence between facial signals emitted and elicited is a valuable criterion to evaluate playmates' attentional state. Adults were more sensitive than immatures in responding to the play faces of others. Probably, previous playful experience, social competence, and neural circuit maturation are at the basis of adult sensitiveness. Similar to humans, where unconscious laughing is deserved for close friends and/or relatives, FPF was extremely frequent during gelada mother-offspring play. Probably, under some intimate circumstances, facial displays should be primarily linked to the spontaneous expression of emotional states of the sender more than to the strategic transfer of actual information to the receiver. PMID- 21244138 TI - Interpreting the effects of image manipulation on picture perception in pigeons (Columba livia) and humans (Homo sapiens). AB - The effects of picture manipulations on humans' and pigeons' performance were examined in a go/no-go discrimination of two perceptually similar categories, cat and dog faces. Four types of manipulation were used to modify the images. Mosaicization and scrambling were used to produce degraded versions of the training stimuli, while morphing and cell exchange were used to manipulate the relative contribution of positive and negative training stimuli to test stimuli. Mosaicization mainly removes information at high spatial frequencies, whereas scrambling removes information at low spatial frequencies to a greater degree. Morphing leads to complex transformations of the stimuli that are not concentrated at any particular spatial frequency band. Cell exchange preserves high spatial frequency details, but sometimes moves them into the "wrong" stimulus. The four manipulations also introduce high-frequency noise to differing degrees. Responses to test stimuli indicated that high and low spatial frequency information were both sufficient but not necessary to maintain discrimination performance in both species, but there were also species differences in relative sensitivity to higher and lower spatial frequency information. PMID- 21244139 TI - An obedient orangutan (Pongo abelii) performs perfectly in peripheral object choice tasks but fails the standard centrally presented versions. AB - Mulcahy and Call (2009) found that bonobos (Pan paniscus) and chimpanzees (Pan troglodytes) but not orangutans (Pongo pygmaeus) perform significantly better in a peripheral version of the object-choice task compared to the original central version. Orangutans may have failed because they avoided direct eye contact with the experimenter when the cue was given. We investigated this possibility by conducting peripheral and central object choice tasks with an obedient orangutan (Pongo abelii) whom the experimenter could elicit eye contact with in each trial. In contrast to Mulcahy and Call's findings, the subject only failed the object choice task when tested with the central and not the peripheral version. We investigated whether success was because of the greater distance the subject was required to move in order to make a choice in peripheral trials. Results show that this was an unlikely factor in the subject's success. We discuss our findings in relation to previous and future object-choice research. PMID- 21244140 TI - Spatial learning in a T-maze by the crayfish Orconectes rusticus. AB - The T-maze has commonly been used to investigate the mechanisms underlying spatial learning in vertebrates and has yielded much information about how animals use response and place cues to orient toward a goal. We designed a T-maze to study the spatial learning abilities of crayfish (Orconectes rusticus), using tactile stimuli as a place cue and escape from warm water for reinforcement. An initial experiment found that most animals did not display a side-turning bias when first placed in the maze, and hence animals were randomly assigned to escape from the left or the right arm, one of which contained a smooth floor and the other a rough floor. We found that, over repeated trials, the latency to escape and the number of turns made prior to escaping significantly decreased indicating that crayfish learned to escape from the maze more rapidly and efficiently. Learning occurred over the course of six trials on a single day, and over 5 days of testing, providing evidence for spatial memory lasting 24 hr. In probe trials, in which experienced animals started the maze in an arm opposite to that used during training trials, crayfish did not display a preference for either response based learning or place-based learning. Instead they engaged in renewed exploration of the entire maze. These findings suggest that, in addition to remembering the location of the exit, crayfish also remembered the overall configuration of the maze. PMID- 21244141 TI - Complexity in object manipulation by Japanese macaques (Macaca fuscata): a cross sectional analysis of manual coordination in stone handling patterns. AB - Defined as a spontaneous stone-directed noninstrumental manipulative behavior, and comprised of multiple one-handed and (a)symmetrical/(un)coordinated two handed patterns, stone handling (SH) is a good candidate for the study of complexity in object manipulation. We present a cross-sectional developmental analysis of SH complexity in Japanese macaques (Macaca fuscata), through the combined investigation of bimanuality, coordination, and symmetry in hand use. Bimanual SH patterns were more frequent than unimanual patterns. Among bimanual patterns, coordinated actions were more frequent than uncoordinated ones. We recorded five asymmetrical coordinated SH patterns with manual role differentiation, a form of hand use reminiscent of complex actions involving the use of tools in monkeys and apes. Bimanuality in SH was affected by body posture. Aging individuals performed less bimanual and less coordinated SH patterns than younger individuals. Our result on senescent males performing less bimanual patterns than senescent females was consistent with sex differences found in the late deterioration of complex manual movements in other species. Although some SH patterns represent a high degree of behavioral complexity, our results suggest that SH behavior is not as complex as tool-use or tool-manufacture in other nonhuman primates and hominids. PMID- 21244142 TI - Developmental environment affects risk-acceptance in the hissing cockroach, Gromphadorhina portentosa. AB - Consistent individual differences in the tendency to accept risk have been demonstrated in invertebrates, fish, birds, and mammals, including humans. These individual differences have been associated with size, growth rate, survival, and reproductive success. Little research, however, has investigated the effect of developmental environment on individual differences in risk-acceptance. Competing hypotheses offer different explanations of how variation in the quality of the developmental environment affects risk-acceptance in adults. The first hypothesis states that individuals developing in poor quality environments take risks because such behavior is their only means of obtaining adequate fitness returns. The second hypothesis states that individuals developing in poor environments avoid risk because their poor physical condition makes them especially vulnerable to injury or death. We measured several forms of risk-accepting behavior (exploration, foraging, and recovery after disturbance) in male hissing cockroaches (Gromphadorhina portentosa) that had developed in nutritional and social environments of varying quality. Individuals raised on poor nutrition diets exhibited lower levels of risk-acceptance than those raised on high nutrition diets. Risk-acceptance among individuals that developed on poor nutrition diets was negatively correlated with body size. We conclude that quality of developmental environment affects risk-acceptance across behavioral contexts in male hissing cockroaches. Our findings are consistent with the hypothesis that condition-dependent vulnerability mediates the relationship between developmental environment and risk-acceptance. PMID- 21244143 TI - Multicultural counseling competencies: an analysis of research on clients' perceptions: comment on Owen, Leach, Wampold, and Rodolfa (2011). AB - J. Owen, M. M. Leach, B. Wampold, and E. Rodolfa (see record 2010-24976-001) tested the hypotheses that (a) some therapists express more multicultural competencies (MCCs) more than other therapists and (b) clients' perceptions of their therapists' MCCs are a function of specific client or therapeutic factors. In the present analysis, the authors critiqued 3 major components of the study: conceptual and methodological underpinnings, interpretation of research findings, and implications for future research. Although the authors agree with the importance of this line of research, the authors also believe that some of the researchers' underlying assumptions are worthy of examination; alternate interpretations of the findings are possible, and several recommendations for future research are imperative. PMID- 21244144 TI - The acceptance model of intuitive eating: a comparison of women in emerging adulthood, early adulthood, and middle adulthood. AB - The acceptance model of intuitive eating (Avalos & Tylka, 2006) posits that body acceptance by others helps women appreciate their body and resist adopting an observer's perspective of their body, which contribute to their eating intuitively/adaptively. We extended this model by integrating body mass index (BMI) into its structure and investigating it with emerging (ages 18-25 years old, n = 318), early (ages 26-39 years old, n = 238), and middle (ages 40-65 years old, n = 245) adult women. Multiple-group analysis revealed that this model fit the data for all age groups. Body appreciation and resistance to adopt an observer's perspective mediated the body acceptance by others-intuitive eating link. Body acceptance by others mediated the social support-body appreciation and BMI-body appreciation links. Early and middle adult women had stronger negative BMI-body acceptance by others and BMI-intuitive eating relationships and a stronger positive body acceptance by others-body appreciation relationship than emerging adult women. Early adult women had a stronger positive resistance to adopt observer's perspective-body appreciation relationship than emerging and middle adult women. PMID- 21244145 TI - Global and domain-specific changes in cognition throughout adulthood. AB - Normative adult age-related decrements are well documented for many diverse forms of effortful cognitive processing. However, it is currently unclear whether each of these decrements reflects a distinct and independent developmental phenomenon, or, in part, a more global phenomenon. A number of studies have recently been published that show moderate to large magnitudes of positive relations among individual differences in rates of changes in different cognitive variables during adulthood. This suggests that a small number of common dimensions or even a single common dimension may underlie substantial proportions of individual differences in aging-related cognitive declines. This possibility was directly examined using data from 1,281 adults 18-95 years of age who were followed longitudinally over up to 7 years on 12 different measures of effortful processing. Multivariate growth curve models were applied to examine the dimensionality of individual differences in longitudinal changes. Results supported a hierarchical structure of aging-related changes, with an average of 39% of individual differences in change in a given variable attributable to global (domain-general) developmental processes, 33% attributable to domain specific developmental processes (abstract reasoning, spatial visualization, episodic memory, and processing speed), and 28% attributable to test-specific developmental processes. Although it is often assumed that systematic and pervasive sources of cognitive decline only emerge in later adulthood, domain general influences on change were apparent for younger (18-49 years), middle aged (50-69 years), and older (70-95 years) adults. PMID- 21244146 TI - Perception of object-context relations: eye-movement analyses in infants and adults. AB - Twenty-eight 4-month-olds' and twenty-two 20-year-olds' attention to object context relations was investigated using a common eye-movement paradigm. Infants and adults scanned both objects and contexts. Infants showed equivalent preferences for animals and vehicles and for congruent and incongruent object context relations overall, more fixations of objects in congruent object-context relations, more fixations of contexts in incongruent object-context relations, more fixations of objects than contexts in vehicle scenes, and more fixation shifts in incongruent than congruent vehicle scenes. Adults showed more fixations of congruent than incongruent scenes, vehicles than animals, and objects than contexts; equal fixations of animals and their contexts but more fixations of vehicles than their contexts; and more shifts of fixation when inspecting animals in context than vehicles in context. These findings for location, number, and order of eye movements indicate that object-context relations play a dynamic role in the development and allocation of attention. PMID- 21244147 TI - Examining dynamic links between perceived control and health: longitudinal evidence for differential effects in midlife and old age. AB - Perceived control and health are often closely linked in adulthood and old age. Little is known, however, about their time-ordered interplay at various phases of adult life. By applying dynamic models to four waves of data over 15.5 years from the Americans' Changing Lives Study, we examined time-ordered relations between perceived control and health in midlife and old age. Results revealed that levels of perceived control predict subsequent changes in health over time in old age (65+ years of age; n = 1,238) but not in midlife (25-64 years of age; n = 2,364). No evidence was found for predictive effects of health for changes in perceived control in either age group. These age-differential findings were corroborated with nested-model comparisons. Predictive effects of perceived control for health were attenuated to the null in models covarying for sociodemographic and psychosocial factors (physical activity, memory, emotional support, and depressive symptoms), suggesting that these variables play an important role in control-health relations. Our discussion focuses on the importance of perceived control for healthy living in old age and the differential implications of perceived control for health in midlife and old age. PMID- 21244148 TI - When all signs point to you: lies told in the face of evidence. AB - Young children's ability to tell a strategic lie by making it consistent with the physical evidence of their transgression was investigated along with the sociocognitive correlates of such lie-telling behaviors. In Experiment 1, 247 Chinese children between 3 and 5 years of age (126 boys) were left alone in a room and asked not to lift a cup to see the contents. If children lifted up the cup, the contents would be spilled and evidence of their transgression would be left behind. Upon returning to the room, the experimenter asked children whether they peeked and how the contents of the cup ended up on the table. Experiment 1 revealed that young children are able to tell strategic lies to be consistent with the physical evidence by about 4 or 5 years of age, and this ability increases in sophistication with age. Experiment 2, which included 252 Chinese 4 year-olds (127 boys), identified 2 sociocognitive factors related to children's ability to tell strategic lies. Specifically, both children's theory-of-mind understanding and inhibitory control skills were significantly related to their ability to tell strategic lies in the face of physical evidence. The present investigation reveals that contrary to the prevailing views, even young children are able to tell strategic lies in some contexts. PMID- 21244149 TI - Young children's emerging ability to make false statements. AB - This study examined the origins of children's ability to make consciously false statements, a necessary component of lying. Children 2 to 5 years of age were rewarded for claiming that they saw a picture of a bird when viewing pictures of fish. They were asked outcome questions ("Do you win/lose?"), recognition questions ("Do you have a bird/fish?"), and recall questions ("What do you have?"), which were hypothesized to vary in difficulty depending on the need for consciousness of falsity (less for outcome questions) and self-generation of an appropriate response (more for recall questions). The youngest children (21/2 to 31/2 years old) were above chance on outcome questions, but it was not until age 31/2 that children performed above chance on recognition questions or were capable of maintaining false claims across question types. Findings have implications for understanding the emergence of deception in young children. PMID- 21244150 TI - Imitation and repetition of prosodic contour in vocal interaction at 3 months. AB - This study investigates vocal imitation of prosodic contour in ongoing spontaneous interaction with 10- to 13-week-old infants. Audio recordings from naturalistic interactions between 20 mothers and infants were analyzed using a vocalization coding system that extracted the pitch and duration of individual vocalizations. Using these data, the authors categorized a sample of 1,359 vocalizations on the basis of 7 predetermined contours. Pairs of identical successive vocalizations were considered to be imitations if they involved both partners or repetitions if they were produced by the same partner. Results show that not only do mothers and infants imitate and repeat prosodic contour types in the course of vocal interaction but they do so selectively. Indeed, different contours are imitated and repeated by each partner. These findings suggest that imitation and repetition of prosodic contours have specific functions for communication and vocal development in the 3rd month of life. PMID- 21244151 TI - Social competence of adult chimpanzees (Pan troglodytes) with severe deprivation history: I. An individual approach. AB - Early social deprivation in highly social mammals interferes with their varying needs for security and stimulation. Toleration of social stimulation was studied in 18 adult ex-laboratory chimpanzees, who had been deprived for 16 to 27 years, during their 1st year after resocialization into 1 of 3 social groups. For this, a model of social competence was developed with 5 grades of social stimulation. The chimpanzees were classified as either early deprived (EDs; M = 1.2 years) or late deprived (LDs; M = 3.6 years) according to their age at entering the laboratory. EDs did not differ significantly from LD chimpanzees in the first 3 grades of social stimulation (i.e., the toleration of stationary vicinity, initiation of brief sociopositive contacts and gentle social play). LDs, however, clearly exceeded EDs in the 4th and 5th grade of social stimulation (i.e., their engagement in allogrooming and their toleration of passive close proximity). Furthermore, LDs showed greater social initiative in changing a social situation and had more expanded grooming networks compared with EDs. Moreover, in LDs and ED females, but not in ED males, toleration of stationary vicinity increased from the 1st to the 2nd year of group living. PMID- 21244153 TI - Relations between coparenting and father involvement in families with preschool age children. AB - A sample (N = 112) composed primarily of European American and middle-class two parent families with a resident father and a 4-year-old child (48% girls) participated in a longitudinal study of associations between coparenting and father involvement. At the initial assessment and 1 year later, fathers reported on their involvement in play and caregiving activities with the focal child, and coparenting behavior was observed during triadic family interactions. Structural equation modeling was used to test cross-lagged associations between coparenting behavior and father involvement. Overall, paths from father involvement to coparenting behavior were significant, but paths from coparenting behavior to father involvement were not. Specifically, greater father involvement in play was associated with an increase in supportive and a decrease in undermining coparenting behavior over time. In contrast, greater father involvement in caregiving was associated with a decrease in supportive and an increase in undermining coparenting behavior. Multigroup analysis further showed that these cross-lagged relations did not differ for dual-earner families and single-earner (father) families, but these relations appeared to differ for families with focal daughters and families with focal sons. These findings highlight the potential for fathering to affect coparenting and the importance of the role of contextual factors in coparenting-fathering relations. PMID- 21244152 TI - Infant physiological regulation and maternal risks as predictors of dyadic interaction trajectories in families with a preterm infant. AB - This longitudinal study examined predictors of rates of growth in dyadic interaction quality in children born preterm who did not experience significant neurological findings during neonatal intensive care unit (NICU) hospitalization. Multiple methods were used to collect data from 120 preterm infants (48% girls, 52% boys) and their mothers. Infant heart rate variability (HRV), gestational age, neonatal health, feeding route, and maternal socioeconomic (SES) risks were assessed at NICU discharge (mean of 36 weeks postconception). Mother-child interactions were observed at 4, 9, 16, and 24 months postterm and analyzed with hierarchical linear modeling. On average, children's quality of play, interest, and attention increased over time while their dysregulation and irritability decreased, whereas average maternal positive affect and involvement declined in quality (ps < .05), although there was individual variation in rates of change. Mothers of infants with higher postfeeding HRV (i.e., vagal regulation) exhibited less decrease in positive affect and involvement between 4 months and 24 months, compared with mothers of infants with lower HRV (p < .05). Although infants with higher postfeeding HRV showed less positive affect and communication at 4 months, they exhibited significantly greater increases in positive affect and social competence and decreases in dysregulation and irritability between 4 months and 24 months, compared with infants with lower HRV (ps < .05). Dyads experiencing more SES risks showed less optimal interactions at 4 months; this difference remained as children grew older (ps < .05). Results have implications for our understanding of social development in preterm infants. PMID- 21244154 TI - The relationship of parental warm responsiveness and negativity to emerging behavior problems following traumatic brain injury in young children. AB - Parenting behaviors play a critical role in the child's behavioral development, particularly for children with neurological deficits. This study examined the relationship of parental warm responsiveness and negativity to changes in behavior following traumatic brain injury (TBI) in young children relative to an age-matched cohort of children with orthopedic injuries (OI). It was hypothesized that responsive parenting would buffer the adverse effects of TBI on child behavior, whereas parental negativity would exacerbate these effects. Children, ages 3-7 years, hospitalized for TBI (n = 80) or OI (n = 113), were seen acutely and again 6 months later. Parent-child dyads were videotaped during free play. Parents completed behavior ratings (Child Behavior Checklist; T. M. Achenbach & L. A. Rescorla, 2001) at both visits, with baseline ratings reflecting preinjury behavior. Hypotheses were tested using multiple regression, with preinjury behavior ratings, race, income, child IQ, family functioning, and acute parental distress serving as covariates. Parental responsiveness and negativity had stronger associations with emerging externalizing behaviors and attention deficit/hyperactivity disorder symptoms among children with severe TBI. Findings suggest that parenting quality may facilitate or impede behavioral recovery following early TBI. Interventions that increase positive parenting may partially ameliorate emerging behavior problems. PMID- 21244155 TI - Head Start and urban children's school readiness: a birth cohort study in 18 cities. AB - We used longitudinal data from a birth cohort study, the Fragile Families and Child Wellbeing Study, to investigate the links between Head Start and school readiness in a large and diverse sample of urban children at age 5 (N = 2,803; 18 cities). We found that Head Start attendance was associated with enhanced cognitive ability and social competence and reduced attention problems but not reduced internalizing or externalizing behavior problems. These findings were robust to model specifications (including models with city-fixed effects and propensity-scoring matching). Furthermore, the effects of Head Start varied by the reference group. Head Start was associated with improved cognitive development when compared with parental care or other nonparental care, as well as improved social competence (compared with parental care) and reduced attention problems (compared with other nonparental care). In contrast, compared with attendance at pre-kindergarten or other center-based care, Head Start attendance was not associated with cognitive gains but with improved social competence and reduced attention and externalizing behavior problems (compared with attendance at other center-based care). These associations were not moderated by child gender or race/ethnicity. PMID- 21244157 TI - Examining the impact of traffic environment and executive functioning on children's pedestrian behaviors. AB - The process of integrating visual information and planning a safe crossing is cognitively demanding for many young children. We assessed relations between traffic characteristics, aspects of children's executive functioning (EF), and pedestrian behavior, with the aim being to determine whether well-developed EF would predict safer pedestrian behaviors beyond the contributions of child demographic and traffic environment factors. Using the pretend road method, we studied a sample of 83 children aged 6-9 in a series of 5 crossing trials beside a real road in response to actual traffic conditions. Traffic characteristics and pedestrian behaviors were observed and measured across crossing trials. Both traffic characteristics and EF, most notably cognitive efficiency, were strongly related to children's pedestrian crossing behaviors. Traffic characteristics were also found to interact with children's ability to monitor their crossing performance. Examining developmental influences in pedestrian injury etiology broadens researchers' knowledge of and ability to prevent injuries by moving beyond describing what happens to children and examining why pedestrian injuries occur. PMID- 21244156 TI - Effects of maternal negativity and of early and recent recurrent depressive disorder on children's false belief understanding. AB - Research has shown that children of depressed mothers are at risk for problems in a variety of developmental domains; however, little is known about the effects of maternal depression on children's emerging understanding of false beliefs. In this study, 3 false belief tasks were administered to 5-year-old children whose mothers had either met criteria for major depressive disorder within the first 20 months of the child's life (n = 91) or had never been depressed (n = 50). Significant difficulties in performance were found among the children of depressed mothers, especially those whose mothers had experienced early and recent recurrent depressive disorder. Regardless of diagnostic status, children whose mothers exhibited negativity during problem-solving tasks administered at an earlier developmental period also were less likely to demonstrate false belief understanding. These effects remained even after child verbal ability was controlled. PMID- 21244158 TI - An exploratory analysis of American Indian children's cultural engagement, fluid cognitive skills, and standardized verbal IQ scores. AB - This exploratory cross-sectional study examined fluid cognitive skills and standardized verbal IQ scores in relation to cultural engagement amongst Tohono O'odham children (N = 99; ages 7 to 12 years). Guardians with higher socioeconomic status engaged their children in more cultural activities, and participation in more cultural activities contributed to higher standardized verbal IQ scores. Mean cognitive skill scores varied as a function of age and Tohono O'odham language knowledge. Children who understood and/or spoke Tohono O'odham started out with lower average scores than did children with no language knowledge, but mean scores generally increased in the older age groups such that they were equal to or higher than those of nonspeakers by age 9. Children with higher fluid cognitive skill scores had higher standardized verbal IQ scores than did children with lower scores. PMID- 21244159 TI - Evaluating expectations about negative emotional states of aggressive boys using Bayesian model selection. AB - Researchers often have expectations about the research outcomes in regard to inequality constraints between, e.g., group means. Consider the example of researchers who investigated the effects of inducing a negative emotional state in aggressive boys. It was expected that highly aggressive boys would, on average, score higher on aggressive responses toward other peers than moderately aggressive boys, who would in turn score higher than nonaggressive boys. In most cases, null hypothesis testing is used to evaluate such hypotheses. We show, however, that hypotheses formulated using inequality constraints between the group means are generally not evaluated properly. The wrong hypotheses are tested, i.e.. the null hypothesis that group means are equal. In this article, we propose an innovative solution to these above-mentioned issues using Bayesian model selection, which we illustrate using a case study. PMID- 21244160 TI - The influence of mother-child emotion regulation strategies on children's expression of anger and sadness. AB - In a sample of 153 children from preschool through second grade, relations between the use of emotion regulation strategy and children's expression of anger and sadness were coded during an observational task in which children were intentionally disappointed in the presence of the mother. Multilevel modeling was used to examine strategy use and current and subsequent expressions of anger and sadness. Results indicate that mothers' use of attention refocusing and joint mother-child cognitive reframing lead to lower intensity of expressed anger and sadness. Younger children expressed more sadness than older children, and maternal attention refocusing was less successful among older children than younger ones. Implications of these results for assessing the socialization of emotion regulation in preschool and school-age children are discussed. PMID- 21244161 TI - Prospective memory across adolescence: the effects of age and cue focality. AB - The present study examined the role of controlled attention in age differences in event-based prospective memory performance across adolescence. The researchers tested whether presenting the prospective memory cue in or out of focal awareness of the ongoing task (resulting in low versus high demands for controlled attention, respectively) might affect age-related prospective memory performance. In total, 119 Chinese participants ages 13 to 20 took part in this study (60 adolescents: age M = 13.26 years, SD = 0.50; 23 boys; 59 young adults: age M = 19.70 years, SD = 0.87; 19 men). Findings demonstrated a significant interaction, F(1, 114) = 6.41, p < .05. No effect of age on prospective memory performance was revealed when a focal cue was used (F < 1), whereas there was a reliable age effect between adolescents and young adults when nonfocal prospective memory cues were presented, F(1, 59) = 16.13, p < .01. This pattern of results suggests that the interplay of both available resources of controlled attention and working memory, along with specific task demands, may contribute to possible age differences in prospective memory performance across adolescence. Results are discussed in the context of the multiprocess theory of prospective memory. PMID- 21244162 TI - Trajectories of school engagement during adolescence: implications for grades, depression, delinquency, and substance use. AB - Using longitudinal data from the 4-H Study of Positive Youth Development, the authors assessed 1,977 adolescents across Grades 5 to 8 to determine if there were distinctive developmental paths for behavioral and emotional school engagement; if these paths varied in relation to sex, race/ethnicity, and family socioeconomic status (SES); and whether links existed between trajectories of school engagement and grades, depression, substance use, and delinquency. Four trajectories for behavioral school engagement and four trajectories of emotional engagement were identified using a semiparametric mixture model. These trajectories were distinct with regard to initial levels of and changes in engagement, as well as to their shapes. Trajectories varied in regard to sex, SES, and race/ethnicity. Different trajectories of behavioral and emotional engagement were linked to grades, depression, delinquency, and substance use. Directions for future research and application are discussed. PMID- 21244163 TI - Being bicultural: a mixed-methods study of adolescents' implicitly and explicitly measured multiethnic identities. AB - Understanding how ethnic identities develop in adolescence is currently limited by a reliance on self-report paper-and-pencil measures. This mixed-methods study presents a novel response time measure, the Multiethnic Identities Processing Task (MIPT), to quantify bicultural adolescents' implicit identifications with ethnic and racial identity labels. Eighty-four adolescents (age 14-21 years) of diverse ethnic and racial backgrounds self-identified as bicultural or not bicultural and described their ethnic identities, pride, and ethnic centrality during a brief interview. Participants were assigned to complete either the interview (self-prime) or the MIPT (no prime) first. Results indicate that bicultural adolescents readily endorsed a variety of ethnic and racial labels in the MIPT, reflecting their multifaceted identities. Younger bicultural adolescents showed a large inhibited response to the label "White," indicating some hesitation in deciding whether the label was "like me" or "not like me." Heart rate monitoring and qualitative analyses of interviews provide some insight into this pattern of results. Findings are discussed with respect to developmental theory, and the strengths of using both implicit and explicit measures to understand multiethnic identity development in adolescence. PMID- 21244164 TI - Accent, perpetual foreigner stereotype, and perceived discrimination as indirect links between English proficiency and depressive symptoms in Chinese American adolescents. AB - The current study uses Garcia Coll et al.'s (1996) developmental competence model of ethnic minority children and Kim's (1999) racial triangulation theory as frameworks for investigating the mechanisms whereby early adolescent English proficiency relates to perceived discriminatory experiences and adolescent depressive symptoms. Data from 444 adolescents (239 girls and 205 boys, with a mean age of 13.0 years for Wave 1 and 17.0 years for Wave 2) and their parents living in major metropolitan areas of Northern California were collected. The structural equation modeling analyses indicate that self-reported low levels of English proficiency among Chinese American adolescents in middle school are related to these same students later reporting that they speak English with an accent in high school, which in turn relates significantly to their perceiving that they have been stereotyped as perpetual foreigners. For girls, a perpetual foreigner stereotype relates to perceptions of chronic daily discrimination, increasing the risk of depressive symptoms. For boys, the path is different: A perpetual foreigner stereotype is apparently related to discriminatory victimization experiences, which increase the risk of depressive symptoms. PMID- 21244166 TI - Consequences of client-initiated workplace violence: the role of fear and perceived prevention. AB - The authors suggested and tested a model of the consequences of client-initiated workplace violence, introducing perceived prevention of violence and perceived coping ability as factors that reduce fear of future violence and mitigate negative personal and organizational consequences. Survey data from 330 frontline staff from job centers and social security offices were analyzed using structural equation modeling. The data supported the model and confirmed the central role of the fear of violence with regard to outcomes such as psychological and physical well-being or irritability. Results point further to perceived prevention of violence as an important factor that influences fear levels in different ways, predicts turnover intentions, and should therefore be considered when managers aim to address the consequences of client-initiated violence and threats. PMID- 21244167 TI - Psychosocial working conditions and well-being among immigrant and German low wage workers. AB - Despite a steady increase of immigrant workers in Germany in the past decades, occupational health research has only peripherally addressed psychosocial working conditions and immigrant worker well-being. This study has two aims: (1) to investigate differences in psychosocial stressors and resources between immigrant and German low-wage workers, and (2) to examine group differences in their association with well-being using a structural equation modeling multiple group analysis approach. Eighty-nine immigrant and 146 German postmen of a German mail service company were surveyed. Results reveal more stressors in the social work environment for the immigrant workers than for their German coworkers but similar levels of task-related stressors in both groups. Stressors are more strongly associated with psychological distress among the German workers. In terms of resources, job control serves as a resource only among German workers, whereas supervisor and coworker support are more important for immigrant workers. These differences suggest that cultural factors, previous work experiences, and expectations influence the worker's experience of psychosocial working conditions and have a direct impact on worker health. PMID- 21244168 TI - Emotional display rules as work unit norms: a multilevel analysis of emotional labor among nurses. AB - Emotional labor theory has conceptualized emotional display rules as shared norms governing the expression of emotions at work. Using a sample of registered nurses working in different units of a hospital system, we provided the first empirical evidence that display rules can be represented as shared, unit-level beliefs. Additionally, controlling for the influence of dispositional affectivity, individual-level display rule perceptions, and emotion regulation, we found that unit-level display rules are associated with individual-level job satisfaction. We also showed that unit-level display rules relate to burnout indirectly through individual-level display rule perceptions and emotion regulation strategies. Finally, unit-level display rules also interacted with individual-level dispositional affectivity to predict employee use of emotion regulation strategies. We discuss how future research on emotional labor and display rules, particularly in the health care setting, can build on these findings. PMID- 21244169 TI - Effects of diurnal variation and caffeine consumption on Test of Variables of Attention (TOVA) performance in healthy young adults. AB - The Test of Variables of Attention (TOVA) is a continuous performance test (CPT) that assesses attention, impulsivity, and processing speed. CPTs are used in the assessment of attention-deficit/hyperactivity disorder (ADHD) in children, but more young adults are being assessed for ADHD as well. The TOVA norms are based on a standardization sample that was tested early in the day, and any TOVA administered after 1:00 p.m. will be flagged as potentially invalid. Whereas the testing time recommendations make sense for pediatric samples, it is unclear whether they are appropriate for young adults in college, who typically show significant phase delay in their diurnal rhythms. In addition, many college students consume large amounts of caffeine, and it is unclear how caffeine consumption affects TOVA performance. The current study examined the impact of time of day, self-reported diurnal preference, and caffeine consumption on TOVA performance in a double-blind, placebo-controlled experiment with healthy college students. There was evidence of diurnal variation on average response time and impulsivity but not on overall ADHD score, with participants tested in the afternoon responding faster but making more commission errors than did participants tested in the morning. Caffeine consumption led to significantly faster response times, but only for participants who typically consumed relatively little caffeine. We conclude that the TOVA can be administered to young adults outside the recommended time constraints without compromising the validity of test score interpretation but that the caffeine consumption of participants should be closely monitored. PMID- 21244170 TI - Perfectionistic self-presentation in children and adolescents: development and validation of the Perfectionistic Self-Presentation Scale--Junior Form. AB - Research on adults indicates that perfectionistic self-presentation, the interpersonal expression of one's perfection, is associated with a variety of psychopathological outcomes independent of trait perfectionism and Big Five traits. The current article reports on the development and evidence for the validity of the subtest score interpretations of an 18-item self-report measure of perfectionistic self-presentation for children and adolescents. Analyses conducted on data from two clinical samples and one nonclinical sample of children and adolescents found that the Perfectionistic Self-Presentation Scale- Junior Form (PSPS-Jr) reflected a multidimensional model of perfectionistic self presentation with three subscales: Perfectionistic Self Promotion, Nondisplay of Imperfection, and Nondisclosure of Imperfection. The subscale scores were found to demonstrate internal consistency, and there was good evidence supporting the validity of the interpretation of subscale scores based on this new measure. The subscales were associated with maladaptive outcomes, but were not influenced unduly by biases that included social desirability and differential item functioning by gender. Overall, the PSPS-Jr appears to be a useful measure of the expression of perfection among youths and an important tool in attempting to understand the nature and the consequences of perfectionistic self-presentation in children and adolescents. PMID- 21244171 TI - Exploring differences in youth and parent reports of antisociality among adolescent sexual and nonsexual offenders. AB - This study examined the extent of, and explored several possible explanations for, the discrepancies found between adolescent and parent reports of conduct problems in adolescent sexual and nonsexual offenders. We found that adolescent sexual offenders scored lower on measures of conduct problems than did nonsexual offenders, whether on the basis of adolescent or parent report, though the difference was much larger for parent reports. Examining this discrepancy more closely, we found that parents of sexual offenders reported less antisocial behavior than did their sons, whereas parents of nonsexual offenders reported more antisocial behavior than did their sons. The same pattern of results was obtained for reports on impulsivity, but much less so with respect to antisocial personality traits such as narcissism and callousness. Measures of family functioning were generally not related to these parent-adolescent discrepancies in reports of conduct problems, but these discrepancies were positively correlated with parental reports of stress. The implications of these findings for the interpretation of research on adolescent sexual offenders and comparisons of sexual and nonsexual offenders are discussed. PMID- 21244172 TI - Theoretical and statistical derivation of a screener for the behavioral assessment of executive functions in children. AB - The problem of valid measurement of psychological constructs remains an impediment to scientific progress, and the measurement of executive functions is not an exception. This study examined the statistical and theoretical derivation of a behavioral screener for the estimation of executive functions in children from the well-established Behavior Assessment System for Children (BASC). The original national standardization sample of the BASC-Teacher Rating Scales for children ages 6 through 11 was used (N = 2,165). Moderate-to-high internal consistency was obtained within each factor (.80-.89). A panel of experts was used for content validity examination. A confirmatory factor analysis model with 25 items loading on 4 latent factors (behavioral control, emotional control, attentional control, and problem solving) was developed, and its statistical properties were examined. The multidimensional model demonstrated adequate fit, and it was deemed invariant after configural, metric, and scalar measurement invariance tests across sex and age. Given its strong psychometric properties, with further tests of item validity, this instrument promises future clinical and research utility for the screening of executive functions in school-age children. PMID- 21244173 TI - What is moral about guilt? Acting "prosocially" at the disadvantage of others. AB - For centuries economists and psychologists have argued that the morality of moral emotions lies in the fact that they stimulate prosocial behavior and benefit others in a person's social environment. Many studies have shown that guilt, arguably the most exemplary moral emotion, indeed motivates prosocial behavior in dyadic social dilemma situations. When multiple persons are involved, however, the moral and prosocial nature of this emotion can be questioned. The present article shows how guilt can have beneficial effects for the victim of one's actions but also disadvantageous effects for other people in the social environment. A series of experiments, with various emotion inductions and dependent measures, all reveal that guilt motivates prosocial behavior toward the victim at the expense of others around-but not at the expense of oneself. These findings illustrate that a thorough understanding of the functioning of emotions is necessary to understand their moral nature. PMID- 21244174 TI - Genetic and environmental influences on personality trait stability and growth during the transition to adulthood: a three-wave longitudinal study. AB - During the transition to adulthood individuals typically settle into adult roles in love and work. This transition also involves significant changes in personality traits that are generally in the direction of greater maturity and increased stability. Competing hypotheses have been offered to account for these personality changes: The intrinsic maturation hypothesis suggests that change trajectories are endogenous, whereas the life-course hypothesis suggests that these changes occur because of transactions with the social environment. This study investigated the patterns and origins of personality trait changes from ages 17 to 29 using 3 waves of Multidimensional Personality Questionnaire data provided by twins. Results suggest that (a) trait changes were more profound in the first relative to the second half of the transition to adulthood; (b) traits tend to become more stable during the second half of this transition, with all the traits yielding retest correlations between .74 and .78; (c) Negative Affectivity declined over time, and Constraint increased over time; minimal change was observed on agentic or communal aspects of Positive Emotionality; and (d) both genetic and nonshared environmental factors accounted for personality changes. Overall, these genetically informed results support a life-course perspective on personality development during the transition to adulthood. PMID- 21244175 TI - Motivational determinants of integrating positive and negative past identities. AB - Five studies examined whether quality of motivation (as individual differences and primed) facilitates or thwarts integration of positive and negative past identities. Specifically, more autonomously motivated participants felt closer to, and were more accepting of, both negative and positive past characteristics and central life events, whereas more control-motivated participants were closer to and more accepting of positive, but not negative, past characteristics and events. Notably, controlled motivation hindered participants' acceptance of their own negative identities but not of others' negative identities, suggesting that control-motivated individuals' rejection of negative past identities was an attempt to distance from undesirable parts of themselves. Defensive processes, reflected in nonpersonal pronouns and escape motives, mediated interaction effects, indicating that lower defense allowed fuller integration. Integration of both positive and negative past identities predicted indicators of well-being, namely, vitality, meaning, and relatedness satisfaction. PMID- 21244176 TI - Only because I love you: why people make and why they break promises in romantic relationships. AB - People make and break promises frequently in interpersonal relationships. In this article, we investigate the processes leading up to making promises and the processes involved in keeping them. Across 4 studies, we demonstrate that people who had the most positive relationship feelings and who were most motivated to be responsive to the partner's needs made bigger promises than did other people but were not any better at keeping them. Instead, promisers' self-regulation skills, such as trait conscientiousness, predicted the extent to which promises were kept or broken. In a causal test of our hypotheses, participants who were focused on their feelings for their partner promised more, whereas participants who generated a plan of self-regulation followed through more on their promises. Thus, people were making promises for very different reasons (positive relationship feelings, responsiveness motivation) than what made them keep these promises (self-regulation skills). Ironically, then, those who are most motivated to be responsive may be most likely to break their romantic promises, as they are making ambitious commitments they will later be unable to keep. PMID- 21244177 TI - Forbidden fruit: inattention to attractive alternatives provokes implicit relationship reactance. AB - Being inattentive to attractive relationship alternatives can enhance relationship well-being. The current investigation, however, demonstrates that implicitly preventing people from attending to desirable relationship alternatives may undermine, rather than bolster, the strength of that person's romantic relationship. Consistent with the notion of "forbidden fruit," we found that subtly limiting people's attention to attractive alternatives reduced relationship satisfaction and commitment and increased positive attitudes toward infidelity (Experiment 1), increased memory for attractive relationship alternatives (Experiment 2), and increased attention to attractive alternatives (Experiment 3). Findings suggest that although attention to attractive alternatives can harm one's relationship, situations that implicitly limit one's attention to alternatives can, rather ironically, increase the temptation of alternatives and undermine relationship well-being. PMID- 21244179 TI - Within- and between-culture variation: individual differences and the cultural logics of honor, face, and dignity cultures. AB - The CuPS (Culture * Person * Situation) approach attempts to jointly consider culture and individual differences, without treating either as noise and without reducing one to the other. Culture is important because it helps define psychological situations and create meaningful clusters of behavior according to particular logics. Individual differences are important because individuals vary in the extent to which they endorse or reject a culture's ideals. Further, because different cultures are organized by different logics, individual differences mean something different in each. Central to these studies are concepts of honor-related violence and individual worth as being inalienable versus socially conferred. We illustrate our argument with 2 experiments involving participants from honor, face, and dignity cultures. The studies showed that the same "type" of person who was most helpful, honest, and likely to behave with integrity in one culture was the "type" of person least likely to do so in another culture. We discuss how CuPS can provide a rudimentary but integrated approach to understanding both within- and between-culture variation. PMID- 21244180 TI - Visceral fit: While in a visceral state, associated states of the world seem more likely. AB - We propose that visceral states can influence beliefs through "visceral fit": People will judge states of the world associated with their current visceral experience as more likely. We found that warmth influenced belief in global warming (Studies 1-3) and that thirst impacted forecasts of drought and desertification (Study 5). These effects emerged in a naturalistic setting (Study 1) and in experimental lab settings (Studies 2, 3, and 5). Studies 2-6 distinguished between 3 mechanistic accounts: temperature as information (Studies 2 and 3), conceptual accessibility (Studies 4 and 5), and fluency of simulation (Studies 6a and 6b). Studies 2 and 3 ruled out the temperature as information account. Feeling warm enhanced belief in global warming even when temperature was manipulated in an uninformative indoor setting, when participants' attention was first directed to the indoor temperature, and when participants' belief about the current outdoor temperature was statistically controlled. Studies 4 and 5 ruled out conceptual accessibility as the key mediator: Priming the corresponding concepts did not produce analogous effects on judgment. Studies 6a and 6b used a causal chain design and found support for a "simulational fluency" account. Participants experiencing the visceral state of warmth constructed more fluent mental representations of hot (vs. cold) outdoor images, and those who were led to construe the same hot outdoor images more fluently believed more in global warming. Together, the results suggest that visceral states can influence one's beliefs by making matching states of the world easier to simulate and therefore seem more likely. PMID- 21244181 TI - How can you resist? Executive control helps romantically involved individuals to stay faithful. AB - In the present research, we examined why some people have more difficulty than others in staying faithful to their romantic partners. Three studies supported our main prediction that executive control is associated with romantically involved individuals' ability to stay faithful. Study 1 showed that participants with a higher level of executive control reported less difficulty in staying faithful to their partners than did those with lower levels of executive control. In Study 2, romantically involved male participants were placed in a waiting room together with an attractive female confederate. Results showed that participants with a higher level of executive control showed less flirting behavior with the confederate than did those with lower levels of executive control. Study 3 demonstrated that a higher level of executive control was related to a lower expressed desire to meet an attractive other, but only for romantically involved participants. Together, these studies showed that executive control helps romantically involved individuals to deal with the lure of attractive alternatives. PMID- 21244182 TI - Mapping the moral domain. AB - The moral domain is broader than the empathy and justice concerns assessed by existing measures of moral competence, and it is not just a subset of the values assessed by value inventories. To fill the need for reliable and theoretically grounded measurement of the full range of moral concerns, we developed the Moral Foundations Questionnaire on the basis of a theoretical model of 5 universally available (but variably developed) sets of moral intuitions: Harm/Care, Fairness/Reciprocity, Ingroup/Loyalty, Authority/Respect, and Purity/Sanctity. We present evidence for the internal and external validity of the scale and the model, and in doing so we present new findings about morality: (a) Comparative model fitting of confirmatory factor analyses provides empirical justification for a 5-factor structure of moral concerns; (b) convergent/discriminant validity evidence suggests that moral concerns predict personality features and social group attitudes not previously considered morally relevant; and (c) we establish pragmatic validity of the measure in providing new knowledge and research opportunities concerning demographic and cultural differences in moral intuitions. These analyses provide evidence for the usefulness of Moral Foundations Theory in simultaneously increasing the scope and sharpening the resolution of psychological views of morality. PMID- 21244184 TI - Bridging the gap between physiology and behavior: evidence from the sSoTS model of human visual attention. AB - We present the case for a role of biologically plausible neural network modeling in bridging the gap between physiology and behavior. We argue that spiking-level networks can allow "vertical" translation between physiological properties of neural systems and emergent "whole-system" performance-enabling psychological results to be simulated from implemented networks and also inferences to be made from simulations concerning processing at a neural level. These models also emphasize particular factors (e.g., the dynamics of performance in relation to real-time neuronal processing) that are not highlighted in other approaches and that can be tested empirically. We illustrate our argument from neural-level models that select stimuli by biased competition. We show that a model with biased competition dynamics can simulate data ranging from physiological studies of single-cell activity (Study 1) to whole-system behavior in human visual search (Study 2), while also capturing effects at an intermediate level, including performance breakdown after neural lesion (Study 3) and data from brain imaging (Study 4). We also show that, at each level of analysis, novel predictions can be derived from the biologically plausible parameters adopted, which we proceed to test (Study 5). We argue that, at least for studying the dynamics of visual attention, the approach productively links single-cell to psychological data. PMID- 21244185 TI - Transitivity of preferences. AB - Transitivity of preferences is a fundamental principle shared by most major contemporary rational, prescriptive, and descriptive models of decision making. To have transitive preferences, a person, group, or society that prefers choice option x to y and y to z must prefer x to z. Any claim of empirical violations of transitivity by individual decision makers requires evidence beyond a reasonable doubt. We discuss why unambiguous evidence is currently lacking and how to clarify the issue. In counterpoint to Tversky's (1969) seminal "Intransitivity of Preferences," we reconsider his data as well as those from more than 20 other studies of intransitive human or animal decision makers. We challenge the standard operationalizations of transitive preferences and discuss pervasive methodological problems in the collection, modeling, and analysis of relevant empirical data. For example, violations of weak stochastic transitivity do not imply violations of transitivity of preference. Building on past multidisciplinary work, we use parsimonious mixture models, where the space of permissible preference states is the family of (transitive) strict linear orders. We show that the data from many of the available studies designed to elicit intransitive choice are consistent with transitive preferences. PMID- 21244187 TI - Moral psychology is relationship regulation: moral motives for unity, hierarchy, equality, and proportionality. AB - Genuine moral disagreement exists and is widespread. To understand such disagreement, we must examine the basic kinds of social relationships people construct across cultures and the distinct moral obligations and prohibitions these relationships entail. We extend relational models theory (Fiske, 1991) to identify 4 fundamental and distinct moral motives. Unity is the motive to care for and support the integrity of in-groups by avoiding or eliminating threats of contamination and providing aid and protection based on need or empathic compassion. Hierarchy is the motive to respect rank in social groups where superiors are entitled to deference and respect but must also lead, guide, direct, and protect subordinates. Equality is the motive for balanced, in-kind reciprocity, equal treatment, equal say, and equal opportunity. Proportionality is the motive for rewards and punishments to be proportionate to merit, benefits to be calibrated to contributions, and judgments to be based on a utilitarian calculus of costs and benefits. The 4 moral motives are universal, but cultures, ideologies, and individuals differ in where they activate these motives and how they implement them. Unlike existing theories (Haidt, 2007; Hauser, 2006; Turiel, 1983), relationship regulation theory predicts that any action, including violence, unequal treatment, and "impure" acts, may be perceived as morally correct depending on the moral motive employed and how the relevant social relationship is construed. This approach facilitates clearer understanding of moral perspectives we disagree with and provides a template for how to influence moral motives and practices in the world. PMID- 21244188 TI - Intuitive and deliberate judgments are based on common principles. AB - A popular distinction in cognitive and social psychology has been between intuitive and deliberate judgments. This juxtaposition has aligned in dual process theories of reasoning associative, unconscious, effortless, heuristic, and suboptimal processes (assumed to foster intuitive judgments) versus rule based, conscious, effortful, analytic, and rational processes (assumed to characterize deliberate judgments). In contrast, we provide convergent arguments and evidence for a unified theoretical approach to both intuitive and deliberative judgments. Both are rule-based, and in fact, the very same rules can underlie both intuitive and deliberate judgments. The important open question is that of rule selection, and we propose a 2-step process in which the task itself and the individual's memory constrain the set of applicable rules, whereas the individual's processing potential and the (perceived) ecological rationality of the rule for the task guide the final selection from that set. Deliberate judgments are not generally more accurate than intuitive judgments; in both cases, accuracy depends on the match between rule and environment: the rules' ecological rationality. Heuristics that are less effortful and in which parts of the information are ignored can be more accurate than cognitive strategies that have more information and computation. The proposed framework adumbrates a unified approach that specifies the critical dimensions on which judgmental situations may vary and the environmental conditions under which rules can be expected to be successful. PMID- 21244189 TI - Learning a theory of causality. AB - The very early appearance of abstract knowledge is often taken as evidence for innateness. We explore the relative learning speeds of abstract and specific knowledge within a Bayesian framework and the role for innate structure. We focus on knowledge about causality, seen as a domain-general intuitive theory, and ask whether this knowledge can be learned from co-occurrence of events. We begin by phrasing the causal Bayes nets theory of causality and a range of alternatives in a logical language for relational theories. This allows us to explore simultaneous inductive learning of an abstract theory of causality and a causal model for each of several causal systems. We find that the correct theory of causality can be learned relatively quickly, often becoming available before specific causal theories have been learned--an effect we term the blessing of abstraction. We then explore the effect of providing a variety of auxiliary evidence and find that a collection of simple perceptual input analyzers can help to bootstrap abstract knowledge. Together, these results suggest that the most efficient route to causal knowledge may be to build in not an abstract notion of causality but a powerful inductive learning mechanism and a variety of perceptual supports. While these results are purely computational, they have implications for cognitive development, which we explore in the conclusion. PMID- 21244191 TI - The belief bias effect is aptly named: a reply to Klauer and Kellen (2011). AB - In "Assessing the Belief Bias Effect With ROCs: It's a Response Bias Effect," Dube, Rotello, and Heit (2010) examined the form of receiver operating characteristic (ROC) curves for reasoning and the effects of belief bias on measurement indices that differ in whether they imply a curved or linear ROC function. We concluded that the ROC data are in fact curved and that analyses using statistics that assume a linear ROC are likely to produce Type I errors. Importantly, we showed that the interaction between logic and belief that has inspired much of the theoretical work on belief bias is in fact an error stemming from inappropriate reliance on a contrast (hit rate-false alarm rate) that implies linear ROCs. Dube et al. advanced a new model of belief bias, which, in light of their data, is currently the only plausible account of the effect. Klauer and Kellen (2011) disputed these conclusions, largely on the basis of speculation about the data collection method used by Dube et al. to construct the ROCs. New data and model-based analyses are presented that refute the speculations made by Klauer and Kellen. We also show that new modeling results presented by Klauer and Kellen actually support the conclusions advanced by Dube et al. Together, these data show that the methods used by Dube et al. are valid and that the belief bias effect is simply a response bias effect. PMID- 21244192 TI - Assessing the belief bias effect with ROCs: reply to Dube, Rotello, and Heit (2010). AB - Dube, Rotello, and Heit (2010) argued (a) that the so-called receiver operating characteristic is nonlinear for data on belief bias in syllogistic reasoning; (b) that their data are inconsistent with Klauer, Musch, and Naumer's (see record 2000-02818-008) model of belief bias; (c) that their data are inconsistent with any of the existing accounts of belief bias and only consistent with a theory provided by signal detection theory; and (d) that in fact, belief bias is a response bias effect. In this reply, we present reanalyses of Dube et al.'s data and of old data suggesting (a) that the receiver operating characteristic is linear for binary "valid" versus "invalid" responses, as employed by the bulk of research in this field; (b) that Klauer et al.'s model describes the old data significantly better than does Dube et al.'s model and that it describes Dube et al.'s data somewhat better than does Dube et al.'s model; (c) that Dube et al.'s data are consistent with the account of belief bias by misinterpreted necessity, whereas Dube et al.'s signal detection model does not fit their data; and (d) that belief bias is more than a response bias effect. PMID- 21244193 TI - Are medical student results affected by allocation to different sites in a dispersed rural medical school? AB - INTRODUCTION: As medical education becomes more decentralised, and greater use is made of rural clinical schools and other dispersed sites, attention is being paid to the quality of the learning experiences across these sites. This article explores this issue by analysing the performance data of 4 cohorts of students in a dispersed clinical school model across 4 sites. The study is set in a newly established medical school in a regional area with a model of dispersed education, using data from the second to fifth cohorts to graduate from this school. METHODS: Summative assessment results of 4 graduating cohorts were examined over the final 2 years of the course. Two analyses were conducted: an analysis of variance of mean scores in both years across the 4 sites; and an analysis of the effect of moving to different clinical schools on the students' rank order of performance by use of the Kruskal-Wallis test. RESULTS: Analysis revealed no significant difference in the mean scores of the students studying at each site, and no significant differences overall in the median ranking across the years. Some small changes in the relative ranking of students were noticed, and workplace-based assessment scores in the final year were higher than the examination-based scores in the previous year. CONCLUSIONS: The choice of clinical school site for the final 2 years of an undergraduate rural medical school appears to have no effect on mean assessment scores and only a minor effect on the rank order of student scores. Workplace-based assessment produces higher scores but also has little effect on student rank order. Further studies are necessary to replicate these findings in other settings and demonstrate that student learning experiences in rural sites, while popular with students, translate into required learning outcomes, as measured by summative assessments. PMID- 21244194 TI - Relationship between metalloprotease expression in tumour and stromal cells and aggressive behaviour in prostate carcinoma: Simultaneous high-throughput study of multiple metalloproteases and their inhibitors using tissue array analysis of radical prostatectomy samples. AB - OBJECTIVE: The aim of this study was to detect a potential association between clinicopathological factors of prostate cancer aggressiveness and the expression of matrix metalloproteases and their inhibitors in tumour and stromal cells. MATERIAL AND METHODS: A tissue array technique and immunochemistry with specific antibodies against matrix metalloproteinases (MMPs)-1, 2, 7, 9, 11, 13, 14, and their tissue inhibitors (TIMPs)-1, 2 and 3 were used to analyse the surgical specimens of 133 patients treated by radical prostatectomy. For each antibody preparation, the cellular location of immunoreactivity was determined. RESULTS: The expression of MMP-2 was negatively associated with high tumour grade. With regard to stromal fibroblasts, TIMP-3 expression was positively associated with histological grade. MMP-7 expression was negatively associated with pretreatment serum levels of PSA, whereas MMP-13 was positively associated with higher levels of the antigen. TIMP-2 expression by mononuclear inflammatory cells correlated significantly and negatively with tumour grade. CONCLUSIONS: The expression of TIMP-3 by fibroblasts was associated with a higher Gleason score. An increased expression of MMP-13 by fibroblasts was associated with a greater preoperative level of PSA. In contrast, MMP-2 expression by tumour as well as TIMP-2 expression by peritumoral inflammatory cells was associated with less aggressive prostate carcinoma characteristics. PMID- 21244195 TI - Bioavailability of Delta9-tetrahydrocannabinol following intranasal administration of a mucoadhesive gel spray delivery system in conscious rabbits. AB - BACKGROUND: The purpose of this study was to investigate the potential of the intranasal route for systemic delivery of solubilized Delta9-tetrahydrocannabinol (THC). A further aim was to investigate the effect of nasally administered chitosan-based nasal bioadhesive gel on THC bioavailability as a formulation strategy to decrease normal mucociliary drug clearance. METHOD: The THC formulations were administered intranasally and compared to intravenous administration utilizing conscious rabbits. RESULTS: After nasal administration, the THC nasal solution afforded a C(max) value of 20 +/- 3 ng/mL at 20 minutes. Interestingly, the THC loaded in chitosan gel formulation followed almost the same profile at early time points and subsequently afforded a higher C(max) value of 31 +/- 4 ng/mL (T(max) = 45 minutes). The absolute bioavailability of THC after nasal delivery was studied to compare plasma THC concentrations after nasal administration with those after intravenous injection. Absolute bioavailability values were 13.3 +/- 7.8% and 15.4 +/- 6.5% for the THC nasal solution and gel formulations, respectively. CONCLUSION: The results of the present study suggest that intranasal administration of THC in solution or in a chitosan-based nasal gel formulation could be an attractive modality for delivery of THC systemically. PMID- 21244197 TI - Introduction. PMID- 21244198 TI - On turning a blind eye and a deaf ear: society's response to the use of torture. AB - The present paper undertakes an individual and group psychoanalytic examination of what happens to the citizens of a society that not only condones but authorizes torture. Drawing on the experiences of countries like those in Latin America during the period of the military dictatorships of the 1970s and 1980s, South Africa during the apartheid years, the Nazi era in Germany in the 1930s and 1940s, and Eastern Europe in the Communist era, the author focuses on the denial that was necessary to maintain daily life. At the same time, such denial and its accompanying "compartmentalization" produced a citizenry that was both blind and deaf to the practices and ultimately supported the dangerous hypocrisy of the respective political regimes. The impact of such "blindness" and "deafness" to the use of torture and abrogation of basic civil rights on the psychological life of individuals and society is examined for its parallels to our current times within the United States. PMID- 21244199 TI - The ethics of trauma: re-traumatization in society's approach to the traumatized subject. AB - The paper starts from a question about the subconscious needs and anxieties which may underlie society's current responses to trauma. In particular, the author argues that the interest in the trauma of torture and man-made violence is a reaction to the increasingly dehumanizing and death-denying culture we live in. After proposing that the various categories of societal responses-the author focuses on evaluation, treatment, and advocacy-to traumatized subjects hide defenses of denial, distortion, refusal, with respect to the challenge of mortality, meaning-making, and mourning, the author then makes the thesis that they can derail and corrupt the project of post-traumatic repair. The paper proceeds with an examination of the ethics and politics that are implicit in contemporary North American society's current approach to trauma. The central argument is that the current approach may contain a collective acting out that often ends up being re-traumatizing to the traumatized subjects. PMID- 21244200 TI - Crimes of obedience: "groupthink" at abu ghraib. AB - Clear evidence of authorization at the highest levels belies administration statements to the effect that the torture at Abu Ghraib was an aberration and simply unauthorized actions by rogue soldiers. The administration reflected a "group mind," demonstrating many qualities of "groupthink." Whatever was necessary, including torture and violation of the Geneva accords, the system in effect authorized, because of the perceived danger to the system and the desperate requirement to get the information out of "them" by whatever means necessary, information that could save lives. The sanctioned violence demonstrated the qualities identified by Kelman and Hamilton (1989) in their study of the Mylai massacre as characteristic of sanctioned massacres: authorization, routinization, and dehumanization. It would seem that officials and participants exhibited all of these characteristics in the decision to conduct extreme interrogation on the "unlawful combatants" imprisoned at Abu Ghraib. PMID- 21244201 TI - Torture, war, and the culture of fear after 9/11. PMID- 21244202 TI - Three perspectives on the treatment of political prisoners and trauma victims. PMID- 21244203 TI - Behavioral group treatment for obsessive-compulsive disorder in adolescence: a pilot study. AB - This pilot study is a preliminary evaluation of the effectiveness of a cognitive behavioral outpatient group treatment (CBT) protocol for adolescents with Obsessive-Compulsive Disorder (OCD). Seven adolescents were treated in a 10 session group CBT program with weekly 2-hour sessions. The treatment protocol was an adaptation of approaches with established effectiveness and emphasized three main components: externalizing the OCD by cultivating mindful detachment; exposure and response prevention (ERP); and refocusing on alternative, constructive behaviors following exposure. An occupational therapy component played a significant role in designing creative exposure and refocusing challenges. Self-report measures at pre, post, and 12-month follow-up suggested clinical improvements for 5 of the 7 patients, thus partially supporting a group treatment format for adolescents with mild to moderate OCD. PMID- 21244205 TI - What is going on inside? PMID- 21244204 TI - An evidence-based group coping intervention for women living with HIV and history of childhood sexual abuse. AB - Women living with HIV/AIDS and a history of childhood sexual abuse often exhibit sexual trauma symptoms and elevated rates of HIV-risk behaviors. In this paper, we describe a coping skills group intervention that reduced traumatic stress and sexual-risk behavior in a recent randomized clinical trial. We focused on clinical issues that emerged among female participants receiving the intervention. Clinical observations showed that recognizing connections between trauma, psychological distress, and high risk behaviors was a new and powerful experience for many participants. Participants successfully applied psychoeducational material, expressing an increased sense of power and control over their relationships and behaviors as they developed more adaptive cognitive and behavioral skills. Women expressed high levels of satisfaction with the intervention. Recommendations for clinical practice are provided. PMID- 21244209 TI - The theory and practice of group psychotherapy. PMID- 21244210 TI - Psychotherapeutic approaches for patients with cognitive impairment. PMID- 21244211 TI - Group therapy: the breakfast of champions:the breakfast club. PMID- 21244212 TI - Tears of sadness, tears of joy: emotional expression and "the curious case of benjamin button. PMID- 21244213 TI - The challenge of early surgery for cryptorchidism. AB - OBJECTIVE: In congenital cryptorchidism, a recent Nordic Consensus report recommends surgical correction at 6-12 months of age to prevent male infertility. In published series of orchiopexies the median age at surgery is often 3 years or more. The aim of this study was to evaluate whether early surgery is technically safe. MATERIAL AND METHODS: The study included 356 boys with 418 orchiopexies and median 1 year of follow-up. RESULTS: At follow-up 367 testes were in the scrotum without iatrogenic atrophy. Eight testes were atrophied and in 43 cases a redo operation was performed to achieve a scrotal position of the testis. All acquired undescended testes had a successful result. The age at operation for the group with congenital undescended testes in the intracanalicular position or in a position close to the external inguinal annulus was 4 months to 14.5 years. In the latter group the median age at operation for the 41 failures was 2 years and 4 months, which is significantly younger than the median age for the more successful operations (3 years and 9 months). CONCLUSION: The standard orchiopexy is technically demanding in small boys. Focus on successful operative results in specialist centres is important when treating cryptorchidism with early surgery, otherwise the positive beneficial biological impact on fertility potential may be lost due to treatment failure. PMID- 21244214 TI - I looked to her as a guide: the therapeutic relationship in hand therapy. AB - PURPOSE: To illustrate important dimensions of the therapeutic relationship in a hand therapy patient-therapist dyad. METHOD: This instrumental case study utilised narrative analysis of semi-structured interviews of a patient-therapist dyad. RESULTS: Four dimensions of the therapeutic relationship were identified. These were (1) humour to promote reciprocity, (2) ordinary conversation to build rapport, (3) social comparison to promote acceptance and (4) attention as caring. CONCLUSIONS: The therapeutic relationship is not a one-way flow from therapist to patient but a mutual exchange between equals. However, it is the therapist who is responsible for establishing the environment for the therapeutic relationship to develop and flourish. PMID- 21244215 TI - Intravaginal dehydroepiandrosterone (prasterone), a highly efficient treatment of dyspareunia. AB - OBJECTIVE: To examine the effect of intravaginal dehydroepiandrosterone (DHEA) on pain at sexual activity (dyspareunia) identified as the most bothersome symptom of vaginal atrophy in postmenopausal women at both screening and day 1. METHODS: This prospective, randomized, double-blind and placebo-controlled phase III clinical trial studied the effect of prasterone (DHEA) applied locally in the vagina on the severity of dyspareunia in 114 postmenopausal women who had identified dyspareunia as their most bothersome symptom of vaginal atrophy, while meeting the criteria for superficial cells <= 5% and pH > 5.0 at both screening and day 1. RESULTS: At the standard duration of 12 weeks of treatment, increasing doses of 0.25%, 0.5% and 1.0% DHEA decreased the percentage of parabasal cells by 48.6 +/- 6.78%, 42.4 +/- 7.36% and 54.9 +/- 6.60% (p < 0.0001 vs. placebo for all) with no change with placebo (p = 0.769). The effects on superficial cells and pH were also highly significant compared to placebo at all DHEA doses. The severity score of pain at sexual activity decreased by 0.5, 1.4, 1.6 and 1.4 units in the placebo and 0.25%, 0.5% and 1.0% DHEA groups, respectively, with the p value of differences from placebo ranging from 0.0017 to < 0.0001. CONCLUSIONS: Intravaginal DHEA, through local estrogen and androgen formation, causes a rapid and highly efficient effect on pain at sexual activity without systemic exposure of the other tissues, thus avoiding the recently reported systemic effects of estrogens. PMID- 21244216 TI - Nanobody; an old concept and new vehicle for immunotargeting. AB - The use of antibodies in cancer therapy has come a long way since the day Paul Ehrlich described the concept and Kohler and Milstein devised the hybridoma technology to bring this theory to reality. The synthesis of murine monoclonal antibodies (mAbs) was the first success in this field, leading to the invention of chimerization, the production of variable fragments (Fv) with the progression to domain antibodies (dAb) and later humanization technologies to maximize the clinical utility of murine mAbs. It was just by chance that dAbs were found to exist in ?heavy chain? immunoglobulins from Camelidae family and cartilaginous fish. These unique antibody fragments interact with antigen by virtue of only one single variable domain, referred to as VHH or nanobody. Several characteristics make nanobody use superior to the abovementioned antibodies. They are non immunogenic and show high thermal and chemical stability. There are several reports of raising specific nanobodies against enzymes, haptens, pathogens, toxins and tumor markers, which are outlined in this paper. All these characteristics make them strong candidates as targeting agents for cancer therapy. PMID- 21244217 TI - The CD40-CD40L system in cardiovascular disease. AB - The CD40-CD40L system is a pathway which is associated with both prothrombotic and proinflammatory effects. CD40 and its ligand were first discovered on the surface of activated T cells, but its presence on B cells, antigen-presenting cells, mast cells, and finally platelets, is evident. The soluble form of CD40L (sCD40L) is derived mainly from activated platelets and contributes to the pathophysiology of atherosclerosis and atherothrombosis. Indeed, sCD40L has autocrine, paracrine, and endocrine activities, and it enhances platelet activation, aggregation, and platelet-leucocyte conjugation that may lead to atherothrombosis. It has even been suggested that sCD40L may play a pathogenic role in triggering acute coronary syndromes. Conversely, blockade of this pathway with anti-CD40L antibodies may prevent or delay the progression of atherosclerosis. Concentrations of sCD40L also predict risk of future cardiovascular disease in healthy women and clinical outcomes in patients with acute coronary syndromes. However, there are controversial and uncertain points over the application of this biomarker to clinical cardiology. In this review, we provide an overview of potential implications of CD40-CD40L signalling and sCD40L as a biomarker in patients with atherosclerotic vascular diseases. PMID- 21244218 TI - Golimumab - a new tool in the armoury against inflammatory arthritis. AB - The development of biological drugs blocking tumour necrosis factor-alpha (TNF alpha) has had a dramatic impact on the treatment of inflammatory arthritis in recent years. Golimumab is a fully human monoclonal antibody which inhibits TNF alpha. It is licensed for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. In this review we evaluate the results of phase III studies using golimumab and explore the place of golimumab in the treatment of these diseases. PMID- 21244219 TI - Exposure, health and ecological effects review of engineered nanoscale cerium and cerium oxide associated with its use as a fuel additive. AB - Advances of nanoscale science have produced nanomaterials with unique physical and chemical properties at commercial levels which are now incorporated into over 1000 products. Nanoscale cerium (di) oxide (CeO(2)) has recently gained a wide range of applications which includes coatings, electronics, biomedical, energy and fuel additives. Many applications of engineered CeO(2) nanoparticles are dispersive in nature increasing the risk of exposure and interactions with a variety of environmental media with unknown health, safety and environmental implications. As evident from a risk assessment perspective, the health effects of CeO(2) nanoparticles are not only dependent on their intrinsic toxicity but also on the level of exposure to these novel materials. Although this may seem logical, numerous studies have assessed the health effects of nanoparticles without this simple but critical risk assessment perspective. This review extends previous exposure and toxicological assessments for CeO(2) particles by summarizing the current state of micro and nano-scale cerium exposure and health risks derived from epidemiology, air quality monitoring, fuel combustion and toxicological studies to serve as a contemporary comprehensive and integrated toxicological assessment. Based on the new information presented in this review there is an ongoing exposure to a large population to new diesel emissions generated using fuel additives containing CeO2 nanoparticles for which the environmental (air quality and climate change) and public health impacts of this new technology are not known. Therefore, there is an absolute critical need for integrated exposure and toxicological studies in order to accurately assess the environmental, ecological and health implications of nanotechnology enabled diesel fuel additives with existing as well as new engine designs and fuel formulations. PMID- 21244220 TI - Evaluation of salicylic acid fatty ester prodrugs for UV protection. AB - The purpose of this study was to investigate the physicochemical properties and in vitro evaluation of fatty ester prodrugs of salicylic acid for ultraviolet (UV) protection. The physicochemical properties such as lipophilicity, chemical stability and enzymatic hydrolysis were investigated with the following fatty ester prodrugs of salicylic acid: octanoyl (C8SA), nonanoyl (C9SA), decanoyl (C10SA), lauroyl (C12SA), myristoyl (C14SA) and palmitoyl oxysalicylate (C16SA). Furthermore, their skin permeation and accumulation were evaluated using a combination of common permeation enhancing techniques such as the use of a lipophilic receptor solution, removal of stratum corneum and delipidization of skin. Their k' values were proportional to the degree of carbon-carbon saturation in the side chain. All these fatty esters were highly stable in 2-propanol, acetonitrile and glycerin, but unstable in methanol and ethanol. They were relatively unstable in liver and skin homogenates. In particular, C16SA was mostly hydrolyzed to its parent compound in hairless mouse liver and skin homogenates, suggesting that it might be converted to salicylic acid after its topical administration. In the skin permeation and accumulation study, C16SA showed the poorest permeation in all skins, suggesting that it could not be permeated in the skin. Furthermore, C14SA and C16SA were less accumulated in delipidized skin compared with normal skin or stripped skin, suggesting that these esters had relatively strong affinities for lipids compared with the other prodrugs in the skin. C16SA showed significantly higher dermal accumulation in all skins compared with its parent salicylic acid. Thus, the palmitoyl oxysalicylate (C16SA) might be a potential candidate for UV protection due to its absence of skin permeation, smaller uptake in the lipid phase and relatively lower skin accumulation. PMID- 21244221 TI - Investigating the effect of lead acetate on rat bone marrow-derived mesenchymal stem cells toxicity: role of apoptosis. AB - Lead exposure continues to be a significant public health problem. Osteoporosis, inhibition of fracture healing, and cartilage functional impairment have been reported from lead exposure. Mesenchymal stem cells (MSCs) are a bone marrow population of cells with the ability to differentiate into various cell types, particularly osteocytes and chondrocytes. Despite intensive investigation on the effect of lead poisoning on various cell types, there is very little if any report on the effect of lead on MSCs. The aim of this study, therefore, was to investigate the effect of lead acetate on rat bone marrow derived MSCs toxicity and its mechanism by examining the role of pro- and anti-apoptotic proteins in this process. It was revealed that lead acetate could induce cell death in a dose dependent manner using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl tetrazolium (MTT) assay. Compared to controls, the significant over-expression of pro apoptotic proteins, including Bax, caspases-9, -3, and p53, with no significant change in anti-apoptotic Bcl(2) protein were obtained in lead-treated cells using western blotting analysis. There was a significant increase in DNA fragmentation in treated MSCs compared to controls using flow-cytometry. Finally, it might be concluded that lead acetate could induce cell toxicity and apoptosis in MSCs, causing instability in mitochondria and in turn activation of the intrinsic pathway including over-expression of Bax, caspase 9 and caspase 3, leading to DNA damage and activation of P53. PMID- 21244222 TI - Signaling via IRAG is essential for NO/cGMP-dependent inhibition of platelet activation. AB - Platelet activation is strongly affected by nitric oxide/cyclic GMP (NO/cGMP) signaling involving cGMP-dependent protein kinase I (cGKI). Previously it was shown that interaction of the cGKI substrate IRAG with InsP(3)RI is essential for NO/cguanosine monophosphate (GMP)-dependent inhibition of platelet aggregation in vitro and in vivo. However, the role of Inositol-trisphosphate receptor associated cGMP kinase substrate (IRAG) for platelet adhesion or granule secretion was unknown. Here, we analysed the functional role of IRAG for platelet activation. Murine IRAG-deficient platelets displayed enhanced aggregability towards several agonists (collagen, thrombin and TxA2). NO- or cGMP-dependent inhibition of agonist induced ATP- or 5-HT secretion from dense granules, and P selectin secretion from alpha granules was severely affected in IRAG-deficient platelets. Concomitantly, the effect of NO/cGMP on platelet aggregation was strongly reduced in IRAG-deficient platelets. Furthermore, GPIIb/IIIa-mediated adhesion of platelets to fibrinogen could only weakly be inhibited in IRAG deficient mice contrary to wild-type (WT) mice. Our results suggest that signaling via IRAG is essential for NO/cGMP-dependent inhibition of platelet activation regarding granule secretion, aggregation and adhesion. This platelet disorder might cause that the bleeding time of IRAG-deficient mice was reduced. PMID- 21244223 TI - Identification of a second Asian soybean rust resistance gene in Hyuuga soybean. AB - ABSTRACT Asian soybean rust (ASR) is an economically significant disease caused by the fungus Phakopsora pachyrhizi. The soybean genes Rpp3 and Rpp?(Hyuuga) confer resistance to specific isolates of the pathogen. Both genes map to chromosome 6 (Gm06) (linkage group [LG] C2). We recently identified 12 additional soybean accessions that harbor ASR resistance mapping to Gm06, within 5 centimorgans of Rpp3 and Rpp?(Hyuuga). To further characterize genotypes with resistance on Gm06, we used a set of eight P. pachyrhizi isolates collected from geographically diverse areas to inoculate plants and evaluate them for differential phenotypic responses. Three isolates elicited different responses from soybean accessions PI 462312 (Ankur) (Rpp3) and PI 506764 (Hyuuga) (Rpp?[Hyuuga]). In all, 11 of the new accessions yielded responses identical to either PI 462312 or Hyuuga and 1 of the new accessions, PI 417089B (Kuro daizu), differed from all others. Additional screening of Hyuuga-derived recombinant inbred lines indicated that Hyuuga carries two resistance genes, one at the Rpp3 locus on Gm06 and a second, unlinked ASR resistance gene mapping to Gm03 (LG-N) near Rpp5. These findings reveal a natural case of gene pyramiding for ASR resistance in Hyuuga and underscore the importance of utilizing multiple isolates of P. pachyrhizi when screening for ASR resistance. PMID- 21244224 TI - Multiple treatment meta-analysis of products evaluated for control of fire blight in the eastern United States. AB - The aim of this analysis was to estimate the effect sizes and consistency of products evaluated for fire blight control in the eastern United States over the last decade. Because only 3% of the 69 studies published from 2000 to 2008 explicitly presented a measure of within-study variability, a method for estimating the least significant difference (LSD) and, hence the sampling variance, for studies with at least two significant mean separations in the presented mean multiple comparisons was developed. Lin's concordance analysis indicated that the estimated LSD was an accurate predictor of the actual LSD based on 35 studies in a calibration evaluation (rho(c) = 0.997). Separate multi treatment random-effects meta-analyses were performed for three control categories: antibiotics, biological control, and plant defense-activating products and mean log response ratios relative to the nontreated controls ([Formula: see text]) were computed for each treatment and then back-transformed to obtain the mean percent disease control. None of the products evaluated performed as well as streptomycin, the standard product for fire blight control, for which the mean disease control was 68.6%. As a group, experimental antibiotics provided the best fire blight control with mean effect sizes ranging from 59.7 to 61.7%. Among the biological controls, the best control was noted for treatments combining the antibiotic streptomycin with a product based on Pantoea agglomerans (55.0% mean disease reduction) or Bacillus subtilis (53.9%). Mean disease control was 31.9, 25.7, and 22.6%, respectively, for products based on B. subtilis, Pantoea agglomerans, and Pseudomonas fluorescens without an antibiotic, suggesting that the higher efficacy of the combination treatments was due to the antibiotic. Among the plant defense-activating products, prohexadione calcium had the highest and most consistent effect size (50.7% control), while other products provided modest mean disease control of between 6.1 and 25.8%. Percent control values were significantly moderated by study location and cultivar used in the study, and were smaller, but more variable, when products were tested under high disease intensity compared with low disease intensity. Results indicate that wide scale use of biological control and plant defense-activating products in the eastern United States is likely to remain low. PMID- 21244225 TI - Trichothecene profiling and population genetic analysis of Gibberella zeae from barley in North Dakota and Minnesota. AB - Gibberella zeae, the principal cause of Fusarium head blight (FHB) of barley, contaminates grains with several mycotoxins, which creates a serious problem for the malting barley industry in the United States, China, and Europe. However, limited studies have been conducted on the trichothecene profiles and population genetic structure of G. zeae isolates collected from barley in the United States. Trichothecene biosynthesis gene (TRI)-based polymerase chain reaction (PCR) assays and 10 variable number tandem repeat (VNTR) markers were used to determine the genetic diversity and compare the trichothecene profiles of an older population (n = 115 isolates) of G. zeae collected in 1997 to 2000 with a newer population (n = 147 isolates) collected in 2008. Samples were from across the major barley-growing regions in North Dakota and Minnesota. The results of TRI based PCR assays were further validated using a subset of 32 and 28 isolates of G. zeae by sequence analysis and gas chromatography, respectively. TRI-based PCR assays revealed that all the G. zeae isolates in both populations had markers for deoxynivalenol (DON), and the frequencies of isolates with a 3 acetyldeoxynivalenol (3-ADON) marker in the newer population were ~11-fold higher than those among isolates in the older population. G. zeae populations from barley in the Midwest of the United States showed no spatial structure, and all the isolates were solidly in clade 7 of G. zeae, which is quite different from other barley-growing areas of world, where multiple species of G. zeae are commonly found in close proximity and display spatial structure. VNTR analysis showed high gene diversity (H = 0.82 to 0.83) and genotypic diversity but low linkage disequilibrium (LD = 0.02 to 0.07) in both populations. Low genetic differentiation (F(ST) = 0.013) and high gene flow (Nm = 36.84) was observed between the two populations and among subpopulations within the same population (Nm = 12.77 to 29.97), suggesting that temporal and spatial variations had little influence on population differentiation in the Upper Midwest. Similarly, low F(ST) (0.02) was observed between 3-ADON and 15-acetyldeoxynivalenol populations, indicating minor influence of the chemotype of G. zeae isolates on population subdivision, although there was a rapid increase in the frequencies of isolates with the 3-ADON marker in the Upper Midwest between the older collection made in 1997 to 2000 and the newer collection made in 2008. This study provides information to barley-breeding programs for their selection of isolates of G. zeae for evaluating barley genotypes for resistance to FHB and DON accumulation. PMID- 21244226 TI - Substrate oxidation in overweight boys at rest, during exercise and acute post exercise recovery. AB - OBJECTIVE: To compare substrate oxidation between normal weight (n = 10) and overweight (n = 10) boys at rest, during exercise at 50% VO(2peak) and during the first 30 minutes of recovery post-exercise. STUDY DESIGN: Twenty boys (8-11 years) were tested over two separate occasions. At the first session, body composition was measured by Dual-Energy X-ray Absorptiometry and peak aerobic capacity (VO(2peak)) was assessed using an incremental treadmill protocol. At least one week later, substrate oxidation was determined via indirect calorimetry in the fasted state at rest, during 10 minutes of exercise at 50% VO(2peak) and during the first 30 minutes of acute recovery post-exercise. RESULTS: There were no significant differences in substrate oxidation between the two groups at rest or during exercise. However, during early recovery, respiratory exchange ratio (RER) transiently increased in the overweight boys (p = 0.034) but not in the normal weight boys (p = 0.796), with a shift towards greater carbohydrate oxidation in the former group at 15-20 (p = 0.044) and 25-30 (p = 0.052) minutes post-exercise. In contrast, absolute post-exercise fat oxidation was similar between the two groups. CONCLUSION: Overweight boys may oxidise fat less efficiently than normal weight boys during recovery post-exercise, deriving a greater proportion of energy from carbohydrate oxidation. PMID- 21244227 TI - Ultrastructural characterization of mouse embryonic stem cell-derived oocytes and granulosa cells. AB - Germ cells are a unique population of cells responsible for transmitting genetic information from one generation to the next. Our understanding of the key mechanisms underlying germ cell development in vivo remains scarce because of insufficient amounts of cell materials available for conducting biological studies. The establishment of in vitro differentiation models that support the generation of germ cells from mouse pluripotent stem cells provides an alternative means for studying reproductive development. The detection and analysis of stem cell-derived germ cells, however, present technical challenges. Methods for determining the developmental stage of germ cells ex vivo, such as gene expression and/or immunochemical analyses are inadequate, frequently necessitating the use of alternative, elaborate methods to prove germ cell identity. We have generated putative oocytes and granulosa cells in vitro from mouse embryonic stem cells and utilized electron microscopy to characterize these cells. Here, we report on the striking ultrastructural similarity of in vitro generated oocytes and granulosa cells to in vivo oocytes developing within follicles. PMID- 21244228 TI - Late and very late catch-up after 90Sr/90Y beta-irradiation for the treatment of coronary in-stent restenosis. AB - Since late vessel failure has been speculated as a significant limitation of vascular brachytherapy (VBT), we conducted a prospective clinical evaluation at 6, 12, 24, 36 and 60 months follow-up after irradiation with (90)Sr/(90)Y for in stent restenosis (ISR) regardless of the patient's symptomatic status. Complete five-year follow-up is reported for 104 consecutive patients. The cumulative rate of death was 13.5% (6 months: 0.96%; 12 months: 2.88%; 24 months: 4.81%; 36 months: 7.69%), of acute myocardial infarction 4.81% (2.88%; 4.81%; 4.81%; 4.81%), of late thrombotic occlusion 4.81% (3.85%; 4.81%; 4.81%; 4.81%), of target lesion revascularization (TLR) 27.9% (8.65%; 12.5%; 17.3%; 21.2%), of target vessel revascularization (TVR) 43.3% (12.5%; 19.2%; 22.1%; 29.8%), and of all major adverse cardiovascular events (MACE) 61.5% (16.3%; 26.9%; 31.7%; 42.3%), respectively. Considered that the annual incidence of TVR after the first year following drug-eluting stenting for in-stent restenosis has been reported as approximately 3% per year, an incidence of 5.8% per year following VBT of our study population clearly indicates a more pronounced, delayed and, even in the fifth year after the index procedure, ongoing restenotic process following beta irradiation of in-stent restenotic lesions associated with clinically relevant adverse cardiovascular events. PMID- 21244229 TI - Evaluation of the performance of echocardiography in acute coronary syndrome patients during their stay in coronary units. AB - OBJECTIVES: To evaluate the frequency and the factors associated with performance of echocardiography in acute coronary syndrome (ACS) patients during their stay in intensive care units or coronary care units (ICU/CCU). METHODS: Retrospective cohort study including all patients diagnosed with acute coronary syndrome unstable angina (UA), acute myocardial infarction (AMI)-included in the 'ARIAM' Spanish multi-centre register. The study period was from June 1996 to December 2005. The follow-up period is limited to the time of stay in the Intensive Care Units or Coronary Care Units (ICUs/CCUs). A univariate analysis was carried out on the patients with UA and AMI according to whether or not echocardiograms were performed during their stay in ICU/CCU. In addition the data was evaluated for any temporal variation in the performance of echocardiography, and two multivariate analyses were carried out to evaluate the factors associated with performance of echocardiography in UA and AMI patients. RESULTS: The study period included 45,688 AMI patients and 17,277 UA patients. Echocardiograms were performed in 26.87% AMI patients and 16.75% UA patients. In total, 15,172 echocardiograms were performed in ACS patients (23.6%). The multivariate analysis demonstrated that the variables associated with the performance of echocardiography in UA were: Killip and Kimball class, cigarette smoking, family history of cardiovascular events, cardiogenic shock, uncontrolled angina, mechanical ventilation and treatment with ACE inhibitors, while the presence of previous AMI was associated with fewer echocardiograms being performed. In AMI, the multivariate analysis showed the following variables to be associated with the performance of echocardiography: Killip and Kimball class, Q-AMI, right heart failure, the need for insertion of Swan-Ganz catheter, cardiogenic shock, high degree AV block and the administration of ACE inhibitors, while age was associated with fewer being performed. Over the 10 years of the study period, there was a discrete but significant increase in the use of echocardiography in patients in ICU/CCU. CONCLUSIONS: Echocardiography is not commonly used in ACS patients while in ICU/CCU. UA and AMI patients who did have echocardiograms during their stay in ICU/CCU were chiefly those presenting heart failure and major complications, and represent a subpopulation with poor prognosis. The performance of echocardiography in ACS patients increased slightly over the length of their stay in ICU/CCU. PMID- 21244230 TI - Relation of cardiac troponin I and microvascular obstruction following ST elevation myocardial infarction. AB - BACKGROUND: Presence of microvascular obstruction (MVO) following primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) confers higher risk of left-ventricular remodelling and dysfunction. Measurement of cardiac troponin I (cTnI) after STEMI reflects the extent of myocardial destruction. We aimed to explore whether cTnI values were associated with presence of MVO independently of infarct size in STEMI patients receiving pPCI. METHODS: 175 patients with STEMI were included. cTnI was sampled at 24 and 48 h. MVO and infarct size was determined by delayed enhancement with cardiac magnetic resonance at five to seven days post index event. RESULTS: The presence of MVO following STEMI was associated with larger infarct size and higher values of cTnI at 24 and 48 h. For any given infarct size or cTnI value, there was a greater risk of MVO development in non-anterior infarctions. cTnI was strongly associated with MVO in both anterior and non-anterior infarctions (P < 0.01) after adjustment for covariates (including infarct size); and was reasonably effective in predicting MVO in individual patients (area-under-the-curve >=0.81). CONCLUSION: Presence of MVO is reflected in levels of cTnI sampled at an early time-point following STEMI and this association persists after adjustment for infarct size. PMID- 21244232 TI - Acoustic cardiographic indices of transmyocardial ischemia during percutaneous coronary intervention. AB - BACKGROUND: Transmyocardial ischemia is manifested as ST-segment elevation (STE). We examined acoustic cardiographic indices of STE that occur during percutaneous coronary intervention (PCI). METHODS: Of 83 patients undergoing coronary angiography, 25 underwent PCI, including 5 who developed STE. Continuous 12-lead ECG and computerized acoustic cardiographic heart sound analysis were performed during PCI. Intensities of the heart sounds (S1 to S4), diastolic time (from S2 to S1), and systolic time intervals (S1 to S2) were recorded. RESULTS: As STE increased, there was no change in heart rate or systolic time. Contractility decreased, with an increase in S3 intensity and a reduction in S1/S2 ratio. Left ventricular stiffness increased, reflected by an increase in S4 intensity. CONCLUSIONS: As transmyocardial ischemia worsened during progressive STE, acoustic cardiographic indices reflected impaired contractility and increased ventricular stiffness. In particular, the S4 was most predictive of increasing degrees of STE. These findings have implications for assessment of transmyocardial ischemia in patients with ECG findings that confound ST segment interpretation. PMID- 21244231 TI - Early revascularization is beneficial across all ages and a wide spectrum of cardiogenic shock severity: A pooled analysis of trials. AB - BACKGROUND: A pooled analysis in cardiogenic shock due to acute coronary syndromes is desirable to assess the effect of early revascularization (ERV) across all ages and a wide spectrum of disease severity. METHODS: Only two randomized controlled trials (RCT), i.e. SMASH and SHOCK, met the inclusion criteria and were combined for a pooled analysis using individual patient data (n = 348). RESULTS: SMASH patients (n = 54, 16%) had more severe disease than SHOCK patients (n = 294, 84%). After adjustment for age, anoxic brain damage, non inferior myocardial infarction, prior coronary artery bypass graft surgery, renal failure, systolic blood pressure, and selection for coronary angiography, one year mortality was similar (relative risk SHOCK versus SMASH 0.87, 95% CI: 0.61 1.25). Relative risk of one-year death for ERV versus initial medical stabilization was 0.82 (95% CI: 0.70-0.96). There was no significant difference in the treatment effect by age (<=75 years relative risk at one year 0.79, 95% CI: 0.63-0.99; > 75 years relative risk at one year 0.93, 95% CI: 0.56-1.53; interaction P = 0.10). CONCLUSIONS: Only two RCT have been published emphasizing the difficulty of enrolling critically ill patients. Despite large differences in shock severity, ERV benefit is similar across all ages and not significantly different for the elderly. PMID- 21244233 TI - The relative importance of predictors of body mass index change, overweight and obesity in adolescent girls. AB - OBJECTIVE: To determine the relative importance of familial, dietary, behavioral, psychological and social risk factors for predicting body mass index (BMI) change, and onset of overweight and obesity among adolescent girls. METHODS: Data from the NHLBI Growth and Health Study (n = 2 150), a longitudinal cohort of girls, were used to identify the most important predictors of change in BMI percentile between the ages of 9 and 19 years, and second, risk for becoming overweight and obese. Forty-one baseline predictors were assessed using a tree based regression method (Random forest) to rank the relative importance of risk factors. RESULTS: The five factors that best predicted change in BMI percentile (p < 0.05) were related to family socio-economic position (income and parent education) and drive to restrict eating and weight (body dissatisfaction, drive for thinness and unhappiness with physical appearance). The factors that were statistically significant (p < 0.05) predictors of both onset of overweight and obesity were income, ineffectiveness and race. CONCLUSIONS: Family socio-economic position and emotion regulation appeared as the top predictors of both BMI change and onset of overweight and obesity. Our results build upon prior findings that policies to prevent the onset of obesity during adolescence be targeted towards girls from lower socio-economic position households. Our findings also suggest several novel psychological factors including ineffectiveness as predictors of obesity during adolescence. These predictive findings offer a direction for future inquiry into adolescent obesity etiology using causal methods. PMID- 21244234 TI - Lymphocytic gastritis in pediatric celiac disease. AB - An increase in gastric intraepithelial lymphocytes has been observed in some patients with the typical small intestinal changes of celiac disease. To date, no clinical parameters have been described that identify the subset of patients more likely to have gastric involvement. In this study we compared the clinical features of celiac disease patients with and without lymphocytic gastritis to determine if the presence of gastric involvement at diagnosis portends a more severe form of celiac disease. We reviewed the pathology reports and hematoxylin and eosin-stained slides of 304 patients with biopsy-proven celiac disease diagnosed over an 11-year period. Thirty-nine of these patients had lymphocytic gastritis. Compared to patients without gastric involvement, those with lymphocytic gastritis were statistically more likely to be diagnosed at an earlier age and present with more profound laboratory findings and duodenal mucosal damage compared to patients with celiac disease without gastric involvement. These findings indicate that in the pediatric population, the presence of lymphocytic gastritis in celiac disease defines a unique group of patients with more severe disease (by clinical and laboratory measures) at the time of diagnosis. PMID- 21244235 TI - Acute lower respiratory tract infections by adenovirus in children: histopathologic findings in 18 fatal cases. AB - Adenoviruses (Ads) are the 2nd-most common cause of acute lower respiratory tract infections of viral etiology in immunocompetent children who require hospitalization in Argentina. A new pathogenic genomic variant, Ad7h, has been identified and was associated with severe sequelae and a high mortality rate. A retrospective observational study was conducted in hospitalized children with acute lower respiratory tract infections between March 1988 and May 2005. Nasopharyngeal or tracheal aspirates, bacteriological analysis on blood samples and pleural fluids, and histopathologic studies on autopsies were performed. A total of 415 children were included in the study. Sixty-two patients died in the acute stage of illness (1-8 weeks), and postmortem examination was performed on 18 of them. Mean age was 8.25 months. The male to female ratio was 1.3?1. The Ad was genome typed in 9% of all children, of whom 29 corresponded to the Ad7h variant. This genome type was diagnosed in 7 of the autopsies performed. Necrotizing bronchitis and bronchiolitis with abundant typical adenoviral inclusion nuclear cells and diffuse alveolar damage were the most important findings. Superimposed bacterial infection occurred in 11 cases, and cytomegalovirus was found in 1. In our population, Ad respiratory infection was found to have a severe course with sequelae or death. No differences were observed between lesions caused by other previously described genome types and those found in cases in which Ad7h was identified. PMID- 21244236 TI - Polymeric three-layered particles for the delivery of prednisolone to the lower gastrointestinal tract in rats. AB - BACKGROUND: The aim of this study is to investigate the feasibility of three layered particles as a drug delivery system to the lower part of small intestine. METHODS: The particle surface and basement layers were made of enteric polymer, Eudragit((r)) S100, and water-insoluble polymer, ethylcellulose. Prednisolone (PSL), as a model drug, was sealed with the surface and basement layers. After the administration of the test preparations to the duodenum of rats, blood samples were collected and plasma PSL levels were measured by high-performance liquid chromatography. The retention and transit characteristics of the three layered particles in rat small intestine were studied by direct observation after abdominal incision up to 8 hours. RESULTS: Three-layered PSL particles showed C(max) of 0.32 +/- 0.07 MUg/mL and T(max) at 6 hours, whereas the mean C(max) and T(max) of PSL powder, as a reference preparation, were 0.42 +/- 0.03 MUg/mL and 1 hour, respectively. With the direct observations, after administration of particles, about 77.5% of them were detected in duodenum at 1 hour, 45% in distal jejunum at 3 hours, and 50% in proximal ileum at 4 hours. Then, they were gradually transferred to the lower part of the small intestine at 5-8 hours time intervals. In comparison with PSL powder, three-layered particles delayed the intestinal transit and released PSL during their passage through the small intestine. CONCLUSION: These results suggested that three-layered particles adhered to the gastrointestinal mucosa and sustained the release of drug, resulting in drug delivery to the lower part of gastrointestinal tract. PMID- 21244237 TI - Effect of varying molecular weight of dextran on acrylic-derivatized dextran and concanavalin A glucose-responsive materials for closed-loop insulin delivery. AB - AIM: Dextran methacrylate (dex-MA) and concanavalin A (con A)-methacrylamide were photopolymerized to produce covalently cross-linked glucose-sensitive gels for the basis of an implantable closed-loop insulin delivery device. METHODS: The viscoelastic properties of these polymerized gels were tested rheologically in the non-destructive oscillatory mode within the linear viscoelastic range at glucose concentrations between 0 and 5% (w/w). RESULTS: For each cross-linked gel, as the glucose concentration was raised, a decrease in storage modulus, loss modulus and complex viscosity (compared at 1 Hz) was observed, indicating that these materials were glucose responsive. The higher molecular weight acrylic derivatized dextrans [degree of substitution (DS) 3 and 8%] produced higher complex viscosities across the glucose concentration range. CONCLUSIONS: These studies coupled with in vitro diffusion experiments show that dex-MA of 70 kDa and DS (3%) was the optimum mass average molar mass to produce gels that show reduced component leach, glucose responsiveness, and insulin transport useful as part of a self-regulating insulin delivery device. PMID- 21244238 TI - Medicinal food meets epigenetics. PMID- 21244239 TI - Grape seed extract regulates androgen receptor-mediated transcription in prostate cancer cells through potent anti-histone acetyltransferase activity. AB - Histone acetylation, which is regulated by histone acetyltransferases (HATs) and deacetylases, is an epigenetic mechanism that influences eukaryotic transcription. Significant changes in histone acetylation are associated with cancer; therefore, manipulating the acetylation status of key gene targets is likely crucial for effective cancer therapy. Grape seed extract (GSE) has a known protective effect against prostate cancer. Here, we showed that GSE significantly inhibited HAT activity by 30-80% in vitro (P < .05). Furthermore, we demonstrated significant repression of androgen receptor (AR)-mediated transcription by GSE in prostate cancer cells by measuring luciferase activity using a pGL3-PSA construct bearing the AR element in the human prostate cancer cell line LNCaP (P < .05). GSE treatment also decreased the mRNA level of the AR-regulated genes PSA and NKX 3.1. Finally, GSE inhibited growth of LNCaP cells. These results indicate that GSE potently inhibits HAT, leading to decreased AR-mediated transcription and cancer cell growth, and implicate GSE as a novel candidate for therapeutic activity against prostate cancer. PMID- 21244240 TI - Beneficial effects of a synbiotic supplement on self-perceived gastrointestinal well-being and immunoinflammatory status of healthy adults. AB - The use of synbiotics as health promoters is still poorly defined, and human intervention studies are scarce. This study was designed to evaluate the effects of a commercialized synbiotic product containing Lactobacillus acidophilus La5, Bifidobacterium animalis ssp. lactis Bb-12, Lactobacillus delbrueckii ssp. bulgaricus, Lactobacillus paracasei ssp. paracasei, Streptococcus thermophilus, and fructooligosaccharides on the self-reported gastrointestinal well-being and the immunoinflammatory status of healthy human subjects. In this randomized, double-blind, placebo-controlled study, 20 women and 16 men (25-45 years old) received either three tablets per day of the synbiotic product (2.4 * 10(9) colony-forming units/day) or placebo during 6 weeks. Gastrointestinal symptoms and bowel habits were evaluated through a self-administered questionnaire. In those subjects suffering from any kind of digestive disturbance (mild dyspepsia, flatulence, postprandial bloating, constipation, etc.), improvements in symptoms after product consumption were also evaluated. Blood lymphocyte subsets, phagocytic activity, serum C-reactive protein, ceruloplasmin, and adhesion molecules concentrations were analyzed prior and after treatment. A significant improvement in overall self-reported gastrointestinal symptoms and bowel habit was found in the synbiotic group. A marginal effect of treatment (analysis of variance P = .050) was observed with L-selectin, which showed a significant decrease in the synbiotic group (P = .019). In addition, basal L-selectin levels correlated with final intercellular adhesion molecule (ICAM)-1 levels (r = 0.468; P = .050), and basal ICAM-1 levels tended to correlate negatively with final L selectin concentration (r = -0.457; P = .056). None of these correlations was found in the placebo group. The rest of the immunological parameters studied were not modified by the intervention. In conclusion, consumption of the synbiotic product improves self-perceived bowel habits and might facilitate a better profile of adhesion molecules in healthy adults. PMID- 21244241 TI - Hypolipidemic and antioxidant potentials of Xylopia aethiopica seed extract in hypercholesterolemic rats. AB - A short-term study was carried out on Wistar strain rats to determine the effects of Xylopia aethiopica extract on serum and postmitochondrial fractions (PMFs) of visceral organs in experimental hypercholesterolemia. Animals received normal diet and were administered cholesterol orally by intubations at a dose of 40 mg/kg/0.3 mL, plant extracts at 250 mg/kg, and cholestyramine (Questran(r), Bristol-Myers Squibb, Hounslow, United Kingdom) at 0.26 g/kg five times a week for 8 consecutive weeks. Thereafter the hypolipidemic effects were assessed by measuring total cholesterol, low-density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol, and triglycerides, whereas the extent of oxidative stress was assayed by measuring thiobarbituric acid-reactive substances and enzymatic antioxidants such as superoxide dismutase, catalase, and reduced glutathione (GSH) in serum and PMF of liver and kidney. We assayed two liver biomarkers-alanine aminotransferase and aspartate aminotransferase-for safety of X. aethiopica at the dose given in this experiment. Cholesterol feeding resulted in a significant increase (P < .05) in body weight of the hypercholesterolemic animals relative to control animals, and administration of X. aethiopica (250 mg/kg) caused a more than 60% reduction in body weight. Simultaneous treatment with X. aethiopica and Questran elicited 33.75% and 23.94% reductions, respectively, in serum cholesterol levels of hypercholesterolemic rats. In addition, the LDL-C level decreased significantly (P < .05) by 49.09% and 78.92% in serum and by 64.97% and 37.29% in the liver with cotreatment with the plant extract and Questran, respectively, compared to untreated hypercholesterolemic rats. X. aethiopica counteracted the decreases in enzymatic antioxidants, especially in GSH, where there was a greater than 300% increase compared with hypercholesterolemic animals. This study has shown that intake of X. aethiopica reduced the composition of lipids and produced a favorable lipid profile in the serum and PMF of visceral organs in experimental hypercholesterolemia. PMID- 21244242 TI - Preventive effect of probiotics and alpha-tocopherol on ethanol-induced gastric mucosal injury in rats. AB - The protective effect of a probiotic mixture of 13 different bacteria and alpha tocopherol on 98% ethanol-induced gastric mucosal injury was evaluated. Levels of gastric mucosal pro- and anti-inflammatory cytokines, malondialdehyde, and secretory immunglobulin A were measured. Rats were allocated into four groups: control, ethanol, probiotic, and alpha-tocopherol. The control and ethanol groups received skim milk for 14 days. Probiotic and alpha-tocopherol groups were administered probiotic mixture suspended in skim milk and 100 mg/kg alpha tocopherol, respectively, by daily gavage for 14 days. On Day 15, gastric lesions were induced by administration of ethanol 98% (1 mL) to all rats except those in the control group. Probiotic, but not alpha-tocopherol, seemed to inhibit ethanol induced gastric mucosal tumor necrosis factor-alpha, interferon-gamma, and interleukin-2 production (P > .05). Ethanol caused the elevation of mucosal interleukin-4 level (compared to the control, P < .05). Probiotic pretreatment significantly suppressed the ethanol-induced increase of gastric mucosal interleukin-4 levels. Pretreatment with either probiotic or alpha-tocopherol inhibited the ethanol-induced increase of mucosal malondialdehyde concentration (P < .01 and P < .05, respectively). Probiotic pretreatment enhanced the gastric mucosal secretory immunoglobulin A concentration (P < .001). In conclusion, probiotic mixture and alpha-tocopherol reduced ethanol-induced gastric mucosal lipid peroxidation, suggesting that they may be beneficial for gastric lesions induced by lower ethanol concentration. PMID- 21244243 TI - Systemic elimination of de novo capsid protein synthesis from replication competent AAV contamination in the liver. AB - The capsid protein synthesis in targeted tissues resulting from residual contaminating replication-competent adeno-associated virus particles (rcAAV) remains a concern for hazardous immune responses that shut down the factor IX expression in the hemophilia B clinical trial. To systematically reduce/eliminate the effects of potential contaminating rcAAV particles, we designed a novel adeno associated virus (AAV) helper (pH22mir) with a microRNA binding cassette containing multiple copies of liver-specific (hsa-mir-122) and hematopoietic specific (has-mir-142-3p) sequences to specifically control cap gene expression. In 293 cells, the rep and cap gene from pH22mir functioned similarly to that of conventional helper pH22. The vector yields and compositions from pH22mir and pH22 were indistinguishable. The performance of vector produced in this new system was comparable to that of similar vectors produced by conventional methods. In the human hepatic cell line, the capsid expression was reduced significantly from cap-mir cassette driven by a cytomegalovirus promoter. In the liver, 99.9% of capsid expression could be suppressed and no cap expression could be detected by western blot. In summary, we demonstrated a new concept in reducing de novo capsid synthesis in the targeted tissue. This strategy may not only help AAV vectors in controlling undesirable capsid gene expression, but can also be adopted for lentiviral or adenoviral vector production. PMID- 21244246 TI - Who should palliative medicine be asked to see? PMID- 21244247 TI - In which journals do active researchers of palliative care publish their articles? PMID- 21244248 TI - Clinical application of ASCEND: a pathway to higher ground for communication. PMID- 21244250 TI - Patients who make "wrong" choices. PMID- 21244249 TI - The palliative care interdisciplinary team: where is the community pharmacist? AB - Palliative care emphasizes an interdisciplinary approach to care to improve quality of life and relieve symptoms. Palliative care is provided in many ways; in hospices, hospital units, and the community. However, the greatest proportion of palliative care is in the community. In hospice and palliative care units in hospitals, clinical pharmacists are part of the interdisciplinary team and work closely with other health care professionals. Their expertise in the therapeutic use of medications is highly regarded, particularly as many palliative care patients have complex medication regimens, involving off-label or off-license prescribing that increases their risk for drug-related problems. However, this active involvement in the palliative care team is not reflected in the community setting, despite the community pharmacist being one of the most accessible professionals in the community, and visiting a community pharmacist is convenient for most people, even those who have limited access to private or public transport. This may be due to a general lack of understanding of skills and knowledge that particular health professionals bring to the interdisciplinary team, a lack of rigorous research supporting the necessity for the community pharmacist's involvement in the team, or it could be due to professional tensions. If these barriers can be overcome, community pharmacists are well positioned to become active members of the community palliative care interdisciplinary team and respond to the palliative care needs of patients with whom they often have a primary relationship. PMID- 21244251 TI - Religiousness and mood in the last week of life: an explorative approach based on after-death proxy interviews. AB - Although religiousness may, to a certain extent, be expected to alleviate emotional suffering in the last week of life, some religious beliefs might also provoke emotional distress. For the current study, after-death interviews with proxy respondents of deceased sample members of the Longitudinal Aging Study Amsterdam provided information on depressive mood and anxiety in the last week of life, as well as on the presence of a sense of peace at the approaching end of life. Proxy respondents also were asked about serious physical symptoms in the last week of life of the respondent, the respondent's cognitive decline, and their estimate of the salience of religion for the sample member. Other characteristics were derived from the last interviews with the sample members when still alive: depressive symptoms, chronic diseases, religious affiliation, church attendance, belief in Heaven, belief in Hell, and salience of religion. None of the characteristics of religiousness was significantly associated with depressive mood or anxiety, as estimated by the proxy respondent. A sense of peace, however, was predicted by higher church attendance, belief in Hell (among church-members), and the proxy's estimate of the salience of religion. It can be concluded that religiousness did not affect depressive mood or anxiety in the last week of life in the current sample. It is possible that religiousness supports a sense of peace, which may be a more-existential facet of mood and is discussed as relevant in the last phase of life and in palliative care. PMID- 21244252 TI - How parents of children receiving pediatric palliative care use religion, spirituality, or life philosophy in tough times. AB - BACKGROUND: How parents of children with life threatening conditions draw upon religion, spirituality, or life philosophy is not empirically well described. METHODS: Participants were parents of children who had enrolled in a prospective cohort study on parental decision-making for children receiving pediatric palliative care. Sixty-four (88%) of the 73 parents interviewed were asked an open-ended question on how religion, spirituality, or life philosophy (RSLP) was helpful in difficult times. Responses were coded and thematically organized utilizing qualitative data analysis methods. Any discrepancies amongst coders regarding codes or themes were resolved through discussion that reached consensus. RESULTS: Most parents of children receiving palliative care felt that RSLP was important in helping them deal with tough times, and most parents reported either participation in formal religious communities, or a sense of personal spirituality. A minority of parents, however, did not wish to discuss the topic at all. For those who described their RSLP, their beliefs and practices were associated with qualities of their overall outlook on life, questions of goodness and human capacity, or that "everything happens for a reason." RSLP was also important in defining the child's value and beliefs about the child's afterlife. Prayer and reading the bible were important spiritual practices in this population, and parents felt that these practices influenced their perspectives on the medical circumstances and decision-making, and their locus of control. From religious participation and practices, parents felt they received support from both their spiritual communities and from God, peace and comfort, and moral guidance. Some parents, however, also reported questioning their faith, feelings of anger and blame towards God, and rejecting religious beliefs or communities. CONCLUSIONS: RSLP play a diverse and important role in the lives of most, but not all, parents whose children are receiving pediatric palliative care. PMID- 21244253 TI - Opioid needs of patients with advanced cancer and the morphine dose-limiting law in Egypt. AB - BACKGROUND: Morphine is the drug of choice for moderate to severe cancer pain management. The Egyptian Narcotics Control Law limits the amount of morphine prescribed in a single prescription to a maximum of 420 mg for tablets and 60 mg for ampoules. The usual practice in Egypt is to provide that limited amount of morphine on a weekly basis. The aim of this study is to estimate the extent to which Egyptian patients may be undertreated because of this law. METHODS: We reviewed the medical records of advanced cancer patients referred to the first palliative care unit in Egypt over a seven-month period. Cancer pain was managed following the WHO guidelines. After modifying the internal institutional policy, patients received adequate amounts of the available opioids without any violations of the law. RESULTS: From 117 eligible advanced cancer patients, 58 (50%) patients required strong opioids, 32 (27%) required weak opioids, and 27 (23%) required no regular opioids. The mean last prescribed opioid dose for those who required strong opioids was 194 mg of oral morphine equivalent/24 h (+/- 180). For this group of patients, a single weekly prescription would supply enough oral morphine for only 26% of them. In the case of parenteral morphine, none of these patients would receive an adequate supply. CONCLUSIONS: In view of the current morphine dose-limiting law and practices in Egypt, the majority of patients suffering severe cancer pain would not have access to adequate morphine doses. That dose-limiting law and other restrictive regulations represent an obstacle to cancer pain control in Egypt and should be revised urgently. PMID- 21244254 TI - Using death rounds to improve end-of-life education for internal medicine residents. AB - While internal medicine interns provide much of the care to patients dying in the hospital, few report that they have received adequate training in end-of-life care. PURPOSE: To address this perceived lack of training, we undertook a study to evaluate Death Rounds as an educational tool in end-of-life care and to address the emotional needs of trainees providing care to dying patients. DESIGN: We used a behavioral interventional study using a pre-post study design. PARTICIPANTS: The study included all internal medicine interns at the University of Washington (n = 62) during the academic year 2007-08. Interns from the 2006-07 academic year (n = 64) received the survey and served as the control group. INTERVENTION: Death Rounds, a one-hour session dedicated to discussion of emotional reactions to patient death. MAIN MEASURES: We used a 14-item electronic measure with questions directed toward the impact of perceived insufficient end of-life care and the role of Death Rounds in resident education. KEY RESULTS: Results are drawn from a total of 39 surveys completed by the intervention group, for a response rate of 63%. Seventy-four percent (29) felt that Death Rounds contributed to their education in end-of-life issues. Seventy-two percent (28) reported that Death Rounds was "somewhat" or "very" helpful in improving their comfort with discussing end-of-life issues. Ninety-seven percent (38) of participants thought that having an opportunity to discuss the emotional aspects of patient death should be included in their training. CONCLUSIONS: This study suggests that learning to deal with the strong emotions that arise in the care of dying patients is an important part of physician training. Death Rounds provides an opportunity to explore these emotions with colleagues in a supportive environment and is a valuable addition to the resident curriculum. PMID- 21244255 TI - The impact of a clinical rotation in hospice: medical students' perspectives. AB - Medical educators agree that training in end-of-life care (EOLC) must be an integral part of medical education at all levels. While progress in this area of education has taken place, many gaps still exist. This article describes the self reported impact of a required one-week hospice rotation for third-year medical students. Students completing their hospice rotation during a one-year period were asked to write an essay describing the most important lessons they learned. Qualitative analyses of the essays revealed 10 core themes and generated a coding schema for detailed analysis. Students' essays reflected knowledge gained, emotional reactions, cognitive insights, and relationship-centered skills. Comments focused on the following themes: benefits and philosophy of hospice; impact on future practice; interdisciplinary team approach; management of pain and suffering; facts about hospice; personal impact; communication with patients and families; dedication and skill of staff; role of families; and value of home care. Students consistently recognized the significance of positive role models. Learning about a new field of medicine helped broaden students' knowledge, skills, and beliefs, and expanded their assumptions about illness and suffering, the role of health care professionals, and the goals of medicine. Reflection and writing brought about self-awareness of the learning process itself. The study demonstrates that a robust clinical EOLC exposure can be effectively incorporated into undergraduate education and that student self-reports constitute a valuable mode of evaluation. Longitudinal assessments of trainees' competencies in EOLC are needed to optimize these educational endeavors. PMID- 21244256 TI - Discharge planning for palliative care patients: a qualitative analysis. AB - For patients hospitalized with life-threatening illnesses and their families, palliative care consultants can provide critical support by providing information about prognosis, ensuring that symptoms are managed, helping to clarify goals of care, and addressing psychosocial and spiritual concerns. However, once patients leave the hospital, many hospital-based palliative care teams (PCTs) cannot continue to play active roles in patient care. Gaps in discharge planning not only decrease quality of life for patients, but also translate into lack of support for caregivers. The palliative care population would be expected to benefit from a customized approach to hospital discharge. The aim of this study was to identify the range of health care experiences of family caregivers and patients who received palliative care consultations after they left the hospital, and to understand how PCTs might best prepare patients and caregivers for the post-hospital experience. PMID- 21244257 TI - Description of a Tertiary Swiss University Hospital palliative population based on the International Classification of Disease (ICD): a retrospective pilot study. AB - BACKGROUND: The factors for assessing the utilization rate of a palliative care service are various and complex. Several authors have described different methods to address this problem. McNamara and colleagues have proposed criteria to determine "minimal," "mid-range," and "maximal" palliative population estimates. In order to evaluate the utilization of our intrahospital palliative care consult team (PCT), it appeared necessary to better describe and define the population who dies in our institution, a Swiss university hospital. The goal of this pilot study was to determine what percentage of patients who died in our hospital over a 4-month period in 2007 was seen by the palliative care consult team (PCT), using "minimal" and "maximal" population estimates. METHODS: The hospital database was searched for all adult patients who died during that period and the "maximal" and "minimal" populations determined. The PCT's database was searched to identify those patients who had been seen by the PCT. The charts of a random sample of patients who did not initially meet the "minimal" criteria were hand searched. RESULTS: A total of 294 adult deaths were reported: 263 (89%) met the "maximal" criteria and 83 (28%) met the "minimal" criteria initially. The random search of 56 charts of the 180 patients who did not meet the "minimal" criteria revealed that 21 (38%) should have been included in the "minimal" population. The PCT saw 67/263 (25.5%) of the "maximal" palliative patient population and 56/151 (37.1%) of the "minimal" palliative population. CONCLUSION: This study highlights the usefulness of the method proposed by McNamara and colleagues to determine palliative populations. However, it also illustrates an important limitation of the "minimal" estimate and reliance on the accuracy of the cause of death as noted on the death certificate. A strategy to address this limitation is suggested. The "maximal" estimate suggests that the PCT is being underutilized. PMID- 21244258 TI - Using small groups to promote self-awareness. PMID- 21244259 TI - Teaching small groups in palliative care. AB - Small group learning (i.e., tutorial, seminar, or small problem-solving class) is uniquely suited to transformative change as the ultimate goal of education, and especially appropriate for use in teaching about palliative care. The small group can be a fertile environment for both individual and communal development on both personal and professional levels by recognizing the unique needs of small group facilitation, and developing necessary faculty skills, and by modeling thoughtful preparation, reflective execution, and perceptive feedback. The small group learning approach focuses on learning facilitation and enhancing students' communications skills, which are vital to providing effective, patient-centered palliative care. PMID- 21244260 TI - Family presence during resuscitation #232. PMID- 21244261 TI - Implementation of a family presence during resuscitation protocol #233. PMID- 21244262 TI - When letting go is hard to do. PMID- 21244263 TI - Insight into my dementia. PMID- 21244264 TI - Lessons from the silence. PMID- 21244265 TI - The use of hospice care in end-stage psychiatric patients. AB - Hospice care is rarely used in end-stage psychiatric patients, yet situations exist where psychiatric intervention is futile and comfort care is the best option. Delusional disorder is rare, typically begins later in life, and has a chronic course that responds poorly to treatment. The prognosis is affected by factors such as chronicity and insight. A case of a chronic and intractable delusional disorder that affected eating behavior and subsequently caused serious medical complications. Due to the severity of the case and the unique ethical issues it presented, the prognosis was determined to be poor and the patient was discharged home with hospice care. The case presented a rare opportunity to assess hospice care provided to an end-stage psychiatric patient. PMID- 21244271 TI - Patient information. Supporting your grieving child. PMID- 21244274 TI - The microstructure characterization of meloxicam microemulsion and its influence on the solubilization capacity. AB - OBJECTIVE: The aim of this study was to characterize the microstructure of microemulsion consisting of oleic acid, Cremophor RH40, ethanol, and water (K(m) = 2), and investigate the influence of microstructure on the solubilization potential of the microemulsion to meloxicam (MLX). METHODS: Pseudo-ternary phase diagrams of microemulsion were constructed using the H2O titration method. The microstructures of microemulsion on dilution line N91 were identified by means of conductivity, viscosity, surface tension, and density. The freeze-fracture electron microscopy proved the specific microstructure. Differential scanning calorimetry (DSC) was used to evaluate the position of MLX in microemulsion, and the solubility of MLX in chosen microemulsions on dilution line N91 was measured. RESULTS: The three microstructures along dilution line N91, including water-in oil (W/O), bicontinuous (BC), and oil-in-water (O/W) microemulsion, were characterized. The solubilization capacity of W/O microemulsion is the best, compared with the other two, whereas the O/W is the weakest. A possible structure model has been applied for the explanation of difference. CONCLUSIONS: The solubilization capacity of microemulsion is closely related with its microstructure. PMID- 21244273 TI - Fast geometric consensus approach for protein model quality assessment. AB - Model quality assessment (MQA) is an integral part of protein structure prediction methods that typically generate multiple candidate models. The challenge lies in ranking and selecting the best models using a variety of physical, knowledge-based, and geometric consensus (GC)-based scoring functions. In particular, 3D-Jury and related GC methods assume that well-predicted (sub )structures are more likely to occur frequently in a population of candidate models, compared to incorrectly folded fragments. While this approach is very successful in the context of diversified sets of models, identifying similar substructures is computationally expensive since all pairs of models need to be superimposed using MaxSub or related heuristics for structure-to-structure alignment. Here, we consider a fast alternative, in which structural similarity is assessed using 1D profiles, e.g., consisting of relative solvent accessibilities and secondary structures of equivalent amino acid residues in the respective models. We show that the new approach, dubbed 1D-Jury, allows to implicitly compare and rank N models in O(N) time, as opposed to quadratic complexity of 3D-Jury and related clustering-based methods. In addition, 1D-Jury avoids computationally expensive 3D superposition of pairs of models. At the same time, structural similarity scores based on 1D profiles are shown to correlate strongly with those obtained using MaxSub. In terms of the ability to select the best models as top candidates 1D-Jury performs on par with other GC methods. Other potential applications of the new approach, including fast clustering of large numbers of intermediate structures generated by folding simulations, are discussed as well. PMID- 21244275 TI - Comparison of a novel fast-dissolving acetaminophen tablet formulation (FD-APAP) and standard acetaminophen tablets using gamma scintigraphy and pharmacokinetic studies. AB - CONTEXT: Acetaminophen (paracetamol, APAP) is widely used to relieve mild-to moderate pain and reduce fever. Absorption of the drug can be impacted by dosage form; this may have implications for pain relief in some individuals, potentially accounting for suboptimal efficacy in analgesia. OBJECTIVE: To assess the disintegration and dissolution of a new fast-dissolving acetaminophen tablet formulation (FD-APAP) and the impact on pharmacokinetic and pharmacodynamic parameters. MATERIALS AND METHODS: Two randomized, single-center, open-label, single-dose, two-way crossover studies in healthy subjects to compare FD-APAP (2 * 500 mg tablets) with standard acetaminophen (2 * 500 mg tablets). Gamma scintigraphy was used to assess tablet disintegration (Study 1, N = 24), and plasma profiles were evaluated in the fasted state (Study 2, N = 40). RESULTS: In Study 1, the mean time to complete disintegration (12.9 vs. 69.6 min, P < 0.0001) and onset of disintegration were both significantly faster with FD-APAP than with standard acetaminophen (P < 0.0001). For Study 2, median T(max) was significantly faster for FD-APAP (0.50 vs. 0.67 h, P < 0.01) and AUC(0-30 min) was significantly greater (4.51 vs. 2.74, P < 0.05). AUC(0-t) and AUC(0-inf) were comparable between the two study treatments. DISCUSSION: Despite the absence of comparative clinical data, the FD-APAP formulation may be expected to overcome some of the issues associated with the slow and variable absorption of standard acetaminophen tablet formulations, improving therapeutic outcome and avoiding the need to switch to alternative therapeutic options. CONCLUSION: Compared with standard acetaminophen, the FD-APAP formulation results in significantly faster onset of disintegration and more rapid absorption. PMID- 21244276 TI - Preparation and characterization of beta-elemene-loaded microemulsion. AB - Intravenously injectable emulsion of beta-elemene was studied in detail. Both blank and beta-elemene-loaded microemulsions were prepared using a simple water titration method. The pseudoternary phase diagram was constructed for the optimization of microemulsion. The loading capacity test, dilutability test, and especially the influence of antioxidants were conducted for further optimization of beta-elemene-loaded microemulsion. Transmission electron microscope showed intact and spherical microemulsion droplets. Conductivity and viscosity measurements were used to study the phase behaviors of beta-elemene-loaded microemulsions, providing convincing explanation. In vitro release study showed that beta-elemene was steadily released until 12 h, which most fitted the first order. PMID- 21244277 TI - The college arms. PMID- 21244278 TI - On the prevention of suicide. PMID- 21244279 TI - Eugenics and mental retardation. PMID- 21244280 TI - Changing patterns of symptomatology in psychiatry. PMID- 21244281 TI - Crime and punishment. PMID- 21244283 TI - Community Psychiatry in the Islands Region of New Guinea: II. A Design. AB - The observations of the Islands Region Psychiatry Research Project Team made between 1965 and 1967 and the principles of community psychiatry as presented by Caplan are used as the basis for a design of a psychiatric service in a setting such as New Guinea. PMID- 21244282 TI - Community psychiatry in the islands region of new Guinea: 1. Epidemiology. AB - From 1965 to 1967 a regional psychiatric service based on Rabaul was offered to the Islands Region of New Guinea. The results of the first year's work, which included three hundred referred cases were reviewed to provide the guide lines for the second year of the existing project and for possible future developments. PMID- 21244284 TI - The lithium excretion test: I. Clinical application and interpretation. AB - The clinical and research applications of the Lithium Excretion Test (L.E.T.) are described. With a 4-hour test it is possible to differentiate manic patients who respond to lithium from those who do not. Significant applications for a small but important group of patients with personality disorders are discussed, as well as the findings in depression and schizophrenia. PMID- 21244285 TI - The Lithium Excretion Test: II. Practical and Biochemical Aspects. AB - The ward technique, practical problems and biochemical methods of the Lithium Excretion Test (L.E.T.) are described. The procedures for the estimation of plasma, urinary and erythrocyte levels of lithium are given in detail. PMID- 21244286 TI - Senile and arteriosclerotic dementia: a study of personal, social and family data. AB - 40 patients with senile dementia, 40 with arteriosclerotic dementia, and 40 people attending an elderly citizens' club have been compared with respect to certain social and personal data. The senile dementia group showed significant tendencies to positive family history, unusual personality characteristics and greater duration of widowhood. PMID- 21244287 TI - Parental deprivation and psychiatric illness in old age. AB - Early parental deprivation was identified from coded information in 1,103 case histories of psychiatric patients over the age of 60. Associations were sought between maternal, paternal or combined deprivation and any diagnostic category in this geriatric group. PMID- 21244289 TI - Selected abstracts Australian and new zealand psychiatry. PMID- 21244295 TI - New trends in the science of botulinum toxin-A as applied in dystonia. AB - New trends and advances in botulinum toxin neuroscience paved the way to the better understanding of the toxin from its behavior at the bench to the clinics. As details of mechanism of action are clarified, we are ready to dispose of product myths, such as diffusion being related to the product being used. Our directions, more precisely on the important subjects such as dose targeting, will translate the science to robust clinical information. Additionally, aspects such as antibody formation, leading to treatment nonresponse, are now understood after long-term treatment series in a variety of dystonic conditions. Avenues leading to combinations of these areas of knowledge will lead to improved botulinum neurotoxin (BoNT) treatment, and further explore the potential of this toxin treatment in association with other treatment modalities, particularly in spasticity and dystonia. PMID- 21244299 TI - The promise of deep brain stimulation in X-linked dystonia parkinsonism. AB - X-Linked dystonia parkinsonism (XDP) is a rapidly progressive and disabling neurodegenerative disease affecting mainly male Filipinos with origins from Panay Island. We reviewed all the past neurosurgical ablative procedures done for XDP patients listed in the Philippine XDP registry. From 1960 to 1982, six patients had undergone bilateral chemopallidotomies or bilateral thalomotomies staged over time. Half of these patients had significant improvement in their symptoms but five of the six patients (83%) developed postoperative morbidities, mainly speech impairment or hemiparesis. All the five reported GPi deep brain stimulation (DBS) cases for XDP were also reviewed, showing consistently immediate improvement of symptoms (61.5%-88.3% decrease in the Burke-Marsden-Fahn Dystonia Rating Scale) lasting up to a year with no adverse effects noted. We also present the first Philippine case of GPi DBS done in the youngest XDP patient to date. This present case showed dramatic improvement (88.3% decrease of the Burke-Marsden-Fahn Dystonia Rating Scale) of his dystonic symptoms, without incurring any persistent adverse effects. The results of these early cases of pallidal DBS for XDP show that DBS is generally a safe and effective procedure for alleviating the disabling symptoms of XDP in contrast to previous ablative surgeries performed on these patients. PMID- 21244301 TI - Wernicke encephalopathy after gastrointestinal surgery for cancer: causes of diagnostic failure or delay. AB - Wernicke encephalopathy (WE) is a neurological emergency due to thiamine deficiency. We aimed to identify clinical course and causes of diagnostic delay or failure of WE in a group of patients who underwent surgery for gastrointestinal tumors. A retrospective review of clinical, laboratory, neuroimaging, and therapeutic features of 10 patients with WE following abdominal surgery for cancer was carried out. Four patients died; in these subjects, diagnosis was delayed and supplementation of vitamin was absent or likely inadequate. Diagnostic delay or failure was also related to the coexistence of several medical complications at presentation masking typical symptoms of WE. In the surviving patients, outcome was influenced by promptness and type of therapy. Postoperative abdominal bleeding and number of subsequent operations may also had an effect. Postsurgical patients with gastrointestinal tumors may develop a subtle WE. The number of subsequent operations and the severity of postoperative complications may increase the risk of unrecognized WE. The disease should be suspected in postsurgical patients who have unexpected mental status changes, even under prophylactic treatment with vitamins. We suggest that prophylaxis with high doses of thiamine should be undertaken in patients with gastrointestinal tumors before surgery. PMID- 21244302 TI - Platelet-rich plasma: a promising product for treatment of peripheral nerve regeneration after nerve injury. AB - Nerve regeneration includes regrowth of injured axons as well as myelination, restoration of synaptic connections and recovery of physiological functions. Platelet-rich plasma (PRP) is prepared from the patient's own blood and contains growth factors that influence wound healing and used in various surgical fields including oral and maxillofacial surgery. When platelets are activated either ex vivo or in vivo, growth factors and proteins were released from platelets' alpha granules. Recent studies proved that PRP could promote regeneration of injured peripheral nerve. This review focuses on current trials using PRP to promote nerve regeneration and repairment, and proposes potential clinical application of PRP for nerve injury in the future. PMID- 21244304 TI - Oral pharmacological treatment of X-linked dystonia parkinsonism: successes and failures. AB - There is a paucity of published literature on the different oral medications tried for X-linked dystonia parkinsonism (XDP). In practice, most XDP patients are tried or have been tried on medications typically used for patients with generalized dystonia. These drugs include anticholinergic agents, baclofen, clonazepam and other benzodiazepines, tetrabenazine, and clozapine. Although several articles have shown that these classes of drugs are beneficial for patients with generalized dystonia, none have been systematically studied specifically for XDP patients. We are currently conducting the first randomized, placebo-controlled trial on the use of levodopa for the symptomatic treatment of XDP. This article reviews the data on the various dystonia medications that have been used in XDP. PMID- 21244305 TI - The broadening application of chemodenervation in X-linked dystonia-parkinsonism (Part I): muscle afferent block versus botulinum toxin-A in cervical and limb dystonias. AB - Botulinum toxin (BoNT) is an established mainstay treatment for dystonia. However, its use, especially in developing countries, is significantly limited by its cost. Chemodenervation with muscle afferent block (MAB) using lidocaine ethanol may provide a more cost-effective alternative to traditional BoNT injections. A study comparing MAB with BoNT type-A in cases of X-linked dystonia Parkinsonism (XDP) having cervical dystonia indicated a modest and short-lived efficacy with MAB, while a more robust efficacy in dystonia and pain parameters, lasting up to 11 weeks, was observed in the two BoNT type-A preparations (Dysport(r) and Botox(r)). In another study comparing BoNT type-A formulations for limb dystonia of XDP, a prior MAB was used to select target muscles for toxin injection. During toxin injections in the limb muscles, Dysport(r) and Botox(r) did not show significant differences with regard to global severity and disability scales, duration of effect, and adverse event (AE) profile. Dysphagia was the most common AE following BoNT type-A injections in cervical dystonia, while weakness was the most frequent AE noted with injections for limb dystonia. MAB injections carried a high incidence of dizziness and pain during injections. However, because MAB is a more cost-effective alternative that can be given repeatedly, it has been used in the XDP population while awaiting funds for BoNT type-A and/or for selecting muscles for injection as a test drug. PMID- 21244307 TI - Long-term, open-label study of once-daily ropinirole prolonged release in early Parkinson's disease. AB - Long-term safety and efficacy of once-daily ropinirole prolonged release (PR) were evaluated in subjects with early Parkinson's disease (PD). Subjects (n = 83) who completed one of two studies were enrolled in this open-label, multicenter, extension study, and followed for up to 78 months. Ropinirole PR was titrated/continued, and adjusted as appropriate during the maintenance phase (maximum 24 mg/day). L-dopa and other non-dopamine agonist PD medications were permitted. Safety outcomes included adverse events (AEs). Efficacy outcomes included Unified Parkinson's Disease Rating Scale (UPDRS) II and III scores, and Clinical Global Impression-Severity (CGI-S) and Improvement (CGI-I) scores. The median duration of ropinirole PR exposure was 1,069 days. Most subjects (97.6%) reported at least one AE, most commonly (>= 30%) nausea (42.2%), dizziness (41.0%), peripheral edema (38.6%), back pain (33.7%), and headache (31.3%). Seventeen (20.5%) subjects discontinued due to an AE. UPDRS and CGI scores indicated that the clinical status of subjects was maintained throughout the treatment period. In patients with early PD, long-term treatment with once-daily ropinirole PR was not associated with any new safety concerns, and was effective in maintaining clinical status. These results support the extended use of ropinirole PR for treatment of PD. PMID- 21244306 TI - Structured exercise does not stabilize cognitive function in individuals with mild cognitive impairment residing in a structured living facility. AB - Exercise has been shown to have positive effects on the brain and cognition in healthy older adults, though no study has directly examined possible cognitive benefits of formal exercise programs in persons with mild cognitive impairment (MCI) living in structured facilities. Thirty-one participants completed neuropsychological testing and measures of cardiovascular fitness at baseline and after 6 months of a structured exercise program that included aerobic and resistance training. While exercise improved cardiovascular fitness in persons with MCI, there was no improvement in cognitive function. Rather, MCI patients in this sample declined in performance on several tests sensitive to Alzheimer's disease. Examined in the context of past work, it appears exercise may be beneficial prior to the onset of MCI, though less helpful after its onset. PMID- 21244325 TI - Unique intracellular trafficking processes associated with neural cell adhesion molecule and its intracellular signaling. AB - Homophilic binding of the neural cell adhesion molecule (NCAM) results in intracellular signaling, which also involves heterophilic engagement of coreceptors such as the fibroblast growth factor receptor (FGFR) and receptor protein tyrosine phosphatase-alpha (RPTPalpha). NCAM's own cellular dynamic itinerary includes endocytosis and recycling to the plasma membrane. Recent works suggest that NCAM could influence the trafficking of other receptor molecules that it associates with, particularly the FGFR. Furthermore, it was demonstrated that NCAM could undergo proteolytic processing upon activation. A processed fragment of NCAM, together with an N-terminal fragment of focal adhesion kinase (FAK), is translocated into the nucleus. Here, the authors discuss these rather unique (though not without precedence and analogues) receptor trafficking activities that are associated with NCAM and NCAM signaling. PMID- 21244326 TI - Feasibility of measurement of a voice range profile with a semi-occluded vocal tract. AB - Semi-occlusion of the vocal tract may provide a new method for assessing ranges of F(0) and a physiological correlate of vocal intensity. Signals can be obtained without concern about room noise, steadiness in mouth-to-microphone distance, and possibly without vocal injury caused by excessive loudness produced. Nine volunteers participated. Steady and acoustic pressures behind the lips were measured. Traditional voice range profiles were obtained on the vowels /alpha/ and /u/ for comparison. Range of F(0) was not limited in most subjects with the semi-occlusion but may be restricted in some subjects. In the lower portion of the F(0) range, the highest and lowest steady pressures at the semi-occlusion constitute an oral pressure range profile. PMID- 21244327 TI - Emerging gonadotropin-releasing hormone agonists. AB - INTRODUCTION: Gonadotropin-releasing hormone agonist analogs (GnRHa) are peptides that mimic the action of gonadotropin-releasing hormone (GnRH) and are used to suppress subsequent sex steroid production. Although the analogs are a rather defined group of drugs, there have been developments in the past decades and there is still ample room for improvement. New therapeutic strategies in the use of GnRHs are discussed. AREAS COVERED: Major points of discussion include: i) the use of concomitant treatment of early breast cancer in premenopausal estrogen positive and -negative patients, ii) the use of GnRHa for fertility preservation in young female patients with malignant diseases and iii) the use of GnRH analogs in assisted reproduction. The manuscript provides a better understanding of GnRH agonists as well as an explanation of their major indications, biochemical pathways and concluding therapeutic strategies. Recent results from international meetings and debates are described to explain current controversies. EXPERT OPINION: This paper highlights the need for more complex GnRH analogs. In the next few years, there will be longer acting GnRHas that may improve adherence. New therapeutic targets in oncological concepts may go beyond fertility preservation and focus on the antiproliferative effects of GnRH analogs. PMID- 21244330 TI - CTLs' repertoire shaping in the thymus: a Monte Carlo simulation. AB - MOTIVATION: The human immune system evolved a multi-layered control mechanism to eliminate self-reactive cells. Of these so-called tolerance induction mechanisms, lymphocytes T education in the thymus gland represents the very first one. This complicated process is not fully understood and quantitative models able to help in this endeavor are lacking. Here, we present a stochastic computational model of the thymus which combines data-driven prediction methods and a novel method based on protein-protein potential measurements for assessing molecular binding among cell receptors, major histocompatibility complex (MHC) molecules, and self peptides. RESULTS: Of all possible specificities of immature T cells entering the thymus, only a small fraction is actually selected for maturation. Monte Carlo simulations of thymocytes selection in the thymus are performed varying the size of the self and a parameter determining the number of encounter with antigen presenting cells (APCs). We score the fraction of self-reacting thymocytes leaving the thymus as mature naive T cells and show that self-reactivity is only marginally dependent on the number of self-molecules presented by APCs, while it is strongly affected by a parameter proportional to the time spent in the thymus. We study how this measure changes when we vary the number of MHC alleles and found an optimal number not too different from what we have in reality. The main result of this study is more methodological than biological as we show that immunoinformatics data and methods can be used in systemic level simulation of immune processes. PMID- 21244328 TI - Topical immunomodulators for management of oral mucosal conditions, a systematic review; Part II: miscellaneous agents. AB - INTRODUCTION: Topical immunomodulating preparations have utility in inflammatory/immune-mediated oral mucosal disease resistant to topical steroids, in immunologically mediated systemic disease with primary oral involvement or more severe lesions primarily involving the oral mucosa. AREAS COVERED: This paper is the second part of a systematic review of a variety of topical immunomodulators for management of immune/inflammatory oral mucosal conditions. The literature search revealed studies of azathioprine, benzydamine, GM-CSF and G CSF, tetracyclines, retinoids, imiquimod, amlexanox, sirolimus and bacillus Calmette-Guerin polysaccharide nucleic acid. Weighted conclusions are provided for the topical use of each of the immunomodulators reviewed in the management of these oral diseases. EXPERT OPINION: Topical immunomodulators may be useful as second line treatment in several oral diseases, particularly oral lichen planus and recurrent aphthous stomatitis. Benzydamine was found to be preventive in radiotherapy-induced mucositis; however, it is unclear if this outcome is related to its immunomodulating effects or other mechanisms of action. Topical application of tetracyclines and retinoic acid also shows potential anti inflammatory actions. PMID- 21244331 TI - Design considerations in building in silico equivalents of common experimental influenza virus assays. AB - Experimentation in vitro is a vital part of the process by which the clinical and epidemiological characteristics of a particular influenza virus strain are determined. We detail the considerations which must be made in designing appropriate theoretical/mathematical models of these experiments and show how modeling can increase the information output of such experiments. Starting from a traditional system of ordinary differential equations, common to infectious disease modeling, we broaden the approach by using an agent-based model, applicable to more general experimental geometries and assumptions about the biological properties of viruses, cell and their interaction. Within this framework, we explore the limits of the assumptions made by more traditional models and the conditions under which these assumptions begin to break down, requiring the use of more sophisticated models. We apply the agent-based model to experimental plaque growth of two influenza strains, one resistant to the antiviral oseltamivir, and extract the values of key infection parameters specific to each strain. PMID- 21244332 TI - Transplantation of retrovirally transduced bone marrow prevents autoimmune disease in aged mice by peripheral tolerance mechanisms. AB - Transplantation of bone marrow (BM) engineered to express self-antigen has been shown to protect 100% of young mice from myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), with thymic clonal deletion as a tolerance mechanism. Here, we asked whether aged mice can also be tolerised following transplantation with self-antigen-engineered BM and whether castration-induced thymus regrowth can enhance this outcomes. Then, 50% of aged mice were protected from EAE regardless of castration-induced thymus regrowth. EAE-free and diseased mice demonstrated MOG-specific lymphocyte proliferation and antibody production regardless of castration-induced thymus regrowth, consistent with lack of intrathymic deletion of self-antigen-reactive T cells. Although low chimerism levels ( < 4%) were observed, EAE-free mice showed significantly higher chimerism levels in lymphocytes in peripheral lymphoid organs compared with thymus. CD4(+)CD25(+) regulatory T cells were elevated in lymph nodes of EAE-free mice. We conclude that transplantation of self-antigen expressing BM protects 50% of aged mice and castration-induced thymic regrowth had no effect on outcomes. Peripheral tolerance mechanisms are implicated since protection is associated with higher chimerism levels in peripheral T and B lymphocytes and with elevated regulatory T cells. PMID- 21244333 TI - Cognate interaction plays a key role in the surveillance of autoreactive B cells in induced mixed bone marrow chimerism in BXSB lupus mice. AB - The effects of bone marrow transplantation (BMT) as a treatment for and/or preventive measure against autoimmune diseases in mice were investigated extensively. The reconstitution of the hematopoietic system with a mixture of autologous and heterologous bone marrow cells was reported to suppress the development of autoimmune diseases. However, the pathological mechanism through which mixed chimerism results in the suppression of disease development is still unknown. We have previously reported that the induction of fully major histocompatibility complex (MHC)-mismatched allogeneic mixed chimerism can prevent the disease development in BXSB mice. Interestingly, serum anti-dsDNA IgM antibody (anti-DNA IgM) levels were not significantly decreased in these chimeric mice, though other symptoms of autoimmune disease were ameliorated. In this study, we showed that self-reactive anti-DNA IgM production was mainly attributable to genetically normal B cells from the donor rather than genetically deficient B cells from the host. Host-type B cells responded normally to foreign antigens and produced the appropriate antibodies. BMT from fully MHC-matched or haplo-identical donors could suppress the production of anti-DNA antibodies. Our present study suggests the existence of a surveillance system dependent on the recognition of MHC molecules on B cells. PMID- 21244334 TI - Peripheral blood lymphocytes analysis detects CD100/SEMA4D alteration in systemic sclerosis patients. AB - It was suggested that the immune system plays an important role at least in the amplification of the main elements in systemic sclerosis (SSc), an autoimmune disease with an incompletely elucidated pathogenesis. Elucidation of the mechanisms involved in the interaction between T and B cells, major players of the immune system, could contribute to a better understanding of some of clinical and pathological manifestations of SSc. Recently, abnormalities in Semaphorin 4D (Sema4D/CD100) or CD72, two contrareceptors involved in T and B cells cooperation, were associated with autoimmunity. Therefore, we investigated CD100 and CD72 expression level on T and B cells in attempting to establish their role in SSc pathogenesis. The results revealed augmented percentages of CD100(high) T and B cells, significantly increased expression of CD100 on CD4(+) T cells and frequently detectable levels of soluble CD100 in SSc patient sera compared to healthy donors. In SSc, CD100 dysregulations were associated with anti-Scl70 antibodies production, disease type, thickening of skin, disease duration, or with active inflammation processes. In consequence, dysregulations in CD100 expression and release could play a role in SSc development and/or maintenance. PMID- 21244335 TI - Inter- and intra-rater reliability of the manual handling component of the WorkHab Functional Capacity Evaluation. AB - The WorkHab Functional Capacity Evaluation (FCE) is widely used in Australian workplace injury management and occupational rehabilitation arenas; however, there is a lack of published literature regarding its reliability and validity. PURPOSE: This study investigated the intra- and inter-rater reliability of the manual handling component of this FCE. METHOD: A DVD was produced containing footage of the manual handling components of the WorkHab conducted with four injured workers. Therapist raters (n = 17) who were trained and accredited in use of the WorkHab FCE scored these components and 14 raters re-evaluated them after approximately 2 weeks. Ratings were compared using intraclass correlation coefficients (ICCs), paired sample t-tests (intra-rater), chi-squared (inter rater) and percentage agreement. RESULTS: Intra-rater agreement was high with ICCs for the manual handling components and manual handling score showing excellent reliability (0.94-0.98) and good reliability for identification of the safe maximal lift (ICC: 0.81). Overall inter-rater agreement ranged from good to excellent for the manual handling components and safe maximal lift determination (ICC > 0.9). Agreement for safe maximal lift identification was good. CONCLUSIONS: Ratings demonstrated substantial levels of intra-rater and inter rater reliability for the lifting components of the WorkHab FCEs. PMID- 21244336 TI - Nephritogenic antibodies bind in glomeruli through interaction with exposed chromatin fragments and not with renal cross-reactive antigens. AB - Cross-reactivity of anti-double stranded DNA (anti-dsDNA) antibodies with glomerular antigens has been postulated as a key factor in the development of lupus nephritis. Because no direct proof has been presented on anti-dsDNA antibodies binding in vivo to glomerular structures, we have analysed the binding of potentially nephritogenic anti-dsDNA antibodies to alpha-actinin and laminin. By enzyme-linked immunosorbent assay and surface plasmon resonance (SPR) analyses, we demonstrate that monoclonal antibodies (mAbs) bind both double stranded DNA and alpha-actinin at high affinity. However, when added to nephritic kidney sections they did not bind to such structures, but rather to nucleosome containing structures within the mesangial matrix or the glomerular basement membranes (GBMs). Nucleosomes, anti-nuclear antibodies and complexes of them were tested for their binding to glomerular components such as agrin, perlecan and laminin using SPR analysis. Nucleosomes bound to laminin, marginally to agrin, but not to perlecan or heparan sulphate-depleted agrin. Anti-histone H2B and anti nucleosome antibodies in complex with nucleosomes slightly increased the binding of nucleosomes to agrin, while binding to laminin was slightly decreased compared to nucleosomes alone. In conclusion, the availability of nucleosomal antigens and the binding of these antigens to components of the mesangial matrix and GBM seem crucial for the glomerular deposition of immune complexes. PMID- 21244338 TI - Ingested (oral) SST inhibits EAE. AB - BACKGROUND: Ingested immunoactive proteins type I interferon, soluble immune response suppressor peptide 1-21 and melanocyte-stimulating hormone inhibit clinical attacks and inflammation in acute experimental autoimmune encephalomyelitis (EAE). OBJECTIVE: We examined whether another immunoactive protein, somatostatin (SST), would have similar anti-inflammatory effects on EAE after oral administration. DESIGN/METHODS: B6 mice were immunized with MOG peptide 35-55 and gavaged with control saline or SST during ongoing disease. Splenocytes from mock-fed or SST-fed mice were adoptively transferred into active MOG peptide 35-55-immunized recipient mice during ongoing disease. RESULTS: In actively fed mice, increased Th2-like cytokines in both the spleen and the central nervous system (CNS) inhibited active disease. In recipients of donor cells from SST-fed donors, reduction of Th1 and Th17 and induction of Th2-like IL 4 cytokines in both the spleen and CNS inhibited disease. T(reg) cells were increased threefold in actively fed spleen cells that are responsible for protection against disease after adoptive transfer. CONCLUSIONS: Ingested (orally administered) SST can inhibit clinical disease, inhibit CNS inflammation by decreasing Th17 and Th1-like cytokines and increasing Th2-like cytokines in the CNS via induction of T(reg) cells. PMID- 21244337 TI - The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes. AB - AIMS: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative. METHODS: A total of 686 patients diagnosed in 1996-2005 in Skane were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes. RESULTS: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%-a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1(*)X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA. CONCLUSIONS: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1(*)X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials. PMID- 21244339 TI - IL-2 production by dendritic cells promotes Foxp3(+) regulatory T-cell expansion in autoimmune-resistant NOD congenic mice. AB - Il2 allelic variation in non-obese diabetic mice imparts marked resistance to type 1 diabetes. IL-2 is pivotal for the fitness and homeostasis of Foxp3(+) regulatory T (T(reg)) cells, and the Idd3(B6) locus augments IL-2 production by effector T cells, which in turn enhances the potency of T(reg) cell functions. Given the important role dendritic cells (DCs) play in T(reg) cell-mediated tolerance induction, we hypothesized that DCs from Idd3(B6) congenic mice contribute to increased T(reg) cell activity. Here, we observed that CD11c(+) DCs, harboring protective Idd3(B6) genes, are endowed with the capacity to secrete IL-2, enabling them to preferentially promote T(reg) cell functions in vitro and in vivo. Our results show that Il2 gene variation may imprint DCs to favor T-cell regulation of autoimmunity. PMID- 21244340 TI - Reactive animation: from piecemeal experimentation to reactive biological systems. AB - Over the past decade, multi-level complex behavior and reactive nature of biological systems, has been a focus point for the biomedical community. We have developed a computational approach, termed Reactive Animation (RA) for simulating such complex biological systems. RA is an approach for describing the dynamic characteristics of biological systems based on facts collected from experiments. These data are integrated bottom-up by computational tools and methods for reactive systems development and are simulated concomitantly to a front-end user friendly visualization and reporting systems. Using RA, the experimenter may intervene mid-simulation, suggest new hypotheses for cellular and molecular interactions, apply them to the simulation and observe their resulting outcomes "on-line". Several RA models have been developed including models of T cell activation, thymocyte development and pancreatic organogenesis, which are describe in the in this review. PMID- 21244341 TI - Bistability in autoimmune diseases. AB - Autoimmune diseases damage host tissue, which, in turn, may trigger a stronger immune response. Systems characterized by such positive feedback loops can display co-existing stable steady states. In a mathematical model of autoimmune disease, one steady state may correspond to the healthy state and another to an autoimmune steady state characterized by widespread tissue damage and immune activation. We show how a triggering event may move the system from the healthy to the autoimmune state and how transient immunosuppressive treatment can move the system back to the healthy state. PMID- 21244343 TI - The effects of high physical activity on pharmacokinetic drug interactions. AB - INTRODUCTION: With the development of new drugs, it is common practice for drug manufacturers to measure their pharmacokinetic parameters. This testing involves the discovery of the absorption, distribution, metabolic, excretory and toxicological properties of drugs. The testing is usually done in non-stressful conditions at rest, however, this does not necessarily tell the entire picture as there is increasing knowledge about the effects that high levels of physical activity can have on the pharmacokinetics of some medications. AREAS COVERED: This review discusses the alterations that physical activity can have on the absorption, distribution, metabolism and elimination parameters of commonly used medications, and clinical outcomes data are reported when known, demonstrating that an interaction exists between exercise and certain medications. This drug exercise pharmacokinetic interaction alters the performance of medications especially under conditions where exercise is performed for a long period of time. Particular medications that may be affected are those with a narrow therapeutic dosing range, such as digoxin, theophylline and warfarin. Other important medications include insulin and those administered via a transdermal patch drug delivery system. For this review, a literature search was performed between 1966 and 2010. EXPERT OPINION: Patients and healthcare providers should be aware that exercise can adversely affect the way some medications are intended to work. Patients taking certain medications should be closely monitored when performing high amounts of physical activity. PMID- 21244342 TI - Safety evaluation of colesevelam therapy to achieve glycemic and lipid goals in type 2 diabetes. AB - INTRODUCTION: Patients with hypercholesterolemia and type 2 diabetes mellitus often require multiple medications to attain their LDL-C and A1C goals. Colesevelam, a bile acid sequestrant (BAS), which was FDA approved 10 years ago for the reduction of LDL-C in patients with dyslipidemia is also the only BAS that is approved for glycemic control in adults with type 2 diabetes to date. From both the physician and patient standpoint, safety and tolerability are the most important factors when considering initiating pharmacological therapy. Several randomized controlled studies have examined the safety, tolerability and efficacy of colesevelam over the last decade. AREAS COVERED: This manuscript focuses on the safety and tolerability based on the evaluation of data obtained from several human randomized controlled studies. In addition, the pharmacology, pharmacodynamics and key clinical efficacy data are reviewed using research articles accessed through MEDLINE/PubMed (2000 - 2010). EXPERT OPINION: Current data suggest that colesevelam is safe, well tolerated and offers the potential for improved adherence. Colesevelam is a valid option for long-term therapy for patients with hypercholesterolemia and type 2 diabetes. It can be used in combination with HMG-CoA reductase inhibitors for hypercholesterolemia, not controlled at their cholesterol goals with HMG-CoA reductase inhibitors, and should be considered in patients with type 2 diabetes mellitus with concomitant hypercholesterolemia to improve both risk factors. PMID- 21244344 TI - Update on the endocannabinoid system as an anticancer target. AB - INTRODUCTION: Recent studies have shown that the endocannabinoid system (ECS) could offer an attractive antitumor target. Numerous findings suggest the involvement of this system (constituted mainly by cannabinoid receptors, endogenous compounds and the enzymes for their synthesis and degradation) in cancer cell growth in vitro and in vivo. AREAS COVERED: This review covers literature from the past decade which highlights the potential of targeting the ECS for cancer treatment. In particular, the levels of endocannabinoids and the expression of their receptors in several types of cancer are discussed, along with the signaling pathways involved in the endocannabinoid antitumor effects. Furthermore, the beneficial and adverse effects of old and novel compounds in clinical use are discussed. EXPERT OPINION: One direction that should be pursued in antitumor therapy is to select compounds with reduced psychoactivity. This is known to be connected to the CB1 receptor; thus, targeting the CB2 receptor is a popular objective. CB1 receptors could be maintained as a target to design new compounds, and mixed CB1-CB2 ligands could be effective if they are able to not cross the BBB. Furthermore, targeting the ECS with agents that activate cannabinoid receptors or inhibitors of endogenous degrading systems such as fatty acid amide hydrolase inhibitors may have relevant therapeutic impact on tumor growth. Additional studies into the downstream consequences of endocannabinoid treatment are required and may illuminate other potential therapeutic targets. PMID- 21244346 TI - Role of intestinal transporters and metabolism in the oral absorption of drug and prodrugs. PMID- 21244347 TI - Multidrug resistance: genes, polymorphisms, biologic effects, reversal and treatment in cancer chemotherapy. PMID- 21244348 TI - How should we deal with missing data in clinical trials involving Alzheimer's disease patients? AB - Missing data are frequent in Alzheimer's disease (AD) trials due to the age of participants and the nature of the disease. This can lead to bias and decreased statistical power. We assessed the level and causes of missing data in a 2-year randomised trial of an AD patient management program (PLASA study), and conducted sensitivity analyses on the primary endpoint (functional decline), using various methods for handling missing data: complete case, LOCF, Z-score LOCF, longitudinal mixed effects model, multiple imputation. By 2 years, 32% of the 1131 subjects had dropped out, with the commonest reasons being death (28% of dropouts) and refusal (22%). Baseline cognitive and functional status were predictive of dropout. All sensitivity analyses led to the same conclusion: no effect of the intervention on the rate of functional decline. All analyses demonstrated significant functional decline over time in both groups, but the magnitude of decline and between-group (intervention versus usual care) differences varied across methods. In particular, the LOCF analysis substantially underestimated 2-year decline in both groups compared to other methods. Our results suggest that data were not "missing completely at random", meaning that the complete case method was unsuitable. The LOCF method was also unsuitable since it assumes no decline after dropout. Methods based on the more plausible "missing at random" hypothesis (multiple imputation, longitudinal mixed effects models, z-score LOCF) appeared more appropriate. This work highlights the importance of considering the validity of the underlying hypotheses of methods used for handling missing data in AD trials. PMID- 21244345 TI - Calpains as potential anti-cancer targets. AB - INTRODUCTION: The intracellular signaling cysteine proteases, calpains (specifically the ubiquitous calpains 1 and 2), are involved in numerous physiological and pathological phenomena. Several works have highlighted the implication of calpains in processes crucial for cancer development and progression. For these reasons, calpains are considered by several authors as potential anti-cancer targets. AREAS COVERED: How calpains are implicated in cancer formation and development, how these enzymes are deregulated in cancer cells and how these proteases could be targeted by anti-cancer drugs. Studies published in the last 10 years are focused on. EXPERT OPINION: Targeting calpain activity with specific inhibitors could be a novel approach to limiting development of primary tumors and formation of metastases, by inhibiting tumor cell migration and invasion, which allows dissemination as well as tumor neovascularization, which in turn allows expansion. However, such drugs could interfere with anti-cancer treatments, as ubiquitous calpains play crucial roles in chemotherapy-induced apoptosis. For these reasons, drugs targeting calpains would have to be used selectively to avoid interference with other treatments and physiological processes. Further studies will be required concerning the other members of the calpain family and their potential implication in cancer development before considering treatments targeting their activity. PMID- 21244349 TI - The potential dual effects of anesthetic isoflurane on Abeta-induced apoptosis. AB - beta-amyloid protein (Abeta)-induced neurotoxicity is the main component of Alzheimer's disease (AD) neuropathogenesis. Inhalation anesthetics have long been considered to protect against neurotoxicity. However, recent research studies have suggested that the inhalation anesthetic isoflurane may promote neurotoxicity by inducing apoptosis and increasing Abeta levels. We therefore set out to determine whether isoflurane can induce dose- and time-dependent dual effects on Abeta-induced apoptosis: protection versus promotion. H4 human neuroglioma cells, primary neurons from naive mice, and naive mice were treated with Abeta and/or isoflurane, and levels of caspase-3 cleavage (activation), apoptosis, Bcl-2, Bax, and cytosolic calcium were determined. Here we show for the first time that the treatment with 2% isoflurane for six hours or 30 minutes potentiated, whereas the treatment with 0.5% isoflurane for six hours or 30 minutes attenuated, the Abeta-induced caspase-3 activation and apoptosis in vitro. Moreover, anesthesia with 1.4% isoflurane for two hours potentiated, whereas the anesthesia with 0.7% isoflurane for 30 minutes attenuated, the Abeta induced caspase-3 activation in vivo. The high concentration isoflurane potentiated the Abeta-induced reduction in Bcl-2/Bax ratio and caused a robust elevation of cytosolic calcium levels. The low concentration isoflurane attenuated the Abeta-induced reduction in Bcl-2/Bax ratio and caused only a mild elevation of cytosolic calcium levels. These results suggest that isoflurane may have dual effects (protection or promotion) on Abeta-induced toxicity, which potentially act through the Bcl-2 family proteins and cytosolic calcium. These findings would lead to more systematic studies to determine the potential dual effects of anesthetics on AD-associated neurotoxicity. PMID- 21244350 TI - Determination of spatial and temporal distribution of microglia by 230nm-high resolution, high-throughput automated analysis reveals different amyloid plaque populations in an APP/PS1 mouse model of Alzheimer's disease. AB - One early and prominent pathologic feature of Alzheimer's disease (AD) is the appearance of activated microglia in the vicinity of developing beta-amyloid deposits. However, the precise role of microglia during the course of AD is still under discussion. Microglia have been reported to degrade and clear beta-amyloid, but they also can exert deleterious effects due to overwhelming inflammatory reactions. Here, we demonstrate the occurrence of developing plaque populations with distinct amounts of associated microglia using time-dependent analyses of plaque morphology and the spatial distribution of microglia in an APP/PS1 mouse model. In addition to a population of larger plaques (>700um(2)) that are occupied by a moderate contingent of microglial cells across the course of aging, a second type of small beta-amyloid deposits develops (<=400um(2)) in which the plaque core is enveloped by a relatively large number of microglia. Our analyses indicate that microglia are strongly activated early in the emergence of senile plaques, but that activation is diminished in the later stages of plaque evolution (>150 days). These findings support the view that microglia serve to restrict the growth of senile plaques, and do so in a way that minimizes local inflammatory damage to other components of the brain. PMID- 21244351 TI - Abeta oligomers induce glutamate release from hippocampal neurons. AB - Soluble oligomers of the amyloid-beta peptide (AbetaOs) accumulate in Alzheimer's disease (AD) brain and have been implicated in mechanisms of pathogenesis. The neurotoxicity of AbetaOs appears to be, at least in part, due to dysregulation of glutamate signaling. Here, we show that AbetaOs promote extracellular accumulation of glutamate and d-serine, a co-agonist at glutamate receptors of the N-methyl-d-aspartate subtype (NMDARs), in hippocampal neuronal cultures. The increase in extracellular glutamate levels induced by AbetaOs was blocked by the sodium channel blocker tetrodotoxin (TTX), by the NMDAR blocker (+)-5-methyl 10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) and by removal of Ca(2+) from the extracellular medium, indicating dependence on excitatory neuronal activity. AbetaOs enhanced both the release of pre-synaptic vesicles labeled by FM1-43 and spontaneous post-synaptic activity measured by whole-cell patch-clamp. Activation of inhibitory GABA(A) receptors by taurine blocked the increase in extracellular glutamate levels, suggesting that selective pharmacological inhibition of neuronal activity can counteract the impact of AbOs on glutamate dyshomeostasis. Results reveal a novel mechanism by which Ab oligomers promote abnormal release of glutamate in hippocampal neurons, which may contribute to dysregulation of excitatory signaling in the brain. PMID- 21244354 TI - The mechanism of memory impairment induced by Abeta chronic administration involves imbalance between cytokines and neurotrophins in the rat hippocampus. AB - It has been demonstrated that the onset and progression of Alzheimer's disease (AD) are associated with inflammatory disorders in the brain. Although the interactions of inflammatory cytokines with neurotrophins have been reported in vitro, the balance change between inflammatory cytokines and neurotrophic factors (NTFs), such as nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF), due to amyloid beta (Abeta) chronic administration in vivo is still unclear. The hypothesis of the present study was that the accumulation of Abeta activated glial cells to produce inflammatory mediators and NTFs to maintain the neurons survival, however the failure of crosstalk between NTFs and inflammatory cytokines might occur in the brain and the NTFs expressions would decrease after Abeta chronic treatment, which, therefore, would contribute to the neuronal death and memory impairments. Thus, the present study measured the learning and memory behavior, glial cells activities, cytokines (IL-1alpha, IL-1beta and TNF-alpha) concentrations and NTFs (NGF, BDNF and GDNF) gene and protein levels in rats after i.c.v injection of Abeta(25-35) for 14 days. The results showed that Abeta (25-35)-treated animals exhibited failure of balance between inflammatory cytokines and NTFs system (increased cytokines levels, decreased NGF protein expression and reduced NTFs gene transcriptions), which might contribute to the cognitive impairments. The findings from this study provide valuable evidence that correct regulation of the crosstalk between inflammatory cytokines and NTFs could be a direction for AD therapy in the future. PMID- 21244352 TI - Cholesterol and LDL relate to neuritic plaques and to APOE4 presence but not to neurofibrillary tangles. AB - Elevated serum total cholesterol (TC) has been considered a risk factor for Alzheimer's disease (AD), but conflicting results have confused understanding of the relationships of serum lipids to the presence of AD in the elderly. METHODS: To clarify these issues, we evaluated correlations of admission TC, low-density (LDL) and high-density (HDL)cholesterol directly with the densities of Alzheimer hallmarks--neuritic plaques (NP) and neurofibrillary tangles (NFT)--in nursing home residents (n=281). RESULTS: Significant positive associations of TC and LDL with NP densities were found in both the neocortex (TC: r=0.151, p=0.013 and LDL: r=0.190, p=0.005) and the hippocampal/entorhinal (allocortical)region (TC: r=0.182, p=0.002 and LDL: r=0.203, p=0.003). Associations of HDL with NP were less strong but also significant.In contrast, after adjustment for confounders, no correlations of NFT with any lipid were significant.When subjects with any non AD neuropathology (largely vascular) were excluded, the TC-plaque and LDL-plaque associations for the remaining "Pure AD" subgroup were consistently stronger than for the full sample. The TC- and LDL-plaque correlations were also stronger for the subgroup of 87 subjects with an APOE epsilon4 allele. CONCLUSIONS: The findings indicate that serum TC and LDL levels clearly relate to densities of NP, but not to densities of NFT. The stronger associations found in the subgroup that excluded all subjects with non-AD neuropathology suggest that cerebrovascular involvement does not explain these lipid-plaque relationships. Since the associations of TC/LDL with NP were particularly stronger in epsilon4 carriers, varying prevalence of this allele may explain some discrepancies among prior studies. PMID- 21244353 TI - Biochemical differentiation of cholinesterases from normal and Alzheimer's disease cortex. AB - In Alzheimer's disease, histochemically visualized cholinesterases with altered pH optimum for activity and inhibitable by indoleamines and the protease inhibitor bacitracin emerge in association with plaques and tangles. It has been suggested that these cholinesterases may participate in the pathologic process. However, it is not known whether the properties of cholinesterases observed in Alzheimer's disease are due to requirements of histochemical procedures or actual biochemical properties of these enzymes. Using biochemical assays of acetylcholinesterase and butyrylcholinesterase activities, we demonstrate here that serotonin and bacitracin result in a significantly greater and dose dependent inhibition of cholinesterases in Alzheimer's disease cortex when compared with age-matched controls. In contrast, variations in pH did not distinguish cholinesterases in Alzheimer's disease and control cortex. We also confirmed significant reduction of acetylcholinesterase activity in Alzheimer's disease cortex and increased butyrylcholinesterase activity that only approached significance. We conclude that inhibition by indoleamines and bacitracin is a biochemical characteristic of a proportion of cholinesterases in Alzheimer's disease that most likely represents the pool associated with plaques and tangles. Most of the available cholinesterase inhibitors are relatively incapable of inhibiting cholinesterases associated with plaques and tangles. The findings of the present investigation open the way for attempts to isolate cholinesterases associated with plaques and tangles and design or discovery of inhibitors specifically targeted to cholinesterases in these lesions. PMID- 21244355 TI - Simvastatin and other HMG-CoA reductase inhibitors on brain cholesterol levels in Alzheimer's disease. AB - Alzheimer's disease, one of the most common forms of dementia, is a neurodegenerative disorder characterized by progressive cognitive decline and affects as many as 5.3 million people in United States alone. Both Alzheimer's and dementia have tripled the cost of health care for elderly people, amounting to about $148 billion each year. Although there have been numerous drugs designed so far, no ideal or successful drug treatment for Alzheimer's and dementia has been translated into clinical setups. One of the most widely accepted theories of Alzheimer's pathology is the aggregation of amyloid-beta (Abeta) into extracellular cortical and hippocampal plaques. It has also been postulated that excessive cholesterol build-up in the brain plays an integral role in Abeta aggregation, and using HMG-coA reductase inhibitors may reduce Abeta accumulation by lowering brain cholesterol levels. Based on the success of animal studies and phase II clinical trials, HMG-coA reductase inhibitors may provide a viable alternative therapy in AD treatment. This review highlights the results of both pre-clinical and clinical trials on HMG-coA reductase inhibitors in order to give a comprehensive overview of their recent progress in Alzheimer's disease research. PMID- 21244356 TI - Mitochondria: the common upstream driver of amyloid-beta and tau pathology in Alzheimer's disease. AB - Mitochondrial dysfunction has been widely implicated in the etiology of Alzheimer's disease (AD). Evidence shows a mitochondrial-mediated impairment of autophagy that potentiates amyloid-beta (Abeta) deposition. Accordingly, recent data obtained from AD models, in which mitochondrial alterations are a prominent feature, demonstrated abnormalities in microtubule network, involving tubulin and tau post-translational modifications. In this review we will discuss mitochondrial-regulated processes where mitochondrial malfunction is likely to start a sequence of events leading to sirtuin-2 activation, microtubule network breakdown, and impairment of the autophagic pathway. Because sirtuin-2 activity depends on cellular NAD+ availability, mitochondrial regulation of NAD+ levels may contribute to an increase in sirtuin-mediated tubulin deacetylation. A vicious cycle become installed which potentiates tau hyperphosphorylation, together with Abeta overproduction and deposition. Overall, targeting microtubule network constitutes a promising strategy for pharmacological therapy in AD. PMID- 21244357 TI - Application of NMR spectroscopy in medicinal chemistry and drug discovery. PMID- 21244358 TI - Applying induced fit in drug discovery: square pegs and round holes? PMID- 21244359 TI - Melatonin-mitochondria interplay in health and disease. AB - Although two main hypotheses of mitochondrial origin have been proposed, i.e., the autogenous and the endosymbiotic, only the second is being seriously considered currently. The 'hydrogen hypothesis' invokes metabolic symbiosis as the driving force for a symbiotic association between an anaerobic, strictly hydrogen-dependent (the host) and an eubacterium (the symbiont) that was able to respire, but which generated molecular hydrogen as an end product of anaerobic metabolism. The resulting proto-eukaryotic cell would have acquired the essentials of eukaryotic energy metabolism, evolving not only aerobic respiration, but also the physiological cost of the oxygen consumption, i.e., generation of reactive oxygen species (ROS) and the associated oxidative damage. This is not the only price to pay for respiring oxygen: mitochondria possess nitric oxide (NO.) for regulatory purposes but, in some instances it may react with superoxide anion radical to produce the toxic reactive nitrogen species (RNS), i.e. peroxynitrite anion, and the subsequent nitrosative damage. New mitochondria contain their own genome with a modified genetic code that is highly conserved among mammals. The transcription of certain mitochondrial genes may depend on the redox potential of the mitochondrial membrane. Mitochondria are related to the life and death of cells. They are involved in energy production and conservation, having an uncoupling mechanism to produce heat instead of ATP, but they are also involved in programmed cell death. Increasing evidence suggest the participation of mitochondria in neurodegenerative and neuromuscular diseases involving alterations in both nuclear (nDNA) and mitochondrial (mtDNA) DNA. Melatonin is a known powerful antioxidant and anti-inflammatory and increasing experimental and clinical evidence shows its beneficial effects against oxidative/nitrosative stress status, including that involving mitochondrial dysfunction. This review summarizes the data and mechanisms of action of melatonin in relation to mitochondrial pathologies. PMID- 21244360 TI - TRP channels: from understanding to action. PMID- 21244361 TI - Structure and mechanism of the chalcogen-detoxifying protein TehB from Escherichia coli. AB - The oxyanion derivatives of the chalcogens tellurium and selenium are toxic to living organisms even at very low levels. Bacteria have developed mechanisms to overcome their toxicity by methylating them. The structure of TehB from Escherichia coli has been determined in the presence of the cofactor analogues SAH (S-adenosylhomocysteine) and sinefungin (a non-hydrolysable form of S adenosyl-L-methionine) at 1.48 A (1 A=0.1 nm) and 1.9 A respectively. Interestingly, our kinetic data show that TehB does not discriminate between selenium or tellurite oxyanions, making it a very powerful detoxifying protein. Analysis of the active site has identified three conserved residues that are capable of binding and orientating the metals for nucleophilic attack: His176, Arg177 and Arg184. Mutagenesis studies revealed that the H176A and R184A mutants retained most of their activity, whereas the R177A mutant had 65% of its activity abolished. Based on the structure and kinetic data we propose an SN2 nucleophilic attack reaction mechanism. These data provide the first molecular understanding of the detoxification of chalcogens by bacteria. PMID- 21244362 TI - Observation of fast release of NO from ferrous d1 haem allows formulation of a unified reaction mechanism for cytochrome cd1 nitrite reductases. AB - Cytochrome cd1 nitrite reductase is a haem-containing enzyme responsible for the reduction of nitrite into NO, a key step in the anaerobic respiratory process of denitrification. The active site of cytochrome cd1 contains the unique d1 haem cofactor, from which NO must be released. In general, reduced haems bind NO tightly relative to oxidized haems. In the present paper, we present experimental evidence that the reduced d1 haem of cytochrome cd1 from Paracoccus pantotrophus releases NO rapidly (k=65-200 s(-1)); this result suggests that NO release is the rate-limiting step of the catalytic cycle (turnover number=72 s(-1)). We also demonstrate, using a complex of the d1 haem and apomyoglobin, that the rapid dissociation of NO is largely controlled by the d1 haem cofactor itself. We present a reaction mechanism proposed to be applicable to all cytochromes cd1 and conclude that the d1 haem has evolved to have low affinity for NO, as compared with other ferrous haems. PMID- 21244364 TI - IGF-1 and atherothrombosis: relevance to pathophysiology and therapy. AB - IGF-1 (insulin-like growth factor-1) plays a unique role in the cell protection of multiple systems, where its fine-tuned signal transduction helps to preserve tissues from hypoxia, ischaemia and oxidative stress, thus mediating functional homoeostatic adjustments. In contrast, its deprivation results in apoptosis and dysfunction. Many prospective epidemiological surveys have associated low IGF-1 levels with late mortality, MI (myocardial infarction), HF (heart failure) and diabetes. Interventional studies suggest that IGF-1 has anti-atherogenic actions, owing to its multifaceted impact on cardiovascular risk factors and diseases. The metabolic ability of IGF-1 in coupling vasodilation with improved function plays a key role in these actions. The endothelial-protective, anti-platelet and anti thrombotic activities of IGF-1 exert critical effects in preventing both vascular damage and mechanisms that lead to unstable coronary plaques and syndromes. The pro-survival and anti-inflammatory short-term properties of IGF-1 appear to reduce infarct size and improve LV (left ventricular) remodelling after MI. An immune-modulatory ability, which is able to suppress 'friendly fire' and autoreactivity, is a proposed important additional mechanism explaining the anti thrombotic and anti-remodelling activities of IGF-1. The concern of cancer risk raised by long-term therapy with IGF-1, however, deserves further study. In the present review, we discuss the large body of published evidence and review data on rhIGF-1 (recombinant human IGF-1) administration in cardiovascular disease and diabetes, with a focus on dosage and safety issues. Perhaps the time has come for the regenerative properties of IGF-1 to be assessed as a new pharmacological tool in cardiovascular medicine. PMID- 21244363 TI - Aging and vascular endothelial function in humans. AB - Advancing age is the major risk factor for the development of CVD (cardiovascular diseases). This is attributable, in part, to the development of vascular endothelial dysfunction, as indicated by reduced peripheral artery EDD (endothelium-dependent dilation) in response to chemical [typically ACh (acetylcholine)] or mechanical (intravascular shear) stimuli. Reduced bioavailability of the endothelium-synthesized dilating molecule NO (nitric oxide) as a result of oxidative stress is the key mechanism mediating reduced EDD with aging. Vascular oxidative stress increases with age as a consequence of greater production of reactive oxygen species (e.g. superoxide) without a compensatory increase in antioxidant defences. Sources of increased superoxide production include up-regulation of the oxidant enzyme NADPH oxidase, uncoupling of the normally NO-producing enzyme, eNOS (endothelial NO synthase) (due to reduced availability of the cofactor tetrahydrobiopterin) and increased mitochondrial synthesis during oxidative phosphorylation. Increased bioactivity of the potent endothelial-derived constricting factor ET-1 (endothelin-1), reduced endothelial production of/responsiveness to dilatory prostaglandins, the development of vascular inflammation, formation of AGEs (advanced glycation end products), an increased rate of endothelial apoptosis and reduced expression of oestrogen receptor alpha (in postmenopausal females) also probably contribute to impaired EDD with aging. Several lifestyle and biological factors modulate vascular endothelial function with aging, including regular aerobic exercise, dietary factors (e.g. processed compared with non-processed foods), body weight/fatness, vitamin D status, menopause/oestrogen deficiency and a number of conventional and non-conventional risk factors for CVD. Given the number of older adults now and in the future, more information is needed on effective strategies for the prevention and treatment of vascular endothelial aging. PMID- 21244365 TI - Endoplasmic reticulum stress induced by hepatitis B virus X protein enhances cyclo-oxygenase 2 expression via activating transcription factor 4. AB - Chronic hepatitis B is a disease of the liver that can progress to cirrhosis and liver cancer. The HBx (hepatitis B virus X) protein of hepatitis B virus is a multifunctional regulator that induces ER (endoplasmic reticulum) stress by previously unknown mechanisms. ER stress plays a critical role in inflammatory induction and COX2 (cyclo-oxygenase 2) is an important mediator of this inflammation. In the present study, we demonstrate the molecular mechanisms of HBx on induction of ER stress and COX2 expression. In addition, HBx reduced expression of enzymes which are involved in mitochondrial beta-oxidation of fatty acids and the mitochondrial inner membrane potential. The reduction in intracellular ATP levels by HBx induced the unfolded protein response and COX2 expression through the eIF2alpha (eukaryotic initiation factor 2alpha)/ATF4 (activating transcription factor 4) pathway. We confirmed that ATF4 binding to the COX2 promoter plays a critical role in HBx-mediated COX2 induction. The results of the present study suggest that HBV infection contributes to induction of hepatic inflammation through dysfunction of cellular organelles including the ER and mitochondria. PMID- 21244366 TI - Grape seed procyanidin B2 inhibits advanced glycation end product-induced endothelial cell apoptosis through regulating GSK3beta phosphorylation. AB - To investigate the effects of GSPB2 (grape seed procyanidin B2) on the apoptosis of HUVECs (human umbilical endothelial cells) induced by AGEs (advanced glycation end products), HUVECs were treated with AGEs (200 MUg/ml) in the presence or absence of GSPB2 (2.5, 5.0 and 10.0 MUmol/l). Our findings showed that (i) AGEs induced HUVEC apoptosis and up-regulated the expression of caspase-3 activation and lactadherin and reduced the phosphorylation of GSK3beta (glycogen synthase kinase 3beta) at baseline. (ii) Treatment of HUVEC with GSPB2 significantly inhibited the cell apoptosis and the expression of caspase-3 activation and lactadherin induced by AGEs. Moreover, GSPB2 inhibited intracellular reactive oxygen species in a dose-dependent manner in AGEs-treated cells as determined by flow cytometry. (iii) GSPB2 increased the phosphorylation of GSK3beta of HUVEC in response to AGEs. These findings suggest that the signalling pathway involving phosphorylation of GSK3beta and lactadherin might play a key role in the endothelial apoptosis. GSPB2 therapy could become an effective approach to battling AGEs-induced endothelial apoptosis. PMID- 21244367 TI - Adipogenic differentiation and EGFP gene transfection of amniotic fluid-derived stem cells from goat fetus at terminal gestational age. AB - The aims of this study were to determine whether stem cells could be isolated from amniotic fluid of goat fetus at terminal gestational age and to determine if these stem cells could differentiate into adipogenic cells and be transfected with a reporter gene, EGFP (enhanced green fluorescent protein). The stem cells were isolated from amniotic fluid of goat fetus at terminal gestational age, induced to differentiate into adipogenic cells in vitro and transfected with the EGFP gene using lipofection. Markers associated with undifferentiated AFS (amniotic fluid-derived stem) cells were tested by RT (reverse transcription) PCR. The results demonstrated that AFS cells could be isolated from amniotic fluid of goat fetus at terminal gestational age and could differentiate into adipogenic cells. The EGFP gene was transfected into AFS cells successfully. EGFP gene transfection efficiency of the three groups of transgenic AFS cells were 26.0, 29.9 and 30.5%, respectively. Both transgenic and wild-type AFS cells could express Hes1 (hairy and enhancer of split 1), Oct4 (octamer-binding protein 4) and Nanog. PMID- 21244368 TI - Regulation of renal sympathetic neurotransmission by renal alpha(2A) adrenoceptors is impaired in chronic renal failure. AB - BACKGROUND AND PURPOSE: The mechanisms underlying increased renal noradrenaline in renal failure are still unclear. In this study, the role of alpha(2A) adrenoceptors in controlling sympathetic neurotransmission in chronic renal failure was evaluated in a subtotal nephrectomy model. Also, the influence of this receptor subtype on angiotensin II (Ang II)-mediated noradrenaline release was evaluated. EXPERIMENTAL APPROACH: alpha(2A)-adrenoceptor-knockout (KO) and wild-type (WT) mice underwent subtotal (5/6) nephrectomy (SNx) or SHAM-operation (SHAM). Kidneys of WT and KO mice were isolated and perfused. Renal nerves were stimulated with platinum electrodes and noradrenaline release was measured by HPLC. KEY RESULTS: Noradrenaline release induced by renal nerve stimulation (RNS) was significantly increased in WT mice after SNx. RNS-induced noradrenaline release was significantly higher in SHAM-KO compared with SHAM-WT, but no further increase in noradrenaline release could be observed in SNx-KO. alpha-adrenoceptor antagonists increased RNS-induced noradrenaline release in SHAM-WT but not in SHAM-KO. After SNx, the effect of alpha2-adrenoceptor blockade on renal noradrenaline release was attenuated in WT mice. The mRNA expression of alpha(2A) adrenoceptors was not altered, but the inhibitory effect of alpha2-adrenoceptor agonists on cAMP formation was abolished after SNx. Ang II facilitated RNS induced noradrenaline release in SHAM-WT but not in SHAM-KO and SNx-WT. CONCLUSION AND IMPLICATIONS: In our model of renal failure autoregulation of renal sympathetic neurotransmission was impaired. Presynaptic inhibition of noradrenaline release was diminished and the facilitatory effect of presynaptic angiotensin AT1 receptors on noradrenaline release was markedly decreased in renal failure and depended on functioning alpha(2A)-adrenoceptors. PMID- 21244369 TI - Vascular hyperpolarization to beta-adrenoceptor agonists evokes spreading dilatation in rat isolated mesenteric arteries. AB - BACKGROUND AND PURPOSE: beta-Adrenoceptor stimulation causes pronounced vasodilatation associated with smooth muscle hyperpolarization. Although the hyperpolarization is known to reflect K(ATP) channel activation, it is not known to what extent it contributes to vasodilatation. EXPERIMENTAL APPROACH: Smooth muscle membrane potential and tension were measured simultaneously in small mesenteric arteries in a wire myograph. The spread of vasodilatation over distance was assessed in pressurized arteries following localized intraluminal perfusion of either isoprenaline, adrenaline or noradrenaline. KEY RESULTS: Isoprenaline stimulated rapid smooth muscle relaxation associated at higher concentrations with robust hyperpolarization. Noradrenaline or adrenaline evoked a similar hyperpolarization to isoprenaline if the alpha(1)-adrenoceptor antagonist prazosin was present. With each agonist, glibenclamide blocked hyperpolarization without reducing relaxation. Focal, intraluminal application of isoprenaline, noradrenaline or adrenaline during block of alpha(1)-adrenoceptors evoked a dilatation that spread along the entire length of the isolated artery. This response was endothelium-dependent and inhibited by glibenclamide. CONCLUSIONS AND IMPLICATIONS: Hyperpolarization is not essential for beta adrenoceptor-mediated vasodilatation. However, following focal beta-adrenoceptor stimulation, this hyperpolarization underlies the ability of vasodilatation to spread along the artery wall. The consequent spread of vasodilatation is dependent upon the endothelium and likely to be of physiological relevance in the coordination of tissue blood flow. PMID- 21244370 TI - Lymphocyte function antigen-1 regulates neutrophil recruitment and tissue damage in acute pancreatitis. AB - BACKGROUND AND PURPOSE: Leucocyte infiltration is a rate-limiting step in the pathophysiology of acute pancreatitis (AP) although the adhesive mechanisms supporting leucocyte-endothelium interactions in the pancreas remain elusive. The aim of this study was to define the role of lymphocyte function antigen-1 (LFA-1) in regulating neutrophil-endothelium interactions and tissue damage in severe AP. EXPERIMENTAL APPROACH: Pancreatitis was induced by retrograde infusion of sodium taurocholate into the pancreatic duct in mice. LFA-1 gene-targeted mice and an antibody directed against LFA-1 were used to define the role of LFA-1. KEY RESULTS: Taurocholate challenge caused a clear-cut increase in serum amylase, neutrophil infiltration, CXCL2 (macrophage inflammatory protein-2) formation, trypsinogen activation and tissue damage in the pancreas. Inhibition of LFA-1 function markedly reduced taurocholate-induced amylase levels, accumulation of neutrophils, production of CXC chemokines and tissue damage in the pancreas. Notably, intravital microscopy revealed that inhibition of LFA-1 abolished taurocholate-induced leucocyte adhesion in postcapillary venules of the pancreas. In addition, pulmonary infiltration of neutrophils was attenuated by inhibition of LFA-1 in mice challenged with taurocholate. However, interference with LFA-1 had no effect on taurocholate-induced activation of trypsinogen in the pancreas. CONCLUSIONS AND IMPLICATIONS: Our novel data suggest that LFA-1 plays a key role in regulating neutrophil recruitment, CXCL2 formation and tissue injury in the pancreas. Moreover, these results suggest that LFA-1-mediated inflammation is a downstream component of trypsinogen activation in the pathophysiology of AP. Thus, we conclude that targeting LFA-1 may be a useful approach to protect against pathological inflammation in the pancreas. PMID- 21244371 TI - Inhibitor of PI3Kgamma ameliorates TNBS-induced colitis in mice by affecting the functional activity of CD4+CD25+FoxP3+ regulatory T cells. AB - BACKGROUND AND PURPOSE: Phosphoinositide 3-kinase-gamma (PI3Kgamma) is implicated in many pathophysiological conditions, and recent evidence has suggested its involvement in colitis. In the present study, we investigated the effects of AS605240, a relatively selective PI3Kgamma inhibitor, in experimental colitis and its underlying mechanisms. EXPERIMENTAL APPROACH: Acute colitis was induced in mice by treatment with trinitrobenzene sulphonic acid (TNBS), and the effect of AS605240 on colonic injury was assessed. Pro-inflammatory mediators and cytokines were measured by immunohistochemistry, elisa, real time-polymerase chain reaction and flow cytometry. KEY RESULTS: Oral administration of AS605240 significantly attenuated TNBS-induced acute colitis and diminished the expression of matrix metalloproteinase-9 and vascular endothelial growth factor. The colonic levels and expression of IL-1beta, CXCL-1/KC, MIP-2 and TNF-alpha were also reduced following therapeutic treatment with AS605240. Moreover, AS605240 reduced MIP-2 levels in a culture of neutrophils stimulated with lipopolysaccharide. The mechanisms underlying these actions of AS605240 are related to nuclear factor kappa (NF-kappaB) inhibition. Importantly, the PI3Kgamma inhibitor also up regulated IL-10, CD25 and FoxP3 expression. In addition, a significant increase in CD25 and FoxP3 expression was found in isolated lamina propria CD4+ T cells of AS605240-treated mice. The effect of AS605240 on Treg induction was further confirmed by showing that concomitant in vivo blockade of IL-10R significantly attenuated its therapeutic activity. CONCLUSIONS AND IMPLICATIONS: These results suggest that AS605240 protects mice against TNBS-induced colitis by inhibiting multiple inflammatory components through the NF-kappaB pathway while simultaneously inducing an increase in the functional activity of CD4+CD25+ Treg. Thus, AS605240 may offer a promising new therapeutic strategy for the treatment of inflammatory bowel diseases. PMID- 21244372 TI - Site-specific PEGylation of exenatide analogues markedly improved their glucoregulatory activity. AB - BACKGROUND AND PURPOSE: Exenatide is a 39-amino-acid peptide widely used to manage type 2 diabetes mellitus. However, it has a short plasma half-life and requires a twice daily injection regime. To overcome these drawbacks we used maleimide-polyethylene glycol to induce site-specific PEGylation. EXPERIMENTAL APPROACH: The analogue PB-105 (ExC39) was produced by replacing cysteine at position 39 of exenatide to provide a free thiol group. PB-105 showed the same glucoregulatory activity as exenatide in mice. Site-specific PEGylation of PB-105 was performed to produce PB-110 (ExC39PEG5kDa), PB-106 (ExC39PEG20kDa), PB-107 (ExC39PEG30kDa) and PB-108 (ExC39PEG40kDa). Their effects on intracellular cAMP, acute glucoregulatory activity and pharmacokinetic profile were compared in mice and rats. KEY RESULTS: PEGylation shifted the concentration-response curve of PB 105 to the right in a parallel, polyethylene glycol mass-dependent manner but with an inflexion point of at least 20 kDa. The activities of PB-107 and PB-108 but not PB-106 were reduced by 90% and 99%. PEGylation affected in vivo glucoregulatory activity in the same 'Inflexion-Shift' fashion at least at 20 kDa, but linearly increased plasma duration and systemic exposure without inflexion. PB-106 had a plasma t(1/2) approximately 10-fold that of PB-105, and exhibited superior glucoregulatory activity compared with PB-105 in normal and diabetic mice. CONCLUSIONS AND IMPLICATIONS: Site-specific PEGylation of exenatide with a permanent amide linkage affects its activity in a new type of 'Inflexion-Shift' fashion. PB-106 is a putative new analogue for treating diabetes; it possesses no loss of in vitro activity, prolonged plasma duration and superior, improved in vivo glucoregulatory activity compared with exenatide. PMID- 21244373 TI - Flavonoid modulation of GABA(A) receptors. AB - There has been a resurgence of interest in synthetic and plant-derived flavonoids as modulators of gamma-amino butyric acid-A (GABA(A) ) receptor function influencing inhibition mediated by the major inhibitory neurotransmitter GABA in the brain. Areas of interest include (i) flavonoids that show subtype selectivity in recombinant receptor studies in vitro consistent with their behavioural effects in vivo, (ii) flumazenil-insensitive modulation of GABA(A) receptor function by flavonoids, (iii) the ability of some flavonoids to act as second order modulators of first-order modulation by benzodiazepines and (iv) the identification of the different sites of action of flavonoids on GABA(A) receptor complexes. An emerging area of interest is the activation of GABA(A) receptors by flavonoids in the absence of GABA. The relatively rigid shape of flavonoids means that they are useful scaffolds for the design of new therapeutic agents. Like steroids, flavonoids have wide-ranging effects on numerous biological targets. The challenge is to understand the structural determinants of flavonoid effects on particular targets and to develop agents specific for these targets. PMID- 21244375 TI - Clinical presentation and management of dermatological toxicities of epidermal growth factor receptor inhibitors. AB - The last decade in oncology has been highlighted by the emergence of novel, highly specific anti-cancer agents, targeting a variety of molecular structures and able to inhibit aberrantly activated oncogenic pathways. Epidermal growth factor receptor inhibitors (EGFRIs) represent one type of such "targeted" agents. Their use made treatment more tolerable and resulted in significant reduction of systemic adverse effects. However, EGFRIs are associated with toxicities affecting the skin and adnexal structures, and mucosal surfaces that affect the majority of treated patients. Significant dermatologic toxicities have changed the role and involvement of dermatologists in their care. It is essential to be familiar with these adverse effects, potential complications, long-term sequelae, and available effective treatment strategies in order to appropriately manage these patients. This review will describe the clinical presentation, histopathology, underlying mechanisms, and management options, emphasizing evidence-based approaches. PMID- 21244376 TI - Blisters and plaques on the extremities. What is your diagnosis? Lichen planus pemphigoides. PMID- 21244374 TI - G protein-coupled receptors: walking hand-in-hand, talking hand-in-hand? AB - Most cells express a panel of different G protein-coupled receptors (GPCRs) allowing them to respond to at least a corresponding variety of extracellular ligands. In order to come to an integrative well-balanced functional response these ligand-receptor pairs can often cross-regulate each other. Although most GPCRs are fully capable to induce intracellular signalling upon agonist binding on their own, many GPCRs, if not all, appear to exist and function in homomeric and/or heteromeric assemblies for at least some time. Such heteromeric organization offers unique allosteric control of receptor pharmacology and function between the protomers and might even unmask 'new' features. However, it is important to realize that some functional consequences that are proposed to originate from heteromeric receptor interactions may also be observed due to intracellular crosstalk between signalling pathways of non-associated GPCRs. PMID- 21244377 TI - The role of dermatopathology in conjunction with teledermatology in resource limited settings: lessons from the African Teledermatology Project. AB - BACKGROUND: Access to dermatology and dermatopathology services is scarce in sub Saharan Africa. Teledermatology provides consultations for healthcare providers in resource-limited settings where specialty medical services are difficult to obtain, and the African Teledermatology Project has helped to bridge the gap in dermatological care in Africa. This program also allows for biopsy specimens to be sent to the USA for processing in cases where the clinical diagnosis is difficult and definitive diagnosis has implications for patient management. This study characterizes conditions diagnosed through clinicopathological correlation in conjunction with photos and tissue submitted to the African Teledermatology Project. MATERIALS AND METHODS: Retrospective case review of tissue specimens submitted over three years. RESULTS: Fifty-five biopsy specimens met inclusion criteria and represent cases of malignancy (35%), infection (7%), suspected infection (15%), lichenoid tissue reaction (5%), dermatitis (15%), and other various conditions (18%). Three biopsy specimens were non-diagnostic (5%). Clinicopathological concordance between submitting clinician and biopsy results occurred in 32 out of 55 cases (58%). Clinical and pathological diagnoses differed in 21 out of 55 cases (38%). Kaposi sarcoma (KS) represents the clinical diagnosis most often suspected in the evaluated biopsy specimens (42%) and was correctly recognized clinically in 13 out of 23 cases (57%). CONCLUSION: Clinical images may not provide sufficient information to definitively diagnose certain infectious and malignant dermatological conditions submitted through telemedicine consultation. Microscopic examination of skin biopsy specimens is an important adjunct for accurate diagnosis of disease and determination of appropriate treatment strategies. PMID- 21244378 TI - Extramammary Paget's disease of the unilateral axilla: a review of seven cases in a 20-year experience. AB - BACKGROUND: Extramammary Paget's disease (EMPD) is an uncommon malignancy that occurs on apocrine-rich skin. EMPD of the axillary region is extremely rare and is not well documented. Objectives The aim of the study is to review our experience with axillary EMPD with regard to initial examination, treatment, and long-term outcome. METHODS: A retrospective study of inpatient files with the diagnosis of axillary EMPD was made. The data were collected regarding patient demographics, symptoms, surgical treatments, and time to recurrence. Follow-up information was obtained as well. RESULTS: Seven patients with a median age of 67.6 years were diagnosed with axillary EMPD during a 20-year period from 1989 to 2008. The male-female ratio was 1 : 1.3. All patients had a unilateral axillary occurrence, with three in the left and four in the right side. Patients typically presented with a chronic erythematous to brownish plaque with or without pruritus. All patients were treated with wide excision with margins up to 2-3 cm. There were no recurrences after surgery during the follow-up period. CONCLUSIONS: Extramammary Paget's disease of the axillary region is a rare finding even in a large medical center. The disease process is generally a prolonged one without remarkable symptoms. The prognosis of axillary EMPD is relatively good, and long term follow-up is recommended. PMID- 21244379 TI - Prevalences of and risk factors for vulvar diseases in Nepal: a hospital-based study. AB - BACKGROUND: The vulvar diseases are common skin conditions, but their frequency and importance are often underestimated. OBJECTIVES: This study is aimed to investigate the frequency and clinical patterns of vulvar diseases and the risk factors associated with these diseases in patients attending a tertiary care hospital in eastern Nepal. METHODS: Patients with vulval symptoms or cutaneous lesions on the vulva were enrolled in the study. Laboratory investigations were carried out according to need. Equal numbers of age-matched females without vulval lesions or symptoms were selected from the outpatient department as controls. RESULTS: Of 5521 female patients attending the Dermatology Department's outpatient clinic during the study period, 105 (1.9%) had vulval symptoms and/or lesions. The most common types of vulvar disease were vulvar dermatoses (62.85%), pruritus vulvae (36.19%) and vulvodynia (0.95%). In vulvar dermatoses, infection was the most common (33.4%) manifestation, with a predominance of vulvovaginal candidiasis. Other dermatoses included: cysts and tumors (5.6%); pigmentary changes (vitiligo) (5.6%); inflammatory dermatoses (6.6%); atrophic vaginitis (1.8%); erosive disease (0.9%); and dermatosis caused by sexual abuse (1.9%). Use of nylon undergarments, occasional detergent use for washing clothes, and an irregular menstrual history were found to be associated with vulvar diseases. CONCLUSIONS: Our study findings indicate that the known frequency of vulvar diseases may represent only a small proportion of actual frequency. Further clinical and population-based research should be carried out with respect to the treatment, follow-up, and true prevalence of these diseases in the community. PMID- 21244380 TI - Sexual precocity in hypomelanosis of Ito: mosaicism-associated case report and literature review. AB - BACKGROUND: Hypomelanosis of Ito (HI), a neurocutaneous disorder characterized by hypopigmented skin lesions along Blaschko's line with multiple accompanying diseases, may occasionally present with sexual precocity. METHODS: We reviewed cases of HI with sexual precocity reported in the literature and focused on collecting information on other associated organ abnormalities, chromosomal karyotype, and type of sexual precocity. We also present our own case report. RESULTS: Five children with sexual precocity in HI were studied. All patients were full-term females without significant family history. Their ages ranged from three years to 11 years. Skin lesions involved the trunk and limbs. Developmental delay was present in all patients. Central nervous system involvement was found in four patients. Craniofacial abnormalities were present in four patients. Eye involvement was present in two patients. Limb abnormalities (brachydactyly and clinodactyly) were present in two patients. Skeletal organ involvement was present in three patients. Other skin lesions were present in three patients. Dental abnormalities occurred in one patient. Of the five patients, four demonstrated a peripheral type of sexual precocity, and one presented with central type sexual precocity. Vaginal bleeding was present in two patients. Chromosomal karyotype abnormalities were found in two patients, and mosaicism was present in one of these. CONCLUSIONS: Hypomelanosis of Ito is a syndrome characterized by cutaneous signs frequently associated with nervous, ocular, and musculoskeletal system abnormalities. Although it is rarely reported in conjunction with HI, physicians should recognize sexual precocity as a possible associated symptom. PMID- 21244381 TI - Relevance of autoimmune thyroiditis in children and adolescents with vitiligo. AB - BACKGROUND: Vitiligo is the most common pigmentation-related disorder worldwide. An autoimmune etiology is widely considered, and genetic factors may play an important role in its pathogenesis. The purpose of this study was to assess the incidence of thyroid dysfunctions and autoimmune thyroiditis in children with vitiligo and to identify related factors. METHODS: Fifty children with vitiligo and 50 control children were enrolled. Data on age, onset, duration, disease activity, presence of thyroid disorder, other autoimmune diseases, halo nevi, poliosis, and mucosal vitiligo were determined. Serum free triiodothyronine, free thyroxine, total T3, total T4, thyroid-stimulating hormone, and antibodies to thyroperoxidase and thyroglobulin were measured. Thyroid gland efficiency was evaluated. RESULTS: The mean age at onset of vitiligo was 7.26 +/- 4.43 years. The duration of vitiligo was 2.26 +/- 2.95 years. Vulgaris-type vitiligo was the most common form in our patients (56%), and 42% reported at least one family member with thyroid disorder, autoimmune disease, or both. Overt hypothyroidism or hyperthyroidism were not detected. We found a significant association between autoimmune thyroiditis and both sex and disease duration (P = 0.046 and P = 0.07, respectively), but no association between autoimmune thyroiditis and age, age at onset of vitiligo, halo nevi, poliosis, mucosal involvement, disease activity, or family history of vitiligo, autoimmunity, or thyroid disorders. CONCLUSIONS: Children with vitiligo show an increased incidence of autoimmune thyroiditis. Children with vitiligo, especially girls and subjects with generalized/vulgaris type vitiligo, should be screened annually for thyroid function and antithyroid antibodies to assist in the early diagnosis and therapy of autoimmune thyroiditis. PMID- 21244382 TI - BRAF, HRAS, KRAS, NRAS and CDKN2A genes analysis in cultured melanocytes used for vitiligo treatment. AB - BACKGROUND: Cultured pigment cells are increasingly being used in the treatment of stable vitiligo. The melanocyte growth media contain synthetic and human recombinant mitogenic factors. High concentration of growth factors, increased melanin biosynthesis, and the rapid cell cycle progression may lead to the genetic material damage and the initiation of melanocyte malignant transformation in cell culture conditions. Mutations of genes of the RAS/RAF/MEK/ERK signaling pathway and CDKN2A gene are often found in the early stages of melanoma development. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA)/phorbol 12-myristate 13 acetate (PMA) is considered to be an oncogenic factor, but there is no evidence that it is responsible for melanomagenesis initiation. The goal of this research was to assess the risk of the development of mutations in selected genes of the RAS/RAF/MEK/ERK signaling pathway and CDKN2A gene during the culturing of pigment cells in various growth media. METHODS: Three-hundred melanocyte cultures were established in 10 various growth media. The population doubling time of cultured cells was calculated for all the tested growth media. Cytogenetic analysis was carried out on the HRAS (exon 1 and 2), KRAS (exon 1 and 2), NRAS (exon 1 and 2), BRAF (exon 11 and 15), and CDKN2A (exon 1) genes. RESULTS: Our study revealed that TPA and high concentrations of other growth factors intensify the proliferation of pigment cells, without the risk of damage to the analyzed genes. CONCLUSIONS: It is necessary to carry out further similar studies on other signaling pathways to confirm cultured melanocytes transplantation safety. PMID- 21244383 TI - Cutaneous malakoplakia: a rare diagnosis of chronic nodules over the buttocks. PMID- 21244384 TI - Control of the myiasis-producing fly, Lucilia sericata, with Egyptian essential oils. AB - BACKGROUND: Myiasis caused by Lucilia sericata (Diptera: Calliphoridae) is widely distributed throughout the world and affects both humans and animals. In addition, L. sericata larvae and adults may play a role in spreading causal agents of mycobacterial infections. Therefore, it is important to establish new and safe alternative methods of controlling this blowfly. METHODS: The insecticidal effectiveness of four commercially available essential oils [lettuce (Lactuca sativa), chamomile (Matricaria chamomilla), anise (Pimpinella anisum), rosemary (Rosmarinus officinalis)] against third larval instars of L. sericata was evaluated. The effects of sublethal concentrations of these oils on pupation rates, adult emergences, sex ratios, and morphological anomalies were also determined. RESULTS: The oils were highly toxic to L. sericata larvae, with median lethal concentrations (LC(50) ) of 0.57%, 0.85%, 2.74%, and 6.77% for lettuce, chamomile, anise, and rosemary oils, respectively. Pupation rates were markedly decreased after treatment with 8% lettuce oil, and adult emergence was suppressed by 2% lettuce and chamomile oils. Morphological abnormalities were recorded after treatment with all tested oils, and lettuce was the major cause of deformation. There was a predominance of males over females (4 : 1) after treatment with lower concentrations of chamomile and rosemary; such a skew toward males would lead to a population decline. CONCLUSIONS: The four tested oils are inexpensive and may represent new botanical insecticides for controlling blowflies. PMID- 21244385 TI - Annular groin eruptions: pityriasis rosea of vidal. PMID- 21244386 TI - Evaluation of educational methods in dermatology and confidence levels: a national survey of UK medical students. AB - BACKGROUND: The high prevalence of skin conditions makes dermatology education an essential part of the undergraduate medical curriculum. The aim of this study was to assess the impact of different educational methods on confidence levels in dermatology among UK medical students. METHODS: A survey-based study was carried out to establish: (i) educational experience in dermatology, and (ii) confidence levels in the British Association of Dermatologists core curriculum learning outcomes. Measures of confidence were rated using a five-point Likert scale. RESULTS: Completed questionnaires were obtained from 449 final-year medical students at 14 medical schools (12.9% of 3485 final-year UK medical students). Students who received teaching from dermatologists (P <= 0.01), dermatology specialist nurses (P <= 0.001), and expert patients (P <= 0.001) reported higher levels of confidence. Learning in clinical settings (P <= 0.001) and small-group settings (P <= 0.001) was associated with higher confidence levels. Student selected components in dermatology were associated with higher confidence levels (P <= 0.001). Confidence levels were consistently lower in dermatological emergencies compared with chronic conditions, reflecting the lack of clinical exposure. Overall, 64.9% of students were at least adequately confident in assessing, and 52.0% were similarly confident in managing patients with skin conditions. CONCLUSIONS: The findings of this study show that specialist clinical experiences and small-group learning had the most significant influence on confidence levels in dermatology. Many medical students nearing qualification were less than adequately confident in their abilities to assess and manage skin conditions, suggesting that a greater emphasis on dermatology is required. PMID- 21244387 TI - A case of lupus erythematosus panniculitis presenting as combined linear and lipoatrophic skin lesions. PMID- 21244388 TI - Cellulitis caused by a methicillin-sensitive Staphylococcus aureus isolate harboring Panton-Valentine toxin in an American soldier returning from Iraq. PMID- 21244389 TI - Solitary fibrous tumor of the shoulder showing diverse distinct histologic patterns. PMID- 21244390 TI - Relapsing polychondritis complicated with Sweet's syndrome and normolipemic neutrophilic xanthomatosis successfully treated by dapsone. PMID- 21244391 TI - Ingrown nails and pachyonychia of the great toes impair lower limb functions: improvement of limb dysfunction by medical foot care. AB - BACKGROUND: Painful feet and lower limb dysfunction are risk factors for falling. Toenail deformities are common disorders in elderly people, but the relationship between nail deformities and lower limb function remains unclear. The aims of the present study were to assess the impairment of lower limb function in patients with deformities of the great toe and to determine whether foot care treatment is beneficial in reducing the risk of falling. METHODS: Functional tests of the lower extremities were performed in 263 adults, including patients with any of hallux valgus, ingrown nail, or pachyonychia, and volunteers. Fifty-five subjects with nail disorders of the great toe received medical foot care treatment. RESULTS: The presence of ingrown nail, pachyonychia, or tenderness of the great toe was significantly correlated with impaired postural performance and reduced muscular strength as assessed by functional tests. Medical foot care markedly reduced pain levels in the great toe and improved scores on functional tests of the lower extremities. CONCLUSIONS: Toenail disorders of the great toe cause dysfunction of the lower extremities and are likely to increase the risk of falling in daily life. Foot care management of toenail disorders has the potential to improve functional abilities in daily life, particularly in elderly individuals. PMID- 21244392 TI - Association of HLA-B*1502 allele with carbamazepine-induced toxic epidermal necrolysis and Stevens-Johnson syndrome in the multi-ethnic Malaysian population. AB - BACKGROUND: Carbamazepine (CBZ), a frequently used anticonvulsant drug, is one of the most common causes of life-threatening cutaneous adverse drug reactions such as toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS). Recent studies have revealed a strong association between HLA-B*1502 and CBZ-induced TEN/SJS in the Taiwan Han Chinese population. OBJECTIVES: This study is aimed to investigate the association between human leucocyte antigens (HLA) and CBZ induced TEN/SJS in the multi-ethnic Malaysian population. METHODS: A sample of 21 unrelated patients with CBZ-induced TEN/SJS and 300 race-matched, healthy controls were genotyped for HLA-A, -B and -DR using polymerase chain reaction (PCR). Allele frequencies were compared. RESULTS: HLA-B*1502 was present in 75.0% (12/16) of Malay patients with CBZ-induced TEN/SJS but in only 15.7% (47/300) of normal controls (odds ratio 16.15, 95% confidence interval 4.57-62.4; corrected P value = 7.87 * 10(-6) ), which suggests a strong association between HLA and CBZ induced TEN/SJS. Additionally, HLA-B*1502 was found in all three Chinese and two Indian patients. Existing data show that frequencies of the HLA-B*1502 allele are generally much higher in Asian populations than in White European populations, which explains the higher incidences of SJS and TEN in Asian countries. CONCLUSIONS: HLA-B*1502 is strongly associated with CBZ-induced TEN/SJS in the Malay population in Malaysia, as has been seen in Han Chinese in Taiwan. This indicates that the genetic association apparent in the incidence of CBZ-induced TEN/SJS is linked with the presence of HLA-B*1502, irrespective of racial origin. Screening of patients for this genetic marker can help to prevent the occurrence of TEN/SJS. PMID- 21244393 TI - Recognizing diversity: listening with a sensitive ear. PMID- 21244394 TI - Areca nut (betel nut) chewing: a popular Indian cultural practice and its mucosal implications. PMID- 21244395 TI - A case of hereditary leukonychia totalis and partialis. PMID- 21244396 TI - Perifollicular inflammatory infiltrate in vitiligo. PMID- 21244397 TI - Pre-treatment with misoprostol prevents food-dependent exercise-induced anaphylaxis (FDEIA). PMID- 21244398 TI - Type XVII collagen ELISA indices significantly decreased after bullous pemphigoid remission. PMID- 21244405 TI - Family-centred research: what does it mean and can we do it? PMID- 21244406 TI - Botulinum toxin: does the black box warning justify change in practice? PMID- 21244407 TI - Bone density and size in ambulatory children with cerebral palsy. PMID- 21244408 TI - The role of motor proficiency in bone health in genetic syndromes. PMID- 21244409 TI - Gross motor problems and psychiatric disorders in children. PMID- 21244410 TI - A 'global' approach to global developmental delay and intellectual disability? PMID- 21244411 TI - The ongoing quandaries of behavioral pain assessment in children with neurocognitive impairment. PMID- 21244412 TI - Adverse events and health status following botulinum toxin type A injections in children with cerebral palsy. AB - AIM: The aim of this study was to assess changes in health status before and after, as well as adverse events after, botulinum toxin type A (BoNT-A) injections in children with cerebral palsy (CP). METHOD: A total of 334 children (190 male; 144 female) aged 1y 6mo to 19y 4mo (mean 9y 2mo, SD 4y) with CP who were undergoing BoNT-A injections (596 injection courses in total) were clinically audited over a 16-month period. Of the 334 children, 62 were classified at Gross Motor Function Classification System (GMFCS) level I, 52 of whom had unilateral CP and 10 of whom had bilateral CP. Eighty-six children were classified at GMFCS level II, 39 of whom had unilateral CP and 47 of whom had bilateral CP. Forty-four children were classified at GMFCS level III, two of whom had unilateral CP and 42 of whom had bilateral CP. Sixty-six of the 334 children were classified at GMFCS level IV and 76 as level V. All the children classified as level IV or V had bilateral involvement. The health status of the children in the month before and a prospective audit of health status and adverse events in the month after BoNT-A injections were examined in order to assess the effects of the toxin. RESULTS: The data gathered for the month before administration of BoNT A indicated that children with CP had significant background morbidities. After injection of BoNT-A, adverse events occurred in 23.2% of children. All adverse events were temporary and there were no deaths. INTERPRETATION: The results of this audit indicate that there is insufficient evidence to warrant restriction of the administration of BoNT-A in children with CP at any GMFCS level in our service. PMID- 21244414 TI - Congenital lower brachial plexus palsy due to cervical ribs. AB - Congenital brachial plexus palsy (CBPP) usually occurs secondarily to intrapartum trauma, but this is not always the case. Cervical ribs have previously been reported to increase the risk of CBPP in association with birth trauma. We report the cases of two children (one female, one male) with congenital lower brachial plexus palsy in whom the presence of non-ossified cervical ribs was the only identified risk factor. In the female child magnetic resonance imaging (MRI) of the brain, spinal cord, and brachial plexus revealed no abnormality except for the presence of bilateral cervical ribs at the level of the seventh cervical (C7) vertebra. Chest radiography was normal, which suggested that the cervical ribs identified on the MRI were fibrous bands or cartilaginous ribs rather than ossified ribs. In the male child, MRI of the spine and brachial plexus was normal but he was noted to have bilateral cervical ribs at C7. These were not identifiable on chest radiography and, therefore, are likely to reflect fibrous bands or cartilaginous ribs. PMID- 21244415 TI - 'Physical activity measurement instruments for children with cerebral palsy: a systematic review'. PMID- 21244417 TI - Methods to derive the differential equation of the free surface boundary. PMID- 21244418 TI - Predicting the optimal prey group size from predator hunting behaviour. AB - 1. How group size affects predator attack and success rate, and so prey vulnerability, is important in determining the nonlethal consequences of predation risk on animal populations and communities. Theory predicts that both predator attack success rate and the dilution effect decline exponentially with group size and that selection generates optimal group sizes at a 'risk threshold' above which antipredation benefits are outweighed by costs, such as those owing to higher attack rates. 2. We examined whether flock size risk thresholds for attack rate, success rate or dilution differed, and therefore whether the strength of selection for group size differed for these three factors, using a system of redshank Tringa totanus flocks being hunted by Eurasian sparrowhawks Accipiter nisus. We also asked which of the three thresholds, on their own or in combination, predicted the most commonly observed group size. 3. Mean redshank flock size increased with a very gradual quadratic function (i.e. approximately linearly) with population size, although at a rate half that possible; when population size was not limiting, individuals almost always avoided flocks of less than 30 and birds were frequently in flocks up to at least 80. Sparrowhawk attack rate showed a quadratic relationship with flock size and peaked at 55 redshanks. Sparrowhawk attack success rate, however, declined exponentially, becoming less steep at flock sizes of about 40 and remaining uniformly low (a 95% decrease) by 70. Combined with dilution, individual risk of death per attack decreased by 95% when group size reached 30 (20 for the dilution effect alone). 4. Redshanks most commonly formed group sizes that gained the maximum individual predation risk reduction. They also commonly formed group sizes far above any further substantial advantages from the dilution effect or from reducing attack rate, but that continued to reduce predation risk by lowering attack success rate. Individuals did not always form the largest groups possible which we suggest is because individual variation in risk-taking subdivides the population. This places a constraint on the ability of individuals to compensate for predation risk and will have a variety of important effects on animal populations. PMID- 21244419 TI - Ecosystem engineering and predation: the multi-trophic impact of two ant species. AB - 1. Ants are ubiquitous ecosystem engineers and generalist predators and are able to affect ecological communities via both pathways. They are likely to influence any other terrestrial arthropod group either directly or indirectly caused by their high abundance and territoriality. 2. We studied the impact of two ant species common in Central Europe, Myrmica rubra and Lasius niger, on an arthropod community. Colony presence and density of these two ant species were manipulated in a field experiment from the start of ant activity in spring to late summer. 3. The experiment revealed a positive influence of the presence of one ant colony on densities of decomposers, herbivores and parasitoids. However, in the case of herbivores and parasitoids, this effect was reversed in the presence of two colonies. 4. Generally, effects of the two ant species were similar with the exception of their effect on Braconidae parasitoid densities that responded positively to one colony of M. rubra but not of L. niger. 5. Spider density was not affected by ant colony manipulation, but species richness of spiders responded positively to ant presence. This effect was independent of ant colony density, but where two colonies were present, spider richness was significantly greater in plots with two M. rubra colonies than in plots with one colony of each ant species. 6. To test whether the positive ecosystem engineering effects were purely caused by modified properties of the soil, we added in an additional experiment (i) the soil from ant nests (without ants) or (ii) unmodified soil or (iii) ant nests (including ants) to experimental plots. Ant nest soil on its own did not have a significant impact on densities of decomposers, herbivores or predators, which were significantly, and positively, affected by the addition of an intact nest. 7. The results suggest an important role of both ant species in the grassland food web, strongly affecting the densities of decomposers, herbivores and higher trophic levels. We discuss how the relative impact via bottom-up and top-down effects of ants depends on nest density, with a relatively greater top-down predatory impact at higher densities. PMID- 21244420 TI - Constraints on host choice: why do parasitic birds rarely exploit some common potential hosts? AB - 1. Why are some common and apparently suitable resources avoided by potential users? This interesting ecological and evolutionary conundrum is vividly illustrated by obligate brood parasites. Parasitic birds lay their eggs into nests of a wide range of host species, including many rare ones, but do not parasitize some commonly co-occurring potential hosts. 2. Attempts to explain the absence of parasitism in common potential hosts are limited and typically focused on single-factor explanations while ignoring other potential factors. We tested why thrushes Turdus spp. are extremely rarely parasitized by common cuckoos Cuculus canorus despite breeding commonly in sympatry and building the most conspicuous nests among forest-breeding passerines. 3. No single examined factor explained cuckoo avoidance of thrushes. Life-history traits of all six European thrush species and the 10 most frequently used cuckoo hosts in Europe were similar except body/egg size, nest design and nestling diet. 4. Experiments (n = 1211) in several populations across Europe showed that host defences at egg laying and incubation stages did not account for the lack of cuckoo parasitism in thrushes. However, cross-fostering experiments disclosed that various factors during the nestling period prevent cuckoos from successfully parasitizing thrushes. Specifically, in some thrush species, the nest cup design forced cuckoo chicks to compete with host chicks with fatal consequences for the parasite. Other species were reluctant to care even for lone cuckoo chicks. 5. Importantly, in an apparently phylogenetically homogenous group of hosts, there were interspecific differences in factors responsible for the absence of cuckoo parasitism. 6. This study highlights the importance of considering multiple potential factors and their interactions for understanding absence of parasitism in potential hosts of parasitic birds. In the present study, comparative and experimental procedures are integrated, which represent a novel approach that should prove useful for the understanding of interspecific ecological relationships in general. PMID- 21244422 TI - The effects of severe psychosocial deprivation and foster care intervention on cognitive development at 8 years of age: findings from the Bucharest Early Intervention Project. AB - BACKGROUND: Previous reports from the Bucharest Early Intervention Project suggested that children removed from institutions and placed into intervention displayed gains in IQ relative to children randomized to remain in institutional care. METHOD: The current report presents data from the 8-year follow-up of these children. One hundred and three of the original 136 children in the study were tested with the WISC IV. RESULTS: Results reveal continued benefit from the intervention even though many of the children in both the intervention and control groups were no longer residing in their initial placements. Gains in IQ were particularly evident for those children who remained with their intervention family. There were also modest timing effects such that children placed earlier displayed higher scores on the WISC processing speed subscale. Early placement was also a significant predictor of a profile of stable, typical IQ scores over time. CONCLUSION: These data suggest the continued importance of early intervention and the negative effects of severe psychosocial deprivation on the development of IQ scores across early childhood. PMID- 21244421 TI - Research review: Constraining heterogeneity: the social brain and its development in autism spectrum disorder. AB - The expression of autism spectrum disorder (ASD) is highly heterogeneous, owing to the complex interactions between genes, the brain, and behavior throughout development. Here we present a model of ASD that implicates an early and initial failure to develop the specialized functions of one or more of the set of neuroanatomical structures involved in social information processing (i.e., the 'social brain'). From this early and primary disruption, abnormal brain development is canalized because the individual with an ASD must develop in a highly social world without the specialized neural systems that would ordinarily allow him or her to partake in the fabric of social life, which is woven from the thread of opportunities for social reciprocity and the tools of social engagement. This brain canalization gives rise to other characteristic behavioral deficits in ASD including deficits in communication, restricted interests, and repetitive behaviors. We propose that focused efforts to explore the brain mechanisms underlying the core, pathognomic deficits in the development of mechanisms for social engagement in ASD will greatly elucidate our understanding and treatment of this complex, devastating family of neurodevelopmental disorders. In particular, developmental studies (i.e., longitudinal studies of young children with and without ASD, as well as infants at increased risk for being identified with ASD) of the neural circuitry supporting key aspects of social information processing are likely to provide important insights into the underlying components of the full-syndrome of ASD. These studies could also contribute to the identification of developmental brain endophenotypes to facilitate genetic studies. The potential for this kind of approach is illustrated via examples of functional neuroimaging research from our own laboratory implicating the posterior superior temporal sulcus (STS) as a key player in the set of neural structures giving rise to ASD. PMID- 21244424 TI - New approach for glyco- and lipidomics--molecular scanning of human brain gangliosides by TLC-Blot and MALDI-QIT-TOF MS. AB - We have developed a TLC-Blot system that makes possible the direct analysis of blotted glycosphingolipids on a polyvinylidene difluoride membrane from a high performance TLC plate by immunological staining, chemical staining, enzymatic treatment and mass spectrometric (MS) analysis. An ion trap type matrix-assisted laser desorption/ionization-quadrupole ion trap-time of flight (MALDI-QIT-TOF) MS apparatus improved not only the molecular identification but also the analysis of molecular species of lipids on the polyvinylidene difluoride membrane. A new approach for glyco- and lipidomics, molecular scanning technology by a combination of TLC-Blot and MALDI-QIT-TOF MS, was developed and applied to human brain gangliosides separated from the tissues of patients with neural diseases and control patients. The results clearly showed a change of ganglioside composition, in addition to identifying individual ganglioside molecular species, in the hippocampus gray matter of patients with Alzheimer's disease. The results strongly suggested that metabolic changes of gangliosides played an important role in the progression of this disease. The present technology with molecular imaging should provide valuable information for elucidating the significance of molecular species in neuronal functions such as neural transmission, memory, and learning. PMID- 21244423 TI - Poor fine-motor and visuospatial skills predict persistence of pediatric-onset obsessive-compulsive disorder into adulthood. AB - BACKGROUND: Half of pediatric-onset OCD cases remit by adulthood. Studies have demonstrated that initial response to pharmacotherapy, age of onset, prominent hoarding symptoms, and the presence of comorbid tic disorders are associated with long-term outcome. Our goal was to examine the association between childhood performance on neuropsychological testing and persistence of OCD into adulthood. METHODS: Twenty-four children with OCD were followed for an average of 7.5 years into early adulthood. Neuropsychological performance in childhood (<16 years) was measured. The battery included the Wechsler Intelligence Scale for Children (WISC III), the Purdue pegboard test, the Rey-Osterreith Complex Figure Task (RCFT) and the Beery-Buktenica test of Visual Motor Integration (VMI). We hypothesized that deficits in fine-motor skills, visuospatial skills, and nonverbal memory as well as overall intelligence would be associated with adulthood outcome. We used a Cox proportional hazard model of survival analysis in which time to remission of OCD symptoms was the main outcome variable. RESULTS: Poor childhood performance on the Purdue pegboard task and the block design subscale of WISC-III was associated with persistence of OCD symptoms into adulthood. IQ, VMI, and nonverbal memory performance did not predict significantly the persistence of OCD. CONCLUSIONS: These results suggest that visuospatial and fine-motor skill deficits are predictive of poor long-term outcome in pediatric-onset OCD. Future longitudinal studies are needed to chart the course of these deficits relative to the course of symptoms in OCD and to determine whether the association of these neuropsychiatric deficits with long-term outcome is specific to pediatric-onset OCD or generalizes to other psychiatric disorders. PMID- 21244425 TI - An inverse correlation between the apparent rate of dopamine clearance and tonic autoinhibition in subdomains of the rat striatum: a possible role of transporter mediated dopamine efflux. AB - The dopaminergic terminal field in the rat striatum is compartmentalized into sub domains that exhibit distinct dynamics of electrically evoked dopamine release. The fast striatal domains, where dopamine release is predominantly vesicular, exhibit conventional dopaminergic activity. However, vesicular dopamine release is tonically autoinhibited in the slow domains, which suggests that dopamine reaches the autoreceptors via a non-vesicular route. Hence, it appears that the domains use distinct mechanisms to regulate the basal dopamine concentration available to activate, or not, pre-synaptic autoinhibitory receptors. However, direct detection of local variations in tonic extracellular dopamine concentrations is not yet possible. So, the present study employed voltammetry to test the hypothesis that the apparent rate of dopamine clearance from the extracellular space should be domain-dependent. The apparent rate of dopamine clearance is equal to the difference in the rates of dopamine release and uptake that determine extracellular dopamine concentrations. This study confirms that the apparent rate of dopamine clearance is slower in the slow striatal domains where vesicular dopamine release is tonically autoinhibited. These findings support the view that the basal concentration in slow domains is maintained by a non-vesicular release process, possibly transporter-mediated efflux. PMID- 21244426 TI - Alternate day fasting impacts the brain insulin-signaling pathway of young adult male C57BL/6 mice. AB - Dietary restriction (DR) has recognized health benefits that may extend to brain. We examined how DR affects bioenergetics-relevant enzymes and signaling pathways in the brains of C57BL/6 mice. Five-month-old male mice were placed in ad libitum or one of two repeated fasting and refeeding (RFR) groups, an alternate day (intermittent fed; IF) or alternate day plus antioxidants (blueberry, pomegranate, and green tea extracts) (IF + AO) fed group. During the 24-h fast blood glucose levels initially fell but stabilized within 6 h of starting the fast, thus avoiding frank hypoglycemia. DR in general appeared to enhance insulin sensitivity. After six weeks brain AKT and glycogen synthase kinase 3 beta phosphorylation were lower in the RFR mice, suggesting RFR reduced brain insulin signaling pathway activity. Pathways that mediate mitochondrial biogenesis were not activated; AMP kinase phosphorylation, silent information regulator 2 phosphorylation, peroxisomal proliferator-activated receptor-gamma coactivator 1 alpha levels, and cytochrome oxidase subunit 4 levels did not change. ATP levels also did not decline, which suggests the RFR protocols did not directly impact brain bioenergetics. Antioxidant supplementation did not affect the brain parameters we evaluated. Our data indicate in young adult male C57BL/6 mice, RFR primarily affects brain energy metabolism by reducing brain insulin signaling, which potentially results indirectly as a consequence of reduced peripheral insulin production. PMID- 21244427 TI - Pituitary adenylate cyclase-activating polypeptide protects astroglial cells against oxidative stress-induced apoptosis. AB - Oxidative stress, associated with a variety of disorders including neurodegenerative diseases, results from accumulation of reactive oxygen species (ROS). Oxidative stress is not only responsible for neuron apoptosis, but can also provoke astroglial cell death. Numerous studies indicate that pituitary adenylate cyclase-activating polypeptide (PACAP) promotes neuron survival, but nothing is known regarding the action of PACAP on astroglial cell survival. Thus, the purpose of the present study was to investigate the potential glioprotective effect of PACAP on H(2)O(2)-induced astrocyte death. Pre-treatment of cultured rat astrocytes with nanomolar concentrations of PACAP prevented cell death provoked by H(2)O(2) (300 MUM), whereas vasoactive intestinal polypeptide was devoid of protective activity. The effect of PACAP on astroglial cell survival was abolished by the type 1 PACAP receptor antagonist, PACAP6-38. The protective action of PACAP was blocked by the protein kinase A inhibitor H89, the protein kinase C inhibitor chelerythrine and the mitogen-activated protein (MAP)-kinase kinase (MEK) inhibitor U0126. PACAP stimulated glutathione formation, and blocked H(2)O(2)-evoked ROS accumulation and glutathione content reduction. In addition, PACAP prevented the decrease of mitochondrial activity and caspase 3 activation induced by H(2)O(2). Taken together, these data indicate for the first time that PACAP, acting through type 1 PACAP receptor, exerts a potent protective effect against oxidative stress-induced astrocyte death. The anti-apoptotic activity of PACAP on astrocytes is mediated through the protein kinase A, protein kinase C and MAPK transduction pathways, and can be accounted for by inhibition of ROS induced mitochondrial dysfunctions and caspase 3 activation. PMID- 21244429 TI - Low-n oligomers as therapeutic targets of Alzheimer's disease. AB - The pathogenesis of Alzheimer's disease involves the progressive accumulation of amyloid beta-protein (Abeta). Recent studies using synthetic Abeta peptides, a cell culture model, Abeta precursor protein transgenic mice models suggest that pre-fibrillar forms of Abeta are more deleterious than extracellular fibril forms. Recent findings obtained using synthetic Abeta peptides and human samples indicated that low-n oligomers (from dimers to octamers) may be proximate toxins for neuron and synapse. Here, we review the recent studies on the soluble oligomers, especially low-n oligomers in Alzheimer's disease. PMID- 21244430 TI - Unmasking of LPA1 receptor-mediated migration response to lysophosphatidic acid by interleukin-1beta-induced attenuation of Rho signaling pathways in rat astrocytes. AB - Action mechanism of lipopolysaccharide (LPS), interleukin-1beta (IL-1beta), and lysophosphatidic acid (LPA) to regulate motility, an important process of astrogliosis, was investigated in rat astrocytes. While LPA exerted no significant effect on the cell migration, the prior treatment of the cells with LPS or IL-1beta resulted in the appearance of migration activity in response to LPA. The LPS induction of the migration response to LPA was associated with the production of IL-1beta precursor protein and inhibited by the IL-1 receptor antagonist. The IL-1beta treatment also allowed LPA to activate Rac1. The LPA induced Rac1 activation and migration were inhibited by pertussis toxin, a small interfering RNA specific to LPA(1) receptors, and LPA(1) receptor antagonists, including Ki16425. However, the IL-1beta treatment had no appreciable effect on LPA(1) receptor mRNA expression and LPA-induced activation of ERK, Akt, and proliferation. The induction of the migration response to LPA by IL-1beta was inhibited by a constitutively active RhoA. Moreover, LPA significantly activated RhoA through the LPA(1) receptor in the control cells but not in the IL-1beta treated cells. These results suggest that IL-1beta inhibits the LPA(1) receptor mediated Rho signaling through the IL-1 receptor, thereby disclosing the LPA(1) receptor-mediated G(i) protein/Rac/migration pathway. PMID- 21244428 TI - The cannabinoid type-1 receptor carboxyl-terminus, more than just a tail. AB - The cannabinoid type-1 (CB(1)) receptor is a G protein-coupled receptor that binds the main active ingredient of marijuana, Delta(9)-tetrahydrocannabinol, and has been implicated in several disease states, including drug addiction, anxiety, depression, obesity, and chronic pain. In the two decades since the discovery of CB(1), studies at the molecular level have centered on the transmembrane core. This interest has now expanded as we discover that other regions of CB(1), including the CB(1) carboxyl-terminus, have critical structures that are important for CB(1) activity and regulation. Following the recent description of the three dimensional structure of the full-length CB(1) carboxyl-terminal tail [Biopolymers (2009) vol. 91, pp. 565-573], several residues and structural motifs including two alpha-helices (termed H8 and H9) have been postulated to interact with common G protein-coupled receptor accessory proteins, such as G-proteins and beta-arrestins. This discourse will focus on the CB(1) carboxyl-terminus; our current understanding of the structural features of this region, evidence for its interaction with proteins, and the impact of structure on the binding and regulatory function of CB(1) accessory proteins. The involvement of the carboxyl terminus in the receptor life cycle including activation, desensitization, and internalization will be highlighted. PMID- 21244431 TI - Comparative analysis between plant species of transcriptional and metabolic responses to hypoxia. AB - * The variation in tolerance to low oxygen is likely explained by divergent sets of molecular and metabolic responses between species. * We analysed the versatility of the response to low oxygen of primary metabolism by comparing nine previously published metabolome profiling studies. Data were juxtaposed with expression profiles of genes encoding enzymes involved in the metabolic pathways of rice, Arabidopsis and poplar. Furthermore, full transcript profiles were compared to determine commonalities in the expression of orthologous genes and genes that serve similar functions. * Activation of fermentation and the accumulation of alanine plus succinate were observed in all species, but transcriptional regulation of these metabolic pathways varied. Global analysis of orthologue expression revealed that most differentially expressed genes either had no orthologues or were not affected in the other species. Expression analysis of nearly all gene clusters with common functions varied significantly between species. * The resemblance of the metabolic response to hypoxia indicates that this occurs independent of the level of tolerance. However, regulation of these processes at transcriptional level varied between species. An important role is suggested for signalling and post-transcriptional regulation to be involved in the mechanisms that lead to tolerance to hypoxia. PMID- 21244432 TI - A meta-analysis of plant responses to dark septate root endophytes. AB - * Dark septate endophytes (DSE) frequently colonize roots in the natural environment, but the effects of these fungi on plants are obscure, with previous studies indicating negative, neutral or positive effects on plant performance. * In order to reach a consensus for how DSE influence plant performance, meta analyses were performed on data from 18 research articles, in which plants had been inoculated with DSE in sterile substrates. * Negative effects of DSE on plant performance were not recorded. Positive effects were identified on total, shoot and root biomass, and on shoot nitrogen (N) and phosphorus contents, with increases of 26-103% in these parameters for plants inoculated with DSE, relative to uninoculated controls. Inoculation increased total, shoot and root biomass by 52-138% when plants had not been supplied with additional inorganic N, or when all, or the majority, of N was supplied in organic form. Inoculation with the DSE Phialocephala fortinii was found to increase shoot and root biomass, shoot P concentration and shoot N content by 44-116%, relative to uninoculated controls. * The analyses here suggest that DSE enhance plant performance under controlled conditions, particularly when all, or the majority, of N is available in organic form. PMID- 21244433 TI - Do Botanophila flies provide reproductive isolation between two species of Epichloe fungi? A field test. AB - Epichloe spp., fungal endophytes of cool season grasses, produce collars of mycelium (stromata) on host stems that Botanophila flies visit for egg laying. Flies transfer fungal gametes among stromata and thereby serve to cross-fertilize fungi. Hence, the interaction is analogous to insect pollination in angiosperms. While most Epichloe species are not interfertile, Epichloe typhina and Epichloe clarkii can hybridize. We investigated whether Botanophila flies play a role in the reproductive isolation of the two Epichloe species at a field site in southwestern Switzerland. We estimated the density of stromata and collected fly larvae and stromata occurring on plants. While most ascospores collected from both species indicated intraspecific mating, 9.3% of fungal fruiting bodies contained spores of hybrid origin. Two species of Botanophila larvae occurred on stromata and both preferred E. typhina. Yet, both fly species laid eggs on both fungal species. While preferences by Botanophila flies should influence reproductive isolation between the fungi, other mechanisms are likely more important. Our data, which show hybrid ascospores are produced, suggest postzygotic isolating mechanisms are an important means of reproductive isolation. PMID- 21244434 TI - Negative reciprocal interactions between gibberellin and cytokinin in tomato. AB - * The hormones gibberellin (GA) and cytokinin (CK) exhibit antagonistic effects on various processes in many species. Previous studies in Arabidopsis have shown that GA inhibits CK signaling. Here, we have investigated the cross-talk between GA and CK in tomato (Solanum lycopersicum). * We altered the balance between GA and CK activities by exogenous applications and genetic manipulations, and tested an array of physiological and developmental responses. * GA and CK showed antagonistic effects on various developmental and molecular processes during tomato plant growth. GA inhibited all tested CK responses, including the induction of the CK primary response genes, type A Tomato Response Regulators (TRRs). CK also inhibited a subset of GA responses. In contrast with exogenous application of GA, the endogenous GA-independent GA signal generated by the loss of the DELLA gene PROCERA (PRO) did not repress CK-regulated processes, such as anthocyanin accumulation, TRR expression and leaf complexity. * Our results suggest a mutual antagonistic interaction between GA and CK in tomato. Although GA may inhibit early steps in the CK response pathway via a DELLA-independent pathway, CK appears to affect downstream branch(es) of the GA signaling pathway. The ratio between the two hormones, rather than their absolute levels, determines the final response. PMID- 21244435 TI - Photoexcitation of aqueous suspensions of titanium dioxide nanoparticles: an electron spin resonance spin trapping study of potentially oxidative reactions. AB - It is well-established that exposure of aqueous suspensions of titanium dioxide (TiO(2)) nanoparticles to ultraviolet A (UVA) light produces reactive oxygen species which leads to biological damage. However, there is disagreement in the literature as to the exact nature of these species and how they are formed. Using a number of different spin traps (i.e. PBN, POBN, DMPO, DEPMPO), we have shown that the primary damaging species produced on irradiation of an aqueous suspension of TiO(2) is the hydroxyl radical, which is formed at the valence band hole under both aerobic and hypoxic conditions. Hydroxyl radical production is enhanced by the presence of oxygen which probably reacts with the conduction band electrons or resultant Ti(3+), inhibiting hole-electron recombination, although we find no evidence of reaction of oxygen to form free superoxide radical anions or of the formation of any other radical at that site. The present results suggest that the resulting O(2)(*-) species may not be as labile as previously thought and may possibly undergo further reduction to the O(2)(2-) dianion. Hydroxyl radicals formed at the surface of the TiO(2) readily react with substrates containing an abstractable hydrogen to produce secondary radicals that, in biological systems, could lead to cell damage. PMID- 21244436 TI - The relationship between attachment, personality and antisocial tendencies in a prison sample: a pilot study. AB - This study examined the role of adult attachment and personality in relation to antisocial tendencies (i.e. convictions for violence and interpersonal problems in romantic relationships) in Norwegian prison inmates (N=92). Attachment styles and personality were measured using self-report questionnaires (RSQ; Griffin & Bartholomew, 1994; and NEO-FFI, Costa & McCrae, 1992a). The prison inmates scored higher on avoidant than on anxious attachment style. While age and agreeableness (negatively associated) emerged as significant predictors of violence, anxious attachment explained most of the variances in aggression in intimate relationships. The study suggests that different types of antisocial tendencies could have different attachment and general personality correlates. PMID- 21244437 TI - Inhibition of cytochrome P450 2A participating in coumarin 7-hydroxylation in pig liver microsomes. AB - Five commonly used human cytochrome P450 (CYP) inhibitors were examined for their effects on coumarin 7-hydroxylase (CYP2A) activity in pig liver microsomes. The K(m) and V(max) values for coumarin 7-hydroxylation in pig liver microsomes were estimated to be 1 MUm and 0.26 nmol.mg/min, respectively. The following human CYP inhibitors caused little or no inhibition of CYP2A as defined by a K(i) > 200 MUm: quinidine (CYP2D6), troleandomycin (CYP3A4), and sulfaphenazole (CYP2C9). The other two human CYP inhibitors were classified as strong inhibitors of CYP2A: 8-methoxypsoralen (CYP2A6) and alpha-naphthoflavone (CYP1A1/2). In the absence of a preincubation period, 8-MOP inhibited the 7-hydroxylation of coumarin with a K(i) value of 1.1 MUm, which decreased to 0.1 MUm when 8-MOP was preincubated with pig liver microsomes for 3 min. alpha-Naphthoflavone inhibited the 7 hydroxylation of coumarin with a K(i) value of 32 MUm, which did not increase ability to inhibitor CYP2A when alpha-naphthoflavone was preincubated with pig liver microsomes for 3 min. These results of this study suggest that 8-MOP is a potent, mechanism-based inhibitor of pig CYP2A activity in pig liver microsomes. PMID- 21244439 TI - Kudzu extract treatment does not increase the intoxicating effects of acute alcohol in human volunteers. AB - BACKGROUND: Isoflavone administration in the form of a purified extract from the herbal medication kudzu root has been shown to reduce, but not eliminate, alcohol consumption in alcohol-abusing and alcohol-dependent men. The precise mechanism of this action is unknown, but 1 possible explanation for these results is that the isoflavones in kudzu might actually increase the intensity or duration of alcohol's effects and thus delay the desire for subsequent drinks. This study was designed to test this hypothesis. METHODS: Twelve (12) healthy adult men and women (27.5 +/- 1.89 years old) who consumed moderate amounts of alcohol (7.8 +/- 0.63 drinks/wk) participated in a double-blinded, placebo-controlled crossover study in which they were treated with either kudzu extract (total isoflavone dose of 750 mg/d) or matched placebo for 9 days. On days 8 and 9, participants received an acute challenge of ethyl alcohol (either 0.35 or 0.7 g/kg alcohol). During the challenges, the following measures were collected: subjective effects, psychomotor (body sway), cognitive performance (vigilance/reaction time), physiological measures (heart rate and skin temperature), and plasma ethanol concentration. RESULTS: Alcohol resulted in a dose-related alteration in subjective measures of intoxication, impairment of stance stability, and vigilance/reaction time. Kudzu extract did not alter participants' subjective responses to the alcohol challenge or to alcohol's effects on stance stability or vigilance/reaction time. However, individuals treated with kudzu extract experienced a slightly more rapid rise in plasma ethanol levels, but only after the 0.7 g/kg dose. This transient effect during the first 30 minutes of the ascending plasma alcohol curve lasted only 10-15 minutes; there were no differences in peak plasma alcohol levels or alcohol elimination kinetics. Additionally, kudzu pretreatment enhanced the effects of the 0.7 g/kg dose of alcohol on heart rate and skin temperature. CONCLUSIONS: These data suggest that individuals who drink alcohol while being treated with kudzu extract experience no adverse consequences, and furthermore the reported reductions in alcohol intake after kudzu extract treatment are not related to an alteration in alcohol's subjective or psychomotor effects. PMID- 21244438 TI - Alcoholic marriage: later start, sooner end. AB - BACKGROUND: Although associations between drinking behavior and marital status are well documented, timing of marital transitions as a function of alcohol use or disorder has received limited empirical attention. METHODS: We examine the relationship between lifetime history of alcohol dependence (AD) and timing and survival of first marriages in a sample of 3,575 female and 1,845 male adult Australian twins born mostly between 1940 and 1964. Survival analyses were conducted using Cox proportional hazards regression models. RESULTS: Results indicate moderate delays in marriage associated with AD for both women and men. Among ever-married respondents, AD was strongly predictive of early separation, with similar effects observed for women and men. Heritable sources of covariation were also documented. For women, genetic influences shared between early-onset AD and marital timing were found. Genetic influences shared between AD and marital survival were observed for women without regard to onset and for men with later onset AD. CONCLUSIONS: Results confirm the importance of AD as a predictor of both timing and survival of first marriages, with genetic influences contributing to observed associations. PMID- 21244440 TI - Risky alcohol use in adolescence: the role of genetics (DRD2, SLC6A4) and coping motives. AB - BACKGROUND: Drinking to cope (i.e., drinking to forget or alleviate negative feelings) has been found to be associated with adolescents' heavy drinking and alcohol-related problems. Additionally, it is widely accepted that genetic factors are involved in alcohol use and dependence. Studies are only beginning to reveal, however, which specific genotypes are related to drinking behaviors, and it is unknown whether they may interact with coping motives in predicting adolescents' risky drinking. The aim of this study was to examine relationships between the dopamine D2 receptor gene (DRD2) Taq1A polymorphism (rs1800497), a serotonin transporter gene (SLC6A4) polymorphism (5-HTTLPR), coping motives, and adolescents' binge drinking and alcohol-related problems. METHODS: Participants in this cross-sectional study were 282 Dutch adolescents (mean age 17.4, 47% men) who had consumed alcohol at least once in their life. RESULTS: Coping motives were positively related to both binge drinking and alcohol-related problems, while DRD2 and SLC6A4 genotypes were not. DRD2, but not the SLC6A4 genotype, interacted with coping motives. The link between coping motives and alcohol outcomes was stronger among those carrying the DRD2 risk (A1) allele. CONCLUSIONS: This study extends the present literature by providing additional insight into the etiological factors of adolescent drinking behavior. An interaction between a vulnerability gene (DRD2) and a cognitive factor (coping drinking) was found to be related to adolescents' binge drinking and alcohol related problems. PMID- 21244441 TI - Surgical technique, postoperative complications and outcome in 14 dogs treated for hydrocephalus by ventriculoperitoneal shunting. AB - OBJECTIVE: To report frequency and type of complications, and outcome in dogs with severe neurologic signs secondary to internal, suspected obstructive hydrocephalus treated by ventriculoperitoneal (VP) shunting. STUDY DESIGN: Case series. ANIMALS: Dogs (n=14). METHODS: Medical records (2001-2006) was reviewed for dogs that had VP shunting. Inclusion criteria were complete medical record, progressive forebrain signs unresponsive to medical treatment, normal metabolic profile, negative antibody titers and/or cerebrospinal PCR for Toxoplasma gondii, Neospora caninum, and canine distemper virus, magnetic resonance images of the brain, confirmed diagnosis of VP shunting, and follow-up information. RESULTS: Hydrocephalus was idiopathic in 5 dogs and acquired (interventricular tumors, intraventricular hemorrhage, inflammatory disease) in 9 dogs. Four dogs developed complications 1 week to 18 months postoperatively, including ventricular catheter migration, infection, shunt under-drainage, kinking of the peritoneal catheter, valve fracture, and abdominal skin necrosis. Three of these dogs had 1 or more successful revision surgeries and 1 dog was successfully treated with antibiotics. All, but 1 dog, were discharged within 1 week of surgery, and had substantial neurologic improvement. Median survival time for all dogs was 320 days (1-2340 days), for dogs with idiopathic hydrocephalus, 274 (60-420) days and for dogs with secondary hydrocephalus, 365 (1-2340) days. CONCLUSIONS: VP shunting was successful in relieving neurologic signs in most dogs and postoperative complications occurred in 29%, but were resolved medically or surgically. PMID- 21244442 TI - Evaluation of composite resin materials for maxillomandibular fixation in cats for treatment of jaw fractures and temporomandibular joint luxations. AB - OBJECTIVE: To identify a method of composite application for maxillomandibular fixation (MMF) in cats that ensures the material will remain bonded during convalescence but be easy to remove with a low complication rate. STUDY DESIGN: Experimental study. SAMPLE POPULATION: Feline cadavers (n=88). METHODS: MMF was applied using composite to 4 groups of 22 feline cadaver heads each. The protocols were: group CR: acid etch and composite resin; group CR+: acid etch, bonding agent, and composite resin; group FR50: partial surface acid etch and flowable composite resin; group FR100: complete surface acid etch and flowable composite resin. Removal time and complication rate were noted. Load to failure was determined by tensile loading. RESULTS: Load to failure was similar for groups CR and CR+ and for groups FR50 and FR100; however, load to failure for groups FR50 and FR100 was higher than groups CR and CR+ (P<.01). Time for material removal for group FR100 was longer (P<.01) and the complication rate was higher (P<.01) compared with the groups CR, CR+, and FR50, with no significant differences in removal times and complication rate between the latter groups. The most frequent complication during material removal in group FR100 was crown fracture. CONCLUSIONS: Partial coronal surface acid etch before use of flowable composite maintained a strong bond, yet resulted in easy material removal with a low complication rate. PMID- 21244443 TI - Evaluation of S-adenosyl l-methionine in a double-blinded, randomized, placebo controlled, clinical trial for treatment of presumptive osteoarthritis in the dog. AB - OBJECTIVE: To evaluate the efficacy of S-adenosyl l-methionine (SAMe) in the treatment of clinically inferred canine osteoarthritis (OA). STUDY DESIGN: Six weeks, double-blinded, placebo-controlled, clinical trial. ANIMALS: Dogs (n=33) with clinical signs, history, and orthopedic exams consistent with OA. METHODS: Dogs were block randomized by body condition score (<6/9, or >=6/9) into either the placebo or SAMe group. Outcome was assessed using pressure platform gait analysis, examination score, goniometry, and the Canine Brief Pain Inventory (CBPI) at the time of study entrance and at 3 and 6 weeks after entry. Groups were compared using parametric and nonparametric paired tests as appropriate, and numbers needed to treat (NNT) were calculated for the CBPI and peak vertical force (PVF). RESULTS: Both groups (n=15 placebo, n=18 SAMe) had a reduction in mean PVF (P=.02) and vertical impulse (VI; P=.06) from the 1st to 3rd visit. There was no significant difference between the placebo group and SAMe group for PVF, VI, or either part of the CBPI (Severity or Impact). The NNT at 6 weeks for the Severity score was 3, Impact score was 25, and PVF was 45. CONCLUSIONS: These data do not support the use of SAMe as an effective stand alone treatment for reducing clinical signs of OA, as measured by PVF, VI, goniometry, CBPI (both Severity and Impact), and examination score within 6 weeks of treatment. PMID- 21244445 TI - Management of femoral fractures in dogs with unilateral semicircular external skeletal fixators. AB - OBJECTIVE: To report use of semicircular external skeletal fixators (ESF) for management of femoral fractures in dogs. STUDY DESIGN: Prospective clinical study. ANIMALS: Dogs (n=16) with femoral fractures (n=18). METHODS: A semicircular ESF system composed of 6-hole 45 degrees or 5-hole 40 degrees carbon-fiber arches, 6 mm threaded rods, half pin fixation bolts, 6 mm nuts, and negative profile end-threaded half pins were used for open repair of femoral fractures. ESF configuration, complications, limb use, fixator removal time, and functional outcomes were evaluated. Outcome was graded as excellent, good, fair, or poor. RESULTS: Seventeen fractures with sufficient follow-up healed. Eight dogs started using the limb immediately after waking up from anesthesia whereas initial limb use was 1-4 days after repair in the other dogs. Time to fixator removal ranged from 28 to 63 days (mean, 38 days). Functional outcome was excellent in 13 cases, good in 4, and poor in 1 nonunion. CONCLUSION: Semicircular ESF combined with open surgical reduction can be used to successfully repair metaphyseal and diaphyseal femoral fractures in young growing dogs. PMID- 21244444 TI - Arthrodesis of the equine proximal interphalangeal joint: a biomechanical comparison of 3-hole 4.5 mm locking compression plate and 3-hole 4.5 mm narrow dynamic compression plate, with two transarticular 5.5 mm cortex screws. AB - OBJECTIVES: To compare the biomechanical characteristics of 2 arthrodesis techniques for the equine proximal interphalangeal joint (PIP) using either a 3 hole 4.5 mm locking compression plate (LCP) or 3-hole 4.5 mm narrow dynamic compression plate (DCP), both with 2 transarticular 5.5 mm cortex screws. STUDY DESIGN: Experimental. SAMPLE POPULATION: Cadaveric adult equine forelimbs (*n=6 pairs). METHODS: For each forelimb pair, 1 limb was randomly assigned to 1 of 2 treatment groups and the contralateral limb by default to the other treatment group. Construct stiffness, gap formation across the PIP joint, and rotation about the PIP joint were determined for each construct before cyclic axial loading and after each of four, 5000 cycle loading regimens. After the 20,000 cycle axial loading regimen, each construct was loaded to failure. RESULTS: There were no significant differences in construct stiffness, gap formation, or sagittal plane rotation between the LCP and DCP treatment groups at any of the measured time points. CONCLUSION: Biomechanically, fixation of the equine PIP joint with a 3-hole 4.5 mm LCP is equivalent to fixation with a 3-hole 4.5 mm narrow DCP under the test conditions used. PMID- 21244446 TI - Evaluation of ethyl alcohol for use in a minimally invasive technique for equine proximal interphalangeal joint arthrodesis. AB - OBJECTIVE: To determine whether intra-articular 70% ethyl alcohol alone (IAEA) or in combination with 2 percutaneously placed transarticular lag screws (EA-TLS) would result in arthrodesis of the equine proximal interphalangeal (PIP) joint. STUDY DESIGN: Experimental. ANIMALS: Healthy horses (n=6), aged 1.5-3 years, free of lameness, diagonally paired front and hind PIP joints. METHODS: Six milliliters 70% ethyl alcohol was injected into randomly selected diagonally paired front and hind PIP joints. Thirty days later, 2 parallel 5.5 mm cortical screws were inserted in lag fashion across the hind PIP joints and the limbs were cast. Horses were confined for 60 days after surgery before free exercise was permitted. Serial lameness examinations were performed at 1, 6, and 10 months. Radiographs of the PIP joints were obtained before injection with alcohol (front, hind PIP joints), at 6 and 10 months (front PIP joints) and 1, 3, 6, and 10 months (hind PIP joints). At 10 months, horses were euthanatized and gross and histopathologic examination of the treated joints was performed. RESULTS: Horses had variable cartilage thinning (more severe in hind PIP joints) and dorsal bone proliferation. One front and 1 hind PIP joint were fused 10 months after alcohol injection. CONCLUSIONS: Ethyl alcohol injected alone or in combination with percutaneously placed transarticular lag screws failed to reliably produce fusion of the PIP joint. PMID- 21244447 TI - Evidence for anaerobic oxidation of methane in sediments of a freshwater system (Lago di Cadagno). AB - Anaerobic oxidation of methane (AOM) has been investigated in sediments of a high alpine sulfate-rich lake. Hot spots of AOM could be identified based on geochemical and isotopic evidence. Very high fractionation of methane (alpha=1.031) during oxidation was observed in the uppermost sediment layers, where methane is oxidized most likely with sulfate-containing bottom waters. However, we could not exclude that other electron acceptors such as iron, or manganese might also be involved. Light carbon isotope values (delta13C = -100/00 vs. Vienna Pee Dee Belemnite [VPDB]) of sedimentary carbonates at 16-20 cm sediment depth are indicative of a zone where methane was oxidized and the resulting bicarbonate ions were used for carbonate precipitation. 16S rRNA gene analysis revealed the presence of sequences belonging to the marine benthic groups B, C, and D and to the recently described clade of AOM-associated archaea (AAA). Catalyzed reporter deposition-FISH analysis revealed a high abundance of Deltaproteobacteria, especially of free-living sulfate-reducing bacteria of the Desulfosarcina/Desulfococcus branch of Deltaproteobacteria in the AOM zone. Here, loose aggregations of AAA cells were found, suggesting that AAA might be responsible for oxidation of methane in Lake Cadagno sediments. PMID- 21244452 TI - Development and evaluation of an immunochromatographic strip for the detection of Human cytomegalovirus. AB - AIMS: To develop and evaluate an immunochromatographic strip for the detection of human cytomegalovirus. METHODS AND RESULTS: An immunochromatographic strip for detecting human cytomegalovirus (HCMV) was developed based on membrane chromatography with monoclonal antibodies (mAbs) against HCMV. Bagg albino C mice that were immunized with HCMV yielded two hybridomas secreting mAbs (3C6 and 5D8) specific for HCMV. In this strip, monoclonal antibody 3C6 was conjugated with colloidal gold as the detector antibody. 5D8, in combination with rabbit anti HCMV polyclonal antibody, was blotted on the nitrocellulose membrane as the capture complex for the test line, and goat anti-mouse immunoglobulin G antibody was used as the capture antibody at the control line. The sensitivity of the strip to HCMV-positive samples reached to 1 : 5.12 * 10(4). The strip test correctly detected the HCMV in known positive samples and did not react with the standard antigens of HSV-1 and HSV-2, CHV, VZV, HHV-6, JEV, DV, WNV. When 400 clinical specimens suspected of infection with HCMV were tested, results from the strip test were nearly identical with those from the hemagglutination/hemagglutination inhibition test, reverse transcription polymerase chain reaction and an enzyme-linked immunosorbent assay kit. CONCLUSIONS: An immunochromatographic strip for detecting HCMV was developed based on membrane chromatography with mAbs against HCMV. SIGNIFICANCE AND IMPACT OF THE STUDY: The immunochromatographic strip is an acceptable alternative for diagnosing the HCMV and for investigating its epidemiology in clinical laboratories lacking specialized equipment. PMID- 21244453 TI - The development of loop-mediated isothermal amplification combined with lateral flow dipstick for detection of Vibrio parahaemolyticus. AB - AIMS: The current study was aimed to develop a loop-mediated isothermal amplification (LAMP) combined with amplicon detection by chromatographic lateral flow dipstick (LFD) assay for rapid and specific detection of Vibrio parahaemolyticus. METHODS AND RESULTS: Biotinylated LAMP amplicons were produced by a set of four designed primers that recognized specifically the V. parahaemolyticus thermolabile haemolysin (tlh) gene followed by hybridization with an FITC-labelled probe and LFD detection. The optimized time and temperature conditions for the LAMP assay were 90 min at 65 degrees C. The LAMP-LFD method accurately identified 28 isolates of V. parahaemolyticus but did not detect 24 non-parahaemolyticus Vibrio isolates and 35 non-Vibrio bacterial isolates. The sensitivity of LAMP-LFD for V. parahaemolyticus detection in pure cultures was 120 CFU ml-1. In the case of spiked shrimp samples without enrichment, the detection limit for V. parahaemolyticus was 1.8 x 103 CFU g-1 or equivalent to 3 CFU per reaction while that of conventional PCR was 30 CFU per reaction. CONCLUSIONS: The established LAMP-LFD assay targeting tlh gene was specific, rapid and sensitive for identification of V. parahaemolyticus. SIGNIFICANCE AND IMPACT OF THE STUDY: The developed LAMP-LFD assay provided a valuable tool for detection of V. parahaemolyticus and can be used effectively for identification of V. parahaemolyticus in contaminated food sample. PMID- 21244454 TI - Detection and enumeration of Dekkera anomala in beer, cola, and cider using real time PCR. AB - AIMS: In this article, a quantitative real-time PCR assay for detection and enumeration of the spoilage yeast Dekkera anomala in beer, cola, apple cider, and brewing wort is presented as an improvement upon existing detection methods, which are very time-consuming and not always accurate. METHODS AND RESULTS: Primers were designed to exclude other organisms common in these beverages, and the assay was linear over 6 log units of cell concentrations. The addition of large amounts of non-target yeast DNA did not affect the efficiency of this assay. A standard curve of known DNA was established by plotting the C(t) values obtained from the QPCR against the log of plate counts on yeast peptone dextrose medium and unknowns showed exceptional correlation when tested against this standard curve. The assay was found to detect D. anomala at levels of 10-14 CFU ml-1 in either cola or beer and at levels of 9.4-25.0 CFU ml-1 in apple cider. The assay was also used to follow the growth of D. anomala in brewing wort. CONCLUSIONS: The results indicate that real-time PCR is an effective tool for rapid, accurate detection and quantitation of D. anomala in beer, cola and apple cider. SIGNIFICANCE AND IMPACT OF THE STUDY: This method gives a faster and more efficient technique to screen beer, cola, and cider samples and reduce spoilage by D. anomala. Faster screening may allow for significant reduction in economic loss because of reduced spoilage. PMID- 21244455 TI - Cryptococcosis: update and emergence of Cryptococcus gattii. AB - Cryptococcosis is a fungal disease that occurs throughout the world. Recent reclassification of Cryptococcus species along with a change in the distribution pattern has prompted reevaluation of the organism and the diseases caused by this pathogen. This review highlights the emergence of Cryptococcus gattii as a primary pathogen in North America and summarizes our current understanding of the disease in mammals and birds. PMID- 21244456 TI - Representations of hysterectomy as a transition process in Finnish women's and health magazines. AB - Representations of hysterectomy as a transition process in Finnish women's and health magazines The purpose of this article was to describe representations of hysterectomy in Finnish women's and health magazines. The data used in the study were obtained from six Finnish women's and health magazines. Using content analysis, 42 articles were analysed. We identified two main categories, information about care and treatment and women's experiences. In the first category, there emerged six subcategories: role of uterus, indications for hysterectomy, operative techniques of hysterectomy, alternative methods of treatment, pros and cons of hysterectomy and patient guidance. The second category consisted of women's experiences of hysterectomy as a period of transition. The components of the transition theory were confirmed by the women's stories. We also wanted to highlight the fact that the result shows that nurses were missing from the media coverage regarding hysterectomy. PMID- 21244457 TI - Wellbeing among people with dementia and their next of kin over a period of 3 years. AB - Little is known about the dyadic experience over time of people with dementia and their next of kin. The aim of this study was to investigate the state of mind of people with dementia, their next of kin's experience of burden and satisfaction, and factors associated with these experiences over a 3-year period. The sample consisted of 32 people with dementia living at home with family caregivers in the south of Sweden. Data were collected during the period 2004-2007 and consisted of patients self reports (GDS), dementia nurse assessment (MMSE, Berger and ADL) and next-of-kin assessment (patient's state of mind and care provision). Data also consisted of next-of-kin's self reports concerning health, burden and satisfaction. The result showed that patients' state of mind was mainly positive at baseline but a deterioration was seen over time in the patient's mood and cognitive functioning together with an increase in ADL-dependency and suspected depression. Dependency in personal ADL entailed a higher risk of being in a negative state of mind. For next of kin the experience of burden increased while satisfaction decreased over the 3 years. The inter-relationship between the patients' mood and the caregiver's satisfaction and burden seems to get stronger over time. At baseline caregiver burden was mainly related to the next of kins' general health and to patient behaviours that were difficult to handle. During the progression of the disease caregiver satisfaction becomes increasingly related to patient state of mind and dependency. There is, however, a need for more research focusing on the specific inter-relational aspects as previous studies have mainly focused on either the situation for the person with dementia or on the caregiver. PMID- 21244458 TI - Learning to live with illness: experiences of persons with recent diagnoses of diabetes mellitus. AB - BACKGROUND: The process of learning to live with an illness is complex. By better understanding the learning process for persons with diabetes in the early stage of the illness, the role of the health care can be shown. AIM: To reach an understanding of how learning to live with diabetes is experienced in the first 2 months after diagnosis. METHOD: A qualitative descriptive design was used, and interviews were conducted. Thirteen participants with a recent diagnosis of diabetes were included and asked to narrate about their experience of living with diabetes. Qualitative inductive content analysis was used. FINDINGS: Four themes emerged: 'taken over by a new reality', 'the body plays a role in life', 'different ways of learning' and 'the healthcare service as a necessary partner'. CONCLUSION: People with short-term experience of the illness gained knowledge through personal resources such as their own experience and self-reflection. The learning process includes an inner dialogue between the self, the body and the life. Participants were concerned with grasping a new reality and understanding a different self and body where lifestyle changes and uncertainty were present. When health care was accessible and sensitive to their needs, those with short term experience of diabetes chose the staff as key players in the early stages of their life with diabetes. PMID- 21244459 TI - Implementing and sustaining dietary change in the context of social relationships. AB - BACKGROUND: Changing to healthier dietary habits is quite difficult to implement and even more difficult to sustain. As the majority of people have some or all their meals with others, it is likely that their social relationships influence the dietary change process and its sustainability. Thus, the aim of this research was to explore and describe experiences of dietary change and its sustainability in the context of an individual's social relationships. METHODS: Semi-structured interviews were conducted individually with fourteen individuals who had previously been participants in a 3-month dietary intervention study using a Mediterranean diet. Thematic analysis was used on verbatim transcripts of the interviews. RESULTS: Social relationships were the main barrier to sustainability - in particular social relationships within the household where various coping strategies were needed on an everyday basis. Social relationships outside the household were also difficult to manage as dietary change challenged existing traditions and norms of what to eat. The changer was thereby forced to risk social disapproval or to deviate from the diet. CONCLUSIONS: Social relationships within and outside the household complicated the accomplishment of healthy dietary changes. Hence, it is important to acknowledge the social context of the changer when dietary change is to be implemented. PMID- 21244461 TI - Basal cell carcinoma with a bonus. PMID- 21244462 TI - The melanoma 'epidemic', a dermatopathologist's perspective. AB - Over the past several decades, the rise in melanoma incidence has been termed "epidemic." However, detailed analysis of mortality data suggests that the true incidence of melanoma has not increased dramatically. Dermatopathologists, who hold a key position in the diagnosis of melanoma, should have unique insight into this quandary. Factors contributing to the apparent melanoma epidemic likely include intense screening, sampling of earlier lesions, medical-legal pressures, imperfect diagnostic methodology, and lack of a usable gold standard. Consequences of the apparent melanoma epidemic are also explored herein. PMID- 21244463 TI - In my opinion... PMID- 21244466 TI - Cytokines in response to proteins predicted in genomic regions of difference of Mycobacterium tuberculosis. AB - Cellular immune responses are responsible for both protection and pathogenesis in tuberculosis, and are mediated/regulated by a complex network of pro inflammatory, T helper (Th) type 1 and type 2 cytokines. In this study, the secretion of pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-8 and IL-1beta; Th1 cytokines interferon-gamma (IFN gamma), IL-2 and tumor necrosis factor-beta (TNF-beta); and Th2 cytokines IL-4, IL-5 and IL-10 by the peripheral blood mononuclear cells (PBMCs) of pulmonary tuberculosis patients was studied. PBMCs were cultured in vitro in the absence and presence of complex mycobacterial antigens and peptides corresponding to 11 regions of difference (RD) of Mycobacterium tuberculosis that are deleted/absent in all vaccine strains of Mycobacterium bovis bacillus Calmette-Guerin (BCG). The culture supernatants were tested for secreted cytokines by FlowCytomix assay. PBMCs from the majority of patients (53-100%) spontaneously secreted detectable concentrations of all cytokines tested, except for IL2 (29%) and IL-10 (41%). The profiles of proinflammatory cytokines were largely similar for various complex antigens or RD peptides. However, with respect to Th1 and Th2 cytokines, the antigens could be divided into three groups; the first with Th1-bias (culture filtrate of M. tuberculosis, RD1, RD5, RD7, RD9 and RD10), the second with Th2 bias (whole cells and cell walls of M. tuberculosis, RD12, RD13 and RD15), and the third without Th1/Th2-bias (M. bovis BCG, RD4, RD6 and RD11). Complex mycobacterial antigens and RD proteins with Th1- and Th2-biases may have roles in protection and pathogenesis of tuberculosis, respectively. PMID- 21244467 TI - Detection of Staphylococcus hyicus exfoliative toxin genes by dot blot hybridization and multiplex polymerase chain reaction. AB - We designed a novel DNA probe and novel PCR primer sets for detecting the genes coding for Staphylococcus hyicus (S. hyicus) exfoliative toxin (ET). In dot blot hybridization, the novel DNA probe hybridized with chromosomal DNA of ExhA-, ExhB , ExhC-, ExhD-, and SHETA-producing strains. This probe also hybridized with the plasmid DNA of a SHETB-producing strain. In Southern blot hybridization, the probe hybridized with a 1.5 kb HindIII fragment of chromosomal DNA from a SHETA producing strain. The above fragment was cloned into E. coli and the nucleotide sequence of the SHETA gene determined, this gene proved to have almost the same homology (99.6%) as the ExhB gene. It was therefore thought that SHETA is a subtype of ExhB. In multiplex PCR using five primer sets, each gene gave a band distinguishable from the others. This multiplex PCR system has high specificity among the well-known S. hyicus ET genes. Of the 69 known ET-producing S. hyicus strains, 38, 19, 10, 2 and 1 strains have exhB, exhD exhA, shetb and exhC genes, respectively. PMID- 21244468 TI - Serum concentrations of complement anaphylatoxins and proinflammatory mediators in patients with 2009 H1N1 influenza. AB - Anaphylatoxins (C5a, C4a, and C3a) are fragments of activated complement and are leading mediators of the inflammatory response for controlling viral infection. However, an excessive response may increase the severity of infectious diseases. Serum concentrations of proinflammatory mediators, including cytokines, high mobility group box 1 and anaphylatoxins, were measured in pediatric 2009 H1N1 influenza patients in order to investigate the pathology of this new influenza. The concentrations of all three anaphylatoxins were significantly enhanced by 2009 H1N1 influenza infection. However, there were no significant differences in anaphylatoxin concentrations between 2009 H1N1 influenza patients with and without severe complications during the early stages of the disease. C3a concentrations dropped significantly during the recovery phase, whereas there were no significant differences between the acute and recovery phases in C5a and C4a concentrations. There was a correlation between C5a and IL-2. C4a was associated with IL-1ra, eotaxin, MCP-1, PDGFbb, and VEGF. C3a was correlated with IL-2 and IFN-gamma. Taken together, these findings indicate that complement activation occurs in patients infected with 2009 H1N1 influenza virus and demonstrate that anaphylatoxins are involved in increased production of proinflammatory mediators in this new influenza. PMID- 21244469 TI - Nitric oxide-mediated apoptosis in rat macrophages subjected to Shiga toxin 2 from Escherichia coli. AB - Shiga toxin-producing Escherichia coli are important food-borne pathogens. The main factor conferring virulence on this bacterium is its capacity to secrete Shiga toxins (Stxs), which have been reported to induce apoptosis in several cell types. However, the mechanisms of this apoptosis have not yet been fully elucidated. In addition, Stxs have been shown to stimulate macrophages to produce nitric oxide (NO), a well-known apoptosis inductor.The aim of this study was to investigate the participation of NO in apoptosis of rat peritoneal macrophages induced by culture supernatants or Stx2 from E. coli. Peritoneal macrophages incubated in the presence of E. coli supernatants showed an increase in the amounts of apoptosis and NO production. Furthermore, inhibition of NO synthesis induced by addition of aminoguanidine (AG) was correlated with a reduction in the percentage of apoptotic cells, indicating participation of this metabolite in the apoptotic process. Similarly, treatment of cells with Stx2 induced an increase in NO production and amount of apoptosis, these changes being reversed by addition of AG. In summary, these data show that treatment with E. coli supernatants or Stx2 induces NO-mediated apoptosis of macrophages. PMID- 21244470 TI - A candidate inactivated chimeric vaccine PCV1-2 constructed based on PCV1 and PCV2 isolates originating in China and its evaluation in conventional pigs in regard to protective efficacy against PCV2 infection. AB - A chimeric PCV1-2 clone containing the PCV2 capsid gene cloned into the backbone of the nonpathogenic PCV1 genome was recently generated based on PCV2 and PCV1 strains isolated in China. The efficacy of this available candidate inactivated vaccine was evaluated by subjecting conventional pigs to intramuscular immunization with the inactivated chimeric PCV1-2 virus, followed by challenge with wild-type PCV2 strain. By 35 days post-vaccination (DPV), all vaccinated pigs had developed seroconversion, having high indirect immunofluorescence assay (IFA) titers of antibody and neutralizing antibody against PCV2. By 21 days post challenge, gross and microscopic lesions of lymph nodes and lungs in non vaccinated but challenged pigs were significantly more severe than those found in the vaccinated group. PCV2 viral copy loads detected in the tracheobronchial lymph nodes or serum samples of vaccinated pigs were significantly smaller than those in non-vaccinated but challenged pigs (P <= 0.05). The results suggest that inactivated PCV1-2 is effective in inducing protective immunity against PCV2 infection. PMID- 21244471 TI - Prevalence of OXA-type carbapenemase genes and genetic heterogeneity in clinical isolates of Acinetobacter spp. from Mangalore, India. AB - The prevalence of OXA-type carbapenemase genes, ISAba1 insertion sequence, carbapenem resistance, biofilm forming ability and genetic heterogeneity in clinical isolates of Acinetobacter spp. from hospitals in Mangalore, South India was studied. Based on the presence of the bla(OXA-51) -like gene, the 62 isolates of Acinetobacter spp. were identified as 48 A. baumannii and 14 other Acinetobacter spp. The prevalence of bla(OXA-23) -like, bla(OXA-24) -like and bla(OXA-58) -like genes in A. baumannii was 47.9%, 22.9% and 4.2%, while in other Acinetobacter spp. it was 28.5%, 64.3% and 35.7% respectively. Several A. baumannii isolates (16/48) harbored the insertion sequence ISAba1 in the upstream region of the bla(OXA-23) -like gene. Resistance to meropenem was seen in 39.6% and 14.2% of A. baumannii and other Acinetobacter spp. isolates, respectively. The ability to form biofilm was observed to be higher among A. baumannii in comparison to other Acinetobacter spp. The present study shows that bla(OXA-23) like genes are more common in A. baumannii,whereas bla(OXA-24) -like genes are common to other Acinetobacter spp. The study revealed genetic heterogeneity among the isolates, indicating multiple sources in the hospitals. PMID- 21244472 TI - The implications of the new International Association of Diabetes and Pregnancy Study Groups (IADPSG) diagnostic criteria for gestational diabetes. PMID- 21244473 TI - High oolong tea consumption predicts future risk of diabetes among Japanese male workers: a prospective cohort study. AB - AIMS: Acute administration of oolong tea decreases blood glucose levels. We investigated the association between long-term oolong tea intake and subsequent risk of developing diabetes among men of working age. METHODS: Data were analysed from a cohort of participants in the High-risk and Population Strategy for Occupational Health Promotion Study (HIPOP-OHP), conducted in Japan from 1999 to 2004. Oolong tea intake at baseline and subsequent risk of diabetes was evaluated using a Cox proportional hazards model. RESULTS: Of 4975 male workers, a total of 201 cases of diabetes were reported over a median of 3.4 years of follow-up. Mean age and BMI of all participants at baseline were 38.3 years and 22.9 kg/m(2) , respectively. Compared with those not consuming oolong tea, multivariable adjusted hazard ratios for developing diabetes were 1.00 (95% CI 0.67-1.49) for those who drank one cup of oolong tea per day and 1.64 (95% CI 1.11-2.40) for those drinking two or more cups per day. Fasting blood glucose increment per year was 0.11 mmol/l (95% CI 0.09-0.12 mmol/l), 0.12 mmol/l (95% CI 0.09-0.15 mmol/l) and 0.15 mmol/l (95% CI 0.11-0.18 mmol/l), respectively, for oolong tea consumption of 0, 1 and >= 2 cups/day, with a significant linear trend (P < 0.0001). CONCLUSIONS: Long-term consumption of oolong tea may be a predictive factor for new onset diabetes. Further studies are necessary to elucidate the role of oolong tea in the risk of developing diabetes. PMID- 21244474 TI - Distinct effects of pitavastatin and atorvastatin on lipoprotein subclasses in patients with Type 2 diabetes mellitus. AB - AIMS: Effects of pitavastatin and atorvastatin on the lipid profile and lipoprotein subclasses were compared in patients with Type 2 diabetes with dyslipidaemia. METHODS: Patients with Type 2 diabetes with hypercholesterolaemia and/or hypertriglyceridaemia were randomized to receive pitavastatin 2 mg (n = 16) or atorvastatin 10 mg (n = 15) for 6 months, and blood lipid and lipoprotein profiles and cholesterol and triglyceride contents of 20 lipoprotein subclasses, determined by high-performance liquid chromatography, were compared. RESULTS: At baseline, cholesterol in VLDL and LDL subclasses were increased equally in two groups of patients with diabetes as compared with normolipidaemic control subjects. As compared with baseline, serum levels of total cholesterol, LDL cholesterol, non-HDL cholesterol, LDL cholesterol:HDL cholesterol ratio and apolipoprotein B were decreased after 1, 3 and 6 months of treatment with atorvastatin and pitavastatin. Serum triglyceride levels were decreased after 1, 3 and 6 months of atorvastatin, but only at 3 months of pitavastatin. Serum HDL cholesterol was increased after 1, 3 and 6 months of pitavastatin, whereas HDL cholesterol was even decreased after 6 months of atorvastatin. Cholesterol levels of most VLDL and LDL subclasses were decreased equally in both groups. However, only pitavastatin increased cholesterol of medium HDL subclass. Serum triglyceride and triglyceride contents in VLDL and LDL subclasses were decreased only by atorvastatin. CONCLUSIONS: The impact on lipoprotein subclass profiles was different between pitavastatin and atorvastatin. It may be beneficial to determine lipoprotein subclass profile and select the appropriate statin for each profile in patients with diabetes with an additional cardiovascular risk such as low HDL cholesterol or hypertriglyceridaemia. PMID- 21244475 TI - Cerebral infarction associated with transient visual loss in child with diabetic ketoacidosis. AB - BACKGROUND: Diabetic ketoacidosis is a metabolic disorder caused by insulin deficiency and is the most important cause of mortality and morbidity in children with Type 1 diabetes mellitus. Acute neurological complications related to diabetic ketoacidosis include cerebral oedema, cerebral infarction, brain herniation, cortical venous thrombosis and cerebral haemorrhage. Cerebral infarction is rare in juvenile diabetic ketoacidosis. CASE REPORT: We report a girl with a newly diagnosed Type 1 diabetes mellitus who presented with diabetic ketoacidosis and developed cerebral infarction with transient visual loss. CONCLUSIONS: Our findings emphasize the importance of prompt evaluation and proper management of intracranial crises in diabetic ketoacidosis. PMID- 21244476 TI - Alterations in HbA(1c) with advancing age in subjects with normal glucose tolerance: Chandigarh Urban Diabetes Study (CUDS). AB - OBJECTIVE: To study the alterations in HbA(1c) with advancing age in subjects with normal glucose tolerance. METHODS: Community-based cross-sectional study involving 2368 subjects aged >= 20 years from Chandigarh, India. All the subjects underwent an oral glucose tolerance test with 75 g anhydrous glucose and were classified as having normal glucose tolerance, pre-diabetes or diabetes according to World Health Organization 1999 criteria. HbA(1c) was measured on a National Glycohemoglobin Standardization Program-certified Bio-Rad D-10 system and the data were available for 1972 subjects. RESULTS: Out of 1972 subjects, 1317 (67%) subjects had normal glucose tolerance. There was a significant positive correlation between mean HbA(1c) and age in these subjects (r = 0.308, P(trend) < 0.001). The increase in HbA(1c) with each advancing year was 0.01% above the age of 20 years and corrected HbA(1c) (%) for age was 5.09 + 0.01 (age). The 95th percentile of HbA(1c) exceeded 6.5% (48 mmol/mol) (the American Diabetes Association cut-off for diagnosis of diabetes) in subjects aged >= 70 years. A significantly higher number (6.5%, 21/325) of subjects had HbA(1c) of >= 6.5% (48 mmol/mol) in those above the age of 50 years compared with those below the age of 50 years (1.7%, 17/992) in the group with normal glucose tolerance (P < 0.001). On multivariate regression analysis, after adjusting for BMI, fasting plasma glucose and 2-h plasma glucose post-glucose load, the correlation of HbA(1c) with age still remained significant (r = 0.241, P < 0.01). CONCLUSION: HbA(1c) increases with advancing age independent of glycaemia, suggesting caution when seeking to achieve the recommended HbA(1c) targets in the elderly population. PMID- 21244477 TI - How and why do patients with Type 1 diabetes sustain their use of flexible intensive insulin therapy? A qualitative longitudinal investigation of patients' self-management practices following attendance at a Dose Adjustment for Normal Eating (DAFNE) course. AB - BACKGROUND: Conventional insulin therapy requires patients with Type 1 diabetes to adhere to rigid dietary and insulin injection practices. Recent trends towards flexible intensive insulin therapy enable patients to match insulin to dietary intake and lifestyle; however, little work has examined patients' experiences of incorporating these practices into real-life contexts. This qualitative longitudinal study explored patients' experiences of using flexible intensive insulin therapy to help inform the development of effective long-term support. METHODS: Semi-structured interviews were conducted with 30 adult patients with Type 1 diabetes following participation in a structured education programme on using flexible intensive insulin therapy, and 6 and 12 months post-course. Longitudinal data analysis used an inductive, thematic approach. RESULTS: Patients consistently reported feeling committed to and wanting to sustain flexible intensive insulin therapy. This regimen was seen as a logical and effective method of self-management, as patients experienced improved blood glucose readings and/or reported feeling better. Implementing and sustaining flexible intensive insulin therapy was enhanced when patients had stable routines, with more challenges reported by those working irregular hours and during weekends/holidays. Some patients re-crafted their lives to make this approach work for them; for instance, by creating dietary routines or adjusting dietary choices. CONCLUSIONS: Clinical data have shown that flexible intensive insulin therapy can lead to improvement in glycaemic control. This study, drawing on patients' perspectives, provides further endorsement for flexible intensive insulin therapy by demonstrating patients' liking of, and their motivation to sustain, this approach over time. To help patients implement and sustain flexible intensive insulin therapy, follow-up support should encourage them to identify routines to better integrate this regimen into their lives. PMID- 21244478 TI - Melatonin reduces the impairment of axonal transport and axonopathy induced by calyculin A. AB - Previous studies have reported that calyculin A (CA), a selective inhibitor of protein phosphatase (PP)-2A and PP-1, impairs axonal transport in neuroblastoma N2a cells. Melatonin prevents Alzheimer-like hyperphosphorylation of cytoskeletal proteins and the impairment of spatial memory retention induced by CA. In this study, we tested the effects of melatonin on the impairment of axonal transport induced by CA in neuroblastoma N2a cells. We found that melatonin protected the cells from CA-induced toxicity in metabolism and viability as well as hyperphosphorylation of tau and neurofilaments. Furthermore, melatonin partially reversed the CA-induced phosphorylation of the catalytic subunit of PP-2A at tyrosine 307, a crucial site that negatively regulates the activity of PP-2A, and reduced the levels of malondialdehyde and the activity of superoxide dismutase, which are markers of oxidative stress. Melatonin also significantly reversed the CA-induced impairment of axonal transport. These results suggest that melatonin may have a role in protecting against the CA-induced impairment of axonal transport by modulating the activity of PP-2A and oxidative stress. PMID- 21244479 TI - Reaction mechanism of melatonin oxidation by reactive oxygen species in vitro. AB - Melatonin (N-acetyl-5-hydroxytryptamine) is a pineal hormone widely known for its antioxidant properties, both in vivo and by direct capture of free radicals in vitro. Although some metabolites and oxidation products of melatonin have been identified, the molecular mechanism by which melatonin exerts its antioxidant properties has not been totally unravelled. This study investigated the reaction mechanism of oxidation of melatonin by radio-induced reactive oxygen species, generated by gamma radiolysis of water for aqueous solutions of melatonin (from 20 to 200 MUm), in the presence or absence of molecular oxygen. The hydroxyl radical was found to be the unique species able to initiate the oxidation process, leading to three main products, e.g. N(1)-acetyl-N(2)-formyl-5 methoxykynurenin (AFMK), N(1)-acetyl-5-methoxykynurenin (AMK) and hydroxymelatonin (HO-MLT). The generation of AFMK and HO-MLT strongly depended on the presence of molecular oxygen in solution: AFMK was the major product in aerated solutions (84%), whereas HO-MLT was favoured in the absence of oxygen (86%). Concentrations of AMK remained quite low, and AMK was proposed to result from a chemical hydrolysis of AFMK in solution. A K-value of 1.1 * 10(-4) was calculated for this equilibrium. Both hydrogen peroxide and superoxide dismutase had no effect on the radio-induced oxidation of melatonin, in good accordance for the second case with the poor reactivity of the superoxide anion towards melatonin. Finally, a reaction mechanism was proposed for the oxidation of melatonin in vitro. PMID- 21244480 TI - Melatonin stimulates glucagon secretion in vitro and in vivo. AB - Recent investigations have demonstrated that melatonin influences carbohydrate metabolism mediated by insulin-inhibiting effects on pancreatic beta-cells. This study evaluated whether melatonin has also an effect on pancreatic alpha-cells and glucagon expression as well as the glucagon secretion in vitro and in vivo. Glucagon-producing pancreatic alpha-cell line alphaTC1 clone 9 (alphaTC1.9) was used, which was characterized as an appropriate model with glucose responsiveness and expression of the melatonin receptors MT1 and MT2. The results demonstrate that melatonin incubation significantly enhanced the expression as well as the secretion of glucagon. These effects appeared to be more pronounced under hyperglycemic conditions compared to basal glucose concentrations. Notably, in vivo studies demonstrated that long-term oral melatonin administration led to significantly elevated plasma glucagon concentrations in Wistar rats. In contrast, plasma glucagon levels were found to be slightly decreased in type 2 diabetic Goto-Kakizaki rats. Moreover, investigations measuring the relative glucagon receptor mRNA expression showed marked differences in the liver of melatonin-substituted rats as well as in melatonin receptor knockout mice. In conclusion, these findings revealed evidence that melatonin influences pancreatic glucagon expression and secretion as well as the peripheral glucagon action. PMID- 21244481 TI - Melatonin sensitizes Caki renal cancer cells to kahweol-induced apoptosis through CHOP-mediated up-regulation of PUMA. AB - Melatonin has recently gained attention as a regulator of biologic processes in addition to its effects on circadian rhythms. The mechanisms whereby melatonin regulates the apoptotic program remain poorly understood. In this study, we investigated the combined effect of melatonin and kahweol on apoptosis of cancer cells, but not in most normal human cell types, thus presenting an attractive novel strategy for cancer treatment. In our experiments, treatment with a combination of melatonin and kahweol induced apoptosis, stimulated DEVDase activity, and DNA fragmentation. Co-treatment with melatonin and kahweol induced up-regulation of p53-upregulated modulator of apoptosis (PUMA) while down regulation of PUMA expression using small interfering RNAs attenuated melatonin plus kahweol-induced apoptosis. In addition, co-treatment with kahweol and melatonin induced PUMA up-regulation through endoplasmic reticulum stress mediated C/EBP homologous protein induction and the p53-independent pathway. Our results collectively demonstrate that up-regulation of PUMA contributes to the sensitizing effect of melatonin plus kahweol on apoptosis in cancer cells. PMID- 21244482 TI - Melatonin promotes puromycin-induced apoptosis with activation of caspase-3 and 5'-adenosine monophosphate-activated kinase-alpha in human leukemia HL-60 cells. AB - Melatonin, a naturally occurring molecule, is produced by the pineal gland in a circadian manner to regulate biologic rhythms in humans. Recent studies report that melatonin may be an attractive candidate as an anticancer agent or for combined therapy because of its antioxidant, oncostatic and immunoregulatory activities. In this study, the potentiating effect of melatonin was evaluated on the apoptosis induced by puromycin as an anticancer drug in acute promyelocytic leukemia HL-60 cells. Melatonin did not show significant cytotoxicity against HL 60 cells compared to puromycin. However, melatonin significantly augmented the cytotoxicity of puromycin. Consistently, combined treatment of melatonin and puromycin reduced the expression of anti-apoptotic proteins, such as bcl-2 and bcl-x(L) , and also induced caspase-3 activation and poly (ADP-ribose) polymerase (PARP) cleavage compared to puromycin treatment alone. Furthermore, cell cycle analysis revealed that melatonin promoted puromycin-induced apoptosis by increasing the sub-G1 population, but suppressing G2/M arrest in HL-60 cells. Interestingly, melatonin activated the phosphorylation of 5'-adenosine monophosphate-activated kinase (AMPK) in combination with puromycin. Taken together, our results suggest that melatonin potentiates puromycin-induced apoptosis with caspase-3 and AMPK activation in HL-60 cells, and thus, melatonin treatment can be effectively applied to leukemia treatment as a potential sensitizer for chemotherapeutic agents. PMID- 21244483 TI - Can one question be a useful indicator of psychosocial problems in adolescents with diabetes mellitus? AB - AIM: A screening tool for psychosocial functioning of adolescents with diabetes is unavailable. We investigated whether one question using a Visual Analogue Scale that indicates a rating from the worst (0) to the best possible life (10) is related to standardized indices of psychosocial functioning and well-being in adolescents with diabetes mellitus type 1 (T1DM). METHOD: One hundred and fifty one adolescents with T1DM and 122 healthy peers between 12 and 18 years of age were asked to rate their life on a scale, varying from 0 to 10. Behaviour problems and depressive symptoms were measured with the Youth Self-Report (YSR) and the Children's Depression Inventory (CDI). RESULTS: Adolescents with T1DM rated their life less positive in comparison with their healthy peers (F(1,269) = 14.01, p = 0.000). Adolescents with T1DM who rated their life with a 6 or lower reported more depressive symptoms and behaviour problems (F(2,131) = 24.19, p = 0.00) compared to those with higher scores (7 or up). CONCLUSION: One question the 'rate your life scale' identified most of the adolescents at risk of internalizing behaviour problems, especially depression. The results of this first step in exploring the validity of this question as a screening tool for psychological functioning are promising. PMID- 21244484 TI - The risk of psychiatric disorders in individuals born prematurely in Denmark from 1974 to 1996. AB - AIM: To investigate the risk of developing psychiatric disorders in individuals born prematurely (born before 37 weeks of gestation). METHODS: The study is a longitudinal register-based study including all live-born individuals in Denmark from 1974 to 1996. Poisson regression models including well-known confounders were used to investigate the rate ratio of psychiatric disorders at the age of 11 34 years in the individuals born prematurely. RESULTS: A total of 1,545,641 individuals were born from 1974 to 1996. Of these, 1,348,106 live-born individuals constituted the study cohort. Rate ratios of psychiatric disorders, in total, increased in proportion to the degree of prematurity. The rate ratio of major psychiatric disorder was increased in individuals born with a gestational age below 28 weeks compared to persons born with a gestational age of 39-45 weeks (RR = 1.88 (95% CI: 1.25-2.83)). Similarly, the rate ratios of minor psychiatric disorder (RR = 1.63 (95% CI: 1.29-2.06)) and psychotropic drugs purchased (RR = 1.35 (95% CI: 0.98-1.86)) were increased. CONCLUSION: The risk of minor as well as major psychiatric disorders during adolescence and young adulthood increases in proportion to the degree of prematurity. The relative risk, however, is small compared to the risks of cerebral palsy or low intelligence. PMID- 21244485 TI - Predictive value of body mass index and waist circumference for metabolic syndrome in 6-12-year-olds. AB - AIM: To determine the predictive value of body mass index (BMI) and waist circumference (WC) and their optimal cut-off points for metabolic syndrome (MetS), and also the incidence of MetS. METHODS: This study included 888 children, aged 6-12 years, who were followed for a mean of 6.6 years. BMI, WC and their optimal cut-off points to predict MetS were investigated. RESULTS: The cumulative incidence of MetS was 10.7%. The adjusted ORs for age, sex and family history to predict MetS for BMI and WC z-scores were 2.6 (95% CI, 2.0-3.5) and 2.6 (95% CI, 1.9-3.5), respectively. In their correspondent models, area under the receiver operating characteristic (ROC) curve was 0.73 (95% CI, 0.68-0.79) for BMI z-scores and 0.72 (95% CI, 0.67-0.78) for WC z-scores with no statistically significant difference. The optimal cut-off values for BMI were 16.5 kg/m(2) for boys and 16.3 kg/m(2) for girls and those for WC were 57.5 cm for boys and 56.5 cm for girls. CONCLUSIONS: Our findings suggest that both BMI and WC have the same power to predict MetS and also children with higher BMI or WC are more susceptible to MetS. Moreover, a high incidence of MetS in children highlights the importance of interventional strategies during early childhood. PMID- 21244486 TI - Paracetamol and asthma and lactation. PMID- 21244487 TI - Transcutaneous blood gas monitoring during neonatal intensive care. AB - AIM: To evaluate the accuracy in transcutaneous (Tc) blood gas monitoring in newborn infants, including extremely low birth weight infants, during neonatal intensive care. METHODS: Tc PO(2) /PCO(2) was monitored in the neonatal intensive care unit (NICU) during stable infant conditions. In comparison, simultaneous arterial PO(2) and PCO(2) was measured. Sixty measurements were taken in 46 infants with median (range) birth weight of 0.93 (0.53-4.7) kg and at median (range) age of 8.5 (1-44) days. Comparison of measurements was performed using Bland-Altman plots, and the mean (95% CI) of the difference was calculated. Comparison was also performed in relation to body weight, postnatal age and oxygen requirement. RESULTS: The mean (95% CI) difference in PO(2) (TcPO(2) aPO(2)) was 0.3 (-0.2-0.9) kPa, and the corresponding difference in PCO(2) (TcPCO(2)-aPCO(2)) was 0.4 (0.03-0.8, p < 0.05) kPa. Some differences were related to body weight, age and oxygen requirement, but these differences were small. CONCLUSION: There was good agreement between TcPO(2)/TcPCO(2) and corresponding arterial measurements. The mean difference between the methods was small and clinically acceptable in a current NICU. Tc blood gas monitoring could be recommended as a valuable complement for blood gas monitoring also in extremely low birth weight infants. PMID- 21244488 TI - Anaphylactic reactions to measles-mumps-rubella vaccine in three children with allergies to hen's egg and cow's milk. AB - AIM: Allergies to hen's egg and cow's milk are the most frequent food allergies in infancy and childhood. Current guidelines recommend safe administration of measles-mumps-rubella (MMR) vaccine in egg allergic patients. METHODS: We present three cases of anaphylaxis that we encountered after MMR vaccination in children sensitized to hen's egg and cow's milk. RESULTS: Even though MMR vaccine is generally known to be safe in children with egg allergy, there may still be isolated cases of anaphylaxis. CONCLUSION: Therefore, we recommend that all children not only those who were sensitized to foods should receive the MMR vaccination in a setting that is equipped to deal with anaphylactic reactions. As stated by WHO in immunization safety surveillance, 'Each vaccinator must have an emergency kit with adrenaline, and be familiar with its dosage and administration'. PMID- 21244489 TI - Comparison of television viewing between children with autism spectrum disorder and controls. AB - AIM: To examine the pattern and extent of television viewing in children with autism spectrum disorder (ASD) compared with typically developing controls and those with delayed language development (DLD). METHODS: Fifty-four individuals with ASD (mean age 2.56 +/- 0.66 years) and 84 controls (mean age 2.43 +/- 0.81 years) were enrolled. Fifty-six individuals with DLD, who had language developmental levels similar to those with ASD, were enrolled in our previous study. Main outcome measures included onset and frequency of television viewing, in addition to the type of programme and whether a caregiver cowatched television. RESULTS: Those with ASD began to watch television significantly earlier than controls (6.44 +/- 6.35 vs. 12.41 +/- 6.00 months of age, p <= 0.0001*) and spent more time watching television than those with DLD (4.60 +/- 1.91 vs. 3.05 +/- 1.90 h/day, p <= 0.0001*) and controls (4.60 +/- 1.91 vs. 2.06 +/- 1.21 h/day, p <= 0.0001*). Those with ASD appeared to watch more adult programmes than normal controls, and they were less likely to watch television with caregivers than both control groups. CONCLUSION: There is an earlier onset and higher frequency of television viewing in autistic children compared with children with typical development. PMID- 21244490 TI - Let the celebration begin! PMID- 21244491 TI - The importance of culture in childbearing. AB - In 1972, Mary Lou Moore wrote about the importance of nurses in the United States becoming aware of childbirth traditions of other countries. In 2010, North America has become more culturally diverse, and the dominant culture related to childbirth has become the hospital culture. Nurses must acknowledge this unique culture and work to make women of all cultures comfortable in this setting to ensure a safe and satisfying childbearing experience. PMID- 21244492 TI - The paradox of breastfeeding-associated morbidity among late preterm infants. AB - OBJECTIVE: To synthesize the published research pertaining to breastfeeding establishment and outcomes among late preterm infants and to describe the state of the science on breastfeeding within this population. DATA SOURCES: Online databases Ovid MEDLINE, CINAHL, PubMed, and reference lists of reviewed articles. STUDY SELECTION: Nine data-based research articles examining breastfeeding patterns and outcomes among infants born between 34 0/7 and 36 6/7 weeks gestation or overlapping with this time period by at least 2 weeks. DATA EXTRACTION: Effect sizes and descriptive statistics pertaining to breastfeeding initiation, duration, exclusivity, and health outcomes among late preterm breastfed infants. DATA SYNTHESIS: Among late preterm mother/infant dyads, breastfeeding initiation appears to be approximately 59% to 70% (U.S.), whereas the odds of breastfeeding beyond 4 weeks or to the recommended 6 months (exclusive breastfeeding) appears to be significantly less than for term infants, and possibly less than infants <=34 to 35 weeks gestation. Breastfeeding exclusivity is not routinely reported. Rehospitalization, often related to "jaundice" and "poor feeding," is nearly twice as common among late preterm breastfed infants as breastfed term or nonbreastfed late preterm infants. Barriers to optimal breastfeeding in this population are often inferred from research on younger preterm infants, and evidence-based breastfeeding guidelines are lacking. CONCLUSIONS: Late preterm infants are at greater risk for breastfeeding-associated rehospitalization and poor breastfeeding establishment compared to their term (and possibly early preterm) counterparts. Contributing factors have yet to be investigated systematically. PMID- 21244493 TI - A pilot randomized controlled trial of a breastfeeding self-efficacy intervention with primiparous mothers. AB - OBJECTIVES: To pilot test a newly developed breastfeeding self-efficacy intervention. DESIGN: Pilot randomized controlled trial (RCT). SETTING: An acute care hospital located in Northwestern Ontario that is the sole provider of maternity care for the city and referral center for the region. PARTICIPANTS: One hundred-and-fifty primiparous women intending to breastfeed their healthy, term, singleton infant. INTERVENTION: A standardized, individualized nursing intervention protocol was designed and administered to increase mothers' breastfeeding self-efficacy. Participants were randomly allocated to the intervention group or control group using sealed, opaque envelopes. Participants in the intervention group received three individualized, self-efficacy enhancing sessions with the researcher: two in-hospital and one by telephone. Participants in the control group received standard in-hospital and community care. MAIN OUTCOME MEASURES: Feasibility, compliance, and the acceptability of the breastfeeding self-efficacy intervention. Other outcomes assessed were breastfeeding self-efficacy, duration, and exclusivity. RESULTS: Findings suggest that the intervention was feasible; there was a high degree of protocol compliance, and the majority of mothers reported that the intervention was beneficial. Mothers in the intervention group had higher rates of breastfeeding self-efficacy, duration, and exclusivity at 4 and 8 weeks postpartum. However, the differences between groups were not statistically significant. CONCLUSION: The pilot RCT provided valuable information in examining the feasibility of the trial design and intervention. PMID- 21244494 TI - Severe antenatal depressive symptoms before and after the 2008 Wenchuan earthquake in Chengdu, China. AB - OBJECTIVE: To investigate the prevalence and correlates of severe antenatal depressive symptoms among pregnant women in Chengdu before and after the Wenchuan earthquake. DESIGN: An exploratory and comparative cross-sectional study. SETTINGS: Four regional public hospitals in Chengdu located 90 km from the epicenter of the Wenchuan earthquake. PARTICIPANTS: The convenience sample was composed of 1,156 pregnant women at 12 to 24 weeks' gestation. METHODS: The women were identified as having depressive symptoms using the Edinburgh Postnatal Depression Scale (EPDS). Marital conflict and parent-in-law conflict were assessed using the Dyadic Adjustment Scale (DAS) and the Stryker Adjustment Checklist (SAC), respectively. The Interpersonal Support Evaluation List (ISEL) was used to measure the functional aspects of the perceived availability of social support. RESULTS: Using the EPDS with a cutoff score of 14/15 for severe symptoms of depression, 9.2% and 7.1% of the women screened positive before and after the earthquake. Women who had been married for a shorter time were more likely to have depressive symptoms before the earthquake; those who had lived in Chengdu for a shorter period and who had more infants were more likely to suffer after it. Marital conflict and lack of social support were consistent risk factors before and after the earthquake. CONCLUSION: Additional research is needed to investigate the long-term, earthquake-related psychopathology. Nurses should receive more education about disaster-related psychological health skills to provide more effective prenatal screening and intervene successfully to assist women to optimize their psychological health status after a disaster. PMID- 21244495 TI - miR-181 as a putative biomarker for lymph-node metastasis of oral squamous cell carcinoma. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is an important malignant disease around the world. Aberrant expression of MicroRNAs (miRNAs) has been implicated in carcinogenesis of various cancers. In previous studies, up-regulation of miR 181 was observed when OSCC progressed from leukoplakia, dysplasia to invasive carcinoma. However, the function of miR-181 in oral tumorigenesis remains unclear. MATERIALS AND METHODS: The expression levels of miR-181 in the tissue and plasma of OSCC patients were measured by quantitative RT-PCR. The correlation between miR-181 level and multiple clinical variables were then checked by Mann Whitney test and Wilcoxon matched pairs test. To study the functional meaning of up-regulated miR-181, migration assay and invasion assay by transwells and colony forming assay were applied to analyze the tumorigenic phenotypes of OSCC cells with ectopical expression of miR-181. RESULTS: Among different clinical variables, over-expression of miR-181 was correlated with lymph-node metastasis, vascular invasion, and a poor survival. Functional assays revealed ectopically over-expressed miR-181 would enhance cell migration and invasion, but not the ability of anchorage-independent growth of OSCC cells. In addition, the up regulation of miR-181 could be detected both in tumor tissues and plasma. CONCLUSION: miR-181 may enhance lymph-node metastasis through regulating migration, which could potentially be exploited as a putative biomarker for patients with OSCC. PMID- 21244496 TI - The impact of ovariectomy and hyperglycemia on graft consolidation in rat calvaria. AB - OBJECTIVE: Implant placement frequently depends on bone augmentation. However, the impact of systemic metabolic diseases on the consolidation of bone substitutes remains poorly understood. Our goal is to study the impact of ovariectomy and hyperglycemia on graft consolidation in rat calvaria. MATERIAL AND METHODS: We determined a rat model in which methacrylate hemispheres filled with deproteinized bovine bone mineral were fixed on the calvaria. The first group received streptozotocin (STZ) to induce diabetes. The second group of animals underwent ovariectomy (OVX), causing osteoporosis. Control animals remained untreated, only receiving vehicle injections (STZ-control) but not sham operation, respectively. Specimens were assessed by histomorphometry and MUCT. RESULTS: Graft consolidation was similar between the two groups. The rate of new bone formation after 4 weeks was 0.61+/-0.53% in the STZ group (n=10) and 0.69+/ 0.91% in the control group (n=8). After 8 weeks, the rates of new bone formation were 4.98+/-3.16% in the OVX group (n=7) and 2.35+/-1.30% in the control group (n=10). The volume occupied by the bone substitute was not affected by STZ or OVX treatment. The low amount of newly formed bone could not be quantified by MUCT. CONCLUSION: We conclude that neither STZ nor OVX altered the early phase of graft consolidation. Our findings are limited by the weak osteogenic potential of the rat calvaria in this augmentation model. PMID- 21244497 TI - Bone response to hydroxyapatites with open porosity of animal origin (porcine [OsteoBiol mp3] and bovine [Endobon]): a radiological and histomorphometric study. AB - PURPOSE: To carry out a radiological and histomorphometric evaluation of bone response to two xenografts of animal origin, one porcine, and the other bovine, inserted in rabbits' tibiae. MATERIAL AND METHODS: Twenty New Zealand rabbits weighing 3900-4500 g were used. Twenty bovine bone grafts (Endobon) in granulated form of 500-1000 MUm granulometry were inserted in the proximal metaphyseal area of the animals' right tibia, and 20 porcine bone grafts (OsteoBiol mp3) in granulated form of 600-1000 MUm granulometry were inserted in the proximal metaphyseal area of the animals' left tibia. Following graft insertion, the animals were sacrificed in four groups of five, after 1, 2, 3 and 4 months, respectively. Anteroposterior and lateral radiographs were taken. Samples were processed for observation under light microscopy. Histomorphometric measurements were presented as mean values +/- standard deviations. RESULTS: At 4 months after treatment, the bone defects displayed radiological images that showed complete repair of osseous defects. Histomorphometric evaluation showed that for the porcine xenograft, the study averages for newly formed bone represented 22.8 +/- 1.8%, for residual graft material 23.6 +/- 3% and for connective tissue 53.5 +/- 2.5%, while for the bovine xenograft newly formed bone represented 23.1 +/- 1.8%, residual graft material 39.4 +/- 3% and non-mineralized connective tissue 37.5 +/ 2.5%. CONCLUSIONS: The biomaterials assessed in the study were shown to be biocompatible and osteoconductive. Collagenized porcine xenografts proved more resorbable than bovine xenografts. Both can be used as possible bone substitutes without interfering with normal reparative bone processes. PMID- 21244499 TI - Location of posterior superior alveolar artery and evaluation of maxillary sinus anatomy with computerized tomography: a clinical study. AB - OBJECTIVES: Knowledge and evaluation of the maxillary sinus anatomy before sinus augmentation are essential for avoiding surgical complications. Posterior superior alveolar artery (PSAA) is the branch of maxillary artery that supplies lateral sinus wall and overlying membrane. The aims of this study were to examine the prevalence, diameter, and location of the PSAA and its relationship to the alveolar ridge and to study the prevalence of the sinus pathology and septum using computerized tomography (CT) scans. MATERIALS AND METHODS: One hundred and twenty-one CT scans (242 sinuses) from patients undergoing sinus augmentation procedure and/or implant therapy were included. Lower border of the artery to the alveolar crest, bone height below the sinus floor to the ridge crest, distance of the artery to the medial sinus wall, diameter of the artery, and position of the artery were measured; presence of septa and pathology were recorded from CT sections. RESULTS: Prevalence of sinus septa and sinus pathology was 16.1% and 24.8%, respectively. Artery was seen in 64.5% of all sinuses and was mostly intraosseous (68.2%). Mean diameter of PSAA was found 1.3 +/- 0.5 mm. No significant correlation between the diameter of the artery and age was observed. CONCLUSIONS: The results from this study suggested that CT scan is a valuable tool in evaluating presence of sinus pathology, septa, and arteries before maxillary sinus surgery. Although variations exist in every patient, the findings from this study suggest limiting the superior border of the lateral window up to 18 mm from the ridge to avoid any potential vascular damage. PMID- 21244498 TI - Computed tomography-based evaluation of template (NobelGuideTM)-guided implant positions: a prospective radiological study. AB - OBJECTIVES: This prospective study was intended to evaluate the overall deviation in a clinical treatment setting to provide for quantification of the potential impairment of treatment safety and reliability with computer-assisted, template guided transgingival implantation. MATERIAL AND METHODS: The patient population enrolled (male/female=10/8) presented with partially dentate and edentulous maxillae and mandibles. Overall, 86 implants were placed by two experienced dental surgeons strictly following the NobelGuideTM protocol for template-guided implantation. All patients had a postoperative computed tomography (CT) with identical settings to the preoperative examination. Using the triple scan technique, pre- and postoperative CT data were merged in the Procera planning software, a newly developed procedure - initially presented in 2007 allowing measurement of the deviations at implant shoulder and apex. RESULTS: The deviations measured were an average of 0.43 mm (bucco-lingual), 0.46 mm (mesio distal) and 0.53 mm (depth) at the level of the implant shoulder and slightly higher at the implant apex with an average of 0.7 mm (bucco-lingual), 0.63 mm (mesio-distal) and 0.52 mm (depth). The maximum deviation of 2.02 mm was encountered in the corono-apical direction. Significantly lower deviations were seen for implants in the anterior region vs. the posterior tooth region (P<0.01, 0.31 vs. 0.5 mm), and deviations were also significantly lower in the mandible than in the maxilla (P=0.04, 0.36 vs. 0.45 mm) in the mesio-distal direction. Moreover, a significant correlation between deviation and mucosal thickness was seen and a learning effect was found over the time period of performance of the surgical procedures. CONCLUSION: Template-guided implantation will ensure reliable transfer of preoperative computer-assisted planning into surgical practice. With regard to the required verification of treatment reliability of an implantation system with flapless access, all maximum deviations measured in this clinical study were within the safety margins recommended by the planning software. PMID- 21244500 TI - Effect of anorganic bovine bone to autogenous cortical bone ratio upon bone remodeling patterns following maxillary sinus augmentation. AB - INTRODUCTION: Maxillary sinus augmentation is a predictable implant site development technique, although several local and systemic factors may influence outcomes. The aim of this study was to evaluate healing patterns and bone remodeling activity following the use of two different graft mixtures for maxillary sinus augmentation. MATERIALS AND METHODS: Patients in need of maxillary sinus augmentation were randomly assigned to two different groups. A graft mixture using a 50% autologous bone (AB) to 50% anorganic bovine bone (ABB) ratio was used in group 1, while a 20% AB to 80% ABB ratio was utilized for group 2. After a 6-month healing period, bone core biopsies were harvested for histological, histomorphometrical, and immunohistochemical analyses. RESULTS: Twenty-eight subjects participated in this study. No statistically significant differences were found between groups in regards to vital bone and non mineralized tissue proportions. Higher number of osteoid lines (18.05 +/- 10.06 in group 1 vs. 9.01 +/- 7.53 in group 2; P = 0.023) and higher cellularity, particularly regarding the number of osteocytes (631.85 +/- 607.98 in group 1 vs. 219.08 +/- 103.26 in group 2; P = 0.002), were observed in specimens from group 1. Differences in expression patterns of osteopontin and tartrate-resistant acid phosphatase were also detected between groups. CONCLUSION: AB to ABB ratio appears to influence bone remodeling patterns and cell content following maxillary sinus augmentation procedures. Similar proportion of vital bone was found in specimens obtained from both groups. More cellular presence was observed in samples containing higher proportions of AB. PMID- 21244502 TI - Analysis of intensity variability in multislice and cone beam computed tomography. AB - OBJECTIVES: The aim of this study was to evaluate the variability of intensity values in cone beam computed tomography (CBCT) imaging compared with multislice computed tomography Hounsfield units (MSCT HU) in order to assess the reliability of density assessments using CBCT images. MATERIAL AND METHODS: A quality control phantom was scanned with an MSCT scanner and five CBCT scanners. In one CBCT scanner, the phantom was scanned repeatedly in the same and in different positions. Images were analyzed using registration to a mathematical model. MSCT images were used as a reference. RESULTS: Density profiles of MSCT showed stable HU values, whereas in CBCT imaging the intensity values were variable over the profile. Repositioning of the phantom resulted in large fluctuations in intensity values. CONCLUSIONS: The use of intensity values in CBCT images is not reliable, because the values are influenced by device, imaging parameters and positioning. PMID- 21244501 TI - Osteoblast response to titanium surfaces functionalized with extracellular matrix peptide biomimetics. AB - OBJECTIVE: Functionalizing surfaces with specific peptides may aid osteointegration of orthopedic implants by favoring attachment of osteoprogenitor cells and promoting osteoblastic differentiation. This study addressed the hypothesis that implant surfaces functionalized with peptides targeting multiple ligands will enhance osteoblast attachment and/or differentiation. To test this hypothesis, we used titanium (Ti) surfaces coated with poly-l-lysine-grafted polyethylene glycol (PLL-g-PEG) and functionalized with two peptides found in extracellular matrix proteins, arginine-glycine-aspartic acid (RGD) and lysine arginine-serine-arginine (KRSR), which have been shown to increase osteoblast attachment. KSSR, which does not promote osteoblast attachment, was used as a control. MATERIALS AND METHODS: Sandblasted acid-etched titanium surfaces were coated with PLL-g-PEG functionalized with varying combinations of RGD and KRSR, as well as KSSR. Effects of these surfaces on osteoblasts were assessed by measuring cell number, alkaline phosphatase-specific activity, and levels of osteocalcin, transforming growth factor beta-1 (TGF-beta1), and PGE(2). RESULTS: RGD increased cell number, but decreased markers for osteoblast differentiation. KRSR alone had no effect on cell number, but decreased levels of TGF-beta1 and PGE(2). KRSR and RGD/KRSR coatings inhibited osteoblast differentiation vs. PLL-g PEG. KSSR decreased cell number and increased osteoblast differentiation, indicated by increased levels of osteocalcin and PGE(2). CONCLUSIONS: The RGD and KRSR functionalized surfaces supported attachment but did not enhance osteoblast differentiation, whereas KSSR increased differentiation. RGD decreased this effect, suggesting that multifunctional peptide surfaces can be designed that improve peri-implant healing by optimizing attachment and proliferation as well as differentiation of osteoblasts, but peptide combination, dose and presentation are critical variables. PMID- 21244503 TI - A 2-year prospective study on immediate loading with fluoride-modified implants in the edentulous mandible. AB - OBJECTIVES: Chemically modified surfaces were introduced during the last decade to improve indications for implant treatment. The fluoride-modified implant (Osseospeed((r))) was launched in 2004 and clinical studies suggest a more rapid bone formation and stronger bone to implant contact. However, limited clinical data are available on marginal bone loss and the outcome after >1 year under immediate loading conditions is not fully understood. Hence, the purpose of this prospective study was to present implant survival and marginal bone level data when fluoride-modified implants are supporting a fully functional rehabilitation from the day after surgery in the completely edentulous mandible. MATERIALS AND METHODS: Twenty-five patients, completely edentulous in the mandible, were consecutively treated with five fluoride-modified implants that were functionally loaded with a provisional screw retained restoration. Marginal bone loss was measured from day of surgery to 3, 6, 12 and 24 months. Implants were considered successful after 24 months if radiographic bone loss did not exceed 1 mm and no pain or mobility was caused under a torque of 20 N cm. Statistical analysis was carried out on both patient and implant levels. RESULTS: All implants survived and mean bone loss on implant level after 3, 6, 12 and 24 months was 0.14, 0.13, 0.11 and 0.11 mm, respectively. Bone loss was only statistically significant between baseline and 3 months (P<0.001) and remained unchanged afterward. None of the implants lost >1 mm of bone after 2 years. On the patient level, the mean bone loss after 2 years was 0.12 mm (SD 0.14; range -0.06 to 0.55) with probing pocket depth 2.45 mm (SD 0.43; range 1.3-3.1) and bleeding index 0.55% (SD 0.34; range 0-1). CONCLUSION: Immediate loading of fluoride-modified implants is a predictable treatment yielding a high survival and success rate after 2 years. PMID- 21244504 TI - Association of matrix metalloproteinase gene polymorphism with temporomandibular joint degeneration. AB - Temporomandibular joint (TMJ) degeneration is a frequent cause of orofacial pain. Matrix metalloproteinases (MMPs) degrade extracellular matrix components and play an important role in TMJ degeneration. We investigated the frequency of the MMP1 1G/2G polymorphism (rs1799750), the MMP3 5A/6A polymorphism (rs3025058), and the MMP9 C/T polymorphism (rs3918242) in individuals with TMJ degeneration, in order to analyze the association of polymorphisms in these genes with TMJ degeneration. The population studied comprised 117 healthy controls and 115 individuals diagnosed with TMJ degeneration upon examination of magnetic resonance imaging (MRI) and computed tomography (CT) images. Genotypes were determined using PCR restriction fragment length polymorphism (RFLP). Logistic regression analyses revealed an association between the MMP1 2G/2G genotype and degeneration; in contrast, there was no association between either the MMP3 or the MMP9 genotype and degeneration. Our results may indicate a role for the MMP1 polymorphism in TMJ degeneration. PMID- 21244505 TI - Effect of diabetes on orthodontic tooth movement in a mouse model. AB - Orthodontic tooth movement is achieved by the remodeling of alveolar bone in response to mechanical loading. Type 1 diabetes results in bone remodeling, suggesting that this disease might affect orthodontic tooth movement. The present study investigated the effects of the diabetic state on orthodontic tooth movement. An orthodontic appliance was placed in normoglycemic (NG), streptozotocin-induced diabetes (DB), and insulin-treated DB (IT) C57BL6/J mice. Histomorphometric analysis and quantitative PCR of periodontium were performed. The DB mice exhibited greater orthodontic tooth movement and had a higher number of tartrate-resistant acid phosphate (TRAP) -positive osteoclasts than NG mice. This was associated with increased expression of factors involved in osteoclast activity and recruitment (Rankl, Csf1, Ccl2, Ccl5, and Tnfa) in DB mice. The expression of osteoblastic markers (Runx2, Ocn, Col1, and Alp) was decreased in DB mice. Reversal of the diabetic state by insulin treatment resulted in morphological findings similar to those of NG mice. These results suggest that the diabetic state up-regulates osteoclast migration and activity and down regulates osteoblast differentiation, resulting in greater orthodontic tooth movement. PMID- 21244506 TI - Salivary IgA in minor-gland saliva of children, adolescents, and young adults. AB - According to previous studies, minor glands produce about 35% of the total salivary immunoglobulin A (salivary IgA). The age-dependent increase in whole saliva salivary IgA concentrations has been studied extensively, but we found no published reports comparing the minor-gland saliva concentrations of salivary IgA in children, adolescents, and adults. In this study we measured the concentration of salivary IgA in saliva from the labial and the buccal minor glands of children, adolescents, and adults. Three age groups donated saliva for analysis: 3-yr-old children, 14-yr-old adolescents, and 20- to 25-yr-old adults. Minor gland saliva was collected on filter paper and unstimulated whole saliva was collected by draining into a tube, and the salivary IgA concentration was determined by ELISA. The salivary IgA concentration in labial saliva was significantly lower among 3-yr-old children (0.037 mg 100 ml(-1), SD = 0.035) than among 14-yr-old adolescents (0.126 mg 100 ml(-1), SD = 0.128) and adults (0.128 mg 100 ml(-1), SD = 0.13). The 3-yr-old children also had significantly lower whole-saliva salivary IgA values compared with the other age groups (0.09 mg 100 ml(-1), SD = 0.091; 0.179 mg 100 ml(-1), SD = 0.149; and 0.170 mg 100 ml( 1), SD = 0.099, respectively). This increase in salivary IgA concentrations with age might reflect a developing immune response in the growing child. PMID- 21244507 TI - Influence of fluoride-detergent combinations on the visco-elasticity of adsorbed salivary protein films. AB - The visco-elasticity of salivary-protein films is related to mouthfeel, lubrication, biofilm formation, and protection against erosion and is influenced by the adsorption of toothpaste components. The thickness and the visco elasticity of hydrated films (determined using a quartz crystal microbalance) of 2-h-old in vitro-adsorbed salivary-protein films were 43.5 nm and 9.4 MHz, respectively, whereas the dehydrated thickness, measured using X-ray photoelectron spectroscopy, was 2.4 nm. Treatment with toothpaste slurries decreased the thickness of the film, depending on the fluoride-detergent combination involved. Secondary exposure to saliva resulted in a regained thickness of the film to a level similar to its original thickness; however, no association was found between the thickness of hydrated and dehydrated films, indicating differences in film structure. Treatment with stannous fluoride/sodium lauryl sulphate (SnF(2)/SLS)-containing toothpaste slurries yielded a strong, immediate two-fold increase in characteristic film frequency (f(c)) with respect to untreated films, indicating cross-linking in adsorbed salivary-protein films by Sn(2+) that was absent when SLS was replaced with sodium hexametaphosphate (NaHMP). Secondary exposure to saliva of films treated with SnF(2) caused a strong, six-fold increase in f(c) compared with primary salivary-protein films, regardless of whether SLS or NaHMP was the detergent. This suggests that ionized stannous is not directly available for cross-linking in combination with highly negatively charged NaHMP, but becomes slowly available after initial treatment to cause cross-linking during secondary exposure to saliva. PMID- 21244508 TI - Orofacial function and oral health in patients with Parkinson's disease. AB - No comprehensive study has previously been published on orofacial function in patients with well-defined Parkinson's disease (PD). Therefore, the aim of this study was to perform an overall assessment of orofacial function and oral health in patients, and to compare the findings with matched control subjects. Fifteen outpatients (nine women and six men, 61-82 yr of age; Hoehn & Yahr Stages 2-4; and with motor impairment ranging from 17 to 61 according to the Unified Parkinson's Disease Rating Scale, Objective Motor Part III) were examined in their 'on' state together with 15 age- and gender-matched controls. Orofacial function and oral health were assessed using the Nordic Orofacial Test, masticatory ability, performance and efficiency, oral stereognosis, jaw opening, jaw muscle tenderness, the Oral Health Impact Profile-49, number of natural teeth, and oral hygiene. Orofacial dysfunction was more prevalent, mastication and jaw opening poorer, and impact of oral health on daily life more negative, in patients with PD than in controls. The results indicate that mastication and orofacial function are impaired in moderate to advanced PD, and with progression of the disease both orofacial and dental problems become more marked. It is suggested that greater awareness of the special needs in PD patients and frequent dental visits are desirable to prevent dental diseases and decay and to support masticatory function. PMID- 21244509 TI - Molar-incisor hypomineralization and oral hygiene in 10- to-12-yr-old Swedish children born preterm. AB - Although preterm birth is associated with an increased risk of medical problems and impairments, there is limited knowledge of how this affects oral health. It was hypothesized that when 10-12 yr of age, children who were preterm at birth would present with a higher prevalence of molar-incisor hypomineralization (MIH), more dental plaque, and a higher degree of gingival inflammation than full-term control children. Eighty-two preterm children, born between 24 and 32 wk of gestation, and 82 control children, born between 37 and 43 wk of gestation, were clinically examined for developmental defects in enamel, MIH, dental plaque, and gingival health. In addition, behaviour management problems were evaluated. Information on any aetiological factors with a potential influence on MIH and oral health was collected via questionnaires. Molar-incisor hypomineralization was more common in preterm children than in controls (38% vs. 16%), as were enamel developmental defects (69.5% vs. 51%). Low gestational age and low birth weight increased the risk of MIH. Preterm children had more plaque, a higher degree of gingival inflammation, and more behaviour-management problems than controls. In conclusion, oral health problems were more common in preterm children than in control children. PMID- 21244510 TI - The role of sugar, xylitol, toothbrushing frequency, and use of fluoride toothpaste in maintenance of adults' dental health: findings from the Finnish National Health 2000 Survey. AB - We assessed the effect of certain oral health-related behaviours on adults' dental health. As part of the Finnish nationwide Health 2000 Survey, dentate subjects, 30-64 yr of age, reported their frequency of consumption of eight sugar and xylitol-containing products, together with toothbrushing frequency and use of fluoride toothpaste, and underwent clinical oral examination (n = 4,361). The mean number of teeth present (NoT) was 24.2 and the mean numbers of sound teeth (ST), filled teeth (FT), and decayed teeth (DT) were 10.8, 12.1, and 1.1 for men and 9.6, 13.8, and 0.5 for women, respectively. Consumption of sugar-sweetened beverages was more frequent than that of other sugar-containing products, and greater in men than in women. Daily use of xylitol chewing gum was reported by 13% of the men and by 22% of the women. Toothbrushing at least twice daily was reported by 47% of the men and by 79% of the women; 86% and 96%, respectively, reported daily use of fluoride toothpaste. The frequency of consumption of sugar- and xylitol-containing products and of toothbrushing, as well as use of fluoride toothpaste, play a role in the dental health of dentate adults, with the impact being weak on NoT, ST, and FT, but stronger on DT, especially concerning toothbrushing frequency (relative risk = 1.5) and use of fluoride toothpaste (relative risk = 1.8). Understanding the impact of certain oral health-related behaviours on dental health in adults would facilitate better targeting of oral self-care messages. PMID- 21244511 TI - The relationship among educational achievement, career aspiration, and oral hygiene behaviours in Iranian adolescents. AB - The objectives of this study were to examine: (i) the association between toothbrushing frequency and educational achievement; (ii) the influence of social status and career aspiration on this association; and (iii) whether educational achievement and career aspiration explain the gender difference in oral hygiene behaviours in Iranian adolescents in Mashhad. The sample population was sixth grade adolescents in Mashhad, Iran. Participants completed a 37-item questionnaire with questions on socio-demographic variables, frequency of toothbrushing, educational achievement, and their career aspiration. The associations between toothbrushing frequency and other study-outcome variables were tested using binary logistic regression. The association between toothbrushing frequency and educational achievement was significant only after adjusting for the father's level of education and the child's career aspiration. Toothbrushing frequency was highly significantly associated with gender, and this association remained unaltered after adjusting for educational achievement and career aspiration. Career aspiration and toothbrushing frequency were significantly associated. In conclusion, educational achievement was not an independent indicator of reported toothbrushing frequency in Iranian adolescents in Mashhad. Father's educational level and child's career aspiration mediated the association between toothbrushing frequency and educational achievement. Educational achievement and career aspiration did not explain the gender difference in toothbrushing behaviours of Iranian adolescents. PMID- 21244512 TI - Anxiety and depressive disorders and dental fear among adults in Finland. AB - We studied the association between dental fear and anxiety or depressive disorders, as well as the comorbidity of dental fear with anxiety and depressive disorders, controlling for socio-demographic characteristics, dental attendance, and dental health. Nationally representative data on Finnish adults, >= 30 yr of age (n = 5,953), were gathered through interviews and clinical examination. Dental fear was measured using the question: 'How afraid are you of visiting a dentist?' Anxiety and/or depressive disorders were assessed using a standardized structured psychiatric interview according to criteria presented in the Diagnostic and Statistical Manual of Mental Disorders (4th edition) (DSM IV).Those with depressive disorders, generalized anxiety disorder or social phobia more commonly reported high dental fear than did those without these disorders. When age, gender, education, dental attendance, and the number of decayed, missing, and restored teeth were considered, those with generalized anxiety disorder were more likely to have high dental fear than were participants with neither anxiety nor depressive disorders. The comorbidity of depressive and anxiety disorders also remained statistically significantly associated with dental fear; those with both depressive and anxiety disorders were more likely to have high dental fear than were those without these disorders. Our findings support the suggestion that some individuals may have a personality that is vulnerable to dental fear. PMID- 21244513 TI - Symptom provocation in dental anxiety using cross-phobic video stimulation. AB - Although video stimulation has been successfully employed in dental phobia, conclusions regarding the specificity of reactions are limited. A novel, video based paradigm using cross-phobic video stimulation was validated based on subjective and autonomic responses. Forty subjects were stratified according to dental anxiety as measured by the Dental Fear Survey (DFS) using a median-split procedure (high-DFS and low-DFS groups). Anxiety stimuli comprised dental-anxiety scenes and non-dental-anxiety control scenes (snake stimuli). Neutral scenes were tailored to each anxiety stimulus. Dental, but not snake, stimuli were rated as more anxiety provoking only in the high-DFS group. Elevated skin-conductance amplitudes were observed in the high-DFS group for dental anxiety vs. neutral videos, but not for snake anxiety vs. neutral videos. State and trait anxiety and autonomic reactivity were correlated according to expectations. Using cross phobic video stimulation, it was demonstrated that phobogenic reactions in dental anxiety are specific to the respective stimulus material and do not generalize to other non-dental-anxiety control conditions. The validation of the paradigm may support and stimulate future research on the characterization of dental anxiety on different response systems, including its underlying neural substrates. PMID- 21244514 TI - Instrument-order effects: using the Oral Health Impact Profile 49 and the Short Form 12. AB - Whereas it is well known that the ordering of items can influence research outcomes considerably, very little literature addresses instrument-order effects. Therefore, the aim of this study was to evaluate the effect of changing the administrative order of the Short-Form-12 (SF-12) and the Oral Health Impact Profile-49 (OHIP-49). It was hypothesized that if the SF-12 was administered first, the results would show poorer scores on the SF-12 subscales, as responses would not be restrained to only the oral impacts described by the OHIP-49. Using the Mann-Whitney U-test no significant instrument-order effects were found, except for the Psychological discomfort scale of the OHIP-49, where subjects scored higher when receiving the OHIP-49 first. However, the effect size was negligible (-0.08). These results suggest that no instrument-order effects occurred. Nonetheless, more research dealing with different instruments is needed. This study was performed within a dental setting and we recommend that instrument-order effects should be studied outside this domain. PMID- 21244515 TI - Influence of administration method on oral health-related quality of life assessment using the Oral Health Impact Profile. AB - The influence of the administration method used to collect oral health-related quality of life (OHRQoL) data is largely unknown. Therefore, the aim of this study was to determine whether OHRQoL information obtained using the Oral Health Impact Profile (OHIP) differed with different methods of collection (personal interview, via telephone or as a self-administered questionnaire). The OHRQoL was measured using the German version of the OHIP. The instrument was administered to each of 42 patients using three different methods, in a randomized order, about 1 wk apart. The test-retest reliability coefficient for the repeated OHIP assessment across the three methods of administration, and the magnitude of the variance component for administration method, were determined, characterizing the degree of OHIP score variation that is caused by this factor. Whereas OHIP mean score differences of 3.9 points were present between administration methods, the reliability coefficient of 0.90 (95% CI, 0.85-0.95) indicated that 90% of the OHIP score variation was caused by differences between subjects (and not by the administration method or measurement error). The variance component for administration method explained 0.5% of the OHIP score variation. In conclusion, the method of administration (personal interview, telephone interview or self administered questionnaire) did not influence substantially OHIP scores in prosthodontic patients. PMID- 21244516 TI - Effect of dentin etching and chlorhexidine application on metalloproteinase mediated collagen degradation. AB - Dentin matrix metalloproteinases (MMPs) are involved in the degradation of collagen in resin-dentin interfaces. This study evaluated whether collagen degradation can be prevented by chlorhexidine digluconate (CHX) after different dentin demineralization procedures. The demineralization of human dentin was performed with phosphoric acid (PA), EDTA or acidic monomers (Clearfil SE Bond and Xeno V). Specimens were stored (for 24 h, or for 1 or 3 wk) in the presence or absence of CHX. In half of the groups, active MMP-2 was incorporated into the storage solution. At the end of each storage period, the C-terminal telopeptide (ICTP) concentration (which indicates the amount of collagen degradation) was measured in the storage solution. Collagen degradation was higher in PA- and EDTA demineralized dentin. Chlorhexidine digluconate reduced collagen degradation in these groups only for 24 h. When dentin was demineralized with Clearfil SE Bond or Xeno V, collagen degradation was reduced by up to 30%, but the addition of exogenous MMP-2 significantly increased collagen degradation. In self-etchant treated dentin, the inhibitory effect of CHX on MMPs lasted for up to 3 wk. Treating dentin with EDTA, PA or self-etching agents produces enough demineralization to permit cleavage of the exposed collagen. Monomer infiltration may exert protection on demineralized collagen, probably through immobilization of MMPs. The partial inhibitory action of CHX on MMP activity produced by self etching adhesives was prolonged compared with the short-acting PA- or EDTA treated dentin. PMID- 21244517 TI - Effect of pretreatment with mildly acidic hypochlorous acid on adhesion to caries affected dentin using a self-etch adhesive. AB - Caries-affected dentin is covered with a thicker and organically enriched smear layer than normal dentin. This may affect the demineralization ability and the infiltration of self-etch adhesives, thus reducing the efficacy of bonding to caries-affected dentin. This study evaluated the adhesion of a two-step self etching adhesive to normal and caries-affected dentin after pretreatment with mildly acidic hypochlorous acid (HOCl) solutions. We used a microtensile bond strength (MUTBS) test to compare the MUTBS of Clearfil SE Bond to either caries affected dentin or to normal dentin, after pretreatment for 5 s with one of three solutions (806 mM NaOCl, or 0.95 or 1.91 mM HOCl). The MUTBS of the self-etch adhesive was significantly lower to caries-affected dentin than to normal dentin. Pretreatment with 0.95 mM HOCl improved the MUTBS of the self-etch adhesive to caries-affected dentin, but there was no significant difference compared with normal dentin. On the other hand, pretreatment with 806 mM NaOCl or 1.91 mM HOCl did not demonstrate a significant improvement in the MUTBS to caries-affected dentin. None of the pretreatments demonstrated a negative effect on adhesion to normal dentin. PMID- 21244518 TI - Corrosion behaviour and surface analysis of a Co-Cr and two Ni-Cr dental alloys before and after simulated porcelain firing. AB - This study evaluated the corrosion behaviour and surface properties of a commercial cobalt-chromium (Co-Cr) alloy and two nickel-chromium (Ni-Cr) alloys [beryllium (Be)-free and Be-containing] before and after a simulated porcelain firing process. Before porcelain firing, the microstructure, surface composition and hardness, electrochemical corrosion properties, and metal-ion release of as cast alloy specimens were examined. After firing, similar alloy specimens were examined for the same properties. In both as-cast and fired conditions, the Co-Cr alloy (Wirobond C) showed significantly more resistance to corrosion than the two Ni-Cr alloys. After firing, the corrosion rate of the Be-free Ni-Cr alloy (Stellite N9) increased significantly, which corresponded to a reduction in the levels of Cr, molybdenum (Mo), and Ni in the surface oxides and to a reduction in the thickness of the surface oxide film. The corrosion properties of the Co-Cr alloy and the Be-containing Ni-Cr alloy (ChangPing) were not significantly affected by the firing process. Porcelain firing also changed the microstructure and microhardness values of the alloys, and there were increases in the release of Co and Ni ions, especially for Ni from the Be-free Ni-Cr alloy. Thus, the corrosion rate of the Be-free Ni-Cr alloy increased significantly after porcelain firing, whereas the firing process had little effect on the corrosion susceptibility of the Co-Cr alloy and the Be-containing Ni-Cr alloy. PMID- 21244519 TI - No evidence for a role of CRISPLD2 in non-syndromic cleft lip with or without cleft palate in an Italian population. AB - Non-syndromic cleft lip with or without cleft palate (NSCLP) is a malformation with variable phenotypes, resulting from a mixture of genetic and environmental factors. Some studies have supported a role for the 16q24 region and its candidate gene, CRISPLD2, in clefting. A replication study is necessary to confirm these findings. The aim of the present study was to test, by genetic linkage and association analyses, whether the candidate gene, CRISPLD2, represents a risk factor for NSCLP. The analysis of 39 multigenerational families provided formal exclusion of a linkage between NSCLP and the CRISPLD2 locus under different genetic models and non-parametric analyses. The family-based study of 239 unrelated probands and their parents revealed no association between any particular allele or haplotype and NSCLP. Therefore, the present investigation did not support the hypothesis of the involvement of CRISPLD2 in NSCLP malformation, at least with regard to the Italian population. PMID- 21244520 TI - Unstimulated flow rates from minor salivary glands in the buccal mucosa. PMID- 21244521 TI - Deviating results with measurements of flow rates from minor salivary glands. PMID- 21244522 TI - The effect of tannic acid and polyethylene glycol on the absorption capacity of chicken intestine for d-xylose and beta-carotene. AB - In an experiment, the possible influence of tannic acid (TA) and polyethylene glycol (PEG) on the absorption capacity of intestine for d-xylose and beta carotene in broiler chicken was investigated. Four groups of nine 28-day-old broiler cockerels received d-xylose (500 mg) and beta-carotene (52 MUg) solutions (Group 1 to 4) with TA (1 g, Group 2 to 4) and PEG (500 mg Group 3 and 1 g Group 4), orally. One blood sample prior to, and four others after the administration of test materials, were collected from wing vein on 40 min basis, for 160 min and the concentration of plasma d-xylose was determined. The concentration of beta carotene was also measured in plasma of blood samples taken prior to and 160 min post-administration of the test materials. Plasma d-xylose concentration of all groups showed quadratic correlations with time (p < 0.001, r(2) = 0.84, 0.60, 0.70 and 0.74 for Group 1 to 4, respectively). Administration of TA reduced the plasma concentration of d-xylose in Group 2. However, feeding PEG after TA raised the concentration of d-xylose in Group 4 to the level that there was no difference in that variable between this group and Group 1. Although the plasma concentration of beta-carotene was increased in 160 min post-ingestion of the test material, no difference was found in that variable among the experimental groups. In conclusion, TA and its interaction with PEG have impacts on the absorption capacity of intestine for d-xylose and highly likely other simple sugars, but TA or PEG have no influence on the absorption of beta-carotene and most probably other fat soluble vitamins. PMID- 21244523 TI - The effect of supplementary bacterial phytase on dietary metabolisable energy, nutrient retention and endogenous losses in precision fed broiler chickens. AB - Thirty-two Ross 308 male broiler chickens were used in a precision feeding assay to investigate the effect of exogenous phytase (EC 3.1.3.26) on dietary apparent metabolisable energy (AME), dry matter digestibility (DMD) coefficient, nitrogen (NR), amino acid and mineral retentions. The excretion of endogenous losses measured as sialic acid (SA) was also determined. Four dietary treatments (control (C), C + 250 FTU (phytase units per kg feed), C + 500 FTU, and C + 2500 FTU) were studied with each treatment replicated eight times in randomised complete block design. Diets were formulated to be nutritionally adequate with the exception of available P content (2.3 g/kg non-phytate P). Over the 48-h collection period, the phytase fed birds retained 29.3 mg more Na and 2.3 mg more Zn (p < 0.05) than the control fed birds, with the relationship between phytase dose and Na and Zn retention being best described by a linear function (p < 0.05 and p < 0.001, for Na and Zn, respectively). Phytase supplementation did not have an effect on dietary AME, DMD and NR. However, increasing the dose of phytase led to a linear increase in dietary amino acid retention (p < 0.05). Dietary phytase decreased total sialic acid excretion in a linear fashion (p < 0.05). It can be concluded that supplementary phytase increases the retention (reduces the excretion) of dietary Zn and Na in broiler chickens. The beneficial effects of the addition of exogenous phytases to poultry diets seems to be mediated through improved dietary nutrients absorption and reduced endogenous losses. PMID- 21244524 TI - Distinct and combined effects of acute immobilization and chronic isolation stress on MAO activity and antioxidative protection in the heart of normotensive and spontaneously hypertensive rats. AB - The heart is an organ especially sensitive to the sympathetic overstimulation and therefore to the influence of stressors and hypertension. The aim of the present study was to investigate the effect of two distinct types of stressors, acute immobilization (2 h) and chronic isolation stress (21 days), as well as their combined effect on the activity of monoamine oxidase (MAO), superoxide dismutase, catalase (CAT) and the ascorbic acid (AA) content in the heart of normotensive and spontaneously hypertensive rats (SHR). The results obtained show that in basal conditions heart MAO and CAT activity (p < 0.05), as well as AA concentration (p < 0.01) were higher in SHR than in normotensive ones. The acute immobilization significantly decreased heart MAO activity in both examined strains (p < 0.01). On the other hand, chronic isolation, separately or in combination with immobilization, did not affect this enzyme, in the heart of either hypertensive or normotensive rats, which was associated with the reduced antioxidative protection (p < 0.01, p < 0.05). PMID- 21244525 TI - Resveratrol protects quail hepatocytes against heat stress: modulation of the Nrf2 transcription factor and heat shock proteins. AB - In the present study, the effects of dietary resveratrol on the induction of heat shock proteins, transcription factors and antioxidative enzyme system in liver of quails under heat stress were investigated. A total of 180 (55-day-old) female Japanese quails (Coturnix coturnix japonica) were reared either at 22 degrees C for 24 h/day (thermoneutral, TN) or 34 degrees C for 8 h/day (heat stress, HS; 09:00-17:00 hours) for 12 weeks. Birds in both environments were randomly fed one of three diets: basal diet and basal diet added with either 200 or 400 mg of resveratrol per kg of diet. The results showed that exposure to high ambient temperature induced decreases in feed intake, egg production, and hepatic superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities but increases in hepatic malondialdehyde (MDA) concentrations (p < 0.001). Liver Hsp70, Hsp90 and NF-kappaB expression was greater while Nrf2 expression was lower for quails reared under the heat stress than for those reared under the TN environment (p < 0.0001). There were linear increases in feed intake, egg production, hepatic SOD, CAT, and GSH-Px activities as well as Nrf2 expression, but linear decreases in hepatic MDA concentrations and Hsp70, Hsp90, and NF-kappaB expressions with increasing supplemental resveratrol level (p < 0.0001). Two-way treatment interactions revealed that the degree of restorations in all response variables was more notable under the high ambient temperature than that of the TN environment as dietary resveratrol concentration was increased. The results of the present study suggest that supplemental resveratrol reduces oxidative stress in heat-stressed quails through modulating the hepatic heat shock proteins and nuclear transcription factors. PMID- 21244526 TI - Identification of plasma and hepatic parameters related to metabolic robustness in dairy cows. AB - Blood plasma and hepatic parameters were identified that describe the differences between metabolically robust or vulnerable dairy cows grouped according to their past health status. Data from a field study on dairy cows were used from which metabolically challenged dairy cows were selected that had a milk fat percentage of >4.5 mg/g and a fat to protein ratio of >1.5 in their previous early lactation. The selected cows were either classified as metabolically robust or vulnerable based on the occurrence of various metabolic and (re)production disorders in their previous lactations. Blood and liver tissue samples were collected in week 3 ante partum (a.p.) (-3 wk), in week 4 (+4 wk) and in week 13 (+13 wk) post-partum (p.p.). Plasma concentrations of metabolites and hormones and mRNA expression of genes involved in metabolic pathways in the liver were used as variables for a two-group discriminant analysis (DA). Average discriminant scores (centroids) were different (p < 0.05) in -3 wk, +4 wk and in +13 wk. In -3 wk, significant variables that best explained the differences between metabolically robust and vulnerable cows were parity, plasma triglycerides, glucose and mRNA abundance of carnitine palmitoyltransferase 2 (CPT2). In addition, based on the classification matrix, 69% of the dairy cows were correctly classified. In +4 wk, identified significant parameters were parity, plasma glucose and urea, and 67% of the cows were correctly classified. In +13 wk, significant variables that explained the differences between the groups were parity, mRNA abundance of acyl-CoA synthetase long-chain 1 and CPT1, and 66% of the cows were correctly classified. In conclusion, the identified variables may distinguish from metabolically challenged cows, those cows that had a poorer health performance in their previous lactations. PMID- 21244527 TI - Proteins encoded by the mre gene cluster in Streptomyces coelicolor A3(2) cooperate in spore wall synthesis. AB - It is still an open question how an intracellular cytoskeleton directs the synthesis of the peptidoglycan exoskeleton. In contrast to MreB of rod-shaped bacteria, which is essential for lateral cell wall synthesis, MreB of Streptomyces coelicolor has a role in sporulation. To study the function of the S. coelicolor mre gene cluster consisting of mreB, mreC, mreD, pbp2 and sfr, we generated non-polar replacement mutants. The individual mutants were viable and growth of substrate mycelium was not affected. However, all mutants produced enlarged spores, which frequently germinated prematurely and were sensitive to heat, high osmolarity and cell wall damaging agents. Protein-protein interaction assays by bacterial two-hybrid analyses indicated that the S. coelicolor Mre proteins form a spore wall synthesizing complex, which closely resembles the lateral wall synthesizing complex of rod-shaped bacteria. Screening of a genomic library identified several novel putative components of this complex. One of them (sco2097) was deleted. The Deltasco2097 mutant formed sensitive spores with an aberrant morphology, demonstrating that SCO2097 is a new player in cell morphogenesis of Streptomyces. Our results suggest that all Mre proteins cooperate with the newly identified proteins in the synthesis of the thickened spore wall required to resist detrimental environmental conditions. PMID- 21244528 TI - The outer membrane protein LptO is essential for the O-deacylation of LPS and the co-ordinated secretion and attachment of A-LPS and CTD proteins in Porphyromonas gingivalis. AB - Protein substrates of a novel secretion system of Porphyromonas gingivalis contain a conserved C-terminal domain (CTD) essential for secretion and attachment to the cell surface. Inactivation of lptO (PG0027) or porT produced mutants that lacked surface protease activity and an electron-dense surface layer. Both mutants showed co-accumulation of A-LPS and unmodified CTD proteins in the periplasm. Lipid profiling by mass spectrometry showed the presence of both tetra- and penta-acylated forms of mono-phosphorylated lipid A in the wild type and porT mutant, while only the penta-acylated forms of mono-phosphorylated lipid A were found in the lptO mutant, indicating a specific role of LptO in the O-deacylation of mono-phosphorylated lipid A. Increased levels of non phosphorylated lipid A and the presence of novel phospholipids in the lptO mutant were also observed that may compensate for the missing mono-phosphorylated tetra acylated lipid A in the outer membrane (OM). Molecular modelling predicted LptO to adopt a beta-barrel structure characteristic of an OM protein, supported by the enrichment of LptO in OM vesicles. The results suggest that LPS deacylation by LptO is linked to the co-ordinated secretion of A-LPS and CTD proteins by a novel secretion and attachment system to form a structured surface layer. PMID- 21244529 TI - tRNA accumulation and suppression of the bldA phenotype during development in Streptomyces coelicolor. AB - Streptomyces coelicolor undergoes distinct morphological changes as it grows on solid media where spores differentiate into vegetative and aerial mycelium that is followed by the production of spores. Deletion of bldA, encoding the rare tRNA(Leu) UAA, blocks development at the stage of vegetative mycelium formation. From previous data it appears that tRNA(Leu) UAA accumulates relatively late during growth while two other tRNAs do not. Here, we studied the expression of 17 different tRNAs including bldA tRNA, and the RNA subunit of the tRNA processing endoribonuclease RNase P. Our results showed that all selected tRNAs and RNase P RNA increased with time during development. However, accumulation of bldA tRNA and another rare tRNA(Leu) isoacceptor started at an earlier stage compared with the other tRNAs. We also introduced the bldA tRNA anticodon (UAA) into other tRNAs and introduced these into a bldA deletion strain. In particular, one such mutant tRNA derived from the tRNA(Leu) CAA isoacceptor suppressed the bldA phenotype. Thus, the bldA tRNA scaffold is not critical for function as a regulator of S. coelicolor cell differentiation. Further substitution experiments, in which the 5'- and 3'-flanking regions of the suppressor tRNA were changed, indicated that these regions were important for the suppression. PMID- 21244530 TI - Magnesium depletion triggers production of an immune modulating diterpenoid in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) is the causative agent of the human disease Tuberculosis, and remains a worldwide health threat responsible for ~1.7 million deaths annually. During infection, Mtb prevents acidification of the engulfing phagosome, thus blocking endocytic progression and eventually leading to stable residence. The diterpenoid metabolite isotuberculosinol (isoTb) exhibits biological activity indicative of a role in this early arrest of phagosome maturation. Presumably, isoTb production should be induced by phagosomal entry. However, the relevant enzymatic genes are not transcriptionally upregulated during engulfment. Previous examination of the initial biosynthetic enzyme (Rv3377c/MtHPS) involved in isoTb biosynthesis revealed striking inhibition by its Mg(2+) cofactor, leading to the hypothesis that the depletion of Mg(2+) observed upon phagosomal engulfment may act to trigger isoTb biosynthesis. While Mtb is typically grown in relatively high levels of Mg(2+) (0.43 mM), shifting Mtb to media with phagosomal levels (0.1 mM) led to a significant (~10-fold) increase in accumulation of the MtHPS product, halimadienyl diphosphate, as well as easily detectable amounts of the derived bioactive isoTb. These results demonstrate isoTb production by Mtb specifically under conditions that mimic phagosomal cation concentrations, and further support a role for isoTb in the Mtb infection process. PMID- 21244531 TI - Downregulation of katG expression is associated with isoniazid resistance in Mycobacterium tuberculosis. AB - Isoniazid (INH) is a key agent in the treatment of tuberculosis. In Mycobacterium tuberculosis, INH is converted to its active form by KatG, a catalase-peroxidase, and attacks InhA, which is essential for the synthesis of mycolic acids. We sequenced furA-katG and fabG1-inhA in 108 INH-resistant (INH(r) ) and 51 INH susceptible (INH(s) ) isolates, and found three mutations in the furA-katG intergenic region (Int(g-7a) , Int(a-10c) and Int(g-12a) ) in four of 108 INH(r) isolates (4%), and the furA(c41t) mutation with an amino acid substitution in 18 INH(r) isolates (17%). These mutations were not found in any of 51 INH(s) isolates tested. We reconstructed these mutations in isogenic strains to determine whether they conferred INH resistance. We found that the Int(g-7a) , Int(a-10c) and Int(g-12a) single mutations in the furA-katG intergenic region decreased katG expression and conferred INH resistance. In contrast, the furA(c41t) mutation was not sufficient to confer INH resistance. These results suggested that downregulation of katG is a mechanism of INH resistance in M. tuberculosis and that mutations in the furA-katG intergenic region play a role in this resistance mechanism. PMID- 21244532 TI - GI-type T4SS-mediated horizontal transfer of the 89K pathogenicity island in epidemic Streptococcus suis serotype 2. AB - Pathogenicity islands (PAIs), a distinct type of genomic island (GI), play important roles in the rapid adaptation and increased virulence of pathogens. 89K is a newly identified PAI in epidemic Streptococcus suis isolates that are related to the two recent large-scale outbreaks of human infection in China. However, its mechanism of evolution and contribution to the epidemic spread of S. suis 2 remain unknown. In this study, the potential for mobilization of 89K was evaluated, and its putative transfer mechanism was investigated. We report that 89K can spontaneously excise to form an extrachromosomal circular product. The precise excision is mediated by an 89K-borne integrase through site-specific recombination, with help from an excisionase. The 89K excision intermediate acts as a substrate for lateral transfer to non-89K S. suis 2 recipients, where it reintegrates site-specifically into the target site. The conjugal transfer of 89K occurred via a GI type IV secretion system (T4SS) encoded in 89K, at a frequency of 10(-6) transconjugants per donor. This is the first demonstration of horizontal transfer of a Gram-positive PAI mediated by a GI-type T4SS. We propose that these genetic events are important in the emergence, pathogenesis and persistence of epidemic S. suis 2 strains. PMID- 21244533 TI - The morphogene AmiC2 is pivotal for multicellular development in the cyanobacterium Nostoc punctiforme. AB - Filamentous cyanobacteria of the order Nostocales are primordial multicellular organisms, a property widely considered unique to eukaryotes. Their filaments are composed of hundreds of mutually dependent vegetative cells and regularly spaced N(2)-fixing heterocysts, exchanging metabolites and signalling molecules. Furthermore, they may differentiate specialized spore-like cells and motile filaments. However, the structural basis for cellular communication within the filament remained elusive. Here we present that mutation of a single gene, encoding cell wall amidase AmiC2, completely changes the morphology and abrogates cell differentiation and intercellular communication. Ultrastructural analysis revealed for the first time a contiguous peptidoglycan sacculus with individual cells connected by a single-layered septal cross-wall. The mutant forms irregular clusters of twisted cells connected by aberrant septa. Rapid intercellular molecule exchange takes place in wild-type filaments, but is completely abolished in the mutant, and this blockage obstructs any cell differentiation, indicating a fundamental importance of intercellular communication for cell differentiation in Nostoc. AmiC2-GFP localizes in the cell wall with a focus in the cross walls of dividing cells, implying that AmiC2 processes the newly synthesized septum into a functional cell-cell communication structure during cell division. AmiC2 thus can be considered as a novel morphogene required for cell-cell communication, cellular development and multicellularity. PMID- 21244534 TI - Assembly and stability of flagellar motor in Escherichia coli. AB - Bacterial flagellar motor is a highly ordered and complex supramolecular structure that powers rotation of flagella and serves as a type III export apparatus for flagellar assembly. Motor biogenesis represents a formidable example of self-assembly, but little is known about early steps of the motor structure formation. Here we used a combination of fluorescence microscopy techniques to dissect the order of the motor assembly in Escherichia coli cells, to map in vivo the underlying protein interactions and to investigate dynamics of protein exchange in the assembled motor structure. Our data suggest that motor self-assembly is initiated by oligomerization of the membrane export apparatus protein FlhA, which is followed by the recruitment of the MS ring component FliF and by the ordered association of other motor proteins. The assembly process combines the hierarchy with cooperativity, whereby the association of each subsequent motor structure stabilizes the growing assembly. Our results provide a novel and so far the most complete view of the early steps in flagellar motor assembly and improve understanding of the motor structure and regulation. PMID- 21244535 TI - MtCRE1-dependent cytokinin signaling integrates bacterial and plant cues to coordinate symbiotic nodule organogenesis in Medicago truncatula. AB - Phytohormonal interactions are essential to regulate plant organogenesis. In response to the presence of signals from symbiotic bacteria, the Nod factors, legume roots generate a new organ: the nitrogen-fixing nodule. Analysis of mutants in the Medicago truncatula CRE1 cytokinin receptor and of the MtRR4 cytokinin primary response gene expression pattern revealed that cytokinin acts in initial cortical cell divisions and later in the transition between meristematic and differentiation zones of the mature nodule. MtCRE1 signaling is required for activation of the downstream nodulation-related transcription factors MtERN1, MtNSP2 and MtNIN, as well as to regulate expression and accumulation of PIN auxin efflux carriers. Whereas the MtCRE1 pathway is required to allow the inhibition of polar auxin transport in response to rhizobia, nodulation is still negatively regulated by the MtEIN2/SICKLE-dependent ethylene pathway in cre1 mutants. Hence, MtCRE1 signaling acts as a regulatory knob, integrating positive plant and bacterial cues to control legume nodule organogenesis. PMID- 21244536 TI - Bayesian analysis of hybridization and introgression between the endangered european mink (Mustela lutreola) and the polecat (Mustela putorius). AB - Human-mediated global change will probably increase the rates of natural hybridization and genetic introgression between closely related species, and this will have major implications for conservation of the taxa involved. In this study, we analyse both mitochondrial and nuclear data to characterize ongoing hybridization and genetic introgression between two sympatric sister species of mustelids, the endangered European mink (Mustela lutreola) and the more abundant polecat (M. putorius). A total of 317 European mink, 114 polecats and 15 putative hybrid individuals were collected from different localities in Europe and genotyped with 13 microsatellite nuclear markers. Recently developed Bayesian methods for assigning individuals to populations and identifying admixture proportions were applied to the genetic data. To identify the direction of hybridization, we additionally sequenced mtDNA and Y chromosomes from 78 individuals and 29 males respectively. We found that both hybridization and genetic introgression occurred at low levels (3% and 0.9% respectively) and indicated that hybridization is asymmetric, as only pure polecat males mate with pure European mink females. Furthermore, backcrossing and genetic introgression was detected only from female first-generation (F1) hybrids of European mink to polecats. This latter result implies that Haldane's rule may apply. Our results suggest that hybridization and genetic introgression between the two species should be considered a rather uncommon event. However, the current low densities of European mink might be changing this trend. PMID- 21244537 TI - Genealogical lineage sorting leads to significant, but incorrect Bayesian multilocus inference of population structure. AB - Over the past decades, the use of molecular markers has revolutionized biology and led to the foundation of a new research discipline-phylogeography. Of particular interest has been the inference of population structure and biogeography. While initial studies focused on mtDNA as a molecular marker, it has become apparent that selection and genealogical lineage sorting could lead to erroneous inferences. As it is not clear to what extent these forces affect a given marker, it has become common practice to use the combined evidence from a set of molecular markers as an attempt to recover the signals that approximate the true underlying demography. Typically, the number of markers used is determined by either budget constraints or by statistical power required to recognize significant population differentiation. Using microsatellite markers from Drosophila and humans, we show that even large numbers of loci (>50) can frequently result in statistically well-supported, but incorrect inference of population structure using the software BAPS. Most importantly, genomic features, such as chromosomal location, variability of the markers, or recombination rate, cannot explain this observation. Instead, it can be attributed to sampling variation among loci with different realizations of the stochastic lineage sorting. This phenomenon is particularly pronounced for low levels of population differentiation. Our results have important implications for ongoing studies of population differentiation, as we unambiguously demonstrate that statistical significance of population structure inferred from a random set of genetic markers cannot necessarily be taken as evidence for a reliable demographic inference. PMID- 21244538 TI - Who are the missing parents? Grandparentage analysis identifies multiple sources of gene flow into a wild population. AB - In order to increase the size of declining salmonid populations, supplementation programmes intentionally release fish raised in hatcheries into the wild. Because hatchery-born fish often have lower fitness than wild-born fish, estimating rates of gene flow from hatcheries into wild populations is essential for predicting the fitness cost to wild populations. Steelhead trout (Oncorhynchus mykiss) have both freshwater resident and anadromous (ocean-going) life history forms, known as rainbow trout and steelhead, respectively. Juvenile hatchery steelhead that 'residualize' (become residents rather than go to sea as intended) provide a previously unmeasured route for gene flow from hatchery into wild populations. We apply a combination of parentage and grandparentage methods to a three-generation pedigree of steelhead from the Hood River, Oregon, to identify the missing parents of anadromous fish. For fish with only one anadromous parent, 83% were identified as having a resident father while 17% were identified as having a resident mother. Additionally, we documented that resident hatchery males produced more offspring with wild anadromous females than with hatchery anadromous females. One explanation is the high fitness cost associated with matings between two hatchery fish. After accounting for all of the possible matings involving steelhead, we find that only 1% of steelhead genes come from residualized hatchery fish, while 20% of steelhead genes come from wild residents. A further 23% of anadromous steelhead genes come from matings between two resident parents. If these matings mirror the proportion of matings between residualized hatchery fish and anadromous partners, then closer to 40% of all steelhead genes come from wild trout each generation. These results suggest that wild resident fish contribute substantially to endangered steelhead 'populations' and highlight the need for conservation and management efforts to fully account for interconnected Oncorhynchus mykiss life histories. PMID- 21244539 TI - Pleistocene origin and population history of a neoendemic alpine butterfly. AB - Alpine environments underwent dramatic transformation during glacial-interglacial cycles, with the consequence that geographical, ecological and demographic changes of alpine populations provided the opportunity for formation of neoendemic species. Several biogeographical models have been proposed to account for the unique history of alpine populations, with different expectations of genetic divergence and speciation. The expanding alpine archipelago model proposes that alpine populations expand spatially and demographically during glacial events, dispersing between mountain ranges. Under this model, alpine populations are unlikely to diverge in isolation due to substantial interpopulation gene flow. In contrast, the alpine archipelago refuge model proposes that gene flow during glacial phases is limited and populations expand demographically during interglacial phases, increasing genetic isolation and the likelihood of speciation. We assess these models by reconstructing the evolutionary history of Colias behrii, a morphologically and ecologically distinct alpine butterfly restricted to the California Sierra Nevada. C. behrii exhibits very low genetic diversity at mitochondrial and nuclear loci, limited population structure and evidence of population expansion. C. behrii and Rocky Mountain C. meadii share identical mitochondrial haplotypes, while in contrast, nuclear data indicate common ancestry between C. behrii and Cascades Range Colias pelidne. The conflict in gene genealogies may be a result of recent expansion in North American Colias, but an isolation with migration analysis indicates that genetic patterns in C. behrii might result from differential introgression following hybridization. Based on the timing of population expansion and gene flow between mountain ranges, the expanding alpine archipelago model is supported in C. behrii. PMID- 21244540 TI - A two-dimensional approach to assessing affective states in good and poor sleepers. AB - This study examined a two-dimensional approach to assessing affective states among good and poor sleepers using the self-assessment manikin (SAM), a brief non verbal self-report measure of affective states with separate ratings of valence and arousal. A sample of 286 undergraduate students completed the Pittsburgh Sleep Quality Index (PSQI) and the SAM. Participants were classified post hoc as either good (PSQI <= 5) or poor sleepers (PSQI > 5) using the PSQI and used the SAM to rate their current affective states (day) and their affective state at bedtime (night) the previous night. Compared to good sleepers, poor sleepers reported more negative affect and arousal at night and more negative affect during the day. Among poor sleepers, lower sleep quality and shorter sleep duration on the components of the PSQI were associated with more negative daytime valence. Among good sleepers, higher scores on the sleep medication and daytime dysfunction components of the PSQI were associated with more negative daytime valence. These findings indicate that the SAM appears to detect differences between good and poor sleepers on both valence and arousal of current daytime and retrospective night-time emotional states. This approach could be useful for the assessment of affective states related to sleep disturbance. PMID- 21244541 TI - Impact on alcohol-related mortality of a rapid rise in the density of private liquor outlets in British Columbia: a local area multi-level analysis. AB - AIMS: To study relationships between rates of alcohol-related deaths and (i) the density of liquor outlets and (ii) the proportion of liquor stores owned privately in British Columbia (BC) during a period of rapid increase in private stores. DESIGN: Multi-level regression analyses assessed the relationship between population rates of private liquor stores and alcohol-related mortality after adjusting for potential confounding. SETTING: The 89 local health areas of BC, Canada across a 6-year period from 2003 to 2008, for a longitudinal sample with n = 534. MEASUREMENTS: Population rates of liquor store density, alcohol-related death and socio-economic variables obtained from government sources. FINDINGS: The total number of liquor stores per 1000 residents was associated significantly and positively with population rates of alcohol-related death (P < 0.01). A conservative estimate is that rates of alcohol-related death increased by 3.25% for each 20% increase in private store density. The percentage of liquor stores in private ownership was also associated independently with local rates of alcohol-related death after controlling for overall liquor store density (P < 0.05). Alternative models confirmed significant relationships between changes in private store density and mortality over time. CONCLUSIONS: The rapidly rising densities of private liquor stores in British Columbia from 2003 to 2008 was associated with a significant local-area increase in rates of alcohol-related death. PMID- 21244542 TI - Chylothorax secondary to catheter related thrombosis successfully treated with heparin. AB - It has been well recognized that intra-thoracic surgery is a major cause of chylothorax in the newborn period; however, catheter-related thrombosis could also be a cause. We report a preterm baby who presented with right chylothorax secondary to venous thrombosis postinadvertent right internal jugular vein catheterization. The complication resolved with drainage, catheter removal and low molecular weight heparin. The literature on neonatal chylothorax and thrombosis and case reports reporting thrombosis-related chylothorax that have been successfully treated with anticoagulation are reviewed. PMID- 21244543 TI - Why parents and children consent to become involved in medical student teaching. AB - AIM: Clinical experience in paediatrics is essential for medical undergraduates. This is the first study, of which we are aware, to examine why children of different ages admitted acutely to hospital and their parents agree to become involved in medical student teaching. We wanted to establish whether they considered that they needed to give consent before seeing medical students, whether this was routinely sought and what influenced their decisions. METHODS: Data were collected using questionnaires and semi-structured interviews of parents and children. RESULTS: Questionnaires were completed by 105 parents of children less than 6 years old, and 34 children between 10 years and 15 years old and their parents. Interviews were conducted with 32 children between the ages of 6 and 10 years and their parents. Most parents and children consider that they have a responsibility to teaching but must always be asked for consent. They were motivated by altruism, but fear of emotional distress or pain can lead them to refuse. Younger children may not be able to give reasons for not wanting to see a medical student but sometimes have firm views, which must be respected. Having seen a medical student previously did influence children's or parents' opinions. Most children who have seen a medical student were prepared to see students again. CONCLUSION: Medical students can be reassured that parents and children admitted acutely to a children's hospital have a positive attitude to student involvement and are prepared to help them learn clinical skills, but consent must always be obtained and the child's perspective must always be considered. PMID- 21244544 TI - Blood pressure or blood flow: which is important in the preterm infant? A case report of twins. AB - There is a poor association between systemic blood flow and blood pressure in preterm infants in the first days of life. Very preterm babies can have early low systemic blood flow with poor myocardial contractility but normal blood pressure. Superior vena cava flow measured by echocardiography can be used to determine systemic blood flow. Low superior vena cava flow is a risk factor for mortality and morbidity in preterm infants. We report the case of preterm twins with contrasting relationships among systemic blood flow, myocardial contractility and blood pressure. The first twin with normal blood pressure, but low superior vena cava flow and poor myocardial contractility in the first hours of life developed a severe intraventricular haemorrhage and died, despite cardiovascular support. The second twin with low blood pressure but normal superior vena cava flow did not develop adverse outcomes in the first days of life. These cases underline the usefulness of neonatal functional echocardiography in early understanding and management of the preterm infant, and the inaccuracy of other clinical parameters used to assess cardiovascular function. PMID- 21244545 TI - Norms and demographic differences of the short form-12 health survey version 2 in Chinese adolescents. AB - AIM: This study aimed to establish the normative values for the 12-item Short Form Health Survey version 2 (SF-12v2) and examine demographic differences among Hong Kong Chinese adolescents. METHODS: A total of 28,981 Hong Kong Chinese adolescents aged 12-18 participated in a school-based survey in 2006-2007. Sex- and age-specific SF-12v2 scores were obtained. Ordinal logistic regression models and linear regression models were used to examine the demographic differences for the eight subscales including physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health, and two component summary scores of Physical Component Summary and Mental Component Summary. RESULTS: The mean (standard deviation) Physical Component Summary score was 50.28 (6.82) for boys and 49.37 (6.47) for girls. The corresponding Mental Component Summary score was 45.86 (9.86) for boys and 44.77 (9.56) for girls. Ceiling effects were observed in some of the eight subscales but not the two component summary scores. Ordinal logistic regression showed that girls had significantly lower scores than boys in most subscales including physical functioning with odds ratio (95% confidence interval) of 0.89 (0.84 0.93); role physical, 0.94 (0.90-0.98); bodily pain, 0.76 (0.73-0.80); general health, 0.55 (0.53-0.57); vitality, 0.72 (0.69-0.75); role emotional, 0.78 (0.74 0.81); and mental health, 0.91 (0.88-0.95). In general, older and non-local-born adolescents had lower component summary scores than their peers. CONCLUSIONS: This study has provided norms and identified demographic differences of the Chinese SF-12v2. PMID- 21244546 TI - Obesity and the developmental origins of health and disease. AB - The concept that environmental stimuli imparted on a developing organism have the potential to affect both its short- and long-term developmental profiles is intuitively appealing and, more importantly, supported by a growing body of experimental and observational evidence. A number of groups have posited model hypotheses in tandem with experimental data, linking extrinsic factors to the development of a host of human diseases. Here, we review the evolution of 'the developmental origins of health and disease' as a concept and discuss recent advances in the association of specific stimuli to obesity, an epidemic cause of human morbidity and mortality. PMID- 21244547 TI - Management of attention-deficit/hyperactivity disorder: the importance of psychosocial and medication treatments. AB - Attention-deficit/hyperactivity disorder (ADHD) assessment and treatment in children and adolescents is complex. Key biological and psychosocial risk factors need to be identified and treated because of their potential mediating interaction that affect the onset, progression, and psychosocial and medication treatment response of core ADHD symptoms and common associated co-morbid conditions. Both psychosocial and medication treatments, alone and in combination, have been shown to reduce the core ADHD symptoms and those of its key co-morbid disorders. Yet, to date, the potential synergism between targeted and specific medication and psychosocial treatments remains poorly understood and under-researched. Interestingly, recent positron emission tomography findings emphasise the importance of contextual salience and positive reinforcement strategies for stimulant medication, the primary medication treatment for ADHD, to have its effect. This is not surprising, given recent epigenetic models of gene-environment interaction that are revolutionising our understanding of developmental disorders like ADHD. This annotation briefly outlines the emerging evidence that supports the role of psychosocial treatment alongside medication treatment in the management of ADHD. Future significant clinical directions are noted. PMID- 21244548 TI - Caffeine citrate for very preterm infants: Effects on development, temperament and behaviour. AB - AIM: To compare two dosing regimens for caffeine citrate for neonates born less than 30 weeks gestation in terms of development, temperament and behaviour. METHODS: A multi-centre, randomised, controlled trial design was undertaken. A total of 287 infants with apnoea of prematurity or in the peri-extubation period were randomised to receive one of two dosage regimens (20 vs. 5 mg/kg/day). The main outcome measure was cognitive development at 1 year of age on the Griffiths Mental Development Scales. Secondary outcome measures included neonatal morbidity, death and disability, temperament at 1 year and behaviour at 2 years of age. RESULTS: Data on the primary outcome were available for 190 survivors at 12 months corrected for prematurity. A significantly greater mean general quotient was found in the high-dose group (mean (standard deviation), 98.0 (13.8) vs. 93.6 (16.5), P = 0.048). On omission of two infants for whom cognitive assessment was not possible because of disability while the mean general quotient remained higher for infants in the high-dose group, this was no longer statistically significant (P= 0.075). There was a non-significant trend for benefit in the high-dose caffeine group for death or major disability, 15.4% versus 24.2%; relative risk 0.75 (95% confidence interval 0.49-1.14). No differences in the mean values between the two groups were shown for temperament and behaviour. CONCLUSIONS: Caffeine citrate with a dosage regimen of 20 mg/kg/day did not result in adverse outcomes for development, temperament and behaviour. The borderline benefit in cognition with high-dose caffeine needs further investigation. PMID- 21244549 TI - Risk factors associated with pneumothorax in Malaysian neonatal intensive care units. AB - AIMS: This study aimed to determine the risk factors associated with the development of pneumothorax among infants admitted to the Malaysian neonatal intensive care units (NICUs). METHODS: Twenty-nine of forty NICUs in Malaysian public hospitals participated in the 2006 Malaysian National Neonatal Registry (MNNR). Data of infants from this registry with and without pneumothorax were analysed. A diagnosis of pneumothorax was made in the presence of extra-pleural air detected by chest radiograph or needle aspiration. RESULTS: There were 10,387 infants admitted to these NICUs who met the MNNR inclusion criteria and were included in this study. Pneumothorax developed in 505 (4.9%) of them. Pneumothorax was most common (7.3%) among the extremely low birthweight infants (birthweight equal or less than 1000 g) and the extremely preterm infants of gestation equal or less than 26 weeks (6.8%). Logistic regression analysis showed that the significant risk factors associated with increased risk of development of pneumothorax were: meconium aspiration syndrome (adjusted odds ratio (OR) = 2.1, 95% confidence intervals (CI): 1.7, 2.7), intermittent mandatory ventilation (adjusted OR = 1.5, 95% CI: 1.2, 2.0), high-frequency oscillatory ventilation (adjusted OR = 3.9, 95% CI: 3.0, 5.2) and confirmed sepsis (adjusted OR = 1.6, 95% CI: 1.3, 2.1). Infants on nasal continuous positive airway pressure (nCPAP) therapy were associated with significantly lower risk of pneumothorax (adjusted OR = 0.5, 95% CI: 0.4, 0.6). CONCLUSION: Meconium aspiration syndrome, mechanical ventilation and sepsis were associated with increased risk and the use of nCPAP with decreased risk of pneumothorax in Malaysian NICUs. PMID- 21244550 TI - Health and well-being of young people who attend secondary school in Aotearoa, New Zealand: what has changed from 2001 to 2007? AB - AIM: To describe the changes in the health and well-being of secondary school students from 2001 to 2007. METHODS: A total of 9107 secondary school students were randomly selected to participate in a comprehensive health and well-being survey using Internet tablets conducted in 2007. Comparisons are made with the first health and well-being survey conducted in 2001. RESULTS: Students from 2007 reported good relationships with their families, people in their schools and neighbourhoods. Compared with the 2001 survey, students surveyed in 2007 were more likely to report positive mental health, better nutritional habits and higher levels of physical activity, and were less likely to report using tobacco and marijuana than students in 2001. In addition, the proportion of students who reported significant depressive symptoms and suicidal behaviours had decreased since 2001. However, concerning proportions of students in 2007 reported: binge drinking, experience of physical and sexual abuse, and witnessing violence in their homes. CONCLUSION: While students' health and well-being have significantly improved from 2001 to 2007, there remain significant areas of concern. PMID- 21244551 TI - Comparison of two ventilator circuits for Drager Babylog high-frequency ventilation. AB - AIM: The Drager Babylog 8000plus ventilator (Drager Medical Systems, Lubeck, Germany) can provide both conventional and high-frequency ventilation (HFV). Drager recommends specific circuits for each of these modes. We investigated the performance of the Babylog ventilator in HFV mode when used with the recommended circuits for both conventional and HFV. METHODS: The Fisher and Paykel RT235 (conventional; Fisher and Paykel Healthcare, Auckland, New Zealand) and Hytrel (HFV; Fisher and Paykel Healthcare) circuits were studied using a 50-mL test lung. Tidal volume, high-frequency minute volume and ventilator alarms were compared at 100 combinations of mean airway pressures (10-16 cm H2O), frequencies (6-14 Hz) and amplitudes (20-60%). RESULTS: Tidal volume with the two circuits differed by < 5% for tidal volumes <= 2.5 mL. Above this, tidal volumes delivered with the HFV circuit were up to 15% more than that obtained with the conventional ventilation circuit, and high-frequency minute volume differed by up to 30%. With the exception of the highest tidal/minute volumes, the tidal volume delivered using the HFV circuit could also be achieved with adjusted frequency or amplitude when using the conventional circuit. More 'pressure measurement out of range' alarms were noted with the conventional ventilation circuit, particularly at mean airway pressure >= 14 cm H2O and frequency <= 10 Hz. CONCLUSIONS: The conventional ventilation circuit may allow delivery of adequate tidal volume for some infants. Where requirements are higher, the HFV circuit allows the Babylog to deliver higher tidal volumes and higher minute volume, and reduce alarms. PMID- 21244552 TI - Citrullinaemia type I: a common mutation in the Pacific Island population. AB - AIM: The aim of this study was to develop and apply a mutation screening protocol for the ASS1 gene in order to confirm the diagnosis of citrullinaemia type I in neonates with elevated citrulline on expanded newborn screening (E-NBS). METHODS: Three patients with an elevated citrulline level were identified via routine E NBS between January and October 2008. Analysis of the ASS1 gene using a polymerase chain reaction and sequencing-based method was successfully applied to all three patients, together with a rapid mutation-specific detection method. Their clinical progress was followed for 16-22 months. RESULTS: All three patients were homozygous for a previously reported missense mutation, c.787G>A (p.Val263Met), associated with a mild or asymptomatic clinical course. CONCLUSIONS: As a consequence of E-NBS, an increasing number of neonates with elevated citrulline of uncertain clinical significance are being identified. Rapid sequence analysis of the ASS1 gene can be used to confirm citrullinaemia type I and, increasingly, to infer phenotypic severity. Homozygosity for the same mutation was found in all three patients despite non-consanguinity and variable Pacific Island origin. These data suggest that this mutation may be relatively prevalent in these ethnic groups and imply a possible founder effect. PMID- 21244553 TI - Stability and sterility of diluted enoxaparin under three different storage conditions. AB - AIM: This study assessed whether enoxaparin sodium diluted to a concentration of 20 mg/mL for clinical use with 0.9% sodium chloride remained stable and sterile for up to 43 days under three different storage conditions. METHODS: Enoxaparin dilutions in polypropylene syringes were stored under three different controlled conditions of temperature and light: (i) room temperature (22-26 degrees C) under natural light; (ii) room temperature (22-26 degrees C) in the dark; and (iii) controlled refrigeration (2-8 degrees C) in the dark. A weekly assay of anti-Xa and anti-IIa activity was undertaken to determine if the diluted enoxaparin preparations retained anticoagulant activity, thus remaining suitable for clinical application. RESULTS: Our findings indicate that diluted enoxaparin, when stored under the tested varied conditions of light and temperature, retained greater than or equal to 90% of baseline anticoagulant activity for anti-Xa and anti-IIa effect for up to 43 days. CONCLUSIONS: The study results are significant for families, in that they suggest that at least a month's supply of enoxaparin could be dispensed at a time, reducing the frequency of patients/families returning for supply and providing a more convenient service for paediatric patients. PMID- 21244555 TI - Head-up tilt testing in children and young people: a retrospective observational study. AB - AIM: Head-up tilt testing (HUTT) is the gold standard investigation for adults with transient loss of consciousness (TLOC), but it is controversial in children and young people, because of a lack of systematic investigation and because the test can be uncomfortable. As it was introduced recently for children attending our hospital, we undertook a retrospective registered clinical audit of its usefulness. METHODS: The medical records of 100 consecutive patients aged less than 18 years undergoing HUTT from October 2001 to December 2008 were reviewed. Information about their episodes, prodromes, triggers, previous tests, indications for the HUTT, the HUTT and clinical outcomes was extracted. RESULTS: Children were 6-17 years old; 68/100 were female. In 32/100, no trigger was reported. The most reported triggers included standing up (20%) and prolonged standing (18%). Dizziness (64%) and altered vision (39%) were the most experienced prodromal symptoms. Twenty-eight of 100 had a positive test, with reproduction of symptoms in 24. Seventeen of 100 tests were negative but symptomatic; 55/100 had a negative asymptomatic test. In 17/28 positive HUTTs, the tilt confirmed the suspected diagnosis and elucidated the mechanism. Two of 28 were started on medication. However, in 9/28, neither was the diagnosis clarified nor was therapy instigated. CONCLUSIONS: Potentially useful information about the TLOC was obtained in 45/100 cases. The 17/100 with negative but symptomatic results may have had medically unexplained TLOC or emotional attacks, although without concurrent electroencephalogram, some uncertainty remains. Therefore, a new protocol with video-electroencephalogram-polygraphy and beat-to beat finger blood pressure recording, and more explicit clinical reporting is being developed. PMID- 21244554 TI - Levetiracetam in children and adolescents with epilepsy and hemiplegic cerebral palsy. AB - AIM: To monitor the effect of adding levetiracetam in paediatric patients with hemiplegic cerebral palsy and uncontrolled epilepsy. METHODS: A case series of eight patients with hemiplegic cerebral palsy whose focal seizures were not adequately controlled by their current anticonvulsants were monitored after levetiracetam was added to their medications. If there was a 50% reduction in seizure frequency, then the other anticonvulsants were discontinued. Prolonged follow-up occurred for a minimum of 2 years. RESULTS: There were seven males and one female whose ages ranged from 4 years to 17 years. All had focal onset seizures, while seven also had secondarily generalised tonic clonic seizures. Levetiracetam resulted in at least a 50% reduction in seizure frequency in seven, with no change in one. Three were able to wean successfully to monotherapy and remained seizure free for over 2 years. They had a prior history of infrequent seizures, one to six per year. Those who continued to require multiple anticonvulsants had a prior history of more frequent seizures, 6-50/year. Levetiracetam was well tolerated, and none ceased this because of side effects. CONCLUSION: Levetiracetam is likely to be an effective anticonvulsant in children and adolescents with hemiplegic cerebral palsy and infrequent but persistent focal seizures. PMID- 21244556 TI - Personalised epilepsy education intervention for adolescents and impact on knowledge acquisition and psychosocial function. AB - AIM: Patients frequently have poor knowledge of epilepsy, and this is associated with low self-esteem in adolescence. There is a paucity of data determining whether education alone can improve psychosocial outcome. The study investigated whether an educational intervention in adolescence: 1 Increased understanding of epilepsy syndrome and general epilepsy knowledge. 2 Improved self-esteem, seizure self-efficacy and attitudes towards epilepsy. METHODS: In session 1, adolescents were educated about their epilepsy syndrome in a one-on-one session, producing a personalised epilepsy medical record. In session 2, the impact of epilepsy on life-style was discussed. Pre- and post-intervention measures of knowledge, self esteem, seizure self-efficacy and attitudes towards epilepsy were completed using validated scales. Focus groups explored the intervention's value. RESULTS: Thirty adolescents with epilepsy participated (female: 24, male: 6; median age: 16 years; partial symptomatic epilepsy: 15, generalised idiopathic epilepsy: 15). Self-knowledge of syndrome (P < 0.0001), general knowledge of epilepsy (P < 0.0001), attitudes towards epilepsy (P= 0.008) and seizure self-efficacy (P= 0.049) improved. Focus group data indicated that sessions were enjoyable and valuable, and the medical record was helpful. CONCLUSIONS: The intervention significantly improved self-knowledge and general knowledge of epilepsy, attitudes towards epilepsy and seizure self-efficacy. This is the first study to demonstrate a positive impact on psychosocial outcomes following an educational intervention without a psychological component. The model has widespread application. PMID- 21244557 TI - Decline in rotavirus hospitalisations following introduction of Australia's national rotavirus immunisation programme. AB - AIM: To determine the impact of rotavirus immunisation on rotavirus hospitalisations in young children. methods: Annual hospitalisations for rotavirus gastroenteritis to The Children's Hospital at Westmead, a tertiary care paediatric hospital in Sydney, were recorded from 2001 for 6 years prior to and 2.5 years following the introduction of rotavirus vaccines to the National Immunisation Program. Data on hospital-acquired rotavirus gastroenteritis were collected prospectively. RESULTS: Hospitalisations for rotavirus gastroenteritis declined in the two full rotavirus seasons (2008 and 2009) after vaccine introduction by 75% compared with mean annual hospitalisations from 2001 to 2006. The greatest decline was seen in those <12 months of age (93%), but the reduction occurred consistently across all age groups, even in children not eligible for immunisation, suggesting an effect on herd immunity. A substantial decline in nosocomial rotavirus gastroenteritis was seen from 2007 to 2009, suggesting a reduction in virus transmission in the hospital setting. CONCLUSION: This study demonstrates a substantial reduction in hospitalisations in children of all ages to a large paediatric hospital and reduced nosocomial infections since the introduction of a nationally funded rotavirus immunisation programme in Australia. PMID- 21244558 TI - Improving nutritional status of children with cystic fibrosis at Red Cross War Memorial Children's Hospital. AB - AIM: To determine the nutritional status of children attending a cystic fibrosis clinic in a tertiary hospital in South Africa and compare it to previously reported 10-year rates. METHODS: Weights and heights were measured of 69 (37 male and 32 female) children aged between 1 year and 18 years. Expected weight-for age, expected height-for-age, expected weight-for-height and body mass index (BMI) were compared with international standards for underweight, stunting, wasting and BMI goal. RESULTS: The nutritional status of the patients has improved over the last 10 years, most significantly for wasting, which decreased from 58.3% in 1996 to 15.9% in 2006 (95% confidence interval (CI), 1.315-14.09, P < 0.05). Fifty-two percent of the children were underweight in 2006, compared with 66.7% in 1996 (95% CI, 0.044-13.96, P < 0.05). Stunting was found in 31.9% of the current sample. Females over 15 years had expected weight-for-age 25.9% lower than those between 10 years and 15 years, while no difference was found between the male age groups. Female height-for-age was 7.06 percentage points greater than males between 10 years and 15 years (95% CI, 2.16-11.96, P < 0.01). Males between 10 years and 15 years had significantly lower BMIs than the corresponding female group. Coloured patients had significantly lower BMIs than white patients in all age groups. CONCLUSIONS: These children demonstrated continuing improvement in nutritional status, although deficits remain. The normalisation of mean weight-for-age and weight-for-height with far fewer wasted patients is encouraging. Interventions are needed in some areas to ensure that all children show progress. PMID- 21244559 TI - Lipoprotein(a) identifies cardiovascular risk in childhood: the Australian Aboriginal Birth Cohort Study. AB - AIM: To describe the lipoprotein(a) (Lp(a))profile and its relationship to cardiovascular risk factors in Australian Aboriginal children. METHODS: A cross sectional study within a longitudinal birth cohort study in the Darwin Health Region (Northern Territory, Australia). Subjects were Aboriginal children born between 1987 and 1990 who were re-examined between 1998 and 2001. Outcome measures were cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apoB, apoA1, apoA1/B ratio, anthropometric measures, cardiovascular disease (CVD) risk factors, maternal smoking and nutrition. RESULTS: At a mean age of 11.4 years, results showed that high concentrations of Lp(a) were significantly related to well-known lipid-based CVD risk factors for both boys and girls, and that only one anthropometric factor, height, was significant for girls. Non-genetic factors and maternal smoking were not found to be significant contributors to Lp(a) concentrations. CONCLUSIONS: Lp(a) should be considered as a more effective marker of CVD than anthropometric measures, and children from families with a history of premature CVD should be regularly screened for this factor. PMID- 21244560 TI - Maternal reasons for non-immunisation and partial immunisation in northern Nigeria. AB - AIM: To compare maternal reasons for non-immunisation and for partial immunisation in northern Nigeria, and determine the link between specific reasons and future intentions to immunise. METHODS: Responses to open-ended questions collected through a 2007 questionnaire survey were individually coded for key words using the regexm command in Stata (StataCorp, College Station, TX, USA). Simple percentages are used to analyse the differences in reasons for non immunisation and partial immunisation. Logistic regression serves to assess the relationship between specific reasons for non-immunisation and future intentions to immunise. RESULTS: The reasons for non-immunisation generally differ from those advanced for partial immunisation. In general, reasons for non-immunisation have to do with ideational and normative factors. In contrast, supply-side factors are the reasons most often advanced for partial immunisation, although lack of knowledge also plays a strong role. Some reasons for non-immunisation are more compatible with future intention to immunise than others. CONCLUSIONS: Efforts to promote the uptake of immunisation need to address both demand- and supply-side factors. Increasing knowledge about immunisation, changing negative attitudes about immunisation, debunking myths and rumours about immunisation, and addressing religious, ethnic and political bases for resistance to immunisation are necessary to encourage parents to initiate child immunisation. To promote timely completion of immunisation schedule, programmes will need to improve vaccine supply, strengthen provider's capacity for quality service and increase community knowledge about immunisation. PMID- 21244561 TI - The pro-inflammatory role of adiponectin at the maternal-fetal interface. AB - PROBLEM: A successful pregnancy is contingent on maternal tolerance of the immunologically foreign fetus. Prevalent diseases such as preeclampsia arise in part due to an inappropriate immune response by the placenta. A number of molecules have been proposed to temper cellular response to pro-inflammatory mediators, including CD24 and Siglec10. METHODS: Cytotrophoblast cells from healthy term placentas were treated with adiponectin in vitro and analyzed with qPCR and ELISA-based assays. Immunohistochemistry was performed on term villous sections and cultured trophoblasts. RESULTS: Treatment with adiponectin increased expression of IL-1beta and IL-8. Term villi express CD24 in cytotrophoblasts and the syncytiotrophoblast, and Siglec10 by the syncytiotrophoblast. Treatment of trophoblast cells with adiponectin increased Siglec10 expression. CONCLUSION: These data describe a role for adiponectin in enhancing pro-inflammatory signals in in vitro syncytialized trophoblasts. Additionally, this represents the first time the CD24/Siglec10 pathway has been implicated in a trophoblast response to a pro-inflammatory mediator. PMID- 21244562 TI - Endometriosis-associated infertility: double intrauterine insemination improves fecundity in patients positive for antiendometrial antibodies. AB - PROBLEM: Prospective registry study evaluating effects of endometriosis (E) and serum antiendometrial antibodies (AEA) on fecundity in intrauterine insemination (IUI) cycles. METHOD OF STUDY: AEA assays on 572 consecutive women receiving 969 single and 274 double IUI cycles. Logistic regression was utilized. RESULTS: Fecundity was 11.5% (143/1243 cycles). Double IUI improved fecundity with significance achieved in certain study groups. Compared to the AEA- subgroup, all study groups except for the E+ AEA- group had significantly lower fecundity. Two study groups receiving double IUI had significantly increased fecundity, E- AEA+ (OR: 5.1, CI: 1.1-22.7, P=0.032) and E+ AEA+ (OR: 4.1, CI: 1.2-14.0, P=0.025) and significant predictors of pregnancy (E- AEA+, OR: 7.8, CI: 1.7-36.2, P=0.009 and E+ AEA+, OR: 4.2, CI: 1.2-15.1, P=0.026). CONCLUSION: Double IUI improves fecundity in AEA+ patients. E-associated infertility is better diagnosed by the AEA assay than by surgery. Double IUI should be attempted prior to assisted reproductive technologies in AEA+ patients with normal fallopian tubes. PMID- 21244563 TI - Study on the relationship between different cytokines in the semen of infertility patients. AB - PROBLEM: The relationship between different cytokines in the semen of infertility patients was investigated. METHOD OF STUDY: Fifty-seven semen samples were collected from infertility and normal group at Lianyungang Maternal and Child Hospital. Routine analysis including determination of the levels of IL-23, IL-6, and TNF-alpha was carried out. RESULTS: Density, percentage of sperm moving forward, activity, survival rate, and proportion of normal morphology of sperm of normal group were significantly higher than those of infertility group (P<0.001). Amount and pH of the semen from the two groups showed no difference. However, there is a significant difference in IL-23 contents of semen in the normal (5.87 pg/mL) and abnormal (11.14 pg/mL) group (P<0.001). The correlation coefficients (R) of the contents of IL-23 to IL-6, IL-8, and TNF-alpha were 0.8706 (R(2)=0.758, P<0.001), 0.9725 (R(2)=0.9458, P<0.001), and 0.9499 (R(2)=0.9024, P<0.001), respectively. CONCLUSION: IL-23 contents of semen are different in the normal and abnormal group and have positive correlations between IL-6, IL-8, and TNF-alpha, respectively. PMID- 21244564 TI - Serum anti-carbonic anhydrase II antibodies and oxidant-antioxidant balance in pre-eclampsia. AB - PROBLEM The aim of this study was to investigate the presence of anti-carbonic anhydrase II antibodies (anti-CA II) antibodies in pre-eclampsia and the relationships between the autoantibodies, total antioxidant capacity (TAC) and total oxidant capacity (TOC), malondialdehyde (MDA) and oxidative stres index (OSI) parameters. METHOD OF STUDY We studied 40 early and late onset pre eclamptic patients and 40 healthy pregnant control and 39 healthy non-pregnant control subjects. Serum CA II antibodies, TAC and TOC, and MDA parameters were studied by ELISA. RESULTS The mean values for TAC, TOC, OSI, MDA, and anti-CA II were significantly increased in patients with pre-eclampsia compared to the other groups. The anti-CA II antibody levels for the pregnant control subjects were 0.129 +/- 0.04 and that for the pre-eclamptic patients were 0.282 +/- 0.18. In this study, any absorbance value higher than 0.136, the mean absorbance + 2 S.D. of pregnant control subjects, was defined as positive. Positive results were obtained in 29 of 40 pre-eclamptic patients (72.5%). There were significant positive correlations between serum anti-CA II antibodies and TOC, MDA levels, and OSI levels. CONCLUSION The results suggest that anti-CA II antibodies and impairment in oxidant-antioxidant balance may be involved in multifactorial etiology of pre-eclampsia. PMID- 21244565 TI - Commentary: Efficacy and safety of a novel botulinum toxin topical gel. PMID- 21244566 TI - Commentary: The effect of botulinum toxin type A injection on lower facial contouring evaluated using a three-dimensional laser scan. PMID- 21244567 TI - Commentary: Revisiting the data: mild resting glabellar lines improve with onabotulinumtoxinA. PMID- 21244568 TI - A comparison of GlideScope((r)) videolaryngoscopy and direct laryngoscopy for nasotracheal intubation in children. AB - BACKGROUND: The relative effectiveness of GlideScope((r)) videolaryngoscopy (GV) for nasotracheal intubation in pediatric patients is unclear. The purpose of this study is to evaluate the usefulness of GV for nasotracheal intubation compared with direct laryngoscopy (DL) in pediatric patients. METHODS: Our patient cohort consisted of 80 children <10 years of age who required nasotracheal intubation for elective dental or facial surgery. The patients were randomly allocated to GV (n = 40) or DL (n = 40) group. The time to intubation (TTI), glottic view grade, frequency of Magill forceps use, and degree of difficulty in intubation were evaluated. RESULTS: The median TTI was similar between the groups. The TTI of the former 20 patients was faster in the DL group (53.3 s, interquartile range: 42.0 64.3) than GV group (65.9 s, interquartile range: 56.0-93.9) (P = 0.007), whereas the TTI of the latter 20 patients was comparable between the groups. There were no significant differences in glottic view grade, frequency of Magill forceps use, and degree of difficulty in intubation between the two groups. CONCLUSIONS: GV can provide similar intubation performance characteristics compared with DL when used for nasotracheal intubation in pediatric patients. However, experience is needed to be skillful in the GV to acquire comparable TTI with DL. PMID- 21244569 TI - Role of modeling and simulation in pediatric investigation plans. AB - Ethical and practical constraints encourage the optimal use of resources in pediatric drug development. Modeling and simulation has emerged as a promising methodology acknowledged by industry, academia, and regulators. We previously proposed a paradigm in pediatric drug development, whereby modeling and simulation is used as a decision tool, for study optimization and/or as a data analysis tool. Three and a half years since the Paediatric Regulation came into force in 2007, the European Medicines Agency has gained substantial experience in the use of modeling and simulation in pediatric drug development. In this review, we present examples on how the proposed paradigm applies in real case scenarios of planned pharmaceutical developments. We also report the results of a pediatric database search to further 'validate' the paradigm. There were 47 of 210 positive pediatric investigation plan (PIP) opinions that made reference to modeling and simulation (data included all positive opinions issued up to January 2010). This reflects a major shift in regulatory thinking. The ratio of PIPs with modeling and simulation rose to two in five based on the summary reports. Population pharmacokinetic (POP-PK) and pharmacodynamics (POP-PD) and physiologically based pharmacokinetic models are widely used by industry and endorsed or even imposed by regulators as a way to circumvent some difficulties in developing medicinal products in children. The knowledge of the effects of age and size on PK is improving, and models are widely employed to make optimal use of this knowledge but less is known about the effects of size and maturation on PD, disease progression, and safety. Extrapolation of efficacy from different age groups is often used in pediatric medicinal development as another means to alleviate the burden of clinical trials in children, and this can be aided by modeling and simulation to supplement clinical data. The regulatory assessment is finally judged on clinical grounds such as feasibility, ethical issues, prioritization of studies, and unmet medical need. The regulators are eager to expand the use of modeling and simulation to elucidate safety issues, to evaluate the effects of disease (e.g., renal or hepatic dysfunction), and to qualify mechanistic models that could help shift the current medicinal development paradigm. PMID- 21244570 TI - Natural disasters and the lung. AB - As the world population expands, an increasing number of people are living in areas which may be threatened by natural disasters. Most of these major natural disasters occur in the Asian region. Pulmonary complications are common following natural disasters and can result from direct insults to the lung or may be indirect, secondary to overcrowding and the collapse in infrastructure and health care systems which often occur in the aftermath of a disaster. Delivery of health care in disaster situations is challenging and anticipation of the types of clinical and public health problems faced in disaster situations is crucial when preparing disaster responses. In this article we review the pulmonary effects of natural disasters in the immediate setting and in the post-disaster aftermath and we discuss how this could inform planning for future disasters. PMID- 21244571 TI - Vitamin D, innate immunity and outcomes in community acquired pneumonia. AB - BACKGROUND AND OBJECTIVE: Vitamin D regulates the production of the antimicrobial peptides cathelicidin and beta-defensin-2, which play an important role in the innate immune response to infection. We hypothesized that vitamin D deficiency would be associated with lower levels of these peptides and worse outcomes in patients admitted to hospital with community acquired pneumonia. METHODS: Associations between mortality and serum levels of 25-hydroxyvitamin D, cathelicidin and beta-defensin-2 were investigated in a prospective cohort of 112 patients admitted with community acquired pneumonia during winter. RESULTS: Severe 25-hydroxyvitamin D deficiency (<30nmol/L) was common in this population (15%) and was associated with a higher 30-day mortality compared with patients with sufficient 25-hydroxyvitamin D (>50nmol/L) (odds ratio 12.7, 95% confidence interval: 2.2-73.3, P=0.004). These associations were not explained by differences in age, comorbidities, or the severity of the acute illness. Neither cathelicidin nor beta-defensin-2 levels predicted mortality, although there was a trend towards increased mortality with lower cathelicidin (P=0.053). Neither cathelicidin nor beta-defensin-2 levels correlated with 25-hydroxyvitamin D. CONCLUSIONS: 25-hydroxyvitamin D deficiency is associated with increased mortality in patients admitted to hospital with community acquired pneumonia during winter. Contrary to our hypothesis, 25-hydroxyvitamin D levels were not associated with levels of cathelicidin or beta-defensin-2. PMID- 21244572 TI - The origin of frequency dependence of respiratory resistance: an airflow simulation study using a 4D pulmonary lobule model. AB - BACKGROUND AND OBJECTIVE: The origin of frequency dependence of respiratory resistance has been explained by ventilation inhomogeneity; however, it is unclear which components in the respiratory system generate the frequency dependence. The author constructed a 4D pulmonary lobule model and analysed relationships between airflow rate, pressure and airway resistance by the use of computational fluid dynamics. METHODS: The lobule model contained bifurcated bronchioles with two adjacent acini in which deformable inter-acinar septa and alveolar duct walls were designed. Constrictive conditions of respective bronchioles were designed, too. 4D finite element models for computational fluid dynamics were generated and airflow simulations were performed under moving boundary conditions of the arbitrary Lagrangean-Eulerean method. From the simulation results, airway resistances for various conditions were calculated. RESULTS: Tissue resistance emerged under the condition of different acinar pressures caused by unequal airway resistances. If the inter-acinar septum was shifted so as to cancel the pressure difference, the acinar pressures were equal in spite of unequal airway resistances, and hence, tissue resistances did not emerge. Therefore, the tissue resistance in the former case is thought to be an index of alveolar pressure inequality (which could be cancelled by mechanical interaction of lung parenchyma), rather than a material property of the tissue itself. CONCLUSIONS: Inequality of alveolar pressure decreases as the input oscillatory frequency increases. Therefore, frequency dependence of the respiratory resistance should be regarded as a conditional index of the alveolar pressure inequality caused by heterogeneous changes in the intra-pulmonary airway and/or the lung parenchyma. PMID- 21244573 TI - The value of the CRB65 score to predict mortality in exacerbations of COPD requiring hospital admission. AB - BACKGROUND AND OBJECTIVE: The CRB65 score, a risk stratification method validated for use in community-acquired pneumonia, has recently been shown to have utility in acute exacerbations of COPD (AECOPD). The objective of this study was to independently validate the CRB65 score as a predictor of mortality in patients who required hospital admission with AECOPD. METHODS: The medical records of patients admitted to Wellington Hospital with AECOPD during a 12-month period from June 2006 were reviewed. Logistic regression was used to determine the strength of the association between the CRB65 score and death at three measurement times: in-hospital, 30days and 12months. RESULTS: Complete data were available in 133/174 patient admissions. In-hospital and 30-day mortality increased progressively with increasing CRB65 score and was markedly higher in the CRB 3-4 group (3%, 5%, 29%, and 4%, 9%, 43% for CRB65 scores 0-1, 2, 3-4 for in-hospital and 30-day mortality, respectively). Differences in 1-year mortality were less apparent (24%, 25%, 57% for CRB65 scores 0-1, 2, 3-4, respectively). The CRB65 score demonstrated a modest value for predicting in-hospital and 30-day mortality with a c statistic of 0.68 at both time points. CONCLUSIONS: The CRB65 score shows similar characteristics for predicting short-term mortality in AECOPD as its use in community-acquired pneumonia. We recommend its use in clinical practice, particularly in patients with a score >=3, which is associated with a high risk of early mortality, and need for intensive hospital management. PMID- 21244574 TI - Year in review 2010: interstitial lung diseases, acute lung injury, sleep, physiology, imaging, bronchoscopic intervention and lung cancer. PMID- 21244576 TI - c-Maf suppresses human T-cell leukemia virus type 1 Tax by competing for CREB binding protein. AB - Latent infection of human T-cell leukemia virus type 1 (HTLV-1) is considered to be preferentially associated with CCR4(+) CD4(+) T cells. Here we report that c Maf, one of the critical transcription factors for Th2 differentiation, suppresses the transcriptional activity of HTLV-1 Tax by competing for CREB binding protein. Notably, c-maf expression is selectively induced in a fraction of CCR4(+) CD4(+) T cells upon activation. Furthermore, c-Maf significantly decreases Tax-induced HTLV-1 envelope gp46 gene expression from an infectious HTLV-1 molecular clone and tax expression in a cell-free HTLV-1 infection system. Collectively, c-Maf may play a role in latent infection of HTLV-1 in CCR4(+) CD4(+) T cells by negatively regulating Tax activity. PMID- 21244575 TI - Microarray analysis identifies versican and CD9 as potent prognostic markers in gastric gastrointestinal stromal tumors. AB - Although the main cause of gastrointestinal stromal tumor (GIST) is gain-of function mutations in the c-kit gene in the interstitial cells of Cajal, concomitant genetic or epigenetic changes other than c-kit appear to occur in the development of metastasis. We sought to identify the genes involved in the metastatic process of gastric GIST. Microarray analysis was performed to compare gene expressions between three gastric GIST and four metastatic liver GIST. Expression levels were higher for 165 genes and lower for 146 genes in metastatic liver GIST. The upregulation of five oncogenes and downregulation of four tumor suppressor genes including versican and CD9 were confirmed by quantitative reverse transcriptional PCR. Immunohistochemistry in 117 GIST revealed that protein levels of versican and CD9 were higher and lower, respectively, in metastatic GIST. High expression of versican and low expression of CD9 in 104 primary gastric GIST correlated with poor disease-free survival (P = 0.0078 and P = 0.0018). In addition to the c-kit gene mutation, genetic or epigenetic changes other than c-kit play important roles in the metastatic process. In particular, versican and CD9 are potential prognostic markers in gastric GIST. PMID- 21244577 TI - Catalase suppression-mediated H(2)O(2) accumulation in cancer cells by wogonin effectively blocks tumor necrosis factor-induced NF-kappaB activation and sensitizes apoptosis. AB - Tremendous effort has been made to improve the anticancer value of tumor necrosis factor (TNF). In this study, we show that wogonin, a flavonoid isolated from Huang-Qin (Scutellaria baicalensis), synergistically sensitizes cancer cells derived from the cervix, ovary and lung to TNF-induced apoptosis, which was associated with inhibition of catalase activity and an increase of cellular hydrogen peroxide (H(2)O(2)). Wogonin-induced reactive oxygen species block TNF induced NF-kappaB activation through inhibiting phosphorylation on the NF-kappaB p65 subunit and consequently the DNA binding of NF-kappaB. In addition, wogonin suppressed the expression of the antiapoptotic factor c-FLIP, which is accompanied with potentiation of TNF-induced caspase 8 activation that initiates apoptosis. Importantly, wogonin did not sensitize normal bronchial epithelial cells to TNF-induced cell death, which was associated with the defect in induction of H(2)O(2). Thus, wogonin specifically sensitizes cancer cells to TNF induced cytotoxicity through H(2)O(2)-mediated NF-kappaB suppression and apoptosis activation. Our data provide important insights into the molecular mechanism underlying wogonin's anticancer activity, and suggest this common flavonoid could be used as a TNF adjuvant for cancer therapy. PMID- 21244578 TI - Clinical utility of highly sensitive Lens culinaris agglutinin-reactive alpha fetoprotein in hepatocellular carcinoma patients with alpha-fetoprotein <20 ng/mL. AB - The Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) has been used as a diagnostic and prognostic marker of hepatocellular carcinoma (HCC). The analytical sensitivity of a conventional method for AFP-L3% is not sufficient in patients with a low AFP level. This study was performed to determine the clinical utility of a newly developed highly sensitive AFP-L3% (hs AFP-L3%) assay in patients with an AFP level <20 ng/mL. In the cohort study, serum samples obtained from 270 patients with newly diagnosed HCC before treatment and 396 patients with chronic liver disease at Ogaki Municipal Hospital, in both of which the AFP level was <20 ng/mL, were measured for conventional AFP-L3% (c-AFP-L3%), hs-AFP-L3% and des-gamma-carboxy prothrombin (DCP). Diagnostic sensitivity and specificity of hs-AFP-L3% at a cut-off level of 5% were 41.5% and 85.1%, respectively, significantly increasing the sensitivity from 7.0% for c-AFP-L3%. Multivariate analysis identified hs-AFP-L3% as an independent factor associated with reduced long-term survival. The survival rate of patients with high hs-AFP-L3% (>= 5%) before treatment was significantly poorer than that of patients with low hs-AFP-L3% (<5%) (P < 0.001). In patients with AFP <20 ng/mL, measurements of AFP-L3% by the highly sensitive method before treatment were more useful for diagnosis and prognosis of HCC than by the conventional method. PMID- 21244579 TI - The psychosocial burden of essential tremor in an outpatient- and a community based cohort. AB - BACKGROUND AND PURPOSE: To compare psychosocial burden in patients with essential tremor (ET) in an outpatient (OPC)- and a community-based cohort (CBC). METHODS: A sample of outpatients of a tertiary referral center (n = 180) and a community based sample (n = 100) with ET were asked for study participation. Psychosocial aspects were assessed by a questionnaire on psychosocial aspects of ET, neuropsychological scales, quality of life, personality traits, and coping strategies. RESULTS: One hundred and seven patients of the OPC and 90 individuals of the CBC participated and their results are descriptively presented. Statistical analysis was restricted to 38 pairs of OPC and CBC individuals matched for age, sex, and tremor severity. One-third of these individuals reported a profound impairment in everyday or professional life. Neuropsychological scales showed a severe depression in 8% of the individuals and pathologic values for the general level of psychiatric symptoms in 26%. The main coping strategy was 'active problem-orientated coping'. Patients of the OPC perceived a more severe impact of ET on their life. Multivariate analysis revealed the Beck Depression Inventory score as the only predictive factor for the outcome variables, physical and mental component scores, of the SF-12 health survey. CONCLUSIONS: ET causes a significant psychosocial impairment, which does depend on symptom severity but also on mood with depression as the main driving factor and other so far undetermined factors. PMID- 21244580 TI - Idiopathic NBIA--clinical spectrum and transcranial sonography findings. PMID- 21244581 TI - The left parietal lobe plays a role in the pathogenesis of blepharospasm? PMID- 21244582 TI - The impact of cerebral amyloid angiopathy on the occurrence of cerebrovascular lesions in demented patients with Alzheimer features: a neuropathological study. AB - OBJECTIVE: The aim of this neuropathological study was to determine the prevalence of the different cerebrovascular lesions to be attributed to cerebral amyloid angiopathy (CAA) and of those associated with the severity of the Alzheimer dementia (AD) itself. PATIENTS AND METHODS: The cerebrovascular lesions were compared separately in 40 brains of patients with mild and 50 with severe AD features. In the two groups, the number of lesions were compared between the brains with severe and those with mild of absent CAA. RESULTS: The age of the patients, the vascular risk factors and antithrombotic treatment were similar in all the compared groups. The brains with mild and severe AD features and with CAA contained more haematomas, cortical micro-infarcts and micro-bleeds, and more severe white matter changes, and cortico-subcortical and white matter mini bleeds. In the CAA brains with severe AD features, also more cortical territorial infarcts were observed, compared to those with mild AD features. CONCLUSIONS: The increase in cortical infarcts cannot be attributed to the CAA alone, but also to the severity of the degenerative features, implying additional vascular factors in the pathogenesis of AD. PMID- 21244583 TI - Analysis of thrombin-antithrombin complex contents in plasma and hematoma fluid of hypertensive intracerebral hemorrhage patients after clot removal. AB - BACKGROUND AND PURPOSE: Animal experiments indicate that the cerebral thrombin is associated with secondary brain damage after intracerebral hemorrhage (ICH). This study was aimed to investigate the concentrations of thrombin-antithrombin complex (TAT) in hematoma fluid and plasma of the patients with ICH after surgery and analyze the correlation between TAT complex levels and severity of ICH. METHODS: Sixty patients with ICH were enrolled. Craniotomy for removal of intracranial blood clot was performed within 24h after ICH. Hematoma fluid and plasma were collected on postoperative days 1, 2, and 4. The plasma obtained from healthy subjects and cerebrospinal fluid from patients without cerebrovascular diseases served as controls, respectively. Enzyme-linked immunosorbent assay was used to determine the concentrations of TAT complex in the patients and controls. RESULTS: TAT complex concentrations in both postoperative plasma and hematoma fluid of patients with ICH were significantly higher than those of the controls (P<0.01). In patients with ICH, hematoma fluid had a higher TAT complex level than plasma (P<0.01). The preoperative hemorrhage volume and postoperative TAT complex levels in plasma and hematoma fluid correlated positively with National Institutes of Health stroke scale and negatively with Glasgow coma score (P<0.01). CONCLUSION: This study indicates that TAT complex levels of plasma and hematoma fluid correlate positively with the severity of ICH. Determination of the plasma TAT complex concentration is helpful for the evaluation of the severity of post-ICH brain injury. PMID- 21244584 TI - Association of lung function with cognitive decline and dementia: the Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Previous studies reported a higher risk of cognitive decline and dementia amongst individuals with impaired lung function. However, many did not adjust for important confounders or did not include women and non-whites. METHODS: We studied 10,975 men and women aged 47-70 years (23% African-Americans) enrolled in the Atherosclerosis Risk in Communities Study. Pulmonary function tests and a cognitive assessment, including the Delayed Word Recall, the Digit Symbol Substitution, and the World Fluency Tests, were carried out in 1990-1992. Repeated cognitive assessments were performed in 1996-1998 for the entire cohort, and in 1993-1995, and 2004-2006 in 904 eligible individuals. Dementia hospitalization was ascertained through 2005. RESULTS: In analysis adjusted for lifestyles, APOE genotype, and cardiovascular risk factors, impaired lung function was associated with worse cognitive function at baseline. No association was found between lung function and cognitive decline over time. Impaired lung function at baseline was associated with higher risk of dementia hospitalization during follow-up, particularly amongst younger individuals. The hazard ratios (95% confidence intervals) of dementia hospitalization were 1.6 (0.9, 2.8) and 2.1 (1.2, 3.7) comparing the lowest with the highest quartile of forced expiratory volume in 1 s and forced vital capacity, respectively. Presence of a restrictive ventilatory pattern, but not of an obstructive pattern, was associated with reduced cognitive scores and higher dementia risk. CONCLUSION: Reduced lung function was associated with worse performance in cognitive assessments and with an increased risk of dementia hospitalization. Future research should determine whether maintaining optimal pulmonary health might prevent cognitive impairment and dementia. PMID- 21244585 TI - Poor lung function and associated patterns of cognitive decline. PMID- 21244587 TI - Daily survival and human blood index of major malaria vectors associated with oil palm cultivation in Cameroon and their role in malaria transmission. AB - OBJECTIVE: To describe the daily survival rate, biting habits, feeding behaviour, sporozoite and entomological inoculation rates of Anopheles species and their relative contribution to Plasmodium falciparum transmission in large-scale oil palm-growing zones in Cameroon. METHODS: Entomological surveys by employing human landing catches, both indoors and outdoors, two nights per month for 12 months from October 2004. RESULTS: A total of 2485 Anopheles were collected and four species recorded: An. funestus, An. hancocki, An. gambiae s.s. and An. nili. There was substantial indoors to outdoors variation and seasonality in the distribution of the Anopheles population. All four species showed similar nocturnal biting patterns and were sympatrically involved in malaria transmission simultaneously or replacing each other seasonally. Their constant presence throughout the year and longevity suggest that transmission can occur at any time if parasite reservoirs are present in the area. The circumsporozoite protein rates were 5.8%, 6.3%, 8.4% and 4.1%; mean anthropophilic rates were 97.1%, 94.5%, 73.9% and 77.6%, respectively, for An. funestus, An. gambiae s.l, An. nili and An. hancocki. The annual entomological inoculation rate was 1077 infectious bites per person. Of those An. gambiae specimens testing positive for P. falciparum sporozoites, 69.01% were M form and 30.99% were S form. CONCLUSION: Any vector control strategy intending to significantly reduce the malaria burden in the palm estate will have to take into account entomological heterogeneity in addition to ecological and socio-economic multiplicity. PMID- 21244588 TI - Application of PFGE to source tracking of faecal pollution in coastal recreation area: a case study in Aoshima Beach, Japan. AB - AIMS: The development of a microbial source tracking (MST) method is strongly desired to ensure public health and bacteriological safety in coastal recreation areas. We try to specify the source of faecal pollution by applying pulsed-field gel electrophoresis (PFGE) to the study of the aquatic environment on Aoshima Beach, Japan. METHODS AND RESULTS: Enterococcus faecium, an enterococcus, was used as a faecal indicator bacterium in this study. Enterococcus faecium strains were isolated and identified from each water sample collected from Aoshima Beach and five rivers (Oyodo, Kiyotake, Kaeda, Chifuku and Tsukunami Rivers) that might be potential sources of faecal pollution. Enterococcus faecium strains collected from water samples were analysed using PFGE. The similarities of all the PFGE types of the Ent. faecium strains were compared using dendrogram analysis. The PFGE types of the strains isolated from Aoshima Beach showed a high similarity to those of the strains isolated from the Oyodo River at a 0.9 similarity level. It was suggested that the Oyodo River is the source of faecal pollution on Aoshima Beach. CONCLUSIONS: The PFGE analysis using enterococci is a potential tool for the MST of faecal indicator bacteria that can be applied to the study of the coastal environment. SIGNIFICANCE AND IMPACT OF THE STUDY: This is one of the studies that PFGE was applied to the coastal environment. The approach using PFGE could estimate the river that is source of faecal pollution in Aoshima Beach. By applying PFGE as a tool of MST method, detailed information of faecal pollution in coastal area can be provided. PMID- 21244590 TI - Consulting parents about the design of a randomized controlled trial of osteopathy for children with cerebral palsy. AB - BACKGROUND: Although the UK Department of Health has advocated the involvement of service users and carers in health research for several years, there is little evidence about their contribution to the design of randomized controlled trials (RCTs). OBJECTIVE: To demonstrate how consulting parents about the design of a study, including which outcomes to use, led to the design and successful delivery of a RCT of osteopathy for children with cerebral palsy (CP). DESIGN: Semi structured interviews were carried out with 20 parents of children with CP and other neurological conditions, asking them to choose between four different trial designs, to talk about noticeable changes in their child's condition and their views about payment for trial treatment. SETTING AND PARTICIPANTS: The parents interviewed were all members of Cerebra, a charity for 'brain-injured' children and young people. All interviews were carried out at the parents' homes. RESULTS: Parents had mixed views about possible trial designs; however, a waitlist design which allowed all children eventually to receive the treatment emerged as a clear favourite. Parents did not focus on isolated outcomes, but suggested a range of factors relevant to their child's quality of life. They expressed a clear preference for the costs of treatment to be funded by the trial. CONCLUSIONS: Involvement of parents helped design a trial which was acceptable to families and addressed outcomes that mattered to them. By consulting parents about the design of the research, the subsequent trial achieved excellent recruitment and retention rates. PMID- 21244591 TI - Exercise testing in pediatric lung transplant candidates with cystic fibrosis. AB - Exercise testing is considered an important prognostic tool for the selection of pediatric lung transplant candidates with end-stage CF lung disease. To better understand the current practice as it pertains to exercise testing, a self administered questionnaire was distributed to 25 pediatric lung transplant centers within the IPLTC across Australia, Europe, and North America. All centers perform standardized exercise tests. Fifteen centers perform one single-field test (6MWT/12MWT), while seven perform a six-min walk plus an additional test: SWT (N = 1), 3MST (N = 1), and CPET (N = 5). Frequency of testing is markedly different among centers. Two centers conduct exercise testing once, all others at multiple time points. Equipment availability and cost were no limitations, but lack of time (20%) and personnel (16%), and paucity of prognostic evidence (16%) and reference values (12%) were stated. Exercise testing is considered important and extensively used in the evaluation of pediatric lung transplant candidates with CF; methods of exercise test and the frequency of testing vary widely. We propose a prospective multicenter study to evaluate the efficacy of exercise testing and its prognostic value using a standardized protocol. PMID- 21244592 TI - The evolution of unconditional strategies via the 'multiplier effect'. AB - Ostensibly, it makes sense in a changeable world to condition behaviour and development on information when it is available. Nevertheless, unconditional behavioural and life history strategies are widespread. Here, we show how intergenerational effects can limit the evolutionary value of responding to reliable environmental cues, and thus favour the evolutionary persistence of otherwise paradoxical unconditional strategies. While cue-ignoring genotypes do poorly in the wrong environments, in the right environment they will leave many copies of themselves, which will themselves leave many copies, and so on, leading genotypes to accumulate in habitats in which they do well. We call this 'The Multiplier Effect'. We explore the consequences of the multiplier effect by focussing on the ecologically important phenomenon of natal philopatry. We model the environment as a large number of temporally varying breeding sites connected by natal dispersal between sites. Our aim is to identify which aspects of an environment promote the multiplier effect. We show, if sites remain connected through some background level of 'accidental' dispersal, unconditional natal philopatry can evolve even when there is density dependence (with its accompanying kin competition effects), and cues that are only mildly erroneous. Thus, the multiplier effect may underpin the evolution and maintenance of unconditional strategies such as natal philopatry in many biological systems. PMID- 21244593 TI - The origins of the Redfield nitrogen-to-phosphorus ratio are in a homoeostatic protein-to-rRNA ratio. AB - One of the most intriguing patterns in the biosphere is the similarity of the atomic nitrogen-to-phosphorus ratio (N:P) = 16 found in waters throughout the deep ocean and in the plankton in the upper ocean. Although A.C. Redfield proposed in 1934 that the intracellular properties of plankton were central to this pattern, no theoretical significance for N:P = 16 in cells had been found. Here, we use theoretical modelling and a compilation of literature data for prokaryotic and eukaryotic microbes to show that the balance between two fundamental processes, protein and rRNA synthesis, results in a stable biochemical attractor that homoeostatically produces a given protein:rRNA ratio. Furthermore, when biochemical constants and reasonable kinetic parameters for protein synthesis and ribosome production under nutrient-replete conditions are applied in the model, it predicts a stable protein:rRNA ratio of 3 +/- 0.7, which corresponds to N:P = 16 +/- 3. The model also predicts that N-limitation, by constraining protein synthesis rates, will result in N:P ratios below the Redfield value while P-limitation, by constraining RNA production rates, will produce ratios above the Redfield value. Hence, one of most biogeochemically significant patterns on Earth is inherently rooted in the fundamental structure of life. PMID- 21244594 TI - Natural and within-farmland biodiversity enhances crop productivity. AB - Ongoing expansion of large-scale agriculture critically threatens natural habitats and the pollination services they offer. Creating patches with high plant diversity within farmland is commonly suggested as a measure to benefit pollinators. However, farmers rarely adopt such practice, instead removing naturally occurring plants (weeds). By combining pollinator exclusion experiments with analysis of honeybee behaviour and flower-visitation webs, we found that the presence of weeds allowed pollinators to persist within sunflower fields, maximizing the benefits of the remaining patches of natural habitat to productivity of this large-scale crop. Weed diversity increased flower visitor diversity, hence ameliorating the measured negative effects of isolation from natural habitat. Although honeybees were the most abundant visitors, diversity of flower visitors enhanced honeybee movement, being the main factor influencing productivity. Conservation of natural patches combined with promoting flowering plants within crops can maximize productivity and, therefore, reduce the need for cropland expansion, contributing towards sustainable agriculture. PMID- 21244595 TI - Is dinitrogen fixation significant in the Levantine Basin, East Mediterranean Sea? AB - We report N(2) fixation rates measured from two stations monitored monthly off the Mediterranean coast of Israel during 2006 and 2007, and along a transect from Israel to Crete in September 2008. Analyses of time-series data revealed expression of nifH genes from diazotrophs in nifH clusters I and II, including cyanobacterial bloom-formers Trichodesmium and diatom-Richelia intracellularis associations. However, nifH gene abundance and rates of N(2) fixation were very low in all size fractions measured (> 0.7 um). Volumetric (15) N uptake ranged from below detection (~ 36% of > 300 samples) to a high of 0.3 nmol N l(-1) d(-1) and did not vary distinctly with depth or season. Areal N(2) fixation averaged ~ 1 to 4 umol N m(-2) d(-1) and contributed only ~ 1% and 2% of new production and ~ 0.25% and 0.5% of primary production for the mixed (winter) and stratified (spring-fall) periods respectively. N(2) fixation rates along the 2008 east-west transect were also extremely low (0-0.04 nmol N l(-1) d(-1), integrated average 2.6 umol N m(-2) d(-1) ) with 37% of samples below detection and no discernable difference between stations. We demonstrate that diazotrophy and N(2) fixation contribute only a minor amount of new N to the P impoverished eastern Mediterranean Sea. PMID- 21244596 TI - Catabolic pathway for 2-nitroimidazole involves a novel nitrohydrolase that also confers drug resistance. AB - Antibiotic resistance in pathogens can be mediated by catabolic enzymes thought to originate from soil bacteria, but the physiological functions and evolutionary origins of the enzymes in natural ecosystems are poorly understood. 2 Nitroimidazole (2NI) is a natural antibiotic and an analogue of the synthetic nitroimidazoles used for treatment of tuberculosis, Chagas' disease and cancer. Mycobacterium sp. JS330 was isolated from soil based on its ability to use 2NI as a sole growth substrate. The initial step in the degradation pathway is the hydrolytic denitration of 2NI to produce imidazol-2-one and nitrite. The amino acid sequence of 2NI nitrohydrolase is highly divergent from those of biochemically characterized enzymes, and it confers drug resistance when it is heterologously expressed in Escherichia coli. The unusual enzymatic reaction seems likely to determine the flux of nitroimidazole in natural ecosystems and also represents the discovery of a previously unreported drug resistance mechanism in soil before its identification in clinical situations. PMID- 21244597 TI - In situ activity of NAC11-7 roseobacters in coastal waters off the Chesapeake Bay based on ftsZ expression. AB - Determining in situ growth rates for specific bacterioplankton is of critical importance to understanding their contributions to energy and matter flow in the Ocean. Quantifying expression of genes central to cell division is a plausible approach for obtaining these measurements. In order to test this approach's assumptions, a quantitative PCR assay targeting the cell division gene ftsZ in the ubiquitous NAC11-7 group of the Rhodobacterales order of marine bacteria was developed. ftsZ genes and their corresponding mRNAs were measured in diel in situ samples and in parallel on-deck incubations. Strong correlations between ftsZ expression and gene abundance (R-squared = 0.62) were observed in situ. Rapid changes in NAC11-7 ftsZ gene copies suggested that different populations from different water types were sampled with a significant positive correlation between ftsZ expression and water temperature (R-squared = 0.68, P < 0.001). An outlier to this trend occurred at a single time point (9:00), which was remarkably consistent with a concomitant peak in ftsZ expression in on-deck incubations, suggesting the possibility of synchronous population growth. PMID- 21244598 TI - Convergent dynamics of the juvenile European sea bass gut microbiota induced by poly-beta-hydroxybutyrate. AB - Poly-beta-hydroxybutyrate (PHB) is a bacterial energy and carbon storage compound which exhibits a controlling effect on the gastrointestinal microbiota. Its beneficial activities for aquaculture have already been shown in terms of increased disease resistance and growth performance in a number of studies. However, the action of PHB on the intestinal microbial community in the treated animals has not yet been studied in depth. In this research, the effects of PHB on the microbiota composition in the intestinal tract of juvenile sea bass were examined. It was found that fish cohabiting in the same tank were on average 87% similar regarding the intestinal microbiota. When subjected to the same treatment and environmental conditions but reared in different tanks, the compositions of the enteric communities diverged. The provision of PHB overruled this tank effect by sustaining a microbial core community in the gut that represented 60% of the total bacterial diversity at the highest PHB level of 10%. The microbial community compositions converged between replicate tanks upon supplementation of PHB and were characterized by high dynamics and increased evenness. The results are discussed in the framework of hypotheses that try to relate the intestinal microbial community composition to the health status of the host organisms. PMID- 21244599 TI - Growth and release of extracellular organic compounds by benthic diatoms depend on interactions with bacteria. AB - Phototrophic epilithic biofilms harbour a distinct assemblage of heterotrophic bacteria, cyanobacteria and photoautotrophic algae. Secretion of extracellular polymeric substances (EPS) by these organisms and the physicochemical properties of the EPS are important factors for the development of the biofilms. We have isolated representative diatom and bacteria strains from epilithic biofilms of Lake Constance. By pairwise co-cultivating these strains we found that diatom growth and EPS secretion by diatoms may depend on the presence of individual bacteria. Similar results were obtained after addition of spent bacterial medium to diatom cultures, suggesting that soluble substances from bacteria have an impact on diatom physiology. While searching for putative bacterial signal substances, we found that concentrations of various dissolved free amino acids (DFAA) within the diatom cultures changed drastically during co-cultivation with bacteria. Further, the secretion of extracellular carbohydrates and proteins can be influenced by bacteria or their extracellular substances. We have performed mass spectrometric peptide mapping to identify proteins which are secreted when co-cultivating the diatom Phaeodactylum tricornutum Bohlin and Escherichia coli. The identified proteins are possibly involved in signalling, extracellular carbohydrate modification and uptake, protein and amino acid modification, and cell/cell aggregation of diatom and bacteria strains. Our data indicate that diatom-bacteria biofilms might be regulated by a complex network of chemical factors involving EPS, amino acid monomers and other substances. Thus interactions with bacteria can be considered as one of the main factors driving biofilm formation by benthic diatoms. PMID- 21244600 TI - HIV/hepatitis C virus and HIV/hepatitis B virus coinfections protect against antiretroviral-related hyperlipidaemia. AB - INTRODUCTION: Hyperlipidaemia is a recognized complication of HIV antiretroviral therapy. The interactions among HIV, viral hepatitis, antiretroviral therapies and lipids are poorly understood. METHODS: Ontario HIV Treatment Network Cohort Study participants with at least one lipid level after highly active antiretroviral therapy (HAART) initiation were assessed. Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-coinfected patients were identified by serology or chart review. HCV antiviral recipients, diabetics and those on lipid-lowering drugs at baseline were excluded from the study. Factors associated with a decreased risk of grade 3 or 4 hyperlipidaemia or lipid-lowering drug use were assessed by multivariate logistic regression. RESULTS: A total of 1587 HIV monoinfected, 190 HIV/HBV-coinfected and 255 HIV/HCV-coinfected patients were evaluated. Most were male (85-92% for the 3 groups evaluated: HIV, HIV/HBV, HIV/HCV). The median [interquartile range (IQR)] age at HAART initiation was 48 (44-56) years and was similar between groups. The median (IQR) CD4 count at HAART initiation was 245 (120-370) cells/MUL in HIV-monoinfected participants, 195 (110 330) cells/MUL in HIV/HBV-coinfected participants and 268 (140-409) cells/MUL in HIV/HCV-coinfected participants. Factors associated with a decreased risk of grade 3 or 4 hyperlipidaemia or lipid-lowering drug use included HIV/HCV coinfection [odds ratio (OR) 0.46; 95% confidence interval (CI) 0.34, 0.61; P<0.0001], HIV/HBV coinfection (OR 0.74; 95% CI 0.55, 0.99; P=0.04), year of starting HAART after 2004 vs. 1997 or earlier (OR 0.37; 95% CI 0.29, 0.48; P<0.0001) and year of starting HAART between 1998 and 2003 vs. 1997 or earlier (OR 0.75; 95% CI 0.61, 0.92; P<0.01). Factors associated with increased risk included age (OR 1.55; 95% CI 1.39, 1.72; per 10 years, P<0.0001) and male gender (OR 1.84; 95% CI 1.36, 2.48; P<0.0001). CONCLUSIONS: HIV/HCV and to a lesser extent HIV/HBV coinfections are protective against HAART-related hyperlipidaemia. PMID- 21244601 TI - Phase I/II trial of subcutaneous interleukin-2, granulocyte-macrophage colony stimulating factor and interferon-alpha in patients with metastatic renal cell carcinoma. AB - OBJECTIVE: To determine, in a phase I/II trial, the maximum tolerated dose (MTD), clinical activity and safety of concurrent subcutaneous (s.c.) interleukin-2 (IL 2), interferon-alpha2b (IFN-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF). PATIENTS AND METHODS: Patients with metastatic renal cell carcinoma (RCC) received on a 3+3 trial design escalating doses of s.c. GM-CSF, IL-2 and IFN-alpha. Dose-limiting toxicities (DLTs) during the first 6-week cycle were used to determine the MTD. A phase II trial was then initiated to determine clinical activity. RESULTS: A total of sixty patients were enrolled in the study (phase I = 31; phase II = 29). Two DLTs were observed (G3 nausea/vomiting and fatigue) and the MTD was determined to be GM-CSF 5.0 ug/kg/day, IL-2 9.0 mIU/m(2)/day and IFN-alpha 5.0 mU/m(2)/day. Patients received a median (range) of four (one to 11) cycles of therapy. G3 adverse events were reported in 10 of 31 (32%) patients. The overall response rate was 20% (one complete response and 11 partial responses), including patients who were rendered free of disease with surgery. The median progression-free survival and overall survival were 6.0 and 23.4 months, respectively. CONCLUSIONS: Immunotherapy with concurrent s.c. GM CSF, IL-2 and IFN-alpha is generally well tolerated. The overall response rate observed with this combination continues to show the efficacy of immunotherapy in a selected group of metastatic RCC patients. PMID- 21244602 TI - The impact of cavernosal nerve preservation on continence after robotic radical prostatectomy. AB - OBJECTIVE: * To evaluate associations between baseline characteristics, nerve sparing (NS) status and return of continence, as a relationship may exist between return to continence and preservation of the neurovascular bundles for potency during radical prostatectomy (RP). PATIENTS AND METHODS: * The study included 592 consecutive robotic RPs completed between 2002 and 2007. * All data were entered prospectively into an electronic database. * Continence data (defined as zero pads) was collected using self-administered validated questionnaires. * Baseline characteristics (age, International Index of Erectile Function [IIEF-5] score, American Urological Association symptom score, body mass index [BMI], clinical T stage, Gleason score, and prostate-specific antigen level), NS status and learning curve were retrospectively evaluated for association with overall continence at 1, 3 and 12 months after RP using univariate and multivariable methods. * Any patient taking preoperative phosphodiesterase inhibitors was excluded from the postoperative analysis. RESULTS: * Complete data were available for 537 of 592 patients (91%). * Continence rates at 12 months after RP were 89.2%, 88.9% and 84.8% for bilateral NS, unilateral NS and non-NS respectively (P= 0.56). * In multivariable analysis age, IIEF-5 score and BMI were significant independent predictors of continence. * CavernosalNS status did not significantly affect continence after adjusting for other co-variables. CONCLUSION: * After careful multivariable analysis of baseline characteristics age, IIEF-5 score and BMI affected continence in a statistically significant fashion. This suggests that baseline factors and not the physical preservation of the cavernosal nerves predict overall return to continence. PMID- 21244603 TI - FOXP3 and survival in urinary bladder cancer. AB - OBJECTIVE: To investigate the possible impact of FOXP3 expression in T-cells, as well as in tumour cells, on long-term survival in patients with urinary bladder cancer (UBC) invading muscle. PATIENTS AND METHODS: In a retrospective study, tumour specimens from 37 patients cystectomized for T1-T4 UBC during 1999-2002 at the Karolinska University Hospital were examined by immunohistochemistry for tumour expression and/or infiltration of immune cells expressing FOXP3 as well as CD3. The results obtained were correlated with clinicopathological parameters, where the primary and secondary outcomes investigated were overall survival and progression-free survival, respectively. RESULTS: Infiltration of CD3(+) and FOXP3(+) lymphocytes (>=3 cells per high-power field) were both correlated with better survival, and this relationship persisted throughout the whole study period (all P < 0.05). Patients with FOXP3(+) tumour cells had decreased long term survival compared to those patients with FOXP3(-) tumours (P < 0.05). Despite a limited amount of patient material, the results of the present study indicate that FOXP3 expression, in both lymphocytes and tumour cells, is an important prognostic factor in UBC. CONCLUSIONS: FOXP3 expression in UBC cells is associated with decreased long-term survival and thus may be a novel negative prognostic factor in UBC invading muscle. By contrast, the presence of FOXP3(+) tumour-infiltrating lymphocytes was correlated with a positive prognosis. Because FOXP3 is up-regulated upon activation in human T-cells, FOXP3 may serve more as an activation marker than as a regulatory T-cell indicator in this case. These results support the need for larger prospective studies aiming to confirm the results obtained and to examine the underlying mechanisms in detail. PMID- 21244604 TI - Discrepancy between clinical and pathological stage: external validation of the impact on prognosis in an international radical cystectomy cohort. AB - OBJECTIVE: * To compare the clinical and pathologic stage among a large, multi institutional series of patients undergoing radical and to determine the effect of stage discrepancy on outcomes. PATIENTS AND METHODS: * Data was collected from nine centers and 3,393 patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy and pelvic lymphadenectomy without neo-adjuvant chemotherapy. * A retrospective cohort design was used to assess the percentage of patients experiencing stage discrepancy and the impact of stage discrepancy on time to disease relapse and time to death from UCB. RESULTS: * Clinical under staging occurred in 50% of patients and pathologic down staging occurred in 18% of patients. * Up staging to muscle invasive disease occurred in 45.9% (n = 592) of 1,291 patients with clinical <=T1, including 30.6% of patients with Tis only at transurethral resection. * Of the 3,166 patients with clinically organ confined (OC) tumor stage, 1,357 (42.9%) were up staged to non-organ confined pathologic tumor stage. * Within each clinical stage stratum, patients who were clinically under staged had a higher probability of disease relapse or death from UCB compared to those who were same staged or down staged on pathologic examination (P < 0.05). CONCLUSIONS: * We identified clinical under staging in half of the patients undergoing radical cystectomy for UCB. * Up staging resulted in a higher likelihood of disease progression and eventual death from UCB. * These findings should be considered when utilizing pre-operative risk-adapted strategies for selecting candidates for neoadjuvant chemotherapy. PMID- 21244605 TI - Laparoscopic partial nephrectomy: six degrees of haemostasis. AB - OBJECTIVE: * To describe six steps for haemostasis and collecting system closure ('six degrees of haemostasis') that are reproducible and that minimize the two most concerning complications of laparoscopic partial nephrectomy: haemorrhage and urine leakage. METHODS: * A retrospective study of 23 consecutive laparoscopic partial nephrectomy cases performed by a single surgeon between 2005 and 2008 using the 'six degrees of haemostasis' was carried out. RESULTS: * There were no cases of intraoperative, postoperative or delayed bleeding. * There were no cases of urine leakage. CONCLUSION: * The 'six degrees of haemostasis' technique for laparoscopic partial nephrectomy described in the present study provides a reliable and reproducible method to reassure the surgeon of haemostasis and provide a decreased risk of urine leakage. PMID- 21244606 TI - Tadalafil administered once daily for lower urinary tract symptoms secondary to benign prostatic hyperplasia: a 1-year, open-label extension study. AB - OBJECTIVE: * To evaluate the 1-year safety of 5 mg of tadalafil once daily in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH LUTS); efficacy measures were included to evaluate the maintenance of efficacy after an additional year of treatment. PATIENTS AND METHODS: * In total, 427 men who completed a 12-week, placebo-controlled, dose- finding study assessing once daily tadalafil (2.5, 5, 10 or 20 mg) or placebo elected to continue into the open-label extension period. Safety and efficacy parameters were assessed after 1 month and every 3 months. RESULTS: * In total, 299 patients (69.9%) completed the 1-year, open-label extension period. Treatment-emergent adverse events (TEAEs) were reported by 57.6% of patients, with most TEAEs being mild (44%) or moderate (45%) in severity; the most common TEAEs (>= 2%) were dyspepsia, gastro oesophageal reflux disease, back pain, headache, sinusitis, hypertension and cough. Twenty-two patients (5.2%) discontinued as a result of AEs. During the open-label extension period, mean prostate-specific antigen increased from 1.6 +/ 1.3 ng/mL to 1.8 +/- 1.4 ng/mL. * Mean post-void residual volume was 61.1 +/- 60.4 mL at study entry and 42.2 +/- 64.1 mL after the open-label extension period. Changes in the total International Prostate Symptom Score (IPSS), IPSS irritative and obstructive subscores, IPSS health-related quality of life and BPH Impact Index were maintained after 1 year. In sexually-active patients with erectile dysfunction, improvements in the International Index of Erectile Function-Erectile Function domain were maintained after 1 year. CONCLUSION: * In men with BPH-LUTS, 5 mg of tadalafil once daily during 1 year of treatment was well tolerated and efficacy changes were maintained. PMID- 21244607 TI - Medical therapy for calculus disease. AB - Urolithiasis is a common problem with a high recurrence rate. Medical therapy directed to relieve agonizing pain, expulsion of stone, dissolution of uric acid and cystine stone and prevention of recurrence. NSAIDs are superior to opioids for renoureteral colic because their use doesn't induce vomiting and there is lesser requirement of rescue analgesia. In randomized trials, anticholinergics were not found to be beneficial. Alpha blockers, particularly tamsulosin, reduce pain and facilitate expulsion of stone and fragments of stone following extracorporeal shock wave lithotripsy (SWL) and ureterorenoscopic lithotripsy. Potassium citrate helps in chemodissolution of uric acid and cystine stones and is useful in prevention of stone recurrence in general and in those who have undergone SWL or percutaneious nephrolithotomy. Other measures for prevention of stone recurrence include fluid and dietary therapy, counteracting underlying metabolic abnormalities using suitable medications, phytotheurapeutic agents and probiotics. Once the role of nanobacteria is established in genesis of urinary stones, anti-nanobacteria therapy holds the promise of opening new horizons for prevention of urinary stones. PMID- 21244608 TI - Structural differences between the bladder dome and trigone revealed by mRNA expression analysis of cold-cut biopsies. AB - OBJECTIVE: To establish the mRNA expression profiles of selected genes involved in bladder contractility and epithelial permeability in the bladder dome and trigone in order to evaluate the use of cold-cut biopsies for comparative quantitative studies into the anatomical differences between these two bladder regions. PATIENTS AND METHODS: After informed consent, cold-cut biopsies from the bladder dome and trigone were obtained from eight asymptomatic subjects. RNA was extracted from muscle biopsies, and the expression levels of selected genes were analysed using TaqMan real-time PCR-based gene expression assays. Protein levels and localization were investigated by immunofluorescence. RESULTS: mRNA levels of NK2 receptor, P2X1, ASIC1a and muscarinic cholinergic receptors M(2), and M(3) were significantly higher in the dome than in the trigone (P < 0.05). In contrast, the mRNA levels of cellular adhesion and tight junction proteins were up-regulated in the trigone. There were no significant differences in expression levels of NK1R, and TRPV1 between the dome and trigone. Although the mRNA levels of uroplakin UP2 were similar in both sample groups, the smooth muscle (SM) markers were up-regulated in the dome biopsies, indicating the higher SM content of these biopsies. Consistent with these observations, when normalizing for the SM content, there were no significant differences in the levels of SM-specific markers between the two sample groups. In contrast, occludin, junctional adhesion molecule 1, claudins 1 and 4, gamma-catenin and E-cadherin were up-regulated in the trigone. These observations were confirmed by immunofluorescence labelling, showing differences in the amount of SM and in the structure of urothelium of the dome and trigone. CONCLUSIONS: Our mRNA and immunofluorescence data show that cold-cut biopsies from the bladder dome have a higher relative SM content compared with the trigone, reflecting a well-developed network of suburothelial myofibroblasts and muscularis mucosae present in the bladder dome. An up regulation of the genes encoding the tight junction proteins in the bladder trigone is independent of the urothelium content, and might imply further discrepancy between these regions. PMID- 21244609 TI - Provider and partner interactions in the treatment decision-making process for newly diagnosed localized prostate cancer. AB - OBJECTIVE: * To evaluate the degree to which the partners of prostate cancer patients participate in the shared decision-making process with the patients' providers during the time between diagnosis and initiating treatment. PATIENTS AND METHODS: * We recruited patients with newly diagnosed local-stage prostate cancer and their partners to complete take-home surveys after biopsy but before initiating treatment at urology practices in three states. * We asked partners to describe their roles in the decision-making process, including participation in clinic visits, and perceptions of encouragement from providers to participate in the treatment decision-making process. We also asked partners to rate their satisfaction with the patients' providers. RESULTS: * Family members of 80% of newly diagnosed patients agreed to participate; most (93%) were partners (i.e. spouses or significant others). Most partners (93%) had direct contact with the patients' physicians. * Among the partners who had contact with providers, most (67%) were very satisfied with the patients' providers and 80% indicated that the doctor encouraged them to participate in the treatment decision. Overall, 91% of partners reported very frequent discussions with their loved one about the pending treatment decision, and 69% reported that their role was to help the patient make a decision. * In multivariate models, provider encouragement of partner participation was associated with higher partner satisfaction (odds ratio 3.4, 95% CI 1.4-8.4) and an increased likelihood of partners reporting very frequent discussions with their loved one (odds ratio 6.1, 95% CI 1.3-27.7). CONCLUSIONS: * Partners often attended clinic visits and were very involved in discussions about treatment options with both loved ones and providers. * Provider encouragement of participation by partners greatly facilitates shared decision-making between patients and partners. PMID- 21244610 TI - Antibiotics and observation have a similar impact on asymptomatic patients with a raised PSA. AB - OBJECTIVES: * To compare the influence of a 4-week course of empirical antimicrobial therapy or observation on the prostate-specific antigen (PSA) levels of asymptomatic patients with a raised baseline PSA. * To identify whether a decrease in PSA can predict the risk of prostate cancer (PCa) detection on prostate biopsy. PATIENTS AND METHODS: * Patients were referred to our ambulatory centre because of a raised PSA level (>2.5 ng/mL) with a normal digital rectal examination. A 12-core prostate biopsy was indicated in these patients and they were offered antibiotic treatment with levofloxacin 500 mg daily for 30 days. * Patients who did not agree to use antibiotics but who still showed interest in participating underwent simple observation, serving as controls. * Total and free PSA levels at baseline and after 45 days were measured. Variation in PSA level was calculated. * All patients underwent a 12-core prostate biopsy 6 weeks after the initial visit. RESULTS: * In all, 245 men were enrolled, but 43 were lost due to follow-up. A total of 145 patients who used antibiotics and 57 controls were included in the analysis. * The median baseline PSA levels were 7.6 and 7.7 ng/mL in the antibiotic and control groups, respectively, with median follow-up levels of 6.8 and 7.0 ng/mL. The follow-up PSA level was significantly lower than the initial PSA level (P = 0.009). * Mean absolute and percentage variation in PSA level were similar in both groups (P = 0.828 and 0.128, respectively). * The overall PCa detection rate was 15.8%, and did not differ among the groups (P = 0.203). Regarding the percentage variation in PSA level, patients diagnosed with PCa tended to have their PSA level increased (22.4 vs -5.3%; P = 0.001). Indeed, a decrease of 20% in PSA was not predictive of a negative prostate biopsy (P = 0.41). * The area under the receiver operating characteristic curve for percentage PSA variation as a predictor of PCa was 0.660. CONCLUSIONS: * PSA levels tend to fall when repeated after 45 days, regardless of antibiotic use. * Despite being associated with the chance of PCa, no percentage PSA variation threshold value exhibits satisfactory discriminatory properties. PMID- 21244611 TI - Early vs delayed radical cystectomy for 'high-risk' carcinoma not invading bladder muscle: delay of cystectomy reduces cancer-specific survival. AB - OBJECTIVE: *To analyze the impact of a delayed radical cystectomy (rCx) and clinical variables on cancer-specific survival (CSS) in patients presenting 'high risk' carcinoma not invading bladder muscle (nmiBCA). PATIENTS AND METHODS: *Between 1989 and 2006, 278 patients who presented 'high-risk' nmiBCA finally underwent rCx in our institution. *CSS was correlated with clinical variables such as the number of transurethral resections of the bladder (TURBs), interval between first TURB and rCx, adjuvant therapies, tumour upstaging at rCx, tumour stage and lymph node (LN) status. RESULTS: *The overall 5- and 10-year CSS was 82% and 76%, respectively. Significant correlations were found between the 5-year CSS and categorized number of TURBs (<=2 vs >2: 88% vs 71%; P= 0.001), interval between first TURB and rCx (<=4 months vs >4 months: 86% vs 77%; P= 0.04), adjuvant therapies (no vs yes: 86% vs 66%; P= 0.001), tumour upstaging at rCx (no vs yes: 89% vs 67%; P < 0.001), tumour stage at rCx (bladder confined vs non confined: 88% vs 56%; P < 0.001) and LN status (no vs yes: 88% vs 36%; P < 0.001). *Multivariate analysis identified categorized number of TURBs (hazard ratio, HR, 0.14; 95% CI, 0.07-0.44; P < 0.001), categorized interval between first TURB and rCx (HR, 3.27; 95% CI, 1.24-8.59; P= 0.017), LN status (HR, 0.13; 95% CI, 0.06-0.26; P < 0.001) and tumour stage at rCx (HR, 0.49; 95% CI, 0.26 0.92; P= 0.03) as independent risk factors for CSS. CONCLUSION: *Delay of rCx in 'high-risk' nmiBCA deteriorates CSS and should be avoided. The number of TURBs and the interval between first TURB and rCx are causative factors for delayed rCx and are independently correlated with CSS. PMID- 21244612 TI - Inverse stage migration in patients undergoing radical prostatectomy: results of 8916 European patients treated within the last decade. AB - OBJECTIVE: * To investigate the stage migration patterns during the last decade in European men treated with radical prostatectomy (RP). PATIENTS AND METHODS: * Between 2000 and 2009, RP was performed in 8916 patients at a single European tertiary-care institution. * Age at diagnosis, clinical and pathological data were prospectively collected, and trends and proportions of preoperative and pathological findings were analysed over time. RESULTS: * The median (mean) age of patients increased from 62 (62) to 63 (65) years between 2000 and 2009 (P < 0.001). * When patients were stratified based on their clinical findings according to the D'Amico risk groups for disease progression, the proportion of low-risk patients dropped from 66% in 2004 to 35% (P= 0.016) in the final year of the study period. * Similarly, histopathological evaluation of RP specimens showed a decrease of favourable disease (organ confinement and Gleason 3 + 3 grade) from 53 to 17% (P= 0.008). * This trend was accompanied by an increase in the number of patients with non-organ-confined prostate cancer (PCa) from 19% in 2003 to 33% in 2009 (P= 0.008). * The restriction of the analyses in the present study to a single tertiary-care centre could limit the generalizeability of the results. CONCLUSIONS: * During the last decade, we observed an inverse stage migration trend in those European patients with PCa who were treated with RP. * The recorded increase in patients with non-organ-confined disease after RP could be related to changes in patient selection and the growing adoption of RP in multimodal treatment settings for locally advanced tumours as well as the availability of new treatment alternatives for low-risk disease. PMID- 21244613 TI - Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma with severe renal impairment or on haemodialysis. AB - OBJECTIVE: To further investigate the effect of sunitinib, which is currently a standard of care for the treatment of metastatic renal cell carcinoma (mRCC), in patients with severe renal impairment or those undergoing dialysis. PATIENTS AND METHODS: Clinical databases were used to identify all patients with mRCC treated with sunitinib in seven institutions internationally. Databases were searched to identify only those patients with an estimated glomerular filtration rate of < 30 mL/min/1.73 m2 or those who had end-stage renal disease requiring dialysis. Baseline characteristics, adverse event data, response and progression-free survival were recorded. RESULTS: Nineteen patients met the inclusion criteria, 10 of whom were undergoing haemodialysis. Of the nine non-dialysis-dependent patients at drug initiation, the median estimated glomerular filtration rate was 27 mL/min/1.73 m2 (range 23-29). Baseline characteristics included a median age of 61 years (range 44-77); 17 patients had a Karnofsky performance status of >80; eight patients had more than two metastatic sites and 17 had undergone prior nephrectomy. The estimated median progression-free survival of this cohort was 43 weeks (range 7 to 158+) and progression has not yet been reached in six patients. Partial response or stable disease was observed as best response in 15 patients. The most common treatment-related adverse events included fatigue, diarrhoea, hand-foot skin reaction (HFSR), nausea and vomiting and rash. Grade three treatment-related adverse events including fatigue (seven patients), HFSR (two patients), diarrhoea (one patient), rash (one patient) and stomatitis (one patient) occurred in a total of 12 patients. Only one patient experienced a grade four adverse event (HFSR). Only diarrhoea (P = 0.0002), HFSR (P < 0.0001) and neutropenia (P = 0.001) were more common in patients undergoing haemodialysis compared with non-dialysis-dependent patients. Four of the non-dialysis dependent patients started at a dose of 50 mg compared with three of the patients undergoing haemodialysis. However five and two of the patients undergoing haemodialysis started at doses of 37.5 mg and 25 mg daily, respectively, compared with four and one of the non-dialysis-dependent patients. All patients took sunitinib for 4 out of every 6 weeks. Dose reductions during treatment were performed in eight patients but only one patient required discontinuation of treatment. CONCLUSION: These data suggest that patients with severe renal impairment or end-stage renal disease on haemodialysis can be safely treated with sunitinib at doses of 25-50 mg daily for 4 weeks followed by a 2-week break. The observed efficacy of therapy is similar to that reported in patients with normal renal function. These preliminary results warrant confirmation in a larger cohort of patients. PMID- 21244614 TI - Explaining differences in birth outcomes in relation to maternal age: the Generation R Study. AB - OBJECTIVE: To examine the association between maternal age and birth outcomes, and to investigate the role of sociodemographic and lifestyle-related determinants. DESIGN: Population-based prospective cohort study from early pregnancy onwards. SETTING: Rotterdam, the Netherlands. POPULATION: A cohort of 8568 mothers and their children. METHODS: Maternal age was assessed at enrolment. Information about sociodemographic (height, weight, educational level, ethnicity, parity) and lifestyle-related determinants (alcohol consumption, smoking habits, folic acid supplement use, caffeine intake, daily energy intake) and birth outcomes was obtained from questionnaires and hospital records. Multivariate linear and logistic regression analyses were used. MAIN OUTCOMES MEASURES: Birthweight, preterm delivery, small-for-gestational-age, and large-for gestational-age. RESULTS: As compared with mothers aged 30-34.9 years, no differences in risk of preterm delivery were found. Mothers younger than 20 years had the highest risk of delivering small-for-gestational-age babies(OR 1.6, 95% CI: 1.1-2.5); however, this increased risk disappeared after adjustment for sociodemographic and lifestyle-related determinants. Mothers older than 40 years had the highest risk of delivering large-for-gestational-age babies (OR 1.3, 95% CI: 0.8-2.4). The associations of maternal age with the risks of delivering large for-gestational-age babies could not be explained by sociodemographic and lifestyle-related determinants. CONCLUSIONS: As compared with mothers aged 30 34.9 years, younger mothers have an increased risk of small-for-gestational-age babies, whereas older mothers have an increased risk of large-for-gestational-age babies. Sociodemographic and lifestyle-related determinants cannot fully explain these differences. PMID- 21244615 TI - Acupuncture for pain relief during induced labour in nulliparae: a randomised controlled study. AB - OBJECTIVE: To assess the role of acupuncture for analgesia during labour. DESIGN: Double-blind study of manual, electro and sham acupuncture, and single-blind study comparing acupuncture with a control group for analgesia for labour induction. SETTING: A major obstetric unit in the UK. POPULATION: A cohort of 105 nulliparae undergoing labour induction at term. METHODS: Twenty-three subjects needed to be randomised to each group to have an 80% power of detecting a 50% relative reduction in epidural rate with an alpha value of 0.05. MAIN OUTCOME MEASURES: The primary end point was the rate of intrapartum epidural analgesia, and the secondary end points were parenteral analgesia requirement, labour length, delivery mode, neonatal condition and postpartum haemorrhage. RESULTS: There was no difference in epidural analgesia between acupuncture and sham acupuncture, relative risk 1.18 (95% CI 0.8-1.74), or between acupuncture and control, relative risk 0.88 (95% CI 0.66-1.19). There were no significant differences in the secondary end points between the acupuncture groups and the control group. Side effects or complications of acupuncture were not identified. CONCLUSIONS: Using the protocols studied, there was no analgesic benefit with acupuncture for pain relief during induced labour in nulliparae. PMID- 21244616 TI - Planned vaginal delivery or planned caesarean delivery in women with extreme obesity. AB - OBJECTIVE: To compare the outcomes of planned vaginal versus planned caesarean delivery in a cohort of extremely obese women (body mass index >= 50 kg/m(2)). DESIGN: A national cohort study using the UK Obstetric Surveillance System (UKOSS). SETTING: All hospitals with consultant-led maternity units in the UK. POPULATION: Five hundred and ninety-one extremely obese women delivering in the UK between September 2007 and August 2008. METHODS: Prospective cohort identification through UKOSS routine monthly mailings. MAIN OUTCOME MEASURES: Anaesthetic, postnatal and neonatal complication rates. RESULTS: After adjustment, there were no significant differences in anaesthetic, postnatal or neonatal complications between women with planned vaginal delivery and planned caesarean delivery, with the exception of shoulder dystocia (3% versus 0%, P = 0.019). There were no significant differences in any outcomes in the subgroup of women who had no identified medical or antenatal complications. CONCLUSIONS: This study does not provide evidence to support a routine policy of caesarean delivery for extremely obese women on the basis of concern about higher rates of delivery complications, but does support a policy of individualised decision-making on the mode of delivery based on a thorough assessment of potential risk factors for poor delivery outcomes. PMID- 21244617 TI - PARP inhibitors and epithelial ovarian cancer: an approach to targeted chemotherapy and personalised medicine. AB - Poly-ADP ribose polymerase (PARP) inhibitors have emerged as exciting new chemotherapy options for women with ovarian cancer. They exploit a mechanism known as synthetic lethality by targeting specific DNA repair pathways. Recent Phase II clinical trials have shown great promise in treating women with hereditary breast and ovarian cancers associated with BRCA1/2 mutations. Most importantly, they appear to be associated with only minimal adverse effects. However, up to 50-60% of epithelial ovarian cancers are defective in their ability to repair DNA damage using homologous recombination and could potentially benefit from these agents providing a scope both for targeted chemotherapy and personalised medicine. Ongoing clinical trials are investigating the potential benefit of this agent in treatment of high-grade serous epithelial ovarian cancers and in platinum-resistant disease. PMID- 21244618 TI - Haemodynamic effects of long-term administration of sildenafil in normotensive pregnant and non-pregnant rats. AB - OBJECTIVE: To determine the effects of chronic administration of sildenafil citrate on healthy pregnant rats. DESIGN: In vivo animal experimental study. SETTING: Fundacion IVI-Instituto Universitario IVI, Valencia, Spain. SAMPLE: Pregnant and non-pregnant Wistar rats exposed to chronic administration of sildenafil. METHODS: Placental cross-barrier and feto-maternal relationship levels, maternal blood pressure, and haemodymamic effects on uterine arteries were evaluated. The effect of growth on weight and fetal tissues, and on perinatal outcome, was investigated. MAIN OUTCOME MEASURES: Maternal blood pressure, blood viscosity, vascular indices of uterine arteries and fetal ductus venosus, plasmatic levels of sildenafil, embryo/fetal and litter weights, perinatal/postnatal survival rates. RESULTS: Sildenafil citrate crossed the placenta. The maternal and fetal levels of sildenafil, and its metabolite desmethyl-sildenafil, demonstrated a positive linear correlation in treated pregnant animals versus controls; a selective maternal hypotensive effect without changes in uterine vascular resistance was noted on days E8 and E11 (embryonic day). The lower pulsatility index of the ductus venosus on day E18 suggests fetal overflow at the end of the pregnancy. Effects on offspring were placental and liver enlargement, and increased fetal weight gain in the second half of pregnancy (irrespective of liver enlargement) and at birth. Perinatal and postnatal survival rates in the sildenafil group remained unaltered. No haemodynamic effects were evident in non-pregnant animals. CONCLUSIONS: In normotensive rats, sildenafil appears to have a selective effect at the onset of pregnancy, implying increased fetal blood supply, and increased fetal weight, and placental and liver enlargement, but no increased perinatal mortality. PMID- 21244619 TI - Recurrent miscarriage is associated with a family history of ischaemic heart disease: a retrospective cohort study. AB - OBJECTIVE: To determine whether women experiencing recurrent miscarriage were more likely to have a family history of cardiovascular disease. DESIGN: Retrospective cohort study. SETTING: Women having a first birth in Scotland between 1992 and 2006. SAMPLE: A total of 74, 730 first births were linked to the hospital admission and death certification data for the women's parents through the women's birth certificates. METHODS: The incidence of cardiovascular disease in the women's parents was related to the number of miscarriages experienced before their daughters' first births using a Cox proportional hazards model. MAIN OUTCOME MEASURES: Death or hospital admission of the women's parents for ischaemic heart disease (IHD), cerebrovascular disease (CVD) or venous thromboembolism (VTE). MAIN RESULTS: There was an increased incidence of IHD in the parents of women who experienced two miscarriages before their first birth (hazard ratio 1.25, 95% CI 1.04-1.49) and parents of women who experienced three or more miscarriages before their first birth (hazard ratio 1.56, 95% CI 1.14 2.15). Adjustment for the characteristics of the women at the time of the first birth was without material effect. There was no significant association between miscarriage and family history of CVD or VTE. There was no significant association between the number of therapeutic terminations of pregnancy before the first birth and the incidence of any type of cardiovascular disease in the women's parents. CONCLUSIONS: The parents of women who experience recurrent miscarriage are more likely to experience IHD. Recurrent miscarriage and IHD may have common patho-physiological pathways and genetic predispositions. PMID- 21244620 TI - Insights into chemotaxonomic composition and carbon cycling of phototrophic communities in an artesian sulfur-rich spring (Zodletone, Oklahoma, USA), a possible analog for ancient microbial mat systems. AB - Zodletone spring in Oklahoma is a unique environment with high concentrations of dissolved-sulfide (10 mm) and short-chain gaseous alkanes, exhibiting characteristics that are reminiscent of conditions that are thought to have existed in Earth's history, in particular the late Archean and early-to-mid Proterozoic. Here, we present a process-oriented investigation of the microbial community in two distinct mat formations at the spring source, (1) the top of the sediment in the source pool and (2) the purple streamers attached to the side walls. We applied a combination of pigment and lipid biomarker analyses, while functional activities were investigated in terms of oxygen production (microsensor analysis) and carbon utilization ((13)C incorporation experiments). Pigment analysis showed cyanobacterial pigments, in addition to pigments from purple sulfur bacteria (PSB), green sulfur bacteria (GSB) and Chloroflexus-like bacteria (CLB). Analysis of intact polar lipids (IPLs) in the source sediment confirmed the presence of phototrophic organisms via diacylglycerol phospholipids and betaine lipids, whereas glyceroldialkylglyceroltetraether additionally indicated the presence of archaea. No archaeal IPLs were found in the purple streamers, which were strongly dominated by betaine lipids. (13)C-bicarbonate- and -acetate-labeling experiments indicated cyanobacteria as predominant phototrophs in the source sediment, carbon was actively fixed by PSB/CLB/GSB in purple streamers by using near infrared light. Despite the presence of cyanobacteria, no oxygen could be detected in the presence of light, suggesting anoxygenic photosynthesis as the major metabolic process at this site. Our investigations furthermore indicated photoheterotrophy as an important process in both habitats. We obtained insights into a syntrophically operating phototrophic community in an ecosystem that bears resemblance to early Earth conditions, where cyanobacteria constitute an important contributor to carbon fixation despite the presence of high sulfide concentrations. PMID- 21244621 TI - Hydraulics of Asteroxylon mackei, an early Devonian vascular plant, and the early evolution of water transport tissue in terrestrial plants. AB - The core of plant physiology is a set of functional solutions to a tradeoff between CO(2) acquisition and water loss. To provide an important evolutionary perspective on how the earliest land plants met this tradeoff, we constructed a mathematical model (constrained geometrically with measurements of fossils) of the hydraulic resistance of Asteroxylon, an Early Devonian plant. The model results illuminate the water transport physiology of one of the earliest vascular plants. Results show that Asteroxylon's vascular system contains cells with low hydraulic resistances; these resistances are low because cells were covered by scalariform pits, elliptical structures that permit individual cells to have large areas for water to pass from one cell to another. Asteroxylon could move a large amount of water quickly given its large pit areas; however, this would have left these plants particularly vulnerable to damage from excessive evapotranspiration. These results highlight a repeated pattern in plant evolution, wherein the evolution of highly conductive vascular tissue precedes the appearance of adaptations to increase water transport safety. Quantitative insight into the vascular transport of Asteroxylon also allows us to reflect on the quality of CO(2) proxy estimates based on early land plant fossils. Because Asteroxylon's vascular tissue lacked any safety features to prevent permanent damage, it probably used stomatal abundance and behavior to prevent desiccation. If correct, low stomatal frequencies in Asteroxylon reflect the need to limit evapotranspiration, rather than adaptation to high CO(2) concentrations in the atmosphere. More broadly, methods to reveal and understand water transport in extinct plants have a clear use in testing and bolstering fossil plant-based paleoclimate proxies. PMID- 21244622 TI - Road traffic accidents - a cause of death and trauma. PMID- 21244623 TI - Dentoalveolar injury related to general anaesthesia: a 14 years review and a statement from the surgical point of view based on a retrospective analysis of the documentation of a university hospital. AB - INTRODUCTION: Damage to dentoalveolar structures related to general anaesthesia is a well-known complication and may represent a relevant morbidity for affected patients. Central documentation of perioperative dentoalveolar injuries was performed since 1990 in the Department of Anaesthesiology and Intensive Care Medicine in cooperation with the Department of Oral and Maxillofacial Surgery at the Charite Universitatsmedizin Berlin, Campus Virchow-Klinikum. Documentation of perioperative dentoalveolar injury consisted of anaesthesia charts, reports of the anaesthesiologists and consultant maxillofacial surgeons. MATERIALS AND METHODS: Retrospective analysis of the data from 1990 to 2004 was performed according to this documentation with respect to incidence, matter, distribution of dental injury and therapeutic consequences. RESULTS: Within 14 years 82 'dental injuries' with 103 affected teeth were documented in calculated 375,000 general anaesthesias. Incidence of 0.02% was very constant with an average of 5.5 events/year. Eighty-nine percent of the documented injuries occurred during scheduled operative procedures. Only 32.9% of the injuries took place during endotracheal intubation. In about 50% the injury was not related to intubation or extubation but happened during general anaesthesia. In 80% the dental injury was estimated by the anaesthesiologist as 'not avoidable'. In 83% pre-existing affection or structural injury of intraoral tissues was documented, in 32.7% of the affections sufficient therapy could be provided already during inhospital stay. CONCLUSION: Perioperative dentoalveolar injury is surely an annoying complication of general anaesthesia. However incidence is rare and seems to be unavoidable. Pre-existing damage to dentoalveolar structures is the main risk for additional injuries related to general anaesthesia. Adequate therapy can be provided by interdisciplinary concepts. There should be a fair balance between the benefit of the surgical procedure and the risk of dental injury related to general anaesthesia. Awareness of the problem and proper documentation are important factors for adequate management in liability cases. PMID- 21244624 TI - Evaluation of the fracture resistance of reattached incisal fragments using different materials and techniques. AB - OBJECTIVES: When coronal fracture occurs in anterior teeth, fragment reattachment can be a valid alternative to a direct restoration. The aim of this study was to evaluate the influence of the material and the technique used to reattach the fragment. MATERIALS AND METHODS: Eighty sound maxillary and mandibular incisors were selected and randomly divided into eight groups (n = 10). The incisal third of each tooth was removed using a saw machine. The fragments in groups 1-4 were reattached using resin-based materials: group 1 adhesive, group 2 flow, group 3 composite, group 4 cement; in groups 5-8, the same materials mentioned before were used but a bevel was also performed on both labial and lingual surfaces. Shear bond strength (SBS) was calculated by applying a load incisal to the reattachment line. A two-way Anova was used to evaluate the influence of materials and techniques on the SBS. RESULTS: The technique used was statistically significant (P < 0.001), while the material was not (P = 0.793). CONCLUSIONS: The choice of material seems to have no influence on the SBS, whereas a bevel performed on the labial and lingual surfaces can significantly improve the SBS of the reattached fragment. PMID- 21244625 TI - Motorcycle accident is the main cause of maxillofacial injuries in the Penang Mainland, Malaysia. AB - BACKGROUND/AIM: Maxillofacial injuries are among the commonest forms of body injuries. There are three divisions, namely, facial bone fractures, soft tissue injuries, and dentoalveolar injuries. Etiologies include motor vehicle accidents, assaults, falls, and sporting injuries. The aim of this study was to determine the profiles including the causes of maxillofacial injuries seen in an urban government hospital in the mainland of Penang State, Malaysia. MATERIALS AND METHODS: This was a cross-sectional study that recruited cases reported within a period of 1 year. The source population was maxillofacial injury patients presenting to the Oral and Maxillofacial Surgery Department of an urban hospital in the Penang Mainland, North Malaysia between May 2007 and May 2008. Cases of patients involved in accidents that occurred outside the reference vicinity were excluded. A case report form was developed and completed by the attending clinicians. Data were analyzed using spss version 12.0. RESULTS: A total of 194 cases were studied, with the mean patient age being 27.8 (SD 15.20) years. The majority of patients were Malay men between 20 and 29 years of age. The main cause of injury was motorcycle accident (53.6%). The commonest injury (in isolation/combination with other injuries) involved the soft tissues (87.2%), dentoalveolar region (33.4%), and facial bones (23.9%). Laceration was the commonest soft tissue injury, and crown fracture was the most frequent dentoalveolar injury. The facial bone that was most highly involved in the injury was the zygoma. Subjects involved in motorcycle accidents had a significantly higher incidence of sustaining facial bone fractures. CONCLUSIONS: Motorcycle accidents were the commonest cause of maxillofacial injuries in the Penang Mainland, Malaysia. Most patients were young men. Hence, it is prudent to reinforce appropriate road safety and awareness interventions particularly focusing young male motorcyclists so as to reduce the risk of accidents. PMID- 21244626 TI - Effect of low-level laser therapy on the healing process after tooth replantation: a histomorphometrical and immunohistochemical analysis. AB - Success of tooth replantation is limited because part of the replanted tooth is lost because of progressive root resorption. This study used histomorphometry and immunohistochemistry to evaluate the effect of low-level laser therapy (LLLT) on the healing process of rat teeth replanted after different extra-oral periods, simulating immediate and delayed replantation. Sixty Wistar rats (Rattus norvegicus albinus) had their maxillary right incisors extracted and randomly assigned to six groups (n = 10): C4, C30 and C45, in which the teeth were replanted 4 min (immediate), 30 min (delayed) and 45 min (delayed) after extraction, respectively, and L4, L30 and L45, in which the teeth were replanted after the same extra-alveolar times, but the root surfaces and the alveolar wounds were irradiated with a gallium-aluminum-arsenate (GaAlAs) diode laser before replantation. The animals were sacrificed after 60 days. The anatomic pieces containing the replanted teeth were obtained and processed for either histomorphometrical analysis under optical microscopy or immunohistochemical expression of receptor activator of nuclear factor Kappa-B (RANK), and its ligand (RANKL), osteoprotegerin (OPG) and tartrate-resistant acid phosphatase (TRAP) proteins. Areas of external replacement and inflammatory root resorption were observed in all groups, without statistically significant differences (P > 0.05). Ankylosis was more frequent in L30 than in C30 (P < 0.05). RANKL immunostaining predominated over RANK and OPG immunostaining in both groups with immediate tooth replantation (P < 0.05). For the 45-min extra-alveolar time, however, there was greater evidence of RANK immunostaining compared to RANKL for both control and laser-treated groups (P < 0.05). Positive TRAP immunostaining predominated in L4 and L30 (P < 0.05). In conclusion, under the tested conditions, the treatment of the root surface and the alveolar wound with LLLT did not improve the healing process after immediate and delayed tooth replantation in rats. PMID- 21244627 TI - Traumatic dental injuries during anaesthesia. Part II: medico-legal evaluation and liability. AB - INTRODUCTION: Claims for tooth damage following intubation are increasing. An anaesthetic chart (AC) has been proposed to describe patient's pre-existent dental diseases and any possible lesions caused during intubation and extubation. MATERIALS AND METHODS: We conducted a retrospective study of 235 cases of dental lesions reported in litigation files from January 2000 to June 2009. Based on preoperative oral inspection the anaesthetist decided whether or not to use a protective aid. Two different tooth protectors were applied: (i) a standard mouthguard and (ii) silicone impression putty. RESULTS: The study population consisted of 110 female (age 6-88 years) and 125 male patients (11-90 years) patients. In 66% of cases greater risk of perianesthetic dental injury was reported in the AC due to pre-existing poor dentition. In intubation procedures without protective devices dental subluxation/luxation occurred in 55% of patients, dental avulsion in 43%, exfoliation in 2%, and soft tissue damage in five patients. One patient suffered from transient facial nerve paralysis. The costs of treatments and of impression materials, as well as the total value of compensation for injuries are reported. DISCUSSION: Definition and demonstrability of damages on the AC is important in order to separate the cases worthy of compensation from the non-compensable ones, as to evaluate the possibility of solving the litigation by extrajudicial channels. There are cases in which, based on AC reporting and device adoption the damage resulted to be compensable, but the costs were defined on different estimates of lesions. The use of a protective device makes it possible to down-modulate the damage compensation. CONCLUSION: The analysis of litigation records and 'incident reports' has suggested that the choice of accurate proceeding and the use of protection aids could reduce the number of claims, insurance premiums and the costs of litigation process, thus improving physician-patient relationship. PMID- 21244628 TI - Recent trends in the management of dentoalveolar traumatic injuries to primary and young permanent teeth. AB - One of the commonly encountered dental emergencies is dentoalveolar traumatic injuries (DTIs). Unfortunately, DTIs result in fractured, displaced, or lost anterior teeth and this could have significant negative functional, esthetic, speech, and psychological effects on children thus affecting their quality of life. Although it is impossible to guarantee permanent retention of a traumatized tooth, patient age, severity of injury, and timely treatment and follow up of the tooth using recommended procedures can maximize the chances for success. This review examines the recent trends in the management of DTI to primary and young permanent teeth. Electronic search of scientific papers written in English from 1990s to 2009 was accomplished using Pub Med search engine. Dental practitioners should follow current literature and consider carefully evidenced-based recommendations that may enhance periodontal healing and revascularization of avulsed permanent teeth. PMID- 21244629 TI - Revascularization of an immature permanent tooth with periradicular abscess after luxation. AB - An immature permanent mandibular central incisor with periapical involvement in a 7-year-old boy was treated to promote revascularization. The tooth suffered from acute apical periodontitis after periodontal treatment by a general practitioner. An access cavity was prepared in the tooth and the cavity was left open until the next visit to achieve drainage through the canal. The root canal was not mechanically cleaned during the treatment period, but was irrigated with hydrogen peroxide and sodium hypochlorite. Calcium hydroxide compound was used for disinfection. At the fifth visit vital tissue appeared in the canal near the apical region, and calcium hydroxide compound was placed in contact with the soft tissue in the root canal. The access cavity was sealed with glass-ionomer cement followed by an adhesive composite resin filling. Radiographic examination 30 months after the initial treatment confirmed closure of the apex and thickening of the root wall. The case was observed for up to 13 years and root development was confirmed. PMID- 21244630 TI - Management of multiple sequelaes in permanent dentition: 3 years follow-up. AB - A 12-year-old patient with multiple sequelaes of permanent dentition due to trauma in primary dentition at the age of 8 months, is presented. Clinical and radiographical examinations revealed aesthetical defects, crown-root malformations (#21), hypoplasia (#12, #22), tooth transposition (#13) and odontoma-like malformation (#11). The performed conservative, endo-surgical and prosthetic treatment to gain back the aesthetic and function is reported. PMID- 21244631 TI - Reattachment of anterior teeth fragments using a modified Simonsen's technique after dental trauma: report of a case. AB - This is a case report of a 9-year-old boy with complicated crown fractures of two traumatized teeth: left maxillary central and lateral incisors. The central incisor presented a small pulpal exposure of approximately 1 mm and the lateral incisor had an ulcerated and exposed pulp. Endodontic management included direct pulp capping, partial pulpotomy, and restorative management including reattachment of the teeth fragments using a modified Simonsen's technique. The reattached fragments were assessed clinically and radiographically at 12 months. The teeth remained vital, there were no color changes, and the restorations had an acceptable appearance. PMID- 21244632 TI - Oncogenetics of melanoma: basis for molecular diagnostics and therapy. AB - Our understanding of oncogenetics and of the molecular mechanisms involved in melanoma development and signaling has dramatically changed in recent years. Today, melanomas are also classified based on molecular alterations. Emerging molecular therapies are targeted against specific mutations in melanoma. An example of targeted therapies is the successful treatment of KIT-mutant melanoma with the kinase inhibitor imatinib. Highly selective BRAF-inhibitors are likewise under clinical development and show encouraging clinical responses. An increasing number of targeted drugs will emerge in the coming years, based on molecular diagnostics and classification. The present article reviews signaling pathways in melanocytes and alterations in melanoma that are a prerequisite to understanding modern cancer therapies in melanoma. PMID- 21244633 TI - Identification of Ewing's sarcoma protein as a G-quadruplex DNA- and RNA-binding protein. AB - The Ewing's sarcoma (EWS) oncogene contains an N-terminal transcription activation domain and a C-terminal RNA-binding domain. Although the EWS activation domain is a potent transactivation domain that is required for the oncogenic activity of several EWS fusion proteins, the normal role of intact EWS is poorly characterized because little is known about its nucleic acid recognition specificity. Here we show that the Arg-Gly-Gly (RGG) domain of the C terminal in EWS binds to the G-rich single-stranded DNA and RNA fold in the G quadruplex structure. Furthermore, inhibition of DNA polymerase on a template containing a human telomere sequence in the presence of RGG occurs in an RGG concentration-dependent manner by the formation of a stabilized G-quadruplex DNA RGG complex. In addition, mutated RGG containing Lys residues replacing Arg residues at specific Arg-Gly-Gly sites and RGG containing Arg methylated by protein arginine N-methyltransferase 3 decrease the binding ability of EWS to G quadruplex DNA and RNA. These findings suggest that the RGG of EWS binds to G quadruplex DNA and RNA via the Arg residues in it. PMID- 21244634 TI - Therapeutic effects of inhaled 1,8-cineole on allergic airway inflammation. PMID- 21244635 TI - Docking, synthesis, and in vitro evaluation of antimitotic estrone analogs. AB - In the present study, Autodock 4.0 was employed to discover potential carbonic anhydrase IX inhibitors that are able to interfere with microtubule dynamics by binding to the Colchicine binding site of tubulin. Modifications at position 2' of estrone were made to include moieties that are known to improve the antimitotic activity of estradiol analogs. 2-ethyl-3-O-sulphamoyl-estra 1,3,5(10),15-tetraen-3-ol-17-one estronem (C9) and 2-ethyl-3-O-sulphamoyl-estra 1,3,5(10)16-tetraene (C12) were synthesized and tested in vitro. Growth studies were conducted utilizing spectrophotometrical analysis with crystal violet as DNA stain. Compounds C9 and C12 were cytotoxic in MCF-7 and MDA-MB-231 tumorigenic and metastatic breast cancer cells, SNO non-keratinizing squamous epithelium cancer cells and HeLa cells after 48 h exposure. Compounds C9 inhibited cell proliferation to 50% of the vehicle-treated controls from 110 to 160 nm and C12 at concentrations ranging from 180 to 220 nm. Confocal microscopy revealed abnormal spindle morphology in mitotic cells. Cell cycle analysis showed an increase in the number of cells in the G(2) /M fraction after 24 h and an increase in the number of cell in the sub-G(1) fraction after 48 h, indicating that the compounds are antimitotic and able to induce apoptosis. PMID- 21244636 TI - Structural features underlying selective inhibition of GSK3beta by dibromocantharelline: implications for rational drug design. AB - Hymenialdisine and dibromocantharelline are marine sponge constituents with unique biological activity. Hymenialdisine potently inhibits glycogen synthase kinase 3beta, cyclin-dependent kinase 2, and cyclin-dependent kinase 5, whereas dibromocantharelline only displays a significant inhibitory effect toward glycogen synthase kinase 3beta (IC(50) = 3 MUmol). Based on the crystal structure of cyclin-dependent kinase 2-hymenialdisine complex, we employed three docking methods, namely Autodock, FlexX, and Genetic Optimization for Ligand Docking, as well as molecular dynamics simulations to investigate the structural determinants that govern target selectivity. The similar binding modes of hymenialdisine in complex with cyclin-dependent kinase 5 and glycogen synthase kinase 3beta are consistent with the poor selectivity of hymenialdisine toward the two kinases. The shape of cyclin-dependent kinase 5 binding pocket characterized by the inward-orientation of Asp144 and dense electrostatic interaction networks, as well as the stereochemical configuration of dibromocantharelline, provides a considerable structural basis for the lack of binding of dibromocantharelline with cyclin-dependent kinase 5. The specific residue Cys199 near the binding site of glycogen synthase kinase 3beta provides new clues for the design of potent and selective inhibitor of glycogen synthase kinase 3beta. PMID- 21244637 TI - Antifungal activity of xanthones: evaluation of their effect on ergosterol biosynthesis by high-performance liquid chromatography. AB - The increasing resistance of pathogenic fungi to antifungal compounds and the reduced number of available drugs led to the search for therapeutic alternatives among natural products, including xanthones. The antifungal activity of 27 simple oxygenated xanthones was evaluated by determination of their minimal inhibitory concentration on clinical and type strains of Candida, Cryptococcus, Aspergillus and dermatophytes, and their preponderance on the dermatophytic filamentous fungi was observed. Furthermore, a simple and efficient HPLC method with UV detection to study the effect of the active xanthones on the biosynthesis of ergosterol was developed and validated. Using this methodology, the identification and quantification of fungal sterols in whole cells of Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, and Trichophyton mentagrophytes were accomplished. In summary, 1,2-dihydroxyxanthone was found to be the most active compound against all strains tested, showing its effect on sterol biosynthesis by reducing the amount of ergosterol detected. PMID- 21244638 TI - Design, synthesis, and sustained-release property of 1,3-cyclic propanyl phosphate ester of 18beta-glycyrrhetinic acid. AB - A new class of potential prodrugs, 1,3-cyclic propanyl phosphate esters of 18beta glycyrrhetic acid, was designed and synthesized through the key reaction of 18beta-glycyrrhetic acid with 1,3-cyclic propanyl phosphate ester catalysed by lithium diisopropylamide. The sustained-release properties of 1,3-cyclic propanyl phosphate esters of 18beta-glycyrrhetic acid in vivo were also investigated. The animal experiments showed that 18beta-glycyrrhetic acid was released from 1,3 cyclic propanyl phosphate esters of 18beta-glycyrrhetic acid at a steady rate in rats and the plasma concentrations of 18beta-glycyrrhetic acid were nearly stable. The result indicated that 1,3-cyclic propanyl phosphate esters of 18beta glycyrrhetic acid have sustained-release properties to avoid the quick metabolism of 18beta-glycyrrhetic acid. These prodrugs are highlighted as a promising new strategy to improve 18beta-glycyrrhetic acid metabolism. PMID- 21244639 TI - Synthesis and biological evaluation of new quinoxaline derivatives as antioxidant and anti-inflammatory agents. AB - We report the synthesis, anti-inflammatory, and antioxidant activities of novel quinoxaline and quinoxaline 1,4-di-N-oxide derivatives. Microwave-assisted methods have been used to optimize reaction times and to improve yields. The tested compounds presented important scavenging activities and promising in vitro inhibition of soybean lipoxygenase (LOX). Two of the best LOX inhibitors (compounds 7b and 8f) were evaluated as in vivo anti-inflammatory agents using the carrageenin-induced edema model. One of them (compound 7b) showed important in vivo anti-inflammatory effect (41%) similar to that of indomethacin (47%) used as the reference drug. PMID- 21244640 TI - Interaction of a curcumin analogue dimethoxycurcumin with DNA. AB - Dimethoxycurcumin (Dimc), a synthetic analogue of curcumin, that has been reported to exhibit better in vivo stability and anti-tumour activity, was investigated for its interaction with DNA, employing spectroscopic methods based on absorption, fluorescence, circular dichroism (CD), ethidium bromide (EtBr) competitive binding assay, 4'-6-diamidino-2-phenylindole (DAPI) displacement assay and fluorescence resonance energy transfer (FRET) assay. The mean binding constant for its interaction with calf thymus DNA (ct-DNA) was estimated to be 4.4+/-0.8 * 10(4) m(-1) . The studies using CD revealed that Dimc did not cause unwinding of the ct-DNA helix or induce major conformational changes. The EtBr and DAPI assays indicated that Dimc is not an intercalator but a minor groove binder. FRET assay also confirmed that Dimc interacts with DNA strands. Furthermore, viscosity measurements of ct-DNA solutions in the presence of Dimc supported these spectroscopic observations. Addition of Dimc to MCF-7 cells showed nuclear localization as visualized by confocal microscopy. In conclusion, the present studies addressed the mode of interaction of Dimc with biomolecules, which may have implications in developing Dimc as a DNA-targeted drug. PMID- 21244641 TI - Sequential virtual screening approach to the identification of small organic molecules as potential BACE-1 inhibitors. AB - In this letter, we report on the sequential application of two different in silico screening approaches combined with bioassays aimed at the identification of small organic molecules as potential BACE-1 inhibitors. Two hits endowed of micromolar inhibitory potency were selected, and the binding mode of the most potent compound was further characterized through docking simulations. PMID- 21244642 TI - Understanding small-molecule binding to MDM2: insights into structural effects of isoindolinone inhibitors from NMR spectroscopy. AB - The interaction between murine double minute (MDM2) and p53 is a major target in anticancer drug design. Several potent compound series, including the nutlins and spirooxindoles, have previously been established as high-affinity antagonists of MDM2. In this paper, we describe the interaction of isoindolinone inhibitors with MDM2, as characterized by nuclear magnetic resonance spectroscopy. Isoindolinone inhibitors bind specifically to the MDM2 p53 binding site and exploit all sub pockets used by p53, nutlins and spirooxindoles. Furthermore, isoindolinones bind with low micromolar to high nanomolar affinities, with the best compound approaching the potency of nutlin-3. PMID- 21244643 TI - Evaluation of the efficacy of the 'nasal airflow-inducing manoeuvre' for smell rehabilitation in laryngectomees by means of the Sniffin' Sticks test. AB - OBJECTIVE: To determine the efficacy of the nasal airflow-inducing manoeuvre (NAIM) as a method for olfactory rehabilitation in laryngectomees by the means of the Sniffin' Sticks test. STUDY DESIGN: Prospective open interventional trial. SETTING: Tertiary academic hospital. PARTICIPANTS: Thirty-seven patients after laryngectomy have been screened and 25 patients have been included into the study. The participant's sense of smell was tested with the Sniffin' Sticks test before and after learning the nasal airflow inducing manoeuvre. The individual level of threshold, discrimination and identification (TDI) was determined and the individual threshold, discrimination and identification score was used to classify the patients as being anosmic, hyposmic or normosmic. MAIN OUTCOME MEASURES: The primary endpoint was the change of the threshold, discrimination and identification score before and after learning the nasal airflow inducing manoeuvre. The secondary endpoint was a change in the diagnostic group (normosmic, hyposmic and anosmic) after learning of the nasal airflow inducing manoeuvre. RESULTS: There was a statistically significant increase in the total threshold, discrimination and identification score (P < 0.001) and the three sub scores (P <= 0.02) before and after the learning of the nasal airflow inducing manoeuvre. Patients gained seven points on average in the threshold, discrimination and identification score. Twenty of 25 patients showed an increase of five or more point in the threshold, discrimination and identification score. In the classification of the smell ability, 15 of 25 patients showed a change to a higher class (hyposmic to normosmic or from anosmic to hyposmic or normosmic). CONCLUSION: The nasal airflow inducing manoeuvre is a method for the successful rehabilitation of the sense of smell in laryngectomees. The evaluation with the Sniffin' Sticks tests showed a clinically relevant increase of olfaction in 80% of patients. The teaching of the nasal airflow inducing manoeuvre should be included in post-laryngectomy rehabilitation programmes. PMID- 21244644 TI - Comparison of a singleplex real-time RT-PCR assay and multiplex respiratory viral panel assay for detection of influenza "A" in respiratory specimens. AB - BACKGROUND: Evaluation of different molecular tests for the detection of pandemic (H1N1) 2009 virus is important before the next wave of the pandemic. OBJECTIVES: To compare a hydrolysis probe-based real-time RTPCR assay recommended by the CDC to the xTAG respiratory viral panel (RVP) (Luminex Molecular Diagnostics) for the detection of influenza A. METHODS: Eleven thousand eight hundred and ninety-eight respiratory specimens were tested by the real-time RT-PCR and RVP assays for the detection of influenza A. The distribution of seasonal H1, H3 and pandemic H1N1 subtypes in these specimens was compared. RESULTS: The RVP assay was generally unable to identify influenza A-positive samples with a low viral load, whereas the real-time RT-PCR assay detected most of these samples resulting in a subset of specimens that could not be confirmed as either seasonal or pandemic influenza A subtypes. CONCLUSIONS: When the prevalence of influenza A is high, the CDC recommended real-time RT-PCR has significant advantages as a frontline assay, namely higher sensitivity and shorter time to reporting a result. Anticipated scenarios would be during the peaks of the pandemic and episodes of seasonal influenza. Furthermore, the better sensitivity of the RT-PCR makes it the preferred assay to detect influenza in patients with severe respiratory disease tested late in their clinical course. If pandemic (H1N1) 2009 virus is not the dominant virus and there is a high proportion of other respiratory viruses circulating, laboratories will be faced with the decision to use the RVP assay for the detection of pandemic (H1N1) 2009 virus. PMID- 21244645 TI - Prevalence and risk factors of latent tuberculosis infection among health care workers in Malaysia. AB - BACKGROUND: Health care workers are exposed to patients with tuberculosis and are at risk of nosocomial infection. The aim of this study was to determine the prevalence and factors associated with latent tuberculosis infection among health care workers in Malaysia and also to evaluate the agreement between Quantiferon TB Gold in tube test with Tuberculin Skin Test. METHODS: A cross sectional study was conducted at four randomly selected hospitals in the Klang Valley from December 2008 to May 2009. Self administered questionnaire was used to obtain information on health care workers and possible risk factors. The response rate for this study was 90.8% with 954 respondents completed the questionnaire and were tested with Quantiferon TB Gold in tube for latent tuberculosis infection. Agreement between Quantiferon TB Gold in tube and Tuberculin Skin Test was assessed among 95 health care workers who consented to undergo both tests. RESULTS: The overall prevalence of latent tuberculosis infection among health care workers was 10.6% (CI: 8.6%; 12.6%). Factors significantly associated with latent tuberculosis infection were aged 35 years and older [9.49 (CI: 2.22; 40.50)], history of living in the same house with close family members or friends who had active tuberculosis [8.69 (CI: 3.00; 25.18)], worked as a nurse [4.65 (CI: 1.10; 19.65)] and being male [3.70 (CI: 1.36; 10.02)]. Agreement between Quantiferon TB Gold in tube test and tuberculin skin test at cut-off points of 10 mm and 15 mm was 50.5% and 82.1% respectively. However, Kappa-agreement was poor for both cut-off points. CONCLUSION: The prevalence of latent tuberculosis infection in Malaysia was relatively low for an intermediate TB burden country. We could not comment on the occupational risk of latent tuberculosis infection among health care worker compared to the general population as there were no prevalence data available for latent tuberculosis infection in the general population. Kappa agreement between Quantiferon TB gold in-tube and tuberculin skin test was poor. PMID- 21244646 TI - easyDAS: automatic creation of DAS servers. AB - BACKGROUND: The Distributed Annotation System (DAS) has proven to be a successful way to publish and share biological data. Although there are more than 750 active registered servers from around 50 organizations, setting up a DAS server comprises a fair amount of work, making it difficult for many research groups to share their biological annotations. Given the clear advantage that the generalized sharing of relevant biological data is for the research community it would be desirable to facilitate the sharing process. RESULTS: Here we present easyDAS, a web-based system enabling anyone to publish biological annotations with just some clicks. The system, available at http://www.ebi.ac.uk/panda srv/easydas is capable of reading different standard data file formats, process the data and create a new publicly available DAS source in a completely automated way. The created sources are hosted on the EBI systems and can take advantage of its high storage capacity and network connection, freeing the data provider from any network management work. easyDAS is an open source project under the GNU LGPL license. CONCLUSIONS: easyDAS is an automated DAS source creation system which can help many researchers in sharing their biological data, potentially increasing the amount of relevant biological data available to the scientific community. PMID- 21244647 TI - Effect of children's shoes on gait: a systematic review and meta-analysis. AB - BACKGROUND: The effect of footwear on the gait of children is poorly understood. This systematic review synthesises the evidence of the biomechanical effects of shoes on children during walking and running. METHODS: Study inclusion criteria were: barefoot and shod conditions; healthy children aged <= 16 years; sample size of n > 1. Novelty footwear was excluded. Studies were located by online database-searching, hand-searching and contact with experts. Two authors selected studies and assessed study methodology using the Quality Index. Meta-analysis of continuous variables for homogeneous studies was undertaken using the inverse variance approach. Significance level was set at P < 0.05. Heterogeneity was measured by I2. Where I2 > 25%, a random-effects model analysis was used and where I2 < 25%, a fixed-effects model was used. RESULTS: Eleven studies were included. Sample size ranged from 4-898. Median Quality Index was 20/32 (range 11 27). Five studies randomised shoe order, six studies standardised footwear. Shod walking increased: velocity, step length, step time, base of support, double support time, stance time, time to toe-off, sagittal tibia-rearfoot range of motion (ROM), sagittal tibia-foot ROM, ankle max-plantarflexion, Ankle ROM, foot lift to max-plantarflexion, 'subtalar' rotation ROM, knee sagittal ROM and tibialis anterior activity. Shod walking decreased: cadence, single-support time, ankle max-dorsiflexion, ankle at foot-lift, hallux ROM, arch length change, foot torsion, forefoot supination, forefoot width and midfoot ROM in all planes. Shod running decreased: long axis maximum tibial-acceleration, shock-wave transmission as a ratio of maximum tibial-acceleration, ankle plantarflexion at foot strike, knee angular velocity and tibial swing velocity. No variables increased during shod running. CONCLUSIONS: Shoes affect the gait of children. With shoes, children walk faster by taking longer steps with greater ankle and knee motion and increased tibialis anterior activity. Shoes reduce foot motion and increase the support phases of the gait cycle. During running, shoes reduce swing phase leg speed, attenuate some shock and encourage a rearfoot strike pattern. The long term effect of these changes on growth and development are currently unknown. The impact of footwear on gait should be considered when assessing the paediatric patient and evaluating the effect of shoe or in-shoe interventions. PMID- 21244649 TI - Prior exposure to an attenuated Listeria vaccine does not reduce immunogenicity: pre-clinical assessment of the efficacy of a Listeria vaccine in the induction of immune responses against HIV. AB - BACKGROUND: We have evaluated an attenuated Listeria monocytogenes (Lm) candidate vaccine vector in nonhuman primates using a delivery regimen relying solely on oral vaccination. We sought to determine the impact of prior Lm vector exposure on the development of new immune responses against HIV antigens. FINDINGS: Two groups of rhesus macaques one Lm naive, the other having documented prior Lm vector exposures, were evaluated in response to oral inoculations of the same vector expressing recombinant HIV-1 Gag protein. The efficacy of the Lm vector was determined by ELISA to assess the generation of anti-Listerial antibodies; cellular responses were measured by HIV-Gag specific ELISpot assay. Our results show that prior Lm exposures did not diminish the generation of de novo cellular responses against HIV, as compared to Listeria-naive monkeys. Moreover, empty vector exposures did not elicit potent antibody responses, consistent with the intracellular nature of Lm. CONCLUSIONS: The present study demonstrates in a pre clinical vaccine model, that prior oral immunization with an empty Lm vector does not diminish immunogenicity to Lm-expressed HIV genes. This work underscores the need for the continued development of attenuated Lm as an orally deliverable vaccine. PMID- 21244648 TI - Leucine-rich repeat kinase 2 and alpha-synuclein: intersecting pathways in the pathogenesis of Parkinson's disease? AB - Although Parkinson's disease (PD) is generally a sporadic neurological disorder, the discovery of monogenic, hereditable forms of the disease has been crucial in delineating the molecular pathways that lead to this pathology. Genes responsible for familial PD can be ascribed to two categories based both on their mode of inheritance and their suggested biological function. Mutations in parkin, PINK1 and DJ-1 cause of recessive Parkinsonism, with a variable pathology often lacking the characteristic Lewy bodies (LBs) in the surviving neurons. Intriguingly, recent findings highlight a converging role of all these genes in mitochondria function, suggesting a common molecular pathway for recessive Parkinsonism. Mutations in a second group of genes, encoding alpha-synuclein (alpha-syn) and LRRK2, are transmitted in a dominant fashion and generally lead to LB pathology, with alpha-syn being the major component of these proteinaceous aggregates. In experimental systems, overexpression of mutant proteins is toxic, as predicted for dominant mutations, but the normal function of both proteins is still elusive. The fact that alpha-syn is heavily phosphorylated in LBs and that LRRK2 is a protein kinase, suggests that a link, not necessarily direct, exists between the two. What are the experimental data supporting a common molecular pathway for dominant PD genes? Do alpha-syn and LRRK2 target common molecules? Does LRRK2 act upstream of alpha-syn? In this review we will try to address these of questions based on the recent findings available in the literature. PMID- 21244650 TI - Is interleukin-18 associated with polycystic ovary syndrome? AB - BACKGROUND: Recent research show that polycystic ovary syndrome (PCOS) may have an association with low-grade chronic inflammation, IL-18 is considered as a strong risk marker of inflammation. METHODS: To investigate serum IL-18 concentrations in PCOS patients and focus on its relationship between obesity and insulin resistance (IR). Sixty consecutive women with PCOS and thirty controls were recruited. Serum level of IL-18 and fasting blood glucose, fasting insulin, follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) were measured. RESULTS: Serum levels of IL-18 was significantly higher in the PCOS group than in the control group. Serum level of IL-18 was higher in the PCOS group with IR than in the PCOS group without IR. Serum level of IL-18 was higher in obese PCOS patients than in lean PCOS patients. Serum level of IL-18 was higher in lean PCOS patients than in the lean control group. Serum level of IL-18 in the PCOS group was positively related to BMI, IR index and T. CONCLUSION: IL 18 level was increased in PCOS patients, and correlated with insulin resistance, obesity and hyperandrogenism. PMID- 21244651 TI - Effect of nitrogen-rich cell culture surfaces on type X collagen expression by bovine growth plate chondrocytes. AB - BACKGROUND: Recent evidence indicates that osteoarthritis (OA) may be a systemic disease since mesenchymal stem cells (MSCs) from OA patients express type X collagen, a marker of late stage chondrocyte hypertrophy (associated with endochondral ossification). We recently showed that the expression of type X collagen was suppressed when MSCs from OA patients were cultured on nitrogen (N) rich plasma polymer layers, which we call "PPE:N" (N-doped plasma-polymerized ethylene, containing up to 36 atomic percentage (at.% ) of N. METHODS: In the present study, we examined the expression of type X collagen in fetal bovine growth plate chondrocytes (containing hypertrophic chondrocytes) cultured on PPE:N. We also studied the effect of PPE:N on the expression of matrix molecules such as type II collagen and aggrecan, as well as on proteases (matrix metalloproteinase-13 (MMP-13) and molecules implicated in cell division (cyclin B2). Two other culture surfaces, "hydrophilic" polystyrene (PS, regular culture dishes) and nitrogen-containing cation polystyrene (Primaria(r)), were also investigated for comparison. RESULTS: Results showed that type X collagen mRNA levels were suppressed when cultured for 4 days on PPE:N, suggesting that type X collagen is regulated similarly in hypertrophic chondrocytes and in human MSCs from OA patients. However, the levels of type X collagen mRNA almost returned to control value after 20 days in culture on these surfaces. Culture on the various surfaces had no significant effects on type II collagen, aggrecan, MMP-13, and cyclin B2 mRNA levels. CONCLUSION: Hypertrophy is diminished by culturing growth plate chondrocytes on nitrogen-rich surfaces, a mechanism that is beneficial for MSC chondrogenesis. Furthermore, one major advantage of such "intelligent surfaces" over recombinant growth factors for tissue engineering and cartilage repair is potentially large cost-saving. PMID- 21244652 TI - A new fetal RHD genotyping test: costs and benefits of mass testing to target antenatal anti-D prophylaxis in England and Wales. AB - BACKGROUND: Postnatal and antenatal anti-D prophylaxis have dramatically reduced maternal sensitisations and cases of rhesus disease in babies born to women with RhD negative blood group. Recent scientific advances mean that non-invasive prenatal diagnosis (NIPD), based on the presence of cell-free fetal DNA in maternal plasma, could be used to target prophylaxis on "at risk" pregnancies where the fetus is RhD positive. This paper provides the first assessment of cost effectiveness of NIPD-targeted prophylaxis compared to current policies. METHODS: We conducted an economic analysis of NIPD implementation in England and Wales. Two scenarios were considered. Scenario 1 assumed that NIPD will be only used to target antenatal prophylaxis with serology tests continuing to direct post delivery prophylaxis. In Scenario 2, NIPD would also displace postnatal serology testing if an RhD negative fetus was identified. Costs were estimated from the provider's perspective for both scenarios together with a threshold royalty fee per test. Incremental costs were compared with clinical implications. RESULTS: The basic cost of an NIPD in-house test is L16.25 per sample (excluding royalty fee). The two-dose antenatal prophylaxis policy recommended by NICE is estimated to cost the NHS L3.37 million each year. The estimated threshold royalty fee is L2.18 and L8.83 for Scenarios 1 and 2 respectively. At a L2.00 royalty fee, mass NIPD testing would produce no saving for Scenario 1 and L507,154 per annum for Scenario 2. Incremental cost-effectiveness analysis indicates that, at a test sensitivity of 99.7% and this royalty fee, NIPD testing in Scenario 2 will generate one additional sensitisation for every L9,190 saved. If a single-dose prophylaxis policy were implemented nationally, as recently recommended by NICE, Scenario 2 savings would fall. CONCLUSIONS: Currently, NIPD testing to target anti-D prophylaxis is unlikely to be sufficiently cost-effective to warrant its large scale introduction in England and Wales. Only minor savings are calculated and, balanced against this, the predicted increase in maternal sensitisations may be unacceptably high. Reliability of NIPD assays still needs to be demonstrated rigorously in different ethnic minority populations. First trimester testing is unlikely to alter this picture significantly although other emerging technologies may. PMID- 21244653 TI - Primary malignant mixed Mullerian tumor arising from the mesorectum with a synchronous ovarian cancer: a case report and review of the literature. AB - INTRODUCTION: Extragenital malignant mixed Mullerian tumor is an extremely rare presentation of malignant mixed Mullerian tumor, especially when combined with a synchronous ovarian cancer. CASE PRESENTATION: We report the clinical course and pathologic findings of a case of mesorectal malignant mixed Mullerian tumor with synchronous ovarian cancer, in a 50-year-old, gravida 0, para 0, Han Chinese woman with regular menstruation. This is the sixteenth case in the English literature of extragenital malignant mixed Mullerian tumor combined with synchronous or metachronous malignancy reported. CONCLUSION: Although extragenital malignant mixed Mullerian tumor is very rare and has a poor prognososis, a longer survival time might be achieved with treatment by cytoreductive surgery, radiotherapy and chemotherapy. PMID- 21244654 TI - Presumptive myocarditis with ST-Elevation myocardial infarction presentation in young males as a new syndrome. Clinical significance and long term follow up. AB - BACKGROUND: Acute myocarditis may mimic myocardial infarction, since affected patients complain of "typical" chest pain, the ECG changes are identical to those observed in acute coronary syndromes, and serum markers are increased. We describe a case series of presumptive myocarditis with ST segment elevation on admission ECG. METHODS AND RESULTS: From 1998 to 2009, 21 patients (20 males; age 17-42 years) were admitted with chest pain, persistent ST segment elevation, serum enzyme and troponine release. All but one patients had fever and flu-like symptoms prior to admission. No abnormal Q wave appeared in any ECG tracing, and angiography did not show significant coronary artery disease. Patients remained asymptomatic at long term follow-up, except 2 who experienced a late relapse, with the same clinical, electrocardiographic and serum findings as in the first clinical presentation. CONCLUSION: Presumptive myocarditis of possible viral origin characterized by ST elevation mimicking myocardial infarction, good short term prognosis and some risk for recurrence is relatively frequent in young males and appears as a distinct clinical condition. PMID- 21244655 TI - Use of complementary and alternative medicine at Norwegian and Danish hospitals. AB - BACKGROUND: Several studies have found that a high proportion of the population in western countries use complementary and alternative medicine (CAM). However, little is known about whether CAM is offered in hospitals. The aim of this study was to describe to what extent CAM is offered in Norwegian and Danish hospitals and investigate possible changes in Norway since 2001. METHODS: A one-page questionnaire was sent to all included hospitals in both countries. The questionnaire was sent to the person responsible for the clinical activity, typically the medical director. 99 hospitals in the authority (85%) in Norway and 126 in Denmark (97%) responded. Given contact persons were interviewed. RESULTS: CAM is presently offered in about 50% of Norwegian hospitals and one-third of Danish hospitals. In Norway CAM was offered in 50 hospitals, 40 of which involved acupuncture. 19 hospitals gave other alternative therapies like biofeedback, hypnosis, cupping, ear-acupuncture, herbal medicine, art therapy, homeopathy, reflexology, thought field therapy, gestalt therapy, aromatherapy, tai chi, acupressure, yoga, pilates and other. 9 hospitals offered more than one therapy form. In Denmark 38 hospitals offered acupuncture and one Eye Movement Desensitization and Reprocessing Light Therapy. The most commonly reported reason for offering CAM was scientific evidence in Denmark. In Norway it was the interest of a hospital employee, except for acupuncture where the introduction is more often initiated by the leadership and is more based on scientific evidence of effect. All persons (except one) responsible for the alternative treatment had a medical or allied health professional background and their education/training in CAM treatment varied substantially. CONCLUSIONS: The extent of CAM being offered has increased substantially in Norway during the first decade of the 21(st) century. This might indicate a shift in attitude regarding CAM within the conventional health care system. PMID- 21244656 TI - Assessing access barriers to tuberculosis care with the tool to Estimate Patients' Costs: pilot results from two districts in Kenya. AB - BACKGROUND: The poor face geographical, socio-cultural and health system barriers in accessing tuberculosis care. These may cause delays to timely diagnosis and treatment resulting in more advanced disease and continued transmission of TB. By addressing barriers and reasons for delay, costs incurred by TB patients can be effectively reduced. A Tool to Estimate Patients' Costs has been developed. It can assist TB control programs in assessing such barriers. This study presents the Tool and results of its pilot in Kenya. METHODS: The Tool was adapted to the local setting, translated into Kiswahili and pretested. Nine public health facilities in two districts in Eastern Province were purposively sampled. Responses gathered from TB patients above 15 years of age with at least one month of treatment completed and signed informed consent were double entered and analyzed. Follow-up interviews with key informants on district and national level were conducted to assess the impact of the pilot and to explore potential interventions. RESULTS: A total of 208 patients were interviewed in September 2008. TB patients in both districts have a substantial burden of direct (out of pocket; USD 55.8) and indirect (opportunity; USD 294.2) costs due to TB. Inability to work is a major cause of increased poverty. Results confirm a 'medical poverty trap' situation in the two districts: expenditures increased while incomes decreased. Subsequently, TB treatment services were decentralized to fifteen more facilities and other health programs were approached for nutritional support of TB patients and sputum sample transport. On the national level, a TB and poverty sub-committee was convened to develop a comprehensive pro poor approach. CONCLUSIONS: The Tool to Estimate Patients' Costs proved to be a valuable instrument to assess the costs incurred by TB patients, socioeconomic situations, health-seeking behavior patterns, concurrent illnesses such as HIV, and social and gender-related impacts. The Tool helps to identify and tackle bottlenecks in access to TB care, especially for the poor. Reducing delays in diagnosis, decentralization of services, fully integrated TB/HIV care and expansion of health insurance coverage would alleviate patients' economic constraints due to TB. PMID- 21244658 TI - Toxoplasmosis in a patient who was immunocompetent: a case report. AB - INTRODUCTION: Toxoplasma gondii is an obligate intracellular protozoan that infects up to one-third of the world's population. Although this case is not the first of its kind, it is clinically important since it will help doctors keep a broad differential diagnosis in mind when attending to similar patients. CASE PRESENTATION: We present the case of a 20-year-old man of Middle Eastern heritage presenting with only generalized lymphadenopathy who was diagnosed with acute toxoplasmosis. CONCLUSION: This case illustrates the important fact that toxoplasmosis can present with just simple lymphadenopathy, and thus can be confused with other infections such as Epstein-Barr virus and other mononucleosis like illnesses such as cytomegalovirus, HIV with acute retroviral syndrome, cat scratch disease, leishmaniasis and syphilis. This case underlines why appropriate testing should be performed in confusing cases, and helps increase the knowledge about the diagnosis of this disease. PMID- 21244657 TI - Variability of the chronic obstructive pulmonary disease key epidemiological data in Europe: systematic review. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is predicted to become a major cause of death worldwide. Studies on the variability in the estimates of key epidemiological parameters of COPD may contribute to better assessment of the burden of this disease and to helpful guidance for future research and public policies. In the present study, we examined differences in the main epidemiological characteristics of COPD derived from studies across countries of the European Union, focusing on prevalence, severity, frequency of exacerbations and mortality, as well as on differences between the studies' methods. METHODS: This systematic review was based on a search for the relevant literature in the Science Citation Index database via the Web of Science and on COPD mortality rates issued from national statistics. Analysis was finally based on 65 articles and Eurostat COPD mortality data for 21 European countries. RESULTS: Epidemiological characteristics of COPD varied widely from country to country. For example, prevalence estimates ranged between 2.1% and 26.1%, depending on the country, the age group and the methods used. Likewise, COPD mortality rates ranged from 7.2 to 36.1 per 10(5) inhabitants. The methods used to estimate these epidemiological parameters were highly variable in terms of the definition of COPD, severity scales, methods of investigation and target populations. Nevertheless, to a large extent, several recent international guidelines or research initiatives, such as GOLD, BOLD or PLATINO, have boosted a substantial standardization of methodology in data collection and have resulted in the availability of more comparable epidemiological estimates across countries. On the basis of such standardization, severity estimates as well as prevalence estimates present much less variation across countries. The contribution of these recent guidelines and initiatives is outlined, as are the problems remaining in arriving at more accurate COPD epidemiological estimates across European countries. CONCLUSIONS: The accuracy of COPD epidemiological parameters is important for guiding decision making with regard to preventive measures, interventions and patient management in various health care systems. Therefore, the recent initiatives for standardizing data collection should be enhanced to result in COPD epidemiological estimates of improved quality. Moreover, establishing international guidelines for reporting research on COPD may also constitute a major contribution. PMID- 21244659 TI - Risk assessment in the first fifteen minutes: a prospective cohort study of a simple physiological scoring system in the emergency department. AB - INTRODUCTION: The survival of patients admitted to an emergency department is determined by the severity of acute illness and the quality of care provided. The high number and the wide spectrum of severity of illness of admitted patients make an immediate assessment of all patients unrealistic. The aim of this study is to evaluate a scoring system based on readily available physiological parameters immediately after admission to an emergency department (ED) for the purpose of identification of at-risk patients. METHODS: This prospective observational cohort study includes 4,388 consecutive adult patients admitted via the ED of a 960-bed tertiary referral hospital over a period of six months. Occurrence of each of seven potential vital sign abnormalities (threat to airway, abnormal respiratory rate, oxygen saturation, systolic blood pressure, heart rate, low Glasgow Coma Scale and seizures) was collected and added up to generate the vital sign score (VSS). VSSinitial was defined as the VSS in the first 15 minutes after admission, VSSmax as the maximum VSS throughout the stay in ED. Occurrence of single vital sign abnormalities in the first 15 minutes and VSSinitial and VSSmax were evaluated as potential predictors of hospital mortality. RESULTS: Logistic regression analysis identified all evaluated single vital sign abnormalities except seizures and abnormal respiratory rate to be independent predictors of hospital mortality. Increasing VSSinitial and VSSmax were significantly correlated to hospital mortality (odds ratio (OR) 2.80, 95% confidence interval (CI) 2.50 to 3.14, P < 0.0001 for VSSinitial; OR 2.36, 95% CI 2.15 to 2.60, P < 0.0001 for VSSmax). The predictive power of VSS was highest if collected in the first 15 minutes after ED admission (log rank Chi-square 468.1, P < 0.0001 for VSSinitial;,log rank Chi square 361.5, P < 0.0001 for VSSmax). CONCLUSIONS: Vital sign abnormalities and VSS collected in the first minutes after ED admission can identify patients at risk of an unfavourable outcome. PMID- 21244660 TI - Epidemiology of urinary tract infections and antibiotics sensitivity among pregnant women at Khartoum North Hospital. AB - BACKGROUND: Urinary tract infections (UTI) can lead to poor maternal and perinatal outcomes. Investigating epidemiology of UTI and antibiotics sensitivity among pregnant women is fundamental for care-givers and health planners. METHODS: A cross sectional study has been conducted at Khartoum north teaching hospital Antenatal Care Clinic between February-June 2010, to investigate epidemiology of UTI and antibiotics resistance among pregnant women. Structured questionnaires were used to gather data from pregnant women. UTI was diagnosed using mid stream urine culture on standard culture media RESULTS: Out of 235 pregnant women included, 66 (28.0%) were symptomatic and 169 (71.9%) asymptomatic. the prevalence of bacteriuria among symptomatic and asymptomatic pregnant women were (12.1%), and (14.7%) respectively, with no significant difference between the two groups (P = 0.596), and the overall prevalence of UTI was (14.0%). In multivariate analyses, age, gestational age, parity, and history of UTI in index pregnancy were not associated with bacteriuria. Escherichia coli (42.4%) and S. aureus (39.3%) were the commonest isolated bacteria. Four, 2, 2, 3, 4, 2 and 0 out of 14 E. coli isolates, showed resistance to amoxicillin, naladixic acid, nitrofurantoin, ciprofloxacin, co-trimoxazole, amoxicillin/clavulanate and norfloxacin, respectively. CONCLUSION: Escherichia coli were the most prevalent causative organisms and showing multi drug resistance pattern, asymptomatic bacteriuria is more prevalent than symptomatic among pregnant women. Urine culture for screening and diagnosis purpose for all pregnant is recommended. PMID- 21244661 TI - Network analysis of skin tumor progression identifies a rewired genetic architecture affecting inflammation and tumor susceptibility. AB - BACKGROUND: Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits, including inflammation and cancer susceptibility. Whether germline variants affect gene expression in tumors that have undergone somatic alterations, and the extent to which these variants influence tumor progression, is unknown. RESULTS: Using an integrated linkage and genomic analysis of a mouse model of skin cancer that produces both benign tumors and malignant carcinomas, we document major changes in germline control of gene expression during skin tumor development resulting from cell selection, somatic genetic events, and changes in the tumor microenvironment. The number of significant expression quantitative trait loci (eQTL) is progressively reduced in benign and malignant skin tumors when compared to normal skin. However, novel tumor-specific eQTL are detected for several genes associated with tumor susceptibility, including IL18 (Il18), Granzyme E (Gzme), Sprouty homolog 2 (Spry2), and Mitogen-activated protein kinase kinase 4 (Map2k4). CONCLUSIONS: We conclude that the genetic architecture is substantially altered in tumors, and that eQTL analysis of tumors can identify host factors that influence the tumor microenvironment, mitogen-activated protein (MAP) kinase signaling, and cancer susceptibility. PMID- 21244662 TI - E2 allele of the apolipoprotein E gene polymorphism is predictive for obesity status in Roma minority population of Croatia. AB - BACKGROUND AND AIMS: The Roma (Gypsies) are a transnational minority, founder population characterized by unique genetic background modeled by culturally determined endogamy. The present study explores whether the widely found cardiovascular diseases (CVD) risk effects of ACE I/D, APOE (epsilon2, epsilon3, epsilon4), eNOS-VNTR and LEP G2548A polymorphisms can be replicated in this specific population. METHODS AND RESULTS: The community-based study was carried on 208 adult Bayash Roma living in rural settlements of eastern and northern Croatia. Risk effect of four CVD candidate polymorphisms are related to the most prominent classical CVD risk phenotypes: obesity indicators (body mass index and waist circumference), hypertension and hyperlipidemia (triglycerides, HDL and LDL cholesterol). For all of them the standard risk cut-offs were applied. The extent to which the phenotypic status is related to genotype was assessed by logistic regression analysis. The strongest associations were found for epsilon2 allele of the APOE as a predictor of waist circumference (OR 3.301; 95%CI 1.254-8.688; p = 0.016) as well as for BMI (OR 3.547; 95%CI 1.471-8.557; p = 0.005). It is notable that epsilon3 allele of APOE gene turned out to be a protective genetic factor determining low lipid levels. CONCLUSION: The strength of the relation and the similarity of the results obtained for both tested indicators of obesity provide firm evidence that APOE plays an important role in obesity development in the Roma population. PMID- 21244663 TI - Methodological considerations regarding response bias effect in substance use research: is correlation between the measured variables sufficient? AB - Efforts for drug free sport include developing a better understanding of the behavioural determinants that underline doping with an increased interest in developing anti-doping prevention and intervention programmes. Empirical testing of both is dominated by self-report questionnaires, which is the most widely used method in psychological assessments and sociology polls. Disturbingly, the potential distorting effect of socially desirable responding (SD) is seldom considered in doping research, or dismissed based on weak correlation between some SD measure and the variables of interest. The aim of this report is to draw attention to i) the potential distorting effect of SD and ii) the limitation of using correlation analysis between a SD measure and the individual measures. Models of doping opinion as a potentially contentious issue was tested using structural equation modeling technique (SEM) with and without the SD variable, on a dataset of 278 athletes, assessing the SD effect both at the i) indicator and ii) construct levels, as well as iii) testing SD as an independent variable affecting expressed doping opinion. Participants were categorised by their SD score into high- and low SD groups. Based on low correlation coefficients (<|0.22|) observed in the overall sample, SD effect on the indicator variables could be disregarded. Regression weights between predictors and the outcome variable varied between groups with high and low SD but despite the practically non-existing relationship between SD and predictors (<|0.11|) in the low SD group, both groups showed improved model fit with SD, independently. The results of this study clearly demonstrate the presence of SD effect and the inadequacy of the commonly used pairwise correlation to assess social desirability at model level. In the absence of direct observation of the target behaviour (i.e. doping use), evaluation of the effectiveness of future anti-doping campaign, along with empirical testing of refined doping behavioural models, will likely to continue to rely on self-reported information. Over and above controlling the effect of socially desirable responding in research that makes inferences based on self reported information on social cognitive and behavioural measures, it is recommended that SD effect is appropriately assessed during data analysis. PMID- 21244664 TI - Technical note on the validation of a semi-automated image analysis software application for estrogen and progesterone receptor detection in breast cancer. AB - BACKGROUND: The immunohistochemical detection of estrogen (ER) and progesterone (PR) receptors in breast cancer is routinely used for prognostic and predictive testing. Whole slide digitalization supported by dedicated software tools allows quantization of the image objects (e.g. cell membrane, nuclei) and an unbiased analysis of immunostaining results. Validation studies of image analysis applications for the detection of ER and PR in breast cancer specimens provided strong concordance between the pathologist's manual assessment of slides and scoring performed using different software applications. METHODS: The effectiveness of two connected semi-automated image analysis software (NuclearQuant v. 1.13 application for PannoramicTM Viewer v. 1.14) for determination of ER and PR status in formalin-fixed paraffin embedded breast cancer specimens immunostained with the automated Leica Bond Max system was studied. First the detection algorithm was calibrated to the scores provided an independent assessors (pathologist), using selected areas from 38 small digital slides (created from 16 cases) containing a mean number of 195 cells. Each cell was manually marked and scored according to the Allred-system combining frequency and intensity scores. The performance of the calibrated algorithm was tested on 16 cases (14 invasive ductal carcinoma, 2 invasive lobular carcinoma) against the pathologist's manual scoring of digital slides. RESULTS: The detection was calibrated to 87 percent object detection agreement and almost perfect Total Score agreement (Cohen's kappa 0.859, quadratic weighted kappa 0.986) from slight or moderate agreement at the start of the study, using the un-calibrated algorithm. The performance of the application was tested against the pathologist's manual scoring of digital slides on 53 regions of interest of 16 ER and PR slides covering all positivity ranges, and the quadratic weighted kappa provided almost perfect agreement (kappa = 0.981) among the two scoring schemes. CONCLUSIONS: NuclearQuant v. 1.13 application for PannoramicTM Viewer v. 1.14 software application proved to be a reliable image analysis tool for pathologists testing ER and PR status in breast cancer. PMID- 21244665 TI - Fear causes tears - perineal injuries in home birth settings. A Swedish interview study. AB - BACKGROUND: Perineal injury is a serious complication of vaginal delivery that has a severe impact on the quality of life of healthy women. The prevalence of perineal injuries among women who give birth in hospital has increased over the last decade, while it is lower among women who give birth at home. The aim of this study was to describe the practice of midwives in home birth settings with the focus on the occurrence of perineal injuries. METHODS: Twenty midwives who had assisted home births for between one and 29 years were interviewed using an interview guide. The midwives also had experience of working in a hospital delivery ward. All the interviews were tape-recorded and transcribed. Content analysis was used. RESULTS: The overall theme was "No rushing and tearing about", describing the midwives' focus on the natural process taking its time. The subcategories 1) preparing for the birth; 2) going along with the physiological process; 3) creating a sense of security; 4) the critical moment and 5) midwifery skills illuminate the management of labor as experienced by the midwives when assisting births at home. CONCLUSIONS: Midwives who assist women who give birth at home take many things into account in order to minimize the risk of complications during birth. Protection of the woman's perineum is an act of awareness that is not limited to the actual moment of the pushing phase but starts earlier, along with the communication between the midwife and the woman. PMID- 21244666 TI - The national burden of road traffic injuries in Thailand. AB - BACKGROUND: This study quantifies the burden of road traffic injuries (RTIs) in Thailand in 2004, incorporating new Thai data on mortality and the frequency and severity of long-term disability. METHODS: We quantified the uncertainty around national RTI mortality estimates based on a verbal autopsy study that was conducted to correct for the large proportion of ill-defined deaths in the vital registration system. The number of nonfatal RTI victims was estimated using hospital and survey data. We used the proportion and severity of long-term disabilities from a recent Thai study, instead of the standard Global Burden of Disease assumptions, to calculate the burden due to long-term disability. To evaluate changes over time, we also calculated the burden of RTIs in 2004 using the method and assumptions used in 1999, when standard Global Burden of Disease assumptions were used. RESULTS: The total loss of disability-adjusted life years due to RTIs was 673,000 (95% uncertainty interval [UI]: 546,000-881,000). Mortality contributed 88% of this burden. The use of local data led to a significantly higher estimate of the burden of long-term disability due to RTIs (74,000 DALYs [95% UI: 55,400-88,500] vs. 43,000 [UI: 42,700-43,600]) using standard Global Burden of Disease methods. However, this difference constituted only a small proportion of the total burden. CONCLUSIONS: The burden of RTIs in 2004 remained at the same high level as in 1999. The use of local data on the long-term health consequences of RTIs enabled an estimate of this burden and its uncertainty that is likely to be more valid. PMID- 21244667 TI - Revisiting the value of pre-hospital tracheal intubation: an all time systematic literature review extracting the Utstein airway core variables. AB - INTRODUCTION: Although tracheal intubation (TI) in the pre-hospital setting is regularly carried out by emergency medical service (EMS) providers throughout the world, its value is widely debated. Heterogeneity in procedures, providers, patients, systems and stated outcomes, and inconsistency in data reporting make scientific reports difficult to interpret and compare, and the majority are of limited quality. To hunt down what is really known about the value of pre hospital TI, we determined the rate of reported Utstein airway variables (28 core variables and 12 fixed-system variables) found in current scientific publications on pre-hospital TI. METHODS: We performed an all time systematic search according to the PRISMA guidelines of Medline and EMBASE to identify original research pertaining to pre-hospital TI in adult patients. RESULTS: From 1,076 identified records, 73 original papers were selected. Information was extracted according to an Utstein template for data reporting from in-the-field advanced airway management. Fifty-nine studies were from North American EMS systems. Of these, 46 (78%) described services in which non-physicians conducted TI. In 12 of the 13 non-North American EMS systems, physicians performed the pre-hospital TI. Overall, two were randomised controlled trials (RCTs), and 65 were observational studies. None of the studies presented the complete set of recommended Utstein airway variables. The median number of core variables reported was 10 (max 21, min 2, IQR 8-12), and the median number of fixed system variables was 5 (max 11, min 0, IQR 4-8). Among the most frequently reported variables were "patient category" and "service mission type", reported in 86% and 71% of the studies, respectively. Among the least-reported variables were "co-morbidity" and "type of available ventilator", both reported in 2% and 1% of the studies, respectively. CONCLUSIONS: Core data required for proper interpretation of results were frequently not recorded and reported in studies investigating TI in adults. This makes it difficult to compare scientific reports, assess their validity, and extrapolate to other EMS systems. Pre-hospital TI is a complex intervention, and terminology and study design must be improved to substantiate future evidence based clinical practice. PMID- 21244668 TI - A cluster randomised controlled trial evaluating the effectiveness of a structured pulmonary rehabilitation education programme for improving the health status of people with chronic obstructive pulmonary disease (COPD): The PRINCE Study protocol. AB - BACKGROUND: A key strategy in improving care for people with chronic obstructive pulmonary disease (COPD) is the provision of pulmonary rehabilitation programmes. Pulmonary rehabilitation programmes have been successful in improving patients' sense of dyspnoea and Health Related Quality of Life. However, the effectiveness of structured education pulmonary rehabilitation programmes delivered at the level of the general practice on the health status of people with COPD remains uncertain and there is a need for a robust and fair assessment of this. The PRINCE study will evaluate the effectiveness of a Structured Education Pulmonary Rehabilitation Programme (SEPRP), delivered at the level of the general practice, on the health status of people with COPD. METHODS/DESIGN: The PRINCE Trial is a two-armed, single blind cluster randomised trial conducted in the primary care setting in Ireland. Randomisation to control and intervention is at the level of the General Practice. Participants in the intervention arm will receive a SEPRP and those allocated to the control arm will receive usual care. Delivery of the SEPRP will be by a practice nurse and physiotherapist in the General Practice (GP) site. The primary outcome measure of the study will be health status as measured by the Chronic Respiratory Questionnaire (CRQ). Blinded outcome assessment will be undertaken at baseline and at twelve-fourteen weeks after completion of the programme. A comparison of outcomes between the intervention and control sites will be made to examine if differences exist and, if so, to what extent between control and experimental groups. Sample size calculations estimate that 32 practices with a minimum of 10 participants per practice are required, in total, to be randomised to control and intervention arms for power of at least 80% with alpha levels of 0.05, to determine a clinically significant change of 0.5 units in the CRQ. A cost effectiveness analysis will also be conducted. DISCUSSION: The results of this trial are directly applicable to primary care settings in Ireland. Should a SEPRP delivered by practice nurses and physiotherapists in primary care be found to be effective in improving patients' sense of dyspnoea and HRQoL, then the findings would be applicable to many thousands of individuals in Ireland and beyond. PMID- 21244669 TI - The incidence of venous thromboembolism and practice of deep venous thrombosis prophylaxis in hospitalized cirrhotic patients. AB - BACKGROUND: Cirrhotic patients are characterized by a decreased synthesis of coagulation and anticoagulation factors. The coagulopathy of cirrhotic patients is considered to be auto-anticoagulation. Our aim was to determine the incidence and predictors of venous thromboembolism (VTE) and examine the practice of deep venous thrombosis (DVT) prophylaxis among hospitalized cirrhotic patients. METHODS: A retrospective cohort study was performed in a tertiary teaching hospital. We included all adult patients admitted to the hospital with a diagnosis of liver cirrhosis from January 1, 2009 to December 31, 2009. We grouped our cohort patients in two groups, cirrhotic patients without VTE and cirrhotic with VTE. RESULTS: Over one year, we included 226 cirrhotic patients, and the characteristics of both groups were similar regarding their clinical and laboratory parameters and their outcomes. Six patients (2.7%) developed VTE, and all of the VTEs were DVT. Hepatitis C was the most common (51%) underlying cause of liver cirrhosis, followed by hepatitis B (22%); 76% of the cirrhotic patients received neither pharmacological nor mechanical DVT prophylaxis. CONCLUSION: Cirrhotic patients are at risk for developing VTE. The utilization of DVT prophylaxis was suboptimal. PMID- 21244670 TI - Inhibition of caspase-1 activation in Gram-negative sepsis and experimental endotoxemia. AB - INTRODUCTION: Down-regulation of ex-vivo cytokine production is a specific feature in patients with sepsis. Cytokine downregulation was studied focusing on caspase-1 activation and conversion of pro-interleukin-1beta into interleukin 1beta (IL-1beta). METHODS: Peripheral blood mononuclear cells were isolated from a) 92 patients with sepsis mainly of Gram-negative etiology; b) 34 healthy volunteers; and c) 5 healthy individuals enrolled in an experimental endotoxemia study. Cytokine stimulation was assessed in vitro after stimulation with a variety of microbial stimuli. RESULTS: Inhibition of IL-1beta in sepsis was more profound than tumour necrosis factor (TNF). Down-regulation of IL-1beta response could not be entirely explained by the moderate inhibition of transcription. We investigated inflammasome activation and found that in patients with sepsis, both pro-caspase-1 and activated caspase-1 were markedly decreased. Blocking caspase-1 inhibited the release of IL-1beta in healthy volunteers, an effect that was lost in septic patients. Finally, urate crystals, which specifically induce the NLPR3 inflammasome activation, induced significant IL-1beta production in healthy controls but not in patients with sepsis. These findings were complemented by inhibition of caspase-1 autocleavage as early as two hours after lipopolysaccharide exposure in volunteers. CONCLUSIONS: These data demonstrate that the inhibition of caspase-1 and defective IL-1 beta production is an important immunological feature in sepsis. PMID- 21244671 TI - Impact of delayed admission to intensive care units on mortality of critically ill patients: a cohort study. AB - INTRODUCTION: When the number of patients who require intensive care is greater than the number of beds available, intensive care unit (ICU) entry flow is obstructed. This phenomenon has been associated with higher mortality rates in patients that are not admitted despite their need, and in patients that are admitted but are waiting for a bed. The purpose of this study is to evaluate if a delay in ICU admission affects mortality for critically ill patients. METHODS: A prospective cohort of adult patients admitted to the ICU of our institution between January and December 2005 were analyzed. Patients for whom a bed was available were immediately admitted; when no bed was available, patients waited for ICU admission. ICU admission was classified as either delayed or immediate. Confounding variables examined were: age, sex, originating hospital ward, ICU diagnosis, co-morbidity, Acute Physiology and Chronic Health Evaluation (APACHE) II score, therapeutic intervention, and Sequential Organ Failure Assessment (SOFA) score. All patients were followed until hospital discharge. RESULTS: A total of 401 patients were evaluated; 125 (31.2%) patients were immediately admitted and 276 (68.8%) patients had delayed admission. There was a significant increase in ICU mortality rates with a delay in ICU admission (P = 0.002). The fraction of mortality risk attributable to ICU delay was 30% (95% confidence interval (CI): 11.2% to 44.8%). Each hour of waiting was independently associated with a 1.5% increased risk of ICU death (hazard ratio (HR): 1.015; 95% CI 1.006 to 1.023; P = 0.001). CONCLUSIONS: There is a significant association between time to admission and survival rates. Early admission to the ICU is more likely to produce positive outcomes. PMID- 21244672 TI - Suicidality and divalproex sodium: analysis of controlled studies in multiple indications. AB - BACKGROUND: Recent analyses of antiepileptic drugs have indicated an increase in the risk of suicidality. The objective of this report was to provide clinical information and an independent meta-analysis of divalproex sodium and suicidality events by analyzing data from 13 placebo-controlled studies and 1 low-dose controlled study. METHODS: Adverse events considered to be possibly suicide related were identified using the Columbia Classification Algorithm of Suicide Assessment (C-CASA) methodology. Indications included epilepsy, bipolar disorder, migraine prophylaxis, impulsive aggression, and dementia. Narratives were produced for every event, and suicidality event ratings were performed by a third party blinded to treatment assignment. Statistical analyses were conducted using methodology similar to that reported by the US Food and Drug Administration (FDA). RESULTS: Suicidality events were identified in 5 of the 13 placebo controlled studies. Of the 1,327 (0.83%) subjects taking divalproex sodium, 11 had suicidality events: 2 suicide attempts and 9 suicidal ideation. Of 992 (0.91%) subjects taking placebo, 9 had suicidality events: 1 preparatory act toward suicide, 2 suicide attempts, and 6 suicidal ideation. Across placebo controlled studies, the overall estimated odds ratio (OR) of suicidal behavior or ideation was 0.72 (95% CI 0.29 to 1.84). The OR for suicidal behavior was 0.37 (95% CI 0.04 to 2.58), and the OR for suicidal ideation was 0.90 (95% CI 0.31 to 2.79). CONCLUSIONS: In this meta-analysis, divalproex sodium does not appear to increase the risk of suicide-related adverse events relative to placebo in the populations studied. Clinicians should nonetheless remain vigilant in assessing suicidality, not only in patients treated for mental disorders with inherently high suicide risk, but also in patients taking antiepileptic medications. PMID- 21244674 TI - Extracorporeal life support following out-of-hospital refractory cardiac arrest. AB - INTRODUCTION: Extracorporeal life support (ECLS) has recently shown encouraging results in the resuscitation of in-hospital (IH) refractory cardiac arrest. We assessed the use of ECLS following out-of-hospital (OH) refractory cardiac arrest. METHODS: We evaluated 51 consecutive patients who experienced witnessed OH refractory cardiac arrest and received automated chest compression and ECLS upon arrival in the hospital. Patients with preexisting severe hypothermia who experienced IH cardiac arrest were excluded. A femorofemoral ECLS was set up on admission to the hospital by a mobile cardiothoracic surgical team. RESULTS: Fifty-one patients were included (mean age, 42 +/- 15 years). The median delays from cardiac arrest to cardiopulmonary resuscitation and ECLS were, respectively, 3 minutes (25th to 75th interquartile range, 1 to 7) and 120 minutes (25th to 75th interquartile range, 102-149). Initial rhythm was ventricular fibrillation in 32 patients (63%), asystole in 15 patients (29%) patients and pulseless rhythm in 4 patients (8%). ECLS failed in 9 patients (18%). Only two patients (4%) (95% confidence interval, 1% to 13%) were alive at day 28 with a favourable neurological outcome. There was a significant correlation (r = 0.36, P = 0.01) between blood lactate and delay between cardiac arrest and onset of ECLS, but not with arterial pH or blood potassium level. Deaths were the consequence of multiorgan failure (n = 43; 47%), brain death (n = 10; 20%) and refractory hemorrhagic shock (n = 7; 14%), and most patients (n = 46; 90%) died within 48 hours. CONCLUSIONS: This poor outcome suggests that the use of ECLS should be more restricted following OH refractory cardiac arrest. PMID- 21244673 TI - Testing the thrifty gene hypothesis: the Gly482Ser variant in PPARGC1A is associated with BMI in Tongans. AB - BACKGROUND: the thrifty gene hypothesis posits that, in populations that experienced periods of feast and famine, natural selection favoured individuals carrying thrifty alleles that promote the storage of fat and energy. Polynesians likely experienced long periods of cold stress and starvation during their settlement of the Pacific and today have high rates of obesity and type 2 diabetes (T2DM), possibly due to past positive selection for thrifty alleles. Alternatively, T2DM risk alleles may simply have drifted to high frequency in Polynesians. To identify thrifty alleles in Polynesians, we previously examined evidence of positive selection on T2DM-associated SNPs and identified a T2DM risk allele at unusually high frequency in Polynesians. We suggested that the risk allele of the Gly482Ser variant in the PPARGC1A gene was driven to high frequency in Polynesians by positive selection and therefore possibly represented a thrifty allele in the Pacific. METHODS: here we examine whether PPARGC1A is a thrifty gene in Pacific populations by testing for an association between Gly482Ser genotypes and BMI in two Pacific populations (Maori and Tongans) and by evaluating the frequency of the risk allele of the Gly482Ser variant in a sample of worldwide populations. RESULTS: we find that the Gly482Ser variant is associated with BMI in Tongans but not in Maori. In a sample of 58 populations worldwide, we also show that the 482Ser risk allele reaches its highest frequency in the Pacific. CONCLUSION: the association between Gly482Ser genotypes and BMI in Tongans together with the worldwide frequency distribution of the Gly482Ser risk allele suggests that PPARGC1A remains a candidate thrifty gene in Pacific populations. PMID- 21244675 TI - Red blood cell transfusion in patients with subarachnoid hemorrhage: a multidisciplinary North American survey. AB - INTRODUCTION: Anemia is associated with poor outcomes in patients with aneurysmal subarachnoid hemorrhage (SAH). It remains unclear whether this association can be modified with more aggressive use of red blood cell (RBC) transfusions. The degree to which restrictive thresholds have been adopted in neurocritical care patients remains unknown. METHODS: We performed a survey of North American academic neurointensivists, vascular neurosurgeons and multidisciplinary intensivists who regularly care for patients with SAH to determine hemoglobin (Hb) concentrations which commonly trigger a decision to initiate transfusion. We also assessed minimum and maximum acceptable Hb goals in the context of a clinical trial and how decision-making is influenced by advanced neurological monitoring, clinician characteristics and patient-specific factors. RESULTS: The survey was sent to 531 clinicians, of whom 282 (53%) responded. In a hypothetical patient with high-grade SAH (WFNS 4), the mean Hb concentration at which clinicians administered RBCs was 8.19 g/dL (95% CI, 8.07 to 8.30 g/dL). Transfusion practices were comparatively more restrictive in patients with low grade SAH (mean Hb 7.85 g/dL (95% CI, 7.73 to 7.97 g/dL)) (P < 0.0001) and more liberal in patients with delayed cerebral ischemia (DCI) (mean Hb 8.58 g/dL (95% CI, 8.45 to 8.72 g/dL)) (P < 0.0001). In each setting, there was a broad range of opinions. The majority of respondents expressed a willingness to study a restrictive threshold of <=8 g/dL (92%) and a liberal goal of >=10 g/dl (75%); in both cases, the preferred transfusion thresholds were significantly higher for patients with DCI (P < 0.0001). Neurosurgeons expressed higher minimum Hb goals than intensivists, especially for patients with high-grade SAH (beta = 0.46, P = 0.003), and were more likely to administer two rather than one unit of RBCs (56% vs. 19%; P < 0.0001). Institutional use of transfusion protocols was associated with more restrictive practices. More senior clinicians preferred higher Hb goals in the context of a clinical trial. Respondents were more likely to transfuse patients with brain tissue oxygen tension values <15 mmHg and lactate-to-pyruvate ratios >40. CONCLUSIONS: There is widespread variation in the use of RBC transfusions in SAH patients. Practices are heavily influenced by the specific dynamic clinical characteristics of patients and may be further modified by clinician specialty and seniority, the use of protocols and advanced neurological monitoring. PMID- 21244676 TI - Polyunsaturated fatty acids reduce fatty acid synthase and hydroxy-methyl glutaryl CoA-reductase gene expression and promote apoptosis in HepG2 cell line. AB - BACKGROUND: n-3 and n-6 polyunsaturated fatty acids (PUFAs) are the two major classes of PUFAs encountered in the diet, and both classes of fatty acids are required for normal human health. Moreover, PUFAs have effects on diverse pathological processes impacting chronic disease, such as cardiovascular and immune disease, neurological disease, and cancer. AIM: To investigate the effects of eicosapentaenoic acid (EPA) and arachidonic acid (ARA) on the proliferation and apoptosis of human hepatoma cell line HepG2 after exposure to increasing concentrations of EPA or ARA for 48 h. Moreover, in the same cells the gene expression of Fatty Acid Synthase (FAS) and 3-Hydroxy-3-Methyl-Glutaryl Coenzyme A Reductase (HMG-CoAR) was also investigated. METHOD: Cell growth and apoptosis were assayed by MTT and ELISA test, respectively after cell exposure to increasing concentrations of EPA and ARA. Reverse-transcription and real-time PCR was used to detect FAS and HMG-CoAR mRNA levels in treated cells. RESULTS: Our findings show that EPA inhibits HepG2 cell growth in a dose-dependent manner, starting from 25 MUM (P < 0.01, one-way ANOVA test and Dunnett's post test) and exerts a statistically significant pro-apoptotic effect already at 1 MUM of EPA. Higher doses of ARA were need to obtain a statistically significant inhibition of cell proliferation and a pro-apoptotic effect in these cells (100 MUM, P < 0.01, one-way ANOVA test and Dunnett's post test). Moreover, a down-regulation of FAS and HMG-CoAR gene expression was observed after EPA and ARA treatment in HepG2 cells, starting at 10 MUM (P < 0.05, one-way ANOVA test and Dunnett's post test). CONCLUSION: Our results demonstrate that EPA and ARA inhibit HepG2 cell proliferation and induce apoptosis. The down-regulation of FAS and HMG-CoAR gene expression by EPA and ARA might be one of the mechanisms for the anti proliferative properties of PUFAs in an in vitro model of hepatocellular carcinoma. PMID- 21244677 TI - Acute thrombosis of the superior mesenteric artery in a 39-year-old woman with protein-S deficiency: a case report. AB - INTRODUCTION: Acute thromboembolic occlusion of the superior mesenteric artery is a condition with an unfavorable prognosis. Treatment of this condition is focused on early diagnosis, surgical or intravascular restoration of blood flow to the ischemic intestine, surgical resection of the necrotic bowel and supportive intensive care. In this report, we describe a case of a 39-year-old woman who developed a small bowel infarct because of an acute thrombotic occlusion of the superior mesenteric artery, also involving the splenic artery. CASE PRESENTATION: A 39-year-old Caucasian woman presented with acute abdominal pain and signs of intestinal occlusion. The patient was given an abdominal computed tomography scan and ultrasonography in association with Doppler ultrasonography, highlighting a thrombosis of the celiac trunk, of the superior mesenteric artery, and of the splenic artery. She immediately underwent an explorative laparotomy, and revascularization was performed by thromboendarterectomy with a Fogarty catheter. In the following postoperative days, she was given a scheduled second and third look, evidencing necrotic jejunal and ileal handles. During all the surgical procedures, we performed intraoperative Doppler ultrasound of the superior mesenteric artery and celiac trunk to control the arterial flow without evidence of a new thrombosis. CONCLUSION: Acute mesenteric ischemia is a rare abdominal emergency that is characterized by a high mortality rate. Generally, acute mesenteric ischemia is due to an impaired blood supply to the intestine caused by thromboembolic phenomena. These phenomena may be associated with a variety of congenital prothrombotic disorders. A prompt diagnosis is a prerequisite for successful treatment. The treatment of choice remains laparotomy and thromboendarterectomy, although some prefer an endovascular approach. A second look laparotomy could be required to evaluate viable intestinal handles. Some authors support a laparoscopic second-look. The possibility of evaluating the arteriotomy, during a repeated laparotomy with a Doppler ultrasound, is crucial to show a new thrombosis. Although the prognosis of acute mesenteric ischemia due to an acute arterial mesenteric thrombosis remains poor, a prompt diagnosis, aggressive surgical treatment and supportive intensive care unit could improve the outcome for patients with this condition. PMID- 21244678 TI - A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonella Typhimurium LT2. AB - BACKGROUND: Metabolic reconstructions (MRs) are common denominators in systems biology and represent biochemical, genetic, and genomic (BiGG) knowledge-bases for target organisms by capturing currently available information in a consistent, structured manner. Salmonella enterica subspecies I serovar Typhimurium is a human pathogen, causes various diseases and its increasing antibiotic resistance poses a public health problem. RESULTS: Here, we describe a community-driven effort, in which more than 20 experts in S. Typhimurium biology and systems biology collaborated to reconcile and expand the S. Typhimurium BiGG knowledge-base. The consensus MR was obtained starting from two independently developed MRs for S. Typhimurium. Key results of this reconstruction jamboree include i) development and implementation of a community-based workflow for MR annotation and reconciliation; ii) incorporation of thermodynamic information; and iii) use of the consensus MR to identify potential multi-target drug therapy approaches. CONCLUSION: Taken together, with the growing number of parallel MRs a structured, community-driven approach will be necessary to maximize quality while increasing adoption of MRs in experimental design and interpretation. PMID- 21244679 TI - Angiogenic properties of aged adipose derived mesenchymal stem cells after hypoxic conditioning. AB - BACKGROUND: Mesenchymal stem cells derived from adipose tissue (ADSC) are multipotent stem cells, originated from the vascular-stromal compartment of fat tissue. ADSC are used as an alternative cell source for many different cell therapies, however in ischemic cardiovascular diseases the therapeutic benefit was modest. One of the reasons could be the use of autologous aged ADSC, which recently were found to have impaired functions. We therefore analysed the effects of age on age markers and angiogenic properties of ADSC. Hypoxic conditioning was investigated as a form of angiogenic stimulation. METHODS: ADSC were harvested from young (1-3 month), adult (12 month) and aged (18-24 month) mice and cultured under normoxic (20%) and hypoxic (1%) conditions for 48 h. Differences in proliferation, apoptosis and telomere length were assessed in addition to angiogenic properties of ADSC. RESULTS: Proliferation potential and telomere length were decreased in aged ADSC compared to young ADSC. Frequency of apoptotic cells was higher in aged ADSC. Gene expression of pro-angiogenic factors including vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and hepatic growth factor (HGF) were down-regulated with age, which could be restored by hypoxia. Transforming growth factor (TGF-beta) increased in the old ADSC but was reduced by hypoxia.Expression of anti-angiogenic factors including thrombospondin-1 (TBS1) and plasminogen activator inhibitor-1 (PAI-1) did increase in old ADSC, but could be reduced by hypoxic stimulation. Endostatin (ENDS) was the highest in aged ADSC and was also down-regulated by hypoxia. We noted higher gene expression of proteases system factors like urokinase-type plasminogen activator receptor (uPAR), matrix metalloproteinases (MMP2 and MMP9) and PAI-1 in aged ADSC compared to young ADSC, but they decreased in old ADSC. Tube formation on matrigel was higher in the presence of conditioned medium from young ADSC in comparison to aged ADSC. CONCLUSIONS: ADSC isolated from older animals show changes, including impaired proliferation and angiogenic stimulation. Angiogenic gene expression can be partially be improved by hypoxic preconditioning, however the effect is age-dependent. This supports the hypothesis that autologous ADSC from aged subjects might have an impaired therapeutic potential. PMID- 21244680 TI - Myocardium-derived conditioned medium improves left ventricular function in rodent acute myocardial infarction. AB - BACKGROUND: We investigated whether myocardium-derived conditioned medium (MDCM) is effective in preserving left ventricular (LV) function in a rat acute myocardial infarction (AMI) model. METHODS: Adult male Sprague-Dawley (SD) rats (n = 36) randomized to receive either left coronary artery ligation (AMI induction) or thoracotomy only (sham procedure) were grouped as follows (n = 6 per group): Group I, II, and III were sham-controls treated by fresh medium, normal rat MDCM, and infarct-related MDCM, respectively. Group IV, V, and VI were AMI rats treated by fresh medium, normal MDCM, and infarct-related MDCM, respectively. Either 75 MUL MDCM or fresh medium was administered into infarct myocardium, followed by intravenous injection (3 mL) at postoperative 1, 12, and 24 h. RESULTS: In vitro studies showed higher phosphorylated MMP-2 and MMP-9, but lower alpha-smooth muscle actin and collagen expressions in neonatal cardiac fibroblasts treated with MDCM compared with those in the cardiac fibroblasts treated with fresh medium (all p < 0.05). Sirius-red staining showed larger collagen deposition area in LV myocardium in Group IV than in other groups (all p < 0.05). Stromal cell-derived factor-1alpha and CXCR4 protein expressions were higher in Group VI than in other groups (all p < 0.05). The number of von Willebrand factor- and BrdU-positive cells and small vessels in LV myocardium as well as 90-day LV ejection fraction were higher, whereas oxidative stress was lower in Group VI than in Group IV and Group V (all p < 0.05). CONCLUSION: MDCM therapy reduced cardiac fibrosis and oxidative stress, enhanced angiogenesis, and preserved 90-day LV function in a rat AMI model. PMID- 21244681 TI - Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma. AB - BACKGROUND: Allergic rhinitis (AR) affects up to 80% of children with asthma and increases asthma severity. Thymic stromal lymphopoietin (TSLP) is a key mediator of allergic inflammation. The role of the TSLP gene (TSLP) in the pathogenesis of AR has not been studied. OBJECTIVE: To test for associations between variants in TSLP, TSLP-related genes, and AR in children with asthma. METHODS: We genotyped 15 single nucleotide polymorphisms (SNPs) in TSLP, OX40L, IL7R, and RXRalpha in three independent cohorts: 592 asthmatic Costa Rican children and their parents, 422 nuclear families of North American children with asthma, and 239 Swedish children with asthma. We tested for associations between these SNPs and AR. As we previously reported sex-specific effects for TSLP, we performed overall and sex stratified analyses. We additionally performed secondary analyses for gene-by gene interactions. RESULTS: Across the three cohorts, the T allele of TSLP SNP rs1837253 was undertransmitted in boys with AR and asthma as compared to boys with asthma alone. The SNP was associated with reduced odds for AR (odds ratios ranging from 0.56 to 0.63, with corresponding Fisher's combined P value of 1.2 * 10-4). Our findings were significant after accounting for multiple comparisons. SNPs in OX40L, IL7R, and RXRalpha were not consistently associated with AR in children with asthma. There were nominally significant interactions between gene pairs. CONCLUSIONS: TSLP SNP rs1837253 is associated with reduced odds for AR in boys with asthma. Our findings support a role for TSLP in the pathogenesis of AR in children with asthma. PMID- 21244682 TI - An integrative pharmacological approach to radio telemetry and blood sampling in pharmaceutical drug discovery and safety assessment. AB - BACKGROUND: A successful integration of the automated blood sampling (ABS) and telemetry (ABST) system is described. The new ABST system facilitates concomitant collection of physiological variables with blood and urine samples for determination of drug concentrations and other biochemical measures in the same rat without handling artifact. METHOD: Integration was achieved by designing a 13 inch circular receiving antenna that operates as a plug-in replacement for the existing pair of DSI's orthogonal antennas which is compatible with the rotating cage and open floor design of the BASi Culex(r) ABS system. The circular receiving antenna's electrical configuration consists of a pair of electrically orthogonal half-toroids that reinforce reception of a dipole transmitter operating within the coil's interior while reducing both external noise pickup and interference from other adjacent dipole transmitters. RESULTS: For validation, measured baclofen concentration (ABST vs. satellite (MUM): 69.6 +/- 23.8 vs. 76.6 +/- 19.5, p = NS) and mean arterial pressure (ABST vs. traditional DSI telemetry (mm Hg): 150 +/- 5 vs.147 +/- 4, p = NS) variables were quantitatively and qualitatively similar between rats housed in the ABST system and traditional home cage approaches. CONCLUSION: The ABST system offers unique advantages over traditional between-group study paradigms that include improved data quality and significantly reduced animal use. The superior within-group model facilitates assessment of multiple physiological and biochemical responses to test compounds in the same animal. The ABST also provides opportunities to evaluate temporal relations between parameters and to investigate anomalous outlier events because drug concentrations, physiological and biochemical measures for each animal are available for comparisons. PMID- 21244683 TI - Clinical and demographic features of pediatric burns in the eastern provinces of Turkey. AB - BACKGROUND: The aim of this study is to perform a retrospective analysis of the causes of burns observed in children in the eastern provinces of Turkey. METHOD: In this study, patients were studied retrospectively with regard to their age, sex, cause of burns, seasonal variations, social and economic factors, length of hospital stay, burned body surface area, medical history, site of injury, and mortality. RESULTS: A total of 125 patients undergoing inpatient treatment were male, (53.2%) and 110 were female (46.8%). The most common causes of burns in patients treated on an inpatient basis were scald burns (65.5%) and tandir burns (15.7%). The mean total body surface area of all the patients was 12.17+9.86%. When the patients were grouped according to tandir, cauldron, and other burn causes, a significant difference was seen between the in burn percentages caused by tandir and cauldron burns and other causes (p < 0.001). Higher burn percentages were seen for cauldron burns than for tandir burns (p < 0.05). The average length of hospital stay was 17.67+13.64 days. When the patients were grouped according to burn causes (tandir, cauldron, and others), a significant difference was determined between the hospitalization periods of patients with tandir burns and other burn causes (p = 0.001) The most commonly proliferating microorganism in burned areas was Pseudomonas aeruginosa (20.4%). Of the 235 patients, 61 were treated in operating rooms. During the 24-month period of the study, 2 of the 235 patients died (0.85%). CONCLUSION: Pediatric burns in the eastern part of Turkey are different from those in other parts of Turkey, as well as in other countries. Due to the lifestyle of the region, tandir and cauldron burns, which cause extensive burn areas and high morbidity, are frequently seen in children. Therefore, precautions and educational programs related to the use of tandirs and cauldrons are needed in this region. PMID- 21244684 TI - Monitoring community pharmacist's quality of care: a feasibility study of using pharmacy claims data to assess performance. AB - BACKGROUND: Public pressure has increasingly emphasized the need to ensure the continuing quality of care provided by health professionals over their careers. Health profession's regulatory authorities, mandated to be publicly accountable for safe and effective care, are revising their quality assurance programs to focus on regular evaluations of practitioner performance. New methods for routine screening of performance are required and the use of administrative data for measuring performance on quality of care indicators has been suggested as one attractive option. Preliminary studies have shown that community pharmacy claims databases contain the information required to operationalize quality of care indicators. The purpose of this project was to determine the feasibility of routine use of information from these databases by regulatory authorities to screen the quality of care provided at community pharmacies. METHODS: Information from the Canadian province of Quebec's medication insurance program provided data on prescriptions dispensed in 2002 by more than 5000 pharmacists in 1799 community pharmacies. Pharmacy-specific performance rates were calculated on four quality of care indicators: two safety indicators (dispensing of contra-indicated benzodiazepines to seniors and dispensing of nonselective beta-blockers to patients with respiratory disease) and two effectiveness indicators (dispensing asthma or hypertension medications to non-compliant patients). Descriptive statistics were used to summarize performance. RESULTS: Reliable estimates of performance could be obtained for more than 90% of pharmacies. The average rate of dispensing was 4.3% (range 0 - 42.5%) for contra-indicated benzodiazepines, 15.2% (range 0 - 100%) for nonselective beta-blockers to respiratory patients, 10.7% (range 0 - 70%) for hypertension medications to noncompliant patients, and 43.3% (0 - 91.6%) for short-acting beta-agonists in over-use situations. There were modest correlations in performance across the four indicators. Nine pharmacies (0.5%) performed in the lowest quartile in all four of the indicators, and 5.3% (n = 95) performed in the lowest quartile on three of four indicators. CONCLUSIONS: Routinely collected pharmacy claims data can be used to monitor indicators of the quality of care provided in community pharmacies, and may be useful in future to identify underperforming pharmacists, measure the impact of policy changes and determine predictors of best practices. PMID- 21244685 TI - High levels of circulating leukocyte microparticles are associated with better outcome in acute respiratory distress syndrome. AB - INTRODUCTION: The current study has addressed the presence and the cellular origin of microparticles (MP) isolated from bronchoalveolar lavage (BAL) fluid and from blood samples from patients with acute respiratory distress syndrome (ARDS). Their prognostic interest was also investigated. METHODS: Fifty-two patients were included within the first 24 hours of ARDS. They were compared to spontaneous breathing (SB) and ventilated control (VC) groups. Bronchoalveolar lavage (BAL) and blood samples were obtained on Day 1 and Day 3 in an ARDS group. Leukocyte microparticles (LeuMP), neutrophil microparticles (NeuMP), endothelial microparticles (EMP), and platelet microparticles (PMP) were measured in arterial blood and in BAL samples by flow cytometry. Mortality from all causes was recorded at Day 28. RESULTS: All MP subpopulations were detected in BAL. However, only LeuMP and NeuMP were elevated in ARDS patients compared to the SB group (P = 0.002 for both). Among ARDS patients, higher levels of LeuMP were detected in blood (Day 1) and in BAL (Day 3) in survivors as compared with the non survivors. Circulating LeuMP >60 elements/microliter detectable on Day 1 of ARDS, was associated with a higher survival rate (odds ratio, 5.26; 95% confidence interval, 1.10 to 24.99; P = 0.037). CONCLUSIONS: The identification of the cellular origin of microparticles at the onset of ARDS has identified LeuMP as a biomarker of prognostic significance. The higher levels of LeuMP in survivors could be associated with a protective role of this MP subpopulation. This hypothesis needs further investigations. PMID- 21244686 TI - KCNE1 D85N polymorphism--a sex-specific modifier in type 1 long QT syndrome? AB - BACKGROUND: Long QT syndrome (LQTS) is an inherited ion channel disorder manifesting with prolongation of the cardiac repolarization phase and severe ventricular arrhythmias. The common KCNE1 D85N potassium channel variant prolongs QT interval by inhibiting IKs (KCNQ1) and IKr (KCNH2) currents and is therefore a suitable candidate for a modifier gene in LQTS. METHODS: We studied the effect of D85N on age-, sex-, and heart rate-adjusted QT-interval duration by linear regression in LQTS patients carrying the Finnish founder mutations KCNQ1 G589D (n = 492), KCNQ1 IVS7-2A>G (n = 66), KCNH2 L552S (n = 73), and KCNH2 R176W (n = 88). We also investigated the association between D85N and clinical variables reflecting the severity of the disease. RESULTS: D85N was associated with a QT prolongation by 26 ms (SE 8.6, p = 0.003) in males with KCNQ1 G589D (n = 213), but not in females with G589D (n = 279). In linear regression, the interaction between D85N genotype and sex was significant (p = 0.028). Within the KCNQ1 G589D mutation group, KCNE1 D85N carriers were more often probands of the family (p = 0.042) and were more likely to use beta blocker medication (p = 0.010) than non carriers. The number of D85N carriers in other founder mutation groups was too small to assess its effects. CONCLUSIONS: We propose that KCNE1 D85N is a sex specific QT-interval modifier in type 1 LQTS and may also associate with increased severity of disease. Our data warrant additional studies on the role of KCNE1 D85N in other genetically homogeneous groups of LQTS patients. PMID- 21244687 TI - Comparative nucleic acid transfection efficacy in primary hepatocytes for gene silencing and functional studies. AB - BACKGROUND: Primary hepatocytes are the best resource for in vitro studies directed at understanding hepatic processes at the cellular and molecular levels, necessary for novel drug development to treat highly prevalent diseases such as non-alcoholic steatohepatitis, cardiovascular disease and type 2 diabetes. There is a need to identify simple methods to genetically manipulate primary hepatocytes and conduct functional studies with plasmids, small interfering RNA (siRNA) or microRNA (miRNA). New lipofection reagents are available that have the potential to yield higher levels of transfection with reduced toxicity. FINDINGS: We have tested several liposome-based transfection reagents used in molecular biology research. We show that transfection efficiency with one of the most recently developed formulations, Metafectene Pro, is high with plasmid DNA (>45% cells) as well as double stranded RNA (>90% with siRNA or microRNA). In addition, negligible cytotoxicity was present with all of these nucleic acids, even if cells were incubated with the DNA:lipid complex for 16 hours. To provide the proof of concept that these conditions can be used not only for overexpression of a gene of interest, but also in RNA interference applications, we targeted two liver expressed genes, Sterol Regulatory Element-Binding Protein-1 and Fatty Acid Binding Protein 5 using plasmid-mediated short hairpin RNA expression. In addition, similar transfection conditions were used to optimally deliver siRNA and microRNA. CONCLUSIONS: We have identified a lipid-based reagent for primary hepatocyte transfection of nucleic acids currently used in molecular biology laboratories. The conditions described here can be used to expedite a large variety of research applications, from gene function studies to microRNA target identification. PMID- 21244688 TI - Socio-economic status, racial composition and the affordability of fresh fruits and vegetables in neighborhoods of a large rural region in Texas. AB - BACKGROUND: Little is known about how affordability of healthy food varies with community characteristics in rural settings. We examined how the cost of fresh fruit and vegetables varies with the economic and demographic characteristics in six rural counties of Texas. METHODS: Ground-truthed data from the Brazos Valley Food Environment Project were used to identify all food stores in the rural region and the availability and lowest price of fresh whole fruit and vegetables in the food stores. Socioeconomic characteristics were extracted from the 2000 U.S. Census Summary Files 3 at the level of the census block group. We used an imputation strategy to calculate two types of price indices for both fresh fruit and fresh vegetables: a high variety and a basic index; and evaluated the relationship between neighborhood economic and demographic characteristics and affordability of fresh produce, using linear regression models. RESULTS: The mean cost of meeting the USDA recommendation of fruit consumption from a high variety basket of fruit types in our sample of stores was just over $27.50 per week. Relying on the three most common fruits lowered the weekly expense to under $17.25 per week, a reduction of 37.6%. The effect of moving from a high variety to a low variety basket was much less when considering vegetable consumption: a 4.3% decline from $29.23 to $27.97 per week. Univariate regression analysis revealed that the cost of fresh produce is not associated with the racial/ethnic composition of the local community. However, multivariate regression showed that holding median income constant, stores in neighborhoods with higher percentages of Black residents paid more for fresh fruits and vegetables. The proportion of Hispanic residents was not associated with cost in either the univariate or multivariate analysis. CONCLUSION: This study extends prior work by examining the affordability of fresh fruit and vegetables from food stores in a large rural area; and how access to an affordable supply of fresh fruit and vegetables differs by neighborhood inequalities. The approach and findings of this study are relevant and have important research and policy implications for understanding access and availability of affordable, healthy foods. PMID- 21244689 TI - Next-generation sequencing for HLA typing of class I loci. AB - BACKGROUND: Comprehensive sequence characterization across the MHC is important for successful organ transplantation and genetic association studies. To this end, we have developed an automated sample preparation, molecular barcoding and multiplexing protocol for the amplification and sequence-determination of class I HLA loci. We have coupled this process to a novel HLA calling algorithm to determine the most likely pair of alleles at each locus. RESULTS: We have benchmarked our protocol with 270 HapMap individuals from four worldwide populations with 96.4% accuracy at 4-digit resolution. A variation of this initial protocol, more suitable for large sample sizes, in which molecular barcodes are added during PCR rather than library construction, was tested on 95 HapMap individuals with 98.6% accuracy at 4-digit resolution. CONCLUSIONS: Next generation sequencing on the 454 FLX Titanium platform is a reliable, efficient, and scalable technology for HLA typing. PMID- 21244690 TI - Phase IIb randomized trial of adjunct immunotherapy in patients with first diagnosed tuberculosis, relapsed and multi-drug-resistant (MDR) TB. AB - Placebo-controlled, randomized, phase 2b trial was conducted in 34 adults comprising 18 first-diagnosed (52.9%), 6 relapsed (17.6%), and 10 MDR-TB (29.4%) cases to investigate the safety and efficacy of an oral immune adjunct (V5). The immunotherapy (N = 24) and placebo (N = 10) arms received once-daily tablet of V5 or placebo for one month in addition to conventional anti-TB therapy (ATT) administered under directly observed therapy (DOT).The enlarged liver, total bilirubin, erythrocyte sedimentation rate, lymphocyte and leukocyte counts improved significantly in V5 recipients (P = 0.002; 0.03; 8.3E-007; 2.8E-005; and 0.002) but remained statistically unchanged in the placebo group (P = 0.68; 0.96; 0.61; 0.91; and 0.43 respectively). The changes in hemoglobin and ALT levels in both treatment arms were not significant. The body weight increased in all V5 treated patients by an average 3.5 +/- 1.8 kg (P = 2.3E-009), while 6 out of 10 patients on placebo gained mean 0.9 +/- 0.9 kg (P = 0.01). Mycobacterial clearance in sputum smears was observed in 78.3% and 0% of patients on V5 and placebo (P = 0.009). The conversion rate in V5-receiving subjects with MDR-TB (87.5%) seemed to be higher than in first-diagnosed TB (61.5%) but the difference was not significant (P = 0.62). Scoring of sputum bacillary load (range 3-0) at baseline and post-treatment revealed score reduction in 23 out of 24 (95.8%) V5 recipients (from mean/median 2.2/3 to 0.3/0; P = 6E-010) but only in 1 out of 10 (10%) patients on placebo (1.9/1.5 vs. 1.8/1; P = 0.34). No adverse effects or TB reactivation were seen at any time during follow-up. V5 is safe as an immune adjunct to chemotherapeutic management of TB and can shorten substantially the duration of treatment. PMID- 21244691 TI - Cannabidiol reduces lipopolysaccharide-induced vascular changes and inflammation in the mouse brain: an intravital microscopy study. AB - BACKGROUND: The phytocannabinoid cannabidiol (CBD) exhibits antioxidant and antiinflammatory properties. The present study was designed to explore its effects in a mouse model of sepsis-related encephalitis by intravenous administration of lipopolysaccharide (LPS). METHODS: Vascular responses of pial vessels were analyzed by intravital microscopy and inflammatory parameters measured by qRT-PCR. RESULTS: CBD prevented LPS-induced arteriolar and venular vasodilation as well as leukocyte margination. In addition, CBD abolished LPS induced increases in tumor necrosis factor-alpha and cyclooxygenase-2 expression as measured by quantitative real time PCR. The expression of the inducible-nitric oxide synthase was also reduced by CBD. Finally, preservation of Blood Brain Barrier integrity was also associated to the treatment with CBD. CONCLUSIONS: These data highlight the antiinflammatory and vascular-stabilizing effects of CBD in endotoxic shock and suggest a possible beneficial effect of this natural cannabinoid. PMID- 21244692 TI - Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case control mutation-screening study. AB - INTRODUCTION: Both protein-truncating variants and some missense substitutions in CHEK2 confer increased risk of breast cancer. However, no large-scale study has used full open reading frame mutation screening to assess the contribution of rare missense substitutions in CHEK2 to breast cancer risk. This absence has been due in part to a lack of validated statistical methods for summarizing risk attributable to large numbers of individually rare missense substitutions. METHODS: Previously, we adapted an in silico assessment of missense substitutions used for analysis of unclassified missense substitutions in BRCA1 and BRCA2 to the problem of assessing candidate genes using rare missense substitution data observed in case-control mutation-screening studies. The method involves stratifying rare missense substitutions observed in cases and/or controls into a series of grades ordered a priori from least to most likely to be evolutionarily deleterious, followed by a logistic regression test for trends to compare the frequency distributions of the graded missense substitutions in cases versus controls. Here we used this approach to analyze CHEK2 mutation-screening data from a population-based series of 1,303 female breast cancer patients and 1,109 unaffected female controls. RESULTS: We found evidence of risk associated with rare, evolutionarily unlikely CHEK2 missense substitutions. Additional findings were that (1) the risk estimate for the most severe grade of CHEK2 missense substitutions (denoted C65) is approximately equivalent to that of CHEK2 protein truncating variants; (2) the population attributable fraction and the familial relative risk explained by the pool of rare missense substitutions were similar to those explained by the pool of protein-truncating variants; and (3) post hoc power calculations implied that scaling up case-control mutation screening to examine entire biochemical pathways would require roughly 2,000 cases and controls to achieve acceptable statistical power. CONCLUSIONS: This study shows that CHEK2 harbors many rare sequence variants that confer increased risk of breast cancer and that a substantial proportion of these are missense substitutions. The study validates our analytic approach to rare missense substitutions and provides a method to combine data from protein-truncating variants and rare missense substitutions into a one degree of freedom per gene test. PMID- 21244693 TI - Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 or oral metronomic chemotherapy. AB - BACKGROUND: The treatment of high-risk neuroblastoma patients consists of multimodal induction therapy to achieve remission followed by consolidation therapy to prevent relapses. However, the type of consolidation therapy is still discussed controversial. We applied metronomic chemotherapy in the prospective NB90 trial and monoclonal anti-GD2-antibody (MAB) ch14.18 in the NB97 trial. Here, we present the long term outcome data of the patient cohort. METHODS: A total of 334 stage 4 neuroblastoma patients one year or older were included. All patients successfully completed the induction therapy. In the NB90 trial, 99 patients received at least one cycle of the oral maintenance chemotherapy (NB90 MT, 12 alternating cycles of oral melphalan/etoposide and vincristine/cyclophosphamide). In the NB97 trial, 166 patients commenced the MAB ch14.18 consolidation therapy (six cycles over 12 months). Patients who received no maintenance therapy according to the NB90 protocol or by refusal in NB97 (n = 69) served as controls. RESULTS: The median observation time was 11.11 years. The nine-year event-free survival rates were 41 +/- 4%, 31 +/- 5%, and 32 +/- 6% for MAB ch14.18, NB90 MT, and no consolidation, respectively (p = 0.098). In contrast to earlier reports, MAB ch14.18 treatment improved the long-term outcome compared to no additional therapy (p = 0.038). The overall survival was better in the MAB ch14.18-treated group (9-y-OS 46 +/- 4%) compared to NB90 MT (34 +/- 5%, p = 0.026) and to no consolidation (35 +/- 6%, p = 0.019). Multivariable Cox regression analysis revealed ch14.18 consolidation to improve outcome compared to no consolidation, however, no difference between NB90 MT and MAB ch14.18-treated patients was found. CONCLUSIONS: Follow-up analysis of the patient cohort indicated that immunotherapy with MAB ch14.18 may prevent late relapses. Finally, metronomic oral maintenance chemotherapy also appeared effective. PMID- 21244694 TI - Fraternal twins: Swiprosin-1/EFhd2 and Swiprosin-2/EFhd1, two homologous EF-hand containing calcium binding adaptor proteins with distinct functions. AB - Changes in the intracellular calcium concentration govern cytoskeletal rearrangement, mitosis, apoptosis, transcriptional regulation or synaptic transmission, thereby, regulating cellular effector and organ functions. Calcium binding proteins respond to changes in the intracellular calcium concentration with structural changes, triggering enzymatic activation and association with downstream proteins. One type of calcium binding proteins are EF-hand super family proteins. Here, we describe two recently discovered homologous EF-hand containing adaptor proteins, Swiprosin-1/EF-hand domain containing 2 (EFhd2) and Swiprosin-2/EF-hand domain containing 1 (EFhd1), which are related to allograft inflammatory factor-1 (AIF-1). For reasons of simplicity and concision we propose to name Swiprosin-1/EFhd2 and Swiprosin-2/EFhd1 from now on EFhd2 and EFhd1, according to their respective gene symbols. AIF-1 and Swiprosin-1/EFhd2 are already present in Bilateria, for instance in Drosophila melanogaster and Caenhorhabditis elegans. Swiprosin-2/EFhd1 arose later from gene duplication in the tetrapodal lineage. Secondary structure prediction of AIF-1 reveals disordered regions and one functional EF-hand. Swiprosin-1/EFhd2 and Swiprosin 2/EFhd1 exhibit a disordered region at the N-terminus, followed by two EF-hands and a coiled-coil domain. Whereas both proteins are similar in their predicted overall structure they differ in a non-homologous stretch of 60 amino acids just in front of the EF-hands. AIF-1 controls calcium-dependent cytoskeletal rearrangement in innate immune cells by means of its functional EF-hand. We propose that Swiprosin-1/EFhd2 as well is a cytoskeleton associated adaptor protein involved in immune and brain cell function. Pro-inflammatory conditions are likely to modulate expression and function of Swiprosin-1/EFhd2. Swiprosin 2/EFhd1, on the other hand, modulates apoptosis and differentiation of neuronal and muscle precursor cells, probably through an association with mitochondria. We suggest furthermore that Swiprosin-2/EFhd1 is part of a cellular response to oxidative stress, which could explain its pro-survival activity in neuronal, muscle and perhaps some malignant tissues. PMID- 21244695 TI - Brain metastases from solid tumors: disease outcome according to type of treatment and therapeutic resources of the treating center. AB - BACKGROUND: To evaluate the therapeutic strategies commonly employed in the clinic for the management of brain metastases (BMs) and to correlate disease outcome with type of treatment and therapeutic resources available at the treating center. METHODS: Four Cancer centres participated to the survey. Data were collected through a questionnaire filled in by one physician for each centre. RESULTS: Clinical data regarding 290 cancer patients with BMs from solid tumors were collected. Median age was 59 and 59% of patients had <= 3 brain metastases. A local approach (surgery and stereotactic radiosurgery) was adopted in 31% of patients. The local approach demonstrated to be superior in terms of survival compared to the regional/systemic approach (whole brain radiotherapy and chemotherapy, p = <.0001 for survival at 2 years). In the multivariate analysis local treatment was an independent prognostic factor for survival. When patients were divided into 2 groups whether they were treated in centers where local approaches were available or not (group A vs group B respectively, 58% of patients with <= 3 BMs in both cohorts), more patients in group A received local strategies although no difference in time to brain progression at 1 year was observed between the two groups of patients. CONCLUSIONS: In clinical practice, local strategies should be integrated in the management of brain metastases. Proper selection of patients who are candidate to local treatments is of crucial importance. PMID- 21244696 TI - Challenges to diagnose metaplastic carcinoma of the breast through cytologic methods: an eight-case series. AB - Because metaplastic carcinoma of the breast encompasses a great variety of histopathology, diagnostic challenges abound, especially within the realm of cytology. The authors compiled and studied an eight-case series comprised of metaplastic breast carcinomas and lesions initially suspicious cytologically for metaplastic carcinoma in order to assess the degree of cytologic-histologic correlation and to identify recurring problematic themes surrounding the cytology based diagnosis of this neoplasm. The cytologic and histologic slides from eight cases suspicious for metaplastic breast carcinoma diagnosed by fine needle aspiration (FNA) were collected and analyzed through a seven-year retrospective search of case files at our institution. Based on cytologic characteristics, the cases were separated into three groups. Group 1 consisted of three cases presenting with poorly differentiated adenocarcinoma and squamoid components on FNA. Group 2 was composed of two cases that featured a monophasic, malignant ductal cell population on cytology, while the cytologic specimens for the third group of cases presented with a mesenchymal component with or without a malignant glandular constituent. Cytologic-histologic correlation was present in two of three cases demonstrating a mesenchymal component, and there was 100% sensitivity in the cytologic detection of those mesenchymal elements. However, in only one of three cases was there an accurate cytologic diagnosis of metaplastic carcinoma when squamoid changes were present on FNA. Both cases demonstrating only malignant glandular elements on cytologic specimens revealed an additional component of malignant squamous differentiation upon the examination of mastectomy-derived tissue.These results indicate that squamous-like changes identified on FNA should be interpreted with caution and that sampling error remains a problematic recurrence in cytology. Regardless, there appears to be promise concerning the accurate cytologic diagnosis of metaplastic carcinoma when the lesion is characterized by a mesenchymal component. A study implementing a larger case number is essential in determining the significance of these findings. PMID- 21244697 TI - Prevalent de novo somatic mutations in superantigen genes of mouse mammary tumor viruses in the genome of C57BL/6J mice and its potential implication in the immune system. AB - BACKGROUND: Superantigens (SAgs) of mouse mammary tumor viruses (MMTVs) play a crucial role in T cell selection in the thymus in a T cell receptor (TCR) Vbeta specific manner and SAgs presented by B cells activate T cells in the periphery. The peripheral T cell repertoire is dynamically shaped by the steady induction of T cell tolerance against self antigens throughout the lifespan. We hypothesize that de novo somatic mutation of endogenous MMTV SAgs contributes to the modulation of the peripheral T cell repertoire. RESULTS: SAg coding sequences were cloned from the genomic DNAs and/or cDNAs of various tissues of female C57BL/6J mice. A total of 68 unique SAg sequences (54 translated sequences) were identified from the genomic DNAs of liver, lungs, and bone marrow, which are presumed to harbor only three endogenous MMTV loci (Mtv-8, Mtv-9, and Mtv-17). Similarly, 69 unique SAg sequences (58 translated sequences) were cloned from the cDNAs of 18 different tissues. Examination of putative TCR Vbeta specificity suggested that some of the SAg isoforms identified in this study have Vbeta specificities different from the reference SAgs of Mtv-8, Mtv-9, or Mtv-17. CONCLUSION: The pool of diverse SAg isoforms, generated by de novo somatic mutation, may play a role in the shaping of the peripheral T cell repertoire including the autoimmune T cell population. PMID- 21244699 TI - A role for pancreatic beta-cell secretory hyperresponsiveness in catch-up growth hyperinsulinemia: Relevance to thrifty catch-up fat phenotype and risks for type 2 diabetes. AB - Current notions about mechanisms by which catch-up growth predisposes to later type 2 diabetes center upon those that link hyperinsulinemia with an accelerated rate of fat deposition (catch-up fat). Using a rat model of semistarvation refeeding in which catch-up fat is driven solely by elevated metabolic efficiency associated with hyperinsulinemia, we previously reported that insulin-stimulated glucose utilization is diminished in skeletal muscle but increased in white adipose tissue. Here, we investigated the possibility that hyperinsulinemia during catch-up fat can be contributed by changes in the secretory response of pancreatic beta-cells to glucose. Using the rat model of semistarvation-refeeding showing catch-up fat and hyperinsulinemia, we compared isocalorically refed and control groups for potential differences in pancreatic morphology and in glucose stimulated insulin secretion during in situ pancreas perfusions as well as ex vivo isolated islet perifusions. Between refed and control animals, no differences were found in islet morphology, insulin content, and the secretory responses of perifused isolated islets upon glucose stimulation. By contrast, the rates of insulin secretion from in situ perfused pancreas showed that raising glucose from 2.8 to 16.7 mmol/l produced a much more pronounced increase in insulin release in refed than in control groups (p < 0.01). These results indicate a role for islet secretory hyperresponsiveness to glucose in the thrifty mechanisms that drive catch-up fat through glucose redistribution between skeletal muscle and adipose tissue. Such beta-cell hyperresponsiveness to glucose may be a key event in the link between catch-up growth, hyperinsulinemia and risks for later type 2 diabetes. PMID- 21244700 TI - An unexpected case of venous and pulmonary thrombo-embolism in a patient treated with thalidomide for refractory erythema nodosum leprosum: a case report. AB - Recent literature reports an increased incidence of venous thrombosis following thalidomide use in the treatment of diseases with disease-related thrombotic risks such as malignancy, as well as concomitant use with chemotherapy and/or systemic corticosteroids. We report a case of deep vein thrombosis (DVT) and pulmonary embolism (PE) following thalidomide use in a patient with erythema nodosum leprosum (ENL) reaction who was concurrently treated with prednisolone, as well as a review of relevant literature. PMID- 21244698 TI - Protocol for a randomized controlled study of Iyengar yoga for youth with irritable bowel syndrome. AB - INTRODUCTION: Irritable bowel syndrome affects as many as 14% of high school-aged students. Symptoms include discomfort in the abdomen, along with diarrhea and/or constipation and other gastroenterological symptoms that can significantly impact quality of life and daily functioning. Emotional stress appears to exacerbate irritable bowel syndrome symptoms suggesting that mind-body interventions reducing arousal may prove beneficial. For many sufferers, symptoms can be traced to childhood and adolescence, making the early manifestation of irritable bowel syndrome important to understand. The current study will focus on young people aged 14-26 years with irritable bowel syndrome. The study will test the potential benefits of Iyengar yoga on clinical symptoms, psychospiritual functioning and visceral sensitivity. Yoga is thought to bring physical, psychological and spiritual benefits to practitioners and has been associated with reduced stress and pain. Through its focus on restoration and use of props, Iyengar yoga is especially designed to decrease arousal and promote psychospiritual resources in physically compromised individuals. An extensive and standardized teacher training program support Iyengar yoga's reliability and safety. It is hypothesized that yoga will be feasible with less than 20% attrition; and the yoga group will demonstrate significantly improved outcomes compared to controls, with physiological and psychospiritual mechanisms contributing to improvements. METHODS/DESIGN: Sixty irritable bowel syndrome patients aged 14-26 will be randomly assigned to a standardized 6-week twice weekly Iyengar yoga group-based program or a wait-list usual care control group. The groups will be compared on the primary clinical outcomes of irritable bowel syndrome symptoms, quality of life and global improvement at post-treatment and 2-month follow-up. Secondary outcomes will include visceral pain sensitivity assessed with a standardized laboratory task (water load task), functional disability and psychospiritual variables including catastrophizing, self-efficacy, mood, acceptance and mindfulness. Mechanisms of action involved in the proposed beneficial effects of yoga upon clinical outcomes will be explored, and include the mediating effects of visceral sensitivity, increased psychospiritual resources, regulated autonomic nervous system responses and regulated hormonal stress response assessed via salivary cortisol. TRIAL REGISTRATION: ClinicalTrials.gov NCT01107977. PMID- 21244701 TI - Long-term CD4+ lymphocyte response following HAART initiation in a U.S. Military prospective cohort. AB - BACKGROUND: Among HIV-infected persons initiating highly active antiretroviral therapy (HAART), early CD4+ lymphocyte count increases are well described. However, whether CD4+ levels continue to increase or plateau after 4-6 years is controversial. METHODS: To address this question and identify other determinants of CD4+ response, we analyzed data for 1,846 persons from a prospective HIV military cohort study who initiated HAART, who had post-HAART CD4+ measurements, and for whom HIV seroconversion (SC) date was estimated. RESULTS: CD4+ count at HAART initiation was <= 200 cells/mm3 for 23%, 201-349 for 31%, 350-499 for 27%, and >=500 for 19%. The first 6 months post-HAART, the greatest CD4+ increases (93 151 cells) occurred, with lesser increases (22-36 cells/year) through the first four years. Although CD4+ changes for the entire cohort were relatively flat thereafter, HIV viral load (VL) suppressors showed continued increases of 12-16 cells/year. In multivariate analysis adjusting for baseline CD4+ and post-HAART time interval, CD4+ responses were poorer in those with: longer time from HIV SC to HAART start, lower pre-HAART CD4+ nadir, higher pre-HAART VL, and clinical AIDS before HAART (P < 0.05). CONCLUSIONS: Small but positive long-term increases in CD4+ count in virally suppressed patients were observed. CD4+ response to HAART is influenced by multiple factors including duration of preceding HIV infection, and optimized if treatment is started with virally suppressive therapy as early as possible. PMID- 21244702 TI - High-fat diet and glucocorticoid treatment cause hyperglycemia associated with adiponectin receptor alterations. AB - BACKGROUND: Adiponectin is the most abundant plasma protein synthesized for the most part in adipose tissue, and it is an insulin-sensitive hormone, playing a central role in glucose and lipid metabolism. In addition, it increases fatty acid oxidation in the muscle and potentiates insulin inhibition of hepatic gluconeogenesis. Two adiponectin receptors have been identified: AdipoR1 is the major receptor expressed in skeletal muscle, whereas AdipoR2 is mainly expressed in liver. Consumption of high levels of dietary fat is thought to be a major factor in the promotion of obesity and insulin resistance. Excessive levels of cortisol are characterized by the symptoms of abdominal obesity, hypertension, glucose intolerance or diabetes and dyslipidemia; of note, all of these features are shared by the condition of insulin resistance. Although it has been shown that glucocorticoids inhibit adiponectin expression in vitro and in vivo, little is known about the regulation of adiponectin receptors. The link between glucocorticoids and insulin resistance may involve the adiponectin receptors and adrenalectomy might play a role not only in regulate expression and secretion of adiponectin, as well regulate the respective receptors in several tissues. RESULTS: Feeding of a high-fat diet increased serum glucose levels and decreased adiponectin and adipoR2 mRNA expression in subcutaneous and retroperitoneal adipose tissues, respectively. Moreover, it increased both adipoR1 and adipoR2 mRNA levels in muscle and adipoR2 protein levels in liver. Adrenalectomy combined with the synthetic glucocorticoid dexamethasone treatment resulted in increased glucose and insulin levels, decreased serum adiponectin levels, reduced adiponectin mRNA in epididymal adipose tissue, reduction of adipoR2 mRNA by 7 fold in muscle and reduced adipoR1 and adipoR2 protein levels in muscle. Adrenalectomy alone increased adiponectin mRNA expression 3-fold in subcutaneous adipose tissue and reduced adipoR2 mRNA expression 2-fold in liver. CONCLUSION: Hyperglycemia as a result of a high-fat diet is associated with an increase in the expression of the adiponectin receptors in muscle. An excess of glucocorticoids, rather than their absence, increase glucose and insulin and decrease adiponectin levels. PMID- 21244703 TI - Modeling the cumulative genetic risk for multiple sclerosis from genome-wide association data. AB - BACKGROUND: Multiple sclerosis (MS) is the most common cause of chronic neurologic disability beginning in early to middle adult life. Results from recent genome-wide association studies (GWAS) have substantially lengthened the list of disease loci and provide convincing evidence supporting a multifactorial and polygenic model of inheritance. Nevertheless, the knowledge of MS genetics remains incomplete, with many risk alleles still to be revealed. METHODS: We used a discovery GWAS dataset (8,844 samples, 2,124 cases and 6,720 controls) and a multi-step logistic regression protocol to identify novel genetic associations. The emerging genetic profile included 350 independent markers and was used to calculate and estimate the cumulative genetic risk in an independent validation dataset (3,606 samples). Analysis of covariance (ANCOVA) was implemented to compare clinical characteristics of individuals with various degrees of genetic risk. Gene ontology and pathway enrichment analysis was done using the DAVID functional annotation tool, the GO Tree Machine, and the Pathway-Express profiling tool. RESULTS: In the discovery dataset, the median cumulative genetic risk (P-Hat) was 0.903 and 0.007 in the case and control groups, respectively, together with 79.9% classification sensitivity and 95.8% specificity. The identified profile shows a significant enrichment of genes involved in the immune response, cell adhesion, cell communication/signaling, nervous system development, and neuronal signaling, including ionotropic glutamate receptors, which have been implicated in the pathological mechanism driving neurodegeneration. In the validation dataset, the median cumulative genetic risk was 0.59 and 0.32 in the case and control groups, respectively, with classification sensitivity 62.3% and specificity 75.9%. No differences in disease progression or T2-lesion volumes were observed among four levels of predicted genetic risk groups (high, medium, low, misclassified). On the other hand, a significant difference (F = 2.75, P = 0.04) was detected for age of disease onset between the affected misclassified as controls (mean = 36 years) and the other three groups (high, 33.5 years; medium, 33.4 years; low, 33.1 years). CONCLUSIONS: The results are consistent with the polygenic model of inheritance. The cumulative genetic risk established using currently available genome-wide association data provides important insights into disease heterogeneity and completeness of current knowledge in MS genetics. PMID- 21244704 TI - Right-sided diaphragmatic rupture after blunt trauma. An unusual entity. AB - Traumatic injuries of the diaphragm remain an entity of difficult diagnosis despite having been recognised early in the history of surgery, especially when it comes to blunt trauma and injuries of the right diaphragm. We report the case of a patient with blunt trauma with right diaphragmatic rupture that required urgent surgical treatment for hepatothorax and iatrogenic severe liver injury. Blunt trauma can cause substantial diaphragmatic rupture. It must have a high index of suspicion for diaphragmatic injury in patients, victims of vehicle collisions, mainly if they have suffered frontal impacts and/or side precipitates in patients with severe thoracoabdominal trauma. The diagnosis can be performed clinically and confirmation should be radiological. The general measures for the management of multiple trauma patients must be applied. Surgery at the time of diagnosis should restore continuity. PMID- 21244705 TI - Relationship between static foot posture and foot mobility. AB - BACKGROUND: It is not uncommon for a person's foot posture and/or mobility to be assessed during a clinical examination. The exact relationship, however, between static posture and mobility is not known. OBJECTIVE: The purpose of this study was to determine the degree of association between static foot posture and mobility. METHOD: The static foot posture and foot mobility of 203 healthy individuals was assessed and then analyzed to determine if low arched or "pronated" feet are more mobile than high arched or "supinated" feet. RESULTS: The study demonstrated that those individuals with a lower standing dorsal arch height and/or a wider standing midfoot width had greater mobility in their foot. In addition, those individuals with higher Foot Posture Index (FPI) values demonstrated greater mobility and those with lower FPI values demonstrated less mobility. Finally, the amount of foot mobility that an individual has can be predicted reasonably well using either a 3 or 4 variable linear regression model. CONCLUSIONS: Because of the relationship between static foot posture and mobility, it is recommended that both be assessed as part of a comprehensive evaluation of a individual with foot problems. PMID- 21244706 TI - Pattern and outcome of chest injuries at Bugando Medical Centre in Northwestern Tanzania. AB - BACKGROUND: Chest injuries constitute a continuing challenge to the trauma or general surgeon practicing in developing countries. This study was conducted to outline the etiological spectrum, injury patterns and short term outcome of these injuries in our setting. PATIENTS AND METHODS: This was a prospective study involving chest injury patients admitted to Bugando Medical Centre over a six month period from November 2009 to April 2010 inclusive. RESULTS: A total of 150 chest injury patients were studied. Males outnumbered females by a ratio of 3.8:1. Their ages ranged from 1 to 80 years (mean = 32.17 years). The majority of patients (72.7%) sustained blunt injuries. Road traffic crush was the most common cause of injuries affecting 50.7% of patients. Chest wall wounds, hemothorax and rib fractures were the most common type of injuries accounting for 30.0%, 21.3% and 20.7% respectively. Associated injuries were noted in 56.0% of patients and head/neck (33.3%) and musculoskeletal regions (26.7%) were commonly affected. The majority of patients (55.3%) were treated successfully with non-operative approach. Underwater seal drainage was performed in 39 patients (19.3%). One patient (0.7%) underwent thoracotomy due to hemopericardium. Thirty nine patients (26.0%) had complications of which wound sepsis (14.7%) and complications of long bone fractures (12.0%) were the most common complications. The mean LOS was 13.17 days and mortality rate was 3.3%. Using multivariate logistic regression analysis, associated injuries, the type of injury, trauma scores (ISS, RTS and PTS) were found to be significant predictors of the LOS (P < 0.001), whereas mortality was significantly associated with pre-morbid illness, associated injuries, trauma scores (ISS, RTS and PTS), the need for ICU admission and the presence of complications (P < 0.001). CONCLUSION: Chest injuries resulting from RTCs remain a major public health problem in this part of Tanzania. Urgent preventive measures targeting at reducing the occurrence of RTCs is necessary to reduce the incidence of chest injuries in this region. PMID- 21244707 TI - Re-expression of ARHI (DIRAS3) induces autophagy in breast cancer cells and enhances the inhibitory effect of paclitaxel. AB - BACKGROUND: ARHI is a Ras-related imprinted gene that inhibits cancer cell growth and motility. ARHI is downregulated in the majority of breast cancers, and loss of its expression is associated with its progression from ductal carcinoma in situ (DCIS) to invasive disease. In ovarian cancer, re-expression of ARHI induces autophagy and leads to autophagic death in cell culture; however, ARHI re expression enables ovarian cancer cells to remain dormant when they are grown in mice as xenografts. The purpose of this study is to examine whether ARHI induces autophagy in breast cancer cells and to evaluate the effects of ARHI gene re expression in combination with paclitaxel. METHODS: Re-expression of ARHI was achieved by transfection, by treatment with trichostatin A (TSA) or by a combination of TSA and 5-aza-2'-deoxycytidine (DAC) in breast cancer cell cultures and by liposomal delivery of ARHI in breast tumor xenografts. RESULTS: ARHI re-expression induces autophagy in breast cancer cells, and ARHI is essential for the induction of autophagy. When ARHI was re-expressed in breast cancer cells treated with paclitaxel, the growth inhibitory effect of paclitaxel was enhanced in both the cell culture and the xenografts. Although paclitaxel alone did not induce autophagy in breast cancer cells, it enhanced ARHI-induced autophagy. Conversely, ARHI re-expression promoted paclitaxel-induced apoptosis and G2/M cell cycle arrest. CONCLUSIONS: ARHI re-expression induces autophagic cell death in breast cancer cells and enhances the inhibitory effects of paclitaxel by promoting autophagy, apoptosis, and G2/M cell cycle arrest. PMID- 21244708 TI - DNA moves sequentially towards the nuclear matrix during DNA replication in vivo. AB - BACKGROUND: In the interphase nucleus of metazoan cells DNA is organized in supercoiled loops anchored to a nuclear matrix (NM). There is varied evidence indicating that DNA replication occurs in replication factories organized upon the NM and that DNA loops may correspond to the actual replicons in vivo. In normal rat liver the hepatocytes are arrested in G0 but they synchronously re enter the cell cycle after partial-hepatectomy leading to liver regeneration in vivo. We have previously determined in quiescent rat hepatocytes that a 162 kbp genomic region containing members of the albumin gene family is organized into five structural DNA loops. RESULTS: In the present work we tracked down the movement relative to the NM of DNA sequences located at different points within such five structural DNA loops during the S phase and after the return to cellular quiescence during liver regeneration. Our results indicate that looped DNA moves sequentially towards the NM during replication and then returns to its original position in newly quiescent cells, once the liver regeneration has been achieved. CONCLUSIONS: Looped DNA moves in a sequential fashion, as if reeled in, towards the NM during DNA replication in vivo thus supporting the notion that the DNA template is pulled progressively towards the replication factories on the NM so as to be replicated. These results provide further evidence that the structural DNA loops correspond to the actual replicons in vivo. PMID- 21244709 TI - Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response. AB - BACKGROUND: 1-{4-[Bis(2-chloroethyl)amino]phenyl}-3-[2-methyl-5-(4-methylacridin 9-ylamino)phenyl]urea (BO-1051) is an N-mustard DNA alkylating agent reported to exhibit antitumor activity. Here we further investigate the effects of this compound on radiation responses of human gliomas, which are notorious for the high resistance to radiotherapy. METHODS: The clonogenic assay was used to determine the IC50 and radiosensitivity of human glioma cell lines (U87MG, U251MG and GBM-3) following BO-1051. DNA histogram and propidium iodide-Annexin V staining were used to determine the cell cycle distribution and the apoptosis, respectively. DNA damage and repair state were determined by gamma-H2AX foci, and mitotic catastrophe was measure using nuclear fragmentation. Xenograft tumors were measured with a caliper, and the survival rate was determined using Kaplan Meier method. RESULTS: BO-1051 inhibited growth of human gliomas in a dose- and time-dependent manner. Using the dosage at IC50, BO-1051 significantly enhanced radiosensitivity to different extents [The sensitizer enhancement ratio was between 1.24 and 1.50 at 10% of survival fraction]. The radiosensitive G2/M population was raised by BO-1051, whereas apoptosis and mitotic catastrophe were not affected. gamma-H2AX foci was greatly increased and sustained by combined BO 1051 and gamma-rays, suggested that DNA damage or repair capacity was impaired during treatment. In vivo studies further demonstrated that BO-1051 enhanced the radiotherapeutic effects on GBM-3-beared xenograft tumors, by which the sensitizer enhancement ratio was 1.97. The survival rate of treated mice was also increased accordingly. CONCLUSIONS: These results indicate that BO-1051 can effectively enhance glioma cell radiosensitivity in vitro and in vivo. It suggests that BO-1051 is a potent radiosensitizer for treating human glioma cells. PMID- 21244710 TI - Tracheostomy and mechanical ventilation weaning in children affected by respiratory virus according to a weaning protocol in a pediatric intensive care unit in Argentina: an observational restrospective trial. AB - We describe difficult weaning after prolonged mechanical ventilation in three tracheostomized children affected by respiratory virus infection. Although the spontaneous breathing trials were successful, the patients failed all extubations. Therefore a tracheostomy was performed and the weaning plan was begun. The strategy for weaning was the decrease of ventilation support combining pressure control ventilation (PCV) with increasing periods of continuous positive airway pressure + pressure support ventilation (CPAP + PSV) and then CPAP + PSV with increasing intervals of T-piece. They presented acute respiratory distress syndrome on admission with high requirements of mechanical ventilation (MV). Intervening factors in the capabilities and loads of the respiratory system were considered and optimized. The average MV time was 69 days and weaning time 31 days.We report satisfactory results within the context of a directed weaning protocol. PMID- 21244711 TI - MMP1 bimodal expression and differential response to inflammatory mediators is linked to promoter polymorphisms. AB - BACKGROUND: Identifying the functional importance of the millions of single nucleotide polymorphisms (SNPs) in the human genome is a difficult challenge. Therefore, a reverse strategy, which identifies functionally important SNPs by virtue of the bimodal abundance across the human population of the SNP-related mRNAs will be useful. Those mRNA transcripts that are expressed at two distinct abundances in proportion to SNP allele frequency may warrant further study. Matrix metalloproteinase 1 (MMP1) is important in both normal development and in numerous pathologies. Although much research has been conducted to investigate the expression of MMP1 in many different cell types and conditions, the regulation of its expression is still not fully understood. RESULTS: In this study, we used a novel but straightforward method based on agglomerative hierarchical clustering to identify bimodally expressed transcripts in human umbilical vein endothelial cell (HUVEC) microarray data from 15 individuals. We found that MMP1 mRNA abundance was bimodally distributed in un-treated HUVECs and showed a bimodal response to inflammatory mediator treatment. RT-PCR and MMP1 activity assays confirmed the bimodal regulation and DNA sequencing of 69 individuals identified an MMP1 gene promoter polymorphism that segregated precisely with the MMP1 bimodal expression. Chromatin immunoprecipitation (ChIP) experiments indicated that the transcription factors (TFs) ETS1, ETS2 and GATA3, bind to the MMP1 promoter in the region of this polymorphism and may contribute to the bimodal expression. CONCLUSIONS: We describe a simple method to identify putative bimodally expressed RNAs from transcriptome data that is effective yet easy for non-statisticians to understand and use. This method identified bimodal endothelial cell expression of MMP1, which appears to be biologically significant with implications for inflammatory disease. (271 Words). PMID- 21244712 TI - Antepartum fetal heart rate feature extraction and classification using empirical mode decomposition and support vector machine. AB - BACKGROUND: Cardiotocography (CTG) is the most widely used tool for fetal surveillance. The visual analysis of fetal heart rate (FHR) traces largely depends on the expertise and experience of the clinician involved. Several approaches have been proposed for the effective interpretation of FHR. In this paper, a new approach for FHR feature extraction based on empirical mode decomposition (EMD) is proposed, which was used along with support vector machine (SVM) for the classification of FHR recordings as 'normal' or 'at risk'. METHODS: The FHR were recorded from 15 subjects at a sampling rate of 4 Hz and a dataset consisting of 90 randomly selected records of 20 minutes duration was formed from these. All records were labelled as 'normal' or 'at risk' by two experienced obstetricians. A training set was formed by 60 records, the remaining 30 left as the testing set. The standard deviations of the EMD components are input as features to a support vector machine (SVM) to classify FHR samples. RESULTS: For the training set, a five-fold cross validation test resulted in an accuracy of 86% whereas the overall geometric mean of sensitivity and specificity was 94.8%. The Kappa value for the training set was .923. Application of the proposed method to the testing set (30 records) resulted in a geometric mean of 81.5%. The Kappa value for the testing set was .684. CONCLUSIONS: Based on the overall performance of the system it can be stated that the proposed methodology is a promising new approach for the feature extraction and classification of FHR signals. PMID- 21244713 TI - Intracranial metastasis from primary transitional cell carcinoma of female urethra: case report & review of the literature. AB - BACKGROUND: Transitional cell carcinoma (TCC) of the female urethra is a rare urological malignancy, and intracranial metastasis of this cancer has not yet been reported in the literature. This review is intended to present a case of multiple intracranial metastasis in a female patient with a remote history of primary urethral TCC. CASE PRESENTATION: A 49-year-old woman, presented with a prolapsed mass in urethral orifice that was diagnosed as primary urethral TCC with distant lung and multiple bone metastases. The patient subsequently underwent chemotherapy under various regimens. A year later, the patient developed headache and vomiting which as was found to be due to multiple intracranial metastasis. The patient underwent surgical resection of the largest lesion located on the cerebellum, and consecutively gamma knife radiosurgery was performed for other small-sized lesions. Pathological examination of the resected mass revealed a metastatic carcinoma from a known urethral TCC. Serial work-up of systemic metastasis revealed concomitant aggravation of lung, spleen, and liver metastasis. The patient died of lung complication 2 months after the diagnosis of brain metastasis. CONCLUSION: To the best of our knowledge, this is the first reported case of cerebral metastasis from primary urethral TCC, with pathological confirmation. As shown in intracranial metastasis of other urinary tract carcinoma, this case occurred in the setting of uncontrolled systemic disease and led to dismal prognosis in spite of aggressive interventional modalities. PMID- 21244714 TI - Why is it difficult to implement e-health initiatives? A qualitative study. AB - BACKGROUND: The use of information and communication technologies in healthcare is seen as essential for high quality and cost-effective healthcare. However, implementation of e-health initiatives has often been problematic, with many failing to demonstrate predicted benefits. This study aimed to explore and understand the experiences of implementers -- the senior managers and other staff charged with implementing e-health initiatives and their assessment of factors which promote or inhibit the successful implementation, embedding, and integration of e-health initiatives. METHODS: We used a case study methodology, using semi-structured interviews with implementers for data collection. Case studies were selected to provide a range of healthcare contexts (primary, secondary, community care), e-health initiatives, and degrees of normalization. The initiatives studied were Picture Archiving and Communication System (PACS) in secondary care, a Community Nurse Information System (CNIS) in community care, and Choose and Book (C&B) across the primary-secondary care interface. Implementers were selected to provide a range of seniority, including chief executive officers, middle managers, and staff with 'on the ground' experience. Interview data were analyzed using a framework derived from Normalization Process Theory (NPT). RESULTS: Twenty-three interviews were completed across the three case studies. There were wide differences in experiences of implementation and embedding across these case studies; these differences were well explained by collective action components of NPT. New technology was most likely to 'normalize' where implementers perceived that it had a positive impact on interactions between professionals and patients and between different professional groups, and fit well with the organisational goals and skill sets of existing staff. However, where implementers perceived problems in one or more of these areas, they also perceived a lower level of normalization. CONCLUSIONS: Implementers had rich understandings of barriers and facilitators to successful implementation of e-health initiatives, and their views should continue to be sought in future research. NPT can be used to explain observed variations in implementation processes, and may be useful in drawing planners' attention to potential problems with a view to addressing them during implementation planning. PMID- 21244715 TI - GraphCrunch 2: Software tool for network modeling, alignment and clustering. AB - BACKGROUND: Recent advancements in experimental biotechnology have produced large amounts of protein-protein interaction (PPI) data. The topology of PPI networks is believed to have a strong link to their function. Hence, the abundance of PPI data for many organisms stimulates the development of computational techniques for the modeling, comparison, alignment, and clustering of networks. In addition, finding representative models for PPI networks will improve our understanding of the cell just as a model of gravity has helped us understand planetary motion. To decide if a model is representative, we need quantitative comparisons of model networks to real ones. However, exact network comparison is computationally intractable and therefore several heuristics have been used instead. Some of these heuristics are easily computable "network properties," such as the degree distribution, or the clustering coefficient. An important special case of network comparison is the network alignment problem. Analogous to sequence alignment, this problem asks to find the "best" mapping between regions in two networks. It is expected that network alignment might have as strong an impact on our understanding of biology as sequence alignment has had. Topology-based clustering of nodes in PPI networks is another example of an important network analysis problem that can uncover relationships between interaction patterns and phenotype. RESULTS: We introduce the GraphCrunch 2 software tool, which addresses these problems. It is a significant extension of GraphCrunch which implements the most popular random network models and compares them with the data networks with respect to many network properties. Also, GraphCrunch 2 implements the GRAph ALigner algorithm ("GRAAL") for purely topological network alignment. GRAAL can align any pair of networks and exposes large, dense, contiguous regions of topological and functional similarities far larger than any other existing tool. Finally, GraphCruch 2 implements an algorithm for clustering nodes within a network based solely on their topological similarities. Using GraphCrunch 2, we demonstrate that eukaryotic and viral PPI networks may belong to different graph model families and show that topology-based clustering can reveal important functional similarities between proteins within yeast and human PPI networks. CONCLUSIONS: GraphCrunch 2 is a software tool that implements the latest research on biological network analysis. It parallelizes computationally intensive tasks to fully utilize the potential of modern multi-core CPUs. It is open-source and freely available for research use. It runs under the Windows and Linux platforms. PMID- 21244717 TI - Cardiac beriberi: morphological findings in two fatal cases. AB - Cardiovascular beriberi is categorized into two main groups, according to its cause: alcoholic and non-alcoholic (dietary). Cardiovascular beriberi can also be divided into a fulminant form (Shoshin beriberi) and a chronic form. Shoshin beriberi is characterized by hypotension, tachycardia, and lactic acidosis and is mainly encountered in non-alcoholic patients in Asian countries, although it has also been seen in alcoholics in Western countries. Due to the complex clinical presentation and to the lack of diagnostic tests, thiamine deficiency is still being missed, especially among non-alcoholics patients. We present two fatal cases of non - alcohol associated cardiac beriberi. An acute myocardial infarction was observed in one case; extensive colliquative myocytolisis (grade 2) was described in the second case respectively. Morphologically, myocardial necrosis and colliquative myocytolysis are the histologic hallmarks of this acute, rare clinical entity. An increase in apoptotic myocytes was demonstrated probably sustaining the cardiogenic shock. PMID- 21244716 TI - Induction and requirement of gene expression in the anterior cingulate cortex and medial prefrontal cortex for the consolidation of inhibitory avoidance memory. AB - BACKGROUND: Memory consolidation is a process to stabilize short-term memory, generating long-term memory. A critical biochemical feature of memory consolidation is a requirement for gene expression. Previous studies have shown that fear memories are consolidated through the activation of gene expression in the amygdala and hippocampus, indicating essential roles of these brain regions in memory formation. However, it is still poorly understood whether gene expression in brain regions other than the amygdala/hippocampus is required for the consolidation of fear memory; however, several brain regions are known to play modulatory roles in fear memory formation. RESULTS: To further understand the mechanisms underlying the formation of fear memory, we first identified brain regions where gene expression is activated after learning inhibitory avoidance (IA) by analyzing the expression of the immediately early genes c-fos and Arc as markers. Similarly with previous findings, the induction of c-fos and Arc expression was observed in the amygdala and hippocampus. Interestingly, we also observed the induction of c-fos and Arc expression in the medial prefrontal cortex (mPFC: prelimbic (PL) and infralimbic (IL) regions) and Arc expression in the anterior cingulate cortex (ACC). We next examined the roles of these brain regions in the consolidation of IA memory. Consistent with previous findings, inhibiting protein synthesis in the hippocampus blocked the consolidation of IA memory. More importantly, inhibition in the mPFC or ACC also blocked the formation of IA memory. CONCLUSION: Our observations indicated that the formation of IA memory requires gene expression in the ACC and mPFC as well as in the amygdala and hippocampus, suggesting essential roles of the ACC and mPFC in IA memory formation. PMID- 21244718 TI - Feature extraction and selection for objective gait analysis and fall risk assessment by accelerometry. AB - BACKGROUND: Falls in the elderly is nowadays a major concern because of their consequences on elderly general health and moral states. Moreover, the aging of the population and the increasing life expectancy make the prediction of falls more and more important. The analysis presented in this article makes a first step in this direction providing a way to analyze gait and classify hospitalized elderly fallers and non-faller. This tool, based on an accelerometer network and signal processing, gives objective informations about the gait and does not need any special gait laboratory as optical analysis do. The tool is also simple to use by a non expert and can therefore be widely used on a large set of patients. METHOD: A population of 20 hospitalized elderlies was asked to execute several classical clinical tests evaluating their risk of falling. They were also asked if they experienced any fall in the last 12 months. The accelerations of the limbs were recorded during the clinical tests with an accelerometer network distributed on the body. A total of 67 features were extracted from the accelerometric signal recorded during a simple 25 m walking test at comfort speed. A feature selection algorithm was used to select those able to classify subjects at risk and not at risk for several classification algorithms types. RESULTS: The results showed that several classification algorithms were able to discriminate people from the two groups of interest: fallers and non-fallers hospitalized elderlies. The classification performances of the used algorithms were compared. Moreover a subset of the 67 features was considered to be significantly different between the two groups using a t-test. CONCLUSIONS: This study gives a method to classify a population of hospitalized elderlies in two groups: at risk of falling or not at risk based on accelerometric data. This is a first step to design a risk of falling assessment system that could be used to provide the right treatment as soon as possible before the fall and its consequences. This tool could also be used to evaluate the risk several times during the revalidation procedure. PMID- 21244719 TI - Improving outcome in out-of-hospital cardiac arrest: impact of bystander cardiopulmonary resuscitation and prehospital physician care. AB - Evidence for the impact of prehospital, physician-delivered advanced cardiac life support (ACLS) on survival from out-of-hospital cardiac arrest is conflicting. The prospective observational study by Yasunaga and co-workers demonstrates an improved survival at 1 month associated with prehospital physician-delivered ACLS over emergency life-saving technician-delivered ACLS. These effects are additive to the survival benefit seen with bystander-initiated cardiopulmonary resuscitation (BCPR) compared with no BCPR. The present commentary places these findings in the context of the existing literature and discusses some of the unresolved controversies. PMID- 21244720 TI - Surface phosphorylation for polyelectrolyte complex of chitosan and its sulfonated derivative: surface analysis, blood compatibility and adipose derived stem cell contact properties. AB - Many studies have tried to look for the application of chitosan in tissue engineering since its structure is similar to glycoaminoglycans, the main components of the extracellular matrix. Previous studies had indicated that the incorporation of sulfonic or phosphonic functionalities would be beneficial to the growth of certain cells. However, no study has explored the effect of incorporation of both above-mentioned anionic functionalities onto the chitosan structure. In this study, we have surface-phosphorylated the polyelectrolyte film formed by chitosan and water-soluble sulfonated chitosan with the aim to incorporate phosphonic and sulfonic functionalities onto the film surface. Surface analyses by ESCA and ATR-FT-IR have shown that these two functional groups have been successfully grafted onto the surface, and that the ratio of P/S was dependent upon the weight ratio of phosphorylation agents added. Blood compatibility evaluation indicated that phosphorylated polyelectrolyte complexes extended the plasma recalcification time as compared to non-treated chitosan and direct-phosphorylated chitosan film. In addition, these phosphorylated polyelectrolyte complexes showed similar or slightly less platelet reactivity than the non-phosphorylated counterpart. In contrast, significant platelet activation and adhesion were noted on the direct-phosphorylated chitosan. This implicated the incorporation of sulfonic acid onto the phosphorylated surface can increase the platelet compatibility. An adipose-derived stem cell incubation study has demonstrated that the incorporation of both phosphonic and sulfonic acid functionalities onto the chitosan surface can enhance the stem cell growth. Therefore, the phosphorylated polyelectrolyte complexes were not only blood compatible but also stem cell compatible, and could be a novel biomaterial in tissue-engineering applications. PMID- 21244721 TI - Effect of polymer type on the dynamics of phase inversion and drug release in injectable in situ gelling systems. AB - The objective of this study was to evaluate the effect of the nature of the polymer on the dynamics of phase inversion and drug release in an in situ forming gel drug-delivery system composed of a biodegradable polymer and the solvent N methyl-2-pyrrolidone (NMP), with metoclopramide monohydrochloride (metosalt) used as a low-molecular-weight model drug. Injection of this solution into an aqueous medium leads to the formation of a solid gel due to the rapid solvent/water exchange, followed by sustained release of the incorporated drug. The release of solvent from the injectable gel into phosphate buffer, which influences the polymer precipitation rate, was investigated as a function of the type of polymer using UV-Vis spectrophotometry. The cross-sectional gel morphology and its water uptake were characterized to relate the initial burst release (and thus the dynamics of phase inversion) to the polymer lactide/glycolide ratio and to the end-group characteristics. The results show that the phase inversion of hydrophobic polymers (e.g., PdlLA) occurs faster than the phase inversion of relatively more hydrophilic polymers (e.g., PLGA75/25, RG502 and RG502H). Three of the four polymers exhibit a four-phase profile, with the characteristics of each phase dependent on the hydrophobicity and degradation kinetics of the individual polymer. PMID- 21244722 TI - Tannic acid cross-linked collagen scaffolds and their anti-cancer potential in a tissue engineered breast implant. AB - Tannic acid (TA) is a hydrolysable plant tannin, and it has been determined that TA functions as a collagen cross-linking agent through hydrogen-bonding mechanisms and hydrophobic effects. Since TA may have anti-tumor properties, it may be a viable cross-linking agent for collagen-based breast tissue scaffolds. The goal of this work was to determine if TA cross-linked scaffolds induce apoptotic processes in MCF-7 cancer cells, with minimal toxic effect on healthy D1 mesenchymal stem-like stromal cells. Cross-linked collagen scaffolds that were uniform, easily reproduced, easily characterized, and readily used in cell culture were manufactured. Thermal denaturation temperatures of the cross-linked scaffolds (68 degrees C) were shown to be significantly higher when compared to those of uncross-linked scaffolds (55 degrees C). Scanning electron microscopy images demonstrated the replacement of irregular collagen fibers with sheet-like structures upon cross-linking. The cross-linking solution concentration of TA that appears to be best for inducing apoptotic processes in MCF-7 cells, while minimizing toxic effect on D1 cells, is 1 mg/ml. At this concentration, the MCF 7 cell metabolic activity did not change over a 72-h period (i.e., proliferation was limited) while there was an increase in metabolic activity of D1 cells over the 72-h period. TA did appear to inhibit the production of lipid by D1 cells cultured in an adipogenic cocktail; in the future, the rate and duration of inhibition could be tailored to allow gradual bulking of the implant. The results suggest that the level of TA cross-linking can be modulated to provide optimal use in a tissue engineering composite. PMID- 21244723 TI - Olfactory and gustatory function in patients with multiple sclerosis. AB - BACKGROUND: The olfactory function (OF) and gustatory function in patients with multiple sclerosis (MS) can be limited. METHODS: We performed the testing of orthonasal (Threshold Discrimination Identification [TDI] score with Sniffin' Sticks) and retronasal (Taste Powder) OF and gustatory function (Taste Strips; Burghart, Wedel, Germany) in patients diagnosed with MS and healthy controls matching in age, sex, and smoking habits. RESULTS: Eight of 16 MS patients (50%) displayed hyposmia (TDI score, 28.75 +/- 1.28; p = 0.06); the identification subtest significantly was restricted (12.63 +/- 1.67; p = 0.001). Four of 16 MS patients (25%) had limited retronasal OF with a Taste Powder score of 4.5 +/- 1.29. The gustatory function in 19% of MS patients was significantly limited (Taste Strip score, 5.33 +/- 2.52; p = 0.02). Patients who estimated their ability to smell as diminished performed more poorly on retronasal OF testing (r =0.657; p = 0.046). CONCLUSION: This study confirms the incidence of olfactory disorder in MS patients that has been reported in the literature. Interestingly, a significant correlation between orthonasal and retronasal OF testing was not shown. A higher incidence of gustatory dysfunction was shown and might serve as another potential marker for this disease. PMID- 21244724 TI - Effect of area of residence on patterns of aeroallergen sensitization in atopic patients. AB - BACKGROUND: An association with sensitization to inhaled allergens and allergic rhinitis and asthma has been established. A recent study concluded that the disparity in allergen sensitization might primarily be caused by environmental factors rather than genetic differences. The primary objective was to identify potential differences in sensitization among subjects with the same ethnicity in South India who reside in different environments. METHODS: Five hundred forty-six patients presenting to a tertiary allergy center with allergic rhinitis and or asthma underwent evaluation using a structured questionnaire, skin-prick testing to common aeroallergens, and spirometry and were categorized according to area of residence. RESULTS: The most common allergens causing sensitization were house dust mite (range, 65-70%), trees (range, 52-56%), and cockroaches (range, 39 53%). There was lower risk of sensitization to cockroach allergens for subjects <21 years old living in suburban (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.12-0.81) and rural environments (OR, 0.33; 95% CI, 0.11-0.96) compared with subjects <21 years old living in urban areas. There was higher risk of sensitization to fungi in subjects <21 years old living in suburban areas (OR, 1.51; 95% CI, 0.60-3.77) and rural environments (OR, 2.71; 95% CI, 0.98-7.48) compared with subjects <21 years old living in urban environments. CONCLUSION: Sensitization patterns are similar in different areas of residence except in younger subjects. Sensitization to fungi was higher in younger subjects from the rural area and cockroach sensitization were higher in younger subjects from urban areas. Sensitization is an important precursor of clinical allergic disease and further studies to unravel the complex gene-environment interactions of aeroallergen sensitization in different environments are needed. PMID- 21244725 TI - Efficacy and safety of a glutaraldehyde-modified house dust mite extract in allergic rhinitis. AB - BACKGROUND: Modification of allergens by glutaraldehyde in extracts used for immunotherapy reduces the risk for side effects, but therapeutic efficacy of such extracts requires further evaluation. The aim of this study was to evaluate the efficacy and safety of immunotherapy with PURETHAL Mites (PM), a single-strength glutaraldehyde-modified aluminum hydroxide-adsorbed extract of house-dust mites (HDM). METHODS: In a multicenter, randomized, placebo-controlled double-blind setting, HDM-allergic subjects (n = 140) were treated with modified allergen extract or placebo over a 1-year period. The primary outcome parameter was a combined symptom and medication score (clinical index score [CIS]). Secondary efficacy parameters were the result of a titrated conjunctival provocation test (CPT), rhinitis/rhinoconjunctivitis quality of life (RQL) score, and serum concentrations of IgE and IgG against specific HDM allergens and a documentation of adverse events (AE). RESULTS: We evaluated 140 patients (66 treatment and 74 placebo) for clinical efficacy. The allergoid treatment for 1 year resulted in significantly greater CIS improvement and higher RQL scores. The response threshold in the titrated CPT (p = 0.009) and the serum concentrations of IgG4 (p < 0.001) against Dermatophagoides pteronyssinus allergens after treatment were also significantly different between groups. In total, 88 patients (46 PM/42 placebo) out of a safety population of 145 reported 278 (158 PM/120 placebo) AE. Except for local reactions, no specific AE appeared to be associated with PURETHAL Mites (HAL-Allergy, Leiden, The Netherlands). CONCLUSION: The findings of this study indicate that allergen injection therapy with modified HDM extract is superior to placebo in allergic rhinitis therapy. The treatment was well tolerated and no serious drug-related AE were observed. PMID- 21244726 TI - Economic burden of allergic rhinitis in Korea. AB - BACKGROUND: Allergic rhinitis is one of most prevalent chronic diseases and results in relatively high medical expenses and economic burden; however, in Korea, studies on economic costs are limited. Therefore, this study investigated the health care use and socioeconomic costs of allergic rhinitis in Korea. METHODS: This study extracted the insurance claims records from the Korea National Health Insurance Corporation (NHIC) claims database for determining the health care services provided to patients with allergic rhinitis in 2007. The total allergic rhinitis-related cost was the sum of the direct medical care costs, the direct nonmedical care costs, and the indirect cost. The direct medical care consists of the costs paid by insurers and patients, the noncovered service costs, the prescribed drug costs, and the over-the-counter drug costs. RESULTS: A total of 4,068,517 people were identified as having allergic rhinitis, yielding a prevalence of 8.4%. The prevalence for children <20 years of age was 13.5% and higher than that of adults. Especially the prevalence of preschool children was higher. The total direct cost was $223.68 million and the lost productivity was estimated to be $49.25 million. Therefore, we approximated the economic burden of allergic rhinitis to be $272.92 million. CONCLUSION: Allergic rhinitis was a frequently occurring disease in the NHIC Claims database and the economic burden has been estimated to be almost $272.92 million. Although this study has some limitations, it is the first study of economic burden in allergic rhinitis representing the entire Korean population. PMID- 21244727 TI - Exercise-induced rhinitis in competitive swimmers. AB - BACKGROUND: Elite swimmers are at increased risk of asthma, which has been related to chronic effects of pool chlorine environment. However acute effects of swimming on rhinitis remain unknown. OBJECTIVE: We aimed to assess the nasal response to exercise in competitive swimmers compared with competitive runners. METHODS: Measurements of nasal symptoms, peak nasal inspiratory flow, lung function, dyspnea, and of airway inflammation were obtained before and after a training session of 19 international-level swimmers and 13 professional runners. Exercise-induced rhinitis was defined as a fall in peak nasal inspiratory flow above 20% from baseline and atopy by positivity to skin-prick testing. Changes within groups were compared using paired t test and differences compared by analysis of covariance. RESULTS: Prevalence of exercise-induced rhinitis was similar between swimmers and runners, respectively 21% and 23%. Contrary to runners, swimmers experienced a decrease in nasal inspiratory flow levels and increase in sneezing, nasal congestion, itching, and postnasal drip after exercise. However, difference in changes was only significant for postnasal drip (p = 0.050). All subjects experiencing exercise-induced rhinitis were nonatopic. An overall improvement in nasal flows, sneezing, and itching after exercise was observed in atopic athletes, although no significant differences in changes compared with nonatopic athletes existed. CONCLUSION: Swimmers, contrary to runners, experience a worsening of nasal function after training. Although these differences were only significant for postnasal drip, our results provide support to the existence of a "swimming-induced rhinitis" independent of the atopic status of the athlete. PMID- 21244728 TI - Numerical simulation of the effects of inferior turbinate surgery on nasal airway heating capacity. AB - BACKGROUND: The aim of this study was to evaluate the effects of inferior turbinate surgery on nasal airway heating capacity using computational fluid dynamics (CFD) simulations. METHODS: Heat transfer simulations were performed for a normal nasal cavity and others with severely enlarged inferior turbinates, before and after three simulated surgical procedures: (1) resection of the lower third free edge of the inferior turbinate, (2) excision of the head of the inferior turbinate, and (3) radical inferior turbinate resection. The models were run with three different environmental temperatures. RESULTS: The changes of airflow pattern with the reduction of inferior turbinate affected heat transfer greatly. However, the distribution of wall heat flux showed that the main location for heat exchange was still the anterior region. Under the cold environment, the nasal cavities with the head of inferior turbinate reduction were capable of heating the inspired air to 98.40% of that of the healthy one; however, for the case with lower third of inferior turbinate excised, the temperature was 11.65% lower and for the case with radical inferior turbinate resection, 18.27% lower temperature compared with the healthy nasal cavity. CONCLUSION: The healthy nasal cavity is able to warm up or cool down the inspiratory airflow under different environmental temperature conditions; for the nasal cavities with turbinate surgeries, partial inferior turbinate reduction can still sustain such heating capacity. However, too much or total turbinate resection may impair the normal function of temperature adjustment by nasal mucosa. PMID- 21244729 TI - Comparison of local anesthesia with articaine and lidocaine in septoplasty procedure. AB - BACKGROUND: Only a few studies have so far compared the use of different local anesthetic agents in septoplasty procedure with regard to reduction in pain, effectiveness, and related complications. The aim of this study was to compare articaine and lidocaine as local anesthetics for septoplasty surgery, in terms of their efficacy and safety. METHODS: Seventy patients randomized into two groups were included in this study. For local anesthesia, 35 patients received articaine and 35 received lidocaine. All patients were asked to rate their pain levels on a visual analog scale (VAS) at the 1st, 2nd, 4th, 6th, 8th, 12th, 18th, and 24th postoperative hours. In addition, analgesic consumption of each patient as well as postoperative complications was recorded in both groups. RESULTS: VAS scores for pain were significantly lower in the articaine group than in the lidocaine group at the 2nd, 6th, 8th, 12th, and 24th postoperative hours (p< 0.05). Comparison of the patients' usage of analgesics during the first 24 hours postoperatively showed that in the articaine group, the percentage of patients that had not used analgesics was 58.5%, and in the lidocaine group the corresponding figure was 41.5%. CONCLUSION: Articaine is a safe local anesthetic agent with rapid onset of action. When compared with lidocaine, it is associated with improved tissue diffusion, rare postoperative complications, and less postoperative pain, thus, representing a safe and effective local anesthetic agent for septoplasty procedure. PMID- 21244730 TI - Aberrant mucin glycoprotein patterns of chronic rhinosinusitis patients with bacterial biofilms. AB - BACKGROUND: Increasingly bacterial biofilms have been implicated in chronic rhinosinusitis (CRS), and conventional treatment methods have failed to completely eradicate biofilms. (1) Terminal sialic acids present on sinus mucosal glycoproteins are targets for bacterial adherence and biofilm formation. (2) A subpopulation of CRS patients is more susceptible to biofilm formation due to aberrant terminal sialic residue distribution patterns of glycoproteins on their mucosa. (3) The higher levels of sialyl transferase (ST)6Gal1 gene expression contribute to the overall aberrant glycosylation patterns on the host mucosa that predispose this patient cohort to developing biofilms. (4) Mucin glycoprotein MUC7 that has known bactericidal activity displays an overall reduced terminal sugar profile in biofilm positive CRS patients. METHODS: Confocal scanning laser microscopy, glycoarray analysis, real-time polymerase chain reaction of ST6Gal1, neuraminidase assays and multivariate analysis were used to compare production of sialic acid-degrading enzymes in sinus biopsies from biofilm positive and negative CRS patients with mucosa from healthy controls. RESULTS: Biofilm positive CRS patients expressed aberrant glycoprotein patterns with terminal sialics of between 70 and 90 kD (stress value = 0.1414). The ST6Gal1 gene was upregulated, and bacteria isolated from these patients exhibit significantly higher neuraminidase activity (p = 0.0343). We detected a significant lack in the overall expression of terminal sugar residues of MUC7 (stress value = 0.088). CONCLUSIONS: We observed a strong positive correlation between the aberrant terminal sugar patterns in this sub group of CRS patients with biofilms. The innate immunity function of their MUC7 glycoprotein against bacterial invasion may be compromised in CRS patients. PMID- 21244731 TI - Cigarette smoking increases risk of recurrence for sinonasal inverted papilloma. AB - BACKGROUND: Sinonasal inverted papilloma (IP) is a neoplasm in the nasal cavity, characterized by its local aggressiveness and tendency to cause malignancy. Despite the frequent recurrence of IP, few studies have reported the effects of situational parameters including smoking on the recurrence rate of IP. This study was performed to evaluate clinical and environmental factors including smoking that can predict neoplasm recurrence after surgery in patients with IP. METHODS: This study was conducted retrospectively on 132 patients who were diagnosed with IP between November 1985 and September 2007. The study focused on the risk factors of recurrence, such as smoking behaviors, diabetes mellitus (DM), hypertension (HTN), allergic rhinitis (AR), the sites of tumor origin and involvement, neoplasm staging, and the surgical method. The age of the patients ranged from 22 to 85 years, and among the 132 patients, 39 patients were smokers (29.5%), 17 (13.3%) with DM, 31 (24.4%) with HTN, and 11 (9.3%) with AR. RESULTS: The recurrence rate showed great disparity between the groups of smokers and nonsmokers: 28.2% of smokers suffered recurrence compared with 10.7% recurrence from the nonsmoker group. The Krouse stage IV group experienced more frequent recurrence than the stage I, II, and III groups. Some patients in Krouse stage III (5/72, 6.9%) and IV (3/3, 100%) groups underwent malignant transformation of IP. Histories of DM, HTN, and AR did not exert a statistically meaningful influence on the recurrence and malignant transformation. CONCLUSION: The smoking behavior and tumor with extranasal/sinus extension appear to be associated with recurrence of IP after surgical resection. PMID- 21244732 TI - Olfactory event-related potential in patients with rhinosinusitis-induced olfactory dysfunction. AB - BACKGROUND: Olfactory disorders are a common syndrome in the rhinology clinic. Olfactory event-related potential (OERP) has been considered as an important alternative method to evaluate olfactory function. The aim of this study was to find the consistency of OERP and the psychophysics olfactory test (T&T olfactometry assessment) in rhinosinusitis patients with or without nasal polyposis. METHODS: Both the psychophysics olfactory test and the OERP were performed in all patients before functional endoscopic sinus surgery (FESS). Detailed information including demographic, comorbidity, subjective symptoms, CT, and endoscopic examination were recorded. Six months later, the T&T test and OERP were reexamined in patients with preoperative identified OERP. RESULTS: Preoperative OERP was identified in 26 patients of the nonpolyp group and 12 patients of the polyp group. Good correlation existed between T&T scores and amplitude and latency of N1 and P2 in 26 nonpolyp patients (p < 0.05). No meaningful correlation was apparent in 12 polyp patients (p > 0.05). Significant correlation existed in 7 polyp patients with a free olfactory cleft (OC) according to CT (p < 0.05). The other 5 patients with partial OC obstruction were anosmic according to the psychophysics olfactory test; however, OERP was present. Six months later, T&T scores decreased significantly only in these five patients (p < 0.05). Significant correlation was obtained between postoperative T&T scores and OERP in both polyp and nonpolyp groups (p < 0.05). CONCLUSION: OERP can be used to investigate olfactory function of rhinosinusitis patients. Nasal polyp obstruction in specific parts of the OC might influence the consistency between the psychophysics olfactory test and OERP. PMID- 21244733 TI - Experimentally induced eosinophilic polyps in rabbit sinuses. AB - BACKGROUND: Nasal polyps are one of the most common findings of physical examination in the otolaryngology area and the experimental model of nasal polyps in the rabbit maxillary sinus is helpful for clarifying the mechanism of polyp formation. Several protocols have been reported for this model, but most of them involved infectious polyps without eosinophil infiltration. We have attempted to establish a novel rabbit model of polyps associated with eosinophil infiltration. METHODS: Rabbits were either untreated (group A) or sensitized with ovalbumin (OVA; groups B-D). After repeated exposure to OVA, some animals further received valine-glycine-serine-glutamine (group C) or poly-L-arginine (group D) in their maxillary sinuses for 4 weeks. Subsequently, sinus tissues were dissected and subjected to histological analysis. The changes in mRNA expression were analyzed by DNA microarray. RESULTS: Remarkable histological changes were observed in groups C and D but not in group B in eosinophil number in the maxillary sinus mucosa, the width of the lamina propria, and polyp scoring. These changes in group D were greater than those in group C. DNA microarray analysis revealed that up-regulated genes in group D included those related to inflammation and extracellular matrix metabolism. On the other hand, down-regulated genes in group D involved those related to anti-inflammation. CONCLUSION: Our results indicate that treatment with inflammatory agents, in combination with an antigen-dependent immune response, could induce nasal polyp formation associated with eosinophil infiltration and mucosal hypertrophy. The gene expression profile supported the clinical relevance of this model. PMID- 21244734 TI - The effect of macrolides on myofibroblast differentiation and collagen production in nasal polyp-derived fibroblasts. AB - BACKGROUND: Macrolides are known to have anti-inflammatory, immunomodulatory, and tissue reparative effects. The purpose of this study was to determine the effect of macrolides (erythromycin [EM] and roxithromycin [RXM]) on the differentiation of fibroblasts into myofibroblasts and extracellular matrix accumulation in transforming growth factor (TGF) beta1-induced nasal polyp-derived fibroblasts (NPDFs) and to determine if NADPH oxidase (Nox) 4 and reactive oxygen species (ROS) are involved in the aforementioned processes. METHODS: Nasal polyps of six patients (three women and three men; 32.3 +/- 5.2 years of age) were acquired during surgery and NPDFs were isolated from surgical tissues. NPDFs were pretreated with macrolides for 2 hours before differentiation induction by TGF beta1. The mRNA expressions of alpha-smooth muscle actin (SMA), collagen types I and III, and Nox4 were determined by reverse-transcription-polymerase chain reaction, and the expression of alpha-SMA protein was determined by immunocytochemical staining. The amount of total collagen production was analyzed by SirCol collagen dye-binding assay. ROS activity was measured by nitroblue tetrazolium reduction assay and was visualized by fluorescent microscopy. RESULTS: In TGF-beta1-induced NPDFs, EM, and RXM significantly inhibited expressions of alpha-SMA and collagen types I and III mRNA and reduced alpha-SMA and collagen protein levels at concentrations of 5 and 10 MUg/mL. EM and RXM also inhibited TGF-beta1-induced ROS production and Nox4 mRNA expression at the same concentrations. CONCLUSION: These results suggest the possibility that EM and RXM may play an important role in inhibiting the development of nasal polyps through their antioxidant effect. PMID- 21244735 TI - Associations of serum leptin with atopic asthma and allergic rhinitis in children. AB - BACKGROUND: There is growing evidence of positive correlations between asthma (AS) and obesity in adults and children. Leptin is an obesity gene product secreted by white adipose tissue; elevated serum levels are found in obese adults and children. Recently, leptin has also been found to be associated with allergic rhinitis (AR). However, the links between serum leptin, atopic AS, and AR remained undetermined. Because AS and AR share common allergic inflammatory mechanisms, our aim was to determine if there were any differences in serum leptin levels between asthmatic children and nonasthmatic children with AR. METHODS: We studied 114 children (67 boys and 47 girls): 68 with mild intermittent-to-moderate persistent atopic AS (AS children) and 46 with mild-to moderate persistent AR without AS (AR children; overall mean age, 8.51 years; range, 5-18 years). Body mass index (BMI), serum leptin, pulmonary function, and atopy parameters (serum IgE and eosinophil levels) were measured. RESULTS: Compared with AR children, AS children had higher body weights (kg), body mass indices (kg/cm2), and serum leptin levels (ng/mL). Multiple linear regression analyses showed that serum leptin concentrations differed significantly for girls, being overweight and between disease groups (AS and AR children). CONCLUSION: Our results indicate that a higher serum leptin level has stronger association with mild-to-moderate persistent AS compared with AR. Hence, serum leptin may be a stronger predictor for childhood AS compared with AR. Among the asthmatic children, higher serum leptin levels also showed stronger associations with female gender and being overweight. PMID- 21244736 TI - Nasal polyps: An independent risk factor for bronchial hyperresponsiveness in patients with allergic rhinitis. AB - BACKGROUND: Many studies were conducted to figure out the relationship between allergic rhinitis (AR) and lower airway diseases. This study was designed to elucidate the clinical parameters that could predict the coexistence of bronchial hyperresponsiveness (BHR) in AR and suggest a guideline for lower airway evaluation in these patients. METHODS: One hundred seventy-three patients newly diagnosed with AR were evaluated for the lower airway with the methacholine bronchoprovocation test. RESULTS: BHR was more prevalent in patients with nasal polyps (p = 0.01), in patients complaining of moderate to severe symptoms (p = 0.023), with higher serum total IgE levels (p = 0.001), and with blood eosinophil count (p = 0.008). No statistically significant difference was observed between intermittent and persistent AR patients (p = 0.364). Blood eosinophil count that could predict BHR was calculated as 320 cells/MUL (p = 0.004). CONCLUSION: Instead of a routine lower airway evaluation for all AR patients, we recommend lower airway evaluation for the selected patients with nasal polyps, moderate to severe symptoms, and high blood eosinophil count. PMID- 21244737 TI - Selective irrigation of paranasal sinuses in the treatment of recalcitrant chronic sinusitis. AB - BACKGROUND: Chronic rhinosinusitis (CRS) refractory to medical and surgical therapy is a challenging entity to treat. Topical antibiotics and anti inflammatory drugs have been increasingly used in managing this disorder. The aim of this pilot study is to evaluate the role of maxillary sinus antrostomy tubes (MAST) in selectively irrigating paranasal sinuses with topical antibiotics with anti-inflammatory in treating recalcitrant CRS. A prospective clinical trial was performed at a tertiary referral center. METHODS: Thirteen patients with failed maximal medical and surgical therapies for chronic sinusitis were enrolled in the study. Endoscopic scores as well as the Sino-Nasal Outcome Test 16 (SNOT-16) scores were obtained before and 3, 8, and 16 weeks after maxillary sinus intubation with MAST. All patients received topical antibiotics with anti inflammatory medication for 21 days. RESULTS: Statistically significant reductions in SNOT-16 and endoscopic scores were found before and after topical irrigations. Both scores continued to improve at the 8th and 16th weeks. CONCLUSION: Selective irrigation of maxillary sinuses using MAST is a viable alternative in treating recalcitrant CRS. PMID- 21244738 TI - Decreased rhinovirus shedding after intranasal oxymetazoline application in adults with induced colds compared with intranasal saline. AB - BACKGROUND: Intranasal oxymetazoline (OMZ) is used as a decongestant during common colds. Recently, intracellular adhesion molecule (ICAM) 1 receptor expression in vitro has been shown to be diminished by OMZ. ICAM-1 is the major receptor used by rhinovirus to gain entry to human cells. The objective of this study was to assess the effect of OMZ on geometric mean titer of rhinovirus in nasal lavage fluid after rhinovirus inoculation. METHODS: Volunteers with antibody titers of <=1:4 to rhinovirus type 39 were enrolled in a randomized, reference-controlled, double-blind study. Beginning 3 hours after intranasal challenge with 100-300 tissue culture infectious dose (TCID)50 of virus, subjects received active 0.05% OMZ (45 MUL containing 22.5 MUg of OMZ hydrochloride in citrate buffer) or reference control (physiological saline solution [PSS]) three times daily for 5 days. Rhinovirus was detected in fibroblast cultures. RESULTS: Geometric mean viral titer (log10) in 34 rhinovirus-infected subjects receiving OMZ was 1.49 on day 2 compared with 2.24 in the 38 infected subjects receiving PSS (p = 0.04). On day 3, the mean titers were 1.45 and 2.08, respectively. Median length of viral shedding was 3.3 days (OMZ) and 3.4 (PSS). Duration of clinical illness was 6.1 days in both groups. CONCLUSION: Topical OMZ decreased viral titer on day 2 during experimental rhinovirus infection in normal volunteers. PMID- 21244739 TI - Three-dimensional CT reconstruction and virtual endoscopic study of the ostial orientations of the frontal recess. AB - BACKGROUND: Safe and efficient endoscopic frontal sinus surgery requires a thorough knowledge of the location of the frontal sinus outflow tract. This study was designed to describe the prevalence of the different frontal recess cells and 3D analysis by virtual endoscopy of their ostial orientation in relation to the frontal ostium. METHODS: Fifty high-resolution CT scans (100 sides) of disease free paranasal sinuses were reviewed using triplanar and virtual 3D analysis. The prevalence and ostial locations of the frontal recess cells and the relationship of the various ostia to the frontal sinus ostium were mapped and analyzed. RESULTS: The cell type, prevalence, and most common relationship of the cell's ostium to the frontal ostium were intersinus septal cells, 7% medial and anterior; Kuhn type 1 cells, 28%, lateral and anterior; Kuhn type 2 cells, 6%, anterior and lateral; Kuhn type 3 cells, 11%, medial or lateral; supraorbital ethmoid cells, 11%, posterior; suprabullar cells, 68%, posterior; and frontal bullar cells, 16%, posterior or lateral. In 35% of the sides, none of the aforementioned cell types were found. There were many blind recesses that were seen in all locations except anterolateral to the frontal ostium. Openings of adjacent pneumatized middle turbinates were often posteromedial to the frontal ostium. Agger nasi cells were present in at least 86%, opening lateral to frontal ostium. CONCLUSION: Frontal outflow tract mapping by virtual endoscopy and knowledge of the ostial configurations will help surgeons perform more efficient and accurate surgery particularly for minimally invasive approaches including balloon dilation. PMID- 21244740 TI - Transpalatal greater palatine canal injection: Radioanatomic analysis of where to bend the needle for pediatric sinus surgery. AB - BACKGROUND: The greater palatine canal (GPC) local injection is used to limit posterior bleeding during sinus surgery in adults. Given the potential for causing iatrogenic damage to the intraorbital contents, this procedure is not commonly used in the pediatric population. No studies have described the anatomic development of the GPC during facial growth. By using age-stratified radioanatomic analysis, the dimensions of the GPC and the clinical implications are described for pediatric patients. An age-stratified radioanatomic study was performed. METHODS: High-resolution computed tomography measurements included the thickness of the mucosal plane overlying the GPC, the length of the GPC, and the distance between the base of the pterygopalatine fossa (PPF) and the orbital floor. Mean distance and standard deviation were calculated for each age cohort and compared using the one-way ANOVA test. RESULTS: The GPC length correlated directly with patient age. It varied from 9.14 +/- 0.11 mm in the youngest age group (<2 years) to 19.36 +/- 2.76 mm in adults (18-64 years). The height of the orbit relative to the hard palate approximated the adult dimensions described in the literature by 12-13 years (49.58 +/- 1.72 mm). CONCLUSION: These radioanatomic results suggest that the GPC injection described for adult patients may be safely administered to selected pediatric patients. For patients >12 years old, we recommend bending the needle 45 degrees and inserting it 25 mm. For patients 6-12 years old, the needle should be inserted 20 mm to enter into the PPF. In patients <6 years old, the needle may safely be placed 12 mm into the GPC. Each of these descriptions is based on the minimal distance required to effectively access the PPF but with maximal safety in regard to the orbit. Further clinical correlation of these findings is necessary through future investigation. PMID- 21244741 TI - Safety of sphenoid aspiration for diagnosis and treatment of intensive care unit rhinosinusitis. AB - BACKGROUND: In intensive care units (ICUs), critically ill patients may be exposed to several risk factors for developing acute rhinosinusitis, including nasogastric tubes, mechanical ventilation, and prolonged periods in the supine position. The incidence of acute rhinosinusitis can be as high as 83%, the third or fourth most frequent ICU infection and it increases the risk of developing ventilator-associated pneumonia. Diagnosis and therapeutic approaches should be more aggressive than in non-ICU patients. Antral puncture plays a central role in the diagnosis and treatment of these patients. This study was designed to show the development of a method for sphenoid puncture in the diagnosis and treatment of acute infectious rhinosinusitis in critically ill patients, analyzing safety and complications. METHODS: Patients in ICUs with endoscopic and radiological diagnosis of acute rhinosinusitis were included. Maxillary puncture was performed through the inferior meatus; sphenoid puncture was performed by endoscopic identification of the sphenoethmoidal recess. An aspiration probe was introduced into the natural sphenoidal ostium, followed by aspiration of secretions and saline irrigation. RESULTS: Twenty-nine patients were included. Twenty-seven patients (93.1%) presented with sphenoidal sinusitis, 24 patients (82.7%) had maxillary sinusitis, 21 patients (72.4%) had ethmoidal sinusitis, and 13 patients (44.8%) had frontal sinusitis. Forty-seven sphenoidal and 39 maxillary punctures were performed. No major bleeding or other complications were recorded. CONCLUSION: The sphenoid puncture is a possible procedure to be performed in an ICU and might complement the paranasal puncture in cases of acute rhinosinusitis. PMID- 21244742 TI - The effect of expandable polyvinyl acetate packing for preventing stenosis of the frontal sinus ostium. AB - BACKGROUND: The aim of this study was to evaluate the effect of repeated expandable polyvinyl acetate (EPA) packing for preventing stenosis of the frontal sinus ostium after patients undergo functional endoscopic sinus surgery (FESS). METHODS: A nonrandomized, prospective study of 20 patients with chronic frontal sinusitis was conducted based on the Lund-Mackay scoring system. EPA was packed, for 3 days/week, in total, three times for 3 weeks, into the left frontal sinus ostium right after FESS. For the control, the right side frontal sinus ostium was left unpacked. After 6 months, the patency of the frontal sinus ostium was measured with a ruler under endoscopic guidance and the patency was classified as obstructed, stenotic, or patent according to the size. RESULTS: Obstruction developed in the right side in four patients and in the left side in two patients. Stenosis was found in the right side in eight patients and in the left side in one patient. The ostium of the frontal sinus was patent in the right side in 8 patients and patent in the left side in 17 patients. The sizes of the ostia were significantly different between the frontal sinuses on both sides 6 months after FESS (p < 0.05). CONCLUSION: The outcome of repeated EPA packing was favorable in patients undergoing FESS. PMID- 21244743 TI - Assessing current technical limitations in the small-hole endoscopic approach to the maxillary sinus. AB - BACKGROUND: Endoscopic sinus surgery has evolved to become the standard surgical approach to address paranasal sinus disease. To access inflammatory mucosal disease and other benign processes, it is desirable to reach all parts of the maxillary sinus. This project explores the combination of three medial wall small hole antrostomies with multiple angled microdebrider blades to determine if an ideal combination exists. A prospective cadaveric study was performed. METHODS: Each 3.5-mm blade was passed through the natural ostium and two separate inferior meatal antrostomies. The space reached by the tip of four different microdebrider blades (12, 60, 90 and 120 degrees ) within each maxillary sinus was mapped using an image guidance system. Percent volume of the sinus reached and access to subsites were determined. RESULTS: Regardless of instrument or antrostomy combination, mean percent volume of maxillary sinus reached was 28% (range, 24 34%). The anterior wall was rarely reached by any combination, with the best blade/antrostomy combination (90 degrees blade/anterior inferior antrostomy) only reaching 28% of the anterior wall. Likewise, the floor of the maxillary sinus was also poorly reached in general. The lateral and posterior maxillary sinus walls were most reliably reached with the roof and medial walls being intermediate. CONCLUSION: Using the endoscopic small-hole approach to the maxillary sinus results in <1/3 of the sinus being routinely reached regardless of antrostomy or angled microdebrider instrument selected. Further study and development of new technologies to more thoroughly reach benign processes within the maxillary sinus via a small-hole approach is warranted. PMID- 21244744 TI - Biocompatibility of electrospun halloysite nanotube-doped poly(lactic-co-glycolic acid) composite nanofibers. AB - Organic/inorganic hybrid nanofiber systems have generated great interest in the area of tissue engineering and drug delivery. In this study, halloysite nanotube (HNT)-doped poly(lactic-co-glycolic acid) (PLGA) composite nanofibers were fabricated via electrospinning and the influence of the incorporation of HNTs within PLGA nanofibers on their in vitro biocompatibility was investigated. The morphology, mechanical and thermal properties of the composite nanofibers were characterized by scanning electron microscopy (SEM), tensile test, differential scanning calorimetry and thermogravimetric analysis. The adhesion and proliferation of mouse fibroblast cells cultured on both PLGA and HNT-doped PLGA fibrous scaffolds were compared through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay of cell viability and SEM observation of cell morphology. We show that the morphology of the PLGA nanofibers does not appreciably change with the incorporation of HNTs, except that the mean diameter of the fibers increased with the increase of HNT incorporation in the composite. More importantly, the mechanical properties of the nanofibers were greatly improved. Similar to electrospun PLGA nanofibers, HNT-doped PLGA nanofibers were able to promote cell attachment and proliferation, suggesting that the incorporation of HNTs within PLGA nanofibers does not compromise the biocompatibility of the PLGA nanofibers. In addition, we show that HNT-doped PLGA scaffolds allow more protein adsorption than those without HNTs, which may provide sufficient nutrition for cell growth and proliferation. The developed electrospun HNT-doped composite fibrous scaffold may find applications in tissue engineering and pharmaceutical sciences. PMID- 21244745 TI - Alginate-graft-PEI as a gene delivery vector with high efficiency and low cytotoxicity. AB - To overcome the efficiency-cytotoxicity dilemma of native PEI and incorporate the advantages of alginate, we designed a novel gene vector by grafting PEI 2000 onto alginate, an anionic polysaccharide with excellent biocompatibility. The alginate graft-PEI (Alg-g-PEI) was successfully synthesized and then characterized by elemental analysis, (1)H-NMR and (13)C-NMR. The M(w) of Alg-g-PEI is ca. 17 000. Acid-base titration confirmed that Alg-g-PEI retained the buffering capacity of native PEI. The DNA binding ability of the polymer was confirmed by gel retardation assay. DSL analysis showed that Alg-g-PEI had a particle size and zeta-potential similar to PEI 25K. AFM detected a clear and well-shaped morphology of the complexes. Additionally, Alg-g-PEI exhibited lower cytotoxicity than PEI 25K in BEL7402, MSC and RVMSC cells. Compared with PEI 25K, Alg-g-PEI had comparable or even higher transfection efficiency. Similarly, Alg-g-PEI mediated VEGF expression was significantly higher compared with PEI 25K-mediated VEGF expression. All together, our results suggest that Alg-g-PEI has a potential to be a safe and efficient agent for gene therapy. PMID- 21244746 TI - Immunopathogenetic and pharmacological aspects of interstitial lung diseases. AB - Interstitial lung diseases (ILDs) are inflammatory diseases characterized by slow and progressive destruction of alveolar-capillary functional units, often leading to respiratory failure and death. A first stage of alveolitis and a following stage of fibrosis provoke an anatomical distortion of the peripheral airways and the interstitium, and for their smoldering evolution and non-specificity of symptoms ILDs may remain undiagnosed and untreated for a long time. In this review we exploited the immunopathogenetic aspects and the therapeutical approaches to this frequently unrecognized and severe disease. PMID- 21244747 TI - Chronic fatigue syndrome/myalgic encephalomyelitis: an update. AB - Chronic Fatigue Syndrome (CFS), also referred to as Myalgic Encephalomyelitis (ME), is a disease of unknown origin. It is classified as Post Viral Fatigue Syndrome (PVFS) in the WHO International Classification of Diseases (ICD) and listed as sub-category at G93.3 under chapter G93, other disorders of the brain. ME/CFS is primarily an endemic disorder but occurs in both epidemic and sporadic forms. It affects all racial-ethnic groups and is seen in all socioeconomic strata. A diagnosis of CFS is a diagnosis of exclusion, meaning other medical conditions, including psychiatric disorders, must be first ruled out. CFS is diagnosed if there is no other explanation for the fatigue and if the other symptoms did not develop before the fatigue. The estimated worldwide prevalence of CFS is 0.4?1 percent. The disease predominantly affects young adults, with a peak age of onset of between 20 and 40 years, and women, with a female to male ratio of 6:1. Mean illness duration ranges from 3 to 9 years. The patho physiological mechanism of CFS is unclear but the immunological pattern of CFS patients gleaned from various studies indicates that the immune system is chronically activated. Besides the role of environmental insults (xenobiotics, infectious agents, stress) the genetic features of patients are studied to evaluate their role in triggering the pathology. At present there are no specific pharmacological therapies to treat the disease but a variety of therapeutic approaches have been described as benefiting patients. Treatment programs are directed at relief of symptoms, with the goal of the patient regaining some level of preexisting function and well-being. PMID- 21244748 TI - Vitamins and mast cells. AB - The immune system is a highly complex, intricately regulated group of cells whose integrated function is essential to health. The mast cell inflammatory response is characterized by an early phase with massive discharge of mediators stored in cytoplasmic secretory granules. Through multigranular/compound exocytosis and a late phase that involves generation of arachidonic acid metabolites and de novo synthesis of cytokines/chemokines and growth factors. Vitamins have been shown to have a protective effect on the body's immune cells. Vitamin C and E are necessary in allergic disease treatment where mast cells are involved. In addition, ascorbic acid and pyridoxine are useful compounds for the treatment of inflammatory disorder of the respiratory airways. Here we revisited the inter relationship between vitamins and mast cells. PMID- 21244749 TI - Limited joint mobility in diabetes and ageing: recent advances in pathogenesis and therapy. AB - Limited joint mobility is frequently observed in elderly people and in patients suffering from diabetes, who represent a growing segment of the population of western countries. Our review wishes to offer the state of art about this interesting topic, which may have important clinical implications, leading to impairment of both basic and instrumental activities of daily living. The main causes of a reduced range of motion are degenerative joint diseases and increased stiffness of collagen tissue. The main biochemical abnormality, common to aging and diabetes, is the non-enzymatic glycosilation of collagen, with advanced glycation end product (AGE) formation, which in turn leads to an increase of collagen cross-links. The most extensive accumulation of AGEs occurs in tissues that contain proteins with low turnover, such as the collagen in the extracellular matrix of articular capsule, ligaments and muscle-tendon units. The increase in collagen cross-linking alters the mechanical properties of these tissues with a decrease in elasticity and tensile strength, and an increase in mechanical stiffness. Besides this, AGEs react with specific cell surface receptors (RAGEs). The engagement of the ligand by RAGEs triggers cell-specific signalling, resulting in enhanced generation of reactive oxygen species and sustained up-regulation of pro-inflammatory mediators and adhesion molecules. An appropriate control of the glucose levels and a diet rich in antioxidant agents are recommended in patients with diabetes. Stretching and strengthening programmes are widely used, in order to prevent and to reduce joint stiffness, but the improvements with physiotherapy are little and short-lasting. Several drugs, which can interfere with AGE formation and removal, or with the cellular effects of AGEs, are under study (among them pyridoxamine, an active form of Vitamin B6, AGE-breaker compounds, glucosamine, rutin and derivatives, soluble RAGE isoforms, and statins). In experimental animal models, these drugs are effective in reducing diabetic complications due to AGE formation; however, further study is necessary before their extensive use in the clinical setting. PMID- 21244750 TI - Infection following bone tumor resection and reconstruction with tumoral prostheses: a literature review. AB - Bone resection is the choice treatment of malignant bone tumors. Tumor prosthesis is one of the most common solutions of reconstruction following resection of bone tumor located to the metaphysis of long bones. Periprosthetic infections are a frequent complication of limb-salvage surgery which is largely due to prolonged and repeated surgeries, as well as to the immunocompromised condition of these patients due to neoplastic treatment. Furthermore, the large exposure of tissues during this type of surgery and the dissection across vascular distributions also contributes to the high risk of infection. The authors reviewed the literature discussing the incidence of infections of tumor prosthesis implanted following resection of bone tumors, taking into account the different sites of implantation. In the English literature, the highest risk of infection which led to limb amputation was observed after proximal tibia resection and this difference was considered to be due to the poor condition of soft tissue and also after pelvic resection due to huge dead space after sarcoma resection not filled by implant. Independent of the location, the management of infected prosthesis is similar. That is, after one or more attempts at debridement and antibiotic therapy, it consists of implant removal and insertion of a new implant in a one- or two-stage procedure, with a decreased risk of failure with the two-stage procedure. PMID- 21244751 TI - Luteolin and thiosalicylate inhibit HgCl(2) and thimerosal-induced VEGF release from human mast cells. AB - HgCl2 is a known environemental neurotoxin, but is also used as preservative in vaccines as thimerosal containing ethyl mercury covalently linked to thiosalicylate. We recently reported that mercury choloride (HgCl(2)) can stimulate human mast cells to release vascular endothelial growth factor (VEGF), which is also vasoactive and pro-inflammatory. Here we show that thimerosal induces significant VEGF release from human leukemic cultured LAD2 mast cells (at 1 microM 326 +/- 12 pg/106 cells and 335.5 +/- 12 pg/106 cells at 10 microM) compared to control cells (242 +/- 21 pg/106 cells, n=5, p less than 0.05); this effect is weaker than that induced by HgCl2 at 10 microM (448 +/- 14 pg/106 cells) (n=3, p less than 0.05). In view of this finding, we hypothesize that the thiosalicylate component of thimerosal may have an inhibitory effect on VEGF release. Thimerosal (10 microM) added together with the peptide Substance P (SP) at 2 microM, used as a positive control, reduced VEGF release by 90 percent. Methyl thiosalicylate (1 or 10 microM) added with either SP or HgCl2 (10 microM) inhibited VEGF release by 100 percent, while sodium salicylate or ibuprofen had no effect. Pretreatment for 10 min with the flavonoid luteolin (0.1 mM) before HgCl2 or thimerosal compeletly blocked their effect. Luteolin and methyl thiosalicylate may be useful in preventing mercury-induced toxicity. PMID- 21244752 TI - Monomeric allergoid intragastric administration induces local and systemic tolerogenic response involving IL-10-producing CD4(+)CD25(+) T regulatory cells in mice. AB - The efficacy of sublingual immunotherapy, at present one of the treatments of choice for respiratory allergy, relies on the tolerance induced by oral mucosa associated immune system; however, the gut-associated lymphoid tissue (GALT: Peyers patches and isolated lymphoid follicles) and mesenteric lymph nodes could also be involved, being stimulated by the ingested part of the allergen extract. The aim of the present study is to assess whether the exposure of the allergen exclusively to the GALT induces a tolerogenic response. For this purpose, mice were sensitized with ovalbumin or Par j 1 allergens. The corresponding gastric resistant monomeric allergoids were then administered via orogastric gavage. After treatment, all mice were tested for: serum IgE, in vitro Th1 and Th2 cytokine release by allergen-stimulated peripheral blood lymphocytes, CD4(+)CD25(+) and CD4(+)CD25(+)IL-10(+) T cells in Peyers patches, mesenteric lymph nodes and spleen. Compared to the control, sensitized groups showed higher levels of serum IgE, lower frequency of CD4+CD25+IL-10+ T cells, at all sites, and higher amounts of in vitroreleased IL-4, IL-6 and TNF-alpha. Compared to the sensitized groups, higher frequency of CD4(+)CD25(+)IL-10(+) T cells was observed in the spleen of both Par-j 1 and OVA sensitized/treated groups and, only for ovalbumin-treated mice, in the Peyers patches and mesenteric lymph nodes, IgE and in vitro cytokines were significantly lower and equivalent to the control group. The results give the first evidence that the intragastric-restricted administration of gastric-resistant allergens restores local and peripheral tolerance in allergen-sensitized mice. PMID- 21244753 TI - GW0742, a high affinity PPAR-beta/delta agonist reduces lung inflammation induced by bleomycin instillation in mice. AB - Peroxisome Proliferator-Activated Receptor beta/delta belongs to a family of ligand-activated transcription factors. Recent data have clarified its metabolic roles and enhanced the potential role of this receptor as a pharmacological target. Moreover, although its role in acute inflammation remains unclear, being the nuclear receptor PPAR beta/delta widely expressed in many tissues, including the vascular endothelium, we assume that the infiltration of PMNs into tissues, a prominent feature in inflammation, may also be related to PPAR beta/delta. Mice subjected to intratracheal instillation of bleomycin (BLEO, 1 mg/kg), a glycopeptide produced by the bacterium Streptomyces verticillus, develop lung inflammation and injury characterized by a significant neutrophil infiltration and tissue oedema. Therefore, the aim of this study is to investigate the effects of GW0742, a synthetic high affinity PPAR beta/delta agonist, and its possible role in preventing the advance of inflammatory and apoptotic processes induced by bleomycin, that long-term leads to the appearance of pulmonary fibrosis. Our data showed that GW0742-treatment (0.3 mg/Kg, 10 percent DMSO, i.p.) has therapeutic effects on pulmonary damage, decreasing many inflammatory and apoptotic parameters detected by measurement of: 1) cytokine production; 2) leukocyte accumulation, indirectly measured as decrease of myeloperoxidase (MPO) activity; 3) IkBalpha degradation and NF-kB nuclear translocation; 4) ERK phosphorylation; 5) stress oxidative by NO formation due to iNOS expression; 6) nitrotyrosine and PAR localization; 7) the degree of apoptosis, evaluated by Bax and Bcl-2 balance, FAS ligand expression and TUNEL staining. Taken together, our results clearly show that GW0742 reduces the lung injury and inflammation due to the intratracheal BLEO--instillation in mice. PMID- 21244754 TI - Controversial role of antibodies against linear epitopes of desmoglein 3 in pemphigus vulgaris, as revealed by semiquantitative living cell immunofluorescence microscopy and in-cell ELISA. AB - A novel explanation of pemphigus vulgaris (PV) pathogenesis suggests that serum autoantibodies may affect desmoglein 3 (Dsg3)-mediated adhesion by triggering depletion of Dsg3 from desmosomes. Furthermore, abrogation of Dsg3 from the cell seems to depend on anti-Dsg3 pemphigus IgG. In this study we sought to gain more insights into the role of PV IgG recognizing non-conformational epitopes of Dsg3 (anti-Dsg3-L IgG) by semi-quantitative living cell immunofluorescence (LCIF) microscopy, in-cell ELISA and morphometric analysis of acantholysis. Our data demonstrate that PV serum and PV IgG can induce acantholysis and reduce the total amount of Dsg3 in cultured keratinocytes, whereas anti-Dsg3-L IgG fail to do so when administered at concentrations comparable to those present in pathogenic PV sera. However, the Dsg3-depleting activity of such polyclonal anti-Dsg3 IgG was acquired when used at 1 microg/ml. Interestingly, both PV sera and IgG, including anti-Dsg3-L IgG, caused early depletion of surface Dsg3 while slightly affecting the total cell content of Dsg3 until late acantholysis. This raises a possibility that depletion of Dsg3 from cell membrane and reduction of the total cellular levels of Dsg3 represent distinct phenomena in PV acantholysis. Taken together, our data demonstrate that anti-Dsg3 PV IgG against linear epitopes of Dsg3 can induce acantholytic changes of keratinocytes in a dose- and time-dependent manner. Specifically, both morphological and biochemical changes suggestive of acantholysis are seen only at high IgG concentrations. We conclude that anti Dsg3L IgG play a minor role in experimental PV under physiologic conditions. PMID- 21244755 TI - Effects of TNF-alpha and IL-1 beta on the activation of genes related to inflammatory, immune responses and cell death in immortalized human HaCat keratinocytes. AB - The present experiments were designed to characterize by microarray analysis the transcriptional responses of human keratinocytes (HaCat) to TNF-alpha and IL-1 beta, given alone or in combination, in order to better understand the mechanisms underlying inflammatory, immune responses and cell death in which both cytokines play a pathophysiological role. Significant differences in the percentage and quality of genes dysregulated by TNF-alpha and IL-1 beta were shown. Both cytokines activated a series of genes involved in inflammatory, immune response as well as in cell death. In our experimental conditions, TNF-alpha, in contrast to IL-1 beta, did not induce a significant level of apoptosis in keratinocytes. However, given together both cytokines produced a significant decrease in apoptotic cells and synergistic transcriptional response which was due to the activation of several specific genes occurring after application of each cytokine. TNF-alpha and IL-1 beta evoked apoptotic effect and transcriptional responses were linked to the stimulation of their specific receptors since a pre treatment with monoclonal antibodies vs TNF-alpha and/or IL-1 beta receptors was able to significantly reduce them. PMID- 21244756 TI - Cafeteria diet increases prostaglandin E2 levels in rat prostate, kidney and testis. AB - Nutrient composition, particularly the omega-6/omega-3 polyunsaturated fatty acids ratio, may differently affect inflammatory mediators production in tissues, which could be causally related to increased cancer incidence in obesity. We evaluated prostaglandin E(2) levels in male Wistar rat prostate, kidney and testicle tissues after 15 days of either a high fat, cafeteria-style diet (5.50 Kcal/g, 30 percent calories from fat, omega-6/omega-3 ratio 2.33) or a standard laboratory chow diet (3.35 Kcal/g, 3 percent calories from fat, omega-6/omega-3 ratio 0.56). In the cafeteria diet compared to standard laboratory diet rats, we found both an increase in weight gain and increased prostaglandin E(2) (PGE(2)) levels in prostate, kidney and testicle tissues. The increased levels of PGE(2) induced by the cafeteria diet could drive an inflammatory process leading to increased incidence of prostate, kidney and testicular cancer in overweight patients. PMID- 21244757 TI - Dendritic cell differentiation blocked by primary effusion lymphoma-released factors is partially restored by inhibition of P38 MAPK. AB - To better understand the molecular mechanisms underlying the dendritic cell (DC) defects in cancer, we analyzed which signaling pathway is implicated in the abnormal monocyte differentiation into DC determined by the presence of Primary effusion lymphoma (PEL) released factors. Our results indicate that the DC, obtained in this condition, together with phenotypic abnormalities and reduced allostimulatory function, showed hyperphosphorylation of signal transducer and activator of transcription 3 (STAT3) and p38 mitogen-activated protein kinase (MAPK) molecules, in comparison to the DC differentiated in the absence of PEL released factors. The inhibition of p38 MAPK but not of STAT3 phosphorylation, with specific inhibitors, was able to revert the effect of the PEL-released factors on the DC phenotype. This study suggests that p38 MAPK signaling pathway is an important contributor to the abnormal differentiation of DC in PEL. PMID- 21244758 TI - Ethyl pyruvate therapy attenuates experimental severe arthritis caused by type II collagen (CII) in the mouse (CIA). AB - This study tested the hypothesis that ethyl pyruvate (EP), a simple aliphatic ester with anti-inflammatory effects, can reduce type II collagen-induced mouse arthritis (CIA). DBA/1J mice were used for the study, developing erosive hind paw arthritis when immunized with CII in an emulsion in complete Freund?s adjuvant (CFA). The incidence of CIA was 100 percent by day 28 in the CII-challenged mice, and the severity of CIA progressed over a 35-day period with radiographic evaluation revealing focal resorption of bone. The histopathology of CIA included erosion of the cartilage at the joint margins. EP-treatment (40 mg/kg/day i.p.) starting at the onset of arthritis (day 25) ameliorated the clinical signs at days 26-35 and improved histological status in the joint and paw. Immunohistochemical analysis for nitrotyrosine, poly (ADP-ribose) (PAR), inducible nitric oxide synthase (iNOS) revealed a positive staining in inflamed joints from mice subjected to CIA, while no staining was observed for HO-1 and Nrf-2 in the same group. The degree of staining for nitrotyrosine, PAR, iNOS, was significantly reduced in CII-challenged mice treated with the EP. Immuno-positive staining for HO-1 and Nrf-2 was observed instead, in joints obtained from the EP treated group. Plasma levels of TNF-alpha, IL-6 and the joint tissue levels of macrophage inflammatory protein (MIP)-1alpha and MIP-2 were also significantly reduced by EP treatment. Thirty-five days after immunization, EP-treatment significantly increased plasma levels of IL-10. These data demonstrate that EP treatment exerts an anti-inflammatory effect during chronic inflammation and is able to ameliorate the tissue damage associated with CIA. PMID- 21244759 TI - Reductive alteration of the regulatory function of the CD4(+)CD25(+) T cell fraction in silicosis patients. AB - Causal links have been documented between silica and rheumatoid arthritis, lupus erythematosus, systemic sclerosis and glomerulonephritis. Two different effects of silica have been suggested, an enhanced inflammatory response in the pulmonary region (e.g. activation of alveolar macrophages) and dysregulation of autoimmunity. Based on our previous reports showing in vitro activation of peripheral T cells by silica and reduced regulatory function of the peripheral CD4(+)CD25(+) fraction in which FoxP(3)+ regulatory T cells (Treg) are located, reconstitution of the CD4(+)CD25(+) fraction in silicosis patients (SILs) was investigated. Since T cells in peripheral CD4(+)CD25(+) and CD4(+)CD25(-) (effector T cells; Teff) fractions from SILs showed higher expression of pd-1 (a marker gene for T cell activation) in comparison to that of healthy donors (HDs), chronic T cell activation was considered to have occurred in SILs. In this study, a higher expression of the CD95/Fas molecule in Treg was recorded from silicosis patients (SILs) compared to healthy donors (HDs), and excess loss of FoxP3(+) Treg in freshly isolated peripheral blood mononuclear cells (PBMCs) from SILs relative to HDs was demonstrated when these cells were cultured with silica ex vivo, whereas CD25(+) cells were not reduced due to contamination of activated Teff in the CD4(+)CD25(+) fraction. The activation of both Teff and Treg results in reconstitution of the peripheral CD4(+)CD25(+) fraction, loss of Treg and contamination of activated Teff, resulting in reduction of the number and function of Treg. These results contribute to our understanding of the development of autoimmune diseases found in SILs. PMID- 21244760 TI - Response of crypt paneth cells in the small intestine following total-body gamma irradiation. AB - Ionizing irradiation causes damage and functional failure of irradiation sensitive systems and tissues such as small intestine. The molecular mechanisms underlying inflammatory and adaptive responses to acute irradiation damage are poorly understood. Using a mouse model of total-body gamma-irradiation, we assessed the irradiation response of crypt host-defense Paneth cells by measuring alpha-defensin 4 (AD4) expression and correlated the gathered data with activation of the caspase-1/IL-1beta inflammatory signaling cascade. The irradiation injury was produced in CD2F1 mice exposed to 9.25 Gy gamma-radiation. This dose resulted in 85-100 percent mortality at the 15(th) day post irradiation. Small intestine tissue samples were collected at the 7th day post irradiation. Assessment of irradiation-associated pro-inflammatory alterations in small intestine tissue and expression of AD4 in Paneth cells was conducted using confocal immunofluorescence imaging, transmission electron microscopy (TEM), light microscopy, and immunoblotting techniques. The small intestine analysis revealed an increase in the precursor form of IL-1beta, the activated form of IL 1beta, and the activated form of caspase-1 (p10 CASP-1) at the 7(th) day post irradiation. Immunoprecipitation analysis showed increased interaction between IL 1beta and p10 CASP-1 after irradiation. This effect was observed in the irradiated small intestine and CD15-positive Paneth cells using confocal imaging techniques. The pro-inflammatory alterations in Paneth cells were accompanied by increases in AD4 mRNA and its 8 kD peptide product. Paneth cell secretory activity was observed at the sites of bacterial translocation in the crypt lumens. These data suggest that Paneth cells can contribute to small intestine inflammatory remodeling during the post-irradiation period. PMID- 21244761 TI - Effects of toluidine blue-mediated photodynamic therapy on periopathogens and periodontal biofilm: in vitro evaluation. AB - Photodynamic therapy (PDT) is a selective modality of killing targeted cells, mostly known for its application in neoplasms. PDT can be considered to be an alternative method for the elimination of periodontal bacteria from the pocket without harms for the resident tissues. Therefore, PDT may replace systemic antibiotics and enhance the effect of mechanical treatments of periodontal defects. This effort focused on the in vitro sensitization of periopathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Fusobacterium nucleatum and Prevotella intermedia ) Toluidine Blue mediated and on the use of a Diode laser emitting source. The objective of this research was to evaluate the bactericidal in vitro effect of laser diodes 830 nm (as the light source) after photosensitization with Toluidine Blue (TBO) on the following periopathogenic bacteria: Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Fusobacterium nucleatum and Prevotella intermedia. After evaluating the effect on the single bacterial strain, the ability of Diode Laser to disrupt the structure of biofilms produced by A. actinomycetemcomitans after photosensitization with TBO was also analyzed. The study suggests that the association of TBO and diode laser light 830 nm is effective for the killing of bacteria strains and determines the photoinactivation of Aggregatibacter biofilms. In summary, photodynamic therapy has effectively shown its capabilities and, therefore, it can be considered a valid alternative approach to antimicrobial therapy of periodontitis. PMID- 21244762 TI - Development and preliminary validation of a diagnostic score for identifying patients affected with adult-onset autoinflammatory disorders. AB - To date, the rate of detection of autoinflammatory gene mutations in patients suspected of having an autoinflammatory disorder is very low. However, most of these data refer to pediatric populations. The relative rarity and lack of information on adult-onset autoinflammatory diseases make it likely that mutations will be found in an even smaller percentage of cases. Our aim was to develop and validate a set of variables for predicting the risk that a given adult patient presenting with recurrent fever episodes carries mutations in the MEFV or TNFRSF1A genes, in order to increase the probability of obtaining positive results on genetic testing. One hundred and ten consecutive patients with a clinical history of periodic fever attacks were screened for mutations in the TNFRSF1A and the MEFV genes. The mean age at disease onset was 27.85 years. Detailed information about each patient?s family history, personal history, and clinical manifestations were retrospectively collected. A diagnostic score was constructed based on univariate and multivariate analysis in a randomly-selected dataset (training set; n=40). The score was validated on an independent set of the remaining patients (validation set; n=70). Age at onset (odds ratio 0.958, P =0.050), positive family history of recurrent fever episodes (OR 5.738, P = 0.006 ), thoracic pain (OR 7.390, P = 0.002), abdominal pain (OR 2.853, P = 0.038) and skin involvement (OR 8.241, P = 0.003) were independently correlated with a positive genetic test result. A diagnostic score was calculated using the linear combination of the estimated coefficients of the logistic model (cut off equal to 0.24) revealing high sensitivity (0.94), high specificity (0.94) and high accuracy (0.94). We have identified variables that appear to be strongly related to the probability of detecting gene mutations in MEF and TNFRSF1A in adults, thus improving the evaluation of patients with suspected autoinflammatory disorders. PMID- 21244763 TI - Psoriasis relapse evaluation with week-end cyclosporine A treatment: results of a randomized, double-blind, multicenter study. AB - Cyclosporine A (CsA) effectively controls psoriasis, however, its long-term continuous use is not recommended. This study aims to evaluate the efficacy and tolerability of week-end CsA microemulsion for the reduction of relapse rate in patients with chronic plaque psoriasis who had achieved clinical remission following continuous CsA therapy. The PREWENT (Psoriasis Relapse Evaluation with Week-End Neoral Treatment) study was a 24 week, randomized, double-blind, multicenter study, carried out in 22 Italian hospital or University Dermatology units. CsA was discontinued for 8 days previous to the patients being randomized to oral CsA 5 mg/kg/day or placebo for two consecutive days/week, for a total period of 24 weeks. The primary endpoint was clinical success rate at week 24, defined as the proportion of patients with no clinical worsening (no relapse or a Psoriasis Area and Severity Index (PASI) < 75 percent of pre-treatment PASI). A total of 162 patients were randomized to CsA and 81 to placebo. Clinical success rates at 24 weeks were 66.9 and 53.2 percent with CsA and placebo, respectively (p = 0.072). Time to first relapse was significantly prolonged with CsA versus placebo (p = 0.023), and PASI was significantly lower from weeks 4 to 16 in CsA recipients. In patients with moderate-severe psoriasis, the clinical success rate was significantly increased with CsA compared to placebo (69.9% vs 46.3%; p = 0.011), and significantly lower increases in PASI were observed from week 4 to week 24 (p < 0.05 vs placebo). CsA was well tolerated, with no differences in mean blood creatinine or blood pressure between CsA and placebo recipients. However, the high withdrawal rate (22.2% of randomized patients), which was not related to side effects, may have led to an overestimation of efficacy, but the study had a good statistical power (88% greater than that observed in similar studies, i.e. 80%). Week-end CsA administration was shown to prolong safely and effectively the time to first relapse in psoriasis patients. PMID- 21244764 TI - Dexamethasone affects Fas- and serum deprivation-induced cell death of human osteoblastic cells through survivin regulation. AB - Glucocorticoid-induced bone loss is the most prevalent form of secondary osteoporosis. Such loss could be due to the alteration of osteoclast and osteoblast lifespan through regulated apoptosis. The current study investigated the effect of dexamethasone on Fas- and starvation-induced apoptosis of mature osteoblasts and their precursors. Using the human osteoblastic hFOB1.19 and the MG63 osteosarcoma cell lines, we found that sub-lethal doses of dexamethasone act on pre-osteoblasts but not on mature cells by increasing their susceptibility to apoptosis. Apoptosis occurs in a caspase-dependent manner as both DNA fragmentation and mitochondrial transmembrane potential dissipation (DeltaPsim) are inhibited by the pan-caspase inhibitor zVAD. The increased susceptibility of osteoblast precursors to apoptosis could be due to dexamethasonemediated down regulation of survivin expression. Dexamethasone can up-regulate survivin, and to a lesser extent Bcl-2, in mature cells but not in pre-osteoblasts. In addition, it can induce FLIP over-expression in osteosarcoma cells. All these effects are inhibited by the glucocorticoid antagonist RU486, indicating that dexamethasone action is specific and, furthermore, that it depends on glucocorticoid receptor. Finally, we have found that survivin and Bcl-2 are essential for pre- and mature osteoblast survival as their silencing is sufficient to induce spontaneous apoptosis in both cell types. In conclusion, our data outline a new molecular mechanism of glucocorticoid-mediated bone loss due to the enhanced apoptosis of precursors compared to mature osteoblasts. Furthermore, the data suggest a mechanism of dexamethasone-induced resistance of osteosarcoma cells to Fas- and stress-induced apoptosis. PMID- 21244765 TI - Inhibition of HSV-1 replication by laser diode-irradiation: possible mechanism of action. AB - Herpes labialis are the most frequent clinical manifestations of HSV-1 infection. Epithelial cells are able to respond to HSV-1 presence inducing the expression of IL-6, IL-1, TNF-alpha and IL-8. These proinflammatory cytokines have a function in the acute-phase response mediation, chemotaxis, inflammatory cell activation and antigen-presenting cells. In the human epithelial cell models, it has been demonstrated that, after an early induction of proinflammatory host response, HSV 1 down-modulates the proinflammatory cytokine production through the accumulation of two viral proteins, ICP4 and ICP27, whose transcription is induced by tegument protein VP16. These viral proteins, through the decreasing of stabilizing the mRNAs of proinflammatory genes, delay cytokine production to an extent that allows the virus to replicate. Moreover, viral transactivating proteins, ICP-0 and VP-16 induce IL-10 expression. The conventional treatment of herpes labialis involves the topical and systemic use of antiviral drugs but it is necessary to find new therapies that can act in a selective and non-cytotoxic manner in viral infection. Laser diode therapy has been considered as a non-invasive alternative treatment to the conventional treatment of herpes labialis in pain therapy, in modulation of inflammation and in wound healing. This study aims to report a possible mechanism of action of laser diode irradiation in prevention and reduction of severity of labial manifestations of herpes labialis virus. We investigated, in an in vitro model of epithelial cells HaCat, the laser-effect on HSV-1 replication and we evaluated the modulation of expression of certain proinflammatory cytokines (TNF-alpha, IL-1beta and IL-6), antimicrobial peptide HBD2, chemokine IL-8 and the immunosuppressive cytokine, IL-10. Our results lead us to hypothesize that LD-irradiation acts in the final stage of HSV-1 replication by limiting viral spread from cell to cell and that laser therapy acts also on the host immune response unblocking the suppression of proinflammatory mediators induced by accumulation of progeny virus in infected epithelial cells. PMID- 21244766 TI - Bioavailability of Sandimmun(r) versus Sandimmun Neoral(r): a meta-analysis of published studies. AB - For the past 25 years, cyclosporine A (CyA) has played a pivotal role in transplant immunosuppressant therapy. From the availability of the 2 primary marketed formulations (Sandimmun(r) and Sandimmun Neoral(r), Novartis), confusion has existed with regard to whether these two formulations are bioequivalent. Due to the underlying clinical relevance of this information, we therefore conducted a meta-analysis of all available comparative pharmacokinetic studies to assess whether the two different CyA formulations, Sandimmun(r) and Sandimmun Neoral(r), can be considered bioequivalent. All clinical studies that compared the bioavailability of the 2 formulations in organ transplant recipients were considered for analysis. We searched computerised databases (Embase/Excerpta Medica and Medline/PubMed) from their inception to May 2010. Only studies with AUC values determined at 12 hours were considered for analysis. Relative bioavailability was calculated with 90 percent confidence intervals (CI) for Sandimmun(r) (test substance) versus Sandimmun Neoral(r) (reference substance) according to Schuirmann?s Two One-Sided Tests Procedure and the Classical Shortest CI. Homogeneity of data was tested using the Chi(2) test. Fifteen studies were considered for meta-analysis and none of these studies reported AUC values in the 80-125 percent range required for the bioequivalence of two formulations. The overall bioavailability for Sandimmun(r) versus the microemulsion formulation Sandimmun Neoral(r) was 76 percent, with upper CI limits lower than 80 percent in some cases. Mean AUC values for Sandimmun(r) were significantly lower than those for Sandimmun Neoral(r) (p<0.01). This study demonstrates that the 2 main cyclosporine formulations, Sandimmun(r) and Sandimmun Neoral(r), cannot be considered bioequivalent. PMID- 21244767 TI - Bosentan treatment for Raynauds phenomenon and skin fibrosis in patients with Systemic Sclerosis and pulmonary arterial hypertension: an open-label, observational, retrospective study. AB - Raynaud?s phenomenon (RP) and cutaneous fibrosis are the distinctive manifestations of scleroderma, in which Endothelin-1 plays a fundamental pathogenetic role. Bosentan, an Endothelin-1 receptor antagonist used for the treatment of pulmonary arterial hypertension, retards the beginning of new sclerodermic digital ulcers (DU). This open-label, observational, retrospective study verified the effect of Bosentan on RP and skin fibrosis in sclerodermic outpatients affected by pulmonary arterial hypertension without DU. Fourteen subjects (13 women, 1 man; mean age 60 +/- 7.5 years; ten with limited and four with diffuse scleroderma) were observed at baseline (T0) and after four (T1), twelve (T2), twenty-four (T3) and forty-eight (T4) weeks during treatment with Bosentan. They were evaluated for daily quantity and duration of RP attacks and skin thickness (using modified Rodnan total skin score, MRSS). Videocapillaroscopic evaluation was performed at T0 and T4. Bosentan decreased significantly the number and duration of RP attacks, beginning at T2 (p<0.05). Videocapillaroscopy showed significant improvement of microcirculatory patterns at T4 (p<0.05). MRSS decreased throughout the study, reaching the statistical significance at T3 and T4 (p<0.01) in the whole cohort. The present data suggest that Bosentan is effective in stabilizing the microcirculation involvement and in improving skin fibrosis irrespective of scleroderma patterns. PMID- 21244768 TI - C-reactive protein and markers for thrombophilia in patients with chronic plaque psoriasis. AB - Chronic plaque psoriasis is associated to an increased risk of cardiovascular events. The aim of our study is to test patients with psoriasis for common markers of acquired and inherited thrombophilia. A cross-sectional study on 172 patients with psoriasis and 198 controls was carried out. The plasma levels of coagulation protein C, coagulation protein S, homocysteine, folic acid, C reactive protein (CRP) and fibrinogen as well as activated protein C resistance and antithrombin III activity, were measured. CRP and homocysteine levels were higher in patients with psoriasis than in controls (5.9 +/- 7.1 vs 3.1 +/- 2.4 mg/L, p=0.0003 and 16.3 +/- 12.8 vs 10.4 +/- 4.6 umol/L, p=0.0001; mean +/- SD) whereas folic acid was lower in psoriatic patients compared to controls (4.3 +/- 7.2 vs 12.6 +/- 7.9 p=0.006). Levels of coagulation protein C, coagulation protein S, fibrinogen as well as activated protein C resistance, antithrombin III activity were within normal ranges both in cases and controls. In a multivariate regression analysis, psoriasis severity was an independent predictor of higher CRP. In conclusion, high levels of serum CRP and homocysteine were found in patients with psoriasis, related to the severity of the disease. These data suggest that the increased risk of thrombotic cardiovascular events observed in psoriasis patients should be ascribed to an acquired rather than inherited thrombophilic status. PMID- 21244769 TI - The presence of non-segmental vitiligo modifies intracellular cytokine subsets in patients with chronic lymphocytic thyroiditis. AB - Chronic lymphocytic thyroiditis and vitiligo often occur in association and seem to be characterized by a prevalent Th1-driven autoimmune process. The aim of this study is to analyze selected intracellular Tauh1 and Th2 cytokines in patients with Hashimoto?s thyroiditis when associated with non-segmental vitiligo. We analyzed intracellular interleukin-2, interferon-gamma (Tauh1) and interleukin-4 (Th2), in peripheral blood lymphocytes of 23 patients with isolated Hashimoto?s thyroiditis (group A) and of 11 patients with Hashimoto?s thyroiditis associated with non-segmental vitiligo (group B). Peripheral blood lymphocytes were stimulated and incubated with specific monoclonal antibodies. Intracellular cytokines were assayed by flow cytometric analysis. Interleukin-2 and interferon gamma positive cells were increased in almost all patients but the median values were similar in patients with isolated Hashimoto?s thyroiditis and in those with concurrent vitiligo. In contrast, the number of patients with increased interleukin-4 positive cells was higher in patients with thyroiditis and vitiligo (9/11) than in those with isolated thyroiditis (2/23; p<0.0001). The median values of IL-4 positive cells in the two groups confirmed this difference (A: 5.8 percent, vs B: 20.6 percent; p=0.0011). Increased interleukin-4 positive lymphocytes characterize Hashimoto?s thyroiditis when associated with non segmental vitiligo, suggesting a modified balance from highly prevalent Th1 to mixed Th1/Th2 subset. PMID- 21244770 TI - Novel perspectives in the detection of oral and nasal oxidative stress and inflammation in pediatric united airway diseases. AB - United airway disease (UAD) concept proposed that asthma and rhinitis are both different clinical manifestation of a single inflammatory process. The aim of this study is to assess in upper and lower airways the level of inflammation and oxidative stress and to investigate the relationship between biomarkers in persistent allergic rhinitis (PER) and in concomitant asthma with PER. By a crosssectional study we measured oral and nasal (FENO) and oral and nasal EBC 8 isoprostane, LTB4 and PGE2 in children with PER (n=14) and with PER and concomitant intermittent asthma (IA; n=25), mild persistent asthma (mA; n=28), moderate persistent asthma (MA; n=13) and in Healthy Controls (HCs; n=13). Oral and nasal FENO concentrations were increased in children with PER, IA, mA and MA when compared with HCs. Nasal 8-isoprostane was higher in EBC of children with PER and asthma than in HCs. Oral and nasal LTB4 were higher in EBC of children with PER and mA than in HCs. Oral and nasal PGE2 concentrations were higher in EBC of children with PER than in HCs. Positive correlations between oral and nasal biomarkers were found in IA for LTB4 and PGE2, in mA for FENO, 8 isoprostane, LTB4 and PGE2, and in MA for PGE2. No correlations were observed in children with PER and HCs. Our results suggest that non-invasive markers of inflammation and oxidative stress might be useful to study the relationships between oral and nasal compartments in allergic children with PER and concomitant asthma with the aim of defining the UAD. PMID- 21244771 TI - The clinical impact of a cardiologic follow-up in breast cancer survivors: an observational study. AB - Anthracycline-containing chemotherapy (A-CHT) can induce late cardiotoxicity adding a considerable burden to cardiovascular risk. Irradiation of left breast cancer has also been associated to an increased risk of cardiovascular disease. The aim of this observational study is to prove the usefulness of an accurate cardiovascular evaluation in left breast cancer survivors treated with radiotherapy (RT) and A-CHT. Patients with left breast cancer, on follow-up after treatment with A-CHT plus RT in an adjuvant setting, were eligible for this observational study. Patients underwent cardiovascular assessment with myocardial perfusion imaging. Thirty patients were enrolled in the study: mean age at diagnosis 55.8 years; stage: I/III; Er and/or pgR status: positive in 24/30 pts; 3 patients in pre-menopausal status. Twenty-two patients (73.3 percent) had normal perfusion imaging, 1 patient (3.3 percent) had a fixed myocardial perfusion defect, 7 patients (23.3 percent) had reversible myocardial perfusion defects; 1 patient (3 percent) with normal perfusion scan showed depressed rest and stress LVEF. Only 1 patient had a large defect and underwent coronary angiography and percutaneous coronary intervention. Five patients with small defect showed normal coronary arteries at Multislice Computed Tomography. Cardiovascular followup may reveal signs of A-CHT or RT-induced cardiotoxicity. A stress test combined with MPI- and GATED-derived data of ventricular systolic performance after stress can give information on the coronary reserve and the contractile reserve and allow early appropriate treatment. PMID- 21244772 TI - MicroRNA expression profiling of oral carcinoma identifies new markers of tumor progression. AB - Oral squamous cell carcinoma, the most frequently occurring malignant head and neck tumour, generally exhibits poor prognosis and metastases are the main cause of death. The discovery of reliable prognostic indicators of tumour progression could greatly improve clinical practice. MicroRNAs are involved in the regulation of basic cellular processes such as cell proliferation, differentiation, and apoptosis. Since miRNAs have been shown to be abnormally expressed in different tumours their importance as potential cancer prognostic indicators is increasing. To define the role of miRNA in OSCC tumours we investigated the expression profile of 15 OSCC (8 without metastasis and 7 with lymph node metastasis) using microarray analysis. Thirteen miRNA were significantly overexpressed (miR-489, miR-129, miR-23a, miR-214, miR-23b, miR-92, miR-25, miR-210, miR-212, miR-515, miR-146b, miR-21, miR-338) and 6 miRNA were underexpressed (miR-520h, miR-197, miR-378, miR-135b, miR-224, miR-34a) in oral tumours. Underexpression of mir-155, let-7i, mir-146a was found to characterize progression to metastastatic tumours. Further investigations will elucidate whether differentially expressed miRNAs will help to better classify OSCCs, thus improving diagnoses and patient care. PMID- 21244773 TI - Adjuvant effect of a probiotic fermented milk in the protection against Salmonella enteritidis serovar typhimurium infection: mechanisms involved. AB - Probiotics may offer protection against Salmonella enteritidis serovar Typhimurium infection via different mechanisms. The aim of this study is to investigate, using mouse models, the effect of the administration of fermented milk containing the probiotic bacteria L. casei DN-114 001 in the protection against Salmonella enteritidis serovar Typhimurium when this product is administered continuously before and after infection or only post-infection. The adjuvant effect of this probiotic fermented milk (PFM) against S. Typhimurium was also evaluated in newborn mice, whose mothers received the PFM during the suckling period or their offspring after weaning. The results obtained showed that PFM administration after salmonella infection was useful to decrease the severity of the infection. The best effect was obtained with continuous PFM administration. In the newborn mice model, PFM administration to the newborn mice after weaning showed the best effect against the pathogen. PFM administration to the mother during the suckling period was beneficial against this enterophatogen when their offspring did not receive probiotics after weaning. Continuous PFM administration to adult mice (before and after infection) was important to maintain the intestinal barrier and the immune surveillance in optimal conditions to diminish the pathway of entrance of salmonella and the spread of this pathogen to deeper tissues. In the newborn mice model, it was observed that PFM administration to the offspring after weaning or their mother during the suckling period had a protective effect against salmonella infection, however, in the mice from mothers that received PFM during nursing which were fed with PFM after weaning, we found a down regulated immune maturity that was not protective against this infection. PMID- 21244774 TI - Chlamydophila pneumoniae infection in patients undergoing carotid artery stent. AB - Although several reports have correlated Chlamydophila pneumoniae (CP) infection with carotid endarterectomy and coronary stent, no data have been reported on the potential relationship between this pathogen and carotid artery stenting (CAS). Hence, we evaluated 47 subjects, 27 symptomatic and 20 asymptomatic, before CAS intervention and during the follow up, for the presence of CP DNA and anti-CP antibodies, including chlamydial HSP60 (Cp-HSP60). Before stent placement, CP DNA was detected exclusively in symptomatic patients, all of whom were also positive for CP IgG and IgA and 85.7 percent of them also had CP-HSP60 antibodies. At the follow-up, all CP DNA positive and 11 out of the 13 symptomatic patients with Cp HSP60 antibodies became negatives. In contrast, no change was observed for CP- IgA antibodies. Despite the small number of patients, the present study advocates an important role of CP infection in symptomatic patients with carotid artery disease. Our findings also suggest that stent placement and/or therapy might have a role in favouring resolution of inflammation, though not affecting persistence of CP infection. PMID- 21244775 TI - Streptococcus mutans and Streptococcus sobrinus are able to adhere and invade human gingival fibroblast cell line. AB - Streptococcus mutans and Streptococcus sobrinus, the principal etiologic agents of caries decay of teeth, are generally acquired in oral cavity at the moment of tooth eruption. However, as S. mutans has been detected in oral cavity of predentate children, the eruption of teeth seems not to be a necessary prerequisite, suggesting that this species may be not confined to dental plaque. Here, we evaluate the ability of S. mutans and S. sobrinus in planktonic and biofilm lifestyle to adhere, invade and survive within human gingival fibroblast (HGF-1) cells. Planktonic and biofilm streptococci adhered and invaded host cells to different extents, showing higher efficiencies of biofilm than planktonic counterparts. Moreover, planktonic and biofilm streptococci showed the same percentage of survival within host cells. Transmission electron and confocal microscopy observations confirmed intracellular localization of planktonic and biofilm bacteria. The adhesion, invasion and survival abilities within human oral cells may be considered S. mutans and S. sobrinus virulence mechanisms to colonize and persist in the oral cavity in the absence of tooth surface. PMID- 21244776 TI - Celiac disease, primary biliary cirrhosis and helicobacter pylori infection: one link for three diseases. AB - The association between celiac disease (CD) and primary biliary cirrhosis (PBC) has been reported in literature. Recent epidemiological studies showed an increased prevalence of CD in patients with PBC and vice versa. The cause of PBC is unknown. However, considerable evidence points to an autoimmune basis. The role of infectious agents, such as Helicobacter pylori (H. pylori), has been proposed to stimulate antibody cross-reaction with mitochondria of the bile duct cells. We report a case of a 36-year-old woman with diagnosis of CD, PBC and H. pylori infection. Strict adherence to gluten-free diet, associated to ursodeoxycholic acid (UDCA) administration and eradication treatment for H. pylori infection, led to a marked improvement of clinical status. Our experience supports the pathogenetic role of increased intestinal permeability in the course of CD and H. pylori infection to induce PBC. Future studies are needed to clarify this link to, and in particular the role played by abnormal intestinal permeability and infectious agents in the pathogenesis of PBC. PMID- 21244778 TI - Severe giant cell arteritis associated with essential thrombocythaemia. AB - Giant-cell arteritis (GCA) is a chronic vasculitis of the elderly usually involving the ophthalmic arteries, which can result in visual loss. High platelet counts may have some pathogenic significance in the obstruction of the ophthalmic circulation and a few cases of associated essential thrombocythaemia and GCA have been described. Here we report a case of severe temporal arteritis associated with essential thrombocythaemia. PMID- 21244777 TI - Can immune disorders influence therapeutic approaches in treatment of epilepsy among neurologists? A first cooperative national recognition in Italy. AB - Functional disturbances of the immune system have been detected more often among persons affected by epilepsy than in the general population. In the February-July period of 2007 a specific questionnaire on the relationship between epilepsy and immunological response was sent to 27 specialized Centres for Epilepsy in nine Italian regions. 15,388 epileptic patients attended twenty-seven Centers during this six-month period. 3.3 percent (n=502) of these patients suffered an immune disease. This is the first National survey on the relationship between epilepsy and immunological response in current clinical practice. PMID- 21244779 TI - Is hypogammaglobulinemia a constant feature in Good's syndrome? AB - Thymomas are rare tumors, which can be associated to a variety of paraneoplastic syndromes, including a fatal hypogammaglobulinemia, namely Good?s Syndrome (GS). Although the combination of thymoma and hypogammaglobulinemia is regarded as sufficient for diagnosis of Good?s syndrome, some thymoma patients with a clear clinical picture of immunodeficiency present normal levels of immunoglobulins. We describe the case of a patient, with a 20-year history of thymoma, who underwent several operations and lines of chemotherapy, and suffered from recurrent infections, including one rare skin infection from Pseudoallescheria boydii. The patient constantly presented normal levels of gammaglobulins. PMID- 21244781 TI - Skin reactions triggered by the use of cosmetic products in nonspecific lipid transfer protein-sensitive patients. AB - Nonspecific lipid transfer proteins (nsLTPs) are members of the prolamine superfamily and they are found in pollen and food, as well as in latex. Due to the strong stability both against pepsin digestion and thermal denaturation, sensitisation towards these proteins is often associated with severe systemic reactions (angioedema, urticaria, asthma, anaphylaxis, etc.) following the ingestion of both raw or fresh food and cooked or preserved food. Many studies have shown reactivity towards nsLTPs both via inhalation and orally and in this study we present two cases of nsLTPs-sensitive patients who manifested the immediate onset of skin reactions following the use of cosmetic products containing these proteins. Thus, in order to prevent immediate reactions linked to their use, it is necessary to recommend nsLTPssensitive patients to avoid the topical use of products containing these proteins (and obviously the ingestion of foods containing these proteins). PMID- 21244780 TI - Paraneoplastic sensitive neuropathy associated with anti-hu antibodies in a neuroendocrine tumor of duodenum: a case report. AB - Paraneoplastic sensitive neuropathy is one of the most common presentations among a group of cancer-related disorders known as Paraneoplastic Neurological Syndromes (PNS). PNS likely have an autoimmune etiology since they have been associated with the presence of antibodies against neuronal antigens expressed by tumor cells (such as anti-Hu, anti-Ri and anti-Yo). The tumors most frequently associated with PSN and onconeural antibodies are lung cancer, lymphomas and gynaecological tumors; however, they have also been described in other tumors. We report, for the first time, a case of neuroendocrine tumor of duodenum and PNS associated with anti-Hu antibodies. Moreover, we analyze and discuss the clinical implications that PNS and anti-Hu could have in patients with tumors. PMID- 21244783 TI - Comparison of serum specific IgE and skin prick test in polysensitized patients. AB - The aim of this study is to evaluate serum specific-IgE in a large group of polysensitized patients with the same SPT result (such as ++++) comparing two diagnostic methods. Six hundred ten patients (310 females; median age 32 years) suffering from allergic rhinitis were studied. Serum specific-IgE were measured by ImmunoCap assay. Skin prick test was also performed. There was a significant difference between serum specific-IgE values in these polysensitized patients. In conclusion, the serum specific-IgE measurement in polysensitized patients seems to be more appropriate than SPT. PMID- 21244782 TI - Acute pneumonia in a fire-eater. AB - Fire-eater's lung, an acute exogenous lipoid pneumonia, is caused when street performers accidentally inhale pyrofluids. We report the case of a young fire eater who, 12 hours after inhaling an iso-alkanebased pyrofluid, developed fever, dyspnoea, dry cough and intense right chest pain. Radiographic signs of pneumonia emerged two days later. Computed tomography (CT) scans visualized an irregular area of parenchymal consolidation with an air bronchiologram and peripheral ground-glass opacities in the right middle lobe. The diagnostic work-up included microbiological and lung function tests, optic fibre bronchoscopy and an in-depth cyto-immunological analysis of bronchoalveolar lavage fluid. Symptoms gradually improved over a few days. A CT scan one month later showed the thickened parenchymal area in the right middle lobe had almost completely disappeared. PMID- 21244784 TI - Preterm newborns are provided with triggering receptor expressed on myeloid cells 1. AB - Triggering receptor expressed on myeloid cells-1 (TREM-1) and soluble fraction (sTREM-1) are useful markers of infection in adults. Neonates, especially preterm infants, are exposed to high risk of sepsis due to the immature immune system and few data are available regarding TREM-1, mainly focused on the soluble form. We therefore decided to investigate the baseline assessment of TREM-1, membrane and soluble receptors, in preterm newborns without clinical or microbiological evidence of infection, in order to precociously measure the possible changes due to sepsis and compare them to the obtained reference values. Fifty-nine newborns were enrolled in the study. Median and Interquartile range of TREM-1 were: in monocytes 96 percent with 71 Mean Fluorescence Intensity (50-94); in PMNs: 80 percent (68-87); soluble TREM-1: 29.1 pg/ml (14.55-103.93). Monocyte expression and soluble TREM-1 concentrations appeared comparable to healthy adults, while not all PMNs expressed this receptor, possibly due to their immaturity. Birth weight negatively correlated with sTREM-1, while there were no statistical significances with gestational age, maternal age, gender, mode of delivery, patent ductus arteriosus, intrauterine growth restriction, premature rupture of membranes and TREM-1 or sTREM-1. We also reported a statistical relationship between monocyte TREM-1 and surfactant administration and between sTREM-1 and antenatal steroid prophylaxis. Even if untrained, the neonatal immune system of preterm newborns is equipped with TREM-1 system, but further studies are needed to evaluate the functionality in newborns. PMID- 21244785 TI - Long-term assessment of plasma lipids in transplant recipients treated with tacrolimus in relation to fatty liver. AB - Immunosuppression has improved graft and recipient survival in transplantation but is associated with possible adverse effects including cardiovascular diseases. The impact of tacrolimus on the lipidic profile has been debated for several years. Twenty-nine kidney transplant recipients on tacrolimus treatment were monitored for six years, and multiple laboratory parameters investigating the lipid asset, as well as glucose profile, were carried out. Tacrolimus has been responsible for significant changes in plasma lipid concentrations only for the first six months, but not for the remaining time of observation. Similarly, in the same periods, glycemic imbalance was highlighted. The liver enzyme activity showed a modest derangement during the tacrolimus treatment, suggesting the presence of lipid accumulation in the liver. Fatty liver reversed in the long term follow-up. Tacrolimus, although it is not a completely safe option in the first months of the immunosuppressive protocols in organ transplanted recipients, still retains a certain role in the long-term post-transplantation immunosuppressive approach with high cardiovascular risks. PMID- 21244786 TI - [The anti-lung cancer activity of a modified HPV 16 type mE6Delta/mE7 fusion protein based vaccine in an experimental animal model]. AB - BACKGROUND: To investigate the outgrowth inhibition of the HPV16-positive murine lung tumor induced by a modified HPV16 mE6Delta/mE7 recombinant fusion protein vaccine in vivo and provide a new clue for the further immunotherapy. METHODS: For prophylactic experiments, C57BL/6 mice were immunized with mE6Delta/mE7 fusion protein, and then inoculated with the TC-1 tumor cell, expressing HPV16 E6 and E7 viral proteins. On day 33 after inoculation, the tumor-free mice were re challenged with a larger dose of TC-1 tumor cells. For therapeutic experiments, mice were vaccinated with mE6Delta/mE7 on days 3 and 14 after tumor cell inoculation. On day 60, the tumor-free mice were re-challenged with a larger dose of tumor cells. Tumor incidence and tumor volume of each group were calculated. MTT method was used to determine the proliferation of lymphocyte. RESULTS: In the prophylactic experiments, immunization with the mE6Delta/mE7 completely protected the mice against the tumor cell challenge and rechallenge, and all the mice remained tumor free during the 100 days' observation period. In contrast, all the mice in PBS and IFA-treated groups developed tumors within 6-12 days after the first tumor cell inoculation, and died of tumor burden within 30 days. In the therapeutic experiments, the tumor formation rates were 20%, 90% and 60% in vaccinated, PBS and IFA groups respectively. In the next larger dose of tumor cells rechallenge experiment, 87.5% of vaccinated mice still remained tumor free, but all the mice from either PBS or IFA group developed tumors with 4-6 days. In addition, the results of MTT indicated that the proliferation of lymphocytes from vaccinated mice was stronger than that from control group. CONCLUSIONS: The modified mE6Delta/mE7 can efficiently inhibit the growth of lung cancer in the animal model, indicating that mE6Delta/mE7 protein-based vaccine might show promise for the future clinical application. PMID- 21244787 TI - [Expression of SOCS3 gene and its effect on cell proliferation in human lung adenocarcinoma cell line A549]. AB - BACKGROUND: To investigate the expression of the SOCS3 gene and its effect on proliferation of A549 cells. METHODS: A549 cells were cotransfected with pEFSOCS3 and pSV2neo by liposome, then G418 was used to screen the positive cells. Expression of SOCS3 mRNA and protein was detected by RT-PCR and immunocytochemistry respectively before and after transfection. MTT assay was used to detect the cell growth. Flow cytometric DNA analysis was used to determine the cell cycle. RESULTS: RT-PCR and immunocytochemistry showed that no expression of SOCS3 mRNA and protein was detected in A549 cells before transfection, but a stable expression of SOCS3 gene was observed after transfection with SOCS3 gene. Compared with control group, growth of A549 cells transfected with SOCS3 gene was significantly suppressed, with a suppressive rate of 41.07%. The cells at G0/G1 cell phases increased, and those at S and G2/M phases decreased significantly after transfection. CONCLUSIONS: SOCS3 protein might inhibit the proliferation of A549 cells by negatively regulating cellular signal pathways. PMID- 21244788 TI - [Inhibitive effect of LAK cells induced by dendritic cells on implanted lung cancer in nude mice]. AB - BACKGROUND: To study the inhibitive effect of LAK cells induced by dendritic cells (DCs) on implanted lung adenocarcinoma in nude mice. METHODS: The lung adenocarcinoma model was constructed in nude mice using the resected samples of lung cancer patient. The lung cancer cell lysate was obtained by free-zing and thrawing cycles. Peripheral blood mononuclear cells (PBMNC) were obtained from venous blood of the same patient, in which the adherent PBMNC fraction was cultured with DCGF, and the non-adherent PBMNC fraction was cultured with rhIL-2. DCs were pulsed with lung cancer cell lysates. And then mature DCs were incubated with LAK cells and the mixed cells were named DC-LAK cells. DC-LAK cells were injected into lung cancer-bearing nude mice to observe the inhibitive effect. RESULTS: The lung adenocarcinoma mo-del was successfully constructed. The average tumor weights of DC-LAK, LAK, DC and saline control groups were 0.47, 1.05, 1.30 and 1.58 g respectively, and the inhibitive rates of DC-LAK, LAK and DC were 70.3%, 33.5% and 17.9% respectively. The antitumor activity of DC-LAK cells was significantly stronger than that of LAK cells (P < 0.05). CONCLUSIONS: The results of in vivo experiment show that the antitumor activity of DC-LAK cells is stronger than that of LAK cells, so DC-LAK cells treatment may be a more efficient approach of lung cancer biological therapy. This experiment may provide a foundation for clinical application of DC vaccine. PMID- 21244789 TI - [Overexpression of p73 gene inhibits VEGF and bFGF mRNA expression in lung adenocarcinoma cell]. AB - BACKGROUND: To study the effect of overexpression of p73 gene on cell growth curve and vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) mRNA expression in lung adenocarcinoma cell, and to explore its effect on angiogenesis in lung adenocarcinoma. METHODS: p73alpha and p73beta were transferred into A549 cell and H1299 cell by liposome, the positive cell clones were chosen by G418. The cell growth curves were drawn by cell counting. The expressions of VEGF and bFGF mRNA were detected by RT-PCR. RESULTS: Overexpression of p73 gene could inhibit the growth of A549 cell and H1299 cell. VEGF and bFGF mRNA expressions in A549 cell and H1299 cell were decreased after transfer of p73 gene (P < 0.05), VEGF mRNA was decreased more obviously after transfer of p73beta (P < 0.01). CONCLUSIONS: Overexpression of p73 gene can inhibit the growth of lung adenocarcinoma cell, decrease VEGF and bFGF mRNA expression. The results suggest that overexpression of p73 gene might be involved in the regulation of VEGF and bFGF gene expression in lung adenocarcinoma and act as an antioncogene. PMID- 21244790 TI - [Effects of photodynamic therapy on human lung adenocarcinoma cell line A549]. AB - BACKGROUND: To observe the effects of photodynamic therapy (PDT) on human lung adenocarcinoma cell line A549 in vitro. METHODS: Human lung adenocarcinoma cell line A549 was used to investigate the killing role of PDT with hematoporphyrin derivative (HPD) as photosensitizer and semiconductor successive laser as light source. The cultured cell was treated with different concentrations of HPD and different do-sages of laser, then MTT colorometric assay was applied to measure the OD492. RESULTS: 5 mg/L of HPD was confirmed no effect. 10 mg/L of HPD could produce a marked therapeutical effect under the condition of same laser dosage. When the concentration of HPD was increased, the effect was not risen obviously. 10 J/cm2 of laser could lead OD492 to decrease to platform under the condition of same HPD concentration. So the killing effect was saturated when the PDT parameters were selected as 10 mg/L of HPD and 10 J/cm2 of laser. Under the same laser capacity density of 10 J/cm2, A549 cells were exposured to three different duty-time fabrications which were 214 mw*10 min, 428 mw*5 min and 714 mw*3 min.The outcomes showed that OD492 had no statistical difference. CONCLUSIONS: PDT has a significant killing effect on human lung adenocarcinoma cell line A549. 10 mg/L of HPD and 10 J/cm2 of laser were the best parameters of this experiment. The PDT effect is not influenced by different duty-time fabrications under the best laser capacity density. PMID- 21244791 TI - [Guideline of surgical practice for non-small cell lung cancer based staging]. AB - The clinical evidences of the guideline came from clinical trials based evidence based medicine. Applied principle of the evidence was: systematic reviews, RCTs, the results from multiple factors ana-lysis, consensus, especially combined with Chinese experience and some lung cancer guidelines used in USA or Europe. All doctors who use the guideline in making therapeutic strategy must combine patients' conditions with the knowledge of biological behavior, dynamic change and response to treatment of lung cancer. PMID- 21244792 TI - [Relationship between protein kinase CbetaI(PKC-betaI) expression, apoptosis and prognosis in patients with non-small cell lung cancer]. AB - BACKGROUND: To investigate the relationship between expression of PKC-betaI, apoptosis and prognosis of non-small cell lung cancer (NSCLC). METHODS: The expression of PKC-betaI and apoptosis index (AI) were detected in 119 human NSCLC tissues and paracancerous tissues by LSAB and TUNEL, with 32 benign pulmonary disease tissues as control. RESULTS: (1)The expression of PKC-betaI (82.27%) in NSCLC tissues was significantly higher than those (62.85% and 50.47%) in paracancerous tissues and benign pulmonary disease tissues (P < 0.05). The AI (5.27%) in NSCLC tissues was significantly lower than that ( 15.84%) in benign pulmonary disease tissues (P < 0.05). (2) No significant relationship was observed between the expression of PKC-betaI and clinical physiopathological characteristics of NSCLC (P > 0.05). The AI was closely related to pTNM stage of the cancer, size of primary tumor and lymph node metastasis (P < 0.05), but not to the histological classification, cell differentiation, sex and age of the patients with NSCLC (P > 0.05). (3) A highly significant negative correlation was observed between PKC-betaI expression and AI in NSCLC group (P < 0.01). (4) The 5 year survival rate (7.37%) in patients with high PKC-betaI expression was much lower than that (37.06%) in patients with low PKC-betaI expression (P < 0.01). The 5-year survi-val rate ( 39.24%) in patients with high AI was much higher than that (6.14%) in patients with low AI (P < 0.01). CONCLUSIONS: The abnormal activation of PKC-betaI and suppression of apoptosis may play important roles in the oncogenesis and prognosis of lung cancer. Detection of PKC-betaI expression and AI may help to predict the prognosis of patients with NSCLC and guide the postoperative multimodality therapy. PMID- 21244793 TI - [Expression and mutation of beta-catenin in non-small cell lung cancer]. AB - BACKGROUND: To study the expression and mutation of beta-catenin in non-small cell lung cancer (NSCLC) and the relationships between expression, mutation and clinicopathological parameters and prognosis. METHODS: All the 120 samples (fixed with 10% formalin and embedded in paraffin blocks) were obtained from patients with NSCLC, who underwent surgery in the First Affiliated Hospital of China Medical University from 2001 to 2002 and Anshan Tumor Hospital from 1980 to 2001. Follow-up was available in 67 patients. The 53 fresh NSCLC samples and corresponding normal lung tissues were obtained from the First Affiliated Hospital of China Medical University. The pattern of beta-catenin protein expression was detected by immunohistochemistry method (120 samples) using anti beta-catenin antibody (1:600). The level of beta-catenin protein expression was detected by Western Blotting method using anti-beta-catenin antibody (1:1500) in 53 fresh NSCLC samples and corresponding normal lung tissues. The mutation of beta-catenin gene exon 3 was detected by polymerase chain reaction (PCR) and direct sequencing method (53 samples). RESULTS: In 120 patients, abnormal expression rate of beta-catenin was 80% (96/120) and nuclear expression rate was 36.7% (44/120). There was significant difference in beta-catenin expression between well differentiated and poorly differentiated NSCLC. In well and moderately differentiated NSCLC cells the abnormal expression rate was 69.2% (45/65), which was much lower than 92.7% (51/55) of poorly differentiated ones (P=0.003). beta-catenin expressed abnormally in 86.5% (64/74) cases with lymph node metastasis and in 69.6% (32/46) cases without lymph node metastasis (P=0.044). The results of Western Blotting showed that the expression of beta catenin in NSCLC tissues was significantly higher than that in normal lung tissues (t=2.935, P=0.005). The 53 patients' DNA were analysed by PCR and direct sequencing method, but no mutation in beta-catenin gene exon 3 was found. CONCLUSIONS: Abnormal expression of beta-catenin is negatively associated with differentiation and positively associated with lymph node metastasis of NSCLC. The beta-catenin gene exon 3 mutation is not the main reason of beta-catenin abnormal expression in NSCLC. PMID- 21244794 TI - [Expression of fas and P53 protein in resected non-small cell lung cancer and its prognostic significance]. AB - BACKGROUND: To study the expressions and its clinical significances of fas and P53 protein in human non-small cell lung cancer (NSCLC) after complete surgical resection. METHODS: Immunohistochemical stain of fas and P53 was performed on paraffin-embedded sections from 269 NSCLC patients who underwent surgery and were followed up for 1.1 to 122.2 (median, 48.4) months postoperatively. Differences in survival rates and clinical characteristics were evaluated by SPSS10.0 statistical software packet. RESULTS: The rate of fas and P53 expression in NSCLC cancer tissue was 43.1% and 49.4% respectively. Fas expressions were seen more frequently in female patients (59.3% vs 39.1%, P < 0.01). Univariate analysis showed that fas expression was a good factor for predicting prognosis. The 5-year survival rate of the patients whose tumors had positive fas expression was significantly better than those individuals whose tumors had negative fas expression (51.4% vs 42.4%, P=0.02), especially in patients in stage I and IIIA . The expression of P53 had no significant influence on the prognosis of these 269 NSCLC patients. Combined analysis of fas and P53 expression in NSCLC cancer tissues showed significant prognostic influence (P=0.01). The 5-year survival were 40.1% (fas+ and P53-), 45.4% (both positive or both negative) and 57.2% (fas and P53+), respectively. COX multivariate analysis showed that reduced fas expression in 269 NSCLC is an independent risk factor, especially in stage IIIA NSCLC. CONCLUSIONS: Fas and P53 protein are indicators of NSCLC biological behavior. Reduced fas expression in NSCLC is an independent risk factor for early stage patients. Analysis of apoptosis related proteins expression in tumors might be helpful to predict the prognosis of patients with NSCLC. PMID- 21244795 TI - [Study on relationship between p63 expression and 3q27-q29 alteration in non small cell lung cancer]. AB - BACKGROUND: To investigate the relationship of p63 expression and p63 locus at chromosomal 3q27-q29 in non-small cell lung cancer (NSCLC). METHODS: Chromosomal imbalance in 30 cases of squamous cell carcinoma (SCC) and 40 cases of adenocarcinoma of the lung were evaluated by comparative genomic hybridization (CGH) technology. A tissue microarray of specimens from 122 primary NSCLC specimens was employed and used for immunohistochemical detection of p63 protein expression. RESULTS: p63 positivity was found in 54 (44.26%) cases of NSCLC. p63 immunostaining was observed in 51 (86.44%) of 59 SCC, whereas only one adenocarcinoma (1.67%) showed immunoreactivity. Immunopositivity was seen in 2 (66.66%) of 3 large cell lung cancer (LCLC). No correlation existed between p63 protein expression and the age of patient, sex, tumor grading, tumor metastasis, prognosis (P > 0.05). The CGH results revealed that the gain of chromosome 3q27 q29 was identified in 32 (48.57%) of 70 NSCLC samples tested. Overrepresentation was detected in 24 cases of 30 SCC. In 40 adenocarcinoma, only 8 cases showed chromosome gain at chromosomal 3q27-q29. The comparison of p63 immunostaining with chromosomal alteration of 3q27-q29 demonstrated that pronounced gain was detected in 23 (95.83%) cases of 24 SCC with p63 immunopositivity. One case of adenocarcinoma that was p63 positive showed a chromosomal 3q27-q29 normal representation but not pronounced gain. CONCLUSIONS: The results suggest that p63 immuno-positivity correlates significantly with pronounced gains of the p63 locus at chromosomal 3q27-q29, and p63 gene amplification correlates with development and progression of lung SCC. PMID- 21244796 TI - [The influence of cryosurgery on great vessels and heart in patients with lung cancer]. AB - BACKGROUND: To evaluate the effects of cryosurgery on the great vessels and heart in patients with lung cancer. METHODS: At first, the changes of rabbit cervical artery were observed during and after cryosurgery. Then, CT-guided percutaneous lung cryotherapy (PLC) was performed in 69 patients with 73 pulmonary masses encroaching on the great vessels and heart using 2 or 3 mm cryoprobes. RESULTS: In animal model, rabbit cervical artery looked well and blood flow was normal after ice thawing. In patients with lung cancer, CT-visualized immediate ice formation appeared beyond tumor margins within 10 minutes after cryotherapy. No major bleeding or other severe sequelae was observed. CONCLUSIONS: CT-guided PLC is a promising treatment for pulmonary neoplasms invading or abutting the great vessels or heart, as well as showing minimal procedural complications or treatment sequelae. PMID- 21244797 TI - [The clinical significance of detection of vascular endothelial growth factor and CD44v6 expression in human non-small cell lung cancer]. AB - BACKGROUND: To investigate the expression of vascular endothelial growth factor (VEGF) and CD44v6 in non-small cell lung cancer (NSCLC) and to explore their association with invasion, metastasis and prognosis of NSCLC. METHODS: A rapid immunohistochemical method (streptoavidin-peroxidase, SP) was used to detect VEGF and CD44v6 proteins expression in 43 paraffin-embedded resected NSCLC tissues retrospectively. All the patients were initially treated. RESULTS: The expression rates of VEGF in squamous cell carcinoma and adenocarcinoma were 62.5% (15/24) and 68.42% (13/19) respectively. The positive rates of CD44v6 expression in squamous cell carcinoma and adenocarcinoma were 58.33% (15/24) and 68.42% (13/19) respectively. The positive expressions of VEGF and CD44v6 were significantly correlated with lymph node metastasis and TNM stage (P < 0.05), and also significantly correlated with postoperative hematogenous metastasis (P < 0.05). The 3- and 5-year survival rates of patients with VEGF positive expression were 19.23% and 6.41% respectively, whereas those with negative expression were 67.41% and 58.82%, there was signi-ficant difference of survival rate between the two groups (P < 0.05). The 3- and 5-year survival rates of CD44v6 positive expression group and negative expression group were 18.67%, 10.67% and 67.83%, 53.50%, there was also significance difference of survival rate between two groups (P < 0.05). The positive expression of VEGF was significantly correated with the positive expression of CD44v6 (P < 0.05). CONCLUSIONS: Detection of VEGF and CD44v6 expression in NSCLC is helpful to evaluate the lymph node metastasis, TNM stage and prognosis. It is also helpful to guide postoperative multiple modality therapy. PMID- 21244799 TI - [Resection and reconstruction of carina in the treatment of advanced lung cancer involving carina]. AB - BACKGROUND: To summarize the operative indication, surgical technique and perioperative ma-nagement of resection and reconstruction of carina for advanced lung cancer involving the carina. METHODS: There were 67 patients with lung cancer invaded the carina, right central lung cancer in 46 cases, peripheral lung cancer in 4 cases, involved superior vena cava (SVC) or with bilateral anonymous veins in 11 cases, left central lung cancer in 17 cases, respectively. Surgical procedure included carinal right pneumonectomy or lobectomy in 50 cases, concomitant replacement of SVC or with bilateral anonymous veins with vascular prosthesis in 11 cases, carinal left pneumonectomy in 17 cases. Follow-up was performed in long-term. RESULTS: Perioperative death occured in 8 cases (11.94%), circulatory failure in 6 cases (8.96%), and respiratory failure in 2 cases (2.99%). The overall 1-, 3- and 5-survival rate was 77.21%, 48.23% and 32.54% respectively. CONCLUSIONS: Complete resection and reconstruction of carina, SVC or bilateral anonymous veins combined with postoperatively multiple modality therapy can get good prognosis for the patients with advanced lung cancer. PMID- 21244798 TI - [Surgical treatment of lung cancer by video-assisted thoracoscopic surgery]. AB - BACKGROUND: To investigate the role of curative and palliative surgical treatment of lung cancer with video-assisted thoracoscopic surgery (VATS). METHODS: Forty three patients with lung cancer were prescribed operations with VATS, which included 5 cases of stage IA, 14 cases of IB, 1 case of IIA, 4 cases of IIB, 7 cases of IIIA, 6 cases of T4-IIIB and 6 cases of IV. The 7 patients of stage IIIA were previously staged as N0 before operation, but reevaluated as N2-IIIA after operation. There were 3 cases of malignant pleural effusion and 3 cases of pleural implantation in stage IIIB cases. There were 2 cases of cardiac tamponade, 1 case of solitary brain metastasis, and 3 cases of ipsilateral or contralateral solitary lung metastasis in cases of stage IV. The main methods of operation performed included lobectomy in 36 cases, wedge resection in 5 cases, and pericardial opening in 2 cases. Systemly mediastinal lymph node dissections were performed in 36 cases. Concurrent contralateral pulmonary wedge resections were performed in 2 cases of contralateral solitary lung metastasis. Malignant pleural effusions were prescribed resection of implantation nodules, electrocautery and pleurodesis. RESULTS: There was no perioperative death or bronchial leak. Five cases suffered lung infection, and 2 cases occurred with incision infection. Malignant pleural effusion in the 3 cases was controlled satisfactorily. Two cases of pericardial opening died in 4 months and 8 months after operation respectively. The other patients were alive till present. Postoperative hospital stay was 5-15 days with average of 7.4 days, except of two cases of pericardial opening. CONCLUSIONS: VATS is an alternative way for complete resection of early stage lung cancer. It is technically feasible to dissect mediastinal lymph node for accidental N2 lung cancer. VATS has significant advantage in concurrent bilateral pulmonary resection. The palliative operation of malignant pleural effusion and cardiac tamponade by VATS can markedly improve the quality of life of patients. PMID- 21244800 TI - [Clinical analysis of the characteristics of thoracic lymph node metastasis in lung cancer: A report of 318 cases]. AB - BACKGROUND: To investigate the clinical characteristics of thoracic lymph node metastasis in lung cancer. METHODS: Three hundred and eighteen patients with lung cancer underwent pneumonectomy or lobectomy and lymphadenectomy from Jan 2000 to Jan 2002. RESULTS: A total of 1534 groups of lymph nodes were removed. Metastatic frequency of thoracic lymph nodes was 58.5% (186/318), in which N1 was 27.0% (86/318), N2 was 31.4% (100/318). There were higher frequencies of lymph node metastasis in 4, 7, 10, 11 regions around the root of lung. Among the skipping N2 metastasis (14.5%, 46/318), upper lobe cancer led to only upper mediastinal lymph node metastasis, however, lower or right middle lobe cancer caused both upper and lower mediastinal lymph node metastasis. Of the patients with swelling hilar and mediastinal lymph nodes reported by preoperative CT scan, only 48.2% were confirmed with lymph node metastasis by postoperative histopathology; while 22.4% of the patients with normal size lymph nodes had lymph node metastasis. CONCLUSIONS: If there is no hilar and inferior carinal metastatic lymph node in patients with upper lobe cancer, the lower mediastinal lymph node dissection might not be necessary. But systematic mediastinal lymph node dissection should be performed in patients with lower lobe or right middle lobe cancer whether there is hilar or inferior carinal metastatic lymph node or not. The extent of lymph node dissection should not depend on the results of preoperative chest CT scan. PMID- 21244801 TI - [Clinical observation of gemcitabine and concurrent three-dimensional conformal radiotherapy (3D-CRT) in the treatment of locally advanced non-small cell lung cancer]. AB - BACKGROUND: To evaluate the clinical effect of gemcitabine and concurrent three dimensional conformal radiation therapy (3D-CRT) for locally advanced non-small cell lung cancer (NSCLC). METHODS: From April 2002 to June 2003, 28 patients with inoperable stage III NSCLC were treated with gemcitabine and 3D-CRT simultaneously. Chemotherapy consisted of intravenously gemcitabine 350 mg/m 2 on days 1, 8, 15, 22, 29, 36. 3D-CRT was delivered up to a total dose of 60-64 Gy with a 2.0 Gy dose fraction per day, 5 days per week. RESULTS: The overall response rates of primary tumor and mediastinum metastatic node were 89.3%(25/28) and 96.0%(24/25) respectively, and 94.7%(18/19) and 77.8%(7/9) for squamous cell carcinoma and adenocarcinoma respectively. The acute side effects of patients were mostly myelosuppression, nausea, vomiting, radiation-induced esophagitis and pneumonitis (RTOGI/II), however, all of them were cured. CONCLUSIONS: Concurrent application of gemcitabine and 3D-CRT can improve the overall response rate for locally advanced NSCLC without aggravating the side effects. PMID- 21244802 TI - [Analysis of three-dimensional conformal radiotherapy for elderly patients with stage I-III non-small cell lung cancer: results of 30 cases]. AB - BACKGROUND: To investigate the effect and complication of three-dimensional conformal radiotherapy (3D-CRT) for elderly patients with stage I-III non-small cell lung cancer. METHODS: Thirty elderly patients with stage I-III NSCLC who were treated with 3D-CRT from January, 1998 to January, 2002 were retrospectively analyzed. In the 30 patients, 46 targets were treated with 3-5 Gy per fraction to a total dose of 42-66 Gy. The effect and complication were analysed. RESULTS: The overall 1-, 2-, 3-year survival rates and the median survival time were 65.8%, 41.2%, 20.6%, and 23 months respectively. The overall 1-, 2-, 3-year local control rates were 59.8%, 31.1%, and 28.3%. The overall incidence of radiation pneumonitis was 16.7% (15/30) with grade>=3 of 6.7%, and one case was died from rediation pneumonitis. The incidence of radiation pulmonary fibrosis was 10.0% (3/30), and the incidence of radiation esophagistis was 43.3% (13/30), but both two side effects were slight. CONCLUSIONS: 3D-CRT can improved the survival in elderly patients with stage I-III non-small cell lung cancer by escalating radiotherapy doses. PMID- 21244803 TI - [Comparative study on gemcitabine plus cisplatin and vinorelbine plus ifosfamide plus cisplatin combined chemotherapy in the treatment of advanced non-small cell lung cancer]. AB - BACKGROUND: To compare the effect and toxicity between gemcitabine and cisplatin (GP) with vinorelbine, ifosfamide and cisplatin (NIP) combined chemotherapy in the treatment of patients with advanced non-small cell lung cancer (NSCLC). METHODS: Eighty patients received either gemcitabine 1 000 mg/m2 on days 1, 8, or 15 plus cisplatin 70-80 mg/m2 on day 1, or vinorelbine 25 mg/m2 on days 1, 8, ifosfamide 1.2 g/m2 on days 1-4 plus cisplatin 70-80 mg/m2 on day 1, every 28 days as a cycle. RESULTS: The objective response rate was 40.0% in GP goup, compared with 52.5% in NIP group (P > 0.05). Median survival time of GP and NIP groups was 13.68 and 15.34 months respectively, and 1-year survival rates were 54.29% and 59.46% respectively (P > 0.05). Leukopenia at grade III+IV was significantly lower in GP arm (27.5%) than that in NIP arm (55.0%) (P < 0.05). Non-hematological toxicities were less frequent in GP group than those in NIP group (P < 0.05). CONCLUSIONS: Although the response rate tends to be higher in three-drug than in two-drug combined chemotherapy, but no significant difference is observed. Three-drug combinations often result in more toxicities. Two-drug combination GP may be the standard protocol for chemotherapy of advanced NSCLC. Three-drug combination NIP should be given to young patients with good performance status. PMID- 21244804 TI - Medium-term results of total knee arthroplasty using a medially pivoting implant: a multicenter study. AB - A multicenter study was conducted to determine the durability and performance of a medially pivoting knee prosthesis in total knee arthroplasty (TKA). Between February 1999 and June 2001, 276 patients underwent 298 primary TKAs at five centers. There were 189 patients (204 knees) available for clinical evaluation after surgery, with an average follow-up of 5.4 years (range, 5.0-7.6 years). The mean age at follow-up was 69 years (range, 39-87 years). The posterior cruciate ligament was resected in 65% of the procedures. Knee Society scores (KSS) and radiographs were assessed for patients who returned for follow-up evaluation. Patients unwilling or unable to return were asked their status via telephone. There were a total of five revisions, and 5-year survivorship using Kaplan-Meier analysis was 97.2%. All radiographs exhibited well-fixed implants with no signs of gross migration or pending failure. Preoperative mean KSS and flexion were 33 and 107 degrees , respectively, improving at latest follow-up to 90 and 121 degrees , respectively. The medial-pivot prosthesis resulted in excellent survivorship with good functional results at medium-term follow-up. PMID- 21244805 TI - Open versus percutaneous tendo-achilles lengthening in spastic cerebral palsy with equines deformity of the foot in children. AB - The purpose of this study was to compare open to percutaneous tendo-achilles lengthening (TAL) as treatment for equinus deformity (ED) in children with cerebral palsy (CP). Eighteen ambulatory spastic CP children (28 feet) with isolated primary fixed ED were randomized to these two methods and prospectively followed up 7 to 18 months postoperatively (mean 11 months). The study found that the percutaneous TAL gave shorter operative time, shorter hospitalization period, better active dorsal and plantarflexion abilities, better parent satisfaction, and lower complication rate. It was concluded that percutaneous TAL seemed to be superior to the open TAL regarding the studied parameters. PMID- 21244806 TI - Analysis of sex and race and the size and shape of the distal femur using virtual surgery and archived computed tomography images. AB - Anthropometric data and stature profiling are needed for the accurate sizing of prosthetic systems in total knee arthroplasty (TKA). The purpose of this study was to collect and analyze anthropometric knee data using a virtual surgical method. Computed tomography images (107) from patients (66) of three races were converted to virtual models and oriented with an anatomical coordinate system. The models were used to obtain anterior-posterior, medial-lateral, and condylar spacing measurements. Mean values for all measurements were larger for males than females in the overall population and within each race, and differences between races were observed. Comparisons of males to females from different races showed overlapping mean measurements for males of one race and females of another. These overlaps indicate that certain measurements relevant to TKA system sizing are not strictly related to sex. PMID- 21244807 TI - Surgical outcome of scaphoid nonunions in heavy manual workers. AB - The management of scaphoid nonunion in heavy manual workers is challenging. Symptoms appear earlier and manual labor-related stress at the operated nonunion site may worsen the postoperative outcome. This study involved 16 heavy manual workers with scaphoid nonunion (11 cases involving the dominant hand) treated by internal fixation and autologous bone grafting. The nonunion was in 12 patients in the waist, in 3 patients in the proximal, and in 1 patient in the distal pole of the scaphoid. Clinical and radiographic evaluation of union was done according to the criteria of Bynum et al. and Fernandez and Eggli. Pain, wrist motion, and grip strength were evaluated and compared to the contralateral side. At a mean follow-up of 24 months (range, 10 months to 6 years), the mean range of motion and the grip strength compared to the contralateral hand were 95% and 91%, respectively. Overall hand function was excellent in 13 patients, good in 2 patients, and fair in 1 patient. All except one patient were pain free and returned to their work without or with minimal complaints at an average of 3.4 months (range, 2-6 months), postoperatively. In 15 patients, scaphoid nonunions healed at a mean time of 64 days. One patient had a reoperation, and union was observed at 90 days after the second operation. In all patients, the radiolunate angle was restored to normal. One patient developed complex regional pain syndrome that resolved completely after 2 months with adequate intensive physical therapy. Clinical symptoms of scaphoid nonunions are more severe and appear earlier in heavy manual workers; in this group of patients, surgical treatment is necessary. The double-threaded screw provides adequate stabilization for union. Autologous cancellous bone graft, because of its plasticity and malleability to exactly fill the scaphoid defect, is recommended. PMID- 21244808 TI - A magnetic emergency release system for halo traction. AB - A magnetic emergency release system was developed for use in halo traction systems. Commercially available rare earth mounting magnets, with selected weight carrying capacities, along with ferromagnetic receptacles, were used in line between halos and overhead pulleys to both carry the prescribed traction force and provide an emergency release in the event of excessive applied force due to a transportation accident and/or sudden application of full body weight when using overhead walkers equipped with traction systems. The magnet-receptacle pairs were calibrated with an in-line digital scale. Load rate dependencies were noted, indicating that prescribed magnet-receptacle pairs should be chosen to carry at least 110% body weight. This weight capacity is reduced to approximately 88% of body weight during higher loading rates, such as transportation accidents and accidental falls. PMID- 21244809 TI - The treatment of ulnar impaction syndrome: a systematic review of the literature. AB - Ulnar impaction syndrome is a common cause of ulnar-sided wrist pain that is thought to be a result of abutment between the ulna and the ulnar carpus. A systematic review of the literature was conducted to determine the effectiveness of different treatment options in managing ulnar impaction syndrome. PubMed, the Cochrane database, and secondary references were reviewed to identify all English language articles with reported results on the treatment of ulnar impaction syndrome. A total of 16 articles met the criteria for review. Three procedures were identified as the most commonly used in treating this syndrome: ulnar shortening osteotomy, the wafer procedure, and the arthroscopic wafer procedure. Mean time to union and percentage nonunion for the osteotomy group was 10.3 weeks and 1.7%, respectively. The overall complication rate for patients in the ulnar shortening osteotomy group, the wafer procedure group, and the arthroscopic wafer group was 30%, 8.8%, and 21%, respectively. The authors were unable to determine a single best treatment option based on the available studies, mainly due to the variability in the reporting of subjective outcome measures. Ulnar shortening osteotomy was associated with a higher complication rate than other procedures. PMID- 21244810 TI - Eight-year follow-up on the effect of a hip fracture service on patient care and outcome. AB - The purpose of this study was to evaluate the 8-year effect of a hip fracture service on time to surgery; duration of surgery; length of stay in acute care, intensive care, and rehabilitation unit; and incidence of postoperative complications and in-hospital mortality. The study group consisted of 50 female patients 65 years of age or older who were treated for hip fractures in 1999 and 50 case-, age-, and American Society of Anesthesiologists score-matched female patients treated in 2006. Group differences were compared via the Student paired t test and chi2 analysis (statistical significance, p <= .05). The 2006 group had a significantly shorter mean surgical time than did the 1999 group, but time to surgery did not change. The 2006 group showed improvements (but not statistically significant ones) in length of stay in acute care, intensive care, and rehabilitation unit, and in the incidence of complications and in-hospital mortality. PMID- 21244811 TI - Wire-guided resection of a muscular axillary arch causing neurovascular compression. AB - The axillary arch is a variant muscle found in approximately 7% of individuals. Most reports describe its incidental finding in cadaveric limbs. Several reports describe its potential clinical relevance, typically axillary neurovascular compression due to an axillary arch detected at surgical exploration. This report presents a case in which preoperative identification of this muscle led to a limited surgical approach using computed tomography (CT) guided, percutaneously placed, localizing wires. A 32-year-old man presented with intermittent, vague left arm pain and forearm and hand paresthesias that were aggravated with overhead activity. Routine neurologic examination, electrophysiologic testing, as well as CT and magnetic resonance imaging of the shoulder were interpreted as normal. Focused diagnostic ultrasonography of the axillary region did not reveal a definite abnormality. However, retrospective review of the CT with arms overhead during the ultrasound appointment confirmed the presence of an axillary arch compressing the neurovascular bundle. Percutaneous CT-guided needle localization wires were placed preoperatively to mark the axillary arch, limit the operative exposure, and simplify the resection. Postoperatively, the patient had complete resolution of his arm symptoms and returned to his premorbid activity as a telephone lineman within 6 weeks. At 3-month follow-up, CT with arms overhead confirmed decompression of the neurovascular bundle. PMID- 21244812 TI - Traumatic subchondral fracture of the femoral head: a case report. AB - Subchondral insufficiency fractures of the femoral head have been described in elderly, osteoporotic patients and most commonly occur at the superolateral aspect of the femoral head. This case report describes an insufficiency fracture that involves the posterior inferior aspect of the femoral head in a thin, elderly woman. PMID- 21244813 TI - Effectiveness of health education program for type 2 diabetes mellitus patients attending zagazig university diabetes clinic, egypt. AB - BACKGROUND: Diabetes mellitus is a major public health problem. OBJECTIVES: To i) assess knowledge, attitude, random blood sugar and glycosylated hemoglobin (HbA1c) levels in type 2 diabetics, ii) investigate the effect of different socio demographic factors on acquiring knowledge about diabetes, iii) assess the effectiveness of health education on knowledge, attitude, blood sugar and HbA1c levels in type 2 diabetics. METHODS: This intervention study was carried out on 122 randomly selected type 2 diabetics attending diabetes outpatient clinic in Zagazig University, from January 2009 to April 2009. A questionnaire (pretest) was used to collect data on socio-demographic characteristics, knowledge and attitude, then a blood sample was taken for testing random blood sugar and HbA1c. Patients were subjected to the first health education session where information about diabetes was provided. In the second visit patients were informed about the results of their investigations, and the remaining part of the educational message was delivered. In the 3rd visit, patients were subjected to the post test and blood samples were tested for random blood sugar and HbA1c. RESULTS: The majority of patients had low levels of knowledge regarding different aspects of diabetes (Correct answers ranged from 16.39% to 49.18%). Knowledge level was significantly poor, among females, not educated, low social class, and rural residence and of older age group. After implementation of the educational message, a significant improvement was revealed in patients' knowledge and attitude with lowering of their mean levels of blood sugar and HbA 1c. CONCLUSION AND RECOMMENDATIONS: Health education was an effective tool that implicated change in diabetic patients' knowledge, attitude towards diabetes, random blood sugar and HbA1c levels. Training of health care providers working in outpatient diabetes clinic regarding different aspects of type 2 diabetes is highly needed. PMID- 21244814 TI - Waterpipe Smoking And The DRD2/ANKK1 Genotype. AB - BACKGROUND: Waterpipe smoking is increasingly a worldwide phenomenon. Few studies have been conducted on the epidemiology of waterpipe smoking behavior and its genetic determinants. A polymorphism (TaqI) in the 3' untranslated region of the dopamine receptor gene (DRD2), later localized to the neighboring ANKK1 gene, has been previously linked to cigarette smoking. Since all tobacco products share the ability of stimulating the dopaminergic reward system, variation in the DRD2 genotype might be associated with waterpipe smoking addiction. AIM: This study aims to explore genetic variations in DRD2 gene and waterpipe smoking, motives and addiction in Egyptian rural males. MATERIAL AND METHODS: The subjects (N=154) were selected from participants in a household smoking prevalence survey if they were adults, males, currently smoking waterpipe and not smoking cigarettes. Participants were interviewed about their smoking behaviors. Blood samples were genotyped by polymerase chain reaction (PCR). Subjects were subsequently classified as either the A1 (presence of at least one A1 allele) or A2 group (A2 homozygotes). RESULTS: The prevalence of A1 genotype was 34.4 % in current waterpipe users, and was associated with the maximum duration before smokers experienced craving to smoke: after adjusting for age of smoking initiation, smoking for addictive motives, and average daily tobacco consumption, the A1 carriers were more likely to experience craving within a shorter duration after abstinence (the first 24 hours) compared to subjects with A2/A2 genotype (Odds ratio [OR] 2.70, 95% confidence interval [CI]: 1.18 - 6.23). In addition, the frequent visitors of shisha cafes were more likely to be younger, heavy smokers and carriers of A1 allele (OR, 2.52, 95% CI: 1.06-6.02). CONCLUSION AND RECOMMENDATIONS: This study revealed that the maximum duration before experiencing craving to smoke waterpipe and frequency of visiting cafes to smoke may be influenced by an inherited variations in the DRD2 genotype. PMID- 21244815 TI - Knowledge and practices related to occupational hazards among cement workers in United arab emirates. AB - BACKGROUND: In United Arab Emirates (UAE), the rate of industrialization has increased significantly over the past decades. However, few studies have been conducted to investigate the occupational hazards and the knowledge & practice of the working population relevant to these hazards. OBJECTIVES: To assess the knowledge and practice of workers in cement factory in Ras Al-Khaimah, UAE on the occupational hazards of their work. MATERIAL AND METHODS: A cross-sectional study involving 153 cement factory workers. A semi- structured interview questionnaire was used to assess the knowledge and practice of workers towards occupational hazards in general and dust in particular. RESULTS: The majority 114 (74.5 %) of the workers knew that exposure to the dust was a serious hazard to their health, but only 52.9 % of the workers knew the hazards other than the dust that were associated with their work. All the workers mentioned that they had been provided with masks to protect them from dust, however, only 28.8 % of them claimed that they used the masks all the time during working hours. The variables: years of education, being informed about the hazards associated with the worker's job, and attending a training course about occupational health and safety were found to have a significant influence on the workers' knowledge about the occupational hazards and on their use of the personal protective equipment at work. CONCLUSION AND RECOMMENDATIONS: Despite the relatively high knowledge of the cement factory workers about the adverse health effects of exposure to dust, the use of respiratory protective equipment was poor. A program to promote safety education and the use of personal protective equipment among cement factory workers is recommended. PMID- 21244816 TI - Development of low-cost technology for the removal of iron and manganese from ground water in siwa oasis. AB - BACKGROUND: Ground water is the only water resource for Siwa Oasis. It is obtained from natural freshwater wells and springs fed by the Nubian aquifer. Water samples collected from Siwa Oasis had relatively higher iron (Fe) and manganese (Mn) than the permissible limits specified in WHO Guidelines and Egyptian Standards for drinking water quality. Aeration followed by sand filtration is the most commonly used method for the removal of iron from ground water. AIM: The study aimed at development of low-cost technology for the removal of iron and manganese from ground water in Siwa Oasis. MATERIAL AND METHODS: The study was carried out on Laboratory-scale columns experiments sand filters with variable depths of 15, 30, 45, 60, 75, 90 cm and three graded types of sand were studied. RESULTS: The graded sand (E.S. =0.205 mm, U.C. =3.366, depth of sand = 60 cm and filtration rate = 1.44 m3/m2/hr) was the best type of filter media. Iron and manganese concentrations measured in ground water with aeration only, decreased with an average removal percentage of 16%, 13% respectively. Iron and manganese concentrations after filtration with aeration came down to 0.1123, 0.05 mg/L respectively in all cases from an initial concentration of 1.14, 0.34 mg/L respectively. CONCLUSION AND RECOMMENDATIONS: Advantages of such treatment unit included simplicity, low cost design, and no need for chemical addition. In addition, the only maintenance required was periodic washing of the sand filter or replacement of the sand in order to maintain reasonable flow rate through the system. PMID- 21244817 TI - Health care providers' views on supervisory visits in family health centers and units in alexandria, egypt. AB - BACKGROUND: Clinical supervision is considered one of the vital support systems for effective high-quality health services. The quality of the relationship between supervisor and provider is the single most important factor for effective supervision. OBJECTIVES: This study was conducted to identify the health care providers' views in family health centers (FHC) and units (FHU) regarding the supervisory visits in terms of supervisor roles. MATERIAL AND METHODS: A descriptive cross-sectional study was conducted in 20% of FHC and FHU of four randomly selected districts (out of seven administrative districts) affiliated to MOH in Alexandria governorate, Egypt. The study population included all family physicians, pharmacists, and dentists, who were present in the study settings at the time of the study (40 physicians, 23 dentists and 19 pharmacists). A self administered questionnaire was used and included 11 categories of key supervision practices to be assessed. RESULTS: High rating had the highest percentage for giving feedback to supervisees and facility (57.3%), seeking client input (56.1%), discussing data (53.7%), making suggestions (47.6%), promoting participation of supervisees (46.3%), discussing previous visit (43.9%) and roles of developing rapport with supervisees (36.6%). The highest percentage of moderate rating was accounted for the role of problem identification with supervisees (50.0%). Low rating had the highest percentage for the roles of giving education or on-the-job training (40.2%), problem solving with supervisees (43.9%), and discussing the next visit (44.9%). CONCLUSION AND RECOMMENDATIONS: All newly appointed clinic supervisors should have access to a formal induction program which introduces them to particular aspects of management, leadership and communication skills as well as technical aspects of their job. Training sessions for both supervisors and providers on problem solving, problem identification, and team building are also required. PMID- 21244818 TI - Health-related quality of life of school- age children with rheumatic Fever. AB - BACKGROUND: Rheumatic fever (RF) is a major public health problem and it is an important cause of acquired cardiovascular disease in childhood and adolescence. The goal of effective management of rheumatic fever is to allow children with RF to function with minimal restrictions and enjoy a good quality of life(QOL) throughout their lives. The aim of this study was to identify the health-related quality of life of school- age children with rheumatic fever. MATERIALS AND METHODS: A convenient sample of 100 school-age children with rheumatic fever and their mothers were selected from outpatient clinic and inpatient pediatric cardiac departments of EL-Shatby Children University Hospital, Alexandria, Egypt. Data was collected from children in the previously mentioned settings who fulfil the following criteria, the children's age ranged from 8 to 12 years & free from any associated disease. Two tools were used in Clinical Data of Rheumatic School Age Children Questionnaire that was developed by the researcher and Pediatric Quality of Life Inventory scale (Peds QL). RESULTS: The majority (78.3%) of school-age children with rheumatic fever had a neutral HRQOL and less than a quarter of them had high HRQOL. Only small percent (8.7%) of studied subjects had poor HRQOL. Children's parents' reports confirmed such results, where there were a significant positive correlations between children reports and their parents reports in the majority of studied items of HRQOL regarding rheumatic fever. CONCLUSION AND RECOMMENDATIONS: Health education program for school-age children who had rheumatic fever and their parents towards the different measures of high HRQOL is recommended to help those children to improve their quality of life. PMID- 21244819 TI - Environmental engineering interventions to control the expansion of salty lakes and marshes in siwa oasis. AB - BACKGROUND: The main activity in Siwa Oasis society is the agriculture, it depends on the groundwater. The agricultural drainage water and the unused saline water of naturally flowing springs are poured into four main salty lakes. This leads to an increase in the surface area of the saltwater lakes, marshes and rise in water table levels. AIM: to investigate some environmental engineering interventions to control the expansion of saltwater surface area in Siwa Oasis. MATERIAL AND METHODS: Field visits, observation sheets and questionnaire survey with farmers were carried out to find out the main environmental problems in the Oasis. Environmental survey was carried out to collect different rocks and stones samples as natural construction materials from the desert that surrounds Siwa Oasis. Physical analyses, chemical composition and principal mechanical parameters were conducted on the collected samples. RESULTS: After the analysis, the safa rocks were the best natural construction materials in the Siwa Oasis. So, it could be used to build a construction wall around the salty lakes and marshes. Walls could convert the lakes into basins. The water will be evaporated at high rate during summer season by solar energy. After evaporation, the remaining salty rock named "karshef" can be easily collected from the lakes to be used as a low cost construction material for traditional building houses in Siwa Oasis. Therefore, the water level of lakes will be reduced to dryness and land could be reused as agricultural land. CONCLUSION AND RECOMMENDATIONS: Among different rocks, safa rocks proved to be the best natural construction materials to construct a defense wall around the lakes and marshes. They will save about 80% of the concrete cost. The formed karshef rocks from the lakes will be used in the construction of the traditional building houses which will save about 90% of the concrete buildings. This intervention will save energy as it exchanges fuel consuming man-made material such as cement with naturally made material. This can reduce the green house gases generated from the cement industry. Economical feasibility study should be carried out to estimate the capital cost for the retaining wall. PMID- 21244820 TI - The morphology and composition of cholesterol-rich micellar nanostructures determine transmembrane protein (GPCR) activity. AB - We examined model mixed micelles consisting of the nonionic surfactant n-dodecyl beta-D-maltoside, 3-(3-cholamidopropyl)-dimethylammoniopropane sulfonate, and the cholesterol derivative cholesteryl hemisuccinate (CHS) to identify micellar properties that are correlated with the in vitro conformational stability and activity of the human adenosine A2a receptor, a G-protein coupled receptor. Small angle neutron scattering was used to determine micellar structure and composition as a function of concentration of the various components, and radioligand binding was used as a sensitive probe for receptor activity. Micelles adopted an oblate ellipsoidal morphology and exhibited a reduction in size and change in curvature upon addition of CHS. Our results show a strong correlation between the number of CHS monomers per micelle and the activity of the receptor reconstituted in those micelles. Micelles that yield optimal human adenosine A2a receptor stability closely mimic the cholesterol composition and thickness of mammalian membranes. Thus, successful reconstitution of the receptor is dependent on both specific lipid-protein interactions and the geometry of the micelle environment. PMID- 21244821 TI - Characterizing the energetic states of the GluR2 ligand binding domain core dimer. AB - Tetrameric ligand binding domains of the family of ionotropic glutamate receptors assemble as dimers-of-dimers. Crystallographic studies of several glutamate receptor subtype isolated core-dimers suggest a single stable dimeric conformation. A binding domain dimer has not been captured in other conformations without the aid of biochemical methods to disrupt a critical dimer interface. Molecular dynamics simulations and continuum electrostatics calculations reveal that the active glutamate bound form of the ligand-binding domain found in typical crystal structures is the preferred energetic state of the isolated core dimer in the presence of agonist glutamate. A desensitized conformational state is a higher energy ligand-bound state of the core-dimer. The resting apo conformational state is comparatively the least energetically favored conformation and does not contain a single state but a set of energetically equivalent conformational core-dimer states. We hypothesize the energetic balance of an open versus closed transmembrane region must be included to characterize the absolute energetic states of the full receptor, which in the presence of the ligand is believed to be a desensitized state. PMID- 21244822 TI - Nanoscale fluorescence correlation spectroscopy on intact living cell membranes with NSOM probes. AB - Characterization of molecular dynamics on living cell membranes at the nanoscale is fundamental to unravel the mechanisms of membrane organization and compartmentalization. Here we demonstrate the feasibility of fluorescence correlation spectroscopy (FCS) based on the nanometric illumination of near-field scanning optical microscopy (NSOM) probes on intact living cells. NSOM-FCS applied to fluorescent lipid analogs allowed us to reveal details of the diffusion hidden by larger illumination areas. Moreover, the technique offers the unique advantages of evanescent axial illumination and straightforward implementation of multiple color excitation. As such, NSOM-FCS represents a powerful tool to study a variety of dynamic processes occurring at the nanometer scale on cell membranes. PMID- 21244823 TI - Synchronization of stochastic Ca2(+) release units creates a rhythmic Ca2(+) clock in cardiac pacemaker cells. AB - In sinoatrial node cells of the heart, beating rate is controlled, in part, by local Ca2(+) releases (LCRs) from the sarcoplasmic reticulum, which couple to the action potential via electrogenic Na(+)/Ca2(+) exchange. We observed persisting, roughly periodic LCRs in depolarized rabbit sinoatrial node cells (SANCs). The features of these LCRs were reproduced by a numerical model consisting of a two dimensional array of stochastic, diffusively coupled Ca2(+) release units (CRUs) with fixed refractory period. Because previous experimental studies showed that beta-adrenergic receptor stimulation increases the rate of Ca2(+) release through each CRU (dubbed I(spark)), we explored the link between LCRs and I(spark) in our model. Increasing the CRU release current I(spark) facilitated Ca2(+)-induced Ca2(+) release and local recruitment of neighboring CRUs to fire more synchronously. This resulted in a progression in simulated LCR size (from sparks to wavelets to global waves), LCR rhythmicity, and decrease of LCR period that parallels the changes observed experimentally with beta-adrenergic receptor stimulation. The transition in LCR characteristics was steeply nonlinear over a narrow range of I(spark), resembling a phase transition. We conclude that the (partial) periodicity and rate regulation of the "Calcium clock" in SANCs are emergent properties of the diffusive coupling of an ensemble of interacting stochastic CRUs. The variation in LCR period and size with I(spark) is sufficient to account for beta-adrenergic regulation of SANC beating rate. PMID- 21244824 TI - Elucidating the role of matrix stiffness in 3D cell migration and remodeling. AB - Reductionist in vitro model systems which mimic specific extracellular matrix functions in a highly controlled manner, termed artificial extracellular matrices (aECM), have increasingly been used to elucidate the role of cell-ECM interactions in regulating cell fate. To better understand the interplay of biophysical and biochemical effectors in controlling three-dimensional cell migration, a poly(ethylene glycol)-based aECM platform was used in this study to explore the influence of matrix cross-linking density, represented here by stiffness, on cell migration in vitro and in vivo. In vitro, the migration behavior of single preosteoblastic cells within hydrogels of varying stiffness and susceptibilities to degradation by matrix metalloproteases was assessed by time-lapse microscopy. Migration behavior was seen to be strongly dependent on matrix stiffness, with two regimes identified: a nonproteolytic migration mode dominating at relatively low matrix stiffness and proteolytic migration at higher stiffness. Subsequent in vivo experiments revealed a similar stiffness dependence of matrix remodeling, albeit less sensitive to the matrix metalloprotease sensitivity. Therefore, our aECM model system is well suited to unveil the role of biophysical and biochemical determinants of physiologically relevant cell migration phenomena. PMID- 21244825 TI - Precision of sensing cell length via concentration gradients. AB - Unicellular organisms are typically found to have a characteristic cell size. To achieve a homeostatic distribution of cell sizes over many generations requires that cell length is actively sensed and regulated. However, the mechanisms by which cell size is controlled remain poorly understood. Recent experiments in fission yeast have shown that cell length is controlled in part by polar gradients of the protein Pom1 together with localized measurement of concentration at midcell. Dilution as the cell grows leads to a reduction in the midcell protein concentration, which lifts a block on mitosis. Here we analyze the precision of this mechanism for length sensing in the presence of inevitable intrinsic noise in the processes leading to formation and measurement of this gradient. We find that the use of concentration gradients allows for more robust length sensing than a comparable spatially uniform system, and allows for reliable length determination even if the average protein concentration throughout the cell remains constant as the cell grows. Optimal values for the gradient decay length and receptor dissociation constant emerge from maximizing sensitivity while minimizing the impact of density fluctuations. PMID- 21244826 TI - GPIbalpha-vWF rolling under shear stress shows differences between type 2B and 2M von Willebrand disease. AB - Both type 2B and type 2M von Willebrand disease result in bleeding disorders; however, whereas type 2B has increased binding affinity between platelet glycoprotein Ibalpha and von Willebrand factor (vWF), type 2M has decreased binding affinity between these two molecules. We used R687E type 2B and G561S type 2M vWF-A1 mutations to study binding between flowing platelets and insolubilized vWF mutants. We measured rolling velocities, mean stop times, and mean go times at 37 degrees C using high-speed video microscopy. The rolling velocities for wt-wt interactions first decrease, reach a minimum, and then increase with increasing shear stress, indicating a catch-slip transition. By changing the viscosity, we were able to quantify the effects of force versus shear rate for rolling velocities and mean stop times. Platelet interactions with loss-of-function vWF-A1 retain the catch-slip bond transition seen in wt-wt interactions, but at a higher shear stress compared with the wt-wt transition. The mean stop time for all vWF-A1 molecules reveals catch-slip transitions at different shear stresses (gain-of-function vWF-A1 < wt vWF-A1< loss-of-function vWF-A1). The shift in the catch-slip transition may indicate changes in how the different mutants become conformationally active, indicating different mechanisms leading to similar bleeding characteristics. PMID- 21244827 TI - Key players in the genetic switch of bacteriophage TP901-1. AB - After infection of a sensitive host temperate phages may enter either a lytic or a lysogenic pathway leading to new phage assembly or silencing as a prophage, respectively. The decision about which pathway to enter is centered in the genetic switch of the phage. In this work, we explore the bistable genetic switch of bacteriophage TP901-1 through experiments and statistical mechanical modeling. We examine the activity of the lysogenic promoter P(R) at different concentrations of the phage repressor, CI, and compare the effect of CI on P(R) in the presence or absence of the phage-encoded MOR protein expressed from the lytic promoter P(L). We find that the presence of large amounts of MOR prevents repression of the P(R) promoter, verifying that MOR works as an antirepressor. We compare our experimental data with simulations based on previous mathematical formulations of this switch. Good agreement between data and simulations verify the model of CI repression of P(R). By including MOR in the simulations, we are able to discard a model that assumes that CI and MOR do not interact before binding together at the DNA to repress P(R). The second model of Pr repression assumes the formation of a CI:MOR complex in the cytoplasm. We suggest that a CI:MOR complex may exist in different forms that either prevent or invoke P(R) repression, introducing a new twist on mixed feedback systems. PMID- 21244828 TI - Calcium dynamics in the ventricular myocytes of SERCA2 knockout mice: A modeling study. AB - We describe a simulation study of Ca2(+) dynamics in mice with cardiomyocyte specific conditional excision of the sarco(endo)plasmic reticulum calcium ATPase (SERCA) gene, using an experimental data-driven biophysically-based modeling framework. Previously, we reported a moderately impaired heart function measured in mice at 4 weeks after SERCA2 gene deletion (knockout (KO)), along with a >95% reduction in the level of SERCA2 protein. We also reported enhanced Ca2(+) flux through the L-type Ca2(+) channels and the Na(+)/Ca2(+) exchanger in ventricular myocytes isolated from these mice, compared to the control Serca2(flox/flox) mice (flox-flox (FF)). In the current study, a mathematical model-based analysis was applied to enable further quantitative investigation into changes in the Ca2(+) handling mechanisms in these KO cardiomyocytes. Model parameterization based on a wide range of experimental measurements showed a 67% reduction in SERCA activity and an over threefold increase in the activity of the Na(+)/Ca2(+) exchanger. The FF and KO models were then validated against experimentally measured [Ca2(+)](i) transients and experimentally estimated sarco(endo)plasmic reticulum (SR) function. Simulation results were in quantitative agreement with experimental measurements, confirming that sustained [Ca2(+)](i) transients could be maintained in the KO cardiomyocytes despite severely impaired SERCA function. In silico analysis shows that diastolic [Ca2(+)](i) rises sharply with progressive reductions in SERCA activity at physiologically relevant pacing frequencies. Furthermore, an analysis of the roles of the compensatory mechanisms revealed that the major combined effect of the compensatory mechanisms is to lower diastolic [Ca2(+)](i). Finally, by using a comprehensive sensitivity analysis of the role of all cellular calcium handling mechanisms, we show that the combination of upregulation of the Na(+)/Ca2(+) exchanger and increased L-type Ca2(+) current is the most effective means to maintain diastolic and systolic calcium levels after loss of SERCA function. PMID- 21244829 TI - Vinculin activation is necessary for complete talin binding. AB - Focal adhesions are critical to a number of cellular processes that involve mechanotransduction and mechanical interaction with the cellular environment. The growth and strengthening of these focal adhesions is dependent on the interaction between talin and vinculin. This study investigates said interaction and how vinculin activation influences it. Using molecular dynamics, the interaction between talin's vinculin binding site (VBS) and vinculin's domain 1 (D1) is simulated both before and after vinculin activation. The simulations of VBS binding to vinculin before activation suggest the proximity of the vinculin tail to D1 prevents helical movement in D1 and thus prevents binding of VBS. In contrast, interaction of VBS with activated vinculin shows the possibility of complete VBS insertion into D1. In the simulations of both activated and autoinhibited vinculin where VBS fails to fully bind, VBS demonstrates significant hydrophobic interaction with surface residues in D1. These interactions link VBS to D1 even without its proper insertion into the hydrophobic core. Together these simulations suggest VBS binds to vinculin with the following mechanism: 1), VBS links to D1 via surface hydrophobic interactions; 2), vinculin undergoes activation and D1 is moved away from the vinculin tail; 3), helices in D1 undergo conformational change to allow VBS binding; and 4), VBS inserts itself into the hydrophobic core of D1. PMID- 21244830 TI - Shear stress increases the residence time of adhesion of Pseudomonas aeruginosa. AB - Although ubiquitous, the processes by which bacteria colonize surfaces remain poorly understood. Here we report results for the influence of the wall shear stress on the early-stage adhesion of Pseudomonas aeruginosa PA14 on glass and polydimethylsiloxane surfaces. We use image analysis to measure the residence time of each adhering bacterium under flow. Our main finding is that, on either surface, the characteristic residence time of bacteria increases approximately linearly as the shear stress increases (~0-3.5 Pa). To investigate this phenomenon, we used mutant strains defective in surface organelles (type I pili, type IV pili, or the flagellum) or extracellular matrix production. Our results show that, although these bacterial surface features influence the frequency of adhesion events and the early-stage detachment probability, none of them is responsible for the trend in the shear-enhanced adhesion time. These observations bring what we believe are new insights into the mechanism of bacterial attachment in shear flows, and suggest a role for other intrinsic features of the cell surface, or a dynamic cell response to shear stress. PMID- 21244831 TI - The role of stretching in slow axonal transport. AB - Axonal stretching is linked to rapid rates of axonal elongation. Yet the impact of stretching on elongation and slow axonal transport is unclear. Here, we develop a mathematical model of slow axonal transport that incorporates the rate of axonal elongation, protein half-life, protein density, adhesion strength, and axonal viscosity to quantify the effects of axonal stretching. We find that under conditions where the axon (or nerve) is free of a substrate and lengthens at rapid rates (>4 mm day-1), stretching can account for almost 50% of total anterograde axonal transport. These results suggest that it is possible to accelerate elongation and transport simultaneously by increasing either the axon's susceptibility to stretching or the forces that induce stretching. To our knowledge, this work is the first to incorporate the effects of stretching in a model of slow axonal transport. It has relevance to our understanding of neurite outgrowth during development and peripheral nerve regeneration after trauma, and hence to the development of treatments for spinal cord injury. PMID- 21244832 TI - Organization of higher-order oligomers of the serotonin1(A) receptor explored utilizing homo-FRET in live cells. AB - The serotonin1(A) receptor is a representative member of the GPCR superfamily and serves as an important drug target. The possible role of GPCR oligomerization in receptor function is an active area of research. We monitored the oligomerization state of serotonin1(A) receptors using homo-FRET and fluorescence lifetime measurements. Homo-FRET is estimated by a reduction in fluorescence anisotropy and provides a superior approach for exploring oligomerization. In addition, homo FRET offers the possibility of detecting higher-order oligomers. On the basis of an observed increase in fluorescence anisotropy upon progressive photobleaching and analysis of the difference between the extrapolated anisotropy and the predicted anisotropy of an immobile monomer, we propose the presence of constitutive oligomers of the serotonin1(A) receptor. To the best of our knowledge, these results constitute the first report of higher-order oligomers for the serotonin1(A) receptor. We further show that cholesterol depletion and antagonist treatment result in a reduced population of higher-order oligomers. In contrast, agonist stimulation and destabilization of the actin cytoskeleton lead to an increased contribution from higher oligomers. These results provide novel insight into the oligomerization status of the serotonin1(A) receptor that could enhance the ability to design better therapeutic strategies to combat diseases related to malfunctioning of GPCRs. PMID- 21244833 TI - Kinetic analysis and design of experiments to identify the catalytic mechanism of the monocarboxylate transporter isoforms 4 and 1. AB - Transport of lactate, pyruvate, and other monocarboxylates across the sarcolemma of skeletal and cardiac myocytes occurs via passive diffusion and by monocarboxylate transporter (MCT) mediated transport. The flux of lactate and protons through the MCT plays an important role in muscle energy metabolism during rest and exercise and in pH regulation during exercise. The MCT isoforms 1 and 4 are the major isoforms of this transporter in skeletal and cardiac muscle. The current consensus on the mechanism of these transporters, based on experimental measurements of labeled lactate fluxes, is that monocarboxylate proton symport occurs via a rapid-equilibrium ordered mechanism with proton binding followed by monocarboxylate binding. This study tests ordered and random mechanisms by fitting experimental measurements of tracer exchange fluxes from MCT1 and MCT4 isoforms to theoretical predictions derived using relationships between one-way fluxes and thermodynamic forces. Analysis shows that: 1), the available kinetic data are insufficient to distinguish between a rapid equilibrium ordered and a rapid-equilibrium random-binding model for MCT4; 2), MCT1 has a higher affinity to lactate than does MCT4; 3), the theoretical conditions for the so-called trans-acceleration phenomenon (e.g., increased tracer efflux from a vesicle caused by increased substrate concentration outside the vesicle) do not necessarily require the rate constant for the lactate and proton bound transporter to reorient across the membrane to be higher than that for the unbound transporter; and finally, 4), based on model analysis, additional experiments are proposed to be able to distinguish between ordered and random binding mechanisms. PMID- 21244834 TI - Cholesterol sensitivity of KIR2.1 is controlled by a belt of residues around the cytosolic pore. AB - Kir channels play an important role in setting the resting membrane potential and modulating membrane excitability. A common feature of several Kir channels is that they are regulated by cholesterol. Yet, the mechanism by which cholesterol affects channel function is unclear. We recently showed that the cholesterol sensitivity of Kir2 channels depends on several CD-loop residues. Here we show that this cytosolic loop is part of a regulatory site that also includes residues in the G-loop, the N-terminus, and the connecting segment between the C-terminus and the inner transmembrane helix. Together, these residues form a cytosolic belt that surrounds the pore of the channel close to its interface with the transmembrane domain, and modulate the cholesterol sensitivity of the channel. Furthermore, we show that residues in this cluster are correlated with residues located in the most flexible region of the G-loop, the major cytosolic gate of Kir2.1, implying that the importance of these residues extends beyond their effect on the channel's cholesterol sensitivity. We suggest that the residues of the cholesterol sensitivity belt are critical for channel gating. PMID- 21244835 TI - Ion selectivity mechanism in a bacterial pentameric ligand-gated ion channel. AB - The proton-gated ion channel from Gloeobacter violaceus (GLIC) is a prokaryotic homolog of the eukaryotic nicotinic acetylcholine receptor that responds to the binding of neurotransmitter acetylcholine and mediates fast signal transmission. Recent emergence of a high-resolution crystal structure of GLIC captured in a potentially open state allowed detailed, atomic-level insight into ion conduction and selectivity mechanisms in these channels. Herein, we have examined the barriers to ion conduction and origins of ion selectivity in the GLIC channel by the construction of potential-of-mean-force profiles for sodium and chloride ions inside the transmembrane region. Our calculations reveal that the GLIC channel is open for a sodium ion to transport, but presents a ~11 kcal/mol free energy barrier for a chloride ion. Our collective findings identify three distinct contributions to the observed preference for the permeant ions. First, there is a substantial contribution due to a ring of negatively charged glutamate residues (E-2') at the narrow intracellular end of the channel. The negative electrostatics of this region and the ability of the glutamate side chains to directly bind cations would strongly favor the passage of sodium ions while hindering translocation of chloride ions. Second, our results imply a significant hydrophobic contribution to selectivity linked to differences in the desolvation penalty for the sodium versus chloride ions in the central hydrophobic region of the pore. This hydrophobic contribution is evidenced by the large free energy barriers experienced by Cl- in the middle of the pore for both GLIC and the E-2'A mutant. Finally, there is a distinct contribution arising from the overall negative electrostatics of the channel. PMID- 21244836 TI - Selective acylation enhances membrane charge sensitivity of the antimicrobial peptide mastoparan-x. AB - The partitioning of the wasp venom peptide mastoparan-X (MPX) into neutral and negatively charged lipid membranes has been compared with two new synthetic analogs of MPX where the N(alpha)-terminal of MPX was acylated with propanoic acid (PA) and octanoic acid (OA). The acylation caused a considerable change in the membrane partitioning properties of MPX and it was found that the shorter acylation with PA gave improved affinity and selectivity toward negatively charged membranes, whereas OA decreased the selectivity. Based on these findings, we hypothesize that minor differences in the embedding and positioning of the peptide in the membrane caused by either PA or OA acylation play a critical role in the fine-tuning of the effective charge of the peptide and thereby the fine tuning of the peptide's selectivity between neutral and negatively charged lipid membranes. This finding is unique compared to previous reports where peptide acylation enhanced membrane affinity but also resulted in impaired selectivity. Our result may provide a method of enhancing selectivity of antimicrobial peptides toward bacterial membranes due to their high negative charge-a finding that should be investigated for other, more potent antimicrobial peptides in future studies. PMID- 21244837 TI - Membrane insertion of a voltage sensor helix. AB - Most membrane proteins contain a transmembrane (TM) domain made up of a bundle of lipid-bilayer-spanning alpha-helices. TM alpha-helices are generally composed of a core of largely hydrophobic amino acids, with basic and aromatic amino acids at each end of the helix forming interactions with the lipid headgroups and water. In contrast, the S4 helix of ion channel voltage sensor (VS) domains contains four or five basic (largely arginine) side chains along its length and yet adopts a TM orientation as part of an independently stable VS domain. Multiscale molecular dynamics simulations are used to explore how a charged TM S4 alpha helix may be stabilized in a lipid bilayer, which is of relevance in the context of mechanisms of translocon-mediated insertion of S4. Free-energy profiles for insertion of the S4 helix into a phospholipid bilayer suggest that it is thermodynamically favorable for S4 to insert from water to the center of the membrane, where the helix adopts a TM orientation. This is consistent with crystal structures of Kv channels, biophysical studies of isolated VS domains in lipid bilayers, and studies of translocon-mediated S4 helix insertion. Decomposition of the free-energy profiles reveals the underlying physical basis for TM stability, whereby the preference of the hydrophobic residues of S4 to enter the bilayer dominates over the free-energy penalty for inserting charged residues, accompanied by local distortion of the bilayer and penetration of waters. We show that the unique combination of charged and hydrophobic residues in S4 allows it to insert stably into the membrane. PMID- 21244838 TI - A simple thermodynamic model of the liquid-ordered state and the interactions between phospholipids and cholesterol. AB - A theoretical model is proposed to describe the heat capacity function and the phase behavior of binary mixtures of phospholipids and cholesterol. The central idea is that the liquid-ordered state (L(o)) is a thermodynamic state or an ensemble of conformations of the phospholipid, characterized by enthalpy and entropy functions that are intermediate between those of the solid and the liquid disordered (L(d)) states. The values of those thermodynamic functions are such that the L(o) state is not appreciably populated in the pure phospholipid, at any temperature, because either the solid or the L(d) state have much lower free energies. Cholesterol stabilizes the L(o) state by nearest-neighbor interactions, giving rise to the appearance of the L(o) phase. The model is studied by Monte Carlo simulations on a lattice with nearest-neighbor interactions, which are derived from experiment as much as possible. The calculated heat capacity function closely resembles that obtained by calorimetry. The phase behavior produced by the model is also in agreement with experimental data. The simulations indicate that separation between solid and L(o) phases occurs below the melting temperature of the phospholipid (T(m)). Above T(m), small L(d) and L(o) domains do exist, but there is no phase separation. PMID- 21244839 TI - Detailed tuning of structure and intramolecular communication are dispensable for processive motion of myosin VI. AB - Dimeric myosin VI moves processively hand-over-hand along actin filaments. We have characterized the mechanism of this processive motion by measuring the impact of structural and chemical perturbations on single-molecule processivity. Processivity is maintained despite major alterations in lever arm structure, including replacement of light chain binding regions and elimination of the medial tail. We present kinetic models that can explain the ATP concentration dependent processivities of myosin VI constructs containing either native or artificial lever arms. We conclude that detailed tuning of structure and intramolecular communication are dispensable for processive motion, and further show theoretically that one proposed type of nucleotide gating can be detrimental rather than beneficial for myosin processivity. PMID- 21244840 TI - Cluster analysis of time-dependent crystallographic data: Direct identification of time-independent structural intermediates. AB - The initial output of a time-resolved macromolecular crystallography experiment is a time-dependent series of difference electron density maps that displays the time-dependent changes in underlying structure as a reaction progresses. The goal is to interpret such data in terms of a small number of crystallographically refinable, time-independent structures, each associated with a reaction intermediate; to establish the pathways and rate coefficients by which these intermediates interconvert; and thereby to elucidate a chemical kinetic mechanism. One strategy toward achieving this goal is to use cluster analysis, a statistical method that groups objects based on their similarity. If the difference electron density at a particular voxel in the time-dependent difference electron density (TDED) maps is sensitive to the presence of one and only one intermediate, then its temporal evolution will exactly parallel the concentration profile of that intermediate with time. The rationale is therefore to cluster voxels with respect to the shapes of their TDEDs, so that each group or cluster of voxels corresponds to one structural intermediate. Clusters of voxels whose TDEDs reflect the presence of two or more specific intermediates can also be identified. From such groupings one can then infer the number of intermediates, obtain their time-independent difference density characteristics, and refine the structure of each intermediate. We review the principles of cluster analysis and clustering algorithms in a crystallographic context, and describe the application of the method to simulated and experimental time resolved crystallographic data for the photocycle of photoactive yellow protein. PMID- 21244841 TI - What drives amyloid molecules to assemble into oligomers and fibrils? AB - We develop a theory for three states of equilibrium of amyloid peptides: the monomer, oligomer, and fibril. We assume that the oligomeric state is a disordered micellelike collection of a few peptide chains held together loosely by hydrophobic interactions into a spherical hydrophobic core. We assume that fibrillar amyloid chains are aligned and further stabilized by steric zipper interactions-hydrogen bonding, steric packing, and specific hydrophobic side chain contacts. The model makes a broad set of predictions that are consistent with experimental results: 1), Similar to surfactant micellization, amyloid oligomerization should increase with peptide concentration in solution. 2), The onset of fibrillization limits the concentration of oligomers in the solution. 3), The extent of Abeta fibrillization increases with peptide concentration. 4), The predicted average fibril length versus monomer concentration agrees with data on alpha-synuclein. 5), Full fibril length distributions agree with data on alpha synuclein. 6), Denaturants should melt out fibrils. And finally, 7), added salt should stabilize fibrils by reducing repulsions between amyloid peptide chains. It is of interest that small changes in solvent conditions can tip the equilibrium balance between oligomer and fibril and cause large changes in rates through effects on the transition-state barrier. This model may provide useful insights into the physical processes underlying amyloid diseases. PMID- 21244842 TI - An effective solvent theory connecting the underlying mechanisms of osmolytes and denaturants for protein stability. AB - An all-atom Go model of Trp-cage protein is simulated using discontinuous molecular dynamics in an explicit minimal solvent, using a single, contact-based interaction energy between protein and solvent particles. An effective denaturant or osmolyte solution can be constructed by making the interaction energy attractive or repulsive. A statistical mechanical equivalence is demonstrated between this effective solvent model and models in which proteins are immersed in solutions consisting of water and osmolytes or denaturants. Analysis of these studies yields the following conclusions: 1), Osmolytes impart extra stability to the protein by reducing the entropy of the unfolded state. 2), Unfolded states in the presence of osmolyte are more collapsed than in water. 3), The folding transition in osmolyte solutions tends to be less cooperative than in water, as determined by the ratio of van 't Hoff to calorimetric enthalpy changes. The decrease in cooperativity arises from an increase in native structure in the unfolded state, and thus a lower thermodynamic barrier at the transition midpoint. 4), Weak denaturants were observed to destabilize small proteins not by lowering the unfolded enthalpy, but primarily by swelling the unfolded state and raising its entropy. However, adding a strong denaturant destabilizes proteins enthalpically. 5), The folding transition in denaturant-containing solutions is more cooperative than in water. 6), Transfer to a concentrated osmolyte solution with purely hard-sphere steric repulsion significantly stabilizes the protein, due to excluded volume interactions not present in the canonical Tanford transfer model. 7), Although a solution with hard-sphere interactions adds a solvation barrier to native contacts, the folding is nevertheless less cooperative for reasons 1-3 above, because a hard-sphere solvent acts as a protecting osmolyte. PMID- 21244843 TI - Dual role of protein phosphorylation in DNA activator/coactivator binding. AB - Binding free energies are calculated for the phosphorylated and unphosphorylated complexes between the kinase inducible domain (KID) of the DNA transcriptional activator cAMP response element binding (CREB) protein and the KIX domain of its coactivator, CREB-binding protein (CBP). To our knowledge, this is the first application of a method based on a potential of mean force (PMF) with restraining potentials to compute the binding free energy of protein-protein complexes. The KID:KIX complexes are chosen here because of their biological relevance to the DNA transcription process and their relatively small size (81 residues for the KIX domain of CBP, and 28 residues for KID). The results for pKID:KIX and KID:KIX are -9.55 and -4.96 kcal/mol, respectively, in good agreement with experimental estimates (-8.8 and -5.8 kcal/mol, respectively). A comparison between specific contributions to protein-protein binding for the phosphorylated and unphosphorylated complexes reveals a dual role for the phosphorylation of KID at Ser-133 in effecting a more favorable free energy of the bound system: 1), stabilization of the unbound conformation of phosphorylated KID due to favorable intramolecular interactions of the phosphate group of Ser-133 with the charged groups of an arginine-rich region spanning both alpha-helices, which lowers the configurational entropy; and 2), more favorable intermolecular electrostatic interactions between pSer-133 and Arg-131 of KID, and Lys-662, Tyr-658, and Glu 666 of KIX. Charge reduction through ligand phosphorylation emerges as a possible mechanism for controlling the unbound state conformation of KID and, ultimately, gene expression. This work also demonstrates that the PMF-based method with restraining potentials provides an added benefit in that important elements of the binding pathway are evidenced. Furthermore, the practicality of the PMF-based method for larger systems is validated by agreement with experiment. In addition, we provide a somewhat differently structured exposition of the PMF-based method with restraining potentials and outline its generalization to systems in which both protein and ligand may adopt unbound conformations that are different from those of the bound state. PMID- 21244844 TI - Accurate flexible fitting of high-resolution protein structures into cryo electron microscopy maps using coarse-grained pseudo-energy minimization. AB - Cryo-electron microscopy (cryo-EM) has been widely used to explore conformational states of large biomolecular assemblies. The detailed interpretation of cryo-EM data requires the flexible fitting of a known high-resolution protein structure into a low-resolution cryo-EM map. To this end, we have developed what we believe is a new method based on a two-bead-per-residue protein representation, and a modified form of the elastic network model that allows large-scale conformational changes while maintaining pseudobonds and secondary structures. Our method minimizes a pseudo-energy which linearly combines various terms of the modified elastic network model energy with a cryo-EM-fitting score and a collision energy that penalizes steric collisions. Unlike previous flexible fitting efforts using the lowest few normal modes, our method effectively utilizes all normal modes so that both global and local structural changes can be fully modeled. We have validated our method for a diverse set of 10 pairs of protein structures using simulated cryo-EM maps with a range of resolutions and in the absence/presence of random noise. We have shown that our method is both accurate and efficient compared with alternative techniques, and its performance is robust to the addition of random noise. Our method is also shown to be useful for the flexible fitting of three experimental cryo-EM maps. PMID- 21244845 TI - Force spectroscopy of substrate molecules en route to the proteasome's active sites. AB - We used an atomic force microscope to study the mechanism underlying the translocation of substrate molecules inside the proteasome. Our specific experimental setup allowed us to measure interaction forces between the 20S proteasome and its substrates. The substrate (beta-casein) was covalently bound either via a thiol-Au bond or by a PEG-based binding procedure to the atomic force microscope cantilever tip and offered as bait to proteasomes from Methanosarcina mazei. The proteasomes were immobilized densely in an upright orientation on mica, which made their upper pores accessible for substrates to enter. Besides performing conventional single-molecule force spectroscopy experiments, we developed a three-step procedure that allows the detection of specific proteasome-substrate single-molecule events without tip-sample contact. Using the active 20S wild type and an inactive active-site mutant, as well as two casein mutants bound with opposite termini to the microscope tip, we detected no directional preference of the proteasome-substrate interactions. By comparing the distribution of the measured forces for the proteasome-substrate interactions, were observed that a significant proportion of interaction events occurred at higher forces for the active versus the inactive proteasome. These forces can be attributed to the translocation of substrate en route to the active sites that are harbored deep inside the proteasome. PMID- 21244846 TI - Separating instability from aggregation propensity in gammaS-crystallin variants. AB - Molecular dynamics (MD) simulations, circular dichroism (CD), and dynamic light scattering (DLS) measurements were used to investigate the aggregation propensity of the eye-lens protein gammaS-crystallin. The wild-type protein was investigated along with the cataract-related G18V variant and the symmetry-related G106V variant. The MD simulations suggest that local sequence differences result in dramatic differences in dynamics and hydration between these two apparently similar point mutations. This finding is supported by the experimental measurements, which show that although both variants appear to be mostly folded at room temperature, both display increased aggregation propensity. Although the disease-related G18V variant is not the most strongly destabilized, it aggregates more readily than either the wild-type or the G106V variant. These results indicate that gammaS-crystallin provides an excellent model system for investigating the role of dynamics and hydration in aggregation by locally unfolded proteins. PMID- 21244847 TI - A nonfitting method using a spatial sine window transform for inhomogeneous effective-diffusion measurements by FRAP. AB - Determining averaged effective diffusion constants from experimental measurements of fluorescent proteins in an inhomogeneous medium in the presence of ligand receptor interactions poses problems of analytical tractability. Here, we introduced a nonfitting method to evaluate the averaged effective diffusion coefficient of a region of interest (which may include a whole nucleus) by mathematical processing of the entire cellular two-dimensional spatial pattern of recovered fluorescence. Spatially and temporally resolved measurements of protein transport inside cells were obtained using the fluorescence recovery after photobleaching technique. Two-dimensional images of fluorescence patterns were collected by laser-scanning confocal microscopy. The method was demonstrated by applying it to an estimation of the mobility of green fluorescent protein-tagged heterochromatin protein 1 in the nuclei of living mouse embryonic fibroblasts. This approach does not require the mathematical solution of a corresponding system of diffusion-reaction equations that is typical of conventional fluorescence recovery after photobleaching data processing, and is most useful for investigating highly inhomogeneous areas, such as cell nuclei, which contain many protein foci and chromatin domains. PMID- 21244848 TI - Improved high-force magnetic tweezers for stretching and refolding of proteins and short DNA. AB - Although magnetic tweezers have many unique advantages in terms of specificity, throughput, and force stability, this tool has had limited application on short tethers because accurate measurement of force has been difficult for short tethers under large tension. Here, we report a method that allows us to apply magnetic tweezers to stretch short biomolecules with accurate force calibration over a wide range of up to 100 pN. We demonstrate the use of the method by overstretching of a short DNA and unfolding/refolding a protein of filamin A immunoglobulin domains 1-8. Other potential applications of this method are also discussed. PMID- 21244849 TI - Flavonoid conjugates interact with organic anion transporters (OATs) and attenuate cytotoxicity of adefovir mediated by organic anion transporter 1 (OAT1/SLC22A6). AB - Flavonoids are conjugated by phase II enzymes in humans to form glucuronidated and sulfated metabolites that are excreted in urine via the kidney. In this study, we examined the interaction between metabolites of quercetin and isoflavonoids found in vivo with human organic anion transporters 1 (OAT1) and 3 (OAT3) and their potential in attenuating OAT-induced cytotoxicity of adefovir. Accumulation of flavonoid conjugates was studied in human embryonic kidney 293H cells overexpressing OAT1 or OAT3. OAT1-overexpressing cells exhibited an increased uptake of the sulfated conjugates, genistein-4'-O-sulfate and quercetin 3'-O-sulfate. OAT3-overexpressing cells demonstrated enhanced uptake of glucuronide conjugates, such as daidzein-7-O-glucuronide, genistein-7-O glucuronide, glycitein-7-O-glucuronide and quercetin-3'-O-glucuronide. Position of conjugation was important since quercetin-3-O-glucuronide and quercetin-7-O glucuronide were poorly transported. Kinetic analysis revealed high affinity uptake of quercetin-3'-O-sulfate by OAT1 (K(m)=1.73MUM; V(max)=105 pmol/min/mg). OAT3 transported isoflavone glucuronides with lower affinity (K(m)=7.9-19.1 MUM) but with higher V(max) (171-420 pmol/min/mg). Quercetin-3'-O-sulfate strongly inhibited OAT1-mediated p-aminohippuric acid uptake with an IC(50) of 1.22MUM. Transport of 5-carboxyfluorescein by OAT3 was potently inhibited by quercetin-3-O glucuronide, quercetin-3'-O-glucuronide and quercetin-3'-O-sulfate (IC(50)=0.43 1.31MUM). In addition, quercetin-3'-O-sulfate was shown to effectively reduce OAT1-mediated cytotoxicity of adefovir, an antiviral drug, in a dose-dependent manner. These data suggest that OAT1 and OAT3 are responsible for basolateral uptake of flavonoid conjugates in kidney, and flavonoid conjugates inhibit OAT1 and OAT3 activity at physiologically relevant concentrations. Interaction with OATs limits systemic availability of flavonoids and may be a mechanism of food drug interaction via inhibition of renal uptake. PMID- 21244850 TI - Therapeutic effects of TACI-Ig on collagen-induced arthritis by regulating T and B lymphocytes function in DBA/1 mice. AB - To investigate the abnormal function of T and B lymphocytes involved in collagen induced arthritis in DBA/1 mice and the regulation role of TACI-Ig on T and B lymphocytes, collagen-induced arthritis models were established in DBA/1 mice. Mice were divided randomly into eight groups, including normal, collagen-induced arthritis model, TACI-Ig (0.350, 1.105, 3.333, 10, and 30 mg/kg) and IgG-Fc (10mg/kg) treated groups. The effect of TACI-Ig on collagen-induced arthritis was evaluated by arthritis scores, joints and spleens histopathology, paws radiology, and indices of thymus and spleen. T and B lymphocyte proliferations were assayed by [(3)H]-TdR method. B lymphocyte stimulator and prostaglandin E(2) in serum were assayed by enzyme linked immunosorbent assay. The subsets of T and B lymphocytes were assayed by flow cytometry. Results showed that the onset of paw swelling was on day 31 after immunization. The peak of inflammation appeared on day 42 and then declined after day 63. Compared with normal mice, collagen induced arthritis mice have increased arthritis scores, spleen and thymus indices, radiograph scores of joints, and pathology scores of joints and spleens. TACI-Ig could ameliorate these changes and reduce the increased serum level of B lymphocyte stimulator and prostaglandin E(2). Further studies showed that TACI-Ig inhibited T and B lymphocyte proliferation response, and inhibited differentiation and activity of T and B lymphocytes in collagen-induced arthritis mice. In conclusion, TACI-Ig has a good therapeutic action on collagen-induced arthritis mice, which might be related to the regulation of TACI-Ig on inflammation mediators and abnormal function of T and B lymphocytes. PMID- 21244851 TI - Minocycline attenuates ischemia-induced ventricular arrhythmias in rats. AB - Minocycline has been shown to protect against myocardial ischemia-reperfusion injury. This study investigated the effects of minocycline on ischemia-induced ventricular arrhythmias in rats. Anesthetized male rats were once treated with minocycline (45mg/kg, i.p.) 1h before ischemia in the absence and/or presence of 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002, 0.3mg/kg, i.v., a PI3K inhibitor) and 5-hydroxydecanoic acid [5-HD, 10mg/kg, i.v., a specific inhibitor of mitochondrial ATP-sensitive potassium (K(ATP)) channels] which were once injected 10min before ischemia and then subjected to ischemia for 30min. Ventricular arrhythmias were assessed. L-type Ca(2+) current was measured by the patch-clamp technique. During the 30-minute ischemia, minocycline significantly reduced the incidence of ventricular fibrillation (VF) (P<0.05). The duration of VT+VF, the number of VT+VF episodes and the severity of arrhythmias were all significantly reduced by minocycline compared to those in myocardial ischemia group (P<0.05 for all). Administration of LY294002 or 5-HD abolished the protective effects of minocycline on VF incidence, the duration of VT+VF, the number of VT+VF episodes and the severity of arrhythmias (P<0.05 for all). In addition, minocycline inhibited L-type Ca(2+) currents of normal myocardial cell membrane in a dose-dependent manner. This study suggested that minocycline could attenuate ischemia-induced ventricular arrhythmias in rats in which PI3K/Akt signaling pathway, mitochondrial K(ATP) channels and L-type Ca(2+) channels may be involved. PMID- 21244852 TI - A synergetic role of 1,25-dihydroxyvitamin D(3) in 17beta-estradial induced proliferation and differentiation of osteoblastic MC3T3-E1 cells. AB - Although the effect of 17beta-estradial, a polyphenolic phytoestrogen, on bone cell function has been studied in numerous cell models, the synergetic role of 1, 25-dihydroxyvitamin D(3) on 17beta-estradial induced-proliferation and differentiation of osteoblastic cells, and the underlying mechanism are obscure. Here, we investigated the in vitro effect of 17beta-estradial on cell proliferation and osteoblastic maturation in MC3T3-E1 cells. 17beta-estradial could promote the proliferation and viability of MC3T3-E1 cells, associated with upregulation of cyclin E and proliferation cell nuclear antigen (PCNA) mRNA expression, and downregulation of cyclin-dependent kinase inhibitor 2b (Cdkn2b) mRNA expression. Moreover, 17beta-estradial also could stimulate osteoblastic differentiation and bone formation as assessed by alkaline phosphatase (ALP) and Alizarin Red S staining, through induction of the expression of osteoblastic markers, including ALP, osteopontin and type I collagen in MC3T3-E1 cells. However, 1,25-dihydroxyvitamin D(3) treatment alone showed no effect on proliferation and differentiation of MC3T3-E1 cells, but could coordinately augment effects of 17beta-estradial on MC3T3-E1 cells. The mechanism conducted demonstrated that 17beta-estradial activated ERK1/2 but not JNK and p38, and U0126, an ERK1/2 pathway inhibitor, significantly downregulated vitamin D receptor expression induced by 17beta-estradial in MC3T3-E1 cells. Thus, our data demonstrated a synergistical role of 1,25-dihydroxyvitamin D(3) and 17beta estradial in proliferation and differentiation of osteoblasts, and this coordinated regulation might depend on the upregulation of vitamin D receptor in osteoblasts by 17beta-estradial. Moreover, during the process of vitamin D receptor upregulation by 17beta-estradial, ERK1/2 signaling is involved. PMID- 21244853 TI - Bioreducible poly (beta-amino esters)/shRNA complex nanoparticles for efficient RNA delivery. AB - RNA interference (RNAi) mediating gene silencing is a promising approach in the area of gene therapy, but it still is a major challenge to find new non-viral vectors with high transfection efficiency and low toxicity until today. In this work, three novel bioreducible poly (beta-amine esters) (PAEs) with different amino monomers in the main chain were designed and synthesized by Michael addition polymerization. All PAEs could condense shRNA into complex nanoparticles with particle size (60-200nm) and positive surface charges (>+10mV). The PAEs/shRNA complex nanoparticles (PAENs) were stable under the extracellular physiological condition, while it would degrade in the reductive environment due to the cleavage of the disulfide bonds in the PAEs main chain. PAENs could achieve efficient cellular uptake and EGFP silencing in HEK-293 cells and U-87 MG cells with low cytotoxicity. The high accumulation of PAENs in tumor and high silencing efficiency of intra-tumor EGFP expression occurred when PAENs were intravenously injected into BALB/c mice bearing U-87 MG-GFP tumor. The relationship between the polymer structure and RNAi efficiency and cytotoxicity showed that the density of nitrogen atoms in PAEs backbone and the existence of disulfide bonds demonstrated the remarkable influence on in vitro and in vivo gene silencing efficiency and cytotoxicity. These experimental results suggested that the PAENs could be a promising non-viral vector for efficient RNA delivery. PMID- 21244854 TI - Reward magnitude and timing in pigeons. AB - We investigated the interaction of motivation and timing by manipulating the expected reward magnitude during a peak procedure. Four pigeons were tested with three different reward magnitudes, operationalized as duration of food access. Each stimulus predicted a different reward magnitude on a 5s fixed-interval schedule. Trials with different reward magnitudes were randomly intermingled in a session. Most pigeons responded less often and started responding later on peak trials when a smaller reward was expected, but showed no differences in response termination or peak times. Reward magnitude was independently corroborated through unreinforced choice trials, when pigeons chose between the three stimuli presented simultaneously. These results contribute to a growing body of evidence that the expected reward magnitude influences the decision to start anticipatory responding in tasks where the reward becomes available after a fixed interval, but does not alter peak times, nor the decision to stop responding on peak trials. PMID- 21244855 TI - HB-EGF induces cardiomyocyte hypertrophy via an ERK5-MEF2A-COX2 signaling pathway. AB - Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family that binds to and activates the EGF receptor. Transactivated by angiotensin II, ET-1, and various growth factors in cardiomyocytes, HB-EGF is known to induce cardiac hypertrophy via the PI3K-Akt, MAP kinase, and JAK-STAT pathways. However, little is known about the potential involvement of the ERK5 pathway in HB-EGF induced cardiac hypertrophy. In the present report, we identify and characterize a novel MEK5-ERK5 pathway that is involved in HB-EGF-induced cardiomyocyte hypertrophy. HB-EGF (10ng/ml) significantly increased [(3)H]-leucine incorporation and atrial natriuretic factor (ANF) mRNA expression in H9c2 cells. In addition, HB-EGF activated a MEK5-ERK5 pathway. Pretreatment with the EGFR inhibitor AG1478 attenuated the activation of ERK5. Blockade of MEK5-ERK5 signaling using MEK5 siRNA reduced the ability of HB-EGF to increase cell size and the expression of ANF mRNA, suggesting the involvement of an EGFR-ERK5 pathway in HB-EGF-induced cardiomyocyte hypertrophy. We further analyzed cyclooxygenase-2 (COX-2). HB-EGF enhanced the expression of COX-2, a response mediated by MEK5-ERK5 signaling, while the COX-2 inhibitor rofecoxib attenuated HB-EGF-induced ANF mRNA expression, suggesting that COX-2 is also associated with HB-EGF-induced cardiomyocyte hypertrophy. It has been known that ERK5 activates the myocyte enhancer factor (MEF) 2 family of transcription factor, we next tested whether activation of MEF2A contributes to HB-EGF-induced COX-2 expression. Inhibition of MEF2A using siRNA attenuated HB-EGF-induced COX-2, ANF expression and cell size. In conclusion, HB-EGF induces cardiomyocyte hypertrophy through an EGFR-ERK5-MEF2A-COX-2 pathway. Our findings will help us to better understand the molecular mechanisms behind HB-EGF-induced cardiomyocyte hypertrophy. PMID- 21244856 TI - Fatty acid modification of Wnt1 and Wnt3a at serine is prerequisite for lipidation at cysteine and is essential for Wnt signalling. AB - The Wnt family of proteins is a group of extracellular signalling molecules that regulate cell-fate decisions in developing and adult tissues. It is presumed that all 19 mammalian Wnt family members contain two types of post-translational modification: the covalent attachment of fatty acids at two distinct positions, and the N-glycosylation of multiple asparagines. We examined how these modifications contribute to the secretion, extracellular movement and signalling activity of mouse Wnt1 and Wnt3a ligands. We revealed that O-linked acylation of serine is required for the subsequent S-palmitoylation of cysteine. As such, mutant proteins that lack the crucial serine residue are not lipidated. Interestingly, although double-acylation of Wnt1 was indispensable for signalling in mammalian cells, in Xenopus embryos the S-palmitoyl-deficient form retained the signalling activity. In the case of Wnt3a, the functional duality of the attached acyls was less prominent, since the ligand lacking S-linked palmitate was still capable of signalling in various cellular contexts. Finally, we show that the signalling competency of both Wnt1 and Wnt3a is related to their ability to associate with the extracellular matrix. PMID- 21244857 TI - Lysyl oxidase-like 3b is critical for cartilage maturation during zebrafish craniofacial development. AB - Vertebrate craniofacial development requires coordinated morphogenetic interactions between the extracellular matrix (ECM) and the differentiating chondrocytes essential for cartilage formation. Recent studies reveal a critical role for specific lysyl oxidases in ECM integrity required for embryonic development. We now demonstrate that loxl3b is abundantly expressed within the head mesenchyme of the zebrafish and is critically important for maturation of neural crest derived cartilage elements. Histological and ultrastructural analyses of cartilage elements in loxl3b morphant embryos reveal abnormal maturation of cartilage and altered chondrocyte morphology. Spatiotemporal analysis of craniofacial markers in loxl3b morphant embryos shows that cranial neural crest cells migrate normally into the developing pharyngeal arches but that differentiation and condensation markers are aberrantly expressed. We further show that the loxl3b morphant phenotype is not due to P53 mediated cell death but likely to be due to reduced chondrogenic progenitor cell proliferation within the pharyngeal arches. Taken together, these data demonstrate a novel role for loxl3b in the maturation of craniofacial cartilage and can provide new insight into the specific genetic factors important in the pathogenesis of craniofacial birth defects. PMID- 21244858 TI - Tanshinone IIA ameliorates seawater exposure-induced lung injury by inhibiting aquaporins (AQP) 1 and AQP5 expression in lung. AB - Aquaporins (AQPs), a family of transmembrane water channels, mediate physiological response to changes of fluid volume and osmolarity. It is still unknown what role of AQPs plays in seawater drowning-induced acute lung injury (ALI) and whether pharmacologic modulation of AQPs could alleviate the severity of ALI caused by seawater aspiration. In our study, the results from RT-PCR and Western blotting showed that intratracheal installation of seawater up-regulated the mRNA and protein levels of AQP1 and AQP5 in lung tissues. Furthermore, we found that treatment of tanshinone IIA (TIIA, one of the main active components from Chinese herb Danshen) significantly reduced the elevation of AQP1 and AQP5 expression induced by seawater in rats, A549 cells and primary alveolar type II cells. Treatment of TIIA also improved lung histopathologic changes and blood-gas indices, and reduced lung edema and vascular leakage. These findings demonstrated that AQP1 and AQP5 might play an important role in the development of lung edema and lung injury, and that treatment with TIIA could significantly alleviate seawater exposure-induced ALI, which was probably through the inhibition of AQP1 and AQP5 over-expression in lungs. PMID- 21244859 TI - Highly pathogenic avian influenza virus H5N1 from Egypt escapes vaccine-induced immunity but confers clinical protection against a heterologous clade 2.2.1 Egyptian isolate. AB - The poultry populations of Egypt are endemically infected by highly pathogenic avian influenza viruses (HPAIV) of subtype H5N1. Vaccination was chosen as an auxiliary tool to control HPAIV in poultry. Potency of commercial vaccines regarding emerging variants is under discussion. In the current study efficacy of four different inactivated whole H5 virus vaccines representing different sublineages of HPAIV H5N1 were tested in chickens against challenge viruses currently co-circulating in Egypt and representing two antigenically widely distinct HPAIV H5N1 lineages, i.e., "variant" (clade 2.2.1var) and "proper" (clade 2.2.1pro) viruses. All vaccines induced clinical protection against challenge with 2.2.1pro Egyptian strains. In contrast, when challenged with a variant strain, only chickens vaccinated with the homologous Egyptian clade 2.2.1var virus or an inactivated re-assorted H5N1 strain (Re-5, clade 2.3) were protected. However, only the homologous virus induced sterile immunity whereas chickens clinically protected after Re-5 vaccination shed virus at day two after infection indistinguishable to H5N2 vaccines. In conclusion, monitoring vaccine driven evolution of HPAIV H5N1 by surveillance, antigenic characterization, and challenge studies is essential to assess efficacy of AIV vaccination campaigns. PMID- 21244861 TI - The role of low-molecular-weight heparin in recurrent implantation failure: a prospective, quasi-randomized, controlled study. AB - Low-molecular-weight heparin did not provide any beneficial effect on pregnancy outcomes in patients with two or more implantation failures. Further trials are needed to confirm a trend in favor of low-molecular-weight heparin in the subgroup with women with three or more implantation failures. PMID- 21244860 TI - Icariin and its derivative, ICT, exert anti-inflammatory, anti-tumor effects, and modulate myeloid derived suppressive cells (MDSCs) functions. AB - 3, 5,7-trihydroxy-4'-methoxy-8-(3-hydroxy-3-methylbutyl)-flavone (ICT) is a novel derivative of Icariin (ICA), the major active ingredient of Herba Epimedii, a herb used in traditional Chinese and alternative medicine. We previously demonstrated its anti-inflammatory effect in murine innate immune cells and activated human PBMCs. We report herein that ICA or ICT treatment reduces the expression of MRP8/MRP14 and toll-like receptor 4 (TLR4) on human PBMCs. Administration of ICA or ICT inhibited tumor growth in 4T1-Neu tumor-bearing mice and considerably decreased MDSC numbers in the spleen of these mice. Further, we saw a restoration of IFN-gamma production by CD8+ T cells in tumor bearing mice when treated with ICA or ICT. ICA and ICT significantly decreased the amounts of nitric oxide and reactive oxygen species in MDSC in vivo. When MDSC were treated in vitro with ICT, we saw a significant reduction in the percent of these cells with concomitant differentiation into dendritic cells and macrophages. Concomitant with this cell type conversion was a down-regulation of IL-10, IL-6 and TNF-alpha production. Decreased expression of S100A8/9 and inhibition of activation of STAT3 and AKT may in part be responsible for the observed results. In conclusion, our results showed that ICA, and more robustly, ICT, directly modulate MDSC signaling and therefore altered the phenotype and function of these cells, in vitro and in vivo. PMID- 21244862 TI - Health promotion intervention in low socioeconomic kindergarten children. AB - OBJECTIVE: To prospectively examine the effects of a randomized school-based intervention on nutrition and physical activity knowledge and preferences, anthropometric measures, and fitness in low socioeconomic kindergarten children. STUDY DESIGN: A total of 376 children completed a school-year combined dietary behavioral-physical activity intervention and were compared with 349 control subjects (age 3.8 to 6.8 years). RESULTS: The prevalence of overweight and obesity among the kindergarten children was 27.7%. Even though the intervention was not associated with between group differences in body mass index changes, it was associated with significantly (P < .05) greater increase in nutrition knowledge and preferences, physical activity knowledge and preferences, and improvement in fitness. There was a greater (P < .05) decrease in the number of overweight children in the intervention group (-31.9%) compared with the controls (-17.5%). CONCLUSIONS: A kindergarten dietary-physical activity intervention applied by the kindergarten teachers, had no effect on body mass index changes between the groups, but improved nutrition and physical activity knowledge and preferences, improved fitness, and decreased the percent of overweight children. This intervention may play an important role in health promotion, prevention and treatment of childhood obesity. PMID- 21244863 TI - Outcomes of elective abdominal aortic aneurysm repair among the elderly: endovascular versus open repair. AB - BACKGROUND: National outcomes for elective abdominal aortic aneurysm (AAA) repair in elderly populations are needed. The purpose of this study was to analyze outcomes of endovascular (EVAR) and open surgical repair (OSR) of elective AAA among the elderly (>=80 years). METHODS: Patients undergoing non emergent AAA repair between January 1, 2005 and December 31, 2008, were identified using the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP). Logistic regression models were used to compare risk-adjusted 30-day outcomes. RESULTS: Of 7,936 patients identified, 2,034 (25.6%) were >=80 years. Older patients were more likely to experience adverse 30-day outcomes as compared with patients <80 years: overall morbidity (17.4% vs. 15.4%, OR 1.33, 95% CI 1.14 1.55) and mortality (2.6% vs. 1.4%, OR 1.83, 95% CI 1.37-2.90). A majority (80.8%) of patients >=80 years were treated with EVAR, which was associated with lesser overall morbidity (13.6% vs 33.2%, OR 2.64, 95% CI 2.02-3.45) and mortality (1.8% vs 6.1%, OR 3.37, 95% CI 1.92-5.91) as compared with OSR. Multivariable analysis showed that elderly patients undergoing OSR, as compared with EVAR, had a greater likelihood of infectious (OR 3.48, 95% CI 2.51-4.83), pulmonary (OR 5.70, 95% CI 3.87-8.41), cardiac (OR 5.60, 95% CI 2.57-12.22), and renal complications (1.96, 95% CI 1.13-3.38), greater requirements for blood transfusion (OR 5.66, 95% CI 2.65-12.09), and longer duration of stay (OR 10.64, 95% CI 7.95-14.23). CONCLUSION: Although elderly patients have worse outcomes compared with younger patients regardless of approach, endovascular repair among elderly patients is associated with less morbidity and mortality compared with open repair. PMID- 21244864 TI - Nudge smudge: UK Government misrepresents "nudge". PMID- 21244865 TI - Retained nuclear fragment found during Descemet-stripping automated endothelial keratoplasty. AB - An 82-year-old man with a 2- to 3-month history of progressive visual loss due to corneal edema was referred to our center. The ocular history was significant for uneventful cataract surgery approximately 3 years earlier. Pseudophakic bullous keratopathy was diagnosed and Descemet-stripping automated endothelial keratoplasty (DSAEK) performed. During surgery, a retained nuclear fragment was discovered in the anterior chamber. The fragment was removed and the DSAEK completed successfully. At the 4-month follow-up, the symptoms had completely resolved and the uncorrected distance visual acuity in the affected eye was 20/40. PMID- 21244866 TI - Evaluation of 2 new optical biometry devices and comparison with the current gold standard biometer. AB - PURPOSE: To compare 2 new optical biometry devices with the present gold standard biometer. SETTING: Vienna Institute for Research in Ocular Surgery, Department of Ophthalmology, Hanusch Hospital, Vienna, Austria. DESIGN: Evaluation of diagnostic test or technology. METHODS: In patients scheduled for cataract surgery, measurements performed with the current gold standard optical biometer (IOLMaster) were compared with those of 2 new optical biometers, the Lenstar LS 900 (optical low-coherence reflectometry [OLCR] device; substudy 1) and the IOLMaster 500 (partial coherence interferometry [PCI] device; substudy 2). The duration of patient data entry and of the actual measurement process and the time from intraocular lens power calculation to printout were calculated. RESULTS: The mean difference in axial length measurements was 0.01 mm +/- 0.05 (SD) between the gold standard device and the new OLCR device and 0.01 +/- 0.02 mm between the gold standard device and the new PCI device (P=.12 and P < .001, respectively). Measurements with the new OLCR device took significantly longer than with the gold standard device (mean difference 209 +/- 127 seconds), and measurements with the gold standard device took significantly longer than with the new PCI device (mean difference 82 +/- 46 seconds) (both P < .001). CONCLUSIONS: All 3 devices were easy to use for biometry before cataract surgery. Measurements with the new PCI device took half as long as those with the gold standard device. Measurements with the new OLCR device took twice as long as those with the gold standard device. PMID- 21244867 TI - Comprehensive echocardiographic assessment of mechanical tricuspid valve prostheses based on early post-implantation echocardiographic studies. AB - BACKGROUND: Doppler-derived hemodynamic data for normal tricuspid mechanical valve prostheses are limited. METHODS: A comprehensive retrospective Doppler echocardiographic assessment of 78 normal St. Jude Medical Standard (St. Jude Medical, Inc., St. Paul, MN), CarboMedics Standard (CarboMedics, Inc., Sorin Group, Burnaby, British Columbia, Canada), and Starr-Edwards (Edwards Lifesciences, LLC, Irvine, CA) mechanical tricuspid valve prostheses was performed early after implantation. We used all the important Doppler-derived hemodynamic variables reported to date, including peak early diastolic velocity (E velocity), mean gradient, pressure half-time, time velocity integral of the tricuspid valve prosthesis (TVI(TVP)), and ratio of the time velocity integral of the tricuspid valve prosthesis to the time velocity integral of the left ventricular outflow tract (TVI(TVP)/TVI(LVOT)). RESULTS: The mean values obtained for the Doppler parameters did not differ significantly when the measurements from five or nine consecutive cardiac cycles were averaged. Pressure half-time was <130 msec in all 43 patients with St. Jude Medical Standard and CardioMedics Standard prostheses in whom it could be measured. Mean gradient <6 mm Hg, E velocity <1.9 m/s, TVI(TVP) <46 cm, and TVI(TVP)/TVI(LVOT) <2.1 were recorded in 59 (87%) of the 68 patients with either of these prostheses. Hemodynamic variables were considerably less favorable in patients with Starr-Edwards prostheses. CONCLUSION: These calculated threshold values (mean + 2 SD) are useful for identifying normal tricuspid mechanical valve function. Prostheses with values for hemodynamic variables that are outside the mean + 2 SD parameters that we have calculated are most likely to be dysfunctional. However, in rare cases, mechanical tricuspid valve prostheses may be dysfunctional even when their hemodynamic parameters are within these specified ranges because of small body surface area or other factors. PMID- 21244868 TI - The human genome project Genetic and physical mapping. AB - The modern tools of molecular biology, recombinant DNA techniques, have given scientists the ability to isolate and study individual genes from even complex eukaryotic genomes. The availability of genes enables the study of their structure and biologic function, and their role in normal and abnormal physiologic processes. A worldwide effort to study and understand the entire human genome is under way, which will result in information on the location of all genes, their sequences, and their complex regulation and interactions. As this knowledge becomes available, it will be rapidly applied to the practice of medicine through use in the development of diagnostic tests for genetic-based diseases and in the development of therapeutics. PMID- 21244869 TI - The zebrafish as a model system to study cardiovascular development. AB - The zebrafish, Brachydanio rerio, is rapidly becoming a system of choice for vertebrate developmental biologists. It presents unique embryological attributes and is amenable to saturation style mutagenesis, a powerful approach that, in invertebrates, has already led to the identification of a large number of key developmental genes. Since fertilization is external, the zebrafish embryo develops in the dish and is thus accessible for continued observation and manipulation at all stages of development. Furthermore, because the embryo is transparent, the developing heart and vessels can be resolved at the single-cell level. A large number of mutations that affect the development of cardiovascular form and function have recently been isolated from large-scale genetic screens for zygotic embryonic lethals. Our further understanding of the development of the cardiovascular system is important not only because of the high incidence, and familial inheritance, of congenital abnormalities, but also because it should lead to novel, differentiation-based strategies for the analysis and therapy of the diseased state. PMID- 21244870 TI - Use of human tissue specimens obtained by directional atherectomy to study restenosis. AB - Directional atherectomy has provided the opportunity to study the pathology of restenosis in human tissue specimens from live patients. The restenosis lesion is characterized by two distinctive features: a focus of hypercellularity, comprised of cells with phenotypic features of proliferative vascular smooth muscle cells (SMCs), and a rich, loose extracellular matrix (ECM). Analysis of restenosis lesions by in situ hybridization, immunohistochemistry, and cell culture has disclosed evidence of activated SMCs, and in many cases-particularly lesions from the peripheral vasculature-ongoing cellular proliferation. The ECM of restenosis lesions is biglycan rich and decorin poor, a finding that is associated with increased expression of transforming growth factor beta (TGF-beta). While certain restenosis lesions contain foci of microangiogenesis, the pathogenetic significance of this feature remains uncertain. PMID- 21244871 TI - The structure of acyl coenzyme A-cholesterol acyltransferase and its potential relevance to atherosclerosis. AB - Acyl coenzyme A-cholesterol acyltransferase (ACAT) catalyzes the formation of intracellular cholesterol esters. It is present in a variety of tissues and is believed to play significant roles in cholesterol homeostasis. Under pathologic conditions, accumulation of the ACAT reaction product as cytoplasmic cholesterol ester lipid droplets within macrophages and smooth muscle cells is a characteristic feature of early lesions of human atherosclerotic plaques. ACAT is a membrane protein located in the endoplasmic reticulum. Its activity is susceptible to inactivation by detergents, and it has never been purified to homogeneity; no antibodies directed against it have been reported. Through a somatic cell and molecular genetic approach, we have recently succeeded in molecular cloning and functional expression of a human macrophage ACAT cDNA. This cDNA contains an open reading frame of 1650 base pairs encoding an integral membrane protein of 550 amino acids. Protein homology analysis shows that the predicted protein sequence shares short regions of homology with other enzymes involved in the catalysis of acyl adenylate formation with subsequent acyl thioester formation and acyl transfer. The ACAT cDNA will enable the investigation of ACAT biochemistry and molecular biology. It will speed up the design of specific ACAT inhibitors as drugs that may provide more effective therapeutic treatment or prevention of atherosclerosis. In addition, studies on the physiologic roles of ACAT in various tissues can now be undertaken through transgenic animal research. PMID- 21244872 TI - RNA editing of the apolipoprotein B gene A mechanism to regulate the atherogenic potential of intestinal lipoproteins? AB - Apolipoprotein B (apo B) circulates in two distinct isomorphic forms, each the product of a single gene. The larger form, referred to as apo B-100, is the major protein of plasma low-density lipoproteins (LDLs) and is synthesized by the human liver. The smaller form, referred to as apo B-48, is produced in the small intestine as a result of a site-specific cytidine deamination, which alters a CAA codon, encoding glutamine in the unedited (apo B-100) mRNA to UAA, which specifies an in-frame stop codon. Apo B-48 lacks the domains involved in LDL receptor interaction and in complex formation with apolipoprotein(a). DNA sequence analysis of the gene that mediates this site-specific cytidine deamination suggests that apo B mRNA editing is an evolutionary adaptation to limit the atherogenic potential of intestinal lipoproteins. PMID- 21244873 TI - Modulation of myocardial activity by extracellular ATP. AB - Extracellular ATP, at micromolar concentration, induces multiple functional changes in cardiac cells. Stimulation of P(2) purinoceptors is associated with Ca current increase and positive inotropic effect. On rapid application, ATP triggers membrane depolarization by activating a Cl conductance and by inducing an acidification following Cl-HCO(3) exchanger stimulation. Both effects might lead to cardiac arrhythmias following ATP release under pathophysiologic conditions. PMID- 21244874 TI - Genetic and transgenic approaches to dissecting muscle development and contractility using the Drosophila model system. AB - Both genetic and transgenic analyses of Drosophila melanogaster, the common fruit fly, are providing important insights into the mechanisms of muscle cell determination and development, myofibril assembly, and muscle contraction. This model system affords tremendous advantages such as ease of isolating mutants defective in these processes, determining the identity of affected genes, and analyzing protein function by transformation with in vitro mutagenized versions of such genes. These approaches have identified a series of proteins that are critical to mesoderm and muscle determination, many of which are likely to serve similar roles in vertebrates. The effects of mutating structural protein genes upon myofibril assembly and function in Drosophila help to define the differential roles of contractile protein isoforms and the importance of proper protein stoichiometry for physiologic function. These studies may also provide insight into the role of structural proteins in vertebrate contractility. PMID- 21244875 TI - Transgenic analysis of cardiac and skeletal myogenesis. AB - The generation of various cell types in a developing embryo is defined by multiple steps in commitment to a specific cell lineage and by the resulting expression of a particular subset of protein products. Studies of the molecular mechanisms underlying commitment and differentiation to a striated muscle phenotype have been greatly aided by the use of transgenic animals. Recent transgenic models have provided insights into the formation of skeletal muscle. We review here the different forms of transgenesis and their application to the delineation of cardiac and skeletal myogenesis. PMID- 21244876 TI - Molecular anatomy of the developing heart. AB - Why the embryonic heart can function without one-way valves and without a conduction system, and why the embryonic atrium and ventricle function essentially as they do in the adult, are elementary questions in cardiac embryology. These questions can now be addressed, thanks to the recent development of molecular cell markers, their application by immunohistochemistry and/or in situ hybridization, and the development of advanced computer-aided three-dimensional reconstruction programs. PMID- 21244877 TI - Tyrosine-kinase-dependent signaling pathways. AB - Protein tyrosine kinases are important transducers of a variety of extracellular signals that regulate proliferation, differentiation, and specific functions of differentiated cells. Most of the known protein tyrosine kinases are associated with cell surface receptors. Ligand binding to the receptor activates one or more protein tyrosine kinases to initiate a network of signaling pathways that regulate metabolism and gene expression. Recently, a focal adhesion tyrosine kinase (FAK) has been shown to respond to the assembly of adhesion junctions, indicating a role for tyrosine kinase in the transduction of cell adhesion signal. The discovery of a DNA-binding tyrosine kinase, c-Abl, and the identification of RNA polymerase II as a substrate of nuclear tyrosine kinases demonstrate that protein tyrosine kinases may also directly regulate transcription. Highlights of these recent developments in tyrosine-kinase dependent signaling pathways are summarized here. PMID- 21244878 TI - Platelet membrane-mediated coagulation protease complex assembly. AB - Platelet membranes provide procoagulant surfaces for the assembly and expression of a variety of coagulation protease complexes. These assembled complexes promote the proteolytic activation of various coagulation proteins resulting in normal hemostasis. Recent studies from our laboratory and others indicate that platelets possess specific, high-affinity, saturable receptors for factor (F) XI, FXIa, FIX, FIXa, FX, FXa, FV, FVa, prothrombin, and thrombin. The molecular mechanisms involved in the assembly of the intrinsic tenase and prothrombinase enzyme cofactor complexes on platelet membranes are the subject of intense investigation. Whether the procoagulant surface of platelets is defined exclusively by procoagulant phospholipids, or whether specific protein receptors exist for the coagulant cofactors and proteases, is currently unresolved. In this article, we review some of these platelet receptor-mediated coagulation protein interactions and discuss platelet receptor-mediated F-X activation as a point of attack for the development of antithrombotic agents. PMID- 21244879 TI - Toward a molecular view of cardiac arrhythmogenesis. AB - Clinical evidence strongly suggests that the electrophysiologic behavior of the heart, and its response to drugs, is a highly dynamic process. Ion channels are the fundamental molecular units determining cardiac excitability. The cloning of ion channels that are responsible for the generation and maintenance of the cardiac action potential will enable studies of the molecular mechanisms underlying the highly heterogeneous nature of cardiac electrophysiology. The molecular bases of important pathophysiologic events, such as acute regulation of channel function by phosphorylation or drug block, or the long-term electrophysiologic changes accompanying diseases such as hypertension, are now being elucidated. Identification of these molecular mechanisms may point to novel approaches to the treatment of cardiac arrhythmias. PMID- 21244880 TI - Molecular and cellular diversity of heart conduction system myocytes. AB - Conduction system myocytes are a subpopulation of cardiac myocytes that display unique electrophysiologic properties. Significant differences in cellular components of conduction myocytes have been demonstrated by the application of in situ procedures using both immunologic and molecular probes. Although molecular and cellular biology investigations are still at the beginning, they unequivocally show that conduction myocytes are a highly heterogeneous myocyte population, whose difference from working myocytes might reflect both the degree of functional specialization and the origin from a cell lineage distinct from myocardial cells. PMID- 21244881 TI - Molecular biology of the natriuretic peptides. AB - The natriuretic peptides (ANP, BNP, and CNP) are encoded by a family of genes with similar overall structure. They exert their effects through interaction with one or more of three NP receptors. Two of these receptors signal through activation of guanylate cyclase while a third appears to function predominantly in a clearance mode. ANP also belongs to a well-defined group of genes, termed the embryonic repertoire, which is activated early in the process of cardiac hypertrophy. Understanding the signaling mechanism that triggers ANP expression in this setting may provide important insights with regard to the molecular events that initiate and maintain the hypertrophic process. PMID- 21244882 TI - Elastin and vascular disease. AB - Supravalvular aortic stenosis (SVAS) is a vascular disease that primarily affects large arteries, like the aorta and pulmonary arteries. SVAS can be inherited as an isolated, autosomal dominant trait or as part of a complex developmental disorder, Williams syndrome. Molecular genetic studies indicate that mutations affecting part of an elastin allele cause autosomal dominant SVAS while submicroscopic deletions that disrupt the entire elastin gene (and presumably adjacent loci) are responsible for Williams syndrome. These studies suggest that loss of vascular elasticity from any cause may contribute to vascular obstruction. PMID- 21244883 TI - Update on the biology and clinical study of restenosis. AB - Restenosis commonly occurs after coronary interventional procedures, and is largely thought to be a problem of uncontrolled cellular proliferation. Unfortunately, the clinical study of lumen renarrowing is unable to confirm this, as arteriography only provides information about changes in vessel lumen dimension and not wall mass. Recently, we found cell proliferation to be a modest and infrequent event in restenotic coronary atherectomy specimens and have come to question existing concepts of the pathophysiology of restenosis. This review highlights alternate biological and clinical processes that may be important for the understanding of this clinical conundrum. PMID- 21244884 TI - Integrins and other cell adhesion molecules in cardiac development. AB - Cardiac morphogenesis is dependent on the coordinated and programmed expression of cell surface receptors that can mediate cell-cell associations or promote adhesion of the cell to its extracellular environment. This article briefly reviews the unique adhesive characteristics and expression profiles of the integrins and other families of adhesion molecules that have been implicated in critical events of early heart development. Understanding the developmental repertoire of receptor expression, which in most cases cannot be predicted from that seen in the mature heart, is an important component in unraveling the molecular events of normal cardiac development, congenital heart disease, and certain pathologic conditions seen in the adult heart. PMID- 21244885 TI - Adult rat cardiomyocytes in culture A model system to study the plasticity of the differentiated cardiac phenotype at the molecular and cellular levels. AB - Adult rat cardiomyocytes (ARCs) in long-term culture, which show a distinct adaptive flexibility, are presented as a system to study cardiac cell hypertrophy in vitro. In the first 1-2 weeks after isolation, ARCs undergo a process of de- and redifferentiation during which the cell morphology is remodeled and the myofibrillar apparatus is restructured, accompanied by a cell enlargement. The growing cells spread and eventually establish new cell-cell contacts, which display newly formed intercalated discs; synchronous cell beating is resumed in the resulting tissuelike sheet. During myofibrillogenesis, the early fetal program of gene expression is reactivated for several genes, as is observed during hemodynamic overload hypertrophy. The cells resume hormonal activity and express atrial natriuretic factor (ANF); the expression pattern of ANF is also reminiscent of that seen in hypertrophy. In cells grown in a medium conditioned by 12-day ARCs, though, myofibrillogenesis is accelerated and accompanied by a downregulation of ANF. In a creatine-deficient medium, on the other hand, the ARCs display giant mitochondria with paracrystalline inclusions imitating a situation found, for example, in mitochondrial myopathies. PMID- 21244886 TI - ATP-binding cassette proteins Common denominators between ion channels, transporters, and enzymes. AB - Transporters and ion channels are highly specialized and functionally divergent molecules. However, these proteins may be less structurally diverse than previously appreciated. This is clearly apparent for one superfamily of molecules, the so-called ATP-binding cassette (ABC) proteins, which behave as ATP dependent ion channels and/or transporters for a wide variety of substrates. ABC proteins also share common structural motifs with voltage-gated ion channels, transporters for glucose and neurotransmitters, and even adenylylcyclase. Beyond this, agents such as verapamil and forskolin, which inhibit and bind to one ABC protein (P-glycoprotein), may interact in homologous domains compared with some of these related proteins. Comparisons between these proteins are likely to provide a general understanding of pores in the lipid bilayer as well as specific properties that allow regulated movement and/or hydrolysis of selected substrates. This knowledge is important since certain ABC family members play a role in normal function and disease and provide novel therapeutic targets for drug development. PMID- 21244887 TI - Identification of disease genes by positional cloning. AB - Positional cloning or reverse genetics is a combination of techniques that has been extraordinarily successful in finding the genes that cause many inherited disorders, including some that affect the cardiovascular system. This approach consists of finding a DNA marker that cosegregates with the disorder and then using the tools of molecular biology to examine systematically the DNA in the vicinity of such a marker until the gene is identified. In addition to the availability of preclinical diagnostic tests for individuals at risk, the identification of such genes might also provide the basis for targeted drug design. In the longer term, with the emerging technologies for the delivery of genes into cells, finding the genes that cause inherited disorders raises the possibility of eventual therapeutic intervention. PMID- 21244888 TI - Myocardial calcium compartmentation. AB - The mammalian cardiac myocyte contains ~1600 MUmol of exchangeable Ca per liter of cell water. Normal contractile function requires that this exchangeable content be rigorously compartmentalized. A contraction in 1 mM[Ca](0) is triggered by entry of only 6-10 MUmo/L cell water via the sarcolemmal "L" Ca channel, resulting in the secondary release of 50-60 MUnol from the sarcoplasmic reticulum (SR) compartment, which contains 500 MUmol in the junctional (JSR) plus corbular (CSR) components. Maximal contraction in 8 mM[Ca](0) is associated with SR release of 130 MUmol triggered by entry of only 8-14 MUmol via the Ca channel. This indicates the marked amplification ability of the SR-compartmentalized Ca. Ca efflux occurs via the sarcolemmal Na-Ca exchanger, which transports Ca from a newly identified Na-Ca exchange-dependent compartment. Current studies indicate that this compartment is localized to inner sarcolemmal leaflet anionic phospholipids (PLs) in equilibrium with JSR Ca. A recently developed model indicates that the presence of anionic PLs in this restricted space maintains Ca concentration >20 MUM for >200 ms after JSR release, so as to maintain an optimal environment for the operation of the Na-Ca exchanger. A large mitochondrial compartment (400 MUmol) is present, and its contribution to cellular flux is clearly identified in the intact cell. Its low flux rate (1 MUmol Ca/L cell water/s) is consistent with the generally accepted role for Ca in the control of dehydrogenase-related mitochondrial metabolism. The largest single compartment (600 MUmol/L cell water) is the most rapidly exchangeable and is largely lanthanum displaceable, which indicates that it is predominantly sarcolemma bound. It provides a large buffer at the membrane with a portion of its Ca possibly interacting with the Ca channel and Na-Ca exchanger. PMID- 21244889 TI - Angiotensin II signal transduction pathways in the cardiovascular system. AB - The renin-angiotensin system in mammals represents a complex cascade of tightly regulated proteolytic enzymes and peptide products. One important product, angiotensin II (Ang-II), is a circulating hormone that displays a wide range of physiologic effects in many tissues, including those of the cardiovascular system. It is well known that Ang-II increases the contractile state of vascular smooth muscle and cardiac myocytes by triggering multiple intracellular responses following its binding to specific receptor sites. Some of the signal transduction mechanisms that underlie these responses are understood, while others are not defined at present. Further, there has been much recent interest in Ang-II-evoked signaling, since the renin-angiotensin system has been associated with the development of cardiovascular disease. Thus, the identification of Ang-II stimulated signal transduction mechanisms will illuminate the underlying principles of normal hormone-regulated cardiovascular homeostasis as well as those involved in pathologic processes such as human hypertension, cardiac arrhythmias, and the cellular remodeling that follows vascular injury or sustained pressure overload. This review examines the current status and direction of our knowledge regarding Ang-II-stimulated signal transduction mechanisms in vascular smooth muscle and cardiac myocytes. PMID- 21244890 TI - Intracellular signaling pathways in cardiac myocytes induced by mechanical stress. AB - Mechanical stress is a major cause for cardiac hypertrophy. Although the mechanisms by which mechanical load induces cardiomyocyte hypertrophy have long been a subject of great interest for cardiologists, the lack of a good in vitro system has hampered the understanding of the biochemical mechanisms. For these past several years, however, an in vitro neonatal cardiocyte culture system has made it possible to examine the biochemical basis for the signal transduction of mechanical stress. Passive stretch of cardiac myocytes cultured on silicone membranes activates phosphorylation cascades and induces the expression of specific genes as well as the increase in protein synthesis. Although an important question regarding how mechanical stimulus is converted into biochemical signals remains unanswered, cultured cardiac myocytes may be a good model to examine the signal transduction pathways of mechanical stress. PMID- 21244891 TI - Animal models of restenosis. AB - Percutaneous transluminal coronary angioplasty is a widely used technique for recanalizing arteries that are occluded by atherosclerotic plaque, but its usefulness is limited by the occurrence ofrestenosis in a high proportion of patients. The development of new therapies for this currently intractable problem will be facilitated by the use of animal models of restenosis that are predictive of drug efficacy in humans. Two approaches for improving predictivity can be identified. In the first of these, the goal is to maximize the anatomical and procedural resemblance of the model to humans. The second approach seeks to maximize the pathophysiological and molecular biological resemblance of the model to humans. Tangible progress is being made toward the first goal, but lack of understanding of the basic biology of human restenosis is hampering progress toward the second. PMID- 21244892 TI - Apolipoprotein-B-containing plasma lipoproteins in health and in disease. AB - Coronary heart disease is declining slowly in many affluent nations, although it remains their major cause of death and disability. In sharp contrast, many societies in Eastern Europe are experiencing a substantial increase in atherosclerotic heart attack, possibly due largely to diets rich in saturated fat and cholesterol and to smoking. Most fats and cholesterol are transported in blood plasma in lipoproteins. Many studies implicate excessive blood levels of particles containing apolipoprotein B* (apo B) in the atherogenic process although apo-B-containing particles (very low density lipoproteins, low-density lipoproteins, and chylomicrons) are essential for good health as shown by the genetic disease of abetalipoproteinemia (abeta) in which these particles are absent. Recent research has identified a probable defect in abeta, the apparent absence of microsomal triglyceride transfer protein (MTP) that may be obligatory for core lipidation of apo B in the rough endoplasmic reticulum (RER). This discovery coincides with the articulation of a novel concept called the two-step hypothesis of triglyceride-rich particle assembly in hepatocytes and enterocytes forming very low density lipoproteins and chylomicrons, respectively. The first step is predicted to be dependent on MTP core lipidating full-length apo B that is firmly bound to the RER membrane. Core lipidation of apo B releases a small apo-B-rich particle from the RER membrane into the RER lumen. A larger triglyceride-rich but apo-B-deficient particle is formed independently in the smooth endoplasmic reticulum (SER). Usually, an apo-B-rich small particle formed in the RER coalesces with an apo-B-deficient larger particle from the SER as the second step of assembly of nascent triglyceride-rich particles for secretion. In several conditions, small apo-B-rich particles formed in the first step in the RER are secreted directly into the blood, bypassing the second step. These new concepts of the mechanisms of origin of apo-B-containing plasma lipoproteins may soon facilitate dietary and pharmacologic interventions that lower blood levels of apo B, reducing the incidence of heart attack and stroke. PMID- 21244894 TI - Myogenesis in Xenopus laevis. AB - The amphibian embryo provides a convenient experimental system with which to study myogenesis. The earliest steps in the formation of axial and cardiac muscle are accessible for investigation using both embryological and molecular approaches. We review the origins of skeletal and cardiac muscle in the Xenopus embryo, the molecular markers available to detect muscle differentiation, and the use of embryo explants to investigate the regulation of myogenesis. PMID- 21244893 TI - Heparin cofactor II and thrombin Heparin-binding proteins linking hemostasis and inflammation. AB - alpha-Thrombin is a trypsinlike serine proteinase involved in blood coagulation and wound-healing processes, which interacts with many different macromolecular substances. Heparin cofactor II is a serpin (serine proteinase inhibitor) superfamily member that specifically inhibits thrombin but no other proteinase in blood coagulation. Both heparin cofactor II and thrombin interact with highly negatively charged glycosaminoglycans like heparin and dermatan sulfate, and they both are leukocyte chemoattractants. The focus of this brief review is structure function characteristics of heparin cofactor II and thrombin and their physiologic participation in uniting hemostatic and inflammatory processes. PMID- 21244895 TI - Current potential of antisense oligonucleotides as therapeutic drugs. AB - Antisense oligonucleotides have great potential as rationally designed therapeutic drugs by taking advantage of the basic Watson-Crick base pairing of nucleic acids. Such oligonucleotides may block synthesis of a specific protein, such a c-myb, and prevent smooth muscle proliferation involved in restenosis. Although promising, the technology has some major hurdles to overcome before fruition. These include obtaining a stable backbone that can enter cells readily, overcoming problems of chirality, and solving the problems of delivery and metabolism. Although there are many reports of successful experiments using antisense oligonucleotides, one must always keep in mind the complex nature of these experiments, as well as nonspecific effects that may masquerade as antisense effects. PMID- 21244896 TI - Somatic gene therapy for cardiovascular disease Recent advances. AB - The recent development of several novel approaches for in vivo gene transfer into the coronary arteries and myocardium has led to new possibilities for the treatment of both acquired and inherited cardiovascular diseases. This review summarizes the current state of the art of in vivo gene transfer into the heart and coronary arteries with particular emphasis on antisense oligonucleotide mediated suppression of gene expression in vascular smooth muscle cells, liposome mediated gene transfer into the vasculature, and percutaneous transluminal gene transfer (PTGT) into the heart with the use of replication-defective adenoviruses. PMID- 21244897 TI - G-protein control of cardiac potassium channels. AB - Two cardiac potassium (K(+)) channels are activated by pertussis toxin (PTX) sensitive G proteins either directly or in a "membrane-delimited" manner. They are muscarinic K(+)(K(ACH)) and ATP-sensitive K(+)(K(ATP)) channels. K(ACH) channels are responsible for acetylcholine (ACh)- or adenosine-induced deceleration of the heartbeat and atrioventricular conduction, while K(ATP) channels are responsible for the ischemia-induced shortening of the cardiac action potential and possibly for the adenosine-mediated protection from ischemic damage. Distinct molecular mechanisms underlie G-protein activation of these cardiac K(+) channels; the alpha subunit of PTX-sensitive G proteins activates the K(ATP) channels, while betagamma subunits activate the K(ACh) channel. The physiologic significance of this heterogeneous mechanism remains to be determined. PMID- 21244898 TI - In situ analysis of the cardiac muscle gene program during embryogenesis. AB - During the last decade, gene expression in cardiac muscle of the developing embryo has been examined in situ with the use of nucleic acid probes and antibodies. With growth and maturation from a simple tube to a four-chambered organ, the myocardium undergoes a complex series of developmental changes in the temporal and spatial expression patterns of a number of structural and transcription factor genes. Studies of embryonic hearts suggest that different populations of cardiac myocytes might appear during development. These in vivo results are summarized and discussed in the context of the morphogenetic events that shape the myocardium. PMID- 21244899 TI - Thrombin receptor function and cardiovascular disease. AB - Thrombin, a multifunctional protease generated at sites of vascular injury, is a powerful agonist fora variety of cellular processes important in cardiovascular disease. A recently cloned thrombin receptor has provided a framework for understanding how thrombin, a protease rather than a classic ligand, activates cells. It has also yielded new tools for defining the role of thrombin and its receptor in cellular events. This review discusses a working model for how thrombin activates platelets and other cells, and possible roles for the thrombin receptor in thrombotic, proliferative, and inflammatory processes. PMID- 21244900 TI - The metabolism of high-density lipoproteins. AB - Although high-density lipoproteins (HDLs) have been shown to be the best single indicator of the risk of coronary heart disease (CHD), relatively little is known about their metabolism. Accordingly, only limited strategies are available for therapeutically raising plasma HDL levels. The circulating HDL particle is assembled in the blood as the result of remodeling the nascent discoidal HDL followed by transfer of lipid and protein components from other lipoproteins. The catabolism of HDL is equally complex. The receptor-mediated removal mechanism of HDL from the plasma has yet to be substantiated. Despite the extensive studies performed, no clear mechanism has emerged whereby HDL particles protect the arteries from atherosclerosis. Reverse cholesterol transport remains an attractive hypothesis, but several other potential mechanisms may also play a role in the interaction between HDL and the arterial surface. Recent studies related to the regulation of HDL metabolism are discussed with particular emphasis on the potential role of the postprandial state. A brief discussion is also provided on potential future strategies for regulating HDL levels through pharmacologic intervention. PMID- 21244901 TI - G-protein-mediated regulation of phospholipase C Involvement of betagamma subunits. AB - The protein components of the G-protein-linked cell surface receptor-regulated inositol lipid-signaling cascade have been identified recently. The G(q) family of G-protein alpha subunits is responsible for pertussis toxin-insensitive activation of a family of phospholipase C-beta isoenzymes. However, it also has been shown that G-protein betagamma subunits activate certain of these phospholipase C-beta isoenzymes, and that this novel activity may account for activation of phospholipase C by G proteins that are not members of the G(q) family, including those that account for pertussis-toxin-sensitive inositol lipid signaling. PMID- 21244902 TI - Selection, survival, adaptation, and extinction The evolution of molecular physiology. PMID- 21244903 TI - Protein aging Extracellular amyloid formation and intracellular repair. AB - Soluble proteins can undergo spontaneous structural and conformational alterations that lead to their stable aggregation into amyloid fibrils. Amyloidogenic proteins have been implicated in several types of age-related pathologic changes. For example, transthyretin amyloid accumulation in the heart can lead to cardiac failure, while beta-amyloid deposition within the microvasculature and gray matter of the brain is linked to cerebral hemorrhage and neuronal death. Over the course of evolution, protein structures have developed that largely resist such aggregation. Spontaneous chemical modifications correlated with the normal aging process, however, including the deamidation, isomerization, and racemization of asparaginyl and aspartyl residues, as well as the oxidation and glycation of various amino acid residues, may contribute to amyloid formation by altering protein structure. In fact, a recent chemical analysis of neuritic plaque and vascular beta-amyloid deposits from the brains of Alzheimer's disease victims has revealed that the majority of the aspartyl residues in beta-amyloid are in the isomerized and/or racemized configuration. Although enzymes exist that can reverse at least part of this damage for intracellular proteins, the accumulation of extracellular proteins containing altered residues might contribute to the deterioration of heart, brain, and other tissues that occurs with aging and disease. PMID- 21244904 TI - The genetic contribution to the risk of thrombosis and cardiovascular disease. AB - In the general population, variation at certain identified gene loci determines in part the plasma levels of such well-established risk factors for cardiovascular disease (CVD) as cholesterol and fibrinogen, and good progress is being made in understanding the mechanisms of these genetic effects. For any individual, estimation of such risk factors is most appropriately and accurately accomplished by conventional direct methods rather than by genetic tests. However, a DNA test may be more predictive of an individual's future risk than a current measurement if genes also determine the changes seen in the plasma levels of risk factors that occur, for example, with increasing age, with obesity, life style changes such as diet or smoking, or the onset of disorders such as hypertension or diabetes. Future research should be focused on the precise molecular mechanisms of such gene-environment interaction for genes involved in the control of plasma lipids, coagulation, and the structural components of the vessel wall. When these mechanisms have been determined at the DNA level, this will enable the development of tests that will have a high degree of accuracy and diagnostic potential that will complement current testing strategies to identify individuals at risk of CVD. PMID- 21244905 TI - Ionic channels in vascular endothelial cells. AB - Vascular endothelial cells respond to neurohumoral and physical stimuli to secrete mediators that modulate blood pressure and tissue perfusion. The initial response of endothelial cells usually involves an elevation of cytoplasmic Ca(2+), due to Ca(2+) release from intracellular stores and Ca(2+) influx from the extracellular space, and subsequent activation of Ca(2+)-dependent enzymes. The activation of cell-surface receptors by vasoactive substances stimulates Ca(2+) entry via plasmalemmal ion channels and the rate of Ca(2+) influx depends on the electrochemical gradient, which is modulated by the resting membrane potential. Membrane potential is regulated by a variety of voltage- and ligand gated potassium channels that may function to repolarize the stimulated endothelial cell. This review focuses on ionic channels involved in receptor mediated Ca(2+) entry and control of the membrane potential that are critical to stimulus-secretion coupling in vascular endothelium. PMID- 21244906 TI - Lipid modification of G proteins. AB - The heterotrimeric guanine nucleotide-binding G proteins, composed of alpha, beta, and gamma subunits, act as signal transducers between cell surface receptors and downstream effector molecules, leading to changes in intracellular second messengers. The superfamily of ras-related low-molecular-mass GTP-binding G proteins is involved in a number of cellular functions, including cell differentiation and growth control, actin polymerization and cytoskeleton arrangement, and intracellular vesicular transport. The heterotrimeric G proteins and the ras-related low-molecular-mass G proteins are modified in vivo by a number of lipid groups, including palmitate, myristate, heterogeneous fatty-acyl groups (C12:0, C14:1, or C14:2 fatty-acyl groups), and C15 farnesyl or C20 geranylgeranyl isoprenoids. Lipid modification of G proteins increases the hydrophobicity of the proteins. In this review, we describe the various types of lipid modification of G proteins and discuss the significance of lipid modification with respect to G-protein function. PMID- 21244907 TI - Molecular and cellular biology of von Willebrand factor. AB - Von Willebrand factor (vWF), a central protein in the regulation of blood coagulation, serves as a major adhesive link between platelets and the blood vessel wall and also functions as a carrier in plasma for factor VIII. Abnormalities of vWF result in von Willebrand disease (vWD), a common inherited human bleeding disorder. Deficient von Willebrand factor function has been proposed as potentially protective against the development of coronary vascular disease and several recent investigational therapies are directed at the vWF platelet interaction. This review summarizes the current state of knowledge regarding the biosynthesis and processing of vWF and the relationship of vWF structure to function. Finally, recent progress in identifying specific genetic mutations responsible for the many variants of vWD is discussed. PMID- 21244908 TI - Lipoprotein(a) and atherogenesis. AB - Lipoprotein(a) is a major inherited risk factor for atherosclerosis. Many of its activities depend on its plasminlike component, apolipoprotein(a). In vitro studies suggest that apolipoprotein(a) could enhance lipid deposition through binding to sites in the vessel wall, interfere with fibrinolysis, and modulate smooth muscle cell activity. Human and animal studies will be necessary to establish the physiologic importance of these mechanisms. PMID- 21244909 TI - Mechanism of calcification in atherosclerosis. AB - Calcification is commonly associated with atherosclerosis, and it has important clinical implications, especially in coronary arteries. The mineral has been identified as the same mineral as in bone, hydroxyapatite, and several features of its development suggest a mechanism similar to osteogenesis and not merely passive precipitation. The artery wall has been shown to contain several bone related proteins, including those for osteopontin, osteonectin, and osteocalcin, as well as proteoglycan core proteins homologous with bone biglycan. Our laboratory recently demonstrated that a potent osteogenic differentiation factor, bone morphogenetic protein 2a, is expressed in calcified human atherosclerotic lesions, suggesting that arterial calcification may be initiated by an osteogenic differentiation. In addition, a cell capable of calcium mineral formation in vitro has been isolated from bovine and human aorta and identified by immunostaining as having a surface marker characteristic of microvascular pericytes. These findings suggest the possibility that plaque calcification develops when a signal from atherosclerotic plaque or a factor associated with atherosclerosis induces expression of bone morphogenetic protein, leading to osteogenic differentiation of pluripotential, pericytelike cells located in the arterial intima, which then produce bonelike matrix and hydroxyapatite mineral. These findings also raise questions as to whether osteogenic-promoting factors used to prevent osteoporosis may also increase risk of arterial calcification. PMID- 21244910 TI - The impact of biotechnology on advances in cardiovascular medicine. PMID- 21244911 TI - Smooth muscle cell and endothelial cell growth factors. AB - Blood vessels are composed basically of two cell types, vascular endothelial cells (ECs) and vascular smooth muscle cells (SMCs), whose proliferation in vivo is tightly regulated. A number of growth regulatory polypeptides have been identified that stimulate the proliferation of vascular cells. This article reviews briefly the structural properties and biologic activities of the best characterized vascular cell growth factors. A fuller understanding of the properties of vascular cell growth modulators is an important element in delineating the proliferative events that are associated with vascular injury; with SMC hyperplasia such as occurs in restenosis following angioplasty, in atherosclerosis, and in hypertension; and with angiogenesis, both physiologic and pathologic. PMID- 21244912 TI - Tyrosine phosphorylation in platelets Potential roles in intracellular signal transduction. AB - Tyrosine phosphorylation has been shown to play a critical role in the induction of cellular responses to extracellular stimuli in a wide variety of cell types. In platelets, many diverse agonists induce multiple waves of tyrosine phosphorylation, suggesting a potential role for these protein modifications throughout the platelet activation process. Tyrosine phosphorylation of several platelet proteins is regulated by fibrinogen binding to its integrin receptor and subsequent platelet aggregation, suggesting specific functions for tyrosine phosphorylation in integrin-regulated intracellular processes. In this article, we review the regulation of tyrosine phosphorylation and the role of tyrosine phosphorylation in platelet activation events. PMID- 21244913 TI - From academic vision to clinical reality A case study of acadesine. AB - Acadesine is the prototype of a new class of therapeutic compounds termed adenosine-regulating agents (ARAs). The concept of adenosine regulation by acadesine and recognition of its potential therapeutic importance in myocardial ischemia was initiated in academia and led to the founding of a new biopharmaceutical company to develop acadesine and other ARAs. The historical background and preclinical studies that led to the discovery of acadesine and identification of its cardioprotective properties, culminating in international multicenter trials in patients undergoing cardiac surgery, are discussed. PMID- 21244915 TI - Vascular endothelial growth factor. AB - An understanding of the mechanisms regulating growth and differentiation of vascular endothelial cells is very important for cardiovascular biology and medicine. Several potential regulators of angiogenesis have been identified, including acidic and basic fibroblast growth factors, epidermal growth factor, platelet-derived endothelial cell growth factor, transforming growth factors alpha and beta, and tumor necrosis factor alpha (TNF-alpha). Vascular endothelial growth factor (VEGF) is unique among these agents by virtue of its direct and specific mitogenic effects on endothelial cells combined with the fact that it is a secreted polypeptide. By alternative splicing of mRNA, VEGF may exist in four different isoforms that have similar biologic activities but differ markedly in their secretion pattern. VEGF is emerging as an important regulator of developmental and ovarian angiogenesis. Its action is purely paracrine as it is produced by a variety of cell types, but its receptors are only in endothelial cells. There is no evidence that endothelial cells in vivo produce VEGF. The VEGF mRNA is expressed at high level by a variety of human tumors, suggesting that VEGF may be a tumor angiogenesis factor. This hypothesis is supported by the finding that monoclonal antibodies specific for VEGF are able to suppress tumor growth in vivo. Therefore, VEGF antagonists may be used for the treatment of malignancies and, possibly, other angiogenic diseases. The VEGF protein has therapeutic potential as an inducer of neovascularization in conditions characterized by impaired tissue perfusion like obstructive atherosclerosis. PMID- 21244914 TI - Molecular atherectomy for restenosis. AB - Receptors for basic (b) and acidic (a) fibroblast growth factor (FGF) are upregulated in activated smooth muscle cells. These cells, which proliferate in response to bFGF, can thus be killed by a conjugate of bFGF and the ribosome inactivating enzyme, saporin (which, by itself, does not enter the cells). Quiescent smooth muscle cells and other cells that have few FGF receptors are not killed. In vivo, bFGF-saporin transiently inhibits smooth muscle cell proliferation and neointimal accumulation after balloon injury to the rat carotid artery. Delivery of saporin, diagnostic imaging agents, or antisense oligodeoxynucleotides might be made even more selective by linking these substances to antibodies against the extracellular domains of the putative FGF receptor isoform specific for activated smooth muscle cells. PMID- 21244917 TI - Insights into blindsight. AB - Toward a science of consciousness (Tucson III): 27 April-2 May 1998, Tucson, Arizona, USA. PMID- 21244916 TI - Renin-angiotensin system genes as candidate genes in cardiovascular diseases. AB - Through binding to its specific receptors, the peptide hormone angiotensin II (Ang II) has multiple actions. Among them, its ability to regulate smooth muscle cell contractility and growth, as well as sodium and water homeostasis, making Ang II a major hormone of the cardiovascular system. Polymorphic variations, affecting the function of the expression of the genes involved in Ang II generation or action, may be the basis for particular genetic predisposition to cardiovascular diseases, such as hypertension or myocardial infarction. This hypothesis is now being tested by the use of informative DNA markers on the renin angiotensin system (RAS) genes in genetic studies involving animal models or collections of patients affected by the disease. Results available on the RAS genes are presented here together with the future extensions of the strategy for identifying genes that predispose patients to common cardiovascular diseases. PMID- 21244918 TI - Faces, trust and the amygdala. PMID- 21244919 TI - Dopamine observed in the arcade. PMID- 21244920 TI - Working memory in dorsolateral frontal cortex. PMID- 21244921 TI - Stimulating thoughts about heading perception. PMID- 21244922 TI - Specific language impairment: a deficit in grammar or processing? AB - Specific Language Impairment (SLI) is observed in children who fail to acquire age-appropriate language skills but otherwise appear to be developing normally. There are two main hypotheses about the nature of these impairments. One assumes that they reflect impairments in the child's innate knowledge of grammar. The other is that they derive from information-processing deficits that interfere with several aspects of language learning. There is considerable evidence that SLI is associated with impaired speech processing; however, the link between this deficit and the kinds of grammatical impairments observed in these children has been unclear. We suggest that the link is provided by phonology, a speech-based code that plays important roles in learning linguistic generalizations and in working memory. PMID- 21244923 TI - Crossmodal identification. AB - Everyday experience involves the continuous integration of information from multiple sensory inputs. Such crossmodal interactions are advantageous since the combined action of different sensory cues can provide information unavailable from their individual operation, reducing perceptual ambiguity and enhancing responsiveness. The behavioural consequences of such multimodal processes and their putative neural mechanisms have been investigated extensively with respect to orienting behaviour and, to a lesser extent, the crossmodal coordination of spatial attention. These operations are concerned mainly with the determination of stimulus location. However, information from different sensory streams can also be combined to assist stimulus identification. Psychophysical and physiological data indicate that these two crossmodal processes are subject to different temporal and spatial constraints both at the behavioural and neuronal level and involve the participation of distinct neural substrates. Here we review the evidence for such a dissociation and discuss recent neurophysiological, neuroanatomical and neuroimaging findings that shed light on the mechanisms underlying crossmodal identification, with specific reference to audio-visual speech perception. PMID- 21244924 TI - Attention and the crossmodal construction of space. AB - Traditional studies of spatial attention consider only a single sensory modality at a time (e.g. just vision, or just audition). In daily life, however, our spatial attention often has to be coordinated across several modalities. This is a non-trivial problem, given that each modality initially codes space in entirely different ways. In the last five years, there has been a spate of studies on crossmodal attention. These have demonstrated numerous crossmodal links in spatial attention, such that attending to a particular location in one modality tends to produce corresponding shifts of attention in other modalities. The spatial coordinates of these crossmodal links illustrate that the internal representation of external space depends on extensive crossmodal integration. Recent neuroscience studies are discussed that suggest possible brain mechanisms for the crossmodal links in spatial attention. PMID- 21244925 TI - Constraints on sentence comprehension. AB - The process of comprehending sentences involves the integration of a variety of different information sources, constrained by the available computational resources. This paper surveys the evidence for four types of constraints on sentence comprehension: (1) lexical constraints, (2) contextual constraints, (3) locality-based computational resource constraints, and (4) phrase-level contingent frequency constraints. These four constraints, in combination with grammatical phrase-formation information and prosody, are sufficient to explain how interpretations are constructed for sentences as they are encountered, including complexity effects in unambiguous sentences and interpretation preferences in ambiguous sentences. PMID- 21244926 TI - Cognitive neuroscience. AB - edited by Michael D. Rugg, MIT Press, 1997. $45.00 (hbk)/$25.00 (pbk) (xi+373 pages) ISBN 0 262 18181 9 (hbk), ISBN 0 262 68094 7 (pbk). PMID- 21244927 TI - Affective computing. AB - by Rosalind Picard, MIT Press, 1997. $27.50 (xii+292 pages) ISBN 0 262 16170 2. PMID- 21244928 TI - Methods and devices for local drug delivery in coronary and peripheral arteries. AB - New developments in catheter design, molecular biology, and polymer chemistry have made it possible to deliver pharmaceutical agents and genetic material directly into the arterial wall to modulate the response to injury. Several local drug delivery catheters of various designs in addition to biodegradable and coated stents are currently being evaluated as devices to facilitate local delivery of agents into the arterial wall. Approaches to locally sustained delivery include the controlled release of medications, the affinity-based delivery of medications administered systemically but accumulated locally, and gene therapy. PMID- 21244929 TI - Adenovirus-mediated gene transfer. AB - The introduction of foreign genetic material into somatic cells in intact organisms is an important investigational technique that holds considerable promise as a therapeutic tool. Although successful gene transfer has been achieved by the use of both cell-mediated and direct techniques, most strategies have been limited either by constraints on the type, accessibility, and growth state of the target cell population, or by the low efficiency of genetic modification. Among the available vectors for somatic cell gene transfer, recombinant adenoviruses have several properties that make them particularly attractive for direct, in vivo introduction of foreign genes into adult animals and people. Simple techniques for the efficient generation and propagation of recombinant adenoviruses have been developed, and early studies employing recombinant adenoviral vectors demonstrate their potential for broad experimental and eventual clinical application. To exploit this potential properly, a number of important issues, including the efficiency of genetic modification of a targeted cell population, stability of foreign gene expression, effects of host immune response, and cell-type specific targeting of gene transfer, remain to be addressed. PMID- 21244930 TI - Molecular and cellular biology of plasma membrane calcium ATPase. AB - The plasma membrane calcium ATPase plays an essential role in the ejection of calcium from cells and in the control of its cytosolic concentration. The role of the pump is minor with respect to that of the sodium-calcium exchanger in heart, but is most probably predominant in skeletal and smooth muscle. Biochemical studies combined with molecular biological approaches have led to the elucidation of the primary structure of the pump and have advanced the understanding of its mechanism of action. A spatial model of the pump predicts that ~20% of the protein mass is embedded in the membrane, 80% protrudes into the cytosol, and only a minor portion of the molecule is in contact with the extracellular space. An unexpected complexity has been detected on the genetic level. The human pump is encoded by four independent genes, showing different patterns of tissue specific expression and alternative splicing of the primary transcripts. PMID- 21244931 TI - Homeobox transcription factor regulation in the cardiovascular system. AB - Tissue remodeling and alterations in cellular differentiation occur in the cardiovascular system during normal development and pathologic conditions such as cardiac hypertrophy and atherosclerosis. Homeobox genes encode transcription factors that have been shown to be regulators of body-plan formation, cell growth, differentiation, and region-specific cell migration in developing embryos. Recently, several homeobox genes have been either isolated from or detected in cardiovascular tissues, and evidence suggests that some of them may have a regulatory function in the cardiovascular system. We review here what is known about the role of homeobox transcription factors in the control of development and gene expression in the cardiovascular system. PMID- 21244932 TI - Recent insights into the pathogenesis of type III hyperlipoproteinemia. AB - Type III hyperlipoproteinemia is a genetic disorder of lipoprotein metabolism characterized by high plasma cholesterol and triglycerides, the presence of a characteristic lipoprotein termed beta-very low density lipoprotein (gb-VLDL), xanthomatosis, and premature atherosclerosis. Defects in the gene for apolipoprotein (apo) E represent the molecular cause of this disorder. ApoE serves as a ligand for the receptor-mediated clearance of the triglyceride-rich lipoproteins from the circulation. All defects in apoE cause impaired lipoprotein clearance through the same mechanism, that is, the disruption, either direct or indirect, of the receptor-binding region of the apoE molecule. However, the receptor-binding defect alone does not fully explain the pathogenesis of beta VLDL formation, the development of type III hyperlipoproteinemia, and its mode of inheritance, which can be either recessive or dominant, depending on the apoE mutation. Recent studies suggest that other functional properties of apoE might play a role in the formation of beta-VLDL. Modulation of the receptor-binding defect, association with VLDL, heparin-binding affinity, and interaction with lipolytic enzymes could all contribute to the expression of the disease phenotype and determine its mode of inheritance. PMID- 21244933 TI - Initiation of cardiac allograft rejection New developments in cellular and molecular mechanisms. AB - Although cardiac transplantation has become a viable therapeutic option for end stage heart disease, long-term success is limited by rejection and medical complications of immunosuppression. Earliest events in rejection revolve around T lymphocyte recognition of foreign antigen through a panel of specialized cell surface proteins. This is followed by a cascade of signaling events, transcription of multiple genes, and cytokine production. The central importance of these events, collectively known as T-cell activation, to the rejection process is underscored by the clinical utility of cyclosporine, which prevents T cell activation. The specific site of action of cyclosporine within the T cell has recently been elucidated at the molecular level, revealing important details of T-cell biology. Once the immune response has been initiated, localization of inflammatory cells to the graft requires alteration in the functional state of the vascular endothelium, which can then express adhesive ligands for immune effector cells. Recent evidence suggests that host natural killer lymphocytes may play a role in this process. Understanding the molecular details of these and other early events in rejection will facilitate the development of more specific and effective immunosuppressive therapies. PMID- 21244934 TI - In the form of an addendum to the article "Cardiac Chloride Channels". PMID- 21244935 TI - Reply. PMID- 21244936 TI - Genetics of familial hypertrophic cardiomyopathy Results and strategies. PMID- 21244937 TI - New genetic models for hypertension research. AB - Recent linkage studies in segregating populations derived from crosses of genetically hypertensive rats and normotensive rats have identified several chromosome regions that may contain genes involved in the pathogenesis of spontaneous hypertension. New genetic models for hypertension research, including recombinant inbred strains, congenic strains, and transgenic strains, are beginning to provide important opportunities for investigating whether certain candidate genes contribute to inherited variations in blood pressure. However, gene-targeting techniques that will enable the creation of new animal models with selective nucleotide substitutions will ultimately be required to determine the role of specific DNA variants in the pathogenesis of hypertension. PMID- 21244938 TI - Update on the cellular and molecular basis of capillary permeability. AB - The attenuated layer of endothelial cells lining the blood vessels forms the critical barrier controlling the exchange of molecules from the blood to the interstitial fluid. The interactions of normally circulating blood molecules with the endothelial glycocalyx can either restrict transcapillary exchange in general or selectively increase transendothelial transport of a specific group of ligands. Investigations into the mechanisms responsible for the effects of serum have identified specific receptors, some of which appear to be involved in receptor-mediated transcytosis and endocytosis via noncoated plasmalemma vesicles (also known as caveolae). Such studies suggest that regional differences in endothelial expression of cell surface glycoproteins can be exploited for the development of tissue-directed drug therapies. PMID- 21244939 TI - Atherogenesis Insights from the study of transgenic and gene-targeted mice. AB - Owing to the investigative power of classical mouse genetics and the development of transgenic and gene-targeting technologies, the mouse has increasingly been used to study atherogenesis. Investigators have manipulated the plasma levels of several proteins involved in lipid metabolism through the engineering of mice and assessed the impact of these changes on the progression of murine atherogenesis. These studies have established causal relationships between the expression of defined genetic elements and atherosclerosis in a manner not feasible in humans. Studies of transgenic mice with genetically altered levels of apolipoproteins A I, (a), and E have provided important insights into the in vivo role of these proteins in atherogenesis. These studies illustrate the potential to dissect the complex genetics of atherosclerosis susceptibility with the use of transgenic and gene-targeted mice. PMID- 21244940 TI - The mouse model for atherosclerosis. AB - The mouse model provides unique tools for studies of the complex environmental and genetic interactions underlying atherosclerosis. In particular, a great variety of inbred strains exhibit variations affecting lipoprotein metabolism, diabetes, obesity, immune regulation, and other processes relevant to the disease. The development of many genetic markers in the mouse has made it feasible to identify the genes contributing to these complex traits. In addition, techniques for gene manipulation in vivo are much more advanced in the mouse than in any other mammal. The application of these techniques has been particularly informative in the area of lipoprotein metabolism and atherosclerosis. PMID- 21244941 TI - The very low density lipoprotein receptor A second lipoprotein receptor that may mediate uptake of fatty acids into muscle and fat cells. AB - The isolation of a cDNA highly homologous to that of the low-density lipoprotein (LDL) receptor revealed the presence of a lipoprotein receptor that specifically binds apolipoprotein-E-containing lipoproteins, including very low density lipoprotein (VLDL), intermediate-density lipoprotein, and beta-migrating VLDL. This new receptor, designated VLDL receptor, consists of five domains that resemble those of the LDL receptor. The VLDL receptor mRNA is abundant in tissues performing active fatty acid metabolism, suggesting that the receptor may be responsible for the uptake of fatty acids in triglyceride-rich lipoproteins into muscle and fat cells. PMID- 21244942 TI - Potassium channels in the heart Cellular, molecular, and clinical implications. AB - Potassium channels are membrane-spanning proteins that regulate the flow of potassium ions across the cell membrane. Because of the electrochemical gradient for potassium ions in almost all cell types, opening of potassium channels causes an efflux, of potassium ions that in turn tends to make the interior of the cell more negative than its extracellular environment. During the last 5 years, there has been a rapidly expanding base of information about the structure, function, and pharmacologic regulation of this type of ion channel, and the integration of this information is particularly important to cardiac electrophysiology, where control of potassium efflux is relevant to the design of class-III antiarrhythmic agents and to the understanding of genetic basis of certain disorders. This brief review highlights the functional importance of various potassium channels to the electrophysiology of the heart and presents relevant molecular information about the structures that constitute this important family of integral membrane proteins. PMID- 21244943 TI - Cardioprotective actions of transforming growth factor-beta. AB - Transforming growth factor-beta (TGF-beta) has been shown to have protective effects in experimental models of myocardial, mesenteric, and cerebral ischemia reperfusion injury. These effects are mediated by its ability to block adhesion of neutrophils to endothelium and to preserve endothelial function in terms of physiologic release of nitric oxide (NO). TGF-beta also maintains the rhythmicity of cultured cardiac myocytes and blocks the suppressive effects of interleukin-1 on their beating rate by antagonizing the pathologic induction of NO synthase. These data suggest that TGF-beta will be useful clinically in treatment of both reperfusion injury and inflammatory diseases of the heart. PMID- 21244944 TI - Molecular genetics of myotonic dystrophy. AB - Myotonic muscular dystrophy (DM) has been shown to be caused by the expansion of an unstable triplet nucleotide repeat sequence located in the 3' untranslated region of a gene coding for a putative serine-threonine protein kinase. Isolation of genomic and cDNA clones for the DM kinase have significantly simplified the genetic diagnosis of DM. The cellular localization, enzymatic activity, and role in the pathophysiology of DM of the kinase protein are as yet unknown. PMID- 21244945 TI - Integration of transmembrane signaling Cross-talk among G-protein-linked receptors and other signal transduction pathways. AB - The heart is a point of convergence for many transmembrane signal transduction pathways and, as such, exemplifies the complexities of sorting out their interactions. In the heart and cardiovascular system, hormone and neurotransmitter signals are propagated via G-protein-and non-G-protein-linked receptors. The receptors, in turn, are coupled to many effectors, including adenylylcyclases, phospholipases, and ion channels, as well as protein kinases and phosphatases. Integrating the information from numerous signaling pathways requires "cross-talk" among the different pathways. This article provides a perspective and attempts to describe in some detail what is known about a few of these interactions. Cross-talk from stimulatory to inhibitory adenylylcyclase pathways, from inhibitory to stimulatory adenylylcyclase pathways, from the adenylylcyclase to the phospholipase-C pathway, and from tyrosine kinase to G protein-coupled receptors is described. Because of its central importance in the regulation of the cardiovascular system, and due to the availability of good model systems, the powerful responses mediated by the beta-adrenergic receptor pathway serve as an excellent model to approach this subject. PMID- 21244946 TI - A common theme in endothelial activation Insights from the structural analysis of the genes for E-selectin and VCAM-1. AB - An important early step in the development of an inflammatory infiltrate is the induction of new endothelial cell surface proteins. Cytokine-induced expression of endothelial-leukocyte adhesion molecule-1 (E-selectin or ELAM-1) may mediate neutrophil adhesion to endothelium, whereas induced expression of vascular cell adhesion molecule (VCAM-1) may be important in the adhesion of mononuclear cells. Both the corresponding genes are transcriptionally regulated by the inflammatory cytokines. Structural analysis of the promoters of these genes reveals binding sites for the transcription factor nuclear factor kappaB (NF-kappaB). Activation of the pleiotropic mediator NF-kappaB in endothelial cells could coordinate the expression of numerous endothelial products that are important in endothelial activation, including some cell surface adhesion proteins, cytokines, growth factors, and components of the coagulation system. PMID- 21244947 TI - Modulation of myocardial contraction by endocardial and coronary vascular endothelium. AB - Endothelial cells in the heart, both endocardial endothelium and coronary vascular endothelium, influence myocardial contraction in isolated tissue and pump function in intact hearts by releasing diffusible agents that affect subjacent myocardium. Endocardial endothelium releases both nitric oxide (NO) and an unidentified "contraction-prolonging substance" ("endocardin") that respectively decrease and increase the duration of twitch contraction, probably by altering myofibrillar calcium sensitivity. These agents modulate the duration of ejection and the timing of relaxation, but without significantly altering early systolic behavior. Coronary vascular endothelium also releases NO, with similar effects on contraction, and in addition probably releases several other agents. Current work is aimed at identifying all of the agents involved in these novel endothelial influences and studying their potential physiologic and pathophysiologic roles in cardiac contractile and other functions. PMID- 21244948 TI - Nitric oxide synthases in the cardiovascular system. AB - The endothelium-derived relaxing factor that mediates the endothelium-dependent vasodilatation first observed in 1980 has been identified as nitric oxide (NO). In addition to the endothelium, NO is formed in other cells such as neuronal cells of the brain (where it mediates synoptic plasticity), peripheral nonadrenergic noncholinergic (NANC) nerves (where it acts as an atypical neurotransmitter relaxing vascular and nonvascular smooth muscle), and various specialized epithelial cells. Other cell types such as macrophages and smooth muscle cells can be induced with bacterial endotoxin and/or cytokines to synthesize large amounts of the radical. At low concentrations, NO is an inter- and intracellular messenger molecule whose target enzyme is the soluble isoform of guanylyl cyclase. At high concentrations, the NO radical has cytostatic effects on parasitic microorganisms and tumor cells. In the vascular system, endothelium-derived NO is a physiologically significant vasodilator and inhibitor of platelet aggregation and adhesion. NANC nerve-derived NO may also contribute to vasodilatation. In addition, NO can prevent leukocyte adhesion to the endothelium by interfering with the adhesion molecule CD11/CD18, and NO has been shown to inhibit the proliferation of vascular smooth muscle cells. In sepsis and during cytokine therapy, a different NOS is induced in the vascular wall (presumably in smooth muscle cells) where it synthesizes large amounts of NO that contribute to the massive vasodilatation and shock. PMID- 21244949 TI - Recombinant DNA and gene isolation. AB - Although a formidable array of approaches fall under the broad umbrella of molecular genetics, the basic technology is elegant and conceptually simple (Watson et al. 1983, Roberts et al. 1992). It has enabled a reductionist approach to be applied to the study of genes and their sequences, as well as the transcripts that underlie organ development and function. Cardiovascular research has, in the past, utilized the systemic and integrative approaches that are inherent in the study of an organ system. Molecular genetics and recombinant DNA offer the cardiologist a complementary focus, as both normal and abnormal heart functions can be defined in terms of the underlying genetic complement and its regulation. One can approach heart function in terms of defining the basic components that participate in the developmental and functional processes of the heart at different developmental times. A future challenge will be to integrate the information regarding these different components with the heart's function in an intact biological system. PMID- 21244950 TI - Acute myocardial infarction in a young man Are there any risk factors? PMID- 21244951 TI - Tissue-specific expression of calcium channels. AB - The high-voltage-activated calcium channel is a multimeric protein complex containing alpha(1), alpha(2)/delta, beta, and gamma subunits. The alpha(1) subunit is the ion conduction channel and contains the binding sites for calcium channel blockers and toxins. Three genes code for distinct L-type, dihydropyridine-sensitive alpha(1) subunits; one gene codes for the neuronal P type (Purkinje) alpha(1) subunit; and one gene codes for the neuronal N-type alpha(1) subunit. The smooth and cardiac muscle L-type calcium channel alpha(1) subunits are splice variants of the same gene. The alpha(1) subunits are coexpressed with a common alpha(2)/delta subunit and tissue-specific beta subunits (at least three genes). The gamma subunit apparently is expressed only in skeletal muscle. The properties of these cloned and expressed calcium channels are discussed here. PMID- 21244952 TI - Ca(2+)-activated potassium channels and ATP-sensitive potassium channels as modulators of vascular tone. AB - Membrane hyperpolarization through activation of potassium channels in arterial smooth muscle appears to be an effective mechanism to dilate arteries. Conversely, membrane depolarization through inhibition of potassium channels can lead to vasoconstriction. Here, I briefly review the roles of Ca(2+)-activated K(+) (K(Ca)) channels and ATP-sensitive K(+) (K(ATP)) channels in the control of arterial smooth muscle function. K(Ca) channels regulate arterial tone in response to changes in intravascular pressure and possibly to a variety of vasoconstrictors. K(ATP) channels respond to changes in the cellular metabolic state and are targets of a variety of synthetic and endogenous vasodilators. PMID- 21244953 TI - Control of clot lysis by gene transfer. AB - Intravascular clot formation is a local process that can result in serious clinical consequences, including limb loss and death. Gene transfer and expression of recombinant plasminogen activators in the endothelial cells of the vessel wall offer an attractive approach to the enhancement of local fibrinolytic activity. In vitro studies have demonstrated that endothelial cell fibrinolytic activity can be increased by gene transfer of either secreted or cell surface anchored plasminogen activators. Future work will define the ability of gene transfer to facilitate clot lysis in vivo. PMID- 21244954 TI - Evidence for a role of an intracardiac renin-angiotensin system in normal and failing hearts. AB - Although substantial evidence of a cardiac RAS has been obtained in the past decade, a number of important questions remain unanswered. These include identification and localization of the cell types responsible for production of the system's components as well as the regulation of synthesis, storage, and secretion pathways for each component. Future studies, which will utilize tools of molecular biology that have become recently available (for example, transgenic animal models), renin inhibitors, angiotensin receptor antagonists, and bradykinin antagonists, will help to elucidate specific roles of the cardiac RAS in normal and failing hearts. PMID- 21244955 TI - Advances in dyslexia research. AB - Dyslexia: Advances in theory and practice, Dyslexia Research Foundation and Center for Reading Research, 20-23 November 1997, Stavanger, Norway. PMID- 21244956 TI - Statistical inference: learning in artificial neural networks. AB - Artificial neural networks (ANNs) are widely used to model low-level neural activities and high-level cognitive functions. In this article, we review the applications of statistical inference for learning in ANNs. Statistical inference provides an objective way to derive learning algorithms both for training and for evaluation of the performance of trained ANNs. Solutions to the over-fitting problem by model-selection methods, based on either conventional statistical approaches or on a Bayesian approach, are discussed. The use of supervised and unsupervised learning algorithms for ANNs are reviewed. Training a multilayer ANN by supervised learning is equivalent to nonlinear regression. The ensemble methods, bagging and arching, described here, can be applied to combine ANNs to form a new predictor with improved performance. Unsupervised learning algorithms that are derived either by the Hebbian law for bottom-up self-organization, or by global objective functions for top-down self-organization are also discussed. PMID- 21244957 TI - Indexing and the object concept: developing 'what' and 'where' systems. AB - The study of object cognition over the past 25 years has proceeded in two largely non-interacting camps. One camp has studied object-based visual attention in adults, while the other has studied the object concept in infants. We briefly review both sets of literature and distill from the adult research a theoretical model that we apply to findings from the infant studies. The key notion in our model of object representation is the 'sticky' index, a mechanism of selective attention that points at a physical object in a location. An object index does not represent any of the properties of the entity at which it points. However, once an index is pointing to an object, the properties of that object can be examined and featural information can be associated with, or 'bound' to, its index. The distinction between indexing and feature binding underwrites the distinction between object individuation and object identification, a distinction that turns out to be crucial in both the adult attention and the infant object concept literature. By developing the indexing model, we draw together two disparate sets of literature and suggest new ways to study object-based attention in infancy. PMID- 21244958 TI - Object perception and object naming in early development. AB - Among our most fundamental capacities are those that allow us to perceive, categorize and name objects. Recently, controversy has surrounded the question of how young children learn names for objects, in particular, the relative roles of perception and higher-level world knowledge. It is well known that adults depend strongly on conceptual knowledge in a variety of categorization tasks, including object naming. We argue, however, that perception may play a special role in early object naming and, in particular, that certain kinds of world knowledge known to guide adult naming may come to guide naming only rather late in development. Building early mechanisms of naming on a perceptual foundation that may be encapsulated, and thus shut off from more reflective processes, may explain in part why young children can easily and rapidly learn names for things from the adults around them, despite the fact that adults and children may possess very different conceptual organizations. PMID- 21244959 TI - Streams and consciousness: visual awareness and the brain. AB - Vision is our most powerful sense and, arguably, it gives us our most vivid sensory and imaginal experiences. It is also one of the best understood systems in contemporary neuroscience. Yet, contrary to both traditional assumptions and our phenomenological intuition, recent research has shown that vision is not a monolithic system that creates a single general-purpose representation in the brain. For example, selective brain damage can compromise visuomotor control while leaving perception intact, and damage elsewhere can compromise visual perception while leaving visuomotor control intact. Thus, it is becoming apparent that we have two (largely) separate visual systems. One of them is dedicated to the rapid and accurate guidance of our movements: it is a complex and powerful system, and yet it lies outside the realm of our conscious visual awareness. The other seems to provide our perceptual phenomenology, although its primary purpose is probably to provide suitably coded visual inputs for storage in and retrieval from memory. According to this conceptualization, both systems can be seen as serving our behaviour, but each does so on a different time scale. Recent studies suggest that neuropsychological research in humans can play a central role in bridging the gap between neurobiological studies of the monkey's visual system and the search to narrow down the brain mechanisms that mediate our visual awareness. PMID- 21244961 TI - How the mind works. AB - by Steven Pinker, W.W. Norton & Co., 1997. $29.95 (xii+660 pages) ISBN 0 393 04535 8. PMID- 21244960 TI - 'Babbling' and social context in infant monkeys: parallels to human infants. AB - Although only humans use spoken language, the vocal communication of many animals shares some features with language. Within the context of their family, normal children and young non-human primates develop proficiency in the nuances of their species-specific vocal communication system. Engaging in speech-like phonetic activity, or babbling, occurs in all normal children regardless of their native language. Similar periods of vocal development have not been described previously for non-human primates. However, in the pygmy marmoset, a South American monkey, we found that the primary vocal behavior of infants parallels many characteristics of human infant babbling. These analogous features include universality, repetition, use of a subset of the adult vocal repertoire, recognizably adult-like vocal structure and lack of a clear vocal referent. Also, like human infants, young marmosets develop in a closely knit family unit that includes both parents and often older siblings. In this context, the babbling like behavior of the marmoset infant stimulates interaction with caregivers, thereby serving a key role in the infant's own development. These developmental and social processes indicate that the study of vocal development in non-human primate species can provide insights into the function of babbling in humans. PMID- 21244962 TI - Lessons from lincoln. PMID- 21244963 TI - Multiple digitalis receptors A molecular perspective. AB - The Na,K-ATPase is the only established receptor for cardiac glycosides like digoxin or ouabain. There are now known to be three different isoforms of its principal subunit. These isoforms can differ from one another in their intrinsic affinity for cardiac glycosides. Recent work examines the molecular structure of the binding site. The relative level of expression of the isoforms in cardiac tissue is modified in several developmental, hormonal, and pathological states, contributing to alterations in the digitalis sensitivity of the tissue. PMID- 21244964 TI - rDNA transcription and cardiac hypertrophy. AB - A common result of the various stimuli that alter the growth rates of cells is a parallel alteration of the rate of ribosome biogenesis. In many cell types, this mandates an altered rate of ribosomal RNA synthesis. Preliminary studies indicate that rDNA transcription may in fact be regulated at more than one level or step. Our understanding of the process of transcription and the mechanisms by which it is regulated are discussed. PMID- 21244965 TI - Troponin isoform switching in the developing heart and its functional consequences. AB - The subunits of the troponin complex-troponin C, troponin T, and troponin I-are responsible for the Ca(2+)-dependent regulation of contractile activity in heart and skeletal muscle. Distinct troponin T and I isoforms, generated by different genes or by alternative splicing from the same gene, are expressed during cardiac development. Troponin switching affects the Ca(2+) sensitivity of the contractile system and may account for the greater resistance to hypoxia and acidosis, and the impaired responsiveness to adrenergic stimulation of the fetal and neonatal heart. PMID- 21244966 TI - Cellular and molecular contributions of the cardiac neural crest to cardiovascular development. AB - Normal development of the heart and great arteries requires participation of the cardiac neural crest. Ectomesenchymal cells from this area of the neural crest migrate to pharyngeal arches 3, 4, and 6, where they support development of the aortic arch arteries. Cells continue migration from the pharyngeal arches to specific sites in the outflow tract. Removal of the neural crest results in two types of malformations: outflow septation defects and alignment defects. The genesis of these two types of defects is by two different mechanisms. Outflow septation is disturbed when a critical number of cells does not reach the outflow tract. Alignment is altered by an as yet unknown secondary mechanism that is transmitted upstream to the heart from the pharyngeal arches. Aortic arch artery and ventricular development as well as hemodynamic parameters are abnormal from an early age. Some possible molecular mechanisms involved in specifying neural crest for participation in heart development are discussed. PMID- 21244967 TI - Cardiac chloride channels. AB - Cardiac chloride channels, once largely ignored, are the subject of renewed exploration. Consequently, their molecular identities and electrophysiologic properties are being defined and have revealed a distinct family of ionic channels capable of uniquely influencing the cardiac action potential. Targeting these channel proteins may provide novel antiarrhythmic strategies. PMID- 21244968 TI - (31)P NMR spectroscopy The noninvasive tool for the study of the biochemistry of the cardiovascular system. AB - Recent advances in nuclear magnetic resonance (NMR) spectroscopy have allowed the transition to be made from using animal models for studies of the biochemistry of the cardiovascular system to direct measurements in human myocardium. (31)P NMR spectroscopy is now being used to define changes in the relative concentrations of phosphocreatine and ATP (the abundant high-energy phosphate compounds in muscle) in normal, ischemic, hypertrophied, and failing human hearts. Use of (31)P magnetization transfer to measure turnover of high-energy phosphate containing compounds provides new insights into myocardial energetics. PMID- 21244969 TI - Precision close-to-carrier phase noise simulation of BAW oscillators. AB - Based on a commercial simulation tool, the influence of BAW resonator noise on the resulting oscillator phase noise is revisited. The parametric model of the resonator uses experimental data, and includes an f(-2) noise not often considered in measurements, in addition to its flicker noise. PMID- 21244970 TI - Cyclic energy harvesting from pyroelectric materials. AB - A method of continuously harvesting energy from pyroelectric materials is demonstrated using an innovative cyclic heating scheme. In traditional pyroelectric energy harvesting methods, static heating sources are used, and most of the available energy has to be harvested at once. A cyclic heating system is developed such that the temperature varies between hot and cold regions. Although the energy harvested during each period of the heating cycle is small, the accumulated total energy over time may exceed traditional methods. Three materials are studied: a commonly available soft lead zirconate titanate (PZT), a pre-stressed PZT composite, and single-crystal PMN-30PT. Radiation heating and natural cooling are used such that, at smaller cyclic frequencies, the temporal rate of change in temperature is large enough to produce high power densities. The maximum power density of 8.64 MUW/cm3 is generated with a PMN-30PT single crystal at an angular velocity of 0.64 rad/s with a rate of 8.5 degrees C/s. The pre-stressed PZT composite generated a power density of 6.31 MUW/cm(3), which is 40% larger than the density of 4.48 MUW/cm3 obtained from standard PZT. PMID- 21244971 TI - Millimeter-wave dielectric properties of single-crystal ferroelectric and dielectric materials. AB - Transmittance measurements on various single crystal ferroelectric and dielectric materials, BaTiO(3), SrTiO(3), LiNbO(3), LiTaO(3), (PbMg(1/3)Nb(2/3)O(3))0.73 (PbTiO(3))0.27, LaAlO(3), and Bi(4)Ge(3)O(12), over a broad millimeter-wave (MMW) frequency range have been performed. Frequency dependence of the complex dielectric permittivity has been measured in the MMW region using high-power sources for the first time, using a free-space, quasi-optical MMW spectrometer equipped with high-power backward wave oscillators (BWOs) as sources of coherent radiation, tunable in the range from 30 to 120 and 180 to 260 GHz. These results are compared with MMW permittivity of these materials obtained by other methods as well as to RF, microwave, and optical frequency permittivities for all the materials tested. The effects of both crystallographic orientation and quality of the surface polishing of the crystals have been examined. Uncertainties and possible sources of instrumentation and measurement errors related to the freespace MMW technique are discussed. This work demonstrates that precise MMW permittivity data can be obtained even on relatively small and thin crystals of different surface conditions and orientations using the high-power BWO-based quasioptical approach. PMID- 21244972 TI - Analysis of ac-dc conversion for energy harvesting using an electrostrictive polymer P(VDF-TrFE-CFE). AB - Harvesting systems capable of transforming unused environmental energy into useful electrical energy have been extensively studied for the last two decades. The recent development of electrostrictive polymers has generated new opportunities for harvesting energy. The contribution of this study lies in the design and validation of electrostrictive polymer- based harvesters able to deliver dc output voltage to the load terminal, making the practical application of such material for self-powered devices much more realistic. Theoretical analysis supported by experimental investigations showed that an energy harvesting module with ac-to-dc conversion allows scavenging power up to 7 MUW using a bias electric field of 10 V/MUm and a transverse strain of 0.2%. This represents a power density of 280 MUW/cm(3) at 100 Hz, which is much higher than the corresponding values of most piezo-based harvesters. PMID- 21244973 TI - Adaptive correction method for an OCXO and investigation of analytical cumulative time error upper bound. AB - Traditional oscillators used in timing modules of CDMA and WiMAX base stations are large and expensive. Applying cheaper and smaller, albeit more inaccurate, oscillators in timing modules is an interesting research challenge. An adaptive control algorithm is presented to enhance the oscillators to meet the requirements of base stations during holdover mode. An oscillator frequency stability model is developed for the adaptive control algorithm. This model takes into account the control loop which creates the correction signal when the timing module is in locked mode. A recursive prediction error method is used to identify the system model parameters. Simulation results show that an oscillator enhanced by our adaptive control algorithm improves the oscillator performance significantly, compared with uncorrected oscillators. Our results also show the benefit of explicitly modeling the control loop. Finally, the cumulative time error upper bound of such enhanced oscillators is investigated analytically and comparison results between the analytical and simulated upper bound are provided. The results show that the analytical upper bound can serve as a practical guide for system designers. PMID- 21244974 TI - A multi-band fast-locking delay-locked loop with jitter-bounded feature. AB - In this paper, a fast-locking delay-locked loop (DLL) with jitter-bounded feature is presented. In the proposed fast-locking mechanism, a frequency estimator and a programmable voltage circuit are developed to rapidly switch the control node of voltage-controlled delay line to a voltage level near the final required value. After that, the DLL output will be quickly locked by the following charge pumping on the loop filter. In the jitter-bounded approach, two phase-frequency detectors and a tunable delay are employed to hold the output clock jitter between two reference inputs after the DLL is locked. Furthermore, to enhance the flexibility of the presented DLL, a frequency multiplier with fewer active devices is also developed to provide high-frequency clock output for wideband applications. The presented DLL is implemented in a 0.18-MUm 1P6M CMOS technology. The active area without contact pads is 0.34 * 0.41 mm(2). A minimum lock time of six clock cycles is measured from no reference input to locked state. The output frequency ranges of the DLL and the frequency multiplier can be measured from 200 to 400 MHz and from 1 to 2 GHz, respectively. The power dissipation of the presented DLL is 31.5 mW at a 1.8 V supply voltage. PMID- 21244975 TI - Image-based cardiac phase retrieval in intravascular ultrasound sequences. AB - Longitudinal motion during in vivo pullbacks acquisition of intravascular ultrasound (IVUS) sequences is a major artifact for 3-D exploring of coronary arteries. Most current techniques are based on the electrocardiogram (ECG) signal to obtain a gated pullback without longitudinal motion by using specific hardware or the ECG signal itself. We present an image-based approach for cardiac phase retrieval from coronary IVUS sequences without an ECG signal. A signal reflecting cardiac motion is computed by exploring the image intensity local mean evolution. The signal is filtered by a band-pass filter centered at the main cardiac frequency. Phase is retrieved by computing signal extrema. The average frame processing time using our setup is 36 ms. Comparison to manually sampled sequences encourages a deeper study comparing them to ECG signals. PMID- 21244976 TI - Comparison of pulse subtraction Doppler and pulse inversion Doppler. AB - In this paper, a new Doppler technique based on pulse subtraction imaging (PSD) is described and compared with pulse inversion Doppler (PID). Combining a nonlinear contrast agent imaging technique with a Doppler process provides a tool for detecting motion of both contrast agents and tissues. This has potential in targeted imaging in which attached microbubbles need to be separated from moving ones and surrounding tissues. The results from both simulation and experiment show that PSD is able to differentiate bubble motion from tissue motion. For Doppler processing conducted at the fundamental frequency, the contrast-to-tissue ratio (CTR) in PSD was 3.3 (+/-0.4) times higher on average than PID at a mechanical index (MI) of 0.1. At the harmonic frequency, PID was shown to have a 3.1 (+/-0.4) times higher CTR than PSD. Overall, taken in their optimum processing conditions, PID has a CTR up to 1.9 (+/-0.4) times higher than PSD. The CTRs for both techniques have also been shown to increase with increasing MI. However, for the same axial Doppler resolution. PSD also allows less energy to be transmitted into the medium, which makes it less disruptive. The relative performances of PSD and PID in terms of the bandwidth of the imaging system are also discussed. PMID- 21244977 TI - Echocardiographic speckle reduction comparison. AB - In this paper, a detailed description and comparison of speckle reduction of medical ultrasound, and in particular echocardiography, is presented. Fifteen speckle reduction filters are described in a detailed fashion to facilitate implementation for research and evaluation. The filtering techniques considered include anisotropic diffusion, wavelet denoising, and local statistics. Common nomenclature and notation are adopted, to expedite comparison between approaches. Comparison of the filters is based on their application to simulated images, clinical videos, and a computational requirement analysis. The ultrasound simulation method provides a realistic model of the image acquisition process, and permits the use of a noise-free reference image for comparison. Application of objective quality metrics quantifies the preservation of image edges, overall image distortion, and improvement in image contrast. The computational analysis quantifies the number of operations required for each speckle reduction method. A speed-accuracy analysis of discretization methods for anisotropic diffusion is included. It is concluded that the optimal method is the OSRAD diffusion filter. This method is capable of strong speckle suppression, increasing the average SNRA of the simulated images by a factor of two. This method also shows favorable edge preservation and contrast improvement, and may be efficiently implemented. PMID- 21244978 TI - Ultrasonic backscatter imaging by shear-wave-induced echo phase encoding of target locations. AB - We present a novel method for ultrasound backscatter image formation wherein lateral resolution of the target is obtained by using traveling shear waves to encode the lateral position of targets in the phase of the received echo. We demonstrate that the phase modulation as a function of shear wavenumber can be expressed in terms of a Fourier transform of the lateral component of the target echogenicity. The inverse transform, obtained by measurements of the phase modulation over a range of shear wave spatial frequencies, yields the lateral scatterer distribution. Range data are recovered from time of flight as in conventional ultrasound, yielding a B-mode-like image. In contrast to conventional ultrasound imaging, where mechanical or electronic focusing is used and lateral resolution is determined by aperture size and wavelength, we demonstrate that lateral resolution using the proposed method is independent of the properties of the aperture. Lateral resolution of the target is achieved using a stationary, unfocused, single-element transducer. We present simulated images of targets of uniform and non-uniform shear modulus. Compounding for speckle reduction is demonstrated. Finally, we demonstrate image formation with an unfocused transducer in gelatin phantoms of uniform shear modulus. PMID- 21244979 TI - Fresnel-based beamforming for low-cost portable ultrasound. AB - In this paper, we propose a modified electronic Fresnel-based beamforming method for low-cost portable ultrasound systems. This method uses a unique combination of analog and digital beamforming methods. Two versions of Fresnel beamforming are presented in this paper: 4-phase (4 different time delays or phase shifts) and 8-phase (8 different time delays or phase shifts). The advantage of this method is that a system with 4 to 8 transmit channels and 2 receive channels with a network of switches can be used to focus an array with 64 to 128 elements. The simulation and experimental results show that Fresnel beamforming image quality is comparable to traditional delay-and-sum (DAS) beamforming in terms of spatial resolution and contrast-to-noise ratio (CNR) under certain system parameters. With an f-number of 2 and 50% signal bandwidth, the experimental lateral beamwidths are 0.54, 0.67, and 0.66 mm and the axial pulse lengths are 0.50, 0.51, and 0.50 mm for DAS, 8-phase, and 4-phase Fresnel beamforming, respectively. The experimental CNRs are 4.66, 4.42, and 3.98, respectively. These experimental results are in good agreement with simulation results. PMID- 21244980 TI - High-resolution ultrasound displacement measurement using coded excitations. AB - Resolution of displacement measurements based on ultrasound pulse-echo techniques is limited by the center frequency of the transmitted wave, echo sampling rate, quantization errors, and electronic noises in the measurement system. We developed a new method utilizing the clutter signal in coded excitations to determine the displacement of an object or a desired region of an object with much improved resolution. The method includes transmitting a pair of Golay complementary sequences, receiving echoes from the object or a region of the object, compressing the pulse, eliminating the main lobe, and determining the object displacement between the two transmissions from the residual clutter signal around the main lobe of the compressed pulse. Results of computer simulations showed that the new method improved the resolution by several orders of magnitude and was more robust to noise than traditional pulse-echo methods. The new method was also evaluated using an experimental ultrasound system (10 MHz center frequency, 100 MHz sampling rate, and 8-bit sampling precision). A high precision in the displacement measurement was achieved with a measurement error of ?5.76 nm +/-36.27 nm (mean +/- standard deviation). The method has the potential to be applied in biomedical and industrial measurements of distance, displacement, and thickness. PMID- 21244981 TI - Ultrafast compound Doppler imaging: providing full blood flow characterization. AB - Doppler-based flow analysis methods require acquisition of ultrasound data at high spatio-temporal sampling rates. These rates represent a major technical challenge for ultrasound systems because a compromise between spatial and temporal resolution must be made in conventional approaches. Consequently, ultrasound scanners can either provide full quantitative Doppler information on a limited sample volume (spectral Doppler), or averaged Doppler velocity and/or power estimation on a large region of interest (Doppler flow imaging). In this work, we investigate a different strategy for acquiring Doppler information that can overcome the limitations of the existing Doppler modes by significantly reducing the required acquisition time. This technique is called ultrafast compound Doppler imaging and is based on the following concept: instead of successively insonifying the medium with focused beams, several tilted plane waves are sent into the medium and the backscattered signals are coherently summed to produce high-resolution ultrasound images. We demonstrate that this strategy allows reduction of the acquisition time by a factor of up to of 16 while keeping the same Doppler performance. Depending on the application, different directions to increase performance of Doppler analysis are proposed and the improvement is quantified: the ultrafast compound Doppler method allows faster acquisition frame rates for high-velocity flow imaging, or very high sensitivity for low-flow applications. Full quantitative Doppler flow analysis can be performed on a large region of interest, leading to much more information and improved functionality for the physician. By leveraging the recent emergence of ultrafast parallel beamforming systems, this paper demonstrates that breakthrough performances in flow analysis can be reached using this concept of ultrafast compound Doppler. PMID- 21244982 TI - Ultrasound evaluation of mechanical injury of bovine knee articular cartilage under arthroscopic control. AB - A local cartilage injury can trigger development of posttraumatic osteoarthritis (OA). Surgical methods have been developed for repairing cartilage injuries. Objective and sensitive methods are needed for planning an optimal surgery as well as for monitoring the surgical outcome. In this laboratory study, the feasibility of an arthroscopic ultrasound technique for diagnosing cartilage injuries was investigated. In bovine knees (n = 7) articular cartilage in the central patella and femoral sulcus was mechanically degraded with a steel brush modified for use under arthroscopic control. Subsequently, mechanically degraded and intact adjacent tissue was imaged with a high frequency (40 MHz) intravascular ultrasound device operated under arthroscopic guidance. After opening the knee joint, mechanical indentation measurements were also conducted with an arthroscopic device at each predefined anatomical site. Finally, cylindrical osteochondral samples were extracted from the measurement sites and prepared for histological analysis. Quantitative parameters, i.e., reflection coefficient (R), integrated reflection coefficient (IRC), apparent integrated backscattering (AIB), and ultrasound roughness index (URI) were calculated from the ultrasound signals. The reproducibilities (sCV %) of the measurements of ultrasound parameters were variable (3.7% to 26.1%). Reflection and roughness parameters were significantly different between mechanically degraded and adjacent intact tissue (p < 0.05). Surface fibrillation of mechanically degraded tissue could be visualized in ultrasound images. Furthermore, R and IRC correlated significantly with the indentation stiffness. The present results are encouraging; however, further technical development of the arthroscopic ultrasound technique is needed for evaluation of the integrity of human articular cartilage in vivo. PMID- 21244983 TI - High-temperature (>500 degrees c) wall thickness monitoring using dry-coupled ultrasonic waveguide transducers. AB - Conventional ultrasonic transducers cannot withstand high temperatures for two main reasons: the piezoelectric elements within them depolarize, and differential thermal expansion of the different materials within a transducer causes them to fail. In this paper, the design of a high-temperature ultrasonic thickness gauge that bypasses these problems is described. The system uses a waveguide to isolate the vulnerable transducer and piezoelectric elements from the high-temperature measurement zone. Use of thin and long waveguides of rectangular cross section allows large temperature gradients to be sustained over short distances without the need for additional cooling equipment. The main problems that had to be addressed were the transmission and reception of ultrasonic waves into and from the testpiece that the waveguides are coupled to, and optimization of the wave propagation along the waveguide itself. It was found that anti-plane shear loading performs best at transmitting and receiving from the surface of a component that is to be inspected. Therefore, a nondispersive guided wave mode in large-aspect-ratio rectangular strips was employed to transmit the anti-plane shear loading from the transducer to the measurement zone. Different joining methods to attach the waveguides to the component were investigated and experiments showed that clamping the waveguides to the component surface gave the best results. The thickness of different plate samples was consistently measured to within less than 0.1 mm. Performance at high temperatures was tested in a furnace at 730 degrees C for 4 weeks without signal degradation. Thicknesses in the range of 3 to 25 mm could be monitored using Hanning windowed tonebursts with 2 MHz center frequency. PMID- 21244984 TI - Driving mechanism, design, fabrication process, and experiments of a cylindrical ultrasonic linear microactuator. AB - A new type of cylindrical ultrasonic linear microactuator (CULMA) is introduced. The traveling wave generation condition in the stator is presented, which was confirmed using simulation and experimentation. The design and fabrication process to develop the stator is described. The stator was successfully fabricated using metallic glass and a sputtering method, and the vibration of the prototype matched the simulation results. When the driving frequency is at 626 kHz, the traveling wave in the stator was observed. Loaded with a pipe slider, the slider movement was experimentally demonstrated and the motion measured with 26 mm/s in peak speed. This paper presents a traveling wave generation method in a CULMA which would also available in other microactuators or MEMS-scale ones. PMID- 21244985 TI - Analysis of elastic waves transmitted through a 2-D phononic crystal exhibiting negative refraction. AB - A two-dimensional phononic crystal (PC) made of a square lattice of air holes in an aluminum matrix is studied. The band structure calculated in the irreducible Brillouin zone of the PC exhibits a branch with a negative slope that allows negative refraction. This phenomenon has been numerically verified using a prism shaped PC for plane waves entering the PC with two different incidences. A detailed study of the waves at the exit of the PC shows that the plane wave is reconstructed after several wavelengths. Finally, the description of the refracted waves is interpreted using a point source array, giving information about the angular spreading and the relative amplitude of each refracted beam. PMID- 21244986 TI - A laser probe based on a Sagnac interferometer with fast mechanical scan for RF surface and bulk acoustic wave devices. AB - This paper describes the development of a phasesensitive laser probe with fast mechanical scan for RF surface and bulk acoustic wave (SAW/BAW) devices. The Sagnac interferometer composed of micro-optic elements was introduced for the selective detection of RF vertical motion associated with RF SAW/BAW propagation and vibration. A high-pass characteristic of the interferometer makes the measurement very insensitive to low-frequency vibration. This feature allows us to apply the fast mechanical scan to the interferometric measurement without badly sacrificing its SNR and spatial resolution. The system was applied to the visualization of a field pattern on the vibrating surface of an RF BAW resonator operating in the 2 GHz range. The field pattern was obtained in 17 min as a 2-D image (500 * 750 pixel with 0.4 MUm resolution and SNR of 40 dB). The system was also applied to the characterization of an RF SAW resonator operating in the 1 GHz range, and the applicability of the system was demonstrated. PMID- 21244987 TI - Oscillator phase noise: systematic construction of an analytical model encompassing nonlinearity. AB - This paper offers a derivation of phase noise in oscillators resulting in a closed-form analytic formula that is both general and convenient to use. This model provides a transparent connection between oscillator phase noise and the fundamental device physics and noise processes. The derivation accommodates noise and nonlinearity in both the resonator and feedback circuit, and includes the effects of environmental disturbances. The analysis clearly shows the mechanism by which both resonator noise and electronics noise manifest as phase noise, and directly links the manifestation of phase noise to specific sources of noise, nonlinearity, and external disturbances. This model sets a new precedent, in that detailed knowledge of component-level performance can be used to predict oscillator phase noise without the use of empirical fitting parameters. PMID- 21244988 TI - A high-frequency annular-array transducer using an interdigital bonded 1-3 composite. AB - This paper reports the design, fabrication, and characterization of a 1-3 composite annular-array transducer. An interdigital bonded (IB) 1-3 composite was prepared using two IB operations on a fine-grain piezoelectric ceramic. The final composite had 19-MUm-wide posts separated by 6-MUm-wide polymer kerfs. A novel method to remove metal electrodes from polymer portions of the 1-3 composite was established to eliminate the need for patterning and aligning the electrode on the composite to the electrodes on a flexible circuit. Unloaded epoxy was used for both the matching and backing layers and a flexible circuit was used for interconnect. A prototype array was successfully fabricated and tested. The results were in reasonable agreement with those predicted by a circuit-analogous model. The average center frequency estimated from the measured pulse-echo responses of array elements was 33.5 MHz and the -6-dB fractional bandwidth was 57%. The average insertion loss recorded was 14.3 dB, and the maximum crosstalk between the nearest-neighbor elements was less than -37 dB. Images of a wire phantom and excised porcine eye were obtained to show the capabilities of the array for high-frequency ultrasound imaging. PMID- 21244989 TI - Dispersion and mirror transmission characteristics of bulk acoustic wave resonators. AB - A heterodyne laser interferometer is used for a detailed study of the acoustic wave fields excited in a 932-MHz solidly mounted ZnO thin-film BAW resonator. The sample is manufactured on a glass substrate, which also allows direct measurement of the vibration fields from the bottom of the acoustic mirror. Vibration fields are measured both on top of the resonator and at the mirror-substrate interface in a frequency range of 350 to 1200 MHz. Plate wave dispersion diagrams are calculated from the experimental data in both cases and the transmission characteristics of the acoustic mirror are determined as a function of both frequency and lateral wave number. The experimental data are compared with 1-D and 2-D simulations to evaluate the validity of the modeling tools commonly used in mirror design. All the major features observed in the 1-D model are identified in the measured dispersion diagrams, and the mirror transmission characteristics predicted for the longitudinal waves, by both the 1-D and the 2-D models, match the measured values well. PMID- 21244990 TI - High-spatial-resolution sub-surface imaging using a laser-based acoustic microscopy technique. AB - Scanning acoustic microscopy techniques operating at frequencies in the gigahertz range are suitable for the elastic characterization and interior imaging of solid media with micrometer-scale spatial resolution. Acoustic wave propagation at these frequencies is strongly limited by energy losses, particularly from attenuation in the coupling media used to transmit ultrasound to a specimen, leading to a decrease in the depth in a specimen that can be interrogated. In this work, a laser-based acoustic microscopy technique is presented that uses a pulsed laser source for the generation of broadband acoustic waves and an optical interferometer for detection. The use of a 900-ps microchip pulsed laser facilitates the generation of acoustic waves with frequencies extending up to 1 GHz which allows for the resolution of micrometer-scale features in a specimen. Furthermore, the combination of optical generation and detection approaches eliminates the use of an ultrasonic coupling medium, and allows for elastic characterization and interior imaging at penetration depths on the order of several hundred micrometers. Experimental results illustrating the use of the laser-based acoustic microscopy technique for imaging micrometer-scale subsurface geometrical features in a 70-MUm-thick single-crystal silicon wafer with a (100) orientation are presented. PMID- 21244992 TI - Influence of the external electric field on propagation of Lamb waves in piezoelectric plates. AB - The influence of the electric field on the properties of the Lamb and SH-waves in piezoelectric Bi(12)GeO(20) and La(3)Ga(5)SiO1(4) crystal plates has been investigated. Using basic equations and boundary conditions, the formulas for computer simulation have been obtained. The effect of acoustic modes hybridization has been considered. PMID- 21244991 TI - Efficient implementation of spatially-varying 3-D ultrasound deconvolution. AB - There are sometimes occasions when ultrasound beamforming is performed with only a subset of the total data that will eventually be available. The most obvious example is a mechanically-swept (wobbler) probe in which the three-dimensional data block is formed from a set of individual B-scans. In these circumstances, non-blind deconvolution can be used to improve the resolution of the data. Unfortunately, most of these situations involve large blocks of three-dimensional data. Furthermore, the ultrasound blur function varies spatially with distance from the transducer. These two facts make the deconvolution process time consuming to implement. This paper is about ways to address this problem and produce spatially-varying deconvolution of large blocks of three-dimensional data in a matter of seconds. We present two approaches, one based on hardware and the other based on software. We compare the time they each take to achieve similar results and discuss the computational resources and form of blur model that each requires. PMID- 21244993 TI - Computational efficiency of ultrasonic guided wave imaging algorithms. AB - Guided wave imaging techniques employed for structural health monitoring (SHM) can be computationally demanding, especially for adaptive techniques such as minimum variance distortionless response (MVDR) imaging, which requires a matrix inversion for each pixel calculation. Instantaneous windowing has been shown in previous work to improve guided wave imaging performance. The use of instantaneous windowing has the additional benefit of significantly reducing the computational requirements of image generation. This paper derives a formulation for MVDR imaging using instantaneous windowing and shows that the matrix inversion associated with MVDR imaging can be optimized, reducing the computational complexity to that of conventional delay-and-sum imaging algorithms. Additionally, a vectorized approach is presented for implementing guided wave imaging algorithms, including delay-and-sum imaging, in matrix-based software packages. The improvements in computational efficiency are quantified by measuring computation time for different array sizes, windowing assumptions, and imaging methods. PMID- 21244995 TI - Miniature high-frequency longitudinal wave mass sensors in liquid. AB - In this paper, micromachined longitudinal wave resonant mass sensors operating near 1 GHz in a liquid environment are investigated and characterized. Mass sensitivities of the film bulk acoustic resonator (FBAR) and high-tone bulk acoustic resonator (HBAR) microbalances with small size are measured to be 782.7 cm(2)/g (50 times larger than that of conventional bulky quartz crystal microbalance) and 9.3 cm(2)/g, respectively. Based on the mass sensitivities and frequency noise floor, the minimum detectable mass of the FBAR and HBAR are estimated to be 2.8 ng/cm(2) and 11.9 ng/cm(2) in liquid, respectively. PMID- 21244994 TI - KNN/BNT composite lead-free films for high-frequency ultrasonic transducer applications. AB - Lead-free K(0.5)Na(0.5)NbO(3)/Bi(0.5)Na(0.5)TiO(3) (KNN/ BNT) films have been fabricated by a composite sol-gel technique. Crystalline KNN fine powder was dispersed in the BNT precursor solution to form a composite slurry which was then spin-coated onto a platinum-buffered Si substrate. Repeated layering and vacuum infiltration were applied to produce 5-MUm-thick dense composite film. By optimizing the sintering temperature, the films exhibited good dielectric and ferroelectric properties comparable to PZT films. A 193-MHz high-frequency ultrasonic transducer fabricated from this composite film showed a -6-dB bandwidth of approximately 34%. A tungsten wire phantom was imaged to demonstrate the capability of the transducer. PMID- 21244996 TI - Design of a configurable multispectral imaging system based on an AOTF. AB - In this paper, we present a configurable multispectral imaging system based on an acousto-optic tunable filter (AOTF). Typically, AOTFs are used to filter a single wavelength at a time, but thanks to the use of a versatile sweeping frequency generator implemented with a direct digital synthesizer, the imager may capture a configurable spectral range. Experimental results show a good spectral and imaging response of the system for spectral bandwidth up to a 50 nm. PMID- 21244997 TI - Optimal electrode shape and size of lateral-field-excited piezoelectric crystal resonators. AB - We determine optimal electrode shape and size of lateral-field-excited (LFE) thickness-shear resonators. The determined electrodes are optimal in that they satisfy the criterion for Bechmann's number in every direction. Numerical and graphical results are provided for AT-cut quartz, (yxl)- 45 degrees langasite, and (yxl)-16.5 degrees LiTaO(3) LFE resonators. The optimal electrodes of AT-cut quartz LFE resonators are also compared with those of AT-cut quartz thickness field-excited (TFE) resonators. PMID- 21244999 TI - Application of a rat hindlimb model: a prediction of force spaces reachable through stimulation of nerve fascicles. AB - A device to generate standing or locomotion through chronically placed electrodes has not been fully developed due in part to limitations of clinical experimentation and the high number of muscle activation inputs of the leg. We investigated the feasibility of functional electrical stimulation paradigms that minimize the input dimensions for controlling the limbs by stimulating at nerve fascicles, utilizing a model of the rat hindlimb, which combined previously collected morphological data with muscle physiological parameters presented herein. As validation of the model, we investigated the suitability of a lumped parameter model for the prediction of muscle activation during dynamic tasks. Using the validated model, we found that the space of forces producible through activation of muscle groups sharing common nerve fascicles was nonlinearly dependent on the number of discrete muscle groups that could be individually activated (equivalently, the neuroanatomical level of activation). Seven commonly innervated muscle groups were sufficient to produce 78% of the force space producible through individual activation of the 42 modeled hindlimb muscles. This novel, neuroanatomically derived reduction in input dimension emphasizes the potential to simplify controllers for functional electrical stimulation to improve functional recovery after a neuromuscular injury. PMID- 21245000 TI - Inference of nonlinear state-space models for sandwich-type lateral flow immunoassay using extended Kalman filtering. AB - In this paper, a mathematical model for sandwich-type lateral flow immunoassay is developed via short available time series. A nonlinear dynamic stochastic model is considered that consists of the biochemical reaction system equations and the observation equation. After specifying the model structure, we apply the extended Kalman filter (EKF) algorithm for identifying both the states and parameters of the nonlinear state-space model. It is shown that the EKF algorithm can accurately identify the parameters and also predict the system states in the nonlinear dynamic stochastic model through an iterative procedure by using a small number of observations. The identified mathematical model provides a powerful tool for testing the system hypotheses and also for inspecting the effects from various design parameters in both rapid and inexpensive way. Furthermore, by means of the established model, the dynamic changes in the concentration of antigens and antibodies can be predicted, thereby making it possible for us to analyze, optimize, and design the properties of lateral flow immunoassay devices. PMID- 21245001 TI - A linear correction for principal component analysis of dynamic fluorescence diffuse optical tomography images. AB - The analysis of dynamic fluorescence diffuse optical tomography (D-FDOT) is important both for drug delivery research and for medical diagnosis and treatment. The low spatial resolution and complex kinetics, however, limit the ability of FDOT in resolving drug distributions within small animals. Principal component analysis (PCA) provides the capability of detecting and visualizing functional structures with different kinetic patterns from D-FDOT images. A particular challenge in using PCA is to reduce the level of noise in D-FDOT images. This is particularly relevant in drug study, where the time-varying fluorophore concentration (drug concentration) will result in the reconstructed images containing more noise and, therefore, affect the performance of PCA. In this paper, a new linear corrected method is proposed for modeling these time varying fluorescence measurements before performing PCA. To evaluate the performance of the new method in resolving drug biodistribution, the metabolic processes of indocyanine green within mouse is dynamically simulated and used as the input data of PCA. Simulation results suggest that the principal component (PC) images generated using the new method improve SNR and discrimination capability, compared to the PC images generated using the uncorrected D-FDOT images. PMID- 21245002 TI - Bayesian regularization applied to ultrasound strain imaging. AB - Noise artifacts due to signal decorrelation and reverberation are a considerable problem in ultrasound strain imaging. For block-matching methods, information from neighboring matching blocks has been utilized to regularize the estimated displacements. We apply a recursive Bayesian regularization algorithm developed by Hayton et al. [Artif. Intell., vol. 114, pp. 125-156, 1999] to phase-sensitive ultrasound RF signals to improve displacement estimation. The parameter of regularization is reformulated, and its meaning examined in the context of strain imaging. Tissue-mimicking experimental phantoms and RF data incorporating finite element models for the tissue deformation and frequency-domain ultrasound simulations are used to compute the optimal parameter with respect to nominal strain and algorithmic iterations. The optimal strain regularization parameter was found to be twice the nominal strain and did not vary significantly with algorithmic iterations. The technique demonstrates superior performance over median filtering in noise reduction at strains 5% and higher for all quantitative experiments performed. For example, the strain SNR was 11 dB higher than that obtained using a median filter at 7% strain. It has to be noted that for applied deformations lower than 1%, since signal decorrelation errors are minimal, using this approach may degrade the displacement image. PMID- 21245003 TI - Automated segmentation of cells with IHC membrane staining. AB - This study presents a fully automated membrane segmentation technique for immunohistochemical tissue images with membrane staining, which is a critical task in computerized immunohistochemistry (IHC). Membrane segmentation is particularly tricky in immunohistochemical tissue images because the cellular membranes are visible only in the stained tracts of the cell, while the unstained tracts are not visible. Our automated method provides accurate segmentation of the cellular membranes in the stained tracts and reconstructs the approximate location of the unstained tracts using nuclear membranes as a spatial reference. Accurate cell-by-cell membrane segmentation allows per cell morphological analysis and quantification of the target membrane proteins that is fundamental in several medical applications such as cancer characterization and classification, personalized therapy design, and for any other applications requiring cell morphology characterization. Experimental results on real datasets from different anatomical locations demonstrate the wide applicability and high accuracy of our approach in the context of IHC analysis. PMID- 21245004 TI - Rayleigh mixture model for plaque characterization in intravascular ultrasound. AB - Vulnerable plaques are the major cause of carotid and coronary vascular problems, such as heart attack or stroke. A correct modeling of plaque echomorphology and composition can help the identification of such lesions. The Rayleigh distribution is widely used to describe (nearly) homogeneous areas in ultrasound images. Since plaques may contain tissues with heterogeneous regions, more complex distributions depending on multiple parameters are usually needed, such as Rice, K or Nakagami distributions. In such cases, the problem formulation becomes more complex, and the optimization procedure to estimate the plaque echomorphology is more difficult. Here, we propose to model the tissue echomorphology by means of a mixture of Rayleigh distributions, known as the Rayleigh mixture model (RMM). The problem formulation is still simple, but its ability to describe complex textural patterns is very powerful. In this paper, we present a method for the automatic estimation of the RMM mixture parameters by means of the expectation maximization algorithm, which aims at characterizing tissue echomorphology in ultrasound (US). The performance of the proposed model is evaluated with a database of in vitro intravascular US cases. We show that the mixture coefficients and Rayleigh parameters explicitly derived from the mixture model are able to accurately describe different plaque types and to significantly improve the characterization performance of an already existing methodology. PMID- 21245005 TI - Focus shift and phase correction in soft tissues during focused ultrasound surgery. AB - During the treatment of soft tissue tumors using focused ultrasound surgery (FUS), the focus can shift away from the desired point due to tissue inhomogeneity. In this paper, a numerical method to calculate the focus shift in multiple-layered tissues and a faster phase-correction method to restore the focus were developed. Data from the simulations showed that the focus shifted about 2 mm along the transducer axis in multiple-layered soft tissues. After phase correction, the focus was restored at the desired point. The ex vivo experiments were conducted to verify the simulations, and the results agreed well with those of the simulations. An empirical formula was obtained to estimate the focus shift in a two-layered water-tissue model and was verified by numerical calculations. Moreover, the focus shift in multiple-layered tissues can be summed by the shifts in the component of each layer of tissues. The factors affecting the focus shift were studied. The focus shift varied linearly with the tissue acoustic speed and tissue thickness, whereas it slightly changed with transducer F number (radius of curvature/diameter). Overall, the findings of this study can help in the development of a better treatment plan for FUS in soft tissues. PMID- 21245006 TI - Domain-specific image analysis for cervical neoplasia detection based on conditional random fields. AB - This paper presents a domain-specific automated image analysis framework for the detection of pre-cancerous and cancerous lesions of the uterine cervix. Our proposed framework departs from previous methods in that we include domain specific diagnostic features in a probabilistic manner using conditional random fields. Likewise, we provide a novel window-based performance assessment scheme for 2D image analysis which addresses the intrinsic problem of image misalignment. Image regions corresponding to different tissue types are indentified for the extraction of domain-specific anatomical features. The unique optical properties of each tissue type and the diagnostic relationships between neighboring regions are incorporated in the proposed conditional random field model. The validity of our method is examined using clinical data from 48 patients, and its diagnostic potential is demonstrated by a performance comparison with expert colposcopy annotations, using histopathology as the ground truth. The proposed automated diagnostic approach can support or potentially replace conventional colposcopy, allow tissue specimen sampling to be performed in a more objective manner, and lower the number of cervical cancer cases in developing countries by providing a cost effective screening solution in low resource settings. PMID- 21245007 TI - Real-time recurrent neural state estimation. AB - A nonlinear discrete-time neural observer for discrete-time unknown nonlinear systems in presence of external disturbances and parameter uncertainties is presented. It is based on a discrete-time recurrent high-order neural network trained with an extended Kalman-filter based algorithm. This brief includes the stability proof based on the Lyapunov approach. The applicability of the proposed scheme is illustrated by real-time implementation for a three phase induction motor. PMID- 21245008 TI - Active learning for solving the incomplete data problem in facial age classification by the furthest nearest-neighbor criterion. AB - Facial age classification is an approach to classify face images into one of several predefined age groups. One of the difficulties in applying learning techniques to the age classification problem is the large amount of labeled training data required. Acquiring such training data is very costly in terms of age progress, privacy, human time, and effort. Although unlabeled face images can be obtained easily, it would be expensive to manually label them on a large scale and getting the ground truth. The frugal selection of the unlabeled data for labeling to quickly reach high classification performance with minimal labeling efforts is a challenging problem. In this paper, we present an active learning approach based on an online incremental bilateral two-dimension linear discriminant analysis (IB2DLDA) which initially learns from a small pool of labeled data and then iteratively selects the most informative samples from the unlabeled set to increasingly improve the classifier. Specifically, we propose a novel data selection criterion called the furthest nearest-neighbor (FNN) that generalizes the margin-based uncertainty to the multiclass case and which is easy to compute, so that the proposed active learning algorithm can handle a large number of classes and large data sizes efficiently. Empirical experiments on FG NET and Morph databases together with a large unlabeled data set for age categorization problems show that the proposed approach can achieve results comparable or even outperform a conventionally trained active classifier that requires much more labeling effort. Our IB2DLDA-FNN algorithm can achieve similar results much faster than random selection and with fewer samples for age categorization. It also can achieve comparable results with active SVM but is much faster than active SVM in terms of training because kernel methods are not needed. The results on the face recognition database and palmprint/palm vein database showed that our approach can handle problems with large number of classes. Our contributions in this paper are twofold. First, we proposed the IB2DLDA-FNN, the FNN being our novel idea, as a generic on-line or active learning paradigm. Second, we showed that it can be another viable tool for active learning of facial age range classification. PMID- 21245009 TI - Video super-resolution using simultaneous motion and intensity calculations. AB - In this paper, we propose an energy-based algorithm for motion-compensated video super-resolution (VSR) targeted on upscaling of standard definition (SD) video to high-definition (HD) video. Since the motion (flow field) of the image sequence is generally unknown, we introduce a formulation for the joint estimation of a super-resolution (SR) sequence and its flow field. Via the calculus of variations, this leads to a coupled system of partial differential equations for image sequence and motion estimation. We solve a simplified form of this system and, as a by-product, we indeed provide a motion field for super-resolved sequences. To the best of our knowledge, computing super-resolved flows has not been done before. Most advanced SR methods found in literature cannot be applied to general video with arbitrary scene content and/or arbitrary optical flows, as it is possible with our simultaneous VSR method. A series of experiments shows that our method outperforms other VSR methods when dealing with general video input and that it continues to provide good results even for large scaling factors up to 8 * 8. PMID- 21245010 TI - Compressive sensing SAR image reconstruction based on Bayesian framework and evolutionary computation. AB - Compressive sensing (CS) is a theory that one may achieve an exact signal reconstruction from sufficient CS measurements taken from a sparse signal. However, in practical applications, the transform coefficients of SAR images usually have weak sparsity. Exactly reconstructing these images is very challenging. A new Bayesian evolutionary pursuit algorithm (BEPA) is proposed in this paper. A signal is represented as the sum of a main signal and some residual signals, and the generalized Gaussian distribution (GGD) is employed as the prior of the main signal and the residual signals. BEPA decomposes the residual iteratively and estimates the maximum a posteriori of the main signal and the residual signals by solving a sequence of subproblems to achieve the approximate CS reconstruction of the signal. Under the assumption of GGD with the parameter 0 < p < 1, the evolutionary algorithm (EA) is introduced to CS reconstruction for the first time. The better reconstruction performance can be achieved by searching the global optimal solutions of subproblems with EA. Numerical experiments demonstrate that the important features of SAR images (e.g., the point and line targets) can be well preserved by our algorithm, and the superior reconstruction performance can be obtained at the same time. PMID- 21245011 TI - Radial Basis Function Neural Network With Incremental Learning for Face Recognition. AB - Conventional face recognition suffers from problems such as extending the classifier for newly added people and learning updated information about the existing people. The way to address these problems is to retrain the system which will require expensive computational complexity. In this paper, a radial basis function (RBF) neural network with a new incremental learning method based on the regularized orthogonal least square (ROLS) algorithm is proposed for face recognition. It is designed to accommodate new information without retraining the initial network. In our proposed method, the selection of the regressors for the new data is done locally, hence avoiding the expensive reselecting process. In addition, it accumulates previous experience and learns updated new knowledge of the existing groups to increase the robustness of the system. The experimental results show that the proposed method gives higher average recognition accuracy compared to the conventional ROLS-algorithm-based RBF neural network with much lower computational complexity. Furthermore, the proposed method achieves higher recognition accuracy as compared to other incremental learning algorithms such as incremental principal component analysis and incremental linear discriminant analysis in face recognition. PMID- 21245012 TI - Fuzzily Connected Multimodel Systems Evolving Autonomously From Data Streams. AB - A general framework and a holistic concept are proposed in this paper that combine computationally light machine learning from streaming data with the online identification and adaptation of dynamic systems in regard to their structure and parameters. According to this concept, the system is assumed to be decomposable into a set of fuzzily connected simple local models. The main thrust of this paper is in the development of an original approach for the self-design, self-monitoring, self-management, and self-learning of such systems in a dynamic manner from data streams which automatically detect and react to the shift in the data distribution by evolving the system structure. Novelties of this contribution lie in the following: 1) the computationally simple approach (simpl_e_Clustering-simplified evolving Clustering) to data space partitioning by recursive evolving clustering based on the relative position of the new data sample to the mean of the overall data, 2) the learning technique for online structure evolution as a reaction to the shift in the data distribution, 3) the method for online system structure simplification based on utility and inputs/feature selection, and 4) the novel graphical illustration of the spatiotemporal evolution of the data stream. The application domain for this computationally efficient technique ranges from clustering, modeling, prognostics, classification, and time-series prediction to pattern recognition, image segmentation, vector quantization, etc., to more general problems in various application areas, e.g., intelligent sensors, mobile robotics, advanced manufacturing processes, etc. PMID- 21245013 TI - TRPV4-mediated calcium influx into human bronchial epithelia upon exposure to diesel exhaust particles. AB - BACKGROUND: Human respiratory epithelia function in airway mucociliary clearance and barrier function and have recently been implicated in sensory functions. OBJECTIVE: We investigated a link between chronic obstructive pulmonary disease (COPD) pathogenesis and molecular mechanisms underlying Ca2+ influx into human airway epithelia elicited by diesel exhaust particles (DEP). METHODS AND RESULTS: Using primary cultures of human respiratory epithelial (HRE) cells, we determined that these cells possess proteolytic signaling machinery, whereby proteinase activated receptor-2 (PAR-2) activates Ca2+-permeable TRPV4, which leads to activation of human respiratory disease-enhancing matrix metalloproteinase-1 (MMP 1), a signaling cascade initiated by diesel exhaust particles (DEP), a globally relevant air pollutant. Moreover, we observed ciliary expression of PAR-2, TRPV4, and phospholipase-Cbeta3 in human airway epithelia and their DEP-enhanced protein protein complex formation. We also found that the chronic obstructive pulmonary disease (COPD)-predisposing TRPV4P19S variant enhances Ca2+ influx and MMP 1 activation, providing mechanistic linkage between man-made air pollution and human airway disease. CONCLUSION: DEP evoked protracted Ca2+ influx via TRPV4, enhanced by the COPD-predisposing human genetic polymorphism TRPV4P19S. This mechanism reprograms maladaptive inflammatory and extracellular-matrix-remodeling responses in human airways. The novel concept of air pollution-responsive ciliary signal transduction from PAR-2 to TRPV4 in human respiratory epithelia will accelerate rationally targeted therapies, possibly via the inhalatory route. PMID- 21245015 TI - Neuroinflammation and alpha-synuclein dysfunction potentiate each other, driving chronic progression of neurodegeneration in a mouse model of Parkinson's disease. AB - BACKGROUND: Mechanisms whereby gene-environment interactions mediate chronic, progressive neurodegenerative processes in Parkinson's disease (PD)-the second most common neurodegenerative disease-remain elusive. OBJECTIVE: We created a two hit [neuroinflammation and mutant alpha-synuclein (alpha-syn) overexpression] animal model to investigate mechanisms through which mutant alpha-syn and inflammation work in concert to mediate chronic PD neurodegeneration. METHODS: We used an intraperitoneal injection of the inflammogen lipopolysaccharide (LPS; 3 * 106 EU/kg) to initiate systemic and brain inflammation in wild-type (WT) mice and transgenic (Tg) mice overexpressing human A53T mutant alpha-syn. We then evaluated nigral dopaminergic neurodegeneration, alpha-syn pathology, and neuroinflammation. RESULTS: After LPS injection, both WT and Tg mice initially displayed indistinguishable acute neuroinflammation; however, only Tg mice developed persistent neuroinflammation, chronic progressive degeneration of the nigrostriatal dopamine pathway, accumulation of aggregated, nitrated alpha-syn, and formation of Lewy body-like inclusions in nigral neurons. Further mechanistic studies indicated that 4-week infusion of two inhibitors of inducible nitric oxide synthase and NADPH oxidase, major free radical-generating enzymes in activated microglia, blocked nigral alpha-syn pathology and neurodegeneration in LPS-injected Tg mice. CONCLUSIONS: Microglia-derived oxidative stress bridged neuroinflammation and alpha-syn pathogenic alteration in mediating chronic PD progression. Our two-hit animal model involving both a genetic lesion and an environmental trigger reproduced key features of PD and demonstrated synergistic effects of genetic predisposition and environmental exposures in the development of PD. The chronic progressive nature of dopaminergic neurodegeneration, which is absent in most existing PD models, makes this new model invaluable for the study of mechanisms of PD progression. PMID- 21245014 TI - Neurotoxicity of brominated flame retardants: (in)direct effects of parent and hydroxylated polybrominated diphenyl ethers on the (developing) nervous system. AB - BACKGROUND/OBJECTIVE: Polybrominated diphenyl ethers (PBDEs) and their hydroxylated (OH-) or methoxylated forms have been detected in humans. Because this raises concern about adverse effects on the developing brain, we reviewed the scientific literature on these mechanisms. DATA SYNTHESIS: Many rodent studies reported behavioral changes after developmental, neonatal, or adult exposure to PBDEs, and other studies documented subtle structural and functional alterations in brains of PBDE-exposed animals. Functional effects have been observed on synaptic plasticity and the glutamate-nitric oxide-cyclic guanosine monophosphate pathway. In the brain, changes have been observed in the expression of genes and proteins involved in synapse and axon formation, neuronal morphology, cell migration, synaptic plasticity, ion channels, and vesicular neurotransmitter release. Cellular and molecular mechanisms include effects on neuronal viability ?(via apoptosis and oxidative stress), neuronal differentiation and migration, neurotransmitter release/uptake, neurotransmitter receptors and ion channels, calcium (Ca2+) homeostasis, and intracellular signaling pathways. DISCUSSION: Bioactivation of PBDEs by hydroxylation has been observed for several endocrine end points. This has also been observed for mechanisms related to neurodevelopment, including binding to thyroid hormone receptors and transport proteins, disruption of Ca2+ homeostasis, and modulation of GABA and nicotinic acetylcholine receptor function. CONCLUSIONS: The increased hazard for developmental neurotoxicity by hydroxylated (OH-)PBDEs compared with their parent congeners via direct neurotoxicity and thyroid disruption clearly warrants further investigation into a) the role of oxidative metabolism in producing active metabolites of PBDEs and their impact on brain development; b) concentrations of parent and OH-PBDEs in the brain; and c) interactions between different environmental contaminants during exposure to mixtures, which may increase neurotoxicity. PMID- 21245018 TI - Prurigo-like eczema as an unsuspected presentation of textile dermatitis. PMID- 21245016 TI - Long-term exposure to airborne particles and arterial stiffness: the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Increased arterial stiffness could represent an intermediate subclinical outcome in the mechanistic pathway underlying associations between average long-term pollution exposure and cardiovascular events. OBJECTIVE: We hypothesized that 20 years of exposure to particulate matter (PM) <= 2.5 and 10 MUm in aerodynamic diameter (PM2.5 and PM10, respectively) would be positively associated with arterial stiffness in 3,996 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) who were seen at six U.S. study sites. METHODS: We assigned pollution exposure during two decades preceding a clinical exam (2000 2002) using observed PM10 from monitors nearest participants' residences and PM10 and PM2.5 imputed from a space-time model. We examined three log-transformed arterial stiffness outcome measures: Young's modulus (YM) from carotid artery ultrasound and large (C1) and small (C2) artery vessel compliance from the radial artery pulse wave. All associations are expressed per 10 MUg/m3 increment in PM and were adjusted for weather, age, sex, race, glucose, triglycerides, diabetes, waist:hip ratio, seated mean arterial pressure, smoking status, pack-years, cigarettes per day, environmental tobacco smoke, and physical activity. C1 and C2 models were further adjusted for heart rate, weight, and height. RESULTS: Long term average particle exposure was not associated with greater arterial stiffness measured by YM, C1, or C2, and the few associations observed were not robust across metrics and adjustment schemes. CONCLUSIONS: Long-term particle mass exposure did not appear to be associated with greater arterial stiffness in this study sample. PMID- 21245017 TI - DDT and malaria prevention: addressing the paradox. AB - BACKGROUND: The debate regarding dichlorodiphenyltrichloroethane (DDT) in malaria prevention and human health is polarized and can be classified into three positions: anti-DDT, centrist-DDT, pro-DDT. OBJECTIVE: We attempted to arrive at a synthesis by matching a series of questions on the use of DDT for indoor residual spraying (IRS) with literature and insights, and to identify options and opportunities. DISCUSSION: Overall, community health is significantly improved through all available malaria control measures, which include IRS with DDT. Is DDT "good"? Yes, because it has saved many lives. Is DDT safe as used in IRS? Recent publications have increasingly raised concerns about the health implications of DDT. Therefore, an unqualified statement that DDT used in IRS is safe is untenable. Are inhabitants and applicators exposed? Yes, and to high levels. Should DDT be used? The fact that DDT is "good" because it saves lives, and "not safe" because it has health and environmental consequences, raises ethical issues. The evidence of adverse human health effects due to DDT is mounting. However, under certain circumstances, malaria control using DDT cannot yet be halted. Therefore, the continued use of DDT poses a paradox recognized by a centrist-DDT position. At the very least, it is now time to invoke precaution. Precautionary actions could include use and exposure reduction. CONCLUSIONS: There are situations where DDT will provide the best achievable health benefit, but maintaining that DDT is safe ignores the cumulative indications of many studies. In such situations, addressing the paradox from a centrist-DDT position and invoking precaution will help design choices for healthier lives. PMID- 21245019 TI - Direct detection and differentiation of causative fungi of onychomycosis by multiplex polymerase chain reaction-based assay. AB - A rapid and reliable triplex PCR procedure was developed to detect pathogenic fungi directly from specimens of onychomycosis. One hundred and four patients were included in this study. Of them, forty-five (43.3%) were finally diagnosed with onychomycosis according to the diagnostic criteria. The sensitivity of PCR, microscopy and culture were 93.3%, 100% and 64.4%, respectively; the specificities were 100%, 86.4% and 100%, respectively; the positive predictive values were 100%, 84.9% and 100%, respectively; the negative predictive values were 95.2%, 100% and 78.7%, respectively. This molecular diagnostic process could distinguish the 3 groups of pathogens in onychomycosis (dermatophyte, yeast and mold) and could be completed within 8 h. This multiplex PCR assay could used in laboratories with no mycological specialization for rapid etiologic diagnosis and treatment selection, especially in suspected fungus cases if they can not be detected by conventional methods or if a rapid diagnosis of onychomycosis is needed. PMID- 21245020 TI - Pyogenic granuloma-like lesion: a wolf in sheep's clothing. PMID- 21245021 TI - Disseminated histoplasmosis with cutaneous lesions in an HIV patient. PMID- 21245022 TI - Measuring quality of life in psoriasis: the CALIPSO questionnaire. AB - In dermatology, several instruments are available to measure health-related quality of life (HRQoL) of patients. They vary in content emphasis and in the extent to which their measurement properties have been investigated and reported. In this study, we summarized five dermatology- and psoriasis-specific HRQoL questionnaires into a new psoriasis-specific questionnaire, the Comprehensive Appraisal of Life Impact of PSOriasis (CALIPSO). The questionnaires were completed by 936 patients with a diagnosis of psoriasis. Rasch's unidimensional measurement model was used to verify the construct validity and the operational characteristics of each instrument separately. The items with the best performance according to the Rasch model were selected. The final 30 items constitute the CALIPSO. Responses are given on a 3-point scale: "never", "sometimes/quite frequently", "often/all the time". The properties of the CALIPSO now need to be verified through the analysis of new data from different populations of people with psoriasis. In future, clinicians may use it without having to decide amongst several competing scales, to evaluate HRQoL in patients with psoriasis. PMID- 21245023 TI - The role of pregnancy outcomes in the maternal mortality rates of two areas in Matlab, Bangladesh. AB - CONTEXT: The Matlab Maternal Child Health-Family Planning (MCH-FP) project provides maternity care as part of its reproductive health services. It is important to assess whether this project has reduced maternal mortality and, if so, whether this was due to differences between the MCH-FP area (which received project services) and the comparison area (which did not) in pregnancy rates, pregnancy outcomes or case-fatality rates. METHODS: Data from the Matlab Demographic Surveillance System on 165,894 pregnancies over the period 1982-2005 were used to calculate four measures of maternal mortality for the MCH-FP and comparison areas. Mortality risk was examined by type of pregnancy outcome and by area, and bivariate and logistic regression analyses were used to generate unadjusted and adjusted odds ratios, respectively. RESULTS: The maternal mortality rate of 35 deaths per 100,000 women of reproductive age in the MCH-FP area was 37% lower than that in the comparison area (56 deaths per 100,000). In both areas, the maternal mortality risk was considerably higher for pregnancies that ended in induced abortion, miscarriage or stillbirth than for those that resulted in live birth (odds ratios, 4.2, 2.0 and 17.4, respectively). The difference in maternal mortality rates between the two areas was mainly a result of the MCH-FP area's lower pregnancy rate and its lower case-fatality rates for induced abortions, miscarriages and stillbirths. CONCLUSIONS: Interventions to increase contraceptive use; to reduce the incidence of induced abortion, miscarriage and stillbirth; to improve the management of such outcomes; and to strengthen antenatal care could substantially reduce maternal mortality in Bangladesh and similar countries. PMID- 21245024 TI - Community-level gender equity and extramarital sexual risk-taking among married men in eight African countries. AB - CONTEXT: In many parts of Africa, women are most likely to become infected with HIV by having unprotected sex with their husbands, who may have acquired the virus through extramarital sex. However, the ways in which aspects of community environments-particularly those related to gender equity-shape men's extramarital sexual risk-taking are not well understood. METHODS: Demographic and Health Survey data from eight African countries (Chad, Ghana, Malawi, Nigeria, Tanzania, Uganda, Zambia and Zimbabwe) were used to examine associations between married men's engaging in risky extramarital sex (i.e., having had both unprotected sex and extramarital sex) and indicators of gender equity and other community characteristics. Separate multilevel logistic regression models that incorporated individual, household and community measures were created for each country. RESULTS: In five countries, men who lived in communities with more equal ratios of women to men with at least a primary education were less likely to report risky extramarital sexual activity (odds ratios, 0.4-0.6). A similar relationship was found in four countries for the ratio of women to men who were employed (0.4 0.5). In three countries, men who lived in communities with more conservative attitudes toward wife-beating or male decision making had elevated odds of extramarital sexual risk-taking (1.1-1.5). CONCLUSIONS: While HIV prevention programs should focus on reducing gender inequities, they also need to recognize the conservative cultural factors that influence the formation of men's masculine identities and, in turn, affect their sexual behavior. PMID- 21245025 TI - The integration of family planning with other health services: a literature review. AB - CONTEXT: Integrating family planning services with other health services may be an effective way to reduce unmet need. However, greater understanding of the evidence on integration is needed. METHODS: Studies that evaluated the integration of family planning with any other type of health service were identified by searching five databases. To be included, studies had to have: been published in English between 1994 and 2009; used either a single-group pre- and posttest design or a two-group control or comparison design; and reported a family planning-related behavioral or reproductive health outcome. RESULTS: Nine studies met the inclusion criteria. The integration interventions ranged from simple referrals between providers of existing services to fully integrated, community-based delivery of education and services. One evaluation used a quasi experimental design; two used case-control comparison designs; two used combination designs; and the rest used either a single-group pre- and posttest design or a two-group cross-sectional design. Seven studies found improvements in family planning-related outcomes, although not all reported the significance of these changes; another reported mixed results and one found no effect. Of the studies that examined providers', clients' or community members' perspectives of integration, all reported overall satisfaction. No studies provided an economic analysis. CONCLUSIONS: The evidence supporting the integration of family planning with other health services remains weak, and well-designed evaluation research is still needed. Future research should report outcomes for all health areas being integrated and should investigate in more detail the perspectives of providers, clients and community members and assess the cost-effectiveness of integration. PMID- 21245026 TI - Health system costs of menstrual regulation and care for abortion complications in Bangladesh. AB - CONTEXT: Treatment of complications of unsafe abortion can be a significant financial drain on health system resources, particularly in developing countries. In Bangladesh, menstrual regulation is provided by the government as a backup to contraception. The comparison of economic costs of providing menstrual regulation care with those of providing treatment of abortion complications has implications for policy in Bangladesh and internationally. METHODS: Data on incremental costs of providing menstrual regulation and care for abortion complications were collected through surveys of providers at 21 public-sector facilities in Bangladesh. These data were entered into an abortion-oriented costing spreadsheet to estimate the health system costs of providing such services. RESULTS: The incremental costs per case of providing menstrual regulation care in 2008 were 8 13% of those associated with treating severe abortion complications, depending on the level of care. An estimated 263,688 menstrual regulation procedures were provided at public-sector facilities in 2008, with incremental costs estimated at US$2.2 million, and 70,098 women were treated for abortion-related complications in such facilities, with incremental costs estimated at US$1.6 million. CONCLUSION: The provision of menstrual regulation averts unsafe abortion and associated maternal morbidity and mortality, and on a per case basis, saves scarce health system resources. Increasing access to menstrual regulation would enable more women to obtain much-needed care and health system resources to be utilized more efficiently. PMID- 21245027 TI - Making the list: the role of essential medicines lists in reproductive health. PMID- 21245028 TI - Niemann-Pick Type C disease: characterizing lipid levels in patients with variant lysosomal cholesterol storage. AB - A central feature of Niemann-Pick Type C (NPC) disease is sequestration of cholesterol and glycosphingolipids in lysosomes. A large phenotypic variability, on both a clinical as well as a molecular level, challenges NPC diagnosis. For example, substantial difficulties in identifying or excluding NPC in a patient exist in cases with a "variant" biochemical phenotype, where cholesterol levels in cultured fibroblasts, the primary diagnostic indicator, are only moderately elevated. Here we apply quantitative microscopy as an accurate and objective diagnostic tool to measure cholesterol accumulation at the level of single cells. When employed to characterize cholesterol enrichment in fibroblasts from 20 NPC patients and 11 controls, considerable heterogeneity became evident both within the population of cells cultured from one individual as well as between samples from different probands. An obvious correlation between biochemical phenotype and clinical disease course was not apparent from our dataset. However, plasma levels of HDL-cholesterol (HDL-c) tended to be in the normal range in patients with a "variant" as opposed to a "classic" biochemical phenotype. Attenuated lysosomal cholesterol accumulation in "variant" cells was associated with detectable NPC1 protein and residual capability to upregulate expression of ABCA1 in response to LDL. Taken together, our approach opens perspectives not only to support diagnosis, but also to better characterize mechanisms impacting cholesterol accumulation in NPC patient-derived cells. PMID- 21245029 TI - Adipocyte expression of the glucose-dependent insulinotropic polypeptide receptor involves gene regulation by PPARgamma and histone acetylation. AB - Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that exerts insulinotropic and growth and survival effects on pancreatic beta cells. Additionally, there is increasing evidence supporting an important role for GIP in the regulation of adipocyte metabolism. In the current study we examined the molecular mechanisms involved in the regulation of GIP receptor (GIPR) expression in 3T3-L1 cells. GIP acted synergistically with insulin to increase neutral lipid accumulation during progression of 3T3-L1 preadipocytes to the adipocyte phenotype. Both GIPR protein and mRNA expression increased during 3T3-L1 cell differentiation, and this increase was associated with upregulation of nuclear levels of sterol response element binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor gamma (PPARgamma), as well as acetylation of histones H3/H4. The PPARgamma receptor agonists LY171883 and rosiglitazone increased GIPR expression in differentiated 3T3-L1 adipocytes, whereas the antagonist GW9662 ablated expression. Additionally, both PPARgamma and acetylated histones H3/H4 were shown to bind to a region of the GIPR promoter containing the peroxisome proliferator response element (PPRE). Knockdown of PPARgamma in differentiated 3T3-L1 adipocytes, using RNA interference, reduced GIPR expression, supporting a functional regulatory role. Taken together, these studies show that GIP and insulin act in a synergistic manner on 3T3-L1 cell development and that adipocyte GIPR expression is upregulated through a mechanism involving interactions between PPARgamma and a GIPR promoter region containing an acetylated histone region. PMID- 21245031 TI - OrchidBase: a collection of sequences of the transcriptome derived from orchids. AB - Orchids are one of the most ecological and evolutionarily significant plants, and the Orchidaceae is one of the most abundant families of the angiosperms. Genetic databases will be useful not only for gene discovery but also for future genomic annotation. For this purpose, OrchidBase was established from 37,979,342 sequence reads collected from 11 in-house Phalaenopsis orchid cDNA libraries. Among them, 41,310 expressed sequence tags (ESTs) were obtained by using Sanger sequencing, whereas 37,908,032 reads were obtained by using next-generation sequencing (NGS) including both Roche 454 and Solexa Illumina sequencers. These reads were assembled into 8,501 contigs and 76,116 singletons, resulting in 84,617 non redundant transcribed sequences with an average length of 459 bp. The analysis pipeline of the database is an automated system written in Perl and C#, and consists of the following components: automatic pre-processing of EST reads, assembly of raw sequences, annotation of the assembled sequences and storage of the analyzed information in SQL databases. A web application was implemented with HTML and a Microsoft .NET Framework C# program for browsing and querying the database, creating dynamic web pages on the client side, analyzing gene ontology (GO) and mapping annotated enzymes to KEGG pathways. The online resources for putative annotation can be searched either by text or by using BLAST, and the results can be explored on the website and downloaded. Consequently, the establishment of OrchidBase will provide researchers with a high-quality genetic resource for data mining and facilitate efficient experimental studies on orchid biology and biotechnology. The OrchidBase database is freely available at http://lab.fhes.tn.edu.tw/est. PMID- 21245032 TI - M540 bodies interfere with TUNEL analyses in human semen samples. PMID- 21245033 TI - RNA-Seq analysis of splicing in Plasmodium falciparum uncovers new splice junctions, alternative splicing and splicing of antisense transcripts. AB - Over 50% of genes in Plasmodium falciparum, the deadliest human malaria parasite, contain predicted introns, yet experimental characterization of splicing in this organism remains incomplete. We present here a transcriptome-wide characterization of intraerythrocytic splicing events, as captured by RNA-Seq data from four timepoints of a single highly synchronous culture. Gene model independent analysis of these data in conjunction with publically available RNA Seq data with HMMSplicer, an in-house developed splice site detection algorithm, revealed a total of 977 new 5' GU-AG 3' and 5 new 5' GC-AG 3' junctions absent from gene models and ESTs (11% increase to the current annotation). In addition, 310 alternative splicing events were detected in 254 (4.5%) genes, most of which truncate open reading frames. Splicing events antisense to gene models were also detected, revealing complex transcriptional arrangements within the parasite's transcriptome. Interestingly, antisense introns overlap sense introns more than would be expected by chance, perhaps indicating a functional relationship between overlapping transcripts or an inherent organizational property of the transcriptome. Independent experimental validation confirmed over 30 new antisense and alternative junctions. Thus, this largest assemblage of new and alternative splicing events to date in Plasmodium falciparum provides a more precise, dynamic view of the parasite's transcriptome. PMID- 21245030 TI - Genetic determinants of hepatic steatosis in man. AB - Hepatic steatosis is one of the most common liver disorders in the general population. The main cause of hepatic steatosis is nonalcoholic fatty liver disease (NAFLD), representing the hepatic component of the metabolic syndrome, which is characterized by type 2 diabetes, obesity, and dyslipidemia. Insulin resistance and excess adiposity are considered to play key roles in the pathogenesis of NAFLD. Although the risk factors for NAFLD are well established, the genetic basis of hepatic steatosis is largely unknown. Here we review recent progress on genomic variants and their association with hepatic steatosis and discuss the potential impact of these genetic studies on clinical practice. Identifying the genetic determinants of hepatic steatosis will lead to a better understanding of the pathogenesis and progression of NAFLD. PMID- 21245034 TI - Direct observation of cytosine flipping and covalent catalysis in a DNA methyltransferase. AB - Methylation of the five position of cytosine in DNA plays important roles in epigenetic regulation in diverse organisms including humans. The transfer of methyl groups from the cofactor S-adenosyl-L-methionine is carried out by methyltransferase enzymes. Using the paradigm bacterial methyltransferase M.HhaI we demonstrate, in a chemically unperturbed system, the first direct real-time analysis of the key mechanistic events-the flipping of the target cytosine base and its covalent activation; these changes were followed by monitoring the hyperchromicity in the DNA and the loss of the cytosine chromophore in the target nucleotide, respectively. Combined with studies of M.HhaI variants containing redesigned tryptophan fluorophores, we find that the target base flipping and the closure of the mobile catalytic loop occur simultaneously, and the rate of this concerted motion inversely correlates with the stability of the target base pair. Subsequently, the covalent activation of the target cytosine is closely followed by but is not coincident with the methyl group transfer from the bound cofactor. These findings provide new insights into the temporal mechanism of this physiologically important reaction and pave the way to in-depth studies of other base-flipping systems. PMID- 21245035 TI - Recognition of an expanded genetic alphabet by type-II restriction endonucleases and their application to analyze polymerase fidelity. AB - To explore the possibility of using restriction enzymes in a synthetic biology based on artificially expanded genetic information systems (AEGIS), 24 type-II restriction endonucleases (REases) were challenged to digest DNA duplexes containing recognition sites where individual Cs and Gs were replaced by the AEGIS nucleotides Z and P [respectively, 6-amino-5-nitro-3-(1'-beta-D-2' deoxyribofuranosyl)-2(1H)-pyridone and 2-amino-8-(1'-beta-D-2' deoxyribofuranosyl)-imidazo[1,2-a]-1,3,5-triazin-4(8H)-one]. These AEGIS nucleotides implement complementary hydrogen bond donor-donor-acceptor and acceptor-acceptor-donor patterns. Results allowed us to classify type-II REases into five groups based on their performance, and to infer some specifics of their interactions with functional groups in the major and minor grooves of the target DNA. For three enzymes among these 24 where crystal structures are available (BcnI, EcoO109I and NotI), these interactions were modeled. Further, we applied a type-II REase to quantitate the fidelity polymerases challenged to maintain in a DNA duplex C:G, T:A and Z:P pairs through repetitive PCR cycles. This work thus adds tools that are able to manipulate this expanded genetic alphabet in vitro, provides some structural insights into the working of restriction enzymes, and offers some preliminary data needed to take the next step in synthetic biology to use an artificial genetic system inside of living bacterial cells. PMID- 21245036 TI - Loqs-PD and R2D2 define independent pathways for RISC generation in Drosophila. AB - In Drosophila, siRNAs are classified as endo- or exo-siRNAs based on their origin. Both are processed from double-stranded RNA precursors by Dcr-2 and then loaded into the Argonaute protein Ago2. While exo-siRNAs serve to defend the cell against viruses, endo-siRNAs restrict the spread of selfish DNA in somatic cells, analogous to piRNAs in the germ line. Endo- and exo-siRNAs display a differential requirement for double-stranded RNA binding domain proteins (dsRBPs): R2D2 is needed to load exo-siRNAs into Ago2 while the PD isoform of Loquacious (Loqs-PD) stimulates Dcr-2 during the nucleolytic processing of hairpin-derived endo siRNAs. In cell culture assays, R2D2 antagonizes Loqs-PD in endo-siRNA silencing and Loqs-PD is an inhibitor of RNA interference. Loqs-PD can interact via the C terminus unique to this isoform with the DExH/D-helicase domain of Drosophila Dcr 2, where binding of R2D2 has also been localized. Separation of the two pathways is not complete; rather, the dicing and Ago2-loading steps appear uncoupled, analogous to the corresponding steps in miRNA biogenesis. Analysis of deep sequencing data further demonstrates that in r2d2 mutant flies, siRNAs can be loaded into Ago2 but not all siRNA classes are equally proficient for this. Thus, the canonical Ago2-RISC loading complex can be bypassed under certain circumstances. PMID- 21245037 TI - Synthesis, structure and imaging of oligodeoxyribonucleotides with tellurium nucleobase derivatization. AB - We report here the first synthesis of 5-phenyl-telluride-thymidine derivatives and the Te-phosphoramidite. We also report here the synthesis, structure and STM current-imaging studies of DNA oligonucleotides containing the nucleobases (thymine) derivatized with 5-phenyl-telluride functionality (5-Te). Our results show that the 5-Te-DNA is stable, and that the Te-DNA duplex has the thermo stability similar to the corresponding native duplex. The crystal structure indicates that the 5-Te-DNA duplex structure is virtually identical to the native one, and that the Te-modified T and native A interact similarly to the native T and A pair. Furthermore, while the corresponding native showed weak signals, the DNA duplex modified with electron-rich tellurium functionality showed strong topographic and current peaks by STM imaging, suggesting a potential strategy to directly image DNA without structural perturbation. PMID- 21245038 TI - Human 2'-phosphodiesterase localizes to the mitochondrial matrix with a putative function in mitochondrial RNA turnover. AB - The vertebrate 2-5A system is part of the innate immune system and central to cellular antiviral defense. Upon activation by viral double-stranded RNA, 5' triphosphorylated, 2'-5'-linked oligoadenylate polyribonucleotides (2-5As) are synthesized by one of several 2'-5'-oligoadenylate synthetases. These unusual oligonucleotides activate RNase L, an unspecific endoribonuclease that mediates viral and cellular RNA breakdown. Subsequently, the 2-5As are removed by a 2' phosphodiesterase (2'-PDE), an enzyme that apart from breaking 2'-5' bonds also degrades regular, 3'-5'-linked oligoadenylates. Interestingly, 2'-PDE shares both functionally and structurally characteristics with the CCR4-type exonuclease endonuclease-phosphatase family of deadenylases. Here we show that 2'-PDE locates to the mitochondrial matrix of human cells, and comprise an active 3'-5' exoribonuclease exhibiting a preference for oligo-adenosine RNA like canonical cytoplasmic deadenylases. Furthermore, we document a marked negative association between 2'-PDE and mitochondrial mRNA levels following siRNA-directed knockdown and plasmid-mediated overexpression, respectively. The results indicate that 2' PDE, apart from playing a role in the cellular immune system, may also function in mitochondrial RNA turnover. PMID- 21245039 TI - Identification of residues in the N-terminal PAS domains important for dimerization of Arnt and AhR. AB - The basic helix-loop-helix (bHLH).PAS dimeric transcription factors have crucial roles in development, stress response, oxygen homeostasis and neurogenesis. Their target gene specificity depends in part on partner protein choices, where dimerization with common partner Aryl hydrocarbon receptor nuclear translocator (Arnt) is an essential step towards forming active, DNA binding complexes. Using a new bacterial two-hybrid system that selects for loss of protein interactions, we have identified 22 amino acids in the N-terminal PAS domain of Arnt that are involved in heterodimerization with aryl hydrocarbon receptor (AhR). Of these, Arnt E163 and Arnt S190 were selective for the AhR/Arnt interaction, since mutations at these positions had little effect on Arnt dimerization with other bHLH.PAS partners, while substitution of Arnt D217 affected the interaction with both AhR and hypoxia inducible factor-1alpha but not with single minded 1 and 2 or neuronal PAS4. Arnt uses the same face of the N-terminal PAS domain for homo- and heterodimerization and mutational analysis of AhR demonstrated that the equivalent region is used by AhR when dimerizing with Arnt. These interfaces differ from the PAS beta-scaffold surfaces used for dimerization between the C terminal PAS domains of hypoxia inducible factor-2alpha and Arnt, commonly used for PAS domain interactions. PMID- 21245040 TI - A cytoplasm-specific activity encoded by the Trithorax-like ATX1 gene. AB - Eukaryotes produce multiple products from a single gene locus by alternative splicing, translation or promoter usage as mechanisms expanding the complexity of their proteome. Trithorax proteins, including the Arabidopsis Trithorax-like protein ATX1, are histone modifiers regulating gene activity. Here, we report that a novel member of the Trithorax family has a role unrelated to chromatin. It is encoded from an internal promoter in the ATX1 locus as an isoform containing only the SET domain (soloSET). It is located exclusively in the cytoplasm and its substrate is the elongation factor 1A (EF1A). Loss of SET, but not of the histone modifying ATX1-SET activity, affects cytoskeletal actin bundling illustrating that the two isoforms have distinct functions in Arabidopsis cells. PMID- 21245041 TI - PCNA directs type 2 RNase H activity on DNA replication and repair substrates. AB - Ribonuclease H2 is the major nuclear enzyme degrading cellular RNA/DNA hybrids in eukaryotes and the sole nuclease known to be able to hydrolyze ribonucleotides misincorporated during genomic replication. Mutation in RNASEH2 causes Aicardi Goutieres syndrome, an auto-inflammatory disorder that may arise from nucleic acid byproducts generated during DNA replication. Here, we report the crystal structures of Archaeoglobus fulgidus RNase HII in complex with PCNA, and human PCNA bound to a C-terminal peptide of RNASEH2B. In the archaeal structure, three binding modes are observed as the enzyme rotates about a flexible hinge while anchored to PCNA by its PIP-box motif. PCNA binding promotes RNase HII activity in a hinge-dependent manner. It enhances both cleavage of ribonucleotides misincorporated in DNA duplexes, and the comprehensive hydrolysis of RNA primers formed during Okazaki fragment maturation. In addition, PCNA imposes strand specificity on enzyme function, and by localizing RNase H2 and not RNase H1 to nuclear replication foci in vivo it ensures that RNase H2 is the dominant RNase H activity during nuclear replication. Our findings provide insights into how type 2 RNase H activity is directed during genome replication and repair, and suggest a mechanism by which RNase H2 may suppress generation of immunostimulatory nucleic acids. PMID- 21245042 TI - USP10 deubiquitylates the histone variant H2A.Z and both are required for androgen receptor-mediated gene activation. AB - H2A.Z, a variant of H2A, is found at the promoters of inducible genes in both yeast and higher eukaryotes. However, its role in transcriptional regulation is complex since it has been reported to function both as a repressor and activator. We have previously found that mono-ubiquitylation of H2A.Z is linked to transcriptional silencing. Here, we provide new evidence linking H2A.Z deubiquitylation to transcription activation. We found that H2A.Z and ubiquitin specific protease 10 (USP10) are each required for transcriptional activation of the androgen receptor (AR)-regulated PSA and KLK3 genes. USP10 directly deubiquitylates H2A.Z in vitro and in vivo, and reducing USP10 expression in prostate cancer cells results in elevated steady-state levels of mono ubiquitylated H2A.Z (H2A.Zub1). Moreover, knockdown of USP10 ablates hormone induced deubiquitylation of chromatin proteins at the AR-regulated genes. Finally, by sequential ChIP assays, we found that H2A.Zub1 is enriched at the PSA and KLK3 regulatory regions, and loss of H2A.Zub1 is associated with transcriptional activation of these genes. Together, these data provide novel insights into how H2A.Z ubiquitylation/deubiquitylation and USP10 function in AR regulated gene expression. PMID- 21245043 TI - Design of a peptide-based vector, PepFect6, for efficient delivery of siRNA in cell culture and systemically in vivo. AB - While small interfering RNAs (siRNAs) have been rapidly appreciated to silence genes, efficient and non-toxic vectors for primary cells and for systemic in vivo delivery are lacking. Several siRNA-delivery vehicles, including cell-penetrating peptides (CPPs), have been developed but their utility is often restricted by entrapment following endocytosis. Hence, developing CPPs that promote endosomal escape is a prerequisite for successful siRNA implementation. We here present a novel CPP, PepFect 6 (PF6), comprising the previously reported stearyl-TP10 peptide, having pH titratable trifluoromethylquinoline moieties covalently incorporated to facilitate endosomal release. Stable PF6/siRNA nanoparticles enter entire cell populations and rapidly promote endosomal escape, resulting in robust RNAi responses in various cell types (including primary cells), with minimal associated transcriptomic or proteomic changes. Furthermore, PF6-mediated delivery is independent of cell confluence and, in most cases, not significantly hampered by serum proteins. Finally, these nanoparticles promote strong RNAi responses in different organs following systemic delivery in mice without any associated toxicity. Strikingly, similar knockdown in liver is achieved by PF6/siRNA nanoparticles and siRNA injected by hydrodynamic infusion, a golden standard technique for liver transfection. These results imply that the peptide, in addition to having utility for RNAi screens in vitro, displays therapeutic potential. PMID- 21245044 TI - Ikaros interacts with P-TEFb and cooperates with GATA-1 to enhance transcription elongation. AB - Ikaros is associated with both gene transcriptional activation and repression in lymphocytes. Ikaros acts also as repressor of human gamma-globin (hugamma-) gene transcription in fetal and adult erythroid cells. Whether and eventually, how Ikaros can function as a transcriptional activator in erythroid cells remains poorly understood. Results presented herein demonstrate that Ikaros is a developmental-specific activator of hugamma-gene expression in yolk sac erythroid cells. Molecular analysis in primary cells revealed that Ikaros interacts with Gata-1 and favors Brg1 recruitment to the human beta-globin Locus Control Region and the hugamma-promoters, supporting long-range chromatin interactions between these regions. Additionally, we demonstrate that Ikaros contributes to transcription initiation and elongation of the hugamma-genes, since it is not only required for TBP and RNA Polymerase II (Pol II) assembly at the hugamma promoters but also for conversion of Pol II into the elongation-competent phosphorylated form. In agreement with the latter, we show that Ikaros interacts with Cyclin-dependent kinase 9 (Cdk9), which contributes to efficient transcription elongation by phosphorylating the C-terminal domain of the large subunit of Pol II on Serine 2, and favours Cdk9 recruitment to hugamma-promoters. Our results show that Ikaros exerts dual functionality during gene activation, by promoting efficient transcription initiation and elongation. PMID- 21245045 TI - The small RNA SgrS controls sugar-phosphate accumulation by regulating multiple PTS genes. AB - A number of bacterial small RNAs (sRNAs) act as global regulators of stress responses by controlling expression of multiple genes. The sRNA SgrS is expressed in response to glucose-phosphate stress, a condition associated with disruption of glycolytic flux and accumulation of sugar-phosphates. SgrS has been shown to stimulate degradation of the ptsG mRNA, encoding the major glucose transporter. This study demonstrates that SgrS regulates the genes encoding the mannose and secondary glucose transporter, manXYZ. Analysis of manXYZ mRNA stability and translation in the presence and absence of SgrS indicate that manXYZ is regulated by SgrS under stress conditions and when SgrS is ectopically expressed. In vitro footprinting and in vivo mutational analyses showed that SgrS base pairs with manXYZ within the manX coding sequence to prevent manX translation. Regulation of manX did not require the RNase E degradosome complex, suggesting that the primary mechanism of regulation is translational. An Escherichia coli ptsG mutant strain that is manXYZ(+) experiences stress when exposed to the glucose analogs alpha methyl glucoside or 2-deoxyglucose. A ptsG manXYZ double mutant is resistant to the stress, indicating that PTS transporters encoded by both SgrS targets are involved in taking up substrates that cause stress. PMID- 21245046 TI - Influence of C-5 substituted cytosine and related nucleoside analogs on the formation of benzo[a]pyrene diol epoxide-dG adducts at CG base pairs of DNA. AB - Endogenous 5-methylcytosine ((Me)C) residues are found at all CG dinucleotides of the p53 tumor suppressor gene, including the mutational 'hotspots' for smoking induced lung cancer. (Me)C enhances the reactivity of its base paired guanine towards carcinogenic diolepoxide metabolites of polycyclic aromatic hydrocarbons (PAH) present in cigarette smoke. In the present study, the structural basis for these effects was investigated using a series of unnatural nucleoside analogs and a representative PAH diolepoxide, benzo[a]pyrene diolepoxide (BPDE). Synthetic DNA duplexes derived from a frequently mutated region of the p53 gene (5' CCCGGCACCC GC[(15)N(3),(13)C(1)-G]TCCGCG-3', + strand) were prepared containing [(15)N(3), (13)C(1)]-guanine opposite unsubstituted cytosine, (Me)C, abasic site, or unnatural nucleobase analogs. Following BPDE treatment and hydrolysis of the modified DNA to 2'-deoxynucleosides, N(2)-BPDE-dG adducts formed at the [(15)N(3), (13)C(1)]-labeled guanine and elsewhere in the sequence were quantified by mass spectrometry. We found that C-5 alkylcytosines and related structural analogs specifically enhance the reactivity of the base paired guanine towards BPDE and modify the diastereomeric composition of N(2)-BPDE-dG adducts. Fluorescence and molecular docking studies revealed that 5-alkylcytosines and unnatural nucleobase analogs with extended aromatic systems facilitate the formation of intercalative BPDE-DNA complexes, placing BPDE in a favorable orientation for nucleophilic attack by the N(2) position of guanine. PMID- 21245047 TI - Single-molecule studies of the stringency factors and rates governing the polymerization of RecA on double-stranded DNA. AB - RecA is a key protein in homologous recombination. During recombination, one single-stranded DNA (ssDNA) bound to site I in RecA exchanges Watson-Crick pairing with a sequence-matched ssDNA that was part of a double-stranded DNA molecule (dsDNA) bound to site II in RecA. After strand exchange, heteroduplex dsDNA is bound to site I. In vivo, direct polymerization of RecA on dsDNA through site I does not occur, though it does in vitro. The mechanisms underlying the difference have been unclear. We use single-molecule experiments to decouple the two steps involved in polymerization: nucleation and elongation. We find that elongation is governed by a fundamental clock that is insensitive to force and RecA concentration from 0.2 and 6 uM, though rates depend on ionic conditions. Thus, we can probe nucleation site stability by creating nucleation sites at high force and then measuring elongation as a function of applied force. We find that in the presence of ATP hydrolysis a minimum force is required for polymerization. The minimum force decreases with increasing RecA or ATP concentrations. We propose that force reduces the off-rate for nucleation site binding and that nucleation site stability is the stringency factor that prevents in vivo polymerization. PMID- 21245048 TI - NF-kB and c-Jun induce the expression of the oncogenic miR-221 and miR-222 in prostate carcinoma and glioblastoma cells. AB - MicroRNAs (miRNAs) are potent negative regulators of gene expression involved in all aspects of cell biology. They finely modulate virtually all physiological pathways in metazoans, and are deeply implicated in all main pathologies, among which cancer. Mir-221 and miR-222, two closely related miRNAs encoded in cluster from a genomic region on chromosome X, are strongly upregulated in several forms of human tumours. In this work, we report that the ectopic modulation of NF-kB modifies miR-221/222 expression in prostate carcinoma and glioblastoma cell lines, where we had previously shown their oncogenic activity. We identify two separate distal regions upstream of miR-221/222 promoter which are bound by the NF-kB subunit p65 and drive efficient transcription in luciferase reporter assays; consistently, the site-directed mutagenesis disrupting p65 binding sites or the ectopical inhibition of NF-kB activity significantly reduce luciferase activity. In the most distal enhancer region, we also define a binding site for c Jun, and we show that the binding of this factor cooperates with that of p65, fully accounting for the observed upregulation of miR-221/222. Thus our work uncovers an additional mechanism through which NF-kB and c-Jun, two transcription factors deeply involved in cancer onset and progression, contribute to oncogenesis, by inducing miR-221/222 transcription. PMID- 21245050 TI - Use of the long and short forms of the depression in the medically ill questionnaire in a Spanish population. AB - This study sought to translate, using a back-translation procedure, and evaluate the psychometric characteristics of Depression in the Medically Ill questionnaire (DMI-18) and its short version (DMI-10) in a Spanish population. Patients with somatic disorders (N = 366) completed the translated DMI-18 and another depression questionnaire. Among these, 167 were also assessed by a mental health professional (gold standard) to test criterion validity. Furthermore, coefficient alpha for both the versions were high (>.90), and convergent validity assessed against the Beck Depression Inventory for Primary Care, the Hospital Anxiety and Depression Scale, and the Patient Health Questionnaire-9 was satisfactory (r > .74). Confirmatory factor analysis results supported the one-factor model. When compared with the gold standard, sensitivity and specificity were 93% and 73% for DMI-18 and 87% and 74% for DMI-10, respectively. Thus, both the versions are acceptable measures that can be used by nonpsychiatric professionals to detect affective comorbidities in their patients. PMID- 21245049 TI - A polar barrier to transcription can be circumvented by remodeler-induced nucleosome translocation. AB - Many eukaryotic genes are regulated at the level of transcript elongation. Nucleosomes are likely targets for this regulation. Previously, we have shown that nucleosomes formed on very strong positioning sequences (601 and 603), present a high, orientation-dependent barrier to transcription by RNA polymerase II in vitro. The existence of this polar barrier correlates with the interaction of a 16-bp polar barrier signal (PBS) with the promoter-distal histone H3-H4 dimer. Here, we show that the polar barrier is relieved by ISW2, an ATP-dependent chromatin remodeler, which translocates the nucleosome over a short distance, such that the PBS no longer interacts with the distal H3-H4 dimer, although it remains within the nucleosome. In vivo, insertion of the 603 positioning sequence into the yeast CUP1 gene results in a modest reduction in transcription, but this reduction is orientation-independent, indicating that the polar barrier can be circumvented. However, the 603-nucleosome is present at the expected position in only a small fraction of cells. Thus, the polar barrier is probably non functional in vivo because the nucleosome is not positioned appropriately, presumably due to nucleosome sliding activities. We suggest that interactions between PBSs and chromatin remodelers might have significant regulatory potential. PMID- 21245051 TI - Automated bond order assignment as an optimization problem. AB - MOTIVATION: Numerous applications in Computational Biology process molecular structures and hence strongly rely not only on correct atomic coordinates but also on correct bond order information. For proteins and nucleic acids, bond orders can be easily deduced but this does not hold for other types of molecules like ligands. For ligands, bond order information is not always provided in molecular databases and thus a variety of approaches tackling this problem have been developed. In this work, we extend an ansatz proposed by Wang et al. that assigns connectivity-based penalty scores and tries to heuristically approximate its optimum. In this work, we present three efficient and exact solvers for the problem replacing the heuristic approximation scheme of the original approach: an A*, an ILP and an fixed-parameter approach (FPT) approach. RESULTS: We implemented and evaluated the original implementation, our A*, ILP and FPT formulation on the MMFF94 validation suite and the KEGG Drug database. We show the benefit of computing exact solutions of the penalty minimization problem and the additional gain when computing all optimal (or even suboptimal) solutions. We close with a detailed comparison of our methods. AVAILABILITY: The A* and ILP solution are integrated into the open-source C++ LGPL library BALL and the molecular visualization and modelling tool BALLView and can be downloaded from our homepage www.ball-project.org. The FPT implementation can be downloaded from http://bio.informatik.uni-jena.de/software/. PMID- 21245052 TI - Identifying viral integration sites using SeqMap 2.0. AB - Retroviral integration has been implicated in several biomedical applications, including identification of cancer-associated genes and malignant transformation in gene therapy clinical trials. We introduce an efficient and scalable method for fast identification of viral vector integration sites from long read high throughput sequencing. Individual sequence reads are masked to remove non-genomic sequence, aligned to the host genome and assembled into contiguous fragments used to pinpoint the position of integration. AVAILABILITY AND IMPLEMENTATION: The method is implemented in a publicly accessible web server platform, SeqMap 2.0, containing analysis tools and both private and shared lab workspaces that facilitate collaboration among researchers. Available at http://seqmap.compbio.iupui.edu/. PMID- 21245053 TI - Succinct data structures for assembling large genomes. AB - MOTIVATION: Second-generation sequencing technology makes it feasible for many researches to obtain enough sequence reads to attempt the de novo assembly of higher eukaryotes (including mammals). De novo assembly not only provides a tool for understanding wide scale biological variation, but within human biomedicine, it offers a direct way of observing both large-scale structural variation and fine-scale sequence variation. Unfortunately, improvements in the computational feasibility for de novo assembly have not matched the improvements in the gathering of sequence data. This is for two reasons: the inherent computational complexity of the problem and the in-practice memory requirements of tools. RESULTS: In this article, we use entropy compressed or succinct data structures to create a practical representation of the de Bruijn assembly graph, which requires at least a factor of 10 less storage than the kinds of structures used by deployed methods. Moreover, because our representation is entropy compressed, in the presence of sequencing errors it has better scaling behaviour asymptotically than conventional approaches. We present results of a proof-of concept assembly of a human genome performed on a modest commodity server. PMID- 21245054 TI - BayesPeak--an R package for analysing ChIP-seq data. AB - MOTIVATION: Identification of genomic regions of interest in ChIP-seq data, commonly referred to as peak-calling, aims to find the locations of transcription factor binding sites, modified histones or nucleosomes. The BayesPeak algorithm was developed to model the data structure using Bayesian statistical techniques and was shown to be a reliable method, but did not have a full-genome implementation. RESULTS: In this note we present BayesPeak, an R package for genome-wide peak-calling that provides a flexible implementation of the BayesPeak algorithm and is compatible with downstream BioConductor packages. The BayesPeak package introduces a new method for summarizing posterior probability output, along with methods for handling overfitting and support for parallel processing. We briefly compare the package with other common peak-callers. AVAILABILITY: Available as part of BioConductor version 2.6. URL: http://bioconductor.org/packages/release/bioc/html/BayesPeak.html. PMID- 21245055 TI - Up-regulation of p27(kip1) contributes to Nrf2-mediated protection against angiotensin II-induced cardiac hypertrophy. AB - AIMS: Nuclear factor erythroid-2-related factor 2 (Nrf2) appears to be a negative regulator of maladaptive cardiac remodelling and dysfunction; however, a potential of the Nrf2-mediated cardiac protection in diverse pathological settings remains to be determined. This study was aimed to explore the role of Nrf2 in angiotensin II (Ang II)-induced cardiac hypertrophy. METHODS AND RESULTS: Littermate wild-type (WT) and Nrf2 knockout (Nrf2(-/-)) mice were administered Ang II via osmotic mini-pumps for 2 weeks to induce cardiac hypertrophy. Elevation of blood pressure by the continuous Ang II infusion was comparable between WT and Nrf2(-/-) mice. Relative to WT mice, however, Nrf2(-/-) mice exhibited exaggerated myocardial oxidative stress with an impaired induction of a group of antioxidant genes and increased cardiac hypertrophy in response to the sustained Ang II stimulation. In cultured cardiomyocytes, adenoviral overexpression of Nrf2 shRNA enhanced Ang II-induced reactive oxygen species (ROS) production and protein synthesis, whereas adenoviral overexpression of Nrf2 exerted opposite effects. Moreover, Nrf2 deficiency exacerbated Ang II-induced down-regulation of p27(kip1) expression in the heart via a mechanism of post transcriptional regulation. In contrast, adenoviral overexpression of Nrf2 increased p27(kip1) protein but not mRNA expression and reversed Ang II-induced down-regulation of p27(kip1) protein expression in cultured cardiomyocytes by suppressing ROS formation. Finally, the enhancement of Ang II-induced hypertrophic growth due to the Nrf2 deficiency was negated by overexpressing p27(kip1) in cultured cardiomyocytes. CONCLUSION: The Nrf2-p27(kip1) pathway serves as a novel negative feedback mechanism in Ang II-induced pathogenesis of cardiac hypertrophy, independent of changes in blood pressure. PMID- 21245056 TI - Effect of S-adenosylmethionine on neointimal formation after balloon injury in obese diabetic rats. AB - AIMS: The association between hyperhomocysteinaemia and cardiovascular disease has been attributed to low levels of S-adenosylmethionine (SAM), a metabolic intermediate of homocysteine. However, the role of SAM in the development of restenosis has not been explored. Therefore, we investigated the effects of SAM on neointimal formation after balloon injury in obese diabetic rats and cultured cells. METHODS AND RESULTS: Otsuka Long-Evans Tokushima fatty rats were divided into the following three groups: control (normal saline); SAM15; and SAM30 (15 and 30 mg/kg per day, respectively; n = 10 per group). SAM was administered orally from 1 week before carotid injury to 2 weeks thereafter. SAM treatment for 3 weeks caused a significant dose-dependent reduction in the intima-to-media ratio. SAM treatment significantly reduced the proliferation of vascular smooth muscle cells (VSMCs) and induced more apoptosis than was observed in the control group. This effect was accompanied by reduced circulating levels of high sensitivity C-reactive protein and monocyte chemoattractant protein-1, reduced urine 8-hydroxy-2'-deoxyguanosine (8-OHdG), and increased adiponectin. Intima-to media ratio correlated significantly with the levels of inflammatory markers, adiponectin, and 8-OHdG. In vitro experiments demonstrated that VSMC proliferation and migration and the adhesion of monocytes decreased in response to SAM. SAM treatment also reduced tumour necrosis factor-alpha-induced reactive oxygen species and tunicamycin-induced GRP78 expression in VSMCs. CONCLUSION: These findings suggest that SAM exerts protective effects against restenosis after balloon injury in a rat model of type 2 diabetes by reducing the proliferation and inducing the apoptosis of VSMCs, modifying the inflammatory processes and reducing oxidative and endoplasmic reticulum stresses. PMID- 21245057 TI - Parathyroid hormone is a DPP-IV inhibitor and increases SDF-1-driven homing of CXCR4(+) stem cells into the ischaemic heart. AB - AIMS: Parathyroid hormone (PTH) has been shown to promote stem cell mobilization into peripheral blood. Moreover, PTH treatment after myocardial infarction (MI) improved survival and myocardial function associated with enhanced homing of bone marrow-derived stem cells (BMCs). To unravel the molecular mechanisms of PTH mediated stem cell trafficking, we analysed wild-type (wt) and green fluorescent protein (GFP)-transgenic mice after MI with respect to the pivotal stromal cell derived factor-1 (SDF-1)/chemokine receptor type 4 (CXCR4) axis. METHODS AND RESULTS: WT and GFP-transgenic mice (C57BL/6J) were infarcted by coronary artery ligation and PTH (80 MUg/kg/day) was injected for 6 days afterwards. Number of BMCs was analysed by flow cytometry. SDF-1 protein levels and activity of dipeptidyl peptidase-IV (DPP-IV) were investigated by ELISA and activity assay. Functional analyses were performed at day 30 after MI. PTH-treated animals revealed an enhanced homing of CXCR4(+) BMCs associated with an increased protein level of the corresponding homing factor SDF-1 in the ischaemic heart. In vitro and in vivo, PTH inhibited the activity of DPP-IV, which cleaves and inactivates SDF-1. Functionally, PTH significantly improved myocardial function after MI. Both stem cell homing as well as functional recovery were reversed by the CXCR4 antagonist AMD3100. CONCLUSION: In summary, PTH is a DPP-IV inhibitor leading to an increased cardiac SDF-1 level, which enhances recruitment of CXCR4(+) BMCs into the ischaemic heart associated with attenuated ischaemic cardiomyopathy. Since PTH is already clinically used our findings may have direct impact on the initiation of studies in patients with ischaemic disorders. PMID- 21245058 TI - Genome-wide association studies of atrial fibrillation: past, present, and future. AB - Genome-wide association studies (GWAS) for atrial fibrillation (AF) have identified three distinct genetic loci on chromosomes 1q21, 4q25, and 16q22 that are associated with the arrhythmia. Susceptibility loci also have been identified by GWAS for PR interval duration, a quantitative phenotype related to AF. In this review article, we have sought to summarize the latest findings for population based genetic studies of AF, to highlight ongoing functional studies, and to explore the future directions of genetic research on AF. PMID- 21245059 TI - Proteins mediating collagen biosynthesis and accumulation in arterial repair: novel targets for anti-restenosis therapy. AB - Events contributing to restenosis after coronary interventions include platelet aggregation, inflammatory cell infiltration, growth factor release, and accumulation of smooth muscle cells (SMCs) and extracellular matrix (ECM). The ECM is composed of various collagen subtypes and proteoglycans and over time constitutes the major component of the mature restenotic plaque. The pathophysiology of collagen accumulation in the ECM during arterial restenosis is reviewed. Factors regulating collagen synthesis and degradation, including various cytokines and growth factors involved in the process, may be targets for therapies aimed at prevention of in-stent restenosis. PMID- 21245060 TI - Impact of aortic stenosis on longitudinal myocardial deformation during exercise. AB - In aortic stenosis (AS), left ventricular (LV) adaptation to exercise has poorly been examined. Changes in LV ejection fraction may lack accuracy in identifying the presence of intrinsic myocardial impairment. AIMS: We sought to determine the impact of aortic stenosis (AS) on left ventricular (LV) longitudinal function at exercise in a series of asymptomatic patients with AS and preserved LV ejection fraction. METHODS AND RESULTS: Long-axis function was assessed at rest and at exercise by using 2D speckle tracking of myocardial deformation in 207 AS patients (aortic valve area 0.87 +/- 0.19 cm2) and 43 aged-matched control subjects. When compared with control subjects, patients with AS have reduced longitudinal myocardial function at rest (-20.2 +/- 2.7 vs. -15.4 +/- 4.0%) and at peak exercise (-25.0 +/- 3.7 vs. -16.5 +/- 4.9%) (P < 0.0001 for both). Exercise changes in global longitudinal strain were correlated with changes in LV ejection in controls but not in patients with AS. Changes in LV global longitudinal strain during test were lower in AS patients with an abnormal response to exercise (-0.5 +/- 2.7 vs. -1.5 +/- 2.8%, P = 0.001). In multivariate analysis, a lower global longitudinal strain at rest (P = 0.04), a higher increase in mean trans-valvular pressure gradient (P < 0.001) at exercise, and smaller exercise-induced changes in global longitudinal strain (P < 0.001) were associated with an abnormal exercise test. CONCLUSION: In AS, subnormal LV function can be reliably identified by 2D strain imaging at rest and during a sub maximal exercise. That sensitive measure of LV systolic function is depressed in AS and even more in patients having the most severe AS. PMID- 21245061 TI - Pathological gambling in treatment-seeking alcoholics: a national survey in France. AB - AIMS: To estimate the prevalence of pathological gambling (pG) in people addicted to alcohol and drugs, particularly those with alcohol use disorders (AUDs), including new forms of gambling such as video and on-line games; and to update the socio-demographic profile of people suffering from both AUD and pG. METHOD: A cross-sectional survey was conducted in 1 week of 2009 in 55 French addiction treatment centres, including all consecutive patients attending that centre, using an anonymous questionnaire which included a tool specific for pG screening, the DEBA-jeu questionnaire (Detection et Besoin d'Aide en regard du Jeu Excessif). RESULTS: A total of 2790 patients entered the study. The most frequent reason for attending the Addiction Centres was AUD (77%). According to the DEBA test, 6.5% of the patients were pathological gamblers and 12% were subsyndromal gamblers. pG affected all age groups and did not decrease with abstinence from alcohol. pG was significantly associated with male sex [relative risk (RR) = 2.4; P < 0.001)] and, at a lower level of significance, with homelessness (RR = 1.52; P = 0.03) and unemployment (RR = 1.47; P = 0.04). CONCLUSIONS: pG appears to be a common feature of the French people with alcohol and drug disorders. Apart from male sex, no parameter had discriminatory power sufficient to target pG screening on a specific subgroup. Therefore, any patient attending a centre for drug or AUD should be asked about his gambling. Moreover, clinical teams should be trained to treat this addiction. PMID- 21245062 TI - Associations of social phobia and general anxiety with alcohol and drug use in a community sample of adolescents. AB - AIMS: This study explores whether associations between anxiety and alcohol and other substance use are already evident in middle adolescence, and whether general anxiety or symptoms of social phobia affect continuity of frequent alcohol use, frequent drunkenness and cannabis use. METHODS: Data from the Adolescent Mental Health Cohort Study, a school-based Finnish survey among adolescents aged 15-16 years at baseline, was utilized to assess prevalence, incidence and continuity of symptoms of social phobia, general anxiety, frequent alcohol use, frequent drunkenness and cannabis use (which in this context was smoked 'hashish' of unknown constituency), and the associations between the substance use variables and the anxiety variables in 2-year follow-up. RESULTS: Anxiety preceded substance use while no reciprocal associations were observed. Depression mediated the associations between anxiety and substance use. Symptoms of social phobia did not elevate the incidence of substance use, but general anxiety did. Frequent drunkenness was less significantly associated with anxiety than the other two substance use variables. Co-morbid general anxiety increased the persistence of frequent alcohol use while co-morbid social phobia decreased its persistence. Continuity of frequent drunkenness and cannabis use were unaffected by co-morbid anxiety. CONCLUSIONS: General anxiety in middle adolescence places adolescents at risk for concurrent and subsequent substance use. The risk may, however, be associated with co-morbid depression. Social phobia in middle adolescence may protect from substance use. Adolescents with internalizing symptoms may need guidance in coping with the symptoms even if the symptoms do not fulfil the criteria of mood or anxiety disorder. PMID- 21245063 TI - Severe hypertriglyceridemia influenced by alcohol (SHIBA). AB - AIMS: This study was conducted to examine the relationship between triglyceride (TG) levels and a history of excessive drinking in patients with severe hypertriglyceridemia (HT). METHODS: Alcohol intake as well as other risk factors associated with HT were searched for in case records of 300 patients known to the laboratory to have had a TG level over 11.3 mmol/l. RESULTS: The majority of severe HT could be attributed to obesity, diabetes mellitus, excessive alcohol consumption or combinations of these. Excessive alcohol intake (over 210 g/week for males; over 140 g/week for females) was recorded for 24% of the total, and for 43% in the highest TG quartile. TG levels were significantly higher in the excessive drinkers (P < 0.001) and in patients with acute pancreatitis (P = 0.001). The incidence of pancreatitis in this cohort was 4% and limited to very high TG levels. CONCLUSION: Excessive alcohol consumption was recorded in a quarter of patients with severe HT. Patients with the combination of obesity, diabetes and alcohol excess are prone to develop extremely high TG values. PMID- 21245064 TI - Spectra of linear energy transfer and other dosimetry characteristics as measured in C290 MeV/n MONO and SOBP ion beams at HIMAC-BIO (NIRS, Japan) with different detectors. AB - Active mobile dosimetry unit (Liulin), passive plastic nuclear track detectors (PNTD) and thermoluminescent detectors (TLD) were exposed in a C290 MeV/n beam at HIMAC-BIO (NIRS, Japan). Two different types of beam configuration were used- monoenergetic beam (MONO) and spread-out Bragg peak (SOBP); the detectors were placed at several depths from the entrance up to the depths behind the Bragg peak. Relative response of TLDs in beams has been studied as a function of the depth, and it was re-proved that it can depend on the linear energy transfer (LET). Liulin measures energy deposition in Si; the spectra of energy deposited in Si can be transformed to the spectra of lineal energy or LET. PNTDs are able to determine the LET of registered particles directly. The limitation of both methods is in the range in which they can determine the LET-Liulin is able to measure perpendicularly incident charged particles up to ~35 keV/um (in water), PNTD can measure from ~7 to 400 keV/um, independently of the registration angle. The results from both methods are compared and combined for both beams' configuration, and a good agreement is observed. PMID- 21245065 TI - Uncertainty assessment of a two element LiF:Mg,Ti TL personal dosemeter using Monte-Carlo techniques. AB - This paper presents the results of an uncertainty assessment and a comparison study of dose algorithms for H(p)(10) and H(p)(0.07) used for evaluating a routine two-element thermoluminescent whole-body dosemeter. Due to the photon energy response of the two different filtered LiF:Mg,Ti detector elements, the application of a dose algorithm is necessary to assess the relevant photon doses over the rated energy range with an acceptable energy dependence. A linear dose algorithm with two different sets of parameters was designed to assess the personal dose equivalent in the relevant quantity H(p)(10) and H(p)(0.07). Based on the experimental results from calibrations on the ISO water slab phantom, a detailed uncertainty analysis was performed by means of Monte-Carlo (MC) techniques and other analytical methods. The uncertainty contribution of the individual detector element signals was taken into special consideration. For this analysis, realistic energy and angular distributions were applied to calculate the dosemeter response. It is concluded that the MC method is an appropriate tool to perform uncertainty calculations. The possibility to assign arbitrary probability density functions to the input quantities, as well as to define a complex model function (dose algorithm) allows the simulation of irradiation conditions close to reality. PMID- 21245066 TI - Perioperative outcomes of laparoendoscopic single-site surgery (LESS) versus conventional laparoscopy for adnexal disease: a case--control study. AB - OBJECTIVE: This study aimed to evaluate the potential advantages of laparoendoscopic single-site surgery (LESS) approach with respect to conventional laparoscopy. METHODS: Thirty LESS patients were matched 2:1 with a previous cohort of 58 patients undergoing conventional laparoscopy for the same type of surgery (controls). RESULTS: Median operative time (38.5 vs 54 minutes; P = .09) and estimated blood loss (20 vs 30 mL; P = .008) were more favorable in patients undergoing LESS treatment compared with those undergoing conventional laparoscopy. Rupture of the cyst was observed in 11 out of 30 cases (36.6%) and 26 of 58 controls (44.8%; P = .46). Median length of stay was 1 day in the cases and 2 in the controls (P = .03). CONCLUSIONS: Decreases in operative time, estimated blood loss, or length of stay should not be considered a benefit attributable to LESS; rather it seems there are no differences between these 2 surgical approaches after an adequate selection of patients. PMID- 21245067 TI - Feasibility and safety of adhesiolysis using transgastric NOTES approach: a pilot survival study in a porcine model. AB - OBJECTIVES: Although adhesions can be removed by adhesiolysis using laparotomy or laparoscopy, they typically recur sometimes with equal severity. It is suggested that minimizing the invasiveness of the operative technique by using natural orifice translumenal endoscopic surgery (NOTES) may reduce adhesion re-formation. The aim of the study was to evaluate the feasibility and safety of adhesiolysis by using a novel transgastric NOTES approach and collect pilot data on adhesion recurrence after transgastric NOTES adhesiolysis. METHODS: One nonsurvival and 5 survival female pigs were used in this experimental survival study. Interventions included (a) induction of adhesions by laparotomy, (b) 2 weeks survival, (c) transgastric NOTES adhesiolysis with endoscopic evaluation and scoring of adhesions before and immediately after adhesiolysis, (d) 2 weeks survival, and (e) necropsy with endoscopic and necroscopic evaluation and scoring of recurrent adhesions. Main outcome measures were (a) survival and complication rates and (b) assessment of adhesion formation and re-formation using the Hopkins Adhesion Formation Score. RESULTS: No mortality and no complications were observed. A total of 11 adhesions formed before the adhesiolysis in 5 survival study animals. All were successfully divided. The frequency of adhesions and median adhesion formation score decreased significantly immediately after adhesiolysis compared with that prior to the procedure (frequency, 11 vs 0, P = .011; the median score = 2.0 [range 1-3] vs 0.0 [range 0-0], P = .004). The treatment gains maintained at 2 weeks after the adhesiolysis. LIMITATIONS: The limitations of this study were the low number of study animals and short-term follow-up data. CONCLUSIONS: Adhesiolysis using NOTES transgastric approach is feasible, safe, and effective with minimal adhesion re-formation. PMID- 21245068 TI - Video gaming in children improves performance on a virtual reality trainer but does not yet make a laparoscopic surgeon. AB - BACKGROUND: In children, video game experience improves spatial performance, a predictor of surgical performance. This study aims at comparing laparoscopic virtual reality (VR) task performance of children with different levels of experience in video games and residents. PARTICIPANTS AND METHODS: A total of 32 children (8.4 to 12.1 years), 20 residents, and 14 board-certified surgeons (total n = 66) performed several VR and 2 conventional tasks (cube/spatial and pegboard/fine motor). Performance between the groups was compared (primary outcome). VR performance was correlated with conventional task performance (secondary outcome). RESULTS: Lowest VR performance was found in children with low video game experience, followed by those with high video game experience, residents, and board-certified surgeons. VR performance correlated well with the spatial test and moderately with the fine motor test. CONCLUSIONS: The use of computer games can be considered not only as pure entertainment but may also contribute to the development of skills relevant for adequate performance in VR laparoscopic tasks. Spatial skills are relevant for VR laparoscopic task performance. PMID- 21245069 TI - Endoscopic treatment of postgastrectomy duodenal fistula with an over-the-scope clip. AB - Bleeding peptic ulcer is a life threatening condition with high mortality rate but often treatable by endoscopy. Surgical indications in case of gastroduodenal ulcers are confined to endoscopic and radiological failures in bleeding control. Duodenal fistula (DF) is a rare complication of gastric resection and even if a rare event it may be a life threatening condition. Surgical and medical options could not solve the DF. Herein we report a case of an old patient underwent emergency gastrectomy for ulcer's bleeding who developed DF associated to sepsis, malnutrition and, hydro-electrolyte disorders not responding to surgical and medical attempts. We demonstrated, for the first time, the efficacy of over the scope clips (OTSC(r)) in the treatment of postoperative duodenal fistulas not responding to surgical and medical treatment in high risk patient. PMID- 21245070 TI - Laparoscopy entry in patients with previous abdominal and pelvic surgery. AB - BACKGROUND: The background of this investigation is based on a common surgical problem: The access in laparoscopic surgery is more difficult in women with previous abdominopelvic surgery, since adhesions and viscera could be close to the point of trocar insertion. PURPOSE: The authors analyzed the safety and the efficacy of a modified direct optical entry (DOE) method versus the Hasson's method by open laparoscopy (OL) in women with previous abdominopelvic surgery in a preliminary prospective case-control study. MATERIALS AND METHODS: A total of 168 women underwent laparoscopic surgery in university-affiliated hospitals: 86 were assigned to abdominal DOE (group A) and 82 to OL (group B). The main outcome measures were statistically compared: time required for entry into abdomen, blood loss, and occurrence of vascular and/or bowel injury. All patients had an intraperitoneal view of the primary port site during surgical procedure. RESULTS: Statistical differences, in favor of the DOE group (P < .01), were found in duration of entry and blood loss. The vascular and bowel injuries in OL versus DOE were not statistically different. CONCLUSIONS: Obtaining access to the peritoneal cavity in laparoscopic surgery is more difficult in patients with previous abdominopelvic surgery, since it can become a difficult, time-consuming, and occasionally hazardous procedure. The study results suggest that DOE is advantageous when compared with OL in terms of saving time enabling a safe and expeditious visually guided entry for laparoscopy. PMID- 21245071 TI - Quality of life and functional results of submucosal injection therapy using dextranomer hyaluronic acid for fecal incontinence. AB - BACKGROUND AND AIM: The aim of this prospective study was to analyze safety and functional outcome of transanal submucosal injection of dextranomer hyaluronic acid ("bulking agents therapy") in patients with passive fecal incontinence. METHODS: All patients who underwent transanal injection therapy were prospectively enrolled in this study. Inclusion criteria included fecal incontinence (internal anal sphincter dysfunction) after failed conservative treatment. The procedure was performed in a standardized technique, including submucosal injection of 4 * 1 mL dextranomer hyaluronic acid 5 mm above the dentate line. The primary endpoint focused on symptom improvement provided as the change in incontinence status and quality of life using validated scores (Wexner incontinence score, symptom-specific Fecal Incontinence Quality of Life [FIQoL] scale, and generic EQ-5D-Visual Analogue Scale [EQ-5D-VAS]). RESULTS: Within the observation period (July 2007 to May 2009), a total of 21 patients (17 women) with passive fecal incontinence were treated. Neither morbidity nor adverse events were documented. Three months postoperatively, 61.1% (11/18) showed significant improvement of symptoms (reduction of incontinence episodes and soiling), which was sustained after 20 months in 55.6% (10/18). Wexner incontinence score decreased from 16.8 to 12.3 (P > .05). Significant improvement was documented for FIQoL and EQ-5D-VAS (P < .05). CONCLUSION: The current results indicate that injection therapy using hyaluronic acid is an innovative and minimally invasive procedure with no morbidity. Although Wexner incontinence score is not significantly influenced, a significant improvement in quality of life was observed in more than 50% of patients. PMID- 21245072 TI - Physical activity change during adolescence: a systematic review and a pooled analysis. AB - BACKGROUND: It is presumed that physical activity (PA) level declines during the lifespan, particularly in adolescence. However, currently, there is no study that quantifies these changes and pools results for a common interpretation. Therefore, the purpose was to systematically review the international literature regarding PA change during adolescence, and to quantify that change according to a series of study variables, exploring gender-and-age differences. METHODS: An electronic search was conducted in the Medline/PubMed and Web of Science databases. Longitudinal studies with, at least, two PA measures throughout adolescence (10-19 years old) or the first PA measure during childhood and the second one during adolescence were selected. From each article, study project name, country, year of the first data collection, sample size, baseline age, follow-up duration, characteristics of the instrument (type, recall time, PA intensity and PA domain), unit of PA measure and report of statistical significance were collected. RESULTS: Overall, 26 studies matched the inclusion criteria. Most were carried out in the USA, assessed PA by questionnaire, and found a decline in PA levels during the adolescence. On average, the mean percentage PA change per year, across all studies, was -7.0 (95% confidence interval: -8.8 to -5.2), ranging from -18.8 to 7.8. The decline was significant according to most sub-groups of variables analysed. Although earlier studies revealed a higher PA decline in boys, the decline has been greater in girls in more recent studies (commenced after 1997). Moreover, although the decline among girls was higher in younger ages at baseline (9-12 years), it was higher in older ages (13-16 years) among boys. CONCLUSIONS: The decline of PA during adolescence is a consistent finding in the literature. Differences between boys and girls were observed and should be explored in future studies. Interventions that attempt to attenuate the PA decline, even without an increase in PA levels, could be considered as effective. PMID- 21245073 TI - The use of Systemic Lupus Erythematosus Disease Activity Index-2000 to define active disease and minimal clinically meaningful change based on data from a large cohort of systemic lupus erythematosus patients. AB - OBJECTIVES: To examine SLEDAI-2000 cut-off scores for definition of active SLE and to determine the sensitivity to change of SLEDAI-2000 for the assessment of SLE disease activity and minimal clinically meaningful changes in score. METHODS: Data from two multi-centre studies were used in the analysis: in a cross sectional and a longitudinal fashion. At every assessment, data were collected on SLEDAI-2000 and treatment. The cross-sectional analysis with receiver operating characteristic (ROC) curves was used to examine the appropriate SLEDAI-2000 score to define active disease and increase in therapy was the reference standard. In the longitudinal analysis, sensitivity to change of SLEDAI-2000 was assessed with multinomial logistic regression. ROC curves analysis was used to examine possible cut-points in score changes associated with change in therapy, and mean changes were estimated. RESULTS: In the cross-sectional analysis, the most appropriate cut-off scores for active disease were 3 or 4. In the longitudinal analysis, the best model for predicting treatment increase was with the change in SLEDAI-2000 score and the score from the previous visit as continuous variables. The use of cut-points was less predictive of treatment change than the use of continuous score. The mean difference in the change in SLEDAI-2000 scores, adjusted for prior score, between patients with treatment increase and those without was 2.64 (95% CI 2.16, 3.14). CONCLUSIONS: An appropriate SLEDAI-2000 score to define active disease is 3 or 4. SLEDAI-2000 index is sensitive to change. The use of SLEDAI-2000 as a continuous outcome is recommended for comparative purposes. PMID- 21245074 TI - Quantifying the economic burden of productivity loss in rheumatoid arthritis. AB - OBJECTIVE: In light of the large number of recent studies and systematic reviews investigating the cost of RA, this article examines the methods used to assess the impact of RA on employment and work productivity, and provides an overview of the issues surrounding work productivity loss in the RA population. METHODS: A review of the published literature was conducted in order to identify relevant articles. These articles were then reviewed and their methodologies compared. The various methods used to calculate economic loss were then explained and discussed. RESULTS: We found that although methods of lost productivity and associated costs varied between studies, all suggest that RA is associated with significant burden of illness. Economic analyses that exclude indirect costs will therefore underestimate the full economic impact of RA. However, the methods used to calculate productivity loss have a significant impact on the results of indirect cost analyses, and should be selected carefully when designing such studies. Several factors relating to the disease, the job and socio-demographics have been found to predict work disability. CONCLUSIONS: Consideration of these factors is vital when measuring the extent of both absenteeism and presenteeism, and will allow for more accurate estimation of the impact of RA on work productivity. This information may also guide interventions aiming to prevent or postpone work disability and job loss. PMID- 21245075 TI - A comparison of different methods of temperature measurements in sick newborns. AB - We aimed to compare the accuracy of digital axillary thermometer (DAT), rectal glass mercury thermometer (RGMT), infrared tympanic thermometer (ITT) and infrared forehead skin thermometer (IFST) measurements with traditional axillary glass mercury thermometer (AGMT) for intermittent temperature measurement in sick newborns. A prospective, descriptive and comparative study in which five different types of thermometer readings were performed sequentially for 3 days. A total of 1989 measurements were collected from 663 newborns. DAT and ITT measurements correlated most closely to AGMT (r = 0.94). The correlation coefficent for IFST and RGMT were 0.74 and 0.87, respectively. The mean differences for DAT, ITT, RGMT and IFST were +0.02 degrees C, +0.03 degrees C, +0.25 degrees C and +0.55 degrees C, respectively. There were not any clinical differences (defined as a mean difference of 0.2 degrees C) between both mean AGMT&DAT and AGMT&ITT measurements. Our study suggests that tympanic thermometer measurement could be used as an acceptable and practical method for sick newborn in neonatal units. PMID- 21245076 TI - PubMed and beyond: a survey of web tools for searching biomedical literature. AB - The past decade has witnessed the modern advances of high-throughput technology and rapid growth of research capacity in producing large-scale biological data, both of which were concomitant with an exponential growth of biomedical literature. This wealth of scholarly knowledge is of significant importance for researchers in making scientific discoveries and healthcare professionals in managing health-related matters. However, the acquisition of such information is becoming increasingly difficult due to its large volume and rapid growth. In response, the National Center for Biotechnology Information (NCBI) is continuously making changes to its PubMed Web service for improvement. Meanwhile, different entities have devoted themselves to developing Web tools for helping users quickly and efficiently search and retrieve relevant publications. These practices, together with maturity in the field of text mining, have led to an increase in the number and quality of various Web tools that provide comparable literature search service to PubMed. In this study, we review 28 such tools, highlight their respective innovations, compare them to the PubMed system and one another, and discuss directions for future development. Furthermore, we have built a website dedicated to tracking existing systems and future advances in the field of biomedical literature search. Taken together, our work serves information seekers in choosing tools for their needs and service providers and developers in keeping current in the field. Database URL: http://www.ncbi.nlm.nih.gov/CBBresearch/Lu/search. PMID- 21245077 TI - Mortality from diabetic renal disease: a hidden epidemic. AB - BACKGROUND: Population-level mortality indicators can be useful outcome measures of diabetes care. Death registration systems serve as the main source of data for such measures. However, standard mortality indicators based on underlying causes do not adequately reflect the burden from diabetic renal disease. METHODS: This article presents findings from analysis of multiple causes of death available from death registration data for Australia and USA. Both countries use an automated system that applies prescribed rules to select and code the underlying cause for each registered death. Deaths with diabetes as underlying cause were grouped according to their diabetic complications as defined by the International Classification of Diseases. Age-standardized mortality rates were calculated for the underlying cause rubric 'diabetes with renal complications'. These were contrasted with rates calculated using additional deaths where diabetes was the underlying cause and renal failure was listed as a consequence. RESULTS: These analyses identified that current automated programmes code three-fourths of all diabetes deaths to 'diabetes without complications', despite additional factors being listed. Estimated multiple cause death rates from diabetic renal disease are four to nine times higher than underlying cause rates for 'diabetes with renal complications' in both countries; and show a rising trend in contrast to the latter. CONCLUSION: These findings indicate that routine underlying cause statistics for USA and Australia grossly under estimate mortality from diabetic renal disease. Clear guidelines on the certification, coding and statistical presentation of diabetes mortality are needed for epidemiology and health policy. PMID- 21245078 TI - Added predictive value of high-throughput molecular data to clinical data and its validation. AB - Hundreds of 'molecular signatures' have been proposed in the literature to predict patient outcome in clinical settings from high-dimensional data, many of which eventually failed to get validated. Validation of such molecular research findings is thus becoming an increasingly important branch of clinical bioinformatics. Moreover, in practice well-known clinical predictors are often already available. From a statistical and bioinformatics point of view, poor attention has been given to the evaluation of the added predictive value of a molecular signature given that clinical predictors or an established index are available. This article reviews procedures that assess and validate the added predictive value of high-dimensional molecular data. It critically surveys various approaches for the construction of combined prediction models using both clinical and molecular data, for validating added predictive value based on independent data, and for assessing added predictive value using a single data set. PMID- 21245079 TI - Base-calling for next-generation sequencing platforms. AB - Next-generation sequencing platforms are dramatically reducing the cost of DNA sequencing. With these technologies, bases are inferred from light intensity signals, a process commonly referred to as base-calling. Thus, understanding and improving the quality of sequence data generated using these approaches are of high interest. Recently, a number of papers have characterized the biases associated with base-calling and proposed methodological improvements. In this review, we summarize recent development of base-calling approaches for the Illumina and Roche 454 sequencing platforms. PMID- 21245080 TI - Hope beyond (redundant) hope: how chaplains work with dying patients. AB - Using Grounded Theory, this study examines the experience of 19 palliative care chaplains in counselling dying people. Taking a broad-based definition of counselling, and using unstructured individual interviews and group work, the study aimed to understand how palliative care chaplains work with patients at the point when it has been decided to cease active treatment, the point where they risk losing hope and falling into despair. Analysing the data using code-based theory building software, the author identified four organic moments in the chaplain-patient relationship, each moment being a discernable development in the chaplain's being-with the patient: 'evocative presence'; 'accompanying presence'; 'comforting presence'; and 'hopeful presence'. The author represents the four moments as a theory of 'chaplain as hopeful presence', and offers a description of the way in which the quality of presence can facilitate patients to develop 'a hopeful manner' in which hope is reconfigured into an attribute of being. The author concludes (with Levinas) that chaplains and other palliative care staff should be aware that simply being-with an other can, in itself, be hope fostering. PMID- 21245081 TI - Using epidemiological surveillance systems and routine data sets to study place of care and place of death: strengths and weaknesses. PMID- 21245082 TI - Cone photoreceptors are the main targets for gene therapy of NPHP5 (IQCB1) or NPHP6 (CEP290) blindness: generation of an all-cone Nphp6 hypomorph mouse that mimics the human retinal ciliopathy. AB - Leber congenital amaurosis (LCA), a severe autosomal recessive childhood blindness, is caused by mutations in at least 15 genes. The most common molecular form is a ciliopathy due to NPHP6 (CEP290) mutations and subjects have profound loss of vision. A similarly severe phenotype occurs in the related ciliopathy NPHP5 (IQCB1)-LCA. Recent success of retinal gene therapy in one form of LCA prompted the question whether we know enough about human NPHP5 and NPHP6 disease to plan such treatment. We determined that there was early-onset rapid degeneration of rod photoreceptors in young subjects with these ciliopathies. Rod outer segment (OS) lamination, when detectable, was disorganized. Retinal pigment epithelium lipofuscin accumulation indicated that rods had existed in the past in most subjects. In contrast to early rod losses, the all-cone human fovea in NPHP5 and NPHP6-LCA of all ages retained cone nuclei, albeit with abnormal inner segments and OS. The rd16 mouse, carrying a hypomorphic Nphp6 allele, was a good model of the rod-dominant human extra-foveal retina. Rd16 mice showed normal genesis of photoreceptors, including the formation of cilia, followed by abnormal elaboration of OS and rapid degeneration. To produce a model of the all-cone human fovea in NPHP6-LCA, we generated rd16;Nrl-/- double-mutant mice. They showed substantially retained cone photoreceptors with disproportionate cone function loss, such as in the human disease. NPHP5- and NPHP6-LCA across a wide age spectrum are thus excellent candidates for cone-directed gene augmentation therapy, and the rd16;Nrl-/- mouse is an appropriate model for pre-clinical proof of-concept studies. PMID- 21245083 TI - Myogenic Akt signaling attenuates muscular degeneration, promotes myofiber regeneration and improves muscle function in dystrophin-deficient mdx mice. AB - Duchenne muscular dystrophy, the most common form of childhood muscular dystrophy, is caused by X-linked inherited mutations in the dystrophin gene. Dystrophin deficiencies result in the loss of the dystrophin-glycoprotein complex at the plasma membrane, which leads to structural instability and muscle degeneration. Previously, we induced muscle-specific overexpression of Akt, a regulator of cellular metabolism and survival, in mdx mice at pre-necrotic (<3.5 weeks) ages and demonstrated upregulation of the utrophin-glycoprotein complex and protection against contractile-induced stress. Here, we found that delaying exogenous Akt treatment of mdx mice after the onset of peak pathology (>6 weeks) similarly increased the abundance of compensatory adhesion complexes at the extrasynaptic sarcolemma. Akt introduction after onset of pathology reverses the mdx histopathological measures, including decreases in blood serum albumin infiltration. Akt also improves muscle function in mdx mice as demonstrated through in vivo grip strength tests and in vitro contraction measurements of the extensor digitorum longus muscle. To further explore the significance of Akt in myofiber regeneration, we injured wild-type muscle with cardiotoxin and found that Akt induced a faster regenerative response relative to controls at equivalent time points. We demonstrate that Akt signaling pathways counteract mdx pathogenesis by enhancing endogenous compensatory mechanisms. These findings provide a rationale for investigating the therapeutic activation of the Akt pathway to counteract muscle wasting. PMID- 21245084 TI - Preferential accumulation of N-terminal mutant huntingtin in the nuclei of striatal neurons is regulated by phosphorylation. AB - An expanded polyglutamine tract (>37 glutamines) in the N-terminal region of huntingtin (htt) causes htt to accumulate in the nucleus, leading to transcriptional dysregulation in Huntington disease (HD). In HD knock-in mice that express full-length mutant htt at the endogenous level, mutant htt preferentially accumulates in the nuclei of striatal neurons, which are affected most profoundly in HD. The mechanism underlying this preferential nuclear accumulation of mutant htt in striatal neurons remains unknown. Here, we report that serine 16 (S16) in htt is important for the generation of small N-terminal fragments that are able to accumulate in the nucleus and form aggregates. Phosphorylation of N-terminal S16 in htt promotes the nuclear accumulation of small N-terminal fragments and reduces the interaction of N-terminal htt with the nuclear pore complex protein Tpr. Mouse brain striatal tissues show increased S16 phosphorylation and a decreased association between mutant N-terminal htt and Tpr. These findings provide mechanistic insight into the nuclear accumulation of mutant htt and the selective neuropathology of HD, revealing potential therapeutic targets for treating this disease. PMID- 21245085 TI - Effect of nicotine replacement therapy on agitation in smokers with schizophrenia: a double-blind, randomized, placebo-controlled study. AB - OBJECTIVE: The authors conducted a randomized, placebo-controlled study of nicotine replacement therapy for the reduction of agitation and aggression in smokers with schizophrenia. METHOD: Participants were 40 smokers 18-65 years of age admitted to a psychiatric emergency service with a diagnosis of schizophrenia confirmed by the Mini International Neuropsychiatric Interview. Patients were screened for agitation with the excited component subscale of the Positive and Negative Syndrome Scale (PANSS) and for nicotine dependence with the Fagerstrom Test for Nicotine Dependence. A score of at least 14 on the PANSS excited component subscale and at least 6 on the Fagerstrom test were required for study eligibility. Participants in the nicotine replacement group received a 21-mg nicotine transdermal patch, and those in the placebo group were treated with a placebo patch. Participants received usual care with antipsychotics. The Agitated Behavior Scale and other agitation measures were administered at baseline and again at 4 and 24 hours. RESULTS: At baseline, participants were at least moderately agitated, and 28% reported aggressive behavior in the previous week. The mean Agitated Behavior Scale score for the nicotine replacement group was 33% lower at 4 hours and 23% lower at 24 hours than for the placebo group. Participants with lower levels of nicotine dependence responded better than those with higher levels of dependence. CONCLUSIONS: The drug-placebo difference in this study was similar to that obtained in trials of parenteral antipsychotics in similar populations. This finding suggests that in patients with schizophrenia, smoking status should be included in the assessment of agitation and nicotine replacement included in the treatment of those who are smokers. PMID- 21245086 TI - Effectiveness of mental health screening and coordination of in-theater care prior to deployment to Iraq: a cohort study. AB - OBJECTIVE: The authors assessed the effectiveness of a systematic method of predeployment mental health screening to determine whether screening decreased negative outcomes during deployment in Iraq's combat setting. METHOD: Primary care providers performed directed mental health screenings during standard predeployment medical screening. If indicated, on-site mental health providers assessed occupational functioning with unit leaders and coordinated in-theater care for those cleared for deployment. Mental health-related clinical encounters and evacuations during the first 6 months of deployment in 2007 were compared for 10,678 soldiers from three screened combat brigades and 10,353 soldiers from three comparable unscreened combat brigades. RESULTS: Of 10,678 soldiers screened, 819 (7.7%, 95% confidence interval [CI]=7.2-8.2) received further mental health evaluation; of these, 74 (9.0%, 95% CI=7.1-11.0) were not cleared to deploy and 96 (11.7%, 95% CI=9.5-13.9) were deployed with additional requirements. After 6 months, soldiers in screened brigades had significantly lower rates of clinical contacts than did those in unscreened brigades for suicidal ideation (0.4%, 95% CI=0.3-0.5, compared with 0.9%, 95% CI=0.7-1.1), for combat stress (15.7%, 95% CI=15.0-16.4, compared with 22.0%, 95% CI=21.2-22.8), and for psychiatric disorders (2.9%, 95% CI=2.6-3.2, compared with 13.2%, 95% CI=12.5-13.8), as well as lower rates of occupational impairment (0.6%, 95% CI=0.4-0.7, compared with 1.8%, 95% CI=1.5-2.1) and air evacuation for behavioral health reasons (0.1%, 95% CI=0.1-0.2, compared with 0.3%, 95% CI=0.2-0.4). CONCLUSIONS: Predeployment mental health screening was associated with significant reductions in occupationally impairing mental health problems, medical evacuations from Iraq for mental health reasons, and suicidal ideation. This predeployment screening process provides a feasible system for screening soldiers and coordinating mental health support during deployment. PMID- 21245087 TI - Hippocampal volume development in healthy siblings of childhood-onset schizophrenia patients. AB - OBJECTIVE: Previous anatomic studies have established a reduction in hippocampal volume in schizophrenia, but few have investigated the progressive course of these changes and whether they are trait markers. In the present study, the authors examined hippocampal volumes in relation to age for patients with childhood-onset schizophrenia, their nonpsychotic healthy siblings, and healthy comparison subjects. METHOD: Anatomic brain magnetic resonance scans were obtained in childhood-onset schizophrenia probands (N=89, 198 scans), their nonpsychotic full siblings (N=78, 172 scans), and matched healthy comparison subjects (N=79, 198 scans) between the ages of 10 and 29 years. Total, left, and right hippocampal volumes were measured using FreeSurfer software and analyzed using a linear mixed-model regression covarying for sex and intracranial volume. RESULTS: Childhood-onset schizophrenia probands had a fixed reduction in hippocampal volumes (total, left, and right) relative to both nonpsychotic siblings and healthy comparison subjects, whereas there were no significant volumetric or trajectory differences between nonpsychotic siblings and healthy comparison subjects. CONCLUSIONS: Fixed hippocampal volume loss seen in childhood onset schizophrenia, which is not shared by healthy siblings, appears to be related to the illness. Decreased hippocampal volume is not strongly genetically related but represents an important intermediate disease phenotype. PMID- 21245088 TI - Relationship of personality disorders to the course of major depressive disorder in a nationally representative sample. AB - OBJECTIVE: The purpose of this study was to examine the effects of specific personality disorder comorbidity on the course of major depressive disorder in a nationally representative sample. METHOD: Data were drawn from 1,996 participants in a national survey. Participants who met criteria for major depressive disorder at baseline in face-to-face interviews (in 2001-2002) were reinterviewed 3 years later (in 2004-2005) to determine persistence and recurrence. Predictors included all DSM-IV personality disorders. Control variables included demographic characteristics, other axis I disorders, family and treatment histories, and previously established predictors of the course of major depressive disorder. RESULTS: A total of 15.1% of participants had persistent major depressive disorder, and 7.3% of those who remitted had a recurrence. Univariate analyses indicated that avoidant, borderline, histrionic, paranoid, schizoid, and schizotypal personality disorders all elevated the risk for persistence. With axis I comorbidity controlled, all personality disorders except histrionic personality disorder remained significant. With all other personality disorders controlled, borderline and schizotypal disorders remained significant predictors. In final, multivariate analyses that controlled for age at onset of major depressive disorder, the number of previous episodes, duration of the current episode, family history, and treatment, borderline personality disorder remained a robust predictor of major depressive disorder persistence. Neither personality disorders nor other clinical variables predicted recurrence. CONCLUSIONS: In this nationally representative sample of adults with major depressive disorder, borderline personality disorder robustly predicted persistence, a finding that converges with recent clinical studies. Personality psychopathology, particularly borderline personality disorder, should be assessed in all patients with major depressive disorder, considered in prognosis, and addressed in treatment. PMID- 21245089 TI - GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. AB - PURPOSE: Despite their preclinical promise, previous MEK inhibitors have shown little benefit for patients. This likely reflects the narrow therapeutic window for MEK inhibitors due to the essential role of the P42/44 MAPK pathway in many nontumor tissues. GSK1120212 is a potent and selective allosteric inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes with promising antitumor activity in a phase I clinical trial (ASCO 2010). Our studies characterize GSK1120212' enzymatic, cellular, and in vivo activities, describing its unusually long circulating half life. EXPERIMENTAL DESIGN: Enzymatic studies were conducted to determine GSK1120212 inhibition of recombinant MEK, following or preceding RAF kinase activation. Cellular studies examined GSK1120212 inhibition of ERK1 and 2 phosphorylation (p-ERK1/2) as well as MEK1/2 phosphorylation and activation. Further studies explored the sensitivity of cancer cell lines, and drug pharmacokinetics and efficacy in multiple tumor xenograft models. RESULTS: In enzymatic and cellular studies, GSK1120212 inhibits MEK1/2 kinase activity and prevents Raf-dependent MEK phosphorylation (S217 for MEK1), producing prolonged p ERK1/2 inhibition. Potent cell growth inhibition was evident in most tumor lines with mutant BRAF or Ras. In xenografted tumor models, GSK1120212 orally dosed once daily had a long circulating half-life and sustained suppression of p-ERK1/2 for more than 24 hours; GSK1120212 also reduced tumor Ki67, increased p27(Kip1/CDKN1B), and caused tumor growth inhibition in multiple tumor models. The largest antitumor effect was among tumors harboring mutant BRAF or Ras. CONCLUSIONS: GSK1120212 combines high potency, selectivity, and long circulating half-life, offering promise for successfully targeting the narrow therapeutic window anticipated for clinical MEK inhibitors. PMID- 21245091 TI - An antibody-drug conjugate targeting the endothelin B receptor for the treatment of melanoma. AB - PURPOSE: To identify and evaluate targets amenable to antibody therapy in melanoma. EXPERIMENTAL DESIGN: We searched for mRNA transcripts coding for cell surface proteins with expression patterns similar to that of the melanoma oncogene MITF. One such candidate, the endothelin B receptor (EDNBR), was first analyzed for a functional contribution to tumor growth by conditional induction of shRNA. Second, antibodies were raised to the receptor, conjugated with monomethyl auristatin E, and tested for efficacy against melanoma tumor models generated from cell lines. RESULTS: Conditional knockdown of the receptor in tumor xenograft models resulted in only a modest impact on tumor growth. A monoclonal antibody reactive with the N-terminal tail of EDNBR was found to internalize rapidly into melanoma cells. When conjugated with monomethyl auristatin E, the antibody-drug conjugate (ADC) showed remarkable efficacy against human melanoma cell lines and xenograft tumor models that was commensurate with levels of receptor expression. Comparative immunohistochemistry revealed a range of EDNBR expression across a panel of human melanomas, with the majority expressing levels equivalent to or greater than that in the models responsive to the ADC. CONCLUSION: An ADC targeting the EDNBR is highly efficacious in preclinical models of melanoma. PMID- 21245090 TI - Imaging colon cancer response following treatment with AZD1152: a preclinical analysis of [18F]fluoro-2-deoxyglucose and 3'-deoxy-3'-[18F]fluorothymidine imaging. AB - PURPOSE: To determine whether treatment response to the Aurora B kinase inhibitor, AZD1152, could be monitored early in the course of therapy by noninvasive [(18)F]-labeled fluoro-2-deoxyglucose, [(18)F]FDG, and/or 3'-deoxy-3' [(18)F]fluorothymidine, [(18)F]FLT, PET imaging. EXPERIMENTAL DESIGN: AZD1152 treated and control HCT116 and SW620 xenograft-bearing animals were monitored for tumor size and by [(18)F]FDG, and [(18)F]FLT PET imaging. Additional studies assessed the endogenous and exogenous contributions of thymidine synthesis in the two cell lines. RESULTS: Both xenografts showed a significant volume-reduction to AZD1152. In contrast, [(18)F]FDG uptake did not demonstrate a treatment response. [(18)F]FLT uptake decreased to less than 20% of control values in AZD1152-treated HCT116 xenografts, whereas [(18)F]FLT uptake was near background levels in both treated and untreated SW620 xenografts. The EC(50) for AZD1152-HQPA was approximately 10 nmol/L in both SW620 and HCT116 cells; in contrast, SW620 cells were much more sensitive to methotrexate (MTX) and 5-Fluorouracil (5FU) than HCT116 cells. Immunoblot analysis demonstrated marginally lower expression of thymidine kinase in SW620 compared with HCT116 cells. The aforementioned results suggest that SW620 xenografts have a higher dependency on the de novo pathway of thymidine utilization than HCT116 xenografts. CONCLUSIONS: AZD1152 treatment showed antitumor efficacy in both colon cancer xenografts. Although [(18)F]FDG PET was inadequate in monitoring treatment response, [(18)F]FLT PET was very effective in monitoring response in HCT116 xenografts, but not in SW620 xenografts. These observations suggest that de novo thymidine synthesis could be a limitation and confounding factor for [(18)F]FLT PET imaging and quantification of tumor proliferation, and this may apply to some clinical studies as well. PMID- 21245092 TI - Retraction. The chemokine receptor CXCR6 and its ligand CXCL16 are expressed in carcinomas and inhibit proliferation. PMID- 21245093 TI - Dual IGF-I/II-neutralizing antibody MEDI-573 potently inhibits IGF signaling and tumor growth. AB - Insulin-like growth factors (IGF), IGF-I and IGF-II, are small polypeptides involved in regulating cell proliferation, survival, differentiation, and transformation. IGF activities are mediated through binding and activation of IGF 1R or insulin receptor isoform A (IR-A). The role of the IGF-1R pathway in promoting tumor growth and survival is well documented. Overexpression of IGF-II and IR-A is reported in multiple types of cancer and is proposed as a potential mechanism for cancer cells to develop resistance to IGF-1R-targeting therapy. MEDI-573 is a fully human antibody that neutralizes both IGF-I and IGF-II and inhibits IGF signaling through both the IGF-1R and IR-A pathways. Here, we show that MEDI-573 blocks the binding of IGF-I and IGF-II to IGF-1R or IR-A, leading to the inhibition of IGF-induced signaling pathways and cell proliferation. MEDI 573 significantly inhibited the in vivo growth of IGF-I- or IGF-II-driven tumors. Pharmacodynamic analysis demonstrated inhibition of IGF-1R phosphorylation in tumors in mice dosed with MEDI-573, indicating that the antitumor activity is mediated via inhibition of IGF-1R signaling pathways. Finally, MEDI-573 significantly decreased (18)F-fluorodeoxyglucose ((18)F-FDG) uptake in IGF-driven tumor models, highlighting the potential utility of (18)F-FDG-PET as a noninvasive pharmacodynamic readout for evaluating the use of MEDI-573 in the clinic. Taken together, these results demonstrate that the inhibition of IGF-I and IGF-II ligands by MEDI-573 results in potent antitumor activity and offers an effective approach to selectively target both the IGF-1R and IR-A signaling pathways. PMID- 21245095 TI - Notch3 activation promotes invasive glioma formation in a tissue site-specific manner. AB - Although Notch signaling has been widely implicated in neoplastic growth, direct evidence for in vivo initiation of neoplasia by the pathway in murine models has been limited to tumors of lymphoid, breast, and choroid plexus cells. To examine tumorigenic potential in the eye and brain, we injected retroviruses encoding activated forms of Notch1, Notch2, or Notch3 into embryonic mice. Interestingly, the majority of animals infected with active Notch3 developed proliferative lesions comprised of pigmented ocular choroid cells, retinal and optic nerve glia, and lens epithelium. Notch3-induced lesions in the choroid, retina, and optic nerve were capable of invading adjacent tissues, suggesting that they were malignant tumors. Although Notch3 activation induced choroidal tumors in up to 67% of eyes, Notch1 or Notch2 activation never resulted in such tumors. Active forms of Notch1 and Notch2 did generate a few small proliferative glial nodules in the retina and optic nerve, whereas Notch3 was 10-fold more efficient at generating growths, many of which were large invasive gliomas. Expression of active Notch1/Notch3 chimeric receptors implicated the RBPjk-association molecule and transactivation domains of Notch3 in generating choroidal and glial tumors, respectively. In contrast to our findings in the optic nerve and retina, introduction of active Notch receptors, including Notch3, into the brain never caused glial tumors. Our results highlight the differential ability of Notch receptor paralogs to initiate malignant tumor formation, and suggest that glial precursors of the optic nerve, but not the brain, are susceptible to transformation by Notch3. PMID- 21245096 TI - LATS2 is a tumor suppressor gene of malignant mesothelioma. AB - Malignant mesothelioma (MM) is an aggressive neoplasm associated with asbestos exposure. We carried out genome-wide array-based comparative genomic hybridization analysis with 14 MM cell lines. Three cell lines showed overlapping homozygous deletion at chromosome 13q12, which harbored the LATS2 (large tumor suppressor homolog 2) gene. With 6 other MM cell lines and 25 MM tumors, we found 10 inactivating homozygous deletions or mutations of LATS2 among 45 MMs. LATS2 encodes a serine/threonine kinase, a component of the Hippo tumor-suppressive signaling pathway, and we transduced LATS2 in MM cells with its mutation. Transduction of LATS2 inactivated oncoprotein YAP, a transcriptional coactivator, via phosphorylation, and inhibited MM cell growth. We also analyzed LATS2 immunohistochemically and found that 13 of 45 MM tumors had low expression of LATS2. Because NF2 is genetically mutated in 40% to 50% of MM, our data indicate that Hippo pathway dysregulation is frequent in MM cells with inactivation of LATS2 or an upstream regulator of this pathway, Merlin, which is encoded by NF2. Thus, our results suggest that the inactivation of LATS2 is one of the key mechanisms for constitutive activation of YAP, which induces deregulation of MM cell proliferation. PMID- 21245094 TI - Smad4 inactivation promotes malignancy and drug resistance of colon cancer. AB - SMAD4 is localized to chromosome 18q21, a frequent site for loss of heterozygosity in advanced stage colon cancers. Although Smad4 is regarded as a signaling mediator of the TGFbeta signaling pathway, its role as a major suppressor of colorectal cancer progression and the molecular events underlying this phenomenon remain elusive. Here, we describe the establishment and use of colon cancer cell line model systems to dissect the functional roles of TGFbeta and Smad4 inactivation in the manifestation of a malignant phenotype. We found that loss of function of Smad4 and retention of intact TGFbeta receptors could synergistically increase the levels of VEGF, a major proangiogenic factor. Pharmacologic inhibition studies suggest that overactivation of the TGFbeta induced MEK-Erk and p38-MAPK (mitogen-activated protein kinase) auxiliary pathways are involved in the induction of VEGF expression in SMAD4 null cells. Overall, SMAD4 deficiency was responsible for the enhanced migration of colon cancer cells with a corresponding increase in matrix metalloprotease 9 enhanced hypoxia-induced GLUT1 expression, increased aerobic glycolysis, and resistance to 5'-fluoruracil-mediated apoptosis. Interestingly, Smad4 specifically interacts with hypoxia-inducible factor (HIF) 1alpha under hypoxic conditions providing a molecular basis for the differential regulation of target genes to suppress a malignant phenotype. In summary, our results define a molecular mechanism that explains how loss of the tumor suppressor Smad4 promotes colorectal cancer progression. These findings are also consistent with targeting TGFbeta-induced auxiliary pathways, such as MEK-ERK, and p38-MAPK and the glycolytic cascade, in SMAD4-deficient tumors as attractive strategies for therapeutic intervention. PMID- 21245097 TI - Alpha- versus beta-particle radiopeptide therapy in a human prostate cancer model (213Bi-DOTA-PESIN and 213Bi-AMBA versus 177Lu-DOTA-PESIN). AB - Recurrent prostate cancer presents a challenge to conventional treatment, particularly so to address micrometastatic and small-volume disease. Use of alpha radionuclide therapy is considered as a highly effective treatment in such applications due to the shorter range and exquisite cytotoxicity of alpha particles as compared with beta-particles. (213)Bi is considered an alpha-emitter with high clinical potential, due to its short half-life (45.6 minutes) being well matched for use in peptide-receptor radionuclide alpha-therapy; however, there is limited knowledge available within this context of use. In this study, two novel (213)Bi-labeled peptides, DOTA-PEG(4)-bombesin (DOTA-PESIN) and DO3A CH(2)CO-8-aminooctanoyl-Q-W-A-V-G-H-L-M-NH(2) (AMBA), were compared with (177)Lu (beta-emitter)-labeled DOTA-PESIN in a human androgen-independent prostate carcinoma xenograft model (PC-3 tumor). Animals were injected with (177)Lu-DOTA PESIN, (213)Bi-DOTA-PESIN, or (213)Bi-AMBA to determine the maximum tolerated dose (MTD), biodistribution, and dosimetry of each agent; controls were left untreated or were given nonradioactive (175)Lu-DOTA-PESIN. The MTD of (213)Bi DOTA-PESIN and (213)Bi-AMBA was 25 MBq (0.68 mCi) whereas (177)Lu-DOTA-PESIN showed an MTD of 112 MBq (3 mCi). At these dose levels, (213)Bi-DOTA-PESIN and (213)Bi-AMBA were significantly more effective than (177)Lu-DOTA-PESIN. At the same time, (177)Lu-DOTA-PESIN showed minimal, (213)Bi-DOTA-PESIN slight, and (213)Bi-AMBA marked kidney damage 20 to 30 weeks posttreatment. These preclinical data indicate that alpha-therapy with (213)Bi-DOTA-PESIN or (213)Bi-AMBA is more efficacious than beta-therapy. Furthermore, (213)Bi-DOTA-PESIN has a better safety profile than (213)Bi-AMBA, and represents a possible new approach for use in peptide-receptor radionuclide alpha-therapy treating recurrent prostate cancer. PMID- 21245098 TI - Tumor cell invasion is promoted by interstitial flow-induced matrix priming by stromal fibroblasts. AB - Interstitial flow emanates from tumors into the microenvironment where it promotes tumor cell invasion. Fibroblasts are key constituents of the tumor stroma that modulate the mechanical environment by matrix remodeling and contraction. Here, we explore how interstitial fluid flow affects fibroblast tumor cell interactions. Using a 3-dimensional invasion assay and MDA-MB-435S cells cocultured with dermal fibroblasts in a collagen matrix, we showed a synergistic enhancement of tumor cell invasion by fibroblasts in the presence of interstitial flow. Interstitial flow also drove transforming growth factor (TGF) beta1 and collagenase-dependent fibroblast migration, consistent with previously described mechanisms in which flow promotes invasion through autologous chemotaxis and increased motility. Concurrently, migrating fibroblasts enhanced tumor cell invasion by matrix priming via Rho-mediated contraction. We propose a model in which interstitial flow promotes fibroblast migration through increased TGF-beta1 activation and collagen degradation, positioning fibroblasts to locally reorganize collagen fibers via Rho-dependent contractility, in turn enhancing tumor cell invasion via mechanotactic cues. This represents a novel mechanism in which interstitial flow causes fibroblast-mediated stromal remodeling that facilitates tumor invasion. PMID- 21245099 TI - Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1 dependent manner. AB - The proapoptotic protein Noxa, a member of the BH3-only Bcl-2 protein family, can effectively induce apoptosis in cancer cells, although the relevant regulatory pathways have been obscure. Previous studies of the cytotoxic effects of alpha tocopheryl succinate (alpha-TOS) on cancer cells identified a mechanism whereby alpha-TOS caused apoptosis requiring the Noxa-Bak axis. In the present study, ab initio analysis revealed a conserved FoxO-binding site (DBE; DAF-16 binding element) in the NOXA promoter, and specific affinity of FoxO proteins to this DBE was confirmed by fluorescence anisotropy. FoxO1 and FoxO3a proteins accumulated in the nucleus of alpha-TOS-treated cells, and the drug-induced specific FoxO1 association with the NOXA promoter and its activation were validated by chromatin immunoprecipitation. Using siRNA knockdown, a specific role for the FoxO1 protein in activating NOXA transcription in cancer cells was identified. Furthermore, the proapoptotic kinase Hippo/Mst1 was found to be strongly activated by alpha-TOS, and inhibiting Hippo/Mst1 by specific siRNA prevented phosphorylation of FoxO1 and its nuclear translocation, thereby reducing levels of NOXA transcription and apoptosis in cancer cells exposed to alpha-TOS. Thus, we have demonstrated that anticancer drugs, exemplified by alpha-TOS, induce apoptosis by a mechanism involving the Hippo/Mst1-FoxO1-Noxa pathway. We propose that activation of this pathway provides a new paradigm for developing targeted cancer treatments. PMID- 21245101 TI - Prediction and genetic demonstration of a role for activator E2Fs in Myc-induced tumors. AB - Advances in genomic signatures have begun to dissect breast cancer heterogeneity and application of these signatures will allow the prediction of which pathways are important in tumor development. Here we used genomic signatures to predict involvement of specific E2F transcription factors in Myc-induced tumors. We genetically tested this prediction by interbreeding Myc transgenics with mice lacking various activator E2F alleles. Tumor latency decreased in the E2F1 mutant background and significantly increased in both the E2F2 and E2F3 mutants. Investigating the mechanism behind these changes revealed a reduction in apoptosis in the E2F1 knockout strain. E2F2 and E2F3 mutant backgrounds alleviated Myc proliferative effects on the pregnant mammary gland, reducing the susceptible tumor target population. Gene expression data from tumors revealed that the E2F2 knockout background resulted in fewer tumors with EMT, corresponding with a reduction in probability of Ras activation. In human breast cancer we found that a low probability of E2F2 pathway activation was associated with increased relapse-free survival time. Together these data illustrate the predictive utility of genomic signatures in deciphering the heterogeneity within breast cancer and illustrate the unique genetic requirements for individual E2Fs in mediating tumorigenesis in both mouse models and human breast cancer. PMID- 21245100 TI - Functional activation of the estrogen receptor-alpha and aromatase by the HDAC inhibitor entinostat sensitizes ER-negative tumors to letrozole. AB - Approximately 25% of breast cancers do not express the estrogen receptor-alpha (ERalpha) and consequently do not respond to endocrine therapy. In these tumors, ERalpha repression is often due to epigenetic modifications such as methylation and histone deacetylation. For this reason, we investigated the ability of the histone deacetylase inhibitor entinostat (ENT) to trigger reexpression of ERalpha and aromatase in breast cancer cells, with the notion that this treatment would restore sensitivity to the aromatase inhibitor (AI) letrozole. ENT treatment of tumor cells increased expression of ERalpha and aromatase, along with the enzymatic activity of aromatase, in a dose-dependent manner both in vitro and in vivo. Notably, ERalpha and aromatase upregulation resulted in sensitization of breast cancer cells to estrogen and letrozole. Tumor growth rate was significantly lower in tumor xenografts following treatment with ENT alone and in combination with letrozole than in control tumors (P > 0.001). ENT plus letrozole also prevented lung colonization and growth of tumor cells, with a significant reduction (P > 0.03) in both visible and microscopic foci. Our results show that ENT treatment can be used to restore the letrozole responsiveness of ER-negative tumors. More generally, they provide a strong rationale for immediate clinical evaluation of combinations of histone deacetylase and aromatase inhibitors to treat ER-negative and endocrine-resistant breast cancers. PMID- 21245102 TI - Deoxycytidine kinase modulates the impact of the ABC transporter ABCG2 on clofarabine cytotoxicity. AB - Purine nucleoside antimetabolites, such as clofarabine, are effective antileukemic agents. However, their effectiveness depends on an initial activation step in which they are monophosphorylated by deoxycytidine kinase (dCK). Some purine nucleoside antimetabolites and their monophosphate derivatives are exported by the ABC transporter ABCG2. Because clofarabine is a dCK substrate, and we show substantial variation in dCK and ABCG2 in myeloid leukemia, we hypothesized that the activity of dCK may modulate ABCG2-mediated resistance to clofarabine by regulating the formation of clofarabine monophosphate. We show that ABCG2 influence on clofarabine cytotoxicity was markedly influenced by dCK activity. When dCK expression was reduced by siRNA, clofarabine cytotoxicity was strongly reduced by enhanced ABCG2-mediated efflux. Conversely, dCK overexpression blunted ABCG2-mediated efflux of clofarabine by increasing the formation of clofarabine nucleotides. The use of an ABCG2 inhibitor confirmed that ABCG2 export of clofarabine is maximal when dCK levels are minimal. Analysis of intracellular clofarabine metabolites suggested that ABCG2 exported clofarabine more readily than clofarabine monophosphate. That ABCG2 primarily effluxes clofarabine, but not chlorfarabine-monophosphate, was confirmed by HPLC analysis of drug exported from ABCG2-overexpressing cells. Because the level and function of dCK and ABCG2 vary substantially among other types of cancer, these findings have important implications not only for clofarabine therapy but for purine nucleoside therapy in general. Therefore, we propose that addition of ABCG2 inhibitors would effectively increase the antitumor efficacy of purine nucleosides by blocking drug efflux that may be a significant mode of resistance when dCK levels are low. PMID- 21245103 TI - Targeted signal-amplifying enzymes enhance MRI of EGFR expression in an orthotopic model of human glioma. AB - Epidermal growth factor receptor (EGFR) imaging in brain tumors is essential to visualize overexpression of EGFRvIII variants as a signature of highly aggressive gliomas and to identify patients that would benefit from anti-EGFR therapy. Seeking imaging improvements, we tested a novel pretargeting approach that relies on initial administration of enzyme-linked anti-EGFR monoclonal antibodies (mAb; EMD72000) followed by administration of a low-molecular-weight paramagnetic molecule (diTyr-GdDTPA) retained at the site of EGFR mAb accumulation. We hypothesized that diTyr-GdDTPA would become enzyme activated and retained on cells due to binding to tissue proteins. In support of this hypothesis, mAb enzyme conjugates reacted with both membrane-isolated wild-type (wt) EGFR and EGFRvIII, but they bound primarily to EGFRvIII-expressing cells and not to EGFRwt expressing cells. In vivo analysis of magnetic resonance (MR) tumor signal revealed differences in MR signal decay following diTyr-GdDTPA substrate administration. These differences were significant in that they suggested differences in substrate elimination from the tissue which relied on the specificity of the initial mAb binding: a biexponential signal decay was observed in tumors only upon preinjection with EGFR-targeted conjugates. Endpoint MRI in this setting revealed detailed images of tumors which correlated with immunohistochemical detection of EGFR expression. Together, our findings suggest an improved method to identify EGFRvIII-expressing gliomas in vivo that are best suited for treatment with therapeutic EGFR antibodies. PMID- 21245104 TI - American Heart Association and nonprofit advocacy: past, present, and future. A policy recommendation from the American Heart Association. PMID- 21245107 TI - Transplantations fall in Israel as new law complicates procedures. PMID- 21245105 TI - Evaluation of large scale quantitative proteomic assay development using peptide affinity-based mass spectrometry. AB - Stable isotope standards and capture by antipeptide antibodies (SISCAPA) couples affinity enrichment of peptides with stable isotope dilution and detection by multiple reaction monitoring mass spectrometry to provide quantitative measurement of peptides as surrogates for their respective proteins. In this report, we describe a feasibility study to determine the success rate for production of suitable antibodies for SISCAPA assays in order to inform strategies for large-scale assay development. A workflow was designed that included a multiplex immunization strategy in which up to five proteotypic peptides from a single protein target were used to immunize individual rabbits. A total of 403 proteotypic tryptic peptides representing 89 protein targets were used as immunogens. Antipeptide antibody titers were measured by ELISA and 220 antipeptide antibodies representing 89 proteins were chosen for affinity purification. These antibodies were characterized with respect to their performance in SISCAPA-multiple reaction monitoring assays using trypsin-digested human plasma matrix. More than half of the assays generated were capable of detecting the target peptide at concentrations of less than 0.5 fmol/MUl in human plasma, corresponding to protein concentrations of less than 100 ng/ml. The strategy of multiplexing five peptide immunogens was successful in generating a working assay for 100% of the targeted proteins in this evaluation study. These results indicate it is feasible for a single laboratory to develop hundreds of assays per year and allow planning for cost-effective generation of SISCAPA assays. PMID- 21245109 TI - Brazil puts emergency medical plan into action. PMID- 21245112 TI - Cameron defends moving NHS "from closed markets to open systems". PMID- 21245111 TI - Australia faces huge rebuild after devastating floods. PMID- 21245113 TI - New oral anticoagulants for thromboprophylaxis in patients having hip or knee arthroplasty. PMID- 21245115 TI - Regulator drops cases against pharmacies offering homoeopathic malaria prophylaxis. PMID- 21245117 TI - Optimality of the Munch mechanism for translocation of sugars in plants. AB - Plants require effective vascular systems for the transport of water and dissolved molecules between distal regions. Their survival depends on the ability to transport sugars from the leaves where they are produced to sites of active growth; a flow driven, according to the Munch hypothesis, by osmotic gradients generated by differences in sugar concentration. The length scales over which sugars are produced (Lleaf) and over which they are transported (L(stem)), as well as the radius r of the cylindrical phloem cells through which the transport takes place, vary among species over several orders of magnitude; a major unsettled question is whether the Munch transport mechanism is effective over this wide range of sizes. Optimization of translocation speed predicts a scaling relation between radius r and the characteristic lengths as r~(Lleaf Lstem)1/3. Direct measurements using novel in vivo techniques and biomimicking microfluidic devices support this scaling relation and provide the first quantitative support for a unified mechanism of sugar translocation in plants spanning several orders of magnitude in size. The existence of a general scaling law for phloem dimensions provides a new framework for investigating the physical principles governing the morphological diversity of plants. PMID- 21245118 TI - Secrets of the MMR scare. The Lancet's two days to bury bad news. PMID- 21245120 TI - Assuring research integrity in the wake of Wakefield. PMID- 21245119 TI - Headache, migraine, and structural brain lesions and function: population based Epidemiology of Vascular Ageing-MRI study. AB - OBJECTIVE: To evaluate the association of overall and specific headaches with volume of white matter hyperintensities, brain infarcts, and cognition. DESIGN: Population based, cross sectional study. SETTING: Epidemiology of Vascular Ageing study, Nantes, France. PARTICIPANTS: 780 participants (mean age 69, 58.5% women) with detailed headache assessment. MAIN OUTCOME MEASURES: Brain scans were evaluated for volume of white matter hyperintensities (by fully automated imaging processing) and for classification of infarcts (by visual reading with a standardised assessment grid). Cognitive function was assessed by a battery of tests including the mini-mental state examination. RESULTS: 163 (20.9%) participants reported a history of severe headache and 116 had migraine, of whom 17 (14.7%) reported aura symptoms. An association was found between any history of severe headache and increasing volume of white matter hyperintensities. The adjusted odds ratio of being in the highest third for total volume of white matter hyperintensities was 2.0 (95% confidence interval 1.3 to 3.1, P for trend 0.002) for participants with any history of severe headache when compared with participants without severe headache being in the lowest third. The association pattern was similar for all headache types. Migraine with aura was the only headache type strongly associated with volume of deep white matter hyperintensities (highest third odds ratio 12.4, 1.6 to 99.4, P for trend 0.005) and with brain infarcts (3.4, 1.2 to 9.3). The location of infarcts was predominantly outside the cerebellum and brain stem. Evidence was lacking for cognitive impairment for any headache type with or without brain lesions. CONCLUSIONS: In this population based study, any history of severe headache was associated with an increased volume of white matter hyperintensities. Migraine with aura was the only headache type associated with brain infarcts. Evidence that headache of any type by itself or in combination with brain lesions was associated with cognitive impairment was lacking. PMID- 21245122 TI - Travel websites should highlight malaria risks. PMID- 21245124 TI - Food and Drug Administration commentary on methodological issues in negative symptom trials. PMID- 21245125 TI - Langerhans cell histiocytosis: an orphan disease. PMID- 21245126 TI - Morphological and functional 3-Tesla magnetic resonance imaging of saphenous vein coronary artery bypass grafts. AB - Evaluation of a novel non-invasive tool for postoperative follow-up of patients postelective saphenous vein coronary artery bypass graft (CABG) was performed. Ten patients were included. Their bypass grafts supplied the right coronary artery (7), marginal branches (1), diagonal branches (2), and the circumflex artery (n=1). Each bypass was examined intraoperatively using Doppler flow measurement. Patients were examined with a 3-Tesla magnetic resonance imaging (MRI) scanner (MAGNETOM Verio, Siemens, Erlangen, Germany) within one week postsurgery using MR-angiography with an intravasal contrast agent and velocity encoded phase-contrast flow measurements. Intraoperative Doppler flow measurements revealed regular flow patterns in all vascular territories supplied. The median intraoperative flow rate was 50 ml/min with an inter-quartile range (IQR) of 42-70 ml/min. The clinical postoperative course was uneventful. MRI showed all grafts to be patent. The median postoperative flow rate was 50 ml/min (IQR: 32-65 ml/min). MRI flow rates agreed well with intraoperative Doppler flow measurements (mean difference: -2.8+/-20.1 ml/min). This initial study demonstrates that 3-Tesla MRI flow measurements correlated well with Doppler thus reconfirming the graft patency postCABG. Further refinement and broader application of this technique may facilitate follow-up postCABG potentially replacing empiric clinical judgment by reliable non-invasive imaging. PMID- 21245128 TI - Hepcidin as well as TNF-alpha are significant predictors of arterial stiffness in patients on maintenance hemodialysis. AB - BACKGROUND: Dysregulated iron metabolism has been suspected to be linked to anemia of chronic disease and to cardiovascular disease (CVD). For the purpose of clarifying the factors affecting arterial stiffness, we evaluated the relationship between iron metabolism, brachial-ankle (ba)-pulse wave velocity (PWV) and several risk factors for CVD in maintenance hemodialysis (MHD) patients. METHODS: A total of 168 MHD patients were recruited, and the levels of iron parameters, hepcidin, CVD risk factors and ba-PWV were evaluated. The level of serum hepcidin-25 was specifically measured by liquid chromatography-tandem mass spectrometry. RESULTS: Serum levels of tumor necrosis factor-alpha (TNF alpha), interleukin-6 (IL-6) and hepcidin were higher in MHD patients, which was consistent with results from our previous study. ba-PWV significantly correlated with age (P < 0.01, R = 0.34), total cholesterol (T-CHO; P = 0.02, R = 0.21), TNF alpha (P < 0.01, R = 0.24) and hepcidin (P < 0.01, R = 0.25) but not with other iron parameters and CVD risk factors. According to multiple regression analysis, age (beta = 0.30), T-CHO (beta = 0.24) TNF-alpha (beta = 0.19) and hepcidin (beta = 0.23) were selected as the significant predictors of ba-PWV in MHD patients. CONCLUSION: Serum levels of both hepcidin and TNF-alpha are independently associated with arterial stiffness in MHD patients, suggesting that microinflammation and iron metabolism might affect the integrity of arterial walls. PMID- 21245127 TI - Oral activated charcoal adsorbent (AST-120) ameliorates extent and instability of atherosclerosis accelerated by kidney disease in apolipoprotein E-deficient mice. AB - BACKGROUND: Accelerated atherosclerosis and increased cardiovascular events are not only more common in chronic kidney disease (CKD) but are more resistant to therapeutic interventions effective in the general population. The oral charcoal adsorbent, AST-120, currently used to delay start of dialysis, reduces circulating and tissue uremic toxins, which may contribute to vasculopathy, including atherosclerosis. We, therefore, investigated whether AST-120 affects CKD-induced atherosclerosis. METHODS: Apolipoprotein E-deficient mice, a model of atherosclerosis, underwent uninephrectomy, subtotal nephrectomy or sham operation at 8 weeks of age and were treated with AST-120 after renal ablation. Atherosclerosis and its characteristics were assessed at 25 weeks of age. RESULTS: Uninephrectomy and subtotal nephrectomised mice had significantly increased acceleration of atherosclerosis. AST-120 treatment dramatically reduced the atherosclerotic burden in mice with kidney damage, while there was no beneficial effect in sham-operated mice. The benefit was independent of blood pressure, serum total cholesterol or creatinine clearance. AST-120 significantly decreased necrotic areas and lessened aortic deposition of the uremic toxin indoxyl sulfate without affecting lesional macrophage or collagen content. Furthermore, AST-120 lessened aortic expression of monocyte chemoattractant protein-1, tumor necrosis factor-alpha and interleukin-1beta messenger RNA. CONCLUSIONS: AST-120 lessens the extent of atherosclerosis induced by kidney injury and alters lesion characteristics in apolipoprotein E-deficient mice, resulting in plaques with a more stable phenotype with less necrosis and reduced inflammation. PMID- 21245129 TI - Polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) are associated with the progression of IgA nephropathy in Chinese. AB - BACKGROUND: IgA nephropathy (IgAN) is the leading cause of end-stage renal disease (ESRD) in China considering different compositions of ESRD causes in different ethnicities. A recent genome-wide association study (GWAS) indicated that the MYH9 gene was significantly associated with non-diabetic ESRD in African Americans and also influenced kidney function in Europeans. Thus, in the present study, we aim to clarify whether MYH9 confers a shared mechanism among different causes of ESRD and to seek possible further insight into our understanding of IgAN by applying GWAS data from ESRD to IgAN. METHODS: One thousand one hundred and sixteen Chinese, including 527 patients with renal biopsy-proven IgAN and 589 healthy controls, were enrolled in the present study. Four single neucleotide polymorphisms (SNPs) (rs3752462, rs4821480, rs11089788 and rs2413396) reported to be associated with ESRD with the most significance were genotyped by TaqMan assay or a restriction fragment length polymorphism assay for a further case-control study. RESULTS: None of the four SNPs was associated with the susceptibility to IgAN or clinical and pathological characters at the time of renal biopsy. However, estimated glomerular filtration rate decline rate was associated with rs11089788 in the dominant model (P = 0.021). Cox regression showed that rs11089788 (hazard ratio, 3.95; 95% confidence interval, 1.23-12.63; P = 2.1 * 10(-2)) was an independent predictive factor for renal survival. CONCLUSIONS: Based on a large Chinese IgAN cohort, we found an association between rs11089788 and prognosis of IgAN, adding to the mounting evidence of MYH9 as an important gene in IgAN to ESRD. PMID- 21245130 TI - Long-term effects of high-efficiency on-line haemodiafiltration on uraemic toxicity. A multicentre prospective randomized study. AB - BACKGROUND: Haemodiafiltration (HDF) may improve survival of chronic dialysis patients. This prospective, multicentre randomized cross-over study evaluated the effects of long-term on-line HDF on the levels of solutes of different molecular weight markers or causative agents of the most common metabolic derangements in uraemia. METHODS: Sixty-nine patients from eight Italian centres were randomly assigned to two 6-month treatment sequences: A-B and B-A [A, low-flux haemodialysis (HD) and B, on-line HDF]. Comparative evaluation of basal levels of small, medium-sized and protein-bound solutes at the end of the two treatment periods and analysis of parameters dependence during the interventions were performed. RESULTS: On-line HDF showed greater efficiency than low-flux HD in removing small solutes (eKt/Vurea 1.60 +/- 0.31 versus 1.44 +/- 0.26, P < 0.0001) and in reducing basal levels of beta2-microglobulin (22.2 +/- 7.8 versus 33.5 +/- 11.8 mg/L, P < 0.0001), total homocysteine (15.4 +/- 5.0 versus 18.7 +/- 8.2 MUmol/L, P = 0 .003), phosphate (4.6 +/- 1.3 versus 5.0 +/- 1.4 mg/dL, P = 0.008) and, remarkably, of intact parathyroid hormone (202 +/- 154 versus 228 +/- 176 pg/mL, P = 0.03). Moreover, in on-line HDF, lower levels of C-reactive protein (5.5 +/- 5.5 versus 6.7 +/- 6.1 mg/L, P = 0.03) and triglycerides (148 +/- 77 versus 167 +/- 87 mg/dL, P = 0.008) and increased HDL cholesterol (49.2 +/- 12.7 versus 44.7 +/- 12.4 mg/dL, P = <0.0001) were observed. The asymmetric dimethylarginine level was not significantly affected (0.97 +/- 0.4 versus 0.84 +/- 0.37 MUmol/L). Erythropoietin and phosphate binders' doses could be reduced. CONCLUSIONS: On-line high-efficiency HDF resulted in enhanced removal and lower basal levels of small, medium-sized and protein-bound solutes, which are markers or causative agents of uraemic pathologies, mainly inflammation, secondary hyperparathyroidism and dyslipidaemia. This may contribute to reducing uraemic complications and possibly to improving patient survival. PMID- 21245131 TI - Global variation in renal replacement therapy for end-stage renal disease. AB - BACKGROUND: Incidence rates of renal replacement therapy (RRT) for end-stage renal disease vary considerably worldwide. This study examines the independent association between the general population, health care system and renal service characteristics and RRT incidence rates. METHODS: RRT incidence data (2003-2005) were obtained from renal registries; general population age and health and macroeconomic indices were collected from secondary sources. Renal service organization and resource data were obtained through interviews and questionnaires. Linear regression models were built to establish the factors independently associated with RRT incidence, stratified by the Human Development Index where required. False discovery rate (FDR) correction was adjusted for multiple testing. RESULTS: Across the 46 countries (population 1.25 billion), RRT incidence rates ranged from 12 to 455 (median 130) per million population. Gross domestic product (GDP) per capita [incidence rate ratio (IRR): 1.02 per $1000 increase, P(FDR) = 0.047], percentage of GDP spent on health care (IRR: 1.11 per % increase, P(FDR) = 0.006) and dialysis facility reimbursement rate relative to GDP (IRR: 0.76 per GDP per capita-sized increase in reimbursement rate, P(FDR) = 0.007) were independently associated with RRT incidence. In more developed countries, the private for-profit share of haemodialysis facilities was also associated with higher incidence (IRR: 1.009 per % increase, P(FDR) = 0.003). CONCLUSIONS: Macroeconomic and renal service factors are more often associated with RRT incidence rates than measured demographic or general population health status factors. PMID- 21245132 TI - Exercise increases mitochondrial PGC-1alpha content and promotes nuclear mitochondrial cross-talk to coordinate mitochondrial biogenesis. AB - Endurance exercise is known to induce metabolic adaptations in skeletal muscle via activation of the transcriptional co-activator peroxisome proliferator activated receptor gamma co-activator 1alpha (PGC-1alpha). PGC-1alpha regulates mitochondrial biogenesis via regulating transcription of nuclear-encoded mitochondrial genes. Recently, PGC-1alpha has been shown to reside in mitochondria; however, the physiological consequences of mitochondrial PGC-1alpha remain unknown. We sought to delineate if an acute bout of endurance exercise can mediate an increase in mitochondrial PGC-1alpha content where it may co-activate mitochondrial transcription factor A to promote mtDNA transcription. C57Bl/6J mice (n = 12/group; ? = ?) were randomly assigned to sedentary (SED), forced endurance (END) exercise (15 m/min for 90 min), or forced endurance +3 h of recovery (END+3h) group. The END group was sacrificed immediately after exercise, whereas the SED and END+3h groups were euthanized 3 h after acute exercise. Acute exercise coordinately increased the mRNA expression of nuclear and mitochondrial DNA-encoded mitochondrial transcripts. Nuclear and mitochondrial abundance of PGC 1alpha in END and END+3h groups was significantly higher versus SED mice. In mitochondria, PGC-1alpha is in a complex with mitochondrial transcription factor A at mtDNA D-loop, and this interaction was positively modulated by exercise, similar to the increased binding of PGC-1alpha at the NRF-1 promoter. We conclude that in response to acute altered energy demands, PGC-1alpha re-localizes into nuclear and mitochondrial compartments where it functions as a transcriptional co activator for both nuclear and mitochondrial DNA transcription factors. These results suggest that PGC-1alpha may dynamically facilitate nuclear-mitochondrial DNA cross-talk to promote net mitochondrial biogenesis. PMID- 21245133 TI - Complex regulation of the TRPM8 cold receptor channel: role of arachidonic acid release following M3 muscarinic receptor stimulation. AB - Cold/menthol-activated TRPM8 (transient receptor potential channel melastatin member 8) is primarily expressed in sensory neurons, where it constitutes the principal receptor of environmental innocuous cold. TRPM8 has been shown to be regulated by multiple influences such as phosphorylation, pH, Ca(2+), and lipid messengers. One such messenger is arachidonic acid (AA), which has been shown to inhibit TRPM8 channel activity. However, the physiological pathways mediating the inhibitory effect of AA on TRPM8 still remain unknown. Here, we demonstrate that TRPM8 is regulated via M3 muscarinic acetylcholine receptor-coupled signaling cascade based on the activation of cytosolic phospholipase A2 (cPLA2) and cPLA2 catalyzed derivation of AA. Stimulation of M3 receptors heterologously co expressed with TRPM8 in HEK-293 cells by nonselective muscarinic agonist, oxotremorine methiodide (Oxo-M), caused inhibition of TRPM8-mediated membrane current, which could be mimicked by AA and antagonized by pharmacological or siRNA-mediated cPLA2 silencing. Our results demonstrate the intracellular functional link between M3 receptor and TRPM8 channel via cPLA2/AA and suggest a novel physiological mechanism of arachidonate-mediated regulation of TRPM8 channel activity through muscarinic receptors. We also summarize the existing TRPM8 regulations and discuss their physiological and pathological significance. PMID- 21245134 TI - Mucolipin-3 regulates luminal calcium, acidification, and membrane fusion in the endosomal pathway. AB - Mucolipin-3 (MCOLN3) is a pH-regulated Ca(2+) channel that localizes to the endosomal pathway. Gain-of-function mutation in MCOLN3 causes the varitint waddler (Va) phenotype in mice, which is characterized by hearing loss, vestibular dysfunction, and coat color dilution. The Va phenotype results from a punctual mutation (A419P) in the pore region of MCOLN3 that locks the channel in an open conformation causing massive entry of Ca(2+) inside cells and inducing cell death by apoptosis. Overexpression of wild-type MCOLN3 produces severe alterations of the endosomal pathway, including enlargement and clustering of endosomes, delayed EGF receptor degradation, and impaired autophagosome maturation, thus suggesting that MCOLN3 plays an important role in the regulation of endosomal function. To understand better the physiological role of MCOLN3, we inhibited MCOLN3 function by expression of a channel-dead dominant negative mutant (458DD/KK) or by knockdown of endogenous MCOLN3. Remarkably, we found that impairment of MCOLN3 activity caused a significant accumulation of luminal Ca(2+) in endosomes. This accumulation led to severe defects in endosomal acidification as well as to increased endosomal fusion. Our findings reveal a prominent role for MCOLN3 in regulating Ca(2+) homeostasis at the endosomal pathway and confirm the importance of luminal Ca(2+) for proper acidification and membrane fusion. PMID- 21245135 TI - NAD+-dependent SIRT1 deacetylase participates in epigenetic reprogramming during endotoxin tolerance. AB - Gene-selective epigenetic reprogramming and shifts in cellular bioenergetics develop when Toll-like receptors (TLR) recognize and respond to systemic life threatening infections. Using a human monocyte cell model of endotoxin tolerance and human leukocytes from acute systemic inflammation with sepsis, we report that energy sensor sirtuin 1 (SIRT1) coordinates the epigenetic and bioenergy shifts. After TLR4 signaling, SIRT1 rapidly accumulated at the promoters of TNF-alpha and IL-1beta, but not IkappaBalpha; SIRT1 promoter binding was dependent on its co factor, NAD(+). During this initial process, SIRT1 deacetylated RelA/p65 lysine 310 and nucleosomal histone H4 lysine 16 to promote termination of NFkappaB dependent transcription. SIRT1 then remained promoter bound and recruited de novo induced RelB, which directed assembly of the mature transcription repressor complex that generates endotoxin tolerance. SIRT1 also promoted de novo expression of RelB. During sustained endotoxin tolerance, nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme for endogenous production of NAD(+), and SIRT1 expression increased. The elevation of SIRT1 required protein stabilization and enhanced translation. To support the coordination of bioenergetics in human sepsis, we observed elevated NAD(+) levels concomitant with SIRT1 and RelB accumulation at the TNF-alpha promoter of endotoxin tolerant sepsis blood leukocytes. We conclude that TLR4 stimulation and human sepsis activate pathways that couple NAD(+) and its sensor SIRT1 with epigenetic reprogramming. PMID- 21245136 TI - Cardiac myocyte-specific ablation of follistatin-like 3 attenuates stress-induced myocardial hypertrophy. AB - Transforming growth factor-beta family cytokines have diverse actions in the maintenance of cardiac homeostasis. Follistatin-like 3 (Fstl3) is an extracellular regulator of certain TGF-beta family members, including activin A. The aim of this study was to examine the role of Fstl3 in cardiac hypertrophy. Cardiac myocyte-specific Fstl3 knock-out (KO) mice and control mice were subjected to pressure overload induced by transverse aortic constriction (TAC). Cardiac hypertrophy was assessed by echocardiography and histological and biochemical methods. KO mice showed reduced cardiac hypertrophy, pulmonary congestion, concentric LV wall thickness, LV dilatation, and LV systolic dysfunction after TAC compared with control mice. KO mice displayed attenuated increases in cardiomyocyte cell surface area and interstitial fibrosis following pressure overload. Although activin A was similarly up-regulated in KO and control mice after TAC, a significant increase in Smad2 phosphorylation only occurred in KO mice. Knockdown of Fstl3 in cultured cardiomyocytes inhibited PE induced cardiac hypertrophy. Conversely, adenovirus-mediated Fstl3 overexpression blocked the inhibitory action of activin A on hypertrophy and Smad2 activation. Transduction with Smad7, a negative regulator of Smad2 signaling, blocked the antihypertrophic actions of activin A stimulation or Fstl3 ablation. These findings identify Fstl3 as a stress-induced regulator of hypertrophy that controls myocyte size via regulation of Smad signaling. PMID- 21245137 TI - Peroxisome proliferator-activated receptor (PPAR) gene profiling uncovers insulin like growth factor-1 as a PPARalpha target gene in cardioprotection. AB - Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors and consist of the three isoforms, PPARalpha, PPARbeta/delta, and PPARgamma. Considerable evidence indicates the importance of PPARs in cardiovascular lipid homeostasis and diabetes, yet the isoform-dependent cardiac target genes remain unknown. Here, we constructed murine ventricular clones allowing stable expression of siRNAs to achieve specifically knockdown for each of the PPAR isoforms. By combining gene profiling and computational peroxisome proliferator response element analysis following PPAR isoform activation in normal versus PPAR isoform-deficient cardiomyocyte-like cells, we have, for the first time, determined PPAR isoform specific endogenous target genes in the heart. Electromobility shift and chromatin immunoprecipitation assays demonstrated the existence of an evolutionary conserved peroxisome proliferator response element consensus-binding site in an insulin-like growth factor-1 (igf-1) enhancer. In line, Wy-14643 mediated PPARalpha activation in the wild-type mouse heart resulted in up regulation of igf-1 transcript abundance and provided protection against cardiomyocyte apoptosis following ischemia/reperfusion or biomechanical stress. Taken together, these data confirm igf-1 as an in vivo target of PPARalpha and the involvement of a PPARalpha/IGF-1 signaling pathway in the protection of cardiomyocytes under ischemic and hemodynamic loading conditions. PMID- 21245138 TI - Hallmarks of molecular action of microtubule stabilizing agents: effects of epothilone B, ixabepilone, peloruside A, and laulimalide on microtubule conformation. AB - Microtubule stabilizing agents (MSAs) comprise a class of drugs that bind to microtubule (MT) polymers and stabilize them against disassembly. Several of these agents are currently in clinical use as anticancer drugs, whereas others are in various stages of development. Nonetheless, there is insufficient knowledge about the molecular modes of their action. Recent studies from our laboratory utilizing hydrogen-deuterium exchange in combination with mass spectrometry (MS) provide new information on the conformational effects of Taxol and discodermolide on microtubules isolated from chicken erythrocytes (CET). We report here a comprehensive analysis of the effects of epothilone B, ixabepilone (IXEMPRA(TM)), laulimalide, and peloruside A on CET conformation. The results of our comparative hydrogen-deuterium exchange MS studies indicate that all MSAs have significant conformational effects on the C-terminal H12 helix of alpha tubulin, which is a likely molecular mechanism for the previously observed modulations of MT interactions with microtubule-associated and motor proteins. More importantly, the major mode of MT stabilization by MSAs is the tightening of the longitudinal interactions between two adjacent alphabeta-tubulin heterodimers at the interdimer interface. In contrast to previous observations reported with bovine brain tubulin, the lateral interactions between the adjacent protofilaments in CET are particularly strongly stabilized by peloruside A and laulimalide, drugs that bind outside the taxane site. This not only highlights the significance of tubulin isotype composition in modulating drug effects on MT conformation and stability but also provides a potential explanation for the synergy observed when combinations of taxane and alternative site binding drugs are used. PMID- 21245139 TI - Myosin Va is required for P body but not stress granule formation. AB - In the present study we demonstrate an association between mammalian myosin Va and cytoplasmic P bodies, microscopic ribonucleoprotein granules that contain components of the 5'-3' mRNA degradation machinery. Myosin Va colocalizes with several P body markers and its RNAi-mediated knockdown results in the disassembly of P bodies. Overexpression of a dominant-negative mutant of myosin Va reduced the motility of P bodies in living cells. Co-immunoprecipitation experiments demonstrate that myosin Va physically associates with eIF4E, an mRNA binding protein that localizes to P bodies. In contrast, we find that myosin Va does not play a role in stress granule formation. Stress granules are ribonucleoprotein structures that are involved in translational silencing and are spatially, functionally, and compositionally linked to P bodies. Myosin Va is found adjacent to stress granules in stressed cells but displays minimal localization within stress granules, and myosin Va knockdown has no effect on stress granule assembly or disassembly. Combined with recently published reports demonstrating a role for Drosophila and mammalian class V myosins in mRNA transport and the involvement of the yeast myosin V orthologue Myo2p in P body assembly, our results provide further evidence that the class V myosins serve an important role in the transport and turnover of mRNA. PMID- 21245141 TI - Up-regulation of AMP-activated protein kinase in cancer cell lines is mediated through c-Src activation. AB - We report that the activation level of AMP-dependent protein kinase AMPK is elevated in cancer cell lines as a hallmark of their transformed state. In OVCAR3 and A431 cells, c-Src signals through protein kinase Calpha, phospholipase Cgamma, and LKB1 to AMPK. AMPK controls internal ribosome entry site (IRES) dependent translation in these cells. We suggest that AMPK activation via PKC might be a general mechanism to regulate IRES-dependent translation in cancer cells. PMID- 21245140 TI - SKP2 oncogene is a direct MYC target gene and MYC down-regulates p27(KIP1) through SKP2 in human leukemia cells. AB - SKP2 is the ubiquitin ligase subunit that targets p27(KIP1) (p27) for degradation. SKP2 is induced in the G(1)-S transit of the cell cycle, is frequently overexpressed in human cancer, and displays transformation activity in experimental models. Here we show that MYC induces SKP2 expression at the mRNA and protein levels in human myeloid leukemia K562 cells with conditional MYC expression. Importantly, in these systems, induction of MYC did not activate cell proliferation, ruling out SKP2 up-regulation as a consequence of cell cycle entry. MYC-dependent SKP2 expression was also detected in other cell types such as lymphoid, fibroblastic, and epithelial cell lines. MYC induced SKP2 mRNA expression in the absence of protein synthesis and activated the SKP2 promoter in luciferase reporter assays. With chromatin immunoprecipitation assays, MYC was detected bound to a region of human SKP2 gene promoter that includes E-boxes. The K562 cell line derives from human chronic myeloid leukemia. In a cohort of chronic myeloid leukemia bone marrow samples, we found a correlation between MYC and SKP2 mRNA levels. Analysis of cancer expression databases also indicated a correlation between MYC and SKP2 expression in lymphoma. Finally, MYC-induced SKP2 expression resulted in a decrease in p27 protein in K562 cells. Moreover, silencing of SKP2 abrogated the MYC-mediated down-regulation of p27. Our data show that SKP2 is a direct MYC target gene and that MYC-mediated SKP2 induction leads to reduced p27 levels. The results suggest the induction of SKP2 oncogene as a new mechanism for MYC-dependent transformation. PMID- 21245142 TI - Reversible activation of cellular factor XIII by calcium. AB - Factor XIII (FXIII) is a pro-transglutaminase found in the plasma as well as intracellularly in platelets and macrophages. Plasma FXIII is activated by thrombin cleavage (FXIIIa*) and acts in the final stages of blood coagulation cascade. In contrast, the function and activation of cellular FXIII are less characterized. Cellular FXIII relies on a conformational activation of the protein. The nonproteolytic activation of FXIII to FXIIIa degrees induced by Ca(2+) alone is well known, but up until now it has been discussed under which conditions the process can be induced and whether it can be reversed. Here, we study the nature of the Ca(2+)-induced FXIII activation. Previously used methods to evaluate FXIII activity detect both FXIIIa* and FXIIIa degrees because they rely on occurrence of enzyme activity or on active site Cys-314 solvent accessibility. Therefore, an analytical HPLC method was developed that separates zymogen recombinant FXIII (rFXIII) from rFXIIIa degrees . The data demonstrate that nonproteolytic activation and deactivation are highly dependent on Ca(2+) concentration, buffer, and salt components. Moreover, it is established that Ca(2+) activation of rFXIII is fully reversible, and only 2-5 mm CaCl(2) is sufficient to retain full rFXIIIa degrees activity. However, below 2 mm CaCl(2) the rFXIIIa degrees molecule deactivates. The deactivated molecule can subsequently undergo a new activation round. Furthermore, it is demonstrated that thermal stress of freeze-dried rFXIII can induce a new predisposed form that activates faster than nonstressed rFXIII. PMID- 21245143 TI - Cyclophilin A (CyPA) induces chemotaxis independent of its peptidylprolyl cis trans isomerase activity: direct binding between CyPA and the ectodomain of CD147. AB - Cyclophilin A (CyPA) is a ubiquitously distributed peptidylprolyl cis-trans isomerase (PPIase) that possesses diverse biological functions. Extracellular CyPA is a potent chemokine, which can directly induce leukocyte chemotaxis and contribute to the pathogenesis of inflammation-mediated diseases. Although it has been identified that the chemotaxis activity of CyPA is mediated through its cell surface signaling receptor CD147, the role of CyPA PPIase activity in this process is disputable, and the underlying molecular mechanism is still poorly understood. In this study, we present the first evidence that CyPA induces leukocyte chemotaxis through a direct binding with the ectodomain of CD147 (CD147(ECT)), independent of its PPIase activity. Although NMR study indicates that the CD147(ECT) binding site on CyPA overlaps with the PPIase active site, the PPIase inactive mutant CyPA(R55A) exhibits similar CD147(ECT) binding ability and chemotaxis activity to those of CyPA(WT). Furthermore, we have identified three key residues of CyPA involved in CD147(ECT) binding and found that mutations H70A, T107A, and R69A result in similar levels of reduction in CD147(ECT) binding ability and chemotaxis activity for CyPA, without affecting the PPIase activity. Our findings indicate that there exists a novel mechanism for CyPA to regulate cellular signaling processes, shedding new light on its applications in drug development and providing a new targeting site for drug design. PMID- 21245144 TI - The common modification in alphaA-crystallin in the lens, N101D, is associated with increased opacity in a mouse model. AB - To elucidate the morphological and cellular changes due to introduction of a charge during development and the possible mechanism that underlies cataract development in humans as a consequence of an additional charge, we generated a transgenic mouse model mimicking deamidation of Asn at position 101. The mouse model expresses a human alphaA-crystallin gene in which Asn-101 was replaced with Asp, which is referred to as alphaAN101D-transgene and is considered to be "deamidated" in this study. Mice expressing alphaAN101D-transgene are referred to here CRYAA(N101D) mice. All of the lines showed the expression of alphaAN101D transgene. Compared with the lenses of mice expressing wild-type (WT) alphaA transgene (referred to as CRYAA(WT) mice), the lenses of CRYAA(N101D) mice showed (a) altered alphaA-crystallin membrane protein (aquaporin-0 (AQP0), a specific lens membrane protein) interaction, (b) extracellular spaces between outer cortical fiber cells, (c) attenuated denucleation during confocal microscopic examination, (d) disrupted normal fiber cell organization and structure during scanning electron microscopic examination, (e) distorted posterior suture lines by bright field microscopy, and (f) development of a mild anterior lens opacity in the superior cortical region during the optical coherence tomography scan analysis. Relative to lenses with WT alphaA-crystallin, the lenses containing the deamidated alphaA-crystallin also showed an aggregation of alphaA-crystallin and a higher level of water-insoluble proteins, suggesting that the morphological and cellular changes in these lenses are due to the N101D mutation. This study provides evidence for the first time that expression of deamidated alphaA crystallin caused disruption of fiber cell structural integrity, protein aggregation, insolubilization, and mild cortical lens opacity. PMID- 21245145 TI - BACE1 retrograde trafficking is uniquely regulated by the cytoplasmic domain of sortilin. AB - BACE1 (beta-site beta-amyloid precursor protein (APP)-cleaving enzyme 1) mediates the first proteolytic cleavage of APP, leading to amyloid beta-peptide (Abeta) production. It has been reported that BACE1 intracellular trafficking, in particular endosome-to-TGN sorting, is mediated by adaptor complexes, such as retromer and Golgi-localized gamma-ear-containing ARF-binding proteins (GGAs). Here we investigated whether sortilin, a Vps10p domain-sorting receptor believed to participate in retromer-mediated transport of select membrane cargoes, contributes to the subcellular trafficking and activity of BACE1. Our initial studies revealed increased levels of sortilin in post-mortem brain tissue of AD patients and that overexpression of sortilin leads to increased BACE1-mediated cleavage of APP in cultured cells. In contrast, RNAi suppression of sortilin results in decreased BACE1-mediated cleavage of APP. We also found that sortilin interacts with BACE1 and that a sortilin construct lacking its cytoplasmic domain, which contains putative retromer sorting motifs, remains bound to BACE1. However, expression of this truncated sortilin redistributes BACE1 from the trans Golgi network to the endosomes and substantially reduces the retrograde trafficking of BACE1. Site-directed mutagenesis and chimera experiments reveal that the cytoplasmic tail of sortilin, but not those from other VPS10p domain receptors (e.g. SorCs1b and SorLA), plays a unique role in BACE1 trafficking. Our studies suggest a new function for sortilin as a modulator of BACE1 retrograde trafficking and subsequent generation of Abeta. PMID- 21245146 TI - Identification of the synthetic cannabinoid R(+)WIN55,212-2 as a novel regulator of IFN regulatory factor 3 activation and IFN-beta expression: relevance to therapeutic effects in models of multiple sclerosis. AB - beta-Interferons (IFN-betas) represent one of the first line treatments for relapsing-remitting multiple sclerosis, slowing disease progression while reducing the frequency of relapses. Despite this, more effective, well tolerated therapeutic strategies are needed. Cannabinoids palliate experimental autoimmune encephalomyelitis (EAE) symptoms and have therapeutic potential in MS patients although the precise molecular mechanism for these effects is not understood. Toll-like receptor (TLR) signaling controls innate immune responses and TLRs are implicated in MS. Here we demonstrate that the synthetic cannabinoid R(+)WIN55,212-2 is a novel regulator of TLR3 and TLR4 signaling by inhibiting the pro-inflammatory signaling axis triggered by TLR3 and TLR4, whereas selectively augmenting TLR3-induced activation of IFN regulatory factor 3 (IRF3) and expression of IFN-beta. We present evidence that R(+)WIN55,212-2 strongly promotes the nuclear localization of IRF3. The potentiation of IFN-beta expression by R(+)WIN55,212-2 is critical for manifesting its protective effects in the murine MS model EAE as evidenced by its reduced therapeutic efficacy in the presence of an anti-IFN-beta antibody. R(+)WIN55,212-2 also induces IFN-beta expression in MS patient peripheral blood mononuclear cells, whereas down regulating inflammatory signaling in these cells. These findings identify R(+)WIN55,212-2 as a novel regulator of TLR3 signaling to IRF3 activation and IFN beta expression and highlights a new mechanism that may be open to exploitation in the development of new therapeutics for the treatment of MS. PMID- 21245147 TI - Mhp107 is a member of the multifunctional adhesin family of Mycoplasma hyopneumoniae. AB - Mycoplasma hyopneumoniae is the causative pathogen of porcine enzootic pneumonia, an economically significant disease that disrupts the mucociliary escalator in the swine respiratory tract. Expression of Mhp107, a P97 paralog encoded by the gene mhp107, was confirmed using ESI-MS/MS. To investigate the function of Mhp107, three recombinant proteins, F1(Mhp107), F2(Mhp107), and F3(Mhp107), spanning the N-terminal, central, and C-terminal regions of Mhp107 were constructed. Colonization of swine by M. hyopneumoniae requires adherence of the bacterium to ciliated cells of the respiratory tract. Recent studies have identified a number of M. hyopneumoniae adhesins that bind heparin, fibronectin, and plasminogen. F1(Mhp107) was found to bind porcine heparin (K(D) ~90 nM) in a dose-dependent and saturable manner, whereas F3(Mhp107) bound fibronectin (K(D) ~180 nM) at physiologically relevant concentrations. F1(Mhp107) also bound porcine plasminogen (K(D) = 24 nM) in a dose-dependent and physiologically relevant manner. Microspheres coated with F3(Mhp107) mediate adherence to porcine kidney epithelial-like (PK15) cells, and all three recombinant proteins (F1(Mhp107)-F3(Mhp107)) bound swine respiratory cilia. Together, these findings indicate that Mhp107 is a member of the multifunctional M. hyopneumoniae adhesin family of surface proteins and contributes to both adherence to the host and pathogenesis. PMID- 21245148 TI - P2Y purinergic regulation of the glycine neurotransmitter transporters. AB - The sodium- and chloride-coupled glycine neurotransmitter transporters (GLYTs) control the availability of glycine at glycine-mediated synapses. The mainly glial GLYT1 is the key regulator of the glycine levels in glycinergic and glutamatergic pathways, whereas the neuronal GLYT2 is involved in the recycling of synaptic glycine from the inhibitory synaptic cleft. In this study, we report that stimulation of P2Y purinergic receptors with 2-methylthioadenosine 5' diphosphate in rat brainstem/spinal cord primary neuronal cultures and adult rat synaptosomes leads to the inhibition of GLYT2 and the stimulation of GLYT1 by a paracrine regulation. These effects are mainly mediated by the ADP-preferring subtypes P2Y(1) and P2Y(13) because the effects are partially reversed by the specific antagonists N(6)-methyl-2'-deoxyadenosine-3',5'-bisphosphate and pyridoxal-5'-phosphate-6-azo(2-chloro-5-nitrophenyl)-2,4-disulfonate and are totally blocked by suramin. P2Y(12) receptor is additionally involved in GLYT1 stimulation. Using pharmacological approaches and siRNA-mediated protein knockdown methodology, we elucidate the molecular mechanisms of GLYT regulation. Modulation takes place through a signaling cascade involving phospholipase C activation, inositol 1,4,5-trisphosphate production, intracellular Ca(2+) mobilization, protein kinase C stimulation, nitric oxide formation, cyclic guanosine monophosphate production, and protein kinase G-I (PKG-I) activation. GLYT1 and GLYT2 are differentially sensitive to NO/cGMP/PKG-I both in brain derived preparations and in heterologous systems expressing the recombinant transporters and P2Y(1) receptor. Sensitivity to 2-methylthioadenosine 5' diphosphate by GLYT1 and GLYT2 was abolished by small interfering RNA (siRNA) mediated knockdown of nitric-oxide synthase. Our data may help define the role of GLYTs in nociception and pain sensitization. PMID- 21245149 TI - Morphine inhibits murine dendritic cell IL-23 production by modulating Toll-like receptor 2 and Nod2 signaling. AB - IL-23, produced by dendritic cells (DCs) and macrophages, plays a critical role in innate immunity against bacterial infection. Our previous studies show that morphine disrupts the IL-23/IL-17 mediated pulmonary mucosal host defense and increases susceptibility to Streptococcus pneumoniae lung infection. To determine the mechanism by which morphine modulates IL-23 production, mouse bone marrow derived dendritic cells (BMDCs) and macrophages (BMDMs) were treated with morphine, and infected with S. pneumoniae or stimulated with Toll-like receptor (TLR) and Nod2 ligands. We found that a significant increase in IL-23 protein production was observed in S. pneumoniae, TLR2 ligand lipoteichoic acid (LTA), and TLR4 ligand pneumolysin (PLY) stimulated BMDCs and BMDMs. Interestingly, although Nod2 ligand muramyldipeptide (MDP) alone had no effect on IL-23 production, it potentiated LTA induced IL-23 production to the same level as that observed following S. pneumoniae infection, suggesting that S. pneumoniae induced IL-23 production in DCs involves activation of both TLR2 and Nod2 signaling mechanisms. Furthermore, pretreatment of DCs with MyD88 (myeloid differentiation primary response gene 88) and IL-1 receptor-associated kinase (IRAK) 1/4 inhibitors, or TLR2 antibody diminished the S. pneumoniae induced IL-23 and abolished the inhibitory effects of morphine, indicating that S. pneumoniae induced IL-23 production depends on activation of the TLR2-MyD88-IRAK1/4 signaling pathway. Moreover, morphine decreased S. pneumoniae induced phosphorylation of interferon regulatory factor 3 (IRF3) and activating transcription factor 2 in DCs. Taken together, our study shows that morphine impairs S. pneumoniae induced IL-23 production through MyD88-IRAK1/4-dependent TLR2 and Nod2 signaling in DCs. PMID- 21245150 TI - Meningococcal group W-135 and Y capsular polysaccharides paradoxically enhance activation of the alternative pathway of complement. AB - Although capsular polysaccharide (CPS) is critical for meningococcal virulence, the molecular basis of alternative complement pathway (AP) regulation by meningococcal CPSs remains unclear. Using serum with only the AP active, the ability of strains to generate C3a (a measure of C3 activation) and subsequently deposit C3 fragments on bacteria was studied in encapsulated group A, B, C, W 135, and Y strains and their isogenic unencapsulated mutants. To eliminate confounding AP regulation by membrane-bound factor H (fH; AP inhibitor) and lipooligosaccharide sialic acid, the meningococcal fH ligands (fHbp and NspA) and lipooligosaccharide sialylation were deleted in all strains. Group A CPS expression did not affect C3a generation or C3 deposition. C3a generated by encapsulated and unencapsulated group B and C strains was similar, but CPS expression was associated with reduced C3 deposition, suggesting that these CPSs blocked C3 deposition on membrane targets. Paradoxically, encapsulated W-135 and Y strains (including the wild-type parent strains) enhanced C3 activation and showed marked C3 deposition as early as 10 min; at this time point C3 was barely activated by the unencapsulated mutants. W-135 and Y CPSs themselves served as a site for C3 deposition; this observation was confirmed using immobilized purified CPSs. Purified CPSs bound to unencapsulated meningococci, simulated findings with naturally encapsulated strains. These data highlight the heterogeneity of AP activation on the various meningococcal serogroups that may contribute to differences in their pathogenic mechanisms. PMID- 21245152 TI - Interpretations of faecal concentrations of corticosteroids. PMID- 21245151 TI - A multiprotein binding interface in an intrinsically disordered region of the tumor suppressor protein interferon regulatory factor-1. AB - The interferon-regulated transcription factor and tumor suppressor protein IRF-1 is predicted to be largely disordered outside of the DNA-binding domain. One of the advantages of intrinsically disordered protein domains is thought to be their ability to take part in multiple, specific but low affinity protein interactions; however, relatively few IRF-1-interacting proteins have been described. The recent identification of a functional binding interface for the E3-ubiquitin ligase CHIP within the major disordered domain of IRF-1 led us to ask whether this region might be employed more widely by regulators of IRF-1 function. Here we describe the use of peptide aptamer-based affinity chromatography coupled with mass spectrometry to define a multiprotein binding interface on IRF-1 (Mf2 domain; amino acids 106-140) and to identify Mf2-binding proteins from A375 cells. Based on their function as known transcriptional regulators, a selection of the Mf2 domain-binding proteins (NPM1, TRIM28, and YB-1) have been validated using in vitro and cell-based assays. Interestingly, although NPM1, TRIM28, and YB-1 all bind to the Mf2 domain, they have differing amino acid specificities, demonstrating the degree of combinatorial diversity and specificity available through linear interaction motifs. PMID- 21245154 TI - HIV-specific CD4+ T cells may contribute to viral persistence in HIV controllers. AB - BACKGROUND: Human immunodeficiency virus (HIV)--infected individuals maintaining plasma HIV RNA levels <75 copies/mL in the absence of therapy ("HIV controllers") often maintain high HIV-specific T cell responses, which likely contribute to the control of viral replication. Despite robust immune responses, these individuals never eradicate HIV infection. We hypothesized that HIV-specific CD4(+) T cells might serve as target cells for HIV, contributing to viral persistence in this setting. METHODS: We measured frequencies of activated (CD38(+) HLA-DR(+)) and HIV Gag-specific CD4(+) and CD8(+) T cells and plasma- and cell-associated levels of HIV RNA and DNA in a cohort of 38 HIV controllers. RESULTS: Although there was no evidence of a relationship between the extent of low-level viremia and the frequency of either activated or HIV-specific CD4(+) T cells, controllers with higher HIV-specific CD4(+) T cell frequencies had higher cell-associated HIV DNA levels (rho = 0.53; P = .019). Higher activated CD4+ T cell frequencies were also associated with higher levels of cell-associated DNA (P = .027) and RNA (P = .0096). However, there was no evidence of a relationship between cell-associated HIV RNA or DNA levels and HIV-specific CD8(+) T cell frequencies. CONCLUSIONS: These data support a model in which strong HIV-specific CD4(+) T cell responses in HIV controllers, while contributing to a potent adaptive immune response, may also contribute to viral persistence, preventing the natural eradication of HIV infection. PMID- 21245155 TI - Transmissibility of hepatitis B virus (HBV) infection through blood transfusion from blood donors with occult HBV infection. AB - BACKGROUND: Studies of the transmissibility of hepatitis B virus (HBV) in occult hepatitis B (OHB) through blood transfusion are scarce. We aimed to determine the transmissibility of HBV in blood donors with OHB through transfusion in animal and human studies. METHODS: Among 217,595 blood donors, 67 donors with OHB were identified. Four chimeric mice populated with human hepatocytes were inoculated with 2 donor serum samples. Serial serum and liver HBV DNA levels were measured. Forty-nine recipients of blood transfusions traced from 10 donors with OHB (9 of whom were positive for antibody to hepatitis B surface antigen [anti-HBs]) were tested for HBV infection. Homology and phylogenetic analyses between the HBV genomic sequences of donors and recipients were performed. RESULTS: Serum HBV DNA was detectable (10(4) copies/mL) in 1 mouse at weeks 5 and 7 after inoculation. Total HBV DNA and HBV replication template (covalently closed circular DNA) and hepatitis B core antigen were detected in the mouse liver. After transfusion, 45 recipients (91.8%) had no HBV infection (ie, they tested negative for hepatitis B surface antigen and HBV DNA). Four tested positive for HBV DNA. In 3 recipients, 83%-86% homology and distant phylogenetic relatedness with their donor HBV excluded transmission through transfusion. The remaining recipient HBV had 95% sequence homology with her donor HBV, compatible with acquisition of HBV infection from the transfusion. High anti-HBs levels in 7 other recipients suggested recent transfusion-related HBV immune response. CONCLUSIONS: OHB donor blood infectivity was shown in our animal and human studies. However, the risk of HBV transmission in humans was low, especially from blood products obtained from donors with OHB who were anti-HBs positive. PMID- 21245156 TI - Pharmacy adherence measures to assess adherence to antiretroviral therapy: review of the literature and implications for treatment monitoring. AB - Prescription or pill-based methods for estimating adherence to antiretroviral therapy (ART), pharmacy adherence measures (PAMs), are objective estimates calculated from routinely collected pharmacy data. We conducted a literature review to evaluate PAMs, including their association with virological and other clinical outcomes, their efficacy compared with other adherence measures, and factors to consider when selecting a PAM to monitor adherence. PAMs were classified into 3 categories: medication possession ratio (MPR), pill count (PC), and pill pick-up (PPU). Data exist to recommend PAMs over self-reported adherence. PAMs consistently predicted patient outcomes, but additional studies are needed to determine the most predictive PAM parameters. Current evidence suggests that shorter duration of adherence assessment (<= 6 months) and use of PAMs to predict future outcomes may be less accurate. PAMs which incorporate the number of days for which ART was prescribed without the counting of remnant pills, are reasonable minimum-resource methods to assess adherence to ART. PMID- 21245158 TI - Gender, race, and geography: do they matter in primary human immunodeficiency virus infection? PMID- 21245157 TI - Sex, race, and geographic region influence clinical outcomes following primary HIV-1 infection. AB - BACKGROUND: It is unknown whether sex and race influence clinical outcomes following primary human immunodeficiency virus type 1 (HIV-1) infection. METHODS: Data were evaluated from an observational, multicenter, primarily North American cohort of HIV-1 seroconverters. RESULTS: Of 2277 seroconverters, 5.4% were women. At enrollment, women averaged .40 log10 fewer copies/mL of HIV-1 RNA (P < .001) and 66 more CD4(+) T cells/MUL (P = .006) than men, controlling for age and race. Antiretroviral therapy (ART) was less likely to be initiated at any time point by nonwhite women and men compared to white men (P < .005), and by individuals from the southern United States compared to others (P = .047). Sex and race did not affect responses to ART after 6 months (P > .73). Women were 2.17-fold more likely than men to experience >1 HIV/AIDS-related event (P < .001). Nonwhite women were most likely to experience an HIV/AIDS-related event compared to all others (P = .035), after adjusting for intravenous drug use and ART. Eight years after diagnosis, >1 HIV/AIDS-related event had occurred in 78% of nonwhites and 37% of whites from the southern United States, and 24% of whites and 17% of nonwhites from other regions (P < .001). CONCLUSIONS: Despite more favorable clinical parameters initially, female HIV-1-seroconverters had worse outcomes than did male seroconverters. Elevated morbidity was associated with being nonwhite and residing in the southern United States. PMID- 21245159 TI - No improvement of survival with reduced- versus high-intensity conditioning for allogeneic stem cell transplants in Ewing tumor patients. AB - BACKGROUND: Outcomes of Ewing tumor (ET) patients treated with allogeneic stem cell transplantation (allo-SCT) were compared regarding the use of reduced intensity conditioning (RIC) and high-intensity conditioning (HIC) regimens as well as human leukocyte antigen (HLA)-matched and HLA-mismatched grafts. PATIENTS AND METHODS: We retrospectively analyzed data of 87 ET patients from the European Group for Blood and Marrow Transplantation, Pediatric Registry for Stem Cell Transplantations, Asia Pacific Blood and Marrow Transplantation and MetaEICESS registries treated with allo-SCT. Fifty patients received RIC (group A) and 37 patients received HIC (group B). Twenty-four patients received HLA-mismatched grafts and 63 received HLA-matched grafts. RESULTS: Median overall survival was 7.9 months [+/-1.24, 95% confidence interval (CI) 5.44-10.31] for group A and 4.4 months (+/-1.06, 95% CI 2.29-6.43) for group B patients (P = 1.3). Death of complications (DOC) occurred in 4 of 50 (0.08) and death of disease (DOD) in 33 of 50 (0.66) group A and in 16 of 37 (0.43) and 17 of 37 (0.46) group B patients, respectively. DOC incidence was decreased (P < 0.01) and DOD/relapse increased (P < 0.01) in group A compared with group B. HLA mismatch was not generally associated with graft-versus-Ewing tumor effect (GvETE). CONCLUSIONS: There was no improvement of survival with RIC compared with HIC due to increased DOD/relapse incidence after RIC despite less DOC incidence. This implicates general absence of a clinically relevant GvETE with current protocols. PMID- 21245160 TI - Cigar and pipe smoking, smokeless tobacco use and pancreatic cancer: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4). AB - BACKGROUND: Cigarette smoking is the best-characterized risk factor for pancreatic cancer. However, data are limited for other tobacco smoking products and smokeless tobacco. MATERIALS AND METHODS: We conducted a pooled analysis of cigar and pipe smoking and smokeless tobacco use and risk of pancreatic cancer using data from 11 case-control studies (6056 cases and 11,338 controls) within the International Pancreatic Cancer Case-Control Consortium (PanC4). Pooled odds ratios (OR) and the corresponding 95% confidence intervals (CI) were estimated by unconditional multiple logistic regression models adjusted for study center and selected covariates. RESULTS: Compared with never tobacco users, the OR for cigar only smokers was 1.6 (95% CI: 1.2-2.3), i.e. comparable to that of cigarette-only smokers (OR 1.5; 95% CI 1.4-1.6). The OR was 1.1 (95% CI 0.69-1.6) for pipe-only smokers. There was some evidence of increasing risk with increasing amount of cigar smoked per day (OR 1.82 for >= 10 grams of tobacco), although not with duration. The OR for ever smokeless tobacco users as compared with never tobacco users was 0.98 (95% CI 0.75-1.3). CONCLUSION: This collaborative analysis provides evidence that cigar smoking is associated with an excess risk of pancreatic cancer, while no significant association emerged for pipe smoking and smokeless tobacco use. PMID- 21245161 TI - ERG dependence distinguishes developmental control of hematopoietic stem cell maintenance from hematopoietic specification. AB - Although many genes are known to be critical for early hematopoiesis in the embryo, it remains unclear whether distinct regulatory pathways exist to control hematopoietic specification versus hematopoietic stem cell (HSC) emergence and function. Due to their interaction with key regulators of hematopoietic commitment, particular interest has focused on the role of the ETS family of transcription factors; of these, ERG is predicted to play an important role in the initiation of hematopoiesis, yet we do not know if or when ERG is required. Using in vitro and in vivo models of hematopoiesis and HSC development, we provide strong evidence that ERG is at the center of a distinct regulatory program that is not required for hematopoietic specification or differentiation but is critical for HSC maintenance during embryonic development. We show that, from the fetal period, ERG acts as a direct upstream regulator of Gata2 and Runx1 gene activity. Without ERG, physiological HSC maintenance fails, leading to the rapid exhaustion of definitive hematopoiesis. PMID- 21245162 TI - Pluripotency factors regulate definitive endoderm specification through eomesodermin. AB - Understanding the molecular mechanisms controlling early cell fate decisions in mammals is a major objective toward the development of robust methods for the differentiation of human pluripotent stem cells into clinically relevant cell types. Here, we used human embryonic stem cells and mouse epiblast stem cells to study specification of definitive endoderm in vitro. Using a combination of whole genome expression and chromatin immunoprecipitation (ChIP) deep sequencing (ChIP seq) analyses, we established an hierarchy of transcription factors regulating endoderm specification. Importantly, the pluripotency factors NANOG, OCT4, and SOX2 have an essential function in this network by actively directing differentiation. Indeed, these transcription factors control the expression of EOMESODERMIN (EOMES), which marks the onset of endoderm specification. In turn, EOMES interacts with SMAD2/3 to initiate the transcriptional network governing endoderm formation. Together, these results provide for the first time a comprehensive molecular model connecting the transition from pluripotency to endoderm specification during mammalian development. PMID- 21245163 TI - The genomic landscapes of inflammation. AB - Inflammation involves the activation of a highly coordinated gene expression program that is specific for the initial stimulus and occurs in a different manner in bystander parenchymal cells and professional immune system cells recruited to the inflamed site. Recent data demonstrate that developmental transcription factors like the macrophage fate-determining Pu.1 set the stage for the activity of ubiquitous transcription factors activated by inflammatory stimuli, like NF-kB, AP-1, and interferon regulatory factors (IRFs). The intersection of lineage-determining and stimulus-activated transcription factors at enhancers explains cell type specificity in inflammatory responses. PMID- 21245164 TI - The evolution of dorsal-ventral patterning mechanisms in insects. AB - The gene regulatory network (GRN) underpinning dorsal-ventral (DV) patterning of the Drosophila embryo is among the most thoroughly understood GRNs, making it an ideal system for comparative studies seeking to understand the evolution of development. With the emergence of widely applicable techniques for testing gene function, species with sequenced genomes, and multiple tractable species with diverse developmental modes, a phylogenetically broad and molecularly deep understanding of the evolution of DV axis formation in insects is feasible. Here, we review recent progress made in this field, compare our emerging molecular understanding to classical embryological experiments, and suggest future directions of inquiry. PMID- 21245165 TI - miR-29b is activated during neuronal maturation and targets BH3-only genes to restrict apoptosis. AB - The execution of apoptosis is critical for proper development of the nervous system. However, it is equally important that neurons strictly inhibit apoptosis after development to ensure their survival throughout the lifetime of the organism. Here we show that a microRNA, miR-29b, is markedly induced with neuronal maturation and functions as a novel inhibitor of neuronal apoptosis. The prosurvival function of miR-29b is mediated by targeting genes in the proapoptotic BH3-only family. Our results identify a unique strategy evolved by maturing neurons that uses a single microRNA to inhibit the multiple, redundant BH3-only proteins that are key initiators of apoptosis. PMID- 21245166 TI - Planar polarization of the atypical myosin Dachs orients cell divisions in Drosophila. AB - Tissues can grow in a particular direction by controlling the orientation of cell divisions. This phenomenon is evident in the developing Drosophila wing epithelium, where the tissue becomes elongated along the proximal-distal axis. We show that orientation of cell divisions in the wing requires planar polarization of an atypical myosin, Dachs. Our evidence suggests that Dachs constricts cell cell junctions to alter the geometry of cell shapes at the apical surface, and that cell shape then determines the orientation of the mitotic spindle. Using a computational model of a growing epithelium, we show that polarized cell tension is sufficient to orient cell shapes, cell divisions, and tissue growth. Planar polarization of Dachs is ultimately oriented by long-range gradients emanating from compartment boundaries, and is therefore a mechanism linking these gradients with the control of tissue shape. PMID- 21245167 TI - A dual flip-out mechanism for 5mC recognition by the Arabidopsis SUVH5 SRA domain and its impact on DNA methylation and H3K9 dimethylation in vivo. AB - Cytosine DNA methylation is evolutionarily ancient, and in eukaryotes this epigenetic modification is associated with gene silencing. Proteins with SRA (SET or RING-associated) methyl-binding domains are required for the establishment and/or maintenance of DNA methylation in both plants and mammals. The 5-methyl cytosine (5mC)-binding specificity of several SRA domains have been characterized, and each one has a preference for DNA methylation in different sequence contexts. Here we demonstrate through mobility shift assays and calorimetric measurements that the SU(VAR)3-9 HOMOLOG 5 (SUVH5) SRA domain differs from other SRA domains in that it can bind methylated DNA in all contexts to similar extents. Crystal structures of the SUVH5 SRA domain bound to 5mC containing DNA in either the fully or hemimethylated CG context or the methylated CHH context revealed a dual flip-out mechanism where both the 5mC and a base (5mC, C, or G, respectively) from the partner strand are simultaneously extruded from the DNA duplex and positioned within binding pockets of individual SRA domains. Our structure-based in vivo studies suggest that a functional SUVH5 SRA domain is required for both DNA methylation and accumulation of the H3K9 dimethyl modification in vivo, suggesting a role for the SRA domain in recruitment of SUVH5 to genomic loci. PMID- 21245168 TI - The nonsense-mediated mRNA decay SMG-1 kinase is regulated by large-scale conformational changes controlled by SMG-8. AB - Nonsense-mediated mRNA decay (NMD) is a eukaryotic surveillance pathway that regulates the degradation of mRNAs harboring premature translation termination codons. NMD also influences the expression of many physiological transcripts. SMG 1 is a large kinase essential to NMD that phosphorylates Upf1, which seems to be the definitive signal triggering mRNA decay. However, the regulation of the kinase activity of SMG-1 remains poorly understood. Here, we reveal the three dimensional architecture of SMG-1 in complex with SMG-8 and SMG-9, and the structural mechanisms regulating SMG-1 kinase. A bent arm comprising a long region of HEAT (huntington, elongation factor 3, a subunit of PP2A and TOR1) repeats at the N terminus of SMG-1 functions as a scaffold for SMG-8 and SMG-9, and projects from the C-terminal core containing the phosphatidylinositol 3 kinase domain. SMG-9 seems to control the activity of SMG-1 indirectly through the recruitment of SMG-8 to the N-terminal HEAT repeat region of SMG-1. Notably, SMG-8 binding to the SMG-1:SMG-9 complex specifically down-regulates the kinase activity of SMG-1 on Upf1 without contacting the catalytic domain. Assembly of the SMG-1:SMG-8:SMG-9 complex induces a significant motion of the HEAT repeats that is signaled to the kinase domain. Thus, large-scale conformational changes induced by SMG-8 after SMG-9-mediated recruitment tune SMG-1 kinase activity to modulate NMD. PMID- 21245169 TI - Regulated recruitment of tumor suppressor BRCA1 to the p21 gene by coactivator methylation. AB - Tumor suppression by p53 and BRCA1 involves regulation of cell cycle, apoptosis, and DNA repair and is influenced by transcriptional coactivators and post translational modifications. Here we show that coactivator-associated arginine methyltransferase 1 (CARM1) methylates Arg 754 in the KIX region of coactivator p300. Methylated p300 and p300 protein fragments are preferentially recognized by BRCT domains of BRCA1, identifying the BRCT domain as a novel methylarginine binding module. CARM1 and p300 cooperate with BRCA1 and p53 to induce expression of the critical cell cycle and proliferation regulator p21(WAF1/CIP1) in response to DNA damage. This induction was severely attenuated by elimination of CARM1 or its methyltransferase activity, or by mutation of Arg 754 of p300. Absence of CARM1 methyltransferase activity led to failure of cells to arrest in the G1 phase of the cell cycle in response to DNA damage. CARM1 methyltransferase activity was required for induction of some p53 target genes (p21 and Gadd45) but not others (Bax) by DNA damage. Recruitment of BRCA1 to the p53-binding region of the p21 promoter in response to DNA damage required methylation of Arg 754 of p300 by CARM1. Thus, coactivator methylation may be crucial for fine-tuning the tumor suppressor function of BRCA1 and other BRCT domain proteins. PMID- 21245170 TI - Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in Drosophila. AB - The epidemic of obesity and diabetes is causing an increased incidence of dyslipidemia-related heart failure. While the primary etiology of lipotoxic cardiomyopathy is an elevation of lipid levels resulting from an imbalance in energy availability and expenditure, increasing evidence suggests a relationship between dysregulation of membrane phospholipid homeostasis and lipid-induced cardiomyopathy. In the present study, we report that the Drosophila easily shocked (eas) mutants that harbor a disturbance in phosphatidylethanolamine (PE) synthesis display tachycardia and defects in cardiac relaxation and are prone to developing cardiac arrest and fibrillation under stress. The eas mutant hearts exhibit elevated concentrations of triglycerides, suggestive of a metabolic, diabetic-like heart phenotype. Moreover, the low PE levels in eas flies mimic the effects of cholesterol deficiency in vertebrates by stimulating the Drosophila sterol regulatory element-binding protein (dSREBP) pathway. Significantly, cardiac-specific elevation of dSREBP signaling adversely affects heart function, reflecting the cardiac eas phenotype, whereas suppressing dSREBP or lipogenic target gene function in eas hearts rescues the cardiac hyperlipidemia and heart function disorders. These findings suggest that dysregulated phospholipid signaling that alters SREBP activity contributes to the progression of impaired heart function in flies and identifies a potential link to lipotoxic cardiac diseases in humans. PMID- 21245172 TI - The cover. Monk by the sea. PMID- 21245171 TI - Live kidney donation: a 36-year-old woman hoping to donate a kidney to her mother. AB - Ms D, a healthy 36-year old-woman, wishes to donate a kidney to her mother, who has diabetes and end-stage renal disease. Ms D has been evaluated as a donor at another medical center and was told to lose weight and quit smoking. Evidence from cohort studies suggests that live kidney donation is a safe procedure in the short and long terms, although donor follow-up studies have often had incomplete data on limited populations. The benefits of live donation are mostly for the recipient, but kidney donors often have improved quality of life as a result of both their generous act and the improved health of the recipient. Evaluation and eligibility of live kidney donors and their short- and long-term risks are discussed. PMID- 21245173 TI - A piece of my mind. Impact factor. PMID- 21245174 TI - Scientists look to emerging technology to treat chronic neurological disorders. PMID- 21245175 TI - Advances reshaping sickle cell therapy. PMID- 21245176 TI - Teen marijuana use on the rise. PMID- 21245177 TI - Buprenorphine implants and opioid dependence. PMID- 21245178 TI - Buprenorphine implants and opioid dependence. PMID- 21245179 TI - The American right to bear arms. PMID- 21245181 TI - Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline. AB - CONTEXT: Lower plasma beta-amyloid 42 and 42/40 levels have been associated with incident dementia, but results are conflicting and few have investigated cognitive decline among elders without dementia. OBJECTIVE: To determine if plasma beta-amyloid is associated with cognitive decline and if this association is modified by measures of cognitive reserve. DESIGN, SETTING, AND PARTICIPANTS: We studied 997 black and white community-dwelling older adults from Memphis, Tennessee, and Pittsburgh, Pennsylvania, who were enrolled in the Health ABC Study, a prospective observational study begun in 1997-1998 with 10-year follow up in 2006-2007. Participant mean age was 74.0 (SD, 3.0) years; 55.2% (n = 550) were female; and 54.0% (n = 538) were black. MAIN OUTCOME MEASURES: Association of near-baseline plasma beta-amyloid levels (42 and 42/40 measured in 2010) and repeatedly measured Modified Mini-Mental State Examination (3MS) results. RESULTS: Low beta-amyloid 42/40 level was associated with greater 9-year 3MS cognitive decline (lowest beta-amyloid tertile: mean change in 3MS score, -6.59 [95% confidence interval [CI], -5.21 to -7.67] points; middle tertile: -6.16 [95% CI, -4.92 to -7.32] points; and highest tertile: -3.60 [95% CI, -2.27 to -4.73] points; P < .001). Results were similar after multivariate adjustment for age, race, education, diabetes, smoking, and apolipoprotein E [APOE ] e4 status and after excluding the 72 participants with incident dementia. Measures of cognitive reserve modified this association whereby among those with high reserve (at least a high school diploma, higher than sixth-grade literacy, or no APOE e4 allele), beta-amyloid 42/40 was less associated with multivariate adjusted 9-year decline. For example, among participants with less than a high school diploma, the 3MS score decline was -8.94 (95% CI, -6.94 to -10.94) for the lowest tertile compared with -4.45 (95% CI, -2.31 to -6.59) for the highest tertile, but for those with at least a high school diploma, 3MS score decline was -4.60 (95% CI,-3.07 to 6.13) for the lowest tertile and -2.88 (95% CI,-1.41 to -4.35) for the highest tertile (P = .004 for interaction). Interactions were also observed for literacy (P = .005) and for APOE e4 allele (P = .02). CONCLUSION: Lower plasma beta amyloid 42/40 is associated with greater cognitive decline among elderly persons without dementia over 9 years, and this association is stronger among those with low measures of cognitive reserve. PMID- 21245182 TI - Efficacy of escitalopram for hot flashes in healthy menopausal women: a randomized controlled trial. AB - CONTEXT: Concerns regarding the risks associated with estrogen and progesterone to manage menopausal symptoms have resulted in its declining use and increased interest in nonhormonal treatments with demonstrated efficacy for hot flashes. OBJECTIVE: To determine the efficacy and tolerability of 10 to 20 mg/d escitalopram, a selective serotonin reuptake inhibitor, in alleviating the frequency, severity, and bother of menopausal hot flashes. DESIGN, SETTING, AND PATIENTS: A multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel group trial that enrolled 205 women (95 African American; 102 white; 8 other) between July 2009 and June 2010. INTERVENTION: Women received 10 to 20 mg/d of escitalopram or a matching placebo for 8 weeks. MAIN OUTCOME MEASURES: Primary outcomes were the frequency and severity of hot flashes assessed by prospective daily diaries at weeks 4 and 8. Secondary outcomes were hot flash bother, recorded on daily diaries, and clinical improvement (defined as hot flash frequency >=50% decrease from baseline). RESULTS: Mean (SD) daily hot flash frequency was 9.78 (5.60) at baseline. In a modified intent-to-treat analysis that included all randomized participants who provided hot flash diary data, the mean difference in hot flash frequency reduction was 1.41 (95% CI, 0.13-2.69) fewer hot flashes per day at week 8 among women taking escitalopram (P < .001), with mean reductions of 4.60 (95% CI, 3.74-5.47) and 3.20 (95% CI, 2.24-4.15) hot flashes per day in the escitalopram and placebo groups, respectively. Fifty-five percent of women in the escitalopram group vs 36% in the placebo group reported a decrease of at least 50% in hot flash frequency (P = .009) at the 8-week follow up. Reductions in hot flash severity scores were significantly greater in the escitalopram group (-0.52; 95% CI, -0.64 to -0.40 vs -0.30; 95% CI, -0.42 to 0.17 for placebo; P < .001). Race did not significantly modify the treatment effect (P = .62). Overall discontinuation due to adverse events was 4% (7 in the active group, 2 in the placebo group). Three weeks after treatment ended, women in the escitalopram group reported a mean 1.59 (95% CI, 0.55-2.63; P = .02) more hot flashes per day than women in the placebo group. CONCLUSION: Among healthy women, the use of escitalopram (10-20 mg/d) compared with placebo resulted in fewer and less severe menopausal hot flashes at 8 weeks of follow-up. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00894543. PMID- 21245183 TI - Use of florbetapir-PET for imaging beta-amyloid pathology. AB - CONTEXT: The ability to identify and quantify brain beta-amyloid could increase the accuracy of a clinical diagnosis of Alzheimer disease. OBJECTIVE: To determine if florbetapir F 18 positron emission tomographic (PET) imaging performed during life accurately predicts the presence of beta-amyloid in the brain at autopsy. DESIGN, SETTING, AND PARTICIPANTS: Prospective clinical evaluation conducted February 2009 through March 2010 of florbetapir-PET imaging performed on 35 patients from hospice, long-term care, and community health care facilities near the end of their lives (6 patients to establish the protocol and 29 to validate) compared with immunohistochemistry and silver stain measures of brain beta-amyloid after their death used as the reference standard. PET images were also obtained in 74 young individuals (18-50 years) presumed free of brain amyloid to better understand the frequency of a false-positive interpretation of a florbetapir-PET image. MAIN OUTCOME MEASURES: Correlation of florbetapir-PET image interpretation (based on the median of 3 nuclear medicine physicians' ratings) and semiautomated quantification of cortical retention with postmortem beta-amyloid burden, neuritic amyloid plaque density, and neuropathological diagnosis of Alzheimer disease in the first 35 participants autopsied (out of 152 individuals enrolled in the PET pathological correlation study). RESULTS: Florbetapir-PET imaging was performed a mean of 99 days (range, 1-377 days) before death for the 29 individuals in the primary analysis cohort. Fifteen of the 29 individuals (51.7%) met pathological criteria for Alzheimer disease. Both visual interpretation of the florbetapir-PET images and mean quantitative estimates of cortical uptake were correlated with presence and quantity of beta amyloid pathology at autopsy as measured by immunohistochemistry (Bonferroni rho, 0.78 [95% confidence interval, 0.58-0.89]; P <.001]) and silver stain neuritic plaque score (Bonferroni rho, 0.71 [95% confidence interval, 0.47-0.86]; P <.001). Florbetapir-PET images and postmortem results rated as positive or negative for beta-amyloid agreed in 96% of the 29 individuals in the primary analysis cohort. The florbetapir-PET image was rated as amyloid negative in the 74 younger individuals in the nonautopsy cohort. CONCLUSIONS: Florbetapir-PET imaging was correlated with the presence and density of beta-amyloid. These data provide evidence that a molecular imaging procedure can identify beta-amyloid pathology in the brains of individuals during life. Additional studies are required to understand the appropriate use of florbetapir-PET imaging in the clinical diagnosis of Alzheimer disease and for the prediction of progression to dementia. PMID- 21245184 TI - Finding the right level of posthospital care: "We didn't realize there was any other option for him". AB - Many families considering posthospital care options are ill-prepared and in need of guidance. They may not know the range of available options, the relative benefits of each, or have considered their therapeutic goals. Physicians should be informants, advocates, and facilitators of this big leap for their patients. Making a good long-term care decision requires information and structure, but such decisions are often made under great time pressure as part of a hospital discharge. Professional intervention and guidance by an informed but disinterested facilitator may be needed, but hospital discharge planners may not be well suited for this role because their mandate is a rapid discharge. Physicians have 2 crucial roles in these transitions: to ensure the seamless delivery of primary care and to advocate for and facilitate, however possible, better decision making. Physicians need at least a rudimentary knowledge of the array of options and the implications of each. Even if the physician cannot serve as the planning facilitator, the physician should ensure that this task is done well. This review describes the range of options and the implications of each option for long-term care in the United States. It suggests the need for evaluating each patient's care goals, family circumstances and resources, and clinical status to determine if more aggressive medical care might improve an individual's clinical trajectory. PMID- 21245185 TI - Implications of the principle of question propagation for comparative effectiveness and "data mining" research. PMID- 21245186 TI - A vision for patient-centered health information systems. PMID- 21245187 TI - Policy options to improve discharge planning and reduce rehospitalization. PMID- 21245188 TI - Mapping out biomarkers for Alzheimer disease. PMID- 21245189 TI - Cole Porter's eventful nights and days. PMID- 21245190 TI - JAMA patient page. Guillain-Barre syndrome. PMID- 21245191 TI - Differentiation of Arabidopsis guard cells: analysis of the networks incorporating the basic helix-loop-helix transcription factor, FAMA. AB - Nearly all extant land plants possess stomata, the epidermal structures that mediate gas exchange between the plant and the environment. The developmental pathways, cell division patterns, and molecules employed in the generation of these structures are simple examples of processes used in many developmental contexts. One specific module is a set of "master regulator" basic helix-loop helix transcription factors that regulate individual consecutive steps in stomatal development. Here, we profile transcriptional changes in response to inducible expression of Arabidopsis (Arabidopsis thaliana) FAMA, a basic helix loop-helix protein whose actions during the final stage in stomatal development regulate both cell division and cell fate. Genes identified by microarray and candidate approaches were then further analyzed to test specific hypothesis about the activity of FAMA, the shape of its regulatory network, and to create a new set of stomata-specific or stomata-enriched reporters. PMID- 21245192 TI - Expression of fungal diacylglycerol acyltransferase2 genes to increase kernel oil in maize. AB - Maize (Zea mays) oil has high value but is only about 4% of the grain by weight. To increase kernel oil content, fungal diacylglycerol acyltransferase2 (DGAT2) genes from Umbelopsis (formerly Mortierella) ramanniana and Neurospora crassa were introduced into maize using an embryo-enhanced promoter. The protein encoded by the N. crassa gene was longer than that of U. ramanniana. It included 353 amino acids that aligned to the U. ramanniana DGAT2A protein and a 243-amino acid sequence at the amino terminus that was unique to the N. crassa DGAT2 protein. Two forms of N. crassa DGAT2 were tested: the predicted full-length protein (L NcDGAT2) and a shorter form (S-NcDGAT2) that encoded just the sequences that share homology with the U. ramanniana protein. Expression of all three transgenes in maize resulted in small but statistically significant increases in kernel oil. S-NcDGAT2 had the biggest impact on kernel oil, with a 26% (relative) increase in oil in kernels of the best events (inbred). Increases in kernel oil were also obtained in both conventional and high-oil hybrids, and grain yield was not affected by expression of these fungal DGAT2 transgenes. PMID- 21245193 TI - Systemic regulation of leaf anatomical structure, photosynthetic performance, and high-light tolerance in sorghum. AB - Leaf anatomy of C3 plants is mainly regulated by a systemic irradiance signal. Since the anatomical features of C4 plants are different from that of C3 plants, we investigated whether the systemic irradiance signal regulates leaf anatomical structure and photosynthetic performance in sorghum (Sorghum bicolor), a C4 plant. Compared with growth under ambient conditions (A), no significant changes in anatomical structure were observed in newly developed leaves by shading young leaves alone (YS). Shading mature leaves (MS) or whole plants (S), on the other hand, caused shade-leaf anatomy in newly developed leaves. By contrast, chloroplast ultrastructure in developing leaves depended only on their local light conditions. Functionally, shading young leaves alone had little effect on their net photosynthetic capacity and stomatal conductance, but shading mature leaves or whole plants significantly decreased these two parameters in newly developed leaves. Specifically, the net photosynthetic rate in newly developed leaves exhibited a positive linear correlation with that of mature leaves, as did stomatal conductance. In MS and S treatments, newly developed leaves exhibited severe photoinhibition under high light. By contrast, newly developed leaves in A and YS treatments were more resistant to high light relative to those in MS- and S-treated seedlings. We suggest that (1) leaf anatomical structure, photosynthetic capacity, and high-light tolerance in newly developed sorghum leaves were regulated by a systemic irradiance signal from mature leaves; and (2) chloroplast ultrastructure only weakly influenced the development of photosynthetic capacity and high-light tolerance. The potential significance of the regulation by a systemic irradiance signal is discussed. PMID- 21245195 TI - Annexin A1 is a new functional linker between actin filaments and phagosomes during phagocytosis. AB - Remodelling of the actin cytoskeleton plays a key role in particle internalisation and the phagosome maturation processes. Actin-binding proteins (ABPs) are the main players in actin remodelling but the precise role of these proteins in phagocytosis needs to be clarified. Annexins, a group of ABPs, are known to be present on phagosomes. Here, we identified annexin A1 as a factor that binds to isolated latex bead phagosomes (LBPs) in the presence of Ca(2+) and facilitates the F-actin-LBP interaction in vitro. In macrophages the association of endogenous annexin A1 with LBP membranes was strongly correlated with the spatial and temporal accumulation of F-actin at the LBP. Annexin A1 was found on phagocytic cups and around early phagosomes, where the F-actin was prominently concentrated. After uptake was completed, annexin A1, along with F-actin, dissociated from the nascent LBP surface. At later stages of phagocytosis annexin A1 transiently concentrated only around those LBPs that showed transient F-actin accumulation ('actin flashing'). Downregulation of annexin A1 expression resulted in impaired phagocytosis and actin flashing. These data identify annexin A1 as an important component of phagocytosis that appears to link actin accumulation to different steps of phagosome formation. PMID- 21245194 TI - Wnt signaling in estrogen-induced lactotroph proliferation. AB - Prolactinomas are the most common type of functioning pituitary adenoma in humans, but the control of lactotroph proliferation remains unclear. Here, using microarray analysis, we show that estrogen treatment increased expression of Wnt4 mRNA in adult Fischer rat pituitary tissue. Dual immunofluorescence analysis revealed that Wnt4 expression was not confined to lactotrophs, but that it was expressed in all anterior pituitary cell types. Estradiol induced proliferation in the somatolactotroph GH3 cell line, in parallel with Wnt4 mRNA and protein induction. A reporter gene assay for TCF- and LEF-dependent transcription revealed that there was no activation of the canonical Wnt pathway in GH3 cells upon stimulation with Wnt-conditioned culture medium or coexpression of constitutively active mutant beta-catenin. Expression of beta-catenin in both GH3 cells and normal rat anterior pituitary cells was restricted to the cell membrane and was unaltered by treatment with estradiol, with no nuclear beta-catenin being detected under any of the conditions tested. We show for the first time that Wnt4 affects non-canonical signaling in the pituitary by inhibiting Ca(2+) oscillations in GH3 cells, although the downstream effects are as yet unknown. In summary, Wnt4 is expressed in the adult pituitary gland, and its expression is increased by estrogen exposure, suggesting that its involvement in adult tissue plasticity is likely to involve beta-catenin-independent signaling pathways. PMID- 21245196 TI - Bax-derived membrane-active peptides act as potent and direct inducers of apoptosis in cancer cells. AB - Although many cancer cells are primed for apoptosis, they usually develop resistance to cell death at several levels. Permeabilization of the outer mitochondrial membrane, which is mediated by proapoptotic Bcl-2 family members such as Bax, is considered as a point of no return for initiating apoptotic cell death. This crucial role has placed Bcl-2 family proteins as recurrent targets for anticancer drug development. Here, we propose and demonstrate a new concept based on minimal active versions of Bax to induce cell death independently of endogenous Bcl-2 proteins. We show that membrane-active segments of Bax can directly induce the release of mitochondria-residing apoptogenic factors and commit tumor cells promptly and irreversibly to caspase-dependent apoptosis. On this basis, we designed a peptide encompassing part of the Bax pore-forming domain, which can target mitochondria, induce cytochrome c release and trigger caspase-dependent apoptosis. Moreover, this Bax-derived 'poropeptide' produced effective tumor regression after peritumoral injection in a nude mouse xenograft model. Thus, peptides derived from proteins that form pores in the mitochondrial outer membrane represent novel templates for anticancer agents. PMID- 21245197 TI - Troponin T is essential for sarcomere assembly in zebrafish skeletal muscle. AB - In striated muscle, the basic contractile unit is the sarcomere, which comprises myosin-rich thick filaments intercalated with thin filaments made of actin, tropomyosin and troponin. Troponin is required to regulate Ca(2+)-dependent contraction, and mutant forms of troponins are associated with muscle diseases. We have disrupted several genes simultaneously in zebrafish embryos and have followed the progression of muscle degeneration in the absence of troponin. Complete loss of troponin T activity leads to loss of sarcomere structure, in part owing to the destructive nature of deregulated actin-myosin activity. When troponin T and myosin activity are simultaneously disrupted, immature sarcomeres are rescued. However, tropomyosin fails to localise to sarcomeres, and intercalating thin filaments are missing from electron microscopic cross sections, indicating that loss of troponin T affects thin filament composition. If troponin activity is only partially disrupted, myofibrils are formed but eventually disintegrate owing to deregulated actin-myosin activity. We conclude that the troponin complex has at least two distinct activities: regulation of actin-myosin activity and, independently, a role in the proper assembly of thin filaments. Our results also indicate that sarcomere assembly can occur in the absence of normal thin filaments. PMID- 21245199 TI - LSR defines cell corners for tricellular tight junction formation in epithelial cells. AB - Epithelial cell contacts consist of not only bicellular contacts but also tricellular contacts, where the corners of three cells meet. At tricellular contacts, tight junctions (TJs) generate specialized structures termed tricellular TJs (tTJs) to seal the intercellular space. Tricellulin is the only known molecular component of tTJs and is involved in the formation of tTJs, as well as in the normal epithelial barrier function. However, the detailed molecular mechanism of how tTJs are formed and maintained remains elusive. Using a localization-based expression cloning method, we identified a novel tTJ associated protein known as lipolysis-stimulated lipoprotein receptor (LSR). Upon LSR knockdown in epithelial cells, tTJ formation was affected and the epithelial barrier function was diminished. Tricellulin accumulation at the tricellular contacts was also diminished in these cells. By contrast, LSR still accumulated at the tricellular contacts upon tricellulin knockdown. Analyses of deletion mutants revealed that the cytoplasmic domain of LSR was responsible for the recruitment of tricellulin. On the basis of these observations, we propose that LSR defines tricellular contacts in epithelial cellular sheets by acting as a landmark to recruit tricellulin for tTJ formation. PMID- 21245200 TI - Professional exposure to urban stressors and effects on urinary metanephrines. AB - The aim of the study is to assess whether occupational exposure to urban stressors could cause alterations in urinary metanephrines levels in traffic policemen vs administrative staff of municipal police. A total of 258 subjects were included in the study: 129 traffic policemen exposed to urban stressors (68 males and 61 females) and 129 controls (68 males and 61 females). Urinary metanephrines mean levels were significantly higher in male traffic policemen compared to controls (p < 0.01). No significant differences were in female traffic policemen compared to controls. In the control group, urinary metanephrines mean levels were significantly higher in females compared to males (p < 0.01). There were no significant differences in urinary metanephrines mean levels in female traffic policemen vs male traffic policemen. The increase in urinary metanephrines mean levels observed in male exposed compared to controls could be related to chronic occupational exposure to low doses of chemical, physical and psychosocial urban stressors. PMID- 21245198 TI - The Stil protein regulates centrosome integrity and mitosis through suppression of Chfr. AB - Stil (Sil, SCL/TAL1 interrupting locus) is a cytosolic and centrosomal protein expressed in proliferating cells that is required for mouse and zebrafish neural development and is mutated in familial microcephaly. Recently the Drosophila melanogaster ortholog of Stil was found to be important for centriole duplication. Consistent with this finding, we report here that mouse embryonic fibroblasts lacking Stil are characterized by slow growth, low mitotic index and absence of clear centrosomes. We hypothesized that Stil regulates mitosis through the tumor suppressor Chfr, an E3 ligase that blocks mitotic entry in response to mitotic stress. Mouse fibroblasts lacking Stil by genomic or RNA interference approaches, as well as E9.5 Stil(-/-) embryos, express high levels of the Chfr protein and reduced levels of the Chfr substrate Plk1. Exogenous expression of Stil, knockdown of Chfr or overexpression of Plk1 reverse the abnormal mitotic phenotypes of fibroblasts lacking Stil. We further demonstrate that Stil increases Chfr auto-ubiquitination and reduces its protein stability. Thus, Stil is required for centrosome organization, entry into mitosis and cell proliferation, and these functions are at least partially mediated by Chfr and its targets. This is the first identification of a negative regulator of the Chfr mitotic checkpoint. PMID- 21245201 TI - Protective role of diallyl tetrasulfide on cadmium-induced testicular damage in adult rats: a biochemical and histological study. AB - Cadmium (Cd)-induced oxidative damage is the most serious problem that leads to reproductive system failure in both human and animals. Our previous studies indicate that diallyl tetrasulfide (DTS) from garlic has the cytoprotective and antioxidant activity against Cd-induced toxicity in vivo and in vitro. The present investigation was carried out to find the influence of DTS on peroxidative damage induced by Cd in rat testes. The Cd-exposed rat testis showed a significant (p < 0.05) decrease in testes to body weight ratio, along with a significant (p < 0.05) increase in Cd accumulation, lipid peroxidation and protein carbonyl levels. In Cd-exposed rats, we also observed a significant (p < 0.05) decrease in the activities of antioxidant (superoxide dismutase, catalase and glutathione peroxidase) and glutathione metabolizing (glutathione-S transferase, glutathione reductase and glucose-6-phosphate dehydrogenase) enzymes as well as reduced levels of non-enzymic (reduced glutathione, ascorbate and total sulphydryl groups) antioxidants. In contrast, treatment with DTS (40 mg/kg body weight orally) significantly (p < 0.05) reduced the accumulation of Cd and lipid peroxidation markers and also significantly improved the activities of antioxidant defense system in testes. Testicular protection by DTS is further substantiated by remarkable reduction of Cd-induced pathological changes. Our study has revealed that DTS renders protection against Cd-induced testicular injury by reducing Cd-mediated oxidative damage. PMID- 21245202 TI - Antioxidative effects of curcumin, beta-myrcene and 1,8-cineole against 2,3,7,8 tetrachlorodibenzo-p-dioxin-induced oxidative stress in rats liver. AB - The aim of this study was to investigate the effectiveness of curcumin, beta myrcene (myrcene) and 1,8-cineole (cineole) on antioxidant defense system in rats given a persistent environmental pollutant (2,3,7,8-tetrachlorodibenzo-p-dioxin, TCDD). Rats (n = 112) were divided randomly into 8 equal groups. One group was kept as control and given corn oil as carrier. TCDD was orally administered at the dose of 2 MUg/kg/week. Curcumin, myrcene and cineole were orally administered at the doses of 100 mg/kg/day, 200 mg/kg/day and 100 mg/kg/ day, respectively, by gavages dissolved in corn oil with and without TCDD. The liver samples were taken from half of all rats on day 30 and from the remaining half on day 60 for the determination of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH), catalase (CAT), glutathione peroxidase (GSH-Px) and CuZn-SOD levels by spectrophotometric method. The results indicated that although TCDD significantly (p <= 0.01) increased formation of TBARS, it caused a significant decline in the levels of GSH, CAT, GSH-Px and CuZn-SOD in rats. In contrast, curcumin, myrcene and cineole significantly increased GSH, CAT, GSH-Px and CuZn SOD levels but decreased formation of TBARS. Additionally, the antioxidative effects of curcumin, myrcene and cineole were increased at day 60 compared to day 30. In the TCDD groups given curcumin, myrcene and cineole, oxidative stress decreased by time. In conclusion, curcumin, myrcene and cineole showed antioxidant activity and eliminated TCDD-induced oxidative stress in rats in a time-dependent manner. PMID- 21245203 TI - The effect of ascorbic acid supplementation on endosulfan toxicity in rabbits. AB - We investigated the endosulfan-induced alterations and the effect of vitamin C supplementation on endosulfan-induced alterations in serum biochemical markers of oxidative stress and antioxidant capacity in rabbits. Basal, 4th and 6th week serum levels of total oxidant status (TOS), thiobarbituric acid reactive substances (TBARS), advanced oxidation protein products (AOPP), total antioxidant capacity (TAC), total protein sulfhydryl (T-SH) and glutathione-S-transferase (GST) were measured in rabbits administered endosulfan (1 mg/kg) alone or in combination with vitamin C (20 mg/kg) for 6 weeks. Control rabbits received either vehicles or vitamin C. Serum TOS, TBARS and AOPP levels at 4th and 6th week were significantly higher whereas T-SH levels were significantly lower than basal values in endosulfan-administered rabbits. GST increased significantly at 4th week but decreased below basal value at 6th week. Similarly, TAC decreased significantly at 6th week. Vitamin C supplementation increased TAC at 4th and 6th weeks in controls and increased T-SH and GST and decreased TOS, TBARS and AOPP at 4th week in endosulfan-administered rabbits. TAC increased significantly at 6th week by vitamin C supplementation in endosulfan-administered rabbits. There were significant increments in TBARS and decrements in TAC and GST levels at 6th week compared to 4th week in endosulfan-administered rabbits. Present findings indicated to an increased and progressively uncompensated oxidant stress in endosulfan-administered rabbits that was substantially ameliorated by vitamin C supplementation through an improvement in antioxidant capacity. It was suggested that vitamin C supplementation might be helpful in preventing the detrimental effects of increased oxidative stress caused by endosulfan exposure. PMID- 21245204 TI - Chelation of cadmium by combining deferasirox and deferiprone in rats. AB - The present research aimed to characterize the potential efficiency of two chelators after cadmium administration for 60 days following two dose levels of 20 and 40 mg/kg body weight daily to male rats. However, the hypothesis that the two chelators might be more efficient as combined therapy than as single therapy in removing cadmium from the body was considered. In this way, two known chelators deferasirox and deferiprone (L(1)) were chosen and tested in the acute rat model. Two chelators were given orally as a single or combined therapy for the period of a week. Cadmium and iron concentrations in various tissues were determined by graphite furnace and flame atomic absorption spectrometry methods, respectively. The combined chelation therapy results show that Deferasirox and L(1) are able to remove cadmium ions from the body while iron concentration returned to the normal level and symptoms are also decreased. PMID- 21245205 TI - Effectiveness of community-based ambulation training for walking function of post stroke hemiparesis: a randomized controlled pilot trial. AB - OBJECTIVE: To investigate the effect of community-based ambulation training on walking function of patients with post-stroke hemiparesis. DESIGN: Randomized, single-blind, controlled pilot study. SETTING: Inpatient rehabilitation hospital. SUBJECTS: Twenty-five subjects were randomly assigned to either the experimental group or the control group, with 13 and 12 subjects, respectively. INTERVENTIONS: All subjects received a routine physical therapy. The subjects in the experimental group also received community-based ambulation training, which was performed for an hour, once a day, three times a week for a four-week period. MAIN MEASURES: Ten-metre walk test, 6-minute walk test, community walk test, walking ability questionnaire and activities-specific balance confidence scale before and after the intervention. RESULTS: The change values of the 10-m walk test (0.21 +/- 0.12 m/s versus 0.07 +/- 0.10 m/s), community walk test (-13.61 +/ 10.31 minutes versus -3.27 +/- 11.99 minutes), walking ability questionnaire (6.15 +/- 3.60 score versus 2.75 +/- 2.38 score) and activities-specific balance confidence scale (17.45 +/- 11.55 score versus 2.55 +/- 10.14 score) were significantly higher in the experimental group than in the control group (P < 0.05). At post-test, the 10-m walk test was significantly higher in the experimental group than in the control group (0.72 +/- 0.24 m/s versus 0.50 +/- 0.23 m/s) (P < 0.05). In the experimental group, there were significant differences for all variables between pre-test and post-test (P < 0.01), whereas the subjects of the control group showed a significant difference in only the walking ability questionnaire (P < 0.01). CONCLUSIONS: The findings demonstrate that community-based ambulation training can be helpful in improving walking ability of patients with post-stroke hemiparesis and may be used as a practical adjunct to routine rehabilitation therapy. PMID- 21245206 TI - Therapeutic targeting of B cells for rheumatic autoimmune diseases. AB - Autoreactive B cells are characterized by their ability to secrete autoantibodies directed against self-peptides. During the last decade, it has become increasingly apparent that B lymphocytes not only produce autoantibodies but also exert important regulatory roles independent of their function as antibody producing cells. This is especially relevant in the context of autoimmunity, because autoreactive B cells have been shown to possess the ability to activate pathogenic T cells, to produce pro-inflammatory cytokines, and to promote the formation of tertiary lymphoid tissue in target organs. The production of monoclonal antibodies against B-cell-surface molecules has facilitated the characterization of several distinct B lymphocyte subsets. These cell-surface molecules have not only served as useful cell differentiation markers but have also helped to unravel the important biological functions of these cells. Some of these molecules, all of which are expressed on the cell surface, have proven to be effective therapeutic targets. In both animal models and in clinical assays, the efficient elimination of B lymphocytes has been shown to be useful in the treatment of rheumatoid arthritis and other autoimmune diseases. The treatment of most rheumatic autoimmune diseases relies mainly on the use of cytotoxic immunosuppressants and corticosteroids. Although this has resulted in improved disease survival, patients may nonetheless suffer severe adverse events and, in some cases, their relapse rate remains high. The increasing need for safer and more effective drugs along with burgeoning new insights into the pathogenesis of these disorders has fueled interest in biological agents; clinical trials involving the B-cell depletion agent rituximab have been especially promising. This article reviews the current knowledge of B-cell biology and pathogenesis as well as the modern therapeutic approaches for rheumatic autoimmune diseases focusing in particular on the targeting of B-cell-specific surface molecules and on the blocking of B-cell activation and survival. PMID- 21245207 TI - Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. AB - The importance of membrane transporters for drug pharmacokinetics has been increasingly recognized during the last decade. Organic anion transporting polypeptide 1B1 (OATP1B1) is a genetically polymorphic influx transporter expressed on the sinusoidal membrane of human hepatocytes, and it mediates the hepatic uptake of many endogenous compounds and xenobiotics. Recent studies have demonstrated that OATP1B1 plays a major, clinically important role in the hepatic uptake of many drugs. A common single-nucleotide variation (coding DNA c.521T>C, protein p.V174A, rs4149056) in the SLCO1B1 gene encoding OATP1B1 decreases the transporting activity of OATP1B1, resulting in markedly increased plasma concentrations of, for example, many statins, particularly of active simvastatin acid. The variant thereby enhances the risk of statin-induced myopathy and decreases the therapeutic indexes of statins. However, the effect of the SLCO1B1 c.521T>C variant is different on different statins. The same variant also markedly affects the pharmacokinetics of several other drugs. Furthermore, certain SLCO1B1 variants associated with an enhanced clearance of methotrexate increase the risk of gastrointestinal toxicity by methotrexate in the treatment of children with acute lymphoblastic leukemia. Certain drugs (e.g., cyclosporine) potently inhibit OATP1B1, causing clinically significant drug interactions. Thus, OATP1B1 plays a major role in the hepatic uptake of drugs, and genetic variants and drug interactions affecting OATP1B1 activity are important determinants of individual drug responses. In this article, we review the current knowledge about the expression, function, substrate characteristics, and pharmacogenetics of OATP1B1 as well as its role in drug interactions, in parts comparing with those of other hepatocyte-expressed organic anion transporting polypeptides, OATP1B3 and OATP2B1. PMID- 21245208 TI - Enhancement of GABAergic activity: neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology. AB - GABA is the major inhibitory neurotransmitter in the central nervous system (CNS). The type A GABA receptor (GABA(A)R) system is the primary pharmacological target for many drugs used in clinical anesthesia. The alpha1, beta2, and gamma2 subunit-containing GABA(A)Rs located in the various parts of CNS are thought to be involved in versatile effects caused by inhaled anesthetics and classic benzodiazepines (BZD), both of which are widely used in clinical anesthesiology. During the past decade, the emergence of tonic inhibitory conductance in extrasynaptic GABA(A)Rs has coincided with evidence showing that these receptors are highly sensitive to the sedatives and hypnotics used in anesthesia. Anesthetic enhancement of tonic GABAergic inhibition seems to be preferentially increased in regions shown to be important in controlling memory, awareness, and sleep. This review focuses on the physiology of the GABA(A)Rs and the pharmacological properties of clinically used BZDs. Although classic BZDs are widely used in anesthesiological practice, there is a constant need for new drugs with more favorable pharmacokinetic and pharmacodynamic effects and fewer side effects. New hypnotics are currently developed, and promising results for one of these, the GABA(A)R agonist remimazolam, have recently been published. PMID- 21245209 TI - Kappa opioid receptors mediate where fear is expressed following extinction training. AB - Six experiments used a within-subjects renewal design to examine the involvement of kappa opioid receptors (KORs) in regulating the expression and recovery of extinguished fear. Rats were trained to fear a tone conditioned stimulus (CS) via pairings with foot shock in a distinctive context (A). This was followed by extinction training of the CS in a second context (B). Finally, all rats were tested for fear to the tone in the extinction context (ABB) and the training (ABA) or a novel (ABC) context. Intracerebroventricular (ICV) infusion of the KOR antagonist nor-binaltorphimine dihydrochloride (nor-BNI) dose-dependently prevented ABA renewal of fear, but had no effect on the expression of ABC renewal, the expression of extinction, or the expression of nonextinguished fear. Conversely, pretest infusion of the KOR agonist U50,488 hydrochloride (U50,488) selectively facilitated the expression of ABA renewal and had no effect on the expression of extinction. Pretest infusion of nor-BNI had no effect on the expression of context-specific latent inhibition. Collectively, these results suggest that KORs gate the expression of fear following extinction training and may comprise a critical neuropeptide component of the circuitry underlying context-dependent expression of fear. PMID- 21245210 TI - Whereas short-term facilitation is presynaptic, intermediate-term facilitation involves both presynaptic and postsynaptic protein kinases and protein synthesis. AB - Whereas short-term plasticity involves covalent modifications that are generally restricted to either presynaptic or postsynaptic structures, long-term plasticity involves the growth of new synapses, which by its nature involves both pre- and postsynaptic alterations. In addition, an intermediate-term stage of plasticity has been identified that might form a bridge between short- and long-term plasticity. Consistent with that idea, although short-term term behavioral sensitization in Aplysia involves presynaptic mechanisms, intermediate-term sensitization involves both pre- and postsynaptic mechanisms. However, it has not been known whether that is also true of facilitation in vitro, where a more detailed analysis of the mechanisms involved in the different stages and their interrelations is feasible. To address those questions, we have examined pre- and postsynaptic mechanisms of short- and intermediate-term facilitation at Aplysia sensory-motor neuron synapses in isolated cell culture. Whereas short-term facilitation by 1-min 5-HT involves presynaptic PKA and CamKII, intermediate-term facilitation by 10-min 5-HT involves presynaptic PKC and postsynaptic Ca(2+) and CamKII, as well as both pre- and postsynaptic protein synthesis. These results support the idea that the intermediate-term stage is the first to involve both pre- and postsynaptic molecular mechanisms, which could in turn serve as some of the initial steps in a cascade leading to synaptic growth during long-term plasticity. PMID- 21245211 TI - Endurance factors improve hippocampal neurogenesis and spatial memory in mice. AB - Physical activity improves learning and hippocampal neurogenesis. It is unknown whether compounds that increase endurance in muscle also enhance cognition. We investigated the effects of endurance factors, peroxisome proliferator-activated receptor delta agonist GW501516 and AICAR, activator of AMP-activated protein kinase on memory and neurogenesis. Mice were injected with GW for 7 d or AICAR for 7 or 14 d. Two weeks thereafter mice were tested in the Morris water maze. AICAR (7 d) and GW improved spatial memory. Moreover, AICAR significantly, and GW modestly, elevated dentate gyrus neurogenesis. Thus, pharmacological activation of skeletal muscle may mediate cognitive effects. PMID- 21245213 TI - Preface. PMID- 21245214 TI - Techniques for studying ion channels: an introduction. AB - In this Introduction to the Special Issue on Ion Channels in Plants, the techniques used to study ion channels are reviewed. In particular, the basic approaches used for the electrophysiological study of ion channels are explained, from voltage clamping membranes and observing current changes over time, to the construction of current-voltage relations and the use of tail current protocols to determine channel selectivity. This is done for whole-cell and single channel records. PMID- 21245212 TI - PKG-mediated MAPK signaling is necessary for long-term operant memory in Aplysia. AB - Signaling pathways necessary for memory formation, such as the mitogen-activated protein kinase (MAPK) pathway, appear highly conserved across species and paradigms. Learning that food is inedible (LFI) represents a robust form of associative, operant learning that induces short- (STM) and long-term memory (LTM) in Aplysia. We investigated the role of MAPK signaling in LFI memory in vivo. Inhibition of MAPK activation in animals prior to training blocked STM and LTM. Discontinuing MAPK signaling immediately after training inhibited LTM with no impact on STM. Therefore, MAPK signaling appears necessary early in memory formation for STM and LTM, with prolonged MAPK activity required for LTM. We found that LFI training significantly increased phospho-MAPK levels in the buccal ganglia. Increased MAPK activation was apparent immediately after training with greater than basal levels persisting for 2 h. We examined the mechanisms underlying training-induced MAPK activation and found that PKG activity was necessary for the prolonged phase of MAPK activation, but not for the early MAPK phase required for STM. Furthermore, we found that neither the immediate nor the prolonged phase of MAPK activation was dependent upon nitric oxide (NO) signaling, although expression of memory was dependent on NO as previously reported. These studies emphasize the role of MAPK and PKG in negatively reinforced operant memory and demonstrate a role for PKG-dependent MAPK signaling in invertebrate associative memory. PMID- 21245215 TI - A unified procedure for the correction of liquid junction potentials in patch clamp experiments on endo- and plasma membranes. AB - Correct determination of absolute values and polarities of liquid junction potentials (LJPs) is essential in patch clamp experiments for the estimation of ionic selectivities and activation voltages of ion channels. A simple approach for the correction of membrane voltages for LJPs has been developed. The method covers all combinations of LJPs between the solutions of bath, patch pipette and reference salt bridge and is applicable to all patch configurations on plasma membranes and endomembranes. PMID- 21245216 TI - Gating and permeation models of plant channels. AB - Models of different level are applied to plant membrane transport. For the evaluation of I/V curves, models based on enzyme kinetics, limitation by diffusion and the ion well are described. Physical models of ion-ion interaction deal with the Woodhull model, the multi-site single-file ion pore, the ion-ion ion-water interaction model and the effect of screening. The discussion of channel gating starts with pre-patch evidence of gating and the biological importance of gating. State models play a dominant role in the analysis of patch clamp records. Gating may strongly interfere with permeation models. With respect to this, the limits of temporal resolution are of great importance. The effects of Na(+) and Tl(+) are examples of the influence of fast gating on modelling and the problems of its detection. The highest level of modelling is achieved when the knowledge about the structure of channels is employed for the modelling of gating. Major topics in this field are blockade by ions and phosphorylation. PMID- 21245217 TI - Anion channel activity in the Chara plasma membrane: co-operative subunit phenomena and a model. AB - Anion channel activity in the plasma membrane of internodal cells of Chara australis has been studied using the patch clamp method and the records analysed with a program based on the Hidden Markov Model. The activity was variable in time, and often showed very noisy periods. At other times there were one or more of five types of channel-like activity. These are believed, like the noise, to arise from the same anion-conducting mechanism in the membrane. The channel-like activity shows many current levels, the actual levels varying on a time-scale of the order of seconds. The records show non-independent transitions between levels, and thus the activity is not the result of the patch containing many independent channels. The currents often move sequentially between adjacent levels. The current levels are at times more closely spaced as the magnitude of the current increases. Underlying this sequential transition scheme it is found that current and conductance frequently show levels that are integer multiples of a unit. Typically about 10 levels occur, a typical transition scheme being (in units) 0<->4<->7<->9. It is shown that it is possible to model such sequential transition schemes with underlying units by considering a new model based on a random walk on a semiregular fragmentary tessellation of a plane. PMID- 21245218 TI - Oscillatory interactions between voltage gated electroenzymes. AB - The activities of the major ion pathways in the plasma membranes of plants are sensitive to the membrane voltage, V. Therefore, these 'electroenzymes' interact with each other via the free running voltage under physiological conditions. A physical background is given here, of how to calculate these interactions on the basis of experimental data on these electroenzymes. Simplifying model calculations with five major electroenzymes from plant cells (H(+) pump, inward and outward rectifying channels for K(+), a Cl(-) channel, and a 2H(+)/Cl(-) symporter) show that osmotic relations are balanced in the long-term not by an appropriate steady-state, but by alternation between a state of salt uptake at V < < E(K) (the Nernst equilibrium voltage for K(+) diffusion) and a state of salt loss at V > E(K). Several specific properties of the model are discussed numerically, e.g. minimum configuration for oscillations (with two electroenzymes), temperature-compensation, the physiological impact of fast gating in plant membranes, and solution of possible paradoxes, such as flux stimulation by conductance inhibition. PMID- 21245219 TI - Functional comparison of plant inward-rectifier channels expressed in yeast. AB - Functional expression of plant ion channels in the yeast Saccharomyces cerevisiae is readily demonstrated by the successful screening of plant cDNA libraries for complementation of transport defects in especially constructed strains of yeast. The first experiments of this sort identified two potassium-channel genes from Arabidopsis thaliana, designated KAT1 and AKT1 (Anderson et al., 1992; Sentenac et al., 1992), both of which code for proteins resembling the Shaker superfamily of K(+) channels in animal cells. Patch-clamp analysis, directly in yeast, of the two channel proteins (Kat1 and Akt1) reveals both functional similarities and functional differences: similarities in selectivity and in normal gating kinetics; and differences in time-dependent effects of ion replacement, in the affinities of blocking ions, and in dependence of gating kinetics on extracellular K(+). Kat1, previously described in yeast (Bertl et al., 1995), is about 20-fold more permeable to K(+) than to Na(+) or NH(+)(4), shows K(+) independent gating kinetics, and is blocked with moderate effectiveness (30-50% at 10 mM) by barium and tetraethylammonium (TEA(+)) ions. Akt1, by contrast, is weakly inhibited by TEA(+), more strongly inhibited by Ba(2+), and very strongly inhibited by Cs(+). Furthermore Na(+) and NH(+)(4), while having about the same permeance to Akt1 as to Kat1, have delayed effects on Akt1: brief replacement of extracellular K(+) by Na(+) enhances by nearly 100% the subsequent K(+) currents after sodium removal; and brief replacement of K(+) by NH(+)(4) reduces subsequent K(+) currents by nearly 75%. Furthermore, lowering of extracellular K(+) concentration, by replacement with osmotically equivalent sorbitol, significantly retards the opening of Akt1 channels; that is, the gating kinetics for Akt1 are clearly influenced by the concentration of permeant ions. In this respect, Akt1 resembles the native yeast outward rectifier, Ypk1 (Duk1; Reid et al., 1996). The data suggest that all of the ions tested bind within the open channels, such that the weakly permeant species (Na(+), NH(+)(4)) are easily displaced by K(+), but the blocking species (Cs(+), Ba(2+), TEA(+)) are not easily displaced. With Akt1, furthermore, the permeant ions bind to a modulator site where they persist after removal from the medium, and through which they can alter the channel conductance. Extracellular K(+) itself also binds to a modulator site, thereby enhancing the rate of opening of Akt1. PMID- 21245220 TI - Mutational analysis of functional domains within plant K+ uptake channels. AB - Site-directed mutations have been generated in the pore and voltage sensor regions of the inwardly rectifying potassium channels KAT1 and KST1. The properties of mutant channels have been analysed in Xenopus oocytes, and give insights into the structure-function relations of these channels. PMID- 21245221 TI - Function and regulation of seed aquaporins. AB - The discovery of water channel proteins named aquaporins has shed new light on the molecular mechanisms of transmembrane water transport in higher plants. As with their animal counterparts, plant aquaporins belong to the large MIP family of transmembrane channels. An increasing number of aquaporins is now being identified on both the vacuolar and plasma membranes of plant cells, but their integrated function remains unclear. Aquaporin alpha-TIP is specifically expressed in the membrane of protein storage vacuoles in seeds of many plant species. alpha-TIP was previously shown to undergo phosphorylation in bean seeds. The functional significance of this process was further investigated after heterologous expression of the protein in Xenopus oocytes. Using site-directed mutagenesis of alpha-TIP and in vitro and in vivo phosphorylation by animal cAMP dependent protein kinase, it is shown that, in oocytes, direct phosphorylation of alpha-TIP occurs at three distinct sites and stimulates its water channel activity. In addition to aquaporin phosphorylation, other mechanisms that target aquaporin function are used by living cells to regulate their membrane water permeability. These are the fine control of aquaporin gene expression and, in animal cells only, the regulated trafficking of water channel-containing vesicles. The present work and studies by others on the phosphorylation of nodulin-26, an ion channel protein homologous to alpha-TIP, provide novel insights into the mechanisms of plant membrane protein regulation. These studies might help identifying and characterizing novel membrane-bound protein kinases and phosphatases. Finally, an integrated function for seed vacuolar aquaporins is discussed. During germination, the rehydration of seed cells, the drastic changes in vacuole morphology, the breakdown and the mobilization of storage products from the vacuole may create osmotic perturbations in the cytoplasm. The fine tuning of TIP aquaporin activity may help control the kinetics and amplitude of osmotic water flows across the tonoplast to achieve proper cytoplasm osmoregulation and control of vacuolar volume. PMID- 21245222 TI - A patch clamp study of Na+ transport in maize roots. AB - The mechanisms mediating Na(+) transpdrt in higher plant roots were investigated by applying the patch clamp technique to protoplasts isolated from the cortex and stele of maize roots. In the cortex, permeation of Na+ through a time-dependent K(+)-selective inward rectifier was negligible. Instead, Na(+) influx into maize roots probably occurs via an instantaneously-activating current. This current was partially inhibited by extracellular Ca(2+), but was insensitive to extracellular TEA(+), Cs(+) and TTX. In outside-out patches, a plasma membrane ion channel was found which mediated an inward Na(+) current which, at least in part, underlies the whole-cell instantaneously-activating current. The unitary conductance of this channel was 15 pS in 102:121 mM Na(+) (outsidexytosol). Channel gating was voltage-independent and distinct from that observed for the inwardly rectifying K(+)-selective channel in the same cell type. Increasing extracellular Ca(2+) from 0.1 to 1 mM reduced the open probability and unitary conductance of this channel. In 102 mM Na(+) : 123 mM K(+) (outside:cytosol) a P(Na):P(K) of 2.1 was calculated. It is suggested that the plasma membrane Na(+)-permeable channel identified in the cortex of maize roots represents a pathway for low affinity Na(+) uptake by intact maize roots. In the stele, permeation of Na(+) through outwardly rectifying K(+) channels was found to be negligible and the channels are thus unlikely to be involved in the transport of Na(+) from the root symplasm. PMID- 21245223 TI - Regulatory mechanisms of ion channels in xylem parenchyma cells. AB - Xylem parenchyma cells surround the xylem vessels and control the composition of the transpiration stream which flows through the vessels. In the plasma membrane of the xylem parenchyma cells, one inward rectifying channel (denoted KIRC) and two outward rectifying channels (denoted KORC and NORC) have been identified. In the present study it is shown that KIRC was activated by Gpp(NH)p, in contrast to the inward rectifier in guard cells. In the inside-out patch configuration, Gpp(NH)p elicited single channel KIRC activity as well and the conclusion is, therefore, that KIRC is G-protein regulated in a membrane-delimited fashion. NORC gating is affected by the calcium buffering capacity of the pipette solution as determined by the amount of EGTA. KORC conductance is shown to be strongly dependent upon the apoplastic K(+)-concentration. The role of the above-mentioned transporters and their regulation mechanisms are discussed in the light of root:shoot communication and long-distance signalling. PMID- 21245224 TI - Regulation of K+ absorption in plant root cells by external K+: interplay of different plasma membrane K+ transporters. AB - Plant roots accumulate potassium from a wide range of soil concentrations, utilizing at least two distinct plasma membrane uptake systems with different affinities for the cation. Details on the structure and function of these K(+) transporters are accumulating, but many prominent questions remain regarding regulation of these uptake pathways in varying physiological conditions. Efficient use of the K(+) absorption capacity requires that the activity of all membrane K(+) conductances interact. In this paper, it is shown how intrinsic properties of the major K(+) transporters in the root plasma membrane generate sufficient inward K(+) flux at varying levels of external [K(+)]. In the high affinity range, uptake proceeds via K(+):H(+) symport and kinetic control prevents outward K(+) leakage through inward rectifying channels. Leakage through outward rectifying channels is minimized due to a combination of kinetic control and intrinsic open channel rectification as predicted by the constant field theory. At millimolar external K(+), symport activity is down regulated by the K(+) induced membrane depolarization. In these conditions, channel-mediated K(+) uptake can only explain the observed unidirectional fluxes in intact tissue if the cell switches from a state where the K(+) conductance dominates (K(+)-state) to one where the primary pumps dominate the membrane conductance (pump-state). PMID- 21245225 TI - Pathways for the permeation of Na+ and Cl- into protoplasts derived from the cortex of wheat roots. AB - Sodium permeation into cortex cells of wheat roots was examined under conditions of high external NaCI and low Ca(2+). Two types of K(+) inward rectifier were observed in some cells. The time-dependent K(+) inward rectifier was Ca(2+) sensitive, increasing in magnitude as external Ca(2+) was decreased from 10 mM to 0.1 mM, but did not show significant permeability to Na(+). However, the spiky inward rectifier showed significant Na+ permeation at Ca(2+) concentrations of 1 and 10 mM. In cells that initially did not show K(+) inward rectifier channels, fast and sometimes slowly activating whole-cell inward currents were induced at membrane potentials negative of zero with high external Na(+) and low Ca(2+) concentrations. With 1 mM Ca(2+) in the external solution, large inward currents were carried by Rb(+), Cs(+), K(+), Li(+), and Na(+). The permeability sequence shows that K(+), Rb(+) and Cs(+) are all more permeant than Na(+), which is about equally as permeant as Li(+). When some K(+) was present with high concentrations of Na(+) the inward currents were larger than with K(+) or Na(+) alone. About 60% of the inward current was reversibly blocked when the external Ca(2+) activity was increased from 0.03 mM to 2.7 mM (half inhibition at 0.31 mM Ca(2+) activity). Changes in the characteristics of the current noise indicated that increased Ca(2+) reduced the apparent single channel amplitude. In outside-out patches inward currents were observed at membrane potentials more positive than the equilibrium potentials for K(+) and Cl(-) when the external Na(+) concentration was high. These channels were difficult to analyse but three analysis methods yielded similar conductances of about 30 pS. PMID- 21245226 TI - Multiple inward channels provide flexibility in Na+/K+ discrimination at the plasma membrane of barley suspension culture cells. AB - Ion transport across the plasma membrane of suspension-culture cells derived from immature barley embryos has been studied in low (15 mM KCl) and high (additional 150 mM NaCl) salt conditions to understand how plants discriminate between K(+) and Na(+) during ion uptake. In both media about 50% of the cells exhibited resting potentials more negative than any of the passive diffusion potentials. In whole-cell patch clamp experiments membrane hyperpolarization activated large inward currents. Whilst the instantaneous current components did not discriminate between K(+) and Na(+), the time-dependent current, I(in), was selective for K(+) over Na(+). Further analysis of I(in) revealed the following properties: double exponential current activation (time-constants 0.03 s and 0.3 s, half activation potential - 171 mV); no inactivation; complete block by Ba(2+) (30 mM in 100 mM KCl) and part block by TEA(+) (maximum 50% with 20 mM); dependence on millimolar concentrations of cytoplasmic ATP; no block by external or cytoplasmic Na(+). The selectivity sequences K(+) ? Rb(+) > NH(+)(4) > Na(+) ? Cl(-) and K(+) ? NH(+)(4) > Na(+) > Rb(+) were determined from measurements of reversal potentials and relative steady-state currents respectively. P(Na):P(K) was 0.07 +/- 0.02 (from reversal potentials) and I(Na):I(K) was 0.17 + 0.05 (from relative currents). A high variance among the observed permeability ratios suggested that several channels with different ion-selectivities contributed to the time-dependent whole cell currents. In single channel experiments, several inward channels with distinct properties were found. The major channels were (i) a voltage-gated, K(+) selective channel (12 pS), (ii) an ATP-activated non-selective cation channel (7 pS) and (iii) an inward-rectifying anion-channel (150 pS, all unitary conductances given for 100 mM KCI). No significant differences were found in whole-cell currents or single-channel characteristics between cells that had been adapted to a high-salt growth-medium (150 mM NaCl) and non-adapted cells. The idea that differential regulation of plasma membrane ion channels gives rise to a physiological flexibility, allowing the cells to control Na(+) uptake under varying external conditions, is discussed. PMID- 21245227 TI - Cation channels in the plasma membrane of rye roots. AB - Voltage-dependent cation channels in the plasma membrane of rye (Secale cereale L.) root cells have been studied electrically both in vivo, by patch-clamping protoplasts of epidermal cells, and in vitro, following the reconstitution of plasma-membrane vesicles into planar lipid bilayers (PLB). The patch-clamp technique has identified a time-dependent inward-rectified K(+) current and two time-dependent outward-rectified currents, one of which is relatively selective for K(+) whilst the other is non-selective between cations. In addition, a time independent K(+)-current has been observed in patch-clamp recordings. This current is believed to be carried by voltage-independent channels, which are permeable to monovalent cations and whose biophysical properties correspond to those of the channel most frequently observed in PLB. Two further cation channels are frequently observed in PLB. These channels are permeable to both monovalent and divalent cations and are activated by plasmamembrane depolarization. They may have a role in intracellular signalling since they would mediate Ca(2+) influx in response to plasma-membrane depolarization in vivo. In this paper the biophysical properties and physiological roles of each cation channel are discussed and compared with cation channels in the plasma membrane of root cells from contrasting cell types and plant species. PMID- 21245228 TI - Signalling in guard cells and regulation of ion channel activity. AB - A review is presented of the properties of ion channels in plasmalemma and tonoplast of stomatal guard cells, their regulation, with particular reference to Ca(2+) and protein phosphorylation/dephosphorylation, and of the evidence for ABA induced changes in specific ion channels, with an attempt to identify the signalling chains involved in each such change. A key question is whether a local increase in Ca(2+), close to cell membranes and capable of triggering Ca(2+) dependent changes in a variety of ion channels, is a universal feature of the ABA reponse. If this is so, then there exist Ca(2+)-coupled mechanisms for most of the observed changes, including inhibition of the inward K(+) channel and activation of the slow anion channel in the plasmalemma, and activation of two channels in the tonoplast, the K(+)-selective (VK) channel and the slow vacuolar (SV) channel, initiating efflux of both anions and cations from the vacuole. The detailed signalling chains are not complete, and the role of protein phosphorylation/dephosphorylation is not clearly defined, nor linked to ABA. Control of the outward K(+) channel is Ca(2+)-independent; its activation by ABA may be mediated by cytoplasmic alkalinization, but the role of protein dephosphorylation in the signalling chain has still to be clarified. If Ca(2+) is not available as second messenger, then the signalling chains involved have hardly begun to be understood. Detailed comparison of the efflux transients in different conditions provides evidence that ABA changes the 'set-point' of a stretch-activated channel, initiating loss of vacuolar K(+). The inclusion of Ba(2+) in the bathing solution has effects similar to those of reduced ABA concentration, a delay in initiating the vacuolar transient, and a slower rise to a reduced peak height. It is suggested that this could be the result of inhibition of the process of Ca(2+) release from internal stores, by blocking a charge-balancing K(+) flux. PMID- 21245229 TI - Signal redundancy, gates and integration in the control of ion channels for stomatal movement. AB - As many as three distinct signalling pathways and their messengers-entailing changes in cytoplasmic-free Ca(2+) ([Ca(2+)](i)), cytoplasmic pH (pH(i)) and protein phosphorylation-may underpin K(+) and anion channel control during stomatal movements. Such a degree of redundancy is probably not unique among plant cells, and is wholly consistent with the ability of the guard cells to integrate the wide range of environmental and hormonal stimuli that affect stomatal aperture. In principle, signal convergence enables a spectrum of graded responses extending beyond simple interference ('crosstalk'): it allows one pathway to gate transmission via the next, so boosting or muting the final 'integrated signal' that reaches the effector. Current evidence supports such a role for the ABI1 protein phosphatase and, by inference, protein kinase elements in gating K(+) channel sensitivity to pH(i) and ABA. In turn, gating of changes in [Ca(2+)](i) may also be subject to pH(i). Because these signal pathways affect discrete subsets of ion channels at the guard cell plasma membrane, their coupling may be seen to add a further layer of control necessary for co ordinating the ensemble of channel response during stomatal movements. PMID- 21245230 TI - Characterization of ion channel modulator effects on ABA- and malate-induced stomatal movements: strong regulation by kinase and phosphatase inhibitors, and relative insensitivity to mastoparans. AB - In the present study abscisic acid-induced stomatal closing, and malate effects on stomatal apertures were analysed in the presence of guard cell ion channel regulators. A recent study has suggested that abscisic acid (ABA) activation of protein kinases and/or inhibition of protein phosphatases may be central to activation of guard cell slow anion channels and mediation of stomatal closing in Vicia faba (Schmidt et al., 1995). These findings were confirmed and extended in the present study showing that both in Vicia faba and in Commelina communis ABA induced stomatal closings were abolished by kinase inhibitors and enhanced by the protein phosphatase inhibitor okadaic acid. Further detailed studies demonstrate that very high 40 mM extracellular malate concentrations are required to close stomata only partially and that okadaic acid also enhances malate-induced stomatal closing. In addition, when stomata are widely opened, even at 40 mM malate concentrations, no malate effect on stomatal apertures was observed. This finding may be explained by a complete inactivation of guard cell anion channels when stomatal apertures are opened very widely and suggests that extracellular malate cannot function as a primary CO(2) signal in stomatal regulation. The G protein regulators mastoparan and mas7 as well as neomycin showed no significant effects on light-induced stomatal opening and ABA-induced stomatal closing. Findings reported here correlate closely to recent findings on slow anion channel regulation in guard cells and support the hypothesis that activation of these anion channels by phosphorylation events and complete inactivation by dephosphorylation events is a rate-limiting component in guard cell signal transduction. Furthermore, the presented data support a model in which ABA activation of protein kinases and/or inhibition of okadaic acidsensitive protein phosphatases is central to ABA regulation of stomatal movements in Vicia faba and Commelina communis. PMID- 21245231 TI - Calcium channels in higher plant cells: selectivity, regulation and pharmacology. AB - Rapid influx of Ca(2+) into the cytosol from extracellular pools or intracellular stores via ion channels can have wide-ranging physiological consequences. In addition, influx of Ca(2+) across the plasma membrane is necessary for the large net accumulation of Ca(2+) essential for cellular integrity. In this paper, the properties of Ca(2+) channels in various plant membranes are reviewed, and compared with new results on the Ca(2+) channel from the plasma membrane of wheat roots (rca channel) described originally by Pineros and Tester (1995). The rca channel has been studied at the single channel level by incorporation of plasma membrane-enriched vesicles into planar lipid bilayers. It has a high affinity for Ca(2+) permeation (K(m) = 99 uM) and a maximal conductance of 30 pS. It is highly selective for Ca(2+) over Cl(-), but allows the movement both of other divalent cations (with a conductivity sequence: Ba(2+) > Sr(2+) > Ca(2+) >Mg(2+) > Mn(2+)) and of monovalent cations. The affinity for K(+) permeation was 6 mM, and the maximal conductance was 164 pS. The permeability ratio, P(Ca(2+))/P(K(+)) ranged from 17 to 41, decreasing with increasing extracellular Ca(2+). With physiologically reasonable membrane potentials and ionic conditions, the channel will catalyse Ca(2+) influx. At normal resting potentials (negative of about -135 mV) the channel remains largely closed, but activates rapidly upon depolarization. It is insensitive to ABA and Ins 1,4,5-P(3), but the voltage dependence for activation was shifted to more negative potentials upon addition of cytosolic ATP. The channel was inhibited by a range of trivalent cations (La(3+), Al(3+) and Gd(3+)) and by some organic Ca2+ channel effectors (verapamil, diltiazem, ruthenium red), although it was insensitive to bepridil and 1,4 dihydropyridines [nifedipine and (+) and (-) 202-791], at least in the conditions described here. The properties of this channel are compared with those of other plant and animal Ca(2+) channels, and are shown to be consistent with its proposed physiological role of divalent cation uptake into roots. PMID- 21245232 TI - Regulation of channel activity underlying cell volume and polarity signals in Fucus. AB - Polarized zygotes of the marine alga Fucus have been used to investigate the spatial control of Ca(2+) signals in a plant cell during apical growth and cell volume regulation in response to external osmotic fluctuations. UV laser microsurgery has been refined to enable plasma membrane patch clamp recordings from localized regions of the polarizing or polarized zygote. A plasma membrane cation channel that is mechanosensitive and significantly permeable to Ca(2+) was characterized in cell-attached and excised patch configurations. Parallel measurements of intracellular Ca(2+) using ratio photometric and imaging techniques were used to monitor temporal and spatial changes in cytoplasmic Ca(2+) (Ca(2+)(cyt)) in response to activation of these ion channels by osmotic swelling of the rhizoid. In polarized rhizoid cells spatial regulation of voltage and mechanosensitive-Ca(2+) channels in the plasma membrane underlie changes in Ca(2+) that are crucial in signal-response transduction. Direct mechanical stimulation of channels in the plasma membrane of isolated sub-protoplasts from the apex of rhizoid cells can elicit changes in Ca(2+) in the underlying cytosol. PMID- 21245233 TI - Ligand-gated Ca2+ channels and Ca2+ signalling in higher plants. AB - Ligand-gated Ca(2+) channels provide a possible mechanism for linking perception of stimuli to intracellular Ca(2+) mobilization. Evidence for ligand-gated Ca(2+) release in plant cells arises from radiolabeled ligand binding, microsomal ion flux, and electrophysiological approaches. Results from these diverse approaches demonstrate that two classes of ligand-gated channels are present at the plant cell vacuolar membrane. One class of channel is gated by inositol 1,4,5 trisphosphate (InsP(3)) and the second is gated by cyclic adenosine 5' diphosphoribose (cADPR). Previous biochemical studies on plant InsP(3) binding sites have been hampered by low density of specific binding. The present work reports optimization of yield for solubilized InsP(3) binding sites with respect to detergent type and concentration, and the originating tissue. Further studies reveal a pharmacological similarity between cADPR-activated Ca(2+) release in plant and animal cells and demonstrate that the extent of cADPR-induced Ca(2+) release is dependent on the plant tissue type. In animal cells cADPR releases Ca(2+) through activation of at least one isoform of the so-called ryanodine receptor. It is shown here that ryanodine itself is able to activate single channel currents in vacuolar membranes. These observations are integrated into current models for ligand-gated Ca(2+) release in plant and animal cells and their role in Ca(2+)-based cell signalling. PMID- 21245234 TI - Red light-induced membrane potential transients in the moss Physcomitrella patens: ion channel interaction in phytochrome signalling. AB - In caulonemal filaments of the moss Physcomitrella patens red light (fluence rate 85 umol m(-2) s(-1)) triggers within 2-15 s a transient membrane depolarization, and 3 d later the development of side branch initial cells. Both the rapid electrical events at the plasma membrane and the morphological response are Ca(2+)-dependent, phytochrome-mediated and effectively inhibited by the cation channel blocker TEA (10 mM) and the anion channel blocker niflumic acid (1 uM). This suggests that both responses are connected. Current voltage analyses of the red light-induced current combined with ion flux measurements revealed that Ca(2+), K(+) and anion-permeable channels are open at the peak of the depolarization. While Ca(2+) influx and anion efflux coincide with the depolarizing phase, K(+) entry occurs during the first 30 s only and is followed by a dramatic transient K(+) efflux leading to repolarization. Patch clamp studies have revealed the presence of a class of depolarization-activated outward rectifying cation channel with a likely role in the rapid repolarization. Furthermore, the channel has a small permeability for Ca(2+) and could provide an additional mode of Ca(2+) entry. The sequence of events which underlie the red light-induced membrane potential transient is discussed with respect to ion channel interaction during phytochrome signalling. PMID- 21245235 TI - Ion channel activity during the action potential in Chara: new insights with new techniques. AB - The dynamics of macroscopic currents underlying the electrically triggered action potential (AP) in the giant alga Chara corallina were directly recorded with an action potential clamp method. In this technique an AP is recorded and repetitively replayed as the command voltage to the same cell under voltage control. Upon adding the channel blockers niflumic acid and/or Ba(2+) to the bath, the excitation current, i.e. the current crossing the membrane during an AP, can be dissected into a transient, fast-appearing Cl(-) inward current and a transient delayed K(+) outward current. The delayed onset of the K(+) outward current demands the postulation of an additional outward current in order to balance the excess Cl(-) inward current at the onset of the AP. The capacitive current that alters the charge on the membrane during excitation is several orders of magnitude too small to be relevant for charge balance. Measurements of single channel activity in the plasma membrane of C. corallina by the patch clamp method shows two types of Cl(-) channel (15 and 38 pS with 100 mM Cl(-) in the pipette) and one type of K(+) channel (about 40 pS with 100 mM K(+) in the pipette) which become transiently active during an AP. Typically, variable numbers of CI(-) channels activate in a random fashion for short periods of time when favoured by positive voltages in combination with high concentrations of extracellular Ca(2+) (Ca(2+)(o)) or during an AP of the whole cell. The peak values of these Cl(-) channel currents measured in a patch are such that they can account quantitatively for the peak of the whole cell Cl(-) excitation current studied under comparable ionic conditions. Furthermore, the short dura- tion of channel activity, as well as the fast rising and somewhat slower trailing kinetics is similar in duration and dynamics to AP-associated changes in membrane permeability of the whole Chara cell to Cl(-) (P(Cl(-))). Taken together, the data stress that the characteristic, transient activation of random numbers of Cl(-) channels seen in membrane patches is the elementary unit of the Cl(-) excitation current. However, due to the random nature of this transient activity, gating of Cl(-) channels can not be explained on the basis of previous models for excitation: gating can neither be due to intrinsic voltage sensitivity of the Cl( ) channels, nor to a voltage-dependent influx of Ca(2+) and subsequent activation of Ca(2+)-sensitive Cl(-) channels. To account for the short life-time and for the randomness of Cl(-) channel activity, the putative gating factors Ca(2+) and voltage must be uncoupled in time. This could be explained by a random release of Ca(2+) from stores, the latter being filled in a voltage-sensitive manner via non specific cation channels from the outside. A 4 pS non-selective cation channel in the plasma membrane may serve this purpose. The 40 pS K(+) channel, which becomes transiently active in C. corallina during a cell AP, is an outward rectifier. At negative resting voltages the channel has a low open probability (< <1%). At voltages reached during an AP the open probability rises significantly reaching half-maximal open probability at -25 mV. The elevated activity of the 40 pS channel associated with membrane excitation relaxes at the end of an AP with a time constant of about 2.5 s. A comparable time constant of 2 s can be obtained for the decay of the transiently elevated permeability of the membrane to K(+) (P(K(+))), stressing that the kinetic properties of the 40 pS K(+) channel are responsible for the course of whole cell P(K(+)) changes. Voltage sensitivity of the K(+) channels suggests that they are activated during an AP by the drop in membrane voltage in order to aid repolarization. However, the rise and decay of P(K(+)) during an AP also shares similarity with the time-course of transient changes in cytoplasmic concentration of free Ca(2+), [Ca(2+)](cyt), the latter being measured in parallel experiments with the Ca(2+)-sensitive fluorescent dye, Fura-2, in excited C. corallina cells. This similarity could suggest that gating of the 40 pS K(+) channel is also sensitive to [Ca(2+)](cyt) and that the latter sensitivity is rate-limiting for activity during an AP. PMID- 21245236 TI - Malate transport and vacuolar ion channels in CAM plants. AB - Malate is a ubiquitous vacuolar anion in terrestrial plants that plays an important role in carbon metabolism and ionic homeostasis. In plants showing crassulacean acid metabolism (CAM), malate is accumulated as a central intermediary in the process of photosynthetic carbon assimilation, and it is also one of the major charge-balancing anions present in the vacuole. During the CAM cycle, malic acid produced as a result of dark CO(2) fixation accumulates in the vacuole at night (2 H(+) per malate), and is remobilized from the vacuole in the following light period. CAM plants thus provide a good model for studying both the mechanism and control of malate transport across the tonoplast. Thermodynamic considerations suggest that malate(2-) (the anionic species transported out of the cytosol) is passively distributed across the tonoplast. Malic acid accumulation could thus be explained by malate(2-) transport into the vacuole occurring electrophoretically in response to the transmembrane electrical potential difference established by the tonoplast H(+)-ATPase and/or H(+)-PPase. Recent studies using the patch-clamp technique have provided evidence for the existence of a vacuolar malate-selective anion channel (VMAL) in both CAM species and C(3) species. The VMAL current has a number of distinctive properties that include strong rectification (opening only at cytosolicside negative membrane potentials that would favour malate uptake into the vacuole), lack of Ca(2+) dependence, and slow activation kinetics. The kinetics of VMAL activation can be resolved into three components, consisting of an instantaneous current and two slower components with voltage-independent time constants of 0.76 s and 5.3 s in Kalanchoe daigremontiana. These characteristics suggest that the VMAL channel represents the major pathway for malate transport into the vacuole, although the strong rectification of the channel means there may be a separate, still-to-be identified, transport mechanism for malate efflux. PMID- 21245237 TI - Low inter-rater reliability in traditional Chinese medicine for female infertility. AB - BACKGROUND: Treatment of patients according to individual pattern diagnoses is an important feature of acupuncture rooted in traditional Chinese medicine (TCM). Little is known about the reliability of TCM pattern diagnoses. OBJECTIVE: To examine in a cross-sectional study the inter-rater reliability of TCM diagnoses and acupuncture point selection. METHODS: 30 infertile and 24 previously pregnant women were examined for TCM patterns by two acupuncturists. An operational interview guide related to gynaecology was used. The acupuncturists independently decided on the TCM patterns (categorised as excess, deficiency and merged patterns) and the prescription of acupuncture points. Kappa Statistics were used in the analyses. RESULTS: 39 different TCM patterns and 36 different acupuncture points were used. For the choice of acupuncture points, poor to no agreement was found. Moderate to fair agreement was seen in excess/deficiency and merged patterns. Perfect match to moderate agreement on treatment was obtained when choosing meridians given certain TCM patterns. CONCLUSIONS: The low agreement on diagnoses indicates that acupuncturists follow individual pattern differentiation processes. The selection of acupuncture points seem to be closely related to the choice of TCM pattern diagnoses. The results indicate that the poor reliability in the diagnoses and thus treatment received by a patient will vary individually, which in turn is a challenge for clinical trials of acupuncture. PMID- 21245238 TI - Validation of a sham acupuncture procedure in a randomised, controlled clinical trial of chronic pelvic pain treatment. AB - BACKGROUND: Acupuncture is an attractive treatment option for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) that has proved refractory to conventional medical treatments. Unfortunately, it is difficult to determine the benefit of acupuncture because few studies have employed controls or had physiological outcome measures. OBJECTIVE: To determine the feasibility of a sham, or minimally invasive, acupuncture as a control for studies evaluating the efficacy of acupuncture treatment for chronic pelvic pain. METHODS: Participants were recruited from a double-blind randomised trial comparing acupuncture with a sham procedure for patients with CP/CPPS. Acupuncture or sham procedures were performed over a 10-week period. Sham acupuncture involved placement of short needles at sites 0.5 cm away from true acupuncture points (CV1, CV4, SP6 and SP9). Participants were asked to determine their procedure allocation at the end of treatment. A total of 35 participants also agreed to have blood analyses for cortisol, beta-endorphin and leucine-enkephalin. RESULTS: Thirty-five (78%) of the 45 participants randomised to the sham treatment thought they had received acupuncture compared with 27 (61%) of the 44 participants randomised to acupuncture (p=0.11). Biochemical data showed no differences between the groups immediately after treatment. Thirty-two (73%) of 44 acupuncture participants met the predefined clinical response criterion compared with 21 (47%) of 45 sham acupuncture participants (p=0.017, relative risk 1.81, 95% CI 1.3 to 3.1). At the end of the study, beta-endorphin and leucine-enkephalin levels were both higher in the acupuncture group (p<0.01). CONCLUSIONS: Minimally penetrating acupuncture was found to be a valid sham control and may prove useful for evaluating the efficacy of acupuncture for other conditions. PMID- 21245240 TI - Preface. PMID- 21245239 TI - Acupuncture prevents relapses of recurrent otitis in dogs: a 1-year follow-up of a randomised controlled trial. AB - BACKGROUND: Recurrent infections within a particular, well-localised body location are often seen in veterinary and medical practice. This condition could represent a localised or segmental immune deficiency. Recurrent canine otitis seems to be one example of this problem. It has been reported that acupuncture increased the efficacy of conventional treatment for canine otitis by >50%. OBJECTIVE: To assess whether the relapse rate of recurrent canine otitis over 1 year can be modified by acupuncture in adult dogs. METHODS: One-year follow-up of a randomised controlled trial. 31 dogs with a history of recurring otitis were randomised into two groups. In addition to conventional treatment, each group received four sessions of either real acupuncture, group A (n=16), or sham acupuncture, group B (n=15). The main outcome for the follow-up was the rate of acute otitis episodes in each group over 1 year, with blinded evaluation. A chi(2) test was used for statistical analysis. RESULTS: There was one dropout in each group. Fourteen (93%) dogs in group A: were free of otitis relapses, compared with 7 (50%) in group B (p<0.01). CONCLUSION: Acupuncture seems effective for preventing relapses in cases of recurrent canine otitis. This result suggests that acupuncture could be tested as a treatment of other recurrent localised infections. Given the ability of acupuncture to modulate neurotransmitters and opioid peptides, which can in turn modulate the immune system, the immune response to acupuncture also seems worth exploring. PMID- 21245241 TI - Plasmodesmal companion cell-mesophyll communication in the control over carbon metabolism and phloem transport: insights gained from viral movement proteins. AB - Many plant viruses encode for a protein(s) that is essential for movement from the site of replication to surrounding, uninfected cells. These proteins have the ability to interact with endogenous plasmodesmal proteins to increase the plasmodesmal size exclusion limit (SEL). When expressed in transgenic tobacco plants, the movement protein of tobacco mosaic virus (TMV-MP), in addition to increasing the SEL, also alters the biomass partitioning and carbon allocation within these plants. During the day, source leaves of transgenic plants that express the TMV-MP accumulate sugars and starch and biomass partitioning into root tissue is reduced when compared with vector control plants. However, studies with transgenic tobacco plants expressing various mutant forms of the TMV-MP, as well as plants expressing the MP of cucumber mosaic virus, established that the effect on biomass partitioning and carbon allocation is independent of its effect on plasmodesmal SEL. Graft experiments and analysis of transgenic tobacco and potato plants expressing the TMV-MP under tissue-specific promoters indicated that mesophyll cells may be the site of TMV-MP action. In the light of these results and evidence that plasmodesmata are capable of trafficking macromolecules, it is proposed that plasmodesmata within the leaf establish a special communication network between the companion cells (CC) and the mesophyll. In this model, output signals from the CC to the mesophyll and input signals from the mesophyll to the CC are involved in regulating photosynthesis occurring within the mesophyll and loading/export that takes place in the CC-SE complex. It is proposed that the TMV-MP-mediated influence on plasmodesmal trafficking of these signal molecules alters this endogenous control mechanism resulting in a shift in biomass partitioning and carbon allocation. PMID- 21245242 TI - Interaction between sieve element and companion cell and the consequences for photoassimilate distribution. Two structural hardware frames with associated physiological software packages in dicotyledons? AB - The unique properties of the sieve element/companion cell complex (SE/CC complex) are based on the concerted action of SE and CC. A prominent role in this interaction is played by the branched plasmodesmata (pore-plasmodesma units, PPUs) between SE and CC. The large molecular exclusion limit of the PPUs enables an intensive exchange of macromolecular materials and messengers. Further, the degree of symplasmic autonomy of the SE/CC complex and the structural/functional properties of the SE/CC modules may differ between the dicotyledonous families. The speculation is advanced that the difference in building blocks produces two distinct phloem frames ('hardware') with associated physiological programmes ('software'). The implications of two phloem types for photosynthate distribution and relative growth rate are discussed. PMID- 21245243 TI - Post-phloem transport: principles and problems. AB - The movement of assimilates from the sieve element/companion cell complex to sites of utilization has been examined in an extensive array of sinks possessing diverse anatomies. This work has been reviewed with respect to the pathways taken, the conductances and driving forces for movement along the pathways, and interaction between the apoplast and symplast. Most investigations to date have been concerned primarily with determining the pathway of assimilate movement. A symplastic pathway is followed in the great majority of cases studied. However, available methods are less suited for demonstrating apoplastic transport in those instances where it occurs. Far less information is available on quantitative aspects of post-phloem transport. Only a very limited number of observations are available on the diffusive or hydraulic conductances of the apoplast or symplast. In some cases, symplastic conductance appears to be enhanced by a larger-than usual size exclusion limit for cell-to-cell transport. Measurements of the driving forces for post-phloem transport (i.e. gradients in concentration and/or pressure) are also very few in number nor, to date, are they always readily interpretable. Evaluation of solute movement is complicated by interactions between the apoplastic and symplastic pathways, including water relations effects and solute exchange. The presence of apoplastic domains or, simply, high resistance to movement in the apoplast, can lead to steep water relations gradients within sinks, with important implications for transport. To understand how import into sinks is controlled, many more quantitative measurements are needed. This will require considerable experimental ingenuity. PMID- 21245244 TI - Phloem loading--not metaphysical, only complex: towards a unified model of phloem loading. AB - Phloem loading comprises the entire pathway of phloem-mobile solutes from their place of generation (or delivery) to the sieve tubes in a sequence of transport steps across or passing by several different cell types. Each of these steps can be classified as symplastic or apoplastic. The detailed anatomical-cytological work in the past ten years made clear that the symplastic continuity from mesophyll to sieve tubes may be very different for different plant species or even in different vein orders. Therefore data from one species are not transferable to another species and a well-rounded picture involving different experimental methods has to be aimed at for each species separately. The information obtained with the Ricinus seedling, where phloem loading and sieve tube sap analysis can be achieved relatively easily, is presented. The analysis of the radioactive labelling of sucrose from the sieve tubes of cotyledons, in which external and intracellular sucrose had been differently labelled, revealed that at sucrose concentrations close to the natural one, 50% of sucrose is loaded directly from the external medium. The other 50% is first taken up by mesophyll and then released for uptake into the sieve tubes. No bundle tissue works as obligate, intermediate sucrose storage. The apoplast therefore definitely serves as a transit reservoir for sucrose destined to be loaded into the sieve tubes. The sieve tube sap contains glycolytic metabolites at concentrations higher than found in the hypocotyl tissue, whereas the corresponding glycolytic enzymes are missing. It is concluded that the enzymes are sequestered in the companion cell or by parietal membrane stacks. Not only the sieve tubes but nearly all cotyledonary cells are equipped with a sucrose-H(+) symporter able to achieve sucrose accumulation and sensitive to inhibition by high salt concentrations or SH reagents. A cDNA clone coding for a sucrose carrier was isolated. It is transcribed at approximately the same level in most organs of the seedling and throughout the germination period. Leaves of adult Ricinus have significantly lower levels of this transcript. Recirculation of excess, phloem-delivered solutes from the sink back to the source is shown not only to be a common feature of long-distance transport, but the only way that an imbalance between supply to and consumption of nutrients in the sink can be adjusted in the source. It is a pathway by which sink activity regulates phloem loading. Non-invasive NMR imaging revealed the flow rates and flow speeds in phloem and xylem in the intact seedling and proved directly the existence of an internal circulating solution flow. A unified model of phloem loading is proposed, based on a pump-and-leak model, where active sucrose carriers (and other carriers) accumulate solutes in the sieve tubes with a concomitant build-up of pressure resulting in mass flow. Plasmodesmata are leaks (as are the transport carriers, too), slowing down the transport rate, but they also serve as diffusion channels for substances which are produced in the neighbouring cell. Therefore, compounds, which are not made in the sieve tubes themselves are translocated together with the bulk solution of sieve tube sap. PMID- 21245245 TI - Post-sieve element transport of photoassimilates in sink regions. AB - Photoassimilate transport from the sieve elements to the recipient sink cells, principally in the form of sucrose, provides a link between sink metabolism and compartmentation with phloem import. Phloem unloading has focused attention on photoassimilate transport across the sieve element boundary. However, post-sieve element transport can be of equal or greater significance. Three cellular pathways of sieve element unloading and post-sieve element transport are identified. These are apoplastic, symplastic and symplastic interrupted by an apoplastic step. The symplastic path is considered to be the common path, while the remaining pathways serve specialized functions. In particular, the apoplastic step isolates the sieve element transport function from the effects of solute concentration or osmotic changes in the sink cells. Switching between apo- and symplastic routes within a given sink has been found to be linked with such changes. Plasmodesmatal transport undoubtedly involves a diffusive component, but whether bulk flow contributes to the symplastic flux of photoassimilate from the sieve elements to the recipient sink cells is yet to be established unequivocally. Efflux across the plasma membranes of the sieve element-companion cell (se-cc) complexes and other vascular cells occurs by passive diffusion. Along the axial route, retrieval from the phloem apoplast is mediated by sucrose/proton symport. However, this mechanism is absent in terminal sinks. Non vascular efflux from the maternal tissues of developing seed is passive in cereals and energy-coupled in certain grain legumes. Accumulation of sugars from the apoplast of all sinks with an apoplastic step universally occurs by a plasma membrane-bound sugar/proton symport mechanism. Regulation of symplastic transport could be mediated by a combination of sink metabolism and compartmentation coupled with changes in the transport properties of the interconnecting plasmodesmata. PMID- 21245246 TI - Sugar and metabolic regulation of genes for sucrose metabolism: potential influence of maize sucrose synthase and soluble invertase responses on carbon partitioning and sugar sensing. AB - Sugar responsiveness of genes for both paths of sucrose metabolism could provide a mechanism not only for transcriptional regulation of the first step in the use of imported carbon, but also for altering signals to the sugar-sensing system. This hypothesis was examined by comparison of (1) sugar regulation among maize genes for sucrose synthase and invertase, (2) their contrasting patterns of tissue expression, and (3) their influence on production of effectors for other sugar-responsive genes. Cloning and characterization of the Ivr1 and Ivr2 invertase genes of maize indicated that these genes belong to distinct subfamilies of the maize soluble invertase gene family. In addition, maize invertases can be grouped with the sucrose synthases (Sh1 and Sus1) on the basis of shared patterns of differential sugar-responsiveness and tissue-specific expression. Extension of this comparison to include genes for sucrose metabolism from other species revealed a more widespread association between starvation tolerant expression and restricted patterns of tissue distribution. Consideration of current models for plant sugar-sensing systems and transport pathways suggested that the site and mechanism of sucrose cleavage in the cell could affect the magnitude and type of signal generated. PMID- 21245247 TI - Molecular characterization and functional analysis of sucrose-cleaving enzymes in carrot (Daucus carota L.). AB - The amount of carbon transported into storage organs of crop plants to a large degree determines crop yield. The role of sucrose-cleaving enzymes in this process is not clear and it is the main goal of our work to tackle this question. Sucrose cleavage is catalysed either by invertase or sucrose synthase both of which exist in several isoforms with different subcellular locations. Carrot (Daucus carota L.) contains three major isoenzymes of acid invertase, which either accumulate as soluble polypeptides in the vacuole (isoenzymes I and II) or are ionically bound to the cell wall. Carrot sucrose synthase is thought to be a cytoplasmic enzyme encoded by two genes. cDNA clones have been isolated and characterized for cell wall invertase, for isoenzymes I and II of vacuolar invertase, and for sucrose synthase. Gene-specific fragments of these clones were used to determine the steady-state levels of transcripts in the prominent sink and source organs of developing carrot plants. The expression patterns of each gene were different and were organ- and development-specific. Developing tap roots contained only transcripts for isoenzyme II of vacuolar invertase and sucrose synthase. The source/sink balance of these plants was manipulated and only the expression of these two genes was markedly altered, indicating their importance in sucrose partitioning. Based on these results, a model is proposed for sucrose partitioning in carrot plants with developing tap roots in which sucrose synthase regulates sucrose utilization, whereas isoenzyme II of vacuolar invertase controls sucrose storage and sugar composition. PMID- 21245248 TI - Regulation of cell wall invertase by a proteinaceous inhibitor. AB - Suspension-cultured tobacco cells express a cell wall invertase (CWI) and a proteinaceous invertase inhibitor. Both proteins have been purified and characterized. A CWI cDNA clone has been isolated. The N-terminal protein sequence of the inhibitor has been determined showing high similarity with the N terminal sequence of a tomato invertase inhibitor. A polyclonal antiserum has been raised against the denatured inhibitor protein. The observed changes of CWI activity during cell culture are partially the result of changes in gene expression, however, evidence has accumulated for further regulation by the inhibitor protein. In vivo regulation of CWI by the inhibitor is likely for the following reasons: (1) CWI inhibition is dependent on pH within the range relevant for the apoplasmic space, (2) divalent cations in the millimolar range affect CWI inhibition, (3) substrate protects CWI (but not vacuolar invertase) against inhibition, (4) CWI and inhibitor are co-expressed and co-localized in the apoplasmic space, (5) addition of inhibitor to intact cells causes substrate protectable inhibition of CWI, (6) an in situ formation of tight complexes between CWI and inhibitor upon starvation of cells could be demonstrated. The results indicate that suspension-cultured tobacco cells are a suitable system to study the effects of an invertase inhibitor on CWI. PMID- 21245249 TI - Molecular approaches towards an understanding of loading and unloading of assimilates in higher plants. AB - The combination of two sets of molecular tools, namely yeast expression cloning and the possibility of constructing transgenic plants, has allowed analysis of the transport processes occurring at the plasma membrane in higher plants. To date, more than 30 different plant genes for plasma membrane transporters of sugars and amino acids have been identified, mainly by expression cloning. Furthermore, the functional expression of genes in Schizosaccharomyces pombe, Saccharomyces cerevisiae and Xenopus oocytes has been applied to obtain detailed information on the biochemical properties of the transporters. The expression systems have also allowed the purification of the proteins for structural analysis and to study structure-function relationship using mutagenesis approaches. A number of mutants and transgenic plants defective in certain transport properties are available and these will help in understanding the physiology of the long-distance transport of assimilates. PMID- 21245250 TI - Molecular analysis of plant sugar and amino acid transporters. AB - Although plants are photoautotrophic organisms, they are composed of many heterotrophic tissue systems that must import sugars and amino acids in a process known as assimilate partitioning. While the general features of assimilate partitioning were well described by the early 1980s, little was known about the various transport proteins involved in this essential activity associated with multicellular growth. In the past seven years, however, significant progress has been made in describing the transport properties and molecular genetics of these critical transport systems. Initially, these porters were well characterized using purified membrane vesicles and imposed proton electrochemical potential differences. This approach allowed for a detailed analysis of their transport kinetics, bioenergetics, and substrate specificity. Subsequently, several transporters were cloned using differential hybridization and functional complementation of yeast transport mutants. At first, isolation of transporter genes seemed to simplify our understanding by filling in gaps associated with transporter function. However, it has become increasingly clear that assimilate partitioning has many levels of complexity yet to be penetrated. This is best illustrated by the large number of carriers cloned. For example, at least 12 genes encoding putative sugar transporters in the Major Facilitator Superfamily have been identified in plants. Moreover, recent work in this laboratory has demonstrated that a sugar beet member of this superfamily is targeted to the tonoplast membrane, thus implicating that porter in intracellular sugar partitioning. Similar complexity is emerging in the number of plant amino acid transporters identified. Therefore, a detailed analysis of AAP1/NAT2 as a prototypical example of one class of amino acid carriers has been initiated. The topology of this porter is being mapped, and site-directed and random mutagenesis are being used to identify functionally important amino acid residues and protein domains. The major challenges facing this field are to determine the unique contributions made by these many transport systems, to understand their structure and function relationships and, ultimately, to identify the mechanisms which regulate activity and integrate assimilate distribution in the plant as a multicellular organism. PMID- 21245251 TI - Biochemical and molecular characterization of sucrose and amino acid carriers in Ricinus communis. AB - The use of energized plasma membrane vesicle preparations from cotyledons and roots of Ricinus communis seedlings is described, and evidence is presented for the existence of plasma membrane H(+)/sucrose and H(+)/amino acid symporters. Using fractions isolated from roots, there is evidence for at least two carriers which can transport neutral amino acids and one which can also transport basic amino acids. A method for the solubilization and reconstitution of glutamine transport activity is described. Preliminary results on the molecular characterization of two putative amino acid carriers and a putative sucrose transporter from Ricinus are presented. PMID- 21245252 TI - Functional characterization of sucrose binding protein-mediated sucrose uptake in yeast. AB - A sucrose binding protein was identified whose temporal and spatial patterns of mRNA expression and localization patterns of protein were tightly correlated with the active uptake of sucrose in several cell types. Heterologous expression of the sucrose binding protein in yeast strains have allowed a functional characterization of sucrose uptake as mediated by this protein. Ectopic expression of the sucrose binding protein in the susy7/ura3 yeast strain restored the ability of this strain to grow on medium containing sucrose as a sole carbon source. Further characterization of the kinetics of [(14)C]-sucrose uptake indicate that the sucrose binding protein mediates the uptake of sucrose in a non saturable, linear manner and that this uptake is relatively insensitive to pH or treatment with protonophores. These biochemical attributes of sucrose binding protein-mediated sucrose uptake mimic the well characterized linear, non saturable uptake of sucrose described in higher plants. The sucrose binding protein is a unique plasma membrane protein and shares sequence similarity to the seed storage proteins. The sucrose binding protein may mediate sucrose uptake across the plasma membrane in a plant-specific manner. PMID- 21245253 TI - Characterization of leucine-leucine transport in leaf tissues. AB - Uptake of the dipeptide [(3)H]Leu-Leu into leaf discs from mature broad bean (Vicia faba L.) was characterized. Uptake was maximal at pH 6.0 and appeared to be mediated by three systems with apparent K(m) values of 20 uM, 350 uM and 43 mM, respectively. Leu-Leu uptake was sensitive to N-ethylmaleimide, p chloromercuribenzenesulphonic acid, diethylpyrocarbonate, and carbonyl-cyanide-m chlorophenylhydrazone. Nitrate did not compete with peptide uptake, although the peptide transporter and the nitrate transporter have been reported to be homologous. The ability of leaf tissues to take up peptides strongly decreased with leaf age, and the phloem export of peptides as measured by exudation experiments was very low. It is concluded that the leaf tissues contain a peptide transporter that may take up some peptides with a high affinity, but that this transporter is not involved in the long-distance transport of nitrogen under the form of di- or tri-peptides. PMID- 21245254 TI - Effect of environmental factors on whole plant assimilate partitioning and associated gene expression. AB - Partitioning of assimilated carbon among sink organs is a critical factor that controls the rate and pattern of plant growth. Time-course measurements of plant and organ growth rates are useful for determining how regulation of carbon partitioning controls plant growth. Measuring growth rates over a 24 h period reveals the current pattern of carbon partitioning that can be used to predict growth rates of specific sinks. Comparison of growth rates among sinks under defined conditions can point out key factors that regulate partitioning of recently assimilated carbon among sinks. Internal control of carbon partitioning by developmental programmes regulates the timing and site of carbon distribution among developing parts, thereby establishing the adaptive traits of a species, cultivar or transgenic construct. Regulation of partitioning in response to environmental factors establishes or restores allometric growth among plant parts and functional balance between the supply and use of carbon. Environmental stress often restricts resource availability while successful acclimation sets in motion processes that restore the supply. A key mechanism contributing to regulation of carbon partitioning is an expression of genes that control activity of the enzymes which initiate sucrose metabolism at specific sites and stages of ontogeny. PMID- 21245255 TI - The mechanism of assimilate partitioning and carbohydrate compartmentation in fruit in relation to the quality and yield of tomato. AB - The limitation of tomato yield was investigated in a number of cultivars with contrasting fruiting habits. Unless light is limiting, yield is mainly restricted by the number or the size of the fruit (i.e. the sink strength) rather than the supply of assimilate (i.e. the source strength). Fruit size is determined by both cell number and cell size. The rate of fruit expansion is affected by assimilate supply, temperature and water relations in the plant. The size or the growth rate of a tomato fruit is regulated by the import of assimilate and water. The sink strength for assimilate of a tomato fruit measured by the rate of assimilate import may be related to the routes of sugar transport into the sink cells during fruit development. Enzymic regulation of the hydrolysis of sucrose by sucrose synthase and the accumulation of starch by ADPG pyrophosphorylase may determine the rate of assimilate import in the young fruit. Vacuolar invertase activity may determine the sugar composition of a mature fruit, but may not affect the overall dry matter accumulation of a tomato fruit. While yield is determined by the balance between source and sink strengths of the plant, quality is determined by the transport and metabolism of sugars within the fruit. PMID- 21245256 TI - Plant nutrition, dry matter gain and partitioning at the whole-plant level. AB - Differential flows of photoassimilate result in patterns of dry matter distribution among plant organs. The extent to which these patterns are dependent on the flux of different mineral nutrients entering the root and the extent to which the distribution of dry matter in the whole plant is affected by differentials in nutrient (primarily nitrate) flux among parts of the root system is considered. It is concluded that patterns of dry matter distribution and nutritional status may depend on how nutrient supply has been manipulated about the root. Where the flux density of nutrient has been decreased and has become limiting to plant growth, two categories of response have been observed. In the case of N, P or S, limiting flux density results in a proportionately greater amount of plant dry matter in roots than is found at higher flux densities. This contrasts with the case of limiting K, Mg or Mn supply, where proportionately less plant dry matter is found in roots at lower nutrient flux densities than at higher flux densities. In the case of N, particular attention is paid as to how sink strength may be related to differences between root and leaf cells in their capacity for loosening and synthesis processes in the primary cell wall. PMID- 21245257 TI - Effect of mineral nutritional status on shoot-root partitioning of photoassimilates and cycling of mineral nutrients. AB - Mineral nutrients taken up by the roots are, as a rule, transported in the xylem to the shoot, and photoassimilates transported in the phloem to the roots. According to the Thornley model of photosynthate partitioning, nutrient deficiencies should favour photosynthate partitioning to the roots. Examples are cited to show that this preferential partitioning is dependent on phloem mobility and hence on nutrient cycling from shoot to roots. Thus, root growth is enhanced under nitrogen and phosphorus deficiencies, but not under deficiencies of nutrients of low mobility in the phloem, such as calcium and boron. Enhanced root growth under nutrient deficiency relies on the import of both photosynthates and mineral nutrients. Cycling of mineral nutrients serves a number of other functions. These include the root supply of nutrients assimilated in the shoot (nitrate and sulphate reduction), maintenance of cation-anion balance in the shoot, providing an additional driving force for solute volume flow in the phloem and xylem, and acting as a shoot signal to convey nutrient demand to the root. Cycling of certain mineral nutrients through source leaves has a considerable impact on photosynthate export as demonstrated in impaired export under magnesium, potassium, or zinc deficiencies. Mineral nutrient deficiency can, therefore, affect photosynthate partitioning either directly via phloem loading and transport or indirectly by depressing sink demand. PMID- 21245258 TI - Phloem mobility of xenobiotics VIII. A short review. AB - Great strides have been made in the last 15 years in our understanding of phloem mobility of xenobiotics. The subject has been transformed from a poorly understood phenomenon to a process that can be accurately described by the physicochemical properties of the xenobiotic and the nature of the vascular system through which it moves. The basic tenet of the unified mathematical model is that the combination of the permeability and the acid dissociation constant (pK(a)) determines phloem mobility, and this has been largely validated for many compounds in many plant systems. More precise testing of the model is, however, difficult due to the lack of requisite knowledge on the membrane composition of the sieve tube, permeation characteristics and sieve-cell biochemistry. Furthermore, attempts to relate quantitatively a compound's intrinsic mobility to its whole-plant mobility are often confounded by competing loss mechanisms. On the practical side, there is the challenge of coming up with efficacious phloem mobile pesticides. Considerations are forwarded to explain why so far there are numerous phloem-mobile herbicides and yet precious few such insecticides and fungicides, and why the situation might be difficult to change. The knowledge of phloem mobility is robust enough to allow specific structural prescriptions to impart such mobility to existing pesticides. However, such structural changes often lead to a reduction of pesticidal activity. Recently, it has been demonstrated that this problem can be circumvented by combining oxamyl glucuronide (a phloem-mobile pro-nematicide) with a transgenic tobacco plant harboring a root-specific beta-glucuronidase gene to release oxamyl for root-knot nematode control. This propesticide and in situ activation strategy is one way to use the existing body of knowledge for practical purposes. The same principle should be generally applicable to other plant-xenobiotic technologies. PMID- 21245259 TI - Sinks--integral parts of a whole plant. AB - It is argued that it is not possible to predict the flux of assimilate into a sink by making a measurement on that sink alone. Rather carbon flux is a whole plant property and can only be predicted from measurements made simultaneously in source leaves and sinks, and the transport system itself. PMID- 21245260 TI - Sink strength as a determinant of dry matter partitioning in the whole plant. AB - Dry matter partitioning is the end result of the flow of assimilates from source organs via a transport path to the sink organs. The dry matter partitioning among the sinks of a plant is primarily regulated by the sinks themselves. The effect of source strength on dry matter partitioning is often not a direct one, but indirect via the formation of sink organs. Although the translocation rate of assimilates may depend on the transport path, the transport path is only of minor importance for the regulation of dry matter partitioning at the whole plant level. To understand the regulation of dry matter partitioning by the sinks, a parameter like sink strength is needed that describes a sink's ability to influence assimilate import and is independent of the rest of the plant. The term sink strength can be defined as the competitive ability of an organ to attract assimilates. However, there is much debate and confusion about the term sink strength because this term is often not clearly defined. Sink strength has been proposed to be the product of sink size and sink activity. Although cell number is often considered as a suitable measure of sink size, it appears not always to be an important determinant of sink size. Moreover, sink strength may depend on sink age rather than sink size. A model for dry matter partitioning into generative plant parts, which is based on sink strengths of the organs, is described. The potential growth rate (potential capacity to accumulate assimilates) has been shown to be an important parameter that quantitatively reflects the sink strength of an organ. The potential growth rates of the plant's organs are not static but change dynamically. The potential growth rate of a fruit is a function of both its age and temperature. For several crops it has been shown that the dry matter partitioning into an organ can be quantitatively described as a function of its potential growth rate relative to that of the other plant organs. PMID- 21245261 TI - What determines carbon partitioning between competing sinks? AB - Carbohydrate sinks have been described by their ability to attract photosynthate, denoted by sink strength, and by their priority rank ordering for supply in the presence of a reduced availability of photosynthate. Sink strength has been defined as the rate of carbohydrate flow into a sink, but this flow rate is also dependent upon supply, other sinks, and resistance to flow of the transport pathway, so it is not a property of the sink alone. It is a property of the entire system. Hence sink strength defined as a flow rate is not a valid descriptor of a sink. However, a simple model of phloem flow based upon Munch's ideas and with saturable unloading has many properties similar to a plant's carbohydrate source-sink relations, including priorities of sinks, and leads to a set of sink descriptors. This model's ability to mimic observed source-sink relations is reviewed here. PMID- 21245262 TI - Abstracts of other oral and poster papers. PMID- 21245263 TI - Human cardiomyopathy mutations induce myocyte hyperplasia and activate hypertrophic pathways during cardiogenesis in zebrafish. AB - To assess the effects during cardiac development of mutations that cause human cardiomyopathy, we modeled a sarcomeric gene mutation in the embryonic zebrafish. We designed morpholino antisense oligonucleotides targeting the exon 13 splice donor site in the zebrafish cardiac troponin T (tnnt2) gene, in order to precisely recapitulate a human TNNT2 mutation that causes hypertrophic cardiomyopathy (HCM). HCM is a disease characterized by myocardial hypertrophy, myocyte and myofibrillar disarray, as well as an increased risk of sudden death. Similar to humans with HCM, the morphant zebrafish embryos displayed sarcomere disarray and there was a robust induction of myocardial hypertrophic pathways. Microarray analysis uncovered a number of shared transcriptional responses between this zebrafish model and a well-characterized mouse model of HCM. However, in contrast to adult hearts, these embryonic hearts developed cardiomyocyte hyperplasia in response to this genetic perturbation. The re creation of a human disease-causing TNNT2 splice variant demonstrates that sarcomeric mutations can alter cardiomyocyte biology at the earliest stages of heart development with distinct effects from those observed in adult hearts despite shared transcriptional responses. PMID- 21245264 TI - The atherogenic bacterium Porphyromonas gingivalis evades circulating phagocytes by adhering to erythrocytes. AB - A relationship between periodontitis and coronary heart disease has been investigated intensively. A pathogenic role for the oral bacterium Porphyromonas gingivalis has been suggested for both diseases. We examined whether complement activation by P. gingivalis strain ATCC 33277 allows the bacterium to adhere to human red blood cells (RBCs) and thereby evade attack by circulating phagocytes. On incubation with normal human serum, the P. gingivalis strain efficiently fixed complement component 3 (C3). Incubation of bacteria with washed whole blood cells suspended in autologous serum resulted in a dose- and time-dependent adherence to RBCs. The adherence required functionally intact complement receptor 1 (CR1; also called CD35) on the RBCs and significantly inhibited the uptake of P. gingivalis by neutrophils and B cells within 1 min of incubation (by 64% and 51%, respectively) and that by monocytes after between 15 min and 30 min of incubation (by 66% and 53%, respectively). The attachment of C3b/iC3b to bacterium-bearing RBCs decreased progressively after 15 min, indicating that conversion of C3 fragments into C3dg occurred, decreasing the affinity for CR1 on RBCs. We propose that P. gingivalis exploits RBCs as a transport vehicle, rendering it inaccessible to attack by phagocytes, and by doing so plays a role in the development of systemic diseases. PMID- 21245265 TI - Beta interferon suppresses the development of experimental cerebral malaria. AB - Cerebral malaria (CM) is a major complication of Plasmodium falciparum infection, particularly in children. The pathogenesis of cerebral malaria involves parasitized red blood cell (RBC)-mediated vascular inflammation, immune stimulation, loss of blood-brain barrier integrity, and obstruction of cerebral capillaries. Therefore, blunting vascular inflammation and immune cell recruitment is crucial in limiting the disease course. Beta interferon (IFN-beta) has been used in the treatment of diseases, such as multiple sclerosis (MS) but has not yet been explored in the treatment of CM. Therefore, we sought to determine whether IFN-beta also limits disease progression in experimental cerebral malaria (ECM). Plasmodium berghei-infected mice treated with IFN-beta died later and showed increased survival, with improved blood-brain barrier function, compared to infected mice. IFN-beta did not alter systemic parasitemia. However, we identified multiple action sites that were modified by IFN-beta administration. P. berghei infection resulted in increased expression of chemokine (C-X-C motif) ligand 9 (CXCL9) in brain vascular endothelial cells that attract T cells to the brain, as well as increased T-cell chemokine (C-X-C motif) receptor 3 (CXCR3) expression. The infection also increased the cellular content of intercellular adhesion molecule 1 (ICAM-1), a molecule important for attachment of parasitized RBCs to the endothelial cell. In this article, we report that IFN-beta treatment leads to reduction of CXCL9 and ICAM-1 in the brain, reduction of T-cell CXCR3 expression, and downregulation of serum tumor necrosis factor alpha (TNF-alpha). In addition, IFN-beta-treated P. berghei infected mice also had fewer brain T-cell infiltrates, further demonstrating its protective effects. Hence, IFN-beta has important anti-inflammatory properties that ameliorate the severity of ECM and prolong mouse survival. PMID- 21245266 TI - Cpa, the outer membrane protease of Cronobacter sakazakii, activates plasminogen and mediates resistance to serum bactericidal activity. AB - Cronobacter spp. are emerging neonatal pathogens in humans, associated with outbreaks of meningitis and sepsis. To cause disease, they must survive in blood and invade the central nervous system by penetrating the blood-brain barrier. C. sakazakii BAA-894 possesses an ~131-kb plasmid (pESA3) that encodes an outer membrane protease (Cpa) that has significant identity to proteins that belong to the Pla subfamily of omptins. Members of this subfamily of proteins degrade a number of serum proteins, including circulating complement, providing protection from the complement-dependent serum killing. Moreover, proteins of the Pla subfamily can cause uncontrolled plasmin activity by converting plasminogen to plasmin and inactivating the plasmin inhibitor alpha2-antiplasmin (alpha2-AP). These reactions enhance the spread and invasion of bacteria in the host. In this study, we found that an isogenic cpa mutant showed reduced resistance to serum in comparison to its parent C. sakazakii BAA-894 strain. Overexpression of Cpa in C. sakazakii or Escherichia coli DH5alpha showed that Cpa proteolytically cleaved complement components C3, C3a, and C4b. Furthermore, a strain of C. sakazakii overexpressing Cpa caused a rapid activation of plasminogen and inactivation of alpha2-AP. These results strongly suggest that Cpa may be an important virulence factor involved in serum resistance, as well as in the spread and invasion of C. sakazakii. PMID- 21245267 TI - Virulence inhibition by zinc in shiga-toxigenic Escherichia coli. AB - Previously, our laboratories reported that zinc inhibited expression of several important virulence factors in enteropathogenic Escherichia coli (EPEC) and reduced EPEC-induced intestinal damage in vivo. Since EPEC is genetically related to Shiga-toxigenic E. coli (STEC), we wondered whether the beneficial effects of zinc extended to STEC as well. Treatment options for STEC infection are very limited, since antibiotics tend to exacerbate disease via enhanced toxin production, so a safe intervention for this infection would be welcome. In this study, we report that in STEC strains zinc inhibits adherence to cultured cells as well as expression of EHEC secreted protein A (EspA). In addition, zinc inhibits the expression of Shiga toxin (Stx) at both the protein and the RNA level. Zinc inhibits basal and antibiotic-induced Stx production and inhibits both Stx1 and Stx2 by >=90% at a concentration of 0.4 mM zinc. Rabbit EPEC strains were selected for acquisition of Stx-encoding bacteriophages, and these rabbit STEC strains (designated RDEC-H19A and E22-stx2) were used to test the effects of zinc in vivo in ligated rabbit intestinal loops. In vivo, zinc reduced fluid secretion into loops, inhibited mucosal adherence, reduced the amount of toxin in the loops, and reduced STEC-induced histological damage (villus blunting). Zinc has beneficial inhibitory effects against STEC strains that parallel those observed in EPEC. In addition, zinc strongly inhibits Stx expression; since Stx is responsible for the extraintestinal effects of STEC infection, such as hemolytic-uremic syndrome (HUS), zinc might be capable of preventing severe sequelae of STEC infection. PMID- 21245268 TI - Chlamydial infection increases gonococcal colonization in a novel murine coinfection model. AB - Genital tract infections caused by Neisseria gonorrhoeae and Chlamydia trachomatis serovars D to K occur at high incidence in many areas of the world. Despite high rates of coinfection with these pathogens, investigations of host parasite interactions have focused on each pathogen individually. We describe here a coinfection model in which female BALB/c mice were first infected with the mouse Chlamydia species C. muridarum and then inoculated with N. gonorrhoeae following treatment with water-soluble 17beta-estradiol to promote long-term gonococcal infection. Viable gonococci and chlamydiae were recovered for an average of 8 to 10 days, and diplococci and chlamydial inclusions were observed in lower genital tract tissue by immunohistochemical staining. Estradiol treatment reduced proinflammatory cytokine and chemokine levels in chlamydia infected mice; however, coinfected mice had a higher percentage of vaginal neutrophils compared to mice infected with either pathogen alone. We detected no difference in pathogen-specific antibody levels due to coinfection. Interestingly, significantly more gonococci were recovered from coinfected mice compared to mice infected with N. gonorrhoeae alone. We found no evidence that C. muridarum increases gonococcal adherence to, or invasion of, immortalized murine epithelial cells. However, increased vaginal concentrations of inflammatory mediators macrophage inflammatory protein 2 and tumor necrosis factor alpha were detected in C. muridarum-infected mice prior to inoculation with N. gonorrhoeae concurrently with the downregulation of cathelicidin-related antimicrobial peptide and secretory leukocyte peptidase inhibitor genes. We conclude that female mice can be successfully infected with both C. muridarum and N. gonorrhoeae and that chlamydia-induced alterations in host innate responses may enhance gonococcal infection. PMID- 21245269 TI - Identification of a putative chaperone involved in stress resistance and virulence in Francisella tularensis. AB - Francisella tularensis is a highly infectious bacterium causing the zoonotic disease tularemia. This facultative intracellular bacterium replicates in vivo mainly inside macrophages and therefore has developed strategies to resist this stressful environment. Here, we identified a novel genetic locus that is important for stress resistance and intracellular survival of F. tularensis. In silico and transcriptional analyses suggest that this locus (genes FTL_0200 to FTL_0209 in the live vaccine strain [LVS]) constitutes an operon controlled by the alternative sigma factor sigma32. The first gene, FTL_0200, encodes a putative AAA+ ATPase of the MoxR subfamily. Insertion mutagenesis into genes FTL_0200, FTL_0205, and FTL_0206 revealed a role for the locus in both intracellular multiplication and in vivo survival of F. tularensis. Deletion of gene FTL_0200 led to a mutant bacterium with increased vulnerability to various stress conditions, including oxidative and pH stresses. Proteomic analyses revealed a pleiotropic impact of the DeltaFTL_0200 deletion, supporting a role as a chaperone for FTL_0200. This is the first report of a role for a MoxR family member in bacterial pathogenesis. This class of proteins is remarkably conserved among pathogenic species and may thus constitute a novel player in bacterial virulence. PMID- 21245270 TI - Regulation of innate immune response to Candida albicans infections by alphaMbeta2-Pra1p interaction. AB - Candida albicans is a common opportunistic fungal pathogen and is the leading cause of invasive fungal diseases in immunocompromised individuals. The induction of cell-mediated immunity to C. albicans is one of the main tasks of cells of the innate immune system, and in vitro evidence suggests that integrin alpha(M)beta2 (CR3, Mac-1, and CD11b/CD18) is the principal leukocyte receptor involved in recognition of the fungus. Using alpha(M)beta2-KO mice and mutated strains of C. albicans in two models of murine candidiasis, we demonstrate that neutrophils derived from mice deficient in alpha(M)beta2 have a reduced ability to kill C. albicans and that the deficient mice themselves exhibit increased susceptibility to fungal infection. Disruption of the PRA1 gene of C. albicans, the primary ligand for alpha(M)beta2, protects the fungus against leukocyte killing in vitro and in vivo, impedes the innate immune response to the infection, and increases fungal virulence and organ invasion in vivo. Thus, recognition of pH-regulated antigen 1 protein (Pra1p) by alpha(M)beta2 plays a pivotal role in determining fungal virulence and host response and protection against C. albicans infection. PMID- 21245271 TI - The pathogenicity of an enteric Citrobacter rodentium Infection is enhanced by deficiencies in the antioxidants selenium and vitamin E. AB - The pathogenesis of a Citrobacter rodentium infection was evaluated in mice fed diets with a single deficiency in either selenium or vitamin E or with a double deficiency in both selenium and vitamin E compared to mice on nutritionally adequate diets. Mice fed the selenium- and vitamin E-deficient diet for 6 weeks had increased loads of C. rodentium in the colon and spleen, which were not observed in mice fed either of the singly deficient diets or the adequate diet. Infected mice fed the doubly deficient diet had increased colon crypt hyperplasia and an influx of infiltrating cells along with gross changes to crypt architecture, including ulceration and denuding of the epithelial layer. Cytokine and chemokine mRNA levels in the colon were measured by real-time PCR. Expression of proinflammatory cytokines and chemokines was upregulated on day 12 after infection with C. rodentium in mice fed the doubly deficient diet compared to mice fed the control diet. Heme oxygenase 1, an enzyme upregulated by oxidative stress, also was more highly induced in infected mice fed the doubly deficient diet. Production of C. rodentium antigen-specific IgM and IgG antibodies was not affected by feeding the doubly deficient diet. The results indicated that selenium and vitamin E play an important role in host resistance and in the pathology induced by C. rodentium, an infection that mimics disease caused by common food-borne bacterial pathogens in humans. PMID- 21245272 TI - Staphylococcal alpha-toxin is a strong inducer of interleukin-17 in humans. AB - Patients with atopic dermatitis (AD) are frequently colonized with Staphylococcus aureus, with one-third of isolates producing alpha-toxin. Moreover, S. aureus colonization is positively correlated with the severity of eczema. Interleukin 17A (IL-17A) has gained attention in diseases associated with chronic skin infections. The aim of this study was to investigate the effects of sublytic alpha-toxin concentrations on IL-17A production. Sublytic alpha-toxin concentrations strongly induced IL-17A in peripheral blood mononuclear cells (PBMCs), isolated CD4(+) T cells, polarized Th17 cells, and Th17 clones from reactive atopy patch test lesions and blood from AD patients. Alpha-toxin induced IL-17A directly in T cells. The effect of alpha-toxin was further amplified by upregulation of IL-1 in monocytes. In conclusion, higher levels of IL-17A secretion induced by alpha-toxin in the skin partially explain how colonization with S. aureus can contribute to chronic skin inflammation. PMID- 21245273 TI - Primary human colonic myofibroblasts are resistant to Clostridium difficile toxin A-induced, but not toxin B-induced, cell death. AB - Colonic inflammation in Clostridium difficile infection is mediated by released toxins A and B. We investigated responses to C. difficile toxins A and B by isolated primary human colonic myofibroblasts, which represent a distinct subpopulation of mucosal cells that are normally located below the intestinal epithelium. Following incubation with either purified toxin A or B, there was a change in myofibroblast morphology to stellate cells with processes that were immunoreactive for alpha-smooth muscle actin. Most of the myofibroblasts remained viable, with persistence of stellate morphology, despite exposure to high concentrations (up to 10 MUg/ml) of toxin A for 72 h. In contrast, a majority of the toxin B-exposed myofibroblasts lost their processes prior to cell death over 24 to 72 h. At low concentrations, toxin A provided protection against toxin B induced cell death. Within 4 h, myofibroblasts exposed to either toxin A or toxin B lost expression of the nonglucosylated form of Rac1, and there was also a loss of the active form of RhoA. Despite preexposure to high concentrations of toxin A for 3 h, colonic myofibroblasts were able to recover their morphology and proliferative capacity during prolonged culture in medium. However, toxin B preexposed myofibroblasts were not able to recover. In conclusion, primary human colonic mucosal myofibroblasts are resistant to toxin A (but not toxin B)-induced cell death. Responses by colonic myofibroblasts may play an important role in mucosal protection, repair, and regeneration in colitis due to C. difficile infection. PMID- 21245274 TI - Toll-like receptor 5 stimulation protects mice from acute Clostridium difficile colitis. AB - Clostridium difficile is a spore-forming bacterium that infects the lower intestinal tract of humans and is the most common known cause of diarrhea among hospitalized patients. Clostridium difficile colitis is mediated by toxins and develops during or following antibiotic administration. We have used a murine model of C. difficile infection, which reproduces the major features of the human disease, to study the effect of innate immune activation on resistance to C. difficile infection. We found that administration of purified Salmonella-derived flagellin, a Toll-like receptor 5 (TLR5) agonist, protects mice from C. difficile colitis by delaying C. difficile growth and toxin production in the colon and cecum. TLR5 stimulation significantly improves pathological changes in the cecum and colon of C. difficile-infected mice and reduces epithelial cell loss. Flagellin treatment reduces epithelial apoptosis in the large intestine, thereby protecting the integrity of the intestinal epithelial barrier during C. difficile infection. We demonstrate that restoring intestinal innate immune tone by TLR stimulation in antibiotic-treated mice ameliorates intestinal inflammation and prevents death from C. difficile colitis, potentially providing an approach to prevent C. difficile-induced pathology. PMID- 21245276 TI - Interference in character processing reflects common perceptual expertise across writing systems. AB - Perceptual expertise, even within the visual domain, can take many forms, depending on the goals of the practiced task and the visual information available to support performance. Given the same goals, expertise for different categories can recruit common perceptual resources, which could lead to interference during concurrent processing. We measured whether irrelevant characters of one writing system produce interference during visual search for characters of another writing system, as a function of expertise. Chinese-English bilinguals and English readers searched for target Roman letters among other distractors in a rapid serial visual presentation (RSVP) sequence. Chinese character distractors interfered with Roman letter search more than pseudoletter distractors, only for bilingual readers, suggesting a common perceptual bottleneck for Roman and Chinese processing in experts with both domains. We ruled out an explanation at the level of phonetic codes, by showing that concurrent verbal rehearsal has no effect on the magnitude of such interference. These findings converge with results showing competition between faces and cars in car experts to suggest that different domains of expertise that overlap in their cortical representations also possess a common perceptual bottleneck. PMID- 21245275 TI - HIV-1/mycobacterium tuberculosis coinfection immunology: how does HIV-1 exacerbate tuberculosis? AB - Human immunodeficiency virus type 1 (HIV) and Mycobacterium tuberculosis have become intertwined over the past few decades in a "syndemic" that exacerbates the morbidity and mortality associated with each pathogen alone. The severity of the coinfection has been extensively examined in clinical studies. The extrapolation of peripheral evidence from clinical studies has increased our basic understanding of how HIV increases susceptibility to TB. These studies have resulted in multiple hypotheses of how HIV exacerbates TB pathology through the manipulation of granulomas. Granulomas can be located in many tissues, most prominently the lungs and associated lymph nodes, and are made up of multiple immune cells that can actively contain M. tuberculosis. Granuloma-based research involving both animal models and clinical studies is needed to confirm these hypotheses, which will further our understanding of this coinfection and may lead to better treatment options. This review examines the data that support each hypothesis of how HIV manipulates TB pathology while emphasizing a need for more tissue-based experiments. PMID- 21245277 TI - Seeing grating-textured surface begins at the border. AB - Two experiments were conducted to reveal that the human visual system represents grating texture surface using a border-to-interior strategy. This strategy dictates that the visual system first registers the surface boundary contour and then sequentially spreads texture from the border to the interior of the image. Our experiments measured the perceived grating texture surface at various stimulus durations after the onset of a grating texture image. We found that the grating texture is initially seen near the boundary contours, with eventual spreading inward to the center of the image. To quantify the observation, the extent of the texture spreading from the boundary contour is measured as a function of the stimulus duration (30-500 ms). This allows us to analyze the texture spreading in retinal and cortical distances, based on human fMRI studies of the cortical magnification factor in cortical areas V1-V4, and to derive the spreading speed. We found that the spreading speed is constant when scaled according to the cortical distance. Similar findings are obtained no matter whether the grating texture image is presented monocularly or dichoptically, suggesting the generality of the border-to-interior strategy for representing surfaces. PMID- 21245278 TI - Remapped visual masking. AB - Cells in saccade control areas respond if a saccade is about to bring a target into their receptive fields (J. R. Duhamel, C. L. Colby, & M. R. Goldberg, 1992). This remapping process should shift the retinal location from which attention selects target information (P. Cavanagh, A. R. Hunt, S. R. Afraz, & M. Rolfs, 2010). We examined this attention shift in a masking experiment where target and mask were presented just before an eye movement. In a control condition with no eye movement, masks interfered with target identification only when they spatially overlapped. Just before a saccade, however, a mask overlapping the target had less effect, whereas a mask placed in the target's remapped location was quite effective. The remapped location is the retinal position the target will have after the upcoming saccade, which corresponds to neither the retinotopic nor spatiotopic location of the target before the saccade. Both effects are consistent with a pre-saccadic shift in the location from which attention selects target information. In the case of retinally aligned target and mask, the shift of attention away from the target location reduces masking, but when the mask appears at the target's remapped location, attention's shift to that location brings in mask information that interferes with the target identification. PMID- 21245279 TI - Efficient storage of high throughput DNA sequencing data using reference-based compression. AB - Data storage costs have become an appreciable proportion of total cost in the creation and analysis of DNA sequence data. Of particular concern is that the rate of increase in DNA sequencing is significantly outstripping the rate of increase in disk storage capacity. In this paper we present a new reference-based compression method that efficiently compresses DNA sequences for storage. Our approach works for resequencing experiments that target well-studied genomes. We align new sequences to a reference genome and then encode the differences between the new sequence and the reference genome for storage. Our compression method is most efficient when we allow controlled loss of data in the saving of quality information and unaligned sequences. With this new compression method we observe exponential efficiency gains as read lengths increase, and the magnitude of this efficiency gain can be controlled by changing the amount of quality information stored. Our compression method is tunable: The storage of quality scores and unaligned sequences may be adjusted for different experiments to conserve information or to minimize storage costs, and provides one opportunity to address the threat that increasing DNA sequence volumes will overcome our ability to store the sequences. PMID- 21245280 TI - Cloning, pharmacological characterization, and expression analysis of Atlantic salmon (Salmo salar L.) nuclear progesterone receptor. AB - To better understand the role(s) of progestogens during early stages of spermatogenesis, we carried out studies on the nuclear progesterone receptor (Pgr) of the Atlantic salmon. Its open-reading frame shows the highest similarity with other piscine Pgr proteins. When expressed in mammalian cells, salmon Pgr exhibited progestogen-specific, dose-dependent induction of reporter gene expression, with 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) showing the highest potency. We then analyzed testicular pgr mRNA and DHP plasma levels in animals during the onset of spermatogenesis, which were exposed to natural light or to constant light, to induce significant differences in testis growth. Grouping of the animals according to their progress through spermatogenesis showed that testicular pgr mRNA levels as well as DHP plasma levels first increased when germ cells had reached the stage of late type B spermatogonia and further increased when entered meiosis, i.e. when spermatocytes were present. However, in situ hybridization studies revealed that pgr mRNA expression was restricted to Sertoli cells, with a strong signal in Sertoli cells contacting type A/early type B spermatogonia, while Sertoli cells contacting larger germ cell clones with further differentiated stages (e.g. late type B spermatogonia) were less intensely/not stained. We conclude that the increase in pgr mRNA levels per pair of testis reflects, at least in part, the increased number of Sertoli cells enveloping type A and early type B spermatogonia. We propose that Sertoli cell-expressed Pgr may mediate DHP-stimulated early steps in spermatogenesis in Atlantic salmon, such as an increase in the number of new spermatogonial cysts. PMID- 21245281 TI - Pathogenesis of a bovine enterovirus-1 isolate in experimentally infected calves. AB - The pathogenesis and virulence of Bovine enterovirus-1 (BEV-1) in cattle is largely unknown. Reports concerning its virulence suggest that there might be an association between BEV-1 infections and a range of diseases in cattle that vary from respiratory to enteric to reproductive disease and infertility. In the current study, the pathogenesis associated with acute infection of BEV-1 in calves experimentally inoculated with the Oklahoma isolate of BEV-1 was described. Although interpretation of the study was limited by lack of an effective control group, results suggest that an association between inoculation of BEV-1, virus localization, and the potential development of lesions in the brain and heart probably exists. In the experiment, BEV-1 virus localized to the terminal ileum, ileocecal and cecocolonic junctions, spiral colon, and ileocecal lymph nodes; BEV-1 virus was detected in the cytoplasm of enterocytes, lamina propria macrophages, endothelium, neurons of the submucosal and myenteric plexi, and lymphocytes of the submucosal lymphoid tissue. Although no clinical signs were noted following acute infection, BEV-1 was localized in the cerebellar white matter of a calf with encephalitis and in the heart of another calf with coronary arteritis. The current study suggests that the BEV-1 isolate is infectious to young calves and that BEV-1 potentially can have a similar pathogenesis to that observed in natural or experimental enterovirus infections in other species. PMID- 21245282 TI - Identification of cancer stem cells derived from a canine lung adenocarcinoma cell line. AB - Accumulating evidence supporting the cancer stem cell (CSC) hypothesis is based on the finding that tumors contain a small population of self-renewing cells that generate differentiated progeny and thereby contribute to tumor heterogeneity. CSCs are reported to exist in several human cancers, yet only a few reports demonstrate the existence of CSCs in primary lung cancer in dogs. In this study, the authors established a cancer cell line derived from a canine primary lung adenocarcinoma and identified a side population (SP) of cells that displayed drug resistant features. To confirm the characteristics of these SP cells, the authors investigated the tumorigenicity of the cells in vivo by using a nude mouse xenograft model. Only 100 SP cells were able to give rise to new tumors, giving a 10-fold enrichment over the main population (MP) of cells, suggesting that these cells have the cancer-initiating ability of CSCs. Further studies characterizing CSCs in canine lung adenocarcinoma might contribute to the elucidation of the mechanisms of tumorigenesis and to the establishment of novel therapeutic strategies. PMID- 21245283 TI - Severe bilaterally symmetrical alopecia in a horse. AB - A 9-year-old Tennessee Walking Horse gelding was presented for diagnosis of the cause of extensive alopecia. Complete hair loss was noted over the head, neck, shoulder, thigh, and proximal limbs, but the trunk, distal limbs, pelvic area, mane, and tail were unaffected. The alopecic areas were visually noninflammatory with no exudate or crust except on the shoulder and along the back, where multifocal patchy areas of alopecia with scales and crust were evident. The horse was slightly pruritic. Microscopically, the hair bulbs, inner and outer root sheaths of inferior segments, and perifollicular regions were infiltrated by small to moderate numbers of small lymphocytes. Similar inflammation was occasionally evident in isthmus follicular walls as well as some apocrine glands. No sebaceous glands were affected. Immunohistochemistry confirmed that the small lymphocytes were CD3(+) T lymphocytes. The epidermis from the skin with scale and crusts along the horse's back exhibited mild to moderate hyperplasia, mild lymphocytic exocytosis, mild eosinophilic dermatitis, and diffuse parakeratosis with numerous budding yeasts, consistent with Malassezia spp. The final disease diagnosis was made as alopecia areata with Malassezia dermatitis. Alopecia areata could be a contributing underlying factor for Malassezia dermatitis. PMID- 21245284 TI - Comparison of brain PrPd distribution in ovine BSE and scrapie. AB - Scrapie and bovine spongiform encephalopathy (BSE) are both prion diseases affecting ruminants, and these diseases do not share the same public health concerns. Surveillance of the BSE agent in small ruminants has been a great challenge, and the recent identification of diverse prion diseases in ruminants has led to the development of new methods for strain typing. In our study, using immunohistochemistry (IHC), we assessed the distribution of PrP(d) in the brains of 2 experimentally BSE-infected sheep with the ARQ/ARQ genotype. Distribution of PrP(d) in the brain, from the spinal cord to the frontal cortex, was remarkably similar in the 2 sheep despite different inoculation routes and incubation periods. Comparatively, overall PrP(d) brain distribution, evaluated by IHC, in 19 scrapie cases with the ARQ/ARQ, ARQ/VRQ, and VRQ/VRQ genotypes, in some cases showed similarities to the experimentally BSE-infected sheep. There was no exclusive neuroanatomical site with a characteristic and specific PrP(d) type of accumulation induced by the BSE agent. However, a detailed analysis of the topography, types, and intensity of PrP(d) deposits in the frontal cortex, striatum, piriform cortex, hippocampus, mesencephalon, and cerebellum allowed the BSE-affected sheep group to be distinguished from the 19 scrapie cases analyzed in our study. These results strengthen and emphasize the potential interest of PrP(d) brain mapping to help in identifying prion strains in small ruminants. PMID- 21245285 TI - Role of technology in supporting quality control and treatment fidelity in a family caregiver clinical trial. AB - This article describes how a family caregiver lifestyle physical activity clinical trial uses research technology to enhance quality control and treatment fidelity. This trial uses a range of Internet, Blaise((r)) Windows-based software and Echo Server technologies to support quality control issues, such as data collection, data entry, and study management advocated by the clinical trials literature, and to ensure treatment fidelity concerning intervention implementation (i.e., design, training, delivery, receipt, and enactment) as proposed by the National Institutes of Health Behavior Change Consortium. All research staff are trained to use these technologies. Strengths of this technological approach to support quality control and treatment fidelity include the comprehensive plan, involvement of all staff, and ability to maintain accurate and timely data. Limitations include the upfront time and costs for developing and testing these technological methods, and having support staff readily available to address technological issues if they occur. PMID- 21245286 TI - Hepatic pharmacokinetics of cationic drugs in a high-fat emulsion-induced rat model of nonalcoholic steatohepatitis. AB - The hepatic pharmacokinetics of five selected cationic drugs (propranolol, labetalol, metoprolol, antipyrine, and atenolol) was studied in the liver from control rats and from those with high-fat emulsion-induced nonalcoholic steatohepatitis (NASH). Studies were undertaken using an in situ-perfused rat liver and multiple indicator dilution, and outflow data were analyzed with a physiologically based organ pharmacokinetic model. Hepatic extraction (E) was significantly lower in the NASH model, and lipophilicity was the main solute structural determinant of the observed differences in intrinsic elimination clearance (CL(int)) and permeability-surface area product (PS) with pK(a) defining the extent of sequestration in the liver [apparent distribution ratio (K(v))]. The main pathophysiological determinants were liver fibrosis, leading to a decreased PS, liver fat causing an increase in K(v), and an increase in both total liver cytochrome P450 (P450) concentration and P450 isoform expression for Cyp3a2 and Cyp2d2, causing an increase CL(int) in NASH rat livers compared with control livers. Changes in hepatic pharmacokinetics (PS, K(v), CL(int), and E ratio) as a result of NASH were related to the physicochemical properties of drugs (lipophilicity or pK(a)) and hepatic histopathological changes (fibrosis index, steatosis index, and P450 concentration) by stepwise regression analysis. Thus, it appears that in NASH, counteracting mechanisms to facilitate hepatic removal are created in NASH-induced P450 expression, whereas NASH-induced fibrosis and steatohepatitis inhibit E by decreasing hepatocyte permeability through fibrosis and hepatic sequestration. PMID- 21245287 TI - Discovery of a novel allelic variant of CYP2C8, CYP2C8*11, in Asian populations and its clinical effect on the rosiglitazone disposition in vivo. AB - The objectives of this study were to identify the genetic variants of CYP2C8, analyze CYP2C8 single nucleotide polymorphisms (SNPs), and characterize their functional consequences in the CYP2C8 substrate drug rosiglitazone in humans. The direct full sequencing of CYP2C8 genomic DNA was performed in a Korean population (n = 50). A total of 17 CYP2C8 variants including a novel coding variant (E274Stop) were identified. The novel CYP2C8 E274Stop variant was assigned as CYP2C8*11 by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee. Seventeen SNPs were used to characterize linkage disequilibrium, haplotype structures, and haplotype tagging SNPs. Genotyping for CYP2C8*11 in an extended set of Koreans (n = 400), whites (n = 100), Han Chinese (n = 348), Vietnamese (n = 100), and African Americans (n = 93) was performed by a newly developed pyrosequencing method. The frequency of CYP2C8*11 was 0.3% in Koreans, 1% in Vietnamese, and 0.14% in Chinese. However, none of the whites or African Americans contained the CYP2C8*11 allele. Subjects with CYP2C8*1/*11 exhibited higher plasma concentration-time profiles of rosiglitazone than those of nine control subjects carrying CYP2C8*1/*1. The area under the concentration-time curve and peak plasma concentration of rosiglitazone in individuals carrying CYP2C8*1/*11 (n = 5) were 54 and 34% higher than the mean values observed in the control subjects carrying CYP2C8*1/*1 (P = 0.015 and P = 0.025, respectively). In summary, this is the first report to characterize the allele frequency and haplotype distribution of CYP2C8 in a Korean population, and it provides functional analysis of a new variant CYP2C8*11. Our findings suggest that individuals carrying CYP2C8*11, a null allele found in Asians only, may have lower activity for metabolizing CYP2C8 substrate drugs. PMID- 21245288 TI - Characterization of niflumic acid as a selective inhibitor of human liver microsomal UDP-glucuronosyltransferase 1A9: application to the reaction phenotyping of acetaminophen glucuronidation. AB - Enzyme selective inhibitors represent the most valuable experimental tool for reaction phenotyping. However, only a limited number of UDP glucuronosyltransferase (UGT) enzyme-selective inhibitors have been identified to date. This study characterized the UGT enzyme selectivity of niflumic acid (NFA). It was demonstrated that 2.5 MUM NFA is a highly selective inhibitor of recombinant and human liver microsomal UGT1A9 activity. Higher NFA concentrations (50-100 MUM) inhibited UGT1A1 and UGT2B15 but had little effect on the activities of UGT1A3, UGT1A4, UGT1A6, UGT2B4, UGT2B7, and UGT2B17. NFA inhibited 4 methylumbelliferone and propofol (PRO) glucuronidation by recombinant UGT1A9 and PRO glucuronidation by human liver microsomes (HLM) according to a mixed (competitive-noncompetitive) mechanism, with K(i) values ranging from 0.10 to 0.40 MUM. Likewise, NFA was a mixed or noncompetitive inhibitor of recombinant and human liver microsomal UGT1A1 (K(i) range 14-18 MUM), whereas competitive inhibition (K(i) 62 MUM) was observed with UGT2B15. NFA was subsequently applied to the reaction phenotyping of human liver microsomal acetaminophen (APAP) glucuronidation. Consistent with previous reports, APAP was glucuronidated by recombinant UGT1A1, UGT1A6, UGT1A9, and UGT2B15. NFA concentrations in the range of 2.5 to 100 MUM inhibited APAP glucuronidation by UGT1A1, UGT1A9, and UGT2B15 but not by UGT1A6. The mean V(max) for APAP glucuronidation by HLM was reduced by 20, 35, and 40%, respectively, in the presence of 2.5, 50, and 100 MUM NFA. Mean K(m) values decreased in parallel with V(max), although the magnitude of the decrease was smaller. Taken together, the NFA inhibition data suggest that UGT1A6 is the major enzyme involved in APAP glucuronidation. PMID- 21245289 TI - Prescriber Compliance with a New Computerized Insulin Guideline for Noncritically Ill Adults. AB - BACKGROUND: In March 2008, the University of California, Davis Medical Center (UCDMC), implemented a guideline for the inpatient management of diabetes in noncritically ill adults. In accordance with national guidelines, all patients with type 2 diabetes are prescribed basal, nutritional, and correctional insulin. The guideline was added to the electronic medical record as a standardized physician order set in April 2008 and provider training on the insulin guideline occurred in May 2008. OBJECTIVE: To evaluate provider compliance with a new electronic standardized insulin order set in a hospital setting. METHODS: All patients with insulin orders admitted to the general internal medicine service between June 1, 2008, and November 1, 2008, were evaluated in this single-center retrospective chart review at UCDMC in Sacramento. Patients older than 18 years with a history of type 2 diabetes were included in the analysis. Insulin orders were categorized as preferred (followed the guideline) or nonpreferred regimens (did not follow all components of the guideline). RESULTS: A total of 265 patients were identified during the study period. The preferred regimen was ordered in 82 (30.9%) of the evaluated patient admissions. Of the 183 (69.1%) nonpreferred regimens, more than half (54.6%) contained correctional insulin alone; 84.2% of patient admissions prescribed nonpreferred regimens lacked nutritional insulin. Average admission blood glucose readings were higher in the preferred versus nonpreferred regimen group (224.4 vs 164.8 mg/dL, p < 0.001). CONCLUSIONS: The preferred regimen was not prescribed for the majority of patients admitted with a history of type 2 diabetes, despite computerized decision support. Nutritional insulin was the most common missing component in the nonpreferred regimens. Baseline clinical factors, educational modalities, and guideline content may have influenced prescribing patterns. PMID- 21245291 TI - Dynamic histone acetylation is critical for cotranscriptional spliceosome assembly and spliceosomal rearrangements. AB - Assembly of the spliceosome onto pre-mRNA is a dynamic process involving the ordered exchange of snRNPs to form the catalytically active spliceosome. These ordered rearrangements have recently been shown to occur cotranscriptionally, while the RNA polymerase is still actively engaged with the chromatin template. We previously demonstrated that the histone acetyltransferase Gcn5 is required for U2 snRNP association with the branchpoint. Here we provide evidence that histone acetylation and deacetylation facilitate proper cotranscriptional association of spliceosomal snRNPs. As with GCN5, mutation or deletion of Gcn5 targeted histone H3 residues leads to synthetic lethality when combined with deletion of the genes encoding the U2 snRNP components Lea1 or Msl1. Gcn5 associates throughout intron-containing genes and, in the absence of the histone deacetylases Hos3 and Hos2, enhanced histone H3 acetylation is observed throughout the body of genes. Deletion of histone deacetylaces also results in persistent association of the U2 snRNP and a severe defect in the association of downstream factors. These studies show that cotranscriptional spliceosome rearrangements are driven by dynamic changes in the acetylation state of histones and provide a model whereby yeast spliceosome assembly is tightly coupled to histone modification. PMID- 21245292 TI - LTbetaR signaling in dendritic cells induces a type I IFN response that is required for optimal clonal expansion of CD8+ T cells. AB - During an immune response, antigen-bearing dendritic cells (DCs) migrate to the local draining lymph node and present antigen to CD4(+) helper T cells. Antigen activated CD4(+) T cells then up-regulate TNF superfamily members including CD40 ligand and lymphotoxin (LT)alphabeta. Although it is well-accepted that CD40 stimulation on DCs is required for DC licensing and cross-priming of CD8(+) T cell responses, it is likely that other signals are integrated into a comprehensive DC activation program. Here we show that a cognate interaction between LTalphabeta on CD4(+) helper T cells and LTbeta receptor on DCs results in unique signals that are necessary for optimal CD8(+) T-cell expansion via a type I IFN-dependent mechanism. In contrast, CD40 signaling appears to be more critical for CD8(+) T-cell IFNgamma production. Therefore, different TNF family members provide integrative signals that shape the licensing potential of antigen presenting DCs. PMID- 21245293 TI - Correlated genotypes in friendship networks. AB - It is well known that humans tend to associate with other humans who have similar characteristics, but it is unclear whether this tendency has consequences for the distribution of genotypes in a population. Although geneticists have shown that populations tend to stratify genetically, this process results from geographic sorting or assortative mating, and it is unknown whether genotypes may be correlated as a consequence of nonreproductive associations or other processes. Here, we study six available genotypes from the National Longitudinal Study of Adolescent Health to test for genetic similarity between friends. Maps of the friendship networks show clustering of genotypes and, after we apply strict controls for population stratification, the results show that one genotype is positively correlated (homophily) and one genotype is negatively correlated (heterophily). A replication study in an independent sample from the Framingham Heart Study verifies that DRD2 exhibits significant homophily and that CYP2A6 exhibits significant heterophily. These unique results show that homophily and heterophily obtain on a genetic (indeed, an allelic) level, which has implications for the study of population genetics and social behavior. In particular, the results suggest that association tests should include friends' genes and that theories of evolution should take into account the fact that humans might, in some sense, be metagenomic with respect to the humans around them. PMID- 21245294 TI - Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming. AB - Despite the availability of vaccines, human papillomavirus (HPV) infections remain a cause of significant cancer morbidity and mortality. We have previously shown that HPV16 E7 associates with and diminishes E2F6-containing polycomb repressive complexes. Here, we show that repressive trimethyl marks on lysine 27 of histone 3, which are necessary for binding of polycomb repressive complexes, are decreased in HPV16 E7-expressing cells and HPV16-positive cervical lesions. This is caused by transcriptional induction of the KDM6A and KDM6B histone 3 lysine 27-specific demethylases. HPV16 E7-mediated KDM6B induction accounts for expression of the cervical cancer biomarker, p16(INK4A). Moreover, KDM6A- and KDM6B-responsive Homeobox genes are expressed at significantly higher levels, suggesting that HPV16 E7 results in reprogramming of host epithelial cells. These effects are independent of the ability of E7 to inhibit the retinoblastoma tumor suppressor protein. Most importantly, these effects are reversed when E7 expression is silenced, indicating that this pathway may have prognostic and/or therapeutic significance. PMID- 21245295 TI - Brain angiogenesis inhibitor 1 (BAI1) is a pattern recognition receptor that mediates macrophage binding and engulfment of Gram-negative bacteria. AB - Bacterial recognition by host cells is essential for initiation of infection and the host response. Bacteria interact with host cells via multiple pattern recognition receptors that recognize microbial products or pathogen-associated molecular patterns. In response to this interaction, host cell signaling cascades are activated that lead to inflammatory responses and/or phagocytic clearance of attached bacteria. Brain angiogenesis inhibitor 1 (BAI1) is a receptor that recognizes apoptotic cells through its conserved type I thrombospondin repeats and triggers their engulfment through an ELMO1/Dock/Rac1 signaling module. Because thrombospondin repeats in other proteins have been shown to bind bacterial surface components, we hypothesized that BAI1 may also mediate the recognition and clearance of pathogenic bacteria. We found that preincubation of bacteria with recombinant soluble BAI1 ectodomain or knockdown of endogenous BAI1 in primary macrophages significantly reduced binding and internalization of the Gram-negative pathogen Salmonella typhimurium. Conversely, overexpression of BAI1 enhanced attachment and engulfment of Salmonella in macrophages and in heterologous nonphagocytic cells. Bacterial uptake is triggered by the BAI1 mediated activation of Rac through an ELMO/Dock-dependent mechanism, and inhibition of the BAI1/ELMO1 interaction prevents both Rac activation and bacterial uptake. Moreover, inhibition of ELMO1 or Rac function significantly impairs the proinflammatory response to infection. Finally, we show that BAI1 interacts with a variety of Gram-negative, but not Gram-positive, bacteria through recognition of their surface lipopolysaccharide. Together these findings identify BAI1 as a pattern recognition receptor that mediates nonopsonic phagocytosis of Gram-negative bacteria by macrophages and directly affects the host response to infection. PMID- 21245296 TI - HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation. AB - The assembly of MHC class I molecules is governed by stringent endoplasmic reticulum (ER) quality control mechanisms. MHC class I heavy chains that fail to achieve their native conformation in complex with beta2-microglobulin (beta2m) and peptide are targeted for ER-associated degradation. This requires ubiquitination of the MHC class I heavy chain and its dislocation from the ER to the cytosol for proteasome-mediated degradation, although the cellular machinery involved in this process is unknown. Using an siRNA functional screen in beta2m depleted cells, we identify an essential role for the E3 ligase HRD1 (Synoviolin) together with the E2 ubiquitin-conjugating enzyme UBE2J1 in the ubiquitination and dislocation of misfolded MHC class I heavy chains. HRD1 is also required for the ubiquitination and degradation of the naturally occurring hemochromatosis associated HFE-C282Y mutant, which is unable to bind beta2m. In the absence of HRD1, misfolded HLA-B27 accumulated in cells with a normal MHC class I assembly pathway, and HRD1 depletion prevented the appearance of low levels of cytosolic unfolded MHC I heavy chains. HRD1 and UBE2J1 associate in a complex together with non-beta2m bound MHC class I heavy chains, Derlin 1, and p97 and discriminate misfolded MHC class I from conformational MHC I-beta2m-peptide heterotrimers. Together these data support a physiological role for HRD1 and UBE2J1 in the homeostatic regulation of MHC class I assembly and expression. PMID- 21245297 TI - Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. AB - There has been a consistent gap in understanding how TNF-alpha neutralization affects the disease state of arthritis patients so rapidly, considering that joint inflammation in rheumatoid arthritis is a chronic condition with structural changes. We thus hypothesized that neutralization of TNF-alpha acts through the CNS before directly affecting joint inflammation. Through use of functional MRI (fMRI), we demonstrate that within 24 h after neutralization of TNF-alpha, nociceptive CNS activity in the thalamus and somatosensoric cortex, but also the activation of the limbic system, is blocked. Brain areas showing blood-oxygen level-dependent signals, a validated method to assess neuronal activity elicited by pain, were significantly reduced as early as 24 h after an infusion of a monoclonal antibody to TNF-alpha. In contrast, clinical and laboratory markers of inflammation, such as joint swelling and acute phase reactants, were not affected by anti-TNF-alpha at these early time points. Moreover, arthritic mice overexpressing human TNF-alpha showed an altered pain behavior and a more intensive, widespread, and prolonged brain activity upon nociceptive stimuli compared with wild-type mice. Similar to humans, these changes, as well as the rewiring of CNS activity resulting in tight clustering in the thalamus, were rapidly reversed after neutralization of TNF-alpha. These results suggest that neutralization of TNF-alpha affects nociceptive brain activity in the context of arthritis, long before it achieves anti-inflammatory effects in the joints. PMID- 21245298 TI - Differential regulation of the p73 cistrome by mammalian target of rapamycin reveals transcriptional programs of mesenchymal differentiation and tumorigenesis. AB - The transcription factor p73 plays critical roles during development and tumorigenesis. It exhibits sequence identity and structural homology with p53, and can engage p53-like tumor-suppressive programs. However, different pathways regulate p53 and p73, and p73 is not mutated in human tumors. Therefore, p73 represents a therapeutic target, and there is a critical need to understand genes and noncoding RNAs regulated by p73 and how they change during treatment regimens. Here, we define the p73 genomic binding profile and demonstrate its modulation by rapamycin, an inhibitor of mammalian target of rapamycin (mTOR) and inducer of p73. Rapamycin selectively increased p73 occupancy at a subset of its binding sites. In addition, multiple determinants of p73 binding, activity, and function were evident, and were modulated by mTOR. We generated an mTOR-p73 signature that is enriched for p73 target genes and miRNAs that are involved in mesenchymal differentiation and tumorigenesis, can classify rhabdomyosarcomas by clinical subtype, and can predict patient outcome. PMID- 21245299 TI - Strong evidence for terrestrial support of zooplankton in small lakes based on stable isotopes of carbon, nitrogen, and hydrogen. AB - Cross-ecosystem subsidies to food webs can alter metabolic balances in the receiving (subsidized) system and free the food web, or particular consumers, from the energetic constraints of local primary production. Although cross ecosystem subsidies between terrestrial and aquatic systems have been well recognized for benthic organisms in streams, rivers, and the littoral zones of lakes, terrestrial subsidies to pelagic consumers are more difficult to demonstrate and remain controversial. Here, we adopt a unique approach by using stable isotopes of H, C, and N to estimate terrestrial support to zooplankton in two contrasting lakes. Zooplankton (Holopedium, Daphnia, and Leptodiaptomus) are comprised of ~ 20-40% of organic material of terrestrial origin. These estimates are as high as, or higher than, prior measures obtained by experimentally manipulating the inorganic (13)C content of these lakes to augment the small, natural contrast in (13)C between terrestrial and algal photosynthesis. Our study gives credence to a growing literature, which we review here, suggesting that significant terrestrial support of pelagic crustaceans (zooplankton) is widespread. PMID- 21245300 TI - Organ boundary1 defines a gene expressed at the junction between the shoot apical meristem and lateral organs. AB - We identify a gene, organ boundary1 (OBO1), by its unique pattern of enhancer- driven GFP expression at the boundaries between the apical meristems and lateral organs in Arabidopsis embryos, seedlings, and mature plants. OBO1 also is expressed at the root apical meristem and in distinct cell files surrounding this area. OBO1 is one of a 10-member plant-specific gene family encoding a single small domain (133 amino acids) with unknown function. One member of this gene family, OBO2, is identical to a previously studied gene, light-sensitive hypocotyl1. Overexpression of OBO1 causes an abnormal number and size of petals and petal-stamen fusions. The patterns of OBO1 gene expression are distinct but overlap with other genes involved in boundary formation in the Arabidopsis shoot apical meristem, including cup-shaped cotyledon, lateral organ boundaries, blade on-petiole, asymmetric leaves, and lateral organ fusion. Nuclear localization of OBO1 suggests that it might act with one or more of the transcription factors encoded by the foregoing genes. Ablation of the specific cells expressing OBO1 leads to loss of the shoot apical meristem and lateral organs. Thus, the cells expressing OBO1 are important for meristem maintenance and organogenesis in Arabidopsis. PMID- 21245301 TI - Climate and population density drive changes in cod body size throughout a century on the Norwegian coast. AB - Understanding how populations respond to changes in climate requires long-term, high-quality datasets, which are rare for marine systems. We estimated the effects of climate warming on cod lengths and length variability using a unique 91-y time series of more than 100,000 individual juvenile cod lengths from surveys that began in 1919 along the Norwegian Skagerrak coast. Using linear mixed-effects models, we accounted for spatial population structure and the nested structure of the survey data to reveal opposite effects of spring and summer warming on juvenile cod lengths. Warm summer temperatures in the coastal Skagerrak have limited juvenile growth. In contrast, warmer springs have resulted in larger juvenile cod, with less variation in lengths within a cohort, possibly because of a temperature-driven contraction in the spring spawning period. A density-dependent reduction in length was evident only at the highest population densities in the time series, which have rarely been observed in the last decade. If temperatures rise because of global warming, nonlinearities in the opposing temperature effects suggest that negative effects of warmer summers will increasingly outweigh positive effects of warmer springs, and the coastal Skagerrak will become ill-suited for Atlantic cod. PMID- 21245302 TI - Contractility of the cell rear drives invasion of breast tumor cells in 3D Matrigel. AB - Cancer cells use different modes of migration, including integrin-dependent mesenchymal migration of elongated cells along elements of the 3D matrix as opposed to low-adhesion-, contraction-based amoeboid motility of rounded cells. We report that MDA-MB-231 human breast adenocarcinoma cells invade 3D Matrigel with a characteristic rounded morphology and with F-actin and myosin-IIa accumulating at the cell rear in a uropod-like structure. MDA-MB-231 cells display neither lamellipodia nor bleb extensions at the leading edge and do not require Arp2/3 complex activity for 3D invasion in Matrigel. Accumulation of phospho-MLC and blebbing activity were restricted to the uropod as reporters of actomyosin contractility, and velocimetric analysis of fluorescent beads embedded within the 3D matrix showed that pulling forces exerted to the matrix are restricted to the side and rear of cells. Inhibition of actomyosin contractility or beta1 integrin function interferes with uropod formation, matrix deformation, and invasion through Matrigel. These findings support a model whereby actomyosin based uropod contractility generates traction forces on the beta1 integrin adhesion system to drive cell propulsion within the 3D matrix, with no contribution of lamellipodia extension or blebbing to movement. PMID- 21245303 TI - Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down-regulating beta-catenin. AB - Wnt/beta-catenin signaling controls numerous steps in normal animal development and can also cause cancer if inappropriately activated. In the absence of Wnt, beta-catenin is targeted continuously for proteasomal degradation by the Axin destruction complex, whose activity is blocked upon Wnt stimulation by Dishevelled, which recruits Axin to the plasma membrane and assembles it into a signalosome. This key event during Wnt signal transduction depends on dynamic head-to-tail polymerization by the DIX domain of Dishevelled. Here, we use rescue assays in Drosophila tissues and functional assays in human cells to show that polymerization-blocking mutations in the DIX domain of Axin disable its effector function in down-regulating Armadillo/beta-catenin and its response to Dishevelled during Wnt signaling. Intriguingly, NMR spectroscopy revealed that the purified DIX domains of the two proteins interact with each other directly through their polymerization interfaces, whereby the same residues mediate both homo- and heterotypic interactions. This result implies that Dishevelled has the potential to act as a "natural" dominant-negative, binding to the polymerization interface of Axin's DIX domain to interfere with its self-assembly, thereby blocking its effector function. PMID- 21245304 TI - Funneling of gibberellin signaling by the GRAS transcription regulator scarecrow like 3 in the Arabidopsis root. AB - During plant development, because no cell movement takes place, control of the timing and extent of cell division and coordination of the direction and extent of cell expansion are particularly important for growth and development. The plant hormone gibberellins (GAs) play key roles in the control of these developmental processes. However, little is known about the molecular components that integrate the generic GA signaling into a specific cell/tissue to coordinate cell division and cell expansion. Here we report that scarecrow-like 3 (SCL3), a GRAS protein, acts as a positive regulator to integrate and maintain a functional GA pathway by attenuating the DELLA repressors in the root endodermis. The tissue specific maintenance of GA signaling in the root endodermis plays distinct roles along the longitudinal root axis. While in the elongation/differentiation zone (EDZ), the endodermis-confined GA pathway by SCL3 controls primarily coordination of root cell elongation; in the meristem zone (MZ) SCL3 in conjunction with the short-root/scarecrow (SHR/SCR) pathway controls GA-modulated ground tissue maturation. Our findings highlight the regulatory network of the GRAS transcription regulators (SCL3, DELLAs, and SHR/SCR) in the root endodermis, shedding light on how GA homeostasis is achieved and how the maintenance of GA signaling controls developmental processes in roots. PMID- 21245305 TI - Outcrossing, mitotic recombination, and life-history trade-offs shape genome evolution in Saccharomyces cerevisiae. AB - We carried out a population genomic survey of Saccharomyces cerevisiae diploid isolates and find that many budding yeast strains have high levels of genomic heterozygosity, much of which is likely due to outcrossing. We demonstrate that variation in heterozygosity among strains is correlated with a life-history trade off that involves how readily yeast switch from asexual to sexual reproduction under nutrient stress. This trade-off is reflected in a negative relationship between sporulation efficiency and pseudohyphal development and correlates with variation in the expression of RME1, a transcription factor with pleiotropic effects on meiosis and filamentous growth. Selection for alternate life-history strategies in natural versus human-associated environments likely contributes to differential maintenance of genomic heterozygosity through its effect on the frequency that yeast lineages experience sexual cycles and hence the opportunity for inbreeding. In addition to elevated levels of heterozygosity, many strains exhibit large genomic regions of loss-of-heterozygosity (LOH), suggesting that mitotic recombination has a significant impact on genetic variation in this species. This study provides new insights into the roles that both outcrossing and mitotic recombination play in shaping the genome architecture of Saccharomyces cerevisiae. This study also provides a unique case where stark differences in the genomic distribution of genetic variation among individuals of the same species can be largely explained by a life-history trade-off. PMID- 21245306 TI - Bitter taste receptors and alpha-gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying. AB - Ghrelin is a hunger hormone with gastroprokinetic properties but the factors controlling ghrelin secretion from the stomach are unknown. Bitter taste receptors (T2R) and the gustatory G proteins, alpha-gustducin (gust) and alpha transducin, are expressed in the gut and are involved in the chemosensation of nutrients. This study aimed to investigate whether T2R-agonists affect (i) ghrelin release via alpha-gustducin and (ii) food intake and gastric emptying via the release of ghrelin. The mouse stomach contains two ghrelin cell populations: cells containing octanoyl and desoctanoyl ghrelin, which were colocalized with alpha-gustducin and alpha-transducin, and cells staining for desoctanoyl ghrelin. Gavage of T2R-agonists increased plasma octanoyl ghrelin levels in WT mice but the effect was partially blunted in gust(-/-) mice. Intragastric administration of T2R-agonists increased food intake during the first 30 min in WT but not in gust(-/-) and ghrelin receptor knockout mice. This increase was accompanied by an increase in the mRNA expression of agouti-related peptide in the hypothalamus of WT but not of gust(-/-) mice. The temporary increase in food intake was followed by a prolonged decrease (next 4 h), which correlated with an inhibition of gastric emptying. The delay in emptying, which was partially counteracted by ghrelin, was not mediated by cholecystokinin and GLP-1 but involved a direct inhibitory effect of T2R-agonists on gastric contractility. This study is unique in providing functional evidence that activation of bitter taste receptors stimulates ghrelin secretion. Modulation of endogenous ghrelin levels by tastants may provide novel therapeutic applications for the treatment of weight -and gastrointestinal motility disorders. PMID- 21245307 TI - miR-96 regulates the progression of differentiation in mammalian cochlear inner and outer hair cells. AB - MicroRNAs (miRNAs) are small noncoding RNAs able to regulate a broad range of protein-coding genes involved in many biological processes. miR-96 is a sensory organ-specific miRNA expressed in the mammalian cochlea during development. Mutations in miR-96 cause nonsyndromic progressive hearing loss in humans and mice. The mouse mutant diminuendo has a single base change in the seed region of the Mir96 gene leading to widespread changes in the expression of many genes. We have used this mutant to explore the role of miR-96 in the maturation of the auditory organ. We found that the physiological development of mutant sensory hair cells is arrested at around the day of birth, before their biophysical differentiation into inner and outer hair cells. Moreover, maturation of the hair cell stereocilia bundle and remodelling of auditory nerve connections within the cochlea fail to occur in miR-96 mutants. We conclude that miR-96 regulates the progression of the physiological and morphological differentiation of cochlear hair cells and, as such, coordinates one of the most distinctive functional refinements of the mammalian auditory system. PMID- 21245308 TI - Zinc transporter ZnT-3 regulates presynaptic Erk1/2 signaling and hippocampus dependent memory. AB - The physiological role of vesicular zinc at central glutamatergic synapses remains poorly understood. Here we show that mice lacking the synapse-specific vesicular zinc transporter ZnT3 (ZnT3KO mice) have reduced activation of the Erk1/2 MAPK in hippocampal mossy fiber terminals, disinhibition of zinc-sensitive MAPK tyrosine phosphatase activity, and impaired MAPK signaling during hippocampus-dependent learning. Activity-dependent exocytosis is required for the effect of zinc on presynaptic MAPK and phosphatase activity. ZnT3KO mice have complete deficits in contextual discrimination and spatial working memory. Local blockade of zinc or MAPK in the mossy fiber pathway of wild-type mice impairs contextual discrimination. We conclude that ZnT3 is important for zinc homeostasis modulating presynaptic MAPK signaling and is required for hippocampus dependent memory. PMID- 21245309 TI - Diversity-oriented synthesis leads to an effective class of bifunctional linchpins uniting anion relay chemistry (ARC) with benzyne reactivity. AB - In conjunction with the construction of a diversity-oriented synthesis library of 10-membered ring "natural product-like" macrolides, the design, synthesis, and validation of a unique class of bifunctional linchpins, uniting benzyne reactivity initiated by type II anion relay chemistry (ARC) has been achieved, permitting access to diverse [2+2], [3+2], and [4+2] cycloadducts. PMID- 21245310 TI - Ataxia telangiectasia-mutated protein and DNA-dependent protein kinase have complementary V(D)J recombination functions. AB - Antigen receptor variable region exons are assembled during lymphocyte development from variable (V), diversity (D), and joining (J) gene segments. Each germ-line gene segment is flanked by recombination signal sequences (RSs). Recombination-activating gene endonuclease initiates V(D)J recombination by cleaving a pair of gene segments at their junction with flanking RSs to generate covalently sealed (hairpinned) coding ends (CEs) and blunt 5'-phosphorylated RS ends (SEs). Subsequently, nonhomologous end joining (NHEJ) opens, processes, and fuses CEs to form coding joins (CJs) and precisely joins SEs to form signal joins (SJs). DNA-dependent protein kinase catalytic subunit (DNA-PKcs) activates Artemis endonuclease to open and process hairpinned CEs before their fusion into CJs by other NHEJ factors. Although DNA-PKcs is absolutely required for CJs, SJs are formed to variable degrees and with variable fidelity in different DNA-PKcs deficient cell types. Thus, other factors may compensate for DNA-PKcs function in SJ formation. DNA-PKcs and the ataxia telangiectasia-mutated (ATM) kinase are members of the same family, and they share common substrates in the DNA damage response. Although ATM deficiency compromises chromosomal V(D)J CJ formation, it has no reported role in SJ formation in normal cells. Here, we report that DNA PKcs and ATM have redundant functions in SJ formation. Thus, combined DNA-PKcs and ATM deficiency during V(D)J recombination leads to accumulation of unjoined SEs and lack of SJ fidelity. Moreover, treatment of DNA-PKcs- or ATM-deficient cells, respectively, with specific kinase inhibitors for ATM or DNA-PKcs recapitulates SJ defects, indicating that the overlapping V(D)J recombination functions of ATM and DNA-PKcs are mediated through their kinase activities. PMID- 21245311 TI - Chemical basis of the synergism and antagonism in microbial communities in the nests of leaf-cutting ants. AB - Leaf-cutting ants cultivate the fungus Leucoagaricus gongylophorus, which serves as a major food source. This symbiosis is threatened by microbial pathogens that can severely infect L. gongylophorus. Microbial symbionts of leaf-cutting ants, mainly Pseudonocardia and Streptomyces, support the ants in defending their fungus gardens against infections by supplying antimicrobial and antifungal compounds. The ecological role of microorganisms in the nests of leaf-cutting ants can only be addressed in detail if their secondary metabolites are known. Here, we use an approach for the rapid identification of established bioactive compounds from microorganisms in ecological contexts by combining phylogenetic data, database searches, and liquid chromatography electrospray ionisation high resolution mass spectrometry (LC-ESI-HR-MS) screening. Antimycins A(1)-A(4), valinomycins, and actinomycins were identified in this manner from Streptomyces symbionts of leaf-cutting ants. Matrix-assisted laser desorption ionization (MALDI) imaging revealed the distribution of valinomycin directly on the integument of Acromyrmex echinatior workers. Valinomycins and actinomycins were also directly identified in samples from the waste of A. echinatior and A. niger leaf-cutting ants, suggesting that the compounds exert their antimicrobial and antifungal potential in the nests of leaf-cutting ants. Strong synergistic effects of the secondary meta-bolites produced by ant-associated Streptomyces were observed in the agar diffusion assay against Escovopsis weberi. Actinomycins strongly inhibit soil bacteria as well as other Streptomyces and Pseudonocardia symbionts. The antifungal antimycins are not only active against pathogenic fungi but also the garden fungus L. gongylophorus itself. In conclusion, secondary metabolites of microbial symbionts of leaf-cutting ants contribute to shaping the microbial communities within the nests of leaf-cutting ants. PMID- 21245314 TI - Being surveyed can change later behavior and related parameter estimates. AB - Does completing a household survey change the later behavior of those surveyed? In three field studies of health and two of microlending, we randomly assigned subjects to be surveyed about health and/or household finances and then measured subsequent use of a related product with data that does not rely on subjects' self-reports. In the three health experiments, we find that being surveyed increases use of water treatment products and take-up of medical insurance. Frequent surveys on reported diarrhea also led to biased estimates of the impact of improved source water quality. In two microlending studies, we do not find an effect of being surveyed on borrowing behavior. The results suggest that limited attention could play an important but context-dependent role in consumer choice, with the implication that researchers should reconsider whether, how, and how much to survey their subjects. PMID- 21245313 TI - mut-16 and other mutator class genes modulate 22G and 26G siRNA pathways in Caenorhabditis elegans. AB - Argonaute-associated siRNAs and Piwi-associated piRNAs have overlapping roles in silencing mobile genetic elements in animals. In Caenorhabditis elegans, mutator (mut) class genes mediate siRNA-guided repression of transposons as well as exogenous RNAi, but their roles in endogenous RNA silencing pathways are not well understood. To characterize the endogenous small RNAs dependent on mut class genes, small RNA populations from a null allele of mut-16 as well as a regulatory mut-16(mg461) allele that disables only somatic RNAi were subjected to deep sequencing. Additionally, each of the mut class genes was tested for a requirement in 26G siRNA pathways. The results indicate that mut-16 is an essential factor in multiple endogenous germline and somatic siRNA pathways involving several distinct Argonautes and RNA-dependent RNA polymerases. The results also reveal essential roles for mut-2 and mut-7 in the ERGO-1 class 26G siRNA pathway and less critical roles for mut-8, mut-14, and mut-15. We show that transposons are hypersusceptible to mut-16-dependent silencing and identify a requirement for the siRNA machinery in piRNA biogenesis from Tc1 transposons. We also show that the soma-specific mut-16(mg461) mutant allele is present in multiple C. elegans laboratory strains. PMID- 21245315 TI - Signal integration by DegS and RseB governs the σ E-mediated envelope stress response in Escherichia coli. AB - In Escherichia coli, the sigma(E) transcription factor monitors and maintains outer membrane (OM) integrity by activating genes required for assembly of its two key components, outer membrane proteins (OMPs) and lipopolysaccharide (LPS) and by transcribing small RNAs to down-regulate excess unassembled OMPs. sigma(E) activity is governed by the rate of degradation of its membrane-spanning anti sigma factor, RseA. Importantly, the DegS protease can initiate RseA cleavage only when activated by binding to unassembled OMPs. The prevalent paradigm has been that the sigma(E) response is controlled by the amount of activated DegS. Here we demonstrate that inactivation of a second negative regulator, the periplasmic protein RseB, is also required for sigma(E) induction in vivo. Moreover, OMPs, previously known only to activate DegS, also generate a signal to antagonize RseB inhibition. This signal may be lipid related, as RseB is structurally similar to proteins that bind lipids. We propose that the use of an AND gate enables sigma(E) to sense and integrate multivariate signals from the envelope. PMID- 21245316 TI - Ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases have overlapping activities during chromosomal signal joint formation. AB - Lymphocyte antigen receptor gene assembly occurs through the process of V(D)J recombination, which is initiated when the RAG endonuclease introduces DNA DSBs at two recombining gene segments to form broken DNA coding end pairs and signal end pairs. These paired DNA ends are joined by proteins of the nonhomologous end joining (NHEJ) pathway of DSB repair to form a coding joint and signal joint, respectively. RAG DSBs are generated in G1-phase developing lymphocytes, where they activate the ataxia telangiectasia mutated (Atm) and DNA-PKcs kinases to orchestrate diverse cellular DNA damage responses including DSB repair. Paradoxically, although Atm and DNA-PKcs both function during coding joint formation, Atm appears to be dispensible for signal joint formation; and although some studies have revealed an activity for DNA-PKcs during signal joint formation, others have not. Here we show that Atm and DNA-PKcs have overlapping catalytic activities that are required for chromosomal signal joint formation and for preventing the aberrant resolution of signal ends as potentially oncogenic chromosomal translocations. PMID- 21245317 TI - Activation of IFN-β expression by a viral mRNA through RNase L and MDA5. AB - IFNs play a critical role in innate immunity against viral infections. Melanoma differentiation-associated protein 5 (MDA5), an RNA helicase, is a key component in activating the expression of type I IFNs in response to certain types of viral infection. MDA5 senses noncellular RNA and triggers the signaling cascade that leads to IFN production. Synthetic double-stranded RNAs are known activators of MDA5. Natural single-stranded RNAs have not been reported to activate MDA5, however. We have serendipitously identified a viral mRNA from parainfluenza virus 5 (PIV5) that activates IFN expression through MDA5. We provide evidence that the signaling pathway includes the antiviral enzyme RNase L. The L mRNA of PIV5 activated expression of IFN-beta. We have mapped the RNA to a region of 430 nucleotides within the L mRNA of PIV5. Our results indicate that a viral mRNA, with 5'-cap and 3'-poly (A), can activate IFN expression through an RNase L-MDA5 pathway. PMID- 21245318 TI - Cut homeobox 1 causes chromosomal instability by promoting bipolar division after cytokinesis failure. AB - Cell populations able to generate a large repertoire of genetic variants have increased potential to generate tumor cells that survive through the multiple selection steps involved in tumor progression. A mechanism for the generation of aneuploid cancer cells involves passage through a tetraploid stage. Supernumerary centrosomes, however, can lead to multipolar mitosis and cell death. Using tissue culture and transgenic mouse models of breast cancer, we report that Cut homeobox 1 (CUX1) causes chromosomal instability by activating a transcriptional program that prevents multipolar divisions and enables the survival of tetraploid cells that evolve to become genetically unstable and tumorigenic. Transcriptional targets of CUX1 involved in DNA replication and bipolar mitosis defined a gene expression signature that, across 12 breast cancer gene expression datasets, was associated with poor clinical outcome. The signature not only was higher in breast tumor subtypes of worse prognosis, like the basal-like and HER2(+) subtypes, but also identified poor outcome among estrogen receptor-positive/node negative tumors, a subgroup considered to be at lower risk. The CUX1 signature therefore represents a unique criterion to stratify patients and provides insight into the molecular determinants of poor clinical outcome. PMID- 21245319 TI - Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1). AB - Numerous studies indicate that Sirtuin 1 (SIRT1), a mammalian nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylase (HDAC), plays a crucial role in p53-mediated stress responses by deacetylating p53. Nevertheless, the acetylation levels of p53 are dramatically increased upon DNA damage, and it is not well understood how the SIRT1-p53 interaction is regulated during the stress responses. Here, we identified Set7/9 as a unique regulator of SIRT1. SIRT1 interacts with Set7/9 both in vitro and in vivo. In response to DNA damage in human cells, the interaction between Set7/9 and SIRT1 is significantly enhanced and coincident with an increase in p53 acetylation levels. Importantly, the interaction of SIRT1 and p53 is strongly suppressed in the presence of Set7/9. Consequently, SIRT1-mediated deacetylation of p53 is abrogated by Set7/9, and p53-mediated transactivation is increased during the DNA damage response. Of note, whereas SIRT1 can be methylated at multiple sites within its N terminus by Set7/9, a methylation-defective mutant of SIRT1 still retains its ability to inhibit p53 activity. Taken together, our results reveal that Set7/9 is a critical regulator of the SIRT1-p53 interaction and suggest that Set7/9 can modulate p53 function indirectly in addition to acting through a methylation dependent mechanism. PMID- 21245320 TI - Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart. AB - VEGF and angiopoietin-1 (Ang1) are two major angiogenic factors being investigated for the treatment of myocardial infarction (MI). Targeting VEGF and Ang1 expression in the ischemic myocardium can increase their local therapeutic effects and reduce possible adverse effects. Adeno-associated viral vectors (AAVs) expressing cardiac-specific and hypoxia-inducible VEGF [AAV-myosin light chain-2v (MLC)VEGF] and Ang1 (AAV-MLCAng1) were coinjected (VEGF/Ang1 group) into six different sites of the porcine myocardium at the peri-infarct zone immediately after ligating the left descending coronary artery. An identical dose of AAV-Cytomegalovirus (CMV)LacZ or saline was injected into control animals. AAV genomes were detected in the liver in addition to the heart. RT-PCR, Western blotting, and ELISA analyses showed that VEGF and Ang1 were predominantly expressed in the myocardium in the infarct core and border of the infarct heart. Gated single-photon emission computed tomography analyses showed that the VEGF/Ang1 group had better cardiac function and myocardial perfusion at 8 wk than at 2 wk after vector injection. Compared with the saline and LacZ controls, the VEGF/Ang1 group expressed higher phosphorylated Akt and Bcl-xL, less Caspase-3 and Bad, and had higher vascular density, more proliferating cardiomyocytes, and less apoptotic cells in the infarct and peri-infarct zones. Thus, cardiac specific and hypoxia-induced coexpression of VEGF and Ang1 improves the perfusion and function of porcine MI heart through the induction of angiogenesis and cardiomyocyte proliferation, activation of prosurvival pathways, and reduction of cell apoptosis. PMID- 21245321 TI - Wild-type LRP6 inhibits, whereas atherosclerosis-linked LRP6R611C increases PDGF dependent vascular smooth muscle cell proliferation. AB - Vascular smooth muscle cell (VSMC) proliferation is an important event in atherosclerosis and other vasculopathies. PDGF signaling is a key mediator of SMC proliferation, but the mechanisms that control its activity remain unclear. We previously identified a mutation in LDL receptor-related protein 6 (LRP6), LRP6(R611C), that causes early atherosclerosis. Examination of human atherosclerotic coronary arteries showed markedly increased expression of LRP6 and colocalization with PDGF receptor beta (PDGFR-beta). Further investigation showed that wild-type LRP6 inhibits but LRP6(R611C) promotes VSMC proliferation in response to PDGF. We found that wild-type LRP6 forms a complex with PDGFR-beta and enhances its lysosomal degradation, functions that are severely impaired in LRP6(R611C). Further, we observed that wild-type and mutant LRP6 regulate cell cycle activity by triggering differential effects on PDGF-dependent pathways. These findings implicate LRP6 as a critical modulator of PDGF-dependent regulation of cell cycle in smooth muscle and indicate that loss of this function contributes to development of early atherosclerosis in humans. PMID- 21245322 TI - Cellulose (delta)18O is an index of leaf-to-air vapor pressure difference (VPD) in tropical plants. AB - Cellulose in plants contains oxygen that derives in most cases from precipitation. Because the stable oxygen isotope composition, delta(18)O, of precipitation is associated with environmental conditions, cellulose delta(18)O should be as well. However, plant physiological models using delta(18)O suggest that cellulose delta(18)O is influenced by a complex mix of both climatic and physiological drivers. This influence complicates the interpretation of cellulose delta(18)O values in a paleo-context. Here, we combined empirical data analyses with mechanistic model simulations to i) quantify the impacts that the primary climatic drivers humidity (e(a)) and air temperature (T(air)) have on cellulose delta(18)O values in different tropical ecosystems and ii) determine which environmental signal is dominating cellulose delta(18)O values. Our results revealed that e(a) and T(air) equally influence cellulose delta(18)O values and that distinguishing which of these factors dominates the delta(18)O values of cellulose cannot be accomplished in the absence of additional environmental information. However, the individual impacts of e(a) and T(air) on the delta(18)O values of cellulose can be integrated into a single index of plant-experienced atmospheric vapor demand: the leaf-to-air vapor pressure difference (VPD). We found a robust relationship between VPD and cellulose delta(18)O values in both empirical and modeled data in all ecosystems that we investigated. Our analysis revealed therefore that delta(18)O values in plant cellulose can be used as a proxy for VPD in tropical ecosystems. As VPD is an essential variable that determines the biogeochemical dynamics of ecosystems, our study has applications in ecological-, climate-, or forensic-sciences. PMID- 21245323 TI - Neonatal helper-dependent adenoviral vector gene therapy mediates correction of hemophilia A and tolerance to human factor VIII. AB - Neonatal gene therapy is a promising strategy for treating a number of congenital diseases diagnosed shortly after birth as expression of therapeutic proteins during postnatal life may limit the pathologic consequences and result in a potential "cure." Hemophilia A is often complicated by the development of antibodies to recombinant protein resulting in treatment failure. Neonatal administration of vectors may avoid inhibitory antibody formation to factor VIII (FVIII) by taking advantage of immune immaturity. A helper-dependent adenoviral vector expressing human factor VIII was administered i.v. to neonatal hemophilia A knockout mice. Three days later, mice produced high levels of FVIII. Levels declined rapidly with animal growth to 5 wk of age with stable factor VIII expression thereafter to >1 y of age. Decline in factor VIII expression was not related to cell-mediated or humoral responses with lack of development of antibodies to capsid or human factor VIII proteins. Subsequent readministration and augmentation of expression was possible as operational tolerance was established to factor VIII without development of inhibitors; however, protective immunity to adenovirus remained. PMID- 21245324 TI - Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation. AB - Uric acid (UA) is known to activate the NLRP3 (Nacht, leucine-rich repeat and pyrin domain containing protein 3) inflammasome. When activated, the NLRP3 (also known as NALP3) inflammasome leads to the production of IL-18 and IL-1beta. In this cohort of subjects with knee osteoarthritis (OA), synovial fluid uric acid was strongly correlated with synovial fluid IL-18 and IL-1beta. Synovial fluid uric acid and IL-18 were strongly and positively associated with OA severity as measured by both radiograph and bone scintigraphy, and synovial fluid IL-1beta was associated with OA severity but only by radiograph. Furthermore, synovial fluid IL-18 was associated with a 3-y change in OA severity, on the basis of the radiograph. We conclude that synovial fluid uric acid is a marker of knee OA severity. The correlation of synovial fluid uric acid with the two cytokines (IL 18 and IL-1beta) known to be produced by uric acid-activated inflammasomes and the association of synovial fluid IL-18 with OA progression, lend strong support to the potential involvement of the innate immune system in OA pathology and OA progression. PMID- 21245325 TI - SPK-1, an SR protein kinase, inhibits programmed cell death in Caenorhabditis elegans. AB - To identify genes involved in protecting cells from programmed cell death in Caenorhabditis elegans, we performed a genetic screen to isolate mutations that cause an increase in the number of programmed cell deaths. We screened for suppressors of the cell-death defect caused by a partial loss-of-function mutation in ced-4, which encodes an Apaf-1 homolog that promotes programmed cell death by activating the caspase CED-3. We identified one extragenic ced-4 suppressor, which has a mutation in the gene spk-1. The spk-1 gene encodes a protein homologous to serine-arginine-rich (SR) protein kinases, which are thought to regulate splicing. Previous work suggests that ced-4 can be alternatively spliced and that the splice variants function oppositely, with the longer transcript (ced-4L) inhibiting programmed cell death. spk-1 might promote cell survival by increasing the amount of the protective ced-4L splice variant. We conclude that programmed cell death in C. elegans is regulated by an alternative splicing event controlled by the SR protein kinase SPK-1. PMID- 21245326 TI - Climate change induces demographic resistance to disease in novel coral assemblages. AB - Climate change is reshaping biological communities and has already generated novel ecosystems. The functioning of novel ecosystems could depart markedly from that of existing systems and therefore obscure the impacts of climate change. We illustrate this possibility for coral reefs, which are at the forefront of climatic stress. Disease has been a principal cause of reef degradation and is expected to worsen with increased future thermal stress. However, using a field tested epizoological model, we show that high population turnover within novel ecosystems enhances coral resistance to epizootics. Thus, disease could become a less important driver of change in the future. We emphasize the need to move away from projections based on historic trends toward predictions that account for novel behavior of ecosystems under climate change. PMID- 21245327 TI - Scarecrow-like 3 promotes gibberellin signaling by antagonizing master growth repressor DELLA in Arabidopsis. AB - The diterpenoid phytohormone gibberellin (GA) controls diverse developmental processes throughout the plant life cycle. DELLA proteins are master growth repressors that function immediately downstream of the GA receptor to inhibit GA signaling. By doing so, DELLAs also play pivotal roles as integrators of internal developmental signals from multiple hormone pathways and external cues. DELLAs are likely nuclear transcriptional regulators, which interact with other transcription factors to modulate expression of GA-responsive genes. DELLAs are also involved in maintaining GA homeostasis through feedback up-regulating expression of GA biosynthesis and receptor genes. However, the molecular mechanisms by which DELLAs restrict growth and development are largely unknown. This study reveals an important step of the mechanism. Previous microarray studies identified scarecrow-like 3 (SCL3) as a direct target gene of DELLA in Arabidopsis seedlings. SCL3 expression is induced by DELLA and repressed by GA. Unexpectedly, a scl3 null mutant displays reduced GA responses and elevated expression of GA biosynthesis genes during seed germination and seedling growth, indicating that SCL3 functions as a positive regulator of GA signaling. SCL3 seems to act as an attenuator of DELLA proteins. Transient expression, ChIP, and co-IP studies show that SCL3 autoregulates its own transcription by directly interacting with DELLA. Our data further show that SCL3 and DELLA antagonize each other in controlling both downstream GA responses and upstream GA biosynthetic genes. This work is beginning to shed light on how this complex regulatory network achieves GA homeostasis and controls GA-mediated growth and development in the plant. PMID- 21245328 TI - Neuropilin-1 attenuates autoreactivity in experimental autoimmune encephalomyelitis. AB - Neuropilin-1 (Nrp1) is a cell surface molecule originally identified for its role in neuronal development. Recently, Nrp1 has been implicated in several aspects of immune function including maintenance of the immune synapse and development of regulatory T (T(reg)) cells. In this study, we provide evidence for a central role of Nrp1 in the regulation of CD4 T-cell immune responses in experimental autoimmune encephalitis (EAE). EAE serves as an animal model for the central nervous system (CNS) inflammatory disorder multiple sclerosis (MS). EAE is mediated primarily by CD4(+) T cells that migrate to the CNS and mount an inflammatory attack against myelin components, resulting in CNS pathology. Using a tissue-specific deletion system, we observed that the lack of Nrp1 on CD4(+) T cells results in increased EAE severity. These conditional knockout mice exhibit preferential T(H)-17 lineage commitment and decreased T(reg)-cell functionality. Conversely, CD4(+) T cells expressing Nrp1 suppress effector T-cell proliferation and cytokine production both in vivo and in vitro independent of T(reg) cells. Nrp1-mediated suppression can be inhibited by TGF-beta blockade but not by IL-10 blockade. These results suggest that Nrp1 is essential for proper maintenance of peripheral tolerance and its absence can result in unchecked autoreactive responses, leading to diseases like EAE and potentially MS. PMID- 21245329 TI - PDGF-BB and TGF-{beta}1 on cross-talk between endothelial and smooth muscle cells in vascular remodeling induced by low shear stress. AB - Shear stress, especially low shear stress (LowSS), plays an important role in vascular remodeling during atherosclerosis. Endothelial cells (ECs), which are directly exposed to shear stress, convert mechanical stimuli into intracellular signals and interact with the underlying vascular smooth muscle cells (VSMCs). The interactions between ECs and VSMCs modulate the LowSS-induced vascular remodeling. With the use of proteomic analysis, the protein profiles of rat aorta cultured under LowSS (5 dyn/cm(2)) and normal shear stress (15 dyn/cm(2)) were compared. By using Ingenuity Pathway Analysis to identify protein-protein association, a network was disclosed that involves two secretary molecules, PDGF BB and TGF-beta1, and three other linked proteins, lamin A, lysyl oxidase, and ERK 1/2. The roles of this network in cellular communication, migration, and proliferation were further studied in vitro by a cocultured parallel-plate flow chamber system. LowSS up-regulated migration and proliferation of ECs and VSMCs, increased productions of PDGF-BB and TGF-beta1, enhanced expressions of lysyl oxidase and phospho-ERK1/2, and decreased Lamin A in ECs and VSMCs. These changes induced by LowSS were confirmed by using PDGF-BB recombinant protein, siRNA, and neutralizing antibody. TGF-beta1 had similar influences on ECs as PDGF-BB, but not on VSMCs. Our results suggest that ECs convert the LowSS stimuli into up regulations of PDGF-BB and TGF-beta1, but these two factors play different roles in LowSS-induced vascular remodeling. PDGF-BB is involved in the paracrine control of VSMCs by ECs, whereas TGF-beta1 participates in the feedback control from VSMCs to ECs. PMID- 21245330 TI - An experimentally anchored map of transcriptional start sites in the model cyanobacterium Synechocystis sp. PCC6803. AB - There has been an increasing interest in cyanobacteria because these photosynthetic organisms convert solar energy into biomass and because of their potential for the production of biofuels. However, the exploitation of cyanobacteria for bioengineering requires knowledge of their transcriptional organization. Using differential RNA sequencing, we have established a genome wide map of 3,527 transcriptional start sites (TSS) of the model organism Synechocystis sp. PCC6803. One-third of all TSS were located upstream of an annotated gene; another third were on the reverse complementary strand of 866 genes, suggesting massive antisense transcription. Orphan TSS located in intergenic regions led us to predict 314 noncoding RNAs (ncRNAs). Complementary microarray-based RNA profiling verified a high number of noncoding transcripts and identified strong ncRNA regulations. Thus, ~64% of all TSS give rise to antisense or ncRNAs in a genome that is to 87% protein coding. Our data enhance the information on promoters by a factor of 40, suggest the existence of additional small peptide-encoding mRNAs, and provide corrected 5' annotations for many genes of this cyanobacterium. The global TSS map will facilitate the use of Synechocystis sp. PCC6803 as a model organism for further research on photosynthesis and energy research. PMID- 21245331 TI - Epstein-Barr virus nuclear antigens 3C and 3A maintain lymphoblastoid cell growth by repressing p16INK4A and p14ARF expression. AB - Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) and EBNA3A are each essential for EBV conversion of primary human B lymphocytes into continuously proliferating lymphoblast cell lines (LCLs) and for maintaining LCL growth. We now find that EBNA3C and EBNA3A's essential roles are to repress p16(INK4A) and p14(ARF). In the absence of EBNA3C or EBNA3A, p16(INK4A) and p14(ARF) expression increased and cell growth ceased. EBNA3C inactivation did not alter p16(INK4A) promoter CpG methylation, but reduced already low H3K27me3, relative to resting B cells, and increased H3K4me3 and H3-acetylation, linking EBNA3C inactivation to histone modifications associated with increased transcription. Importantly, knockdown of p16(INK4A) or p14(ARF) partially rescued LCLs from EBNA3C or EBNA3A inactivation-induced growth arrest and knockdown of both rescued LCL growth, confirming central roles for p16(INK4A) and p14(ARF) in LCL growth arrest following EBNA3C or EBNA3A inactivation. Moreover, blockade of p16(INK4A) and p14(ARF) effects on pRb and p53 by human papilloma virus type 16 E7 and E6 expression, sustained LCL growth after EBNA3C or EBNA3A inactivation. These data indicate that EBNA3C and EBNA3A joint repression of CDKN2A p16(INK4A) and p14(ARF) is essential for LCL growth. PMID- 21245332 TI - Urm1 couples sulfur transfer to ubiquitin-like protein function in oxidative stress. PMID- 21245333 TI - Killer cell Ig-like receptor (KIR) 3DL1 down-regulation enhances inhibition of type 1 diabetes by autoantigen-specific regulatory T cells. AB - Both Foxp3(+) regulatory T cells (Tregs) and antigen-expanded Foxp3(-) Tregs play an important role in regulating immune responses as well as in preventing autoimmune diseases and graft rejection. Molecular mechanisms modulating Treg function remain largely unclear, however. We report here on the expression and function of an inhibitory killer cell Ig-like receptor, KIR3DL1, in a nonobese diabetic (NOD) mouse-derived autoantigen-specific Treg (2D2), which protects from type 1 diabetes (T1D) in adoptive transfer experiments. This gene is not expressed in T1D pathogenic T cells (Tpaths) or non-Tpath T cells. KIR genes are known to play an important role in regulating natural killer (NK) cell function, but their role in Tregs and T1D is unknown. To examine whether KIR3DL1 expression may modulate Treg function, we used shRNA to down-regulate KIR3DL1 expression (2D2-shKIR). We find that KIR3DL1 down-regulation enhances in vitro function, as measured by improved suppression of target cell proliferation. Antibody blockade of IL-10 but not IL-4 partially abrogated suppressive function. In vivo function is also improved. Adoptive transfer of 2D2-shKIR into 10-wk-old NOD mice prevented spontaneous insulitis and T1D, and the inhibitory effect was further improved if the cells were transferred earlier into 6-wk-old NOD mice. These studies indicate that KIR3DL1 expression may negatively regulate Treg function and suggest a previously undescribed target for improving immune tolerance for potential treatment of autoimmune diseases like T1D. PMID- 21245334 TI - Genetic structure and domestication history of the grape. AB - The grape is one of the earliest domesticated fruit crops and, since antiquity, it has been widely cultivated and prized for its fruit and wine. Here, we characterize genome-wide patterns of genetic variation in over 1,000 samples of the domesticated grape, Vitis vinifera subsp. vinifera, and its wild relative, V. vinifera subsp. sylvestris from the US Department of Agriculture grape germplasm collection. We find support for a Near East origin of vinifera and present evidence of introgression from local sylvestris as the grape moved into Europe. High levels of genetic diversity and rapid linkage disequilibrium (LD) decay have been maintained in vinifera, which is consistent with a weak domestication bottleneck followed by thousands of years of widespread vegetative propagation. The considerable genetic diversity within vinifera, however, is contained within a complex network of close pedigree relationships that has been generated by crosses among elite cultivars. We show that first-degree relationships are rare between wine and table grapes and among grapes from geographically distant regions. Our results suggest that although substantial genetic diversity has been maintained in the grape subsequent to domestication, there has been a limited exploration of this diversity. We propose that the adoption of vegetative propagation was a double-edged sword: Although it provided a benefit by ensuring true breeding cultivars, it also discouraged the generation of unique cultivars through crosses. The grape currently faces severe pathogen pressures, and the long-term sustainability of the grape and wine industries will rely on the exploitation of the grape's tremendous natural genetic diversity. PMID- 21245335 TI - Recalibrating Polynesian prehistory. PMID- 21245336 TI - Low body temperature governs the decline of circulating lymphocytes during hibernation through sphingosine-1-phosphate. AB - Hibernation is an energy-conserving behavior consisting of periods of inhibited metabolism ('torpor') with lowered body temperature. Torpor bouts are interspersed by arousal periods, in which metabolism increases and body temperature returns to euthermia. In deep torpor, the body temperature typically decreases to 2-10 degrees C, and major physiological and immunological changes occur. One of these alterations constitutes an almost complete depletion of circulating lymphocytes that is reversed rapidly upon arousal. Here we show that torpor induces the storage of lymphocytes in secondary lymphoid organs in response to a temperature-dependent drop in plasma levels of sphingosine-1 phosphate (S1P). Regulation of lymphocyte numbers was mediated through the type 1 S1P receptor (S1P(1)), because administration of a specific antagonist (W146) during torpor (in a Syrian hamster at ~8 degrees C) precluded restoration of lymphocyte numbers upon subsequent arousal. Furthermore, S1P release from erythrocytes via ATP-binding cassette (ABC)-transporters was significantly inhibited at low body temperature (4 degrees C) but was restored upon rewarming. Reversible lymphopenia also was observed during daily torpor (in a Djungarian hamster at +/- 25 degrees C), during forced hypothermia in anesthetized (summer active) hamsters (at +/- 9 degrees C), and in a nonhibernator (rat at ~19 degrees C). Our results demonstrate that lymphopenia during hibernation in small mammals is driven by body temperature, via altered plasma S1P levels. S1P is recognized as an important bioactive lipid involved in regulating several other physiological processes as well and may be an important factor regulating additional physiological processes in hibernation as well as in mediating the effects of therapeutic hypothermia in patients. PMID- 21245337 TI - Membrane lipidome of an epithelial cell line. AB - Tissue differentiation is an important process that involves major cellular membrane remodeling. We used Madin-Darby canine kidney cells as a model for epithelium formation and investigated the remodeling of the total cell membrane lipidome during the transition from a nonpolarized morphology to an epithelial morphology and vice versa. To achieve this, we developed a shotgun-based lipidomics workflow that enabled the absolute quantification of mammalian membrane lipidomes with minimal sample processing from low sample amounts. Epithelial morphogenesis was accompanied by a major shift from sphingomyelin to glycosphingolipid, together with an increase in plasmalogen, phosphatidylethanolamine, and cholesterol content, whereas the opposite changes took place during an epithelial-to-mesenchymal transition. Moreover, during polarization, the sphingolipids became longer, more saturated, and more hydroxylated as required to generate an apical membrane domain that serves as a protective barrier for the epithelial sheet. PMID- 21245338 TI - A modest decrease in endothelial NOS in mice comparable to that associated with human NOS3 variants exacerbates diabetic nephropathy. AB - Polymorphisms in the human endothelial nitric oxide synthase (eNOS) gene (NOS3) have been associated with advanced nephropathy in diabetic patients and with decreased expression in tissue culture. However, direct proof that modest genetic decreases in eNOS expression worsen diabetic nephropathy is lacking. To investigate this effect, we took advantage of the hybrid vigor and genetic uniformity of the F1 progeny (eNOS(+/+), eNOS(+/-), or eNOS(-/-) with or without diabetes) of a cross between heterozygous 129S6/SvEvTac eNOS(+/-) inbred females and heterozygous C57BL/6J eNOS(+/-) inbred males carrying the dominant Akita diabetogenic mutation Ins2(C96Y/+). Whereas all C57BL/6J inbred eNOS(-/-) and eNOS(+/-) diabetic mice died before 5 mo, almost half of the F1 hybrid eNOS(-/-) and eNOS(+/-) diabetic mice lived until killed at 7 mo. Heterozygous eNOS(+/-) diabetic mice expressed ~35% eNOS mRNA in the kidney and ~25% glomerular eNOS protein relative to their eNOS(+/+) diabetic littermates. These decreases in eNOS elevated blood pressure (BP) but not blood glucose. Urinary albumin excretion, mesangial expansion, glomerulosclerosis, mesangiolysis, and glomerular filtration rate increased in the order: eNOS(+/+) Akita < eNOS(+/-) Akita < eNOS(-/-) Akita, independently of BP. Glomerular basement membrane thickening depended on increased BP. Renal expression of tissue factor and other inflammatory factors increased with the nephropathy; Nos2 also increased. Surprisingly, however, decreased eNOS expression ameliorated the increases in oxidative stress and tubulointerstitial fibrosis caused by diabetes. Our data demonstrate that a modest decrease in eNOS, comparable to that associated with human NOS3 variants, is sufficient to enhance diabetic nephropathy independently of its effects on BP. PMID- 21245340 TI - Determinants of lemming outbreaks. AB - Population outbreaks in tundra rodents have intrigued scientists for a century as a result of their spectacular appearances and their general lessons in ecology. One outstanding question that has led to competing hypotheses is why sympatric lemmings and voles differ in regularity and shape of their outbreaks. Lemming outbreaks may be lost for decades while vole populations maintain regular population cycles. Moreover, when lemming populations eventually irrupt, they do so more steeply than the vole populations. Norwegian lemmings exhibited a large scale outbreak synchronously with gray-sided voles in Finnmark, northern Fennoscandia, during 2006 to 2007 for the first time in two decades. Analyses of spatial variability of this outbreak across altitudinal gradients allowed us to identify determinants of the contrasting lemming and vole dynamics. The steeper lemming outbreak trajectories were caused by breeding and population growth during winter, when nonbreeding vole populations consistently declined. The differently shaped lemming and vole outbreaks appear to result from a particular demographic tactic of lemmings that evolved as an adaptation to the long and cold Arctic-Alpine winters. The lemming outbreak amplitude increased with altitude and vole density, indicating that lemming outbreaks are jointly facilitated by low temperatures and apparent mutualism with voles mediated by shared predators. High sensitivity to variation in climate and predation is likely to be the reasons why lemmings have more erratic population dynamics than sympatric voles. The combination of continued climatic warming and dampened vole cycles is expected to further decrease the frequency, amplitude, and geographic range of lemming outbreaks in tundra ecosystems. PMID- 21245339 TI - Multistage nanoparticle delivery system for deep penetration into tumor tissue. AB - Current Food and Drug Administration-approved cancer nanotherapeutics, which passively accumulate around leaky regions of the tumor vasculature because of an enhanced permeation and retention (EPR) effect, have provided only modest survival benefits. This suboptimal outcome is likely due to physiological barriers that hinder delivery of the nanotherapeutics throughout the tumor. Many of these nanotherapeutics are ~ 100 nm in diameter and exhibit enhanced accumulation around the leaky regions of the tumor vasculature, but their large size hinders penetration into the dense collagen matrix. Therefore, we propose a multistage system in which 100-nm nanoparticles "shrink" to 10-nm nanoparticles after they extravasate from leaky regions of the tumor vasculature and are exposed to the tumor microenvironment. The shrunken nanoparticles can more readily diffuse throughout the tumor's interstitial space. This size change is triggered by proteases that are highly expressed in the tumor microenvironment such as MMP-2, which degrade the cores of 100-nm gelatin nanoparticles, releasing smaller 10-nm nanoparticles from their surface. We used quantum dots (QD) as a model system for the 10-nm particles because their fluorescence can be used to demonstrate the validity of our approach. In vitro MMP-2 activation of the multistage nanoparticles revealed that the size change was efficient and effective in the enhancement of diffusive transport. In vivo circulation half life and intratumoral diffusion measurements indicate that our multistage nanoparticles exhibited both the long circulation half-life necessary for the EPR effect and the deep tumor penetration required for delivery into the tumor's dense collagen matrix. PMID- 21245342 TI - Structures of sequential open states in a symmetrical opening transition of the TolC exit duct. AB - In bacterial drug resistance and virulence pumps, an inner membrane (IM) transporter and periplasmic adaptor recruit an outer membrane (OM) trimeric TolC exit duct that projects an alpha-helical tunnel across the periplasm. The TolC periplasmic entrance is closed by densely packed alpha-helical coiled coils, inner H7/H8, and outer H3/H4, constrained by a hydrogen bond network. On recruitment, these coiled coils must undergo transition to the open state. We present 2.9 A resolution crystal structures of two sequential TolC open states in which the network is incrementally disrupted and channel conductances defined in lipid bilayers. Superimposition of TolC(RS) (370 pS) and TolC(YFRS) (1,000 pS) on the TolC(WT) closed state (80 pS) showed that in the initial open-state TolC(RS), relaxation already causes approximately 14 degrees twisting and expansion of helix H7 at the periplasmic tip, increasing interprotomer distances from 12.2 A in TolC(WT) to 18.9 A. However, in the crystal structure, the weakened Asp(374) pore constriction was maintained at the closed state 11.3 A(2). In the advanced open-state TolC(YFRS), there was little further expansion at the tip, to interprotomer 21.3 A, but substantial movement of inner and outer coiled coils dilated the pore constriction. In particular, upon abolition of the TolC(YFRS) intraprotomer Tyr(362)-Asp(153) link, a redirection of Tyr(362) and "bulge" in H3 allowed a simple movement outward of H8, establishing a 50.3 A(2) opening. Root mean square deviations (rmsds) over the coiled coils of the three protomers of TolC(RS) and TolC(YFRS) illustrate that, whereas independent movement at the periplasmic tips may feature in the initial stages of opening, full dilation of the pore constriction is entirely symmetrical. PMID- 21245341 TI - Regional rescue of spinocerebellar ataxia type 1 phenotypes by 14-3-3epsilon haploinsufficiency in mice underscores complex pathogenicity in neurodegeneration. AB - Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease caused by the expansion of a CAG repeat encoding a polyglutamine tract in Ataxin-1 (ATXN1). Both WT and mutant ATXN1 interact with 14-3-3 proteins, and 14-3-3 overexpression stabilizes ATXN1 levels in cells and increases ATXN1 toxicity in flies. To determine whether reducing 14-3-3 levels might mitigate SCA1 pathogenesis, we bred Sca1(154Q/+) mice to mice lacking one allele of 14-3-3epsilon. 14-3-3epsilon haploinsufficiency rescued cerebellar pathology and motor phenotypes but, surprisingly, not weight loss, respiratory dysfunction, or premature lethality. Biochemical studies revealed that reducing 14-3-3epsilon levels exerted different effects in two brain regions especially vulnerable in SCA1: Although diminishing levels of both WT and mutant ATXN1 in the cerebellum, 14-3-3epsilon haploinsufficiency did not alter ATXN1 levels in the brainstem. Furthermore, 14-3 3epsilon haploinsufficiency decreased the incorporation of expanded ATXN1 into its large toxic complexes in the cerebellum but not in the brainstem, and the distribution of ATXN1's small and large native complexes differed significantly between the two regions. These data suggest that distinct pathogenic mechanisms operate in different vulnerable brain regions, adding another level of complexity to SCA1 pathogenesis. PMID- 21245343 TI - Architecture of the DNA polymerase B-proliferating cell nuclear antigen (PCNA) DNA ternary complex. AB - DNA replication in archaea and eukaryotes is executed by family B DNA polymerases, which exhibit full activity when complexed with the DNA clamp, proliferating cell nuclear antigen (PCNA). This replication enzyme consists of the polymerase and exonuclease moieties responsible for DNA synthesis and editing (proofreading), respectively. Because of the editing activity, this enzyme ensures the high fidelity of DNA replication. However, it remains unclear how the PCNA-complexed enzyme temporally switches between the polymerizing and editing modes. Here, we present the three-dimensional structure of the Pyrococcus furiosus DNA polymerase B-PCNA-DNA ternary complex, which is the core component of the replisome, determined by single particle electron microscopy of negatively stained samples. This structural view, representing the complex in the editing mode, revealed the whole domain configuration of the trimeric PCNA ring and the DNA polymerase, including protein-protein and protein-DNA contacts. Notably, besides the authentic DNA polymerase-PCNA interaction through a PCNA-interacting protein (PIP) box, a novel contact was found between DNA polymerase and the PCNA subunit adjacent to that with the PIP contact. This contact appears to be responsible for the configuration of the complex specific for the editing mode. The DNA was located almost at the center of PCNA and exhibited a substantial and particular tilt angle against the PCNA ring plane. The obtained molecular architecture of the complex, including the new contact found in this work, provides clearer insights into the switching mechanism between the two distinct modes, thus highlighting the functional significance of PCNA in the replication process. PMID- 21245344 TI - Structural basis for the removal of ubiquitin and interferon-stimulated gene 15 by a viral ovarian tumor domain-containing protease. AB - The attachment of ubiquitin (Ub) and the Ub-like (Ubl) molecule interferon stimulated gene 15 (ISG15) to cellular proteins mediates important innate antiviral responses. Ovarian tumor (OTU) domain proteases from nairoviruses and arteriviruses were recently found to remove these molecules from host proteins, which inhibits Ub and ISG15-dependent antiviral pathways. This contrasts with the Ub-specific activity of known eukaryotic OTU-domain proteases. Here we describe crystal structures of a viral OTU domain from the highly pathogenic Crimean-Congo haemorrhagic fever virus (CCHFV) bound to Ub and to ISG15 at 2.5-A and 2.3-A resolution, respectively. The complexes provide a unique structural example of ISG15 bound to another protein and reveal the molecular mechanism of an ISG15 cross-reactive deubiquitinase. To accommodate structural differences between Ub and ISG15, the viral protease binds the beta-grasp folds of Ub and C-terminal Ub like domain of ISG15 in an orientation that is rotated nearly 75 degrees with respect to that observed for Ub bound to a representative eukaryotic OTU domain from yeast. Distinct structural determinants necessary for binding either substrate were identified and allowed the reengineering of the viral OTU protease into enzymes with increased substrate specificity, either for Ub or for ISG15. Our findings now provide the basis to determine in vivo the relative contributions of deubiquitination and deISGylation to viral immune evasion tactics, and a structural template of a promiscuous deubiquitinase from a haemorrhagic fever virus that can be targeted for inhibition using small-molecule based strategies. PMID- 21245345 TI - Optimal pulse design in quantum control: a unified computational method. AB - Many key aspects of control of quantum systems involve manipulating a large quantum ensemble exhibiting variation in the value of parameters characterizing the system dynamics. Developing electromagnetic pulses to produce a desired evolution in the presence of such variation is a fundamental and challenging problem in this research area. We present such robust pulse designs as an optimal control problem of a continuum of bilinear systems with a common control function. We map this control problem of infinite dimension to a problem of polynomial approximation employing tools from geometric control theory. We then adopt this new notion and develop a unified computational method for optimal pulse design using ideas from pseudospectral approximations, by which a continuous-time optimal control problem of pulse design can be discretized to a constrained optimization problem with spectral accuracy. Furthermore, this is a highly flexible and efficient numerical method that requires low order of discretization and yields inherently smooth solutions. We demonstrate this method by designing effective broadband pi/2 and pi pulses with reduced rf energy and pulse duration, which show significant sensitivity enhancement at the edge of the spectrum over conventional pulses in 1D and 2D NMR spectroscopy experiments. PMID- 21245346 TI - Reconciliation of opposing views on membrane-sugar interactions. AB - It is well established that small sugars exert different types of stabilization of biomembranes both in vivo and in vitro. However, the essential question of whether sugars are bound to or expelled from membrane surfaces, i.e., the sign and size of the free energy of the interaction, remains unresolved, and this prevents a molecular understanding of the stabilizing mechanism. We have used small-angle neutron scattering and thermodynamic measurements to show that sugars may be either bound or expelled depending on the concentration of sugar. At low concentration, small sugars bind quite strongly to a lipid bilayer, and the accumulation of sugar at the interface makes the membrane thinner and laterally expanded. Above ~0.2 M the sugars gradually become expelled from the membrane surface, and this repulsive mode of interaction counteracts membrane thinning. The dual nature of sugar-membrane interactions offers a reconciliation of conflicting views in earlier reports on sugar-induced modulations of membrane properties. PMID- 21245347 TI - Arsenic pollution of groundwater in Vietnam exacerbated by deep aquifer exploitation for more than a century. AB - Arsenic contamination of shallow groundwater is among the biggest health threats in the developing world. Targeting uncontaminated deep aquifers is a popular mitigation option although its long-term impact remains unknown. Here we present the alarming results of a large-scale groundwater survey covering the entire Red River Delta and a unique probability model based on three-dimensional Quaternary geology. Our unprecedented dataset reveals that ~7 million delta inhabitants use groundwater contaminated with toxic elements, including manganese, selenium, and barium. Depth-resolved probabilities and arsenic concentrations indicate drawdown of arsenic-enriched waters from Holocene aquifers to naturally uncontaminated Pleistocene aquifers as a result of > 100 years of groundwater abstraction. Vertical arsenic migration induced by large-scale pumping from deep aquifers has been discussed to occur elsewhere, but has never been shown to occur at the scale seen here. The present situation in the Red River Delta is a warning for other As affected regions where groundwater is extensively pumped from uncontaminated aquifers underlying high arsenic aquifers or zones. PMID- 21245348 TI - Kikuchi ultrafast nanodiffraction in four-dimensional electron microscopy. AB - Coherent atomic motions in materials can be revealed using time-resolved X-ray and electron Bragg diffraction. Because of the size of the beam used, typically on the micron scale, the detection of nanoscale propagating waves in extended structures hitherto has not been reported. For elastic waves of complex motions, Bragg intensities contain all polarizations and they are not straightforward to disentangle. Here, we introduce Kikuchi diffraction dynamics, using convergent beam geometry in an ultrafast electron microscope, to selectively probe propagating transverse elastic waves with nanoscale resolution. It is shown that Kikuchi band shifts, which are sensitive only to the tilting of atomic planes, reveal the resonance oscillations, unit cell angular amplitudes, and the polarization directions. For silicon, the observed wave packet temporal envelope (resonance frequency of 33 GHz), the out-of-phase temporal behavior of Kikuchi's edges, and the magnitude of angular amplitude (0.3 mrad) and polarization elucidate the nature of the motion: one that preserves the mass density (i.e., no compression or expansion) but leads to sliding of planes in the antisymmetric shear eigenmode of the elastic waveguide. As such, the method of Kikuchi diffraction dynamics, which is unique to electron imaging, can be used to characterize the atomic motions of propagating waves and their interactions with interfaces, defects, and grain boundaries at the nanoscale. PMID- 21245349 TI - Simultaneous single-molecule measurements of phage T7 replisome composition and function reveal the mechanism of polymerase exchange. AB - A complete understanding of the molecular mechanisms underlying the functioning of large, multiprotein complexes requires experimental tools capable of simultaneously visualizing molecular architecture and enzymatic activity in real time. We developed a novel single-molecule assay that combines the flow stretching of individual DNA molecules to measure the activity of the DNA replication machinery with the visualization of fluorescently labeled DNA polymerases at the replication fork. By correlating polymerase stoichiometry with DNA synthesis of T7 bacteriophage replisomes, we are able to quantitatively describe the mechanism of polymerase exchange. We find that even at relatively modest polymerase concentration (~2 nM), soluble polymerases are recruited to an actively synthesizing replisome, dramatically increasing local polymerase concentration. These excess polymerases remain passively associated with the replisome through electrostatic interactions with the T7 helicase for ~50 s until a stochastic and transient dissociation of the synthesizing polymerase from the primer-template allows for a polymerase exchange event to occur. PMID- 21245350 TI - A multiply convergent platform for the synthesis of trioxacarcins. AB - Many first-line cancer drugs are natural products or are derived from them by chemical modification. The trioxacarcins are an emerging class of molecules of microbial origin with potent antiproliferative effects, which may derive from their ability to covalently modify duplex DNA. All trioxacarcins appear to be derivatives of a nonglycosylated natural product known as DC-45-A2. To explore the potential of the trioxacarcins for the development of small-molecule drugs and probes, we have designed a synthetic strategy toward the trioxacarcin scaffold that enables access to both the natural trioxacarcins and nonnatural structural variants. Here, we report a synthetic route to DC-45-A2 from a differentially protected precursor, which in turn is assembled in just six steps from three components of similar structural complexity. The brevity of the sequence arises from strict adherence to a plan in which strategic bond-pair constructions are staged at or near the end of the synthetic route. PMID- 21245351 TI - Design, synthesis, and biological evaluation of a biyouyanagin compound library. AB - Modern drug discovery efforts rely, to a large extent, on lead compounds from two classes of small organic molecules; namely, natural products (i.e., secondary metabolites) and designed compounds (i.e., synthetic molecules). In this article, we demonstrate how these two domains of lead compounds can be merged through total synthesis and molecular design of analogs patterned after the targeted natural products, whose promising biological properties provide the motivation. Specifically, the present study targeted the naturally occurring biyouyanagins A and B and their analogs through modular chemical synthesis and led to the discovery of small organic molecules possessing anti-HIV and anti-arenavirus properties. PMID- 21245352 TI - Crystal structures of complexes containing domains from two viral internal ribosome entry site (IRES) RNAs bound to the 70S ribosome. AB - Internal ribosome entry site (IRES) RNAs are elements of viral or cellular mRNAs that bypass steps of canonical eukaryotic cap-dependent translation initiation. Understanding of the structural basis of IRES mechanisms is limited, partially due to a lack of high-resolution structures of IRES RNAs bound to their cellular targets. Prompted by the universal phylogenetic conservation of the ribosomal P site, we solved the crystal structures of proposed P site binding domains from two intergenic region IRES RNAs bound to bacterial 70S ribosomes. The structures show that these IRES domains nearly perfectly mimic a tRNA * mRNA interaction. However, there are clear differences in the global shape and position of this IRES domain in the intersubunit space compared to those of tRNA, supporting a mechanism for IRES action that invokes hybrid state mimicry to drive a noncanonical mode of translocation. These structures suggest how relatively small structured RNAs can manipulate complex biological machines. PMID- 21245353 TI - From polariton condensates to highly photonic quantum degenerate states of bosonic matter. AB - Bose-Einstein condensation (BEC) is a thermodynamic phase transition of an interacting Bose gas. Its key signatures are remarkable quantum effects like superfluidity and a phonon-like Bogoliubov excitation spectrum, which have been verified for atomic BECs. In the solid state, BEC of exciton-polaritons has been reported. Polaritons are strongly coupled light-matter quasiparticles in semiconductor microcavities and composite bosons. However, they are subject to dephasing and decay and need external pumping to reach a steady state. Accordingly the polariton BEC is a nonequilibrium process of a degenerate polariton gas in self-equilibrium, but out of equilibrium with the baths it is coupled to and therefore deviates from the thermodynamic phase transition seen in atomic BECs. Here we show that key signatures of BEC can even be observed without fulfilling the self-equilibrium condition in a highly photonic quantum degenerate nonequilibrium system. PMID- 21245354 TI - Tension-dependent structural deformation alters single-molecule transition kinetics. AB - We analyze the response of a single nucleosome to tension, which serves as a prototypical biophysical measurement where tension-dependent deformation alters transition kinetics. We develop a statistical-mechanics model of a nucleosome as a wormlike chain bound to a spool, incorporating fluctuations in the number of bases bound, the spool orientation, and the conformations of the unbound polymer segments. With the resulting free-energy surface, we perform dynamic simulations that permit a direct comparison with experiments. This simple approach demonstrates that the experimentally observed structural states at nonzero tension are a consequence of the tension and that these tension-induced states cease to exist at zero tension. The transitions between states exhibit substantial deformation of the unbound polymer segments. The associated deformation energy increases with tension; thus, the application of tension alters the kinetics due to tension-induced deformation of the transition states. This mechanism would arise in any system where the tether molecule is deformed in the transition state under the influence of tension. PMID- 21245355 TI - Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair. AB - Herein we investigated a new strategy for the modulation of cardiac macrophages to a reparative state, at a predetermined time after myocardial infarction (MI), in aim to promote resolution of inflammation and elicit infarct repair. The strategy employed intravenous injections of phosphatidylserine (PS)-presenting liposomes, mimicking the anti-inflammatory effects of apoptotic cells. Following PS-liposome uptake by macrophages in vitro and in vivo, the cells secreted high levels of anti-inflammatory cytokines [transforming growth factor beta (TGFbeta) and interleukin 10 (IL-10)] and upregulated the expression of the mannose receptor--CD206, concomitant with downregulation of proinflammatory markers, such as tumor necrosis factor alpha (TNFalpha) and the surface marker CD86. In a rat model of acute MI, targeting of PS-presenting liposomes to infarct macrophages after injection via the femoral vein was demonstrated by magnetic resonance imaging (MRI). The treatment promoted angiogenesis, the preservation of small scars, and prevented ventricular dilatation and remodeling. This strategy represents a unique and accessible approach for myocardial infarct repair. PMID- 21245356 TI - Dynamically tunable hemispherical electronic eye camera system with adjustable zoom capability. AB - Imaging systems that exploit arrays of photodetectors in curvilinear layouts are attractive due to their ability to match the strongly nonplanar image surfaces (i.e., Petzval surfaces) that form with simple lenses, thereby creating new design options. Recent work has yielded significant progress in the realization of such "eyeball" cameras, including examples of fully functional silicon devices capable of collecting realistic images. Although these systems provide advantages compared to those with conventional, planar designs, their fixed detector curvature renders them incompatible with changes in the Petzval surface that accompany variable zoom achieved with simple lenses. This paper describes a class of digital imaging device that overcomes this limitation, through the use of photodetector arrays on thin elastomeric membranes, capable of reversible deformation into hemispherical shapes with radii of curvature that can be adjusted dynamically, via hydraulics. Combining this type of detector with a similarly tunable, fluidic plano-convex lens yields a hemispherical camera with variable zoom and excellent imaging characteristics. Systematic experimental and theoretical studies of the mechanics and optics reveal all underlying principles of operation. This type of technology could be useful for night-vision surveillance, endoscopic imaging, and other areas that require compact cameras with simple zoom optics and wide-angle fields of view. PMID- 21245357 TI - Structural kinetics of myosin by transient time-resolved FRET. AB - For many proteins, especially for molecular motors and other enzymes, the functional mechanisms remain unsolved due to a gap between static structural data and kinetics. We have filled this gap by detecting structure and kinetics simultaneously. This structural kinetics experiment is made possible by a new technique, (TR)(2)FRET (transient time-resolved FRET), which resolves protein structural states on the submillisecond timescale during the transient phase of a biochemical reaction. (TR)(2)FRET is accomplished with a fluorescence instrument that uses a pulsed laser and direct waveform recording to acquire an accurate subnanosecond time-resolved fluorescence decay every 0.1 ms after stopped flow. To apply this method to myosin, we labeled the force-generating region site specifically with two probes, mixed rapidly with ATP to initiate the recovery stroke, and measured the interprobe distance by (TR)(2)FRET with high resolution in both space and time. We found that the relay helix bends during the recovery stroke, most of which occurs before ATP is hydrolyzed, and two structural states (relay helix straight and bent) are resolved in each nucleotide-bound biochemical state. Thus the structural transition of the force-generating region of myosin is only loosely coupled to the ATPase reaction, with conformational selection driving the motor mechanism. PMID- 21245358 TI - Noncontact estimation of intercellular breaking force using a femtosecond laser impulse quantified by atomic force microscopy. AB - When a femtosecond laser pulse (fsLP) is focused through an objective lens into a culture medium, an impulsive force (fsLP-IF) is generated that propagates from the laser focal point (O(f)) in a micron-sized space. This force can detach individual adherent cells without causing considerable cell damage. In this study, an fsLP-IF was reflected in the vibratory movement of an atomic force microscopy (AFM) cantilever. Based on the magnitude of the vibration and the geometrical relationship between O(f) and the cantilever, the fsLP-IF generated at O(f) was calculated as a unit of impulse [N-s]. This impulsive force broke adhesion molecule-mediated intercellular interactions in a manner that depended on the adhesion strength that was estimated by the cell aggregation assay. The force also broke the interactions between streptavidin-coated microspheres and a biotin-coated substrate with a measurement error of approximately 7%. These results suggest that fsLP-IF can be used to break intermolecular and intercellular interactions and estimate the adhesion strength. The fsLP-IF was used to break intercellular contacts in two biologically relevant cultures: a coculture of leukocytes seeded over on an endothelial cell monolayer, and a polarized monolayer culture of epithelial cells. The impulses needed to break leukocyte-endothelial and interepithelial interactions, which were calculated based on the geometrical relationship between O(f) and the adhesive interface, were on the order of 10(-13) and 10(-12) N-s, respectively. When the total impulse at O(f) is well-defined, fsLP-IF can be used to estimate the force required to break intercellular adhesions in a noncontact manner under biologically relevant conditions. PMID- 21245359 TI - Surface chemistry: key to control and advance myriad technologies. AB - This special issue on surface chemistry is introduced with a brief history of the field, a summary of the importance of surface chemistry in technological applications, a brief overview of some of the most important recent developments in this field, and a look forward to some of its most exciting future directions. This collection of invited articles is intended to provide a snapshot of current developments in the field, exemplify the state of the art in fundamental research in surface chemistry, and highlight some possibilities in the future. Here, we show how those articles fit together in the bigger picture of this field. PMID- 21245360 TI - Noninvasive estimation of the rate of relaxation by the analysis of intraventricular pressure gradients. AB - BACKGROUND: During late ejection, myocardial relaxation causes systolic flow to decelerate and stop, and this phenomenon is coupled with the generation of a pressure gradient inside the left ventricle (LV). We hypothesized that the peak reverse ejection intraventricular pressure difference (REIVPD) between the LV apex and the outflow tract could be a useful method to improve the assessment of LV relaxation using Doppler echocardiography. METHODS AND RESULTS: Three sets of animal experiments and 1 clinical study were designed. In 6 pigs, a close relationship between REIVPD and the intensity of the relaxation wave (R(rm)=0.89) was demonstrated using wave intensity analysis of high-fidelity pressure-volume velocity data. In 19 animals, REIVPD sensitively detected modifications of the lusotropic state and closely correlated with the time constant of LV relaxation (tau) within animals (R(rm)=-0.93). Load-dependence analysis in 5 pigs showed that REIVPD remained stable up to values of 35% to 40% acute preload reduction. Clinical validation was tested in 50 patients (23 with normal systolic function) undergoing simultaneous Doppler echocardiography and high-fidelity LV pressure measurements on the same beat. REIVPD and tissue Doppler mitral annulus velocity (e') were independently related to tau, but the REIVPD . e' product correlated better with tau than either variable separately (bootstrap-corrected correlation coefficients: R=-0.84 versus -0.71, and -0.70, respectively, P<0.05). Area under the receiver operating characteristic curve to predict impaired relaxation (tau>50 ms) for e' . REIVPD was 0.96 (95% confidence interval, 0.85 to 0.99). CONCLUSIONS: The Doppler-derived REIVPD provides a sensitive, reliable, reproducible, and relatively load-independent index of the rate of LV relaxation. Combined with tissue Doppler measurements of longitudinal function, this method improves noninvasive assessment of LV relaxation in the clinical setting. PMID- 21245362 TI - Extrapolation from mouse to man. PMID- 21245363 TI - New toys for nuclear cardiologists. PMID- 21245365 TI - Epicardial lipomatous hypertrophy mimicking pericardial effusion: characterization with cardiovascular magnetic resonance. PMID- 21245364 TI - Cardiac involvement in patients with muscular dystrophies: magnetic resonance imaging phenotype and genotypic considerations. PMID- 21245366 TI - Left ventricular torsion: feeling the heat. PMID- 21245367 TI - Molecular characterization of circulating tumor cells in breast cancer by a liquid bead array hybridization assay. AB - BACKGROUND: Molecular characterization of circulating tumor cells (CTCs) is crucial to identify novel diagnostic and therapeutic targets for individualized therapies. We developed a multiplexed PCR-coupled liquid bead array to detect the expression of multiple genes in CTCs. METHODS: mRNA isolated from immunomagnetically enriched CTCs was subjected to multiplex PCR for KRT19 (keratin 19; also known as CK19), ERBB2 [v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived oncogene homolog (avian); also known as HER2], SCGB2A2 (secretoglobin, family 2A, member 2; also known as MGB1, mammaglobin A), MAGEA3 (melanoma antigen family A, 3), TWIST-1 [twist homolog 1 (Drosophila)], and HMBS (hydroxymethylbilane synthase; also known as PBGD). Biotinylated amplicons were hybridized against fluorescent microspheres carrying gene-specific capture probes and incubated with streptavidin-phycoerythrin. We quantified the captured labeled amplicons and decoded the beads by Luminex flow cytometry. The assay was validated for limit of detection, specificity, and comparison with reverse-transcription quantitative PCR (RT-qPCR), and its clinical performance was evaluated in 64 patients with operable breast cancer, 20 patients with metastasis, and 17 healthy individuals. RESULTS: The assay was specific for each gene in complex multiplexed formats and could detect the expression of each gene at the level of a single SK-BR-3 cell. The assay produced results comparable to those for RT-qPCR for each gene. None of the genes tested was detected in the CTC fraction of healthy donors. We detected KRT19, ERBB2, MAGEA3, SCGB2A2, and TWIST1 in 26.6%, 12.5%, 18.7%, 10.9%, and 31.2% of operable breast cancer patients, respectively, and detected the corresponding genes in 65%, 20%, 30%, 20%, and 20% of patients with verified metastasis, respectively. CONCLUSIONS: The expression of 6 genes in CTCs can be measured simultaneously and reliably, thereby saving precious sample and reducing the costs and time of analysis. PMID- 21245368 TI - Gene targeting through o-methylated catecholamine metabolite patterns. PMID- 21245370 TI - Whither the lipid profile: feast, famine, or no free lunch? PMID- 21245371 TI - Increasing liquid chromatography-tandem mass spectrometry throughput by mass tagging: a sample-multiplexed high-throughput assay for 25-hydroxyvitamin D2 and D3. AB - BACKGROUND: The limits of chromatographic speed and mechanical frontend capabilities have been reached for many high-volume liquid chromatography-tandem mass spectrometry (LC-MS/MS) tests, curtailing the maximal achievable sample throughput. To overcome these boundaries, we developed and validated a derivatization-based sample-multiplex LC-MS/MS assay for detection of 25 hydroxyvitamins D2 and D3 [25(OH)D2 and 25(OH)D3], which increased sample throughput 5-fold. METHODS: After separate derivatization with 1 of 5 different triazoline-diones (TADs), 5 calibrators, controls, or patient specimens were combined and injected together into an LC-MS/MS. On the basis of mass differences between TADs, the MS/MS quantified analyte and stable isotope internal standards for 25(OH)D2 and 25(OH)D3 for each respective multiplexed sample within the injection. Limits of detection and quantification, spiked recovery, linearity, imprecision, and patient results were determined and compared against our standard LC-MS/MS assay. RESULTS: TAD multiplexing increased throughput on an LC quadruplexed LC-MS/MS system from 60 samples/h to 300 samples/h. Limits of detection and quantification were 4.9 nmol/L [2 MUg/L, 25(OH)D2], 2.2 nmol/L [0.9 MUg/L, 25(OH)D3], and 10 nmol/L [4 MUg/L, 25(OH)D2], 5 nmol/L [2 MUg/L, 25(OH)D3], respectively. The assay was linear to 250 nmol/L (100 MUg/L). Interassay CVs across the reportable range were 3.7%-15.2%. Spiked recoveries were 94%-119%. The method comparison with the standard LC-MS/MS method showed slopes of 0.96 and 0.97 (Deming regression) for 25(OH)D2 (n=1733) and 25(OH)D3 (n=7614) (R2=0.96 and 0.97), respectively. CONCLUSIONS: Multiplexing samples by differential mass tagging in LC-MS/MS measurement of 25(OH)D2 and 25(OH)D3 allows for reliable quantification, with throughput increased over standard methods by the multiplexing factor. PMID- 21245372 TI - Maternal methadone dose, placental methadone concentrations, and neonatal outcomes. AB - BACKGROUND: Few investigations have used placenta as an alternative matrix to detect in utero drug exposure, despite its availability at the time of birth and the large amount of sample. Methadone-maintained opioid-dependent pregnant women provide a unique opportunity to examine the placental disposition of methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)], to explore their correlations with maternal methadone dose and neonatal outcomes, and to test the ability to detect in utero exposure to illicit drugs. METHODS: We calculated the correlations of placental methadone and EDDP concentrations and their correlations with maternal methadone doses and neonatal outcomes. Cocaine- and opiate-positive placenta results were compared with the results for meconium samples and for urine samples collected throughout gestation. RESULTS: Positive correlations were found between placental methadone and EDDP concentrations (r=0.685), and between methadone concentration and methadone dose at delivery (r=0.542), mean daily dose (r=0.554), mean third-trimester dose (r=0.591), and cumulative daily dose (r=0.639). The EDDP/methadone concentration ratio was negatively correlated with cumulative daily dose (r=-0.541) and positively correlated with peak neonatal abstinence syndrome (NAS) score (r=0.513). Placental EDDP concentration was negatively correlated with newborn head circumference (r=-0.579). Cocaine and opiate use was detected in far fewer placenta samples than in thrice-weekly urine and meconium samples, a result suggesting a short detection window for placenta. CONCLUSIONS: Quantitative methadone and EDDP measurement may predict NAS severity. The placenta reflects in utero drug exposure for a shorter time than meconium but may be useful when meconium is unavailable or if documentation of recent exposure is needed. PMID- 21245373 TI - Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. AB - Mitofusin-2 (Mfn-2) is a dynamin-like protein that is involved in the rearrangement of the outer mitochondrial membrane. Research using various experimental systems has shown that Mfn-2 is a mediator of mitochondrial fusion, an evolutionarily conserved process responsible for the surveillance of mitochondrial homeostasis. Here, we find that cardiac myocyte mitochondria lacking Mfn-2 are pleiomorphic and have the propensity to become enlarged. Consistent with an underlying mild mitochondrial dysfunction, Mfn-2-deficient mice display modest cardiac hypertrophy accompanied by slight functional deterioration. The absence of Mfn-2 is associated with a marked delay in mitochondrial permeability transition downstream of Ca(2+) stimulation or due to local generation of reactive oxygen species (ROS). Consequently, Mfn-2-deficient adult cardiomyocytes are protected from a number of cell death-inducing stimuli and Mfn-2 knockout hearts display better recovery following reperfusion injury. We conclude that in cardiac myocytes, Mfn-2 controls mitochondrial morphogenesis and serves to predispose cells to mitochondrial permeability transition and to trigger cell death. PMID- 21245374 TI - Mouse cardiac acyl coenzyme a synthetase 1 deficiency impairs Fatty Acid oxidation and induces cardiac hypertrophy. AB - Long-chain acyl coenzyme A (acyl-CoA) synthetase isoform 1 (ACSL1) catalyzes the synthesis of acyl-CoA from long-chain fatty acids and contributes the majority of cardiac long-chain acyl-CoA synthetase activity. To understand its functional role in the heart, we studied mice lacking ACSL1 globally (Acsl1(T-/-)) and mice lacking ACSL1 in heart ventricles (Acsl1(H-/-)) at different times. Compared to littermate controls, heart ventricular ACSL activity in Acsl1(T-/-) mice was reduced more than 90%, acyl-CoA content was 65% lower, and long-chain acyl carnitine content was 80 to 90% lower. The rate of [(14)C]palmitate oxidation in both heart homogenate and mitochondria was 90% lower than in the controls, and the maximal rates of [(14)C]pyruvate and [(14)C]glucose oxidation were each 20% higher. The mitochondrial area was 54% greater than in the controls with twice as much mitochondrial DNA, and the mRNA abundance of Pgc1alpha and Erralpha increased by 100% and 41%, respectively. Compared to the controls, Acsl1(T-/-) and Acsl1(H-/-) hearts were hypertrophied, and the phosphorylation of S6 kinase, a target of mammalian target of rapamycin (mTOR) kinase, increased 5-fold. Our data suggest that ACSL1 is required to synthesize the acyl-CoAs that are oxidized by the heart, and that without ACSL1, diminished fatty acid (FA) oxidation and compensatory catabolism of glucose and amino acids lead to mTOR activation and cardiac hypertrophy without lipid accumulation or immediate cardiac dysfunction. PMID- 21245375 TI - Cardiac tissue-restricted deletion of plakoglobin results in progressive cardiomyopathy and activation of {beta}-catenin signaling. AB - Mutations in the plakoglobin (JUP) gene have been identified in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. However, the mechanisms underlying plakoglobin dysfunction involved in the pathogenesis of ARVC remain poorly understood. Plakoglobin is a component of both desmosomes and adherens junctions located at the intercalated disc (ICD) of cardiomyocytes, where it functions to link cadherins to the cytoskeleton. In addition, plakoglobin functions as a signaling protein via its ability to modulate the Wnt/beta-catenin signaling pathway. To investigate the role of plakoglobin in ARVC, we generated an inducible cardiorestricted knockout (CKO) of the plakoglobin gene in mice. Plakoglobin CKO mice exhibited progressive loss of cardiac myocytes, extensive inflammatory infiltration, fibrous tissue replacement, and cardiac dysfunction similar to those of ARVC patients. Desmosomal proteins from the ICD were decreased, consistent with altered desmosome ultrastructure in plakoglobin CKO hearts. Despite gap junction remodeling, plakoglobin CKO hearts were refractory to induced arrhythmias. Ablation of plakoglobin caused increase beta-catenin stabilization associated with activated AKT and inhibition of glycogen synthase kinase 3beta. Finally, beta-catenin/TCF transcriptional activity may contribute to the cardiac hypertrophy response in plakoglobin CKO mice. This novel model of ARVC demonstrates for the first time how plakoglobin affects beta-catenin activity in the heart and its implications for disease pathogenesis. PMID- 21245376 TI - N-terminal phosphorylation of HP1{alpha} promotes its chromatin binding. AB - The phosphorylation of heterochromatin protein 1 (HP1) has been previously described in studies of mammals, but the biological implications of this modification remain largely elusive. Here, we show that the N-terminal phosphorylation of HP1alpha plays a central role in its targeting to chromatin. Recombinant HP1alpha prepared from mammalian cultured cells exhibited a stronger binding affinity for K9-methylated histone H3 (H3K9me) than that produced in Escherichia coli. Biochemical analyses revealed that HP1alpha was multiply phosphorylated at N-terminal serine residues (S11-14) in human and mouse cells and that this phosphorylation enhanced HP1alpha's affinity for H3K9me. Importantly, the N-terminal phosphorylation appeared to facilitate the initial binding of HP1alpha to H3K9me by mediating the interaction between HP1alpha and a part of the H3 tail that was distinct from the methylated K9. Unphosphorylatable mutant HP1alpha exhibited severe heterochromatin localization defects in vivo, and its prolonged expression led to increased chromosomal instability. Our results suggest that HP1alpha's N-terminal phosphorylation is essential for its proper targeting to heterochromatin and that its binding to the methylated histone tail is achieved by the cooperative action of the chromodomain and neighboring posttranslational modifications. PMID- 21245377 TI - SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. AB - Regulation of transcription factor Nrf2 (NF-E2-related factor 2) involves redox sensitive proteasomal degradation via the E3 ubiquitin ligase Keap1/Cul3. However, Nrf2 is controlled by other mechanisms that have not yet been elucidated. We now show that glycogen synthase kinase 3 (GSK-3) phosphorylates a group of Ser residues in the Neh6 domain of mouse Nrf2 that overlap with an SCF/beta-TrCP destruction motif (DSGIS, residues 334 to 338) and promotes its degradation in a Keap1-independent manner. Nrf2 was stabilized by GSK-3 inhibitors in Keap1-null mouse embryo fibroblasts. Similarly, an Nrf2(DeltaETGE) mutant, which cannot be degraded via Keap1, accumulated when GSK-3 activity was blocked. Phosphorylation of a Ser cluster in the Neh6 domain of Nrf2 stimulated its degradation because a mutant Nrf2(DeltaETGE 6S/6A) protein, lacking these Ser residues, exhibited a longer half-life than Nrf2(DeltaETGE). Moreover, Nrf2(DeltaETGE 6S/6A) was insensitive to beta-TrCP regulation and exhibited lower levels of ubiquitination than Nrf2(DeltaETGE). GSK-3beta enhanced ubiquitination of Nrf2(DeltaETGE) but not that of Nrf2(DeltaETGE 6S/6A). The Nrf2(DeltaETGE) protein but not Nrf2(DeltaETGE 6S/6A) coimmunoprecipitated with beta-TrCP, and this association was enhanced by GSK-3beta. Our results show for the first time that Nrf2 is targeted by GSK-3 for SCF/beta-TrCP-dependent degradation. We propose a "dual degradation" model to describe the regulation of Nrf2 under different pathophysiological conditions. PMID- 21245378 TI - Novel core promoter elements and a cognate transcription factor in the divergent unicellular eukaryote Trichomonas vaginalis. AB - A highly conserved DNA initiator (Inr) element has been the only core promoter element described in the divergent unicellular eukaryote Trichomonas vaginalis, although genome analyses reveal that only ~75% of protein-coding genes appear to contain an Inr. In search of another core promoter element(s), a nonredundant database containing 5' untranslated regions of expressed T. vaginalis genes was searched for overrepresented DNA motifs and known eukaryotic core promoter elements. In addition to identifying the Inr, two elements that lack sequence similarity to the known protein-coding gene core promoter, motif 3 (M3) and motif 5 (M5), were identified. Mutational and functional analyses demonstrate that both are novel core promoter elements. M3 [(A/G/T)(A/G)C(G/C)G(T/C)T(T/A/G)] resembles a Myb recognition element (MRE) and is bound specifically by a unique protein with a Myb-like DNA binding domain. The M5 element (CCTTT) overlaps the transcription start site and replaces the Inr as an alternative, gene-specific initiator element. Transcription specifically initiates at the second cytosine within M5, in contrast to characteristic initiation by RNA polymerase II at an adenosine. In promoters that combine M3 with either M5 or Inr, transcription initiation is regulated by the M3 motif. PMID- 21245379 TI - The codon 72 polymorphism of p53 regulates interaction with NF-{kappa}B and transactivation of genes involved in immunity and inflammation. AB - A common polymorphism at codon 72 in the p53 tumor suppressor gene encodes either proline (P72) or arginine (R72). Several groups have reported that in cultured cells, this polymorphism influences p53's transcriptional, senescence, and apoptotic functions. However, the impact of this polymorphism within the context of a living organism is poorly understood. We generated knock-in mice with the P72 and R72 variants and analyzed the tissues of these mice for apoptosis and transcription. In the thymus, we find that the P72 variant induces increased apoptosis following ionizing radiation, along with increased transactivation of a subset of p53 target genes, which includes murine Caspase 4 (also called Caspase 11), which we show is a direct p53 target gene. Interestingly, the majority of genes in this subset have roles in inflammation, and their promoters contain NF kappaB binding sites. We show that caspase 4/11 requires both p53 and NF-kappaB for full induction after DNA damage and that the P72 variant shows increased interaction with p65 RelA, a subunit of NF-kappaB. Consistent with this, we show that P72 mice have a markedly enhanced response to inflammatory challenge compared to that of R72 mice. Our data indicate that the codon 72 polymorphism impacts p53's role in inflammation. PMID- 21245380 TI - The rhox homeobox gene cluster is imprinted and selectively targeted for regulation by histone h1 and DNA methylation. AB - Histone H1 is an abundant and essential component of chromatin whose precise role in regulating gene expression is poorly understood. Here, we report that a major target of H1-mediated regulation in embryonic stem (ES) cells is the X-linked Rhox homeobox gene cluster. To address the underlying mechanism, we examined the founding member of the Rhox gene cluster-Rhox5-and found that its distal promoter (Pd) loses H1, undergoes demethylation, and is transcriptionally activated in response to loss of H1 genes in ES cells. Demethylation of the Pd is required for its transcriptional induction and we identified a single cytosine in the Pd that, when methylated, is sufficient to inhibit Pd transcription. Methylation of this single cytosine prevents the Pd from binding GA-binding protein (GABP), a transcription factor essential for Pd transcription. Thus, H1 silences Rhox5 transcription by promoting methylation of one of its promoters, a mechanism likely to extend to other H1-regulated Rhox genes, based on analysis of ES cells lacking DNA methyltransferases. The Rhox cluster genes targeted for H1-mediated transcriptional repression are also subject to another DNA methylation-regulated process: Xp imprinting. Remarkably, we found that only H1-regulated Rhox genes are imprinted, not those immune to H1-mediated repression. Together, our results indicate that the Rhox gene cluster is a major target of H1-mediated transcriptional repression in ES cells and that H1 is a candidate to have a role in Xp imprinting. PMID- 21245381 TI - Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells. AB - Neuropilin-1 (NRP1) is a receptor for vascular endothelial growth factor (VEGF) and plays an important role in mediating cell motility. However, the NRP1 signaling pathways important for cell motility are poorly understood. Here we report that p130(Cas) tyrosine phosphorylation is stimulated by hepatocyte growth factor and platelet-derived growth factor in U87MG glioma cells and VEGF in endothelial cells and is dependent on NRP1 via its intracellular domain. In endothelial cells, NRP1 silencing reduced, but did not prevent, VEGF receptor 2 (VEGFR2) phosphorylation, while expression of a mutant form of NRP1 lacking the intracellular domain (NRP1DeltaC) did not affect receptor phosphorylation in U87MG cells or human umbilical vein endothelial cells (HUVECs). In HUVECs, NRP1 was also required for VEGF-induced phosphorylation of proline-rich tyrosine kinase 2, which was necessary for p130(Cas) phosphorylation. Importantly, knockdown of NRP1 or p130(Cas) or expression of either NRP1DeltaC or a non tyrosine-phosphorylatable substrate domain mutant protein (p130(Cas15F)) was sufficient to inhibit growth factor-mediated migration of glioma and endothelial cells. These data demonstrate for the first time the importance of the NRP1 intracellular domain in mediating a specific signaling pathway downstream of several receptor tyrosine kinases and identify a critical role for a novel NRP1 p130(Cas) pathway in the regulation of chemotaxis. PMID- 21245382 TI - Membrane environment exerts an important influence on rac-mediated activation of phospholipase Cgamma2. AB - We performed analyses of the molecular mechanisms involved in the regulation of phospholipase Cgamma2 (PLCgamma2). We identified several regions in the PLCgamma specific array, gammaSA, that contribute to autoinhibition in the basal state by occlusion of the catalytic domain. While the activation of PLCgamma2 by Rac2 requires stable translocation to the membrane, the removal of the domains required for membrane translocation in the context of an enzyme with impaired autoinhibition generated constitutive, highly active PLC in cells. We further tested the possibility that the interaction of PLCgamma2 with its activator protein Rac2 was sufficient for activation through the release of autoinhibition. However, we found that Rac2 binding in the absence of lipid surfaces was not able to activate PLCgamma2. Together with other observations, these data suggest that an important consequence of Rac2 binding and translocation to the membrane is that membrane proximity, on its own or together with Rac2, has a role in the release of autoinhibition, resulting in interfacial activation. PMID- 21245383 TI - Transient activation of meox1 is an early component of the gene regulatory network downstream of hoxa2. AB - Hox genes encode transcription factors that regulate morphogenesis in all animals with bilateral symmetry. Although Hox genes have been extensively studied, their molecular function is not clear in vertebrates, and only a limited number of genes regulated by Hox transcription factors have been identified. Hoxa2 is required for correct development of the second branchial arch, its major domain of expression. We now show that Meox1 is genetically downstream from Hoxa2 and is a direct target. Meox1 expression is downregulated in the second arch of Hoxa2 mouse mutant embryos. In chromatin immunoprecipitation (ChIP), Hoxa2 binds to the Meox1 proximal promoter. Two highly conserved binding sites contained in this sequence are required for Hoxa2-dependent activation of the Meox1 promoter. Remarkably, in the absence of Meox1 and its close homolog Meox2, the second branchial arch develops abnormally and two of the three skeletal elements patterned by Hoxa2 are malformed. Finally, we show that Meox1 can specifically bind the DNA sequences recognized by Hoxa2 on its functional target genes. These results provide new insight into the Hoxa2 regulatory network that controls branchial arch identity. PMID- 21245384 TI - Therapeutic levels of the hydroxmethylglutaryl-coenzyme A reductase inhibitor lovastatin activate ras signaling via phospholipase D2. AB - Hydroxmethylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) lower serum cholesterol but exhibit pleiotropic biological effects that are difficult to ascribe solely to cholesterol depletion. Here, we investigated the effect of lovastatin on protein prenylation and cell signaling. We show that high concentrations (50 MUM) of lovastatin inhibit Ras, Rho, and Rap prenylation but that therapeutic levels of lovastatin (50 nM to 500 nM) do not. In contrast, depletion of cellular cholesterol by therapeutic levels of lovastatin increased Ras GTP loading and mitogen-activated protein kinase (MAPK) activation in human umbilical vein endothelial cells and rodent fibroblasts. Elevated Ras signaling was not seen in statin-treated cells if cholesterol levels were maintained by supplementation. Activation of Ras-MAPK signaling was a consequence of, and dependent on, activation of phospholipase D2 (PLD2). Expression of dominant interfering PLD2 or biochemical inhibition of PLD2 abrogated Ras and MAPK activation induced by lovastatin. In contrast, ectopic expression of wild-type PLD2 enhanced Ras and MAPK activation in response to therapeutic levels of lovastatin. Statin-induced cholesterol depletion also modestly activated the epidermal growth factor receptor (EGFR), resulting in downregulation of EGFR expression. These results suggest that statins modulate key cell signaling pathways as a direct consequence of cholesterol depletion and identify the EGFR PLD2-Ras-MAPK axis as an important statin target. PMID- 21245385 TI - Plk5, a polo box domain-only protein with specific roles in neuron differentiation and glioblastoma suppression. AB - Polo-like kinases (Plks) are characterized by the presence of a specific domain, known as the polo box (PBD), involved in protein-protein interactions. Plk1 to Plk4 are involved in centrosome biology as well as the regulation of mitosis, cytokinesis, and cell cycle checkpoints in response to genotoxic stress. We have analyzed here the new member of the vertebrate family, Plk5, a protein that lacks the kinase domain in humans. Plk5 does not seem to have a role in cell cycle progression; in fact, it is downregulated in proliferating cells and accumulates in quiescent cells. This protein is mostly expressed in the brain of both mice and humans, and it modulates the formation of neuritic processes upon stimulation of the brain-derived neurotrophic factor (BDNF)/nerve growth factor (NGF)-Ras pathway in neurons. The human PLK5 gene is significantly silenced in astrocytoma and glioblastoma multiforme by promoter hypermethylation, suggesting a tumor suppressor function for this gene. Indeed, overexpression of Plk5 has potent apoptotic effects in these tumor cells. Thus, Plk5 seems to have evolved as a kinase-deficient PBD-containing protein with nervous system-specific functions and tumor suppressor activity in brain cancer. PMID- 21245386 TI - Chaperone Hsp27 modulates AUF1 proteolysis and AU-rich element-mediated mRNA degradation. AB - AUF1 is an AU-rich element (ARE)-binding protein that recruits translation initiation factors, molecular chaperones, and mRNA degradation enzymes to the ARE for mRNA destruction. We recently found chaperone Hsp27 to be an AUF1-associated ARE-binding protein required for tumor necrosis factor alpha (TNF-alpha) mRNA degradation in monocytes. Hsp27 is a multifunctional protein that participates in ubiquitination of proteins for their degradation by proteasomes. A variety of extracellular stimuli promote Hsp27 phosphorylation on three serine residues- Ser(15), Ser(78), and Ser(82)-by a number of kinases, including the mitogen activated protein (MAP) pathway kinases p38 and MK2. Activating either kinase stabilizes ARE mRNAs. Likewise, ectopic expression of phosphomimetic mutant forms of Hsp27 stabilizes reporter ARE mRNAs. Here, we continued to examine the contributions of Hsp27 to mRNA degradation. As AUF1 is ubiquitinated and degraded by proteasomes, we addressed the hypothesis that Hsp27 phosphorylation controls AUF1 levels to modulate ARE mRNA degradation. Indeed, selected phosphomimetic mutants of Hsp27 promote proteolysis of AUF1 in a proteasome-dependent fashion and render ARE mRNAs more stable. Our results suggest that the p38 MAP kinase (MAPK)-MK2-Hsp27 signaling axis may target AUF1 destruction by proteasomes, thereby promoting ARE mRNA stabilization. PMID- 21245387 TI - Assembly of a Notch transcriptional activation complex requires multimerization. AB - Notch transmembrane receptors direct essential cellular processes, such as proliferation and differentiation, through direct cell-to-cell interactions. Inappropriate release of the intracellular domain of Notch (N(ICD)) from the plasma membrane results in the accumulation of deregulated nuclear N(ICD) that has been linked to human cancers, notably T-cell acute lymphoblastic leukemia (T ALL). Nuclear N(ICD) forms a transcriptional activation complex by interacting with the coactivator protein Mastermind-like 1 and the DNA binding protein CSL (for CBF-1/Suppressor of Hairless/Lag-1) to regulate target gene expression. Although it is well understood that N(ICD) forms a transcriptional activation complex, little is known about how the complex is assembled. In this study, we demonstrate that N(ICD) multimerizes and that these multimers function as precursors for the stepwise assembly of the Notch activation complex. Importantly, we demonstrate that the assembly is mediated by N(ICD) multimers interacting with Skip and Mastermind. These interactions form a preactivation complex that is then resolved by CSL to form the Notch transcriptional activation complex on DNA. PMID- 21245388 TI - The chaperone network connected to human ribosome-associated complex. AB - Mammalian ribosome-associated complex (mRAC), consisting of the J-domain protein MPP11 and the atypical Hsp70 homolog (70-homolog) Hsp70L1, can partly complement the function of RAC, which is the homologous complex from Saccharomyces cerevisiae. RAC is the J-domain partner exclusively of the 70-homolog Ssb, which directly and independently of RAC binds to the ribosome. We here show that growth defects due to mRAC depletion in HeLa cells resemble those of yeast strains lacking RAC. Functional conservation, however, did not extend to the 70-homolog partner of mRAC. None of the major human 70-homologs was able to complement the growth defects of yeast strains lacking Ssb or was bound to ribosomes in an Ssb like manner. Instead, our data suggest that mRAC was a specific partner of human Hsp70 but not of its close homolog Hsc70. On a mechanistic level, ATP binding, but not ATP hydrolysis, by Hsp70L1 affected mRAC's function as a J-domain partner of Hsp70. The combined data indicate that, while functionally conserved, yeast and mammalian cells have evolved distinct solutions to ensure that Hsp70-type chaperones can efficiently assist the biogenesis of newly synthesized polypeptide chains. PMID- 21245389 TI - FLASH is required for the endonucleolytic cleavage of histone pre-mRNAs but is dispensable for the 5' exonucleolytic degradation of the downstream cleavage product. AB - 3'-end cleavage of histone pre-mRNAs is catalyzed by CPSF-73 and requires the interaction of two U7 snRNP-associated proteins, FLASH and Lsm11. Here, by using scanning mutagenesis we identify critical residues in human FLASH and Lsm11 that are involved in the interaction between these two proteins. We also demonstrate that mutations in the region of FLASH located between amino acids 50 and 99 do not affect binding of Lsm11. Interestingly, these mutations convert FLASH into an inhibitory protein that reduces in vitro processing efficiency of highly active nuclear extracts. Our results suggest that this region in FLASH in conjunction with Lsm11 is involved in recruiting a yet-unknown processing factor(s) to histone pre-mRNA. Following endonucleolytic cleavage of histone pre-mRNA, the downstream cleavage product (DCP) is degraded by the 5'-3' exonuclease activity of CPSF-73, which also depends on Lsm11. Strikingly, while cleavage of histone pre-mRNA is stimulated by FLASH and inhibited by both dominant negative mutants of FLASH and anti-FLASH antibodies, the 5'-3' degradation of the DCP is not affected. Thus, the recruitment of FLASH to the processing complex plays a critical role in activating the endonuclease mode of CPSF-73 but is dispensable for its 5'-3' exonuclease activity. These results suggest that CPSF-73, the catalytic component in both reactions, can be recruited to histone pre-mRNA largely in a manner independent of FLASH, possibly by a separate domain in Lsm11. PMID- 21245390 TI - Roles of vertebrate Smc5 in sister chromatid cohesion and homologous recombinational repair. AB - The structural maintenance of chromosomes (Smc) family members Smc5 and Smc6 are both essential in budding and fission yeasts. Yeast smc5/6 mutants are hypersensitive to DNA damage, and Smc5/6 is recruited to HO-induced double-strand breaks (DSBs), facilitating intersister chromatid recombinational repair. To determine the role of the vertebrate Smc5/6 complex during the normal cell cycle, we generated an Smc5-deficient chicken DT40 cell line using gene targeting. Surprisingly, Smc5(-) cells were viable, although they proliferated more slowly than controls and showed mitotic abnormalities. Smc5-deficient cells were sensitive to methyl methanesulfonate and ionizing radiation (IR) and showed increased chromosome aberration levels upon irradiation. Formation and resolution of Rad51 and gamma-H2AX foci after irradiation were altered in Smc5 mutants, suggesting defects in homologous recombinational (HR) repair of DNA damage. Ku70( /-) Smc5(-) cells were more sensitive to IR than either single mutant, with Rad54(-/-) Smc5(-) cells being no more sensitive than Rad54(-/-) cells, consistent with an HR function for the vertebrate Smc5/6 complex. Although gene targeting occurred at wild-type levels, recombinational repair of induced double strand breaks was reduced in Smc5(-) cells. Smc5 loss increased sister chromatid exchanges and sister chromatid separation distances in mitotic chromosomes. We conclude that Smc5/6 regulates recombinational repair by ensuring appropriate sister chromatid cohesion. PMID- 21245392 TI - Force analysis of bacterial transmission from contact lens cases to corneas, with the contact lens as the intermediary. AB - PURPOSE: To determine the probability of transmission of a Staphylococcus aureus strain from a contact lens case, to the contact lens (CL) surfaces, to the cornea, on the basis of bacterial adhesion forces measured by using atomic force microscopy (AFM). METHODS: Adhesion forces between S. aureus strain 835 probes with rigid and soft CLs, storage cases, and porcine corneas were measured with AFM and used to calculate Weibull distributions, from which the transmission probability from one surface to another was derived. Bacterial transmission probabilities from force analyses were compared with experimentally obtained transmission data. RESULTS: After bond-strengthening, S. aureus adhered to the surface of a lens case with a median force of 10.8 nN. Adhesion forces were different on the soft and rigid CLs (7.7 and 13.6 nN, respectively). Adhesion forces on porcine corneas amounted to 11.8 nN. Data variations were used to calculate the Weibull distribution, from which the probability of transmission from the lens case to a CL and from the CL to the cornea can be directly read. Final transmission probabilities from lens case to the cornea were slightly higher for the rigid (24%) than for the soft (19%) CL. Bacterial transmission determined experimentally increased with increasing contact times, but were within the range of the probabilities derived from Weibull analyses. CONCLUSIONS: Probabilities of bacterial transmission from contaminated lens cases to corneas can be derived from Weibull analyses of measured forces of adhesion to the surfaces involved. PMID- 21245391 TI - Distortion of axonal cytoskeleton: an early sign of glaucomatous damage. AB - PURPOSE: Glaucoma damages the retinal nerve fiber layer (RNFL). The purpose of this study was to investigate the distribution of major cytoskeleton components, F-actin, microtubules (MTs), and neurofilaments (NFs), in the RNFL during the development of glaucoma. methods: Intraocular hypertension was induced in a rat model by laser photocoagulation of the trabecular meshwork. Retinas were obtained after 2 to 3.5 weeks of treatment. Multiple fluorescent stains were used to identify F-actin, MTs, NFs, and nuclei simultaneously in the same tissue. Distribution of these components in a whole-mounted retina was examined by confocal microscopy. Fluorescent stain was quantitatively described. RESULTS: In normal RNFL F-actin, MTs, and NFs were intensely stained. Along the bundles, F actin and MTs were strongly colocalized, but alternating strands of F-actin and NFs were apparent. Normal RNFL lacked nuclei. In glaucomatous retinas, irregular staining of F-actin, MTs, and NFs was found within the bundles. A strong network of F-actin appeared on the RNFL surface and between the bundles. In severely damaged retinal regions total loss of F-actin and MTs was found, whereas residual strands of NFs were evident. Before the decrease in RNFL thickness, irregularity of F-actin stain and density of nuclei in the RNFL significantly increased. CONCLUSIONS: The results suggest that F-actin, MTs, and NFs are rich and approximately uniformly distributed in the normal RNFL. Glaucoma causes alteration of the cytoskeleton in the RNFL. F-actin is the most sensitive component in its response to stress on the retina. An increase in the number of nuclei in the RNFL may be an early sign of glaucomatous damage. PMID- 21245393 TI - Induction of T regulatory cells by cytotoxic T-lymphocyte antigen-2alpha on corneal endothelial cells. AB - PURPOSE: To determine whether murine corneal endothelial (CE) cells can promote the generation of T regulatory (Treg) cells in vitro. METHODS: To induce Treg cells in vitro by CE cell lines, T cells exposed to CE cells were used as Treg cells. T cells exposed to CE cells in the presence of anti-mouse CD3 antibody were harvested and added to target bystander T cells in vitro. T-cell activation was assessed for proliferation by [(3)H]-thymidine incorporation. Expression of CD25 or Foxp3 on Treg cells was evaluated by flow cytometry. Expression of cytotoxic T-lymphocyte antigen-2 alpha (CTLA-2alpha) on CE cells was evaluated by flow cytometry, RT-PCR, immunohistochemistry, or in situ hybridization. Anti-CTLA 2alpha neutralizing antibodies, CTLA-2alpha siRNA, or pro-cathepsin L blocking proteins were used to abolish the CE-inhibitory function. RESULTS: Cultured CE cells produced CTLA-2alpha on their surfaces, thereby enabling bystander CD4(+) T cells to be converted to Treg cells by TGFbeta promotion. CE-induced Treg cells had immunosuppressive capacities by highly expressing CD25(high) and Foxp3. When mRNA downregulation (siRNA transfection), neutralizing antibodies, or blocking proteins were used to block CTLA-2alpha expression on CE cells, CE-induced Treg cells failed to acquire Treg function. CONCLUSIONS: These findings indicate that cell surface CTLA-2alpha contributes to the CE-dependent suppression of bystander T cells. Thus, ocular resident tissue-exposed T cells can be induced to become regulators within the peripheral microenvironment. PMID- 21245394 TI - Long-term in vivo imaging and measurement of dendritic shrinkage of retinal ganglion cells. AB - PURPOSE: To monitor and measure dendritic shrinkage of retinal ganglion cells (RGCs) in a strain of transgenic mice (Thy-1 YFP) that expresses yellow fluorescent proteins in neurons under the control of a Thy-1 promoter. METHODS: A total of 125 RGCs from 16 eyes of Thy-1 YFP transgenic mice were serially imaged with a confocal scanning laser ophthalmoscope for 6 months after optic nerve crush. Quantitative analysis of cell body area, axon diameter, dendritic field, number of terminal branches, total dendritic branch length, branching complexity, symmetry, and distance from the optic disc was used to characterize the morphology of RGCs, describe the patterns of axonal and dendritic degeneration, identify the morphologic predictors for cell survival, and estimate the rate of dendritic shrinkage. RESULTS: RGC damage was observed prospectively to begin with progressive dendritic shrinkage, followed by loss of the axon and the cell body. In a small proportion of RGCs, progressive axonal changes including fragmentation, beading, retraction, and bulb formation were also observed. RGCs with a larger dendritic field and a longer total dendritic branch length in general have a better survival probability. The rate of dendritic shrinkage was variable with a slower rate observed in cells having a larger dendritic field, a longer total dendritic branch length, and a greater distance from the optic disc. CONCLUSIONS: Estimating the probability of RGC survival and measuring the rate of dendritic shrinkage could become a new paradigm for investigating neuronal degeneration and evaluating the response of neuroprotective treatment. PMID- 21245395 TI - Plasmin treatment accelerates vascular endothelial growth factor clearance from rabbit eyes. AB - PURPOSE: To investigate the clearance of vascular endothelial growth factor (VEGF) after the induction of posterior vitreous detachment by plasmin and/or SF(6). METHODS: The study design included four groups of rabbits: group 1 received an intravitreal injection of plasmin and SF(6) in the right eye, group 2 received an intravitreal injection of plasmin in the right eye, group 3 received an intravitreal injection of SF(6) in the right eye, and group 4 received an intravitreal injection of balanced salt solution in the right eye. Intravitreal injection of human VEGF (50 MUL, 10 ng/MUL) was performed in study eyes and control eyes 1 month after plasmin and/or SF(6) injection. Serum and vitreous samples were collected on days 1, 3, and 7 after VEGF injection to determine the serum and vitreous concentrations of VEGF. RESULTS: One day after VEGF injection, residual human VEGF concentration in the vitreous cavity was significantly lower in the plasmin- and SF(6)-treated eyes (group 1) and the plasmin-treated eyes (group 2) when compared with the control eyes (group 4) (P = 0.047 and 0.027, respectively). Three days after VEGF injection, the residual VEGF concentration in the vitreous cavity was still significantly lower in the plasmin- and SF(6) treated eyes (group 1) when compared with the control eyes (group 4) (P = 0.025). CONCLUSIONS: Eyes treated with plasmin exhibit a more rapid clearance of exogenous VEGF than control eyes. This finding suggests a novel treatment for retinopathies associated with vitreous traction and VEGF elevation. PMID- 21245396 TI - Disruption of contact lens-associated Pseudomonas aeruginosa biofilms formed in the presence of neutrophils. AB - PURPOSE: To evaluate the capacity of neutrophils to enhance biofilm formation on contact lenses by an infectious Pseudomonas aeruginosa (PA) corneal isolate. Agents that target F-actin and DNA were tested as a therapeutic strategy for disrupting biofilms formed in the setting of neutrophils in vitro and for limiting the infectious bioburden in vivo. METHODS: Biofilm formation by infectious PA strain 6294 was assessed in the presence of neutrophils on a static biofilm plate and on unworn etafilcon A soft contact lenses. A d-isomer of poly(aspartic acid) was used alone and with DNase to reduce biofilm formation on test contact lenses. The gentamicin survival assay was used to determine the effectiveness of the test compound in reducing subsequent intracellular bacterial load in the corneal epithelium in a contact lens infection model in the rabbit. RESULTS: In a static reactor and on hydrogel lenses, PA biofilm density was enhanced 30-fold at 24 hours in the presence of neutrophils (P < 0.0001). The combination of DNase and anionic poly(aspartic acid) reduced the PA biofilms formed in the presence of activated neutrophils by 79.2% on hydrogel contact lenses (P < 0.001). An identical treatment resulted in a 41% reduction in internalized PA in the rabbit corneal epithelium after 24 hours (P = 0.03). CONCLUSIONS: These results demonstrate that PA can exploit the presence of neutrophils to form biofilm on contact lenses within a short time. Incorporation of F-actin and DNA represent a mechanism for neutrophil-induced biofilm enhancement and are targets for available agents to disrupt pathogenic biofilms formed on contact lenses and as a treatment for established corneal infections. PMID- 21245397 TI - Imaging retinal capillaries using ultrahigh-resolution optical coherence tomography and adaptive optics. AB - PURPOSE: Ultrahigh-resolution optical coherence tomography (UHR-OCT) with adaptive optics (AO) provides micrometer-scale 3D resolution that is attractive for imaging the retinal microvasculature. Such imaging may be useful for early detection of pathologic changes as in diabetic retinopathy. Here the authors investigate this potential for detecting individual capillaries in healthy subjects. METHODS: UHR-AO-OCT volumes centered on the fovea were acquired from seven subjects (age range, 25-61 years) with three preselected with no foveal avascular zone (FAZ). Images were compared with entoptic diagrams using the capillaries at the rim of the FAZ. Methods of comparison were testing for the presence of a FAZ, noting distinct features in the capillary pattern, and measuring the size of the FAZ. Additional analysis included measurements of capillary diameter and depth range with retinal eccentricity. RESULTS: UHR-AO-OCT results are consistent with entoptic observations for all three methods of comparison. FAZ diameters measured by UHR-AO-OCT and entoptic imaging are strongly correlated (R(2) = 0.86). Average capillary diameter near the FAZ rim is 5.1 (4.6) +/- 1.4 MUm, with the value in parentheses accounting for axial image blur. This is consistent with histology (average, ~4.7 MUm). Depth range of the capillaries increases monotonically with eccentricity (0 degrees -1.25 degrees ) and is larger and more variable for subjects without FAZ. CONCLUSIONS: UHR-AO-OCT permits observation of many of the capillaries proximal to the FAZ, including those of average size based on published histology. This supports the view that the vast majority of capillaries in the retina are likely detectable with UHR-AO OCT. PMID- 21245399 TI - Simvastatin improves retinal ganglion cell survival and spatial vision after acute retinal ischemia/reperfusion in mice. AB - PURPOSE: The major aims of this study were to evaluate the effect of retinal ischemia by behavioral testing and histologic analyses, to visualize ischemia induced changes of cortical activity by optical imaging of intrinsic signals, and to test the therapeutic effectiveness of simvastatin. METHODS: Retinal ischemia was induced monocularly by elevating intraocular pressure. Visual function was tested behaviorally with a virtual reality optomotor system, physiologically with optical imaging of intrinsic signals, and histologically by counting the surviving retinal ganglion cells (RGCs) in the same animal. RESULTS: Visual acuity (-38%) and contrast sensitivity (-78%) were significantly reduced 6 days after ischemia compared with controls. The number of RGCs was reduced by 16%. In contrast, optical imaging revealed essentially unchanged cortical activity maps in spite of the lesion. Treatment of mice with simvastatin applied after the ischemic insult significantly improved both visual function as measured behaviorally (~95% visual acuity, ~165% contrast sensitivity) and RGC survival (~30%) compared with vehicle-treated animals (~42% visual acuity, ~85% contrast sensitivity). CONCLUSIONS: This specific combination of behavioral measurements of visual function, cortical activity imaging, and histologic analyses is ideally suited to follow ischemia-induced changes and to monitor the effect of therapeutic approaches. Statin therapy may be a promising pharmacologic tool for the treatment of acute retinal ischemia in particular because, in our study, simvastatin was applied after ischemia, a treatment regimen with much greater clinical relevance than preventive administration, as in previous studies. PMID- 21245398 TI - Replication of the TCF4 intronic variant in late-onset Fuchs corneal dystrophy and evidence of independence from the FCD2 locus. AB - PURPOSE: Fuchs corneal dystrophy (FCD) is an autosomal dominant disease of the corneal endothelium with variable penetrance and expressivity. Recently, rs613872, an intronic variation of TCF4 associated with late-onset FCD, was reported. The present study was undertaken to examine this association in our cohort of FCD patients, to assess the significance of this finding, and to investigate the candidacy of TCF4 in the context of the mapped FCD2 locus. METHODS: The authors recruited 170 patients with late-onset FCD and 180 age matched controls. Blood samples were collected, and genomic DNA was extracted. A panel of nine SNPs spanning the entire TCF4 locus was genotyped both on this cohort and on three previously reported FCD2-linked families. The association of an individual SNP with late-onset FCD was evaluated with the Fisher exact test, and the coding exons and exon-intron boundaries of TCF4 were sequenced in 96 affected persons. RESULTS: The risk allele G of rs613872 is associated significantly with late-onset FCD (odds ratio, 4.2; P = 4.28 x 10-15) and was present in male and female affected persons without any sex bias, replicating recent findings, though the authors found no apparent correlation with the severity of the disease phenotype. Moreover, the risk allele did not cosegregate with the disease phenotype in any of the three FCD2-linked families. The authors did not identify any pathogenic variants in the coding region of TCF4. CONCLUSIONS: The authors report the first independent replication of rs613872 conferring risk of late-onset FCD. Their data suggest that this risk factor is likely independent of the FCD2 locus, whose causality remains unknown. PMID- 21245401 TI - Automatic characterization of classic choroidal neovascularization by using AdaBoost for supervised learning. AB - PURPOSE: To provide a computer-aided visualization tool for accurate diagnosis and quantification of choroidal neovascularization (CNV) on the basis of fluorescence leakage characteristics. METHODS: All image frames of a fluorescein angiography (FA) sequence are first aligned and mapped to a global space. To automatically determine the severity of each pixel in the global space and hence the extent of CNV, the system matches the intensity variation of each set of spatially corresponding pixels across the sequence with the targeted leakage pattern, learned from a sampled population graded by a retina specialist. The learning strategy, known as the AdaBoost algorithm, has 12 classifiers for 12 features that summarize the variation in fluorescence intensity over time. Given a new sequence, the severity map image is generated using the contribution scores of the 12 classifiers. Initialized with points of low and high severity, regions of CNV are delineated using the random walk algorithm. RESULTS: A dataset of 33 FA sequences of classic CNV showed the average accuracy of CNV delineation to be 83.26%. In addition, the 30- to 60-second interval provided the most reliable information for differentiating CNV from the background. Using eight sequences of multiple visits of four patients for evaluation of the postphotodynamic therapy (PDT), the statistics derived from the segmented regions correlate closely with the clinical observed changes. CONCLUSIONS: The clinician can easily visualize the temporal characteristics of CNV fluorescence leakage using the severity map, which is a two-dimensional summary of a complete FA sequence. The computer-aided tool allows objective evaluation and computation of statistical data from the automatic delineation for surgical assessment. PMID- 21245400 TI - Population and high-risk group screening for glaucoma: the Los Angeles Latino Eye Study. AB - PURPOSE: To evaluate the ability of various screening tests, both individually and in combination, to detect glaucoma in the general Latino population and high risk subgroups. METHODS: The Los Angeles Latino Eye Study is a population-based study of eye disease in Latinos 40 years of age and older. Participants (n = 6082) underwent Humphrey visual field testing (HVF), frequency doubling technology (FDT) perimetry, measurement of intraocular pressure (IOP) and central corneal thickness (CCT), and independent assessment of optic nerve vertical cup disc (C/D) ratio. Screening parameters were evaluated for three definitions of glaucoma based on optic disc, visual field, and a combination of both. Analyses were also conducted for high-risk subgroups (family history of glaucoma, diabetes mellitus, and age >=65 years). Sensitivity, specificity, and receiver operating characteristic curves were calculated for those continuous parameters independently associated with glaucoma. Classification and regression tree (CART) analysis was used to develop a multivariate algorithm for glaucoma screening. RESULTS: Preset cutoffs for screening parameters yielded a generally poor balance of sensitivity and specificity (sensitivity/specificity for IOP >=21 mm Hg and C/D >=0.8 was 0.24/0.97 and 0.60/0.98, respectively). Assessment of high-risk subgroups did not improve the sensitivity/specificity of individual screening parameters. A CART analysis using multiple screening parameters-C/D, HVF, and IOP substantially improved the balance of sensitivity and specificity (sensitivity/specificity 0.92/0.92). CONCLUSIONS: No single screening parameter is useful for glaucoma screening. However, a combination of vertical C/D ratio, HVF, and IOP provides the best balance of sensitivity/specificity and is likely to provide the highest yield in glaucoma screening programs. PMID- 21245402 TI - The role of the prostaglandin EP4 receptor in the regulation of human outflow facility. AB - PURPOSE: Activation of prostaglandin (PG)-EP(4) receptors by 3,7-dithiaPGE(1) robustly lowers intraocular pressure in nonhuman primate eyes, which increases outflow facility but has no effect on aqueous secretion or uveoscleral outflow. Because of differences in PG efficacy in outflow function between nonhuman primates and humans, we tested the impact of 3,7-dithiaPGE(1) on conventional outflow function in human donor eyes. METHODS: The expression pattern of PG-EP(4) receptors was determined in corneoscleral tissues of human donor eyes and in cultures of human outflow cells by immunofluorescence microscopy and Western blot, respectively. The efficacy of 3,7-dithiaPGE(1) was determined by assaying agonist-stimulated cAMP accumulation and beta-arrestin mobilization in cultured human cells. Agonist effects on outflow facility were examined in paired human donor eyes that were perfused at 8 mm Hg of constant pressure, equivalent to 15 mm Hg in vivo. RESULTS: The trabecular meshwork (TM) and Schlemm's canal (SC) cells expressed PG-EP(4) receptors. Agonist-mediated effects on the PG-EP(4) receptors were detected in SC (EC(50) = 6.3 * 10(-9) M, n = 4), but not TM (EC(50) = 1.7 * 10(-7) M, n = 5) cells. Effects in SC cells were blocked by the PG-EP(4) receptor-selective antagonist GW627368 (EC(50) = 1.09 * 10(-2) M, n = 4), but not the PG-EP(2) receptor-selective antagonist AH6809 (EC(50) = 4.10 * 10(-9) M, n = 5). Perfused into human eyes at a concentration that selectively activates PG-EP(4) receptors, 3,7-dithiaPGE(1) (10 nM) increased outflow facility by 51% +/- 18% over baseline levels in individual drug-treated eyes after drug exchange (n = 6 eyes; P = 0.05) and by 69% +/- 23% (P < 0.01) compared with that in contralateral eyes. CONCLUSIONS: Activation of PG-EP(4) receptors expressed by SC cells of the human conventional outflow pathway appears to contribute to PG regulation of outflow facility. PMID- 21245403 TI - Naloxone ameliorates retinal lesions in Ccl2/Cx3cr1 double-deficient mice via modulation of microglia. AB - PURPOSE: The role of naloxone, an opioid receptor antagonist, on microglial inhibition and neuroprotective effects has been reported in lipopolysaccharide (LPS)-induced neurodegeneration and light-induced photoreceptor degeneration. The authors evaluated the effects of naloxone on Ccl2(-/-)/Cx3cr1(-/-) (DKO) mice, a murine model of age-related macular degeneration (AMD). METHODS: Two-month-old DKO and wild-type controls were given daily intraperitoneal injections of naloxone or PBS for 2 months. Animals were examined monthly by funduscopy. Ocular tissue was analyzed histologically and in retinal flat mount preparations. Ocular A2E was measured using HPLC. Quantitative RT-PCR analyzed TNF-alpha, IL-1beta, IL 10 and TLR4 transcripts in the DKO eyes and LPS activated culture microglial cells. Serum nitrite was measured using Griess colorimetric reaction. RESULTS: Naloxone ameliorated the clinical progression and severity of retinal lesions in the DKO mice compared with those of untreated controls. Histopathology also showed less focal retinal degeneration in the treated DKO mice than in controls. The aggregation of microglia in the outer retina in DKO mice was significantly reduced in naloxone-treated animals compared with control untreated DKO. Ocular TNF-alpha, IL-1beta, and TLR4 transcripts and A2E were significantly lower in naloxone-treated DKO animals and cultured microglial cells than in controls, as were serum nitrite levels. CONCLUSIONS: Naloxone significantly reduces the progress of retinal lesions in DKO mice. Naloxone modulates microglia accumulation and activation at the site of retinal degeneration, which may be mediated by inhibition of the proinflammatory molecules of NO, TNF-alpha, and IL beta. The potential therapeutic effects of naloxone on retinal degeneration, including AMD, warrants further investigation. PMID- 21245404 TI - Nutritional manipulation of primate retinas, V: effects of lutein, zeaxanthin, and n-3 fatty acids on retinal sensitivity to blue-light-induced damage. AB - PURPOSE: Blue-light photooxidative damage has been implicated in the etiology of age-related macular degeneration (AMD). The macular pigment xanthophylls lutein (L) and zeaxanthin (Z) and n-3 fatty acids may reduce this damage and lower the risk of AMD. This study investigated the effects of the lifelong absence of xanthophylls followed by L or Z supplementation, combined with the effects of n-3 fatty acid deficiency, on acute blue-light photochemical damage. METHODS: Subjects included eight rhesus monkeys with no lifelong intake of xanthophylls and no detectable macular pigment. Of these, four had low n-3 fatty acid intake and four had adequate intakes. Control subjects had typical L, Z, and n-3 fatty acid intake. Retinas received 150-MUm-diameter exposures of low-power 476-nm laser light at 0.5 mm (~2 degrees ) eccentricity, which is adjacent to the macular pigment peak, and parafoveally at 1.5 mm (~6 degrees ). Exposures of xanthophyll-free animals were repeated after supplementation with pure L or Z for 22 to 28 weeks. Ophthalmoscopically visible lesion areas were plotted as a function of exposure energy, with greater slopes of the regression lines indicating greater sensitivity to damage. RESULTS: In control animals, the fovea was less sensitive to blue-light-induced damage than the parafovea. Foveal protection was absent in xanthophyll-free animals but was evident after supplementation. In the parafovea, animals low in n-3 fatty acids showed greater sensitivity to damage than animals with adequate levels. CONCLUSIONS: After long term xanthophyll deficiency, L or Z supplementation protected the fovea from blue light-induced damage, whereas adequate n-3 fatty acid levels reduced the damage in the parafovea. PMID- 21245405 TI - Mucoadhesive microparticles in a rapidly dissolving tablet for sustained drug delivery to the eye. AB - PURPOSE: To test the hypothesis that mucoadhesive microparticles formulated in a rapidly dissolving tablet can achieve sustained drug delivery to the eye. METHODS: Mucoadhesive microparticles, smaller than 5 MUm were fabricated with poly(lactic-co-glycolic acid) and poly(ethylene glycol) as a core material and mucoadhesion promoter, respectively, and encapsulated pilocarpine as a model drug. These microparticles were embedded in a poly(vinyl alcohol) matrix to form a dry tablet designed to reduce rapid clearance of the microparticles on initial application to the eye. RESULTS: This in vitro drug release study exhibited that for all formulations, approximately 90% of pilocarpine was released during the first 10 minutes, and the remaining 10% was released slowly for 3 hours. In vivo mucoadhesion test on the rabbit eye indicated that mucoadhesive microparticles adhered significantly better to the preocular surface than other formulations. To assess the pharmacodynamics, the most prolonged pilocarpine-induced pupil constriction was observed in rabbit eyes in vivo using a tablet with mucoadhesive microparticles; it lasted up to 330 minutes. CONCLUSIONS: The authors conclude that mucoadhesive microparticles formulated into a dry dosage form is a promising system for sustained drug delivery to the eye. PMID- 21245406 TI - Population-based estimate of the sibling recurrence risk ratio for rhegmatogenous retinal detachment. AB - PURPOSE: The influence of genetic predisposition on nonsyndromic primary rhegmatogenous retinal detachment (RRD) is poorly characterized. The purpose of this study was to investigate the magnitude of genetic risk for RRD. METHODS: All participants (probands) in the Scottish Retinal Detachment Study (N = 922) with known postal addresses were contacted by questionnaire to assess the personal and family history of RRD. Sibling affection status was modeled by logistic regression and generalizing estimating equations accounting for the effect of proband covariates of age, sex, spherical equivalent refraction, index birth order, and body mass index (BMI). Sibling-sibling recurrence risk ratios (lambdas) and parent-offspring recurrence risk ratios were calculated. RESULTS: Sixty-five percent of probands returned completed questionnaires. Of these, 602 families (parents, siblings, offspring), 7.8% (47) had one affected member, and 0.5% (3) had two affected members. A total of 501 sibships were included in the regression analysis. The odds ratio (OR) that a sibling would be affected, given another affected sibling, was 1.91 (95% confidence interval [CI], 1.18-3.05). With adjustment for age and sex, the OR that a sibling would be affected increased by 9.8% for each additional diopter of spherical equivalent refractive error (SER) toward myopia in the proband. The lambdas and the parent-offspring recurrence risk ratio of RRD were 2.1 (95% CI, 1.3-3.2) and 2.9 (95% CI, 1.9 4.2), respectively. CONCLUSIONS: Genetic factors are important in the etiology of myopic and nonmyopic RRD. The risk of having an affected sibling with RRD increases twofold, given that a sibling has had the condition. The sibling risk increases with the level of spherical equivalent myopia in the proband. PMID- 21245408 TI - In vivo high-frequency, contrast-enhanced ultrasonography of uveal melanoma in mice: imaging features and histopathologic correlations. AB - PURPOSE: To evaluate the usefulness of in vivo imaging of uveal melanoma in mice using high-frequency contrast-enhanced ultrasound (HF-CE-US) with 2D or 3D modes and to correlate the sonographic findings with histopathologic characteristics. METHODS: Fourteen 12-week-old C57BL6 mice were inoculated into their right eyes with aliquots of 5 * 10(5)/2.5 MUL B16LS9 melanoma cells and were randomly assigned to either of two groups. At 7 days after inoculation, tumor-bearing eyes in group 1 (n = 8) were imaged using HF-CE-US to determine the 2D tumor size and relative blood volume; eyes in group 2 (n = 6) were imaged by 3D microbubble contrast-enhanced ultrasound, and the tumor volume was determined. Histologic tumor burden was quantified in enucleated eyes by image processing software, and microvascular density was determined by counting von Willebrand factor-positive vascular channels. Ultrasound images were evaluated and compared with histopathologic findings. RESULTS: Using HF-CE-US, melanomas were visualized as relatively hyperechoic regions. The intraobserver variability of sonographic measurements was 9.65% +/- 7.89%, and the coefficient of variation for multiple measurements was 7.33% +/- 5.71%. The correlation coefficient of sonographic volume or size and histologic area was 0.71 (P = 0.11) and 0.79 (P = 0.32). The relative blood volume within the tumor demonstrated sonographically correlated significantly with histologic tumor vascularity (r = 0.83; P < 0.001). CONCLUSIONS: There was a positive linear correlation between sonographic tumor measurements and histologic tumor burden in the mouse ocular melanoma model. Contrast-enhanced intensity corresponded with microvascular density and blood volume. HF-CE-US is a real-time, noninvasive, reliable method for in vivo evaluation of experimental intraocular melanoma tumor area and relative blood volume. PMID- 21245407 TI - Functional neuroimaging to characterize visual system development in children with retinoblastoma. AB - PURPOSE: To use functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) to investigate visual system development in children being treated for retinoblastoma. METHODS: Informed consent was obtained for all participants (N = 42) in this institutional review board-approved study. Participants were imaged with a 1.5-T scanner while under propofol sedation. Diagnostic brain and orbital imaging was followed by investigational functional neuroimaging, which included fMRI during photic stimulation through closed eyelids, to measure functional activation in the visual cortex, and DTI, to evaluate diffusion parameters of white matter tracts in the corpus callosum and the periventricular optic radiations. Analysis included 115 examinations of 39 patients with a median age of 16.4 months and age range from 1.5 to 101.5 months at first evaluation. RESULTS: The blood oxygen level-dependent signal was predominantly negative and located in the anterior visual cortex. Activation was affected by tumor lateralization (unilateral or bilateral), macular involvement, and retinal detachment. Patients who had undergone unilateral enucleation showed cortical dominance corresponding to the projection from the nasal hemiretina in the unaffected eye. Diffusion parameters followed a normal developmental trajectory in the optic radiations and corpus callosum, but variability was greater in the splenium than in the genu of the corpus callosum. CONCLUSIONS: Longitudinal functional neuroimaging demonstrated important effects of disease and treatment. Therefore, fMRI and DTI may be useful for characterizing the impact of retinoblastoma on the developing visual system and improving the prediction of visual outcome in survivors. PMID- 21245409 TI - Erythropoietin protects the developing retina in an ovine model of endotoxin induced retinal injury. AB - PURPOSE: Intrauterine infection is a common antecedent of preterm birth. Infants born very preterm are at increased risk for neurologic dysfunction, including visual deficits. With increasing survival of very preterm infants, there is a need for therapies that prevent adverse neurologic outcomes. Using an ovine model, the authors investigated the neuroprotective potential of recombinant human erythropoietin (rhEPO) on retinal injury induced by intrauterine inflammation. METHODS: At 107 +/- 1 days of gestational age (DGA), chronically catheterized fetal sheep received either of the following on 3 consecutive days: intravenous (IV) bolus dose of lipopolysaccharide (LPS; ~0.9 MUg/kg; n = 8); IV bolus dose of LPS, followed at 1 hour by 5000 IU/kg rhEPO (LPS + rhEPO; n = 8); rhEPO alone (n = 5). Untreated fetuses (n = 8) were used for comparison with the three treatment groups. Fetal physiological parameters were monitored. At 116 +/- 1 DGA, fetal retinas were assessed quantitatively for morphologic and neurochemical alterations. RESULTS: Exposure to LPS alone, but not to rhEPO alone, resulted in fetal hypoxemia and hypotension (P < 0.05). Exposure to LPS alone caused retinal changes, including reductions in thickness of the inner nuclear layer (INL), somal areas of INL neurons, process growth in the plexiform layers, and numbers of ganglion and tyrosine hydroxylase immunoreactive (TH-IR) dopaminergic amacrine cells. Treatment of LPS-exposed fetuses with rhEPO did not alter the physiological effects of LPS but significantly reduced alterations in retinal layers and ganglion and TH-IR cell numbers. CONCLUSIONS: rhEPO treatment was beneficial in protecting the developing retina after LPS-induced inflammation. Retinal protection could occur by the antiapoptotic or anti inflammatory actions of EPO. PMID- 21245410 TI - Variants in the APOE gene are associated with improved outcome after anti-VEGF treatment for neovascular AMD. AB - PURPOSE: Anti-vascular endothelial growth factor (anti-VEGF) drugs have dramatically improved the treatment of neovascular AMD. In pivotal studies, almost 90% of patients maintain vision, with approximately 30% showing significant improvement. Despite these successes, 10% to 15% of patients continue to lose vision, even with treatment. It has been reported that variants in some AMD-associated genes influence treatment outcome. This study showed an association of treatment outcome with variants in the apolipoprotein E (APOE) gene. METHODS: One hundred ninety-two patients receiving anti-VEGF treatment for subfoveal choroidal neovascularization secondary to AMD were enrolled. Information on demographics, lesion characteristics, delay until treatment, visual acuity (VA), and number of treatments was collected, and variants of APOE were assessed in all patients at baseline. Best corrected logarithm of the minimum angle of resolution (logMAR) VA was recorded in all patients. RESULTS: The presence of the APOE epsilon4 allele was associated with improved treatment outcome at 3 (P = 0.02) and 12 (P = 0.06) months, compared with the presence of the epsilon2 allele, after adjustment for baseline acuity, treatment delay after first symptoms, age, and sex. Patients with an APOE epsilon4 allele had an odds ratio (OR) of 4.04 (95% confidence interval [CI], 1.11-14.70) for a 2-line gain in vision from baseline at 3 months (P = 0.03) and an OR of 2.54 (95% CI, 0.61 10.52; P = 0.20) at 12 months after treatment, based on multivariate analysis. CONCLUSIONS: In patients with neovascular AMD, the presence of the APOE epsilon4 allele conferred significantly better visual outcomes after anti-VEGF treatment than did the epsilon2 allele. These findings suggest a possible role for a personalized approach to treatment with anti-VEGF. PMID- 21245411 TI - The cyclin-dependent kinase inhibitor p57Kip2 regulates cell cycle exit, differentiation, and migration of embryonic cerebral cortical precursors. AB - Mounting evidence indicates cyclin-dependent kinase (CDK) inhibitors (CKIs) of the Cip/Kip family, including p57(Kip2) and p27(Kip1), control not only cell cycle exit but also corticogenesis. Nevertheless, distinct activities of p57(Kip2) remain poorly defined. Using in vivo and culture approaches, we show p57(Kip2) overexpression at E14.5-15.5 elicits precursor cell cycle exit, promotes transition from proliferation to neuronal differentiation, and enhances process outgrowth, while opposite effects occur in p57(Kip2)-deficient precursors. Studies at later ages indicate p57(Kip2) overexpression also induces precocious glial differentiation, suggesting stage-dependent effects. In embryonic cortex, p57(Kip2) overexpression advances cell radial migration and alters postnatal laminar positioning. While both CKIs induce differentiation, p57(Kip2) was twice as effective as p27(Kip1) in inducing neuronal differentiation and was not permissive to astrogliogenic effects of ciliary neurotrophic factor, suggesting that the CKIs differentially modulate cell fate decisions. At molecular levels, although highly conserved N-terminal regions of both CKIs elicit cycle withdrawal and differentiation, the C-terminal region of p57(Kip2) alone inhibits in vivo migration. Furthermore, p57(Kip2) effects on neurogenesis and gliogenesis require the N-terminal cyclin/CDK binding/inhibitory domains, while previous p27(Kip1) studies report cell cycle-independent functions. These observations suggest p57(Kip2) coordinates multiple stages of corticogenesis and exhibits distinct and common activities compared with related family member p27(Kip1). PMID- 21245412 TI - Zinc supplementation suppresses 4-nitroquinoline 1-oxide-induced rat oral carcinogenesis. AB - Dietary zinc (Zn) deficiency is implicated in the pathogenesis of human oral esophageal cancers. In rats, Zn deficiency causes increased cell proliferation and cyclooxygenase-2 (COX-2) overexpression and enhances oral carcinogenesis by 4 nitroquinoline 1-oxide (NQO). Zn replenishment reverses all these effects. We questioned whether Zn has antitumor efficacy in a Zn-sufficient animal by investigating in Zn-sufficient rats (i) the efficacy of Zn supplementation on the progression of tongue squamous cell carcinogenesis induced by drinking water exposure to high (20-30 p.p.m.) and low (10 p.p.m.) doses of NQO and (ii) the modulating effects of Zn supplementation on biomarker expression in tongue lesions by immunohistochemistry. In rats exposed to high doses of NQO, Zn supplementation significantly reduced the incidence of papillomas from 100 to 64.7% (P=0.018) and invasive carcinomas from 93.8 to 52.9% (P=0.017). In rats exposed to low doses of NQO, where only minimally invasive carcinomas developed, Zn supplementation significantly reduced tumor multiplicity, incidence of tumors (1-2 mm), hyperplasia, dysplasia, papillomas and progression to carcinoma. Immunohistochemical analysis of carcinomas showed that Zn supplementation caused a shift to a less proliferative/aggressive cancer phenotype by reducing cell proliferation, stimulating apoptosis and decreasing expression of the key tumor markers cyclin D1, p53 and COX-2. Additionally, Zn supplementation significantly reduced cell proliferation in non-lesional tongue squamous epithelia, thereby suppressing tumor development. Together, the results demonstrate that Zn supplementation has chemopreventive efficacy against oral carcinogenesis in nutritionally complete animals. Our data suggest that Zn supplementation may be efficacious in the chemoprevention of human oral cancer. PMID- 21245413 TI - The evolution of milk casein genes from tooth genes before the origin of mammals. AB - Caseins are among cardinal proteins that evolved in the lineage leading to mammals. In milk, caseins and calcium phosphate (CaP) form a huge complex called casein micelle. By forming the micelle, milk maintains high CaP concentrations, which help altricial mammalian neonates to grow bone and teeth. Two types of caseins are known. Ca-sensitive caseins (alpha(s)- and beta-caseins) bind Ca but precipitate at high Ca concentrations, whereas Ca-insensitive casein (kappa casein) does not usually interact with Ca but instead stabilizes the micelle. Thus, it is thought that these two types of caseins are both necessary for stable micelle formation. Both types of caseins show high substitution rates, which make it difficult to elucidate the evolution of caseins. Yet, recent studies have revealed that all casein genes belong to the secretory calcium-binding phosphoprotein (SCPP) gene family that arose by gene duplication. In the present study, we investigated exon-intron structures and phylogenetic distributions of casein and other SCPP genes, particularly the odontogenic ameloblast-associated (ODAM) gene, the SCPP-Pro-Gln-rich 1 (SCPPPQ1) gene, and the follicular dendritic cell secreted peptide (FDCSP) gene. The results suggest that contemporary Ca sensitive casein genes arose from a putative common ancestor, which we refer to as CSN1/2. The six putative exons comprising CSN1/2 are all found in SCPPPQ1, although ODAM also shares four of these exons. By contrast, the five exons of the Ca-insensitive casein gene are all reminiscent of FDCSP. The phylogenetic distribution of these genes suggests that both SCPPPQ1 and FDCSP arose from ODAM. We thus argue that all casein genes evolved from ODAM via two different pathways; Ca-sensitive casein genes likely originated directly from SCPPPQ1, whereas the Ca insensitive casein genes directly differentiated from FDCSP. Further, expression of ODAM, SCPPPQ1, and FDCSP was detected in dental tissues, supporting the idea that both types of caseins evolved as Ca-binding proteins. Based on these findings, we propose two alternative hypotheses for micelle formation in primitive milk. The conserved biochemical characteristics in caseins and their immediate ancestors also suggest that many slight genetic modifications have created modern caseins, proteins vital to the sustained success of mammals. PMID- 21245414 TI - Ancient gene duplication provided a key molecular step for anaerobic growth of Baker's yeast. AB - Mitochondria are essential organelles required for a number of key cellular processes. As most mitochondrial proteins are nuclear encoded, their efficient translocation into the organelle is critical. Transport of proteins across the inner membrane is driven by a multicomponent, matrix-localized "import motor," which is based on the activity of the molecular chaperone Hsp70 and a J-protein cochaperone. In Saccharomyces cerevisiae, two paralogous J-proteins, Pam18 and Mdj2, can form the import motor. Both contain transmembrane and matrix domains, with Pam18 having an additional intermembrane space (IMS) domain. Evolutionary analyses revealed that the origin of the IMS domain of S. cerevisiae Pam18 coincides with a gene duplication event that generated the PAM18/MDJ2 gene pair. The duplication event and origin of the Pam18 IMS domain occurred at the relatively ancient divergence of the fungal subphylum Saccharomycotina. The timing of the duplication event also corresponds with a number of additional functional changes related to mitochondrial function and respiration. Physiological and genetic studies revealed that the IMS domain of Pam18 is required for efficient growth under anaerobic conditions, even though it is dispensable when oxygen is present. Thus, the gene duplication was beneficial for growth capacity under particular environmental conditions as well as diversification of the import motor components. PMID- 21245415 TI - Functional proteomic analysis reveals sex-dependent differences in structural and energy-producing myocardial proteins in rat model of alcoholic cardiomyopathy. AB - Long-term ethanol exposure leads to a sexually dimorphic response in both the susceptibility to cardiac pathology (protective effect of the female heart) and the expression of selected myocardial proteins. The purpose of the present study was to use proteomics to examine the effect of chronic alcohol consumption on a broader array of cardiac proteins and how these were affected between the sexes. Male and female rats were maintained for 18 wk on a 40% ethanol-containing diet in which alcohol was provided in drinking water and agar blocks. Differences in the content of specific cardiac proteins in isopycnic centrifugal fractions were determined using mass spectrometry on iTRAQ-labeled tryptic fragments. A random effects model of meta-analysis was developed to combine the results from multiple iTRAQ experiments. Analysis of a network of proteins involved in cardiovascular system development and function showed that troponins were oppositely regulated by alcohol exposure in females (upregulated) vs. males (downregulated), and this effect was validated by Western blot analysis. Pathway analysis also revealed that alcohol-consuming males showed increased expression of proteins involved in various steps of oxidative phosphorylation including complexes I, III, IV, and V, whereas females showed no change or decreased content. One implication from these findings is that females may be protected from the toxic effects of alcohol due to their ability to maintain contractile function, maintain efficiency of force generation, and minimize oxidative stress. However, the alcohol-induced insult may lead to increased production of reactive oxygen species and structural abnormalities in male myocardium. PMID- 21245416 TI - MicroRNA expression profile during adipogenic differentiation in mouse embryonic stem cells. AB - Pluripotent embryonic stem cells (ESC) have the potential to differentiate into any cell type of the three germ layers. Differentiation processes depend on genetic and epigenetic factors. The guidance of cell fate determination by microRNAs (miRs) seems important for embryonic development and cell lineage decisions. MiRs are short, single-stranded, noncoding RNA molecules that regulate through posttranscriptional modulation, a subset of target genes involved in cell differentiation and specific cell function. We have used microarray profiling of miRs in the mouse embryonic stem cell line CGR8. Comparison of the miR profiles of undifferentiated stem cells with mesodermal progenitors cells (day 5), preadipocytes (day 10), and adipocytes (day 21) showed that the expression level of 129 miRs changed (twofold) during adipogenic differentiation. We identified 10 clusters of differentially expressed miRs, which contain putative markers and regulators of mesodermal differentiation and cell fate determination into adipocytes. Notably, the adipocyte-specific miRs 143 and 103 were upregulated from day 10 onward. We have therefore demonstrated and characterized the dynamic profile of miR expression during murine adipogenic differentiation in vitro, including the initial differentiation from ESC via mesenchymal progenitors up to adipocytes. Our findings and experimental approach provide a suitable system to directly interrogate the role of miRs during adipogenic differentiation of embryonic stem cells. PMID- 21245417 TI - VeryGene: linking tissue-specific genes to diseases, drugs, and beyond for knowledge discovery. AB - In addition to many other genes, tissue-specific genes (TSGs) represent a set of genes of great importance for human physiology. However, the links among TSGs, diseases, and potential therapeutic agents are often missing, hidden, or too scattered to find. There is a need to establish a knowledgebase for researchers to share this and additional information in order to speed up discovery and clinical practice. As an initiative toward systems biology, the VeryGene web server was developed to fill this gap. A significant effort has been made to integrate TSGs from two large-scale data analyses with respective information on subcellular localization, Gene Ontology, Reactome, KEGG pathway, Mouse Genome Informatics (MGI) Mammalian Phenotype, disease association, and targeting drugs. The current release carefully selected 3,960 annotated TSGs derived from 127 normal human tissues and cell types, including 5,672 gene-disease and 2,171 drug target relationships. In addition to being a specialized source for TSGs, VeryGene can be used as a discovery tool by generating novel inferences. Some inherently useful but hidden relations among genes, diseases, drugs, and other important aspects can be inferred to form testable hypotheses. VeryGene is available online at http://www.verygene.com. PMID- 21245418 TI - Rumen epithelial adaptation to high-grain diets involves the coordinated regulation of genes involved in cholesterol homeostasis. AB - The molecular mechanisms underlying rumen epithelial adaption to high-grain (HG) diets are unknown. To gain insight into the metabolic mechanisms governing epithelial adaptation, mature nonlactating dairy cattle (n = 4) were transitioned from a high-forage diet (HF, 0% grain) to an HG diet (65% grain). After the cattle were fed the HG diet for 3 wk, they returned to the original HF diet, which they were fed for an additional 3 wk. Continuous ruminal pH, ruminal short chain fatty acids, and plasma beta-hydroxybutyrate were measured on a weekly basis, and rumen papillae were biopsied from the ventral sac to assess alterations in mRNA expression profiles. The subacute form of ruminal acidosis was diagnosed during the first week of the HG period (4.6 +/- 1.6 h/day 5.0 copies/nucleus) was associated with additional benefit from adjuvant trastuzumab in patients with early-stage breast cancer. To further explore this relationship, we investigated associations between MYC amplification and disease-free survival (DFS) in a similar adjuvant trastuzumab HER2-positive breast cancer trial-North Central Cancer Treatment Group (NCCTG) N9831. PATIENTS AND METHODS: This analysis included 799 patients randomly assigned to receive chemotherapy alone or with concurrent trastuzumab on N9831. Fluorescence in situ hybridization (FISH) was performed by using a dual probe mixture for MYC and centromere 8 (MYC:CEP8) on tissue microarrays. MYC amplification was prespecified as MYC:CEP8 ratio > 2.2 or average MYC copies/nucleus > 5.0. Exploratory variables included polysomy 8. RESULTS: In comparing DFS (median follow-up, 4.0 years) between treatments, patients with MYC:CEP8 ratio <= 2.2 (n = 618; 77%) and > 2.2 (n = 181; 23%) had hazard ratios (HRs) of 0.46 (P < .001) and 0.67 (P = .33), respectively (interaction P = .38). Patients with MYC copies/nucleus <= 5.0 (n = 534; 67%) and > 5.0 (n = 265; 33%) had HRs of 0.52 (P = .002) and 0.48 (P = .02), respectively (interaction P = .94). Patients with MYC:CEP8 ratio < 1.3 with normal chromosome 8 copy number (n = 141; 18%) and >= 1.3 or < 1.3 with polysomy 8 (n = 658; 82%) had HRs of 0.66 (P = .28) and 0.44 (P < .001), respectively (interaction P = .23). Patients with MYC copies/nucleus < 2.5 (n = 130; 16%) and >= 2.5 (n = 669; 84%) had HRs of 1.07 (P = .87) and 0.42 (P < .001), respectively (interaction P = .05). CONCLUSION: We did not confirm the B31 association between MYC amplification and additional trastuzumab benefit. Exploratory analyses revealed potential associations between alternative MYC/chromosome 8 copy number alterations and differential benefit of adjuvant trastuzumab. PMID- 21245422 TI - Tumor-to-tumor metastasis: report of a case of renal cell carcinoma metastasizing to a pancreatic endocrine neoplasm. PMID- 21245423 TI - Validation of a new risk assessment model for predicting adverse events in children with fever and chemotherapy-induced neutropenia. PMID- 21245424 TI - Genetic predisposition for chemotherapy-induced neuropathy in multiple myeloma. PMID- 21245425 TI - Primary nongestational choriocarcinoma of the uterine cervix. PMID- 21245426 TI - Chromophobe renal cell carcinoma with prolonged response to sequential sunitinib and everolimus. PMID- 21245427 TI - Clinical Dutch-English Lambert-Eaton Myasthenic syndrome (LEMS) tumor association prediction score accurately predicts small-cell lung cancer in the LEMS. AB - PURPOSE: Approximately one half of patients with Lambert-Eaton myasthenic syndrome (LEMS) have small-cell lung carcinomas (SCLC), aggressive tumors with poor prognosis. In view of its profound impact on therapy and survival, we developed and validated a score to identify the presence of SCLC early in the course of LEMS. PATIENTS AND METHODS: We derived a prediction score for SCLC in LEMS in a nationwide cohort of 107 Dutch patients, and validated it in a similar cohort of 112 British patients. A Dutch-English LEMS Tumor Association Prediction (DELTA-P) score was developed based on multivariate logistic regression. RESULTS: Age at onset, smoking behavior, weight loss, Karnofsky performance status, bulbar involvement, male sexual impotence, and the presence of Sry-like high-mobility group box protein 1 serum antibodies were independent predictors for SCLC in LEMS. A DELTA-P score was derived allocating 1 point for the presence of each of the following items at or within 3 months from onset: age at onset >= 50 years, smoking at diagnosis, weight loss >= 5%, bulbar involvement, erectile dysfunction, and Karnofsky performance status lower than 70. The area under the curve of the receiver operating curve was 94.4% in the derivation cohort and 94.6% in the validation set. A DELTA-P score of 0 or 1 corresponded to a 0% to 2.6% chance of SCLC, whereas scores of 4, 5, and 6 corresponded to chances of SCLC of 93.5%, 96.6%, and 100%, respectively. CONCLUSION: The simple clinical DELTA-P score discriminated patients with LEMS with and without SCLC with high accuracy early in the course of LEMS. PMID- 21245428 TI - Histopathologic-based prognostic factors of colorectal cancers are associated with the state of the local immune reaction. AB - PURPOSE: The prognosis of patients with colorectal cancer has sometimes proved uncertain; thus, the prognostic significance of immune criteria was compared with that of the tumor extension criteria using the American Joint Committee on Cancer/International Union Against Cancer-TNM (AJCC/UICC-TNM) staging system. PATIENTS AND METHODS: We studied the intratumoral immune infiltrates in the center of the tumor and in the invasive margin of 599 specimens of stage I to IV colorectal cancers from two independent cohorts. We analyzed these findings in relation to the degree of tumor extension and to the frequency of recurrence. RESULTS: Growth of the primary tumor and metastatic spread were associated with decreased intratumoral immune T-cell densities. Sixty percent of patients with high densities of CD8(+) cytotoxic T-lymphocyte infiltrate presented with stage Tis/T1 tumor, whereas no patients with low densities presented with such early stage tumor. In patients who did not relapse, the density of CD8 infiltrates was inversely correlated with T stage. In contrast, in patients whose tumor recurred, the number of CD8 cells was low regardless of the T stage of the tumor. Univariate analysis showed that the immune score was significantly associated with differences in disease-free, disease-specific, and overall survival (hazard ratio [HR], 0.64, 0.60, and 0.70, respectively; P < .005). Time-dependent receiver operating characteristic curve analysis illustrated the predictive accuracy of the immune parameters (c-index = 65.3%, time-dependent c-index [Ctau] = 66.5%). A final stepwise model for Cox multivariate analysis supports the advantage of the immune score (HR, 0.64; P < .001; Ctau = 67.9%) compared with histopathologic features in predicting recurrence as well as survival. CONCLUSION: Assessment of CD8(+) cytotoxic T lymphocytes in combined tumor regions provides an indicator of tumor recurrence beyond that predicted by AJCC/UICC-TNM staging. PMID- 21245429 TI - Helicobacter pylori-negative gastric mucosa-associated lymphoid tissue lymphoma. PMID- 21245430 TI - Relapse of ovarian cancer with bone marrow infiltration and concurrent emergence of therapy-related acute myeloid leukemia: a case report. PMID- 21245431 TI - [90Y]yttrium microspheres radioembolotherapy in desmoplastic small round cell tumor hepatic metastases. PMID- 21245432 TI - HLA-DQA1*02:01 is a major risk factor for lapatinib-induced hepatotoxicity in women with advanced breast cancer. AB - PURPOSE: Hepatobiliary adverse events (AEs) have been observed in a small proportion of patients with metastatic breast cancer (MBC) treated with lapatinib. This study sought to identify gene variants associated with lapatinib induced ALT elevation and hepatobiliary AEs. PATIENTS AND METHODS: A two-stage pharmacogenetic investigation of ALT elevation was conducted in lapatinib-treated patients with MBC. Exploratory marker identification evaluated classical HLA alleles, candidate genes, and genome-wide screening in 37 cases with ALT greater than 3 times the upper limit of normal (ULN) and 286 controls with ALT <= 1* ULN, selected from 901 lapatinib-treated patients in 12 trials. Markers achieving prespecified association thresholds were progressed to an independent confirmatory data set of 24 ALT cases and 155 controls selected from a subsequent trial of 374 lapatinib-treated patients. RESULTS: Of 58 variants associated with ALT elevation in the exploratory data set, four exceeded the prespecified significance threshold in the confirmatory analysis. These variants reside in the same MHC genomic locus and include HLA-DQA1*02:01. In the confirmatory study, DQA1*02:01 allele carriage was present in 71% of ALT cases and in 21% of controls (P < .001; odds ratio, 9.0; 95% CI, 3.2 to 27.4). As a predictor of liver safety risk in ALT cases versus noncases, DQA1*02:01 had negative and positive predictive values of 0.97 (95% CI, 0.95 to 0.99) and 0.17 (95% CI 0.10 to 0.26), respectively. CONCLUSION: These results support a role for immune mechanisms in lapatinib-induced hepatotoxicity. Further work is required to determine whether testing for DQA1*02:01 allele carriage is clinically useful in managing liver safety risk during lapatinib treatment. PMID- 21245433 TI - Parent reports of quality of life for pediatric patients with cancer with no realistic chance of cure. AB - PURPOSE: To compare quality of life of children with cancer with no reasonable chance of cure reported by parents 6 months or fewer versus more than 6 months before death. PATIENTS AND METHODS: This cross-sectional study included children between the ages of 2 and 18 years with cancer and no reasonable chance of cure at The Hospital for Sick Children, Toronto, Ontario, Canada. Parents reported quality of life on behalf of their children. Outcomes were the PedsQL 4.0 Generic Core Scales, Acute Cancer Module, and Multidimensional Fatigue Scale. RESULTS: Seventy-three parents of children participated. Compared with children who survived more than 6 months (n = 43), those who died at 6 months or fewer (n = 30) had significantly worse physical health (mean difference, 15.9; 95% CI, 1.8 to 30.0; P = .028), more pain and hurt (mean difference, 15.5; 95% CI, 0.9 to 30.0; P = .037), and worse general fatigue (mean difference, 15.8; 95% CI, 2.4 to 29.1; P = .021) and sleep/rest fatigue (mean difference, 16.0; 95% CI, 3.5 to 28.5; P = .013). Among the entire cohort, those with leukemia/lymphoma had worse physical and psychosocial quality of life compared with those with solid or brain tumors. Recent stem-cell transplantation was associated with worse psychosocial health. CONCLUSION: Parents of children with cancer reported worse physical health, pain, and fatigue proximal to death. Those with leukemia/lymphoma were at higher risk for impaired quality of life. This knowledge can help in the design of targeted interventions to improve quality of life for children dying as a result of cancer. PMID- 21245434 TI - TNM staging in colorectal cancer: T is for T cell and M is for memory. PMID- 21245435 TI - Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study. AB - PURPOSE: Peripheral T-cell lymphoma (PTCL) is a poor prognosis subtype of non Hodgkin's lymphoma with no accepted standard of care. This study evaluated the efficacy and tolerability of pralatrexate, a novel antifolate with promising activity. PATIENTS AND METHODS: Patients with independently confirmed PTCL who progressed following >= 1 line of prior therapy received pralatrexate intravenously at 30 mg/m(2)/wk for 6 weeks in 7-week cycles. Primary assessment of response was made by independent central review using the International Workshop Criteria. The primary end point was overall response rate. Secondary end points included duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: Of 115 patients enrolled, 111 were treated with pralatrexate. The median number of prior systemic therapies was three (range, 1 to 12). The response rate in 109 evaluable patients was 29% (32 of 109), including 12 complete responses (11%) and 20 partial responses (18%), with a median DoR of 10.1 months. Median PFS and OS were 3.5 and 14.5 months, respectively. The most common grade 3/4 adverse events were thrombocytopenia (32%), mucositis (22%), neutropenia (22%), and anemia (18%). CONCLUSION: To our knowledge, PROPEL (Pralatrexate in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma) is the largest prospective study conducted in patients with relapsed or refractory PTCL. Pralatrexate induced durable responses in relapsed or refractory PTCL irrespective of age, histologic subtypes, amount of prior therapy, prior methotrexate, and prior autologous stem-cell transplant. These data formed the basis for the US Food and Drug Administration approval of pralatrexate, the first drug approved for this disease. PMID- 21245436 TI - "And what other medications are you taking?". PMID- 21245437 TI - Vaginal microbicide gel for delivery of IQP-0528, a pyrimidinedione analog with a dual mechanism of action against HIV-1. AB - Pyrimidinediones, a novel class of compounds, have previously been shown to possess antiviral activity at nanomolar concentrations. One member of this class of compounds, IQP-0528, was selected as the lead molecule for formulation development owing to its stability at physiologically relevant conditions, wide therapeutic window, and antiviral activity in the nanomolar range. Here, we report the development of two vaginal gels--3.0% hydroxyethyl cellulose (HEC) formulation and a 0.65% Carbopol formulation--for the sustained delivery of IQP 0528. Stability studies under accelerated conditions confirmed the chemical stability of IQP-0528 and mechanical stability of the gel formulation for 3 months. In vitro release studies revealed that diffusion-controlled release of IQP-0528 occurred over 6 h, with an initial lag time of approximately 1 h. Based on the drug release profile, the 3.0% HEC gel was selected as the lead formulation for safety and activity evaluations. The in vitro and ex vivo safety evaluations showed no significant loss in cell viability or significant inflammatory response after treatment with a 3.0% HEC gel containing 0.25% IQP 0528. In an in vitro HIV-1 entry inhibition assay, the lead formulation showed an 50% effective concentration of 0.14 MUg/ml for gel in culture media, which corresponds to ~0.001 MUM IQP-0528. The antiviral activity was further confirmed by using polarized cervical explants, in which the formulation showed complete protection against HIV infection. In summary, these results are encouraging and warrant further evaluation of IQP-0528 gel formulations in in vivo models, as well as the development of alternative formulations for the delivery of IQP-0528 as a microbicide. PMID- 21245438 TI - Process analysis of variables for standardization of antifungal susceptibility testing of nonfermentative yeasts. AB - Nonfermentative yeasts, such as Cryptococcus spp., have emerged as fungal pathogens during the last few years. However, standard methods to measure their antifungal susceptibility (antifungal susceptibility testing [AST]) are not completely reliable due to the impaired growth of these yeasts in standard media. In this work, we have compared the growth kinetics and the antifungal susceptibilities of representative species of nonfermentative yeasts such as Cryptococcus neoformans, Cryptococcus gattii, Cryptococcus albidus, Rhodotorula spp., Yarrowia lipolytica, Geotrichum spp., and Trichosporon spp. The effect of the growth medium (RPMI medium versus yeast nitrogen base [YNB]), glucose concentration (0.2% versus 2%), nitrogen source (ammonium sulfate), temperature (30 degrees C versus 35 degrees C), shaking, and inoculum size (10(3), 10(4), and 10(5) cells) were analyzed. The growth rate, lag phase, and maximum optical density were obtained from each growth experiment, and after multivariate analysis, YNB-based media demonstrated a significant improvement in the growth of yeasts. Shaking, an inoculum size of 10(5) CFU/ml, and incubation at 30 degrees C also improved the growth kinetics of organisms. Supplementation with ammonium sulfate and with 2% glucose did not have any effect on growth. We also tested the antifungal susceptibilities of all the isolates by the reference methods of the CLSI and EUCAST, the EUCAST method with shaking, YNB under static conditions, and YNB with shaking. MIC values obtained under different conditions showed high percentages of agreement and significant correlation coefficient values between them. MIC value determinations according to CLSI and EUCAST standards were rather complicated, since more than half of isolates tested showed a limited growth index, hampering endpoint determinations. We conclude that AST conditions including YNB as an assay medium, agitation of the plates, reading after 48 h of incubation, an inoculum size of 10(5) CFU/ml, and incubation at 30 degrees C made MIC determinations easier without an overestimation of MIC values. PMID- 21245439 TI - Time-kill activity of the streptogramin NXL 103 against Gram-positive and negative bacteria. AB - Against 33 Gram-positive and -negative bacteria, NXL 103 MICs were 0.03 to 1 MUg/ml. NXL 103 was bactericidal by 12 h at 2 * MIC against all 5 pneumococci and at 2 * MIC after 24 h against all 5 group A and B beta-hemolytic streptococci. NXL 103 was bactericidal against all 8 Haemophilus influenzae strains at 2 * MIC and all 5 Moraxella catarrhalis strains at 4 * MIC after 24 h but was mainly bacteriostatic against 5 methicillin-resistant Staphylococcus aureus strains. After the exposure of one strain of each species to NXL 103 for 10 daily subcultures, the MICs remained within +/- 1 dilution. PMID- 21245440 TI - Echinocandin susceptibility testing of Candida spp. Using EUCAST EDef 7.1 and CLSI M27-A3 standard procedures: analysis of the influence of bovine serum albumin supplementation, storage time, and drug lots. AB - The MICs of echinocandins against Candida isolates with fks mutations are higher than those for wild-type (WT) isolates. However, the MIC ranges for susceptible and mutant populations overlap or are poorly separated. It was recently reported that a greater separation could be achieved in the presence of serum. To more fully explore this possibility, we compared the performances of the reference microdilution methods by using standard and bovine serum albumin (BSA) supplemented growth medium. Anidulafungin, caspofungin, and micafungin MICs were determined according to EUCAST and CLSI methods and with 50% BSA in the medium for 93 clinical isolates, including Candida albicans (20/10 [number of isolates/number of mutants]), C. glabrata (19/10), C. dubliniensis (2/1), C. krusei (16/3), C. parapsilosis (19), and C. tropicalis (19/4) isolates. Stability of the plates was tested after storage at -80 degrees C for 2 and 6 months, and the performance of two different lots of caspofungin was investigated. The addition of BSA to the medium resulted in higher MICs (1 to 9 2-fold dilution steps) for all isolates and compounds. The increases were greatest for anidulafungin and micafungin and, among WT isolates, for C. parapsilosis. The number of very major errors (VMEs) was reduced (24% [20/84 isolates] versus <= 7% [6/84 isolates]) using BSA-supplemented EUCAST medium but not using BSA supplemented CLSI medium (6% versus 9%). MIC results were unchanged after 6 months of storage of test plates. The two lots of caspofungin yielded identical results. Addition of BSA to the EUCAST medium increases the ability to differentiate between WT isolates and isolates harboring resistance mutations. PMID- 21245441 TI - In vitro and in vivo properties of BAL30376, a beta-lactam and dual beta lactamase inhibitor combination with enhanced activity against Gram-negative Bacilli that express multiple beta-lactamases. AB - BAL30376 is a triple combination comprising a siderophore monobactam, BAL19764; a novel bridged monobactam, BAL29880, which specifically inhibits class C beta lactamases; and clavulanic acid, which inhibits many class A and some class D beta-lactamases. The MIC(90) was <= 4 MUg/ml (expressed as the concentration of BAL19764) for most species of the Enterobacteriaceae family, including strains that produced metallo-beta-lactamases and were resistant to all of the other beta lactams tested. The MIC(90) for Stenotrophomonas maltophilia was 2 MUg/ml, for multidrug-resistant (MDR) Pseudomonas aeruginosa it was 8 MUg/ml, and for MDR Acinetobacter and Burkholderia spp. it was 16 MUg/ml. The presence of the class C beta-lactamase inhibitor BAL29880 contributed significantly to the activity of BAL30376 against strains of Citrobacter freundii, Enterobacter species, Serratia marcescens, and P. aeruginosa. The presence of clavulanic acid contributed significantly to the activity against many strains of Escherichia coli and Klebsiella pneumoniae that produced class A extended-spectrum beta-lactamases. The activity of BAL30376 against strains with metallo-beta-lactamases was largely attributable to the intrinsic stability of the monobactam BAL19764 toward these enzymes. Considering its three components, BAL30376 was unexpectedly refractory toward the development of stable resistance. PMID- 21245442 TI - International transfer of NDM-1-producing Klebsiella pneumoniae from Iraq to France. PMID- 21245443 TI - GS-8374, a novel HIV protease inhibitor, does not alter glucose homeostasis in cultured adipocytes or in a healthy-rodent model system. AB - Adverse effects induced by HIV protease inhibitors (PIs) are a significant factor in limiting their clinical success. PIs directly contribute to peripheral insulin resistance and alterations in lipid metabolism. GS-8374 is a novel PI with potent antiretroviral activity and a favorable resistance profile. Here we report on the potential of GS-8374 to adversely affect glucose and lipid homeostasis. Acute effects of GS-8374 and control PIs on glucose uptake and lipid accumulation were assessed in vitro in mouse OP9 and primary human adipocytes, respectively. GS 8374 and atazanavir showed no effect on insulin-stimulated deoxyglucose uptake, whereas ritonavir and lopinavir caused significant reductions. Similarly, in vitro lipid accumulation was not significantly affected in adipocytes treated with either GS-8374 or atazanavir. In euglycemic-hyperinsulinemic clamp experiments performed in rats during acute infusion of therapeutic levels of PIs, sustained serum GS-8374 levels of 8 MUM had no effect on peripheral glucose disposal (similar to the findings for atazanavir). Comparable serum levels of lopinavir and ritonavir produced acute 19% and 53% reductions in in vivo glucose disposal, respectively. In conclusion, similar to atazanavir, but unlike ritonavir and lopinavir, GS-8374 neither affects insulin-stimulated glucose uptake in adipocytes in culture nor acutely alters peripheral glucose disposal in a rodent model system. These results dissociate the antiretroviral activity of GS 8374 from adverse effects on insulin sensitivity observed with some of the first generation PIs and provide further support for the use of these experimental systems in the preclinical evaluation of novel PIs. PMID- 21245444 TI - Comparative in vitro activities of the novel antibacterial finafloxacin against selected Gram-positive and Gram-negative bacteria tested in Mueller-Hinton broth and synthetic urine. AB - Kill kinetics and MICs of finafloxacin and ciprofloxacin against 34 strains with defined resistance mechanisms grown in cation-adjusted Mueller-Hinton broth (CAMHB) at pH values of 7.2 and 5.8 and in synthetic urine at pH 5.8 were determined. In general, finafloxacin gained activity at low pH values in CAMHB and remained almost unchanged in artificial urine. Ciprofloxacin MICs increased and bactericidal activity decreased strain dependently in acidic CAMHB and particularly in artificial urine. PMID- 21245445 TI - Thiostrepton and derivatives exhibit antimalarial and gametocytocidal activity by dually targeting parasite proteasome and apicoplast. AB - Ribosome-targeting antibiotics exert their antimalarial activity on the apicoplast of the malaria parasite, an organelle of prokaryote origin having essential metabolic functions. These antibiotics typically cause a delayed-death phenotype, which manifests in parasite killing during the second replication cycle following administration. As an exception, treatment with the antibiotic thiostrepton results in an immediate killing. We recently demonstrated that thiostrepton and its derivatives interfere with the eukaryotic proteasome, a multimeric protease complex that is important for the degradation of ubiquitinated proteins. Here, we report that the thiostrepton-based compounds are active against chloroquine-sensitive and -resistant Plasmodium falciparum, where they rapidly eliminate parasites before DNA replication. The minor parasite fraction that escapes the fast killing of the first replication cycle is arrested in the schizont stage of the following cycle, displaying a delayed-death phenotype. Thiostrepton further exhibits gametocytocidal activity by eliminating gametocytes, the sexual precursor cells that are crucial for parasite transmission to the mosquito. Compound treatment results in an accumulation of ubiquitinated proteins in the blood stages, indicating an effect on the parasite proteasome. In accordance with these findings, expression profiling revealed that the proteasome is present in the nucleus and cytoplasm of trophozoites, schizonts, and gametocytes. In conclusion, thiostrepton derivatives represent promising candidates for malaria therapy by dually acting on two independent targets, the parasite proteasome and the apicoplast, with the capacity to eliminate both intraerythrocytic asexual and transmission stages of the parasite. PMID- 21245446 TI - Properties and therapeutic efficacy of broadly reactive chimeric and humanized H5 specific monoclonal antibodies against H5N1 influenza viruses. AB - Highly pathogenic H5N1 virus infection causes severe disease and a high rate of fatality in humans. Development of humanized monoclonal antibodies may provide an efficient therapeutic regime for H5N1 virus infection. In the present study, broadly cross-reactive monoclonal antibodies (MAbs) derived from mice were humanized to minimize immunogenicity. One chimeric antibody (cAb) and seven humanized antibodies (hAbs) were constructed. These antibodies retained broad spectrum reactivity to H5N1 viruses, binding to recombinant H5-subtype HA1 molecules expressed in CHO cells in a dose-dependent manner and exhibiting similar reactivities against antigenically distinct H5N1 viruses in hemagglutination inhibition (HI) assays. One humanized antibody, 37 hAb, showed HI and neutralization activities comparable to that of the parental murine antibody, 13D4 MAb, while the other six antibodies were less reactive to H5N1 viruses. Analysis of amino acid sequences in the variable region frameworks of the seven humanized antibodies found that Q5 and Y27 in the VH region are highly conserved murine residues. Comparison of the three-dimensional structures derived from the variable regions of MAbs 37 hAb, H1202-34, and 13D4 revealed that residue substitutions at sites 70 and 46 may be the major cause for the observed differences in binding affinity. Examination of the chimeric antibody and one of the humanized antibodies, 37 hAb, showed that both antibodies offered postinfection protection against lethal challenge with antigenically diverse H5N1 viruses in the mouse model. Chimeric and humanized antibodies which retain the broadly reactive and protective properties of murine H5-specific monoclonal antibodies have great potential for use in the treatment of human H5N1 infection. PMID- 21245447 TI - Cross-resistance to lincosamides, streptogramins A, and pleuromutilins due to the lsa(C) gene in Streptococcus agalactiae UCN70. AB - Streptococcus agalactiae UCN70, isolated from a vaginal swab obtained in New Zealand, is resistant to lincosamides and streptogramins A (LS(A) phenotype) and also to tiamulin (a pleuromutilin). By whole-genome sequencing, we identified a 5,224-bp chromosomal extra-element that comprised a 1,479-bp open reading frame coding for an ABC protein (492 amino acids) 45% identical to Lsa(A), a protein related to intrinsic LS(A) resistance in Enterococcus faecalis. Expression of this novel gene, named lsa(C), in S. agalactiae BM132 after cloning led to an increase in MICs of lincomycin (0.06 to 4 MUg/ml), clindamycin (0.03 to 2 MUg/ml), dalfopristin (2 to >32 MUg/ml), and tiamulin (0.12 to 32 MUg/ml), whereas no change in MICs of erythromycin (0.06 MUg/ml), azithromycin (0.03 MUg/ml), spiramycin (0.25 MUg/ml), telithromycin (0.03 MUg/ml), and quinupristin (8 MUg/ml) was observed. The phenotype was renamed the LS(A)P phenotype on the basis of cross-resistance to lincosamides, streptogramins A, and pleuromutilins. This gene was also identified in similar genetic environments in 17 other S. agalactiae clinical isolates from New Zealand exhibiting the same LS(A)P phenotype, whereas it was absent in susceptible S. agalactiae strains. Interestingly, this extra-element was bracketed by a 7-bp duplication of a target site (ATTAGAA), suggesting that this structure was likely a mobile genetic element. In conclusion, we identified a novel gene, lsa(C), responsible for the acquired LS(A)P resistance phenotype in S. agalactiae. Dissection of the biochemical basis of resistance, as well as demonstration of in vitro mobilization of lsa(C), remains to be performed. PMID- 21245448 TI - Lactobacilli reduce cell cytotoxicity caused by Streptococcus pyogenes by producing lactic acid that degrades the toxic component lipoteichoic acid. AB - Lactobacilli are known to prevent colonization by many pathogens; nevertheless, the mechanisms of their protective effect are largely unknown. In this work, we investigated the role of lactobacilli during infection of epithelial cells with group A streptococci (GAS). GAS cause a variety of illnesses ranging from noninvasive disease to more severe invasive infections, such as necrotizing fasciitis and toxic shock-like syndrome. Invasion of deeper tissues is facilitated by GAS-induced apoptosis and cell death. We found that lactobacilli inhibit GAS-induced host cell cytotoxicity and shedding of the complement regulator CD46. Further, survival assays demonstrated that lactic acid secreted by lactobacilli is highly bactericidal toward GAS. In addition, lactic acid treatment of GAS, but not heat killing, prior to infection abolishes the cytotoxic effects against human cells. Since lipoteichoic acid (LTA) of GAS is heat resistant and cytotoxic, we explored the effects of lactic acid on LTA. By applying such an approach, we demonstrate that lactic acid reduces epithelial cell damage caused by GAS by degrading both secreted and cell-bound LTA. Taken together, our experiments reveal a mechanism by which lactobacilli prevent pathogen-induced host cell damage. PMID- 21245449 TI - In vitro characterization of GS-8374, a novel phosphonate-containing inhibitor of HIV-1 protease with a favorable resistance profile. AB - GS-8374 is a novel bis-tetrahydrofuran HIV-1 protease (PR) inhibitor (PI) with a unique diethylphosphonate moiety. It was selected from a series of analogs containing various di(alkyl)phosphonate substitutions connected via a linker to the para position of a P-1 phenyl ring. GS-8374 inhibits HIV-1 PR with high potency (K(i) = 8.1 pM) and with no known effect on host proteases. Kinetic and thermodynamic analysis of GS-8374 binding to PR demonstrated an extremely slow off rate for the inhibitor and favorable contributions of both the enthalpic and entropic components to the total free binding energy. GS-8374 showed potent antiretroviral activity in T-cell lines, primary CD4(+) T cells (50% effective concentration [EC(50)] = 3.4 to 11.5 nM), and macrophages (EC(50) = 25.5 nM) and exhibited low cytotoxicity in multiple human cell types. The antiviral potency of GS-8374 was only moderately affected by human serum protein binding, and its combination with multiple approved antiretrovirals showed synergistic effects. When it was tested in a PhenoSense assay against a panel of 24 patient-derived viruses with high-level PI resistance, GS-8374 showed lower mean EC(50)s and lower fold resistance than any of the clinically approved PIs. Similar to other PIs, in vitro hepatic microsomal metabolism of GS-8374 was efficiently blocked by ritonavir, suggesting a potential for effective pharmacokinetic boosting in vivo. In summary, results from this broad in vitro pharmacological profiling indicate that GS-8374 is a promising candidate to be further assessed as a new antiretroviral agent with potential for clinical efficacy in both treatment-naive and -experienced patients. PMID- 21245451 TI - Radiation-induced heart disease. PMID- 21245450 TI - Experimental phage therapy in treating Klebsiella pneumoniae-mediated liver abscesses and bacteremia in mice. AB - Intragastric inoculation of mice with Klebsiella pneumoniae can cause liver abscesses, necrosis of liver tissues, and bacteremia. A newly isolated phage (phiNK5) with lytic activity for K. pneumoniae was used to treat K. pneumoniae infection in an intragastric model. Both intraperitoneal and intragastric administration of a single dose of phiNK5 lower than 2 * 10(8) PFU at 30 min after K. pneumoniae infection was able to protect mice from death in a dose dependent manner, but the efficacy achieved with a low dose of phiNK5 by intragastric treatment provided the more significant protection. Phage phiNK5 administered as late as 24 h after K. pneumoniae inoculation was still protective, while intraperitoneal treatment with phage was more efficient than intragastric treatment as a result of the dissemination of bacteria into the circulation at 24 h postinfection. Surveys of bacterial counts for mice treated with phiNK5 by the intraperitoneal route revealed that the bacteria were eliminated effectively from both blood and liver tissue. K. pneumoniae-induced liver injury, such as liver necrosis, as well as blood levels of aspartate aminotransferase and alanine aminotransferase and inflammatory cytokine production, was significantly inhibited by phiNK5 treatment. These data suggest that a low dose of phiNK5 is a potential therapeutic agent for K. pneumoniae induced liver infection. PMID- 21245452 TI - Ruptured noncoronary sinus of valsalva aneurysm: an unusual cause of chronic right-sided heart failure. PMID- 21245453 TI - Letter by Marcadenti and Oliveira de Abreu Silva regarding article, "Chocolate intake and incidence of heart failure: a population-based, prospective study of middle-aged and elderly women". PMID- 21245454 TI - Res-erection of Viagra as a heart drug. PMID- 21245455 TI - Transforming growth factor-beta: governing the transition from inflammation to fibrosis in heart failure with preserved left ventricular function. PMID- 21245457 TI - Reflections on performance measurement in cardiovascular disease. PMID- 21245458 TI - Quality of stroke prevention care in atrial fibrillation: many moving targets. PMID- 21245459 TI - Measuring value from the patient's perspective. PMID- 21245460 TI - Expanding the frontier of outcomes measurement for public reporting. PMID- 21245461 TI - Randomized trial of targeted performance feedback to facilitate quality improvement in acute myocardial infarction care. AB - BACKGROUND: Efforts to improve quality of care for patients with acute myocardial infarction (AMI) are a national priority. To date, there have been few studies that have prospectively evaluated hospital quality improvement (QI) interventions. METHODS AND RESULTS: Using hospitals in the National Cardiovascular Data Registry (NCDR) ACTION Registry-GWTG, a cluster randomized trial of the effectiveness of targeted performance feedback to facilitate process improvement for AMI care will be conducted. ACTION Registry-GWTG hospitals with a minimum of 50 AMI patients per 2 quarters are eligible for randomization. The control arm receives standard performance feedback reports, and the intervention arm receives standard performance feedback reports in addition to a supplemental report on the "top 3" centrally identified, hospital-specific performance gaps. The primary outcome will be improvement in a composite of all metrics, and the secondary outcome will be improvement in the targeted metrics. At study inception in January 2009, 149 sites were randomized: 76 to the intervention arm, and 73 to the control arm. Intervention and control sites were well balanced in terms of baseline performance, center characteristics, and AMI volume (~70 patients per quarter). The intervention phase will continue for 5 feedback cycles, each containing 2 quarters of data feedback over 18 months. A final trial outcome report will follow. CONCLUSIONS: This randomized trial will evaluate a novel hospital-level QI intervention of targeted performance feedback for AMI, thereby demonstrating the effective use of national registries for QI and furthering our understanding of effective QI methods. PMID- 21245462 TI - Pancreatic islet-specific overexpression of Reg3beta protein induced the expression of pro-islet genes and protected the mice against streptozotocin induced diabetes mellitus. AB - Reg family proteins have been implicated in islet beta-cell proliferation, survival, and regeneration. The expression of Reg3beta (pancreatitis-associated protein) is highly induced in experimental diabetes and acute pancreatitis, but its precise role has not been established. Through knockout studies, this protein was shown to be mitogenic, antiapoptotic, and anti-inflammatory in the liver and pancreatic acinars. To test whether it can promote islet cell growth or survival against experimental damage, we developed beta-cell-specific overexpression using rat insulin I promoter, evaluated the changes in normal islet function, gene expression profile, and the response to streptozotocin-induced diabetes. Significant and specific overexpression of Reg3beta was achieved in the pancreatic islets of RIP-I/Reg3beta mice, which exhibited normal islet histology, beta-cell mass, and in vivo and in vitro insulin secretion in response to high glucose yet were slightly hyperglycemic and low in islet GLUT2 level. Upon streptozotocin treatment, in contrast to wild-type littermates that became hyperglycemic in 3 days and lost 15% of their weight, RIP-I/Reg3beta mice were significantly protected from hyperglycemia and weight loss. To identify specific targets affected by Reg3beta overexpression, a whole genome DNA microarray on islet RNA isolated from the transgenic mice revealed more than 45 genes significantly either up- or downregulated. Among them, islet-protective osteopontin/SPP1 and acute responsive nuclear protein p8/NUPR1 were significantly induced, a result further confirmed by real-time PCR, Western blots, and immunohistochemistry. Our results suggest that Reg3beta is unlikely an islet growth factor but a putative protector that prevents streptozotocin-induced damage by inducing the expression of specific genes. PMID- 21245463 TI - Endothelium-derived microparticles inhibit angiogenesis in the heart and enhance the inhibitory effects of hypercholesterolemia on angiogenesis. AB - Therapeutic angiogenesis remains unsuccessful in coronary artery disease. It is known that plasma endothelium-derived microparticles (EMPs) are increased in coronary artery disease and that hypercholesterolemia can inhibit angiogenesis. We evaluated the relationship between EMPs and hypercholesterolemia in the impairment of angiogenesis. EMPs isolated from human umbilical vein endothelial cells were injected into low-density lipoprotein receptor-null (LDLr(-/-)) mice fed a Western diet for 2 wk and C57BL6 mice for 6 h or were directly added to the tissue culture media. Hearts isolated from mice were sectioned and cultured, and endothelial tube formation was measured. The expression and phosphorylation of endothelial NO synthase (eNOS) and the generation of NO in the hearts were determined. Angiogenesis was inhibited by pathophysiological concentrations of EMPs but not physiological concentrations of EMPs in hearts from C57BL6 mice. However, angiogenesis was inhibited by EMPs at both physiological and pathophysiological concentrations of EMPs in hearts from hypercholesterolemic LDLr(-/-) mice. Pathophysiological concentrations of EMPs decreased eNOS phosphorylation at Ser(1177) and NO generation without altering eNOS expression in hearts from C57BL6 mice. Both physiological and pathophysiological concentrations of EMPs decreased not only eNOS phosphorylation at Ser(1177) and NO generation, but eNOS expression in hypercholesterolemic hearts from LDLr(-/-) mice. These data demonstrated that pathophysiological concentrations of EMPs could inhibit angiogenesis in hearts by decreasing eNOS activity. EMPs and hypercholesterolemia mutually enhanced their inhibitory effect of angiogenesis by inducing eNOS dysfunction. Our findings suggest a novel mechanism by which hypercholesterolemia impairs angiogenesis. PMID- 21245464 TI - CCR5 mediates pro-osteoclastic and osteoclastogenic leukocyte chemoattraction. AB - Periodontal disease (PD) progression involves the selective leukocyte infiltration into periodontium, supposedly mediated by the chemokine/chemokine receptor system. In this study, we investigated the role of chemokine receptor CCR5 in the immunoregulation of experimental PD in C57BL/6 (WT) and CCR5KO mice. Aggregatibacter actinomycetem comitans infection triggered the chemoattraction of distinct CCR5+ leukocyte subpopulations (determined by flow cytometry): CCR5+F4/80+ leukocytes, which co-express CD14 , CCR2, TNF-alpha, and IL-1beta, indicative of activated macrophages; and CCR5+CD4+ cells, which co-express CXCR3, IFN-gamma, and RANKL, indicative of Th1 lymphocytes, therefore comprising pro osteoclastic and osteoclastogenic cell subsets, respectively. CCR5KO mice presented a lower PD severity (lower inflammation and alveolar bone loss) when compared with the WT strain, since the migration of F4/80+, TNF-alpha+, CD4+, and RANKL+ cells specifically decreased due to the lack of CCR5. Also, ELISA analysis demonstrated that the production of TNF-alpha, IL-1beta, IL-6, IFN-gamma, and RANKL in periodontal tissues was significantly decreased in the CCR5KO strain. The periodontal bacterial load and antimicrobial patterns were unaltered in CCR5KO mice. Our results demonstrate that the chemokine receptor is involved in the migration of distinct leukocyte subpopulations throughout experimental PD, being a potential target for therapeutic intervention in PD. PMID- 21245465 TI - Does incomplete caries removal increase restoration failure? PMID- 21245467 TI - Signals from the nucleus: activation of NF-kappaB by cytosolic ATM in the DNA damage response. AB - In response to genotoxic stress induced by DNA double-stranded breaks (DSBs), the inhibitor of kappaB kinase (IKK) to nuclear factor kappaB (NF-kappaB) pathway is activated, which can promote cancer progression and increase the resistance of cancer cells to ionizing radiation or chemotherapeutic drugs. The kinase ataxia telangiectasia mutated (ATM) has a critical role in the activation of NF-kappaB in response to genotoxic stress. Two reports reveal key cytoplasmic functions of ATM in triggering IKK activation upon DNA damage. After induction of DSBs, ATM is exported from the nucleus and stimulates the ubiquitin ligase activity of tumor necrosis factor receptor-associated factor 6 (TRAF6) or X-linked inhibitor of apoptosis protein, which catalyze the auto-polyubiquitylation of TRAF6 and the polyubiquitylation of the IKK adaptor ELKS, respectively. Ubiquitylation promotes the assembly of signalosomes containing the kinase TAK1 (transforming growth factor b-activated kinase 1). These signalosomes are the site of activation of the cytosolic IKK complex, which stimulates NF-kappaB-dependent induction of a proliferative and antiapoptotic gene program. These studies show that ATM executes essential functions outside the nucleus in response to DSBs. PMID- 21245466 TI - BSCTV C2 attenuates the degradation of SAMDC1 to suppress DNA methylation mediated gene silencing in Arabidopsis. AB - Plant viruses are excellent tools for studying microbial-plant interactions as well as the complexities of host activities. Our study focuses on the role of C2 encoded by Beet severe curly top virus (BSCTV) in the virus-plant interaction. Using BSCTV C2 as bait in a yeast two-hybrid screen, a C2-interacting protein, S adenosyl-methionine decarboxylase 1 (SAMDC1), was identified from an Arabidopsis thaliana cDNA library. The interaction was confirmed by an in vitro pull-down assay and a firefly luciferase complemention imaging assay in planta. Biochemical analysis further showed that the degradation of the SAMDC1 protein was inhibited by MG132, a 26S proteasome inhibitor, and that C2 could attenuate the degradation of the SAMDC1 protein. Genetic analysis showed that loss of function of SAMDC1 resulted in reduced susceptibility to BSCTV infection and reduced viral DNA accumulation, similar to the effect of BSCTV C2 deficiency. Bisulfite sequencing analysis further showed that C2 deficiency caused enhanced DNA methylation of the viral genome in infected plants. We also showed that C2 can suppress de novo methylation in the FWA transgenic assay in the C2 transgene background. Overexpression of SAMDC1 can mimic the suppressive activity of C2 against green fluorescent protein-directed silencing. These results suggest that C2 interferes with the host defense mechanism of DNA methylation-mediated gene silencing by attenuating the 26S proteasome-mediated degradation of SAMDC1. PMID- 21245468 TI - The kinase SGK1 in the endoderm and mesoderm promotes ectodermal survival by down regulating components of the death-inducing signaling complex. AB - A balance between cell survival and apoptosis is essential for animal development. Although proper development involves multiple interactions between germ layers, little is known about the intercellular and intertissue signaling pathways that promote cell survival in neighboring or distant germ layers. We found that serum- and glucocorticoid-inducible kinase 1 (SGK1) promoted ectodermal cell survival during early Xenopus embryogenesis through a non-cell autonomous mechanism. Dorsal depletion of SGK1 in Xenopus embryos resulted in shortened axes and reduced head structures with defective eyes, and ventral depletion led to defective tail morphologies. Although the gene encoding SGK1 was mainly expressed in the endoderm and dorsal mesoderm, knockdown of SGK1 caused excessive apoptosis in the ectoderm. SGK1-depleted ectodermal explants showed little or no apoptosis, suggesting non-cell-autonomous effects of SGK1 on ectodermal cells. Microarray analysis revealed that SGK1 knockdown increased the expression of genes encoding FADD (Fas-associated death domain protein) and caspase-10, components of the death-inducing signaling complex (DISC). Inhibition of DISC function suppressed excessive apoptosis in SGK1-knockdown embryos. SGK1 acted through the transcription factor nuclear factor kappaB (NF-kappaB) to stimulate production of bone morphogenetic protein 7 (BMP7), and overexpression of BMP7 in SGK1-knockdown embryos reduced the abundance of DISC components. We show that phosphoinositide 3-kinase (PI3K) functioned upstream of SGK1, thus revealing an endodermal and mesodermal pathway from PI3K to SGK1 to NF-kappaB that produces BMP7, which promotes ectodermal survival by decreasing DISC function. PMID- 21245470 TI - Screening and characterization of high-affinity ssDNA aptamers against anthrax protective antigen. AB - The protective antigen (PA) of Bacillus anthracis is a secreted protein that functions as a critical virulence factor. Protective antigen has been selected as a biomarker in detecting bacterial infection. The in vitro selection method, systematic evolution of ligands by exponential enrichment (SELEX), was used to find single-stranded DNAs that were tightly bound to PA. After 8 rounds of the SELEX process with PA, 4 different oligonucleotides (referred to as aptamers) that contain a 30-residue ssDNA sequence were identified. Dissociation constant (K(d)) values with Cy3-attached aptamers were determined via fluorophotometry to be within a nanomolar range. The authors attempted to visualize the detection of PA using an aptamer-based enzyme-linked immunosorbent assay method, which has proven to be successful within a nanomolar K(d) value range. Furthermore, 2 of the 4 aptamers exhibited specificity to PA against bovine serum albumin and bovine serum. The results of this study demonstrate the analytical potential of an oligonucleotide-based biosensor for a wide variety of applications, particularly in diagnosing disease through specific protein biomarkers. PMID- 21245469 TI - A high-throughput fluorescence polarization assay for inhibitors of gyrase B. AB - DNA gyrase, a type II topoisomerase that introduces negative supercoils into DNA, is a validated antibacterial drug target. The holoenzyme is composed of 2 subunits, gyrase A (GyrA) and gyrase B (GyrB), which form a functional A(2)B(2) heterotetramer required for bacterial viability. A novel fluorescence polarization (FP) assay has been developed and optimized to detect inhibitors that bind to the adenosine triphosphate (ATP) binding domain of GyrB. Guided by the crystal structure of the natural product novobiocin bound to GyrB, a novel novobiocin-Texas Red probe (Novo-TRX) was designed and synthesized for use in a high-throughput FP assay. The binding kinetics of the interaction of Novo-TRX with GyrB from Francisella tularensis has been characterized, as well as the effect of common buffer additives on the interaction. The assay was developed into a 21-uL, 384-well assay format and has been validated for use in high throughput screening against a collection of Food and Drug Administration approved compounds. The assay performed with an average Z' factor of 0.80 and was able to identify GyrB inhibitors from a screening library. PMID- 21245471 TI - High-throughput fluorescence assay for small-molecule inhibitors of autophagins/Atg4. AB - Autophagy is an evolutionarily conserved process for catabolizing damaged proteins and organelles in a lysosome-dependent manner. Dysregulation of autophagy may cause various diseases, such as cancer and neurodegeneration. However, the relevance of autophagy to diseases remains controversial because of the limited availability of chemical modulators. Herein, the authors developed a fluorescence-based assay for measuring activity of the autophagy protease, autophagin-1(Atg4B). The assay employs a novel reporter substrate of Atg4B composed of a natural substrate (LC3B) fused to an assayable enzyme (PLA(2)) that becomes active upon cleavage by this cysteine protease. A high-throughput screening (HTS) assay was validated with excellent Z' factor (>0.7), remaining robust for more than 5 h and suitable for screening of large chemical libraries. The HTS assay was validated by performing pilot screens with 2 small collections of compounds enriched in bioactive molecules (n = 1280 for LopacTM and 2000 for SpectrumTM library), yielding confirmed hit rates of 0.23% and 0.70%, respectively. As counterscreens, PLA(2) and caspase-3 assays were employed to eliminate nonspecific inhibitors. In conclusion, the LC3B-PLA(2) reporter assay provides a platform for compound library screening for identification and characterization of Atg4B-specific inhibitors that may be useful as tools for interrogating the role of autophagy in disease models. PMID- 21245473 TI - Does intracerebral haemorrhage mimic benign dizziness presentations? A population based study. AB - OBJECTIVE: A principal reason to order a head CT scan for dizziness patients is to exclude stroke. As CT imaging is substantially limited in assessing for any acute lesions other than haemorrhage, the most important stroke syndrome adequately evaluated by CT is intracerebral haemorrhage (ICH). A population based stroke database was used to assess the frequency with which ICH might mimic a benign dizziness presentation. METHODS: The Brain Attack Surveillance in Corpus Christi project was used to identify cases of ICH from 1 January 2000 to 26 December 2007. The hospital records of ICH cases with a National Institutes of Health Stroke Scale of <2 were abstracted for more detailed information. Cases were classified as benign dizziness presentations when isolated dizziness and a normal general neurological examination were documented. RESULTS: Of 595 ICH cases, only 2.2% (13 of 595) had dizziness as the primary presenting symptom and a National Institutes of Health Stroke Scale of <2. No case mimicked a benign dizziness presentation. Only one case had isolated dizziness symptoms but this patient had dysmetria documented on the examination. All other cases had either focal or global neurological symptoms or examination abnormalities. CONCLUSIONS: This study provides further support for the notion that ICH is highly unlikely to mimic a benign dizziness presentation. Coupled with the limitations of CT to show acute ischaemia in the posterior fossa, these results suggest that screening for ICH may not be necessary in benign appearing dizziness presentations although more research is needed. PMID- 21245474 TI - ECG scar quantification correlates with cardiac magnetic resonance scar size and prognostic factors in Chagas' disease. AB - OBJECTIVE: To test the hypothesis that 12-lead ECG QRS scoring quantifies myocardial scar and correlates with disease severity in Chagas' heart disease. DESIGN: Patients underwent 12-lead ECG for QRS scoring and cardiac magnetic resonance with late gadolinium enhancement (CMR-LGE) to assess myocardial scar. SETTING: University of Sao Paulo Medical School, Sao Paulo, Brazil. PATIENTS: 44 Seropositive patients with Chagas' disease without a history of myocardial infarction and at low risk for coronary artery disease. MAIN OUTCOME MEASURES: Correlation between QRS score, CMR-LGE scar size and left ventricular ejection fraction. Relation between QRS score, heart failure (HF) class and history of ventricular tachycardia (VT). RESULTS: QRS score correlated directly with CMR-LGE scar size (R=0.69, p<0.0001) and inversely with left ventricular ejection fraction (R=-0.54, p=0.0002), which remained significant in the subgroup with conduction defects. Patients with class II or III HF had significantly higher QRS scores than those with class I HF (5.1+/-3.4 vs 2.1+/-3.1 QRS points (p=0.002)) and patients with a history of VT had significantly higher QRS scores than those without a history of VT (5.3+/-3.2% vs 2.6+/-3.4 QRS points (p=0.02)). A QRS score >=2 points had particularly good sensitivity and specificity (95% and 83%, respectively) for prediction of large CMR-LGE, and a QRS score >=7 points had particularly high specificity (92% and 89%, respectively) for predicting significant left ventricular dysfunction and history of VT. CONCLUSIONS: The wide availability of 12-lead ECG makes it an attractive screening tool and may enhance clinical risk stratification of patients at risk for more severe, symptomatic Chagas' heart disease. PMID- 21245475 TI - Applause sign: is it really specific for Parkinsonian disorders? Evidence from cortical dementias. AB - OBJECTIVE: The applause sign, originally reported as a specific sign of progressive supranuclear palsy (PSP), has recently been found in several parkinsonian disorders. Its nature is still uncertain. It has been interpreted as a motor perseveration or a form of apraxia. The present study aims to: (a) verify the specificity of the applause sign for parkinsonian disorders, examining the presence of the applause sign in cortical dementias which should be error free and (b) clarify the nature of the applause sign (resulting or not from apraxia). METHODS: 77 subjects were included: 10 PSP, 15 frontotemporal dementia (FTD), 29 Alzheimer's disease (AD) and 23 normal controls. The presence of apraxia was an exclusion criterion. All patients underwent a detailed neuropsychological examination, and cognitive performance was correlated to the applause sign. RESULTS: All patient groups showed the applause sign and differed significantly from normal subjects who were error free. No difference was found when comparing PSP with FTD and FTD with AD. AD differed significantly from PSP but they were not error free (31% of patients with AD showed the applause sign). The only correlation with background neuropsychology was found for measures of executive functions. CONCLUSIONS: The presence of the applause sign in cortical dementia does not confirm the specificity of the applause sign for parkinsonian disorders. The applause sign should be interpreted as a sign of frontal lobe dysfunction rather than a form of apraxia, and can likely be detected in any kind of disease which involves frontal lobe structures to some extent. PMID- 21245476 TI - A novel method to enhance informed consent: a prospective and randomised trial of form-based versus electronic assisted informed consent in paediatric endoscopy. AB - OBJECTIVES: To evaluate the adequacy of paediatric informed consent and its augmentation by a supplemental computer-based module in paediatric endoscopy. METHODS: The Consent-20 instrument was developed and piloted on 47 subjects. Subsequently, parents of 101 children undergoing first-time, diagnostic upper endoscopy performed under moderate IV sedation were prospectively and consecutively, blinded, randomised and enrolled into two groups that received either standard form-based informed consent or standard form-based informed consent plus a commercial (Emmi Solutions, Inc, Chicago, Il), sixth grade level, interactive learning module (electronic assisted consent). Anonymously and electronically, the subjects' anxiety (State Trait Anxiety Inventory), satisfaction (Modified Group Health Association of America), number of questions asked, and attainment of informed consent were assessed (Consent-20). Statistics were calculated using t test, paired t test, and Mann Whitney tests. RESULTS: The ability to achieve informed consent, as measured by the new instrument, was 10% in the control form-based consent group and 33% in the electronic assisted consent group (p<0.0001). Electronically assisting form-based informed consent did not alter secondary outcome measures of subject satisfaction, anxiety or number of questions asked in a paediatric endoscopy unit. CONCLUSIONS: This study demonstrates the limitations of form-based informed consent methods for paediatric endoscopy. It also shows that even when necessary information was repeated electronically in a comprehensive and standardised video, informed consent as measured by our instrument was incompletely achieved. The supplemental information did, however, significantly improve understanding in a manner that did not negatively impact workflow, subject anxiety or subject satisfaction. Additional study of informed consent is required. PMID- 21245477 TI - Gametes or organs? How should we legally classify ovaries used for transplantation in the USA? AB - Ovarian tissue transplantation is an experimental procedure that can be used to treat both infertility and premature menopause. Working within the current legal framework in the USA, I examine whether ovarian tissue should be legally treated like gametes or organs in the case of ovarian tissue transplantation between two women. One option is to base classification upon its intended use: ovarian tissue used to treat infertility would be classified like gametes, and ovarian tissue used to treat premature menopause would be classified like organs. In the end, however, I argue that this approach will not work because it engenders too many legal, cultural and logistical concerns and that, at least for the near future, we should treat ovarian tissue like gametes. PMID- 21245478 TI - Associations of hip osteoarthritis with history of recurrent exposure to manual handling of loads over 20 kg and work participation: a population-based study of men and women. AB - OBJECTIVES: We reviewed work histories of manual handling of loads >20 kg in relation to hip osteoarthritis by age, exposure and work participation. METHODS: A nationally representative sample of 3110 Finnish men and 3446 women aged 30-97 was recruited. Diagnosis of hip osteoarthritis was based on standardised clinical examination by trained physicians. Previous exposure to physically loading work was evaluated through interviews. Logistic regression was used to estimate associations between work factors and hip osteoarthritis. RESULTS: 1.9% of men and 2.1% of women had hip osteoarthritis. Almost half the men and a quarter of the women had recurrently handled heavy loads at work. Subjects who had manually handled loads >20 kg had a 1.8-fold increased risk of hip osteoarthritis compared to non-exposed references, when age, body mass index, traumatic fractures and smoking were accounted for. Results were similar for men (OR 2.0; 95% CI 1.0 to 4.0) and women (1.8; 1.1 to 2.8). In a sub-analysis of subjects with hip replacement, the OR was 1.7 (1.0 to 2.9). Risk increased first after 12 years' exposure: among men it was 2.2 (0.8 to 5.9) for 13-24 years' exposure, and 2.3 (1.2 to 4.3) for >24 years' exposure. Among women it was 3.8 (1.7 to 8.1) for 13 24 years' exposure. Work participation among men aged <60 years with hip osteoarthritis was 20% lower compared with subjects without osteoarthritis. CONCLUSIONS: A work history of manual handling of loads >20 kg showed a strong association with hip osteoarthritis in all age groups except the youngest. PMID- 21245479 TI - Differential requirements for CD45 in NK-cell function reveal distinct roles for Syk-family kinases. AB - The protein tyrosine phosphatase CD45 is an important regulator of Src-family kinase activity. We found that in the absence of CD45, natural killer (NK) cells are defective in protecting the host from mouse cytomegalovirus infection. We show that although CD45 is necessary for all immunoreceptor tyrosine-based activation motif (ITAM)-specific NK-cell functions and processes such as degranulation, cytokine production, and expansion during viral infection, the impact of CD45 deficiency on ITAM signaling differs depending on the downstream function. CD45-deficient NK cells are normal in their response to inflammatory cytokines when administered ex vivo and in the context of viral infection. Syk and zeta chain-associated protein kinase 70 (Zap70) are thought to play redundant roles in transmitting ITAM signals in NK cells. We show that Syk, but not Zap70, controls the remaining CD45-independent, ITAM-specific NK-cell functions, demonstrating a functional difference between these 2 Syk-kinase family members in primary NK cells. PMID- 21245480 TI - Gene expression analysis uncovers similarity and differences among Burkitt lymphoma subtypes. AB - Burkitt lymphoma (BL) is classified into 3 clinical subsets: endemic, sporadic, and immunodeficiency-associated BL. So far, possible differences in their gene expression profiles (GEPs) have not been investigated. We studied GEPs of BL subtypes, other B-cell lymphomas, and B lymphocytes; first, we found that BL is a unique molecular entity, distinct from other B-cell malignancies. Indeed, by unsupervised analysis all BLs clearly clustered apart of other lymphomas. Second, we found that BL subtypes presented slight differences in GEPs. Particularly, they differed for genes involved in cell cycle control, B-cell receptor signaling, and tumor necrosis factor/nuclear factor kappaB pathways. Notably, by reverse engineering, we found that endemic and sporadic BLs diverged for genes dependent on RBL2 activity. Furthermore, we found that all BLs were intimately related to germinal center cells, differing from them for molecules involved in cell proliferation, immune response, and signal transduction. Finally, to validate GEP, we applied immunohistochemistry to a large panel of cases and showed that RBL2 can cooperate with MYC in inducing a neoplastic phenotype in vitro and in vivo. In conclusion, our study provided substantial insights on the pathobiology of BLs, by offering novel evidences that may be relevant for its classification and possibly future treatment. PMID- 21245481 TI - beta2-Glycoprotein-1 autoantibodies from patients with antiphospholipid syndrome are sufficient to potentiate arterial thrombus formation in a mouse model. AB - Antiphospholipid syndrome is characterized by thrombosis, recurrent fetal loss, and the presence of the lupus anticoagulant, anticardiolipin antibodies, or anti beta(2)-glycoprotein-1 (anti-beta(2)-GP1) antibodies. Although anti-beta(2)-GP1 antibodies have been documented as a biomarker for diagnosis of antiphospholipid syndrome, their direct role in the pathogenesis of thrombosis is unknown. We have demonstrated using intravital microscopy that anti-beta(2)-GP1 autoantibodies purified from the sera of patients with antiphospholipid syndrome complicated by thrombosis greatly amplify thrombus size after laser-induced vessel wall injury in live mice. Anti-beta(2)-GP1 autoantibodies from 3 patients with antiphospholipid syndrome were affinity-purified using human beta(2)-GP1 bound to agarose. The effects of purified anti-beta(2)-GP1 IgG autoantibodies, of anti beta(2)-GP1-depleted IgG, and of IgG from normal human sera on thrombus formation were measured in mice after arterial injury in the cremaster muscle. Before injury, purified anti-beta(2)-GP1 IgG autoantibodies, anti-beta(2)-GP1 antibody depleted IgG, or IgG from normal human sera were infused. Increasing amounts of purified anti-beta(2)-GP1 autoantibodies increased thrombus size in a dose dependent manner, whereas neither anti-beta(2)-GP1 antibody-depleted IgG nor IgG from normal serum affected thrombus size. These results indicate that anti beta(2)-GP1 IgG autoantibodies in antiphospholipid syndrome patient sera are not only a marker of antiphospholipid syndrome but are directly involved in the pathogenesis of thrombosis. PMID- 21245482 TI - Blunted hepcidin response to inflammation in the absence of Hfe and transferrin receptor 2. AB - The induction of the iron-regulatory peptide hepcidin by proinflammatory cytokines is thought to result in the withholding of iron from invading pathogens. Hfe and transferrin receptor 2 (Tfr2) are involved in the homeostatic regulation of hepcidin and their disruption causes hereditary hemochromatosis (HH). To determine whether either Hfe or Tfr2 is involved in the inflammatory pathway regulating hepcidin, we analyzed the effect of inflammation in 3 mouse models of HH. The inflammatory response and indicators of iron homeostasis were measured in wild-type, Hfe(-/-), Tfr2(-/-), and Hfe(-/-)/Tfr2(-/-) mice injected with lipopolysaccharide (LPS). The administration of LPS significantly reduced serum iron in wild-type and Hfe(-/-) mice, with smaller reductions in Tfr2(-/-) and Hfe(-/-)/Tfr2(-/-) mice. Low basal levels of hepcidin in the Hfe(-/-)/Tfr2(-/ ) mice were increased in response to LPS, but remained significantly lower than in the other strains of mice. These results suggest that despite the absence of Hfe and Tfr2, hepcidin is responsive to inflammation; however, the low basal expression and subsequent low levels of circulating hepcidin are insufficient to reduce serum iron effectively. This suggests that in HH, the iron-withholding response to invading pathogens may be inadequate, and this is especially the case in the absence of both Hfe and Tfr2. PMID- 21245483 TI - Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new. AB - GVHD is a syndrome that results from minor and major histocompatibility complex incompatibilities between the donor and recipient. More than 50 years after its initial description, the pathophysiology of GVHD remains poorly understood. Nonetheless, donor T cells have been shown to be critical to the pathophysiology of acute and chronic GVHD, yet precisely how they function remains unclear. The effector mechanisms by which donor T cells mediate tissue inflammation is even less well understood. Identification of several new lineages of CD4(+) T cells made in the past decade and their roles in the pathophysiology of T cell-mediated diseases has shed new light on these effector mechanisms. In this review, we summarize the recent descriptions of these T-cell lineages and the current data supporting their role in acute and to a lesser extent chronic GVHD. Investigations into the activity of these new T-cell lineages may provide more rationale approaches to the treatment or prevention of GVHD. PMID- 21245484 TI - Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling. AB - CD28 costimulation is required for the generation of naturally derived regulatory T cells (nTregs) in the thymus through lymphocyte-specific protein tyrosine kinase (Lck) signaling. However, it is not clear how CD28 costimulation regulates the generation of induced Tregs (iTregs) from naive CD4 T-cell precursors in the periphery. To address this question, we induced iTregs (CD25(+)Foxp3(+)) from naive CD4 T cells (CD25(-)Foxp3(-)) by T-cell receptor stimulation with additional transforming growth factorbeta (TGFbeta) in vitro, and found that the generation of iTregs was inversely related to the level of CD28 costimulation independently of IL-2. Using a series of transgenic mice on a CD28-deficient background that bears wild-type or mutated CD28 in its cytosolic tail that is incapable of binding to Lck, phosphoinositide 3-kinase (PI3K), or IL-2-inducible T-cell kinase (Itk), we found that CD28-mediated Lck signaling plays an essential role in the suppression of iTreg generation under strong CD28 costimulation. Furthermore, we demonstrate that T cells with the CD28 receptor incapable of activating Lck were prone to iTreg induction in vivo, which contributed to their reduced ability to cause graft-versus-host disease. These findings reveal a novel mechanistic insight into how CD28 costimulation negatively regulates the generation of iTregs, and provide a rationale for promoting T-cell immunity or tolerance by regulating Tregs through targeting CD28 signaling. PMID- 21245485 TI - Expression of p16(INK4a) prevents cancer and promotes aging in lymphocytes. AB - Previous authors have suggested that tumor suppressor expression promotes aging while preventing cancer, but direct experimental support for this cancer-aging hypothesis has been elusive. Here, by using somatic, tissue-specific inactivation of the p16(INK4a) tumor suppressor in murine T- or B-lymphoid progenitors, we report that ablation of p16(INK4a) can either rescue aging or promote cancer in a lineage-specific manner. Deletion of p16(INK4a) in the T lineage ameliorated several aging phenotypes, including thymic involution, decreased production of naive T cells, reduction in homeostatic T-cell proliferation, and attenuation of antigen-specific immune responses. Increased T-cell neoplasia was not observed with somatic p16(INK4a) inactivation in T cells. In contrast, B lineage-specific ablation of p16(INK4a) was associated with a markedly increased incidence of systemic, high-grade B-cell neoplasms, which limited studies of the effects of somatic p16(INK4a) ablation on B-cell aging. Together, these data show that expression of p16(INK4a) can promote aging and prevent cancer in related lymphoid progeny of a common stem cell. PMID- 21245486 TI - NK314 potentiates antitumor activity with adult T-cell leukemia-lymphoma cells by inhibition of dual targets on topoisomerase II{alpha} and DNA-dependent protein kinase. AB - Adult T-cell leukemia-lymphoma (ATL) is an aggressive disease, incurable by standard chemotherapy. NK314, a new anticancer agent possessing inhibitory activity specific for topoisomerase IIalpha (Top2alpha), inhibited the growth of various ATL cell lines (50% inhibitory concentration: 23-70nM) with more potent activity than that of etoposide. In addition to the induction of DNA double strand breaks by inhibition of Top2alpha, NK314 induced degradation of the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), resulting in impaired DNA double-strand break repair. The contribution of DNA-PK to inhibition of cell growth was affirmed by the following results: NK314 inhibited cell growth of M059J (a DNA-PKcs-deficient cell line) and M059K (a cell line with DNA-PKcs present) with the same potency, whereas etoposide exhibited weak inhibition of cell growth with M059K cells. A DNA-PK specific inhibitor, NU7026, enhanced inhibitory activity of etoposide on M059K as well as on ATL cells. These results suggest that NK314 is a dual inhibitor of Top2alpha and DNA-PK. Because ATL cells express a high amount of DNA-PKcs, NK314 as a dual molecular targeting anticancer agent is a potential therapeutic tool for treatment of ATL. PMID- 21245487 TI - Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. AB - Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) is dictated by patient characteristics, prior therapy, and response to prior therapy. We report the final analysis of combined fludarabine, cyclophosphamide, and rituximab (FCR) for previously treated patients with CLL and identify patients who benefit most from this therapy. We explore efficacy of FCR in patients beyond first relapse, patients with prior exposure to fludarabine and alkylating agent combinations, and patients with prior exposure to rituximab. The FCR regimen was administered to 284 previously treated patients with CLL. Patients were assessed for response and progression by 1996 National Cancer Institute-Working Group (NCI-WG) criteria for CLL and followed for survival. The overall response rate was 74%, with 30% complete remission. The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months. Subgroup analyses indicated that the following patients were most suitable for FCR treatment: patients with up to 3 prior treatments, fludarabine-sensitive patients irrespective of prior rituximab exposure, and patients without chromosome 17 abnormalities. FCR is an active and well-tolerated therapy for patients with relapsed CLL. The addition of rituximab to FC improved quality and durability of response in this patient population. PMID- 21245488 TI - AML1/ETO induces self-renewal in hematopoietic progenitor cells via the Groucho related amino-terminal AES protein. AB - The most frequent translocation t(8;21) in acute myeloid leukemia (AML) generates the chimeric AML1/ETO protein, which blocks differentiation and induces self renewal in hematopoietic progenitor cells. The underlying mechanisms mediating AML1/ETO-induced self-renewal are largely unknown. Using expression microarray analysis, we identified the Groucho-related amino-terminal enhancer of split (AES) as a consistently up-regulated AML1/ETO target. Elevated levels of AES mRNA and protein were confirmed in AML1/ETO-expressing leukemia cells, as well as in other AML specimens. High expression of AES mRNA or protein was associated with improved survival of AML patients, even in the absence of t(8;21). On a functional level, knockdown of AES by RNAi in AML1/ETO-expressing cell lines inhibited colony formation. Similarly, self-renewal induced by AML1/ETO in primary murine progenitors was inhibited when AES was decreased or absent. High levels of AES expression enhanced formation of immature colonies, serial replating capacity of primary cells, and colony formation in colony-forming unit spleen assays. These findings establish AES as a novel AML1/ETO-induced target gene that plays an important role in the self-renewal phenotype of t(8;21) positive AML. PMID- 21245489 TI - Fruit and vegetable intake reduces risk of fatal coronary heart disease. PMID- 21245491 TI - Recovering from conflict in romantic relationships: a developmental perspective. AB - This study adopted a developmental perspective on recovery from conflict in romantic relationships. Participants were 73 young adults (target participants), studied since birth, and their romantic partners. A novel observational coding scheme was used to evaluate each participant's degree of conflict recovery, operationalized as the extent to which the participant disengaged from conflict during a 4-min "cool-down" task immediately following a 10-min conflict discussion. Conflict recovery was systematically associated with developmental and dyadic processes. Targets who were rated as securely attached more times in infancy recovered from conflict better, as did their romantic partners. Concurrently, having a romantic partner who displayed better recovery predicted more positive relationship emotions and greater relationship satisfaction. Prospectively, target participants' early attachment security and their partners' degree of conflict recovery interacted to predict relationship stability 2 years later, such that having a partner who recovered from conflict better buffered targets with insecure histories. PMID- 21245490 TI - Fruit and vegetable intake and mortality from ischaemic heart disease: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Heart study. AB - AIMS: A higher intake of fruits and vegetables has been associated with a lower risk of ischaemic heart disease (IHD), but there is some uncertainty about the interpretation of this association. The objective was to assess the relation between fruit and vegetable intake and risk of mortality from IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study. METHODS AND RESULTS: After an average of 8.4 years of follow-up, there were 1636 deaths from IHD among 313 074 men and women without previous myocardial infarction or stroke from eight European countries. Participants consuming at least eight portions (80 g each) of fruits and vegetables a day had a 22% lower risk of fatal IHD [relative risk (RR) = 0.78, 95% confidence interval (CI): 0.65-0.95] compared with those consuming fewer than three portions a day. After calibration of fruit and vegetable intake to account for differences in dietary assessment between the participating centres, a one portion (80 g) increment in fruit and vegetable intake was associated with a 4% lower risk of fatal IHD (RR = 0.96, 95% CI: 0.92 1.00, P for trend = 0.033). CONCLUSION: Results from this large observational study suggest that a higher intake of fruits and vegetables is associated with a reduced risk of IHD mortality. Whether this association is causal and, if so, the biological mechanism(s) by which fruits and vegetables operate to lower IHD risks remains unclear. PMID- 21245492 TI - Controlling the unconscious: attentional task sets modulate subliminal semantic and visuomotor processes differentially. AB - Are unconscious processes susceptible to attentional influences? In two subliminal priming experiments, we investigated whether task sets differentially modulate the sensitivity of unconscious processing pathways. We developed a novel procedure for masked semantic priming of words (Experiment 1) and masked visuomotor priming of geometrical shapes (Experiment 2). Before presentation of the masked prime, participants performed an induction task in which they attended to either semantic or perceptual object features designed to activate a semantic or perceptual task set, respectively. Behavioral and electrophysiological effects showed that the induction tasks differentially modulated subliminal priming: Semantic priming, which involves access to conceptual meaning, was found after the semantic induction task but not after the perceptual induction task. Visuomotor priming was observed after the perceptual induction task but not after the semantic induction task. These results demonstrate that unconscious cognition is influenced by attentional control. Unconscious processes in perceptual and semantic processing streams are coordinated congruently with higher-level action goals. PMID- 21245493 TI - Cleansing the soul by hurting the flesh: the guilt-reducing effect of pain. PMID- 21245494 TI - Specifying the attentional selection that moderates the fearlessness of psychopathic offenders. AB - Our previous research demonstrated that psychopathy-related fear deficits involve abnormalities in attention that undermine sensitivity to peripheral information. In the present study, we specified this attention-mediated abnormality in a new sample of 87 prisoners assessed with Hare's Psychopathy Checklist-Revised (Hare, 2003). We measured fear-potentiated startle (FPS) under four conditions that crossed attentional focus (threat vs. alternative) with early versus late presentation of threat cues. The psychopathic deficit in FPS was apparent only in the early-alternative-focus condition, in which threat cues were presented after the alternative goal-directed focus was established. Furthermore, psychopathy interacted with working memory capacity in the late-alternative-focus condition, which suggests that individuals high in psychopathy and working memory capacity were able to maintain a set-related alternative focus that reduced FPS. The results not only provide new evidence that attention moderates the fearlessness of psychopathic individuals, but also implicate an early attention bottleneck as a proximal mechanism for deficient response modulation in psychopathy. PMID- 21245495 TI - Idealizing parenthood to rationalize parental investments. AB - Although raising children has largely negative effects on parents' emotional well being, parenthood is often idealized as a uniquely emotionally rewarding role. We tested the hypothesis that belief in myths idealizing parenthood helps parents cope with the dissonance aroused by the high financial cost of raising children. In Study 1, parents endorsed the idealization of parenthood more when only the costs of parenting were made salient than when both the costs of parenting and the long-term benefits of having children were made salient. When dissonant feelings were measured before idealization of parenthood, these feelings mediated the influence of the salient information on idealization of parenthood. In Study 2, participants reported greater enjoyment of the time they spent with their children and intended to spend more leisure time with their children when only parenting costs were made salient than when the long-term benefits of having children were also made salient (or when no costs or benefits of having children were made salient). We discuss the implications of our results for parental investment theory and for the propagation of myths idealizing parenthood. PMID- 21245497 TI - Energetics and passive dynamics of the ankle in downhill walking. AB - This study investigated the energetics of the human ankle during the stance phase of downhill walking with the goal of modeling ankle behavior with a passive spring and damper mechanism. Kinematic and kinetic data were collected on eight male participants while walking down a ramp with inclination varying from 0 degrees to 8 degrees . The ankle joint moment in the sagittal plane was calculated using inverse dynamics. Mechanical energy injected or dissipated at the ankle joint was computed by integrating the power across the duration of the stance phase. The net mechanical energy of the ankle was approximately zero for level walking and monotonically decreased (i.e., became increasingly negative) during downhill walking as the slope decreased. The indication is that the behavior of the ankle is energetically passive during downhill walking, playing a key role in dissipating energy from one step to the next. A passive mechanical model consisting of a pin joint coupled with a revolute spring and damper was fit to the ankle torque and its parameters were estimated for each downhill slope using linear regression. The passive model demonstrated good agreement with actual ankle dynamics as indicated by low root-mean-square error values. These results indicate the stance phase behavior of the human ankle during downhill walking may be effectively duplicated by a passive mechanism with appropriately selected spring and damping characteristics. PMID- 21245496 TI - Natural killer cells mediate severe liver injury in a murine model of halothane hepatitis. AB - Severe halothane (HAL)-induced hepatotoxicity occurs in one in 6000-30,000 patients by an unknown mechanism. Female sex is a risk factor in humans and rodents. We tested the hypothesis that a sex difference in natural killer (NK) cell activity contributes to HAL-induced liver injury. HAL (15 mmol/kg, ip) treatment resulted in severe liver injury by 12 h in female, wild-type BALB/cJ mice, and the magnitude of liver injury varied with stage of the estrous cycle. Ovariectomized (OVX) mice developed only mild liver injury. Plasma interferon gamma (IFN-gamma) was elevated 10-fold in HAL-treated females compared with similarly treated male mice or with OVX female mice. IFN-gamma knockout mice were resistant to severe HAL-induced liver injury. The deactivation of NK cells with anti-asialo GM1 treatment attenuated liver injury and the increase in plasma IFN gamma compared with immunoglobulin G-treated control mice. Mice with a mutated form of perforin, a protein involved in granule-mediated cytotoxicity, were protected from severe liver injury. Furthermore, HAL increased the activity of NK cells in vivo, as indicated by increased surface expression of CD69, an early activation marker. In response to HAL, NK cell receptor ligands on the surface of hepatocytes were expressed in a manner that can activate NK cells. These results confirm the sexual dimorphic hepatotoxic response to HAL in mice and suggest that IFN-gamma and NK cells have essential roles in the development of severe HAL induced hepatotoxicity. PMID- 21245498 TI - Influence of custom foot orthotic intervention on lower extremity intralimb coupling during a 30-minute run. AB - The purpose of this study was to analyze the influence of a custom foot orthotic (CFO) intervention on lower extremity intralimb coupling during a 30-min run in a group of injured runners and to compare the results to a control group of healthy runners. Three-dimensional kinematic data were collected during a 30-min run on healthy female runners (Shoe-only) and a group of female runners who had a recent history of overuse injury (Shoe-only and Shoe with custom foot orthoses). Results from the study revealed that the coordination variability and pattern for the some couplings were influenced by history of injury, foot orthotic intervention and the duration of the run. These data suggest that custom foot orthoses worn by injured runners may play a role in the maintenance of coordination variability of the tibia (transverse plane) and calcaneus (frontal plane) coupling during the Early Stance phase. In addition, it appears that the coupling angle between the knee (transverse plane) and rearfoot (frontal plane) joints becomes more symmetrical in the late stance phase as a run progresses. PMID- 21245499 TI - A comparison of craniocervical and cervicothoracic muscle strength in healthy individuals. AB - The purpose of this study was to compare maximal torque exerted about the craniocervical (CC) and cervicothoracic (CT) axes in the sagittal plane using a novel dynamometry device. Maximal voluntary contraction (MVC) recordings in newton-meters (N.m) were measured in 20 males and 20 females for each of 4 tests: CT extension, CT flexion, CC extension, CC flexion. Twenty of the volunteers repeated the testing procedure on a second occasion to determine the test-retest repeatability of the measures. MVC recordings at the CT axis (extension, 30.24 +/ 12.15 N.m; flexion, 18.90 +/- 8.21 N.m) were 1.4-2 times greater than recordings at the CC axis (extension, 16.46 +/- 7.26 N.m; flexion, 13.34 +/- 5.97 N.m). Extensor to flexor strength ratios reduced from 1.75 at the CT axis to 1.24 at the CC axis, but were similar for both males and females. Good to excellent test retest repeatability was demonstrated for all tests (ICC = 0.75-0.99, SEM = 0.50 2.44 N.m). Consistent with differences in the muscle morphology at the CC and CT axes, torque exerted about these axes differ. Separate measurement of torque about these axes potentially offers a more comprehensive profile of cervical muscle strength. PMID- 21245500 TI - Comparison of lower extremity kinematic curves during overground and treadmill running. AB - Researchers conduct gait analyses utilizing both overground and treadmill modes of running. Previous studies comparing these modes analyzed discrete variables. Recently, techniques involving quantitative pattern analysis have assessed kinematic curve similarity in gait. Therefore, the purpose of this study was to compare hip, knee and rearfoot 3-D kinematics between overground and treadmill running using quantitative kinematic curve analysis. Twenty runners ran at 3.35 m/s +/- 5% during treadmill and overground conditions while right lower extremity kinematics were recorded. Kinematics of the hip, knee and rearfoot at footstrike and peak were compared using intraclass correlation coefficients. Kinematic curves during stance phase were compared using the trend symmetry method within each subject. The overall average trend symmetry was high, 0.94 (1.0 is perfect symmetry) between running modes. The transverse plane and knee frontal plane exhibited lower similarity (0.86-0.90). Other than a 4.5 degree reduction in rearfoot dorsiflexion at footstrike during treadmill running, all differences were <=1.5 degrees. 17/18 discrete variables exhibited modest correlations (>0.6) and 8/18 exhibited strong correlations (>0.8). In conclusion, overground and treadmill running kinematic curves were generally similar when averaged across subjects. Although some subjects exhibited differences in transverse plane curves, overall, treadmill running was representative of overground running for most subjects. PMID- 21245501 TI - Quantification of patellofemoral joint reaction forces during functional activities using a subject-specific three-dimensional model. AB - The purpose of this study was to describe an imaging based, subject specific model that was developed to quantify patellofemoral joint reaction forces (PFJRF's). The secondary purpose was to test the model in a group of healthy individuals while performing various functional tasks. Twenty healthy subjects (10 males, 10 females) were recruited. All participants underwent two phases of data collection: 1) magnetic resonance imaging of the knee, patellofemoral joint, and thigh, and 2) kinematic, kinetic and EMG analysis during walking, running, stair ascent, and stair descent. Using data obtained from MRI, a subject specific representation of the extensor mechanism was created. Individual gait data were used to drive the model (via an optimization routine) and three-dimensional vasti muscle forces and subsequent three-dimensional PFJRF's were computed. The average peak PFJRF was found to be highest during running (58.2 N/kg-bwt), followed by stair ascent (33.9 N/kg-bwt), stair descent (27.9 N/kg-bwt), and walking (10.1 N/kg-bwt). No differences were found between males and females. For all conditions, the direction of the PFJRF was always in the posterior, superior, and lateral directions. The posterior component of the PFJRF always had the greatest magnitude, followed by superior and lateral components. Our results indicate that estimates of the magnitude and direction of the PFJRF during functional tasks can be obtained using a 3D-imaging based model. PMID- 21245502 TI - Validation of a wireless head acceleration measurement system for use in soccer play. AB - Soccer heading has been studied previously with conflicting results. One major issue is the lack of knowledge regarding what actually occurs biomechanically during soccer heading impacts. The purpose of the current study is to validate a wireless head acceleration measurement system, head impact telemetry system (HITS) that can be used to collect head accelerations during soccer play. The HIT system was fitted to a Hybrid III (HIII) head form that was instrumented with a 3 2-2-2 accelerometer setup. Fifteen impact conditions were tested to simulate impacts commonly experienced during soccer play. Linear and angular acceleration were calculated for both systems and compared. Root mean square (RMS) error and cross correlations were also calculated and compared for both systems. Cross correlation values were very strong with r = .95 +/- 0.02 for ball to head forehead impacts and r = .96 +/- 0.02 for head to head forehead impacts. The systems showed a strong relationship when comparing RMS error, linear head acceleration, angular head acceleration, and the cross correlation values. PMID- 21245503 TI - The effect of the frontal plane tibiofemoral angle and varus knee moment on the contact stress and strain at the knee cartilage. AB - Subject-specific models were developed and finite element analysis was performed to observe the effect of the frontal plane tibiofemoral angle on the normal stress, Tresca shear stress and normal strain at the surface of the knee cartilage. Finite element models were created for three subjects with different tibiofemoral angle and physiological loading conditions were defined from motion analysis and muscle force mathematical models to simulate static single-leg stance. The results showed that the greatest magnitude of the normal stress, Tresca shear stress and normal strain at the medial compartment was for the varus aligned individual. Considering the lateral knee compartment, the individual with valgus alignment had the largest stress and strain at the cartilage. The present investigation is the first known attempt to analyze the effects of tibiofemoral alignment during single-leg support on the contact variables of the cartilage at the knee joint. The method could be potentially used to help identify individuals most susceptible to osteoarthritis and to prescribe preventive measures. PMID- 21245504 TI - Gender comparisons between unilateral and bilateral landings. AB - The increased number of women participating in sports has led to a higher knee injury rate in women compared with men. Among these injuries, those occurring to the ACL are commonly observed during landing maneuvers. The purpose of this study was to determine gender differences in landing strategies during unilateral and bilateral landings. Sixteen male and 17 female recreational athletes were recruited to perform unilateral and bilateral landings from a raised platform, scaled to match their individual jumping abilities. Three-dimensional kinematics and kinetics of the dominant leg were calculated during the landing phase and reported as initial ground contact angle, ranges of motion (ROM) and peak moments. Lower extremity energy absorption was also calculated for the duration of the landing phase. Results showed that gender differences were only observed in sagittal plane hip and knee ROM, potentially due to the use of a relative drop height versus the commonly used absolute drop height. Unilateral landings were characterized by significant differences in hip and knee kinematics that have been linked to increased injury risk and would best be classified as "stiff" landings. The ankle musculature was used more for impact absorption during unilateral landing, which required increased joint extension at touchdown and may increase injury risk during an unbalanced landing. In addition, there was only an 11% increase in total energy absorption during unilateral landings, suggesting that there was a substantial amount of passive energy transfer during unilateral landings. PMID- 21245505 TI - How gate setup and turn radii influence energy dissipation in slalom ski racing. AB - This study examined whether gate setup and turn radii influence energy dissipation in slalom skiing. 3D kinematical measurements were performed over two runs on the same slope in a WC slalom competition with two different gate setups: 1) open gates (OG) and 2) open gates with a delayed gate (DG). Using the arithmetic mean of the skis' turn radii (R(AMS)) the slalom turns were divided into 1) initiation phase (R(AMS) > 15 m) and steering phase (R(AMS) < 15 m). The results show differences between OG and DG regarding: 1) the absolute center of gravity's (CG) velocity, 2) absolute acceleration, 3) CG turn radii and R(AMS), 4) ground reaction forces (F) and 5) energy dissipation during skiing (all p < .05). In both gate setups the highest F and the highest energy dissipation were present in the steering phase, whereas the correlation between R(AMS) and energy dissipation was low (OG: r = .364 and DG: r = .214, both p < .001). In summary, compared with plain open gates, an additional delayed gate prolonged the turn radii and decreased energy dissipation in the beginning of the initiation phase, despite the fact that the relative frequency of occurrence of the highest energy dissipation was higher in DG. PMID- 21245506 TI - Three-dimensional kinematics of the breast during a two-step star jump. AB - Anecdotal reports suggest two-step star jumps cause excessive breast movement and discomfort, leading to recommendations for this activity as a diagnostic tool to determine effective breast support in a retail environment. The aim was to investigate multiplanar bare-breast kinematics during the two-step star jump and to establish the relationship between breast kinematics, discomfort and cup size. Thirty-nine females completed five two-step star jumps with no breast support after which breast discomfort was rated. To establish relative breast kinematics infrared cameras tracked the 3D co-ordinates of breast and body markers. Maximum resultant breast displacement, velocity and acceleration during jumping reached 18.7 cm, 93.1 cm.s-1 and 3.6 g, respectively. Significantly more vertical breast displacement (p < 0.01) and velocity (p < 0.01) occurred compared with mediolateral and anteroposterior kinematics. Breast discomfort increased as cup size increased (r = .61). Two-step star jumping stimulated multiplanar breast kinematics and high levels of breast discomfort. Therefore, this activity may be useful in a retail outlet to determine the function and comfort of a sports bra. PMID- 21245507 TI - Dynamics and energetics of impacts in crutch walking. AB - The impulsive dynamics associated with the impact of the crutch with the ground is an important topic of research, since this is known to be the main cause of energy loss during crutch gait. In this article, a four-segmental 2D model based on anthropometric body segment parameters is used to analyze various dynamics aspects of such impact. For this purpose, a novel formulation based on the decomposition of the tangent space of the biomechanical system to two subspaces associated with the constrained and admissible motions is developed. Detailed numerical analysis is presented to discuss the effects of body configuration and crutch length on the kinetic energy redistribution, velocity change and impulsive contact forces generated. The conclusions reached via this analysis give guidelines for optimal crutch selection or crutch-use teaching that can be applied to injured subjects. For instance, to reduce energy consumption which leads to a reduction of muscular fatigue. PMID- 21245508 TI - Kinematic and kinetic analysis of the fouette turn in classical ballet. AB - The fouette turn in classical ballet dancing is a continuous turn with the whipping of the gesture leg and the arms and the bending and stretching of the supporting leg. The knowledge of the movement intensities of both legs for the turn would be favorable for the conditioning of the dancer's body. The purpose of this study was to estimate the intensities. The hypothesis of this study was that the intensities were higher in the supporting leg than in the gesture leg. The joint torques of both legs were determined in the turns performed by seven experienced female classical ballet dancers with inverse dynamics using three high-speed cine cameras and a force platform. The hip abductor torque, knee extensor and plantar flexor torques of the supporting leg were estimated to be exerted up to their maximum levels and the peaks of the torques were larger than the peaks of their matching torques of the gesture leg. Thus, the hypothesis was partly supported. Training of the supporting leg rather than the gesture leg would help ballet dancers perform many revolutions of the fouette turn continuously. PMID- 21245509 TI - The influence of seat configuration on maximal average crank power during pedaling: a simulation study. AB - Manipulating seat configuration (i.e., seat tube angle, seat height and pelvic orientation) alters the bicycle-rider geometry, which influences lower extremity muscle kinematics and ultimately muscle force and power generation during pedaling. Previous studies have sought to identify the optimal configuration, but isolating the effects of specific variables on rider performance from the confounding effect of rider adaptation makes such studies challenging. Of particular interest is the influence of seat tube angle on rider performance, as seat tube angle varies across riding disciplines (e.g., road racers vs. triathletes). The goals of the current study were to use muscle-actuated forward dynamics simulations of pedaling to 1) identify the overall optimal seat configuration that produces maximum crank power and 2) systematically vary seat tube angle to assess how it influences maximum crank power. The simulations showed that a seat height of 0.76 m (or 102% greater than trochanter height), seat tube angle of 85.1 deg, and pelvic orientation of 20.5 deg placed the major power-producing muscles on more favorable regions of the intrinsic force-length velocity relationships to generate a maximum average crank power of 981 W. However, seat tube angle had little influence on crank power, with maximal values varying at most by 1% across a wide range of seat tube angles (65 to 110 deg). The similar power values across the wide range of seat tube angles were the result of nearly identical joint kinematics, which occurred using a similar optimal seat height and pelvic orientation while systematically shifting the pedal angle with increasing seat tube angles. PMID- 21245510 TI - High-level swimmers' kinetic efficiency during the underwater phase of a grab start. AB - The purpose of the present work was to study swimmers' efficiency during the underwater phase of the grab start. Eight high-level swimmers participated in this study. They performed two types of start: a regular grab start (with underwater leg propulsion after the glide) and a grab start with no underwater movement (swimmers had to remain in a streamlined position). Four cameras filmed the entire underwater phase of all starts. Nine anatomic landmarks were identified on the swimmers' bodies and their positions were calculated using a modified double plan DLT technique. From these positions and Dempster's anthropometric data, the center of mass position and velocity were also determined. Kinetic energies were also calculated. This velocity and kinetic energies for the two types of start were compared. Swimmers began underwater leg propulsion 1.69 m too soon. The global and internal energies were significantly higher for the start with underwater leg propulsion. Nevertheless, swimmers' velocities were equivalent for both starts. These results suggest that the swimmers did not use the underwater phase of the start efficiently: By kicking too soon, they did not succeed in producing higher velocities and thus wasted energy. PMID- 21245511 TI - Pelvic kinematic method for determining vertical jump height. AB - Sacral marker and pelvis reconstruction methods have been proposed to approximate total body center of mass during relatively low intensity gait and hopping tasks, but not during a maximum effort vertical jumping task. In this study, center of mass displacement was calculated using the pelvic kinematic method and compared with center of mass displacement using the ground-reaction force-impulse method, in experienced athletes (n = 13) performing restricted countermovement vertical jumps. Maximal vertical jumps were performed in a biomechanics laboratory, with data collected using an 8-camera motion analysis system and two force platforms. The pelvis center of mass was reconstructed from retro-reflective markers placed on the pelvis. Jump height was determined from the peak height of the pelvis center of mass minus the standing height. Strong linear relationships were observed between the pelvic kinematic and impulse methods (R2 = .86; p < .01). The pelvic kinematic method underestimated jump height versus the impulse method, however, the difference was small (CV = 4.34%). This investigation demonstrates concurrent validity for the pelvic kinematic method to determine vertical jump height. PMID- 21245512 TI - Detecting postoperative change in children with cerebral palsy: net nondimensional versus body mass oxygen normalization. AB - The aim of the study is to investigate whether the net nondimensional oxygen utilization scheme is able to detect postoperative improvement in the energy cost of walking in children with cerebral palsy and to compare it with a body mass normalization scheme. We evaluated 10 children with spastic cerebral palsy before and 9 months after equinus deformity surgery. Participants walked at a given speed of 2 km/hr and 3 km/hr on a treadmill. Oxygen utilization was measured, and mass relative VO2 and net nondimensional VO2 were calculated. Coefficient of variation was used for the description of variability among subjects. Postoperatively, gait kinematics normalized and the mass relative VO2 and net nondimensional VO2 showed significant improvement. Net nondimensional VO2 is able to detect postoperative improvement with smaller variability among subjects than body mass related normalization in children with cerebral palsy. PMID- 21245513 TI - Application of a full body inertial measurement system in alpine skiing: a comparison with an optical video based system. AB - This study aims at determining the accuracy of a full body inertial measurement system in a real skiing environment in comparison with an optical video based system. Recent studies have shown the use of inertial measurement systems for the determination of kinematical parameters in alpine skiing. However, a quantitative validation of a full body inertial measurement system for the application in alpine skiing is so far not available. For the purpose of this study, a skier performed a test-run equipped with a full body inertial measurement system in combination with a DGPS. In addition, one turn of the test-run was analyzed by an optical video based system. With respect to the analyzed angles, a maximum mean difference of 4.9 degrees was measured. No differences in the measured angles between the inertial measurement system and the combined usage with a DGPS were found. Concerning the determination of the skier's trajectory, an additional system (e.g., DGPS) must be used. As opposed to optical methods, the main advantages of the inertial measurement system are the determination of kinematical parameters without the limitation of restricted capture volume, and small time costs for the measurement preparation and data analysis. PMID- 21245514 TI - One-legged stance as a representative static body position for calculation of hip contact stress distribution in clinical studies. AB - It was shown in several clinical studies that static one-legged stance may be a relevant body position to describe the loads acting at the hip. However, the stress distribution averaged during movement may better describe hip load than hip contact stress distribution in the static body position. Using data on the resultant hip force during walking taken from the measurements of Bergmann (2001), spatial distribution of contact stress over the articular surface was calculated by the HIPSTRESS method and compared with the stress distribution in one-legged stance. It is shown, that the shape of the contact stress distribution during one-legged stance closely resembled the averaged contact stress distribution during the walking cycle (Pearson's correlation coefficient R2 equals; .986; p < .001). This finding presents a link between the hypothesis that the averaged contact stress distribution during a walking cycle is crucial for cartilage development and the results of clinical studies in which the calculated distribution of contact stress in one-legged stance was successfully used to predict the clinical status of the hip. PMID- 21245515 TI - Bone alignment using the iterative closest point algorithm. AB - Computer assisted surgical interventions and research in joint kinematics rely heavily on the accurate registration of three-dimensional bone surface models reconstructed from various imaging technologies. Anomalous results were seen in a kinematic study of carpal bones using a principal axes alignment approach for the registration. The study was repeated using an iterative closest point algorithm, which is more accurate, but also more demanding to apply. The principal axes method showed errors between 0.35 mm and 0.49 mm for the scaphoid, and between 0.40 mm and 1.22 mm for the pisiform. The iterative closest point method produced errors of less than 0.4 mm. These results show that while the principal axes method approached the accuracy of the iterative closest point algorithm in asymmetrical bones, there were more pronounced errors in bones with some symmetry. Principal axes registration for carpal bones should be avoided. PMID- 21245516 TI - Update of the drug resistance mutations in HIV-1: December 2010. AB - This December 2010 version of the International AIDS Society-USA (IAS-USA) drug resistance mutations list updates the figures last published in December 2009 (Johnson VA et al, Top HIV Med, 2009;17:138-145). This update includes 9 new mutations- E138G and E138K for etravirine (Haddad M et al, CROI, 2010; Abstract 574, and Vingerhoets J et al, Antivir Ther, 2010;15 [Suppl 2]:A125); E92Q for raltegravir (Geretti AM et al, Antivir Ther, 2010;15 [Suppl 2]:A62; Cooper et al, N Engl J Med, 2008;359:355-365; and Malet I et al, Antimicrob Agents Chemother, 2008;52:1351-1358); and M36L, M36V, H69R, L89I, L89M, and L89V for tipranavir/ritonavir. In addition, the tipranavir/ritonavir N83D mutation designation was changed to boldface to indicate its recognition as a major mutation rather than a minor mutation. The mutations I13V, K20M/R, E35G, and L90M were removed from the tipranavir/ritonavir bar, reflecting new understanding. For etravirine, L100I*, K101P*, and Y181C*/I*/V* are denoted with asterisks (instead of bolded) to reflect that these individual mutations each have the greatest impact (ie, highest weighting scores) on reduced phenotypic susceptibility and impaired clinical response when compared with other etravirine mutations (Haddad M et al, CROI, 2010; Abstract 574). In addition, user notes d, n, r, w, and z were revised. PMID- 21245517 TI - Evaluating and managing cardiovascular disease risk factors in HIV-infected patients. AB - The primary risk factors for cardiovascular disease (CVD) in patients with HIV infection are the same as those for the general population. Some antiretroviral drugs are associated with a small increase in short-term risk of CVD that may become greater over longer periods of exposure. However, the absolute risk associated with use of these drugs is of greatest importance for patients already at moderate or high risk of CVD. The guiding principle in managing CVD risk for HIV-infected patients is to maintain control of the HIV infection while addressing the metabolic abnormalities that increase CVD risk. Lipid-lowering therapy with statins is very effective in reducing CVD risk, with levels of low density lipoprotein cholesterol and non-high-density lipoprotein cholesterol constituting the primary treatment targets for most patients with dyslipidemia. This article summarizes a lecture by James H. Stein, MD, at the International AIDS Society-USA continuing medical education program held in Washington, DC, in June 2010. PMID- 21245518 TI - Recalcitrant giant molluscum contagiosum in a patient with advanced HIV disease - eradication of disease with paclitaxel. PMID- 21245519 TI - Occupational postexposure prophylaxis for HIV: The PEPline perspective. AB - Transmission of HIV through occupational exposure in healthcare personnel is rare. Risk of transmission from an HIV-infected source person is estimated at 0.3% for percutaneous exposures and 0.09% for mucous membrane or nonintact skin exposures, with risk modulated by exposure and source-patient characteristics. Counseling on risk assessment, postexposure prophylaxis (PEP), and baseline and follow-up testing after exposure is provided through PEPline, the National Clinicians' Post-Exposure Prophylaxis Hotline. PEPline receives approximately 900 calls per month, most from treating clinicians. HIV PEP consists of a 28-day course of a basic or an expanded regimen, depending on the severity or volume of exposure and HIV infection characteristics of the source person. An update to the 2005 US Department of Health PEP drug recommendations is expected in 2011. This article summarizes a lecture given by Ronald H. Goldschmidt, MD, at the 13th Annual Ryan White HIV-AIDS Program Clinical Conference held in August 2010 in Washington, DC. PMID- 21245520 TI - A mechanical analysis of woodpecker drumming and its application to shock absorbing systems. AB - A woodpecker is known to drum the hard woody surface of a tree at a rate of 18 to 22 times per second with a deceleration of 1200 g, yet with no sign of blackout or brain damage. As a model in nature, a woodpecker is studied to find clues to develop a shock-absorbing system for micromachined devices. Its advanced shock absorbing mechanism, which cannot be explained merely by allometric scaling, is analyzed in terms of endoskeletal structures. In this analysis, the head structures (beak, hyoid, spongy bone, and skull bone with cerebrospinal fluid) of the golden-fronted woodpecker, Melanerpes aurifrons, are explored with x-ray computed tomography images, and their shock-absorbing mechanism is analyzed with a mechanical vibration model and an empirical method. Based on these analyses, a new shock-absorbing system is designed to protect commercial micromachined devices from unwanted high-g and high-frequency mechanical excitations. The new shock-absorbing system consists of close-packed microglasses within two metal enclosures and a viscoelastic layer fastened by steel bolts, which are biologically inspired from a spongy bone contained within a skull bone encompassed with the hyoid of a woodpecker. In the experimental characterizations using a 60 mm smoothbore air-gun, this bio-inspired shock-absorbing system shows a failure rate of 0.7% for the commercial micromachined devices at 60 000 g, whereas a conventional hard-resin method yields a failure rate of 26.4%, thus verifying remarkable improvement in the g-force tolerance of the commercial micromachined devices. PMID- 21245521 TI - Photon to thermal response of a single patterned gold nanorod cluster under near infrared laser irradiation. AB - The potential applications of the photon to thermal conversion technique by gold nanorods has attracted attention for biomedical applications since they show an intense absorption spectrum in the near-infrared region, and therefore, penetrate more deeply into biological tissues. The goal in this study is to assess a local heating phenomenon with a single patterned cluster of gold nanorods that are prepared as a wet chemically synthesized gold nanorod solution and mixed with aqueous 1% alginate and 0.1 M calcium chloride. In particular, we utilized the initiated chemical vapor deposition method to coat the cluster with poly(2 hydroxyethyl methacrylate) to enhance its high temperature resistance in the solution. The influence of the thermal energy on the surroundings is studied by measuring the surface temperature of the single patterned gold nanorod cluster as a function of laser irradiation time. The experimental results were compared with numerical simulation results. The results showed that the irradiated gold nanorods could rapidly heat to maximum surface temperatures of over 60 degrees C within 120 s. Furthermore, the temperature remained almost constant (i.e. reached a steady state) under continuous laser irradiation and rapidly cooled to the initial temperature within 90 s when the laser was turned off. PMID- 21245522 TI - Optimized fabrication of Ca-P/PHBV nanocomposite scaffolds via selective laser sintering for bone tissue engineering. AB - Biomaterials for scaffolds and scaffold fabrication techniques are two key elements in scaffold-based tissue engineering. Nanocomposites that consist of biodegradable polymers and osteoconductive bioceramic nanoparticles and advanced scaffold manufacturing techniques, such as rapid prototyping (RP) technologies, have attracted much attention for developing new bone tissue engineering strategies. In the current study, poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) microspheres and calcium phosphate (Ca-P)/PHBV nanocomposite microspheres were fabricated using the oil-in-water (O/W) and solid-in-oil-in-water (S/O/W) emulsion solvent evaporation methods. The microspheres with suitable sizes were then used as raw materials for scaffold fabrication via selective laser sintering (SLS), which is a mature RP technique. A three-factor three-level complete factorial design was applied to investigate the effects of the three factors (laser power, scan spacing, and layer thickness) in SLS and to optimize SLS parameters for producing good-quality PHBV polymer scaffolds and Ca-P/PHBV nanocomposite scaffolds. The plots of the main effects of these three factors and the three-dimensional response surface were constructed and discussed. Based on the regression equation, optimized PHBV scaffolds and Ca-P/PHBV scaffolds were fabricated using the optimized values of SLS parameters. Characterization of optimized PHBV scaffolds and Ca-P/PHBV scaffolds verified the optimization process. It has also been demonstrated that SLS has the capability of constructing good-quality, sophisticated porous structures of complex shape, which some tissue engineering applications may require. PMID- 21245524 TI - A robust sensor-selection method for P300 brain-computer interfaces. AB - A brain-computer interface (BCI) is a specific type of human-computer interface that enables direct communication between human and computer through decoding of brain activity. As such, event-related potentials like the P300 can be obtained with an oddball paradigm whose targets are selected by the user. This paper deals with methods to reduce the needed set of EEG sensors in the P300 speller application. A reduced number of sensors yields more comfort for the user, decreases installation time duration, may substantially reduce the financial cost of the BCI setup and may reduce the power consumption for wireless EEG caps. Our new approach to select relevant sensors is based on backward elimination using a cost function based on the signal to signal-plus-noise ratio, after some spatial filtering. We show that this cost function selects sensors' subsets that provide a better accuracy in the speller recognition rate during the test sessions than selected subsets based on classification accuracy. We validate our selection strategy on data from 20 healthy subjects. PMID- 21245523 TI - Micro-scale fabrication and characterization of a silver-polymer-based electrically activated antibacterial surface. AB - This paper reports the fabrication methodology and characterization results for an electrically activated silver-polymer-based antibacterial surface with primary applications in preventing indirect contact transmission of infections. The surface consists of a micro-scale grating pattern of alternate silver electrodes and SU-8 partitions with a minimum feature size of 20 um, and activated by an external voltage. In this study, prototype coupons (15 mm * 15 mm) of the antibacterial surface were fabricated on silicon substrates using two sets of lithographies, and analyzed for their physical characteristics using microscopy and surface profilometry. The prototypes were also electrically analyzed to determine their current-voltage characteristics, and hence silver ion (Ag(+)) release concentrations. Finally, they were tested for their antibacterial efficacy against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram negative) using a newly engineered microbiological testing procedure. The antibacterial efficacy testing results show significant reductions in the number of viable organisms of both the species after 45 min of testing with 15 uA system current. Due to the growing incidences of hospital-acquired infections and rising treatment costs, study and application of such alternative antibacterial systems in critical touch-contact and work surfaces (e.g., door push plates, countertops, medical instrument trays) for healthcare environments has become essential. PMID- 21245525 TI - State-space decoding of primary afferent neuron firing rates. AB - Kinematic state feedback is important for neuroprostheses to generate stable and adaptive movements of an extremity. State information, represented in the firing rates of populations of primary afferent (PA) neurons, can be recorded at the level of the dorsal root ganglia (DRG). Previous work in cats showed the feasibility of using DRG recordings to predict the kinematic state of the hind limb using reverse regression. Although accurate decoding results were attained, reverse regression does not make efficient use of the information embedded in the firing rates of the neural population. In this paper, we present decoding results based on state-space modeling, and show that it is a more principled and more efficient method for decoding the firing rates in an ensemble of PA neurons. In particular, we show that we can extract confounded information from neurons that respond to multiple kinematic parameters, and that including velocity components in the firing rate models significantly increases the accuracy of the decoded trajectory. We show that, on average, state-space decoding is twice as efficient as reverse regression for decoding joint and endpoint kinematics. PMID- 21245526 TI - Carbon nanotubes in neural interfacing applications. AB - Carbon nanotubes (CNT) are remarkable materials with a simple and inert molecular structure that gives rise to a range of potentially valuable physical and electronic properties, including high aspect ratio, high mechanical strength and excellent electrical conductivity. This review summarizes recent research on the application of CNT-based materials to study and control cells of the nervous system. It includes the use of CNT as cell culture substrates, to create patterned surfaces and to study cell-matrix interactions. It also summarizes recent investigations of CNT toxicity, particularly as related to neural cells. The application of CNT-based materials to directing the differentiation of progenitor and stem cells toward neural lineages is also discussed. The emphasis is on how CNT surface chemistry and nanotopography can be altered, and how such changes can affect neural cell function. This knowledge can be applied to creating improved neural interfaces and devices, as well as providing new approaches to neural tissue engineering and regeneration. PMID- 21245527 TI - Poly(3,4-ethylenedioxythiophene) (PEDOT) polymer coatings facilitate smaller neural recording electrodes. AB - We investigated using poly(3,4-ethylenedioxythiophene) (PEDOT) to lower the impedance of small, gold recording electrodes with initial impedances outside of the effective recording range. Smaller electrode sites enable more densely packed arrays, increasing the number of input and output channels to and from the brain. Moreover, smaller electrode sizes promote smaller probe designs; decreasing the dimensions of the implanted probe has been demonstrated to decrease the inherent immune response, a known contributor to the failure of long-term implants. As expected, chronically implanted control electrodes were unable to record well isolated unit activity, primarily as a result of a dramatically increased noise floor. Conversely, electrodes coated with PEDOT consistently recorded high quality neural activity, and exhibited a much lower noise floor than controls. These results demonstrate that PEDOT coatings enable electrode designs 15 um in diameter. PMID- 21245528 TI - Structure of the effector-binding domain of the LysR-type transcription factor RovM from Yersinia pseudotuberculosis. AB - In enteropathogenic Yersinia, the expression of several early-phase virulence factors such as invasin is tightly regulated in response to environmental cues. The responsible regulatory network is complex, involving several regulatory RNAs and proteins such as the LysR-type transcription regulator (LTTR) RovM. In this study, the crystal structure of the effector-binding domain (EBD) of RovM, the first LTTR protein described as being involved in virulence regulation, was determined at a resolution of 2.4 A. Size-exclusion chromatography and comparison with structures of full-length LTTRs show that RovM is most likely to adopt a tetrameric arrangement with two distant DNA-binding domains (DBDs), causing the DNA to bend around it. Additionally, a cavity was detected in RovM which could bind small inducer molecules. PMID- 21245529 TI - Structure of PduT, a trimeric bacterial microcompartment protein with a 4Fe-4S cluster-binding site. AB - Propanediol metabolism in Citrobacter freundii occurs within a metabolosome, a subcellular proteinaceous bacterial microcompartment. The propanediol-utilization (Pdu) microcompartment shell is constructed from thousands of hexagonal-shaped protein complexes made from seven different types of protein subunit. Here, the structure of the bacterial microcompartment protein PduT, which has a tandem structural repeat within the subunit and forms trimers with pseudo-hexagonal symmetry, is reported. This trimeric assembly forms a flat approximately hexagonally shaped disc with a central pore that is suitable for a 4Fe-4S cluster. The essentially cubic shaped 4Fe-4S cluster conforms to the threefold symmetry of the trimer with one free iron, the role of which could be to supply electrons to an associated microcompartment enzyme, PduS. PMID- 21245530 TI - Structure of an RNA dimer of a regulatory element from human thymidylate synthase mRNA. AB - A sequence around the start codon of the mRNA of human thymidylate synthase (TS) folds into a secondary-structure motif in which the initiation site is sequestered in a metastable hairpin. Binding of the protein to its own mRNA at the hairpin prevents the production of TS through a translation-repression feedback mechanism. Stabilization of the mRNA hairpin by other ligands has been proposed as a strategy to reduce TS levels in anticancer therapy. Rapidly proliferating cells require high TS activity to maintain the production of thymidine as a building block for DNA synthesis. The crystal structure of a model oligonucleotide (TS1) that represents the TS-binding site of the mRNA has been determined. While fluorescence studies showed that the TS1 RNA preferentially adopts a hairpin structure in solution, even at high RNA concentrations, an asymmetric dimer of two hybridized TS1 strands was obtained in the crystal. The TS1 dimer contains an unusual S-turn motif that also occurs in the 'off' state of the human ribosomal decoding site RNA. PMID- 21245531 TI - The structure of TTHA0988 from Thermus thermophilus, a KipI-KipA homologue incorrectly annotated as an allophanate hydrolase. AB - The Thermus thermophilus protein TTHA0988 is a protein of unknown function which represents a fusion of two proteins found almost ubiquitously across the bacterial kingdom. These two proteins perform a role regulating sporulation in Bacillus subtilis, where they are known as KipI and KipA. kipI and kipA genes are usually found immediately adjacent to each other and are often fused to produce a single polypeptide, as is the case with TTHA0988. Here, three crystal forms are reported of TTHA0988, the first structure to be solved from the family of 'KipI KipA fusion' proteins. Comparison of the three forms reveals structural flexibility which can be described as a hinge motion between the 'KipI' and 'KipA' components. TTHA0988 is annotated in various databases as a putative allophanate hydrolase. However, no such activity could be identified and genetic analysis across species with known allophanate hydrolases indicates that a misannotation has occurred. PMID- 21245532 TI - Structural and biochemical analyses of the human PAD4 variant encoded by a functional haplotype gene. AB - PAD4 is a peptidylarginine deiminase that catalyzes citrullination, a type of post-translational modification. In this reaction, arginine residues in proteins are converted to citrulline. PAD4 promotes the deimination of arginine residues in histones and may regulate transcription in the context of the chromatin. Single-nucleotide polymorphisms (SNP) in the gene encoding PAD4 identified it as one of the genes associated with susceptibility to rheumatoid arthritis. The PAD4 SNP involve three amino-acid substitutions: Ser55 to Gly, Ala82 to Val and Ala112 to Gly. Autoantibodies for improperly citrullinated proteins have been found in rheumatoid arthritis patients, suggesting that the PAD4(SNP) mRNA is more stable than the conventional PAD4 mRNA and/or the PAD4(SNP) protein possesses a higher citrullination activity than the PAD4 protein. In order to study the effects of the three amino-acid substitutions found in PAD4(SNP), the crystal structure of PAD4(SNP) was determined and it was found that the amino-acid substitutions in PAD4(SNP) only induced conformational changes within the N-terminal domain, not in the active centre for citrullination located in the C-terminal domain. Biochemical analyses also suggested that the citrullination activity of PAD4(SNP) may not substantially differ from that of conventional PAD4. These structural and biochemical findings suggested that the improper protein citrullination found in rheumatoid arthritis patients is not caused by defects in the citrullination activity of PAD4(SNP) but by other reasons such as enhanced PAD4(SNP) mRNA stability. PMID- 21245533 TI - Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). AB - E-ISA247 (voclosporin) is a cyclosporin A analogue that is in late-stage clinical development for the treatment of autoimmune diseases and the prevention of organ graft rejection. The X-ray crystal structures of E-ISA247 and its stereoisomer Z ISA247 bound to cyclophilin A have been determined and their binding affinities were measured to be 15 and 61 nM, respectively, by fluorescence spectroscopy. The higher affinity of E-ISA247 can be explained by superior van der Waals contacts between its unique side chain and cyclophilin A. Comparison with the known ternary structure including calcineurin suggests that the higher immunosuppressive efficacy of E-ISA247 relative to cyclosporin A could be a consequence of structural changes in calcineurin induced by the modified E-ISA247 side chain. PMID- 21245535 TI - Crystal structure analysis of icosahedral lumazine synthase from Salmonella typhimurium, an antibacterial drug target. AB - Riboflavin biosynthesis is an essential pathway in bacteria, in contrast to animals, which obtain riboflavin from their diet. Therefore, the enzymes involved in the riboflavin-biosynthesis pathway are potential targets for the development of antibacterial drugs. Lumazine synthase, an enzyme that is involved in the penultimate step of riboflavin biosynthesis, catalyzes the formation of 6,7 dimethyl-8-ribityllumazine from 3,4-dihydroxy-2-butanone 4-phosphate and 5-amino 6-ribitylamino-2,4-(1H,3H)-pyrimidinedione. Lumazine synthase from Salmonella typhimurium (sLS) has been cloned, overexpressed, purified and was crystallized in three forms, each with different crystal packing. The crystal structure of sLS in the monoclinic space group P2(1) has been determined with 60 subunits per asymmetric unit, packed as an icosahedron, at 3.57 A resolution. Interestingly, sLS contains an N-terminal proline residue (Pro11) which had previously been suggested to disrupt the formation of the icosohedral assembly. In addition, comparison of the structure of sLS with known orthologous lumazine synthase structures allowed identification of the amino-acid residues involved in substrate binding and catalysis. The sLS structure reported here could serve as a starting point for the development of species-specific antibacterial drugs. PMID- 21245534 TI - Structure of the minor pseudopilin XcpW from the Pseudomonas aeruginosa type II secretion system. AB - Pseudomonas aeruginosa utilizes the type II secretion machinery to transport virulence factors through the outer membrane into the extracellular space. Five proteins in the type II secretion system share sequence homology with pilin subunits of type IV pili and are called the pseudopilins. The major pseudopilin XcpT(G) assembles into an intraperiplasmic pilus and is thought to act in a piston-like manner to push substrates through an outer membrane secretin. The other four minor pseudopilins, XcpU(H), XcpV(I), XcpW(J) and XcpX(K), play less well defined roles in pseudopilus formation. It was recently discovered that these four minor pseudopilins form a quaternary complex that is presumed to initiate the formation of the pseudopilus and to localize to its tip. Here, the structure of XcpW(J) was refined to 1.85 A resolution. The structure revealed the type IVa pilin fold with an embellished variable antiparallel beta-sheet as also found in the XcpW(J) homologue enterotoxigenic Escherichia coli GspJ(W) and the XcpU(H) homologue Vibrio cholerae EpsU(H). It is proposed that the exposed surface of this sheet may cradle the long N-terminal alpha1 helix of another pseudopilin. The final 31 amino acids of the XcpW(J) structure are instrinsically disordered. Deletion of this unstructured region of XcpW(J) did not prevent type II secretion in vivo. PMID- 21245536 TI - X-ray and neutron protein crystallographic analysis of the trypsin-BPTI complex. AB - In this work, the crystal structure of the beta-trypsin-bovine pancreatic trypsin inhibitor (BPTI) complex was refined and the D and H atoms in the complex were identified using data from both 1.6 A resolution X-ray diffraction and 2.15 A resolution neutron diffraction. After crystallization in an H(2)O solution, the sample crystal was soaked in a D(2)O solution for about two weeks. The protonation states of the catalytic triad (Asp102, His57 and Ser195) were observed. These results confirmed that the nucleophilic reactivity of the hydroxyl group of Ser195 was increased by forming a hydrogen bond with His57. According to structural analysis, the trypsin-BPTI interfaces located at the scissile peptide and the active sites were inaccessible to solvent water, and the amide H atoms of P2' Arg17/I, Gly216/E and Gly193/E at the binding interface were protected from H/D exchange. In contrast, both the amide H atom of P1' Ala16/I of the scissile peptide bond P1-P1' and the H atom between His57 N(E2) and Ser195 O(gamma) were replaced by D atoms. The hydrogen-bond networks at the S1 pocket were also confirmed and discussed from the viewpoint of substrate recognition. Moreover, the first neutron crystallographic structure of the Michaelis complex state of trypsin-BPTI is presented. PMID- 21245537 TI - Unifying cluster-based structure models of decagonal Al-Co-Ni, Al-Co-Cu and Al-Fe Ni. AB - The geometrical building principles of Al-based decagonal quasicrystals and their approximants are discussed from a cluster-based approach. Our investigations cover 11 modifications with two- or four-layer periodicity in the systems Al-Co Ni, Al-Co-Cu and Al-Fe-Ni. We identified a cluster that leads to a unifying view of all these phases. This unit cluster has ~20 A diameter, four-layer periodicity along its tenfold axis and rod symmetry group p102m. The models obtained are in agreement with all the electron-density maps and electron-microscopy images available. PMID- 21245538 TI - Modulated structure of nepheline. AB - The incommensurately modulated structure of a natural nepheline of composition K(0.54)Na(3.24)Ca(0.03)Al(3.84)Si(4.16)O(16) has been determined in superspace. The compound crystallizes in the trigonal centered superspace group X3(00gamma)0 with gamma = 0.2048 (10), X = (0, 0, 0, 0), (1/3, 2/3, 0, 2/3), (2/3, 1/3, 0, 1/3), a = 17.2889 (8) and c = 8.3622 (10) A. The structure is characterized by a framework of corner-connected (Al,Si)O(4) tetrahedra. The additional cations are incorporated in two different types of channels of the framework. All atoms in the structure are displacively modulated with amplitudes below 0.1 A. The modulation can be well described taking into account harmonics of first order only. Atomic positions in the smaller channels of the framework are fully occupied by Na(+). Cationic positions in the larger channel are occupationally modulated, yet the variation of electron density as a function of the internal coordinate t is very small and indicates that the incorporation of different types of cations (K(+), Na(+), Ca(2+)) and vacancies is realised in a highly disordered way. Average T-O distances indicate a nearly complete Al/Si ordering in the tetrahedral framework. A large part of the O atoms are approximated by split-atom positions, which are additionally affected by occupational modulation resulting in a high degree of disorder in the modulated structure. Occupational probabilities for the split-atom positions are complementary. Occupational modulations of the cations in the larger channels and the O atoms of the tetrahedral framework are coupled and correlations between occupational and displacive modulations exist. PMID- 21245539 TI - Structures of two new high-pressure forms of AlPO4 by X-ray powder diffraction and NMR spectroscopy. AB - The crystal structures of two new high-pressure AlPO(4) phases are reported. One phase synthesized at 6 GPa and 1523 K is triclinic (P1) whilst the other phase synthesized at 7 GPa and 1773 K is monoclinic (P2(1)/c). (31)P MAS (magic-angle spinning) NMR suggests three tetrahedral P sites with equal abundance in both phases. (27)Al 3Q MAS NMR spectra provided evidence for two octahedral sites and one five-coordinated Al site in each phase. The crystal structures were solved using an ab initio structure determination technique from synchrotron powder X ray diffraction data utilizing the local structural information from NMR, and were further refined by the Rietveld method. Both phases contain doubly bent chains made of six edge-shared Al polyhedra (including five-coordinated Al), which are joined by PO(4) tetrahedra. The P1 phase is isostructural with FeVO(4) and AlVO(4). The two phases differ in the packing manner of the chains. This study has demonstrated that the combined application of ab initio structure determination via X-ray powder diffraction and solid-state NMR spectroscopy is a powerful approach to the rapid solution of complex inorganic crystal structures. PMID- 21245540 TI - Investigation of the structure and phase transitions of the polymeric inorganic organic hybrids: [M(Im)4V2O6]infinity; M = Mn, Co, Ni, Im = imidazole. AB - The polymeric isomorphous hybrid inorganic-organic vanadium oxide compounds [M(Im)(4)V(2)O(6)](infinity), M = Mn, Co, Ni, Im = imidazole, were investigated at various temperatures between 100 and 295 K by single-crystal X-ray diffraction. The crystals all contain two-dimensional polymeric sheets packed perpendicular to c* and are 1:1 disordered in the space group P4(2)/n (Z = 8) at 295 K. The disordered phase is reversibly transformed to an I4(1)/a ordered phase (Z = 32) below 281 K for the Mn compound and below 175 K for the Co compound. Within a localized region of the I4(1)/a phase eight imidazoles are in close proximity and seven of these are hydrogen bonded to framework O atoms. The hydrogen-bond connectivity of six of these ligands is unchanged by the phase transition that allows an inversion of the local geometry using an inversion operator that is a symmetry element of P4(2)/n, but not I4(1)/a. The Mn structure has a well defined phase transition but the Co structure shows a large hysteresis and it was necessary to include stacking faults in the modelling of the Co structure at low temperatures. The Ni structure was shown to be partially twinned, but ordered in the space group P2/n (Z = 8) at 100 K, with two different localized regions each containing four pairs of inversion-related imidazoles, hydrogen bonding to framework O atoms involving eight imidazoles in one region and six imidazoles in the other. Models for the phase transition mechanisms are considered. PMID- 21245541 TI - Temperature-dependent analysis of thermal motion, disorder and structures of tris(ethylenediamine)zinc(II) sulfate and tris(ethylenediamine)copper(II) sulfate. AB - The crystal structures of the title compounds have been determined in the temperature range 140-290 K for the zinc complex, and 190-270 K for the copper complex. The two structures are isostructural in the trigonal space group P31c with the sulfate anion severely disordered on a site with 32 (D(3)) symmetry. This sulfate disorder leads to a disordered three-dimensional hydrogen-bond network, with the N-H atoms acting as donors and the sulfate O atoms as acceptors. The displacement parameters of the N and C atoms in both compounds contain disorder contributions in the out-of-ligand plane direction owing to ring puckering and/or disorder in hydrogen bonding. In the Zn compound the vibrational amplitudes in the bond directions are closely similar. Their differences show no significant deviations from rigid-bond behaviour. In the Cu compound, a (presumably) dynamic Jahn-Teller effect is identified from a temperature independent contribution to the displacement ellipsoids of the N atom along the N Cu bond. These conclusions derive from analyses of the atomic displacement parameters with the Hirshfeld test, with rigid-body models at different temperatures, and with a normal coordinate analysis. This analysis considers the atomic displacement parameters (ADPs) from all different temperatures simultaneously and provides a detailed description of both the thermal motion and the disorder in the cation. The Jahn-Teller radii of the Cu compound derived on the basis of the ADP analysis and from the bond distances in the statically distorted low-temperature phase [Lutz (2010). Acta Cryst. C66, m330-m335] are found to be the same. PMID- 21245543 TI - Failures of fractional crystallization: ordered co-crystals of isomers and near isomers. AB - A list of 270 structures of ordered co-crystals of isomers, near isomers and molecules that are almost the same has been compiled. Searches for structures containing isomers could be automated by the use of IUPAC International Chemical Identifier (InChITM) strings but searches for co-crystals of very similar molecules were more labor intensive. Compounds in which the heteromolecular A...B interactions are clearly better than the average of the homomolecular A...A and B...B interactions were excluded. The two largest structural classes found include co-crystals of configurational diastereomers and of quasienantiomers (or quasiracemates). These two groups overlap. There are 114 co-crystals of diastereomers and the same number of quasiracemates, with 71 structures being counted in both groups; together the groups account for 157 structures or 58% of the total. The large number of quasiracemates is strong evidence for inversion symmetry being very favorable for crystal packing. Co-crystallization of two diastereomers is especially likely if a 1,1 switch of a methyl group and an H atom, or of an inversion of a [2.2.1] or [2.2.2] cage, in one of the diastereomers would make the two molecules enantiomers. PMID- 21245542 TI - Structural analysis and multipole modelling of quercetin monohydrate--a quantitative and comparative study. AB - The multipolar atom model, constructed by transferring the charge-density parameters from an experimental or theoretical database, is considered to be an easy replacement of the widely used independent atom model. The present study on a new crystal structure of quercetin monohydrate [2-(3,4-dihydroxyphenyl)-3,5,7 trihydroxy-4H-chromen-4-one monohydrate], a plant flavonoid, determined by X-ray diffraction, demonstrates that the transferred multipolar atom model approach greatly improves several factors: the accuracy of atomic positions and the magnitudes of atomic displacement parameters, the residual electron densities and the crystallographic figures of merit. The charge-density features, topological analysis and electrostatic interaction energies obtained from the multipole models based on experimental database transfer and periodic quantum mechanical calculations are found to compare well. This quantitative and comparative study shows that in the absence of high-resolution diffraction data, the database transfer approach can be applied to the multipolar electron density features very accurately. PMID- 21245544 TI - Conformation and geometry of cyclopropane rings having pi-acceptor substituents: a theoretical and database study. AB - The 3e' orbitals of cyclopropane have the correct symmetry to interact with low lying unoccupied orbitals of pi-acceptor substituents and maximum overlap occurs when the two orbital systems are parallel, i.e. when the pi-acceptor bisects the ring in projection down the substituent bond. Since the cyclopropyl group is a common component of active pharmaceutical and agrochemical ingredients, it is important that these strong conjugative interactions are well modelled by computational techniques, and clearly represented in experimental crystal structures. Here we show that torsion angle distributions derived from crystal structure data in the Cambridge Structural Database are in excellent correspondence with torsional energy profiles computed using density functional theory (DFT) for a range of substituents: -COOR, -CONR(2), -NO(2), vinyl and phenyl. We also show that crystal structure information is invaluable in modelling conformations of compounds that contain multiply substituted rings, where steric interactions require some substituents to adopt energetically disfavoured conformations. Further, conjugative interactions with pi-acceptors lead to significant asymmetry in the cyclopropane ring bond lengths and again the experimental and computational results are in excellent agreement. Such asymmetry effects are additive, and this explains bond-length variations in cyclopropane rings bearing two or more pi-acceptor substituents. PMID- 21245546 TI - Mathematical modeling of aeration efficiency and dissolved oxygen provided by stepped cascade aeration. AB - Mathematical modeling has been a vital tool in the field of environmental engineering. Various models have been developed to simulate the level of aeration efficiency (AE) provided by different aerating structures to raise levels of dissolved oxygen (DO) in streams; one of which is the stepped cascade structure. Three models developed by Gameson et al. WRL, and Nakasone, in addition to Qual2k, a computer program for stream modeling, have been used in this research; values of AEs obtained have been compared to those computed using DO measured from a built model at a WWTP. A stepped cascade structure was installed with different heights to aerate five flowrates with different levels of COD. An adjustment has been made to the Nakasone model to test the effect of pollutant load on the amount of aeration that could be reached. Values of AEs computed using the Gameson model were 30%, 39.5%, and 40% for cascade heights (H(d)) 45, 60, and 75 cm respectively for the five flowrates (q) that ranged from 21-66 m3/hr. Values of AEs from WRL model were 32.8%, 42%, and 43% consequently. Values of AEs from Nakasone model ranged from 4.6-7.5%, 6-10%, and 7.6-12% respectively. For the adjusted Nakasone model, values of AEs ranged from 3.2-4.9%, 3.3-5.3%, and 4.1-6.7% respectively. Finally, the AEs computed using the values of downstream DO generated by Qual2k ranged from 4-18%, 2-15%, and 2.5-5.1% correspondingly. Around 80% of the downstream DO values computed using the Nakasone and adjusted Nakasone model were closer to those measured in the field, thus more reliable in cascade design. PMID- 21245547 TI - Water reuse for irrigation in Jordan: plant beneficial nutrients, farmers' awareness and management strategies. AB - The reuse of treated wastewater (reclaimed water) is particularly well suited for irrigated agriculture as it often contains significant quantities of plant essential nutrients. This work has shown that reclaimed water in Jordan can have adequate concentrations of potassium, phosphate, sulphate and magnesium to meet all or part of the crop's requirements. To fully benefit from these inputs farmers must have an awareness of the water quality and reduce the application of inorganic fertilisers accordingly. Interviews with farmers have shown that 75 per cent of farmers indirectly using reclaimed water are aware of the nutrients. Farmers' decision making as to the application of inorganic fertilisers appears to be influenced by a range of factors which include the type of crops being cultivated, the provision of training on nutrient management and the availability of information on the nutrient content of the reclaimed water. PMID- 21245548 TI - Centralised urban stormwater harvesting for potable reuse. AB - Urban impervious areas provide a guaranteed source of runoff, especially in cities with high rainfall - this represents a source of water with low sensitivity to unfavourable climate change. Whilst the potential to reuse stormwater has long been recognised, its quality has largely limited usage to non potable applications requiring the use of a third-pipe network, a prohibitively expensive option in established urban areas. Given recent advances in membrane filtration, this study investigates the potential of harvesting and treating stormwater to a potable standard to enable use of the potable distribution network. A case study based on the Throsby Creek catchment in Newcastle explores the issue. The high seasonally uniform rainfall provides insight into the maximum potential of such an option. Multicriterion optimisation was used to identify Pareto optimal solutions for harvesting, storing and treating stormwater. It is shown that harvesting and treating stormwater from a 13 km2 catchment can produce yields ranging from 8.5 to 14.2 ML/day at costs ranging from AU$2.60/kL to AU$2.89/kL, which may become viable as the cost of traditional supply continues to grow. However, there are significant social impacts to deal with including alienation of public land for storage and community acceptance of treated stormwater. PMID- 21245549 TI - Treating municipal wastewater with the goal of resource recovery. AB - A new municipal wastewater treatment flowsheet was developed with the objectives of energy sustainability, and water and nutrient recovery. Energy is derived by shunting a large fraction of the organic carbon in the wastewater to an anaerobic digestion system. Aerobic and anaerobic membrane bioreactors play a key role in energy recovery. Phosphorus and nitrogen are removed from the wastewater and recovered through physical-chemical processes. Computer modeling and simulation results together with energy balance calculations, imply the new flowsheet will result in a dramatic reduction in energy usage at lower treatment plant capital costs in comparison to conventional methods. PMID- 21245550 TI - Ten persistent myths and the realities of membrane bioreactor technology for municipal applications. AB - Twelve years after the first full scale municipal application in Europe of membrane bioreactor (MBR) technology, the process is now accepted as a technology of choice for wastewater treatment, and the market is showing sustained growth. However early misconceptions about the technology are persistent and false statements are commonly encountered in articles and conferences, generating unnecessary research efforts or even fuelling either fascination or scepticism with regards to the technology, which is ultimately detrimental to the perception of the process by water professionals. We try to provide some factual and rational clarifications on ten issues which are often wrongly reported about MBR technology. PMID- 21245551 TI - Quantifying the formation of nitrogen-containing disinfection by-products in chlorinated water using absorbance and fluorescence indexes. AB - Among known but unregulated disinfection by-products (DBPs), several nitrogenous species (N-DBPs) have been found in drinking waters. While concentrations of N DBP are much lower than those of trihalomethanes (THMs) and haloacetic acids (HAAs), their potential toxicity is higher. In this study the relationships between the formation of N-DBPs and the changes in NOM caused by the chlorination of raw Ancipa water quantified by the use of differential absorbance and fluorescence indexes were investigated. Very strong relationships were found between selected N-DBPs (i.e. trichloronitromethane and dichloroacetonitrile) and the proposed spectroscopic indexes that were previously developed to quantify the changes in natural organic matter (NOM) during chlorination at varying reaction conditions (chlorine dose, reaction time and temperature) and the generation of DBPs. Obtained results clearly indicate that the changes in NOM absorbance and fluorescence are fundamental descriptors of the formation of both commonly controlled halogenated DBPs and N-DBPs. This approach may be suitable for real time monitoring of emerging N-DBPs and for studying their formation pathways. PMID- 21245552 TI - Adsorption of dimethylamine from aqueous solution by manganese dioxide. AB - Removal of precursors of N-nitrosodimethylamine (NDMA), such as the most direct precursor dimethylamine (DMA), might be an effective method to control NDMA formation during practical water treatment process. Adsorption of DMA onto manganese dioxide (MnO2) from aqueous solution has been investigated using batch experiments in this study. Results indicate that DMA adsorption is initially rapid (in the first 5 h) and the adsorption process reaches a steady state after 15 h. The adsorption isotherms are well described by the Freundlich models. The desorption shows an irreversibility of DMA adsorption onto MnO2. The effects of temperature, pH, ionic strength, humic acid, and the presence of other secondary aliphatic amines on adsorption processes are also examined. According to the experimental results, the amount of DMA adsorbed increases with an increase of temperature from 288 to 308 K, and with a decrease of ionic strength from 1 to 10 mM. The maximum adsorption appeared at pH 7.0. However, the amount of DMA adsorbed onto MnO2 does not show obvious difference in the presence of humic acid. According to the results, it suggests that the adsorption is primarily brought about by electrostatic interaction between DMA and MnO2 surface. PMID- 21245553 TI - Removal and fate of estrogens in an anaerobic-anoxic-oxic activated sludge system. AB - Laboratory-scale experiments were conducted to investigate the removal and fate of estrogens 17beta-estradiol (E2) and 17alpha-ethinylestradiol (EE2) in an anaerobic-anoxic-oxic (AAO) activated sludge system. Estrogen concentrations in the aqueous and solid phases in each reactor of AAO system were analyzed separately. E2 was not detected in the final effluent. The anaerobic, anoxic and oxic reactors accounted for 71%, 7% and 22% of the overall E2 removal, respectively. The overall EE2 removal efficiency was about 80%, and the anaerobic, anoxic and oxic reactors were responsible for 44%, 8% and 48% of the overall EE2 removal, respectively. In anaerobic unit, sorption was the dominant mechanism for the removal of E2 and EE2. While E2 was degraded in all the three units of the AAO system, EE2 was only degraded in the anoxic and aerobic units. Biodegradation is important for the fate of E2 compared to sorption. Of the total influent E2 in the AAO system, 99.99% was biodegraded and 0.01% remained in the waste sludge. Nevertheless, both sorption and biodegradation play important roles in the removal of EE2. Of the total influent EE2, 79.1% was degraded by activated sludge, 19.9% was discharged in the effluent and 1% remained in the waste sludge. PMID- 21245554 TI - Limiting the emissions of micro-pollutants: what efficiency can we expect from wastewater treatment plants? AB - The next challenge of wastewater treatment is to reliably remove micro-pollutants at the microgram per litre range in order to meet the environmental quality standards set by new regulations like the Water Framework Directive. The present work assessed the efficiency of different types of primary, secondary and tertiary processes for the removal of more than 100 priority substances and other relevant emerging pollutants through on-site mass balances over 19 municipal wastewater treatment lines. Secondary biological processes proved to be in average 30% more efficient than primary settling processes. The activated sludge (AS) process led to a significant reduction of pollution loads (more than 50% removal for 70% of the substances detected). Biofilm processes led to equivalent removal efficiencies compared to AS, except for some pharmaceuticals. The membrane bioreactor (MBR) process allowed to upgrade removal efficiencies of some substances only partially degraded during conventional AS processes. Preliminary tertiary processes like tertiary settling and sand filtration could achieve significant removal for adsorbable substances. Advanced tertiary processes, like ozonation, activated carbon and reverse osmosis were all very efficient (close to 100%) to complete the removal of polar pesticides and pharmaceuticals; less polar substances being better retained by reverse osmosis. PMID- 21245555 TI - Full scale membrane bioreactor treatment of hospital wastewater as forerunner for hot-spot wastewater treatment solutions in high density urban areas. AB - Membrane Bioreactors (MBR) are a very attractive option for the treatment of hospital wastewater and elimination of pharmaceuticals in high density urban areas. The present investigation showed that, depending on the substance, between 19% and 94% of the level of antibiotics found in the environment originate from hospitals. Because of their ecotoxic potential, hospital wastewaters can have a significant impact on the environment. The segregation of these wastewaters and their separate treatment at the source can reduce the entry of drugs in waterways and enable water reuse after adequate polishing treatment processes. PMID- 21245556 TI - Removal of micropollutants in WWTP effluent by biological assisted membrane carbon filtration (BioMAC). AB - In the frame of the European FP6 project Neptune, a combination of biological activated carbon with ultrafiltration (BioMAC) was investigated for micropollutant, pathogen and ecotoxicity removal. One pilot scale set-up and two lab-scale set-ups, of which in one set-up the granular activated carbon (GAC) was replaced by sand, were followed up during a period of 11 months. It was found that a combination of GAC and ultrafiltration led to an almost complete removal of antibiotics and a high removal (>80%) of most of the investigated acidic pharmaceuticals and iodinated contrast media. The duration of the tests did however not allow to conclude that the biological activation was able to extend the lifetime of the GAC. Furthermore, a significant decrease in estrogenic and anti-androgenic activity could be illustrated. The set-up in which GAC was replaced by sand showed a considerably lower removal efficiency for micropollutants, especially for antibiotics but no influence on steroid activity. PMID- 21245557 TI - London Tideway Tunnels: tackling London's Victorian legacy of combined sewer overflows. AB - It takes a few millimetres of rainfall to cause the 34 most polluting combined sewer overflows (CSOs) to discharge into the River Thames. Currently, in a typical year, spillages to the tidal reaches of the River Thames occur about 60 times, with an estimated spill volume of 39 million cubic metres. Both the UK Government and the European Union have determined that the CSO discharges have an adverse environmental impact on fish species, introduce unacceptable aesthetics and elevate the health risks for recreational users of the Thames, with a frequency of discharge which is in breach of the Urban Wastewater Treatment Directive. Studies have established that the environmental objectives can be fully met on the most cost-effective basis by completing both quality improvements to treatment works and by the provision of a storage and transfer tunnel to intercept unsatisfactory CSOs. Extensive modelling has been undertaken to develop an optimised solution. In parallel with the design development a rigorous and comprehensive site selection methodology has been established to select sites and consult stakeholders and the public on the preferred sites and scheme, with the first stage of public consultation planned for later in 2010. The London Tideway Tunnels are an essential part of the delivery of improvements to the water quality of the tidal River Thames, and this ambitious, historic scheme represents a vital strategic investment in London's infrastructure. PMID- 21245558 TI - Water and energy as inseparable twins for sustainable solutions. AB - Although the water cycle is only a minor contributor to the energy demand in society, it is a matter of good housekeeping to minimize the energy need within a sustainable water cycle. Wastewater treatment should not only be applied to purify the water, but also recover the energy present in this water, as well as to recover essential elements like nitrogen and phosphorus. From an energy analysis of the Dutch water cycle it is concluded that creating an energy neutral water cycle by using the heat content or by making use of the organic load of wastewater is within hands. PMID- 21245559 TI - Investigating the mechanism of sludge reduction in activated sludge with an anaerobic side-stream reactor. AB - To investigate the mechanism of sludge reduction in activated sludge (AS) with an anaerobic side-stream reactor (ASSR), four AS systems with different digestion schemes were operated in the laboratory. The four systems are: a) AS+ASSR; b) AS+aerobic digester; c) AS+anaerobic digester; and d) AS with no solids wastage. The average sludge yield of AS+ASSR from two phases was 0.14 mgVSS/mgCOD, which is 22-54% less than that from the three other systems. The accounting of biomass in AS+ASSR system revealed that 50% of sludge is degraded in ASSR while the other half is degraded in the aeration basin. Furthermore, both whole sludge and centrate from ASSR led to a significant oxygen uptake in AS, indicating the importance of aerobic biodegradation in AS+ASSR system. The extracellular polymeric substances (EPS) data showed that base-extractable EPS was much smaller for AS with ASSR than with no wastage. In contrast, cation exchange resin-EPS was similar for both systems. These results indicate that degradation of base extractable EPS accounts for the lower sludge yield in AS+ASSR, and based on the literature this organic pool is believed to be aluminium and/or iron-bound EPS. The microbial profile data suggests that recirculation in AS+ASSR selects some unique microorganisms. Further research is warranted to study their role in sludge reduction. PMID- 21245560 TI - Performance review of large scale up-flow anaerobic sludge blanket sewage treatment plants. AB - This article evaluates the performance of 10 large scale upflow anaerobic sludge blanket (UASB) sewage treatment plants (STP) located in semi-tropical areas, 7 plants were located in Brazil, 2 in India and 1 in the Middle East. In addition to the UASB, essential functional units of the STP which potentially impact on the UASB are also evaluated. Most grit removal systems were performing adequately, however in one plant very little grit was being removed. This could have serious implications for the performance of the plant as in a relatively short period of time the reactors could become full of grit. The performance results obtained in this study (COD, BOD and TSS removal efficiencies) are compared to the results of recent literature publications and also to the results of some early pilot and full scale studies. The results found here are broadly similar to those result reported in the recent literature but show a lower performance in comparison with the early pilot scale plants. Factors such as improper design, poor operating procedures, insufficient maintenance and the presence of high sulphate concentrations have been identified as the main reasons for the lower performance. PMID- 21245561 TI - Preliminary study on the occurrence and risk arising from bacteria internalized in zooplankton in drinking water. AB - In this study, an environmental sampling campaign was conducted to detect internalized E. coli and C. jejuni bacteria in zooplankton and amoebae samples collected at various stages of three water treatment plants in Amsterdam, the Netherlands. Eight sampling locations were selected and sampling was performed twice, at a two-week interval, at each location. Chlorination was used to inactivate free (external) bacteria in the concentrated zooplankton samples and sonication was used to disrupt zooplankton organisms in order to release and recover internalized bacteria. Zooplankton enumeration was performed by microscopy. No internalized E. coli or C. jejuni bacteria were recovered from all of the samples analyzed. The occurrence of internalized E. coli or C. jejuni bacteria in drinking water was estimated to be lower than one internalized bacteria in 105 zooplankton organisms, as derived from the detection limit of the sampling campaign. By using the QMRA approach and the Beta-Poisson model, a risk of infection of less than 9.2E-6 and 5.9E-5 was estimated for internalized E. coli and C. jejuni in drinking water, respectively. This study remains preliminary due to the limited number of samples taken at each location. PMID- 21245562 TI - Perfluorinated compounds (PFCs) in Yodo River system, Japan. AB - There is increasing concern about occurrences of perfluorinated compounds (PFCs) in the environment due to their persistent, bioaccumulation, and potentially toxic effects. We investigated contamination of 11 PFCs (C4-C12) in the Yodo River system, which is a major source of drinking water for more than 11 million people of Kansai region in Japan. PFCs were detected in higher concentration even exceeding more than 1000 ng/L in some cases. Composition profile of total PFCs concentration showed that PFOS, PFHxA, PFOA, and PFNA were occurring dominantly in the river system. PFOS and PFOA concentration were nearly proportional to a previous study in the same river system, indicating continuous sink of the compounds into the river system. Although discharge of PFCs from wastewater effluents at upstream could be one of the major point sources, concentration did not exceed 29.4 ng/L at the downstream of main Yodo River, possibly, due to dilution effects. Total mass load of PFCs in mainstream of Yodo River was estimated 451.7 g/d based on observed river discharge and PFCs concentration. Results showed that Yodo River system could have a unique upstream-downstream linkage of PFCs contamination and the river could be a continuous pathway of PFCs exposure to the people of Kansai region. PMID- 21245563 TI - Biological removal of cationic fission products from nuclear wastewater. AB - Nuclear energy is becoming a preferred energy source amidst rising concerns over the impacts of fossil fuel based energy on global warming and climate change. However, the radioactive waste generated during nuclear power generation contains harmful long-lived fission products such as strontium (Sr). In this study, cationic strontium uptake from solution by microbial cultures obtained from mine wastewater is evaluated. A high strontium removal capacity (q(max)) with maximum loading of 444 mg/g biomass was achieved by a mixed sulphate reducing bacteria (SRB) culture. Sr removal in SRB was facilitated by cell surface based electrostatic interactions with the formation of weak ionic bonds, as 68% of the adsorbed Sr(2+) was easily desorbed from the biomass in an ion exchange reaction with MgCl2. To a lesser extent, precipitation reactions were also found to account for the removal of Sr from aqueous solution as about 3% of the sorbed Sr was precipitated due to the presence of chemical ligands while the remainder occurred as an immobile fraction. Further analysis of the Sr-loaded SRB biomass by scanning electron microscopy (SEM) coupled to energy dispersive X-ray (EDX) confirmed extracellular Sr(2+) precipitation as a result of chemical interaction. In summary, the obtained results demonstrate the prospects of using biological technologies for the remediation of industrial wastewaters contaminated by fission products. PMID- 21245564 TI - Optimization of lead (II) biosorption in an aqueous solution using chemically modified aerobic digested sludge. AB - Biosorption of Pb(II) by using digested sludge obtained from a municipal wastewater treatment plant in Tehran was examined. The aims of this investigation were biosorption of Pb(II) ions onto chemically treated digested sludge with hydrogen peroxide (H2O2) solution and determination of kinetic and isotherm of biosorption. Biosorption capacity of two types of sludge (treated and untreated) for biosorption of Pb(II) ions was investigated as function of initial Pb(II) concentration and pH using batch biosorption systems. The equilibrium biosorption capacity increased with increasing of initial metal ion concentrations and pH for both of digested sludge. The pseudo-second order kinetic model was found to be slightly suitable than the pseudo-first order kinetic model to correlate the experimental data for two types of digested sludge (R2>0.9). Regarding the applicability of the isotherm models, the freundlich model was found to be suitable than the other isotherm models. According to obtained q(max) from Langmuir isotherm, biosorption of Pb(II) by H2O2 treated digested sludge was found to perform better than untreated digested sludge. The maximum biosorption capacity was given 185.19 and 144.93 mgg-1 for H2O2 treated and untreated digested sludge, respectively. Also, the constant of energy (B) between the Pb(II) ions and the adsorbent surface, calculated using BET isotherm model, obtained 5401 and 3401 for H2O2 treated and untreated digested sludge, respectively. These results indicate the usefulness of H2O2 treated digested sludge as a biosorbent for Pb(II) biosorption. PMID- 21245565 TI - Modelling of lead removal by an aquatic moss. AB - Aquatic bryophytes are frequently used as biomonitors for trace metals in aquatic ecosystems. Nevertheless, their special characteristics also allow using them as biosorbents to clean industrial wastewaters. As biosorption is a low cost and effective method for treating metal-bearing wastewaters, understanding the process kinetics is relevant for design purposes. In this study, the ability of the aquatic bryophyte Fontinalis antipyretica to remove lead from simulated wastewaters was evaluated. Three kinetic models (pseudo-first order, pseudo second order and Elovich) were fitted to the experimental data and compared by the F-test. Previously, the effect on biosorption of parameters such as the initial solution pH, contact time and initial metal ion concentration was investigated. The initial pH of the solution was found to have an optimum value is in the range 4.0-6.0. The equilibrium sorption capacity of lead by Fontinalis antipyretica increased with the initial metal concentration. For an initial metal concentration of 10 mg L-1, the uptake capacity at equilibrium was 4.8 mg g-1. Nevertheless, when the initial concentration increased up to 100 mg L-1, the uptake of lead was 10 times higher. The pseudo-second order biosorption kinetic model provided the better correlation with the experimental data (R2=1.00). The applicability of the Langmuir and Freundlich adsorption isotherms to the present system was also assessed. The maximum lead sorption capacity by Fontinalis antipyretica was 68 mg g-1. PMID- 21245566 TI - MBBR evaluation for oil refinery wastewater treatment, with post-ozonation and BAC, for wastewater reuse. AB - This work evaluated the performance of a Moving Bed Biofilm Reactor (MBBR) in the treatment of an oil refinery wastewater. Also, it investigated the possibility of reuse of the MBBR effluent, after ozonation in series with a biological activated carbon (BAC) column. The best performance of the MBBR was achieved with a hydraulic retention time (HRT) of 6 hours, employing a bed to bioreactor volume ratio (V(B)/V(R)) of 0.6. COD and N-NH4(+) MBBR effluent concentrations ranged from 40 to 75 mg L-1 (removal efficiency of 69-89%) and 2 to 6 mg L-1 (removal efficiency of 45-86%), respectively. Ozonation carried out for 15 min with an ozone concentration of 5 mg L-1 was able to improve the treated wastewater biodegradability. The treatment performance of the BAC columns was practically the same for ozonated and non ozonated MBBR effluents. The dissolved organic carbon (DOC) content of the columns of the activated carbon columns (CAG) was in the range of 2.1-3.8 mg L-1, and the corresponding DOC removal efficiencies were comprised between 52 and 75%. The effluent obtained at the end of the proposed treatment presented a quality, which meet the requirements for water reuse in the oil refinery. PMID- 21245567 TI - Biosorptive recovery of platinum from platinum group metal refining wastewaters by immobilised Saccharomyces cerevisiae. AB - The process of platinum group metal (PGM) refining can be up to 99.99% efficient at best, and although it may seem small, the amount of valuable metal lost to waste streams is appreciable enough to warrant recovery. The method currently used to remove entrained metal ions from refinery wastewaters, chemical precipitation, is not effective for selective recovery of PGMs. The yeast Saccharomyces cerevisiae has been found capable of sorbing numerous precious and base metals, and is a cheap and abundant source of biomass. In this investigation, S. cerevisiae was immobilised using polyethyleneimine and glutaraldehyde to produce a suitable sorbent, capable of high platinum uptake (150-170 mg/g) at low pH (<2). The sorption mechanism was found to be a chemical reaction, which made effective desorption impossible. When applied to PGM refinery wastewater, two key wastewater characteristics limited the success of the sorption process; high inorganic ion content and complex speciation of the platinum ions. The results proved the concept principle of platinum recovery by immobilised yeast biosorption and indicated that a more detailed understanding of the platinum speciation within the wastewater is required before biosorption can be applied. Overall, the sorption of platinum by the S. cerevisiae sorbent was demonstrated to be highly effective in principle, but the complexity of the wastewater requires that pretreatment steps be taken before the successful application of this process to industrial wastewater. PMID- 21245568 TI - Evaluation of a new model for the reduction of excess sludge production by ozonation of return activated sludge: what solids COD fraction is affected? AB - This paper aims at clarifying the effect of ozone on the RAS solids to model activated sludge systems equipped with RAS-ozonation processes for the reduction of sludge production. A common hypothesis is that ozone only affects active biomass by promoting cryptic growth. Data from a pilot-scale study were used to test this and two other model extensions to IWA-ASM3. All model extensions were able to simulate the observed linear reduction in sludge production with increasing ozone dose when the MLVSS are kept constant. However, model simulations showed the inconsistency of the cryptic growth hypothesis with the extent of sludge reduction. The second tested model extensions assumes that ozone affects all the solids fractions (active biomass, endogenous residue, and influent inert particulate COD) equally. This extension could properly simulate the observed sludge reduction, but it failed to predict the trends in effluent BOD5, ATP/VSS, and nitrification rates. A third tested model extension, which performed better, assumes that biomass is inactivated at a specific rate higher than the specific rate of transformation by ozone of the other solids fractions. Finally, the predictions from this model extension were most accurate if either (i) the nitrifiers were inactivated at a lower rate then heterotrophs, (ii) the nitrifiers model parameters (e.g., maximum growth rate) were changed under ozone (i.e., metabolic adaptation, (iii) or both. PMID- 21245569 TI - Cost optimisation and minimisation of the environmental impact through life cycle analysis of the waste water treatment plant of Bree (Belgium). AB - An ASM2da model of the full-scale waste water plant of Bree (Belgium) has been made. It showed very good correlation with reference operational data. This basic model has been extended to include an accurate calculation of environmental footprint and operational costs (energy consumption, dosing of chemicals and sludge treatment). Two optimisation strategies were compared: lowest cost meeting the effluent consent versus lowest environmental footprint. Six optimisation scenarios have been studied, namely (i) implementation of an online control system based on ammonium and nitrate sensors, (ii) implementation of a control on MLSS concentration, (iii) evaluation of internal recirculation flow, (iv) oxygen set point, (v) installation of mixing in the aeration tank, and (vi) evaluation of nitrate setpoint for post denitrification. Both an environmental impact or Life Cycle Assessment (LCA) based approach for optimisation are able to significantly lower the cost and environmental footprint. However, the LCA approach has some advantages over cost minimisation of an existing full-scale plant. LCA tends to chose control settings that are more logic: it results in a safer operation of the plant with less risks regarding the consents. It results in a better effluent at a slightly increased cost. PMID- 21245570 TI - QualViz: a tool for visual representation of water quality models. AB - As water quality models and their implementation have become increasingly diverse, complex and proprietary, a need for more thorough understanding of the differences between each alternative arises. The work presented here proposes a novel visualization paradigm for water quality applications which can be used to understand difference between implementations of identical and different conceptual models. A proof-of-concept visualization tool was developed and tested again three scenarios for four different conceptual models of biochemical kinetics. Results show representative figures illustrating how the approach can communicate differences in model complexity and dynamic behaviour. The proposed tool should help ensure more suitable application of water quality models in varied contexts. A discussion of quantifying model complexity in a single metric is also presented, and recommendations are made on the selection of various representational forms for communicating and exploring specific model characteristics. PMID- 21245571 TI - 2,4-D removal via denitrification using volatile fatty acids. AB - Many countries have waters contaminated with both herbicides and nitrates; however, information is limited with respect to removal rates for combined nitrate and herbicide elimination. This research investigates the removal of 2,4 D via denitrification, with a particular emphasis on the effect of adding naturally generated volatile fatty acids (VFAs). The acids were produced from an acid-phase anaerobic digester with a mean VFA concentration of 3153+/-801 mg/L (as acetic acid). Initially, 2,4-D degrading bacteria were developed in an SBR fed with both sewage and 2,4-D (30-100 mg/L). Subsequent denitrification batch tests demonstrated that the specific denitrification rate increased from 0.0119+/ 0.0039 using 2,4-D alone to 0.0192+/-0.0079 g NO3-N/g VSS per day, when 2,4-D was combined with natural VFAs from the digester. Similarly, the specific 2,4-D consumption rate increased from 0.0016+/-0.0009 using 2,4-D alone to 0.0055+/ 0.0021 g 2,4-D/g VSS per day, when using 2,4-D plus natural VFAs. Finally, a parallel increase in the percent 2,4-D removal was observed, rising from 28.33+/ 11.88 using 2,4-D alone to 54.17+/-21.89 using 2,4-D plus natural VFAs. PMID- 21245572 TI - Water and energy link in the cities of the future - achieving net zero carbon and pollution emissions footprint. AB - This article discusses the link between water conservation, reclamation, reuse and energy use as related to the goal of achieving the net zero carbon emission footprint in future sustainable cities. It defines sustainable ecocities and outlines quantitatively steps towards the reduction of energy use due to water and used water flows, management and limits in linear and closed loop water/stormwater/wastewater management systems. The three phase water energy nexus diagram may have a minimum inflection point beyond which reduction of water demand may not result in a reduction of energy and carbon emissions. Hence, water conservation is the best alternative solution to water shortages and minimizing the carbon footprint. A marginal water/energy chart is developed and proposed to assist planners in developing future ecocities and retrofitting older communities to achieve sustainability. PMID- 21245573 TI - One-year monthly survey of rotavirus, astrovirus and norovirus in three sewage treatment plants in Beijing, China and associated health risk assessment. AB - To evaluate the presence and distribution of the three main viruses (rotavirus, astrovirus, and norovirus) responsible for human acute gastroenteritis in sewerage system an one-year study was carried out in Beijing, China. A total of 96 samples of influent and effluents from three sewage treatment plants (STPs) were collected from November 2006 to October 2007. Silica was used to concentrate viral particles from water samples and a reverse transcriptase-nested polymerase chain reaction (RT-nested PCR) method was used for detection of viruses. Viruses could be detected in 35.4% (34/96) of the water samples analyzed, where human rotavirus was the most frequently detected (32.3%, 31/96), followed by human astrovirus (6.3%, 6/96) and human norovirus (3.1%, 3/96). According to the quantitation results of rotaviruses, which were gained by the real-time quantitative RT-PCR method with SYBR Green I , it was known that the distributions of rotaviruses in influents and effluents of three STPs were quite similar, i.e., abundant in cold weather (from October to March) and less prevalent in warm weather (from April to September). According to the estimated exposure dose, exposure frequency, as well as the acceptable annual risk level, it was shown that the rotaviruses in the reused wastewater after conventional treatment process presented potential risk to human health through both occupational and accidental exposure. PMID- 21245574 TI - KSHV infects a subset of human tonsillar B cells, driving proliferation and plasmablast differentiation. AB - Kaposi sarcoma-associated herpesvirus (KSHV; also known as HHV8) is the causative agent of two B cell tumors, multicentric Castleman disease (MCD) and primary effusion lymphoma (PEL). However, little is known about the nature of the specific B cell subtype(s) most susceptible to infection. Identifying these cells would provide direct insight into KSHV transmission and virus-induced transformation. To identify this subset and to determine whether infection alters its cellular phenotype, we exposed human tonsillar cells to KSHV and characterized infected cells using high-throughput multispectral imaging flow cytometry (MIFC). Stable expression of the virally encoded latency-associated nuclear antigen (LANA), a marker of latent KSHV infection, was observed predominantly in cells expressing the l light chain of the B cell receptor. These LANA+ B cells proliferated and exhibited similarities to the cells characteristic of MCD (IgMl-expressing plasmablasts), including blasting morphology with elevated expression of Ki67, variable expression of CD27, and high levels of IgM and IL-6 receptor. Furthermore, the proportion of infected cells showing a blasting phenotype increased upon addition of exogenous IL-6. Our data lead us to propose that oral transmission of KSHV involves the latent infection of a subset of tonsillar IgMl-expressing B cells, which then proliferate as they acquire the plasmablast phenotype characteristic of MCD. PMID- 21245575 TI - Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice. AB - Transplantation of allogeneic stem cells into the early gestational fetus, a treatment termed in utero hematopoietic cell transplantation (IUHCTx), could potentially overcome the limitations of bone marrow transplants, including graft rejection and the chronic immunosuppression required to prevent rejection. However, clinical use of IUHCTx has been hampered by poor engraftment, possibly due to a host immune response against the graft. Since the fetal immune system is relatively immature, we hypothesized that maternal cells trafficking into the fetus may pose the true barrier to effective IUHCTx. Here, we have demonstrated that there is macrochimerism of maternal leukocytes in the blood of unmanipulated mouse fetuses, with substantial increases in T cell trafficking after IUHCTx. To determine the contribution of these maternal lymphocytes to rejection after IUHCTx, we bred T and/or B cell-deficient mothers to wild-type fathers and performed allogeneic IUHCTx into the immunocompetent fetuses. There was a marked improvement in engraftment if the mother lacked T cells but not B cells, indicating that maternal T cells are the main barrier to engraftment. Furthermore, when the graft was matched to the mother, there was no difference in engraftment between syngeneic and allogeneic fetal recipients. Our study suggests that the clinical success of IUHCTx may be improved by transplanting cells matched to the mother. PMID- 21245577 TI - alpha-Synuclein propagates from mouse brain to grafted dopaminergic neurons and seeds aggregation in cultured human cells. AB - Post-mortem analyses of brains from patients with Parkinson disease who received fetal mesencephalic transplants show that alpha-synuclein-containing (alpha-syn containing) Lewy bodies gradually appear in grafted neurons. Here, we explored whether intercellular transfer of alpha-syn from host to graft, followed by seeding of alpha-syn aggregation in recipient neurons, can contribute to this phenomenon. We assessed alpha-syn cell-to-cell transfer using microscopy, flow cytometry, and high-content screening in several coculture model systems. Coculturing cells engineered to express either GFP- or DsRed-tagged alpha-syn resulted in a gradual increase in double-labeled cells. Importantly, alpha-syn GFP derived from 1 neuroblastoma cell line localized to red fluorescent aggregates in other cells expressing DsRed-alpha-syn, suggesting a seeding effect of transmitted alpha-syn. Extracellular alpha-syn was taken up by cells through endocytosis and interacted with intracellular alpha-syn. Next, following intracortical injection of recombinant alpha-syn in rats, we found neuronal uptake was attenuated by coinjection of an endocytosis inhibitor. Finally, we demonstrated in vivo transfer of alpha-syn between host cells and grafted dopaminergic neurons in mice overexpressing human alpha-syn. In summary, intercellularly transferred alpha-syn interacts with cytoplasmic alpha-syn and can propagate alpha-syn pathology. These results suggest that alpha-syn propagation is a key element in the progression of Parkinson disease pathology. PMID- 21245576 TI - Genetic rescue of nonclassical ERalpha signaling normalizes energy balance in obese Eralpha-null mutant mice. AB - In addition to its role in reproduction, estradiol-17beta is critical to the regulation of energy balance and body weight. Estrogen receptor alpha-null (Eralpha-/-) mutant mice develop an obese state characterized by decreased energy expenditure, decreased locomotion, increased adiposity, altered glucose homeostasis, and hyperleptinemia. Such features are reminiscent of the propensity of postmenopausal women to develop obesity and type 2 diabetes. The mechanisms by which ERalpha signaling maintains normal energy balance, however, have remained unclear. Here we used knockin mice that express mutant ERalpha that can only signal through the noncanonical pathway to assess the role of nonclassical ERalpha signaling in energy homeostasis. In these mice, we found that nonclassical ERalpha signaling restored metabolic parameters dysregulated in Eralpha-/- mutant mice to normal or near-normal values. The rescue of body weight and metabolic function by nonclassical ERalpha signaling was mediated by normalization of energy expenditure, including voluntary locomotor activity. These findings indicate that nonclassical ERalpha signaling mediates major effects of estradiol-17beta on energy balance, raising the possibility that selective ERalpha agonists may be developed to reduce the risks of obesity and metabolic disturbances in postmenopausal women. PMID- 21245579 TI - Health promotion: the new public health agenda. PMID- 21245578 TI - Mouse and human iNKT cell agonist beta-mannosylceramide reveals a distinct mechanism of tumor immunity. AB - Type 1 or invariant NKT (iNKT) cell agonists, epitomized by alpha galactosylceramide, protect against cancer largely by IFN-gamma-dependent mechanisms. Here we describe what we believe to be a novel IFN-gamma-independent mechanism induced by beta-mannosylceramide, which also defines a potentially new class of iNKT cell agonist, with an unusual beta-linked sugar. Like alpha galactosylceramide, beta-mannosylceramide directly activates iNKT cells from both mice and humans. In contrast to alpha-galactosylceramide, protection by beta mannosylceramide was completely dependent on NOS and TNF-alpha, neither of which was required to achieve protection with alpha-galactosylceramide. Moreover, at doses too low for either alone to protect, beta-mannosylceramide synergized with alpha-galactosylceramide to protect mice against tumors. These results suggest that treatment with beta-mannosylceramide provides a distinct mechanism of tumor protection that may allow efficacy where other agonists have failed. Furthermore, the ability of beta-mannosylceramide to synergize with alpha-galactosylceramide suggests treatment with this class of iNKT agonist may provide protection against tumors in humans. PMID- 21245580 TI - A review of tracking progress towards elimination of iodine deficiency disorders in Tamil Nadu, India. AB - BACKGROUND: Iodine deficiency disorders (IDD) are significant health problem in India. But there is dearth of regional/state level information for the same. OBJECTIVE: This study was designed to study the current status of IDD in Tamil Nadu. MATERIALS AND METHODS: A cross-sectional community-based survey was conducted in the state of Tamil Nadu. The study population was children in the age group of 6-12 years and the probability proportional to size 30 cluster methodology was used for sample selection. The parameters studied were prevalence of goiter, urinary iodine excretion, and iodine content in salt at the household level. RESULTS: A total of 1230 children aged between 6 and 12 years were studied. The total goiter rate was 13.5% (95% CI: 11.1-14.9). The median urinary iodine excretion was found to be 89.5 MUg/L (range, 10.2-378 MUg/L). The 56% of the urinary iodine excretion values were <100 MUg/L. The proportion of households consuming adequately iodized salt (iodine content >= 15 parts per million) was 18.2% (95% CI: 16.1-20.5). CONCLUSION: The total goiter rate of 13.5% and median urinary iodine excretion of 89.5 MUg/L is indicative of iodine deficiency in Tamil Nadu. PMID- 21245581 TI - Hand washing practices in two communities of two states of Eastern India: an intervention study. AB - BACKGROUND: Public health importance of hand washing as well as its importance in reduction of communicable diseases such as diarrhea and acute respiratory infections have been highlighted in many studies worldwide. OBJECTIVE: This study was designed to study the hand washing practices followed in two urban slums as well as to assess and compare the status of different components of hand washing at the pre- and post-intervention phases. MATERIALS AND METHODS: A community based cross-sectional intervention study on hand washing practices was carried out at two urban slums situated in two states of Eastern India with similar sociocultural and linguistic background. The study was carried out by using an interview technique as well as observation of hand washing practices. Interpersonal communication for behavioural change was chosen as a method of intervention. RESULTS: The majority (>90%) practiced hand washing after defecation in both the study areas. However, hand washing following all six steps and for stipulated time period was seen to be poor before intervention. Significant improvement was observed in all the aspects of hand washing after intervention in both the areas. The poor practice of hand washing was observed in some situations and needed attention. Use of soap and clean material for drying hands after hand washing was poor initially followed by improvement after intervention. CONCLUSION: Based on the findings of the study, it could be suggested that Behaviour Change Communication program should be further planned with emphasis on different components of hand washing with a final objective to bring down the incidence of target diseases. PMID- 21245582 TI - Public health informatics in India: the potential and the challenges. AB - Public health informatics is emerging as a new and distinct specialty area in the global scenario within the broader discipline of health informatics. The potential role of informatics in reducing health disparities in underserved populations has been identified by a number of reports from all over the world. The article discusses the scope, the limitations, and future perspective of this novice discipline in context to India. It also highlights information and technology related tools namely Geographical Information Systems, Telemedicine and Electronic Medical Record/Electronic Health Record. India needs to leverage its "technology" oriented growth until now (e.g., few satellite-based telemedicine projects, etc.) simultaneously toward development of "information" based public health informatics systems in future. Under the rapidly evolving scenario of global public health, the future of the public health governance and population health in India would depend upon building and integrating the comprehensive and responsive domain of public health informatics. PMID- 21245583 TI - Public health manpower: an alternative model. AB - The Bhore committee observed that "if nation's health is to be built, the health program should be developed on the foundation of preventive health work and that such activities should proceed side by side with the treatment of patients." The committee defined two categories of workforce: one for the personal care and the other for the public health namely, public health nurses and sanitary inspectors for public health and nurse, midwife, and pharmacist for personal care. Recommendations of successive health committees lead to amalgamation of personal care services and public health services. Single focus programs and amalgamation of different cadre of Grassroots staff lead to dilution of public health services and more focused on different program-based personal care services. To carry out public health services, we need a sufficiently knowledgeable, well-skilled and competent mid-level supervisory public health workforce who can support and strengthen the performance of the existing multipurpose workers. Increased understanding of the influence of different determinants on health and well-being and also scientific progress to combat the environmental and biological effects on health has widened the gap between the actual need of human resources and expanding public health services needs. Keeping in view of the above and meet the challenges, a 3-year course of Bachelor in Public Health is conceived by the Indian Academy of Public Health. Professional responsibilities expected from this new cadre of workforce are also discussed in this article. PMID- 21245584 TI - Operations research in public health. AB - Operations Research (OR) is gaining importance in public health interventions and programmes increasingly both nationally and internationally. The focus of these research techniques is to constantly guide the programme implementation to achieve best results. It modulates inputs and processes involved in the programme cycle and strive to produce optimal gains in achieving targets and goals. Utilizing the vast range of qualitative and quantitative tools, this research has produced significant results worth applying and testing in the real field. It also identifies problems; often programme managers encompass in operations of public health goods and test the feasible solutions for them. This paper highlights the relevance, themes, and methodological approaches in context to OR in public health. Multiple research and training opportunities currently exist locally and globally, to carry out OR for bringing out timely improvements. PMID- 21245585 TI - Is NDM-1 actually being imported to UK from India? AB - A recent article in Lancet Infectious Diseases suggested that Enterobacteriaceae containing New Delhi metallo-betalactamase (NDM-1) gene were being imported into UK from India. Since the study findings had widespread public health implications, it was necessary to scrutinise the adequacy of the evidence. The article was critically appraised on epidemiological, biological, and molecular evidence, the ethical principle of research, potential conflict of interest, and the justifiability of the recommendations. The study design was inappropriate to establish a causal chain between hospitalization in India and importation of NDM 1 in UK. Out of the total 29 NDM-1 positive UK patients, the NDM-1 gene was present in equal proportion among those who were hospitalized in India (44.3%) and those who were not (51.7%). Statistically significant strain relatedness between Indian and UK isolates could not be proved through dendrogram. There was a potential conflict of interest that was not disclosed. We found that the study findings did not support the authors' conclusion that India was a source for NDM 1 positive UK patients. Misplaced conclusions had the potential to cause unfounded scare and panic. PMID- 21245586 TI - Prevalence of knee osteoarthritis amongst perimenopausal women in an urban resettlement colony in South Delhi. AB - A community-based cross-sectional study was carried out in an urban resettlement colony in South Delhi to study the prevalence of knee osteoarthritis in women aged >=40 years and treatment seeking behavior of women suffering from osteoarthritis. Osteoarthritis was diagnosed by using clinical criteria given by American College of Rheumatology for diagnosis of Idiopathic Osteoarthritis of knee joints. A total 260 women were interviewed out of which 123 (47.3%) women were found to be suffering from knee osteoarthritis. Prevalence of osteoarthritis found to be increased with age. Less than half of those with osteoarthritis underwent treatment. With this high prevalence of osteoarthritis, there is need to spread awareness about the disease, its prevention, and rehabilitation in the community. PMID- 21245587 TI - Obesity among adolescents of affluent public schools in Meerut. AB - The prevalence of obesity has increased worldwide in all segments of the population due to increased industrialization, urbanization, mechanization, and associated changes in diet and lifestyles. Change in diet habit of consuming more high energy fast foods and shifting to sedentary lifestyle has affected our children and also increased the risk of chronic diseases among adolescents. Childhood obesity has association with increased risk of coronary heart disease, stroke, and cancer in later life. Therefore, its control and prevention is one of the major concerns for all developing nations. The present school-based cross sectional study was carried out among 2785 affluent adolescents of six public schools in Meerut during the period October 2003 to March 2004. The objective is to assess the magnitude of overweight and obesity in adolescents and associated risk factors, with the help of the ELIZ health pathway based on body mass index criteria. Prevalence of overweight and obesity was found to be 19.7% and 5.3% in girls and 18.36% and 10.82% in boys. Obesity was found to be significantly associated with high intake of junk foods (P < 0.05), binge eating, high calorie intake (P < 0.05), lower physical activity (P < 0.05), and prolonged TV watching (P < 0.05). PMID- 21245588 TI - Awareness, perception and myths towards swine flu in school children of Bareilly, Uttar Pradesh. AB - The deadly disease swine flu is, without a speck of doubt, causing a massive havoc among the common people of India and has created fear across the various strata of the society. The objective was to find out the awareness, perception, and myths of school going children of class 9 th to 12 th toward swine flu. The present cross-sectional study was carried out in two randomly selected (using random number table) senior secondary schools of Bareilly among 400 students of class 9 th to 12 th . A total of 200 students were selected from each school. Chi square test was applied for statistical analysis. Almost all the students (97.75%) have heard about of swine flu and are aware of it as a disease entity. Fever was found to be the main symptom while coughing and sneezing were main way of spread of swine flu known to them. About 97% of the students mention use of mask as most effective way to prevent them from swine flu. Knowledge of availability of medicine was present in less than half of the students. TV was found to be the main source from which they get knowledge (79%), and they are trying to get knowledge (53.2%) of swine flu. Among them, 74% students were taking precaution against swine flu. PMID- 21245589 TI - Prevalence of bronchial asthma and its association with smoking habits among adult population in rural area. AB - A cross-sectional study was conducted in the rural field practice area of Kempegowda Institute of Medical Sciences, Bangalore. A total of 3194 adult individuals (18-70 years) were selected from 30 villages (clusters) using a cluster-sampling technique. Individuals with symptoms suggestive of asthma were subjected for clinical examination for the diagnosis of asthma. Among the 3194 respondents, 1518 (47.5%) were males and 1676 (52.5%) were females. The prevalence of bronchial asthma was 2.88%. The prevalence of asthma was higher among those reporting a history of current smoking. Among current smokers, the number of cigarettes/bidis/hookah smoked daily did not differ (P > 0.05) between individuals without asthma and with asthma, whereas the mean number of years of smoking did differ (P < 0.001). There was significant association between tobacco smoking and bronchial asthma. PMID- 21245590 TI - Lymphatic filariasis in Andhra Pradesh paper mill colony, Rajahmundry, after nine rounds of MDA program. PMID- 21245591 TI - Obstructive sleep apnea: from simple upper airway obstruction to systemic inflammation. PMID- 21245593 TI - Consequences of hypoxia-reoxygenation phenomena in patients with obstructive sleep apnea syndrome. AB - BACKGROUND AND OBJECTIVES: Obstructive sleep apnea syndrome (OSAS) is a common disorder characterized by numerous episodes of absence of respiratory flow during sleep, which can be followed by a decrease in SaO2, which is rapidly normalized when ventilation resumes. We hypothesize that this hypoxia-reoxygenation phenomena may affect the generation of vascular endothelial growth factor (VEGF), erythropoietin (EPO), endothelin-1 (ENDO-1), and inducible nitric oxide synthase (iNOS). DESIGN AND SETTING: Prospective, patients referred to sleep disorders center. PATIENTS AND METHODS: The presence and severity of OSAS were determined using the standard overnight polysomnography. Diagnosis of OSAS was made when the apnea-hypopnea index (AHI) was >=15, independent of the appearance of symptoms. Serum levels of VEGF, EPO, ENDO-1, and nitrite-nitrate were measured after overnight fasting in 69 patients with OSAS and in 17 healthy control subjects. Serum levels of VEGF and nitrite-nitrate were measured again after 12 weeks of treatment with continuous positive airway pressure (CPAP) in OSAS patients. RESULTS: Serum VEGF levels were found to be significantly higher and nitrite nitrate levels were found to be significantly lower in OSAS patients than in controls (P=.003, .008, respectively), but no differences in EPO and ENDO-1 levels were found between the groups. We demonstrated that in OSAS patients, the serum VEGF levels were decreased and nitrate levels were increased after 12 weeks of CPAP treatment (P=.001, .002, respectively). CONCLUSION: According to our data, it is likely that hypoxia-reoxygenation phenomena affect the VEGF and nitrite-nitrate levels, which may be pathogenic factors in generating cardiovascular complications in OSAS. PMID- 21245594 TI - Prevalence of diabetes mellitus in a Saudi community. AB - BACKGROUND AND OBJECTIVES: Quantifying the prevalence of diabetes mellitus is important to allow for rational planning and allocation of resources. Therefore, we designed this study to determine the prevalence of diabetes among Saudi nationals. DESIGN AND SETTING: A cross-sectional study among patients attending a primary care clinic in June 2009. PATIENTS AND METHODS: Patients were interviewed with structured questionnaires to determine the presence of diabetes by questioning for history of the disease, and charts were reviewed to document any diabetic therapies that the patients may have undergone in the past or were undergoing at that time. RESULTS: Of 6024 subjects, diabetes mellitus was present in 1792 (30%) patients. The mean (SD) age of the patients was 55.3 (13.2) years. The prevalence of diabetes was 34.1% in males and 27.6% in females (P<.0001). The mean (SD) age for onset of diabetes in males and females was 57.5 (13.1) and 53.4 (13.1) years, respectively (P<.0001). Females <50 years old had a higher prevalence than males in the corresponding age range-34.1% and 25.1%, respectively (P<.0001). The prevalence of diabetes decreased in patients older than 70 years. The prevalence of body mass index of >=25 was 72.5%. Among patients with diabetes, the prevalence of body mass index of >=25 was 85.7% (P<.0001). There was a higher prevalence of obesity (body mass index, >=25) in females (87.7%) as compared to males (83.1%) (P=.008). CONCLUSION: The prevalence of diabetes is high among the Saudi population and represents a major clinical and public health problem. A national prevention program to prevent diabetes and address the modifiable risk factors at the community level, targeting high-risk groups, should be implemented soon. PMID- 21245592 TI - 18F-FDG PET/CT imaging in oncology. AB - Accurate diagnosis and staging are essential for the optimal management of cancer patients. Positron emission tomography with 2-deoxy-2-[fluorine-18]fluoro-D glucose integrated with computed tomography (18F-FDG PET/CT) has emerged as a powerful imaging tool for the detection of various cancers. The combined acquisition of PET and CT has synergistic advantages over PET or CT alone and minimizes their individual limitations. It is a valuable tool for staging and restaging of some tumors and has an important role in the detection of recurrence in asymptomatic patients with rising tumor marker levels and patients with negative or equivocal findings on conventional imaging techniques. It also allows for monitoring response to therapy and permitting timely modification of therapeutic regimens. In about 27% of the patients, the course of management is changed. This review provides guidance for oncologists/radiotherapists and clinical and surgical specialists on the use of 18F-FDG PET/CT in oncology. PMID- 21245595 TI - Outcome of a newborn hearing screening program in a tertiary hospital in Malaysia: the first five years. AB - BACKGROUND AND OBJECTIVE: Universal newborn hearing screening (UNHS) was started in the Hospital Universiti Sains Malaysia (HUSM) in January 2003. To comply with international standards, we determined the outcome of the newborn hearing screening program for the first 5 years of its implementation, from January 2003 to December 2007. METHODS: The program screened all infants who were delivered in HUSM. In a retrospective review, the outcomes in terms of coverage, prevalence of hearing impairment, referral rate for each screening, age at detection of hearing impairment and at hearing aid-fitting were analyzed. RESULTS: Ninety-eight percent of newborns were screened. The study included 16,100 randomly selected newborns. The initial screening referral rate was 25.5%. The prevalence of default for second and third screening was 33.9% and 40.7%, respectively. The mean (SD) age at detection of hearing impairment was 3.3 months (0.86). The mean (SD) age at fitting of a hearing aid was 13.6 (4.8) months.The prevalence of hearing impairment was 0.09%. CONCLUSION: A newborn hearing screening program is an important tool for early diagnosis and treatment. Even though the prevalence of hearing impairment may be low, the problem needs to be addressed early as the development of infants requires normal hearing. PMID- 21245596 TI - OX40/OX40L in systemic lupus erythematosus: association with disease activity and lupus nephritis. AB - BACKGROUND AND OBJECTIVES: OX40-OX40L interaction is implicated in the pathogenesis of systemic lupus erythematosus (SLE). We evaluated the role of OX40/OX40L as markers of disease activity and nephritis in SLE patients. DESIGN AND SETTING: Case-control study conducted in 2009 on SLE patients attending the outpatient clinics of Ain Shams University Hospital, Egypt. PATIENTS AND METHODS: We assessed the percentage of CD4+ T-lymphocytes expressing OX40 by flowcytometry, and serum OX40 ligand (OX40L) levels in 40 patients with SLE (20 with lupus nephritis and 20 without) and in 20 healthy controls. Disease activity was assessed by the University of Toronto SLE disease activity index (SLEDAI). RESULTS: The percentage of CD4+ T-lymphocytes expressing OX40 was significantly higher in SLE patients than in controls, and in patients with lupus nephritis than in those without. OX40 expression correlated positively with both serum creatinine levels and SLEDAI. OX40 expression was the highest in patients with class V lupus nephritis and lowest in class II. Serum OX40L levels were significantly higher in SLE patients than in controls, and in patients with nephritis than in those without. Serum OX40L levels correlated with serum creatinine levels but not with SLEDAI. OX40 expression on CD4+ T-cells had a higher sensitivity and specificity in diagnosing lupus nephritis than both OX40L and anti-double-stranded DNA levels. CONCLUSION: OX40-OX40L interaction plays a role in the pathogenesis of SLE. The expression of OX40 on CD4+ T-lymphocytes and the serum level of OX40L may act as markers of lupus nephritis. Measurements of percentages of CD4+ T-lymphocytes expressing OX40 may serve as an indicator of disease activity in SLE. PMID- 21245597 TI - Prevalence of the Pro12Ala missense mutation in the PPARG2 gene in Kuwaiti patients with primary knee osteoarthritis. AB - BACKGROUND AND OBJECTIVES: Peroxisome proliferator-activated receptors (PPARs) play an important role in a number of cellular and metabolic functions. This study was carried out to determine the prevalence of a missense mutation (Pro12Ala) in the PPARG2 gene in Kuwaiti Arab patients with primary knee osteoarthritis (OA) and healthy controls with the aim of identifying a possible association. DESIGN AND SETTING: A prospective cross-sectional study carried out at three major teaching hospitals (referral centers) in the country over a one year period. PATIENTS AND METHODS: The prevalence of PPARG2 gene Pro12Ala missense mutation was determined in 104 Kuwaiti Arab patients with primary knee OA and 111 ethnically matched healthy controls. The prevalence of this Pro12Ala missense mutation was also determined in clinical subgroups of OA patients divided on the basis of age at onset, function and radiologic grading. RESULTS: The Pro-Pro genotype of the PPARG2 gene Pro12Ala missense mutation was detected in 95/104 (91.3%) cases compared to 111/111 (100%) in the control subjects. The heterozygous Pro-Ala genotype was detected in 9/104 (8.7%) of the OA patients, while it was not detected in any of the controls. The Ala-Ala genotype was not detected in any of the OA patients or the controls. No significant differences were detected in the PPARG2 gene Pro12Ala genotypes in the subgroups of patients classified on the basis of age at onset, functional assessment using Lequesne's functional index, and radiological grading using Kellgren-Lawrence (K-L) grading. CONCLUSIONS: This study found no significant association between the PPARG2 gene Pro12Ala missense mutation and knee OA. However, the presence of the Pro-Pro genotype of the PPARG2 gene mutation has a protective effect against development of OA. PMID- 21245598 TI - -174G>C interleukin-6 gene polymorphism in Tunisian patients with coronary artery disease. AB - BACKGROUND AND OBJECTIVES: A state of low-grade inflammation accompanies the pathogenesis of atherosclerotic events. Interleukin-6 (IL-6) is a pleotropic pro inflammatory cytokine that modulates the development of acute coronary syndromes (ACSs), partly by destabilizing coronary atherosclerotic plaques. We have examined the contribution of the -174G>C IL-6 promoter variant on the risk of coronary artery disease (CAD) among Tunisians. PATIENTS AND METHODS: Study subjects included 418 CAD patients and 406 age- and sex-matched controls. IL-6 genotyping was done by PCR-restriction fragment length polymorphism. RESULTS: The frequency of the -174C allele (mutant) was lower in Tunisians than in Europeans, and the distribution of -174 G>C genotypes was similar between CAD patients and control subjects. Moreover, compared to GG genotype carriers, -174C allele carriage did not increase the CAD relative risk (odds ratio and 95% confidence interval=1.09 and 0.80-1.49), which remained nonsignificant after adjusting for traditional risk factors for CAD (age, smoking, hypertension, diabetes and obesity). CONCLUSION: The -174G>C IL-6 promoter variant is not associated with an increased risk of CAD among Tunisians. PMID- 21245599 TI - Detection of nucleophosmin and FMS-like tyrosine kinase-3 gene mutations in acute myeloid leukemia. AB - BACKGROUND AND OBJECTIVES: Nucleophosmin gene mutations are frequently reported in acute myeloid leukemia (AML) patients with normal karyotype, which is also frequently associated with internal tandem duplication mutations in the FMS-like tyrosine kinase-3 gene. We sought to detect the nucleophosmin and FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (ITD) mutations among Iranian patients with AML and to assess the relationship between these mutations and the subtypes of the disease. DESIGN AND SETTING: Cross-sectional study of patients referred during 2007 through 2009. PATIENTS AND METHODS: Bone marrow and peripheral blood samples of 131 AML patients were randomly collected at the time of diagnosis and prior to treatment and the DNA extracted. After amplifying the nucleophosmin and FLT3 gene regions, positive cases were screened by conformation sensitive gel electrophoresis and agarose gel electrophoresis techniques. RESULTS: Of 131 patients, 23 (17.5%) (0.95% CI=0.107-0.244) had nucleophosmin gene mutations. The highest frequency of such mutations was found among the subtypes of M4 (30.4%), M3 (21.7%) and M5 (17.4%). There was a high frequency of these mutations in the M3 subtype as well as a high frequency of allele D in all subtypes. Also, 21 (16.0%) samples (0.95% CI=0.092-0.229) had FLT3/ITD mutation, of which 8 samples had mutant nucleophosmin (8 of 23, 35%), and another 13 samples had wild-type nucleophosmin gene (13 of 108, 12%). There was a high degree of association between the occurrence of nucleophosmin and FLT3/ITD mutations (P=.012). CONCLUSION: Our data showed a high frequency of NPM1 mutations in the monocytic subtypes of AML, as well as a high degree of association between the occurrence of NPM1 and FLT3/ITD mutations. PMID- 21245600 TI - Celiac disease in children and adolescents at a singe center in Saudi Arabia. AB - BACKGROUND AND OBJECTIVES: Celiac disease (CD) is an immune-mediated enteropathy, induced by gluten in genetically susceptible individuals. The objective of this study was to describe the clinical pattern of CD in children from the western region of Saudi Arabia. DESIGN AND SETTING: Retrospective, hospital-based. PATIENTS AND METHODS: This study included children with a biopsy-proven diagnosis of CD made between September 2002 and July 2007. Children were admitted to the endoscopy unit for a small-bowel biopsy if they had gastrointestinal symptoms suggestive of CD or if they were positive for a CD-antibody screen performed for the high-risk groups. RESULTS: Eighty children were identified with a diagnosis of CD. Their mean (SD) age was 9.6 (4.9) years (range, 0.5-18 years). There were 44 (55%) female patients. Forty-one (51%) patients were detected during screening of high-risk groups, while 39 (49%) patients had classical symptoms of malabsorption. The screening also detected asymptomatic patients. Of 65 patients tested, 11 (17%) had elevated liver function tests, which reverted to normal after introduction of a gluten-free diet (GFD) except in one case. Seventy-three (91%) patients were positive for anti-tissue transglutaminase antibodies, 18 (23%), for IgG anti-gliadin antibodies; and 46 (58%), for IgA anti-gliadin antibodies. Forty-one (56%) patients showed good adherence to GFD as assessed by dietary history and the decline in anti-tTG level. CONCLUSION: CD may present with classical symptoms or be identified through screening programs. Growth and laboratory abnormalities usually improve after introduction of a GFD. Adherence to a GFD remains a problem; therefore, thorough assessment and counseling at the time of diagnosis and ongoing care are crucial. PMID- 21245601 TI - How do medical students in their clinical years perceive basic sciences courses at King Saud University? AB - BACKGROUND AND OBJECTIVES: The inclusion of detailed basic science courses in medical school curricula has been a concern of students. The main objective of this study was to explore the attitudes of medical students towards basic sciences courses taught to them in the preclinical years and the applicability of these courses to current clinical practice. DESIGN AND SETTING: A cross-sectional survey was conducted during 2008-2009 among medical students in their clinical years at King Saud University, Riyadh, Saudi Arabia. METHODS: Thirty percent of all students (n=314) were randomly selected to receive a questionnaire designed to evaluate their opinions about course load, ability to recall information, value of practical sessions, availability of references and course guidelines, and the applicability of individual courses to clinical practice. RESULTS: Students identified anatomy and pathology as the courses most overloaded with content (76% and 70%, respectively). Half of the students felt they retained the most knowledge of physiology (50%), while less than a quarter of students (19%) felt they retained the most information from biochemistry coursework. The role of practical sessions in facilitating theoretical understanding was more evident in anatomy (69%). Physiology was perceived as the subject with the highest applicability to clinical practice (66%), while pathology (29%) was identified as the subject with the least practical application. Students became increasingly negative in their opinions about basic science courses as they progressed through their medical education. CONCLUSION: Current attitudes of medical students towards their basic science courses indicate a need to reform the curricula so as to maximize the benefit of these courses. PMID- 21245603 TI - Getting your paper published: an editor's perspective. AB - By means of 10 simple lessons the problems and pitfalls of getting a manuscript published are considered. Working through each lesson in turn will provide the reader with a step-by-step guide to effective publishing in the biomedical arena. PMID- 21245604 TI - A cytogenetic study of couples with repeated spontaneous abortions. AB - BACKGROUND AND OBJECTIVE: The frequency of chromosomal aberrations in Iran is not definitely known. This study determined the frequency of chromosomal aberrations in a series of couples with two or more spontaneous abortions and compared the findings with that reported from other countries. METHODS: This was a descriptive study conducted on 100 couples with recurrent abortions. Both partners were karyotyped as part of the primary investigation. Other probable causes of abortion were also investigated. RESULTS: Chromosomal aberrations were found in 8 (8%) of the females and 5 (5%) of the males. The prevalence of chromosomal abnormalities was as follows: 4 (30.8%) balanced reciprocal translocations, 3 (23%) Robertsonian translocations, 3 (23%) pericentric inversions, 1 (7.7%) paracentric inversion, 1 (7.7%) chromosomal marker, and 1 (7.7%) polymorphism 9qh+. CONCLUSIONS: The pattern of chromosomal aberrations was similar to that reported in other studies, but the prevalence of chromosomal aberrations was higher. PMID- 21245602 TI - A reappraisal of saphenous vein grafting. AB - Autologous saphenous vein grafting has been broadly used as a bypass conduit, interposition graft, and patch graft in a variety of operations in cardiac, thoracic, neurovascular, general vascular, vascular access, and urology surgeries, since they are superior to prosthetic veins. Modified saphenous vein grafts (SVG), including spiral and cylindrical grafts, and vein cuffs or patches, are employed in vascular revascularization to satisfy the large size of the receipt vessels or to obtain a better patency. A loop SVG helps flap survival in a muscle flap transfer in plastic and reconstructive surgery. For dialysis or transfusion purposes, a straight or loop arteriovenous fistula created in the forearm or the thigh with an SVG has acceptable patency. The saphenous vein has even been used as a stent cover to minimize the potential complications of standard angioplasty technique. However, the use of saphenous vein grafting is now largely diminished in treating cerebrovascular disorders, superior vena cava syndrome, and visceral revascularization due to the introduction of angioplasty and stenting techniques. The SVG remains the preferable biomaterial in coronary artery bypass, coronary osteoplasty, free flap transfer, and surgical treatment of Peyronie disease. Implications associated with saphenous vein grafting in vascular access surgery for the purpose of dialysis and chemotherapy are considerable. Vascular cuffs and patches have been developed as an important and effective means of enhancing the patency rates of the grafts by linking the synthetic material to the receipt vessel. In addition, saphenous veins can be a cell source for tissue engineering. We review the versatile roles that saphenous vein grafting has played as well as its current status in therapy. PMID- 21245605 TI - Involvement of the cervical cord and medulla in posterior reversible encephalopathy syndrome. AB - The posterior reversible encephalopathy syndrome (PRES) is characterized by patchy cortical and subcortical lesions in the distribution of the posterior circulation. The lesions are classically reversible. This syndrome has multiple etiologies, most of which cause acute hypertension. We present a case of PRES with involvement of the medulla and cervical cord (apart from the typical parieto occipital lesions)--an extremely rare imaging manifestation of PRES. It is important to recognize the imaging findings of PRES in spinal cord, and avoid misdiagnosis as myelitis by proper clinical correlation. Typically patients with myelitis have a profound neurodeficit, while patients with spinal manifestations of PRES are asymptomatic. Involvement of the cord in PRES has probably been an underrecognized entity as spinal imaging is not routinely performed in posterior reversible encephalopathy syndrome. PMID- 21245606 TI - A rare human infection of Raoultella ornithinolytica in a diabetic foot lesion. PMID- 21245607 TI - RE: A guideline for the inpatient care of children with pyelonephritis. PMID- 21245608 TI - RE: Water pipe (shisha) smoking among male students of medical colleges in the eastern region of Saudi Arabia. PMID- 21245609 TI - Need for improved access to HIV prevention programmes. PMID- 21245610 TI - Microbicides & their implications in HIV prevention. PMID- 21245611 TI - HIV-2 goes global: an unaddressed issue in Indian anti-retroviral programmes. PMID- 21245612 TI - Serotonin transporter gene polymorphisms & obsessive-compulsive disorder. PMID- 21245613 TI - A review on peripheral blood CD4+ T lymphocyte counts in healthy adult Indians. AB - The CD4+ T lymphocytes are the crucial cells in the cascade of events in forming immune response to the foreign antigen and hence monitoring the CD4+ T cell counts to understand the extent of immune deficiency is a common practice. CD4+ T cells are also the primary target cells for human immunodeficiency virus (HIV). Hence CD4+ T lymphocyte count is the most important marker of immune dysfunction in HIV disease progression. The estimation of CD4+ T cell counts is used to decide the initiation of anti retroviral therapy (ART), to monitor the efficacy of ART and to start treatment for opportunistic infections (OIs). To develop the threshold levels of CD4+ T cell counts, data from western countries are being used in India. The CD4+ T cell counts are known to be influenced by race and environmental factors. Hence it is important to establish the reference ranges for the CD4+ T cell counts in the target population to understand the immune dysfunction. The information on the lower limits of the CD4+ T cells count is necessary to decide the initiation and monitoring of ART. The published data on the CD4+ T cells count in healthy Indian adult population have been reviewed, analyzed and discussed in this review article. The requirement of establishment of reference ranges in Indian population is discussed. PMID- 21245614 TI - Zinc: a promising agent in dietary chemoprevention of cancer. AB - Proper intake of dietary nutrients is considered crucial for preventing the initiation of events leading to the development of carcinoma. Many dietary compounds have been considered to contribute in cancer prevention including zinc, which plays a pivotal role in host defense against the initiation and promotion of several malignancies. Zinc is an essential element that is integral to many proteins and transcription factors which regulate key cellular functions such as the response to oxidative stress, DNA replication, DNA damage repair, cell cycle progression, and apoptosis. Zinc has been ascribed roles in the metabolism and interaction of malignant cells, particularly in apoptosis. Zinc is involved in structural stabilization and activation of the p53 that appears to be an important component of the apoptotic process and also in activation of certain members of the caspase family of proteases. Zinc exerts a positive beneficial effect against chemically induced preneoplastic progression in rats and provides an effective dietary chemopreventive approach to disease in vulnerable section of population with family history of carcinoma. The present review provides an insight into the research conducted on animals as well as on human subjects for providing the concept that zinc deficiency is an important factor in the development and progression of malignancy and that zinc could be efficacious in the prevention and treatment of several cancers viz., colon, pancreas, oesophageal and head and neck. However, it needs further exploration with regard to other definitive bioassays including protein expression and documentation of specific molecular markers to establish the exact mechanism for zinc-mediated cancer chemoprevention. Preclinical trials need to investigate the genetic and epigenetic pathways of chemoprevention by zinc. PMID- 21245615 TI - Characteristics, immunological response & treatment outcomes of HIV-2 compared with HIV-1 & dual infections (HIV 1/2) in Mumbai. AB - BACKGROUND AND OBJECTIVES: Information available on HIV-2 and dual infection (HIV 1/2) is limited. This study was carried out among HIV positive individuals in an urban referral clinic in Khar, Mumbai, India, to report on relative proportions of HIV-1, HIV-2 and HIV-1/2 and baseline characteristics, response to and outcomes on antiretroviral treatment (ART). METHODS: Retrospective analysis of programme data (May 2006-May 2009) at Khar HIV/AIDS clinic at Mumbai, India was done. Three test algorithm was used to diagnose HIV-1 and -2 infection. Standard ART was given to infected individuals. Information was collected on standardized forms. RESULTS: A total of 524 individuals (male=51%; median age=37 yr) were included in the analysis over a 3 year period (2006-2009) - 489 (93%) with HIV-1, 28 (6%) with HIV-2 and 7(1%) with dual HIV-1/2 infection. HIV-2 individuals were significantly older than HIV-1 individuals (P<0.001). A significantly higher proportion of HIV-2 patients and those with dual infections had CD4 counts <200 cells/MUl compared to HIV-1. HIV-2 individuals were more likely to present in WHO Clinical Stage 4. Of the 443 patients who were started on ART, 358 (81%) were still alive and on ART, 38 (8.5%) died and 3 were transferred out. CD4 count recovery at 6 and 12 months was satisfactory for HIV-1 and HIV-2 patients on protease inhibitor based regimens while this was significantly lower in HIV-2 individuals receiving 3 nucleoside reverse transcriptase inhibitors. INTERPRETATION AND CONCLUSIONS: In an urban HIV clinic in Mumbai, India, HIV-2 and dual infections are not uncommon. Adaptation of the current national diagnostic and management protocols to include discriminatory testing for HIV types and providing access to appropriate and effective ART regimens will prevent the development of viral resistance and preserve future therapeutic options. PMID- 21245616 TI - Association of serotonin transporter gene polymorphisms with obsessive-compulsive disorder (OCD) in a south Indian population. AB - BACKGROUND AND OBJECTIVES: Serotonin transporter polymorphisms, 5-HTTVNTR and 5 HTTLPR, have been found to be associated with obsessive-compulsive disorder (OCD) and particularly with neurotic characteristics. In the present study we looked for an association between OCD and these polymorphisms in OCD patients and controls of south Indian origin. METHODS: 5-HTTVNTR and 5-HTTLPR/rs25531 were genotyped in 93 OCD patients and 92 healthy controls. The allelic distribution and genotype frequency in cases and controls were compared using chi square test. In order to test for the effects of genotype on heterogeneity of the illness, linear regression analysis was undertaken for co-morbid depression status and YBOCS score (severity index). RESULTS: There was no significant association with the 5-HTTVNTR or the 5-HTTLPR polymorphism. No significant association of OCD with the 5-HTTLPR genotype was found even on inclusion of the rs25531 locus, which is part of the transcription factor binding site as reported in earlier studies. However, severity of the illness showed a modest association with the dominant model. INTERPRETATION AND CONCLUSIONS: Our data show that genetic variation in the SLC6A4 gene regulatory region may not have a significant effect on OCD in the present population. Further replication in a large and independent cohort with an equal number of female subjects would help to ascertain if the absence of association in this cohort is due to the nullifying effect of the larger proportion of male subjects in our sample population. The marginal effect of the 5-HTTLPR (A/G) genotype obtained on linear regression with disease severity is suggestive of a potential role for this locus in the disease process. PMID- 21245617 TI - HIV in Indian prisons: risk behaviour, prevalence, prevention & treatment. AB - BACKGROUND AND OBJECTIVES: HIV is a major health challenge for prison authorities. HIV in prisons has implications for HIV in the general community. The aim of this paper was to gather information on HIV risk, prevalence, prevention and treatment in prisons in India. METHODS: Relevant published and unpublished reports and information were sought in order to provide a coherent picture of the current situation relating to HIV prevention, treatment and care in prisons in India. Information covered prison management and population statistics, general conditions in prisons, provision of general medical care and the HIV situation in prison. RESULTS: No data on drug injection in prison were identified. Sex between men was reported to be common in some Indian prisons. A national study found that 1.7 per cent of inmates were HIV positive. Some prisons provided HIV education. Condom provision was considered illegal. A few prisoners received drug treatment for drug use, HIV infection or co-infection with sexually transmitted infections (STIs). INTERPRETATION AND CONCLUSIONS: HIV prevalence in prisons in India was higher than that in the general community. Regular monitoring of information on HIV risk behaviours and prevalence in Indian prisons is strongly recommended. Evidence based treatment for drug injectors and nation wide provision of HIV prevention strategies are urgently required. Voluntary counselling, testing and treatment for HIV and STIs should be provided. PMID- 21245618 TI - Metabolic syndrome in adult population of rural Wardha, central India. AB - BACKGROUND AND OBJECTIVES: Prevalence of metabolic syndrome is high among Asians including Indians. Scarce information is available about the magnitude of metabolic syndrome in rural areas and hence present study in rural area of Wardha district, central India. METHODS: In 300 randomly selected subjects, blood pressure and anthropometric measurements such as height, weight, waist circumference and hip circumference were noted. Blood sample was collected after overnight fasting and was subjected to biochemical quantification such as fasting blood sugar, total cholesterol, triglycerides, HDL-C, VLDL-C and LDL-C. Data were analyzed using ATP-III definition as well as by modifying the waist circumference cut-offs as per Asia-Pacific guidelines. RESULTS: Overall metabolic syndrome as per ATP-III criteria was observed in 5.0 per cent adult rural population. When ATP-III criteria were modified using waist circumference cut-offs recommended by Asia-Pacific guidelines, metabolic syndrome was seen in 9.3 per cent. It was 10.7 per cent among females and 8.2 per cent among males. Receiver operating characteristic curve was plotted to find out the best cut-off of BMI to identify the individuals with metabolic syndrome. The best cut-off for BMI came out to be 23.32 kg/m 2. INTERPRETATION AND CONCLUSIONS: The magnitude of metabolic syndrome was low among rural adults of Wardha as compared to reported values in urban areas. BMI of 23.32 kg/m 2 and higher was found to predict significant risk of metabolic syndrome in these study subjects. However, studies with larger sample need to be conducted to confirm these findings. PMID- 21245619 TI - Epidemiology of hepatitis C virus infection & liver disease among injection drug users (IDUs) in Chennai, India. AB - BACKGROUND AND OBJECTIVES: We characterized HCV antibody prevalence, viral persistence, genotype and liver disease prevalence among IDUs in Chennai, India as the study of the association of HIV with each of these states is important and there are no data available. METHODS: Between 2005-2006, 1158 IDUs were recruited and followed semi-annually. All were tested for HCV antibodies at baseline; a random sample of 400 antibody positives (200 HIV-positive and 200 HIV-negative) were tested for HCV RNA; 13 of these were sequenced. Assessment of asparate amino transferase (AST)-to-platelet ratio index (APRI) was done on 557 IDUs. Prevalence ratios of each outcome were examined. RESULTS: Median age was 35 yr; 99 per cent were male. HCV antibody prevalence was 55 per cent and was associated with older age, being unmarried, longer injection history, tattoo and injecting at a dealer's place. Of the 400 HCV antibody positive IDUs, 281 (70.3%) had persistent infection which was less common among hepatitis B-infected persons but not associated with HIV. Of the 13 samples sequenced, 11 (85%) were HCV genotype 3a. Fibrosis prevalence according to APRI was: HIV/HCV-uninfected, 4 per cent; HIV mono-infected, 3 per cent; HCV mono-infected, 11 per cent; HIV/HCV co-infected, 12 per cent (P<0.001). In addition to being associated with HCV and HIV/HCV, fibrosis prevalence was higher among those drinking alcohol frequently; daily marijuana use was protective. INTERPRETATION AND CONCLUSIONS: Our findings show that IDUs in Chennai have high HCV prevalence and associated disease burden. The burden will increase as access to antiretroviral therapy improves particularly given the high prevalence of HIV, HCV and alcohol use. PMID- 21245620 TI - Serial assessment of biochemical parameters of red cell preparations to evaluate safety for neonatal transfusions. AB - BACKGROUND AND OBJECTIVES: Neonatologists often prefer fresh blood (<7 days) for neonatal transfusions. The main concerns for stored RBCs are ex vivo storage lesions that undermine red cell functions and may affect metabolic status of neonatal recipients. This study was designed to evaluate serial in vitro changes of biochemical parameters in different RBC preparations during storage to consider for neonatal transfusions even after storage beyond one week. METHODS: Twenty five units each of whole blood (CPDA-1 RBC, SAGM RBC) were selected for serial biochemical parameter assessment after each fulfilled the quality criteria (volume and haematocrit). These units were tested serially for supernatant potassium, pH, lactate, haemoglobin, glucose and red cell 2,3 diphosphoglycerate (2,3 DPG) up to 21 days of storage. RESULTS: Within each group of RBC, rise in mean concentration of potassium, lactate and plasma haemoglobin from day 1 to 21 of storage was significant in CPDA-1 RBC having the highest levels at day 21. From day 3 to 21, SAGM RBC had higher mean pH value than CPDA-1 RBC though this difference was not statistically significant. SAGM RBC had highest mean glucose concentration during storage than other two types of red cell preparations (P<0.005). Within each group, fall in mean 2,3 DPG concentration from day 1 to 7 was significant (P<0.05). A positive correlation existed between mean plasma potassium and haemoglobin in all three types of red cells (r=0.726, 0.419, 0.605 for CPDA-1 RBC, SAGM RBC and whole blood respectively, P<0.005). INTERPRETATION AND CONCLUSIONS: All the three red cell preparations tested revealed biochemical changes within acceptable limits of safety till 21 days of storage. CPDA-1 RBCs had the highest degree of these changes. PMID- 21245621 TI - Faecal bifidobacteria in Indian neonates & the effect of asymptomatic rotavirus infection during the first month of life. AB - BACKGROUND AND OBJECTIVES: Bifidobacteria colonize the gut after the first week of life and remain an important component of the gut microbiota in infancy. This study was carried out to characterize the diversity and number of bifidobacteria colonizing the gut in Indian neonates and to investigate whether asymptomatic infection with rotavirus in the first month of life affected gut colonization by bifidobacteria. METHODS: DNA was isolated from faeces of 14 term-born neonates who were under surveillance for rotavirus infection. Bacterial and bifidobacterial diversity was evaluated by temporal temperature gradient electrophoresis (TTGE) of 16S rDNA amplified using total bacteria and bifidobacteria-specific primers. Real time PCR, targeting 16S rDNA, was used to quantitate faecal bifidobacteria and enterobacteria. RESULTS: TTGE of conserved bacterial 16S rDNA showed 3 dominant bands of which Escherichia coli (family Enterobacteriaceae) and Bifidobacterium (family Bifidobacteriaceae) were constant. TTGE of Bifidobacterium genus-specific DNA showed a single band in all neonates identified by sequencing as Bifidobacterium longum subsp. infantis. Faecal bifidobacterial counts (log 10 cfu/g faeces) ranged from 6.1 to 9.3 and enterobacterial counts from 6.3 to 9.5. Neonates without and with rotavirus infection in the first week of life did not show significant differences in the median count of bifidobacteria (log 10 count 7.48 vs. 7.41) or enterobacteria (log 10 count 8.79 vs. 7.92). INTERPRETATION AND CONCLUSIONS: B. longum subsp. infantis was the sole bifidobacterial species colonizing the gut of Indian neonates. Asymptomatic rotavirus infection in the first month of life was not associated with alteration in faecal bifidobacteria or enterobacteria. PMID- 21245622 TI - Attenuation of oxidative stress & DNA damage in varicocelectomy: implications in infertility management. AB - Sperm DNA integrity is of vital importance for foetal development and birth of healthy offspring. Oxidative stress and consequent DNA damage are the major cause of decline in semen quality in men with varicocele. A preliminary study was conducted on 11 men with clinical varicocele who also had high levels of reactive oxygen species (ROS), to assess DNA damage in sperms and ROS levels before and after varicocelectomy. Varicocelectomy resulted in rapid (1 month) significant (P<0.001) decline in free radical levels and slow (3-6 months) significant decline in DNA damage levels. Thus men undergoing varicocelectomy should try concieving only 6 months following surgery. PMID- 21245623 TI - Influenza A virus outbreak in Police Training School, Nazafgarh, Delhi 2009. PMID- 21245624 TI - Breeding potential of Aedes albopictus (Skuse, 1895) in chikungunya affected areas of Kerala, India. PMID- 21245625 TI - The need for rejuvenation of Indian biomedical journals. PMID- 21245626 TI - Dengue haemorrhagic fever among adults--an observational study in Chennai, south India. PMID- 21245627 TI - emm Type distribution pattern of group A streptococcus in north India: need for a new preventive approach. PMID- 21245628 TI - Serial changes of elevated serum IgG4 levels in IgG4-related systemic disease. AB - OBJECTIVE: Autoimmune pancreatitis (AIP) and Mikulicz's disease have recently been recognized as pancreatic or salivary gland lesions of IgG4-related systemic disease. These are frequently associated with elevated serum IgG4 levels. This study aimed to clarify clinical implications of serial changes of elevated serum IgG4 levels in IgG4-related systemic diseases. METHODS: Serial changes of elevated serum IgG4 levels were examined in patients with IgG4-related systemic diseases. Patients Serial changes of elevated serum IgG4 levels were examined in 44 patients: AIP (n=24), Mikulicz's disease (n=8), pancreatic cancer (n=5), bile duct cancer (n=1), sclerosing cholangitis (n=1), hypereosinophilic syndrome (n=1), chronic thyroiditis (n=1), hypophysitis (n=1), idiopathic pancreatitis (n=1), and Behcet's disease (n=1). RESULTS: The serum IgG4 levels decreased in all patients with AIP and Mikulicz's disease after steroid therapy. The serum IgG4 levels were normalized in 46% of AIP patients and 38% of Mikulicz's disease patients. The serum IgG4 levels were not normalized at remission in 3 of 4 relapsed AIP patients, and re-elevation of serum IgG4 levels was detected in all relapsed patients. Elevated serum IgG4 levels decreased in 3 patients with pancreatic cancer after resection or chemotherapy, and decreased in patients with hypereosinophilic syndrome, sclerosing cholangitis, and hypophysitis after steroid therapy. CONCLUSION: Measurement of serial serum IgG4 levels is useful to determine the disease activity of IgG4-related systemic diseases. PMID- 21245629 TI - Acute exacerbation of idiopathic interstitial pneumonia following lung surgery in 3 of 68 consecutive patients: a retrospective study. AB - BACKGROUND: Acute exacerbation (AE) of idiopathic interstitial pneumonia (IIP) is occasionally observed after lung surgery. However, the risk of lung surgery in patients with IIPs is not yet clearly known. SUBJECTS AND METHODS: We conducted a retrospective study of consecutive patients who underwent lung surgery for cancer or for the diagnosis of interstitial pneumonia (IP) between 2000 and 2006. Patients who developed AE following the lung operation were assessed. RESULTS: The data of 68 consecutive patients (males: 56, females: 12) with IP who underwent lung surgery were analyzed. The lung surgery included lobectomy for lung cancer in 48 patients [idiopathic pulmonary fibrosis (IPF) 31, non-IPF 17], and lung biopsy in 20 patients [IPF 8, non-specific interstitial pneumonia (NSIP) 8, unclassified 4]. Three patients with IPF (4.4% in total) developed AE after the operation (2 lobectomy, 1 biopsy). The triggers of AE were considered to be prolonged ventilation at a large tidal volume with oxygen supplementation at a high concentration. At the time of the AE, the extent of parenchymal involvement on the HRCT images was greater on the non-operated side. All three patients died of respiratory failure 12 to 82 days after the onset of AE despite corticosteroid therapy. CONCLUSION: It is essential to be aware of the risk of AE of IPF following lung operation. Intraoperative respiratory management, such as oxygen supplementation at a high concentration and/or prolonged mechanical ventilation are likely possible etiologic factors. PMID- 21245630 TI - FEV6 and FEV1/FEV6 in Japanese participants of the community-based annual health check: the Takahata study. AB - BACKGROUND: Forced expiratory volume in 6 seconds (FEV(6)) is becoming a substitute of forced vital capacity (FVC). However, the Japanese predictive equation for FEV(6) has not been established, and the validity for the use of FEV(1)/FEV(6) for diagnosing airflow limitation in Japanese has not been confirmed. METHODS: Subjects aged 40 or older, who had participated in a community-based health check in Takahata, Japan, from 2004 through 2005, were enrolled. The smoking histories of these subjects were investigated using a self reporting questionnaire. FVC, FEV(1), and FEV(6) were measured using spirometric machines. Predictive equations of FEV(6) were obtained from never-smoking subjects without history of pulmonary diseases by multiple linear regression assay. RESULTS: FEV(6) and FEV(1)/FEV(6) were significantly correlated with FVC (r=0.998, p<0.001) and FEV(1)/FVC (r=0.989, p<0.001), respectively. The cutoff values of percent predicted (%) FEV(6) and FEV(1)/FEV(6) for discrimination of having the restrictive lung disorder determined by %FVC <0.8 and having the airflow limitation determined by FEV(1)/FVC <0.7 were 0.80 and 0.72, respectively (%FEV(6): sensitivity=0.995, specificity=0.983, positive predictive value =0.832, negative predictive value =1.000; FEV(1)/FEV(6): sensitivity=0.942; specificity=0.971; PPV=0.787; NPV=0.993). When the 5th percentile the lower limit of normal values was used as criterion for discrimination of having airflow limitation, sensitivity, specificity, PPV, and NPV of FEV(1)/FEV(6) were 0.932, 0.985, 0.808, and 0.995, respectively. CONCLUSION: The results of the present study suggest that %FEV(6) and FEV(1)/FEV(6) are excellent substitutes for %FVC and FEV(1)/FVC, respectively. We confirmed the validity of the use of FEV(6) and FEV(1)/FEV(6) for identifying pulmonary diseases in Japanese individuals. PMID- 21245631 TI - Clinical symptoms and courses of primary HIV-1 infection in recent years in Japan. AB - BACKGROUND: The natural course of HIV-1 infection includes 10 years of an asymptomatic period before the development of AIDS. However, in Japan, the disease progression process seems faster in recent years. METHODS: The study subjects were 108 new patients with primary HIV-1 infection during the period from 1997 through 2007. We evaluated their clinical symptoms and laboratory data, and then analyzed disease progression in 82 eligible patients. Disease progression was defined as a fall in CD4 count below 350/uL and/or initiation of antiretroviral therapy. RESULTS: Ninety percent of the patients were infected via homosexual intercourse. All patients had at least one clinical symptom (mean; 4.75+/-1.99) related to primary HIV-1 infection, with a mean duration of 23.2 days (+/-14.8) and 53.3% of them had to be hospitalized due to severe symptoms. The mean CD4 count and viral load at first visit were 390/uL (+/-220.1) and 4.81 log10/mL (+/-0.78), respectively. None developed AIDS during the study period. Estimates of risk of disease progression were 61.0% at 48 weeks and 82.2% at 144 weeks. In patients who required antiretroviral therapy, the median CD4 count was 215/uL (range, 52-858) at initiation of such therapy. Among the patients with a CD4 count of <350/uL at first visit, 53% never showed recovery of CD4 count (>350/uL) without antiretroviral therapy. CONCLUSION: Despite possible bias in patient population, disease progression seemed faster in symptomatic Japanese patients with recently acquired primary HIV-1 infection than the previously defined natural course of the disease. PMID- 21245633 TI - Effectiveness of repeated intragastric balloon therapy in a morbidly obese Japanese patient. AB - A 19-year-old Japanese male with a BMI of 55.4 kg/m(2) who also had liver dysfunction, dyslipidemia and hyperuricemia underwent repeated intragastric balloon therapy. The percent excess weight loss was 22.5% at the first balloon removal and 28.6% at the second balloon removal. The hepatic dysfunction resolved after the second balloon therapy, however, the dyslipidemia and hyperuricemia did not improve. The Japanese population is regarded as a high-risk race for obesity related diseases at lower BMI values, and morbidly obese Japanese patients may need more serious weight reduction protocols to improve the comorbidities than similarly obese Americans or Europeans. PMID- 21245632 TI - Relation between metabolic syndrome and sleep duration in Japan: a large scale cross-sectional study. AB - OBJECTIVE: Previous research suggests that sleep duration is related to metabolic syndrome, based on Western criteria. However, the criteria for metabolic syndrome vary among countries and populations. We therefore evaluated the relationship between sleep duration and the presence of metabolic syndrome in Japan. METHODS: A cross-sectional study was conducted involving 44,452 apparently healthy individuals aged 20 years or older who underwent annual health checkup the Center for Preventive Medicine at St. Luke's International Hospital in 2008. Participants were divided into 4 groups according to their average reported nightly sleep duration (<6 hours, 6-6.9 hours, 7-7.9 hours, >=8 hours). Based on criteria by the Japan Society for the Study of Obesity, we identified individuals with metabolic syndrome. Multivariable logistic regression was used to explore the relationship adjusting for age, gender, alcohol consumption, current smoking, past medical history, and level of physical activity. RESULTS: The prevalence of metabolic syndrome was 8.7% (3,876/44,452; 95% CI, 8.5-9.0%). The mean age of participants was 44.8 years (SD, 12.8) and 49.5% were male. Those with sleep duration less than 6 hours were more likely to meet metabolic syndrome criteria (OR=1.42; 95% CI=1.20-1.68) than those with longer sleep duration (>=8 hours). CONCLUSION: Short sleep duration is associated with the presence of metabolic syndrome despite the difference between Japanese and Western criteria. PMID- 21245634 TI - Onset of reentrant ventricular tachycardia modulated by variable impulse propagation through the zone of slow conduction. AB - We report an 18-year-old woman, who had undergone surgical repair of tetralogy of Fallot, and then underwent successful intracardiac recordings within the zone of slow conduction (ZSC) of the reentry circuit on the initiation of premature ventricular contractions (PVC) and reentrant ventricular tachycardia (VT), obtained with multielectrode basket catheter. PVC a) were caused by wavefronts of sinus cycles entering and exiting the ZSC, and b) were not repetitive because the wavefront of the PVC could not reenter the ZSC. Similarly, VT developed after delayed potentials of sinus cycles, and was sustained because the wavefront following the 1st cycle of VT was able to repetitively reenter and exit the ZSC. Thus, spontaneous changes in the conductivity of the ZSC, like an on-off switch, appeared to determine the onset and sustenance of reentrant VT. PMID- 21245635 TI - Pulmonary arterial hypertension associated with chronic active Epstein-Barr virus infection. AB - A 45-year-old man with chronic active Epstein-Barr virus (EBV) infection (CAEBV) with natural killer cell type developed pulmonary arterial hypertension (PAH). After chemotherapy, he showed marked depression of the EBV DNA genome in the peripheral blood, but PAH sustained. He died of heart failure due to PAH, and the histo-pathological examination revealed pulmonary vascular abnormalities without lung disease on autopsy. Although the EBV DNA genome and the infiltrating lymphocytes were not detected in the lung, his clinical course suggested that his PAH might be caused by CAEBV. This is the first reported case of PAH associated CAEBV in an adult. PMID- 21245636 TI - Absence of left atrium-coronary sinus musculature electrical connection at coronary sinus ostium unmasked by unique double coronary sinus potentials pattern. AB - We describe a 77-year-old man with Wolff-Parkinson-White syndrome exhibiting double coronary sinus (CS) potentials during retrograde conduction over accessory pathway (AP). The first, low-frequency potential (DP1) was first recorded in the left posterolateral region, while the second, higher frequency signal (DP2) was recorded in a lateral-to-septal direction. The two signals were fused near the left lateral wall. Successful ablation of the AP was obtained at its ventricular insertion site in the postero-septal region. The unexpectedly delayed activation of the paraseptal RA following activation of the paraseptal left atrium (DP1) can be explained by the absence of a LA-CS musculature (CSM) electrical connection at the proximal CS, which forces a detour of the activation wavefront from LA to RA via the distal CS (DP2). This is a rare case exhibiting unique double CS potentials which unmasked the absence of a LA-CSM electrical connection at CS ostium. PMID- 21245637 TI - Tracheobronchial aspergillosis following primary cutaneous aspergillosis in a lung-transplant recipient. AB - Invasive aspergillosis, a major problem during the post-transplant period, typically presents with pneumonia or tracheobronchitis in lung transplant recipients. In contrast, primary cutaneous aspergillosis is very rarely observed in lung-transplant recipients. In this report, we describe a case of tracheobronchial aspergillosis following primary cutaneous aspergillosis in a lung-transplant recipient. Early diagnosis of tracheobronchial aspergillosis is important because occult tracheobronchial aspergillosis can be potentially lethal. Our report suggests that surveillance bronchoscopy may facilitate identification of occult tracheobronchial invasion in lung-transplant recipients with primary cutaneous aspergillosis. PMID- 21245638 TI - Bronchial artery embolization before interventional bronchoscopy to avoid uncontrollable bleeding: a case report of endobronchial metastasis of renal cell carcinoma. AB - Extreme caution should be taken to avoid uncontrollable bleeding in treating hypervascular tumors via bronchoscope. We report two cases of endobronchial metastasis of renal cell carcinoma treated with bronchial artery embolization (BAE) before endoscopic treatments. The intraluminal lesions were removed swiftly and safely. Although arterial embolization is not always efficacious in cases of tracheal lesions, BAE is effective for tumors located in the carina, bilateral main bronchus or intermediate bronchus. The addition of BAE before endoscopic tumor removal should be considered a treatment option in patients suffering from airway obstructions due to hypervascular tumors such as renal cell carcinoma. PMID- 21245639 TI - Paradoxical brain embolism with Klippel-Trenaunay syndrome. AB - Cerebrovascular diseases in patients with Klippel-Trenaunay Syndrome (KTS) are uncommon, and the mechanism of stroke has remained elusive. We describe a patient with KTS who experienced a transient ischemic attack (TIA). Contrast-transcranial Doppler with the Valsalva maneuver revealed a right-to-left shunt and contrast transesophageal echocardiography confirmed patent foramen ovale. Ultrasonography revealed dilated superficial and deep veins in the lower extremities; the D-dimer level was high and indicated hypercoagulability. Therefore, the mechanism of TIA was diagnosed as paradoxical embolism. To the best of our knowledge, this is the first case report of paradoxical embolism in a patient with KTS. PMID- 21245640 TI - A case of Marinesco-Sjogren syndrome: MRI observations of skeletal muscles, bone metabolism, and treatment with testosterone and risedronate. AB - Marinesco-Sjogren syndrome (MSS) is a rare autosomal recessive disorder characterized by cerebellar ataxia, congenital cataracts, mental retardation, primary hypogonadism, skeletal abnormalities and myopathy, and patients with MSS are considered to be at risk of falls and bone fractures. We report a patient with MSS who received testosterone replacement therapy and risedronate administration. Muscle strength and the MRI features of the skeletal muscles were not changed, but low bone mass was improved by these treatments, and improvement has continued after risedronate treatment alone. This case suggests that treatment of MSS-related low bone mass using bisphosphonates is likely beneficial. PMID- 21245641 TI - A case of Takayasu's arteritis associated with human leukocyte antigen A24 and B52 following resolution of ulcerative colitis and subacute thyroiditis. AB - A 46-year-old female with a past history of ulcerative colitis (UC) was diagnosed with subacute thyroiditis (SAT), which improved with prednisolone (PSL) treatment (60 mg/day). The dose of PSL was gradually decreased, however upper back and neck pain and chest discomfort developed. The patient was diagnosed with Takayasu's arteritis (TA) based on wall thickening and luminal narrowing of the left common carotid artery and the left subclavian artery. The result of human leukocyte antigen typing analysis was A24 and B52 positive. These findings suggested that common genetic factors may be important for the etiology of TA, UC and SAT. This is the first report of TA that developed following UC and SAT. PMID- 21245642 TI - Peripheral T-cell lymphoma that developed during the follow-up of IgG4-related disease. AB - IgG4-related disease is a recently recognized fibroinflammatory disorder characterized by extensive IgG4-positive plasma cell and lymphocyte infiltration of various organs. The pancreatic manifestation of IgG4-related disease is called autoimmune pancreatitis (AIP), in which autoimmune mechanisms are likely involved. On the other hand, some autoimmune and chronic inflammatory disorders, such as Sjogren's syndrome and rheumatoid arthritis, are associated with increased risks of non-Hodgkin lymphoma (NHL). There have been a few reports of cases with IgG4-related disease that had subsequently developed NHL, however, all of them suffered from B-cell lymphoma. We describe the first case of NHL, compatible with a subtype of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), which arose in IgG4-related sclerosing cholangitis. As patients with IgG4-related disease may be at an increased risk of developing NHL, such presentation during the follow-up of IgG4-related disease should be carefully scrutinized to exclude NHL. PMID- 21245643 TI - Rapidly progressing mycotic aortic aneurysm. PMID- 21245644 TI - Spatial illusion revealing "shrinking" stent. PMID- 21245645 TI - Inflammatory myofibroblastic tumor mimicking adrenal incidentaloma. PMID- 21245646 TI - Bronchiolitis caused by pandemic influenza A (H1N1) 2009. PMID- 21245647 TI - Rare presentation of pulmonary cryptococcosis as a calcified nodule. PMID- 21245648 TI - Lupus vulgaris preceding tuberculous meningitis. PMID- 21245649 TI - Invasive mechanical ventilation in patients with idiopathic pulmonary fibrosis or idiopathic non-specific interstitial pneumonia. PMID- 21245651 TI - Iranian clinical nurses' coping strategies for job stress. AB - OBJECTIVES: Since the existence of work-related stressors is inevitable in nurses' workplace, nurses usually use a variety of coping strategies which can be called cognitive, affective, and behavioral techniques. In this study, we aimed to explore the coping strategies employed by the Iranian clinical nurses in depth. METHODS: This work was a qualitative study using Straus and Corbin's grounded theory approach focusing on the process of coping with job stress used by Iranian clinical nurses. RESULTS: The results of the present qualitative study indicate that the core category was "on the route to coping" which contained six categories comprising work management, self-control, emotional, spiritual, cognitive, and interactional strategies. CONCLUSIONS: We conclude that in nursing it is inevitable that different kinds of strategies are used to cope with the many stressors. The conceptual model emerging from the data indicate that nurses are engaged in a dynamic process of struggling to cope with job stressors. In fact, they are "on the route to coping" with the job stressors. Considering the high level of stress in the nursing profession, the findings of this study have implications for both hospital managers and Iranian clinical nurses. PMID- 21245652 TI - Occupational exposure to phenolic compounds at coke plants--urinary excretion of methoxyphenols as an indicator of exposure to methoxyphenols. AB - OBJECTIVES: This study describes the exposure of coke plant workers to methoxyphenols. The relationship between exposure to methoxyphenols and urinary excretion of metabolites was examined. METHODS: We determined concentrations of 2 methoxyphenol, 2-methoxy-4-methylphenol and 1-(4-hydroxy-3-methoxyphenyl)ethanone in the breathing-zone air and in the urine of workers, collected after the workshift. Urine metabolites were extracted after enzymatic hydrolysis by solid phase extraction. Concentrations of methoxyphenols in air and urine were determined by gas chromatography with flame-ionization. RESULTS: The time weighted average concentrations (median) of methoxyphenols in the breathing zone air were as follows: 9.9 ng/m(3), 15.4 ng/m(3) and 92.5 ng/m(3) for 2 methoxyphenol, 2-methoxy-4-methylphenol and 1-(4-hydroxy-3 methoxyphenyl)ethanone, respectively. The median values of urinary concentrations were as follows: 582.5, 190.1, 235.0 and 21.8 umol/mol creatinine for 2 methoxyphenol, 2-methoxy-4 methylphenol, 1-(4-hydroxy-3-methoxyphenyl)ethanone and 2,6-dimethoxyphenol, respectively. A statistically significant correlation between the exposure level and the urinary level was found for 2-methoxyphenol (r=0.573, p<0.01). CONCLUSION: We found that the presence of 2-methoxyphenol in urine can be used as a biomarker for 2-methoxyphenol exposure. The analysis performed at the coke plant showed that the workers were exposed to relatively low concentrations of methoxyphenols. PMID- 21245653 TI - Binding of human serum proteins to titanium dioxide particles in vitro. AB - OBJECTIVES: To determine the capacity of human serum proteins to bind to titanium dioxide (TiO(2)) particles of different polymorphs and sizes. METHODS: TiO(2) particles were mixed with diluted human serum, purified human serum albumin (HSA) or purified human serum gamma-globulin (HGG) solutions. After incubation at 37 degrees C for 1 h, the particles were sedimented by centrifugation, and proteins in the supernatant, as well as those bound to the particles, were analyzed. RESULTS: The total protein concentration in the supernatant was lowered by TiO(2), whereas the albumin/globulin ratio was elevated by the particles. Incubation with TiO(2) also lowered the immunoglobulin, pre-albumin, beta2 microglobulin, ceruloplasmin and retinol-binding protein levels, but not ferritin levels, in the supernatant. After sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), proteins in the supernatant, especially HGG, were observed to decrease, while those released from the particles (after adding 1% SDS and heating) increased, depending on the dose of TiO(2). Purified HGG and HSA were also bound to TiO(2), although the former appeared to have a higher affinity. All the proteins tested showed the highest binding potency to the amorphous particles (<50 nm) and the lowest to the rutile particles (<5,000 nm), while binding to anatase particles was intermediate. The affinity to the larger anatase was higher than that to smaller anatase particles in most cases. CONCLUSIONS: Human serum proteins, including the two major components, HSA and HGG, are bound by TiO(2) particles. The polymorph of the particles seems to be important for determining the binding capacity of the particles and it may affect distribution of the particles in the body. PMID- 21245654 TI - Growth of primordial oocytes in neonatal and adult mammals. AB - Mammalian ovaries are endowed with a huge number of small oocytes (primordial oocytes) in primordial follicles. A small number of primordial oocytes start to grow, while others remain quiescent. Little is known about the mechanism regulating the activation of primordial oocytes. Recently, we found that primordial follicles in mature cows and prepubertal pigs took longer to initiate growth in xenografts compared with those in neonatal animals. We think that primordial oocytes in adult mammals are different from those in neonatal mammals. In this review, we summarize the results regarding the activation of primordial oocytes in neonatal and adult ovaries of different species and propose a model in which ovaries of neonatal mammals contain a mixed population of both quiescent and activated primordial oocytes, while almost all primordial oocytes are quiescent in adult females. The dormancy of primordial oocytes may be required to reserve the non-growing oocyte pool for the long reproductive life in mammals. FOXO3 is considered one of the molecules responsible for the dormancy of primordial oocytes in adult ovaries. These quiescent primordial oocytes are activated, perhaps by certain mechanisms involving the interaction between stimulatory and inhibitory factors, to enter the growth phase. PMID- 21245655 TI - Adjuvants and alternative routes of administration towards the development of the ideal influenza vaccine. AB - Vaccination is universally considered as the principal measure for the control of influenza, which represents a significant burden worldwide, both from a health care and a socio-economic viewpoint. Conventional non-adjuvanted trivalent influenza vaccines (TIVs) have been recognized as having some deficiencies, such as suboptimal immunogenicity particularly in the elderly, in patients with severe chronic diseases and immunocompromized, indeed, those groups of the population at higher risk of developing severe complications following influenza infection, when compared to healthy adults. Moreover, the protection offered by conventional vaccines may be reduced by periodic antigenic drifts, resulting in a mismatch between the circulating and vaccinal viral strains. Another gap regarding currently available vaccines is related to the egg-based manufacturing system for their production: not only the length of time involved with the latter but also the limited capacity of this platform technology represent a major limitation for the active prevention of influenza, which is particularly important in the case of a new pandemic strain. New technologies used in vaccine composition, administration and manufacture have led to major advances during the last few years, and clinical researchers have continued to work hard, investigating several different strategies to improve the performance of influenza vaccines: namely, the addition of different adjuvants (i.e., MF59- and AS03-vaccines, virosomal formulations), the use of alternative routes of administration or manufacture (i.e., intradermal, nasal and oral vaccines and cell culture- and reverse genetic-based vaccines) or of high doses of antigen, and the development of DNA-vaccines, or the use of conserved viral epitopes (i.e., the extracellular portion of the M2 protein, the nucleoprotein and some domains of the hemagglutinin), in the attempt to produce a "universal target" antigen vaccine. The knowledge acquired represents a fundamental challenge for the control of influenza. An overview of the most recent and interesting results, some of which gained from our own research experience, particularly concerning two successful approaches, of those outlined above, namely the use of: (i) the oil-in-water MF59 adjuvant, and (ii) the intradermal (ID) route for vaccine administration, through a novel microinjection system, will be reported and discussed, together with the possible implications and perspectives to optimize immunization policies against influenza in the near future. PMID- 21245656 TI - Challenges for the evaluation of Staphylococcus aureus protein based vaccines: monitoring antigenic diversity. AB - Clumping factors A (ClfA) and B (ClfB) are Staphylococcus aureus virulence proteins that are displayed on the cell surface of the organism and have potential as vaccine antigens for the prevention of S. aureus disease. Here we evaluate the phylogeny of S. aureus in the context of antigenic variation of these two surface proteins. ClfA and ClfB gene sequences, along with epidemiological markers (MLST, spa and capsule genotype) were obtained for 224 S. aureus isolates including both historical strains and a collection representative of current MRSA isolates from the United States. Variation within ClfA and ClfB was consistent with the established population biology of S. aureus, namely, that S. aureus strains belong to a relatively small number of clonal lineages, with evolution proceeding mainly by mutation and with little to no recombination between clades. Thus most variation in ClfA and ClfB occurs between but not within lineages, and particular groups of ClfA and ClfB variants are closely linked. This has important implications for vaccine development and assessment as it suggests that a relatively small survey of strains will be representative of the total population variation, whereas for species that evolve mainly by recombination, such as Neisseria meningitidis, analysis of a much larger number of strains is needed to accomplish the same purpose. Our study also revealed evidence for the de-evolution of ClfB and therefore its reduced suitability as a target for vaccine development compared to ClfA. PMID- 21245658 TI - Toll-like receptor-mediated adjuvanticity and immunomodulation in dendritic cells: Implications for peptide vaccines. AB - Considerable success has been made with many peptide antigen formulations and it appears that peptide-based vaccines are emerging as the next generation of prophylactic and remedial immunotherapy. However, peptides are typically poorly immunogenic and rely on delivery with potent immunostimulatory adjuvants that activate the innate and adaptive arms of the immune system. Our research aims to develop novel peptide antigen delivery systems that incorporate multiple pattern recognition receptor (PRR) agonists and is focused on those designed to stimulate Toll-like receptors (TLRs) on dendritic cells (DCs). The cytokine (IL-4, IL-6, IL 10, IL-12 and IL-23) profiles of DCs induced by individual TLR agonists have been evaluated. From this data we predicted which TLR agonists may influence a particular T helper cell (Th) response. Using purified DCs that were derived from precursor cells in murine bone marrow and then stimulated simultaneously with multiple TLR agonists, we have shown synergy between various TLR agonist pairs leading to enhanced cytokine production. Using various mitogen-activated protein kinase (MAPK) inhibitors (c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK) and p38 MAPK) we have demonstrated the importance of p38 MAPK and ERK signaling pathways in IL-12p70 and IL-12p40 production in DCs induced by TLR stimulation, whereas the JNK pathway appeared to have a negative regulatory role on cytokine production in DCs stimulated with certain TLR agonists. An important role for nuclear factor-kappa B and phosphoinositol-3 kinase as positive regulators of TLR signaling in DCs leading to cytokine production was also demonstrated. The significance of this research lies not only in improving potency, but by understanding the immunological mechanisms of adjuvanticity, in being able to tailor peptide vaccines to generate specific types of Th responses required for immunity against various types of pathogens. PMID- 21245657 TI - Preclinical evidence for the potential of a bivalent fHBP vaccine to prevent Neisseria meningitidis Serogroup C Disease. AB - A bivalent factor H binding protein (fHBP) vaccine for the prevention of disease caused by Neisseria meningitidis serogroup B is currently in clinical development. Since fHBP is also expressed by other meningococcal serogroups, anti fHBP antibodies may have bactericidal activity against meningococci independent of serogroup. To begin examining the susceptibility of other meningococcal serogroups to anti-fHBP antibodies, meningococcal serogroup C invasive isolates (n = 116) were collected from the Centers for Disease Control and Prevention's Active Bacterial Core surveillance (ABCs) sites during 2000-2001. These isolates were analyzed for the presence of the fhbp gene. All serogroup C isolates contained the gene, and sequence analysis grouped the proteins into two subfamilies, A and B. Flow cytometry analysis demonstrated that fHBP was expressed on the surface of ~70% of isolates in vitro with varying levels of expression. fHBP was accessible to antibodies on the cell surface even in the presence of the polysaccharide capsule. Nine isolates from different geographic regions were identified which harboured an identical single nucleotide deletion that could result in a truncated subfamily B fHBP. Analysis by flow cytometry using a polyclonal fHBP antibody preparation revealed that a subpopulation of each of these isolates expressed fHBP. Rabbit and non-human primate immune sera generated with bivalent fHBP vaccine were tested for bactericidal activity against a panel of diverse serogroup C clinical isolates using human complement. Sera from both species demonstrated serum bactericidal antibody activity against the serogroup C isolates tested. These promising findings suggest that a bivalent fHBP vaccine may be capable of providing protection against meningococcal disease caused by both serogroup C and B. PMID- 21245659 TI - An overview on the implementation of HPV vaccination in Europe. AB - The discovery that the Human PapillomaVirus (HPV) is the necessary cause of cervical cancer has led to the development of prophylactic vaccines. Cervical cancer is the second most common cause of death from cancer among young women in Europe: mortality is still high, despite its important reduction due to screening programs for early detection. Besides cervical cancer, HPV is responsible for a significant proportion of other anogenital cancers and an increasing number of oropharyngeal cancers, representing together an at least equal burden compared to cervical cancer. HPV is also responsible for conditions such as condyloma acuminata (genital warts) and recurrent respiratory papillomatosis. Organized vaccination programs against HPV have the potential to prevent about 70% of cervical cancers and the vast majority of the other HPV-related conditions. Recommendations for HPV vaccination of at least one cohort of females have been issued in nearly all western European countries, and national/regional publicly funded vaccination programs have been introduced in most of them. Different approaches have been chosen for the implementation of HPV vaccination, based on the organization of each country's health care system. A brief outline of these programs in Europe is presented. As for all preventive public health interventions, high coverage of the target population with HPV vaccines pre exposure is essential to achieve maximum reduction of cases: therefore, in order to obtain the maximum and most equitable coverage and future benefit, programs targeting adolescents before exposure to HPV should be preferred and population based. Catch-up programs should also be implemented wherever possible, in order to deliver more and even earlier benefits, and effective communication strategies need to be adopted. PMID- 21245660 TI - Recent advances in cloning herpesviral genomes as infectious bacterial artificial chromosomes. AB - Herpesviruses are common but important pathogens in humans and animals. These viruses have large complex genomes encoding genes with diverse functions in different phases of their life cycle and associated diseases. In the last decade, genomes of herpesviruses cloned as infectious bacterial artificial chromosomes (BACs) have become powerful tools for delineating the functions of viral genes and understanding the pathogenesis of their associated diseases. Here we review the history of herpesviral genetics and recent advances in methods for cloning herpesviral genomes as infectious BACs. PMID- 21245661 TI - Vaccines for leishmaniasis: from proteome to vaccine candidates. AB - Leishmania spp. cause a wide spectrum of tropical diseases which are threatening an estimated 350 million people around the globe. While in most cases non-fatal, the disease is associated with high morbidity, social stigmata and poverty. However, the most severe form visceral leishmaniasis can be fatal if left untreated. Chemotherapeutics are available but show high toxicity, costs and are prone to resistance development due to prolonged treatment periods. Healing is associated with a life-long resistance to re-infection and this argues for the feasibility of vaccination. However, despite much effort, no such vaccine has become available yet. Here, the status of vaccine development in this field is briefly summarized before the focus is set on the promise of reverse vaccinology for anti-Leishmania vaccine development in the post-genomic era. We report on our own experience with this approach using an instructive example of successful candidate vaccine antigen identification. PMID- 21245662 TI - Evaluation of adjuvants for a candidate conjugate vaccine against benzo[a]pyrene. AB - We have recently developed an experimental vaccine based on benzo[a]pyrene (B[a]P) conjugated to tetanus toxoid as a carrier protein. In combination with Freund adjuvant, this vaccine induces high levels of B[a]P-specific antibodies to protect against detrimental effects of this carcinogen. Here we evaluate this conjugate vaccine by replacing Freund adjuvant by adjuvants that are potentially compatible with their use in humans. We showed that all adjuvants tested induced specific antibodies against B[a]P and 7,8-diol-B[a]P, its carcinogenic metabolite. The best antibody levels were obtained with Quil A, MF-59 and Alum. Biological activity in terms of enhanced retention of B[a]P was confirmed in mice immunised with Quil A, Montanide, Alum and MF-59. Our findings demonstrate that a vaccination against B[a]P is feasible in combination with adjuvants licensed in humans. PMID- 21245663 TI - Planar cell polarity: fashioning solutions. AB - Scientists like to consider themselves as especially objective, but, however hard we try we cannot be very different from everyone else. Like them we helplessly absorb our knowledge, our perspectives, our valuation of whether something is exciting or boring from those around us. In this "extra view" I reflect on fashion, illustrating by a small discovery of ours, and discussing why it was not made before. PMID- 21245664 TI - Requirements of Lgl in cell differentiation and motility during Drosophila ovarian follicular epithelium morphogenesis. AB - The epithelial follicle cell layer over the egg chamber in Drosophila ovary undergoes patterning and morphogenesis at oogenesis. These developmental processes are essential for constructing the eggshell and establishing the body axes of the egg and resultant embryo, thereby being crucial for the egg development. We have previously shown that lethal(2)giant larvae (lgl), a Drosophila neoplastic tumor suppressor gene (nTSG) is required for the posterior follicle cell (PFC) fate induction during antero-posterior pattern formation of the follicular epithelium. In this report, we further characterize lgl in this epithelium patterning and the morphogenetic changes of specified border cells. Genetic interactions of lgl with discs large (dlg) and scribble (scrib), another two nTSGs in specifying the PFC fate reveal a cooperative role of this group of genes. Meanwhile, we find that loss of lgl function causes failure of follicle cells at the anterior to differentiate properly. The clonal analysis further indicates that lgl is necessary not only for the border cell differentiation, but also for control of the collective border cell migration via presumably modulating the apico-basal polarity and cell adhesion. Overall, we identify Lgl as an essential factor in regulating differentiation and morphogenetic movement of the ovarian epithelial follicle cells. PMID- 21245665 TI - Hfp, the Drosophila homolog of the mammalian c-myc transcriptional-repressor and tumor suppressor FIR, inhibits dmyc transcription and cell growth. AB - Here we highlight our recent study, which revealed a mechanism critical for tight regulation of Drosophila myc (dmyc) transcription. Our previous work demonstrated that the RRM (RNA recognition motif) protein Half pint (Hfp) behaves as a growth and cell cycle inhibitor and work from D. Levens group has shown the mammalian ortholog, FIR (the FBP Interacting Repressor), is a tumor suppressor. Although RRM domain containing proteins such as Hfp and FIR have been ascribed splicing and transcriptional roles, our work suggests that Hfp is likely to achieve cell cycle inhibition via direct repression of dmyc transcription. We have demonstrated that Hfp binds to the dmyc promoter and is essential for repression of dmyc transcription, which requires interaction between Hfp and the DNA helicase subunit of Transcription Factor IIH (TFIIH), Haywire (Hay). Consistent with the increased levels of dmyc transcription, loss of Hfp makes cells overgrow in a manner dependent on the presence of dMyc. Thus our work has demonstrated that Hfp is critical for repression of dmyc and suggested a transcriptional, rather than splicing, mechanism underlies the ability of Hfp to regulate dMyc and function as a tumor suppressor. Thus we have extended knowledge from previous mammalian studies by providing in vivo evidence that the FIR homolog Hfp is required for repression of dmyc transcription, suggesting the mechanism proposed for repression of c-myc transcription by the mammalian RRM protein FIR is conserved in Drosophila. PMID- 21245666 TI - Therapeutic vaccination for cancer immunotherapy: antigen selection and clinical responses. AB - BACKGROUND: Because of its high specificity and low toxicity therapeutic vaccination is considered a desirable treatment for cancer. So far, however, the results of cancer vaccination trials have been disappointing, which is often attributed to the problem identifying appropriate vaccine antigens. Tumorassociated antigens are mostly autoantigens and therefore expected to be subject to immunosuppressive mechanisms. Cancer-testis antigens are the most prominent exception as, still being self, they are physiologically only expressed in immunopriviledged tissues and should therefore not induce autotolerance. This leads to the widely accepted hypothesis that cancer-testis antigens should be more efficient inducers of anti-tumor cellular immune responses than differentiation antigens. Aim of the study was to test this hypothesis by evaluating the published reports on clinical therapeutic vaccination trials for the objective clinical response rates to vaccination with cancer testis antigen vs. differentiation antigens. APPROACH: The results of vaccination clinical trials with cancer testis and/or differentiation antigens published in literature and databanks were analyzed for clinical outcome versus vaccine antigens. 21 publications on cancer testis antigen-based trials in which clinical outcome was reported according to WHO or RECIST were identified and analyzed. RESULTS: The rate of objective responses to cancer testis antigen vaccines in 239 patients was 3.8% and for the 235 patients vaccinated with cancer testis plus 3 differentiation antigens 4.3% compared to 2.6% for the 496 patients vaccinated with differentiation antigens alone. CONCLUSIONS: Cancer testis antigen-based vaccines seem slightly superior over vaccines based on differentiation antigens providing support for the hypothesis. PMID- 21245667 TI - A reassessment of needs and practice patterns in pharmacologic prophylaxis of venous thromboembolism following elective major surgery. PMID- 21245668 TI - Ischemic cholangiopathy after controlled donation after cardiac death liver transplantation: a meta-analysis. AB - OBJECTIVE: To conduct a meta-analysis to enhance understanding of the risks of biliary complications, particularly ischemic cholangiopathy (IC), after donation after cardiac death (DCD) compared with donation after brain death (DBD) liver transplantation. BACKGROUND: Biliary complications after liver transplantation have profound health and economic implications which merit further investigation. METHODS: The MEDLINE (1950-2009), EMBASE, and Cochrane Library databases were searched and supplemented by review of conference proceedings and publication bibliographies. All original single institution studies reporting outcomes for DCD and DBD liver transplant recipients were considered. Odds ratios (OR) and 95% confidence intervals (CI) based on random effects models were calculated. RESULTS: Eleven publications, all retrospective cohort studies, involving 489 DCD and 4455 DBD recipients, were included. Donation after cardiac death recipients had a 2.4 times increased odds of biliary complications (95% CI= 1.8-3.4) and a 10.8 times increased odds of IC (95% CI = 4.8-24.2).Ischemic cholangiopathy was present in 16% of DCD compared with 3% of DBD recipients. Donation after cardiac death recipients also experienced higher odds of 1-year patient mortality (OR = 1.6, 95% CI = 1.04-2.5) and graft failure (OR = 2.1, 95% CI = 1.5-2.8). CONCLUSIONS: Donation after cardiac death liver transplantation is marred by inferior outcomes including higher rates of biliary complications and IC as well as increased mortality and graft failure. Despite current federal mandates to increase DCD donation, these serious complications translate into poor outcomes for individuals and increased healthcare costs. These risks should be considered in decisions regarding the utilization of these grafts. PMID- 21245669 TI - Mental practice enhances surgical technical skills: a randomized controlled study. AB - OBJECTIVE: To assess the effects of mental practice on surgical performance. BACKGROUND: Increasing concerns for patient safety have highlighted a need for alternative training strategies outside the operating room. Mental practice (MP), "the cognitive rehearsal of a task before performance," has been successful in sport and music to enhance skill. This study investigates whether MP enhances performance in laparoscopic surgery. METHODS: After baseline skills testing, 20 novice surgeons underwent training on an evidence-based virtual reality curriculum. After randomization using the closed envelope technique, all participants performed 5 Virtual Reality (VR) laparoscopic cholecystectomies (LC). Mental practice participants performed 30 minutes of MP before each LC; control participants viewed an online lecture. Technical performance was assessed using video Objective Structured Assessment of Technical Skills-based global ratings scale (scored from 7 to 35). Mental imagery was assessed using a previously validated Mental Imagery Questionnaire. RESULTS: Eighteen participants completed the study. There were no intergroup differences in baseline technical ability. Learning curves were demonstrated for both MP and control groups. Mental practice was superior to control (global ratings) for the first LC (median 20 vs 15, P = 0.005), second LC (20.5 vs 13.5, P = 0.001), third LC (24 vs 15.5, P < 0.001), fourth LC (25.5 vs 15.5, P < 0.001) and the fifth LC (27.5 vs 19.5, P = 0.00). The imagery for the MP group was also significantly superior to the control group across all sessions (P < 0.05). Improved imagery significantly correlated with better quality of performance (rho 0.51-0.62, Ps < 0.05). CONCLUSIONS: This is the first randomized controlled study to show that MP enhances the quality of performance based on VR laparoscopic cholecystectomy. This may be a time- and cost-effective strategy to augment traditional training in the OR thus potentially improving patient care. PMID- 21245670 TI - Early diagnosis of intestinal ischemia using urinary and plasma fatty acid binding proteins. AB - OBJECTIVE: This study aims at improving diagnosis of intestinal ischemia, by measuring plasma and urinary fatty acid binding protein (FABP) levels. METHODS: Fifty consecutive patients suspected of intestinal ischemia were included and blood and urine were sampled at time of suspicion. Plasma and urinary concentrations of intestinal FABP (I-FABP), liver FABP (L-FABP) and ileal bile acid binding protein (I-BABP) were measured using enzyme-linked immunosorbent assays. RESULTS: Twenty-two patients suspected of intestinal ischemia were diagnosed with intestinal ischemia, 24 patients were diagnosed with other diseases, and 4 patients were excluded from further analysis fulfilling exclusion criteria. Median plasma concentrations of I-FABP and L-FABP and urinary concentrations of all 3 markers were significantly higher in patients with proven intestinal ischemia than in patients suspected of intestinal ischemia with other final diagnoses (plasma I-FABP; 653 pg/mL vs. 109 pg/mL, P = 0.02, plasma L-FABP; 117 ng/mL vs. 25 ng/mL, P = 0.006, urine I-FABP; 3377 pg/mL vs. 115 pg/mL, P = 0.001, urine L-FABP; 1,199 ng/mL vs. 37 ng/mL, P =0.004, urine I-BABP; 48.6 ng/mL vs. 0.6 ng/mL, P = 0.002). Positive and negative likelihood ratios significantly increased positive posttest probability and decreased negative posttest probability on intestinal ischemia. In patients with intestinal ischemia a trend to higher plasma I-BABP levels was observed when the ileum was involved (18.4 ng/mL vs. 2.9 ng/mL, P = 0.05). CONCLUSION: Plasma and especially urinary I-FABP and L-FABP levels and urinary I-BABP levels can improve early diagnosis of intestinal ischemia. Furthermore, plasma I-BABP levels can help in localizing ileal ischemia. PMID- 21245672 TI - The cancer screening controversy. PMID- 21245673 TI - Uptake of breast cancer screening in women aged over 75 years: a controversy to come? AB - In France, the age range for organized screening for breast cancer is 50-74 years. From a layperson's perspective, the public health message focusing on a specific target population may be difficult to understand. The aim of this study is to assess how women aged over 75 years deal with this absence of screening recommendations for their age group. The population-based survey, EDIFICE, was carried out by telephone in 2008. Women were interviewed with regard to their behaviour, and in particular relating to breast cancer screening. For 136 breast cancer-free women, aged 75 and above and who had undergone at least one mammography in their lifetime, the test had been done within the last 2 years for only 62 (51%) of them. In a multiregression analysis, only one item (i.e. already having undergone at least five mammographies) was statistically associated with a higher rate of attendance (odds ratio=3.3, 95% confidence interval=1.03-11.1). According to our data, for women aged 75 and above, an estimated 17,000,000 Euros are spent each year on breast cancer screening in France, the net benefit of which is still unknown. PMID- 21245674 TI - Mammography utilization in women aged 40-49 years: the French EDIFICE survey. AB - In France, mammography screening is offered to women aged between 50 and 74 years. EDIFICE, the iterative nationwide survey, collected data on a national level about consumers utilization of available cancer screening procedures. This analysis compared data from a subset of 241 women aged between 40 and 50 years with that of 488 women aged between 50 and 74 years. Multivariate analysis showed the following significant factors to be linked with screening attendance for women younger than 50 years: age, with a threshold value at 44 years; awareness of the recommended screening period (2 years); consultation within the last 12 months with a general practitioner or a gynaecologist; and long standing local programme for colon cancer screening. Notwithstanding the debate on risk/benefit of breast cancer screening for women in their 40s, we observed more differences with regard to attendance between women aged 40-45 years versus that of 46-74 years than between women aged 40-49 years versus that of 50-74 years. The issue that is unanswered as yet is, do women make a kind of heuristic for starting breast cancer screening, leading them to a threshold choice of 45 years or alternatively to a collective answer of standard age minus 5 years! PMID- 21245675 TI - Cancer screening: more information, more action, more benefits. AB - The EDIFICE survey was performed to ascertain how both the targeted general population and GPs in France deal with cancer screening and especially with screening programmes. The assessment of compliance to national official statements and professional guidelines, rates and trends of compliance, specific profiles of individuals who do and those who do not attend were investigated and are presented in this supplement. PMID- 21245676 TI - Organized colorectal cancer screening programmes: how to optimize efficiency in the general population. AB - In France, free faecal occult blood testing is offered to individuals aged between 50 and 74 years every 2 years as a method of screening for colorectal cancer (CRC). To assess how a proposed organized programme of CRC screening would be perceived among a representative sample of individuals living in France, aged between 40 and 75 years, and by a representative sample of general practitioners, two nationwide observational telephone surveys were carried out in 2005 (EDIFICE 1; 1601 individuals) and 2008 (EDIFICE 2; 1801 individuals). In 2008, 38% of individuals aged between 50 and 74 years reported undergoing screening for CRC; this corresponded to a statistically significant 13% increase in CRC screening rate compared with 2005 (P=0.01). When asked whether it was possible to screen for CRC, 94% of individuals who had undergone screening (N=350) responded positively compared with 87% of individuals who had not been screened. The main reason for individuals not to undergo screening was a lack of awareness (35% of men and 37% of women, P=not significant); the second reason was lack of advice and referral from their general practitioner (21% of women versus 15% of men, P=0.03). The French population is aware of the potential benefit of CRC screening; however, many do not undergo regular screening. It is therefore important to identify the hurdles associated with CRC screening. PMID- 21245677 TI - Organized colorectal cancer screening programmes: how to optimize efficiency among general practitioners. AB - Colorectal cancer (CRC) is an important public health issue in France, justifying a screening policy adapted to individual risk. The general practitioner (GP) is most commonly the initiator of CRC screening. The EDIFICE 2 survey, carried out in 2008 among 600 GPs, showed that 83% of GPs were convinced of the importance of screening, but that only 30% of GPs systematically recommended the procedure. The main underlying reasons were that only 50% of GPs declared themselves sufficiently trained, GPs needed clear guidelines and information supports for patients and a better implication in the programme's overall organization. This important role was confirmed by patients as the second most important reason for not undergoing screening: the absence of recommendation from their treating physician. The optimization of the screening procedure thus requires a stronger implication of GPs, by confirming their pivotal role in CRC screening and by relying on clear reference documentation guaranteeing quality assurance of a national organized screening programme. PMID- 21245678 TI - Screening for prostate cancer: growth without control. AB - In France, no official recommendations for or against systematic screening for prostate cancer have been issued yet. Therefore, individuals' choices with regard to screening or non-screening, and general practitioners' (GPs) recommendations for or against systematic screening should reflect personal preferences. Four nationwide observational studies (surveys) were conducted in France, two in 2005 and two in 2008, on a representative sample of participants aged between 40 and 75 years and a representative sample of GPs. In 2005, 36% of the male population interviewed, and aged between 50 and 75 years declared having undergone a screening test, compared with 49% in 2008 [odds ratio (OR)=1.63; 95% confidence interval (CI)=1.25-2.12]. In 2008, the number of men interviewed who reported having undergone screening less than 1 year earlier increased from 51% in 2005 to 74% (OR=2.18; 95% CI=1.40-3.40). The screening rate for young men (45-49 years) was only 7% in 2008 (data not available in 2005). In 2005, 58% of GPs systematically recommended prostate cancer screening for their patients aged 50 74 years, whereas in 2008, the figure was 65% (OR=1.32; 95% CI=1.04-1.66). The sex or age of the GPs had no significant impact on this rate. In France, we have observed a highly significant increase in prostate cancer screening: more men are screened, more often, at a younger age and more frequently using a prostate specific antigen blood test. In our surveys, the observed threshold age for onset of prostate cancer screening is 50 years, almost the same as that for approved organized breast and colorectal screening programmes. PMID- 21245679 TI - Impact of awareness of cancer among acquaintances on cancer screening attendance. AB - Two nationwide observational surveys were carried out in France in 2005 and 2008 with the aim of assessing the impact on attitudes towards cancer screening of a positive history of cancer among a person's close circle of acquaintances (relatives, friends or colleagues). In 2005, 67% (993/1482) of people interviewed reported having someone in their close circle of acquaintances affected by cancer and in 2008, the rate was 80% (1158/1454). In 2008, having someone within a person's close circle of acquaintances affected by cancer did not increase the rate of screening for breast cancer (already high at >80%). However, it did increase the rate of screening for colorectal cancer [odds ratio (OR)=2.3; 95% confidence interval (CI)=1.6-3.3] and prostate cancer (OR=2.2; 95% CI=1.4-3.5). Knowing someone affected by cancer within the close circle of acquaintances clearly increases awareness, and thus could be an incentive for undergoing cancer screening. With regard to cancer types, such as prostate cancer, for which there is no national programme or media communication, this awareness might be the main source of information and motivation. The impact of awareness on screening behaviour seems to be greatest for the same cancer location as that in the affected acquaintance, as opposed to cancers at other sites. Increased awareness as observed in our survey, which may be attributable to less social stigma associated with a diagnosis of cancer, might increase the rate of screening attendance in the general population. PMID- 21245680 TI - Impact of general practitioners' sex and age on systematic recommendation for cancer screening. AB - Characteristics of primary-care providers have been associated with their patients' participation in breast cancer screening. A nationwide observational survey, 'EDIFICE', was conducted by telephone from December 2007 to January 2008 on a representative sample of 600 general practitioners (GPs) working in France, to investigate how a GP's characteristics may influence patient participation in screening for breast, colorectal and prostate cancer. For breast cancer screening, systematic recommendation was associated with female physicians [odds ratio (OR) =1.9; 95% confidence interval (CI) 1.2-3.1]. This systematic recommendation was also correlated with systematic referral for colorectal cancer (OR=1.5; 95% CI=1.0-2.5) and prostate cancer screening (OR=2.7; 95% CI=1.8-4.1). For colorectal cancer screening, the sex of the GP had no significant impact. However, systematic recommendation for both breast and prostate cancer screening was shown to be associated with systematic recommendation for colorectal cancer screening (OR=2.7; 95% CI=1.6-4.7 and OR=1.8; 95% CI=1.1-3.0, respectively). For prostate cancer screening, there was no significant sex specificity. However, systematic recommendation for both breast and colorectal cancer screening was associated with an advice on prostate cancer screening (OR=2.9; 95% CI=2.0-4.4 and OR=2.0; 95% CI=1.3-3.2, respectively). The age of the GP was not associated with a higher rate of systematic recommendation for screening for the three types of cancer. Male GPs were more likely than female GPs to perform digital rectal examinations on male patients (69 vs. 54%; OR=1.86; 95% CI=1.31-2.63). There is a global pattern of physicians being screening-prone (as suggested by the cross impact of recommendations from one cancer type to another). Although the frequency of systematic recommendation for breast cancer screening is higher with female GPs, systematic recommendation for prostate cancer is not higher among male GPs. The factors associated with systematic recommendation for screening are both a matter of concern and a target for action, to improve adherence of individuals through GP commitment. PMID- 21245681 TI - Cancer screening: reaching the limits or terra incognita? Lessons from the EDIFICE surveys. AB - The main lessons from the EDIFICE surveys can be summed up in five points. (i) Evidence talks but very quietly: cancer-screening practices in the French general population do not match scientific evidence; (ii) Give time to time: the rate of appropriation of screening behaviour is slow; (iii) Where there is a will there is a way: the organization of screening decreases inequalities for cancer screening; (iv) Do not aim only at the target: although monitoring of adhesion and compliance for the targeted population is mandatory, monitoring the utilization of screening resources, particularly in countries such as France that have no financial constraints (screening outside the official range is still almost fully reimbursed) is also useful; and (v) Trees do not reach the sky: we have observed a ceiling effect for breast cancer with 90-95% of women who have had a mammogram in their lifetime and 80-85% of women from the targeted population who had a mammogram within the previous 2 years. For colorectal cancer, even with the longstanding programme, the ceiling level observed in France is close to 60%. PMID- 21245682 TI - Large population survey: strengths and limits. Methodology of the EDIFICE survey. AB - In France, mass screening for breast and colon cancer issupported by the French National Cancer Institute (INCa). In these nationwide screening campaigns, individuals aged between 50 and 74 years receive a personalized letter inviting them for a screening examination every 2 years. Prostate cancer screening is, however, still controversial and has not been included in the INCa recommendations so far. Research organizations are particularly interested in screening and indeed, several studies have been conducted in France and other countries to examine the different aspects of the subject. To provide actual benefits, screening should be undertaken on a regular scheduled basis. Therefore, several studies have assessed the factors influencing the participation rate of women in breast cancer screening in France (). The Institut National de Prevention et d'Education pour la Sante conducted one of these in 2005: the Barometre Cancer (including 4046 individuals aged 15 years or older, interviewed by telephone) analysed beliefs and perceptions about cancer screening and studied attendance rates for breast, colon and prostate cancer (including scheduled screening). No previous survey has ever been conducted simultaneously among the general population and physicians with regard to individual and scheduled screening for breast cancer and colorectal cancer (CRC) or individual screening for prostate cancer. EDIFICE is thus the first large-scale survey to assess screening practices in France by analysing the targeted population on the one hand and the clinical practice of French general practitioners (GPs) on the other hand, using the 'mirror study' method to compare results. Two national surveys were conducted in 2005 and 2008. In 2005, only 22 geographical regions were included in the screening programme for CRC. PMID- 21245683 TI - Breast cancer screening in women aged 50-74 years: is there room for improvement? AB - Regular mammography screening has been available in France, free of charge, for all women aged 50-74 years since 2005. Two nationwide surveys [EDIFICE 1 (507 women interviewed; age 50-74 years) and EDIFICE 2 (488 women)] recently collected data on individuals' access to cancer screening procedures. Two further surveys interviewed 600 general practitioners (GPs) each to determine their attitudes towards screening in general and screening for breast cancer in particular. The method of quotas ensured the populations surveyed were representative. In 2005, 93%, and in 2008, 94% of women reported having undergone a screening mammography. Anage-related effect was apparent in the 70-74 year subgroup in 2005, whereas in 2008, over 90% of women aged 50-74 years had had a mammography in their lifetime. In 2008, 66% of women had undergone a mammography as a part of an organized screening programme, versus 45% in 2005. In 2005, 15% of women reported having received no recommendation from their GP, whereas this figure fell to 4% in 2008. In both EDIFICE surveys, two thirds of GPs systematically recommended breast cancer screening to female patients aged 50-74 years; however, female GPs were more likely to systematically recommend this screening. In 2008, 77% of the GPs questioned were aware of the recommended frequency for breast cancer screening, compared with 71% in 2005. Results of studies such as EDIFICE may help increase the proportion of women who undergo breast cancer screening. Successful implementation of organized screening relies heavily on treating physicians. The impact of mammography in breast cancer screening may be further improved by systematic organized screening, by encouraging regular examination and by targeting women who give up screening. PMID- 21245684 TI - Postsurgical spinal magnetic resonance imaging with iterative decomposition of water and fat with echo asymmetry and least-squares estimation. AB - OBJECTIVE: Magnetic resonance imaging (MRI) is the most popular follow-up study for patients who have undergone spinal surgery. However, the image quality often becomes poor because of artifacts from metal implants and/or from failed fat suppression, which obscure diagnosis. Iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) is a new fat suppression method that is less affected by inhomogeneity of the magnetic field. Here, we compared postsurgical spinal MRI with IDEAL versus chemical shift selective saturation (CHESS). METHODS: For 35 patients who had spinal surgery, we examined T2-weighted fast spin-echo sagittal images of the spine with both IDEAL and CHESS. Two radiologists evaluated the degrees of fat suppression and spinal canal projection from 0 (least/worst) to 2 (most/best). RESULTS: Fat suppression and spinal canal scores for IDEAL were statistically higher than those for CHESS (P < 0.05). CONCLUSIONS: Iterative decomposition of water and fat with echo asymmetry and least-squares estimation is clinically useful for postoperative spinal MRI. PMID- 21245685 TI - Role of perfusion magnetic resonance imaging in cervical lymphadenopathy. AB - PURPOSE: To assess the role of perfusion magnetic resonance (MR) imaging in patients with cervical lymphadenopathy. MATERIALS AND METHODS: Dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging was performed on 45 cervical lymph nodes after a bolus injection of gadolinium-DTPA (0.1 mmol/kg body weight). Time signal intensity curve was created and dynamic susceptibility contrast (DSC) percentage of the lymph nodes was calculated. Receiver operating characteristic curve analysis was used to investigate whether DSC percentage could aid in the characterization of cervical lymphadenopathy. RESULTS: The mean (SD) DSC percentage of malignant nodes (44.8% [6.2%]) was significantly different (P = 0.001) from that of benign nodes (28.8% [4.8%]). The mean (SD) DSC percentage of metastatic nodes (48.72% [2.4%]) was significantly different (P = 0.001) than that of lymphoma (37.09% [3.5%]). The DSC percentage threshold value used for differentiating malignant from benign nodes and metastatic from lymphomatous nodes were 34.3% and 43.5%, with areas under the curve of 0.95 and 0.97, respectively. CONCLUSIONS: Perfusion MR imaging is a noninvasive promising method that can be used for differentiation of malignant from benign cervical lymph nodes, and it helps in the characterization of malignant cervical lymphadenopathy. PMID- 21245686 TI - Double inversion recovery magnetic resonance imaging of subcortical band heterotopia: a report of 2 cases. AB - We report 2 cases of subcortical band heterotopia (SBH) with emphasis on double inversion recovery (DIR) magnetic resonance imaging (MRI). The heterotopic gray matter demonstrated homogeneous high signal intensity and the delineation between the SBH and white matter was distinctly depicted on DIR MRI. Double inversion recovery is a useful adjunct to conventional MRI for the diagnosis of SBH. PMID- 21245687 TI - Magnetic resonance perfusion imaging in proliferative cerebral angiopathy. AB - Cerebral proliferative angiopathy (CPA) is an unusual type of vascular malformation with unique clinical and imaging characteristics that distinguish it from the classic arteriovenous malformations. The features of CPA include absence of dominant arterial feeders or flow-related aneurysms, capillary angioectasia without large draining veins, and presence of intermingled normal brain parenchyma that is hypoperfused. We describe the magnetic resonance imaging findings including perfusion in 3 patients with CPA. PMID- 21245688 TI - Silicone oil migrating from intraocular tamponade into the ventricles: case report with magnetic resonance image findings. AB - Silicone oil is an important adjunct for intraocular tamponade in treating retinal detachment. We report a case in which image findings suggested migration and intracranial accumulation of intraocular silicone. We detected silicone oil in the lateral ventricle that showed hyperdensity on computed tomography, slight hyperintensity on T1-weighted magnetic resonance images, and slight hypointensity on T2-weighted images. Applied silicone-selective imaging and proton magnetic resonance spectroscopy confirmed the diagnosis of intraventricular silicone. PMID- 21245689 TI - Magnetic resonance imaging sialolithography: direct visualization of calculi in the submandibular gland using susceptibility-weighted imaging (SWI) at 3 Tesla. AB - Magnetic resonance imaging (MRI) sialolithography is a useful technique for evaluating acute and chronic sialadenitis. However, its major weakness is that stones are not imaged directly. We have developed an MRI technique that allows specific identification and localization of calculi within the submandibular salivary gland or duct. This test is noninvasive and does not require ionizing radiation or a sialogogue. By using 3-dimensional susceptibility-weighted imaging, one can probe MRI signal phase changes. Corrected positive filtered phase and magnitude images, acquired using susceptibility-weighted imaging, allowed identification and anatomical localization of calcified calculi in the submandibular gland with efficacy comparable to computed tomography. PMID- 21245690 TI - Extra Z-axis coverage at CT imaging resulting in excess radiation dose: frequency, degree, and contributory factors. AB - OBJECTIVE: To assess the degree of extra scanning beyond the prescribed anatomic boundaries for thoracic and body computed tomographic (CT) scans and to identify associated factors. METHODS: For 442 consecutive chest, abdomen, and/or pelvis CT examinations, the length of extra scanning beyond the prescribed anatomic boundaries was determined. Examinations were grouped according to the locations/types of the prescribed boundaries and compared with regard to length of extra scanning. RESULTS: Of 442 CT examinations, 438 (99%) included extraneous imaging, showing a mean excess scanning length of 43.2 mm per examination (range, 0-180 mm). Significantly more extraneous imaging was performed when soft tissue or vascular structures defined anatomic boundaries compared to when osseous (P < 0.001) or air/soft tissue interfaces (P < 0.0001) defined the boundaries. The average percent of total scan dose attributable to extra imaging was 8.64% to 10.38%. CONCLUSIONS: Computed tomographic scanning beyond the prescribed anatomic boundaries occurs commonly, resulting in moderate extra radiation dose. PMID- 21245691 TI - Differential computed tomographic attenuation of metabolically active and inactive adipose tissues: preliminary findings. AB - This study investigates differences in computed tomography Hounsfield units between metabolically active (brown fat) and inactive adipose tissues (white fat) due to variations in their densities. Positron emission and computed tomographic data from 101 pediatric and adolescent patients were analyzed. Regions of metabolically active and inactive adipose tissues were identified, and standard uptake values and Hounsfield units were measured. Hounsfield units of active brown fat were more positive (P < 0.001) than inactive fat (-62.4 +/- 5.3 vs 86.7 +/- 7.0) and the difference was observed in both males and females. PMID- 21245692 TI - Imaging of carcinoid tumors: spectrum of findings with pathologic and clinical correlation. AB - Carcinoid tumors are primary malignant neoplasms that arise from neuroendocrine cells. These cells are located throughout the body, resulting in many possible locations for the development of carcinoid tumor. The most common primary location is the gastrointestinal tract, followed by respiratory and thymic carcinoids. The presentations of these tumors are variable depending on their location, aggressiveness, production of functional peptides, and tendency to invade or metastasize. Carcinoid tumors can be imaged by various modalities including gastrointestinal studies, ultrasound, computed tomography, and magnetic resonance imaging as well as nuclear medicine studies (radioactive octreotide). In this review, we illustrate the spectrum of imaging features of carcinoid tumors in various locations of the human body. PMID- 21245693 TI - Tumor fistulization associated with targeted therapy: computed tomographic findings and clinical consequences. AB - PURPOSE: To describe the computed tomographic (CT) appearances and clinical consequences of tumor fistulization as a complication of targeted therapy for cancer. METHODS: The committee on human research approved this Health Insurance Portability and Accountability Act-compliant study and waived written informed consent. Based on the records of the senior author and our multidisciplinary Tumor Boards, we retrospectively identified 4 patients (1 man and 3 women with a mean age of 55.25 years; range, 47 to 64 years) who developed tumor fistulization while being treated with targeted therapy consisting of sunitinib (n = 2); bevacizumab (n = 1); and XL184, an investigational c-Met inhibitor (n = 1). All available clinical, imaging, and histopathological records were reviewed, with particular emphasis on treatment administered, CT findings, and clinical course. RESULTS: All 4 patients developed fistulae from large metastatic deposits in the abdomen (mean size before treatment, 10.55 cm; range, 7.4-13.4 cm) to the gastrointestinal tract, and one patient also developed fistulae from a lung metastasis of undetermined size to the bronchial tree. All fistulae manifested as the appearance of air within a pre-existing tumor mass. At the time of fistula detection, disease at other sites in the 4 patients showed signs of regression (n = 1), progression (n = 2), or stability (n = 1). Currently, one patient is alive without evidence of disease, and the 3 other patients are deceased. CONCLUSIONS: Targeted therapy can be associated with tumor fistulization to the gastrointestinal tract or tracheobronchial tree; familiarity with the CT findings should facilitate the diagnosis of this complication, which seems to be of variable and patient-specific prognostic significance. PMID- 21245694 TI - Diffusion-weighted magnetic resonance imaging for prediction of response of advanced cervical cancer to chemoradiation. AB - PURPOSE: The aim of the study was to investigate diffusion-weighted imaging as an early predictor in detection of response to chemoradiation in advanced cervical cancer. METHODS: Fourteen advanced cervical cancer patients treated with chemoradiation were enrolled in this study. All patients underwent conventional magnetic resonance imaging and diffusion-weighted imaging before the start of therapy, after 2 weeks of therapy, and at the completion of therapy. The tumor volumes and apparent diffusion coefficient (ADC) values of cervical lesions were measured at each examination. The correlation of ADC values and tumor regression was investigated. RESULTS: The mean ADC value of cervical lesion significantly increased as early as 2 weeks after chemoradiation. The ADC values before therapy did not significantly correlate with tumor response. The ADC values after 2 weeks of therapy did not show a significant correlation with tumor response. The change in ADC values after 2 weeks of therapy correlated with tumor response. CONCLUSIONS: Diffusion-weighted imaging may provide an early surrogate biomarker for tumor response in advanced cervical cancers. PMID- 21245695 TI - Assessment of left ventricular diastolic function using 4-dimensional phase contrast cardiac magnetic resonance. AB - OBJECTIVES: Phase-contrast magnetic resonance imaging can potentially assess the dynamics of left ventricular (LV) early diastolic filling. METHODS: Fifteen participants underwent phase-contrast magnetic resonance imaging on a 1.5-T whole body Avanto scanner (Siemens Healthcare, Erlangen, Germany). Left ventricular intracavitary velocities were measured in 3 orthogonal directions. Imaging parameters included a repetition time of 92.45 milliseconds, an echo time of 2.88 milliseconds, a flip angle of 30 degrees, and a velocity-encoding range of 100 to 150 cm/s. RESULTS: The color vector analysis provided a visual assessment of LV diastolic flow. In normal subjects, there was rapid organized early diastolic flow that extended from the mitral valve to the LV apex. In patients with LV diastolic dysfunction, organized high-velocity flow stopped in the mid-left ventricle. CONCLUSIONS: Four-dimensional phase-contrast cardiovascular magnetic resonance can differentiate between normal and abnormal diastolic flow propagation within the left ventricle. PMID- 21245696 TI - Coronary vessel and luminal area measurement using dual-source computed tomography in comparison with intravascular ultrasound: effect of window settings on measurement accuracy. AB - BACKGROUND: Image display settings (window and level) have a substantial impact on measurements of coronary artery and plaque dimensions in computed tomography (CT), and their influence on measurement accuracy has not been systematically evaluated. We analyzed the influence of window width/level settings on the accuracy for determining cross-sectional lumen and outer vessel diameters in contrast-enhanced CT angiography compared with intravascular ultrasound (IVUS). METHODS: We evaluated the data sets of 35 patients. Coronary CT angiography was performed as part of a research protocol before invasive coronary angiography. A contrast-enhanced volume data set was acquired using a dual-source CT (DSCT) scanner (Siemens Healthcare, Forchheim, Germany). Intravascular ultrasound was performed using a 40-MHz IVUS catheter (Atlantis, Boston Scientific Corporation, Natick, Mass) and motorized pullback at 0.5 mm/s. One hundred exactly corresponding sites within the coronary artery system were identified in both DSCT and IVUS using bifurcation points as fiducial markers. In DSCT data sets, multiplanar reconstructions (0.75-mm slice thickness) were rendered orthogonally to the centerline of the coronary artery at each of the 100 sites. Computed tomographic images were displayed using 4 previously published settings (700/200, 700/140, and 500/150 Hounsfield units [HU], and 1 HU/65% of the mean luminal intensity [HU] and 155%/65% of the mean luminal intensity [HU] for window width/level) as well as with a visually adjusted setting for subjectively optimal lumen and outer vessel area measurement. Coronary lumen and cross-sectional vessel areas were manually traced using all 5 display settings and compared with IVUS measurements. RESULTS: Concerning cross-sectional vessel area measurements, correlation was close and significant compared with IVUS using all settings (r >= 0.93, P = 0.01 for all settings). Bland-Altman analysis revealed a good agreement between both modalities with a systematic bias toward overestimation in CT. Least bias was demonstrated using the setting 155%/65% of the mean luminal intensity for window width/level, with a mean (SD) difference of 0.2 (1.73) mm2. For the measurement of the luminal area, the window setting using a width of 1 HU and a level of 65% of the mean luminal intensity showed the lowest correlation to IVUS (r = 0.85), with a systematic bias toward underestimation of the lumen in CT. Bland-Altman analysis revealed a moderate agreement with a mean (SD) difference of -2.1 (1.6) mm2. For all other settings, a very close correlation was observed (r > 0.9, P = 0.01), and Bland-Altman analysis revealed a slight trend toward lumen underestimation in CT, yet with a good agreement. The least bias was demonstrated using the setting 700/200 HU for window width/level with a mean (SD) difference of -0.1 (0.9) mm2. CONCLUSION: Previously published window settings and visually adjusted window setting correlate very well with IVUS measurements regarding coronary artery cross-sectional and luminal area, with a better agreement for luminal area measurements. A systematic bias toward overestimation of vessel area in CT was observed as well as a slight trend toward lumen underestimation. This bias was least for vessel area measurement using 155%/65% of the mean luminal intensity (HU) for window width/level, whereas for luminal area measurement, the setting 700/200 HU for window width/level yielded the least bias. PMID- 21245697 TI - High-temporal resolution dual-energy computed tomography of the heart using a novel hybrid image reconstruction algorithm: initial experience. AB - OBJECTIVES: Dual-energy computed tomography (DECT) has been proposed for the comprehensive assessment of coronary artery stenosis and myocardial perfusion yet traditionally required reducing the temporal resolution of cardiac studies. We evaluated a reconstruction algorithm that preserves high temporal resolution at cardiac DECT. METHODS: Twelve consecutive patients (3 women; mean [SD] age, 64 [10] years) with an abnormal single photon emission CT result underwent invasive coronary angiography and cardiac DECT. Dual-energy CT studies were reconstructed using the standard algorithm with 165-millisecond temporal resolution and a hybrid algorithm providing 83-millisecond temporal resolution. These studies were rated for coronary image quality and motion artifacts and compared with invasive coronary angiographic studies. RESULTS: One hundred sixty-eight coronary artery segments (82%) were evaluated. The standard 165-millisecond reconstruction provided 95% diagnostic segments compared with 100% using the 83-millisecond hybrid reconstruction. Image quality was rated significantly (P < 0.05) better with hybrid reconstruction and had 91.4% sensitivity, 94.7% specificity, 82.1% positive predictive value, and 97.7% negative predictive value for detecting significant stenosis versus 85.7%, 93.2%, 76.9%, and 96.1% with standard reconstruction, respectively. CONCLUSIONS: Hybrid image reconstruction mitigates the former limitations in temporal resolution of cardiac DECT. PMID- 21245698 TI - Interobserver reliability in the assessment of coronary stenoses by multidetector computed tomography. AB - OBJECTIVE: To determine the interobserver reliability for grading coronary stenosis severity with coronary computed tomographic angiography (CCTA). METHODS: Five readers independently reviewed 40 CCTA studies, first the axial images alone, then in combination with multiplanar reconstructions. The stenosis severity in each segment was scored on a 5-point scale. Intraclass correlation (ICC) analysis was performed to assess interobserver reliability on a segmental basis. RESULTS: The reliability was good to moderate in the right coronary artery, left main artery, left anterior descending artery and branches, and the proximal circumflex (ICC: 0.44-0.75) but fair to poor for the posterior descending artery, the posterolateral branch, the obtuse marginal branches, and the distal circumflex (ICC: 0.15-0.39). The ICC correlated with the reference diameter. Although there was no significant difference in the ICC between the scanner types, there were more unevaluable segments in the 16-row scanner compared with the 64-row scanner (2.4 vs 1.4 segments/patient). Addition of multiplanar reconstruction to axial images led to fewer uninterpretable segments and reclassification of stenosis grade in 23% of the segments. CONCLUSIONS: Interobserver reliability for stenosis severity by CCTA varies between segments and correlates with the reference diameter. PMID- 21245699 TI - A low-kilovolt (peak) high-tube current technique improves venous enhancement and reduces the radiation dose at indirect multidetector-row CT venography: initial experience. AB - OBJECTIVE: The purpose was to evaluate the image noise, contrast-to-noise ratio, and radiation dose at indirect multidetector-row computed tomographic venography (CTV) using a low-kilovolt (peak) (kV[p]) high-tube current technique. MATERIALS AND METHODS: Thirty patients underwent indirect CTV of the lower extremity at 120 kV(p) with 170 mA and at 80 kV(p) with 426 mA (CT dose index volumes 11.8 and 9.0 mGy, respectively) on a 64-detector CT scanner. We assessed CT numbers, image noise, and contrast-to-noise ratio of deep (femoral and popliteal) veins. RESULTS: The mean (SD) CT numbers of the femoral and popliteal veins were significantly greater at 80 kV(p) than at 120 kV(p) (142.8 [24.5] and 147.0 [19.4] Hounsfield units [HU], respectively, vs 93.1 [15.5] and 105.0 [14.9] HU, respectively; P < 0.01). The mean (SD) image noise was significantly higher at 80 kV(p) than at 120 kV(p) (11.6 [2.6] and 7.4 [1.4] HU, respectively, vs 8.9 [1.6] and 6.2 [1.5] HU, respectively; P < 0.01). Contrast-to-noise ratios at the femoral and popliteal veins were significantly higher at 80 kV(p) than at 120 kV(p) (6.0 [2.2] and 9.7 [2.4], respectively vs 3.3 [1.8] and 6.9 [2.5], respectively; P < 0.01). CONCLUSION: At indirect CTV, 80 kV(p) and a high tube current setting yielded significantly improved image quality at a reduced radiation dose compared with 120 kV(p). PMID- 21245700 TI - Successful use of multi-detector row computed tomography for detecting contralateral breast cancer. AB - OBJECTIVE: We retrospectively evaluated whether multi-detector row computed tomography (MDCT) could contribute to the early detection of contralateral breast cancer in women with a diagnosis of breast cancer and no suspicious lesions on a mammogram or an ultrasonogram of the contralateral breast. METHODS: A total of 518 women with newly diagnosed unilateral breast cancer underwent MDCT. Multi detector row CT was performed using a 16-detector row CT scanner set for 2-mm collimation, 120 kilovolt (peak), and 180 mA. Axial images of the contralateral breast were evaluated. RESULTS: Four hundred fifty-nine women were eligible for this study. There were suspicious malignant lesions only on MDCT in 21. Multi detector row CT contributed to the diagnosis of contralateral occult breast cancer in 12 women (2.6%), including 1 in whom breast cancer was later diagnosed at another institution. CONCLUSIONS: Multi-detector row CT has a potential role in detecting contralateral breast cancer in women who are at high risk. PMID- 21245701 TI - Magnetic resonance imaging of intraductal papillomas of the breast. AB - PURPOSE: To conduct magnetic resonance imaging (MRI) studies of intraductal papillomas of the breast and to establish correlations with pathologic features. MATERIALS AND METHODS: Magnetic resonance images of the breast from 32 patients identified with surgically resected intraductal papillomas were retrospectively analyzed. were obtained. Interpretation of the MRI findings was based on evaluation of the configuration, internal signal intensity, contrast enhancement, type of the time-intensity curve, and presence or absence of dilated ducts associated with the lesion. Intraductal papillomas of our series were classified into several MR types and were compared to each of the surgically resected specimens. RESULTS: Intraductal papillomas of the breast were classified into 4 MR types: oval nodule in 14 patients; irregular nodule in 6, solid and cystic mass in 8; and occult lesion in 4. Each of the MR types reflected its unique pathologic features: oval nodule composed of papillary fronds surrounded by narrow luminal space inside the duct; irregular nodule of papillary fronds entirely filling up the luminal space and adhering to the duct wall, with irregular margins surrounded by fibrosis or collagenization of fibroglandular stroma; solid and cystic mass of solid nodular protrusion of papillary fronds attached to the dilated cystic duct wall; and occult lesion of 1 to 2 mm in diameter with dilated ducts. They showed various contrast enhancements and time intensity curves. Dilated ducts associated with the lesions were recognized in 20 patients. CONCLUSION: Classifying the MR images of intraductal papillomas could be useful for understanding their pathologic background. PMID- 21245702 TI - Femoral fracture after harvesting of autologous bone graft using a reamer/irrigator/aspirator. AB - A case of postoperative fracture in the donor femur after obtaining autologous bone graft with a reamer/irrigator/aspirator is presented. This procedure was successful in healing a difficult femoral nonunion, but the patient sustained a fracture of the contralateral (bone graft donor) femur 20 days after surgery. A mechanical analysis is conducted of this case and recommendations are made. Unrestricted weightbearing on a limb that has undergone reamer/irrigator/aspirator bone graft harvesting, particularly in a noncompliant patient, is probably inadvisable. If possible, one should obtain bone graft from the same limb as the fracture being treated because this will leave the patient with one unaltered limb for mobilization. PMID- 21245703 TI - Fracture consolidation in a tibial nonunion after revascularization: a case report. AB - Poor vascularity can be a potential contributor in the development of fracture nonunion. There is little evidence in orthopaedic literature suggesting that poor vascularity alone may lead to the development of nonunion. Experimental models addressing the effects of ischemia on fracture healing have yielded conflicting views. The case presented here describes a patient who sustained a Type IIIC tibial shaft fracture requiring vascular repair and soft tissue coverage. The patient developed an aseptic, atrophic nonunion. In preparation for operative management of her nonunion, the patient underwent angioplasty in the lower extremity for stenotic vessels. Shortly thereafter, the patient's nonunion went on to unite with no additional intervention, suggesting that revascularization alone resulted in this dramatic progress to union. Further prospective clinical studies may reveal a role for the use of vascular evaluation and intervention in the diagnosis and treatment of nonunion. PMID- 21245704 TI - Locked plating of distal femur fractures leads to inconsistent and asymmetric callus formation. PMID- 21245707 TI - Threaded screw head inserts improve locking plate biomechanical properties. AB - OBJECTIVES: The purpose of this study was to determine if the stiffness and fatigue life of locking one third tubular plates are enhanced by placing a locking screw head to fill the empty hole of the plate. We hypothesize that both the stiffness and fatigue life of the plates will be improved at physiologically relevant loads by filling the empty center hole of each plate. METHODS: The mechanical stiffness and fatigue life of plates with an open versus filled center hole were assessed through finite element analysis and experimentally using a synthetic bone model under four-point bending. Two plate manufacturers were evaluated, Synthes (n) and Stryker (r). Five-hole one third tubular plates were mechanically cycled with and without filling the central screw hole while load, displacement, and number of cycles were collected. Stiffness was calculated and cycles to failure and mode of failure were monitored. Five plates were evaluated for the filled (F) and open (O) configurations for the n and r plates. RESULTS: Finite element analysis indicated that filling the hole resulted in reduction in maximum stress at the periphery of the center hole by a factor of 2.43 and 2.29 for the n and r plates, respectively. Experimentally, a fourfold improvement was observed in fatigue life of the Synthes plates when a screw head was used to fill the central screw hole (P < 0.005; nF = 45,450 cycles versus nO = 10,305 cycles). The Stryker plates reached the maximum number of cycles (1 million) without fatigue failure in both O and F configurations. Improved bending stiffness was noted for both the n and r plates when the central hole was filled compared with open. For the Stryker plate, this increase was statistically significant (P < 0.011). CONCLUSIONS: The methodology proposed in this study for extending fatigue life and increasing stiffness of locking plates can potentially be extended to any locking plate. Adding a screw head or screw heads to open holes in locking plates adds little additional time or expense and no morbidity to the procedure but can have substantial effects on the mechanical properties of the implant, particularly in lower-profile plates that are initially less rigid and robust. PMID- 21245708 TI - An effective team approach to improve postoperative hip fracture care. AB - OBJECTIVE: To develop an initiative using standardized discharge orders to improve the posthip fracture care of patients aged 50 years or older. DESIGN: Prospective nonrandomized study. SETTING: Hospital orthopaedic service. PARTICIPANTS: Patients at our institution older than age 50 years sustaining a hip fracture who were followed for at least 6 months and qualified for osteoporosis medication. INTERVENTION: The endocrinology and orthopaedic areas agreed to add calcium/vitamin D supplementation, a dual-energy x-ray absorptiometry scan request, and a consult with endocrinology to the hospital discharge orders. OUTCOME MEASURES: The proportions of patients using calcium or bisphosphonate before and after the intervention were compared using the McNemar test. The designated level of significance was 0.05. RESULTS: Originally, 37 of 137 patients were taking calcium/vitamin D supplements. Following this initiative, 92 of 137 were taking the supplement (P < 0.0001). Seventeen of 137 patients were taking bisphosphonate initially and 65 of 137 after the initiative (P < 0.0001). After the initiative, 100% of the discharged patients were offered calcium/vitamin D, a dual-energy x-ray absorptiometry scan, and an endocrinology appointment. All of the patients who reported for the endocrinology consult appointment were offered bisphosphonate therapy. Eighty-two patients kept the appointment for the dual-energy x-ray absorptiometry scan, and 54 saw the endocrinologist. CONCLUSION: The addition of a calcium/vitamin D supplement and an endocrinology appointment to the hospital discharge orders was an effective method of improving treatment and enhancing compliance. PMID- 21245709 TI - Failure of proximal femoral locking compression plate: a case series. AB - OBJECTIVES: The treatment of fractures of the proximal femur has evolved significantly over recent years. The most recent advance is the proximal femoral locking compression plate (PF-LCP; Synthes, West Chester, PA). We present seven failures of the PF-LCP in an attempt to elicit reasons for the failures so that these pitfalls can be avoided in the future. DESIGN: Retrospective chart review. SETTING: Level I trauma centers, tertiary referral hospitals. PATIENTS/PARTICIPANTS: Ten patients at five institutions. INTERVENTION: Open reduction and internal fixation with a PF-LCP. MAIN OUTCOME MEASUREMENTS: Failure mode, time until failure, need for further surgery, bony union, or conversion to arthroplasty. RESULTS: Of the seven cases, two were acute peritrochanteric fractures, one was a periprosthetic fracture at the site of a prior hip fusion, one was an early failure of a compression hip screw, and three were nonunions. The failure mode was implant fracture in four cases and loss of fixation in three cases resulting from varus collapse and implant cutout. Five of seven failures were within the first 3 weeks (average, 12.4 days). The average time to failure for all cases was 37.9 days (range, 5-175 days). The average patient age was 56.7 years (range, 36-72 years). CONCLUSION: Biomechanical studies have shown the PF LCP to be stronger or equivalent to other fixation methods for fractures of the femoral neck and subtrochanteric femur fractures. The seven failures in our cases may be partially the result of patient factors as well as technical factors; however, there appears to be a high rate of failure even when surgery is performed by experienced and fellowship-trained traumatologists. PMID- 21245710 TI - Plate fixation of femoral nonunions over an intramedullary nail with autogenous bone grafting. AB - OBJECTIVE: To describe a novel approach for the treatment of nonunions of diaphyseal femur fractures. DESIGN: Retrospective review. SETTING: University hospital. PATIENTS: Seven patients (six men, one woman, average age 42.5 years) with diaphyseal femoral fracture nonunions treated between November 2006 and November 2007 were reviewed. The injuries included two open and five closed fractures. All were treated initially with intramedullary nail fixation (two antegrade, five retrograde) and went on to develop a symptomatic nonunion by radiographic and clinical criteria. INTERVENTION: Nonunions were treated with operative debridement of the nonunion with plate fixation and autogenous bone grafting without removal or exchange of the intramedullary nail. MAIN OUTCOME MEASURES: Clinical criteria of decreased pain and return to function as well as radiographic evidence of fracture consolidation. RESULTS: All patients demonstrated radiographic evidence of fracture consolidation with an average follow-up time of 17.9 months (range 12-26 months). All were allowed immediate weightbearing and reported decreased pain with improved function. Six patients reported absolutely no pain with ambulation as related to the fracture site, whereas one noted discomfort about the distal femoral compression plate. Independent ambulation was observed in six subjects. None of the patients required additional operations for implant removal or bone grafting procedures. CONCLUSION: Treatment of diaphyseal femoral fracture nonunion after intramedullary nail fixation with large fragmentary compression plating and bone grafting is a reasonable option, especially for complex fractures about the metadiaphyseal region. The procedure appears to be successful in reducing pain, improving function, and predictably leads to radiographic consolidation of the nonunion. PMID- 21245711 TI - Tibial plateau fracture repairs augmented with calcium phosphate cement have higher in situ fatigue strength than those with autograft. AB - OBJECTIVES: This study compared the biomechanical fatigue strength of calcium phosphate augmented repairs versus autogenous bone graft (ABG) repairs in lateral tibia plateau fractures. METHODS: Eight matched pairs of tibias (six male, two female; age, 75 +/- 14 years) were harvested from fresh-frozen cadavers. Reproducible split-depression fractures were simulated and repaired by an orthopaedic traumatologist using a lateral tibial plateau plate. One tibia from each donor was randomly assigned to either calcium phosphate (Callos; Acumed, Hillsboro, OR) or ABG as augmentation. The femoral component of a hemitotal knee arthroplasty was attached to the actuator of a servohydraulic press and centered above the repair site. Cyclic, physiological compression loads were applied at 4Hz starting with a maximum load of 15% body weight and increasing by 15% body weight every 70,000 cycles. Loading conditions were determined from calculations of weight distribution, joint contact area, and gait characterization from existing literature. Repair site depression and stiffness were measured at regular intervals. Specimens were then loaded to failure at 1 mm/min. RESULTS: Calcium phosphate augmented repairs subsided less and were more stiff during the fatigue loading than were ABG repairs at the 70,000, 140,000, and 210,000 cycle intervals (P < 0.03) All repairs survived to 210,000 cycles. The average ultimate load of the calcium phosphate repairs was 2241 +/- 455 N (N = 6) and 1717 +/- 508 N (N = 8) for ABG repairs (P = 0.02). CONCLUSION: Calcium phosphate repairs have significantly higher fatigue strength and ultimate load than ABG repairs and may increase the immediate weightbearing capabilities of the repaired knee. PMID- 21245713 TI - Surgical treatment of extra-articular or simple intra-articular distal tibial fractures: external fixation versus intramedullary nailing. AB - OBJECTIVE: To compare intramedullary nailing (IMN) with external fixation (EF) in the treatment of tibial shaft fractures located within 5 cm of the ankle. SETTING: University teaching hospital. DESIGN: Retrospective comparative study. PATIENTS: Sixty-seven patients with a mean age of 48 years (range, 16-78 years; 24 women, 43 men). INTERVENTION: Thirty-three fractures were treated with EF from 1998 to 2004 and 34 fractures were treated with reamed IMN from 2004 to 2007. MAIN OUTCOME MEASURES: Olerud-Molander ankle score, RAND-36 Item Health Survey, and the number of secondary interventions. RESULTS: The healing time was 21 weeks in the IMN group and 23 weeks in the EF group (P = 0.53). One fracture in the IMN group and three in the EF group malunited (P = 0.62). Olerud-Molander ankle score was 75 in the IMN group and 74 in the EF group (P = 0.51). There was no difference in any of the RAND-36 subscores measuring physical functioning. More patients in the EF group had secondary intervention resulting from delayed healing (8 versus 1, P = 0.03). The patients in the EF group also needed more secondary interventions as a result of any complication (15 versus 2, P < 0.001). There was one deep infection in the IMN group. CONCLUSION: Distal extra-articular or simple intra-articular fractures can be treated with modern IMNs or nonbridging EF. Although functional results are similar, EF carries a significant greater risk of secondary interventions; based on these data, IMN is recommended. PMID- 21245712 TI - The incidence of wound complications related to negative pressure wound therapy power outage and interruption of treatment in orthopaedic trauma patients. AB - OBJECTIVE: Negative pressure wound therapy (NPWT) using the Vacuum Assisted Closure system is an invaluable tool for use on patients with complex limb and soft tissue problems. Recently, the manufacturer (Kinetic Concepts, Inc, San Antonio, TX) made significant modifications to the NPWT platform, including computer software, battery, alarming systems, electric cord and plug apparatus, and others. Since these modifications, we have seen several cases in which the NPWT device has powered off resulting in an unrecognized interruption of therapy. We sought to evaluate the conditions and clinical effects, if any, to orthopaedic trauma patients who experienced an interruption of NPWT therapy when the device powers off. DESIGN: Retrospective study of consecutive patients. SETTING: Two neighboring regional trauma centers. PATIENTS: One hundred twenty-three consecutive orthopaedic trauma patients treated with NPWT by two orthopaedic trauma surgeons between May and November 2008. MAIN OUTCOME MEASUREMENTS: Patient/injury, treatment, and perioperative clinical outcomes data (with emphasis on wound complications such as infection, graft loss, and unscheduled surgery) were collected from medical records and wound care databases. RESULTS: Twelve patients (10%) had problems with the NPWT device powering off causing an unrecognized interruption of therapy. Eleven patients underwent early (less than 6 hours) wound debridement and reapplication of NPWT after detection, of which nine required unplanned surgery. Seven of the 12 patients recognized as having failed NPWT of this type ultimately experienced wound complications, including five deep infections and both patients being treated with an Integra graft (loss of graft). CONCLUSIONS: We have seen substantial problems in orthopaedic trauma patients treated with the NPWT, in which the device has powered off resulting in an unrecognized interruption of therapy. This has resulted in atypically unhealthy-appearing wounds, unplanned surgeries for debridement, and most importantly, an increased incidence of wound complications, including infection and graft loss (P < 0.05). PMID- 21245714 TI - Lateral ankle radiographs: do we really understand what we are seeing? AB - OBJECTIVES: To evaluate the validity of using lateral intraoperative fluoroscopic imaging to assess the reduction of the tibial plafond articular surface, two hypotheses were tested: 1) the distal tibial subchondral shadow on the lateral ankle radiograph is created equally by the medial, central, and lateral portions of the distal tibia; and (2) displacement of a 5-mm width osteochondral fragment is consistently recognizable on lateral fluoroscopic imaging. METHODS: Six human fresh-frozen tibial plafond cadaveric specimens were sagitally sectioned in 5-mm increments after removal of the anterior soft tissue and stabilization of the position of the ankle through external fixation. To test the first hypothesis, a perfect lateral radiograph was taken after sectioning the specimens. The sagittal sections were then removed sequentially from medial to lateral. A perfect lateral radiograph was taken after each change. The sagittal sections were then removed beginning laterally and moving medially. A perfect lateral radiograph was taken after each change. The images were then compared with specific evaluation of the change in the subchondral shadow density. To test the second hypothesis, three malreductions were created by displacing a 5-mm osteochondral segment. After each malreduction, a perfect lateral radiograph was saved. These saved fluoroscopic images were placed in random order with lateral images of normal specimens. Four experienced ankle surgeons were then asked to determine whether the radiographs revealed displacement. Inter- and intraobserver reliability was then evaluated. RESULTS: First, the subchondral shadow of the distal tibia appears to be created by an equal confluence of the subchondral bone of the medial, central, and lateral aspects of the tibial plafond. Second, fellowship-trained observers experienced in pilon fracture treatment correctly identified malreduction only 45% of the time. Intraclass correlation coefficient revealed very poor interobserver reliability with an alpha reliability statistic of 0.183. Intraobserver reliability across all four observers yielded an alpha statistic of 0.474, indicating inconsistencies in observers' evaluation of identical images at separate viewings. CONCLUSIONS: It is difficult to discern rotational or translational displacement of a 5-mm osteochondral fragment on a perfect lateral fluoroscopic view of the ankle. Even with what appears to be a perfect lateral fluoroscopic view intraoperatively, displacement may still be present. When small osteochondral fragments are present, direct visualization of the articular surface is necessary to confidently establish that an anatomic reduction has been achieved. PMID- 21245715 TI - Minimally invasive plate osteosynthesis of the distal fibula with the locking compression plate: first experience of 20 cases. AB - OBJECTIVES: The aim of this study was to evaluate the clinical feasibility and the possible complications associated with minimally invasive plate osteosynthesis of the distal fibula. DESIGN/SETTING: Regional county hospital. PATIENTS/PARTICIPANTS: All patients with Orthopaedic Trauma Association 42, 43, 44 fractures of the distal tibia requiring plate fixation of the distal fibula were included in this cohort study. A consecutive series of 701 internally fixed fractures of tibia and ankle yielded 20 fibular fractures treated with this technique. INTERVENTION: Fractures were treated with the minimally invasive plate osteosynthesis technique using an angular stable screw-plate system for the fibula. MAIN OUTCOME MEASUREMENTS: Clinical and radiologic outcomes at 24 months. RESULTS: Seventeen fractures healed without complication at an average of 9 weeks. Three aseptic nonunions were recorded: one in a pilon fracture (Orthopaedic Trauma Association 43-C3) and one in a distal lower leg fracture (Orthopaedic Trauma Association 43-A3), both with severe closed soft tissue injury (as a result of a crush mechanism). The third one was in an ankle fracture dislocation (OTA 44-C1) with delayed treatment and inadequate reduction of the simple fibula fracture. CONCLUSION: Although this technique is comparable to minimally invasive plate osteosynthesis in the tibia or femur, it appears to be more difficult as a result of small bone size. As a result, we reserve this technique for selected complex fractures of the distal fibula with critical soft tissue conditions. PMID- 21245716 TI - Reduction strategies through the anterolateral exposure for fixation of type B and C pilon fractures. AB - The surgical management of pilon fractures has evolved over the last several years with treatment shifting from acute definitive fixation to delayed fixation. One of the driving forces behind this change was the high incidence of soft tissue complications in those patients with high-energy pilon fractures (Orthopaedic Trauma Association 43B and 43C) managed with acute stabilization. Meticulous soft tissue handling along with delayed definitive fixation based on the soft tissue envelope has decreased the short-term complications associated with treatment of these injuries. Anterolateral exposure to the distal tibial articular surface allows for adequate visualization of most fracture patterns, novel reduction strategies, and successful implant placements. This exposure is useful in certain Type C pilon fractures, anterior and anterolateral Type B pilon fractures, and some extra-articular distal tibial fractures. The anterolateral exposure is not suitable in fractures with medial comminution, medial crush, impaction at the medial shoulder of the joint, segmental medial malleolar injuries, or varus deformity at the time of injury. The exposure has the advantage of excellent visualization of the articular surface up to the medial shoulder of the plafond while avoiding dissection of the anteromedial tibial surface. PMID- 21245717 TI - The posterolateral approach to the tibia for displaced posterior malleolar injuries. AB - Fractures involving the posterior malleolus of the tibia can be difficult to manage. Failure to address these fractures can lead to posterior ankle instability and altered ankle reaction forces. The posterolateral approach to the posterior ankle provides access to both the lateral and posterior malleoli. Displaced fractures of the posterior malleolus can be reduced and fixed under direct visualization through a posterolateral incision. We have had excellent results using this technique for management of displaced posterior malleolar fractures with few complications. Surgeons should be aware of the effectiveness of this technique for managing displaced fractures of the posterior malleolus. PMID- 21245718 TI - Interim guidelines for average-risk women with ovarian cancer symptoms. PMID- 21245719 TI - DNP students' clinical practice hours. PMID- 21245722 TI - Depression in the college population: An E-S-A approach to primary prevention. AB - Nurse practitioners working on college campuses are vital to the prevention, diagnosis, and treatment of depression. Every year, untreated depression results in school failure, social isolation, promiscuity, self-medication with drugs and alcohol, and suicide. On a college campus, collaboration between the student health clinic and the counseling center is an optimal approach to preventive counseling and treatment for depression. PMID- 21245723 TI - Huntington disease: Implications for practice. AB - This article reviews the normal function of the huntingtin gene, mutation-induced changes in the gene product (protein), possible causes of Huntington disease, and associated symptoms. An educational tool with recommendations the practitioner can use for interventions and counseling with patients and their families is also included. PMID- 21245724 TI - Myocardial infarction & sudden death in recreational master marathon runners. AB - This review of the current literature on myocardial infarction and sudden death in recreational master marathon runners aims to help raise awareness of the scope of the problem to primary care providers, and to provide guidelines for educating and screening in recreational master marathon runners. PMID- 21245727 TI - Anti-HIV-1 antibodies 2F5 and 4E10 interact differently with lipids to bind their epitopes. AB - OBJECTIVES: 2F5 and 4E10 are two broadly neutralizing monoclonal antibodies (mAbs) targeting the membrane proximal external region (MPER) of HIV-1 gp41 envelope protein. This region, which contacts the viral membrane, is highly conserved and has been regarded as a promising target for vaccine development. We aimed to clarify the basis of 2F5 and 4E10 molecular interactions with epitope cores in MPER and lipid bilayers. DESIGN: Microscopy-based approaches were used to infer and quantify the effects of both mAbs on membranes, in the presence and absence of the epitope cores. Supported lipid bilayers (SLBs), with and without phase separation, were used as membrane models. Fluorescent-labeled and nonlabeled MPER-derived peptides containing both 2F5 and 4E10 epitopes were used. METHODS: mAbs 2F5 and 4E10 membrane interactions, in the presence or absence of MPER-derived peptides, were evaluated by combined atomic force and confocal microscopies. RESULTS: Both mAbs form lipid-segregated aggregates on SLBs and do not induce other significant membrane perturbations. Furthermore, the affinity of MPER toward membranes is differently affected by both mAbs and correlates with the mAbs-epitope core lipid interactions. 2F5 is able to dock the MPER peptide on the membrane, whereas 4E10 extracts the MPER from the lipid bilayer. CONCLUSION: The results reveal the molecular details underneath 2F5/4E10 membrane-epitope binding and a model is proposed to explain the differential mAbs neutralization efficacies, which relates to the exposure of the epitopes in the lipid bilayers and the role of the lipids in mAb-epitope binding. PMID- 21245726 TI - N-terminal-proB-type natriuretic peptide predicts cardiovascular disease events in HIV-infected patients. AB - BACKGROUND: Cardiovascular disease (CVD) is increasing in HIV-infected patients. N-terminal pro-B-type natriuretic peptide (NT-proBNP) is a significant predictor of CVD in the general population. We aimed to quantify the risk of CVD events associated with NT-proBNP at baseline in the Strategies for Management of Anti Retroviral Therapy study. METHODS: In a nested case-control study, NT-proBNP was measured at baseline in 186 patients who experienced a CVD event over an average of 2.8 years of follow-up and in 329 matched controls. Odds ratios (ORs) associated with baseline levels of NT-proBNP for CVD were estimated using conditional logistic regression. RESULTS: At baseline median NT-proBNP [interquartile range (IQR)] was 48.1 (18.5, 112.9) pg/ml in patients who developed a CVD event and 25.7 (12.4, 50.2) pg/ml in controls. The unadjusted OR for the highest versus the lowest quartile was 3.7 [95% confidence interval (CI) 2.1-6.5, P < 0.0001]. After adjustment for baseline covariates and CVD risk factors, OR was 2.8 (95% CI 1.4-5.6, P = 0.003); with additional adjustment for IL-6, high-sensitivity C-reactive protein and D-dimer, OR was 2.3 (95% CI 1.1 4.9, P = 0.02). CONCLUSIONS: Higher levels of NT-proBNP are associated with increased risk of CVD in HIV patients after considering established CVD risk factors and markers for inflammation and thrombosis. PMID- 21245729 TI - Glycemic control in the intensive care unit and during the postoperative period. PMID- 21245731 TI - Midazolam suppresses maturation of murine dendritic cells and priming of lipopolysaccharide-induced t helper 1-type immune response. AB - BACKGROUND: Dendritic cells (DCs), as antigen-presenting cells, play a key role in the induction and regulation of adaptive immune response. Midazolam is reported to have immunomodulatory properties that affect immune cells. However, the effect of midazolam on DCs has not been characterized. We examined the immunomodulatory properties of midazolam on DC-mediated immune response. METHODS: After allowing murine bone marrow-derived DCs induced by granulocyte macrophage colony stimulating factor to mature, we analyzed their expression of costimulatory molecules (CD80 and CD86), major histocompatibility complex class II molecules, and the secretion of interleukin-12 p40. In vitro, we evaluated the effect of midazolam on maturing DCs in mixed cell cultures containing DCs and T cells. In vivo, we investigated the contact-hypersensitivity response. RESULTS: Midazolam suppressed the expression of CD80, CD86, and major histocompatibility complex class II molecules from murine DCs. Treated with midazolam, DCs also secreted less interleukin-12 p40. In mixed cell cultures with CD3-positive T cells, midazolam-treated DCs showed less propensity to stimulate the proliferation of CD3-positive T cells and the secretion of interferon-gamma from CD4-positive T cells. Midazolam-treated DCs impaired the induction of contact hypersensitivity response. Treatment with ligands for peripheral benzodiazepine receptor inhibited the up-regulation of CD80 during DC maturation. CONCLUSION: Midazolam inhibits the functional maturation of murine DCs and interferes with DC induction of T helper 1 immunity in the whole mouse. In addition, it appears that the immunomodulatory effect of midazolam is mediated via the action of midazolam on the peripheral benzodiazepine receptor. PMID- 21245730 TI - Isoflurane activates intestinal sphingosine kinase to protect against renal ischemia-reperfusion-induced liver and intestine injury. AB - BACKGROUND: Renal ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury and often leads to multiorgan dysfunction and systemic inflammation. Volatile anesthetics have potent antiinflammatory effects. We aimed to determine whether the representative volatile anesthetic isoflurane protects against acute kidney injury-induced liver and intestinal injury and to determine the mechanisms involved in this protection. METHODS: Mice were anesthetized with pentobarbital and subjected to 30 min of left renal ischemia after right nephrectomy, followed by exposure to 4 h of equianesthetic doses of pentobarbital or isoflurane. Five hours after renal IRI, plasma creatinine and alanine aminotransferase concentrations were measured. Liver and intestine tissues were analyzed for proinflammatory messenger RNA (mRNA) concentrations, histologic features, sphingosine kinase-1 (SK1) immunoblotting, SK1 activity, and sphingosine-1-phosphate concentrations. RESULTS: Renal IRI with pentobarbital led to severe renal, hepatic, and intestinal injury with focused periportal hepatocyte vacuolization; small-intestinal apoptosis; and proinflammatory mRNA up regulation. Isoflurane protected against renal IRI and reduced hepatic and intestinal injury via induction of small-intestinal crypt SK1 mRNA, protein and enzyme activity, and increased sphingosine-1-phosphate. We confirmed the importance of SK1 because mice treated with a selective SK inhibitor or mice deficient in the SK1 enzyme were not protected against hepatic and intestinal dysfunction with isoflurane. CONCLUSIONS: Isoflurane protects against multiorgan injury after renal IRI via induction of the SK1/sphingosine-1-phosphate pathway. Our findings may help to unravel the cellular signaling pathways of volatile anesthetic-mediated hepatic and intestinal protection and may lead to new therapeutic applications of volatile anesthetics during the perioperative period. PMID- 21245733 TI - S(+)-ketamine suppresses desensitization of gamma-aminobutyric acid type B receptor-mediated signaling by inhibition of the interaction of gamma aminobutyric acid type B receptors with G protein-coupled receptor kinase 4 or 5. AB - BACKGROUND: Intrathecal baclofen therapy is an established treatment for severe spasticity. However, long-term management occasionally results in the development of tolerance. One of the mechanisms of tolerance is desensitization of gamma aminobutyric acid type B receptor (GABABR) because of the complex formation of the GABAB2 subunit (GB2R) and G protein-coupled receptor kinase (GRK) 4 or 5. The current study focused on S(+)-ketamine, which reduces the development of morphine tolerance. This study was designed to investigate whether S(+)-ketamine affects the GABABR desensitization processes by baclofen. METHODS: The G protein activated inwardly rectifying K channel currents induced by baclofen were recorded using Xenopus oocytes coexpressing G protein-activated inwardly rectifying K channel 1/2, GABAB1a receptor subunit, GB2R, and GRK. Translocation of GRKs 4 and 5 and protein complex formation of GB2R with GRKs were analyzed by confocal microscopy and fluorescence resonance energy transfer analysis in baby hamster kidney cells coexpressing GABAB1a receptor subunit, fluorescent protein tagged GB2R, and GRKs. The formation of protein complexes of GB2R with GRKs was also determined by coimmunoprecipitation and Western blot analysis. RESULTS: Desensitization of GABABR-mediated signaling was suppressed by S(+)-ketamine in a concentration-dependent manner in the electrophysiologic assay. Confocal microscopy revealed that S(+)-ketamine inhibited translocation of GRKs 4 and 5 to the plasma membranes and protein complex formation of GB2R with the GRKs. Western blot analysis also showed that S(+)-ketamine inhibited the protein complex formation of GB2R with the GRKs. CONCLUSION: S(+)-Ketamine suppressed the desensitization of GABABR-mediated signaling at least in part through inhibition of formation of protein complexes of GB2R with GRK 4 or 5. PMID- 21245732 TI - Effect of inhibition of spinal cord glutamate transporters on inflammatory pain induced by formalin and complete Freund's adjuvant. AB - BACKGROUND: Spinal cord glutamate transporters clear synaptically released glutamate and maintain normal sensory transmission. However, their ultrastructural localization is unknown. Moreover, whether and how they participate in inflammatory pain has not been carefully studied. METHODS: Immunogold labeling with electron microscopy was carried out to characterize synaptic and nonsynaptic localization of glutamate transporters in the superficial dorsal horn. Their expression and uptake activity after formalin- and complete Freund's adjuvant (CFA)-induced inflammation were evaluated by Western blot analysis and glutamate uptake assay. Effects of intrathecal glutamate transporter activator (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline and inhibitors (DL-threo-beta-benzyloxyaspartate [TBOA], dihydrokainate, and DL-threo-beta hydroxyaspartate), or TBOA plus group III metabotropic glutamate receptor antagonist (RS)-alpha-methylserine-O-phosphate, on formalin- and CFA-induced inflammatory pain were examined. RESULTS: In the superficial dorsal horn, excitatory amino acid carrier 1 is localized in presynaptic membrane, postsynaptic membrane, and axonal and dendritic membranes at nonsynaptic sites, whereas glutamate transporter-1 and glutamate/aspartate transporter are prominent in glial membranes. Although expression of these three spinal glutamate transporters was not altered 1 h after formalin injection or 6 h after CFA injection, glutamate uptake activity was decreased at these time points. Intrathecal (R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline had no effect on formalin induced pain behaviors. In contrast, intrathecal TBOA, dihydrokainate, and DL threo-beta-hydroxyaspartate reduced formalin-evoked pain behaviors in the second phase. Intrathecal TBOA also attenuated CFA-induced thermal hyperalgesia at 6 h after CFA injection. The antinociceptive effects of TBOA were blocked by coadministration of (RS)-alpha-methylserine-O-phosphate. CONCLUSION: Our findings suggest that spinal glutamate transporter inhibition relieves inflammatory pain through activation of inhibitory presynaptic group III metabotropic glutamate receptors. PMID- 21245734 TI - Salvinorin A produces cerebrovasodilation through activation of nitric oxide synthase, kappa receptor, and adenosine triphosphate-sensitive potassium channel. AB - BACKGROUND: Salvinorin A is a nonopioid, selective kappa opioid-receptor agonist. Despite its high potential for clinical application, its pharmacologic profile is not well known. In the current study, we hypothesized that salvinorin A dilates pial arteries via activation of nitric oxide synthase, adenosine triphosphate sensitive potassium channels, and opioid receptors. METHODS: Cerebral artery diameters and cyclic guanosine monophosphate in cortical periarachnoid cerebrospinal fluid were monitored in piglets equipped with closed cranial windows. Observation took place before and after salvinorin A administration in the presence or absence of an opioid antagonist (naloxone), a kappa opioid receptor-selective antagonist (norbinaltorphimine), nitric oxide synthase inhibitors (N(G)-nitro-L-arginine and 7-nitroindazole), a dopamine receptor D2 antagonist (sulpiride), and adenosine triphosphate-sensitive potassium and Ca activated K channel antagonists (glibenclamide and iberiotoxin). The effects of salvinorin A on the constricted cerebral artery induced by hypocarbia and endothelin were investigated. Data were analyzed by repeated measures ANOVA (n = 5) with statistical significance set at a P value of less than 0.05. RESULTS: Salvinorin A induced immediate but brief vasodilatation that was sustained for 30 min via continual administration every 2 min. Vasodilatation and the associated cyclic guanosine monophosphate elevation in cerebrospinal fluid were abolished by preadministration N(G)-nitro-L-arginine, but not 7-nitroindazole. Although naloxone, norbinaltorphimine, and glibenclamide abolished salvinorin A-induced cerebrovasodilation, this response was unchanged by iberiotoxin and sulpiride. Hypocarbia and endothelin-constricted pial arteries responded similarly to salvinorin A, to the extent observed under resting tone. CONCLUSIONS: Salvinorin A dilates cerebral arteries via activation of nitric oxide synthase, adenosine triphosphate-sensitive potassium channel, and the kappa opioid receptor. PMID- 21245735 TI - Thoracic epidural anesthesia improves early outcomes in patients undergoing off pump coronary artery bypass surgery: a prospective, randomized, controlled trial. AB - BACKGROUND: The aim of this two-center, open, randomized, controlled trial was to evaluate the impact of thoracic epidural anesthesia on early clinical outcomes in patients undergoing off-pump coronary artery bypass surgery. METHODS: Two hundred and twenty-six patients were randomized to either general anesthesia plus epidural (GAE) (n = 109) or general anesthesia only (GA) (n = 117). The primary outcome was length of postoperative hospital stay. Secondary outcomes were: arrhythmia, inotropic support, intubation time, perioperative myocardial infarction, neurologic events, intensive care stay, pain scores, and analgesia requirement. RESULTS: Baseline characteristics were similar in the two groups. One patient died in the GAE group. Median postoperative stay was significantly reduced in the GAE, compared with the GA, group (5 days, interquartile range [5 6] vs. 6 days, interquartile range [5-7], hazard ratio = 1.39, 95% CI [1.06 1.82]; P = 0.017). The incidence of arrhythmias and the median intubation time were both significantly lower in the GAE, compared with the GA, group (odds ratio = 0.41, 95% CI [0.22-0.78], P = 0.006 and hazard ratio = 1.73, 95% CI [1.31 2.27], P < 0.001, respectively). Patients in the GAE group were more likely to need vasoconstrictors intraoperatively than in the GA group (odds ratio = 2.50, 95% CI [1.22-5.12]; P = 0.012). The GAE, compared with GA, group reported significantly lower levels of impairment for all pain domains and reduced morphine usage (odds ratio = 0.07, 95% CI [0.03-0.17]; P < 0.001). CONCLUSION: In patients undergoing off-pump coronary artery bypass surgery, the addition of thoracic epidural to general anesthesia significantly reduces the incidence of postoperative arrhythmias and improves pain control and overall quality of recovery, allowing earlier extubation and hospital discharge. PMID- 21245736 TI - Possible intravascular caudal injection. PMID- 21245737 TI - Practice advisory for the perioperative management of patients with cardiac implantable electronic devices: pacemakers and implantable cardioverter defibrillators: an updated report by the american society of anesthesiologists task force on perioperative management of patients with cardiac implantable electronic devices. PMID- 21245738 TI - Case scenario: self-extraction of intrathecal pump medication with a concomitant intrathecal granulomatous mass. PMID- 21245739 TI - Celecoxib impairs heart development via inhibiting cyclooxygenase-2 activity in zebrafish embryos. AB - BACKGROUND: Celecoxib, a cyclooxygenase-2 inhibitor, is a commonly ingested drug that is used by some women during pregnancy. Although use of celecoxib is associated with increased cardiovascular risk in adults, its effect on fetal heart development remains unknown. METHODS: Zebrafish embryos were exposed to celecoxib or other relevant drugs from tailbud stage (10.3-72 h postfertilization). Heart looping and valve formation were examined at different developmental stages by in vivo confocal imaging. In addition, whole mount in situ hybridization was performed to examine drug-induced changes in the expression of heart valve marker genes. RESULTS: In celecoxib-treated zebrafish embryos, the heart failed to undergo normal looping and the heart valve was absent, causing serious blood regurgitation. Furthermore, celecoxib treatment disturbed the restricted expression of the heart valve markers bone morphogenetic protein 4 and versican-but not the cardiac chamber markers cardiac myosin light chain 2, ventricular myosin heavy chain, and atrial myosin heavy chain. These defects in heart development were markedly relieved by treatment with the cyclooxygenase-2 downstream product prostaglandin E2, and mimicked by the cyclooxygenase-2 inhibitor NS398, implying that celecoxib-induced heart defects were caused by the inhibition of cyclooxygenase-2 activity. CONCLUSIONS: These findings provide the first in vivo evidence that celecoxib exposure impairs heart development in zebrafish embryos by inhibiting cyclooxygenase-2 activity. PMID- 21245740 TI - Preoperative pain sensitivity and its correlation with postoperative pain and analgesic consumption: a qualitative systematic review. AB - Pain perception to minor physical stimuli has been hypothesized to be related to subsequent pain ratings after surgery. The objective of this systematic review was to evaluate the correlation between preoperative pain sensitivity and postoperative pain intensity. After a literature search of MEDLINE, EMBASE, and meeting abstracts, we identified 15 studies (n = 948 patients) with univariate and/or multivariate analysis on the topic. In these studies, three types of pain stimuli were applied: thermal, pressure, and electrical pain. The intensity of suprathreshold heat pain (i.e., pain beyond patient threshold) was most consistently shown to correlate with postoperative pain. The most common limitation of the included studies was the method of statistical analysis and lack of multivariate analysis. More research is required to establish the correlation of other pain sensitivity variables with postoperative pain outcomes. PMID- 21245741 TI - Long-term prevention of mortality in morbid obesity through bariatric surgery. a systematic review and meta-analysis of trials performed with gastric banding and gastric bypass. AB - BACKGROUND: Bariatric surgery has been reported to reduce long-term mortality in operated participants in comparison with nonoperated participants. METHODS: We performed a systematic review and meta-analysis of clinical trials published as full articles dealing with cardiovascular (CV) mortality, all-cause mortality (noncardiovascular), and global mortality (sum of CV and all-cause mortality). Pooled-fixed effects of estimates of the risk of mortality in participants undergoing surgery were calculated compared with controls. RESULTS: Of 44,022 participants from 8 trials (14,052 undergoing surgery and 29,970 controls), death occurred in 3317 participants (400 in surgery, 2917 in controls); when the kind of death was specified, 321 CV deaths (118 in surgery, 203 in controls), and 523 all-cause deaths (218 in surgery, 305 in controls) occurred. Compared with controls, surgery was associated with a reduced risk of global mortality (OR = 0.55, CI, 0.49-0.63), of CV mortality (OR = 0.58, CI, 0.46-0.73), and of all cause mortality (OR = 0.70, CI, 0.59-0.84).Data of all-cause mortality were not heterogeneous; heterogeneity of data of CV mortality decreased when studies were grouped according to size (large vs small studies). The reduction of risk was smaller in large than in small studies (OR = 0.61 vs 0.21, 0.63 vs 0.16, 0.74 vs 0.35 for global, CV, and all-cause mortality, respectively). The effect of gastric banding and gastric by-pass (3797 vs 10,255 interventions) was similar for global and all-cause mortality (OR = 0.57 vs 0.55, and 0.66 vs 0.70, respectively), different for CV mortality (OR = 0.71 vs 0.48). At meta-regression analysis, a trend for a decrease of global mortality (Log OR) linked to increasing BMI appeared. CONCLUSION: This meta-analysis indicates that (1) bariatric surgery reduces long-term mortality; (2) risk reduction is smaller in large than in small studies; and (3) both gastric banding and gastric by-pass reduce mortality with a greater effect of the latter on CV mortality. PMID- 21245742 TI - Aurintricarboxylic acid inhibits the nuclear factor-kappaB-dependent expression of intercellular cell adhesion molecule-1 and endothelial cell selectin on activated human endothelial cells. AB - Activation of the vascular endothelium and increased adhesion of circulating leukocytes to the activated endothelium are important events in inflammation and coagulation. Aurintricarboxylic acid (ATA), a triphenylmethyl dye compound, is known to inhibit platelet adhesion by interfering with the binding of von Willebrand factor to platelet glycoprotein Ib. However, the effect of ATA on the inflammatory response of endothelial cells has not yet been investigated. Here, we investigated the functional role and molecular mechanism of ATA on the activation of human endothelial cells. ATA inhibited the expression of intercellular adhesion molecule-1 (ICAM-1), and endothelial cell selectin (E selectin) was upregulated on human umbilical vein endothelial cells (HUVECs) in response to tumor necrosis factor-alpha or lipopolysaccharide (LPS). We also observed the inhibitory effect of ATA on LPS-induced mRNA expression of ICAM-1 and E-selectin. Furthermore, ATA inhibited the binding of leukocytes to activated HUVECs. ATA significantly inhibited the nuclear translocation of nuclear factor kappaB (NF-kappaB) and degradation of IkappaB on activated HUVECs, suggesting that ATA inhibits NF-kappaB signaling. Finally, three NF-kappaB inhibitors effectively inhibited the expressions of ICAM-1 and E-selectin on activated endothelial cells. The present data suggest that ATA exerts beneficial effect in various inflammation conditions through inhibition of adhesion molecule expression in activated endothelial cells and the resulting inhibition of leukocytes tissue accumulation. PMID- 21245743 TI - A novel frameshift mutation in FGA (c.1846 del A) leading to congenital afibrinogenemia in a consanguineous Syrian family. AB - Congenital afibrinogenemia is a rare autosomal recessive coagulation disorder characterized essentially by bleeding symptoms, but miscarriages and, paradoxically, thromboembolic events can also occur. Most reported mutations leading to congenital afibrinogenemia are located in FGA encoding the fibrinogen A alpha-chain. In this study, we analysed 12 individuals from a consanguineous Syrian family with reduced or absent fibrinogen levels: those with fibrinogen levels around 1 g/l (n = 7) were found to be heterozygous for a novel frameshift mutation in FGA exon 5 (c.1846 del A) and those with undetectable fibrinogen levels (n = 5) were homozygous for the same mutation. This novel frameshift mutation is the most C-terminal causative FGA mutation identified to date in afibrinogenemic patients. The resulting aberrant Aalpha-chain (p.Thr616HisfsX32) is most likely synthesized, but is less efficiently assembled and/or secreted into the circulation given the phenotype of asymptomatic hypofibrinogenemia in heterozygous individuals and bleeding diathesis in homozygous individuals. PMID- 21245744 TI - An assessment of the utility of unselected coagulation screening in general hospital practice. AB - Coagulation screening using prothrombin time (PT) and activated partial thromboplastin time (APTT) is widely used. We performed an audit of coagulation screening in an Irish teaching hospital. We analysed PT and/or APTT results received during normal working hours during a 1-week period in our hospital. Abnormal results due to anticoagulants were excluded from further study. In samples with PT longer than 15.5 s and/or APTT longer than 42 s, we proceeded to 1: 1 mixing studies if the PT was prolonged and 1: 1 mixing studies, factor XII assay and lupus screen if the APTT was prolonged. We also obtained referral source for all samples and clinical details for abnormal samples. Six hundred and seventy-one coagulation requests were received during the study period. Three hundred and eighteen of 671 (47.4%) coagulation requests were for monitoring of anticoagulation. Three hundred and fifty-three of 671 (52.6%) requests were for coagulation screening rather than anticoagulant monitoring. In the coagulation screens received, PT was prolonged in 19 of 353 (5.4%). PT was longer than 20 s in four of 353 cases (1.1%). APTT was prolonged in 19 of 353 (5.4%). APTT was longer than 50 s in four of 353 (1.1%). No patients with abnormal PT or APTT had any bleeding sequelae during the study period. Unregulated coagulation screening has a low yield of abnormal results; the majority of these abnormal results show mild prolongation of PT or APTT with no evidence that they are associated with an increased bleeding risk. PMID- 21245745 TI - Platelet function alterations and their relation to P-selectin (CD62P) expression in children with iron deficiency anemia. AB - Iron deficiency anemia (IDA) may cause platelet aggregation dysfunction and this can be reversed by iron therapy. On the other hand, it has been reported that the platelet fractions carrying the platelet activation markers, CD62P and CD63, are increased in thalassemic patients and there is a significant correlation between the increased levels of soluble P-selectin and free iron in sickle cell disease. This study was performed to investigate the alterations of platelet functions and whether iron deficiency results in diminished expression of activation marker (P selectin; CD62P) leading to platelet aggregation dysfunction in children with IDA. Hemoglobin, erythrocyte indices (mean erythrocyte volume and red blood cell distribution width), serum levels of iron, transferrin and ferritin, platelet aggregation tests (with ADP, collagen, and ristocetin), PFA-100 closure time, and CD62P expression were evaluated in fasting blood samples of 22 children with IDA and 20 children without anemia. CD62P expression was detected by flow cytometry in normal and 5 MUmol/l ADP-activated platelets. Mean closure times were longer in the patient group than control. In platelet aggregation tests, mean values of maximum aggregation times by ristocetin, ADP, and collagen were also more prolonged in patient group. Ristocetin-induced maximum aggregation rates (amplitude) were significantly higher in patients. However, ADP and collagen induction did not produce the same effect. CD62P expressions were significantly higher on activated platelets of the patient group, although they were similar in both groups before activation by ADP. These findings suggest that platelet aggregation and adhesion have been delayed in children with IDA; however, platelet function abnormalities are not associated with CD62P expression on platelet surface. PMID- 21245746 TI - Risk of recurrent venous thromboembolism according to malignancy characteristics in patients with cancer-associated thrombosis: a systematic review of observational and intervention studies. AB - Patients with cancer-associated venous thromboembolism (VTE) should be treated with low molecular weight heparin. The ideal duration of anticoagulation in this population is unknown. It is important to evaluate whether there is variation in susceptibility for recurrent VTE according to malignancy characteristics. In this systematic review we sought to evaluate cancer characteristics that may influence the risk for VTE recurrence and the success of anticoagulation in patients with cancer-associated VTE. A systematic literature search strategy identified potential studies on MEDLINE, Embase, the Cochrane Register of Controlled Trials, MEDLINE In-Process and other nonindexed citations using the Ovid interface. There was no restriction to study design or language. No randomized controlled trials fulfilled our inclusion criteria. We included four retrospective and six prospective studies. VTE recurrence rate according to tumour stage suggested an increased risk for patients with metastatic malignancy compared with patients with localized disease (relative risk 1.36; 95% confidence interval 1.06-1.74, P = 0.01). We were unable to pool data to evaluate VTE recurrence according to tumour site and histology. The isolated evaluation of the included studies suggested that younger patients with adenocarcinoma, lung or gastrointestinal malignancy have the highest risk. There is paucity of data regarding detailed malignancy characteristics in patients with cancer-associated VTE. It appears that metastatic malignancy, or adenocarcinoma, or lung malignancy confers a higher risk of VTE recurrence than patients with localized malignancy, nonadenocarcinoma or breast cancer. PMID- 21245747 TI - Postoperative changes in procoagulant factors after major surgery. AB - Surgical patients are primarily at an increased risk of perioperative bleeding; however, after surgery, these patients develop hypercoagulability that favors thrombotic events. Currently, the time course of postoperative coagulation is not well characterized. Thus, the aim of the present study was to provide a detailed description of the changes in procoagulant factors in patients after major surgery and to evaluate coagulation tests based on their ability to detect hypercoagulability. Fifty-one consecutive patients undergoing different types of major surgery were analyzed. Blood samples were taken preoperatively and on postoperative days (PODs) 1, 2, 3, and 6. In addition to prothrombin time (PT) and activated partial thromboplastin time (aPTT), all PT-dependent and aPTT dependent clotting factors, von Willebrand factor (vWF), and fibrinogen were obtained, and thrombelastometry and multiplate electrode aggregometry (MEA) were performed. On POD 1, the majority of clotting factors, including factors II, VII, X, XI, and XII, showed a significant decrease from baseline. Factors II, X, XI, and XII remained significantly reduced until POD 3. In contrast, starting on POD 2, fibrinogen, factor VIII, and vWF continuously increased. No relevant changes were found for PT or aPTT. Thrombelastometry revealed a continuous increase in clot firmness, and MEA demonstrated an increase in platelet aggregation on POD 6. However, absolute values remained within normal ranges, and only serial measurements showed hypercoagulation. Beginning on POD 2 after major surgery, significant hypercoagulability developed in patients. However, clinically used global coagulation tests and point-of-care devices did not reliably reflect the hypercoagulatory state. PMID- 21245748 TI - Development of a new modified Bethesda method for coagulation inhibitors: the Osaka modified Bethesda method. AB - The Nijmegen assay for the factor VIII (F-VIII) inhibitor is recommended by the International Society on Thrombosis and Haemostasis/Scientific and Standardization Committee. However, due to cumbersome and complicated preprocessing, it is presently difficult to introduce this assay into hospital laboratories. We used buffered plasma that was made by addition of 1 volume of 1 mol/l HEPES buffer at pH 7.35 to 9 volumes of plasma to form the test samples. The inhibitor titer was calculated by the remaining rate of F-VIII coagulation activity (F-VIII:C), using the ratio of actual value to the theoretical value. Five hundred microliters of the buffered test plasma and the control (30 mmol/l HEPES buffered saline at pH 7.35) were each mixed with equal volumes (500 MUl) of normal pooled plasma in a test tube (11 mm internal diameter and 6.5 ml volume capacity), and incubated at 37 degrees C for 2 h. In our modified Bethesda method, there were no significant changes in pH and F-VIII:C of control and test mixtures after incubation tests for stability. With the modified method, the inhibitor titers (mean, SD) from examining three hemophilia A plasma samples (F VIII:C, <1-3%) and 40 normal samples (F-VIII:C, 34.5-168.3%) were 0.032, 0.057 and -0.009, 0.057, respectively. By our method, the F-VIII inhibitor titer of type I inhibitor-positive samples was higher than the Nijmegen method, and for type II inhibitor-positive samples, the titer was similar. We believe that our method can be applied to not only the type I inhibitor, but also to assays of type II inhibitor, without cumbersome and complicated preprocessing. PMID- 21245749 TI - A novel human microplasmin fold: new perspective to thrombosis treatment. AB - The purpose of the present study was to obtain polypeptide chains with more specific fibrinolytic activity from normal human plasma. The isolation procedure was carried out in the presence of acetic acid and sodium borate (pH 9.9) purified with affinity and ionic interchange chromatography. Activity of microplasmin studied in vitro shows that the fibrin plate was used to measure the fibrinolytic activity. Rabbit thrombosis model was used to probe in-vivo fibrinolytic effects. Out of 13 male and female rabbits, seven (group A) were treated with microplasmin and six (group B) as placebo, weighing 2500-3200 g. Comparison of groups was made by analysis of variance with a statistical significance of 0.05%. In-vitro assay lysis (25 IU) was produced by microplasmin and tissue plasminogen activator. The fibrinolytic activity in rabbits showed 100% (7/7) reperfusion with microplasmin and 0% (0/7) with placebo (P = 0.002). The proposed scheme in this research for the fibrinolytic activity of microplasmin obtained by autolysis cleavage at new specific sites Lys-97-Val-98 and Ser-364-Thr-365 in the plasminogen involved in-vitro and in-vivo assays as a new specific fibrinolytic activity without haemorrhagic events. This microplasmin is different to the others and with more specific fibrinolysis. PMID- 21245750 TI - Inherited and acquired factor V deficiency. AB - The clotting factor V, also known as proaccelerin or labile factor, is synthesized by the liver and possibly by the megakaryocytes. Factor V exerts a pivotal role in hemostasis, as it participates in both procoagulant and anticoagulant pathways, being an essential cofactor of the prothrombinase complex in the former case and participating in the inactivation of factor VIII (FVIII) in the latter. Isolated factor V deficiency due to mutations in the F5 gene is a rare inherited coagulopathy typically associated with a broad spectrum of bleeding symptoms, ranging from easy bruising, delayed bleeding after haemostatic challenges such as trauma or surgery to more severe joint bleeds. The combined deficiency of factor V and FVIII, commonly known as F5F8D, is a recessive disorder not attributable to the association of isolated factor V and FVIII deficiencies, but rather to defective intracellular processing of both proteins due to mutations involving the LMAN1 and MCFD2 genes, which encode two proteins forming an essential cargo receptor complex. Overall, patients affected by F5F8D do not bleed more in terms of both frequency and severity than those carrying specific deficiencies of both factors and the bleeding phenotype is generally mild. Although now increasingly rare, inhibitors directed against factor V may also develop in individuals of any age and are characterized by a very heterogeneous clinical phenotype. The aim of the current review is to provide an overview on the physiopathology, diagnostics, and clinical management of both inherited and acquired factor V deficiency. PMID- 21245752 TI - Should we still do the Ross operation in adults? AB - PURPOSE OF REVIEW: To update the long-term results of the Ross procedure in adults and to establish the current role of this operation for the management of aortic valve disease. RECENT FINDINGS: Early outcomes continue to be excellent. Follow-up beyond 10 years, however, demonstrates continued deterioration of the autografts and need for reoperation in a substantial percentage of patients, particularly those in whom the root replacement technique was used. SUMMARY: Until the long-term results of alternatives to the aortic root technique for implantation (i.e., subcoronary) become available, and until the long-term results with other techniques, such as implantation of the autograft root within a synthetic vascular graft, are known, the Ross procedure should not be routinely performed in adult patients. PMID- 21245751 TI - Should all ischemic mitral regurgitation be repaired? When should we replace? AB - PURPOSE OF REVIEW: Ischemic mitral regurgitation (IMR) is a major source of morbidity and mortality. Although mitral valve repair has become recently popularized for the treatment of IMR, select patients may derive benefits from replacement. The purpose of this review is to describe current surgical options for IMR and to discuss when mitral valve replacement (MVR) may be favored over mitral valve repair. RECENT FINDINGS: Current surgical options for the treatment of IMR include surgical revascularization alone, mitral valve repair, or MVR. Although surgical revascularization alone may benefit patients with mild-moderate IMR, most surgeons advocate the performance of revascularization in combination with either mitral valve repair or replacement. In the current era, mitral valve repair has proven to offer improved short-term and long-term survival, decreased valve-related morbidity, and improved left ventricular function compared with MVR. However, MVR should be considered for high-risk patients and those with specific underlying mechanisms of IMR. SUMMARY: In the absence of level one evidence, mitral valve repair offers an effective and durable surgical approach to the treatment of mitral insufficiency and remains the operation of choice for IMR. MVR, however, is preferred for select patients. Future randomized, prospective clinical trials are needed to directly compare these surgical techniques. PMID- 21245753 TI - Left ventricular assist device management in patients chronically supported for advanced heart failure. AB - PURPOSE OF REVIEW: This review summarizes management strategies to reduce morbidity and mortality in heart failure patients supported chronically with implantable left ventricular assist devices (LVADs). RECENT FINDINGS: As the population of patients supported with long-term LVADs has grown, patient selection, operative technique, and patient management strategies have been refined, leading to improved outcomes. This review summarizes recent findings on LVAD candidate selection, and discusses outpatient strategies to optimize device performance and heart failure management. It also reviews important device complications that warrant close outpatient monitoring. SUMMARY: Managing patients on chronic LVAD support requires regular patient follow-up, multidisciplinary care teams, and frequent laboratory and echocardiographic surveillance to ensure optimal outcomes. PMID- 21245754 TI - New imaging modalities in the catheterization laboratory. AB - PURPOSE OF REVIEW: To provide an overview of the various modalities that have emerged in the last years as adjunctive tools to provide detailed imaging of the cardiovascular system in the catheterization laboratory. RECENT FINDINGS: Completion angiography after cardiac surgery for congenital heart disease using a dedicated hybrid operating cardiac suite may aid in early diagnosis and therapy of postsurgical abnormalities. The application of three-dimensional rotational digital angiography results in a more precise delineation of the three dimensional anatomy of vascular structures outside the heart with rapid image processing and reduction of the amount of contrast used and ionizing radiation dose. Combined catheterization/magnetic resonance (MR) hybrid laboratories have the potential to accurately assess changes in the anatomy and physiology pretranscatheter and posttranscatheter interventions. Fully MR-guided transcatheter procedures have become possible in animal models. Real-time three dimensional transesophageal echocardiography (TEE) has helped to guide transcatheter procedures in septal and valvar structures. Miniaturization of probes has expanded the applications of TEE for smaller neonates. The use of intravascular ultrasound has helped to better understand the mechanisms of vascular diseases and transcatheter treatments. SUMMARY: Knowledge and proper application of new imaging modalities during interventions in the catheterization laboratory may improve the outcomes of patients with congenital and acquired structural heart disease. PMID- 21245755 TI - Update on rhythm mapping and catheter navigation. AB - PURPOSE OF REVIEW: Rhythm mapping in electrophysiology is a critical step in the catheter ablation of arrhythmia substrates. The past decade has seen major advances in the technology used by electrophysiologists to visualize and treat arrhythmias. This review will summarize the most recent developments in three dimensional electroanatomic mapping and in catheter navigation. RECENT FINDINGS: Three-dimensional contact and noncontact mapping systems have a proven efficacy in multiple clinical studies. Advances in technology have led to the integration of imaging and mapping to produce an increasingly realistic representation of arrhythmias. These systems have been used both to improve success in the treatment of arrhythmias and to enhance our understanding of cardiac electroanatomy and electrophysiology. Additionally, remote catheter mapping technology, although not widely used in pediatrics, may be an important tool to decrease procedural risks to both the patient and physician. SUMMARY: Technological developments have occurred rapidly over the past several years. Three-dimensional electroanatomic mapping has proven to be a key tool for the success of complex arrhythmia ablations, especially in patients with congenital heart disease. The integration of imaging technology and arrhythmia mapping technology has greatly enhanced the understanding and visualization of arrhythmias. Remote catheter navigation may become an important tool to improve safety. PMID- 21245756 TI - Novel transplant strategies for generating graft-versus-leukemia effect in acute myeloid leukemia. AB - PURPOSE OF REVIEW: This review summarizes the recent developments in the clinical research and therapeutic applications for prevention and treatment of postallogeneic stem cell transplant (SCT) relapse. Specifically, we address various maneuvers to optimize the graft-versus-leukemia (GVL) effect while preventing graft-versus-host-disease (GVHD). RECENT FINDINGS: Alloreactive natural killer (NK) cells can be recruited to mediate GVL effect by careful mismatching on the killer-cell immunoglobulin-like receptors (KIRs) ligand. Donor posttransplant NK cell infusions have led to remission in poor-risk acute myeloid leukemia (AML). Donor lymphocyte infusions may also be used both prophylactically or at the time of leukemia relapse. Posttransplant hypomethylating agents have emerged as promising therapies to safeguard against relapse. Prevention of GVHD while preserving GVL effect using third-party regulatory T cells is under investigation. Adoptive T-cell transfer against specific leukemic antigens and immunotherapy exploiting the marrow microenvironment seem promising as well. SUMMARY: In the setting of allogeneic SCT, cellular and immunotherapy needs to be thoroughly investigated for its potential to fight minimal residual disease. The tight balance between GVL and GVHD needs to be harnessed in an optimal fashion to lead to long-term durable remission. PMID- 21245758 TI - Mutational analysis in chronic myeloid leukemia: when and what to do? AB - PURPOSE OF REVIEW: Imatinib, which was the first targeted therapy for patients with chronic myeloid leukemia (CML), has led to the significant prolongation of life for most patients. However, approximately 30% fail therapy. The major mechanism of acquired resistance is somatic mutation within the BCR-ABL1 kinase domain, which affects imatinib binding. Recently, more potent inhibitors have been approved that retain activity against most of the more than 100 mutations. However, some mutations remain problematic for one or more of the new inhibitors. The most frequently detected mutation, T315I, remains resistant to all of the currently approved inhibitors. More sensitive mutation techniques that focus on the detection of a limited number of specific mutations may be beneficial, but are yet to prove their clinical utility for the early detection of relapse in routine practice. RECENT FINDINGS: Inhibitors with alternate binding modes that may overcome T315I-associated resistance are at the preclinical stage or are undergoing clinical trial. SUMMARY: Each of the new, more potent kinase inhibitor drugs appear to have a partially overlapping set of mutations that confer a degree of resistance. Mutation detection techniques may need to adapt to provide clinicians with a more timely indication of mutation acquisition and pending relapse. PMID- 21245759 TI - Induction and postremission strategies in acute myeloid leukemia: what is new? AB - PURPOSE OF REVIEW: Induction followed by postremission therapy is recognized as the main road toward cure in acute myeloid leukemia (AML). Induction approach has not changed substantially for many years. Despite identifying numerous heterogeneous factors in AML, bench-derived insights are sluggishly translated into clinical protocols. In the current review, advances in intensified dose induction protocols, risk stratification, and disease monitoring are presented. Some promising as well as disappointing agents used for tailoring and targeting therapies in AML are also discussed. RECENT FINDINGS: Intensifying anthracycline dose in young AML patients was recently shown to improve induction results. Importantly, maximal doses in induction have been shown to be safe also in older adults, negating a common perception that too often led to attenuation of induction therapy in this population. Novel targeted agents and the explosive number of newly identified prognostic factors or disease-specific biomarkers are promoting AML therapy toward a more personalized future. SUMMARY: Survival of AML patients is constantly improving. High doses of 'old drugs' for chemotherapy induction, followed by a postremission combination of chemotherapy and novel targeted agents may hold the key for cure. Disease-specific molecular abnormalities may play a role in monitoring and guiding therapy. PMID- 21245757 TI - FLT3 inhibitors: a story of the old and the new. AB - PURPOSE OF REVIEW: Ever since the recognition that FMS-like tyrosine kinase 3 (FLT3) mutations exert a profound negative prognostic impact on the clinical outcome of patients with acute myeloid leukemia (AML), researchers have sought to find effective small-molecule inhibitors of this receptor tyrosine kinase. This review will attempt to provide a survey of the FLT3 inhibitors currently under investigation and provide a discussion on their current status in clinical trials. RECENT FINDINGS: Over the past 10 years, a number of different compounds have been studied in vitro and clinically as FLT3 inhibitors. The first inhibitors studied were hampered by cumbersome pharmacokinetics and a general lack of potency. However, some agents have shown promise in clinical trials with transient responses in AML. Newer compounds, such as AC220, have demonstrated profound selectivity and potency against the FLT3 target, and are currently being investigated in clinical trials. SUMMARY: Clinical trials have so far demonstrated that inhibitors of FLT3 do have clinical activity in patients with FLT3-mutant AML, although this activity is often transient and correlates with effective in-vivo suppression of the FLT3 target. As newer, more potent agents are now entering advanced clinical trials, opportunities will emerge for real progress against this grim disease. PMID- 21245760 TI - Targeting myeloproliferative neoplasms with JAK inhibitors. AB - PURPOSE OF REVIEW: The discovery of JAK2V617F and other JAK-STAT-activating mutations in BCR-ABL1-negative myeloproliferative neoplasms (MPN) has led to the development of small-molecule ATP-mimetics that inhibit wild-type and mutant JAK. Here, we review the current experience with JAK inhibitors used for the treatment of myelofibrosis and polycythemia vera/essential thrombocythemia. RECENT FINDINGS: Consistent with the clonal complexity of MPN, JAK inhibitors have not thus far shown disease-modifying activity; treatment with these agents has however shown clinically meaningful benefits, particularly decreased splenomegaly and improvement in constitutional symptoms, in myelofibrosis patients. Although these benefits accrue with both JAK-2 (TG101348) and JAK-1/2 (INCB018424, CYT387) inhibitors, the mode of action (predominant anticlonal versus anticytokine activity) may be different between the two groups. It is possible that an optimal balance between JAK-1-inhibitory and JAK-2-inhibitory activities may broaden the therapeutic activity (i.e. anemia improvement), as has been preliminarily seen (CYT387). SUMMARY: Although JAK inhibitors have important benefits in myelofibrosis therapy, their role in polycythemia vera/essential thrombocythemia treatment is still being defined. The optimal dosing strategy and feasibility for combination with other therapeutic agents remains to be established. Another challenge is the identification of robust primary end-points that will support labeling claims for JAK inhibitors for the aforementioned indications. PMID- 21245761 TI - Increased serum phosphate and adverse clinical outcomes: unraveling mechanisms of disease. AB - PURPOSE OF REVIEW: Higher serum phosphate levels are associated with adverse clinical outcomes across the spectrum of kidney function. Recent epidemiologic studies have focused on identifying potential mechanisms of these associations as well as risk factors for increased serum phosphate in the general population. RECENT FINDINGS: Higher serum phosphate levels were independently associated with coronary artery calcification, vascular stiffness, left ventricular hypertrophy, and carotid artery disease, even among individuals with normal kidney function and serum phosphate levels within the normal range. Interestingly, effect modification was observed by gender in older populations, with the strength of these associations being weaker in women than in men. In addition, socioeconomic status, sex hormone levels, and common genetic variants were found to be independent predictors of serum phosphate levels, suggesting that common demographic and biological factors may predispose to higher serum phosphate in the general population. SUMMARY: The association of increased serum phosphate with adverse outcomes may be mediated by a link between higher serum phosphate and subclinical vascular disease. Common environmental and biological factors may modulate these relationships, with potentially important implications for designing future interventional studies meant to assess the effect of lowering serum phosphate on long-term outcomes. PMID- 21245762 TI - Angiotensin type 2 receptor in hypertensive cardiovascular disease. AB - PURPOSE OF REVIEW: The renin angiotensin system plays a key role in the development of hypertension-induced cardiovascular remodeling and cardiovascular damage. Angiotensin II (Ang II) exerts its effects by acting on two distinct subtypes of receptor, the angiotensin type 1 receptor (AT1R) and the angiotensin type 2 receptor (AT2R). Whereas AT1R mediates most of the recognized actions of Ang II, it appears that AT2R opposes, in part, the actions mediated by AT1R. As the AT2R is expressed in adult tissues in smaller numbers than AT1R, the actions and cell signaling of AT2R have been less well characterized than those of AT1R. RECENT FINDINGS: Current knowledge suggests that AT2R stimulation mediates vasodilation, antigrowth, proapoptotic and antiinflammatory effects. Hence, AT2R can modulate cardiovascular remodeling as well as the progression of atherosclerosis. A protective role of AT2R in the cardiovascular system has been also documented in humans, mainly during chronic AT1R inhibition. Furthermore, a new nonpeptide AT2R agonist has been developed, with potential future therapeutic applications in hypertensive conditions. SUMMARY: This article reviews the role of AT2R expression signaling and function in the pathogenesis of the functional and structural alterations induced by hypertension on the cardiovascular system. PMID- 21245763 TI - Immune-related effects in hypertension and target-organ damage. AB - PURPOSE OF REVIEW: Several studies published in the past three decades have suggested that inflammation and activation of immunity are central features in the pathogenesis of atherosclerosis, ischemic myocardial injury, and also in hypertension-induced target organ damage. A better understanding of this field could help us to explain the increased cardiovascular risk in patients with chronic inflammation. RECENT FINDINGS: Recent studies have demonstrated that macrophages and various T-cell subtypes play a pivotal role in the regulation of blood pressure and target organ damage. Hypertensive stimuli such as the effector molecule of the renin-angiotensin system, angiotensin II, not only regulate vascular tone and sodium balance, but also activate immune cells and promote cell infiltration into target organs. Experimental and clinical evidence show that adaptive transfer of immune cells, rendering mice deficient for a certain subset of immune cells, or immunosuppressive treatment affects blood pressure and ameliorates target organ damage. SUMMARY: The aim of this review is to summarize and discuss some of the more recent insights as to how immune cells might affect the regulation of blood pressure and the pathogenesis of hypertension-induced target organ damage. PMID- 21245764 TI - Role of statins in preventing adverse cardiovascular outcomes in patients with chronic kidney disease. AB - PURPOSE OF REVIEW: Cardiovascular disease accounts for the majority of deaths in chronic kidney disease (CKD). Dyslipidemia is a well established cardiovascular risk factor. We summarize key aspects of available evidence relating to beneficial effects of statins in nondialysis-dependent CKD, dialysis-dependent CKD and renal transplant recipients. RECENT FINDINGS: Previous trials and their meta-analyses suggested that statins reduce lipid levels, the risk of cardiovascular disease and all-cause mortality in nondialysis-dependent CKD. The Study of Heart and Renal Protection (SHARP) study that enrolled both dialysis dependent and nondialysis-dependent CKD patients showed a 17% decrease in major atherosclerotic events with statins or ezetimibe. Similar cardiovascular benefits are observed in renal transplant recipients. However, such positive effects were not found in two recent clinical trials that enrolled hemodialysis patients alone. This lack of benefit might be attributed to differences in the cause of cardiovascular death seen in dialysis patients and smaller sample size. The overall benefits-harms tradeoff may benefit from meta-analysis and individual patient data meta-analysis in hemodialysis patients including the SHARP data. SUMMARY: Nondialysis-dependent CKD patients and renal transplant recipients benefit from statins. Statins have also been found to be beneficial in one of the three large trials in hemodialysis patients, a matter which may be further explored. PMID- 21245765 TI - Gastric feedings effectively prophylax against upper gastrointestinal hemorrhage in burn patients. AB - The purpose of this study was to examine the effectiveness of gastric feeding in prevention of upper gastrointestinal (GI) hemorrhage. A retrospective chart review of 50 consecutive burn intensive care unit patients with admission dates from January 1, 2005, to December 31, 2007, was conducted. Five of 50 patients (10%) developed GI hemorrhage. Three men of 36 developed a GI hemorrhage (8%) compared with 2 of 14 women (14%). Patients who developed hemorrhage had a higher abbreviated burn severity index score of 11 compared with the control group of 9 and having a higher mortality rate of 80% compared with controls of 27%. Those patients who developed abdominal compartment syndrome were more likely to develop GI hemorrhage (40% rate compared with 4% in patients who did not develop abdominal compartment syndrome). Of 13 patients who were not tolerating their tube feed at some point during treatment, 4 developed hemorrhage (31%), whereas only 1 patient who was tolerating his or her tube feed developed hemorrhage (3%). Three of 19 (16%) patients on proton pump inhibitor prophylaxis developed a GI hemorrhage compared with 2 of 31 (6%) of patients who were not undergoing prophylaxis. Because of the potential side effects of proton pump inhibitor prophylaxis, the authors believe that when tolerated, gastric feedings should be the standard prophylaxis to prevent upper gastrointestinal hemorrhage. Acid suppression therapy may only be necessary for patients who are not tolerating their tube feeds, have other abdominal pathologies, or with a previous history of peptic ulcer disease. PMID- 21245766 TI - Psychosocial needs of burns nurses: a descriptive phenomenological inquiry. AB - The purpose of this qualitative study was to explore the psychosocial needs of nurses who care for patients with severe burn injuries. Burns nurses work in an emotionally challenging and confronting environment, for which they are in need of emotional and clinical support. Exposure to such high levels of stress in this occupational environment has implications for nurses' health and psychosocial well-being. Seven burns nurses were recruited in 2009 from a severe burn injury unit in New South Wales, Australia. A qualitative phenomenological methodology was used to construct themes depicting nurses' experiences. Participants were selected through purposeful sampling, and data were collected through in-depth individual semistructured interviews using open-ended questions. Data were analyzed with Colaizzi's phenomenological method of data analysis. The psychosocial needs of burns nurses were identified and organized into five categories: peer nursing support, informal support, lack of support, multidisciplinary team collaboration, and professional support. The findings clearly demonstrate that support and unity within the workplace are fundamental factors for the psychosocial well-being of nurses caring for patients who have sustained a severe burn injury. Support for nurses in the form of regular professional or collegial debriefing sessions and utilization of employee assistance programs could ease the impact of the stressful environment in which they operate, and could influence staff retention. However, a supportive workplace culture is necessary to encourage nurses to access these services. PMID- 21245767 TI - Factor structure of the brief COPE in people with mild traumatic brain injury. AB - OBJECTIVE: To investigate the factor structure and internal consistency of the Brief COPE, adapted for use with adults with mild traumatic brain injury (MTBI). DESIGN: Prospective cohort study. SETTING: Hospital based emergency department and concussion clinic. PARTICIPANTS: A total of 147 adults meeting diagnostic criteria for MTBI. MAIN MEASURE: Brief COPE. ANALYSES: The previously reported 9 factor structure of the Brief COPE was tested by using confirmatory factor analysis (CFA) and then exploratory factor analysis (EFA). The Cronbach alpha was computed for both the original subscales and those derived from EFA. RESULTS: The CFA provided a less than satisfactory fit for the 9-factor model. While the EFA solution was very similar to that of the original scale, the reliability of some derived subscales was low. Further analyses identified improved internal consistency with a 3-factor model reflecting approach, avoidance, and help seeking coping styles. CONCLUSIONS: The Brief COPE has satisfactory psychometric properties for use in MTBI but may be more reliably and meaningfully interpreted using 3 dimensions/subscales rather than 9. PMID- 21245768 TI - Using startle to objectively measure anger and other emotional responses after traumatic brain injury: a pilot study. AB - OBJECTIVE: To determine the effectiveness of a modulated acoustic startle reflex paradigm with emotional imagery in studying physiological changes associated with emotional responses in persons with traumatic brain injury (TBI). SETTING: Outpatient rehabilitation hospital. PARTICIPANTS: Six individuals with moderate to severe TBI. Mean age was 32 years and mean years postinjury were 9.9. METHOD: The modulated acoustic startle reflex procedure involved imagery of emotional scripts (joy, anger, fear, and neutral) followed by a startle noise, versus startle noise alone (no script). MEASURES: Eyeblink and skin conductance response, subjective arousal and valence ratings of the scripts, and general anger questionnaire. RESULTS: Startle blink responses following anger imagery were significantly smaller than those following fear (P = .006) and neutral (P = .023) imagery. Skin conductance response did not change significantly based on the content of the scripts (P = .070). CONCLUSIONS: Large startle blink responses indicate avoidance of a stimulus. Our findings suggest that participants with TBI did not have an avoidant reaction to anger-inducing stimuli. Skin conductance response findings may imply arousal impairments. The modulated acoustic startle reflex was effective in measuring emotional responses; however, larger studies comparing persons with TBI with control groups are needed to further explore these findings. PMID- 21245769 TI - Your idea and your university: issues in academic technology transfer. AB - Research discoveries may lead to products for commercial development. A central consideration for the researcher is how involved she or he will be in the commercialization process. In some cases, a university out-licenses the intellectual property, whereas in other cases, the investigator may want to be involved in the development process and choose to start his or her own company to develop and possibly to manufacture and sell the product. Before undertaking such a challenge, however, the investigator-turned-entrepreneur must consider a variety of issues, including career goals, financial and time commitments, potential conflicts of interest and/or commitment, start-up funding, and his or her ability to run a company or step aside to allow business experts to make necessary decisions. This paper discusses some personal considerations in deciding to start a spinout company and provides information on some of the available government grants to assist you should you decide to undertake your product's commercial development. In particular, the Small Business Innovative Research and Small Business Technology Transfer programs of federal funding agencies often are the source of early funding for new biomedical companies. PMID- 21245770 TI - Vascular endothelial growth factor gene polymorphisms and rheumatoid arthritis. AB - OBJECTIVE: To investigate polymorphisms of the vascular endothelial growth factor (VEGF) gene in patients with rheumatoid arthritis (RA) and their relationship to clinical features. METHOD: A total of 198 unrelated Chinese individuals were enrolled in this study, including 98 patients with RA and 100 healthy controls. Eight different polymorphisms of the VEGF gene were analyzed using Sequenom MassArray platform. RESULT: All 8 polymorphisms were in Hardy-Weinberg equilibrium in controls. The frequencies of rs833070 A allele and rs325010 C allele were elevated in the patients with RA compared with the controls. There were increased genotype frequencies in GA of rs833070, GC of rs3025030, CT of rs3025039 and decreased genotype frequencies in GG of rs833070, GG of rs3025030, CC of rs3025039 in the patients with RA compared with the controls. The frequencies of haplotype GA in rs2010963 and rs833070 were higher in the patients with RA than in the controls. There was no significant difference in the genotype or allele frequencies in the RA group sorted by complications, serum markers, or age of onset. CONCLUSION: Our data suggested a trend of association between VEGF gene polymorphisms and RA, and patients who carried the haplotype GA of rs2010963 and rs833070 were more susceptible to RA. Our study was performed in a small population, and further studies in other populations are needed to confirm these results. PMID- 21245771 TI - Increased platelet and erythrocyte arginase activity in chronic obstructive pulmonary disease associated with tobacco or wood smoke exposure. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory disease that is characterized by a progressive and irreversible decline in lung function and is caused primarily by chronic exposure to tobacco and to wood smoke. It is linked to oxidative stress and to an up-regulation of airway arginases and is also associated with alterations in platelets and erythrocytes. In the present study, arginase activity was studied in platelets and erythrocytes of 2 groups of COPD patients: 31 tobacco ex-smokers and 27 patients who had been exposed to wood smoke. A total of 15 healthy controls were also included. METHODS: Plasma, platelets, and erythrocytes were obtained from the blood samples. Levels of the oxidative stress biomarkers, carbonyls and malondialdehyde, were measured in the plasma, and arginase activity was quantified in platelets and erythrocytes. RESULTS: In both groups of COPD patients, an increase in the oxidative stress biomarkers was found. Platelet arginase activity in both COPD groups was 2-fold higher than that in the control group. In the erythrocytes, the arginase activity increased 1.7-fold over the control only in the wood smoke-induced COPD group. DISCUSSION AND CONCLUSIONS: These results suggest that the increase in arginase activity in platelets and erythrocytes participates in the alteration in nitric oxide metabolism in COPD patients and that there may be some differences between the tobacco smoke- and wood smoke-induced COPD. PMID- 21245772 TI - Telmisartan improves insulin resistance in patients with low cytokine levels. AB - Metabolic syndrome (MS) is a disease with an inflammatory component. Telmisartan improves insulin resistance in MS, but its relationship with the inflammatory state is unknown. We investigated the effect of 3-month telmisartan therapy on homeostatic model assessment-insulin resistance (HOMA-IR) in hypertensive subjects with MS with regard to the levels of circulating plasma cytokines. METHODS: A total of 42 patients were included in this study; 30 were men (71%), aged 50 +/- 8.2 years (mean +/- SD). Cytokines and metabolic parameters were analyzed before and after treatment with telmisartan. RESULTS: Twenty-eight patients showed low plasma levels of cytokines (group 1) similar to control subjects, and 14 showed high levels (group 2). Treatment with telmisartan diminished by 35% HOMA-IR in group 1 (4.5 +/- 3.1 vs 2.9 +/- 2.1), without improvement in group 2. In the multivariate analysis, the predictors of improvement of HOMA-IR in response to telmisartan treatment were low levels of cytokines, whereas systolic and diastolic blood pressure and the elevation of high-sensitivity C-reactive protein had a negative effect. CONCLUSIONS: Our study provides evidence of a more favorable effect of telmisartan on glucose homeostasis in patients with MS and low levels of serum cytokines. PMID- 21245773 TI - Antimullerian hormone as a potential predictor for the late menopausal transition. PMID- 21245775 TI - Too fast, too slow, too ugly: Dangerous Dysrhythmias. PMID- 21245774 TI - Research in a community hospital: some lessons from the Clarkson-Schnatz mentor mentee pair in The North American Menopause Society Mentorship Program. PMID- 21245776 TI - Isolated nasal septum necrosis caused by Aspergillus flavus in an immunocompromised child. AB - Nontraumatic isolated nasal septal aspergillosis in the absence of sinusitis is a rare but serious infection in immunocompromised patients. Adequate management requires early diagnosis, prompt empiric antifungal therapy, and surgical debridement to prevent progression of life-threatening complications. With the increasing population of immunocompromised children, it is essential for timely management that clinicians have a high index of suspicion for this unusual presentation of aspergillosis. PMID- 21245777 TI - Intravenous colistin administration in neonates. AB - BACKGROUND: Nosocomial infection due to multidrug-resistant Gram-negative pathogens in intensive care units is a challenge for clinicians and microbiologists, and has led to resurgence of parenteral colistin use in the last decade. Safety and efficacy data regarding intravenous colistin (colistimethate) use in neonates is sparse. We present our experience of efficacy and safety of colistimethate in the treatment of sepsis in critically sick term and preterm neonates. METHODS: The records of the neonates who received colistimethate in a neonatal intensive care unit of a tertiary care center from January 2009 to December 2009 were reviewed. RESULTS: Eighteen critically sick neonates (10 term and 8 preterm) received 21 courses of colistimethate (dose ranging from 50,000 to 75,000 IU/kg/d) for treatment of pneumonia, blood stream infections, meningitis, and empyema thoracis. The isolated pathogens in decreasing order of frequency were Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonos aeruginosa, and Enterobacter. Mean duration of colistimethate was 13.1 days/course (range: 5-21 days). At least one other antibiotic was coadministered in all courses. A favorable clinical outcome occurred in 16 of 21 (76%) courses, 5 patients died due to severe sepsis with multiple organ dysfunction. Microbiologic clearance was documented in 17 courses. Increase in serum creatinine by > 0.5 mg/dL above baseline in 2 babies was associated with the presence of multiple organ dysfunction syndrome in both and coadministration of netilmicin in one. CONCLUSIONS: Colistimethate intravenous administration appears to be safe and efficacious for multidrug-resistant Gram-negative infections in neonates, including preterm and extremely low birth weight neonates. PMID- 21245778 TI - New method of scoliosis assessment: preliminary results using computerized photogrammetry. AB - STUDY DESIGN: A new method for nonradiographic evaluation of scoliosis was independently compared with the Cobb radiographic method, for the quantification of scoliotic curvature. OBJECTIVE: To develop a protocol for computerized photogrammetry, as a nonradiographic method, for the quantification of scoliosis, and to mathematically relate this proposed method with the Cobb radiographic method. SUMMARY OF BACKGROUND DATA: Repeated exposure to radiation of children can be harmful to their health. Nevertheless, no nonradiographic method until now proposed has gained popularity as a routine method for evaluation, mainly due to a low correspondence to the Cobb radiographic method. METHODS: Patients undergoing standing posteroanterior full-length spine radiographs, who were willing to participate in this study, were submitted to dorsal digital photography in the orthostatic position with special surface markers over the spinous process, specifically the vertebrae C7 to L5. The radiographic and photographic images were sent separately for independent analysis to two examiners, trained in quantification of scoliosis for the types of images received. The scoliosis curvature angles obtained through computerized photogrammetry (the new method) were compared to those obtained through the Cobb radiographic method. RESULTS: Sixteen individuals were evaluated (14 female and 2 male). All presented idiopathic scoliosis, and were between 21.4 +/- 6.1 years of age; 52.9 +/- 5.8 kg in weight; 1.63 +/- 0.05 m in height, with a body mass index of 19.8 +/- 0.2. There was no statistically significant difference between the scoliosis angle measurements obtained in the comparative analysis of both methods, and a mathematical relationship was formulated between both methods. CONCLUSION: The preliminary results presented demonstrate equivalence between the two methods. More studies are needed to firmly assess the potential of this new method as a coadjuvant tool in the routine following of scoliosis treatment. PMID- 21245779 TI - Utility of a combined current procedural terminology and International Classification of Diseases, Ninth Revision, Clinical Modification code algorithm in classifying cervical spine surgery for degenerative changes. AB - STUDY DESIGN: Retrospective study. OBJECTIVE: To evaluate the sensitivity and specificity of a combined Current Procedural Terminology (CPT) and International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) algorithm in defining cervical spine surgery in comparison to patient operative reports in the medical record. SUMMARY OF BACKGROUND DATA: Epidemiological studies of spine surgery often use ICD-9-CM billing codes in administrative databases to study trends and outcome of surgery. However, ICD-9-CM codes do not clearly identify specific surgical factors that may be related to outcome, such as instrumentation or number of levels treated. Previous studies have not investigated the sensitivity and specificity of a combined CPT and ICD-9-CM code algorithm for defining cervical spine surgical procedures. METHODS: We performed a retrospective study comparing the sensitivity and specificity of a combined CPT and ICD-9-CM code algorithm to the operative note, the gold standard, in a single academic center. We also compared the accuracy of our combined algorithm with our published ICD-9-CM-only algorithm. RESULTS: The combined algorithm has high sensitivity and specificity for defining cervical spine surgery, specific surgical procedures such as discectomy and fusion, and surgical approach. Compared to the ICD-9-CM-only algorithm, the combined algorithm significantly improves identification of discectomy, laminectomy, and fusion procedures and allows identification of specific procedures such as laminaplasty and instrumentation with high sensitivity and specificity. Identification of reoperations has low sensitivity and specificity, but identification of number of levels instrumented, fused, and decompressed has high specificity. CONCLUSION: The use of our combined CPT and ICD-9-CM algorithm to identify cervical spine surgery was highly sensitive and specific. For categories such as surgical approach, accuracy of our combined algorithm was similar to that of our ICD-9-CM only algorithm. However, the combined algorithm improves sensitivity, and allows identification of procedures not defined by ICD-9-CM procedure codes, and number of levels instrumented and decompressed. The combined algorithm better defines cervical spine surgery and specific factors that may impact outcome and cost. PMID- 21245780 TI - Intercellular signaling pathways active during and after growth and differentiation of the lumbar vertebral growth plate. AB - STUDY DESIGN: Vertebral growth plates at different postnatal ages were assessed for active intercellular signaling pathways. OBJECTIVE: To generate a spatial and temporal map of the major signaling pathways active in the postnatal mouse lumbar vertebral growth plate. SUMMARY OF BACKGROUND DATA: The growth of all long bones is known to occur by cartilaginous growth plates. The growth plate is composed of layers of chondrocyets that actively proliferate, differentiate, die and, are replaced by bone. The role of major cell signaling pathways has been suggested for regulation of the fetal long bones. But not much is known about the molecular or cellular signals that control the postnatal vertebral growth plate and hence postnatal vertebral bone growth. Understanding such molecular mechanisms will help design therapeutic treatments for vertebral growth disorders such as scoliosis. METHODS: Antibodies against activated downstream intermediates were used to identify cells in the growth plate responding to BMP, TGFbeta, and FGF in cryosections of lumbar vertebrae from different postnatal age mice to identify the zones that were responding to these signals. Reporter mice were used to identify the chondrocytes responding to hedgehog (Ihh), and Wnt signaling. RESULTS: We present a spatial/temporal map of these signaling pathways during growth, and differentiation of the mouse lumbar vertebral growth plate. CONCLUSION: During growth and differentiation of the vertebral growth plate, its different components respond at different times to different intercellular signaling ligands. Response to most of these signals is dramatically downregulated at the end of vertebral growth. PMID- 21245782 TI - Sacropelvic fixation: two case reports of a new percutaneous technique. AB - STUDY DESIGN: Case report. OBJECTIVE: To describe a new method of minimally invasive percutaneous sacropelvic fixation and to report on its use in two patients. SUMMARY OF BACKGROUND DATA: The Galveston and iliac screw techniques are in widespread use for sacropelvic fixation, but neither technique is amenable to a percutaneous approach. The S2-alar-iliac technique is a recently described method that involves finding a pathway from the S2 sacrum into the ilium with fluoroscopy. We describe a new minimally invasive approach for this technique that allows percutaneous insertion of the screws and spinal construct. METHODS: A 69-year-old female with follicular thyroid carcinoma metastatic to the sacrum and a 55-year-old male with a sacral fracture were both treated with the new technique. We have described this new technique and reviewed the patients' clinical history, radiographic imaging, and outcomes. RESULTS: Stable fixation was achieved in both cases. Blood loss was 70 and 45 mL, respectively. There were no intraoperative complications. CONCLUSION: To our knowledge, this report is the first description of a percutaneous minimally invasive approach to sacropelvic fixation in spinal fusion surgery. It is likely that this minimally invasive technique will result in less blood loss, lower infection rates, and a more rapid postoperative recovery than that associated with the more widely used open techniques. PMID- 21245781 TI - How does lumbar degenerative disc disease affect the disc deformation at the cephalic levels in vivo? AB - STUDY DESIGN: Case-control study. OBJECTIVE: To evaluate the effect of lumbar degenerative disc disease (DDD) on the disc deformation at the adjacent level and at the level one above the adjacent level during end ranges of lumbar motion. SUMMARY OF BACKGROUND DATA: It has been reported that in patients with DDD, the intervertebral discs adjacent to the diseased levels have a greater tendency to degenerate. Although altered biomechanics have been suggested to be the causative factors, few data have been reported on the deformation characteristics of the adjacent discs in patients with DDD. METHODS: Ten symptomatic patients with discogenic low back pain between L4 and S1 and with healthy discs at the cephalic segments were involved. Eight healthy subjects recruited in our previous studies were used as a reference comparison. The In Vivo kinematics of L3-L4 (the cephalic adjacent level to the degenerated discs) and L2-L3 (the level one above the adjacent level) lumbar discs of both groups were obtained using a combined magnetic resonance imaging and dual fluoroscopic imaging technique at functional postures. Deformation characteristics, in terms of areas of minimal deformation (defined as less than 5%), deformations at the center of the discs, and maximum tensile and shear deformations, were compared between the two groups at the two disc levels. RESULTS: In the patients with DDD, there were significantly smaller areas of minimal disc deformation at L3-L4 and L2-L3 than the healthy subjects (18% compared with 45% of the total disc area, on average). Both L2-L3 and L3-L4 discs underwent larger tensile and shear deformations in all postures than the healthy subjects. The maximum tensile deformations were higher by up to 23% (of the local disc height in standing) and the maximum shear deformations were higher by approximately 25% to 40% (of the local disc height in standing) compared with those of the healthy subjects. CONCLUSION: Both the discs of the adjacent level and the level one above experienced higher tensile and shear deformations during end ranges of lumbar motion in the patients with DDD before surgical treatments when compared with the healthy subjects. The larger disc deformations at the cephalic segments were otherwise not detectable using conventional magnetic resonance imaging techniques. Future studies should investigate the effect of surgical treatments, such as fusion or disc replacement, on the biomechanics of the adjacent segments during end ranges of lumbar motion. PMID- 21245783 TI - Facet dimensions, orientation, and symmetry at L5-S1 junction in lumbosacral transitional States. AB - STUDY DESIGN: Study analyses dimensions, angular orientations, and symmetry of articular facets at the L5-S1 junction associated with transitional anomalies comprising (1) L5-S1 accessory articulations; (2) complete sacralization of the L5 vertebrae; and (3) completely lumbarized S1 sacral segments. Data were compared with same parameters evaluated in normal sacrum. OBJECTIVE: Investigating probable morphologic differences in facet joints at the normal and transition affected lumbosacral junctions. SUMMARY OF BACKGROUND DATA: Facet joints at the L5-S1 play an important role in load sharing and imparting stability at this area as well as are involved in conditions such as isthmic spondylolysis, degenerative spondylolisthesis, and osteoarthritis, giving rise to low back pain situations. Several morphologic variations at the lumbosacral junction have been studied and inconsistently alluded to be associated with these painful conditions. Lumbosacral transitional anomalies, on the other hand, have also been linked to low back pain situations. L5-S1 transitions have been shown to be associated with altered L5-S1 articular morphology as well as load-sharing pattern at the region. The analysis of L5-S1 zygapophysial anatomy in context of transitional anomalies at this region has rarely been documented. METHODS: Both the superior articulating facets in the normal as well as in transition associated sacra were measured for (1) height, (2) width, (3) surface area, and (4) angulation of the articular surfaces with reference to the midsagittal plane. Data were also analyzed to find structural asymmetry between the two sides. RESULTS: Facets demonstrated smallest linear dimensions, surface areas, and maximum coronal orientation in lumbarized specimens. Facets areas associated with accessory articulations were also smaller and coronally oriented. Sacralization induced insignificant alteration in the facet morphology. Asymmetry (tropism) was observed in facets predominantly associated with accessory L5-S1 articulations. CONCLUSIONS: L5-S1 transitions possess altered facet morphology. These alterations are possibly related to low back pain situations. PMID- 21245784 TI - Biomechanical analysis of osteotomy type and rod diameter for treatment of cervicothoracic kyphosis. AB - STUDY DESIGN: Biomechanical laboratory research. OBJECTIVE: To characterize the structural stiffness of opening and closing wedge osteotomies and the independent effect of rod diameter. SUMMARY OF BACKGROUND DATA: Traditionally, C7 opening wedge osteotomy (OWO) has been performed for patients with ankylosing spondylitis. For patients without ankylosing spondylitis, closing wedge osteotomy (CWO) may be considered for more controlled closure. Biomechanical characteristics of the two osteotomy alternatives have not yet been analyzed. METHODS: Nondestructive pure moment flexion/extension (FE), lateral bending (LB), and axial rotation (AR) tests were conducted to 4.5 Nm on cadaveric specimens (C4 T3). All specimens underwent posterior bilateral screw-rod fixation with 3.5 mm and 4.5 mm Ti rods, whereas half received OWO and half received CWO. RESULTS: Independent of osteotomy type, constructs with 4.5 mm rods exhibited a significant increase in stiffness compared to 3.5 mm rods in all bending modes (P < 0.01). Relative to 3.5 mm rods, 4.5 mm constructs showed an increase in stiffness of 31 +/- 12% for FE, 37 +/- 39% for LB, and 31 +/- 11% for AR. At the osteotomy site, there was a 43 +/- 23% increase in FE stiffness, 45 +/- 36% in LB, and 41 +/- 17% in AR. Independent of rod diameter, CWO was significantly stiffer than OWO (42% for the construct and 56% across the osteotomy) in FE bending only (P < 0.05). CONCLUSION: The surgeon can expect a similar increase in stiffness in switching from 3.5 mm to 4.5 mm rod independent of osteotomy type. The increased stiffness of CWOs has an anatomic basis. OWOs disrupt the anterior longitudinal ligament (ALL) and leave a significant anterior gap whereas CWOs create a wedge through the vertebral body and leave the ALL and the discs above and below the osteotomy intact. The closure in CWOs leaves no anterior gap providing greater axial loading stability. This greater bone on bone contact in CWOs is likely a significant reason for the anterior stiffness and may provide greater fusion rates in the nonankylosing spondylitis patient population. PMID- 21245785 TI - The impact of fear-avoidance model variables on disability in patients with specific or nonspecific chronic low back pain. AB - STUDY DESIGN: A prospective cross-sectional design. OBJECTIVE: The objectives were to describe the occurrence and to investigate the association of the fear avoidance model variables (pain intensity, kinesiophobia, depression, and disability) in patients with specific or nonspecific chronic low back pain (CLBP). SUMMARY OF BACKGROUND DATA: Affective factors, particularly fear, have proven to be central in the explanation and understanding of chronic pain. The fear-avoidance model has shown that fearful patients with CLBP are at risk of becoming trapped in a vicious cycle of pain, fear, disability, and depressive symptoms. Little is known about the relationship between these factors in patients subgrouped as specific or nonspecific CLBP. METHODS: All 147 patients (81 women and 66 men) were examined by an orthopedic surgeon and diagnosed as either specific or nonspecific CLBP on the basis of that examination. Hierarchical multiple regression analysis was used to assess the ability of three independent variables (back pain intensity, VAS; kinesiophobia, TSK; depressed mood, Zung) to predict levels of disability after controlling for the influence of age and sex. RESULTS.: Both groups (specific and nonspecific CLBP) presented elevated values on the fear-avoidance model variables. All the independent fear avoidance variables contributed in a statistically significant manner to predict disability in patients with specific CLBP, 67.0%, F (5, 59) = 24.46, P < 0.000. In patients with nonspecific CLBP, all variables except kinesiophobia predicted disability in a statistically significant manner, 63.0%, F (5, 59) = 22.64, P < 0.000. CONCLUSION: We conclude that persistent musculoskeletal pain affects the individual in a similar manner, regardless of the cause of the pain. In clinical terms, this means that pain must be analyzed and treated as a parallel process to searching for the cause of the pain. PMID- 21245786 TI - Sacral tumor resection: the effect of surgical staging on patient outcomes, resource management, and hospital cost. AB - STUDY DESIGN: Single-institution retrospective study. OBJECTIVE: To assess the effect surgical staging (i.e., sequencing) has on clinical and economic outcomes for patients undergoing sacropelvic tumor resection requiring lumbopelvic stabilization. SUMMARY OF BACKGROUND DATA: Sacral corpectomy with lumbopelvic stabilization is an extensive surgical procedure that can be performed in either a single episode or multiple episodes of care on different days. The impact of varied sequencing of surgical episodes of care on patient, resource, and financial outcomes is unknown. METHODS: This single-center retrospective case series identified all cases of sacropelvic tumor resection requiring lumbopelvic stabilization over an 8-year period. We assessed and compared clinical and economic outcomes for patients whose anterior exposure and posterior resection were separated into two distinct surgical episodes of care (staged) versus patients whose anterior exposure and posterior resection occurred in a single encounter (nonstaged procedures). Primary endpoints included procedural outcomes (operative and after-hours surgical time), resuscitative requirements, adverse perioperative events, mortality, and direct medical costs (hospital and physician) associated with the surgical episodes of interest. RESULTS: From January 1, 2000, to July 15, 2008, a total of 25 patients were identified. Eight patients had their procedure staged. Surgical staging was associated with a significant increase in intensive care unit free days (P = 0.03), ventilator free days (P < 0.01), and reduced morbidity (P < 0.01). Surgical staging significantly reduced postoperative red blood cell (P = 0.03), and after-hours red blood cell (P < 0.01) and component requirements (P = 0.04). Mean total inpatient costs were $89,132 lower for patients undergoing the staged procedure (95% confidence interval of mean cost difference = -$178,899 to -$4661). CONCLUSION: Separating the anterior exposure and posterior resection phases of complex sacral tumor resection into two separate surgical episodes of care is associated with improved clinical outcomes and reduced inpatient cost. PMID- 21245787 TI - Are we making progress?: the tenth international forum for primary care research on low back pain. AB - STUDY DESIGN: Synthesis and analysis of presentation and discussion highlights, with a focus on emerging trends and promising new directions in primary care research on low back pain (LBP). OBJECTIVE: To present a summary of findings, themes, and insights from the Tenth International Forum on Primary Care Research on Low Back Pain, a meeting of researchers designed to share the latest concepts, methods, and results of research on LBP diagnosis, treatment, and disability prevention. SUMMARY OF BACKGROUND DATA: Earlier Forum meetings have developed several common themes and general conclusions. These are contrasted with the presentations and discussions at the 10th International Forum. RESULTS: Major themes included concerns about the epidemic of chronic, disabling LBP, associated treatments, iatrogenesis, and the "LBP medical industrial complex"; the variability and complexity of outcomes and how their importance differed across patients in defining recovery and recurrence; the power of nonspecific effects, expectations, and therapeutic alliance; and the challenges of identifying important therapeutic subgroups. New research addressed early risk factor screening and linked intervention, nonmedical approaches to reframe the LBP problem and avoid unnecessary care, cognitive and behavioral aspects of LBP, and ways to train clinicians to implement these innovations. More appropriate use of longitudinal designs and a greater focus on implementation research was called for. CONCLUSION: Although the field of primary care LBP research often seems to progress slowly, the Forum highlighted several important, promising developments that could substantially improve LBP research and primary care practice. PMID- 21245788 TI - Selective versus nonselective fusion for idiopathic scoliosis: does lumbosacral takeoff angle change? AB - STUDY DESIGN: Retrospective review of a prospective, multicentered database. OBJECTIVE: To determine the relationship between preoperative lumbosacral takeoff angle (LSTOA) and postoperative thoracolumbar/lumbar Cobb angle (TL/L Cobb angle) in patients undergoing selective thoracic fusions SUMMARY OF BACKGROUND DATA: Selective fusion of the thoracic curve can improve the lumbar curve inpatients with idiopathic thoracic scoliosis and a compensatory lumbar curve. Predicting improvement is controversial and determining whether to perform a selective fusion or nonselective fusion can be difficult. METHODS: Patients had undergone either nonselective or selective spinal fusion for adolescent or juvenile idiopathic scoliosis (Lenke 1B/3B/1C/3C). Outcome measures were: coronal and sagittal thoracic Cobb angle, TL/L Cobb angles, lumbar apical vertebral translation, LSTOA and coronal decompensation. Analyses compared relationships between preoperative and postoperative radiographic measures. RESULTS: Positive, significant correlations were found between preoperative LSTOA and preoperative TL/L Cobb angle in the nonselective (r=0.7; P<0.001) and selective (r=0.5; P<0.001) fusion groups. Mean two-year postoperative coronal TL/L Cobb angles were significantly improved in nonselective and selective fusion groups (32 degrees and 20 degrees , respectively, P<0.001). In the nonselective fusion group, LSTOA significantly decreased by 11 degrees (P<0.001), and in the selective group, the LSTOA had a modest but significant decrease of 2 degrees (P<0.001). The nonselective fusion also resulted in more lordosis between T10 and L2 (7.5 degrees of lordosis) than the selective approach (2.7 degrees kyphosis, P<0.001). For both groups, upper thoracic kyphosis increased after surgery (P<0.001, P<0.001). For nonselective fusions, regression modeling predicted TL/L Cobb angle at two-year follow-up based on preoperative TL/L Cobb angle and preoperative LSTOA (r=0.4, P<0.001). CONCLUSION: Collectively, these data demonstrate the preoperative TL/L Cobb angle and LSTOA can be useful predictors of postoperative TL/L Cobb angle after a selective instrumented fusion. Analyses of distal fixation levels demonstrated that to appreciably change the LSTOA using a posterior instrumented fusion, the distal level of fixation must be beyond the lumbar apex. PMID- 21245789 TI - Histological features of the degenerating intervertebral disc in a goat disc injury model. AB - STUDY DESIGN: An in vivo study to develop a goat large-animal model for intervertebral disc (IVD) degeneration. OBJECTIVE: To determine an optimal method for inducing goat IVD degeneration suitable for testing disc regeneration therapies. SUMMARY OF BACKGROUND DATA: Although rodent, rabbit, and other small animal studies are useful, the narrow dimensions of IVDs in these species limit studies requiring injection of a relevant volume of therapeutics or implantation of engineered tissue constructs. For this study, the goat was selected because the size and shape of their IVDs are comparable with those of adult humans. METHODS: A minimally invasive approach that did not cause significant morbidity or mortality to adult goats (n = 6) was used. Under fluoroscopic guidance, goat lumbar IVDs were injured with a 4.5-mm drill bit or #15 or #10 surgical blades. Two months postinjury, the goats were killed and their IVDs with adjacent end plates were isolated, decalcified, and stained. RESULTS.: A numerical histologic scale to categorize the degree of goat IVD degeneration was developed on the basis of the histologic features of rabbit IVDs previously described by Masuda et al, goat IVDs described by Hoogendoorn et al, and human IVDs described by Boos et al. The interrater agreement of our scoring system was assessed (weighted kappa value = 0.6646). Mann-Whitney U tests were used to compare the injured IVDs with uninjured control. A 4.5-mm drill bit inserted to a 15-mm depth resulted in a significantly higher histologic score than uninjured controls (P = 0.01). Injury with a #15 or #10 blade did not result in increased histologic scores compared with uninjured controls. CONCLUSION: A comparison of the various injuries inflicted showed that the use of a 4.5-mm drill bit resulted in the most significant histologic changes. PMID- 21245790 TI - Does maintained spinal manipulation therapy for chronic nonspecific low back pain result in better long-term outcome? AB - STUDY DESIGN: A prospective single blinded placebo controlled study was conducted. OBJECTIVE: To assess the effectiveness of spinal manipulation therapy (SMT) for the management of chronic nonspecific low back pain (LBP) and to determine the effectiveness of maintenance SMT in long-term reduction of pain and disability levels associated with chronic low back conditions after an initial phase of treatments. SUMMARY OF BACKGROUND DATA: SMT is a common treatment option for LBP. Numerous clinical trials have attempted to evaluate its effectiveness for different subgroups of acute and chronic LBP but the efficacy of maintenance SMT in chronic nonspecific LBP has not been studied. METHODS: Sixty patients, with chronic, nonspecific LBP lasting at least 6 months, were randomized to receive either (1) 12 treatments of sham SMT over a 1-month period, (2) 12 treatments, consisting of SMT over a 1-month period, but no treatments for the subsequent 9 months, or (3) 12 treatments over a 1-month period, along with "maintenance spinal manipulation" every 2 weeks for the following 9 months. To determine any difference among therapies, we measured pain and disability scores, generic health status, and back-specific patient satisfaction at baseline and at 1-, 4-, 7-, and 10-month intervals. RESULTS: Patients in second and third groups experienced significantly lower pain and disability scores than first group at the end of 1-month period (P = 0.0027 and 0.0029, respectively). However, only the third group that was given spinal manipulations (SM) during the follow-up period showed more improvement in pain and disability scores at the 10-month evaluation. In the nonmaintained SMT group, however, the mean pain and disability scores returned back near to their pretreatment level. CONCLUSION: SMT is effective for the treatment of chronic nonspecific LBP. To obtain long-term benefit, this study suggests maintenance SM after the initial intensive manipulative therapy. PMID- 21245791 TI - Anterior Z-plate and titanic mesh fixation for acute burst thoracolumbar fracture. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To evaluate the clinical outcome, effectiveness, and security of the surgical management of acute thoracolumbar burst fracture with corpectomy, titanic mesh autograft, and Z-plate fixation by anterior approach. SUMMARY OF BACKGROUND DATA: Many surgical methods were adopted to treat acute burst thoracolumbar fracture. But the optimal surgical management remains controversial. METHODS: A retrospective review of a consecutive series of 48 patients with thoracolumbar burst fracture treated with anterior corpectomy, titanic mesh autograft, and Z-plate internal fixation was carried out. Preoperative clinical and radiographic data of all cases were originally collected. Surgical indications were motor neurologic deficit and thoracolumbar column instability. Twenty-two patients (45.8%) with acute thoracolumbar burst fractures presented with a neurologic deficit. The postoperative recovery of neural function, restoration of anterior cortex collapse, kyphotic angle, and spinal canal compromise were observed. RESULTS: The preoperative kyphotic angle was improved to a mean of 5.6 degrees , radiographic height restored to 95.8% of the adjacent normal levels, and canal compromise was 0%. None of the patients had neurologic deterioration. Mean follow-up time was 32.4 months (range, 24-47 months). All 22 patients with neurologic deficit demonstrated at least one Frankel grade improvement on final observation, with 16 (73%) patients had accomplished complete neurologic recovery. Forty-six (96%) patients reported minimal or no pain at final follow-up observation, and 40 (83%) patients who had been working before injury returned to original work. CONCLUSION: The authors considered spinal cord decompression with anterior corpectomy and stability reconstruction with titanic mesh autograft and Z-plate fixation at same time in one incision as an effective technique for unstable thoracolumbar burst fracture with and without neurologic deficit. PMID- 21245792 TI - Comparison of cervical spine biomechanics after fixed- and mobile-core artificial disc replacement: a finite element analysis. AB - STUDY DESIGN: A biomechanical comparison between the intact C2-C7 segments and the C5-C6 segments implanted with two different constrained types (fixed and mobile core) of artificial disc replacement (ADR) using a three-dimensional nonlinear finite element (FE) model. OBJECTIVE: To analyze the biomechanical changes in subaxial cervical spine after ADR and the differences between fixed- and mobile-core prostheses. SUMMARY OF BACKGROUND DATA: Few studies have investigated the changes in kinematics after cervical ADR, particularly in relation to the influence of constrain types. METHODS: A FE model of intact C2-C7 segments was developed and validated. Fixed-core (Prodisc-C, Synthes) and mobile core (Mobi-C, LDR Spine) artificial disc prostheses were integrated at the C5-C6 segment into the validated FE model. All models were subjected to a follower load of 50 N and a moment of 1 Nm in flexion-extension, lateral bending, and axial torsion. The range of segmental motion (ROM), facet joint force, tension on major ligaments, and stress on the polyethylene (PE) cores were analyzed. RESULTS.: The ROM in the intact segments after ADR was not significantly different from those of the normal cervical spine model. The ROM in the implanted segment (C5-C6) increased during flexion (19% for fixed and 33% for mobile core), extension (48% for fixed and 56% for mobile core), lateral bending (28% for fixed and 35% for mobile core) and axial torsion (45% for fixed and 105% for mobile core). The facet joint force increased by 210% in both fixed and mobile core models during extension and the tension increased (range, 66%-166%) in all ligaments during flexion. The peak stress on a PE core was greater than the yield stress (51 MPa for fixed and 36 MPa for mobile core). CONCLUSION: The results of our study presented an increase in ROM, facet joint force, and ligament tension at the ADR segments. The mobile-core model showed a higher increase in segmental motion, facet force, and ligament tension, but lower stress on the PE core than the fixed core model. PMID- 21245793 TI - Analysis of the risk factors for severity of neurologic status in 216 patients with thoracolumbar and lumbar burst fractures. AB - STUDY DESIGN: A retrospective, consecutive case series. OBJECTIVE: To determine the risk factors that have a significant correlation with the severity of neurologic impairment in thoracolumbar and lumbar burst fractures. SUMMARY OF BACKGROUND DATA: The correlation between spinal canal stenosis due to bony fragments and the severity of neurologic deficits in thoracolumbar and lumbar burst fractures remains controversial. Moreover, there have so far been no reports in the literature in which the risk factors (spinal canal stenosis and the disruption of posterior ligamentous complex) causing a severe neurologic deficit were analyzed using a multiple logistic regression model. METHODS: A review of the clinical data (neurologic impairments on admission and a finding of posterior ligamentous complex disruption at the time of operation), axial computed tomography, and plain lateral radiography of 216 patients in thoracolumbar (T11-L1) and lumbar (L2-L5) burst fractures was performed. The factors related to neurologic impairments were analyzed using a multiple logistic regression model. RESULTS: In all cases, both the spinal canal stenosis (P < 0.01) and disruption of posterior ligamentous complex (P < 0.01) were significant risk factors. Interestingly, these two risk factors varied according to the injury levels: at thoracic level, the spinal canal stenosis (P < 0.01); at the first lumbar spine, the disruption of the posterior ligamentous complex (P < 0.01); and at the lumbar spine below L2, both of the spinal canal stenosis (P < 0.01) and the disruption of posterior ligamentous complex (P < 0.05) were significant risk factors, respectively. CONCLUSION: In the patients with thoracolumbar and lumbar burst fractures, the significance of the two important risk factors related to clinical results, namely, the stenosis ratio of spinal canal and the disruption of posterior ligamentous complex, were found to vary depending on the level of injury. PMID- 21245794 TI - Enteric-coated mycophenolate sodium versus mycophenolate mofetil in renal transplant recipients experiencing gastrointestinal intolerance: a multicenter, double-blind, randomized study. AB - BACKGROUND: Two open-label studies demonstrated that conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) significantly reduces gastrointestinal (GI) symptom burden and improves GI specific health-related quality of life. Using a randomized design, this study evaluated changes in GI symptoms and health-related quality of life in patients converted from MMF to EC-MPS versus patients who continued with MMF-based treatment. METHODS: In this 4-week, multicenter, randomized, prospective, double blind, parallel-group trial, renal transplant recipients with GI symptoms receiving MMF plus a calcineurin inhibitor +/- corticosteroids were randomized to an equimolar dose of EC-MPS+MMF placebo or continue on their MMF-based regimen+EC MPS placebo. The primary efficacy outcome was a change from baseline in total Gastrointestinal Symptom Rating Scale score of a minimally important difference of more than or equal to 0.3. RESULTS: Three hundred ninety-six patients (EC-MPS group: n=199; MMF group: n=197) were included. A greater proportion of EC-MPS patients (62%) reached the primary efficacy outcome compared with MMF patients (55%); however, the difference was not statistically significant (P=0.15). EC-MPS patients had a significantly greater decrease in the Gastrointestinal Symptom Rating Scale indigestion syndrome dimension versus MMF patients. Within the subgroups of patients with diabetes, patients transplanted 6 to 12 months of study enrollment, and patients on steroids, a statistically significant greater proportion of EC-MPS versus MMF patients reached the primary efficacy outcome. CONCLUSIONS: Conversion from MMF to EC-MPS may be associated with improvements in presence and severity of GI symptoms, particularly in patients with indigestion, diabetes, on steroids, and in patients converted between 6 and 12 months posttransplantation. PMID- 21245795 TI - Modeling and identification of an intra-aorta pump. AB - The intra-aorta pump is a novel left ventricular assist device (LVAD) that assists the heart without the need for percutaneous wires and conduits. It is implanted between the radix aortae and the aortic arch to avoid damage to the aortic valve. To predict the mean pressure head and blood flow, a nonlinear lumped parameter model, which does not need the parameters of the circulatory system, is established. The model includes a speed-controlled current source, an internal resistor, and an inductance for simulating the pressure-flow rate relationship. The speed-controlled current source is used to represent the blood flow caused by the kinetic energy from the impeller, the internal resistor is used to stimulate the resistance character of the radial clearance of the intra aorta pump, and the inductance is used to model the inertia of the blood that passes through the radial clearance. Each part of the model has clear physical significance, which is helpful for extending the model to other blood pumps. It can generate all status of the pump from suction to pulmonary congestion. The model is summarized as a function of the pressure head, the blood flow, and rotational speed of which the values of parameters in the model are determined by experiment. The model and prediction method are tested experimentally on an in vitro mock loop. A comparison of the predicted pressure head obtained from our model with experimental data shows that our model can predict the differential pressure accurately with error <5% for all experimental conditions over the entire range of intended use of the intra-aorta pump. PMID- 21245796 TI - A global sliding mode controller design for an intra-aorta pump. AB - Both the intra-aorta pump system and the circulation system are nonlinear systems with external perturbation and internal uncertainty. Classical control methods are suggested for linear systems. Therefore, a global sliding mode controller (GSMC) is reported in this article. A dynamic disturbance compensator was used to estimate the uncertainty of the controlled intra-aorta pump system for eliminating chattering effect. Simulations were performed to verify the robustness and dynamic characters of the controller. Simulation results demonstrate that the chattering effect of the controller output is eliminated. The settling time of step response of flow rate (5 L/min) is 0.08 seconds without overshot or steady-state error. When the load torque step disturbance increases to 0.4 Nm, the settling time of the controlled system is 0.025 seconds. When the desired flow rate is pulsatile flow, the dynamic response time is 0.08 seconds, and the maximum flow rate error is 0.03 L/min. To verify the dynamic character of the GSMC, an experiment was conducted. Because the feedback frequencies of rotational speed and flow rate in the experiment were slower than the ones in the simulation, the performance of the controller deteriorates. The experiment results illustrate that the settling time of step response of flow rate (5 L/min) is 0.26 seconds, and the flow rate error is 0.1 L/min. PMID- 21245797 TI - Commentary: successful combined use of the Impella Recover 2.5 device and intraaortic balloon pump support for cardiogenic shock after acute myocardial infarction. PMID- 21245798 TI - Flow-regulated extracorporeal arteriovenous tubing loop for cardiac output measurements by ultrasound velocity dilution: validation in post-cardiac surgery intensive care unit patients. AB - Assessment of cardiac output (CO) is crucial in the management of the critically ill, especially in post cardiac surgery intensive care unit (ICU) patients. In this study, we validated CO measured by the novel ultrasound dilution (COUD) with those measured by pulmonary artery (PA) thermodilution (COTD) in 26 adult post cardiac surgery patients. For COUD, blood was circulated through an extracorporeal arteriovenous (AV) loop from the radial artery catheter to the introducer of PA catheter for 5-8 minutes. Three to four injections of 25 ml body temperature isotonic saline were performed into the venous limb of the AV loop. For COTD, five injections of 10 ml ice cold saline were performed. A total of 77 COUD and COTD measurement sets were compared. Cardiac output measured by thermodilution ranged from 3.28 to 9.4 L/min, whereas COUD ranged from 2.85 to 10.1 L/min. The correlation between the methods was found to be r = 0.91, COUD = 0.93(COTD) + 0.42 L/min. Bias and precision (mean difference +/- 2SDs) was -0.004 +/- 1.34 L/min between the two methods. The percentage error (2SD/mean) was 22.2%, which is below the clinically acceptable limit (<30%). Cardiac output measured by ultrasound dilution and thermodilution methods agreed well in post cardiac surgery ICU patients and hence can be interchangeably used. PMID- 21245799 TI - B-type natriuretic peptide levels and continuous-flow left ventricular assist devices. AB - We postulated that postoperative B-type natriuretic peptide (BNP) levels would be reflective of the degree of hemodynamic support rendered by various pump speeds settings (RPM) of continuous-flow left ventricular assist devices (LVADs). Twenty LVAD patients were evaluated prospectively (Jarvik 2000: n = 9, HeartMate II: n = 11). The mean age was 57.7 +/- 14.9 years, and 14 were male. B-type natriuretic peptide levels were drawn while the patients were supported on LVADs at variable RPM settings. The RPM settings were correlated with the changes in BNP levels. Eleven patients underwent LVAD implantation for a lifelong support while the rest were as a bridge therapy to transplantation. Four patients required LVAD change out for various causes of pump failure. Postoperative BNP levels decreased dramatically with the initiation of LVAD support. The levels correlated inversely with the degree of hemodynamic support rendered at various RPM settings of the HeartMate II (p < 0.001). Overall, BNP levels decreased significantly in 2 days after RPM increase. We observed a significant inverse correlation between the postoperative BNP levels and the degree of LVAD support. The effective LVAD support seems to result in a marked reduction in BNP levels, and monitoring serial BNP levels may be helpful in managing patients supported on continuous LVAD. PMID- 21245801 TI - Non-pharmacological management of periodic limb movements during hemodialysis session in patients with uremic restless legs syndrome. AB - Restless legs syndrome (RLS) is very common in hemodialysis patients. RLS induces motor excitability and discomfort during rest periods, and those symptoms have also been observed during hemodialysis sessions. The aim of the study was to assess whether a single bout of exercise could reduce periodic limb movements (PLM) occurring during hemodialysis. Eighteen hemodialysis patients were eligible and participated in the study. Using the RLS criteria and further verified by the presence of PLM during sleep, patients were divided to non-RLS and RLS groups. Three scenarios were studied during three different sessions: 1) light exercise, including cycling for 45 minutes with no added resistance, 2) heavy exercise, including cycling for 45 minutes with a resistance set at 60% of their exercise capacity, and 3) no exercise, including rest for the same period of time. In all sessions, PLM per hour of hemodialysis (PLM/hHD) was recorded. A single bout of either light or heavy exercise was equally effective in significantly reducing PLM/hHD in patients with RLS compared with the no-exercise scenario, whereas in non-RLS patients, no effect was observed. Independent of intensity, a single bout of intradialytic exercise reduces PLM/hHD in hemodialysis patients with RLS. Further research is needed to establish the acute role of exercise in ameliorating the RLS symptoms. PMID- 21245800 TI - Myocardial protection in patients undergoing coronary artery bypass grafting surgery using minimized extracorporeal circulation in combination with volatile anesthetic. AB - The minimized extracorporeal circulation (ECC) is a safe alternative for coronary artery bypass grafting (CABG) and allows a reduction of the negative effects associated with conventional extracorporeal circulation. Experimental and clinical data indicate that the anesthetic regime might influence the ischemia reperfusion injury in CABG surgery. The aim of our retrospective study was to investigate the cardioprotective effects of two different minimized ECC systems in combination with two different anesthetic concepts and to determine the impact on oxygen consumption during aortic cross-clamping (ACC). Data of 1,182 patients who underwent elective isolated CABG with minimized ECC from January 1, 2003, to December 31, 2008, were enrolled in a retrospective manner. Patients were allocated either to sevoflurane-based volatile anesthesia using PRECiSe system (SEVO group) or to propofol-based intravenous anesthesia using MECC system (PROP group). Postoperatively, the SEVO group showed lower concentrations of myocardial fraction of creatine kinase compared with the PROP group (p < 0.001). During the period of ACC, the values of systemic vascular resistance (SVR) were higher in SEVO group (p < 0.005). Also, the SEVO group showed lower oxygen consumption at each time point ACC (p < 0.0001). In conclusion, PRECiSe system using a microporous capillary oxygenator in combination with sevoflurane-based volatile anesthetic regimen seem to provide lower postoperative myocardial cell damage and to allow improved perfusion with higher SVRs and lower oxygen consumption during ACC. PMID- 21245802 TI - Zirconium: biomedical and nephrological applications. AB - Recent years have witnessed a rapid increase in the use of zirconium (Zr) containing compounds in artificial internal organs. Examples include dental implants and other restorative practices, total knee and hip replacement, and middle-ear ossicular chain reconstruction. In nephrological practice, Zr containing sorbents have been used in hemofiltration, hemodialysis, peritoneal dialysis, and in the design and construction of wearable artificial kidneys. Zr compounds continue to be widely and extensively used in deodorant and antiperspirant preparations. In the public health arena, Zr compounds have been studied or used in controlling phosphorus pollution and in the reclamation of poison and bacteria-contaminated water. Experimental and clinical studies support the general consensus that Zr compounds are biocompatible and exhibit low toxicity. Reports on possible Zr-associated adverse reactions are rare and, in general, have not rigorously established a cause-and-effect relationship. Although publications on the use of Zr compounds have continued to increase in recent years, reports on Zr toxicity have virtually disappeared from the medical literature. Nevertheless, familiarity with, and continued vigilant monitoring of, the use of these compounds are warranted. This article provides an updated review on the biomedical use of Zr compounds. PMID- 21245804 TI - Two new chroman derivations from the endophytic Penicillium sp. DCS523. AB - Strain DCS523 was isolated from the branch tissue of Daphniphyllum longeracemosum and determined to be a Penicillium sp. according to the ITS sequence analysis. The extracts from the PDA solid fermentation media of Penicillium sp. DCS523 were purified to give two new chroman derivatives as well as six known compounds. Based on their spectral data the new compounds were identified as (Z)-6-acetyl- 3 (1,2-dihydroxypropylidene)-5-hydroxy-8-methylchroman-2-one and 6-acetyl-2alpha,5- dihydroxy-2-(2-hydroxypropyl)- 3alpha,8-dimethylchroman, respectively. PMID- 21245803 TI - Experimental validation of cardiac index measurement using transpulmonary thermodilution technique in neonatal total liquid ventilation. AB - This study aimed to assess the precision and the interchangeability of cardiac index measurement by transpulmonary thermodilution (TPTD) and pulmonary thermodilution (PTD) devices on a neonatal animal model of acute respiratory distress syndrome under total liquid ventilation (TLV) and conventional mechanical ventilation (CMV). After acute respiratory distress induction by tracheal instillation of hydrochloric acid, transpulmonary (CI(TPTD)) and pulmonary (CI(PTD)) cardiac index were simultaneously measured every 30 minutes for a 240-minute experiment. Reproducibility of both thermodilution techniques was very good to excellent in both groups of ventilation with intrainstrument intraclass correlation coefficient >0.60. Disagreement was found between TPTD and PTD in TLV and CMV. Bland-Altman analysis revealed mean biases of 0.98 L/min/m2 (22.8%) with limits of agreement of -1.33 to 3.25 L/min/m2 in CMV and 1.28 L/min/m2 (17.3%) with limits of agreement of -1.17 to 3.72 L/min/m2 in TLV. Bias between TPTD and PTD was not statistically different in TLV than in CMV (p = 0.11). Transpulmonary thermodilution and PTD remained precise but not interchangeable techniques under TLV as well as CMV. Because TLV does not bring additional bias between both thermodilution techniques, we advocate the use of the less-invasive TPTD under TLV as currently recommended in CMV. PMID- 21245805 TI - Bioinformatics resources and tools for phage display. AB - Databases and computational tools for mimotopes have been an important part of phage display study. Five special databases and eighteen algorithms, programs and web servers and their applications are reviewed in this paper. Although these bioinformatics resources have been widely used to exclude target-unrelated peptides, characterize small molecules-protein interactions and map protein protein interactions, a lot of problems are still waiting to be solved. With the improvement of these tools, they are expected to serve the phage display community better. PMID- 21245806 TI - Sequestration and transport of lignin monomeric precursors. AB - Lignin is the second most abundant terrestrial biopolymer after cellulose. It is essential for the viability of vascular plants. Lignin precursors, the monolignols, are synthesized within the cytosol of the cell. Thereafter, these monomeric precursors are exported into the cell wall, where they are polymerized and integrated into the wall matrix. Accordingly, transport of monolignols across cell membranes is a critical step affecting deposition of lignin in the secondarily thickened cell wall. While the biosynthesis of monolignols is relatively well understood, our knowledge of sequestration and transport of these monomers is sketchy. In this article, we review different hypotheses on monolignol transport and summarize the recent progresses toward the understanding of the molecular mechanisms underlying monolignol sequestration and transport across membranes. Deciphering molecular mechanisms for lignin precursor transport will support a better biotechnological solution to manipulate plant lignification for more efficient agricultural and industrial applications of cell wall biomass. PMID- 21245807 TI - Emodin-8-O-beta-D-glucoside from Polygonum amplexicaule D. Don var. sinense Forb. promotes proliferation and differentiation of osteoblastic MC3T3-E1 cells. AB - Polygonum amplexicaule D. Don var. sinense Forb. (Polygonaceae) (PAF) is a famous traditional herb used to treat fractures, rheumatoid arthritis, muscle injury and pain. The present study was designed to investigate a PAF derived-chemical compound emodin-8-O-beta-D-glucoside (EG) on the proliferation and differentiation of osteoblastic MC3T3-E1 cell in vitro. A compound was isolated from PAF extract by HPLC and identified as emodin-8-O-beta-D-glucoside (EG) by spectroscopic methods. EG significantly promoted cell proliferation at 0.1-100 ng/mL, and increased the cell proportion in S-phase from 16.34% to 32.16%. Moreover, EG increased alkaline phosphatase (ALP) expression in MC3T3-E1 cells at the concentration from 0.1 to 100 ng/mL and inhibited PGE(2 )production induced by TNF-alpha in osteoblasts at the concentrations ranging from 10-100 ng/mL, suggesting that cell differentiation was induced in MC3T3-E1 osteoblasts. Taken together, these results indicated compound EG directly stimulated cell proliferation and differentiation of osteoblasts, therefore this study preliminarily explored the pharmacological mechanism of PAF to promote the healing of bone rheumatism and various fractures. PMID- 21245808 TI - Modulation of the pharmacological activities of secretory phospholipase A2 from Crotalus durissus cascavella induced by naringin. AB - In this work we have characterized the action of the naringin, a flavonoid found in grapefruit and known for its various pharmacological effects, which include antioxidant blood lipid lowering and anticancer activity, on the structure and biochemical activities of a secretory phospholipase A (sPLA2) from Crotalus durissus cascavella, an important protein involved in the releasinge of arachidonic acid in phospholipid membranes. sPLA2 was incubated with naringin (mol:mol) at 37 degrees C and a discrete reduction in the UV scanning signal and a modification of the circular dichroism spectra were observed after treatment with naringin, suggesting modifications of the secondary structure of the protein. This flavonoid was able to decrease enzymatic activity and some pharmacological effects, such as myonecrosis, platelet aggregation, and neurotoxic activity caused by sPLA2, however, the inflammatory effect was not affected by naringin. In addition, small angle X-ray scattering (SAXS) data were collected for sPLA2 and naringin-treated sPLA2 to evaluate possible modifications of the protein structure. These structural investigations have shown that sPLA2 is an elongated dimer in solution and after treatment with naringin a conformational change in the dimeric configuration was observed. Our results suggest that structural modification may be correlated with the loss of enzymatic activity and alterations in pharmacological properties. PMID- 21245809 TI - Schistosomicidal activity of the essential oil of Ageratum conyzoides L. (Asteraceae) against adult Schistosoma mansoni worms. AB - The in vitro schistosomicidal effects of the essential oil of Ageratum conyzoides L. (Ac-EO) against adult worms of Schistosoma mansoni is reported in this paper. Concerning this activity, Ac-EO was considered to be active, but less effective than the positive control (praziquantel, PZQ) in terms of separation of coupled pairs, mortality, decrease in motor activity, and tegumental alterations. However, Ac-EO caused an interesting dose-dependent reduction in the number of eggs of S. mansoni. Precocene I (74.30%) and (E)-caryophyllene (14.23%) were identified as the two major constituents of Ac-EO. These compounds were tested individually and were found to be much less effective than Ac-EO and PZQ. A mixture of the two major compounds in a ratio similar to that found in the Ac-EO was also less effective than Ac-EO, thus revealing that there are no synergistic effects between these components. These results suggest that the essential oil of A. conyzoides is very promising for the development of new schistosomicidal agents. PMID- 21245810 TI - [Articular cartilage: structure and histochemical composition]. AB - Articular cartilage is a main component of the synovial joints that provides a low friction surface in joint motion and, during locomotion and standing distributes the load applied to the joint, therefore minimizing the stresses on the subchondral bone. One of the initial sign of Osteoarthritis (OA) consists in the degeneration of the extracellular matrix of articular cartilage leading to a progressive failure in the biomechanical properties of cartilage, compromising its full functionality. Because osteoarthritis is one of the most common diseases in humans, is highly prevalent in clinical rheumatology and its pathophysiology based on changes of cartilage, it is important for rheumatologists and physicians interested in this area are updated with regard to its structure, composition and key regulatory mechanisms. Thus, this article intends to make an updated review of the structure and histochemical composition of normal cartilage, from which depends the viscoelasticity and dynamic stiffness to compression properties. Furthermore, the nonhomogeneous stratified architecture in the typical four layers, as well as the main macromolecules of the solid matrix, collagen and proteoglicans are described. Finally, a description of the chondrocytes at their ultrastructural level, variations with depth of cartilage and metabolism is done. PMID- 21245811 TI - [Prevalence of analgesic consumption in the northern of Portugal]. AB - INTRODUCTION: Analgesic drugs are frequently used in developed countries and their in take seems to be rising, despite the associated risks. Counselling about the appropriate and safe use of this medication should be based on the characterization of their consumption. The goal of this study was to evaluate the prevalence and to characterize analgesic consumption patterns in northern Portugal, analysing related socio demographic factors. METHODS: This multicentric, observational, transversal and analytic study took place between May 2005 and May 2007, based on the lists of 45 family doctors in northern Portugal. The authors used a simple randomised sample of 4500 patients who answered a personal questionnaire. The chi-square test was used to compare proportions and the T student test and ANOVA were used to compare distributions. A significance level of 0.05 was adopted. In order to control possible confounders, a multivariate analysis was made. RESULTS: The questionnaire was answered by 3492 adults; 30,8% (n=1077, IC 95% 29,3-32,4) of them had taken analgesics in the last fifteen days. Non steroidal anti-inflammatory drugs (NSAID) and salicilates were the most frequently consumed (66%), followed by non opioids (46,6%). Opioids were consumed by 2,7% of the analgesic users, of which the most prevalent pattern of use was the "frequent consumption" (more than three ti mes per week). Most of the patients with a "frequent consumption" pattern used them for more than three months. Age and gender were in dependent risk factors for analgesic in take; women took three times more analgesics than men and consumption rose 1,02 ti mes per year. DISCUSSION: The methodological variability found between this and other studies limited the comparison of our results with theirs. The only study with similar methods was performed in Sweden and found a higher prevalence (35%) of analgesic intake. In studies that only evaluated NSAID consumption, the results were similar to those of this study. Most of the stu dies were concordant about the higher analgesic in take by women, but not with its rise with age. PMID- 21245812 TI - The effects of balneotherapy on disease activity, functional status, pulmonary function and quality of life in patients with ankylosing spondylitis. AB - OBJECTIVE: This study aimed to determine the effects of balneotherapy on disease activity, functional status, metrology index, pulmonary function and quality of life in patients with ankylosing spondylitis (AS). MATERIALS AND METHODS: The study included 28 patients (27 male and 1 female) diagnosed with AS according to modified New York criteria. The patients were treated with balneotherapy for 3 weeks (30 min/day, 5 days/week). The patients were evaluated using the global index, Bath ankylosing spondylitis disease activity index (BASDAI), disease functional index (BASFI), metrology index (BASMI), chest expansion measures, pulmonary function testing, and the medical outcomes study-short form-36 Health Survey (SF-36) (measure of quality of life) before balneotherapy and 1 month after treatment. RESULTS: Post balneotherapy BASDAI and global index decreased, BASMI parameters improved, chest expansion increased, and some SF-36 parameters improved; however, none of these changes were statistically significant (P > 0.05), except for the decrease in BASMI total score (P < 0.05). Before balneotherapy 6 patients had restrictive pulmonary disorder, according to pulmonary function test results. Pulmonary function test results in 3 (50%) patients were normalized following balneotherapy; however, as for the other index, balneotherapy did not significantly affect pulmonary function test results. CONCLUSION: The AS patients' symptoms, clinical findings, pulmonary function test results, and quality of life showed a trend to improve following balneotherapy, although without reaching significant differences. Comprehensive randomized controlled spa intervention studies with longer follow-up periods may be helpful in further delineating the therapeutic efficacy of balneotherapy in AS patients. PMID- 21245813 TI - [Non steroidal anti-inflammatory drugs prescription in General Practice in the centre of Portugal from 2007 to 2009]. AB - BACKGROUND: Non steroidal anti-inflammatory drugs computer-assisted prescription in General Practice/Family Medicine (GP/FM) ambience can give information about the prescription profile during a period of time and understand its trend. Such prescription profile could vary according to the urban (city) vs non urban (village) setting of the GP/FM practice. OBJECTIVES: To characterize the prescription trends of non steroidal inflammatory drugs (NSAIDs) in General Practice, from 2007 to 2009, by public sales price per inscript, daily defined doses (DDD) per inscript and price of DDD. To verify differences of the three fractions according to the urban vs non urban health centre. MATERIAL AND METHODS: Retrospective observational study conducted in February 2010, by the analysis of prescription informatic files automatically generated when the prescription was made. Population calculated at the middle point of each period of study. The differences in volume prescription in Daily Defined Dose (DDD) per registered patient in the middle of 2006 and 2007 two semesters, as well as the value of prescription measured by the price per registered patient were calculated and medicines were studied by the third level of the Portuguese medicines classification very similar to the ATC. The price per DDD was calculated as well. RESULTS: The studied population was of 315.377 subjects in 2007, 321.784 in 2008 and 331.106 in 2009. In price per inscript urban health centres showed a growth from 2007 to 2009 in "Indol and Inden" derivatives (+51.6%), in "Propionic acid derivatives" (+39.4%) and in "Selective cox-2 inhibitors" (+33.6%). For "Sulfanilamidic derivatives, a reduction of 3.8% was verified. For non urban Health Centres prescription a generalised reduction in price per inscript was observed. For DDD/per inscript from 2007 to 2009 we found a generalised increase for urban health centres, except for "Oxicans". For non urban Health Centres there is a generalised decrease of DDD/per inscript from 2007 to 2009, with a special decrease for non-acidic compounds. As for Price of DDD from 2007 to 2009 there is a generalised reduction of such ratio with the only exception of "non acidic compounds" (+9,1%) for urban Health Centres. In view of the calculated ratios, the differences by urban vs non urban Health Centre in each of the studied years there is a significant higher value in non urban health centre, with the exception of Price of DDD for 2008 and 2009 where such ratio is non significantly higher in urban heath centre. CONCLUSIONS: During the study period, demographic growth was higher than the prescription growth in volume and in value. Prescription was more frequent and expensive in non-urban Health Centres. Price of DDD decreases from 2007 to 2009 signifying a much cheaper NSAIDs therapeutics. PMID- 21245814 TI - [Assessment of erythrocyte sedimentation rate (ESR) and C- reactive protein (CRP) on rheumatoid arthritis activity prediction]. AB - OBJECTIVE: Rheumatoid Arthritis (RA) disease activity plays an important role in patients disability. A standardized approach to measure it was achieved by using disease activity score (DAS) based on erythrocyte sedimentation rate (ESR) and more recently C-reactive protein (CRP). In this study we will assess the role and influence of ESR and CRP in evaluating and assessing the disease activity. METHODS: This is a retrospective, longitudinal study, whose data was obtained from the national RA patient clinical database BioreportAR (following ACR criteria) under biological disease modifying anti-rheumatic drugs (BDMARDs), involving 71 patients from CHLO-Hospital Egas Moniz. The ESR and CRP of each patient were recorded from 2 separated visits. The swollen joint counts (SJC), tender joint counts (TJC), visual analog scale (VAS) for pain, patient global assessment and physician global assessment were also recorded. DAS 28-ESR, DAS 28 CRP, simplified disease activity index (SDAI) and clinical disease activity index (CDAI) were calculated. The relevant Pearson correlations were established between variables. RESULTS: A sample of 71 patients with an average age of 55 years old and an average RA duration of 9,8 years, was analysed. ESR and CRP correlated poorly between themselves (r=0,31, p<0,001) and they were shown not to be significant predictors of SJC (ESR r=0,29 p< 0,001 and CRP r=0,089 p<0,001) or TJC (ESR r=0,28 p<0,001 and CRP r=0,072 p<0,001). However DAS-ESR and DAS-CRP were highly correlated (r=0,88, p<0,001) as also as, DAS ESR-CDAI (r=0,89, p<0,001), DAS RCP-CDAI (r= 0,88 p< 0,001) and SDAI-CDAI (r=0,89 p<0,001). DAS-CRP values were lower than those in DAS-ESR, but in 84,7% of the visits disease activity status were. CONCLUSIONS: The significant correlation between DAS-ESR and DAS-CRP, indicated that it will not be necessary to perform both evaluations. DAS-CRP yielded a better activity score more often than DAS-ESR, but with 84,7% of concordance in the disease activity status, indicating that both measures are useful for assessing disease activity in RA. Furthermore the correlation between DAS scores and CDAI, and also between SDAI-CDAI may enable physicians to easily assess the disease activity without ESR or CRP values. PMID- 21245815 TI - Compliance in gout patients. AB - INTRODUCTION: Despite its relative high prevalence,potential devastating clinical consequences and socio-economic impact, the existence of effective drugs to treat it, and the well recognised direct relation between acute flares and treatment interruptions and its resumption, gout is still often considered the chronic disease with the worst rate of adherence to therapy. The reason for this is unknown. We proposed to thoroughly evaluate a subgroup of patients, aiming at identifying the clinical features predictive of non-compliance, and 5 different ways to assess those. METHODS: We analysed a number of clinical, analytical and ultrasound data relating to 34 gout patients (according to the Wallace-ARA diagnostic criteria for gout 1977 and the EULAR recommendations for gout diagnosis 2006), which were followed in a specialized rheumatology consultation as part of an ongoing study for ultrasound validation in gout. To assess non compliance, we compared the prevalence of each one of these clinical features with 5 outcomes (2 of which related to "non-compliance": self-report of non adherence to therapy and missing consultation, and 3 other outcomes related to "non-response": gout flare(s), final serum uric acid (sUA) >= 6 mg/dL, and no sonographic improvement) registered during a 1 year of follow-up assessment. RESULTS: We have found an association between younger age, higher body mass index, previous treatment with urate lowering drugs, self-report of previous non compliance, nephrolithiasis and hyperuricosuria and the "outcomes of non compliance". These patients tended to be less often treated with NSAID and allopurinol, and more often treated with corticosteroid and benzbromarone during the 1 year follow-up. They have also presented higher rate of gout flares and final sUA. Evaluating the 3 "outcomes of non-response", we have noticed a tendency for association with long disease duration, self-report of previous non compliance (frequently attributed to gout flare), higher initial sUA and kidney failure. These patients tended to be less often treated with NSAID, and more often treated with allopurinol. Gout flare correlated to self-report of non compliance and no sonographic improvement. Sonographic non response also correlated to higher final sUA. CONCLUSIONS: This study shows an association between some clinical features and non-compliance, but above all, and unlike the majority of other studies, it has found a correlation between non-compliance with possible causes of worst response or lower rate of treatment, such as hyperuricosuria, nephrolithiasis, kidney failure, and contraindication for NSAID treatment. The data which is based on a comprehensive and detailed clinical assessment, might point out hidden elements, which might go beyond the visible non-compliance, contributing to the frequent lack of control of the disease. PMID- 21245816 TI - [Portuguese recommendations on "How to diagnose, monitor, and treat undifferentiated peripheral arthritis": systematic review of the literature and the experts' opinion]. AB - OBJECTIVE: The 3E (Evidence, Expertise, Exchange) Initiative is a multinational effort of rheumatologists aimed at developing evidence-based recommendations addressing specific questions relevant to clinical practice. The objective of the Portuguese contribution for the 3E Initiative was to develop evidence-based recommendations on how to investigate, follow-up and treat undifferentiated peripheral inflammatory arthritis (UPIA) adapted to local reality and develop additional recommendations considered relevant in the national context. METHODS: An international scientific committee from 17 countries selected a set of questions concerning the diagnosis and monitoring of UPIA using a Delphi procedure. Evidence-based answers to each question were sought by a systematic literature search, performed in Medline, Embase, the Cochrane Library and ACR/EULAR 2007-2009 meeting abstracts. Relevant articles were reviewed for quality assessment, data extraction and synthesis. In a national meeting, a panel of 63 Portuguese rheumatologists used the evidence which was gathered to develop recommendations, and filled the gaps in the evidence with their expert opinion. Finally, national recommendations were formulated and agreement among the participants was assessed. RESULTS: A total of 54754 references were identified, of which 267 were systematically reviewed. Thirteen national key recommendations about the investigation, follow-up and treatment of UPIA were formulated. One recommendation addressed differential diagnosis and investigations prior to the established operational diagnosis of UPIA, eight recommendations were related to the diagnostic and prognostic value of clinical and laboratory assessments in established UPIA (history and physical examination, acute phase reactants, serologies, autoantibodies, radiographs, magnetic resonance imaging and ultrasound, genetic markers and synovial biopsy), one recommendation highlighted predictors of persistence (chronicity), one addressed monitoring of clinical disease activity in UPIA, one aimed to find an useful method/score to predict a definitive diagnosis and the last one was related to treatment. CONCLUSION: Portuguese evidence-based recommendations for the management of UPIA in everyday practice were developed. Their dissemination and implementation in daily clinical practice should help to improve practice uniformity and optimize the management of UPIA patients. PMID- 21245817 TI - [Fibrous dysplasia and McCune-Albright syndrome: case-report and differential diagnose with Paget bone disease]. AB - Fibrous dysplasia of bone or Jaffe Lischtenstein's disease is a genetic, non inheritable disease of bone development, characterized by bone pain, deformities and fracture, mainly observed in yo ung adults. The frequency is equal between sexes. Mutations in the gene coding the Gsalpha, GNAS complex, results in osteoblastic differentiation defects, and bone resorption. The disease can have a monostotic or polyostotic form, or be associated with cafe-au-lait skin spots and precocious puberty (McCune-Al bright syndrome). The normal bone and bone marrow is replaced with abnormal benign intramedullary fibro-osseous tissue, and can involve any bone in the body. The vertebral involvement is rare. Radiological and pathological findings can be diagnostic. Biphosphonates and calcium, vitamin D and phosphorus supplements have been used in fibrous dysplasia treatment. Osteosarcoma is a rare, but serious malignant complication. We report the case of a 68 year old woman with a history of hypofisectomy, with a progressive low back pain, without systemic or neurological symptoms. The bone scan, the ra di o graphs and the computed tomography findings revealed polyostotic fibrous dysplasia, with vertebral and mandibular involvement. In this paper we compared fibrous dysplasia of bone with Paget bone disease. PMID- 21245818 TI - [Osteomyelitis after septic trochanteric bursitis - clinical case]. AB - We report the clinical case of a 76 years-old woman with a subacute trochanteric inflammatory pain with low-grade fever and laboratory markers of acute inflammation, associated with the ultrasonographic evidence of bursitis and radiologic evidence of femoral erosions, that resolved after intravenous antibiotherapy. Although rare, the infectious etiology should be considered in patients with clinical manifestations of bursitis and signs of systemic involvement. PMID- 21245819 TI - [Bilateral femoral fracture secondary to a severe osteomalacia in a patient with renal tubular acidosis type II]. AB - Renal tubular acidosis is a rare disease that can present in a primary, resulting from genetic defects in transport mechanisms of the renal tubules, or secondary, consequent to systemic diseases or drugs. The authors report a case of a patient with renal tubular acidosis type II who developed bilateral femoral fracture secondary to severe osteomalacia, with the intention of highlighting the importance of understanding this disease since the late diagnosis and treatment may generate serious repercussions for the patient. PMID- 21245820 TI - Chronic active Epstein-Barr virus infection mimicking Henoch-Schonlein purpura. AB - INTRODUCTION: Chronic active Epstein-Barr virus (CAEBV) infection is characterized by chronic or recurrent symptoms for at least 3 months, such as fever, hepatosplenomegaly and lymphadenopathy. The diagnosis is established due to the presence of anti-EBV antibodies or isolation of this infectious agent in affected tissues. Three cases of CAEBV infection mimicking Henoch-Schonlein purpura (HSP) were described. CASE 1: Female 3-year old patient with cervical adenomegaly, anemia and fever developed palpable purpura, haematuria and arthritis. CAEBV infection was established by serology test. She received methylprednisolone and acyclovir. She had generalized lymphadenopathy, hepatomegaly, splenomegaly, disseminated intravascular coagulation and deceased. CASE 2: Male 12-year old patient with persistent anemia, lymphadenopathy, hepatomegaly and splenomegaly had CAEBV infection diagnosis by serology test. He developed purpura and arthritis and received methylprednisolone. CASE 3: Male 13 year old patient had purpura, abdominal pain, haematuria, hepatomegaly, splenomegaly, lymphadenopathy, anemia and elevated liver enzymes. The cervical lymph node biopsy was positive to EBV infection. He received methylprednisolone and acyclovir, developing acute fulminant hepatitis and death. DISCUSSION: CAEBV infection mimicking HSP was rarely observed in our population. PMID- 21245821 TI - Amyloidosis secondary to rheumatic diseases - 16 cases. AB - INTRODUCTION: Secondary amyloidosis (SA) results of tissue deposition of an acute phase reactant protein produced by chronic inflammation. Its incidence appears to be declining, following the improvement of medical care to primary diseases. Our aim is to assess a group of Portuguese patients with amyloidosis secondary to inflammatory rheumatic diseases, and their evolution over the past 10 years. METHODS: The study comprised 16 patients with SA confirmed by tissue biopsy, hospitalized in the Rheumatology Department of Hospital Sao Joao in Oporto in the last 10 years. We made a protocol on epidemiological, clinical and analytical data focusing the rheumatic disease and SA, and possible elements of connection between them. RESULTS: Of the 16 patients, mainly women (81,2%), with mean age at entry of 56 years, 68,8% had rheumatoid arthritis. Amyloidosis was diagnosed in average at 13,5 years of primary rheumatic disease, and its main manifestation was kidney involvement, which together with infection and orthopaedic surgery or its complications, were the leading causes of hospitalization. In this time interval, 6 patients died. They were older, with longer duration and lower rate of treatment of the primary rheumatic disease, and had SA diagnosed 1,5 years before death (different of the 5 years of those that still alive). They had higher rate of gastrointestinal, neurological and serious kidney involvement, and hospitalizations. CONCLUSIONS: Improving medical care in rheumatic inflammatory diseases has reduced the incidence of SA. Also, biotherapy appears to be achieving positive results in established amyloidosis, whatever the mechanisms involved. Our data, on Portuguese patients, seems to follow this trend. PMID- 21245822 TI - Coexistence of short fifth metacarpals in a female patient with ankylosing spondylitis associated with complex regional pain syndrome type-I. PMID- 21245823 TI - [Chronic tophaceous arthropathy and leprosy in the same patient]. PMID- 21245824 TI - [Ledderhose disease - a clinical case report]. PMID- 21245825 TI - Evolution: Young genes are essential too. PMID- 21245826 TI - Functional genomics: the modENCODE guide to the genome. PMID- 21245827 TI - Epigenetics: Dad's diet lives on. PMID- 21245828 TI - Gene silencing by microRNAs: contributions of translational repression and mRNA decay. AB - Despite their widespread roles as regulators of gene expression, important questions remain about target regulation by microRNAs. Animal microRNAs were originally thought to repress target translation, with little or no influence on mRNA abundance, whereas the reverse was thought to be true in plants. Now, however, it is clear that microRNAs can induce mRNA degradation in animals and, conversely, translational repression in plants. Recent studies have made important advances in elucidating the relative contributions of these two different modes of target regulation by microRNAs. They have also shed light on the specific mechanisms of target silencing, which, although it differs fundamentally between plants and animals, shares some common features between the two kingdoms. PMID- 21245829 TI - Forest tree genomics: growing resources and applications. AB - Over the past two decades, research in forest tree genomics has lagged behind that of model and agricultural systems. However, genomic research in forest trees is poised to enter into an important and productive phase owing to the advent of next-generation sequencing technologies, the enormous genetic diversity in forest trees and the need to mitigate the effects of climate change. Research on long lived woody perennials is extending our molecular knowledge of complex life histories and adaptations to the environment - enriching a field that has traditionally drawn biological inference from a few short-lived herbaceous species. PMID- 21245831 TI - Membrane surface charge dictates the structure and function of the epithelial Na+/H+ exchanger. AB - The Na(+)/H(+) exchanger NHE3 plays a central role in intravascular volume and acid-base homeostasis. Ion exchange activity is conferred by its transmembrane domain, while regulation of the rate of transport by a variety of stimuli is dependent on its cytosolic C-terminal region. Liposome- and cell-based assays employing synthetic or recombinant segments of the cytosolic tail demonstrated preferential association with anionic membranes, which was abrogated by perturbations that interfere with electrostatic interactions. Resonance energy transfer measurements indicated that segments of the C-terminal domain approach the bilayer. In intact cells, neutralization of basic residues in the cytosolic tail by mutagenesis or disruption of electrostatic interactions inhibited Na(+)/H(+) exchange activity. An electrostatic switch model is proposed to account for multiple aspects of the regulation of NHE3 activity. PMID- 21245832 TI - Serologic antiglycan antibodies in inflammatory bowel disease. AB - At diagnosis, the clinical presentation of both entities of inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC), can be highly heterogeneous, leading to a delay in correct identification or differentiation between CD and UC in a subgroup of patients. In addition, the natural history of IBD patients is strikingly variable. During the life of a CD patient, in the majority of instances, stricturing or perforating complications occur, leading to surgery. Serologic antiglycan antibodies directed against various microbial carbohydrate epitopes are useful in differentiation of CD vs. UC and are a promising tool for identification of CD patients at risk for rapid progression and need for surgical intervention. Instruments for prediction of CD behavior are critical, as the use of immunomodulators and/or biologicals early in the disease course might be justified for patients with a high hazard for complicated disease behavior. PMID- 21245830 TI - Non-coding RNAs as regulators of embryogenesis. AB - Non-coding RNAs (ncRNAs) are emerging as key regulators of embryogenesis. They control embryonic gene expression by several means, ranging from microRNA-induced degradation of mRNAs to long ncRNA-mediated modification of chromatin. Many aspects of embryogenesis seem to be controlled by ncRNAs, including the maternal zygotic transition, the maintenance of pluripotency, the patterning of the body axes, the specification and differentiation of cell types and the morphogenesis of organs. Drawing from several animal model systems, we describe two emerging themes for ncRNA function: promoting developmental transitions and maintaining developmental states. These examples also highlight the roles of ncRNAs in ensuring a robust commitment to one of two possible cell fates. PMID- 21245833 TI - Causes of death in people with celiac disease spanning the pre- and post-serology era: a population-based cohort study from Derby, UK. AB - OBJECTIVES: The objective of the study was to compare cause-specific mortality risks in the periods before and after the introduction of accurate and specific serological tests for diagnosing celiac disease. METHODS: This was a prospective cohort study of people with celiac disease diagnosed in Southern Derbyshire, United Kingdom, from the late 1950s onward, and followed-up from 1978 until death or 31 December 2006. Standardized mortality ratios (SMRs) were calculated for all cause mortality and various cause-specific groups concentrating on the period commencing 2 years after diagnosis of celiac disease. RESULTS: A total of 1,092 celiac patients (of whom 90% were incident) contributed 10,152 person-years of follow-up beyond 2 years of diagnosis and 142 deaths. A statistically significant increase in all-cause mortality was observed (SMR 1.37; 95% confidence interval (CI) 1.16-1.62), along with an increase in deaths from cancer (SMR 1.61; 95% CI 1.19-2.13), digestive disease (SMR 2.19; 10 deaths, 4 due to liver disease), and respiratory disease (SMR 1.57; 21 deaths, 11 due to pneumonia). The overall increase in mortality risk was higher for males (SMR 1.86; 95% CI 1.45-2.34) than it was for females (SMR 1.10; 95% CI 0.86-1.38). When results were stratified by period of diagnosis (pre-1990, 1990-1999, and 2000 onward), we found no evidence of differing all-cause mortality between cases diagnosed within these periods. CONCLUSIONS: Mortality in people with celiac disease has not materially changed over the 25 years of this study with the introduction of serological tests to aid diagnosis. The excess overall mortality we observed was partly explained by deaths from cancer, digestive disease, and respiratory diseases, of which the majority were deaths from pneumonia, supporting existing guidelines that advise pneumococcal vaccination for celiac patients. PMID- 21245835 TI - Admission visfatin levels predict pancreatic and peripancreatic necrosis in acute pancreatitis and correlate with clinical severity. AB - OBJECTIVES: Adipocytes of peripancreatic and intrapancreatic adipose tissue secret adipocytokines such as leptin, adiponectin, and resistin. For resistin, a role as an early predictor of peripancreatic necrosis and clinical severity in acute pancreatitis has been reported. It was the aim of this study to investigate whether the adipocytokine visfatin is able to serve as an early marker predicting peripancreatic necrosis and clinical severity. METHODS: A total of 50 patients (20 females and 30 males) with acute pancreatitis were included in this noninterventional, prospective, and monocentric cohort study on diagnostic accuracy. Clinical severity was classified by the Ranson score and APACHE-II (Acute Physiology and Chronic Health Evaluation II) score. Pancreatic and peripancreatic necrosis were quantified by the computed tomography-based Balthazar score, the Schroeder score, and the pancreatic necrosis score. Visfatin was measured at admission and daily for 10 days by enzyme-linked immunosorbent assay (ELISA). RESULTS: Visfatin values were significantly and positively correlated with clinical severity (APACHE-II score and Ranson score) and with clinical end points such as death and need for interventions. Admission visfatin levels were significantly elevated in patients with higher pancreatic and extrapancreatic necrosis scores. It was shown by receiver operator characteristics that admission visfatin concentration provides a positive predictive value of 93.3% in predicting the extent of peripancreatic necrosis (area under the curve (AUC): 0.89, P<0.001, sensitivity: 93.3%, specificity: 81.8%, likelihood ratio: 5.1, post-test probability: 93%) by using a cutoff value of 1.8 ng/ml. CONCLUSIONS: Admission visfatin concentration serves as an early predictive marker of peripancreatic necrosis and clinical severity in acute pancreatitis. Visfatin may have potential for clinical use as a new and diagnostic serum marker. PMID- 21245834 TI - Small bowel homing T cells are associated with symptoms and delayed gastric emptying in functional dyspepsia. AB - OBJECTIVES: Immune activation may have an important pathogenic role in the irritable bowel syndrome (IBS). While little is known about immunologic function in functional dyspepsia (FD), we have observed an association between cytokine secretion by peripheral blood mononuclear cells (PBMCs) and symptoms in IBS. Upper gastrointestinal inflammatory diseases are characterized by enhanced small bowel homing alpha4-, beta7-integrin, chemokine receptor 9 (CCR9) positive T lymphocytes. We hypothesized that increased cytokine release and elevated circulating small bowel homing T cells are linked to the severity of symptoms in patients with FD. Thus, we aimed to (i) compare cytokine release in FD and healthy controls (HCs), (ii) quantify "gut homing" T cells in FD compared with HC and patients with IBS, and (iii) correlate the findings to symptom severity and gastric emptying. METHODS: PBMC from 45 (Helicobacter pylori negative) patients with FD (Rome II) and 35 matched HC were isolated by density gradient centrifugation and cultured for 24 h. Cytokine production (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-10) was measured by enzyme-linked immunosorbent assay. CD4+ alpha4beta7+CCR9+ T cells were quantified by flow cytometry in FD, HC and 23 patients with IBS. Gastric emptying was measured by scintigraphy. Symptom severity was assessed utilizing the standardized Gastrointestinal Symptom Score. RESULTS: FD patients had significantly higher TNF alpha (107.2 +/- 42.8 vs. 58.7 +/- 7.4 pg/ml), IL-1beta (204.8 +/- 71.5 vs. 80.2 +/- 17.4 pg/ml), and IL-10 (218 +/- 63.3 vs. 110.9 +/- 18.5 pg/ml) levels compared with HC, and enhanced gut homing lymphocytes compared with HC or IBS. Cytokine release and CD4+alpha4beta7+CCR9+ lymphocytes were correlated with the symptom intensity of pain, cramps, nausea, and vomiting. Delayed gastric emptying was significantly associated (r = 0.78, P = 0.021) with CD4+alpha4beta7+CCR9+ lymphocytes and IL-1beta, TNF-alpha, and IL-10 secretion. CONCLUSIONS: Cellular immune activation with increased small bowel homing T cells may be key factors in the clinical manifestations of H. pylori-negative FD. PMID- 21245836 TI - The missense variation Q705K in CIAS1/NALP3/NLRP3 gene and an NLRP1 haplotype are associated with celiac disease. AB - OBJECTIVES: Celiac disease (CD) is a multifactorial common disorder with several susceptibility loci. Variations in the NALP1/NLRP1 and NALP3/NLRP3 genes have been reported to confer risk for several autoimmune conditions. We hypothesized that polymorphisms in these genes, due to their role in innate immunity and inflammatory processes, may affect susceptibility to CD. METHODS: Two single nucleotide polymorphisms (SNPs) in NLRP1 (rs12150220, rs2670660) and two SNPs (rs10754558, rs35829419) in NLRP3 genes were genotyped in 504 CD Italian patients and 256 healthy controls. RESULTS: The minor A allele of NLRP3 rs35829419 (Q705K) polymorphism appeared to exert a protective role against the development of CD (P=0.029; odds ratio (OR)=0.56). Moreover, a particular NLRP1 haplotype was associated with predisposition to CD (P=0.003; OR=1.38), even more when present in combination with the rs35829419 major C allele (P=0.002; OR=1.42). CONCLUSIONS: We hypothesized that the deregulation of CIAS1/NALP3/NLRP3 and NALP1/NLRP1 inflammasomes could have a role in CD pathogenesis. PMID- 21245837 TI - Differential use of importin-alpha isoforms governs cell tropism and host adaptation of influenza virus. AB - Influenza A viruses are a threat to humans due to their ability to cross species barriers, as illustrated by the 2009 H1N1v pandemic and sporadic H5N1 transmissions. Interspecies transmission requires adaptation of the viral polymerase to importin-alpha, a cellular protein that mediates transport into the nucleus where transcription and replication of the viral genome takes place. In this study, we analysed replication, host specificity and pathogenicity of avian and mammalian influenza viruses, in importin-alpha-silenced cells and importin alpha-knockout mice, to understand the role of individual importin-alpha isoforms in adaptation. For efficient virus replication, the polymerase subunit PB2 and the nucleoprotein (NP) of avian viruses required importin-alpha3, whereas PB2 and NP of mammalian viruses showed importin-alpha7 specificity. H1N1v replication depended on both, importin-alpha3 and -alpha7, suggesting ongoing adaptation of this virus. Thus, differences in importin-alpha specificity are determinants of host range underlining the importance of the nuclear envelope in interspecies transmission. PMID- 21245838 TI - Asymmetric spermatocyte division as a mechanism for controlling sex ratios. AB - Although Mendel's first law predicts that crosses between XY (or XO) males and XX females should yield equal numbers of males and females, individuals in a wide variety of metazoans transmit their sex chromosomes unequally and produce broods with highly skewed sex ratios. Here, we report two modifications to the cellular programme of spermatogenesis, which, in combination, help to explain why males of the free-living nematode species Rhabditis sp. SB347 sire <5% male progeny. First, the spermatogenesis programme involves a modified meiosis in which chromatids of the unpaired X chromosome separate prematurely, in meiosis I. Second, during anaphase II, cellular components essential for sperm motility are partitioned almost exclusively to the X-bearing sperm. Our studies reveal a novel cellular mechanism for the differential transmission of X-bearing sperm and suggest Rhabditis sp. SB347 as a useful model for studying sex chromosome drive and the evolution of new mating systems. PMID- 21245839 TI - Leucine-rich repeat kinase LRRK1 regulates endosomal trafficking of the EGF receptor. AB - Activation of the epidermal growth factor receptor (EGFR) not only initiates multiple signal-transduction pathways, including the MAP kinase (MAPK) pathway, but also triggers trafficking events that relocalize receptors from the cell surface to intracellular endocytic compartments. In this paper, we demonstrate that leucine-rich repeat kinase LRRK1, which contains a MAPKKK-like kinase domain, forms a complex with activated EGFR through an interaction with Grb2. Subsequently, LRRK1 and epidermal growth factor (EGF) are internalized and co localized in early endosomes. LRRK1 regulates EGFR transport from early to late endosomes and regulates the motility of EGF-containing early endosomes in a manner dependent on its kinase activity. Furthermore, LRRK1 serves as a scaffold facilitating the interaction of EGFR with the endosomal sorting complex required for transport-0 complex, thus enabling efficient sorting of EGFR to the inner vesicles of multivesicular bodies. Our findings provide the first evidence that a MAPKKK-like protein regulates the endosomal trafficking of EGFR. PMID- 21245840 TI - Impact of the Mertz Glacier Tongue calving on dense water formation and export. AB - Antarctic Bottom Water (AABW) is a critical component of the global climate system, occupying the abyssal layer of the World Ocean and driving the lower limb of the global meridional overturning circulation. Around East Antarctica, the dense shelf water (DSW) precursor to AABW is predominantly formed by enhanced sea ice formation in coastal polynyas. The dominant source region of AABW supply to the Australian-Antarctic Basin is the Adelie and George V Land coast, in particular, polynyas formed in the western lee of the Mertz Glacier Tongue (MGT) and the grounded iceberg B9b over the Adelie and the Mertz Depressions, respectively. The calving of the MGT, which occurred on 12-13 February 2010, dramatically changed the environment for producing DSW. Here, we assess its impact using a state-of-the-art ice-ocean model. The model shows that oceanic circulation and sea ice production in the region changes immediately after the calving event, and that the DSW export is reduced by up to 23%. PMID- 21245841 TI - Synthetic human cell fate regulation by protein-driven RNA switches. AB - Understanding how to control cell fate is crucial in biology, medical science and engineering. In this study, we introduce a method that uses an intracellular protein as a trigger for regulating human cell fate. The ON/OFF translational switches, composed of an intracellular protein L7Ae and its binding RNA motif, regulate the expression of a desired target protein and control two distinct apoptosis pathways in target human cells. Combined use of the switches demonstrates that a specific protein can simultaneously repress and activate the translation of two different mRNAs: one protein achieves both up- and downregulation of two different proteins/pathways. A genome-encoded protein fused to L7Ae controlled apoptosis in both directions (death or survival) depending on its cellular expression. The method has potential for curing cellular defects or improving the intracellular production of useful molecules by bypassing or rewiring intrinsic signal networks. PMID- 21245842 TI - PAR2 absence completely rescues inflammation and ichthyosis caused by altered CAP1/Prss8 expression in mouse skin. AB - Altered serine protease activity is associated with skin disorders in humans and in mice. The serine protease channel-activating protease-1 (CAP1; also termed protease serine S1 family member 8 (Prss8)) is important for epidermal homeostasis and is thus indispensable for postnatal survival in mice, but its roles and effectors in skin pathology are poorly defined. In this paper, we report that transgenic expression in mouse skin of either CAP1/Prss8 (K14 CAP1/Prss8) or protease-activated receptor-2 (PAR2; Grhl3(PAR2/+)), one candidate downstream target, causes epidermal hyperplasia, ichthyosis and itching. K14 CAP1/Prss8 ectopic expression impairs epidermal barrier function and causes skin inflammation characterized by an increase in thymic stromal lymphopoietin levels and immune cell infiltrations. Strikingly, both gross and functional K14 CAP1/Prss8-induced phenotypes are completely negated when superimposed on a PAR2 null background, establishing PAR2 as a pivotal mediator of pathogenesis. Our data provide genetic evidence for PAR2 as a downstream effector of CAP1/Prss8 in a signalling cascade that may provide novel therapeutic targets for ichthyoses, pruritus and inflammatory skin diseases. PMID- 21245843 TI - Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF kappaB signalling. AB - Androgen depletion is a key strategy for treating human prostate cancer, but the presence of hormone-independent cells escaping treatment remains a major therapeutic challenge. Here, we identify a minor subset of stem-like human prostate tumour-initiating cells (TICs) that do not express prostate cancer markers, such as androgen receptor or prostate specific antigen. These TICs possess stem cell characteristics and multipotency as demonstrated by in vitro sphere-formation and in vivo tumour-initiation, respectively. The cells represent an undifferentiated subtype of basal cells and can be purified from prostate tumours based on coexpression of the human pluripotent stem cell marker TRA-1-60 with CD151 and CD166. Such triple-marker-positive TICs recapitulate the original parent tumour heterogeneity in serial xeno-transplantations indicating a tumour cell hierarchy in human prostate cancer development. These TICs exhibit increased nuclear factor-kappaB activity. These findings are important in understanding the molecular basis of human prostate cancer. PMID- 21245844 TI - A stele-enriched gene regulatory network in the Arabidopsis root. AB - Tightly controlled gene expression is a hallmark of multicellular development and is accomplished by transcription factors (TFs) and microRNAs (miRNAs). Although many studies have focused on identifying downstream targets of these molecules, less is known about the factors that regulate their differential expression. We used data from high spatial resolution gene expression experiments and yeast one hybrid (Y1H) and two-hybrid (Y2H) assays to delineate a subset of interactions occurring within a gene regulatory network (GRN) that determines tissue-specific TF and miRNA expression in plants. We find that upstream TFs are expressed in more diverse cell types than their targets and that promoters that are bound by a relatively large number of TFs correspond to key developmental regulators. The regulatory consequence of many TFs for their target was experimentally determined using genetic analysis. Remarkably, molecular phenotypes were identified for 65% of the TFs, but morphological phenotypes were associated with only 16%. This indicates that the GRN is robust, and that gene expression changes may be canalized or buffered. PMID- 21245845 TI - Integrative genome-scale metabolic analysis of Vibrio vulnificus for drug targeting and discovery. AB - Although the genomes of many microbial pathogens have been studied to help identify effective drug targets and novel drugs, such efforts have not yet reached full fruition. In this study, we report a systems biological approach that efficiently utilizes genomic information for drug targeting and discovery, and apply this approach to the opportunistic pathogen Vibrio vulnificus CMCP6. First, we partially re-sequenced and fully re-annotated the V. vulnificus CMCP6 genome, and accordingly reconstructed its genome-scale metabolic network, VvuMBEL943. The validated network model was employed to systematically predict drug targets using the concept of metabolite essentiality, along with additional filtering criteria. Target genes encoding enzymes that interact with the five essential metabolites finally selected were experimentally validated. These five essential metabolites are critical to the survival of the cell, and hence were used to guide the cost-effective selection of chemical analogs, which were then screened for antimicrobial activity in a whole-cell assay. This approach is expected to help fill the existing gap between genomics and drug discovery. PMID- 21245846 TI - Proteome-wide systems analysis of a cellulosic biofuel-producing microbe. AB - Fermentation of plant biomass by microbes like Clostridium phytofermentans recycles carbon globally and can make biofuels from inedible feedstocks. We analyzed C. phytofermentans fermenting cellulosic substrates by integrating quantitative mass spectrometry of more than 2500 proteins with measurements of growth, enzyme activities, fermentation products, and electron microscopy. Absolute protein concentrations were estimated using Absolute Protein EXpression (APEX); relative changes between treatments were quantified with chemical stable isotope labeling by reductive dimethylation (ReDi). We identified the different combinations of carbohydratases used to degrade cellulose and hemicellulose, many of which were secreted based on quantification of supernatant proteins, as well as the repertoires of glycolytic enzymes and alcohol dehydrogenases (ADHs) enabling ethanol production at near maximal yields. Growth on cellulose also resulted in diverse changes such as increased expression of tryptophan synthesis proteins and repression of proteins for fatty acid metabolism and cell motility. This study gives a systems-level understanding of how this microbe ferments biomass and provides a rational, empirical basis to identify engineering targets for industrial cellulosic fermentation. PMID- 21245847 TI - Proteomic snapshot of the EGF-induced ubiquitin network. AB - The activity, localization and fate of many cellular proteins are regulated through ubiquitination, a process whereby one or more ubiquitin (Ub) monomers or chains are covalently attached to target proteins. While Ub-conjugated and Ub associated proteomes have been described, we lack a high-resolution picture of the dynamics of ubiquitination in response to signaling. In this study, we describe the epidermal growth factor (EGF)-regulated Ubiproteome, as obtained by two complementary purification strategies coupled to quantitative proteomics. Our results unveil the complex impact of growth factor signaling on Ub-based intracellular networks to levels that extend well beyond what might have been expected. In addition to endocytic proteins, the EGF-regulated Ubiproteome includes a large number of signaling proteins, ubiquitinating and deubiquitinating enzymes, transporters and proteins involved in translation and transcription. The Ub-based signaling network appears to intersect both housekeeping and regulatory circuitries of cellular physiology. Finally, as proof of principle of the biological relevance of the EGF-Ubiproteome, we demonstrated that EphA2 is a novel, downstream ubiquitinated target of epidermal growth factor receptor (EGFR), critically involved in EGFR biological responses. PMID- 21245848 TI - Rewiring makes the difference. PMID- 21245849 TI - Long-term safety and efficacy following systemic administration of a self complementary AAV vector encoding human FIX pseudotyped with serotype 5 and 8 capsid proteins. AB - Adeno-associated virus vectors (AAV) show promise for liver-targeted gene therapy. In this study, we examined the long-term consequences of a single intravenous administration of a self-complementary AAV vector (scAAV2/ 8-LP1 hFIXco) encoding a codon optimized human factor IX (hFIX) gene in 24 nonhuman primates (NHPs). A dose-response relationship between vector titer and transgene expression was observed. Peak hFIX expression following the highest dose of vector (2 * 10(12) pcr-vector genomes (vg)/kg) was 21 +/- 3 ug/ml (~420% of normal). Fluorescent in-situ hybridization demonstrated scAAV provirus in almost 100% of hepatocytes at that dose. No perturbations of clinical or laboratory parameters were noted and vector genomes were cleared from bodily fluids by 10 days. Macaques transduced with 2 * 10(11) pcr-vg/kg were followed for the longest period (~5 years), during which time expression of hFIX remained >10% of normal level, despite a gradual decline in transgene copy number and the proportion of transduced hepatocytes. All macaques developed serotype-specific antibodies but no capsid-specific cytotoxic T lymphocytes were detected. The liver was preferentially transduced with 300-fold more proviral copies than extrahepatic tissues. Long-term biochemical, ultrasound imaging, and histologic follow-up of this large cohort of NHP revealed no toxicity. These data support further evaluation of this vector in hemophilia B patients. PMID- 21245850 TI - Epidermal growth factor receptor-targeted (131)I-therapy of liver cancer following systemic delivery of the sodium iodide symporter gene. AB - We recently demonstrated tumor-selective iodide uptake and therapeutic efficacy of radioiodine in neuroblastoma tumors after systemic nonviral polyplex-mediated sodium iodide symporter (NIS) gene delivery. In the present study, we used novel polyplexes based on linear polyethylenimine (LPEI), polyethylene glycol (PEG), and the synthetic peptide GE11 as an epidermal growth factor receptor (EGFR) specific ligand to target a NIS-expressing plasmid to hepatocellular carcinoma (HCC) (HuH7). Incubation of HuH7 cells with LPEI-PEG-GE11/NIS polyplexes resulted in a 22-fold increase in iodide uptake, which was confirmed in other cancer cell lines correlating well with EGFR expression levels. Using (123)I-scintigraphy and ex vivo gamma-counting, HuH7 xenografts accumulated 6.5-9% injected dose per gram (ID/g) (123)I, resulting in a tumor-absorbed dose of 47 mGray/Megabecquerel (mGy/MBq) (131)Iodide ((131)I) after intravenous (i.v.) application of LPEI-PEG GE11/NIS. No iodide uptake was observed in other tissues. After pretreatment with the EGFR-specific antibody cetuximab, tumoral iodide uptake was markedly reduced confirming the specificity of EGFR-targeted polyplexes. After three or four cycles of polyplex/(131)I application, a significant delay in tumor growth was observed associated with prolonged survival. These results demonstrate that systemic NIS gene transfer using polyplexes coupled with an EGFR-targeting ligand is capable of inducing tumor-specific iodide uptake, which represents a promising innovative strategy for systemic NIS gene therapy in metastatic cancers. PMID- 21245851 TI - Hypoxia-inducible vascular endothelial growth factor-engineered mesenchymal stem cells prevent myocardial ischemic injury. AB - In the absence of repair mechanisms involving angiogenesis and cardiomyogenesis, loss of cardiomyocytes after myocardial injury is a primary causative factor in the progression toward heart failure. In an effort to reduce ischemic myocardial damage, we investigated the effects on infarcted myocardium of transplantation of genetically modified mesenchymal stem cells (MSCs) that specifically expressed vascular endothelial growth factor (VEGF) under hypoxic conditions. A hypoxia inducible VEGF expression vector was introduced into MSCs (HI-VEGF-MSCs) using a nonviral delivery method, which were then used for the treatment of ischemic myocardial injury in rats. In HI-VEGF-MSCs, VEGF expression was significantly increased by hypoxia in vitro as compared to normoxia. Likewise, in vivo administration of HI-VEGF-MSCs induced ischemia-responsive VEGF production, leading to a significant increase in myocardial neovascularization after myocardial infarction. When compared with unmodified-MSCs, HI-VEGF-MSCs were retained in infarcted myocardium in greater numbers and remarkably reduced the number of apoptotic cells the infarcted area. Transplantation of HI-VEGF-MSCs resulted in a substantial attenuation of left ventricular remodeling in rat myocardial infarction. This study demonstrates that cell-based gene therapy using genetically engineered MSCs to express VEGF in response to hypoxic stress can be a promising therapeutic strategy for the treatment of ischemic heart disease. PMID- 21245853 TI - Compelling comments. PMID- 21245852 TI - Oncolytic virus-initiated protective immunity against prostate cancer. AB - Recently reovirus-based oncotherapy has been successfully implemented for the treatment of prostate cancer. In this report, we show that apart from its primary direct cancer-killing activity, reovirus oncotherapy overrides tumor-associated immune evasion strategies and confers protective antiprostate cancer immunity. Prostate cancer represents an ideal target for immunotherapies. However, currently available immune interventions fail to induce clinically significant antiprostate cancer immune responses, owing to the immunosuppressive microenvironment associated with this disease. We show here that during the process of oncolysis, reovirus acts upon prostate cancer cells and initiates proinflammatory cytokines and major histocompatibility complex (MHC) class I molecule expression. In an immunocompetent transgenic adenocarcinoma of mouse prostate (TRAMP) model, reovirus oncotherapy induces the homing of CD8(+) T and NK cells in tumors and the display of tumor-associated antigens (TAAs) on antigen presenting cells (APCs), and endows dendritic cells (DCs) with a capacity to successfully present TAAs to tumor-specific CD8(+) T cells. These newly generated immunological events lead to the development of strong antiprostate cancer T cell responses, which restrict the growth of subsequently, implanted syngeneic tumor in an antigen-specific, but reovirus-independent manner. Such reovirus-initiated antiprostate cancer immunity represents a clinically valuable entity that can promote long-term cancer-free health even after discontinuation of the primary oncotherapy. PMID- 21245855 TI - Chromatin: a ubiquitin crowbar opens chromatin. PMID- 21245856 TI - Post-translational modifications: S-linked sugars lost and found. PMID- 21245857 TI - Metabolite imaging: knock, nox-ROS there? PMID- 21245858 TI - Proteomics: mapping reactive cysteines. PMID- 21245859 TI - Alcohol consumption and risk of renal cell cancer: the NIH-AARP diet and health study. AB - BACKGROUND: The effect of moderate to heavy drinking (>15 g per day) on renal cell cancer (RCC) risk is unclear. METHOD: The relationship between alcohol consumption and RCC was examined in the NIH-AARP Diet and Health Study (n=49 2187, 1814 cases). RESULTS: Compared with >0 to <5 g per day of alcohol consumption, the multivariate relative risk (95% confidence intervals) for 15 to <30 and ?30 g per day was, 0.75 (0.63-0.90) and 0.71 (0.59-0.85), respectively, in men and 0.67 (0.42-1.07) and 0.43 (0.22-0.84), respectively, in women. CONCLUSION: Alcohol consumption was inversely associated with RCC in a dose response manner. The inverse association may be extended to ?30 g per day of alcohol intake. PMID- 21245860 TI - Mammographic density and its interaction with other breast cancer risk factors in an Asian population. AB - BACKGROUND: Joint effects of mammographic density and other risk factors on breast cancer risk remain unclear. METHODS: From The Singapore Breast Screening Project, we selected 491 cases and 982 controls. Mammographic density was measured quantitatively. Data analysis was by conditional logistic regression. RESULTS: Density was a significant risk factor, adjusting for other factors. Density of 76-100% had an odds ratio of 5.54 (95% CI 2.38-12.90) compared with 0 10%. Density had significant interactions with body mass index and oral contraceptive use (P=0.02). CONCLUSIONS: Percent density increases breast cancer risk in addition to effects of other risk factors, and modifies the effects of BMI and OCs. PMID- 21245861 TI - Genome-wide functions of PML-RARalpha in acute promyelocytic leukaemia. AB - PML-RAR (retinoic acid receptor)alpha is the hallmark protein of acute promyelocytic leukaemia, a highly malignant subtype of acute myeloid leukaemia that accounts for approximately 10% of all AML cases. Recently, several studies have been set out to obtain a comprehensive genome-wide view of the molecular actions of this chimeric protein. In this review, we highlight the new insights that arose from these studies, in particular focussing on newly identified PML RARalpha target genes, its interplay with RXR and deregulation of epigenetic modifications. PMID- 21245862 TI - Enhanced ZAG production by subcutaneous adipose tissue is linked to weight loss in gastrointestinal cancer patients. AB - BACKGROUND: Profound loss of adipose tissue is a hallmark of cancer cachexia. Zinc-alpha2-glycoprotein (ZAG), a recently identified adipokine, is suggested as a candidate in lipid catabolism. METHODS: In the first study, eight weight-stable and 17 cachectic cancer patients (weight loss ?5% in previous 6 months) were recruited. Zinc-alpha2-glycoprotein mRNA and protein expression were assessed in subcutaneous adipose tissue (SAT), subcutaneous adipose tissue morphology was examined and serum ZAG concentrations were quantified. In the second cohort, ZAG release by SAT was determined in 18 weight-stable and 15 cachectic cancer patients. The effect of ZAG on lipolysis was evaluated in vitro. RESULTS: Subcutaneous adipose tissue remodelling in cancer cachexia was evident through shrunken adipocytes with increased fibrosis. In cachectic cancer patients, ZAG mRNA was upregulated (2.7-fold, P=0.028) while leptin mRNA decreased (2.2-fold, P=0.018); serum ZAG levels were found to be unaffected. Zinc-alpha2-glycoprotein mRNA correlated positively with weight loss (r=0.51, P=0.01) and serum glycerol levels (r=0.57, P=0.003). Zinc-alpha2-glycoprotein release by SAT was also elevated in cachectic patients (1.5-fold, P=0.024) and correlated with weight loss (r=0.50, P=0.003). Recombinant ZAG stimulated lipolysis in human adipocytes. CONCLUSIONS: Zinc-alpha2-glycoprotein expression and secretion by adipose tissue is enhanced in cachectic cancer patients. Given its lipid-mobilising effect, ZAG may contribute to adipose atrophy associated with cancer cachexia in human beings. PMID- 21245863 TI - Poly(A) RT-PCR measurement of diagnostic genes in pancreatic juice in pancreatic cancer. AB - BACKGROUND: The last decade has seen significant progress in understanding the molecular biology of pancreatic adenocarcinoma. There is now an urgent need to translate these molecular techniques to clinical practice in order to improve diagnosis and prediction of response to treatment. The objectives of this study are to utilise poly(A) RT-PCR to measure expression levels of diagnostic Indicator genes, selected from microarray studies, of RNA from intraoperatively sampled pancreatic ductal juice and to correlate these expression levels with those in matched pancreatic tissue resection samples. METHODS: Intraoperative sampling of pancreatic juice and collection of matched tissue samples was undertaken in patients undergoing pancreaticoduodenectomy for suspected tumour. RNA was isolated and poly(A) PCR and real-time PCR used to measure expression levels of 30 genes. Spearman's rank correlation test was used to examine the relationship of gene expression between pancreatic juice and tissue. RESULTS: Of the 30 Indicator genes measured, just one, ANXA1, showed a significant correlation of expression level between pancreatic juice and tissue samples, whereas three genes, IGFBP3 (P?0.035), PSCA (P?0.001) and SPINK1 (P?0.05), showed significantly different expression between cancerous and benign pancreatic tissue samples. CONCLUSIONS: These results demonstrate that RNA analysis of pancreatic juice is feasible using the poly(A) cDNA technique, that correlation of gene expression exists between pancreatic juice and tissue for very few genes and that gene expression profiling can distinguish between benign and malignant pancreatic tissue. This indicates possible use of the technique for measurement of Indicator genes in pancreatic tissue for diagnosis of pancreatic cancer from very small tissue samples. PMID- 21245864 TI - Delayed-type hypersensitivity in classic Kaposi sarcoma patients and controls. AB - BACKGROUND: Immune perturbation likely affects the development of Kaposi sarcoma (KS) among people infected with the KS-associated herpesvirus (KSHV). We tested whether KSHV-seropositive individuals or cases of classic KS (cKS), which typically originates in the leg, had differing delayed-type hypersensitivity (DTH) in the forearm or leg. METHODS: Mantoux DTH with three antigens (Candida, tetanus, PPD) was performed on the forearm and leg of 15 cKS cases, 14 KSHV positives without KS, and 15 KSHV-negative controls. The diameters of induration responses were compared by group and body site. RESULTS: Leg DTH was greater than forearm DTH among controls (mean difference 5.6 mm, P=0.0004), whereas this was not observed in cKS cases (-2.2 mm, P=0.32) or KSHV-positives (0.5 mm, P=0.56). Leg-minus-forearm DTH difference was greater in controls compared with cKS cases (P=0.004) and KSHV-positives (P=0.002). Leg-plus-forearm DTH was similar in controls (mean 28.2 mm) and cKS cases (24.5 mm, P=0.60), but it was reduced in KSHV-positives (11.8 mm, P=0.02), particularly in the leg (P=0.004) and marginally in the forearm (P=0.07). CONCLUSION: KS cases had weaker DTH only in the leg, whereas both body sites appeared weaker in KSHV-positives without KS. Both systemic and regional immune alterations may influence the development of this malignancy. PMID- 21245865 TI - A multicenter phase II study of induction chemotherapy with FOLFOX-4 and cetuximab followed by radiation and cetuximab in locally advanced oesophageal cancer. AB - BACKGROUND: Preoperative chemoradiotherapy (CRT) improves the survival of patients with oesophageal cancer when compared with surgery alone. METHODS: We conducted a phase II, multicenter trial of FOLFOX-4 and cetuximab in patients with locally advanced oesophageal cancer (LAEC) followed by daily radiotherapy (180 cGy fractions to 5040 cGy) with concurrent weekly cetuximab. Cytokines levels potentially related to cetuximab efficacy were assessed using multiplex bead assays and enzyme-linked immunosorbent assay at baseline, at week 8 and at week 17. Primary end point was complete pathological response rate (pCR). RESULTS: In all, 41 patients were enroled. Among 30 patients who underwent surgery, a pCR was observed in 8 patients corresponding to a rate of 27%. The most frequent grade 3/4 toxicity was skin (30%) and neutropenia (30%). The 36 month survival rates were 85 and 52% in patients with pathological CR or PR vs 38 and 33% in patients with SD or PD. CONCLUSIONS: Incorporating cetuximab into a preoperative regimen for LAEC is feasible; no correlation between cytokines changes and patient outcome was observed. Positron emission tomography/computed tomography study even if influenced by the small number of patients appears to be able to predict patients outcome both as early and late metabolic response. PMID- 21245867 TI - The semisynthetic flavonoid monoHER sensitises human soft tissue sarcoma cells to doxorubicin-induced apoptosis via inhibition of nuclear factor-kappaB. AB - BACKGROUND: Despite therapeutic advances, the prognosis of patients with metastatic soft tissue sarcoma (STS) remains extremely poor. The results of a recent clinical phase II study, evaluating the protective effects of the semisynthetic flavonoid 7-mono-O-(beta-hydroxyethyl)-rutoside (monoHER) on doxorubicin-induced cardiotoxicity, suggest that monoHER enhances the antitumour activity of doxorubicin in STSs. METHODS: To molecularly explain this unexpected finding, we investigated the effect of monoHER on the cytotoxicity of doxorubicin, and the potential involvement of glutathione (GSH) depletion and nuclear factor-kappaB (NF-kappaB) inactivation in the chemosensitising effect of monoHER. RESULTS: MonoHER potentiated the antitumour activity of doxorubicin in the human liposarcoma cell line WLS-160. Moreover, the combination of monoHER with doxorubicin induced more apoptosis in WLS-160 cells compared with doxorubicin alone. MonoHER did not reduce intracellular GSH levels. On the other hand, monoHER pretreatment significantly reduced doxorubicin-induced NF-kappaB activation. CONCLUSION: These results suggest that reduction of doxorubicin induced NF-kappaB activation by monoHER, which sensitises cancer cells to apoptosis, is involved in the chemosensitising effect of monoHER in human liposarcoma cells. PMID- 21245866 TI - Assessment of circulating biomarkers for potential pharmacodynamic utility in patients with lymphoma. AB - PURPOSE: Treatment efficacy and toxicity are difficult to predict in lymphoma patients. In this study, the utility of circulating biomarkers in predicting and/or monitoring treatment efficacy/toxicity were investigated. PATIENTS AND METHODS: Circulating biomarkers of cell death (nucleosomal DNA (nDNA) and cytokeratin 18 (CK18)), and circulating FLT3 ligand, a potential biomarker of myelosuppression, were assessed before and serially after standard chemotherapy in 49 patients with Hodgkin and non-Hodgkin lymphoma. Cytokeratin 18 is not expressed in lymphoma cells so is a potential biomarker of epithelial toxicity in this setting. Tumour response was assessed before and after completion of chemotherapy by 2D and 3D computed tomography radiological response. RESULTS: Baseline nDNA level was significantly higher in all lymphoma subtypes compared with 61 healthy controls and was prognostic for progression-free survival in diffuse large B-cell lymphoma (DLBCL). Decreases in nDNA levels were observed in the first week after chemotherapy; in FL, early falls in nDNA predicted for long remission following therapy. In DLBCL, elevations in nDNA occurred in cases with progressive disease. Circulating CK18 increased within 48 h of chemotherapy and was significantly higher in patients experiencing epithelial toxicity graded >3 by Common Terminology for Classification of Adverse Events criteria. FLT3 ligand was elevated within 3-8 days of chemotherapy initiation and predicted those patients who subsequently developed neutropenic sepsis. CONCLUSION: These data suggest circulating biomarkers contribute useful information regarding tumour response and toxicity in patients receiving standard chemotherapy and have potential utility in the development of individualised treatment approaches in lymphoma. These biomarkers are now being tested within multicentre phase III trials to progress their qualification. PMID- 21245869 TI - N,N'-diphenethylurea isolated from Okinawan ascidian Didemnum molle enhances adipocyte differentiation in 3T3-L1 cells. PMID- 21245868 TI - Bleeding events in bevacizumab-treated cancer patients who received full-dose anticoagulation and remained on study. AB - BACKGROUND: Bevacizumab provides clinical benefit in multiple solid tumours, but is associated with some increase in bleeding risk. Thrombotic events necessitating therapeutic anticoagulation (TA) are common in cancer. This report describes the safety of concurrent bevacizumab and TA in three large placebo controlled clinical studies. METHODS: Study 1 (metastatic colorectal cancer (mCRC)), study 2 (mCRC), and study 3 (advanced non-small cell lung cancer) were blinded phase III studies. Eligibility criteria excluded patients on TA. Patients on protocol treatment who developed thrombotic events requiring TA were permitted to continue bevacizumab or placebo under specified conditions. Adverse events in patients who received bevacizumab and TA concurrently were assessed using the NCI CTCAE scale. RESULTS: While experience is limited, venous thrombotic events were the most common reason for TA initiation in the three studies. Severe bleeding event rates for patients receiving TA in the bevacizumab-treated groups were similar in frequency to the placebo groups, ranging from 0 to 8% or 0 to 67 events per 100 patient-years. No severe pulmonary bleeding was reported in any of the TA-treated populations. CONCLUSIONS: These data suggest that bevacizumab did not increase the risk of severe bleeding in cancer patients who received TA. PMID- 21245870 TI - Synthesis and antibacterial activity of new 4"-O-carbamates of 11,12-cyclic carbonate erythromycin A 6,9-imino ether. AB - A series of new 4"-O-carbamates of 11,12-cyclic carbonate erythromycin A 6,9 imino ether were synthesized and evaluated for their in vitro antibacterial activity. All the desired compounds demonstrated favorable activity (0.03 MUg ml(-1)) against erythromycin-susceptible Streptococcus pneumoniae comparable to the references, exhibiting 133-fold higher activity than precursor 2 or 3. Similarly, all of the analogs exhibited improved activity against the erythromycin-resistant S. pneumoniae encoded by the erm gene and the erm and mef genes, showing 4-32-fold more effectiveness than erythromycin A. PMID- 21245871 TI - Visualization of cell death in mice with focal cerebral ischemia using fluorescent annexin A5, propidium iodide, and TUNEL staining. AB - To monitor stroke-induced brain damage and assess neuroprotective therapies, specific imaging of cell death after cerebral ischemia in a noninvasive manner is highly desirable. Annexin A5 has been suggested as a marker for imaging cell death under various disease conditions including stroke. In this study, C57BL6/N mice received middle cerebral artery occlusion (MCAO) and were injected intravenously with either active or inactive Cy5.5-annexin A5 48 hours after reperfusion. Some mice also received propidium iodide (PI), a cell integrity marker. Only in mice receiving active Cy5.5-annexin A5 were fluorescence intensities significantly higher over the hemisphere ipsilateral to MCAO than on the contralateral side. This was detected noninvasively and ex vivo 4 and 8 hours after injection. The majority of cells positive for fluorescent annexin A5 were also positive for PI and fragmented DNA as detected by terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling (TUNEL) staining. This study demonstrates the high specificity of annexin A5 for visualization of cell death in a mouse model of stroke. To our knowledge, this is the first study to compare the distribution of injected active and inactive annexin A5, PI, and TUNEL staining. It provides important information on the experimental and potential clinical applications of annexin A5-based imaging agents in stroke. PMID- 21245872 TI - Pseudocontinuous arterial spin labeling reveals dissociable effects of morphine and alcohol on regional cerebral blood flow. AB - We have examined sensitivity and specificity of pseudocontinuous arterial spin labeling (PCASL) to detect global and regional changes in cerebral blood flow (CBF) in response to two different psychoactive drugs. We tested alcohol and morphine in a placebo-controlled, double-blind randomized study in 12 healthy young men. Drugs were administered intravenously. Validated pharmacokinetic protocols achieved minimal intersubject and intrasubject variance in plasma drug concentration. Permutation-based statistical testing of a mixed effect repeated measures model revealed a widespread increase in absolute CBF because of both morphine and alcohol. Conjunction analysis revealed overlapping effects of morphine and alcohol on absolute CBF in the left anterior cingulate, right hippocampus, right insula, and left primary sensorimotor areas. Effects of morphine and alcohol on relative CBF (obtained from z-normalization of absolute CBF maps) were significantly different in the left putamen, left frontoparietal network, cerebellum, and the brainstem. Corroborating previous PET results, our findings suggest that PCASL is a promising tool for central nervous system drug research. PMID- 21245873 TI - Prophylactic neuroprotection against stroke: low-dose, prolonged treatment with deferoxamine or deferasirox establishes prolonged neuroprotection independent of HIF-1 function. AB - Prophylactic neuroprotection against stroke could reduce stroke burden in thousands of patients at high risk of stroke, including those with recent transient ischemic attacks (TIAs). Prolyl hydroxylase inhibitors (PHIs), such as deferoxamine (DFO), reduce stroke volume when administered at high doses in the peristroke period, which is largely mediated by the hypoxia-inducible transcription factor (HIF-1). Yet, in vitro experiments suggest that PHIs may also induce neuroprotection independent of HIF-1. In this study, we examine chronic, prophylactic, low-dose treatment with DFO, or another iron chelator deferasirox (DFR), to determine whether they are neuroprotective with this paradigm and mediate their effects through a HIF-1-dependent mechanism. In fact, prophylactic administration of low-dose DFO or DFR significantly reduces stroke volume. Surprisingly, DFO remained neuroprotective in mice haploinsufficient for HIF-1 (HIF-1+/-) and transgenic mice with conditional loss of HIF-1 function in neurons and astrocytes. Similarly, DFR was neuroprotective in HIF-1+/- mice. Neither DFO nor DFR induced expression of HIF-1 targets. Thus, low-dose chronic administration of DFO or DFR induced a prolonged neuroprotective state independent of HIF-1 function. As DFR is an orally administered and well tolerated medication in clinical use, it has promise for prophylaxis against stroke in patients at high risk of stroke. PMID- 21245875 TI - Relationship of folate, vitamin B12 and methylation of insulin-like growth factor II in maternal and cord blood. AB - BACKGROUND/OBJECTIVE: One of the speculated mechanisms underlying fetal origin hypothesis of breast cancer is the possible influence of maternal environment on epigenetic regulation, such as changes in DNA methylation of the insulin-like growth factor-2 (IGF2) gene. The aim of the study is to investigate the relationship between folate, vitamin B(12) and methylation of the IGF2 gene in maternal and cord blood. SUBJECTS/METHODS: We conducted a cross-sectional study to measure methylation patterns of IGF2 in promoters 2 (P2) and promoters 3 (P3). RESULTS: The percentage of methylation in IGF2 P3 was higher in maternal blood than in cord blood (P<0.0001), whereas the methylation in P2 was higher in cord blood than in maternal blood (P=0.016). P3 methylation was correlated between maternal and cord blood (P<0.0001), but not P2 (P=0.06). The multivariate linear regression model showed that methylation patterns of both promoters in cord blood were not associated with serum folate levels in either cord or maternal blood, whereas the P3 methylation patterns were associated with serum levels of vitamin B(12) in mother's blood (mean change (MC)=-0.22, P=0.0014). Methylation patterns in P2 of maternal blood were associated with serum levels of vitamin B(12) in mother's blood (MC=-0.23, P=0.012), exposure to passive smoking (MC=0.46, P=0.034) and mother's weight gain during pregnancy (MC=0.23, P=0.019). CONCLUSIONS: The study suggests that environment influences methylation patterns in maternal blood, and then the maternal patterns influence the methylation status and levels of folate and vitamin B(12) in cord blood. PMID- 21245876 TI - Applications of nutrient profiling: potential role in diet-related chronic disease prevention and the feasibility of a core nutrient-profiling system. AB - BACKGROUND/OBJECTIVES: A number of different nutrient-profiling models have been proposed and several applications of nutrient profiling have been identified. This paper outlines the potential role of nutrient-profiling applications in the prevention of diet-related chronic disease (DRCD), and considers the feasibility of a core nutrient-profiling system, which could be modified for purpose, to underpin the multiple potential applications in a particular country. METHODS: The 'Four 'P's of Marketing' (Product, Promotion, Place and Price) are used as a framework for identifying and for classifying potential applications of nutrient profiling. A logic pathway is then presented that can be used to gauge the potential impact of nutrient-profiling interventions on changes in behaviour, changes in diet and, ultimately, changes in DRCD outcomes. The feasibility of a core nutrient-profiling system is assessed by examining the implications of different model design decisions and their suitability to different purposes. RESULTS AND CONCLUSIONS: There is substantial scope to use nutrient profiling as part of the policies for the prevention of DRCD. A core nutrient-profiling system underpinning the various applications is likely to reduce discrepancies and minimise the confusion for regulators, manufacturers and consumers. It seems feasible that common elements, such as a standard scoring method, a core set of nutrients and food components, and defined food categories, could be incorporated as part of a core system, with additional application-specific criteria applying. However, in developing and in implementing such a system, several country specific contextual and technical factors would need to be balanced. PMID- 21245878 TI - Ethnic differences in maternal total cholesterol and triglyceride levels during pregnancy: the contribution of demographics, behavioural factors and clinical characteristics. AB - BACKGROUND/OBJECTIVES: Lipid disturbances during pregnancy may lead to early onset of metabolic diseases in the offspring. However, there is little knowledge on ethnic differences in lipid levels during pregnancy. We evaluated ethnic differences in non-fasting total cholesterol (TC) and triglyceride (TG) levels during early gestation and the role of demographics, behavioural factors and clinical characteristics. SUBJECTS/METHODS: Non-diabetic pregnant women (N=3025) from the Amsterdam Born Children and their Development (ABCD) study. The studied ethnic groups were Dutch, Surinam-Hindustani, African-Caribbean, Turkish, Moroccan and Ghanaian. A multilingual questionnaire was used to gather information on maternal demographics, behavioural factors and clinical characteristics. Non-fasting TC, TG, percentage saturated fatty acid (%SFA) and percentage linoleic acid status (%LA) were assessed in blood samples collected at the first antenatal visit. RESULTS: Ghanaian (-0.51 mmol/l), African-Caribbean ( 0.19 mmol/l) and Moroccan (-0.15 mmol/l) women had significant lower TC levels compared with Dutch women. TG levels were lower in Ghanaian (log transformed 0.12 mmol/l) but significantly higher in Surinam-Hindustani (0.10 mmol/l) and Turkish women (0.07 mmol/l). Age, physical activity, pre-pregnancy body mass index (BMI), smoking, %SFA and %LA were independently related to TC and/or TG. However, only pre-pregnancy BMI could partly explain observed disparities. Furthermore, pre-pregnancy BMI had a relatively large effect on TG levels in Surinam-Hindustani and Turkish women. CONCLUSIONS: TC and TG levels differed between ethnic groups during early gestation. Only pre-pregnancy BMI partly explained the ethnic differences to a relevant degree. Reduction in BMI before pregnancy may improve lipid profile, especially in Surinam-Hindustani and Turkish women. PMID- 21245879 TI - Effects of oral ingestion of sucralose on gut hormone response and appetite in healthy normal-weight subjects. AB - BACKGROUND/OBJECTIVE: The sweet-taste receptor (T1r2+T1r3) is expressed by enteroendocrine L-cells throughout the gastrointestinal tract. Application of sucralose (a non-calorific, non-metabolisable sweetener) to L-cells in vitro stimulates glucagon-like peptide (GLP)-1 secretion, an effect that is inhibited with co-administration of a T1r2+T1r3 inhibitor. We conducted a randomised, single-blinded, crossover study in eight healthy subjects to investigate whether oral ingestion of sucralose could stimulate L-cell-derived GLP-1 and peptide YY (PYY) release in vivo. METHODS: Fasted subjects were studied on 4 study days in random order. Subjects consumed 50 ml of either water, sucralose (0.083% w/v), a non-sweet, glucose-polymer matched for sweetness with sucralose addition (50% w/v maltodextrin+0.083% sucralose) or a modified sham-feeding protocol (MSF=oral stimulation) of sucralose (0.083% w/v). Appetite ratings and plasma GLP-1, PYY, insulin and glucose were measured at regular time points for 120 min. At 120 min, energy intake at a buffet meal was measured. RESULTS: Sucralose ingestion did not increase plasma GLP-1 or PYY. MSF of sucralose did not elicit a cephalic phase response for insulin or GLP-1. Maltodextrin ingestion significantly increased insulin and glucose compared with water (P<0.001). Appetite ratings and energy intake were similar for all groups. CONCLUSIONS: At this dose, oral ingestion of sucralose does not increase plasma GLP-1 or PYY concentrations and hence, does not reduce appetite in healthy subjects. Oral stimulation with sucralose had no effect on GLP-1, insulin or appetite. PMID- 21245880 TI - The public health impacts of a fat tax. AB - BACKGROUND/OBJECTIVES: Previous studies have analysed impacts on average intakes. Agueably however intakes that are of real concern are those which are some distance away from the recommendations. Fiscal measures might have a limited impact on such diets, and as a result, on health. We measure the impact of a fiscal intervention on the the risks of diet-related disease, accounting for the full range of diets. SUBJECTS/METHODS: Demand equations are estimated with data collected from 6760 households in the UK Expenditure and Food Survey. The model is used to simulate the impacts of a policy, in which a tax based on saturated fat content is combined with subsidy on fruit and vegetables. Changes in consumption are used to compute the effects on the risks of a range of diet related disease using measures of relative risk. In contrast with other studies, we simulate the impacts of the fiscal regime at the level of the individual households in the sample. RESULTS: The subsidy brings mean levels of fruit and vegetable consumption in line with dietary recommendations, but the tax is insufficient to achieve this goal for fat intakes. Once the changes in diet are converted into changes in the risks of disease, the impacts of the policy are negligible. A substantial part of the population continues to consume an unhealthy diet. CONCLUSION: Fiscally based interventions should be considered amongst a suite of policy interventions, which also include policies aimed at improving the poorest of diets. PMID- 21245881 TI - Fatty fish and the relation between 25(OH) vitamin D and triacylglycerol. PMID- 21245877 TI - Evaluation of iron status in European adolescents through biochemical iron indicators: the HELENA Study. AB - BACKGROUND/OBJECTIVES: To assess the iron status among European adolescents through selected biochemical parameters in a cross-sectional study performed in 10 European cities. SUBJECTS/METHODS: Iron status was defined utilising biochemical indicators. Iron depletion was defined as low serum ferritin (SF<15 MUg/l). Iron deficiency (ID) was defined as high-soluble transferrin receptor (sTfR>8.5 mg/l) plus iron depletion. Iron deficiency anaemia (IDA) was defined as ID with haemoglobin (Hb) below the WHO cutoff for age and sex: 12.0 g/dl for girls and for boys aged 12.5-14.99 years and 13.0 g/dl for boys aged >=15 years. Enzyme linked immunosorbent assay was used as analytical method for SF, sTfR and C-reactive protein (CRP). Subjects with indication of inflammation (CRP >5 mg/l) were excluded from the analyses. A total of 940 adolescents aged 12.5-17.49 years (438 boys and 502 girls) were involved. RESULTS: The percentage of iron depletion was 17.6%, significantly higher in girls (21.0%) compared with boys (13.8%). The overall percentage of ID and IDA was 4.7 and 1.3%, respectively, with no significant differences between boys and girls. A correlation was observed between log (SF) and Hb (r = 0.36, P < 0.01), and between log (sTfR) and mean corpuscular haemoglobin (r = -0.30, P < 0.01). Iron body stores were estimated on the basis of log (sTfR/SF). A higher percentage of negative values of body iron was recorded in girls (16.5%) with respect to boys (8.3%), and body iron values tended to increase with age in boys, whereas the values remained stable in girls. CONCLUSIONS: To ensure adequate iron stores, specific attention should be given to girls at European level to ensure that their dietary intake of iron is adequate. PMID- 21245882 TI - A pilot randomized controlled trial of oral calcium and vitamin D supplementation using fortified laddoos in underprivileged Indian toddlers. AB - BACKGROUND/OBJECTIVES: Low habitual dietary calcium intake and vitamin D deficiency are common among Indian children. Using 'laddoo', an Indian snack, as a vehicle for administering calcium and vitamin D supplements, a randomized double-blind controlled trial was conducted for 12 months to assess its efficacy on total body less head (TBLH) bone mineral content (BMC) in underprivileged toddlers. SUBJECTS/METHODS: A total of 60 toddlers (mean age 2.7+/-0.52 years, boys=31) were randomized to two groups, (i) study group receiving one calcium fortified laddoo (cereal-legume snack) containing 405 mg calcium per day and (ii) control receiving a non-fortified laddoo, containing 156 mg of indigenous calcium. Both groups also received a laddoo fortified with 30,000 IU of vitamin D(3) per month. Outcome measures included TBLH bone area (BA) and TBLH BMC by GE Lunar DPX Pro Pencil Beam Dual-Energy X-ray absorptiometry. RESULTS: At baseline, mean energy, protein and calcium intakes were 71, 72 and 47% of Indian Recommended Dietary allowances. In all, 87 and 83% toddlers were hypocalcaemia and vitamin D deficient, respectively. Mean TBLH BMC was 289.5+/-45.8 g. Post supplementation, mean TBLH BMC of study group showed a significantly greater (P<0.01) increase of 35% as against 28% in controls and the difference remained significant after adjusting for vitamin D status, calcium intake, height and TBLH BA. CONCLUSIONS: Daily supplementation with calcium fortified laddoo, and monthly vitamin D supplement resulted in a significant increase in TBLH BMC of underprivileged toddlers. We believe that such strategies have the potential of addressing nutritional problems in developing countries. PMID- 21245883 TI - The relationship between diet and subclinical atherosclerosis: results from the Asklepios Study. AB - BACKGROUND/OBJECTIVES: Nutritional epidemiology shifted its focus from effects of single foods/nutrients toward the overall diet. Food-based dietary guidelines (FBDGs) are promoted worldwide to stimulate a healthy diet, including a variety of foods, to meet nutrient needs and to reduce the risk for non-communicable diseases. The objective of this study was to investigate whether adherence to the FBDG is associated with reduced femoral/carotid atherosclerosis and/or inflammation. SUBJECTS/METHODS: In October 2002, 2524 healthy men and women aged 35-55 years were recruited for the Belgian Asklepios cohort study. Subjects were extensively phenotyped, including echographic assessment of (carotid and femoral) atherosclerosis. A dietary index consisting of three subscores (dietary quality, diversity and equilibrium) was calculated to measure adherence to the Flemish FBDG, using data from a semi-quantitative food-frequency questionnaire. General linear models were used to investigate associations between these scores and cardiovascular (CV) risk factors and atherosclerosis and inflammation markers. RESULTS: Women had better overall dietary scores than men (69 vs 59%). Participants with higher dietary scores showed better age-adjusted CV risk profiles (lower waist/hip ratio, blood pressure, non-high-density lipoprotein cholesterol, blood triglycerides and homocystein), although most of these associations were only significant in men. Higher dietary scores were also inversely associated with inflammation makers (interleukin-6 and leukocyte count). Associations between diet and atherosclerosis were only found for femoral atherosclerosis and significance disappeared after adjustment for confounders. CONCLUSIONS: Better adherence to the Flemish FBDG is associated with a better CV risk profile and less inflammation, mainly among men. There was no direct effect on the presence of carotid or femoral atherosclerosis. PMID- 21245884 TI - Intake of antioxidants and risk of type 2 diabetes in a cohort of male smokers. AB - BACKGROUND/OBJECTIVES: Oxidative stress may induce insulin resistance in peripheral tissues and impair insulin secretion from pancreatic beta-cells. Antioxidants are suggested to decrease the risk of diabetes through reduction of oxidative stress. However, only a few studies exist on dietary antioxidants and the risk of type 2 diabetes. We investigated the association of dietary antioxidants with incident type 2 diabetes in the alpha-Tocopherol, beta-Carotene Cancer Prevention Study cohort. SUBJECT/METHODS: The study cohort included 29,133 male smokers aged 50-69 years. During a median follow-up of 10.2 years 660 incident cases of diabetes were observed among the 25,505 men with a completed baseline food frequency questionnaire. RESULTS: Dietary alpha-tocopherol, beta tocopherol and beta-tocotrienol were positively associated with the risk of diabetes when adjusted for age and supplementation (relative risk (RR) 1.17 (95% confidence interval (CI) 0.91-1.51) P for trend 0.02; RR 1.31 (95% CI 1.02-1.68) P for trend 0.01; RR 1.28 (95% CI 1.00-1.63) P for trend 0.01, respectively), but the association disappeared after multivariate adjustment (RR 0.92 (95% CI 0.71 1.19) P for trend 0.97; RR 1.06 (95% CI 0.82-1.36) P for trend 0.48; RR 1.04 (95% CI 0.80-1.35) P for trend 0.46, respectively). Other tocopherols and tocotrienols as well as vitamin C, carotenoids, flavonols and flavones had no association with risk of diabetes. CONCLUSIONS: Dietary antioxidants were not associated with a decreased risk of incident diabetes in middle-aged male smokers. PMID- 21245885 TI - Vitamin D status in infants: relation to nutrition and season. AB - In a cross-sectional study, the primary objective was to assess the plasma concentration of 25-hydroxyvitamin D (25(OH)D) in healthy 9-month-old infants (n=255). The secondary objective was to evaluate nutritional variables and season in relation to 25(OH)D. The concentration of 25(OH)D was 77.2 +/- 22.7 nmol/l (mean +/- s.d.), ranging from 12 to 151 nmol/l. During the first 9 months, 97% received vitamin D supplementation (10 MUg/day) and 89% had sufficient levels of 25(OH)D (50-250 nmol/l). In multiple regression analysis, controlled for body mass index (BMI) and intake of infant formula, a longer period of exclusive breastfeeding (P=0.026) and breastfeeding at 9 months (P=0.001) were both associated with lower levels. Dietary vitamin D intake was 4.4 +/- 3.1 MUg/day and in multiple regression analysis, controlled for BMI, intake of infant formula and mean energy intake, it was positively associated with 25(OH)D (P=0.001). There was a significant seasonal difference in 25(OH)D, with higher levels during summer-autumn compared with winter-spring (P=0.021) after control for BMI. PMID- 21245886 TI - Diagnosing lactase deficiency in three breaths. AB - BACKGROUND: Lactose hydrogen breath tests (H(2)-BTs) are widely used to diagnose lactase deficiency, the most common cause of lactose intolerance. The main time consuming part of the test relates to the sampling frequency and number of breath samples. AIM: Evaluate sensitivities and specificities of two- and three-sample breath tests compared with standard breath sampling every 15 min. METHODS: Lactose H(2)-BT with probes samples every 15 min served as gold standard. Sensitivity, specificity, positive and negative predictive value of two-sample tests (0-60 min, 0-90 min or 0-120 min) and three-sample tests (0-60-90 min, 0-60 120 min or 0-90-120 min) were calculated. RESULTS: Among 1049 lactose H(2)-BT performed between July 1999 and December 2005, 337 (32%) had a positive result. Two-sample tests had sensitivity and specificity of 52.5 and 100.0% (0-60 min), 81.9 and 99.7% (0-90 min), and 92.6 and 99.2% (0-120 min), respectively. Three sample tests had sensitivity and specificity of 83.4 and 99.7% (0-60-90 min), 95.0 and 99.2% (0-60-120 min), and 95.0 and 98.9% (0-90-120 min), respectively. CONCLUSION: A three-sample breath test (baseline, 60/90 min and 120 min) has excellent sensitivity and specificity for lactase deficiency. Lactose H(2)-BT can be simplified but not shortened to <2 h. PMID- 21245887 TI - Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial. AB - BACKGROUND/OBJECTIVE: The identification of probiotic species involved in gut homeostasis and their potential therapeutic benefits have led to an interest in their use for preventing necrotizing enterocolitis (NEC). Although bifidobacterium and lactobacilli sp. have been used to reduce the incidence of NEC in clinical trials. Lactobacillus sporogenes has not been used in the prevention of NEC in very low-birth weight infants yet. The objective of this study was to evaluate the efficacy of orally administered L sporogenes in reducing the incidence and severity of NEC in very low-birth weight (VLBW) infants. SUBJECTS/METHODS: A prospective, blinded, randomized controlled trial was conducted in preterm infants with a gestational age of <33 weeks or birth weight of <1500 g. VLBW infants who survived to start enteral feeding were randomized into two groups The infants in the study group were given L. sporogenes with a dose of 350,000,000 c.f.u. added to breast milk or formula, once a day, starting with the first feed until discharged. The infants in the control group were fed without L. sporogenes supplementation. The primary outcome measurement was death or NEC (Bell's stage >=2). RESULTS: A total of 221 infants were studied: 110 in the study group and 111 in the control group. There was no significant difference in the incidence of death or NEC between the groups. Feeding intolerance was significantly lower in the probiotics group than in the control group (44.5% (n: 49) vs 63.1% (n: 70), respectively; P=0.006). CONCLUSIONS: L. sporogenes supplementation at the dose of 350,000,000 c.f.u/day is not effective in reducing the incidence of death or NEC in VLBW infants, however, it could improve the feeding tolerance. PMID- 21245888 TI - Sunlight is an important determinant of vitamin D serum concentrations in cystic fibrosis. AB - BACKGROUND/OBJECTIVES: The increase of bone disease in adult cystic fibrosis (CF) patients is partly attributed to inadequate serum concentrations of 25-OH cholecalciferol (25 (OH) D) blamed on fat malabsorption. Based on physiological, clinical and biochemical observations this pathogenesis is debatable. The objective was to ascertain the relative importance of different 25 (OH) D sources. SUBJECTS/METHODS: Over 4 consecutive years, 474 annual 25 (OH) D serum concentrations from 141 CF patients of all ages were compared with values of healthy peers and weighed against annual ultraviolet B (UVB) exposure. RESULTS: Ranked per month, 25 (OH) D concentrations depicted a curve strikingly parallel to the amount of UVB exposure in the preceding months. A significant difference exists between 25 (OH) D concentrations in the 'Months with high UVB exposure' (May-October) and the 'Months with low UVB exposure' (November-April) but not with healthy controls in the same period. CONCLUSIONS: 25 (OH) D concentrations clearly respond to the amount of sunshine in preceding months. They are not clearly influenced by daily oral supplements of 800 IU of cholecalciferol. Sun exposure should be encouraged, and the recommended dosage of oral supplements increased. PMID- 21245889 TI - Histone H3K4 methylation keeps centromeres open for business. PMID- 21245890 TI - A condensed view of chromatin during T cell development. PMID- 21245891 TI - Automictic parthenogenesis and rate of transition to homozygosity. PMID- 21245892 TI - Association genetics of carbon isotope discrimination, height and foliar nitrogen in a natural population of Pinus taeda L. AB - Loblolly pine, Pinus taeda L., is one of the most widely planted, commercially and ecologically important tree species in North America. We took an association genetics approach, using an unimproved population of 380 clonally replicated unrelated trees, to test 3,938 single nucleotide polymorphisms (SNPs) in as many genes for association with phenotypic variation in carbon isotope discrimination, foliar nitrogen concentration and total tree height after two growing seasons. Best linear unbiased prediction (BLUP) was used with a spatial adjustment to remove environmental variation from phenotypic data derived from a common garden experiment. After correction for multiple testing, a total of 14 SNPs were associated with the traits of carbon isotope discrimination (n = 7), height (n = 1) and foliar nitrogen concentration (n = 6) using 380 clones. Tails of the population phenotypic distribution were compared for allele frequency differences, revealing 10 SNPs with allele frequency in at least one tail significantly different from the overall population. Eight associated SNPs were in sequences similar to known genes, such as an AP2 transcription factor related to carbon isotope discrimination and glutamate decarboxylase associated with foliar nitrogen concentration, and others were from unknown genes without homologs in Arabidopsis. PMID- 21245893 TI - Fitness effects of derived deleterious mutations in four closely related wild tomato species with spatial structure. AB - A key issue in evolutionary biology is an improved understanding of the genetic mechanisms by which species adapt to various environments. Using DNA sequence data, it is possible to quantify the number of adaptive and deleterious mutations, and the distribution of fitness effects of new mutations (its mean and variance) by simultaneously taking into account the demography of a given species. We investigated how selection functions at eight housekeeping genes of four closely related, outcrossing species of wild tomatoes that are native to diverse environments in western South America (Solanum arcanum, S. chilense, S. habrochaites and S. peruvianum). We found little evidence for adaptive mutations but pervasive evidence for strong purifying selection in coding regions of the four species. In contrast, the strength of purifying selection seems to vary among the four species in non-coding (NC) regions (introns). Using F(ST)-based measures of fixation in subdivided populations, we suggest that weak purifying selection has affected the NC regions of S. habrochaites, S. chilense and S. peruvianum. In contrast, NC regions in S. arcanum show a distribution of fitness effects with mutations being either nearly neutral or very strongly deleterious. These results suggest that closely related species with similar genetic backgrounds but experiencing contrasting environments differ in the variance of deleterious fitness effects. PMID- 21245895 TI - Cytoplasmic male sterility in Mimulus hybrids has pleiotropic effects on corolla and pistil traits. AB - The mechanisms underlying genetic associations have important consequences for evolutionary outcomes, but distinguishing linkage from pleiotropy is often difficult. Here, we use a fine mapping approach to determine the genetic basis of association between cytonuclear male sterility and other floral traits in Mimulus hybrids. Previous work has shown that male sterility in hybrids between Mimulus guttatus and Mimulus nasutus is due to interactions between a mitochondrial gene from M. guttatus and two tightly linked nuclear restorer alleles on Linkage Group 7, and that male sterility is associated with reduced corolla size. In the present study, we generated a set of nearly isogenic lines segregating for the restorer region and male sterility, but with unique flanking introgressions. Male sterile flowers had significantly smaller corollas, longer styles and greater stigmatic exsertion than fertile flowers. Because these effects were significant regardless of the genotypic composition of introgressions flanking the restorer region, they suggest that these floral differences are a direct byproduct of the genetic incompatibility causing anther abortion. In addition, we found a non significant but intriguing trend for male-sterile plants to produce more seeds per flower than fertile siblings after supplemental pollination. Such pleiotropic effects may underlie the corolla dimorphism frequently observed in gynodioecious taxa and may affect selection on cytoplasmic male sterility genes when they initially arise. PMID- 21245894 TI - MHC class II DRB diversity, selection pattern and population structure in a neotropical bat species, Noctilio albiventris. AB - Genes of the major histocompatibility complex (MHC) have a crucial role in the immune response of vertebrates, alter the individual odour and are involved in shaping mating preferences. Pathogen-mediated selection, sexual selection and maternal-fetal interactions have been proposed as the main drivers of frequently observed high levels of polymorphism in functionally important parts of the MHC. Bats constitute the second largest mammalian order and have recently emerged as important vectors of infectious diseases. In addition, Chiroptera are interesting study subjects in evolutionary ecology in the context of olfactory communication, mate choice and associated fitness benefits. Thus, it is surprising that they belong to the least studied mammalian taxa in terms of their MHC diversity. In this study, we investigated the variability in the functionally important MHC class II gene DRB, evidence for selection and population structure in the group living lesser bulldog bat, Noctilio albiventris, in Panama. We found a single expressed, polymorphic Noal-DRB gene. The substitution pattern of the nucleotide sequences of the 18 detected alleles provided evidence for positive selection acting above the evolutionary history of the species in shaping MHC diversity. Roosting colonies were not genetically differentiated but females showed lower levels of heterozygosity than males, which might be a sign that the sexes differ in the selection pressures acting on the MHC. This study provides the prerequisites for further investigations of the role of the individual MHC constitution in parasite resistance, olfactory communication and mate choice in N. albiventris and other bats. PMID- 21245896 TI - Fitness costs linked to dinitroaniline resistance mutation in Setaria. AB - A mutant Thr-239-Ileu at the alpha2-tubulin gene was found to confer resistance to dinitroanilines, a family of mitosis-disrupting herbicides. However, mutations affecting microtubule polymerization and cell division are expected to impact growth and reproduction, that is, the fitness of a resistant weed or the yield of a tolerant crop, although it has not been demonstrated yet. This study was designed to test this hypothesis for the growth and reproduction of near-isogenic resistant and susceptible materials that were created in F(2) and F(3) generations after a Setaria viridis x S. italica cross. Differential growth was noticeable at the very onset of seedling growth. The homozygous resistant plants, grown both in a greenhouse cabinet and in the field, were smaller and had lower 1000-grain weight and therefore a lower yield. This fitness penalty is certainly due to modified cell division kinetics. Although the presence of the mutant allele accounted for 20% yield losses, there were also measurable benefits of dinitroaniline resistance, and these benefits are discussed. PMID- 21245897 TI - Natural killer cells: fighting viruses and much more. AB - More than 450 immunologists recently met in Cavtat, Croatia to discuss advances in natural killer (NK) cell biology. The meeting highlighted emerging themes in NK cell responses to viruses, NK cell tolerance and potential use of NK cells in the therapy of malignancies. PMID- 21245898 TI - CCL8 and skin T cells--an allergic attraction. PMID- 21245899 TI - Ldb1, a new guardian of hematopoietic stem cell maintenance. PMID- 21245900 TI - 2 methylate or not 2 methylate: viral evasion of the type I interferon response. PMID- 21245901 TI - New friends for bone marrow plasma cells. PMID- 21245904 TI - Epigenetic regulation of learning and memory by Drosophila EHMT/G9a. AB - The epigenetic modification of chromatin structure and its effect on complex neuronal processes like learning and memory is an emerging field in neuroscience. However, little is known about the "writers" of the neuronal epigenome and how they lay down the basis for proper cognition. Here, we have dissected the neuronal function of the Drosophila euchromatin histone methyltransferase (EHMT), a member of a conserved protein family that methylates histone 3 at lysine 9 (H3K9). EHMT is widely expressed in the nervous system and other tissues, yet EHMT mutant flies are viable. Neurodevelopmental and behavioral analyses identified EHMT as a regulator of peripheral dendrite development, larval locomotor behavior, non-associative learning, and courtship memory. The requirement for EHMT in memory was mapped to 7B-Gal4 positive cells, which are, in adult brains, predominantly mushroom body neurons. Moreover, memory was restored by EHMT re-expression during adulthood, indicating that cognitive defects are reversible in EHMT mutants. To uncover the underlying molecular mechanisms, we generated genome-wide H3K9 dimethylation profiles by ChIP-seq. Loss of H3K9 dimethylation in EHMT mutants occurs at 5% of the euchromatic genome and is enriched at the 5' and 3' ends of distinct classes of genes that control neuronal and behavioral processes that are corrupted in EHMT mutants. Our study identifies Drosophila EHMT as a key regulator of cognition that orchestrates an epigenetic program featuring classic learning and memory genes. Our findings are relevant to the pathophysiological mechanisms underlying Kleefstra Syndrome, a severe form of intellectual disability caused by mutations in human EHMT1, and have potential therapeutic implications. Our work thus provides novel insights into the epigenetic control of cognition in health and disease. PMID- 21245903 TI - NLR functions beyond pathogen recognition. AB - The last 10 years have witnessed the identification of a new class of intracellular pattern-recognition molecules--the nucleotide-binding domain and leucine-rich repeat-containing family (NLR). Members of this family garnered interest as pattern-recognition receptors able to trigger inflammatory responses against pathogens. Many studies support a pathogen-recognition function for human NLR proteins and shed light on their role in the broader control of adaptive immunity and various disease states. Other evidence suggests that NLRs function in processes unrelated to pathogen detection. Here we discuss recent advances in our understanding of the biology of the human NLR proteins and their non-pathogen recognition function in tissue homeostasis, apoptosis, graft-versus-host disease and early development. PMID- 21245905 TI - Predicting live birth, preterm delivery, and low birth weight in infants born from in vitro fertilisation: a prospective study of 144,018 treatment cycles. AB - BACKGROUND: The extent to which baseline couple characteristics affect the probability of live birth and adverse perinatal outcomes after assisted conception is unknown. METHODS AND FINDINGS: We utilised the Human Fertilisation and Embryology Authority database to examine the predictors of live birth in all in vitro fertilisation (IVF) cycles undertaken in the UK between 2003 and 2007 (n = 144,018). We examined the potential clinical utility of a validated model that pre-dated the introduction of intracytoplasmic sperm injection (ICSI) as compared to a novel model. For those treatment cycles that resulted in a live singleton birth (n = 24,226), we determined the associates of potential risk factors with preterm birth, low birth weight, and macrosomia. The overall rate of at least one live birth was 23.4 per 100 cycles (95% confidence interval [CI] 23.2-23.7). In multivariable models the odds of at least one live birth decreased with increasing maternal age, increasing duration of infertility, a greater number of previously unsuccessful IVF treatments, use of own oocytes, necessity for a second or third treatment cycle, or if it was not unexplained infertility. The association of own versus donor oocyte with reduced odds of live birth strengthened with increasing age of the mother. A previous IVF live birth increased the odds of future success (OR 1.58, 95% CI 1.46-1.71) more than that of a previous spontaneous live birth (OR 1.19, 95% CI 0.99-1.24); p-value for difference in estimate <0.001. Use of ICSI increased the odds of live birth, and male causes of infertility were associated with reduced odds of live birth only in couples who had not received ICSI. Prediction of live birth was feasible with moderate discrimination and excellent calibration; calibration was markedly improved in the novel compared to the established model. Preterm birth and low birth weight were increased if oocyte donation was required and ICSI was not used. Risk of macrosomia increased with advancing maternal age and a history of previous live births. Infertility due to cervical problems was associated with increased odds of all three outcomes-preterm birth, low birth weight, and macrosomia. CONCLUSIONS: Pending external validation, our results show that couple- and treatment-specific factors can be used to provide infertile couples with an accurate assessment of whether they have low or high risk of a successful outcome following IVF. PMID- 21245906 TI - Laminar analysis of excitatory local circuits in vibrissal motor and sensory cortical areas. AB - Rodents move their whiskers to locate and identify objects. Cortical areas involved in vibrissal somatosensation and sensorimotor integration include the vibrissal area of the primary motor cortex (vM1), primary somatosensory cortex (vS1; barrel cortex), and secondary somatosensory cortex (S2). We mapped local excitatory pathways in each area across all cortical layers using glutamate uncaging and laser scanning photostimulation. We analyzed these maps to derive laminar connectivity matrices describing the average strengths of pathways between individual neurons in different layers and between entire cortical layers. In vM1, the strongest projection was L2/3->L5. In vS1, strong projections were L2/3->L5 and L4->L3. L6 input and output were weak in both areas. In S2, L2/3->L5 exceeded the strength of the ascending L4->L3 projection, and local input to L6 was prominent. The most conserved pathways were L2/3->L5, and the most variable were L4->L2/3 and pathways involving L6. Local excitatory circuits in different cortical areas are organized around a prominent descending pathway from L2/3->L5, suggesting that sensory cortices are elaborations on a basic motor cortex-like plan. PMID- 21245907 TI - Setting implementation research priorities to reduce preterm births and stillbirths at the community level. AB - Asha George and colleagues from the GAPPS group report the implementation research priorities to address prematurity and stillbirths at the community level that resulted from their recent expert consensus exercise. PMID- 21245908 TI - An engineered cardiac reporter cell line identifies human embryonic stem cell derived myocardial precursors. AB - Unlike some organs, the heart is unable to repair itself after injury. Human embryonic stem cells (hESCs) grow and divide indefinitely while maintaining the potential to develop into many tissues of the body. As such, they provide an unprecedented opportunity to treat human diseases characterized by tissue loss. We have identified early myocardial precursors derived from hESCs (hMPs) using an alpha-myosin heavy chain (alphaMHC)-GFP reporter line. We have demonstrated by immunocytochemistry and quantitative real-time PCR (qPCR) that reporter activation is restricted to hESC-derived cardiomyocytes (CMs) differentiated in vitro, and that hMPs give rise exclusively to muscle in an in vivo teratoma formation assay. We also demonstrate that the reporter does not interfere with hESC genomic stability. Importantly, we show that hMPs give rise to atrial, ventricular and specialized conduction CM subtypes by qPCR and microelectrode array analysis. Expression profiling of hMPs over the course of differentiation implicate Wnt and transforming growth factor-beta signaling pathways in CM development. The identification of hMPs using this alphaMHC-GFP reporter line will provide important insight into the pathways regulating human myocardial development, and may provide a novel therapeutic reagent for the treatment of cardiac disease. PMID- 21245909 TI - CD4+ T cells modulate expansion and survival but not functional properties of effector and memory CD8+ T cells induced by malaria sporozoites. AB - CD4(+) helper T cells are critical orchestrators of immune responses to infection and vaccination. During primary responses, naive CD8(+) T cells may need "CD4 help" for optimal development of memory populations. The immunological factors attributed to CD4 help depend on the context of immunization and vary depending on the priming system. In response to immunization with radiation-attenuated Plasmodium yoelii sporozoites, CD8(+) T cells in BALB/c mice fail to generate large numbers of effector cells without help from CD4(+) T cells--a defect not observed in most systems. Given this unique early dependence on CD4 help, we evaluated the effects of CD4(+) cells on the development of functional properties of CD8(+) T cells and on their ability to abolish infection. First, we determined that this effect was not mediated by CD4(+) non-T cells and did not involve CD1d restricted NKT cells. We found that CD8(+) T cells induced by sporozoites without CD4 help formed memory populations severely reduced in magnitude that could not limit parasite development in the liver. The inability of these "helpless" memory T cells to protect is not a result of defects in effector function, as their capacity to produce cytokines and undergo cytotoxic degranulation was indistinguishable from control memory T cells. These data indicate that CD4(+) T help may not be necessary to develop the functional attributes of CD8(+) T cells; however they are crucial to ensure the survival of effector and memory cells induced in primary responses. PMID- 21245910 TI - Schistosoma mansoni Infections in young children: when are schistosome antigens in urine, eggs in stool and antibodies to eggs first detectable? AB - BACKGROUND: in uganda, control of intestinal schistosomiasis with preventive chemotherapy is typically focused towards treatment of school-aged children; the needs of younger children are presently being investigated as in lakeshore communities very young children can be infected. In the context of future epidemiological monitoring, we sought to compare the detection thresholds of available diagnostic tools for Schistosoma mansoni and estimate a likely age of first infection for these children. METHODS AND FINDINGS: a total of 242 infants and preschool children (134 boys and 108 girls, mean age 2.9 years, minimum 5 months and maximum 5 years) were examined from Bugoigo, a well-known disease endemic village on Lake Albert. Schistosome antigens in urine, eggs in stool and host antibodies to eggs were inspected to reveal a general prevalence of 47.5% (CI(95) 41.1-54.0%), as ascertained by a positive criterion from at least one diagnostic method. Although children as young as 6 months old could be found infected, the average age of infected children was between 31/4-33/4 years, when diagnostic techniques became broadly congruent. CONCLUSION: whilst different assays have particular (dis)advantages, direct detection of eggs in stool was least sensitive having a temporal lag behind antigen and antibody methods. Setting precisely a general age of first infection is problematic but if present Ugandan policies continue, a large proportion of infected children could wait up to 3-4 years before receiving first medication. To better tailor treatment needs for this younger ageclass, we suggest that the circulating cathodic antigen urine dipstick method to be used as an epidemiological indicator. PMID- 21245911 TI - Towards delineating functions within the fasciola secreted cathepsin l protease family by integrating in vivo based sub-proteomics and phylogenetics. AB - BACKGROUND: fasciola hepatica, along with Fasciola gigantica, is the causative agent of fasciolosis, a foodborne zoonotic disease affecting grazing animals and humans worldwide. Pathology is directly related to the release of parasite proteins that facilitate establishment within the host. The dominant components of these excretory-secretory (ES) products are also the most promising vaccine candidates, the cathepsin L (Cat L) protease family. METHODOLOGY/PRINCIPAL FINDINGS: the sub-proteome of Cat L proteases from adult F. hepatica ES products derived from in vitro culture and in vivo from ovine host bile were compared by 2 DE. The individual Cat L proteases were identified by tandem mass spectrometry with the support of an in-house translated liver fluke EST database. The study reveals plasticity within the CL1 clade of Cat L proteases; highlighted by the identification of a novel isoform and CL1 sub-clade, resulting in a new Cat L phylogenetic analysis including representatives from other adult Cat L phylogenetic clades. Additionally, for the first time, mass spectrometry was shown to be sufficiently sensitive to reveal single amino acid polymorphisms in a resolved 2-DE protein spot derived from pooled population samples. CONCLUSIONS/SIGNIFICANCE: we have investigated the sub-proteome at the population level of a vaccine target family using the Cat L proteases from F. hepatica as a case study. We have confirmed that F. hepatica exhibits more plasticity in the expression of the secreted CL1 clade of Cat L proteases at the protein level than previously realised. We recommend that superfamily based vaccine discovery programmes should screen parasite populations from different host populations and, if required, different host species via sub-proteomic assay in order to confirm the relative expression at the protein level prior to the vaccine development phase. PMID- 21245912 TI - RIG-I, MDA5 and TLR3 synergistically play an important role in restriction of dengue virus infection. AB - Dengue virus (DV) infection is one of the most common mosquito-borne viral diseases in the world. The innate immune system is important for the early detection of virus and for mounting a cascade of defense measures which include the production of type 1 interferon (IFN). Hence, a thorough understanding of the innate immune response during DV infection would be essential for our understanding of the DV pathogenesis. A recent application of the microarray to dengue virus type 1 (DV1) infected lung carcinoma cells revealed the increased expression of both extracellular and cytoplasmic pattern recognition receptors; retinoic acid inducible gene-I (RIG-I), melanoma differentiation associated gene 5 (MDA-5) and Toll-like receptor-3 (TLR3). These intracellular RNA sensors were previously reported to sense DV infection in different cells. In this study, we show that they are collectively involved in initiating an effective IFN production against DV. Cells silenced for these genes were highly susceptible to DV infection. RIG-I and MDA5 knockdown HUH-7 cells and TLR3 knockout macrophages were highly susceptible to DV infection. When cells were silenced for only RIG-I and MDA5 (but not TLR3), substantial production of IFN-beta was observed upon virus infection and vice versa. High susceptibility to virus infection led to ER stress induced apoptosis in HUH-7 cells. Collectively, our studies demonstrate that the intracellular RNA virus sensors (RIG-I, MDA5 and TLR3) are activated upon DV infection and are essential for host defense against the virus. PMID- 21245913 TI - Factors associated with the prevalence of circulating antigens to porcine cysticercosis in three villages of burkina faso. AB - BACKGROUND: little is known about porcine cysticercosis in Burkina Faso. We conducted a pilot study to estimate the prevalence of antigens of Taenia solium cysticercosis and to identify associated factors in pigs of three villages in Burkina Faso, selected to represent different pig management practices: one village where pigs are allowed to roam freely (Batondo), one village where pigs are penned part of the time (Pabre) and one village with limited pig farming (Nyonyogo). METHODS/PRINCIPAL FINDINGS: a clustered random sampling design was used. Data on socio-demographic characteristics (source of drinking water, presence of latrines in the household, type and number of breeding animals) and pig management practices were collected using a standardized questionnaire. Blood samples were collected from one pig per household to determine the presence of antigens of the larval stages of T. solium by the B158/B60 Ag-ELISA. The associations between seropositivity and socio-demographic and pig management practices were estimated using logistic regression. Proportions of 32.5% (95% CI 25.4-40.3), 39.6% (31.9-47.8), and 0% of pigs, were found positive for the presence of circulating antigens of T. solium in Batondo, Pabre, and Nyonyogo, respectively. The results of the logistic regression analyses suggested that people acquire knowledge on porcine cysticercosis following the contamination of their animals. The presence of antigens in the pigs' sera was not associated with the absence of latrines in the household, the source of drinking water or the status of infection in humans but was associated with pig rearing practices during the rainy season. CONCLUSIONS/SIGNIFICANCE: the results suggest that education of pig farmers is urgently needed to reduce the prevalence of this infection. PMID- 21245914 TI - Repulsive forces between looping chromosomes induce entropy-driven segregation. AB - One striking feature of chromatin organization is that chromosomes are compartmentalized into distinct territories during interphase, the degree of intermingling being much smaller than expected for linear chains. A growing body of evidence indicates that the formation of loops plays a dominant role in transcriptional regulation as well as the entropic organization of interphase chromosomes. Using a recently proposed model, we quantitatively determine the entropic forces between chromosomes. This Dynamic Loop Model assumes that loops form solely on the basis of diffusional motion without invoking other long-range interactions. We find that introducing loops into the structure of chromatin results in a multi-fold higher repulsion between chromosomes compared to linear chains. Strong effects are observed for the tendency of a non-random alignment; the overlap volume between chromosomes decays fast with increasing loop number. Our results suggest that the formation of chromatin loops imposes both compartmentalization as well as order on the system without requiring additional energy-consuming processes. PMID- 21245915 TI - BALB/c mice deficient in CD4 T cell IL-4Ralpha expression control Leishmania mexicana Load although female but not male mice develop a healer phenotype. AB - Immunologically intact BALB/c mice infected with Leishmania mexicana develop non healing progressively growing lesions associated with a biased Th2 response while similarly infected IL-4Ralpha-deficient mice fail to develop lesions and develop a robust Th1 response. In order to determine the functional target(s) for IL-4/IL 13 inducing non-healing disease, the course of L. mexicana infection was monitored in mice lacking IL-4Ralpha expression in specific cellular compartments. A deficiency of IL-4Ralpha expression on macrophages/neutrophils (in LysM(cre)IL-4Ralpha(-/lox) animals) had minimal effect on the outcome of L. mexicana infection compared with control (IL-4Ralpha(-/flox)) mice. In contrast, CD4(+) T cell specific (Lck(cre)IL-4Ralpha(-/lox)) IL-4Ralpha(-/-) mice infected with L. mexicana developed small lesions, which subsequently healed in female mice, but persisted in adult male mice. While a strong Th1 response was manifest in both male and female CD4(+) T cell specific IL-4Ralpha(-/-) mice infected with L. mexicana, induction of IL-4 was manifest in males but not females, independently of CD4(+) T cell IL-4 responsiveness. Similar results were obtained using pan-T cell specific (iLck(cre)IL-4Ralpha(-/lox)) IL-4Ralpha(-/-) mice. Collectively these data demonstrate that upon infection with L. mexicana, initial lesion growth in BALB/c mice is dependent on non-T cell population(s) responsive to IL-4/IL-13 while progressive infection is dependent on CD4(+) T cells responsive to IL-4. PMID- 21245916 TI - Temporal fluctuation of multidrug resistant salmonella typhi haplotypes in the mekong river delta region of Vietnam. AB - BACKGROUND: typhoid fever remains a public health problem in Vietnam, with a significant burden in the Mekong River delta region. Typhoid fever is caused by the bacterial pathogen Salmonella enterica serovar Typhi (S. Typhi), which is frequently multidrug resistant with reduced susceptibility to fluoroquinolone based drugs, the first choice for the treatment of typhoid fever. We used a GoldenGate (Illumina) assay to type 1,500 single nucleotide polymorphisms (SNPs) and analyse the genetic variation of S. Typhi isolated from 267 typhoid fever patients in the Mekong delta region participating in a randomized trial conducted between 2004 and 2005. PRINCIPAL FINDINGS: the population of S. Typhi circulating during the study was highly clonal, with 91% of isolates belonging to a single clonal complex of the S. Typhi H58 haplogroup. The patterns of disease were consistent with the presence of an endemic haplotype H58-C and a localised outbreak of S. Typhi haplotype H58-E2 in 2004. H58-E2-associated typhoid fever cases exhibited evidence of significant geo-spatial clustering along the Song H u branch of the Mekong River. Multidrug resistance was common in the established clone H58-C but not in the outbreak clone H58-E2, however all H58 S. Typhi were nalidixic acid resistant and carried a Ser83Phe amino acid substitution in the gyrA gene. SIGNIFICANCE: the H58 haplogroup dominates S. Typhi populations in other endemic areas, but the population described here was more homogeneous than previously examined populations, and the dominant clonal complex (H58-C, -E1, E2) observed in this study has not been detected outside Vietnam. IncHI1 plasmid bearing S. Typhi H58-C was endemic during the study period whilst H58-E2, which rarely carried the plasmid, was only transient, suggesting a selective advantage for the plasmid. These data add insight into the outbreak dynamics and local molecular epidemiology of S. Typhi in southern Vietnam. PMID- 21245917 TI - Sequence alignment, mutual information, and dissimilarity measures for constructing phylogenies. AB - BACKGROUND: Existing sequence alignment algorithms use heuristic scoring schemes based on biological expertise, which cannot be used as objective distance metrics. As a result one relies on crude measures, like the p- or log-det distances, or makes explicit, and often too simplistic, a priori assumptions about sequence evolution. Information theory provides an alternative, in the form of mutual information (MI). MI is, in principle, an objective and model independent similarity measure, but it is not widely used in this context and no algorithm for extracting MI from a given alignment (without assuming an evolutionary model) is known. MI can be estimated without alignments, by concatenating and zipping sequences, but so far this has only produced estimates with uncontrolled errors, despite the fact that the normalized compression distance based on it has shown promising results. RESULTS: We describe a simple approach to get robust estimates of MI from global pairwise alignments. Our main result uses algorithmic (Kolmogorov) information theory, but we show that similar results can also be obtained from Shannon theory. For animal mitochondrial DNA our approach uses the alignments made by popular global alignment algorithms to produce MI estimates that are strikingly close to estimates obtained from the alignment free methods mentioned above. We point out that, due to the fact that it is not additive, normalized compression distance is not an optimal metric for phylogenetics but we propose a simple modification that overcomes the issue of additivity. We test several versions of our MI based distance measures on a large number of randomly chosen quartets and demonstrate that they all perform better than traditional measures like the Kimura or log-det (resp. paralinear) distances. CONCLUSIONS: Several versions of MI based distances outperform conventional distances in distance-based phylogeny. Even a simplified version based on single letter Shannon entropies, which can be easily incorporated in existing software packages, gave superior results throughout the entire animal kingdom. But we see the main virtue of our approach in a more general way. For example, it can also help to judge the relative merits of different alignment algorithms, by estimating the significance of specific alignments. It strongly suggests that information theory concepts can be exploited further in sequence analysis. PMID- 21245918 TI - Subacute sclerosing panencephalitis in papua new guinean children: the cost of continuing inadequate measles vaccine coverage. AB - INTRODUCTION: subacute sclerosing panencephalitis (SSPE) is a late, rare and usually fatal complication of measles infection. Although a very high incidence of SSPE in Papua New Guinea (PNG) was first recognized 20 years ago, estimated measles vaccine coverage has remained at <= 70% since and a large measles epidemic occurred in 2002. We report a series of 22 SSPE cases presenting between November 2007 and July 2009 in Madang Province, PNG, including localized clusters with the highest ever reported annual incidence. METHODOLOGY/PRINCIPAL FINDINGS: as part of a prospective observational study of severe childhood illness at Modilon Hospital, the provincial referral center, children presenting with evidence of meningo-encephalitis were assessed in detail including lumbar puncture in most cases. A diagnosis of SSPE was based on clinical features and presence of measles-specific IgG in cerebrospinal fluid and/or plasma. The estimated annual SSPE incidence in Madang province was 54/million population aged <20 years, but four sub-districts had an incidence >100/million/year. The distribution of year of birth of the 22 children with SSPE closely matched the reported annual measles incidence in PNG, including a peak in 2002. CONCLUSIONS/SIGNIFICANCE: SSPE follows measles infections in very young PNG children. Because PNG children have known low seroconversion rates to the first measles vaccine given at 6 months of age, efforts such as supplementary measles immunisation programs should continue in order to reduce the pool of non-immune people surrounding the youngest and most vulnerable members of PNG communities. PMID- 21245919 TI - Antibodies elicited in response to EBNA-1 may cross-react with dsDNA. AB - BACKGROUND: Several genetic and environmental factors have been linked to Systemic Lupus Erythematosus (SLE). One environmental trigger that has a strong association with SLE is the Epstein Barr Virus (EBV). Our laboratory previously demonstrated that BALB/c mice expressing the complete EBNA-1 protein can develop antibodies to double stranded DNA (dsDNA). The present study was undertaken to understand why anti-dsDNA antibodies arise during the immune response to EBNA-1. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we demonstrated that mouse antibodies elicited in response to EBNA-1 cross-react with dsDNA. First, we showed that adsorption of sera reactive with EBNA-1 and dsDNA, on dsDNA cellulose columns, diminished reactivity with EBNA-1. Next, we generated monoclonal antibodies (MAbs) to EBNA-1 and showed, by several methods, that they also reacted with dsDNA. Examination of two cross-reactive MAbs--3D4, generated in this laboratory, and 0211, a commercial MAb--revealed that 3D4 recognizes the carboxyl region of EBNA-1, while 0211 recognizes both the amino and carboxyl regions. In addition, 0211 binds moderately well to the ribonucleoprotein, Sm, which has been reported by others to elicit a cross-reactive response with EBNA 1, while 3D4 binds only weakly to Sm. This suggests that the epitope in the carboxyl region may be more important for cross-reactivity with dsDNA while the epitope in the amino region may be more important for cross-reactivity with Sm. CONCLUSIONS/SIGNIFICANCE: In conclusion, our results demonstrate that antibodies to the EBNA-1 protein cross-react with dsDNA. This study is significant because it demonstrates a direct link between the viral antigen and the development of anti-dsDNA antibodies, which are the hallmark of SLE. Furthermore, it illustrates the crucial need to identify the epitopes in EBNA-1 responsible for this cross reactivity so that therapeutic strategies can be designed to mask these regions from the immune system following EBV exposure. PMID- 21245920 TI - Activities of rifampin, Rifapentine and clarithromycin alone and in combination against mycobacterium ulcerans disease in mice. AB - BACKGROUND: treatment of Mycobacterium ulcerans disease, or Buruli ulcer (BU), has shifted from surgery to treatment with streptomycin(STR)+rifampin(RIF) since 2004 based on studies in a mouse model and clinical trials. We tested two entirely oral regimens for BU treatment, rifampin(RIF)+clarithromycin(CLR) and rifapentine(RPT)+clarithromycin(CLR) in the mouse model. METHODOLOGY/PRINCIPAL FINDINGS: BALB/c mice were infected in the right hind footpad with M. ulcerans strain 1059 and treated daily (5 days/week) for 4 weeks, beginning 11 days after infection. Treatment groups included an untreated control, STR+RIF as a positive control, and test regimens of RIF, RPT, STR and CLR given alone and the RIF+CLR and RPT+CLR combinations. The relative efficacy of the drug treatments was compared on the basis of footpad CFU counts and median time to footpad swelling. Except for CLR, which was bacteriostatic, treatment with all other drugs reduced CFU counts by approximately 2 or 3 log(10). Median time to footpad swelling after infection was 5.5, 16, 17, 23.5 and 36.5 weeks in mice receiving no treatment, CLR alone, RIF+CLR, RIF alone, and STR alone, respectively. At the end of follow up, 39 weeks after infection, only 48%, 26.4% and 16.3% of mice treated with RPT+CLR, RPT alone and STR+RIF had developed swollen footpads. An in vitro checkerboard assay showed the interaction of CLR and RIF to be indifferent. However, in mice, co-administration with CLR resulted in a roughly 25% decrease in the maximal serum concentration (Cmax) and area under the serum concentration time curve (AUC) of each rifamycin. Delaying the administration of CLR by one hour restored Cmax and AUC values of RIF to levels obtained with RIF alone. CONCLUSIONS/SIGNIFICANCE: these results suggest that an entirely oral daily regimen of RPT+CLR may be at least as effective as the currently recommended combination of injected STR+oral RIF. PMID- 21245921 TI - DC-SIGN (CD209) Promoter -336 A/G polymorphism is associated with dengue hemorrhagic fever and correlated to DC-SIGN expression and immune augmentation. AB - BACKGROUND: the C-type lectin DC-SIGN (CD209) is known to be the major dengue receptor on human dendritic cells, and a single nucleotide polymorphism (SNP) in the promoter region of CD209 (-336 A/G; rs4804803) is susceptible to many infectious diseases. We reason that variations in the DC-SIGN gene might have a broad influence on viral replication and host immune responses. METHODS AND FINDINGS: we studied whether the rs4804803 SNP was associated with a susceptibility to dengue fever (DF) and/or dengue hemorrhagic fever (DHF) through genotyping analysis in a Taiwanese cohort. We generated monocyte-derived dendritic cells (MDDCs) from individuals with AA or AG genotype of rs4804803 to study the viral replication and immune responses for functional validation. A total of 574 DNA samples were genotyped, including 176 DF, 135 DHF, 143 other non dengue febrile illnesses (OFI) and 120 population controls. A strong association between GG/AG genotypes of rs4804803 and risk of DHF was found when compared among DF, OFI and controls (p = 0.004, 3*10(-5) and 0.001, respectively). The AA genotype was associated with protection against dengue infection compared with OFI and controls (p = 0.002 and 0.020, respectively). Moreover, MDDCs from individuals with AG genotype with a higher cell surface DC-SIGN expression had a significantly higher TNFalpha, IL-12p40, and IP-10 production than those with AA genotype in response to dengue infection. However, the viral replication in MDDCs with AG genotype was significantly lower than those with AA genotype. With both genotypes, MDDCs revealed an increase in viral replication following the addition of anti-IP-10 neutralizing antibody. CONCLUSIONS/SIGNIFICANCE: the rs4804803 SNP in the CD209 promoter contributed to susceptibility to dengue infection and complication of DHF. This SNP with AG genotype affects the cell surface DC-SIGN expression related to immune augmentation and less viral replication. PMID- 21245922 TI - From re-emergence to hyperendemicity: the natural history of the dengue epidemic in Brazil. AB - BACKGROUND: dengue virus (DENV) was reintroduced into Brazil in 1986 and by 1995 it had spread throughout the country. In 2007 the number of dengue hemorrhagic fever (DHF) cases more than doubled and a shift in the age distribution was reported. While previously the majority of DHF cases occurred among adults, in 2007 53% of cases occurred in children under 15 years old. The reasons for this shift have not been determined. METHODS AND FINDINGS: age stratified cross sectional seroepidemiologic survey conducted in Recife, Brazil in 2006. Serostatus was determined by ELISA based detection of Dengue IgG. We estimated time-constant and time-varying forces of infection of DENV between 1986 and 2006. We used discrete-time simulation to estimate the accumulation of monotypic and multitypic immunity over time in a population previously completely susceptible to DENV. We projected the age distribution of population immunity to dengue assuming similar hazards of infection in future years. The overall prevalence of DENV IgG was 0.80 (n = 1427). The time-constant force of infection for the period was estimated to be 0.052 (95% CI 0.041, 0.063), corresponding to 5.2% of susceptible individuals becoming infected each year by each serotype. Simulations show that as time since re-emergence of dengue goes by, multitypic immunity accumulates in adults while an increasing proportion of susceptible individuals and those with monotypic immunity are among young age groups. The median age of those monotypically immune can be expected to shift from 24 years, 10 years after introduction, to 13 years, 50 years after introduction. Of those monotypically immune, the proportion under 15 years old shifts from 27% to 58%. These results are consistent with the dengue notification records from the same region since 1995. INTERPRETATION: assuming that persons who have been monotypically exposed are at highest risk for severe dengue, the shift towards younger patient ages observed in Brazil can be partially explained by the accumulation of multitypic immunity against DENV-1, 2, and 3 in older age groups, 22 years after the re introduction of these viruses. Serotype specific seroepidemiologic studies are necessary to accurately estimate the serotype specific forces of infection. PMID- 21245923 TI - De novo designed proteins from a library of artificial sequences function in Escherichia coli and enable cell growth. AB - A central challenge of synthetic biology is to enable the growth of living systems using parts that are not derived from nature, but designed and synthesized in the laboratory. As an initial step toward achieving this goal, we probed the ability of a collection of >10(6) de novo designed proteins to provide biological functions necessary to sustain cell growth. Our collection of proteins was drawn from a combinatorial library of 102-residue sequences, designed by binary patterning of polar and nonpolar residues to fold into stable 4-helix bundles. We probed the capacity of proteins from this library to function in vivo by testing their abilities to rescue 27 different knockout strains of Escherichia coli, each deleted for a conditionally essential gene. Four different strains- DeltaserB, DeltagltA, DeltailvA, and Deltafes--were rescued by specific sequences from our library. Further experiments demonstrated that a strain simultaneously deleted for all four genes was rescued by co-expression of four novel sequences. Thus, cells deleted for ~0.1% of the E. coli genome (and ~1% of the genes required for growth under nutrient-poor conditions) can be sustained by sequences designed de novo. PMID- 21245924 TI - Comparative production analysis of three phlebovirus nucleoproteins under denaturing or non-denaturing conditions for crystallographic studies. AB - Nucleoproteins (NPs) encapsidate the Phlebovirus genomic (-)RNA. Upon recombinant expression, NPs tend to form heterogeneous oligomers impeding characterization of the encapsidation process through crystallographic studies. To overcome this problem, we set up a standard protocol in which production under both non denaturing and denaturing/refolding conditions can be investigated and compared. The protocol was applied for three phlebovirus NPs, allowing an optimized production strategy for each of them. Remarkably, the Rift Valley fever virus NP was purified as a trimer under native conditions and yielded protein crystals whereas the refolded version could be purified as a dimer. Yields of trimeric Toscana virus NP were higher from denaturing than from native condition and lead to crystals. The production of Sandfly Fever Sicilian virus NP failed in both protocols. The comparative protocols described here should help in rationally choosing between denaturing or non-denaturing conditions, which would finally result in the most appropriate and relevant oligomerized protein species. The structure of the Rift Valley fever virus NP has been recently published using a refolded monomeric protein and we believe that the process we devised will contribute to shed light in the genome encapsidation process, a key stage in the viral life cycle. PMID- 21245925 TI - Ecology and geography of plague transmission areas in northeastern Brazil. AB - Plague in Brazil is poorly known and now rarely seen, so studies of its ecology are difficult. We used ecological niche models of historical (1966-present) records of human plague cases across northeastern Brazil to assess hypotheses regarding environmental correlates of plague occurrences across the region. Results indicate that the apparently focal distribution of plague in northeastern Brazil is indeed discontinuous, and that the causes of the discontinuity are not necessarily only related to elevation-rather, a diversity of environmental dimensions correlate to presence of plague foci in the region. Perhaps most interesting is that suitable areas for plague show marked seasonal variation in photosynthetic mass, with peaks in April and May, suggesting links to particular land cover types. Next steps in this line of research will require more detailed and specific examination of reservoir ecology and natural history. PMID- 21245926 TI - Discovering networks of perturbed biological processes in hepatocyte cultures. AB - The liver plays a vital role in glucose homeostasis, the synthesis of bile acids and the detoxification of foreign substances. Liver culture systems are widely used to test adverse effects of drugs and environmental toxicants. The two most prevalent liver culture systems are hepatocyte monolayers (HMs) and collagen sandwiches (CS). Despite their wide use, comprehensive transcriptional programs and interaction networks in these culture systems have not been systematically investigated. We integrated an existing temporal transcriptional dataset for HM and CS cultures of rat hepatocytes with a functional interaction network of rat genes. We aimed to exploit the functional interactions to identify statistically significant linkages between perturbed biological processes. To this end, we developed a novel approach to compute Contextual Biological Process Linkage Networks (CBPLNs). CBPLNs revealed numerous meaningful connections between different biological processes and gene sets, which we were successful in interpreting within the context of liver metabolism. Multiple phenomena captured by CBPLNs at the process level such as regulation, downstream effects, and feedback loops have well described counterparts at the gene and protein level. CBPLNs reveal high-level linkages between pathways and processes, making the identification of important biological trends more tractable than through interactions between individual genes and molecules alone. Our approach may provide a new route to explore, analyze, and understand cellular responses to internal and external cues within the context of the intricate networks of molecular interactions that control cellular behavior. PMID- 21245927 TI - Rapid recovery of fat mass in small for gestational age preterm infants after term. AB - BACKGROUND: Preterm small for gestational age (SGA) infants may be at risk for increased adiposity, especially when experiencing rapid postnatal weight gain. Data on the dynamic features of body weight and fat mass (FM) gain that occurs early in life is scarce. We investigated the postnatal weight and FM gain during the first five months after term in a cohort of preterm infants. METHODOLOGY/PRINCIPAL FINDINGS: Changes in growth parameters and FM were prospectively monitored in 195 infants with birth weight <=1500 g. The infants were categorized as born adequate for gestational age (AGA) without growth retardation at term (GR-), born AGA with growth retardation at term (GR+), born SGA. Weight and FM were assessed by an air displacement plethysmography system. At five months, weight z-score was comparable between the AGA (GR+) and the AGA (GR-), whereas the SGA showed a significantly lower weight.The mean weight (g) differences (95% CI) between SGA and AGA (GR-) and between SGA and AGA (GR+) infants at 5 months were -613 (-1215; -12) and -573 (-1227; -79), respectively. At term, the AGA (GR+) and the SGA groups showed a significantly lower FM than the AGA (GR-) group. In the first three months, change in FM was comparable between the AGA (GR+) and the SGA groups and significantly higher than that of the AGA (GR-) group.The mean difference (95% CI) in FM change between SGA and AGA (GR-) and between AGA (GR+) and AGA (GR-) from term to 3 months were 38.6 (12; 65); and 37.7 (10; 65). At three months, the FM was similar in all groups. CONCLUSIONS: Our data suggests that fetal growth pattern influences the potential to rapidly correct anthropometry whereas the restoration of fat stores takes place irrespective of birth weight. The metabolic consequences of these findings need to be elucidated. PMID- 21245928 TI - Thermal image scanning for influenza border screening: results of an airport screening study. AB - BACKGROUND: Infrared thermal image scanners (ITIS) appear an attractive option for the mass screening of travellers for influenza, but there are no published data on their performance in airports. METHODS: ITIS was used to measure cutaneous temperature in 1275 airline travellers who had agreed to tympanic temperature measurement and respiratory sampling. The prediction by ITIS of tympanic temperature (37.8 degrees C and 37.5 degrees C) and of influenza infection was assessed using Receiver Operating Characteristic (ROC) curves and estimated sensitivity, specificity and positive predictive value (PPV). FINDINGS: Using front of face ITIS for prediction of tympanic temperature >=37.8 degrees C, the area under the ROC curve was 0.86 (95%CI 0.75-0.97) and setting sensitivity at 86% gave specificity of 71%. The PPV in this population of travellers, of whom 0.5% were febrile using this definition, was 1.5%. We identified influenza virus infection in 30 travellers (3 Type A and 27 Type B). For ITIS prediction of influenza infection the area under the ROC curve was 0.66 (0.56-0.75), a sensitivity of 87% gave specificity of 39%, and PPV of 2.8%. None of the 30 influenza-positive travellers had tympanic temperature >=37.8 degrees C at screening (95%CI 0% to 12%); three had no influenza symptoms. CONCLUSION: ITIS performed moderately well in detecting fever but in this study, during a seasonal epidemic of predominantly influenza type B, the proportion of influenza-infected travellers who were febrile was low and ITIS were not much better than chance at identifying travellers likely to be influenza-infected. Although febrile illness is more common in influenza A infections than influenza B infections, many influenza A infections are afebrile. Our findings therefore suggest that ITIS is unlikely to be effective for entry screening of travellers to detect influenza infection with the intention of preventing entry of the virus into a country. PMID- 21245930 TI - Scalable rules for coherent group motion in a gregarious vertebrate. AB - Individuals of gregarious species that initiate collective movement require mechanisms of cohesion in order to maintain advantages of group living. One fundamental question in the study of collective movement is what individual rules are employed when making movement decisions. Previous studies have revealed that group movements often depend on social interactions among individual members and specifically that collective decisions to move often follow a quorum-like response. However, these studies either did not quantify the response function at the individual scale (but rather tested hypotheses based on group-level behaviours), or they used a single group size and did not demonstrate which social stimuli influence the individual decision-making process. One challenge in the study of collective movement has been to discriminate between a common response to an external stimulus and the synchronization of behaviours resulting from social interactions. Here we discriminate between these two mechanisms by triggering the departure of one trained Merino sheep (Ovis aries) from groups containing one, three, five and seven naive individuals. Each individual was thus exposed to various combinations of already-departed and non-departed individuals, depending on its rank of departure. To investigate which individual mechanisms are involved in maintaining group cohesion under conditions of leadership, we quantified the temporal dynamic of response at the individual scale. We found that individuals' decisions to move do not follow a quorum response but rather follow a rule based on a double mimetic effect: attraction to already-departed individuals and attraction to non-departed individuals. This rule is shown to be in agreement with an adaptive strategy that is inherently scalable as a function of group size. PMID- 21245929 TI - Radiation rescue: mesenchymal stromal cells protect from lethal irradiation. AB - BACKGROUND: Successful treatment of acute radiation syndromes relies on immediate supportive care. In patients with limited hematopoietic recovery potential, hematopoietic stem cell (HSC) transplantation is the only curative treatment option. Because of time consuming donor search and uncertain outcome we propose MSC treatment as an alternative treatment for severely radiation-affected individuals. METHODS AND FINDINGS: Mouse mesenchymal stromal cells (mMSCs) were expanded from bone marrow, retrovirally labeled with eGFP (bulk cultures) and cloned. Bulk and five selected clonal mMSCs populations were characterized in vitro for their multilineage differentiation potential and phenotype showing no contamination with hematopoietic cells. Lethally irradiated recipients were i.v. transplanted with bulk or clonal mMSCs. We found a long-term survival of recipients with fast hematopoietic recovery after the transplantation of MSCs exclusively without support by HSCs. Quantitative PCR based chimerism analysis detected eGFP-positive donor cells in peripheral blood immediately after injection and in lungs within 24 hours. However, no donor cells in any investigated tissue remained long-term. Despite the rapidly disappearing donor cells, microarray and quantitative RT-PCR gene expression analysis in the bone marrow of MSC-transplanted animals displayed enhanced regenerative features characterized by (i) decreased proinflammatory, ECM formation and adhesion properties and (ii) boosted anti-inflammation, detoxification, cell cycle and anti-oxidative stress control as compared to HSC-transplanted animals. CONCLUSIONS: Our data revealed that systemically administered MSCs provoke a protective mechanism counteracting the inflammatory events and also supporting detoxification and stress management after radiation exposure. Further our results suggest that MSCs, their release of trophic factors and their HSC-niche modulating activity rescue endogenous hematopoiesis thereby serving as fast and effective first-line treatment to combat radiation-induced hematopoietic failure. PMID- 21245931 TI - Exopolysaccharide-independent social motility of Myxococcus xanthus. AB - Social motility (S motility), the coordinated movement of large cell groups on agar surfaces, of Myxococcus xanthus requires type IV pili (TFP) and exopolysaccharides (EPS). Previous models proposed that this behavior, which only occurred within cell groups, requires cycles of TFP extension and retraction triggered by the close interaction of TFP with EPS. However, the curious observation that M. xanthus can perform TFP-dependent motility at a single-cell level when placed onto polystyrene surfaces in a highly viscous medium containing 1% methylcellulose indicated that "S motility" is not limited to group movements. In an apparent further challenge of the previous findings for S motility, mutants defective in EPS production were found to perform TFP-dependent motility on polystyrene surface in methylcellulose-containing medium. By exploring the interactions between pilin and surface materials, we found that the binding of TFP onto polystyrene surfaces eliminated the requirement for EPS in EPS(-) cells and thus enabled TFP-dependent motility on a single cell level. However, the presence of a general anchoring surface in a viscous environment could not substitute for the role of cell surface EPS in group movement. Furthermore, EPS was found to serve as a self-produced anchoring substrate that can be shed onto surfaces to enable cells to conduct TFP-dependent motility regardless of surface properties. These results suggested that in certain environments, such as in methylcellulose solution, the cells could bypass the need for EPS to anchor their TPF and conduct single-cell S motility to promote exploratory movement of colonies over new specific surfaces. PMID- 21245932 TI - Ocean acidification at high latitudes: potential effects on functioning of the Antarctic bivalve Laternula elliptica. AB - Ocean acidification is a well recognised threat to marine ecosystems. High latitude regions are predicted to be particularly affected due to cold waters and naturally low carbonate saturation levels. This is of concern for organisms utilising calcium carbonate (CaCO(3)) to generate shells or skeletons. Studies of potential effects of future levels of pCO(2) on high latitude calcifiers are at present limited, and there is little understanding of their potential to acclimate to these changes. We describe a laboratory experiment to compare physiological and metabolic responses of a key benthic bivalve, Laternula elliptica, at pCO(2) levels of their natural environment (430 uatm, pH 7.99; based on field measurements) with those predicted for 2100 (735 uatm, pH 7.78) and glacial levels (187 uatm, pH 8.32). Adult L. elliptica basal metabolism (oxygen consumption rates) and heat shock protein HSP70 gene expression levels increased in response both to lowering and elevation of pH. Expression of chitin synthase (CHS), a key enzyme involved in synthesis of bivalve shells, was significantly up-regulated in individuals at pH 7.78, indicating L. elliptica were working harder to calcify in seawater undersaturated in aragonite (Omega(Ar) = 0.71), the CaCO(3) polymorph of which their shells are comprised. The different response variables were influenced by pH in differing ways, highlighting the importance of assessing a variety of factors to determine the likely impact of pH change. In combination, the results indicate a negative effect of ocean acidification on whole-organism functioning of L. elliptica over relatively short terms (weeks-months) that may be energetically difficult to maintain over longer time periods. Importantly, however, the observed changes in L. elliptica CHS gene expression provides evidence for biological control over the shell formation process, which may enable some degree of adaptation or acclimation to future ocean acidification scenarios. PMID- 21245933 TI - A need for "good eyes": Experiences told by patients diagnosed with psychosis. AB - This study highlights experiences of psychiatric care described by patients diagnosed with psychosis. The aim was to investigate how patients, based on earlier experiences, described their wishes and needs regarding the psychiatric care system. Data comprised material from four focus groups; analysis used an inductive thematic approach. Relationships with staff emerged as a recurring theme. During periods of psychosis, patients needed staff to act as "parental figures," providing care, safety, and help in dealing with overwhelming stimulation from the outside word. In the ensuing struggle to devise a livable life, the need for relationships recurred. In this phase, staff needed to give their time, provide support through information, and mirror the patient's capacity and hope. The patient's trials were described as threatened by a lack of continuity and non-listening professionals. It was important for staff to listen and understand, and to see and respect the patients' viewpoints. PMID- 21245934 TI - The 2008 ERA-EDTA Registry Annual Report-a precis. AB - Background. This study provides a summary of the 2008 ERA-EDTA Registry Report (this report is available at www.era-edta-reg.org).Methods. The data on renal replacement therapy (RRT) were available from 55 national and regional registries in 30 countries in Europe and bordering the Mediterranean Sea. Datasets with individual patient data were received from 36 registries, whereas 19 registries contributed data in aggregated form. We presented incidence and prevalence of RRT, and transplant rates. Survival analysis was solely based on individual patient records.Results. In 2008, the overall incidence rate of RRT for end-stage renal disease (ESRD) among all registries reporting to the ERA-EDTA Registry was 122 per million population (pmp), and the prevalence was 644 pmp. Incidence rates varied from 264 pmp in Turkey to 15 pmp in Ukraine. The mean age of patients starting RRT in 2008 ranged from 69 years in Dutch-speaking Belgium to 44 years in Ukraine. The highest prevalence of RRT for ESRD was reported by Portugal (1408 pmp) and the lowest by Ukraine (89 pmp). The prevalence of haemodialysis on 31 December 2008 ranged from 66 pmp (Ukraine) to 875 pmp (Portugal) and the prevalence of peritoneal dialysis from 8 pmp (Montenegro) to 115 pmp (Denmark). In Norway, 70% of the patients on RRT on 31 December 2008 were living with a functioning graft (572 pmp). In 2008, the number of transplants performed pmp was highest in Spain (Catalonia) (64 pmp), whereas the highest transplant rates with living-donor kidneys were reported from the Netherlands (25 pmp) and Norway (21 pmp). In the cohort 1999-2003, the unadjusted 1-, 2- and 5-year survival of patients on RRT was 80.8% (95% CI: 80.6-81.0), 69.1% (95% CI: 68.9-69.3) and 46.1% (95% CI: 45.9-46.3), respectively. PMID- 21245935 TI - Evaluation of EML4-ALK fusion proteins in non-small cell lung cancer using small molecule inhibitors. AB - The echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion gene resulting from an inversion within chromosome 2p occurs in approximately 5% of non-small cell lung cancer and is mutually exclusive with Ras and EGFR mutations. In this study, we have used a potent and selective ALK small molecule inhibitor, NPV-TAE684, to assess the oncogenic role of EML4-ALK in non small cell lung cancer (NSCLC). We show here that TAE684 inhibits proliferation and induces cell cycle arrest, apoptosis, and tumor regression in two NSCLC models that harbor EML4-ALK fusions. TAE684 inhibits EML4-ALK activation and its downstream signaling including ERK, AKT, and STAT3. We used microarray analysis to carry out targeted pathway studies of gene expression changes in H2228 NSCLC xenograft model after TAE684 treatment and identified a gene signature of EML4 ALK inhibition. The gene signature represents 1210 known human genes, and the top biologic processes represented by these genes are cell cycle, DNA synthesis, cell proliferation, and cell death. We also compared the effect of TAE684 with PF2341066, a c-Met and ALK small molecule inhibitor currently in clinical trial in cancers harboring ALK fusions, and demonstrated that TAE684 is a much more potent inhibitor of EML4-ALK. Our data demonstrate that EML4-ALK plays an important role in the pathogenesis of a subset of NSCLC and provides insight into the mechanism of EML4-ALK inhibition by a small molecule inhibitor. PMID- 21245936 TI - Targeted inhibition of multiple receptor tyrosine kinases in mesothelioma. AB - The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR) and MET are activated in subsets of mesothelioma, suggesting that these kinases might represent novel therapeutic targets in this notoriously chemotherapy-resistant cancer. However, clinical trials have shown little activity for EGFR inhibitors in mesothelioma. Despite the evidence for RTK activation in mesothelioma pathogenesis, it is unclear whether transforming activity is dependent on an individual kinase oncoprotein or the coordinated activity of multiple kinases. Using phospho-RTK and immunoblot assays, we herein demonstrate activation of multiple RTKs (EGFR, MET, AXL, and ERBB3) in individual mesothelioma cell lines but not in normal mesothelioma cells. Inhibition of mesothelioma multi-RTK signaling was accomplished using combinations of RTK direct inhibitors or by inhibition of the RTK chaperone, heat shock protein 90 (HSP90). Multi-RTK inhibition by the HSP90 inhibitor 17-allyloamino-17-demethoxygeldanamycin (17 AAG) had a substantially greater effect on mesothelioma proliferation and survival compared with inhibition of individual activated RTKs. HSP90 inhibition also suppressed phosphorylation of downstream signaling intermediates (AKT, mitogen-activated protein kinase, and S6); upregulated the p53, p21, and p27 cell cycle checkpoints; induced G(2) phase arrest; induced caspase 3/7 activity; and led to an increase in the sub-G(1) apoptotic population. These compelling proapoptotic and antiproliferative responses indicate that HSP90 inhibition warrants clinical evaluation as a novel therapeutic strategy in mesothelioma. PMID- 21245937 TI - Activation of urokinase plasminogen activator and its receptor axis is essential for macrophage infiltration in a prostate cancer mouse model. AB - Macrophages within the tumor microenvironment promote angiogenesis, extracellular matrix breakdown, and tumor cell migration, invasion, and metastasis. Activation of the urokinase plasminogen activator (uPA) and its receptor (uPAR) axis promotes prostate cancer tumorigenicity, invasion, metastasis, and survival within the tumor microenvironment. The link between macrophage infiltration and the uPA/uPAR axis in prostate cancer development has not been established, although it has been reported that uPA plays a critical role inmonocyte and macrophage chemotaxis. In this study, murine prostate cancer RM-1 cells were subcutaneously inoculated into wild-type (WT), uPA(-/-), and uPAR(-/-) mice. Tumor volume was significantly diminished in both uPA(-/-) and uPAR(-/-) mice compared with WT controls. Greater inhibition of tumor volume was also observed in uPA(-/-) mice compared with uPAR(-/-) mice, suggesting the important contribution of stromal-derived uPA to sustain the tumor growth. Immunohistochemical staining revealed that tumors in uPA(-/-) and uPAR(-/-) mice displayed significantly lower proliferative indices, higher apoptotic indices, and less neovascularity compared with the tumors in WT mice. Tumors in uPA(-/-) and uPAR(-/-) mice displayed significantly less macrophage infiltration as demonstrated by F4/80 staining and MAC3(+) cell numbers by flow cytometry compared with the tumors from WT mice. These findings suggest that the uPA/uPAR axis acts in both autocrine and paracrine manners in the tumor microenvironment, and activation of uPA/uPAR axis is essential for macrophage infiltration into prostate tumors. PMID- 21245938 TI - Augmented osteolysis in SPARC-deficient mice with bone-residing prostate cancer. AB - Prostate cancer preferentially metastasizes to bone, which is rich in structural and matricellular proteins capable of altering prostate cancer progression. This study explores the role of the bone stromal matricellular protein SPARC (osteonectin/BM-40) in the progression of bone metastatic prostate cancer. Quantification of bone destruction analyzed by micro-computed tomography showed augmented osteoclastic resorption, characterized by decreases in several morphometric bone parameters in SPARC knock out (KO) tibiae harboring RM1 murine prostate cancer cells compared with wild type (WT) animals. Tumor progression stimulated osteoclast formation, which was augmented in SPARC KO mice. In vitro differentiation of SPARC KO osteoclasts indicated accelerated progenitor expansion and formation of tartrate-resistant acid phosphatase-positive osteoclast-like cells with increased resorptive capacity, a mechanism resulting in enhanced tumor-induced bone loss in vivo. Whereas altered bone structure due to SPARC KO played a role in increased osteolysis, the enhanced osteolysis was primarily the result of increased resorption by SPARC KO osteoclasts. Our findings indicate that bone stromal SPARC suppresses tumor-induced bone lesion expansion by limiting osteoclast maturation and function. PMID- 21245939 TI - Tumors that acquire resistance to low-dose metronomic cyclophosphamide retain sensitivity to maximum tolerated dose cyclophosphamide. AB - Low-dose metronomic (LDM) chemotherapy is emerging as an alternative or supplemental dosing strategy to conventional maximum tolerated dose (MTD) chemotherapy. It is characterized primarily, but not exclusively, by antiangiogenic mechanisms of action and the absence of high-grade adverse effects commonly seen with MTD chemotherapy. However, similar to other anticancer therapies, inherent resistance to LDM chemotherapy is common. Moreover, even tumors that initially respond to metronomic regimens eventually develop resistance through mechanisms that are as yet unknown. Thus, we have developed in vivo models of PC-3 human prostate cancer cells resistant to extended LDM cyclophosphamide therapy. Such PC-3 variants show stable resistance to LDM cyclophosphamide in vivo yet retain in vitro sensitivity to 4-hydroperoxy cyclophosphamide (precursor of the active cyclophosphamide metabolite 4-hydroxy cyclophosphamide) and other chemotherapeutic agents, namely, docetaxel and doxorubicin. Moreover, LDM cyclophosphamide-resistant PC-3 variants remain sensitive to MTD cyclophosphamide therapy in vivo. Conversely, PC-3 variants made resistant in vivo to MTD cyclophosphamide show varying levels of resistance to metronomic cyclophosphamide when grown in mice. These results and additional studies of variants of the breast cancer cell line MDA-MB-231 suggest that resistance to LDM cyclophosphamide is a distinct phenomenon from resistance to MTD cyclophosphamide and that LDM cyclophosphamide administration does not select for MTD chemotherapy resistance. As such, our findings have various implications for the clinical use of metronomic chemotherapy. PMID- 21245940 TI - Pleiotropic stromal effects of vascular endothelial growth factor receptor 2 antibody therapy in renal cell carcinoma models. AB - The benefits of inhibiting vascular endothelial growth factor (VEGF) signaling in cancer patients are predominantly attributed to effects on tumor endothelial cells. Targeting non-endothelial stromal cells to further impact tumor cell growth and survival is being pursued through the inhibition of additional growth factor pathways important for the survival and/or proliferation of these cells. However, recent data suggest that VEGF receptor (VEGFR)-specific inhibitors may target lymphatic vessels and pericytes in addition to blood vessels. Here, in fact, we demonstrate that DC101 (40 mg/kg, thrice a week), an antibody specific to murine VEGFR2, significantly reduces all three of these stromal components in subcutaneous (SKRC-29) and orthotopic (786-O-LP) models of renal cell carcinoma (RCC) established in nu/nu athymic mice. Sunitinib (40 mg/kg, once daily), a receptor tyrosine kinase inhibitor of VEGFR2 and other growth factor receptors, also caused significant loss of tumor blood vessels in RCC models but had weaker effects than DC101 on pericytes and lymphatic vessels. In combination, sunitinib did not significantly add to the effects of DC101 on tumor blood vessels, lymphatic vessels, or pericytes. Nevertheless, sunitinib increased the effect of DC101 on tumor burden in the SKRC-29 model, perhaps related to its broader specificity. Our data have important implications for combination therapy design, supporting the conclusion that targeting VEGFR2 alone in RCC has the potential to have pleiotropic effects on tumor stroma. PMID- 21245942 TI - Temperature independent shear piezoelectric response in relaxor-PbTiO(3) based crystals. AB - The temperature dependence of the shear piezoelectric responses in relaxor PbTiO(3) based perovskite crystals with rhombohedral, orthorhombic, and tetragonal phases were investigated. Based on thermodynamic analysis, high shear piezoelectric coefficients (d(24)) and good thermal stability were predicted in orthorhombic crystals, owing to the "vertical" orthorhombic-rhombohedral phase boundary. By resonance measurements, shear piezoelectric coefficient d(24) was found to be on the order of ~2100 pC/N at room temperature, maintaining same value over the temperature range of -50-100 degrees C. In contrast, the shear piezoelectric coefficients d(15), with values of 3300, 3600, and 2000 pC/N at room temperature for rhombohedral, orthorhombic, and tetragonal crystals, respectively, exhibited strong temperature dependent behavior due to their respective ferroelectric-ferroelectric phase transitions. PMID- 21245941 TI - On-target inhibition of tumor fermentative glycolysis as visualized by hyperpolarized pyruvate. AB - Many cancer cells display the Warburg effect, that is, enhanced glycolysis followed by fermentation (conversion of pyruvate to lactate). Recently, the molecular basis for these effects has started to be elucidated, and the up regulation of the lactate dehydrogenase A (LDH-A) isoform of lactate dehydrogenase is felt to be a major molecular mediator of this phenomenon. Moreover, LDH-A expression in tumor tissue and LDH-A levels in blood portend a bad prognosis, and LDH-A blockade can lead to tumor growth inhibition in tumor transplant models. We have extended existing data (some of which were published during the time when we were carrying out our studies) in two important ways: 1) inhibition of LDH-A in a glycolytic lung cancer cell line results in reactive oxygen species-mediated apoptosis and increased sensitivity to the chemotherapeutic drug paclitaxel and 2) inhibition of fermentative glycolysis can also be accomplished by activation of the pyruvate dehydrogenase complex by the drug dichloroacetate, now undergoing clinical trials, and that this phenomenon can be monitored in vivo in a noninvasive real-time manner through magnetic resonance spectroscopy using hyperpolarized pyruvate. Collectively, these data suggest that in vivo effects of drugs that redirect the fate of pyruvate, and hence are aimed at reversing the Warburg effect, could be monitored through the use of hyperpolarized magnetic resonance spectroscopy, a method that is scalable to human use. PMID- 21245943 TI - Quantitative analyses of oxidation states for cubic SrMnO(3) and orthorhombic SrMnO(2.5) with electron energy loss spectroscopy. AB - The oxidation state of Mn in cubic SrMnO(3) and orthorhombic SrMnO(2.5) was investigated by electron energy loss (EEL) spectroscopy. Change in the oxidation state of Mn produced some spectral changes in the O-K edge as well as in the Mn L(2,3) edge EEL spectra. This study demonstrated that the oxidation state of Mn and the amount of oxygen vacancies in cubic SrMnO(3) and orthorhombic SrMnO(2.5) could be quantified by analyzing the features of the O-K edge spectrum and the Mn L(3)/L(2) ratio in the Mn-L(2,3) edge spectrum. Our quantitative analysis showed that the spectral changes in the Mn-L(2,3) edge were mainly caused by the oxidation state of Mn, whereas those in the O-K edge could be sensitive to both the oxidation state of Mn and to lattice distortions. PMID- 21245944 TI - A giant, complex fronto-ethmoidal ivory osteoma: Surgical technique in a resource limited practice. AB - BACKGROUND: Unlike small and medium size fronto-ethmoidal osteomas which are amenable to surgical excision through limited craniofacial openings, giant lesions require extensive and complex craniofacial dissection, and post lesionectomy reconstruction using an array of modern-day surgical adjuncts. This is a report of our surgical technique for the successful and esthetically fair operative resection of a giant fronto-ethmoidal osteoma in a difficult practice setting. CASE DESCRIPTION: A 32-year-old Nigerian lady harbored a giant complex fronto-ethmoidal ivory osteoma. Deploying our understanding of modern-day advanced microsurgical anatomy and technique of skull base surgery, but under severe resource limitations, a radical total surgical resection was performed and an esthetically fair post lesionectomy reconstruction was achieved. The patient remains tumor-free in 20 months, so far, of postoperative follow-up. CONCLUSIONS: Even under severe resource limitations, inventive adaptations of modern-day skull base surgery techniques can facilitate hitherto unusual functional and esthetically successful resection of giant osteomas of the fronto-ethmoidal sinus complex. PMID- 21245945 TI - A pregnant female with a large intracranial mass: Reviewing the evidence to obtain management guidelines for intracranial meningiomas during pregnancy. AB - INTRODUCTION: Non-obstetric surgery for intracranial meningioma is uncommon during pregnancy and poses significant risks to both the mother and the fetus. We present a case of a parturient that presented with acute mental status changes and we illustrate the decision making process that resulted in a best-possible outcome. CASE DESCRIPTION: A woman at 29-week gestation presented with acute language and speech deficits and deteriorating mental status after 2 weeks of headache. Imaging demonstrated a large intracranial mass. A multidisciplinary meeting was held to determine the best treatment plan. The decision was to proceed with caesarean delivery under epidural anesthesia to allow intraoperative monitoring of neurological function. Six hours after successful delivery, the patient had acute mental status changes and she was taken to the operating room immediately for resection of her tumor, which turned out to be a clear cell meningioma. DISCUSSION: Cerebral meningioma is usually a slow-growing tumor; however, during pregnancy, the mass may expand rapidly due to hormonal receptor expression. The presentation of this patient would have normally led to urgent resection of the mass. But the complicating factor was her 29-week pregnancy as standard intraoperative treatment during neurosurgery is known to adversely affect the fetus. A multidisciplinary meeting was critical for this patient's care, and is recommended by us when treating such patients. PMID- 21245946 TI - Identifying a Transcription Factor's Regulatory Targets from its Binding Targets. AB - ChIP-chip data, which shows binding of transcription factors (TFs) to promoter regions in vivo, are widely used by biologists to identify the regulatory targets of TFs. However, the binding of a TF to a gene does not necessarily imply regulation. Thus, it is important to develop computational methods which can extract a TF's regulatory targets from its binding targets. We developed a method, called REgulatory Targets Extraction Algorithm (RETEA), which uses partial correlation analysis on gene expression data to extract a TF's regulatory targets from its binding targets inferred from ChIP-chip data. We applied RETEA to yeast cell cycle microarray data and identified the plausible regulatory targets of eleven known cell cycle TFs. We validated our predictions by checking the enrichments for cell cycle-regulated genes, common cellular processes and common molecular functions. Finally, we showed that RETEA performs better than three published methods (MA-Network, TRIA and Garten et al's method). PMID- 21245947 TI - Molecular Cloning of the Genes Encoding the PR55/Bbeta/delta Regulatory Subunits for PP-2A and Analysis of Their Functions in Regulating Development of Goldfish, Carassius auratus. AB - The protein phosphatase-2A (PP-2A), one of the major phosphatases in eukaryotes, is a heterotrimer, consisting of a scaffold A subunit, a catalytic C subunit and a regulatory B subunit. Previous studies have shown that besides regulating specific PP-2A activity, various B subunits encoded by more than 16 different genes, may have other functions. To explore the possible roles of the regulatory subunits of PP-2A in vertebrate development, we have cloned the PR55/B family regulatory subunits: beta and delta, analyzed their tissue specific and developmental expression patterns in Goldfish ( Carassius auratus). Our results revealed that the full-length cDNA for PR55/Bbeta consists of 1940 bp with an open reading frame of 1332 nucleotides coding for a deduced protein of 443 amino acids. The full length PR55/Bdelta cDNA is 2163 bp containing an open reading frame of 1347 nucleotides encoding a deduced protein of 448 amino acids. The two isoforms of PR55/B display high levels of sequence identity with their counterparts in other species. The PR55/Bbeta mRNA and protein are detected in brain and heart. In contrast, the PR55/Bdelta is expressed in all 9 tissues examined at both mRNA and protein levels. During development of goldfish, the mRNAs for PR55/Bbeta and PR55/Bdelta show distinct patterns. At the protein level, PR55/Bdelta is expressed at all developmental stages examined, suggesting its important role in regulating goldfish development. Expression of the PR55/Bdelta anti-sense RNA leads to significant downregulation of PR55/Bdelta proteins and caused severe abnormality in goldfish trunk and eye development. Together, our results suggested that PR55/Bdelta plays an important role in governing normal trunk and eye formation during goldfish development. PMID- 21245948 TI - Identification of predictive pathways for non-hodgkin lymphoma prognosis. AB - Despite decades of intensive research, NHL (non-Hodgkin lymphoma) still remains poorly understood and is largely incurable. Recent molecular studies suggest that genomic variants measured with SNPs (single nucleotide polymorphisms) in genes may have additional predictive power for NHL prognosis beyond clinical risk factors. We analyzed a genetic association study. The prognostic cohort consisted of 346 patients, among whom 138 had DLBCL (diffuse large B-cell lymphoma) and 101 had FL ( follicular lymphoma). For DLBCL, we analyzed 1229 SNPs which represented 122 KEGG pathways. For FL, we analyzed 1228 SNPs which represented 122 KEGG pathways. Unlike in existing studies, we targeted at identifying pathways with significant additional predictive power beyond clinical factors. In addition, we accounted for the joint effects of multiple SNPs within pathways, whereas some existing studies drew pathway-level conclusions based on separate analysis of individual SNPs. For DLBCL, we identified four pathways, which, combined with the clinical factors, had medians of the prediction logrank statistics as 2.535, 2.220, 2.094, 2.453, and 2.512, respectively. As a comparison, the clinical factors had a median of the prediction logrank statistics around 0.552. For FL, we identified two pathways, which, combined with the clinical factors, had medians of the prediction logrank statistics as 4.320 and 3.532, respectively. As a comparison, the clinical factors had a median of the prediction logrank statistics around 1.212. For NHL overall, we identified three pathways, which, combined with the clinical factors, had medians of the prediction logrank statistics as 5.722, 5.314, and 5.441, respective. As a comparison, the clinical factors had a median of the prediction logrank statistics around 4.411. The identified pathways have sound biological bases. In addition, they are different from those identified using existing approaches. They may provide further insights into the biological mechanisms underlying the prognosis of NHL. PMID- 21245949 TI - Effects of rat anti-VEGF antibody in a rat model of corneal graft rejection by topical and subconjunctival routes. AB - PURPOSE: To compare the effect of a rat anti-VEGF antibody, administered either by topical or subconjunctival (SC) routes, on a rat model of corneal transplant rejection. METHODS: Twenty-four rats underwent corneal transplantation and were randomized into four treatment groups (n=6 in each group). G1 and G2 received six SC injections (0.02 ml 10 ug/ml) of denatured (G1) or active (G2) anti-VEGF from Day 0 to Day 21 every third day. G3 and G4 were instilled three times a day with denatured (G3) or active (G4) anti-VEGF drops (10 ug/ml) from Day 0 to Day 21. Corneal mean clinical scores (MCSs) of edema (E), transparency (T), and neovessels (nv) were recorded at Days 3, 9, 15, and 21. Quantification of neovessels was performed after lectin staining of vessels on flat mounted corneas. RESULTS: Twenty-one days after surgery, MCSs differed significantly between G1 and G2, but not between G3 and G4, and the rejection rate was significantly reduced in rats receiving active antibodies regardless of the route of administration (G2=50%, G4=66.65% versus G1 and G3=100%; p<0.05). The mean surfaces of neovessels were significantly reduced in groups treated with active anti-VEGF (G2, G4). However, anti-VEGF therapy did not completely suppress corneal neovessels. CONCLUSIONS: Specific rat anti-VEGF antibodies significantly reduced neovascularization and subsequent corneal graft rejection. The SC administration of the anti-VEGF antibody was more effective than topical instillation. PMID- 21245950 TI - Light-induced retinal ganglion cell damage in vivo involves Dexras1. AB - PURPOSE: Light-induced retinal degeneration is a vision-threatening retinal disease. Light can damage not only photoreceptor cells but also retinal ganglion cells (RGCs). This study was aimed to observe the spatiotemporal expression of dexamethasone-induced Ras protein 1 (Dexras1) and document the effect of Dexras1 on RGC damage after light exposure. METHODS: Adult Sprague-Dawley rats were exposed to bright white light for 2 h. Reverse transcriptase-PCR (RT-PCR) and western blot analysis were used to analyze mRNA and protein expression of Dexras1. The spatial distribution of Dexras1 and outer nuclear layer (ONL) thickness were evaluated by immunohistochemistry. Immunofluorescence was performed to observe the colocalization of Dexras1. In addition, cell apoptosis in this model was measured using terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL). Finally, the effect of systemic administration of nitric oxide synthase (NOS) inhibitor on the retina was investigated by western blot analysis and immunofluorescence. RESULTS: Dexras1 expression increased at 6 h and reached the peak at 1 day, gradually recovering to the baseline level at 7 days after light exposure. Dexras1 immunoreactivity was detected in RGCs and colabeled with cleaved caspase-3 after light exposure, whereas cleaved caspase-3 immunoreactivity was undetectable in the ONL. However, immunohistochemistry demonstrated that the ONL thickness decreased after light exposure and TUNEL revealed that photoreceptor cell apoptosis also occurred. In addition, the ternary complex of Dexras1, neuronal NOS (nNOS), and the C-terminal PSD95/DLG/ZO-1 ligand of nNOS was observed in RGCs. Administration of NOS inhibitor decreased the expression of cleaved caspase 3 and Dexras1. CONCLUSIONS: Exposure to light caused the transient high expression of Dexras1, which was colabeled with apoptotic marker, nNOS, and the C terminal PSD95/DLG/ZO-1 ligand of nNOS in RGCs. Administration of the NOS inhibitor prevented RGC apoptosis by decreasing cleaved caspase-3 and Dexras1 expression. Dexras1-mediated RGC damage appears to act through activation of nNOS in this model. PMID- 21245951 TI - Gene expression profiling of connective tissue growth factor (CTGF) stimulated primary human tenon fibroblasts reveals an inflammatory and wound healing response in vitro. AB - PURPOSE: The biologic relevance of human connective tissue growth factor (hCTGF) for primary human tenon fibroblasts (HTFs) was investigated by RNA expression profiling using affymetrix(TM) oligonucleotide array technology to identify genes that are regulated by hCTGF. METHODS: Recombinant hCTGF was expressed in HEK293T cells and purified by affinity and gel chromatography. Specificity and biologic activity of hCTGF was confirmed by biosensor interaction analysis and proliferation assays. For RNA expression profiling HTFs were stimulated with hCTGF for 48h and analyzed using affymetrix(TM) oligonucleotide array technology. Results were validated by real time RT-PCR. RESULTS: hCTGF induces various groups of genes responsible for a wound healing and inflammatory response in HTFs. A new subset of CTGF inducible inflammatory genes was discovered (e.g., chemokine [C-X C motif] ligand 1 [CXCL1], chemokine [C-X-C motif] ligand 6 [CXCL6], interleukin 6 [IL6], and interleukin 8 [IL8]). We also identified genes that can transmit the known biologic functions initiated by CTGF such as proliferation and extracellular matrix remodelling. Of special interest is a group of genes, e.g., osteoglycin (OGN) and osteomodulin (OMD), which are known to play a key role in osteoblast biology. CONCLUSIONS: This study specifies the important role of hCTGF for primary tenon fibroblast function. The RNA expression profile yields new insights into the relevance of hCTGF in influencing biologic processes like wound healing, inflammation, proliferation, and extracellular matrix remodelling in vitro via transcriptional regulation of specific genes. The results suggest that CTGF potentially acts as a modulating factor in inflammatory and wound healing response in fibroblasts of the human eye. PMID- 21245952 TI - Molecular mechanism of ocular surface damage: application to an in vitro dry eye model on human corneal epithelium. AB - PURPOSE: The present study was concerned with the development of a new experimental model of dry eye using human reconstructed in vitro corneal epithelium (HCE). The model is based on the use of adapted culture conditions that induce relevant modifications at the cellular and molecular level thus mimicking dry eye. METHODS: The HCE model was maintained in a controlled environmental setting (relative humidity <40% and 40 degrees C temperature) for 24 h and up to 72 h to induce dry eye. The evolution of the dry eye condition was assessed by histology, immunohistochemistry staining, scanning electron microscopy, and gene expression by using TaqMan gene assay technology (mucin-4 [MUC4], matrix metallopeptidase-9 [MMP9], tumor necrosis factor-alpha [TNF alpha], and defensin beta-2 [DEFB2). The effects of different commercially available tear substitutes on the induced dry eye condition were tested. RESULTS: This in vitro dry eye HCE model, that was well established within 24 h, has the characteristic features of a dry eye epithelium and could be satisfactorily used for preliminary assessment of the protective activity of some artificial tears. The transcriptional study of selected biomarkers showed an increase in MUC4, MMP9, TNF-alpha, and hBD-2 (DEFB2) gene expression. CONCLUSIONS: By using a dynamic approach, we were able to define a biomarker gene signature of dry eye induced effects that could be predictive of corneal damage in vivo and to discriminate the efficacy among different commercial artificial tears. PMID- 21245953 TI - Association of genetic polymorphisms of eNOS with glaucoma. AB - PURPOSE: Several studies suggest that vascular dysregulation play a role in the etiology of glaucoma. In the present study, we aimed to investigate the association of endothelial nitric oxide synthase (eNOS) gene polymorphisms with primary open angle glaucoma (POAG) and primary closed angle glaucoma (PCAG). METHODS: There were 102 POAG and 88 PCAG patients, diagnosed on the basis of clinical history, raised intraocular pressure (IOP), cup-to-disc ratio (CDR) and visual field defects, and 120 age- and sex-matched control subjects genotyped for 5 tagging single nucleotide polymorphisms (SNPs; rs743507, rs3793342, rs11771443, rs7830, and rs3918188) of the human eNOS gene. RESULTS: rs3793342, rs743507, rs11771443, rs7830, and rs3918188 were not found to be associated with POAG or with PCAG. In the haplotype-based case-control analysis, the frequency of the C-T haplotype established by rs3793342 and rs11771443 was significantly higher for POAG patients than for control subjects (p<0.001, OR=5.111, 95%CI=1.766~14.788). CONCLUSIONS: The C-T haplotype established by rs3793342 and rs11771443 may be genetic marks of POAG in the Han Chinese population. PMID- 21245954 TI - Polymorphisms in two DNA repair genes (XPD and XRCC1)--association with age related cataracts. AB - PURPOSE: Age related cataract is the leading cause of blindness in the world today. The association between DNA damage to the lens epithelium and the development of lens opacities has been reported in many studies. Polymorphisms of DNA repair enzymes may affect repair efficiency and thereby lead to the development of age related cataract. METHODS: In this study, we aimed to determine the frequency of polymorphisms in two DNA repair enzyme genes, xeroderma pigmentosum complementation group (XPD) codon 312 and X-ray complementing group1 (XRCC1) codon 399, in a sample of 208 cataract patients (69 with cortical, 69 with nuclear and 70 with posterior sub capsular) and 151 sex and age matched healthy controls. XPD genotype was determined by Amplification Refractory Mutation System (ARMS) while XRCC1 was genotyped using the PCR-RFLP method. RESULTS: There was a significant difference between frequencies for XPD 312 Asn/Asn genotype in cataract patients (21.6%) and healthy controls (13.2%; p=0.03, OR=1.97, 95% CI=1.06-3.63). Considering the types of cataract, XPD-312 Asn/Asn genotype was found to be significantly different in patients with cortical (29%) type in comparison to controls (13.2%; p=0.03, OR=2.39, 95% CI=1.11-5.12). No statistically significant difference was found for the genotypic and allelic distributions of the polymorphism in XRCC1. The MDR interaction analysis revealed weak synergism between the markers XPD-Asp312Asn and XRCC1-Arg399Gln contributing to cataract. It also showed that the AA genotype of XPD-Asp312Asn polymorphism when present in combination with the GA genotype of XRCC1-Arg399Gln had a fivefold and with AA had a fourfold risk for developing cataract. CONCLUSIONS: The present study suggests that a polymorphism in XPD codon 312 may be associated with the development of maturity onset cataract. This is the first report on the association of XPD Asp312Asn polymorphism with maturity onset cataract. PMID- 21245956 TI - A novel mutation in MIP associated with congenital nuclear cataract in a Chinese family. AB - PURPOSE: To identify the underlying genetic defect in a Chinese family affected with autosomal dominant congenital nuclear cataract. METHODS: A four-generation Chinese family with inherited nuclear cataract phenotype was recruited. Detailed family history and clinical data were recorded. All reported nuclear cataract related candidate genes were screened for causative mutations by direct DNA sequencing. Effects of amino acid changes on the structure and function of protein were predicted by bioinformatics analysis. RESULTS: All affected individuals in this family showed nuclear cataracts. Sequencing of the candidate genes revealed a heterozygous c.559C>T change in the coding region of the major intrinsic protein (MIP), which caused a substitution of highly conserved arginine by cysteine at codon 187 (p.R187C). This mutation co-segregated with all affected individuals and was not observed in unaffected family members or 110 ethnically matched controls. Bioinformatics analysis showed that the mutation was predicted to affect the function and secondary structure of MIP protein. CONCLUSIONS: This study identified a novel disease-causing mutation p.R187C in MIP in a Chinese cataract family, expanding the mutation spectrum of MIP causing congenital cataract. PMID- 21245955 TI - Inhibition of glucocorticoid-induced alteration of vimentin by a glucocorticoid receptor antagonist RU486 in the organ-cultured rat lens. AB - PURPOSE: Long-term application of glucocorticoids as a treatment for conditions such as allergy, autoimmune diseases, and transplantation presents a high risk of development of steroid-induced cataract. The presence of a functional glucocorticoid receptor (GR) in human and rat lens epithelial cells suggests a direct and specific targeting of these lens cells by glucocorticoids. One important cytoskeletal protein in lens epithelial cells is vimentin, which plays an important role in maintaining the normal lens morphology and function. Previous studies have shown that vimentin is involved in signal transduction, changes in cell structure and differentiation, and apoptosis. Based on a model of steroid-induced cataract from our previous study, the present study focuses on whether changes in vimentin can be induced in vitro through specific GR activation in glucocorticoid-induced cataracts of the rat lens. METHODS: Clear rat lenses, cultured in vitro, were treated with or without dexamethasone (Dex) or RU486 (a glucocorticoid receptor antagonist). Lenses were cultured for 7 days at 37 degrees C under 5% CO2, and were observed daily with an inverted microscope. Changes in morphology were followed by Hematoxylin-eosin (HE) staining, transmission electron microscopy, and immunohistochemistry. The expression of vimentin mRNA and protein was examined by reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis, respectively, in the capsule-epithelium and fiber tissue of the lenses. RESULTS: Opacity was obviously present at day 7 in the Dex group. The lenses of the untreated group and the RU486+Dex group remained transparent throughout the incubation. Electron microscopy showed an orderly arrangement of fiber cells and normal cell junctions in the control group and the RU486+Dex group. However, in the Dex group, fiber cells were disarranged and the cell-cell junctions exhibited lacunae. The expression of vimentin protein in the lens capsule-epithelium and fiber tissue decreased in the Dex-treated group, but normal expression of vimentin mRNA was maintained. CONCLUSIONS: These results suggest that the GR-mediated reduction in vimentin may be involved in the formation of steroid-induced cataract. PMID- 21245957 TI - Oxidative DNA damage and total antioxidant status in glaucoma patients. AB - PURPOSE: To evaluate DNA damage markers and the antioxidant status of serum and aqueous humor in glaucoma patients. METHODS: Aqueous humor and serum samples were obtained at the time of surgery from 28 patients with glaucoma and 27 patients with cataracts. Total antioxidant status (TAS) and 8-hydroxy-2'-deoxyguanosine (8 OHdG) levels of all samples were determined by spectrophotometric and enzyme linked immunosorbent assay methods. RESULTS: Aqueous levels of 8-OHdG were higher in glaucoma patients than in the cataract group (4.61+/-2.97 ng/ml versus 1.98+/ 0.70 ng/ml, p=0.002). Serum levels of 8-OHdG were also higher in glaucoma patients than in the cataract group (17.80+/-8.06 ng/ml versus 13.63+/-3.54 ng/ml, p=0.046). The TAS levels of serum (0.55+/-0.13 mmol/lit versus 0.70+/ 0.14, p=0.001), and aqueous humor (0.23+/-0.13 mmol/lit versus 0.34+/-0.15, p=0.001) in glaucoma patients were lower than in cataract patients. CONCLUSIONS: Our findings provide evidence that oxidative DNA damage increases and TAS decreases in the serum and aqueous humor of glaucoma patients. These findings support the hypothesis that the formation of reactive oxygen species and/or a decrease in TAS may have an important role in the pathogenesis of glaucoma. PMID- 21245958 TI - Tear levels of neuropeptides increase after specific allergen challenge in allergic conjunctivitis. AB - PURPOSE: Growing evidence is showing a role of neurogenic inflammation in allergic reactions, with sensory and autonomic nerve fibers releasing neuromediators, which may actively participate in the allergic inflammatory cascade. Although the cornea is the most densely innervated tissue of the human body, little is known on the role of neuromediators at the ocular surface. In this study, we aimed at evaluating the role of substance P (SP), calcitonine gene related peptide (CGRP), neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP) in allergic reactions of the ocular surface. METHODS: Fifteen patients with allergic conjunctivitis (6 female, 9 male, mean age 30+/-8 years) in non-active phase, and 10 age-matched healthy subjects were included in this study. The conjunctival provocation test (CPT) with allergen was performed in all allergic patients and in 5 healthy subjects. Tear samples were collected and the tear content of VIP, NPY, CGRP, and SP was measured by ELISA at baseline and after CPT. The Mann-Whitney U-test and Wilcoxon test were used to compare neuromediator tear levels. RESULTS: No significant differences in neuropeptide tear levels were observed between healthy and allergic patients in non-active phase. CPT induced conjunctival hyperemia and itching in all allergic patients, while no reaction was observed in the control eyes and in healthy subjects. In allergic patients SP, CGRP, and VIP, but not NPY, were significantly higher after CPT as compared to baseline (SP: 3.9+/-1.3 ng/ml versus 5.8+/-1.1 ng/ml, p=0.011; CGRP: 5.5+/-2.3 ng/ml versus 7.3+/-2.7 ng/ml; p=0.002; VIP: 4+/-0.9 ng/ml versus 5.1+/-1.5 ng/ml, p=0.007). No significant changes were observed in the control eyes of allergic patients challenged with diluent and in healthy subjects after allergen provocation. CONCLUSIONS: Locally-released neuromediators may participate in modulating the allergic response of the ocular surface. PMID- 21245959 TI - SU5416 induces premature senescence in endothelial progenitor cells from patients with age-related macular degeneration. AB - PURPOSE: We recently demonstrated increased frequency and growth potential of late outgrowth endothelial progenitor cells (OECs) in patients with neovascular age-related macular degeneration (nvAMD). This study investigated the effects of short- and long-term in vitro inhibition of vascular endothelial growth factor (VEGF) Receptor-2 (VEGFR-2) signaling by SU5416 and other inhibitors of the VEGF signaling pathway in OECs. METHODS: OECs, from the peripheral blood of patients with nvAMD, and human umbilical vein endothelial cells were grown in the presence of SU5416, other VEGFR-2 tyrosine kinase inhibitors (TKIs), and inhibitors of phosphatidylinositol 3'-Kinase (PI3K)/protein kinase B (Akt) and protein kinase C (PKC) in complete angiogenic medium. Apotosis was assessed after 48 h using the fluorescein isothiocyanate Annexin V method. Cell counts were performed for 10 days, and features of senescence were analyzed using senescence-associated beta galactosidase staining, the telomeric repeat amplification protocol for telomerase activity, Southern blot analysis for mean telomere length, flow cytometric analysis for cell-cycle arrest, and western blot for p53 and p21. Control OECs, cells treated for 7 days with inhibitors, as well as naturally senescent OECs were analyzed for expression of different endothelial antigens, including VEGFR-2 and the receptor for stromal cell-derived factor 1, chemokine receptor 4 (CXCR-4). Migration in vitro to VEGF and stromal cell-derived factor 1 of OECs was assessed. RESULTS: SU5416, other VEGFR-2 TKIs, and inhibitors of PI3K, Akt, and PKC induced apoptosis, inhibited long-term proliferation, reduced telomerase activity, and induced premature senescence and cell-cycle arrest in OECs as well as in human umbilical vein endothelial cells. Naturally senescent cells and cells rendered senescent by VEGFR-2 TKIs had reduced VEGFR-2 and CXCR-4 expression and demonstrated reduced migratory ability to VEGF. CONCLUSIONS: This study demonstrates apoptosis upon short-term inhibition and inhibition of long term survival of OECs from patients with nvAMD by SU5416, presumably via PI3K/Akt and/or PKC-mediated reduction in telomerase activity and subsequent induction of premature senescence, which is accompanied by impaired endothelial activity. Therefore, induction of premature senescence in endothelial cells may represent a potential therapeutic target in nvAMD. PMID- 21245960 TI - Functional characterization of 58-kilodalton inhibitor of protein kinase in protecting against diabetic retinopathy via the endoplasmic reticulum stress pathway. AB - OBJECTIVE: 58-kilodalton inhibitor of protein kinase (P58(IPK)) plays an important role in preventing endoplasmic reticulum (ER) stress. It is an interferon-induced kinase that targets the eukaryotic translation initiation factor eukaryotic initiation factor 2 alpha. The aim of this study was to determine the roles of P58(IPK) in protecting against diabetic retinopathy (DR) by inhibiting ER stress-signaling mediators. METHODS: A rat diabetic model was established by intraperitoneal injection of streptozotocin. Overexpression of P58(IPK) was achieved by intravitreal injection of purified recombinant adeno associated virus vector (rAAV2)-P58(IPK) or transfection into rat retinal capillary endothelial cells. Retinal vascular permeability was determined by assessing the Evans Blue retinal leakage. To downregulate the P58(IPK) level in cultured rat retinal capillary endothelial cells, pGIPZ-P58(IPK) RNA interference (P58(IPK)RNAi) was introduced in these cells. Real time reverse transcription (RT)-PCR and western blot analyses were performed to evaluate the mRNA and protein levels of Core/emopamil binding protein (C/EBP) homologous protein (CHOP), vascular endothelial growth factor (VEGF), and tumor necrosis factor alpha (TNF-alpha). RESULTS: Retinal blood vessel leakage was significantly decreased in rAAV2-P58(IPK)-transfected diabetic rats compared with the control diabetic rats. Both mRNA and protein levels of CHOP, TNF-alpha, and VEGF in the retina of diabetic rats were remarkably reduced in P58(IPK)-transfected rats. In vitro study further demonstrated that overexpression of P58(IPK) downregulated the expression of CHOP, TNF-alpha, and VEGF under high glucose conditions, whereas introduction of P58(IPK)RNAi enhanced the expression of CHOP, TNF-alpha, and VEGF. CONCLUSIONS: These results revealed the protecting role of P58(IPK) against ER stress-mediated DR in diabetic rats, suggesting that P58(IPK) may act as a DR-resistant gene during diabetes. PMID- 21245961 TI - Characterization of a novel mutation in the CRYBB2 gene associated with autosomal dominant congenital posterior subcapsular cataract in a Chinese family. AB - PURPOSE: To identify the underlying genetic defect in four generations of a Chinese family affected with bilateral congenital posterior subcapsular cataracts. METHODS: Clinical data from patients in the family were recorded by slit-lamp photography. Genomic DNA samples were extracted from peripheral blood of the pedigree members. Mutation screening was performed in the candidate gene by bidirectional sequencing of the amplified products. The mutation was verified by restriction fragment length polymorphism (RFLP) analysis. RESULTS: The congenital cataract phenotype of the pedigree was identified as posterior subcapsular by slit-lamp photography. Sequencing of the candidate genes detected a heterozygous c.5C->T change in the coding region of the betaB2-crystallin gene (CRYBB2), resulting in the substitution of a highly conserved alanine to valine (p. A2V). All nine family members affected with cataracts were positive for this change, but it was not observed in any of the unaffected members of the family. The transition resulted in the loss of a HaeIII restriction site in the affected members of the pedigree, which was present in the unaffected family members and in all of the 100 unrelated individuals tested. CONCLUSIONS: This study has identified a novel CRYBB2 gene mutation, resulting in the amino substitution p. A2V in a Chinese family with posterior subcapsular congenital cataracts. This mutation is probably the causative lesion for the observed phenotype in this family. PMID- 21245962 TI - The effect of Helicobacter pylori treatment on remission of idiopathic central serous chorioretinopathy. AB - PURPOSE: The aim of this study was to evaluate the effect of Helicobacter pylori (H. pylori) treatment on remission of idiopathic central serous chorioretinopathy. METHODS: Twenty-five patients with idiopathic central serous chorioretinopathy (ICSCR) who were infected with H. pylori were treated with an anti-H. pylori treatment; another twenty-five patients with the same clinical presentations served as the control. Baseline examination and follow up visits at 2, 4, 6, 8, 12, and 16 weeks after the onset of treatment included visual acuity testing and subretinal fluid measurement. The difference between mean visual acuity at the end of 16 weeks and the time of subretinal fluid reabsorption was compared between the two groups. RESULTS: Subretinal fluid reabsorption time was 9.28+/-3.20 weeks in the treatment group and 11.63+/-3.18 weeks in the control group, which was statistically significant (p=0.015). After 16 weeks, mean visual acuity improved to 0.003+/-0.01 (logMAR) in the treatment group and 0.004+/-0.02 (logMAR) in the control group. This improvement did not represent a statistically significant difference (p=0.97). CONCLUSIONS: An anti-H. pylori treatment regimen is effective in the treatment of idiopathic central serous chorioretinopathy patients and anti-H. pylori treatment can provoke the faster reabsorption of subretinal fluid. PMID- 21245965 TI - Cross-Sectional Guidelines: Cutting Edge in Scientific Evidence and Practical Guidance. PMID- 21245963 TI - Ultraviolet B-induced expression of amphiregulin and growth differentiation factor 15 in human lens epithelial cells. AB - PURPOSE: Epidemiological and experimental studies have revealed that exposure to ultraviolet B (UVB) light can induce cataractogenesis. The objective of this study was to determine gene expression changes in human lens epithelial cells in response to UVB exposure and identify factors that can be involved in UVB-induced cataractogenesis. METHODS: SV40 T-antigen-transformed human lens epithelial cells (SRA01/04) were irradiated at various UVB-energy levels (10-80 mJ/cm2) and checked for viability. An irradiation condition of 30 mJ/cm2 was adopted for transcriptome analysis. Total RNAs isolated from UVB-exposed and unexposed cells at 12 h and 24 h after UVB exposure were examined for global gene expression changes using Affymetrix Human Gene 1.0 ST array. mRNA levels of specific genes were examined by RT-PCR and real-time PCR, and protein levels in the conditioned media were assayed by ELISA. To examine mRNA expression in human lens, primary cultured human lens epithelial (HLE) cells were prepared from surgically removed lens epithelium, and used for UVB-irradiation and expression analysis. Effects of certain gene products on SRA01/04 cell metabolism were examined using commercially available recombinant proteins. RESULTS: Expression of most the genes analyzed was essentially unchanged (between 0.5 and 2.0 fold) in UVB irradiated cells compared to non-irradiated cells at both 12 and 24 h after UVB exposure. Sixty one and 44 genes were upregulated more than twofold by UVB exposure at 12 h and 24 h, respectively. Emphasis was placed on genes encoding extracellular proteins, especially growth factors and cytokines. A total of 18 secreted protein genes were upregulated more than twofold at either or both time points. Amphiregulin (AREG) and growth differentiation factor 15 (GDF15) were chosen because of their higher upregulation and novelty, and their upregulation was confirmed in SRA01/04 cells using RT-PCR and real-time PCR analysis. AREG and GDF15 protein levels in conditioned media significantly increased at all UVB energy points at 24 h, while they were scarcely detectable at 12 h. AREG and GDF15 mRNA levels were also significantly upregulated in UVB-irradiated primary cultured HLE cells compared with the corresponding control culture. AREG significantly stimulated 3H-thymidine and 3H-leucine uptake in SRA01/04 cells as did a positive control epidermal growth factor (EGF). Recombinant GDF15 did not stimulate 3H-thymidine incorporation at any concentration tested, but significantly stimulated 3H-leucine uptake. RT-PCR analysis demonstrated that primary cultured HLE and SRA01/04 cells expressed not only epidermal growth factor receptor (EGFR) mRNA but also transforming growth factor beta receptors (TGFBR1 and TGFBR2) mRNAs. CONCLUSIONS: These results indicate that AREG and GDF15 produced in response to UVB exposure can affect the growth and protein synthesis of lens epithelial cells, suggesting that they have autocrine and paracrine roles related to pathological changes of lens tissue during long-term UVB exposure. PMID- 21245964 TI - Tissue factor expression in human pterygium. AB - PURPOSE: A pterygium shows tumor-like characteristics, such as proliferation, invasion, and epithelial-mesenchymal transition (EMT). Previous reports suggest that tissue factor (TF) expression is closely related to the EMT of tumor cells, and subsequent tumor development. In this study, we analyzed the expression and immunolocalization of TF in pterygial and normal conjunctival tissues of humans. METHODS: Eight pterygia and three normal bulbar conjunctivas, surgically removed, were used in this study. Formalin-fixed, paraffin-embedded tissues were submitted for immunohistochemical analysis with anti-TF antibody. Double staining immunohistochemistry was performed to assess TF and alpha-smooth muscle actin (alpha-SMA) or epidermal growth factor receptor (EGFR) expression in the pterygia. RESULTS: Immunoreactivity for TF was detected in all pterygial tissues examined. TF immunoreactivity was localized in the cytoplasm of basal, suprabasal, and superficial epithelial cells. The number of TF-immunopositive cells in pterygial epithelial cells was significantly higher than in normal conjunctival epithelial cells (p<0.001). TF immunoreactivity was detected in alpha-SMA-positive or -negative pterygial epithelial cells. EGFR immunoreactivity was detected in pterygial epithelium, which was colocalized with TF. CONCLUSIONS: These results suggest that TF plays a potential role in the pathogenesis and development of a pterygium, and that TF expression might be involved through EMT dependent and -independent pathways. PMID- 21245966 TI - 0 General Explanations. PMID- 21245967 TI - 1 RBC Concentrates. PMID- 21245968 TI - 2 Platelet Concentrates. PMID- 21245969 TI - 3 Granulocyte Concentrates. PMID- 21245970 TI - 4 Plasma for Therapeutic Use. PMID- 21245971 TI - 5 Human Albumin. PMID- 21245972 TI - 6 Factor VIII Concentrates, Factor VIII/von Willebrand Factor Concentrates, Factor IX Concentrates, Activated Prothrombin Complex Concentrates. PMID- 21245973 TI - 7 Procoagulators. PMID- 21245974 TI - 8 Inhibitors. PMID- 21245976 TI - 10 Autologous Hemotherapy. PMID- 21245975 TI - 9 Human Immunoglobulins. PMID- 21245977 TI - 11 Adverse Reactions. PMID- 21245978 TI - Transplantation of adipose derived stromal cells into the developing mouse eye. AB - Adipose derived stromal cells (ADSCs) were transplanted into a developing mouse eye to investigate the influence of a developing host micro environment on integration and differentiation. Green fluorescent protein-expressing ADSCs were transplanted by intraocular injections. The age of the mouse was in the range of 1 to 10 days postnatal (PN). Survival dates ranged from 7 to 28 post transplantation (DPT), at which time immunohistochemistry was performed. The transplanted ADSCs displayed some morphological differentiations in the host eye. Some cells expressed microtubule associated protein 2 (marker for mature neuron), or glial fibrillary acid protein (marker for glial cell). In addition, some cells integrated into the ganglion cell layer. The integration and differentiation of the transplanted ADSCs in the 5 and 10 PN 7 DPT were better than in the host eye the other age ranges. This study was aimed at demonstrating how the age of host micro environment would influence the differentiation and integration of the transplanted ADSCs. However, it was found that the integration and differentiation into the developing retina were very limited when compared with other stem cells, such as murine brain progenitor cell. PMID- 21245979 TI - Fibulin-4 and -5, but not Fibulin-2, are Associated with Tropoelastin Deposition in Elastin-Producing Cell Culture. AB - Elastic system fibers consist of microfibrils and tropoelastin. During development, microfibrils act as a template on which tropoelastin is deposited. Fibrillin-1 is the major component of microfibrils. It is not clear whether elastic fiber-associated molecules, such as fibulins, contribute to tropoelastin deposition. Among the fibulin family, fibulin-2, -4 and -5 are capable of binding to tropoelastin and fibrillin-1. In the present study, we used the RNA interference (RNAi) technique to establish individual gene-specific knockdown of fibulin-2, -4 and -5 in elastin-producing cells (human gingival fibroblasts; HGF). We then examined the extracellular deposition of tropoelastin using immunofluorescence. RNAi-mediated down-regulation of fibulin-4 and -5 was responsible for the diminution of tropoelastin deposition. Suppression of fibulin 5 appeared to inhibit the formation of fibrillin-1 microfibrils, while that of fibulin-4 did not. Similar results to those for HGF were obtained with human dermal fibroblasts. These results suggest that fibulin-4 and -5 may be associated in different ways with the extracellular deposition of tropoelastin during elastic fiber formation in elastin-producing cells in culture. PMID- 21245980 TI - Expression and Role of the BDNF Receptor-TrkB in Rat Adrenal Gland under Acute Immobilization Stress. AB - We reported that plasma brain-derived neurotrophic factor (BDNF) was maximally elevated following a 60-min period of acute immobilization stress and that salivary glands were the main source of plasma BDNF under this stress condition. However, the expression pattern of the BDNF receptor, Tyrosine receptor kinase B (TrkB), under this condition has yet to be determined. We therefore investigated the effect of this stress on the expression level of TrkB in various rat organs using real-time PCR. No significant differences were found between controls and 60 min-stressed rats with respect to TrkB level in various organs. Only adrenal glands showed significantly increased TrkB mRNA levels after 60 min of stress. TrkB mRNA and protein were observed to localize in chromaffin cells. In addition, we investigated whether BDNF-TrkB interaction influences the release of stress hormones from PC12 cells, derived from chromaffin cells. Truncated receptor, TrkB T1, was identified in PC12 cells using RT-PCR. Exposure of PC12 cells to BDNF induced the release of catecholamine. This BDNF-evoked release was totally blocked by administration of the K252a in which an inhibitor of Trk receptors. Thus, BDNF-TrkB interactions may modulate catecholamine release from adrenal chromaffin cells under acute stress conditions. PMID- 21245981 TI - Neuropathology does not Correlate with Regional Differences in the Extent of Expansion of CTG Repeats in the Brain with Myotonic Dystrophy Type 1. AB - Myotonic dystrophy (DM1) is known to be an adult-onset muscular dystrophy caused by the expansion of CTG repeats within the 3' untranslated region of the dystrophin myotonin protein kinase (DMPK) gene. The clinical features of DM1 include CNS symptoms, such as cognitive impairment and personality changes, the pathogenesis of which remains to be elucidated. We hypothesized that the distribution of neuropathological changes might be correlated with the extent of the length of the CTG repeats in the DMPK genes in DM1 patients. We studied the neuropathological changes in the brains of subjects with DM1 and investigated the extent of somatic instability in terms of CTG repeat expansion in the different brain regions of the same individuals by Southern blot analysis. The neuropathological changes included etat crible in the cerebral deep white matter and neurofibrillary tangles immunoreactive for phosphorylated tau in the hippocampus and entorhinal cortex, both of which were compatible with the subcortical dementia in DM1 patients. However, the length of the CTG repeats did not correlate with the regional differences in the extent of neuropathological changes. Our data suggested that pathomechanisms of dementia in DM1 might be more multifactorial rather than a toxic gain-of-function due to mutant RNA. PMID- 21245982 TI - Infiltration of T lymphocytes and expression of icam-1 in the hippocampus of patients with hippocampal sclerosis. AB - We and others have previously shown that reactive microglia express the major histocompatibility complex (MHC) class I and class II antigens in the hippocampus of patients suffering from epilepsy. Although the MHC glycoproteins serve as restriction elements for T lymphocytes, there is little information available regarding T lymphocytes in hippocampal sclerosis. In the present study, we investigated T lymphocyte infiltration in human hippocampi in four cases of epilepsy with hippocampal sclerosis, as well as in four control cases without neurological disease. No CD8- or CD4-positive T lymphocytes were seen in hippocampi from the control cases. In contrast, CD8- and CD4-positive T lymphocytes had infiltrated into the hippocampi of patients with hippocampal sclerosis. In addition, expression of intercellular adhesion molecule-1 was diffusely upregulated in the hippocampi with hippocampal sclerosis. These results indicate that T lymphocyte infiltration is involved in the pathology of hippocampal sclerosis. PMID- 21245983 TI - Visualization of the Activity of Rac1 Small GTPase in a Cell. AB - Rho family G proteins including Rac regulate a variety of cellular functions, such as morphology, motility, and gene expression. Here we developed a fluorescence resonance energy transfer-based analysis in which we could monitor the activity of Rac1. To detect fluorescence resonance energy transfer, yellow fluorescent protein fused Rac1 and cyan fluorescent protein fused Cdc42-Rac1 interaction-binding domain of Pak1 protein were used as intermolecular probes of FRET. The fluorophores were separated with linear unmixing method. The fluorescence resonance energy transfer efficiency was measured by acceptor photobleaching assisted assay. With these methods, the Rac1 activity was visualized in a cell. The present findings indicate that this approach is sensitive enough to achieve results similar to those from ratiometric fluorescence resonance energy transfer analysis. PMID- 21245984 TI - Wound healing trajectories to determine pressure ulcer treatment efficacy. AB - BACKGROUND: Wound healing trajectories (percent healing vs time) provide a dynamic picture of the decrease in wound burden over the entire continuum of the healing process. Trajectories can be robustly compared using survival statistics methodology. Improvement in healing can be determined by shifting the curve from "impaired" healing toward "ideal" healing. Although this concept of shifting the curve "to the left" has been demonstrated in acute incisional healing depicted by the gain in tensile strength, and in other chronic wounds, it has not been utilized for chronic pressure ulcers. METHODS: Wound healing trajectories were constructed for 211 patients enrolled in 8 separate randomized clinical trials for grade III and IV pressure ulcers. Trajectories were constructed for patients achieving >=90% or more healing within 112 days and those who achieved less than <90% wound closure. Kaplan-Meier curves were constructed for all patients receiving an experimental treatment and for those receiving placebo vehicles. RESULTS: Different trajectories were achieved for the faster healing patients. Eighty-one percent of patients reached 90% healing within 112 days; 80% of those in treatment groups and 85% of those in placebo groups. Linear regression suggested that all patients entered into the clinical trials would achieve 90% healing by 18 weeks. Only 17% of the patients achieved total healing (100% wound closure) within the 112-day study period. Linear regression suggested that it would take 110 weeks to achieve total healing in all patients. CONCLUSION: Wound healing trajectories provide a more complete description of treatment efficacy than do fixed endpoints, such as the number of patients achieving 100% closure at one defined time point. Since more successful healers have different trajectories than less successful healers, shifting the trajectory to the left from "impaired" toward "ideal" healing may provide a better endpoint to determine treatment efficacy. PMID- 21245985 TI - Pathologic pancreatic endocrine cell hyperplasia. AB - Pathologic hyperplasia of various pancreatic endocrine cells is rare but has been long known. beta cell hyperplasia contributes to persistent hyperinsulinemic hypoglycemia of infancy, which is commonly caused by mutations in the islet ATP sensitive potassium channel, and to non-insulinoma pancreatogenous hypoglycemia in adults, which may or may not be associated with bariatric surgery. alpha cell hyperplasia may cause glucagonoma syndrome or induce pancreatic neuroendocrine tumors. An inactivating mutation of the glucagon receptor causes alpha cell hyperplasia and asymptomatic hyperglucagonemia. Pancreatic polypeptide cell hyperplasia has been described without a clearly-characterized clinical syndrome and hyperplasia of other endocrine cells inside the pancreas has not been reported to our knowledge. Based on morphological evidence, the main pathogenetic mechanism for pancreatic endocrine cell hyperplasia is increased endocrine cell neogenesis from exocrine ductal epithelium. Pancreatic endocrine cell hyperplasia should be considered in the diagnosis and management of hypoglycemia, elevated islet hormone levels, and pancreatic neuroendocrine tumors. Further studies of pathologic pancreatic endocrine cell hyperplasia will likely yield insights into the pathogenesis and treatment of diabetes and pancreatic neuroendocrine tumors. PMID- 21245986 TI - Quality of life in patients with esophageal stenting for the palliation of malignant dysphagia. AB - Incidence of esophageal cancer (EC) is rising more rapidly in the Western world than that of any other cancer. Despite advances in therapy, more than 50% of patients have incurable disease at the time of presentation. This precludes curative treatment and makes palliative treatment a more realistic option for most of these patients. Dysphagia is the predominant symptom in more than 70% of patients with EC and although several management options have been developed in recent years to palliate this symptom, the optimum management is not established. Self-expanding metal stents (SEMS) are a well-established palliation modality for dysphagia in such patients. Health-related quality of life (HRQoL) is becoming a major issue in the evaluation of any therapeutic or palliative intervention. To date, only a few published studies can be found on Medline examining HRQoL in patients with advanced EC treated with SEMS implantation. The aim of this study was to review the impact on HRQoL of SEMS implantation as palliative treatment in patients with EC. All Medline articles regarding HRQoL in patients with advanced EC, particularly those related to SEMS, were reviewed. In most studies, relief of dysphagia was the only aspect of HRQoL being measured and SEMS implantation was compared with other palliative treatments such as brachytherapy and laser therapy. SEMS insertion provides a swift palliation of dysphagia compared to brachytherapy and no evidence was found to suggest that stent implantation is different to laser treatment in terms of improving dysphagia, recurrent dysphagia and better HRQoL, although SEMS insertion has a better technical success rate and also reduces the number of repeat interventions. PMID- 21245987 TI - Connective tissue growth factor reacts as an IL-6/STAT3-regulated hepatic negative acute phase protein. AB - AIM: To investigate the mechanisms involved in a possible modulator role of interleukin (IL)-6 signalling on CYR61-CTGF-NOV (CCN) 2/connective tissue growth factor (CTGF) expression in hepatocytes (PC) and to look for a relation between serum concentrations of these two parameters in patients with acute inflammation. METHODS: Expression of CCN2/CTGF, p-STAT3, p-Smad3/1 and p-Smad2 was examined in primary freshly isolated rat or cryo-preserved human PC exposed to various stimuli by Western blotting, electrophoretic mobility shift assay (EMSA), reporter-gene-assays and reverse-transcriptase polymerase chain reaction. RESULTS: IL-6 strongly down-regulated CCN2/CTGF protein and mRNA expression in PC, enhanceable by extracellular presence of the soluble IL-6 receptor gp80, and supported by an inverse relation between IL-6 and CCN2/CTGF concentrations in patients' sera. The inhibition of TGFbeta1 driven CCN2/CTGF expression by IL-6 did not involve a modulation of Smad2 (and Smad1/3) signalling. However, the STAT3 SH2 domain binding peptide, a selective inhibitor of STAT3 DNA binding activity, counteracted the inhibitory effect of IL-6 on CCN2/CTGF expression much more pronounced than pyrrolidine-dithiocarbamate, an inhibitor primarily of STAT3 phosphorylation. An EMSA confirmed STAT3 binding to the proposed proximal STAT binding site in the CCN2/CTGF promoter. CONCLUSION: CCN2/CTGF is identified as a hepatocellular negative acute phase protein which is down-regulated by IL-6 via the STAT3 pathway through interaction on the DNA binding level. PMID- 21245988 TI - Switching-on of serotonergic calcium signaling in activated hepatic stellate cells. AB - AIM: To investigate serotonergic Ca2+ signaling and the expression of 5 hydroxytryptamine (5-HT) receptors, as well as Ca2+ transporting proteins, in hepatic stellate cells (HSCs). METHODS: The intracellular Ca2+ concentration [Ca2+](i) of isolated rat HSCs was measured with a fluorescence microscopic imaging system. Quantitative PCR was performed to determine the transcriptional levels of 5-HT receptors and endoplasmic reticulum (ER) proteins involved in Ca2+ storage and release in cultured rat HSCs. RESULTS: Distinct from quiescent cells, activated HSCs exhibited [Ca2+](i) transients following treatment with 5-HT, which was abolished by U-73122, a phospholipase C inhibitor. Upregulation of 5 HT(2A) and 5-HT(2B) receptors, but not 5-HT3, was prominent during trans differentiation of HSCs. Pretreatment with ritanserin, a 5-HT2 antagonist, inhibited [Ca2+](i) changes upon application of 5-HT. Expression of type 1 inositol-5'-triphosphate receptor and type 2 sarcoplasmic/endoplasmic reticulum Ca2+ ATPase were also increased during activation of HSCs and serve as the major isotypes for ER Ca2+ storage and release in activated HSCs. Ca2+ binding chaperone proteins of the ER, including calreticulin, calnexin and calsequestrin, were up-regulated following activation of HSCs. CONCLUSION: The appearance of 5 HT-induced [Ca2+](i) response accompanied by upregulation of metabotropic 5-HT2 receptors and Ca2+ transporting/chaperone ER proteins may participate in the activating process of HSCs. PMID- 21245989 TI - Systematic review on the surgical treatment for T1 gallbladder cancer. AB - AIM: To evaluate the efficacy of simple and extended cholecystectomy for mucosa (T1a) or muscularis (T1b) gallbladder (GB) cancer. METHODS: Original studies on simple and extended cholecystectomy for T1a or T1b GB cancer were searched from MEDLINE (PubMed), Cochrane Library, EMBase, and CancerLit using the search terms of GB, cancer/carcinoma/tumor/neoplasm. RESULTS: Twenty-nine out of the 2312 potentially relevant publications met the eligibility criteria. Of the 1266 patients with GB cancer included in the publications, 706 (55.8%) and 560 (44.2%) had T1a and T1b GB cancer, respectively. Simple cholecystectomy for T1a and T1b GB cancer was performed in 590 (83.6%) and 375 (67.0%) patients, respectively (P < 0.01). In most series, the treatment of choice was simple cholecystectomy for T1a GB cancer patients with a 5-year survival rate of 100%. Lymph node metastasis was detected in 10.9% of the T1b GB cancer patients and in 1.8% of the T1a GB cancer patients, respectively (P < 0.01). Eight patients (1.1%) with T1a GB cancer and 52 patients (9.3%) with T1b GB cancer died of recurrent GB cancer (P < 0.01). CONCLUSION: Simple cholecystectomy represents the adequate treatment of T1a GB cancer. There is no definite evidence that extended cholecystectomy is advantageous over simple cholecystectomy for T1b GB cancer. PMID- 21245990 TI - LY294002 potentiates the anti-cancer effect of oxaliplatin for gastric cancer via death receptor pathway. AB - AIM: To examine the effects of combined treatment of oxaliplatin and phosphatidylinositol 3'-kinase inhibitor, 2-(4-morpholinyl)-8-phenyl-4H-1 benzopyran-4-one (LY294002) for gastric cancer. METHODS: Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Apoptotic cells were detected by flow cytometric analysis and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Western blotting and immuno-precipitation were used to examine protein expression and recruitment, respectively. Nuclear factor kappaB (NFkappaB) binding activities were investigated using electrophoretic mobility shift assay. Nude mice were used to investigate tumor growth. RESULTS: Treatment with combined oxaliplatin and LY294002 resulted in increased cell growth inhibition and cell apoptosis in vitro, and increased tumor growth inhibition and cell death in the tumor mass in vivo. In MKN45 and AGS cells, oxaliplatin treatment promoted both protein kinase B (Akt) and NFkappaB activation, while pretreatment with LY294002 significantly attenuated oxaliplatin-induced Akt activity and NFkappaB binding. LY294002 promoted oxaliplatin-induced Fas ligand (FasL) expression, Fas-associated death domain protein recruitment, caspase-8, Bid, and caspase-3 activation, and the short form of cellular caspase-8/FLICE-inhibitory protein (c-FLIP(S)) inhibition. In vivo, LY294002 inhibited oxaliplatin-induced activation of Akt and NFkappaB, and increased oxaliplatin-induced expression of FasL, inhibition of c-FLIP(S), and activation of caspase-8, Bid, and caspase-3. CONCLUSION: Combination of oxaliplatin and LY294002 was therapeutically promising for gastric cancer treatment. The enhanced sensitivity of the combined treatment was associated with the activation of the death receptor pathway. PMID- 21245991 TI - Percutaneous endoscopic gastrostomy and gastro-oesophageal reflux in neurologically impaired children. AB - AIM: To investigate the effects of percutaneous endoscopic gastrostomy (PEG) feeding on gastro-oesophageal reflux (GOR) in a group of these children using combined intraluminal pH and multiple intraluminal impedance (pH/MII). METHODS: Ten neurologically impaired children underwent 12 h combined pH/MII procedures at least 1 d before and at least 12 d after PEG placement. METHODS: Prior to PEG placement (pre-PEG) a total of 183 GOR episodes were detected, 156 (85.2%) were non-acidic. After PEG placement (post-PEG) a total of 355 episodes were detected, 182 (51.3%) were non-acidic. The total number of distal acid reflux events statistically significantly increased post-PEG placement (pre-PEG total 27, post PEG total 173, P = 0.028) and the mean distal pH decreased by 1.1 units. The distal reflux index therefore also significantly increased post-PEG [pre-PEG 0.25 (0-2), post-PEG 2.95 (0-40)]. Average proximal pH was lower post-PEG but the within subject difference was not statistically significant (P = 0.058). Median number of non-acid GOR, average reflux height, total acid clearance time and total bolus clearance time were all lower pre-PEG, but not statistically significant. CONCLUSION: PEG placement increases GOR episodes in neurologically impaired children. PMID- 21245992 TI - Polymorphisms in NF-kappaB, PXR, LXR, PPARgamma and risk of inflammatory bowel disease. AB - AIM: To investigate the contribution of polymorphisms in nuclear receptors to risk of inflammatory bowel disease (IBD). METHODS: Genotypes of nuclear factor (NF)-kappaB (NFKB1) NFkappaB -94ins/del (rs28362491); peroxisome proliferator activated receptor (PPAR)-gamma (PPARgamma) PPARgamma Pro12Ala (rs 1801282) and C1431T (rs 3856806); pregnane X receptor (PXR) (NR1I2) PXR A-24381C (rs1523127), C8055T (2276707), and A7635G (rs 6785049); and liver X receptor (LXR) (NR1H2) LXR T-rs1405655-C and T-rs2695121-C were assessed in a Danish case-control study of 327 Crohn's disease patients, 495 ulcerative colitis (UC) patients, and 779 healthy controls. Odds ratio (OR) and 95% CI were estimated by logistic regression models. RESULTS: The PXR A7635G variant, the PPARgamma Pro12Ala and LXR T-rs2695121-C homozygous variant genotypes were associated with risk of UC (OR: 1.31, 95% CI: 1.03-1.66, P = 0.03, OR: 2.30, 95% CI: 1.04-5.08, P = 0.04, and OR: 1.41, 95% CI: 1.00-1.98, P = 0.05, respectively) compared to the corresponding homozygous wild-type genotypes. Among never smokers, PXR A7635G and the LXR T-rs1405655-C and T-rs2695121-C variant genotypes were associated with risk of IBD (OR: 1.41, 95% CI: 1.05-1.91, P = 0.02, OR: 1.63, 95% CI: 1.21-2.20, P = 0.001, and OR: 2.02, 95% CI: 1.36-2.99, P = 0.0005, respectively) compared to the respective homozygous variant genotypes. PXR A7635G (rs6785049) variant genotype was associated with a higher risk of UC diagnosis before the age of 40 years and with a higher risk of extensive disease (OR: 1.34, 95% CI: 1.03-1.75 and OR: 2.49, 95% CI: 1.24-5.03, respectively). CONCLUSION: Common PXR and LXR polymorphisms may contribute to risk of IBD, especially among never smokers. PMID- 21245993 TI - Acute diverticulitis in younger patients: any rationale for a different approach? AB - AIM: To compare the natural history and course of acute diverticulitis in a younger age group with an older population and to evaluate whether younger patients should be managed differently. METHODS: This study was a retrospective review of 157 patients treated with acute diverticulitis between January 1, 2004 and December 31, 2007. Diverticulitis was stratified according to the Hinchey classification. Patients were divided into 2 populations: group A <= 50 years (n = 31); group B > 50 years (n = 126). Mean patient follow-up was 15 mo. RESULTS: The median age was 60 years. A significantly higher proportion of patients in group B presented with complicated diverticulitis (36.5% vs 12.9%, P = 0.01). Recurrence was more frequent in group A (25.8% vs 11.1%, P = 0.03) and the mean time-to-recurrence was shorter (12 mo vs 28 mo, P = 0.26). The most severe recurrent episodes of acute diverticulitis were classified as Hinchey stage I and none of the patients required emergency surgery. In multivariate analysis, only age (P = 0.024) was identified as an independent prognostic factor for recurrence. CONCLUSION: Based on the results of this study, the authors recommend that diverticulitis management should be based on the severity of the disease and not on the age of the patient. PMID- 21245994 TI - Hemolysis results in impaired intestinal microcirculation and intestinal epithelial cell injury. AB - AIM: To study the effect of circulating cell-free oxyhemoglobin (FHb) on intestinal microcirculation and intestinal epithelial injury in a rat model. METHODS: To induce elevated intravascular circulating FHb, male Sprague-Dawley rats received water or FHb infusion. Microcirculatory changes in jejunum, ileum and colon were evaluated using fluorescent microspheres. Intestinal injury was quantified as plasmatic release of ileal lipid binding protein (iLBP) and verified by histological analysis of the ileum. RESULTS: Water and FHb infusions resulted, when compared with saline infusion, in reduced intestinal microcirculation (after 30 min P < 0.05, or better; after 60 min FHb infusion P < 0.05 for jejunum and colon). Circulating FHb levels correlated significantly with release of iLBP (Spearman r = 0.72, P = 0.0011). Epithelial cell injury of the villi was histologically observed after water and FHb infusions. CONCLUSION: This study shows that circulating FHb leads to a reduction in intestinal microcirculatory blood flow with marked injury to intestinal epithelial cells. These data support the hypothesis that circulating FHb contributes to the development of intestinal injury. PMID- 21245995 TI - Angiogenic markers endoglin and vascular endothelial growth factor in gastroenteropancreatic neuroendocrine tumors. AB - AIM: To investigate the expression and potential prognostic role of vascular endothelial growth factor (VEGF) and endoglin in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). METHODS: Microvessel density (MVD) in GEP-NETs was evaluated using endoglin and CD31 immunohistochemistry. In addition, tissue levels of endoglin and VEGF were determined in homogenates by ELISA. RESULTS: Endoglin was highly expressed on tumor endothelial cells. CD31 MVD in GEP-NETs was significantly higher compared to endoglin MVD (P < 0.01). Two- to four-fold higher tissue levels of endoglin and VEGF were seen in tumors compared to associated normal tissue. This increased endoglin tissue expression in tumors was significantly related to tumor size (P < 0.01), presence of metastases (P = 0.04), and a more advanced tumor stage (P = 0.02), whereas expression of VEGF was not. CONCLUSION: We suggest that endoglin is a potential marker to indicate and predict metastases, which might be useful in the post-resection therapeutic approach of patients with GEP-NETs. PMID- 21245996 TI - Evaluation of small bowel blood flow in healthy subjects receiving low-dose aspirin. AB - AIM: To investigate the relationship between low-dose aspirin-induced small bowel mucosal damage and blood flow, and the effect of rebamipide. METHODS: Ten healthy volunteers were enrolled in this study. The subjects were divided into two groups: a placebo group given low-dose aspirin plus placebo and a rebamipide group given low-dose aspirin plus rebamipide for a period of 14 d. Capsule endoscopy and contrast-enhanced ultrasonography were performed before and after administration of drugs. Areas under the curves and peak value of time-intensity curve were calculated. RESULTS: Absolute differences in areas under the curves were -1102.5 (95% CI: -1980.3 to -224.7, P = 0.0194) in the placebo group and 152.7 (95% CI: -1604.2 to 641.6, P = 0.8172) in the rebamipide group. Peak values of time intensity curves were -148.0 (95% CI: -269.4 to -26.2, P = 0.0225) in the placebo group and 28.3 (95% CI: -269.0 to 325.6, P = 0.8343) in the rebamipide group. Capsule endoscopy showed mucosal breaks only in the placebo group. CONCLUSION: Short-term administration of low-dose aspirin is associated with small bowel injuries and blood flow. PMID- 21245997 TI - 18F-fluorodeoxyglucose positron emission tomography in the diagnosis of small pancreatic cancer. AB - AIM: To investigate the role of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the diagnosis of small pancreatic cancer. METHODS: This study involved 31 patients with proven invasive ductal cancer of the pancreas. The patients were divided into 3 groups according to the maximum diameter of the tumor: TS1 (maximum tumor size <= 2.0 cm), TS2 (> 2.0 cm and <= 4.0 cm) or TS3-4 (> 4.0 cm). The relationships between the TS and various diagnostic tools, including FDG-PET with dual time point evaluation, were analyzed. RESULTS: The tumors ranged from 1.3 to 11.0 cm in diameter. Thirty of the 31 patients (97%) had a positive FDG-PET study. There were 5 patients classified as TS1, 15 as TS2 and 11 as TS3-4. The sensitivity of FDG-PET, computed tomography (CT) and magnetic resonance imaging (MRI) were 100%, 40%, 0% in TS1, 93%, 93%, 89% in TS2 and 100%, 100%, 100% in TS3-4. The sensitivity of FDG-PET was significantly higher in comparison to CT and MRI in patients with TS1 (P < 0.032). The mean standardized uptake values (SUVs) did not show a significant difference in relation to the TS (TS1: 5.8 +/- 4.5, TS2: 5.7 +/- 2.2, TS3-4: 8.2 +/- 3.9), respectively. All the TS1 tumors (from 13 to 20 mm) showed higher SUVs in FDG-PET with dual time point evaluation in the delayed phase compared with the early phase, which suggested the lesions were malignant. CONCLUSION: These results indicate that FDG-PET with dual time point evaluation is a useful modality for the detection of small pancreatic cancers with a diameter of less than 20 mm. PMID- 21245999 TI - Magnesium citrate with a single dose of sodium phosphate for colonoscopy bowel preparation. AB - AIM: To evaluate the efficacy and acceptability of magnesium citrate and a single dose of oral sodium phosphate (45 mL) solution for morning colonoscopy bowel preparation. METHODS: A total of 159 patients were randomly assigned to receive two split doses of 90 mg of sodium phosphate (Group I, n = 79) or magnesium citrate (250 mL, the day before the procedure) followed by 45 mL of sodium phosphate (the day of procedure, Group II, n = 80). The quality of bowel cleansing and the acceptability of each regimen were compared, including the satisfaction, taste, willing to repeat and adverse effects of each regimen. RESULTS: The quality of bowel cleansing of Group II was as good as that of Group I (An Aronchick scale score of good or excellent: 70.9% vs 81.0%, respectively, P = 0.34; the Ottawa system score: 4.4 +/- 2.6 vs 3.8 +/- 3.0, respectively, P = 0.76). There was no statistically significant difference between both groups with regard to acceptability, including the satisfaction, taste and willingness to repeat the regimen. A significantly greater number of older patients (over 65 years old) in Group II graded the overall satisfaction as satisfactory (48.1% vs 78.1%, respectively; Group I vs Group II, P = 0.01). There were no significant adverse reactions. CONCLUSION: Magnesium citrate and a single dose of sodium phosphate was as effective and tolerable as the conventional sodium phosphate regimen and is a satisfactory option. PMID- 21245998 TI - Seroprevalence of anti-HAV among patients with chronic viral liver disease. AB - AIM: To investigate the current seroprevalence of hepatitis A virus (HAV) antibodies in patients with chronic viral liver disease in Korea. We also tried to identify the factors affecting the prevalence of HAV antibodies. METHODS: We performed an analysis of the clinical records of 986 patients (mean age: 49 +/- 9 years, 714 males/272 females) with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection who had undergone HAV antibody testing between January 2008 and December 2009. RESULTS: The overall prevalence of IgG anti-HAV was 86.61% (854/986) in patients with chronic liver disease and was 88.13% (869/986) in age- and gender-matched patients from the Center for Health Promotion. The anti-HAV prevalence was 80.04% (405/506) in patients with chronic hepatitis B, 86.96% (20/23) in patients with chronic hepatitis C, 93.78% (422/450) in patients with HBV related liver cirrhosis, and 100% (7/7) in patients with HCV related liver cirrhosis. The anti-HAV prevalence according to the decade of age was as follows: 20s (6.67%), 30s (50.86%), 40s (92.29%), 50s (97.77%), and 60s (100%). The anti HAV prevalence was significantly higher in patients older than 40 years compared with that in patients younger than 40 years of age. Multivariable analysis showed that age >= 40 years, female gender and metropolitan cities as the place of residence were independent risk factors for IgG anti-HAV seropositivity. CONCLUSION: Most Korean patients with chronic liver disease and who are above 40 years of age have already been exposed to hepatitis A virus. PMID- 21246000 TI - Risk factors for hilar cholangiocarcinoma: a case-control study in China. AB - AIM: To study the association between hilar cholangiocarcinoma (HC) and pre existing medical conditions. METHODS: Three hundred and thirteen HC patients admitted to the Eastern Hepatobiliary Surgery Hospital (Shanghai, China) in 2000 2005 and 608 healthy controls were enrolled in this study. Association between HC and pre-existing medical conditions was studied with their adjusted odds ratio (OR) calculated by logistic regression analysis. RESULTS: The prevalence of choledocholithiasis (adjusted OR = 2.704, P = 0.039), hepatolithiasis (adjusted OR = 3.278, P = 0.018), cholecystolithiasis (adjusted OR = 4.499, P < 0.0001), cholecystectomy (adjusted OR = 7.012, P = 0.004), biliary ascariasis (adjusted OR = 7.188, P = 0.001), liver fluke (adjusted OR = 10.088, P = 0.042) and liver schistosomiasis (adjusted OR = 9.913, P = 0.001) was higher in HC patients than in healthy controls. CONCLUSION: Biliary tract stone disease (choledocholithiasis, hepatolithiasis, cholecystolithiasis) and parasitic liver disease (biliary ascariasis, liver fluke, liver schistosomiasis) are the risk factors for HC in Chinese population. PMID- 21246001 TI - Effects of penehyclidine hydrochloride in small intestinal damage caused by limb ischemia-reperfusion. AB - AIM: To investigate the protective effect of penehyclidine hydrochloride post conditioning in the damage to the barrier function of the small intestinal mucosa caused by limb ischemia-reperfusion (LIR) injury. METHODS: Male Wistar rats were randomly divided into three groups (36 rats each): the sham-operation group (group S), lower limb ischemia-reperfusion group (group LIR), and penehyclidine hydrochloride post-conditioning group (group PHC). Each group was divided into subgroups (n = 6 in each group) according to ischemic-reperfusion time, i.e. immediately 0 h (T1), 1 h (T2), 3 h (T3), 6 h (T4), 12 h (T5), and 24 h (T6). Bilateral hind-limb ischemia was induced by rubber band application proximal to the level of the greater trochanter for 3 h. In group PHC, 0.15 mg/kg of penehyclidine hydrochloride was injected into the tail vein immediately after 3 h of bilateral hind-limb ischemia. The designated rats were sacrificed at different time-points of reperfusion; diamine oxidase (DAO), superoxide dismutase (SOD) activity, myeloperoxidase (MPO) of small intestinal tissue, plasma endotoxin, DAO, tumor necrosis factor-alpha (TNF-alpha), and interleukin (IL)-10 in serum were detected in the rats. RESULTS: The pathological changes in the small intestine were observed under light microscope. The levels of MPO, endotoxin, serum DAO, and IL-10 at T1-T6, and TNF-alpha level at T1-T4 increased in groups LIR and PHC (P < 0.05) compared with those in group S, but tissue DAO and SOD activity at T1-T6 decreased (P < 0.05). In group PHC, the tissue DAO and SOD activity at T2-T6, and IL-10 at T2-T5 increased to higher levels than those in group LIR (P < 0.05); however, the levels of MPO, endotoxin, and DAO in the blood at T2-T6, and TNF-alpha at T2 and T4 decreased (P < 0.05). CONCLUSION: Penehyclidine hydrochloride post-conditioning may reduce the permeability of the small intestines after LIR. Its protection mechanisms may be related to inhibiting oxygen free radicals and inflammatory cytokines for organ damage. PMID- 21246002 TI - CYP1A1 Ile462Val polymorphism contributes to colorectal cancer risk: a meta analysis. AB - AIM: To study the relation between CYP1A1 Ile462Val polymorphism and colorectal cancer risk by meta-analysis. METHODS: A meta-analysis was performed to investigate the relation between CYP1A1 Ile462Val polymorphism and colorectal cancer risk by reviewing the related studies until September 2010. Data were extracted and analyzed. Crude odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of relation between CYP1A1 Ile462Val polymorphism and colorectal cancer risk. RESULTS: Thirteen published case-control studies including 5336 cases and 6226 controls were acquired. The pooled OR with 95% CI indicated that CYP1A1 Ile462Val polymorphism was significantly related with colorectal cancer risk (Val/Val vs Ile/Ile: OR = 1.47, 95% CI: 1.16-1.86, P = 0.002; dominant model: OR = 1.33, 95% CI: 1.01-1.75, P = 0.04; recessive model: OR = 1.49, 95% CI: 1.18-1.88, P = 0.0009). Subgroup ethnicity analysis showed that CYP1A1 Ile462Val polymorphism was also significantly related with colorectal cancer risk in Europeans (Ile/Val vs Ile/Ile: OR = 1.22, 95% CI: 1.05-1.42, P = 0.008; dominant model: OR = 1.24, 95% CI: 1.07-1.43, P = 0.004) and Asians (Val/Val vs Ile/Ile: OR = 1.40, 95% CI: 1.07-1.82, P = 0.01; recessive model: OR = 1.46, 95% CI: 1.12-1.89, P = 0.005). CONCLUSION: CYP1A1 Ile462Val may be an increased risk factor for colorectal cancer. PMID- 21246003 TI - Splenic infarction associated with sorafenib use in a hepatocellular carcinoma patient. AB - Sorafenib, a multitargeted tyrosine kinase inhibitor, has been shown to improve survival in patients with advanced hepatocellular carcinoma (HCC). As the clinical use of sorafenib increases, many adverse effects have been reported, such as hand-foot skin reaction, diarrhea, anorexia, asthenia, alopecia, weight loss, hypertension and arterial thromboembolism. However, there are no prior reports of splenic infarction as an adverse effect of sorafenib. Here, a case of splenic infarction in a patient with HCC who was treated with sorafenib is reported. The patient had no other predisposing factors to explain the splenic infarction except for the administration of sorafenib. The splenic infarction improved after sorafenib was discontinued; however, the HCC progressed. PMID- 21246004 TI - Potential efficacy of ginger as a natural supplement for nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases and its prevalence is likely to reach epidemic proportions. According to the "two stage hypothesis" proposed for the pathophysiology of NAFLD, insulin resistance, oxidative stress and pro-inflammatory cytokines are among the key promoters of the disease. Here, ginger has been hypothesized to prevent NAFLD or blunt its progression via several mechanisms, such as sensitizing insulin effects, activating peroxisome proliferator-activated receptor gamma which induces adiponectin and down-regulates pro-inflammatory cytokines, changing the balance between adiponectin and tumor necrosis factor-alpha in favor of adiponectin, promoting considerable antioxidant effects and antidyslipidemic properties, and reducing hepatic triglyceride content which can prevent steatosis. The aforementioned mechanisms imply that ginger possesses interesting potentials for serving as a natural supplement for the prevention and treatment of NAFLD. Therefore, conducting trials to explore its benefits in clinical practice is greatly recommended. PMID- 21246005 TI - Triple Combination Therapy Using Metformin, Thiazolidinedione, and a GLP-1 Analog or DPP-IV Inhibitor in Patients with Type 2 Diabetes Mellitus. AB - Although there is no HbA1c threshold for cardiovascular risk, the American Diabetic Association-recommended goal of HbA1c < 7.0% appears to be unacceptably high. To achieve an optimal HbA1c level goal of 6.0% or less, a high dosage of sulfonylureas and insulin would be required; the trade-off would be the common adverse effects of hypoglycemia and weight gain. In contrast, hypoglycemia is uncommon with insulin sensitizers and GLP-1 analogs, allowing the physician to titrate these drugs to maximum dosage to reduce HbA1c levels below 6.0% and they have been shown to preserve beta-cell function. Lastly, weight gain is common with sulfonylurea and insulin therapy, whereas GLP-1 analogs induce weight loss and offset the weight gain associated with TZDs. A treatment paradigm shift is recommended in which combination therapy is initiated with diet/exercise, metformin (which has antiatherogenic effects and improves hepatic insulin sensitivity), a TZD (which improves insulin sensitivity and preserves beta-cell function with proven durability), and a GLP-1 analog (which improves beta, alpha cell function and promotes weight loss) or a dipeptidyl peptidase IV inhibitor in patients with type 2 diabetes mellitus. PMID- 21246006 TI - Correlations of glucose levels in interstitial fluid estimated by continuous glucose monitoring systems and venous plasma. PMID- 21246007 TI - The Small Rice Bowl-Based Meal Plan was Effective at Reducing Dietary Energy Intake, Body Weight, and Blood Glucose Levels in Korean Women with Type 2 Diabetes Mellitus. AB - BACKGROUND: The typical Korean diet includes rice, which is usually served in a rice bowl. We investigated the effects of a meal plan using rice bowls of varying sizes on dietary energy intake (EI), body weight (BW), and blood glucose levels. METHODS: Forty-two obese women with type 2 diabetes mellitus were randomly assigned to use either a 200 mL small rice bowl (SB), a 380 mL regular rice bowl (RB), or to a control group (C). Both intervention groups were asked to reduce their EI by 500 kcal/day for 12 weeks and simple instructions for using the assigned bowl were provided. Dietary EI and proportion of macronutrients (PMN) were estimated from 3-day dietary records. RESULTS: Reduction of EI was more prominent in the SB group compared to the RB and C group, although EI decreased significantly from baseline in all groups. Carbohydrate and fat intakes of the SB group were decreased greater than those of the RB and C group. However, changes in PMN were not significant across the 3 groups. Reduction of BW and HbA1c levels in the SB group was more prominent compared to the C group. Although, BW and HbA1c were decreased significantly from baseline in both bowl groups. There was no statistical difference between the two groups. CONCLUSION: The small rice bowl based meal plan was effective at reducing EI, BW, and blood glucose levels, and the observed reductions in EI, carbohydrate, and fat intake were greater than those of the regular rice bowl-based meal plan. PMID- 21246008 TI - The Correlation and Accuracy of Glucose Levels between Interstitial Fluid and Venous Plasma by Continuous Glucose Monitoring System. AB - BACKGROUND: Clinical experience with the continuous glucose monitoring systems (CGMS) is limited in Korea. The objective of this study is to evaluate the accuracy of the CGMS and the correlation between interstitial fluid and venous plasma glucose level in Korean healthy male subjects. METHODS: Thirty-two subjects were served with glucose solution contained same amount of test food's carbohydrate and test foods after separate overnight fasts. CGMS was performed over 3 days during hopitalization for each subjects. Venous plasma glucose measurements were carried out during 4 hours (0, 0.25, 0.5, 0.75, 1, 2, 4 hours) just before and after glucose solution and test food load. The performance of the CGMS was evaluated by comparing its readings to those obtained at the same time by the hexokinase method using the auto biochemistry machine (Hitachi 7600-110). Also, correlations between glucose recorded with CGMS and venous plasma glucose value were examined. RESULTS: CGMS slightly underestimated the glucose value as compared with the venous plasma glucose level (16.3 +/- 22.2 mg/dL). Correlation between CGMS and venous plasma glucose values throughout sensor lifetime is 0.73 (regression analysis: slope = 1.08, intercept = 8.38 mg/dL). Sensor sensitivity can deteriorate over time, with correlations between venous blood glucose and CGMS values dropping from 0.77 during 1st day to 0.65 during 2nd and 3rd day. CONCLUSION: The accuracy of data provided by CGMS may be less than expected. CGMS sensor sensitivity is decreased with the passage of time. But, from this study, CGMS can be used for glucose variability tendency monitoring conveniently to the Korean. PMID- 21246009 TI - A retrospective study on the efficacy of a ten-milligram dosage of atorvastatin for treatment of hypercholesterolemia in type 2 diabetes mellitus patients. AB - BACKGROUND: There have been few clinical studies on 10 mg atorvastatin as a starting dosage for treatment of hypercholesterolemia in type 2 diabetes mellitus (T2DM) patients. This retrospective study aims to evaluate the efficacy of 10 mg dosage of atorvastatin in clinical setting. METHODS: One hundred five enrolled patients with high levels of low density lipoprotein cholesterol (LDL-C, > 100 mg/dL) took 10 mg atorvastatin. After 6 months, they were divided into 'Responder group' (LDL-C < 100 mg/dL) and 'Non-responder group' (LDL-C >= 100 mg/dL), and the response rate was calculated. Thereafter, we subdivided the 'Responder group' into Maintenance (10 mg), Reduced dosage (5 mg), and Discontinuance group (0 mg). The 'Non-Responder group' was subdivided into Maintenance (10 mg) and Double dosage group (20 mg). After consecutive 6 months, the response rates of each 10 mg Maintenance groups were compared to those of the other groups, respectively. RESULTS: Following the first 6 months, the response rate of 10 mg fixed dosage was 74.3%. In the 'Responder group', response rates of 10 mg, 5 mg and Discontinuance groups following 6 months were 52.6%, 53.1%, and 12.5%, respectively. In the 'Non-responder group', response rates of 10 mg and 20 mg groups were 28.6% and 50.0%. Baseline LDL-C levels and body mass index (BMI) of 'Responder group' were significantly lower than those of 'Non-responder group' (P = 0.004, respectively). CONCLUSION: Hypercholesterolemia treatment with 10 mg, fixed dosage of atorvastatin was effective in three quarters of the subjects during the first 6-month treatment; however, a significant number of patients with high LDL-C levels and/or BMI require higher starting and maintenance dosage. PMID- 21246010 TI - R1467H Variants of Rho Guanine Nucleotide Exchange Factor 11 (ARHGEF11) are Associated with Type 2 Diabetes Mellitus in Koreans. AB - BACKGROUND: The human Rho guanine nucleotide exchange factor 11 (ARHGEF11) functions as an activator of Rho GTPases and is thought to influence insulin signaling. The R1467H variant of ARHGEF11 has been reported to be associated with susceptibility to type 2 diabetes mellitus (T2DM) in Western populations. METHODS: We investigated the effects of the R1467H variant on susceptibility to T2DM as well as related traits in a Korean population. We genotyped the R1467H (rs945508) of ARHGEF11 in 689 unrelated T2DM patients and 249 non-diabetic individuals and compared the clinical and biochemical characteristics according to different alleles. RESULTS: The H allele was significantly more frequent in T2DM cases than in controls (P = 0.037, 17.1% and 13.1%; respectively). H homozygocity was associated with a higher risk of T2DM compared to those with R/R or R/H genotype (odds ratio, 5.24; 95% confidence interval, 1.06 to 25.83; P = 0.042). The fasting plasma glucose, HbA1c, fasting insulin, HOMA2-IR and HOMA2 %beta levels did not differ significantly between different genotypes. CONCLUSION: Our study replicated associations of the ARHGEF11 polymorphism with increased risk of T2DM in a Korean population and thus supports previous data implicating a potential role of ARHGEF11 in the etiology of T2DM. Further studies revealing the underlying mechanism for this association are needed. PMID- 21246011 TI - The usefulness of an accelerometer for monitoring total energy expenditure and its clinical application for predicting body weight changes in type 2 diabetic korean women. AB - BACKGROUND: The purpose of this study was to evaluate the usefulness of an accelerometer in predicting body weight (BW) change during a lifestyle intervention and to find out whether exercise or overall physical activity is associated with change in insulin sensitivity and body composition. METHODS: A total of 49 overweight (body mass index [BMI] >= 23 kg/m(2)) women with diabetes were enrolled and performed lifestyle intervention while monitoring BW, total energy expenditure (TEE) and physical activity energy expenditure (PAEE) using an accelerometer, and energy intake (EI) using a three-day dietary record at baseline and every 2 weeks for 12 weeks. We assessed body composition using bioimpedance analysis and compared the actual BW change to the predicted BW change, which was calculated from the energy deficit (ED) between EI and TEE (ED = EI-TEE). RESULTS: Mean age was 57.2 years, duration of diabetes was 8.0 years, and BMI was 27.8 kg/m(2). There was no significant difference between EI and TEE at baseline. For 12 weeks, the ED was 474.0 kcal.day(-1), which was significantly correlated with BW change (-3.1 kg) (r = 0.725, P < 0.001). However, the actual BW change was 50% lower than the predicted BW change. Both TEE and PAEE correlated with change in K(ITT) (r = 0.334, P = 0.019; r = 0.358, P = 0.012, respectively), BMI (r = -0.395, P = 0.005; r = -0.347, P = 0.015, respectively), and fat mass (r = -0.383, P = 0.007; r = -0.395, P = 0.005, respectively), but only TEE correlated with fat free mass change (r = -0.314, P = 0.030). CONCLUSION: The accelerometer appears to be a useful tool for measuring TEE under free-living conditions for both short- and long-term periods. PMID- 21246012 TI - Bone mineral density in prediabetic men (korean diabetes j 2010;34:294-302). PMID- 21246013 TI - Bone mineral density in prediabetic men (korean diabetes j 2010;34:294-302). PMID- 21246014 TI - Genesis revisited. PMID- 21246015 TI - Biological effects of a root conditioning agent for dentin surface modification in vitro. AB - PURPOSE: Connective tissue reattachment to periodontally damaged root surfaces is one of the most important goals of periodontal therapy. The aim of this study was to develop a root conditioning agent that can demineralize and detoxify the infected root surface. METHODS: Dentin slices obtained from human teeth were treated with a novel root planing agent for 2 minutes and then washed with phosphate-buffered saline. Smear layer removal and type I collagen exposure were observed by scanning electron microscopy (SEM) and type I collagen immunostaining, respectively. Cell attachment and lipopolysaccharides (LPS) removal demonstrated the efficiency of the root conditioning agent. RESULTS: SEM revealed that the smear layer was entirely removed and the dentinal tubules were opened by the experimental gel. Type I collagen was exposed on the surfaces of the dentin slices treated by the experimental gel, which were compared with dentin treated with other root planing agents. Dentin slices treated with the experimental gel showed the highest number of attached fibroblasts and flattened cell morphology. The agar diffusion assay demonstrated that the experimental gel also has effective antimicrobial activity. Escherichia coli LPS were effectively removed from well plates by the experimental gel. CONCLUSIONS: These results demonstrated that this experimental gel is a useful tool for root conditioning of infected root surfaces and can also be applied for detoxification of ailing implant surface threads. PMID- 21246016 TI - Immunomodulatory effect of canine periodontal ligament stem cells on allogenic and xenogenic peripheral blood mononuclear cells. AB - PURPOSE: The aim of this study was to investigate the immunomodulatory effects of canine periodontal ligament stem cells on allogenic and xenogenic immune cells in vitro. METHODS: Mixed cell cultures consisting of canine stem cells (periodontal ligament stem cells and bone marrow stem cells) and allogenic canine/xenogenic human peripheral blood mononuclear cells (PBMCs) were established following the addition of phytohemagglutinin. The proliferation of PBMCs was evaluated using the MTS assay. The cell division of PBMCs was analyzed using the CFSE assay. The apoptosis of PBMCs was assessed using the trypan blue uptake method. RESULTS: Periodontal ligament stem cells and bone marrow stem cells inhibited the proliferation of allogenic and xenogenic PBMCs. Both periodontal ligament stem cells and bone marrow stem cells suppressed the cell division of PBMCs despite the existence of a mitogen. No significant differences in the percentages of apoptotic PBMCs were found among the groups. CONCLUSIONS: Canine periodontal ligament stem cells have an immunomodulatory effect on allogenic and xenogenic PBMCs. This effect is not a product of apoptosis of PBMCs but is caused by the inhibition of cell division of PBMCs. PMID- 21246017 TI - Histologic evaluation of low-intensity pulsed ultrasound effects on bone regeneration in sinus lift. AB - PURPOSE: Many techniques have been described for achieving vertical augmentation of the maxillary sinus. The aim of this study is to evaluate the effect of low intensity pulsed ultrasound (LIPUS) to enhance bone regeneration after sinus floor elevation. METHODS: The sinus lifting technique was performed through a lateral approach on 8 different sites of 5 patients (3 males and 2 females) and their mean age was 45.7 years old. The sites were randomly assigned to the control or test groups. The control group had 4 sites that received lateral sinus lifting procedure only, while the test group had 4 sites that received LIPUS application after the lateral sinus lifting procedure. 24-32 weeks (an average of 29 weeks) postoperatively, new bone formation in the augmented sinus sites was evaluated through histologic and histomorphometric analyses of the biopsy specimens obtained during implant placement. RESULTS: In the test group, the mean percentage of newly formed bone was 19.0+/-2.8%. In the control group, the mean percentage of newly formed bone was 15.2+/-3.1%. The percentage of newly formed bone was approximately 4% higher in those cases where the sinus was treated by LIPUS than the percentage in those cases where it was not used. The difference was statistically significant. CONCLUSIONS: Within the scope of this study, low intensity pulsed ultrasound application after sinus lifting appeared to have a significant effect on the development of new bone formation. PMID- 21246018 TI - The effect of Er:YAG laser irradiation on the surface microstructure and roughness of hydroxyapatite-coated implant. AB - PURPOSE: The present study was performed to evaluate the effect of erbium:yttrium aluminium-garnet (Er:YAG) laser irradiation on the change of hydroxyapatite (HA) coated implant surface microstructure according to the laser energy and the application time. METHODS: The implant surface was irradiated by Er:YAG laser under combination condition using the laser energy of 100 mJ/pulse, 140 mJ/pulse and 180 mJ/pulse and application time of 1 minute, 1.5 minutes and 2 minutes. The specimens were examined by surface roughness evaluation and scanning electron microscopic observation. RESULTS: In scanning electron microscope, HA-coated implant surface was not altered by Er:YAG laser irradiation under experimental condition on 100 mJ/pulse, 1 minute. Local areas with surface melting and cracks were founded on 100 mJ/pulse, 1.5 minutes and 2 minutes. One hundred forty mJ/pulse and 180 mJ/pulse group had surface melting and peeling area of HA particles, which condition was more severe depending on the increase of application time. Under all experimental condition, the difference of surface roughness value on implant surface was not statistically significant. CONCLUSIONS: Er:YAG laser on HA-coated implant surface is recommended to be irradiated below 100 mJ/pulse, 1 minute for detoxification of implant surface without surface alteration. PMID- 21246019 TI - Incomplete bone formation after sinus augmentation: A case report on radiological findings by computerized tomography at follow-up. AB - PURPOSE: The aim of this case report is to present a case of incomplete bone formation after sinus augmentation. METHODS: A patient having alveolar bone resorption of the maxillary posterior edentulous region and advanced pneumatization of the maxillary sinus was treated with sinus elevation using deproteinized bovine bone in the Department of Periodontology, Kyung Hee University School of Dentistry and re-evaluated with computed tomography (CT) follow-up. RESULTS: Even though there were no significant findings or abnormal radiolucency on the panoramic radiograph, incomplete bone formation in the central portion of the augmented sinus was found fortuitously in the CT scan. The CT scan revealed peri-implant radiolucency in the apical portion of the implant placed in the augmented maxillary sinus. Nevertheless, the dental implants placed in the grafted sinus still functioned well at over 15 months follow-up. CONCLUSIONS: The result of this case suggests that patients who received maxillary sinus augmentation may experience incomplete bone formation. It is possible that 1) osteoconductive graft material with poor osteogenic potential, 2) overpacking of graft material that restricts the blood supply, and 3) bone microbial contamination may cause the appearance of incomplete bone formation after sinus augmentation. Further studies are needed to elucidate the mechanism of this unexpected result and care must be taken to prevent it. PMID- 21246022 TI - Validity and user-friendliness of the minimal eating observation and nutrition form - version II (MEONF - II) for undernutrition risk screening. AB - OBJECTIVE: To analyze the criterion-related validity and user-friendliness of the Minimal Eating Observation and Nutrition Form - Version II (MEONF - II) and Malnutrition Universal Screening Tool (MUST) in relation to the Mini Nutritional Assessment (MNA). In addition, the effect of substituting body mass index (BMI) with calf circumference (CC) was explored for the MEONF-II. METHODS: The study included 100 patients who were assessed for nutritional status with the MNA (full version), considered here to be the gold standard, and screened with the MUST and the MEONF-II. The MEONF-II includes assessments of involuntary weight loss, BMI (or calf circumference), eating difficulties, and presence of clinical signs of undernutrition. RESULTS: The MEONF-II sensitivity (0.73) and specificity (0.88) were acceptable. Sensitivity and specificity for the MUST were 0.57 and 0.93, respectively. Replacing the BMI with CC in the MEONF-II gave similar results (sensitivity 0.68, specificity 0.90). Assessors considered MEONF-II instructions and items to be relevant, easy to understand and complete (100%), and the questions to be relevant (98%). MEONF-II and MUST took 8.8 and 4.7 minutes to complete, respectively, and both were considered relevant and easy to finish. In addition, MEONF-II was thought to reveal problems that allows for nursing interventions. CONCLUSIONS: The MEONF-II is an easy to use, relatively quick, and sensitive screening tool to assess risk of undernutrition among hospital inpatients, which allows for substituting BMI with CC in situations where measures of patient height and weight cannot be easily obtained. High sensitivity is of primary concern in nutritional screening and the MEONF-II outperforms the MUST in this regard. PMID- 21246023 TI - Linnaeus: alive and well. PMID- 21246024 TI - Deficits in the management of patients with adrenocortical carcinoma in Germany. AB - BACKGROUND: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Often, the physicians who first treat patients with ACC have no prior experience with the disease. The aim of our study was to evaluate the quality of medical care for patients with ACC in Germany. METHODS: Data from the German ACC registry were analyzed with regard to the patients' preoperative diagnostic evaluation, histopathological reporting, and clinical follow-up. The findings were compared with the recommendations of the European Network for the Study of Adrenal Tumors (ENSAT). RESULTS: Data were analyzed from 387 patients who had been given an initial diagnosis of ACC in the years 1998 to 2009. 21% of them underwent no hormonal evaluation before surgery, and 59% underwent an inadequate hormonal evaluation. This exposed the patients to unnecessary perioperative risks and impaired their follow-up. 48% did not undergo CT scanning of the chest, even though the lungs are the most frequent site of metastases of ACC. For 13% of the patients, the diagnosis of ACC was later revised by a reference pathologist. For 11% of the patients, the histopathology report contained no information about resection status, even though this is an important determinant of further treatment and prognosis. Optimal management requires re-staging at three-month intervals, yet some patients underwent re-staging only after a longer delay, or not at all. CONCLUSION: We have identified significant deficits in the care of patients with ACC in Germany. We suspect that the situation is similar for other rare diseases. The prerequisite to better care is close and early cooperation of the treating physicians with specialized centers. PMID- 21246025 TI - Modern triage in the emergency department. AB - BACKGROUND: Because the volume of patient admissions to an emergency department (ED) cannot be precisely planned, the available resources may become overwhelmed at times ("crowding"), with resulting risks for patient safety. The aim of this study is to identify modern triage instruments and assess their validity and reliability. METHODS: Review of selected literature retrieved by a search on the terms "emergency department" and "triage." RESULTS: Emergency departments around the world use different triage systems to assess the severity of incoming patients' conditions and assign treatment priorities. Our study identified four such instruments: the Australasian Triage Scale (ATS), the Canadian Triage and Acuity Scale (CTAS), the Manchester Triage System (MTS), and the Emergency Severity Index (ESI). Triage instruments with 5 levels are superior to those with 3 levels in both validity and reliability (p<0.01). Good to very good reliability has been shown for the best-studied instruments, CTAS and ESI (kappa-statistics: 0.7 to 0.95), while ATS and MTS have been found to be only moderately reliable (kappa-statistics: 0.3 to 0.6). MTS and ESI are both available in German; of these two, only the ESI has been validated in German-speaking countries. CONCLUSION: Five-level triage systems are valid and reliable methods for assessment of the severity of incoming patients' conditions by nursing staff in the emergency department. They should be used in German emergency departments to assign treatment priorities in a structured and dependable fashion. PMID- 21246026 TI - Correspondence (letter to the editor):Definition of age. PMID- 21246027 TI - Correspondence (letter to the editor): Computerized Physician Order System (CPOE). PMID- 21246028 TI - Correspondence (letter to the editor):Pain Therapy. PMID- 21246031 TI - Correspondence (letter to the editor):Inconsistent terminology. PMID- 21246032 TI - Influences of the common FTO rs9939609 variant on inflammatory markers throughout a broad range of body mass index. AB - BACKGROUND: A recent study reported that the fatness associated A-allele of FTO rs9939609 increased plasma high sensitivity C-reactive protein (hs-CRP) levels independent of fatness. We aimed to investigate if this gene variant had fatness independent effects on plasma hs-CRP and 10 additional circulating obesity related adipokines throughout a broad range of body mass index (BMI) among Danish men. METHODOLOGY/PRINCIPAL FINDINGS: In a population of 362,200 young men, examined for military service between 1943 and 1977, two groups were identified: 1) a random 1% sample and 2) all obese men (BMI = 31.0 kg/m(2), all of whom were above the 99(th) percentile of this population). At an average age of 49 years (range: 39 through 65 years), 551 men, hereof 231 of the obese, were re-examined, including genotyping and measurement of the fasting circulating inflammatory markers hs-CRP, IL-1beta, IL-6, IL-10, IL-18, mip1alpha, mip1beta, sTNFalpha-R1, TGF-beta, TNF-alpha and leptin. Men with known disease were excluded from the examination. All the inflammatory markers were log-transformed to approximate a normal distribution. Genotype-phenotype relationships were studied using linear regression analyses with the inflammatory markers as the response variable. Significant positive associations between hs-CRP, leptin and a broad range of BMI were observed, but the associations did not significantly differ across FTO rs9939609 genotype. There were no significant associations between the other inflammatory markers, FTO rs9939609 genotype or BMI, respectively. CONCLUSION: No fatness-independent effects of the FTO rs9939609 A-allele on a series of inflammatory markers were observed in this cohort of healthy middle-aged men representing a broad range of fatness. PMID- 21246033 TI - Can score databanks help teaching? AB - BACKGROUND: Basic courses in most medical schools assess students' performance by conferring scores. The objective of this work is to use a large score databank for the early identification of students with low performance and to identify course trends based on the mean of students' grades. METHODOLOGY/PRINCIPAL FINDINGS: We studied scores from 2,398 medical students registered in courses over a period of 10 years. Students in the first semester were grouped into those whose ratings remained in the lower quartile in two or more courses (low performance) and students who had up to one course in the lower quartile (high performance). ROC curves were built, aimed at the identification of a cut-off average score in the first semesters that would be able to predict low performances in future semesters. Moreover, to follow the long-term pattern of each course, the mean of all scores conferred in a semester was compared to the overall course mean obtained by averaging 10 years of data. Individuals in the low-performance group had a higher risk of being in the lower quartile of at least one course in the second semester (relative risk 3.907; 95% CI: 3.378 4.519) and in the eighth semester (relative risk 2.873; 95% CI: 2.495-3.308). The prediction analysis revealed that an average score of 7.188 in the first semester could identify students that presented scores below the lower quartiles in both the second and eighth semesters (p<0.0001 for both AUC). When scores conferred by single courses were compared over time, three time-trend patterns emerged: low variation, upward trend and erratic pattern. CONCLUSION/SIGNIFICANCE: An early identification of students with low performance may be useful in promoting pedagogical strategies for these individuals. Evaluation of the time trend of scores conferred by courses may help departments monitoring changes in personnel and methodology that may affect a student's performance. PMID- 21246034 TI - Pressure load: the main factor for altered gene expression in right ventricular hypertrophy in chronic hypoxic rats. AB - BACKGROUND: The present study investigated whether changes in gene expression in the right ventricle following pulmonary hypertension can be attributed to hypoxia or pressure loading. METHODOLOGY/PRINCIPAL FINDINGS: To distinguish hypoxia from pressure-induced alterations, a group of rats underwent banding of the pulmonary trunk (PTB), sham operation, or the rats were exposed to normoxia or chronic, hypobaric hypoxia. Pressure measurements were performed and the right ventricle was analyzed by Affymetrix GeneChip, and selected genes were confirmed by quantitative PCR and immunoblotting. Right ventricular systolic blood pressure and right ventricle to body weight ratio were elevated in the PTB and the hypoxic rats. Expression of the same 172 genes was altered in the chronic hypoxic and PTB rats. Thus, gene expression of enzymes participating in fatty acid oxidation and the glycerol channel were downregulated. mRNA expression of aquaporin 7 was downregulated, but this was not the case for the protein expression. In contrast, monoamine oxidase A and tissue transglutaminase were upregulated both at gene and protein levels. 11 genes (e.g. insulin-like growth factor binding protein) were upregulated in the PTB experiment and downregulated in the hypoxic experiment, and 3 genes (e.g. c-kit tyrosine kinase) were downregulated in the PTB and upregulated in the hypoxic experiment. CONCLUSION/SIGNIFICANCE: Pressure load of the right ventricle induces a marked shift in the gene expression, which in case of the metabolic genes appears compensated at the protein level, while both expression of genes and proteins of importance for myocardial function and remodelling are altered by the increased pressure load of the right ventricle. These findings imply that treatment of pulmonary hypertension should also aim at reducing right ventricular pressure. PMID- 21246035 TI - Environmental modeling and exposure assessment of sediment-associated pyrethroids in an agricultural watershed. AB - Synthetic pyrethroid insecticides have generated public concerns due to their increasing use and potential effects on aquatic ecosystems. A modeling system was developed in this study for simulating the transport processes and associated sediment toxicity of pyrethroids at coupled field/watershed scales. The model was tested in the Orestimba Creek watershed, an agriculturally intensive area in California' Central Valley. Model predictions were satisfactory when compared with measured suspended solid concentration (R(2) = 0.536), pyrethroid toxic unit (0.576), and cumulative mortality of Hyalella azteca (0.570). The results indicated that sediment toxicity in the study area was strongly related to the concentration of pyrethroids in bed sediment. Bifenthrin was identified as the dominant contributor to the sediment toxicity in recent years, accounting for 50 85% of predicted toxicity units. In addition, more than 90% of the variation on the annual maximum toxic unit of pyrethroids was attributed to precipitation and prior application of bifenthrin in the late irrigation season. As one of the first studies simulating the dynamics and spatial variability of pyrethroids in fields and instreams, the modeling results provided useful information on new policies to be considered with respect to pyrethroid regulation. This study suggested two potential measures to efficiently reduce sediment toxicity by pyrethroids in the study area: [1] limiting bifenthrin use immediately before rainfall season; and [2] implementing conservation practices to retain soil on cropland. PMID- 21246036 TI - Identification and characterization of Ixodes scapularis antigens that elicit tick immunity using yeast surface display. AB - Repeated exposure of rabbits and other animals to ticks results in acquired resistance or immunity to subsequent tick bites and is partially elicited by antibodies directed against tick antigens. In this study we demonstrate the utility of a yeast surface display approach to identify tick salivary antigens that react with tick-immune serum. We constructed an Ixodes scapularis nymphal salivary gland yeast surface display library and screened the library with nymph immune rabbit sera and identified five salivary antigens. Four of these proteins, designated P8, P19, P23 and P32, had a predicted signal sequence. We generated recombinant (r) P8, P19 and P23 in a Drosophila expression system for functional and immunization studies. rP8 showed anti-complement activity and rP23 demonstrated anti-coagulant activity. Ixodes scapularis feeding was significantly impaired when nymphs were fed on rabbits immunized with a cocktail of rP8, rP19 and rP23, a hall mark of tick-immunity. These studies also suggest that these antigens may serve as potential vaccine candidates to thwart tick feeding. PMID- 21246037 TI - Extending the Implicit Association Test (IAT): assessing consumer attitudes based on multi-dimensional implicit associations. AB - BACKGROUND: The authors present a procedural extension of the popular Implicit Association Test (IAT) that allows for indirect measurement of attitudes on multiple dimensions (e.g., safe-unsafe; young-old; innovative-conventional, etc.) rather than on a single evaluative dimension only (e.g., good-bad). METHODOLOGY/PRINCIPAL FINDINGS: In two within-subjects studies, attitudes toward three automobile brands were measured on six attribute dimensions. Emphasis was placed on evaluating the methodological appropriateness of the new procedure, providing strong evidence for its reliability, validity, and sensitivity. CONCLUSIONS/SIGNIFICANCE: This new procedure yields detailed information on the multifaceted nature of brand associations that can add up to a more abstract overall attitude. Just as the IAT, its multi-dimensional extension/application (dubbed md-IAT) is suited for reliably measuring attitudes consumers may not be consciously aware of, able to express, or willing to share with the researcher. PMID- 21246038 TI - Predicting changes of body weight, body fat, energy expenditure and metabolic fuel selection in C57BL/6 mice. AB - The mouse is an important model organism for investigating the molecular mechanisms of body weight regulation, but a quantitative understanding of mouse energy metabolism remains lacking. Therefore, we created a mathematical model of mouse energy metabolism to predict dynamic changes of body weight, body fat, energy expenditure, and metabolic fuel selection. Based on the principle of energy balance, we constructed ordinary differential equations representing the dynamics of body fat mass (FM) and fat-free mass (FFM) as a function of dietary intake and energy expenditure (EE). The EE model included the cost of tissue deposition, physical activity, diet-induced thermogenesis, and the influence of FM and FFM on metabolic rate. The model was calibrated using previously published data and validated by comparing its predictions to measurements in five groups of male C57/BL6 mice (N = 30) provided ad libitum access to either chow or high fat diets for varying time periods. The mathematical model accurately predicted the observed body weight and FM changes. Physical activity was predicted to decrease immediately upon switching from the chow to the high fat diet and the model coefficients relating EE to FM and FFM agreed with previous independent estimates. Metabolic fuel selection was predicted to depend on a complex interplay between diet composition, the degree of energy imbalance, and body composition. This is the first validated mathematical model of mouse energy metabolism and it provides a quantitative framework for investigating energy balance relationships in mouse models of obesity and diabetes. PMID- 21246039 TI - Ex vivo activity of cardiac glycosides in acute leukaemia. AB - BACKGROUND: Despite years of interest in the anti-cancerous effects of cardiac glycosides (CGs), and numerous studies in vitro and in animals, it has not yet been possible to utilize this potential clinically. Reports have demonstrated promising in vitro effects on different targets as well as a possible therapeutic index/selectivity in vitro and in experimental animals. Recently, however, general inhibition of protein synthesis was suggested as the main mechanism of the anti-cancerous effects of CGs. In addition, evidence of species differences of a magnitude sufficient to explain the results of many studies called for reconsideration of earlier results. PRINCIPAL FINDINGS: In this report we identified primary B-precursor and T-ALL cells as being particularly susceptible to the cytotoxic effects of CGs. Digitoxin appeared most potent and IC(50) values for several patient samples were at concentrations that may be achieved in the clinic. Significant protein synthesis inhibition at concentrations corresponding to IC(50) was demonstrated in colorectal tumour cell lines moderately resistant to the cytotoxic effects of digoxin and digitoxin, but not in highly sensitive leukaemia cell lines. CONCLUSION: It is suggested that further investigation regarding CGs may be focused on diagnoses like T- and B-precursor ALL. PMID- 21246040 TI - Interaction of Sesbania mosaic virus movement protein with VPg and P10: implication to specificity of genome recognition. AB - Sesbania mosaic virus (SeMV) is a single strand positive-sense RNA plant virus that belongs to the genus Sobemovirus. The mechanism of cell-to-cell movement in sobemoviruses has not been well studied. With a view to identify the viral encoded ancillary proteins of SeMV that may assist in cell-to-cell movement of the virus, all the proteins encoded by SeMV genome were cloned into yeast Matchmaker system 3 and interaction studies were performed. Two proteins namely, viral protein genome linked (VPg) and a 10-kDa protein (P10) c v gft encoded by OFR 2a, were identified as possible interacting partners in addition to the viral coat protein (CP). Further characterization of these interactions revealed that the movement protein (MP) recognizes cognate RNA through interaction with VPg, which is covalently linked to the 5' end of the RNA. Analysis of the deletion mutants delineated the domains of MP involved in the interaction with VPg and P10. This study implicates for the first time that VPg might play an important role in specific recognition of viral genome by MP in SeMV and shed light on the possible role of P10 in the viral movement. PMID- 21246041 TI - Hepatitis B virus lacks immune activating capacity, but actively inhibits plasmacytoid dendritic cell function. AB - Chronic hepatitis B virus (HBV) infection is caused by inadequate anti-viral immunity. Activation of plasmacytoid dendritic cells (pDC) leading to IFNalpha production is important for effective anti-viral immunity. Hepatitis B virus (HBV) infection lacks IFNalpha induction in animal models and patients and chronic HBV patients display impaired IFNalpha production by pDC. Therefore, HBV and HBV-derived proteins were examined for their effect on human pDC in vitro. In addition, the in vitro findings were compared to the function of pDC derived from chronic HBV patients ex vivo. In contrast to other viruses, HBV did not activate pDC. Moreover, HBV and HBsAg abrogated CpG-A/TLR9-induced, but not Loxoribine/TLR7-induced, mTOR-mediated S6 phosphorylation, subsequent IRF7 phosphorylation and IFNalpha gene transcription. HBV/HBsAg also diminished upregulation of co-stimulatory molecules, production of TNFalpha, IP-10 and IL-6 and pDC-induced NK cell function, whereas TLR7-induced pDC function was hardly affected. In line, HBsAg preferentially bound to TLR9-triggered pDC demonstrating that once pDC are able to bind HBV/HBsAg, the virus exerts its immune regulatory effect. HBV not only directly interfered with pDC function, but also indirectly by interfering with monocyte-pDC interaction. Also HBeAg diminished pDC function to a certain extent, but via another unknown mechanism. Interestingly, patients with HBeAg-positive chronic hepatitis B displayed impaired CpG-induced IFNalpha production by pDC without significant alterations in Loxoribine-induced pDC function compared to HBeAg-negative patients and healthy controls. The lack of activation and the active inhibition of pDC by HBV may both contribute to HBV persistence. The finding that the interaction between pDC and HBV may change upon activation may aid in the identification of a scavenging receptor supporting immunosuppressive effects of HBV and also in the design of novel treatment strategies for chronic HBV. PMID- 21246042 TI - Lack of trehalose accelerates H2O2-induced Candida albicans apoptosis through regulating Ca2+ signaling pathway and caspase activity. AB - Trehalose is a non-reducing disaccharide and can be accumulated in response to heat or oxidative stresses in Candida albicans. Here we showed that a C. albicans tps1Delta mutant, which is deficient in trehalose synthesis, exhibited increased apoptosis rate upon H(2)O(2) treatment together with an increase of intracellular Ca(2+) level and caspase activity. When the intracellular Ca(2+) level was stimulated by adding CaCl(2) or A23187, both the apoptosis rate and caspase activity were increased. In contrast, the presence of two calcium chelators, EGTA and BAPTA, could attenuate these effects. Moreover, we investigated the role of Ca(2+) pathway in C. albicans apoptosis and found that both calcineurin and the calcineurin-dependent transcription factor, Crz1p, mutants showed decreased apoptosis and caspase activity upon H(2)O(2) treatment compared to the wild-type cells. Expression of CaMCA1, the only gene found encoding a C. albicans metacaspase, in calcineurin-deleted or Crz1p-deleted cells restored the cell sensitivity to H(2)O(2). Our results suggest that Ca(2+) and its downstream calcineurin/Crz1p/CaMCA1 pathway are involved in H(2)O(2)-induced C. albicans apoptosis. Inhibition of this pathway might be the mechanism for the protective role of trehalose in C. albicans. PMID- 21246043 TI - Applying an empirical hydropathic forcefield in refinement may improve low resolution protein X-ray crystal structures. AB - BACKGROUND: The quality of X-ray crystallographic models for biomacromolecules refined from data obtained at high-resolution is assured by the data itself. However, at low-resolution, >3.0 A, additional information is supplied by a forcefield coupled with an associated refinement protocol. These resulting structures are often of lower quality and thus unsuitable for downstream activities like structure-based drug discovery. METHODOLOGY: An X-ray crystallography refinement protocol that enhances standard methodology by incorporating energy terms from the HINT (Hydropathic INTeractions) empirical forcefield is described. This protocol was tested by refining synthetic low resolution structural data derived from 25 diverse high-resolution structures, and referencing the resulting models to these structures. The models were also evaluated with global structural quality metrics, e.g., Ramachandran score and MolProbity clashscore. Three additional structures, for which only low-resolution data are available, were also re-refined with this methodology. RESULTS: The enhanced refinement protocol is most beneficial for reflection data at resolutions of 3.0 A or worse. At the low-resolution limit, >=4.0 A, the new protocol generated models with Calpha positions that have RMSDs that are 0.18 A more similar to the reference high-resolution structure, Ramachandran scores improved by 13%, and clashscores improved by 51%, all in comparison to models generated with the standard refinement protocol. The hydropathic forcefield terms are at least as effective as Coulombic electrostatic terms in maintaining polar interaction networks, and significantly more effective in maintaining hydrophobic networks, as synthetic resolution is decremented. Even at resolutions >=4.0 A, these latter networks are generally native-like, as measured with a hydropathic interactions scoring tool. PMID- 21246044 TI - Variation in Symbiodinium ITS2 sequence assemblages among coral colonies. AB - Endosymbiotic dinoflagellates in the genus Symbiodinium are fundamentally important to the biology of scleractinian corals, as well as to a variety of other marine organisms. The genus Symbiodinium is genetically and functionally diverse and the taxonomic nature of the union between Symbiodinium and corals is implicated as a key trait determining the environmental tolerance of the symbiosis. Surprisingly, the question of how Symbiodinium diversity partitions within a species across spatial scales of meters to kilometers has received little attention, but is important to understanding the intrinsic biological scope of a given coral population and adaptations to the local environment. Here we address this gap by describing the Symbiodinium ITS2 sequence assemblages recovered from colonies of the reef building coral Montipora capitata sampled across Kane'ohe Bay, Hawai'i. A total of 52 corals were sampled in a nested design of Coral Colony(Site(Region)) reflecting spatial scales of meters to kilometers. A diversity of Symbiodinium ITS2 sequences was recovered with the majority of variance partitioning at the level of the Coral Colony. To confirm this result, the Symbiodinium ITS2 sequence diversity in six M. capitata colonies were analyzed in much greater depth with 35 to 55 clones per colony. The ITS2 sequences and quantitative composition recovered from these colonies varied significantly, indicating that each coral hosted a different assemblage of Symbiodinium. The diversity of Symbiodinium ITS2 sequence assemblages retrieved from individual colonies of M. capitata here highlights the problems inherent in interpreting multi-copy and intra-genomically variable molecular markers, and serves as a context for discussing the utility and biological relevance of assigning species names based on Symbiodinium ITS2 genotyping. PMID- 21246045 TI - Long-distance effects of insertional mutagenesis. AB - BACKGROUND: Most common systems of genetic engineering of mammalian cells are associated with insertional mutagenesis of the modified cells. Insertional mutagenesis is also a popular approach to generate random alterations for gene discovery projects. A better understanding of the interaction of the structural elements within an insertional mutagen and the ability of such elements to influence host genes at various distances away from the insertion site is a matter of considerable practical importance. METHODOLOGY/PRINCIPAL FINDINGS: We observed that, in the context of a lentiviral construct, a transcript, which is initiated at an internal CMV promoter/enhancer region and incorporates a splice donor site, is able to extend past a collinear viral LTR and trap exons of host genes, while the polyadenylation signal, which is naturally present in the LTR, is spliced out. Unexpectedly, when a vector, which utilizes this phenomenon, was used to produce mutants with elevated activity of NF-kappaB, we found mutants, which owed their phenotype to the effect of the insert on a gene located tens or even hundreds of kilobases away from the insertion site. This effect did not result from a CMV-driven transcript, but was sensitive to functional suppression of the insert. Interestingly, despite the long-distance effect, expression of loci most closely positioned to the insert appeared unaffected. CONCLUSIONS/SIGNIFICANCE: We concluded that a polyadenylation signal in a retroviral LTR, when occurring within an intron, is an inefficient barrier against the formation of a hybrid transcript, and that a vector containing a strong enhancer may selectively affect the function of genes far away from its insertion site. These phenomena have to be considered when experimental or therapeutic transduction is performed. In particular, the long-distance effects of insertional mutagenesis bring into question the relevance of the lists of disease-associated retroviral integration targets, which did not undergo functional validation. PMID- 21246046 TI - Connections between classical and parametric network entropies. AB - This paper explores relationships between classical and parametric measures of graph (or network) complexity. Classical measures are based on vertex decompositions induced by equivalence relations. Parametric measures, on the other hand, are constructed by using information functions to assign probabilities to the vertices. The inequalities established in this paper relating classical and parametric measures lay a foundation for systematic classification of entropy-based measures of graph complexity. PMID- 21246047 TI - Adult raphe-specific deletion of Lmx1b leads to central serotonin deficiency. AB - The transcription factor Lmx1b is essential for the differentiation and survival of central serotonergic (5-HTergic) neurons during embryonic development. However, the role of Lmx1b in adult 5-HTergic neurons is unknown. We used an inducible Cre-LoxP system to selectively inactivate Lmx1b expression in the raphe nuclei of adult mice. Pet1-CreER(T2) mice were generated and crossed with Lmx1b(flox/flox) mice to obtain Pet1-CreER(T2); Lmx1b(flox/flox) mice (which termed as Lmx1b iCKO). After administration of tamoxifen, the level of 5-HT in the brain of Lmx1b iCKO mice was reduced to 60% of that in control mice, and the expression of tryptophan hydroxylase 2 (Tph2), serotonin transporter (Sert) and vesicular monoamine transporter 2 (Vmat2) was greatly down-regulated. On the other hand, the expression of dopamine and norepinephrine as well as aromatic L amino acid decarboxylase (Aadc) and Pet1 was unchanged. Our results reveal that Lmx1b is required for the biosynthesis of 5-HT in adult mouse brain, and it may be involved in maintaining normal functions of central 5-HTergic neurons by regulating the expression of Tph2, Sert and Vmat2. PMID- 21246048 TI - Compensatory development and costs of plasticity: larval responses to desiccated conspecifics. AB - Understanding constraints on phenotypic plasticity is central to explaining its evolution and the evolution of phenotypes in general, yet there is an ongoing debate on the classification and relationships among types of constraints. Since plasticity is often a developmental process, studies that consider the ontogeny of traits and their developmental mechanisms are beneficial. We manipulated the timing and reliability of cues perceived by fire salamander larvae for the future desiccation of their ephemeral pools to determine whether flexibility in developmental rates is constrained to early ontogeny. We hypothesized that higher rates of development, and particularly compensation for contradictory cues, would incur greater endogenous costs. We found that larvae respond early in ontogeny to dried conspecifics as a cue for future desiccation, but can fully compensate for this response in case more reliable but contradictory cues are later perceived. Patterns of mortality suggested that endogenous costs may depend on instantaneous rates of development, and revealed asymmetrical costs of compensatory development between false positive and false negative early information. Based on the results, we suggest a simple model of costs of development that implies a tradeoff between production costs of plasticity and phenotype-environment mismatch costs, which may potentially underlie the phenomenon of ontogenetic windows constraining plasticity. PMID- 21246049 TI - The emergence of Miller's magic number on a sparse distributed memory. AB - Human memory is limited in the number of items held in one's mind--a limit known as "Miller's magic number". We study the emergence of such limits as a result of the statistics of large bitvectors used to represent items in memory, given two postulates: i) the Sparse Distributed Memory; and ii) chunking through averaging. Potential implications for theoretical neuroscience are discussed. PMID- 21246050 TI - Stiffness gradients mimicking in vivo tissue variation regulate mesenchymal stem cell fate. AB - Mesenchymal stem cell (MSC) differentiation is regulated in part by tissue stiffness, yet MSCs can often encounter stiffness gradients within tissues caused by pathological, e.g., myocardial infarction ~8.7+/-1.5 kPa/mm, or normal tissue variation, e.g., myocardium ~0.6+/-0.9 kPa/mm; since migration predominantly occurs through physiological rather than pathological gradients, it is not clear whether MSC differentiate or migrate first. MSCs cultured up to 21 days on a hydrogel containing a physiological gradient of 1.0+/-0.1 kPa/mm undergo directed migration, or durotaxis, up stiffness gradients rather than remain stationary. Temporal assessment of morphology and differentiation markers indicates that MSCs migrate to stiffer matrix and then differentiate into a more contractile myogenic phenotype. In those cells migrating from soft to stiff regions however, phenotype is not completely determined by the stiff hydrogel as some cells retain expression of a neural marker. These data may indicate that stiffness variation, not just stiffness alone, can be an important regulator of MSC behavior. PMID- 21246051 TI - Heparan sulfate proteoglycans mediate interstitial flow mechanotransduction regulating MMP-13 expression and cell motility via FAK-ERK in 3D collagen. AB - BACKGROUND: Interstitial flow directly affects cells that reside in tissues and regulates tissue physiology and pathology by modulating important cellular processes including proliferation, differentiation, and migration. However, the structures that cells utilize to sense interstitial flow in a 3-dimensional (3D) environment have not yet been elucidated. Previously, we have shown that interstitial flow upregulates matrix metalloproteinase (MMP) expression in rat vascular smooth muscle cells (SMCs) and fibroblasts/myofibroblasts via activation of an ERK1/2-c-Jun pathway, which in turn promotes cell migration in collagen. Herein, we focused on uncovering the flow-induced mechanotransduction mechanism in 3D. METHODOLOGY/PRINCIPAL FINDINGS: Cleavage of rat vascular SMC surface glycocalyx heparan sulfate (HS) chains from proteoglycan (PG) core proteins by heparinase or disruption of HS biosynthesis by silencing N-deacetylase/N sulfotransferase 1 (NDST1) suppressed interstitial flow-induced ERK1/2 activation, interstitial collagenase (MMP-13) expression, and SMC motility in 3D collagen. Inhibition or knockdown of focal adhesion kinase (FAK) also attenuated or blocked flow-induced ERK1/2 activation, MMP-13 expression, and cell motility. Interstitial flow induced FAK phosphorylation at Tyr925, and this activation was blocked when heparan sulfate proteoglycans (HSPGs) were disrupted. These data suggest that HSPGs mediate interstitial flow-induced mechanotransduction through FAK-ERK. In addition, we show that integrins are crucial for mechanotransduction through HSPGs as they mediate cell spreading and maintain cytoskeletal rigidity. CONCLUSIONS/SIGNIFICANCE: We propose a conceptual mechanotransduction model wherein cell surface glycocalyx HSPGs, in the presence of integrin-mediated cell matrix adhesions and cytoskeleton organization, sense interstitial flow and activate the FAK-ERK signaling axis, leading to upregulation of MMP expression and cell motility in 3D. This is the first study to describe a flow-induced mechanotransduction mechanism via HSPG-mediated FAK activation in 3D. This study will be of interest in understanding the flow-related mechanobiology in vascular lesion formation, tissue morphogenesis, cancer cell metastasis, and stem cell differentiation in 3D, and also has implications in tissue engineering. PMID- 21246052 TI - An antiretroviral/zinc combination gel provides 24 hours of complete protection against vaginal SHIV infection in macaques. AB - BACKGROUND: Repeated use, coitus-independent microbicide gels that do not contain antiretroviral agents also used as first line HIV therapy are urgently needed to curb HIV spread. Current formulations require high doses (millimolar range) of antiretroviral drugs and typically only provide short-term protection in macaques. We used the macaque model to test the efficacy of a novel combination microbicide gel containing zinc acetate and micromolar doses of the novel non nucleoside reverse transcriptase inhibitor MIV-150 for up to 24 h after repeated gel application. METHODS AND FINDINGS: Rhesus macaques were vaginally challenged with SHIV-RT up to 24 h after repeated administration of microbicide versus placebo gels. Infection status was determined by measuring virologic and immunologic parameters. Combination microbicide gels containing 14 mM zinc acetate dihydrate and 50 uM MIV-150 afforded full protection (21 of 21 animals) for up to 24 h after 2 weeks of daily application. Partial protection was achieved with the MIV-150 gel (56% of control at 8 h after last application, 11% at 24 h), while the zinc acetate gel afforded more pronounced protection (67% at 8-24 h). Marked protection persisted when the zinc acetate or MIV-150/zinc acetate gels were applied every other day for 4 weeks prior to challenge 24 h after the last gel was administered (11 of 14 protected). More MIV-150 was associated with cervical tissue 8 h after daily dosing of MIV-150/zinc acetate versus MIV-150, while comparable MIV-150 levels were associated with vaginal tissues and at 24 h. CONCLUSIONS: A combination MIV-150/zinc acetate gel and a zinc acetate gel provide significant protection against SHIV-RT infection for up to 24 h. This represents a novel advancement, identifying microbicides that do not contain anti-viral agents used to treat HIV infection and which can be used repeatedly and independently of coitus, and underscores the need for future clinical testing of their safety and ability to prevent HIV transmission in humans. PMID- 21246053 TI - Irreversible AE1 tyrosine phosphorylation leads to membrane vesiculation in G6PD deficient red cells. AB - BACKGROUND: While G6PD deficiency is one of the major causes of acute hemolytic anemia, the membrane changes leading to red cell lysis have not been extensively studied. New findings concerning the mechanisms of G6PD deficient red cell destruction may facilitate our understanding of the large individual variations in susceptibility to pro-oxidant compounds and aid the prediction of the hemolytic activity of new drugs. METHODOLOGY/PRINCIPAL FINDINGS: Our results show that treatment of G6PD deficient red cells with diamide (0.25 mM) or divicine (0.5 mM) causes: (1) an increase in the oxidation and tyrosine phosphorylation of AE1; (2) progressive recruitment of phosphorylated AE1 in large membrane complexes which also contain hemichromes; (3) parallel red cell lysis and a massive release of vesicles containing hemichromes. We have observed that inhibition of AE1 phosphorylation by Syk kinase inhibitors prevented its clustering and the membrane vesiculation while increases in AE1 phosphorylation by tyrosine phosphatase inhibitors increased both red cell lysis and vesiculation rates. In control RBCs we observed only transient AE1 phosphorylation. CONCLUSIONS/SIGNIFICANCE: Collectively, our findings indicate that persistent tyrosine phosphorylation produces extensive membrane destabilization leading to the loss of vesicles which contain hemichromes. The proposed mechanism of hemolysis may be applied to other hemolytic diseases characterized by the accumulation of hemoglobin denaturation products. PMID- 21246054 TI - The relationship between diet breadth and geographic range size in the butterfly subfamily Nymphalinae--a study of global scale. AB - The "oscillation hypothesis" has been proposed as a general explanation for the exceptional diversification of herbivorous insect species. The hypothesis states that speciation rates are elevated through repeated correlated changes- oscillations--in degree of host plant specificity and geographic range. The aim of this study is to test one of the predictions from the oscillation hypothesis: a positive correlation between diet breadth (number of host plants used) and geographic range size, using the globally distributed butterfly subfamily Nymphalinae. Data on diet breadth and global geographic range were collected for 182 Nymphalinae butterflies species and the size of the geographic range was measured using a GIS. We tested both diet breadth and geographic range size for phylogenetic signal to see if species are independent of each other with respect to these characters. As this test gave inconclusive results, data was analysed both using cross-species comparisons and taking phylogeny into account using generalised estimating equations as applied in the APE package in R. Irrespective of which method was used, we found a significant positive correlation between diet breadth and geographic range size. These results are consistent for two different measures of diet breadth and removal of outliers. We conclude that the global range sizes of Nymphalinae butterflies are correlated to diet breadth. That is, butterflies that feed on a large number of host plants tend to have larger geographic ranges than do butterflies that feed on fewer plants. These results lend support for an important step in the oscillation hypothesis of plant driven diversification, in that it can provide the necessary fuel for future population fragmentation and speciation. PMID- 21246055 TI - Rapid host defense against Aspergillus fumigatus involves alveolar macrophages with a predominance of alternatively activated phenotype. AB - The ubiquitous fungus Aspergillus fumigatus is associated with chronic diseases such as invasive pulmonary aspergillosis in immunosuppressed patients and allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis or severe asthma. Because of constant exposure to this fungus, it is critical for the host to exercise an immediate and decisive immune response to clear fungal spores to ward off disease. In this study, we observed that rapidly after infection by A. fumigatus, alveolar macrophages predominantly express Arginase 1 (Arg1), a key marker of alternatively activated macrophages (AAMs). The macrophages were also found to express Ym1 and CD206 that are also expressed by AAMs but not NOS2, which is expressed by classically activated macrophages. The expression of Arg1 was reduced in the absence of the known signaling axis, IL 4Ralpha/STAT6, for AAM development. While both Dectin-1 and TLR expressed on the cell surface have been shown to sense A. fumigatus, fungus-induced Arg1 expression in CD11c(+) alveolar macrophages was not dependent on either Dectin-1 or the adaptor MyD88 that mediates intracellular signaling by most TLRs. Alveolar macrophages from WT mice efficiently phagocytosed fungal conidia, but those from mice deficient in Dectin-1 showed impaired fungal uptake. Depletion of macrophages with clodronate-filled liposomes increased fungal burden in infected mice. Collectively, our studies suggest that alveolar macrophages, which predominantly acquire an AAM phenotype following A. fumigatus infection, have a protective role in defense against this fungus. PMID- 21246056 TI - Determination of somatic and cancer stem cell self-renewing symmetric division rate using sphere assays. AB - Representing a renewable source for cell replacement, neural stem cells have received substantial attention in recent years. The neurosphere assay represents a method to detect the presence of neural stem cells, however owing to a deficiency of specific and definitive markers to identify them, their quantification and the rate they expand is still indefinite. Here we propose a mathematical interpretation of the neurosphere assay allowing actual measurement of neural stem cell symmetric division frequency. The algorithm of the modeling demonstrates a direct correlation between the overall cell fold expansion over time measured in the sphere assay and the rate stem cells expand via symmetric division. The model offers a methodology to evaluate specifically the effect of diseases and treatments on neural stem cell activity and function. Not only providing new insights in the evaluation of the kinetic features of neural stem cells, our modeling further contemplates cancer biology as cancer stem-like cells have been suggested to maintain tumor growth as somatic stem cells maintain tissue homeostasis. Indeed, tumor stem cell's resistance to therapy makes these cells a necessary target for effective treatment. The neurosphere assay mathematical model presented here allows the assessment of the rate malignant stem-like cells expand via symmetric division and the evaluation of the effects of therapeutics on the self-renewal and proliferative activity of this clinically relevant population that drive tumor growth and recurrence. PMID- 21246057 TI - Docosahexaenoic acid-derived neuroprotectin D1 induces neuronal survival via secretase- and PPARgamma-mediated mechanisms in Alzheimer's disease models. AB - Neuroprotectin D1 (NPD1) is a stereoselective mediator derived from the omega-3 essential fatty acid docosahexaenoic acid (DHA) with potent inflammatory resolving and neuroprotective bioactivity. NPD1 reduces Abeta42 peptide release from aging human brain cells and is severely depleted in Alzheimer's disease (AD) brain. Here we further characterize the mechanism of NPD1's neurogenic actions using 3xTg-AD mouse models and human neuronal-glial (HNG) cells in primary culture, either challenged with Abeta42 oligomeric peptide, or transfected with beta amyloid precursor protein (betaAPP)(sw) (Swedish double mutation APP695(sw), K595N-M596L). We also show that NPD1 downregulates Abeta42-triggered expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2) and of B-94 (a TNF-alpha inducible pro-inflammatory element) and apoptosis in HNG cells. Moreover, NPD1 suppresses Abeta42 peptide shedding by down-regulating beta-secretase-1 (BACE1) while activating the alpha-secretase ADAM10 and up-regulating sAPPalpha, thus shifting the cleavage of betaAPP holoenzyme from an amyloidogenic into the non amyloidogenic pathway. Use of the thiazolidinedione peroxisome proliferator activated receptor gamma (PPARgamma) agonist rosiglitazone, the irreversible PPARgamma antagonist GW9662, and overexpressing PPARgamma suggests that the NPD1 mediated down-regulation of BACE1 and Abeta42 peptide release is PPARgamma dependent. In conclusion, NPD1 bioactivity potently down regulates inflammatory signaling, amyloidogenic APP cleavage and apoptosis, underscoring the potential of this lipid mediator to rescue human brain cells in early stages of neurodegenerations. PMID- 21246058 TI - CT Ventriculography for diagnosis of occult ventricular cysticerci. AB - BACKGROUND: Neurocysticercosis is the most common parasitic infection of the central nervous system (CNS). Intraventricular lesions are seen in 7-20% of CNS cysticercosis. Intraventricular lesions can be missed by computed tomography (CT) and magnetic resonance imaging (MRI) as they are typically isodense/isointense to the cerebrospinal fluid. We present our experience with CT ventriculography to visualize occult cysts. CASE DESCRIPTION: Two patients presented with hydrocephalus and suspected neurocysticercosis were evaluated with CT and MRI with and without contrast failing to reveal intraventricular lesions. CT ventriculography was used: 10 ml of cerebrospinal fluid was drained from the ventriculostomy catheter, and 10 ml of iohexol 240 diluted 1:1 with preservative free saline was injected through the ventriculostomy catheter. Immediate CT of the brain was performed. The first patient had multiple cysts located throughout the body of the left lateral ventricle. The second patient had a single lesion located in the body of the lateral ventricle. The CT-ventriculography findings helped in identifying the lesions and plan the surgical intervention that was performed with the aid of an endoscope to remove the cysts. CONCLUSIONS: Intraventricular neurocysticercosis is a common parasitic disease which can be difficult to diagnose. We used CT-ventriculography with injection of contrast through the ventriculostomy catheter in two patients where CT and MRI failed to demonstrate the lesions. This technique is a safe and useful tool in the imaging armamentarium when intraventricular cystic lesions are suspected. PMID- 21246059 TI - Gliomas: Survival, origin and early detection. PMID- 21246061 TI - Retained transorbital foreign body with intracranial extension after pipe bomb explosion. AB - BACKGROUND: Penetrating brain injuries caused by explosions are survived in extremely rare cases only. However, potential casualties of such cases may be encountered by regular physicians even outside a war zone, e.g., due to an assault or terror blast. There is very limited literature to this end; therefore, we report the successful neurosurgical management of a penetrating head injury due to a pipe bomb explosion. CASE DESCRIPTION: A 19-year-old man was brought to the ER with a swollen, bleeding right orbit, and a severely injured left hand after having sustained an unwitnessed explosion from a self-made pipe bomb. He presented with a GCS (Glasgow Coma Scale) of 15 at time of admission, work-up revealed an intracranial retained metal fragment measuring 5 * 1 * 0.2 cm lodged retro-orbitally and in the skull base. The patient underwent emergent right temporal craniotomy and temporal lobectomy and simultaneous right enucleation before the petrous bone and sphenoid wing lodged metal fragment was successfully removed. CONCLUSION: This case underscores the importance of having a high suspicion for the presence of an intracranial injury and a retained foreign body in the setting of a penetrating head injury. Aggressive and timely workup as well as expeditious surgical management are crucial in these settings and can generate exceptionally good outcomes despite a major trauma. PMID- 21246062 TI - Double-blind peer review: a crucial process. PMID- 21246060 TI - Stem cells for spinal cord regeneration: Current status. AB - BACKGROUND: Nearly 11,000 cases of spinal cord injury (SCI) are reported in the United States annually. Current management options give a median survival time of 38 years; however, no rehabilitative measures are available. Stem cells have been under constant research given their ability to differentiate into neural cell lines replacing non functional tissue. Efforts have been made to establish new synapses and provide a conducive environment, by grafting cells from autologous and fetal sources; including embryonic or adult stem cells, Schwann cells, genetically modified fibroblasts, bone stromal cells, and olfactory ensheathing cells and combinations/ variants thereof. METHODS: In order to discuss the underlying mechanism of SCI along with the previously mentioned sources of stem cells in context to SCI, a simple review of literature was conducted. An extensive literature search was conducted using the PubMed data base and online search engines and articles published in the last 15 years were considered along with some historical articles where a background was required. RESULTS: Stem cell transplantation for SCI is at the forefront with animal and in vitro studies providing a solid platform to enable well-designed human studies. Olfactory ensheathing cells seem to be the most promising; whilst bone marrow stromal cells appear as strong candidates for an adjunctive role. CONCLUSION: The key strategy in developing the therapeutic basis of stem cell transplantation for spinal cord regeneration is to weed out the pseudo-science and opportunism. All the trials should be based on stringent scientific criteria and effort to bypass that should be strongly discouraged at the international level. PMID- 21246063 TI - Microtensile vs microshear bond strength of all-in-one adhesives to unground enamel. AB - PURPOSE: to determine the bond strength to unground enamel of all-in-one adhesives in comparison with an etch-andrinse system and to compare the reliability of microtensile and microshear methods in providing such measurements. MATERIALS AND METHODS: the bonding procedure was performed on enamel of 64 extracted molars. The tested all-inone adhesives were: Bond Force (Tokuyama), AdheSE One (Ivoclar-Vivadent), and Xeno V (Dentsply). Prime&Bond NT (Dentsply) served as control. Microtensile specimens were obtained from 4 teeth per group. Twelve teeth per group were used for microshear testing. Microtensile specimens that failed prior to testing were included in statistical calculations; they were assigned the lowest value measured in the respective group. Failure modes were observed under light microscope and classified (cohesive within substrates, adhesive, mixed). Statistically significant differences in bond strength were assessed among the adhesives within each testing method and between microshear and microtensile data for each adhesive. Failure mode distributions were compared using the chi-square test. RESULTS: all-in-one adhesives had similar microshear and microtensile bond strengths. In both testing methods, the etch-and-rinse system achieved the strongest bond. For all adhesives, significantly higher bond strengths were measured with the microshear test. In microtensile testing, specimens bonded with the etch-and-rinse adhesive exhibited a significantly different distribution of failure modes. The coefficients of variation were extremely high for microtensile bond strength data, particularly of all-in-one adhesives. CONCLUSION: the adhesive potential to intact enamel of recently introduced all-in-one adhesives was inferior to that of an etch-and rinse system. When testing bond strength to enamel of all-in-one adhesives, microshear testing may be a more accurate method than microtensile. PMID- 21246064 TI - Micromorphological effects and the thickness of the hybrid layer - a comparison of current adhesive systems. AB - PURPOSE: the aim of this study was to evaluate the effect of dental conditioners in terms of dentin micromorphology and the thickness of the hybrid layer obtained by using the self-etching adhesive systems Adhe SE (AD), G Bond (GB), Adper Prompt L Pop (LP) and Tyrian (TY) and the etch-and-rinse Single Bond (SB). MATERIALS AND METHODS: dentin sticks from 50 third human molars were obtained by first cutting dentin disks out of crowns; the disks were subsequently sectioned into sticks. The sticks were assigned to experimental groups as follows: G1: phosphoric acid 37%, Single Bond (SB); G2: Adhe SE (AD); G3: G Bond (GB); G4: Adper Prompt L-Pop (LP); G5: Tyrian SPE (TY). Half the samples served to investigate the dentin micromorphology. To this end, the proprietary conditioner of the respective adhesive system was applied to these samples, and conditioner effects were examined with SEM. The other half of the samples was hybridized and restored with composite resin to investigate the thickness of the hybrid layer, which was also evaluated with SEM. Statistical analysis was performed with ANOVA, Tukey's, and the Kruskal-Wallis tests. RESULTS: SEM observation showed significant differences of the hybrid layer thickness. LP presented the highest average thickness, 3.45 microm, while SB presented an average of 2.44 microm and AD an average of 1.43 microm. The averages of TY and SB did not show any statistically significant differences. The adhesive system GB presented the lowest average in hybrid layer, 0.37 microm. The micromorphological evaluation showed that the conditioners commonly removed the smear layer. CONCLUSION: all the micromorphological alterations and the hybrid layer thickness show that the adhesive systems studied performed distinct actions. Although there is no apparent correlation of the pH of the conditioners with the thickness of the hybrid layer, it is clear that more acidic conditioners promote more severe transformations in the dentin micromorphology. PMID- 21246065 TI - Retention loss of class v restorations after artificial aging. AB - PURPOSE: to evaluate whether retention loss of Class V restorations can be simulated in the laboratory and to compare these results with those from clinical trials. MATERIALS AND METHODS: nonretentive v-shaped Class V cavities were prepared on the lingual and buccal side of extracted premolars, half in dentin and half in enamel. Different adhesive systems (AS) were used with the same composite resin (Tetric EvoCeram) and 12 restorations per group: 1-step self etching AS (AdheSE One, Adper Prompt L-Pop, Futurabond N, Hybrid Bond, iBond, Xeno III, Xeno IV), 2-step self-etching AS (AdheSE), 2-step etch-and-rinse AS (Excite, Prime & Bond NT), 3-step etch-and-rinse AS (Syntac) as well as a conventional glass ionomer (Ketac Fil) with and without conditioner. The comparison groups were the composite without adhesive and a 2-step etch-and-rinse AS (Prime & Bond NT) without etching of enamel and dentin. The restored teeth were submitted to an aging process involving 18 months of water storage, three intermittent phases of thermocycling (TC 10,000 times), and two phases of thermomechanical loading (1 x 640,000 chewing cycles after 12 months, 1 x 1,200,000 chewing cycles after 18 months; 100 N sine-wave force profile, pressing with steel ball without lifting). Retention loss of the restorations was evaluated after every 1000 thermocycles and every 120,000 cycles of thermomechanical loading. The databases MEDLINE and IADR abstracts were used to search for clinical studies on retention loss involving the adhesive systems that were included in the present study. RESULTS: retention loss was only observed in the following groups: composite without adhesive (100% after first 1000 TC), glass ionomer without conditioner (8% after 6 months; 33% after 12 months, 100% after 18 months), adhesive without etching (17% after 6 months, 42% after 12 months). The laboratory results, however, matched with the clinical results only for three adhesive systems (Futurabond NR, Hybrid Bond, Xeno IV, 0% retention loss, 5 studies, observation period between 1.5 and 2 years). CONCLUSIONS: if the materials were applied according to the manufacturer's instructions, no retention loss was observed in the laboratory model. The laboratory model did not reflect the clinical findings. PMID- 21246066 TI - Effect of cleaning methods after reduced-pressure air abrasion on bonding to zirconia ceramic. AB - PURPOSE: To evaluate in vitro the influence of different cleaning methods after low-pressure air abrasion on the bond strength of a phosphate monomer-containing luting resin to zirconia ceramic. MATERIALS AND METHODS: A total of 112 zirconia ceramic disks were divided into 7 groups (n = 16). In the test groups, disks were air abraded at low pressure (L) 0.05 MPa using 50-MUm alumina particles. Prior to bonding, the disks were ultrasonically (U) cleaned either in isopropanol alcohol (AC), hydrofluoric acid (HF), demineralized water (DW), or tap water (TW), or they were used without ultrasonic cleaning. Disks air abraded at a high (H) pressure of 0.25 MPa and cleaned ultrasonically in isopropanol served as positive control; original (O) milled disks used without air abrasion served as the negative control group. Plexiglas tubes filled with composite resin were bonded with the adhesive luting resin Panavia 21 to the ceramic disks. Prior to testing tensile bond strength (TBS), each main group was further subdivided into 2 subgroups (n=8) which were stored in distilled water either at 37 degrees C for 3 days or for 30 days with 7500 thermal cycles. Statistical analyses were conducted with two- and one-way analyses of variance (ANOVA) and Tukey's HSD test. RESULTS: Initial tensile bond strength (TBS) ranged from 32.6 to 42.8 MPa. After 30 days storage in water with thermocycling, TBS ranged from 21.9 to 36.3 MPa. Storage in water and thermocycling significantly decreased the TBS of test groups which were not air abraded (p = 0.05) or which were air abraded but cleaned in tap water (p = 0.002), but not the TBS of the other groups (p > 0.05). Also, the TBS of air abraded groups were significantly higher than the TBS of the original milled (p < 0.01). Cleaning procedures did not significantly affect TBS either after 3 days or 30 days storage in water and thermocycling (p > 0.05). CONCLUSION: Air abrasion at 0.05 MPa and ultrasonic cleaning are important factors for improving bonding to zirconia ceramic. PMID- 21246067 TI - Evaluation of self-adhesive resin cement bond strength to yttria-stabilized zirconia ceramic (Y-TZP) using four surface treatments. AB - PURPOSE: To evaluate the influence of four surface treatments on the bond strength of a self-adhesive resin cement to an yttria-stabilized zirconia (Y-TZP) ceramic material (Lava Frame zirconia). MATERIALS AND METHODS: Forty plates (8 x 6 x 1 mm) of a Y-TZP ceramic restorative material were randomly assigned to four groups (n = 10) according to the surface treatments: control, no treatment; airborne-particle abrasion with 50-MUm Al2O3; coating with an MDP-based primer; conditioning with Rocatec System. The ceramic plates treated with each of the four methods were further divided into 2 subgroups according to the resin cement tested: RelyXTM ARC (ARC, conventional) and RelyXTM Unicem (Ucem, self-adhesive). The resin cements were put into PVC tubes (diameter 0.75 mm, 0.5 mm height) placed on the ceramic plate surfaces. After water storage at 37 degrees C for 24 h, the specimens were submitted to a microshear bond strength (MUSBS) test at a crosshead speed of 1.0 mm/min. RESULTS: The surface treatments significantly influenced the MUSBS (p < 0.05). For the four surface treatments, UCem presented significantly higher MUSBS than ARC (p < 0.05). For both resin cements, the best result was produced by the MDP-based primer: ARC 15.9 +/- 5.0 MPa and UCem 36.2 +/- 2.1 MPa. The highest MUSBS values were presented by UCem on ceramic plates treated with the MDP-based primer (36.2 +/- 2.1 MPa) and Rocatec system (37.4 +/- 2.3 MPa). CONCLUSION: Irrespective of the surface treatment, the self-adhesive resin cement performed better in terms of bond strength to yttria-stabilized zirconia ceramic than did conventional resin cement. PMID- 21246068 TI - The importance of adhesive area delimitation in a microshear bond strength experimental design. AB - PURPOSE: The purpose of this study was to assess the influence of adhesive area delimitation on the microshear bond strength of different adhesives to dentin. MATERIALS AND METHODS: Eighteen bovine incisors were sectioned and the exposed dentin surfaces were prepared with 600-grit SiC paper. These teeth were randomly divided into three groups, according to the adhesive to be applied: two-step etch and-rinse Adper Single Bond 2 (3M ESPE), two-step self-etching Clearfil SE Bond (Kuraray), and one-step Clearfil S3 Bond (Kuraray). On each dentin surface, 4 samples were built up with the composite resin Z100 (3M ESPE); on 2 of these, a suggested area delimitation technique was employed. After 24 h of storage in water at 37 degrees C, samples were subjected to the microshear bond strength test, and the failure modes were evaluated under optical and scanning electron microscopes. The obtained results were statistical analyzed using two-way ANOVA and Tukey's test. RESULTS: Groups without area delimitation presented significantly higher bond strength results (p < 0.05) and a higher incidence of cohesive failures. In these groups, fractures tended to occur beyond the limits of the actual adhesive area, while the area restriction technique succeeded in avoiding this phenomenon. The three adhesives performed similarly when area delimitation was employed (p > 0.05), but Clearfil S3 Bond showed significantly higher bond strength results when no area delimitation was taken into account (p < 0.05). CONCLUSION: The extension of the adhesive area beyond the limits of the composite cylinder may play an important role in the results of microshear bond strength tests, while the suggested area delimitation technique may lead to less questionable outcomes. PMID- 21246070 TI - Effect of maleic anhydride pretreatment on tensile bond strength of a silicone soft liner to a denture base polymer. AB - PURPOSE: To determine the effect of resin surface treatment with dissolved maleic anhydride in butanone added into primer on the tensile bond strength between an acrylic denture base resin and a silicone soft liner. MATERIALS AND METHODS: To test tensile bond strength, standard dumbbell-shaped acrylic specimens were prepared. Five experimental groups, including the control, were tested (n = 5). Maleic anhydride solutions prepared in butanone at concentrations of 1%, 5%, 10% or 20% were then mixed with 1 ml of Primo adhesive and the mixtures were applied onto the resin bonding surfaces. Silicone liner material was applied to resin surfaces in the conventional manner. Tensile bond strength of the specimens was measured in a universal testing machine. Fractured surfaces were observed under the scanning electron microscope, and resulting chemical changes with the solutions used were analyzed spectroscopically. RESULTS: The highest bond strength value was obtained for the group treated with 5% maleic anhydride (2.53 +/- 0.48 MPa); the lowest value was for the group treated with 20% maleic anhydride (1.59 +/- 0.29 MPa). Mixed failure was the dominant type seen in the experimental groups. Spectroscopic analysis showed the interaction of the anhydride carbonyl groups with the Primo primer. CONCLUSION: The treatment of resin surfaces with maleic anhydride added to Primo adhesive effectively increased bond strength between silicone soft liner and denture base resin. PMID- 21246069 TI - Expansion of nanotechnology for dentistry: effect of colloidal platinum nanoparticles on dentin adhesion mediated by 4-META/MMA-TBB. AB - PURPOSE: To investigate the effect of Colloidal Platinum Nanoparticles (CPN) on the bond strength between dentin and 4-META/MMA-TBB resin using different concentrations of CPN. MATERIALS AND METHODS: Twenty-five extracted human third molars were stored in 0.5% chloramine T. The occlusal dentin slices were prepared by grinding occlusal surfaces of each tooth and polishing with 600-grit silicon carbide paper under running water. One control and four experimental groups (2 specimens per group) were used as follows: a) dentin surfaces treated with 10-3 solution, followed by rinsing with water and subsequently an acrylic rod bonded with hand-mixed 4META/MMA-TBB resin (Super-Bond C&B, Sun Medical) (control); b) dentin surfaces treated with 10-3 etching solution, followed by rinsing with water and application of CPN (100% or 10%) as a primer solution for 60 s and rinsed with water for 20 s, then an acrylic rod bonded with Super-Bond C&B(Etch CPN [100% or 10%]); c) dentin surfaces treated with CPN (100% or 10%) for 60 s, rinsed with water for 20 s, followed by application of 10-3 solution, then an acrylic rod bonded with Super-Bond C&B (CPN-Etch [100% or 10%]). After storage in 37 degrees C water, specimens were sectioned into beams (cross-sectional area: 1 mm2) for microtensile bond strength testing at a crosshead speed of 1mm/min. The data were analyzed using the Games-Howell method (p < 0.05; n = 15). RESULTS: Etch-CPN (100), CPN-Etch(100) and CPN-Etch (10) showed significantly higher bond strengths compared to the control. When using 10% CPN, the highest bond strength was demonstrated. The bond strength of 4META/MMA-TBB resin was approximately doubled by CPN application. CONCLUSION: The results of this study showed that higher bond strengths are obtained when treating dentin with a lower concentration of CPN. Further evaluation to optimize conditions such as the application time and rinsing time are required. PMID- 21246071 TI - Regional bond strength to lateral walls in class I and II ceramic inlays luted with four resin cements and glass-ionomer luting agent. AB - PURPOSE: To investigate regional shear bond strength to lateral walls of ceramic inlays in occlusal and occlusoproximal cavities using etch-and-rinse and self adhesive resin cements and a glass-ionomer luting agent. MATERIALS AND METHODS: IPS e.max Press ceramic inlays were made in 50 Class I and 50 Class II standardized cavities in intact extracted human molars and divided into 5 luting agent subgroups (n = 10): Variolink II (VL); Multilink Sprint (MLS); Multilink Automix (MLA); RelyX Unicem (RLX), and Ketac Cem Aplicap (KC). Inlays were pre etched with IPS Ceramic etching gel for 60s. After 48 h, two disks of ca 1.0 mm thickness, one of superficial and the other of deep dentin, were push-out tested in a universal testing machine at a crosshead speed of 1.0 mm/min. The mode of failure was determined under a stereomicroscope at 20X. Data were analyzed with one way ANOVA, and Scheffe's test was used for post-hoc comparisons (alpha = 0.05). RESULTS: There were no significant differences in shear bond strength between Class I and Class II cavities for the dual-curing system in light-curing mode (VL=MLS=RLX), except that RLX demonstrated greater bond strength to deep dentin in Class II cavities. Bond strength values were significantly higher on deep than on superficial dentin. KC showed the worst result. Failures were mixed (adhesive/cohesive) for the resin luting cements and solely adhesive (cement/ceramic) for the glass-ionomer luting agent. CONCLUSION: Dual-curing etch and-rinse or self-etching self-adhesive resin luting cements achieved greater bond strength when light curing was applied, with no differences between Class I and Class II cavities but higher values for deep vs superficial dentin. The weakest adhesion was obtained with glass-ionomer luting agent in both cavity types. PMID- 21246072 TI - Resin bonding to a feldspar ceramic after different ceramic surface conditioning methods: evaluation of contact angle, surface pH, and microtensile bond strength durability. AB - PURPOSE: To evaluate the surface pH, contact angle and microtensile bond strength (MTBS) of a resin-cement to feldspathic ceramic after various surface conditioning methods (SC). MATERIALS AND METHODS: For pH measurements, 96 glass ceramic disks were assigned into 12 groups (n = 8): SC1-pH: No ceramic surface conditioning (control); SC2-pH: hydrofluoric-acid (HF) 9% 1 min; SC3-pH: SC2 pH+wash/dry; SC4-pH: SC3-pH+silane; SC5-pH: HF 4% 1 min; SC6-pH: SC5-pH+wash/dry; SC7-pH: SC6 -pH +silane; SC8-pH: HF 5% 1 min; SC9-pH: SC8-pH+wash/dry; SC10-pH: SC9-pH+silane; SC11-pH: SC9-pH +neutralizer+wash/dry+sonic-cleaning; SC12-pH: SC11-pH+silane. For contact angle analysis, 40 disks were divided into 5 groups (n = 8): SC1-ca: no conditioning; SC2-ca: HF 9%+wash/dry; SC3-ca: HF 4%+wash/dry; SC4 -ca: HF 5%+wash/dry; SC5-ca: HF 5%+neutralizer+wash/dry+ultrasonic-cleaning. To evaluate the MTBS, 40 blocks were distributed into 4 groups SC (N = 10): SC1 bond: HF 9% 1 min+silane; SC2-bond: HF 4% 1 min+silane; SC3-bond: HF 5% 1 min+silane; SC4-bond: HF 5% 1 min+neutralizer+wash/dry+ultrasonic cleaning+silane. The resin cement was applied on the treated surfaces and bar specimens were produced that were submitted to 2 conditions: dry: immediate MTBS; TC: storage for 150 days and thermocycling 5000x. Fifty bar specimens were produced per group (n = 50). Contact angle and pH results were submitted to one way ANOVA and Tukey's test (alpha = 0.05). Microtensile data were submitted to two-way ANOVA and Tukey's test (a = 0.05). RESULTS: pH values were significantly higher for SC6-ph (11.5 +/- 2.6) when compared to those of SC5-pH (2.7 +/- 0.4), SC8-pH (2.7 +/- 0.2) and SC2-pH (2.2 +/- 0.2) (p < 0.00, ANOVA). SC1-ca had the largest contact angle (48 +/- 16 degrees) and SC3-ca the smallest (9.4 +/- 7.7 degrees). The results of the MTBS test were as follows: independent of the storage condition, SC2-bond = SC1-bond > SC3-bond = SC4-bond. SC4-bond had the lowest MTBS value after TC (10.6 +/- 2.6 MPa). CONCLUSION: The acid neutralization step appears to be dispensable, since the washing/drying promoted similar pH values. That condition promoted a high contact angle and unstable resin microtensile bond strength to glass ceramic. PMID- 21246073 TI - Effect of multiple coats of ultra-mild all-in-one adhesives on bond strength to dentin covered with two different smear layer thicknesses. AB - PURPOSE: To evaluate the effect on bond strength of 1, 2, or 3 coats of two one step self-etching adhesives on dentin covered with two different smear layer thicknesses. MATERIALS AND METHODS: Flat dentin surfaces from recently extracted third molars were wet ground with 60- or 600-grit SiC paper to produce smear layers of different thicknesses. Adper Easy Bond (3M ESPE) and Clearfil S3 Bond (Kuraray) were applied in 1, 2, or 3 consecutive coats after air drying each coat. ScotchBond Multi Purpose (3M) and Clearfil SE Bond (Kuraray) were used as controls. Composite resin crowns (Filtek Z250, 3M ESPE) were built up, stored for 24 h, and cut in x and y directions. Eight to twelve sticks (0.65 +/- 0.05 mm2 of area) from the central area of each tooth were fractured in tension (0.5 mm/min). Sticks from each group were processed for interfacial micromorphological evaluation with SEM. RESULTS: Three-way ANOVA revealed a significant interaction between factors (p < 0.05). Tukey's post-hoc test showed that only when Adper Easy Bond was applied on dentin prepared with 600-grit SiC paper, microtensile bond strength was not significantly affected by the number of coatings. However, the effect of smear layer thickness was only statistically significant when the adhesives were applied in one coat, for both adhesives. When they were applied in two or three coats, smear layer thickness did not significantly affect bond strength (p > 0.05). CONCLUSIONS: The thickness of the smear layer affected the bond strength of both all-in-one adhesives. Additional coats can be beneficial to bond strength, especially with Clearfil S3 Bond. PMID- 21246074 TI - Effect of bleaching treatment and reduced application time of an antioxidant on bond strength to bleached enamel and subjacent dentin. AB - PURPOSE: To evaluate the influence of bleaching on bond strength to enamel and subjacent dentin, and to determine whether a reduced application time (1 min) of the antioxidizing agent can obviate the compromised bond strength after bleaching. MATERIALS AND METHODS: One hundred twelve bovine incisors were obtained, and the enamel and dentin surfaces were standardized to a thickness of 1 mm. The specimens were divided into two control groups (enamel and dentin without treatment) and 12 experimental groups (n = 10), based on the concentration of bleaching agents (carbamide peroxide 16% and hydrogen peroxide 35%), time interval between bleaching and restorative procedures (24 h; 24 h + sodium ascorbate (SA) 10%/1 min; 14 days), and substrate (enamel or dentin). All samples were submitted to the bleaching treatment on enamel. After the stipulated interval, a microshear test was performed. RESULTS: The bleaching treatment compromised the bond strength to the enamel when the restoration was performed 24 h after the end of bleaching. The bond strength to dentin was not affected by bleaching. CONCLUSIONS: The SA 10% application for 1 min obviates the detrimental effect of bleaching on bond strength. The bleaching performed on enamel does not affect the bond strength to the subjacent dentin. PMID- 21246076 TI - Bonding effectiveness of a self-adhesive resin-based luting cement to dentin after provisional cement contamination. AB - PURPOSE: To evaluate the influence of provisional luting cements on the bonding performance of a resin-based self-adhesive luting cement to dentin vs that of currently used resin-based luting agents with different adhesion strategies. MATERIALS AND METHODS: Forty-five prepared human molars were randomly and equally divided into three main groups according to the type of provisional luting cement applied: eugenol-containing provisional cement (Temp Bond, Kerr), eugenol-free provisional cement (Temp Bond NE, Kerr), and control where the provisionalization step was omitted. Each group was further subdivided into 3 groups based on the category of adhesive systems/ luting materials used: a two-step etch-and-rinse system (Single Bond/RelyX ARC; 3M ESPE) (RX), a two-step self-etching system (Clearfil Liner Bond 2V/ Panavia F; Kuraray) (PF), and a self-adhesive luting cement (Rely X Unicem; 3M ESPE) (RU). Finally, 9 groups of 5 teeth each were prepared for the microtensile test. RESULTS: Two-way analysis of variance (ANOVA) and post-hoc Bonferroni tests revealed that definitive luting cement, provisional luting cement, and the interactions of these two factors had significant influences on dentin bond strength. The highest bond strength was obtained for PF (32.05 MPa), followed by RX (26.57 MPa) and RU (16.56 MPa) for the controls. Contamination with either eugenol-containing or eugenol-free provisional cement significantly decreased the bonding effectiveness of RX (19.08 and 19.69 MPa, respectively) and PF (14.21 and 16.67 MPa respectively) to dentin (p < 0.05). RU showed comparable bond strength values before and after provisional cement (13.93 and 14.49 MPa, respectively) application (p > 0.05). Eugenol in provisional luting cement did not produce material-related alterations in the bonding performance of the resin luting cements tested (p > 0.05). CONCLUSION: Based on these results, the self-adhesive cement which was not influenced by the provisional cement application may be promising. However, long-term laboratory and clinical performance of this cement needs to be assessed before recommending it as an alternative to the technically more demanding approaches. Moreover, an effective surface cleansing procedure is critical to achieve a successful bond between the contaminated dentin and luting cement. PMID- 21246075 TI - Influence of adhesive properties on resin-dentin bond strength of one-step self etching adhesives. AB - PURPOSE: To evaluate the association between the resin-dentin bond strength (microtensile bond strength, MUTBS) and the physical properties (ultimate tensile strength [UTS] and microhardness [VHN]) of the cured adhesive resin using five commercial one-step self-etching systems. MATERIALS AND METHODS: Futurabond NR, Go, G Bond, 1-step All Bond SE and Clearfil S3 Bond were applied on flat superficial dentin surfaces. Each adhesive system was applied in five teeth. A resin buildup was then made. After 24 h, resin-dentin beams (0.9 mm2) were prepared to be tested immediately at 0.5 mm/min. For the UTS measurement, hourglass specimens were prepared with each adhesive system (n = 5) to be tested under tensile stress at 0.5 mm/min. The fractured specimens from the UTS test were taken to a Vickers microhardness tester (25 gf/20 s). MUTBS, UTS, and VHN values were submitted to a one-way ANOVA and Tukey's test (alpha = 0.05) for pairwise comparisons. Correlations between MUTBS, UTS and VHN were analyzed using the Pearson product moment correlation test (alpha = 0.05). RESULTS: Significantly higher MUTBS values were observed for 1-step All Bond SE and Clearfil S3 Bond (p > 0.05). The adhesive All Bond SE showed the highest UTSmean among all systems (p < 0.05). The adhesives All Bond SE and G-Bond showed the highest microhardness mean among all systems (p < 0.05). A strong (r = 0.93) and significant (p = 0.021) correlation was only found between the MUTBS and UTS values. CONCLUSION: The ultimate tensile strength of one-step self-etching systems correlates with the resin-dentin bond strength values. PMID- 21246077 TI - Effect of silica coating on fracture strength of glass-infiltrated alumina ceramic cemented to dentin. AB - PURPOSE: To examine the availability of sol-gel processed silica coating for alumina-based ceramic bonding, and determine which silica sol concentration was appropriate for silica coating. MATERIALS AND METHODS: Sixty disks of In-Ceram alumina ceramic were fabricated and randomly divided into 5 main groups. The disks received 5 different surface conditioning treatments: Group Al, sandblasted; Group AlC, sandblasted + silane coupling agent applied; Groups Al20C, Al30C, and Al40C, sandblasted, silica coating via sol-gel process prepared using 20 wt%, 30 wt%, and 40 wt% silica sols, and then silane coupling agent applied. Before bonding, one-step adhesives were applied on pre-prepared ceramic surfaces of all groups. Then, 60 dentin specimens were prepared and conditioned with phosphoric acid and one-step adhesive. Ceramic disks of all groups were cemented to dentin specimens with dual-curing resin cements. Fracture strength was determined at 24 h and after 20 days of storage in water. RESULTS: Groups Al20C, Al30C, and Al40C revealed significantly higher fracture strength than groups Al and AlC. No statistically significant difference in fracture strength was found between groups Al and AlC, or among groups Al20C, Al30C, and Al40C. Fracture strength values of all the groups did not change after 20 days of water storage. CONCLUSION: Sol-gel processed silica coating can enhance fracture strength of In-Ceram alumina ceramic after bonding to dentin, and different silica sol concentrations produced the same effects. Twenty days of water storage did not decrease the fracture strength. PMID- 21246078 TI - Adhesive restoration of endodontically treated premolars: influence of posts on cuspal deflection. AB - PURPOSE: To determine, by means of a non-destructive experimental procedure, the effectiveness of adhesive restorations in reducing the cuspal deflection of endodontically treated premolars, with or without root canal fiber posts. MATERIALS AND METHODS: The cuspal deflection of ten sound, intact maxillary premolars was evaluated. A loading device induced deformation by axial force (ranging from 98 to 294 N) applied on the occlusal surface of teeth while laser sensors registered the amount of deflection. Once tested, teeth were endodontically treated and the marginal ridges were removed. The teeth were randomly divided into two groups and restored with: group 1) dual curing adhesive, flowable composite, and microhybrid composite; group 2) the same materials associated with root canal glass fiber post and composite cement. The cuspal deflection test was repeated with the same protocol after restorative procedures, allowing a direct comparison of the same samples. Statistical analysis was performed using ANOVA at a significance level of 0.05. RESULTS: Different average cuspal deflection was detected in the two groups: composite resin with post insertion resulted in lower deformation compared with composite alone. Mean deflection ranged from 3.43 to 12.17 MUm in intact teeth, from 14.42 to 26.93 MUm in group 1, and from 15.35 to 20.39 MUm in group 2. ANOVA found significant differences (p = 0.02). CONCLUSION: Bonded composite restorations with fiber posts may be more effective than composite alone in reducing the cuspal deflection in endodontically treated premolars in which the marginal ridges have been lost. PMID- 21246079 TI - Effects of 8-OH-DPAT and NAN-190 on anxious-depressive-like behavior of female rats during the estrous cycle. AB - We studied the effect of chronic administration of 5-HT(1A)-receptor agonist 8-OH DPAT (0.05 mg/kg subcutaneously) or antagonist NAN-190 (0.1 mg/kg intraperitoneally) for 14 days on anxious-depressive-like behavior of female rats during the key phases of the estrous cycle. Chronic administration of NAN-190 during the estrus phase produced an anxiogenic effect, while its administration during proestrus phase induced an anxiolytic effect. Administration of 8-OH-DPAT had no effect on anxiety level, but produced a pronounced antidepressive effect irrespective of the phase of the estrous cycle. PMID- 21246080 TI - Peripheral administration of loperamide and methylnaloxone decreases the degree of anxiety in rats. AB - We studied the effect of MU-opioid receptor ligands on anxious and depressive behavior of rats. Intragastric administration of loperamide and methylnaloxone reduced animal anxiety evaluated by an increase in the number of entries into and time spent in open arms of the elevated plus-maze. MU-Opioid receptor agonist loperamide had the most pronounced anxiolytic effect. Analysis of animal behavior in the forced swimming test showed that administration of MU-opioid receptor antagonist methylnaloxone reduced the latency of the first submersion, increased the total time of submersion episodes, and shortened the time of active swimming, which attested to depressive properties of this agent. Loperamide had little effect on behavior of rats in the forced swimming test. Thus, MU-opioid receptor agonist loperamide has the antianxiety properties and produced no sedative effect. Therefore, this agent holds much promise as an anxiolytic drug. PMID- 21246081 TI - Effect of fast and slow calcium buffers on induced secretion of neurotransmitter. AB - Loading of mouse motor nerve terminals with EGTA-AM, but not with BAPTA-AM, inhibited the release of the neurotransmitter in response to stimulation of the nerve with rare (0.3 Hz) "single" pulses. During rhythmic stimulation with short (50 EPP) high-frequency (20 Hz) series, BAPTA-AM buffer modified burst pattern in a dose-dependent manner: it replaced the phase of initial facilitation by persistent depression of secretion and decreased its plateau level at the end of the burst. In contrast, loading of the nerve terminals with EGTA-AM buffer produced no effect on the phase of initial facilitation, but decreased the plateau level to the same degree as BAPTA-AM did. Probably, the different effects of both buffers on secretion of neurotransmitter reflect peculiarities of involvement of fast and slow Ca(2+)signals of motor terminals in single and rhythmic release of the neurotransmitter. PMID- 21246082 TI - Effect of interleukin-1beta on the expression of tight junction proteins in the culture of HaCaT keratinocytes. AB - We studied the effect of IL-1beta on the expression of tight junction proteins (occludin and claudins) in cultured HaCaT keratinocytes and changes of transepithelial resistance. Addition of IL-1beta had little effect on transepithelial resistance, increased the expression of claudin-1, and did not modify the expression of occludin. In other tissues, IL-1beta also increases claudin-1 expression, but significantly decreases occludin expression. These changes are accompanied by the reduction of transepithelial resistance. The IL 1beta-induced increase in the expression of claudin-1 in cultured HaCaT keratinocytes simulates the appearance of claudin-1 at the early stage of skin wound healing. It is accompanied by an increase in IL-1beta concentration in the wound fluid. PMID- 21246083 TI - Effect of immobilized granulocyte colony-stimulating factor on hemopoietic precursors of various classes during cytostatic-induced myelosuppression. AB - Experiments were performed on the model of cytostatic myelosuppression induced by cyclophosphamide. We compared the effect of immobilized granulocyte CSF (the preparation was created in Russia) and reference standard preparation of granulocyte CSF on the development of neutrophilic leukopenia and hemopoietic precursors of various classes. It was found that preparations of granulocyte CSF decreased the duration and degree of peripheral blood neutropenia. The granulocytopoiesis-stimulating effect was related to stimulation of multipotent hemopoietic precursors, granulocyte-erythroid-macrophage-megakaryocyte precursors, and granulocyte precursors. Induction of division and maturation of multipotent hemopoietic precursors, granulocyte-erythroid-macrophage megakaryocyte precursors, and granulocyte precursors and recovery of cellularity of the granulocytic hemopoietic stem after administration of immobilized granulocyte CSF were observed at later terms compared to treatment with the reference preparation of granulocyte CSF. PMID- 21246084 TI - Effect of antibodies to glutamate on retention of conditioned passive avoidance response in rats with ischemic injury of the prefrontal cortex. AB - Experiments were performed on rats with bilateral photothrombosis of vessels in the prefrontal cortex. Intranasal administration of antibodies to glutamate (1 h after ischemia of the brain cortex) improved retention of conditioned passive avoidance response, which was elicited before ischemic damage. The content of antibodies to glutamate in the serum of rats increased significantly on day 8 after bilateral photochemical thrombosis of vessels in the prefrontal cortex compared to that in the control. PMID- 21246086 TI - Reactivity of arterial vessels during antiorthostasis and systemic hypotension. AB - In experiments on rats, changes in blood pressure and cardiac output in response to antiorthostatic (head-down) tilt 15 degrees and 45 degrees were examined under conditions of decreased arterial tone induced by sodium nitroprusside. The decrease in initial systemic blood pressure to 90 mm Hg attenuated the pressor responses to antiorthostasis, while further drop in blood pressure to 70-60 mm Hg provoked depressor responses in half cases. No blood pressure responses to antiorthostasis were observed when blood pressure dropped to 50 mm Hg. Correlation analysis confirmed the existence of a direct dependence of pressor responses to orthostasis on the initial blood pressure. PMID- 21246085 TI - Characteristics of leukemia stem cells of murine myeloproliferative disease involving the liver. AB - We studied surface phenotype of tumor cells and characterized leukemia stem cells in various cell populations with phenotypes of stem and committed precursor cells in the hierarchy of hemopoietic stem cells. Transplantable murine leukemia was used as the model. Bone marrow and liver cells from mice in the terminal phase of the disease were stained with antibodies to various surface markers and analyzed on a flow cytofuorometer. The cells were sorted by various differentiation markers using a system of magnetic separation Miltenyi Biotec MACS and then transplanted to syngeneic recipients. In some cases, limiting dilutions were used for measuring the concentration of leukemia-initiating cells. All transplanted cell populations caused death of recipients: c-kit- CD45- over 23.9 days, c-kit+ over 22.2 days, c-kit- CD45+ over 15.4 days, Ter119+ over 18.2 days, and Ter119- over 17.7 days. The concentrations of leukemia cells determined by the method of limiting dilutions was 1 per 37,000 c-kit+ bone marrow cells and 1 per 45 unsorted liver cells from sick animals. Thus, leukemia stem cells retain hierarchic organization in the studied model and can differentiate at least into myeloid and erythroid cells without loosing self-maintenance capacity. This model can be used for the study of regulation of self-maintenance mechanisms in various hierarchic populations of leukemia stem cells. PMID- 21246087 TI - Inhibition of GSK-3beta decreases the ischemia-induced death of renal cells. AB - Pharmacological preconditioning with insulin and lithium ions prevented the death of renal cells under conditions of ischemia/reperfusion. Preincubation of cells with insulin or lithium ions decreased production of reactive oxygen species after ischemia/reoxygenation. These agents also prevented the development of mitochondrial dysfunction in renal cells induced by ischemia/reoxygenation. It was hypothesized that the protective effects of these agents are related to inhibition of glycogen synthase kinase-3(. This enzyme is inactivated upon phosphorylation of serine residue in position 9. We found that in vivo administration of lithium ions to animals before renal ischemia prevents the development of kidney failure. PMID- 21246088 TI - Approaches to prediction of the adaptive state of the brain energetic system under conditions of hypoxia. AB - We showed that mitochondrial creatine kinase activity can be predicted from the ATP level and that changes in ATP content can be evaluated by activity of mitochondrial creatine kinase under experimental conditions. PMID- 21246089 TI - Effect of afobazole on genotoxic effects of tobacco smoke in the placenta and embryonic tissues of rats. AB - The DNA comet assay was used to evaluate the severity of genotoxic changes in embryonic tissues and placenta of rats daily exposed to tobacco smoke per se or in combination with an anxiolytic agent afobazole. The exposure to tobacco smoke (4 cigarettes containing 13 mg tar and 1 mg nicotine per 72 dm(3)) for 20 min on days 1-13 of pregnancy increased the degree of DNA damage and elevation of apoptotic DNA comets in cells of the placenta and embryo from pregnant rats. Afobazole (1 and 10 mg/kg orally) reduced the genotoxic effect of tobacco smoke and decreased the amount of apoptotic DNA comets in placental tissue and embryonic tissue from rats. PMID- 21246090 TI - On the mechanism of antifibrillatory effect of afobazole. AB - Effect of afobazole on the threshold of electrical fibrillation of the heart was studied on anesthetized rats with intact myocardium. It was shown that the drug considerably increased the threshold of electrical fibrillation of the heart, being not inferior to reference class I antiarrhythmic drugs (lidocaine and procainamide) according to V. Williamse classification. Against the background of preliminary injection of sigma-receptor antagonist haloperidol, afobazole exhibited no antifibrillatory activity. These findings and analysis of published reports suggest that antifibrillatory activity of afobazole is determined by its antagonistic influence on sigma1-receptors localized in cardiomyocyte cytosol. PMID- 21246091 TI - Comparative analysis of tissue availability for afobazole and compound M-11. AB - Comparative analysis of pharmacokinetic parameters of afobazole and its main metabolite M-11 after single intraperitoneal injections of their solutions (25 mg/kg) to rats showed much more intense penetration of M-11 compared to afobazole into rat tissues and organs, judging from the area under the pharmacokinetic curve (AUC) and maximum concentrations (C(max)). The half-life periods (T(l/2e)l) of afobazole and M-11 were similar. PMID- 21246092 TI - Pharmacokinetics and antitumor effects of the drug containing TNF-alpha in nanoparticles. AB - Antitumor activity of TNF-alpha incorporated in nanoparticles (VLP-TNF-alpha) and dynamics of its accumulation and elimination from the blood and tumor tissue were studied in ICR mice. The VLP-TNF-alpha preparation exhibited higher antitumor activity compared to free TNF-alpha, presumably due to longer circulation of the cytokine in the blood and its more intensive accumulation by tumor tissue. PMID- 21246093 TI - Evaluation of the neurological status in experimental acute alcohol intoxication. AB - Approaches to evaluation of the severity of neurological disorders in animals with experimental acute severe alcohol intoxication were developed. Using the method of statistical analysis, we selected criteria, which can be used for evaluation of the severity of inhibition of the nervous system in studies of the alcoholism pathogenesis and for improvement of methods for correction of severe intoxication at the preclinical stage of drug efficiency evaluation. PMID- 21246094 TI - Stimulation of immune response: resistance to proliferation inhibitors. AB - Additional dose of the antigen at the end of the log phase of developing IgM response to T-dependent antigen leads to a drastic increase in the counts of IgM and IgG antibody-producing cells in the spleens of experimental animals. The effect is dose-dependent and more pronounced after the first immunization with the antigen in the suboptimal dose. Elimination of proliferating antibody producers has an ambiguous effect on IgM and IgG antibody production in the spleen: it limits the increase in the count of IgM-producing cells, but does not abolish the stimulation of IgG response. It seems that the increase in the count of IgG producers is not linked with simultaneous active proliferation of IgG producing cell precursors. PMID- 21246095 TI - Evaluation of the relationship between chromosome aberrations and transcription activity of nucleolus organizer regions in indigenous population of the Kursk region. AB - The relationship between activity of chromosomal nucleolus-organizer regions and levels of chromosome aberrations was studied in 215 residents of the Kursk region by visual semiquantitative method (silver staining of the nucleolus-organizer regions, NOR) in chromosomes of peripheral blood lymphocytes. The levels of chromosome aberrations differed significantly in three groups differing by the levels of 10AgNOR, which can be explained by different proliferative activity in these groups. The lowest level of chromosome aberrations was found in subjects with high transcription activity of NOR, presumably due to high proliferative activity in this group and more intensive synthesis of proteins, including the reparation enzymes. The highest level of chromosome aberrations was detected in the group with the medium level of 10AgNOR. PMID- 21246096 TI - Enzymatic status of blood lymphocytes in young children with Epstein-Barr virus infection. AB - Activities of NAD(PH)-dependent dehydrogenases in peripheral blood lymphocytes were studied in children aged 1-3 years in the dynamics of the disease caused by Epstein-Barr virus. A relationship between changes in activities of the studied enzymes and disease period was revealed. The disorders of blood lymphocyte enzymatic status persisted during convalescence. PMID- 21246097 TI - Expression of matrix metalloproteinases 1, 2, 9 and their tissue inhibitor-1 in cartilage-forming osteal tumors. AB - The expression of MMP-1, -2, -9 and TIMP-1 was studied in 10 benign cartilage forming osteal tumors (5 osteochondromas and 5 chondromas) and 39 chondrosarcomas (14 central, 4 periosteal, 7 dedifferentiated, and 14 secondary tumors). No expression of MMP and TIMP-1 was detected in benign cartilage-forming osteal tumors. In chondrosarcomas, the expression of MMP-1 was detected in 84.6%, of MMP 2 in 71.8, of MMP-9 in 97.4, and of TIMP-1 in 82.4% cases, the levels of expression of these markers varied from 10 to 60%. The expression of MMP-1 was not associated with patient gender, maximum size and degree of differentiation of the tumor, but was linked with age. The expression of MMP-1 was more often detected in central and dedifferentiated chondrosarcomas; the expression of MMP 1(+) was significantly associated with 3-year relapse-free and 5-year overall survival of the patients. The expression of MMP-1 in the tumor was associated with unfavorable course of the disease. The values of MMP-2 expression in chondrosarcomas did not reflect the main clinical morphological characteristics of the disease and its prognosis. The level of MMP-9 protein expression in chondrosarcomas >=40% is prognostically unfavorable, while <40% is a favorable factor for 3-year relapse-free survival. The risk of disease relapse within 1 year after the beginning of therapy was maximum in T3 tumors with expression of MMP-9 protein >=40%. No relationships between the parameters of TIMP-1 expression in chondrosarcomas and the main clinical morphological characteristics of the disease and its prognosis were detected. PMID- 21246098 TI - Urokinase and tissue plasminogen activators and their PAI-1 inhibitor in tumors of patients with oral mucosal cancer: relationship with the main clinical morphological factors. AB - Enhanced activation of plasminogen by the urokinase pathway (uPA elevation) in patients with cancer of the oral mucosa paralleled by an increase of PAI-1 level in the tumor compared to the adjacent mucosa was shown by enzyme immunoassay. No statistically significant associations of the level of the studied proteins in the tumor with such prognostic factors as location, growth form, histological structure, differentiation degree, size, and dissemination of the primary tumor, involvement of the regional lymph nodes, and stage of the disease were detected. PMID- 21246099 TI - Study of biological activity of Lys-Glu-Asp-Trp-NH2 endogenous tetrapeptide. AB - Biological effect of natural tetrapeptide Lys-Glu-Asp-Trp-NH(2)was evaluated during the ontogeny and in experimental streptozotocin-induced diabetes mellitus (a model of rapid experimental aging) by the sum of metabolic parameters characterizing apoptosis. PMID- 21246100 TI - Antioxidant system and energy provision of the rat heart during aging depend on illumination regimen and are resistant to exogenous melatonin. AB - Activities of antioxidant enzymes, vitamin E level, lactate dehydrogenase isoenzyme spectrum, and effects of melatonin on these parameters were studied in the myocardium of rats aged 6, 12, 18, and 24 months exposed to different illumination regimens. The greatest number of changes was recorded in rats exposed to permanent illumination and light deprivation. Activity of SOD decreased with age, while catalase activity increased. Melatonin treatment did not modify activities of antioxidant enzymes and negligibly modified the level of tocopherol and isoenzyme spectrum of lactate dehydrogenase in rat heart. PMID- 21246101 TI - Effect of dopamine on viability of BHK-21 cells. AB - We studied the effects of dopamine added to culture medium on survival of floating or adherent BHK-21 cells differing by organization of actin cytoskeleton. The viability of floating cells more drastically decreased with increasing dopamine concentration and duration of exposure than that of adherent cells. The cells worse adhered to the substrate and formed a monolayer. The formed monolayer degrades, cell borders become blurred, cells, polygonal in the control, are rounded. Preliminary blockade of dopamine receptors with haloperidol, inessential for cell survival and morphology, does not prevent the destructive effect of dopamine on the cells. Ultrastructural study revealed increased density of filamentous actin threads in deep compartments of cell cytoplasm after dopamine treatment, this increase being more pronounced in cells grown in suspension. Bearing in mind the polymerizing effect of dopamine on globular actin in vitro and the fact that the content of this protein in floating cells is higher than in adherent cells, we can conclude that the decrease in viability of BHK-21 cells is caused by interaction of dopamine with cytoplasmic globular actin. PMID- 21246102 TI - Age-associated characteristics of vasomotor regulation of the pia mater arteries in rats. AB - The endothelium-dependent and myogenic reactions of pia mater arteries of the 1st 5th branching orders were studied in 1-, 3-, and 24-month-old rats by biomicroscopy method. The endothelium-independent (myogenic) reaction predominated in the 1st-3rd order branches and the endothelium-dependent vascular reaction in the 5th order branches of 3-month-old rats. Both regulatory mechanisms were equally developed in the 4th order branches. In 1-month-old rats, the endothelium-dependent reaction was more active in the majority of branches. In 24-month-old rats, this reaction was significantly higher than the endothelium independent one only in the 4th and 5th order branches. In contrast to 3-month old rats, the myogenic reaction of 24-month-old animals predominated in the 1st and 2nd order branches and the endothelium-dependent one in the 4th and 5th order branches. Vascular reactivity of 24-month-old rats was lower than in younger rats in all cases. PMID- 21246103 TI - Structural and molecular reorganization of cardiomyocytes in transposition of the main vessels. AB - Studies of myocardial autopsy specimens from infants (0-12 months) with transposition of the main vessels showed the formation of a complex of compensatory adaptive, degenerative, and destructive changes, manifesting at a tissue level in cardiomyocyte heterogeneity and formation of cardiosclerosis zones. Cardiac myosin synthesis was replaced by synthesis of skeletal myosin, which was detected at the molecular level. Clinically it manifested in the progress of heart failure. Hyperplastic processes (intensive polyploid transformation of the nuclei) play an important role in heart remodeling in patients aged over 6 months. The findings of immunohistochemical and fluorescent studies seem to be prognostically important and provide more accurate data on the pathological processes in the myocardium at the initial stages of heart disease development starting from birth. PMID- 21246104 TI - Laser-induced fluorescence and X-ray spectral analysis of carious process in hard dental tissues. AB - Morphological and spectral X-ray analysis of carious and noncarious extracted teeth showed the patterns of dentin ossification in caries of different degree. Parietal ectopic ossification of the canal and cavity lumens in stages III and IV dental caries is regarded as a specific structural marker of pathological regeneration. The X-ray spectral analysis showed that the progress of carious process is paralleled by loss of mineral components. Laser-induced fluorescent study of tissues in extracted teeth showed 4 spectral bands corresponding to mineral and protein components of the tooth. The progress of carious process was associated with reduction of the fluorescence intensities of the spectral bands characteristic of dental collagen and mineral components. PMID- 21246105 TI - Study of the efficiency of transplantation of human neural stem cells to rats with spinal trauma: the use of functional load tests and BBB test. AB - Human ensheating neural stem cells of the olfactory epithelium were transplanted to adult male rats immediately after contusion trauma of the spinal cord at T9 level rostrally and caudally to the injury. Voluntary movements (by a 21-point BBB scale), rota-rod performance, and walking along a narrowing beam were monitored weekly over 60 days. In rats receiving cell transplantation, the mean BBB score significantly increased by 11% by the end of the experiment. The mean parameters of load tests also regularly surpassed the corresponding parameters in controls. The efficiency of transplantation (percent of animals with motor function recovery parameters surpassing the corresponding mean values in the control groups) was 62% by the state of voluntary motions, 37% by the rota-rod test, and 32% by the narrowing beam test. Morphometry revealed considerable shrinking of the zone of traumatic damage in the spinal cord and activation of posttraumatic remyelination in animals receiving transplantation of human neural stem cells. PMID- 21246106 TI - Single-step kinase inhibitor screening using a peptide-modified gold nanoparticle platform. AB - Two complementary formats for kinase inhibitor screening are presented in which peptide-modified gold nanoparticles are enzymatically phosphorylated and rapidly aggregate on a surface or in solution by action of phosphospecific antibodies. The simple and rapid colourimetric response of the assays makes them an attractive approach for drug-screening applications. PMID- 21246107 TI - Self-formation phenomenon to hierarchically structured porous materials: design, synthesis, formation mechanism and applications. AB - In this paper, we will thoroughly review a novel and versatile self-formation phenomenon that can be exploited to target porous hierarchies of materials without need of any external templates only on the basis of the chemistry of metal alkoxides and alkylmetals. These hierarchically porous materials have unique structures, which are made of either parallel funnel-like/straight macrochannels or 3D continuous interconnected macroporous foams with micro/mesoporous walls. The self-generated porogen mechanism has been proposed, leading to a series of techniques to tailor porous hierarchy, i.e. the use of different chemical precursors (single metal alkoxides, mixed metal alkoxides, single molecular precursors with two different alkoxide functionalities, alkylmetals, etc., ...), the control of their hydrolysis and condensation rates (pH, chelating agents,...) and the addition of alkoxysilanes as co-reactant. Various chemical compositions from single or binary metal oxides, to aluminosilicates, aluminophosphates, silicoaluminophosphates, metallophosphates,... can be prepared, offering a panel of potential applications. Some perspectives have been proposed to transform the synthesized materials with a hierarchy of pore sizes to micro-meso-macroporous crystalline materials with zeolite architectures. The advantages of this self-formation preparation method have been discussed compared to traditional templating methods. The possibility to combine with other strategies, for example soft or hard templating, to target even more sophisticated hierarchically meso macroporous materials with specific structure and function for various applications has been presented. The "hierarchical catalysis" concept has been re visited. PMID- 21246108 TI - An image-based 384-well high-throughput screening method for the discovery of biofilm inhibitors in Vibrio cholerae. AB - Bacterial biofilms are assemblages of bacterial cells and extracellular matrix that result in the creation of surface-associated macrocolony formation. Most bacteria are capable of forming biofilms under suitable conditions. Biofilm formation by pathogenic bacteria on medical implant devices has been linked to implant rejection in up to 10% of cases, due to biofilm-related secondary infections. In addition, biofilm formation has been implicated in both bacterial persistence and antibiotic resistance. In this study, a method has been developed for the discovery of small molecule inhibitors of biofilm formation in Vibrio cholerae, through the use of high-throughput epifluorescence microscopy imaging. Adaptation of a strategy for the growth of bacterial biofilms in wellplates, and the subsequent quantification of biofilm coverage within these wells, provides the first example of an image-based 384-well format system for the evaluation of biofilm inhibition in V. cholerae. Application of this method to the high throughput screening of small molecule libraries has lead to the discovery of 29 biofilm lead structures, many of which eliminate biofilm formation without altering bacterial cell viability. PMID- 21246109 TI - Direct acetoxylation and etherification of anilides using phenyliodine bis(trifluoroacetate). AB - Treatment of various anilides with 1.5 equiv. of phenyliodine bis(trifluoroacetate) (PIFA) and 1.0 equiv. of BF(3).OEt(2) in AcOH at room temperature afforded the corresponding para-acetoxylated products with high regioselectivity. In addition, this reaction could be expanded to the etherification of anilides. In the presence of 2.0 equiv. of PIFA and 2.0 equiv. of BF(3).OEt(2), the reaction of anilides with alcohols provided the corresponding para-etherified products in good yields. PMID- 21246114 TI - Spectroscopy and dynamics of methyl-4-hydroxycinnamate: the influence of isotopic substitution and water complexation. AB - High-resolution Resonance Enhanced MultiPhoton Ionization (REMPI) and Laser Induced Fluorescence (LIF) excitation spectra of jet-cooled methyl-4 hydroxycinnamate, methyl-4-OD-cinnamate, and of their water clusters have been recorded. Whereas water complexation leads to significant linewidth narrowing, isotopic substitution does for all practical purposes not influence the excited state dynamics. In this light, we evaluate two previously proposed decay channels of the photoexcited pipi* state involving the dissociative pisigma* state (analogous to phenol) and involving the optically dark npi* state (as concluded for para-coumaric acid). To come to an unambiguous interpretation of the REMPI studies, it has been necessary to determine ionization thresholds. For methyl-4 hydroxycinnamate and its water cluster values of 8.078 and 7.636 eV have been found. Apart from the electronic excitation studies, IR absorption studies have been performed as well. These studies provide important vibrational markers for the assignment of the various conformations that are present under molecular beam conditions, and offer a direct measure of the influence of hydrogen bonding on the properties of the hydroxyl group. PMID- 21246115 TI - The structure and interaction energies of the weak complexes of CHClF2 and CHF3 with HCCH: a test of density functional theory methods. AB - The structure and interaction energies of the weak non-covalent complexes of CHClF(2) and CHF(3) with HCCH have been predicted using a number of density functional based approaches, and compared with both high resolution spectroscopic data recently reported by Sexton et al. [Phys. Chem. Chem. Phys., 2010, 12, 14263 14270], and with high level benchmark calculations reported herein. We find that this is another case where the M05 and M06 families of functionals, as well as the DFT-D approach, are competitive with the more costly wavefunction based methods. We highlight the problem of deriving unique intermolecular structural parameters from the experimental microwave data. PMID- 21246122 TI - Compartmental Schiff-base ligands--a rich library of tectons in designing magnetic and luminescent materials. AB - The binuclear complexes (3d-3d, 3d-3d', 3d-4f) with compartmental ligands can efficiently act as tectons in crystal engineering. Various high nuclearity clusters and coordination polymers can be easily obtained by choosing the appropriate spacers. The main interest in such systems arises from their magnetic and photophysical properties. Moreover, 3d-3d' and 3d-4f complexes are useful precursors in designing heterotrimetallic systems with relevance in molecular magnetism. PMID- 21246116 TI - Identification of an FHL1 protein complex containing ACTN1, ACTN4, and PDLIM1 using affinity purifications and MS-based protein-protein interaction analysis. AB - INTRODUCTION: Four and a half LIM domains protein 1 (FHL1) is the most widely expressed member of the FHL family of proteins, consisting of four and a half highly conserved LIM domains. A multifunctional and integral role for FHL1 has been implicated in muscle development, structural maintenance, and signaling. To date, 27 FHL1 mutations have been identified that result in at least six different X-linked myopathies, with patients often presenting with cardiovascular complications. Since proteins assemble into dynamic complexes within the cell, FHL1 likely mediates its biological functions in conjunction with other proteins. Delineation of FHL1 interactions could provide insight into its regulatory functions. METHODS: We performed tandem affinity purification from human embryonic kidney 293 (HEK-293) cells to purify FHL1 and interacting proteins. To identify the potential interactors of FHL1 we performed a total of 9 different purifications from HEK-293 cells which included 3 experimental replicates for each biological condition: FHL1, tag control (DPYSL3), and negative control (empty vector). Purified samples were analyzed by liquid chromatography mass spectrometry (LC-MS). Potential interactors were then verified by immunoprecipitation from mouse heart ventricles and interactions visualized in adult cardiomyocytes using 3D fluorescence microscopy. RESULTS: We identified a total of 310 different proteins from all 9 purifications and by applying stringent filtering criteria we eliminated all proteins found in any of the controls and only allowed those that were detected in two or more bait purification. We identified 34 high confidence potential binding partners of FHL1. We then showed that FHL1 exists as part of a complex that binds with PDLIM1, GSN and ACTN1. PMID- 21246123 TI - Super Bronsted acid catalysis. AB - Bronsted acid catalysis has emerged as a new class of catalysis in modern organic synthesis. However, in order to make the utility of the Bronsted acid catalysis as broad as the well-developed Lewis acid catalysis, it is desirable to develop Bronsted acids demonstrating both high reactivities and selectivities. In this feature article, we will present our achievement in the design and development of strong Bronsted acids and their application to organic reactions. Furthermore, we will describe the Tf(2)NH-catalyzed Mukaiyama aldol reaction of super silyl enol ethers. We also will highlight the differences in reactivity and chemo- and stereo-selectivity between Bronsted and Lewis acid catalysis. PMID- 21246124 TI - Synthesis of silica supported AuCu nanoparticle catalysts and the effects of pretreatment conditions for the CO oxidation reaction. AB - Supported gold nanoparticles have generated an immense interest in the field of catalysis due to their extremely high reactivity and selectivity. Recently, alloy nanoparticles of gold have received a lot of attention due to their enhanced catalytic properties. Here we report the synthesis of silica supported AuCu nanoparticles through the conversion of supported Au nanoparticles in a solution of Cu(C(2)H(3)O(2))(2) at 300 degrees C. The AuCu alloy structure was confirmed through powder XRD (which indicated a weakly ordered alloy phase), XANES, and EXAFS. It was also shown that heating the AuCu/SiO(2) in an O(2) atmosphere segregated the catalyst into a Au-CuO(x) heterostructure between 150 degrees C to 240 degrees C. Heating the catalyst in H(2) at 300 degrees C reduced the CuO(x) back to Cu(0) to reform the AuCu alloy phase. It was found that the AuCu/SiO(2) catalysts were inactive for CO oxidation. However, various pretreatment conditions were required to form a highly active and stable Au CuO(x)/SiO(2) catalyst to achieve 100% CO conversion below room-temperature. This is explained by the in situ FTIR result, which shows that CO molecules can be chemisorbed and activated only on the Au-CuO(x)/SiO(2) catalyst but not on the AuCu/SiO(2) catalyst. PMID- 21246125 TI - Temperature responsive surface layers of modified celluloses. AB - The temperature-dependent properties of pre-adsorbed layers of methylcellulose (MC) and hydroxypropylmethylcellulose (HPMC) were investigated on silica and hydrophobized silica surfaces. Three different techniques, quartz crystal microbalance with dissipation monitoring, ellipsometry, and atomic force microscopy imaging, were used, providing complementary and concise information on the structure, mass and viscoelastic properties of the polymer layer. Adsorption was conducted at 25 degrees C, followed by a rinsing step. The properties of such pre-adsorbed layers were determined as a function of temperature in the range 25 degrees C to 50 degrees C. It was found that the layers became more compact with increasing temperature and that this effect was reversible, when decreasing the temperature. The compaction was more prominent for MC, as shown in the AFM images and in the thickness data derived from the QCM analysis. This is consistent with the fact that the phase transition temperature is lower, in the vicinity of 50 degrees C, for MC than for HPMC. The water content of the adsorbed layers was found to be high, even at the highest temperature, 50 degrees C, explored in this investigation. PMID- 21246126 TI - Eu3+-doped beta-Ga2O3 nanophosphors: annealing effect, electronic structure and optical spectroscopy. AB - A comprehensive survey of electronic structure and optical properties of rare earth ions-doped semiconductor is of vital importance for their potential applications. In this work, Eu(3+)-doped beta-Ga(2)O(3) nanocrystals were synthesized via a combustion method. The evolution of the optical properties of nanophosphors with increasing the annealing temperature was investigated in detail by means of excitation and emission spectra at room temperature and 10 K. Eu(3+) ions were proved to be incorporated into the crystal lattice of the beta Ga(2)O(3) phase after annealing the as-prepared nanoparticles at 1100 degrees C. It was observed that the substitution of Eu(3+) for Ga(3+) occurred at merely single site, in spite of two crystallographically nonequivalent sites of Ga(3+) in beta-Ga(2)O(3). Spectroscopic evidence corroborated and clarified the local symmetry of C(s) for Eu(3+) at this single site. From the high-resolution excitation and emission spectra, 71 crystal-field levels of Eu(3+) in beta Ga(2)O(3) were identified and analyzed in terms of 19 freely varied free-ions and crystal-field parameters based on C(s) symmetry. The standard deviation of the final fitting is as low as 12.9 cm(-1), indicating an excellent agreement between experimental and calculated energy levels. The temperature-dependent luminescence dynamics of the (5)D(0) multiplet for Eu(3+) in beta-Ga(2)O(3) phosphors has also been revealed for the first time from 10 to 300 K. PMID- 21246127 TI - Colloidal metal nanoparticles as a component of designed catalyst. AB - Recent advances in the synthesis of colloidal metal nanoparticles of controlled sizes and shapes that are relevant for catalyst design are reviewed. Three main methods, based on colloid chemistry techniques in solution, i.e., chemical reduction of metal salt precursors, electrochemical synthesis, and controlled decomposition of organometallic compounds and metal-surfactant complexes, are used to synthesize metal nanoparticles. Their catalytic activity and selectivity depend on the shape, size and composition of the metal nanoparticles, and the support effect, as shown for many reactions in quasi-homogeneous and heterogeneous catalysis. A specially designed type of thermally stable catalysts- "embedded" metal catalysts, in which metal nanoparticles are isolated by porous support shells so that metal sintering is effectively avoided at high temperatures, are also introduced. The utilization of pre-prepared colloidal metal nanoparticles with tuned size, shape and composition as components of designed catalysts opens up new field in catalysis. PMID- 21246128 TI - Synthesis and characterisation of aluminium(III) and tin(II) complexes bearing quinoline-based N,N,O-tridentate ligands and their catalysis in the ring-opening polymerisation of epsilon-caprolactone. AB - The synthesis and catalysis in the ring-opening polymerisation (ROP) of epsilon caprolactone (epsilon-CL) of aluminium(iii) and tin(ii) complexes supported by quinoline-based N,N,O-tridentate ligands are reported. Reaction of 8 {RC(O)CH(2)P(Ph(2)) = N}C(9)H(6)N (R = Bu(t), 2; R = Ph, 3) with AlMe(3) gave [Al(Me(2)){OCR = CHP(Ph(2)) = N(8-C(9)H(6)N)}] (R = Bu(t), 4; R = Ph, 5). Treatment of 2 and 3 with Sn[N(SiMe(3))(2)](2) generated tin(ii) complexes [Sn{OC(R) = CHP(Ph(2)) = N(8-C(9)H(6)N)}{N(SiMe(3))(2)}] (R = Bu(t), 6; R = Ph, 7). A similar reaction of AlMe(3) with 8-{MeC(O)CH(2)C(Me) = N}C(9)H(6)N gave [Al(Me(2)){OC(Me) = CHC(Me) = NC(9)H(6)N}] (9). Compounds 2-9 were characterised by NMR spectroscopy and elemental analysis. The molecular structures of complexes 4, 6 and 9 were determined by single crystal X-ray diffraction techniques. Investigation of catalysis of complexes 4-7 and 9 in the ROP of epsilon-CL revealed that the aluminium complexes, 4, 5 and 9, are much more active than the tin(ii) complexes. The kinetic studies for the polymerisation of epsilon-CL catalysed by complexes 4, 5 and 9 in the presence of benzyl alcohol (BnOH) indicated that the polymerisations proceed with the first-order dependence on monomer concentration. The polymerisation was well controlled and gave a polymer with narrow molecular weight distribution. PMID- 21246129 TI - Mononuclear iron(III) complexes of 3N ligands in organized assemblies: spectral and redox properties and attainment of regioselective extradiol dioxygenase activity. AB - Four octahedral iron(III) complexes of the type [Fe(L)Cl(3)], where L is a tridentate 3N ligand like N,N-bis(pyrid-2-ylmethyl)amine (bpa, L1), N,N bis(benzimidazol-2-ylmethyl)amine (bba, L2), 1,4,7-triazacyclononane (tacn, L3) and 2,2';6',2''-terpyridine (terpy, L4), have been isolated and their catechol dioxygenase activity investigated in dichloromethane, water and different aqueous micellar media. The positions of both the catecholato-to-iron(III) LMCT bands observed for the DBC(2-) (H(2)DBC = 3,5-di-tert-butylcatechol) adducts reveal that the adducts are present as cationic [Fe(L)(DBC)(H(2)O)](+) species, which interact strongly with anionic SDS micelles and dock themselves on the anionic micellar surface, and that they exist in the aqueous phase in CTAB and TX 100 micelles. The Fe(III)/Fe(II) redox potentials of the complexes throw light on the Lewis acidity of the iron(III) center as modified by the ligand donor atoms and hence the interaction of the complexes with different micelles. The DBSQ/DBC(2-) redox potentials in SDS micellar media are more positive than those in aqueous solution confirming the presence of the aqua species [Fe(L)(DBC)(H(2)O)](+). The DBC(2-) adducts of the iron(III) complexes of bpa, bba and tacn ligands, all with facial coordination, elicit extradiol (E) cleavage to different extents while the adduct of the terpy complex with meridional coordination of the ligand shows always intradiol (I) cleavage. It is remarkable that the bpa complex shows the highest yield of extradiol product and high product selectivity in aqueous SDS solution (E, 84.0%; E/I, 61.0 : 1) and in SDS : n-hexane reverse micellar medium (E, 93.7%) illustrating that a vacant or solvent coordinated site is essential for observing extradiol cleavage. Interestingly, the rates of dioxygenase reactions in aqueous and aqueous micellar solutions are significantly higher than those in non-aqueous solvents. Also, they diminish in the order, SDS > TX-100 > CTAB, illustrating the facile substitution of coordinated water molecule by molecular oxygen in [Fe(L)(DBC)(H(2)O)](+) bound to anionic SDS micelles. PMID- 21246130 TI - Luminescence tuning of imidazole-based lanthanide(III) complexes [Ln = Sm, Eu, Gd, Tb, Dy]. AB - To tune the lanthanide luminescence in related molecular structures, we synthesized and characterized a series of lanthanide complexes with imidazole based ligands: two tripodal ligands, tris{[2-{(1-methylimidazol-2 yl)methylidene}amino]ethyl}amine (Me(3)L), and tris{[2-{(imidazol-4 yl)methylidene}amino]ethyl}amine (H(3)L), and the dipodal ligand bis{[2 {(imidazol-4-yl)methylidene}amino]ethyl}amine (H(2)L). The general formulas are [Ln(Me(3)L)(H(2)O)(2)](NO(3))(3).3H(2)O (Ln = 3+ lanthanide ion: Sm (1), Eu (2), Gd (3), Tb (4), and Dy (5)), [Ln(H(3)L)(NO(3))](NO(3))(2).MeOH (Ln(3+) = Sm (6), Eu (7), Gd (8), Tb (9), and Dy (10)), and [Ln(H(2)L)(NO(3))(2)(MeOH)](NO(3)).MeOH (Ln(3+) = Sm (11), Eu (12), Gd (13), Tb (14), and Dy (15)). Each lanthanide ion is 9-coordinate in the complexes with the Me(3)L and H(3)L ligands and 10 coordinate in the complexes with the H(2)L ligand, in which counter anion and solvent molecules are also coordinated. The complexes show a screw arrangement of ligands around the lanthanide ions, and their enantiomorphs form racemate crystals. Luminescence studies have been carried out on the solid and solution state samples. The triplet energy levels of Me(3)L, H(3)L, and H(2)L are 21 000, 22 700, and 23 000 cm(-1), respectively, which were determined from the phosphorescence spectra of their Gd(3+) complexes. The Me(3)L ligand is an effective sensitizer for Sm(3+) and Eu(3+) ions. Efficient luminescence of Sm(3+), Eu(3+), Tb(3+), and Dy(3+) ions was observed in complexes with the H(3)L and H(2)L ligands. Ligand modification by changing imidazole groups alters their triplet energy, and results in different sensitizing ability towards lanthanide ions. PMID- 21246131 TI - Spectroscopic and redox properties of amine-functionalized K2[OsII(bpy)(CN)4] complexes. AB - We report the first examples of amine-functionalized K(2)[Os(II)(bpy)(CN)(4)] (bpy = 2,2'-bipyridine) complexes. The tetracyanoosmate complexes were prepared by UV irradiation (lambda = 254 nm) of K(4)[Os(II)(CN)(6)] and primary amine functionalized bpy ligands in acidic aqueous media. The aqueous solution pH dependences of the spectroscopic and redox properties of 4,4'- and 5,5' substituted complexes have been investigated. The pendant amine functional groups and coordinated cyanide ligands are basic sites that can be sequentially protonated, thereby allowing systematic tuning of electrochemical and optical spectroscopic properties. PMID- 21246132 TI - Natural disesquiterpenoids. AB - This review covers the isolation, structural determination, biological activities and biomimetic synthesis of all natural dimeric sesquiterpenoids, along with a detailed discussion of the biogenesis of these metabolites. Syntheses leading to the revision of structures have also been included, and 368 references are cited. PMID- 21246133 TI - Inorganic-organic hybrid compounds based on face-sharing octahedral [PbI3]infinity chains: self-assemblies, crystal structures, and ferroelectric, photoluminescence properties. AB - Eight inorganic-organic hybrid compounds with a formula of [R-Bz-1-APy][PbI(3)] (R-Bz-1-APy(+) = mono-substituted benzylidene-1-aminopyridinium Schiff base derivative; R = m-CN (1), m-CH(3) (2), H (3), p-F (4), p-Cl (5), p-Br (6), o-Cl (7), o-Br (8)) have been synthesized and characterized structurally. The common characteristic of the crystal structures of 1-8 is that the inorganic components form straight and face-sharing octahedral [PbI(3)](infinity) chains and the Schiff base cations surround the [PbI(3)](infinity) chains to form molecular stacks. The substituent (R) on the phenyl ring of the Schiff base cation clearly influences the packing structures of 1-8, and the hybrid compound crystallizes in the space group P6(3) when R = CN (1) in the meta-position of the phenyl ring, and in a central symmetric space group when R is in the ortho- or para-position of the phenyl ring. The conformation of the Schiff base cation is related to the R position, and the dihedral angle between the phenyl and pyridyl rings increases in the order of para- < meta- < ortho-position substitution of the phenyl ring. The long molecular axis of the Schiff base cation adopts a manner approximately parallel to the straight inorganic [PbI(3)](infinity) chain in the para substituted hybrid compounds, and perpendicular to the straight inorganic [PbI(3)](infinity) chain in the ortho-substituted hybrid compounds. 1 is second harmonic generation (SHG) active with a comparable response as that of urea and also exhibits ferroelectricity with larger P(s) and P(r) values; 1-8 emit multi band luminescence in the 300-650 nm regions under the excitation of ultraviolet light. PMID- 21246134 TI - Ionic liquid-assisted synthesis of CdSe dendrites from nanospheres through oriented attachment. AB - CdSe nanospheres and dendrites have been successfully synthesized via an ionic liquid-assisted hydrothermal synthetic method. The samples are characterized by X ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS), transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HRTEM). Our experimental results demonstrate that the CdSe dendrites are obtained by self-assembly from nanospheres under the driving force of oriented attachment process. Moreover, we found that the sizes and morphologies of the crystals depended on the concentration of the ionic liquid, and we obtained the CdSe nanospheres with low concentration of [BMIm][SeO(2)(OCH(3))] and CdSe dendrites with high concentration of [BMIm][SeO(2)(OCH(3))]. The effects of [BMIm][SeO(2)(OCH(3))] on the formation of the CdSe have been investigated systematically. This method is expected to be a useful technique to prepare other metal selenides for controlling the diverse shapes and sizes. PMID- 21246135 TI - Synthesis and characterisation of trigonal C2-chiral di- and tetra-substituted bis(oxazoline) alkyl zinc complexes and their reactivity towards protic reagents. AB - A series of zinc(ii) alkyl complexes stabilised by the C(2)-chiral bis(oxazoline) ligand ((R(1),R(2))BOX, with R(1) = (4S)-tBu, R(2) = H (a); R(1) = (4S)-Ph, R(2) = H (b); R(1) = (4R)-Ph, R(2) = (5S)-Ph (c)), has been synthesised and structurally characterised. ((R(1),R(2))BOX)H ligands react with ZnEt(2) in toluene to give the heteroleptic three-coordinate compounds of ((R(1),R(2))BOX)ZnEt, 1a, 1b and 1c in high yield. However, when the addition of (BOX)H ligands (a-b) over ZnEt(2) is "uncontrolled", the formation of homoleptic four-coordinate compounds are favoured (2a-b), but not for the more sterically crowded ligand (c). The zinc-ethyl derivatives (1a-c) react readily with protic reagents such as acetic acid (HOAc) and methanol (MeOH). For compounds 1a-c a redistribution of ligands is observed leading preferentially to homoleptic compounds, except for the bulkier ligand c providing a three-coordinate complex identified as ((Ph,Ph)BOX)Zn(OMe), 4c. The reaction of acetylacetone (acacH) with compounds 1a-c leads straightforwardly to the more stable four-coordinate compounds corresponding to ((R(1),R(2))BOX)Zn(eta(2)-acac), 5a-c. The potential of these compounds as initiators for the copolymerisation of epoxides with CO(2) was investigated. PMID- 21246136 TI - Structural and magnetic studies of original tetranuclear CoII-LnIII complexes (LnIII = Gd, Tb, Y). AB - The syntheses, structural determinations and magnetic studies of tetranuclear Co(II)-Ln(III) complexes (Ln = Y, Gd, Tb) involving orthovanillin as main ligand are described. The structural studies demonstrate that centrosymmetric tetranuclear Co(2)-Ln(2) complex molecules with a defect-dicubane central core are obtained, with hexacoordinate Co ions in deformed octahedral environments and nine-coordinate lanthanide ions. The Co ions are linked by two hydroxo bridges and each Co ion is also involved in a double phenoxo-hydroxo bridge with the two Ln ions, so that each hydroxo group is triply linked to the two Co and one Gd ions. The four metal ions are coplanar. A ferromagnetic Co-Ln interaction operates in the Co(2)-Ln(2) complexes (Ln = Gd, Tb), along with a D zero-field splitting term for the cobalt ion and a weak ferromagnetic Co-Co interaction. The SMM behaviour of the Co(2)-Gd(2) complex is confirmed by observation of hysteresis loops, as a consequence of the slowing down of relaxation for this tetranuclear complex. The Co(2)-Tb(2) complex does not behave as a SMM, what could result from a subtractive combination of the Tb and Co anisotropies and an increased transverse anisotropy, leading to large tunnel splittings and quantum tunneling of magnetization. PMID- 21246137 TI - Esterification of carboxylate-based ionic liquids with alkyl halides. AB - A facile reaction of 1-ethyl-3-methylimidazolium acetate ([EMIm]Ac) with dichloromethane at room temperature was observed with esters among the products. This esterification can be exploited for mild solvent-free esterification with a range of other carboxylate-based ionic liquids and alkyl halides. PMID- 21246142 TI - Asymmetric catalysis with chiral oxazolidine ligands. AB - Asymmetric catalysis with chiral 1,3-oxazolidine ligands, which have a sterically tunable, rigid structure that can accommodate several chiral centers, has found increasing attention in recent years. This trend is partly due to the intriguing ring topology of oxazolidines and the prospect of modular synthesis of a diverse set of ligands from a wide range of readily available amino alcohols. The general promise and pitfalls of the synthesis of chiral oxazolidines and the success of selected catalysts including pyridinyl and phosphine derivatives in asymmetric alkylations, alkynylations, allylic alkylations, cycloadditions, and aldol reactions is discussed. PMID- 21246138 TI - Design, synthesis and biological evaluation of choline based SPECT imaging agent: Ga(III)-DO3A-EA-Choline. AB - The enhanced choline uptake and phosphorylation in tumor cells has motivated the development of radiolabeled choline derivatives as diagnostic markers for imaging cell membrane proliferation and noninvasive detection of prostate, brain and breast tumors. In the present work, we report a facile strategy for the synthesis of choline functionalized macrocyclic chelating agent (DO3A-EA-choline) and its radiocomplexation with (67)Ga for potential tumor imaging applications. The synthesis of the desired compound featured quaternization of N,N dimethylaminoethanol with 1,2-dibromoethane followed by subsequent alkylation with trisubstituted cyclen (DO3A). All intermediates and final compounds have been fully characterized by spectroscopic techniques, namely, (1)H, (13)C NMR and mass spectroscopy. The compound has been successively labeled with (67)Ga-citrate in ammonium acetate buffer (pH 6.5) at 80 degrees C. MTT assays have been performed on the HEK cell line to determine the cytotoxicity of the compound. Cell uptake studies carried out on the U-87 MG cell line exhibited saturable binding of the radioconjugate in picomolar range with a K(d) value of 0.528 pM. The in vivo biodistribution and blood kinetics studies exhibited rapid clearance of the radiolabeled complex and excretion through the renal and hepatobiliary route. The present studies demonstrate the potential applications of (67)Ga-DO3A EA-choline as a radiopharmaceutical for molecular imaging using ((67/68)Ga) SPECT and PET modalities. PMID- 21246143 TI - Generation of bis(dithiolene)dioxomolybdenum(VI) complexes from bis(dithiolene)monooxomolybdenum(IV) complexes by proton-coupled electron transfer in aqueous media. AB - Electron transfer oxidation reaction of bis(dithiolene)monooxomolybdenum(iv) (Mo(IV)OL(x)) complexes is studied as a model of oxidative-half reaction of arsenite oxidase molybdenum enzymes. The reactions are revealed to involve proton coupled electron transfer. Electrochemical oxidation of Mo(IV)OL(x) yields the corresponding bis(dithiolene)dioxomolybdenum(vi) complexes in basic solution, where the conversion of Mo(IV)OL(dmed) supported by a smaller electron donating dithiolene ligand (1,2-dicarbomethoxyethylene-1,2-dithiolate, L(dmed)) to Mo(VI)O(2)L(dmed) is faster than that of Mo(IV)OL(bdt) with a larger electron donating dithiolene ligand (1,2-benzenedithiolate, L(bdt)) under the same conditions. Titration experiments for the electrochemical oxidation reveal that the reaction involves two-electron oxidation and two equivalents of OH(-) consumption per Mo(IV)OL(x). In the conversion process of Mo(IV)OL(x) to Mo(VI)O(2)L(x), the five-coordinate bis(dithiolene)monooxomolybdenum(v) complex (Mo(V)OL(x)) being a one-electron oxidized species of Mo(IV)OL(x) is suggested to react with OH(-). Mo(V)OL(x) reacts with OH(-) in CH(3)CN or C(2)H(5)CN in a 2 : 2 ratio to give one equivalent Mo(IV)OL(x) and one equivalent Mo(VI)O(2)L(x), which is confirmed by the UV-vis and IR spectroscopies. The low temperature stopped-flow analysis allows investigations of the mechanism for the reaction of Mo(V)OL(x) with OH(-). The kinetic study for the reaction of Mo(V)OL(dmed) with OH(-) suggests that Mo(V)OL(dmed) reacts with OH(-) to give a six-coordinate oxo hydroxo-molybdenum(v) species, Mo(V)O(OH), and, then, the resulting species undergoes successive deprotonation by another OH(-) and oxidation by a remaining Mo(V)OL(dmed) to yield the final products Mo(IV)OL(dmed) and Mo(VI)O(2)L(dmed) complexes in a 1 : 1 ratio. In this case, the Mo(V)O(2) species are involved as an intermediate in the reaction. On the other hand, in the reaction of Mo(V)OL(bdt) with OH(-), coordination of OH(-) to the Mo(V) centre to give a six coordinate Mo(V)O(OH)L(bdt) species becomes the rate limiting step and other intermediates are not suggested. On the basis of these results, the ligand effects of the dithiolene ligands on the reactivity of the bis(dithiolene)molybdenum complexes are discussed. PMID- 21246144 TI - Self-assembly and characterization of copper 3,4-pyridinedicarboxylate complexes based on a variety of polynuclear hydroxo clusters. AB - Self-assembly of copper(ii) ion, 3,4-pyridinedicarboxylate (PDC), and 1,10 phenanthroline (phen) under basic conditions at 100 degrees C affords four PDC linked copper(ii) complexes, [Cu(4)(MU(2)-OH)(3)(MU(3) OH)(PDC)(phen)(4)](n).n(PDC).11.5 nH2O (1), [Cu(4)(MU(2)-OH)(2)(MU(3) OH)(2)(PDC)(phen)(4)](n).n(PDC). 11.5 nH(2)O (2), [Cu(8)(MU(2)-OH)(2)(MU(3) OH)(6)(PDC)(2)(phen)(8)].2(PDC).23 H(2)O (3), and [Cu(3.5)(MU(2)-OH)(3) (PDC)(2)(phen)](n) (4). 1-4 are copper hydroxo complexes, and 1, 2 and 3 co crystallized from the one-pot reaction. X-ray single crystal diffraction analyses indicate that complexes 1 and 2 are linkage isomers and contain tetranuclear copper cluster cores with different geometry, and that PDC links the cluster core to form a one-dimensional chain. Complex 3 is a discrete step-like octanuclear copper hydroxo cluster complex. The involvement of hydroxo and phen in the coordination makes some coordination sites of PDC idle, which leads to rich hydrogen bonds and pi-pi interactions in complexes 1, 2 and 3. Complex 4 contains two types of copper hydroxo cluster cores: chair-like tetranuclear and linear trinuclear units, and the cluster cores are linked by PDC to a double-layer metal organic framework. Magnetic properties of 1, 3 and 4 were investigated. The results reveal that complexes 3 and 4 exhibit strong antiferromagnetic interactions whereas ferromagnetic coupling is predominant for complex 1. The magnetic properties are analyzed in connection with their structures. PMID- 21246145 TI - Self-assembly of neutral and cationic PdII organometallic molecular rectangles: synthesis, characterization and nitroaromatic sensing. AB - Design and synthesis of three novel [2 + 2] self-assembled molecular rectangles 1 3via coordination driven self-assembly of predesigned Pd(ii) ligands is reported. 1,8-Diethynylanthracene was assembled with trans-Pd(PEt(3))(2)Cl(2) in the presence of CuCl catalyst to yield a neutral rectangle 1via Pd-C bond formation. Complex 1 represents the first example of a neutral molecular rectangle obtained via C-Pd coordination driven self-assembly. A new Pd(2)(II) organometallic building block with 180 degrees bite-angle 1,4-bis[trans (ethynyl)Pd(PEt(3))(2)(NO(3))]benzene (M(2)) containing ethynyl functionality was synthesized in reasonable yield by employing Sonagashira coupling reaction. Self assembly of M(2) with two organic clip-type donors (L(2)-L(3)) afforded [2 + 2] self-assembled molecular rectangles 2 and 3, respectively [L(2) = 1,8-bis(4 pyridylethynyl)anthracene; L(3) = 1,3-bis(3-pyridyl)isophthalamide]. The macrocycles 1-3 were fully characterized by multinuclear NMR and ESI-MS spectroscopic techniques, and in case of 1 the structure was unambiguously determined by single crystal X-ray diffraction analysis. Incorporation of Pd ethynyl bonds helped to make the assemblies pi-electron rich and fluorescent in nature. Complexes 1-2 showed quenching of fluorescence intensity in solution in presence of nitroaromatics, which are the chemical signatures of many commercially available explosives. PMID- 21246146 TI - Negative thermal expansion emerging upon structural phase transition in ZrV2O7 and HfV2O7. AB - ZrV(2)O(7) and HfV(2)O(7), which show negative thermal expansion (NTE) in the high-temperature phase, were investigated using X-ray diffraction and heat capacity calorimetry. Two sharp anomalies due to successive phase transitions were observed in the temperature dependence of heat capacity at 345.5 K and 373.4 K for ZrV(2)O(7) and 341.8 K and 370.3 K for HfV(2)O(7). The smallness of their combined entropies of transition suggested that the phase transitions are of displacive type. Effective phonon densities of states (DOS) described by a simple model, and mode-Gruneisen parameters of the low-temperature phase were obtained through the spectrum analyses of heat capacities of ZrV(2)O(7) and HfV(2)O(7). Their effective phonon DOS's show the three features common to NTE compounds: low energy phonon mode, high-energy phonon mode, and a wide phonon gap in between. The mode-Gruneisen parameter of low-energy modes corresponding to translational and librational vibrations of the constituent polyhedra is negative but with a small absolute value due to the distortion of V(2)O(7) group in the low temperature phase, resulting in positive thermal expansion. It is revealed that the release of the structural distortion upon the successive phase transitions with large volume increase leads to the NTE of ZrV(2)O(7) and HfV(2)O(7) in the high-temperature phase. PMID- 21246147 TI - Crystallographic characterisation of Ti(IV) piperazine complexes and their exploitation for the ring opening polymerisation of rac-lactide. AB - In this paper a series of eight Ti(IV) piperazine based complexes have been prepared and fully characterised in the solid-state by X-ray crystallography and in solution via NMR spectroscopy. In the solid-state either Ti(2)(L)(O(i)Pr)(6) or Ti(2)(L)(2)(O(i)Pr)(4) were observed depending upon the nature of the starting ligand. For complexes with less sterically demanding ligands (1H(2) and 2H(2)) an equilibrium was observed: 2 Ti(2)(L)(O(i)Pr)(6) <=> Ti(2)(L)(2)(O(i)Pr)(4) + 2 Ti(O(i)Pr)(4). The thermodynamic properties (DeltaG, DeltaH and DeltaS) have been investigated via variable temperature NMR spectroscopy. With more sterically demanding ligands (3-8H(2)) the Ti(2)(L)(O(i)Pr)(6) form was the most prevalent in the solid-state and in solution. These complexes have been tested for the production of polylactide under melt and solution conditions with high conversions being obtained. PMID- 21246148 TI - 31P,89Y shift correlation. Application to the speciation of yttrium complexes with triphenylphosphine oxide. AB - Correlation experiments between (89)Y and (31)P nuclei through scalar coupling using (31)P detection are described for the first time. The utility of the new method of characterizing (89)Y is demonstrated by identifying the species formed in the reaction of yttrium nitrate with triphenylphosphine oxide in THF solution. PMID- 21246149 TI - Impact of salinity and pH on phytoplankton communities in a tropical freshwater system: An investigation with pigment analysis by HPLC. AB - An in vitro study was carried out to understand the effects of salinity shock and variation in pH on phytoplankton communities in a tropical freshwater system of the Godavari River (a major peninsular river in India). The distributions of, and variations in, phytoplankton communities were assessed by quantitative determination of their class specific marker pigments, using HPLC. Subtle changes in salinity of the freshwater by one practical salinity unit (PSU) completely removed green algae from the system and allowed the cyanobacteria to come into dominance. The cyanobacteria were found to tolerate higher osmotic stress until the salinity reached a PSU of 16. The higher salinity tolerance range of the cyanobacteria was attributed to the enhanced synthesis of zeaxanthin as protective xanthophylls against the osmotic stress. However, the effects of changing pH were not as dramatic as salinity where the green algae and the cyanobacteria from the same freshwater system showed a considerable acclimation towards the fluctuating pH. These findings are environmentally relevant to understand the likely impact of salt water intrusion and pH variation on phytoplankton communities in a tropical freshwater system. PMID- 21246150 TI - 'Supramolecular wrapping chemistry' by helix-forming polysaccharides: a powerful strategy for generating diverse polymeric nano-architectures. AB - We have exploited novel supramolecular wrapping techniques by helix-forming polysaccharides, beta-1,3-glucans, which have strong tendency to form regular helical structures on versatile nanomaterials in an induced-fit manner. This approach is totally different from that using the conventional interpolymer interactions seen in both natural and synthetic polymeric architectures, and therefore has potential to create novel polymeric architectures with diverse and unexpected functionalities. The wrapping by beta-1,3-glucans enforces the entrapped guest polymer to adopt helical or twisted conformations through the convergent interpolymer interactions. On the contrary, the wrapping by chemically modified semi-artificial beta-1,3-glucans can bestow the divergent self assembling abilities on the entrapped guest polymer to create hierarchical polymeric architectures, where the polymer/beta-1,3-glucan composite acts as a huge one-dimensional building block. Based on the established wrapping strategy, we have further extended the wrapping techniques toward the creation of three dimensional polymeric architectures, in which the polymer/beta-1,3-glucan composite behaves as a sort of amphiphilic block copolymers. The present wrapping system would open several paths to accelerate the development of the polymeric supramolecular assembly systems, giving the strong stimuli to the frontier of polysaccharide-based functional chemistry. PMID- 21246151 TI - DNA assembly for synthetic biology: from parts to pathways and beyond. AB - The assembly of DNA from small fragments into large constructs has seen significant recent development, becoming a pivotal technology in the ability to implement the vision of synthetic biology. As the cost of whole gene synthesis is decreasing, whole genome synthesis at the other end of the spectrum has expanded our horizons to the prospect of fully engineered synthetic cells. However, the recently proven ability to synthesise genome-scale DNA is at odds with our ability to rationally engineer biological devices, which lags significantly behind. Most work in synthetic biology takes place on an intermediate scale with the combinatorial construction of networks and metabolic pathways from registries of modular biopart components. Implementation for rapid prototyping of engineered biological circuits requires quick and reliable DNA assembly according to specific architectures. It is apparent that DNA assembly is now a limiting technology in advancing synthetic biology. Current techniques employ standardised restriction enzyme assembly protocols such as BioBricksTM, BglBricks and Golden Gate methods. Alternatively, sequence-independent overlap techniques, such as In FusionTM, SLIC and Gibson isothermal assembly are becoming popular for larger assemblies, and in vivo DNA assembly in yeast and bacillus appears adept for chromosome fabrication. It is important to consider how the use of different technologies may impact the outcome of a construction, since the assembly technique can direct the architecture and diversity of systems that can be made. This review provides a critical examination of recent DNA assembly strategies and considers how this important facilitating aspect of synthetic biology may proceed in the future. PMID- 21246152 TI - UV polymerization of hydrodynamically shaped fibers. AB - Most natural and man-made fibers have circular cross-sections; thus the properties of materials composed of non-circular fibers are largely unexplored. We demonstrate the technology for fabricating fibers with predetermined cross sectional shape. Passive hydrodynamic focusing and UV polymerization of a shaped acrylate stream produced metre-long fibers for structural and mechanical characterization. PMID- 21246153 TI - A simple and sensitive method for visual detection of heparin using positively charged gold nanoparticles as colorimetric probes. AB - The electrostatic interaction between the negatively-charged heparin and the positively-charged gold nanoparticles leads to aggregation of gold nanoparticles and a color change from red to blue in solution, thus providing a simple and visual approach to colorimetric detection of heparin. PMID- 21246161 TI - Fully automated immunoassay for quantitative determination of FXIII. AB - Coagulation factor XIII (FXIII) is essential for clot stabilization. Deficiency of FXIII is associated with a risk of bleeding and impaired wound healing. Substitution therapy with FXIII remedies for patients with low plasma levels of FXIII requires diagnostic quantification of the factor before and during therapy. Here, we describe a prototype of a preliminary research immunoassay for quantification of FXIII antigen on automated coagulation instruments. The prototype assay is based on a monoclonal antibody (mAb) directed against FXIII A chain, whereas the mAbs are coupled to latex particles. FXIII in a plasma specimen causes agglutination of the latex particles, which can be quantified turbidimetrically. Performance data of the assay prototype processed on BCS(r) XP and Sysmex(r) CA-1500 instruments demonstrate a good correlation to the Berichrom(r) factor XIII activity assay1 from Siemens Healthcare Diagnostics (r = 0.94). RESULTS: Comparability of instruments was excellent (r = 0.98). Coefficients of variation of total imprecision measurements ranged from 2.2 to 3.4%. Linearity was excellent over the range tested (12-121% FXIII). Analytical sensitivity was 0.51% FXIII on BCS XP and 0.44% FXIII on Sysmex CA-1500, respectively. No interference (>10% bias) was observed with haemoglobin (up to 400 mg/dl), cholesterol (up to 300 mg/dl), bilirubin (up to 60 mg/dl) or triglycerides (up to 3000 mg/dl). CONCLUSION: The preliminary research assay prototype has the potential for excellent analytical sensitivity, precision, and dynamic range suitable to measure reliably FXIII antigen levels in human plasma. PMID- 21246162 TI - Can (18)F-FDG PET/CT predict recurrence in patients with cutaneous malignant melanoma? AB - The AIM of this study was to evaluate the prognostic significance of maximum standardized uptake value (SUVmax) of primary cutaneous malignant melanoma (CMM) lesions by (18)F-FDG positron emission tomography/computerized tomography (PET/CT) in terms of recurrence. PATIENTS, METHODS: 37 CMM patients (17 men, mean age: 61.7 +/- 13.6 years) that underwent PET/CT at presentation were enrolled in this study. Recurrence was determined by histological confirmation or by radiological and clinical follow-up for at least 8 months after curative surgery. Clinical variables such as age, sex, clinical stage, and primary lesion location, thickness, and ulceration, and SUVmax values were analyzed with respect to their usefulness for predicting recurrence. RESULTS: SUVmax was found to be significantly higher in patients with ulceration of primary lesion of CMM (p = 0.004) and in patients with a stage >= III (p < 0.000). Patients that experience recurrence had a significantly higher mean SUVmax value (4.9 +/- 2.9) than patients who did not (2.1 +/- 1.5, p = 0.024). ROC analysis showed that a SUVmax cut-off value 2.2 had high sensitivity (88.9%) and specificity (67.9%) for predicting recurrence. Kaplan-Meier analysis identified ulceration of primary lesion (p = 0.034), stage >= III (p = 0.019) and SUVmax >= 2.2 (p = 0.002) as predictors of recurrence. However, Cox proportional-hazards analysis showed that only SUVmax (p = 0.025, relative risk 11.063) significantly predicted recurrence. CONCLUSION: Preoperative SUVmax of primary lesion was found to be the most potent predictor of recurrence in CMM patient. Patients with high SUV max of primary lesion should be followed meticulously for recurrence. PMID- 21246163 TI - "Merinoff symposium 2010: sepsis"-speaking with one voice. PMID- 21246165 TI - Dr. Ella ware, 'the country doc:' educated and practicing in Texas. PMID- 21246166 TI - "An American Contribution to Social Welfare:" The Human Betterment Foundation's Advocacy of Compulsory Eugenic Sterilization. PMID- 21246167 TI - Necrotizing fascitis and streptococcal toxic shock syndrome complicating herpes zoster: a vaccine talking point? PMID- 21246168 TI - Computed tomographic angiography aid in post mastectomy breast reconstruction using the deep inferior epigastric artery perforator flap. PMID- 21246169 TI - Osteochondritis dissecans of the talus: a report of two male siblings. PMID- 21246170 TI - A medical home for our children. PMID- 21246171 TI - Discharges from academic medical centers. PMID- 21246172 TI - Graduate medical education: a brief history and its role in physician supply. PMID- 21246173 TI - Combining traditional neuroscience disciplines to promote academic growth: the creation of a department of neurosciences. PMID- 21246174 TI - Listening to our colleagues: generation x and beyond. PMID- 21246175 TI - Discharge summaries. PMID- 21246176 TI - Blue-enriched office light competes with natural light as a zeitgeber. AB - OBJECTIVES: Circadian regulation of human physiology and behavior (eg, body temperature or sleep-timing), depends on the "zeitgeber" light that synchronizes them to the 24-hour day. This study investigated the effect of changing light temperature at the workplace from 4000 Kelvin (K) to 8000 K on sleep-wake and activity-rest behavior. METHODS: An experimental group (N=27) that experienced the light change was compared with a non-intervention group (N=27) that remained in the 4000 K environment throughout the 5-week study period (14 January to 17 February). Sleep logs and actimetry continuously assessed sleep-wake behavior and activity patterns. RESULTS: Over the study period, the timing of sleep and activity on free days steadily advanced parallel to the seasonal progression of sunrise in the non-intervention group. In contrast, the temporal pattern of sleep and activity in the experimental group remained associated with the constant onset of work. CONCLUSION: The results suggest that artificial blue-enriched light competes with natural light as a zeitgeber. While subjects working under the warmer light (4000 K) appear to entrain (or synchronize) to natural dawn, the subjects who were exposed to blue-enriched (8000 K) light appear to entrain to office hours. The results confirm that light is the dominant zeitgeber for the human clock and that its efficacy depends on spectral composition. The results also indicate that blue-enriched artificial light is a potent zeitgeber that has to be used with diligence. PMID- 21246177 TI - In vivo analysis of solar lentigines by reflectance confocal microscopy before and after Q-switched ruby laser treatment. AB - Solar lentigines are benign lesions usually found on sun-damaged skin. We investigated twelve cases of solar lentigines through dermoscopy and reflectance confocal microscopy, performed before, and 30 min and 10 days after, a single treatment with a Q-switched ruby laser. At baseline, all lesions showed characteristic features of solar lentigines in reflectance confocal microscopy analysis: regular honeycomb patterns, edged dermal papillae and cord-like rete ridges at the dermoepidermal junction. Thirty minutes post-laser treatment, blurred epidermal intercellular connections, dark structureless areas of different sizes and shapes in the lower epidermal layers, and hyporeflective dermal papillae, reflecting epidermal and dermal oedema, were observed. Ten days post-treatment highly reflective round-to polygonal areas and aggregated granules, representing extracellular melanin, were detected in all epidermal layers featuring regular honeycomb patterns. Reflectance confocal microscopy can be used to visualise dynamic skin processes, allowing non-invasive in vivo follow up of skin lesions after treatment. PMID- 21246178 TI - [The various forms of left ventricular hypertrophy: diagnostic value of echocardiography]. AB - Left ventricular hypertrophy is a non-specific physiological or maladaptive cardiac response to a large array of stimuli mediated by exercise and numerous cardiac and systemic diseases. The precise characterization and quantification of left ventricular hypertrophy may allow a more timely diagnosis of the underlying condition. The clinical reference standard to assess left ventricular hypertrophy is echocardiography, but a comprehensive description of how to approach this frequent finding in clinical practice is lacking. The current review systematically describes the typical echocardiographic patterns of important types of cardiac hypertrophy using both established and advanced imaging modalities. In hypertrophic obstructive cardiomyopathy a markedly reduced regional systolic function is found in the prominent thickened septum, whereas in essential arterial hypertension a typical concentric left ventricular hypertrophy with a less prominent basal septal bulge is present. The echocardiographic characteristics of cardiac amyloidosis are ventricular hypertrophy with sparkling granular myocardial texture and a small epicardial effusion. In addition, the strain rate curve for longitudinal function shows a typically reduced function which reaches maximum already in early systole. The typical feature of Friedreich cardiomyopathy is concentric left ventricular hypertrophy and sparkling granular texture with preserved regional systolic function. In Fabry cardiomyopathy a prominent papillary muscle is presented and a typical strain rate curve can be extracted from the basal lateral wall, indicating replacement fibrosis. Prominent hypertrabecularisation (ratio of non-compacted to compacted myocardium >2) in the apical and mid left ventricular segments is typical for non-compaction cardiomyopathy. Knowledge of these typical echocardiographic features enables the cardiologist to distinguish between the different hypertrophic entities, thus paving the way to early diagnosis. PMID- 21246179 TI - Pneumorrhachis: a rare finding on computed tomography scans. PMID- 21246180 TI - Features of positional magnetic resonance imaging in tethered cord syndrome. AB - PURPOSE: Tethered cord syndrome (TCS) is a clinical entity in which symptoms are induced through excessive tension on the spinal cord. The radiological method of choice to confirm TCS is magnetic resonance imaging (MRI), however limitations exist especially in patients with no underlying spinal dysraphism. MATERIALS AND METHODS: The positional MRI features of TCS in a series of four patients with suspected or proven TCS are described, especially with respect to contact of the myelon or the cauda equina with the dorsal elements of the lumbar spinal canal. The findings are correlated with the lordosis angle of the lumbar spine. RESULTS: In flexion contact of the myelon or the cauda equina with the dorsal elements of the lumbar spinal canal is reduced due to a straightening of the lumbar spine. With increasing lordosis of the lumbar spine, the degree of contact increases and detection of TCS is more difficult. The site of tethering could be identified in all four patients in flexion. CONCLUSION: Positional MRI can be useful to confirm or rule out TCS and helpful to identify the site of tethering. The value of positional MRI is limited to patients who are able to fully flex the lumbar spine and in patients without spinal canal stenosis and spondylolisthesis. PMID- 21246181 TI - Carotidynia: magnetic resonance imaging and ultrasonographic imaging of a self limiting disease. AB - This article describes the characteristic symptoms of carotidynia and the diagnostic options for this rare and not yet officially recognized disease entity. Based on a case report the findings of magnetic resonance imaging (MRI) and ultrasound scanning are presented. PMID- 21246182 TI - [Laryngeal tube II : alternative airway for children?]. AB - Difficult airway situations both expected and unexpected, present major challenges to every anesthesiologist, especially in pediatric anesthesia. However, the integration of extraglottic airway devices, such as the laryngeal mask, into the algorithm of difficult airways has improved the handling of difficult airway situations. A device for establishing a supraglottic airway, the laryngeal tube (LT), was introduced in 1999. The LT is an extraglottic airway designed to secure a patent airway during either spontaneous breathing or controlled ventilation. The design of the device has been revised several times and a further development is the LTS II/LTS-D, which provides an additional channel for the insertion of a gastric drain tube. This article reports on the successful use of the LTS II in 12 children aged from 2 days to 6 years when endotracheal intubation, alternative mask or laryngeal mask ventilation failed. Use of the LTS II was associated with a high level of success, securing the airway when other techniques had failed. The potential advantage of the LTS II over the standard LT is an additional suction port, which allows gastric tube placement and can be used as an indirect indicator of correct placement. With a modified insertion technique using an Esmarch manoeuvre, placement was simple and fast to perform. In emergency situations when direct laryngoscopy fails or is too time-consuming the LTS II tube is recommended as an alternative device to secure the airway. As with all extraglottic airway devices, familiarity and clinical experience with the respective device and the corresponding insertion technique are essential for safe and successful use, especially in emergency situations. PMID- 21246183 TI - Selection of a core set of RILs from Forrest x Williams 82 to develop a framework map in soybean. AB - Soybean BAC-based physical maps provide a useful platform for gene and QTL map based cloning, EST mapping, marker development, genome sequencing, and comparative genomic research. Soybean physical maps for "Forrest" and "Williams 82" representing the southern and northern US soybean germplasm base, respectively, have been constructed with different fingerprinting methods. These physical maps are complementary for coverage of gaps on the 20 soybean linkage groups. More than 5,000 genetic markers have been anchored onto the Williams 82 physical map, but only a limited number of markers have been anchored to the Forrest physical map. A mapping population of Forrest * Williams 82 made up of 1,025 F(8) recombinant inbred lines (RILs) was used to construct a reference genetic map. A framework map with almost 1,000 genetic markers was constructed using a core set of these RILs. The core set of the population was evaluated with the theoretical population using equality, symmetry and representativeness tests. A high-resolution genetic map will allow integration and utilization of the physical maps to target QTL regions of interest, and to place a larger number of markers into a map in a more efficient way using a core set of RILs. PMID- 21246185 TI - The effect of high-protein, low-carbohydrate diets in the treatment of type 2 diabetes: a 12 month randomised controlled trial. AB - AIMS/HYPOTHESIS: Short-term dietary studies suggest that high-protein diets can enhance weight loss and improve glycaemic control in people with type 2 diabetes. However, the long-term effects of such diets are unknown. The aim of this study was to determine whether high-protein diets are superior to high-carbohydrate diets for improving glycaemic control in individuals with type 2 diabetes. METHODS: Overweight/obese individuals (BMI 27-40 kg/m(2)) with type 2 diabetes (HbA(1c) 6.5-10%) were recruited for a 12 month, parallel design, dietary intervention trial conducted at a diabetes specialist clinic (Melbourne, VIC, Australia). Of the 108 initially randomised, 99 received advice to follow low-fat (30% total energy) diets that were either high in protein (30% total energy, n = 53) or high in carbohydrate (55% total energy, n = 46). Dietary assignment was done by a third party using computer-generated random numbers. The primary endpoint was change in HbA(1c). Secondary endpoints included changes in weight, lipids, blood pressure, renal function and calcium loss. Study endpoints were assessed blinded to the diet group, but the statistical analysis was performed unblinded. This study used an intention-to-treat model for all participants who received dietary advice. Follow-up visits were encouraged regardless of dietary adherence and last measurements were carried forward for study non-completers. RESULTS: Ninety-nine individuals were included in the analysis (53 in high protein group, 46 in high carbohydrate group). HbA(1c) decreased in both groups over time, with no significant difference between groups (mean difference of the change at 12 months; 0.04 [95% CI -0.37, 0.46]; p = 0.44). Both groups also demonstrated decreases over time in weight, serum triacylglycerol and total cholesterol, and increases in HDL-cholesterol. No differences in blood pressure, renal function or calcium loss were seen. CONCLUSIONS/INTERPRETATION: These results suggest that there is no superior long-term metabolic benefit of a high protein diet over a high-carbohydrate in the management of type 2 diabetes. TRIAL REGISTRATION: ACTRN12605000063617 ( www.anzctr.org.au ). FUNDING: This study was funded by a nutritional research grant from Meat and Livestock Australia (MLA). J.E. Shaw is supported by NHMRC Fellowship 586623. PMID- 21246186 TI - A controlled trial of problem-solving counseling for war-affected adults in Aceh, Indonesia. AB - PURPOSE: War and conflict have consequences on the mental health of individuals and entire communities and the communities in Aceh, Indonesia, having experienced more than 30 years of armed conflict, are no exception. This study presents results from an evaluation of a non-specific mental health group counseling program among adults affected by conflict. Interventions such as these need to be evaluated to further the limited empirical evidence base for efficacious community-based treatments for improving the mental health and psychosocial problems in humanitarian settings. METHODS: A total of 589 adults were screened using a locally validated measure of mental health and functioning. Of all, 420 (71%) met the study inclusion criteria of elevated symptom levels and functional impairment: 214 and 206 in three intervention and three control villages, respectively. Intervention participants met weekly for eight sessions in groups of eight to ten adults. Following completion of treatment, 175 (85%) controls and 158 (74%) intervention participants were re-assessed. Regression analyses compared pre- and post-intervention scale scores. RESULTS: We did not find an intervention effect for reducing the burden of depression and anxiety symptoms when compared with the control sample. Impact on functioning was mixed and there was an increase in use of positive coping strategies. CONCLUSIONS: The lack of mental health impact may be because the mental health problems and dysfunction were not due to disorder, but were normal responses to struggles of daily living experienced by this community and not addressed by the intervention. PMID- 21246187 TI - Tolerance and cross-tolerance to cannabinoids in mice: schedule-controlled responding and hypothermia. AB - RATIONALE: Cannabinoid CB(1) receptor agonists vary in efficacy in vitro; however, relationships between efficacy and behavioral effects are unclear. OBJECTIVE: This study examined the relationship between apparent CB(1) agonist efficacy and in vivo effects. METHODS: Male C57BL/6J mice responded for food under a fixed ratio 30 schedule; rectal temperature was measured. Sensitivity of the mice to cannabinoid agonists (rank order efficacy in vitro reported to be CP 55940 > anandamide > Delta(9)-tetrahydrocannabinol; Delta(9)-THC) and a non cannabinoid (the benzodiazepine midazolam) was determined before, during, and after discontinuation of daily Delta(9)-THC treatment (32 mg/kg/day, i.p.). Rimonabant was combined with cannabinoids to examine whether CB(1) receptors mediated effects on response rate. RESULTS: Delta(9)-THC, CP 55940, anandamide, and midazolam decreased responding at doses smaller than those producing hypothermia. Rimonabant antagonized the rate-decreasing effects of Delta(9)-THC and CP 55940, but not those of anandamide. Delta(9)-THC treatment produced tolerance for both rate-decreasing and hypothermic effects. Delta(9)-THC treatment did not change sensitivity to the rate-decreasing effects of CP 55940, but produced cross-tolerance to CP 55940 for hypothermic effects. Delta(9)-THC treatment did not modify sensitivity to anandamide and midazolam. CONCLUSIONS: CB(1) receptors mediate the operant rate-decreasing effects of Delta(9)-THC and CP 55940, but not anandamide, in mice. CB(1) agonist efficacy is an important determinant of in vivo effects, especially with regard to the magnitude of tolerance and cross-tolerance resulting from daily Delta(9)-THC treatment. This applies not only to different cannabinoids when measuring the same effect but also to the same cannabinoid when measuring different effects. PMID- 21246189 TI - Selective determination of ubiquinone in human plasma by HPLC with chemiluminescence reaction based on the redox cycle of quinone. AB - Ubiquinone is an important biologically active compound in the living body. The determination of ubiquinone in human plasma is useful for the investigation of bioavailability of ubiquinone and for early diagnosis of several diseases. Therefore, we developed a high-performance liquid chromatography (HPLC) with chemiluminescence detection method for the analysis of ubiquinone in plasma samples. The method is based on luminol chemiluminescence detection of super oxide anion that is generated by the redox cycle reaction between ubiquinone and dithiothreitol. The HPLC system involved an octyl column with a mobile phase of methanol. Ubiquinone eluted from the column was mixed with dithiothreitol and luminol solutions simultaneously, and generated chemiluminescence was monitored by chemiluminescence detector. The calibration curve for standard ubiquinone solution was linear from 0.09 to 43.2 MUg/mL (0.45-216 ng on column) with the correlation coefficient of 0.999, and the detection limit (S/N = 3) was 26 ng/mL (130 pg on column). Using the proposed HPLC method, the peak of ubiquinone in human plasma could be clearly detected on the chromatogram without any interference from plasma components. PMID- 21246188 TI - Residual effects of esmirtazapine on actual driving performance: overall findings and an exploratory analysis into the role of CYP2D6 phenotype. AB - INTRODUCTION: Esmirtazapine is evaluated as a novel drug for treatment of insomnia. PURPOSE: The present study was designed to assess residual effects of single and repeated doses of esmirtazapine 1.5 and 4.5 mg on actual driving in 32 healthy volunteers in a double-blind, placebo-controlled study. Treatment with single doses of zopiclone 7.5 mg was included as active control. METHODS: Treatments were administered in the evening. Driving performance was assessed in the morning, 11 h after drug intake, in a standardized on-the-road highway driving test. The primary study parameter was standard deviation of lateral position (SDLP), a measure of "weaving". All subjects were subjected to CYP2D6 phenotyping in order to distinguish poor metabolizers from extensive metabolizers of esmirtazapine. RESULTS: Overall, esmirtazapine 1.5 mg did not produce any clinically relevant change in SDLP after single and repeated dosing. Driving impairment, i.e., a rise in SDLP, did occur after a single-dose administration of esmirtazapine 4.5 mg but was resolved after repeated doses. Acute driving impairment was more pronounced after both doses of esmirtazapine in a select group of poor metabolizers (N = 7). A single-dose zopiclone 7.5 mg also increased SDLP as expected. CONCLUSION: It is concluded that single and repeated doses of 1.5 mg esmirtazapine are generally not associated with residual impairment. Single-dose administration of 4.5 mg esmirtazapine was associated with residual impairment that generally resolved after repeated administration. Exploratory analysis in a small group of poor CYP 2D6 metabolizers suggested that these subjects are more sensitive to the impairing effects of esmirtazapine on car driving. PMID- 21246190 TI - Field-amplified sample injection combined with pressure-assisted capillary electrophoresis UV detection for the simultaneous analysis of allantoin, uric acid, and malondialdehyde in human plasma. AB - The allantoin/uric acid (All/UA) ratio and malondialdehyde (MDA) plasma levels have been proposed as important markers for monitoring oxidation triggered by the action of free radicals (FR). Here, we describe an easy field amplified sample injection capillary electrophoresis method with UV detection for the separation and quantification of All, UA, and free MDA in human plasma. The plasma samples were simply filtered through centrifugation membrane tubes for protein elimination and directly injected on a capillary without complex cleanup and/or sample derivatization procedures. The use of a run buffer composed of 300 mmol/L sodium borate at pH 10 with 50 mmol/L of N-methyl-D: -glucamine and an overimposed pressure/voltage of 0.1 psi during the electrophoretic run allows basline resolution of the analytes within 17 min. The electrokinetic injection allows a detection limit of 15 nmol/L for All, 20 nmol/L for UA and 10 nmol/L for MDA in a plasma sample, thus significantly improving the LOD of previous described methods based on capillary electrophoresis. Precision tests indicate a good repeatability of our method both for migration times (CV = 1.85%) and areas (CV = 2.87%). Moreover, a good reproducibility of intra- and inter-assay tests was obtained (CV = 4.63% and CV = 6.59% respectively). The suitability of the method was tested by measuring analyte levels in 40 healthy volunteers. PMID- 21246191 TI - Hollow fiber-based liquid-phase microextraction (HF-LPME) of isradipine and its main metabolite followed by chiral HPLC analysis: application to an in vitro biotransformation study. AB - An enantioselective liquid chromatographic method using two-phase hollow fiber liquid-phase microextraction (HF-LPME-HPLC) was developed for the determination of isradipine (ISR) enantiomers and its main metabolite (pyridine derivative of isradipine, PDI) in microsomal fractions isolated from rat liver. The analytes were extracted from 1 mL of microsomal medium using a two-phase HF-LPME procedure with hexyl acetate as the acceptor phase, 30 min of extraction, and sample agitation at 1,500 rpm. For the first time, ISR enantiomers and PDI were resolved. For this separation, a Chiralpak((r)) AD column with hexane/2 propanol/ethanol (94:04:02, v/v/v) as the mobile phase at a flow rate of 1.5 mL min(-1) was used. The column was kept at 23 +/- 2 degrees C. The drug and metabolite detection was performed at 325 nm and the internal standard oxybutynin was detected at 225 nm. The recoveries were 23% for PDI and 19% for each ISR enantiomer. The method presented quantification limits (LOQ) of 50 ng mL(-1) and was linear over the concentration range of 50-5,000 and 50-2,500 ng mL(-1) for PDI and each ISR enantiomer, respectively. The validated method was employed to an in vitro biotransformation study of ISR using rat liver microsomal fraction showing that (+)-(S)-ISR is preferentially biotransformed. PMID- 21246192 TI - Protein adhesion on dental surfaces-a combined surface analytical approach. AB - Protein adsorption is a field of huge interest in a number of application fields. Information on protein adhesion is accessible by a variety of methods. However, the results obtained are significantly influenced by the applied technique. The objective of this work was to understand the role of adhesion forces (obtained by scanning force spectroscopy, SFS) in the process of protein adsorption and desorption. In SFS, the protein is forced to and retracted from the surface, even under unfavorable conditions, in contrast to the natural situation. Furthermore, adhesion forces are correlated with adhesion energies, neglecting the entropic part in the Gibbs enthalpy. In this context, dynamic contact angle (DCA) measurements were performed to identify the potential of this method to complement SFS data. In DCA measurements, the protein diffuses voluntarily to the surface and information on surface coverage and reversibility of adsorption is obtained, including entropic effects (conformational changes and hydrophobic effect). It could be shown that the surface coverage (by DCA) of bovine serum albumin on dental materials correlates well with the adhesion forces (by SFS) if no hydrophobic surface is involved. On those, the entropic hydrophobic effect plays a major role. As a second task, the reversibility of the protein adsorption, i.e., the voluntary desorption as studied by DCA, was compared to the adhesion forces. Here, a correlation between low adhesion forces and good reversibility could be found as long as no covalent bonds were involved. The comparative study of DCA and SFS, thus, leads to a more detailed picture of the complete adsorption/desorption cycle. PMID- 21246193 TI - A hypothesis of calcium stone formation: an interpretation of stone research during the past decades. AB - An interpretation of previous and recent observation on calcium salt crystallization and calcium stone formation provide the basis for formulation of a hypothetical series of events leading to calcium oxalate (CaOx) stone formation in the urinary tract. The various steps comprise a primary precipitation of calcium phosphate (CaP) at high nephron levels, establishment of large intratubular and/or interstitial (sub-epithelial) aggregates of CaP. These crystal masses subsequently might be dissolved during periods with low urine pH. On the denuded surface of subepithelial or intratubularly trapped CaP, release of calcium ions can result in very high ion-activity products of CaOx, particularly during simultaneous periods with peaks of CaOx supersaturation. Crystals of CaOx may result from nucleation in the macromolecular environment surrounding the apatite crystal phase. In the presence of low pH, low citrate and high ion strength of urine, formation of large CaOx crystal masses can be accomplished by self-aggregation of Tamm-Horsfall mucoprotein. Following dislodgment of the initially fixed CaOx stone embryo, the further development into to clinically relevant stone is accomplished by CaOx crystal growth and CaOx crystal aggregation of the retained stone material. The latter process is modified by a number of inhibitors and promoters present in urine. The retention of the stone is a consequence of anatomical as well as hydrodynamic factors. PMID- 21246194 TI - Differences between bacterial communities associated with the surface or tissue of Mediterranean sponge species. AB - Bacterial communities associated with the surfaces of several Mediterranean sponge species (Agelas oroides, Chondrosia reniformis, Petrosia ficiformis, Geodia sp., Tethya sp., Axinella polypoides, Dysidea avara, and Oscarella lobularis) were compared to those associated with the mesohyl of sponges and other animate or inanimate reference surfaces as well as with those from bulk seawater. Denaturing gradient gel electrophoresis (DGGE) analysis of PCR amplified bacterial 16S ribosomal RNA genes obtained from the surfaces and tissues of these sponges demonstrated that the bacterial communities were generally different from each other. The bacterial communities from sponges were different from those on reference surfaces or from bulk seawater. Additionally, clear distinctions in 16S rDNA fingerprint patterns between the bacterial communities from mesohyl samples of "high-microbial abundance (HMA) sponges" and "low-microbial abundance sponges" were revealed by DGGE and cluster analysis. A dominant occurrence of particularly GC-rich 16S ribosomal DNA (rDNA) fragments was found only in the DGGE banding pattern obtained from the mesohyl of HMA sponges. Furthermore, sequencing analysis of 16S rDNA fragments obtained from mesohyl samples of HMA sponges revealed a dominant occurrence of sponge associated bacteria. The bacterial communities within the mesohyl of HMA sponges showed a close relationship to each other and seem to be sponge-specific. PMID- 21246195 TI - Species composition of saproxylic fungal communities on decaying logs in the boreal forest. AB - Coarse woody debris supports large numbers of saproxylic fungal species. However, most of the current knowledge comes from Scandinavia and studies relating the effect of stand or log characteristics on the diversity and composition of decomposer fungi have not been conducted in Northeastern Canada. Logs from five tree species were sampled along a decomposition gradient in nine stands representing three successional stages of the boreal mixed forest of Northwestern Quebec, Canada. Using a molecular fingerprinting technique, we assessed fungal community Shannon-Weaver diversity index, richness, and composition. We used linear mixed models and multivariate analyses to link changes in fungal communities to log and stand characteristics. We found a total of 33 operational taxonomic units (OTUs) including an indicator species for balsam fir (similar to Athelia sp.) and one found only in aspen stands (similar to Calocera cornea). Spruce logs supported the highest fungal Shannon-Weaver diversity index and OTU number. Our results support the hypothesis that log species influences fungal richness and diversity. However, log decay class does not. Stand composition, volume of coarse woody debris, and log chemical composition were all involved in structuring fungal communities. Maintaining the diversity of wood-decomposing communities therefore requires the presence of dead wood from diverse log species. PMID- 21246196 TI - A polymorphism in PTPN2 gene is associated with an earlier onset of type 1 diabetes. AB - The Wellcome Trust Case Control Consortium (WTCCC) genome-wide study found association of PTPN2 with three autoimmune diseases, among them is type 1 diabetes (T1D). This result was confirmed by a follow-up study that pointed to new independent signals within the region. However, both studies were performed in patients with an early-onset T1D. We aimed at replicating the previous results and studying the influence of these polymorphisms in the age at T1D debut. We genotyped 439 T1D Spanish subjects (age at onset, 1 to 65 years) and 861 controls for two PTPN2 single nucleotide polymorphisms (SNPs), rs2542151 and rs478582, and studied the effect of both polymorphisms in age at onset through stratified and continuous analyses. The frequency of rs2542151*G carriers was significantly higher in the early-onset group compared with late-onset patients (p = 0.023) and with controls (OR = 1.61 [1.14-2.26]; p = 0.005). No significant differences were found between controls and late-onset patients. The log-rank chi-square test for the Kaplan-Meier plots (carriers of susceptibility allele vs non carriers) was statistically significant (chi (1df) (2) = 4.485; p = 0.034), yielding an earlier disease debut for G carriers. The analysis of the SNP rs478582 did not reach statistical significance. In summary, we replicate the association detected by the WTCCC and propose that the rs2542151*G allele confers risk to an earlier onset of T1D. PMID- 21246197 TI - A parieto-occipital artery arising from ICA directly and resultant incomplete PCA. AB - A parieto-occipital artery arising from internal carotid artery (ICA) directly was identified in a 46-year old man. The left ICA angiograms showed that a parieto-occipital artery was arising from ICA located between posterior communicating artery (PcomA) and anterior choroidal artery (AchoA). And also, incomplete posterior cerebral artery (PCA) which had not a parieto-occipital branch was arising from prominent PcomA. AchoA arose from ICA located just distal to the anomalous origin of the parieto-occipital artery. The vertebral angiograms showed no contrast filling of left PCA. Herein, we present a very rare case which has an anomalous origin of the parieto-occipital artery and resultant incomplete PCA. PMID- 21246198 TI - Fusarium verticillioides chitin synthases CHS5 and CHS7 are required for normal growth and pathogenicity. AB - Fusarium verticillioides is both an endophyte and a pathogen of maize and is a health threat in many areas of the world because it can contaminate maize with fumonisins, a toxic secondary metabolite. We identified eight putative chitin synthase (CHS) genes in F. verticillioides genomic sequence, and phylogenetic evidence shows that they group into seven established CHS gene classes. We targeted two CHSs (CHS5 and CHS7) for deletion analysis and found that both are required for normal hyphal growth and maximal disease of maize seedlings and ears. CHS5 and CHS7 encode a putative class V and class VII fungal chitin synthase, respectively; they are located adjacent to each other and are divergently transcribed. Fluorescent microscopy found that both CHS deficient strains produce balloon-shaped hyphae, while growth assays indicated that they were more sensitive to cell wall stressing compounds (e.g., the antifungal compound Nikkomycin Z) than wild type. Pathogenicity assays on maize seedlings and ears indicated that both strains were significantly reduced in their ability to cause disease. Our results demonstrate that both CHS5 and CHS7 are necessary for proper hyphal growth and pathogenicity of F. verticillioides on maize. PMID- 21246199 TI - Embryo and endosperm development in wheat (Triticum aestivum L.) kernels subjected to drought stress. AB - The aim of the present work was to reveal the histological alterations triggered in developing wheat kernels by soil drought stress during early seed development resulting in yield losses at harvest. For this purpose, observations were made on the effect of drought stress, applied in a controlled environment from the 5th to the 9th day after pollination, on the kernel morphology, starch content and grain yield of the drought-sensitive Cappelle Desprez and drought-tolerant Plainsman V winter wheat (Triticum aestivum L.) varieties. As a consequence of water withdrawal, there was a decrease in the size of the embryos and the number of A type starch granules deposited in the endosperm, while the development of aleurone cells and the degradation of the cell layers surrounding the ovule were significantly accelerated in both genotypes. In addition, the number of B-type starch granules per cell was significantly reduced. Drought stress affected the rate of grain filling shortened the grain-filling and ripening period and severely reduced the yield. With respect to the recovery of vegetative tissues, seed set and yield, the drought-tolerant Plainsman V responded significantly better to drought stress than Cappelle Desprez. The reduction in the size of the mature embryos was significantly greater in the sensitive genotype. Compared to Plainsman V, the endosperm cells of Cappelle Desprez accumulated significantly fewer B-type starch granules. In stressed kernels of the tolerant genotype, the accumulation of protein bodies occurred significantly earlier than in the sensitive variety. PMID- 21246200 TI - Protocol modifications for CT perfusion (CTp) examinations of abdomen-pelvic tumors: impact on radiation dose and data processing time. AB - PURPOSE: To evaluate the effect of CT perfusion (CTp) protocol modifications on quantitative perfusion parameters, radiation dose and data processing time. MATERIALS & METHODS: CTp datasets of 30 patients (21M:9F) with rectal (n = 24) or retroperitoneal (n = 6) tumours were studied. Standard CTp protocol included 50 sec cine-phase (0.5 sec/rotation) and delayed-phase after 70 ml contrast bolus at 5-7 ml/sec. CTp-data was sub-sampled to generate modified datasets (n = 105) with cine-phase(n = 15) alone, varying cine-phase duration (20-40 sec, n = 45) and varying temporal sampling-interval (1-3 sec, n = 45). The estimated CTp parameters (BF,BV,MTT&PS) and radiation dose of standard CTp served as reference for comparison. RESULTS: CTp with 50 sec cine-phase showed moderate to high correlation with standard CTp for BF&MTT (r = 0.96&0.85) and low correlation for BV (0.75, p = 0.04). Limiting cine-phase duration to 30 sec demonstrated comparable results for BF&MTT, while considerable variation in CTp values existed at 20 sec. There was moderate-to-high correlation of CTp parameters with sampling interval of 1&2 sec (r = 0.83-0.97, p > 0.05), while at 3 sec only BF showed high correlation (r = 0.96, p = 0.05). Increasing sampling interval (47-60%) and reducing cine-phase duration substantially reduced dose(30.8-65%) which paralleled reduced data processing time (3-10 min). CONCLUSION: Limiting CTp cine phase to 30 sec results in comparable BF&MTT values and increasing cine-phase sampling interval to 2 sec provides good correlation for all CTp parameters with substantial dose reduction and improved computational efficiency. PMID- 21246201 TI - Ontogeny of auditory saccular sensitivity in the plainfin midshipman fish, Porichthys notatus. AB - The auditory system of the plainfin midshipman fish, Porichthys notatus, is an important sensory receiver system used to encode intraspecific social communication signals in adults, but the response properties and function of this receiver system in pre-adult stages are less known. In this study we examined the response properties of auditory-evoked potentials from the midshipman saccule, the main organ of hearing in this species, to determine whether the frequency response and auditory threshold of saccular hair cells to behaviorally relevant single tone stimuli change during ontogeny. Saccular potentials were recorded from three relative sizes of midshipman fish: small juveniles [1.9-3.1 cm standard length (SL), large juveniles (6.8-8.0 cm SL) and non-reproductive adults (9.0-22.6 cm SL)]. The auditory evoked potentials were recorded from the rostral, middle and caudal regions of the saccule while single tone stimuli (75-1,025 Hz) were presented via an underwater speaker. We show that the frequency response and auditory threshold of the midshipman saccule is established early in development and retained throughout ontogeny. We also show that saccular sensitivity to frequencies greater than 385 Hz increases with age/size and that the midshipman saccule of small and large juveniles, like that of non-reproductive adults, is best suited to detect low frequency sounds (<105 Hz) in their natural acoustic environment. PMID- 21246202 TI - Adaptive behavior for texture discrimination by the free-flying big brown bat, Eptesicus fuscus. AB - This study examined behavioral strategies for texture discrimination by echolocation in free-flying bats. Big brown bats, Eptesicus fuscus, were trained to discriminate a smooth 16 mm diameter object (S+) from a size-matched textured object (S-), both of which were tethered in random locations in a flight room. The bat's three-dimensional flight path was reconstructed using stereo images from high-speed video recordings, and the bat's sonar vocalizations were recorded for each trial and analyzed off-line. A microphone array permitted reconstruction of the sonar beam pattern, allowing us to study the bat's directional gaze and inspection of the objects. Bats learned the discrimination, but performance varied with S-. In acoustic studies of the objects, the S+ and S- stimuli were ensonified with frequency-modulated sonar pulses. Mean intensity differences between S+ and S- were within 4 dB. Performance data, combined with analyses of echo recordings, suggest that the big brown bat listens to changes in sound spectra from echo to echo to discriminate between objects. Bats adapted their sonar calls as they inspected the stimuli, and their sonar behavior resembled that of animals foraging for insects. Analysis of sonar beam-directing behavior in certain trials clearly showed that the bat sequentially inspected S+ and S-. PMID- 21246203 TI - Intralaparoscopic endoscopy: its value during laparoscopic repair of choledochal cyst. AB - AIM: We report our experience of laparoscopic repair of choledochal cyst (CC). METHODS: We reviewed 10 CC patients (mean age 3.3 years) who had lap CC repair. Eight patients had minimally dilated/fusiform type CC (fusiform CC) and presented with pancreatitis, and two had cystic type CC (cystic CC). Using conventional trocar placement (right upper quadrant, left paraumbilical, left upper quadrant; laparoscope in the umbilicus), the CC was isolated and transected at mid level. An additional 3.9 mm trocar in the left epigastrium was used to introduce a fine ureteroscope. Its tip was inserted into the common channel through the distal CC to remove protein plugs (PP) under laparoscopic guidance. To perform intralaparoscopic endoscopy of the intrahepatic ducts, a trocar placed in the left lower quadrant was used. Two extra trocars (3 and 5 mm) were added for hepatico-jejunostomy anastomosis (HJA); one lateral right subcostal, and one between the right subcostal and right upper quadrant trocars, respectively. HJA was performed using interrupted 5/0 absorbable sutures with the right upper quadrant trocar as a needle holder in the right hand, 5 mm for the laparoscope, and 3 mm subcostal trocar as a needle receiver in the left hand. Both the right and left edge sutures were exteriorized and used as traction sutures during anastomosis of the anterior wall. RESULTS: Seven of eight fusiform CC patients had PP (massive in 3, moderate in 3, little in 1) in the common channel successfully removed with normal saline washouts through the side channel of the ureteroscope. Eight of ten CC patients had debris (moderate in 4, little in 4) in the intrahepatic ducts. Two complications were encountered; pancreatitis that resolved with conservative management and duodenal obstruction due to inadequate Roux-en-Y limb fixation that was treated by laparoscopic intervention. All are well after a mean follow-up of 12 months with cosmetically attractive wounds. CONCLUSION: Although three additional trocars are required, we recommend our HJA technique and intraoperative common channel endoscopy during laparoscopic repair of CC. PMID- 21246204 TI - Evidence for an intracellular localization of the adenosine A2B receptor in rat cardiomyocytes. AB - Protection achieved by ischemic preconditioning is dependent on A(2B) adenosine receptors (A(2B)AR) in rabbit and mouse hearts and, predictably, an A(2B)AR agonist protects them. But it is controversial whether cardiomyocytes themselves actually express A(2B)AR. The present study tested whether A(2B)AR could be demonstrated on rat cardiomyocytes. Isolated rat hearts experienced 30 min of ischemia and 120 min of reperfusion. The highly selective, cell-permeant A(2B)AR agonist BAY60-6583 (500 nM) infused at reperfusion reduced infarct size from 40.4 +/- 2.0% of the risk zone in control hearts to 19.9 +/- 2.8% indicating that A(2B)AR are protective in rat heart as well. Furthermore, BAY60-6583 reduced calcium-induced mitochondrial permeability transition in isolated rat cardiomyocytes. A(2B)AR protein could be demonstrated in isolated cardiomyocytes by western blotting. In addition, message for A(2B)AR was found in individual cardiomyocytes using quantitative RT-PCR. Surprisingly, immunofluorescence microscopy did not show A(2B)AR on the cardiomyocyte's sarcolemma but rather at intracellular sites. Co-staining with MitoTracker Red in isolated cardiomyocytes revealed A(2B)AR are localized to mitochondria. Western blot analysis of a mitochondrial fraction from either rat heart biopsies or isolated cardiomyocytes revealed a strong A(2B)AR band. Thus, the present study demonstrates that activation of A(2B)AR is strongly cardioprotective in rat heart and suppresses transition pores in isolated cardiomyocytes, and A(2B)AR are expressed in individual cardiomyocytes. However, surprisingly, A(2B)AR are present in or near mitochondria rather than on the sarcolemma as are other adenosine receptors. Because A(2B)AR signaling is thought to result in inhibition of mitochondrial transition pores, this convenient location may be important. PMID- 21246205 TI - Mitochondrial complex I and NAD(P)H oxidase are major sources of exacerbated oxidative stress in pressure-overloaded ischemic-reperfused hearts. AB - We tested the hypothesis that pressure overload exacerbates oxidative stress associated with augmented mitochondrial permeability transition (MPT) pore opening and cell death in ischemic-reperfused hearts. Pressure overload decreased the level of reduced glutathione but increased nitrotyrosine and 8 hydroxydeoxyguanosine levels in ischemic-reperfused hearts. The activity of catalase, but not superoxide dismutase (SOD), was lower in ischemic-reperfused hearts perfused at higher pressure. Mitochondria from ischemic-reperfused hearts subjected to higher perfusion pressure displayed significantly greater [3H]-2 deoxyglucose-6-P entrapment suggestive of greater MPT pore opening and consistent with greater necrosis and apoptosis. Tempol (SOD mimetic) reduced infarct size in both groups but it remained greater in the higher pressure group. By contrast, uric acid (peroxynitrite scavenger) markedly reduced infarct size at higher pressure, effectively eliminating the differential between the two groups. Inhibition of xanthine oxidase, with allopurinol, reduced infarct size but did not eliminate the differential between the two groups. However, amobarbital (inhibitor of mitochondrial complex I) or apocynin [inhibitor of NAD(P)H oxidase] reduced infarct size at both pressures and also abrogated the differential between the two groups. Consistent with the effect of apocynin, pressure overloaded hearts displayed significantly higher NAD(P)H oxidase activity. Furthermore, pressure-overloaded hearts displayed increased nitric oxide synthase activity which, along with increased propensity to superoxide generation, may underlie uric acid-induced cardioprotection. In conclusion, increased oxidative and nitrosative stress, coupled with lack of augmented SOD and catalase activities, contributes importantly to the exacerbating impact of pressure overload on MPT pore opening and cell death in ischemic-reperfused hearts. PMID- 21246206 TI - Central TNF inhibition results in attenuated neurohumoral excitation in heart failure: a role for superoxide and nitric oxide. AB - This study examined the effect of central tumor necrosis factor-alpha (TNF) blockade on the imbalance between nitric oxide and superoxide production in the paraventricular nucleus (PVN) and ventrolateral medulla (VLM), key autonomic regulators, and their contribution to enhanced sympathetic drive in mice with congestive heart failure (CHF). We also used a TNF gene knockout (KO) mouse model to study the involvement of TNF in body fluid homeostasis and sympathoexcitation in CHF. After implantation of intracerebroventricular (ICV) cannulae, myocardial infarction (MI) was induced in wild-type (WT) and KO mice by coronary artery ligation. Osmotic mini-pumps were implanted into one set of WT + MI/Sham mice for continuous ICV infusion of Etanercept (ETN), a TNF receptor fusion protein, or vehicle (VEH). Gene expressions of neuronal nitric oxide synthase (NOS) and angiotensin receptor-type 2 were reduced, while those of inducible NOS, Nox2 homologs, superoxide, peroxynitrite and angiotensin receptor-type 1 were elevated in the brainstem and hypothalamus of MI + VEH. Plasma norepinephrine levels and the number of Fos-positive neurons were also increased in the PVN and VLM in MI + VEH. MI + ETN and KO + MI mice exhibited reduced oxidative stress, reduced sympathoexcitation and an improved cardiac function. These changes in WT + MI were associated with increased sodium and fluid retention. These results indicate that elevated TNF in these autonomic regulatory regions of the brain alter the production of superoxide and nitric oxide, contributing to fluid imbalance and sympathoexcitation in CHF. PMID- 21246207 TI - Extracranial head and neck Schwannomas: a study of the nerve of origin. AB - Schwannoma is a type of benign nerve sheath tumour arising from the Schwann cell. Because of the close relationship between the tumour and the nerve of origin (NOO), the operation of extracranial head and neck schwannoma may lead to palsy of major nerve. For this reason, an accurate diagnosis of schwannoma with the identification of the NOO is crucial to the management. The aim of this review was to find out the distribution of the NOO and the usefulness of the investigations in the diagnosis of schwannoma. Medical records of the patients who underwent operation of the extracranial head and neck schwannoma in our division were reviewed. Between January 2000 and December 2009, 30 cases of extracranial head and neck schwannoma were operated. Sympathetic trunk (10, 33%) and vagus nerve (6, 20%) were the two most common NOOs. In five (17%) cases, the NOO was not found to be arising from any major nerve. For these 30 patients, 20 received fine needle aspiration cytology (FNAC) and 26 underwent imaging studies (computed tomography or magnetic resonance imaging) before operation. The specificity of FNAC and imaging studies in making the diagnosis of schwannoma was 20 and 38%, respectively. For the patients who had nerve palsies on presentation, their deficits remained after operation. The rate of nerve palsy after tumour excision with division of NOO and intracapsular enucleation was 100 and 67%, respectively. The diagnosis of schwannoma is suggested by clinical features and supported by investigations. Most of the time, the diagnosis can only be confirmed on the histological study of the surgical specimen. Sympathetic trunk and vagus nerve are the two common NOOs. MRI is the investigation of choice in the diagnosis of schwannoma and the identification of NOO. PMID- 21246208 TI - Surgical indication in Meniere's disease therapy: clinical and epidemiological aspects. AB - The aim of this study was to evaluate the frequency of surgical approach in a population of patients affected by definite Meniere's disease (MD). In the majority of patients, relief from vertigo attacks can be achieved by means of medical therapy (MT). In cases in which MT fails surgery may offer relief to vertigo. The most applied surgical procedures are intratympanic gentamicin (ITG) and vestibular neurectomy (VN), based on vestibular deafferentation. Until now, the real incidence of the different therapeutic approaches for MD has not been evaluated. The study design was a retrospective study. The study was performed in 177 patients affected by definite MD. Subjects referred directly for surgery by other centers were excluded from the study. All the patients were medically treated with salt restriction and diuretics. In case of MT failure, surgical therapy, ITG or retrosigmoid VN were proposed. In the 75% of cases, the only therapeutic approach was MT, while in 20% of cases we carried out ITG and in 5% VN. In 33% of VN group, this operation was carried out after ITG failure and in 67% as the first surgical approach. The VN group was characterized by younger age and higher disability degree. The primary therapy in definite MD seems to be MT. Ablative therapy represents the second choice: ITG was carried out in 80% of cases, while VN was performed in 20%. PMID- 21246210 TI - Intracochlear perfusion of leupeptin and z-VAD-FMK: influence of antiapoptotic agents on gunshot-induced hearing loss. AB - The therapeutic efficiency of cochlear infusion of two anti-apoptotic substances: a potent calpain inhibitor, leupeptin and a caspase inhibitor, z-VAD-FMK was evaluated in guinea pigs after a gunshot noise-induced trauma (170 dB SPL). A preliminary study showed that hair cell apoptosis appeared within 7 days of the noise trauma. For each animal, one of the cochleae was perfused directly starting 1 h after the trauma with leupeptin or z-VAD-FMK for 7 days via a mini-osmotic pump whereas the other cochlea was untreated. ABR threshold shifts were measured over a 14-day recovery period. The functional hearing study was supplemented by histological analysis. Two days after the trauma significant differences were observed between threshold shifts in the z-VAD-FMK-treated and the non-treated ears. Cochleograms showed that hair cell losses were significantly lower in z-VAD FMK-treated ears. Regarding the leupeptin treatment, no significant difference between treated and non-treated ears was observed. This work indicates that early direct infusion of z-VAD-FMK into the cochlea accelerates hearing recovery and reduces hair cell loss after gunshot noise-induced trauma. These results suggest that the gunshot noise-induced trauma may involve the caspase pathway rather than the calpain pathway in the apoptotic process. PMID- 21246209 TI - Carbonic anhydrase-9 expression in head and neck cancer: a meta-analysis. AB - The purpose of the study was to compare CA-9 positivity versus CA-9 negativity in head and neck malignancies and to correlate levels of CA-9 with tumor grade, size, and nodal status. Overall and disease-free survival were also compared for CA-9 positive and negative tumors. A literature search was performed using Medline, Embase, Ovid and Cochrane databases for studies between 1990 and 2009. Carbonic anhydrase IX, CA IX, CA-9, head and neck, and survival were used as search terms. Random-effect meta-analytical techniques were conducted for outcome measures of overall survival and disease-free survival. Sixteen studies matched the selection criteria, reporting on 1,470 patients. Eight hundred and forty two specimens were reported as being CA-9 positive or negative: 512 (60.81%) were CA 9 positive and 330 (39.19%) were CA-9 negative. Nine hundred and eighty specimens had levels of CA-9 expression recorded: 547 (55.82%) had high levels of CA-9 and 433 (44.18%) had low CA-9 levels. Survival was significantly reduced if the tumor was positive for CA-9 (P < 0.0001). Disease-free survival is significantly reduced in patients with CA-9 positive (P = 0.0008) head and neck malignant tumors. The presence of CA-9 in head and neck malignant tumors is associated with reduced overall survival and disease-free survival. PMID- 21246211 TI - Hearing loss in divers: a 6-year prospective study. AB - Occupational diving is associated with hearing loss, but the cause is disputed. Our aim was to follow a cohort of divers through the first 6 years of their career in order to look for evidence of permanent threshold shift associated with diving activity, occupational noise exposure or acute injuries. Hearing was measured by pure tone audiometry in 67 participants at a basic course for working divers. Hearing thresholds were adjusted for age (ISO 7029). The subjects were examined and interviewed by an otologist. Additional medical and exposure data were recorded in questionnaires and personal logbooks. The procedure was repeated after 3 and 6 years. None of the subjects suffered inner ear barotrauma or inner ear decompression sickness during follow-up. Middle ear barotrauma was common. The prevalence of subjective hearing difficulties increased during follow-up, and there was a significant threshold shift at 4 kHz (mean 2.6 dB, 95% confidence interval 0.9-4.3 dB). Both subjective and objective hearing loss was associated with occupational noise exposure, but not with diving frequency or with a history of middle ear barotrauma. In the absence of manifest inner ear barotrauma or inner ear decompression sickness, noise seems to be the most important cause of long-term hearing loss in occupational divers. This study did not find evidence of long-term hearing loss caused by uneventful diving per se. PMID- 21246212 TI - Acoustic overstimulation-induced apoptosis in fibrocytes of the cochlear spiral limbus of mice. AB - Fibrocytes of the spiral limbus are thought to play a significant role in maintaining ion homeostasis in the cochlea. The present study measured physiological and morphological changes in spiral limbus of mice in response to noise exposure. 6-week-old male C3H/HeJJcl mice were exposed to octave-band noise (120 dB SPL) for 2 h and evaluated at a series of times thereafter, up to 8 weeks. Permanent hearing loss resulted in the mice, as assessed by auditory brainstem response (ABR) recordings. The fibrocytes loss was found in the spiral limbus of the apical turn, which has been proved to be induced by apoptosis. These results suggest that noise exposure might result in apoptosis of fibrocytes in spiral limbus, which suggest a mechanism for noise-induced hearing loss. PMID- 21246214 TI - Modulation of reflex responses in activated ankle dorsiflexors differs in healthy young and elderly subjects. AB - During voluntary contractions, motor neurone activity is modulated by descending input and sensory feedback. Impaired excitatory afferent feedback with ageing may, therefore, alter motor control. This study investigated the age-related changes in afferent feedback through the recording of reflex responses during voluntary muscle activation. Short- and long-latency components of the stretch reflex and Hoffmann reflex (H-reflex) were recorded during voluntary contractions (10% of maximal voluntary contraction; MVC) of the ankle dorsiflexor muscles of young and elderly adults (>=70 years). Furthermore, the modulation of spinal reflex excitability was analyzed at different torque levels (10-50% MVC). The short-latency stretch reflex and the H-reflex areas were similar in the two age groups at 10% MVC whereas the area of the long-latency component of the stretch reflex augmented with ageing (P < 0.05). However, the area of the H-reflex increased linearly with the level of contraction up to 50% MVC in young adults, whereas it slightly increased to 30% MVC and plateaued thereafter in elderly adults. The absence of age-related changes in the short-latency stretch reflex and H-reflex areas suggests that the reflex circuitry and the sensitivity of the muscle spindles are not substantially affected by ageing. The modest increase in the H-reflex area with the contraction intensity in elderly adults, however, indicates that the modulation of afferent feedback is reduced with advancing age. This observation, associated with a greater long-latency stretch reflex, suggests that elderly adults rely more on central than peripheral mechanisms to regulate motor output of the dorsiflexor muscles. PMID- 21246215 TI - Protein and metabolite composition of xylem sap from field-grown soybeans (Glycine max). AB - The xylem, in addition to transporting water, nutrients and metabolites, is also involved in long-distance signaling in response to pathogens, symbionts and environmental stresses. Xylem sap has been shown to contain a number of proteins including metabolic enzymes, stress-related proteins, signal transduction proteins and putative transcription factors. Previous studies on xylem sap have mostly utilized plants grown in controlled environmental chambers. However, plants in the field are subjected to high light and to environmental stress that is not normally found in growth chambers. In this study, we have examined the protein and metabolite composition of xylem sap from field-grown cultivated soybean plants. One-dimensional gel electrophoresis of xylem sap from determinate, indeterminate, nodulating and non-nodulating soybean cultivars revealed similar protein profiles consisting of about 8-10 prominent polypeptides. Two-dimensional gel electrophoresis of soybean xylem sap resulted in the visualization of about 60 distinct protein spots. A total of 38 protein spots were identified using MALDI-TOF MS and LC-MS/MS. The most abundant proteins present in the xylem sap were identified as 31 and 28 kDa vegetative storage proteins. In addition, several proteins that are conserved among different plant species were also identified. Diurnal changes in the metabolite profile of xylem sap collected during a 24-h cycle revealed that asparagine and aspartate were the two predominant amino acids irrespective of the time collected. Pinitol (D-3-O methyl-chiro-inositol) was the most abundant carbohydrate present. The possible roles of xylem sap proteins and metabolites as nutrient reserves for sink tissue and as an indicator of biotic stress are also discussed. PMID- 21246216 TI - Long-term outcomes of pneumococcal meningitis in childhood and adolescence. AB - A vaccine to prevent pneumococcal meningitis (PM) has recently been introduced. However, contemporary data to inform cost-effectiveness analysis and justify its routine use are sparse. We examined the cognitive, educational, psychological and social outcomes of PM in childhood. We completed a population-based case-control study in two regions of the UK. Children and young people currently between 3 and 20 years of age that had been diagnosed with PM <=14 years of age were identified from active regional surveillance. Controls were siblings or neighbours of similar age. Standardised questionnaires and neuropsychological testing was administered to assess IQ, educational attainments, memory, psychological distress, quality of life and hearing impairment. Data were available on 97 patients and 93 controls. Eighty-four patients had a sibling/neighbour-matched control. Both matched and unmatched analyses were completed, and results of the 84 matched comparisons were highly similar to the unmatched. For the total sample, controls were similar in age, ethnicity and socioeconomic status. Median age at meningitis was 11 months. Median time between meningitis and assessment was 6.0 years. In the matched analysis, partial or profound hearing impairment was reported in 14% of patients and 1% of controls. Patients had significantly lower mean full-scale IQ (p = 0.05), verbal IQ (p = 0.0008), numeracy (p = 0.02), total quality of life (p = 0.04), school functioning (p = 0.005), psychosocial functioning (p = 0.001) and psychological difficulties (p = 0.01). Parents of patients reported greater functional disability (p = 0.008), impairment in all aspects of quality of life (p = 0.001) and psychological difficulties (p < 0.0006). Findings for IQ were not materially different when analyses were repeated only in those without hearing impairment. In multivariate regression analysis that included both case-control status and hearing status, both being a patient (p = 0.001) and having profound hearing impairment (p = 0.001) were independently associated with lower full-scale IQ. Conclusions Pneumococcal meningitis is associated with major sequelae. Our findings strongly support the introduction of pneumococcal conjugate vaccine as part of routine childhood vaccination programmes internationally. PMID- 21246217 TI - BR-squared: a practical solution to the winner's curse in genome-wide scans. AB - The detrimental effects of the winner's curse, including overestimation of the genetic effects of associated variants and underestimation of sufficient sample sizes for replication studies are well-recognized in genome-wide association studies (GWAS). These effects can be expected to worsen as the field moves from GWAS into whole genome sequencing. To date, few studies have reported statistical adjustments to the naive estimates, due to the lack of suitable statistical methods and computational tools. We have developed an efficient genome-wide non parametric method that explicitly accounts for the threshold, ranking, and allele frequency effects in whole genome scans. Here, we implement the method to provide bias-reduced estimates via bootstrap re-sampling (BR-squared) for association studies of both disease status and quantitative traits, and we report the results of applying BR-squared to GWAS of psoriasis and HbA1c. We observed over 50% reduction in the genetic effect size estimation for many associated SNPs. This translates into a greater than fourfold increase in sample size requirements for successful replication studies, which in part explains some of the apparent failures in replicating the original signals. Our analysis suggests that adjusting for the winner's curse is critical for interpreting findings from whole genome scans and planning replication and meta-GWAS studies, as well as in attempts to translate findings into the clinical setting. PMID- 21246218 TI - From process to pattern: how fluctuating predation risk impacts the stress axis of snowshoe hares during the 10-year cycle. AB - Predation is a central organizing process affecting populations and communities. Traditionally, ecologists have focused on the direct effects of predation--the killing of prey. However, predators also have significant sublethal effects on prey populations. We investigated how fluctuating predation risk affected the stress physiology of a cyclic population of snowshoe hares (Lepus americanus) in the Yukon, finding that they are extremely sensitive to the fluctuating risk of predation. In years of high predator numbers, hares had greater plasma cortisol levels at capture, greater fecal cortisol metabolite levels, a greater plasma cortisol response to a hormone challenge, a greater ability to mobilize energy and poorer body condition. These indices of stress had the same pattern within years, during the winter and over the breeding season when the hare:lynx ratio was lowest and the food availability the worst. Previously we have shown that predator-induced maternal stress lowers reproduction and compromises offspring's stress axis. We propose that predator-induced changes in hare stress physiology affect their demography through negative impacts on reproduction and that the low phase of cyclic populations may be the result of predator-induced maternal stress reducing the fitness of progeny. The hare population cycle has far reaching ramifications on predators, alternate prey, and vegetation. Thus, predation is the predominant organizing process for much of the North American boreal forest community, with its indirect signature--stress in hares--producing a pattern of hormonal changes that provides a sensitive reflection of fluctuating predator pressure that may have long-term demographic consequences. PMID- 21246219 TI - Phenotypic variability of Bardet-Biedl syndrome: focusing on the kidney. AB - Bardet-Biedl syndrome (BBS) is a multisystemic developmental disorder diagnosed on the basis of the presence of obesity, retinal defects, polydactyly, hypogonadism, renal dysfunction, and learning disabilities. The syndrome is genetically heterogeneous with 14 BBS genes identified to date. Since the cloning of the first gene in 2000, a combination of genetic, in vitro, and in vivo studies have highlighted ciliary dysfunction as a primary cause of BBS pathology. Pleiotropy of ciliopathy phenotypes and complex genetic interactions between causal and modifying alleles of ciliary genes contribute to phenotypic variability. In particular, kidney disease in BBS is clinically heterogeneous, but is now recognized as a cardinal feature and a major cause of mortality in BBS. PMID- 21246220 TI - Bone assessment in children with chronic kidney disease: data from two new bone imaging techniques in a single-center pilot study. AB - Bone damage in children with chronic kidney disease (CKD) is a challenge for pediatric nephrologists. Areal measurements of bone mineral density (BMD) by dual x-ray absorptiometry (DXA) have been routinely performed to assess bone mass but recent international guidelines have concluded that DXA was of less value in CKD. The aim of this study is to evaluate bone quality in CKD children using new bone imaging techniques in a pilot cross-sectional single-center study. We performed bone imaging (high-resolution peripheral quantitative computed tomography, HR pQCT, XtremeCT, Scanco Medical AG, Switzerland), to assess compartmental volumetric BMD and trabecular microarchitecture in 22 CKD children and 19 controls. In seven younger patients (i.e., under 10 years of age), we performed bone texture analysis (BMA, D3A Medical Systems, France) in comparison to 15 healthy prepubertal controls. Among older children, CKD patients had significantly lower height and body weight without significant impairment of BMD and microarchitecture than healthy controls. In univariate analysis, there were significant correlations between cortical BMD and glomerular filtration rate (r= 0.46), age (r=0.60) and body mass index (r=0.67). In younger children, bone texture parameters were not different between patients and controls. Our results did not show significant differences between healthy controls and CKD children for compartmental bone densities and microarchitecture, but the small sample size and the heterogeneity of the CKD group require caution in the interpretation. Novel bone imaging techniques seem feasible in children, and further longitudinal studies are required to thoroughly explore long-term cardiovascular and bone consequences of phosphate-calcium metabolism deregulation during CKD. PMID- 21246221 TI - Accuracy of arterial pressure waveform analysis for cardiac output measurement in comparison with thermodilution methods in patients undergoing living donor liver transplantation. AB - PURPOSE: The aim of this study was to assess the accuracy of the first and third versions of arterial pressure waveform cardiac output (APCO(v.1.0) and APCO(v.3.0)) measurements in comparison with thermodilution methods in patients undergoing living donor liver transplantation. METHODS: Twenty patients were anesthetized and mechanically ventilated. A radial arterial line was connected to a dedicated transducer for the APCO evaluation (FloTracTM). A pulmonary artery catheter was placed and connected to a computer system (VigilanceTM) to measure intermittent thermodilution cardiac output (CO(TD)) and continuous cardiac output (CCO). RESULTS: A total of 138 measurements were analyzed. Bland-Altman analysis showed that the mean biases for CO(TD)-APCO(v.3.0), CO(TD)-APCO(v.1.0), and CO(TD)-CCO were 0.89, 1.73, and -0.79 L/min, and the adjusted percentage errors were 37.5, 30.3, and 43%, respectively. While the variance for CO(TD)-APCO(v3.0) was greater, the accuracy (bias) improved by 0.8 L/min as compared with CO(TD) APCO(v1.0). The difference CO(TD)-APCO(v.3.0) became apparent when systemic vascular resistance was lower than 1000 dyne * s/cm(5), especially below 700 dyne * s/cm(5). CONCLUSION: These data suggest that the accuracy of APCO(v.3.0) has improved compared to APCO(v.1.0) due to the updated algorithm, but additional improvements should be evaluated, especially in patients undergoing living donor liver transplantation with low systemic vascular resistance. PMID- 21246222 TI - Beneficial effect of repetitive transcranial magnetic stimulation combined with cognitive training for the treatment of Alzheimer's disease: a proof of concept study. AB - The current drug treatment for Alzheimer's disease (AD) is only partially and temporary effective. Transcranial magnetic stimulation (TMS) is a non-invasive technique that generates an electric current inducing modulation in cortical excitability. In addition, cognitive training (COG) may improve cognitive functions in AD. Our aim was to treat AD patients combining high-frequency repetitive TMS interlaced with COG (rTMS-COG). Eight patients with probable AD, treated for more than 2 months with cholinesterase inhibitors, were subjected to daily rTMS-COG sessions (5/week) for 6 weeks, followed by maintenance sessions (2/week) for an additional 3 months. Six brain regions, located individually by MRI, were stimulated. COG tasks were developed to fit these regions. Primary objectives were average improvement of Alzheimer Disease Assessment Scale Cognitive (ADAS-cog) and Clinical Global Impression of Change (CGIC) (after 6 weeks and 4.5 months, compared to baseline). Secondary objectives were average improvement of MMSE, ADAS-ADL, Hamilton Depression Scale (HAMILTON) and Neuropsychiatric Inventory (NPI). One patient abandoned the study after 2 months (severe urinary sepsis). ADAS-cog (average) improved by approximately 4 points after both 6 weeks and 4.5 months of treatment (P < 0.01 and P < 0.05) and CGIC by 1.0 and 1.6 points, respectively. MMSE, ADAS-ADL and HAMILTON improved, but without statistical significance. NPI did not change. No side effects were recorded. In this study, rTMS-COG (provided by Neuronix Ltd., Yokneam, Israel) seems a promising effective and safe modality for AD treatment, possibly as good as cholinesterase inhibitors. A European double blind study is underway. PMID- 21246223 TI - The effect of acetylcholine on pain-related electric activities in the hippocampal CA3 of rats. AB - Acetylcholine (ACh) regulates pain perception in the central nervous system. However, the mechanism of action of ACh on pain-related neurons in the hippocampal CA3 is not clear. The present study aimed to determine the effect of ACh, muscarinic ACh receptors (mAChRs) agonist pilocarpine and mAChRs antagonist atropine on the pain-evoked responses of pain-excited neuron (PEN) and pain inhibited neuron (PIN) in the hippocampal CA3 of normal rats. The trains of electric impulses applied to the sciatic nerve were used as noxious stimulation. The electric activities of PEN or PIN in the hippocampal CA3 were recorded by using a glass microelectrode. Our results showed that, in the hippocampal CA3, the intra-CA3 microinjection of ACh (2 MUg/1 MUl) or pilocarpine (2 MUg/1 MUl) decreased the discharge frequency and prolonged firing latency of PEN, and increased the discharge frequency and shortened firing inhibitory duration (ID) of PIN, i.e. exhibiting the analgesic effect of ACh or pilocarpine. The intra-CA3 administration of atropine (0.5 MUg/1 MUl) produced an opposite effect. On the basis of the above-mentioned findings, we can deduce that ACh and mAChRs in the hippocampal CA3 are involved in the modulation of nociceptive response by regulating the electric activities of PEN and PIN. PMID- 21246224 TI - Micrographia induced by pallidal DBS for segmental dystonia: a subtle sign of hypokinesia? AB - Recently parkinsonism has been reported as a rare side effect of globus pallidus internus (GPi) deep brain stimulation (DBS) for dystonia. In the present systematic prospective study in 11 patients with segmental dystonia not affecting distal arm function, we could demonstrate significant changes in handwriting characterized by mild micrographia following GPi-DBS. We propose that this finding reflects GPi-DBS-induced disturbances of basal ganglia function in terms of a mild hypokinetic syndrome, as a result of outflow alterations in pallido thalamo-cortical pathways. PMID- 21246225 TI - Quantitative structure-activity relationship modeling of renin-inhibiting dipeptides. AB - Partial least squares regression method was used to analyze a peptide dataset and construct inhibitory models for renin-inhibitory natural dipeptides. The models were computed with the renin-inhibitory activity as dependent variable (Y) and the peptide structural properties as predictors (X); validation was conducted using cross-validation and permutation tests. The amino acid descriptors were based on the 3- and 5-z scales of 20 coded amino acids to produce models that explained 71.6% of Y with a 33.8% predictive ability and 75.2% of Y with a predictive power of 50.8%, respectively. In both models, low molecular size amino acids with hydrophobic side chains were preferred at the N-terminus, while amino acids with bulky side chains were preferred at the C-terminus for potency. Based on the 5-z model, four Trp (W)-containing antihypertensive dipeptides (IW, LW, VW and AW) were predicted as the most potent renin inhibitors. The peptides were synthesized and in vitro inhibition assay showed that IW and LW inhibited 70% (IC(50), 2.3 mM) and 37% renin activity at 3.2 mM, respectively, whereas VW and AW were inactive. There was no correlation between the observed renin-inhibitory activities and angiotensin-converting enzyme inhibitory activities of the dipeptides. We concluded that the structural similarities between isoleucine and leucine could have contributed to their distinct inhibitory activity when compared to alanine and valine. Therefore, IW may be a useful template for the development of advanced forms of highly active low molecular size antihypertensive peptides and peptidomimetics. PMID- 21246226 TI - Application of cyanuric chloride-based six new chiral derivatizing reagents having amino acids and amino acid amides as chiral auxiliaries for enantioresolution of proteinogenic amino acids by reversed-phase high-performance liquid chromatography. AB - Six dichloro-s-triazine (DCT) reagents having L-Leu, D-Phg, L-Val, L-Met, L-Ala and L-Met-NH(2) as chiral auxiliaries in cyanuric chloride were introduced for enantioseparation of 13 proteinogenic amino acids. Four other DCTs and six monochloro-s-triazine (MCT) reagents having amino acid amides as chiral auxiliaries were also synthesized. These 16 chiral derivatizing reagents (CDRs) were used for synthesis of diastereomers of all the 13 analytes using microwave irradiation, which were resolved by reversed-phase high-performance liquid chromatography (RP-HPLC) using C18 column and gradient eluting mixture of aqueous TFA and acetonitrile with UV detection at 230 nm. It required only 60-90 s for derivatization using microwave irradiation. Better resolution and lower retention times were observed for the diastereomers prepared with CDRs having amino acids as chiral auxiliaries as compared to counterparts prepared with reagents having amino acid amides as chiral auxiliaries. As the best resolution of all the 13 analytes was observed for their diastereomers prepared using the DCT reagent having L-Leu as chiral auxiliary, this CDR was further employed for derivatization of Lys, Tyr, His and Arg followed by RP-HPLC analysis of resulting diastereomers. The results are discussed in light of acid and amide groups of chiral auxiliaries constituting CDRs, electronegativities of the atoms of achiral moieties constituting CDRs and hydrophobicities of side chains of amino acids constituting CDRs and analytes. PMID- 21246227 TI - L-type calcium channel activity in osteoblast cells is regulated by the actin cytoskeleton independent of protein trafficking. AB - Voltage-dependent L-type calcium channels (VDCC) play important roles in many cellular processes. The interaction of the actin cytoskeleton with the channel in nonexcitable cells is less well understood. We performed whole-cell patch-clamp surface biotinylation and calcium imaging on different osteoblast cells to determine channel kinetics, amplitude, surface abundance, and intracellular calcium, respectively. Patch-clamp studies showed that actin polymerization by phalloidin increased the peak current density of I (Ca), whereas actin depolymerization by cytochalasin D (CD) significantly decreased the current amplitude. This result is consistent with calcium imaging, which showed that CD significantly decreased Bay K8644-induced intracellular calcium increase. Surface biotinylation studies showed that CD is not able to affect the surface expression of the pore-forming subunit alpha(1C). Interestingly, application of CD caused a significantly negative shift in the steady-state inactivation kinetics of I (Ca). There were decreases in the voltage at half-maximal inactivation that changed in a dose-dependent manner. CD also reduced the effect of activated vitamin D(3) (1alpha,25-D3) on VDCC and intracellular calcium. We conclude that in osteoblasts the actin cytoskeleton affects alpha(1C) by altering the channel kinetic properties, instead of changing the surface expression, and it is able to regulate 1alpha,25-D3 signaling through VDCC. Our study provides a new insight into calcium regulation in osteoblasts, which are essential in many physiological functions of this cell. PMID- 21246228 TI - Bilateral posterior shoulder dislocation with defect secondary to hypoglycemic coma. PMID- 21246229 TI - Development of a force-determining tensor to measure "physiologic knee ligament gaps" without bone resection using a total knee arthroplasty approach. AB - BACKGROUND: Ligament balancing is a challenging but essential part of successful total knee arthroplasty. There is general agreement that flexion and extension gaps should be equal and symmetrical. However, to date there are no available comparisons to physiologically normal knee joints that have not undergone bone resection. There are also no standards specifying which instruments (e.g., spacers, distractors, trial components, navigation systems) and particularly what degree of force should be used for gap distraction. METHODS: To measure the physiological extension and flexion gaps, a prototypical force-determining tensor (Aesculap, Tuttlingen, Germany) was constructed and adapted so that force could be applied directly through Schanz screws inserted medially and laterally on the tibia and femur, independent of each other and without the need for bony resection. Ten normal cadaveric knees were assessed using a standard medial parapatellar total knee arthroplasty approach with patellar subluxation. Gap measurements were carried out twice, alternating distraction forces of 100 and 200 N each time. RESULTS: The prototype was implemented successfully. Repeat measurements showed only slight deviation from the original, resulting in minimal standard error. Precision did not vary with the application of greater force (200 N), but gap size increased significantly (p < 0.001). CONCLUSIONS: The success of this assessment with cadaveric knees indicates that this prototype can be applied to measure flexion and extension gaps without the need for bony resection. Increasing the distraction force to 200 N does not improve results, so 100 N per compartment appears adequate. Most likely, the extension and flexion gaps are physiologically asymmetric and unequal, and the kinematics are markedly altered after resection of the PCL and/or ACL. This new force-determining tensor can be used for further analyses, e.g., to explore the effects of selective ligament resection. PMID- 21246230 TI - Serum IL-33 levels are raised in patients with systemic sclerosis: association with extent of skin sclerosis and severity of pulmonary fibrosis. AB - To determine serum interleukin-33 (IL-33) levels and their associations with clinical parameters in patients with systemic sclerosis (SSc). Serum IL-33 levels were examined by enzyme-linked immunosorbent assay in 69 patients with SSc and 30 healthy individuals. In a retrospective longitudinal study, sera from 14 patients with SSc were analyzed (follow-up, 1-7 years). Serum IL-33 levels were elevated in SSc patients (261.7 +/- 141.9 pg/ml) compared with healthy individuals (174.9 +/- 72.4 pg/ml; P < 0.001). Patients with diffuse cutaneous SSc had higher levels of IL-33 (287.5 +/- 146.6 pg/ml) than those with limited cutaneous SSc (221.5 +/- 126.5 pg/ml; P < 0.05). Pulmonary fibrosis and decreased forced vital capacity were more commonly found in patients with elevated IL-33 levels than in those with normal IL-33 levels. IL-33 levels correlated positively with the extent of skin sclerosis, and inversely with percent predicted forced vital capacity. IL-33 levels were increased in SSc patients and correlated with the extent of skin sclerosis and the severity of pulmonary fibrosis. Therefore, IL-33 possibly plays a role in cutaneous and pulmonary fibrosis in SSc patients. PMID- 21246231 TI - Irrelevant relations and the active search for pattern structure in rat serial pattern learning. AB - Hersh (Mem Cogn 2:771-774, 1974) investigated the role of irrelevant relations in college students' pattern learning and performance for letter series completion problems. He created irrelevant relations in sequences by inserting items to make pattern structure ambiguous such that it was open to multiple interpretations during initial pattern processing. He reported irrelevant relations impaired humans' performance more when placed at the beginning of patterns than at the end. However, once pattern structure was induced, irrelevant relations were not impairing. Here, we examined the impact on rat serial pattern learning of irrelevant relations positioned at the beginning or end of a serial pattern. Rats pressed levers in a circular array according to the same structured serial pattern, 123 234 345 456 567, where digits indicated the clockwise position of the correct lever. This structured serial pattern was interleaved with repeating responses on lever 2 to produce irrelevant relations at the beginning of the pattern (Beginning: 122232 223242 324252 425262 526272), on lever 6 to produce irrelevant relations at the end of the pattern (End: 162636 263646 364656 465666 566676), or on lever 8 to produce no irrelevant relations (No Irrelevant Relations: 182838 283848 384858 485868 586878. Irrelevant relations significantly retarded learning regardless of their placement within the pattern. However, irrelevant relations retarded learning significantly more when placed at the pattern beginning versus end. The results indicate that rats, like humans, process patterns from beginning to end. PMID- 21246232 TI - Surface display of Aeromonas hydrophila GAPDH in attenuated Vibrio anguillarum to develop a Noval multivalent vector vaccine. AB - Displaying foreign antigens on the surface of attenuated or avirulent bacteria is an important strategy to develop live multivalent vector vaccines. In our previous work, several efficient surface display systems have been established based on outer membrane anchoring elements, which could successfully display heterologous proteins in attenuated Vibrio anguillarum. In this work, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from pathogenic Aeromonas hydrophila LSA34 was fused to seven display systems and introduced into attenuated V. anguillarum strain MVAV6203 (AV) to get seven GAPDH-display strains. The strain AV/pN-gapA showed the best display efficacy of GAPDH and was tested as the multivalent vaccine candidate. Further immune protection evaluation of AV/pN-gapA in turbot (Scophtalmus maximus) demonstrated that the attenuated V. anguillarum with surface-displayed GAPDH of A. hydrophila LSA34 effectively protected turbot from the infections of A. hydrophila and V. anguillarum and showed potential value for further multivalent vaccine development. PMID- 21246233 TI - Evaluation of global gene expression during cold shock in the human pathogen Vibrio vulnificus. AB - Vibrio vulnificus can adapt to cold temperatures by changing the expression profiles of certain genes and their resulting proteins. In this study, the complete V. vulnificus transcriptome was analyzed under cold shock by looking at gene expression changes occurring during the shift from 35 degrees C to 4 degrees C. A DNA microarray-based global transcript profiling of V. vulnificus showed that 165 genes out of 4,488 altered their expression profiles by more than twofold. From 35 degrees C to 10 degrees C, an overall gene repression was observed while changes occurring below 10 degrees C mainly resulted in upregulation. The highest induction observed occurred in two of the five categorized cold-shock genes, cspA and cspB, which showed a complementary expression pattern during cold shock suggesting a homologous role. Other genes showing a significant fold increase included ribosomal genes, protein folding regulators, and membrane genes. Repressions were observed in all orthologous groups. Genes with top fold changes in repression include those coding for catalytic enzymes responsible for non temperature-related stress regulation. These included antioxidants, sugar uptake, and amino acid scavengers. V. vulnificus maintained a high level of cspA and cspB transcripts during the entire experiment suggesting that these class I cold-shock genes are required beyond the initial phase of the acclimation period. PMID- 21246234 TI - Cellular localization of debromohymenialdisine and hymenialdisine in the marine sponge Axinella sp. using a newly developed cell purification protocol. AB - Sponges (Porifera), as the best known source of bioactive marine natural products in metazoans, play a significant role in marine drug discovery and development. As sessile filter-feeding animals, a considerable portion of the sponge biomass can be made of endosymbiotic and associated microorganisms. Understanding the cellular origin of targeted bioactive compounds from sponges is therefore important not only for providing chemotaxonomic information but also for defining the bioactive production strategy in terms of sponge aquaculture, cell culture, or fermentation of associated bacteria. The two alkaloids debromohymenialdisine (DBH) and hymenialdisine (HD), which are cyclin-dependent kinase inhibitors with pharmacological activities for treating osteoarthritis and Alzheimer's disease, have been isolated from the sponge Axinella sp. In this study, the cellular localization of these two alkaloids was determined through the quantification of these alkaloids in different cell fractions by high-performance liquid chromatography (HPLC). First, using a differential centrifugation method, the dissociated cells were separated into different groups according to their sizes. The two bioactive alkaloids were mainly found in sponge cells obtained from low speed centrifugation. Further cell purifications were accomplished by a newly developed multi-step protocol. Four enriched cell fractions (C1, C2, C3, and C4) were obtained and subjected to light and transmission electron microscopy, cytochemical staining, and HPLC quantification. Compared to the low concentrations in other cell fractions, DBH and HD accounted for 10.9% and 6.1%, respectively, of dry weight in the C1 fraction. Using the morphological characteristics and cytochemical staining results, cells in the C1 fraction were speculated to be spherulous cells. This result shows that DBH and HD in Axinella sp. are located in sponge cells and mostly stored in spherulous cells. PMID- 21246235 TI - Disruption of bacterial cell-to-cell communication by marine organisms and its relevance to aquaculture. AB - Bacterial disease is one of the most critical problems in commercial aquaculture. Although various methods and treatments have been developed to curb the problem, yet they still have significant drawbacks. A novel and environmental-friendly approach in solving this problem is through the disruption of bacterial communication or quorum sensing (QS). In this communication scheme, bacteria regulate their own gene expression by producing, releasing, and sensing chemical signals from the environment. There seems to be a link between QS and diseases through the regulation of certain phenotypes and the induction of virulence factors responsible for pathogen-host association. Several findings have reported that numerous aquatic organisms such as micro-algae, macro-algae, invertebrates, or even other bacteria have the potential to disrupt QS. The mechanism of action varies from degradation of signals through enzymatic or chemical inactivation to antagonistic as well as agonistic activities. This review focuses on the existing marine organisms that are able to interfere with QS with potential application for aquaculture as bacterial control. PMID- 21246237 TI - Splenic trauma: pictorial review of contrast-enhanced CT findings. AB - Splenic trauma is a common entity of high clinical significance that may have a variety of imaging manifestations. This article reviews splenic anatomy and function, mechanisms of splenic trauma, and the classification and grading of splenic trauma, with a particular focus on contrast-enhanced CT. Heterogeneous early enhancement of the spleen and technical suggestions to minimize this artifact are discussed. Mechanisms of trauma and their classification under the American Association for the Surgery of Trauma are discussed and illustrated. The merits of an alternative classification system by Marmery et al. are also considered. We conclude that knowledge of the mechanisms, classifications, and grades of splenic trauma can assist the clinician in clinical decision making and promote improved patient outcomes. PMID- 21246236 TI - Diversity of coding sequences and gene structures of the antifungal peptide mytimycin (MytM) from the Mediterranean mussel, Mytilus galloprovincialis. AB - Knowledge on antifungal biomolecules is limited compared to antibacterial peptides. A strictly antifungal peptide from the blue mussel, Mytilus edulis named mytimycin (MytM) was reported in 1996 as partial NH(2) 33 amino acid sequence. Using back-translations of the previous sequence, MytM-related nucleotide sequences were identified from a normalized Mytilus galloprovincialis expressed sequence tag library. Primers designed from a consensus sequence have been used to obtain a fragment of 560 nucleotides, including the complete coding sequence of 456 nucleotides. Precursor is constituted by a signal peptide of 23 amino acids, followed by MytM of 54 amino acids (6.2-6.3 kDa, 12 cysteines) and C terminal extension of 75 amino acids. Only two major amino acid precursor sequences emerged, one shared by M. galloprovincialis from Venice and Vigo, the other belonging to M. galloprovincialis from Palavas, with nine amino acid differences between the two MytM. Predicted disulfide bonds suggested the presence of two constrained domains joined by amino acidic NIFG track. Intriguing was the presence of conserved canonical EF hand-motif located in the C-terminus extension of the precursor. The MytM gene was found interrupted by two introns. Intron 2 existed in two forms, a long (1,112 nucleotides) and a short (716 nucleotides) one resulting from the removal of the central part of the long one. Both the short (GenBank FJ804479) and the long (GenBank FJ804478) genes are simultaneously present in the mussel genome. PMID- 21246238 TI - Mitochondrial proteomics analysis of tumorigenic and metastatic breast cancer markers. AB - Mitochondria are key organelles in mammary cells responsible for several cellular functions including growth, division, and energy metabolism. In this study, mitochondrial proteins were enriched for proteomics analysis with the state-of the-art two-dimensional differential gel electrophoresis and matrix-assistant laser desorption ionization-time-of-flight mass spectrometry strategy to compare and identify the mitochondrial protein profiling changes between three breast cell lines with different tumorigenicity and metastasis. The proteomics results demonstrate more than 1,500 protein features were resolved from the equal amount pooled from three purified mitochondrial proteins, and 125 differentially expressed spots were identified by their peptide finger print, in which, 33 identified proteins belonged to mitochondrial proteins. Eighteen out of these 33 identified mitochondrial proteins such as SCaMC-1 have not been reported in breast cancer research to our knowledge. Additionally, mitochondrial protein prohibitin has shown to be differentially distributed in mitochondria and in nucleus for normal breast cells and breast cancer cell lines, respectively. To sum up, our approach to identify the mitochondrial proteins in various stages of breast cancer progression and the identified proteins may be further evaluated as potential breast cancer markers in prognosis and therapy. PMID- 21246239 TI - A simple model for predicting incidence of chronic kidney disease in HIV-infected patients. AB - BACKGROUND: Human immunodeficiency virus (HIV)-infected individuals have concurrent risk factors for chronic kidney disease (CKD), but there are no prediction models to quantify the effect of multiple factors on the development of incident CKD. METHODS: A 1-year prognostic model was developed using prospective data between January 2008 and March 2009, from a derivation cohort of 623 patients with an estimated glomerular filtration rate (eGFR) exceeding 60 ml/min/1.73 m(2) at baseline. Incident CKD was defined as both an eGFR falling below 60 ml/min/1.73 m(2) and a decrease in eGFR of at least 25% during the period. Continuous variables were divided into categories using the mean value of the whole cohort. Multivariate logistic regression was used to determine baseline categories associated with incident CKD. The model was tested with prospective data between April 2009 and March 2010, from a validation cohort of 534 patients exceeding 60 ml/min/1.73 m(2) at baseline, consisting of part of the derivation cohort and newly enrolled patients. The discriminative ability was evaluated using the area under the receiver operating characteristic (AROC) curve. RESULTS: Eighteen subjects developed incident CKD (2.9%). In a multivariate logistic regression analysis of the derivation cohort, 5 variables (age, CD4 cell count, diabetes, proteinuria, and eGFR at baseline) were independently associated with the incidence of CKD. The AROC curve was 0.841 (95% CI 0.799-0.894) in the validation cohort. CONCLUSION: This prediction model may be a useful tool for identifying HIV-infected individuals with a high likelihood of new-onset CKD. PMID- 21246240 TI - Dual myeloperoxidase-antineutrophil cytoplasmic antibody- and antiglomerular basement membrane antibody-positive cases associated with prior pulmonary fibrosis: a report of four cases. AB - BACKGROUND: Both myeloperoxidase-associated antineutrophil cytoplasmic antibody (MPO-ANCA) and antiglomerular basement membrane antibody (anti-GBM Ab) positivity have been demonstrated in patients with rapidly progressive glomerulonephritis (RPGN), either with or without pulmonary hemorrhage; however, the implications of these antibodies in such patients have not yet been elucidated. The cases with dual positive antibodies were studied clinically, serologically, and pathologically, and the implications of antibodies are discussed here. PATIENTS AND METHODS: Four patients with prior pulmonary fibrosis, who subsequently developed RPGN and pulmonary hemorrhage, were studied clinically, serologically, and pathologically. The clinical data were reviewed extensively and the dual positive antibodies were detected by enzyme-linked immunosorbent assays. Pathological studies were performed with a renal biopsy in one patient, a gastric biopsy in another patient, and autopsy materials in the remaining 2 patients. RESULTS: All 4 patients had prior pulmonary fibrosis before the symptoms of RPGN when the dual positivity of MPO-ANCA and anti-GBM Ab was detected. Three cases were accompanied by pulmonary hemorrhage around the time of RPGN whereas the remaining case demonstrated pulmonary hemorrhage a few years later. Renal tissue specimens in 3 cases showed circumferential crescents and linear immunoglobulin G deposits along the glomerular capillary loops in glomeruli. Two autopsy specimens revealed vasculitis of the small arteries and arterioles of the kidney, and one of them showed similar vasculitic findings in both the gastrointestinal tract walls and the adipose tissues of the adrenal glands. Additionally, a case with pulmonary hemorrhage occurring after remission was associated with re-elevated MPO-ANCA levels but without anti-GBM Ab positivity. A gastric biopsy was unremarkable and non-contributory for the diagnosis, but this case showed vasculitic symptoms of peripheral neuritis and retinal hemorrhage. Taken together, all 4 cases demonstrated prior pulmonary fibrosis and dual positivity of MPO-ANCA as well as anti-GBM Abs at the time of RPGN, and were associated with either pulmonary hemorrhage or its occurrence thereafter. CONCLUSION: Four cases that showed prior pulmonary fibrosis as well as subsequent RPGN and pulmonary hemorrhage were both MPO-ANCA- and anti-GBM Ab-positive at the time of RPGN. The glomeruli disclosed features compatible with anti-GBM Ab disease, but the clinical and pathological vasculitic manifestations, including prior pulmonary fibrosis that might be an early manifestation of ANCA disease, suggested the occurrence of MPO-ANCA-associated vasculitis. Furthermore, 1 case subsequently showed repetitive pulmonary hemorrhage with re-elevated MPO-ANCA positivity but without anti-GBM Ab positivity, and this event was possibly due to MPO-ANCA associated alveolar capillaritis. As anti-GBM Ab disease is generally thought not to manifest the clinical and pathological features of vasculitis excluding the kidney, MPO-ANCA might be a key factor regarding the occurrence of this dual positive disease. PMID- 21246241 TI - One case of sporadic hemiplegic migraine with multiple pulmonary arteriovenous malformation. PMID- 21246242 TI - Dispute settlement understanding on the use of Botox in chronic migraine. PMID- 21246243 TI - Effect of IL-1beta and TNF-alpha polymorphisms on the prognosis and survival of gastric cancer patients. AB - So far, a number of association studies have focused on the effect of polymorphisms in IL-1beta and TNF-alpha genes on the susceptibility to gastric cancer (GC). Here, we evaluate the possible association between common polymorphisms in the IL-1beta and TNF-alpha genes with various clinicopathological characteristics, including overall survival of GC patients. Restriction fragment length polymorphism analysis was performed for IL-1beta-31(T > C) and IL-1beta-511(C > T) and TNF-alpha-857 (C > T) polymorphisms in 130 GC patients. IL-1beta-31CC and IL-1beta-511TT genotypes held a significantly lower risk of lymphatic invasion (IL-1beta-31CC vs. others: adjusted OR = 0.39, 95% CI = 0.15-0.96, P = 0.04, IL-1beta-511TT vs. others: adjusted OR = 0.23, 95% CI = 0.08-0.67, P = 0.007). The IL-1beta-31CC and IL-1beta-511TT genotypes were weakly associated with reduced risk of venous invasion (IL-1beta-31CC vs. others: adjusted OR = 0.35, 95% CI = 0.12-1.05, P = 0.06, IL-1beta-511TT vs. others: adjusted OR = 0.32, 95% CI = 0.08-1.20, P = 0.09). The IL-1beta-511TT genotype was also weakly associated with reduced risk of lymph node metastasis (IL-1beta 511TT vs. others: adjusted OR = 0.42, 95% CI = 0.17-1.04, P = 0.06). When the TNF alpha-857CT and TNF-alpha-857-TT genotypes were considered as T carrier, the patients with TNF-alpha-857T carrier showed significantly better overall survival than patients with CC genotype (P = 0.011). GC patients who have both IL-1beta-31 CC and IL-1beta-511 TT genotypes and have at least one of protective genotypes (IL-1beta-31 CC, IL-1beta-511 TT, TNF-alpha-857 T carrier) were also associated with better prognostic factors, such as lymphatic and venous invasion better survival. IL-1beta-31CC, IL-1beta-511TT genotype, and TNF-alpha-857T carrier may have protective effect against GC progression. PMID- 21246245 TI - Osteomyelitis due to trimethoprim/sulfamethoxazole-resistant Edwardsiella tarda infection in a patient with X-linked chronic granulomatous disease. AB - Edwardsiella tarda, a catalase-positive bacillus widely distributed throughout nature, is generally susceptible to trimethoprim/sulfamethoxazole. We describe osteomyelitis due to trimethoprim/sulfamethoxazole-resistant E. tarda in a patient with chronic granulomatous disease (CGD). Once E. tarda acquires antibiotic resistance, infected CGD patients may develop severe infections with unforeseeable consequences. PMID- 21246246 TI - Causes of death and risk factors among HIV-infected persons in the HAART era: analysis of a large urban cohort. AB - OBJECTIVE: We aimed to examine the clinical outcome in HIV-1-infected patients after more than 10 years of highly active antiretroviral therapy (HAART). METHODS: We analyzed data from 1,236 treatment-naive adults who had started HAART. The primary endpoint was the yearly prevalence of death for AIDS-related causes (ARC) or for non-AIDS related causes (non-ARC). The data from our cohort were compared with that of the general population (GP) of our region. RESULTS: We observed that 116 patients died, and 58.6% of deaths were non-ARC. The death incidence decreased from 18.8% in 1998-1999 to 1.2% in 2008-2009. The leading causes of death were malignancies (35.3%), infections (21.6%), end-stage liver diseases (18.1%), and cardiovascular diseases (CVD) (6.9%). Yearly death rates were similar in the HIV-infected cohort and in the crude GP (odds ratio [OR] 1.1, 95% confidence interval [CI] 0.5-2.5), but when adjusted for age, HIV-infected patients showed a greater risk (OR 7.4, 95% CI 4.1-13.4). The difference was still highly significant when the analysis was restricted to non-ARCs (OR 4.3, 95% CI 2.07-9.2). Overall, malignancies (OR 5.7, 95% CI 2.6-12.8) and end-stage liver diseases (OR 35.0, 95% CI 15.5-78.8) were significantly more frequent than in the age-adjusted GP. CONCLUSIONS: Despite HAART, HIV-infected patients are at greater risk of death compared to a reference uninfected population. PMID- 21246247 TI - Septic shock, pneumonia, and soft tissue infection due to Myroides odoratimimus: report of a case and review of Myroides infections. AB - The genus Myroides comprises aerobic, yellow-pigmented, non-motile, non fermenting gram-negative rods formerly classified as Flavobacterium odoratum. Members of the genus are widely distributed in the environment, especially in water, and usually behave as low-grade opportunistic pathogens, having been found to cause urinary tract infection, endocarditis, ventriculitis, and cutaneous infections in severely immunocompromised patients. We report a case of soft tissue infection, septic shock, and pneumonia due to M. odoratimimus in an immunocompetent male. To our knowledge, this is the first description of life threatening infection caused by this organism in an immunocompetent host. We have also reviewed the medical literature on the genus Myroides. PMID- 21246248 TI - A meta-analysis of the relation of polymorphism at sites -1082 and -592 of the IL 10 gene promoter with susceptibility and clearance to persistent hepatitis B virus infection in the Chinese population. AB - BACKGROUND: Up to now, many publications about the Chinese population have evaluated the correlation between interleukin-10 (IL-10) -1082 and -592 polymorphisms and persistent hepatitis B virus (HBV) infection. However, the results remain inconclusive. In order to resolve this conflict, a meta-analysis was performed. METHODS: Seven studies were included and dichotomous data are presented as the odds ratio (OR) with a 95% confidence interval (CI). RESULTS: The results of our study suggest that carriers of the IL-10 -592A allele were more likely to clear HBV spontaneously in the Chinese pooled population (A vs. C: OR = 0.799, 95% CI = 0.678-0.941, P = 0.007; AC vs. AA: OR = 1.343, 95% CI = 1.017-1.684, P = 0.011; AA vs. AC + CC: OR = 0.736, 95% CI = 0.594-0.912; AA + AC vs. CC: OR = 0.588, 95% CI = 0.408-0.848, P = 0.004) and the IL-10 -1082A allele was associated with significantly reduced persistent HBV infection risk in Chinese (A vs. G: OR = 0.701, 95% CI = 0.494-0.996, P = 0.047; AA vs. GG + GA: OR = 0.684, 95% CI = 0.476-0.982, P = 0.040). CONCLUSIONS: Persistent HBV infection susceptibility is associated with the gene polymorphism IL-10 -1082GA in the Chinese population and the clearance of HBV is associated with the gene polymorphism IL-10 -592CA in the Chinese population. PMID- 21246249 TI - Acute cytomegalovirus pneumonia and hepatitis presenting during acute HIV retroviral syndrome. AB - Cytomegalovirus (CMV) disease is a frequent opportunistic infection that usually occurs in the late stages of HIV infection as a result of reactivation of a latent infection. We report a case of a 23-year-old man with acute retroviral syndrome complicated by coexisting CMV pneumonia and CMV hepatitis, which were documented by histopathological examination. His CMV pneumonia and hepatitis were assumed to be primary CMV diseases owing to the absence of CMV IgG antibody. To the best of our knowledge, this is the first case of simultaneous CMV pneumonia and hepatitis occurring as primary CMV diseases during primary HIV infection. This case indicates that invasive CMV diseases such as pneumonia and hepatitis should be considered even in patients with primary HIV infection. PMID- 21246250 TI - SAR reduced black-blood cine TPM for increased temporal resolution at 3T. AB - OBJECT: The objective was to improve the temporal resolution in black-blood CINE tissue phase mapping sequences at high field MR systems. The temporal resolution is limited due to SAR constraints causing idle times into the sequence. The aim was to avoid these idle times and therefore providing an increased number of heart phases. MATERIALS AND METHODS: Thirteen volunteers were enrolled in this study. Each volunteer underwent different myocardial short-axis scans comprising scans with application of both presaturation pulses, with alternating application of presaturation pulses and with an attenuation of the excitation angle. The last two approaches enable a SAR reduction or increased temporal resolution. The contrast to noise ratio (CNR) between myocardium and blood and the influence on the measured tissue motion were investigated. RESULTS: High CNR between myocardium and blood could be obtained with the application of alternating presaturation-pulses. Reduction of the flip angle of the presaturation-pulses provided reduced CNR relative to both the original and the alternated presaturation-pulses approach. More details of the myocardial motion were observed with increased temporal resolution. CONCLUSION: It is feasible to increase the temporal resolution at high field strength by reducing the SAR with either alternating presaturation-pulses or decreased flip angle of these pulses. PMID- 21246252 TI - Rapid estimation of triacylglycerol content of Chlorella sp. by thermogravimetric analysis. AB - A simple and reliable method based on thermogravimetric analysis has been developed for determining triacylglycerol content in Chlorella sp. KR-1. There are two decomposing steps during pyrolysis of the microalgal cells and the second step of weight loss may be attributed to degradation and volatilization of triacylglycerols. The second peak height in the temperature derivatives of weight loss increased with the triacylglycerol content of the microalgal cells and the peak was around 390 degrees C regardless of the triacylglycerol contents. Based on these findings, a linear equation for determining triacylglycerol content was derived. The proposed method gives satisfactory results, showing small variance and a good interpolation capability. PMID- 21246251 TI - Phase I trial of sorafenib in combination with interferon-alpha in Japanese patients with unresectable or metastatic renal cell carcinoma. AB - BACKGROUND: We investigated the safety, pharmacokinetics, tumor response, and immunological parameters of sorafenib plus interferon alpha-2b [corrected] (IFN) in Japanese patients with advanced RCC. PATIENTS AND METHODS: After 2 weeks of IFN-alone treatment, eligible patients received 28-day cycles of continuous sorafenib 200 mg (Cohort 1) or 400 mg (Cohorts 2 and 3) twice daily combined with intramuscular IFN 6 (Cohorts 1 and 2) or 9 (Cohort 3) million international units (MIU) three times a week. RESULTS: A total of 18 patients received at least one dose of sorafenib plus IFN. Five patients had dose-limiting toxicities (DLTs). The most common DLT was fatigue, experienced in four DLT patients. All 18 patients experienced at least one treatment-emergent adverse event (AE). The most common treatment-emergent AEs included fatigue, fever, platelets, leukocytes, hemoglobin, weight loss and anorexia. Five patients had confirmed partial response and 11 had stable disease, a response rate of 27.8%. IFN had no relevant impact on the pharmacokinetics of sorafenib. CONCLUSIONS: Sorafenib administered in combination with IFN was well tolerated, with promising results in efficacy. Continuous sorafenib 400 mg twice daily in combination with IFN 6 MIU three times a week is recommended in Japanese patients with advanced RCC. PMID- 21246253 TI - Construction of an Escherichia coli mutant producing monophosphoryl lipid A. AB - Lipid A is a major component in the outer membrane of most gram-negative bacteria. Monophosphoryl lipid A contains no phosphate group at 1-position and can be used as an adjuvant. We constructed an Escherichia coli mutant CW001 by integrating a gene lpxE into the chromosome of E. coli W3110. The gene lpxE encodes an enzyme LpxE which removes the 1-phosphate group of lipid A. CW001 predominantly produces 1-dephosphorylated lipid A in vivo, as adjudged by thin layer chromatography and electro-spray ionization mass spectrometry. This study not only is important for the development of lipid A adjuvants but also provides a novel method for integration of heterologous genes into the chromosome of E. coli. PMID- 21246254 TI - Biotechnological potential of pectinolytic complexes of fungi. AB - Plant cell wall-degrading enzymes, such as cellulases, hemicellulases and pectinases, have been extensively studied because of their well documented biotechnological potential, mainly in the food industry. In particular, lytic enzymes from filamentous fungi have been the subject of a vast number of studies due both to their advantages as models for enzyme production and their characteristics. The demand for such enzymes is rapidly increasing, as are the efforts to improve their production and to implement their use in several industrial processes, with the goal of making them more efficient and environment friendly. The present review focuses mainly on pectinolytic enzymes of filamentous fungi, which are responsible for degradation of pectin, one of the major components of the plant cell wall. Also discussed are the past and current strategies for the production of cell wall-degrading enzymes and their present applications in a number of biotechnological areas. PMID- 21246255 TI - Increase of ethanol tolerance of Saccharomyces cerevisiae by error-prone whole genome amplification. AB - Saccharomyces cerevisiae was transformed for higher ethanol tolerance by error prone whole genome amplification. The resulting PCR products were transformed back to the parental strain for homologous recombination to create a library of mutants with the perturbed genomic networks. A few rounds of transformation led to the isolation of mutants that grew in 9% (v/v) ethanol and 100 g glucose l(-1) compared to untransformed yeast which grew only at 6% (v/v) ethanol and 100 g glucose l(-1). PMID- 21246256 TI - Uniform isotope labeling of a eukaryotic seven-transmembrane helical protein in yeast enables high-resolution solid-state NMR studies in the lipid environment. AB - Overexpression of isotope-labeled multi-spanning eukaryotic membrane proteins for structural NMR studies is often challenging. On the one hand, difficulties with achieving proper folding, membrane insertion, and native-like post-translational modifications frequently disqualify bacterial expression systems. On the other hand, eukaryotic cell cultures can be prohibitively expensive. One of the viable alternatives, successfully used for producing proteins for solution NMR studies, is yeast expression systems, particularly Pichia pastoris. We report on successful implementation and optimization of isotope labeling protocols, previously used for soluble secreted proteins, to produce homogeneous samples of a eukaryotic seven-transmembrane helical protein, rhodopsin from Leptosphaeria maculans. Even in shake-flask cultures, yields exceeded 5 mg of purified uniformly (13)C,(15)N-labeled protein per liter of culture. The protein was stable (at least several weeks at 5 degrees C) and functionally active upon reconstitution into lipid membranes at high protein-to-lipid ratio required for solid-state NMR. The samples gave high-resolution (13)C and (15)N solid-state magic angle spinning NMR spectra, amenable to a detailed structural analysis. We believe that similar protocols can be adopted for challenging mammalian targets, which often resist characterization by other structural methods. PMID- 21246257 TI - Overproduction of a rice aldo-keto reductase increases oxidative and heat stress tolerance by malondialdehyde and methylglyoxal detoxification. AB - The accumulation of toxic compounds generated by the interaction between reactive oxygen species and polyunsaturated fatty acids of membrane lipids can significantly damage plant cells. A plethora of enzymes act on these reactive carbonyls, reducing their toxicity. Based on the chromosomal localization and on their homology with other stress-induced aldo-keto reductases (AKRs) we have selected three rice AKR genes. The transcription level of OsAKR1 was greatly induced by abscisic acid and various stress treatments; the other two AKR genes tested were moderately stress-inducible. The OsAKR1 recombinant protein exhibited a high nicotinamide adenine dinucleotide phosphate-dependent catalytic activity to reduce toxic aldehydes including glycolysis-derived methylglyoxal (MG) and lipid peroxidation-originated malondialdehyde (MDA). The function of this enzyme in MG detoxification was demonstrated in vivo in E. coli and in transgenic plants overproducing the OsAKR1 protein. Heterologous synthesis of the OsAKR1 enzyme in transgenic tobacco plants resulted in increased tolerance against oxidative stress generated by methylviologen (MV) and improved resistance to high temperature. In these plants lower levels of MDA were detected both following MV and heat treatment due to the activity of the OsAKR1 enzyme. The transgenic tobaccos also exhibited higher AKR activity and accumulated less MG in their leaves than the wild type plants; both in the presence and absence of heat stress. These results support the positive role of OsAKR1 in abiotic stress related reactive aldehyde detoxification pathways and its use for improvement of stress tolerance in plants. PMID- 21246258 TI - Two GCC boxes and AP2/ERF-domain transcription factor ORA59 in jasmonate/ethylene mediated activation of the PDF1.2 promoter in Arabidopsis. AB - Plant defense against microbial pathogens depends on the action of several endogenously produced hormones, including jasmonic acid (JA) and ethylene (ET). In defense against necrotrophic pathogens, the JA and ET signaling pathways synergize to activate a specific set of defense genes including PLANT DEFENSIN1.2 (PDF1.2). The APETALA2/Ethylene Response Factor (AP2/ERF)-domain transcription factor ORA59 acts as the integrator of the JA and ET signaling pathways and is the key regulator of JA- and ET-responsive PDF1.2 expression. The present study was aimed at the identification of elements in the PDF1.2 promoter conferring the synergistic response to JA/ET and interacting with ORA59. We show that the PDF1.2 promoter was activated synergistically by JA and the ET-releasing agent ethephon due to the activity of two GCC boxes. ORA59 bound in vitro to these GCC boxes and trans-activated the PDF1.2 promoter in transient assays via these two boxes. Using the chromatin immunoprecipitation technique we were able to show that ORA59 bound the PDF1.2 promoter in vivo. Finally, we show that a tetramer of a single GCC box conferred JA/ethephon-responsive expression, demonstrating that the JA and ET signaling pathways converge to a single type of GCC box. Therefore ORA59 and two functionally equivalent GCC box binding sites form the module that enables the PDF1.2 gene to respond synergistically to simultaneous activation of the JA and ET signaling pathways. PMID- 21246259 TI - Simultaneous leaching and carbon sequestration in constrained aqueous solutions. AB - The behavior of metal ions' leaching and precipitated mineral phases of metal rich fly ash (FA) was examined in order to evaluate microbial impacts on carbon sequestration and metal immobilization. The leaching solutions consisted of aerobic deionized water (DW) and artificial eutrophic water (AEW) that was anaerobic, organic- and mineral-rich, and higher salinity as is typical of bottom water in eutrophic algae ponds. The Fe- and Ca-rich FAs were predominantly composed of quartz, mullite, portlandite, calcite, hannebachite, maghemite, and hematite. After 86 days, only Fe and Ca contents exhibited a decrease in leaching solutions while other major and trace elements showed increasing or steady trends in preference to the type of FA and leaching solution. Ca-rich FA showed strong carbon sequestration efficiency ranging up to 32.3 g CO(2)/kg FA after 86 days, corresponding to almost 65% of biotic carbon sequestration potential under some conditions. Variations in the properties of FAs such as chemical compositions, mineral constituents as well as the type of leaching solution impacted CO(2) capture. Even though the relative amount of calcite increased sixfold in the AEW and the relative amount of mineral phase reached 37.3 wt% using Ca-rich FA for 86 days, chemical sequestration did not accomplish simultaneous precipitation and sequestration of several heavy metals. PMID- 21246260 TI - Treatments with sodium selenate or doxycycline offset diabetes-induced perturbations of thioredoxin-1 levels and antioxidant capacity. AB - Diabetes is associated with increased oxidative stress and impaired antioxidant defenses. Thioredoxin-1 (TRX-1) is a cytosolic thiol antioxidant and redox-active protein which plays a vital role in the maintenance of reduced intracellular redox state. In this study, the authors examined whether 4-week treatments with sodium selenate and doxycycline--a metalloproteinase-2 inhibitor which also has antioxidant-like effects--offset perturbations in oxidative stress and antioxidant protection in rat liver and skeletal muscle in streptozotocin-induced diabetes (SID) model. Experimental diabetes decreased TRX-1 levels in skeletal muscle and liver. On the other hand, SID increased oxidative stress marker protein carbonyl levels and decreased oxygen radical absorbance capacity (ORAC), an indicator of antioxidant capacity, in liver. A 4-week treatment of sodium selenate to diabetic rats decreased blood glucose levels moderately, while doxycycline treatment caused a reduction in weight loss of diabetic rats. Both doxycycline and sodium selenate prevented diabetes-induced decrease of TRX-1 levels in skeletal muscle, whereas only doxyxycline was effectively preventing diabetes-induced decrease of TRX-1 in liver. Furthermore, both treatments prevented diabetes-induced altered levels of protein carbonyls and ORAC in liver, and restored free and total protein thiol levels in both skeletal muscle and liver. In conclusion, the data of this study provides further evidence that sodium selenate and doxycycline treatments may control oxidative stress and improve antioxidant defense in diabetes. PMID- 21246261 TI - Malignant transformation of 293 cells induced by ectopic expression of human Nanog. AB - Tumor development has long been known to resemble abnormal embryogenesis. The ESC self-renewal gene NANOG is purportedly expressed in some epithelial cancer cells and solid tumors, but a casual role in tumor development has remained unclear. In order to more comprehensively elucidate the relationship between human Nanog and tumorigenesis, the hNanog was ectopically expressed in the 293 cell line to investigate its potential for malignant transformation of cells both in vitro and in vivo. Here we provide compelling evidence that the overexpression of hNanog resulted in increased cell proliferation, anchor-independent growth in soft agar, and formation of tumors after subcutaneous injection of athymic nude mice. Pathologic analysis revealed that these tumors were poorly differentiated. In analysis of the underlying molecular mechanism, two proteins, FAK and Ezrin, were identified to be upregulated in the hNanog expressing 293 cells. Our results demonstrate that hNanog is a potent human oncogene and has the ability to induce cellular transformation of human cells. PMID- 21246262 TI - Adipose derived stem cells: efficiency, toxicity, stability of BrdU labeling and effects on self-renewal and adipose differentiation. AB - 5-bromo-2-deoxyurudine (BrdU) can be used as a methodological tool for in vivo investigations following in vitro prelabeling of isolated stem cells for subsequent cell tracking within the recipient host. The objective of this study was to determine how useful BrdU may be as a labeling modality for adipose derived stem cells (ASC) by examining BrdU toxicity, BrdU intracellular stability, and potential effects on ASC differentiation. Porcine and human ASC (pASC and hASC, respectively) were labeled with BrdU at 5 or 10 MUM for 2, 6, 24, and 48 h. BrdU toxicity and stability over time in monolayer cultures, in 3-D collagen scaffolds implanted to a porcine model and after thawing from long-term storage were evaluated by MTT assays and immunohistochemistry. ASC differentiation was evaluated by Oil Red O staining. BrdU was not cytotoxic at all tested concentrations and incubation times. BrdU color intensity within each cell and the number of ASC labeled with BrdU decreased as a function of both incubation time and BrdU concentrations. Labeling intensities decreased over time and were undetectable after 6 passages for pASC and 4 passages for hASC. In 3-D scaffolds, BrdU-labeled ASC were identifiable after 90 days of in vitro cultures and for 30 days in a porcine model. BrdU did not prevent preadipocyte differentiation and BrdU labeling was still detectable after subsequent thawing after long-term storage of ASC. BrdU is an excellent candidate reagent to label and track ASC that will allow distinction between BrdU-labeled donor cells and host cells. The data provides a foundation for conducting future tissue engineering projects using BrdU-labeled ASC. PMID- 21246263 TI - The influence of temperature on Coumarin 153 fluorescence kinetics. AB - The influence of temperature varied in the range 183 K-323 K on the fluorescence quantum yield, fluorescence lifetime, absorption and emission transition moments and non-radiative deactivation rate was determined for the well known and largely used dye Coumarin 153, dissolved in 1-chloropropane. The Kennard-Stepanov relation connecting the absorption and emission spectra was used to check for the presence of more than one absorbing/emitting species and to investigate whether intramolecular vibrational redistribution completes in the C153 excited S(1) state before the emission takes place. The emission spectrum corresponding to S(1)->S(0) transition, was fitted at each temperature to the model function including the information on the dye vibrational modes coupling. In this way the displacement in equilibrium distance for the most active vibrational mode was determined for C153 in S(1) and in S(0). Using the temperature dependence of the fluorescence decay time and quantum yield, the non-radiative deactivation rate was determined. Its temperature dependence was compared to that calculated using the theoretical model with the most active vibrational mode displacement values taken from steady-state spectra analysis. The somewhat surprising dependence of the fluorescence decay time and quantum yield on temperature was related to non trivial coupling between low-frequency vibrational modes of C153 in the excited and ground states. PMID- 21246264 TI - Ultrasensitive study of gatifloxacin based on its enhancing effect on the cerium (IV)-sodium hyposulfite chemiluminescence reaction in a micellar medium. AB - A sensitive and rapid flow-injection chemiluminescence (CL) method has been developed for the determination of gatifloxacin in pharmaceutical preparations and biological samples. The method is based on the enhancing effect of gatifloxacin on CL emission generated by the interaction of Ce (IV) in sulphuric acid and sodium hyposulphite (Na(2)S(2)O(4)) sensitized by sodium dodecyl benzene sulfonate (SDBS). Strong CL emission was observed when gatifloxacin was injected into the Ce (IV) in sulphuric acid and Na(2)S(2)O(4) solution incorporated with SDBS in a flow-cell. Several experimental parameters affecting the CL reaction were investigated and optimized systematically. Under the optimum conditions, it was found that the CL intensity is proportional to the concentration of gatifloxacin in the range of 1.12 * 10(-11)-4.40 * 10(-9) g mL(-1) with a co relation coefficient of 0.9994. The limit of detection was found to be 4.87 * 10( 12) g mL(-1) and the relative standard deviation (RSD, n=7) was 1.8% for 4 * 10( 8) g mL(-1) of GFLX. The proposed method offers higher sensitivity, wide linear range and better stability without requiring sophisticated instrumentation. Thus, the proposed method has been successfully applied to the determination of gatifloxacin in pharmaceuticals, serum and human urine. PMID- 21246265 TI - Drying of polyacrylamide composite gels formed with various kappa- carrageenan content. AB - Drying of polyacrylamide (PAAm)-kappa-carrageenan (kappaC) composite gels were monitored by using steady-state fluorescence technique. Disc shaped gels were formed from acrylamide (AAm) and N, N'- methylenebisacrylamide(Bis) with various kappa- carrageenan (kappaC) contents by free radical crosslinking copolymerization in water. Pyranine (P) was doped as a fluorescence probe, and scattered light, I (sc), and fluorescence intensities, I, were monitored during drying of these gels. It is observed that fluorescence intensity of pyranine increased as drying time is increased for all samples. The increase in I was modeled using Stern- Volmer equation and diffusion with moving boundary. It is found that desorption coefficient, D decreased as kappaC contents were increased. Supporting gravimetrical and volumetric experiments were also carried out during drying of PAAm- kappaC composite gels. PMID- 21246266 TI - The nature of trapping centers in amorphous biphenyl-containing polymer. AB - Study of optical properties of methyl methacrylate and 4-vinylbiphenyl copolymers in a rigid amorphous polymer allowed establishing the non-excimer nature of energy traps in a polymer chain. These traps are probably related to possibility of collective states formed by macromolecule's chromophore groups. The shortening of the trap states decay time in 4-vinylbiphenyl homopolymer comparing to copolymer is observed. PMID- 21246267 TI - Shifting of fluorescence peak in CdS nanoparticles by excitation wavelength change. AB - CdS nanoparticles with different size are prepared by chemical bath deposition method. These particles show strong fluorescence at emission wavelength of 507 nm. It has been observed that this emission peak changes through a range of 147 nm, by varying the excitation wavelengths through 370-480 nm.The emission peak can thus be tuned by varying the excitation wavelengths. This peak emission wavelength shift is due to the selective excitation of vibronic levels in the surface state of the CdS nanoparticles. PMID- 21246268 TI - A selective spectrofluorometric determination of micromolar level of cyanide in water using naphthoquinone imidazole boronic-based sensors and a surfactant cationic CTAB micellar system. AB - We developed a new spectrofluorometric method for qualitative and quantitative determination of cyanide in water using the incorporation of naphthoquinone imidazole boronic-based sensors (m-NQB and p-NQB) and a cationic surfactant, certyltrimethyl ammonium bromide (CTAB). This micellar system exhibited great selectivity for cyanide detection with an assistance of the cationic surface of micelle. The interaction of boronic acid of the sensor toward cyanide in CTAB micellar media gave a quantitative measure of cyanide concentration in the micromolar level. Under the optimal condition, fluorescence intensity at 460 nm of m-NQB and p-NQB provided two sets of linear ranges, 0.5-15 MUM and 20-40 MUM and the limit of cyanide detection of 1.4 MUM. Hence, both sensors in CTAB aqueous micellar system offered a considerably promising cyanide detection with 1000-fold enhancement of the detection limit compared to those studied in DMSO: H(2)O. The proposed sensors could also be used to determine cyanide in water with good analytical characteristics. PMID- 21246269 TI - Interaction of serine proteases from polymorphonuclear leucocytes with the cell surface and heparin. AB - Polymorphonuclear leucocytes (PMNs) accumulate at inflammatory sites and contribute to host defence, regulation of the inflammatory process, and also to tissue injury. Upon activation, these cells release the serine proteases elastase, cathepsin G, and proteinase 3 that are involved in multiple processes such as microbicidal activity, penetration of PMNs through endothelium and adjacent connective tissue to inflammatory sites, and processing of various cytokines. Here, we compared the three serine proteases for their release from PMNs and their ability to interact with resting PMNs and the highly sulphated glycosaminoglycan heparin. Unlike elastase, proteinase 3 and cathepsin G were released from resting PMNs as evidenced by flow cytometry, confocal fluorescence microscopy, and activity measurements. While proteinase 3 binds heavily to surface targets on vital PMNs, cathepsin G and elastase interact preferentially with sulphated glycosaminoglycans. These data revealed a differentiated picture about the individual functions of the PMN serine proteases during inflammatory response. PMID- 21246270 TI - Phylogenetic analysis of NS5B gene of classical swine fever virus isolates indicates plausible Chinese origin of Indian subgroup 2.2 viruses. AB - Twenty-three CSFV isolates recovered from field outbreaks in various parts of India during 2006-2009 were used for genetic analysis in the NS5B region (409 nts). Seventeen of these were studied earlier [16] in the 5'UTR region. Phylogenetic analysis indicated the continued dominance of subgroup 1.1 strains in the country. Detailed analysis of a subgroup 2.2 virus indicated the plausible Chinese origin of this subgroup in India and provided indirect evidence of routes of CSFV movement within South East Asia region. PMID- 21246272 TI - Connecting youth violence prevention, positive youth development, and community mobilization. AB - Several disconnects serve to weaken the use of evidence based programming in community settings. Communities face the need to address the challenges of multiple risk behaviors faced by adolescents in their communities, but must also work to support successful transitions to adulthood and the broader positive development of their youth. The stronger integration of positive youth development and prevention of youth risk at the community level may offer an opportunity to support the implementation and ongoing development of evidence based practices (EBPs). This article provides an overview of the VCU Clark-Hill Institute for Positive Youth Development Institute's community mobilization effort in Richmond, Virginia and reports preliminary findings from our integrated mobilization efforts. First, we review the role of our Community Advisory Council in their collaborative work to support positive youth development and reduce risk for youth violence. Next, we present examples of institute efforts in providing technical assistance relevant to supporting the use and development of EBPs. We then discuss the adaptation of an evidence-based program to target positive youth development. We also present overviews from qualitative investigations examining barriers and supports that inform and are relevant to the implementation of EBPs. Finally, we consider ways in which community efforts inform and shape institute efforts to develop EPBs. Taken together, these activities provide examples of how community-based mobilization efforts can integrate and inform the implementation of EBPs and the role and use of prevention science as a tool in supporting effective programming to promote positive youth development and prevent youth violence. PMID- 21246271 TI - Characterization of satellite CentC repeats from heterochromatic regions on the long arm of maize B-chromosome. AB - The B-chromosome of maize contains an A-chromosome centromere-specific satellite CentC repeat in its centromere region (CENB) and at multiple locations in its distal heterochromatic regions (BDHs). Because CentC is highly repetitive, it is a challenge to study CentC sequences within individual centromeres or chromosome regions. The combined structure of CentC and a BDH-specific CL-repeat has allowed us to isolate CentC sequences from BDHs. In the study described herein, we have used a PCR method to amplify 13 CL-CentC variant products that were specifically mapped to A-centromeres (CENAs), the CENB, and BDHs via the tertiary trisomes and hypoploids of five B-10L translocations. Cloning and sequence analyses of these CL-CentC products have revealed a local CentC homogenization within the three CentC-containing regions. Phylogenetic analysis has indicated that the CentC sequences of BDHs are more closely related to those of CENAs in comparison to that of the CENB. Furthermore, the CentC monomers that are within the CENB are more diverse than those within BDHs and CENAs. These results shed light on the evolution of CentC repeats on the B-chromosome and provide a better understanding of B-chromosome evolution. PMID- 21246273 TI - Subjective distress associated with sudden loss in clients with severe mental illness. AB - Data from interviews with 276 community mental health clients diagnosed with a severe mental illness were used to examine the association between clients' subjective distress from sudden loss of a close friend or loved one and PTSD symptoms. Over three-quarters of these clients reported sudden losses in their lives, and regression analysis showed that distress related to sudden losses accounted for significant and unique variance in PTSD symptoms when all other sources of traumatic distress were controlled. Practitioners should routinely assess interpersonal losses among clients with SMI and offer brief interventions specifically aimed at helping clients cope with such losses. PMID- 21246274 TI - Supported housing and supported independent living in the Netherlands, with a comparison with England. AB - Research into community housing programs for people with severe mental illness is underexposed. The Dutch UTOPIA study describes characteristics of their service users, which may predict their allocation to either supported housing or supported independent living programs. Additionally, a comparison is made with English studies. 119 Care coordinators of Dutch residential care institutes and 534 service users participated in a cross-sectional survey which includes socio demographic data, clinical data, measures of functioning, needs for care and quality of life. Differences between Dutch residents and independent living service users were small, making predictions of care allocation difficult. This similarity suggests a possible lack of methodical assessment in the allocation procedure of people who are eligible for residential housing or independent living programs. This is largely comparable to the English situation. In comparison with their English counterparts, Dutch service users have more met needs and are more engaged in occupational activities. PMID- 21246275 TI - Psychosocial risk factors for inconsistent condom use in young people with first episode psychosis. AB - There is evidence of high rates of unprotected sex among young people with first episode psychosis compared to their peers. Little research has explored factors associated with condom use in this population. The current study examined the association between previously identified psychosocial risk factors and condom use in young people with early psychosis and their peers. Sixty-seven sexually active young people with first episode psychosis and 48 sexually active control participants matched on a number of sociodemographic factors completed a self report survey. Increased probability of inconsistent condom use was associated with clinical status, younger age, unemployment, and the absence of peer support for condom use. Psychological distress, self-esteem, social support, substance use, and impulsivity were not associated with condom use. The results suggest that sexual risk-reduction interventions for young people with psychosis should target peer norms, particularly among those who are younger and unemployed. PMID- 21246276 TI - Isolated aspartate aminotransferase elevation: think macro-AST. PMID- 21246277 TI - God give me strength: exploring prayer as self-disclosure. AB - The current project was designed to examine the contention that written prayers about difficult life events function as self-disclosure to God and are structurally and effectively the same as other forms of written self-disclosure, at least in the short term. Over four writing sessions, 155 participants either wrote about mundane experiences (the control group) or wrote narratives about traumatic or stressful life events that were targeted at no one, targeted at a person of their choice, or construed as prayers to God. The results indicate that written prayers are lexically similar to the other two types of written narratives and distinct from the control group. Furthermore, the immediate effects of trauma writing on mood and physical well-being were similar as well. These findings have potentially important implications for understanding the relationship between personal prayer and a variety of health outcomes. PMID- 21246278 TI - Where can I find consolation? A theoretical analysis of the meaning of consolation as experienced by job in the Book of Job in the Hebrew Bible. AB - The aim of the study was to explore the meaning of consolation as experienced by Job in the Book of Job and as presented in literature and how consolation relates to suffering and care. The study's theoretical design applied Ricoeur's view on phenomenology and hermeneutics. The resulting themes were as follows: consolation that is present, that originates in confrontation, that keeps suffering at a distance, that does not alleviate suffering, that originates in experience from giving comfort, and that facilitates a change of perspective. The authentic and caring consolation accepts the sufferer's incomprehensible "otherness" but however provides no answers about how to console. PMID- 21246279 TI - Measuring religiosity/spirituality in diverse religious groups: a consideration of methods. AB - Minority religious groups continue to grow in the United States, and traditional religious groups are becoming more diverse. The purpose of this paper is to detail the methodology of the measure adaptation and psychometric phase of an ongoing study that is designed to describe the relationship between R/S, emotional extremes, and risk behaviors in Christian, Jewish, and Muslim high school students as they transition to college. Unique challenges associated with measurement, recruitment, and research team dynamics were encountered. These challenges and possible solutions are discussed in the context of conducting research that focuses on religious minority groups. PMID- 21246280 TI - Spirituality and confidence to resist substance use among celebrate recovery participants. AB - Since self-efficacy is a positive predictor of substance use treatment outcome, we investigated whether it is associated with spirituality within a religious 12 step program. This was a cross-sectional survey (N = 91) of 10 different Celebrate Recovery sites held at community churches. The mean spirituality score for those with high confidence was significantly greater than those with low confidence. Spirituality associated with greater confidence to resist substance use (OR = 1.09, 95% CI 1.02-1.17, P < 0.05). So every unit increase of measured spirituality increased the odds of being above the median in self-efficacy by 9%. We conclude that spirituality may be an important explanatory variable in outcomes of a faith-based 12-step recovery program. PMID- 21246281 TI - The role of patient religiosity in the evaluation and treatment outcomes for chronic HCV infection. AB - To determine the influence of patient religiosity on the outcome of treatment of hepatitis C infection, a prospective, blinded, cohort study was performed on hepatitis C-infected patients categorized as 'higher religiosity' and 'lower religiosity' based on responses to a religiosity questionnaire. Comparisons were made between high and low religiosity patients on demographics, pre-treatment laboratory values, and response to treatment. Eighty-seven patients with complete questionnaires were placed in either higher (38) or lower (49) religiosity cohort. The patients (60% female) were ethnically diverse: African-American 39%; Hispanic 31%; white 29%. African-American race (P = 0.001) and female gender (P = 0.026) were associated with higher religiosity. The frequency of being offered treatment, accepting treatment, and completing treatment was similar in both religiosity cohorts (P = 0.234, 0.809, 0.367). Fifty-six patients completed the 24- or 48-week treatment with peginterferon and ribavirin. Depression was more frequent in the low religiosity group (38.2% vs. 4.6%, P = 0.005). Sustained viral response rate at 3-6-month post-therapy was similar in the higher (50%) and lower (57.6%) religiosity cohorts (P = 0.580; n = 55). Logistic regression modeling revealed that males having higher religiosity gave greater odds of SVR than those with lower religiosity (OR 21.3; 95% CI 1.1-403.9). The level of religiosity did not affect the decision to begin treatment for chronic HCV infection and was not associated with a better treatment outcome. A higher level of religiosity was associated with less depression among patients. PMID- 21246283 TI - God stammers with longing, then shows sacrificial love. PMID- 21246282 TI - Assessing the role of spirituality in coping among African Americans diagnosed with cancer. AB - Spirituality plays an important role in cancer coping among African Americans. The purpose of this study was to report on the initial psychometric properties of instruments specific to the cancer context, assessing the role of spirituality in coping. Items were developed based on a theoretical model of spirituality and qualitative patient interviews. The instruments reflected connections to self, others, God, and the world. One hundred African American cancer survivors completed the instruments by telephone. The instruments showed adequate internal reliability, mixed convergent validity, discriminant validity, and interpretable factor structures. PMID- 21246284 TI - Richard Pryor: melancholy and the religion of tragicomedy. AB - Drawing on Donald Capps' discussion in Men and Their Religion (2000) on the development of the melancholy self in early childhood and the emergence of three religious impulses as a consequence of its development (the religions of honor, hope, and humor), this article focuses on the early childhood experience of Richard Pryor and the role that the religion of humor plays in helping him cope with these experiences. Particular attention is given to his grandmother's paradoxical role in his life and his identification of her as his spiritual mother. PMID- 21246285 TI - Molecular cloning and expression analysis of signal transducer and activator of transcription (STAT) from the Chinese white shrimp Fenneropenaeus chinensis. AB - Innate immunity is the first line of defense by a host against invading pathogens. Several signaling pathways participate in the immune response, one of which is the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. Various evidences have been provided to suggest that the JAK/STAT pathway is involved in both antibacterial and antiviral immunities. In this study, the full-length cDNA and gene sequence of STAT (designated as FcSTAT) was cloned from the Chinese white shrimp, Fenneropenaeus chinensis. Phylogenetic analysis reveals that the FcSTAT is clustered with STAT5s and STAT6s from vertebrates and STATs from invertebrates. Quantitative real-time PCR exhibited that the FcSTAT had a wide distribution in all detected tissues and developmental stages. Time course analysis of the transcription level after WSSV challenge showed a noticeably early up-regulation of FcSTAT in hemocytes, hepatopancreas, and intestines. The expression levels of FcSTAT increased corresponding to Vibrio anguillarum stimulation in both hemocytes and hepatopancreas as well. All these imply that the JAK/STAT pathway participates in the immune response against bacteria and virus in F. chinensis. PMID- 21246287 TI - Developmental expression changes of the genes involved in IGFI signaling pathway in longissimus dorsi muscle of Tongcheng and Yorkshire pigs during postnatal growth. AB - IGFI signaling pathway is sufficient to regulate myofibre hypertrophy postnatally, which is associated with muscle mass in economically livestock. In the present study, we drafted the developmental expression pattern of eight genes implicated in IGFI system across six stages of postnatal myofibre growth in Yorkshire and Tongcheng pigs. The results indicated that GRB2 may contribute to increased DNA content in postnatal myofibre hypertrophy via GRB2-Ras-Raf-MEK-ERK sub-pathway; INSR, PDK1, IRS1 and eIF4E may contribute to high growth rate via stimulating the rate of protein synthesis and inhibiting the rate of protein degradation. In addition, the results suggested 60 days maybe a very important stage in postnatal myofibre growth. Moreover, higher mRNA level of IRS1 and GLUT4 maybe associated with inferior meat quality in Yorkshire compared to Tongcheng pig. Therefore, IGFI signaling pathway regulates myofibre hypertrophy postnatally via complicated signal effectors, which may have negative impact on meat quality simultaneously. PMID- 21246286 TI - Analysis of gene expression by ESTs from suppression subtractive hybridization library in Chenopodium album L. under salt stress. AB - To identify genes expression in Chenopodium album exposed to NaCl stress and screen ESTs related to salt stress, a subtractive suppression hybridization (SSH) library of C. album under salt stress was constructed in the present study. Random EST sequencing produced 825 high-quality ESTs with GenBank ID GE746311 GE747007, which had 301 bp of average size and were clustered into 88 contigs and 550 singletons. They were classified into 12 categories according to their function annotations. 635 ESTs (76.97%) showed similarities to gene sequences in the non-redundancy database, while 190 ESTs (23.03%) showed low or no similarities. The transcriptional profiles of 56 ESTs randomly selected from 347 unknown or novel ESTs of SSH library under varying NaCl concentration and at different time points were analyzed. The results indicated that a high proportion of tested ESTs were activated by salt stress. Four in 56 ESTs responded to NaCl were also enhanced in expression level when exposed to ABA and PEG stresses. The above four ESTs were validated by northern blotting which was consistent with the results of RT-PCR. The results suggested that genes corresponded to these ESTs might be involved in stress response or regulation. The complete sequences and detailed function of these ESTs need to be further studied. PMID- 21246288 TI - Reply to letter of Peter Good. PMID- 21246289 TI - Using structural equation modeling to detect response shift in performance and health-related quality of life scores of multiple sclerosis patients. AB - PURPOSE: To illustrate how structural equation modeling (SEM) can be used for response shift detection with random measurement occasions and health state operationalized as fixed group membership (Study 1) or with fixed measurement occasions and health state operationalized as time-varying covariates (Study 2). METHODS: In Study 1, we explored seven items of the Performance Scales measuring physical and mental aspects of perceived disability of 771 stable, 629 progressive, and 1,552 relapsing MS patients. Time lags between the three measurements varied and were accounted for by introducing time since diagnosis as an exogenous variable. In Study 2, we considered the SF-12 scales measuring physical and mental components of HRQoL of 1,767 patients. Health state was accounted for by exogenous variables relapse (yes/no) and symptoms (worse/same/better). RESULTS: In Study 1, progressive and relapsing patients reported greater disability than stable patients but little longitudinal change. Some response shift was found with stable and relapsing patients. In Study 2, relapse and symptoms were associated with HRQoL, but no change and only little response shift was found. CONCLUSIONS: While small response shifts were found, they had little impact on the evaluation of true change in performance and HRQoL. PMID- 21246291 TI - Cardiac allografts: a 24-year South African experience. AB - The history of using homologous cardiac valves dates back more than 30 years. Through the years emphasis was placed on the optimization of graft retrieval, preservation techniques and clinical application. A cardiac homograft valve bank was established at the Department of Cardiothoracic Surgery, University of the Free State, Bloemfontein in 1982. A retrospective analysis was performed on all allograft data since 1984. Since the first valve was successfully procured and transplanted in 1984, 2,540 aortic and pulmonary homografts were harvested from 1,792 donors, of which 1,545 [989 (64%) aortic and 556 (36%) pulmonary] were released for clinical use. Valves were discarded for various reasons, the main reasons being Human Immunodeficiency Virus (32.4%), Hepatitis B (9.6%) and venereal diseases (8.9%). The mean donor age was 26.98 years with a male predominance of 1,368 males versus 424 females. The average ischemic time was 33 h mainly due to medico-legal autopsies exceeding the desired 24 h time limit. The valves were disinfected in an antibiotic cocktail of Mefoxin, Piperacillin, Amikacin and Amphotericin B prior to cryopreservation. The surgical procedures utilizing the majority of homografts were aortic valve replacements (42.9%), aortic root replacements (19.3%) and right ventricular-pulmonary artery conduits (33.3%). The bank also supplied 23 other centers with homografts (402 aortic and 301 pulmonary). The Bloemfontein bank has established itself over the years as a viable and functional cardiac homograft bank. However, with increasing activity in the procurement arena and widened applications in the operating room the role of the homograft seems assured but availability still remains a major concern. PMID- 21246290 TI - Fatigue in children: reliability and validity of the Dutch PedsQLTM Multidimensional Fatigue Scale. AB - PURPOSE: The aim of the study is to report on the feasibility, reliability, validity, and the norm-references of the Dutch version of the PedsQLTM Multidimensional Fatigue Scale. METHODS: The study participants are four hundred and ninety-seven parents of children aged 2-18 years and 366 children aged 5-18 years from various day care facilities, elementary schools, and a high school who completed the Dutch version of the PedsQLTM Multidimensional Fatigue Scale. RESULTS: The number of missing items was minimal. All scales showed satisfactory internal consistency reliability, with Cronbach's coefficient alpha exceeding 0.70. Test-retest reliability was good to excellent (ICCs 0.68-0.84) and inter observer reliability varied from moderate to excellent (ICCs 0.56-0.93) for total scores. Parent/child concordance for total scores was poor to good (ICCs 0.25 0.68). The PedsQLTM Multidimensional Fatigue Scale was able to distinguish between healthy children and children with an impaired health condition. CONCLUSIONS: The Dutch version of the PedsQLTM Multidimensional Fatigue Scale demonstrates an adequate feasibility, reliability, and validity in another sociocultural context. With the obtained norm-references, it can be utilized as a tool in the evaluation of fatigue in healthy and chronically ill children aged 2 18 years. PMID- 21246292 TI - A clinical perspective on genetic counseling and testing during end of life care for women with recurrent progressive ovarian cancer: opportunities and challenges. AB - 10-15% of invasive epithelial ovarian cancer is attributable to hereditary breast and ovarian cancer. The identification of BRCA1/BRCA2 mutations in women with ovarian cancer allows for accurate predictive genetic testing of their at-risk relatives, who can then avail themselves of early detection and risk reduction strategies. In the case of women with recurrent progressive ovarian cancer, the window of opportunity for genetic testing can be particularly limited. Here we describe our perspective on providing genetic counseling during these patients' end of life care, incorporating two illustrative examples from our clinical practice. While these situations pose unique challenges, they also present a significant opportunity to benefit the patient and her family. Further attention and research should be directed towards provision of genetic counseling and testing during end of life care. PMID- 21246293 TI - Labeling of Luciferase/eGFP-expressing bone marrow-derived stromal cells with fluorescent micron-sized iron oxide particles improves quantitative and qualitative multimodal imaging of cellular grafts in vivo. AB - PURPOSE: Development of multimodal imaging strategies is currently of utmost importance for the validation of preclinical stem cell therapy studies. PROCEDURES: We performed a combined labeling strategy for bone marrow-derived stromal cells (BMSC) based on genetic modification with the reporter genes Luciferase and eGFP (BMSC-Luc/eGFP) and physical labeling with blue fluorescent micron-sized iron oxide particles (MPIO) in order to unambiguously identify BMSC localization, survival, and differentiation following engraftment in the central nervous system of mice by in vivo bioluminescence (BLI) and magnetic resonance imaging and postmortem histological analysis. RESULTS: Using this combination, a significant increase of in vivo BLI signal was observed for MPIO-labeled BMSC Luc/eGFP. Moreover, MPIO labeling of BMSC-Luc/eGFP allows for the improved identification of implanted cells within host tissue during histological observation. CONCLUSIONS: This study describes an optimized labeling strategy for multimodal stem cell imaging resulting in improved quantitative and qualitative detection of cellular grafts. PMID- 21246297 TI - Isotopes for improved management of nitrate pollution in aqueous resources: review of surface water field studies. AB - BACKGROUND: Environmental agencies have to take measures to either reduce discharges and emissions of nitrate or to remediate nitrate-polluted water bodies where the nitrate concentrations exceed threshold values. Isotope data can support the identification of nitrate pollution sources and natural attenuation processes of nitrate. REVIEW: This review article gives an overview of the information available to date regarding nitrate source apportionment in surface waters with the ambition to help improving future studies. Different isotope approaches in combination with physicochemical and hydrological data can successfully be used in source apportionment studies. A sampling strategy needs to be developed based on possible nitrate sources, hydrology and land use. Transformations, transport and mixing processes should also be considered as they can change the isotope composition of the original nitrate source. CONCLUSION: Nitrate isotope data interpreted in combination with hydrological and chemical data provide valuable information on the nitrate pollution sources and on the processes nitrate has undergone during its retention and transport in the watershed. This information is useful for the development of an appropriate water management policy. PMID- 21246298 TI - Methyl galbanate, a novel inhibitor of nitric oxide production in mouse macrophage RAW264.7 cells. AB - It is well known that inflammation is associated with various neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. An inflammatory mediator, nitric oxide (NO), is produced by inducible NO synthase (iNOS) in microglia and seems to be one of the possible causes of neurodegeneration. Several natural and synthetic compounds which exert anti-inflammatory effects by inhibiting NO production have been reported to date. The aim of this work was to investigate whether any of the 6 terpenoid coumarins (methyl galbanate, galbanic acid, farnesiferol A, badrakemone, umbelliprenin, and aurapten) isolated from Ferula szowitsiana DC. have inhibitory activity against NO production in RAW264.7 mouse macrophage cells stimulated with lipopolysaccharide (LPS) and interferon gamma (IFN-gamma). Of the 6 terpenoid coumarins tested, methyl galbanate significantly decreased NO production in LPS/IFN-gamma-stimulated RAW264.7 cells. In the presence of methyl galbanate, LPS/IFN-gamma-induced iNOS mRNA expression was significantly decreased to 52% of the level found with LPS/IFN-gamma stimulation alone. Methyl galbanate slightly attenuated COX-2 mRNA expression. Using the RAW264.7-tsAM5NE co-culture system, we showed that methyl galbanate protected neuronally differentiated tsAM5NE cells from NO-induced cell death by inhibiting the production of NO. Our finding suggests that methyl galbanate may be useful for developing a new drug against neurodegenerative diseases. PMID- 21246299 TI - Risk factors for nonfatal overdose at Seattle-area syringe exchanges. AB - Opioid-involved overdose deaths are on the rise, both nationwide and in the state of Washington. In a survey of 443 participants at syringe exchanges in Seattle, Washington, 16% had overdosed in the last year. Several factors were significantly associated in bivariate analysis: lack of permanent housing; incarceration of five or more days in the past year; gender of sex partners; sharing of syringes and other injection paraphernalia; use of speedballs (cocaine and heroin together), goofballs (methamphetamine and heroin together), buprenorphine; injection use of crack cocaine and sedatives; and use of opioids with sedatives. Adjusting for other variables in multivariate logistic regression analyses, only recent incarceration and sharing of injection materials were still significantly associated with overdose. Correctional facilities, syringe exchange programs, and other agencies serving opioid injectors should include overdose prevention components in release planning and services. PMID- 21246300 TI - Targeting social and economic correlates of cancer treatment appointment keeping among immigrant Chinese patients. AB - Chinese immigrants have high rates of a variety of cancers and face numerous social and economic barriers to cancer treatment appointment keeping. This study is a nested cohort of 82 Chinese patients participating in the Immigrant Cancer Portal Project. Twenty-two percent reported having missed appointments for oncology follow-up, radiation therapy, and/or chemotherapy. Patients most commonly reported needing assistance with financial support to enable appointment keeping. Efforts to further address social and economic correlates in cancer care should be developed for this population. PMID- 21246301 TI - A qualitative view of drug use behaviors of Mexican male injection drug users deported from the United States. AB - Deportees are a hidden yet highly vulnerable and numerous population. Significantly, little data exists about the substance use and deportation experiences of Mexicans deported from the United States. This pilot qualitative study describes illicit drug use behaviors among 24 Mexico-born male injection drug users (IDUs), >= 18 years old, residing in Tijuana, Mexico who self identified as deportees from the United States. In-person interviews were conducted in Tijuana, Mexico in 2008. Content analysis of interview transcripts identified major themes in participants' experiences. Few participants had personal or family exposures to illicit drugs prior to their first U.S. migration. Participants reported numerous deportations. Social (i.e., friends/family, post-migration stressors) and environmental factors (e.g., drug availability) were perceived to contribute to substance use initiation in the U.S. Drugs consumed in the United States included marijuana, heroin, cocaine, methamphetamine, and crack. More than half of men were IDUs prior to deportation. Addiction and justice system experiences reportedly contributed to deportation. After deportation, several men injected new drugs, primarily heroin or methamphetamine, or a combination of both drugs. Many men perceived an increase in their substance use after deportation and reported shame and loss of familial social and economic support. Early intervention is needed to stem illicit drug use in Mexican migrant youths. Binational cooperation around migrant health issues is warranted. Migrant-oriented programs may expand components that address mental health and drug use behaviors in an effort to reduce transmission of blood borne infections. Special considerations are merited for substance users in correctional systems in the United States and Mexico, as well as substance users in United States immigration detention centers. The health status and health behaviors of deportees are likely to impact receiving Mexican communities. Programs that address health, social, and economic issues may aid deportees in resettling in Mexico. PMID- 21246302 TI - Virtual reality laparoscopy: which potential trainee starts with a higher proficiency level? AB - PURPOSE: Minimally invasive surgery requires technical skills distinct from those used in conventional surgery. The aim of this prospective study was to identify personal characteristics that may predict the attainable proficiency level of first-time virtual reality laparoscopy (VRL) trainees. METHODS: Two hundred and seventy-nine consecutive undergraduate medical students without experience attended a standardized VRL training. Performance data of an abstract and a procedural task were correlated with possible predictive factors providing potential competence in VRL. RESULTS: Median global score requirement status was 86.7% (interquartile range (IQR) 75-93) for the abstract task and 74.4% (IQR 67 88) for the procedural task. Unadjusted analysis showed significant increase in the global score in both tasks for trainees who had a gaming console at home and frequently used it as well as for trainees who felt self-confident to assist in a laparoscopic operation. Multiple logistic regression analysis identified frequency of video gaming (often/frequently vs. rarely/not at all, odds ratio: abstract model 2.1 (95% confidence interval 1.2; 3.6), P = 0.009; virtual reality operation procedure 2.4 (95% confidence interval 1.3; 4.2), P = 0.003) as a predictive factor for VRL performance. CONCLUSION: Frequency of video gaming is associated with quality of first-time VRL performance. Video game experience may be used as trainee selection criteria for tailored concepts of VRL training programs. PMID- 21246303 TI - Professionally responsible malpractice reform. AB - Medical malpractice reform is both necessary and desirable, yet certain types of reform are clearly preferable to others. We argue that "traditional" tort reform remedies such as stringent damage caps not only fail to address the root causes of negligence and the adverse effects that fear of suit can have on physicians, but also fail to address the needs of patients. Physicians ought to view themselves as professionals who are dedicated to putting patients' interests ahead of their own. Professionally responsible malpractice reform should therefore be at least as patient-centered as it is physician-centered. Examples of more professionally responsible malpractice reform exist where institutions take a pro-active approach to identification, investigation, and remediation of possible malpractice. Such programs should be implemented more generally, and state laws enacted to facilitate them. PMID- 21246304 TI - Treatment considerations for recurrent MRSA bacteremia leading to cholecystitis. AB - We present an end-stage renal disease patient with acute cholecystitis caused by a recurrence of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Timely antibiotic therapy with vancomycin did not eradicate the patient's infection. In this patient, the minimum inhibitory concentration (MIC) of the organism for vancomycin was at the upper limit of susceptibility. The ability to thoroughly understand and interpret mean inhibitory concentrations is crucial in antibiotic selection. For high-risk patients with Staphylococcus aureus infection with reduced susceptibility to vancomycin as demonstrated by an MIC of 2 mg/L or greater, we suggest further investigation into linezolid as an alternative antibiotic to vancomycin therapy. Compared to vancomycin, linezolid has similar effectiveness in patients with MRSA bacteremia as well as improved penetration, particularly in bile. PMID- 21246305 TI - One final sip. PMID- 21246306 TI - Therapeutic hypothermia for adult viral meningoencephalitis. AB - BACKGROUND: Despite the advances in critical care, severe viral meningoencephalitis continues to impose high rates of morbidity and mortality. Consequently, new treatment strategies are needed and we present therapeutic hypothermia (TH) as one of the possible efficacious treatment tools. METHODS: We present the case series in an adult intensive care unit of a tertiary care hospital. Eleven patients suffering from severe viral meningoencephalitis were treated with hypothermia. The major indication for TH was severely impaired consciousness associated with carbon dioxide reactivity loss assessed by Transcranial Doppler. Besides from the established treatment, all the patients underwent TH. Mild hypothermia (rectal temperature of 32-34 degrees C) was maintained with continuous veno-venous hemofiltration. RESULTS: Median Glasgow coma scale score in our patients at admission was 8 (3-10) and median Acute Physiology and Chronic Health Evaluation score was 24 (12-32). The overall mortality rate was 9% (1/11). Among survivors, the outcome was favorable in five patients [Glasgow Outcome Scale score (GOS) 4-5]. Remaining five patients had severe residual neurological deficit (GOS 3). Median GCS at discharge was 15 (8 15). With respect to disease severity, the outcome in presented patients was generally satisfactory. CONCLUSIONS: Our results suggest that use of mild hypothermia in selected adult patients with viral meningoencephalitis could be a promising treatment tool. PMID- 21246307 TI - Clinical diagnosis and successful treatment of inflammatory cerebral amyloid angiopathy. AB - INTRODUCTION: Cerebral amyloid angiopathy is a major cause of lobar hemorrhage in older adults, and of microvascular ischemic disease. The rarest form of this disease is an inflammatory form causing seizures. It is important to recognize because the patients usually respond to a brief course of immunosuppression. METHODS: Case report. RESULTS: A 66-year-old man developed gradual cognitive decline, insidiously increasing headaches, and then had a likely seizure. MRI showed diffuse white matter edema, and innumerable superficial microhemorrhages characteristic of amyloid angiopathy. He was empirically treated with oral prednisone and an anticonvulsant. His symptoms improved and the white matter edema resolved over several months. ApoE genotype was 4/4, which is commonly found in inflammatory amyloid angiopathy. CONCLUSIONS: Inflammatory cerebral amyloid angiopathy can be clinically diagnosed and treated without brain biopsy. Clinical diagnosis is important because of the good response to a brief course of steroids in most cases. PMID- 21246309 TI - mRNA quantification after fluorescence activated cell sorting using locked nucleic acid probes. AB - Recently, we have established an in-tube in situ hybridization method named mRNA quantification after fluorescence activated cell sorting (FACS-mQ), in which a specific RNA in a particular cell type is stained with a florescent dye, allowing the stained cells to be selected by FACS without suffering excessive RNA degradation. Using this method, the biological characteristics of the sorted cells can be determined by analyzing their gene expression profile. In this study, we used locked nucleic acid (LNA) oligonucleotides, which are known to enhance both the sensitivity and specificity of RNA detection, as hybridization probes in FACS-mQ. When we used a LNA probe targeting the human 28S sequence, we were able to efficiently separate human cells from rat cells. Using LNA probes, the hybridization step was shortened to 1 h. After the hybridization step, 84.6% RNA was preserved; thus, we were able to successfully measure gene expression levels in each type of cell after FACS. Providing the LNA probe efficiently hybridizes with the target sequence, FACS-mQ with an LNA probe is a powerful tool for separating particular cells and determining their biological characteristics by analyzing their gene expression profile. PMID- 21246310 TI - Drug-resistant hypertension: is renal sympathetic denervation the answer? PMID- 21246308 TI - The etiology of paraneoplastic autoimmunity. AB - Although they may sometimes appear similar, paraneoplastic autoimmunity has a unique pathogenesis, different from the classical autoimmune diseases not associated with cancer. When distinguished clinically, paraneoplastic autoimmunity is more severe and often presents with a broader range of clinical signs and symptoms. Management of these patients is difficult and is usually centered in part on treatment of the underlying malignancy. Self-antigens recognized in the setting of paraneoplastic autoimmunity can be diverse, and the number of determinants recognized within a single antigen can be numerous. This review uses prototypic examples of paraneoplastic immune-mediated diseases and their associated malignancies to describe the mechanisms by which immune dysregulation can occur in the setting of cancer. Specific diseases covered include paraneoplastic pemphigus, Sweet's syndrome, pyoderma gangrenosum, thymoma associated multiorgan autoimmunity, myasthenia gravis, autoimmune hemolytic anemia, immune thrombocytopenia, and the paraneoplastic neurological syndromes. The malignancies discussed include thymoma, non-Hodgkin's lymphoma, and chronic lymphocytic leukemia, among others. The mechanisms by which cancers induce autoimmunity are broken down into the following categories: disruption of central tolerance, peripheral immune dysregulation, and alteration of self-antigens. For each category, examples of paraneoplastic autoimmune diseases and their associated malignancies are discussed. Finally, mechanisms by which cancer treatment can lead to autoimmunity and examples of polymorphisms that are linked to both cancer and autoimmunity are discussed. PMID- 21246312 TI - Editorial: myelomeningocele. PMID- 21246311 TI - Targeted IV busulfan and fludarabine followed by post-allogeneic hematopoietic cell transplantation rituximab demonstrate encouraging activity in CD20+ lymphoid malignancies without increased risk of infectious complications. AB - We examined pharmacokinetic-targeted IV busulfan (75-170 mg/m(2), with target AUC of 3500-6000 MUmol min) and fludarabine (40 mg/m(2)) * 4 days with rituximab (t IV Bu/Flu + rituximab) 375 mg/m(2) on days +1 and +8 followed by allogeneic hematopoietic cell transplantation in 19 patients (median age 56, range 35-68 years) with CD20+ lymphoid malignancies. Median time to neutrophil and platelet engraftment was 15 and 12 days. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 58% (95% confidence interval, CI 39-85%), and chronic GVHD was 50% (95% CI 28-88%). With a median follow up of 7 (range 1 31) months, overall response was observed in 15, and stable or progressive disease in 4. Overall survival at 1 year was 67%. Engraftment, chimerism, and infectious complications did not differ significantly from a contemporaneous non rituximab containing comparator group. The addition of rituximab 375 mg/m(2) to t IV Bu/Flu does not appear to adversely affect engraftment, donor chimerism, or increase the risk of infectious complications. PMID- 21246313 TI - Rationale for and methods of superiority, noninferiority, or equivalence designs in orthopaedic, controlled trials. AB - BACKGROUND: To provide value-based healthcare in orthopaedics, controlled trials are needed to assess the comparative effectiveness of treatments. Typically comparative trials are based on superiority testing using statistical tests that produce a p value. However, as orthopaedic treatments continue to improve, superiority becomes more difficult to show and, perhaps, less important as margins of improvement shrink to clinically irrelevant levels. Alternative methods to compare groups in controlled trials are noninferiority and equivalence. It is important to equip the reader of the orthopaedic literature with the knowledge to understand and critically evaluate the methods and findings of trials attempting to establish superiority, noninferiority, and equivalence. QUESTIONS/PURPOSES: I will discuss supplemental and alternative methods to superiority for assessment of the outcome of controlled trials in the context of diminishing returns on new therapies over old ones. METHODS: The three methods superiority, noninferiority, and equivalence-are presented and compared, with a discussion of implied pitfalls and problems. RESULTS: Noninferiority and equivalence offer alternatives to superiority testing and allow one to judge whether a new treatment is no worse (within a margin) or substantively the same as an active control. Noninferiority testing also allows for inclusion of superiority testing in the same study without the need for adjustment of the statistical methods. CONCLUSIONS: Noninferiority and equivalence testing might prove most valuable in orthopaedic, controlled trials as they allow for comparative assessment of treatments with similar primary end points but potentially important differences in secondary outcomes, safety profiles, and cost-effectiveness. PMID- 21246314 TI - The in vitro elution characteristics of vancomycin from tendons. AB - BACKGROUND: Infection after ACL reconstruction is uncommon but catastrophic. Prophylactic graft saturation in vancomycin reportedly reduces infection rates. QUESTIONS/PURPOSES: We characterized vancomycin elution from soaked tendons. Specifically, the effect of rinsing was studied. We also determined how vancomycin concentration in the soak solution and tendon dimension influenced this elution rate, and examined whether the vancomycin amount released was lower than osteoblast and chondroblast toxic concentrations. METHODS: Bovine tendons were wrapped in sterile gauze swabs presoaked with 5-, 2.5-, or 1.25-mg/mL vancomycin solutions. After 10 minutes, rinsed and unrinsed tendons were placed in 100 mL agitated 37 degrees C phosphate-buffered saline (PBS). One-milliliter samples taken at 10 minutes and 1, 6, 12, 24, and 72 hours were analyzed by high performance liquid chromatography. RESULTS: The maximum elution rate occurred between 10 minutes and 1 hour, with no lag between experiment initiation and drug appearance in the solution. Rinsing affected the initial amount in solution but had little influence on drug release after 10 minutes. Vancomycin diffusion rates were dependent on soak solution concentration at all sampling intervals. The vancomycin amount released or eluted did not increase after the 1-hour interval. At 24 hours, concentrations were 45 +/- 12, 16 +/- 1, and 9 +/- 3 MUg/mL for the 5-, 2.5-, and 1.25-mg/mL solutions, respectively. Higher elution rates were observed in larger-volume tendons. CONCLUSIONS: Soaked tendon grafts can act as reservoirs for vancomycin, with the amount released and elution profile dependent on rinsing, tendon volume, and soak solution concentration. Vancomycin elution was lower than previously reported osteoblast and chondroblast toxicity concentrations and above the minimum inhibitory concentration for Staphylococcus. CLINICAL RELEVANCE: Presoaking ACL reconstruction autografts with vancomycin may reduce the risk of ACL reconstruction infection without the risk of local or general toxicity. PMID- 21246316 TI - Fractal properties of postural sway during quiet stance with changed visual and proprioceptive inputs. AB - We studied the fractal dynamics of postural sway during quiet stance with changed visual and/or proprioceptive information. Radius-vector length and angle of rotation of center of foot pressure (COP) displacements were used as parameters of postural sway. The experiments were performed on 24 healthy volunteers of both sexes aged 20-30 years. Using a battery of nonlinearity tests, differences in the degree of fractality of both parameters during stance were found. We found that the behavior of radius-vector was similar to fractional Brownian motion, while that of angle of rotation was similar to flicker noise. Quantitative parameters that can be used to characterize the changes in radius-vector length and angle of rotation include self-similarity intervals and fractal dimension. In healthy subjects, the process of postural control maintains its fractal structure independently of altered sensory information. We believe that this analysis provides information about new methods for evaluating postural sway behavior during quiet stance. PMID- 21246315 TI - The pharmacokinetic/pharmacodynamic pipeline: translating anticancer drug pharmacology to the clinic. AB - Progress in an understanding of the genetic basis of cancer coupled to molecular pharmacology of potential new anticancer drugs calls for new approaches that are able to address key issues in the drug development process, including pharmacokinetic (PK) and pharmacodynamic (PD) relationships. The incorporation of predictive preclinical PK/PD models into rationally designed early-stage clinical trials offers a promising way to relieve a significant bottleneck in the drug discovery pipeline. The aim of the current review is to discuss some considerations for how quantitative PK and PD analyses for anticancer drugs may be conducted and integrated into a global translational effort, and the importance of examining drug disposition and dynamics in target tissues to support the development of preclinical PK/PD models that can be subsequently extrapolated to predict pharmacologic characteristics in patients. In this article, we describe three different physiologically based (PB) PK modeling approaches, i.e., the whole-body PBPK model, the hybrid PBPK model, and the two pore model for macromolecules, as well as their applications. General conclusions are that greater effort should be made to generate more clinical data that could validate scaled preclinical PB-PK/PD tumor-based models and, thus, stimulate a framework for preclinical to clinical translation. Finally, given the innovative techniques to measure tissue drug concentrations and associated biomarkers of drug responses, development of predictive PK/PD models will become a standard approach for drug discovery and development. PMID- 21246317 TI - Differences of smoking knowledge, attitudes, and behaviors between medical and non-medical students. AB - BACKGROUND: Previous studies in the world reported inconsistent results about the relationship of medical professional education with medical students' smoking behaviors, and no similar research had been published in China. PURPOSE: This paper aims to explore whether the differences of smoking-related knowledge, attitudes, and behaviors existed between medical and non-medical undergraduate students. METHODS: Eight thousand one hundred thirty-eight undergraduate students sampled from a university in Guangzhou were investigated with a self-administered structured questionnaire about their smoking-related knowledge, attitude and behaviors, and other relevant factors. General linear model and multinomial logistic regression were conducted to test the differences in smoking-related knowledge, attitude, and behaviors between medical and non-medical students while controlling for potential confounding variables. RESULTS: There was no difference in smoking-related knowledge scores between medical and non-medical freshmen, but medical sophomores and juniors had higher scores of smoking-related knowledge than their non-medical counterparts. The medical sophomores had higher mean score of attitudes towards smoking than non-medical ones. Before entering university, the difference in the prevalence of experimental and regular smoking between medical and non-medical college students was not significant. After entering university, in contrast, the overall prevalence of regular smoking was significantly higher among male non-medical college students than among male medical students. Stratified by current academic year, this difference was significant only among male sophomores. CONCLUSIONS: Medical students have higher smoking-related knowledge, stronger anti-smoking attitude, and lower prevalence of regular smoking than non-medical college students of similar age, which may be associated with medical professional education. PMID- 21246318 TI - Prolonged methylene blue infusion in refractory septic shock: a case report. AB - PURPOSE: Methylene blue (MB) has been advocated for the treatment of refractory hemodynamic instability in patients with septic shock. However, the use of MB infusions in septic shock is not considered standard treatment, and the available literature describes infusions of short duration, typically less than six hours. CLINICAL FEATURES: We report a case of septic shock in a 67-yr-old male who required maximal vasopressor support with norepinephrine, epinephrine, and vasopressin. Despite standard protocols for the treatment of septic shock, the patient's hemodynamic status was refractory 80 hr post admission. However, initiation of a MB infusion resulted in the rapid restoration of hemodynamic stability and a subsequent decrease in vasopressor requirements. Multiple attempts to discontinue the MB infusion resulted in immediate and repeated increases in vasopressor requirements, necessitating a continuous infusion with a slow taper of MB for 120 hr. Ultimately, the patient survived the illness and was discharged home. We observed no adverse events that could be attributed to the use of MB. CONCLUSION: In our patient, the use of MB resulted in hemodynamic stability unattained with standard vasopressor support. Further research is warranted on the use of MB in patients with septic shock. PMID- 21246319 TI - Changing pattern and pathophysiology of cognitive dysfunction with HIV infection in the era of antiretroviral therapy. PMID- 21246321 TI - [Chronic somatic disorders and psychological comorbidity]. PMID- 21246320 TI - Chemokines in cerebrospinal fluid correlate with cerebral metabolite patterns in HIV-infected individuals. AB - Chemokines influence HIV neuropathogenesis by affecting the HIV life cycle, trafficking of macrophages into the nervous system, glial activation, and neuronal signaling and repair processes; however, knowledge of their relationship to in vivo measures of cerebral injury is limited. The primary objective of this study was to determine the relationship between a panel of chemokines in cerebrospinal fluid (CSF) and cerebral metabolites measured by proton magnetic resonance spectroscopy (MRS) in a cohort of HIV-infected individuals. One hundred seventy-one stored CSF specimens were assayed from HIV-infected individuals who were enrolled in two ACTG studies that evaluated the relationship between neuropsychological performance and cerebral metabolites. Concentrations of six chemokines (fractalkine, IL-8, IP-10, MCP-1, MIP-1beta, and SDF-1) were measured and compared with cerebral metabolites individually and as composite neuronal, basal ganglia, and inflammatory patterns. IP-10 and MCP-1 were the chemokines most strongly associated with individual cerebral metabolites. Specifically, (1) higher IP-10 levels correlated with lower N-acetyl aspartate (NAA)/creatine (Cr) ratios in the frontal white matter and higher MI/Cr ratios in all three brain regions considered and (2) higher MCP-1 levels correlated with lower NAA/Cr ratios in frontal white matter and the parietal cortex. IP-10, MCP-1, and IL-8 had the strongest associations with patterns of cerebral metabolites. In particular, higher levels of IP-10 correlated with lower neuronal pattern scores and higher basal ganglia and inflammatory pattern scores, the same pattern which has been associated with HIV-associated neurocognitive disorders (HAND). Subgroup analysis indicated that the effects of IP-10 and IL-8 were influenced by effective antiretroviral therapy and that memantine treatment may mitigate the neuronal effects of IP-10. This study supports the role of chemokines in HAND and the validity of MRS as an assessment tool. In particular, the findings identify relationships between the immune response-particularly an interferon-inducible chemokine, IP-10-and cerebral metabolites and suggest that antiretroviral therapy and memantine modify the impact of the immune response on neurons. PMID- 21246322 TI - [Chronic diseases. Definition and basic concept]. AB - The baroque deity Chronos symbolizes much of what we intuitively connect with "chronic", but it must not obscure our view of the diversity of chronic diseases. Common to all forms is a prognostic implication: a chronic disease and all associated burden will accompany the patient for the rest of his/her life. Chronic diseases are in general multifocal disorders simultaneously affecting biological, psychic, and social equilibria. This requires systematic problem screening and -assessment, including possible comorbidities. Comorbidity in a strict sense should be distinguished from risk factors, implications, complications, and consequences of the index disorder of interest. The assessment is usually followed by the shared identification of therapeutic goals and indications. In chronic disorders, a wide spectrum of diagnostic and therapeutic approaches, methods, and professions becomes relevant. PMID- 21246323 TI - [Somatic-psychiatric comorbidity. Definition and basic concept]. AB - Patients with a complex history of illness and multiple diseases are increasingly the rule rather than the exception. To describe these patients, the term comorbidity is frequently used. The present overview provides a definition and description of the construct comorbidity. Thereby, the overview focuses on specifics of somatic-psychiatric comorbidities. The description of comorbidity comprises definition of the term against the similar constructs multimorbidity, burden of illness, and patient complexity as well as a subcategorization of types of comorbidity. With regard to measuring comorbidity, possibilities of aggregating comorbidities into a single sum score are presented. Finally, specific aspects of somatic-psychiatric comorbidity are critically discussed. PMID- 21246324 TI - [Comorbid psychological disorders in patients with chronic somatic diseases]. AB - Based on the literature, the assessment of psychological comorbidity in epidemiological studies is reviewed along with prevalence rates of psychological comorbidity and the effect of mental diseases on the development and course of chronic disease as exemplified by coronary heart disease. Psychological comorbidity is associated with reduced quality of life, disease progression, and increased mortality, as numerous studies in coronary heart disease and other chronic diseases have shown. In spite of available valid screening measures which enable large population surveys, diagnostic problems remain, especially with respect to separating mental and somatic symptoms and diagnosing somatic diseases reliably. Psychological comorbidity is frequently overlooked in medical care and poses a high risk for the future somatic and mental course of disease, associated with individual suffering and serious health economic consequences. There is a need for research on suitable interventions for patients with chronic disorders and psychological comorbidity in order to improve their care. PMID- 21246325 TI - [Screening and diagnostic procedures of comorbid mental disorders in somatic illnesses]. AB - Because of the close association between physical diseases and mental disorders, early and precise detection of mental disorders is of high clinical importance in medical care. Specific aspects have to be considered for diagnosis of mental disorders in somatic diseases. Therefore, the important categories of mental disorders related to chronic somatic illnesses are discussed and specified instruments for dimensional (screening tools) and categorical (clinical interview) diagnostic procedures are presented. Furthermore, the article introduces current developments of new instruments from a methodological point of view and, with regard to content, meeting the specific problems of psychiatric diagnosis in somatic illnesses. PMID- 21246326 TI - [Psychological interventions in patients with chronic physical diseases and psychological comorbidity]. AB - The term chronic physical disease summarizes various diseases characterized by a multifactorial genesis, long-term and often progressive course, as well as frequent restricting physical and psychosocial sequelae. Over the last 2 decades, research in medical psychology has demonstrated high prevalence rates of psychological comorbidity among patients with chronic medical conditions, indicating an urgent need for psychosocial treatment. The goal of psychosocial interventions is to reduce adverse disease consequences and improve quality of life. The intervention programs can be differentiated according to target populations, healthcare models, indications, treatment models, and treatment settings. They range from rather general approaches based on broad psychosocial support, health promotion, and patient education programs to problem-specific interventions. Concerning theoretical approaches, cognitive-behavioral interventions currently dominate; however, psychodynamic oriented and mixed approaches are being increasingly implemented. Reviews and meta-analyses of evaluation studies demonstrate the efficacy of these programs. However, there is still a discrepancy between psychotherapeutic options for patients with chronic physical diseases and their practical implementation. PMID- 21246327 TI - [Possibilities and limitations of psychopharmacological treatments in patients with psychological comorbidity]. AB - Comorbid depressive and anxiety disorders are associated with chronic physical illnesses. Treatment with antidepressants and mood stabilizers require knowledge about toxicity, potential side effects, and drug interactions. According to controlled studies in comorbid cardiovascular diseases, diabetes mellitus, and cerebrovascular disorders (post-stroke depression), serotonin-selective reuptake inhibitors (SSRIs), e.g., sertraline and citalopram, are preferred. Pramipexole, reboxetine, mirtazapine, or nortriptyline showed efficacy in treatment of Parkinson depression. Chronic pain syndromes can be improved with low-dose tricyclic antidepressants. Both establishment of compliance and follow-up examinations are essential. Combined treatment with psychotherapeutic interventions, including coping strategies, should be used whenever possible. PMID- 21246328 TI - [Psychological comorbidity in patients with cancer]. AB - In western industrial nations, cancer is one of the most frequent somatic diseases showing increasing incidence rates. Although the options for medical treatment and the survival rates for most cancer diagnoses have improved over the last few decades, cancer is still a life-threatening illness associated with psychosocial issues, suffering, and distress. Depending on the severity and duration of symptoms, psychosocial distress due to cancer ranges from normal reactions to psychological comorbidity based on ICD classification criteria. In cancer patients, the most frequent psychological diagnoses are adjustment disorders, anxiety, and depression; prevalence rates in the literature show high variations depending on the tumor type studied and the assessment instrument used. Today, standardized and validated screening instruments and diagnostic interviews are available for the screening and assessment of psychosocial distress and psychiatric comorbidity. The screening of psychosocial distress in cancer patients and the assessment of psychiatric disorders are important tasks of modern cancer treatment in order to determine the need for psychosocial counseling and psychooncological treatment. PMID- 21246329 TI - [Psychological comorbidity in patients with musculoskeletal diseases]. AB - The present review summarizes the evidence on epidemiology, etiology, and treatment of comorbid mental disorders in patients with musculoskeletal diseases. Epidemiological studies highlight a significantly increased risk of comorbid mental disorders in patients with musculoskeletal diseases compared to patients without musculoskeletal diseases and physically healthy persons. With regard to the question of the causal link between these comorbidities, specific musculoskeletal disease-mental disorder combinations show specific pathogenetic pathways. Using the example of arthritis-depression comorbidity, a causality model is presented. This model describes depression as following arthritis and, in turn, aggravating the course of arthritis. Treatment studies emphasize the effectiveness of both psychotherapeutic and psychopharmacological interventions for the treatment of patients with musculoskeletal diseases and comorbid mental disorders. In particular, collaborative care interventions are promising approaches to improve the routine care of comorbid patients. PMID- 21246330 TI - [Depression. An underestimated risk for the development and progression of coronary heart disease]. AB - The aim of this article is to provide an overview on depression as a risk factor for the onset and follow-up of cardiovascular disease (CVD). In brief, the current state of psychobiological mechanisms bridging the gap between affective states and somatic consequences are presented. Four meta-analyses dealing with depression as a CVD risk factor in apparently healthy populations with >100,000 participants included, extracted an adjusted effect estimator of 1.60-1.90. Depressed subjects present with an unhealthier lifestyle (nutrition, smoking, physical activity). Three major psychobiological pathways directly acting on the circulatory system are under discussion: (1) hyperregulation of the autonomic nervous system (e.g., increased mean heart rate, increased heart rate responses, impaired heart rate variability), (2) overshooting stress responses of the endocrine system with impaired feedback mechanisms (e.g., for cortisol release), and (3) the immune system with dysregulated release of acute phase proteins and proinflammatory cytokines, all involved in a bidirectional crosstalk with the patient's affective state and leading to platelet activation and flow mediated endothelial (dys-)function. Nonadherence and adverse side effects of medications also contribute to the lethal properties of depression in CVD. PMID- 21246331 TI - [Psychological comorbidity in children and adolescents with chronic somatic diseases]. AB - This article analyzes emotional and behavioral problems in children and adolescents with chronic somatic disorders. Within the German Health Interview and Examination Survey for Children and Adolescents (Kinder- und Jugendgesundheitssurvey, KIGGS), chronic somatic conditions and obesity were assessed in 11,529 children and adolescents aged 7-17 years old. Special health care needs (CSHCN), emotional and behavioral problems (SDQ), as well as personal, familial, and social resources were surveyed. About 10.8% of the respondents displayed special health care needs and declared a chronic somatic disorder. Of these cases, 20.6% were classified as abnormal in the SDQ (non-somatic conditions: 6.4%). In a logistic regression analysis, male gender (OR=2.0), low socioeconomic status (Winkler index; OR=2.6), family structure (OR>1), and deficits in familial (OR=2.4) and personal (OR=2.1) resources were found to be significantly associated with psychological comorbidity in chronic somatic conditions. The results confirmed previous findings. Especially socioeconomic, structural, and functional aspects of a family have to be considered in the development and prevention of psychological comorbidity in chronic somatic conditions in childhood and adolescence. PMID- 21246332 TI - [Psychological comorbidity in elderly patients with cancer]. AB - Human life expectancy has increased, nationally and internationally, during recent years and will continue to increase in the future. Old age is commonly associated with health-related impairments, chronic diseases, increasing multimorbidity, as well as with psychosocial burdens, such as social deprivation, reduced social participation, and impairment in activities of daily living. Against this background, studies on mental health addressing psychological distress and mental disorders of older people have gained increasing attention. The aim of the present overview is to provide insight into psychological comorbidity in elderly with chronic illnesses. The following questions are addressed: (1) what are the prevalence rates of mental disorders in the elderly in general and, specifically, in patients with cancer? (2) How are mental disorders and cancer, respectively, diagnosed in elderly patients? (3) What are common risk factors associated with the development of mental disorders? (4) Which treatment options are available, and which aspects of health care for elderly patients with chronic diseases need to be considered? PMID- 21246333 TI - [Psychological comorbidity. A challenge in acute care]. AB - Comorbid mental disorders are common in patients with chronic conditions. It can be assumed that around 30% of all inpatients have some kind of mental disorder. Most frequent are depressive disorders, anxiety disorders, somatoform disorders, and addictive disorders. Mental disorders are not only a subjective burden for the patient, but may also lead to an unfavourable course of the disease, longer hospital stay, and increased treatment costs. However, despite its importance comorbid mental disorders are often not recognized or appropriately treated. Wherever possible, patients with psychological issues should be presented to a psychosomatic or psychiatric consultation-liaison service for further diagnosis and treatment. To treat patients with comorbid mental disorders, physicians must be well experienced in psychotherapeutic treatment and a collaborative interdisciplinary working environment must have been established. PMID- 21246334 TI - [Psychological comorbidity. Diagnosis and indications for further treatment in medical rehabilitation]. AB - Psychosocial comorbidity in somatic disorders is considered an important problem from the epidemiological point of view as well as from the perspective of care. Therefore, the different origins or development are etiologically discussed. In this article, an overview of the prevalence of psychiatric comorbidity of musculoskeletal disorders, using chronic back pain in somatic medical rehabilitation as an example, is given. According to the statistics of the German pension insurance fund, musculoskeletal diseases are the most common indication. In this article, the opportunities and the challenges for medical rehabilitation in managing psychosocial comorbidity are discussed. Starting with the description of medical rehabilitation in Germany, the significance of psychosocial comorbidity in medical rehabilitation and the resulting opportunities arising from this special setting to screen for psychological comorbidity are examined. These aspects are discussed based on articles from 2000-2010 in the field of orthopedic inpatient medical rehabilitation. A total of ten studies, focusing on the medical rehabilitation of chronic back pain, were identified. It was found that three papers reported data on the prevalence of psychological comorbidity and addressed diagnostic screening. This is discussed from a perspective that addresses potential barriers on the part of therapists as well as the patients. More attention should be directed to implementing the appropriate screening and follow-up care. PMID- 21246335 TI - [Longitudinal associations between depressive symptoms and type 2 diabetes and their impact on mortality in primary care patients]. AB - It is unclear whether depressive symptoms are a risk factor for incident diabetes or diabetes is a risk factor for depressive conditions. Therefore, we examined the longitudinal bidirectional associations between depressive symptoms and type 2 diabetes (T2D) as well as the impact of both diseases on (all cause) mortality in a sample of primary care patients over a 3.5-years follow-up period on average. Depressive symptomatology, defined by the Depression Screening Questionnaire (DSQ), was examined both categorically and dimensionally. Patients were categorized as normal fasting glucose (NFG), impaired fasting glucose (IFG), and T2D (untreated, oral antidiabetics, insulin/combined treatment) according to physician ratings and baseline lab values. Incidence rates of T2D were 25.6 and 20.9 per 1000 person-years for those with and without depressive symptoms, respectively. The unadjusted risk of incident type 2 diabetes was 1.03 times higher (CI(95%): 1.01-1.06) for each 1-point increment in DSQ score. The incidence rates of elevated depressive symptoms per 1000 person-years were 30.5 for NFG, 34.2 for IFG, 36.4 for untreated T2D, 32.3 for oral treated T2D, and 47.8 for insulin/combined-treated T2D patients. Compared to NFG patients, insulin treated patients had a higher risk of incident depressive symptoms (HR: 1.71; CI(95%): 1.03-2.83) and oral-treated patients had a lower risk (HR: 0.58; CI(95%): 0.36-0.96). Higher mortality rates were associated with both diseases compared to patients without T2D or depressive symptoms at baseline (HR: 2.49; CI(95%):1.45-4.28). Results indicate that especially insulin treatment in T2D patients is associated with incident depressive symptoms. PMID- 21246336 TI - [Comorbidity of chronic somatic illness and psychological disorders. Problems in outpatient mental health care]. AB - Especially when chronic, the presence of a somatic disorder is accompanied by various levels of psychological stress, which can range up to comorbidity with mental disorders. In addition, chronic somatic diseases and mental disorders are often interdependent. Treatment for persons with mental and somatic comorbidity is frequently offered in the context of medical rehabilitation. As skills of psychotherapists are concerned, comorbidity needs a bio-psychosocial approach in which knowledge of medicine, psychology, and social sciences is integrated. In addition to the expert skills of psychotherapists, interprofessional training, basic knowledge, and communication with physicians are necessary. The present article outlines conditions for outpatient psychotherapeutic care of persons with chronic somatic diseases and addresses central problems in the differential diagnosis of mental and somatic disorders as well as treatment indications when comorbidity is present. Selected examples for the diagnosis and treatment of patients with cardiovascular disorder and diabetes, respectively, illustrate these aspects. PMID- 21246337 TI - [Health economic aspects of physical-mental comorbidity]. AB - Physical-mental comorbidity is often associated with worse clinical and psychosocial outcomes, reduced health-related quality of life, and increased healthcare utilization. The following article is dedicated to the health economic aspects of physical-mental comorbidity. It presents basic theoretical and methodological aspects of cost-of-illness studies and economic evaluations related to physical-mental comorbidity, which are explained and discussed for the practical example of comorbid depression in diabetes mellitus. The results show that mental comorbidity in diabetes is associated with increased healthcare costs, which can in part be attributed to an increased somatic health service use. Appropriate interventions can lower these excess costs. Economic evaluations assessing the effectiveness of interventions for depressive diabetics have shown that overall health can be improved and costs saved. However, especially in health economics, mental comorbidity in somatic diseases has not been comprehensively investigated and further research is warranted. PMID- 21246338 TI - [Overweight and obesity in childhood and adolescence. Evaluation of inpatient and outpatient care in Germany: the EvAKuJ study]. AB - Numerous forms of therapy exist for the increasing number of obese children and adolescents in Germany, but these are heterogeneous and have not been evaluated. Access to health care, long- and short-term treatment outcome, as well as factors determining success of therapy were examined for the first time using standardized instruments to measure somatic and psychosocial variables. A total of 1,916 children aged 8-16 years from 48 (5 rehabilitation, 43 outpatient) institutions were examined. Data were collected for height, weight, blood pressure, and lipid status before treatment started (t0), at the end of treatment (t1), and 1 year after completion of treatment (t2). Furthermore, psychosocial variables were documented using questionnaires for parents and children. The mean BMI-SDS (body mass index standard deviation score) reduction at t1 was -0.27 and 1 year later at t2 was -0.23 (per protocol analysis; intention to treat: t1= 0.24; t2=-0.06). Psychological health and quality of life, which were markedly impaired at the beginning, improved. However, physical activity, media consumption, and nutrition remained basically unchanged. A reduction in weight is associated with an improvement in cardiovascular risk profiles, and long-term behavior changes are possible. However, the institutions differed considerably in the percentage of follow-up examinations and in the weight reduction accomplished. PMID- 21246339 TI - [Current aspects of swimming pool water hygiene - pool water chemistry and health. Report on an international symposium held 2-3 March 2009 in Dessau Robetalau]. PMID- 21246340 TI - [Baby swimming and disinfection by-products in swimming pools. Communication from the Federal Environment Agency following the swimming and wading pool water commission hearings of the Federal Ministry of Health at the Federal Environment Agency]. PMID- 21246341 TI - [Traumatology update]. PMID- 21246342 TI - [Symposium for experimental orthopedics at the Orthopedic Clinic of the Ludwig Maximilians University Munich]. PMID- 21246343 TI - [Recommendations for the treatment of thoracolumbar and lumbar spine injuries]. AB - This paper gives recommendations for treatment of thoracolumbar and lumbar spine injuries. The recommendations are based on the experience of the involved spine surgeons, who are part of a study group of the "Deutsche Gesellschaft fur Unfallchirurgie" and a review of the current literature. Basics of diagnostic, conservative, and operative therapy are demonstrated. Fractures are evaluated by using morphologic criteria like destruction of the vertebral body, fragment dislocation, narrowing of the spinal canal, and deviation from the individual physiologic profile. Deviations from the individual sagittal profile are described by using the monosegmental or bisegmental end plate angle. The recommendations are developed for acute traumatic fractures in patients without severe osteoporotic disease. PMID- 21246344 TI - [Testicular metastases from prostate cancer]. AB - Testicular metastases from prostate cancer is an uncommon occurrence and only 100 cases have been reported in the literature. Bilateral metastases are even more uncommon; however, testicular metatases may occur especially in cases of advanced prostate cancer. This article reports two cases with bilateral testicular metastases from prostate cancer. PMID- 21246345 TI - [Education of medical students in urology in Germany: present status]. AB - BACKGROUND: There is a growing demand for doctors in Germany and diseases of the genitourinary tract have become more prevalent in recent years. Politicians plan to increase the number of students in an already heavily overloaded system but data on quality and structure of medical education in Urology are lacking. The purpose of this study was to investigate the extent and quality of undergraduate medical education in urology. MATERIAL AND METHODS: Departments of Urology at German University Hospitals were surveyed using a questionnaire. Questions covered four different fields of medical education and answers were analyzed by descriptive statistics. RESULTS: Of the teachers involved in medical education 97% are physicians and 4% of these have special didactic qualifications. On average 1 teacher is responsible for 13 students and 44% of departments also have to carry out medical duties during teaching lessons. More than half of the departments offer modern learning forms, such as e-learning, problem-oriented learning or skills laboratory training. CONCLUSIONS: Urology departments at German University Hospitals spend much time on medical education. Nearly all physicians are involved in medical education, whether they are experienced or not and in many cases teaching is carried out in parallel to patient care. In more than half of the cases modern education tools were employed which implies a good standard of quality but there are no data on outcome. PMID- 21246346 TI - [Influencing of the PSA concentration in serum by physical exercise (especially bicycle riding)]. AB - BACKGROUND: Sports and in particular cycling are assumed to influence PSA in serum. Controversial scientific results were the motivation to examine the influence of a standardized test on a cycling ergometer and a treadmill on PSA concentrations in elderly men with elevated PSA levels and a benign prostate hyperplasia. MATERIAL AND METHODS: A total of 21 male volunteers (aged 61 +/- 5 years, tPSA 7.7 +/- 3.0 ng/ml and benign prostate hyperplasia with a prostate volume of 54 +/- 18 ml) performed a 1 h cycling test on a cycling ergometer. A subgroup of 15 volunteers also performed a 1 h test on a treadmill. Blood samples were drawn before and several times after the cycling stress test up to 7 days afterwards (up to 120 min after the test on the treadmill) to determine total PSA (tPSA), complexed PSA (cPSA) and free PSA (fPSA). RESULTS: The average increase in tPSA of 1.9 +/- 1.7 ng/ml (25%) after the cycling exercise test was significant. After the treadmill exercise the PSA increase was not as high, but with 1.0 +/- 1.0 ng/ml (12%) was also significant. On average the levels of PSA returned to the basic level 48 h after the cycling test, but in individual cases it took longer. fPSA showed the most noticeable increase after cycling with 92% on average. There was no correlation between increase in PSA and prostate volume. CONCLUSIONS: Men should abstain from physical exercise, especially from cycling for several days and at least for 24 h before PSA measurements are carried out. This applies to patients with elevated PSA levels (>4 ng/ml) when a PSA follow-up is being carried out. PMID- 21246347 TI - [Bladder cancer update: what was new at the 2010 annual congress of the German Association of Urology in Dusseldorf?]. AB - One of the principal objects of the scientific research network "German Bladder Cancer Network" is to consolidate research activities on bladder cancer. An overview about directions of current projects on this research topic was given at the annual meeting of the German Association of Urology in Dusseldorf from September 22 to 25 September 2010. As representatives of the"German Bladder Cancer Network" we summarize and comment on some of the most interesting projects on bladder cancer presented at this meeting. A special focus will be on current developments in the field of uropathology and on different aspects in preclinical research on bladder cancer. PMID- 21246348 TI - [Plasmacytoid and micropapillary urothelial carcinoma: rare forms of urothelial carcinoma]. AB - Plasmacytoid urothelial carcinomas (PUC) along with micropapillary urothelial carcinoma (MPC), small cell cancer, and nested-typed tumors are among the rare variations of urothelial carcinomas. The molecular characterization of PUC and MPC is currently the focus of our research on bladder cancer which we are conducting in cooperation with the Institute of Pathology in Erlangen. PUCs account for approximately 0.9% of all urothelial carcinomas. The diagnosis of these rare variants has acquired increasing importance since this may have prognostic and possibly therapeutic consequences for the patients. By analysis of 32 PUCs we were able to demonstrate the most comprehensive results available to date on the underlying molecular and clinical characteristics of these variants. Micropapillary cancers have already been described in multiple organs. Micropapillary breast cancer represent an individual entity with characteristic genomic aberrations and corresponding clinical and pathological features. PMID- 21246349 TI - [Influence of tourniquet ischemia on perioperative blood loss after total knee arthroplasty]. AB - The purpose of this study was to evaluate the effect of tourniquet use with constant pressure until wound closure on perioperative blood loss in total knee arthroplasty (TKA). Sufficient patients were included in the study to produce statistically relevant conclusions. In this retrospective case control study 547 patients who were treated with TKA because of osteoarthritis of the knee joint were included and of these 262 patients were operated with the use of a tourniquet (300 mmHg) and 285 without. The perioperative blood loss was calculated using patient height, body weight and preoperative and postoperative hematocrit values. The patient collectives were comparable in mean age, gender distribution and ASA classification. In the group with an operation using a tourniquet, 24 patients (9.2%) received erythrocyte transfusions compared to 36 patients (12.6%) in the group without tourniquet use (not significant). The average perioperative blood loss without tourniquet use was 1.5+/-0.6 l (range 0.2 to 4.3 l). In contrast patients treated with the use of a tourniquet lost on average only 1.2+/-0.5 l (range -0.2 to 3.4 l) (p<0.001). The use of a tourniquet reduces the perioperative blood loss in TKA if it is kept tight during the operation. PMID- 21246350 TI - Adverse drug events in an intensive care unit of a university hospital. AB - PURPOSE: Adverse drug events (ADEs) are harmful and occur with alarming frequency in critically ill patients. Complex pharmacotherapy with multiple medications increases the probability of a drug interaction (DI) and ADEs in patients in intensive care units (ICUs). The objective of the study is to determine the frequency of ADEs among patients in the ICU of a university hospital and the drugs implicated. Also, factors associated with ADEs are investigated. METHODS: This cross-sectional study investigated 299 medical records of patients hospitalized for 5 or more days in an ICU. ADEs were identified through intensive monitoring adopted in hospital pharmacovigilance and also ADE triggers. Adverse drug reactions (ADR) causality was classified using the Naranjo algorithm. Data were analyzed through descriptive analysis, and through univariate and multiple logistic regression. RESULTS: The most frequent ADEs were ADRs type A, of possible causality and moderate severity. The most frequent ADR was drug-induced acute kidney injury. Patients with ADEs related to DIs corresponded to 7% of the sample. The multiple logistic regression showed that length of hospitalization (OR = 1.06) and administration of cardiovascular drugs (OR = 2.2) were associated with the occurrence of ADEs. CONCLUSION: Adverse drug reactions of clinical significance were the most frequent ADEs in the ICU studied, which reduces patient safety. The number of ADEs related to drug interactions was small, suggesting that clinical manifestations of drug interactions that harm patients are not frequent in ICUs. PMID- 21246351 TI - Cytochrome P450 3A activity in mothers and their neonates as determined by plasma 4beta-hydroxycholesterol. AB - PURPOSE: The purpose of this study was to determine the 4beta-hydroxycholesterol to cholesterol ratio in mothers and neonates at the time of birth and 4 months post-partum. METHOD: 21 mothers and 22 neonates were recruited at the delivery ward at Karolinska University Hospital, Huddinge, Sweden. Blood samples taken from mothers and neonates at birth and 4 months post-partum were analysed for 4beta-hydroxycholesterol and cholesterol. RESULTS: The median plasma concentration of 4beta-hydroxycholesterol was higher in mothers at delivery (50 ng/mL) compared to healthy non-pregnant women (29 ng/mL). The pregnant women had a higher median cholesterol concentration (6.2 mmol/L) compared to healthy non pregnant women (4.6 mmol/L) but this could only partly explain the increased 4beta-hydroxycholesterol. The major cause is an increased CYP3A activity during pregnancy. The median 4beta-hydroxycholesterol/cholesterol ratio.10(4) was elevated in mothers at time of birth compared to non-pregnant women (0.19 and 0.15, respectively) but decreased to 0.15 4 months post-partum. Neonates had a median 4beta-hydroxycholesterol/cholesterol ratio.10(4) (0.19) comparable to adults already at birth, but lower 4beta-hydroxycholesterol (12 ng/mL) and cholesterol (1.8 mmol/L) concentrations. CONCLUSION: Pregnancy leads to increased CYP3A enzyme activity as determined by the 4beta-hydroxycholesterol/cholesterol ratio. Neonates have low 4beta-hydroxycholesterol and cholesterol concentrations but similar total CYP3A activity as adults already at birth. PMID- 21246352 TI - Modelling and simulation as research tools in paediatric drug development. AB - PURPOSE: Although practical and ethical constraints impose special requirements for the evaluation of treatment safety and efficacy in children, the main issue remains the empirical basis for patient stratification and dose selection at the early stage of the development of new chemical and biological entities. The aim of this review is to highlight the advantages and limitations of modelling and simulation (M&S) in supporting decision making during paediatric drug development. METHODS: A literature search on Pubmed's database Medical Subject Headings (MeSH) has been performed to retrieve relevant publications on the use of model-based approaches in paediatric drug development and therapeutics. RESULTS: M&S enable the assessment of the impact of different regimens as well as of different populations on a drug's safety and efficacy profile. It has been widely used in the last two decades to support pre-clinical and early clinical drug development. In fact, M&S have been applied to drug development as decision tools, as study optimization tools and as data analysis tools. In particular, this approach can be used to support dose adjustment in specific subgroups of a population. M&S may therefore allow the individualisation of drug therapy in children, improving the risk-benefit ratio in this population. CONCLUSIONS: The lack of consensus on how to assess the impact of developmental factors on pharmacokinetics, pharmacodynamics, efficacy and safety has so far prevented a broader use of M&S. This problem is compounded by the limited collaboration between stakeholders, which prevents data sharing in this field. In this article, we emphasise the need for a concerted effort to promote the effective use of this technology in paediatric drug development and avoid unnecessary exposure of children to clinical trials. PMID- 21246353 TI - Covalent immobilization of recombinant Rhizobium etli CFN42 xylitol dehydrogenase onto modified silica nanoparticles. AB - Rare sugars have many applications in food industry, as well as pharmaceutical and nutrition industries. Xylitol dehydrogenase (XDH) can be used to synthesize various rare sugars enzymatically. However, the immobilization of XDH has not been performed to improve the industrial production of rare sugars. In this study, silica nanoparticles which have high immobilization efficiency were selected from among several carriers for immobilization of recombinant Rhizobium etli CFN42 xylitol dehydrogenase (ReXDH) and subjected to characterization. Among four different chemical modification methods to give different functional groups, the silica nanoparticle derivatized with epoxy groups showed the highest immobilization efficiency (92%). The thermostability of ReXDH was improved more than tenfold by immobilization on epoxy-silica nanoparticles; the t(1/2) of the ReXDH was enhanced from 120 min to 1,410 min at 40 degrees C and from 30 min to 450 min at 50 degrees C. The K(m) of ReXDH was slightly altered from 17.9 to only 19.2 mM by immobilization. The immobilized ReXDH had significant reusability, as it retained 81% activity after eight cycles of batch conversion of xylitol into L-xylulose. A~71% conversion and a productivity of 10.7 g h(-1)l( 1) were achieved when the immobilized ReXDH was employed to catalyze the biotransformation of xylitol to L-xylulose, a sugar that has been used in medicine and in the diagnosis of hepatitis. These results suggest that immobilization of ReXDH onto epoxy-silica nanoparticles has potential industrial application in rare sugar production. PMID- 21246354 TI - Increase of lycopene production by supplementing auxiliary carbon sources in metabolically engineered Escherichia coli. AB - In the fed-batch culture of glycerol using a metabolically engineered strain of Escherichia coli, supplementation with glucose as an auxiliary carbon source increased lycopene production due to a significant increase in cell mass, despite a reduction in specific lycopene content. L-Arabinose supplementation increased lycopene production due to increases in cell mass and specific lycopene content. Supplementation with both glucose and L-arabinose increased lycopene production significantly due to the synergistic effect of the two sugars. Cell growth by the consumption of carbon sources was related to endogenous metabolism in the host E. coli. Supplementation with L-arabinose stimulated only the mevalonate pathway for lycopene biosynthesis and supplementation with both glucose and L-arabinose stimulated synergistically only the mevalonate pathway. In the fed-batch culture of glycerol with 10 gl(-1) glucose and 7.5 gl(-1) L-arabinose, the cell mass, lycopene concentration, specific lycopene content, and lycopene productivity after 34 h were 42 gl(-1), 1,350 mgl(-1), 32 mg g cells(-1), and 40 mgl(-1)h(-1), respectively. These values were 3.9-, 7.1-, 1.9-, and 11.7-fold higher than those without the auxiliary carbon sources, respectively. This is the highest reported concentration and productivity of lycopene. PMID- 21246355 TI - Efficient fermentation of xylose to ethanol at high formic acid concentrations by metabolically engineered Saccharomyces cerevisiae. AB - Recombinant yeast strains highly tolerant to formic acid during xylose fermentation were constructed. Microarray analysis of xylose-fermenting Saccharomyces cerevisiae strain overexpressing endogenous xylulokinase in addition to xylose reductase and xylitol dehydrogenase from Pichia stipitis revealed that upregulation of formate dehydrogenase genes (FDH1 and FDH2) was one of the most prominent transcriptional events against excess formic acid. The quantification of formic acid in medium indicated that the innate activity of FDH was too weak to detoxify formic acid. To reinforce the capability for formic acid breakdown, the FDH1 gene was additionally overexpressed in the xylose metabolizing recombinant yeast. This modification allowed the yeast to rapidly decompose excess formic acid. The yield and final ethanol concentration in the presence of 20 mM formic acid is as essentially same as that of control. The fermentation profile also indicated that the production of xylitol and glycerol, major by-products in xylose fermentation, was not affected by the upregulation of FDH activity. PMID- 21246356 TI - Effects of nitrogen catabolite repression and di-ammonium phosphate addition during wine fermentation by a commercial strain of S. cerevisiae. AB - Two deletion mutants expected to be defective in nitrogen catabolite repression (NCR) were constructed in a commercial wine yeast background M2: a ure2 mutant and a dal80 gzf3 double mutant. Wild-type and both mutant strains were fermented in Sauvignon Blanc grape juice with and without addition of di-ammonium phosphate (DAP). The dal80 gzf3 double mutant exhibited a long fermentative lag phase, which was offset by DAP addition (corresponding to 300 mg/L of N). Neither the NCR mutations nor DAP addition affected the content of volatile thiols in the final wine. Microarray analyses of transcripts in the wild-type and dal80 gzf3 double-mutant strains were performed after 2% and 70% sugars were fermented. Of 80 genes previously identified as NCR-regulated, only 13 were upregulated during fermentation of the dal80 gzf3 double-mutant strain in grape juice. Following DAP addition, 34 of the known NCR genes were downregulated, including 17 that were downregulated even in the NCR mutant strain. The results demonstrate an unexpected complexity of the NCR response that may reflect differences between strains of yeast or differences in gene regulation during alcoholic fermentation compared with standard aerobic growth. PMID- 21246357 TI - HLA-DRB1 allele distribution and its relation to rheumatoid arthritis in eastern Black Sea Turkish population. AB - Rheumatoid arthritis (RA [MIM 180300]) is a complex, polygenic inflammatory autoimmune disease, resulting from interactions between genetic and environmental factors. Some of the RA-associated HLA-DRB1 alleles have shared epitope, but their distribution varies among different racial/ethnic groups. This study was aimed at investigating the distribution of HLA-DRB1 alleles in patients with RA in eastern Black Sea region of Turkey. DNA samples of 320 patients with RA and 360 healthy controls were studied for the determination of HLA-DRB1 allele distribution using PCR-SSP method. The allele frequencies of HLA-DRB1*01, *04, and *09 were higher in patients with RA compared with the controls (P < 0.005, P < 0.0001, and P < 0.01, respectively). On the other hand, in patients with RA, HLA-DRB1*13 allele was lower than the controls (P < 0.001). Of the HLA-DRB1*04 subgroups, *0401 (40.83% vs. 18.75%, P < 0.001) was the most frequent allele in patients with RA, while DRB1*0402 (30.00% vs. 12.50%, P < 0.005) allele in the controls. HLA-DRB1 allele frequencies in the patients with RA and the controls showed Hardy-Weinberg rule compliance. Results of this study indicate that HLA DRB1*01, *04, and *09 alleles were associated with RA, and HLA-DRB1*13 was protective allele against RA. Among the subgroups of HLA-DRB1*04, *0401 was detected to be RA associated, while *0402 was being protective. These results have some differences compared with previous reports originating from other regions of Turkey. PMID- 21246358 TI - The prevalence and the clinical relevance of anti-Ro52 in Korean patients with primary Sjogren's syndrome. AB - So far, there was no report on the prevalence and clinical relevance of anti-Ro52 in primary Sjogren's syndrome (pSS) patients in Korea. In this study, we investigated the prevalence and the clinical relevance of anti-Ro52 in Korean patients with pSS. We retrospectively reviewed the medical records of 96 patients with pSS. On the first visit clinical manifestations, laboratory features and autoantibodies were assessed. We divided subjects into 4 groups according to the presence of anti-Ro60 or anti-Ro52 and investigated the association between those autoantibodies and clinical manifestations. Anti-Ro52 (66.7%) was the most frequently detected autoantibody, followed by anti-Ro60 (52.1%) and anti-La (49.0%). Patients with anti-Ro52 had higher frequency of liver and muscle involvements than those without, while anti-Ro60 exhibited negative association with liver involvement. Anti-Ro52 showed significant relative risk for liver involvement (OR = 5.987, P = 0.038, 95% CI = 1.109-32.326), while anti-Ro60 showed inverse relative risk for liver involvement (OR = 0.122, P = 0.003, 95% CI = 0.031-0.479). Anti-Ro52 also showed significant OR for muscle involvement (OR = 9.533, P = 0.044, 95% CI = 1.059-85.793). In conclusion, anti-Ro52 was the most frequently detected autoantibody except ANA in patients with pSS in Korea. Anti Ro52 was significantly associated with liver and muscle involvements, while anti Ro60 was inversely associated with liver involvement in Korean patients with pSS. PMID- 21246360 TI - Tenosynovitis of the flexor foot tendons secondary to pes cavus: value of sonography. PMID- 21246359 TI - Cross-cultural adaptation and validation of the knee and hip health-related quality of life (OAKHQoL) in a Moroccan Arabic-speaking population. AB - The aim of this study was to adapt the knee and hip osteoarthritis quality of life questionnaire (OAKHQoL) into Moroccan Arabic and to determine its psychometric properties. After translation, back-translation and pretesting, the translated version was submitted to an expert committee. The psychometric properties were tested on patients with hip or knee osteoarthritis. Internal consistency was tested using Cronbach's alpha coefficient (alpha), and the test retest reliability using intraclass correlation coefficients (ICC). Construct validity was assessed by examining item-convergent and divergent validity and by comparing the average scores between age groups and walk perimeter groups. The study was conducted on 131 patients (115 with osteoarthritis of the knee and 16 with osteoarthritis of the hip). The "physical activities" (alpha = 0.93), "mental health" (alpha = 0.84) and "pain" (alpha = 0.88) dimensions of the Arabic version were internally reliable. The ICC were adequate to good; 0.83 for "physical activities", 0.65 for "mental health" and 0.70 for "pain" dimensions. The instrument demonstrated good construct validity; all items exceeded the 0.4 criterion for convergent validity, except items 13 and 41 and most of the correlations between items and their own scale were significantly higher than their correlations with other scales. A semantically equivalent translation has been developed with cultural adaptation of OAKHQoL. It is quite reliable and a valid measure of the effect of osteoarthritis on the quality of life on Moroccan patients. PMID- 21246361 TI - Relapsing polychondritis: a description of a case and review article. AB - Relapsing polychondritis (RPC) is a rare autoimmune disease in which the cartilaginous tissues are the target for inflammation and destruction, the associated immune reaction causes inflammation in non-cartilaginous tissues like kidney and blood vessels. This article provides a description of a case of RPC and a review article about the disease. PMID- 21246362 TI - Adherence to methotrexate in juvenile idiopathic arthritis. AB - Non-adherence to treatments for chronic diseases may jeopardize patients' health, increase costs of care, and cause unnecessary clinic appointments and diagnostic studies, as well as additional treatments with potentially serious side effects. Little is known about adherence to methotrexate in pediatric rheumatology. Because this medication is commonly used in JIA, we assessed adherence among children receiving methotrexate in two countries. A total of 76 outpatients (M:F 21:55) with JIA seen in Rio de Janeiro (Brazil) and in Boston (US) taking methotrexate for >2 months were enrolled. Questionnaires were completed by the parents from both centers. Non-adherence was defined as omission of >=3 prescribed doses in the previous 8 weeks. Patients' ages ranged from 1 to 17 years. Mean time on methotrexate was 20.5 months (+/-25). Overall rate of non adherence was 18%. The rate of reported non-adherence was 8% in Boston and 24% in Rio de Janeiro (P = 0.012). The main reason for non-adherence in Boston was "child refused"; in Rio de Janeiro, the main reason was inability to obtain medication. Age had a negative association with adherence (P < 0.0001). Sex, time on methotrexate, route of administration, or concomitant use of other medications were not associated with adherence. Eighteen percent of children with JIA prescribed methotrexate were non-compliant. The difference in reasons for poor adherence between patients in Rio de Janeiro and Boston suggests that different strategies may be needed to improve adherence in these 2 settings. The rate of non-adherence warrants further investigation. PMID- 21246363 TI - Spatial versus verbal memory impairments in patients with fibromyalgia. AB - Mounting evidence suggests that individuals with fibromyalgia (FM) have impairments in general cognitive functions. However, few studies have explored the possibility of dissociation between verbal and visuospatial memory impairments in FM. Therefore, the purpose of this study was to investigate the asymmetrical impairment of cognitive functions between verbal and visuospatial memory and between short-term and long-term memory. Neuropsychological assessments were carried out on 23 female patients with FM and 24 healthy female controls. Verbal memory abilities were assessed using the Korean version of the Rey auditory verbal learning test (KAVLT) and digit span task, and visuospatial memory abilities were assessed using the Korean version of the Rey complex figure test (KCFT) and spatial span task. The analysis of covariance was used to assess group differences in performance on cognitive tests after controlling for depression. The two groups did not significantly differ in terms of age, years of education, or in their estimated verbal and performance IQ, but FM patients reported more severe depressive symptoms than did controls on the Beck depression inventory. Significant group differences were found in immediate and delayed recall on the KCFT (F (1,44) = 6.49, p = 0.014 and F (1,44) = 6.96, p = 0.011, respectively), whereas no difference was found in immediate and delayed recall on the KAVLT. In terms of short-term memory, neither the digit span task nor spatial span task showed any difference between groups, regardless of whether repetition was forward or backward. These findings suggest that spatial memory abilities may be more impaired than verbal memory abilities in patients with FM. PMID- 21246364 TI - Comparison of serological markers between ACPA+ and ACPA- of RA patients. AB - Anti-citrullinated protein/peptide antibodies (ACPA) have recently emerged as sensitive and specific serological markers of rheumatoid arthritis (RA), providing superior alternative of the rheumatoid factor (RF) test in the laboratory diagnostics of RA. We compare the change of serum RF, CRP, IgG, IgM, IgA, total complement, C3 and C4. The sera sample was collected from 123 patients with RA. ACPA were detected with ELISA, and RF, CRP and total complement (Ct), C3 and C4 were examined by automatic biochemical analyzer. Serum RF and total complement concentrations were significantly higher in ACPA+ than in ACPA-, but there were no correlation between ACPA and RF and Ct. Between ACPA+ and ACPA-, there were no significant difference of CRP, IgG, IgM, IgA, total complement, C3 and C4. While there were significant correlation between the concentration of C3 and IgM and ACPA in ACPA+. CONCLUSION: This is the first study to show that ACPA concentration in ACPA+ patients with RA is positively related to serum IgM and C3 levels. PMID- 21246365 TI - Effects of three different conservative treatments on pain, disability, quality of life, and mood in patients with cervical spondylosis. AB - This aim of this study was to determine the effect of different conservative treatment methods on pain intensity, disability, quality of life, and mood in patients with cervical spondylosis during a 6-month period. The patients were randomized into three groups. The 1st group (n = 20) was treated with active and passive physiotherapy methods, the 2nd group (n = 20) with active treatment methods, and the 3rd group (n = 20) with medication, including nonsteroid anti inflammatory and muscle relaxing medicines. The 1st and 2nd groups received individual exercise treatment according to their current problems as determined by the assessment. Pain recovery was found to be statistically significant after treatment and long-term follow-up for all three groups (P < 0.05). Disability improvement was significant in all groups after treatment and 3rd months and only in 1st group after 6 months (P < 0.05). Quality of life improvement was significant in all groups after treatment, at 3 months, and in the 1st and 2nd groups at 6 months (P < 0.05). Psychological recovery was significant in all groups after treatment and in the 1st and 2nd groups during long-term follow-up (P < 0.05). It was determined that patient satisfaction did not change in the 1st and 2nd group (P > 0.05), but decreased in the 3rd group (P < 0.05) during long term follow-up. There was more improvement in the two groups receiving exercise treatment than the group receiving medical treatment. In conclusion, exercise treatment has an important role in achieving long-term recovery of problems occurring with cervical spondylosis. PMID- 21246366 TI - Membrano-cystic lesions associated with rheumatoid arthritis. PMID- 21246367 TI - The status of serum vitamin D in patients with rheumatoid arthritis and undifferentiated inflammatory arthritis compared with controls. AB - Inadequate vitamin D may be involved in the pathogenesis and or progression of several disorders, including connective tissue diseases. To determine the status of vitamin D in different stages of inflammatory arthritis, the levels of vitamin D in established rheumatoid arthritis (RA) and undifferentiated inflammatory arthritis (UIA) were compared with controls. Patients with RA and UIA entered the study. Serum 25-hydroxyvitamin D (25-OHD) was measured by ELISA method, and concentrations less than 20 ng/ml were considered as deficient levels. In statistical analysis, the Mann-Whitney U test was used for comparing differences between groups and logistic regression analysis with calculation of adjusted odds ratio (OR) was used to determine the association between serum 25-OHD deficiency and disease condition. A total of 108 RA, 39 UIA, and 239 controls were studied. There were no significant differences in mean serum 25-OHD level and frequency of serum 25-OHD deficiency between RA and controls (37 +/- 37.7 vs. 33.2 +/- 28.6 ng/ml, P = 0.96). But the mean serum 25-OHD level in UIA was significantly lower than in the controls (25.1 +/- 23.9 vs. 33.2 +/- 28.6 ng ml, P = 0.04). A significant positive association was observed between serum 25-OHD deficiency and UIA (56.4% vs. 35.5%, OR = 2.34, 95% CI, 1.18-4.65, P = 0.021) which remained significant after adjustment for sex and age (adjusted OR = 2.24, 95% CI, 1.01 4.55, P = 0.026). Whereas the association between serum 25-OHD deficiency and RA did not reach statistical significance (40.7% vs. 35.5%, OR = 1.24, 95% CI, 0.78 1.99). These findings indicate higher serum vitamin D deficiency in patients with ongoing arthritis rather than established arthritis. Respecting to deleterious effects of vitamin D deficiency on immune system and progressive nature of UIA, a significant proportion of high risk UIA can be recognized by serum 25-OHD determination. PMID- 21246368 TI - MEFV mutations in Moroccan patients suffering from familial Mediterranean Fever. AB - Familial Mediterranean Fever (FMF, MIM 249100) is an autosomal recessive disease mainly affecting patients of the Mediterranean basin. It is an autoinflammatory periodic disorder characterised by recurrent episodes of fever and abdominal pain, synovitis and pleuritis. FMF is caused by mutations in the Mediterranean Fever (MEFV) gene located on chromosome 16p13.3. Several mutations in the MEFV gene have been characterised in different populations. However, very little is known about mutations in the MEFV gene in patients with Moroccan origin. The aim of this study is to determine the clinical components of FMF and characterise mutations in the MEFV gene in Moroccan patients. The study was carried out on 120 unrelated Moroccan patients referred to the department of medical genetics in Rabat for suspicious FMF over a period of 10 years. Patients were screened for the most common MEFV mutations by direct sequencing of exons 2 and 10. Of the 120 unrelated patients investigated, 56 patients (47%) were carriers of one or two MEFV mutations, and 64 patients (53%) had no detected mutations. Of those with mutations, 24 were homozygous (44%), 13 were compound heterozygotes (24%), and 19 patients had only 1 identifiable mutation (32%). The most frequent mutation in Moroccan patients is M694V (47%), followed by M694I (32%), A744S (6.5%), M680L (4%), M694del (2%) and E148Q (6.5%). The R761H, K695R and I692del mutations were rarely encountered (less than 1%). The V726A mutation was not found in our study. Our data represent the first report of MEFV gene mutations causing FMF in Moroccans patients. The M694V and M694I mutations are the most common mutations found in MEFV gene in Moroccan population; while the most common mutation in Arabs from the Middle-East region, the V726A, was not found in our population. PMID- 21246369 TI - Increased synovial fluid visfatin is positively linked to cartilage degradation biomarkers in osteoarthritis. AB - The aim of this study is to investigate visfatin levels in both synovial fluid (SF) and plasma of patients with primary knee osteoarthritis (OA) and its relationship with biomarkers of cartilage degradation in SF. Thirty OA patients, 12 SF control, and 12 plasma control subjects were enrolled in this study. Visfatin levels in both SF and plasma were measured using enzyme-linked immunosorbent assay (ELISA). Degradation biomarkers of collagen II and aggrecan in SF were also measured. The radiographic grading of OA in the knee was performed by the Kellgren-Lawrence (KL) criteria. Compared to controls, OA patients had higher SF visfatin concentration (8.95 +/- 2.5 vs. 4.48 +/- 2.49 ng/ml, P < 0.001). SF visfatin levels in KL grade 4 were significantly elevated compared with those of KL grade 3 (10.57 +/- 2.49 vs. 7.54 +/- 1.5 ng/ml, P = 0.001). SF visfatin positively correlated with degradation biomarker of collagen II, CTX-II (r = 0.497, P = 0.005), and degradation biomarker of aggrecan, AGG1 (r = 0.451, P = 0.012) and AGG2 (r = 0.434, P = 0.017). These findings suggest that SF visfatin might involved in cartilage matrix degradation. PMID- 21246370 TI - Circulating endothelial progenitor cells are reduced in SLE in the absence of coronary artery calcification. AB - Circulating endothelial progenitor cells (EPCs) are reduced in patients with systemic lupus erythematosus (SLE). A reduced number of EPCs are associated with the presence of atherosclerosis in other populations. We sought to determine whether the reduction in EPC numbers in SLE is dependent on the presence of advanced coronary artery calcification (CAC). Patients with SLE had previous coronary calcium scores which placed them in either the >75th percentile or <25th percentile for their age. Seventeen patients with SLE and 13 healthy controls (HC) were included in the study. White blood cells were stained for EPC and progenitor cell markers including CD34, CD133, and VEGFR and analyzed by flow cytometry. SLE patients had repeated coronary imaging as well as carotid ultrasound. There was no difference in age between groups. SLE patients with advanced CAC were more likely to be hypertensive, to be smokers, and to have longer disease duration than SLE patients without CAC. SLE patients without evidence of CAC had a significantly lower number of EPCs (CD34+/CD133+/VEGFR+) compared to HC (median (IQR)) 0 (0, 6.7) vs. 10.2 (5.8, 12.3) (P = 0.02). Total numbers of PCs (CD133+/CD34+) were not significantly decreased in patients with SLE ((mean +/- SEM) 1,007 +/- 154 vs. 824 +/- 170 (P = 0.20)). No significant difference was seen in EPC number between SLE patients without CAC and those with advanced CAC. Increased carotid intima-media thickness did not correlate with CAC or EPC number in SLE patients. Reduced numbers of EPCs in SLE patients may be observed compared to HC even in the absence of CAC. Differences in measured risk factor profiles and depletion of total circulating PCs do not fully explain this finding. PMID- 21246371 TI - Clinical significance of different effects of static and pulsed electromagnetic fields on human osteoclast cultures. AB - Electromagnetic fields are known to affect the bone metabolism by modifying some relevant physiologic cell parameters of cells, even though the underlying mechanisms are still unclear. The aim of our study was to evaluate the effect of both static magnetic fields (SMFs) of the same intensity of the one generated by spinal metal devices and pulsed electromagnetic fields (PEMFs) of the same intensity used for the management of nonunion on human osteoclasts cell culture. Primary osteoclast cells were isolated from primary human osteoclast precursors and were exposed to SMFs and to PEMFs. Morphology and tartrate-resistant acid phosphatase (TRAP) activity were evaluated in the osteoclast cultures after 7, 10, and 14 days of exposure. The SMF-exposed cells show a more differentiated phenotype and a significantly higher TRAP activity after 7 and 10 days of treatment with respect to a sham control. PEMF-exposed cells have a less differentiated phenotype after 7 days of exposure compared with the relative sham control, while the TRAP activity shows no statistically significant differences between exposed and control cells at any observation time. Our results indicate that SMFs of the same intensity of the one generated around spinal devices can affect osteoclast differentiation and activity. Aseptic loosening around titanium implants might be due in part to an increased osteoclast activity and differentiation. PEMFs of the same intensity than the one used for the management of nonunions can affect osteoclasts phenotype after 7 days of exposure, while osteoclasts TRAP activity is not affected by this kind of electromagnetic fields. PMID- 21246372 TI - Moderate loading of the human osteoarthritic knee joint leads to lowering of intraarticular cartilage oligomeric matrix protein. AB - The non-pharmacological treatment of osteoarthritis (OA) includes exercise therapy; however, little is known about the specific effect of exercise on the joint per se. The purpose of the present study was to investigate the direct effects of a load-bearing exercise upon cartilage in a single, human osteoarthritic joint determined by biochemical markers of cartilage turnover and inflammation in the synovial fluid (SF), serum and urine. Eleven subjects with OA of the knee(s), but with no other joint- or inflammatory disorders, volunteered for the study and had samples of blood, urine and synovial fluid drawn both at baseline and following 30-min one-legged knee-extension exercise. Workload: 60% of 1 RM (Repetition Maximum). Determination of cartilage oligomeric matrix protein (COMP), aggrecan, C-terminal collagen II peptide (CTX-II) and interleukin (IL)-6 were performed in synovial fluid (SF), serum and urine. A significant decrease was found in SF concentration of COMP following exercise, whereas aggrecan, CTX-II and IL-6 remained unchanged. No differences in any of the tested markers were found in serum and urine between baseline and post-exercise. Thirty minutes of mechanical loading of a single knee joint in human subjects with knee OA resulted in a reduced COMP concentration in SF. PMID- 21246373 TI - Insulin-like growth factor I receptor density on CD4+T-lymphocytes from active early steroid- and DMARD-naive rheumatoid arthritis patients is up-regulated and not influenced by 1 year of clinically effective treatment. AB - The IGF-IR density on CD4+T-lymphocytes was studied using flow cytometry in 40 early steroid- and DMARD-naive rheumatoid arthritis (RA) patients before and after 52 weeks of treatment with methotrexate+placebo or methotrexate+cyclosporine A and in 15 controls. RA patients had increased IGF-IR density on CD4+T-lymphocytes at week 0 and week 52, irrespective of treatment. IGF-IR-positive CD4+T-lymphocytes fraction decreased during treatment, but neither at week 0 nor at week 52 did it differ from healthy controls. No correlations were found to disease activity parameters. PMID- 21246374 TI - Rapid onset aggressive vertebral haemangioma. AB - INTRODUCTION: Vertebral haemangiomas are generally benign asymptomatic vascular tumours seen commonly in the adult population. Presentations in paediatric populations are extremely rare, which can result in rapid onset of neurological symptoms. We present a highly unusual case of an aggressive paediatric vertebral haemangioma causing significant cord compression. CASE REPORT: A 13-year-old boy presented with only 2 weeks duration of progressive gait disturbance, truncal ataxia and loss of bladder control. Magnetic resonance imaging (MRI) of the spine revealed a large vascular epidural mass extending between T6 and T8 vertebral bodies. Associated displacement and compression of the spinal cord was present. A highly vascular bony lesion was found during surgery. Histopathology identified this tumour to be a vertebral haemangioma. DISCUSSION: We present an extremely unusual acute presentation of a paediatric vertebral haemangioma. This study highlights the need for early diagnosis, MRI for investigation and urgent surgical management. PMID- 21246375 TI - A comparative study of the posterolateral and anterolateral approaches for isolated acetabular revision. AB - PURPOSE: Although isolated revision of the acetabular component has become an increasingly common option for revision hip surgery, opinions differ regarding the ideal surgical approach for reducing postoperative instability. The purpose of this study was to compare the clinical and radiographic results of isolated acetabular revision performed using a posterolateral and an anterolateral approach. MATERIALS AND METHODS: The authors retrospectively compared the clinical and radiographic results of isolated acetabular revision performed in 33 hips using a posterolateral approach with those performed in 36 hips using an anterolateral approach. All procedures were performed by a single surgeon and all patients received the same postoperative protocol. Mean duration of follow-up was 4.6 years (range 2-13.2). RESULTS: Mean postoperative Harris hip scores were similar in the posterolateral and anterolateral groups (86.5 and 87.2 points, respectively). In the entire series of 69 hips, 6 (9%) underwent re-revision of the acetabular component because of aseptic cup loosening in 4, recurrent dislocation in 1, and deep infection in 1. No significant difference was found between the two groups with respect to complication or re-revision rates, but the dislocation rate in the anterolateral approach group was significantly lower than that in the posterolateral group (0 vs. 12%, p = 0.047). CONCLUSION: Isolated acetabular revision performed using an anterolateral approach seems to be the more viable option in selected patients, and in particular, it has a significantly lower postoperative dislocation rate than posterolateral acetabular revision. PMID- 21246376 TI - Association between intercondylar notch narrowing and bilateral anterior cruciate ligament injuries in athletes. AB - BACKGROUND: Intercondylar notch narrowing is a risk factor for anterior cruciate ligament (ACL) injuries, but it is unclear whether a narrow intercondylar notch correlates with bilateral ACL injuries. PURPOSE: To determine whether a narrow intercondylar notch is associated with bilateral ACL knee injuries in athletes, using magnetic resonance imaging (MRI) and radiography to investigate the notch size. STUDY DESIGN: A retrospective case-control study. METHODS: This was a comparative cohort study on 50 subjects of which 25 patients with sport trauma associated bilateral ACL injuries, 30 with unilateral ACL injuries, and 20 healthy subjects. The notch width index (NWI) was measured as the ratio of the width of the intercondylar notch to the femoral condylar width on radiography and the MRI slice containing the region near the ACL attachment site on the femoral side (NWI-A) and on the following posterior slice (NWI-P). RESULTS: The mean NWI values on radiography were 0.257 (SD 0.040), 0.332 (SD 0.036), and 0.341 (SD 0.027) in the bilateral, unilateral, and control groups, respectively, with significant differences between the bilateral and unilateral groups and the bilateral and healthy groups. On MRI, the mean NWI-A values were 0.236 (SD 0.025), 0.243 (SD 0.048), and 0.266 (SD 0.030), respectively, with a significant difference between the bilateral and healthy groups. The mean NWI-P values were 0.239 (SD 0.021), 0.258 (SD 0.038), and 0.273 (SD 0.033), respectively, with significant differences between the bilateral and unilateral groups and the unilateral and healthy groups. A cutoff value of 0.25 for NWI-P gave an odds ratio of 22.667 for the risk of developing bilateral ACL knee injuries. CONCLUSIONS: The intercondylar notch was significantly narrower in subjects with bilateral ACL injuries than in healthy subjects. NWI measurement using coronal MRI is useful for judging intercondylar notch narrowing. The risk for ACL injuries is very high when NWI is <=0.25. Preventive measures for the unaffected knee are required for patients with a narrow intercondylar notch. PMID- 21246377 TI - An unusual Monteggia type I equivalent fracture: a case report. AB - We report an unusual case of a type I Monteggia equivalent lesion in a 6-year-old girl consisting of fracture of the ulnar diaphysis and fracture of the neck of the radius without dislocation of the radial head. Manual reduction and immobilization in a plaster cast were performed. At 10 years of follow-up, the patient had regained full flexion and extension of the elbow, and nearly full pronation and supination. In the literature, this lesion has been reported only in two paediatric patients indicating that this is an extremely rare trauma. PMID- 21246378 TI - Early periprosthetic bone remodelling around cemented and uncemented custom-made femoral components and their uncemented acetabular cups. AB - INTRODUCTION: Periprosthetic bone remodelling after total hip replacement may contribute to aseptic loosening of the prosthesis. The selection between cemented and uncemented fixation of the stem is mainly determined by patient's age, general constitution and CT scan-estimated bone quality; intra-operative observation may ultimately influence the choice of the fixation method. The influence of cemented versus uncemented stem fixation on periprosthetic bone remodelling around the uncemented cup has, to our knowledge, never been studied until now. METHODS: A total of 75 patients received intra-operatively manufactured stem prostheses and a standard hydroxy apatite-coated pinnacle cup. The pre-operative CT scans provides guidance for the bone quality and hence the type of stem fixation: cemented or uncemented. The influence of either type of stem fixation on periprosthetic bone remodelling around the cup and the stem was measured by bone mineral density at 6 weeks, and 3, 6 and 12 months after surgery. RESULTS: Early changes in bone mineral density were noted. The type of stem fixation had an influence on the bone remodelling of the femur and also of the pelvis. The caudal part of the acetabulum was subject to a greater loss in BMD at 12 months in the group with cemented stem fixation. Changes at 12 months correlated with the changes measured at any time point. CONCLUSIONS: The selection of the stem implant and its type of fixation in the femoral cavity (cemented or uncemented fixation) seems to have an impact on the bone mineral density of the acetabulum. Long-term clinical follow-up is required to draw conclusions regarding the influence on prosthesis survival. PMID- 21246379 TI - Tendon transfers for drop foot correction: long-term results including quality of life assessment, and dynamometric and pedobarographic measurements. AB - BACKGROUND: Drop foot deformity is a common problem with severe restrictions in quality of life and impairment of daily activities. A technique of posterior tibial tendon transfer through the interosseus membrane and fixation to the anterior tibial and the long peroneal tendon "Bridle procedure" (stirrup-plasty) offers a physiological alternative to surgical correction. METHODS: Data of 53 consecutive patients treated by stirrup-plasty were acquired from patient's charts; 31 were interviewed with standardized questionnaires; 20 were examined physically; 19 received pedobarography, and 8 underwent dynamometric muscle function tests. Follow-up time averaged 6.5 years. RESULTS: The mean range of motion (ROM) in the ankle joint was 8 degrees dorsiflexion and 15 degrees plantar flexion. Most patients achieved plantigrade foot position and the majority developed gait without orthotic devices. As expected, maximum dorsiflexion torque averaged a third of the non-operated leg, according to reduced muscle diameter and strength of the transferred muscle. Pressure distribution of the sole during gait was not relevantly altered by the tendon transfer compared to the non-operated leg. Most patients were satisfied with the operative results and reported a significant increase in quality of life. CONCLUSIONS: Fusion of the transposed posterior tibial, anterior tibial and the peroneus longus tendon prevents drop foot deformity sufficiently. The stirrup mechanism, in combination with tenodesis of the toe extensors, provides a balanced foot and avoids equinovarus and cavus deformity without immobilizing the ankle joint. Improvements in quality of life parameters justify the risk of the operative procedure for the patient. PMID- 21246381 TI - beta-Site APP-cleaving enzyme 1 (BACE1) cleaves cerebellar Na+ channel beta4 subunit and promotes Purkinje cell firing by slowing the decay of resurgent Na+ current. AB - In cerebellar Purkinje cells, the beta4-subunit of voltage-dependent Na(+) channels has been proposed to serve as an open-channel blocker giving rise to a "resurgent" Na(+) current (I (NaR)) upon membrane repolarization. Notably, the beta4-subunit was recently identified as a novel substrate of the beta-secretase, BACE1, a key enzyme of the amyloidogenic pathway in Alzheimer's disease. Here, we asked whether BACE1-mediated cleavage of beta4-subunit has an impact on I (NaR) and, consequently, on the firing properties of Purkinje cells. In cerebellar tissue of BACE1-/- mice, mRNA levels of Na(+) channel alpha-subunits 1.1, 1.2, and 1.6 and of beta-subunits 1-4 remained unchanged, but processing of beta4 peptide was profoundly altered. Patch-clamp recordings from acutely isolated Purkinje cells of BACE1-/- and WT mice did not reveal any differences in steady state properties and in current densities of transient, persistent, and resurgent Na(+) currents. However, I (NaR) was found to decay significantly faster in BACE1 deficient Purkinje cells than in WT cells. In modeling studies, the altered time course of I (NaR) decay could be replicated when we decreased the efficiency of open-channel block. In current-clamp recordings, BACE1-/- Purkinje cells displayed lower spontaneous firing rate than normal cells. Computer simulations supported the hypothesis that the accelerated decay kinetics of I (NaR) are responsible for the slower firing rate. Our study elucidates a novel function of BACE1 in the regulation of neuronal excitability that serves to tune the firing pattern of Purkinje cells and presumably other neurons endowed with I (NaR). PMID- 21246380 TI - TRPV1 activation prevents high-salt diet-induced nocturnal hypertension in mice. AB - High dietary salt-caused hypertension is associated with increasing reactive oxygen species generation and reduced nitric oxide (NO) bioavailability. Transient receptor potential vanilloid type 1 (TRPV1), a specific receptor for capsaicin, is proposed to be involved in Dahl salt-sensitive hypertension, as determined in acute or short-term experiments. However, it remains unknown whether activation of TRPV1 by dietary capsaicin could prevent the vascular oxidative stress and hypertension induced by a high-salt diet. Here, we report that consumption of a high-salt diet blunted endothelium-dependent relaxation in mesenteric resistance arteries and elevated nocturnal blood pressure in mice. These effects were associated with increased superoxide anion generation and reduced NO levels in mesenteric vessels in mice on a high-salt diet. However, chronic administration of capsaicin reduced the high-salt diet-induced endothelial dysfunction and nocturnal hypertension in part by preventing the generation of superoxide anions and NO reduction of mesenteric arteries through vascular TRPV1 activation. Our findings provide new insights into the role of TRPV1 channels in the long-term regulation of blood pressure in response to high salt intake. TRPV1 activation through chronic dietary capsaicin may represent a promising lifestyle intervention in populations with salt-sensitive hypertension. PMID- 21246382 TI - The adaptive evolution divergence of triosephosphate isomerases between parasitic and free-living flatworms and the discovery of a potential universal target against flatworm parasites. AB - Triosephosphate isomerase (TIM) is an important drug target or vaccine candidate for pathogenetic organisms such as schistosomes. Parasitic and free-living flatworms shared their last common ancestor but diverged from each other for adapting to parasitic and free-living lives afterwards, respectively. Therefore, adaptive evolution divergence must have occurred between them. Here, for the first time, TIMs were identified from three free-living planarian flatworms, namely Dugesia japonica, Dugesia ryukyuensis, and Schmidtea mediterranea. When these were compared with parasitic flatworms and other organisms, the following results were obtained: (1) planarian TIM genes each contain only one intron, while parasitic flatworm genes each contain other four introns, which are usually present in common metazoans, suggesting planarian-specific intron loss must have occurred; (2) planarian TIM protein sequences are more similar to those of vertebrates rather than to their parasitic relatives or other invertebrates. This implies that relatively rapid evolution occurred in parasitic flatworm TIMs; (3) All the investigated parasitic flatworm TIMs contain a unique tripeptide insert (SXD/E), which may imply its insertion importance to the adaptation of parasitic life. Moreover, our homology modeling results showed the insert region was largely surface-exposed and predicted to be of a B cell epitope location. Finally, the insert is located within one of the three regions previously suggested to be promising immunogenic epitopes in Schistosoma mansoni TIM. Therefore, this unique insert might be significant to developing new effective vaccines or specific drugs against all parasitic flatworm diseases such as schistosomiasis and taeniosis/cysticercosis. PMID- 21246383 TI - Prospective study of reactivation of hepatitis B virus in patients with rheumatoid arthritis who received immunosuppressive therapy: evaluation of both HBsAg-positive and HBsAg-negative cohorts. AB - BACKGROUND: Screening and prophylactic treatment for hepatitis B virus (HBV) reactivation is recommended for patients who receive immunosuppressive or cytotoxic therapy. The aim of this study was to clarify the prevalence of HBV reactivation in rheumatoid arthritis (RA) patients who had received more than 1 year of immunosuppressive therapy. This study also evaluated guidelines for determining HBV reactivation in patients with RA. METHODS: This was a prospective non-randomized, non-controlled study. We enrolled 50 patients with RA who had antibodies against hepatitis B core antigen (anti-HBc) and who had started treatment with disease-modifying anti-rheumatic drugs, including those who had additionally received anti-tumor necrosis factor-alpha (anti-TNF-alpha). HBV DNA levels were measured every 2-3 months by a real-time, polymerase chain reaction based method. Entecavir was administered to patients with HBV DNA levels >2.1 log/ml. RESULTS: The mean observation period was 23 months (range 12-32 months). HBV reactivation occurred in 2 of 5 patients with HBV surface antigen (HBsAg) and in 1 of 45 patients without HBsAg. In patients who received anti-TNF-alpha therapy, antibodies against HBsAg decreased significantly. Entecavir therapy inhibited HBV amplification and prevented HBV-associated flares of hepatitis. CONCLUSIONS: The incidence of HBV reactivation was low in RA patients in whom HBV infection had been resolved. Screening for HBV reactivation and prophylactic therapy with entecavir were effective means of preventing HBV-associated hepatic failure in patients with HBsAg, as well as in those with only anti-HBc who received immunosuppressive therapy for RA. PMID- 21246385 TI - Establishment of infectious HCV virion-producing cells with newly designed full genome replicon RNA. AB - Hepatitis C virus (HCV) replicon systems enable in-depth analysis of the life cycle of HCV. However, the previously reported full-genome replicon system is unable to produce authentic virions. On the basis of these results, we constructed newly designed full-genomic replicon RNA, which is composed of the intact 5'-terminal-half RNA extending to the NS2 region flanked by an extra selection marker gene. Huh-7 cells harboring this full-genomic RNA proliferated well under G418 selection and secreted virion-like particles into the supernatant. These particles, which were round and 50 nm in diameter when analyzed by electron microscopy, had a buoyant density of 1.08 g/mL that shifted to 1.19 g/mL after NP-40 treatment; these figures match the putative densities of intact virions and nucleocapsids without envelope. The particles also showed infectivity in a colony-forming assay. This system may offer another option for investigating the life cycle of HCV. PMID- 21246384 TI - Factors predictive of sustained virological response following 72 weeks of combination therapy for genotype 1b hepatitis C. AB - BACKGROUND: Treatment of genotype 1b chronic hepatitis C virus (HCV) infection has been improved by extending peg-interferon plus ribavirin combination therapy to 72 weeks, but predictive factors are needed to identify those patients who are likely to respond to long-term therapy. METHODS: We analyzed amino acid (aa) substitutions in the core protein and the interferon sensitivity determining region (ISDR) of nonstructural protein (NS) 5A in 840 genotype 1b chronic hepatitis C patients with high viral load. We used logistic regression and classification and regression tree (CART) analysis to identify predictive factors for sustained virological response (SVR) for patients undergoing 72 weeks of treatment. RESULTS: When patients were separately analyzed by treatment duration using multivariate logistic regression, several factors, including sex, age, viral load, and core aa70 and ISDR substitutions (P = 0.0003, P = 0.02, P = 0.01, P = 0.0001, and P = 0.0004, respectively) were significant predictive factors for SVR with 48 weeks of treatment, whereas age, previous interferon treatment history, and ISDR substitutions (P = 0.03, P = 0.01, and P = 0.02, respectively) were the only significant predictive factors with 72 weeks of treatment. Using CART analysis, a decision tree was generated that identified age, cholesterol, sex, treatment length, and aa70 and ISDR substitutions as the most important predictive factors. The CART model had a sensitivity of 69.2% and specificity of 60%, with a positive predictive value of 68.4%. CONCLUSIONS: Complementary statistical and data mining approaches were used to identify a subgroup of patients likely to benefit from 72 weeks of therapy. PMID- 21246386 TI - Human saliva exposure modulates bone cell performance in vitro. AB - Various situations encountered by a clinician during the daily routine including surgical periodontitis therapy, dental implant insertion, or tooth extraction involve the contact of saliva with the jaw bone. However, there are only sparse data concerning the influence of saliva on bone cells. Saliva specimens were incorporated within culture medium and administered to murine MC3T3 osteoblasts, of which the morphology (REM), proliferation (EZ4U), and differentiation (qRT PCR, alkaline phosphatase activity, extracellular matrix calcification) were assessed. Simultaneously, the composition of saliva media was analyzed with respect to the content of lactoferrin, activities of classical salivary enzymes, and the ability to provoke inflammatory cytokine production (enzyme-linked immunosorbent assay) in MC3T3 osteoblasts. The morphology, proliferation, and expression of differentiation-associated genes were seriously handicapped by saliva contact. Saliva-touched cells exhibited less alkaline phosphatase but normal levels of extracellular matrix mineralization. Saliva-containing culture media featured physiological activities of salivary enzymes and considerable amounts of lactoferrin but almost completely lacked salivary alkaline phosphatase and unspecific proteases. Upon saliva incubation, MC3T3 osteoblasts did not release noteworthy levels of interleukin-1 beta or tumor necrosis factor alpha. Although saliva is generally considered to vitalize oral tissues, this study reveals that it harms osteoblast-like cells more due to the presence of salivary enzymes than by triggering of inflammation. This issue is clinically relevant because it broadens the understanding of the bone cell fate within the rather complex cosmos of the oral cavity thereby providing a basis for clinical decision making and treatment guidelines. It seems to be reasonable to restrict the contact period between saliva and bone. PMID- 21246387 TI - Effects of different setting of diode laser on the mRNA expression of growth factors and type I collagen of human gingival fibroblasts. AB - The aim of this study was to analyze the influence of non-surgical applications of diode laser (940 nm) on the cell proliferation and mRNA expressions of type I collagen and growth factors in human gingival fibroblasts (GF). Gingival fibroblasts were isolated from human gingival connective tissue of systemically healthy individuals. Cells were treated with different laser parameters as follows; (1) Infected pocket setting (power: 2 W, pulse interval: 1 ms, pulse length: 1 ms, 20 s/cm(2)); (2) Perio-pocket setting (power: 1.5 W, pulse interval: 20 ms, pulse length: 20 ms, 20 s/cm(2)); and (3) Biostimulation setting (power: 0.3 W in continuous wave, 20 s/cm(2)). Proliferation of GF was evaluated after different laser applications using a real-time cell analyzer. Total RNA was isolated on day 2 and cDNA synthesis was performed. Type I collagen, insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF) and transforming growth factor-beta (TGF-beta) mRNA expressions were determined with quantitative RT-PCR. In a proliferation experiment, no significant differences were observed in the different laser applications when compared to the control group. Statistically significant increases in IGF, VEGF, and TGF-beta mRNA expressions were noted in the laser groups when compared to the untreated control group (p < 0.05). A significant increase in collagen type I mRNA expression was noted in only biostimulation set-up of diode laser (p < 0.05). The results of this study demonstrate that non-surgical laser applications modulate behavior of gingival fibroblasts inducing growth factors mRNA expressions and these applications can be used to improve periodontal wound healing. PMID- 21246388 TI - Evaluation of the osteogenic effect of low-level laser therapy (808 nm and 660 nm) on bone defects induced in the femurs of female rats submitted to ovariectomy. AB - The present study aimed to evaluate the effects of LLLT (660- and 808-nm wavelengths) on the process of repairing bone defects induced in the femurs of female rats submitted to ovariectomy. Bilateral ovariectomies were performed on 18 female Wistar rats, which were divided into control and irradiated groups after the digital analysis of bone density showed decreased bone mass and after standardized drilling of the femurs. The irradiated groups received 133 J/cm(2) of AsGaAl (660-nm) and InGaAlP (880-nm) laser radiation. The animals were euthanized on days 14 and 21 after the bone defects were established. Detailed descriptive histological evaluations were performed, followed by semi quantitative histomorphometry. The results from days 14 and 21 showed that the irradiated groups presented increased density of osteoblasts, fibroblasts, and immature osteocytes on the tissue surface compared with the control (non irradiated) groups (p < 0.05). Additionally, inflammatory infiltrate evaluations showed that LLLT decreased the accumulation of leukocytes when compared to the control treatment (p < 0.05). We concluded that, in our experimental model, both wavelengths (660-nm and 880-nm) inhibited the inflammatory process and induced the proliferation of cells responsible for bone remodeling and repair. PMID- 21246389 TI - Postoperative intracranial haemorrhage: a review. AB - Postoperative haemorrhage (POH) is one of the most serious complications of any cranial neurosurgical procedure and is associated with significant morbidity and mortality. The relative paucity of work investigating this postoperative complication prompted us to undertake a review of the literature, focussing on demographic, clinical, and surgical risk factors. A literature search was undertaken using Ovid MEDLINE (1950-2009) using keywords including craniectomy, craniotomy, neurosurgery, intracranial, reoperation, repeat craniotomy, postoperative, haemorrhage, haematoma, and bleeding. The rates of POH following intracranial procedures reported in the literature vary greatly, and meaningful comparison is difficult. We defined postoperative haemorrhage as that following craniotomy, which is clinically significant and requires surgical evacuation. Risk factors include pre-existing medical comorbidities including hypertension, coagulopathies and haematological abnormalities, intraoperative hypertension and blood loss, certain lesion pathologies including tumours, chronic subdural haematomas, and deficiencies in haemostasis. We conclude by providing recommendations for clinical practice based on the literature reviewed to aid clinicians in the detection and avoidance of POH. PMID- 21246390 TI - Desmoplastic infantile and non-infantile ganglioglioma. Review of the literature. AB - Desmoplastic gangliogliomas (DIG) are rare primary neoplasms that comprise 0.5 1.0% of all intracranial tumors. Clinically, there are two forms of DIG, the infantile and the non-infantile. These tumors invariably arise in the supratentorial region and commonly involve more than one lobe, preferentially the temporal and frontal. On neuroimaging are seen as large hypodense cystic masses with a solid isodense or slightly hyperdense superficial portion. The histologic diagnosis is characterized by the presence of three different cell lines: astrocytic, neuronal, and primitive neuroectodermal marker sites, which were demonstrable. The treatment of choice is radical surgical excision, and if this is done, achieved complete healing of the patient does not require additional treatment. A literature review of DIG was compiled through Medline/Ovid using the keywords "desmoplastic infantile ganglioglioma", "desmoplastic non-infantile ganglioglioma" covering the years 1984-2009. We present a review of a total of 113 cases of infantile (94) and non-infantile gangliogliomas (19) published to date, examining the clinical, radiologic, surgical, and pathological aspects, as well as the outcome. Desmoplastic gangliogliomas represent a rare tumor group with two well-defined age groups, the children and non-children. Desmoplastic infantile gangliogliomas are the most common and occur in children below 5 years of age, and the large majority of them present within the first year of life. Surgery is the treatment of choice and no complementary treatment is needed in cases of complete tumor resection. PMID- 21246392 TI - Italian intersociety consensus statement on antithrombotic prophylaxis in hip and knee replacement and in femoral neck fracture surgery. AB - Anticoagulant prophylaxis for preventing venous thromboembolism (VTE) is a worldwide established procedure in hip and knee replacement surgery, as well as in the treatment of femoral neck fractures (FNF). Different guidelines are available in the literature, with quite different recommendations. None of them is a multidisciplinary effort as the one presented. The Italian Society for Studies on Haemostasis and Thrombosis (SISET), the Italian Society of Orthopaedics and Traumatology (SIOT), the association of Orthopaedists and Traumatologists of Italian Hospitals (OTODI), together with the Italian Society of Anesthesia, Analgesia, Resuscitation, and Intensive Care (SIAARTI) have set down easy and quick suggestions for VTE prophylaxis in hip and knee surgery as well as in FNF treatment. This inter-society consensus statement aims at simplifying the grading system reported in the literature, and its goal is to benefit its clinical application. Special focus is given to fragile patients, those with high bleeding risk, and those receiving chronic antiplatelet (APT) and vitamin K antagonists treatment. A special chapter is dedicated to regional anaesthesia and VTE prophylaxis. PMID- 21246391 TI - Comparative study of application accuracy of two frameless neuronavigation systems: experimental error assessment quantifying registration methods and clinically influencing factors. AB - This study aimed at comparing the accuracy of two commercial neuronavigation systems. Error assessment and quantification of clinical factors and surface registration, often resulting in decreased accuracy, were intended. Active (Stryker Navigation) and passive (VectorVision Sky, BrainLAB) neuronavigation systems were tested with an anthropomorphic phantom with a deformable layer, simulating skin and soft tissue. True coordinates measured by computer numerical control were compared with coordinates on image data and during navigation, to calculate software and system accuracy respectively. Comparison of image and navigation coordinates was used to evaluate navigation accuracy. Both systems achieved an overall accuracy of <1.5 mm. Stryker achieved better software accuracy, whereas BrainLAB better system and navigation accuracy. Factors with conspicuous influence (P<0.01) were imaging, instrument replacement, sterile cover drape and geometry of instruments. Precision data indicated by the systems did not reflect measured accuracy in general. Surface matching resulted in no improvement of accuracy, confirming former studies. Laser registration showed no differences compared to conventional pointers. Differences between the two systems were limited. Surface registration may improve inaccurate point-based registrations but does not in general affect overall accuracy. Accuracy feedback by the systems does not always match with true target accuracy and requires critical evaluation from the surgeon. PMID- 21246393 TI - Urinary trypsin inhibitor attenuates lipopolysaccharide-induced acute lung injury by blocking the activation of p38 mitogen-activated protein kinase. AB - OBJECTIVE: To investigate the protective effect of urinary trypsin inhibitor (UTI) in a rat model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the underlying molecular mechanism. METHODS: Rats were randomly assigned into three groups: control group, LPS treatment group and LPS/UTI treatment group. The serum concentrations of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 were measured by ELISA. The expression of p38 mitogen-activated protein kinase (MAPK) in lung tissues was determined by Western blot analysis. RESULTS: Administration of UTI reduced the lung wet/dry weight ratio and ameliorated the tissue damage. In the LPS/UTI treatment group, levels of TNF-alpha were significantly lower than those in the LPS treatment group, while the levels of IL 10 were significantly higher than those in the LPS treatment group. Western blot analysis revealed that UTI inhibited the phosphorylation of p38 MAPK in lung tissues. CONCLUSIONS: UTI attenuates LPS-induced ALI, probably by adjusting the balance between proinflammatory and anti-inflammatory cytokines. The mechanism responsible for the decreased TNF-alpha expression may be related to the inhibitory effect of UTI on p38 MAPK activation. PMID- 21246394 TI - Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas. AB - Malignant gliomas are highly lethal tumors resistant to current therapies. The standard treatment modality for these tumors, surgical resection followed by radiation therapy and concurrent temozolomide, has demonstrated activity, but development of resistance and disease progression is common. Although oncogenic Ras mutations are uncommon in gliomas, Ras has been found to be constitutively activated through the action of upstream signaling pathways, suggesting that farnesyltransferase inhibitors may show activity against these tumors. We now report the in vitro and orthotopic in vivo results of combination therapy using radiation, temozolomide and lonafarnib (SCH66336), an oral farnesyl transferase inhibitor, in a murine model of glioblastoma. We examined the viability, proliferation, farnesylation of H-Ras, and activation of downstream signaling of combination-treated U87 cells in vitro. Lonafarnib alone or in combination with radiation and temozolomide had limited tumor cell cytotoxicity in vitro although it did demonstrate significant inhibition in tumor cell proliferation. In vivo, lonafarnib alone had a modest ability to inhibit orthotopic U87 tumors, radiation and temozolomide demonstrated better inhibition, while significant anti-tumor activity was found with concurrent lonafarnib, radiation, and temozolomide, with the majority of animals demonstrating a decrease in tumor volume. The use of tumor neurospheres derived from freshly resected adult human glioblastoma tissue was relatively resistant to both temozolomide and radiation therapy. Lonafarnib had a significant inhibitory activity against these neurospheres and could potentate the activity of temozolomide and radiation. These data support the continued research of high grade glioma treatment combinations of farnesyl transferase inhibitors, temozolomide, and radiation therapy. PMID- 21246395 TI - Porous EH and EH-PEG scaffolds as gene delivery vehicles to skeletal muscle. AB - PURPOSE: Synthetic biomaterials are widely used in an attempt to control the cellular behavior of regenerative tissues. This can be done by altering the chemical and physical properties of the polymeric scaffold to guide tissue repair. This paper addresses the use of a polymeric scaffold (EH network) made from the cyclic acetal monomer, 5-ethyl-5-(hydroxymethyl)-beta,beta-dimethyl-1,3 dioxane-2-ethanol diacrylate (EHD), as a release device for a therapeutic plasmid encoding for an insulin-like growth factor-1 green fluorescent protein fusion protein (IGF-1 GFP). METHODS: Scaffolds were designed to have different porous architectures, and the impact of these architectures on plasmid release was determined. We hypothesized that IGF-1 could be delivered more effectively using a porous scaffold to allow for the release of IGF-1. RESULTS: We showed that by altering the number of pores exposed to the surface of the network, faster plasmid loading and release were achieved. In addition, the IGF-1 GFP plasmids were found to be effective in producing IGF-1 and GFP within human skeletal muscle myoblast cell cultures. CONCLUSIONS: This work aims to show the utility of EH biomaterials for plasmid delivery for potentially localized skeletal muscle regeneration. PMID- 21246397 TI - The Archives of Sexual Behavior: 40 years on. PMID- 21246396 TI - In vivo anti-tumor effect of expressing p14ARF-TAT using a FGF2-targeted cationic lipid vector. AB - PURPOSE: To develop an efficient and safe strategy to introduce a therapeutic gene into target cells in vivo for cancer therapy. The overall efficiency is based on proper selection of the delivery vector and expressed protein. METHODS: A plasmid coding for a specific cytotoxic fusion peptide, p14ARF-TAT, was evaluated in a xenograft mouse tumor model. The expressed peptide consisted of three domains, a secretory signal, a membrane permeability segment and a cytotoxic fragment. Gene expression was verified in U87-MG cells by Western blot and cytotoxicity confirmed with CyQuant assay. To improve the delivery, a FGF2 targeting peptide, MQLPLATC, was incorporated into the vector, which was evaluated using a luciferase-expressing plasmid. RESULTS: The luciferase activity in vitro was two-fold higher with the targeted formulations, and cytotoxicity was three-fold higher with expression of the p14ARF-TAT protein. A murine xenograph model of human glioma (U87-MG cells) tumors was used to address in vivo activity. FGF2-targeted lipoplexes demonstrated increased tumor volume reduction as compared to non-targeted formulations. RT-PCR and Western blot of tumor homogenizes indicated p14ARF-TAT expression in tumors along with other tissues. CONCLUSION: p14ARF-TAT was cytotoxic and is a promising approach when combined with an efficient targeting. PMID- 21246398 TI - Development of insect-resistant transgenic cotton with chimeric TVip3A* accumulating in chloroplasts. AB - An optimized vip3A gene, designated as vip3A* was chemically synthesized and a thi1 gene chloroplast transit peptide coding sequence was attached to its 5' end to produce the tvip3A*. vip3A* and tvip3A* genes were transformed into Gossypium hirsutum cv. Zhongmiansuo35. Of 42 independent transformants, 36 were positive for the vip3A* or tvip3A* gene. Four independent transgenic T1 lines with single copy insertions and unchanged phenotypes (CTV1 and CTV2 for tvip3A*, and CV1 and CV2 for vip3A*) were selected by Southern blotting, and subjected to an insect bioassay and field assessment. Four homozygous T2 transgenic lines were then selected and the amount of expressed Vip3A* protein was determined by western blotting and ELISA. The protein concentrations of CTV1 and CTV2 were about three fold higher than those of CV1 and CV2. As expected, the Vip3A* protein of CTV1 and CTV2 were transported to the chloroplasts, where they accumulated. The Vip3A* protein concentration in the chloroplasts of CTV1 and CTV2 was about 15-fold of that of CV1 and CV2. All four transgenic lines showed 100% mortality against fall armyworm (Spodoptera frugiperda) and beet armyworm (Spodoptera exigua) by insect bioassay. Moreover, CTV1 and CTV2 exhibited 100% mortality against cotton bollworm (CBW, Helicoverpa zea), whereas CV1 and CV2 showed 75.0% and 72.5% mortality against CBW, respectively. The field bioassay indicated that CTV1 and CTV2 were more resistant to CBW than CV1 and CV2. Our results suggest that the two tvip3A* transgenic lines (CTV1 and CTV2) can be used to develop insect resistant cultivars and could be used as a resource for raising multi-toxins expressing transgenic cotton. PMID- 21246400 TI - Content of health status reports of people seeking assisted suicide: a qualitative analysis. AB - Two right-to-die organisations offer assisted suicide in Switzerland. The specific legal situation allows assistance to Swiss and foreign citizens. Both organisations require a report of the person's health status before considering assistance. This qualitative study explored these reports filed to legal authorities after the deaths of individuals in the area of Zurich. Health status reports in the legal medical dossiers of the deceased were analysed using content analysis and Grounded Theory. From 421 cases of assisted suicide (2001-2004), 350 reports on health status were filed. Many cases contained diagnosis lists only. Other reports had more elaborate reports revealing that some physicians were aware about the patient's death wish and the intention to solicit assisted suicide. Physicians' attitudes ranged from neutral to rather depreciative. Few physicians openly referred the patient to the organisations and supported the patient's request by highlighting a history of suffering as well as reporting understanding and agreement with the patient's wish to hasten death. In the health status reports five categories could be identified. Some files revealed that physicians were aware of the death wish. The knowledge and recognition of the patient's death wish varied from no apparent awareness to strongly supportive. This variety might be due to difficulties to discuss the death wish with patients, but might also reflect the challenge to avoid legal prosecution in the country of origin. To require comparable health status reports as requirements for the right-to-die organisations might be difficult to pursue. PMID- 21246399 TI - Is prenatal myo-inositol deficiency a mechanism of CNS injury in galactosemia? AB - Classic Galactosemia due to galactose-1-phosphate uridyltransferase (GALT) deficiency is associated with apparent diet-independent complications including cognitive impairment, learning problems and speech defects. As both galactose-1 phosphate and galactitol may be elevated in cord blood erythrocytes and amniotic fluid despite a maternal lactose-free diet, endogenous production of galactose may be responsible for the elevated fetal galactose metabolites, as well as postnatal CNS complications. A prenatal deficiency of myo-inositol due to an accumulation of both galactose-1- phosphate and galactitol may play a role in the production of the postnatal CNS dysfunction. Two independent mechanisms may result in fetal myo-inositol deficiency: competitive inhibition of the inositol monophosphatase1 (IMPA1)-mediated hydrolysis of inositol monophosphate by high galactose-1- phosphate levels leading to a sequestration of cellular myo-inositol as inositol monophosphate and galactitol-induced reduction in SMIT1-mediated myo inositol transport. The subsequent reduction of myo-inositol within fetal brain cells could lead to inositide deficiencies with resultant perturbations in calcium and protein kinase C signaling, the AKT/mTOR/ cell growth and development pathway, cell migration, insulin sensitivity, vescular trafficking, endocytosis and exocytosis, actin cytoskeletal remodeling, nuclear metabolism, mRNA export and nuclear pore complex regulation, phosphatidylinositol-anchored proteins, protein phosphorylation and/or endogenous iron "chelation". Using a knockout animal model we have shown that a marked deficiency of myo-inositol in utero is lethal but the phenotype can be rescued by supplementing the drinking water of the pregnant mouse. If myo-inositol deficiency is found to exist in the GALT deficient fetal brain, then the use of myo-inositol to treat the fetus via oral supplementation of the pregnant female may warrant consideration. PMID- 21246401 TI - Minimizing morbidity while preserving outcome after inguinal lymphadenectomy: navigating between scylla and charybdis. PMID- 21246403 TI - Surveillance and intervention after thyroid lobectomy. AB - BACKGROUND: After thyroid lobectomy, many patients require ongoing care. This study sought to quantify the rates of surveillance and intervention after thyroid lobectomy. METHODS: One hundred one consecutive patients who underwent a thyroid lobectomy for nodular disease were evaluated. Clinical and follow-up data were obtained by a review of patient charts and included an evaluation of resource utilization related to thyroid disease. RESULTS: Nineteen patients required completion thyroidectomy for thyroid cancer, and 11 had hypothyroidism before lobectomy. Of the remaining evaluable patients, 30 (42.2%) of 71 required thyroid hormone replacement after lobectomy, with 24 patients having elevated thyroid stimulating hormone and 6 suppression of nodules in the contralateral lobe. The likelihood of thyroid hormone replacement demonstrated a trend with a contralateral nodule (9 of 14 vs. 21 of 57, P = 0.06) and a significant association with thyroiditis on surgical pathology (10 of 11 vs. 20 of 60, P < 0.001). Of the 82 patients who did not undergo completion lobectomy, 10 (12%) of 82 underwent postoperative fine-needle aspiration of the contralateral lobe, and 25 (30%) of 82 were followed with ultrasound surveillance. Only 27% of patients treated with lobectomy required no further surveillance or intervention. There were no instances of permanent recurrent laryngeal nerve injury. CONCLUSIONS: After thyroid lobectomy, most patients require continued surveillance and intervention. With a near-zero complication rate, total thyroidectomy may be a more effective and efficient option for management of nodular thyroid disease. PMID- 21246404 TI - Comparison of 6th and 7th AJCC TNM staging classification for carcinoma of the stomach in China. AB - BACKGROUND: The 7th edition of American Joint Committee on Cancer tumor-node metastasis (AJCC TNM) staging system was put into use recently. The study aimed to evaluate its predictive ability on survival and compare the difference between the 6th and 7th editions of AJCC TNM system in gastric carcinoma. MATERIALS AND METHODS: A total of 1000 gastric carcinoma patients receiving treatment in our center were selected for the analysis. Patients were staged using both the 6th and 7th editions AJCC TNM staging system. Survival analysis was performed with a Cox regression model. RESULTS: Of previous stage IV patients, 39.9% (112 of 281) migrated to a lower tier in the 7th edition. By setting the cutoff of positive lymph nodes as 0, 2, 6, and 15, the 7th edition strengthens the role of positive lymph nodes. Multivariable regression analysis showed that both 6th and 7th TNM stage systems were independent factors for overall survival. For lymph nodes negative patients, the 5-year overall survival for patients with fewer than 15 resected lymph nodes was significantly lower than those with more than 15. CONCLUSIONS: AJCC 7th is not superior to AJCC 6th in predicting the 5-year overall survival rates of gastric adenocarcinoma patients. The definition of stage IV and the selection of cutoffs for MLNC in the AJCC 7th system is much more reasonable compared with the AJCC 6th system. PMID- 21246405 TI - Association between the number of dissected lymph nodes during pelvic lymphadenectomy and cancer-specific survival in patients with lymph node-negative urothelial carcinoma of the bladder undergoing radical cystectomy. AB - BACKGROUND: A larger number of dissected lymph nodes (LN) during pelvic lymphadenectomy in patients with muscle-invasive transitional-cell carcinoma of the bladder treated by radical cystectomy (RC) is crucial for exact tumor staging and is associated with a positive oncological outcome. METHODS: Clinical and pathological records of 1291 patients undergoing RC due to LN-negative transitional-cell carcinoma of the bladder were summarized and evaluated in a multi-institutional database. The number of removed LNs and the presence or absence of lymphovascular invasion were assessed. On the basis of multivariate Cox regression analyses, a threshold number of removed LNs was defined that exerted an independent influence on cancer-specific survival (CSS). RESULTS: In multivariate Cox regression models for different numbers of removed LNs, a statistically significant enhancement of CSS could be demonstrated for a LN count of 16. Furthermore, the integration of the dichotomized LN count of 16 resulted in a statistically significantly enhanced predictive ability of the model for CSS. Patients with <16 and >=16 removed LNs showed CSS rates after 5 years of 72% and 83%, respectively (P = 0.01). In addition, age, sex, pT stage, and lymphovascular invasion had independent influences on CSS in every Cox regression model. CONCLUSIONS: In patients undergoing RC, removal of a higher LN count is associated with an improved oncological outcome. The information resulting from an assessment of lymphovascular invasion and an extended lymphadenectomy is critical for stratification of risk groups and identification of patients who might benefit from adjuvant treatment. PMID- 21246406 TI - The association of Caveolin-1 genotypes with oral cancer susceptibility in Taiwan. AB - BACKGROUND: Caveolin-1, which has been proposed as a candidate tumor suppressor, plays a regulatory role in several signaling pathways. The aim of this study was to evaluate the association between oral cancer susceptibility and Cav-1 genotypes. In this hospital-based case-control study, the association of Cav-1 polymorphisms with oral cancer risk in a central Taiwanese population was investigated. METHODS: Six hundred patients with oral cancer and 620 age- and sex matched healthy control subjects were genotyped and analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: There were significant differences between oral cancer and control groups in the distributions of their genotypes (P = 1.7 * 10(-18) and 2.6 * 10(-4)) and allelic frequencies (P = 3.3 * 10(-19) and 9.5 * 10(-6)) in the Cav-1 G14713A (rs3807987) and T29107A (rs7804372) polymorphisms, respectively. As for the combined genotype analysis, those who had GG/AT or GG/AA at Cav-1 G14713A/T29107A showed a 0.72 fold (95% confidence interval = 0.52-0.99) decreased risk of oral cancer compared to those with GG/TT, while those of any other combinations were of increased risk. The presence of metastasis was also correlated to both Cav-1 G14713A AA and Cav-1 T29107A TT genotypes. CONCLUSIONS: Cav-1 is involved in oral cancer, the A allele of the Cav-1 G14713A is risky, the A allele of the Cav-1 T29107A is protective, and AA/TT on these two polymorphisms may be the most risky combined genotype for the development of oral cancer and may be novel risk markers for early detection and prediction of distant metastasis. PMID- 21246407 TI - C-reactive protein and glucose regulation in familial longevity. AB - Earlier, we showed that the offspring from exceptionally long-lived families have a more favorable glucose metabolism when compared with controls. As chronic low grade inflammation has been regarded as a strong risk factor for insulin resistance, we evaluated if and to what extent the favorable glucose metabolism in offspring from long-lived families could be explained by differences in subclinical inflammation, as estimated from circulating levels of C-reactive protein. We found no difference between the two groups in C-reactive protein levels or in the distribution of C-reactive protein haplotypes. However, among controls higher levels of C-reactive protein were related to higher glucose levels, whereas among offspring levels of C-reactive protein were unrelated to glucose levels. It is a limitation of the current study that its cross-sectional nature does not allow for assessment of cause-effect relationships. One possible interpretation of these data is that the offspring from long-lived families might be able to regulate glucose levels more tightly under conditions of low-grade inflammation. To test this hypothesis, our future research will be focused on assessing the robustness of insulin sensitivity in response to various challenges in offspring from long-lived families and controls. PMID- 21246408 TI - Relapse of acute lymphoblastic leukemia in children in the context of microarray analyses. AB - Over the last four decades the treatment of patients with newly diagnosed childhood acute lymphoblastic leukemia (ALL) has improved remarkably. However, still about 20% of children with ALL relapse despite risk-adapted polychemotherapy. The prognosis of relapsed ALL is relatively poor, even with modern aggressive chemotherapy. Identification of the biological and genetic mechanisms contributing to recurrence in patients with ALL is critical for the development of effective therapeutic strategies to treat refractory leukemic patients. Allogeneic hematopoietic stem-cell transplantation is the treatment of choice for many children with relapsed ALL. The gene expression profile obtained by microarray technology could provide important determinants of the drug response and clinical outcome in childhood ALL. Incorporation of the data on expression levels of newly identified genes into existing strategies of risk stratification might improve clinical management. Current microarray data show correlation of in vitro drug resistance with significant patterns of gene expression and explain clinical differences between early and late relapse. Genes involved in cell proliferation, self-renewal and differentiation, protein biosynthesis, carbohydrate metabolism, and DNA replication and repair are usually among those highly expressed in relapsed lymphoblasts. Current status and future perspectives of microarray data on gene expression and drug resistance profile in relapsed pediatric ALL are discussed in this review. PMID- 21246410 TI - Measurement and interpretation of patient-reported outcomes in surgery: an opportunity for improvement. AB - BACKGROUND: Surgery may have a profound effect on patients' health-related quality of life (QOL). To be optimally useful, trials that seek to guide clinical decision making should measure outcomes that are important to patients and report the results in a clinically meaningful way. We sought to explore how researchers currently measure and interpret QOL in surgical trials, using gastric cancer as a case study. METHOD: We performed a systematic review of randomized controlled trials (RCTs) of gastric cancer surgery published between 1966 and 2009 that included at least one patient-reported outcome (PRO). Investigators assessed trial eligibility and extracted data in duplicate using standardized forms, then resolved disagreements by consensus. RESULTS: Our search identified 87 RCTs of gastric cancer surgery, of which 11 (13%) included at least one PRO. Ten RCTs measured one or more validated PROs, although six also included ad hoc measures. All manuscripts presented the results as raw scores and nine of the 11 trials identified a statistical difference between groups. All 11 manuscripts prominently reported the PRO results in the abstracts and conclusions, but only one discussed the clinical significance of the differences between groups. CONCLUSIONS: Most RCTs of gastric cancer surgery do not include measures of QOL and those that do suffer from important limitations. RCTs would be more useful to surgeons and patients if authors measured PROs and utilized existing approaches to present the results of PROs in ways that provide an intuitive sense of the magnitude of effects. PMID- 21246411 TI - Pancreatic heterotopia of the duodenum: anatomic anomaly or clinical challenge? AB - INTRODUCTION: Pancreatic heterotopia (PH) is a common congenital anomaly and can occur anywhere in the gastrointestinal tract (GIT). In most cases, these heterotopias are asymptomatic and are only incidentally detected upon pathohistological examination or autopsy. We analyzed our cases of duodenal PH with respect to their clinical relevance and impact. MATERIALS AND METHODS: Our prospectively collected pancreatic database was retrospectively analyzed. Thirty four cases of duodenal PH were found. Specimens were reviewed by a GI pathologist. Classification was performed according to Heinrich (Type I acini, ducts, and islet cells; Type II acini and ducts; Type III only ducts). RESULTS: From January 2000 to June 2009, we performed 534 pancreatic head resections. Thirty-two patients (6.0%) were found to have duodenal PH. Indications for pancreatic resections (pylorus-preserving pancreaticoduodenectomy, n = 26; Whipple, n = 6) were as follows: chronic pancreatitis, n = 16; malignancies, n = 9; cystic neoplasms, n = 5; and neuroendocrine neoplasms, n = 2. PH was also detected after two partial duodenal resections. In total, two cases of duodenal PH were found to be symptomatic. According to Heinrich, the following types were found: Type I, n = 12; Type II, n = 17; and Type III, n = 5 (total n = 34). CONCLUSIONS: PH is rare and in most cases detected incidentally during pathohistological examination. However, in two of our patients, surgery was performed due to symptoms. Therefore, in patients with unclear pancreatoduodenal lesions, PH should be considered as a possible diagnosis. Resection is indicated for symptomatic cases. PMID- 21246412 TI - Prognostic value of cirrhosis for intrahepatic cholangiocarcinoma after surgical treatment. AB - BACKGROUND: The surgical outcome and prognostic factors of intrahepatic cholangiocarcinoma are not fully understood. This study aimed to establish the clinical significance of cirrhosis for prognosis in patients with intrahepatic cholangiocarcinoma after surgery. METHODS: One hundred fifteen patients with intrahepatic cholangiocarcinoma who underwent surgical resection between December 2001 and January 2008 were retrospectively analyzed. The prognostic significance of clinicopathologic factors including cirrhosis was assessed by univariate and multivariate analyses. RESULTS: Thirty-two of the 115 patients (28%) had liver cirrhosis. Complete tumor removal (R0 resection) was performed in 42 patients (75%). Overall median survival time was 21 months, with 1-, 3-, and 5-year actuarial survival rates of 68%, 27%, and 17%, respectively. There was a significant difference in survival between patients with cirrhosis and those without cirrhosis (P = 0.027). Univariate analysis showed that cirrhosis, vascular invasion, hepatic duct invasion, lymph node metastasis, positive surgical margin (R1), and TNM stage were significantly associated with poor survival. Multivariate analysis showed that cirrhosis, positive surgical margin, and lymph node metastases were related to survival, with hazard ratios of 2.49, 3.53, and 4.16, respectively. CONCLUSIONS: Cirrhosis is an independent factor for poor prognosis in intrahepatic cholangiocarcinoma after surgery. PMID- 21246414 TI - Radical surgery in the presence of biliary metallic stents: revising the palliative scenario. AB - BACKGROUND: The application of endobiliary self-expandable metallic stents (SEMS) is considered the palliative treatment of choice in patients with biliary obstruction in the setting of inoperable malignancies. In the presence of SEMS, however, radical surgery is the only curative option when the resectability status is revised in case of malignancies or for overcoming complications arising from their application in benign conditions that masquerade as inoperable tumours. The aim of our study was to report our surgical experience with patients who underwent an operation due to revision of the initial palliative approach, whilst they had already been treated with biliary SEMS exceeding the hilar bifurcation. METHODS: Three patients with hilar cholangiocarcinoma that was considered inoperable and one patient with IgG4 autoimmune cholangio pancreatopathy mimicking pancreatic cancer underwent radical resections in the presence of biliary SEMS. RESULTS: After a detailed preoperative workup, two right trisectionectomies, one left extended hepatectomy and a radical extrahepatic biliary resection were performed. All cases demanded resection and reconstruction of the portal vein. R0 resection was achieved in all the malignant cases. Two patients required multiple biliodigestive anastomoses entailing three and seven bile ducts respectively. There was one perioperative death due to postoperative portal vein and hepatic artery thrombosis, whilst two patients developed grade III complications. At follow-up, one patient died at 13 months due to disease recurrence, whilst the remaining two are free of disease or symptoms at 21 and 12 months, respectively. CONCLUSIONS: Revising the initial palliative approach and operating in the setting of biliary metallic stents is extremely demanding and carries significant mortality and morbidity. Radical resection is the only option for offering cure in such complex cases, and this should only be attempted in advanced hepatopancreaticobiliary centres with active involvement in liver transplantation. PMID- 21246413 TI - Mir-148a improves response to chemotherapy in sensitive and resistant oesophageal adenocarcinoma and squamous cell carcinoma cells. AB - BACKGROUND: Response to chemotherapy varies widely in patients with advanced oesophageal cancer. We investigated the impact of manipulating certain microRNAs on response to cisplatin and 5-fluorouracil (5-FU) in oesophageal cancer cells. METHODS: Cisplatin-/5-fluorouracil-resistant oesophageal squamous cell carcinoma (SCC) and adenocarcinoma (EAC) cell lines were established, and the impact of ectopic upregulation of miR-106a and miR-148a on response to both drugs was assessed. RESULTS: The impact of miR-106a-upregulation was inconsistent. Upregulation was followed by reduced sensitivity to cisplatin in chemotherapy sensitive EAC cells (cell survival, +8.7 +/- 0.8%; p = 0.003) and an improved response to 5-FU in cisplatin-resistant EAC cells (cell survival, -6.4 +/- 2.5%; p = 0.011). MiR-148a upregulation significantly increased sensitivity to chemotherapy in seven out of ten cell lines, represented by a decrease in cell viability of 22.6 +/- 7.9% to 50.5 +/- 10.6% after cisplatin (p <= 0.014) and 6.0 +/- 0.8% to 15.0 +/- 4.1% after 5-FU treatment (p <= 0.012). The only cell lines in which miR-148a upregulation had no effect were cisplatin-resistant EAC exposed to cisplatin and 5-FU-sensitive and 5-FU-resistant SCC cells exposed to 5-FU. CONCLUSION: MiR-148a sensitized chemotherapy-sensitive oesophageal cancer cell lines to cisplatin and, to a lesser extent, to 5-flurouracil and attenuated resistance in chemotherapy-resistant variants. Further experimental and clinical studies to investigate the exact mechanisms involved are warranted. PMID- 21246415 TI - Preoperative infliximab is not associated with an increased risk of short-term postoperative complications after restorative proctocolectomy and ileal pouch anal anastomosis. AB - INTRODUCTION: Considerable controversy exists over whether the preoperative use of infliximab (IFX) for refractory ulcerative colitis (UC) increases the risk for surgical complications after restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA). The aim of this study was to assess the association between preoperative IFX use and short-term surgical complications in a single-surgeon cohort at a tertiary care academic center. METHODS: UC patients who underwent IPAA from September 2005 through May 2009 were retrospectively identified. Twenty nine patients treated with IFX within 12 weeks of surgery and 52 non-IFX control subjects were identified. Short-term postoperative outcomes were compared between groups occurring within 30 days of loop ileostomy closure. RESULTS: Patients were similar with respect to demographics, co-morbidities, rate of emergency surgery, hand-sewn anastomosis, and preoperative use of cyclosporine, azathioprine, and high-dose steroids. IFX patients were more likely to have received a laparoscopic hand-assisted IPAA, low-, medium-, and any-dose steroids, 6-mercaptopurine (6 MP), methotrexate, and to have failed medical therapy. There was no short-term mortality. Overall postoperative and infectious complications were similar between IFX and non-IFX groups. Multivariate regression models revealed no independent predictors for postoperative complications when including IFX [odds ratio (OR) 0.78, p = 0.67], laparoscopic hand-assisted IPAA, 6-MP, methotrexate, steroids, failure of medical therapy, and body mass index. CONCLUSIONS: Preoperative IFX use was not associated with an increased risk of short-term postoperative complications after IPAA. PMID- 21246416 TI - Repair of symptomatic giant paraesophageal hernias in elderly (>70 years) patients results in improved quality of life. AB - INTRODUCTION: Giant paraesophageal hernias (PEH) involve herniation ofstomach and/or other viscera into the mediastinum. These are usually symptomatic and commonly occur in the elderly. The benefits and risks of operating on elderly patients with giant PEH have not been clearly elucidated. MATERIALS AND METHODS: We performed a retrospective chart review of consecutive patients aged 70 or greater with giant PEHs undergoing repair.Quality of life data were gathered using QOLRAD, GERD-HRQL and adysphagia severity score. RESULTS: Fifty-eight patients (34 females), median 78 years old, presented for repair. Nine patients presented urgently. There was no 30-day mortality. Major morbidity was 15.5%. At mean follow-up of 1.3 years, 81% were symptom free compared to baseline (p < 0.0001). Both short-term (p < 0.001) and long term QOLRAD (p < 0.001) scores improved significantly, as did GERD HRQL scores (p < 0.001). Dysphagia scores worsened in the short term but returned to baseline at long term follow up. CONCLUSIONS: Symptomatic giant PEH in this elderly population can be repaired with symptomatic improvement, minimal morbidity and mortality in both the elective and urgent setting. The decision to operate should be made by a physician experienced in managing this complex patient population. PMID- 21246417 TI - Amelioration of experimental autoimmune encephalomyelitis by beta-elemene treatment is associated with Th17 and Treg cell balance. AB - Experimental autoimmune encephalomyelitis (EAE), an animal mode of multiple sclerosis (MS), was previously considered that is mediated by Th1 cells. However, a number of recent studies provided strong evidence that T helper cells that produce interleukin (IL)-17 (Th17) and anti-inflammatory CD4+ Foxp3+ regulatory T cells (Tregs) play a dominant role in the pathogenesis of EAE. beta-elemene is a natural antitumor plant drug with the role of multiple target, and it has been found to pass through the blood-brain barrier easily. It also has been strongly implicated as an immune modulatory agent, but the precise mechanisms of its action are largely unknown. In the present study, we mainly investigated the efficacy and mechanism of beta-elemene against EAE in vivo and vitro. The treatment of C57 mice with beta-elemene significantly delayed the onset of EAE, markedly suppressed MOG-specific T cell proliferation in a dose-dependent manner, dramatically reduced the IL-17, IL-6, IL-23, and RORgammat production and induced the Foxp3 expression in both the periphery and the inflamed spinal cord. These findings indicated that beta-elemene amelioration EAE was, to a large extent, due to inhibit differentiation and development of Th17 cells depends on down regulating expression of IL-6, IL-23, RORgammat signaling, and promoting expansion in Treg cells. Suggesting it is useful in the control of MS and other Th17 cell-mediated inflammatory diseases. PMID- 21246418 TI - Neuropsychological testing and structural magnetic resonance imaging as diagnostic biomarkers early in the course of schizophrenia and related psychoses. AB - Making an accurate diagnosis of schizophrenia and related psychoses early in the course of the disease is important for initiating treatment and counseling patients and families. In this study, we developed classification models for early disease diagnosis using structural MRI (sMRI) and neuropsychological (NP) testing. We used sMRI measurements and NP test results from 28 patients with recent-onset schizophrenia and 47 healthy subjects, drawn from the larger sample of the Mind Clinical Imaging Consortium. We developed diagnostic models based on Linear Discriminant Analysis (LDA) following two approaches; namely, (a) stepwise (STP) LDA on the original measurements, and (b) LDA on variables created through Principal Component Analysis (PCA) and selected using the Humphrey-Ilgen parallel analysis. Error estimation of the modeling algorithms was evaluated by leave-one out external cross-validation. These analyses were performed on sMRI and NP variables separately and in combination. The following classification accuracy was obtained for different variables and modeling algorithms. sMRI only: (a) STP LDA: 64.3% sensitivity and 76.6% specificity, (b) PCA-LDA: 67.9% sensitivity and 72.3% specificity. NP only: (a) STP-LDA: 71.4% sensitivity and 80.9% specificity, (b) PCA-LDA: 78.5% sensitivity and 91.5% specificity. Combined sMRI-NP: (a) STP LDA: 64.3% sensitivity and 83.0% specificity, (b) PCA-LDA: 89.3% sensitivity and 93.6% specificity. (i) Maximal diagnostic accuracy was achieved by combining sMRI and NP variables. (ii) NP variables were more informative than sMRI, indicating that cognitive deficits can be detected earlier than volumetric structural abnormalities. (iii) PCA-LDA yielded more accurate classification than STP-LDA. As these sMRI and NP tests are widely available, they can increase accuracy of early intervention strategies and possibly be used in evaluating treatment response. PMID- 21246419 TI - Towards integrated drug substance and drug product design for an active pharmaceutical ingredient using particle engineering. AB - A novel experimental approach describing the integration of drug substance and drug production design using particle engineering techniques such as sonocrystallization, high shear wet milling (HSWM) and dry impact (hammer) milling were used to manufacture samples of an active pharmaceutical ingredient (API) with diverse particle size and size distributions. The API instability was addressed using particle engineering and through judicious selection of excipients to reduce degradation reactions. API produced using a conventional batch cooling crystallization process resulted in content uniformity issues. Hammer milling increased fine particle formation resulting in reduced content uniformity and increased degradation compared to sonocrystallized and HSWM API in the formulation. To ensure at least a 2-year shelf life based on predictions using an Accelerated Stability Assessment Program, this API should have a D [v, 0.1] of 55 MUm and a D [v, 0.5] of 140 MUm. The particle size of the chief excipient in the drug product formulation needed to be close to that of the API to avoid content uniformity and stability issues but large enough to reduce lactam formation. The novel methodology described here has potential for application to other APIs. PMID- 21246420 TI - A schematic diagram showing the various components of the embryonic aortic arch complex in the retroesophageal right subclavian artery. AB - A retroesophageal right subclavian artery, arising from the arch of the aorta as the terminal branch and passing dorsal to the esophagus, was found in five (1.2%) of 428 bodies donated for student dissection at Kumamoto University between 1993 and 2008. The presence of a retroesophageal right subclavian artery has been generally explained to be caused by the persistence of the normally eliminated part of the right dorsal aorta caudal to the seventh intersegmental artery and the disappearance of the normally patent right fourth aortic arch and the part of the right dorsal aorta cranial to the seventh intersegmental artery during the developmental process. However, the parts which remain or disappear are different in each case. With the aim of determining the portions eliminated or persisting and thereby gaining an understanding of the developmental process of the retroesophageal right subclavian artery in each instance, we made schematic diagrams showing the various components of the embryonic aortic arch complex as the prototype just before the anomaly occurred. Based on these diagrams, we conclude that immediately preceding the disappearance of the distal part of the right dorsal aorta and the dorsal part of the right sixth aortic arch, the third intersegmental artery was situated opposite to the fourth aortic arch and the seventh intersegmental artery was situated cranial to the point of junction of the right and left dorsal aortae. PMID- 21246421 TI - Embryonic stem cells: are useful in clinic treatments? AB - It is not uncommon to find statements in the social media and even in some scientific journals declaring that embryonic stem cells can be used in human medicine for therapeutic purposes. In our opinion, this statement does not fit the medical reality. To go into this subject in depth, and if possible to clarify it, we reviewed the most recent literature on clinical trials conducted with embryonic stem cells, concluding that up to the present time, there is only one ongoing clinical trial being carried out with these types of cells to treat a small group of patients with spinal cord injury. The results of this trial have still not been published. In conclusion, at present, there is only evidence of one phase I clinical trial conducted with embryonic stem cells, in comparison to the numerous trials conducted with adult stem cells. PMID- 21246423 TI - Social reasoning in Tourette syndrome. AB - INTRODUCTION: Tourette syndrome (TS) is thought to be associated with striatal dysfunction. Changes within frontostriatal pathways in TS could lead to changes in abilities reliant on the frontal cortex. Such abilities include executive functions and aspects of social reasoning. METHODS: This study aimed to investigate executive functioning and Theory of Mind (ToM; the ability to reason about mental states, e.g., beliefs and emotions), in 18 patients with TS and 20 controls. A range of tasks involving ToM were used. These required participants to make judgements about mental states based on pictures of whole faces or the eyes alone, reason about humour in cartoons that featured sarcasm, irony or "slapstick" style humour, and make economic decisions. The executive measures assessed inhibition and verbal fluency. RESULTS: Patients with TS exhibited significantly poorer performance than controls on all four tasks involving ToM, even when patients with comorbid obsessive-compulsive disorder were excluded. These difficulties were despite no inhibitory deficits. Patients with TS exhibited impairment on the verbal fluency task but their performance on executive and ToM tasks was not related. CONCLUSIONS: We propose that TS is associated with changes in ToM. The observed deficits could reflect dysfunction in frontostriatal pathways involving ventromedial prefrontal cortex. PMID- 21246422 TI - The role of executive function in children's competent adjustment to middle school. AB - Executive function (EF) skills play an important role in children's cognitive and social functioning. These skills develop throughout childhood, concurrently with a number of developmental transitions and challenges. One of these challenges is the transition from elementary into middle-level schools, which has the potential to significantly disrupt children's academic and social trajectories. However, little is known about the role of EF in children's adjustment during this transition. This study investigated the relation between children's EF skills, assessed both before and during elementary school, and sixth grade academic and social competence. In addition, the influences of the type of school setting attended in sixth grade on children's academic and behavioral outcomes were examined. EF assessed prior to and during elementary school significantly predicted sixth grade competence, as rated by teachers and parents, in both academic and social domains, after controlling for background characteristics. The interactions between type of school setting and EF skills were significant: Parents tended to report more behavioral problems and less regulatory control in children with weaker EF skills who were attending middle school. In contrast, teachers reported greater academic and behavioral difficulty in students with poorer EF attending elementary school settings. In conclusion, children's performance-based EF skills significantly affect adjustment to the academic and behavioral demands of sixth grade, with parent report suggesting greater difficulty for children with poorer EF in settings where children are provided with less external supports (e.g., middle school). PMID- 21246424 TI - The effect of resistance level and stability demands on recruitment patterns and internal loading of spine in dynamic flexion and extension using a simple trunk model. AB - The effects of external resistance on the recruitment of trunk muscles in sagittal movements and the coactivation mechanism to maintain spinal stability were investigated using a simple computational model of iso-resistive spine sagittal movements. Neural excitation of muscles was attained based on inverse dynamics approach along with a stability-based optimisation. The trunk flexion and extension movements between 60 degrees flexion and the upright posture against various resistance levels were simulated. Incorporation of the stability constraint in the optimisation algorithm required higher antagonistic activities for all resistance levels mostly close to the upright position. Extension movements showed higher coactivation with higher resistance, whereas flexion movements demonstrated lower coactivation indicating a greater stability demand in backward extension movements against higher resistance at the neighbourhood of the upright posture. Optimal extension profiles based on minimum jerk, work and power had distinct kinematics profiles which led to recruitment patterns with different timing and amplitude of activation. PMID- 21246425 TI - Constitutive formulation and numerical analysis of the heel pad region. AB - The aim of this work is to provide a numerical approach for the investigation of the mechanical behaviour of the heel pad region. A visco-hyperelastic model is formulated with regard to fat pad tissue, while a fibre-reinforced hyperelastic model is considered for the heel skin tissue. Bone components are defined by means of an orthotropic linear elastic model. Particular attention is paid to the evaluation of constitutive parameters within different models adopted in consideration of experimental tests data. Preliminarily, indentation tests on a skinless cadaveric foot are considered with regard to fat pad tissue. Indentation tests on an intact heel pad of a cadaveric foot are subsequently adopted for the final identification of constitutive parameters of fat pad and skin tissues. A numerical model of the rear foot is defined and different loading conditions are assumed according to experimental data. A comparison between experimental and numerical data leads to the evaluation of the real capability of the procedure to interpret the actual response of the rear foot. PMID- 21246426 TI - Masculinity and the persistence of AIDS stigma. AB - With the expansion of access to HIV testing and antiretroviral therapy in sub Saharan Africa, questions have emerged as to whether stigma remains a useful concept for understanding the effects of AIDS. There is, however, a paucity of research on how HIV-positive Africans--especially African men--experience living with AIDS. This paper addresses this gap and draws on findings from ethnographic fieldwork in 2004 and 2009 with a support group for HIV-positive men in Kampala, Uganda. The paper demonstrates that stigma is central to how men in this context coped with HIV and AIDS and it provides a conceptual framework that links men's experiences of AIDS stigma to conceptions of masculinity. In so doing, findings highlight both the possibilities and challenges of involving African men more fully in HIV prevention. PMID- 21246428 TI - Heteronormativity and 'troubled' masculinities among men who have sex with men in Addis Ababa. AB - In most societies, heterosexuality is the dominant way of expressing sexuality and masculinity and those men outside of it are stigmatised and discriminated against. This paper explores the sexual lives of men who have sex with men and the personal and social conflicts that arise as they attempt to both live up to societal expectations and manage their sexual desires. It critically explores how an overriding heteronormativity structures and influences men's perception and understanding of sexuality and masculinity/femininity. The paper draws on data from 24 in-depth/life history interviews, one focus group discussion and ethnographic observation conducted between July 2006 and June 2007. The study reveals that powerful and dominating beliefs about heteronormativity and masculinity result in men who have sex with men dealing with a number of issues of personal conflict and contradiction resulting in uncertainty, resentment, ambivalence, worry and discomfort. Heteronormativity or the expectations of parents, community and society at large is far more influential on the sexuality of men who have sex with men than their own individual desires and needs. The paper concludes that there is little room for individuality for Ethiopian men who have sex with men with their sexual bodies 'belonging' to parents, families and to society at large. PMID- 21246430 TI - Multiplicative model for assessment of chemical-induced cancer risk. AB - The multiplicative model for estimating incremental cancer risks linked with chemical-specific exposure is developed. The distinguishing feature of the model is that the additional cancer rate in the result of exposure to carcinogenic chemicals changes with age as a value proportional to the background cancer at this age. The proposed methodology enables assessing excess relative risk taking into account age and sex structure of background cancer rate in the exposed population, as well as the existence of a latent time between an exposure and an onset of disease. The model also enables estimating the environment pollution related health damage, defined as the expected number of lost years of forthcoming life in the result of exposure. The model could be of value for the regulatory community and scientists in projecting a chemically-induced increase in cancer rate in one population to increases in cancer rates in other populations. PMID- 21246429 TI - Comparison of four analytical techniques based on atomic spectrometry for the determination of total tin in canned foodstuffs. AB - Different techniques for the determination of total tin in beverages and canned foods by atomic spectrometry were compared. The performance characteristics of inductively coupled plasma-mass spectrometry (ICP-MS), hydride generation inductively coupled plasma-atomic emission spectrometry (HG-ICP-AES), electrothermal atomisation-atomic absorption spectrometry (ETA-AAS) and inductively coupled plasma-atomic emission spectrometry (ICP-AES) were determined in terms of linearity, precision, recovery, limit of detection, decision limit (CCalpha) and detection capability (CCbeta) (Decision 2002/657/EC). Calibration ranges were covered from ng l-1 to mg l-1 level. Limits of detection that ranged from 0.01, 0.05, 2.0 to 200 ug l-1 were reached for ICP-MS; HG-ICP-AES; ETA-AAS and ICP-AES, respectively. Precision, calculated according to ISO 5725-2 for repeatability and within-laboratory reproducibility and expressed as relative standard deviation (RSD), ranged from 1.6% to 4.9%; and recovery, based on Decision 2002/657/EC, was found to be between 95% and 110%. Procedures for the mineralisation or extraction of total tin were compared. Wet digestion, sequentially, with nitric acid and hydrogen peroxide provided the best results. The influence of possible interferences present in canned food and beverage was studied, but no interference in the determination of tin was observed. Since maximum levels for tin established by European Union legislation vary from 50 mg kg-1 in canned baby foods and infant foods up to 200 mg kg-1 in canned food, ICP AES was chosen as the preferred technique for routine analysis thanks to its good precision, reliability and ease of use. The accuracy of this routine method was confirmed by participation in six proficiency test schemes with z-scores ranging from -1.9 to 0.6. Several canned foodstuffs and beverage samples from a local market were analysed with this technique. PMID- 21246431 TI - Air pollution/working activity correlation: a case study in a dental hospital. AB - The paper deals with a multidimensional approach demonstrating a direct link between the entity of ongoing dentistry activity (number and kind of interventions) and specific pollution components. Simultaneously indoor/outdoor air concentrations of a set of volatile organic compounds (VOCs) and activity variables, describing the amount and nature of ongoing dentistry activities, were monitored over a year at a dental hospital located in an urban area. Principal Component Analysis (PCA) was used to single out mutually orthogonal pollution components which were then correlated to "pathology" factors arising from the analysis of dentistry activity indexes. The use of a multidimensional perspective allowed us to obtain a statistically significant model of the link between level of pollution and dentistry activity. In particular, the correlation approach linking pollution results to pathological variables allows us to establish a causative link even in the presence of sub-threshold concentrations of pollutants. PMID- 21246432 TI - Cultivating healthy places and communities: evidenced-based nature contact recommendations. AB - Cultivating healthful places is an important public health focus. This paper presents evidence-based recommendations related to nature contact. A multidisciplinary review was conducted in several fields of study and findings were organized into public health recommendations: (1) cultivate grounds for viewing, (2) maintain healing gardens, (3) incorporate wooded parks and green space in communities, (4) advocate for preservation of pristine wilderness, (5) welcome animals indoors, (6) provide a plethora of indoor potted plants within view, (7) light rooms with bright natural light, (8) provide a clear view of nature outside, (9) allow outside air and sounds in, (10) display nature photography and realistic nature art, (11) watch nature on TV or videos, and (12) listen to recorded sounds of nature. The findings should inform public health promoters in the design of healthy places and communities. Future research needs are highlighted. PMID- 21246434 TI - Microwave-assisted extraction of phenolics from Canarium album L. and identification of the main phenolic compound. AB - Microwave-assisted extraction (MAE) was applied in the extraction of phenolics from Canarium album L. Effects of various conditions including the solvent, solvent to material ratio, microwave power and irradiation time on extraction yield of phenolics were investigated. In terms of the optimal conditions of MAE, it was concluded that 70% (v/v) of ethanol was the proper extraction solvent, the solvent to material ratio was 10 : 1 (mL : g), and the microwave power and irradiation time were 600 W and 15 s, respectively. Compared with normal stirring extraction and ultrasound-assisted extraction, the MAE of phenolics from C. album L. was more time efficient and gave a high extraction rate. More than 1.2% extraction yield was achieved with MAE, and the purity of the phenolics in the extract product was up to 25%. In addition, by ultraviolet-visible (UV) spectrometry and electrospray ionised mass spectrometry (ESI/MS), the main phenolic compound in the extract product was identified as gallic acid. PMID- 21246433 TI - Plasma cortisol concentrations and lifestyle in a population of outdoor workers. AB - The aim of this study was to assess whether exposure to urban pollution in outdoor workers, may alter plasma cortisol concentrations also in relation to the effect of smoking and drinking habits. The research was carried out on 498 outdoor police workers, divided into three groups; Group A: traffic policemen (TP), Group B: drivers (D), Group C: Other duties (OD). To evaluate separately the effect of using alcohol and smoking, each group was divided into three subgroups: (1) non-smokers and non-drinkers, (2) smokers and non-drinkers, (3) non-smokers and drinkers. Our results show cortisol mean values were significantly higher in the TP group compared to the D and OD groups without significant differences between the last two groups. The results suggest that exposure to pollutants associated with urban psychosocial stress may play a more important role on plasma cortisol levels than smoking and alcohol. PMID- 21246435 TI - Identification and quantification of phenolic compounds from Balanites aegyptiaca (L) Del (Balanitaceae) galls and leaves by HPLC-MS. AB - Balanites aegyptiaca is a tropical plant which is widely used for medicinal purposes in several African countries, including Burkina Faso. Despite its widespread use, little is known about its phenolic content. This study sought to carry out a screening of the polyphenols from the leaves and galls of B. aegyptiaca. A high-performance liquid chromatography-mass spectrometry method was used to investigate the phenolic content in the parts of the plant studied here. The phenolic acid profile showed the presence of gentisic, p-coumaric, caffeic, ferulic and sinapic acids in the crude and hydrolysed extracts. The flavonoids pattern showed hyperoside, isoquercitrin, rutoside and quercitrin in the crude extract of leaves. Myricetol, quercetol and kaempferol were found after acid hydrolysis of the leaves extract. Ferulic acid, isoquercitrin, rutoside and quercitrin were identified as major phenolic compounds in this study. PMID- 21246436 TI - Anti-tumour activities and a high-performance liquid chromatography mass spectrometric method for analysis of the constituents of Lomatogonium carinthiacum. AB - In the present study, extracts of CHCl(3), n-BuOH and water of Lomatogonium carinthiacum were tested for their possible anticancer effects on human lung adenocarcinoma A549 cell line, human erythroleukaemia K562 cell line and human cervical carcinoma HeLa cell line. The inhibitory effect of the extracts on cell proliferation was assessed by MTT colourimetric assay in vitro. A high performance liquid chromatography-electrospray-mass spectrometric (HPLC-EIS MS/MS) method was developed for the determination of the constituents of the extracts. According to HPLC-EIS-MS/MS data, the chemical structures of 21 constituents of L. carinthiacum were identified on-line without time-consuming isolation. The L. carinthiacum extracts showed inhibitory effects on the abovementioned cell lines. Extracts of CHCl(3) were found to be the most inhibitory, with IC(50) values of 0.13, 0.75 and 0.60 ug mL(-1) on A549, K562 and HeLa, respectively. According to the IC(50) values, the order of sensitivity of the cell lines was A549 > HeLa > K562 and the inhibitory effects to the cell lines of these extracts were in the order CHCl(3) extract > water extract > n BuOH, as xanthones > iridoids and secoiridoids > flavonols. The present study showed inhibitory activity of L. carinthiacum extracts on tumour cells. PMID- 21246437 TI - Influence of salt stress on essential oil yield and composition of lemon grass (Cymbopogon schoenanthus L. Spreng. ssp. Laniger (Hook) Maire et Weil). AB - Cymbopogon is an aromatic plant valued for its citrus scent aroma. In this article, the effect of saline irrigation water on yield and quality of Cymbopogon schoenanthus L. was evaluated. Compounds of essential oils were identified by gas chromatography-mass spectrometry and/or (13)C-NMR spectroscopy. Results showed that the growth of the aerial part was not affected at a concentration of 50 mmol NaCl. Under salt stress, the content of major chemical compounds was affected differently by the treatment level. PMID- 21246438 TI - Isolation of a nitrobenzoate from the leaves of Cinnamomum tenuifolium. AB - Investigation of leaf extract of Cinnamomum tenuifolium (Lauraceae) led to the isolation of one new nitrobenzoate, ethyl 3,5-dihydroxy-4-nitrobenzoate (1), along with four known compounds. This is the first report of Cinnamomum metabolites with a nitro benzenoid derivative. Their structures were determined through in-depth spectroscopic and mass spectrometric analyses. PMID- 21246439 TI - Comparison of the endemic Azorean Hypericum foliosum with other Hypericum species: antioxidant activity and phenolic profile. AB - Water extracts of Hypericum foliosum (HF) from five Azorean Islands were analysed for their antioxidant activity and total phenolic contents. The results were compared with those from medicinal Hypericum species (H. perforatum, H. androsaemum and H. undulatum) and also with Azorean green tea. HF exhibited strong scavenging activity (87-91%) and moderate inhibition of linoleic acid oxidation (56-72%), and presented no significant difference to the other studied plants; in contrast, the synthetic antioxidant butylated hydroxyltoluene showed antioxidant activity values of 22% and 88%, respectively. The average value of phenolics in HF was higher than that in the other Hypericum species and lower than that in tea. Additionally, the phenolic profiles of the Hypericum species were compared by reverse phase-high performance liquid chromatography/ultraviolet (RP-HPLC/UV). The method presented permits the simultaneous determination of phenolic acids, flavonoids, hypericin and hyperforin within 55 min. The most similar profile was observed between HF and H. androsaemum. This study indicates that HF is a source of bioactive compounds with potential health benefits. PMID- 21246440 TI - Two new compounds from the roots of Myrica rubra. AB - Two new compounds, myrubol (1) and 3-oxo-11alpha-hydroxyfriedelane (2), were isolated from the roots of Myrica rubra along with eight known compounds (3-10). Their structures were determined through (1)H-NMR and (13)C-NMR spectral data, including 2-D experiments (HMBC, HMQC, (1)H-(1)H COSY and NOESY) and high resolution mass spectrometry. PMID- 21246441 TI - Phytochemical investigation and biological studies of Bombax malabaricum flowers. AB - In this study, extracts of the flowers of the folk medicinal plant Bombax malabaricum DC were biologically and chemically screened. Chemical constituents in the n-hexane fraction from the flowers of B. malabaricum DC were investigated using gas-liquid chromatography (GLC) analysis, affording 14 compounds, including cholesterol, stigmasterol, campesterol and alpha-amyrin, while the residual 10 compounds are hydrocarbons. GLC analysis of the fatty acid (FA) esters established the majority abundance of the saturated FA over their unsaturated analogues. The polar methanol fraction afforded seven flavones: vicenin 2 (1), linarin (2), saponarin (3), cosmetin (4), isovitexin (5), xanthomicrol (6) and apigenin (7). Structures 1-7 were established by intensive studies of various spectral data (H-NMR, mass spectroscopy and UV) and comparison with authentic samples. Compounds 1-7 are described here for the first time from this plant. Extracts of n-hexane and methanol exhibited significant antioxidant and antimicrobial activities. PMID- 21246442 TI - Composition and antioxidant activity of essential oil of pimento (Pimenta dioica (L) Merr.) from Jamaica. AB - The composition and antioxidant activity of the essential oil obtained through hydrodistillation of pimento berry [Pimenta dioica (L.) Merr] samples, namely P1 and P2, sourced from Jamaica, were studied. The chemical composition was analysed by GC and GC-MS methods. The antioxidant activities of the oils were evaluated in terms of their free-radical-scavenging activity against 1,1-diphenyl-2 picrylhydrazyl (DPPH), 2,2'-azinobis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) radical cation and superoxide anion ( [image omitted]). Total phenolic content, total reducing power and metal-chelating capacity of the oils were also estimated. Forty-five constituents were identified. The major compound identified was eugenol (74.71%, 73.35%), followed by methyl eugenol (4.08%, 9.54%) and caryophyllene (4.90%, 3.30%). The antioxidant assays showed that the oils possess very high radical scavenging activities (DPPH IC(50) 4.82 +/- 0.08, 5.14 +/- 0.11 ug mL(-1), ABTS IC(50) 2.27 +/- 0.16, 2.94 +/- 0.03 ug mL(-1), superoxide IC(50) 17.78 +/- 1.31, 20.65 +/- 0.82 ug mL(-1)). The metal chelating capacities (IC(50) 83.62 +/- 2.10, 101.77 +/- 1.01 ug mL(-1)) and reducing power were also very high. The results show that the essential oils possess significant antioxidant activity which is comparable to that of pure eugenol. Therefore the oil can be utilised as a natural antioxidant which gives good flavour as well as health benefits. PMID- 21246443 TI - Uvacalols I, J and K: new polyoxygenated cyclohexenes with all trans relative configurations from the roots of Uvaria calamistrata Hance. AB - Three new polyoxygenated cyclohexene derivatives with all trans relative configurations, named uvacalols I, J and K (1-3), were isolated from the roots of Uvaria calamistrata Hance. Their structures were determined to be (1R, 2S, 3S, 4R)-1-ethoxyl-5-benzoyloxymethylcyclohex-5-en-2,4-diol-3-benzoate (1), 1-ethoxyl 5-benzoyloxymethylcyclohex-5-en-3,4-diol-2-benzoate (2), and 5 benzoyloxymethylcyclohex-5-en-1,2,4-triol-3-benzoate (3), respectively, by extensive NMR experiments and chemical derivatisation. PMID- 21246444 TI - Calamenenes--aromatic bicyclic sesquiterpenes--from the Indian gorgonian Subergorgia reticulata (Ellis and Solander, 1786). AB - Three aromatic sesquiterpene derivatives, (+)-(7R, 10S)-2-methoxy calamenene (1), (+)-(7R, 10S)-2,5-dimethoxy calamenene (2) and (+)-(7R, 10S)-2-methoxy-5-acetoxy calamenene (3) were isolated from the methanol extract of the Indian gorgonian Subergorgia reticulata. Compound 2 has not been previously described in the literature. Compound 3 has not been isolated previously from a natural source. Compounds 1, 2 and 3 showed settlement inhibition activity against cyprids of Balanus amphitrite with EC(50) values of 4.4, 7.8 and 0.03 ug mL(-1), respectively. These compounds also exhibited considerable activity against Artemia nauplii at 50 ug mL(-1), indicative of their potential use as cytotoxic agents. PMID- 21246445 TI - Is it time to act? The potential of acceptance and commitment therapy for psychological problems following acquired brain injury. AB - Behaviour therapies have a well-established, useful tradition in psychological treatments and have undergone several major revisions. Acceptance and Commitment Therapy (ACT) and mindfulness-based approaches are considered a third wave of behavioural therapies. Emerging evidence for ACT has demonstrated that this paradigm has promising effectiveness in improving functionality and well-being in a variety of populations that have psychological disturbances and/or medical problems. In this review we first evaluate traditional cognitive behavioural therapy (CBT) interventions used to manage psychological problems in distressed individuals who have sustained an acquired brain injury (ABI). We provide an overview of the ACT paradigm and the existent evidence base for this intervention. A rationale is outlined for why ACT-based interventions may have potential utility in assisting distressed individuals who have sustained a mild to moderate ABI to move forward with their lives. We also review emerging evidence that lends preliminary support to the implementation of acceptance and mindfulness-based interventions in the rehabilitation of ABI patient groups. On the basis of existent literature, we recommend that it is an opportune time for forthcoming research to rigorously test the efficacy of ACT-based interventions in facilitating ABI patient groups to re-engage in living a valued and meaningful life, in spite of their neurocognitive and physical limitations. The promising utility of testing the efficacy of the ACT paradigm in the context of multimodal rehabilitation programmes for ABI populations is also addressed. PMID- 21246447 TI - Relationship between global cognitive decline and depressive symptoms in multiple sclerosis. AB - Cognitive impairment and depressed mood are common symptoms in multiple sclerosis (MS), which significantly impact patients' role functioning and quality of life. Cross-sectional studies indicate a modest association between cognitive impairment and depressive symptoms in MS. Longitudinal studies show inconsistent results but provide some data indicating a relationship between increasing global cognitive decline and increasing depressive symptoms over time. Establishing whether such a relationship exists represents an important first step in understanding the temporal nature of that relationship along with any treatment implications. The current study investigated this relationship by using the adjusted difference between a demographic estimate of premorbid intellectual functioning (Barona) and a performance measure of current intellectual functioning (Shipley Institute of Living) to capture long-term global cognitive decline in MS patients. Degree of global cognitive decline was then related to a self-report measure of mood, evaluative, and vegetative depression symptoms (Chicago Multiscale Depression Inventory). Global cognitive decline accounted for 5% of the variance in mood-evaluative symptoms but none of the variance in vegetative symptoms. When groups experiencing moderate, mild, and no global cognitive decline were compared on depression symptom subscales, MS patients experiencing moderate cognitive decline reported significantly higher mood and evaluative, but not vegetative, depressive symptoms than MS patients with stable cognitive functioning. PMID- 21246448 TI - Executive functioning, motor programming, and functional independence: accounting for variance, people, and time. AB - Assessing functional independence is an important part of making diagnostic decisions and treatment recommendations but is often complicated by the limitations of self-report and behavioral measures. Alternatively, it may be worthwhile to investigate neurocognitive correlates of incipient functional declines including using tests of executive functioning (EF) and motor programming (MP). The current study examined an electronic MP task and pitted it against other assessment instruments to evaluate its relative utility in assessing both EF and functional independence. Participants were 72 community dwelling older adults. Results of this study showed that the MP task was correlated with other measures of EF, an efficient and reliable predictor of functionality, useful for identifying at-risk patients, and comparable to a longer battery in terms of sensitivity and specificity. PMID- 21246450 TI - The aging face 2011. PMID- 21246451 TI - Patient analysis and selection in aging face surgery. AB - Advances in health, increased awareness of preventative medicine, and evolution have led to an increasingly older population worldwide. Surgical aesthetic facial rejuvenation has become increasingly popular, more accessible, and has lost much of the stigma that it once carried. This review will discuss proper patient analysis and selection for aging face surgery, including medical, anatomic, and psychosocial factors that are involved. Although the novice facial plastic surgeon typically focuses on facial analysis and operative techniques in aging face surgery, we caution that the patient's expectations, psychosocial comorbidities, and perioperative interpersonal experiences are the most important factors that yield patient satisfaction, which is the prime outcome that is meaningful in elective cosmetic surgery. PMID- 21246452 TI - Anatomic considerations in the aging face. AB - A thorough knowledge of the anatomy of the aging face is essential to a safe and effective operation. Over time, the face undergoes changes in skin and subcutaneous tissues evidenced by rhytides and thinning. There are also changes in the tone and character of facial muscles. Changes in fat structures in the face cause aesthetic changes that can be addressed surgically. Knowledge of the anatomy of the face and neck will aid in understanding the changes that occur with aging and will allow for a more complete strategy in rejuvenating the aging face. PMID- 21246453 TI - Soft tissue fillers and biofilms. AB - The purpose of this study was to review the clinical course of reported hypersensitivity reactions associated with use of soft tissue fillers and the response of these reactions to treatment. In this comprehensive literature review, we identified ~40 published reports that together reported numerous adverse reactions associated with use of nonpermanent soft tissue fillers; however, very few of these reactions were consistent with type I immediate or type IV delayed hypersensitivity reactions. Based on their clinical course and response to treatment, most reported hypersensitivity reactions are likely due to an infectious process. Although there are no confirmed reports of biofilm reactions associated with nonpermanent fillers, the possibility of bacterial contaminants should be considered in acute or chronic inflammatory reactions associated with use of nonpermanent soft tissue fillers. Early treatment with antibiotics is recommended. PMID- 21246454 TI - An antiaging and regenerative medicine approach to optimal skin health. AB - The optimal health and appearance of the skin is the result of several factors: extrinsic aging (UV damage), intrinsic aging (genetics, lifestyle), and hormonal aging (primarily estrogen loss). This article intends to take an antiaging and regenerative medicine approach to the aging skin and focus on both the hormonal causes and the intrinsic causes of aging; namely, hormones, diet, and lifestyle. By taking a functional approach to the evaluation and treatment of the skin, we hope to elucidate the causation of the condition of the skin and provide targeted treatments to improve its quality. We will sequentially cover the topics of hormonal decline and the skin, understanding hormone replacement, aging and the skin, and key nutrients for youthful skin. We hope to provide a more comprehensive approach to treating the aging face and skin that will provide patients with more long-lasting and youthful results. PMID- 21246455 TI - Current chemical peels and other resurfacing techniques. AB - The currently available methods for resurfacing will be addressed in this article, which has been divided into three areas of focus: chemical peels, lasers, and dermabrasion. Emphasis will be placed on chemical peels, a technique with a long history that provides a very reliable method of resurfacing and that every facial plastic surgeon should be familiar with. PMID- 21246456 TI - Forehead lifting: state of the art. AB - Forehead lifting serves to restore a more youthful appearance as well as a more functional and aesthetically pleasing brow position. The purpose of this review is to describe the pertinent anatomy and forehead aesthetics, then to discuss the patient evaluation, surgical approaches, complications, and nonsurgical adjuncts. Anatomic features reviewed include the layers of the forehead and scalp, blood supply, innervation, musculature, and the temporal branch of the facial nerve anatomy. Forehead aesthetics described include the aging process, with its contributing factors and consequences, and the ideal brow position in women and men. Key aspects of the patient evaluation include assessment of skin type; ptosis; hairline, brow, and lid position; symmetry; and bony contours. Pertinent past medical/surgical history as well as family history are reviewed, and the need for ophthalmology evaluation is discussed. Surgical indications and approaches, including direct, coronal, mid-forehead, endoscopic, and trans blepharoplasty, are reviewed. The advantages and disadvantages of each approach are discussed and techniques briefly described. Complications are mentioned, and the article concludes with a review of nonsurgical adjuncts. PMID- 21246457 TI - The art of blepharoplasty. AB - Blepharoplasty is one of the most popular and common procedures in facial plastic surgery. Initially performed in 1818 for eyelid reconstruction, blepharoplasty has evolved to become a cosmetic or functional operation. Although the surgical approaches are relatively straightforward, achieving natural and predictable results require precision and judgment. After performing more than 3500 blepharoplasties, the senior author has learned that the "art of blepharoplasty" has less to do with how much skin or fat is removed and is more about understanding the anatomic changes associated with aging, developing an individualized surgical plan, and anticipating postoperative outcomes or complications. PMID- 21246458 TI - Extended lower eyelid skin muscle blepharoplasty. AB - A patient presenting to a facial plastic surgeon with lower eyelid aging often has accompanying midface descent. Many surgical options exist to address these deformities. Blepharoplasty techniques include both the transcutaneous skin muscle flap as well as the transconjunctival approach. The midface can be addressed via a multitude of techniques, including percutaneous suspension of the malar fat pad, deep plane dissections, subperiosteal and endoscopic midface lifts, and transorbital approaches. Patients who have some midface ptosis but do not meet the standard criteria for formal midface lifting, or who want to avoid the extended recovery associated with such techniques, could benefit from less invasive procedures. We propose the extended skin muscle blepharoplasty to address midface descent and lower lid aging to patients as an alternative to formal midface lifting. The extended skin muscle blepharoplasty is an excellent technique for patients with orbicularis hypertrophy, skin redundancy, a tear trough deformity, and premalar ptosis, as it addresses each of these deformities with minimal downtime. Results for patients with mild but visible midface descent are gratifying. PMID- 21246459 TI - Midface lifting: current standards. AB - The most significant factor contributing to the overall change in the appearance of an individual's facial features over time is age. This process of gradual structural weakening of the face begins during the third decade and continues to worsen during the remainder of an individual's lifetime. Here, we discuss how the approach to midface rejuvenation has evolved over time owing to our increased understanding of the aging process. In addition, we discuss specific techniques that we use that have helped us achieve more natural and lasting results. PMID- 21246460 TI - Facial rejuvenation and volumization using implants. AB - Whereas traditional concepts of facial aging focus on the descent of soft tissue secondary to gravitational effects, it is now well established that volumetric changes involving different levels of soft tissue loss reveal craniofacial skeletal deficiencies that, together, contribute to the changes evident in the aging face. Thus, effective facial rejuvenation requires a comprehensive paradigm that identifies and addresses all anatomic elements involved in the aging process. Contemporary practices in facial rejuvenation have expanded far beyond the rhytidectomy procedure to involve deeper and more fundamental levels of dissection for the purpose of elevating and replacing volume. Alloplastic implants offer a long-term, multidimensional solution to facial rejuvenation by concomitantly augmenting skeletal deficiency, restoring lost soft tissue volume, and smoothing irregularities in the facial contour. Facial augmentation using implants represents a straightforward, simple procedure with minimal risks and long-lasting benefits. By applying accurate and judicious techniques for preoperative analysis, selecting the appropriate implant, and with correct surgical placement of the implants, the facial plastic surgeon can achieve successful facial volumization and restore the youthful appearance of the aging patient. PMID- 21246461 TI - Rhytidectomy: principles and practice emphasizing safety. AB - There is an unprecedented acceptance of rhytidectomy by today's society. No longer limited to the affluent few, middle class citizens are devoting their expendable income to achieve a more youthful appearance that is natural and inconspicuous. Despite recent difficult economic times, the mindset of the working population continues to be welcoming of rhytidectomy as a way to achieve a refreshed look while expecting minimal downtime and morbidity. To achieve these results, the current literature has described an array of techniques; however, there is no consensus on a preferred method, which reflects limitations and advantages inherent to every style of face-lifting. Each individual patient will have specific needs, and it is key for the facial plastic surgeon to select a technique that can address those areas most affected by the aging process. Whichever method used, an emphasis on safety is of the utmost importance. A solid understanding of the relevant anatomy is imperative as is the awareness of how to best avoid complications. Rhytidectomy can be a challenging procedure, and although complications are fortunately rare, they can be cosmetically devastating and poorly accepted by the elective cosmetic patient. This article aims at providing a summary of the history, the anatomy, and the currently accepted methods in rhytidectomy, emphasizing principles and practices of safety. PMID- 21246462 TI - The McCollough Facial Rejuvenation System: a condition-specific classification algorithm. AB - The search for the holy grail in facial rejuvenation is an ongoing quest. Perhaps the reason the "ideal" face-lift has yet to be discovered is a result of three factors. First, the term FACE-LIFT has never been adequately defined. Second, fads and trends play a role in how the operation is taught and performed. Third, surgeons searching for the prototypic technique have not had a way to index the physical signs of facial aging. After 37 years of practicing facial plastic surgery and performing more than 5000 face-lifts, the author determined that replacing chaos with order is long overdue. To achieve this goal, he developed a classification system that is designed to match each potential patient's problems with the most appropriate facial rejuvenation treatment plan and a "language" by which facial rejuvenation surgeons can communicate. Five progressive stages of aging have been identified and matched with recommended courses of face-lifting, blepharoplasty, volume augmentation, and skin resurfacing techniques. Ancillary procedures have also been included when indicated. It is the author's hope that a new classification system will bring order to mounting confusion within the aesthetic surgery professions as well as within the public sector. PMID- 21246463 TI - Contemporary deep plane rhytidectomy. AB - Many face-lift variations have been described including short skin flap, long skin flap, superficial musculoaponeurotic system flap, deep plane, composite flap, and subperiosteal face-lifts. Each technique offers its set of advantages and disadvantages. Theoretical benefits include a more optimal treatment of the midface, nasolabial fold, and periorbital area. A review of the literature highlights some of the potential advantages of the deep plane face-lift and the difficulty in objectively comparing the various techniques. PMID- 21246464 TI - Association of restrictive ventilatory dysfunction with insulin resistance and type 2 diabetes in koreans. AB - AIMS: To investigate associations of obstructive and restrictive patterns of ventilatory dysfunction with insulin resistance and type 2 diabetes mellitus (DM) in Koreans. METHODS: We cross-sectionally examined clinical, laboratory, and pulmonary function data on 35,456 Korean adults (age 18-93 years, 40% women) recorded during regular health check-ups. Insulin resistance (IR) was determined from fasting serum insulin concentration and homeostasis model assessment (HOMA). RESULTS: Individuals with type 2 DM and those with pre-diabetes (impaired fasting glucose levels) showed a higher prevalence of both restrictive (18% and 11%, respectively, VS. 8%; P<0.01) and obstructive (4.3% and 3.2%, respectively, VS. 2.3%; P<0.01) ventilatory dysfunction than did individuals with normal fasting glucose levels. Compared to subjects with normal ventilatory function, those with restrictive or obstructive ventilatory dysfunction were older, had higher systolic and diastolic blood pressure, and had elevated glucose and HbA1c levels. However, serum triglyceride, fasting insulin, and HOMA-IR were higher only in subjects with restrictive ventilatory dysfunction, and not in those with obstructive ventilatory dysfunction. On logistic regression analysis, the age and gender-adjusted odds ratio (OR) of restrictive ventilatory dysfunction for type 2 DM was 1.59 (95% confidence interval, 1.43-1.78). The increased OR remained significant after controlling for exercise, drinking, and smoking habits, presence of hypertension, body mass index, and waist circumference (OR=1.38 [1.23 1.55]). However, further adjustment for HOMA-IR attenuated the OR (1.11 [0.97 1.26]), making the OR statistically insignificant. In contrast, obstructive ventilatory dysfunction was not independently related to type 2 DM status. CONCLUSION: Restrictive ventilatory dysfunction is independently associated with type 2 DM, probably VIA insulin resistance. PMID- 21246465 TI - Glycaemic rises after waking up in response to an alarm clock in type 1-diabetic patients analysed with continuous glucose monitoring (GlucoDay(r) S). AB - AIMS: Waking up in response to an alarm-clock may evoke a stress reaction that leads to rising glucose concentrations. METHOD: 30 type 1-diabetic patients participated in 3 overnight conditions: (a) with an alarm-clock set at 2 h intervals for glucose self monitoring, (b) with a nurse performing blood glucose determinations, and (c) with the patients left undisturbed. Continuous glucose monitoring (CGM) was performed with a GlucoDay(r) S device. RESULTS: After waking up in response to an alarm-clock, CGM-determined glucose concentrations rose by 18+/-6 mg/dl at 4 a.m. (p=0.0003), whereas negligible increments were seen with nurse assistance (e. g., 0+/-4 mg/dl at 4 a.m.). CONCLUSIONS: Waking up in response to an alarm-clock leads to an arousal reaction that causes significant elevations in glucose concentrations. Continuous glucose monitoring is a suitable method to detect such short-lived increments in glucose concentrations. But at the moment the CGMS is not able to substitute for inpatient glucose profiles. PMID- 21246466 TI - Relationship between HbA1c on target, risk of silent hypoglycemia and glycemic variability in patients with type 2 diabetes mellitus. AB - OBJECTIVE: We aimed to compare time spent at low glucose level (silent hypoglycemia, glucose <3.0 mmol/l) and glycemic variability in patients who reached HbA1c <7.0% with those who did not. RESEARCH DESIGN AND METHODS: In 108 type 2 diabetic patients the interstitial glucose concentration was measured with CGMS (Continuous Glucose Monitoring System) over 72 h. Patients were divided in group 1 with an HbA1c <7.0% (n=63) and group 2 with an HbA1c>=7.0% (n=45). RESULTS: 24% in group 1 experienced silent hypoglycemia vs. 11% in group 2 (n. s.), duration of silent hypoglycemia over 48 h was 27+/-71 min vs. 7+/-36 min (n. s.). This was also valid for the subgroups treated with insulin. Patients in group 2 had a significantly higher standard deviation of average glucose (2.3+/ 0.8 vs. 1.3+/-0.6; p<0.001) and MAGE (mean amplitude of glycemic excursions) (4.8+/-2.1 vs. 2.6+/-1.1; p<0.001). CONCLUSION: Silent hypoglycemia tended to occur more often and to last longer in patients with HbA1c <7%. However, patients with HbA1c >7% had a higher glycemic variability. HbA1c >7% wasn't a reliable indicator of lower risk of hypoglycemia. PMID- 21246467 TI - [A rare complication of takotsubo cardiomyopathy]. AB - HISTORY AND ADMISSION FINDINGS: A 70-year old woman was admitted by the emergency doctor directly to our cardiac catheterization unit with persisting chest pain 60 minutes after onset of symptoms. Except for hypertension and hypercholesterinemia there was no cardiac history. On examination we found a bradykardia of 43/minutes, no other pathological signs. DIAGNOSTIC PROCEDURES: The ECG showed significant ST-segment elevation in I, aVL, V4-V6, and revealed a complete dissociation between p-wave and QRS-complex. This led to the diagnose of a ST elevation myocardial infarction of the lateral wall connected with a third degree AV-block. TREATMENT AND COURSE: First a transvenous pacing was done and the subsequent coronary angiography excluded coronary vascular disease. The laevocardiography showed an apical ballooning, therefore takotsubo cardiomyopathy could be diagnosed. Due to persisting third degree AV-Block, a permanent pacemaker was implanted on the fourth day of treatment. After one week the left ventricular function was nearly normal. The intravascular ultrasound excluded a ruptured plaque. CONCLUSION: In patients presenting acute coronary syndrom and apical ballooning, takotsubo cardiomyopathy should be considered after excluding coronary vascular disease. We presented a rare case of takotsubo cardiomyopathy together with a third degree AV-block. In spite of its persistence and the need of a permanent pacemaker implantation, the prognosis of the disease remained good. PMID- 21246468 TI - [Swelling of the groin after initiation of peritoneal dialysis]. PMID- 21246469 TI - [Evidence-based acute and long-lasting effects of climatotherapy in moderate altitudes and on the seaside]. AB - Evidence has been provided for acute and long-lasting effects of climatotherapeutic rehabilitation of atopic diseases (neurodermatitis, asthma bronchiale) in moderate altitudes. However, to sustain the climatotherapeutical evidence of psoriasis and non-allergic asthma treatment, controlled studies are required, especially for long-lasting benefits. For other indications of climatotherapy in moderate altitudes (heart and circulatory diseases, osteoporosis, metabolic syndrome) the results demonstrate an acute effect. At North Sea and Baltic Sea, the climatotherapeutic effects remain uncertain, especially for the well-known indications such as psoriasis, atopic dermatitis and bronchial asthma. There is evidence for the acute beneficial effects at Canary Islands and long-lasting remissions of Dead Sea climatotherapy and thalassotherapy. PMID- 21246470 TI - [Small bowel diverticula - diagnosis and complications]. AB - Aquired diverticula of the small bowel (not Meckel?s diverticulum) have a prevalence of 1 to 5 % and are relatively common. They are usually asymptomatic. However, in rare cases they can cause unspecific abdominal symptoms and even critical complications that require surgical intervention. Patients with diverticula of the small bowel were selected from all patients treated at an university hospital of maximal care in a retrospective study covering nine years. In 72 patients with diverticula, 47 % were asymptomatic, 47 % had unspecific abdominal symptoms and 6 % presented acute complications. In 83 % diverticula were localised in the duodenum and proximal jejunum. More distal parts of the small intestine were affected with decreasing frequency. A disseminated affection of the entire small bowel was found in 4 % of all patients. Diagnosis was made by endoscopic techniques in most cases (87 %) and to a smaller extent by CT- and MR imaging and by other methods. The pattern of complications found is similar to earlier studies. Endoscopic techniques have replaced enteroclysis as the most widespread diagnostic technique in diagnosis of small bowel diverticula. PMID- 21246471 TI - [Bladder catheterization]. PMID- 21246472 TI - [Immunity against tetanus is often lacking in the elderly]. AB - BACKGROUND AND OBJECTIVE: It is generally recommended to vaccinate elderly people against tetanus. Is this really essential? PATIENTS AND METHODS: The levels of antibodies to tetanus toxin in serum of 2936 individuals of various age groups were determined by means of an ELISA. RESULTS: Obviously, the antibody titers definitely diminish in the old individuals. About 50 % of people > 80 years possess antibody titers < 0.5 IU/ml and about 30 % antibody titers < 0.1 IU/ml, which means that they are not absolutely protected against tetanus. CONCLUSION: This, however is not due to a general decline of antibodies, since levels of immunoglobulins of the classes IgG, IgM and especially of IgA are higher with growing age.It can be assumed that the awareness for the necessity for vaccination is lacking. PMID- 21246473 TI - [Relevance of MRI for endometriosis diagnosis]. AB - Endometriosis is a disease of the uterus with displacement of endometrium-like tissue outside the endometrium. Endometriosis is a common benign chronic often debilitating disease that primarily affects young woman. The estimated prevalence is about 10 %. In addition to the uterus and ovaries, clinically important localisations are the rectovaginal space, rectum, sigmoid colon, urinary bladder, ureter and peritoneum. The most common localisation outside the pelvis is the abdominal wall. Today, MRI is one of the most important tools in the diagnosis of endometriosis. The detection of peritoneal manifestations and the exact definition of the depth of infiltration in the rectum, sigmoid colon and bladder walls are limitations of MRI. PMID- 21246474 TI - [Radiation protection clothing in X-ray diagnostics - comparison of attenuation equivalents in narrow beam and inverse broad-beam geometry]. AB - PURPOSE: Standard DIN EN 61 331-1 for attenuation measurements in the narrow and broad beam as well as DIN 6857-1 for the determination of shielding properties in the inverse broad-beam geometry are available for testing the attenuation of protection clothing. The attenuation measurements in the narrow beam don't consider scattered radiation and fluorescence due to the arrangement. This leads to the fact that the protective effect of lead-free materials will be misestimated when compared to lead. Therefore, the differences in attenuation equivalents, determined by both test methods for topical radiation protection aprons, were examined. MATERIALS AND METHODS: The attenuations in inverse broad beam geometry according to DIN 6857-1 and in the narrow beam according to DIN EN 61 331-1 were measured using commercially available aprons. They were made of lead, lead-reduced and lead-free materials. For determination of the attenuation equivalents, certificated lead-foils with high purity and a precise thickness of 0.1 to 1.25 mm were used. RESULTS: The measurements in the narrow beam according to DIN EN 61 331-1 showed that nearly all aprons reach the required lead equivalent at mid-range tube voltages of 100 kV. At higher and lower tube voltages, the requirements of DIN EN 61 331-3 were largely not met. In contrast, the testing of the same aprons in inverse broad-beam geometry according to DIN 6857-1 showed that only a few aprons meet the requirements for being classified in the nominal protection class. CONCLUSION: The measurements suggest that testing method DIN 6857-1 has yet to prevail and that manufacturers are just beginning to develop the appropriate protective materials. PMID- 21246476 TI - [Bilateral metachronous complex regional pain syndrome (CRPS I) of the lands - diagnosis with quantitative TPBS (3 phase scintigraphy)]. PMID- 21246475 TI - [CT-guided radiofrequency (RF) ablation of osteoid osteoma: clinical long-term results]. AB - PURPOSE: To evaluate CT-guided radiofrequency (RF) ablation of osteoid osteoma using internally cooled monopolar RF electrodes for technical success, complications and clinical long-term success. MATERIALS AND METHODS: Between April 1999 and July 2006, 23 patients were treated under general anesthesia with CT-guided RF ablation using an internally cooled monopolar single RF electrode (Cool-tip, Valleylab, TycoHealthcare, Boulder, USA; active tip: 10 mm). For the removal of the nidus, we used either a manual or an automated drill. The technical success was evaluated by a CT scan (MSCT, Siemens Medical Solutions, Forchheim). The clinical long-term success was investigated by questioning patients prior to discharge, and after 6, 12 and 18 months. After 18 months, patients were interviewed on an annual basis. RESULTS: The technical success rate was 100 %. The nidus was located in n = 19 cases at the lower extremity and in n = 4 cases at the upper extremity. Minor complications were observed for n = 2 patients. The mean hospitalization time was 1.5 d (1-2 d). The mean follow-up was 75.9 months (18-120 months) for n = 23 patients. No local recurrence was observed. One patient had intermediate pain one week after RF ablation without recurrent symptoms. CONCLUSION: CT-guided RF ablation using an internally cooled monopolar single RF electrode is an effective and safe minimally invasive method for the treatment of osteoid osteoma with excellent clinical long-term success. PMID- 21246477 TI - Increasing constipation and abdominal fullness. PMID- 21246478 TI - [Closure of an iatrogenic arteriovenous fistula and an pseudoaneurysm of the lower leg with the Amplatzer vascular plug]. PMID- 21246479 TI - [Gangrene of the small intestine due to mesenteric vein thrombosis]. PMID- 21246480 TI - Liver lesion segmentation in MSCT: effect of slice thickness on segmentation quality, measurement precision and interobserver variability. AB - PURPOSE: To evaluate the effect of slice thickness on semi-automated liver lesion segmentation. MATERIALS AND METHODS: In this retrospective study, liver MSCT scans from 60 patients were reconstructed at a slice thickness of 1.5 mm, 3 mm and 5 mm. 106 liver lesions (8 - 64 mm, mean size 25 +/- 13 mm) were evaluated independently by two radiologists using semi-automated segmentation software (OncoTreat(r)). Lesions were classified as cystic, hypodense and hyperdense according to their contrast-to-noise ratio (CNR). The long axis diameter (LAD), short axis diameter (SAD) and volume were measured. The necessity for manual correction (NOC = relative difference between uncorrected and corrected volume) and the relative interobserver difference (RID) were determined. Precision was calculated in terms of relative measurement deviations (RMD) from the reference standard (mean of 1.5 mm data sets). Wilcoxon test, t-test and intraclass correlation coefficients (ICC) were employed for statistical analysis. All statistical analyses were intended to be exploratory. RESULTS: Regardless of the liver lesion subtype, the NOC was found to be significantly higher for 5 mm than for 3 mm (p = 0.035) and 1.5 mm (p = 0.0002). The RID was consistently low for metric and volumetric parameters with no difference in any of the slice thicknesses for all subtypes (ICC > 0.89). The RMD increased significantly for the LAD, SAD and volume at a slice thickness of 5 mm (p < 0.01), e. g. volume: 0.5 % at 1.5 mm, 5.5 % at 3.0 mm and 7.6 % at 5.0 mm. CONCLUSION: Since the deviations in measurements are significant, and manual corrections made during semi-automated assessment of the liver lesions are considerable, a slice thickness of 1.5 mm, and no more than 3.0 mm, should be used for reconstruction for inconsistently vascularized liver lesions. PMID- 21246481 TI - [On the track of drug runners]. PMID- 21246482 TI - [60-year-old patient with arrhythmia and a history of open heart surgery]. PMID- 21246483 TI - [Diagnostics and expert opinion of asbestos-induced occupational diseases]. PMID- 21246484 TI - Fibular free flap with arteria peronea magna: the role of preoperative balloon occlusion. AB - The free fibular osteocutaneous flap is a commonly used donor for reconstruction of mandibular defects. Vascular abnormalities and leg trauma are relative contraindications to the use of a fibular free flap. Peroneal arteria magna (PAM) is one such vascular abnormality that may preclude the use of the graft due to the high risk of lower-limb ischemia. Lower-limb angiography is the standard for assessing the lower-limb vascular anatomy; however, the indications remain controversial. Although balloon occlusion has been used to assess the vascular supply in distal bypass surgery, there have no reported cases of balloon occlusion to assess the viability of the distal extremity with PAM. Intraoperative assessment of vascular anatomy with an aborted harvest can lead to significant morbidity and cost. Balloon occlusion provides a relatively safe and minimally invasive technique for assessment of potential lower-limb ischemia in patients with PAM. PMID- 21246486 TI - [From normality to modernity]. PMID- 21246485 TI - Gastroprotective effect and cytotoxicity of carnosic acid derivatives. AB - Carnosic acid (CA) is the main phenolic diterpene of rosemary (Rosmarinus officinalis L., Lamiaceae) and presents gastroprotective effect in vitro and in vivo. To determine structure-activity relationships, seventeen esters and ethers of CA were prepared, comprising aliphatic, aromatic, and heterocyclic compounds. The naturally occurring 12-O-methylcarnosic acid (14) was also included in the study. The compounds were evaluated for their gastroprotective activity in the HCl/EtOH-induced gastric lesions model in mice, and for cytotoxicity in human adenocarcinoma AGS cells, Hep G2 hepatocellular carcinoma cells, and human lung fibroblasts. At 10 mg/kg, some of the CA derivatives (5, 8, 9, 12, 14, and 18) were more effective preventing gastric lesions than the reference compound lansoprazole at the same dose. The dibenzoate 9, diindoleacetate 12, and the derivative 18 showed the best gastroprotective effect combined with the lowest cytotoxicity. PMID- 21246487 TI - [Revista de Neurologia and the Spanish neurology]. PMID- 21246488 TI - [Significance of complex analysis of electrical activity in temporal lobe epilepsy: foramen ovale electrodes records]. AB - INTRODUCTION: Temporal lobe epilepsy (TLE) is commonly associated with the process of synchronisation during the interictal stage, which show up as 'spikes' on neurophysiological recordings, and also with hypersynchronic activity during clinical seizures. Nevertheless, desynchronisation also seems to play an important role in the epileptogenic process, favouring the onset of seizures. AIMS: The aim of this work is to show how the latest complex network analysis techniques applied to the recordings from the foramen ovale electrodes provide valuable new information about the dynamics of mesial activity in TLE. The study also seeks to show that desynchronisation of the mesial activity plays an important role in TLE. PATIENTS AND METHODS: A cluster technique was used to analyse the recordings of six patients with TLE during the interictal stage and two seizures during the ictal period. RESULTS. Electrical activity on the ipsilateral side behaves in a less synchronic manner than that of the contralateral side. There is clearly a greater tendency in the mesial zone of the epileptic side to arrange itself in isolated groups of synchronic activity than on the contralateral side, which is organised in large groups of synchronised activity. CONCLUSIONS: Analysis of the neurophysiological recordings, especially from the foramen ovale electrodes, by cluster and network analysis provides novel information that is not accessible by classical spike analysis. The greater degree of desynchronisation on the ipsilateral side would favour the appearance and origin of the seizures on that side. PMID- 21246489 TI - [The levels of expression of toll-like receptors 2 and 4 in neutrophils are associated with the prognosis of ischaemic stroke patients]. AB - INTRODUCTION: Cerebral ischaemia triggers a very intense inflammatory response that is characterised by the infiltration of leukocytes in the brain parenchyma. The first of these cells to reach the brain are the neutrophils. Nevertheless, the role played by neutrophils and the expression of their innate immunity receptors TLR2 and TLR 4 (toll-like receptors 2 and 4) in cerebral ischaemia is still not fully understood. AIM: To examine the association between the levels of neutrophils and the expression of TLR2 and TLR4 in those cells and the prognosis of ischaemic stroke patients. PATIENTS AND METHODS: The study involved a sample of 110 patients with an ischaemic stroke that had started less than 12 hours earlier. The main variables that were taken into account were the modified Rankin scale at three months (poor prognosis > 2) and the volume of the infarction (measured by means of computerised tomography between days 4 and 7). We analysed the percentage of neutrophils and the mean expression of TLR2 and TLR4 in neutrophils by means of flow cytometry on admission, at 24 h, at 72 h and at 7 days. RESULTS: The TLR4 expression in neutrophils at 72 h (odds ratio, OR = 2.1; confidence interval of 95%, CI 95% = 1.4-3.2) and at 7 days (OR = 3.2; CI 95% = 1.7-6.1) was associated independently with the patients' prognosis and with the volume of the infarction at 72 h (B = 5.4; CI 95% = 2.9-7.8) and at 7 days (B = 7.0; CI 95% = 4.5-9.6). CONCLUSIONS: Neutrophils are associated with the prognosis of patients with ischaemic stroke through the expression of their TLR4. PMID- 21246490 TI - [Attentional neural networks impairment in healthy aging]. AB - INTRODUCTION: Diverse evidences have shown that the process of natural aging causes a decline in different cognitive functions, including among them the attentional process. AIM: To determine how the healthy aging affects to the different attentional networks. SUBJECTS AND METHODS: Two groups: young subjects (32.5 +/- 9.7 years) and an elderly group (62.7 +/- 4.7 years). As instrument to evaluate the attention process the ANT (Attention Network Test) was used. RESULTS: Highly significant differences were observed for all conditions involved in the ANT (no cue, center cue, spatial cue, congruent and incongruent) between both groups (p < 0.001). As for the analysis of network effects, no one showed differences between the two groups. Considering the block variable, the post hoc analysis showed that the orienting network for the young subjects exhibited a normal benefit in the first block while the elderly group don't show that benefit caused by the deficiency using spatial cues. Moreover, the alerting network showed a bigger effect in the first block regarding the second one in the older adults and the opposed effect for the executive and orienting network was observed. CONCLUSIONS: The obtained data show that a decrease exists in the speed processing in the elderly group. In the orienting network seems that the older adults require a bigger training period to use the spatial cues, although later on, they can benefit from the same cues almost at the same level that the young subjects. PMID- 21246491 TI - [Background and findings of neuroimaging in schizophrenia: an update]. AB - INTRODUCTION: Neuroimaging of psychiatric disorders, especially on schizophrenia, has been increased in the last decade. Different brain imaging techniques have become a useful tool to discover the pathophysiology of schizophrenia. AIMS: To describe scientific and historical background of neuroimaging in psychiatry, and to describe the current structural, functional and neurochemical findings in schizophrenia using brain imaging techniques, and their potential disadvantages. DEVELOPMENT: This review synthesizes our current knowledge on the neurobiology of psychosis, reviewing studies including structural (magnetic resonance imaging, diffusion tensor imaging), functional (PET and SPECT, functional magnetic resonance imaging) and neurochemical/transmission (neurochemical PET and SPECT, magnetic resonance spectroscopy) neuroimaging techniques on schizophrenia. CONCLUSIONS: Cognitive impairment, structural and functional disturbances, dopaminergic hypothesis, white matter changes, and any other findings, have been reported. Nevertheless, there are still many doubts and discrepancies to solve, regarding to neuroimaging in schizophrenia. Coupling multimodal imaging with genetics and pharmacotherapeutic studies will further assist in understanding the pathophysiology of schizophrenia. PMID- 21246492 TI - [Metatarsalgia and neuropathies of the foot. Differential diagnosis]. AB - INTRODUCTION: Metatarsalgia is the main symptom of a group of frequent ailments characterised by pain in the balls of the feet. Clinical knowledge and the availability of efficient complementary examinations are useful tools for the neurologist. AIM: To describe the range of processes related with metatarsalgia and a basic diagnostic schema that allows the aetiology to be differentiated. DEVELOPMENT: We perform an elementary review of the neurological anatomy of the foot and outline the different neuropathies affecting the region, as well as the extra neurological processes that could call for a differential diagnosis. CONCLUSIONS: Familiarity with the pathologies responsible for metatarsalgias, whether they are neurological or not, is an enriching element for the diagnosis and management of these patients, as well as for greater efficiency in the referral among the medical professionals involved. PMID- 21246493 TI - [Music and brain: neuroscientific foundations and musical disorders]. AB - Music is present in every culture and, from the earliest ages, we all have the basic capacities needed to process it, although this processing takes place in different modules that involve different regions of the brain. Do these regions form paths that are specific to musical processing? As we shall see, the production and perception of music engage a large part of our cognitive capabilities, involving areas of the auditory cortex and the motor cortex. On the other hand, music produces emotional responses within us that involve other cortical and subcortical areas. Are they the same paths as the ones engaged in the processing of emotions in general? We review the existing literature on these questions, as well as the different musical neurological disorders that exist, which range from musicogenic epilepsy to amusia, together with the different possible means of treatment. PMID- 21246494 TI - [Image and symptomatology]. PMID- 21246495 TI - [Posterior reversible leukoencephalopathy syndrome induced by L-asparaginase in a teenage female diagnosed with acute lymphoblastic leukemia]. PMID- 21246496 TI - [Two patients with chronic meningitis due to Angiostrongylus cantonensis]. PMID- 21246497 TI - [Neuropsychiatric side effects of intrathecal ziconotide]. PMID- 21246499 TI - [Focal refractory epilepsy: medical or surgical treatment?]. PMID- 21246504 TI - Improved product-per-glucose yields in P450-dependent propane biotransformations using engineered Escherichia coli. AB - P450-dependent biotransformations in Escherichia coli are attractive for the selective oxidation of organic molecules using mild and sustainable procedures. The overall efficiency of these processes, however, relies on how effectively the NAD(P)H cofactors derived from oxidation of the carbon source are utilized inside the cell to support the heterologous P450-catalyzed reaction. In this work, we investigate the use of metabolic and protein engineering to enhance the product per-glucose yield (Y(PPG)) in whole-cell reactions involving a proficient NADPH dependent P450 propane monooxygenase prepared by directed evolution [P450(PMO)R2; Fasan et al. (2007); Angew Chem Int Ed 46:8414-8418]. Our studies revealed that the metabolism of E. coli (W3110) is able to support only a modest propanol: glucose molar ratio (YPPG ~ 0.5) under aerobic, nongrowing conditions. By altering key processes involved in NAD(P)H metabolism of the host, considerable improvements of this ratio could be achieved. A metabolically engineered E. coli strain featuring partial inactivation of the endogenous respiratory chain (Deltandh) combined with removal of two fermentation pathways (DeltaadhE, Deltaldh) provided the highest Y(PPG) (1.71) among the strains investigated, enabling a 230% more efficient utilization of the energy source (glucose) in the propane biotransformation compared to the native E. coli strain. Using an engineered P450(PMO)R2 variant which can utilize NADPH and NADH with equal efficiency, we also established that dual cofactor specificity of the P450 enzyme can provide an appreciable improvement in Y(PPG). Kinetic analyses suggest, however, that much more favorable parameters (K(M), k(cat)) for the NADH-driven reaction are required to effectively compete with the host's endogenous NADH utilizing enzymes. Overall, the metabolic/protein engineering strategies described here can be of general value for improving the performance of NAD(P)H dependent whole-cell biotransformations in E. coli. PMID- 21246505 TI - Ionic liquid pretreatment of cellulosic biomass: enzymatic hydrolysis and ionic liquid recycle. AB - Ionic liquids (ILs) are promising solvents for the pretreatment of biomass as certain ILs are able to completely solubilize lignocellulose. The cellulose can readily be precipitated with an anti-solvent for further hydrolysis to glucose, but the anti-solvent must be removed for the IL to be recovered and recycled. We describe the use of aqueous kosmotropic salt solutions to form a three-phase system that precipitates the biomass, forming IL-rich and salt-rich phases. The phase behavior of [Emim][Ac] and aqueous phosphate salt systems is presented, together with a process for recycling the [Emim][Ac] and enzymatically hydrolyzing the cellulose. This process reduces the amount of water to be evaporated from recycled IL, permitting efficient recycle of the IL. Material balances on the process, with multiple recycles of the [Emim][Ac], quantify the major components from a Miscanthus feedstock through the pretreatment, separation, and enzymatic hydrolysis steps. A more rapid and higher yielding conversion of cellulose to glucose is obtained by use of the three-phase system as compared to the cellulose obtained from biomass pretreated with IL and precipitated with water. The addition of a kosmotropic salt during the precipitation results in partial delignification of the biomass, which makes the substrate more accessible, enhancing the enzymatic hydrolysis. PMID- 21246506 TI - Enhancing the enzymatic hydrolysis of lignocellulosic biomass by increasing the carboxylic acid content of the associated lignin. AB - To assess the effects that the physical and chemical properties of lignin might have on the enzymatic hydrolysis of pretreated lignocellulosic substrates, protease treated lignin (PTL) and cellulolytic enzyme lignin (CEL) fractions, isolated from steam and organosolv pretreated corn stover, poplar, and lodgepole pine, were prepared and characterized. The adsorption of cellulases to the isolated lignin preparations corresponded to a Langmuir adsorption isotherm. It was apparent that, rather than the physical properties of the isolated lignin, the carboxylic acid functionality of the isolated lignin, as determined by FTIR and NMR spectroscopy, had much more of an influence when lignin was added to typical hydrolysis of pure cellulose (Avicel). An increase in the carboxylic content of the lignin preparation resulted in an increased hydrolysis yield. These results suggested that the carboxylic acids within the lignin partially alleviate non-productive binding of cellulases to lignin. To try to confirm this possible mechanism, dehydrogenative polymers (DHP) of monolignols were synthesized from coniferyl alcohol (CA) and ferulic acid (FA), and these model compounds were added to a typical enzymatic hydrolysis of Avicel. The DHP from FA, which was enriched in carboxylic acid groups compared with the DHP from CA, adsorbed a lower mount of cellulases and did not decrease hydrolysis yields when compared to the DHP from CA, which decreased the hydrolysis of Avicel by 8.4%. Thus, increasing the carboxylic acid content of the lignin seemed to significantly decrease the non-productive binding of cellulases and consequently increased the enzymatic hydrolysis of the cellulose. PMID- 21246507 TI - Microalgal bacterial floc properties are improved by a balanced inorganic/organic carbon ratio. AB - Microalgal bacterial floc (MaB-floc) reactors have been suggested as a more sustainable secondary wastewater treatment. We investigated whether MaB-flocs could be used as tertiary treatment. Tertiary influent has a high inorganic/organic carbon ratio, depending on the efficiency of the secondary treatment. In this study, the effect of this inorganic/organic carbon ratio on the MaB-flocs performance was determined, using three sequencing batch photobioreactors. The MaB-flocs were fed with synthetic wastewater containing 84, 42, and 0 mg L(-1) C-KHCO(3) supplemented with 0, 42, 84 mg L(-1) C-sucrose, respectively, representing inorganic versus organic carbon. Bicarbonate significantly decreased the autotrophic index of the MaB-flocs and resulted in poorly settling flocs. Moreover, sole bicarbonate addition led to a high pH of 9.5 and significant lower nitrogen removal efficiencies. Sucrose without bicarbonate resulted in good settling MaB-flocs, high nitrogen removal efficiencies and neutral pH levels. Despite the lower chlorophyll a content of the biomass and the lower in situ oxygen concentration, 92-96% of the soluble COD sucrose was removed. This study shows that the inorganic/organic carbon ratio of the wastewater is of major importance and that organic carbon is requisite to guarantee a good performance of the MaB-flocs for wastewater treatment. PMID- 21246508 TI - Differential effect of exocytic SNAREs on the production of recombinant proteins in mammalian cells. AB - Mammalian cells play a dominant role in the industrial production of biopharmaceutical proteins. However, the productivity of producer cells is often hindered by a bottleneck in the saturated secretory pathway, where a sophisticated mechanism of vesicle trafficking is mediated by numerous proteins and their complexes, among which are the cross-kingdom conserved SNAREs [soluble NSF (N-ethylmaleimide-sensitive factor) receptor]. The SNAREs assemble into complexes by means of four interactive alpha-helices and, thus, trigger the fusion of transport vesicles with the respective target membranes. We report that the transgenic expression of exocytic SNAREs, which control the fusion of secretory vesicles to the plasma membrane, differentially impacts the secretory capacity of HEK-293, HeLa, and CHO-K1 cells. While other exocytic SNAREs have no effect or a negative effect, SNAP-23 [synaptosome-associated protein of 23 kDa] and VAMP8 [vesicle-associated membrane protein 8] specifically increase the production of recombinant proteins when they are ectopically and stably expressed in mammalian cells. The targeted and effective intervention in the secretory capacity of SNARE proteins is a novel engineering strategy, which could lead to the development of new therapies by increasing the production of biopharmaceutical proteins or by boosting the secretion of cell implants in cell therapy initiatives. PMID- 21246509 TI - Improved galactose fermentation of Saccharomyces cerevisiae through inverse metabolic engineering. AB - Although Saccharomyces cerevisiae is capable of fermenting galactose into ethanol, ethanol yield and productivity from galactose are significantly lower than those from glucose. An inverse metabolic engineering approach was undertaken to improve ethanol yield and productivity from galactose in S. cerevisiae. A genome-wide perturbation library was introduced into S. cerevisiae, and then fast galactose-fermenting transformants were screened using three different enrichment methods. The characterization of genetic perturbations in the isolated transformants revealed three target genes whose overexpression elicited enhanced galactose utilization. One confirmatory (SEC53 coding for phosphomannomutase) and two novel targets (SNR84 coding for a small nuclear RNA and a truncated form of TUP1 coding for a general repressor of transcription) were identified as overexpression targets that potentially improve galactose fermentation. Beneficial effects of overexpression of SEC53 may be similar to the mechanisms exerted by overexpression of PGM2 coding for phosphoglucomutase. While the mechanism is largely unknown, overexpression of SNR84, improved both growth and ethanol production from galactose. The most remarkable improvement of galactose fermentation was achieved by overexpression of the truncated TUP1 (tTUP1) gene, resulting in unrivalled galactose fermentation capability, that is 250% higher in both galactose consumption rate and ethanol productivity compared to the control strain. Moreover, the overexpression of tTUP1 significantly shortened lag periods that occurs when substrate is changed from glucose to galactose. Based on these results we proposed a hypothesis that the mutant Tup1 without C-terminal repression domain might bring in earlier and higher expression of GAL genes through partial alleviation of glucose repression. mRNA levels of GAL genes (GAL1, GAL4, and GAL80) indeed increased upon overexpression of tTUP. The results presented in this study illustrate that alteration of global regulatory networks through overexpression of the identified targets (SNR84 and tTUP1) is as effective as overexpression of a rate limiting metabolic gene (PGM2) in the galactose assimilation pathway for efficient galactose fermentation in S. cerevisiae. In addition, these results will be industrially useful in the biofuels area as galactose is one of the abundant sugars in marine plant biomass such as red seaweed as well as cheese whey and molasses. PMID- 21246510 TI - Hydrophobic salts markedly diminish viscosity of concentrated protein solutions. AB - Reducing viscosities of concentrated solutions of therapeutic proteins is important for their subcutaneous and intravenous delivery. Although inorganic salts and optimizing the pH were previously reported to dramatically lower the viscosity of a monoclonal antibody solution, herein we have determined these effects not to be general. Separately, we have found that hydrophobic ionic excipients, both anionic and cationic, substantially decrease the viscosity of concentrated (300-400 mg/mL) aqueous solutions of bovine serum albumin and gamma globulin. The more hydrophobic the excipient, the greater its viscosity-lowering effect is. With cationic ones, the concomitant contribution of the counter-ion broadly follows the chaotropic order. The most potent excipients lower the viscosity over fourfold to levels far below the 50 cP threshold for subcutaneous injections. The observed viscosity reductions are rationalized in terms of three dimensional transient protein networks formed in concentrated solutions due to hydrophobic and, to a lesser extent, ionic interactions. These reversible protein aggregates are responsible for strong resistance to flow in concentrated protein solutions and hence their high viscosity; hydrophobic ions apparently effectively compete for these interprotein interactions, thereby giving rise to less viscous solutions. PMID- 21246511 TI - Label-free identification of bacterial microcolonies via elastic scattering. AB - Label-free microcolony identification via elastic light scattering was investigated for three different genera: Salmonella enterica serovar Montevideo, Listeria monocytogenes F4244, and Escherichia coli DH5alpha. Microcolonies were defined as bacterial colonies in their late-lag phase to early-exponential phase with the diameter range of 100-200 um. To link biophysical characteristics with corresponding scattering patterns, a phase contrast microscope and a confocal displacement meter were used to measure the colony diameter and its 3D height profile. The results indicated that the growth characteristics of microcolonies were encoded in their morphologies which correlated to the characteristic diffraction patterns. Proposed methodology was able to classify three genera based on comprehensive phenotypic map which incorporated growth speed, ring count, and colony diameter. While the proposed method illustrated the possibility of discriminating microcolonies in their early growth stage, more thorough biophysical understanding is needed to expand the technology to other species. PMID- 21246512 TI - Characterization of combinatorial patterns generated by multiple two-component sensors in E. coli that respond to many stimuli. AB - Two-component systems enable bacteria to sense changes in their environment and adjust gene expression in response. Multiple two-component systems could function as a combinatorial sensor to discriminate environmental conditions. A combinatorial sensor is composed of a set of sensors that are non-specifically activated to different magnitudes by many stimuli, such that their collective activity pattern defines the signal. Using promoter reporters and flow cytometry, we measured the response of three two-component systems in Escherichia coli that have been previously reported to respond to many environmental stimuli (EnvZ/OmpR, CpxA/CpxR, and RcsC/RcsD/RcsB). A chemical library was screened for the ability to activate the sensors and 13 inducers were identified that produce different patterns of sensor activity. The activities of the three systems are uncorrelated with each other and the osmolarity of the inducing media. Five of the seven possible non-trivial patterns generated by three sensors are observed. This data demonstrate one mechanism by which bacteria are able to use a limited set of sensors to identify a diverse set of compounds and environmental conditions. PMID- 21246513 TI - Fabrication of highly porous scaffolds for tissue engineering based on star shaped functional poly(epsilon-caprolactone). AB - The potential of novel functional star-shaped poly(epsilon-caprolactone)s of controlled molecular weight and low molecular weight distribution bearing acrylate end groups as material for biomedical applications was demonstrated in this study. The polymers were functionalized via Michael-type addition of amino acid esters containing amino or thiol groups showing the potential for immobilization of biomolecules. Furthermore, scaffolds of different geometries were prepared by uniaxial freezing of polymer solutions followed by freeze drying. Different solvents and polymer concentrations were investigated, resulting in scaffolds with porosities between 76 and 96%. Mechanical properties of the scaffolds were investigated and the morphology was determined via scanning electron microscopy. Scaffolds with interconnected channels were prepared using benzene, 1,2-dichloroethane or dioxane as solvent. The tubular longitudinal pores in honeycomb arrangement extend throughout the full extent of the scaffolds (typical pore sizes: 20-100 um). PMID- 21246514 TI - Engineered heart tissue enables study of residual undifferentiated embryonic stem cell activity in a cardiac environment. AB - Embryonic stem cell (ESC) derivatives are a promising cell source for cardiac cell therapy. Mechanistic studies upon cell injection in conventional animal models are limited by inefficient delivery and poor cell survival. As an alternative, we have used an engineered heart tissue (EHT) based on neonatal rat cardiomyocytes (CMs) cultivated with electrical field stimulation as an in vitro model to study cell injection. We injected (0.001, 0.01, and 0.1 million) and tracked (by qPCR and histology) undifferentiated yellow-fluorescent protein transgenic mouse ESCs and Flk1 + /PDGFRalpha+ cardiac progenitor (CPs) cells, to investigate the effect of the cardiac environment on cell differentiation, as well as to test whether our in vitro model system could recapitulate the formation of teratoma-like structures commonly observed upon in vivo ESC injection. By 8 days post-injection, ESCs were spatially segregated from the cardiac cell population; however, ESC injection increased survival of CMs. The presence of ESCs blocked electrical conduction through the tissue, resulting in a 46% increase in the excitation threshold. Expression of mouse cardiac troponin I, was markedly increased in CP injected constructs compared to ESC injected constructs at all time points and cell doses tested. As early as 2 weeks, epithelial and ganglion-like structures were observed in ESC injected constructs. By 4 weeks of ESC injection, teratoma-like structures containing neural, epithelial, and connective tissue were observed in the constructs. Non-cardiac structures were observed in the CP injected constructs only after extended culture (4 weeks) and only at high cell doses, suggesting that these cells require further enrichment or differentiation prior to transplantation. Our data indicate that the cardiac environment of host tissue and electrical field stimulation did not preferentially guide the differentiation of ESCs towards the cardiac lineage. In the same environment, injection of CP resulted in a more robust cardiac differentiation than injection of ESC. Our data demonstrate that the model-system developed herein can be used to study the functional effects of candidate stem cells on the host myocardium, as well as to measure the residual activity of undifferentiated cells present in the mixture. PMID- 21246515 TI - Demonstration of the IDEAL recommendations for evaluating and reporting surgical innovation in minimally invasive oesophagectomy. AB - BACKGROUND: The Idea, Development, Evaluation, Assessment and Long term study (IDEAL) framework makes recommendations for evaluating and reporting surgical innovation and adoption, but remains untested. METHODS: A prospective database was created for the introduction of minimally invasive techniques for oesophagectomy. IDEAL stages of development and evaluation were examined retrospectively in a series of patients undergoing laparoscopically assisted oesophagectomy (LAO), two- or three-phase minimally invasive oesophagectomy (MIO) and open oesophagectomy. RESULTS: A total of 192 patients were involved. In IDEAL stages 1 and 2a, LAO in 16 patients was uneventful, but two-phase MIO in six patients was abandoned following consecutive technical complications. Two-phase MIO was modified to a three-phase MIO procedure, and the results of LAO (67 patients), three-phase MIO (35) and open techniques (68) were studied in IDEAL stage 2b. Major complications (Clavien-Dindo grades III and IV) occurred in 12 (18 per cent), nine (26 per cent) and 14 (21 per cent) LAO, three-phase MIO and open procedures respectively. There were four in-hospital deaths (2 LAO and 2 open). CONCLUSION: The IDEAL framework is a feasible method for documenting the development and implementation of a procedure. MIO should now be compared with open surgery in a randomized controlled trial (IDEAL stage 3). PMID- 21246516 TI - Risk factors for survival and local recurrence after particle radiotherapy for single small hepatocellular carcinoma. AB - BACKGROUND: Particle radiotherapy is a novel treatment for malignant tumours. The present study aimed to evaluate risk factors for overall survival and local control after particle radiotherapy of single small hepatocellular carcinoma (HCC), and to identify suitable candidates for this treatment. METHODS: All patients with a single HCC smaller than 5 cm in diameter treated by particle radiotherapy between 2001 and 2008 were identified retrospectively from a prospectively collected database. Clinical outcomes and prognostic factors were analysed. RESULTS: A total of 150 patients were included. Five-year overall survival and local control rates were 50.9 and 92.3 per cent respectively. Multivariable analysis revealed that several factors, including age and Child Pugh classification, significantly influenced overall survival. Proximity to the digestive tract and Child-Pugh classification were independent risk factors for local recurrence. Other tumour factors including size, gross classification, previous treatment, macroscopic vascular invasion, and tumour location in relation to the diaphragm and large vessels did not influence local control rate. CONCLUSION: Particle radiotherapy seems safe and effective, and may be a novel treatment for small HCC. Recurrences are more frequent when the tumour is located close to the gut. PMID- 21246517 TI - Systematic review and meta-analysis of sentinel node biopsy in thyroid cancer. AB - BACKGROUND: Sentinel node biopsy (SNB) is employed as standard treatment in some solid organ cancers to assess lymph node spread and enable targeted treatment. Several studies have investigated the role of SNB in thyroid cancer. This is a systematic review and meta-analysis of the role of SNB in the management of thyroid cancer. METHODS: A systematic search was performed in the PubMed database to identify all original articles on the role of SNB in thyroid cancer. Data on methodologies used, short-term outcomes and adverse effects were summarized, and used to address relevant clinical questions related to the application of the SNB technique in thyroid cancer. RESULTS: Twenty-four studies were included. The overall sentinel node (SN) detection rates for the blue dye, radioisotope and combined techniques were 83.7, 98.4 and 96 per cent respectively. A positive SN was seen in 42.9 per cent of patients with papillary thyroid cancer with an identified SN. The overall false-negative rates for the blue dye, radioisotope and combined techniques were 7.7, 16 and 0 per cent respectively. A negative frozen-section examination of the SN was unreliable in 12.0 per cent of patients. Immunohistochemical assessment of the SN showed evidence of nodal metastases in an additional 15 per cent of patients (7 of 47 sentinel nodes). CONCLUSION: SNB in thyroid cancer is a promising technique that has the potential to avoid prophylactic lymph node surgery in up to 57 per cent of patients with clinically node-negative thyroid cancer. PMID- 21246518 TI - Preventing invasive breast cancer: another benefit from mammographic screening. PMID- 21246520 TI - High-risk extracranial chondrosarcoma: long-term results of surgery and radiation therapy. AB - BACKGROUND: A study was undertaken to evaluate results of surgery and radiotherapy (RT) for high-risk extracranial chondrosarcomas. METHODS: Between 1986 and 2006, 60 patients underwent surgery and RT for extracranial high-risk chondrosarcoma. Preoperative RT (median, 50 gray [Gy]) and postoperative RT (median, 60 Gy) were used in 40% and 60% patients, respectively. Sites included pelvis/lower extremity (48%), chest wall (22%), spine/paraspinal (17%), and head and neck (13%). Overall, median tumor size was 7 cm (range, 1-22 cm), and tumor grade was I, II, and III in 22%, 64%, and 14% of cases, respectively. RESULTS: Pathologically clear surgical margins (R0) were present in 50%, microscopic positive margins (R1) in 28%, and gross positive margins (R2) in 13%, half of whom had clinically detectable residual disease; surgical margin was unknown in 8%. Median follow-up was 75 months (range, 5-230 months). The crude local control rate was 90%. Patients with R0, R1, and R2 resections had local control of 100%, 94%, and 42%, respectively. Of the 8 cases that had R2 resection, 3 experienced uncontrolled progression, but 5 patients had stable disease with long-term follow up. The 10-year overall survival, progression-free survival, and cause-specific survival were 86%, 80.5%, and 89.4%, respectively. Younger age and grade III tumors were associated with worse progression-free survival (P = .03 and .0003, respectively). CONCLUSIONS: Although surgery with complete resection is paramount in management of chondrosarcoma, RT is a useful adjuvant treatment and appears to offer excellent and durable local control where wide surgical resection is difficult to accomplish. PMID- 21246519 TI - Phase 1 trial of concurrent erlotinib, celecoxib, and reirradiation for recurrent head and neck cancer. AB - BACKGROUND: Concurrent inhibition of epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) is an active and well tolerated regimen in recurrent head and neck cancer (HNC). In the current phase 1 trial, the authors sought to determine the maximum tolerated dose (MTD) and efficacy of concurrent erlotinib and celecoxib as a radiosensitizing regimen. METHODS: Fourteen patients with previously irradiated HNC with no distant metastases who required reirradiation were eligible. Treatment consisted of daily erlotinib 150 mg and twice daily celecoxib (escalated from 200 mg to 600 mg using a 3 + 3 design with an expanded cohort at the MTD) starting on Day 1 and was continued during radiation. Daily radiation was started on Day 15, and maintenance erlotinib was recommended. RESULTS: The recommended phase 2 dose of celecoxib was 400 mg. Three dose limiting toxicities included late in-field orocutaneous fistula (Dose Level 2), osteonecrosis (Dose Level 3), and trismus (Dose Level 3). Acute grade >= 3 toxicities were uncommon and included mucositis (21%) and dermatitis (14%). At a median follow-up of 11 months, the 1-year locoregional control, progression-free survival, and overall survival rates were 60%, 37%, and 55%, respectively. CONCLUSIONS: Concurrent erlotinib, celecoxib, and reirradiation was a feasible and clinically active regimen in a population of patients with recurrent HNC who had a poor prognosis. PMID- 21246522 TI - Immunohistochemical subtyping of nonsmall cell lung cancer not otherwise specified in fine-needle aspiration cytology: a retrospective study of 103 cases with surgical correlation. AB - BACKGROUND: Histopathological subtyping of nonsmall cell lung cancer (NSCLC) is currently relevant in treatment decision because of a differential activity of specific therapeutic agents. Immunohistochemistry highlights cell differentiation lineages and, in this study, it was applied to maximize the proportion of accurately subtyped NSCLC not otherwise specified (NOS) on fine-needle aspiration cytology (FNAC) samples. METHODS: Cell blocks from 103 FNAC samples with a morphological diagnosis of NSCLC-NOS were immunostained for cytokeratin (CK) 7, CK5, TTF1, and p63, whereas p40, napsin A (Naps-A), and desmocollin-3 (DSC-3) were only assessed in a subgroup of cases with discordant (CK7 and TTF1+ for nonsquamous, CK5 and p63+ for squamous) findings. Results were correlated with surgical specimens evaluated by morphology alone. RESULTS: Thirty-seven (36%) tumors with CK7/TTF1+ and CK5/p63- corresponded to 35 cases of adenocarcinoma (ADC) and 2 cases of large cell carcinoma, whereas 9 (9%) cases with the reverse immunoprofile were squamous cell carcinoma (SQCC) at surgery (P < .001). Although the remaining 57 cases had different marker combinations, a correlation was found with ADC histology for TTF1+ samples (independent of other markers) and with SQCC for p63+/TTF1- immunophenotype (P < .001). p40 was never expressed in p63+ ADC, whereas Naps-A was restricted to ADC and DSC-3 to SQCC lineage. The percentage of unclassified NSCLC-NOS decreased from 36% to 14%. Combinations of 2 antibodies (TTF1/DSC-3 or p63/Naps-A) in the same section allowed diagnostic optimization in scant cytological samples. CONCLUSIONS: [corrected] This 4-antibody panel approach may contribute to refine lung cancer classification in FNAC cell blocks, remarkably reducing the NSCLC-NOS diagnostic category. PMID- 21246521 TI - Alpha-internexin expression predicts outcome in anaplastic oligodendroglial tumors and may positively impact the efficacy of chemotherapy: European organization for research and treatment of cancer trial 26951. AB - BACKGROUND: Although it has been demonstrated that the neuronal intermediate filament alpha-internexin (INA) is closely related to 1p19q codeletion in gliomas, its prognostic and predictive value has not yet been confirmed in a prospective trial. The authors of this report assessed the prognostic significance of INA expression and its correlation with relevant clinical and molecular characteristics in the prospective, randomized European Organization for Research and Treatment of Cancer (EORTC) 26951 trial of adjuvant procarbazine, lomustine, and vincristine (PCV) in patients with anaplastic oligodendroglial tumors (AOTs). METHODS: INA immunohistochemistry expression in tumors from 92 patients who were included in the EORTC 26951 trial was analyzed independently by 2 observers and was correlated with relevant clinical characteristics, including progression-free survival (PFS) and overall survival (OS), and with molecular features, including 1p/19q codeletion, isocitrate dehydrogenase 1 and 2 gene (IDH1/IDH2) mutation, and O-6 methylguanine-DNA methyltransferase (MGMT) promoter methylation status. RESULTS: INA expression was observed in 33 tumors and was strongly correlated with 1p/19q codeletion, IDH1 mutations, and MGMT promoter methylation. It was associated with significantly better PFS and OS independent of the treatment received. By using Cox proportional hazard modeling for OS with stepwise selection, INA expression, patient age, and performance status were identified as independent prognostic factors. The results indicated that INA expression may have an impact on the efficacy of combined radiotherapy plus PCV. CONCLUSIONS: In a homogeneously treated group of patients with grade III AOTs, INA expression had strong favorable prognostic significance for OS and may have predictive value for sensitivity to chemotherapy. PMID- 21246523 TI - Nodal yield and survival in oral squamous cancer: Defining the standard of care. AB - BACKGROUND: Elective neck dissection (END) is commonly used as a staging and therapeutic procedure for oral squamous cell carcinoma (SCC) at high risk of nodal metastases. The authors aimed to determine whether the extent of lymphadenectomy, as defined by nodal yield, is a prognostic factor in this setting. METHODS: A retrospective database review identified 225 patients undergoing END with curative intent for oral SCC between 1987 and 2009. Nodal yield was studied as a categorical variable for association with overall, disease specific, and disease-free survival in univariate and multivariate analyses. RESULTS: Nodal yield <18 was associated with 5-year overall survival of 51% compared with 74% in those with nodal yield >= 18 (P = .009). Five-year disease specific survival rates were 69% in those with <18 nodes and 87% in patients with >= 18 nodes (P = .022). Similar results were obtained for disease-free survival, with 5-year rates of 44% with <18 nodes versus 71% with >= 18 nodes (P = .043). After adjusting for the effect of age, nodal status, T stage, and adjuvant radiotherapy on multivariate analysis, nodal yield <18 was associated with reduced overall (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.6; P = .020), disease-specific (HR, 2.2; 95% CI, 1.1-4.5; P = .043), and disease-free survival (HR, 1.7; 95% CI, 1.1-2.8; P = .040). In the pathologically lymph node negative subgroup (n = 148), similar results were obtained. CONCLUSIONS: Nodal yield is an independent prognostic factor in patients undergoing END for oral SCC. These results suggest that an adequate lymphadenectomy in this setting should include at least 18 nodes. PMID- 21246524 TI - Isolated limb perfusion for unresectable extremity sarcoma: results of 2 single institution phase 2 trials. AB - BACKGROUND: Controversy has surrounded the role of isolated limb perfusion (ILP) for unresectable extremity sarcomas. However, there remains a group of sarcoma patients for whom amputation is the only potential treatment. Because systemic therapies are limited, the authors evaluated ILP in an effort to provide a limb salvage option. METHODS: Since 1995, patients with unresectable extremity sarcomas were entered in 2 prospective trials using ILP. Study 1 used tumor necrosis factor (TNF) and melphalan in the perfusion circuit at hyperthermic temperatures (39-41 degrees C). Study 2 used doxorubicin at normothermic temperatures. All ILPs were performed using the standard, previously described technique. RESULTS: Seventeen patients were entered into study 1; there were 10 (58%) partial responses, 1 (6%) near complete response (CR), 1 (6%) CR, and 5 (30%) no response/minor response. Fourteen patients died of their disease, with a median follow-up of 17 months. Seven (41%) patients maintained their limb intact until the time of death. Twelve patients were entered into study 2; there were no partial or CRs and 2 (20%) minor responses. With a median follow-up of 35 months, there are 3 patients alive (2 with their extremity intact and 1 with an amputation). Six patients developed myonecrosis with creatine phosphokinase levels up to 54,000 U/dL. CONCLUSIONS: Although doxorubicin is active systemically, TNF and melphalan appear to have greater activity and less toxicity during ILP. Future clinical trials are needed to clearly identify the role for ILP in patients with unresectable extremity sarcomas. Cancer 2011. (c) 2011 American Cancer Society. PMID- 21246526 TI - Experience with rituximab immunotherapy as an early intervention in patients with Rai stage 0 to II chronic lymphocytic leukemia. AB - BACKGROUND: Management of asymptomatic early stage chronic lymphocytic leukemia (CLL) centered on expectant surveillance for active disease warranting chemotherapy. In CLL, elevated serum beta-2 microglobulin (beta2M) levels were associated with more rapid disease progression and shorter survival (OS). METHODS: An early intervention trial was designed to assess response, time-to progression (TTP), and OS after immunotherapy with standard-dose rituximab (375 mg/m2 intravenously weekly for 8 consecutive weeks) in 34 asymptomatic untreated early stage CLL with beta2M level >= 2 mg/dL. RESULTS: Long-term follow-up and results are reported. The overall response rate in 34 patients was 82% (9% complete [CR]), median TTP in the 28 responders was 23 months, the median time to subsequent treatment was 43 months, and the 8-year OS rate was 74% (median follow up, 102 months). CONCLUSIONS: Early treatment with rituximab was well tolerated and safe. Further studies are needed to determine if this intervention can decrease CLL-related morbidity and mortality. PMID- 21246525 TI - A phase 2 trial of bortezomib followed by the addition of doxorubicin at progression in patients with recurrent or metastatic adenoid cystic carcinoma of the head and neck: a trial of the Eastern Cooperative Oncology Group (E1303). AB - BACKGROUND: Bortezomib, an inhibitor of the 26S proteasome and NF-kappaB, may have antitumor activity in adenoid cystic carcinoma (ACC). Preclinical studies have shown synergy between bortezomib and doxorubicin. METHODS: Eligibility criteria included incurable ACC, any number of prior therapies but without an anthracycline, unidimensionally measurable disease, Eastern Cooperative Oncology Group performance status 0-2, and ejection fraction within normal limits. Patients with stable disease for >=9 months were excluded. Patients received bortezomib 1.3 mg/m(2) by intravenous (IV) push on Days 1, 4, 8, and 11, every 21 days until progression. Doxorubicin 20 mg/m(2) IV on Days 1 and 8 was added at the time of progression. RESULTS: Twenty-five patients were enrolled, of whom 24 were eligible; the most common distant metastatic sites were the lung (n = 22) and the liver (n = 7). There was no objective response with single-agent bortezomib; best response was stable disease in 15 (71%) of 21 evaluable patients. The median progression-free survival and overall survival were 6.4 months and 21 months, respectively. Of 10 evaluable patients who received bortezomib plus doxorubicin, 1 had a partial response, and 6 had stable disease. The most frequent toxicity with bortezomib was grade 3 sensory neuropathy (16%). With bortezomib plus doxorubicin, serious toxicities seen more than once were grade 3-4 neutropenia (n = 3) and grade 3 anorexia (n = 2). CONCLUSIONS: Bortezomib was well tolerated and resulted in disease stabilization in a high percentage of patients but no objective responses. The combination of bortezomib and doxorubicin was also well tolerated and may warrant further investigation in ACC. PMID- 21246527 TI - Neuroendocrine tumors of midgut and hindgut origin: tumor-node-metastasis classification determines clinical outcome. AB - BACKGROUND: Prognostic classification of neuroendocrine tumor (NET) patients is difficult due to the complexity of current classification systems. A recent proposal for a tumor-node-metastasis (TNM) classification and a grading system based on the proliferative fraction proved valid in NETs of foregut origin. The purpose of this study was to test the efficacy of a proposal for TNM staging and grading for midgut and hindgut NETs. METHODS: Two hundred seventy patients with histologically proven midgut and hindgut NETs were investigated. Epidemiological, clinicopathological, and tumor-specific data at initial diagnosis were recorded. Tumors were classified according to the World Health Organization (WHO) and the recent European Neuroendocrine Tumor Society-TNM staging and grading proposal. Survival analysis and statistical testing for independent prognostic factors were performed using log-rank tests and Cox regression. RESULTS: Of 270 NETs originating in the midgut or hindgut, 7% (5-year survival rate [YSR], 100%) were stage 1, 8% (5-YSR, 100%) were stage 2, 19% (5-YSR, 89.5%) were stage 3, and 66% (5-YSR, 83.3%) were stage 4 NETs; 62% (5-YSR 95.2%) were grade 1, 32% (5-YSR 82.0%) were grade 2, and 6% (5-YSR, 51.4%) were grade 3 NETs. WHO classification significantly separated poorly from well-differentiated NET or carcinomas but did not further discriminate. TNM staging significantly separated stages 1, 2, and 3 from stage 4 NETs, as did grading according to proliferative capacity for all grades. Multivariate analysis confirmed these results, particularly for Ki67 grading. CONCLUSIONS: The acquired data confirmed the prognostic relevance of the proposed TNM staging and grading system and demonstrated the applicability of these classification tools. The TNM system can therefore facilitate therapeutic stratification and comparison of data from different institutions. PMID- 21246528 TI - Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group. AB - BACKGROUND: Contemporary therapy for medulloblastoma results in adverse neurocognitive effects on young children, particularly those under the age of 3. Stratification of patients by risk group may allow toxic treatment to be avoided. METHODS: Seventy-six patients diagnosed with medulloblastoma and enrolled on CCG 9921 underwent central review of pathology, and histologic subtype was designated as desmoplastic or nondesmoplastic. Nonparametric event-free survival (EFS) and survival (OS) curves were computed using the product limit (Kaplan-Meier) estimates, and the log-rank test was used to compare survival according to histologic subtype. RESULTS: Patients with desmoplastic medulloblastoma experienced a favorable EFS of 77% +/- 9% and OS of 85% +/- 8% compared with EFS of 17% +/- 5% and OS of 29% +/- 6% for patients with tumors in the nondesmoplastic group (P < .0001 for both EFS and OS comparisons). Patients without disease progression did not receive radiation therapy. CONCLUSIONS: Children less than 3 with desmoplastic histology of medulloblastoma represent a lower-risk group for whom reduction of therapy, including elimination of radiation therapy, is an appropriate strategy. PMID- 21246529 TI - Comorbidities and mammography use interact to explain racial/ethnic disparities in breast cancer stage at diagnosis. AB - BACKGROUND: Interactions with comorbidity burden and comorbidity-related care have not been examined as potential explanations for racial/ethnic disparities in advanced-stage breast cancer at diagnosis. METHODS: The authors used linked Surveillance, Epidemiology, and End Results-Medicare data to determine whether comorbidity burden and comorbidity-related care are associated with stage at diagnosis, whether these associations are mediated by mammography use, and whether they explain racial/ethnic disparities. Stage at diagnosis and mammography use were analyzed in multivariate regression models, adjusting for comorbidity burden and comorbidity-race interactions among 118,742 women diagnosed with breast cancer during 1993 to 2005. RESULTS: Mammography utilization was higher among women with >= 3 stable comorbidities than among those without comorbidities. Advanced stage at diagnosis was associated with black race (odds ratio [OR], 1.8; 95% confidence interval [CI], 1.6-1.8), Hispanic ethnicity (OR, 1.3; 95% CI, 1.2-1.5), unstable comorbidity, and age >= 80 years. Mammography was protective in all racial/ethnic groups, but neither mammography use (OR, 0.3; 95% CI, 0.3-0.3 and OR, 0.2; 95% CI, 0.2-0.2 for women with 1 and >= 2 prior mammograms, respectively) nor overall physician service use (OR, 0.7; 95% CI, 0.7-0.8 for women with >= 16 visits) explained the association between race/ethnicity and stage at diagnosis. The black/white OR fell to 1.2 (95% CI, 0.9-1.5) among women with multiple stable comorbidities who received >= 2 screening mammograms, and 1.0 (95% CI, 0.8-1.3) among mammography users with unstable comorbidities. CONCLUSIONS: Comorbidity burden was associated with regular mammography and earlier stage at diagnosis. Racial/ethnic disparities in late stage disease were reduced among women who received both regular mammograms and comorbidity-related care. PMID- 21246530 TI - Occupational outcomes of adult childhood cancer survivors: A report from the childhood cancer survivor study. AB - BACKGROUND: The authors examined whether survivors from the Childhood Cancer Survivor Study were less likely to be in higher-skill occupations than a sibling comparison and whether certain survivors were at higher risk for lower-skill jobs. METHODS: The authors created 3 mutually exclusive occupational categories for participants aged >= 25 years: Managerial/Professional, Nonphysical Service/Blue Collar, and Physical Service/Blue Collar. The authors examined currently employed survivors (4845) and their siblings (1727) in multivariable generalized linear models to evaluate the likelihood of being in 1 of the 3 occupational categories. Multinomial logistic regression was used among all participants to examine the likelihood of these outcomes compared to being unemployed (survivors, 6671; siblings, 2129). Multivariable linear models were used to assess survivor occupational differences by cancer- and treatment related variables. Personal income was compared by occupation. RESULTS: Employed survivors were less often in higher-skilled Managerial/Professional occupations (relative risk, 0.93; 95% confidence interval 0.89-0.98) than their siblings. Survivors who were black, were diagnosed at a younger age, or had high-dose cranial radiation were less likely to hold Managerial/Professional occupations than other survivors. In multinomial models, female survivors' likelihood of being in full-time Managerial/Professional occupations (27%) was lower than male survivors (42%) and female (41%) and male (50%) siblings. Survivors' personal income was lower than siblings within each of the 3 occupational categories in models adjusted for sociodemographic variables. CONCLUSIONS: Adult childhood cancer survivors are employed in lower-skill jobs than siblings. Survivors with certain treatment histories are at higher risk for lower-skill jobs and may require vocational assistance throughout adulthood. PMID- 21246531 TI - Breast cancer screening beliefs, recommendations and practices: primary care physicians in the United States. AB - BACKGROUND: Primary care physicians (PCPs) play a key role in breast cancer screening, yet no current data exist regarding PCP practices. METHODS: The authors analyzed a nationally representative survey of PCPs that was fielded during September 2006 to May 2007 to investigate PCP breast cancer screening beliefs, recommendations, and practices. RESULTS: Most of the 1212 PCPs who participated in the survey (80%) reported that mammography for average-risk women aged >= 50 years was very effective in reducing cancer mortality, and 54% reported that it was very effective for women ages 40 to 49 years. Fewer respondents reported that clinical breast examination (CBE) or breast self examination (BSE) was very effective, but the majority rated CBE and BSE as somewhat effective. The majority of PCPs routinely recommended mammography, CBE, and BSE to patients aged >= 40 years. In multivariate models, family/general practitioners (odds ratio [OR], 2.23; 95% confidence interval [CI], 1.57-3.17 for mammography; OR, 4.42; 95% CI, 2.60-7.52 for CBE) and internal medicine specialists (OR, 3.21; 95% CI, 2.21-4.66 for mammography; OR, 5.34; 95% CI, 3.21 8.88 for CBE) were more likely to recommend an upper age limit for screening than obstetrician/gynecologists. Physicians who reported that US Preventive Services Task Force guidelines were very influential were more likely to recommend an age at which they no longer recommend mammography and CBE. CONCLUSIONS: To the authors' knowledge, the current study is the first national study in over 2 decades to report the breast cancer screening practices of PCPs and provides baseline data for monitoring the impact of changes in clinical practice guidelines. The current findings suggested that virtually all PCPs routinely recommend mammography, CBE, and BSE to their patients aged >= 40 years, although recommendations vary by primary care specialty. PMID- 21246532 TI - Epigenetic mechanisms for silencing glutathione S-transferase m2 expression by hypermethylated specificity protein 1 binding in lung cancer. AB - BACKGROUND: Glutathione S-transferases M2 (GST-M2) is a detoxifying enzyme. Low expression levels of GST-M2 have been detected in lung cancer cells. However, little is known about the regulation of GST-M2 in lung cancer cells. In this study, the authors investigated the epigenetic regulatory mechanisms of GST-M2 in lung cancer cells. METHODS: The authors evaluated the promoter methylation of GST M2 in lung cancer cells after treatment with the DNA methyltransferase (DNMT) inhibitor 5'-aza-2'-deoxycytidine (5'-aza-dC). Reporter activity assays, chromatin immunoprecipitation (ChIP), electrophoretic mobility-shift assays, and small interfering RNA (siRNA) assays were used to determine whether the methylation of specificity protein 1 (Sp1) affected binding to the GST-M2 promoter or regulated GST-M2 transcription. Real-time polymerase chain reaction was used to determine GST-M2 and DNMT-3b messenger RNA levels in 73 nonsmall cell lung cancer (NSCLC) tissues. RESULTS: GST-M2 expression was restored after treatment with 5'-aza-dC in lung cancer cells. GST-M2 exhibited high frequency of promoter hypermethylation in lung cancer cells and NSCLC tumor tissues. CpG hypermethylation abated Sp1 binding to the GST-M2 promoter in lung cancer. Knockdown of Sp1 in normal lung cells reduced GST-M2 expression, and silencing of DNMT-3b increased GST-M2 expression in lung cancer cells. In addition, DNMT-3b expression was significantly higher in lung tumors with low levels of GST-M2 expression than in lung tumors with high levels of GST-M2 expression, especially among women and among patients who had stage I disease. CONCLUSIONS: Epigenetic silencing of GST-M2 was distinguished from Sp1-mediated GST-M2 transcriptional expression. The authors concluded that this represents a mechanism that leads to decreased expression of GST-M2 in lung cancer cells. PMID- 21246533 TI - Patient willingness to undergo pharmacodynamic and pharmacokinetic tests in early phase oncology trials. AB - BACKGROUND: Increasingly, early phase clinical trials involve pharmacodynamic (PD) and pharmacokinetic (PK) assays as well as frequent imaging studies. The authors conducted a prospective study examining patients' willingness to undergo such tests and the number of tests the patients would tolerate. METHODS: A prospective, correlative study was conducted using a self-reported questionnaire to measure patients' willingness on a scale from 1 (not willing) to 10 (very willing) to undergo various procedures (eg, tumor and skin biopsies, blood tests) and imaging studies (eg, magnetic resonance imaging, echocardiogram). In addition, correlations were assessed between the number and type of tests and demographics, previous test experience, inconvenience, and insurance coverage. Sixty-one patients (22 women and 39 men) with advanced malignancies were enrolled. Descriptive, nonparametric, and parametric inferential statistics were used. RESULTS: Overall willingness to undergo study-required tests was very high. Patients were most willing to undergo urine, blood, ultrasound, x-rays, echocardiogram, and computed tomography studies and were least willing to undergo tumor and skin biopsies and magnetic resonance imaging (all P <= .01). Significant inverse relations were observed between the frequency of a particular test and patient's willingness to undergo such tests. Inconvenience and prior negative experiences for more invasive tests (eg, skin biopsies) modestly affected willingness to undergo these tests again. College education, insurance coverage, and the requirement of tests for enrollment were correlated positively with willingness to undergo tests. CONCLUSIONS: The current findings provide the first prospectively collected data on patients' willingness to undergo PK/PD tests and imaging studies associated with early stage oncology drug trials and can serve as basis for further exploration toward the design of patient-friendly, biomarker-driven clinical studies in oncology. PMID- 21246534 TI - Uterine serous papillary carcinomas overexpress human trophoblast-cell-surface marker (Trop-2) and are highly sensitive to immunotherapy with hRS7, a humanized anti-Trop-2 monoclonal antibody. AB - BACKGROUND: Uterine serous papillary carcinoma (USPC) was an aggressive and chemotherapy resistant variant of endometrial cancer. The authors evaluated the expression of human trophoblast-cell-surface-marker (Trop-2) and the potential of hRS7, a humanized anti-Trop-2 monoclonal antibody, as a novel therapeutic strategy against USPC. METHODS: Trop-2 expression was evaluated by immunohistochemistry (IHC) in a total of 23 USPC. Six primary USPC cell lines were assessed by flow cytometry and real-time polymerase chain reaction (PCR) for Trop-2 expression. Sensitivity to hRS7 (Immunomedics, Inc.) antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity was tested in standard 5-hour 51Cr-release assays against primary USPC cell lines. RESULTS: Expression of Trop-2 was found in 15 of 23 (65%) of the tumor tissues tested by IHC and in 50% (3 of 6) of the USPC cell lines tested by real-time PCR and flow cytometry (Trop-2 expression in USPC versus normal endometrial cells; P < .005). USPC cell lines overexpressing Trop-2, regardless of their intrinsic resistance to natural killer cytotoxicity, were highly sensitive to hRS7-mediated ADCC in vitro (range of killing, 28.2% to 64.4%) (P < .001). Negligible cytotoxicity against USPC was seen in the absence of hRS7 or in the presence of rituximab control antibody (range of killing, 1.1% to 12.4%). Incubation with interleukin-2 (50 IU/mL) in addition to hRS7 further increased the cytotoxic activity against USPC cell lines overexpressing Trop-2 (P = .008). CONCLUSIONS: Trop-2 was highly expressed in uterine serous carcinoma at mRNA and protein levels. Primary USPC cell lines are highly sensitivity to hRS7-mediated cytotoxicity in vitro. hRS7 may represent a novel therapeutic agent for USPC refractory to standard treatment modalities. PMID- 21246536 TI - Dapsone-induced methemoglobinemia: a dose-related occurrence? AB - BACKGROUND: Dapsone, used for Pneumocystis jiroveci (PCP) prophylaxis, is associated with increased risk of methemoglobinemia. Absence of cytochrome b5 reductase enzyme activity causes congenital methemoglobinemia, but its role in dapsone-associated methemoglobinemia is unknown. The authors sought to elucidate drug-related risk factors for dapsone-associated methemoglobinemia in pediatric oncology patients, including contribution of cytochrome b5 reductase enzyme activity. METHODS: Among 167 pediatric patients treated for hematologic malignancies or aplastic anemia who received dapsone for PCP prophylaxis, demographic and dapsone treatment data were retrospectively collected. Drug related risk factors were evaluated by Cox proportional hazards, and in a cross sectional subgroup of 40 patients, cytochrome b5 reductase enzyme activity was assessed. RESULTS: Methemoglobinemia (median methemoglobin level = 9.0% [3.5 22.4]) was documented in 32 (19.8%) patients. There was a 73% risk reduction in methemoglobinemia with dosing >=20% below the target dose of 2 mg/kg/d (hazard ratio [HR], 0.27; 95% confidence interval [CI], 0.09-0.78; P = .016), whereas methemoglobinemia risk was increased with dosing >=20% above the target dose (HR, 6.25; 95% CI, 2.45-15.93; P < .001). Sex, body mass index, and age were not associated with increased risk. Cytochrome b5 reductase enzyme activity did not differ by methemoglobinemia status (median 8.6 IU/g hemoglobin [Hb]; [5.5-12.1] vs 9.1 IU/g Hb; [6.7-12.7]). No patient developed PCP on dapsone. CONCLUSIONS: Methemoglobinemia occurred in almost 20% of pediatric oncology patients receiving dapsone for PCP prophylaxis. Higher dapsone dosing is associated with increased risk. A cross-sectionally acquired cytochrome b5 reductase enzyme activity level was not associated with methemoglobinemia risk. Studies are needed to define biologic correlates of methemoglobinemia and evaluate lower dapsone doses for PCP prophylaxis. PMID- 21246537 TI - Performance of a standardized bronchoalveolar lavage protocol in a comprehensive cancer center: a prospective 2-year study. AB - BACKGROUND: Flexible bronchoscopy with bronchoalveolar lavage (BAL) is performed widely for the diagnosis of pulmonary infections in patients with cancer, but there is no consensus regarding the technical parameters of the lavage procedure in this setting. METHODS: The authors evaluated the mechanics (instilled and recovered volumes), diagnostic yield, and safety of a standardized BAL protocol in 284 patients with cancer who underwent bronchoscopy for the evaluation of new radiologic infiltrates. RESULTS: Physician adherence to the BAL protocol was > 90%. The most common protocol deviations were reductions in the saline volume instilled because of actual or anticipated oxyhemoglobin desaturation during the procedure. The mean volume instilled was 121.5 +/- 13.9 mL, the mean volume recovered was 68.7 +/- 18.1 mL, and the mean ratio of volume instilled to that recovered was 56.7% +/- 14.5%. The overall diagnostic yield of BAL was 33.8% and was higher in the nonhematologic malignancy group (42.3% vs 29.4%; P = .021). The diagnostic yield in neutropenic patients was significantly higher than in non neutropenic patients (41.5% vs 24.6%; P = .019). No major complications were encountered. CONCLUSIONS: In summary, the diagnostic performance of a standardized BAL protocol was comparable to that of nonprotocolized BAL reported in the literature with few complications. Adherence to a standardized BAL protocol may improve clinical and laboratory comparisons between studies, potentially facilitating research into the diagnosis and management of pneumonia in patients with cancer. PMID- 21246538 TI - Association between mitochondrial DNA content in leukocytes and colorectal cancer risk: a case-control analysis. AB - BACKGROUND: Compelling epidemiological evidence indicated that alterations of mitochondrial DNA (mtDNA), including mutations and abnormal content of mtDNA, were implicated in the tumorigenesis of several malignancies in a tumor-specific manner, such as lung cancer, breast cancer, and non-Hodgkin lymphoma. This study was undertaken to investigate whether mtDNA content in peripheral blood lymphocytes (PBLs) could be used as a risk predictor for colorectal cancer (CRC). METHODS: The mtDNA content was measured by using quantitative real-time polymerase chain reaction in PBLs from 320 CRC patients and 320 matched controls. RESULTS: The authors found that CRC patients exhibited statistically significantly higher mtDNA content than matched controls (median, 1.03 vs .86; P < .001). They further assessed the association between mtDNA content and CRC risk using multivariate logistic regression. By using the median value in controls as the cutoff point, they found that, compared with low mtDNA content, high mtDNA content was associated with a significantly increased CRC risk (adjusted odds ratio, 2.03; 95% confidence interval, 1.41-2.81). In a trend analysis, they found a statistically significant dose-response relationship between higher mtDNA content and increased CRC risk (P for trend <.001). Stratified analysis showed that the association between mtDNA content and CRC risk was not modulated by major host characteristics. CONCLUSIONS: These findings provide the first epidemiological evidence linking the high mtDNA content in PBLs to elevated CRC risk. PMID- 21246539 TI - Receptive anal intercourse as a potential risk factor for rectal cancer. PMID- 21246540 TI - Lymph node stromal cells strongly influence immune response suppression. AB - Many pathogens are initially encountered in the gut, where the decision is made to mount an immune response or induce tolerance. The mesentric lymph node (mLN) has been shown to be involved in immune response and much more in oral tolerance induction. Furthermore, using an in vivo transplantation model, we showed recently that lymph node (LN) stromal cells can affect T-cell function and influence the IgA response by supporting a site-specific environment. To elucidate the importance of LN stromal cells for tolerance induction, mLN or peripheral LN were transplanted into mice (mLNtx or pLNtx) and oral tolerance was induced via ovalbumin. A reduced delayed-type hypersensitivity (DTH) response was detected in pLNtx compared to mLNtx mice. Reduced IL-10 expression, reduced percentages of Tregs, and increased proportions of B cells were identified within the pLNtx. The increase of B cells resulted in a specific immunoglobulin production undetectable in mLNtx. Moreover, transferred IgG(+) cells of tolerized peripheral LN induced a strong reduction of the delayed-type hypersensitivity response, whereas CD4(+) cells were less efficient. Thus, stromal cells have a high impact on creating a unique environment. Furthermore, the environment of pLNtx induces a tolerogenic phenotype by B-cell accumulation and antibody production. PMID- 21246541 TI - Borrelia burgdorferi infection regulates CD1 expression in human cells and tissues via IL1-beta. AB - The appearance of group 1 CD1 proteins (CD1a, CD1b and CD1c) on maturing myeloid DC is a key event that converts myeloid DC to effective lipid APC. Here, we show that Borrelia burgdorferi, the causative agent of Lyme disease, triggers appearance of group 1 CD1 proteins at high density on the surface of human myeloid DC during infection. Within human skin, CD1b and CD1c expression was low or absent prior to infection, but increased significantly after experimental infections and in erythema migrans lesions from Lyme disease patients. The induction of CD1 was initiated by borrelial lipids acting through TLR-2 within minutes, but required 3 days for maximum effect. The delay in CD1 protein appearance involved a multi-step process whereby TLR-2 stimulated cells release soluble factors, which are sufficient to transfer the CD1-inducing effect in trans to other cells. Analysis of these soluble factors identified IL-1beta as a previously unknown pathway leading to group 1 CD1 protein function. This study establishes that upregulation of group 1 CD1 proteins is an early event in B. burgdorferi infection and suggests a stepwise mechanism whereby bacterial cell walls, TLR activation and cytokine release cause DC precursors to express group 1 CD1 proteins. PMID- 21246542 TI - High-frequency and adaptive-like dynamics of human CD1 self-reactive T cells. AB - CD1 molecules present lipid antigens to T cells. An intriguing subset of human T cells recognize CD1-expressing cells without deliberately added lipids. Frequency, subset distribution, clonal composition, naive-to-memory dynamic transition of these CD1 self-reactive T cells remain largely unknown. By screening libraries of T-cell clones, generated from CD4(+) or CD4(-) CD8(-) double negative (DN) T cells sorted from the same donors, and by limiting dilution analysis, we find that the frequency of CD1 self-reactive T cells is unexpectedly high in both T-cell subsets, in the range of 1/10-1/300 circulating T cells. These T cells predominantly recognize CD1a and CD1c and express diverse TCRs. Frequency comparisons of T-cell clones from sorted naive and memory compartments of umbilical cord and adult blood show that CD1 self-reactive T cells are naive at birth and undergo an age-dependent increase in the memory compartment, suggesting a naive/memory adaptive-like population dynamics. CD1 self-reactive clones exhibit mostly Th1 and Th0 functional activities, depending on the subset and on the CD1 isotype restriction. These findings unveil the unanticipated relevance of self-lipid T-cell response in humans and clarify the basic parameters of the lipid-specific T-cell physiology. PMID- 21246547 TI - Innervation of the rat uterus at estrus: a study in full-thickness, immunoperoxidase-stained whole-mount preparations. AB - The innervation of the nonpregnant rat uterus has been studied in histological sections, which contain only small samples of nerves and are unlikely to afford a complete picture of uterine innervation. Here we used whole-mount preparations of entire full-thickness uterine horns from nonpregnant rats in estrus to visualize autonomic or sensory nerves with peroxidase immunohistochemistry. Immunoreactivity was studied for tyrosine hydroxylase (TH)-labeled sympathetic nerves; vesicular acetylcholine transporter (VAChT), parasympathetic nerves; and substance P (SP) and calcitonin gene-related peptide (CGRP), sensory nerves. Neuropeptide Y (NPY) and nitric oxide synthase (NOS) identified more than one of these functionally distinct nerve types. Axons of all neurochemical classes entered the uterus at the mesometrium and innervated the uterine smooth muscle. The linea uteri, a dense band of longitudinal muscle opposite the mesometrium, contained more TH-, NPY-, CGRP-, and VAChT-immunoreactive axons than the remaining smooth muscle. Axons immunoreactive for NPY, SP, NOS, and VAChT formed a plexus near the circular muscle-endometrium interface. Rare TH- and NPY immunoreactive axons and occasional CGRP-immunoreactive axons occurred close to uterine glands. Blood vessels had dense perivascular plexuses of TH- and NPY containing axons and less dense NOS-, SP-, CGRP-, and VAChT-positive plexuses. The circular muscle plexus and glands were absent opposite the mesometrium. Uterine arterioles formed an interconnected network throughout the uterus. This article provides the first comprehensive description of the autonomic and sensory innervation of the nonpregnant rat uterus and will be a foundation for future studies on changes in uterine innervation caused by normal physiological or pathophysiological challenges. PMID- 21246546 TI - Early microglia activation in a mouse model of chronic glaucoma. AB - Changes in microglial cell activation and distribution are associated with neuronal decline in the central nervous system (CNS), particularly under pathological conditions. Activated microglia converge on the initial site of axonal degeneration in human glaucoma, yet their part in its pathophysiology remains unresolved. To begin with, it is unknown whether microglia activation precedes or is a late consequence of retinal ganglion cell (RGC) neurodegeneration. Here we address this critical element in DBA/2J (D2) mice, an established model of chronic inherited glaucoma, using as a control the congenic substrain DBA/2J Gpnmb(+/SjJ) (D2G), which is not affected by glaucoma. We analyzed the spatial distribution and timecourse of microglial changes in the retina, as well as within the proximal optic nerve prior to and throughout ages when neurodegeneration has been reported. Exclusively in D2 mice, we detected early microglia clustering in the inner central retina and unmyelinated optic nerve regions, with microglia activation peaking by 3 months of age. Between 5 and 8 months of age, activated microglia persisted and concentrated in the optic disc, but also localized to the retinal periphery. Collectively, our findings suggest microglia activation is an early alteration in the retina and optic nerve in D2 glaucoma, potentially contributing to disease onset or progression. Ultimately, detection of microglial activation may have value in early disease diagnosis, while modulation of microglial responses may alter disease progression. PMID- 21246548 TI - Vagal afferent innervation of the proximal gastrointestinal tract mucosa: chemoreceptor and mechanoreceptor architecture. AB - The vagus nerve supplies low-threshold chemo- and mechanosensitive afferents to the mucosa of the proximal gastrointestinal (GI) tract. The absence of a full characterization of the morphology and distributions of these projections has hampered comprehensive functional analyses. In the present experiment, dextran (10K) conjugated with tetramethylrhodamine and biotin was injected into the nodose ganglion and used to label the terminal arbors of individual vagal afferents of both rats and mice. Series of serial 100-MUm thick sections of the initial segment of the duodenum as well as the pyloric antrum were collected and processed with diaminobenzidine for permanent tracer labeling. Examination of over 400 isolated afferent fibers, more than 200 from each species, indicated that three vagal afferent specializations, each distinct in morphology and in targets, innervate the mucosa of the proximal GI tract. One population of fibers, the villus afferents, supplies plates of varicose endings to the apical tips of intestinal villi, immediately subjacent to the epithelial wall. A second type of afferent, the crypt afferent, forms subepithelial rings of varicose processes encircling the intestinal glands or crypts, immediately below the crypt-villus junction. Statistical assessment of the isolated fibers indicated that the villus arbors and the crypt endings are independent, issued by different vagal afferents. A third vagal afferent specialization, the antral gland afferent, arborizes along the gastric antral glands and forms terminal concentrations immediately below the luminal epithelial wall. The terminal locations, morphological features, and regional distributions of these three specializations provide inferences about the sensitivities of the afferents. PMID- 21246549 TI - Lineage-based analysis of the development of the central complex of the Drosophila brain. AB - Most neurons of the central complex belong to 10 secondary (larvally produced) lineages. In the late larva, undifferentiated axon tracts of these lineages form a primordium in which all of the compartments of the central complex can be recognized as discrete entities. Four posterior lineages (DPMm1, DPMpm1, DPMpm2, and CM4) generate the classes of small-field neurons that interconnect the protocerebral bridge, fan-shaped body, noduli, and ellipsoid body. Three lineages located in the anterior brain, DALv2, BAmv1, and DALcl2, form the large-field neurons of the ellipsoid body and fan-shaped body, respectively. These lineages provide an input channel from the optic tubercle and connect the central complex with adjacent anterior brain compartments. Three lineages in the posterior cortex, CM3, CP2, and DPMpl2, connect the posterior brain neuropil with specific layers of the fan-shaped body. Even though all of the compartments of the central complex are prefigured in the late larval brain by the axon tracts of the above mentioned lineages, the neuropil differentiates during the first 2 days of the pupal period when terminal branches and synapses of secondary neurons are formed. During this phase the initially straight horizontal layers of the central complex bend in the frontal plane, which produces the characteristic shape of the fan shaped and ellipsoid body. Our analysis provides a comprehensive picture of the lineages that form the central complex, and will facilitate future studies that address the structure or function of the central complex at the single cell level. PMID- 21246551 TI - Unique photoreceptor arrangements in a fish with polarized light discrimination. AB - In contrast to other vertebrates, some anchovies have cone photoreceptors with longitudinally oriented outer segment lamellae. These photoreceptors are axially dichroic (i.e., they are sensitive to the polarization of axially incident light) and form the basis of a polarization detection system in the northern anchovy, Engraulis mordax. Whether other cone types exist in the retina of this animal, and whether multiple cone opsins are expressed in the retinas of anchovies, is unknown. Likewise, a detailed examination of photoreceptor ultrastructure in nondichroic photoreceptors has not been carried out despite its importance to understand visual specializations within the retina and its use in the formulation of models to explain cellular structure. Here, I combined light and electron microscopy with immunohistochemical studies of opsin expression to infer mechanisms of lamellar formation and to evaluate the potential for color vision in the northern anchovy retina. Morphological observations revealed three cone formations: 1) continuous rows made up of alternating long and short (bilobed) cones with longitudinally oriented lamellae that are orthogonal between cone types; 2) continuous rows of alternating long and short cones in which only the short cones have longitudinally oriented lamellae; and 3) rows of triple cones with transversely oriented lamellae, each triple cone consisting of two lateral cones flanking a small central cone. Ultrastructure investigations supported two models of outer segment formation resulting in the longitudinally oriented lamellae of long and short cones. In the case of the long cone, lateral compression of the outer segment, potentially via the formation of guanine platelet stacks in neighboring pigment epithelium cells, results in a shape transformation from conical to cunate and a tilt from transverse to longitudinal lamellae. In the case of the short (bilobed) cone, membrane invaginations from the connecting ciliary structure grow longitudinally to form a dichroic stack. Opsin expression studies indicated that all cones express middle-to-long wavelength opsins, with long and lateral cones possessing a different opsin from that in short and central cones, confirming the potential for color vision. Together with the ultrastructural observations, these results suggest that the unique cone topography in the northern anchovy retina may underlie a visual system with segregated color and polarization detection channels. PMID- 21246550 TI - Cellular composition and organization of the subventricular zone and rostral migratory stream in the adult and neonatal common marmoset brain. AB - The adult subventricular zone (SVZ) of the lateral ventricle contains neural stem cells. In rodents, these cells generate neuroblasts that migrate as chains toward the olfactory bulb along the rostral migratory stream (RMS). The neural-stem-cell niche at the ventricular wall is conserved in various animal species, including primates. However, it is unclear how the SVZ and RMS organization in nonhuman primates relates to that of rodents and humans. Here we studied the SVZ and RMS of the adult and neonatal common marmoset (Callithrix jacchus), a New World primate used widely in neuroscience, by electron microscopy, and immunohistochemical detection of cell-type-specific markers. The marmoset SVZ contained cells similar to type B, C, and A cells of the rodent SVZ in their marker expression and morphology. The adult marmoset SVZ had a three-layer organization, as in the human brain, with ependymal, hypocellular, and astrocyte ribbon layers. However, the hypocellular layer was very thin or absent in the adult-anterior and neonatal SVZ. Anti-PSA-NCAM staining of the anterior SVZ in whole-mount ventricular wall preparations of adult marmosets revealed an extensive network of elongated cell aggregates similar to the neuroblast chains in rodents. Time-lapse recordings of marmoset SVZ explants cultured in Matrigel showed the neuroblasts migrating in chains, like rodent type A cells. These results suggest that some features of neurogenesis and neuronal migration in the SVZ are common to marmosets, humans, and rodents. This basic description of the adult and neonatal marmoset SVZ will be useful for future studies on adult neurogenesis in primates. PMID- 21246552 TI - Cell-poor septa separate representations of digits in the ventroposterior nucleus of the thalamus in monkeys and prosimian galagos. AB - The architectonic features of the ventroposterior nucleus (VP) were visualized in coronal brain sections from two macaque monkeys, two owl monkeys, two squirrel monkeys, and three galagos that were processed for cytochrome oxidase, Nissl bodies, or the vesicular glutamate transporter 2 (vGluT2). The traditional ventroposterior medial (VPM) and ventroposterior lateral (VPL) subnuclei were easily identified, as well as the forelimb and hindlimb compartments of VPL, as they were separated by poorly staining, cell-poor septa. Septa also separated other cell groups within VPM and VPL, specifically in the medial compartment of VPL representing the hand (hand VPL). In one squirrel monkey and one galago we demonstrated that these five groups of cells represent digits 1-5 in a mediolateral sequence by injecting tracers into the cortical representation of single digits, defined by microelectrode recordings, and relating concentrations of labeled neurons to specific cell groups in hand VPL. The results establish the existence of septa that isolate the representation of the five digits in VPL of primates and demonstrate that the isolated cell groups represent digits 1-5 in a mediolateral sequence. The present results show that the septa are especially prominent in brain sections processed for vGluT2, which is expressed in the synaptic terminals of excitatory neurons in most nuclei of the brainstem and thalamus. As vGluT2 is expressed in the synaptic terminations from dorsal columns and trigeminal brainstem nuclei, the effectiveness of vGluT2 preparations in revealing septa in VP likely reflects a lack of synapses using glutamate in the septa. PMID- 21246553 TI - Bipolar cells of the ground squirrel retina. AB - Parallel processing of an image projected onto the retina starts at the first synapse, the cone pedicle, and each cone feeds its light signal into a minimum of eight different bipolar cell types. Hence, the morphological classification of bipolar cells is a prerequisite for analyzing retinal circuitry. Here we applied common bipolar cell markers to the cone-dominated ground squirrel retina, studied the labeling by confocal microscopy and electron microscopy, and compared the resulting bipolar cell types with those of the mouse (rod dominated) and primate retina. Eight different cone bipolar cell types (three OFF and five ON) and one rod bipolar cell were distinguished. The major criteria for classifying the cells were their immunocytochemical identity, their dendritic branching pattern, and the shape and stratification level of their axons in the inner plexiform layer (IPL). Immunostaining with antibodies against Ggamma13, a marker for ON bipolar cells, made it possible to separate OFF and ON bipolars. Recoverin-positive OFF bipolar cells partly overlapped with ON bipolar axon terminals at the ON/OFF border of the IPL. Antibodies against HCN4 labeled the S-cone selective (bb) bipolar cell. The calcium-binding protein CaB5 was expressed in two OFF and two ON cone bipolar cell types, and CD15 labeled a widefield ON cone bipolar cell comparable to the DB6 in primate. PMID- 21246554 TI - Doublecortin-positive cells in the adult primate cerebral cortex and possible role in brain plasticity and development. AB - We have demonstrated that cortical cell autografts might be a useful therapy in two monkey models of neurological disease: motor cortex lesion and Parkinson's disease. However, the origin of the useful transplanted cells obtained from cortical biopsies is not clear. In this report we describe the expression of doublecortin (DCX) in these cells based on reverse-transcription polymerase chain reaction (RT-PCR) and immunodetection in the adult primate cortex and cell cultures. The results showed that DCX-positive cells were present in the whole primate cerebral cortex and also expressed glial and/or neuronal markers such as glial fibrillary protein (GFAP) or neuronal nuclei (NeuN). We also demonstrated that only DCX/GFAP positive cells were able to proliferate and originate progenitor cells in vitro. We hypothesize that these DCX-positive cells in vivo have a role in cortical plasticity and brain reaction to injury. Moreover, in vitro these DCX-positive cells have the potential to reacquire progenitor characteristics that confirm their potential for brain repair. PMID- 21246555 TI - Cholinergic innervation of pyramidal cells and parvalbumin-immunoreactive interneurons in the rat basolateral amygdala. AB - The basolateral nucleus of the amygdala receives an extremely dense cholinergic innervation from the basal forebrain that is critical for memory consolidation. Although previous electron microscopic studies determined some of the postsynaptic targets of cholinergic afferents, the majority of postsynaptic structures were dendritic shafts whose neurons of origin were not identified. To make this determination, the present study analyzed the cholinergic innervation of the anterior subdivision of the basolateral amygdalar nucleus (BLa) of the rat using electron microscopic dual-labeling immunocytochemistry. The vesicular acetylcholine transporter (VAChT) was used as a marker for cholinergic terminals; calcium/calmodulin-dependent protein kinase II (CaMK) was used as a marker for pyramidal cells, the principal neurons of the BLa; and parvalbumin (PV) was used as a marker for the predominant interneuronal subpopulation in this nucleus. VAChT(+) terminals were visualized by using diaminobenzidine as a chromogen, whereas CAMK(+) or PV(+) neurons were visualized with Vector very intense purple (VIP) as a chromogen. Quantitative analyses revealed that the great majority of dendritic shafts receiving cholinergic inputs were CAMK(+) , indicating that they were of pyramidal cell origin. In fact, 89% of the postsynaptic targets of cholinergic terminals in the BLa were pyramidal cells, including perikarya (3%), dendritic shafts (47%), and dendritic spines (39%). PV(+) structures, including perikarya and dendrites, constituted 7% of the postsynaptic targets of cholinergic axon terminals. The cholinergic innervation of both pyramidal cells and PV(+) interneurons may constitute an anatomical substrate for the generation of oscillatory activity involved in memory consolidation by the BLa. PMID- 21246557 TI - Monitoring of antisolvent crystallization of sodium scutellarein by combined FBRM PVM-NIR. AB - Antisolvent crystallization can be used as an alternative to cooling or evaporation for the separation and purification of solid product in the pharmaceutical industry. To improve the process understanding of antisolvent crystallization, the use of in-line tools is vital. In this study, the process analytical technology (PAT) tools including focused beam reflectance measurement (FBRM), particle video microscope (PVM), and near-infrared spectroscopy (NIRS) were utilized to monitor antisolvent crystallization of sodium scutellarein. FBRM was used to monitor chord count and chord length distribution of sodium scutellarein particles in the crystallizer, and PVM, as an in-line video camera, provided pictures imaging particle shape and dimension. In addition, a quantitative model of PLS was established by in-line NIRS to detect the concentration of sodium scutellarein in the solvent and good calibration statistics were obtained (r(2) = 0.976) with the residual predictive deviation value of 11.3. The discussion over sensitivities, strengths, and weaknesses of the PAT tools may be helpful in selection of suitable PAT techniques. These in line techniques eliminate the need for sample preparation and offer a time-saving approach to understand and monitor antisolvent crystallization process. PMID- 21246556 TI - Design and evaluation of controlled-release niosomes and discomes for naltrexone hydrochloride ocular delivery. AB - This study aimed at preparing and evaluating Span 60-based niosomes for ocular delivery of naltrexone hydrochloride (NTX). Selected charged lipids [dicetyl phosphate (DCP) and stearyl amine (STA)] and surfactants [poly-24-oxyethylene cholesteryl ether (C24) and sodium cholate (CH)] were investigated as bilayer membrane additives and prepared using four different methods. A 5-fold increase in NTX entrapment efficiency (EE%) was achieved with 2%-5% mol/mol additives. Differential scanning calorimetry thermograms revealed that the additives completely abolished gel/liquid transition suggesting that the bilayer membranes could accommodate the additives. The volume diameters D (4, 3) of the prepared niosomes were significantly [p < 0.05, analysis of variance (ANOVA)] dependent on the additive used. D (4,3) values of F-C24 and F-CH were 22.41 +/- 1.40 and 5.37 +/- 1.40 MU m, respectively. F-S60, F-DCP, and F-CH shapes were typical spherical, whereas F-C24 was oval giant niosomes (discomes). In vitro drug release parameters showed that the prepared niosomes significantly (p < 0.01, ANOVA) controlled NTX release rate and extent. Ex vivo transcorneal permeation studies conducted using excised cow corneas showed that niosomes were capable of controlling NTX permeation and enhance its corneal permeability. The prepared niosomal formulations were found practically nonirritant when applied onto the surface of a 10-day-old hen's chorioallantoic membrane. PMID- 21246558 TI - Solid-state studies of the triclinic (Z' = 2) antiprotozoal drug ternidazole. AB - The solid-state properties of antiprotozoal ternidazole (3-(2-methyl-5 nitroimidazol-1-yl)-propan-1-ol) have been studied. Crystals are triclinic in the temperature interval between 100 and 333 K (melting point) with two different molecular conformations present in the asymmetric unit (Z' = 2) and two of each conformer make up a tetramer held together by hydrogen bonding. Its melting enthalpy at 333 K is 25.65 (+/- 1.29) kJ . mol(-1). Linear plots were obtained for the melting temperature versus pressure (dP/dT = 5.67 (+/- 0.08) MPa . K(-1)] and the glass transition versus pressure [dP/dT = 7.73 (+/-1.76) MPa . K(-1)]. No crystalline polymorphism could be detected; thus, the single-crystal structure that has been found is most likely the stable one. PMID- 21246559 TI - Pegylated phosphotidylethanolamine inhibiting P-glycoprotein expression and enhancing retention of doxorubicin in MCF7/ADR cells. AB - The failure of the clinical treatment of cancer patients is often attributed to drug resistance of the tumor to chemotherapeutic agents. P-glycoprotein (P-gp) contributes to drug resistance via adenosine 5'-triphosphate (ATP)-dependent drug efflux pumps and is widely expressed in many human cancers. Up to date, a few of nanomaterials have shown the effects on P-gp function by different ways. To study the mechanism of the increased cytotoxicity of doxorubicin (DOX) by pegylated phosphotidylethanolamine (PEG-PE) in drug-resistant cancer cells, a series of in vitro cell assays were performed, including identification of P-gp function, quantitative studies on uptake and efflux of DOX, inhibitory effects of blank PEG PE micelles on mRNA and protein levels of P-gp, and intracellular ATP content alteration. Finally, combining MDR-1 RNA interference (siRNA) with DOX encapsulated in PEG-PE micelles (M-DOX) to improve cytotoxicity of DOX was also studied. M-DOX showed fivefold lower the concentration that caused 50% killing tumor cell than that of free DOX in the P-gp-overexpressing MCF-7 breast cancer (MCF-7/ADR) cells. M-DOX enhanced the cellular uptake and retention of DOX in MCF 7/ADR cells. PEG-PE block molecules can inhibit P-gp expression through downregulating MDR-1 gene. Cytotoxicity of M-DOX was further improved by knocking down the MDR-1 gene using siRNA in the multidrug-resistant cells. We conclude that the increased cytotoxicity of DOX encapsulated in PEG-PE micelle is due to the reduced P-gp expression by PEG-PE block molecules, and accordingly enhancing the cellular accumulation of DOX. To overcome drug resistance of tumor cells, the combination of nanotechnology and biotechnology could be an effective strategy such as PEG-PE formed micelles and siRNA. PMID- 21246560 TI - Investigation of atypical dissolution behavior of an encapsulated amorphous solid dispersion. AB - Poor dissolution performance is one of the challenges encountered in dosage form design of amorphous solid dispersions (ASDs). This study was aimed to investigate the effect of solid-liquid interactions of an encapsulated ASD on drug release. Drug release profiles of a molecularly interacting amorphous celecoxib solid dispersion (ACSD) comprising of amorphous celecoxib (A-CLB), polyvinylpyrrolidone (PVP), and meglumine (7:2:1, w/w) were compared with crystalline CLB (C-CLB), in powder and capsule form. Although, ACSD powder displayed 28- to 50-fold higher dissolution efficiency at 60 min (DE(60)), the DE(60) in the encapsulated state were drastically reduced due to the formation of a nondispersible plug. The accompanied physical and compositional changes were investigated using X-ray powder diffraction, differential scanning calorimetry, scanning electron microscopy, and chromatographic techniques. ACSD displayed optimal wettability, sustained A-CLB-PVP interactions, and suppressed phase transformations in aqueous media. Furthermore, Fourier transform infrared and texture analysis revealed role of intermolecular interactions of the solid dispersion, which (i) altered PVP's functionality and (ii) promoted interparticle cohesivity via water-mediated hydrogen bonds, resulting in solid mass agglomeration. Parallel evaluation of A CLB, physical mixture of ACSD components, and C-CLB solid dispersion supported the above inferences. On the basis of these findings, rationalized formulation approaches for ASD-based drug products are discussed. PMID- 21246561 TI - Thermal, spectroscopic, and ab initio structural characterization of carprofen polymorphs. AB - Commercial and recrystallized polycrystalline samples of carprofen, a nonsteroidal anti-inflammatory drug, were studied by thermal, spectroscopic, and structural techniques. Our investigations demonstrated that recrystallized sample, stable at room temperature (RT), is a single polymorphic form of carprofen (polymorph I) that undergoes an isostructural polymorphic transformation by heating (polymorph II). Polymorph II remains then metastable at ambient conditions. Commercial sample is instead a mixture of polymorphs I and II. The thermodynamic relationships between the two polymorphs were determined through the construction of an energy/temperature diagram. The ab initio structural determination performed on synchrotron X-Ray powder diffraction patterns recorded at RT on both polymorphs allowed us to elucidate, for the first time, their crystal structure. Both crystallize in the monoclinic space group type P2(1) /c, and the unit cell similarity index and the volumetric isostructurality index indicate that the temperature-induced polymorphic transformation I -> II is isostructural. Polymorphs I and II are conformational polymorphs, sharing a very similar hydrogen bond network, but with different conformation of the propanoic skeleton, which produces two different packing. The small conformational change agrees with the low value of transition enthalpy obtained by differential scanning calorimetry measurements and the small internal energy computed with density functional methods. PMID- 21246562 TI - Prolonged circulation half-life of interferon gamma activity by gene delivery of interferon gamma-serum albumin fusion protein in mice. AB - Gene delivery of mouse interferon (IFN) gamma has been shown to inhibit metastatic tumor growth and onset of atopic dermatitis in mouse models. In this study, we tried to increase the circulation half-life of IFNgamma after its gene delivery by designing a novel fusion protein of IFNgamma with mouse serum albumin (MSA). Western blot analysis confirmed that IFNgamma-MSA was expressed as a fusion protein, but hardly formed dimer as IFNgamma did. The biological activity of IFNgamma-MSA, which was examined using a plasmid expressing luciferase under the control of gamma-activated sequence elements, was about 200-fold lower than the activity of IFNgamma. Intravenous injection of the proteins into mice confirmed that the circulation half-life of IFNgamma was significantly prolonged by the modification. A hydrodynamic injection of a plasmid expressing IFNgamma MSA resulted in a sustained concentration in mouse serum; it resulted in about sixfold greater area under the concentration-time curve and about threefold longer mean residence time of IFNgamma activity than those of IFNgamma. Gene delivery of IFNgamma-MSA inhibited tumor metastasis to a similar level to that of IFNgamma despite the reduced activity of IFNgamma-MSA. These results indicate that gene delivery of IFNgamma-MSA is a promising approach to prolong the circulation half-life of IFNgamma activity. PMID- 21246563 TI - The effect of component of microemulsions on transdermal delivery of buspirone hydrochloride. AB - The aim of this study was to evaluate the influence of components such as type, level, and hydrophilic-lipophilic balance (HLB) value of surfactant, type and amount of cosurfactant, and drug concentration on the permeability of buspirone hydrochloride microemulsions through rat skin. The cumulative amount at 24 h ranged from 502.2 +/- 57.8 to 1754.3 +/- 616.6 MUg/cm(2), flux ranged from 23.03 +/- 1.84 to 83.36 +/- 25.08 MUg/(cm(2)/h), and lag time ranged from 3.0 to 4.7 h, indicating that the permeation parameters of buspirone from microemulsions were markedly influenced by the composition of microemulsions. In comparison with the effect of composition of microemulsions on the buspirone permeation capacity, it was found that microemulsions containing surfactant with HLB value of 11.16 possessed higher flux. The viscosity of microemulsions increased, flux decreased, and lag time was prolonged when amount of surfactant in microemulsions increased. The various cosurfactants can also influence the microemulsion formation and drug permeability. The microemulsion with ethanol as cosurfactant had higher permeation rate. However, the buspirone microemulsion with higher flux can provide the therapeutic minimum effective concentration, at workable administrated area about 3.3-5.8 cm(2), demonstrating microemulsions could be a promising drug carrier for transdermal delivery systems. PMID- 21246565 TI - Obesity augmented breast cancer risk: a potential risk factor for Indian women. AB - BACKGROUND: Obesity is caused by disturbances of energy balance, which is homeostasized by the physiological processes. The study aims to determine the possible impact of rising prevalence of obesity and its effect in the development of breast carcinoma (BC) in Indian population. METHODS: This study is carried out on patients (N = 358) who were diagnosed with BC and breast diseases (BD) by calculating their BMI admitted during the period of 2005 to 2009. NIH criteria were used to categorize the patients. Pathological factors of BC patient were then compared among groups. RESULT: These results were indicative of significant positive association between BC risks with peri/post menopausal status, residence, diet nature, and tobacco uses. Metastases were identified more commonly with increasing weight. It was found to be independently associated with obesity I (OR = 3.103, 95% CI = 1.633-5.895) and obesity II (OR = 6.803, 95% CI = 2.415-19.162). Disease stage and cancer related mortality were significantly associated with increased BMI. CONCLUSION: The higher prevalence of severe obesity among Indian population was associated with BC. The only alteration apart from early diagnosis is opting for a more natural lifestyle that will affect energy equilibrium and prove to be a viable option for prevention in carcinoma of breast for better survival. PMID- 21246564 TI - Histamine release associated with intravenous delivery of a fluorocarbon-based sevoflurane emulsion in canines. AB - The purpose of this study was to evaluate the effectiveness of a novel fluorocarbon-based sevoflurane emulsion in dogs previously shown to produce short term rodent anesthesia. On the basis of an unexpected allergic-type clinical reaction, we also tested the hypothesis that this type of formulation causes histamine release and complement activation. Physiological parameters, plasma histamine levels (radioimmunoassay), and complement activation (enzyme immunoassay) were quantified in response to emulsion components, including F13M5 (the emulsion's fluorocarbon-based polymer) and methoxy poly(ethylene glycol) 5000 (the polymer's hydrophilic block). Although the emulsion produced general anesthesia in dogs, they also experienced hypotension and clinical signs suggestive of an allergic-like response (i.e., vasodilation, urticaria, and pruritus upon recovery). Emulsions lacking sevoflurane failed to induce anesthesia but did elicit the allergic response. Plasma histamine levels were significantly increased following injection of micellar solutions of F13M5. Direct complement activation by the emulsion or its components was weak or absent. An allergic response leading to histamine release, likely initiated by the F13M5 component via an immunoglobulin pathway, is associated with an intravenous fluorocarbon-based emulsion of sevoflurane. Subsequently, its usefulness in medicine in its present formulation is limited. PMID- 21246566 TI - Overexpression of the orphan receptor Nur77 and its translocation induced by PCH4 may inhibit malignant glioma cell growth and induce cell apoptosis. AB - BACKGROUND: In previous study, n-butylidenephthalide (BP), a natural compound from Angelica sinensis, has anti-glioblastoma multiform (GBM) cell effects. In this study, we modified BP structure to increase anti-GBM cell effects. The anti GBM cell effects of one derivative of BP, (Z)-N-(2-(dimethylamino)ethyl)-2-(3-((3 oxoisobenzofuran-1(3H)-ylidene)methyl)phenoxy)acetamide (PCH4) were tested in vitro and in vivo. METHODS: MTT assay and PI/Annexin V assay were performed to evaluate the anti-GBM effects of PCH4. The Nur77 expression and translocation were assayed by RT-PCR and Western blot. The Nur77 siRNA was used to downregulate the Nur77 expression. The JNK inhibitor (SP600125) was used to block the JNK pathway. RESULTS: The anti-GBM effect of PCH4 is four times more than BP. The IC(50) of PCH4 on DBTRG-05MG cells was 50 ug/ml. Nur77 expression and translocation from the nucleus to the cytoplasm were important in PCH4-induced apoptosis. Furthermore, the downregulation of PCH4-induced Nur77 expression by Nur77 siRNA reduced PCH4-induced apoptosis. In addition, PCH4-induced apoptosis was associated with the JNK pathway. The JNK inhibitor, SP600125, inhibited Nur77 mRNA expression and reduced PCH4-induced apoptosis. CONCLUSIONS: In conclusion, PCH4, a derivative of BP, induced Nur77-mediated apoptosis via the JNK pathway and this mechanism, which is different from that of BP, may explain the increase in the anti-tumor effects on GBM. PMID- 21246567 TI - Predictors of cure after hepatic resection of colorectal liver metastases: an analysis of actual 5- and 10-year survivors. AB - BACKGROUND: Hepatic resection of colorectal liver metastases (CLM) is now regarded the standard of care. Evaluation of true long-term survivors will demonstrate the curative potential of this therapy with cure being defined as actual 10-year survival versus a satisfactory oncological outcome of 5-year survival. Limited data exists on outcomes of patients beyond 5 years. Studying the rates of cure and predictive factors for cure are essential to define the true benefit of this therapy. METHODS: Retrospective review of a prospectively maintained hepatobiliary surgical database was performed on patients who underwent hepatic resection of CLM between 1991 and 2005 with a minimum of 5-year follow-up. Survival was calculated from the time of surgery using the Kaplan Meier method. RESULTS: There were 455 consecutive patients with a minimum of 5 year follow-up. The actuarial median overall survival was 33 months (95% CI, 29 37%), actuarial 5-, and 10-year survival rates were 34% and 25%, respectively. Hundred twenty four patients were identified as actual 5-year survivors (27%) with their actuarial median overall survival being 11.1 years, actuarial 10-year survival rate of 59%, and a median disease-free survival of 4.9 years. Patients requiring subsequent treatment of modern systemic chemotherapy for post-resection recurrence (P = 0.003) was a negative predictors of cure from multivariate analysis. CONCLUSION: This study demonstrate that approximately one in three patients undergoing resection for CLM will become actual 5-year survivors from which approximately half will go on to survive 10-years and be cured of CLM. PMID- 21246568 TI - Behavioral and social cognitive processes in preschool children's social dominance. AB - This longitudinal, naturalistic study addressed behavioral and social cognitive processes implicated in preschool children's social dominance. In the first objective, we examined the degree to which peer aggression, affiliation, and postaggression reconciliation predicted social dominance across a school year. Consistent with predictions, all three predicted dominance early in the year while only affiliation predicted dominance later in the year, suggesting that aggression, affiliation, and reconciliation were used to establish social dominance where affiliation was used to maintain it. In the second, exploratory, objective we tested the relative importance of social dominance and reconciliation (the Machiavellian and Vygotskian intelligence hypotheses, respectively) in predicting theory of mind/false belief. Results indicated that social dominance accounted for significant variance, beyond that related to reconciliation and affiliation, in predicting theory of mind/false belief status. Results are discussed in terms of specific behavioral and social cognitive processes employed in establishing and maintaining social dominance. PMID- 21246569 TI - A new, four-item instrument to measure workplace bullying. AB - Studies on workplace bullying either in the U.S. or internationally rarely include nurses. We tested the concurrent validity of the Negative Acts Questionnaire-Revised (22 items) with a sample of nurses. Five hundred eleven registered nurses (RNs) responded to a mailed survey. Factor, reliability, and regression analyses tested dimensionality, reliability, and construct and criterion validity. Workplace bullying is best seen as a one-dimensional construct. A subset of four items was found to be both valid and reliable in measuring bullying in this sample. Findings support the use of a one-dimensional, four-item questionnaire to measure perceived bullying in nursing populations. Using a four-item questionnaire decreases participant and researcher burden and makes available an outcome measure for future descriptive and predictive interventional research. PMID- 21246570 TI - Spirituality and psychological well-being: testing a theory of family interdependence among family caregivers and their elders. AB - The family spirituality-psychological well-being model was developed and tested to explore how spirituality influences psychological well-being among elders and caregivers in the context of Korean family caregiving. The sample consisted of 157 Korean elder-family caregiver dyads in Seoul, Korea. The intraclass correlation coefficient and the actor-partner interdependence statistical model were used to analyze the data. There were significant correlations between elders' and caregivers' spirituality and between elders' and caregivers' psychological well-being. Elders' and caregivers' spirituality significantly influenced their own psychological well-being. The caregiver's spirituality significantly influenced the elder's psychological well-being, but the elder's spirituality did not significantly influence the caregiver's psychological well being. Findings suggest that elders' and caregivers' spirituality should be assessed within the family to provide holistic nursing interventions. PMID- 21246571 TI - Characterization and selectivity studies of molecular imprinted membranes of Puerarin using scanning electron microscopy. AB - Molecular-imprinted membranes of Puerarin were prepared by phase inversion technique with acrylonitrile-acrylic acid copolymer (P (AN-co-AA)). To characterize P (AN-co-AA), ubbelohde viscometer was used to measure its viscosity molecular weight. P (AN-co-AA) with different molecular weight was used to prepare membranes. The copolymer-dimethyl sulfoxide solution with Puerarin (PU) template was coagulated in water at various temperatures. The increase in P (AN co-AA) molecular weight and the decrease in coagulation temperature caused an increase in PU recognition property of the resultant membrane. The PU imprinted membrane prepared with P (AN-co-AA) showed good selective ability to PU. The purity of PU increased from 56.51 to 98.41 wt%. Surface and cross-section morphology of the membranes were analyzed by using scanning electron micrograph. High-performance liquid chromatography was used for the quantification of Puerarin in isolated fraction. PMID- 21246572 TI - Protein structure predictions by parallel simulated annealing molecular dynamics using genetic crossover. AB - We propose a conformational search method to find a global minimum energy structure for protein systems. The simulated annealing is a powerful method for local conformational search. On the other hand, the genetic crossover can search the global conformational space. Our method incorporates these attractive features of the simulated annealing and genetic crossover. In the previous works, we have been using the Monte Carlo algorithm for simulated annealing. In the present work, we use the molecular dynamics algorithm instead. To examine the effectiveness of our method, we compared our results with those of the normal simulated annealing molecular dynamics simulations by using an alpha-helical miniprotein. We used genetic two-point crossover here. The conformations, which have lower energy than those obtained from the conventional simulated annealing, were obtained. PMID- 21246573 TI - Pulsed dye laser treatment of pigmented lesions: a randomized clinical pilot study comparison of 607- and 595-nm wavelength lasers. AB - BACKGROUND: The 595-nm pulsed dye laser has been used for the treatment of benign epidermal pigmented lesions (EPLs), but there is a risk of inducing undesirable purpura with treatment. OBJECTIVE: To compare a 607-nm laser with a commercially available 595-nm laser for the treatment of EPLs. MATERIALS AND METHODS: Monte Carlo simulations were performed to characterize laser interaction with skin. Ten patients with EPLs were treated with a 607-nm study prototype laser and the 595 nm pulsed dye laser twice at 2- to 4-week intervals on the left or right side on a randomized basis. Study endpoints included clearance rate of lesions, side effects immediately after treatment and at final follow-up, and patient discomfort/pain. RESULTS: Monte-Carlo simulations show that the 607-nm is absorbed more specifically by melanin than the 595-nm wavelength. Both lasers were effective in treatment of EPLs. The average degree of improvement overall was 41.2% with the 607-nm laser and 40% with the 595-nm laser. Patients reported less discomfort/pain during treatment with the 607-nm laser. CONCLUSIONS: Our findings suggest that the 607-nm laser is safe and at least as effective as the 595-nm laser in treatment of EPLs. There was less patient discomfort/pain during treatment using the 607-nm laser. PMID- 21246574 TI - The use of non-ablative fractional resurfacing in Asian acne scar patients. AB - BACKGROUND AND OBJECTIVES: Non-ablative fractional resurfacing (NA FR) has been shown to be effective for photorejuvenation and acne scarring. Previous studies indicated that density, more than pulse energy, was associated with post inflammatory hyperpigmentation (PIH) in Asians. The objective of this retrospective study was to assess the efficacy and complications of eight passes of NA FR ('full-NA FR') with the 1,550 nm erbium-doped fibre fractional laser (Fraxel SR laser system, Solta Medical, Hayward, CA) versus four passes ('mini-NA FR') with comparable pulse energy and treatment level as 'full-NA FR', but double the number of treatment sessions in Asian acne scar patients. MATERIALS AND METHODS: Forty-seven Asian atrophic facial acne scar patients who received full face full-NA FR or mini-NA FR treatments between December 2005 and February 2009 were included. All photographic images captured with the Canfield Visia CR system at baseline and follow-ups were assessed for clinical efficacy and complications by an independent, non-treating and blinded physician. RESULTS: The total treatment densities for full-NA FR and mini-NA FR were 442.5 and 210.5 MTZ/cm(2), respectively. For full-NA FR, the PIH risk was 18.2% with cross-polarized images compared to 6.0% for mini-NA FR. This difference was statistically significant (P < 0.001). Improvement in skin texture, acne scarring, enlarged pores and overall pigmentation irregularity all reached statistical significance at last follow-up compared to baseline. There was no statistically significant difference in clinical efficacy between three full-NA FR and six mini-NA FR treatments. CONCLUSIONS: NA FR was effective and safe in Asians. By reducing the number of passes and the total treatment density, the risk of PIH could be reduced. Meanwhile, clinical efficacy could be maintained by increasing the total number of treatment sessions. PMID- 21246575 TI - Pilot clinical study for quantitative spectral diagnosis of non-melanoma skin cancer. AB - BACKGROUND: Several research groups have demonstrated the non-invasive diagnostic potential of diffuse optical spectroscopy (DOS) and laser-induced fluorescence (LIF) techniques for early cancer detection. By combining both modalities, one can simultaneously measure quantitative parameters related to the morphology, function and biochemical composition of tissue and use them to diagnose malignancy. The objective of this study was to use a quantitative reflectance/fluorescence spectroscopic technique to determine the optical properties of normal skin and non-melanoma skin cancers and the ability to accurately classify them. An additional goal was to determine the ability of the technique to differentiate non-melanoma skin cancers from normal skin. STUDY DESIGN: The study comprised 48 lesions measured from 40 patients scheduled for a biopsy of suspected non-melanoma skin cancers. White light reflectance and laser induced fluorescence spectra (wavelength range = 350-700 nm) were collected from each suspected lesion and adjacent clinically normal skin using a custom-built, optical fiber-based clinical instrument. After measurement, the skin sites were biopsied and categorized according to histopathology. Using a quantitative model, we extracted various optical parameters from the measured spectra that could be correlated to the physiological state of tissue. RESULTS: Scattering from cancerous lesions was significantly lower than normal skin for every lesion group, whereas absorption parameters were significantly higher. Using numerical cut-offs for our optical parameters, our clinical instrument could classify basal cell carcinomas with a sensitivity and specificity of 94% and 89%, respectively. Similarly, the instrument classified actinic keratoses and squamous cell carcinomas with a sensitivity of 100% and specificity of 50%. CONCLUSION: The measured optical properties and fluorophore contributions of normal skin and non melanoma skin cancers are significantly different from each other and correlate well with tissue pathology. A diagnostic algorithm that combines these extracted properties holds promise for the potential non-invasive diagnosis of skin cancer. PMID- 21246576 TI - Silicon phthalocyanine (Pc 4) photodynamic therapy is a safe modality for cutaneous neoplasms: results of a phase 1 clinical trial. AB - BACKGROUND: Photodynamic therapy (PDT) is a non-invasive treatment for non melanoma skin cancer. However, PDT systems currently used clinically have limitations such as pain and superficial tissue penetration. The silicon phthalocyanine Pc 4 is a second-generation photosensitizer with peak absorption in the far red at 675 nm. OBJECTIVE: To assess the safety and tolerability of topically applied Pc 4 followed by red light (Pc 4-PDT) in treating cutaneous neoplasms. STUDY DESIGN/MATERIALS AND METHODS: Forty three adults with a diagnosis of neoplasms including actinic keratoses, Bowen's disease, squamous cell carcinoma, basal cell carcinoma, or mycosis fungoides were treated with a single administration of Pc 4-PDT and followed for 14 days. The study utilized a light and Pc 4 dose escalation design in sequential groups of three subjects each. RESULTS: Pc 4-PDT was well tolerated with no significant local toxicity or increased photosensitivity. It has promising biologic effects, particularly in mycosis fungoides where 14 of 35 subjects demonstrated a clinical response, which correlates with Pc 4-PDT-induced apoptosis, as measured by increased active caspase-3 in the treated skin lesions. CONCLUSIONS: Pc 4-PDT is a safe and tolerable treatment modality that effectively triggers apoptosis in cutaneous neoplasms such as mycosis fungoides. PMID- 21246577 TI - A complication of an eyelid hemangioma treated with a long-pulsed 1,064 nm Nd:YAG laser. PMID- 21246578 TI - Clinical assessment of early tooth demineralization using polarization sensitive optical coherence tomography. AB - INTRODUCTION: The aims of this study were to test the hypothesis that polarization sensitive-optical coherence tomography (PS-OCT) can be used to non destructively measure and quantify the severity of the early demineralization of enamel on buccal and occlusal surfaces and assess the inhibitory effect of fluoride varnish in vivo. METHODS: A split mouth design was used to assess the effects of fluoride varnish on inhibiting dissolution on 20 test subjects. Orthodontic bands with a buccal window were cemented on the premolars and small incisions were produced on occlusal surfaces to serve as sites for plaque retention for enhanced demineralization. Bands were removed after 30 days and PS OCT scans were acquired in vivo of occlusal and buccal areas. Teeth were extracted, sectioned, and analyzed using polarized light microscopy (PLM) and transverse microradiography (TMR) for comparison with the PS-OCT images. RESULTS: High contrast PS-OCT images were acquired of both occlusal and buccal surfaces in vivo. Both occlusal and buccal surfaces, showed a significant difference (P < 0.05) in the integrated reflectivity (DeltaR) between the "sound" and "carious" enamel groups. Although the mineral loss (DeltaZ) and DeltaR measured using TMR and PS-OCT were less for the fluoride varnish-treated buccal surfaces the difference was not statistically significant (P > 0.05). CONCLUSIONS: Our results indicate that PS-OCT can non-destructively measure early enamel demineralization on the buccal and occulsal surfaces in vivo. PMID- 21246579 TI - Does laser type impact myocardial function following transmyocardial laser revascularization? AB - BACKGROUND: Transmyocardial laser revascularization (TMR) is currently clinically performed with either a CO(2) or Ho:YAG laser for the treatment of severe angina. While both lasers provide symptomatic relief, there are significant differences in the laser-tissue interactions specific to each device that may impact their ability to enhance the perfusion of myocardium and thereby improve contractile function of the ischemic heart. METHODS: A porcine model of chronic myocardial ischemia was employed. After collecting baseline functional data with cine magnetic resonance imaging (MRI) and dobutamine stress echo (DSE), 14 animals underwent TMR with either a CO(2) or Ho:YAG laser. Transmural channels were created with each laser in a distribution of 1/cm(2) in the ischemic zone. Six weeks post-treatment repeat MRI as well as DSE were obtained after which the animals were sacrificed. Histology was preformed to characterize the laser-tissue interaction. RESULTS: CO(2) TMR led to improvement in wall thickening in the ischemic area as seen with cine MRI (40.3% vs. baseline, P < 0.05) and DSE (20.2% increase vs. baseline, P < 0.05). Ho:YAG treated animals had no improvement in wall thickening by MRI (-11.6% vs. baseline, P = .67) and DSE (-16.7% vs. baseline, P = 0.08). Correlative semi-quantitative histology revealed a significantly higher fibrosis index in Ho:YAG treated myocardium versus CO(2) (1.81 vs. 0.083, P < 0.05). CONCLUSIONS: In a side-by-side comparison CO(2) TMR resulted in improved function of ischemic myocardium as assessed by MRI and echocardiography. Ho:YAG TMR led to no improvement in regional function likely due to concomitant increase in fibrosis in the lasered area. PMID- 21246580 TI - Microarray analysis of cellular thermotolerance. AB - BACKGROUND AND OBJECTIVES: Previously, we have shown that a 43 degrees C pretreatment can provide thermotolerance to a following, more severe, thermal stress at 45 degrees C. Using cells that lack the Hsp70 gene, we have also shown that there is still some thermotolerance in the absence of HSP70 protein. The purpose of this study was to determine which genes play a role in thermotolerance by measuring viability and proliferation of the cells at 2 days after heating. Specifically, we wanted to understand which pathways may be responsible for protecting cells in the absence of HSP70. STUDY DESIGN/MATERIALS AND METHODS: Murine embryonic fibroblast cells with and without Hsp70 (MEF(+/+) and MEF(-/-), respectively) were exposed to a mild heat shock of 43 degrees C for 30 minutes in a constant temperature water bath. After 3 hours of recovery, RNA was harvested from three heated samples alongside three untreated controls using a MicroRNeasy kit with DNAse treatment. RNA quality was verified by an Agilent Bioanalyzer. The RNA was then converted to cDNA and hybridized to Affymetrix gene expression DNA microarrays. The genes that showed a twofold change (up or down) relative to unheated controls were filtered by t-test for significance at a threshold of P < 0.05 using Genespring software. Data were verified by qRT-PCR. Genes were then categorized based upon their ontology. RESULTS: While many genes were similarly upregulated, the main difference between cell types was an increase in transcription factors and nucleic acid binding proteins. Several genes known to be involved in the heat response were upregulated more than twofold (Hsp70, Hsp40, Hsp110, Hsp25, Atf3), however, another well studied heat responsive gene Hsp90 only increased by 1.5-fold under these conditions despite its role in thermotolerance. CONCLUSIONS: The data herein presents genetic pathways which are candidates for further study of pretreatment protocols in laser irradiation. PMID- 21246581 TI - The in vitro PDT efficacy of a novel metallophthalocyanine (MPc) derivative and established 5-ALA photosensitizing dyes against human metastatic melanoma cells. AB - BACKGROUND AND OBJECTIVE: Numerous worldwide clinical trials have shown that photodynamic therapy (PDT) represents an effective and safe modality for various skin disorders, but little research has been done in terms of its effect on malignant melanomas (MM). Thus, the aim of this study was to compare the effect of both established porphyrin photosensitizer 5-aminolevulinic acid (5-ALA) and novel metallophthalocyanine (MPc) photosensitizer on human metastatic skin cells which produce a MM. MATERIALS AND METHODS: The cellular responses following PDT were assessed using changes in cell morphology, cell viability, cytotoxicity, apoptosis, and proliferation. RESULTS: Findings reported that in vitro human MM cell line A375 (EACC no: 88113005) are highly sensitive to growth inhibition and apoptosis induction by the cytotoxic side-effects induced by MPc and 5-ALA photosensitizing treatments post-laser irradiation at 680 and 636 nm, respectively. The decrease of cell viability accompanied by an increased cytotoxicity and apoptotic and necrotic levels, with a time-dependant decrease in cellular proliferation was found to be far more significant for MPc-treated cells than 5-ALA-treated cells, since MPc was applied in far lower concentrations and exhibited far less photoxicity to control cells. CONCLUSION: Hence, novel MPc proved to be the better photosensitizing dye for metastatic melanoma tumor destruction in combination with laser irradiation and is a particularly attractive photosensitizer since it exhibits so many ideal properties of a photosensitizing agent, thus further research of this possible anticancer agent could contribute to its potential application in PDT cancer treatment of MMs. PMID- 21246582 TI - Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir. AB - Polymorphisms of the inosine triphosphatase (ITPA) gene influence anemia during pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, but their effects during triple therapy with PEG-IFN, RBV, and telaprevir are not known. Triple therapy for 12 weeks, followed by PEG-IFN and RBV for 12 weeks, was given to 49 patients with RBV-sensitive (CC at rs1127354) and 12 with RBV-resistant (CA/AA) ITPA genotypes who had been infected with hepatitis C virus (HCV) of genotype 1. Decreases in hemoglobin levels were greater in patients with CC than CA/AA genotypes at week 2 (-1.63 +/- 0.92 vs. -0.48 +/- 0.75 g/dL, P = 0.001) and week 4 (-3.5 +/- 1.1 vs. -2.2 +/- 0.96, P = 0.001), as well as at the end of treatment (-2.9 +/- 1.1 vs. -2.0 +/- 0.86, P = 0.013). Risk factors for hemoglobin <11.0 g/dL at week 4 were female gender, age >50 years, body mass index (BMI) <23, and CC at rs1127354 by multivariate analysis. RBV dose during the first 12 weeks was smaller in patients with CC than CA/AA genotypes (52 +/- 14% vs. 65 +/- 21% of the target dose, P = 0.039), but the total RBV dose was no different between them (49 +/- 17% and 54 +/- 18% of the target, P = 0.531). Sustained virological response (SVR) was achieved in 70% and 64% of them, respectively (P = 0.724). CONCLUSION: ITPA polymorphism influences hemoglobin levels during triple therapy, particularly during the first 12 weeks while telaprevir is given. With careful monitoring of anemia and prompt adjustment of RBV dose, SVR can be achieved comparably frequently between patients with CC and CA/AA genotypes. PMID- 21246584 TI - Neuregulin/erythroblastic leukemia viral oncogene homolog 3 autocrine loop contributes to invasion and early recurrence of human hepatoma. AB - Intrahepatic metastasis is the primary cause of the high recurrence and poor prognosis of human hepatocellular carcinoma (HCC). However, neither its molecular mechanisms nor markers for its prediction before hepatectomy have been identified. We recently revealed up-regulation of erythroblastic leukemia viral oncogene homolog 3 (ERBB3) in human HCC. Here we examined the clinical and biological significance of ERBB3 in HCC. Up-regulation of ERBB3 in HCC was strongly associated with male gender (P < 0.001), chronic hepatitis B (P = 0.002), microscopic vascular invasion (P = 0.034), early recurrence (P = 0.003), and worse prognosis (P = 0.004). Phosphorylated ERBB3 and its ligands [neuregulins (NRGs)] were detected in both HCC tissues and cells. Phosphorylation of ERBB3 could be induced by conditioned media of HCC cells and abolished by the pretreatment of conditioned media with anti-NRG antibodies or by the silencing of the endogenous NRG expression of the donor HCC cells. Human epidermal growth factor receptor 2 was required for ERBB3 phosphorylation. The downstream phosphoinositide 3-kinase/v-akt murine thymoma viral oncogene homolog pathways were primarily elicited by NRG1/ERBB3 signaling, whereas the mitogen-activated protein kinase/extracellular signal-regulated kinase pathways were elicited by both epidermal growth factor/epidermal growth factor receptor and NRG1/ERBB3 signaling. The activation and silencing of ERBB3-dependent signaling had potent effects on both the migration and invasion of HCC cells, but neither had significant effects on the proliferation of HCC cells, tumor formation, or tumor growth in vitro and in vivo. CONCLUSION: The constitutive activation of ERBB3 dependent signaling via the NRG1/ERBB3 autocrine loop plays a crucial role in the regulation of cell motility and invasion, which contribute to intrahepatic metastasis and early recurrence of HCC. ERBB3 is a marker for the prediction of intrahepatic metastasis and early recurrence. ERBB3-dependent signaling is a candidate target for the treatment of microscopic vascular invasion and for the prevention of HCC recurrence. PMID- 21246585 TI - Does social media improve communication? Evaluating the NIOSH science blog. AB - BACKGROUND: In 2007, NIOSH created the Science Blog as its first social media channel. The blog has more than 22,000 subscribers. The purpose of the evaluation was to identify the blog community of readers, its use as a two-way conversation channel and its effectiveness as an information resource. METHODS: Seventy-five readers randomly participated in an online survey from July 2009 to September 2009 to evaluate the Science Blog. RESULTS: Responses indicated that the NIOSH Science Blog was a valued social media resource. Sixty percent of participants planned to continue using the blog in the next 6 months. A significant proportion of readers reported that they would make changes in the workplace based on information obtained from the Science Blog. CONCLUSIONS: The NIOSH Science Blog provides is a useful communication channel to provide workplace safety and health information and expand the Institute's reach to new consumers. PMID- 21246583 TI - Effect of immune pressure on hepatitis C virus evolution: insights from a single source outbreak. AB - The host's immune response to hepatitis C virus (HCV) can result in the selection of characteristic mutations (adaptations) that enable the virus to escape this response. The ability of the virus to mutate at these sites is dependent on the incoming virus, the fitness cost incurred by the mutation, and the benefit to the virus in escaping the response. Studies examining viral adaptation in chronic HCV infection have shown that these characteristic immune escape mutations can be observed at the population level as human leukocyte antigen (HLA)-specific viral polymorphisms. We examined 63 individuals with chronic HCV infection who were infected from a single HCV genotype 1b source. Our aim was to determine the extent to which the host's immune pressure affects HCV diversity and the ways in which the sequence of the incoming virus, including preexisting escape mutations, can influence subsequent mutations in recipients and infection outcomes. CONCLUSION: HCV sequences from these individuals revealed 29 significant associations between specific HLA types within the new hosts and variations within their viruses, which likely represent new viral adaptations. These associations did not overlap with previously reported adaptations for genotypes 1a and 3a and possibly reflected a combination of constraint due to the incoming virus and genetic distance between the strains. However, these sites accounted for only a portion of the sites in which viral diversity was observed in the new hosts. Furthermore, preexisting viral adaptations in the incoming (source) virus likely influenced the outcomes in the new hosts. PMID- 21246586 TI - Long work hours is associated with suboptimal glycemic control among US workers with diabetes. AB - BACKGROUND: Increasing numbers of US workers are diabetic. We assessed the relationship between glycemic control and work hours and type of occupation among employed US adults with type 2 diabetes. METHODS: Data were obtained from the 1999-2004 National Health and Nutrition Examination Survey (NHANES). A representative sample of employed US adults >=20 years with self-reported type 2 diabetes (n = 369) was used. Two dichotomous glycemic control indicators, based on various HbA1c level cut-points, were used as dependent variables in weighted logistic regression analyses with adjustment for confounders. RESULTS: Adults working over 40 hr/week were more likely to have suboptimal glycemic control (HbA1c >= 7%) compared to those working 20 hr or less (odds ratio = 5.09; 95% confidence interval: [1.38-18.76]). CONCLUSIONS: Work-related factors, such as number of hours worked, may affect the ability of adults with type 2 diabetes to reach and maintain glycemic control goals. These factors should be considered in the development of workplace policies and accommodations for the increasing number of workers with type 2 diabetes. PMID- 21246587 TI - Characterization of lead in US workplaces using data from OSHA's integrated management information system. AB - BACKGROUND: Lead hazards continue to be encountered in the workplace. OSHA's Integrated Management Information System (IMIS) is the largest available database containing sampling results in US workplaces. METHODS: Personal airborne lead sampling results in IMIS were extracted for years 1979-2008. Descriptive analyses, geographical mapping, and regression modeling of results were performed. RESULTS: Seventy-nine percent of lead samples were in the manufacturing sector. Lead sample results were highest in the construction sector (median = 0.03 mg/m(3) ). NORA sector, year, OSHA region, number of employees at the worksite, federal/state OSHA plan, unionization, advance notification, and presence of an employee representative were statistically associated with having a lead sample result exceed the PEL. CONCLUSIONS: Lead concentrations within construction have been higher than any other industry. Lead hazards have been most prevalent in the north and northeastern US. IMIS data can be useful as a surveillance tool and for targeting prevention efforts toward hazardous industries. PMID- 21246588 TI - Injury underreporting among small establishments in the construction industry. AB - BACKGROUND: There is convincing evidence that occupational injury and illness rates, particularly those reported by employers in the BLS' Survey of Occupational Injuries and Illnesses (SOII), substantially underestimate the true magnitude of injury and illness in the construction industry. METHODS: Fifteen years of data from five large nationally representative data sources were analyzed, including SOII, CFOI, CBP, CPS, and MEPS. Regression trends and ratio analyses were conducted, and stratified by establishment size and Hispanic ethnicity. RESULTS: Small construction establishments were most likely to underreport injuries. The SOII data only captured 25% of severe injuries among Hispanic workers, and 60% among white workers in small construction establishments. CONCLUSIONS: Underreporting is pervasive in the construction industry for small establishments and Hispanic workers. Given that small establishments are predominant in the U.S. construction industry, they should be the focus of a larger effort to identify the true extent of construction-related injuries. PMID- 21246589 TI - Respiratory symptoms in firefighters. AB - BACKGROUND: The aim of the present study was to determine the prevalence and risk factors associated with respiratory symptoms in common firefighters in the Netherlands. METHODS: A total of 1,330 firefighters from the municipal fire brigades of three provinces of the Netherlands were included in the study. All subjects were administered a Dutch web-based version of the European Community Respiratory Health Survey questionnaire. RESULTS: General respiratory symptoms were associated with the number of fires fought in the last 12 months with odds ratios between 1.2 (95% CI 1.0-1.4) and 1.4 (95% CI 1.2-1.7) per 25 fires. A strong association was found between an inhalation incident and present respiratory symptoms with odds ratios between 1.7 (95% CI 1.1-2.7) and 3.0 (95% CI 1.9-4.7). Adjustments for smoking, sex, atopy, and age did not change any of the associations. After stratification, atopics showed elevated odds ratios. CONCLUSIONS: It is recommended that firefighters are aware of these elevated healthcare risks associated with exposure to fire smoke and that they increase as much as possible the use of self-contained breathing apparatus. PMID- 21246590 TI - The dining etiquette of desert baboons: the roles of social bonds, kinship, and dominance in co-feeding networks. AB - To better understand how individual relationships influence patterns of social foraging in primate groups, we explored networks of co-feeding in wild desert baboons (Papio ursinus). To minimize the risk of aggression and injury associated with contest competition, we expected that individual group members would choose to co-feed with those group-mates that are most likely to show tolerance and a willingness to share food patches. We tested two alternative hypotheses about who those group-mates might be: the "social bonds hypothesis" predicts that preferred foraging partners will be those with whom individuals share strong social bonds, indexed by grooming, whereas the "kinship hypothesis" predicts that preferred foraging partners will be relatives. We also investigated and controlled for the effects of dominance rank, given that competitive ability is known to shape foraging patterns. Social network analyses of over 5,000 foraging events for 14 adults in a single troop revealed that baboon co-feeding was significantly correlated with grooming relationships but not genetic relatedness, and this finding was also true of the female-only co-feeding network. Dominant individuals were also found to be central to the co-feeding network, frequently sharing food patches with multiple group-mates. This polyadic analysis of foraging associations between individuals underlines the importance of dominance and affiliation to patterns of primate social foraging. PMID- 21246591 TI - Pegfilgrastim primary prophylaxis in patients with non-Hodgkin lymphoma: results from an integrated analysis. AB - Severe neutropenia and febrile neutropenia (FN) are serious, dose-limiting side effects of chemotherapy for aggressive non-Hodgkin lymphoma (NHL). Observational data suggest that with current practice neutropenia management up to 23% of patients receiving CHOP-like regimens experience FN, and around half of patients do not receive the planned relative dose intensity (RDI). In this integrated analysis we assessed the efficacy of pegfilgrastim for preventing FN and related outcomes in patients with NHL. A literature search was used to identify chemotherapy regimens with an FN risk >=15% that are used to treat lymphoma. Search results were then used to identify clinical trials in which these regimens were administered with pegfilgrastim primary prophylaxis. Individual patient data were available for three trials meeting the inclusion criteria, and these were combined in an integrated analysis. The primary outcome measure was the incidence of FN in any cycle. A total of 282 patients were included in the analysis [mean age 65 years (SD +/- 12.5 years); 172 (61%) aged >= 65 years]. All patients had NHL and 244 (87%) received RCHOP-21. The incidence of FN in any cycle was 16% (95% CI 12-20%) (13% in patients aged <65 years; 18% in patients aged >=65 years). Chemotherapy dose delays >3 days occurred in 26% (95% CI 20-31%) of patients, and was relatively consistent across age groups. Chemotherapy dose reductions >=10% were seen in 43% (95% CI 37-49%) of patients and were more frequent in the elderly. Overall, 83% (95% CI 78-87%) of patients received >=90% RDI (89% of patients aged <65 years; 78% of patients aged >=65 years). In this integrated analysis of NHL patients at higher risk of FN receiving pegfilgrastim primary prophylaxis, the overall incidence of FN was 16% and a high proportion of both younger and elderly patients achieved RDI >=90%. PMID- 21246592 TI - Detecting social learning using networks: a users guide. AB - Controversy over claims of cultures in nonhuman primates and other animals has led to a call for quantitative methods that are able to infer social learning from freely interacting groups of animals. Network-based diffusion analysis (NBDA) is such a method that infers social transmission of a behavioral trait when the pattern of acquisition follows the social network. As, relative to other animals, primates may be unusual in their heavy reliance on social learning, with learning frequently directed along pathways of association; in this study, we draw attention to the significance of this method for primatologists. We provide a "users guide" to NBDA methodology, discussing the choice of NBDA model and social network, and suggest model selection procedures. We also present the results of simulations that suggest that NBDA works well even when the assumptions of the underlying model are violated. PMID- 21246593 TI - The enigmatic Arunachal macaque: its biogeography, biology and taxonomy in Northeastern India. AB - The purpose of this study was to determine the taxonomic status of an unidentified enigmatic macaque seen by scientists since the late 1990s in Arunachal Pradesh, India. We surveyed 49 troops of enigmatic macaques in four districts of Arunachal Pradesh. The population studied is from the macaque sinica group as defined by the reproductive organs. The main species-separating trait in the sinica-group is tail length to head and body length ratio that decreases with latitude and elevation. We gathered data on morphology, pelage descriptions, tail to head and body ratios and tail to hind foot ratios from photos and live animals (43 individuals from 36 areas) within the range of and between the two subspecies of the Assamese macaque (Macaca assamensis). We compared the data to six western Assamese macaques and studies of Assamese macaques and related species. We found great variability in tail length, pelage color, facial skin color, and facial and hair patterns. The tail/head-body and tail/foot ratios, although varied, supported the hypothesis that these enigmatic forms were part of a population of Assamese macaques found in the gap between the two subspecies ranges and were not a new species as described earlier. Instead, we found evidence that darker pelage, larger body size, and shorter tails occur at higher elevations and latitudes similar to the general trend in the sinica-group's adaptations to colder climates. Thus, the population may be important for its variation, throwing light on the speciation process and how the northern species of Tibetan macaques evolved from an ancestor similar to the Assamese macaques as adaptations to a colder climate. PMID- 21246594 TI - APCI/APPI for synthetic polymer analysis. AB - Modern mass spectrometry of synthetic polymers involves soft ionization techniques. Whereas matrix-assisted laser desorption/ionization (MALDI) and electrospray (ESI) are employed routinely, atmospheric pressure chemical ionization (APCI) and more recently atmospheric pressure photoionization (APPI) are used to a lesser extent. However, these latter ionization methods coupled to liquid-phase separation techniques create new opportunities for the characterization of polymers, especially for low molecular weight compounds or for the polymers that are poorly ionizable by the usual methods. After a part devoted to the description of classical MS methods employed for polymer analysis (MALDI, ESI, and their use with chromatography), APCI and APPI techniques will be described, discussed, and selected examples will present the interest of these ionization sources (or interfaces for LC/MS) in the field of polymer analysis. PMID- 21246595 TI - The submandibular musculature of Phyllomedusinae (Anura: Hylidae): A reappraisal. AB - The submandibular musculature of 37 species of the five currently recognized genera of the subfamily Phyllomedusinae (Anura: Hylidae) is described; observations are made on the variation and ontogeny of these muscles. Supplementary apical elements of the m. intermandibularis occur in all phyllomedusines studied, in addition to the supplementary posterolateral elements previously reported. Our observations are discussed in the context of 1) the proposed homology between supplementary apical and posterolateral elements; 2) the homology with the apical elements reported for Pelodryadinae (sister taxon of Phyllomedusinae); and 3) the implications for our understanding of the relationships between Phyllomedusinae and Pelodryadinae. Anatomical differences between the apical and posterolateral elements and their co-occurrence in phyllomedusines indicate that these supplementary elements are not homologous. Despite differences between phyllomedusines and pelodryadines in the adhesion of supplementary fibers to the principal element of the m. intermandibularis and the occurrence of a broad aponeurosis or a medial raphe, the extensive morphological and developmental resemblances of the apical elements indicate that these structures are homologous, and that the presence of apical elements is a synapomorphy of Phyllomedusinae + Pelodryadinae. PMID- 21246596 TI - Ultrastructural analyses support different morphological lineages in the phylum Placozoa Grell, 1971. AB - The morphology and ultrastructure of 10 clonal placozoan lineages were studied. We scored several morphological characters at a cellular and intracellular level and identified a number of morphological differences among clones. Some differences appear clone specific and allow recognizing five distinct lineages based on morphological criteria only. These data will be crucial for a yet to be established placozoan systematics. Furthermore, we here describe three new diagnostic morphological characters for Placozoa: a new structure in the upper epithelium, called "concave disc," two distinct subpopulations of fiber cells, and especially small cells in the body margin. Besides the fiber cells appear to be arranged in several layers forming a complex, three-dimensional net not previously described. We also describe the marginal cells as the formerly suggested potential stem-cell type. The basic morphology is revised. PMID- 21246597 TI - Study of the carapace shape and growth in two Galapagos tortoise lineages. AB - Galapagos tortoises possess two main shell forms, domed and saddleback, that correlate with the biogeographic history of this species group. However, the lack of description of morphological shell variation within and among populations has prevented the understanding of the contribution of evolutionary forces and the potential role of ontogeny in shaping morphological shell differences. Here, we analyze two lineages of Galapagos tortoises inhabiting Santa Cruz Island by applying geometric morphometrics in combination with a photogrammetry 3D reconstruction method on a set of tortoises of different ages (from juvenile to adult). The aim of this study is to describe morphological features on the carapace that could be used for taxonomic recognition by taking into account confounding factors, such as the morphological changes occurring during growth. Our results indicate that despite the shared similarities of growth patterns and of morphological changes observed during growth, the two lineages and the different sexes can be distinguished on the basis of distinct carapace features. Lineages differ by the shape of the vertebral (especially concerning their width) and pleural scutes, with one lineage having a more compressed carapace shape, whereas the other possesses a carapace that is more elongated and expanded toward the sides as well as an higher positioning of the first vertebral scute. Furthermore, females have a more elongated and wider carapace shape than males. Finally, carapace shape changes with growth, with vertebral scutes becoming narrower and pleural scutes becoming larger during late ontogeny. PMID- 21246598 TI - Divergence of brain and retinal anatomy and histology in pelagic antarctic notothenioid fishes of the sister taxa Dissostichus and Pleuragramma. AB - The neutrally buoyant Antarctic fishes of the sister taxa Dissostichus (D. eleginoides and D. mawsoni) and Pleuragramma antarcticum diverged early in the notothenioid radiation and filled different niches in the pelagic realm of the developing Southern Ocean. To assess the influence of phylogenetic and ecological factors in shaping neural morphology in these taxa, we studied the anatomy and histology of the brains and retinae, and determined the proportional weights of brain regions. With the brain of the non-Antarctic sister taxon Eleginops maclovinus as plesiomorphic, statistically significant departures in the brains of the two Antarctic taxa include reduction of the corpus cerebelli and expansion of the mesencephalon and medulla. Compared to Eleginops, both species also have a relatively smaller telencephalon, although this is significant only in Dissostichus. There are a number of apomorphic features in the brain of Pleuragramma including reduced olfactory nerves and bulbs, an extremely small corpus cerebelli and an expanded mesencephalon. Although there is not a significant difference in the relative weights of the medulla in the two taxa, the prominence of the eminentia granularis and bulging cap-like appearance of the crista cerebellaris are distinctive in Pleuragramma. Brain histology of Dissostichus and Pleuragramma reflects typical perciform patterns and the two species of Dissostichus are histologically identical. Lateral compression in Pleuragramma and notable lobation in Dissostichus also contribute to differences between the taxa. Compression in Pleuragramma is attributable to convergence on an anchovy/herring body shape and to the relatively large brain in this small fish. The less prominent pattern of lobation of the telencephalon, inferior lobes and corpus cerebelli in Pleuragramma probably reflects underlying histology, specifically a reduction in cellularity of the neuropil in the nuclei and lobes. The retinal histology of Dissostichus and Pleuragramma encompasses the extremes seen in Antarctic notothenioids. Dissostichus has a thin scotopic retina with few cones and a high degree of summation. The retina of Pleuragramma is thick and cellular with many small single cones and rods and resembles that of Eleginops. Pedomorphy has not influenced brain morphology in these species but Pleuragramma has superficial neuromasts that are pedomorphic. Although Dissostichus and Pleuragramma are sympatric in the water column, their brains and retinae are highly divergent and reflect the influences of both phylogeny and ecological partitioning of the pelagic realm. Compared to Eleginops, the relatively smaller corpus cerebelli but relatively larger medulla probably indicates, respectively, reduced activity levels of notothenioids in subzero temperatures and expansion of the mechanosensory lateral line system as a supplement to vision under conditions of reduced light. Compared to Dissostichus, Pleuragramma has reduced olfactory bulbs and corpus cerebelli and an expanded mesencephalon. The reduction of the corpus to a small round knob is consistent with physiological parameters and video observations suggesting that, although pelagic, it is relatively inactive. Because mesencephalic weights also include the valvula cerebelli, the relatively large value for Pleuragramma may be attributable to its role in integration and sensorimotor coordination of information from the highly cellular duplex retina and to integration of signals from thewell-developed octavolateralis system. The brain of Dissostichus displays considerable persistent morphology in its overall resemblance to that of Eleginops, especially the large olfactory bulbs and the relatively large caudally projecting corpus, and Dissostichus exhibits olfactory tracking ability and migratory behavior in common with Eleginops. PMID- 21246599 TI - Comparative morphology of the gonadal structure related to reproductive strategies in six species of neotropical catfishes (Teleostei: Siluriformes). AB - We studied the relationship between the morphology of the reproductive system and the reproductive strategies of six neotropical catfishes using macroscopic and microscopic analyses. The reproductive system of the examined Siluriformes showed diversified characteristics, but permitted their being grouped according to three reproductive strategies: pelagic spawning, demersal spawning, and internally fertilizing. The pelagic spawners Pseudoplatystoma corruscans and Conorhynchos conirostris have testes that are characterized by filiform lobes, absence of testicular secretion, full-grown oocytes of small diameter, thin zona radiata, and cuboidal follicular cells. Pimelodus maculatus is morphologically distinct from the other two pelagic spawners catfishes due to the presence of testicular secretion. The demersal spawners Lophiosilurus alexandri and Rhinelepis aspera possess homogeneous testicular secretion, large mature oocytes, and columnar follicular cells. The most specialized reproductive system was observed in the internally fertilizing Trachelyopterus galeatus, which possesses a seminal vesicle accessory to the testes, spermatozoa with elongated nuclei that form spermatozeugmata, and a secretory ovarian lamellar epithelium that is associated with sperm storage. The reproductive system observed in Neotropical catfishes showed a relationship associated with the type of fertilization and the reproductive strategies of the six species studied. PMID- 21246600 TI - Antiepileptic drugs interact with folate and vitamin B12 serum levels. AB - OBJECTIVE: Antiepileptic drugs (AEDs) are important for the treatment of epilepsy, psychiatric diseases, and pain syndromes. Small studies have suggested that AED treatment reduces serum levels of folate and vitamin B12. METHODS: This prospective monocenter study aimed at testing the hypothesis that AED treatment is associated with folate and vitamin B12 serum levels in a large population. A total of 2730 AED-treated and 170 untreated patients with epilepsy and 200 healthy individuals were enrolled. RESULTS: Treatment with carbamazepine, gabapentin, oxcarbazepine, phenytoin, primidone, or valproate was associated with lower mean serum folate levels or with a higher frequency of folate levels below the reference range in comparison with the entire group of patients, untreated patients, or controls. Treatment with phenobarbital, pregabalin, primidone, or topiramate was associated with lower vitamin B12 levels compared with the entire group of patients. Vitamin B12 serum levels were higher in patients treated with valproate compared with the entire group of patients, untreated patients, and healthy controls. Folate or vitamin B12 levels below the reference range were associated with higher mean corpuscular volume (MCV) and higher homocysteine plasma levels. Vitamin substitution for 3 months in 141 patients with folate or vitamin B12 levels below the reference range yielded normal vitamin levels in 95% of the supplemented patients and reduced MCV and homocysteine plasma levels. INTERPRETATION: Treatment with most of the commonly used AEDs is associated with reduced folate or vitamin B12 serum levels and is a risk factor for hyperhomocysteinemia. Oral substitution is effective to restore vitamin, MCV, and homocysteine levels. PMID- 21246601 TI - Nicotinamide phosphoribosyltransferase protects against ischemic stroke through SIRT1-dependent adenosine monophosphate-activated kinase pathway. AB - OBJECTIVE: Stroke is a leading cause of mortality and disability. Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD)(+) biosynthesis and contributes to cell fate decisions. However, the role of Nampt in brain and stroke remains to be investigated. METHODS: We used lentivirus-mediated Nampt overexpression and knockdown to manipulate Nampt expression and explore the effects of Nampt in neuronal survival on ischemic stress both in vivo and in vitro. We also used adenosine monophosphate (AMP)-activated kinase-alpha2 (AMPKalpha2) and silent mating type information regulation 2 homolog 1 (SIRT1) knockout mice to investigate the underlying mechanisms of Nampt neuroprotection. RESULTS: Nampt inhibition by a highly-specific Nampt inhibitor, FK866, aggravated brain infarction in experimentally cerebral ischemia rats, whereas Nampt overexpression in local brain and Nampt enzymatic product nicotinamide mononucleotide (NMN) reduced ischemia-induced cerebral injuries. Nampt overexpression and knockdown regulated neuron survival via the AMPK pathway. Neuroprotection of Nampt was abolished in AMPKalpha2(-/-) neurons. In neurons, Nampt positively modulated NAD(+) levels and thereby controlled SIRT1 activity. SIRT1 coprecipitated with serine/threonine kinase 11 (LKB1), an upstream kinase of AMPK, and promoted LKB1 deacetylation in neurons. Nampt-induced LKB1 deacetylation and AMPK activation disappeared in SIRT1(-/-) neurons. In contrast, Ca(2+) /calmodulin-dependent protein kinase kinase-beta (CaMKK-beta), another upstream kinase of AMPK, was not involved in the neuroprotection of Nampt. More important, Nampt overexpression induced neuroprotection was abolished in SIRT1(+/-) and AMPKalpha2(-/-) mice. INTERPRETATION: Our findings reveal that Nampt protects against ischemic stroke through rescuing neurons from death via the SIRT1-dependent AMPK pathway and indicate that Nampt is a new therapeutic target for stroke. PMID- 21246602 TI - Retinal nerve fiber layer thickness in vigabatrin-exposed patients. AB - OBJECTIVE: Vigabatrin-associated visual field loss (VAVFL) occurs in 25 to 50% of exposed patients and is routinely monitored using perimetry, which has inherent limitations. Using optical coherence tomography (OCT), retinal nerve fiber layer (RNFL) thinning has been described in a small number of vigabatrin-exposed patients. We explored the relationship between RNFL thickness and visual field size, to determine whether OCT is a suitable tool to use in patients exposed to vigabatrin. METHODS: Two hundred one vigabatrin-exposed subjects with epilepsy, divided into 2 groups, and 90 healthy controls participated. Visual fields were obtained using Goldmann kinetic perimetry and quantified using mean radial degrees (MRD). RNFL imaging was performed using either spectral-domain (Group 1) or time-domain (Group 2) OCT. RESULTS: Thirty-nine of 201 (19.4%) patients were unable to perform perimetry. Thirteen (6.5%) patients were unable to perform OCT. A total of 51.6% of patients showed VAVFL. Average RNFL thickness was significantly thinner in patients (77.9 MUm) compared to healthy controls (93.6 MUm) (p < 0.001). There was a strong correlation between MRD and average RNFL thickness for Group 1 (r = 0.768, p < 0.001) and Group 2 (r = 0.814, p < 0.001). OCT RNFL imaging showed high repeatability. INTERPRETATION: OCT provides a useful tool to assess people exposed to vigabatrin, and can provide an accurate estimate of the extent of visual field loss in the absence of a reliable direct measure of the visual field. The strong linear relationship found between RNFL thickness and visual field size provides some evidence that irreversible VAVFL may be related to loss of retinal ganglion cell axons. PMID- 21246603 TI - Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder. AB - OBJECTIVE: For development of neuroprotective therapy, neurodegenerative disease must be identified as early as possible. However, current means of identifying "preclinical" neurodegeneration are limited. Patients with idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) are at >50% risk of synuclein mediated neurodegenerative disease--this provides a unique opportunity to directly observe preclinical synucleinopathy and to test potential markers of preclinical disease. METHODS: Patients with RBD without neurodegenerative disease were enrolled in a prospective cohort starting in 2004. Olfaction and color vision were tested at baseline, then annually for 5 years. Test results were compared between patients who developed neurodegenerative disease and those who remained disease-free. RESULTS: Out of 64 patients, 62 (97%) participated in annual follow-up. During follow-up, 21 developed disease, and 41 remained disease free. Out of 21, 16 developed a combination of parkinsonism and dementia, 4 developed isolated parkinsonism (all with tremor), and 1 developed isolated dementia. Compared to those remaining disease-free, patients destined to develop disease had worse baseline olfaction (University of Pennsylvania Smell Identification Test [UPSIT] = 58.3 +/- 27.0% age/sex-adjusted normal vs 80.2 +/- 26.3%; p = 0.003) and color vision (Farnsworth-Munsell 100-Hue color test [FM 100] errors 153.0 +/- 82.2% normal vs 120.2 +/- 26.5%; p = 0.022). Kaplan-Meier 5 year-disease-free survival in those with normal olfaction was 86.0%, vs 35.4% with impaired olfaction (p = 0.029). Disease-free survival with normal color vision was 70.3%, vs 26.0% with impaired vision (p = 0.009). Both olfaction and color vision were reduced as much as 5 years before disease diagnosis, with only slight decline in preclinical stages. INTERPRETATION: Olfaction and color vision identify early-stage synuclein-mediated neurodegenerative diseases. In most cases, abnormalities are measurable at least 5 years before disease onset, and progress slowly in the preclinical stages. PMID- 21246604 TI - Age-specific progression of nigrostriatal dysfunction in Parkinson's disease. AB - OBJECTIVE: To investigate in vivo the impact of age on nigrostriatal dopamine dysfunction in Parkinson's disease (PD). METHODS: PD patients (n = 78) and healthy control subjects (n = 35) underwent longitudinal positron emission tomography assessments using 3 presynaptic dopamine markers: (1) [11C](+/ )dihydrotetrabenazine (DTBZ), to estimate the density of the vesicular monoamine transporter type 2; (2) [11C]d-threo-methylphenidate, to estimate the density of the plasma membrane dopamine transporter; and (3) 6-[18F]-fluoro-L-dopa, to estimate the activity of the enzyme dopa-decarboxylase. RESULTS: The study comprised 438 PD scans and 241 control scans (679 scans in total). At symptom onset, the loss of putamen DTBZ binding was substantially greater in younger compared to older PD patients (p = 0.015). Remarkably, however, the rate of progression of DTBZ binding loss was significantly slower in younger patients (p < 0.05). The estimated presymptomatic phase of the disease spanned more than 2 decades in younger patients, compared to 1 decade in older patients. INTERPRETATION: Our results suggest that, compared to older patients, younger PD patients progress more slowly and are able to endure more damage to the dopaminergic system before the first motor symptoms appear. These observations suggest that younger PD patients have more efficient compensatory mechanisms. PMID- 21246605 TI - Relevance of GJC2 promoter mutation in Pelizaeus-Merzbacher-like disease. PMID- 21246607 TI - Assay design and sample collection can affect anti-John Cunningham virus antibody detection. PMID- 21246608 TI - Milk composition in free-ranging polar bears (Ursus maritimus) as a model for captive rearing milk formula. AB - The goals of this study were to have an improved understanding of milk composition and to help create a suitable milk formula for cubs raised in captivity. Milk samples were evaluated for fat, fatty acids, carbohydrate, vitamin D(3), 25(OH)D(3), vitamin A (retinol), vitamin E (alpha-tocopherol), protein, and amino acids. Total lipids in milk did not differ for cubs (mean +/- SEM = 26.60 +/- 1.88 g/100 ml vs. yearlings 27.80 +/- 2.20 g/100 ml). Milk lipids were of 23.6% saturated fatty acid for cubs and 22.4% for yearlings. Milk consumed by cubs and yearlings contained 43.8 and 42.0% mono-unsaturated fatty acids and 23.4 and 21.9% polyunsaturated fatty acids, respectively. Carbohydrate content was higher in milk for cubs (4.60 +/- 0.64 g/100 ml) than for yearlings (2.60 +/- 0.40 g/100 ml). Vitamin D(3) concentration of milk was 18.40 +/- 5.00 ng/ml in early lactation compared with 7.60 +/- 2.00 ng/ml for mid-lactation. 25(OH)D(3) was lower in milk consumed by cubs (162.00 +/- 6.70 pg/ml) than in milk consumed by yearlings (205.00 +/- 45.70 pg/ml). Vitamin A concentrations were 0.06 +/- 0.01 and 0.03 +/- 0.01 ug/ml for cubs and yearlings, respectively. Vitamin E was higher in milk consumed by cubs (20.16 +/- 4.46 ug/ml) than by yearlings (7.30 +/- 1.50 ug/ml). Protein content did not differ in milk available to cubs (11.40 +/- 0.80 g/100 ml compared with milk for yearlings 11.80 +/- 0.40 g/100 ml). Taurine was the most abundant free amino acid at 3,165.90 +/- 192.90 nmol/ml (0.04% as fed basis). PMID- 21246609 TI - Age, sex, body anthropometry, and ACL size predict the structural properties of the human anterior cruciate ligament. AB - Anterior cruciate ligament (ACL) injury continues to be at the forefront of sports injury concerns because of its impact on quality of life and joint health prognosis. One strategy is to reduce the occurrence of this injury by identifying at-risk subjects based on key putative risk factors. The purpose of our study was to develop models that predict the structural properties of a subject's ACL based on the combination of known risk factors. We hypothesized that the structural properties of the ACL can be predicted using a multi-linear regression model based on significant covariates that are associated with increased risk of injury, including age, sex, body size, and ACL size. We also hypothesized that ACL size is a significant contributor to the model. The developed models had predictive capabilities for the structural properties of the ACL: load at failure (R2 = 0.914), elongation at failure (R2 = 0.872), energy at failure (R2 = 0.913), and linear stiffness (R2 = 0.756). Furthermore, sex, age, body mass, BMI, and height were contributors (p < 0.05) to all predicted structural properties. ACL minimal area was a contributor to elongation, energy at failure, and linear stiffness (p < 0.05), but not to load at failure. ACL volume was also a contributor to elongation and energy at failure (p < 0.05), but not to linear stiffness and load at failure models. ACL length was not a significant contributor to any structural property. The clinical significance of this research is its potential, after continued development and refinement of the model, for application to prognostic studies that are designed to identify individuals at increased risk for injury to the ligament. PMID- 21246610 TI - Effects of hypertonic dextrose injections in the rabbit carpal tunnel. AB - OBJECTIVE: This study investigated the effects of different doses of hypertonic dextrose injection on the carpal tunnel subsynovial connective tissue (SSCT) and median nerve in a rabbit model. METHODS: Thirty-eight New Zealand white rabbits weighing 4.0-4.5 kg were used. One forepaw carpal tunnel was randomly injected with one of five different treatments: saline-single injection; saline-two injections 1 week apart; 10% dextrose-single injection; 20% dextrose-single injection; or 10% dextrose-two injections 1 week apart. Animals were sacrificed at 12 weeks after the initial injection and were evaluated by electrophysiology (EP), SSCT mechanical testing and histology. RESULTS: There were significant increases in the energy absorption of the SSCT in the 10% dextrose-double injection group compared to the saline injection groups. SSCT stiffness was also significantly increased in the 10% dextrose-double injection group compared to the other groups. There was a significant increase in the thickness of the SSCT in the 10% dextrose-double injection group compared to the saline-single injection group and a significant decrease in the nerve short-long diameter ratio in the 10% dextrose-double injection group compared to the saline-single injection group. There were no changes in EP among the groups. CONCLUSIONS: SSCT fibrosis is present for up to 12 weeks after dextrose injection; multiple injections have bigger effects, including what appears to be a secondary change in nerve flattening. This model may be useful to study the effects of external fibrosis on nerve morphology and physiology, such as occurs clinically in carpal tunnel syndrome. PMID- 21246611 TI - Sustained delivery of transforming growth factor beta three enhances tendon-to bone healing in a rat model. AB - Despite advances in surgical technique, rotator cuff repairs are plagued by a high rate of failure. This failure rate is in part due to poor tendon-to-bone healing; rather than regeneration of a fibrocartilaginous attachment, the repair is filled with disorganized fibrovascular (scar) tissue. Transforming growth factor beta 3 (TGF-beta3) has been implicated in fetal development and scarless fetal healing and, thus, exogenous addition of TGF-beta3 may enhance tendon-to bone healing. We hypothesized that: TGF-beta3 could be released in a controlled manner using a heparin/fibrin-based delivery system (HBDS); and delivery of TGF beta3 at the healing tendon-to-bone insertion would lead to improvements in biomechanical properties compared to untreated controls. After demonstrating that the release kinetics of TGF-beta3 could be controlled using a HBDS in vitro, matrices were incorporated at the repaired supraspinatus tendon-to-bone insertions of rats. Animals were sacrificed at 14-56 days. Repaired insertions were assessed using histology (for inflammation, vascularity, and cell proliferation) and biomechanics (for structural and mechanical properties). TGF beta3 treatment in vivo accelerated the healing process, with increases in inflammation, cellularity, vascularity, and cell proliferation at the early timepoints. Moreover, sustained delivery of TGF-beta3 to the healing tendon-to bone insertion led to significant improvements in structural properties at 28 days and in material properties at 56 days compared to controls. We concluded that TGF-beta3 delivered at a sustained rate using a HBDS enhanced tendon-to-bone healing in a rat model. PMID- 21246612 TI - Effects of adeno-associated virus-2-mediated human BMP-7 gene transfection on the phenotype of nucleus pulposus cells. AB - Bone morphogenetic protein-7 (BMP-7) was found to stimulate the synthesis of proteoglycans (PGs) and collagen type II. To increase the biological function of the nucleus pulposus (NP) cells, the Ad-hBMP-7 vector was also successfully constructed and transfected NP cells. However, the disadvantages of adenovirus limit the usefulness of the Ad-hBMP7 vector for clinical application. The rAAV2 vector has empirical advantages, especially for clinical use, to transfer exogenous genes into cells. The purpose of this study was to first determine whether a rAAV2-hBMP-7 vector could be used to transfect canine NP cells and effect on the biological functions of canine NP cells. The canine NP cells transfected by the rAAV-BMP7 were assessed semi-quantitatively for BMP-7 expression with real-time PCR and westernbloting. Aggrecan and collagens type I and II secreted by the NP cells were qualitatively assessed at 4, 7, and 14 days post-transfection in the transfection and control groups. We found that rAAV2 can successfully transfer the hBMP-7 gene into canine NP cells. NP cells transfected by the rAAV-hBMP-7 vector express hBMP-7 for at least 14 days. At 7 and 14 days, the expressed hBMP-7 promotes a remarkable and significant accumulation of both proteoglycans (42% and 77% higher than non-transfected cells) (p<0.05) and collagen type II (63% and 94% higher than non-transfected cells) (p<0.05). Thus, we could speculate that the rAAV-based gene delivery technique promotes the expression of proteoglycans and collagen type II of nucleus pulposus cells. Moreover, this technique may be applicable for the future treatment of degenerative disc disease. PMID- 21246613 TI - Inhibition of mTOR signaling by oleanolic acid contributes to its anti-tumor activity in osteosarcoma cells. AB - Oleanolic acid (OA), a pentacyclic triterpenoid exhibits potent anti-tumor activity against many tumor cell lines. But the mechanisms through which OA inhibits osteosarcoma cells are not known. The mammalian target of rapamycin (mTOR) serves as a central regulator of cell growth, proliferation, survival, and metabolism by integrating intracellular and extracellular signals. In this study, we examined effects of OA on proliferation, cell cycle progression, apoptosis in osteosarcoma cells, and involvement of mTOR signaling in this process. OA inhibited cell proliferation and colony formation, induced G1 arrest in osteosarcoma MG63 and Saos-2 cells dose and time dependently. The protein level of cyclin D1, which plays critical role in G1 to S phase transition and servers as a downstream target of mTOR complex 1 (mTORC1) was down-regulated by OA. Phosphorylation of p70 ribosomal S6 kinase 1 (p70 S6K1) (T389) and S6 (S235/236), mediators of mTORC1 signaling in controlling protein translation and cell growth, was also inhibited by OA. Furthermore, OA inhibited phosphorylation of Akt, a pro survival factor and substrate for mTORC2. Inactivation of Akt correlated with pro apoptotic role of OA in osteosarcoma cells, as manifested by an increase in annexin V-FITC binding, cleavage of poly (ADP-ribose) polymerase (PARP) and activation of caspases 3. Our results suggest that OA is a promising agent for treatment of osteosarcoma and mTOR signaling may contribute to its anti-tumor effects on osteosarcoma cells. PMID- 21246614 TI - Rapid attachment of adipose stromal cells on resorbable polymeric scaffolds facilitates the one-step surgical procedure for cartilage and bone tissue engineering purposes. AB - The stromal vascular fraction (SVF) of adipose tissue provides an abundant source of mesenchymal stem cells. For clinical application, it would be beneficial to establish treatments in which SVF is obtained, seeded onto a scaffold, and returned into the patient within a single surgical procedure. In this study, we evaluated the suitability of both a macroporous poly(L-lactide-co-caprolactone) and a porous collagen type I/III scaffold for this purpose. Surprisingly, cell attachment was rapid (~10 min) and sequestered the majority of adipose stem cells, as deduced from colony-forming unit assays. Proliferation occurred in both polymeric scaffolds. Upon chondrogenic induction, up-regulation of chondrogenic genes, production of glycosaminoglycans, and accumulation of collagen type II was observed, indicating differentiation of scaffold-attached SVF cells along the chondrogenic lineage. Osteogenic differentiation was achieved in both scaffold types, as visualized by up-regulation of osteogenic genes, increase of alkaline phosphatase production over time, and accumulation of bone sialoprotein and osteonectin. In conclusion, this study identifies both poly(L-lactide-co caprolactone) and collagen type I/III as promising scaffold materials for rapid attachment of adipose stem cell-like (stromal) cells, enhancing the development of one-step surgical concepts for cartilage and bone tissue engineering. PMID- 21246615 TI - Factors explaining chronic knee extensor strength deficits after ACL reconstruction. AB - Persistent quadriceps muscle weakness is common after anterior cruciate ligament (ACL) reconstruction. The mechanisms underlying these chronic strength deficits are not clear. This study examined quadriceps strength in people 2-15 years post ACL reconstruction and tested the hypothesis that chronic quadriceps weakness is related to levels of voluntary quadriceps muscle activation, antagonistic hamstrings moment, and peripheral changes in muscle. Knee extensor strength and activation were evaluated in 15 ACL reconstructed and 15 matched uninjured control subjects using an interpolated triplet technique. Electrically evoked contractile properties were used to evaluate peripheral adaptations in the quadriceps muscle. Antagonistic hamstrings moments were predicted using a practical mathematical model. Knee extensor strength and evoked torque at rest were significantly lower in the reconstructed legs (p < 0.05). Voluntary activation and antagonistic hamstrings activity were similar across legs and between groups (p > 0.05). Regression analyses indicated that side-to-side differences in evoked torque at rest explained 71% of the knee extensor strength differences by side (p < 0.001). Voluntary activation and antagonistic hamstrings moment did not contribute significantly (p > 0.05). Chronic quadriceps weakness in this sample was primarily related to peripheral changes in the quadriceps muscle, not to levels of voluntary activation or antagonistic hamstrings activity. PMID- 21246616 TI - Molecular mechanism of fatty degeneration in rotator cuff muscle with tendon rupture. AB - Fatty degeneration often occurs in rotator cuff muscle with tendon rupture. However, the molecular mechanism underlying this change has not been fully clarified yet. We investigated the gene expression of Wnt10b and adipogenic marker gene, PPARgamma and C/EBPalpha in C2C12 myogenic cell line under inhibition of Wnt10b by adipogenic induction medium, isobutylmethylxanthine, dexamethasone, and insulin (MDI). The role of Wnt-signal was confirmed by adding Lithium chloride (LiCl), which mimics Wnt signaling to the cultured cell with MDI. We also assessed the expression profiles of same genes in the rat rotator cuff tear model in vivo. MDI induced Oil red-O staining positive adipocytes and upregulated PPARgamma and C/EBPalpha expression. LiCl inhibited adipogenic induction of MDI. Rotator cuff muscle with tendon rupture showed positive staining for Oil red-O. Real-time polymerase chain reaction analyses revealed decreased expression of Wnt10b followed by increased PPARgamma and C/EBPalpha gene expression in the supraspinatus muscle. Fatty degeneration and its molecular events were remarkably seen in the distal one-third of the detached supraspinatus muscle versus control. Wnt signaling may regulate adipogenic differentiation both in the myoblasts in vitro and the muscle in vivo. Our results indicate that the reduction of Wnt10b in muscle with a rotator cuff tear is a key signal in fatty degeneration of the muscle. PMID- 21246617 TI - Sildenafil accelerates fracture healing in mice. AB - Sildenafil, a cyclic guanosine monophosphate (cGMP)-dependent phospodiesterase-5 inhibitor, has been shown to be a potent stimulator of angiogenesis through upregulation of pro-angiogenic factors and control of cGMP concentration. Herein, we determined whether sildenafil also influences angiogenic growth factor expression and bone formation during the process of fracture healing. Bone healing was studied in a murine closed femur fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analysis at 2 and 5 weeks after fracture. Thirty mice received 5 mg/kg body weight sildenafil p.o. daily. Controls (n = 30) received equivalent amounts of vehicle. After 2 weeks of fracture healing sildenafil significantly increased osseous fracture bridging, as determined radiologically and histologically. This resulted in an increased biomechanical stiffness compared to controls. A smaller callus area with a slightly reduced amount of cartilaginous tissue indicated an accelerated healing process. After 5 weeks the differences were found blunted, demonstrating successful healing in both groups. Western blot analysis showed a significantly higher expression of the pro-angiogenic and osteogenic cysteine-rich protein (CYR) 61, confirming the increase of bone formation. We show for the first time that sildenafil treatment accelerates fracture healing by enhancing bone formation, most probably by a CYR61-associated pathway. PMID- 21246618 TI - Biceps tendon properties worsen initially but improve over time following rotator cuff tears in a rat model. AB - Damage to the biceps tendon is often seen in conjunction with rotator cuff tears. However, controversy exists regarding its role in the shoulder and its optimal treatment. A previous study determined that biceps tendons were detrimentally affected in the presence of rotator cuff tears in the rat model and this damage worsened over time. However, whether this damage progresses at later time points to provide a chronic model is unknown. The objective of this study was to determine the changes in the biceps tendon in the presence of a cuff tear over time. Our hypothesis was that histological, compositional, organizational, and mechanical properties would worsen with time. We detached the supraspinatus and infraspinatus tendons of 48 rats and evaluated these properties at 1, 4, 8, and 16 weeks postdetachment. Properties worsened through 8 weeks, but improved between 8 and 16 weeks. We therefore conclude that biceps tendon changes in this model are not truly chronic. Additionally, it has been shown that infraspinatus properties in this model return to normal by 16 weeks, when biceps properties improve, indicating that earlier repair of one or more of the rotator cuff tendons may lead to resolved pathology of the long head of the biceps tendon. PMID- 21246619 TI - Diabetes mellitus alters the mechanical properties of the native tendon in an experimental rat model. AB - The purpose of this study was to determine the effect of the diabetic phenotype on the mechanical properties of the native patellar tendon and its enthesis. Diabetes was induced via intraperitoneal injection of streptozotocin in Lewis rats. Control (n = 18) and diabetic animals (n = 20) were killed at 12 and 19 days for analysis. Statistical comparisons were performed using Student's t-tests and a two-tailed Fisher test with significance set at p < 0.05. Pre- and post injection intraperitoneal glucose tolerance tests demonstrated significant impairment of glycemic control in the diabetic compared to control animals (p = 0.001). Mean serum hemoglobin A1c levels at 19 days was 10.6 +/- 2.7% and 6.0 +/- 1.0% for the diabetic and control groups, respectively (p = 0.0001). Fifteen of sixteen diabetic animals demonstrated intrasubstance failure of the patellar tendon, while only 7 of 14 control specimens failed within the tendon substance. The Young's modulus of the diabetic tendon was significantly lower than control specimens by 19 days post-induction (161 +/- 10 N m(-2) compared to 200 +/- 46 N m(-2) , respectively) (p = 0.02). The metabolic condition of poorly controlled diabetes negatively affects the mechanical properties of the native patellar tendon. These altered structural properties may predispose diabetic patients to a greater risk of tendinopathy and/or traumatic rupture. PMID- 21246620 TI - Growth factor and protease expression during different phases of healing after rabbit deep flexor tendon repair. AB - The purpose of the study was to contribute to the mapping of molecular events during flexor tendon healing, in particular the growth factors insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF) and nerve growth factor (NGF), matrix metalloproteinases (MMP-3 and MMP-13) and their inhibitors (tissue inhibitors of metalloproteinases, TIMP-1 and TIMP-3, and the protease cathepsin K. In a rabbit model of flexor tendon injury, the mRNA expression for the growth factors, MMPs and TIMPs were measured in tendon and tendon sheath tissue at several time points (3, 6, 21, and 42 days) representing different phases of the healing process. We found that MMP-13 remained increased during the study period, whereas MMP-3 returned to normal levels within the first week after injury. TIMP-3 was down-regulated in the tendon sheaths. Cathepsin K was up-regulated in tendons and sheaths after injury. NGF was present in both tendons and sheaths, but unaltered. IGF-1 exhibited a late increase in the tendons, while VEGF was down-regulated at the later time points. In conclusion, we have demonstrated the presence of NGF in flexor tendons. MMP-13 expression appears to play a more protracted role in flexor tendon healing than MMP-3. The relatively low levels of endogenous IGF-1 and VEGF mRNA following injury support their potential beneficial role as exogenous modulators to optimize tendon healing and strength without increasing adhesion formation. PMID- 21246621 TI - Structural profile of ultra-high molecular weight polyethylene in acetabular cups worn on hip simulators characterized by confocal Raman spectroscopy. AB - We applied a Raman confocal spectroscopic technique to quantitatively assess the structural features of two kinds of acetabular cups made of ultra-high molecular weight polyethylene. We wanted to know whether polyethylene cups belonging to different generations, and thus manufactured by different procedures, possess different molecular structures and how those differences affected their wear resistance. Emphasis was placed on oxidation profiles developed along the cross sectional depth of the cups in the main wear zone developed during testing in a hip simulator. The micrometric lateral resolution of the laser beam, focused at surface or sub-surface sectional planes, enabled the visualization of highly resolved microstructural property profiles, including crystalline and amorphous phase fractions. Oxidation profiles retrieved from polyethylene cups belonging to different generations greatly differed after wear testing. The highly cross linked polyethylene showed a lower degree of crystallinity and oxidation at an appreciably slower rate as compared to that belonging to an earlier generation. PMID- 21246622 TI - Biochemical identification and immunolocalizaton of aggrecan, ADAMTS5 and inter alpha-trypsin-inhibitor in equine degenerative suspensory ligament desmitis. AB - We describe analysis of suspensory ligaments from horses with advanced degenerative suspensory ligament desmitis (DSLD) to identify the major proteoglycans (PGs), ADAMTS-aggrecanases and inter-alpha-trypsin inhibitor (IalphaI) components associated with ligament degeneration. Specific anatomical regions of suspensory ligaments from two normal horses and four diagnosed with DSLD were analyzed by Western blot and immunohistochemistry for the following: aggrecan, aggrecan fragments, decorin, ADAMTS4, ADAMTS5, and IalphaI components. When compared to normal, DSLD ligaments showed about a 15-fold increase (P < 0.0014) in aggrecan levels and markedly enhanced staining with Safranin O. The aggrecan was composed of two distinct high molecular weight core protein species. The largest species was found only in DSLD samples and it co-migrated with aggrecan synthesized by equine mesenchymal stem cells (MSC). Many of the DSLD samples also contained abnormally high concentrations of ADAMTS4, ADAMTS5, and IalphaI. Notably, the ADAMTS5 in DSLD samples, but not normals, was present largely as a high molecular weight complex. We conclude that ligament degeneration in DSLD is associated with matrix changes characteristic of an inflammatory nonhealing wound, specifically containing chondrogenic progenitor cells. Since aggrecan accumulation is a major feature of incomplete healing in tendon and skin of the ADAMTS5 knockout mouse, we propose that ligament failure in DSLD results from a process involving tissue inflammation and the complexation of ADAMTS5. PMID- 21246624 TI - 19F chemical shifts, coupling constants and conformational preferences in monosubstituted perfluoroparacyclophanes. AB - In the process of studying the chemistry of perfluoro[2.2]paracyclophanes (PFPCs), a novel class of compounds, it became necessary to identify some disubstituted products. To achieve this goal, we characterize in this work some monosubstituted PFPCs, identifying their (19)F-(19) F coupling patterns, and establishing a methodology for the assignment of their (19)F chemical shifts. The pattern of coupling constants indicates a skewed geometry in which the upper deck moves towards or away from the substituent, depending on the substituent electron donor character and size. Quantum chemical calculations, performed at the HF/6 311 + G(d,p)//B3LYP/EPR-III level of theory, confirmed the conformations inferred from coupling constants and reproduced well the values of the couplings. Transmission mechanisms for the FC term of four- and five-bond (19)F-(19) F couplings are discussed in detail. Understanding the conformational preferences of PFPCs and how they are reflected by the coupling constants facilitates the assignment of (19)F chemical shifts in monosubstituted PFPCs and the identification of the disubstituted products. PMID- 21246623 TI - The fidelity of spin trapping with DMPO in biological systems. AB - Unlike direct ESR, spin trap methodology depends on the absolute fidelity of the spin trap reaction. Two alternative reactions of 5,5-dimethyl-1-pyrroline N-oxide (DMPO) leading to radical adduct artifacts have been discovered and investigated: inverted spin trapping and the Forrester-Hepburn nucleophilic mechanism. These two alternate pathways to radical adducts are a combination of one-electron oxidation and nucleophilic addition, in either order. In biological systems, serious artifacts have been reported due to the Forrester-Hepburn mechanism, which is initiated by the addition of a nucleophile to DMPO. It has recently been demonstrated that (bi)sulfite (hydrated sulfur dioxide) can react with DMPO via a nonradical, nucleophilic reaction, and it has been further proposed that DMPO/(*)SO(3)(-) formation in biological systems is an artifact and not the result of spin trapping of sulfur trioxide anion radical ((*)SO(3)(-)). The one electron oxidation of (bi)sulfite catalyzed by horseradish peroxidase (HRP)/hydrogen peroxide (H(2)O(2)) has been reinvestigated by ESR spin trapping with DMPO and oxygen uptake studies to obtain further evidence for the radical reaction mechanism. In the absence of DMPO, the initial rate of (bi)sulfite dependent oxygen and H(2)O(2) consumption was determined to be half of the initial rate of DMPO/(*)SO(3)(-) radical adduct formation as determined by ESR, demonstrating that, under our experimental conditions, DMPO exclusively forms the radical adduct by trapping the (*)SO(3)(-). PMID- 21246625 TI - Anodic oxidation of selenadiazoloquinolones in alkaline media. AB - Newly synthesized derivatives of 6-oxo-6,9-dihydro[1,2,5]selenadiazolo[3,4 h]quinoline variously substituted at position 7 (R = H, COOH, COCH(3), CN, COOC(2)H(5) and COOCH(3)) are established in strongly alkaline aqueous solutions (0.1 M NaOH; pH ~ 13) as N(9)-deprotonated structures, but in less alkaline solutions (0.001 M NaOH; pH ~ 11) the N(9)-protonated oxo tautomeric forms dominate. Upon their anodic oxidation in alkaline solutions, the selenadiazole ring is replaced, forming instead the paramagnetic species analogous to the ortho semiquinone radical anions as monitored by in situ EPR spectroscopy. The quantum chemical calculations for two representative selenadiazoloquinolones (R = H and COOH) and their anodic oxidation products presented are in agreement with experiments. PMID- 21246626 TI - Low-power composite CPMG HSQMBC experiment for accurate measurement of long-range heteronuclear coupling constants. AB - A modified version of CPMG-HSQMBC pulse scheme is presented for the measurement of long-range heteronuclear coupling constants. The method implements adiabatic inversion and refocusing pulses on the heteronucleus. Low-power composite 180 degrees XY-16 CPMG pulse train is applied on both proton and X nuclei during the evolution of long-range couplings to eliminate phase distortions due to co evolution of homonuclear proton-proton couplings. The pulse sequence yields pure absorption antiphase multiplets allowing precise and direct measurement of the (n)J(XH) coupling constants regardless from the size of the proton-proton couplings. The applicability of the method is demonstrated using strychnine as a model compound. The selective 1D version of the method is also presented. PMID- 21246628 TI - TCA cycle-independent acetate metabolism via the glyoxylate cycle in Saccharomyces cerevisiae. AB - In Saccharomyces cerevisiae, the accepted theory is that due to TCA cycle dysfunction, the Deltacit1 mutant lacking the mitochondrial enzyme citrate synthase (Cit1) cannot grow on acetate, regardless of the presence of the peroxisomal isoenzyme (Cit2). In this study, we re-evaluated the roles of Cit1 and Cit2 in acetate utilization and examined the pathway of acetate metabolism by analysing mutants defective in TCA or glyoxylate cycle enzymes. Although Deltacit1 cells showed significantly reduced growth on rich acetate medium (YPA), they exhibited growth similar to Deltacit2 and the wild-type cells on minimal acetate medium (YNBA). Impaired acetate utilization by Deltacit1Deltacit2 cells on YNBA was restored by ectopic expression of either Cit2 or its cytoplasmically localized variants. Deletion of any of the genes for the enzymes solely involved in the TCA cycle (IDH1, KGD1 and LSC1), except for SDH1, caused little defect in acetate utilization on YNBA but resulted in significant growth impairment on YPA. In contrast, cells lacking any of the genes involved in the glyoxylate cycle (ACO1, FUM1, MLS1, ICL1 and MDH2) did not grow on either YNBA or YPA. Deletion of SFC1 encoding the succinate-fumarate carrier also caused similar growth defects on YNBA. Our results suggest that in S. cerevisiae the glyoxylate cycle functions as a competent metabolic pathway for acetate utilization on YNBA, while both the TCA and glyoxylate cycles are essential for growth on YPA. PMID- 21246627 TI - Genetic, genomic, and molecular tools for studying the protoploid yeast, L. waltii. AB - Sequencing of the yeast Kluyveromyces waltii (recently renamed Lachancea waltii) provided evidence of a whole genome duplication event in the lineage leading to the well-studied Saccharomyces cerevisiae. While comparative genomic analyses of these yeasts have proven to be extremely instructive in modeling the loss or maintenance of gene duplicates, experimental tests of the ramifications following such genome alterations remain difficult. To transform L. waltii from an organism of the computational comparative genomic literature into an organism of the functional comparative genomic literature, we have developed genetic, molecular and genomic tools for working with L. waltii. In particular, we have characterized basic properties of L. waltii (growth, ploidy, molecular karyotype, mating type and the sexual cycle), developed transformation, cell cycle arrest and synchronization protocols, and have created centromeric and non-centromeric vectors as well as a genome browser for L. waltii. We hope that these tools will be used by the community to follow up on the ideas generated by sequence data and lead to a greater understanding of eukaryotic biology and genome evolution. PMID- 21246629 TI - Efficient and rapid exact gene replacement without selection. AB - We describe a highly efficient method for exact gene replacement in budding yeast. Induction of rapid and efficient recombination in an entire cell population results in at least 50% of the recombinants undergoing a switch of the endogenous copy to a specific mutated allele, with no remaining markers or remnant of foreign DNA, without selection. To accomplish this, a partial copy of the replacement allele, followed by an HO cut site, is installed adjacent to the wild-type locus, in a GAL-HO MATa-inc background. HO induction results in near quantitative site cleavage and recombination/gene conversion, resulting in either regeneration of wild-type or switch of the endogenous allele to the mutant, with accompanying deletion of intervening marker sequences, yielding an exact replacement. Eliminating the need for selection (over days) of rare recombinants removes concerns about second-site suppressor mutations and also allows direct phenotypic analysis, even of lethal gene replacements, without the need of a method to make the lethality conditional or to employ regulated promoters of unknown strength compared to the endogenous promoter. To test this method, we tried two known lethal gene replacements, substituting the non-essential CDH1 gene with a dominantly lethal version mutated for its Cdk phosphorylation sites and substituting the essential CDC28 gene with two recessively lethal versions, one containing an early stop codon and another inactivating Cdc28 kinase activity. We also tested a gene replacement of unknown phenotypic consequences: replacing the non-essential CLB3 B-type cyclin with a version lacking its destruction box. PMID- 21246630 TI - XANNpred: neural nets that predict the propensity of a protein to yield diffraction-quality crystals. AB - Production of diffracting crystals is a critical step in determining the three dimensional structure of a protein by X-ray crystallography. Computational techniques to rank proteins by their propensity to yield diffraction-quality crystals can improve efficiency in obtaining structural data by guiding both protein selection and construct design. XANNpred comprises a pair of artificial neural networks that each predict the propensity of a selected protein sequence to produce diffraction-quality crystals by current structural biology techniques. Blind tests show XANNpred has accuracy and Matthews correlation values ranging from 75% to 81% and 0.50 to 0.63 respectively; values of area under the receiver operator characteristic (ROC) curve range from 0.81 to 0.88. On blind test data XANNpred outperforms the other available algorithms XtalPred, PXS, OB-Score, and ParCrys. XANNpred also guides construct design by presenting graphs of predicted propensity for diffraction-quality crystals against residue sequence position. The XANNpred-SG algorithm is likely to be most useful to target selection in structural genomics consortia, while the XANNpred-PDB algorithm is more suited to the general structural biology community. XANNpred predictions that include sliding window graphs are freely available from http://www.compbio.dundee.ac.uk/xannpred PMID- 21246631 TI - Sensing the dissociation of a polymeric enzyme by means of an engineered intrinsic probe. AB - One of the most remarkable characteristics of Brucella lumazine synthase (BLS) is its versatility to undergo reversible dissociation and reassociation as a polymeric scaffold. We have proposed a mechanism of dissociation and unfolding of BLS. Using static light scattering (SLS) analysis, we were able to demonstrate that the decameric assembly dissociates into two different conditions [pH 5 or 2M guanidinium chloride (GdnHCl) pH 7] forming stable folded pentamers. The transition from folded pentamers to unfolded monomers by GdnHCl denaturation is highly cooperative and can be measured by different spectroscopic techniques. In this work, we show the successful insertion of an intrinsic probe to study in more detail the equilibria described in previous publications. For that purpose, we performed single-point mutations of Phe residues 121 and 127, located at the pentamer-pentamer and monomer-monomer interface, respectively, to Trp residues. These mutations produced only a marginal perturbation of the BLS structure. We analyzed the unfolding and stability of the mutants through different techniques: far-and near-UV CD, SLS, dynamic light scattering, and fluorescence spectroscopy. The introduced intrinsic probe could be used to gain insights into the detailed folding and assembly mechanism of this protein. PMID- 21246632 TI - Protein rigidity and thermophilic adaptation. AB - We probe the hypothesis of corresponding states, according to which homologues from mesophilic and thermophilic organisms are in corresponding states of similar rigidity and flexibility at their respective optimal temperatures. For this, the local distribution of flexible and rigid regions in 19 pairs of homologous proteins from meso- and thermophilic organisms is analyzed and related to activity characteristics of the enzymes by constraint network analysis (CNA). Two pairs of enzymes are considered in more detail: 3-isopropylmalate dehydrogenase and thermolysin-like protease. By comparing microscopic stability features of homologues with the help of stability maps, introduced for the first time, we show that adaptive mutations in enzymes from thermophilic organisms maintain the balance between overall rigidity, important for thermostability, and local flexibility, important for activity, at the appropriate working temperature. Thermophilic adaptation in general leads to an increase of structural rigidity but conserves the distribution of functionally important flexible regions between homologues. This finding provides direct evidence for the hypothesis of corresponding states. CNA thereby implicitly captures and unifies many different mechanisms that contribute to increased thermostability and to activity at high temperatures. This allows to qualitatively relate changes in the flexibility of active site regions, induced either by a temperature change or by the introduction of mutations, to experimentally observed losses of the enzyme function. As for applications, the results demonstrate that exploiting the principle of corresponding states not only allows for successful thermostability optimization but also for guiding experiments in order to improve enzyme activity in protein engineering. PMID- 21246633 TI - Effect of flanking residues on the conformational sampling of the internal fusion peptide from Ebola virus. AB - Fusion peptides mediate viral and host-cell membrane fusion during viral entry. The monomeric form of the internal fusion peptide from Ebola virus was studied in membrane bilayer and water environments with computer simulations using replica exchange sampling and an implicit solvent description of the environment. Wild type Ebola fusion peptide (EFP), the W8A mutant form, and an extended construct with flanking residues were examined. It was found that the monomeric form of wild-type EFP adopts coil-helix-coil structure with a short helix from residues 8 to 11 mostly sampling orientations parallel to the membrane surface. W8A mutation disrupts the helicity in the N-terminal region of the peptide and leads to a preference for slightly oblique orientation relative to the membrane surface. The addition of flanking residues also alters the fusion peptide conformation with either a helix-break-helix structure or extended N and C-termini and reduced membrane insertion. In water, the fusion peptide is found to adopt structures with low helicity. PMID- 21246634 TI - Building interacting partner predictors using co-varying residue pairs between histidine kinase and response regulator pairs of 48 bacterial two-component systems. AB - The two-component system (TCS) is a signal transduction system that involves a histidine kinase (HK) and a response regulator (RR). Although up to hundreds of TCSs may operate in parallel in a bacterial cell, the high-fidelity of a TCS signaling is well maintained, minimizing irrelevant crosstalk between TCSs. When a HK gene and a RR gene in a given TCS system exist in neighboring positions, it is almost certain that their protein products (i.e., HK and RR) are interacting partners. However, large bacterial genomes often have multiple HK genes and/or cognate RR genes that are not neighboring positions. In many partially assembled genomes, some HK genes and RR genes belong to different contigs. In these cases, it is not clear which HK(s) and RR(s) interact. By combining information theoretic and graph-theoretic approaches, we developed a computational method identifying co-evolving residue pairs between HKs and cognate RRs and predicting the interacting HK:RR pairs for each TCS. In addition, we built a TCSppWWW webserver (http://compath.org/platcom/tcs) that takes query sequences of pairing candidates and predicts their HK:RR pairing using precomputed models. The current release of TCSppWWW provides predictors for 48 TCSs using over 20,000 protein sequences from about 900 bacterial genomes. Three different types of predictors using Random Forest, RBF Network, and Naive Bayes are provided. Once a set of HK and RR candidate sequences are submitted, TCSppWWW aligns query sequences to the precomputed multiple sequence alignment of HK:RR pairs, extracts co-evolving column positions, then returns prediction results with prediction margin and additional information. PMID- 21246635 TI - Structural and functional analysis of the Lmo2642 cyclic nucleotide phosphodiesterase from Listeria monocytogenes. AB - Listeria monocytogenes is a facultative intracellular pathogen invading humans and animals with the highest fatality rate among the food-borne pathogens. The Listeria pathogenic processes, such as cell entry and escape from phagosomes, depend on the actions of diverse bacterial factors, including lipoproteins. Here, we report the crystal structure of Lmo2642, a conserved putative lipoprotein containing a Ser/Thr phosphatase domain. The protein consists of two distinct domains: a catalytic domain that belongs to the metallophosphoesterase superfamily and an auxiliary alpha-helical bundle domain. The active site in the catalytic domain of Lmo2642 contains a dinuclear metal center in which Mn2(+) and Fe3(+) are preferentially positioned at the site1 and site2, respectively. On the basis of the structural analysis and enzymatic assays, we identified the biochemical activity of the protein as a cyclic nucleotide phosphodiesterase toward 2',3'- and 3',5'-cyclic nucleotides. Considering the cNMP phosphodiesterase activity and the putative surface localization of Lmo2642, we speculate that Lmo2642 has some potential roles in the host-pathogen interactions by changing the cAMP concentration of host cells during L. monocytogenes infection. PMID- 21246637 TI - Evodiamine inhibits 12-O-tetradecanoylphorbol-13-acetate-induced activator protein 1 transactivation and cell transformation in human hepatocytes. AB - Evodia rutaecarpa has been used to treat inflammatory digestive disorders in Asian countries. However, little is known about the antitumor activities of E. rutaecarpa and its bioactive constituent evodiamine (EVO). The aim of this study was to characterize the antitumor mechanisms of E. rutaecarpa and EVO in human hepatocytes. Human Chang liver cells were transfected with activator protein 1 (AP-1)-luciferase reporter gene and designated as Chang/AP-1 cells. The Chang/AP 1 cells were treated with E. rutaecarpa and its bioactive constituents, and challenged with the AP-1 stimulator 12-O-tetradecanoylphorbol-13- acetate (TPA). The present study showed that the methanol extract of E. rutaecarpa decreased the TPA-induced AP-1 transactivation in Chang/AP-1 cells, with an EC50 value of 24.72 MUg/mL. EVO inhibited the TPA-induced AP-1 transactivation and colony formation, with EC50 values of 82 MUM and 8.2 MUM, respectively. Moreover, EVO significantly diminished the TPA-induced phosphorylation of extracellular signal-regulated kinases (ERKs). These results suggested that EVO treatment suppressed the TPA induced AP-1 activity via the ERKs pathway. In conclusion, EVO inhibited the AP-1 activity and cellular transformation in human hepatocytes, suggesting that EVO was a potential agent for antitumor therapy. PMID- 21246636 TI - Crystal structure of a bacterial phosphoglucomutase, an enzyme involved in the virulence of multiple human pathogens. AB - The crystal structure of the enzyme phosphoglucomutase from Salmonella typhimurium (StPGM) is reported at 1.7 A resolution. This is the first high resolution structural characterization of a bacterial protein from this large enzyme family, which has a central role in metabolism and is also important to bacterial virulence and infectivity. A comparison of the active site of StPGM with that of other phosphoglucomutases reveals conserved residues that are likely involved in catalysis and ligand binding for the entire enzyme family. An alternate crystal form of StPGM and normal mode analysis give insights into conformational changes of the C-terminal domain that occur upon ligand binding. A novel observation from the StPGM structure is an apparent dimer in the asymmetric unit of the crystal, mediated largely through contacts in an N-terminal helix. Analytical ultracentrifugation and small-angle X-ray scattering confirm that StPGM forms a dimer in solution. Multiple sequence alignments and phylogenetic studies show that a distinct subset of bacterial PGMs share the signature dimerization helix, while other bacterial and eukaryotic PGMs are likely monomers. These structural, biochemical, and bioinformatic studies of StPGM provide insights into the large alpha-D-phosphohexomutase enzyme superfamily to which it belongs, and are also relevant to the design of inhibitors specific to the bacterial PGMs. PMID- 21246638 TI - Expression of MAGE-A4 and MAGE-C1 tumor-associated antigen in benign and malignant thyroid diseases. AB - BACKGROUND: A subset of thyroid tumors characterized by a follicular growth pattern can represent a serious diagnosis. Immunohistochemistry and molecular pathology for genetic profiling have been used in an attempt to resolve some of these issues. METHODS: Tumor tissue samples of thyroid were obtained from 70 patients who underwent surgical therapy. They were divided into 4 groups: 20 adenomatous goiters, 10 follicular adenomas, 24 papillary carcinomas, and 16 follicular carcinomas. Immunohistochemical analysis was carried out using antibodies for MAGE-A4 (melanoma antigen-encoding gene A4) and MAGE-C1 (melanoma antigen-encoding gene C1). RESULTS: Standard histologic analysis and immunohistochemistry analysis of MAGE-A4 and MAGE-C1 expression were performed in all patients. The antigens examined were not expressed in any of the tissues. CONCLUSIONS: The malignant degeneration of normal tissues is a multifactorial process, varying considerably both among tumor types and among individual patients. The present study showed that there was no immunolabeling of the MAGE A4 and MAGE-C1 antigens. PMID- 21246639 TI - Sentinel lymph node biopsy using real-time fluorescence navigation with indocyanine green in cutaneous head and neck/lip mucosa melanomas. AB - BACKGROUND: The triple technique (lymphoscintigraphy, patent-blue staining, and a gamma probe) constitutes a reliable method for the sentinel lymph node (SLN) biopsy. However, in head and neck melanomas, a shine-through phenomenon, which occurs because these SLNs are close to the primary focus, is irreversibly problematic. To get around the shine-through phenomenon, this study uses the fluorescence navigation with indocyanine green (ICG) as well as the triple technique. METHODS: ICG is a green dye and can be used as a marker with infrared fluorescence. ICG solution is intradermally injected around the tumor. By using Photodynamic Eye (PDE) intraoperatively, it is possible to observe the injected ICG as SLNs in the fluorescence images. RESULTS: By use of the fluorescence imaging with ICG, clear identification of the SLN of the case became possible. CONCLUSIONS: We think the fluorescence navigation with ICG will be a useful option for the SLN biopsy in head and neck melanomas. PMID- 21246641 TI - Use of the contralateral retroangular island flap for reconstructing midfacial defects after skin cancer ablation. AB - BACKGROUND: The retroangular flap is usually used to reconstruct small ipsilateral facial defects. The purpose of this study was to explore the use of the contralateral retroangular island flap for reconstructing large midfacial defects. METHODS: Retroangular flaps raised from the contralateral infraorbital region were used to reconstruct midfacial defects in 12 patients after the resection of skin cancers. The defect ranged in size from 3.0 * 3.0 to 5.0 * 7.0 cm, and the flap skin paddle ranged in size from 2.0 * 4.0 to 4.0 * 6.0 cm. RESULTS: All of the flaps survived. Patients were followed up for an average of 8.5 months. The vascularity of the flaps was good, and the match in terms of color and texture was excellent. The cosmetic and functional outcomes were satisfactory in all patients. CONCLUSION: The contralateral retroangular flap is a good alternative for reconstructing moderate to large midfacial defects. PMID- 21246640 TI - Factors associated with pharyngoesophageal stricture in patients treated with concurrent chemotherapy and radiation therapy for oropharyngeal squamous cell carcinoma. AB - BACKGROUND: The purpose of this study was to elucidate factors associated with pharyngoesophageal strictures after treatment for head and neck squamous cell carcinoma (SCC). METHODS: We conducted a retrospective review of patients receiving cisplatin and 5-fluorouracil chemotherapy combined with concurrent hyperfractionated radiation therapy for oropharyngeal squamous cell carcinoma. RESULTS: Strictures developed in 13 of 67 patients (19%). Strictures were associated with tumor location (tonsil vs base of tongue; p = .03), neck dissection after completion of therapy (p = .03), and the duration of treatment induced mucositis (weeks with mucositis grade >=2; National Cancer Institute (NCI) Common Toxicity Criteria; p < .001). Age, sex, race, tumor stage, nodal stage, American Joint Committee on Cancer (AJCC) stage, human papillomavirus (HPV) status, smoking, radiation dose, maximum severity of mucositis, amifostine use, and pretreatment swallow dysfunction were not significantly associated with stricture. In multivariate analysis, only duration of mucositis, after controlling for age, sex, and tumor location, remained highly significant (p < .01). CONCLUSION: The duration of treatment-related mucositis is an independent risk factor for stricture formation in patients with oropharyngeal SCC treated with concurrent chemotherapy and radiation therapy. PMID- 21246642 TI - Implementing neonatal screening for congenital cytomegalovirus: addressing the deafness of policy makers. AB - Congenital cytomegalovirus (CMV) infection is an important public health problem with approximately 7 in 1,000 newborns infected and consequently at risk for hearing impairment. Newborn hearing screening will fail to detect this hearing impairment in approximately half of the cases because late onset hearing loss is frequent. Hearing impairment has profound impact on cognitive and social development of children and their families, determining most of the disease burden of congenital CMV infection. The potential value of newborn screening for congenital CMV is increasingly discussed. To date, many experts acknowledge the benefit of antiviral treatment in the prevention of hearing deterioration in newborns with neurological symptoms, and the benefit of early identification of late-onset hearing impairment by means of extensive audiological follow up of infected infants. These opinions imply that the potential of newborn screening for CMV would lie in the identification of the large proportion of asymptomatic congenitally infected newborns at risk for developing late-onset hearing loss. Experience with postnatal antiviral treatment of symptomatic newborns is encouraging, but has not been studied in asymptomatic congenitally infected newborns. A large-scale study on the safety and effectiveness of combined screening and antiviral therapy for congenital CMV infection is the necessary next step to take and should not be delayed. PMID- 21246643 TI - The medicine use and corresponding subjective health complaints among adolescents, a cross-national survey. AB - BACKGROUND: Medicine use among children and young people is under-researched. Studies that investigated cross-national patterns in adolescents' medicine use practice are rare. This study aims to investigate adolescents' medicine use for corresponding health complaints in Europe and USA. METHODS: Nationally representative samples of adolescents from 19 countries and regions in Europe and USA completed an anonymous, standardised questionnaire as part of the Health Behaviour in School-aged Children 2005/2006 survey. The prevalence of health complaints and medicine use were determined. The influence of the frequency of medicine use, age, gender and country of residence, on the likelihood of medicine use was assessed using multilevel multivariate logistic regression, with separate analyses for boys and girls. RESULTS: Both health complaints and medicine use were common among adolescents. Medicine use was strongly associated with the frequency of health complaints. The prevalence of both medicine use and health complaints was higher among girls than boys. Boys and girls with weekly health complaints were both similarly likely to report elevated rates of medicine use. CONCLUSIONS: The findings indicated that adolescents who report more frequent recurrent health complaints are also more likely to report more frequent medicine use for their health complaints. Adolescent boys with weekly health complaints have the same risk of medicine use as girls with weekly health complaints. The importance of educating school-aged children to interpret their bodily feelings and complaints and to use medicines appropriately is of high priority. PMID- 21246647 TI - Germline cell formation and gonad regeneration in solitary and colonial ascidians. AB - The morphology of ascidian gonad is very similar among species. The testis consists of variable number of testicular follicles; the ovary consists of ovarian tubes that are thickened forming the germinal epithelium with stem cells for female germ cells with the exception of botryllid ascidians. Peculiar accessory cells that would be germline in origin accompany the oocytes. Using vasa homologues as a molecular marker, germline precursor cells can be traced back to the embryonic posterior-most blastomeres and are found in the tail of tailbud embryo in some solitary and colonial ascidians. In Ciona, they are subsequently located in the larval tail, while in colonial botryllid ascidians vasa-expressing cells become obscure in the tail. Recent evidence suggests that ascidian germ cells can regenerate from cells other than embryonic germline. An ensemble of the embryonic stringency of germ cell lineage and the postembryonic flexibility of gonad formation is discussed. PMID- 21246648 TI - Epibranchial placode-derived neurons produce BDNF required for early sensory neuron development. AB - In mice, BDNF provided by the developing taste epithelium is required for gustatory neuron survival following target innervation. However, we find that expression of BDNF, as detected by BDNF-driven beta-galactosidase, begins in the cranial ganglia before its expression in the central (hindbrain) or peripheral (taste papillae) targets of these sensory neurons, and before gustatory ganglion cells innervate either target. To test early BDNF function, we examined the ganglia of bdnf null mice before target innervation, and found that while initial neuron survival is unaltered, early neuron development is disrupted. In addition, fate mapping analysis in mice demonstrates that murine cranial ganglia arise from two embryonic populations, i.e., epibranchial placodes and neural crest, as has been described for these ganglia in non-mammalian vertebrates. Only placodal neurons produce BDNF, however, which indicates that prior to innervation, early ganglionic BDNF produced by placode-derived cells promotes gustatory neuron development. PMID- 21246650 TI - GABAergic and glutamatergic identities of developing midbrain Pitx2 neurons. AB - Pitx2, a paired-like homeodomain transcription factor, is expressed in post mitotic neurons within highly restricted domains of the embryonic mouse brain. Previous reports identified critical roles for PITX2 in histogenesis of the hypothalamus and midbrain, but the cellular identities of PITX2-positive neurons in these regions were not fully explored. This study characterizes Pitx2 expression with respect to midbrain transcription factor and neurotransmitter phenotypes in mid-to-late mouse gestation. In the dorsal midbrain, we identified Pitx2-positive neurons in the stratum griseum intermedium (SGI) as GABAergic and observed a requirement for PITX2 in GABAergic differentiation. We also identified two Pitx2-positive neuronal populations in the ventral midbrain, the red nucleus, and a ventromedial population, both of which contain glutamatergic precursors. Our data suggest that PITX2 is present in regionally restricted subpopulations of midbrain neurons and may have unique functions that promote GABAergic and glutamatergic differentiation. PMID- 21246649 TI - Noncanonical Notch function in motor axon guidance is mediated by Rac GTPase and the GEF1 domain of Trio. AB - The receptor Notch interacts with the Abl tyrosine kinase signaling pathway to control axon growth and guidance in Drosophila motor neurons. In part, this is mediated by binding to Trio, a guanine nucleotide exchange factor (GEF) for Rho GTPases. We show here that one of the two GEF domains of Trio, the Rac-specific GEF1, is essential for Trio-dependent motor axon guidance and for the genetic suppression of Notch function in motor axon patterning, but the Rho-specific GEF2 domain is not. Consistent with this, we show that Rac, and not Rho1 or Cdc42, interacts genetically with Notch in a manner indistinguishable from that of bona fide Abl signaling components. We infer, therefore, that Rac is a key component of Abl signaling in Drosophila motor axons, and specifically that it is the crucial Rho GTPase in "noncanonical" Notch/Abl signaling. PMID- 21246651 TI - An obesogenic diet started before puberty leads to abnormal mammary gland development during pregnancy in the rabbit. AB - Alterations to the metabolic environment during puberty can impact future lactation efficiency and mammary tumorigenesis. During this study, we used a model of rabbits receiving an obesogenic diet (OD), starting before puberty and extending until mid-pregnancy. Three months later, the body weight of OD animals was significantly higher than that of controls and their mammary glands displayed a precocious and abnormal development at mid-pregnancy. OD mammary ducts were filled with dense products, while alveolar structures invaded most of the fat pad. The proportion of secretory epithelium was significantly higher in OD mammary tissue, which contained an abundant accumulation of milk proteins and lipids. In conclusion, an obesogenic diet started before puberty induced an accelerated development of the rabbit mammary gland, leading to an accumulation of secretory products at mid-pregnancy. These results support the critical influence of nutrition on mammary growth and differentiation, which may be deleterious to mammary development and subsequent lactation. PMID- 21246652 TI - Ephrin reverse signaling controls palate fusion via a PI3 kinase-dependent mechanism. AB - Secondary palate fusion requires adhesion and epithelial-to-mesenchymal transition (EMT) of the epithelial layers on opposing palatal shelves. This EMT requires transforming growth factor beta3 (TGFbeta3), and its failure results in cleft palate. Ephrins, and their receptors, the Ephs, are responsible for migration, adhesion, and midline closure events throughout development. Ephrins can also act as signal-transducing receptors in these processes, with the Ephs serving as ligands (termed "reverse" signaling). We found that activation of ephrin reverse signaling in chicken palates induced fusion in the absence of TGFbeta3, and that PI3K inhibition abrogated this effect. Further, blockage of reverse signaling inhibited TGFbeta3-induced fusion in the chicken and natural fusion in the mouse. Thus, ephrin reverse signaling is necessary and sufficient to induce palate fusion independent of TGFbeta3. These data describe both a novel role for ephrins in palate morphogenesis, and a previously unknown mechanism of ephrin signaling. PMID- 21246653 TI - Gpr177/mouse Wntless is essential for Wnt-mediated craniofacial and brain development. AB - We have previously demonstrated that Gpr177, the mouse orthologue of Drosophila Wls/Evi/Srt, is required for establishment of the anterior-posterior axis. The Gpr177 null phenotype is highly reminiscent to the loss of Wnt3, the earliest abnormality among all Wnt knockouts in mice. The expression of Gpr177 in various cell types and tissues lead us to hypothesize that reciprocal regulation of Wnt and Gpr177 is essential for the Wnt-dependent developmental and pathogenic processes. Here, we create a new mouse strain permitting conditional inactivation of Gpr177. The loss of Gpr177 in the Wnt1-expressing cells causes mid/hindbrain and craniofacial defects which are far more severe than the Wnt1 knockout, but resemble the double knockout of Wnt1 and Wnt3a as well as beta-catenin deletion in the Wnt1-expressing cells. Our findings demonstrate the importance of Gpr177 in Wnt1-mediated development of the mouse embryo, suggesting an overlapping function of Wnt family members in the Wnt1-expressing cells. PMID- 21246654 TI - Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development. AB - The loss of Cecr2, which encodes a chromatin remodeling protein, has been associated with the neural tube defect (NTD) exencephaly and open eyelids in mice. Here, we show that two independent mutations of Cecr2 are also associated with specific inner ear defects. Homozygous mutant 18.5 days post coitus (dpc) fetuses exhibited smaller cochleae as well as rotational defects of sensory cells and extra cell rows in the inner ear reminiscent of planar cell polarity (PCP) mutants. Cecr2 was expressed in the neuroepithelium, head mesenchyme, and the cochlear floor. Although limited genetic interaction for NTDs was seen with Vangl2, a microarray analysis of PCP genes did not reveal a direct connection to this pathway. The mechanism of Cecr2 action in neurogenesis and inner ear development is likely complex. PMID- 21246655 TI - The chemokine receptor CXCR7 functions to regulate cardiac valve remodeling. AB - CXCR7 (RDC1), a G-protein-coupled receptor with conserved motifs characteristic of chemokine receptors, is enriched in endocardial and cushion mesenchymal cells in developing hearts, but its function is unclear. Cxcr7 germline deletion resulted in perinatal lethality with complete penetrance. Mutant embryos exhibited aortic and pulmonary valve stenosis due to semilunar valve thickening, with occasional ventricular septal defects. Semilunar valve mesenchymal cell proliferation increased in mutants from embryonic day 14 onward, but the cell death rate remained unchanged. Cxcr7 mutant valves had increased levels of phosphorylated Smad1/5/8, indicating increased BMP signaling, which may partly explain the thickened valve leaflets. The hyperproliferative phenotype appeared to involve Cxcr7 function in endocardial cells and their mesenchymal derivatives, as Tie2-Cre Cxcr7(flox/-) mice had semilunar valve stenosis. Thus, CXCR7 is involved in semilunar valve development, possibly by regulating BMP signaling, and may contribute to aortic and pulmonary valve stenosis. PMID- 21246656 TI - Translocon-associated protein subunit Trap-gamma/Ssr3 is required for vascular network formation in the mouse placenta. AB - The translocon-associated protein (TRAP, also termed the signal sequence receptor) complex is required for the efficient translocation of secretory and membrane proteins in the endoplasmic reticulum, and is also involved in the endoplasmic reticulum stress-mediated unfolded protein response pathway. To investigate the roles of Trap-gamma, a TRAP complex subunit, we generated Trap gamma knockout mice and found that mutant pups died soon after birth because of retarded embryonic organ growth, especially in the lung. The mutant placentae showed severe vascular network malformation in the labyrinth and significant reductions in blood space areas, which had an adverse effect on intrauterine embryonic growth. Placental malformation was already found by the mid-gestation stage mutant placenta, with poor vascular endothelial cell proliferation in the chorionic plate region and increased apoptotic cell death in the labyrinth. Thus, Trap-gamma appears to be required for vascular network formation in murine placental development. PMID- 21246657 TI - Hyaluronan production by means of Has2 gene expression in chondrocytes is essential for long bone development. AB - Mice possessing no Has2 expression in chondrocytes died near birth and displayed abnormalities throughout their skeleton. By embryonic day 18.5, the long bones were short and wide, and possessed excessive mineralization within their diaphysis, with little evidence of diaphyseal bone modeling. However, this does not appear to be associated with an absence of blood vessel invasion or the reduced presence of osteoclasts. There was no evidence for the formation of an organized growth plate between the epiphysis and diaphysis, and while hypertrophic chondrocytes were present in this region they were abnormal in both appearance and organization. There was also increased cellularity in the epiphyseal cartilage and a corresponding decrease in the abundance of extracellular matrix, but aggrecan was still present. Thus, hyaluronan production by chondrocytes is not only essential for formation of an organized growth plate and subsequent long bone growth but also for normal modeling of the diaphyseal bone. PMID- 21246658 TI - Autotaxin is required for the cranial neural tube closure and establishment of the midbrain-hindbrain boundary during mouse development. AB - Autotaxin (ATX) is a lysophospholipid-generating exoenzyme expressed in embryonic and adult neural tissues. We previously showed that ATX is expressed in the neural organizing centers, anterior head process, and midbrain-hindbrain boundary (MHB). To elucidate the role of ATX during neural development, here we examined the neural phenotypes of ATX-deficient mice. Expression analysis of neural marker genes revealed that lateral expansion of the rostral forebrain is reduced and establishment of the MHB is compromised as early as the late headfold stage in ATX mutant embryos. Moreover, ATX mutant embryos fail to complete cranial neural tube closure. These results indicate that ATX is essential for cranial neurulation and MHB establishment. PMID- 21246659 TI - Characterization of the laminin gene family and evolution in zebrafish. AB - Laminins are essential components of all basement membranes and are fundamental to tissue development and homeostasis. Humans possess at least 16 different heterotrimeric laminin complexes formed through different combinations of alpha, beta, and gamma chains. Individual chains appear to exhibit unique expression patterns, leading to the notion that overlap between expression domains governs the constitution of complexes found within particular tissues. However, the spatial and temporal expression of laminin genes has not been comprehensively analyzed in any vertebrate model to date. Here, we describe the tissue-specific expression patterns of all laminin genes in the zebrafish, throughout embryonic development and into the "post-juvenile" period, which is representative of the adult body form. In addition, we present phylogenetic and microsynteny analyses, which demonstrate that the majority of our zebrafish sequences are orthologous to human laminin genes. Together, these data represent a fundamental resource for the study of vertebrate laminins. PMID- 21246660 TI - Wnt5a regulates growth, patterning, and odontoblast differentiation of developing mouse tooth. AB - Wnt/beta-catenin signaling is essential for tooth development beyond the bud stage, but little is known about the role of non-canonical Wnt signaling in odontogenesis. Here we compared the expression of Wnt5a, a representative of noncanonical Wnts, with that of Ror2, the Wnt5a receptor for non-canonical signaling, in the developing tooth, and analyzed tooth phenotype in Wnt5a mutants. Wnt5a-deficient mice exhibit retarded tooth development beginning from E16.5, leading to the formation of smaller and abnormally patterned teeth with a delayed odontoblast differentiation at birth. These defects are associated with upregulated Axin2 and Shh expression in the dental epithelium and reduced levels of cell proliferation in the dental epithelium and mesenchyme. Retarded tooth development and defective odontoblast differentiation were also observed in Ror2 mutant mice. Our results suggest that Wnt5a regulates growth, patterning, and odontoblast differentiation during odontogenesis, at least partially by modulating Wnt/beta-catenin canonical signaling. PMID- 21246661 TI - Cell polarity and spindle orientation in the distal epithelium of embryonic lung. AB - A proper balance between self-renewal and differentiation of lung-specific progenitors at the distal epithelial tips is absolutely required for normal lung morphogenesis. Cell polarity and mitotic spindle orientation play a critical role in the self-renewal/differentiation of epithelial cells and can impact normal physiological processes, including epithelial tissue branching and differentiation. Therefore, understanding the behavior of lung distal epithelial progenitors could identify innovative solutions to restoring normal lung morphogenesis. Yet little is known about cell polarity, spindle orientation, and segregation of cell fate determinant in the embryonic lung epithelium, which contains progenitor cells. Herein, we provide the first evidence that embryonic lung distal epithelium is polarized and highly mitotic with characteristic perpendicular cell divisions. Consistent with these findings, mInsc, LGN, and NuMA polarity proteins, which control spindle orientation, are asymmetrically localized in mitotic distal epithelial progenitors of embryonic lungs. Furthermore, the cell fate determinant Numb is asymmetrically distributed at the apical side of distal epithelial progenitors and segregated to one daughter cell in most mitotic cells. These findings provide evidence for polarity in distal epithelial progenitors of embryonic lungs and provide a framework for future translationally oriented studies in this area. PMID- 21246662 TI - Dependence of cardiac trabeculation on neuregulin signaling and blood flow in zebrafish. AB - Maturation of the developing heart requires the structural elaboration of the embryonic ventricle through the process of trabeculation. Trabeculae form as the ventricular myocardium protrudes into the lumen of the chamber, thereby increasing muscle mass and altering functional output. Little is understood about the cellular basis for trabeculation and its genetic regulation. Here, we establish the utility of the zebrafish embryo for the analysis of the mechanisms driving trabeculation. In zebrafish, we can follow trabeculation in four dimensions and define morphologically discrete stages for the initiation, propagation, and network elaboration that form the ventricular trabeculae. We find that Neuregulin/ErbB signaling is required for the initial protrusion of the myocardium into the ventricular lumen. Additionally, we demonstrate that optimal blood flow through the ventricle is important for the advancement of trabeculation. Thus, our results indicate that the zebrafish provides a valuable model for investigating possible causes of congenital defects in trabeculation. PMID- 21246664 TI - Assessment of Interpersonal Motivation in Transcripts (AIMIT): an inter- and intra-rater reliability study of a new method of detection of interpersonal motivational systems in psychotherapy. AB - Assessing Interpersonal Motivations in Transcripts (AIMIT) is a coding system aiming to systematically detect the activity of interpersonal motivational systems (IMS) in the therapeutic dialogue. An inter- and intra-rater reliability study has been conducted. Sixteen video-recorded psychotherapy sessions were selected and transcribed according to the AIMIT criteria. Sessions relate to 16 patients with an Axis II diagnosis, with a mean Global Assessment of Functioning of 51. For the intra-rater reliability evaluation, five sessions have been selected and assigned to five independent coders who where asked to make a first evaluation, and then a second independent one 14 days later. For the inter-rater reliability study, the sessions coded by the therapist-coder were jointly revised with another coder and finally classified as gold standard. The 16 standard sessions were sent to other evaluators for the independent coding. The agreement (kappa) was estimated according to the following parameters for each coding unit: evaluation units supported by the 'codable' activation of one or more IMS; motivational interaction with reference to the ongoing relation between patient and therapist; an interaction between the patient and another person reported/narrated by the patient; detection of specific IMS: attachment (At), caregiving (CG), rank (Ra), sexuality (Se), peer cooperation (PC); and transitions from one IMS to another were also scored. The intra-rater agreement was evaluated through the parameters 'cod', 'At', 'CG', 'Ra', 'Se' and 'PC' described above. A total of 2443 coding units were analysed. For the nine parameters on which the agreement was calculated, eight ['coded (Cod)', 'ongoing relation (Rel)', 'narrated relation (Nar)', 'At', 'CG', 'Ra', 'Se' and 'PC'] have kappa values comprised between 0.62 (CG) and 0.81 (Cod) and were therefore satisfactory. The scoring of 'transitions' showed agreement values slightly below desired cut-off (0.56). Intra-rater reliability was very good (kappa values for Cod = 0.90; kappa for all IMS = 0.78). Data seem to support the validity of the AIMIT method in terms of reliability, and encourage to further implementation of the AIMIT approach. PMID- 21246665 TI - Cognitive appraisal and life stress moderate the effects of the 5-HTTLPR polymorphism on amygdala reactivity. AB - The short allele of the serotonin-transporter-linked promoter region (5-HTTLPR) polymorphism is associated with increased amygdala activation in response to emotional stimuli. Although top-down processes may moderate this association, available evidence is conflicting, showing the genotype influence on amygdala reactivity to be either decreased or increased during emotion regulation. Because the effects of the 5-HTTLPR polymorphism on amygdala reactivity are also conditional on self-reported life stress, differences in life stress exposure may account for this apparent discrepancy. Here, we hypothesized that self-reported life stress would moderate the relationships between genotype, cognitive appraisal, and amygdala reactivity. Forty-five healthy never-depressed subjects were presented with emotional stimuli and performed two cognitive tasks: a self referential task and an emotion-labeling task. Life-stress exposure was measured through a semistructured interview. First, there was a genotype * condition interaction in the right amygdala: short allele carriers displayed increased amygdala activation and decreased functional connectivity with the subgenual anterior cingulate cortex in self-referential processing versus emotion labeling. Second, in line with our hypothesis, there was a genotype * condition * stress interaction in bilateral amygdala the amygdala activation during self-referential processing was negatively correlated with self-reported life stress in short allele carriers and positively in individuals homozygous for the long allele, whereas an opposite pattern was observed during emotion labeling. These results confirm that the influence of the 5-HTTLPR polymorphism on amygdala reactivity is at least partially under cognitive control. Additionally, they suggest that measuring life stress exposure is a critical step when imaging genetics. PMID- 21246666 TI - Cortical representation of the human hand assessed by two levels of high resolution EEG recordings. AB - Increasing interest in cortical plasticity has prompted the growing use of somatosensory evoked potentials (SEPs) to estimate changes in the cortical representation of body regions. Here, we tested the effect of different sites of hand stimulation and of the density of spatial sampling in the quality of estimation of somatosensory sources. Sources of two SEP components from the primary somatosensory cortex (N20/P20 and P45) were estimated using two levels of spatial sampling (64- vs. 128-channel) and stimulation of four distal sites in the upper limbs, including single digits (first vs. fifth) and distal nerves with comparable cortical projection (superficial branch of the radial nerve and distal ulnar nerve). The most robust separation of somatosensory sources was achieved by comparing the cortical representations of the first digit and the distal ulnar nerve territories on the N20/P20 component of SEPs. Although both the 64- and the 128-electrode montages correctly discriminated these two areas, only the 128 electrode montage was able to significantly separate sources in the other cases, notably when using first versus fifth digit stimulation. Trustworthy distinction of cortical representations was not obtainable when using the P45 component, probably because of greater activation volume, radial orientation of sources in areas 1-2 and increased variability with attention and vigilance. Assessment of tangential SEP components to stimulation of first digit versus ulnar nerve appears the best option to assess plastic somatosensory changes, especially when using relatively low-electrode sampling. PMID- 21246663 TI - Vertebrate intestinal endoderm development. AB - The endoderm gives rise to the lining of the esophagus, stomach and intestines, as well as associated organs. To generate a functional intestine, a series of highly orchestrated developmental processes must occur. In this review, we attempt to cover major events during intestinal development from gastrulation to birth, including endoderm formation, gut tube growth and patterning, intestinal morphogenesis, epithelial reorganization, villus emergence, as well as proliferation and cytodifferentiation. Our discussion includes morphological and anatomical changes during intestinal development as well as molecular mechanisms regulating these processes. PMID- 21246667 TI - Distinct representations of subtraction and multiplication in the neural systems for numerosity and language. AB - It has been proposed that recent cultural inventions such as symbolic arithmetic recycle evolutionary older neural mechanisms. A central assumption of this hypothesis is that the degree to which a preexisting mechanism is recycled depends on the degree of similarity between its initial function and the novel task. To test this assumption, we investigated whether the brain region involved in magnitude comparison in the intraparietal sulcus (IPS), localized by a numerosity comparison task, is recruited to a greater degree by arithmetic problems that involve number comparison (single-digit subtractions) than by problems that involve retrieving number facts from memory (single-digit multiplications). Our results confirmed that subtractions are associated with greater activity in the IPS than multiplications, whereas multiplications elicit greater activity than subtractions in regions involved in verbal processing including the middle temporal gyrus (MTG) and inferior frontal gyrus (IFG) that were localized by a phonological processing task. Pattern analyses further indicated that the neural mechanisms more active for subtraction than multiplication in the IPS overlap with those involved in numerosity comparison and that the strength of this overlap predicts interindividual performance in the subtraction task. These findings provide novel evidence that elementary arithmetic relies on the cooption of evolutionary older neural circuits. PMID- 21246668 TI - Individual voxel-based subtype prediction can differentiate progressive supranuclear palsy from idiopathic Parkinson syndrome and healthy controls. AB - Voxel-based morphometry (VBM) shows a differentiated pattern in patients with atypical Parkinson syndrome but so far has had little impact in individual cases. It is desirable to translate VBM findings into clinical practice and individual classification. To this end, we examined whether a support vector machine (SVM) can provide useful accuracies for the differential diagnosis. We acquired a volumetric 3D T1-weighted MRI of 21 patients with idiopathic Parkinson syndrome (IPS), 11 multiple systems atrophy (MSA-P) and 10 progressive supranuclear palsy (PSP), and 22 healthy controls. Images were segmented, normalized, and compared at group level with SPM8 in a classical VBM design. Next, a SVM analysis was performed on an individual basis with leave-one-out cross-validation. VBM showed a strong white matter loss in the mesencephalon of patients with PSP, a putaminal grey matter loss in MSA, and a cerebellar grey matter loss in patients with PSP compared with IPS. The SVM allowed for an individual classification in PSP versus IPS with up to 96.8% accuracy with 90% sensitivity and 100% specificity. In MSA versus IPS, an accuracy of 71.9% was achieved; sensitivity, however, was low with 36.4%. Patients with IPS could not be differentiated from controls. In summary, a voxel-based SVM analysis allows for a reliable classification of individual cases in PSP that can be directly clinically useful. For patients with MSA and IPS, further developments like quantitative MRI are needed. PMID- 21246671 TI - Editorial: Women in chemistry. PMID- 21246674 TI - Activating platinum anticancer complexes with visible light. PMID- 21246669 TI - Adoptive transfer of macrophage from mice with depression-like behavior enhances susceptibility to colitis. AB - BACKGROUND: Depression is common in patients with inflammatory bowel disease (IBD) but the pathway is not well understood. We examined whether the locus of susceptibility to colitis in mice with depression-like behavior (DLB) resides with the macrophage and implicates the vagus nerve. METHODS: Chronic colitis mimicking ulcerative colitis (UC) was induced by dextran sulfate sodium administered to C57BL/6-mice. Depression was induced by intracerebroventricular infusion of reserpine in healthy or vagotomized mice treated with antidepressant desmethylimipramine (DMI). Colitis was assessed macroscopically, histologically, and by C-reactive protein measurement in serum and by cytokines in colonic samples. Cytokine release was measured on macrophages isolated from these models. Naive macrophage colony-stimulating factor-deficient mice (op/op) were injected with peritoneal macrophages obtained from the different groups and acute colitis was induced. RESULTS: Vagotomy reactivated inflammation in mice with chronic colitis. DLB reactivated colitis and this was prevented by DMI only in mice with intact vagi. Macrophages isolated from vagotomized or DLB-mice showed a selective increase of proinflammatory cytokine release and this was not seen in macrophages isolated from DLB-DMI-treated mice; moreover, vagotomy abolished this beneficial effect. In op/op, adoptive transfer of macrophages from non-DLB mice significantly increased the inflammatory markers. These parameters were significantly increased when transferred with macrophages isolated from DLB or VXP mice. Op/op mice that received macrophages from DLB-DMI-treated mice showed a significant decrease of all parameters and vagotomy abolished this effect. CONCLUSIONS: These data identify the critical role of macrophage in linking depression and susceptibility to intestinal inflammation via the vagus nerve. The results provide a basis for developing new approaches to the management of UC patients with coexisting depression by rebalancing cytokine production by the cell. PMID- 21246675 TI - Luminescent semiconductors. PMID- 21246676 TI - A new direction in enantioselective catalysis: scaffolding ligands in olefin hydroformylation. PMID- 21246677 TI - Keys for unlocking photolabile metal-containing cages. AB - Photolabile metal-containing cages are metal complexes that undergo a change in coordination environment upon exposure to light of an appropriate wavelength. The light-responsive functionality can either be a component of the encapsulating ligand or a property of the metal complex itself. The altered coordination properties of light-responsive complexes can result in release of the coordinated metal ion into its surroundings, a differential reactivity of the metal center, or the liberation of a reactive molecule that had been passivated by binding to the metal center. These triggerable agents can be useful tools for manipulating the bioavailability of metals or their coordinating ligands in order to study biological pathways or for potential therapeutic purposes. PMID- 21246678 TI - Oxide nanomaterials: synthetic developments, mechanistic studies, and technological innovations. AB - Oxide nanomaterials are indispensable for nanotechnological innovations, because they combine an infinite variety of structural motifs and properties with manifold morphological features. Given that new oxide materials are almost reported on a daily basis, considerable synthetic and technological work remains to be done to fully exploit this ever increasing family of compounds for innovative nano-applications. This calls for reliable and scalable preparative approaches to oxide nanomaterials and their development remains a challenge for many complex nanostructured oxides. Oxide nanomaterials with special physicochemical features and unusual morphologies are still difficult to access by classic synthetic pathways. The limitless options for creating nano-oxide building blocks open up new technological perspectives with the potential to revolutionize areas ranging from data processing to biocatalysis. Oxide nanotechnology of the 21st century thus needs a strong interplay of preparative creativity, analytical skills, and new ideas for synergistic implementations. PMID- 21246679 TI - Stereoselective coordination of C5-symmetric corannulene derivatives with an enantiomerically pure [Rh(I)(nbd*)] metal complex. PMID- 21246680 TI - Chemical imaging at atomic resolution as a technique to refine the local structure of nanocrystals. PMID- 21246681 TI - Electrostatic stabilization of a native protein structure in the gas phase. PMID- 21246682 TI - Doubly charged silver clusters stabilized by tryptophan: Ag4(2+) as an optical marker for monitoring particle growth. PMID- 21246683 TI - Polyvalent nucleic acid/mesoporous silica nanoparticle conjugates: dual stimuli responsive vehicles for intracellular drug delivery. PMID- 21246684 TI - Single-electron uranyl reduction by a rare-earth cation. PMID- 21246685 TI - Multifunctional gold nanoshells on silica nanorattles: a platform for the combination of photothermal therapy and chemotherapy with low systemic toxicity. PMID- 21246686 TI - A symmetry-breaking spin-state transition in iron(III). PMID- 21246687 TI - Copper(II) coordination to amyloid beta: murine versus human peptide. PMID- 21246688 TI - Flexible gold-catalyzed regioselective oxidative difunctionalization of unactivated alkenes. PMID- 21246689 TI - Gold-catalyzed cyclopenta- and cycloheptannulation cascades: a stereocontrolled approach to the scaffold of frondosins A and B. PMID- 21246690 TI - Unusually strong binding of dinitrogen to a ruthenium center. PMID- 21246691 TI - Borylcyanocuprate in a one-pot carboboration by a sequential reaction with an electron-deficient alkyne and an organic carbon electrophile. PMID- 21246692 TI - Electrochemical allylation reactions of simple imines in aqueous solution mediated by nanoscale zinc architectures. PMID- 21246693 TI - Nucleophilic alpha-arylation and alpha-alkylation of ketones by polarity inversion of N-alkoxyenamines: entry to the umpolung reaction at the alpha-carbon position of carbonyl compounds. PMID- 21246694 TI - Carbon-sulfur reductive elimination from palladium(IV) sulfinate complexes. PMID- 21246695 TI - Dicyanoborate-based ionic liquids as hypergolic fluids. PMID- 21246696 TI - Gephyronic acid, a missing link between polyketide inhibitors of eukaryotic protein synthesis (part I): Structural revision and stereochemical assignment of gephyronic acid. PMID- 21246697 TI - Gephyronic acid, a missing link between polyketide inhibitors of eukaryotic protein synthesis (part II): Total synthesis of gephyronic acid. PMID- 21246699 TI - Neither electron-precise nor in accordance with Wade-Mingos rules: the ternary cluster anion [Ni2Sn7Bi5]3-. PMID- 21246698 TI - Switching on luminescence by the self-assembly of a platinum(II) complex into gelating nanofibers and electroluminescent films. PMID- 21246700 TI - [Eu@Sn6Bi8]4-: a mini-fullerane-type Zintl anion containing a lanthanide ion. PMID- 21246702 TI - Photochemical reactions as key steps in natural product synthesis. AB - Photochemical reactions contribute in a significant way to the existing repertoire of carbon-carbon bond-forming reactions by allowing access to exceptional molecular structures that cannot be obtained by conventional means. In this Review, the most important photochemical transformations that have been employed in natural product synthesis are presented. Selected total syntheses are discussed as examples, with particular attention given to the photochemical key step and its stereoselectivity. The structural relationship between the photochemically generated molecule and the natural product is shown, and, where necessary, the consecutive reactions in the synthesis are illustrated and classified. PMID- 21246703 TI - C-H???pi interaction-modulated solid-state packing and carrier mobility in thienyl and thieno[3,2-b]thienyl end-capped distyrylarylene derivatives. AB - Research on structure-property relationships in distyrylarylene derivatives is far behind their wide applications in optoelectronic devices due to the absence of crystal structure information. Herein, the single crystals of 4,4'-bis(2 thienylvinyl)biphenyl (1) and 4,4'-bis(2-thieno[3,2-b]thienylvinyl)biphenyl (2) were successfully grown by the vapor transport method. Both molecules adopt the typical herringbone packing motif. However, the intermolecular C-H???pi interaction in compound 2 is much stronger than that in compound 1. The correlations of interchain interaction with film morphology, optical and electronic properties were studied. Compound 2 formed higher crystalline films with (001) and (111) orientations. The organic field-effect transistor properties of both materials were investigated. Compound 2 showed better performance with a hole mobility higher than 0.01 cm(2) V(-1) s(-1) and an on/off current ratio over 10(6) . These results reveal that the intensity of C-H???pi interactions can exert dramatic influences on the optical and electronic properties of distyrylarylene-based materials. PMID- 21246704 TI - Western Australian children with acute lymphoblastic leukemia are taller at diagnosis than unaffected children of the same age and sex. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy in Australian children. Recently published data from Western Australia suggest a link between proportion of optimal birth weight and the risk of ALL, but few studies have investigated the relationship between growth during infancy and early childhood and risk of leukemia. The aim of this study was to determine whether children diagnosed with ALL in Western Australia were taller at the time of diagnosis than children of the same age and sex in the general population. METHODS: Records of children diagnosed with ALL between January 1984 and June 2008 were accessed. Height before the commencement of chemotherapy was recorded and compared to the height of population norms derived from the Longitudinal Study of Australian Children. RESULTS: On average, male cases were 0.67 cm (95% CI -0.21, 1.54 cm) taller and female cases were 0.30 cm (95% CI -0.68, 1.28 cm) taller than population controls. CONCLUSIONS: Our results suggest that children diagnosed with ALL in Western Australia are slightly taller than their counterparts in the general population. These findings are consistent with at least one previous study. While this increase in height may be too small to be recognizable clinically, it is consistent with the notion that growth factors play a role in the pathogenesis of ALL beyond infancy. PMID- 21246705 TI - Veno-occlusive disease in pediatric patients affected by Wilms tumor. AB - BACKGROUND: Hepatic veno-occlusive disease (VOD) is a rare and potentially severe complication of chemotherapy. We describe five patients who developed VOD after chemotherapy for Wilms tumor (WT) and evaluate the role of plasminogen activator inhibitor-1 (PAI-1) and defibrotide for diagnosis and therapy of VOD, respectively. PATIENTS AND METHODS: Thirty-five patients treated from 2002 to 2009 for WT were eligible. Diagnosis of VOD was according McDonald's criteria that required two of the following: jaundice, hepatomegaly and/or right upper quadrant pain, weight gain with or without ascites. RESULTS: VOD occurred in 5 of 35 patients (14%) after 21-105 days from starting chemotherapy. Two patients developed multiorgan failure (MOF). PAI-1 was high in four patients who were tested. Three patients were treated with defibrotide and no side effects were reported while two patients received supportive measures only. Four patients recovered and three of them received defibrotide. They are all alive and well after a median follow-up of 35 months. One of two patients not treated with defibrotide died of MOF. CONCLUSIONS: PAI-1 levels were abnormal in WT-VOD. Defibrotide was a safe, well-tolerated, and potentially efficacious therapy in this group of patients. Further prospective study is needed in WT-VOD to confirm these data. PMID- 21246706 TI - Enumeration, characterization, and collection of intact circulating tumor cells by cross contamination-free flow cytometry. AB - Circulating tumor cells (CTC) are an important biomarker for several solid cancers. Most of the commercially available systems for enumeration of CTC are based on immunomagnetic enrichment of epithelial cell adhesion molecule (EpCAM/CD326)-expressing CTC before microscopic cell imaging or reverse transcription PCR (RT-PCR). The aim of this study was to establish a practical method for enumeration of CTC using a novel flow cytometer that has a disposable microfluidic chip, which is designed to realize absolute cross contamination-free measurements and to collect the analyzed cell sample. Although the process of enumeration and labeling of CTC was optimized for this device, the simplified protocol described here could be applied to other flow cytometers. Cultured cancer cells spiked into normal blood were enriched using MACS(r) EpCAM MicroBeads following cell labeling with an allophycocyanin (APC)-conjugated EpCAM mAb, instead of by intracellular staining of cytokeratins (CK). The EpCAM double positive selection/labeling method allows enumeration of intact CTC, maintenance of cellular integrity, and the concomitant performance of a CTC viability test. The combination of the fine-tuned CTC enrichment process and the cytometric multicolor analysis resulted in a linear relationship between the output cell count and the input cell number from zero to hundreds of cells. In particular, a satisfactory signal/noise ratio was obtained by gate-exclusion of leukocyte signals using an anti-CD45 mAb. The entire process had little influence on the viability of the spiked lung cancer cell PC-9. Measured PC-9 and breast cancer MCF-7 cells bearing EpCAM-MicroBeads, APC-conjugated EpCAM mAb, and the DNA staining dye SYTO9 grew normally, demonstrating the potential usefulness of the collected samples for further studies. This intact CTC enumeration and analysis procedure (iCeap) would be of great benefit to clinicians by providing them with rapid stratification of antitumor therapy, and to basic researchers by permitting further molecular and cellular characterization of CTC. PMID- 21246707 TI - Cellular and muscular growth patterns during sipunculan development. AB - Sipuncula is a lophotrochozoan taxon with annelid affinities, albeit lacking segmentation of the adult body. Here, we present data on cell proliferation and myogenesis during development of three sipunculan species, Phascolosoma agassizii, Thysanocardia nigra, and Themiste pyroides. The first anlagen of the circular body wall muscles appear simultaneously and not subsequently as in the annelids. At the same time, the rudiments of four longitudinal retractor muscles appear. This supports the notion that four introvert retractors were part of the ancestral sipunculan bodyplan. The longitudinal muscle fibers form a pattern of densely arranged fibers around the retractor muscles, indicating that the latter evolved from modified longitudinal body wall muscles. For a short time interval, the distribution of S-phase mitotic cells shows a metameric pattern in the developing ventral nerve cord during the pelagosphera stage. This pattern disappears close to metamorphic competence. Our findings are congruent with data on sipunculan neurogenesis, as well as with recent molecular analyses that place Sipuncula within Annelida, and thus strongly support a segmental ancestry of Sipuncula. PMID- 21246708 TI - Relationships among hemocytes, tunic cells, germ cells, and accessory cells in the colonial ascidian Botryllus schlosseri. AB - Monoclonal antibodies were raised against hemocytes of the colonial ascidian Botryllus schlosseri as possible tools to study hemocyte differentiation. In this species, blood cells are involved in various biological functions, such as immunosurveillance, encapsulation of foreign bodies, metal accumulation, and allorecognition. The latter process drives the fusion or rejection of contacting colonies, according to whether they do or do not share at least one allele at the fusibility/histocompatibility (Fu/HC) locus. Hemocytes take part in the rejection reaction, which suggests that they express molecules, coded by the Fu/HC locus, on their surface. A homozygous colony at the Fu/HC locus was used to produce the antibodies, which were screened by immunocytochemistry on hemocyte monolayers, immunohistochemistry on colony paraffin sections, and immunoblotting on colony homogenates. Here, we report on one of the obtained antibodies (1D8), which recognized a surface epitope on hemocytes of the donor colony and other colonies, apparently in a manner specific to the Fu/HC genotype. It also labeled a single 80-kDa band in colony homogenates. In addition, it specifically recognized tunic cells, germ cells, and their accessory cells. These results strengthen the assumption of a close relationship among these types of cells and blood cells, and suggest a close relationship among the above cells, probably deriving from undifferentiated blood cells. PMID- 21246709 TI - Morphological integration and ontogenetic niche shift: a study of crested newt limbs. AB - This study deals with the ontogenetic and evolutionary aspects of integration patterns in the limbs of crested newt species, which, like most amphibians, have a biphasic life history with two morphologically distinct stages (larval vs. juvenile and adult) that occupy different environments (aquatic vs. terrestrial). We analyzed the structure and pattern of correlation between limb skeletal elements at three ontogenetic stages (larval, juvenile, and adult) of four closely related species that differ in their preferences of aquatic habitats (more terrestrial and more aquatic). We found dynamic changes in the pattern of morphological integration between successive ontogenetic stages, as well as changes over the course of crested newt phylogeny. Generally, equivalent ontogenetic stages of different species of crested newts show higher concordance in the correlation pattern than successive ontogenetic stages within species. Among species, two opposing correlation patterns were observed: in more terrestrial species, homologous limb elements are less correlated and within-limb elements are more correlated; in aquatic species, the reverse pattern occurs. These results indicate that the function seems to be the covariance-generating factor, which has shaped the patterns of morphological integration of crested newt limbs. PMID- 21246710 TI - Effect of anesthesia carrier gas on in vivo circulation times of ultrasound microbubble contrast agents in rats. AB - PURPOSE: Microbubble contrast agents are currently implemented in a variety of both clinical and preclinical ultrasound imaging studies. The therapeutic and diagnostic capabilities of these contrast agents are limited by their short in vivo lifetimes, and research to lengthen their circulation times is on going. In this manuscript, observations are presented from a controlled experiment performed to evaluate differences in circulation times for lipid shelled perfluorocarbon-filled contrast agents circulating within rodents as a function of inhaled anesthesia carrier gas. METHODS: The effects of two common anesthesia carrier gas selections - pure oxygen and medical air were observed within five rats. Contrast agent persistence within the kidney was measured and compared for oxygen and air anesthesia carrier gas for six bolus contrast injections in each animal. Simulations were performed to examine microbubble behavior with changes in external environment gases. RESULTS: A statistically significant extension of contrast circulation time was observed for animals breathing medical air compared to breathing pure oxygen. Simulations support experimental observations and indicate that enhanced contrast persistence may be explained by reduced ventilation/perfusion mismatch and classical diffusion, in which nitrogen plays a key role by contributing to the volume and diluting other gas species in the microbubble gas core. CONCLUSION: Using medical air in place of oxygen as the carrier gas for isoflurane anesthesia can increase the circulation lifetime of ultrasound microbubble contrast agents. PMID- 21246711 TI - Optical probes and the applications in multimodality imaging. AB - Optical imaging essentially refers to in vivo fluorescence imaging and bioluminescence imaging. These types of imaging are widely used visualization methods in biomedical research and are important in molecular imaging. A new generation of imaging agents called multimodal probes have emerged in the past few years. These probes can be detected by two or more imaging modalities, which harnesses the strengths of the different modalities and enables researchers to obtain more information than can be achieved using only one modality. Owing to its low cost and the large number of probes available, the optical method plays an important role in multimodality imaging. In this mini-review, we describe the available multimodal imaging probes for in vivo imaging that combine optical imaging with other modalities. PMID- 21246712 TI - Magnetic nanocomposites with mesoporous structures: synthesis and applications. AB - Magnetic nanocomposites with well-defined mesoporous structures, shapes, and tailored properties are of immense scientific and technological interest. This review article is devoted to the progress in the synthesis and applications of magnetic mesoporous materials. The first part briefly reviews various general methods developed for producing magnetic nanoparticles (NPs). The second presents and categorizes the synthesis of magnetic nanocomposites with mesoporous structures. These nanocomposites are broadly categorized into four types: monodisperse magnetic nanocrystals embedded in mesoporous nanospheres, microspheres encapsulating magnetic cores into perpendicularly aligned mesoporous shells, ordered mesoporous materials loaded with magnetic NPs inside the porous channels or cages, and rattle-type magnetic nanocomposites. The third section reviews the potential applications of the magnetic nanocomposites with mesoporous structures in the areas of heath care, catalysis, and environmental separation. The final section offers a summary and future perspectives on the state-of-the art in this area. PMID- 21246713 TI - Rhythmic crystal growth into hierarchical patterns by polymer-mediated self assembly. AB - Controlled, bottom-up self-assembly of ordered and hierarchical structures remains a major challenge and increasingly attracts attention in basic and technology-driven research. A simple process is described for the generation of such structures, which is based on slow solvent evaporation of a polymer solution blended with a crystal-forming species (Krogmann's salt). Upon drying, the viscosity of the polymer-blend solution increases in a progressing solidification zone, which precisely controls crystal growth by limiting the transport of the crystallizing units through this gel-like solidification zone and gives rise to a position- and time-dependent diffusion rate. The progressing solidification zone also leads to a preferential crystallographic orientation on a centimeter scale and introduces an instability that drives spatial pattern formation and hierarchical ordering on five distinct levels, ranging from the atomic positions in crystals to the assembly on a microscale and up to a centimeter length scale. Together with a quantitative description, the presented findings are envisaged to improve the understanding and application of periodic precipitation processes. PMID- 21246714 TI - Multiwalled carbon-nanotube-functionalized microelectrode arrays fabricated by microcontact printing: platform for studying chemical and electrical neuronal signaling. AB - A facile method is proposed for the deposition of multiwalled carbon nanotube (MWCNT) layers onto microelectrode arrays by means of a microcontact printing technique, leading to the fabrication of MEAs characterized by well defined electrical and morphological properties. Using polydimethyl siloxane stamps, produced from different mold designs, a flexibility of printing is achieved that provides access to microscale, nanostructured electrodes. The thickness of MWCNT layers can be exactly predetermined by evaluating the concentration of the MWCNT solution employed in the process. The electrode morphology is further characterized using laser scanning and scanning electron microscopy. Next, by means of impedance spectroscopy analysis, the MWCNT-electrode contact resistance and MWCNT film resistance is measured, while electrochemical impedance spectroscopy is used to estimate the obtained electrode-electrolyte interface. Structural and electrochemical properties make these electrodes suitable for electrical stimulation and recording of neurons and electrochemical detection of dopamine. MWCNT-functionalized electrodes show the ability to detect micromolar amounts of dopamine with a sensitivity of 19 nA MUm(-1) . In combination with their biosensing properties, preliminary electrophysiological measurements show that MWCNT microelectrodes have recording properties superior to those of commercial TiN microelectrodes when detecting neuronal electrical activity under long-term cell-culture conditions. MWCNT-functionalized microelectrode arrays fabricated by microcontact printing represent a versatile and multipurpose platform for cell-culture monitoring. PMID- 21246715 TI - Formation of peelable rough gold patterns on an ionic liquid template. AB - The ability to control metal patterns at the micro- and nanoscales, along with the development of a simple fabrication method, is important to many applications in the fields of materials science, biological sensing, electronics, and photonics. Herein, a simple approach to fabricating gold micropatterns with controlled roughness is reported. In this approach, gold is evaporated onto a striped liquid micropattern formed on self-organized microwrinkles. Gold nanoribbons with higher roughness form on the liquid part of the substrate because the deposited gold atoms can diffuse, grow, and aggregate at the liquid air interface, whereas flat gold films form on the solid part. The rough gold nanoribbons formed on the liquid can then be peeled off through contact with water. The extinction spectrum of the rough gold nanoribbons suggests characteristic surface-plasmon absorption. This shows the possibility of using rough gold nanoribbons with controlled shape in plasmonic technology. PMID- 21246716 TI - Liquid chromatography/mass spectrometry-based metabolic profiling to elucidate chemical differences of tobacco leaves between Zimbabwe and China. AB - An approach was developed for extracting and analyzing the chemical components of tobacco leaves based on solvent extraction and rapid & resolution liquid chromatography/quadrupole time-of-flight mass spectrometry analysis. Two solvents with different polarities were used to extract hydrophilic components and hydrophobic components, respectively, the combined analytical data can provide a "global" view of metabolites. Based on the evaluation of parallel samples, it was found that this approach provided good repeatability, accurate and reliable profiling data, and is suitable for the metabolomics study of tobacco leaves. In order to find the chemical component differences of tobacco leaves, 56 samples from Zimbabwe and China were analyzed using the developed method. The metabolite data were processed by multivariate statistic technique; an obvious group classification between Zimbabwe and China was observed, 14 significantly changed compounds were found, and 9 of them were identified. PMID- 21246717 TI - Monolithic poly(ethylhexyl methacrylate-co-ethylene dimethacrylate) column with restricted access layers prepared via reversible addition-fragmentation chain transfer polymerization. AB - The "living"/controlled radical polymerization has provided an opportunity in making a more homogeneous polymer, which is favorable for polymer-based monolithic column fabrication. To study its application in the preparation of separation material, a capillary poly(ethylhexyl methacrylate-co-ethylene dimethacrylate) monolithic column has been synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. The correlation between the synthetic conditions and the polymer structures and separation performance was studied. The result indicated RAFT-mediated reaction provides condition for creating polymers with narrower pore size distribution and higher column efficiency compared with traditional polymerization. The "living" property of the RAFT polymerization was further utilized to graft hydrophilic polymer on the surface of poly(ethylhexyl methacrylate-co-ethylene dimethacrylate). The hydrophilic chain modified monolithic column has both abilities of protein exclusion and small hydrophobic compound retention. The result indicated that RAFT polymerization can be used for making multifunctional material. The restricted access monolithic material synthesized by this method can be used in biological sample analysis with HPLC direct injection. PMID- 21246718 TI - Method development and validation for the analysis of a new anti-cancer infusion solution via HPLC. AB - A fast and simple HPLC method has been developed and validated for the quantification of a completely new anti-cancer drug during the manufacturing process. The combination of four compounds including alpha-ketoglutaric acid, hydroxymethylfurfural, N-acetyl-L-methionine and N-acetyl-L-selenomethionine, administered intravenously, is still in test phase but has already shown promising results in cancer therapy. HPLC separation was achieved on an RP-18 column with a gradient system. However, the highly different concentrations of the compounds required a variation in the detection wavelength within one run. In order to produce a chromatogram where peaks were comparable on a similar range scale, detection at absorption maxima for the two most concentrated components was avoided. After optimization of the gradient program it was possible to detect all four substances within 14 min in spite of their strongly different chemical structure. The method developed was validated for accuracy, repeatability, reproducibility and robustness in relation to temperature and pH of buffer. Linearity as well as the limit of detection and quantification were determined. This HPLC method was found to be precise, accurate and reproducible and can be easily used for in-line process control during the manufacture of the anti-tumour infusion solution. PMID- 21246719 TI - Microwave-assisted extraction and in situ clean-up for the determination of fluoroquinolone antibiotics in chicken breast muscle by LC-MS/MS. AB - A new method was developed for the determination of six fluoroquinolone antibiotics including fleroxacin, levofloxacin, ciprofloxacin, lomfloxacin, enrofloxacin, and sparfloxacin in chicken breast muscle, in which the extraction and clean-up were performed in one step by microwave irradiation. The mixture of ACN containing 0.3% v/v phosphoric acid/water pH 3 (70:30, v/v) was used as the extraction solution and hexane was used as the clean-up solution. The extract was analyzed by liquid chromatography-tandem mass spectrometry system. The RSDs of intra- and inter-day obtained are in the range of 1.0-10.4 and 3.8-13.6%, respectively. In the three fortified levels of chicken breast muscle (20, 100, and 500 ng/g), the recoveries of fluoroquinolone antibiotics ranging from 66.0 to 97.2% are obtained. The LODs are in the range of 2.7-6.7 ng/g. This method simplifies the process of the sample preparation and reduces the operation errors. PMID- 21246720 TI - Analysis of anthocyanins in commercial fruit juices by using nano-liquid chromatography-electrospray-mass spectrometry and high-performance liquid chromatography with UV-vis detector. AB - Nano-LC and conventional HPLC techniques were applied for the analysis of anthocyanins present in commercial fruit juices using a capillary column of 100 MUm id and a 2.1 mm id narrow-bore C(18) column. Analytes were detected by UV-Vis at 518 nm and ESI-ion trap MS with HPLC and nano-LC, respectively. Commercial blueberry juice (14 anthocyanins detected) was used to optimize chromatographic separation of analytes and other analysis parameters. Qualitative identification of anthocyanins was performed by comparing the recorded mass spectral data with those of published papers. The use of the same mobile phase composition in both techniques revealed that the miniaturized method exhibited shorter analysis time and higher sensitivity than narrow-bore chromatography. Good intra-day and day-to day precision of retention time was obtained in both methods with values of RSD less than 3.4 and 0.8% for nano-LC and HPLC, respectively. Quantitative analysis was performed by external standard curve calibration of cyanidin-3-O-glucoside standard. Calibration curves were linear in the concentration ranges studied, 0.1 50 and 6-50 MUg/mL for HPLC-UV/Vis and nano-LC-MS, respectively. LOD and LOQ values were good for both methods. In addition to commercial blueberry juice, qualitative and quantitative analysis of other juices (e.g. raspberry, sweet cherry and pomegranate) was performed. The optimized nano-LC-MS method allowed an easy and selective identification and quantification of anthocyanins in commercial fruit juices; it offered good results, shorter analysis time and reduced mobile phase volume with respect to narrow-bore HPLC. PMID- 21246721 TI - Development and application of high-performance liquid chromatography for the study of ampelopsin pharmacokinetics in rat plasma using cloud-point extraction. AB - A simple, rapid and specific method based on cloud-point extraction (CPE) was developed to determine ampelopsin in rat plasma after oral administration by reversed-phase high-performance liquid chromatography. The non-ionic surfactant Genapol X-080 was chosen as the extract solvent. Some important parameters affecting the CPE efficiency, such as the nature and concentration of surfactant, extraction temperature and time, centrifuge time and salt effect, were investigated and optimized. Separation was accomplished using a C(18) column by gradient elution with a acetonitrile-phosphate buffer solution as the mobile phase. The detection wavelength was set at 290 nm. Under optimum conditions, the linear range of ampelopsin in rat plasma was 20-2000 ng/mL (r(2)=0.9996). The limit of detection was 6 ng/mL (S/N=3) with the limit of quantification being 20 ng/mL (S/N=10). The proposed method has been successfully applied for pharmacokinetic studies of ampelopsin from rat plasma after oral administration. PMID- 21246722 TI - Retention behaviors of natural products in reversed-phase liquid chromatography using mobile phase comprising methanol, acetonitrile and water. AB - The three-component mobile phase, methanol-acetonitrile-water, has been frequently used for the separation of natural products in complicated herbal extracts by reversed-phase liquid chromatography, especially when two-component solvent systems do not work. However, the rational for optimization of this three solvent system is not clear, so far. In this study, the retention behavior of different types of natural products in RP-LC with a methanol-acetonitrile-water elution system was studied. A total of 27 compounds from four classes, including steroids, flavonoids, phenolic acids, and triterpene saponins were analyzed by high-performance liquid chromatography coupled with mass spectrometry or ultraviolet detectors. It was interesting to find that prolonged retention times and improved separation capabilities were obtained when the acetonitrile-to methanol ratio was 3-16%. This rule applied to all four classes of natural products under different instrumental conditions, and could be valuable for the separation of natural products in complicated samples. PMID- 21246723 TI - The use of GC*GC/TOF MS with multivariate analysis for the characterization of foodborne pathogen bacteria profiles. AB - The cellular fatty acid profiles of eight strains of Bacillus, Staphylococcus, and Enterobacteriacae (Escherichia coli and Salmonella) were analyzed by comprehensive two-dimensional gas chromatography/time-of-flight mass spectrometry. A novel template method was developed to standardize the raw two dimensional gas chromatography retention data through the use of a chemical indexing mixture. Analyte retention coordinates were normalized in the primary dimension with respect to a series of n-alkanes (Kovats index) and in the secondary dimension with respect to a series of aromatic hydrocarbons (Lee index). Fatty acid profiles extracted from the templates were compared by multidimensional scaling and principal component analysis. Differences in the profiles of Gram-positive and Gram-negative bacteria were observed, and a series of heterogeneous mixtures comprising different fractions (containing one Gram positive and one Gram-negative bacteria strain) were also distinguished from their homogeneous constituents. PMID- 21246724 TI - Fundamental studies on the electrokinetic transfer of net cationic peptides across supported liquid membranes. AB - By the application of an electrical potential difference (25 V), 37 different peptides were extracted from 500 MUL aqueous sample (10 mM formic acid, positive electrode), through a supported liquid membrane (SLM) impregnated in the walls of a porous hollow fiber, and into 25 MUL aqueous acceptor solution (100 mM formic acid, negative electrode) present inside the lumen of the fiber. Most of the peptides were obtained by tryptic digestion of cytochrome c and bovine serum albumin, which yielded complex samples for extraction. Three different SLMs were utilized to correlate the peptides extractability with the highly variable physical-chemical properties of the peptides. The first SLM (pure eugenol) provided an electromembrane extraction system for hydrophobic and intermediate peptides (hydrophilicity values below 0.2), where the extraction of peptides into the SLM was mainly based on solvent interactions. The second SLM (1-octanol/di isobutylketone/di-(2-ethylhexyl) phosphate) extracted both hydrophobic and hydrophilic peptides (hydrophilicity values in the range from -2 to+1) successfully, and the transfer of peptides was principally based on ionic interactions with di-(2-ethylhexyl) phosphate. The third SLM (1-octanol/15-crown 5 ether) was selective for hydrophobic peptides (negative hydrophilicity values), and complexation of the peptides with the crown ether was important for the migration of peptides into the acceptor solution. PMID- 21246725 TI - Separation and determination of beta-casomorphins by using glass microfluidic chip electrophoresis together with laser-induced fluorescence detection. AB - A simple, reliable and reproducible method for the separation and determination of five beta-casomorphins (beta-CMs, namely TPGN, PGPI, TPGI, TPGP and TPPG) based on glass microfluidic chip electrophoresis and laser-induced fluorescence detection is first described in here. The microfluidic chip electrophoresis and laser-induced fluorescence detection system consisted of a home-made glass "double-T" microchip and a simple LIF detector with excitation and emission wavelengths of 473 and 525 nm, respectively. Fluorescein isothiocyanate (FITC) was used as the precolumn derivatization reagent to label fluorophore on five beta-CMs, and the optimum conditions of FITC-derivatization reaction and MCE separation were investigated in detail. Under optimum conditions, five beta-CMs were completely separated and detected within 30 min with a detection limit of 18.7-75.1 nmol/L and an RSD (n=5) of 3.0-5.9%, respectively. The proposed method has been successfully used to detect beta-CMs in real cheese sample with a recovery of 89-109%, suggesting that our method is sensitive and reliable. These features, as well as its low cost, operation convenience, stability and reusability, make it a promising alternative to beta-CMs detection methods. PMID- 21246726 TI - Dispersive liquid-liquid microextraction coupled with high-performance liquid chromatography-diode array detection for the determination of N-methyl carbamate pesticides in vegetables. AB - This paper described a simple, rapid and efficient method for the determination of N-methyl carbamate pesticides in tomato, cucumber, carrot and lettuce samples by dispersive liquid-liquid microextraction coupled with HPLC-diode array detection. Some experimental parameters that influenced the extraction efficiency, such as types and volumes of extraction and disperser solvents, extraction time and salt effect were examined and optimized. Under optimum conditions, the LOD of the method were 0.5-3.0 MUg/kg depending on the compounds and the kind of vegetables. The linearities of the method were obtained in the range of 10.0-300 MUg/kg for aldicarb, MTMC, carbofuran and carbaryl, and 20.0 600 MUg/kg for isoprocarb, with the correlation coefficients ranging from 0.9921 to 0.9993. The RSD varied from 2.9 to 7.5% (n=5). The recoveries of the method for the five carbamates from vegetable samples at two different spiking levels were ranged from 77.8 to 98.2%. Results showed that the method we proposed can meet the requirements for the determination of N-methyl carbamate in vegetable samples and was finally applied to the analysis of target pesticides in vegetable samples taken from local markets. PMID- 21246727 TI - Multi-residue analysis of pesticides in tea by online SEC-GC/MS. AB - A multi-residue method for the analysis of pesticides in tea was developed by online size exclusion chromatography (SEC)-GC/MS with full scan mode. The sample was fortified with chlorpyrifos-d(10) isotope internal standard and extracted by acetonitrile. After purification by primary secondary amine sorbent and solvent exchange by SEC mobile phase, the sample was detected by online SEC-GC/MS. The purification result of the online system was evaluated by comparing the correlation between Chinese cabbage and tea matrix. The factors for method optimization included sample preparation, matrix effects and the instrument parameters of each online component. Scatter plot was introduced in this study to directly illustrate the results of the condition optimization and matrix effects in the online system. For most of the pesticides, the average recoveries ranged from 70 to 130% and the RSD were below 15%. The feasibility of the application of full scan mode in multi-residue determination of trace amounts of pesticides (LODs below 0.01 mg/kg) in a complex matrix was discussed. PMID- 21246728 TI - Synthesis of core-shell molecularly imprinted polymer microspheres by precipitation polymerization for the inline molecularly imprinted solid-phase extraction of thiabendazole from citrus fruits and orange juice samples. AB - In this work, the synthesis of molecularly imprinted polymer microspheres with narrow particle size distributions and core-shell morphology by a two-step precipitation polymerization procedure is described. Polydivinylbenzene (poly DVB 80) core particles were used as seed particles in the production of molecularly imprinted polymer shells by copolymerization of divinylbenzene-80 with methacrylic acid in the presence of thiabendazole (TBZ) and an appropriate porogen. Thereafter, polymer particles were packed into refillable stainless steel HPLC columns used in the development of an inline molecularly imprinted SPE method for the determination of TBZ in citrus fruits and orange juice samples. Under optimized chromatographic conditions, recoveries of TBZ within the range 81.1-106.4%, depending upon the sample, were obtained, with RSDs lower than 10%. This novel method permits the unequivocal determination of TBZ in the samples under study, according to the maximum residue levels allowed within Europe, in less than 20 min and without any need for a clean-up step in the analytical protocol. PMID- 21246729 TI - Proteome profile of zebrafish caudal fin based on one-dimensional gel electrophoresis LCMS/MS and two-dimensional gel electrophoresis MALDI MS/MS analysis. AB - Zebrafish (Danio rerio) is the widely used vertebrate model animal for understanding the complexity of development and disease process. Zebrafish has been also extensively used in understanding the mechanism of regeneration for its extensive capability of regenerating fins and other tissues. We have analyzed the proteome profile of zebrafish caudal fin in its native state based on one dimensional gel electrophoresis LCMS/MS and two-dimensional gel electrophoresis MS/MS analyses. A total of 417 proteins were identified as zebrafish fin tissue specific, which includes 397 proteins identified based on one-dimensional gel electrophoresis LCMS/MS analysis and 101 proteins identified based on two dimensional gel electrophoresis MALDI MS/MS. The proteins mapped to the zebrafish fin tissue were shown to be involved in various biological activities related to development, apoptosis, signaling and metabolic process. Focal adhesion, regulation of actin cytoskeleton, cancer-related pathways, mitogen-activated protein kinase signaling, antigen processing and presentation, and proteasome are some of the important pathways associated with the identified proteome data set of the zebrafish fin. PMID- 21246730 TI - Separation of gamma-linolenic and other polyunsaturated fatty acids from Boraginaceae via supercritical CO2. AB - Essential fatty acids were extracted from Echium amoenum (Boraginaceae) seed oil via supercritical carbon dioxide and the results were compared with conventional Soxhlet method as the base case of 100% recovery. The response surface methodology was used to optimize the effective extraction parameters. The chemical composition of recovered oil was analyzed by polar and non-polar gas chromatograph-flame ionization detector columns. The experimental results indicated that echium seed contained 25 wt% oil and the maximum extraction oil recovery of 92% was obtained via supercritical CO(2) at optimal operating conditions (43 degrees C, 280 bar, 1.5 mL/min, 25 min static time and 130 min dynamic time). At similar operating conditions, applying 2.5 and 5 mol% ethanol as a modifier enhanced the recovery to 96 and 112%, respectively. The results showed that supercritical fluid extraction is a viable technique for separation of constituents such as gamma-linolenic acid (7-8%), palmitic acid (6-7%), stearic acid (3-4%), oleic acid (12-13%), linoleic acid (19-20%), alpha-linolenic acid (40-41%) and stearidonic acid (8-9%) from Boraginaceae. PMID- 21246731 TI - Targeted large-scale analysis of protein acetylation. AB - Protein modifications are biologically important events that may be studied by mass spectrometry-based high-throughput proteome analyses. In recent years, several new technologies have emerged that have widened and deepened the targeted analysis of one important, albeit functionally ill-defined modification, namely protein acetylation. This modification can take place both co- and post translationally by the transfer of acetyl groups under the catalysis of acetyltransferases. The acetyl group can modify either the alpha-amino group at the N-terminus, so-called N-terminal acetylation, or the epsilon-amino group on the side chain of lysine residues. Here, we review several emerging targeted technologies to chart both N-terminal acetylation as well as acetylation at the lysine side chain, on a proteome-wide scale, highlighting in particular studies that have expanded the biological knowledge on the appearance and function of these common but functionally still less investigated co- and post-translational modifications. PMID- 21246732 TI - Protein expression profiling in chemical carcinogenesis: a proteomic-based approach. AB - The simultaneous analysis of a wide array of proteins may provide valuable information on the activation and suppression of cellular systems at different stages of the exposure-disease continuum. In this review, results of proteomic studies in the field of toxicology are covered, focusing on the effects of chemical carcinogens. So far, alterations of highly abundant proteins have been identified which, irrespective of the wide differences in study design and technologies used, can be grossly assigned to three functional classes: proteins related to cellular stress response, inflammation, and stimulation of the immune system. It is obvious that the observed protein alterations are not causal factors in the development of chemically induced cancer but rather reflect common reactions to cellular perturbations. In order to gain deeper insights into the process of chemical carcinogenesis, the previously applied "shotgun" analyses have to be abandoned in favour of targeted proteomic approaches focusing on the accurate identification and quantification of selected proteins. Advanced analytical techniques such as selective reaction monitoring (SRM) and multiple reaction monitoring (MRM) offer this opportunity. If toxicoproteomic research moves into that direction and takes advantage of such techniques it will have the potential to contribute to the elucidation of chemical carcinogenesis. PMID- 21246733 TI - Quantitative plant proteomics. AB - Quantitation is an inherent requirement in comparative proteomics and there is no exception to this for plant proteomics. Quantitative proteomics has high demands on the experimental workflow, requiring a thorough design and often a complex multi-step structure. It has to include sufficient numbers of biological and technical replicates and methods that are able to facilitate a quantitative signal read-out. Quantitative plant proteomics in particular poses many additional challenges but because of the nature of plants it also offers some potential advantages. In general, analysis of plants has been less prominent in proteomics. Low protein concentration, difficulties in protein extraction, genome multiploidy, high Rubisco abundance in green tissue, and an absence of well annotated and completed genome sequences are some of the main challenges in plant proteomics. However, the latter is now changing with several genomes emerging for model plants and crops such as potato, tomato, soybean, rice, maize and barley. This review discusses the current status in quantitative plant proteomics (MS based and non-MS-based) and its challenges and potentials. Both relative and absolute quantitation methods in plant proteomics from DIGE to MS-based analysis after isotope labeling and label-free quantitation are described and illustrated by published studies. In particular, we describe plant-specific quantitative methods such as metabolic labeling methods that can take full advantage of plant metabolism and culture practices, and discuss other potential advantages and challenges that may arise from the unique properties of plants. PMID- 21246734 TI - Proteogenomics. AB - The ability to sequence DNA rapidly, inexpensively and in a high-throughput fashion provides a unique opportunity to sequence whole genomes of a large number of species. The cataloging of protein-coding genes from these species, however, remains a non-trivial task with the majority of initial genome annotation dependent on the use of gene prediction algorithms. Recent advances in mass spectrometry-based proteomics now enable generation of accurate and comprehensive protein sequence of tissues and organisms. Proteogenomics allows us to harness the wealth of information available at the proteome level and apply it to the available genomic information of organisms. This includes identifying novel genes and splice isoforms, assigning correct start sites and validating predicted exons and genes. It is also possible to use proteogenomics to identify protein variants that could cause diseases, to identify protein biomarkers and to study genome variation. We anticipate proteogenomics to become a powerful approach that will be routinely employed by 'Genome and Proteome Centers' of the future. PMID- 21246736 TI - Synthesis and radioprotective properties of pulvinic acid derivatives. AB - A high-throughput screening method has highlighted the marked antioxidant activity of some pulvinic acid derivatives (PADs) towards oxidation of thymidine, under gamma and UV irradiation, and Fenton-like conditions. Here, we report the synthesis of a series of new hydrophilic PADs and the evaluation of their radioprotective efficacy in cell culture. Using a cell-based fluorescent assay, we show that some of these compounds have a pronounced ability to prevent cell death caused by radiation and to allow the subsequent resumption of proliferation. Thus, PADs may be considered as a novel class of radioprotective agents. PMID- 21246735 TI - To live or to die: a matter of processing damaged DNA termini in neurons. AB - Defects in the repair of deoxyribonucleic acid (DNA) damage underpin several hereditary neurological diseases in humans. Of the different activities that repair chromosomal DNA breaks, defects in resolving damaged DNA termini are among the most common causes of neuronal cell death. Here, the molecular mechanisms of some of the DNA end processing activities are reviewed and the association with human neurodegenerative disease is discussed. PMID- 21246737 TI - Discovery of benzamide analogues as a novel class of 5-HT3 receptor agonists. AB - A 5-HT3 receptor agonist based on a benzamide scaffold was identified in a screening of a small commercial compound library, and an elaborate SAR study originating from this hit was performed. The design, synthesis, and functional characterisation of benzamide analogues at the 5-HT3A receptor yielded substantial information concerning the analogues as 5-HT3 receptor agonists. However, the potencies of the derived analogues were not significantly improved over that of the initial hit. The benzamide scaffold constitutes a novel type of 5-HT3 receptor agonist, as it does not possess a positively charged functionality, which is essential for the binding of all orthosteric ligands to the receptor. Preliminary investigations suggest that the compounds may exert their effects on 5-HT3 receptors by binding to an allosteric site in the receptor complex. PMID- 21246738 TI - Modified 5'-trityl nucleosides as inhibitors of Plasmodium falciparum dUTPase. AB - 2'-Deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for the treatment of malaria. We previously reported the discovery of 5' tritylated analogues of deoxyuridine as selective inhibitors of this Plasmodium falciparum enzyme. Herein we report further structure-activity studies; in particular, variations of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base. Compounds were tested against both the enzyme and the parasite. Variations of the 5'-trityl group and of the 3'-substituent were well tolerated and yielded active compounds. However, there is a clear requirement for the uracil base for activity, because modifications of the uracil ring result in loss of enzyme inhibition and significant decreases in antiplasmodial action. PMID- 21246739 TI - A versatile and practical synthesis toward the development of novel HIV-1 integrase inhibitors. AB - As a continuation of our previous work, which resulted in the identification of a new hit compound as an HIV-1 integrase inhibitor, three novel series of salicylic acid derivatives were synthesized using three versatile and practical synthetic strategies and were assayed for their capacity to inhibit the catalytic activity of HIV-1 integrase. Biological evaluations revealed that some of the synthesized compounds possess good inhibitory potency in enzymatic assays and are able to inhibit viral replication in MT-4 cells at low micromolar concentrations. Finally, docking studies were conducted to analyze the binding mode of the synthesized compounds within the DNA binding site of integrase in order to refine their structure-activity relationships. PMID- 21246740 TI - Cardiovascular proteomics: translational studies to develop novel biomarkers in heart failure and left ventricular remodeling. AB - Heart failure (HF) remains a severe disease with a poor prognosis. HF biomarkers may include demographic features, cardiac imaging, or genetic polymorphisms but this term is commonly applied to circulating serum or plasma analytes. Biomarkers may have at least three clinical uses in the context of HF: diagnosis, risk stratification, and guidance in the selection of therapy. Proteomic studies on HF biomarkers can be designed as case/control using clinical endpoints; alternatively, left ventricular remodeling can be used as a surrogate endpoint. The type of samples (tissue, cells, serum or plasma) used for proteomic analysis is a key factor in the research of biomarkers. Since the final aim is the discovery of circulating biomarkers, and since plasma and serum samples are easily accessible, proteomic analysis is frequently used for blood samples. However, standardization of sampling and access to low-abundance proteins remains problematic. Although, proteomics is playing a major role in the discovery phase of biomarkers, validation in independent populations is necessary by using more specific methods. The knowledge of new HF biomarkers may allow a more personalized medicine in the future. PMID- 21246741 TI - Differential expression of red cell proteins in hemoglobinopathy. AB - Red blood cell proteome has not been studied well until recently, as the large abundance of hemoglobin posed challenge to the detection of other cytosolic proteins in the linear dynamic range. However, in the last couple of years, due to emergence of various novel hemoglobin depletion strategies and more state-of the-art detection techniques, a number of works on erythrocyte proteome have appeared in the literature. As a result, we now have much deeper information about both the membrane as well as the cytosolic proteins of erythrocytes. In this review, we have discussed the role of red cell proteome on the two most well studied hemoglobin disorders, sickle cell disease and thalassemia, emphasizing on the differential expression of the redox regulator proteins and chaperones, in particular. We have also touched upon the importance of the association of the varying levels of hemoglobin variants, particularly HbE on the clinical manifestation of composite diseases like HbEbeta thalassemia. PMID- 21246742 TI - Proteome analysis of biological fluids from autoimmune-rheumatological disorders. AB - Autoimmune-rheumatological diseases are worldwide distributed disorders and represent a complex array of illnesses characterized by autoreactivity (reactivity against self-antigens) of T-B lymphocytes and by the synthesis of autoantibodies crucial for diagnosis (biomarkers). Yet, the effects of the autoimmune chronic inflammation on the infiltrated tissues and organs generally lead to profound tissue and organ damage with loss of function (i.e., lung, kidney, joints, exocrine glands). Although progresses have been made on the knowledge of these disorders, much still remains to be investigated on their pathogenesis and identification of new biomarkers useful in clinical practice. The rationale of using proteomics in autoimmune-rheumatological diseases has been the unmet need to collect, from biological fluids that are easily obtainable, a summary of the final biochemical events that represent the effects of the interplay between immune cells, mesenchymal cells and endothelial cells. Proteomic analysis of these fluids shows encouraging results and in this review, we addressed four major autoimmune-rheumatological diseases investigated through proteomic techniques and provide evidence-based data on the highlights obtained in systemic sclerosis, primary and secondary Sjogren's syndrome, systemic lupus erythematosus and rheumatoid arthritis. PMID- 21246744 TI - Fine-needle aspiration for proteomic study of tumour tissues. AB - Fine-needle aspiration (FNA) is a technique largely applied in the diagnosis of tumours. FNA is a safe diagnostic procedure that is widely employed in the examination of masses at relatively low cost and minimal risk to the patient. In this review, we report on the state-of-the-art and the potential role of FNA to search for protein biomarkers by the proteomic approach. PMID- 21246743 TI - In vivo characterization of renal auto-antigens involved in human auto-immune diseases: the case of membranous glomerulonephritis. AB - Renal auto-immune diseases represent a major source of morbidity in humans. For many years the knowledge on mechanisms of auto-immunity involving the kidney has been uniquely based on animal models. However, these findings often could not be readily translated to humans owing to notably difference in antigen expression by human podocytes. One example is Heymann nephritis (HN), the experimental model of human membranous glomerulonephritis (MGN), which is obtained in rats by injecting antibodies against megalin, a protein that is not present in human glomeruli. Human studies could not be done in the past since sequencing required too much material exceeding what obtainable from tissue biopsies in vivo. Research is now on the way to identify auto-antigens and isolate specific auto-antibodies in humans. New technology developments based on tissue microdissection and proteomical analysis have facilitated the recent discoveries, allowing direct analysis of human tissue in vivo. Major advances on the pathogenesis of MGN, the prototype for the formation and glomerular deposition of auto-antibodies, are now in progress. Two independent groups have, in fact, demonstrated the existence of specific IgG(4) against phospholipase A2 receptor, aldose reductase and Mn superoxide dismutase in glomerular eluates and in plasma of a prominent part of patients with MGN, suggesting a major role of these proteins as auto-antigens in human MGN. This review will focalize these aspects outlining the contribution of proteomics in most recent developments. PMID- 21246745 TI - Interferometric fiber optic sensors for biomedical applications of optoacoustic imaging. AB - We present a non-metallic interferometric silica optical fiber ultrasonic wideband sensor for optoacoustic imaging applications. The ultrasonic sensitivity of this sensor has been characterized over the frequency range from 1 to 10 MHz. A comparative analysis has been carried out between this sensor and an array of piezoelectric transducers using optoacoustic signals generated from an optical absorbent embedded in a tissue mimicking phantom. Also, a two dimensional reconstructed image of the phantom using the fiber interferometric sensor is presented and compared to the image obtained using the Laser Optoacoustic Imaging System, LOIS-64B. The feasibility of our fiber optic based sensor for wideband ultrasonic detection is demonstrated. PMID- 21246746 TI - Lignin solubilization and aqueous phase reforming for the production of aromatic chemicals and hydrogen. AB - The solubilization and aqueous phase reforming of lignin, including kraft, soda, and alcell lignin along with sugarcane bagasse, at low temperatures (T<=498 K) and pressures (P<=29 bar) is reported for the first time for the production of aromatic chemicals and hydrogen. Analysis of lignin model compounds and the distribution of products obtained during the lignin aqueous phase reforming revealed that lignin was depolymerized through disruption of the abundant beta-O 4 linkages and, to a lesser extent, the 5-5' carbon-carbon linkages to form monomeric aromatic compounds. The alkyl chains contained on these monomeric compounds were readily reformed to produce hydrogen and simple aromatic platform chemicals, particularly guaiacol and syringol, with the distribution of each depending on the lignin source. The methoxy groups present on the aromatic rings were subject to hydrolysis to form methanol, which was also readily reformed to produce hydrogen and carbon dioxide. The composition of the isolated yields of monomeric aromatic compounds and overall lignin conversion based on these isolated yields varied from 10-15% depending on the lignin sample, with the balance consisting of gaseous products and residual solid material. Furthermore, we introduce the use of a high-pressure autoclave with optical windows and an autoclave with ATR-IR sentinel for on-line in situ spectroscopic monitoring of biomass conversion processes, which provides direct insight into, for example, the solubilization process and aqueous phase reforming reaction of lignin. PMID- 21246747 TI - Chemical synthesis of metal nanoparticles using amine-boranes. AB - The development of new synthetic strategies to obtain monodisperse metal nanoparticles on large scales is an attractive prospect in the context of sustainability. Recently, amine-boranes, the classical Lewis acid-base adducts, have been employed as reducing agents for the synthesis of metal nanoparticles. They offer several advantages over the traditional reducing agents like the borohydrides; for example, a much better control of the rate of reduction and, hence, the particle size distribution of metal nanoparticles; diversity in their reducing abilities by varying the substituents on the nitrogen atom; and solubility in various protic and aprotic solvents. Amine-boranes have not only been used successfully as reducing agents in solution but also in solventless conditions, in which along with the reduction of the metal precursor, they undergo in situ transformation to afford the stabilizing agent for the generated metal nanoparticles, thereby bringing about atom economy as well. The use of amine boranes for the synthesis of metal nanoparticles has experienced an explosive growth in a very short period of time. In this Minireview, recent progress on the use of amine boranes for the synthesis of metal nanoparticles, with a focus towards the development of pathways for sustainability, is discussed. PMID- 21246748 TI - A quantitative electron tomography study of ruthenium particles on the interior and exterior surfaces of carbon nanotubes. AB - The efficiency of filling carbon nanotubes (CNTs) by ultrasound-assisted wet impregnation is quantified by electron tomography (ET). For image analysis, a method that combines edge detection with single-value thresholding is proposed and validated. A high proportion (80 wt %) of the ruthenium was deposited inside the tube at an average particle size of 2-4 nm. Particles located on the outer surface of the CNT had a size of 1-3 nm. The local ruthenium loading measured by ET (3.2 wt %) closely matched the value from elemental analysis (3.5 wt %). In addition, a few 1 nm-sized ruthenium particles were detected inside the carbon wall, which contained pores/cracks. Direct imaging and quantification is a powerful tool to understand and possibly model the unique properties of CNT-based catalysts. PMID- 21246749 TI - Aminosilica materials as adsorbents for the selective removal of aldehydes and ketones from simulated bio-oil. AB - The fast pyrolysis of biomass is a potential route to the production of liquid biorenewable fuel sources. However, degradation of the bio-oil mixtures due to reaction of oxygenates, such as aldehydes and ketones, reduces the stability of the liquids and can impact long-term storage and shipping. Herein, solid aminosilica adsorbents are described for the selective adsorptive removal of reactive aldehyde and ketone species. Three aminosilica adsorbents are prepared through the reaction of amine-containing silanes with pore-expanded mesoporous silica. A fourth aminosilica adsorbent is prepared through the ring-opening polymerization of aziridine from pore-expanded mesoporous silica. Adsorption experiments with a representative mixture of bio-oil model compounds are presented using each adsorbent at room temperature and 45 degrees C. The adsorbent comprising only primary amines adsorbs the largest amount of aldehydes and ketones. The overall reactivity of this adsorbent increases with increasing temperature. Additional aldehyde screening experiments show that the reactivity of aldehydes with aminosilicas varies depending on their chemical functionality. Initial attempts to regenerate an aminosilica adsorbent by acid hydrolysis show that they can be at least partially regenerated for further use. PMID- 21246750 TI - Dye-functionalized polymerization catalysts applied to the coloration of textiles. PMID- 21246751 TI - Improved niobate nanoscroll photocatalysts for partial water splitting. AB - Layered K(4)Nb(6)O(17) is a known UV-light-driven photocatalyst for overall water splitting, with a band gap of 3.5 eV. Following ion exchange and exfoliation with tetrabutylammonium hydroxide, the layered material separates into nanosheets that coil into 1.0+/-0.5 MUm long and 10+/-5 nm wide nanoscrolls to reduce their surface energy. Pt and IrO(x) (x=1.5-2) nanoparticles were photochemically deposited onto the surface of the nanoscrolls to produce two- and three-component photocatalysts. Under UV irradiation, the nanostructures produced H(2) from pure water and aqueous methanol, with turnover numbers ranging from 2.3 and 18.5 over a 5 h period. The activity of the catalysts for H(2) evolution can be directly correlated with the varying overpotentials for water reduction (210-325 mV). From water, no oxygen is evolved. Instead, the formation of surface-bound peroxides in a 1:1 stoichiometry with H(2) is observed. Slow photochemical oxygen evolution can be achieved with the sacrificial electron acceptor AgNO(3), and under an electrochemical bias. The electrochemical water oxidation overpotentials are ca. 600 mV across the series of scrolls. From the photo onset potential the conduction band edge for the unmodified scrolls is estimated as -0.75 V at pH 7. Deposition of a co-catalyst is found to depress this value by 58 mV (IrO(x)), 148 mV (Pt/IrO(x)), and 242 mV (Pt). However, because water oxidation remains rate limiting, this does not affect the overall performance of the catalysts. PMID- 21246753 TI - Amitosis requires gamma-tubulin-mediated microtubule assembly in Tetrahymena thermophila. AB - To reveal the molecular systems involved in the division of a cell and its contents during cell proliferation is one of the major subjects in cell biology. Although cytoskeletal organization during mitosis has been well studied, consensus on the molecular basis of amitosis has not been achieved. Here we adapted an immunofluorescence method and investigated the cellular localization of gamma-tubulin and microtubules (MTs) in dividing Tetrahymena. Although the macronucleus (Mac) lacks a bipolar spindle, gamma-tubulin and MTs are specifically detected in the dividing Mac and show a marked change in the pattern of localization. First, gamma-tubulin and MTs appear in whole Mac, then, gamma tubulin gathers at the center of the Mac where the aster-like structure of MTs forms. On Mac expansion, MTs associated with numerous dots of gamma-tubulin are reorganized into longitudinally arranged bundles, suggesting that the mutual sliding of each filament and polymerization of MTs may induce Mac expansion. Moreover, normal Mac expansion and equal segregation of the Mac are severely disturbed when gamma-tubulin is shut off. We propose that gamma-tubulin-mediated MT assembly is required in Mac amitosis of Tetrahymena. PMID- 21246754 TI - Transformation of rat intestinal epithelial cells by overexpression of Rab25 is microtubule dependent. AB - Little research has addressed the role of membrane trafficking and recycling in the regulation of the transformed phenotype of neoplastic cells. The small GTPase Rab25 is an epithelial-specific modulator of membrane recycling. Recent studies have demonstrated that Rab25 expression is up-regulated in a number of epithelial cancers and overexpression may increase the aggressive phenotype of certain cancers. We have utilized the nontransformed RIE cell line to examine the influence of Rab25 on transformation. Overexpression of Rab25 in RIE cells leads to morphological transformation as well as growth in soft agar, tumor formation in nude mice, disruption of integrin-based focal adhesions, and alteration in modified microtubule subsets. Although the predominance of recent cancer research has focused on the manipulation of the actin-based cytoskeleton, recycling trafficking relies on microtubules. Transformation of RIE cells through overexpression of Rab25, but not with H-Ras(V12) , was reversed by inhibitors of microtubule polymerization. These results suggest that up-regulation of Rab25 in RIE cells leads to microtubule-dependent transformation. Thus, depolymerization of microtubules may be a potent therapeutic target for cancer therapy through the reversal of the invasive phenotype of certain cancer cells. PMID- 21246756 TI - Space flight affects motility and cytoskeletal structures in human monocyte cell line J-111. AB - Certain functions of immune cells in returning astronauts are known to be altered. A dramatic depression of the mitogenic in vitro activation of human lymphocytes was observed in low gravity. T-cell activation requires the interaction of different type of immune cells as T-lymphocytes and monocytes. Cell motility based on a continuous rearrangement of the cytoskeletal network within the cell is essential for cell-cell contacts. In this investigation on the International Space Station we studied the influence of low gravity on different cytoskeletal structures in adherent monocytes and their ability to migrate. J-111 monocytes were incubated on a colloid gold substrate attached to a cover slide. Migrating cells removed the colloid gold, leaving a track recording cell motility. A severe reduction of the motility of J-111 cells was found in low gravity compared to 1g in-flight and ground controls. Cell shape appeared more contracted, whereas the control cells showed the typical morphology of migrating monocytes, i.e., elongated and with pseudopodia. A qualitative and quantitative analysis of the structures of F-actin, beta-tubulin and vinculin revealed that exposure of J-111 cells to low gravity affected the distribution of the different filaments and significantly reduced the fluorescence intensity of F-actin fibers. Cell motility relies on an intact structure of different cytoskeletal elements. The highly reduced motility of monocytes in low gravity must be attributed to the observed severe disruption of the cytoskeletal structures and may be one of the reasons for the dramatic depression of the in vitro activation of human lymphocytes. PMID- 21246755 TI - A role for central spindle proteins in cilia structure and function. AB - Cytokinesis and ciliogenesis are fundamental cellular processes that require strict coordination of microtubule organization and directed membrane trafficking. These processes have been intensely studied, but there has been little indication that regulatory machinery might be extensively shared between them. Here, we show that several central spindle/midbody proteins (PRC1, MKLP-1, INCENP, centriolin) also localize in specific patterns at the basal body complex in vertebrate ciliated epithelial cells. Moreover, bioinformatic comparisons of midbody and cilia proteomes reveal a highly significant degree of overlap. Finally, we used temperature-sensitive alleles of PRC1/spd-1 and MKLP-1/zen-4 in C. elegans to assess ciliary functions while bypassing these proteins' early role in cell division. These mutants displayed defects in both cilia function and cilia morphology. Together, these data suggest the conserved reuse of a surprisingly large number of proteins in the cytokinetic apparatus and in cilia. PMID- 21246752 TI - Dividing the spoils of growth and the cell cycle: The fission yeast as a model for the study of cytokinesis. AB - Cytokinesis is the final stage of the cell cycle, and ensures completion of both genome segregation and organelle distribution to the daughter cells. Cytokinesis requires the cell to solve a spatial problem (to divide in the correct place, orthogonally to the plane of chromosome segregation) and a temporal problem (to coordinate cytokinesis with mitosis). Defects in the spatiotemporal control of cytokinesis may cause cell death, or increase the risk of tumor formation [Fujiwara et al., 2005 (Fujiwara T, Bandi M, Nitta M, Ivanova EV, Bronson RT, Pellman D. 2005. Cytokinesis failure generating tetraploids promotes tumorigenesis in p53-null cells. Nature 437:1043-1047); reviewed by Ganem et al., 2007 (Ganem NJ, Storchova Z, Pellman D. 2007. Tetraploidy, aneuploidy and cancer. Curr Opin Genet Dev 17:157-162.)]. Asymmetric cytokinesis, which permits the generation of two daughter cells that differ in their shape, size and properties, is important both during development, and for cellular homeostasis in multicellular organisms [reviewed by Li, 2007 (Li R. 2007. Cytokinesis in development and disease: variations on a common theme. Cell Mol Life Sci 64:3044 3058)]. The principal focus of this review will be the mechanisms of cytokinesis in the mitotic cycle of the yeast Schizosaccharomyces pombe. This simple model has contributed significantly to our understanding of how the cell cycle is regulated, and serves as an excellent model for studying aspects of cytokinesis. Here we will discuss the state of our knowledge of how the contractile ring is assembled and disassembled, how it contracts, and what we know of the regulatory mechanisms that control these events and assure their coordination with chromosome segregation. PMID- 21246757 TI - Heart rate variability in childhood obstructive sleep apnea. AB - The identification of patients with obstructive sleep apnea (OSA) is important because of morbidities associated with OSA. A previous adult study demonstrated the use of heart rate variability (HRV) as a tool to identify patients with moderate to severe OSA. Either a reduction in time parameters or an increase in LF/HF ratio was seen at overnight or 24-hr studies suggestive of increased sympathetic modulation. To study the feasibility of daytime HRV as a screening tool, a short-term recording of HRV is studied. Since it was shown in adult study that increased normalized LF, decreased normalized HF and increased LF/HF ratio could be detectable during supine rest at daytime awake period, the authors hypothesize that the differences are also detectable in children. Children who underwent sleep polysomnography for suspected OSA were recruited. Subjects were classified OSA if apnea-hypopnea index (AHI) > 1.5/hr and non-OSA if AHI <= 1.5/hr. Continuous 1-hr electrocardiographic monitoring was recorded in awake children during the day. Parameters from time domain and frequency domain were analyzed. Seventy-four male and 17 female snoring subjects were included in this study. Fifty-one (56%) and 40 (44%) of them were classified as "non-OSA" and "OSA," respectively. pNN50, a parameter for parasympathetic modulation, was significantly reduced in the OSA group when compared with the non-OSA group. Using multiple regression, all time domain variables were shown to be decreased in OSA group. Our results suggest that 1-hr study of HRV may be a feasible tool in identifying children with OSA. PMID- 21246758 TI - Clinical, radiological, and physiological differences between obliterative bronchiolitis and problematic severe asthma in adolescents and young adults: the early origins of the overlap syndrome? AB - PURPOSE: Few reports have compared chronic obstructive lung diseases (OLDs) starting in childhood. AIMS: To describe functional, radiological, and biological features of obliterative bronchiolitis (OB) and further discriminate to problematic severe asthma (PSA) or to diagnose a group with overlapping features. RESULTS: Patients with OB showed a greater degree of obstructive lung defect and higher hyperinflation (P < 0.001). The most frequent high-resolution computed tomography (HRCT) features (increased lung volume, inspiratory decreased attenuation, mosaic pattern, and expiratory air trapping) showed significantly greater scores in OB patients. Patients with PSA have shown a higher frequency of atopy (P < 0.05). ROC curve analysis demonstrated discriminative power for the LF variables, HRCT findings and for atopy between diagnoses. Further analysis released five final variables more accurate for the identification of a third diagnostic group (FVC%t, post-bronchodilator DeltaFEV(1) in ml, HRCT mosaic pattern, SPT, and D. pteronyssinus-specific IgE). CONCLUSIONS: We found that OB and PSA possess identifiable characteristic features but overlapping values may turn them undistinguishable. PMID- 21246759 TI - Impact of chorioamnionitis on exhaled nitric oxide and endotracheal aspirate levels of nitrites-nitrates and interleukin-8 in mechanically ventilated preterm neonates. AB - OBJECTIVES: To assess the influence of maternal chorioamnionitis on early exhaled nitric oxide (NO) and levels of nitrites-nitrates and interleukin (IL)-8 in endotracheal aspirate fluid in mechanically ventilated preterm neonates. STUDY DESIGN: Cross-sectional study. PATIENT-SUBJECT SELECTION: Between September 2007 and August 2009, 54 mechanically ventilated preterm neonates were included. Patients were divided into two groups according to the presence or absence of maternal chorioamnionitis, and those without chorioamnionitis (controls) were further stratified into two subgroups by birth weight < or >= 2,000 g. METHODOLOGY: The ventilator used was a Babylog 8000. The NO level assessed was the plateau value given by the software of the Sievers NOA apparatus. Collection of endotracheal aspirate fluid samples was performed coinciding with routine aspirations and using the dry technique. RESULTS: The two groups of control neonates showed statistically significant differences in exhaled NO expressed as nl/min and normalized exhaled NO expressed as either nl/min or nl/min/kg, so they are not homogeneous and cannot be used in clinical practice. Serum C-reactive protein and endotracheal aspirate levels of nitrites-nitrates were significantly higher in the chorioamnionitis group than in controls (3.6 vs. 1.07 umol/L; P = 0.035). Nitrites-nitrates levels were positively correlated with exhaled NO in ppb (rho = 0.367; P = 0.006). Minute exhaled endogenous NO was significantly higher in the chorioamnionitis group (0.48 vs. 0.27 nl/min/kg; P = 0.021). CONCLUSIONS: In mechanically ventilated preterm infants weighing <2,000 g, maternal chorioamnionitis was associated with an increase of early exhaled NO (nl/min/kg) and serum levels of C-reactive protein and levels of nitrites nitrates in endotracheal aspirate fluid. PMID- 21246760 TI - Bacterial co-infection, antiviral therapy, and prevention of spread of H1N1 infection. PMID- 21246761 TI - What happens during a stroke, and how can I prevent one? PMID- 21246762 TI - I hear the term "free radicals" mentioned a lot. What exactly are they, and what can I do about them? PMID- 21246764 TI - Abstracts of the 16th Annual Fall Scientific Meeting of the Sexual Medicine Society of North America (SMSNA). November 10-14, 2010. Miami Beach, Florida, USA. PMID- 21246765 TI - Abstracts of the Gerontological Society of America 60th Annual Scientific Meeting. November 16-20, 2007. San Francisco, California, USA. PMID- 21246766 TI - Abstracts of the 112th Meeting of the British Neuropathological Society. London, United Kingdom. January 5-7, 2011. PMID- 21246767 TI - Time trends in autism. PMID- 21246768 TI - ANA advocates for more work to be done to prevent ongoing sharps injuries. PMID- 21246769 TI - Cardiology meets technology. AB - Today, computers are at the heart of cardiac diagnostics. Nico Brunning from the ESC working group Computers in Cardiology discusses how computers can be further exploited. PMID- 21246771 TI - Abstracts of the 2011 Annual Meeting of the British Paediatric Neurology Association. January 26-28, 2011. Edinburgh, Scotland. PMID- 21246770 TI - The imperative for metrics in training. AB - A twenty-first century model for the training and assessment of cardiac interventionists' skills, outlined by Prof. John Morgan FRCP FESC. PMID- 21246772 TI - [The BARI 2D study]. PMID- 21246773 TI - [Epidemiology of acute coronary syndromes in Italy]. AB - Acute coronary syndromes (ACS) represent the most common cause of death in the western world and determine high morbidity. The objective of this review is to describe the epidemiology of ACS in the Italian setting, using administrative data, clinical surveys and registries. The prevalence of patients with myocardial infarction without persistent ST-segment elevation (NSTE) has increased in comparison with myocardial infarction with persistent ST-segment elevation patients. Females are about 30%, one third of patients is >75 years old, one quarter is affected by diabetes, patients with NSTE ACS show a higher risk profile. The mortality rate of patients with ACS has decreased over the last 10 years as a consequence of new therapeutic strategies. In order to offer primary coronary angioplasty to all ST-elevation myocardial infarction patients, a network between tertiary and peripheral hospitals is under development and implementation. Early experiences show a significant increase in the number of patients treated with reperfusion therapy and a decrease in mortality and morbidity. It has been demonstrated that management of NSTE patients, based on potent antithrombotic medication and coronary angioplasty, is primarily driven by resource availability rather than by clinical predictors of worse outcome. The reduction in recurrent ischemic events was obtained at the cost of an increased rate of major bleeding, which is associated with worse clinical outcomes. Therefore, it is essential the balance between the ischemic and hemorrhagic risk. PMID- 21246774 TI - [The role of molecular biology in the diagnosis and treatment of cardiovascular diseases]. AB - The aim of this review is to emphasize the role of molecular biology in the diagnosis and therapy of major cardiomyopathies and cardiovascular risk factors. Therefore, we have underlined the genes responsible for or associated with these diseases while highlighting a role in the response to therapy (pharmacogenomics). Cardiovascular diseases and its related risk factors were divided into monogenic and polygenic forms. Monogenic forms are much rarer in clinical practice. However, polygenic forms along with most risk factors are of important clinical interest due to their high frequency in the general population. The added value of genetic testing is to provide an individual risk profile assessed in each patient and not only derived from epidemiological data. The prognosis of patients with the same risk profile, assessed using current clinical and medical history data, is often very different. An accurate prediction of the clinical course of cardiovascular disease in each patient will be the best therapeutic approach (tailored medicine) and will also result in a significant cost reduction for national healthcare systems (effective therapy). PMID- 21246775 TI - [Molecular basis of arrhythmias in patients with genetically-based cardiomyopathies: when the cytoskeleton meets the ion channels]. AB - Cardiomyopathies represent a significant clinical and social issue due to their high morbidity and mortality. In addition to myocardial dysfunction, the often associated arrhythmias are an additional risk factor for morbidity and mortality in heart failure individuals. Arrhythmias are frequently correlated to cardiac pump failure, but they may develop in asymptomatic heart failure subjects with preserved ejection fraction and stable hemodynamic performance. Up to date, arrhythmias have been explained by the occurrence of cardiac valve diseases or myocardial morphological alterations. However, recent evidence suggests a tight structural and functional link, at the molecular level, between ion channels and cytoskeletal proteins involved in the structural alterations that lead to heart failure. Furthermore, mutations in these structural proteins may cause ion channel dysfunction resulting in a higher risk of arrhythmias. These new elements of investigation may allow a better understanding of the arrhythmogenic phenomenon in heart failure patients and facilitate alternative research approaches and innovative clinical applications. PMID- 21246776 TI - [Drug-eluting stents in non-coronary arteries]. AB - According to the available literature, drug-eluting stents (DES) are used mainly in coronary arteries. However, DES are used in non-coronary districts as well. The indication for DES implantation in non-coronary arteries is the same as that in the coronary circulation that is to prevent restenosis. Although data from both controlled studies and observational reports do exist, the use of DES in the non-coronary circulation is very limited and is not comparable with that for the treatment of coronary artery disease. The most important factors one has to consider before DES implantation in non-coronary arteries are histologic features, blood flow characteristics and compressive extrinsic forces. Further studies on larger populations are warranted to define the ideal combination stent/drug and the clinical indications for the correct use of DES in non coronary vascular districts. PMID- 21246777 TI - [The evolution of medical research: from trials to tailored therapy]. AB - Medical research and consequently therapy are undergoing dramatic transformation. New science on genomics and proteomics has given us important information on the pathophysiology of many cardiac diseases and personalized responses to specific patient-oriented therapies. The application of cellular genetic and proteome tests is a promising field of research and their clinical use can allow us to both: 1) understand the causes and evolution of heart diseases such as ischemia and heart failure better, 2) lead to personalized medicine. This article focuses on the basic intracellular-related evidence and the unsolved problems and complexity of intracellular signaling that still need to be studied to understand personalized therapies better. In addition, we provide preliminary clinical data that support the potentiality of this new but fundamental approach of curing patients according to their genetic expression and/or protein activation that influence personalized development and the management of cardiovascular diseases. PMID- 21246778 TI - [Genomics in cardiological clinical practice: from the individual response to drug therapy and monogenic cardiovascular disorders]. PMID- 21246779 TI - [Current perspectives in cell therapy in cardiology: an overview of ongoing trials]. AB - BACKGROUND: Cardiac cell therapy is still restricted to experimental studies and clinical trials. This investigation is an analytic overview of worldwide ongoing trials and is aimed to show useful findings for planning new clinical trials. METHODS: Based on the online searching engine of the National Library of Medicine database for clinical trials (www.clinicaltrials.gov), all the ongoing studies registered were analyzed and classified. RESULTS: On May 30, 2009, 95 studies were registered worldwide: 40 of these were conducted in Europe and 4 in Italy. Phase 1, 2, 3 and 4 studies were 28%, 57%, 14% and 1%, respectively; observational and randomized studies were 22% and 78%, respectively. The clinical setting of enrolled patients was acute coronary syndrome in 43 studies (46%), heart failure in 29 studies (30%), chronic heart disease in 23 studies (24%). The treatment strategies investigated are cytokine-induced cell mobilization in 8% and cell implantation in 92%. The cell types used for direct implantation are mononuclear cells in 81%, endothelial precursor cells CD34+ in 11%, endothelial precursor cells CD133+ in 5%, myoblasts in 2% and adipoblasts in 1% of cases. CONCLUSIONS; The present snapshot of worldwide ongoing clinical trials provides useful information for planning an experimental clinical program on cardiac cell therapy. PMID- 21246780 TI - [Cell therapy and the nostalgia of the future]. PMID- 21246781 TI - [Anomalous origin of the coronary arteries: five case reports and review of the literature]. AB - BACKGROUND: Although individual patient outcomes are highly variable, coronary artery anomalies may be associated with sudden cardiac death or acute coronary syndrome. METHODS: We report 5 cases of anomalous origin of coronary arteries: a single coronary artery originating from the right sinus of Valsalva, a case of isolated anomalous right coronary artery originating separately from the left sinus of Valsalva, a case of right coronary artery originating between the right and left sinus of Valsalva, a case of anomalous left circumflex artery originating from the right sinus of Valsalva, and a case of anomalous left anterior descending coronary artery originating from the right sinus of Valsalva. RESULTS: Although in one case the right coronary artery runned between the aorta and the right pulmonary artery, no significant alterations due to coronary artery compression or atheromatous lesions at the anomalous coronary ostia were observed. In all reported cases, symptoms were different as a result of cardiovascular comorbidities. All coronary anomalies were identified at coronary angiography, which was performed for other indications. CONCLUSIONS: The identification of a clear correlation between symptoms and coronary artery anomalies seems challenging in clinical practice. However, it is crucial to confirm or rule out the presence of coronary compression caused by the anomalous origin of coronary arteries. PMID- 21246782 TI - [Feasibility and safety of immediately returning patients transferred for percutaneous coronary intervention in a large metropolitan area]. AB - BACKGROUND: Hospitals without percutaneous coronary intervention (PCI) capabilities are used to transfer patients who need coronary angiography and/or PCI to other centers. In order to optimize economic resources and hospital bed management, PCIs might be performed with an in-service organization, with re transfer to the community hospital immediately after the procedure. The aim of our study was to evaluate the safety of a consecutive, unselected series of in service PCIs compared to PCIs performed in patients admitted to hospitals with cath-lab capabilities. METHODS: During 2008, 1030 PCI procedures were performed at the European Hospital and Aurelia Hospital: 905 in patients admitted to a hospital with PCI capabilities (Group I) and 125 (12%) with an in-service strategy (Group II) referring from the Citta di Roma Hospital. All treatment protocols were preventively uniformed and standardized. RESULTS: The two groups were statistically comparable in terms of baseline clinical characteristics and/or procedural findings, with the exception for older age (66 +/- 10 vs 70 +/- 10 years, p = 0.004) and a higher prevalence of acute coronary syndromes (56 vs 88%, p < 0.001) and femoral vascular access (94 vs 98%, p = 0.03) in Group II. The rate of left ventricular ejection fraction < or = 35% (20 vs 13%, p = 0.06), multivessel PCI (23 vs 19%, p = 0.4), and glycoprotein IIb/IIIa inhibitor use (15 vs 13%, p = 0.5) was similar between the two groups. Among patients treated with an in-service strategy, 2 (1.6%) were not transferred to the community hospital, because of hemodynamic instability. The in-hospital rate of major clinical events (death for cardiovascular causes, cerebrovascular events, urgent revascularization, stent thrombosis) was 0.75% and 0.8% (p = 0.8), 1.8% and 1% (p = 0.4) for periprocedural myocardial infarction, 1.7% and 1.9% (p = 0.5) for major bleeding, 1.1% and 1.6% (p = 0.6) for vascular complications, in Group I and II, respectively. Left ventricular dysfunction was the only independent predictor of major clinical events (p = 0.003). CONCLUSIONS: A strategy of in service organization for PCI presents a similar rate of in-hospital clinical events and complications compared to an overnight stay into a hospital with PCI capabilities. Such a strategy may be utilized in order to optimize economic resources and hospital bed management. PMID- 21246783 TI - [Acute spontaneous failure of a Carpentier-Edwards porcine mitral valve]. AB - We describe the case of a 74-year-old patient with structural valve deterioration of a Carpentier-Edwards porcine mitral valve. He was referred to our institution for a murmur noted about 1 week before. Transthoracic echocardiography showed the presence of severe mitral regurgitation, without disclosing the mechanism of failure. A tear cusp was identified with transesophageal echocardiography that resulted in a lack of coaptation of the leaflets causing mitral insufficiency. The diagnosis was confirmed at surgery. PMID- 21246784 TI - [Valve-in-valve technique to manage acute paraprosthetic leak after transcatheter aortic valve implantation]. PMID- 21246785 TI - [Comparison of reactive oxygen species production in neat semen and washed spermatozoa]. AB - OBJECTIVE: To determine Reactive Oxygen Species (ROS) production in neat semen and spermatozoa suspension using chemiluminescence and to examine correlation between both methods. SUBJECT: Prospective laboratory study. SETTING: Department of Obstetric and Gynecology, University Hospital, Olomouc. METHODS: The study included fertile volunteers (FV, n = 17), men from infertile couples (NM, n = 19) and men with idiopathic infertility (NMI, n = 15). ROS levels were determined by the same method in neat and washed semen samples. RESULTS: The ROS production in neat semen was lower than that in spermatozoa suspension. There was no significant diference in ROS production between volunteers and males from infertile couples. There was a significant correlation between log ROS in neat semen and in spermatozoa suspension in studied groups (FV r = 0.85, p = 1.5 x 10( 5); NM r = 0.76, p < 2 x 10(-4); NMI r = 0.75, p < 1.5 x 10(-3)). CONCLUSIONS: Measurement of ROS in neat semen is simpler, faster and better reflecting the actual level of oxidative stress than the same measurement in spermatozoa suspension. The implementation of this method can complement the algorithm of diagnostics and treatment of male infertility and be helpful in selection of patients for antioxidant or antibiotic treatment. PMID- 21246786 TI - [Amniotic fluid interleukin 6 levels in preterm premature rupture of membranes]. AB - OBJECTIVE: The purpose of this study was to determinate the changes of amniotic fluid interleukin 6 (IL-6) concentrations in patients with preterm premature rupture of the membranes (PPROM), and in the presence of microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA). The aim was to examine amniotic fluid IL-6 in relation to MIAC and HCA. DESIGN: Prospective study. SETTING: Department of Obstetrics and Gynecology Medical Faculty Charles University Hradec Kralove. METHODS: We studied 37 women between 24 and 36 weeks of gestation with PPROM. Samples of amniotic fluid were collected by transabdominal amniocentesis. Polymerase chain reaction for the genital mycoplasmas and culture for aerobic and anaerobic bacteria were performed. Twenty eight of 37 patients placentas were collected and assessed for presence or absence HCA. IL-6 concentration in amniotic fluid were determined using a sensitive and specific diagnostic kit Human IL-6 Quantikine ELISA manufactured R&D Systems, USA. RESULTS: There was significant difference in the median amniotic fluid IL-6 concentration between patients with preterm rupture of the membranes with and without MIAC and HCA (patients with MIAC and HCA: median 915 pg/ml, range 651-1854 pg/ml vs. patients without MIAC and HCA: median 780 pg/ml, range 184-1059 pg/ml; p=0.047). There was no significant difference in the median amniotic fluid IL-6 concentration between patients with preterm rupture of the membranes with and without MIAC (patients with MIAC: median 915 pg/ml, range 195 1854 pg/ml vs. patients without MIAC: median 792 pg/ml, range 184-1993 pg/ml; p=0.53). There was no significant difference in the median amniotic fluid IL-6 concentration between patients with preterm rupture of the membranes with and without HCA (patients with HCA: median 829 pg/ml, range 195-1992 pg/ml vs. patients without HCA: median 768 pg/ml, range 184-1890 pg/ml; p = 0.31). CONCLUSION: Amniotic fluid IL-6 concentrations patients with PPROM with presence HCA and MIAC were significantly higher than IL-6 concentration patients without HCA and MIAC. PMID- 21246787 TI - [Densitometry findings in women using gestagen contraception]. AB - OBJECTIVE: To prove the influence of gestagen contraception on bone mass with x ray osteodensitometry (DEXA) with regard to BMI. DESIGN: Cross-sectional observational descriptive study. SETTING: Osteology centre, NZZ Bormed Ostrava. METHODS: In the study premenopausal women who had been using gestagen contraception (Depo-Provera inj.) at least for one year were included. Bone density was measured in regular manner (whole-body densitometer Hologic W). Z score at lumbar spine, whole femur and femoral neck was assessed. RESULTS AND CONCLUSIONS: 58 of 116 patients had normal bone density. In 58 ill patients the bone density dropped below the age norm. In 11 women the Z-score decreased below 2.5 SD. Inverse relationship between BMI and bone density (BMD) was found, both between BMI and Z-score (p=0.0001), and BMI and T-score (p=0.0001). The relationship between duration of gestagen use and bone density was not statistically significant. Marked decline in BMD and correlation with patients' low BMI was identified. When prescribing gestagen contraception possible negative effect on skeleton, particularly in women with low BMI should be considered. PMID- 21246788 TI - [Combination therapy with anticholinergics and alpha-blockers for the treatment of overactive bladder in female patients--pilot study]. AB - INTRODUCTION: Overactive bladder (OAB) is one of the most common medical conditions with an estimated 16 percent of adult population being affected in Europe. The administration of anticholinergics is considered as the most frequent and most effective treatment. There is a evidence that alpha-blockers affect a detrusor function. The aim of the study is to investigate if the combinant therapy consisting of anticholinergics plus alpha-blockers could be beneficial for women suffering from OAB. MATERIAL AND METHODS: 28 female patients with OAB were included into the pilot study. Mean age of the patients was 54.8 (42-77) years. Patients have been randomised into two groups: one group of patients has been treated by propiverin 30 mg daily, another group of patients has been treated by combination of both propiverin 30 mg daily and tamsulosin 0.4 mg daily. Satisfaction with the treatment has been evaluated by I-QoL questionnaire. Semi-objective parameters have been obtained by analysis of 3-days voiding diaries (number of micturitions, number of urgency episodes, voided volume). Peak flow (Qmax) has been measured as a objective parameter. RESULTS: We observed a decrease of frequency by 2.833 (-23.43%) comparing to base-line, decrease of number of urgency episodes by 1.417 (-36.22%), increase of voided volume by 33.333 ml (+19.14%), increase of quality of life index by 22.583 (+51.52%) and increase of Qmax by 0.17 ml/s (+0.58%) in the propiverin group. We observed decrease of frequency by 3.813 (-30.48%), decrease of number of urgency episodes by 1.875 (-45.52%), increase of voided volume by 51.250 ml (+26.88%), increase of quality of life index by 33.438 (+76.0%) and increase of Qmax by 2.13 ml/s (+7.87%) in the combination treatment group. No significant difference has been found between both groups except the quality of life index. CONCLUSION: Our results can not show explicitly higher efficacy of combination treatment using anticholinergics plus alpha-blockers comparing to standard therapy by anticholinergics alone. Further randomised placebo-controlled studies are needed for final evaluation of the role of alpha-blockers in the treatment of OAB. PMID- 21246789 TI - [Fertility preserving treatment of gynecological malignant tumors]. AB - OBJECTIVE: Factsheet on conservative treatment of gynecological malignant tumors allowing preservation of reproductive function. DESIGN: Literature review with case reports. SETTING: Department of Gynaecology and Obstetrics, Faculty of Medicine, Masaryk's University and Faculty Hospital, Brno. METHODS: Literature review of conservative treatment of gynecological malignant tumors allowing preservation of reproductive function with illustrative case reports. CONCLUSIONS: According to the National Oncological Register data in terms of incidence of certain gynecological malignancies, of a not insignificant group of malignancy occurring in women fertile age. This is a very sensitive area of oncogynecology where it is desirable to highly personalized approach, which is based on the stages of the disease and reflects the possibly patients wish to preserve future fertility. It is crucial to detect the disease in the early stages, which allows fertility preserving conservative procedure. Before to the start of conservative treatment to be made compulsory examinations, which is essential from the perspective of oncogynecologist particularly expert gynecological ultrasound pelvis and the abdominal cavity, which is adequate for investigating erudition seems to be the diagnostic method with sufficient accuracy the parameters expressed sensitivity and specificity, and also as a diagnostic method highly efficient in economic terms. A very important part of the team, which participates in the implementation of this specialized care in oncogynecology is also histopathologist specializing in oncogynecological issue and one of the important assumptions is the possibility to carry out work peroperative histopathological examination. PMID- 21246790 TI - [Molecular characterization of epithelial ovarian borderline tumors with respect to clinical management and prognosis]. AB - OBJECTIVE: To analyze up-to-data knowledge in the field of molecular characterization of epithelial ovarian borderline tumors with respect to clinical management and prognosis. DESIGN: Review. SETTING: Oncogynecological Center, Department of Obstetrics and Gynecology, Charles University in Prague, First Faculty of Medicine, and General Faculty Hospital, Prague. METHODS: Based on literature search and own experimental data in the field of molecular biology of ovarian cancer and borderline tumors of ovary, we summarize up-to-date knowledge of molecular differences and specific features of BTO with respect to implementation of these knowledge into the clinical management. RESULTS AND CONCLUSION: We suppose that spectrum of genomic changes (i.e. genetic and epigenetic) causing tumor transformation is limited and these changes take place in stem or progenitor cell. Analysis of genomic changes can help to define certain subtypes of BTO and, correlated to clinical characteristics, to identify subtypes with different biological behavior. Such molecular typing of BTO allows to individualize treatment. PMID- 21246791 TI - [Reproductive outcome after laparoscopic myomectomy--retrospective analysis 1994 2007]. AB - The aim of the study was to analyse the reproductive outcome after laparoscopic myomectomy (LM) in infertile patients. Between the years 1994-2007 were 351 infertile women operated in our department. The average age of the patients was 33.5. The total number of extirpated fibroids was 643, with the average of 1.7 per patient and the average size of 3.3 cm. 171 women (48.7%) became pregnant after LM. There were 119 deliveries, 16 spontaneous abortions and 6 ectopic pregnancies in this group. The caesarean section (CS) rate was 46.2% . Intramural localisation of the fibroid significantly correlated with the termination of pregnancy by CS. I. and II. trimester pregnancy loss correlated significantly with deep coagulation when conception occurred during 12 months after surgery. No uterine rupture was observed during pregnancy. PMID- 21246792 TI - [Ovarian torsion in the first trimester gravidity after stimulation in vitro fertilization--case report]. AB - OBJECTIVE: To direct attention to ovarian torsion as one of the causes of acute gynecological disorder after ovarian stimulation in vitro fertilization in the first trimester. DESIGN: Case report. SETTINGS: Department of Gynecology and Obstetrics, First faculty of Medicine, Charles University and General Teaching Hospital, Prague. SUBJECT AND METHOD: We present the case of a pregnant patient after ovarian stimulation in vitro fertilization when delay in determining the diagnosis led to ovarectomy. CONCLUSION: Although ovarian torsion is not a frequent cause of acute abdominal pain, it should be borne in mind during the process of differential diagnosis--especially with woman after ovarian stimulation in vitro fertilization. In order to save the ovary is important to determine the diagnosis in time and carry out laparoscopy revision with detorsion of the twisted ovary. This case is intended to draw attention to the clinical characteristics and findings which accompany torsion, thus potentially reducing the time which elapses from patient admission to surgery. PMID- 21246793 TI - [Prenatal intracranial hemorrhagie--diagnosis and follow-up]. AB - AIM: We present a case of difficult prenatal diagnosis and follow-up of severe fetal intracranial hemorrhage. With an analysis of the available literature that is related to this topic, we would like to bring attention to the necessity of accurate evaluation of fetal brain morphology even during routine ultrasound examination in the late third trimester. TYPE OF STUDY: Case report. SETTING: Department of Obstetrics and Gynecology, General Faculty Hospital and 1st Faculty of Medicine, Charles University, Prague. METHODS AND RESULTS: Four cases of prenatal intracranial hemorrhage are presented. All cases were diagnosed during ultrasound examination during the third trimester of pregnancy and the findings were clarified using nuclear magnetic resonance imaging. The etiology of the hemorrhage was determined in only two cases. Postnatal follow-up of the affected children over a range of one to two years of age shows a very severe prognosis of the described hemorrhagic conditions. CONCLUSION: Prenatally diagnosed fetal intracranial hemorrhage is a rare but severe complication in pregnancy associated with fetal and neonatal morbidity and mortality. A detailed description and precise image documentation of the damaged fetal structures have a fundamental forensic significance. Postnatal estimation of the time of hemorrhage using analysis of the cerebrospinal fluid and ultrasound findings (echogenicity of the lesions) is not always unified. PMID- 21246794 TI - [Analysis of perinatal indicators of the Olomouc region in the period 1994-2008]. AB - OBJECTIVE: The aim of this study was to examine the evolution of the main perinatology outcomes in the last fifteen years and their comparison to the Czech Republic. Analysis belong to the control system of quality of care. DESIGN: Retrospective epidemiological study. SETTING: Gynaecology and Obstetrics Clinic Medical Faculty Palacky University and Faculty Hospital in Olomouc. METHODS: For analysis in this study were used results of perinatal databases of the Committee for Perinatal Medicine of the Czech Republic (10 million population) and all hospitals in Olomouc region (600,000 population). RESULTS: Since mid-90th years there is a significant improvement of perinatal indicators and very good results have been achieved since 2000, when the perinatal mortality rate dropped to 2 per mille (in 2008). The downward trend in perinatal mortality rate and early neonatal mortality rate was statistically significant (P for trend = 0.008). Comparison of major perinatal outcomes confirms that perinatal mortality rate exceeds in five years the national average in the reference interval.. Statistically significant worse results were in early neonatal mortality rate without congenital malformations in the year 1994 (P = 0.005) and the year 2001 (P = 0.0008). Stillbirth rate without congenital malformation fluctuated from 1.1 to 3.1 per mile and exceeded republic mean in the year 1998. Since 1994 increased in the Czech Republic frequency of preterm births of children of low birth weight (LBW--less than 2.5 kg) from 5.47% to 7.37%. In recent years, there was a problem with the lack of beds in the neonatology intensive care unists. CONCLUSION: Analysis of the main perinatology data of the last fifteen years acknowledges, that monitored indices of the Olomouc region were more often better than the national average. A major problem of this region, as well as the Czech Republic, is increased frequency of premature labour and associated insufficient capacity of neonatal intensive care unit in perinatal center. PMID- 21246795 TI - [Effect of cranberry extract capsules taken during the perioperative period upon the post-surgical urinary infection in gynecology]. AB - OBJECTIVE: To evaluate the effect of cranberry extract capsules taken during the perioperative period upon the post-surgical urinary infection (UTI) in gynecology. DESIGN: Clinical prospective pilot trial. SETTING: Obstetrics and Gynecology Department, Merciful Brothers Hospital, Brno and Obstetrics and Gynecology Department, Charles University 2nd Medical Faculty and Teaching Hospital Motol, Prague. MATERIALS AND METHODS: The cohort consisted of 286 women who underwent hysterectomy and/or anterior vaginal repair (with or without anti incontinence operation) in the above hospitals in the period 1. 9. 2006 -30. 6. 2007. 132 women from among the total were given cranberry extract capsules (equiv. 17,000 mg of fresh fruit) twice a day, 4 days before and 5 days after the surgery. The rest were the control group. The clinical state and the analysis of catheterized urine including bacteriology were determined on the day of surgery and on the 6th postoperative day. Cases with preoperative UTI and those with antibiotic therapy (due to other than urology indications) were excluded from the study. Thus the statistical analysis was made in the remaining 117 patients with prophylactic cranberry capsules and 139 controls. RESULTS: There were 30.8% of positive cultured urines, 18.0% of pyuric specimens and 6.8% symptomatic urinary infections in the group of cranberry prophylaxis. Controls had significant bacteriuria in 27.3%, pyuria in 23.7% and symptomatic UTI in 5.0%. Differences were not statistically significant. CONCLUSION: The intake of cranberry extracts in the perioperative period (4 days before and 5 days after the surgery) did not affect the number of post-surgical UTIs. PMID- 21246796 TI - [Complications of laparoscopic and laparotomic treatment of endometrial cancer]. AB - OBJECTIVE: The aim of the study is to compare advantages, disadvantages and complications of the laparoscopic and clasical laparotomic operations in the patients treated for endometrial carcinoma at our Department and to find out the optimal strategy. DESIGN: Retrospective study. SETTINGS: Department of Gynaecology and Obstetrics, Medical Faculty, Palacky University and University Hospital, Olomouc. MATERIAL AND METHODS: A total of 165 endometrial cancer patients were operated on since 2004 till 2008 at our department. The clasical laparotomic approach was used in 141 patients and 24 were operated laparoscopically. Both groups were comparable in clinical staging and other parameters. The clinical parameters compared were the frequency of inflammatory complications, urinary passage injury, blood loss, transfusions, operating time and hospital stay. RESULTS: The average operating time for laparotomic operations was 137 minutes and for the laparoscopic ones 175 minutes. The mean hospital stay after clasical operation was 7.8 days, and 6.7 days after laparoscopy. The estimated blood after clasical operation was 410 ml and 8.5% of patients received blood transfusion. Blood loss after laparoscopy was only 214 ml but 12.5% of patients necessitated blood transfusion. Complications due to infection were more often in patients with laparotomy (5.7%) while they occurred only in 4.1% after laparoscopies. The injury of the urinary tract was recorded only in 1 patient (0.7%) in the laparotomy group while it was more frequent in the laparoscopic group (2 patients i.e. 8.3%). CONCLUSIONS: The main advantage of laparoscopy at the operations of the endometrial cancer is the shorter hospital stay resulting in lower costs, less postoperative discomfort and a minimum of inflammatory complications. On the other hand there were more frequent urinary tract injuries and the operating time was usually longer at laparoscopies compared to laparotomies. Nevertheless, it seems that the use of the laparoscopic operations for endometrial cancer will probably be increasing. PMID- 21246797 TI - [Treatment of recurrent ovarian cancer]. AB - OBJECTIVE: The description of current treatment possibilities in recurrent ovarian cancer. DESIGN: Review article. SETTING: Obstetrics and Gynecology Department, Charles University 2nd Medical Faculty and University Hospital Motol, Prague. METHODS: The review of literature on treatment of recurrent ovarian cancer. Current data on chemotherapy, surgery and targeted biological therapy in recurrent ovarian cancer. CONCLUSIONS: Chemotherapy is indicated in most cases of recurrent ovarian cancer, surgery does not play an important role. Standard treatment of platinum-sensitive recurrent ovarian cancer is based on platinum combination chemotherapy. Standard treatment of platinum-refractory ovarian cancer represents non-platinum monotherapy. Targeted biological therapy should be still used only in the studies. PMID- 21246798 TI - [The importance of publishing in English for our journal]. PMID- 21246799 TI - [Functional results of nerve reconstruction in a thoracic limb. A multicenter study]. AB - OBJECTIVE: To assess the functional results of nerve reconstruction with autologous interfascicular nerve grafts in a thoracic limb. MATERIAL AND METHODS: From January 1999 to December 2006. Complete nerve injuries of the radial, median and ulnar nerves. Follow-up was at least 12 months. VARIABLES: age, nerve defect length, location, interval between the injury and the treatment, mechanism, injuries, and adjunctive treatments. The procedures were performed by the authors. Nine and 10-0 sutures were used. The Medical Research Council System (MRCS) scale was used for the functional measurement. The chi2 test was applied to variables and functional results. RESULTS: 43 patients, 48 nerves, mean age 26.7 years; 29 males and 14 females. Nineteen injuries occurred in the ulnar nerve (39.5%), 18 in the median nerve (37.5%) and 11 in the radial nerve (23%). Five patients had injury of the median and ulnar nerves. Twenty three injuries involved the wrist (53.4%), 7 the forearm (16.2%) and 12 the arm (27.9%). The mean time elapsed between the injury and the treatment was 42.09 days. The mean size of the nerve defect was 4.4 cm. The mean followup was 17.5 months. Forty two patients had associated injuries and 37 received adjunctive treatment. Motor function: Results were good in 15 patients (31.2%), fair in 21 (43.8%), poor in 10 (20.8%) and bad in 2 (4.2%). Sensory function: Results were good in 36 nerves (75%), fair in 4 (83%), poor in 6 (12.5%) and bad in 2 (4.2%). DISCUSSION: The results were similar to those reported in the literature. CONCLUSIONS: Good results were obtained in gaps < or = 5 cm, in cases without arterial injury and when the time to treatment did not exceed 40 days (p < 0.05). The age, the nerve and the site of injury were not influencing factors. PMID- 21246800 TI - [Tumor necrosis factor as a biomarker of infection in total knee arthroplasty]. AB - BACKGROUND: Thanks to defense mechanisms, organisms have had to adapt themselves to an adverse natural setting that causes acute and chronic stress. This adaptive response that tries to protect the cells against lethal insults uses its own defense systems. MATERIAL AND METHODS: Prospective, observational, descriptive pilot study with analytic components to determine the baseline preoperative TNF levels of 35 patients undergoing total knee arthroplasty due to gonarthrosis. Ten patients with a diagnosis of infected total knee arthroplasty were also included. In order to find differences and possible associations, the Mann-Whitney U test or the Fisher test was used to compare the variables between the non-infected group of patients and the group with the infection complication. RESULTS: We found a statistically significant difference; higher levels of fibrinogen, erythrocyte sedimentation rate, C-reactive protein, TNF-alpha and temperature were found in the infected patients; temperature was not clinically relevant. CONCLUSIONS: In the absence of a diagnostic specificity, the combined determinations of acute phase reactants may be useful to detect the presence and intensity of the inflammatory and infectious processes. PMID- 21246801 TI - [Utility of 3D computed tomography for the surgical planning of pelvic fractures]. AB - BACKGROUND: To determine the utility of 3D computed tomography for the preoperative planning of pelvic rim fractures assessing possible changes in fracture classification as well as in the surgical indication itself. METHODS: We retrospectively reviewed patients who had undergone surgery for complex pelvic fractures during a 15-month period. The mechanism of injury was recorded and the availability of a multi-slice spiral volumetric CT scan was requested as a preoperative study. RESULTS: Ten cases (58%) were pelvic rim fractures and 7 were acetabular fractures. The mean ISS was 23.82 (9-50), and 82.3% of cases were severe traumas (ISS > 16). After the CT scan was obtained, the initial classification of the fracture was changed in four cases (23.5%), without any changes in the surgical indication. An artifact was detected in the volumetric reconstruction but it did not limit the surgeon's interpretation. CONCLUSION: Tridimensional CT-based modeling is very helpful in the surgical planning of pelvic fractures and is a complement of the plain X-rays. PMID- 21246802 TI - [Assessment of patients with distal radius fracture treated with percutaneous fixation]. AB - The trend in distal radius fracture is towards open reduction and internal fixation; however, treatment with closed reduction and percutaneous nailing continues to provide good results, but physical therapy and appropriate early rehabilitation are needed. MATERIAL AND METHODS: We assessed patients with distal radius fractures treated with reduction with percutaneous maneuvers and nailing; we used clinical functional scales, like the DASH, the Mayo Clinic wrist scale, and the Visual Analog Scale (VAS) to assess pain. Patient results were compared at 12 and 24 weeks. We also compared patients with and without rehabilitation. RESULTS: A total of 60 patients were assessed using the DASH scale; patients with rehabilitation had a score of 4.3, while those without rehabilitation had a score of 10.5 (p = 0.00001). In the Mayo Clinic scale, patients with rehabilitation had a score of 86.7, while those without rehabilitation had a score of 77.8 (p = 0.00001). The VAS was not significant. CONCLUSION: All patients showed improvement in their clinical assessment scales. However, when patients with and without rehabilitation are compared, the difference was greater in the Mayo Clinic scale and in the DASH scale. PMID- 21246803 TI - [Grade III acromioclavicular dislocation treated with a minimally invasive approach]. AB - OBJECTIVE: To determine the efficacy of minimally invasive surgery (MIS) in the treatment of type III acromioclavicular dislocations using the UCLA and DASH evaluations. MATERIAL AND METHODS: Prospective, longitudinal, observational study; clinical series of patients with a diagnosis of type III acromioclavicular dislocation who underwent MIS consisting of percutaneous reduction, placement of a 4.5 mm cortical screw, an 11 mm metallic washer and 1.6 mm Kirschner nails at the Polanco Red Cross Hospital from July 2007 to July 2009. The evaluations were done using the UCLA test and the DASH questionnaire. RESULTS: The total number of patients was 42; 5 females and 37 males. According to the UCLA test, 86% of them had excellent to good results and 14% partial to poor results. The results of the DASH questionnaire were as follows: 80% had no difficulty to mild difficulty; 18% had moderate to severe difficulty, and 2% had disability for performing daily life activities. CONCLUSIONS: MIS is a good treatment for the management of type III acromioclavicular dislocation with long-term results based on the UCLA test and the DASH questionnaire. PMID- 21246804 TI - [Distal femur fractures. Comparative analysis of two different surgical treatments]. AB - INTRODUCTION: The treatment of distal femur fractures has been a controversial topic and it has recently evolved towards indirect reduction and minimally invasive techniques. OBJECTIVE: To compare the results of the surgical treatment of distal femur fractures with a plate with screws for condylar compression purposes with the minimally invasive stabilization system. MATERIAL AND METHODS: Patients with distal femur fractures treated surgically between January 2007 and December 2009 were assessed retrospectively. The following variables were registered from each patient record: age, sex, type of fracture, mechanism of injury, type of implant used, operative time and postoperative bleeding. The Neer scale was used to compare the anatomical, radiologic and functional results of both techniques. RESULTS: The total number of patients was 52; 32 males and 20 females; mean age was 58 years. A plate with screws was used in 31 patients for condylar compression purposes, and a minimally invasive stabilization system in 21. The cases managed with a minimally invasive stabilization system had a shorter operative time and less intraoperative bleeding. The results of the evaluation using the Neer scale were similar for both modalities. CONCLUSIONS: The patients with fracture of the distal third of the femur managed with a minimally invasive stabilization system had better outcomes, which were not significant in the Neer scale, mainly due to less pain intensity, early mobilization and less functional repercussions. PMID- 21246805 TI - [Neuromotor assessment of patients with spastic cerebral palsy treated with orthopedic surgery at the National Rehabilitation Institute]. AB - BACKGROUND: Cerebral palsy (CP) is a static neurologic condition resulting from a brain lesion occurring before the completion of brain development. The goal of management is not cure, but increasing patients' functionality and improving their capabilities and maintaining their locomotion, cognitive development, social interaction and independence. The best results are obtained with an early and intensive management that includes physical and occupational therapy, medical and surgical treatments, mechanical aids and the management of concomitant conditions. OBJECTIVE: To assess the neuromotor improvement in patients with spastic CP after surgical treatment at the National Rehabilitation Institute. PATIENTS AND METHODS: Patients with a diagnosis of spastic CP who presented at the Pediatric Rehabilitation outpatient service were referred to the Joint CP Clinic from January 2007 to January 2008, and underwent surgical treatment of the pelvic limbs. They were assessed 3 times and underwent neuromotor tests with gross motor function measure (GMFM), which was rated with the gross motor function classification system (GMFCS). RESULTS: Most of the patients had improvement in the muscle tone and contracture assessments as well as in the GMFM, and their self-mobility increased one level. CONCLUSIONS: Significant improvements were seen in the muscle tone and contractures after surgery; the GMFM and the self-mobility levels in the GMFCS also improved. Multiple level surgery together with a postoperative physical therapy program results in considerable improvements in the gross motor function measure of patients with spastic CP. PMID- 21246806 TI - [Treatment of Torode and Zieg type IV unstable pelvic fractures in children]. AB - INTRODUCTION: Pelvic fractures are infrequent in pediatric patients; they account for 1% of hospital admissions. Acetabular fractures are still more infrequent, but when they are associated, they are life threatening. To distinguish pelvic fractures in children from those in adults, one first needs to know their anatomical differences. The magnitude of the trauma can usually cause injuries in other organs and systems, including the abdominal organs, the genitourinary system, vascular and nerve injuries, etc., as well as long bone, spinal and chest fractures. These injuries may be life threatening and must be treated before the pelvic fracture is addressed. OBJECTIVE: To show the results obtained from the surgical treatment of Torode and Zieg type IV pelvic fractures. METHODS: This is a retrospective, observational, longitudinal, descriptive study of 26 patients with Torode and Zieg type IV unstable pelvic fractures during a two-year period. RESULTS: The age group 14-16 years was the most affected one, with 83.3% of the fractures, followed by the 12-14 years group with 8.33% and the group under this age with 8.33%. The most frequent mechanism of injury was trauma resulting from being run over, with 41.66%, car crash with 37.5%, and falls from a height with 20.83%; 37.5% of patients were polytraumatized and required intensive care; the mortality rate in the study was 7.69%. CONCLUSIONS: According to the results and the patient assessment, we propose that unstable pelvic fractures be managed surgically. The mechanism of injury observed in these patients was not lateral compression, as the literature states, but rather a combined mechanism. PMID- 21246807 TI - [Hand reconstructive surgery secondary to giant cell tumor]. AB - The giant cell tumor of the bone is a neoplastic low grade lesion that usually appears in the epiphyseal or metaphyseal region of the long bones. The lesion is usually solitary and becomes symptomatic when a considerable proportion of the bone has been destroyed. It is thought to represent approximately 19% of the benign bone tumors and 9% of all the primary bone tumors, according to a review by Schajowicz. The treatment of the giant cell tumor is controversial and the literature is confusing. The giant cell tumor is located mainly in the hand. Its potential aggressiveness makes us consider it in the differential diagnosis of the tumor lesions affecting the hand. The proposed treatment should try to preserve function to the extent possible but, at the same time, it needs to be radical enough to prevent a possible relapse. The purpose of this research work is to describe our experience with the treatment of the giant cell tumor in three cases that presented as a lytic, expansive lesion affecting the bones of the hand. They were treated with tumor resection and a bone graft to fill the defect. All three patients had a favorable course. PMID- 21246809 TI - [When the surgeon was recognized as a doctor]. PMID- 21246808 TI - [Bone manifestations of Gaucher's disease in Mexican patients]. AB - Gaucher's disease (GD) is the most common of the lysosomal storage diseases (LSDs) that have been defined so far. Its incidence rate is quite low, but its organ involvement profile is disrupting as it results in a considerable morbidity and mortality rate, as well as in high health care costs and poor quality of life. It is a recessive and autosomal genetic disease associated with the insufficiency of the enzyme glucocerebrosidase. The storage of the substrate produces considerable organ deterioration in the skeleton, liver, kidneys, lungs, spleen, brain and bone marrow. This report presents several clinical cases of Mexican patients characterized by bone damage with the purpose of disseminating among orthopedic surgeons the typical findings and course of the disease. The particularities of the patients are discussed, as well as their response to enzyme replacement therapy (ERT) and the results of their clinical follow-up with the latest therapeutic resources. PMID- 21246810 TI - [Investigation of fungal populations in seven ochratoxin A contaminated root herbs]. AB - OBJECTIVE: To determine the fungal populations in seven ochratoxin A contaminated root herbs in Jiangxi province, and investigate the mycoflora associated with mycotoxin contamination in the root herbs. METHOD: Single spore isolation was used to obtain the strains from root herb's surface. Fungi were identified according to morphology and molecular evidence. RESULT: Seventeen fungal species belonged to six isolated genera, nine species of Penicillium, three species of Aspergillus, two species of Fusarium and three other species were identified. CONCLUSION: Fungal contamination of root herbs demands urgent attention, ochratoxin A producing fungi possess specific distribution on herbs. PMID- 21246811 TI - [Physiologic characteristics of Panax notoginseng seeds during after-ripening process]. AB - OBJECTIVE: The studies were carried out on the physiologic characteristics of Panax notoginseng seeds during the after--ripening process in order to understand the seed's biochemical and physiological changes and lay the foundation for the germplasm conversation and breeding research of P. notoginseng seeds. METHOD: Dynamic changes of storage material contents, respiratory rate and protective enzymatic activity were determined by normal biochemical and physiological measuring methods. RESULT: The respiratory rate increased continuously during the stratification process, the contents of starch, soluble protein, crude fat decreased and the content of water-soluble saccharide increased with the embryo development, activities of CAT, POD and SOD increased with the raise of MDA content. CONCLUSION: P. notoginseng seed's biochemical and physiological changes interacted with its embryo morphological changes to complete its after-ripening development. PMID- 21246812 TI - [Delphi-based study on scientificity of organoleptic evaluation for rhubarb commercial specification]. AB - OBJECTIVE: In this study the reliability and scientificity of organoleptic evaluation for the commercial specification of Chinese medicinal materials (CMM) was investigated with Delphi method, using rhubarb as an example. The consensus panel of panelists being expert in organoleptic evaluation for CMM was cogitatively selected, with high average authority index of 0.81. The average individual repeatability of selected panelists was 85%, while the group repeatability was above 70%. It was found that the career time of the expert had significant influence on the evaluation result (P < 0.05), which suggested that practice makes repeatability. Some panelists of different career type and education background concluded different results, but no statistical significance was found. Furthermore, four predominant organoleptic parameters, shape, color, texture and section characteristics, were selected based on statistics and panelists' discussion to judge the commercial specification of rhubarb. In conclusion, we firstly demonstrated the organoleptic evaluation is an objective and repeatable approach to judge the commercial specification of CMM; and we recommend Delphi method to do validation and standardization for the conventional experiences of traditional Chinese medicine. PMID- 21246813 TI - [Distribution of chemical constituents in Changium smyrnioides]. AB - OBJECTIVE: To analyze the distribution of chemical constituents in different parts of Changium smyrnioides. METHOD: The content of polysaccharides, mannitol and choline was determined by colorimetry and the water-soluble components was determined by HPLC. similarity coefficient of water-soluble components was calculated by the included angle cosine method. RESULT: The Contents of chemical constituents were significantly different between the leaves and the roots. The contents of choline and polysaccharides in the roots was higher than those in the leaves, but the contents of water-soluble extract and physiological ash in the leaves was higher than those in the roots. Contents of chemical constituents were also significantly different at different segments in the root, which decreased from the upper to the lower parts, increased from the outside to the inside parts except physiological ash, and the difference in horizontal segments was higher than that in vertical segments. Total peak area of water-soluble components in the leaves was 2.81 times higher than that in the roots, and gradually increased from the outside to the inside parts. CONCLUSION: Total content of chemical constituents in the leaves was significantly higher than that in the roots. The quality of medicinal used parts decreased gradually from the inside to the outside parts and from the upper to the lower parts in the root of Ch. smyrnioides. PMID- 21246814 TI - [Comparison of rutin and syringin content between tissue culturing seedlings and botanical drug of Saussurea involucrata]. AB - OBJECTIVE: To compare the rutin and syringin content in tissue culturing seedlings and in botanical drug of Saussurea involucrata. METHOD: The HPLC with Hydro-RP C18 (4.6 mm x 250 mm, 5 microm) column was used, a mixture of acetonitrile-water (5:95) was used as a mobile phase, with flow rate of 1 mL x min(-1), column temperature at 25 degrees C and detection wavelength at 220 nm. RESULT: The effective constituents of tissue culturing seedlings were almost similar to the botanical drug. And syringin in tissue culturing seedlings was increased 4.35 times. CONCLUSION: It has a good prospect to acquire high-quality S. involucrata by tissue culturing seedlings. PMID- 21246815 TI - [Research on growth state and physiological changes of Epimedium wushanense under different shade conditions]. AB - OBJECTIVE: To study the growth state and physiological changes of Epimedium wushanense under different light conditions (100%, 80%, 60%, 40%, 20%), and investigate its adaptation mechanism to shade environment so that it can provide theoretical basis for cultivation and production. METHOD: The growth index, the content of photosynthetic pigments, proline content, MDA content, soluble sugar content, soluble protein content and antioxidant enzymy activity of E. wushanense under different shade conditions were measured. RESULT: Except for length/width, the other form index of E. wushanense changed significantly. The E. wushanense grew well between light intensity 80%-40%, besides, the biomass above the earth was relatively high. The chlorophyll a, chlorophyll b, total chlorophyll content and carotenoids cotent were enhanced after shaded, the values of chlorophyll a?chlorophyll b increased between light intensity 100% -60% and reduced between light intensity 60% -20%. The proline and MDA content decreased after shading, the soluble sugar and soluble protein content increased respectively between light intensity 100% -60%, 100% -40% and reduced respectively between light intensity 60% -20%, 40% -20%. The SOD activity, CAT activity decreased after shading, and the POD activity, APX activity reduced between light intensity 60% 40%, raised under 20% treatment. CONCLUSION: 80% 40% irradiance treatment was favorable to the growth of E. wushanense. PMID- 21246816 TI - [Absorption transport mechanism of puerarin oil-in-oil nanoemulsion]. AB - OBJECTIVE: To investigate the mechanisms of the oil-in-oil nanoemulsions transport through the gastrointestinal tract and the transport efficiency changed with its different particle size in the lymphatic channels. METHOD: The behavior of nanoemulsions in vivo and their absorption via lymph after oral administration was investigated, with the transport efficiency and absorption pathway of nanoemulsions clarified by lymph duct cannulation in rats. RESULT: It suggested about 36.8% of puerarin nanoemulsions was transported into systematic circulation via lymph. Nanoparticles with different size absorbed by the lymphatic channels varied as the degree of transportion. CONCLUSION: The degree of absorption and particle transport is inversely proportional to the size. PMID- 21246817 TI - [Preparation of Ganoderma lucidum polysaccharides and triterpenes microemulsion and its anticancer effect in mice with transplant Heps tumors]. AB - OBJECTIVE: To research the microemulsion preparation of Ganoderma lucidum polysaccharides and triterpenes and investigate its properities. Evaluate the effects of polysaccharides and triterpenes microemulsions against transplant tumor growth. METHOD: The microemulsion formula was optimized by constructing the pseudo-ternary phase diagrams of blank microemulsion. The polysaccharides and triterpenes microemulsions were prepared on the blank microemulsions. The appearance, particle distribution and Zeta potential were investigated by transmission electron microscope and grain size analyzer. The Heps mice were randomly administered with polysaccharides and triterpenes microemulsions (114.5, 57.25 mg x kg(-1) x d(-1)) for 7 days. The effectiveness was assessed based on tumor inhibitory ratio of mice with Heps tumors. The toxicity was evaluated by measurements of the mice weight, immune organ weight. RESULT: The optimal microemulsion formula was composed of tween 20, dimethyl carbinol, water and 9 octadecenoic acid with the ratio of 14.3: 14.3: 33. 3:2. Polysaccharides and triterpenes microemulsions in transmission electron microscope were consisted of small spherical drop. The average particle size was 32.43 nm and the Zeta potential was -3.41 mV. The polysaccharides and triterpenes microemulsions showed an inhibition rate of 37.66% (57.25 mg x kg(-1) x d(-1)) and 52.34% (114.5 mg x kg(-1) x d(-1)) respectively against Heps tumor growth. CONCLUSION: The acquired microemulsion with small particle size is stable. It significantly inhibits the tumor growth in Heps mice. PMID- 21246818 TI - [Effect of processing on metabolism of amygdalin from bitter almond in rat]. AB - OBJECTIVE: To study the influence of processing on metabolism of the main component of bitter almond-amygdalin in rat. METHOD: The blood was collected at different times after amygdalin given by injection and oral, bitter almond and its processed production given by oral respectively, and then detected by both HPLC and HPLC-MS(n) methods after extraction pretreatment. RESULT: After injection, amygdalin was absorbed in prototype to blood rapidly, while the other three kinds of medicine given by oral were all not detected the prototype of amygdalin, but two metabolites were detected which were isomers of prunasin confirmed by mass spectrometry. The metabolic pathway of prunasin in processed bitter almond group was markedly different from the bitter almond group. CONCLUSION: Processing has a significant effect on bitter almond metabolic processes in rats. PMID- 21246819 TI - [Simultaneous determination of nine isoflavonoids in Huangqi Gegen decoction by high performance liquid chromatography]. AB - OBJECTIVE: To develop a reversed-phase high performance liquid chromatographic method (RP-HPLC) for the simultaneous analysis of nine isoflavonoids in Huangqi Gegen decoction. METHOD: HPLC determination was performed on a Kromasil C18 column(4.6 mm x 250 mm, 5 microm) and detected at 250 nm. The mobile phase was consisted of methanol and 0.1% citric acid solution with gradient elution. Flow rate was 1.0 mL x min(-1), and column temperature was 25 degrees C. RESULT: The method was proved to be linear in the ranges of 81.28-406.4, 670.4-3 352, 136.96 684. 8, 33.376-166.88, 22.848-114.24, 10.176-50.88, 31.04-155.2, 44.544-222.72, 26.56-132.8 ng for the nine isoflavonoid, 3'-hydroxypuerarin, puerarin, daidzin, calycosin-7-O-beta-D-glucoside, genistin, ononin, daidzein, calycosin and formononetin respectively. The average recoveries were 99.27%, 102.38%, 98.46%, 103.06%, 101.29%, 99.71%, 102.28%, 97.89% and 100.78%, respectively, RSD was 1.8%, 2.0%, 1.4%, 1.4%, 1.3%, 1.8%, 1.3%, 0.97% and 1.8%, respectively. CONCLUSION: Results obtained show that it's a convenient, accurate and reliable method. The method has been successfully applied to the simultaneous determination of the nine isoflavonoids in Huangqi Gegen decoction. PMID- 21246820 TI - [Optimization of extraction process of total amino acid from Bubali Cornu by orthogonal test]. AB - OBJECTIVE: To optimize the extraction conditions of the total amino acid from Bubali Cornu. METHOD: An orthogonal test of L9 (3(4)) was designed to select optimum exaction conditions of the total amino acid. The influence of solvent concentration, the dosage of solvent and time of extraction were investigated with the content of total amino acid and thrombin-induced fibrin clotting time as index. RESULT: The optimum extraction condition procedure was described as follows: the concentration of the solvent was 4 mol x L(-1), volume of solvent was 6 times amount of the materials. CONCLUSION: The optimum exaction conditions procedure is reasonable and stable. PMID- 21246821 TI - [Simultaneous determination of five effective components in Rhizoma Chuanxiong by RP-HPLC]. AB - OBJECTIVE: To develop a RP-HPLC method for the simultaneous determination of five components including ligustrazine, ferulic acid, butylphthalide, ligustilide and butene-NBP in Rhizoma Chuanxiong, a Chinese herbal medicine. METHOD: The chromatographic analysis was carried out by using a grace smart RP C18 column with the mobile phase consisted of acetonitrile and 0.1% phosphoric acid (volume fraction), which was in gradient elution. A DAD detector was used to detect the components. The peak area was chosen under their maximum absorption wavelength for different components, and quantitated by using the external standard method. RESULT: The calibration curves were linear within the range of 0.008 35-0.668, 0.020 6-1.648, 0.012 2-0.976 , 0.050 75-4.06, 0.015 7-1.256 microg for ligustrazine, ferulic acid, butylphthalide, ligustilide and butene-NBP, respectively. The average recoveries of the five components were 101.98%, 99.91%, 96.94%, 100.85% and 99.04%, respectively. CONCLUSION: This method is simple, quick, reproducible, with high recovery, and has been successfully applied to the simultaneous determination of the five components in Rhizoma Chuanxiong. This method can be used to control the quality of Rhizoma Chuanxiong and its preparations. PMID- 21246822 TI - [Phenolic constituents from stem bark of Morus wittiorum and their anti inflammation and cytotoxicity]. AB - To search for the chemical constituents possessing anti-inflammatory or cytotoxic activities from plants, Morus wittiorum was investigated for the first time. The stem bark of M. wittiorum was extracted with 95% EtOH. The EtOH extract was fractionationed on silica gel by eluting with petroleum ehter, CHCl3 and EtOAc successively. The further isolation and purification of the EtOAc fraction of 95% EtOH extract was performed by various column chromatography such as silica gel, Sephadex LH-20, RP-C18 column chromatography and so on. The structures of compounds were determined on the basis of spectral analysis such as NMR, MS etc. As a result, nine compounds were isolated including six flavonoids and three stilbenoids and elucidated as quercetin (1), 5, 7, 3', 4'-tetrahydroxy-3 methoxyflavone (2), norartocarpanone (3), dihydrokaempferol (4), euchrenone a7 (5), morachalcone A (6), resveratrol (7), oxyresveratrol (8), 4' prenyloxyresveratrol (9). Compounds 1-9 were isolated from this plant for the first time, among which compounds 1-8 were evaluated for their anti-inflammatory and cytotoxic activities, respectively. Wherein compounds 6 and 8 showed inhibition to the release of beta-glucuronidase from rat polymorphonuclear leukocyte (PMNs) induced by platelet activating factor (PAF) at a concentration of 10(-5) mol x L(-1). The inhibitory ratios were 76.8%, 94.2% individually. Compounds 2 and 8 exhibited selective cytotoxicity agaist human ovarian cancer (A2780) and human gastric cancer (BGC-823) with IC50 values as 0.66, 1.31 micromol x L(-1) individually. PMID- 21246823 TI - [Nonvolatile chemical constituents from Pogostemon cablin]. AB - OBJECTIVE: To investigate the nonvolatile chemical constituents from the ethanol extract of the stems of Pogostemon cablin. METHOD: The constituents were isolated and purified by repeated column chromatography on silica gel and Sephadex LH-20. Their structures were identified by physicochemical properties and spectroscopic analysis. RESULT: Twelve compounds were isolated and identified as tilianin (1), diosmetin-7-O-beta-D-glucopyranoside (2), 3"-O-methylcrenatoside (3), uracil (4), soya-cerebroside I and II (5), agastachoside (6), apigenin-7-O-(3", 6"-di-(E) -p coumaroyl) -beta-D-galactopyranoside (7), 5-hydroxy-3, 3', 4', 7- tetramethoxy flavone (8), 4', 5-dihydroxy-3, 3', 7-trimethoxyflavone (9), acacetin (10), crenatoside (11), isocrenatoside (12). CONCLUSION: Compounds 1, 2, 4-7, 10 were isolated from the genus Pogostemon for the first time. PMID- 21246824 TI - [Chemical constituents of Indigofera pseudotinctoria]. AB - OBJECTIVE: To study the chemical constituents in the roots of Indigofera pseudotinctoria. METHOD: The constituents were isolated by column chromatography and their structures were elucidated by spectroscopic methods. RESULT: Fourteen compounds were isolated from the ethanol extract of the plant and identified as maackiain (1), 3beta-hydroxy-olean-9 (11), 12-diene (2), 12-oleanen-3,11-dione (3), 3beta-acetoxy-12-oleanen-11 -one (4), formononetin (5), formononetin-7-O beta-D- glucoside (6), 7,4'-dihydroxy-3'-methoxy isoflavone (7), afromosin (8), genistein (9), calycosin-7-O-beta-D-glucoside (10), vicenin-2 (11), isoliquiritigenin (12), beta-sitosterol (13), and daucosterol (14). CONCLUSION: All compounds were isolated from the plant for the first time, eleven compounds (except 1, 13 and 14) were isolated from the genus Indigofera for the first time. PMID- 21246825 TI - [Simultaneous assay of four isoflavonoids in Astragali Radix by QAMS]. AB - Based on the complexity of the chemical constitutions in traditional Chinese medicines (TCMs), multi-components analysis used for the quality control of TCMs is more scientific and reasonable. However, routine quality control of TCMs by multi-components analysis is limited for the shortage of various chemical reference substances. Herein, the method of quantitative analysis of multi components by single marker (QAMS) was validated and used to simultaneously determine calycosin-7-O-beta-D-glucopyranoside, ononin, calycosin, formononetin in Radix Astragali. Using formononetin as the internal reference substance, the relative correction factors (RCFs) of the other three isoflavonoids were calculated by HPLC-DAD with good reproducibility in different instruments and chromatographic columns. The other three isoflavonoids in 34 batches of samples were simultaneously calculated according to their RCFs. The results of QAMS method were not significantly different from that of external standard method (RSD < 3.5%). It is accurate and feasible to evaluate the quality of Radix Astragali by QAMS. PMID- 21246826 TI - [Rapid assessment of volatile components in Baicao oils by headspace single drop microextraction coupled with gas chromatography]. AB - A simple, fast GC method based on headspace single drop microextraction (HS-SDME) was used for the determination of menthol and methyl salicylate in Baicao oils. A special sample pretreatment method was performed by adding 10 microL the oil its methanol solution into 5 mL water in a caped 10 mL sample vial, a 1.5 microL microdrop of N,N-dimethylformamide with benzyl alcohol as internal standard was formed on the pinpoint of microsyringe needle, exposing 5 min at extraction temperature of 40 degrees C. After extraction, 0.5 microL of extract was directely injected into GC for analysis. The determination was carried out on a capillary column (0.53 mm x 30 m) with PEG as the stationary phase with FID as the detector. A temperature programm was employed. The excellent separation and detection of the target components was accomplished. The average recoveries varied between 95.4% and 99.2%, and relative standard deviations were less than 1.9%. The calibration curves were linear in the range of 1.26-80.5 mg x L(-1) for menthol (r = 0.999 0) and 2.49-1.59 x 10(2) mg x L(-1) for methyl salicylate (r = 0.999 1), respectively. The proposed method is proved to be simple, fast, accurate and low cost without complicated sample pretreatment HS-SDME is expected to be widely applied for the analysis of volatile components in traditional Chinese medicines. PMID- 21246827 TI - [Simultaneous determination of rutin, isoquercitrin and chlorogenic acid in Farfarae Flos by HPLC]. AB - OBJECTIVE: To develop an HPLC method for simultaneous determination of rutin, isoquercitrin and chlorogenic acid in Farfarae Flos. METHOD: The analysis was carried out on a Phenomenex Synergi POLAR-RP 80A column (4.6 mm x 250 mm, 4 microm) with gradient elution using methanol-acetonitrile-water (adjusted to pH 2.5 with formic acid) as mobile phase. The flow rate was 1.2 mL x min(-1) and the detection wavelength was at 255 nm. RESULT: The calibration curves were linear over the range of 0.2-2 000 microg x L(-1) for rutin and isoquercitrin, 10-2 000 microg x L(-1) for chlorogenic acid, respectively. The average recoveries were 99.5% for rutin, 100.1% for isoquercitrin and 99.4% for chlorogenic acid, respectively, with RSD not more than 3.0%. CONCLUSION: The described method is reliable and could be used for the quality control of Farfarae Flos. PMID- 21246828 TI - [Study on establishment of RP-HPLC and GC-MS fingerprints for wild germplasm resource of Ophiopogon japonicus in Sichuan and hierarchical clustering analysis]. AB - The chromatographic fingerprint was established for evaluating and controlling the quality of germplasm resource of Ophiopogon japonicus in Sichuan Basin by reversed-phase high performance liquid chromatography and gas chromatography mass spectrometry. The results showed that each sample the characterized by the peak area of 28 HPLC peaks and 13 GC peaks in each program and these peaks were employed for hierarchical cluster analysis. Furthermore, the discrimination of the sample from different regions was achieved by hierarchical cluster analysis via recognizing the 16 (41 datamatrix. This was the first report of hierarchical cluster analysis of the wild germplasm resource of Ophiopogon japonicus according to their chemical fingerprints. Thus, the results proved it is a simple, rapid and accurate method suitable for the quality control of the traditional Chinese medicines. PMID- 21246829 TI - [Comparative study of effect of Atractylodes lancea between geo-authentic and non authentic producing areas on collagen-induced arthritis in rats]. AB - OBJECTIVE: To compare the effects of Atractylodes lancea from different producing area on collagen-induced arthritis (CIA) in rats. METHOD: Wistar rats were induced by type II bovine collagen. CIA rats were treated daily with oral administration of A. lancea from the geo-authentic and non-authentic producing area of Maoshan, Jiangsu province, and non-geo-authentic and non-authentic producing areas of Yingshan, Hubei province and Huayin, Shanxi province from day 7 after the day of the first immunization to day 35. Clinical symptoms as well as clinical scores and incidence were observed. All rats were sacrificed on day 35 after immunization to observe histopathologic and radiologic changes. Antibody to type II collagen in sera was measured by enzyme-linked immunosorbent assay (ELISA), the levels of pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) in sera and article-homogenated supernants by radiommunoassay, and inflammatory mediator of PGE2 in sera using ELISA. RESULT: A. lancea from Jiangsu province can ameliorate clinical symptom, reduce arthritis index and arthropathy of inflammatory joints, inhibit the production of IgG and IgM in sera, directly suppress the production of exogenous and endogenous cytokines of IL-1beta, TNFalpha and IL-6 and PGE2. A. lances from Hubei and Shanxi provinces can inhibit the production of IgM in sera, and A. lanceas from Hubei province also depress the production of IL-1beta in sera and IL-6 in supernants. CONCLUSION: A. lancea from Jiangsu province is effective in CIA rats through inhibiting the production of pro-inflammatory cytokines and the inflammatory mediators. PMID- 21246830 TI - [Astragalus injection ameliorates cisplatin-induced nephrotoxicity in mice]. AB - OBJECTIVE: To examine the protective effects of Astragalus injection (AI) on cisplatin (DDP)-induced nephrotoxicity and to explore the mechanism of its nephroprotection. METHOD: The S180-bearing model was established, and fifty mice were randomly divided into five groups: control mice, DDP-injected mice (3.5 mg x kg(-1)) and AI-pretreated mice (12, 8, 4 g x kg(-1)). Tumor inhibition rate, renal functions, histological findings were investigated. The apoptotic cells were counted by TUNEL and the presence of Bax, Bcl-2 in renal tissues was determined by immunohistochemistry. RESULTS: Administration of DDP or DDP plus AI showed promising anti-tumor activities as compared with control group. Interestingly, a combination of DDP and AI (12, 8 g x kg(-1)) led to enhanced tumor growth inhibition as compared with DDP alone (all P < 0.05). Compared with that from control, the number of TUNEL-positive cells and the Bax/Bcl-2 ratio was increased significantly in the kidneys of DDP treated mice (P < 0.05). High-dose AI pretreatment significantly reduced the elevated number of TUNEL-positive cells and the Bax/Bcl-2 ratio (P < 0.05), and it showed a superior nephroprotective effect than any other dose. AI significantly also decreased both the damage to renal function and histological pathology. CONCLUSION: Pre-treatment with AI attenuates cisplatin-induced nephrotoxicity without compromising the anti-tumor efficacy of DDP, which might be involved in regulating the Bax and Bcl-2 expression. PMID- 21246831 TI - [Investigation of differences between cold and hot nature of Mahuang decoction and Maxing Shigan decoction based on cold/hot plate differentiating assay]. AB - OBJECTIVE: To investigate the objectivity and authenticity of the difference of the Cold and Hot nature between Mahuang decoction and Maxingshigan decoction based on the cold/hot plate differentiating assay. METHOD: The measuring time and dosage of Mahuang decoction and Maxingshigan decoction were investigated before the compliance experiment. Meanwhile, the activities of adenosine triphosphatase were detected in order to probe into the mechanism of their action. RESULT: It was found that the drug dose should be 10 times amount to human dose (0.80 g x kg(-1) of Mahuang decoction and 2.26 g x kg(-1) of Maxing Shigan decoction) and the measuring time should be from 30 min to 60 min after administering. Compared with the control group, the remaining ratio of the mice treated with Mahuang decoction on the hot pad significantly decreased (P < 0.01). Compared with Mahuang decoction, the remaining ratio of the mice treated with Maxingshigan decoction on the hot pad significantly increased (P < 0.05). Compared with the control group, the Na(+) -K(+) -ATPase activity of liver tissue of the mice treated by Mahuang decoction significantly increased (P < 0.05), while the activity of Na(+) -K(+) -ATPase and Mg(2+) -Ca(2+) -ATPase of liver tissue of the mice treated by Maxingshigan decoction reduced significantly (P < 0.05). CONCLUSION: This study showed that the differences of Cold and Hot nature of Mahuang decoction and Maxingshigan decoction were objectively existent from animal ethology, which was consistent with the traditional theroy of Chinese medicine. And the changes of ATPase activity of liver tissue might be the mechanism of drug action. PMID- 21246833 TI - [Effect of lyophilized powder of Sini powder on 5-HT content and 5-HT(1A) receptor in drosophila heads]. AB - OBJECTIVE: To unveil the mechanism of sleep-improving effect of lyophilized powder of Sini powder on drosophila. METHOD: Drosophila melanogaster whose strain were wild Canton S, unmated, were collected daring 12 h after their emergencing, then they were anaesthetized by small flow of CO2 and divided into different tubes due to their sex. Both male and female flies were distributed randomly into three groups as blank, control and administration, 32 flies each group. The content of 5-HT in the brain was estimated was estimated with ELISA and had a comparison of the expression of 5-HT(1A) receptor in brain, using real-time quantitative PCR. RESULT: Concentration of 5-HT in brain was increased in administration group, and had a significant difference to control group. The expression of 5-HT(1A) receptor was also up-regulated after administrated of Sini powder. CONCLUSION: Sleep-improving effect of Sini powder on drosophila has a contribution to the increasing of 5-HT and 5-HT(1A) receptor in brain. PMID- 21246832 TI - [Permeability of blood-brain barrier oxygen-glucose deprivation induced by tetramethylpyrazine-puerarin in vitro]. AB - OBJECTIVE: To explore permeability of artificial blood-brain barrier (aBBB) by oxygen-glucose deprivation combined (OGD)-induced using tetramethylpyrazine combined with puerarin in vitro. METHOD: Rats were divided into normal control group, model group, tetramethylpyrazine group, puerarin group, tetramethylpyrazine-puerarin group and nimodipine group. Culture rat brain microvascular endothelial cells and astrocytes in vitro and build the OGD-induced aBBB damage model. Evaluate aBBB damage characteristics by TEER, gamma-GT, AKP and LDH. Determine contents of tetramethylpyrazine, puerarin, nimodipine and calculate drug permeating concentration of OGD-induced aBBB model by HPLC. RESULT: Compared with the model, the level of TEER was lower than the control group with significant difference (P < 0.01). The levels of gamma-GT, AKP in tetramethylpyrazine group, tetramethylpyrazine-puerarin group and nimodipine group were higher than the model group, the differences were significant (P < 0.01). Compared with tetramethylpyrazine group or puerarin group, the level of AKP of tetramethylpyrazine-puerarin group increased significantly (P < 0.01). The differences of levels of TEER, gamma-GT, AKP and LDH between tetramethylpyrazine puerarin group and nimodipinthe group were significant (P < 0.05). Tetramethylpyrazine-puerarin group has a synergistic effect of increasing TEER, gamma-GT, AKP and reducing LDH. The permeating rate in tetramethylpyrazine puerarin group was higher than tetramethylpyrazine group and puerarin group. CONCLUSION: Tetramethylpyrazine-puerarin can permeate aBBB more easily and protect aBBB. The cause may relate to reducing the permeability of the OGD induced aBBB. PMID- 21246834 TI - [Effect of ferulic acid on proliferation and mechanism in human breast cancer cells]. AB - OBJECTIVE: To investigate phytoestrogenic effects of ferulic acid in ER-positive T47D and ER-negative MDA-MB231 cells in culture. METHOD: T47D and MDA-MB231 human breast cancer cells were treated with ferulic acid and examined cell proliferation by means of MTT assay. Cell cycle distribution, ERalpha and ERbeta expression were treated by flow cytometer. The pS2 mRNA expressions were detected by real-time fluorescence quantitative PCR. RESULT: The proliferations were enhanced significantly by treatment with ferulic acid on T47D cells and the proliferation effects were inhibited by adding Faslodex (1 x 10(-8) mol x L(-1)). However, there was no significant difference on the proliferation in MDA-MB-231 cells compared with solvent control group by both treatment with ferulic acid and co-treatment with Faslodex (1 x 10(-8) mol x L(-1)). Ferulic acid stimulated the amount of T47D cells in phase S and proliferation index increased significantly. The effects were inhibited by treatment with Faslodex (1 x 10(-8) mol x L(-1)), and the amount of cells in phase S and proliferation index decreased, the amount of cells in G0/G1 phase increased, cell cycle of T47D was arrested in G0/G1 phase. Ferulic acid up-regulated pS2 mRNA expressions and increased the level of ERalpha protein expression in T47D cells. Ferulic acid did not show remarkable effect to the level of ERbeta protein expression in T47D cells. CONCLUSION: Ferulic acid possessed phytoestrogenic effect by up-regulating pS2 gene expression and the receptor subtype of ERalpha. PMID- 21246835 TI - [Study of immunogenicity of chlorogenic acid-BSA with different number of CGA]. AB - OBJECTIVE: To investigate the immunogenicity of chlorogenic acid-BSA(CGA-BSA) and the foundation for the allergization of CGA-BSA. METHOD: The CGA-BSA with different number of CGA was synthesized to allergize the BALB/c mice and SD rats to get antiserum. The level of IgE and histamine was analyzed by ELISA, and the passive cutaneous anaphylaxis (PCA) test was carried to analyze the antibody titer. RESULT: When the coupling rate of CGA-BSA is 20, the highest IgE and histamine level in BALB/c mice and the antibody titer in PCA are the highest. CONCLUSION: It has better immunogenicity when the coupling rate of CGA-BSA is between 10 to 20, while the CGA-BSA 20 with the best immunogenicity. PMID- 21246836 TI - [Effect of assemble flavone of Drynariae Rhizome on activity and calcium deposition of bone marrow stem cells of rabbit]. AB - OBJECTIVE: To observe the effect of assemble flavone of Drynariae Rhizome on the activity and osteogenic differentiation of bone marrow stem cells of rabbit in vitro. METHOD: Density gradient centrifugation was used to isolate bone marrow stem cells from SD rats. The MSCs were also undergone osteogenic induction. Cytochemical and immunocytochemical tainting were performed to verify their multipotential. RESULT: High purity of bone marrow stem cells was successfully obtained. Both ALP activity and mineralization nodes tainting were positive in MSCs after osteogenic differentiation. CONCLUSION: The MSCs sustained their osteogenic differentiation potential in vitro by assemble flavone of rhizome drynaria. PMID- 21246837 TI - [Effect of rhein treatment on first-phase insulin secretory function in db/db mice]. AB - OBJECTIVE: The aim of the present study is to investigate the effect of rhein treatment on the first-phase insulin secretory function in db/db mice. METHOD: Twenty 4-week-old male db/db mice were randomized to treatment with rhein (120 mg x kg(-1), n = 10) and placebo respectively (1% natrium cellulose solution, n = 10) by gavage for 8 weeks respectively. Ten age-matched non-diabetic male littermates db/m mice treated with placebo were studied as non-diabetic control. Body weight and fasting blood glucose level were measured before and after medication. The islets were isolated after 8 weeks' gavage. Islet perifusion system was set up, and all columns were perfused in parallel at a flow rate of 0.5 mL x min(-1) with KRB (2.8 mmol L(-1) glucose) at 37 degrees C. After 60-min static incubation with KRB (2.8 mmol x L(-1) glucose), the islets were stimulated in the continuous presence of a high concentration of 16.7 mmol x L(-1) glucose. Samples were collected every 20-second until 2-min, every 1-min until 5-min, thereafter every 5-min until 30-min. Samples were immediately stocked at -80 degrees C until further analysis. RESULT: Compared with the db/db control group, the fasting glucose concentration was significantly decreased in the rhein treatment group. The first-phase insulin secretory function was impaired significantly in db/db mice, while the first-phase insulin secretory peak was obvious in the rhein treatment mice. CONCLUSION: Rhein treatment significantly improved glucose tolerance, restored the first-phase insulin secretion and protected the islets function. PMID- 21246838 TI - [Preventive effects of berberine on experimental colon cancer and relationship with cyclooxygenase-2 expression]. AB - OBJECTIVE: To investigate the anti-colon cancer effects of berberine and possible relationship with cyclooxygenase-2. METHOD: Wistar rat colon cancer model was induced by 1-2 dimethylhydrazine (DMH) (40 mg x kg(-1), sc) + 1% dextran sodium sulfate solution (DSS) (freely drinking). All rats were randomly divided into 3 groups: Control (DMH + DSS + solvant), meloxicam (Mel) (DMH + DSS + Mel 1.35 mg x kg(-1)), berberine (Ber) (DMH + DSS + Ber 100 mg x kg(-1)). The drugs were given orally once a day for 5 day per week. The body weight, the number of colon ACFs, the incidence and number of colon cancer in rats, as well as the morphological changes of rat colon tissues were evaluated. Human colon cancer lovo cell line was treated by either Ber or Mel in various concentrations (1 10(-6) mol x L(-1), 1 x 10(-5) mol x L(-1), 1 x 10(-4) mol x L(-1), 1 x 10(-3) mol x L(-1)) for 6, 12 and 24 h, respectively, and the cell growth was assayed by MTT method. RT-PCR and western-blot were used to evaluate the mRNA and protein expressions of COX-2 from lovo cells treated with Ber and Mel. RESULT: Ber significantly improved the dyscrasia induced by DMH + DSS, the both of body weight and general condition were better than control group. Ber also significantly inhibited ACF and colon cancer incidence in the rats treated by DMH + DSS for 10 weeks or 20 weeks, which was similar to that of Mel. Ber inhibited the proliferation of lovo cells in concentration- and time-dependent manners, and the IC50 values were significantly smaller than that of Mel at 6, 12 and 24 h after lovo cells were treated by either Ber or Mel. Ber also concentration-dependently decreased expressions of COX-2 mRNA and COX-2 protein from lovo cells. CONCLUSION: Ber can inhibit ACF and tumor formation induced by DMH + DSS, and decrease the lovo cell proliferation index. The anti-tumor effects of Ber may involve in an unknown pathway through which the expressions of COX-2 mRNA and protein were inhibited. PMID- 21246839 TI - [Pharmacological effects of Bailing capsule and its application in lung disease research]. AB - Cordyceps sinensis is a medicinal fungus of Traditional Chinese Medicine. There are a wide range of reported uses of Cordycep sinensis in the literature. However, the production of Cordyceps sinensis is so limited that can not be widely used. Cultured Cordyceps sinensis (Bailing Capsule) and natural Cordyceps sinensis have similar chemical composition. Bailing Capsule possesses anti inflammatory, anti-hypoxia, anti-tumor effect function and regulating the endocrine system, enhanced immune function, which has a protective effect on the kidney, lung, liver and other organs. Recently, Bailing capsule has some beneficial effects on pulmonary diseases, such as COPD, Pulmonary fibrosis, Asthma, which have been gradually applied to the clinical. PMID- 21246840 TI - [Effect of electroacupuncture at Jiaji (EX-B 2) on drug craving of heroin addicts and beta-EP and Dyn-A in plasma]. AB - OBJECTIVE: To explore the clinical effect and mechanism of electroacupuncture at Jiaji (EX-B 2) on drug craving of heroin addicts. METHODS: One hundred and twenty cases of heroin addicts were randomly divided into 4 groups, 30 cases in each. In acupuncture group 1, the Jiaji (EX-B 2) points of T5-T7 and Shenshu (BL 23) were selected with electroacupuncture; in acupuncture group 2, Neiguan (PC 6), Shenmen (HT 7) and Zusanli (ST 36) etc. were selected with electroacupuncture; in simulation group, Zusanli (ST 36) and Sanyinjiao (SP 6) were selected with analog electrical stimulation, and in blank group no any therapy was applied. The changes of drug craving were evaluated by Visual Analogue Scale (VAS) and the changes of beta-EP and Dyn-A in plasma before and after treatment were tested by radioimmunoassay. RESULTS: The relapse rate of 77.3% (17/22) in acupuncture group 1 was lower than those of 88.5% (23/26) in acupuncture group 2, 90.5% (19/21) in simulation group and 95.7% (22/23) in blank group (all P < 0.05). At the 8th and 10th week of treatment, the VAS scores in acupuncture group 1 and 2 were much lower than those in blank group and simulation group (all P < 0.01); in which, it was lower in acupuncture group 1 than that in acupuncture group 2 (P < 0.05), and lower in simulation group than that in blank group. After 10 weeks of treatment, compared with the status before treatment, beta-EP and Dyn-A in plasma were increased in acupuncture group 1 and 2 (P < 0.05, P < 0.01), Dyn-A was decreased in both simulation and blank groups (both P < 0. 01) which was less obvious than those in both acupuncture groups (both P < 0.01) and superior in acupuncture group 1 than that in group 2 (P < 0.05). CONCLUSION: Electroacupuncture at Jiaji (EX-B 2) can suppress the drug craving and reduce the relapse rate, and the mechanism may be related with the content of beta-EP, especially the increase of Dyn-A in plasma. PMID- 21246841 TI - [Comparative observation on therapeutic effect of chronic persistent bronchial asthma treated with heat-sensitive moxibustion and medication]. AB - OBJECTIVE: To probe a better therapy for chronic persistent asthma. METHODS: Thirty-six cases of chronic persistent asthma were randomly divided into a beat sensitive moxibustion group (17 cases) and a western medication group (19 cases). In heat-sensitive moxibustion group, the sensitization points between Feishu (BL 13) and Geshu (BL 17) were selected with heat-sensitive moxibustion; in western medication group, Seretide inhalant was applied. The patients of both groups were continuously treated for 3 months and the therapeutic effects were evaluated by clinical symptom scores and pulmonary ventilation function test. RESULTS: After treatment, the effective rate of 88.2% (15/17) in heat-sensitive moxibustion group was superior to that of 47.4% (9/19) in western medication group (P < 0.05); the clinical symptom scores and pulmonary ventilation function were obviously improved in the two groups, and the heat-sensitive moxibustion group was superior to the western medication group (all P < 0.05). CONCLUSION: For chronic persistent bronchial asthma, heat-sensitive moxibustion can improve the clinical symptoms and the pulmonary ventilation function, and it is better than Seretide inhalant. PMID- 21246842 TI - [Effect of acupoint injection on erythropoietin resistance in patients with chronic renal failure]. AB - OBJECTIVE: To compare the effect on erythropoietin (Epo) resistance between acupoint injection and subcutaneous injection of rHuEpo in patients with chronic renal failure (CRF). METHODS: Thirty-eight cases were randomly divided into two groups, 19 cases in each one. In subcutaneous injection group (control group), subcutaneous injection of rHuEpo was administered, 3 times a week, lasting 2 months. In acupoint group (observation group), rHuEpo was injected on unilateral Shenshu (BL 23) and Zusanli (ST 36), one point was chosen each time, the bilateral acupoints were injected alternatively, 3 times a week, for 2 months. Meanwhile, a normal control group of 19 healthy persons was set up. The levels of CRP, IL-6, TNF-alpha, Scr, BUN, Hb, Hct and SF were observed. RESULTS: Before treatment, the values of CRP, IL-6 and TNF-alpha in two groups were all higher than those in normal control group (all P < 0.01). After treatment for 2 months, the values of CRP, IL-6,TNF-alpha, Scr and BUN in two groups decreased apparently and those of Hb, Hct and SF increased obviously, indicating statistic significant differences as compared with the values before treatment separately (P < 0.05, P < 0.01). In comparison between two groups after treatment, every index above in observation group was improved much significantly (P < 0.05, P < 0.01). CONCLUSION: Acupoint injection of rHuEpo at Zusanli (ST 36) and Shenshu (BL 23) increases significantly the values of Hb, Hct and SF, and decreases apparently the values of BUN, Scr and inflammatory factors, such as CRP, IL-6 and TNF-alpha as compared with subcutaneous injection. Acupoint injection improves Epo resistance and enhances Epo efficacy via alleviating micro-inflammatory state of the body. PMID- 21246843 TI - [Therapeutic effect on essential hypertension treated with combined therapy of acupuncture and medication]. AB - OBJECTIVE: To explore the mechanism of acupuncture combined with medication for treatment of essential hypertension (EH). METHODS: Sixty cases of EH were randomly divided into a combined acupuncture and medication group (group A) and a medication group (group B), 30 cases in each one, treated with acupuncture in combination with oral administration of Felodipine, and simple oral administration of Felodipine respectively. Before and after treatment, the changes of blood pressure, and the contents of E-selectin (Es), iNOS and eNOS were determined. RESULTS: After treatment, the blood pressure declined in either group. The total effective rate in group A was 86.7% (26/30), which was superior to that of 73.3% (22/30) in group B. After treatment, the plasma Es and iNOS contents in two groups decreased as compared with those before treatment (both P < 0.01), of which, plasma Es content in group A decreased apparently as compared with group B (P < 0.01). After treatment, the content of plasma eNOS increased as compared with that before treatment in group A (P < 0.01). CONCLUSION: The mechanism of acupuncture on anti-blood pressure probably relies on the improvements in vascular endothelial cellular function so that Es, iNOS and eNOS expression can be recovered to normal level and ultimately blood pressure is adjusted. PMID- 21246844 TI - [Effect of acupuncture treatment of relieving depression and regulating mind on insomnia accompanied with depressive disorders]. AB - OBJECTIVE: To compare the therapeutic effects of insomnia accompanied with depressive disorders treated by acupuncture of relieving depression and regulating mind and oral administration of Trazodone. METHODS: Sixty-five cases were randomly divided into a acupuncture group (33 cases) and western medication group (32 cases). In acupuncture group, Shenmen (HT 7), Baihui (CV 20), Hegu (LI 4) and Taichong (LR 3) were selected. In western medication group, Trazodone was applied with oral administration for 4 weeks. The curative effect comparison was carried on by Pittsburgh Sleep Quality Index (PSQI), Self-Rating Depression Scale (SDS), and Side Effect Rating Scale (SERS) of Asberg. RESULTS: The cured and markedly effective rate of 72.7% (24/33)in acupuncture group was superior to that of 46.8% (15/32) in western medication group; after treatment, the scores of all items and the total cumulative scores of PSQI and SDS of both groups were reduced (P < 0.01, P < 0.05), of which, the sleep quality and daytime function evaluation in acupuncture group reduced more obviously than those in western medication group (both P < 0.05); the SERS scores of Asberg in western medication group were higher than those in acupuncture group. CONCLUSION: Acupuncture treatment of relieving depression and regulating mind is superior to Trazodone with oral administration for sleep quality and daytime function, with milder adverse reactions. PMID- 21246845 TI - [Clinical observation on acupuncture for treatment of abdominal postoperative pain]. AB - OBJECTIVE: To compare the therapeutic effects between acupuncture based on syndrome differentiation and analgesic on abdominal postoperative pain. METHODS: One hundred cases of abdominal postoperative pain were randomly divided into two groups, 50 cases in each one. In acupuncture group, the treatment was applied according to meridian differentiation and point selection on the affected meridian. Ashi points near to the incision as the main points and those closely connected with Zangfu functions were selected, such as Yanglingquan (GB 34), Taichong (LR 3) and Zusanli (ST 36), etc. In medication group, muscular injection of Bucinnazine was administered. The severity of pain was evaluated with Visual Analogue Scale (VAS) before and after treatment. RESULTS: The remarkably effective rate in acupuncture group was 60.0% (30/50), which was markedly better than that 28.0% (14/50) in medication group (P < 0.01). VAS scores in 30 min and 4 h after treatment as well as 24 h after operation in two groups were all reduced remarkably as compared with those before treatment (all P < 0.01), indicating the satisfactory analgesia in treatment. VAS scores in acupuncture group were lower apparently than those in medication group in 30 min and 4 h after treatment (P < 0.01,P < 0.05). CONCLUSION: Acupuncture has quick analgesia in treatment of abdominal postoperative pain, which is superior to muscular injection of Bucinnazine because of its advantages of long-term and significant efficacy. PMID- 21246846 TI - [Observation on short and long-term effects of cervical spondylotic radiculopathy treated with abdominal acupuncture plus Long's bone-setting manipulation]. AB - OBJECTIVE: To compare the short and long-term therapeutic effects on cervical spondylotic radiculopathy (CSR) treated with simple Long's bone-setting manipulation, abdominal acupuncture and abdominal acupuncture plus Long's bone setting manipulation. METHODS: One hundred and eighty cases of CSR were randomly allocated into abdominal acupuncture plus bone-setting group (combined therapy group), bone-setting group and abdominal acupuncture group, 60 cases in each group. In combined therapy group, the abdominal acupuncture and Long's bone setting were applied in combination. Abdominal acupuncture was applied to Zhongwan (CV 12), Guanyuan (CV 4), Shiguan (KI 18), Shangqu (KI 17), etc. Long's manipulation, such as bone-setting in head-upward posture and bone-setting in head-lateral posture, was adopted. In bone-setting group and abdominal acupuncture group, Long's bone-setting manipulation and abdominal acupuncture were adopted simply and respectively. The clinical therapeutic effects were compared after 2 courses of treatment (short-term) and 1-month after treatment (long-term) among groups. RESULTS: The short and long-term curative and markedly effective rates in combined therapy group were 80.7% (46/57) and 68.4% (39/57) respectively, which were better than those of 63.64% (35/55), 30.9% (17/55) in bone-setting group and 58.9% (33/56), 50.0% (28/56) in abdominal acupuncture group, separately (all P < 0.05). Moreover, the long-term curative and markedly effective rate in abdominal acupuncture group was superior to that in bone setting group (P < 0.05). CONCLUSION: Abdominal acupuncture plus Long's bone setting manipulation has significant efficacy of either short or long-term on CSR, which is superior to the efficacy of either simple abdominal acupuncture or Long's bone-setting manipulation and indicates superimposed effect. Hence, it is one of the better approaches in CSR treatment. PMID- 21246847 TI - [Comparative study on abdominal acupuncture and western medicine for treatment of menopause depressive disorder]. AB - OBJECTIVE: To observe the therapeutic effects between abdominal acupuncture and Deanxit for treatment of menopause depressive disorder, and to explore the efficacy and safety of abdominal acupuncture. METHODS: Sixty cases were randomly divided into an observation group and a control group, 30 cases in each. The observation group was treated with abdominal acupuncture at Zhongwan (CV 12), Xiawan (CV 10), Qihai (CV 6) and Guanyuan (CV 4), etc. The control group was treated with oral administration of Deanxit. The patients in both groups were treated for 4 weeks and followed up for another 4 weeks, and they were evaluated by Hamilton Depression Scale (HAMD) every couple weeks. RESULTS: The total HAMD scores of 2 and 4 weeks treatments and 2 and 4 weeks follow-up were all reduced in both groups (all P < 0.01). The total scores of 2 and 4 weeks follow-up in observation group were lower than those in control group, with significant differences in statistical analysis (both P < 0.05). Compared with the clinical therapeutic effect of both groups after 4 weeks treatment, there was no significant difference (P > 0.05), however, after 4 weeks follow-up, the therapeutic effect in observation group was superior to that in control group, with significant difference in statistical analysis (P < 0.05). The safety indexes before and after treatment of both groups were normal, and the adverse reaction rate in observation group was much lower than that in control group (P < 0.05). CONCLUSION: Abdominal acupuncture is an effective and safe method for menopause depressive disorder, it improves the menopause depressive symptoms with persistent action, less symptoms relapse and adverse reactions. PMID- 21246848 TI - [Clinical study on acupuncture and Tuina for treatment of birth brachial plexus injury]. AB - OBJECTIVE: To compare the difference of therapeutic effect between acupuncture combined with Tuina and Nobex for treatment of birth brachial plexus injury. METHODS: Forty cases with birth brachial plexus injury were randomly divided into a acupuncture combined with Tuina group (group A) and a Nobex group (group B), 20 cases in each group. The group A was treated with acupuncture at 3 points, i. e. Jianyu (LI 15), Jianliao (TE 14), Jianzhen (SI 9) on shoulder, Binao (LI 14), Shouwuli (LI 13), Quchi (LI 11), etc. combined with Tuina using a single thumb and rolling method, and the group B was treated with intramuscular injection of Nobex. The clinical effects and the changes of the symptom, scores and the electromyogram were observed before and after treatment. RESULTS: The total effective rate of 90.0% (18/20) in the group A was better than that of 55.0% (11/20) in the group B, with a significant difference between the two groups (P < 0.05). The effective rate of the electromyogram improvement in the group A was 90.0% (18/20), which was better than 45.0% (9/20) in the group B (P < 0. 05), and the symptom scores in the group A were lower than those in the group B (P < 0.01). CONCLUSION: Acupuncture combined with Tuina can improve the recovery of nerve and upper extremity function and its therapeutic effect is superior to that of intramuscular injection with Nobex. PMID- 21246849 TI - [Clinical observation on post-stroke shoulder pain treated with balance acupuncture]. AB - OBJECTIVE: To observe the difference of therapeutic effect on post-stroke shoulder pain between balance acupuncture and conventional acupuncture. METHODS: Sixty cases were randomly divided into two groups, 30 cases in each one. In balance acupuncture group, the balance technique of acupuncture was used on Jiantong point. In conventional acupuncture group, the conventional acupuncture was applied to Shuigou (GV 26), Neiguan (PC 6), Tongli (HT 5), Zusanlti (ST 36), Xuanzhong (GB 39) and others, combined with the points on the affected meridians. The Visual Analogue Scale (VAS) was adopted to evaluate the efficacy. RESULTS: Separately, before and after the 1st treatment, VAS scores were 5.62 +/- 0.46 and 5.00 +/- 0.31 in balance acupuncture group (P < 0.01), and those were 5.52 +/- 0.65 and 5.22 +/- 0.29 in conventional acupuncture group (P < 0.05). The improvement in balance acupuncture group was superior to that in conventional acupuncture group (P < 0.05). After 10 treatments (one course of treatment), VAS score was 3.75 +/- 0.67 in balance acupuncture group and was 3.77 +/- 0.62 in conventional acupuncture group, which reduced significantly as compared with those before treatment (both P < 0.01), the difference between two groups was not significant (P > 0.05). CONCLUSION: Either balance acupuncture or conventional acupuncture has significant analgesia on post-stroke shoulder pain. But, the instant analgesia of balance acupuncture is superior to that of conventional acupuncture. PMID- 21246850 TI - [Effects of electric-moxibustion on brain mantle accessed with near-infrared imaging]. AB - OBJECTIVE: To observe the influence of electric-moxibustion at Baihui (GV 20) or Shenque (CV 8) on the cerebral blood flow. METHODS: Twenty healthy volunteer were treated by electric-moxibustion at Baihui (GV 20) or Shenque (CV 8) with multi functional electric-moxibustion instrument. The changes of the forehead cortex blood flow during moxibustion were detected by dynamic continuous spectrum near infrared imaging. RESULTS: There were significant differences as the forehead cortex blood flow after electric-moxibustion at Baihui (GV 20) for 20 and 30 minutes compared with their initial data (P < 0.05, P < 0.01); and as the forehead cortex blood flow after electric-moxibustion at Shenque (CV 8) for 10, 20 and 30 minutes compared with their initial data (P<0. 05, P<0. 01). CONCLUSION: Electric-moxibustion at both Baihui (GV 20) and Shenque (CV 8) can improve the volume of brain cortex blood flow and electric-moxibustion at Shenque (CV 8) has rapid effect. PMID- 21246851 TI - [Effects of electroacupuncture on the expression of nestin in endogenous neural stem cell in hippocampus in rats with focal cerebral ischemia-reperfusion]. AB - OBJECTIVE: To explore the mechanism of electroacupuncture for treating focal cerebral ischemia-reperfusion injury. METHODS: Seventy-five Wistar rats were randomly divided into a control group, a model group and an electroacupuncture group, 25 cases in each group. The model of focal cerebral ischemia-reperfusion was established by inserting nylon thread into the internal carotid artery except the control group which was only separated of the carotid artery without occlusion. Electroacupuncture group was treated with electroacupuncture at "Baihui (GV 20)" and "Dazhui (GV 14)" and the other groups without electroacupuncture treatment. The number of nestin positive cells expression at 1st, 3rd, 7th, 14th and 21st days after focal cerebral ischemia reperfusion was observed by use of immunohistochemistry method. RESULTS: The number of nestin positive cells in electroacupuncture group at ischemia side was significantly more than that in the model group at 3rd, 7th, 14th and 21st days (P < 0.05, P < 0.01), and at contralateral ischemia side, the number of nestin positive cells in the electroacupuncture group was significantly more than that in the model group only at 7th day (P < 0.05). CONCLUSION: Electroacupuncture at "Baihui (GV 20)" and "Dazhui (GV 14)" in rats can increase the number of nestin positive cells in hippocampus after focal cerebral ischemia-reperfusion, which may be one of the important mechanisms of electroacupuncture in treating acute cerebral ischemic diseases. PMID- 21246852 TI - [Effects of herbal cake-separated moxibustion on the expression of erythrocyte CD58 in different ages of healthy people]. AB - OBJECTIVE: To observe the efficacy of herbal cake-separated moxibustion on the expression of erythrocyte CD58 in different ages of healthy people and explore the differences of the therapeutic effect in different ages and its mechanism. METHODS: A total of 82 health participants were divided into a young age group and a middle-old age group according to the ages. They were treated with herbal cake-separated moxibustion on Shenque (CV 8), Guanyuan (CV 4), Zusanli (ST 36), Pishu (BL 20), Shenshu (BL 23) with cake made by Shudihuang (Radiz Re hmanniae Preparata), Shanyao (Rhizoma Dioscoreae), Shanzhuyu (Fructus Corni ), etc. The treatment was given for 10 sessions once other day and each acupoint for 3 successive dosages. The mean fluorescence intensities of erythrocyte CD58 were measured by flow cytometry before and after moxibustion. RESULTS: After moxibustion, erythrocyte CD58 expression were significantly higher than that before moxibustion in two groups (both P < 0.01), particularly in young age group, which was significantly higher than that in middle-old age group (P < 0.01). CONCLUSION: The effect of moxibustion in youth is evidently superior to that in middle-old age. Its mechanism is connected with that moxibustion can enhance the expression of erythrocyte CD58. PMID- 21246853 TI - [Effects of different time parameters on hypercholesterolemia treated with mild moxibustion]. AB - OBJECTIVE: To probe into the relevance between the parameters of mild moxibustion (persistent time, interval time, treatment session) and the efficacy, as well as the optimum treatment program of mild moxibustion in hypercholesterolemia. METHODS: The patients with hypercholesterolemia were selected as the observation objects. Mild moxibustion was applied to Shenque (CV 8) and Zusanli (ST 36). The total cholesterol (TC) was taken as the index. The orthogonal experimental design was adopted for paired combination of 3 factors (persistent time, interval time and treatment session) that affected TC reducing in mild moxibustion. Moreover, the changes in blood lipid were observed to choose the optimum treatment program. RESULTS: The importance of the factors of mild moxibustion that induced TC reducing in the patients with hypercholesterolemia was interval time > treatment session > persistent time. The effect of 10 min moxibustion on each point was better than that of 5 min moxibustion. The effect of once moxibustion every other day was better than that of once every day; and the effect of 6-week treatment was better than that of 12-week treatment. CONCLUSION: The interval time of mild moxibustion is the chief factor of the efficacy on hypercholesterolemia. The optimum treatment program is mild moxibustion, 10 min on each point, once every other day and lasting 6 weeks. PMID- 21246854 TI - [Auricular point sticking and the combined therapy of auricular point sticking and body acupuncture for weight gain in 100 cases]. AB - OBJECTIVE: To explore the efficacy difference in weight gain between auricular point sticking and the combined therapy of auricular point sticking and body acupuncture, as well as the efficacy difference among various body constitutions. METHODS: One hundred cases of weight gain were randomized into two groups, auricular point sticking group (group A) and the combined therapy of auricular point sticking and body acupuncture group (group B), 50 cases in each one. In group A, semen vaccariae was fixed with plaster on the spleen, stomach, endocrine, small intestine, buttocks, tibia, forearm, etc. in the ear. Each point was pressed 3 times daily, for 5 mm each time. The ear-points on two sides were alternated every two days. In group B, the auricular point sticking and body acupuncture were applied. The ear points and manipulation were same as the previous. Body points were Zhongwan (CV 12), (Juanyuan (CV 4), Tiansho (ST 25), Zusanli (ST 36), Sanyinjiao (SP 6), etc. Acupuncture was applied with filiform needle, once every two days. The changes in body weight and body mass index (BMI) were observed after 20 treatments. RESULTS: (1) The total effective rate was 94.0% (47/50) in group A and was 98.0% (49/50) in group B, without statistical significant difference (P > 0.05). The comparison of mean body weight and mean BMI after intervention did not show statistical significance between two groups (both P > 0.05), indicating that the simple auricular point sticking could achieve the same effect as the combined therapy. (2) There was no statistical significant difference in the total effective rate between the thin persons with spleen and stomach deficiency constitution and those with normal constitution among 100 cases (P > 0.05). But, the remarkable effective rates were different significantly in statistics (P < 0.05). For the thin persons with spleen and stomach deficiency constitution, after treatment, the body weight increased in big amplitude, but those with normal constitution increased in small amplitude or had no change. CONCLUSION: The efficacy of the simple auricular point sticking on weight gain is same as the combined therapy of auricular point sticking and body acupuncture, and is much better for the cases with spleen and stomach deficiency constitution. PMID- 21246855 TI - [Effect of Tuina on oxygen free radicals metabolism in patients with chronic fatigue syndrome]. AB - OBJECTIVE: To explore the mechanism of Tuina for treatment of chronic fatigue syndrome. METHODS: A total of 90 patients were randomly divided into a Tuina group, a Taijiquan (take exercise) group and a Fluoxetine group, 30 cases in each group. They were treated with Tuina, Taijiquan and Fluoxetine, respectively. After a month, the therapeutic effects and the changes of malondialdehyde (MDA) content and the activity of serum superoxide dismutases (SOD) and serum glutathione peroxidase (GSH-Px) were ohserved. RESULTS: The total effective rate of 93.3% (28/30) in the Tuina group was better than 80.0% (24/30) in the Taijiquan group and 73.3% (22/30) in the Fluoxetine group (both P < 0.05). After treatment, MDA contents in the three groups were all decreased (P < 0.01, P < 0.05), and the activity of SOD. GSH-Px in both the Tuina group and the Fluoxetine group were increased (P < 0.01, P < 0.05), and especially in the Tuina group with a significant difference as compared with the other two groups (P < 0.05, P < 0.01). CONCLUSION: The therapeutic effect of the Tuina group is superior to that of the Taijiquan group and the Fluoxetine group. Tuina can regulate oxygen free radicals metabolism and clean superfluous oxygen free radicals to alleviate fatigue, which may be one of the mechanisms of Tuina in treating chronic fatigue syndrome. PMID- 21246856 TI - [Importance of cultural transmission in acupuncture translation]. AB - The loss of cultural information transmission, inaccurate of translation or misunderstanding of the whole sentence in acupuncture translation are illustrated in this article. It suggests that these mistakes should be paid attention to and avoided; simultaneously, the solutions are stated so as to insure the accurate transmission of acupuncture. PMID- 21246857 TI - [Research on the correlation between the temperature asymmetry at acupoints of healthy and affected side and the severity index of facial paralysis]. AB - OBJECTIVE: To observe the change trend of the temperature asymmetry coefficient at acupoints between healthy side and affected side in patients with facial paralysis, to study the correlation between the temperature asymmetry and Facial Disability Index (FDI), to provide scientific guidance for the application of infrared thermography in the examination of severity of facial paralysis. METHODS: Using the infrared thermography to observe the temperature asymmetry at acupoints, the temperature asymmetry coefficient at acupoints between healthy side and affected side was calculated; the correlation between the temperature asymmetry and FDI was analyzed. RESULTS: The correlation between the temperature asymmetry coefficient and FDI was statistically significant at acupoints of Yang bai (GB 14), Cuanzhu (BL 2), Dicang (ST 4), Yuyao (EX-HN 4), Quanliao (SI 18), Jiache (ST 6) (P < 0.05, P < 0.01). CONCLUSION: The temperature asymmetry coefficient at acupoints between healthy side and affected side could be a scientific measure to evaluate the severity of facial paralysis. PMID- 21246858 TI - [Study on treatment of irritable bowel syndrome: based on relationship between heart and intestines]. AB - The article puts forward the treatment of irritable bowel syndrome through regulating heart vitality since it is held that the pathological factors of the disease lay in dysfunction of heart and intestines as well as disorder of qi circulation. At the same time, the internal-external relationship between the heart the small intestine is discussed from the theory of Brain-gut Axis in modern medicine, which provides theoretical base of modern medicine for the treatment of irritable bowel syndrome through regulation of the heart functions. PMID- 21246859 TI - [DOU Han-qing's academic thought of acupuncture and moxibustion]. AB - DOU Han-qing's academic thought of acupuncture and moxibustion are analyzed, which include "eight confluence points", sensation of qi arrival, 14 manipulations for promotion of qi sensation, point selection, needling technique and observation of the psychological condition of patients. DOU's inheritance and development of Huangdi Neijing (Internal Classic) and Nanjing (Classics on Medical Problems) as well as his influences on the later schools are approved to have great value and significance on the enhancement of clinical effect and development of acupuncture and moxibustion sciences. PMID- 21246861 TI - [And science is sly!]. PMID- 21246860 TI - [Acupuncture analgesia and the direction, angle and depth of needle insertion]. AB - Literatures on acupuncture analgesia of the recent 30 years are analyzed through the target pain syndromes, points and tools selected for needling as well as the chosen direction, angle and depth of insertion. The relationship between effect of acupuncture analgesia and needling direction, angle as well as depth is initially optimized to enhance the analgesic effect. The result shows that the 3 factors are the key influences. However, studies on the above mentioned relation are still far from enough. Aiming at enhancing the effect of acupuncture analgesia and exploring the relative mechanism, it is held that multivariate analysis should be adopted to do systematic analysis on relationship between effect and mechanism of acupuncture analgesia and direction, angle and depth of the needle insertion. PMID- 21246862 TI - [Sign of the time]. PMID- 21246863 TI - [Developing a screen in practice]. PMID- 21246864 TI - [Bachelor degree is an advantage in nursing]. PMID- 21246865 TI - [Blisters and untreated problems reduce healing]. PMID- 21246866 TI - [Cooperation brings us forward]. PMID- 21246867 TI - ["Three small steps can change the whole world"]. PMID- 21246868 TI - [Knowing what nursing work achieves]. PMID- 21246869 TI - ["Nurses deserve more appreciation"]. PMID- 21246870 TI - [Sleep as the source of a happy life]. PMID- 21246871 TI - ["Deception of the professional association is very important" ]. PMID- 21246873 TI - [Finally true perspectives of careers!]. PMID- 21246872 TI - [Knowing how to think, a good benefit]. PMID- 21246874 TI - ["It is time to find our marks"]. PMID- 21246875 TI - [Carrying out changes while respecting what exists]. PMID- 21246876 TI - [The Canadian experience]. PMID- 21246877 TI - [Attending a university is in progress]. PMID- 21246878 TI - [For the exceptional nurses]. PMID- 21246879 TI - ["I am ready for battle"]. PMID- 21246880 TI - [Present, past, future]. PMID- 21246881 TI - [A better opportunity to confront practice]. PMID- 21246882 TI - [Treatment of depression leading to social rehabilitation: toward a true recovery]. PMID- 21246883 TI - Decision-Making for Recommendations and Communication Based on Totality of Food Related Research, an ILSI North America-sponsored Workshop at the Omni Shoreham Hotel, Washington, DC, December 15, 2008. Abstracts. PMID- 21246884 TI - [Crystallization of ribosomes from Thermus thermophilus]. PMID- 21246885 TI - The League of Nations' rescue of Armenian genocide survivors and the making of modern humanitarianism, 1920-1927. AB - The essay centers of the efforts by the League of Nations to rescue women and children survivors of the 1915 Armenian Genocide. This rescue -- a seemingly unambiguous good -- was at once a constitutive act in drawing the boundaries of the international community, a key moment in the definition of humanitarianism, and a site of resistance to the colonial presence in the post-Ottoman Eastern Mediterranean. Drawing from a wide range of source materials in a number of languages, including Turkish, Armenian, and Arabic, the essay brings the intellectual and social context of humanitarianism in initiating societies together with the lived experience of humanitarianism in the places where the act took form. In so doing, it draws our attention to the proper place of the Eastern mediterranean, and its women and children, in the global history of humanitarianism. The prevailing narrative of the history of human rights places much of its emphasis on the post-World War II era, the international reaction to the Holocaust, and the founding of the United Nations. yet contemporary human rights thinking also took place within practices of humanitarianism in the interwar period, and is necessarily inseparable from the histories of refugees, colonialism, and the non-West. PMID- 21246886 TI - Rival ecologies of global commerce: Adam Smith and the natural historians. AB - This essay explores how the defense of global commerce pioneered in the Enlightenment was tied to the improvement of the natural order. Two rival ecologies, one made by natural historians and the other developed by Adam Smith and his liberal successors, vied for intellectual precedence as well as for practical application in the metropole and the colonies. Together they constitute the beginnings of an ongoing quarrel over the environmental foundation of capitalism. PMID- 21246887 TI - Making men: Enlightenment ideas of racial engineering. AB - This essay suggests a colonial and Enlightenment genealogy for racial ideas more commonly associated with the nineteenth and twentieth centuries. Nelson exposes unfulfilled pseudo-eugenic plans, focused on the French Caribbean colony of Saint Domingue, in which racial engineering through controlled "breeding" was seen as a solution to challenges to stability after the Seven Years' War. PMID- 21246888 TI - [Poststroke generalized anxiety disorder: epidemiology, diagnosis, clinical typology]. PMID- 21246889 TI - Gay men vary in their beliefs about what constitutes sex: comment on Sanders et al--Misclassification bias: diversity in conceptualisations about having 'had sex' (Sexual Health 2010;7:31-4). PMID- 21246891 TI - [Reference group focused therapy]. PMID- 21246890 TI - [The role of combat stress in the development of chronic pain syndrom in veterans and its treatment by pantogam active]. PMID- 21246892 TI - [Selection of neuromethabolic drug in severe brain injury]. PMID- 21246893 TI - [Prevention of stenosis of vascular anastomoses after surgical treatment of patients with lower limb ischemia]. PMID- 21246894 TI - [Prevention of venous thrombosis in surgical practice: current points and future issues]. PMID- 21246895 TI - [Sleep disorders and their treatment]. PMID- 21246896 TI - [Multiple damages of abdominal organs]. PMID- 21246897 TI - [Rivastigmine in the treatment of dementia: from the symptomatic effect to neuroprotection]. PMID- 21246898 TI - [Necrosis of caecal segment and phlegmonous appendicitis as complication of the Crohn's disease]. PMID- 21246899 TI - [Surgical treatment of perforative duodenal ulcers]. PMID- 21246900 TI - [Necessity of the planned colon resection by complicated diverticular disease (with comments)]. PMID- 21246901 TI - [The comparative efficacy of therapy with typical and atypical antipsychotics]. PMID- 21246902 TI - [Mitochondrial dysfunction in neurodegenerative diseases]. PMID- 21246903 TI - Advances in contemporary modeling of clinical nursing care. Foreword. PMID- 21246904 TI - Advances in contemporary modelling of clinical nursing care. PMID- 21246905 TI - In memory of Professor Tianqin Cao (Tien-chin Tsao). PMID- 21246907 TI - Doctors face profound changes, but at this point, no one is entirely clear what those changes will entail. PMID- 21246906 TI - China: too little information. PMID- 21246908 TI - Medical marijuana in New Jersey. PMID- 21246909 TI - Perspectives on healthcare from the 2010 Edward J. Ill Excellence in Medicine honorees. PMID- 21246910 TI - A look into the future of medical professional liability: a guide to prevention and protection. PMID- 21246912 TI - Managing political conversations with patients: an interview with Warren Finkelstein, MD. Interviewed by Steve Adubato. PMID- 21246911 TI - The fall and rise of syphilis in America since World War II. PMID- 21246913 TI - Study of formulation of pharmaceutical forms of paracetamol in medical practice. AB - It is a well-known fact that tablets are the most ordinary medicines in daily practice, which along with capsules represents about 70% of pharmaceutical preparations. Experimenting with paracetamol tablets of 500 mg dose was scope of this study. Study of formulation, preparation, quality control, and follow-up of the paracetamol stability in tablets was conducted. Carefully analyzing the physical--chemical properties of the paracetamol, in particular to the high number of excipients utilized in the preparation of tablets (diluting, connective, analyzing, and lubricant excipients), and by researching an considerable number of bibliographic sources, we have conceived four different formulations of the paracetamol tablets 500 mg. Preparation of tablets was realized by the humid method of granulation. Quality control of the paracetamol tablets was performed by implementing a series of trials and analyses forecasted in latest editions of most recognized pharmacopoeias. From these trials and analyses, we can mention as follows: reactions of identification, diameter, and average mass, time of analysis, velocity of dissolution and determination of 4 aminophenol. Requirements deriving from the abovementioned trials and analyses were accomplished, excluding the velocity of dissolution that was not accomplished in two of the last formulation (3 and 4). Since this trial is very important in regard to the quality of solid pharmaceutical forms, two of the abovementioned formulations are considered as inappropriate to be used in practice. From the four formulations of paracetamol tablets, results shows that 1st and 2nd are most appropriate formulations due to its simplicity in preparation and practice to be produced industrially. Defining of the timely depending content of the paracetamol in tablet was performed by the implementing of two contemporary methods of spectrophotometry in UV zone and chromatography in the liquid phase with high pressure (HPLC). Just as it was expected, results of these analyses showed that acting substance did not incur any alteration during the period of storage and that alterations of the analyses results in between these two methods are almost inconsiderable ones. PMID- 21246914 TI - Development ontogenesis of receptor tracheobronchial system in isolated preparations of pigs trachea in vitro. AB - Flow research of the development of receptor bronchial system was conducted in this work since the first day in 4th week of extra-uterine life, by following reactions of isolated tracheal rings in acetylcholine (Ach), histamine (Hist), and prostaglandin (PGF2-alfa) in concentrations of: 10(-4), 10(-3), 10(-2), 10( 1), mol/dm3, at piggy's of ages: 1 day, 1 week, 2 weeks and 4 weeks. Results shows that Ach causes reaction of smooth muscles since the first day of extra uterine life in a significant way (p < 0.01). Whilst propranolol (P) not emphasis the effect of Ach in a significant way (p > 0.1). Whereas histamine, and PGF2- alpha does not cause constriction of tracheal smooth musculature (MLT) in the first days of extra-uterine life. This shows that cholinergic and adrenergic system in airways of pigs is developed in intrauterine life and reaction was registered since the first day of extra-uterine life, whereas other receptor systems are developed in later weeks of extra-uterine life. Potential explanation of this mechanism of constriction of tracheal rings smooth musculature, dependence-age, is increase of the Calcium ions influx throughout "receptor activating" and "voltage operating" channels in cells of the pigs tracheal smooth musculature in the first days of extra-uterine life. PMID- 21246915 TI - Cerebrovascular events: correlation with plaque type, velocity parameters and multiple risk factors. AB - PURPOSE: Cerebrovascular events (CVE) are the third most common cause of death in Western countries and about 65-70% of CVE are due to atherosclerotic disease of carotid arteries. Color Doppler scanning is used to evaluate the presence, severity and type of atheromatous plaques as well as velocity parameters of carotid arteries. We performed this study to correlate data of morphological and velocity parameters with clinical variables in patients following CVE. METHODS: We included total of 211 pts who had CVE, 118 females, 93 males, mean age 71.1 +/ SD 12.5 years. Out of total number of pts (n = 211) 93 pts had transient ischemic attacks (TIAs), 49 had recurrent TIAs (rTIAs), 44 had ischemic stroke (IS), and 25 had recurrent IS (rIS). As a control group we took 50 pts without CVE but with at least three multiple risk factor (MRF). Morphological parameters were; plaque composition and echogenecity. Velocity parameters were: peak systolic velocity (PSV) and end-diastolic velocity (EDV). The following MRF were evaluated: age, gender, hypertension, tobacco smoking, hyperlipidemia (total cholesterol and LDL-cholesterol), obesity, and diabetes mellitus. Examination was performed on CCA/ICA segment. RESULTS: We found significant presence of heterogeneous plaques in TIAs and rIS subgroup, p < 0.014, and borderline significance for the rTIAs and IS subgroups, p < 0.04. We found significant difference in PSV in TIAs and rTIAs subgroups vs. controls (PSV 103 cm/s vs. PSV in controls 87 cm/s, p < 0.01). Decreased EDV, below 20 cm/s, was found in all subgroups, p < 0.01, while EDV, below 16 cm/s, was found in IS and rIS subgroups. MRF score of CVE group was 4.34 vs. 3.65 in controls, p < 0.012, while MRF score in TIAs and rTIAs vs. IS and rIS subgroups was 4.34 vs. 4.51, NS, p = 0.14. We found a significant correlation (95% CI) of tobacco smoking, obesity and arterial hypertension with presence of heterogeneous plaques, p = 0.0069. Interestingly, hyperlipidemia showed no correlation with heterogeneous plaques, p = 0.027. CONCLUSIONS: (i) in CVE group we found significant presence of heterogeneous plaques in TIAs and rIS subgroups, (ii) in the pts with TIAs and rTIAs events we found significant increase in PSV, (iii) EDV below 16 cm/sec was a significant single predictor of IS and rIS events, (iv) MRF score was significantly increase in the pts with CVE compared to controls, but between CVE subgroups there was no significant difference. PMID- 21246916 TI - Effect of probiotics on liver function after surgery resection for malignancy in the liver cirrhotic. AB - INTRODUCTION: Hepatic resection is the accepted treatment for various liver tumors. Increasing evidence suggests that two factors significantly influence outcome and successfulness of the hepatic resection in patients with HCC in cirrhosis. There are liver function recovery and the degree of inflammation during early postoperative period. OBJECTIVE: Aim of this study was to determine whether probiotic use influences on liver function recovery, degree of inflammation during early postoperative period, intraoperative risk, type and frequency of intraoperative and postoperative complications, morbidity, intraoperative and early postoperative mortality and a one-year survival rate in patients who have been used probiotic, and underwent the hepatic resection due to HCC in cirrhosis. PATIENTS AND METHODS: Study was conducted on 120 patients underwent the hepatic resection due to HCC in cirrhosis. This study has been done in University Clinical Centers Tuzla, Maribor and Strasbourg from October 2006 till February 2008. Patients were divided into 2 groups: 1) patients with liver cirrhosis and histologically verified HCC whom underwent liver resection surgery (segmentectomy/ bisegmenctetomy, right and left hemihepatectomy/extended hemihepatectomy) that used preoperatively and postoperatively probiotics (n = 60), 2) a control group of patients with liver cirrhosis and HCC, which did not use preoperative and postoperative probiotics (N = 60). Treatment with probiotics was conducted 3 days preoperatively and postoperatively with 7 day's oral supplementation. RESULTS: This study have shown next: patients underwent to the hepatic resection due to HCC in cirrhosis who have been used preoperatively and postoperatively probiotic had liver function recovery better and faster, acute immune response better, serum level of tumor markers lower, intraoperative and postoperative complications were less frequent, and morbidity and mortality rates were lower than in those who have not been using probiotic. CONCLUSION: Probiotic use may make liver function recovery better and increases immune response in early postoperative period and positively influences outcome and successfulness of the hepatic resection in patients with HCC in cirrhosis. PMID- 21246917 TI - Serum concentrations of interferon-gamma (IFN-g) in patients with alopecia areata: correlation with clinical type and duration of the disease. AB - Alopecia areata (AA) is a heterogeneous disease characterized by nonscarring hair loss on the scalp or other parts of the body. A wide range of clinical presentations can occur-from a single patch of hair loss (alopecia unilocularis, AUl), multiple patches (alopecia multilocularis, AM) to complete loss of hair on the scalp (alopecia totalis, AT) or the entire body (alopecia universalis, AU). The cause ofAA is unknown although most evidence supports the hypothesis that AA is a T-cell mediated autoimmune disease of the hair follicle and that cytokines play an important role. The aim of the study was to evaluate serum concentrations of interferon-gamma (IFN-g) in patients with AA and the healthy subjects and also to assess a possible association between IFN-g and clinical type and duration of the disease. Sixty patients with AA and 20 healthy controls were enrolled in the study. Serum concentrations of IFN-g were determined by ELISA method. The serum concentration of IFN-g in patients with AA was significantly higher than that in the control group (10.62 +/- 1.09 pg/mL vs 10.02 +/- 0.62 pg/mL, respectively). Significantly elevated serum IFN-g were noticed in patients with AU type (11.81 +/- 1.11 pg/mL), expecialy those suffering from AT (12.30 +/- 0.93 pg/mL), compared with both patients with AUl (10.20 +/- 0.59 pg/mL) and patients with AM clinical type (10.21 +/- 0.78 pg/mL). There was no significant difference in serum IFN-g concentration between patients with AUl and AM group, as well as between patients with AT and AU. No correlations were found between duration of disease and the serum levels of IFN-g. Our findings confirm previously published data that the Th1 type cytokine IFN-g is elevated in the serum of AA patients. PMID- 21246918 TI - Induction of chromosome aberrations in the Allium cepa test system caused by the exposure of cells to benzo(a) pyrene. AB - Higher plants have been proposed as test organisms for the detection of genotoxic substances in the environment. Several plant test systems are already in use and are found to be as sensitive and reliable as other short-term tests. Allium cepa is one of these plants, which has been used in different studies to detect chromosome aberrations induced by chemicals. The use of non-animal test methods, including in vitro studies, provides importent tools to enhance our understanding of hazardous effect of chemicals, and for predicting these effects in humans. In vitro systems are used principally for screening purposes, and for generating toxicological profiles. Numerous chemicals can generate the breakage or interchange of DNA segments between chromosomal structures. Allium test is used as a screening method for genotoxicity evaluation of different chemical substances, including polycyclic aromatic hydrocarbons (PAHs). Benzo(a)pyrene (BaP), as representative member of PAHs, were investigated of genotoxicity by using Allium roote chromosomes assay. The treatment with different series of concentrations of BaP, ranging from 1.0-50.0 microg/ml respectively. Used BaP caused decreased in the Mitotic index (MI) and increase frequency of abnormal mitosis when compared with the control. PMID- 21246919 TI - Biochemical markers of iron status in hemodialysis patients. AB - INTRODUCTION: Secondary lack of iron in patients on hemodyalisis is the main cause of inadequate answer on therapy of recombinant human erythropoietin (rHuEPO). Therefore, it is very important to follow the status of iron in these patients. OBJECTIVES: The objectives of our study were to define the value of hemoglobin content in reticulocytes as predictor of functional iron deficiency on hemodialyzed treated patients with erythropoietin (rHuEPO) then evaluate the eficiency of using the value of hemoglobin content in reticulocytes in administration of iron HD (Patients on hemodialyzed ). PATIENTS AND METHODS: It is a prospective study which included 53 patients treated on chronical hemodialysis and continuing hospital peritoneal dialysis (CAPD), all patients were given additional iron therapy intravenously in order to keep the level of ferritin between 300 microg/l and 500 microg/ and transferrin saturation over 20%. The patients were both male and female randomly chosen. The following parameters conected to iron deficiency were compared in this study. The study was taken in the period from august to december 2008 at University Clinical Centar Tuzla. RESULTS AND DISCUSSION: The study included patients from chronical HD programme in therapy with rhEPO, iron intravenously, than patients on CAPD also in therapy with rh EPO and intravenously iron and patients on chronical HD with intravenously iron without rh EPO therapy. There wasn't any significant difference between numbers of male and female patients that were examined and in control group. In this study the following parameters conected to iron deficiency were compared. There wasn't any significant difference in values of seruum ferritin, Ret-he and hemoglobin between the examined and control group. Still, it's clear that members of the examined group had higher values of these parameters comparing to the control group. If we would use criterias like the saturation transferrin and the level of ferritin as referent standard we would have 26/53 (49.1%) patients with iron deficiency in the whole sample. CONCLUSION: Following chematological and biochemic parameters in examined patients on HD are giving us essential information for planing and leading an adequate erythropoietin therapy. For the maximum effect of rhEPO therapy, an adequate compensation of iron is necessary. PMID- 21246920 TI - Musculus extensor digitorum brevis is clinical and electrophysiological marker for L5/S1 radicular lesions. AB - In clinical electromyography (EMG) musculus extensor digitorum brevis (MEDB) is known as "the marker" for L5/sl radiculopathy. Radiculopathy is mainly sensory syndrome in which the pain appears in innervation's zone of one or more spinal nerves. Moreover, in clinical practice it is also known that radiculopathy is not only sensory disorders but also may be followed by muscle weakness and atrophy. Since atrophy of MEDB is often seen clinical feature in careful neurological exam of the patients with lumbosacral radiculopathy, it is made attempt to determine usefulness of this sign, for clinical diagnosis of radicular lesions. For this purpose 100 patients with lumbosacral radiculopathy and MEDB atrophy and 100 patients with low back pain have been studied. Control group consisted of 50 healthy volunteers. The patients underwent neurological examination, CT scan of lumbosacral region and EMG including motor conduction velocity (MCV) of deep peroneal nerve (DPN), F-wave and H-reflex analysis. The most patients in first group had moderate and severe radicular lesions of radix L5/sl proved by EMG examination. MCV in DPN on atrophy side was 43.4+/- 2.65 m/sec, and on side without MEDB atrophy 47.18 +/- 1.63 m/sec (p < 0.001). MCV in control group was significantly higher then in both group of patients (left side - 47.65 +/- 1.53 m7sec: right side--47.70 +/- 1.59 m/sec) (p < 0.001). Significant correlation between the MEDB atrophy and MCV (r = -0.67) and F-wave latency (r = 0.86) and H reflex latency (r = 0.87) has been proved. It is concluded that MEDB atrophy is very important parameter in clinical evaluation of patients with lumbosacral radiculopathy and could be clinical and electrophysiological marker for L5/Sl radicular lesions. PMID- 21246921 TI - The efficiency of Bonviva (Ibadronate) in women with pre-post menopause. AB - AIM: our aim was to see the efficiency of Bonviva(Ibadronates) among in osteoporoses among women. OBJECTIVES: We chose this medicament which has the most acceptable price by all the GDP women's family and also this medicament which is at the new line of biphosphonate (Ibadronates), and has the most commodity of taken ones per monthly. For our proposal we include in our study all women age 45 -60 years old (average 52.6 +/- 41), which have a physiologic menopause. All case was selected from ambulatory service without other diseases such are neoplasic which affect the bone, renal (creatinine clirens < 40 ml/min), gastrointestinal, respiratory and high blood pressure were or have allergy from Bonviva excluded or from our study. The final number of subjects was 89 women. The women at the moment of selection have or no osteoporotic fracture. We measure also the high, age, weight, BMI but except age other were not analyzed form us. The measure of body mass density (BMD) is the gold standard for to establish the diagnosis of osteoporosis. All subjects we measure the index of T-score (which represent the BMD), at the lumbar part of spine, which show the efficiency of Bonviva. T-Score was measure before treatment, after six months and after one year. The T-score was measure by DE XA (lunate one). RESULTS: In order to measure the efficiency of Bonvines all cases the T-Score were analyzed from SPSS version 15 with ANOVA. The results of ANOVA show statistical significance (p < 0.0001) between BMD before treatment (-3.12 +/- 0.49), BMD six months after treatment (-2.9 +/- 0.5) and after BMD one year (-2.7 +/- 0.5). The significance was also high (P < 0.0001) when we compare also BMD six month and after one year. CONCLUSIONS: Our results show the efficiency of Bonviva among women with pre, during and post menopause in osteoporoses. Ibadronate (Bonviva) increase the BMD in women with early menopauses, as results we prevent osteoporosis. Bonviva increases the BMD in women with established osteoporoses, as results we reduce the vertebral risk fracture. PMID- 21246922 TI - Dexamethasone as adjuvant therapy in the treatment of invasive meningococcal diseases. AB - PURPOSE: With this study we want to evaluate the role of dexamethasone adjuvant treatment in different clinical forms of invasive meningococcal diseases. WORK METHODS: This was a randomized, open label trial that was conducted in 147 individuals with meningococcal sepsis. All of the cases have been divided in two groups: (1) Cases with meningococcal disease and CNS infection, and (2) Cases with meningococcal disease and no affection of the CNS. Cases from both groups were treated with dexamethasone, 0.15 mg/kg, every 6 h, for 4 (four) days, as adjuvant therapy. Cases which were not treated with dexamethasone were used as control group. WORK RESULTS: From overall number of cases, in 130 of them, the meningococcal disease was accompanied with meningitis; in other 17 cases only signs of sepsis were present. In both clinical forms, the dexamethasone was used in 92 cases. The higher mortality rate is registered among the cases without meningitis, 17.65%, compared with 6.92% which is registered among cases with meningitis. The overall mortality rate among all cases was 8.2%. The significant difference was recorded only on CSF sugar level between two groups (treated or not with dexamethasone) on the day 1-4 of the hospitalization. DISCUSSION: Our epidemiological data are in correlation with data from other epidemiological studies. Most of the cases 69.4%, were more than 12 hours sick at home before the hospitalization, 7.5 % of cases were hospitalized within 12 hours from the onset of the diseases, while 23.1% of cases data are missing. This is in correlation with similar data from other studies. CONCLUSION: Dexamethasone has a limited effect on outcome of the invasive meningococcal disease. Dexamethasone had some effect only during the days of administration in cases with clinical form of sepsis with meningitis, by normalizing the values of CSF sugar earlier. PMID- 21246923 TI - Comparison of epidural morphine versus intramuscular morphine for postoperative analgesia. AB - OBJECTIVE: To compare effects and side effects or complications of epidural versus intramuscularly administered morphine for relieve of postoperative pain. PATIENTS AND METHODS: In the first group (epidural) analgesia is achieved by application of morphine through epidural catheter. To the amount of morphine is added physiological solution until 10 ml of total volume of the mixture is achieved. This mixture is given to 150 patients, by epidural route before the exit from the operation room. Epidural catheter is removed after 48 hours. Second group (intramuscular) analgesia is realized by application of 10 mg of morphine by intramuscular route. Morphine is injected at the end of surgery. Pain is assessed with combination of verbal categorical scale and visual analog scale. Verbal categorical scale used is 8 points scale and contains words of Tursky: 0 no pain, 1 very low pain, 2 week pain, 3 mild pain, 4 moderate pain, 5 strong pain, 6 severe pain, 7 untolerated pain. Awareness is assed during first 24 hours. For this Reynolds 4 points scale is used: awaked 1, somnolent 2, sleepy 3, deep sleep 4. RESULTS: Pain assessed by visual analog scale (VAS) is 15.17-29.62 in the epidural group patients versus 26.39-70.83 in intramuscular group. Variation of respiration rate in both groups is not significant 22.21 +/- 4.23 and 23.98 +/- 2.72 in minute, in epidural and intramuscular morphine groups, respectively. PaCO2 and PaO2 values are similar without significant variation 35.34 +/- 4.72 mmHg in the epidural morphine group and 31.3 +/- 3.21 mmHg in intramuscular morphine group. CONCLUSION: Epidural administration of morphine provides better analgesia in quality, since it is deeper, longer in duration and with less inhibitory supra-spinal actions when compared to intramuscular administered morphine. PMID- 21246924 TI - Problems in surveillance on safe immunization conducting in everyday practice. AB - PURPOSE: Vaccination is the fastest, most efficient and the cheapest measure to prevent communicable diseases. The purpose of the work was to evaluate the results of primary vaccination as well as the first revaccination by DPT,OPV and MMR vaccines. WORK METHOD: Descriptive epidemiological study was used. The investigation was done in the Primary Health Center in Nis and it involved all the children who were born in 2000, 2001, 2006 and 2007. WORK RESULTS: A total number of 1863 vaccination records were examened. In the sample of examened records of children who were born in 2000 and 2001, there were 155 children (12.05%) who were vaccinated with different vaccines and according to the different vaccination schedules. The number of childern born in 2006 and 2007 was slightly higher and it was (14.70%). In the first group (children who were born in 2000 and 2001) there were 43 children (4.51%) who were not vaccinated (3 children haven't been vaccinated by DPT, and other 40 haven't been vaccinated by MMR). Similar situation was in the second group (children who were born in 2006 and 2007) in which 37 children (4.03%) haven't been vaccinated at all (3 of them by DPT and other 34 by MMR). In both observed groups DPT vaccine immunization started out late. 48.25% of children from the first group haven't been vaccinated with the first dose of DPT on time. 58.53% of children born in 2006 and 2007 haven't been vaccinated with the first dose of DPT on time. The first re vaccination by DPT was also late in children born 2000 and 2001 (16.6% vs 45.36%). It was also delayed the first revaccination by MMR (10.3% vs 22.53%). DISCUSSION: To achieve the expected effects should be vaccinated at least 95% of planned persons but also make timely vaccinations. While the main goal of immunization is to prevent illness and death, the overriding concern of any public health intervention must be "Primum non nocere". CONCLUSION: A small number of post-vaccinal reactions is registered, and there haven't been registered cases of adverse events following immunization or serious reactions that would be contraindications for further immunization. PMID- 21246925 TI - Investigation of health effects of current levels of environmental sanitation and hygienic living conditions of rural population in the municipality of Zenica. AB - The aim of this article is to investigate and identify all the relevant ways of epidemiology significance for transmitting infectious diseases in the existing unsatisfactory hygienic and sanitary conditions in rural areas of the municipality of Zenica, which are positively correlated with occurrence and spread of infectious intestinal diseases. The study was conducted in seven rural localities of Zenica municipality where the dominant livestock are sheep and cows, and the population is mostly dealing with individual production of cheese and milk. This research aimed to examine and identify the conditions favoring life as the primary issues that affect the increase in the risk of and maintenance of intestinal infectious diseases such as: the level of environmental sanitation in investigated villages, sanitary and hygiene habits of families living in the villages studied, ratio of population to personal hygiene, health safety of water supply, hygienic disposal of fecal waste and waste generated in the breeding of animals. The study included the monitoring and statistical analysis of the epidemiological situation in the values of average prevalence rates of the intestinal infectious diseases in the 1000 inhabitants of each village studied. The study identified five major negative epidemiological indicators that have a major impact on the appearance and maintenance of intestinal infectious diseases. The leading indicator is a negative relationship and personal hygiene attitude in the broader sense, the pending state of water supply, sanitary toilets and unresolved rubbish dump with a negative attitude and stance toward general hygiene. Identified are all the relevant ways of epidemiology importance that are positively correlated with occurrence and spread of infectious intestinal disease. Investigations of the epidemiological situation regarding the occurrence of intestinal infectious disease in the study population showed that intestinal infectious diseases in the investigated area is constantly maintained and that the average prevalence rate is shown suffering intestinal infectious diseases in the 1000 inhabitants significantly higher than the prevalence of these diseases in the urban area where they can be identified in a significant number of negative epidemiological indicators. PMID- 21246926 TI - Frequency of the central venous catheter colonization in surgical intensive care unit. AB - The use of central venous catheters (CVC) carries a risk from local and systemic infectious complications, with prevalence of 6% in patients in Intensive care unit. Microorganisms colonizing the CVC usually originate from patient's or staff member's skin, but the source can also be a contaminated infusion solution or hematogenous dissemination from a distant focus. The infective agents often show increased resistance to antibiotics, which is an additional therapeutic problem. There is no knowledge of the frequency of the colonization of CVC by microorganisms in hospitals in Bosnia and Herzegovina, neither of the types of microorganisms which usually colonize CVC, nor their sensitivity to antimicrobial agents. METHODS: During the period 2004-2008, the analysis of 188 CVC samples was performed in patients in ICU at which the doubt for CVC connected infection was present. The microorganism identification was performed by standard microbiological antibiotics sensitivity methods. RESULTS: Out of 188 checked samples, 101 (54%) had positive cultures and 87 (46%) were sterile. Out of 101 positive microbiological cultures, in 33 (32.67%) the gram-positive bacteria had been found, gram-negative in 62 (61.37%) and Candida albicans in 6 (5.94%) cultures. Gram-ne-gative bacteria were 93.55% sensitive to imipenem, and Gram positive bacteria were sensitive to vancomycin. CONCLUSION: Gram-negative bacilli and Coagulase-negative staphylococci are the most frequent micro-organisms which colonize the CVC. The increase of bacteria antibiotics resistance represents a big problem. All those facts leads to the need for bigger control and supervision over the CVC implantation, its proper maintenance and rational use. PMID- 21246927 TI - Helicobacter pylori infection and precancerous lesions of the stomach. AB - INTRODUCTION: Chronic atrophic gastritis, intestinal metaplasia, hereditary non polyposos colon cancer, gastric dysplasia, gastric adenoma, Barrett esophagitis and familiar adenomatous polyposis are confirmed precancerous lesions of the stomach. Most of these conditions are correlated with long-term infections with Helicobacter pylori. MATERIAL AND METHOD: Patients which were included in our study underwent gastro endoscopy with multiple biopsies from antrum and corpus ventricle, also urease test and histopathological examination, using special coloring for Helicobacter pylori. RESULTS: 802 patients entered this study, of which 369 female and 483 male. Among female patients 56.4% resulted Helicobacter pylori positive, whereas among male patients this was at a rate of 62.6%. The most affected age was 40-49 years, in which group Helicobacter pylori infection was 64.2%. In each precancerous lesion positivity of Helicobacter pylori infection was very high.-in patients with intestinal metaplasia: 71.7%, with gastric dysplasia: 71.4%, with gastric ulcer: 68.4%, with atrophic gastritis: 66.0% and with Barrett esophagitis: 55.0%. DISCUSSION: The main purpose of this study was to determine the percentage of Helicobacter pylori infection among patients with precancerous lesions, which resulted to be very high. The highest percentage of infection resulted in patients with intestinal metaplasia (71.7%). CONCLUSIONS: Precancerous lesions of stomach are associated with high percentage of Helicobacter pylori infection. This confirms once more the importance of Helicobacter pylori eradication in early stages and patient's surveillance. PMID- 21246928 TI - Bilateral breast carcinoma in patients with Klinefeleter syndrome: report of case. AB - PURPOSE: Men with Klinefelter syndrome have one or more extra X chromosomes and have endocrine abnormalities. Klinefelter syndrome has been consistently associated with breast cancer in men (MBC). CASE REPORT: We report a 54-year old man was diagnosed as synchronous bilateral breast cancer with Klinefelter syndrome. On clinical examination there was mass in the lateral upper quadrant right breast. The overlying skin was slightly retracted. In the left breast, there was also a subareolar mass. Mammography, ultrasonography imaging showed bilateral suspicious breast masses with microcalcifications. There were no radiological findings of muscle invasion or axillary lymphadenopathy. We performed bilateral fine-needle aspiration biopsy (FNAB), and the aspiration smears were positive for carcinoma. The pathologic diagnosis of infiltrating ductal carcinoma in the biopsy specimen on the bilateral breast. The patient was successfully treated by bilateral radical modified mastectomy according to Madden's technique followed by external irradiation and adjuvant endocrine therapy. CONCLUSION: Breast cancer commonly occurs in women, but now the incidence is also seen in men. Risk factors include age, family history, genes, liver diseases (cirrhosis), alcohol, diet, and obesity. Klinefelter syndrome, in which patients carry XXY chromosome, may be present in men with breast cancer for this reason they often develop gynecomastia. PMID- 21246929 TI - To classics of Arabic medicine. AB - The slamic authors of the medical and other works have become very known for West, but under well changed names, as for example Razes for Ar-Razi, Avicenna for Ibn Sina, Alhazen for Ibn Haitham, Avenzoar for Ibn Zuhr, Avveroes for Ibn Rusd etc. Up to those changes in the names has not come at any case come accidentally. This was the result of the religious striving to the cultural worls of the West, and not to speak about the plebs, only the giants are represented wich was imppossible to avoid. It is indusputable the great contribution of the Islamic authors to the development of the biomedical sciences. They not only succeeded to preserve the achievements of the pre Islamic authors, than they by the own researches gave the great contribution to the development of these sciences and their disciplines, and they have overgiven to us as a dowry. PMID- 21246930 TI - Current concepts in the neuropathology and pathogenesis of multiple sclerosis. AB - Multiple sclerosis (MS) has been classically regarded as an inflammatory demyelinating disease of the central nervous system. In recent years, the classification and pathogenesis of the disease have become controversial, particularly with respect to whether an individual patient demonstrates a single or multiple pathogenetic mechanisms in the establishment of the focal plaque of MS. It is also becoming increasingly apparent that there is a significant neurodegenerative component in the disease, involving not only plaques but the non-plaque parenchyma as well. Magnetic resonance imaging, together with histopathologic studies, will continue to shed light on the pathogenesis of these focal and diffuse abnormalities in MS. PMID- 21246931 TI - Multiple sclerosis: autoimmune disease or autoimmune reaction? AB - Multiple sclerosis (MS) is traditionally considered an autoimmune inflammatory demyelinating disease of the central nervous system (CNS) with much knowledge available to support this view. However, this characterization implies that the primary event is an aberrant immune response directed at CNS antigens, promoting inflammation and later driving progressive axo-glial degeneration. Trials with potent anti-inflammatory agents and detailed neuropathological studies raise questions about this sequence of events. This hypothetical paper argues that MS may be primarily a "cytodegenerative" disease, possibly first involving the oligodendrocyte/myelin unit. Liberation of autoantigens secondarily recruits an immune response, the force of which heavily depends on the host's immune predisposition. Thus, the spectrum of MS from highly aggressive Marburg type, to primary progressive disease with little inflammatory burden, is governed by a "convolution" between the underlying cytodegeneration and the host's immune predilection. Clinical heterogeneity may be a reflection of a variable immune response, whereas in reality, the "real MS" may be a homogeneous degenerative process analogous to well known primary neurodegenerative diseases. PMID- 21246932 TI - The human microbiome in multiple sclerosis: pathogenic or protective constituents? AB - The human microbiome is comprised of commensal and pathogenic microorganisms, which exert diverse effects in close proximity to the site of intection as well as in remote tissues through immune-mediated mechanisms. Multiple infectious agents have been implicated in the pathogenesis of multiple sclerosis (MS) with variable findings depending on the agent, techniques, and disease phenotype. Herein, the contributions of individual infectious agents to MS and their effects on the immune and nervous systems are reviewed, focusing on herpes viruses, coronaviruses, retroviruses, and synchronic infections. While infectious agents are often assumed to be pathogenic, their effects might also be beneficial to the host in the long-term, depending on age and the type of immunogen/pathogen exposure, as proposed by the hygiene hypothesis. The human microbiome has potential impact on future diagnostic and therapeutic issues in MS. PMID- 21246933 TI - White matter repair: skin-derived precursors as a source of myelinating cells. AB - Stem cell based therapies hold great promise for repair and functional restoration following neurological injury and disease. Skin-derived precursors (or "SKPs") are a novel, multipotent somatic stem cell that resides within the mammalian dermis. SKPs persist within the skin throughout adulthood and yet intriguingly, exhibit many similarities to embryonic neural crest stem cells (NCSCs). For example, SKPs give rise to both neural and mesodermal cell types, and the former appear biased to peripheral nervous system fates. As such, SKPs are capable of generating Schwann cells, the myelinating glial cell of the peripheral nervous system. Here we discuss our current understanding of the biological origin of SKPs and specifically the potential therapeutic utility of SKPs as a highly accessible and autologous source of Schwann cells for remyelination and repair of the injured or diseased nervous system. PMID- 21246934 TI - New directions in multiple sclerosis therapy: matching therapy with pathogenesis. AB - All currently approved therapies for multiple sclerosis (MS) modulate systemic immune components prior to their entry into the central nervous system (CNS). Available data indicate they lack impact on the progressive phases of disease; the more potent systemic immune-directed agents predispose to development of infectious or neoplastic disorders. Development of new agents that enhance disease stage related efficacy and limit systemic toxicity will need to consider the underlying mechanisms related to each phase of the clinical disorder, namely relapses, remission, and progression. This report focuses on disease related mechanisms ongoing within the CNS that contribute to the different phases of MS and how these may serve as potential therapeutic targets. Such mechanisms include CNS compartment specific immunologic properties especially as related to the innate immune system and neural cell-related properties that are determinants of the extent of actual tissue injury and repair (or lack thereof). PMID- 21246935 TI - Inverse vaccination to silence immunity to myelin in multiple sclerosis. AB - The adaptive immune response in multiple sclerosis is complex. We have devised large scale arrays to measure the antibody response to myelin proteins and lipids. Despite the widespread immune responses to myelin, we have devised an inverse vaccine aimed at turning off key drivers of this diverse response. Clinical trials in patients with multiple sclerosis show that it is possible to constrain antibody responses to myelin on a large scale with this approach. PMID- 21246936 TI - Haematophageous vector monitoring in Djibouti city from 2008 to 2009: first records of Culex pipiens ssp. torridus (IGLISCH), and Anopheles sergentii (theobald). AB - The Horn of Africa represents a region formerly known to be highly susceptible to mosquito-borne infectious diseases. In order to monitor and analyze the current presence and threat of vector mosquitoes, continuous and standardized trapping using CDC light traps without an additional CO2-generator has been carried out at six selected monitoring sites located in Djibouti City, from August 2008 until December 2009. An overall of 620 haematophageous Diptera were trapped, 603 (97.3%) were mosquitoes, 10 (1.6%) were sand flies, and 7 (1.1%) were biting midges, respectively. Genus distribution of mosquitoes revealed that 600 (99.5%) were Culex spp., 2 (0.3%) were Anopheles sergentii, and 1 (0.2%) was Aedes aegypti. Culex species were represented by Cx. quinquefasciatus (78.5%), and Cx. pipiens ssp. torridus (21.5%). The later species was first detected focally in early December 2009 showing a strongly increasing population density resulting in a maximum trap rate of 25 mosquitoes per trap night. Sand flies were all Sergentomyia antennata, and biting midges of the genus Culicoides were represented by C. nubeculosus (71.4%) and C. vexans (28.6 %). The findings included the first records for Cx. pipiens ssp. torridus and An. sergentii in Djibouti. However, none of the captured female Culex spp, the known vector for West Nile Virus, showed positive results for viral nucleic acids using WNV RT real time PCR system. Also, females An. sergentii were Plasmodium falciparum and P. vivax circumsporozoite protein negative. PMID- 21246937 TI - Seroprevalence of Toxoplasma gondii antibodies in domestic ducks, free-range chickens, turkeys and rabbits in Kafr El-Sheikh Governorate Egypt. AB - In Kafr El-Sheikh, Capital of Kafr El-Sheikh Governorate, Toxoplasma-IHAT was performed on locally bred domestic ducks, free-range chickens, turkey and domestic rabbits. The results revealed an infection rate of 55, 38.1, 29.4, and 37.5% respectively which indicates a soil contamination and environmental zoonotic risk. PMID- 21246938 TI - Quantitative analysis of total proteins and carbohydrates in the digestive gland gonad complex (DGG) and hemolymph of the freshwater prosobranch snail Lanistes carinatus. AB - Laboratory investigations were carried out to quantify the amount of total proteins, carbohydrates and reducing sugar in the hemolymph and Digestive Gland Gonad- complex (DGG) of infected and uinfected lanistes arinatus. Snails were naturally infected with two different types of trematode la:val stages (rediae of gymnocepahalus cercaria and sporocyst of xiphidiocercaria), collected from the River Nile at Sohag governorate, Egypt. Analysis was carried out using an extraction of the DGGs tissue with buffer solution, while snails' hemolymph was applied directly. The results revealed that snail infection by rediae of gymnocephalus cercariae led to non significant increasing in both total carbohydrates and protein in hemolymph. However, infection by sporocysts of xiphidiocercariae caused a significant increasing only in hemolymph total protein. On the other hand, the amount of both reducing sugar and total proteins in DGG did not increase significantly whenever the infection caused by both types of trematode larvae. However, total carbohydrates in DGG increased significantly. PMID- 21246939 TI - Parasitosis among apparently healthy immigrant workers at Dammam, Saudi Arabia. AB - A cross sectional study was conducted on randomly selected 161 apparently healthy immigrant workers in Dammam City, with ages ranged between 21 to 40 years. A required data were taken via a designed questionnaire and stool samples were collected and examined microscopically by direct wet mount (saline and iodine stained smears) and by formalin ether concentration sedimentation technique. The results showed 99/161 (55.3%) suffered parasitosis. These were in a descending order they were E. histolytica (50.5%), Giardia lamblia (38.8%), Enterobius. vermicularis (12.1%), Entamaeba coli (12.1%), Trichuris trichiura (11.1%), Hymenolepis. nana (11.1%), Schisto-soma haematobiumn (10.1%), A.scaris lumbricoides (9.09%), S. mansosoni (7.07%), Dicrocelium dendriticum (5.05%), and Fasciola species (3.03%). On the other hand, 72 (44.7%) of the immigrant workers were Toxoplasma gondii ELISA-IgG positive. The intervention programs including health education, strict supervision of health authorities on immigrant workers as well as environmental sanitation are required. PMID- 21246940 TI - Lupus nephropathy: clinical, immunohistochemistry and quantitative morphometric analysis studies. AB - Lupus nephritis includes a wide range of parenchymal injuries and severity. Better predictors to outcome are needed for patients newly diagnosed with lupus nephritis, so that an appropriate management strategy may be selected. This study aimed to determine whether the ratio of hepatocyte growth factor (HGF) to transforming growth factor beta 1 (TGF beta1) in lupus nephritis could be a prognostic factor for response to therapy with cyclophosphamide and steroids at six months. Also, to determine whether a simple automated system for objective scoring of biopsies of lupus nephritis could be a prognostic factor for response to therapy with cyclophosphamide and steroids at 6 months. Consequently, renal biopsy findings and clinical parameters of thirty parasites-free patients with new onset lupus nephritis were recorded. Histopathologic, clinical, immune histochemical and morphometric data at baseline served to define the predictive value for outcome after 6 months of therapy. The results showed a significant positive relationship between response to therapy and HGF IS (P= 0.007), HGF ES (P= 0.026), HGF IS/ TGFbeta1 IS ratio (P= 0.022) and HGF ES/ TGFbeta1 ES ratio (P= 0.001). A significant inverse relationship was proved between response to therapy and TGFbeta1 IS (P= 0.025) as well as TGFbeta1 ES (P= 0.017). Also, a significant inverse relationship was present between response to therapy and nuclear index, tubular index and matrix index (P = 0.03, 0.03 and 0.029 respectively). PMID- 21246941 TI - Drug resistance evaluation of some commonly used anti-coccidial drugs in broiler chickens. AB - The study investigated some anticoccidial resistance for Amprol, Toltrazuril and sulfaclozine in experimental infected broiler. Eimeria identification depended on necropsy and coproscopic examination. 140 day-old chicks allotted into 7 groups and infected with Eimeria in 2nd day of age. G1: neither infected nor treated (negative control), G2: infected but not treated (positive control), Infected and treated with toltrazuril (G3), or with Amprol+Allicin (G4), or with Amprol+ethobabate (G5), or with Amprol (G6) or with Sulfaclozine (G7). Eimeria infection caused decrease in body gain, total protein, albumin but increase in FCR, ALT, AST, Uric acid, Creatinine. Treatment decreased the harmful effect of infection but some significant differences were between infected treated groups and non infected non-treated one. PMID- 21246942 TI - Molecular and phylogenetic analyses of Cryptosporidium SPP from dairy cattle in Egypt. AB - Cryptosporidium infections in cattle result in considerable'economic loss as well as a significant source for zoonotic infection. This study was devoted to spot analysis on Cryptosporidium parasites derived from dairy cattle at Kafr El Sheikh Province, Egypt, using morphological and molecular tools. Fecal specimens from neonatal calves as well as adult cattle were screened for Cryptosporidium oocysts using modified Ziehl-Neelsen technique. Oocysts in positive samples were concentrated using sugar floatation technique. Small size oocysts from calves and large size ones from adults were identified microscopically with measures correspond to those of C parvum and C. muris-C. andersoni, respectively. DNA was extracted from 8 positive specimens; 4 harbored small and 4 had large oocysts and used for PCR amplification, RFLP analysis and nucleotide sequence. RFLP analysis revealed 2 types of banding patterns coinciding with those of Cryptosporidium parvum and C. muris-C. andersoni. Sequence analysis of amplified fragments of small subunit of ribosomal RNA (SSU rRNA) and heat shock protein (HSP70) genes were used as markers for species identification and genotyping of the parasite. Homology search and phylogenetic analysis of the generated sequences versus those deposited in Genbank revealed that small oocysts were belong to C. parvum genotype II, whereas large ones were belong to C. andersoni. PMID- 21246943 TI - Interleukin (Il)-12, Il-5 and total IgE in hepatosplenic schistosomiasis with or without asthma. AB - There are a number of similarities between protective immune responses against schistosomiasis and asthma. Both are associated with elevated concentrations of IgE and eosinophilia. Chronic schistosomiasis is liked to Th1 like response with involvement of pro-inflammatory cytokines in schistosomal hepatosplenic disease process resulting in low level of IL-5. Meanwhile, association with asthma could modulate the immune response with shift to Th2 side resulting in marked elevation of IL-5 and eosinophilia. This work evaluated the levels of serum IgE, IL-5 and IL-12 in Schistosoma mansoni-infected asthmatic patients. A total of 100 subjects selected from Al-Azhar University's Hospitals were divided into three groups GI: 50 patients with hepatosplenic schistosomiasis associated with asthma. GII: 25 patients with hepatosplenic schistosomiasis without apparent asthma. GIII: 25 patients with neither bilharzial liver cirrhosis nor asthma as control group. All patients were subjected to full history taking and clinical examination, pulmonary function tests, total serum IgE, bilharzial antibody titre, stool and urine examination for parasites, liver function tests and serum IL-5 and IL-12. The results showed very high level of the total serum IgE in GI and GII compared to GIII. There was high significant difference in peripheral blood eosinophil%. GI & GII gave highest levels, IL-5 was elevated in GI, but low GII, I-12 was high in GII than GI. PMID- 21246944 TI - Resistance of gastrointestinal nematodes of sheep to some anthelmintics. AB - The occurrence of resistance to three of commonly used anthelmintics, Pyrantel tartrate (Banminth), Albendazole2.5% (Valbazen) and Duramectin 1% (Dectomax) was studied in locally bred sheep in Kafr El Sheikh Governorate, Egypt, by means of faecal egg count reduction test (FECRT). The faecal egg count reduction test showed that Pyrantel tartrate and Albendazole were less than 95% effective, 77% and 89% FECR% value respectively (i.e.: presence of resistance) while Duramectin showed full efficacy, 100% FECR% value. Culture of faecal samples before and after treatment in groups was done to interpret the anthelmintic resistance of individual nematode species. Where Ostertagia circumcincta and Bunostomum trigonocephalumn were susceptible to Pyrantel tartrate and Albendazole (100% FECR for each) but Nematodirus battus and Homonchus contortus have developed varying degrees of resistance for both drugs (56.3%, 48.2% and 88%, 70% respectively). Meanwhile, all nematode species were susceptible to Duramectin. PMID- 21246945 TI - Prevalence of malnutrition and intestinal parasites among preschool children in the Gaza strip. AB - Helminthiasis is one of the public health problems worldwide. This is especially true in Gaza Strip. This study demonstrated the, parasites prevalent among mal nutritional preschool-children according to the anthropometric cutoff points (WHO, 2007) and their family socio-demographic variability. PMID- 21246946 TI - Biological aspects on Dictyocaulus arnfieldi. AB - In the postmortem examination of 54 adult donkeys slaughtered for the carnivore animals in Kafr El-Sheikh Zoological Garden, Dictyocaulus arnfieldi (Cobbold, 1884) Railliet and Henry, 1907 was demonstrated in their lungs. The biological data of the different developmental stages were recorded and discussed, where the period required for maturation, hatching and development of 2nd and 3rd stage larvae was 84 hours, general discussion was given. PMID- 21246947 TI - Anti-Toxoplasma gondii antibodies among volunteer blood donors in eastern Saudi Arabia. AB - A cross-sectional study was conducted to evaluate the risk factors of Toxoplasma gondii in 100 volunteer blood donors at blood bank. Blood donors were interviewed about sociodemographic characteristics and risk factors toxoplasmosis. A required data were taken through a designed questionnaire. Five ml. venous blood samples were withdrawn by disposable sterile syringes to separate sera. Anti-Toxoplasma antibodies were evaluated by using ELISA. The results showed that 40 volunteers (40%) were positive for anti-T. gondii IgG antibodies. The T. gondii positivity and the risk factors analysis in a descending order were manual activities (95%) compared to (15.0%), Contact with farm animals and/or birds (87.5%) compared to (30.0%) , eating processed meat "shawerma" (87.5%) compared to (41.7%) raw milk or milk product (70%) compared to (50.0%), rural residence (62.5%) compared to (33.3%), non-educated (62.5%) compared to (16.7%), and least one was the contact with cats (55.0%) compared to (16.7%). These findings highlight the prevalent T. gondii among blood donors and focused on the risk factors. It was recom-mended that blood donors should be free from Toxoplasma antibodies PMID- 21246948 TI - Effects of some botanical extracts on the midgut, integument and fat body of the cotton leaf worm, Spodoptera littoralis (Lepidoptera: Noctuidae). AB - Botanical extracts (8%) of four plants (Artemisia monosperma, Zygophyllum cocccineum, Lupinus termis and Brassica tournifortii) fed to the 4th larval instars of Spodoptera littoralis induced histopathological changes in the structure of the midgut, integument and fat body of the 5th instars. Zygophyllum cocci-neum and Lupinus termis induced severe damages in the midgut. The integument of treated larvae showed degeneration in the cuticle and epidermal cells which were also detached from each other. Water extracts of A. monosperma, Z. coccinieum and L. termis were the most promising in inducing shrinkage in the fat body cells and detachment of midgut muscle layers. Also, the degeneration of the midgut membrane and epithelial layer occurs in different degrees with the tested plants. This study supports the use of botanical extracts in pest control programs of lepidopterous insects. PMID- 21246949 TI - Eimeria falconensis sp. n. (Apicomplexa: Eimeriidae) from the lanner falcon, Falco biarmicus (Falconiformes: Falconidae) in Saudi Arabia. AB - The oocysts of Eimeria falconensis sp.n. is described from the feces of the lanner falcon, Falco biarmicus, from the falcon market in Riyadh city, Saudi Arabia. Sporulated oocysts are ellipsoid in shape, measuring 27.2x18.1 (25.4 29.5x 16.3-20.4) JLm; shape index (length/width ratio) is 1.5 (1.35-1.68microm. The oocyst wall is smooth and bi-layered. Mmicropyle and polar granule are present, but an oocyst residuum is absent. Sporocysts are ellipsoid, 11.0 x6.9 (10.1-12.6 x 5.8-7.9) microm; with shape index of 1.59 (1.43-1.68) microm, with a smooth single-layered wall and a prominent Stieda body, but there is no subs tieda body. The sporocyst residuum consists of numerous small granules. Sporozoites are comma-shaped, each contains two refractile bodies. PMID- 21246950 TI - Infestation rate of tick, mite and lice among rodent species in Menoufia governorate, Egypt. AB - A preliminary survey of domestic rodent species and their ectoparasites tick, mite and lice was carried out in ten centers of Menoufia (Quesna, Shebeen El-Kom, Berka El-Saabe, El-Bagour, El-Shohada, Tala, Menoff, Searth El-Lian, Ashmon and El-Sadat) Governorate. Frequency of rodent species and ectoparasites indices (tick, mite and lice) were recorded in spring (2009). The main species of rodent was Norway rat, Rattus norvegicus, the grey-bellied rat, Rattus rattus alexandrinus, the white-bellied rat, Rattus rattus frugivorus and the house mouse, Mus musculus. The common tick species attacking rodents were: Rhipicephalus sp. and Hyalomma sp. The common mite species attacking rodents were: Dermanyssus sangineus, Orithonysus bacoti, Haemolaelaps glas-gowi, Laelaps nutalli, Radfordia sp. and Myobia sp. The only common lice species was Polyplax spinulosa. The fur mites Radfordia sp. and Myobia sp. were recorded at Quesna, Searth El-Lian and El-Sadat centers on R. norvegicus for the first time at Menoufia Governorate. PMID- 21246951 TI - Diarrhea due to parasites particularly Cryptosporidium parvum in great Cairo, Egypt. AB - A total of 110 stool samples from out and in-patients from different areas in Great Cairo suffering from diarrhea were examined for parasitic causes. Stool samples were subjected to the direct wet smear method and Sheather's sugar flotation and stained with Giemsa and/or modified Ziehl-Neelsen. Also, stool samples were cultured on agar plates for strongyloidiasis. The overall parasitic infection rate was 60.9% and non parasitic cause was 39.1%. The parasitic infection rate in a descending order was 31.1% for Cryptosporidium parvurnm, 19.8% for Giardia lamblia, 9.9% for Entamaeba histolytica and lastly 1.8% for Strongyloides stercoralis. The main clinical presentation of diarrheic patients in a descending order was vomiting (31.3%), dehydration (29.86%), abdominal pain (29.86%), flatulence (26.86%), anorexia (23.89%), tenesmus (17.9%) and lastly fever (4.47%). The risk factors were living in rural areas, education level, contact with farm animals and/ or pet animals. However, most of these risk factors although showed high percent, yet they occurred in patients with other causes of diarrheas. Artificial breast feeding was not evaluated as only 3 infants had C. parvum compared to non parasitic cause in 1 on the breast feeding. PMID- 21246952 TI - Seroprevalence of Toxoplasma gondii, cytomegalovirus, rubella virus and Chlamydia trachomatis among infertile women attending in vitro fertilization center, Gaza strip, Palestine. AB - In the present study, the seroprevalence of Toxoplasmia gondii, rubella, cytomegalovirus (CMV) and Chlamydia trachomatis in Palestinian women was determined through antenatal screening. The study included 1954 Palestinian women records which were reviewed and analyzed statistically from 2000-2005. Those women attended In vitro fertilization center in Gaza complaining from infertility and abortion. Anti-Toxoplasma, anti-rubella, anti-CMV and anti-Chlamydia IgM antibodies were assayed using an enzyme linked immunosorbent assay (ELISA). Positive results were found in 7.9%, 6%, 7% and 12.8% for T. gondii, CMV, Rubella and C. trachomatis antibodies. A high significant infection rate was observed in year 2003 (P = 0.001) for T. gondii. A clear variation with statistical significance was observed in the seroprevalence for all the studied pathogens regarding year of collection and age of women. The study indicated that T. gondii, rubella, CMV and C. trachomatis are still constitute a public health problem among pregnant women and considered one of the abortion factors. PMID- 21246953 TI - Anti-Toxoplasma gondii antibodies in working donkeys and donkey's milk in greater Cairo, Egypt. AB - Toxoplasma gondii is one of the important zoonotic parasites of worldwide zoological & geographical distribution. ELISA prevalence of Toxoplasma gondii in Egyptian locally bred working donkeys in greater Cairo was evaluated. The donkeys were 75 females & 25 males aged between 3-10 years. The results showed that ELISA antibodies of T. gondii were found in 45 out of 100 (45%) working donkeys. Donkeys' milk obtained from fifteen pregnant females was T. gondii positive in seven (46.3%). The zoonotic role of donkeys and their milk were discussed. PMID- 21246954 TI - Isoenzyme electrophetic characterization of Leishmania major, the causative agent of zoonotic cutaneous Leishmaniasis in North and West Saudi Arabia. AB - Several expeditions were carried out to four localities (Al-Madinah Almona-warah, Tabouk region, Al-Jouf and Northern Frontiers regions) in Northern and Western Saudi Arabia for sampling zoonotic cutaneous leishmaniasis (ZCL) cases from patients and rodents. Biopsy samples were collected from 51 patients complaining of skin lesions, most of which (40 or 78.4%) proved to be ZCL. Amastigotes were detected in 33 patients (64.7%), but only 30 (58.9%) gave successful growth of promastigotes in the culture media. The positive cases were Saudis 14(35%) and non-Saudis 26 (65%). Five species of rodents were caught, Meriories libycus, Psammomys obesus, Rattus rattus, jaculus and Hystrix indica. The first species was the most dominant (90%) in which Leishmania parasites were detected. The Leishmania isolates from man and rodents were identified by isoenzyme electrophoresis and proved to be Zymodeme LON-4. PMID- 21246955 TI - Frequency of intestinal parasitic infection among children in Hadhramout governorate (Yemen). AB - Six hundred children from urban and rural regions of Hadhramout governorate were examined targeted for the detection of intestinal parasites during the year 2009. The main infective parasites prevailed in children were Gardia lamblia (19.17%), Entamoeba histolytica (16.83%), Ascaris lumbricoides (15.83%), Trichuris trichiura (2.33%), Hymenolepis nana (2.33%), Taenia saginata (1.50%) and Schistosoma mansoni (0.67%). Besides, infections were accompanied by different symptoms as diarrhea (43.5%), abdominal pain (23.3%), abdominal distention (17.3%), constipation (9.1%), nausea and vomiting (8.02%) and fever (5.1%). The parasitosis reflected the hygienic problems and their influence on public health of Hadhramout. PMID- 21246956 TI - Adiponectin in acute myocardial infarction non obese Egyptian men. AB - Adiponectin is an adipose tissue derived mediator with significant anti atherosclerotic properties and is involved in the regulation of insulin sensitivity and lipid oxidation, a few studies were done in acute phase of myocardial infarction, especially in none obese patients. The study investigated the association between adiponectin concentration and acute phase of myocardial infarction (MI) in non obese men patients. The results showed that adiponectin levels in patients with AMI (5.2ug/ml) were significantly lower than that of control group (7.5ug/ml) (P<0.001). Lower adiponectin levels were independently associated with higher risk of AMI (odd ratio= 6.12, 95%CIs: 2.4- 18.6; P=<0.001).Adiponectin levels were negatively correlated with triglyceride (r= 0.34) in case group and (r=- 0.41) in control group (P< 0.001). In addition, negatively correlated with BMI(r=-0.27) in case group and (r=-0.23) in control group (P< 0.001), but adiponectin levels is positively correlated with HDL Cholesterol (r= 0.45) in case group and (r=0.51) in control group with (P<0.001). PMID- 21246957 TI - Efficacy of Ixodes ricinus as a vector of zoonotic babesiosis in Sinai Peninsula, Egypt. AB - Ticks and blood samples were collected every month from March 2009 through April 2010 from different sites in Sinai to detect babesial parasites using PCR assay based on nuclear small subunit rRNA gene. Ticks were found to contain babesial DNA. Sequence determination and analysis of amplified portions of nss-rDNA revealed their identity with B. bovis and a high degree of homology with B. bigemina and B. divergens. The results represent the first genetic evidence of different species of Babesia and identified the role of Ixodes ricinus as a vector of zoonotic B. microti infection. Rodent isolate (HK) and American isolate (GI) were studied in transmission experiments. The present study used in vitro culture of zoonotic Babesia sp. EU1 from blood samples of rodent in Sinai. This study provides an evidence of transovarian and transstadial transmissions of the parasite within I. ricinus, which emphasizes that this tick could be a vector and reservoir of EU1 PMID- 21246958 TI - Prognostic value of TNF a mRNA and VEGF mRNA expression in patients with chronic hepatitis C genotype-4, with and without cirrhosis and hepatocellular carcinoma to predict disease outcome. AB - The study aimed to clarify whether vascular endothelial growth factor mRNA (VEGF mRNA) and TNFa mRNA in the HCC tissues on top of HCV with and without cirrhosis obtained from specimens after curative hepatic resection has a prognostic value and recurrence predictive value compared to other tumor criteria. A total of 160 patients were studied. The preoperative laboratory, radiological and staging to patients was done. Using in situ hybridization technique, VEGF mRNA and TNFa mRNA were determined in liver tissues of, 10 controls, 50 with HCC, 50 with HCV without cirrhosis and 50 HCV with cirrhosis. The results showed that in HCC cases there was positive correlation between increasing age, loss of weight, INR and AFP but not in other cases of CHC with or without cirrhosis. AFP, vascular invasion, encapsulation, tumor size and grade and platelet count were related to patients outcome and recurrence of tumor after follow up of most cases for 3 years. The expression of VEGF in liver tissues was proportional to progress of viral hepatitis to cirrhosis with more expression in cases progressed to malignant changes. More expression of VEGF in HCC was more evident with intense expression in cases with Vascular and capsular invasion and higher level of AFP. Expression of TNF alpha mRNA and VEGF mRNA shows increasing expression with positive correlation to progression of viral hepatitis to cirrhosis with more positive with cases developed HCC. PMID- 21246959 TI - Evaluation of ELISA and IHAT in serological diagnosis of proven cases of human hydatidosis. AB - Cystic hydatid disease (Hydatidosis) is the most serious tape-worm infection prevalent in the cattle and sheep raising area of the world. Hydatidosis in man (as an accidental host) is caused by infection with the ova containing larval stage of Echinococcus granulosus. In the last decade, different techniques have been employed for sero-diagnosis of hydatidosis; as IHA, IFA, ELISA, CCLE (Counter Current Immuno-electrophoresis). This paper evaluated the validity of ELISA and IHA. Since whole hydatid cyst fluid was used as a source of antigen for serodiagnosis. Thirty surgical and pathological hydatidosis proven patients were examined. The sensitivity and specificity of ELISA were 96.7% & 97.5% respectively, and that of IHA were 86.7%, &95% respectively. PMID- 21246960 TI - Chronic hepatitis C virus infection: prevalence of cryoglobulinemia and renal affection in the Egyptian patients. AB - The association between mixed cryoglobulinemia (MC), chronic hepatitis C virus (CHC), and renal insufficiency was documented. This paper aimed to determine the prevalence of cryoglobulinemia (CG), and renal affection drug-naive Egyptian patients suffering from CHC-in a cross-sectional study So, 53 patients with CHC and 20 healthy controls were included. Parameters investigated covered; HCV antibodies, HCV RNA, liver profile (AST, ALT, serum albumin, total bilirubin, prothrombin time), renal profile (urea, uric acid, creatinine clearance, urinary albumin), CG, C3, C4, & three MDRD equations to calculate the GFR. The results showed that CG was found in all patients, but none in controls. The renal markers showed that none of the patients suffered frank nephropathy, but were at increased risk for developing kidney disease. PMID- 21246961 TI - Pomegranate (Punica granatum). PMID- 21246962 TI - Holding pattern. Malpractice premiums plateau overall but still a crushing burden for many. PMID- 21246964 TI - When being uninsured hits home. A physician's effort to help with a relative's medical bill sheds light on the plight of the uninsured. PMID- 21246963 TI - Playing well with others. A doctor finds that not everyone in the profession values respect and collegiality as much as she does. PMID- 21246965 TI - An unexpected turn. Lessen learned about patient advocacy when a family member is hospitalized during vacation. PMID- 21246966 TI - Health coaching good for your patients and your practice. How to cater to a growing segment of patients who want partners in their quest for health. PMID- 21246967 TI - In their shoes. Helping patients and their families come to terms with terminal illness requires empathy and respect. PMID- 21246968 TI - Trusting your gut. An employee's suspicious behavior teaches a doctor the value of following her instincts. PMID- 21246969 TI - Patient-centered approach still requires documentation. PMID- 21246970 TI - Are you going to fire me, too? You can help your patients by being open and honest. PMID- 21246971 TI - Party crashers. Hospitals waking up to implications, benefits of medical homes. AB - As evidence mounts that the savings from medical homes come at hospitals' expense, hospitals have decided they want in on the action. Hospitals have been more interested in forming accountable care organizations because ACOs would have "a greater impact on their financial relationships given the risks and rewards being anticipated," said Michael Kulczycki, left, of the Joint Commission. PMID- 21246973 TI - Bond crisis. As credit relief end looms, deals come to a halt. PMID- 21246972 TI - More evidence piles up. Savings coming from reduced hospital care. PMID- 21246974 TI - Rebound at Joint Commission. Net income up 170%; consulting arm's income dives. PMID- 21246975 TI - Status quo in Congress. Americans suffer while lawmakers are in the dark. PMID- 21246976 TI - Largest healthcare financing companies. Ranked by amount of loans underwritten in 2009. PMID- 21246977 TI - Equal-opportunity burden. Legal order for Florida hospital could mean new hiring rules on top of health reform hurdles for thousands of healthcare providers. AB - A judge's decision that a Florida hospital is a federal subcontractor because it provides care through the military's Tricare program has put the industry on alert. Hospitals fear they'll be forced to to jump through lots of hoops to comply with federal rules regarding hiring. "Many of the substantive obligations that are sought to be imposed ... are already fully applicable to hospitals through state and other federal laws," says Curt Kirschner, left, a lawyer with Jones Day. PMID- 21246978 TI - FTC targets consent. Report addresses concerns over online health info. PMID- 21246980 TI - The Tropical Biology Award 2010 has been awarded to zoologist Diomedes Quintero Arias. PMID- 21246981 TI - Determinants of scientific output: an in-depth view of the productivity of tropical botanist and conservationist, Luis Diego Gomez Pignataro. AB - Bibliometric studies have found that male researchers have their greatest productivity around the age of 40, that female researchers produce less than their male colleagues, that incentives for collaboration are slow to affect productivity and that, just like humans, research institutes become larger, less productive, more expensive to maintain and less able to raise money as they grow old. Almost invariably, these conclusions come from statistical studies of large numbers of European and American scientists, and there are practically no studies about tropical researchers. We present an in-depth analysis of the productivity of an internationally recognized tropical botanist and conservationist, Luis Diego Gomez Pignataro, based on the totality of his published work and on our own knowledge, as co-workers and friends, of the life frame in which that scientific output was produced. His life output departs from the expected pattern in that he had the highest productivity before reaching the expected peak productivity age, and that when he reached it his productivity fell and never recovered. Furthermore, marriage did not produce the expected fall in productivity. A close analysis of his life indicates that in the middle of his career he switched to intense teaching and conservation activities, and this better explains why his output of scientific research articles was low afterwards. This switch may occur in other tropical scientists. PMID- 21246982 TI - Education as a tool for addressing the extinction crisis: moving students from understanding to action. AB - Human activity is leading to mass species extinctions worldwide. Conservation biology (CB) courses, taught worldwide at universities, typically focus on the proximal causes of extinction without teaching students how to respond to this crisis. The Extinction of Species 360 course has been taught yearly each fall semester to several hundred students at the University of Wisconsin-Madison for over two decades. In 2007 the instructor and five teaching assistants combined principles driving extinctions, based on traditional lectures and discussion sections, with action-oriented education targeting individual consumer habits, to a group of 285 students. Students learn the science underpinning conservation efforts, as evidenced by highly significant learning (< .001) gains in a 22 question survey in every measured category, and also make direct and immediate changes in their lifestyle and consumption habits. This course succeeded in each of its three primary goals: a) informed students about the value of and threats to biodiversity, similar to traditional CB courses, b) emphasized our personal role (as consumers) in perpetuating the extinction crisis and c) facilitated activities to reduce our impact and help alleviate the crisis. The results suggested students learned CB concepts and understood biodiversity's value, increased their awareness of the connection between personal consumption and extinction, and reduced their collective ecological footprints. Furthermore, students complemented their learning and multiplied the potential for consumption reduction, by participating in action-based activities. Such academic courses can provide a rigorous treatment of the direct and indirect causes of extinction while developing a student's sense of personal empowerment to help slow the extinction crisis. PMID- 21246983 TI - A new giant species of placented worm and the mechanism by which onychophorans weave their nets (Onychophora: Peripatidae). AB - Onychophorans, or velvet worms, are poorly known and rare animals. Here we report the discovery of a new species that is also the largest onychophoran found so far, a 22 cm long female from the Caribbean coastal forest of Costa Rica. Specimens were examined with Scanning Electron Microscopy; Peripatus solorzanoi sp. nov., is diagnosed as follows: primary papillae convex and conical with rounded bases, with more than 18 scale ranks. Apical section large, spherical, with a basal diameter of at least 20 ranks. Apical piece with 6-7 scale ranks. Outer blade 1 principal tooth, 1 accessory tooth, 1 vestigial accessory tooth (formula: 1/1/1); inner blade 1 principal tooth, 1 accessory tooth, 1 rudimentary accessory tooth, 9 to 10 denticles (formula: 1/1/1/9-10). Accessory tooth blunt in both blades. Four pads in the fourth and fifth oncopods; 4th. pad arched. The previously unknown mechanism by which onychophorans weave their adhesive is simple: muscular action produces a swinging movement of the adhesive-spelling organs; as a result, the streams cross in mid air, weaving the net. Like all onychophorans, P. solorzanoi is a rare species: active protection of the habitat of the largest onychophoran ever described, is considered urgent. PMID- 21246984 TI - On Branchiostoma californiense (Cephalochordata) from the Gulf of Nicoya estuary, Costa Rica. AB - The cephalochordates are represented by the lancelets, of which species of the genus Branchiostoma are the best known. In recent years, these organisms have been the center of activity of studies focusing on the phylogenetic relationships of the chordates. In 1980, a survey of the benthos at 48 stations in the Gulf of Nicoya estuary, Pacific coast of Costa Rica, yielded 265 specimens of the lancelet Branchiostoma californiense. A total of 48 specimens was also collected at an intertidal flat in the mid upper estuary. Of the 48 subtidal stations, only eight had B. californiense, and these sites all had a sand fraction above 72%. The remaining stations ranged in their sand content from as low as 1% to as high as 92%, with an average of 25.9%, with 29 stations having a sand content lower than 72%. Lower salinities and muddy sediments may limit the distribution of the lancelet further upstream. This information is useful when changes over decades in the ecology of the estuary need to be evaluated against the background of local, regional, and global dynamics. PMID- 21246985 TI - A new fish, Peristedion nesium (Scorpaeniformes: Peristediidae) from Isla del Coco, Costa Rica. AB - Several expeditions in recent years to Isla del Coco have increased the total number of species of fishes known from the island. Several of these species have been described as new endemics (Bussing 1983, 1990, 1991a, 1991b, 1997). During the 1972 R/V Searcher Expedition to Costa Rica several trawl collections were made around Isla del Coco. At five localities in depths between 110 and 180m, 86 specimens of a new species of Peristedion were taken and are described herein. A key to the four species of Eastern Pacific Peristedion is included. PMID- 21246986 TI - A fly larva (Syrphidae: Ocyptamus) that preys on adult flies. AB - Predatory syrphid larvae feed on relatively immobile prey, but here we report the first case (as far as we are aware) of obligatory predation on very mobile prey. Larvae of an undescribed species of Ocyptamus (Diptera: Syrphidae) were found in whitefly (Hemiptera: Aleyrodidae) aggregations on the undersides of citrus leaves. However, instead of preying on the whitefly nymphs (as would be expected), the larvae preyed on adult flies (Diptera) that were attracted to the honeydew. In the laboratory, larvae captured significantly more flies on whitefly infested leaves than on washed leaves, and generally abandoned leaves that lacked whiteflies. Most cases of successful prey capture involved flies that probed the anterior part of the larva's body with its proboscis (as if it were honeydew). The syrphid larva lashed out at the fly and entangled it in sticky oral secretion. The prey did not recover when they were removed from the larva, suggesting that this new predatory species also employs venom to subdue its prey. Although the larvae consumed some honeydew, they were unable to complete their development on this diet. Two parasitoids were reared from Ocyptamus puparia, Proaspicera sp. (Hymenoptera: Figitidae) and Paracarotomus sp. (Hymenoptera: Pteromalidae), both of which are endoparasitic koinobionts. PMID- 21246987 TI - Nesting biology of four species of Trypoxylon (Trypargilum) (Hymenoptera: Crabronidae) in Chaco Serrano woodland, Central Argentina. AB - Trypoxylon (Trypargilum) (Crabronidae) wasps are solitary spider predators that can build their nests in artificial trap-nests, which enables study of their nesting architecture and biology. Twenty traps (each containing 15-30 internodes of cane) were placed in each of nine sites of Chaco Serrano Woodland in Central Argentina (Cordoba) in October 2005, and were recovered in June 2006. We obtained 91 nests of four species of Trypoxylon (Trypargilum). In the laboratory, each Trypoxylon nest was sectioned longitudinally to study its architecture. The number of brood cells was counted, and the occurrence and length of vestibular and intercalary cells and the pre-closing plug space were recorded. We measured the diameter of the cane entrance, total length of the nest, length of each brood cell, maximum thickness of mud partitions and closing plug thickness. We also recorded the cell contents: the wasps, their natural enemies and the prey spiders. Mortality was assessed and the sex ratio calculated for each species. Finally, the nests were examined to help clarify the function of the vestibular cell. The nest architecture was similar in the four species, with linear brood cells located one after the other separated by mud partitions, as in other species of the subgenus Trypargilum. Forty-eight percent of the nests had vestibular cells, but only two had intercalary cells. The thickness of the mud partitions and the length of the brood cells differed among species and were related to the size of the emerged wasp. The diameter of the nest entrance was directly related to the average length of the fore-tibia. Sex ratios of all species did not deviate from 0.5. Mortality due to parasitoids (Eulophidae; Melittobia sp.) was similar among species, while the mortality due to cuckoo wasps (Chrysididae) in T. lactitarse was higher than in the other species. The presence of vestibular cells was not related either to the mortality due to natural enemies or to the orientation of the trap in the field. Spiders in the family Araneidae were the most frequently collected prey. PMID- 21246988 TI - Escape tactics and effects of perch height and habituation on flight initiation distance in two Jamaican anoles (Squamata: polychrotidae). AB - Escape by Anolis lizards is influenced by microhabitats and fight initiation distance increases with predation risk. Differences in microhabitat use among ecomorphs affect escape behavior, but only two studies have reported ecomorphological differences in flight initiation distance among Greater Antillean species. I studied effects of predation risk and microhabitats on escape behavior by conducting field experiments using two species of anoles, Anolis lineatopus and A. grahami, on the campus of the University of the West Indies at Mona, Jamaica. Because ecomorphological variation of anoles has evolved independently within each island of the Greater Antilles, but relationships between ecomorphs and escape behaviors are poorly known, I characterized microhabitat use and escape tactics, and determined relationships between flight initiation distance and two risk factors, habituation to human presence and perch height, in Anolis lineatopus, a trunk-ground anole and A. grahami, a trunk-crown anole. Sample sizes for A. lineatopus and A. grahami were 214 and 93, for microhabitat use and escape destinations, 74 and 34 for human presence and 125 and 34 for perch height. The two species occurred in similar microhabitats and exhibited similar escape tactics, but exhibited key differences expected for their ecomorphs. Both species were sighted frequently on the ground and on trees, but A. lineatopus were more frequently on ground and were perched lower than A. grahami. Both species escaped from ground to trees and when on trees hid on far sides and escaped without changing climbing direction with equal frequency. The frequency of fleeing upward was greater for A. grahami than A. lineatopus. Both species exhibited habituation by having shorter flight initiation distances in areas with more frequent exposure to people. In both species flight initiation distance increased as perch height decreased because, lizards had to climb farther to be out of reach when perched lower. The relationship between flight initiation distance and perch height may apply to other anole ecomorphs that flee upward when low perched on trees. PMID- 21246989 TI - Beach erosion and nest site selection by the leatherback sea turtle Dermochelys coriacea (Testudines: Dermochelyidae) and implications for management practices at Playa Gandoca, Costa Rica. AB - Leatherback sea turtles (Dermochelys coriacea) nest on dynamic, erosion-prone beaches. Erosive processes and resulting nest loss have long been presumed to be a hindrance to clutch survival. In order to better understand how leatherbacks cope with unstable nesting beaches, I investigated the role of beach erosion in leatherback nest site selection at Playa Gandoca, Costa Rica. I also examined the potential effect of nest relocation, a conservation strategy in place at Playa Gandoca to prevent nest loss to erosion, on the temperature of incubating clutches. I monitored changes in beach structure as a result of erosion at natural nest sites during the time the nest was laid, as well as in subsequent weeks. To investigate slope as a cue for nest site selection, I measured the slope of the beach where turtles ascended from the sea to nest, as well as the slopes at other random locations on the beach for comparison. I examined temperature differences between natural and relocated nest sites with thermocouples placed in the sand at depths typical of leatherback nests. Nests were distributed non-randomly in a clumped distribution along the length of the beach and laid at locations that were not undergoing erosion. The slope at nest sites was significantly different than at randomly chosen locations on the beach. The sand temperature at nest depths was significantly warmer at natural nest sites than at locations of relocated nests. The findings of this study suggest leatherbacks actively select nest sites that are not undergoing erosive processes, with slope potentially being used as a cue for site selection. The relocation of nests appears to be inadvertently cooling the nest environment. Due to the fact that leatherback clutches undergo temperature-dependent sex determination, the relocation of nests may be producing an unnatural male biasing of hatchlings. The results of this study suggest that the necessity of relocation practices, largely in place to protect nests from erosion, should be reevaluated to ensure the proper conservation of this critically endangered species. PMID- 21246990 TI - Inferring possible population divergence in Espeletia pycnophylla (Asteraceae) through morphometric and paleogeographic approaches. AB - Abstract: The phenotypic structure within and between plant populations is generally influenced by their distribution patterns in space and time; therefore, the study of their divergence is a central issue for the understanding of their microevolutive processes. We boarded the hypothesis that three populations of Espeletia pycnophylla show phenotypic divergence as one of the possible implications of their geographic isolation in the Southern Colombian Andes. We used the Elliptic Fourier Descriptors (leaf shape) and traditional leaf morphometry (leaf size) of 347 leaves to measure inter and intra-population variation and a comparison between a paleogeographic reconstruction with an actual estimate of the distribution areas of E. pycnophylla in order to identify their main changes during the last 14 000 years. The three populations showed significant differences in leaf morphometry and a positive correlation between the matrices of morphometric and geographic dissimilarities, indicating that the inter-population divergence increases between further populations, so that the morphometric structure reflects their spatial distribution. The geographical and paleogeographical estimates evidenced a conspicuous process of reduction and fragmentation of the distribution area of E. pycnophylla since the Late-Glacial until the Holocene. We suggest that these results support possible scenarios of vicariance events, which allow us to approach the divergence of these populations in terms of their historic biogeographic relations. However, genetic analyses are still needed to support these results. PMID- 21246991 TI - Young restored forests increase seedling recruitment in abandoned pastures in the Southern Atlantic rainforest. AB - Planting seedlings is a common technique for abandoned pastures restoration in the tropics, supposedly by increasing the seedling recruitment and accelerating succession. In this study we evaluated the role of a young restored forest (one year old) in enhancing seedling establishment from two sources (seed rain and seed bank), in the Atlantic Rainforest region in Southern Brazil. We compared abandoned pasture, young restored forest and old-growth forest with respect to the seedlings recruited from different sources, by monitoring 40 permanent plots (0.5 m x 0.5 m) over 20 months. From the three studied areas a total of 392 seedlings of 53 species were recruited. Species were mainly herbaceous (85%), pioneers (88%), zoochorous (51%) and small-seeded species (60%). Seedling recruitment from the seed bank (density and species richness) was higher and dominated by herbaceous species in the abandoned pasture and in the young restored forest; on the other hand, the recruitment of woody species from seed rain was more pronounced in the old-growth forest. The young restored forest increased the species richness of woody seedlings recruitment from the seed bank (two-fold) and from seed rain (three-fold) compared to the abandoned pasture. Also, the seedling density in young restored forest was still higher than abandoned pastures (seed bank: four times; seed rain: ten times). Our results show that even young restored areas enhance the establishment of woody species and should be considered an important step for pasture restoration. PMID- 21246992 TI - Growth and mortality patterns in a thinning canopy of post-hurricane regenerating rain forest in eastern Nicaragua (1990-2005). AB - One of the strongest hypothesis about the maintenance of tree species diversity in tropical areas is disturbance. In order to assess this, the effect of intensive natural disturbances on forest growth and mortality in a thinning canopy was studied after the landfall of hurricane Joan in 1988. We evaluated the growth and mortality rates of the 26 most common tree species of that forest in eastern Nicaragua. Permanent plots were established at two study sites within the damaged area. Growth and mortality rates of all individual trees > or = 3.18cm diameter at breast height were assessed annually from 1990 to 2005. During this period the forest underwent two phases: the building phase (marked by increased number of individuals of tree species present after the hurricane) and the canopy thinning phase (marked by increased competition and mortality). Our results from the thinning phase show that tree survival was independent of species identity and was positively related to the increase in growth rates. The analysis of mortality presented here aims to test the null hypothesis that individual trees die independently of their species identity. These findings were influenced by the mortality observed during the late thinning phase (2003-2005) and provide evidence in favor of a non-niche hypothesis at the thinning phase of forest regeneration. PMID- 21246993 TI - Bats (Mammalia: Chiroptera) in native and reforested areas in Rancho Alegre, Parana, Brazil. AB - Abstract: Generally, natural environments have been transformed into small forest remnants, with the consequent habitat loss and species extinction. The North Parana State is not an exception, since only 2 to 4% of the original ecosystem occurs in small fragments of Stational Semidecidual Forest. We studied the species richness and abundance of bats in two forest fragments from the Fazenda Congonhas, in Rancho Alegre city, Parana State, Brazil. Four samplings were undertaken in a legally protected native area (107.8 ha) and in a reforested area (11.8 ha) between April 2007 and March 2008. Samplings began at nightfall and lasted six hours,during two consecutive nights in each location. The individuals were captured using eight mist nets, with the same capture effort in both environments. A total of 397 individuals, 14 species and 10 genera were captured in the native area; while in the reforested area, 105 individuals, six species and four genera. Artibeus lituratus was the most common species in both fragments (n = 328, 65.3%), followed by Artibeus fimbriatus (n = 44, 8.8%) and Artibeus jamaicensis (n = 30, 6.0%). Other species including Platyrrhinus lineatus, Carollia perspicillata, Sturnira lilium, Chrotopterus aurintus, Desmodus rotundus, Michronycteris megalotis, Phyllostomus hastatus, Phyllostomus discolor, Myoti levis, Myotis nigricans and Lasiurus blossevillii, accounted for 19.9% of the captures. The native area presented higher values of species richness (S = 14) and diversity (H' = 1.4802) in comparison to the reforested area (S = 6, H '= 0.57015). The t-test evidenced a significant difference between diversity among the sites (t = 7.1075). Chao 1 index indicated that the sampling effort recorded approximately 78% from the total species richness for the native area and 75% for the reforested area. Therefore, the preservation of the forest fragment is essential since it provides habitat for a diverse community of bats. Forest management and reforestation actions may prevent drastic changes in the microclimate of neighboring areas within the forest fragment, and could allow the occupation of available niches in the area, by opportunistic and generalist species. PMID- 21246994 TI - Population dynamics of the bat Dermanura tolteca (Chiroptera: Phyllostomidae) in a tropical forest in Mexico. AB - The fruit-eating bat, Dermanura tolteca, has a broad geographic distribution in Mexico and it is a very important seed dispersal of Neotropical plants. Nonetheless, information on the biology of this bat species is scarce, especially with regard to demography. We studied some ecological aspects and population dynamics of D. tolteca from Southeastern Mexican State of Oaxaca. The study was conducted in a perennial tropical forest, over a period of 80 nights, a sampling effort of 73 200 mist-net-hour, from May 2006 to August 2007. A total of 176 specimens were captured, 98 females and 78 males. Population size was estimated in 237 individuals in the study area, with a greater number during rainy season. The population density of this bat, in its range of distribution in Mexico is low compared to other nose-leaf bats. Captures were correlated with monthly precipitation, and this result may be linked to food resources abundance in tropical and subtropical areas. The reproductive pattern was bimodal polyestrous, with birth periods between August-September and April-June. Greater body mass was observed in females than males. The male-female ratio and age-related demographics were similar to other nose-leaf bats. The biological characteristics of D. tolteca are typical of nose-leaf bats of the family Phyllostomidae. PMID- 21246995 TI - Urban vegetation change after a hundred years in a tropical city (San Jose de Costa Rica). AB - Urban vegetation is of key importance because a large proportion of the human population lives in cities. Nevertheless, urban vegetation is understudied outside central Europe and particularly, little is known about the flora of tropical Asian, African and Latin American cities. We present an estimate of how the vegetation has changed in the city of San Jose, Costa Rica, after about one century, with the repeat photography technique (based on a collection of 19th and early 20th century photographs by Jose Fidel Tristan and others) and with data from the Costa Rican National Herbarium. We found little vegetation change in the landscape of San Jose during the 20th century, where a total of 95 families and 458 species were collected in the late 19th and early 20th century. The families with most species were Asteraceae, Fabaceae, Poaceae, Lamiaceae, Euphorbiaceae, Solanaceae, Cyperaceae, Acanthaceae, Malvaceae, Piperaceae and Verbenaceae. Similar results have been found in Europe, where the number of plant species often is stable for long periods even when the individual species vary. PMID- 21246996 TI - Temporal variation of phytoplankton in a small tropical crater lake, Costa Rica. AB - The temporal variation in lake's phytoplankton is important to understand its general biodiversity. For tropical lakes, it has been hypothesized that they follow a similar pattern as temperate ones, on a much accelerated pace; nevertheless, few case studies have tried to elucidate this. Most studies in Costa Rica have used a monthly sampling scheme and failed in showing the expected changes. In this study, the phytoplankton of the small Barvas's crater lake was followed for more than three years, first with monthly and later with weekly samplings, that covered almost two years. Additional information on temperature and oxygen vertical profiles was obtained on a monthly basis, and surface temperature was measured during weekly samplings around noon. Results showed that in spite of its shallow condition (max. depth: 7m) and low surface temperature (11 to 19 degrees C), the lake stratifies at least for brief periods. The phytoplankton showed both, rapid change periods, and prolonged ones of relative stasis. The plankton composition fluctuated between three main phases, one characterized by the abundance of small sized desmids (Staurastrum paradoxum, Cosmarium asphaerosporum), a second phase dominated by equally small cryptomonads (Chryptochrysis minor, Chroomonas sp.) and a third phase dominated by the green alga Eutetramorus tetrasporus. Although data evidenced that monthly sampling could miss short term events, the temporal variation did not follow the typical dry and rainy seasons of the region, or any particular annual pattern. Year to year variation was high. As this small lake is located at the summit of Barva Volcano and receives the influence from both the Caribbean and the Pacific weather, seasonality at the lake is not clearly defined as in the rest of the country and short term variations in the local weather might have a stronger effect than broad seasonal trends. The occurrence of this short term changes in the phytoplankton of small tropical lakes in response to weather variations needs to be further explored in other lakes. PMID- 21246997 TI - Structure and dynamics of phytoplankton in an Amazon lake, Brazil. AB - Natural lake systems represent important reservoirs for residential water supply, fish production, recreational activities and enjoyment of their natural beauty. Nevertheless, human impacts may affect their health status resulting in degradation and loss of biodiversity. The aim of the present study was to obtain data on the health status of a natural lake located in an indigenous reservation in the Brazilian Amazon, using the phytoplankton community changes along the rainy (June) and dry (November) seasons of 2006. We collected water (temperature, pH, Secchi depth and conductivity) and phytoplankton samples from the subsurface, middle of the water column, and approximately 30 cm above the bottom, over 24 hour sampling periods, from a central station in the lake. Samples taken from biotic and abiotic variables were correlated using canonical correspondence analysis (CCA). Results showed that the lake exhibited high temperatures in both seasons, and showed thermal stratification only during the rainy season. Dissolved oxygen exhibited a clinograde pattern in the rainy season and high oxygen in the hypolimnion in the dry season. In the rainy season, the water near the bottom was acidic, turbid and had a greater concentration of phosphorus. Dissolved oxygen, conductivity, pH, nitrite, total phosphorus and total dissolved phosphorus exhibited diel variations in the rainy season, whereas water temperature, dissolved oxygen, total nitrogen and total dissolved phosphorus exhibited significant differences between hours of the day in the dry season. The phytoplankton was represented by 39 taxa, and Chlorophyta showed the greatest species richness, totaling 25 taxa. Among Chlorophyta, desmids were the most diverse, accounting 52%. Bacillariophyta (nine species) was the second most diverse group. Cyanophyta was represented by three species, including Merismopedia tenuissima, the most abundant taxon. Despite the occurrence of taxa that indicate organic pollution, their biomass and frequency indicate that the system is not currently threatened. Lake Caracarana is an oligotrophic system, with low algal density and isolated blooming episodes due to its shallow depth. PMID- 21246998 TI - Aquatic macrophytes in the large, sub-tropical Itaipu Reservoir, Brazil. AB - In the last three decades, rapid assessment surveys have become an important approach for measuring aquatic ecosystem biodiversity. These methods can be used to detect anthropogenic impacts and recognize local or global species extinctions. We present a floristic survey of the aquatic macrophytes along the Brazilian margin of the Itaipu Reservoir conducted in 2008 and compare this with a floristic survey conducted ten years earlier. We used ordination analysis to determine whether assemblage composition differed among reservoir arms. Macrophyte species were sampled in each of the 235 sampling stations using a boat, which was positioned inside three places of each macrophyte stand to record species and search for small plants. We also collected submerged plants using a rake with the boat moving at constant velocity for ten minutes. We assigned individual macrophyte species to life form and identified representative species for each life form. A total of 87 macrophyte taxa were identified. The "emergent" life forms contained the highest number of species, followed by "rooted submerged" life forms. The extensive survey of macrophytes undertaken in September 2008 recorded more species than a survey conducted between 1995 and 1998. This could be due to changes in water physico-chemistry, disturbances due to water drawdown and the long period between surveys, which may have allowed natural colonization by other species. Additionally, differences in the classification systems and taxonomic resolution used in the surveys may account for differences in the number of species recorded. Assemblage composition varied among the arms and was affected by underwater radiation (as measured using a Secchi disk) and fetch. Five non-native species were found. Two of these non native species (Urochloa subquadripara and Hydrilla verticillata) are of special concern because they have a high frequency of occurrence and occupy large marginal areas of the reservoir. Future surveys should be conducted to determine the habitat most frequently colonized by these species. This would allow management strategies to be developed to protect native aquatic biota and prevent interference with the recreational and commercial uses of the Itaipu Reservoir. PMID- 21246999 TI - Cyanosis by methemoglobinemia in tadpoles of Cochranella granulosa (Anura: Centrolenidae). AB - Tadpoles inhabit generally well oxygenated rivers and streams, nevertheless they were found in areas with limited oxygen availability inside the rivers. To assess this feature, I examined factors that influence centrolenid tadpole behaviour using Cochranella granulosa. The tadpoles were reared in well-oxygenated and hypoxic environments and their development, survivorship and growth were compared. The tadpoles in oxygenated water acquired a pale color, while tadpoles in hypoxic water grew faster and were bright red and more active. In the oxygenated water, the ammonium, which had its origin in the tadpoles' urine and feces, was oxidized to nitrate. In contrast, in the hypoxic treatment, the nitrogen compounds remained mainly as ammonium. Presumably, the nitrate in oxygenated water was secondarily reduced to nitrite inside the long intestine coils, because all symptoms in the tadpoles point to methemoglobinemia, which can occur when the nitrite passes through the intestine wall into the bloodstream, transforming the hemoglobin into methemoglobin. This could be checked by a blood test where the percentage of methemoglobin was 2.3% in the blood of tadpoles reared in hypoxic condition, while there was a 19.3% level of methemoglobin in the blood of tadpoles reared in oxygenated water. Together with the elevated content of methemoglobin, the growth of the tadpoles was delayed in oxygenated water, which had high nitrate content. The study about quantitative food-uptake showed that the tadpoles benefit more from the food in hypoxic water, although they spent there more energy moving around than the tadpoles living in oxygenated but nitrate-charged water. PMID- 21247000 TI - Mesohabitat indicator species in a coastal stream of the Atlantic rainforest, Rio de Janeiro-Brazil. AB - The Mato Grosso is a typical Atlantic Forest stream located on the East coast of Brazil, approximately 70 km from Rio de Janeiro city. From its source at about 800m a.s.l, the stream drains a 30km2 area of the Northwestern part of the municipality of Saquarema, state of Rio de Janeiro and flows into the Saquarema Lagoon system. We hypothesized that fish species occupy distinct mesohabitats, with the prediction that their occurrences and densities differ among the microhabitats of riffles, runs and pools. A 250m-long stretch of the stream located in its uppermost part was selected for this study, where it becomes second-order. Mesohabitat description and their fish characterization were undertaken. Fish sampling was conducted by electroshocking and after their identification and counting, they were returned to the stream. For mesohabitat characterization, a Discriminant Function Analysis (DA) was applied. The total number of samples was estimated by the Zippin method and the recorded densities were used as an Indicator Species Analysis (ISA), followed by a Monte Carlo test for 1 000 permutations. The DA significantly separated the three predetermined mesohabitats (pool, riffle and run) (WL = 0.13, F = 187.70, p = 0.001). We found five species of fishes, belonging to four families and three orders. The fishes Rhamdia quelen, Phalloceros harpagos, Pimelodella lateristriga and Astyanax taeniatus are indicators of the pool environment in the Mato Grosso stream, whereas Characidium cf. vidali is an indicator of the riffle environment. The Monte Carlo test detected non-random mesohabitat use only for P. lateristriga and A. taeniatus in the pools and for Characidium cf. vidali in the riffles. We concluded that the Mato Grosso stream contains three well-defined mesohabitats, with indicator species present in two of these mesohabitats. PMID- 21247001 TI - The effect of climate and soil conditions on tree species turnover in a Tropical Montane Cloud Forest in Costa Rica. AB - On a global level, Tropical Montane Cloud Forests constitute important centers of vascular plant diversity. Tree species turnover along environmental gradients plays an important role in larger scale diversity patterns in tropical mountains. This study aims to estimate the magnitude of beta diversity across the Tilardn mountain range in North-Western Costa Rica, and to elucidate the impact of climate and soil conditions on tree species turnover at a local scale. Seven climate stations measuring rainfall, horizontal precipitation (clouds and wind driven rain) and temperatures were installed along a 2.5km transect ranging from 1200 m.a.s.l. on the Atlantic to 1200 m.a.s.l. on the Pacific slope. The ridge top climate station was located at 1500 m.a.s.l. Climate data were recorded from March through December 2003. Additionally, seven 0.05 ha plots were established. On all plots soil moisture was monitored for one year, furthermore soil type and soil chemistry were assessed. Woody plants with a diameter at breast height (dbh) > or = 5 cm were identified to species. Species' distributions were explored by feeding pairwise Serensen measures between plots into a Principal Component Analysis. Relationships between floristic similarity and environmental variables were analyzed using Mantel tests. Pronounced gradients in horizontal precipitation, temperatures and soil conditions were found across the transect. In total, 483 woody plants were identified, belonging to 132 species. Environmental gradients were paralleled by tree species turnover; the plots could be divided in three distinctive floristic units which reflected different topographic positions on the transect (lower slopes, mid slopes and ridge). Most notably there was a complete species turnover between the ridge and the lower Pacific slope. Floristic similarity was negatively correlated with differences in elevation, horizontal precipitation, temperatures and soil conditions between plots. It is suggested that beta-diversity in the study area is largely driven by species with narrow spatial ranges, due to the interactions between topography, climate and soil formation processes, especially around the wind-exposed and cloud covered ridge area. The findings emphasize the extraordinary conservation value of tropical montane cloud forests in environmentally heterogeneous areas at mid-elevations. PMID- 21247002 TI - Characterization of biominerals in species of Canna (Cannaceae). AB - Plant biominerals are not always well characterized, although this information is important for plant physiology and can be useful for taxonomic purposes. In this work, fresh plant material of seven wild neotropical species of genus Canna, C. ascendens, C. coccinea, C. indica, C. glauca, C. plurituberosa, C. variegatifolia and C. fuchsina sp. ined., taken from different habitats, were studied to characterize the biominerals in their internal tissues. For the first time, samples from primary and secondary veins of leaves were investigated by means of infrared spectroscopy, complemented with X-ray powder diffractometry and scanning electron microscopy. The spectroscopic results, supported by X-ray powder diffractometry, suggest that the calcium oxalate is present in the form of whewellite (CaC2O4 x H2O) in all the investigated samples. It is interesting to emphasize that all IR spectra obtained were strongly similar in all species studied, thus indicating an identical chemical composition in terms of the biominerals found. In this sense, the results suggest that the species of Canna show similar ability to produce biogenic silica and produce an identical type of calcium oxalate within their tissues. These results can be an additional trait to support the relationship among the families of Zingiberales. PMID- 21247003 TI - Polyphenolic and biological activities of leaves extracts of Argemone subfusiformis (Papaveraceae) and Urtica urens (Urticaceae). AB - Nowadays there is a resurgence of interest in wild plants for their possible medicinal value in diets, since some epidemiological studies have demonstrated their effectiveness against important diseases. Generally, foods of plant origin contain many bioactive compounds, proteins, energy, vitamins and specific minerals; in addition, the popular wild plant species provide fibre, essential fatty acids and enhance the taste and colour in diets. We studied the nutritional and medicinal potential of leaves of A. subfusiformis and U. urens, collected in Alice, South Africa in November 2006. To asses this we analyzed the phytochemical, antioxidant and antibacterial activities of leaves in acetone, methanol and water extracts, using standard analytical methods. The proximate analysis showed that the leaves of both plant species contained appreciable percentages of moisture; ashes; carbohydrates; crude proteins, lipids and fibres. Elemental analysis of macro and microelements showed higher values for U. urens that contained in decreasing order: iron > manganese > zinc > copper > calcium > potassium > nitrogen > magnesium > phosphorus > sodium, for A. subfusiformis resulted in iron > zinc > manganese > copper > calcium > potassium > nitrogen > magnesium > phosphorus > sodium. Besides, the chemical composition showed higher concentration of alkaloids, saponins and phytates in A. subfusiformis. The extracts also caused 1, 1-diphenyl-2-picrylhydrazyl (DPPH) and 2, 2-azinobis-3 ethylbenzothiazoline-6-sulfonic acid (ABTS) radical scavenging activities which were comparable to those of ascorbic acid. The extracts of both plants contained appreciable levels of polyphenols and also caused varied inhibition of some bacterial strains used in this study. When the nutrient and chemical constituents of these plants were compared with recommended dietary allowance (RDA) values, the results revealed that the leaves contain an appreciable amount of nutrients, minerals, and phytochemicals and low levels of toxicants. Since the plants also exhibited some level of antibacterial activities, their use for medicinal purposes is to some extent being justified. PMID- 21247004 TI - Growth, mortality and reproduction of the blue tilapia Oreochromis aureus (Perciformes: Cichlidae) in the Aguamilpa Reservoir, Mexico. AB - Tilapia production has increased in Aguamilpa Reservoir, in Nayarit, Mexico, in the last few years and represents a good economic activity for rural communities and the country. We determined growth parameters, mortality and reproductive aspects for 2413 specimens of blue tilapia Oreochromis aureus in this reservoir. Samples were taken monthly from July 2000 through June 2001, of which 1 371 were males and 1 042 were females. Standard length (SL) and total weight (TW) were measured in each organism. The SL/TW relationships through power models for sexes were determined. The growth parameters L infinity k, and t0 of the von Bertalanffy equation were estimated using frequency distribution of length through ELEFAN-I computer program. Finally the reproductive cycle and size of first maturity were established using morph chromatic maturity scale. The results suggested that the males and females had negative allometric growth (b < 3). Significant differences were found between SL/TW model for the sexes, suggesting separate models for males and females. Results indicate that there are no differences in growth rates between sexes; the proposed parameters were L infinity = 43.33 cm standard length, k = 0.36/year and t0 = -0.43 years. Natural and fishing mortality coefficients were 0.83/year and 1.10/year, respectively. The estimated exploitation rate (0.57/year) suggested that during the study period the fishery showed signs of overfishing. Blue tilapia reproduces year round; the highest activity occurs from January through May and size of first maturity was 23 cm SL. We conclude that it is necessary to establish a minimum catch size in this reservoir based on the reproductive behavior of this species. PMID- 21247005 TI - Health care financing and insurance. Options for design. Preface. PMID- 21247006 TI - Health care financing and insurance. Options for design. PMID- 21247007 TI - Angiotensin converting enzyme inhibitors and angiotensin II receptor blockers in atrial fibrillation. AB - Atrial fibrillation is the most prevalent clinically relevant arrhythmia; a major cause of morbidity and hospitalization. Additionally, atrial fibrillation carries a significant risk of thrombo-embolic events, specifically cerebrovascular accident. Among the most prevalent risk factors for atrial fibrillation, hypertension not only has the strongest correlation but is also the most prevalent. The renin-angiotensin-aldosterone system represents a prime target for the treatment of hypertension through the use of angiotensin-converting enzymes inhibitors and angiotensin II receptor blockers. In addition to blood pressure control, these medications have been shown to reduce the occurrence of atrial fibrillation. They have been shown to have effects at the cellular level in preventing atrial fibrosis. Additionally, these medications may prevent the development ofatrial fibrillation, reduce the duration of atrial fibrillation, and facilitate electrical cardioversion in patients with the arrhythmia. Therefore, patients with, or at risk for atrial fibrillation may benefit from treatment with renin-angiotensin-aldosterone system antagonists; deriving benefits from these medications beyond simple blood pressure control. PMID- 21247008 TI - Detection of BVD/MD. PMID- 21247009 TI - Veterinary nursing in South Africa (1977-2000). AB - The history of the university course in veterinary nursing in South Africa is reviewed from its inception in 1977 to 2000. The motivation for, and initial problems encountered in, its implementation are outlined. Selection criteria and course subjects, including clinical work, are supplied and the changes in these, following the introduction of a new curriculum in 1993/94, are highlighted. Reference is made to the legal status of the nursing profession. PMID- 21247010 TI - An anatomical and clinical review of cricopharyngeal achalasia in the dog. AB - Cricopharyngeal achalasia is a rare cause of dysphagia in the dog. However it must be differentiated from other causes of dysphagia as it is treatable with surgery. It is a disruption of the cricopharyngeal phase of the oropharyngeal phase of deglutition. There appears to be an incoordination in the swallowing process between the relaxation of the rostral, middle pharyngeal muscles and the caudal pharyngeal muscles. It is seen as a primary condition in young animals presenting soon after weaning onto solid food. The dogs appear clinically healthy unless there is secondary aspiration pneumonia or emaciation. These dogs may present as respiratory emergencies and require intensive support and treatment prior to corrective surgery. The diagnosis is made on videofluoroscopy. The condition carries a good prognosis for cure with surgical myectomy of the cricopharyngeal muscle and the thyropharyngeal muscle, which make up the upper oesophageal sphincter. Temporary relief prior to surgery can be achieved by injection of the cricopharyngeal muscle with botulism toxin. Surgical treatment for dysphagia secondary to an underlying neurological, neuromuscular or pharyngeal weakness carries a guarded prognosis and will make aspiration pneumonia worse. PMID- 21247011 TI - Changes in Mithun (Bos frontalis) spermatozoa during epididymal passage. AB - Genital organs of 10 healthy, adult Mithun bulls (6-8 years old) that were slaughtered at the dwellings of tribal people for meat were collected. Immediately after collection, spermatozoa from 3 different regions of the epididymis, i.e. the head, body and tail, were obtained to study morphological changes of the spermatozoa during passage through these regions. The prevalence of proximal cytoplasmic droplets significantly decreased from the head to the tail of the epididymis. Conversely, the percentage of distal cytoplasmic droplets increased significantly from the head to the tail region. The incidence of tailless heads rose significantly from head to body and then reduced significantly in the tail region. The percentage of total head abnormalities did, however, not change markedly, but total mid-piece and tail abnormalities differed significantly between the three epididymal regions. PMID- 21247012 TI - Questionnaire survey on urban and peri-urban livestock farming practices and disease control in Kisumu municipality, Kenya. AB - To characterise the urban livestock keeping practices and constraints in Kisumu municipality, Kenya, a questionnaire survey was carried out. Thirty-four contact farmers were interviewed on general farm characteristics and production constraints. The farming activities were categorised as either livestock only (41%), or mixed crops and livestock (59%). The surveyed farmers kept mainly cattle (100%), chickens (82%) and goats (74%). Most (94%) of the farmers had kept livestock for prolonged periods mainly for income generation (97%) and domestic consumption (59%). These data show that livestock keeping was popular and could be harnessed to increase food security, although the farmers kept mainly low producing indigenous cattle (98%) which were grazed on unutilised land. The main production constraints mentioned by farmers included diseases (100%), poor fertility (68%) and lack of feed (56%). The diseases varied with species of ruminants and included lumpy skin disease (71%), diarrhoea (65%) and helminthosis (62%). The source of advice on management and treatment of the livestock was almost equally from private and government veterinary personnel. To improve livestock productivity, it is recommended that key stakeholders address the constraints mentioned in this study and in particular that the occurrence of diseases should be investigated with a view to developing sustainable control strategies. PMID- 21247013 TI - Evaluation of PCR assays for the detection of Campylobacter fetus in bovine preputial scrapings and the identification of subspecies in South African field isolates. AB - As a result of the high lability and slow growth of Campylobacter fetus subspecies, the laboratory diagnosis of bovine genital campylobacteriosis has always been difficult. This is especially true under South African conditions, where farms are far apart, laboratories are only present in major centres and there are high ambient temperatures. In order to overcome the shortcomings associated with traditional diagnostic methods, the implementation of a molecular assay was sought. This work describes how a previously published PCR assay (MG3F/ MG4R primers) was adapted, optimised and applied in the diagnostic laboratory to test preputial samples directly for the presence of Campylobacter fetus. Field evaluation of the assay revealed an analytical sensitivity and specificity of 85.7% and 99%, respectively. Subsequent genotyping and phenotyping of a diverse collection of South African field isolates revealed that South Africa has an unexpected and previously unreported high incidence of Campylobacter fetus subsp. venerealis biovar intermedius strains. These strains were not identified correctly by the subspecies-specific primer set evaluated. Until such time that cost- effective genotyping methods are available to diagnostic laboratories in South Africa, and other countries with these atypical Campylobacter fetus subsp. venerealis strains, the need for bacterial culture will persist. Identification to subspecies level of isolates at present remains dependent upon a single phenotypic criterion, namely tolerance to 1% glycine. PMID- 21247014 TI - The prevalence of ovine herpesvirus-2 in 4 sheep breeds from different regions in South Africa. AB - About 90% of bovine malignant catarrhal fever (BMCF) PCR-positive cases in South Africa are caused by alcelaphine herpesvirus-1 (AlHV-1) and the other 10% by ovine herpesvirus-2 (OvHV-2). The prevalence of OvHV-2 in different sheep breeds in South Africa was determined in order to investigate whether the lower incidence of BMCF caused by OvHV-2 in comparison with AlHV-1 can be ascribed to a low incidence of the virus in sheep. A single-tube hemi-nested PCR was developed, evaluated and applied to detect OvHV-2 DNA. The prevalence of the virus in 4 sheep breeds from various regions in South Africa was shown to be 77%. No statistically significant difference was found amongst the sheep breeds tested. PMID- 21247015 TI - Prevalence of helminth parasites in free-range chickens from selected rural communities in KwaZulu-Natal province of South Africa. AB - A total of 79 chickens were randomly collected from 4 rural localities and processed to detect the presence of helminth parasites and their prevalences. Sixteen helminth species comprising 12 nematode and 4 cestode species were recorded from the 4 localities. Syngamus trachea and Cyathostoma spp. were the only helminth species recovered from the respiratory tract and the rest of the helminth species were from the gastrointestinal tract. The most prevalent nematode species across the 4 localities were Heterakis gallinarum (prevalence range 80-94.4%), Gongylonema ingluvicola (43.3-867%), Tetrameres american (53.3 66.7%) and Ascaridia galli (22.2-43.8%) and for cestode species, Raillietina tetragona (16.7-40%) and Skrijabinia cesticillus (3.3-13.3%) were the most prevalent in that order. Heterakis gallinarum and T americana had the highest intensity of infection in chickens across all the rural areas compared with other helminth species. There was no significant difference (P > 0.05) observed in the sex distribution for As. galli, Baruscapillaria obsignata (syn. Capillaria obsignata), Eucoleus annulatus (syn. Capillaria annulata), Eucoleus contortus (syn. Capillaria contorta) and Subulura suctoria among the 4 rural areas. However, a significant difference (P < 0.05) was observed in the intensity of infection of both males and females for H. gallinarum and T americana across the 4 localities studied. Tetrameres americana, A. galli, C. obsignata and C. annulata had prevalence and number of females higher than that of males, while H. gallinarum showed the opposite. Prevalence of H. gallinarum and T. americana as determined by faecal egg count were much lower compared with the prevalence as determined by post mortem examination, confirming the limitation of using faecal samples in determining the prevalence of gastrointestinal helminth parasites in chickens. PMID- 21247016 TI - A study of preslaughter pig handling and stunning in selected South African Highveld Region abattoirs. AB - The study hypothesis was that pre-slaughter handling is not conducted in such a way that pigs can be considered humanely slaughtered, nor is it conducive to promoting those properties of fresh meat that could enhance pork quality. The 1st phase of the investigation was aimed at confirming the present compliance level within the prescribed norms. To this end the importance of stunning induction requirements for effective electrical stunning, the welfare implications relating to the pre-slaughter handling of pigs and the stunning and sticking techniques were investigated. Pre-slaughter welfare of the pigs at the abattoir was found to be influenced at the outset by the origin and type of pig slaughtered, the daily throughput range of pigs and the type of abattoir involved. A disappointing pre arrival aspect was that deficiencies in road motor vehicles were observed while off-loading pigs. Through poor design or lack of maintenance, another factor that hampered free movement of pigs was the off-loading facilities. The nature of animal behaviour in the pens, in the passages and when going into the stunning area was directly related to the pig handling efficiency and to the nature and extent of design and maintenance problems with equipment. None of the abattoirs had a well designed in-feed to a well planned stunning area/facility, and a very high level of pig pre-slaughter stress prevailed. The optimum position of the electrodes is virtually impossible to attain under practical conditions and the practice of repeat application of electrical stunning is common. Of the total sample size (n = 1175), 34% were difficult to shackle, 90% of these being from the abattoirs tending to slaughter more routinely a wide range of different sized pigs. In this survey 149 pigs (13%) required more than a single sticking attempt to bleed out properly, considerably higher than in other published reports. PMID- 21247017 TI - Isolation of pathogenic aerobic bacteria from the blood of septicaemic neonatal calves and the susceptibility of isolates to various antibiotics. AB - An automated blood culture system (BACTEC 9240) was used for the isolation of aerobic bacteria from the blood of septicaemic neonatal calves. Blood samples were collected from 90 clinically septicaemic and 20 healthy neonatal calves and inoculated into blood culture bottles. There were 89 significant isolates from 90 positive blood cultures using the BACTEC system. Escherichia coli was the most common pathogen detected accounting for 56 (63%) out of 89 isolates. The other pathogens were beta-haemolytic streptococci (15.7%), Staphylococcus aureus (10.1%), Klebsiella sp. (5.6%) and Corynebacterium sp. (5.6%). All isolates showed a susceptibility rate of 100% to enrofloxacin, cefepim, cefoperazone/sulbactam, imipenem and meropenem while some of them were ranged from 75 to 91.7% susceptible to amoxicillin/clavulanic acid, ampicillin/sulbactam, gentamicin and cephalosporins. PMID- 21247018 TI - First report of oligodendroglioma in a sheep. AB - Oligodendrogliomas occur most commonly in the dog, but have also been reported in cattle, horses and cats. A 1-year-old sheep with neurological disturbances, including blindness, ataxia, circling and incoordination was referred to the veterinary clinic of Shahid Bahonar University of Kerman. Following euthanasia and necropsy, a soft, relatively well-demarcated mass was observed in the white and grey matter of the right cerebral hemisphere, close to the sylvian fissure in the right cerebral hemisphere. Microscopic examination revealed a sheet of densely packed tumour cells with hyperchromatic nuclei, lightly staining cytoplasm and characteristic perinuclear halo effect which is consistent with a diagnosis of oligodendroglioma. This is the 1st report of oligodendroglioma in sheep. PMID- 21247019 TI - Polioencephalomalacia associated with closantel overdosage in a goat. AB - This report describes clinical and pathological findings associated with closantel (a halogenated salicylanilide anthelmintic) overdosage in a 3-year-old goat. The clinical signs included blindness, incoordination, ataxia, depression of the palpebral and pupillary reflexes, and recumbency. No gross lesions were noted in tissue or organs at necropsy, but microscopic lesions were seen in nervous tissue and hepatic cells. Polioencephalomalacia was clearly evident. Bilaterally symmetrical status spongiosus of the white matter of the brain, bilateral laminar necrosis, microcavitations, ischaemic cell change and severe degeneration of the cerebellum were seen in nervous tissue. Fatty change and hydropic degeneration in the liver and hepato-cellular degeneration were observed histologically. PMID- 21247020 TI - Oesophageal obstruction in Dorper ewes caused by impaction of a pelleted ration. AB - Two adult Dorper ewes developed an oesophageal obstruction (choke) by consuming a pelleted ration. The history, clinical signs and method of treatment were recorded in each case. One case was treated surgically via rumenotomy and the other conservatively. Both ewes recovered uneventfully and no recurrence was observed. Reasons for the compaction of the pelleted ration in the oesophagus are discussed. PMID- 21247021 TI - Yolk coelomitis in a white-throated monitor lizard (Varanus albigularis). AB - Yolk coelomitis as a result of pre-ovulatory follicular stasis is a common disorder in captive reptiles, especially in captive lizards of various genera. The clinical signs are generally fairly non-specific and diagnosis is based on clinical signs together with most of the common diagnostic modalities. The condition is most likely a husbandry and environment-related reproductive disorder. It has not been reported in wild free-living specimens. This report describes the clinical presentation and post mortem lesions in a white-throated monitor lizard that died during treatment for non-specific clinical signs related to a severe yolk coelomitis. PMID- 21247022 TI - Prevalence of gastrointestinal parasites of stray dogs impounded by the Society for the Prevention of Cruelty to Animals (SPCA), Durban and Coast, South Africa. AB - Coprological examination was used to determine the prevalence and intensity of gastrointestinal parasites of stray dogs impounded by the Society for the Prevention of Cruelty to Animals (SPCA), Durban and Coast, South Africa. Helminth and protozoan parasites were found in faeces of 240 dogs with an overall prevalence of 82.5% (helminth parasites 93.1% and protozoan parasites 6.9%). The following parasites and their prevalences were detected; Ancylostoma sp. (53.8%), Trichuris vulpis (7.9%), Spirocerca lupi (5.4%), Toxocara canis (7.9%), Toxascaris leonina (0.4%) Giardia intestinalis (5.6%) and Isospora sp. (1.3%). Dogs harbouring a single parasite species were more common (41.7%) than those harbouring 2 (15%) or multiple (2.1%) species. Ancylostoma sp., Toxocara canis and Giardia intestinalis have zoonotic potential and were detected in 66.7% of the samples. PMID- 21247023 TI - Ixodid ticks on domestic dogs in the Northern Cape Province of South Africa and in Namibia. AB - The objective of this study was to determine the species composition of ixodid ticks infesting domestic dogs in the northwestern region of the Northern Cape Province of South Africa and in Namibia. Ticks were collected from February 2008 to January 2009 from dogs presented for a variety of reasons at a veterinary clinic in the Northern Cape Province and at 3 clinics in Namibia. The ticks collected at each place were pooled separately for each month at each locality. Eleven ixodid tick species were collected from dogs in the Northern Cape Province and new locality records for Haemaphysalis colesbergensis and Ixodes rubicundus, new locality and host records for Hyalomma glabrum, and a new host record for Rhipicephalus neumanni are reported. Six tick species were collected from dogs at the 3 clinics in Namibia. The most numerous species on dogs in both countries was R. sanguineus. The present results increase the total number of ixodid tick species collected from dogs in South Africa from 25 to 28. PMID- 21247025 TI - A window into nursing's history. PMID- 21247026 TI - Position statements on euthanasia. PMID- 21247027 TI - The year that was 2010. PMID- 21247028 TI - Reducing medicine errors: multidisciplinary approach. PMID- 21247029 TI - Working life. PMID- 21247030 TI - Facilitating learning in clinical practice: an operational matrix to guide 'point of care' learning activities. PMID- 21247031 TI - Supporting indigenous nursing students. PMID- 21247032 TI - Heart Health: new ways to deliver cardiac rehabilitation. PMID- 21247033 TI - Ancient art delivers modern health advice. PMID- 21247034 TI - QuitSA tackling high tobacco use. PMID- 21247035 TI - Coaching the nursing and midwifery teams. PMID- 21247036 TI - Research on animal blood groups and biochemical polymorphisms at Onderstepoort (1956-1990). AB - The introduction and wide use of artificial insemination in cattle in the 1950s led to a need for accurate parentage identification. Blood group determination by means of the newly emerging scientific discipline called immunogenetics provided the answer. A blood group laboratory was consequently established at Onderstepoort in 1956, initially concentrating on the production of blood typing reagents. Once established the technology was also applied to studies on a variety of problems in various animals as summarised in this paper. Investigations include zygosity in cattle twins, blood transfusion in domestic animals, breed relationships, genetic polymorphisms and the identification of useful genetic markers for production and disease parameters in breeding programmes. PMID- 21247037 TI - Effect of heterologous seminal plasma and semen extenders on motility of frozen thawed ram spermatozoa. AB - Ram seminal plasma increases the fertility of frozen-thawed ram spermatozoa deposited into the cervix. The aim of the current study was to compare the effect of ram seminal plasma to that of bull seminal plasma, dog prostatic fluid, protein-free TALP TrilEq (Triladyl with 0.5 mt of Equex STM paste added to each 100 mt) and heat-treated skim milk on longevity and percentages of progressively motile and aberrantly motile frozen-thawed ram spermatozoa. Three ejaculates from each of 6 rams were extended in TrilEq, pooled and frozen in straws as a single batch per ram. One hundred and eight straws (3 straws from each ram for each fluid) were thawed in random order. Once thawed, a straw was emptied into a tube with 0.85 ml of the appropriate fluid at 37 degrees C and kept at that temperature for 6 h. Motility was assessed at x200 magnification immediately (time zero) and 2, 4 and 6 h after thawing. Progressive motility decreased from each time to the next (P < 0.05) and was 39.0 % (0 h), 26.0 % (2 h), 19.6 % (4 h) and 12.6 % (6 h); SEM 1.24, n = 108 for each group. Ram seminal plasma resulted in higher progressive motility than bull seminal plasma, lower than milk, and similar to the other fluids. Ram seminal plasma resulted in lower aberrant motility than protein-free TALP and similar aberrant motility to other fluids. The effect of ram seminal plasma and dog prostatic fluid was very similar. The effect of ram seminal plasma on the fertility of frozen-thawed ram spermatozoa deposited into the cervix is not due an exceptionally beneficial effect on the motility of spermatozoa. PMID- 21247038 TI - Cardiovascular effects of epidural morphine or ropivacaine in isoflurane anaesthetised pigs during surgical devascularisation of the liver. AB - The cardiovascular effects of non-abdominal and abdominal surgery during isoflurane anaesthesia (A-group) or isoflurane anaesthesia supplemented with either epidural ropivacaine (AR-group; 0.75 % solution, 0.2 ml/kg) or morphine (AM-group; 0.1 mg/kg diluted in saline to 0.2 ml/kg) were evaluated in 28 healthy pigs with a mean body weight of 30.3 kg SD +/- 4.1 during surgical devascularisation of the liver. Anaesthesia was induced with the intramuscular injection of midazolam (0.3 mg/kg) and ketamine (10 mg/kg). Anaesthesia was deepened with intravenous propofol to enable tracheal intubation and maintained with isoflurane on a circle rebreathing circuit. The vaporiser was set at 2.5% for the A-group and 1.5% for the AR- and AM-groups. Differences between treatment groups were not statistically significant (P > 0.05) for any of the variables. Differences between AM- and AR-groups were marginally significant heart rate (HR) (P = 0.06) and mean arterial blood pressure (MAP) (P = 0.08). Within treatment groups, differences for the A-group were statistically significant (P < 0.05) between non-abdominal and abdominal surgery for HR, systolic blood pressure, diastolic blood pressure (DIA) and MAP. Within the AM-group differences were statistically significant (P < 0.05) for DIA and MAE and within the AR group differences for all variables were not statistically significant (P > 0.05). It was concluded that in isoflurane-anaesthetised pigs, the epidural administration of ropivacaine decreased heart rate and improved arterial blood pressure during surgery. PMID- 21247039 TI - Diversity and seasonal occurrence of Eimeria species in a mixed flock of communally reared sheep and goats in Mafikeng in the North West Province, South Africa. AB - Diversity and seasonal occurrence of coccidia in a communally reared mixed flock of sheep and goats at Mafikeng, North West Province, South Africa, was determined between March 2008 and February 2009. Faecal specimens were collected directly from the rectum of the animals and the number of oocysts per gram of faeces (opg) determined. The mean monthly opg for goats was significantly higher than that for sheep. Higher oocyst counts were observed during the hot, rainy season than during the cold, dry season. The highest mean values for both the sheep (862.5 opg) and goats (1200 opg) were recorded during March. Six species (Eimeria crandallis, E. bakuensis, E. weybridgensis, E. ahsata, E. intricata, and E. ovinoidalis) were recovered from sheep, with E. crandallis and E. bakuensis occurring most frequently. The last 2 species, together with E. ahsata, are considered among the most pathogenic species in sheep. In goats, 7 species (E. arloingi, E. jolchijevi, E. caprina, E. alijevi, E. caprovina, E. christenseni and E. hirci) were recovered, with E. arloingi and E. jolchijevi occurring most frequently. Up to 5 Eimeria species were recovered from individual specimens in goats while up to 4 were recovered in sheep. No cross-infections between goats and sheep were recorded and no clinical coccidiosis was noted during the study. It is increasingly becoming evident that the pathogenic E. arloingi is one of the most commonly occurring Eimeria species in goats in South Africa. PMID- 21247040 TI - Prevalent organisms on ostrich carcasses found in a commercial abattoir. AB - The prevalent microbial growth on carcasses before and after overnight cooling in an ostrich abattoir and de-boning plant was investigated. The effect of warm or cold trimming of the carcasses was examined together with possible causes of contamination along the processing line. An attempt was made to link the prevalent microorganisms that were identified from carcasses to those from specific external contamination sources. Samples of carcasses and possible contaminants were collected in the plant, plated out and selected organisms were typed using a commercial rapid identification system. It was indicated that the cold trim (mainly of bruises) of carcasses was advantageous in terms of microbiological meat quality. Results indicated pooled water in the abattoir as the most hazardous vector for carcass contamination and that contaminants from this source are mostly Gram-negative pathogens. Pseudomonas and Shigella were frequently isolated from surface and air samples and indicated that the control of total plant hygiene is a requirement for producing ostrich meat that is safe to consume and has an acceptable shelf-life. PMID- 21247041 TI - A serological survey of antibodies to Leptospira species in dogs in South Africa. AB - Leptospirosis, a disease more common in the tropics, can cause a life-threatening multisystemic syndrome in humans and animals. Immunity, whether natural or vaccine-induced, is serogroup-specific with the infecting serovars varying according to geographical locality. In South Africa, in spite of the fact that the bacterin vaccine for some Leptospira serovars is often used, there is no recent information on the incidence of canine leptospirosis as well as the infecting serovar/s. The aim of this study, which was undertaken on sera collected in 2008 and 2009 from both strays and owned dogs predominantly in the coastal regions of South Africa, was to determine the presence of leptospiral antibodies to 15 serovars known to infect dogs. Of the 530 samples tested, 25 tested positive to 7 different serovars with the microscopic agglutination test (MAT). Nine of the 25 samples tested positive to more than one serovar. The 2 serovars most frequently represented were Canicola, which reacted to 17 sera, and Pyrogenes, which reacted to 10 sera. Currently the only vaccines available in South Africa in different combinations contain serovars Canicola, Icterohaemorrhagiae, Pomona and Grippotyphosa. The results showed that the use of vaccines containing serovar Canicola is still justifiable in certain regions of the country. However, the presence of antibodies to serovar Pyrogenes in several dogs, pending a broader investigation, indicates that this serovar should also be included in the range of Leptospira vaccines for use in South Africa. PMID- 21247042 TI - Veterinary extension on sampling techniques related to heartwater research. AB - Heartwater, a tick-borne disease caused by Ehrlichia ruminantium, is considered to be a significant cause of mortality amongst domestic and wild ruminants in South Africa. The main vector is Amblyomma hebraeum and although previous epidemiological studies have outlined endemic areas based on mortalities, these have been limited by diagnostic methods which relied mainly on positive brain smears. The indirect fluorescent antibody test (IFA) has a low specificity for heartwater organisms as it cross-reacts with some other species. Since the advent of biotechnology and genomics, molecular epidemiology has evolved using the methodology of traditional epidemiology coupled with the new molecular techniques. A new quantitative real-time polymerase chain reaction (qPCR) test has been developed for rapid and accurate diagnosis of heartwater in the live animal. This method can also be used to survey populations of A. hebraeum ticks for heartwater. Sampling whole blood and ticks for this qPCR differs from routine serum sampling, which is used for many serological tests. Veterinary field staff, particularly animal health technicians, are involved in surveillance and monitoring of controlled and other diseases of animals in South Africa. However, it was found that the sampling of whole blood was not done correctly, probably because it is a new sampling technique specific for new technology, where the heartwater organism is much more labile than the serum antibodies required for other tests. This qPCR technique is highly sensitive and can diagnose heartwater in the living animal within 2 hours, in time to treat it. Poor sampling techniques that decrease the sensitivity of the test will, however, result in a false negative diagnosis. This paper describes the development of a skills training programme for para-veterinary field staff, to facilitate research into the molecular epidemiology of heartwater in ruminants and eliminate any sampling bias due to collection errors. Humane handling techniques were also included in the training, in line with the current focus on improved livestock welfare. PMID- 21247043 TI - An investigation of the effects of secondary processing on Mycobacterium spp. in naturally infected game meat and organs. AB - The risk for humans to contract bovine tuberculosis through the consumption of undercooked game meat as well as biltong (traditionally dried game meat) is a concern. The survival potential of Mycobacterium bovis during the cooking and drying processes was researched in a preceding study on beef and the positive results compelled the authors to investigate the results with a similar preliminary study on game meat. Muscular, lymphatic and visceral tissues from skin test positive African buffalo (Syncerus caffer) and greater kudu (Tragelaphus strepsiceros) with tuberculous lesions were collected from the Hluhluwe iMfolozi Park during the park's culling programme. The different tissues were exposed to cooking and the muscular tissue to the drying process prior to culture. All acid-fast isolates were analysed by polymerase chain reaction for the presence of Mycobacterium bovis. All tissues were found negative for Mycobacterium bovis but non-tuberculous mycobacteria were isolated from kidney, liver, heart and lymph nodes. The results showed that these processes will kill Mycobacterium bovis but the unexpected recovery of non-tuberculous mycobacteria suggests possible survival and resistance characteristics of these strains which might be of veterinary public health interest. PMID- 21247044 TI - Gousiekte in African buffalo (Syncerus caffer). AB - Three African buffalo (Syncerus caffer) that died after capture and translocation from Mutirikwe Recreational Park in southern Zimbabwe showed macroscopic and microscopic lesions of cardiomyopathy compatible with a diagnosis of gousiekte. The buffalo had had access to Pavetta schumanniana, a plant that is known to cause gousiekte. Death was attributed to cardiac failure as a result of previous consumption of the plant, exacerbated by the stress of translocation. PMID- 21247045 TI - Surgical uterine drainage and lavage as treatment for canine pyometra. AB - Pyometra is a common post-oestral syndrome in bitches. Classical treatment consists of either ovariohystorectomy or medical intervention. Surgical uterine drainage and lavage via direct trans-cervical catheterisation using a 5% povidone iodine in saline solution was performed successfully in 8 bitches with pyometra. All bitches conceived and whelped without complications subsequent to this treatment. It is concluded that this method offers an effective alternative treatment for canine pyometra with shorter recovery times as well as good clinical recovery and pregnancy rates in bitches destined for further breeding. PMID- 21247046 TI - Providing dental care for those in need. Interview by Michi Trota. PMID- 21247047 TI - An experience to be experienced. PMID- 21247048 TI - The spread of diseases. PMID- 21247049 TI - Evidence shows keeping wisdom teeth may be more harmful than previously thought. PMID- 21247050 TI - Ignite your passion for dental assisting. PMID- 21247051 TI - Meet Dr. Robot. Your next surgeon may not be human. Why that should make you happy--and a little wary. PMID- 21247052 TI - Surgery lite. Pain and trauma have always been part of having an operation. But new machines and methods are changing that. PMID- 21247053 TI - Part D employer retiree drug subsidy: inception, implementation and issues. AB - The Medicare Prescription Drug, Improvement, and Modernization Act of 2003 provided a subsidy to employers that offered a retiree health prescription coverage benefit actuarially equivalent to Medicare Part D. This article reviews the development of the subsidy, the support by the federal government and the issues that have arisen. It also presents analysis of data from a set of companies that offered retiree health in 2006 and 2007. The data show widespread acceptance of the subsidy and continuance of prescription coverage; however, companies that did not take the subsidy were more likely to be smaller and in less robust financial health. Analysis of a subset of the companies shows the magnitude of the benefits paid yearly and the accounting liability caused by retiree health relative to the size of the subsidy. The author concludes that the potential success or failure of the federal subsidy in preserving retiree health benefits will not be known for years. Nevertheless, with the elimination of the deductibility of the subsidy in the Patient Protection and Affordable Care Act (PPACA), employers surely will reexamine their offer of prescription coverage to retirees. PMID- 21247054 TI - Successor corporation--retiree health benefits--vested benefits. Reese v. CNH America LLC, 574 F.3d 315 (6th Cir. 2009). PMID- 21247055 TI - Impact of some external factors on the values of mechanical parameters determined in tests on bone tissue. AB - The knowledge of the mechanical characteristics of bone structures is a prerequisite for theoretical, numerical, and experimental analyses describing the functioning of bone, which is a living organ. The description of the mechanical properties of bone tissue, such as conventional Young's modulus or strength, will enable the assessment of the degree of tissue degeneration through a comparison of the material properties of the examined bones to the properties determined for physiologically normal bones. However, the mechanical parameters published by different research centres often differ from each other by up to several hundred percent. These discrepancies arise primarily from the differences in the research methodology applied, and thus from many additional factors having a direct impact on the values of the mechanical parameters obtained in experimental tests. Therefore, in order to standardize and improve the interpretation of the results of measurements, we should develop universal criteria for the measuring conditions and quantify the impact of the factors being related to sample and measurements on the values obtained. In this paper, the authors present the dependence of some factors, i.e. the site and direction of sample excision as well as the rate and type of loading, on the values of the mechanical parameters. Those values were determined in experimental tests and the additional correlation coefficients proposed enabled an easier comparison of the results obtained with the values presented in the literature. PMID- 21247056 TI - Application of holographic interferometry and speckle photography in the evaluation of mandible stabilization techniques. AB - Application of the holographic interferometry and speckle photography in the primary stability determination of a mandible undergoing the bilateral sagittal split osteotomy (BSSO) is described. Measurements were carried out on Synbone models of human mandibles representing three different techniques of stabilisation. The maximum value criterion of the cut edge displacement components was used for the evaluation of the devices applied (miniplates and bicortical screws). A hybrid technique (miniplate with bicortical screw) of the mandible stabilisation is proposed. PMID- 21247057 TI - The evaluation of selected attachment systems for implant-retained overdenture based on retention characteristics analysis. AB - The results of mechanical characteristics of attachments used for retaining and stabilizing overdenture have been analysed. Two commercially used attachments (a ball attachment and a bar attachment) and elastic frictional attachments designed by the research team with Professor Chladek as the leader have been investigated. The diagrams of force-displacement characteristics have been registered. Retention forces (F(R)) have been determined and total work (W(T)) disconnecting the attachments has been calculated on the basis of these diagrams. The analysis of total work corresponding to different types of attachments made it possible to distinguish some characteristic areas which illustrate specific features of particular designs. It has been revealed that determining the retention force allows us to compare only the attachments which work on similar bases. In order to conduct a purely objective comparison of the efficiency of different designs, it is necessary to analyze complete force-displacement characteristics as well as to determine on this basis the subsequent phases of separating the parts of attachments and to find the value of the work which in fact determines their quality. The comparison of selected commercially used designs and the presented elastic frictional attachments (taking into account the criterion of work) gives clear evidence that the introduced design of attachment enables us to create very good conditions of retaining overdenture. PMID- 21247058 TI - The biomechanics of pathological gait - from muscle to movement. AB - Clinicians face the daily challenge of assessing and treating patients with gait problems. Musculoskeletal models appear to show potential for assisting with the understanding of complex pathological movements, however they are also complex and reliant on multiple assumptions in order to maintain stability. This paper breaks down the process by which muscles produce movement into a series of steps. The contributions and limitations of modelling each separate step are then considered. The calf muscles serve as an illustration throughout the paper, as these muscles are frequently implicated in the development of pathological gait patterns. An argument is put forward for the development of a range of tools for use in clinical practice, leading to an enhanced appreciation of the importance of joint moments. Improved clinical understanding of the link between muscles and movement will allow clinicians to develop better treatment plans for their patients. PMID- 21247059 TI - Friction force and pressure calculations for time-dependent impulsive intelligent lubrication of human hip joint. AB - The core of the present problem was to indicate the values of the optimum synovial fluid velocity and friction forces appearing near the cartilage cells of cooperating surfaces, as well as to find the ways of controlling the friction forces between particles of the liquid and the cells of the biobearing cooperating bodies in the thin boundary layer. In the research, we used a numerical method. Investigations of the physical and strength features are expected to be performed for various kinds of biobearing superficial layer and for damage to biobearings. In order to begin treating the surface structure of a superficial layer on the cooperating biobearing surfaces it is absolutely necessary to build a proper model of a liquid flow in the thin layer and to obtain the proper values of friction forces. PMID- 21247060 TI - Sports biomechanics in the research of the Department of Biomechanics of University School of Physical Education in Poznan. Part 2. Biomechanics of rowing: research conducted in the rowing pool and under real conditions. Reconstruction and synthesis. AB - The purpose of this study was to reconstruct the early phase of scientific research conducted at the Department of Biomechanics of the College of Physical Education and since 1972 at the University School of Physical Education in Poznan, with special attention paid to the works on biomechanics of rowing, carried out as part of the Ministerial Project PR 105 entitled The effectiveness of training, sports competition as well as regeneration in sports. Two kinds of biomechanical research are described: the several years' expert research conducted on the Rowing National Team in an original two-module Rowing Pool Testing Station BTW-1, as well as research on geometric optimization of the rowing station, conducted under real conditions, in reservoirs, with the use of a prototypical, unique at that time, computer measurement system BIOMIK, installed in the rower's own boat. The projects were carried out by doctoral students from the Department of Biomechanics and the Department of Clinical Biomechanics, Andrzej Lisiecki and Wojciech Mikolajczyk, respectively. PMID- 21247061 TI - New egzoluminal circular surgical stapler. AB - The study presents the design, prototype version and preliminary results of in vivo testing of the egzoluminal circular surgical stapler for "end-to-end" anastomosis of bowels after the resection, where staples are put outside the intestinal lumen, and walls of the intestinal tube directly contact the intestinal mucous membrane. The adopted idea of an "end-to-end" intestinal anastomosis as well as a strong need for a device that would be re-usable have determined its specific design. The device is characterised by a kinematic mode of operation, different from the operating mode of commonly used staplers, and hence by a specific combination of the individual components. The in vivo tests, successfully conducted on animals, have proved that this method of anastomosis as well as the device used for its practical performance are fully applicable in clinical practice, as best shown by patent application No. P 386369. PMID- 21247062 TI - Evaluation of LAGE-1 and NY-ESO-1 expression in multiple myeloma patients to explore possible benefits of their homology for immunotherapy. AB - Due to the high homology between the LAGE-1 and NY-ESO-1 proteins, we hypothesized that an anti-NY-ESO-1 vaccine might elicit LAGE-1 immunity and hence may be effective in multiple myeloma (MM) patients with LAGE-1-positive/NY-ESO-1 negative tumors. Therefore, we set out to evaluate LAGE-1 and NY-ESO-1 mRNA and protein expression in MM patients in a bid to evaluate possible benefits of their homology for immunotherapy. LAGE-1 (a and b isoforms) and NY-ESO-1 mRNA expression was studied in 18 normal tissues and 50 bone marrow MM samples by RT PCR. LAGE-1 and NY-ESO-1 protein expression was analyzed by immunohistochemistry (IHC) in 27 MM specimens using mAbs 219-510-23 and E978. Spontaneous serological immune response against both antigens was analyzed by ELISA in sera from 33 MM patients. LAGE-1 (a and b isoforms) was positive in 42% and NY-ESO-1 in 26% of the MM samples analyzed by RT-PCR. Both genes were found to be expressed in 18% of the cases, while at least one of the genes was found to be expressed in 50% of the cases. In LAGE-1 positive samples, 81% were positive for LAGE-1a and 19% were positive for both LAGE-1a and -1b. LAGE-1 and NY-ESO-1 protein expression could only be detected in two cases by IHC and there was a clear strong spontaneous antibody response to LAGE-1 and NY-ESO-1 in only one MM patient. In conclusion, LAGE-1a and NY-ESO-1 homology cannot be easily exploited in an anti-NY-ESO-1 vaccine given the low frequency of protein expression detected by IHC or serum analysis. PMID- 21247063 TI - Single-molecule detection on a protein-array assay platform for the exposure of a tuberculosis antigen. AB - Based on a single-molecule sensitive fluorescence-linked immunosorbent assay, an analytical platform for the detection of lipoarabinomannan (LAM), a lipopolysaccharide marker of tuberculosis, was established that is about 3 orders of magnitude more sensitive than comparable current ELISA assays. No amplification step was required. Also, no particular sample preparation had to be done. Since individual binding events are detected, true quantification was possible simply by counting individual signals. Utilizing a total internal reflection configuration, unprocessed biological samples (human urine and plasma) to which LAM was added could be analyzed without the requirement of sample purification or washing steps during analysis. Samples containing about 600 antigen molecules per microliter produced a distinct signal. The methodology developed can be employed for any set of target molecules for which appropriate antibodies exist. PMID- 21247064 TI - Sweeping with electrokinetic injection and analyte focusing by micelle collapse in two-dimensional separation via integration of micellar electrokinetic chromatography with capillary zone electrophoresis. AB - A novel integrated concentration/separation approach involving online combination of sweeping with electrokinetic injection and analyte focusing by micelle collapse (AFMC) with heart-cutting two-dimensional (2D) capillary electrophoresis (CE) in a single capillary was developed for analysis of Herba Leonuri and mouse blood samples. First, a new sweeping with an electrokinetic injection preconcentration method was developed to inject a large volume sample solution and significantly enhance detection sensitivity. Then, the preconcentration scheme was integrated to the 2D-CE to provide significant analyte concentration and extremely high resolving power. The sample was preconcentrated by sweeping with electrokinetic injection and separated in first dimension micellar electrokinetic chromatography (MEKC). Then, only a desirable fraction of the first dimension separation was transferred into the second dimension of the capillary by pressure and further analyzed by capillary zone electrophoresis (CZE) acting as the second dimension. As the key to successful integration of MEKC and CZE, an AFMC step was integrated between the two dimensions to release analytes from the micelle interior to a liquid zone and to overcome the sample zone diffusion caused by mobilization pressure. The injected sample plug lengths for flavonoids under 15 kV for 60 min were experimentally estimated as 546 cm. The dual concentration methods resulted in the increased detection factors of 6000-fold relative to the traditional pressure injection method. The relative standard deviation (RSD) values of peak height, peak area, and migration time were 2.7-4.5%, 1.9-4.3%, and 4.7-6.8% (n = 10), respectively. The limits of detection (S/N = 3) were in the range of 7.3-36.4 ng/L, and the theoretical plate numbers (N) were in the range of 1.7-4.3 * 10(4) plates/m. This method has been successfully applied to determine flavonoids in Herba Leonuri and postdosing mouse blood samples. The pharmacokinetic study also demonstrated that the proposed concentration/separation method was convenient and sensitive and would become an attractively alternative method for online sample concentration and separation in complex samples. PMID- 21247065 TI - Effector granules in human T lymphocytes: proteomic evidence for two distinct species of cytotoxic effector vesicles. AB - Cytotoxic T cells mobilize effector proteins from prestored lysosomal compartments. Since different activation signals result in alternative routes of target cell killing, utilizing either FasL or the granzyme B/perforin pathway, the existence of distinct forms of effector granules was recently suggested. Applying a protocol for the separation of intact organelles from activated T lymphoblasts, we noticed that FasL-associated secretory lysosomes (SL) segregate from vesicles containing larger amounts of granzymes and granulysin. We previously analyzed the proteome of secretory lysosomes from NK and T cells and now describe the proteome of granzyme-containing vesicles. Moreover, intact FasL associated SL and granzyme-containing vesicles were compared by electron microscopy and respective extracts were characterized by Western blotting. With the present report, we provide a comprehensive proteome map of granzyme containing granules and unequivocally demonstrate that T lymphoblasts contain at least two distinct types of effector vesicles. Moreover, the overall protein content of the two vesicle populations was compared by 2D difference gel electrophoresis. Interestingly, the observed differences in protein distribution were not restricted to effector proteins but also applied to cytoskeleton associated elements that could argue for a differential transport or initiation of degranulation. To our knowledge, this is the first comprehensive description of distinct effector granules in T cells. PMID- 21247066 TI - Photothermal nanoblade for large cargo delivery into mammalian cells. AB - It is difficult to achieve controlled cutting of elastic, mechanically fragile, and rapidly resealing mammalian cell membranes. Here, we report a photothermal nanoblade that utilizes a metallic nanostructure to harvest short laser pulse energy and convert it into a highly localized explosive vapor bubble, which rapidly punctures a lightly contacting cell membrane via high-speed fluidic flows and induced transient shear stress. The cavitation bubble pattern is controlled by the metallic structure configuration and laser pulse duration and energy. Integration of the metallic nanostructure with a micropipet, the nanoblade generates a micrometer-sized membrane access port for delivering highly concentrated cargo (5 * 10(8) live bacteria/mL) with high efficiency (46%) and cell viability (>90%) into mammalian cells. Additional biologic and inanimate cargo over 3-orders of magnitude in size including DNA, RNA, 200 nm polystyrene beads, to 2 MUm bacteria have also been delivered into multiple mammalian cell types. Overall, the photothermal nanoblade is a new approach for delivering difficult cargo into mammalian cells. PMID- 21247067 TI - Self-powered sensor for naked-eye detection of serum trypsin. AB - Here, we report a device for the detection of the proteolytic enzyme trypsin, which is a biomarker for pancreatitis. The sensor is self-powered, easy to use, and signals the presence of trypsin via a light-emitting diode (LED) that is visible to the unaided eye. Assay time is ~3 h, and the limit of detection is 0.5 MUg/mL, which is within the range required for detection of trypsin at levels signaling acute pancreatitis. The sensing mechanism relies on trypsin digestion of a gelled protein layer. Partial digestion of the protein layer permits hydroxide penetration and subsequent etching of an underlying Al membrane. Degradation of both the protein and Al layers exposes an underlying Mg anode and closes an electrochemical circuit that produces ~2.2 V. This is sufficient voltage to illuminate the LED. A logarithmic relationship is observed between the time required for LED illumination and trypsin concentration. The device is equally effective for trypsin dissolved in buffer or serum media. PMID- 21247069 TI - Direct analysis of biological tissue by paper spray mass spectrometry. AB - Paper spray mass spectrometry (PS-MS) is explored as a fast and convenient way for direct analysis of molecules in tissues with minimum sample pretreatment. This technique allows direct detection of different types of compounds such as hormones, lipids, and therapeutic drugs in short total analysis times (less than 1 min) using a small volume of tissue sample (typically 1 mm(3) or less). The tissue sample could be obtained by needle aspiration biopsy, by punch biopsy, or by rubbing a thin tissue section across the paper. There exists potential for the application of paper spray mass spectrometry together with tissue biopsy for clinical diagnostics. PMID- 21247070 TI - Rotational state specific dissociation dynamics of HOD -> H + OD via two-photon excitation to the C electronic state. AB - The dissociation dynamics of HOD via two-photon excitation to the C state have been investigated using the H-atom Rydberg tagging time-of-flight (TOF) technique. The H-atom action spectrum for the C <- X transition shows resolved rotational structure. Product translational energy distributions and angular distributions have also been recorded for the H + OD channel for three excited levels each with k(a)' = 2. From these distributions, quantum state distributions and angular anisotropy parameters (beta2 and beta4) for the OD product were determined. These results are consistent with the nonadiabatic predissociation picture illustrated in the one-photon dissociation process for H2O. The heterogeneous dissociation pathway via Coriolis coupling is the dominant dissociation process in the present study. A high proportion of the total available energy is deposited into the rotational energy of the OD product. The anisotropic recoil distributions reveal the distinctive contributions from the alignment of the excited states and the dissociation process. Comparisons are also made between the results for HOD and H2O via the equivalent rotational transitions. The OH bond energy, D(o)(H-OD), of the HOD molecule is also determined to be 41283.0 +/- 5 cm(-1). PMID- 21247071 TI - Spreading dynamics of a functionalized polymer latex. AB - Functionalized polymer nanoparticles are used as binders for inorganic materials in everyday technologies such as paper and coatings. However, the functionalization can give rise to two opposing effects: It can promote adhesion via specific interactions to the substrate, but a high degree of functionalization can also hamper spreading on substrates. Here, we studied the spreading kinetics of individual functionalized vinyl acetate-co-ethylene polymer nanoparticles on inorganic substrates by atomic force microscopy (AFM) imaging. We found that the kinetics underwent a transition from a fast initial regime to a slower regime. The transition was independent of functionalization of the particles but depended on the wettability of the substrate. Furthermore, the transition from the fast regime to the slow regime occurred at a size-dependent contact angle, leading to a h ~ a(3/2) scaling dependence between the height (h) and the width (a) of the spreading particles. Thereafter, spreading continued on a slower time scale. In the slow regime, the kinetics was blocked by a high degree of functionalization. We interpret the observations in terms of a nanoscale stick-slip transition occurring at interface stress around 6 kPa. We develop models that describe the scaling relations between the particle height and width on different substrates. PMID- 21247072 TI - Yb3AuGe2In3: an ordered variant of the YbAuIn structure exhibiting mixed-valent Yb behavior. AB - Yb(3)AuGe(2)In(3) was obtained as large single crystals in high yield from reactions run in liquid indium. Single crystal X-ray diffraction data show that Yb(3)AuGe(2)In(3) is an ordered variant of YbAuIn with lattice constants, a = b = 7.3153(8) A and c = 4.4210(5) A, and space group P(6)2m. The parent compound YbAuIn was also studied for comparison. YbAuIn crystallizes in the ZrNiAl structure type, hexagonal, P(6)2m space group with lattice parameters a = b = 7.7127(11) A and c = 4.0294(8) A. In Yb(3)AuGe(2)In(3), Ge substitutes for one of the two Au positions in the ternary compound Yb(3)Au(3)In(3). The structure can be described as alternating [Ge(2)In(3)] and [Yb(3)Au] slabs that stack along the c-axis. The magnetic susceptibility data follow a modified Curie-Weiss law. The effective magnetic moment MU(eff) of 0.52 MU(B)/Yb atom was deduced from the Curie constant and Curie-Weiss constant of theta(p) = -1.5 K indicating antiferromagnetic interactions in Yb(3)AuGe(2)In(3). X-ray absorption near edge spectroscopy (XANES) measurements indicate intermediate valency for Yb in both compounds. The metallic nature of both compounds was confirmed by the resistivity measurements. Specific heat data for Yb(3)AuGe(2)In(3) and YbAuIn give an electronic gamma term of 31 and 84 mJ/mol.K(2), respectively, suggesting that the ternary analog is a "light" heavy fermion compound. PMID- 21247073 TI - Ionization of purine tautomers in nucleobases, nucleosides, and nucleotides: from the gas phase to the aqueous environment. AB - We have simulated ionization of purine nucleic acid components in the gas phase and in a water environment. The vertical and adiabatic ionization processes were calculated at the PMP2/aug-cc-pVDZ level with the TDDFT method applied to obtain ionization from the deeper lying orbitals. The water environment was modeled via microsolvation approach and using a nonequilibrium polarizable continuum model. We have characterized a set of guanine tautomers and investigated nucleosides and nucleotides in different conformations. The results for guanine, i.e., the nucleic acid base with the lowest vertical ionization potential, were also compared to those for the other purine base, adenine. The main findings of our study are the following: (i) Guanine remains clearly the base with the lowest ionization energy even upon aqueous solvation. (ii) Water solvent has a strong effect on the ionization energetics of guanine and adenine and their derivatives; the vertical ionization potential (VIP) is lowered by about 1 eV for guanine while it is ~1.5 eV higher in the nucleotides, overall resulting in similar VIPs for GMP(-), guanosine and guanine in water. (iii) Water efficiently screens the electrostatic interactions between nucleic acid components. Consequently, ionization in water always originates from the base unit of the nucleic acid and all the information about conformational state is lost in the ionization energetics. (iv) The energy splitting between ionization of the two least bound electrons increases upon solvation. (v) Tautomerism does not contribute to the width of the photoelectron spectra in water. (vi) The effect of specific short range interactions with individual solvent molecules is negligible for purine bases, compared to the long-range dielectric effects of the aqueous medium. PMID- 21247074 TI - Simple electrochemical deposition of au nanoplates from au(I) cyanide complexes and their electrocatalytic activities. AB - Nanostructured Au surfaces have unique and attractive properties as functional materials in many fields such as heterogeneous catalysis and electrocatalysis. Electrochemical deposition of Au has received much attention as a simple route for the fabrication of Au surface nanostructures. In this study, we report a simple electrodeposition of Au nanoplate structures from Au(CN)(2)(-) on Au surfaces in the absence of additives or premodification of electrode surfaces. The shape of the Au nanoplates as well as their surface structures is unique compared to other Au nanostructures electrodeposited from commonly employed AuCl(4)(-) complexes. The nanoplate Au surfaces exhibit unique electrocatalytic activities for oxygen reduction and glucose oxidation, which originate from the Au(110) and Au(100) facets present on nanoplate surfaces. A simple preparation of well-defined Au nanoplate structures would allow new opportunities in various areas utilizing Au-based substrates through further modification of Au surfaces. PMID- 21247075 TI - Design of a room-temperature phosphorescence-based molecular beacon for highly sensitive detection of nucleic acids in biological fluids. AB - Ultrasensitive fluorescent analysis or monitoring of significant molecules in complex samples is important for many biological studies, clinical diagnosis, and forensic investigations, the major obstacle for which is the background signals from ubiquitous endogenous fluorescent components of the environments. Herein, a room-temperature phosphorescence (RTP)-based molecular beacon (MB), employing a Eu(3+) complex of chlorosulfonylated tetradentate beta-diketone (L) and the quencher BHQ-2, was engineered for highly sensitive detection of DNA sequences in biological fluids. Complexation of Eu(3+) with the ligand L formed a strongly luminescent complex EuL(2). But when EuL(2) and BHQ-2 were labeled to two ends of a DNA molecule with hairpin structure, the luminescence of EuL(2) was quenched by BHQ-2 due to the stem-closed conformation of the beacon. Due to very low background luminescence from the probe molecule, >200-fold signal enhancement was achieved when nanomolar target sequence was introduced. This sensitivity is about 20-fold higher than the level achieved with conventional fluorescence-based molecular beacons. Furthermore, because the Eu(3+) complex has a much longer luminescence lifetime (~0.8 ms) than that of the background (<10 ns), RTP measurements were used to directly detect as low as 500 pM DNA in cell media quantitatively without any sample pretreatment. PMID- 21247076 TI - Hyrtioseragamines A and B, new alkaloids from the sponge Hyrtios species. AB - Two novel alkaloids with a furo[2,3-b]pyrazin-2(1H)-one moiety and a guanidino group, hyrtioseragamines A (1) and B (2), have been isolated from an Okinawan marine sponge Hyrtios species. The structures of 1 and 2 were elucidated on the basis of spectroscopic data and chemical conversions. Compounds 1 and 2 are the first natural products possessing a furo[2,3-b]pyrazine-related moiety. PMID- 21247077 TI - 18O assisted analysis of a gamma,delta-epoxyketone cyclization: synthesis of the C16-C28 fragment of ammocidin D. AB - The C16-C28 fragment common to the cytotoxic macrolide ammocidin D has been prepared by a stereospecific 5-exo closure of a gamma,delta-epoxyketone followed by a rearrangement to a pyran acetal. The reaction pathway was traced by (18)O labeling of the keto carbonyl and observation of (18)O induced (13)C shifts in the pyran acetal product. NMR data of the synthetic C16-C28 fragment compared favorably to the natural product providing support of the assigned stereochemistry. PMID- 21247078 TI - Magnetic structure of Ni(DCOO)2(D2O)2. AB - Ni(HCOO)(2)(H(2)O)(2) is a structurally simple coordination polymer showing interesting magnetic phase transitions at low temperature (<16K). Previously published studies of these phase transitions have yielded inconsistent results, questioning the correctness of the published magnetic structure. Here heat capacity and magnetic susceptibility of a fully, a partly and a non-deuterated sample were measured, and they all exhibit magnetic phase transitions around 3 and 15 K. Neutron powder diffraction data was collected on the fully deuterated sample at various temperatures between 1.5 and 25 K. A magnetic model was refined against the neutron diffraction data using a spin system composed of two canted antiferromagnetic sublattices. The magnetic moments of the two sublattices show different magnitude, 1.7 MU(B) and 1.3 MU(B), and the temperature dependence of the magnetic sublattices is quite different. One of the sublattices shows the expected temperature behavior of an antiferromagnetic compound whereas the other sublattice follows a Brillouin like function with a slowly increasing magnetization below the Neel temperature. PMID- 21247079 TI - A highly selective fluorescent chemosensor for zinc ion and imaging application in living cells. AB - A new 2,6-bis(5,6-dihydrobenzo[4,5]imidazo[1,2-c]quinazolin-6-yl)-4-methylphenol (1) serves as a highly selective and sensitive fluorescent probe for Zn(2+) in a HEPES buffer (50 mM, DMSO:water = 1:9 (v/v), pH = 7.2) at 25 degrees C. The increase in fluorescence in the presence of Zn(2+) is accounted for by the formation of dinuclear Zn(2+) complex [Zn(2)(C(35)H(25)N(6)O)(OH)(NO(3))(2)(H(2)O)] (2), characterized by X-ray crystallography. The fluorescence quantum yield of the chemosensor 1 is only 0.019, and it increases more than 12-fold (0.237) in the presence of 2 equiv of the zinc ion. Interestingly, the introduction of other metal ions causes the fluorescence intensity to be either unchanged or weakened. By incubation of cultured living cells (A375 and HT-29) with the chemosensor 1, intracellular Zn(2+) concentrations could be monitored through selective fluorescence chemosensing. PMID- 21247080 TI - Competitive binding of methanol and propane for water via matrix-isolation spectroscopy: implications for inhibition of clathrate nucleation. AB - Methanol is a well-known thermodynamic inhibitor of clathrate hydrate formation. The interactions responsible for the inhibition, however, are not well identified. Propane is a relatively simple hydrocarbon that forms a clathrate hydrate under mild conditions. This paper reports data about the interaction of methanol with water-propane complex. Methanol, water, and propane are isolated in carbon tetrachloride, and the interaction is probed with infrared spectroscopy. Water is known to interact with propane via the oxygen lone pairs and the propane methylene hydrogens. Experimental evidence indicates that methanol hydrogen bonds to water via donation of the hydroxyl hydrogen (K = 4.4 * 10(2)). Methanol does not have a direct interaction with propane. These results are consistent with an inhibitory mechanism in which methanol competes with propane for the oxygen atom of water. PMID- 21247081 TI - C-O hydrogenolysis catalyzed by Pd-PMHS nanoparticles in the company of chloroarenes. AB - Catalytic Pd(OAc)(2) and polymethylhydrosiloxane (PMHS), in conjunction with aqueous KF, and a catalytic amount of an aromatic chloride, effects the chemo-, regio-, and stereoselective deoxygenation of benzylic oxygenated substrates at room temperature in THF. Preliminary mechanistic experiments suggest the process to involve palladium-nanoparticle-catalyzed hydrosilylation followed by C-O reduction. The chloroarene additive appears to facilitate the hydrogenolysis process through the slow controlled release of HCl. PMID- 21247082 TI - Chemoselectivities in the platinum-catalyzed hydrative carbocyclizations of oxo alkyne-nitrile functionalities. AB - Two new hydrative carbocyclizations of oxa-alkyne-nitrile functionalities are reported to produce distinct nitrogen-containing heterocycles. Protracted heating of oxoalkynyl nitrile substrates with PtCl(2)/CO/H(2)O in hot 1,4-dioxane gave 2,3-dihydro-1H-pyrido[1.2-b]-isoquinolin-4(6H)-ones. In this hydration reaction, dicarbonyl nitrile intermediates were isolated efficiently after a brief period, and they were subjected to an NHC-based crossed benzoin coupling to give spiro alcohols that further reacted with TfOH to give spiro[indene-2,2'-piperidine] 1,6'(3H)-diones. PMID- 21247083 TI - Effect of Bi2O3 addition on electron paramagnetic resonance, optical absorption, and conductivity in vanadyl-doped Li2O-K2O-Bi2O3-B2O3 glasses. AB - Glasses with composition 15Li(2)O-15K(2)O-xBi(2)O(3)-(65 - x)-B(2)O(3)/5V(2)O(5) (3 <= x <= 15) have been prepared by the conventional melt quench technique. The electron paramagnetic resonance spectra of VO(2+) in these glasses have been recorded in the X-band frequency (~9.3 GHz) at room temperature. The spin Hamiltonian parameters and covalency rates were evaluated. It was found that the V(4+) ions exist as vanadyl (VO(2+)) ions and are in an octahedral coordination with a tetragonal compression. The covalency rates (1 - alpha(2)) and (1 - gamma(2)) indicate moderate covalency for the sigma- and pi-bonds. It was observed that the spin-Hamiltonian parameters depend slightly on the relative concentration of Bi(2)O(3). The optical properties of this glass system are studied from the optical absorption spectra recorded in the wavelength range 200 800 nm. The fundamental absorption edge has been identified from the optical absorption spectra. The values of optical band gap for indirect allowed transitions have been determined using available theories. The direct current electrical conductivity, sigma, has been measured in the temperature range 373 573 K. The conductivity decreases with the increase in Bi(2)O(3) concentration. This has been discussed in terms of the decrease in the number of mobile ions and their mobility. An attempt is made to correlate the EPR, optical, and electrical results and to find the effect of Bi(2)O(3) content on these parameters. PMID- 21247084 TI - ACO-zeotype iron aluminum phosphates with variable Al/Fe ratios controlled by F- ions. AB - Three new iron aluminum phosphates |(C(2)H(10)N(2))(4)|[Fe(8 - x)Al(x)F(x)(H(2)O)(2 - x)(PO(4))(8)].2H(2)O (chi = 1.64, 1.33, 0.80) with ACO zeotype structures denoted as FeAPO-CJ66(a), FeAPO-CJ66(b), and FeAPO-CJ66(c), respectively, have been synthesized in the fluoride ion system. Their framework structures are made of double 4-ring (D4R) building units formed by the alternating connection of Fe(Al)O(4)F(O) trigonal bipyramids and PO(4) tetrahedra, which possess 3D intersecting 8-ring channels running along the [001], [010], and [100] directions. Fluoride ions or water molecules reside in the center of D4Rs, and diprotonated ethylenediamine cations and water molecules are occluded in the free space of channels to stabilize the whole structure. Notably, the Al/Fe ratios in the frameworks can be effectively controlled from 1/3.9 to 1/5.0 to 1/9.0 by adjusting the amounts of phosphoric acid and hydrofluoric acid added to the initial reaction mixture. Mossbauer and magnetic measurements show that the Fe ions in the compounds are bivalent and undergo antiferromagnetic ordering at room temperature. PMID- 21247085 TI - Asymmetric synthesis of beta-substituted gamma-lactams via rhodium/diene catalyzed 1,4-additions: application to the synthesis of (R)-baclofen and (R) rolipram. AB - An efficient rhodium/diene-catalyzed asymmetric addition of arylboronic acids to alpha,beta-unsaturated gamma-lactams has been developed. The power of this methodology is further demonstrated by the concise synthesis of (R)-baclofen and (R)-rolipram. PMID- 21247086 TI - Acid-catalyzed synthesis of bicyclo[3.n.1]alkenediones. AB - An acid-catalyzed Dieckmann-type reaction has been developed to access functionalized bicyclo[3.2.1]alkenediones. This methodology has been successfully extended to more substituted and larger ring homologues, providing a new and efficient route to the core of numerous attractive natural products and their analogues. PMID- 21247087 TI - Nanotubular metal-organic frameworks with high porosity based on T-shaped pyridyl dicarboxylate ligands. AB - Two nanotubular metal-organic frameworks (MOFs), {Cu(L1).2H(2)O.1.5DMF}(infinity) (1) and {Cu(2)(L2)(2)(H(2)O)(2).7H(2)O.3DMF}(infinity) (2), with novel topologies have been constructed based on Cu(2+), 5-(pyridin-4-yl)isophthalic acid (L1) and 5-(pyridin-3-yl)isophthalic acid (L2), respectively. Two MOFs were characterized by IR spectroscopy, thermogravimetry, single-crystal, and powder X-ray diffraction methods. Network analysis reveals a two-nodal (3,6)-connected (4.6(2))(2)(4(2).6(10).8(3)) net and a three-nodal (3,4)-connected (4.8(2))(4)(4(2).8(2).10(2))(2)(8(4).12(2)) net. Interpenetration is inherently prevented by both of the topologies of the frameworks. The porosity of MOF 1 was confirmed by N(2) and CO(2) gas adsorption investigations. MOF 1 exhibits remarkable hydrogen sorption hysteresis at low pressure and a H(2) uptake capacity of 1.05 wt% at 77 K and 1 atm. PMID- 21247089 TI - Galvanic replacement of semiconductor phase I CuTCNQ microrods with KAuBr4 to fabricate CuTCNQ/Au nanocomposites with photocatalytic properties. AB - In this study, the reaction of semiconductor microrods of phase I copper 7,7,8,8 tetracyanoquinodimethane (CuTCNQ) with KAuBr(4) in acetonitrile is reported. It was found that the reaction is redox in nature and proceeds via a galvanic replacement mechanism in which the surface of CuTCNQ is replaced with metallic gold nanoparticles. Given the slight solubility of CuTCNQ in acetonitrile, two competing reactions, namely CuTCNQ dissolution and the redox reaction with KAuBr(4), were found to operate in parallel. An increase in the surface coverage of CuTCNQ microrods with gold nanoparticles occurred with an increased KAuBr(4) concentration in acetonitrile, which also inhibited CuTCNQ dissolution. The reaction progress with time was monitored using UV-visible, FT-IR, and Raman spectroscopy as well as XRD and EDX analysis, and SEM imaging. The CuTCNQ/Au nanocomposites were investigated for their photocatalytic properties, wherein the destruction of Congo red, an organic dye, by simulated solar light was found dependent on the surface coverage of gold nanoparticles on the CuTCNQ microrods. This method of decorating CuTCNQ may open the possibility of modifying this and other metal-TCNQ charge transfer complexes with a host of other metals which may have significant applications. PMID- 21247088 TI - Comment on "urea-mediated protein denaturation: a consensus view". PMID- 21247090 TI - Carbon monoxide dehydrogenase reaction mechanism: a likely case of abnormal CO2 insertion to a Ni-H(-) bond. AB - Ni-containing carbon monoxide dehydrogenases (CODH), present in many anaerobic microorganisms, catalyze the reversible oxidation of CO to CO(2) at the so-called C-cluster. This atypical active site is composed of a [NiFe(3)S(4)] cluster and a single unusual iron ion called ferrous component II or Fe(u) that is bridged to the cluster via one sulfide ion. After additional refinement of recently published high-resolution structures of COOH(x)-, OH(x)-, and CN-bound CODH from Carboxydothermus hydrogenoformans (Jeoung and Dobbek Science 2007, 318, 1461 1464; J. Am. Chem. Soc. 2009, 131, 9922-9923), we have used computational methods on the predominant resulting structures to investigate the spectroscopically well characterized catalytic intermediates, C(red1) and the two-electron more-reduced C(red2). Several models were geometry-optimized for both states using hybrid quantum mechanical/molecular mechanical potentials. The comparison of calculated Mossbauer parameters of these active site models with experimental data allows us to propose that the C(red1) state has a Fe(u)-Ni(2+) bridging hydroxide ligand and the C(red2) state has a hydride terminally bound to Ni(2+). Using our combined structural and theoretical data, we put forward a revised version of an earlier proposal for the catalytic cycle of Ni-containing CODH (Volbeda and Fontecilla-Camps Dalton Trans. 2005, 21, 3443-3450) that agrees with available spectroscopic and structural data. This mechanism involves an abnormal CO(2) insertion into the Ni(2+)-H(-) bond. PMID- 21247091 TI - Catalytic mechanism and three-dimensional structure of adenine deaminase. AB - Adenine deaminase (ADE) catalyzes the conversion of adenine to hypoxanthine and ammonia. The enzyme isolated from Escherichia coli using standard expression conditions was low for the deamination of adenine (k(cat) = 2.0 s(-1); k(cat)/K(m) = 2.5 * 10(3) M(-1) s(-1)). However, when iron was sequestered with a metal chelator and the growth medium was supplemented with Mn(2+) prior to induction, the purified enzyme was substantially more active for the deamination of adenine with k(cat) and k(cat)/K(m) values of 200 s(-1) and 5 * 10(5) M(-1) s( 1), respectively. The apoenzyme was prepared and reconstituted with Fe(2+), Zn(2+), or Mn(2+). In each case, two enzyme equivalents of metal were necessary for reconstitution of the deaminase activity. This work provides the first example of any member of the deaminase subfamily of the amidohydrolase superfamily to utilize a binuclear metal center for the catalysis of a deamination reaction. [Fe(II)/Fe(II)]-ADE was oxidized to [Fe(III)/Fe(III)]-ADE with ferricyanide with inactivation of the deaminase activity. Reducing [Fe(III)/Fe(III)]-ADE with dithionite restored the deaminase activity, and thus, the diferrous form of the enzyme is essential for catalytic activity. No evidence of spin coupling between metal ions was evident by electron paramagnetic resonance or Mossbauer spectroscopy. The three-dimensional structure of adenine deaminase from Agrobacterium tumefaciens (Atu4426) was determined by X-ray crystallography at 2.2 A resolution, and adenine was modeled into the active site on the basis of homology to other members of the amidohydrolase superfamily. On the basis of the model of the adenine-ADE complex and subsequent mutagenesis experiments, the roles for each of the highly conserved residues were proposed. Solvent isotope effects, pH-rate profiles, and solvent viscosity were utilized to propose a chemical reaction mechanism and the identity of the rate-limiting steps. PMID- 21247092 TI - Requirements for Skp1 processing by cytosolic prolyl 4(trans)-hydroxylase and alpha-N-acetylglucosaminyltransferase enzymes involved in O2 signaling in dictyostelium. AB - The social amoeba Dictyostelium expresses a hypoxia inducible factor-alpha (HIFalpha) type prolyl 4-hydroxylase (P4H1) and an alpha-N acetylglucosaminyltransferase (Gnt1) that sequentially modify proline-143 of Skp1, a subunit of the SCF (Skp1/Cullin/F-box protein) class of E3 ubiquitin ligases. Prior genetic studies have implicated Skp1 and its modification by these enzymes in O(2) regulation of development, suggesting the existence of an ancient O(2)-sensing mechanism related to modification of the transcription factor HIFalpha by animal prolyl 4-hydroxylases (PHDs). To better understand the role of Skp1 in P4H1-dependent O(2) signaling, biochemical and biophysical studies were conducted to characterize the reaction product and the basis of Skp1 substrate selection by P4H1 and Gnt1. (1)H NMR demonstrated formation of 4(trans) hydroxyproline as previously found for HIFalpha, and highly purified P4H1 was inhibited by Krebs cycle intermediates and other compounds that affect animal P4Hs. However, in contrast to hydroxylation of HIFalpha by PHDs, P4H1 depended on features of full-length Skp1, based on truncation, mutagenesis, and competitive inhibition studies. These features are conserved during animal evolution, as even mammalian Skp1, which lacks the target proline, became a good substrate upon its restoration. P4H1 recognition may depend on features conserved for SCF complex formation as heterodimerization with an F-box protein blocked Skp1 hydroxylation. The hydroxyproline-capping enzyme Gnt1 exhibited similar requirements for Skp1 as a substrate. These and other findings support a model in which the protist P4H1 conditionally hydroxylates Skp1 of E3(SCF)ubiquitin ligases to control half-lives of multiple targets, rather than the mechanism of animal PHDs where individual proteins are hydroxylated leading to ubiquitination by the evolutionarily related E3(VBC)ubiquitin ligases. PMID- 21247093 TI - Development of an indole-based chemically cleavable linker concept for immobilizing bait compounds for protein pull-down experiments. AB - A novel linker chemistry based on a malondialdehyde-indole condensation reaction has been developed for the affinity-independent elution of targeted protein pull downs. Previously developed in our lab for the tagging of tryptophan residues on proteins or peptides, the concept was extended for the design of a chemically cleavable linker system. Target molecules for interaction studies are immobilized on a solid support including the linker scaffold, and a typical pull-down experiment is carried out. After purification, the linker is cleaved by incubation with 50 mM pyrrolidine. A specific tyrosine kinase inhibitor, bosutinib, was coupled to agarose and acrylamide beads, respectively, via the new linker system, and a protein pull-down experiment of putative interaction partners from a K562 whole cell lysate was performed. The system was found to be compatible with targeted protein pull-downs; during the cleavage step, no protein hydrolysis or any degradation of amino acid side-chains was apparent. From the pull-down experiment, key targets of bosutinib such as the tyrosine kinase, Btk, were identified by liquid chromatography-tandem mass spectrometry. PMID- 21247094 TI - Chemistry of soluble beta-diketiminatoalkaline-earth metal complexes with M-X bonds (M=Mg, Ca, Sr; X=OH, Halides, H). AB - Victor Grignard's Nobel Prize-winning preparation of organomagnesium halides (Grignard reagents) marked the formal beginning of organometallic chemistry with alkaline earth metals. Further development of this invaluable synthetic route, RX+Mg->RMgX, with the heavier alkaline earth metals (Ca and Sr) was hampered by limitations in synthetic methodologies. Moreover, the lack of suitable ligands for stabilizing the reactive target molecules, particularly with the more electropositive Ca and Sr, was another obstacle. The absence in the literature, until just recently, of fundamental alkaline earth metal complexes with M-H, M-F, and M-OH (where M is the Group 2 metal Mg, Ca, or Sr) bonds amenable for organometallic reactions is remarkable. The progress in isolating various unstable compounds of p-block elements with beta-diketiminate ligands was recently applied to Group 2 chemistry. The monoanionic beta-diketiminate ligands are versatile tools for addressing synthetic challenges, as amply demonstrated with alkaline earth complexes: the synthesis and structural characterization of soluble beta-diketiminatocalcium hydroxide, beta-diketiminatostrontium hydroxide, and beta-diketiminatocalcium fluoride are just a few examples of our contribution to this area of research. To advance the chemistry beyond synthesis, we have investigated the reactivity and potential for applications of these species, for example, through the demonstration of dip coating surfaces with CaCO(3) and CaF(2) with solutions of the calcium hydroxide and calcium fluoride complexes, respectively. In this Account, we summarize some recent developments in alkaline earth metal complex chemistry, particularly of Mg, Ca, and Sr, through the utilization of beta-diketiminate ligands. We focus on results generated in our laboratory but give due mention to work from other groups as well. We also highlight the closely related chemistry of the Group 12 element Zn, as well as the important chemistry developed by other groups using the complexes we have reported. Although Mg and Ca are more abundant in living organisms, no other metal has as many biological functions as Zn. Thus Zn, the nontoxic alternative to the heavier Group 12 elements Cd and Hg, occupies a unique position ripe for further exploration. PMID- 21247095 TI - Magnetic glyconanoparticles as a versatile platform for selective immunolabeling and imaging of cells. AB - A versatile nanoplatform based on magnetic glyconanoparticles (glyco-ferrites) to attach well-oriented antibodies is described. An efficient ligand exchange process has been used to prepare water-soluble 6-nm-sized core-shell Fe(3)O(4)@Au nanoparticles bearing amphiphilic carbohydrates and aliphatic ethylene glycol chains ended in a carboxyl group. The covalent immobilization through the carboxyl group of an Fc receptor (protein G) enables successful well-oriented capture of immunoglobulins G onto the magnetic glyconanoparticle. A thorough characterization of structure and biofunctionality of the constructs is carried out by different techniques. The selective immunolabeling of cells by the antibody-magnetic glyconanoparticle conjugates is demonstrated by magnetic resonance imaging (MRI), as well as by fluorescence techniques. PMID- 21247096 TI - Thermoreversible hydrogel for in situ generation and release of HepG2 spheroids. AB - Organ printing is an alternative to the classic scaffold-based tissue engineering approach in which functional living macrotissues and organ constructs are fabricated by assembly of the building blocks: microtissue spheroids. However, the method for scalable fabrication of cell spheroids does not exist yet. We propose here that it may be a suitable one to generate cell spheroids in thermoreversible hydrogel scaffold, followed by liquefying the scaffold and releasing the generated spheroids. We show that concentrated poly(N isopropylacrylamide-co-acrylic acid) microgel dispersions solidify upon heating and liquefy upon cooling. A hysteresis in the cooling process was observed and explained by the slow kinetics of the dissolution of the aggregated polymer chains in the cooling process due to additional intra- and interchain interactions. Hep G2 cells are seeded by simple mixing the cells with the microgel dispersions at room temperature. Cell/scaffold constructs form in situ when heated to 37 degrees C. The cells proliferate and form multicellular spheroids. When brought back to room temperature, the hydrogel scaffolds liquefy, thus, releasing the generated cell spheroids. The released spheroids can attach on the cell culture plate, disassemble, and spread on the substrate, confirming the cell viability. The whole process is carried out under mild conditions and does not involve any toxic additives, which may introduce injury to the cells or DNA. It is scalable and may meet the need for large scale fabrication of cell spheroids for organ printing. PMID- 21247097 TI - Emissions of PAHs from indoor crop residue burning in a typical rural stove: emission factors, size distributions, and gas-particle partitioning. AB - Indoor combustion of crop residues for cooking or heating is one of the most important emission sources of polycyclic aromatic hydrocarbons (PAHs) in developing countries. However, data on PAH emission factors (EFs) for burning crop residues indoor, particularly those measured in the field, were scarce, leading to large uncertainties in the emission inventories. In this study, EFs of PAHs for nine commonly used crop residues burned in a typical Chinese rural cooking stove were measured in a simulated kitchen. The measured EFs of total PAHs averaged at 63 +/- 37 mg/kg, ranging from 27 to 142 mg/kg, which were higher than those measured in chamber experiments, implying that the laboratory experiment-based emission and risk assessment should be carefully reviewed. EFs of gaseous and particulate phase PAHs were 27 +/- 13 and 35 +/- 23 mg/kg, respectively. Composition profiles and isomer ratios of emitted PAHs were characterized. Stepwise regressions found that modified combustion efficiency and fuel moisture were the most important factors affecting the emissions. There was 80 +/- 6% of PAHs associated with PM2.5, and the mass percentage of PAHs in fine particles increased as the molecular weight increased. For freshly emitted PAHs, absorption into organic carbon, rather than adsorption, dominated the gas particle partitioning. PMID- 21247098 TI - Temporal trends of hexabromocyclododecane, polybrominated diphenyl ethers and polychlorinated biphenyls in ringed seals from East greenland. AB - Concentrations of hexabromocyclododecane (HBCD) were determined in a combination of archived and fresh blubber samples of juvenile ringed seals from East Greenland collected between 1986 and 2008. alpha-HBCD was the only diastereoisomer consistently above levels of quantification and showed a significant log-linear (exponential) increase from 2.0 to 8.7 ng/g lipid weight (median concentrations) with an annual rate of +6.1%. The concentrations were up to several orders of magnitude lower than those reported for marine mammals from industrialized areas. Previously presented time trends on polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) have been extended with new data for 2006 and 2008. SigmaPBDE in juvenile seals was the only parameter with a slight upward trend, however, dependent on the low 1986 concentration. Removing this data point resulted in a downward trend, which also was found for adult seals with a time trend starting in 1994. SigmaPCB decreased significantly in juvenile seals, again due to the 1986 value, while no trend was found for the adult animals. This indicates stagnating PCB concentrations at a relatively high level, in some cases possibly exceeding tolerable daily intake rates for seal blubber as traditional Arctic food items. PMID- 21247099 TI - Climate change-related temperature impacts on warm season heat mortality: a proof of-concept methodology using BenMAP. AB - Climate change is anticipated to raise overall temperatures and is likely to increase heat-related human health morbidity and mortality risks. The objective of this work was to develop a proof-of-concept approach for estimating excess heat-related premature deaths in the continental United States resulting from potential changes in future temperature using the BenMAP model. In this approach we adapt the methods and tools that the US Environmental Protection Agency uses to assess air pollution health impacts by incorporating temperature modeling and heat mortality health impact functions. This new method demonstrates the ability to apply the existing temperature-health literature to quantify prospective changes in climate-sensitive heat-related mortality. We compared estimates of future temperature with and without climate change and applied heat-mortality health functions to estimate relative changes in heat-related premature mortality. Using the A1B emissions scenario, we applied the GISS-II global circulation model downscaled to 36-km using MM5 and formatted using the Meteorology-Chemistry Interface Processor. For averaged temperatures derived from the 5 years 2048-2052 relative to 1999-2003 we estimated for the warm season May September a national U.S. estimate of annual incidence of heat-related mortality to be 3700-3800 from all causes, 3500 from cardiovascular disease, and 21 000-27 000 from nonaccidental death, applying various health impact functions. Our estimates of mortality, produced to validate the application of a new methodology, suggest the importance of quantifying heat impacts in economic assessments of climate change. PMID- 21247100 TI - Effects of pesticides monitored with three sampling methods in 24 sites on macroinvertebrates and microorganisms. AB - Grab water samples, sediment samples, and 2,2,4-trimethylpentane passive samplers (TRIMPS) were used to determine the exposure to 97 pesticides in 24 southeast Australian stream sites over 5 months. Macroinvertebrate communities and selected microorganisms (bacteria, flagellates, ciliates, amoebas, nematodes, and gastrotrichs) were sampled to detect relationships with pesticide toxicity. Sediment samples had the highest estimated toxicities in terms of toxic units (TU) for Daphnia magna (TUDM) and for Selenastrum capricornutum (TUSC). The pesticide-selective SPEARpesticides and the general SIGNAL index for macroinvertebrates exhibited negative linear relationships (r(2) = 0.67 and 0.36, respectively) with pesticide contamination in terms of log maximum TUDM (log mTUDM), suggesting macroinvertebrate community change due to pesticide exposure. Pesticide contamination was the only measured variable explaining variation in ecological quality. Variation in the densities of several microbial groups was best explained by environmental variables other than log TUs. The log mTUDM values derived from sediment concentrations were most important to establish a link with effects on macroinvertebrates, whereas log mTUDM of grab water samples had only minor contribution. Current-use insecticides and fungicides can affect macroinvertebrate communities and monitoring of sediment and continuous water sampling is needed to detect these effects. PMID- 21247101 TI - Density functional theory analysis of the interplay between Jahn-Teller instability, uniaxial magnetism, spin arrangement, metal-metal interaction, and spin-orbit coupling in Ca3CoMO6 (M = Co, Rh, Ir). AB - In the isostructural oxides Ca(3)CoMO(6) (M = Co, Rh, Ir), the CoMO(6) chains made up of face-sharing CoO(6) trigonal prisms and MO(6) octahedra are separated by Ca atoms. We analyzed the magnetic and electronic properties of these oxides on the basis of density functional theory calculations including on-site repulsion and spin-orbit coupling, and examined the essential one-electron pictures hidden behind results of these calculations. Our analysis reveals an intimate interplay between Jahn-Teller instability, uniaxial magnetism, spin arrangement, metal-metal interaction, and spin-orbit coupling in governing the magnetic and electronic properties of these oxides. These oxides undergo a Jahn Teller distortion, but their distortions are weak, so that their trigonal-prism Co(n+) (n = 2, 3) ions still give rise to strong easy-axis anisotropy along the chain direction. As for the d-state split pattern of these ions, the electronic and magnetic properties of Ca(3)CoMO(6) (M = Co, Rh, Ir) are consistent with d(0) < (d(2), d(-2)) < (d(1), d(-1)) but not with (d(2), d(-2)) < d(0) < (d(1), d( 1)). The trigonal-prism Co(3+) ion in Ca(3)Co(2)O(6) has the L = 2 configuration (d(0))(1)(d(2), d(-2))(3)(d(1), d(-1))(2) because of the metal-metal interaction between adjacent Co(3+) ions in each Co(2)O(6) chain, which is mediated by their z(2) orbitals, and the spin-orbit coupling of the trigonal-prism Co(3+) ion. The spins in each CoMO(6) chain of Ca(3)CoMO(6) prefer the ferromagnetic arrangement for M = Co and Rh but the antiferromagnetic arrangement for M = Ir. The octahedral M(4+) ion of Ca(3)CoMO(6) has the (1a)(1)(1e)(4) configuration for M = Rh but the (1a)(2)(1e)(3) configuration for M = Ir, which arises from the difference in the spin-orbit coupling of the M(4+) ions and the Co...M metal metal interactions. PMID- 21247102 TI - Blinded taste panel evaluations to determine if fish from near the oil sands are preferred less than fish from other locations in Alberta, Canada. AB - The oil sands industry is rapidly expanding surface mining and bitumen extraction operations near the Athabasca River in northeastern Alberta, Canada. There are anecdotal comments that the fish from the Athabasca River have an off-taste, implying that the oil sands operations are the cause. This study was done to determine if the taste of wild fishes caught near the Athabasca oil sands was less preferred than the taste of fishes collected from two other river basins in Alberta. In blinded experiments, consumer sensory panels, of 40 to 44 participants, tasted steamed samples of each of three fish species (walleye (Sander vitreus), northern pike (Esox lucius), and lake whitefish (Coregonus clupeaformis)) from three different sources in Alberta (the Athabasca River, Buck Lake, and McGregor Lake). Data analyses showed that there was no evidence from the consumer preference rankings that the taste of the fish from the Athabasca River was preferred less than the taste of fish from two other water bodies in Alberta. PMID- 21247103 TI - Effects of arsenic compound amendment on arsenic speciation in rice grain. AB - Rice consumption is a major source of arsenic for Asian populations. Arsenic is present in rice grain both as inorganic arsenic and as dimethylarsinic acid (DMA). It is unclear whether DMA in rice is taken up from the soil or synthesized in planta. We investigated the effect of DMA, methylarsonic acid (MMA) and arsenite amendment on arsenic speciation in rice grain grown in soil and in solution culture. We also investigated the methylation of arsenic in solution culture under suppression of bacterial activity. When rice was grown under flooded conditions after the heading stage, DMA amendment to the soil resulted in higher DMA concentration in brown rice and rice straw. In the solution culture, not only DMA amendment but also MMA or arsenite amendment increased the DMA concentration in brown rice and rice straw. DMA was detected in the solution amended by MMA or arsenite with young rice plants. When the solution included the antibacterial agent chloramphenicol, DMA concentration in the solution decreased dramatically. When only the soil was incubated with MMA or arsenite, only a slight amount of DMA was detected in the soil. These results suggest that rice rhizosphere associated bacteria would be involved in the formation of DMA in brown rice. PMID- 21247104 TI - Determination of (235)U, (239)Pu, (240)Pu, and (241)Am in a nuclear bomb particle using a position-sensitive alpha-gamma coincidence technique. AB - A nuclear bomb particle containing 1.6 ng of Pu was investigated nondestructively with a position-sensitive alpha detector and a broad-energy HPGe gamma-ray detector. An event-mode data acquisition system was used to record the data. alpha-gamma coincidence counting was shown to be well suited to nondestructive isotope ratio determination. Because of the very small background, the 51.6 keV gamma rays of (239)Pu and the 45.2 keV gamma rays of (240)Pu were identified, which enabled isotopic ratio calculations. In the present work, the (239)Pu/((239)Pu+(240)Pu) atom ratio was determined to be 0.950 +/- 0.010. The uncertainties were much smaller than in the previous more conventional nondestructive studies on this particle. Obtained results are also in good agreement with the data from the destructive mass spectrometric studies obtained previously by other investigators. PMID- 21247105 TI - Quantitative determination of perfluorochemicals and fluorotelomer alcohols in plants from biosolid-amended fields using LC/MS/MS and GC/MS. AB - Analytical methods for determining perfluorochemicals (PFCs) and fluorotelomer alcohols (FTOHs) in plants using liquid chromatography/tandem mass spectrometry (LC/MS/MS) and gas chromatography/mass spectrometry (GC/MS) were developed, and applied to quantify a suite of analytes in plants from biosolid-amended fields. Dichloromethane-methanol and ethylacetate were chosen as extracting solutions for PFCs and FTOHs, respectively. Nine perfluorocarboxylic acids (PFCAs), three perfluorosulfonic acids (PFSAs), and ten FTOHs were monitored. Most PFCAs and perfluorooctanesulfonate (PFOS) were quantifiable in plants grown in contaminated soils, whereas PFCs went undetected in plants from two background fields. Perfluorooctanoic acid (PFOA) was a major homologue (~10-200 ng/g dry wt), followed by perfluorodecanoic acid (~3-170 ng/g). [PFOS] in plants (1-20 ng/g) generally was less than or equal to most [PFCAs]. The site-specific grass/soil accumulation factor (GSAF = [PFC](Grass)/[PFC](Soil)) was calculated to assess transfer potentials from soils. Perfluorohexanoic acid had the highest GSAF (= 3.8), but the GSAF decreased considerably with increasing PFCA chain length. Log transformed GSAF was significantly correlated with the PFCA carbon-length (p < 0.05). Of the measured alcohols, 8:2nFTOH was the dominant species (<=1.5 ng/g), but generally was present at >=10* lower concentrations than PFOA. PMID- 21247106 TI - Unique ability of BiOBr to decarboxylate d-Glu and d-MeAsp in the photocatalytic degradation of microcystin-LR in water. AB - Bismuth oxide bromide, BiOBr, was used to catalyze the degradation of microcystin LR (MC-LR) in water at neutral pH under visible light. During the investigation, twelve intermediates from MC-LR decomposition were identified by LC-MS. In addition to attacking MC-LR at the typically susceptible sites (i.e., the conjugated double bond of the Adda chain and terminal unsaturated bond of the Mdha chain), the BiOBr photocatalyst has the remarkable ability to decarboxylate the free acid groups on d-glutamic acid (Glu) and methyl-d-aspartic acid (MeAsp). This reactivity has not been previously observed with TiO2 photocatalysis or with other MC-LR treatments in which decarboxylation does not occur until the MC-LR ring has been cleaved or mineralized to CO2. Some expected intermediate products were detected with oxygen-18 labeling by using H2(18)O as the solvent to confirm that the decarboxylation process is mediated by BiOBr. Results from characterizing the intermediates as well as oxygen-18 labeling studies indicates that oxidative decarboxylation of MC-LR by BiOBr photocatalysis is not always initiated by hydroxyl radical attack (and/or interaction with a hole followed by hydrolysis) proposed mechanism in TiO2 photocatalysis, whereas likely caused by a direct interaction between photoinduced hole of BiOBr and free carboxyl groups of MC-LR. This unusual decarboxylation behavior seems to be associated with the particular valence band and conduction band state of BiOBr photocatalyst. Also under BiOBr catalysis, a very stable guanidine group of l-arginine (l-Arg) that is nonreactive with TiO2 photocatalysis is converted to an amino group and subsequently oxidized to a nitro group during the decomposition of MC-LR. This reaction sequence is also related to decarboxylation because the guanidine conversion requires a completely or partially decarboxylated precursor. Our results indicate that BiOBr, a photocatalyst that selectively destroys sites crucial to MC-LR toxicity, shows great promise as a means of effectively treating drinking water. PMID- 21247107 TI - Orientation of diamagnetic layered transition metal oxide particles in 1-tesla magnetic fields. AB - The magnetic field-driven orientation of microcrystals of six diamagnetic layered transition metal oxides (HLaNb(2)O(7), HCa(2)Nb(3)O(10).0.5H(2)O, KNaCa(2)Nb(4)O(13), KTiTaO(5), KTiNbO(5), and H(2.2)K(1.8)Nb(6)O(17).nH(2)O) suspended in epoxy resins was studied by X-ray diffraction using permanent magnets producing a 0.8 T field. Although the degree of orientation, quantified as the Hermans order parameter, was strongly affected by the particle size distribution, in all cases microcrystals with ~1-2 MUm lateral dimensions were found to orient with the magnetic field vector in the layer plane. Control of the orientation of ionically conducting layered oxides is of interest for practical applications in batteries and fuel cells. The consistent direction of orientation of the lamellar oxides studied can be rationalized in the framework of a quantitative bond anisotropy model developed by Uyeda (Phys. Chem. Miner.1993, 20, 77-80). The asymmetry of metal-oxygen bonding at the faces of the octahedral layers results in long and short M-O bonds perpendicular to the plane of the sheets. This distortion of the M-O octahedra, which is a structural feature of almost all layered materials that contain octahedral bonding frameworks, gives rise to the diamagnetic anisotropy and results in an easy axis or plane of magnetization in the plane of the sheets. PMID- 21247108 TI - Real-time high-resolution X-ray imaging and nuclear magnetic resonance study of the hydration of pure and Na-doped C3A in the presence of sulfates. AB - This study details the differences in real-time hydration between pure tricalcium aluminate (cubic C(3)A or 3CaO.Al(2)O(3)) and Na-doped tricalcium aluminate (orthorhombic C(3)A or Na(2)Ca(8)Al(6)O(18)), in aqueous solutions containing sulfate ions. Pure phases were synthesized in the laboratory to develop an independent benchmark for the reactions, meaning that their reactions during hydration in a simulated early age cement pore solution (saturated with respect to gypsum and lime) were able to be isolated. Because the rate of this reaction is extremely rapid, most microscopy methods are not adequate to study the early phases of the reactions in the early stages. Here, a high-resolution full-field soft X-ray imaging technique operating in the X-ray water window, combined with solution analysis by (27)Al nuclear magnetic resonance (NMR) spectroscopy, was used to capture information regarding the mechanism of C(3)A hydration during the early stages. There are differences in the hydration mechanism between the two types of C(3)A, which are also dependent on the concentration of sulfate ions in the solution. The reactions with cubic C(3)A (pure) seem to be more influenced by higher concentrations of sulfate ions, forming smaller ettringite needles at a slower pace than the orthorhombic C(3)A (Na-doped) sample. The rate of release of aluminate species into the solution phase is also accelerated by Na doping. PMID- 21247109 TI - A dinuclear palladium catalyst for alpha-hydroxylation of carbonyls with O2. AB - A chemo- and regioselective alpha-hydroxylation reaction of carbonyl compounds with molecular oxygen as oxidant is reported. The hydroxylation reaction is catalyzed by a dinuclear Pd(II) complex, which functions as an oxygen transfer catalyst, reminiscent of an oxygenase. The development of this oxidation reaction was inspired by discovery and mechanism evaluation of previously unknown Pd(III) Pd(III) complexes. PMID- 21247110 TI - The mobility of water molecules through gas hydrates. AB - Crystal growth simulations of gas hydrates have suggested that hydrate cages may occasionally be occupied by H(2)O rather than guest molecules, leaving interstitial defects within the hydrate crystal. Further inspection of the behavior of these interstitial H(2)O molecules has revealed that they are relatively highly mobile entities within a gas hydrate. In this paper, we report these observations and examine the molecular mechanisms responsible for the transport of these interstitial molecules through hydrate crystals. Four distinct pathways for the H(2)O molecule transport between cages are found, each facilitated by the presence of empty cages. The relative richness of the observed behavior of interstitial defects suggests that interstitial diffusion could be an important mechanism for the mass transport of H(2)O molecules through gas hydrates. PMID- 21247111 TI - H2 separation using defect-free, inorganic composite membranes. AB - Defect-free, microporous Al(2)O(3)/SAPO-34 zeolite composite membranes were prepared by coating hydrothermally grown zeolite membranes with microporous alumina using molecular layer deposition. These inorganic composite membranes are highly efficient for H(2) separation: their highest H(2)/N(2) mixture selectivity was 1040, in contrast with selectivities of 8 for SAPO-34 membranes. The composite membranes were selective for H(2) for temperatures up to at least 473 K and feed pressures up to at least 1.5 MPa; at 473 K and 1.5 MPa, the H(2)/N(2) separation selectivity was 750. The H(2)/CO(2) separation selectivity was lower than the H(2)/N(2) selectivity and decreased slightly with increasing pressure; the selectivity was 20 at 473 K and 1.5 MPa. The high H(2) selectivity resulted either because most of the pores in the Al(2)O(3) layer were slightly smaller than 0.36 nm (the kinetic diameter of N(2)) or because the Al(2)O(3) layer slightly narrowed the SAPO-34 pore entrance. These composite membranes may represent a new class of inorganic membranes for gas separation. PMID- 21247112 TI - DNA-templated fabrication of two-dimensional metallic nanostructures by thermal evaporation coating. AB - A biotemplating strategy for fabrication of metallic nanoparticle arrays has been developed. The templates are self-assembled DNA nanostructures, which dictate nanoparticle synthesis in the gas-solid phase (during thermal evaporation). PMID- 21247113 TI - Metabolites from the induced expression of cryptic single operons found in the genome of Burkholderia pseudomallei. AB - Bacterial genome sequencing projects routinely uncover gene clusters that are predicted to encode the biosynthesis of uncharacterized small molecules. A subset of these cryptic genetic elements appears as individual operons. Here we investigate potential single-operon biosynthetic systems found in the genome of the pathogenic bacterium Burkholderia pseudomallei . Placing these operons under the control of an inducible promoter led to the production of seven new metabolites. Among the molecules we identified are inhibitors of type-4 phosphodiesterases, suggesting that previously cryptic biosynthetic operons may encode metabolites that could contribute to microbial virulence by disrupting host signaling pathways. PMID- 21247114 TI - Synthesis and physicochemical characterization of carbon backbone modified [Gd(TTDA)(H2O)]2- derivatives. AB - The present study was designed to exploit optimum lipophilicity and high water exchange rate (k(ex)) on low molecular weight Gd(III) complexes to generate high bound relaxivity (r(1)(b)), upon binding to the lipophilic site of human serum albumin (HSA). Two new carbon backbone modified TTDA (3,6,10-tri(carboxymethyl) 3,6,10-triazadodecanedioic acid) derivatives, CB-TTDA and Bz-CB-TTDA, were synthesized. The complexes [Gd(CB-TTDA)(H(2)O)](2-) and [Gd(Bz-CB-TTDA)(H(2)O)](2 ) both display high stability constant (log K(GdL) = 20.28 and 20.09, respectively). Furthermore, CB-TTDA (log K(Gd/Zn) = 4.22) and Bz-CB-TTDA (log K(Gd/Zn) = 4.12) exhibit superior selectivity of Gd(III) against Zn(II) than those of TTDA (log K(Gd/Zn) = 2.93), EPTPA-bz-NO(2) (log K(Gd/Zn) = 3.19), and DTPA (log K(Gd/Zn) = 3.76). However, the stability constant values of [Gd(CB TTDA)(H(2)O)](2-) and [Gd(Bz-CB-TTDA)(H(2)O)](2-) are lower than that of MS-325. The parameters that affect proton relaxivity have been determined in a combined variable temperature (17)O NMR and NMRD study. The water exchange rates are comparable for the two complexes, 232 * 10(6) s(-1) for [Gd(CB-TTDA)(H(2)O)](2-) and 271 * 10(6) s(-1) for [Gd(Bz-CB-TTDA)(H(2)O)](2-). They are higher than those of [Gd(TTDA)(H(2)O)](2-) (146 * 10(6) s(-1)), [Gd(DTPA)(H(2)O)](2-) (4.1 * 10(6) s(-1)), and MS-325 (6.1 * 10(6) s(-1)). Elevated stability and water exchange rate indicate that the presence of cyclobutyl on the carbon backbone imparts rigidity and steric constraint to [Gd(CB-TTDA)(H(2)O)](2-)and [Gd(Bz-CB TTDA)(H(2)O)](2-). In addition, the major objective for selecting the cyclobutyl is to tune the lipophilicity of [Gd(Bz-CB-TTDA)(H(2)O)](2-). The binding affinity of [Gd(Bz-CB-TTDA)(H(2)O)](2-) to HSA was evaluated by ultrafiltration study across a membrane with a 30 kDa MW cutoff, and the first three stepwise binding constants were determined by fitting the data to a stoichiometric model. The binding association constants (K(A)) for [Gd(CB-TTDA)(H(2)O)](2-) and [Gd(Bz-CB TTDA)(H(2)O)](2-) are 1.1 * 10(2) and 1.5 * 10(3), respectively. Although the K(A) value for [Gd(Bz-CB-TTDA)(H(2)O)](2-) is lower than that of MS-325 (K(A) = 3.0 * 10(4)), the r(1)(b) value, r(1)(b) = 66.7 mM(-1) s(-1) for [Gd(Bz-CB TTDA)(H(2)O)](2-), is significantly higher than that of MS-325 (r(1)(b) = 47.0 mM(-1) s(-1)). As measured by the Zn(II) transmetalation process, the kinetic stabilities of [Gd(CB-TTDA)(H(2)O)](2-), [Gd(Bz-CB-TTDA)(H(2)O)](2-), and [Gd(DTPA)(H(2)O)](2-) are similar and are significantly higher than that of [Gd(DTPA-BMA)(H(2)O)](2-). High thermodynamic and kinetic stability and optimized lipophilicity of [Gd(CB-TTDA)(H(2)O)](2-) make it a favorable blood pool contrast agent for MRI. PMID- 21247116 TI - Welcome to ACS Combinatorial Science. PMID- 21247117 TI - Open vessel and cooling while heating microwave-assisted synthesis of pyridinyl N aryl hydrazones. AB - We reported the first example of open vessel and cooling while heating microwave assisted synthesis of pyridinyl N-aryl hydrazones. Compounds were prepared in excellent isolated yields (88-98%) in only 5 min, by reacting 4- and 2,4 (di)substituted phenylhydrazines, bearing both electron-donating (4-CH3, 4-OCH3) and -withdrawing (4-Cl, 4-Br, 4-CF3, 4-NO2, 2,4-Cl2) groups with 2-, 3-, and 4 acetylpyridine. The method was successfully extended to other carbonyl compounds. PMID- 21247118 TI - Silica-supported aluminum chloride-assisted solution phase synthesis of pyridazinone-based antiplatelet agents. AB - A solution phase protocol that enabled the synthesis of three diverse libraries of pyridazin-3-ones incorporating alpha,beta-unsaturated moieties at position 5 of the heterocyclic core has been developed using silica-supported aluminum trichloride as a heterogeneous and reusable catalyst. This robust procedure has facilitated the hit to lead process for these series of compounds and allowed the identification of new potent derivatives that elicit antiplatelet activity in the low micromolar range. PMID- 21247119 TI - Efficient assembly of 1-(1H-imidazol-1-yl)-3-methylene-1H-indenes via tandem reaction of (2-(alkynyl)benzylidene)malonates with imidazoles. AB - The tandem nucleophilic addition and 5-exo-cyclization of (2 (alkynyl)benzylidene)malonates with imidazole derivatives in the presence of t BuOK is reported. This reaction proceeds smoothly under mild conditions with high selectivity to afford the corresponding 1-(1H-imidazol-1-yl)-3-methylene-1H indene-2,2(3H)-dicarboxylates in good to excellent yields. PMID- 21247120 TI - Metal-free intramolecular amination: one-pot tandem synthesis of 3-substituted 4 quinolones. AB - 3-Substituted 4-quinolones were synthesized using a one-pot metal-free strategy in moderate to quantitative yields. Carried out in dimethylsulfoxide (DMSO) via a sequential addition of materials, the methodology is tolerant of a wide range of functional groups and applicable to library synthesis. PMID- 21247121 TI - Microwave-mediated synthesis of an arylboronate library. AB - A series of arylboronates has been synthesized from the reaction of 2-(2-, (3-, or (4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1{1-3} respectively with a range of N-, S-, and O-nucleophiles, using microwave-mediated chemistry. For the synthesis of N- and S-substituted boronates, a supported base, PS-NMM, was employed, and many reactions were complete within 15 min. With O nucleophiles, a mixture of tetrabutylammonium bromide, potassium carbonate, and sodium hydroxide was employed. The resulting aminomethyl, mercaptomethyl, or alkoxy-/phenoxymethyl-arylboronates were subjected to microwave-mediated Suzuki Miyaura coupling reactions to afford a range of biaryls in moderate to good yields. The X-ray structures of five boronates were determined. PMID- 21247122 TI - Fluorescence response profiling for small molecule sensors utilizing the green fluorescent protein chromophore and its derivatives. AB - Using a fluorescence response profile, a systematic examination was performed for synthetic chromophores of the green fluorescent protein (GFP) to discover new small molecule sensors. A group of 41 benzylideneimidazolinone compounds (BDI) was prepared and screened toward 94 biologically relevant analytes to generate fluorescence response profiles. From the response pattern, compounds containing aminobenzyl and heteroaromatic cyclic substructures revealed a pH dependent emission decrease effect, and unlike other fluorescence scaffolds, most BDIs showed fluorescence quenching when mixed with proteins. On the basis of the primary response profile, we obtained three selective fluorescence turn-on sensors for pH, human serum albumin (HSA), and total ribonucleic acid (RNA). Following analysis, a fluorescence response profile testing four nucleic acids revealed the alkyloxy (Ph-OR) functional group in the para position of benzyl analogues contributes to RNA selectivity. Among the primary hit compounds, BDI 2 showed outstanding selectivity toward total RNA with 5-fold emission enhancement. Finally, BDI 24 showed selective fluorescence increase to HSA (K(d) = 3.57 MUM) with a blue-shifted emission max wavelength (Deltalambda(em) = 15 nm). These examples of fluorescence sensor discovery by large-scale fluorescence response profiling demonstrate the general applicability of this approach and the usefulness of the response profiles. PMID- 21247123 TI - 2-phenylsubstituted-3-hydroxyquinolin-4(1H)-one-carboxamides: Structure-cytotoxic activity relationship study. AB - A structure-activity relationship of some derivatives of 2-phenylsubstituted- 3 hydroxyquinolin-4(1H)-one-7-carboxamides was systematically studied using combinatorial solid-phase synthesis and in vitro cytotoxic activity screening on representative cancer lines. The effect of substituent type in position 2 as well as of the carboxamide group was investigated via synthesis of generic libraries constructed with respect to polarity and bulkiness of appropriate substituents. The process of development afforded a set of compounds with significant cytotoxic activity. Subsequently, corresponding 2-phenylsubstituted-3-hydroxyquinolin-4(1H) one-6-carboxamides and 2-phenylsubstituted-3-hydroxyquinolin-4(1H)-one-8 carboxamides were prepared to evaluate the influence of the carboxamide group position on the resulting biological activity. PMID- 21247124 TI - Efficient one-pot three-component synthesis of fused pyridine derivatives in ionic liquid. AB - An efficient one-pot synthesis of fused pyridine derivatives (including pyrazolo[3,4-b]pyridine and pyrido[2,3-d]pyrimidine) by three-component reaction of aldehyde, acyl acetonitrile, and electron-rich amino heterocycles (including aminopyrazole and aminouracils) in ionic liquid is reported. This new protocol has the advantages of environmental friendliness, higher yields, shorter reaction times, and convenient operation. PMID- 21247125 TI - Identifying factors controlling protein release from combinatorial biomaterial libraries via hybrid data mining methods. AB - Polyanhydrides are a class of degradable biomaterials that have shown much promise for applications in drug and vaccine delivery. Their properties can be tailored for controlled drug release, drug/protein stability, and immune regulation (adjuvant effect). Identifying the relationship between the molecular structures of the polymers and the drug release kinetics profiles would help understand the release mechanism and aid in the accurate prediction of drug release and the rational design of polymer-based drug carrier systems. The molecular structure descriptors that had the most impact on the release kinetics were identified using a prediction/optimization data mining approach. Using this new approach for modeling nonlinear release kinetics behavior, we determined that the descriptors which had the greatest effect on the release kinetics were the number of backbone -COO- nonconjugated bonds, the number of aromatic rings, and the number of -CH2- bonds. PMID- 21247126 TI - Solid-phase synthesis of disubstituted N-acylureas from resin-bound ureas and acyl chlorides. AB - Acylureas (ureides) are valued for their important biological activities. Whereas cyclic acylureas have frequently been the object of solid-phase chemistry, only few reports have focused on the solid-supported preparation of acyclic representatives. We have prepared different types of acylureas on Rink amide resin in three or four steps. The products are either N-acylated (9, 18), N acylated-N'-alkylated (10, 19), or N-acylated-N-alkylated (22). Characteristic NMR parameters of isomeric acylureas 10, 19, and 22 are discussed. PMID- 21247127 TI - Natural product inspired diversity oriented synthesis of tetrahydroquinoline scaffolds as antitubercular agent. AB - An efficient natural product inspired diversity oriented syn thesis of tetrahydroquinoline analogues has been developed using the natural carbohydrate derived solid acid catalyst via multicomponent aza-Diels-Alder reaction of imine (generated in situ from aromatic amine and aldehyde) with dienophile in acetonitrile in a diastereoselective manner. The use of water as solvent reverses the diastereoselectivity toward the cis isomer. Interestingly, tricyclic pyrano/furano benzopyran with cis diastereoselectivity is obtained when salicylaldehyde is used as an alternative of aromatic aldehyde under the same condition. These synthesized quinolines and benzopyrans analogues have been evaluated for their Antitubercular activity against M. tuberculosis H37Ra, and M. tuberculosis H37Rv, and some of the analogues shows better activity profile than their natural product analogues. The protocol is not only mild, efficient, ecofriendly, but also involves reusable and biodegradable catalyst and provides route for both the diastereoisomer. PMID- 21247128 TI - One-pot tandem copper-catalyzed library synthesis of 1-thiazolyl-1,2,3-triazoles as anticancer agents. AB - One-pot multicomponent synthesis to assemble compounds has been an efficient method for constructing a compound library. We have developed one-pot tandem copper-catalyzed azidation and CuAAC reactions that afford 1-thiazolyl-1,2,3 triazoles with anticancer activity. By utilizing this one-pot synthetic strategy, we constructed a library of 1-thiazolyl-1,2,3-triazoles in search of the potent lead compound. Furthermore, 1-thiazolyl-1,2,3-triazoles were evaluated for anticancer activity against the multidrug-resistant cancer cells MES-SA/Dx5. Most of the 1-thiazolyl-1,2,3-triazoles revealed cytotoxic effect against cancer cells at micromolar to low micromolar range. Testing some of the most potent compounds (5{4,2-4} and 5{5,1-3}) against the normal cell line Vero showed no significant toxicity (except 5{4,2}) to normal cells. This result indicates that compounds 5{4,3-4} and 5{5,1-3} possessed good potency and selectivity to cancer cells over normal cells. PMID- 21247129 TI - Combinatorial Optimization of (Lu1-(x)Gd(x))3Al5O12:Ce3(y) yellow phosphors as precursors for ceramic scintillators. AB - A combinatorial chemistry method was employed to screen the yellow phosphors of (Lu1-(x)Gd(x))3Al5O12:Ce3(y) as luminescent materials. An array of 81 compositions was synthesized by inkjetting nitrate solutions into microreactor wells and sintering at high temperature. The candidate formulations were evaluated by luminescence pictures, and the optimal composition was determined to be Lu(2.7)Gd(0.3)Al(5)O(12):Ce(0.045) after scale-up and detailed characterization. Lu2.7Gd0.3Al5O12:Ce0.045 was also found to have a short decay time (<=53.97 ns). These results demonstrate the great potential of the Lu2.7Gd0.3Al5O12:Ce0.045 as a component of ceramic scintillators. PMID- 21247130 TI - Diversity-oriented synthesis of spiro-substituted 1,3-thiazine library via a one pot, two-step, three-component reaction. AB - A sequential one-pot, two-step, three-component reaction for efficient synthesis of spiro-substituted 1,3-thiazine library has been developed. The syntheses were achieved by reacting cyanoacetamide with isothiocyanate derivatives to give rise to 2-cyano-3-mercaptoacrylamides, which are trapped in situ by various cycloketones through cyclization, providing multifunctionalized spiro-substituted 1,3-thiazine analogues. This procedure features short reaction time, generally good to excellent yields, easily available starting materials, and operational simplicity. This chemistry provides an efficient and promising synthetic strategy to diversity-oriented construction of the 1,3-thiazine skeleton. PMID- 21247131 TI - Supported p-toluenesulfonic acid as a highly robust and eco-friendly isocyanide scavenger. AB - We document here the use of polymer-supported p-toluenesulfonic acid as a highly effective, robust, economical and eco-friendly isocyanide scavenger. The herein described strategy circumvent the intense and repulsive odor of volatile isocyanides, enabling simplified and odorless workup and purifications. The usefulness of the new scavengers has been validated in a set of diverse isocyanide-based organic transformations and this approach is also amenable to parallel synthesis techniques. PMID- 21247132 TI - Simple three-component method for the synthesis of spiroindeno[1,2-b]pyrido[2,3 d]pyrimidine-5,3'-indolines. AB - An efficient, simple, and catalyst-free synthesis of spiroindeno[1,2-b]pyrido[2,3 d]pyrimidine-5,3'-indolines and spiroacenaphthylene-1,4'-indeno-1,5'-pyrido[2,3 d]pyrimidines by the three-component reaction of 1,3-indandione, amino uracils and isatins or acenaphthylene-1,2-dione in refluxing ethanol is reported. PMID- 21247133 TI - Enantioselective organocatalytic alpha-fluorination of cyclic ketones. AB - The first highly enantioselective alpha-fluorination of ketones using organocatalysis has been accomplished. The long-standing problem of enantioselective ketone alpha-fluorination via enamine activation has been overcome via high-throughput evaluation of a new library of amine catalysts. The optimal system, a primary amine functionalized Cinchona alkaloid, allows the direct and asymmetric alpha-fluorination of a variety of carbo- and heterocyclic substrates. Furthermore, this protocol also provides diastereo-, regio-, and chemoselective catalyst control in fluorinations involving complex carbonyl systems. PMID- 21247134 TI - Nonmetal catalyzed insertion reactions of diazocarbonyls to acid derivatives in fluorinated alcohols. AB - The insertion reaction of diazocarbonyls to acids could be performed smoothly in fluorinated alcohols in the absence of metal catalyst. This new procedure allowed the chemoselective preparation of various functionalized compounds such as acyloxyesters, depsipeptides, and sulfonate, phosphonate, or boronate derivatives. PMID- 21247135 TI - A mesogenic triphenylene-perylene-triphenylene triad. AB - A straightforward synthesis of triphenylene-perylene-triphenylene triad structures has been achieved by using versatile triphenylene intermediates bearing a single oxyalkyl amine side chain. Among these, PBITP(10) showed a stable columnar mesophase implying favorably matched core-core separations in the structure. Importantly, the triad can be used as a vehicle for doping columnar triphenylene matrices with functional but incompatible perylene units and a mixture of hexahexyloxytriphenylene matrix doped with 0.1% PBITP(10) is homogeneous and liquid crystalline. PMID- 21247136 TI - Cyclopropenium-activated cyclodehydration of diols. AB - The dehydrative cyclization of diols to cyclic ethers via cyclopropenium activation is described. Using 2,3-diphenylcyclopropene and methanesulfonic anhydride, a series of 1,4- and 1,5-diols are rapidly cyclized to furnish tetrahydrofurans and tetrahydropyrans in high yield. Eleven total substrates are shown, including a gram scale cyclization of a diterpene derivative. PMID- 21247137 TI - Chemistry of SURMOFs: layer-selective installation of functional groups and post synthetic covalent modification probed by fluorescence microscopy. AB - Layer-selective installation of functional groups at SURMOFs (surface-attached metal-organic framework multilayers) is reported. Multilayers of [Cu(ndc)(dabco)(0.5)] grown in [001] orientation on pyridine-terminated organic self-assembled monolayers on Au substrates were functionalized with amino groups by step-by-step liquid-phase epitaxy. The method allows the growth of samples exhibiting one monolayer of functional groups at the external thin-film surface. In situ quartz crystal microbalance monitoring confirmed the presence of amino groups by turning the multilayer film from a non-reactive to a reactive material for covalent binding of fluoresceinisothiocyanate, and fluorescence microscopy displays the expected luminous property. PMID- 21247138 TI - Nanoscale mixing of soft solids. AB - Assessing the state of mixing on the molecular scale in soft solids is challenging. Concentrated solutions of micelles formed by self-assembly of polystyrene-block-poly(ethylene-alt-propylene) (PS-PEP) diblock copolymers in squalane (C(30)H(62)) adopt a body-centered cubic (bcc) lattice, with glassy PS cores. Utilizing small-angle neutron scattering (SANS) and isotopic labeling ((1)H and (2)H (D) polystyrene blocks) in a contrast-matching solvent (a mixture of squalane and perdeuterated squalane), we demonstrate quantitatively the remarkable fact that a commercial mixer can create completely random mixtures of micelles with either normal, PS(H), or deuterium-labeled, PS(D), cores on a well defined bcc lattice. The resulting SANS intensity is quantitatively modeled by the form factor of a single spherical core. These results demonstrate both the possibility of achieving complete nanoscale mixing in a soft solid and the use of SANS to quantify the randomness. PMID- 21247139 TI - Reductive lithiation of methyl substituted diarylmethylsilanes: application to silanediol peptide precursors. AB - Reductive lithiation of methyl-substituted diarylmethylsilanes using lithium naphthalenide represents a practical method for the preparation of the corresponding silyl lithium reagents. Their addition to chiral sulfinimines affords versatile precursors to silanols and silanediols. The replacement of the currently used diphenylsilane motif by a more labile diarylsilane moiety allows the selective hydrolysis of one or two aryl groups by treatment with TFA. PMID- 21247140 TI - Nature of intramolecular transannular interaction in group 13 atranes: a theoretical study. AB - Ab initio molecular orbital (MO) calculations at the MP2/6-31+G* level coupled with quantum theory of atoms in molecules (QTAIM) analysis were carried out on group 13 atranes (M = B, Al, Ga) with special emphasis on the nature of the transannular M...N interaction present in these molecules. Substituents at the equatorial position were found to influence the extent of transannular interaction. Boratrane molecules were found to have the strongest M...N interaction and consequently have higher stabilization energies. QTAIM analysis revealed the presence of significant covalent character in the transannular M...N bonds which decreases down the group. PMID- 21247141 TI - Enantioselective recognition of alpha-hydroxycarboxylic acids and N-Boc-amino acids by counterion-displacement assays with a chiral nickel(II) complex. AB - A new chiral sensor based on an N,N'-dioxide nickel(II) complex was prepared, which could visually recognize a series of chiral alpha-hydroxycarboxylic acid enantiomers by coordination and self-assembly forming into nanospheres or nanofibers. With the help of various techniques, the morphology structures of the colloid or suspension were obtained and the counterion-displacement assays were also confirmed. In addition, this metal complex could act as a highly enantioselective fluorescence sensor to recognize N-Boc-amino acids and chiral alpha-hydroxycarboxylic acids. PMID- 21247142 TI - Redox isomerization via azomethine ylide intermediates: N-alkyl indoles from indolines and aldehydes. AB - Indolines react with aromatic and heteroaromatic aldehydes to yield N-alkyl indoles in a benzoic acid catalyzed redox isomerization reaction. Azomethine ylides are intermediates in this process which was established by intramolecular [3 + 2] trapping experiments. PMID- 21247143 TI - Catalytic asymmetric aza-Michael-Michael addition cascade: enantioselective synthesis of polysubstituted 4-aminobenzopyrans. AB - A catalytic asymmetric aza-Michael-Michael addition cascade of anilines to nitroolefin enoates in the presence of chiral bifunctional thiourea catalysts has been disclosed. This reaction provides a mild and efficient approach to polysubstituted chiral 4-aminobenzopyrans bearing three consecutive stereocenters in high yields with excellent stereoselectivities. PMID- 21247144 TI - Reversible switching between linear and ring polystyrenes bearing porphyrin end groups. AB - A route to macrocyclic polymers based on a new unimolecular ring-closure process has been investigated. It involves the direct end-to-end coupling of an alpha,omega-bis[chloroiron(III) meso-tetraphenylporphyrin] telechelic linear polystyrene synthesized by living polymerization followed by chain-end functionalization. The corresponding macrocyclic polystyrene was obtained readily and selectively by intramolecular condensation of the alpha,omega bis[chloroiron(III) meso-tetraphenylporphyrin] polymer ends in the presence of a base to yield a diiron(III)-MU-oxobis(porphyrin) dimer as ring-closing unit. Addition of dilute HCl was shown to rapidly reconvert the diiron(III)-MU oxobis(porphyrin) unit into the initial bis[chloroiron(III) porphyrin], demonstrating the selectivity and complete reversibility of the cyclization process. The synthesis and detailed structural characterization of the alpha,omega-homodifunctional precursor and the corresponding macrocyclic polystyrene along with an analysis of the porphyrin dimerization reaction using NMR spectroscopy and size-exclusion chromatography coupled with a diode array detector are presented. PMID- 21247145 TI - Effect of water on the behavior of semiconductor quantum dots in zeolite Y: aggregation with framework destruction with H-Y and disaggregation with framework preservation for NH4-Y. AB - Treatment of dry M(2+)-exchanged zeolite Y (M(2+) = Cd(2+), Mn(2+), and Zn(2+)) with dry H(2)S leads to the formation of isolated, ligand-free, subnanometer MS quantum dots (QDs) in zeolite Y with no framework destruction and with H(+) as the countercation. Treatment of the dry H(+)/CdS QD-incorporating zeolites Y with dry NH(3) leads to the neutralization of H(+) to NH(4)(+). During this process, the framework structure remains intact. However, small amounts of interconnected CdS QDs were formed within the zeolite Y by coalition of isolated CdS QDs at the windows. With H(+) as the countercation, isolated CdS QDs rapidly aggregate into interconnected and mesosized QDs with accompanying destruction of ~50% of sodalite cages leading to the framework rupture. With NH(4)(+) as the countercation, however, the isolated QDs and zeolite framework remain intact even after exposure to the moist air for 4 weeks. Interestingly, the interconnected QDs that were formed during neutralization of H(+) with NH(3) disintegrate into isolated QDs in the air. Similar results were obtained from ZnS and MnS QDs generated in zeolite Y. Thus, ligand-free, naked, subnanometer QDs can now be safely preserved within zeolite pores under the ambient conditions for long periods of time. This finding will expedite the generation and dispersion of various QDs in zeolite pores, their physicochemical studies, and applications. PMID- 21247146 TI - A cubic, 12-connected, microporous metal-organometallic phosphate framework sustained by truncated tetrahedral nodes. AB - A rare example of a microporous metal-organic phosphate, [Co(12)(L)(6)(MU(3) PO(4))(4)(MU(3)-F)(4)(MU-H(2)O)(6)][NO(3)](2) (1), is synthesized by the reaction of a [(eta(5)-C(5)H(5))Fe(II)](+)-functionalized terephthalate ligand with Co(NO(3))(2).6H(2)O and phosphate and fluoride ions generated from the in situ hydrolysis of hexafluorophosphate. 1 is a cubic, 12-connected, face-centered cubic framework sustained by the linear connection of unprecedented, dodecanuclear truncated tetrahedral coordination clusters. PMID- 21247147 TI - Functional characterization of mutations in inherited human cPLA2 deficiency. AB - Group IVA cytosolic phospholipase A(2) (cPLA(2)alpha) catalyzes the first step in the arachidonic acid cascade leading to the synthesis of important lipid mediators, the prostaglandins and leukotrienes. We previously described a patient deficient in cPLA(2)alpha activity, which was associated with mutations in both alleles encoding the enzyme. In this paper, we describe the biochemical characterization of each of these mutations. Using saturating concentrations of calcium, we showed that the R485H mutant was nearly devoid of any catalytic activity, that the S111P mutation did not affect the enzyme activity, and that the known K651R polymorphism was associated with activity slightly higher than that of the wild type. Using MDCK cells, we showed that translocation to the Golgi in response to serum activation was impaired for the S111P mutant but not for the other mutants. Using immortalized mouse lung fibroblasts lacking endogenous cPLA(2)alpha activity, we showed that both mutations S111P and R485H/K651R caused a profound defect in the enzyme catalytic activity in response to cell stimulation with serum. Taken together, our results show that the S111P mutation hampers calcium binding and membrane translocation without affecting the catalytic activity, and that the mutation R485H does not affect membrane translocation but blocks catalytic activity that leads to inactivation of the enzyme. Interestingly, our results show that the common K651R polymorphism confers slightly higher activity to the enzyme, suggesting a role of this residue in favoring a catalytically active conformation of cPLA(2)alpha. Our results define how the mutations negatively influence cPLA(2)alpha function and explain the inability of the proband to release arachidonic acid for eicosanoid production. PMID- 21247148 TI - Formation and evolution dynamics of bipolarons in conjugated polymers. AB - Combining the one-dimensional tight-binding Su-Schrieffer-Heeger (SSH) model and the extended Hubbard model (EHM), we analyze the scattering and combination in conjugated polymers of two polarons with the same charges and parallel or antiparallel spins using a nonadiabatic evolution method. Results show that collisions between the two same charge polarons with parallel spin are essentially elastic due to strong Pauli repulsion, whereas the two same charge polarons with antiparallel spins can combine into a singlet bipolaronic state. The dynamics of bipolarons on two coupled polymer chains and at the interface of a polymer/polymer heterojunction are discussed in detail. This knowledge will serve to understand the dynamics of the system when many polarons are created in the system, e.g., by electroluminescence. PMID- 21247149 TI - Structure and biosynthesis of the marine streptomycete ansamycin ansalactam A and its distinctive branched chain polyketide extender unit. AB - Reported is the structure and biosynthesis of ansalactam A, an ansamycin class polyketide produced by an unusual modification of the polyketide pathway. This new metabolite, produced by a marine sediment-derived bacterium of the genus Streptomyces , possesses a novel spiro gamma-lactam moiety and a distinctive isobutyryl polyketide fragment observed for the first time in this class of natural products. The structure of ansalactam A was defined by spectroscopic methods including X-ray crystallographic analysis. Biosynthetic studies with stable isotopes further led to the discovery of a new, branched chain polyketide synthase extender unit derived from (E)-4-methyl-2-pentenoic acid for polyketide assembly observed for the first time in this class of natural products. PMID- 21247150 TI - Bis-N-heterocyclic carbene palladium(IV) tetrachloride complexes: synthesis, reactivity, and mechanisms of direct chlorinations and oxidations of organic substrates. AB - This Article describes the preparation and isolation of novel octahedral CH(2) bridged bis-(N-heterocyclic carbene)palladium(IV) tetrachlorides of the general formula LPd(IV)Cl(4) [L = (NHC)CH(2)(NHC)] from LPd(II)Cl(2) and Cl(2). In intermolecular, nonchelation-controlled transformations LPd(IV)Cl(4) reacted with alkenes and alkynes to 1,2-dichlorination adducts. Aromatic, benzylic, and aliphatic C-H bonds were converted into C-Cl bonds. Detailed mechanistic investigations in the dichlorinations of alkenes were conducted on the 18VE Pd(IV) complex. Positive solvent effects as well as kinetic measurements probing the impact of cyclohexene and chloride concentrations on the rate of alkene chlorination support a Pd(IV)-Cl ionization in the first step. Product stereochemistry and product distributions from various alkenes also support Cl(+) transfer from the pentacoordinated Pd(IV)-intermediate LPd(IV)Cl(3)(+) to olefins. 1-Hexene/3-hexene competition experiments rule out both the formation of pi-complexes along the reaction coordinate as well as in situ generated Cl(2) from a reductive elimination process. Instead, a ligand-mediated direct Cl(+) transfer from LPd(IV)Cl(3)(+) to the pi-system is likely to occur. Similarly, C-H bond chlorinations proceed via an electrophilic process with in situ formed LPd(IV)Cl(3)(+). The presence of a large excess of added Cl(-) slows cyclohexene chlorination while the presence of stoichiometric amounts of chloride accelerates both Pd(IV)-Cl ionization and Cl(+)-transfer from LPd(IV)Cl(3)(+). (1)H NMR titrations, T1 relaxation time measurements, binding isotherms, and Job plot analysis point to the formation of a trifurcated Cl(-)...H-C bond in the NHC ligand periphery as a supramolecular cause for the accelerated chemical events involving the metal center. PMID- 21247151 TI - Two 90Y-labeled multimeric RGD peptides RGD4 and 3PRGD2 for integrin targeted radionuclide therapy. AB - We have recently developed a series of new Arg-Gly-Asp (RGD) dimeric peptides for specific targeting of integrin alpha(v)beta3 with enhanced tumor uptake and improved pharmacokinetics. In this study, we investigated 90Y-labeled RGD tetramer (RGD4) and the new type of RGD dimer (3PRGD2), for the radionuclide therapy of integrin alpha(v)beta3-positive tumors. Biodistribution and gamma imaging studies of 111In labeled RGD4 and 3PRGD2 were performed. Groups of nude mice were used to determine maximum tolerated dose (MTD) of 90Y-DOTA-RGD4 and 90Y DOTA-3PRGD2. The radionuclide therapeutic efficacy of 90Y-DOTA-RGD4 and 90Y-DOTA 3PRGD2 was evaluated in U87MG tumor-bearing nude mice. The U87MG tumor uptake of 111In-DOTA-3PRGD2 was slightly lower than that of the 111In-DOTA-RGD4 (e.g., 6.13 +/- 0.82%ID/g vs 6.43 +/- 1.6%ID/g at 4 h postinjection), but the uptake of 111In DOTA-3PRGD2 in normal organs, such as liver and kidneys, was much lower than that of 111In-DOTA-RGD4, which resulted in much higher tumor-to-nontumor ratios and lower toxicity. The MTD of 90Y-DOTA-RGD4 in nude mice is less than 44.4 MBq, while the MTD of 90Y-DOTA-3PRGD2 in mice is more than 55.5 MBq. 90Y-DOTA-3PRGD2 administration exhibited a similar tumor inhibition effect as compared with 90Y DOTA-RGD4 at the same dose. The tumor vasculature in the 90Y-DOTA-3PRGD2 treatment group was much less than the control groups. Radionuclide therapy studies exhibited that both 90Y-DOTA-RGD4 and 90Y-DOTA-3PRGD2 caused significant tumor growth delay in the U87MG tumor model. Compared to 90Y-DOTA-RGD4, the low accumulation of 90Y-DOTA-3PRGD2 in normal organs led to lower toxicity and higher MTD in nude mice, which would make it more suitable for high dose or multiple dose regimens, in order to achieve maximum therapeutic efficacy. PMID- 21247152 TI - Using azobenzene incorporated DNA aptamers to probe molecular binding interactions. AB - The rational design of DNA/RNA aptamers for use as molecular probes depends on a clear understanding of their structural elements in relation to target-aptamer binding interactions. We present a simple method to create aptamer probes that can occupy two different structural states. Then, based on the difference in binding affinity between these states, target-aptamer binding interactions can be elucidated. The basis of our two-state system comes from the incorporation of azobenzene within the DNA strand. Azobenzene can be used to photoregulate the melting of DNA-duplex structures. When incorporated into aptamers, the light regulated conformational change of azobenzene can be used to analyze how aptamer secondary structure is involved in target binding. Azobenzene-modified aptamers showed no change in target selectivity, but showed differences in binding affinity as a function of the number, position, and conformation of azobenzene modifications. Aptamer probes that can change binding affinity on demand may have future uses in targeted drug delivery and photodynamic therapy. PMID- 21247153 TI - Identification and characterization of the first ovothiol biosynthetic enzyme. AB - Ovothiols are histidine-derived thiols that were first isolated from marine invertebrates. We have identified a 5-histidylcysteine sulfoxide synthase (OvoA) as the first ovothiol biosynthetic enzyme and characterized OvoAs from Erwinia tasmaniensis and Trypanosoma cruzi . Homologous enzymes are encoded in more than 80 genomes ranging from proteobacteria to animalia. PMID- 21247154 TI - Electrochemical investigation of cellular uptake of quantum dots decorated with a proline-rich cell penetrating peptide. AB - The use of square wave voltammetry to monitor the cellular uptake, in HeLa cells, of quantum dots (QD) decorated with sweet arrow peptide (SAP) is reported. A SAP derivative containing an additional N-terminal cysteine residue (C-SAP) was synthesized using the solid-phase method and conjugated to QDs. The obtained results show that QDs-SAP either interact with the extracellular cell membrane matrix or translocate the bilayer. The first situation, membrane adsorption, is probably a transient state before cellular uptake. Both confocal microscopy and SWV results support the detection of this cellular internalization process. The developed electrochemical investigation technique can provide valuable insights into the study of peptide-mediated delivery, as well as the design and development of nanoparticle probes for intracellular imaging, diagnostic, and therapeutic applications. In addition, the described electrochemical interrogation is low cost, is easy to use, and offers future interest for diagnostics including cell analysis. PMID- 21247155 TI - Preparation of water-soluble magnetic nanocrystals using aryl diazonium salt chemistry. AB - A novel and facile methodology for the in situ surface functionalization of Fe(3)O(4) nanoparticles is proposed, based on the use of aryl diazonium salts chemistry. The grafting reaction involves the formation of diazoates in a basic medium. These species are unstable and dediazonize along a homolytic pathway to give aryl radicals which further react with the Fe(3)O(4) NPs during their formation and stop their growth. Advantages of the present approach rely not only on the simplicity, rapidity, and efficiency of the procedure but also on the formation of strong Fe(3)O(4)-aryl surface bonds, highly suitable for further applications. PMID- 21247156 TI - Synergetic effect of surface and subsurface Ni species at Pt-Ni bimetallic catalysts for CO oxidation. AB - Various well-defined Ni-Pt(111) model catalysts are constructed at atomic-level precision under ultra-high-vacuum conditions and characterized by X-ray photoelectron spectroscopy and scanning tunneling microscopy. Subsequent studies of CO oxidation over the surfaces show that a sandwich surface (NiO(1 x)/Pt/Ni/Pt(111)) consisting of both surface Ni oxide nanoislands and subsurface Ni atoms at a Pt(111) surface presents the highest reactivity. A similar sandwich structure has been obtained in supported Pt-Ni nanoparticles via activation in H(2) at an intermediate temperature and established by techniques including acid leaching, inductively coupled plasma, and X-ray adsorption near-edge structure. Among the supported Pt-Ni catalysts studied, the sandwich bimetallic catalysts demonstrate the highest activity to CO oxidation, where 100% CO conversion occurs near room temperature. Both surface science studies of model catalysts and catalytic reaction experiments on supported catalysts illustrate the synergetic effect of the surface and subsurface Ni species on the CO oxidation, in which the surface Ni oxide nanoislands activate O(2), producing atomic O species, while the subsurface Ni atoms further enhance the elementary reaction of CO oxidation with O. PMID- 21247157 TI - Simultaneous quantification and identification of individual chemicals in metabolite mixtures by two-dimensional extrapolated time-zero (1)H-(13)C HSQC (HSQC(0)). AB - Quantitative one-dimensional (1D) (1)H NMR spectroscopy is a useful tool for determining metabolite concentrations because of the direct proportionality of signal intensity to the quantity of analyte. However, severe signal overlap in 1D (1)H NMR spectra of complex metabolite mixtures hinders accurate quantification. Extension of 1D (1)H to 2D (1)H-(13)C HSQC leads to the dispersion of peaks along the (13)C dimension and greatly alleviates peak overlapping. Although peaks are better resolved in 2D (1)H-(13)C HSQC than in 1D (1)H NMR spectra, the simple proportionality of cross peaks to the quantity of individual metabolites is lost by resonance-specific signal attenuation during the coherence transfer periods. As a result, peaks for individual metabolites usually are quantified by reference to calibration data collected from samples of known concentration. We show here that data from a series of HSQC spectra acquired with incremented repetition times (the time between the end of the first (1)H excitation pulse to the beginning of data acquisition) can be extrapolated back to zero time to yield a time-zero 2D (1)H-(13)C HSQC spectrum (HSQC(0)) in which signal intensities are proportional to concentrations of individual metabolites. Relative concentrations determined from cross peak intensities can be converted to absolute concentrations by reference to an internal standard of known concentration. Clustering of the HSQC(0) cross peaks by their normalized intensities identifies those corresponding to metabolites present at a given concentration, and this information can assist in assigning these peaks to specific compounds. The concentration measurement for an individual metabolite can be improved by averaging the intensities of multiple, nonoverlapping cross peaks assigned to that metabolite. PMID- 21247158 TI - Synthesis of aluminosilicate and gallosilicate zeolites via a charge density mismatch approach and their characterization. AB - Aluminosilicate and gallosilicate zeolite syntheses via a charge density mismatch (CDM) approach are compared at intermediate-silica compositions (Si/Me = 5-16, where Me is Al or Ga). With a variation of the crystallization temperature and of the type and/or concentration of alkali metal ions added as a crystallization structure-directing agent (SDA) to tetraethylammonium-tetramethylammonium, tetraethylammonium-hexamethonium, and strontium-choline mixed-SDA systems, we were able to obtain 11 different zeolite structures. However, only 5 out of a total 40 pairs of aluminosilicate and gallosilicate synthesis runs at otherwise identical chemical compositions were found to give the same zeolite product with no detectable impurities, suggesting that the structure-directing ability of Ga is quite different from that of Al even in intermediate-silica synthesis conditions. The CDM approach to offretite synthesis led to hexagonal plate-like crystals with aspect ratios lower than 0.3, and UZM-22 exhibited no significant preference of Al substitution for particular tetrahedral sites, especially for site T1, unlike its framework type material ZSM-18. More interestingly, the EU-1 zeolite obtained from an aluminosilicate synthesis mixture containing Li(+) as an inorganic crystallization SDA in the tetraethylammonium-hexamethonium double organic additive system has been characterized to locate about half of its Li(+) ions in the framework, while the Li distribution over the 10 topologically different tetrahedral sites is nonrandom in nature. PMID- 21247159 TI - Mechanical load induces a 100-fold increase in the rate of collagen proteolysis by MMP-1. AB - Although mechanical stress is known to profoundly influence the composition and structure of the extracellular matrix (ECM), the mechanisms by which this regulation occurs remain poorly understood. We used a single-molecule magnetic tweezers assay to study the effect of force on collagen proteolysis by matrix metalloproteinase-1 (MMP-1). Here we show that the application of ~10 pN in extensional force causes an ~100-fold increase in proteolysis rates. Our results support a mechanistic model in which the collagen triple helix unwinds prior to proteolysis. The data and resulting model predict that biologically relevant forces may increase localized ECM proteolysis, suggesting a possible role for mechanical force in the regulation of ECM remodeling. PMID- 21247160 TI - A peptide aldehyde microarray for high-throughput profiling of cellular events. AB - Microarrays provide exciting opportunities in the field of large-scale proteomics. With the aim to elucidate enzymatic activity and profiles within native biological samples, we developed a microarray comprising a focused positional-scanning library of enzyme inhibitors. The library was diversified across P(1)-P(4) positions, creating 270 different inhibitor sublibraries which were immobilized onto avidin slides. The peptide aldehyde-based small-molecule microarray (SMM) specifically targeted cysteine proteases, thereby enabling large scale functional assessment of this subgroup of proteases, within fluorescently labeled samples, including pure proteins, cellular lysates, and infected samples. The arrays were shown to elicit binding fingerprints consistent with those of model proteins, specifically caspases and purified cysteine proteases from parasites (rhodesein and cruzain). When tested against lysates from apoptotic Hela and red blood cells infected with Plasmodium falciparum, clear signatures were obtained that were readily attributable to the activity of constituent proteases within these samples. Characteristic binding profiles were further able to distinguish various stages of the parasite infection in erythrocyte lysates. By converting one of our brightest microarray hits into a probe, putative protein markers were identified and pulled down from within apoptotic Hela lysates, demonstrating the potential of target validation and discovery. Taken together, these results demonstrate the utility of targeted SMMs in dissecting cellular biology in complex proteomic samples. PMID- 21247161 TI - Nanomechanical stimulus accelerates and directs the self-assembly of silk-elastin like nanofibers. AB - One-dimensional nanostructures are ideal building blocks for functional nanoscale assembly. Peptide-based nanofibers have great potential in building smart hierarchical structures due to their tunable structures at the single residue level and their ability to reconfigure themselves in response to environmental stimuli. We observed that pre-adsorbed silk-elastin-based protein polymers self assemble into nanofibers through conformational changes on a mica substrate. Furthermore, we demonstrate that the rate of self-assembly was significantly enhanced by applying a nanomechanical stimulus using atomic force microscopy. The orientation of the newly grown nanofibers was mostly perpendicular to the scanning direction, implying that the new fiber assembly was locally activated with directional control. Our method provides a novel way to prepare nanofiber patterned substrates using a bottom-up approach. PMID- 21247162 TI - Synthesis of amides from esters and amines with liberation of H2 under neutral conditions. AB - Efficient synthesis of amides directly from esters and amines is achieved under mild, neutral conditions with the liberation of molecular hydrogen. Both primary and secondary amines can be utilized. This unprecedented, general, environmentally benign reaction is homogeneously catalyzed under neutral conditions by a dearomatized ruthenium-pincer PNN complex and proceeds in toluene under an inert atmosphere with a high turnover number (up to 1000). PNP analogues do not catalyze this transformation, underlining the crucial importance of the amine arm of the pincer ligand. A mechanism is proposed involving metal-ligand cooperation via aromatization-dearomatization of the pyridine moiety and hemilability of the amine arm. PMID- 21247163 TI - Montmorillonite-supramolecular hydrogel hybrid for fluorocolorimetric sensing of polyamines. AB - Fluorescent sensor materials for rapidly and conveniently detecting polyamines in biological fluids are highly desirable for cancer diagnosis. We herein describe the hybridization of a supramolecular hydrogel with a layered inorganic host adsorbing a fluorescent dye which produces a fluorocolorimetric sensor for spermine and spermidine, important biomarkers for cancers, in artificial urine. PMID- 21247164 TI - Probes for narcotic receptor mediated phenomena. 41. Unusual inverse MU-agonists and potent MU-opioid antagonists by modification of the N-substituent in enantiomeric 5-(3-hydroxyphenyl)morphans. AB - Conformational restraint in the N-substituent of enantiomeric 5-(3 hydroxyphenyl)morphans was conferred by the addition of a cyclopropane ring or a double bond. All of the possible enantiomers and isomers of the N-substituted compounds were synthesized. Opioid receptor binding assays indicated that some of them had about 20-fold higher MU-affinity than the compound with an N phenylpropyl substituent (K(i) = 2-450 nM for the examined compounds with various N-substituents). Most of the compounds acted unusually as inverse agonists in the [(35)S]GTP-gamma-S functional binding assay using nondependent cells that stably express the cloned human MU-opioid receptor. Two of the N-substituted compounds with a cyclopropane ring were very potent MU-opioid antagonists ((+)-29, K(e) = 0.17 and (-)-30, K(e) =0.3) in the [(35)S]GTP-gamma-S functional binding assay. By comparison of the geometry-optimized structures of the newly synthesized compounds, an attempt was made to rationalize their MU-opioid receptor affinity in terms of the spatial position of N-substituents. PMID- 21247165 TI - A new family of cinchona-derived amino phosphine precatalysts: application to the highly enantio- and diastereoselective silver-catalyzed isocyanoacetate aldol reaction. AB - A new class of readily accessible chiral amino-phosphine precatalysts derived from 9-amino(9-deoxy) epicinchona alkaloids has been developed. In combination with Ag(I) salts, these amino-phosphines performed as effective cooperative Bronsted base/Lewis acid catalysts in the asymmetric aldol reaction of isocyanoacetate nucleophiles. Under optimal conditions, high diastereoselectivities (up to 98%) and enantioselectivities (up to 98%) were obtained. PMID- 21247166 TI - 2-Aminothiazoles as therapeutic leads for prion diseases. AB - 2-Aminothiazoles are a new class of small molecules with antiprion activity in prion-infected neuroblastoma cell lines (J. Virol. 2010, 84, 3408). We report here structure-activity studies undertaken to improve the potency and physiochemical properties of 2-aminothiazoles, with a particular emphasis on achieving and sustaining high drug concentrations in the brain. The results of this effort include the generation of informative structure-activity relationships (SAR) and the identification of lead compounds that are orally absorbed and achieve high brain concentrations in animals. The new aminothiazole analogue (5-methylpyridin-2-yl)-[4-(3-phenylisoxazol-5-yl)-thiazol-2-yl]-amine (27), for example, exhibited an EC(50) of 0.94 MUM in prion-infected neuroblastoma cells (ScN2a-cl3) and reached a concentration of ~25 MUM in the brains of mice following three days of oral administration in a rodent liquid diet. The studies described herein suggest 2-aminothiazoles as promising new leads in the search for effective therapeutics for prion diseases. PMID- 21247167 TI - Discovery, synthesis, and structure-activity relationship development of a series of N-(4-acetamido)phenylpicolinamides as positive allosteric modulators of metabotropic glutamate receptor 4 (mGlu(4)) with CNS exposure in rats. AB - Herein we report the discovery, synthesis, and evaluation of a series of N-(4 acetamido)-phenylpicolinamides as positive allosteric modulators of mGlu(4). Compounds from the series show submicromolar potency at both human and rat mGlu(4). In addition, pharmacokinetic studies utilizing subcutaneous dosing demonstrated good brain exposure in rats. PMID- 21247169 TI - Molecular oxygen adsorption behaviors on the rutile TiO2(110)-1*1 surface: an in situ study with low-temperature scanning tunneling microscopy. AB - A knowledge of adsorption behaviors of oxygen on the model system of the reduced rutile TiO(2)(110)-1*1 surface is of great importance for an atomistic understanding of many chemical processes. We present a scanning tunneling microcopy (STM) study on the adsorption of molecular oxygen either at the bridge bonded oxygen vacancies (BBO(V)) or at the hydroxyls (OH) on the TiO(2)(110)-1*1 surface. Using an in situ O(2) dosing method, we are able to directly verify the exact adsorption sites and the dynamic behaviors of molecular O(2). Our experiments provide direct evidence that an O(2) molecule can intrinsically adsorb at both the BBO(V) and the OH sites. It has been identified that, at a low coverage of O(2), the singly adsorbed molecular O(2) at BBO(V) can be dissociated through an intermediate state as driven by the STM tip. However, singly adsorbed molecular O(2) at OH can survive from such a tip-induced effect, which implies that the singly adsorbed O(2) at OH is more stable than that at BBO(V). It is interesting to observe that when the BBO(V)s are fully filled with excess O(2) dosing, the adsorbed O(2) molecules at BBO(V) tend to be nondissociative even under a higher bias voltage of 2.2 V. Such a nondissociative behavior is most likely attributed to the presence of two or more O(2) molecules simultaneously adsorbed at a BBO(V) with a more stable configuration than singly adsorbed molecular O(2) at a BBO(V). PMID- 21247168 TI - Acyloxy nitroso compounds as nitroxyl (HNO) donors: kinetics, reactions with thiols, and vasodilation properties. AB - Acyloxy nitroso compounds hydrolyze to nitroxyl (HNO), a nitrogen monoxide with distinct chemistry and biology. Ultraviolet-visible spectroscopy and mass spectrometry show hydrolysis rate depends on pH and ester group structure with the observed rate being trifluoroacetate (3) > acetate (1) > pivalate (2). Under all conditions, 3 rapidly hydrolyzes to HNO. A combination of spectroscopic, kinetic, and product studies show that addition of thiols increases the decomposition rate of 1 and 2, leading to hydrolysis and HNO. Under conditions that favor thiolates, the thiolate directly reacts with the nitroso group, yielding oximes without HNO formation. Biologically, 3 behaves like Angeli's salt, demonstrating thiol-sensitive nitric oxide-mediated soluble guanylate cyclase-dependent vasorelaxation, suggesting HNO-mediated vasorelaxation. The slow HNO-donor 1 demonstrates weak thiol-insensitive vasorelaxation, indicating HNO release kinetics determine HNO bioavailability and activity. These results show that acyloxy nitroso compounds represent new HNO donors capable of vasorelaxation depending on HNO release kinetics. PMID- 21247170 TI - Influence of yeast macromolecules on sweetness in dry wines: role of the saccharomyces cerevisiae protein Hsp12. AB - Yeast autolysis during lees contact influences the organoleptic properties of wines especially by increasing their sweet taste. Although observed by winemakers, this phenomenon is poorly explained in enology. Moreover, the compounds responsible for sweetness in wine remain unidentified. This work provides new insights in this way by combining sensorial, biochemical and genetic approaches. First, we verified by sensory analysis that yeast autolysis in red wine has a significant effect on sweetness. Moderate additions of ethanol or glycerol did not have the same effect. Second, a sapid fraction was isolated from lees extracts by successive ultrafiltrations and HPLC purifications. Using nano LC-MS/MS, peptides released by the yeast heat shock protein Hsp12p were distinctly identified in this sample. Third, we confirmed the sweet contribution of this protein by sensorial comparison of red wines incubated with two kinds of yeast strains: a wild-type strain containing the native Hsp12p and a deletion mutant strain that lacks the Hsp12p protein (Delta degrees HSP12 strain). Red wines incubated with wild-type strain showed a significantly higher sweetness than control wines incubated with Delta degrees HSP12 strains. These results demonstrated the contribution of protein Hsp12p in the sweet perception consecutive to yeast autolysis in wine. PMID- 21247171 TI - Improving laccase catalyzed cross-linking of whey protein isolate and their application as emulsifiers. AB - Whey protein isolate (WPI) was chemically modified by vanillic acid in order to enhance its cross-linkability by laccase enzyme. Incorporation of methoxyphenol groups created reactive sites for laccase on the surface of the protein and improved the efficiency of cross-linking. The vanillic acid modified WPI (Van WPI) was characterized using MALDI-TOF mass spectrometry, and the laccase catalyzed cross-linking of Van-WPI was studied. Furthermore, the vanillic acid modification was compared with the conventional approach to improve laccase catalyzed cross-linking by adding free phenolic compounds. A small extent of the vanillic acid modification significantly improved the cross-linkability of the protein and made it possible to avoid color formation in a system that is free of small phenolic compounds. Moreover, the potential application of Van-WPI as emulsifier and the effect of cross-linking on the stability of Van-WPI emulsion were investigated. The post-emulsification cross-linking by laccase was proven to enhance the storage stability of Van-WPI emulsion. PMID- 21247172 TI - Stereoselective synthesis of 2-C-branched (acetylmethyl) oligosaccharides and glycoconjugates: Lewis acid-catalyzed glycosylation from 1,2 cyclopropaneacetylated sugars. AB - 1,2-Cyclopropaneacetylated sugars as glycosyl donors reacted with a series of glycosyl acceptors (monosaccharides, amino acids, and other alcohols) in the presence of Lewis acid to produce oligosaccharides and glycoconjugates containing 2-C-acetylmethylsugars. Galactosyl donor gave good to excellent alpha selectivities with TMSOTf as a catalyst, whereas galactosyl donor offered moderate to good beta-selectivities when BF(3).Et(2)O was used as a catalyst. However, glucosyl donors produced beta-exclusive selectivity under both conditions. The stereoselectivities of glycosylation depend on the reactivity of donor sugars and Lewis acid catalyst, which effectively dictated the glycosylation pathways. The evidence suggests that galactosyl donors (e.g., 7) can undergo S(N)1 pathway with a strong Lewis acid (TMSOTf) and S(N)2 pathway under BF(3).Et(2)O, whereas the glucosyl donors (e.g., 8 and 10) followed S(N)2 pathway. The stereoselectivity was also consequential to the formation of a C2' acetal intermediate formed via the 2-C-acetylmethyl group and the anomeric carbonium intermediate in glycosylation. PMID- 21247173 TI - Derivation and interpretation of hazard quotients to assess ecological risks from the cultivation of insect-resistant transgenic crops. AB - Cost-effective and rigorous risk assessments for chemicals may be based on hazard quotients (HQs): the ratio of a measure of exposure to a substance and a measure of the effect of that substance. HQs have been used for many years in ecological risk assessments for the use of synthetic pesticides in agriculture, and methods for calculating pesticide HQs have been adapted for use with transgenic crops. This paper describes how laboratory methods for assessing the ecotoxicological effects of synthetic pesticides have been modified for the measurement of effects of insecticidal proteins, and how these effect measures are combined with exposure estimates to derive HQs for assessing the ecological risks from the cultivation of insect-resistant transgenic crops. The potential for ecological modeling to inform the design of laboratory effects tests for insecticidal proteins is also discussed. PMID- 21247174 TI - Organic synthesis of new putative lycopene metabolites and preliminary investigation of their cell-signaling effects. AB - Tomato is the main dietary source of lycopene, a carotenoid that is known to have protective effects on health and whose metabolites could also be involved in bioactivity. Herein we present the first organic synthesis of two potentially bioactive lycopene metabolites, namely, 10'-apolycopen-10'-oic acid (6) and 14' apolycopen-14'-oic acid (13), which were obtained in their (all-E) stereoisomeric forms using Wittig and Horner-Wadsworth-Emmons type coupling reactions. Both molecules are shown to up-regulate the carotenoid asymmetric cleavage enzyme BCO2 while having no effect on BCO1 expression. PMID- 21247175 TI - Synthesis of a novel composite imprinted material based on multiwalled carbon nanotubes as a selective melamine absorbent. AB - A novel composite imprinted material, on the basis of a multiwalled carbon nanotube (CNT)-incorporated layer using melamine as a template, methacrylic acid as a functional monomer, and ethylene glycol dimethacrylate as a cross-linker, was synthesized by a surface imprinting technique. The imprinted/CNT sorbent was characterized by a scanning electron microscope (SEM). Adsorption dynamics and a Scatchard adsorption model were employed to evaluate the adsorption process. The results showed that the imprinted/CNT sorbent displayed a rapid dynamic adsorption and a high adsorption capacity of 79.9 MUmol g(-1) toward melamine. Applied as a sorbent, the imprinted/CNT sorbent was used for the determination of melamine in a real sample by online solid-phase extraction-high-performance liquid chromatography (SPE-HPLC). An enrichment ratio of 563-fold, detection limit (S/N = 3) of 0.3 MUg L(-1), and quantification limit of 4.5 MUg L(-1) were achieved. PMID- 21247176 TI - Effect of genetic characteristics and environmental factors on organosulfur compounds in garlic ( Allium sativum L.) grown in Andalusia, Spain. AB - The content of organosulfur compounds was determined in selected garlic cultivars grown at four locations in Andalusia, Spain. The organosulfur compounds studied were three gamma-glutamyl peptides, namely, gamma-l-glutamyl-S-(2-propenyl)-l cysteine (GSAC), gamma-l-glutamyl-S-(trans-1-propenyl)-l-cysteine (GSPC), and gamma-l-glutamyl-S-methyl-l-cysteine (GSMC), and four cysteine sulfoxides (alliin, isoalliin, methiin, and cycloalliin). There was a significant effect of the location, cultivar, and garlic ecotype on individual organosulfur compound contents. Purple-type cultivars showed on average the highest contents of GSMC, GSAC, alliin, and methiin but the lowest isoalliin content. The impact of genotype was relatively high for GSAC, whereas this factor hardly contributed to the total variability in alliin and isoalliin content. Planting date had a significant effect on the content of alliin and isoalliin. Discriminant analysis evidenced the ability of organosulfur compounds to distinguish among garlic bulbs from different locations or ecotypes with 81 or 86% accuracy, respectively. PMID- 21247177 TI - Automated information extraction and structure-activity relationship analysis of cytochrome P450 substrates. AB - Information on CYP-chemical interactions was comprehensively explored by a text mining technique, to confirm our previous structure-activity relationship model for CYP substrates (Yamashita et al. J. Chem. Inf. Model. 2008, 48, 364-369). The text-mining technique is based on natural language processing and can extract chemical names and their interaction patterns according to sentence context. After chemicals were automatically extracted and classified into CYP substrates, inhibitors, and inducers, 709 substrates were retrieved from the PubChem database and categorized as 216, 145, 136, 217, 156, and 379 substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, respectively. Although the previous classification model was developed using data from only 161 compounds, the model classified the substrates found by text-mining analysis with reasonable accuracy. This confirmed the validity of both the multi-objective classification model for CYP substrates and the text-mining procedure. PMID- 21247178 TI - Thermal expansivity of ionic clathrate hydrates including gaseous guest molecules. AB - Although thermal expansion is a key factor in relation to the host-guest interaction of clathrate hydrates, few studies have investigated the thermal behavior of ionic clathrate hydrates. The existence of ionic species in these hydrates creates a unique host-guest interaction compared to that of nonionic clathrate hydrates. It was revealed that X-ray diffraction cannot be used for research of tetramethylammonium hydroxide clathrate hydrates due to damage of the cations by the X-ray, which results in abnormal thermal expansion of the ionic clathrate hydrates. Hence, in the present work, the thermal expansivities of binary sII Me(4)NOD.16D(2)O and sI DClO(4).5.5D(2)O were measured by neutron powder diffraction (NPD) in order to shed light on their thermal behavior. General correlations for the thermal behaviors of given structures were established and lattice expansions depending on the guests were compared between ionic and nonionic clathrate hydrates. The peculiar change in the thermal expansivity of binary DClO(4).5.5D(2)O was also considered in relation to the host-guest configuration. PMID- 21247179 TI - Electron-induced phase transition in hydrogen-bonded solid-state 2-pyridone. AB - This paper presents the results of experimental studies of hydrogen-bonded 2 pyridone crystal IR spectra. Spectral studies have demonstrated the existence of two anhydrous solid-state phases of each compound, namely the alpha and the beta phases. Hydrogen bonds in the high-temperature alpha phase of these crystals have been estimated to be 40% stronger than the hydrogen bonds in the beta phase, which are stable at room temperature. The mechanism of the phase transition in the solid-state 2-pyridone is proposed on the basis of the IR spectral data. This was possible by taking into account small changes in the geometry of heterocyclic molecular skeletons, which accompany the electron density redistribution in the hydrogen bonds occurring during the transition. The phase transition is connected with a partial change in the hydrogen bond nature from the N(+)-H...O(-) in the alpha phase, to the N-H...O hydrogen bonds in the beta phase crystals. PMID- 21247180 TI - Organoiodine(V) reagents in organic synthesis. AB - Organohypervalent iodine reagents have attracted significant recent interest as versatile and environmentally benign oxidants with numerous applications in organic synthesis. This Perspective summarizes synthetic applications of hypervalent iodine(V) reagents: 2-iodoxybenzoic acid (IBX), Dess-Martin periodinane (DMP), pseudocyclic iodylarenes, and their recyclable polymer supported analogues. Recent advances in the development of new catalytic systems based on the generation of hypervalent iodine species in situ are also overviewed. PMID- 21247181 TI - Superhydrophobic and superoleophobic nanocellulose aerogel membranes as bioinspired cargo carriers on water and oil. AB - We demonstrate that superhydrophobic and superoleophobic nanocellulose aerogels, consisting of fibrillar networks and aggregates with structures at different length scales, support considerable load on a water surface and also on oils as inspired by floatation of insects on water due to their superhydrophobic legs. The aerogel is capable of supporting a weight nearly 3 orders of magnitude larger than the weight of the aerogel itself. The load support is achieved by surface tension acting at different length scales: at the macroscopic scale along the perimeter of the carrier, and at the microscopic scale along the cellulose nanofibers by preventing soaking of the aerogel thus ensuring buoyancy. Furthermore, we demonstrate high-adhesive pinning of water and oil droplets, gas permeability, light reflection at the plastron in water and oil, and viscous drag reduction of the fluorinated aerogel in contact with oil. We foresee applications including buoyant, gas permeable, dirt-repellent coatings for miniature sensors and other devices floating on generic liquid surfaces. PMID- 21247182 TI - Kinetic study of trimerization of monocyanate ester in nanopores. AB - A kinetic study of the trimerization of monocyanate ester both in the bulk and in the nanoconfinement of controlled pore glass is performed using differential scanning calorimetry. Both isothermal and dynamic experiments are analyzed. Although the activation energy for the reaction is the same within experimental error for the bulk and nanoconfined samples (approximately 21-23 kcal/mol), the reaction is accelerated under nanoconfinement by approximately 50 times in 13 nm pores compared with bulk. PMID- 21247183 TI - Simple fabrication of asymmetric high-aspect-ratio polymer nanopillars by reusable AAO templates. AB - We present a simple method of utilizing anodized aluminum oxide (AAO) as a reproducible template for fabricating high-aspect-ratio uniformly bent polymeric nanopillars that can be used as a physical adhesive. It is shown how to achieve straight high-aspect-ratio nanopillars with concepts of the work of adhesion and lateral collapse between polymer pillars without serious damage to the master template. With the support of manufacturing polymeric nanopillars from the reusable AAO, a simple route to asymmetric dry adhesive nanopillars bent by residual stresses was demonstrated. PMID- 21247185 TI - Enhancement of second hyperpolarizabilities in open-shell singlet slipped-stack dimers composed of square planar nickel complexes involving o-semiquinonato type ligands. AB - Using the spin-unrestricted hybrid density functional theory method, we have investigated the intermolecular interaction effects on the longitudinal static second hyperpolarizability (gamma) of open-shell singlet slipped-stack dimers composed of singlet diradical square planar nickel complexes involving o semiquinonato type ligands, Ni(o-C(6)H(4)X(2))(2) (where X = O, NH, S, Se, PH). For comparison, we have also examined the gamma values of a closed-shell singlet slipped-stack dimer composed of closed-shell monomers Ni[o-C(6)H(4)S(NH(2))](2). It is found that for interplanar distance ranging between 3.0 and 5.0 A the slipped-stack dimers with intermediate monomer diradical characters exhibit larger gamma values per monomer (gamma(dimer)/2) than those with large monomer diradical characters or than the closed-shell dimer. These results extend the domain of validity of the relationship found between gamma and the diradical character for individual molecules. It also turns out that the ratio R = (gamma(dimer)/2)/gamma(monomer) increases upon decreasing the interplanar distance and that this increase is larger for intermediate diradical character than for the other cases. These phenomena have been analyzed by considering the gamma density distributions of the dimers, demonstrating a significant field induced third-order charge transfer between the monomers in the case of intermediate diradical character. The present results indicate that open-shell singlet slipped-stack aggregates composed of monomers with intermediate diradical characters constitute another mean for achieving highly efficient and tunable third-order nonlinear optical materials. PMID- 21247184 TI - Spontaneous vortex nanodomain arrays at ferroelectric heterointerfaces. AB - The polarization of the ferroelectric BiFeO(3) sub-jected to different electrical boundary conditions by heterointerfaces is imaged with atomic resolution using a spherical aberration-corrected transmission electron microscope. Unusual triangular-shaped nanodomains are seen, and their role in providing polarization closure is understood through phase-field simulations. Heterointerfaces are key to the performance of ferroelectric devices, and this first observation of spontaneous vortex nanodomain arrays at ferroelectric heterointerfaces reveals properties unlike the surrounding film including mixed Ising-Neel domain walls, which will affect switching behavior, and a drastic increase of in-plane polarization. The importance of magnetization closure has long been appreciated in multidomain ferromagnetic systems; imaging this analogous effect with atomic resolution at ferroelectric heterointerfaces provides the ability to see device relevant interface issues. Extension of this technique to visualize domain dynamics is envisioned. PMID- 21247186 TI - Chemiluminogenic features of 10-methyl-9-(phenoxycarbonyl)acridinium trifluoromethanesulfonates alkyl substituted at the benzene ring in aqueous media. AB - 10-Methyl-9-(phenoxycarbonyl)acridinium trifluoromethanesulfonates bearing alkyl substituents at the benzene ring were synthesized, purified, and identified. In the reaction with OOH(-) in basic aqueous media, the cations of the compounds investigated were converted to electronically excited 10-methyl-9-acridinone, whose relaxation was accompanied by chemiluminescence (CL). The kinetic constants of CL decay, relative efficiencies of light emission, chemiluminescence quantum yields, and resistance toward alkaline hydrolysis were determined experimentally under various conditions. The mechanism of CL generation is considered on the basis of thermodynamic and kinetic parameters of the reaction steps predicted at the DFT level of theory. The chemiluminescence efficiency is the result of competition of the electrophilic center at C(9) between nucleophilic substitution by OOH(-) or OH(-) and the ability of the intermediates thus formed to decompose to electronically excited 10-methyl-9-acridinone. Identification of stable and intermediate reaction products corroborated the suggested reaction scheme. The results obtained, particularly the dependency of the "usefulness" parameter, which takes into account the CL quantum yield and the susceptibility to hydrolysis, on the cavity volume of the entity removed during oxidation, form a convenient framework within which to rationally design chemiluminescent 10-methyl 9-(phenoxycarbonyl)acridinium cations. PMID- 21247187 TI - Anisotropic emission from multilayered plasmon resonator nanocomposites of isotropic semiconductor quantum dots. AB - We propose and demonstrate a nanocomposite localized surface plasmon resonator embedded into an artificial three-dimensional construction. Colloidal semiconductor quantum dots are assembled between layers of metal nanoparticles to create a highly strong plasmon-exciton interaction in the plasmonic cavity. In such a multilayered plasmonic resonator architecture of isotropic CdTe quantum dots, we observed polarized light emission of 80% in the vertical polarization with an enhancement factor of 4.4, resulting in a steady-state anisotropy value of 0.26 and reaching the highest quantum efficiency level of 30% ever reported for such CdTe quantum dot solids. Our electromagnetic simulation results are in good agreement with the experimental characterization data showing a significant emission enhancement in the vertical polarization, for which their fluorescence decay lifetimes are substantially shortened by consecutive replication of our unit cell architecture design. Such strongly plasmon-exciton coupling nanocomposites hold great promise for future exploitation and development of quantum dot plasmonic biophotonics and quantum dot plasmonic optoelectronics. PMID- 21247189 TI - NMR characterization of the formation kinetics and structure of di-O-benzylidene sorbitol gels self-assembled in organic solvents. AB - The molecule 1,3:2,4-di-O-benzylidene sorbitol (DBS) is a common "gelator" that forms thermally reversible gels in diverse organic solvents. Solid-state (13)C and (1)H NMR techniques, along with electron microscopy, are utilized in an exploratory study of DBS in the gelled state where we consider both in situ and dried gels. The gels were formed in either acetone or benzene, with the former being a better solvent for DBS. We find the in situ or dried DBS gels to be composed of rigid twisted nanofibrils (~15 to 21 nm in diameter). The fibrils show local molecular ordering, but not crystalline order, and they contain no trapped solvent. The molecular mobility at the fibril surface is modestly enhanced, and all the free hydroxyl groups of the sorbitol moiety are involved in strong hydrogen bonding. We also attempted to find a truly crystalline form of DBS whose structure, as judged by the similarity of (13)C spectra, is close to that of the fibrils. We partially succeeded in this quest, employing melt crystallization followed by slow cooling. However, this sample was a mixed crystal having small domains, where only one type of domain was structurally similar to the fibrils. We also investigated the long-time evolution of the in situ DBS gel network. Specifically, high-resolution NMR kinetic studies were performed over periods of days where the residual concentration of DBS in acetone solution was monitored during and after gel formation. The DBS concentration on these long timescales evolved slowly, and we introduce a simple mathematical model and equation to describe this phenomenon. PMID- 21247188 TI - Sceliphrolactam, a polyene macrocyclic lactam from a wasp-associated Streptomyces sp. AB - A previously unreported 26-membered polyene macrocyclic lactam, sceliphrolactam, was isolated from an actinomycete, Streptomyces sp., associated with the mud dauber, Sceliphron caementarium. Sceliphrolactam's structure was determined by 1D and 2D-NMR, MS, UV, and IR spectral analysis. Sceliphrolactam displays antifungal activity against amphotericin B-resistant Candida albicans (MIC = 4 MUg/mL, 8.3 MUM). PMID- 21247190 TI - Enhanced two-photon singlet oxygen generation by photosensitizer-doped conjugated polymer nanoparticles. AB - We have prepared photosensitizer-doped conjugated polymer nanoparticles by using a reprecipitation method. The conjugated polymer, poly[9,9-dibromohexylfluorene 2,7-ylenethylene-alt-1,4-(2,5-dimethoxy)phenylene] (PFEMO), was used as the host matrix to disperse tetraphenylporphyrin (TPP). These TPP-doped PFEMO nanoparticles are stable and have a uniform size of ~50 nm. Efficient intraparticle energy transfer from PFEMO to TPP has been observed. The TPP emission of the nanoparticles was found to be enhanced by 21-fold by PFEMO under two-photon excitation. Enhanced two-photon excitation singlet oxygen generation efficiency in the TPP-doped PFEMO nanoparticles has been demonstrated. Our results suggest that these photosensitizer-doped conjugated polymer nanoparticles can act as novel photosensitizing agents for two-photon photodynamic therapy and related applications. PMID- 21247191 TI - Optical sizing of immunolabel clusters through multispectral plasmon coupling microscopy. AB - The wavelength dependent scattering cross sections of self-assembled silver nanoparticle clusters of known size (n) were measured on five different wavelength channels between 427 and 510 nm through correlation of multispectral imaging and scanning electron microscopy. A multivariate statistical analysis of the spectral response of this training set provided a correlation between spectral response and cluster size and enabled a classification of new measurements into four distinct nanoparticle association levels (I1-I4) whose compositions were dominated by monomers (I1), dimers (I2), trimers and tetramers (I3), and larger clusters (I4), respectively. One potential application of the optical sizing approach is to map association levels of silver immunolabels on cellular surfaces. We demonstrate the feasibility of this approach using silver immunolabels targeted at the epidermal growth factor receptor on A431 cells in a proof of principle experiment. The ability to measure immunolabel association levels on subcellular length scales in an optical microscope provides new opportunities for experimentally assessing receptor density distributions on living cells in solution. PMID- 21247192 TI - Total synthesis of (-)-brevisin: a concise synthesis of a new marine polycyclic ether. AB - The first and highly efficient total synthesis of (-)-brevisin has been achieved. The title compound was synthesized in only 29 steps (longest linear sequence) from commercially available starting materials. The synthesis provided over 70 mg of a marine polycyclic ether compound. PMID- 21247193 TI - Trifunctionalization of the purine scaffold using Mg and Zn organometallic intermediates. AB - Starting from an appropriate 6-chloro-2-TMS-purine derivative, a regioselective functionalization of the purine scaffold was achieved successively at positions 8, 6, and 2 via zinc and magnesium intermediates which were generated either by a direct zincation with TMPZnCl.LiCl or by an I/Mg exchange with iPrMgCl. PMID- 21247194 TI - A high-affinity adenosine kinase from Anopheles gambiae. AB - Genome analysis revealed a mosquito orthologue of adenosine kinase in Anopheles gambiae (AgAK; the most important vector for the transmission of Plasmodium falciparum in Africa). P. falciparum are purine auxotrophs and do not express an adenosine kinase but rely on their hosts for purines. AgAK was kinetically characterized and found to have the highest affinity for adenosine (K(m) = 8.1 nM) of any known adenosine kinase. AgAK is specific for adenosine at the nucleoside site, but several nucleotide triphosphate phosphoryl donors are tolerated. The AgAK crystal structure with a bound bisubstrate analogue Ap(4)A (2.0 A resolution) reveals interactions for adenosine and ATP and the geometry for phosphoryl transfer. The polyphosphate charge is partly neutralized by a bound Mg(2+) ion and an ion pair to a catalytic site Arg. The AgAK structure consists of a large catalytic core in a three-layer alpha/beta/alpha sandwich, and a small cap domain in contact with adenosine. The specificity and tight binding for adenosine arise from hydrogen bond interactions of Asn14, Leu16, Leu40, Leu133, Leu168, Phe168, and Thr171 and the backbone of Ile39 and Phe168 with the adenine ring as well as through hydrogen bond interactions between Asp18, Gly64, and Asn68 and the ribosyl 2'- and 3'-hydroxyl groups. The structure is more similar to that of human adenosine kinase (48% identical) than to that of AK from Toxoplasma gondii (31% identical). With this extraordinary affinity for AgAK, adenosine is efficiently captured and converted to AMP at near the diffusion limit, suggesting an important role for this enzyme in the maintenance of the adenine nucleotide pool. mRNA analysis verifies that AgAK transcripts are produced in the adult insects. PMID- 21247195 TI - Electrogenerated chemiluminescence detection in paper-based microfluidic sensors. AB - This paper describes the first approach at combining paper microfluidics with electrochemiluminescent (ECL) detection. Inkjet printing is used to produce paper microfluidic substrates which are combined with screen-printed electrodes (SPEs) to create simple, cheap, disposable sensors which can be read without a traditional photodetector. The sensing mechanism is based on the orange luminescence due to the ECL reaction of tris(2,2'-bipyridyl)ruthenium(II) (Ru(bpy)(3)(2+)) with certain analytes. Using a conventional photodetector, 2 (dibutylamino)ethanol (DBAE) and nicotinamide adenine dinucleotide (NADH) could be detected to levels of 0.9 MUM and 72 MUM, respectively. Significantly, a mobile camera phone can also be used to detect the luminescence from the sensors. By analyzing the red pixel intensity in digital images of the ECL emission, a calibration curve was constructed demonstrating that DBAE could be detected to levels of 250 MUM using the phone. PMID- 21247196 TI - High sensitivity luminescence nanoparticle assay for the detection of protein aggregation. AB - Nanoparticle assay utilizing time-resolved luminescence resonance energy transfer (TR-LRET) was developed for the detection of protein aggregation. This mix-and measure nanoparticle assay is based on the competitive adsorption of the sample and the acceptor-labeled protein to donor europium(III) polystyrene particles. The protein aggregation was detected with the developed TR-LRET nanoparticle assay, UV240 absorbance and dynamic light scattering (DLS). All methods well equally detected the aggregation and aggregates, whose size ranged from single protein to more than 1000 nm aggregates. The developed method allowed the aggregation detection of the entire size range at more than 10,000 times lower concentration, 30 MUg/L, compared to UV240 and DLS. The simple-to-use and sensitive nanoparticle assay with existing microtiter plate luminometric instrumentation can find use as a routine tool for protein aggregation studies in biochemical laboratories and for quality assessment of protein products in industry. PMID- 21247197 TI - In-situ X-ray absorption study of evolution of oxidation states and structure of cobalt in Co and CoPt bimetallic nanoparticles (4 nm) under reducing (H2) and oxidizing (O2) environments. AB - In-situ near edge X-ray absorption fine structure spectroscopy was performed to monitor the oxidation states of Co and CoPt nanoparticles (NPs) of 4 nm size in the presence of H(2) and O(2) in the pressure range of 1 bar and 36 Torr respectively. Platinum helps the rapid reduction of cobalt oxides in hydrogen at a rather low temperature (38 degrees C). In addition, reversible changes of the oxidation states of cobalt in the Co and CoPt NPs as a function of cycling oxygen pressure (in the range of millitorr to 36 Torr) are quantified and compared. The role of Pt in the process of Co reducing and oxidizing was explored. Our findings permit the prediction of the cobalt oxidation states as the reaction conditions are altered. The experimental results also suggest the presence of tetrahedral structure of Cobalt oxide that differs from the Co(3)O(4) spinel structure. PMID- 21247198 TI - Phomalevones A-C: dimeric and pseudodimeric polyketides from a fungicolous Hawaiian isolate of Phoma sp. (Cucurbitariaceae). AB - Phomalevones A-C (1-3), three new com-pounds with bis-dihydroxanthone and bis benzophenone systems, were isolated from cultures of a Hawaiian isolate of Phoma sp. (MYC-1734 = NRRL 39060; Cucurbitariaceae). The structures of 1-3 were determined by analysis of NMR and MS data. The absolute configurations of the sp(3) stereocenters in the monomeric unit of 1 were assigned by application of Mosher's method, and overall absolute configurations were proposed on the basis of ECD data using both computational methods and comparisons with literature data for model compounds. All three compounds showed antibacterial activity, and compounds 2 and 3 also exhibited antifungal effects. PMID- 21247199 TI - Island organization of TiO2 hierarchical nanostructures induced by surface wetting and drying. AB - We report on the reorganization and bundling of titanium oxide nanostructured layers, induced by wetting with different solvents and subsequent drying. TiO(2) layers are deposited by pulsed laser deposition and are characterized by vertically oriented, columnar-like structures resulting from assembling of nanosized particles; capillary forces acting during evaporation induce bundling of these structures and lead to a micrometer-size patterning with statistically uniform islands separated by channels. The resulting surface is characterized by a hierarchical, multiscale morphology over the nanometer-micrometer length range. The structural features of the pattern, i.e., characteristic length, island size, and channel width, are shown to depend on properties of the liquid (i.e., surface tension) and thickness and density of the TiO(2) layers. The studied phenomenon permits the controlled production of multiscale hierarchically patterned surfaces of nanostructured TiO(2) with large porosity and large surface area, characterized by superhydrophilic wetting behavior without need for UV irradiation. PMID- 21247200 TI - Inhibition mechanism of rat alpha3beta4 nicotinic acetylcholine receptor by the Alzheimer therapeutic tacrine. AB - Nicotinic acetylcholine receptors (nAChRs) were studied in detail in the past regarding their interaction with therapeutic and drug addiction related compounds. Using fast kinetic whole-cell recording, we have now studied effects of tacrine, an agent used clinically to treat Alzheimer's disease, on currents elicited by activation of rat alpha(3)beta(4) nAChR heterologously expressed in KXalpha3beta4R2 cells. Characterization of receptor activation by nicotine used as agonist revealed a K(d) of 23 +/- 0.2 MUM and 4.3 +/- 1.3 for the channel opening equilibrium constant, Phi(-1). Experiments were performed to investigate whether tacrine is able to activate the alpha(3)beta(4) nAChR. Tacrine did not activate whole-cell currents in KXalpha3beta4R2 cells but inhibited receptor activity at submicromolar concentration. Dose-response curves obtained with increasing agonist or inhibitor concentration revealed competitive inhibition of nAChRs by tacrine, with an apparent inhibition constant, K(I), of 0.8 MUM. The increase of Phi(-1) in the presence of tacrine suggests that the drug stabilizes a nonconducting open channel form of the receptor. Binding studies with TCP and MK-801 ruled out tacrine binding to common allosteric sites of the receptor. Our study suggests a novel mechanism for action of tacrine on nAChRs besides inhibition of acetylcholine esterase. PMID- 21247201 TI - Si/Ge junctions formed by nanomembrane bonding. AB - We demonstrate the feasibility of fabricating heterojunctions of semiconductors with high mismatches in lattice constant and coefficient of thermal expansion by employing nanomembrane bonding. We investigate the structure of and electrical transport across the interface of a Si/Ge bilayer formed by direct, low temperature hydrophobic bonding of a 200 nm thick monocrystalline Si(001) membrane to a bulk Ge(001) wafer. The membrane bond has an extremely high quality, with an interfacial region of ~1 nm. No fracture or delamination is observed for temperature changes greater than 350 degrees C, despite the approximately 2:1 ratio of thermal-expansion coefficients. Both the Si and the Ge maintain a high degree of crystallinity. The junction is highly conductive. The nonlinear transport behavior is fit with a tunneling model, and the bonding behavior is explained with nanomembrane mechanics. PMID- 21247202 TI - Bright unidirectional fluorescence emission of molecules in a nanoaperture with plasmonic corrugations. AB - Controlling the fluorescence emission from nanoscale quantum emitters is a key element for a wide range of applications, from efficient analytical sensing to quantum information processing. Enhancing the fluorescence intensity and narrowing the emission directivity are both essential features to achieve a full control of fluorescence, yet this is rarely obtained simultaneously with optical nanoantennas. Here we report that gold nanoapertures surrounded by periodic corrugations transform standard fluorescent molecules into bright unidirectional sources. We obtain enhancement factors of the fluorescence count rate per molecule up to 120 fold simultaneously with a directional emission of the fluorescence into a narrow angular cone in the direction normal to the sample plane. The bright emission and narrow directionality enable the detection of single molecules with a low numerical aperture objective, and improve the effectiveness of fluorescence-based applications. We thoroughly quantify the increased light-matter coupling as well as the radiation pattern intensity. These results are highly relevant for the development of single molecule sensing, single-photon sources, and light emitting devices. PMID- 21247203 TI - Electron attachment to dye-sensitized solar cell components: cyanoacetic acid. AB - The energies of electron attachment associated with temporary occupation of the lower-lying virtual orbitals of cyanoacetic acid (CAA), proposed as a possible component of dye-sensitized solar cells, and its derivative methyl cyanoacetate (MCA) are measured in the gas phase with electron transmission spectroscopy (ETS). The corresponding orbital energies of the neutral molecule, supplied by B3LYP/6-31G(d) calculations and scaled using an empirically calibrated linear equation, are compared with the experimental vertical attachment energies (VAEs). The vertical and adiabatic electron affinities are also evaluated at the B3LYP/6 31+G(d) level as the anion/neutral total energy difference. Dissociative electron attachment spectroscopy (DEAS) is used to measure the total anion current as a function of the incident electron energy in the 0-4 eV energy range, and the negative fragments generated through the dissociative decay channels of the molecular anion are detected with a mass filter. In both compounds only two intense fragment anion currents are observed, that due to loss of a hydrogen atom from the molecular anion ([M - H](-)) and that due to formation of CN(-). In CAA the former signal displays a very sharp feature at 0.68 eV, assigned to a vibrational Feshbach resonance arising from coupling between a dipole bound anion state and a temporary sigma* anion state. PMID- 21247204 TI - Temperature-dependent infrared spectroscopy of water from a first-principles approach. AB - The structure and dynamics of the hydrogen-bond network in water is investigated as a function of the temperature through the application of a first-principles approach that combines an ab-initio-based water potential with an explicit quantum treatment of the molecular motion. A molecular-level picture of the rearrangement of the hydrogen-bond network is derived from the direct analysis of linear and nonlinear vibrational spectra. The results indicate that good agreement with the available experimental data is obtained when the temperature scale is defined relative to the corresponding melting points. In particular, the theoretically predicted energy barriers and time scales associated with the hydrogen-bond dynamics are closely comparable to the experimental values obtained from two-dimensional and pump-probe infrared spectra. The present analysis will also serve as a guide for future developments of an improved ab-initio-based model capable to reproduce the properties of water in different environments and under different conditions. PMID- 21247205 TI - The role of hydrophobic surfaces in altering water-mediated peptide-peptide interactions in an aqueous environment. AB - Using Born-Oppenheimer molecular dynamics within the density functional framework, we calculated the effective force acting on water-mediated peptide peptide interaction between antiparallel beta-sheets in an aqueous environment and also in the vicinity of a hydrophobic surface. From the magnitude of the effective force (corresponding to the slope of the free energy as a function of the interpeptide distance) and its sign (a negative value indicates an effective attraction, whereas a positive value indicates an effective repulsion) we can elucidate the fundamental differences of the water-mediated peptide-peptide interactions in those two environments. The computed effective forces indicate that the water-mediated interaction between peptides in an aqueous environment is attractive in the range of interpeptide distance d = 7-8 A when hydrophobic surfaces are not nearby. Due to the stabilization of the water molecules bridging between the two beta-sheets, a free energy barrier exists between the direct and indirect (water-mediated) interpeptide interactions. However, when the peptides are in the proximity of hydrophobic surfaces, this free energy barrier decreases because the hydrophobic surfaces enhance the interpeptide attraction by the destabilization and ease-to-libration of the bridging water molecules between them. PMID- 21247206 TI - Does h play a role in multidimensional spectroscopy? Reduced hierarchy equations of motion approach to molecular vibrations. AB - To investigate the role of quantum effects in vibrational spectroscopies, we have carried out numerically exact calculations of linear and nonlinear response functions for an anharmonic potential system nonlinearly coupled to a harmonic oscillator bath. Although one cannot carry out the quantum calculations of the response functions with full molecular dynamics (MD) simulations for a realistic system which consists of many molecules, it is possible to grasp the essence of the quantum effects on the vibrational spectra by employing a model Hamiltonian that describes an intra- or intermolecular vibrational motion in a condensed phase. The present model fully includes vibrational relaxation, while the stochastic model often used to simulate infrared spectra does not. We have employed the reduced quantum hierarchy equations of motion approach in the Wigner space representation to deal with nonperturbative, non-Markovian, and nonsecular system-bath interactions. Taking the classical limit of the hierarchy equations of motion, we have obtained the classical equations of motion that describe the classical dynamics under the same physical conditions as in the quantum case. By comparing the classical and quantum mechanically calculated linear and multidimensional spectra, we found that the profiles of spectra for a fast modulation case were similar, but different for a slow modulation case. In both the classical and quantum cases, we identified the resonant oscillation peak in the spectra, but the quantum peak shifted to the red compared with the classical one if the potential is anharmonic. The prominent quantum effect is the 1-2 transition peak, which appears only in the quantum mechanically calculated spectra as a result of anharmonicity in the potential or nonlinearity of the system-bath coupling. While the contribution of the 1-2 transition is negligible in the fast modulation case, it becomes important in the slow modulation case as long as the amplitude of the frequency fluctuation is small. Thus, we observed a distinct difference between the classical and quantum mechanically calculated multidimensional spectra in the slow modulation case where spectral diffusion plays a role. This fact indicates that one may not reproduce the experimentally obtained multidimensional spectrum for high-frequency vibrational modes based on classical molecular dynamics simulations if the modulation that arises from surrounding molecules is weak and slow. A practical way to overcome the difference between the classical and quantum simulations was discussed. PMID- 21247207 TI - Ring-closure and isomerization capabilities of spiropyran-derived merocyanine isomers. AB - We report the photochemistry of two ring-open isomers, namely TTC and TTT, of a bidirectional photoswitchable spiropyran, 6,8-dinitro-1',3',3'-trimethylspiro[2H 1-benzopyran-2,2'-indoline] (6,8-dinitro BIPS). Both isomers are capable of ring closure after excitation with visible fs laser pulses, as disclosed by pump wavelength-dependent transient absorption experiments in the visible spectral range. The main isomer TTC has its maximum absorption at 560 nm, whereas the minor isomer TTT is red-shifted (600 nm). The excited-state lifetimes differ strongly (tau ~ 900 ps for TTT and tau ~ 95 ps for TTC), nevertheless the quantum efficiencies for ring closure (40% for TTC and 35% for TTT) and isomerization (1 2% for TTC and 1-2% for TTT) are comparable. With regard to the bidirectional photoswitching capabilities, 6,8-dinitro BIPS is the first molecular switch based on a 6pi-electrocyclic reaction where both ring-open isomers are capable of ring closure. PMID- 21247208 TI - Structure and barrier to methyl group internal rotation for (CF3)2CFCF2OCH3 and its isomer n-C4F9OCH3 (HFE-7100). AB - The hydrofluoroether C(4)F(9)OCH(3) (methoxynonafluorobutane, HFE-7100) has been studied by chirped pulse Fourier transform microwave spectroscopy as vapor from the liquid participates in a supersonic expansion of argon. Two isomers are present, (CF(3))(2)CFCF(2)OCH(3) and n-C(4)F(9)OCH(3), and in each case the rotational spectra of only one, dominating, conformer has been assigned. Rotational constants, centrifugal distortion constants, and barriers to methyl group internal rotation for the observed species have been experimentally determined for the first time. We note that Ray's asymmetry parameter for the (CF(3))(2)CFCF(2)OCH(3) isomer is 0.007 083(1), indicating almost "perfect" asymmetry. Also, electronic structure calculations show an extremely short C(frame)-O ether bond length of 1.337 A. PMID- 21247209 TI - Probability of detecting perchlorate under natural conditions in deep groundwater in California and the southwestern United States. AB - We use data from 1626 groundwater samples collected in California, primarily from public drinking water supply wells, to investigate the distribution of perchlorate in deep groundwater under natural conditions. The wells were sampled for the California Groundwater Ambient Monitoring and Assessment Priority Basin Project. We develop a logistic regression model for predicting probabilities of detecting perchlorate at concentrations greater than multiple threshold concentrations as a function of climate (represented by an aridity index) and potential anthropogenic contributions of perchlorate (quantified as an anthropogenic score, AS). AS is a composite categorical variable including terms for nitrate, pesticides, and volatile organic compounds. Incorporating water quality parameters in AS permits identification of perturbation of natural occurrence patterns by flushing of natural perchlorate salts from unsaturated zones by irrigation recharge as well as addition of perchlorate from industrial and agricultural sources. The data and model results indicate low concentrations (0.1-0.5 MUg/L) of perchlorate occur under natural conditions in groundwater across a wide range of climates, beyond the arid to semiarid climates in which they mostly have been previously reported. The probability of detecting perchlorate at concentrations greater than 0.1 MUg/L under natural conditions ranges from 50-70% in semiarid to arid regions of California and the Southwestern United States to 5-15% in the wettest regions sampled (the Northern California coast). The probability of concentrations above 1 MUg/L under natural conditions is low (generally <3%). PMID- 21247210 TI - In-situ sorbent amendments: a new direction in contaminated sediment management. PMID- 21247211 TI - DNA adducts formed from p-benzoquinone, an electrophilic metabolite of benzene, are extensively metabolized in vivo. AB - Benzetheno adducts derived from p-benzoquinone (p-BQ), a reactive metabolite of benzene, were reported to be formed by the reaction of p-BQ with DNA in vitro but have never been detected either in vivo or in experiments with living cells. Two of them, 3-hydroxy-3,N(4)-benzetheno-2'-deoxycytidine (DCBQ) and 7-hydroxy-1,N(2) benzetheno-2'-deoxyguanosine (DGBQ), were administered to rats by single ip injections at the doses of 2 mg/kg each. The excretion of unchanged compounds DCBQ and DGBQ within 2 days amounted to 8.2 +/- 1.9 and 4.5 +/- 1.2% (mean +/- SE) of the dose, respectively. Additionally, deribosylated metabolites of DCBQ and DGBQ, 3-hydroxy-3,N(4)-benzethenocytosine (CBQ) and 7-hydroxy-1,N(2) benzethenoguanine (GBQ), were found amounting to 45.7 +/- 10.2 and 2.9 +/- 2.1% of the dose, respectively. An additional portion of CBQ and GBQ was liberated from their corresponding conjugates by acidic hydrolysis. Therefore, total recoveries of CBQ and GBQ in urine were 82.1 +/- 13.5 and 11.6 +/- 5.1% of the dose. To identify conjugated metabolites, DCBQ and DGBQ were administered intraperitoneally at the doses 10.5 and 11.0 mg/kg, respectively, to one animal each. Glucuronides of DCBQ, DGBQ, and GBQ as well as sulfates of DGBQ, CBQ, and GBQ were identified by ESI-LC-MS according to (M - H)(-) ions and their fragmentation. In addition, two oxygenated metabolites and their corresponding conjugates were detected for DGBQ and GBQ. One of these metabolites was identified as 2,7-dihydroxy-1,N(2)-benzethenoguanine OGBQ1. It coeluted with the product obtained by the reaction of HQ and p-BQ mixture with 8-hydroxy-2' deoxyguanosine followed by acid hydrolysis. These findings suggest that both DCBQ and DGBQ undergo extensive biotransformation in vivo. CBQ appears to be the only p-BQ derived DNA adduct, which can be efficiently recovered from its conjugates and might be therefore useful in molecular dosimetry of benzene. PMID- 21247212 TI - Aligned/unaligned conducting polymer cryogels with three-dimensional macroporous architectures from ice-segregation-induced self-assembly of PEDOT-PSS. AB - Porous conducting polymers are of great interest because of the huge potential to combine high surface areas in the dry state with physical properties relevant to organic electronics. Aligned or unaligned conducting polymer cryogels with 3D macroporous architectures have been prepared using the ice-segregation-induced self-assembly (ISISA) of different poly(3,4-ethylenedioxythiophene) poly(styrenesulfonate) (PEDOT-PSS) freezing precursors as a dispersion or a formed hydrogel. The chemical composition and molecular structure of the resulting conducting polymer cryogels have been investigated by X-ray photoelectron spectroscopy and Raman spectroscopy, respectively. The morphologies of the PEDOT-PSS cryogels, together with their textural structures, have been revealed by scanning electron microscopy, mercury porosimetry, and nitrogen sorption tests. Processing PEDOT-PSS via ISISA endows the conducting polymers with novel properties, as demonstrated by a series of X-ray diffraction, differential scanning calorimetry, and electrical conductivity tests. These conducting polymer cryogels with aligned/unaligned macroporous architectures suggest the potential in the development of electronic components, tissue engineering, and next-generation catalytic and separation supports. PMID- 21247213 TI - Aggregation behavior of long-chain N-aryl imidazolium bromide in aqueous solution. AB - The aggregation behavior of three long-chain N-aryl imidazolium ionic liquids (ILs), 1-(2,4,6-trimethylphenyl)-3-alkylimidazolium bromide [C(n)pim]Br (n = 10, 12, and 14), in aqueous solutions was systematically explored by surface tension, electrical conductivity, and (1)H NMR. A lower critical micelle concentration (cmc) for the N-aryl imidazolium ILs is observed compared with that for 1,3 dialkylimidazolium ILs [C(n)mim]Br, indicating that the incorporation of the 2,4,6-trimethylphenyl group into a headgroup favors micellization. The enhanced pi-pi interactions among the adjacent 2,4,6-trimethylphenyl groups weaken the steric hindrance of headgroups and thus lead to a dense arrangement of [C(n)pim]Br molecules at the air-water interface. An analysis of the (1)H NMR spectra revealed that the introduced 2,4,6-trimethylphenyl group may slightly bend into the hydrophobic regions upon micellization. The micelle formation process for [C(n)pim]Br (n = 10, 12, and 14) was found to be enthalpy-driven in the investigated temperature range, which is attributed to the strong electrostatic self-repulsion of the headgroups and the counterions as well as the pi-pi interactions among headgroups. Strong, stable fluorescence properties are presented by the new N-aryl imidazolium ILs, indicating their potential application in the field of photochemistry. PMID- 21247214 TI - Size-selective carbon nanoclusters as precursors to the growth of epitaxial graphene. AB - The nucleation and growth mechanisms of graphene on Rh(111) via temperature programmed growth of C(2)H(4) are studied by scanning tunneling microscopy and spectroscopy, and by density functional theory calculations. By combining our experimental and first-principles approaches, we show that carbon nanoislands form in the initial stages of graphene growth, possessing an exclusive size of seven honeycomb carbon units (hereafter labeled as 7C(6)). These clusters adopt a domelike hexagonal shape indicating that bonding to the substrate is localized on the peripheral C atoms. Smoluchowski ripening is identified as the dominant mechanism leading to the formation of graphene, with the size-selective carbon islands as precursors. Control experiments and calculations, whereby coronene molecules, the hydrogenated analogues of 7C(6), are deposited on Rh(111), provide an unambiguous structural and chemical identification of the 7C(6) building blocks. PMID- 21247215 TI - The asymmetric Maitland-Japp reaction and its application to the construction of the C1-C19 bis-pyran unit of phorboxazole B. AB - The synthesis of the C1-C19 bis-pyran unit of phorboxazole B has been achieved. The key pyran rings were constructed by means of an asymmetric Maitland-Japp reaction and a second Maitland-Japp resolution/cyclization reaction. The longest linear sequence was 14 steps, and the C1-C19 bis-pyran unit was formed in an impressive 10.4% yield. PMID- 21247217 TI - Binding of a C-end rule peptide to the neuropilin-1 receptor: a molecular modeling approach. AB - Neuropilin-1 (NRP-1) is a receptor that plays an essential role in angiogenesis, vascular permeability, and nervous system development. Previous studies have shown that peptides with an N-terminal Arg, especially peptides with the four residue consensus sequence R/K/XXR/K, bind to NRP-1 cell surfaces. Peptides containing such consensus sequences promote binding and internalization into cells, while blocking the C-terminal Arg (or Lys) prevents the internalization. In this study, we use molecular dynamics simulations to model the structural properties of the NRP-1 complex with a prototypic CendR peptide, RPAR. Our simulations show that RPAR binds NRP-1 through specific interactions of the RPAR C-terminus: three hydrogen bonds and a salt bridge anchor the ligand in the receptor pocket. The modeling results were used as the starting point for a systematic computational study of new RPAR analogues based on chemical modifications of their natural amino acids. Comparison of the structural properties of the new peptide-receptor complexes with the original organization suggests that some of the analogues can increase the binding affinity while reducing the natural sensitivity of RXXR to endogenous proteases. PMID- 21247216 TI - SVM model for quality assessment of medium resolution mass spectra from 18O-water labeling experiments. AB - We describe a method for assessing the quality of mass spectra and improving reliability of relative ratio estimations from (18)O-water labeling experiments acquired from low resolution mass spectrometers. The mass profiles of heavy and light peptide pairs are often affected by artifacts, including coeluting contaminant species, noise signal, instrumental fluctuations in measuring ion position and abundance levels. Such artifacts distort the profiles, leading to erroneous ratio estimations, thus reducing the reliability of ratio estimations in high throughput quantification experiments. We used support vector machines (SVMs) to filter out mass spectra that deviated significantly from expected theoretical isotope distributions. We built an SVM classifier with a decision function that assigns a score to every mass profile based on such spectral features as mass accuracy, signal-to-noise ratio, and differences between experimental and theoretical isotopic distributions. The classifier was trained using a data set obtained from samples of mouse renal cortex. We then tested it on protein samples (bovine serum albumin) mixed in five different ratios of labeled and unlabeled species. We demonstrated that filtering the data using our SVM classifier results in as much as a 9-fold reduction in the coefficient of variance of peptide ratios, thus significantly improving the reliability of ratio estimations. PMID- 21247218 TI - Pharmacovigilance and the null hypothesis: do we do much for public health? PMID- 21247220 TI - Incidence of infusion-associated reactions with rituximab for treating multiple sclerosis: a retrospective analysis of patients treated at a US centre. AB - BACKGROUND: Rituximab is a monoclonal antibody approved for treating CD20 positive B-cell non-Hodgkin's lymphoma and rheumatoid arthritis but is used off label for treating many autoimmune disorders, including multiple sclerosis (MS). Similarly to other monoclonal antibodies, the incidence of infusion-related reactions to rituximab is high. Reactions to monoclonal antibodies, including rituximab, vary widely in type and severity, but may include mild pruritis and rash to more severe complications such as Stevens-Johnson syndrome and anaphylactic reactions. OBJECTIVE: To assess the incidence of infusion-associated reactions in our MS patients receiving rituximab infusions and compare it to previous trials investigating rituximab for treating MS. METHODS: From 1 to 30 November 2009, we retrospectively reviewed medical charts from Partners Multiple Sclerosis Centre, Brookline, MA, USA, of patients being treated with rituximab for MS between 20 November 2007 and 24 November 2009 for evidence of infusion associated reactions and further classified reactions on a grading scale. RESULTS: During the period studied, 70 patients were infused with rituximab. Infusion-associated events occurred in 25.7% of our patients. Reactions were mild to moderate and most commonly occurred during the first infusion. Most patients were able to complete the infusion after appropriate treatment of the reaction was administered, and most patients went on to receive subsequent doses without any further reactions. CONCLUSIONS: The occurrence of infusion-associated reactions to rituximab in patients with MS is fairly common. However, premedication that includes corticosteroids may reduce the incidence of reactions dramatically. Should they occur, proper treatment of reactions with histamine H(1) or H(2) receptor antagonists and infusion rate reduction is an effective management strategy in this situation. PMID- 21247219 TI - Mammalian target of rapamycin (mTOR) inhibitors: potential uses and a review of haematological adverse effects. AB - Mammalian target of rapamycin (mTOR) inhibitors (mTORis) constitute a relatively new category of immunosuppressive and antineoplastic drugs. These share a unique mechanism of action that is focused on the inhibition of the mTOR. Their clinical applications have recently expanded significantly to cover a wide spectrum of immune and non-immune-mediated disorders, including, apart from solid organ transplantation, various solid organ and haematological malignancies, rheumatological and auto-immune diseases such as rheumatoid arthritis, systemic lupus erythematosus, fibrotic conditions, e.g. pulmonary and hepatic fibrosis, and even metabolic problems such as diabetes mellitus and obesity. The most challenging and frequent adverse effects of the mTORis are the haematological ones, especially anaemia, leukopenia and thrombocytopenia. A unique characteristic of mTORi-induced anaemia is concurrent marked microcytosis. Recently, mechanisms have been proposed to explain the microcytic appearance of this anaemia; these include globin production defect, erythropoietin resistance, chronic inflammation, dysregulation of cellular iron metabolism and hepcidin mediated iron homeostasis interference. As the differential diagnosis of microcytic anaemia includes pure iron deficiency, functional iron deficiency and haemoglobinopathies, characterization of the anaemia requires significant investigation, time and costs. Therefore, understanding of the likely interaction between mTORis and patients is valuable in clinical practice. Moreover, this could expand the drugs' therapeutic applications to other disorders, and suggest novel targets for further research. PMID- 21247221 TI - Effects of benzodiazepines, antidepressants and opioids on driving: a systematic review and meta-analysis of epidemiological and experimental evidence. AB - BACKGROUND: Many individuals in the community are prescribed psychoactive drugs with sedative effects. These drugs may affect their daily functions, of which automobile driving is a major component. OBJECTIVE: To examine the association of three classes of commonly used psychoactive drugs (viz. benzodiazepines and newer non-benzodiazepine hypnotics, antidepressants and opioids) with (i) the risk of traffic accidents (as indexed by epidemiological indicators of risk); and (ii) driving performance (as indexed by experimental measures of driving performance). METHODS: A literature search for material published in the English language between January 1966 and January 2010 in PubMed and EMBASE databases was combined with a search for other relevant material referenced in the retrieved articles. Retrieved articles were systematically reviewed, carrying out meta-analyses where possible. Twenty-one epidemiological studies (13 case-control and 8 cohort studies) fulfilled the inclusion criteria by estimating the accident risk associated with drug exposure (ascertained by blood/urine analysis or prescription records). Sixty-nine experimental studies fulfilled the inclusion criteria by testing actual or simulated driving performance after administering a single dose or multiple doses. RESULTS: Two meta-analyses showed that benzodiazepines are associated with a 60% (for case-control studies: pooled odds ratio [OR] 1.59; 95% CI 1.10, 2.31) to 80% (for cohort studies: pooled incidence rate ratio 1.81; 95% CI 1.35, 2.43) increase in the risk of traffic accidents and a 40% (pooled OR 1.41; 95% CI 1.03, 1.94) increase in 'accident responsibility'. Co-ingestion of benzodiazepines and alcohol was associated with a 7.7-fold increase in the accident risk (pooled OR 7.69; 95% CI 4.33, 13.65). Subgroup analysis of case-control studies showed a lower benzodiazepine-associated accident risk in elderly (>65 years of age) drivers (pooled OR 1.13; 95% CI 0.97, 1.31) than in drivers <65 years of age (pooled OR 2.21; 95% CI 1.31, 3.73), a result consistent with age-stratified risk differences reported in cohort studies. Anxiolytics, taken in single or multiple doses during the daytime, impaired driving performance independent of their half-lives. With hypnotics, converging evidence from experimental and epidemiological studies indicates that diazepam, flurazepam, flunitrazepam, nitrazepam and the short half-life non benzodiazepine hypnotic zopiclone significantly impair driving, at least during the first 2-4 weeks of treatment. The accident risk was higher in the elderly (>65 years of age) who use tricyclic antidepressants (TCAs); however, the evidence for an association of antidepressants with accident risk in younger drivers was equivocal. Sedative but not non-sedative antidepressants were found to cause short-term impairment of several measures of driving performance. Limited epidemiological research reported that opioids may be associated with increased accident risk in the first few weeks of treatment. CONCLUSIONS: Benzodiazepine use was associated with a significant increase in the risk of traffic accidents and responsibility of drivers for accidents. The association was more pronounced in the younger drivers. The accident risk was markedly increased by co-ingestion of alcohol. Driving impairment was generally related to plasma half-lives of hypnotics, but with notable exceptions. Anxiolytics, with daytime dosing, impaired driving independent of their half-lives. TCAs appeared to be associated with increased accident risk, at least in the elderly, and caused short-term impairment in driving performance. Opioid users may be at a higher risk of traffic accidents; however, experimental evidence is limited on their effects on driving. PMID- 21247223 TI - Effects of proton pump inhibitors in patients receiving clopidogrel: meta analysis versus clinical practice. PMID- 21247222 TI - Comparing the General Practice Research Database and the UK Epilepsy and Pregnancy Register as tools for postmarketing teratogen surveillance: anticonvulsants and the risk of major congenital malformations. AB - BACKGROUND: Use of pregnancy registries is a common method of postmarketing surveillance of pregnancy outcomes to identify potential teratogens. However, with the increase in electronic capture of healthcare data for administrative, audit and research purposes, data generated during routine clinical practice might be used to address questions similar to those explored using pregnancy registries. OBJECTIVES: To establish how data from the UK General Practice Research Database (GPRD) compares with data from the UK Epilepsy and Pregnancy Register and to assess how it can contribute to postmarketing surveillance of pregnancy outcomes. METHODS: Pregnancy outcomes were identified from the GPRD for women aged 14-49 years with a diagnosis of epilepsy and supporting evidence. Outcomes with a major congenital malformation (MCM) were identified and the relative risks (RRs) of an MCM following a range of first-trimester antiepileptic drug (AED) exposures were calculated and compared with those reported by the UK Epilepsy and Pregnancy Register. In addition, we also evaluated whether the known association between valproate and spina bifida could be identified using data from the GPRD. The study period ran from 1 January 1990 until 31 December 2006. RESULTS: A total of 1766 live mother-baby pairs were identified, as well as 551 pregnancy terminations, 13 stillbirths and 1 neonatal death. Including those that resulted in a termination, there were 62 unique pregnancy outcomes with an MCM. An increased risk of spina bifida was identified using the GPRD following first trimester monotherapy exposure to valproate when compared with those with no AED exposure (RR 8.02; 95% CI 1.5, 43.5). More generally, comparing the GPRD with the UK register, the GPRD ascertained a lower number of first-trimester AED exposures: monotherapy 711 versus 2468; polytherapy 156 versus 718. We reproduced the UK register results of an increased MCM risk following first-trimester polytherapy AED exposure compared with no AED exposure (RR 2.89; 95% CI 1.43, 5.84). Using the GPRD, we identified similar point estimates to the UK register following monotherapy and polytherapy exposures (4.1% vs 3.7% and 7.1% vs 6.0%, respectively) but we were unable to reproduce the level of statistical significance. For individual AEDs, the MCM rate following valproate exposure was 4.9% (11/225) in the GPRD compared with 6.2% (44/715) in the UK register. CONCLUSIONS: The GPRD has potential for the identification of malformations and of a teratogenic association. For epilepsy, the GPRD does, however, identify fewer exposed pregnancies than a pregnancy registry. Therefore, in many circumstances pregnancy registries are likely to remain preferable as a method of surveillance. The GPRD may be better suited to monitoring medicines used in the treatment of more prevalent conditions, such as depression, or for monitoring medicines that have been on the market for a long time and for which no registry has been set up. PMID- 21247226 TI - Extensively drug-resistant tuberculosis at a tuberculosis specialist hospital in Shanghai, China: clinical characteristics and treatment outcomes. AB - BACKGROUND: Extensively drug-resistant tuberculosis (XDR-TB) has recently emerged as a global public health problem. The objective of this study was to investigate the clinical characteristics, management and outcomes of human immunodeficiency virus-negative patients with XDR-TB at a specialist TB hospital in Shanghai, China. METHODS: From July 2007 to June 2009 we analyzed TB patients with culture proven XDR-TB at a specialist TB hospital in Shanghai. RESULTS: Among 1156 TB cases, all culture-positive for Mycobacterium tuberculosis complex, 494 cases (42.7%) were classified as MDR-TB; 126 cases (10.9%) were XDR-TB. At least 3 lung fields were involved in 90.5% of XDR-TB patients and in 80.7% of other MDR-TB patients (p = 0.008). Of the XDR-TB cases, 40.5% were complicated by diabetes and other diseases, significantly higher compared with the other MDR-TB cases (p = 0.002). The rates of resistance to all drugs except isoniazid and rifampicin were significantly higher in patients with XDR-TB than in patients with other MDR-TB (p < 0.001). Treatment failure was more common in patients with XDR-TB than in those with other MDR-TB (p < 0.001), whereas the mortality and default rates did not differ significantly. CONCLUSIONS: The prevalence of XDR-TB is high in some areas of China. The clinical treatment outcome for XDR-TB is usually very poor. PMID- 21247225 TI - A value set for the EQ-5D based on experienced health states: development and testing for the German population. AB - BACKGROUND: Decision makers responsible for allocation of healthcare resources may require that health states are valued by the population for whom they are making decisions. To achieve this, health-state descriptions can be combined with a value set that reflects the valuations of the target population. In the decision-utility approach, such a value set is at least partly based on wants and expectations regarding given health states. This may reflect aspects different from the health state experienced and valued by a respondent. OBJECTIVES: To derive a value set that is completely based on experienced health states, emphasising the patient's perspective, and test its predictive performance in comparison with established approaches. METHODS: Problem descriptions and rating scale valuations of the EQ-5D were drawn from two representative German population surveys in 2006 and 2007. Two models based on given health states but differing in valuation method (1a, b) were analysed, along with three models based on experienced health states: (2) ordinary least squares regression; (3) scale-transformed regression; and (4) a generalized linear model with binomial error distribution and constraint parameter estimation. The models were compared with respect to issues in specification, and accuracy in predicting the actual valuations of experienced health states in a new data set, using correlation, mean error and ranking measures for the latter. In addition, the impact of standardizing experience-based index models for age and sex of the subjects was investigated. RESULTS: Models 1 (a, b), 2 and 3 partly led to plausible and comparable parameter estimates, but also led to problems of insignificance and inconsistencies in some of the estimates. Model 4 achieved consistency and featured partly equivalent and partly better predictive accuracy. Using this model, mean valuations of health states were much better predicted by the experience-based approach than by the decision-utility approach, especially for health states that frequently (>10) occurred in the population sample. Standardizing the experience-based index models for age and sex further improved predictive accuracy and strengthened the position of model 4. CONCLUSIONS: A value set for the EQ-5D can be plausibly estimated from experience-based valuations. The approach offers an alternative to decision makers who prefer experience-based valuation over decision utilities in the measurement of health outcome. Although usefulness in population samples was shown, use in a clinical context will first require indication-specific tests. Current limitations include use in a general population only, and a restricted range of health states covered. PMID- 21247227 TI - Association between the inclination of the lateral incisors and the position of the erupting canines on panoramic radiographs. AB - OBJECTIVE. To analyze correlations between the inclination of the permanent maxillary lateral incisors and the intraosseous position of the erupting permanent maxillary canines on panoramic radiographs. MATERIAL AND METHODS. The inclination of the lateral incisor to the midline, the mesiodistal position of the crown of the canine, and the inclination of the canine to the midline and to the long axis of the adjacent incisor were measured on panoramic radiographs of 1013 subjects aged 8-11 years. RESULTS. The distal inclination of the lateral incisor crown increased until 10 years, after which no significant changes occurred. The canine erupted with increasing mesial inclination of the crown until 9 years, after which it began to progressively right itself. As a result, inclination of the canine to the adjacent incisor increased between 8 and 9 years and decreased between 10 and 11 years. Until the children reached 9 years of age, the more mesial the crown of the unerupted canine, the greater the decrease in the distal inclination of the lateral incisor crown. CONCLUSIONS. The inclination of the crown of the lateral incisor varies during eruption of the canine, increasing distally until 10 years as a physiological stage in the mixed dentition. The inclination of the lateral incisor is also associated with the mesiodistal position of the canine crown. The mesial intraosseous location of the canine crown results in righting of the lateral incisor. PMID- 21247228 TI - Oral health-related quality of life and associated factors in Norwegian adults. AB - OBJECTIVE. To investigate associations between oral health-related quality of life assessed with the Oral Health Impact Profile (OHIP)-14 and demographic factors, number of teeth present, dental visits, dental health behaviour and self rated oral health in a representative sample of 20-80-year-old Norwegians. MATERIAL AND METHODS. The study was conducted in a stratified random sample of 3538 individuals. Questionnaires including questions on demographic factors, number of remaining teeth, dental visits, dental health behaviour, self-rated oral health and OHIP-14 were mailed to the sample. Bivariate and multivariate analyses were performed. RESULTS. The response rate was 69%. The mean OHIP-14 score was 4.1 (standard deviation = 6.2). No problem was reported by 35% of the respondents. The most frequently reported problems were: physical pain (56%), psychological discomfort (39%) and psychological disability (30%). When the effect of all independent variables was analysed in multivariate analysis, self rated oral health, frequency of dental visits, number of teeth, age and sex were significantly (P < 0.05) associated with the prevalence of having problems and frequent problems. Self-rated oral health had the strongest association with having problems [odds ratio (OR) 4.5; 95% confidence interval (CI) 3.4-6.0] and with having frequent problems (OR 4.0; 95% CI 2.7-5.8). Dental health behaviour, use of floss and toothpicks and oral rinsing were not associated with having problems related to oral quality of life in multivariate analyses. CONCLUSION. In this Norwegian adult sample, self-rated oral health, frequency of dental visits, number of teeth, age and sex were associated with having problems as estimated using the OHIP-14. PMID- 21247229 TI - Coccidioidomycosis: knowledge, attitudes, and practices among healthcare providers--Arizona, 2007. AB - Coccidioidomycosis presumably causes <= 33% of community-acquired pneumonias cases, although < 15% of the patients are tested for coccidioidomycosis. We assessed healthcare providers' knowledge, attitudes, and practices regarding coccidioidomycosis diagnosis and treatment in Arizona. A survey was mailed to 7,608 eligible healthcare providers licensed by the Arizona medical, osteopathic, and nursing boards in October and December 2007. We used weights to adjust for non-response and multivariate logistic regression models to identify predictors of >= 70% correct regarding knowledge and treatment practices. Of 1,823 (24%) respondents, 53% were physicians, 52% were male, and the mean age was 51 years. Approximately 50% reported confidence in their ability to treat coccidioidomycosis, and 21% correctly answered all four treatment questions. Predictors of >= 70% correct concerning knowledge and treatment practices included always counseling patients after diagnosis (adjusted odds ratio [AOR]=4.4; 95% confidence interval [CI]: 2.8-7.1); specializing in infectious diseases (AOR=2.4; 95% CI: 1.0-5.7); and having received coccidioidomycosis continuing medical education (CME) in the last year (AOR=1.8; 95% CI: 1.2-2.6). These findings demonstrate that coccidioidomycosis CME improves knowledge of disease diagnosis and management, underscoring the need for a comprehensive coccidioidomycosis education campaign for healthcare providers in Arizona. PMID- 21247230 TI - Labor epidural analgesia is independent risk factor for neonatal pyrexia. AB - OBJECTIVE: To explore whether epidural analgesia (EA) in labor is independent risk factor for neonatal pyrexia after controlling for intrapartum pyrexia. METHODS: Retrospective observational study of 480 consecutive term singleton infants born to mothers who received EA in labor (EA group) and 480 term infants delivered to mothers who did not receive EA (NEA group). RESULTS: Mothers in the EA group had significantly higher incidence of intrapartum pyrexia [54/480 (11%) vs. 4/480 (0.8%), OR = 15.1, p < 0.0001] and neonatal pyrexia [68/480 (14.2%) vs. 15/480 (3.1%), OR = 5.1, p < 0.0001]. Neonates in the EA group had a median duration of pyrexia of 1 h (maximum 5 h) with a peak temperature within 1 h. Stepwise logistic regression analysis showed that maternal EA was independent risk factor for neonatal pyrexia (>37.5 degrees C) after controlling for intrapartum pyrexia (>37.9 degrees C) and other confounders (OR = 3.44, CI = 1.9 6.3, p < 0.0001). Sepsis work-up was performed significantly more frequently in infants in the EA group [11.7% vs. 2.5%, OR= 5.2, CI = 2.7-9.7, p < 0.0001] with negative blood cultures. CONCLUSIONS: EA in labor is an independent risk factor for pyrexia in term neonates. It is unnecessary to investigate febrile offspring of mothers who have had epidurals unless pyrexia persists for longer than 5 h or other signs or risk factors for neonatal sepsis are present. PMID- 21247231 TI - Reduction of twin pregnancy to singleton: does it improve pregnancy outcome? AB - OBJECTIVE: To compare pregnancy complications, obstetrical and neonatal outcome of twin pregnancies reduced to singleton, with both non-reduced twin pregnancies and singleton pregnancies. METHODS: A retrospective case-control study was performed at the Obstetrics and Gynecology Ultrasound unit of a tertiary referral medical center. Patient's population included 32 bi-chorionic bi-amniotic twin pregnancies reduced to singleton and 35 non-reduced twin pregnancies. Thirty-six patients with singleton pregnancies comprised the second control group. Main outcome measures were rates of pregnancy complications, preterm delivery (both before 37 weeks of gestation and before 34 weeks of gestation), late abortions, intra-uterine growth retardation, cesarean section, mean birth weights, and mean gestational age at delivery. RESULTS: The reduced twin pregnancies group had similar rates of total pregnancy complications, preterm deliveries, and cesarean section as non-reduced twins. Gestational age at delivery and mean birth weight were also similar to non-reduced twins and significantly different compared with singletons. Preterm delivery and late abortion incidences were significantly higher when reduction was beyond 15 weeks gestation. CONCLUSIONS: Reduction of twin pregnancy to singleton does not change significantly pregnancy course and outcome. Favorable obstetrical and neonatal outcomes could be achieved by performing early, first trimester reductions. PMID- 21247232 TI - Isolated abnormal value during the 3-hour glucose tolerance test: which value is associated with macrosomia? AB - OBJECTIVE: The aim of this retrospective review was to evaluate obstetric outcomes in patients with an isolated abnormal value on the oral glucose tolerance test (OGTT) at 0, 1, 2, and 3 h. METHODS: From January 2003 through June 2009, all consecutive pregnant women who presented to Baskent University were screened for gestational diabetes mellitus (GDM). Patients with one abnormal value based on findings of the OGTT were grouped according to increased levels of glucose at 0, 1, 2, and 3 h (Group 1 > 95 mg/dl for fasting glucose concentration, Group 2 > 180 mg/dl for the serum glucose concentration in the first hour, Group 3 > 155 mg/dl for the serum glucose concentration in the second hour, Group 4 > 140 mg/dl for serum glucose concentration in the third hour). The four groups were compared for classic GDM risk factors. The primary outcome measures were large for gestational age (LGA) (birthweight > 95th percentile for gestational age using population birth weight centile charts) and macrosomia. RESULTS: The incidence of LGA baby (Group 1, 10%; Group 2, 3.8%; Group 3 20.3%; Group 4, 13.2%; p = 0.008) was significantly highest in Group 3 and macrosomia (Group 1, 30%; Group 2, 5.1%; Group 3, 18.6%; Group 4, 15.8%; p = 0.039) was significantly higher in Groups 1 and 3. CONCLUSIONS: Our results suggest that even with relatively mild degrees of glucose intolerance at 2 h, no treatment is associated with LGA babies. PMID- 21247233 TI - A noninvasive evaluation analysis of amniotic fluid embolism and disseminated intravascular coagulopathy. AB - OBJECTIVE: Amniotic fluid embolism (AFE) is a complication of pregnancy with a high mortality rate. The diagnosis of AFE is currently based on clinical findings, acute respiratory distress, cardiovascular collapse during labor and delivery, and immediate massive postpartum hemorrhaging. The serum biological markers are unreliable, and their detection requires a long time intervals for result. An early diagnosis is very important and prompts the clinical management of the condition. STUDY DESIGN AND RESULTS: We present here a noninvasive method (time frequency, entropy) to analyze heart rate variability (HRV). 3D-Spectrogram and entropy were derived from the RR interval of two pregnant subjects with AFE and disseminated intravascular coagulation (DIC) survived after delivering normal babies admitted to the Taiwan Seventh-day Adventists Hospital, and the entropy values were compared with those of 105 healthy pregnant subjects in the same hospital. CONCLUSIONS: We show that these methods can be successfully applied to the diagnosis of AFE and predict the prognosis of DIC. We also show that CT scans can be applied to the diagnosis of pulmonary embolism, eliminating the need to pathology. PMID- 21247234 TI - The evaluation of polycythemic newborns: efficacy of partial exchange transfusion. AB - OBJECTIVES: To evaluate the clinical characteristics and risk factors of symptomatic and asymptomatic polycythemic neonates performed partial exchange transfusion (PET) and to determine the time of resolution of symptoms and effect of PET on short-term morbidity. METHODS: This prospective cohort study was conducted with symptomatic (hematocrit; Hct>65% plus a clinical symptom) and asymptomatic (Hct level>70% without any symptoms) neonates who underwent PET due to polycythemia. RESULTS: Among the patients performed PET, 43 (69.3%) were symptomatic and 19 (30.7%) asymptomatic. Persistent pulmonary hypertension and minor problems like hypoglycemia, hypocalcemia, hyperbilirubinemia, and thrombocytopenia improved in all patients within 24 h, 2.5 +/- 1.0, 3.1 +/- 1.4, 56.2 +/- 16.9, and 53.5 +/- 10.5 h, respectively, after PET (in except one symptomatic neonate with hypoglycemia). In symptomatic group, in three patients with suspected necrotizing enterocolitis (NEC) prior to PET stage IIa NEC developed. No other clinical and ultrasonographic findings were observed after PET. CONCLUSIONS: Early morbidities, due to polycythemia may be reversed with PET within a short time. PET did not increase or cause any complications except NEC. The issue that either NEC was a sign of polycythemia or a complication of PET could not be definitely outlined. PMID- 21247235 TI - The effects of the mode of delivery on oxidative-antioxidative balance. AB - OBJECTIVE: The purpose of this study was to investigate the effects of the mode of delivery on the oxidant and antioxidant systems in mothers and infants and to demonstrate which mode leads more oxidative stress. METHODS: The participants were divided into two groups according to the mode of their labour and delivery: group 1 (n = 33) women with normal labour and delivery and group 2 (n = 33) with scheduled caesarean section (C/S) and delivery. The maternal, cord, and infant blood samples in both groups were collected. The serum total antioxidant capacity (TAC) and the total oxidant status (TOS) were evaluated by using an automated colorimetric measurement method. RESULTS: The parameters indicating oxidative stress (TOS, oxidative stress index, and lipid hydroperoxide) in maternal, cord, and newborn blood samples were higher in patients delivering with C/S than those normal spontaneous vaginal deliveries (NSVD) patient group, while it was vice versa for TAC. CONCLUSIONS: It may be concluded that both the mothers and neonates in C/S group are exposed to higher oxidative stress as compared with those in NSVD group and the antioxidant mechanisms are insufficient to cope with this stress during C/S. This result indicates that the normal delivery through the physiological route is healthier for the bodies of mothers and infants. PMID- 21247236 TI - Antepartum and postpartum maternal plasma levels of E-selectin and VE-cadherin in preeclampsia, gestational proteinuria and gestational hypertension. AB - OBJECTIVE: To investigate the alterations of maternal antepartum and postpartum plasma levels of sE-selectin and VE-cadherin in normotensive pregnant women, women with preeclampsia (PE), gestational hypertension (GH), and gestational proteinuria (GP). METHODS: A total of 37 pregnant women were included in the present study; 12 with PE, 10 with GH, 5 with GP, and 10 controls. sE-selectin and VE-cadherin levels were assessed in maternal plasma at three periods; before delivery, 3-6 days after delivery, and 12-14 weeks postpartum. RESULTS: Women with severe preeclampsia (SPE) and GP had significantly higher plasma sE-selectin levels as compared to controls in all three periods of sampling. In the GH group, sE-selectin levels did not differ from controls. During the study, even after 12 weeks postpartum, the plasma sE-selectin levels remained unchanged in all preeclamptic groups (PE, GH, and GP). There was no difference in VE-cadherin levels between women with preeclampsia (PE, GH, and GP) and normal pregnancies. CONCLUSIONS: We found no changes in VE-cadherin levels in preeclamptic groups. Increased antepartum and postpartum levels of sE-selectin in women with SPE and GP suggest that endothelial dysfunction may be one of the key processes in the pathogenesis of PE and the underlying mechanism, as well, that links PE with cardiovascular disease in later life. GP, also, appears to be a mild variant of PE. PMID- 21247237 TI - The combination of short cervical length and phIGFBP-1 in the prediction of preterm delivery in symptomatic women. AB - OBJECTIVE: To assess the combined use of cervical length and cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) in the prediction of preterm delivery in symptomatic women. METHODS: Cervical length was prospectively measured in 102 consecutive singleton pregnancies with intact membranes and regular contractions at 24-32 weeks, and phIGFBP-1 was assessed in those with a cervix <=30 mm. RESULTS: Among women with a cervix >30 mm (n = 42), none delivered <34 weeks or within 7 days. Among women with a cervical length <=30 mm (n = 60), eight delivered <34 weeks, four of which within 7 days. A positive phIGFBP-1 conferred a significantly increased risk of delivery before 34 weeks in women with a cervix <=30 mm (likelihood ratio 2.32, 95% confidence interval 1.15-4.67), and a significantly increased risk of delivering within 7 days in the subgroup of women with a cervical length of 20-30 mm (likelihood ratio 3.64, 95% confidence interval 2.20-6.01). CONCLUSIONS: In symptomatic women with a cervical length >30 mm the risk of preterm delivery is very low. In women with a cervix <=30 mm, adding phIGFBP-1 assessment may improve the risk assessment for preterm delivery, and help to plan subsequent pregnancy management. PMID- 21247238 TI - First trimester 3D volumetry. Association of the gestational volumes with the birth weight. AB - OBJECTIVE: To evaluate the three dimensional ultrasound (3D) in the volume assessment of the gestational contents during the 1st trimester of pregnancy. Our aim was to correlate the embryo, gestational sac, and placenta volume with the birth weight. To monitor the increase of these volumes according to the gestational age. METHOD: Prospective study of 199 singleton low risk pregnant women undergoing the 1st trimester ultrasound for fetal anomalies. In these women, gestational volumetry was performed and it was compared with the crown rump length (CRL). Regression models were computed in order to analyze the dependence of birth weight with the volumes. RESULTS: The embryo volume reveals the strongest association with the birth weight at delivery (beta = 0.24), followed by the CRL (beta = 0.20) and the gestational sac volume (beta = 0.20). The placenta volume appears the weakest association with fetal weight at delivery (beta = 0.16). All volumes increased significantly from 11(+0)-11(+6) to 13(+0) 13(+6) weeks of gestation (p < 0.001). Ten cubic millimeter increase in embryo volume corresponds to a mean birth weight increase of 75 g, while 1 mm increase in the CRL corresponds to a birth weight increase of 113 g. CONCLUSION: Our results provide evidence that the embryo volume during the first trimester of pregnancy correlates better with birth weight than the CRL. This might assist in the identification of the high risk pregnancies caring macrosomic and low birth weight fetuses. PMID- 21247239 TI - Can metformin reduce the incidence of gestational diabetes mellitus in pregnant women with polycystic ovary syndrome? Prospective cohort study. AB - BACKGROUND: Women with polycystic ovary syndrome (PCOS) are at a high risk to develop Gestational Diabetes mellitus (GDM). We hypothesized that metformin due to its metabolic, endocrine, vascular, and anti-inflammatory effects may reduce the incidence of GDM in PCOS women. PATIENT AND METHOD: We carried out a prospective cohort study to determine the beneficial effects of metformin on PCOS patients during pregnancy. Three-hundred and sixty non-diabetic PCOS patients were included who were conceived on metformin by different treatment modalities. Two-hundred pregnant women continued on metformin at a dose of 1000-2000 mg daily throughout pregnancy (study group) and 160 women discontinued metformin use at the time of conception (control group). RESULTS: There is a statistically significant reduction in the incidence of GDM in favor of metformin group (OR: 0.17, 95% CI: 0.07-0.37). There is a statistically significant reduction in the incidence of pre-eclampsia in favor of metformin group (OR: 0.35, 95% CI: 0.13 0.94). CONCLUSION: Metformin is a promising medication for the prevention or reduction of the incidence of GDM and pre-eclampsia in PCOS women. PMID- 21247240 TI - Aneuploidy studies in human cells exposed in vitro to GSM-900 MHz radiofrequency radiation using FISH. AB - PURPOSE: Since previous research found an increase in the rate of aneuploidies in human lymphocytes exposed to radiofrequencies, it seems important to perform further studies. The objective of this study was then to investigate whether the exposure to RF (radiofrequency) radiation similar to that emitted by mobile phones of a second generation standard, i.e., Global System for Mobile communication (GSM) may induce aneuploidy in cultured human cells. MATERIALS AND METHODS: The potential induction of genomic instability by GSM-900 MHz radiofrequency (GSM-900) was investigated after in vitro exposure of human amniotic cells for 24 h to average-specific absorption rates (SAR) of 0.25, 1, 2 and 4 W/kg in the temperature range of 36.3-39.7 degrees C. The exposures were carried out in a wire-patch cell (WPC). The rate of aneuploidy of chromosomes 11 and 17 was determined by interphase FISH (Fluorescence In Situ Hybridisation) immediately after independent exposure of three different donors for 24 h. At least 100 interphase cells were analysed per assay. RESULTS: No significant change in the rate of aneuploidy of chromosomes 11 and 17 was found following exposure to GSM-900 for 24 h at average SAR up to 4 W/kg. CONCLUSION: Our study did not show any in vitro aneuploidogenic effect of GSM using FISH and is not in agreement with the results of previous research. PMID- 21247241 TI - Bloodless management of benign prostatic hyperplasia: medical and minimally invasive treatment options. AB - Benign prostatic hyperplasia (BPH) is a medical condition affecting a wide range of the aging male population resulting in various degrees of lower urinary tract symptoms (LUTS). Today, a variety of medical therapies and minimally invasive BPH treatment modalities are available. Medical therapy includes alpha(1) blockers, 5()alpha reductase inhibitors and combination therapy. When these options fail, surgery is indicated. Transurethral resection of the prostate (TURP) is still considered the gold standard surgical treatment for BPH. Nevertheless, numerous minimally invasive treatment alternatives are available that are comparable in effectiveness to TURP, with significantly less morbidity. In this article, current treatment options for BPH are reviewed with respect to their indications, long-term safety and efficacy in relieving BPH related LUTS. The selection of the type of BPH treatment should be based on the physician's experience, patient's co morbidities as well as the prostate size and clinical disease progression. PMID- 21247242 TI - Significant association between serum dihydrotestosterone level and prostate volume among Taiwanese men aged 40-79 years. AB - INTRODUCTION: We evaluated the association between serum sex hormone levels and prostate volume in Taiwanese men. METHODS: A cross-sectional study was conducted in 505 men (aged 40-79 years, mean age 58 years). Serum total testosterone (TT), free testosterone (FT), dihydrotestosterone (DHT) and estradiol (E2) levels were measured. Total prostate volume (TPV) and transition zone volume (TZV) were measured by transrectal ultrasonography. Body mass index (BMI), DHT/TT and E2/TT were calculated. Correlations were determined using univariate and multivariate regression analyses. RESULTS: Apart from DHT, an age-dependent change of sex hormone levels were observed. On univariate analyses, age, BMI, serum DHT level and DHT/TT ratio, as well as serum E2 level and E2/TT ratio, but not serum TT and FT levels showed a significant association with prostate volume. On multivariate analysis, however, only serum DHT level and DHT/TT ratio remained significant. Logistic regression analysis showed that the odds ratios (95% confidence interval) of the second, third, and fourth quartiles of serum DHT levels for benign prostatic hyperplasia (defined as TPV >= 20 ml) risk were 2.06 (1.21 3.51), 2.66(1.56-4.53) and 7.15(4.0-12.6), respectively (p < 0.001). CONCLUSIONS: Higher serum DHT level and DHT/TT ratio were associated with larger prostate volume and higher prevalence of BPH in Taiwanese men. PMID- 21247243 TI - Pleural findings in a patient with persistent pulmonary effusions from systemic amyloidosis. AB - Persistent pleural effusions (PPE) occur in 1-2% of cases of systemic amyloidosis and have been postulated to result from direct disruption of the pleura by amyloid deposits. Patients are typically treated with percutaneous pleural drainage techniques. Pleural biopsies, done most commonly via percutaneous techniques, are infrequently obtained. The macroscopic and histologic pleural findings identified via video assisted thoracoscopic surgery (VATS) for these patients are lacking in the literature. In this case, we present the macroscopic and microscopic pleural findings in a patient who had VATS for the aetiologic diagnosis of PPE. The diagnosis of systemic amyloidosis was made from histologic analysis of the pleural biopsy. PMID- 21247244 TI - Intestinal pseudo-obstruction associated with amyloidosis. AB - Intestinal pseudo-obstruction is a condition characterised by clinical manifestations of mechanical obstruction of the intestine in the absence of any organic occlusion of the lumen. This syndrome has rarely been reported to complicate the course of systemic amyloidosis. We describe the case of a 64-year old man who presented with the syndrome of small bowel pseudo-obstruction secondary to AL amyloid infiltration of the gastrointestinal tract. We comment on the pathophysiology and on the clinical importance of amyloidosis-associated intestinal pseudo-obstruction. PMID- 21247246 TI - High amplitude direct compressive strain enhances mechanical properties of scaffold-free tissue-engineered cartilage. AB - Adult cartilage has a limited healing capacity. Damages resulting from disease or injury increase over time and cause severe pain. One approach to reinstate the cartilage function is tissue engineering (TE). However, the generation of TE cartilage is time consuming and expensive and its properties are so far suboptimal. As in vivo cartilage is subject to loading, it is assumed that mechanical stimulation may enhance the quality of TE cartilage. In this study the short-term influence of variable compressive strain amplitudes on mechanical and biochemical properties of scaffold-free TE cartilage was investigated. Primary porcine chondrocytes were isolated, proliferated, redifferentiated, and transferred onto hydroxyapatite carriers, resulting in scaffold-free cartilage carrier constructs. These constructs were placed in a custom-made bioreactor. Compression amplitudes of 5%, 10%, and 20% were applied. In each experiment four constructs were loaded with dynamic compression (3000 cycles/day, 1 Hz) for 14 days and four constructs served as unloaded control. The cartilage was evaluated biochemically, histological, and mechanically. No difference in glycosaminoglycan or collagen content between the loaded and the control groups was found. However, a positive correlation between compression amplitude and normalized Young's modulus was detected (R(2)=0.59, p<0.001). The highest compression amplitude of 20% had the strongest positive effect on the mechanical properties of the TE cartilage (Young's modulus increase of 241+/-28% compared to unloaded control). The data presented suggest that preconditioning with higher load amplitudes might be an attractive way of generating stiffer tissue and may help accelerating the cultivation of mechanically competent TE cartilage. PMID- 21247245 TI - Early life nutrition modulates muscle stem cell number: implications for muscle mass and repair. AB - Suboptimal nutrition during prenatal and early postnatal development is associated with increased risk for type 2 diabetes during adult life. A hallmark of such diabetes risk is altered body composition, including reduced lean mass and increased adiposity. Since stem cell number and activity are important determinants of muscle mass, modulation of perinatal nutrition could alter stem cell number/function, potentially mediating developmentally programmed reductions in muscle mass. Skeletal muscle precursors (SMP) were purified from muscle of mice subjected to prenatal undernutrition and/or early postnatal high-fat diet (HFD)--experimental models that are both associated with obesity and diabetes risk. SMP number was determined by flow cytometry, proliferative capacity measured in vitro, and regenerative capacity of these cells determined in vivo after muscle freeze injury. Prenatally undernutrition (UN) mice showed significantly reduced SMP frequencies [Control (C) 4.8% +/- 0.3% (% live cells) vs. UN 3.2% +/- 0.4%, P=0.015] at 6 weeks; proliferative capacity was unaltered. Reduced SMP in UN was associated with 32% decrease in regeneration after injury (C 16% +/- 3% of injured area vs. UN 11% +/- 2%; P<0.0001). SMP frequency was also reduced in HFD-fed mice (chow 6.4% +/- 0.6% vs. HFD 4.7% +/- 0.4%, P=0.03), and associated with 44% decreased regeneration (chow 16% +/- 2.7% vs. HFD 9% +/- 2.2%; P<0.0001). Prenatal undernutrition was additive with postnatal HFD. Thus, both prenatal undernutrition and postnatal overnutrition reduce myogenic stem cell frequency and function, indicating that developmentally established differences in muscle-resident stem cell populations may provoke reductions in muscle mass and repair and contribute to diabetes risk. PMID- 21247247 TI - Effects of candesartan versus amlodipine on home-measured blood pressure, QT dispersion and left ventricular hypertrophy in high-risk hypertensive patients. AB - The GIFU substudy of the Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial was conducted to compare the long-term effects of candesartan and amlodipine on office- and home-measured blood pressure (BP), QTc dispersion and left ventricular mass index (LVMI) in high-risk Japanese patients with hypertension. We used a prospective, randomized, open-label design with blinded assessment of endpoints. Patients were assigned to candesartan-based therapy up to 12 mg/day (n = 100) or amlodipine-based therapy up to 10 mg/day (n = 101) and followed for 3 years. LVMI was assessed by echocardiography and QTc dispersion was obtained from electrocardiograms. Both candesartan and amlodipine lowered and controlled office- and home-measured BP levels with no significant between-treatment differences. In patients diagnosed with left ventricular hypertrophy (LVH) at baseline, both candesartan and amlodipine significantly regressed LVMI after 3 years. However, candesartan (41.7 +/- 15.1 ms at baseline vs 32.9 +/- 16.6 ms after 3 years, p < 0.01), but not amlodipine (41.4 +/- 13.5 ms at baseline vs 41.5 +/- 16.1 ms after 3 years), produced a significant reduction in QTc dispersion. Larger studies in patients treated for longer periods are needed to determine whether this candesartan effect will translate into improved prognosis in terms of cardiovascular mortality and morbidity. PMID- 21247248 TI - The use of chromatin insulators to improve the expression and safety of integrating gene transfer vectors. AB - The therapeutic application of recombinant retroviruses and other integrating gene transfer vectors has been limited by problems of vector expression and vector-mediated genotoxicity. These problems arise in large part from the interactions between vector sequences and the genomic environment surrounding sites of integration. Strides have been made in overcoming both of these problems through the modification of deleterious vector sequences, the inclusion of better enhancers and promoters, and the use of alternative virus systems. However, these modifications often add other restrictions on vector design, which in turn can further limit therapeutic applications. As an alternative, several groups have been investigating a class of DNA regulatory elements known as chromatin insulators. These elements provide a means of blocking the interaction between an integrating vector and the target cell genome in a manner that is independent of the vector transgene, regulatory elements, or virus of origin. This review outlines the background, rationale, and evidence for using chromatin insulators to improve the expression and safety of gene transfer vectors. Also reviewed are topological factors that constrain the use of insulators in integrating gene transfer vectors, alternative sources of insulators, and the role of chromatin insulators as one of several components for optimal vector design. PMID- 21247249 TI - Endovascular treatment for a thoracic-abdominal aortic aneurysm without fenestrations or branches. AB - We describe a case of a patient with a thoraco-abdominal aortic aneurysm, affecting the origin of the celiac trunk, with the particularity of the normal aortic diameter in the segment between superior mesenteric artery and both renal arteries. Endovascular treatment was performed with no fenestrated or branch endoprosthesis. The procedure was divided into two steps. In the first attempt, an aortic prosthesis was deployed at the infrarenal aorta. Then, a thoracic endoprosthesis was deployed in a second procedure. In this case, the celiac trunk was intentionally occluded in order to increase the distal landing zone. At the end, the segment between the superior mesenteric artery above and below the renal arteries was covered by the uncovered struts of both endoprosthesis, with no effects in visceral artery flow. Multislice computed tomographic angiography after six months revealed complete patency of the superior mesenteric artery, both renal arteries and good back-filling of the branches of the celiac axis, with no evidence of aortic endoleak. PMID- 21247250 TI - Post-laparoscopic mesh in post-menopausal umbilical hernia repair: a case series. AB - We evaluated the efficacy and safety of the use of a composite PTFE/polypropylene patch, Ventralex (Davol Inc., C.R. Bard, Inc., RI, USA), to repair, concurrent with laparoscopy, umbilical hernia in 51 postmenopausal women. After laparoscopy, patients were submitted to the hernia repair by a patch intraperitoneally placed behind the hernia. Primary outcomes included complication rates, while hernia recurrence was the secondary outcome. Patient age range was 58 +/- 4.3 years, the size of patches was small in 17.6% of women, medium in 68.7% and large in 13.7%. Seventy-six percent of patients had an ASA I-II score, the mean operating time for hernia repair was 7 +/- 2 minutes with 15 cc of related blood loss, with 1.8 days of hospital stay. The visual analogue scale was 0-3 for 62.7%, 4-6 for 27.5% and 7-10 for 9.8% of women. All laparoscopic and umbilical hernia repair terminated without any further intra or postoperative complications, with 36 months of follow-up; none of the patients showed recurrences. Combining laparoscopy and intraperitoneal mesh repair appears to be indicated for umbilical hernia treatment in post-menopausal patients undergoing laparoscopy, resulting in a safe and easy procedure, with short hospital stay and fast dismissal, with no major morbidity or recurrence. PMID- 21247251 TI - Laparoscopic video analysis for training and image-guided surgery. AB - Automatic analysis of Minimally Invasive Surgical video has the potential to drive new solutions for alleviating needs of safe and reproducible training programs, objective and transparent evaluation systems and navigation tools to assist surgeons and improve patient safety. Surgical video is an always available source of information, which can be used without any additional intrusive hardware in the operating room. This paper is focused on surgical video analysis methods and techniques. It describes authors' contributions in two key aspects, the 3D reconstruction of the surgical field and the segmentation and tracking of tools and organs based on laparoscopic video images. Results are given to illustrate the potential of this field of research, like the calculi of the 3D position and orientation of a tool from its 2D image, or the translation of a preoperative resection plan into a hepatectomy surgical procedure using the shading information of the image. Research efforts are required to further develop these technologies in order to harness all the valuable information available in any video-based surgery. PMID- 21247252 TI - Endovascular therapy as a treatment for ruptured pancreaticoduodenal artery aneurysms. AB - Pancreaticoduodenal artery aneurysms (PDAAs) are uncommon. The treatment and prognosis for ruptured PDAAs have changed in recent years. A demonstrative case is reported. A review of the literature has been made and the case of a healthy man operated on an emergency basis because of a massive hemoperitoneum secondary to a ruptured PDAA is reported and analyzed with regard to the clinical presentation, radiologic findings, management, and outcome. A bleeding point was not detected at operation. An intraoperative arteriogram did not show active bleeding. The pancreas appeared infiltrated and oozing blood. The abdomen was gauze packed and the patient transferred for endovascular therapy (ET). Then, an arteriogram showed a bleeding PDAA. After embolization, bleeding ceased and the patient recovered. According to our literature survey, less than 200 cases of true and false PDAAs have been reported. For ruptured PDAAs, surgery is associated with high mortality since the bleeding point is usually not identified at operation. Similarly, intraoperative arteriograms are often fruitless due to the patient's poor hemodynamics plus suboptimal quality of the portable equipment. As shown in the present case and according to the specialized medical literature, ET has often been successful in the management of these patients and may be chosen as a first option for the treatment of ruptured PDAAs. PMID- 21247253 TI - Laparoscopic myomectomy in patients with uterine myomas associated with infertility. AB - Although myomectomy is widely accepted in women of childbearing age who wish to retain their fertility, the extent to which myomas affect fertility and whether their removal improves this remain unclear. This study aimed to elucidate the favourable surgical approach in women with uterine myomas and infertility. This retrospective, follow-up study was carried out in three centres in Germany. Data on women who had undergone myomectomy via laparoscopy, laparotomy or conversion to laparotomy in 2000-04 were collected and analysed. Fertility outcome after myomectomy was assessed by follow-up postal questionnaire in a subgroup of women with myoma-associated infertility. Data on 159 women with otherwise unexplained infertility were included (mean age 35 years (range 17-47), mean number of myomas 2.4 (range 1-8) and mean myoma size 6.1 cm (range 0.5-20)). Women who underwent laparoscopy had fewer complications. 39.6% (63/159) of women completed the questionnaire, which showed that the pregnancy rate after myomectomy was 46% in this group. No uterine rupture occurred. Laparoscopy is associated with fewer postoperative complications and since no preoperative or intraoperative factors seem to influence the fertility outcome in women with uterine myomas, it is the treatment of choice in these patients. PMID- 21247254 TI - A new instrument: a flexible hysteroscope with narrow band imaging system: optical quality comparison between a flexible and a rigid hysteroscope. AB - There are two different types of hysterocopes available: Flexible and rigid. Flexible scopes have the ability to observe the whole intrauterine cavity, but it is difficult to perform an operation on endometrial lesions. Rigid hysteroscopes provide superior optical qualities due to higher pixel count. We report the use of a new flexible hysteroscope with narrow band imaging (NBI) system (HYF-V EndoEYE Flexible Video Hysteroscope) and compared the optical qualities of this flexible to those of a rigid hysteroscope using the vascular analysis software "SolemioENDO ProStudy". Twenty-four images of endometrium in eight cases, and 12 images of submucous myoma in six cases were each photographed by two the hysteroscopes. The vascular densities of both endometrium and myoma under conventional light in the flexible scope were significantly higher than with the rigid scope. However the vascular densities under narrow-band light in the two scopes were not significantly different. The vascular densities of the images taken by flexible scope were higher than the images taken by rigid scopes under conventional light. With the rigid scope, microvascular structure may be crumpled by high water pressure. A flexible hysteroscope with NBI system has superior ability to observe the intrauterine cavity and measure vascular density compared to a rigid scope. PMID- 21247255 TI - Dopaminergic system genes in childhood aggression: possible role for DRD2. AB - Excessive or deficient levels of extracellular dopamine have been hypothesized to contribute to a broad spectrum of mood, motor, and thought abnormalities, and dopaminergic system genes have been implicated in aggressive behaviour from animal and human studies. OBJECTIVE. We examined selected members of the dopaminergic system genes for association with child aggression. METHOD: We analyzed polymorphisms in the dopamine transporter DAT1/SLC6A3, dopamine receptor DRD2, and DRD4 genes in our sample of pervasive childhood aggression consisting of 144 cases paired with 144 healthy controls, matched for sex and ethnicity. RESULTS: Aggressive children were significantly more likely to have the at least one copy of the G allele for the DRD2 A-241G polymorphism (genotypic P=0.02; allelic P=0.01). The DRD2 rs1079598 CC genotype was overrepresented in aggressive children compared to controls (genotype P=0.04). The DRD2 TaqIA T allele (P=0.01) and the TT genotype (P=0.01) were also significantly overrepresented in aggressive children. CONCLUSIONS: Our preliminary results suggest that three polymorphisms in DRD2 are associated with childhood aggression. Future studies are required to replicate the current results and to further explore the relationship between the dopamine system and aggressive behaviour in children. PMID- 21247256 TI - Reduced negative BOLD responses in the default-mode network and increased self focus in depression. AB - OBJECTIVES: Functional imaging studies in major depressive disorder (MDD) indicate abnormal resting state neural activity and negative blood oxygenation level-dependent (BOLD) responses (NBRs) in regions of the default-mode network (DMN). METHODS: Since activity in DMN regions has been associated with self relatedness, we investigated neural activity in these regions during self-related emotional judgement and passive picture viewing in 25 patients with MDD and 25 healthy controls in an event-related fMRI design. RESULTS: Behaviourally, MDD subjects showed significantly higher ratings of self-relatedness that also correlated with depression symptoms such as hopelessness. Neuroimaging results in MDD patients showed significantly lower negative BOLD responses (NBRs) in anterior medial cortical regions during judgement of self-relatedness while posterior medial regions showed increased NBRs. Unlike in healthy subjects, the anterior medial cortical NBRs were no longer parametrically modulated by the degree of self-relatedness in MDD patients. CONCLUSIONS: Our findings suggest that reduced NBRs in the anterior regions of the default-mode network may signify decoupling from self-relatedness in MDD patients with the consecutive abnormal increase of self-focus. PMID- 21247257 TI - Serum brain-derived neurotrophic factor: determinants and relationship with depressive symptoms in a community population of middle-aged and elderly people. AB - OBJECTIVES: Brain-derived neurotrophic factor (BDNF) is involved in major depressive disorder and neurodegenerative diseases. Clinical studies, showing decreased serum BDNF levels, are difficult to interpret due to limited knowledge of potential confounders and mixed results for age and sex effects. We explored potential determinants of serum BDNF levels in a community sample of 1230 subjects. METHODS: Multiple linear regression analyses with serum BDNF level as the dependent variable were conducted to explore the effect of four categories of potential BDNF determinants (sampling characteristics, sociodemographic variables, lifestyle factors and somatic diseases) and of self-reported depressive symptoms (Beck's Depression Inventory (BDI). RESULTS: Our results show that BDNF levels decline with age in women, whereas in men levels remain stable. Moreover, after controlling for age and gender, the assays still showed lower serum BDNF levels with higher BDI sum scores. Effects remained significant after correction for two main confounders (time of sampling and smoking), suggesting that they serve as molecular trait factors independent of lifestyle factors. CONCLUSIONS: Given the age-sex interaction on serum BDNF levels and the known association between BDNF and gonadal hormones, research is warranted to delineate the effects of the latter interaction on the risk of psychiatric and neurodegenerative diseases. PMID- 21247259 TI - Unstable EEG-vigilance in patients with cancer-related fatigue (CRF) in comparison to healthy controls. AB - OBJECTIVES: Cancer-related fatigue (CRF) is associated with tiredness and sleepiness. It remains unclear, whether such complaints are associated with neurophysiological signs of sleep proneness or a state of neurophysiological hyperarousal in which the patient finds it difficult to relax and to initiate sleep. Therefore the goal of this study is to compare the electroencephalographic (EEG)-vigilance regulation of patients with CRF and healthy controls. METHODS: A 15-min resting EEG with eyes closed was recorded in 22 patients with CRF and 22 matched healthy controls. Consecutive 1-s segments were classified into seven different vigilance stages ranging from high alertness to relaxed wakefulness (stage 0, A1, A2, A3) and further on to drowsiness (B1, B2/3) and sleep onset (stage C). RESULTS: Results showed that patients with CRF revealed a higher number of vigilance stages A3 (mean 15.26 vs. 6.67%, P = 0.004) dropped significantly earlier to vigilance levels A3 (drop after 130.8 vs. 533.3 s, P = 0.000) and B2/3&C (407.8 vs. 604.1 s, P = 0.035) and showed significantly more transitions between vigilance stages (46.0 vs. 31.1%, P = 0.003) in comparison to healthy controls. CONCLUSIONS: These findings suggest an unstable vigilance regulation in patients with CRF and provide a neurophysiological framework for the reported efficacy of psychostimulants in CRF. PMID- 21247258 TI - Common SNPs in CSF2RB are associated with major depression and schizophrenia in the Chinese Han population. AB - OBJECTIVES: Colony stimulating factor 2 receptor beta (CSF2RB) encodes the protein which is the common beta chain of the high affinity receptor for IL-3, IL 5 and CSF. It locates in the linkage region 22q12.3 of both bipolar disorder and schizophrenia, and is expressed in most cells. METHODS: We carried out a large scale case-control study to test the association between CSF2RB and three major mental disorders in the Chinese Han population. Seven single nucleotide polymorphisms were genotyped in 1140 bipolar affective disorder patients (including 645 type I bipolar affective disorder patients), 1140 schizophrenia patients, 1139 major depressive disorder patients and 1140 healthy controls. RESULTS: Three SNPs were found to be associated with both schizophrenia and major depressive disorder. Haplotype association analysis revealed one protective haplotype (P value = 0.014 for SCZ and 0.0004 for MDD) and one risk haplotype (P value = 0.006 for SCZ and 0.001 for MDD). Additional 52 SNPs were analyzed for population stratification, which demonstrated that our positive results were not caused by population stratification. CONCLUSIONS: Our results support CSF2RB as a risk factor common to both schizophrenia and major depression in the Chinese Han population. PMID- 21247260 TI - Effects of nanofiber/stem cell composite on wound healing in acute full-thickness skin wounds. AB - Acute full-thickness skin wounds (FTSW) caused by extensive burns or high-energy trauma are not adequately addressed by current clinical treatments. This study hypothesized that biomimetic nanofiber scaffolds (NFSs) functionalized with rich attachment of bone-marrow-derived mesenchymal stem cells (BM-MSCs) can promote wound healing in acute FTSW. Results in a rat model showed that both NFS and BM MSCs contributed to the wound healing. Wounds in NFS group with a higher density of BM-MSCs achieved complete closure 8 days earlier than the control group. Implanted BM-MSCs were found to promote epithelial edge ingrowth and collagen synthesis. The colocation of BM-MSCs (tagged with quantum-dots) with the expression of keratin 10 and filaggrin indicated the participation of BM-MSCs in epidermal differentiation at early and intermediate stages under the local wounding environment. Overall, this study suggests a great potential of using NFS/BM-MSC composites for the treatment of acute FTSW. PMID- 21247261 TI - Adaptation of the Psoriatic Arthritis Quality of Life (PsAQol) instrument for Sweden: comments on the article by Billing et al. PMID- 21247262 TI - Is there a common SUV threshold in oncological FDG PET/CT, at least for some common indications? A retrospective study. AB - PURPOSE: We retrospectively compared the maximum standard uptake value (SUVmax) of FDG PET in four different sites to evaluate whether a common diagnostic SUVmax threshold may exist in these tumor locations. We further postulate that the SUVmax thresholds are higher in thoracic lesions than in extrathoracic lesions. MATERIAL AND METHODS: N = 143 patients in four subgroups underwent a FDG PET/CT: a) 42 patients for solitary pulmonary nodules (SPNs) characterization with b) respective mediastinal lymph nodes (LNs), c) 65 patients for LN staging of head and neck cancer, and d) 36 cancer patients diagnosed with adrenal lesions. Receiver operating characteristics of SUVmax values were evaluated. RESULTS: The SUVmax were statistically significantly greater in malignant than in benign lesions. For SPNs and mediastinal LNs, a SUVmax > 3.6 each resulted in a sensitivity of 81% and 87%, and a specificity of 94% and 89%. For cervical LNs and adrenal glands, a SUVmax > 2.2 each showed a sensitivity of 98% and 100%, and a specificity of 83% and 93%. CONCLUSION: A common SUVmax threshold did not exist in the four studied subgroups. The variable FDG uptake in SPNs and mediastinal LNs are associated with the high prevalence of inflammation/infection within the chest. Similar SUVmax thresholds however may exist for extrathoracic regions where the prevalence of inflammation/infection is low. PMID- 21247263 TI - The therapeutic potential of SA-sCD40L in the orthotopic model of superficial bladder cancer. AB - BACKGROUND: Intravesical administration is an important treatment against superficial bladder cancer and CD40L is essential for the protective anti-tumor immunity. In situ gene therapy with CD40L was demonstrated to successfully inhibit tumor cell growth in the orthotopic mouse model of bladder cancer. In the present study, we prepared streptavidin (SA)-tagged sCD40L and developed a novel immunotherapy for superficial bladder cancer based on the strong interaction between streptavidin and biotin. MATERIAL AND METHODS: The SA-sCD40L fusion protein was expressed in E. coli and purified on the Ni-NTA column. After refolding with dialysis, the bi-function of the fusion protein was determined by flow cytometric analysis for streptaidin-mediated surface modification of MB49 bladder cancer cells and a mouse B cell CD40L-dependent proliferation assay. The mouse orthotopic model of MB49 superficial bladder cancer was used to evaluate the efficacy of SA-sCD40L immunotherapy. RESULTS: The SA-sCD40L fusion protein exhibited both full biotin-binding property and CD40L bioactivity. After intravesical instillation, the SA-sCD40L bi-functional fusion protein was durably immobilized on the biotinylated mucosal surface of bladder wall for up to four days. The SA-sCD40L treatment significantly prolonged the survival of MB49 tumor bearing mice and cured 50% of mice with MB49 superficial bladder cancer without significant adverse effects. In addition, more tumor-infiltrating CD4(+)or CD8(+) T cells were observed in SA-sCD40L-treated group. CONCLUSION: Intravesical immobilization of SA-sCD40L elicited a strong and long-lasting immunity against the MB49 bladder cancer. PMID- 21247264 TI - Patterns of relapse following surgery and postoperative intensity modulated radiotherapy for oral and oropharyngeal cancer. AB - BACKGROUND: To investigate the patterns of relapse following intensity modulated radiotherapy (IMRT) given after radical surgery for oral and oropharyngeal squamous cell cancer. PATIENTS AND METHODS: One hundred and two patients with oral or oropharyngeal cancer were treated with radical surgery followed by IMRT up to a mean total dose of 60 Gy between years 2001 and 2007. Thirty-nine of the patients (%) also received concomitant weekly cisplatin. Forty of the patients had oral and 62 had oropharyngeal cancer. Data on the tumour, patient and treatment factors were collected. Following therapy the patients were followed by clinical examination, endoscopy and MRI/CT at 2- to 3-months interval up to 2 years and thereafter at 6-month intervals. RESULTS: The mean follow-up time of the patients was 55 months (range, 26-106 months). The rate for local tumour control for the whole cohort was 92.2%: 87.5% for oral cancer patients and 96.7% for oropharyngeal cancer patients. The 5-year disease specific survival was 90.2% and 5-year overall survival 84.3%. During the follow-up eight locoregional recurrences were observed, three at the primary tumour site and one at regional nodal site and four at both sites. The mean time to primary tumour recurrence was seven months (range, 2-10 months) and to nodal recurrence seven months (range, 2 12 months). Distant metastasis occurred in six (6%) patients. The factors associated with poor prognosis were the primary tumour size and tumour site with oral cancers having worse outcome. The treatment was well tolerated with no unexpected toxicities. The most frequent late toxicity was dysphagia necessitating permanent PEG in five patients. This was correlated with the advanced primary tumour size and resulting in wide tumour excision and reconstruction. CONCLUSIONS: Surgery combined with postoperative radiotherapy given as IMRT results in low level of tumour recurrence. PMID- 21247265 TI - Ultraviolet radiation-induced cytokines promote mast cell accumulation and matrix metalloproteinase production: potential role in cutaneous lupus erythematosus. AB - OBJECTIVE: To examine the role of mast cells (MCs), cytokines, and matrix metalloproteinases (MMPs) following ultraviolet B (UVB) radiation in cutaneous lupus erythematosus (CLE). METHODS: Immunohistochemistry was used to determine the presence of MCs and the expression of MMP-1, MMP-9, interleukin (IL)-15, and CCL5/RANTES in skin from patients with CLE. Human keratinocytes were exposed to varying doses of UVB and supernatants were collected and assessed for IL-15, CCL5, MMP-1, and MMP-9 by protein assays. MC migration was determined against supernatants from UVB-treated keratinocytes. RESULTS: MCs in the skin of patients with CLE were significantly increased. MMP-1 and MMP-9 expression was abundant in these lesions. Intense reactivity for IL-15 and CCL5 was found in skin, particularly in epidermal keratinocytes, from patients with CLE. UVB irradiation induced IL-15, CCL5, MMP-1, and MMP-9 production from keratinocytes in a dose- and time-dependent manner. Supernatants obtained from UVB-treated keratinocytes induced MC migration, which was attenuated by anti-IL-15 and anti-CCL5 neutralizing antibodies. IL-15 induced MC-derived MMP production. CONCLUSIONS: Our results indicate that MCs and MMPs may play a role in the skin inflammation in CLE. MC recruitment as well as MMP production may be perpetuated by UV irradiation through locally released mediators. PMID- 21247266 TI - A novel L67P SOD1 mutation in an Italian ALS patient. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons. We describe a novel L67P mutation located in exon 3 of the Cu/Zn superoxide dismutase gene in a patient with pure lower motor neuron signs. To date, 11 mutations involving exon 3 of SOD1 have been described, including the present one. Our data confirm that variable penetrance and predominant lower motor neuron involvement are common characteristics in patients bearing mutations in exon 3 of the SOD1 gene. PMID- 21247267 TI - Procalcitonin interference in an immunometric calcitonin assay. AB - BACKGROUND: Procalcitonin (PCT) increases in septic patients, and is not transformed into calcitonin (CT). We found in septic patients, a significant increase of CT, as determined by an immunoassay using polyclonal antibodies. We compare determination using polyclonal and monoclonal AB. METHODS: We included 34 patients: 17 with clinical signs of sepsis, a positive haemoculture (PCT > 0.5 MUg/L) and 17 without them (PCT < 0.1 MUg/L). CT was determined by two above mentioned methods. The influence on CT levels was observed after using the high concentration PCT calibrator addition to a mixed serum sample with a low concentration of CT. The dilution test of the high-concentration calibrator PCT was performed by an IBL calibrator, with a zero calcitonin concentration. RESULTS: In the septic patients we found an interference in calcitonin determination using the polyclonal AB (IRMA); 24.1-718 MUg/L, proportional to the PCT levels (r = 0.814, p < 0.0001). When using the monoclonal AB (ELISA), the calcitonin levels < 6.5-46.3 ng/L, and no interference of PCT was observed. In the non-septic group, we did not record any PCT interference using either the polyclonal or the monoclonal AB, and the CT levels were within the reference ranges using the two methods (r = 0.997, p < 0.0001). The recovery and dilution tests confirmed interference by PCT on the calcitonin determination with the polyclonal antibody. CONCLUSIONS: Results show that in septic patients there is visible interference of PCT in the calcitonin determination, principally in the IRMA method (polyclonal AB); while no such relationship was observed in the ELISA method (monoclonal AB). PMID- 21247269 TI - Personal and social influences regarding oral sex among African American female adolescents. AB - OBJECTIVE: To identify personal and social factors associated with performing oral sex among female adolescents. METHODS: Sexually active African American female adolescents (n = 715) recruited from sexually transmitted infection (STI) clinics were assessed for self-esteem, sexual sensation seeking, unprotected vaginal sex (UVS), self-efficacy to communicate about sex and to refuse sex, fear of negotiating condoms, relationship power, peer norms surrounding risky sexual behavior, ever having performed oral sex, and three vaginally acquired STIs. RESULTS: Prevalence for at least one STI was 29%. More than half reported performing oral sex. Controlling for age, performing oral sex was associated with relatively higher sexual sensation seeking, any UVS in past 60 days, relatively lower self-efficacy to refuse sex, and having peer norms supportive of risky sexual behaviors. CONCLUSIONS: Given the potential for epidemic spread of orally acquired STIs to populations of female adolescents residing in communities with high rates of STI prevalence, this initial research provides guidance for intervention development and expanded research efforts. PMID- 21247268 TI - Mesenchymal stem cell characteristics of human anterior cruciate ligament outgrowth cells. AB - When ruptured, the anterior cruciate ligament (ACL) of the human knee has limited regenerative potential. However, the goal of this report was to show that the cells that migrate out of the human ACL constitute a rich population of progenitor cells and we hypothesize that they display mesenchymal stem cell (MSC) characteristics when compared with adherent cells derived from bone marrow or collagenase digests from ACL. We show that ACL outgrowth cells are adherent, fibroblastic cells with a surface immunophenotype strongly positive for cluster of differentiation (CD)29, CD44, CD49c, CD73, CD90, CD97, CD105, CD146, and CD166, weakly positive for CD106 and CD14, but negative for CD11c, CD31, CD34, CD40, CD45, CD53, CD74, CD133, CD144, and CD163. Staining for STRO-1 was seen by immunohistochemistry but not flow cytometry. Under suitable culture conditions, the ACL outgrowth-derived MSCs differentiated into chondrocytes, osteoblasts, and adipocytes and showed capacity to self-renew in an in vitro assay of ligamentogenesis. MSCs derived from collagenase digests of ACL tissue and human bone marrow were analyzed in parallel and displayed similar, but not identical, properties. In situ staining of the ACL suggests that the MSCs reside both aligned with the collagenous matrix of the ligament and adjacent to small blood vessels. We conclude that the cells that emigrate from damaged ACLs are MSCs and that they have the potential to provide the basis for a superior, biological repair of this ligament. PMID- 21247270 TI - Is there any association of serum high-sensitivity C-reactive protein with various risk factors for metabolic syndrome in a healthy adult population of karachi, pakistan? AB - BACKGROUND: The aim of this study was to discover the association of serum high sensitivity C-reactive protein (hsCRP) with various risk factors for metabolic syndrome in an urban population of Karachi, Pakistan. METHOD: In this cross sectional study, 337 healthy adults (108 males and 229 females, mean age 40.7 +/- 14.2 years) participated. The subjects were randomly selected in Lyari Town in Karachi using a geographical imaging system (GIS). Their demographic, anthropometric [body mass index (BMI), hip and waist circumferences, waist-to-hip circumference ratio (W-HR), and biochemical (fasting blood glucose, fasting insulin, fasting lipid profile, and hsCRP)] parameters were recorded. Insulin resistance was calculated by the homeostasis model assessment (HOMA-IR). Metabolic syndrome was diagnosed according to the International Diabetes Federation (IDF) criteria. Correlation of CRP and fasting insulin levels with various parameters of metabolic syndrome were calculated using Pearson correlation. RESULTS: Median CRP levels were found to be higher in females 0.81 (0.20-1.38) compared with males 0.77 (0.19-1.35). Metabolic syndrome was diagnosed in 108 (31.12%) subjects. No significant difference between CRP levels in the metabolic syndrome-positive and metabolic syndrome-negative groups was observed. Similarly, no correlation was observed between hsCRP and fasting insulin levels, insulin resistance, and other parameters of MS. CONCLUSION: There is lack of correlation between hsCRP levels and various risk factors for metabolic syndrome in our urban population. Further large-scale prospective studies are needed to confirm these findings. PMID- 21247271 TI - Psychological predictors of adiposity: systematic review of longitudinal studies. AB - We aimed to systematically review current literature on temporal relationships between psychological factors and subsequent adiposity gain and obesity onset within childhood/adolescence. Databases were searched for longitudinal, population-based studies assessing psychological predictors and adiposity-related outcomes >= 1 year later. Study characteristics were synthesised into descriptive Tables and quality evaluated. Fifteen papers met inclusion criteria. Predictors broadly related to psychological symptoms or self-esteem. Evidence was mixed as to whether depressive symptoms and other negative emotional states may increase risk for adiposity gain and obesity onset within adolescence. There was some evidence for low self-esteem predicting obesity onset. Among obese adolescents, depressive symptoms exacerbated obesity, while physical appearance self-esteem exerted gender-specific adiposity changes. The literature had substantial limitations and inconsistencies. This review provides some support for psychological components in obesity prevention/intervention programs as part of a multifactorial approach to tackling childhood obesity. Further good-quality longitudinal research would strengthen the sparse literature and clarify inconsistencies. PMID- 21247272 TI - Can partial nephrectomy preserve renal function and modify survival in comparison with radical nephrectomy? AB - OBJECTIVE: To investigate whether radical nephrectomy (RN) and nephron-sparing surgery (NSS) for T1 renal cell carcinoma influence renal function, oncological outcome or survival rate. MATERIAL AND METHODS: A retrospective study was performed, including 290 nephrectomies for tumours of a diameter of less than 7 cm; 174 radical nephrectomies were compared to 116 nephron-sparing surgeries. Preoperative and pathological data were compared between the two groups. The glomerular filtration rate was estimated using the abbreviated Modification of Diet and Renal Disease (MDRD4) study equation. The evolution of renal function was analysed from 6 months to 4 years after surgery, and the oncological outcomes were evaluated by means of cancer and non-cancer survival curves. RESULTS: The results showed a major impairment in renal function in the RN group compared to those who underwent NSS (25 vs 7 ml/min/1.73 m2, 6 months after surgery), a difference that was maintained over time. Moreover, patients undergoing RN had a greater chance of developing renal failure. Overall, the survival curves showed a higher mortality rate for the RN group (p = 0.034), although the cancer-specific mortality rate did not show any statistically significant differences (p = 0.079). CONCLUSIONS: For stage T1 renal cortical tumours, NSS should, whenever possible, be regarded as the primary therapeutic option, given that it obtains similar oncological outcomes to RN and preserves renal function, which seems to translate into a lower overall mortality rate. PMID- 21247273 TI - What's new about empathy? PMID- 21247274 TI - Acculturation, depression, self-esteem, and substance abuse among Hispanic men. AB - The demographics of the United States are rapidly changing as a result of immigration from Latin America. Predictions indicate that by the year 2050, one of every four persons in the United States will be of Hispanic ethnicity. If health disparities relating to substance abuse and related mental health conditions among Hispanics are not fully understood and addressed, these will continue to grow along with this population. The purpose of this pilot study was to describe the relationships among acculturation, depression, self-esteem, and substance abuse among a community sample of Hispanic men in South Florida (N = 164, 82 heterosexual men and 82 men who have sex with men). Standardized instruments measuring acculturation, depression, self-esteem, and substance abuse were administered in English or Spanish in a face-to-face interview format. Descriptive statistics and multiple logistic regression were used to illustrate participant characteristics and test relationships among the variables. Despite the fact that the majority of participants were more acculturated to the Hispanic culture than US culture, reported low levels of education and income, were depressed, and used substances, this group of men reported high levels of self esteem. However, age and depression were the only predictors of substance abuse. Acculturation and self-esteem were not predictors of substance abuse. Clinicians need to be aware of the high rates of depression and substance abuse in this population and screen frequently for signs and symptoms of depression and substance abuse during health care encounters. PMID- 21247275 TI - Online communities of practice to support collaborative mental health practice in rural areas. AB - The provision of quality mental health services in rural areas continues to be an ongoing challenge for nurses and the patients they serve. The use of computer mediated communication to construct collaborative learning environments similar to those suggested in Wenger's community of practice framework has the potential to mitigate a number of the difficulties faced by rural health care providers. The author presents a brief discussion of social learning theories, the communities of practice framework, and related concepts. Examples of current online communities of practice used as a means for knowledge construction in various professional disciplines are presented in building the case for the fit between online communities of practice and the needs of nurses in rural mental health. Nurses providing mental health care in rural areas have documented needs for interdisciplinary teamwork, access to a collaborative learning environment, and ongoing contact with expert resources. The construction of online communities of practice could potentially address a multitude of concerns identified by nurses practicing mental health care in rural areas. PMID- 21247276 TI - The impact of mental health nursing education on undergraduate nursing students' attitudes to consumer participation. AB - Consumer participation in all aspects of mental health service delivery, including the education of mental health professionals, is now a policy expectation in Australia. Whether education programs introducing nurses to mental health nursing lead to more favourable attitudes towards consumer participation is yet to be examined in pre-registration nursing programs in Australia. The current evaluation examined changes in scores for the Consumer Participation Survey for undergraduate nursing students (n = 68) in an Australian University. Data were analysed, using repeated measures t-test, to compare the pre- and post test scores. There was a significant improvement in views on consumers participating as staff members. There were no statistically significant changes in attitudes towards consumer capacity and consumer involvement in care processes. Consumer participation in mental health care is now clearly articulated in Australian Government policy. For this to be successfully implemented a more comprehensive understanding of the ability of education to influence attitudes is required. PMID- 21247277 TI - Korean American parental depressive symptoms and parental acceptance-rejection and control. AB - This study explored the relationships between Korean American parental depressive symptoms and parenting in 64 mothers and 35 fathers of adolescents 11 to 17 years of age. Using multiple regression after controlling for family income, both parents' depressive symptoms were found to significantly influence their acceptance and rejection behaviors, explaining 14% of variance in the mother model and 47% of variance in the father model. Specifically, maternal depressive symptoms were found to significantly positively influence their hostility. Paternal depressive symptoms were found to significantly negatively influence their affection and positively influence their hostility, neglect, and undifferentiated rejection. Educating Korean American parents, especially fathers, regarding the possible influence of their depressive symptoms on their acceptance and rejection of their adolescents could be helpful. PMID- 21247278 TI - How I remember my parents' divorce: a phenomenological investigation. AB - In order to examine the experience of parental divorce for adult women, a phenomenological method was used. Ten women were interviewed and the interviews were transcribed verbatim and thematized. The themes that came from the texts of the interviews transcripts and the researchers' reflections on the phenomenological research group analysis were: Before the Divorce, During the Divorce, and After the Divorce. These themes were centered on a contextual ground of Time Frame of the Divorce. The results of this study can provide individuals with a context for understanding their own experiences of parental divorce. These results could also be helpful for mental health clinicians in anticipating the themes that clients will discuss relative to the stages of their parents' divorce. PMID- 21247280 TI - Parent effectiveness training. PMID- 21247279 TI - The use of expressive methods for developing empathic skills. AB - Empathy is one of the fundamental concepts in nursing, and it is an ability that can be learned. Various education models have been tested for improving empathic skills. Research has focused on using oral presentations, videos, modeling, practiced negotiation based on experiences, and psychodrama methods, such as role playing, as ways to improve empathy in participants. This study looked at the use of expressive arts to improve empathic skills of nursing students. The study was conducted with 48 students who were separated into five different groups. All groups lasted for two hours, and met for 12 weeks. Expressive art and psychodrama methods were used in the group studies. The Scale of Empathic Skill was administered to participants before and after the group studies. Before the group study took place, the average score for empathic skill was 127.97 (SD = 21.26). After the group study, it increased to 138.87 (SD = 20.40). The average score for empathic skill increased after the group (t = 3.996, p = .000). Results show that expressive methods are easier, more effective, and enjoyable processes in nursing training. PMID- 21247281 TI - Treatment of persons with mental illness and substance use disorders in medical emergency departments in the United States. PMID- 21247282 TI - L-methylfolate (Deplin(r)): a new medical food therapy as adjunctive treatment for depression. PMID- 21247284 TI - Pharmacokinetic drug interactions and adverse consequences between psychotropic medications and pharmacotherapy for the treatment of opioid dependence. AB - BACKGROUND: Psychiatric comorbidities among opioid-dependent patients are common. Many medications used to treat both conditions are metabolized through complimentary cytochrome P450 isoenzymes. When medication-assisted treatment for opioid dependence is concurrently used with psychotropic medications, problematic pharmacokinetic drug interactions may occur. METHODS: We reviewed relevant English language articles identified through the MedLine, Scopus, and Embase databases from 1950 to December 2009 using the specific generic names of medications and keywords such as pharmacokinetics and drug interactions with buprenorphine, methadone, and naltrexone. Selected references from these articles were reviewed. Additionally, a review was conducted of abstracts and conference proceedings from national and international meetings from 1990 to 2009. A total of 60 studies were identified and reviewed. RESULTS: Clinical case series and carefully controlled pharmacokinetic interaction studies have been conducted between methadone, buprenorphine, or naltrexone and some psychoactive medications. Important pharmacokinetic drug interactions have been demonstrated within each class of medications affecting either methadone and buprenorphine or psychoactive drugs. Few studies, however, have been conducted with naltrexone. CONCLUSIONS: Several interactions between methadone, buprenorphine, or naltrexone and psychoactive medications are described and may have important clinical consequences. To optimize care, clinicians must be alerted to these interactions. PMID- 21247285 TI - "No one of us is as smart as all of us.". PMID- 21247286 TI - The Clinical Research Office of the Endourological Society Percutaneous Nephrolithotomy Global Study: indications, complications, and outcomes in 5803 patients. AB - PURPOSE: To assess the current indications, perioperative morbidity, and stone free outcomes for percutaneous nephrolithotomy (PCNL) worldwide. PATIENTS AND METHODS: The Clinical Research Office of the Endourological Society (CROES) collected prospective data for consecutive patients who were treated with PCNL at centers around the world for 1 year. PCNL was performed according to study protocol and local clinical practice guidelines. Stone load and location were recorded, and postoperative complications were graded according to the modified Clavien grading system. RESULTS: Between November 2007 and December 2009, 5803 patients were treated at 96 centers in Europe, Asia, North America, South America, and Australia. Staghorn calculus was present in 1466 (27.5%) patients, and 940, 956, and 2603 patients had stones in the upper, interpolar, and lower pole calices, respectively. The majority of procedures (85.5%) were uneventful. Major procedure-related complications included significant bleeding (7.8%), renal pelvis perforation (3.4%), and hydrothorax (1.8%). Blood transfusion was administered in 328 (5.7%) patients, and fever >38.5 degrees C occurred in 10.5% of patients. The distribution of scores in modified Clavien grades was: No complication (79.5%), I (11.1%), II (5.3%), IIIa (2.3%), IIIb (1.3%), IVa (0.3%), IVb (0.2%), or V (0.03%). At follow-up. the 30-day stone-free rate was 75.7%, and 84.5% of patients did not need additional treatment. CONCLUSION: With a high success rate and a low major complication rate, PCNL is an effective and safe technique overall for minimally invasive removal of kidney stones. PMID- 21247287 TI - Narrow-band imaging digital flexible ureteroscopy in detection of upper urinary tract transitional-cell carcinoma: initial experience. AB - PURPOSE: To characterize the appearance of normal and malignant upper urinary tract lesion appearance under narrow-band imaging (NBI) using the new URF-V digital flexible ureteroscope (DFU), and to determine if NBI, when used in conjunction with white light (WL), could improve detection of malignancy. PATIENTS AND METHODS: NBI and WL were performed in 27 patients at our university teaching hospital, 14 with known cases of upper urinary tract transitional-cell carcinoma (UUT-TCC) as follow-up (group A), and 13 patients with first-suspicion of cancer (group B). Full renal collecting system examination was performed first under WL and then under NBI by a single urologist. Biopsies were taken from all detected lesions using the biopsy forceps and sent for examination by a pathologist who was blinded to the gross description of the lesion. Pathology interpretations were then compared with the corresponding WL and NBI images. Holmium laser vaporization was performed for all apparent lesions. RESULTS: Subjectively, NBI significantly improved the endoscopic visualization of the tumors, providing a detailed description of their limits and vascular architecture. Objectively, five additional tumors (14.2%) in four patients, as well the extended limits of three tumors (8.5%) in three patients were detected by NBI when findings by WL imaging were considered normal. CONCLUSION: This is one of the first reports regarding NBI for UUT-TCC. From this study, we recommend this technology as a valuable diagnostic method, because it considerably improves tumor detection rate by 22.7% compared with WL. PMID- 21247288 TI - Percutaneous and transureteral biopsies of renal papillae: safe and appropriate procedures for in vivo histologic analysis in stone formers. AB - BACKGROUND AND PURPOSE: According to the Randall plaque theory, urinary crystals may attach to focal interstitial deposits of calcium phosphate (CaP), localized in the tip of the renal papillae. The aim of this prospective study was to evaluate the feasibility and safety of papillary biopsy, performed during ureterorenoscopy (URS) or percutaneous nephrolithotomy (PCNL), to obtain, in vivo, appropriate samples to investigate interstitial CaP deposits that represent Randall's plaques precursors. PATIENTS AND METHODS: Twenty-eight patients who were affected by recurrent renal stones, 13 males and 15 females, with a median age of 42.5 years (range 17-76 y), underwent rigid and/or flexible URS (8 patients) or PCNLs (20 patients). In all cases, endoscopic biopsies from renal papillae were performed. Papillary samples were obtained by means of 3F or 4F cup biopsy forceps if semirigid and flexible ureterorenoscopes were used. During percutaneous procedures, with rigid and flexible instruments, 5F or 10F cup forceps were used. The same pathologist analyzed all the histologic specimens. RESULTS: All patients underwent successful biopsy procedures. The quality of the obtained tissue allowed for an accurate histochemical analysis in 27 of 28 (96.4%) biopsies. One biopsy was inadequate because of some important regressive phenomena. No specific complications had to be attributed to biopsy procedures. CONCLUSIONS: Percutaneous or transureteral biopsies of renal papillae resulted in being safe and appropriate procedures to obtain papillary samples to identify the presence of interstitial calcium deposits. In the light of the low number of inadequate biopsies, it can be concluded that no difference was found between the percutaneous and transureteral bioptic approach. PMID- 21247289 TI - Pelvic anatomy on preoperative magnetic resonance imaging can predict early continence after robot-assisted radical prostatectomy. AB - BACKGROUND AND PURPOSE: Postoperative incontinence is multifactorial after radical prostatectomy. Using endorectal coil MRI, we examined features of the male urethra and accompanying muscular sphincter to predict continence after robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: 80 patients underwent preoperative 1.5 Tesla endorectal coil MRI. Urethral length was measured in the coronal plane. All patients underwent RARP. Questionnaires were completed by patients at monthly intervals. The primary end point was time to continence defined as necessitating 0 to 1 pad per day (PPD). Statistical analysis was performed using Cox regression models to create both univariate and multivariate survival models. RESULTS: Mean age was 59.7 (standard deviation [SD] 7.1); 98% had bilateral nerve sparing. Mean urethral length was 17.1 mm (SD 4.5 mm). Mean prostate size was 34.7 g (SD 17.8). By 3 months, 60 patients achieved 1 PPD (mean 8.1 weeks, SD 9.4) and 34 patients achieved 0 PPD (mean 10.5 weeks, SD 8.0). Time to social continence was significantly related to prostate size both as a continuous variable (P=0.01), and as a dichotomized variable of >= 50 vs<50 g (P=0.02). Increased urethral length was related to decreased time to continence both as a continuous variable (P=0.06), and when dichotomized to >= 20 vs<20 mm (P=0.08). In addition to larger prostate size (hazard ratio [HR] 0.97, P<0.04), older age (0.95 P<0.025) was also associated with a longer time to achieve 0 PPD. Multivariate analysis revealed that longer urethral length was associated with a faster recovery of continence (HR 1.11, P<0.01). After controlling for age and urethral length, patients with a prostate size >= 50 g had 75% lower likelihood of achieving continence at all time points when compared with patients with prostate size <50 g (HR 0.25; 95% confidence interval: 0.06, 1.06; P=0.06). CONCLUSIONS: Longer urethral length increased the likelihood of achieving continence at all time points postoperatively. Advanced age and larger prostate size were negatively associated with continence outcomes. PMID- 21247290 TI - Pure natural orifice translumenal endoscopic surgery management of simple renal cysts: 2-year follow-up results. AB - BACKGROUND AND PURPOSE: Retrograde ureteroscopic marsupialization is a pure natural orifice translumenal endoscopic surgery (NOTES). We retrospectively examined the feasibility and safety of this technique to manage symptomatic simple renal cysts. PATIENTS AND METHODS: Sixteen patients with simple renal cysts were selected and treated by incising the cyst wall to drain into the collecting system through retrograde ureteroscopy. A retrospective observational study was performed to evaluate the patient's symptomatic and radiologic results after ureteroscopic marsupialization. Symptomatic success based on pain relief was evaluated using a visual analog pain scale preoperatively and postoperatively. Radiologic success was defined as no recurrence of the cyst or a reduction in cyst size by at least half. RESULTS: There were no intraoperative or postoperative complications observed. The mean operative time was 35 minutes (range 20-50 min). The mean hospital stay was 3.4 days (range 2-5 d). Of the 16 patients, one patient was lost at follow-up. The symptoms based on pain had resolved in 13 (83%) cases but remained in 2 cases at a mean follow-up of 24.2 months (range 6-36 mos). The average visual analog pain scale decreased from 6.7 (range 4-9) to 1.1 (range 0-5) at the sixth month. The mean size of all cysts decreased from 6.8 cm (range 4-10 cm) to 1.3 cm (range 0-5 cm). Radiographic success was achieved in 93% (14/15) of patients. Cytology and cyst wall pathology reports revealed no evidence of malignancy. CONCLUSIONS: Retrograde ureteroscopic marsupialization is a complete transurethral NOTES marsupialization. With appropriate patient selection, the minimally invasive retrograde ureteroscopic marsupialization is feasible, safe, and effective. It can be preferred to more invasive laparoscopic or open surgical approaches. PMID- 21247291 TI - Editorial comment for Korman et al. PMID- 21247292 TI - Are urology residents adequately exposed to conservative therapies for managing small renal masses? AB - PURPOSE: Increasing diagnosis of small renal masses (SRMs) necessitates trainees to be familiar with available therapies. We hypothesized that involvement in conservative treatments (ablation and/or active surveillance) occurs infrequently. Therefore, we evaluated resident exposure and participation in treatments as well as proposed management for SRMs. METHODS: A survey was distributed to residents of the American Urologic Association and queried exposure to ablation and surveillance for SRMs. Three case scenarios (SRM in a healthy 55-year-old, healthy 75-year-old, and comorbid 75-year-old patient) were presented for management. RESULTS: Two hundred fifty-seven residents responded to the survey. Two hundred thirty-four (91%) reported ablation was offered at their institution, although only 140 (54%) ever participated in this procedure. Of these, 80 (57%) were involved in fewer than five procedures. Experience with ablation did not increase at higher levels of training (U3-61%, U4-66%, and U5 63%). Two hundred twenty-four (87%) residents noted exposure to surveillance for managing SRMs, increasing from 70% in U1 to 94% in U5. When considering case scenarios, management strategy shifted significantly from extirpation to ablation or surveillance as patient age and comorbidity profile increased. In particular, almost 50% of respondents advocated ablation for SRMs in a comorbid 75-year-old patient. CONCLUSIONS: Although most residents are adequately exposed to surveillance strategies for SRMs, only 54% participated in an ablative procedure. Nonetheless, almost 50% of residents recommended ablation to manage SRMs in the aging, comorbid patient. This suggests a disconnect between training and future practice pattern. PMID- 21247296 TI - Deficits in early-stage face perception in excessive internet users. AB - Excessive Internet use is associated with a limited ability to communicate effectively socially, which depends largely on the capacity for perception of the human face. We used a passive visual detection paradigm to compare the early stages of the processing of face-related information in young excessive Internet users (EIUs) and healthy normal subjects by analyzing event-related potentials (ERPs) elicited by faces and by nonface stimuli (tables), each presented in the upright and inverted position. The P1 and N170 components of the spectrum of ERPs elicited at occipital-temporal sites by the viewing of faces were larger and peaked sooner than the same ERP components elicited by tables, and inverted faces significantly enhanced and delayed the N170 component. EIUs had a generally smaller P1 component than did normal subjects, whether elicited by faces or by tables, and the N170 effect, or difference in amplitude of the N170 component for faces versus tables, was significantly smaller in the EIUs than in normal subjects. However, the N170 inversion effect, or difference in amplitude of the N170 component elicited by upright versus inverted faces, was similar in the EIUs and normal subjects. These data indicate that EIUs have deficits in the early stage of face-perception processing but may have intact holistic/configural processing of faces. Whether some deeper processes of face perception, such as face memory and face identification, are affected in EIUs needs to be investigated further with more specific procedures. PMID- 21247297 TI - A rapid and sensitive method to identify and differentiate Salmonella enterica serotype Typhimurium and Salmonella enterica serotype 4,[5],12:i:- by combining traditional serotyping and multiplex polymerase chain reaction. AB - Salmonella enterica subspecies enterica serotype 4,[5],12:i:- is an emerging serovar considered as a monophasic variant of Salmonella enterica serotype Typhimurium. The antigenic and genetic similarity between Salmonella 4,[5],12:i:- and Salmonella Typhimurium suggests that they may behave in a similar way and represent a comparable threat to public health. As serotyping alone does not necessarily provide for identification of Salmonella 4,[5],12:i:- and its differentiation from Salmonella Typhimurium, a method that combines traditional serotyping and a multiplex polymerase chain reaction has been tested on 208 strains serotyped as Salmonella 4,[5],12:i:-, Salmonella Typhimurium, and similar serovars of serogroup B sharing the same phase-1 antigen "i." For 191 strains, the combined method fully confirmed the results provided by traditional serotyping, whereas for 17 strains of Salmonella 4,[5],12:i:- and Salmonella Typhimurium some inconsistencies emerged between the two methods. The combined method resulted in a more accurate and faster identification of these two relevant serovars. PMID- 21247298 TI - Molecular diversity of Listeria monocytogenes isolated from Irish dairy farms. AB - Many foods originate on the farm where cross-contamination with pathogens can occur, with implications for human health. This study characterized a bank of 51 Listeria monocytogenes isolates originating from 12 farms located in Ireland by pulsed-field gel electrophoresis (PFGE) to establish the molecular diversity of the isolate collection, and examine transmission patterns of L. monocytogenes across the farm environment, and also determined resistances against five different antibiotics (ampicillin, ciprofloxacin, erythromycin, penicillin G, and tetracycline). Analysis using a combination of AscI and ApaI digestion showed the 51 isolates comprised a total of 40 individual PFGE types, compared to individual restriction enzyme analysis, which was less discriminatory (36 types with ApaI analysis and 38 types with AscI analysis). Four of the PFGE types were common to multiple farms, and five farms had isolates with indistinguishable PFGE types in multiple locations on the farm. Indistinguishable PFGE types were common to multiple farms in different geographical locations up to ~200 km apart, and were found in a variety of different sample types, indicating multiple niches for the organism in the dairy farm environment. The presence of L. monocytogenes in samples related to animals other than cattle indicated that there are multiple possible vectors of contamination. The farm environment harbors a diverse collection of L. monocytogenes isolates that must be considered as possible agents of food contamination. PMID- 21247299 TI - Ease of screening for depression and delirium in patients enrolled in inpatient hospice care. AB - BACKGROUND: Major depression and delirium are prevalent, underrecognized, and undertreated in hospice and palliative care settings. Furthermore, they are both associated with significant morbidity and mortality. OBJECTIVE: A screening study of patients receiving inpatient hospice care was conducted in order to determine the ease of screening for depression and delirium in patients with advanced, life threatening illnesses by hospice social workers and nurses, respectively. METHODS: A two-question depression screening tool was administered to 20 consecutive patients on admission to a hospice general inpatient care center by social work staff during their initial assessment. A delirium-screening tool was administered daily to 22 consecutive patients admitted to the ICC daily by nursing staff. Screening results were collected, as were patient and staff feelings about the burden of the screening process. RESULTS: Of the 20 patients screened on admission for depression by social work, 70% (14/20) screened positive. Of the 22 patients screened daily for delirium by nursing, 64% (14/22) screened positive at least once during their admission. Screening for both conditions was considered relatively easy to accomplish by the hospice staff. There were no significant associations between a positive screen of depression or delirium and patient gender, age, ethnicity, terminal diagnosis, or marital status. DISCUSSION: These results support the notion that depression and delirium are very common in hospice inpatients, and that screening for both is relatively easy and practical for hospice clinicians to conduct. PMID- 21247300 TI - Development of a cognitive model for advance care planning discussions: results from a quality improvement initiative. AB - BACKGROUND: Residents struggle with advance care planning (ACP) discussions in the inpatient setting, and may not be aware of newer models for ACP that stress the importance of giving prognostic information and making a recommendation about cardiopulmonary resuscitation to patients and families. METHODS: A controlled study of a cognitive model for ACP embedded in a quality improvement (QI) project. RESULTS: In the setting of a QI project for medical residents and interdisciplinary staff, we developed and implemented a cognitive model of ACP discussions that involved two types of meetings for patients: (1) information sharing meetings for seriously ill but clinically stable patients and (2) decision-making meetings for clinically unstable patients. Patients on the intervention floor were significantly more likely to have a discussion about goals of care (33.8%) than patients on the control floor (21.2%, p = < 0.001) and significantly more likely to have a limitation of life-sustaining treatment upon discharge (19.1% vs. 13.9%, p = 0.04). CONCLUSIONS: For both residents and interdisciplinary staff, application of a cognitive model that clearly defines goals and expectations for ACP discussions prior to meeting with patients and families improves rates of ACP discussions. PMID- 21247301 TI - Adverse events in hospice and palliative care: a pilot study to determine feasibility of collection and baseline rates. AB - BACKGROUND: Continuous quality improvement is fundamental in all health care, including hospice and palliative care. Identifying and systematically reducing symptomatic adverse events is limited in hospice and palliative care because these events are mostly attributed to disease progression. OBJECTIVES: The aim of this study was to assess the feasibility of symptomatic adverse events in hospice and palliative care and assessing their incidence. METHODS: A retrospective, consecutive cohort of notes from a specialist palliative care inpatient service was surveyed by a clinical nurse consultant for symptomatic adverse events: falls, confusion, decreased consciousness, hypo- and hyperglycaemia, urinary retention, and hypotension. Demographic and clinical factors were explored for people at higher risk. RESULTS: Data were available on the most recent admissions of 65 people, generating >900 inpatient days. Fifty people (78%) had events precipitating admission, of whom 31 (62%) had at least one further event during admission. Eleven of 15 people who were admitted without an event experienced at least one during their admissions. Only 4 did not have an adverse event. During their stay, there were 0.13 (standard deviation [SD] = 0.19) events per patient per day. No drug-drug or drug-host events were noted. No clinical or demographic factors predicted groups at higher risk. CONCLUSIONS: This pilot highlights the feasibility of collecting, and ubiquity of, symptomatic adverse events, and forms a baseline against which future interventions to decrease the frequency or intensity can be measured. Given the frailty of hospice and palliative patients, any adverse event is likely to accelerate irreversibly their systemic decline. PMID- 21247302 TI - Is the routine use of drainage after elective laparoscopic cholecystectomy justified? A randomized trial. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) is the gold standard for the surgical treatment of cholelithiasis. However, the use of drainage after elective LC in literature remains controversial. METHODS: A randomized study was performed in Larnaka General Hospital. The purpose of the study was to evaluate drainage of the gallbladder bed after elective LC. One hundred sixteen patients were randomly allocated in two groups, sustained an uneventful LC, and were included in the study after an informed consent was obtained. Sixty-three patients were included in drainage group (YD) and 53 patients in nondrainage group (ND). Drain tubes, made of polyethylene, were placed at the end of the procedure in the patients of YD group. Postoperative pain was assessed using two scales: a 10-point visual analog scale and a 5-point verbal response scale. The two groups were evaluated and compared regarding postoperative pain, the time needed for surgery, length of postoperative hospital stay, the postoperative collection of fluid in the subhepatic space, and the incidence of postoperative complications. Chi-square and t-tests were used to evaluate the data, and statistical significance was established at P < .05. RESULTS: The mean operative time in YD patients was 6.9 minutes longer compared with ND patients (P = .056). The postoperative pain was higher in the YD group by more than one point on the average in the visual analog scale both at 6 and 24 hours (P = .01 and <.001, respectively). When measured with the verbal response scale, the difference in the reported pain was very significant at 24 hours (mean level for YD 1.24 and for ND 0.75). The proportion of patients staying in hospital for >2 days was higher in the YD group: 28.6% of the patients versus 13.2% in the ND group (P = .05). Subhepatic fluid was more often observed in the YD group (47% versus 34% in the ND), but the difference was not statistically significant. There was no statistical difference in the rate of wound infections, shoulder pain, nausea, vomiting, and respiratory infections between the two groups. CONCLUSIONS: Our results indicate that routine drainage of gallbladder bed after elective LC may not be justified. Drainage causes more postoperative pain, prolongs the operative time and hospital stay, increases the occurrence of fluid in the subhepatic space, and does not protect from other complications. PMID- 21247303 TI - Transection of the hernia sac during laparoscopic totally extraperitoneal inguinal hernioplasty: is it safe and feasible? AB - BACKGROUND: Complete reduction of an indirect inguinal hernia sac during laparoscopic totally extraperitoneal (TEP) repair is not always possible when the sac extends to the scrotum or adheres to adjacent tissues. Laparoscopic TEP repair would be much easier to perform in such cases by transecting the hernia sac. Therefore, the purpose of this study was to determine the safety and efficacy of transection of the hernia sac during laparoscopic TEP. MATERIALS AND METHODS: Five hundred twenty laparoscopic TEP repairs were performed on 498 patients by a single surgeon from July 2003 to December 2008. The patients were classified into two groups: the transected sac (TS) group with 269 patients (275 cases) and the completely reduced sac (RS) group with 230 patients (245 cases). RESULTS: Statistical analysis between the TS and RS groups showed no significant differences in postoperative pain, length of hospital stay, and recurrence, except for postoperative seromas, which were more frequent in the TS group (24 of 275) than the RS group (6 of 245; P = .002). And the mean operative time was longer in the TS group (23.62 +/- 10.25 minutes) than the RS group (21.49 +/- 8.17 minutes; P = .010). CONCLUSION: Although transection of the hernia sac during laparoscopic TEP repair may cause seromas, our study demonstrated that transection of the hernia sac did not cause significant postoperative complications, including recurrence. Transection of the hernia sac is an alternative technique for laparoscopic TEP repair in cases with difficult hernia sac reduction. PMID- 21247304 TI - Repeat laparoscopic totally extraperitoneal hernia repair after primary laparoscopic totally extraperitoneal hernia repair for inguinal hernia. AB - INTRODUCTION: Although laparoscopic totally extraperitoneal hernia repair (TEP) is reported to have a low recurrence rate, few reports address treatment for contralateral occurrence after primary TEP. Most studies on surgical treatment for recurrent inguinal hernia reported on laparoscopic transabdominal preperitoneal repair. The aim of this study was to evaluate the efficacy of repeat TEP for contralateral occurrence after primary TEP for unilateral inguinal hernia. METHODS: We retrospectively reviewed the medical charts of 215 patients undergoing TEP performed between April 2003 and May 2009. We employed a similar approach to that of standard TEP for primary hernia. RESULTS: Twenty eight of 215 patients who underwent unilateral TEP also underwent repeat TEP for contralateral side hernia occurring after primary TEP. The initial hernia was on the right side in 15 patients and on the left side in 13. The initial hernia was indirect in 26 patients and direct in 2. Mean duration of primary TEP to contralateral occurrence was 54.4 months. Mean operation time for the contralateral occurrence was 73.3 minutes, and there was little intraoperative blood loss. Three patients were converted to an anterior approach because of insufficient surgical field due to injury of the peritoneum. Although the inferior epigastric artery and vein were divided in 4 patients, there were no difficulties during surgery. The postoperative course in all patients was uneventful. CONCLUSIONS: TEP after primary TEP for contralateral occurrence is feasible. Repeat TEP might be an alternative technique for new occurrence of contralateral inguinal hernia after primary TEP. PMID- 21247305 TI - Laparoscopic repair of perforated marginal ulcer following Roux-en-Y gastric bypass: a case series. AB - INTRODUCTION: Marginal ulcer perforation is a known complication of Roux-en-Y gastric bypass (RYGB), and laparoscopic repair may be a feasible option minimizing the morbidity associated with a large laparotomy incision. We present our experience with laparoscopic repair of perforated marginal ulcers in patients who have previously undergone RYGB. METHODS: A retrospective chart review from August 2005 to April 2007 was performed identifying all patients who underwent laparoscopic repair of perforated marginal ulcer after RYGB at one hospital. The perforation was repaired either by laparoscopic primary suture closure followed by application of an omental patch or by laparoscopic Graham patch without primary suture repair. Operative time, duration of hospitalization, postoperative follow-up, and postoperative complications were recorded. Data are presented as mean +/- standard deviation. RESULTS: Six patients underwent laparoscopic repair of a perforated marginal ulcer. Operative time was 101.8 +/- 50 minutes with a mean hospitalization of 5.3 +/- 2.7 days. Follow-up was 6.2 +/- 7.5 months. Postoperative complications included 2 patients with nausea and vomiting related to an exposed suture at the gastrojejunostomy, 1 patient with chronic gastritis, and 1 patient developed a stricture at the gastrojejunostomy. CONCLUSIONS: We present the largest series to date of laparoscopic repair of perforated marginal ulcers utilizing an omental patch for repair. We demonstrate that a laparoscopic repair can be completed in a reasonable operative time, with minimal postoperative hospitalization, and low associated morbidity. Patients who develop a perforated marginal ulcer after RYGB can be safely and effectively treated with laparoscopic repair with an omental patch. PMID- 21247307 TI - The Wyden-Brown bill--short on state flexibility. PMID- 21247306 TI - Exploring the acceptance of telecare among senior citizens: an application of back-propagation network. AB - OBJECTIVE: This study employed a new method (nonlinear method) called back propagation network [BPN] to analyze the adoption model of telecare. It is important to inform professionals of the need for medical statistics knowledge to better evaluate new technologies, particularly in health technologies assessment agencies. METHODS: This study used face-to-face interviews to collect senior citizens aged over 60 years in Taiwan, and it used BPN based on the technology acceptance model to identify a telecare adoption model. Lastly, this study compared traditional methods and the BPN method. RESULTS: The BPN method is much better than traditional method. Moreover, the main research result showed that people's perceived usefulness must be raised to effectively increase the adoption of telecare. Education and training for ease of use of telecare for users appear especially important. In sum, this research recommends making the operation interfaces of telecare more user-friendly and providing a demonstration system for practice, so that users would be more comfortable using the system. The findings of this research suggest that, to develop training for users to use telecare, it is likely to be helpful to reduce users' anxiety and improve usage of telecare. CONCLUSIONS: The utilization of the adoption model of telecare established by the BPN method of artificial neural networks is feasible. These findings may offer significant reference for subsequent studies. PMID- 21247308 TI - Time to fill the doughnuts--health care reform and Medicare Part D. PMID- 21247309 TI - Harnessing our opportunity to make primary care sustainable. PMID- 21247310 TI - Effect of occult metastases on survival in node-negative breast cancer. AB - BACKGROUND: Retrospective and observational analyses suggest that occult lymph node metastases are an important prognostic factor for disease recurrence or survival among patients with breast cancer. Prospective data on clinical outcomes from randomized trials according to sentinel-node involvement have been lacking. METHODS: We randomly assigned women with breast cancer to sentinel-lymph-node biopsy plus axillary dissection or sentinel-lymph-node biopsy alone. Paraffin embedded tissue blocks of sentinel lymph nodes obtained from patients with pathologically negative sentinel lymph nodes were centrally evaluated for occult metastases deeper in the blocks. Both routine staining and immunohistochemical staining for cytokeratin were used at two widely spaced additional tissue levels. Treating physicians were unaware of the findings, which were not used for clinical treatment decisions. The initial evaluation at participating sites was designed to detect all macrometastases larger than 2 mm in the greatest dimension. RESULTS: Occult metastases were detected in 15.9% (95% confidence interval [CI], 14.7 to 17.1) of 3887 patients. Log-rank tests indicated a significant difference between patients in whom occult metastases were detected and those in whom no occult metastases were detected with respect to overall survival (P=0.03), disease-free survival (P=0.02), and distant-disease-free interval (P=0.04). The corresponding adjusted hazard ratios for death, any outcome event, and distant disease were 1.40 (95% CI, 1.05 to 1.86), 1.31 (95% CI, 1.07 to 1.60), and 1.30 (95% CI, 1.02 to 1.66), respectively. Five-year Kaplan-Meier estimates of overall survival among patients in whom occult metastases were detected and those without detectable metastases were 94.6% and 95.8%, respectively. CONCLUSIONS: Occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination; however, the magnitude of the difference in outcome at 5 years was small (1.2 percentage points). These data do not indicate a clinical benefit of additional evaluation, including immunohistochemical analysis, of initially negative sentinel nodes in patients with breast cancer. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00003830.). PMID- 21247311 TI - Images in clinical medicine. Palmar-plantar rash with cytarabine therapy. PMID- 21247312 TI - A genetic basis for functional hypothalamic amenorrhea. AB - BACKGROUND: Functional hypothalamic amenorrhea is a reversible form of gonadotropin-releasing hormone (GnRH) deficiency commonly triggered by stressors such as excessive exercise, nutritional deficits, or psychological distress. Women vary in their susceptibility to inhibition of the reproductive axis by such stressors, but it is unknown whether this variability reflects a genetic predisposition to hypothalamic amenorrhea. We hypothesized that mutations in genes involved in idiopathic hypogonadotropic hypogonadism, a congenital form of GnRH deficiency, are associated with hypothalamic amenorrhea. METHODS: We analyzed the coding sequence of genes associated with idiopathic hypogonadotropic hypogonadism in 55 women with hypothalamic amenorrhea and performed in vitro studies of the identified mutations. RESULTS: Six heterozygous mutations were identified in 7 of the 55 patients with hypothalamic amenorrhea: two variants in the fibroblast growth factor receptor 1 gene FGFR1 (G260E and R756H), two in the prokineticin receptor 2 gene PROKR2 (R85H and L173R), one in the GnRH receptor gene GNRHR (R262Q), and one in the Kallmann syndrome 1 sequence gene KAL1 (V371I). No mutations were found in a cohort of 422 controls with normal menstrual cycles. In vitro studies showed that FGFR1 G260E, FGFR1 R756H, and PROKR2 R85H are loss-of-function mutations, as has been previously shown for PROKR2 L173R and GNRHR R262Q. CONCLUSIONS: Rare variants in genes associated with idiopathic hypogonadotropic hypogonadism are found in women with hypothalamic amenorrhea, suggesting that these mutations may contribute to the variable susceptibility of women to the functional changes in GnRH secretion that characterize hypothalamic amenorrhea. Our observations provide evidence for the role of rare variants in common multifactorial disease. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00494169.). PMID- 21247313 TI - A prospective natural-history study of coronary atherosclerosis. AB - BACKGROUND: Atherosclerotic plaques that lead to acute coronary syndromes often occur at sites of angiographically mild coronary-artery stenosis. Lesion-related risk factors for such events are poorly understood. METHODS: In a prospective study, 697 patients with acute coronary syndromes underwent three-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after percutaneous coronary intervention. Subsequent major adverse cardiovascular events (death from cardiac causes, cardiac arrest, myocardial infarction, or rehospitalization due to unstable or progressive angina) were adjudicated to be related to either originally treated (culprit) lesions or untreated (nonculprit) lesions. The median follow-up period was 3.4 years. RESULTS: The 3-year cumulative rate of major adverse cardiovascular events was 20.4%. Events were adjudicated to be related to culprit lesions in 12.9% of patients and to nonculprit lesions in 11.6%. Most nonculprit lesions responsible for follow-up events were angiographically mild at baseline (mean [+/-SD] diameter stenosis, 32.3+/-20.6%). However, on multivariate analysis, nonculprit lesions associated with recurrent events were more likely than those not associated with recurrent events to be characterized by a plaque burden of 70% or greater (hazard ratio, 5.03; 95% confidence interval [CI], 2.51 to 10.11; P<0.001) or a minimal luminal area of 4.0 mm(2) or less (hazard ratio, 3.21; 95% CI, 1.61 to 6.42; P=0.001) or to be classified on the basis of radiofrequency intravascular ultrasonography as thin-cap fibroatheromas (hazard ratio, 3.35; 95% CI, 1.77 to 6.36; P<0.001). CONCLUSIONS: In patients who presented with an acute coronary syndrome and underwent percutaneous coronary intervention, major adverse cardiovascular events occurring during follow-up were equally attributable to recurrence at the site of culprit lesions and to nonculprit lesions. Although nonculprit lesions that were responsible for unanticipated events were frequently angiographically mild, most were thin-cap fibroatheromas or were characterized by a large plaque burden, a small luminal area, or some combination of these characteristics, as determined by gray-scale and radiofrequency intravascular ultrasonography. (Funded by Abbott Vascular and Volcano; ClinicalTrials.gov number, NCT00180466.). PMID- 21247314 TI - Nucleic acid testing to detect HBV infection in blood donors. AB - BACKGROUND: The detection of hepatitis B virus (HBV) in blood donors is achieved by screening for hepatitis B surface antigen (HBsAg) and for antibodies against hepatitis B core antigen (anti-HBc). However, donors who are positive for HBV DNA are currently not identified during the window period before seroconversion. The current use of nucleic acid testing for detection of the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) RNA and HBV DNA in a single triplex assay may provide additional safety. METHODS: We performed nucleic acid testing on 3.7 million blood donations and further evaluated those that were HBV DNA-positive but negative for HBsAg and anti-HBc. We determined the serologic, biochemical, and molecular features of samples that were found to contain only HBV DNA and performed similar analyses of follow-up samples and samples from sexual partners of infected donors. Seronegative HIV and HCV-positive donors were also studied. RESULTS: We identified 9 donors who were positive for HBV DNA (1 in 410,540 donations), including 6 samples from donors who had received the HBV vaccine, in whom subclinical infection had developed and resolved. Of the HBV DNA-positive donors, 4 probably acquired HBV infection from a chronically infected sexual partner. Clinically significant liver injury developed in 2 unvaccinated donors. In 5 of the 6 vaccinated donors, a non-A genotype was identified as the dominant strain, whereas subgenotype A2 (represented in the HBV vaccine) was the dominant strain in unvaccinated donors. Of 75 reactive nucleic acid test results identified in seronegative blood donations, 26 (9 HBV, 15 HCV, and 2 HIV) were confirmed as positive. CONCLUSIONS: Triplex nucleic acid testing detected potentially infectious HBV, along with HIV and HCV, during the window period before seroconversion. HBV vaccination appeared to be protective, with a breakthrough subclinical infection occurring with non-A2 HBV subgenotypes and causing clinically inconsequential outcomes. (Funded by the American Red Cross and others.). PMID- 21247315 TI - Clinical practice. Vitamin D insufficiency. PMID- 21247317 TI - Images in clinical medicine. Cholesterol emboli after coronary bypass surgery. PMID- 21247316 TI - Necrotizing enterocolitis. PMID- 21247318 TI - Case records of the Massachusetts General Hospital. Case 2-2011. A 30-year-old woman with shock after treatment of a furuncle. PMID- 21247319 TI - More on screening mammography. PMID- 21247320 TI - More on screening mammography. PMID- 21247321 TI - More on screening mammography. PMID- 21247322 TI - More on screening mammography. PMID- 21247323 TI - More on screening mammography. PMID- 21247324 TI - More on screening mammography. PMID- 21247326 TI - mTOR inhibitors and autosomal dominant polycystic kidney disease. PMID- 21247327 TI - mTOR inhibitors and autosomal dominant polycystic kidney disease. PMID- 21247328 TI - mTOR inhibitors and autosomal dominant polycystic kidney disease. PMID- 21247330 TI - Antibody therapy and neuroblastoma. PMID- 21247335 TI - Cost comparison of robotic, laparoscopic, and open partial nephrectomy. AB - PURPOSE: To compare direct costs associated with open partial nephrectomy (OPN), laparoscopic partial nephrectomy (LPN), and robot-assisted LPN (RALPN). METHODS: A meta-analysis of nonoverlapping studies was performed to determine operating room (OR) time, equipment use, and length of stay (LOS) for OPN, LPN, and RALPN. Cost models using cost data obtained from our institution were created, and robotic cost and maintenance were amortized over 7 years. One- and two-way sensitivity analyses were performed to evaluate the effect of changing variables on the cost effectiveness of each approach. RESULTS: Seven RALPN, 18 LPN, and 8 OPN data series were identified, comprising a total of 477, 2220, and 2745 procedures, respectively. Weighted mean OR time was 188, 200, 193 minutes; weighted mean LOS was 2.6, 3.2, and 5.9 days for RALPN, LPN, and OPN, respectively. LPN was the most cost-effective approach at a mean direct cost of $10,311, with a cost advantage of $1116 and $1652 over OPN ($11,427) and RALPN ($11,962), respectively. Sensitivity analyses demonstrate that significant decreases in robotic costs are required for RALPN to be cost effective. CONCLUSION: Despite similar OR times, LPN is more cost effective than OPN because of shorter LOS. Because of lower instrumentation costs, LPN is the most cost effective despite a longer LOS than RALPN. RALPN has high cost of maintenance and instrumentation, which is partially compensated by the shorter LOS. Evidence of oncological and functional equivalence to OPN is warranted to determine the future role of RALPN. PMID- 21247336 TI - Effect of G-rich oligonucleotides on the proliferation of leukemia cells and its relationship with p53 expression. AB - G-rich oligonucleotides (GROs) can inhibit cell proliferation by inducing cell cycle arrest at S phase in tumor cell lines. GROs bind specific cellular proteins, such as nucleolin, a crucial protein interacting with P53; however, little is known about the relationship between GROs and P53. In this study, we have shown that GROs inhibited the proliferation of U937 cells (a human monocytic leukemia cell line without P53 expression) by inducing S-phase arrest. We also showed that GRO colocalized with nucleolin in U937 cells. GRO treatment induced alteration of a series of cell cycle regulatory proteins in U937 cells. Increased Cdk2 expression might promote the cells to enter S phase and subsequent decrease of Cdk2 might induce cell cycle arrest in S phase. Transfection of U937 cells with a wild-type p53 gene caused the formation of nucleolin-P53 complex, which alleviated the effect of GRO on leukemia cells. This alleviated effect is probably due to the decreased uptake of GRO. PMID- 21247337 TI - Engaging HIV-positive individuals in specialized care from an urban emergency department. AB - Linking patients who test positive for HIV in an emergency department (ED) setting to HIV care can be challenging. The aim of this study was to assess whether a multimedia HIV testing model utilized in an inner-city ED can effectively link HIV-positive individuals into specialized medical care. A prospective cohort study was performed from October 2005 to January 2009 at an urban academic hospital with a Level 1 trauma center and in-house specialized HIV clinic. Patients were HIV tested in the ED using a multimedia video counseling program which included computer-assisted data collection. Patients who tested positive were linked to care by the same counselor who gave the test result. Linkage was immediate for discharged patients during clinic hours and patients tested during off-hours were scheduled a visit on the next business day. All follow-up was conducted through chart review. The public health advocates (PHAs) tested 24,495 patients over the course of the study, of whom 116 (0.47%) were HIV positive and 93 were newly diagnosed. A total of 83.6% (97/116) of HIV-positive individuals were linked into specialized care, defined here as an outpatient clinic visit within 30 days of diagnosis in the ED. The findings suggest that a multimedia testing model that includes a counselor who acts as tester and navigator can successfully link a high percentage of patients into specialized care. PMID- 21247338 TI - Poly(Glycerol sebacate)/gelatin core/shell fibrous structure for regeneration of myocardial infarction. AB - Heart failure remains the leading cause of death in many industrialized nations owing to the inability of the myocardial tissue to regenerate. The main objective of this work was to develop a cardiac patch that is biocompatible and matches the mechanical properties of the heart muscle for myocardial infarction. The present study was to fabricate poly (glycerol sebacate)/gelatin (PGS/gelatin) core/shell fibers and gelatin fibers alone by electrospinning for cardiac tissue engineering. PGS/gelatin core/shell fibers, PGS used as a core polymer to impart the mechanical properties and gelatin as a shell material to achieve favorable cell adhesion and proliferation. These core/shell fibers were characterized by scanning electron microscopy, contact angle, Fourier transform infrared spectroscopy, and tensile testing. The cell-scaffold interactions were analyzed by cell proliferation, confocal analysis for the expression of marker proteins like actinin, troponin-T, and platelet endothelial cell adhesion molecule, and scanning electron microscopy to analyze cell morphology. Dual immunofluorescent staining was performed to further confirm the cardiogenic differentiation of mesenchymal stem cells by employing mesenchymal stem cell-specific marker protein CD 105 and cardiac-specific marker protein actinin. The results observed that PGS/gelatin core/shell fibers have good potential biocompatibility and mechanical properties for fabricating nanofibrous cardiac patch and would be a prognosticating device for the restoration of myocardium. PMID- 21247339 TI - In vitro assessment of the differentiation potential of bone marrow-derived mesenchymal stem cells on genipin-chitosan conjugation scaffold with surface hydroxyapatite nanostructure for bone tissue engineering. AB - Increasing evidence has revealed that the surface characteristics of biomaterials, such as chemical composition, stiffness, and topography, especially nanotopography, significantly influence cell growth and differentiation. In this study, we examined the effect of surface biomimetic apatite nanostructure of a new hydroxyapatite-coated genipin-chitosan conjugation scaffold (HGCCS) on cell shape, cytoskeleton organization, and osteogenic differentiation of rat bone marrow-derived mesenchymal stem cells in vitro. Cell shape and cytoskeleton organization showed significant differences between cells cultured on genipin cross-linked chitosan framework and those cultured on HGCCS with surface apatite network-like nanostructure after 7 days of incubation in the osteogenic medium. The result of specific alkaline phosphatase activity as an indicator of osteogenic differentiation showed that the alkaline phosphatase activity of rat bone marrow-derived mesenchymal stem cells was higher on HGCCS. Based on quantitative real-time polymerase chain reaction, HGCCS induced highest mRNA expression of osteogenic differentiation makers, runt-related transcription factor 2 by 7 days, osteopontin by 7 days, and osteocalcin by 14 days, respectively. The enhanced ability of cells on HGCCS to produce mineralized extracellular matrix and nodules was also assessed on day 14 with Alizarin red staining. The results of this study suggest that the surface biomimetic apatite nanostructure of HGCCS is a critical signal cue to promoting osteogenic differentiation in vitro. These findings open a new research avenue to controlling stem cell lineage commitment and provide a promising scaffold for bone tissue engineering. PMID- 21247341 TI - Trophic effects of mesenchymal stem cells increase chondrocyte proliferation and matrix formation. AB - Previous studies showed that coculture of primary chondrocytes (PCs) with various sources of multipotent cells results in a higher relative amount of cartilage matrix formation than cultures containing only chondrocytes. The aim of this study was to investigate the mechanism underlying this observation. We used coculture pellet models of human mesenchymal stem cells (hMSCs) and human PCs or bovine PCs (bPCs) and studied the fate and the contribution to cartilage formation of the individual cell populations during coculture. Enhanced cartilage matrix deposition was confirmed by histology and quantification of total glycosaminoglycan deposition. Species-specific quantitative polymerase chain reaction demonstrated that cartilage matrix gene expression was mainly from bovine origin when bPCs were used. Short tandem repeat analysis and species specific quantitative polymerase chain reaction analysis of genomic DNA demonstrated the near-complete loss of MSCs in coculture pellets after 4 weeks of culture. In coculture pellets of immortalized MSCs and bPCs, chondrocyte proliferation was increased, which was partly mimicked using conditioned medium, and simultaneously preferential apoptosis of immortalized MSCs was induced. Taken together, our data clearly demonstrate that in pellet cocultures of MSCs and PCs, the former cells disappear over time. Increased cartilage formation in these cocultures is mainly due to a trophic role of the MSCs in stimulating chondrocyte proliferation and matrix deposition by chondrocytes rather than MSCs actively undergoing chondrogenic differentiation. PMID- 21247340 TI - Hyaluronic Acid hydrogels support cord-like structures from endothelial colony forming cells. AB - The generation of functional vascular networks has the potential to improve treatment for vascular diseases and to facilitate successful organ transplantation. Endothelial colony-forming cells (ECFCs) have robust proliferative potential and can form vascular networks in vivo. ECFCs are recruited from a bone marrow niche to the site of vascularization, where cues from the extracellular matrix instigate vascular morphogenesis. Although this process has been elucidated using natural matrix, little is known about vascular morphogenesis by ECFCs in synthetic matrix, a xeno-free scaffold that can provide a more controllable and clinically relevant alternative for regenerative medicine. We sought to study hyaluronic acid (HA) hydrogels as three-dimensional scaffolds for capillary-like structure formation from ECFCs, and to determine the crucial parameters needed to design such synthetic scaffolds. We found that ECFCs express HA-specific receptors and that vascular endothelial growth factor stimulates hyaluronidase expression in ECFCs. Using a well-defined and controllable three-dimensional HA culture system, we were able to decouple the effect of matrix viscoelasticity from changes in adhesion peptide density. We determined that decreasing matrix viscoelasticity, which corresponds to a loose ultrastructure, significantly increases ECFC vascular tube length and area, and that the effect of local delivery of vascular endothelial growth factor within the hydrogel depends on the makeup of the synthetic environment. Collectively, these results set forth initial design criteria that need to be considered in developing vascularized tissue constructs. PMID- 21247342 TI - Dynamic tensile loading improves the functional properties of mesenchymal stem cell-laden nanofiber-based fibrocartilage. AB - Fibrocartilaginous tissues such as the meniscus serve critical load-bearing roles, relying on arrays of collagen fibers to resist tensile loads experienced with normal activity. As these structures are frequently injured and possess limited healing capacity, there exists great demand for tissue-engineered replacements. Toward recreating the structural features of these anisotropic tissues in vitro, we employ scaffolds composed of co-aligned nanofibers that direct mesenchymal stem cell (MSC) orientation and the formation of organized extracellular matrix (ECM). Concomitant with ECM synthesis, the mechanical properties of constructs increase with free-swelling culture, but ultimately failed to achieve equivalence with meniscal fibrocartilage. As mechanical forces are essential to the development and maintenance of musculoskeletal tissues, this work examined the effect of cyclic tensile loading on MSC-laden nanofibrous constructs. We hypothesized that loading would modulate the transcriptional behavior of MSCs, spur the deposition of ECM, and lead to enhancements in construct mechanical properties compared to free-swelling controls. Fiber-aligned scaffolds were seeded with MSCs and dynamically loaded daily in tension or maintained as nonloaded controls for 4 weeks. With mechanical stimulation, fibrous gene expression increased, collagen deposition increased, and the tensile modulus increased by 16% relative to controls. These results show that dynamic tensile loading enhances the maturation of MSC-laden aligned nanofibrous constructs, suggesting that recapitulation of the structural and mechanical environment of load-bearing tissues results in increases in functional properties that can be exploited for tissue engineering applications. PMID- 21247343 TI - Vascular endoluminal delivery of mesenchymal stem cells using acoustic radiation force. AB - Restoration of functional endothelium is a requirement for preventing late stent thrombosis. We propose a novel method for targeted delivery of stem cells to a site of arterial injury using ultrasound-generated acoustic radiation force. Mesenchymal stem cells (MSCs) were surface-coated electrostatically with cationic gas-filled lipid microbubbles (mb-MSC). mb-MSC was characterized microscopically and by flow cytometry. The effect of ultrasound (5 MHz) on directing mb-MSC movement toward the vessel wall under physiologic flow conditions was tested in vitro in a vessel phantom. In vivo testing of acoustic radiation force-mediated delivery of mb-MSCs to balloon-injured aorta was performed in rabbits using intravascular ultrasound (1.7 MHz) during intra-aortic infusion of mb-MSCs. Application of ultrasound led to marginalization and adhesion of mb-MSCs to the vessel phantom wall, whereas no effect was observed on mb-MSCs in the absence of ultrasound. The effect was maximal when there were 7+/-1 microbubbles/cell (n=6). In rabbits (n=6), adherent MSCs were observed in the ultrasound-treated aortic segment 20 min after the injection (334+/-137 MSCs/cm(2)), whereas minimal adhesion was observed in control segments not exposed to ultrasound (2+/-1 MSCs/cm(2), p<0.05). At 24 h after mb-MSC injection and ultrasound treatment, the engrafted MSCs persisted and spread out on the luminal surface of the artery. The data demonstrate proof of principle that acoustic radiation force can target delivery of therapeutic cells to a specific endovascular treatment site. This approach may be used for endoluminal cellular paving and could provide a powerful tool for cell-based re-endothelialization of injured arterial segments. PMID- 21247344 TI - High doses of bone morphogenetic protein 2 induce structurally abnormal bone and inflammation in vivo. AB - The major Food and Drug Association-approved osteoinductive factors in wide clinical use are bone morphogenetic proteins (BMPs). Although BMPs can promote robust bone formation, they also induce adverse clinical effects, including cyst like bone formation and significant soft tissue swelling. In this study, we evaluated multiple BMP2 doses in a rat femoral segmental defect model and in a minimally traumatic rat femoral onlay model to determine its dose-dependent effects. Results of our femoral segmental defect model established a low BMP2 concentration range (5 and 10 MUg/mL, total dose 0.375 and 0.75 MUg in 75 MUg total volume) unable to induce defect fusion, a mid-range BMP2 concentration range able to fuse the defect without adverse effects (30 MUg/mL, total dose 2.25 MUg in 75 MUg total volume), and a high BMP2 concentration range (150, 300, and 600 MUg/mL, total dose 11.25, 22.5, and 45 MUg in 75 MUg total volume) able to fuse the defect, but with formation of cyst-like bony shells filled with histologically confirmed adipose tissue. In addition, compared to control, 4 mg/mL BMP2 also induced significant tissue inflammatory infiltrates and exudates in the femoral onlay model that was accompanied by increased numbers of osteoclast-like cells at 3, 7, and 14 days. Overall, we consistently reproduced BMP2 side effects of cyst-like bone and soft tissue swelling using high BMP2 concentration approaching the typical human 1500 MUg/mL. PMID- 21247346 TI - Lentiviral vectors targeted to MHC II are effective in immunization. AB - Abstract vectors (LVs) that are targeted to APC using a chimeric measles virus (MV) hemagglutinin (H). The MV H protein is mutated to prevent binding to MV receptors and incorporates a single-chain antibody that recognizes murine major histocompatibility complex class II (MHC II). This targeted LV is highly efficient in transduction of freshly isolated mouse B cells and dendritic cells. MHC II-positive cells in spleen are transduced after intravenous injection, and a robust immune response to an antigen transgene is generated. PMID- 21247345 TI - Modification of perioral stiffness in patients with repaired cleft lip and palate. AB - OBJECTIVE: To measure and compare the perioral stiffness among three groups of pediatric subjects: a group of patients with a repaired cleft lip (and palate) who had a secondary lip revision surgery (revision), another group of patients with repaired cleft lip (and palate) who did not have secondary surgery (nonrevision), and a group of noncleft "normal" patients (noncleft). DESIGN: A parallel, three-group, nonrandomized clinical trial. PARTICIPANTS: A total of 16 patients with repaired cleft lip/palate who did not have lip revision, 13 patients with repaired cleft lip/palate who had lip revision surgery and were tested at 18 to 24 months postsurgery, and 27 noncleft patients. ANALYSIS: Nonparticipatory perioral stiffness was sampled using a recently developed face referenced measurement technology known as OroSTIFF. Perioral stiffness, derived as a quotient from resultant force and interangle lip span, was modeled with multilevel regression techniques. Real-time calculation of the perioral stiffness function demonstrated a significant quadratic relation between imposed interangle stretch and resultant force for each of the three groups. RESULTS: This nonlinear stiffness growth function was significantly elevated in the nonrevision patients compared with the noncleft controls and is likely due to the presence of scar tissue in the upper lip; it was significantly lower among patients with cleft lip/palate who completed lip revision surgery. CONCLUSION: This study demonstrates the efficacy of applying an objective measurement to map differences in perioral tissue biomechanics among patients born with orofacial clefts. PMID- 21247349 TI - Viridans streptococcal bacteremia-related encephalopathy in childhood with malignancy. AB - Viridans streptococcal bacteremia is a prognostic factor in pediatric patients with malignant disease accompanied by severe neutropenia. Here the authors describe 4 patients with viridans streptococcal bacteremia-related encephalopathy who showed serious complications, which included seizures and loss of consciousness. Therapy for relief of brain edema on seizures was started quickly, and included the administration of midazolam, dexamethasone, and mannitol with antimicrobial therapy. The treatment was successfully completed without sequelae. The authors registered 28 episodes of viridans streptococcal bacteremia in their hospital. The peak of serum C-reaction protein was higher in viridans streptococcal bacteremia patients with encephalopathy than in those without encephalopathy. The authors concluded that viridans streptococcal bacteremia can induce encephalopathy in pediatric patients with malignancy and that it is crucial to establish an accurate diagnosis and initiate therapy as soon as possible. PMID- 21247350 TI - Olfactory neuroblastoma in children: results of multimodality treatment in 2 patients. AB - Olfactory neuroblastoma, a rare malignancy of the olfactory epithelium, is an uncommon tumor in children. It occurs mostly in older individuals and the treatment strategies are based on the experience with adults. In this report, clinical characteristics and treatment results of 2 patients with olfactory neuroblastoma are described and discussed with those reported in the literature. PMID- 21247352 TI - The course of asthma in Churg-Strauss syndrome. AB - OBJECTIVES: Asthma is one of the key features of Churg-Strauss syndrome (CSS); however its course in the disease is unclear. The aim of this study was to analyze the asthma course in CSS patients. PATIENTS AND METHODS: We conducted a retrospective study of 22 CSS patients. Medical documentation was studied and patients were questioned about asthma symptoms during follow-up visits, which took place at four points of the disease. These points, at which lung function tests were performed, were CSS diagnosis; introduction of treatment at hospital discharge; and assessment of the first and last clinical and laboratory CSS remissions. Asthma control and severity were assessed in compliance with current guidelines. RESULTS: In the asthmatic group examined, 21 patients had an adult onset asthma, with a mean age of onset 35.5 +/- 11.8 years, preceded by sinusitis (100%) and nasal polyposis (36%). Asthma at its onset was severe in 68.5%, moderate in 27%, and very poorly controlled in 21 patients. Atopy was present in 64% of patients. Onset of vasculitic symptoms and CSS diagnosis was accompanied by high blood eosinophilia (maximal 7.2 x 10(3)/l [1.2 - 32], asthma exacerbation with airway obstruction in 16 patients (mean values of FEV1 68.8 +/- 17.5% and FVC 84.8 +/- 19.6%), and lung involvement. After introducing the treatment and achieving stable remission, asthma severity/control and lung function tests (forced expiratory volume in 1 s 92.7 +/- 13.3%, and forced vital capacity 101 +/ 15.5%; p < .001) improved. CONCLUSIONS: Asthma in CSS, although severe as its onset improves after achieving CSS remission. PMID- 21247354 TI - The Waters Bioanalysis World Tour: insights into the next decade of regulated bioanalysis. PMID- 21247353 TI - Mechanisms for Env glycoprotein acquisition by retroviruses. AB - A mandatory step in the formation of an infectious retroviral particle is the acquisition of its envelope glycoprotein (Env). This step invariably occurs by Env positioning itself in the host membrane at the location of viral budding and being incorporated along with the host membrane into the viral particle. In some ways, this step of the viral life cycle would appear to be imprecise. There is no specific sequence in Env or in the retroviral structural protein, Gag, that is inherently required for the production of an infectious Env-containing particle. Additionally, Env-defective proviruses can efficiently produce infectious particles with any of a number of foreign retroviral Env glycoproteins or even glycoproteins from unrelated viral families, a process termed pseudotyping. However, mounting evidence suggests that Env incorporation is neither passive nor random. Rather, several redundant mechanisms appear to contribute to the carefully controlled process of Env acquisition, many of which are apparently used by a wide variety of enveloped viruses. This review presents and discusses the evidence for these different mechanisms contributing to incorporation. PMID- 21247355 TI - Recent insights into the mechanism and consequences of TRIM5alpha retroviral restriction. AB - The cellular factor TRIM5alpha inhibits infection by numerous retroviruses in a species-specific manner. The TRIM5alpha protein from rhesus macaques (rhTRIM5alpha) restricts infection by HIV-1 while human TRIM5alpha (huTRIM5alpha) restricts infection by murine leukemia virus (MLV). In owl monkeys a related protein TRIM-Cyp restricts HIV-1 infection. Several models have been proposed for retroviral restriction by TRIM5 proteins (TRIM5alpha and TRIM-Cyp). These models collectively suggest that TRIM5 proteins mediate restriction by directly binding to specific determinants in the viral capsid. Through their ability to self associate TRIM5 proteins compartmentalize the viral capsid core and mediate its abortive disassembly via a poorly understood mechanism that is sensitive to proteasome inhibitors. In this review, we discuss TRIM5-mediated restriction in detail. We also discuss how polymorphisms within human and rhesus macaque populations have been demonstrated to affect disease progression of immunodeficiency viruses in these species. PMID- 21247356 TI - Lipolytic function of adipocyte/endothelial cocultures. AB - The rising incidence of adipose-related disorders such as obesity has prompted increased interest in the in vitro development of functional human soft tissues to study the disease and treatment options. Further, soft tissues maintained in vitro with a capacity to resemble in vivo tissues in structure and metabolic function would help gain insight into mechanisms involved in adipose tissue development. In the current study, the metabolic potential of adipose/endothelial cocultures on three-dimensional silk fibroin scaffolds was studied. Endothelial contributions to adipose lipogenesis and lipolysis were the focus of the study. Triglyceride accumulation, adipogenic gene transcript expression, and basal lipolysis measurements demonstrated the ability of this coculture system to retain metabolic levels obtained in adipocyte monocultures. Additionally, basal lipolysis was stimulated in mono- and coculture systems to a similar extent at 1.6- and 1.9-fold over controls, respectively. The ability to maintain adipose functions in these cocultures represents a step forward in the development of a tissue-engineered adipose tissue system exhibiting both endothelial lumens and metabolic functions. PMID- 21247357 TI - Defects in cholesterol synthesis genes in mouse and in humans: lessons for drug development and safer treatments. AB - This review describes the mouse knockout models of cholesterol synthesis, together with human malformations and drugs that target cholesterogenic enzymes. Generally, the sooner a gene acts in cholesterol synthesis, the earlier the phenotype occurs. Humans with loss of function of early cholesterogenic enzymes have not yet been described, and in the mouse, loss of Hmgcr is preimplantation lethal. Together, these results indicate that the widely prescribed cholesterol lowering statins are potentially teratogenic. The Mvk knockout is early embryonic lethal in the mouse, the absence of Fdft1 is lethal at E9.5-12.5 dpc, while the Cyp51 knockouts die at 15.0 dpc. Fungal CYP51 inhibitor azoles are teratogenic in humans, potentially leading to symptoms of Antley-Bixler syndrome. The X-linked mutations in Nsdhl and Ebp are embryonic lethal in male mice, while heterozygous females are also affected. Consequently, the anticancer drugs, tamoxifen and toremifene, inhibiting human EBP, may be harmful in early pregnancy. The Dhcr7 and Dhcr24 knockout mice die shortly after birth, while humans survive with Smith Lemli-Opitz syndrome or desmosterolosis. Since cholesterol is essential for hedgehog signaling, disturbance of this pathway by antipsychotics and depressants explains some drug side effects. In conclusion, defects in cholesterol synthesis are generally lethal in mice, while humans with impaired later steps of the pathway can survive with severe malformations. Evidence shows that drugs targeting or, by coincidence, inhibiting human cholesterol synthesis are better avoided in early pregnancy. Since some drugs with teratogenic potential still stay on the market, this should be avoided in new cholesterol related drug development. PMID- 21247359 TI - Improving progression-free and overall survival in patients with cancer: a potential role for bisphosphonates. AB - INTRODUCTION: Bisphosphonates are a well-established therapy for patients with multiple myeloma or bone metastases from advanced cancers and are used routinely to delay the onset and reduce the risk of skeletal-related events. Emerging evidence indicates that they also may provide additional anticancer benefits. These developments warrant reappraisal of their role in patients with cancer and reevaluation of optimal therapeutic regimens. AREAS COVERED: This article reviews the evidence of the anticancer activity of bisphosphonates in patients with solid tumors or multiple myeloma. The underlying mechanisms of the anticancer activity of bisphosphonates are elucidated from preclinical and translational data that show that bisphosphonates suppress tumor growth and survival, inhibit tumor mediated angiogenesis, or stimulate host anticancer immune response. These data also provide insights into the potential for therapeutic combinations. Preclinical and clinical data relating to the anticancer effects of bisphosphonates are reviewed by cancer type. EXPERT OPINION: Future trials of bisphosphonates in cancer patients will explore the underlying mechanism of the anticancer benefit in greater detail and attempt to examine critically the potential clinical benefit in individual cancer types in early/advanced disease. PMID- 21247358 TI - Emerging treatments for noise-induced hearing loss. AB - INTRODUCTION: Approximately 5% of the population worldwide suffers from industrial, military or recreational noise-induced hearing loss (NIHL) at a great economic cost and detriment to the quality of life of the affected individuals. This review discusses pharmacological strategies to attenuate NIHL that have been developed in animal models and that are now beginning to be tested in field trials. AREAS COVERED: The review describes the epidemiology, pathology and pathophysiology of NIHL in experimental animals and humans. The underlying molecular mechanisms of damage are then discussed as a basis for therapeutic approaches to ameliorate the loss of auditory function. Finally, studies in military, industrial and recreational settings are evaluated. Literature was searched using the terms 'noise-induced hearing loss' and 'noise trauma'. EXPERT OPINION: NIHL, in principle, can be prevented. With the current pace of development, oral drugs to protect against NIHL should be available within the next 5-10 years. Positive results from ongoing trials combined with additional laboratory tests might accelerate the time from the bench to clinical treatment. PMID- 21247360 TI - The optimal pharmacological formula for percutaneous coronary intervention. AB - INTRODUCTION: Adjunctive pharmacotherapy is of key importance in determining the outcomes of percutaneous coronary intervention (PCI). In parallel, there has been an increasing body of evidence indicating that the aggressive management of coronary risk factors and changes in lifestyle behavior yield additional positive results in morbidity and mortality reductions. A stream of new data from randomized clinical trials has recently prompted the release of a focused update of the PCI guidelines, endorsing new recommendations on the use of antiplatelet drugs and parenteral anticoagulants. AREAS COVERED: The aim of this manuscript is to provide an up-to-date overview of the current evidence on the use of adjunctive pharmacological therapy in patients undergoing revascularization, with focus on results of recent trials and future directions. EXPERT OPINION: Given the availability of several pharmacological agents with different mechanisms of action, understanding whether a drug should or should not be prescribed, as well as individualizing the pharmacological formula to the patient's need and risk category, is pivotal to balance the safety and efficacy of adjunctive therapies for PCI. Studies on new antiplatelet agents and selective inhibitors of specific coagulation factors are likely to characterize the next years of research on interventional pharmacology. PMID- 21247361 TI - Fondaparinux for the treatment of superficial vein thrombosis in the legs: the CALISTO study. AB - Superficial vein thrombosis (SVT) is quite a common disease that is associated with a non-negligible risk of progression to the deep venous system and, in some cases, of embolization to the lungs. However, SVT has traditionally been regarded as a benign disease and its optimal management has been poorly studied. Recently, fondaparinux, a subcutaneous, selective, indirect Factor Xa inhibitor, has been assessed in the treatment of SVT in the CALISTO study, with encouraging results. Fondaparinux was found to be more effective than placebo in reducing the risk of SVT extension or progression to deep vein thrombosis or pulmonary embolism without a significant increase in the risk of bleeding. Treatment of SVT with a once-daily, 2.5 mg injection of fondaparinux without the need for platelet monitoring appears as a simple, effective, and well-tolerated strategy, and has the potential to change the clinical management of SVT. PMID- 21247362 TI - Treating tension-type headache -- an expert opinion. AB - INTRODUCTION: Tension-type headache (TTH) is a highly prevalent disorder with enormous costs for the individual and the society. AREAS COVERED: Nonpharmacological and pharmacological treatments are reviewed. Electromyographic (EMG) biofeedback has a documented effect in TTH, while cognitive-behavioral therapy and relaxation training are most likely to be effective. Physical therapy and acupuncture may be valuable options for patients with frequent TTH. Simple analgesics and nonsteroidal anti-inflammatory drugs are recommended for treatment of episodic TTH. Combination analgesics containing caffeine are drugs of second choice. Triptans, muscle relaxants and opioids should not be used. It is crucial to avoid frequent and excessive use of analgesics to prevent the development of medication-overuse headache. The tricyclic antidepressant amitriptyline is the drug of first choice for the prophylactic treatment of chronic TTH. Mirtazapine and venlafaxine are second-choice drugs. EXPERT OPINION: There is an urgent need for more research in nonpharmacological as well as pharmacological treatment possibilities of TTH. Future studies should examine the relative efficacy of the various treatment modalities and clarify how treatment programs can be optimized and combined to best suit the individual patient. Frequent TTH may be difficult to treat, but an acceptable result can usually be obtained by a combination of nonpharmacological and pharmacological treatments. PMID- 21247363 TI - Engineering adipose tissue from uncultured human adipose stromal vascular fraction on collagen matrix and gelatin sponge scaffolds. AB - Adipogenic potential was evaluated in uncultured stromal vascular fraction (SVF) loaded onto porous 3D collagen matrix and gelatin sponge scaffolds with predefined shapes. The SVF was isolated from 16 freshly lipectomized fat. Mean cell number was 6.0+/-4.68*10(7) cells/mL, and mean cell viability was 72%. Flow cytometric analysis revealed adipose-derived stromal cells (CD31(-), CD34(-/+), CD45(-), CD90(+), CD105(-), CD146(-), and CD166(+)) in the SVF. Three hours after harvest of fat, 200 MUL of isolated SVF was loaded onto an experimental scaffold (4 mg in weight) and cultured in Dulbecco's modified Eagle's medium. Examination of the construct under an inverted light microscope and a scanning electron microscope demonstrated adequate seeding and active proliferation of the SVF cells on pore surfaces. Cells grew to varying sizes in clusters or in strands. On day 28, histologic study of the constructs by H&E staining revealed viable adipocytes in the microstructure. Positive Oil-Red O stain confirmed lipid accumulation in mature adipocytes. The presence of human adipocytes was further assessed by the presence of genomic DNA detected by GAPDH gene and by the mRNA expression of peroxisome proliferator activated receptor-gamma, and lipoprotein lipase. The results demonstrated that new adipose tissue can be regenerated by seeding freshly isolated, uncultured SVF on 3D porous collagen matrix and gelatin sponge scaffolds. PMID- 21247364 TI - Cathepsin S inhibitors: WO2010070615. AB - This article evaluates a patent application of the company Medivir (SE/UK) describing the synthesis of dipeptide-derived alpha-ketoamides containing a propylene glycine moiety in P1 as selective inhibitors of cathepsin S for the potential treatment of various systemic human diseases such as several autoimmune diseases, MS, rheumatoid arthritis, endometriasis and chronic pain. The claims of the patent are discussed in light of recent results in the field of cathepsin S research. PMID- 21247365 TI - Safety of perioperative beta-blocker use: how do beta-blockers compare in terms of side effects? AB - INTRODUCTION: In the perioperative setting, there is still a high incidence of adverse cardiac events due to sudden coronary plaque rupture or oxygen supply demand imbalance. beta-Blockers play an important role in preventing these cardiac events. Discussion, however, remains on the side effects accompanying this therapy. AREAS COVERED: The evidence for perioperative use of beta-blockers is summarized in this review in terms of risk reduction, perioperative safety and current clinical use. Furthermore, data on pharmacokinetics, pharmacodynamics and pharmacogenetics are presented. EXPERT OPINION: In perioperative care, beta blockers are recommended and can be given safely when started early in a low dose, titrated to heart rate. In the future, there could be a place for added perioperative short-acting beta-blockers to further optimize heart rate control. PMID- 21247366 TI - Amelioration of experimental colitis by a novel nanoselenium-silymarin mixture. AB - BACKGROUND: Silymarin has intracellular antioxidant property and inhibits activation of nuclear factor-kappaB (NF-kappaB) in low concentrations and reduces tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6 levels, cyclooxygenase (COX), and angiogenesis. Selenium is one of the necessary trace element nutrients for human and animals. Selenium nanoparticles (nano-Se) have more bioavailability with less toxicity. AIMS: To investigate the combination effect of silymarin and nano-Se on inhibition of NF-kappaB, proinflammatory cytokines, and oxidative stress biomarkers in the experimental colitis. METHODS: Trinitrobenzene sulfonic acid (TNBS) was used to induce colitis. After TNBS instillation, rats were distributed into six groups, containing silymarin and nano-Se alone or in combination, dexamethasone, negative control with no treatment and the last one was normal sham rats. All drugs were administered for 7 days. Colon samples were scored macroscopically and microscopically. The levels of activated NF-kappaB, IL-1beta, TNF-alpha, myeloperoxidase (MPO), lipid peroxidation, protein carbonyl (PC), and the antioxidant power of the colon homogenates were determined. RESULT: A significant decrease in NF-kappaB activity in treated groups was observed. The levels of TNF alpha, IL-1beta, MPO, lipid peroxidation, and PC were reduced and an improvement in antioxidant power of treated groups was seen. Combination of silymarin and nano-Se were more effective than each one alone in improvement of NF-kappaB, TNF alpha, antioxidant power, and lipid peroxidation values, although this difference was not significant in other factors. CONCLUSION: Co-administration of silymarin and nano-Se with a good antioxidant profile and inhibition of NF-kappaB is a possible candidate for better management of inflammatory bowel disease. PMID- 21247367 TI - Tryptophan degradation and serum neopterin concentrations in intensive care unit patients. AB - Alterations in neopterin concentrations and tryptophan degradation accompany the activation of cellular immune systems. Accordingly, in a variety of diseases, mainly in infections, elevated neopterin levels and tryptophan degradation have been observed. This study aimed to assess serum neopterin levels and tryptophan degradation in intensive care unit (ICU) patients with systemic inflammatory response syndrome (SIRS, n = 9), sepsis (n = 8), septic shock (n = 10), and multiple organ dysfunction syndrome (MODS, n = 7) at the first day of ICU hospitalization. The kynurenine-to-tryptophan (kyn/trp) ratio was used in order to evaluate the degree of tryptophan degradation. The results of each patient group were compared with the control group (n = 30). The differences among the ICU groups and the correlations between APACHE II scores and neopterin concentrations or tryptophan degradation were investigated. All patient groups presented statistically higher kyn/trp and neopterin levels than the controls. The sepsis, septic shock, and MODS group had markedly higher neopterin levels than the SIRS group (all P < 0.05). Additionally, it was found that the survivor group had significantly lower neopterin levels compared with non-survivors (P < 0.05) and lower kyn/trp, but the latter difference was not significant. Neopterin levels and kyn/trp were both correlated with APACHE II score (both P < 0.05). The results indicate that serum neopterin levels and tryptophan degradation correlate well with the severity of the disease in ICU patients, and this was true even at the first day of hospitalization in the unit. PMID- 21247368 TI - Leptin and adiponectin in obese and non-obese subjects with asthma. AB - OBJECTIVE: To understand the role of leptin and adiponectin in obese asthmatics. METHODS: We compared serum leptin, adiponectin and sputum leptin levels in 44 non obese and 44 obese subjects. RESULTS: We found higher serum leptin (P < 0.0001) and lower adiponectin (P = 0.0002) levels in obese asthmatics. Sputum leptin was correlated with body mass index (BMI; r = 0.34, P = 0.03) and serum leptin (r = 0.43, P = 0.005); however, this last correlation was not significant after adjusting for BMI (r = 0.26, P = 0.11). CONCLUSION: Airway inflammation in obese asthmatics may present a different pattern involving leptin. Sputum leptin levels may partially originate from systemic circulation, with other contributing mechanisms. PMID- 21247369 TI - Effect of vernolide-A, a sesquiterpene lactone from Vernonia cinerea L., on cell mediated immune response in B16F-10 metastatic melanoma-bearing mice. AB - One of the major reasons for the rapid progression of cancers is the ability of tumor cells to escape from the immune surveillance mechanism of the body. Modulation of immune responses is highly relevant in tumor cell destruction. Effect of vernolide-A on the cell-mediated immune (CMI) response in metastatic condition was studied using C57BL/6 mice model. Administration of vernolide-A enhanced natural killer (NK) cell activity, antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent complement-mediated cytotoxicity (ACC) and the activity was observed in treated group much earlier compared with the metastatic tumor-bearing control. Administration of vernolide-A significantly enhanced the production of interleukin (IL)-2 and interferon-gamma (IFN-gamma) in metastatic tumor-bearing animals. In addition, vernolide-A significantly down regulated the serum levels of proinflammatory cytokines such as IL-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony stimulating factor (GM-CSF) during metastasis. All these results demonstrate that vernolide-A could enhance the immune response against metastatic progression of B16F-10 melanoma cells in mice. PMID- 21247370 TI - Reduction of interleukin-1beta induced matrix metalloproteinase-3 release by extracts of six plants: inhibitory screening of 35 traditional medicinal plants. AB - Rheumatoid arthritis (RA) is a chronic inflammatory joint disease associated with matrix metalloproteinase (MMP)-3, leading to destruction of the cartilage. The objective of this study was to investigate and discuss the suitability of the 35 medicinal plants as therapeutic candidates to treat RA. Fibroblast-like synoviocytes (FLSs), derived from patients with RA, were adjusted to 2 * 10(6) cells/mL in a 24-well plate and pretreated with the distilled water extracts of the 35 plants (1, 10, and 100 ug/mL) for 1 h followed by interleukin-1beta (IL 1beta) (1 ng/mL) for 24 h. The concentration of MMP-3 was then determined using a Duoset ELISA Kit. The six plants (Artemisiae Capillaris Herba, AC; Bambusae Caulis In Taeniam, BC; Cassiae Semen, CS; Corni Fructus, CF; Leonuri Herba, LH; Schizonepetae Spica, SS) showed no toxicity, including MMP-3. The MMP-3 level was increased by 3.38-fold (212.23 MUg/mL) in IL-1beta-stimulated FLSs. The IL-1beta induced MMP-3 level was significantly and dose-dependently reduced by >50% by the six plants (P < 0.01: at 100 MUg/ mL of CS and LH, P < 0.001: at 10 MUg/mL of all plants, and at 100 MUg/mL of AC, BC, CF, and SS). This is the first study on the MMP-3 inhibitory effect of the examined plants in FLSs isolated from RA patients. From our original research, the six candidate plants were identified. PMID- 21247371 TI - Genetic polymorphisms in placental transporters: implications for fetal drug exposure to oral antidiabetic agents. AB - INTRODUCTION: The prevalence of diabetes among women of childbearing age is increasing. This will inevitably increase the number of pregnancies complicated by diabetes. The management of diabetes mellitus often necessitates the use of oral antidiabetic drugs including biguanides, sulfonylureas, metiglinide analogs and thiazolidinediones. However, a significant concern with the use of these agents in pregnancy is the potential for developmental toxicity. Various antidiabetic drugs have been identified as substrates for transporters present in the syncytiotrophoblast. Therefore, the extent of transfer and fetal exposure to oral antidiabetic drugs used in pregnancy may be altered by polymorphisms in genes encoding these transport proteins. AREAS COVERED: This review covers current research examining genetic polymorphisms in transporters expressed in the syncytiotrophoblast and evidence supporting the involvement of these transporters in the transport of oral antidiabetic agents. The aim is to provide insight into how the transfer of antidiabetic drugs across the placental trophoblast may be altered by polymorphisms in drug transporters. EXPERT OPINION: There is a paucity of studies examining the influence of polymorphisms on transporter activity in the placenta and how the transfer of oral antidiabetics may be altered. Further research employing in vivo models is required to allow for the prediction of the potential consequences of polymorphisms on placental transporter expression and function. PMID- 21247372 TI - Evaluation of hydrophilic matrix tablets based on Carbopol((r)) 971P and low viscosity sodium alginate for pH-independent controlled drug release. AB - BACKGROUND: The aim of this study was to evaluate matrix tablets containing different ratios of Carbopol((r)) 971P (CP) to low-viscosity sodium alginate (SA) and assess their suitability for pH-independent controlled drug release. METHODS: Two processing methods (physical mixing, PM and spray-drying, SD) were applied before compaction and the release from corresponding matrices was compared. The release from CP-SA PM matrices was also investigated using three model drugs (paracetamol, salicylic acid, and verapamil HCl) and two dissolution media (0.1 N HCl or phosphate buffer, pH = 6.8), and the release rate, mechanism, and pH dependence were characterized by fitting of Higuchi and Peppas models, and evaluation of similarity factor. Furthermore, swelling behavior of CP-SA matrix tablets was studied for evaluating its impact on drug release. RESULTS: The processing method (SD or PM) markedly affected the drug release from CP-SA matrices. ANOVA tests showed significant effects of the CP:SA ratio and drug type on the release rate (expressed by the constant, K(H), from Higuchi model) and of the dissolution medium on the release mechanism (expressed by the exponent, n, from Peppas model). Similarity factor (f2) indicated that the CP:SA ratios >= 25:75 and >= 50:50 were suitable for pH-independent release of paracetamol and salicylic acid, respectively, although for verapamil HCl, the matrix with low CP:SA ratio (0:100) showed remarkably reduced pH-dependence of release. Swelling parameters (water uptake and mass loss) were significantly changed with experimental variables (CP:SA ratio, medium, and time) and were in good correlation with drug release. CONCLUSION: Matrix tablets based on CP and SA form a potentially useful versatile system for pH-independent controlled drug release. PMID- 21247373 TI - Semi-solid dosage form of clonazepam for rapid oral mucosal absorption. AB - BACKGROUND: In order to obtain an alternative to the intravenous (i.v.) dosage form of clonazepam (CZ), an oral droplet formulation of CZ was developed previously; however, the droplet was physically unstable. Therefore, in the present study, it was attempted to develop an easily-handled dosage form, which was more physically stable and allowed rapid drug absorption from oral mucosa. METHOD: A semi-solid dosage form, composed of polyethylene glycol 1500 (PEG), CZ, and oleic acid (OA) at 37/1/2 (w/w) and named PEG/CZ/OA, and a semi-solid dosage form containing PEG and CZ at 39/1 (w/w), called PEG/CZ, were prepared. Their physical stability in air at room temperature and oral mucosal absorption in rats were investigated. RESULTS: The semi-solid dosage forms were much more stable physically than the droplet, that is, no recrystallization of CZ was observed for at least 8 days. The effective concentration for humans and rats (20 ng/mL or more) was achieved within 30 min after buccal administration for both PEG/CZ/OA and PEG/CZ. The plasma concentration increased gradually and less varied at each time point for PEG/CZ/OA. PEG/CZ/OA was found to show more rapid and higher absorption of CZ in buccal administration than in sublingual administration. CONCLUSION: Buccal administration with the semi-solid dosage PEG/CZ with or without OA was suggested to be a possibly useful novel dosage form as an alternative to i.v. injection. PMID- 21247374 TI - Characterising the surface adhesive behavior of tablet tooling components by atomic force microscopy. AB - PURPOSE: The aim of this study is to develop an atomic force microscopy (AFM) based approach to study the adhesive forces between tabletting punches and model formulation ingredients, that can ultimately be used to understand and predict issues such as sticking during tabletting compression. METHODS: Adhesive interactions were studied between single lactose particles and coated tablet punches. The adhesion was measured at varying relative humidities (RHs) and the influence of surface roughness was investigated. Roughness parameters were measured with AFM imaging and a modeling approach used to predict the influence of roughness on adhesion. RESULTS: Surface roughness was found to play a significant role in the observed lactose-punch adhesion and the variation of this adhesion across the punch surface. Such differences between punches can be correlated to observations from industrial use. Adhesion forces were spatially mapped to identify "hot spots" of high adhesion. A modeling approach can predict the relative adhesion of different surfaces from roughness data. The adhesion was also significantly affected by RH, for one type of punch causing a greater than 3? increase in adhesion between 30 and 60% RH. Interestingly, different punches showed different RH-adhesion behavior, relating to their hydrophilicity. CONCLUSIONS: The work introduces a new method for screening tablet punch materials and tabletting conditions. Important factors to be considered when evaluating adhesive interactions in tablet compression have been highlighted. Correlations are observed between AFM adhesion results and tabletting behavior during manufacture. This provides a promising basis for a predictive approach toward combating tabletting issues. PMID- 21247375 TI - Daidzein/cyclodextrin/hydrophilic polymer ternary systems. AB - OBJECTIVE: To evaluate the effect of different cyclodextrins (beta-cyclodextrin [beta-CD], methyl-beta-cyclodextrin [Mbeta-CD], or hydroxypropyl-beta cyclodextrin [HPbeta-CD]) and/or hydrophilic polymers (carboxymethylcellulose, hydroxypropylmethylcellulose [HPMC], polyethyleneglycol, or polyvinylpyrrolidone [PVP]) on daidzein solubility in water. MATERIALS AND METHODS: The corresponding associations were characterized in aqueous media using phase-solubility studies. The morphology of daidzein/cyclodextrin freeze-dried complexes was characterized using scanning electron microscopy, and their spatial configuration was proposed by means of nuclear magnetic resonance spectroscopy. RESULTS AND DISCUSSION: In the presence of 6 mM of cyclodextrins, the solubility of daidzein in water was significantly enhanced: 5.7-fold (beta-CD), 7.2-fold (Mbeta-CD), and 9.4-fold (HPbeta-CD). The analysis of the three solid complexes proved that the formation of inclusion complexes occurred through the insertion of the B and C rings of daidzein molecule into the cyclodextrins cavity. The association of daidzein/cyclodextrin complexes to the hydrophilic polymers HPMC or PVP (1%, w/w) was able to improve the solubility of daidzein even further. CONCLUSION: The highest solubilizing effect was obtained for daidzein/HPbeta-CD/PVP ternary system (12.7-fold). PMID- 21247376 TI - Generation of cell-derived three dimensional extracellular matrix substrates from two dimensional endothelial cell cultures. AB - Within the cellular microenvironment, extracellular matrix (ECM) proteins are critical nonsoluble signaling factors that modulate cell attachment, migration, proliferation, and differentiation. We have developed a simple method to isolate and process ECM from endothelial cell cultures to create a three-dimensional (3D) ECM substrate. Endothelial cell monolayers were chemically lysed and enzymatically digested to isolate a thin, two-dimensional (2D) ECM substrate. This thin 1.8 MUm 2D ECM was collected and applied to a solid support to produce 12-16-fold thicker 3D ECM substrates with average thicknesses ranging from 21 to 29 MUm. The biological activity of isolated ECM was assessed by cell culture. Neural progenitor cells were cultured on endothelial-produced ECM, and unlike the thin 2D ECM, which was quickly remodeled by cells, 3D ECM substrates remained in culture for an extended period (>7 days), suggesting that a continuous signaling cue for in vitro experiments may be provided. This simple method for creating 3D ECM substrates can be applied to a variety of cell culture models for studies aimed at identifying the signaling effects of the ECM within cellular microenvironments. PMID- 21247379 TI - Novel strategies in therapy of head and neck cancer. AB - In addition to the currently available conventional therapeutic modalities i.e. chemotherapy, radiotherapy and surgery, there is a desperate need for more effective and less toxic therapies for head and neck malignancies. Chemotherapy alone shows high toxicity and a low survival rate. In some cases, malignant cells develop resistance to a particular drug and to combat this, a variety of approaches like intra-arterial therapy, induction chemotherapy, immunotherapy, photodynamic therapy as well as targeted molecular therapy have recently been employed. Techniques like intra-arterial and induction chemotherapy have showed some improvement in survival rate. Immununotherapy is in the experimental stages while photodynamic therapy is being clinically applied, but because of its side effects it is not very popular. Utilizing specific molecular targets with their inhibitors (like inhibitors of EGFR and VEGF); either alone or in combination with conventional therapy, may improve the survival rate of these patients. Blocking the signaling pathway (P13k/Akt/mTOR), with or without chemotherapy, may also overcome the problem of drug resistance. These modalities hold the promise of being more selective - harming fewer normal cells, reducing side effects and improving the quality of life. The various options and novel strategies currently available to the treating physician are critically examined in this review. PMID- 21247378 TI - Cytokines, inflammation and colon cancer. AB - Patients with inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, are at increased risk of developing colon cancer, confirming that chronic inflammation predisposes to development of tumors. Moreover, it appears that colon cancers that do not develop as a complication of inflammatory bowel disease are also driven by inflammation, because it has been shown that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) lowers the mortality from sporadic colon cancer and results in regression of adenomas in familial adenomatous polyposis (FAP) patients, who inherit a mutation in the Apc gene. Colorectal cancer therefore represents a paradigm for the link between inflammation and cancer. Inflammation is driven by soluble factors, cytokines and chemokines, which can be produced by tumor cells themselves or, more often, by the cells recruited to the tumor microenvironment. Inflammatory cytokines and chemokines promote growth of tumor cells, perturb their differentiation, and support the survival of cancer cells. Tumor cells become addicted to inflammatory stroma, suggesting that the tumor microenvironment represents an attractive target for preventive and therapeutic strategies. Proinflammatory cytokines, such as TNFalpha, IL-6 and IL-1beta, or transcription factors that are required for signaling by these cytokines, including NF-kappaB and STATs, are indeed emerging as potential targets for anticancer therapy. TNFalpha antagonists are in phase I/II clinical trials and have been shown to be well tolerated in patients with solid tumors, and IL-1beta antagonists that ameliorate several inflammatory disorders characterized by excessive IL-1beta production, will likely follow. Therefore, development of drugs that normalize the tumor microenvironment or interrupt the crosstalk between the tumor and the tumor microenvironment is an important approach to the management of cancer. PMID- 21247380 TI - Peptidyl prolyl isomerase, Pin1 is a potential target for enhancing the therapeutic efficacy of etoposide. AB - The peptidyl prolyl isomerase (Pin1) that induces cis-trans isomerization of the peptide bond involving serine/threonine-proline has recently been shown to regulate the activity of many phosphoproteins including the ones involved in damage response pathways. We investigated Pin1 as a potential target for enhancing the efficacy of anticancer therapy by studying the effects of juglone, a Pin1 inhibitor on the cytotoxicity of etoposide (a widely used anticancer drug that targets topoisomerase IIalpha) in human tumor cell lines. Treatment of cells with juglone synergistically enhanced the cytotoxicity of etoposide (loss of clonogenicity) with a tenfold increase when etoposide treatment preceded juglone exposure. On the other hand, the toxicity was than additive when the treatment protocol was reversed (i.e exposure to juglone followed by etoposide treatment). This suggests that Pin1 inhibition possibly reduces the induction of initial DNA damage by etoposide, which was supported by a decrease in the levels of chromatin bound topoIIalpha. Increase in the etoposide induced toxicity by juglone appeared to be mainly due to enhanced mitotic cell death linked to cytogenetic damage, although a moderate increase in interphase (apoptotic) death was also evident as revealed by DNA degradation (hypodiploid population and TUNEL assay). Since the level of Pin1 is found to be higher in cancer cells, this enzyme could be a potential target for developing an adjuvant to enhance the efficacy of anticancer therapies. PMID- 21247381 TI - Autophagy: Molecular mechanisms and their implications for anticancer therapies. AB - Autophagy is a catabolic process whereby cells maintain homeostasis by eliminating unnecessary proteins and damaged organelles. It may be triggered under physiological conditions, such as nutrient starvation, or in response to a variety of stress stimuli, such as exposure to radiations or cytotoxic compounds. Although autophagy is basically a protective mechanism that sustains cell survival under adverse conditions, it has been recently demonstrated that the induction of autophagic process may ultimately lead to cell death. As for the role of autophagy in cancer, it is still very controversial whether it suppresses tumorigenesis or provides cancer cells with a rescue mechanism under unfavourable conditions. Therefore, the dual role of autophagy in tumor progression and in the response of cancer cells to chemotherapeutic drugs is still open to debate. The first part of this review describes the cellular events occurring during the various phases of the autophagic process. Special attention has been given to the morphological aspects and the regulatory molecules involved in autophagic cell death. Specifically, we have focused on the proteins necessary for autophagosome formation, encoded by the ATG (AuTophaGy-related gene) gene family, and their role in the regulation of the process of autophagy. We also examined the effects of autophagy modulators on cell survival and cell death and discussed the recent efforts aimed at finding novel agents that activate or inhibit autophagy by targeting regulatory molecules of the complex autophagy pathways. PMID- 21247383 TI - Disulfiram, and disulfiram derivatives as novel potential anticancer drugs targeting the ubiquitin-proteasome system in both preclinical and clinical studies. AB - Disulfiram is a FDA approved drug for the treatment of alcoholism and available for clinical use since over 5 decades. Despite data from the 1970s and 80s that showed that disulfiram and analogs are able to enhance the activity of anticancer cytotoxic drugs and might be useful chemopreventative agents, the underlying molecular mechanisms remained unknown until recently. Large scale screening efforts for agents that can inhibit the proteasome and be used as novel anticancer drugs, revealed that disulfiram has proteasome inhibitory activity. Moreover, disulfiram was also found to have specific activity against zinc fingers and RING-finger ubiquitin E3 ligases that play an important role in cancer development. Here, we review the preclinical and clinical studies exploring disulfiram as an anticancer agent as well as research programs that focus on the development of disulfiram derivatives as inhibitors of the ubiquitin proteasome system. PMID- 21247382 TI - Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials. AB - The proteasome has emerged as an important clinically relevant target for the treatment of hematologic malignancies. Since the Food and Drug Administration approved the first-in-class proteasome inhibitor bortezomib (Velcade) for the treatment of relapsed/refractory multiple myeloma (MM) and mantle cell lymphoma, it has become clear that new inhibitors are needed that have a better therapeutic ratio, can overcome inherent and acquired bortezomib resistance and exhibit broader anti-cancer activities. Marizomib (NPI-0052; salinosporamide A) is a structurally and pharmacologically unique beta-lactone-gamma-lactam proteasome inhibitor that may fulfill these unmet needs. The potent and sustained inhibition of all three proteolytic activities of the proteasome by marizomib has inspired extensive preclinical evaluation in a variety of hematologic and solid tumor models, where it is efficacious as a single agent and in combination with biologics, chemotherapeutics and targeted therapeutic agents. Specifically, marizomib has been evaluated in models for multiple myeloma, mantle cell lymphoma, Waldenstrom's macroglobulinemia, chronic and acute lymphocytic leukemia, as well as glioma, colorectal and pancreatic cancer models, and has exhibited synergistic activities in tumor models in combination with bortezomib, the immunomodulatory agent lenalidomide (Revlimid), and various histone deacetylase inhibitors. These and other studies provided the framework for ongoing clinical trials in patients with MM, lymphomas, leukemias and solid tumors, including those who have failed bortezomib treatment, as well as in patients with diagnoses where other proteasome inhibitors have not demonstrated significant efficacy. This review captures the remarkable translational studies and contributions from many collaborators that have advanced marizomib from seabed to bench to bedside. PMID- 21247384 TI - Green tea polyphenols as proteasome inhibitors: implication in chemoprevention. AB - Next to water, tea is the most popular beverage in the world. The most abundant and active compound in green tea is (-)-epigallocatechin-3-gallate (EGCG), which is extensively studied for its cancer-preventive and anti-cancer activities as well as its cellular targets. One potential molecular target of EGCG is the proteasome. While molecular docking and structure-activity relationship (SAR) analysis suggests that the ester carbon of EGCG is important for mediating its proteasome-inhibitory activity, EGCG is very unstable under physiological conditions. Therefore, a series of analogs were synthesized aiming to improve stability and bioavailability of EGCG. Among them, peracetate-protected or the prodrug of EGCG was found to have increased bioavailability, stability, and proteasome-inhibitory activities against various human cancer cells and tumors compared to EGCG, suggesting its potential use for cancer prevention and treatment. Epidemiological studies have indicated that green tea consumption is associated with the reduced risk of cancers, especially associated with the reduced risk of late stage of cancers. This risk reduction may be attributed not only to proteasome inhibition, but also to numerous other intracellular molecules targeted by EGCG that are involved in cell cycle regulation, apoptosis, angiogenesis, and metastasis. PMID- 21247386 TI - Clioquinol - a novel copper-dependent and independent proteasome inhibitor. AB - Clioquinol (5-chloro-7-iodo-quinolin-8-ol) was used in the 1950's-1970's as an oral anti-parasitic agent. More recently, studies have demonstrated that Clioquinol displays preclinical efficacy in the treatment of malignancy. Its anti cancer activity relates, at least in part, to its ability to inhibit the proteasome through mechanisms dependent and independent of its ability to bind heavy metals such as copper. By acting as a metal ionophore Clioquinol transports metal ions from the extracellular environment into the cell and mobilizes weakly bound intracellular stores. It then directs the metal to the proteasome resulting in disruption of this enzymatic complex. In addition, Clioquinol is capable of directly inhibiting the proteasome at higher concentrations. Thus, Clioquinol represents a novel therapeutic strategy to inhibit the proteasome. Given the prior toxicology and pharmacology studies, Clioquinol could be rapidly repositioned for a new anti-cancer indication. This review highlights the mechanism of action of Clioquinol as a proteasome inhibitor. In addition, it discusses the human pharmacology and toxicology studies and how this information would guide a phase I clinical trial of this agent for patients with malignancy. PMID- 21247385 TI - SCF E3 ubiquitin ligases as anticancer targets. AB - The SCF multisubunit complex (Skp1, Cullins, F-box proteins) E3 ubiquitin ligase, also known as CRL (Cullin-RING ubiquitin Ligase) is the largest E3 ubiquitin ligase family that promotes the ubiquitination of various regulatory proteins for targeted degradation, thus regulating many biological processes, including cell cycle progression, signal transduction, and DNA replication. The efforts to discover small molecule inhibitors of a SCF-type ligase or its components were expedited by the FDA approval of Bortezomib (also known as Velcade or PS-341), the first (and only) class of general proteasome inhibitor, for the treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma. Although Bortezomib has demonstrated a certain degree of cancer cell selectivity with measurable therapeutic index, the drug is, in general, cytotoxic due to its inhibition of overall protein degradation. An alternative and ideal approach is to target a specific E3 ligase, known to be activated in human cancer, for a high level of specificity and selectivity with less associated toxicity, since such inhibitors would selectively stabilize a specific set of cellular proteins regulated by this E3. Here, we review recent advances in validation of SCF E3 ubiquitin ligase complex as an attractive anti-cancer target and discuss how MLN4924, a small molecule inhibitor of NEDD8-activating enzyme, can be developed as a novel class of anticancer agents by inhibiting SCF E3 ligase complex via removal of cullin neddylation. Finally, we discuss under future perspective how basic research on SCF biology will direct the drug discovery efforts surrounding this target. PMID- 21247387 TI - Second generation proteasome inhibitors: carfilzomib and immunoproteasome specific inhibitors (IPSIs). AB - The ubiquitin-proteasome pathway (UPP) is an attractive chemotherapeutic target due to its intrinsically stringent regulation of cell cycle, pro-survival, and anti-apoptotic regulators that disproportionately favor survival and proliferation in malignant cells. A reversible first-in-class proteasome inhibitor, bortezomib, is Food and Drug Administration approved for multiple myeloma and relapsed/refractory mantle cell lymphoma and has proven to be extremely effective, both as a single agent and in combination. An irreversible second generation proteasome inhibitor, carfilzomib, has shown preclinical effectiveness against hematological and solid malignancies both in vitro and in vivo. Carfilzomib, a peptidyl-epoxyketone functions similarly to bortezomib through primary inhibition of chymotrypsin-like (ChT-L) activity at the b5 subunits of the core 20S proteasome. Carfilzomib is also currently achieving successful response rates within the clinical setting. In addition to conventional proteasome inhibitors, a novel approach may be to specifically target the hematological-specific immunoproteasome, thereby increasing overall effectiveness and reducing negative off-target effects. The immunoproteasome specific inhibitor, IPSI-001, was shown to have inhibitory preference over the constitutive proteasome, and display enhanced efficiency of apoptotic induction of tumor cells from a hematologic origin. Herein, we discuss the preclinical and clinical development of carfilzomib and explore the potential of immunoproteasome specific inhibitors, like IPSI-001, as a rational approach to exclusively target hematological malignancies. PMID- 21247389 TI - Targeting malignancies with disulfiram (Antabuse): multidrug resistance, angiogenesis, and proteasome. AB - An old drug, Antabuse (disulfiram), used for decades in alcohol aversion therapy, and its metabolite Ditiocarb were shown from 1970s to suppress cancer growth in vivo and even in human patients. The drug targets multidrug resistance, angiogenesis, invasion, and proteasome. Today, there are ongoing clinical trials of Antabuse as an adjuvant therapy against lung cancer and as a monotherapy against cancers metastasizing to liver. The larger clinical trials, if appropriate, will need support from governments and charities to get the generic drug into the clinic as a "non-profit" drug. PMID- 21247390 TI - Targeting tumor ubiquitin-proteasome pathway with new and old drugs. PMID- 21247391 TI - Nano drugs: novel agents for cancer chemo-therapy. PMID- 21247388 TI - Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. AB - Targeting the ubiquitin-proteasome pathway has emerged as a rational approach in the treatment of human cancer. Based on positive preclinical and clinical studies, bortezomib was subsequently approved for the clinical use as a front line treatment for newly diagnosed multiple myeloma patients and for the treatment of relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this drug has become the staple of treatment. The approval of bortezomib by the US Food and Drug Administration (FDA) represented a significant milestone as the first proteasome inhibitor to be implemented in the treatment of malignant disease. Bortezomib has shown a positive clinical benefit either alone or as a part of combination therapy to induce chemo-/radio-sensitization or overcome drug resistance. One of the major mechanisms of bortezomib associated with its anticancer activity is through upregulation of NOXA, which is a proapoptotic protein, and NOXA may interact with the anti-apoptotic proteins of Bcl-2 subfamily Bcl-X(L) and Bcl-2, and result in apoptotic cell death in malignant cells. Another important mechanism of bortezomib is through suppression of the NF kappaB signaling pathway resulting in the down-regulation of its anti-apoptotic target genes. Although the majority of success achieved with bortezomib has been in hematological malignancies, its effect toward solid tumors has been less than encouraging. Additionally, the widespread clinical use of bortezomib continues to be hampered by the appearance of dose-limiting toxicities, drug-resistance and interference by some natural compounds. These findings could help guide physicians in refining the clinical use of bortezomib, and encourage basic scientists to generate next generation proteasome inhibitors that broaden the spectrum of efficacy and produce a more durable clinical response in cancer patients. Other desirable applications for the use of proteasome inhibitors include the development of inhibitors against specific E3 ligases, which act at an early step in the ubiquitin-proteasome pathway, and the discovery of less toxic and novel proteasome inhibitors from natural products and traditional medicines, which may provide more viable drug candidates for cancer chemoprevention and the treatment of cancer patients in the future. PMID- 21247392 TI - Mean platelet volume: a link between thrombosis and inflammation? AB - Platelet activation is a link in the pathophysiology of diseases prone to thrombosis and inflammation. Numerous platelet markers, including mean platelet volume (MPV), have been investigated in connection with both thrombosis and inflammation. This review considers MPV as a prognostic and therapeutic marker as well as the factors influencing its measurement. Established cardiovascular risk factors, such as smoking, hypertension, dyslipidemia, and diabetes, can influence MPV, depending on confounding factors. Low-grade inflammation is one such factor. Evidence, particularly derived from prospective studies and a meta-analysis, suggest a correlation between an increase in MPV and the risk of thrombosis. High MPV associates with a variety of established risk factors, cardio- and cerebrovascular disorders, and low-grade inflammatory conditions prone to arterial and venous thromboses. High-grade inflammatory diseases, such as active rheumatoid arthritis or attacks of familial Mediterranean fever, present with low levels of MPV, which reverse in the course of anti-inflammatory therapy. Lifestyle modification, antihypertensive, lipid lowering and diet therapies can also affect MPV values, but these effects need to be investigated in large prospective studies with thrombotic endpoints. PMID- 21247393 TI - Evolving concepts concerning cardiac beta-adrenoceptor function in heart failure. AB - This review describes the clinical application of beta-adrenergic blocking drugs over time in patients with congestive heart failure. The different pharmacological properties of these drugs in relation to clinical outcomes raises questions as to their optimal desirable profile based on studies showing the undesirable effects of excessive beta(2)-AR activation. The rationale for the use of selective beta(2)-AR antagonists in heart failure is discussed. PMID- 21247394 TI - HDL therapy: two kinds of right? AB - Cardiovascular disease remains the leading cause of morbidity and mortality globally. The disease is largely controlled with interventions managing atherogenic lipids including LDL and triglycerides. However a number of studies have shown that increasing HDL levels is likely to provide better outcomes for patients suffering from this disease. There has been an extensive research effort into understanding how HDL levels are regulated in the body and which pathways can be targeted therapeutically. The HDL metabolic pathway is however overwhelmingly complex. This has provided only limited success in trialing drugs designed to raise HDL. To add to the complexity HDL itself is a heterogeneous population of particles and there is controversy surrounding which HDL particle is the most cardio-protective. In addition there is varying opinions on which of the HDL cellular receptors are more important in humans (as opposed to what has been discovered in mice) in regulating these effects. In this article we explore the evidence for and against using the currently suggested methods of raising HDL and provide some evidence for how the adverse effects of these drugs could be corrected. PMID- 21247395 TI - Targeting the platelet integrin GPIIb/IIIa. AB - The platelet integrin GPIIb/IIIa plays an essential role in thrombus formation through interactions with adhesive ligands and has emerged as a primary target for the development of anti-thrombotic agents. Receptor activation is under strict control, with activators, inhibitors, and signalling mechanisms controlling its conformation. Structural biology research has produced high resolution images defining the ligand binding site at the atomic level. Successful blockade of this ligand binding has validated GPIIb/IIIa as a therapeutic target in cardiovascular medicine. GPIIb/IIIa inhibitors were the first rationally designed anti-platelet agents and have been used effectively in a wide variety of clinical scenarios including unstable angina, myocardial infarction, and high risk percutaneous coronary interventions with and without intracoronary stenting. Three inhibitors (abciximab, eptifibatide, and tirofiban) are currently licensed for human use. Surprisingly, oral GPIIb/IIIa antagonists have not been successful and there is an unmet need for effective anti-GPIIb/IIIa drugs that cause less bleeding problems and that can be orally applied. Here we review our current knowledge about GPIIb/IIIa structure, signalling pathways and receptor function, the benefits and limitations of current GPIIb/IIIa blockers and we take a look forward how the lessons learned from the mixture of success and failure of GPIIb/IIIa blocker development can be transformed in new and better GPIIb/IIIa blockers. PMID- 21247396 TI - P-selectin antagonism in inflammatory disease. AB - Inflammation plays a fundamental role in many chronic diseases, including atherosclerosis associated cardiovascular disease. Adhesion of immune cells plays a critical role in the inflammatory response and indeed the pathophysiology of inflammatory related diseases. P-selectin is an inflammatory adhesion molecule, enabling the recruitment of leukocytes to the endothelium and to activated platelets involved with the growing thrombus. P-selectin is critical in the progression of atherosclerosis as evidenced by knockout animal models where P selectin knockout mice crossed with apoE deficient mice exhibit significantly reduced atherosclerosis and leukocyte recruitment in the plaque. A soluble form of P-selectin also exists, which may have pro-atherogenic and pro-thrombotic effects. Thus targeting of P-selectin remains a strong clinical candidate for developing novel therapeutic strategies in inflammatory diseases. This review will discuss the role of P-selectin and describe the function of P-selectin antagonists as clinical targets. PMID- 21247397 TI - Cytoprotection by natural and synthetic polyphenols in the heart: novel mechanisms and perspectives. AB - While many naturally occurring polyphenols have been shown to have therapeutic benefits against myocardial injury following ischemia-reperfusion in various experimental models, our studies have demonstrated that synthetic flavonoids may also have potent cardiac cytoprotective actions. Together with the results reported in the literature, we suggest that synthetic polyphenols may be an ideal replacement for natural compounds in the development of myocardial protective drugs. Polyphenols exert myocardial protective effects via antioxidant activities, preservation of nitric oxide, antiinflammatory activities and modulation of matrix metalloproteinases. Recent studies have identified some novel mechanisms that may also contribute to polyphenol-induced myocardial protection, including prevention of mitochondrial dysfunction, pharmacological preconditioning, and modulation of the function of enzymes involved in epigenetic modifications such as histone acetyltransferases. In addition to the protective effects against acute myocardial injury, there has been experimental evidence showing that polyphenols may also modulate the development of cardiac hypertrophy, ventricular remodeling and fibrosis after myocardial infarction. PMID- 21247398 TI - The biology and therapeutic potential of the DDAH/ADMA pathway. AB - Asymmetric dimethylarginine (ADMA) is an endogenously produced molecule that inhibits nitric oxide synthase and consequently may have adverse effects on physiology, in particular in the cardiovascular system. This review highlights the mechanisms involved in the synthesis and metabolism of ADMA and their role in the control of nitric oxide (NO) synthesis. We describe how the effects of both cellular and circulating ADMA can alter physiological function involving both NO dependent and independent pathways and go on to describe how the metabolism of ADMA by dimethylarginine dimethylaminohydrolase (DDAH) is the major endogenous mechanism by which ADMA levels are regulated. Furthermore, we discuss the association of ADMA concentrations with cardiovascular disease and how ADMA levels can be modulated therapeutically by altering its production and/or metabolism. Finally we discuss the effects of some of the current pharmaceutical therapies used to treat cardiovascular disease and their involvement in the modulation of the ADMA/DDAH pathway. PMID- 21247400 TI - Ectopic ATP synthase in endothelial cells: a novel cardiovascular therapeutic target. AB - Adenosine triphosphate (ATP) synthase produces ATP in cells and is found on the inner membrane of mitochondria or the cell plasma membrane (ectopic ATP synthase). Here, we summarize the functions of ectopic ATP synthase in vascular endothelial cells (ECs). Ectopic ATP synthase is involved in adenosine metabolism on the cell surface through its ATP generation or hydrolysis activity. The ATP/ADP generated by the enzyme on the plasma membrane can bind to P2X/P2Y receptors and activate the related signalling pathways to regulate endothelial function. The beta-chain of ectopic ATP synthase on the EC surface can recruit inflammatory cells and activate cytotoxic activity to damage ECs and induce vascular inflammation. Angiostatin and other angiogenesis inhibitors can have anti-angiogenic functions by inhibiting ectopic ATP synthase on ECs. Moreover, ectopic ATP synthase on ECs is a receptor for apoA-I, the acceptor of cholesterol efflux, which implies that endothelial ectopic ATP synthase is involved in cholesterol metabolism. Coupling factor 6 (CF6), a part of ectopic ATP synthase, is released from ECs and can inhibit prostacyclin synthesis and promote nitric oxide (NO) degradation to enhance NO bioactivity. Because ATP/ADP generated by ectopic ATP synthase can induce NO production, substances such as CF6 can inhibit NO generation by inhibiting surface ATP/ADP production. Thus, the components of ectopic ATP synthase are associated with regulation of vascular tone. Through these functions, ectopic ATP synthase on ECs is considered a potential and novel therapeutic target for atherosclerosis, hypertension and lipid disorders. PMID- 21247401 TI - Synthesis, characterization and in-vitro antiproliferative effects of novel 5 amino pyrazole derivatives against breast cancer cell lines. AB - In search of synthetic chemotherapeutic substances capable of inhibiting, retarding, or reversing the process of multistage carcinogenesis, we synthesised a series of novel 1-(4-methoxybenzyl)-3-cyclopropyl-1H-pyrazol-5-amine derivatives 9(a-h) by a nucleophilic substitution reaction and characterized by (1)H and (13)C nuclear magnetic resonance (NMR), liquid chromatography mass spectrometry (LC/MS), Fourier-transform infrared (FTIR), and elemental analysis. These novel compounds were evaluated for their efficacy in inhibiting VERO normal and MCF-7 breast cancer cells proliferation by trypan blue exclusion assay, MTT assay, [(3)H] thymidine incorporation assay and DNA fragmentation analysis. Among the series, some compounds exhibited interesting growth inhibitory effects against cell lines. From the Structure-Activity Relationship studies, it has been revealed that, both novel patented compounds and therapeutic protocols of N terminal pyrazole ring structures play key role in the antiproliferative activity. PMID- 21247399 TI - C-type natriuretic peptide (CNP): cardiovascular roles and potential as a therapeutic target. AB - Natriuretic peptides play a fundamental role in cardiovascular homeostasis by modulation of fluid and electrolyte balance and vascular tone. C-type natriuretic peptide (CNP) represents the paracrine element of the natriuretic peptide axis which complements the endocrine actions of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). CNP is produced by the endothelium and the heart and appears to play a prominent role in vascular and cardiac function, both physiologically and pathologically. This provides a rationale for the therapeutic potential of pharmacological interventions targeted to CNP signalling. This article provides an overview of the biology and pharmacology of CNP, with emphasis on the cardiovascular system, and discusses pathologies in which drugs designed to manipulate CNP signalling maybe of clinical benefit. PMID- 21247402 TI - Therapeutic targets in triple negative breast cancer - where are we now? AB - Triple negative breast cancers, defined by lack of expression of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (Her2/EGFR2/ERBB2), are increasingly gaining attention for its intricate relationship with basal-like and BRCA1-linked breast carcinomas, and its lack of effective tailored therapies. Triple negative breast tumors usually account for 10-20% of all breast cancers in Asian populations, similarly in Caucasian populations (10-23%), but occur at much higher frequencies in individuals of African descent (20-47%). In addition, triple negative breast cancers are usually of high histological grade and are accompanied by aggressive clinical behavior with shorter time to recurrences and death, and preference for metastasis to the brain and lungs. In this report, we would like to review recent patents and the relationship between triple negative and basal-like breast cancers, as well as BRCA1-linked breast carcinomas. Specifically, potential treatment modalities and current innovations that are designed for the predictive and prognostic values of triple negative breast tumors will be discussed. PMID- 21247403 TI - Targeting IGF-I, IGFBPs and IGF-I receptor system in cancer: the current and future in breast cancer therapy. AB - The IGF system plays a major role in growth, development and maintenance of homeostasis in normal cells and also contributes towards proliferation of malignant cells. Any disruption in the IGF system has its implications on growth retardation, atherosclerosis, insulin resistance and cancer. Imbalances in the IGF axis are known to contribute towards the progression of breast cancer. Due to the ubiquitous nature of the components of the IGF system, targeting specific members of the axis has gained attention over the past decades. The most elaborately investigated component as a therapeutic target in the system is the IGF-IR and studies have been pursued to inhibit IGF-IR by the administration of monoclonal antibodies and tyrosine kinase inhibitors. Very recently, a novel cell death receptor that binds specifically to IGFBP-3 was identified. It has also been shown that the IGFBP-3/IGFBP-3 receptor may be impaired in breast and prostate cancer. In this review, we present the mechanisms used to target the IGF system in various diseased states, emphasizing on breast cancer. We further discuss currently available therapeutic approaches and summarize the latest patents published in the field of IGF-I/IGF-IR and IGFBP-3/IGFBP-3R systems. PMID- 21247404 TI - Tamoxifen and its new derivatives in cancer research. AB - A major challenge in cancer research is to discover drugs with high selectivity and minor side-effects. Tamoxifen has been widely used for more than 30 years in breast cancer treatment and prevention. Tamoxifen acts mainly via estrogen receptors (ER), but also displays anti-tumor activity in breast cancer negative to ERs, suggesting other targets. Actually, tamoxifen has effects on several transduction pathways and diverse ion channels. Despite the successful use of tamoxifen, this drug produces some non-desirable side-effects by acting on different targets. However, such non-specificity of tamoxifen might be used to unravel new targets to inhibit tumor cell proliferation, to elucidate new mechanisms of action of tamoxifen and tamoxifen analogs, and finally, to design new more specific and potent drugs on the benefit of cancer patients. This review will briefly describe first the current and general aspects of tamoxifen and then will focus more deeply on various tamoxifen analogues and new uses of tamoxifen described in recent patents. We will describe the biological effects and the therapeutic targets of the new patented analogues, in order to offer an alternative panorama on tamoxifen-based chemotherapy. PMID- 21247405 TI - Production, novel assay development and clinical applications of monoclonal antibodies. AB - Since the advent of hybridoma technology 35 years ago, research on monoclonal antibodies has developed enormously. Monoclonal antibodies of mouse origin were the first to be produced and continue to be the most popular affinity reagents for investigating the proteome of all organisms. For their adaptability to a variety of biological assays monoclonal antibodies are key tools for basic research as well as for diagnosis and therapy of human diseases. Recently, the expanding demand of high-quality antibodies with better specificities has resulted in a significant improvement in traditional hybridoma production methods. Owing to the ability of these affinity reagents to selectively target tumour cells, cancer has been a major focus of programmes for monoclonal antibody development. This review focuses on patents related to the advances made in the monoclonal antibody manufacture, showing how the traditional production techniques were turned into alternative, faster and more effective methods. Other patents are focussed on new technologies in which monoclonal antibodies are employed for the development of high-performance screening assays. A conclusive series of patents is related to monoclonal antibodies which find application to the diagnosis and the treatment of specific cancer diseases such as haematological malignancies and solid tumours. PMID- 21247406 TI - Emerging therapies in the treatment of locally advanced squamous cell cancers of head and neck. AB - Head and neck squamous cell cancers (HNSCCs) represent 4 to 5% of all solid malignancies. Despite improvements in diagnostic techniques, 60% of patients will present with locally advanced HNSCCs with a median survival of about 12 months and 5-year overall survival of approximately 10-40%. Recent clinical trials have altered the treatment landscape by refining existing forms of radiation, incorporation of IMRT, choice of chemotherapeutic agents, introduction of biological and targeted therapy, immunotherapy and gene therapy. Cetuximab, a monoclonal antibody directed against the human epidermal growth factor receptor (EGFR), has recently been approved in combination with RT in patients with locally advanced HNSCCs. Antiangiogenic therapies and tyrosine kinase inhibitors (gefitinib and erlotinib) have also shown promise in the clinical trials. Vandetanib, an antagonist of both vascular endothelial growth factor receptor (VEGFR) and the EGFR is currently being tested in phase II trial. New patents on hypoxia-inducible factor 1 alpha, mesenchymal-epithelial transition factor, insulin-like growth factor or the PI3K/AKT/mTOR pathway, farnesyl transferase inhibitors have shown promise in the management of HNSCCs. Nevertheless, identification of predictive biomarkers of resistance or sensitivity to these therapies remains a fundamental challenge in the optimal selection of patients most likely to benefit from them. However, increase in efficacy comes at the cost of increased toxicity. The current review focuses on insight into recent patents and updates on the clinical trials using new investigational agents in the management for HNSCCs. PMID- 21247407 TI - Stem cell therapy for cardiovascular diseases: are we still at the beginning of a long road? PMID- 21247408 TI - Changes in cytosolic Mg2+ levels can regulate the activity of the plasma membrane H+-ATPase in maize. AB - Plant PM (plasma membrane) H+-ATPase, a major consumer of cellular ATP, is driven by the MgATP complex which may dissociate at low cytosolic Mg2+ activity. We investigated whether hydrolytic activity of PM H+-ATPase is inhibited at ATP concentrations exceeding the Mg2+ concentration. Activity in isolated maize PMs was measured at pH 6.5 in the presence of 5 mM Mg2+ (high) or 2 mM Mg2+ (low), whereas K+ was applied at concentrations of 155 mM (high) or 55 mM (low). In all experiments, with membrane vesicles either from roots or leaves, the enzyme activity decreased in the presence of Mg2+-free ATP. At inhibitory ATP concentrations, the activity was not influenced by the K+ concentration. The activity was restored after increasing the Mg2+ concentration. ATP inhibition also occurred at pH 7.5. Kinetic modelling shows that Mg2+-free ATP acted as a competitive inhibitor with a Ki in the range of the Km. Ki decreased by 75% at low K+ concentration. Ki was one order of magnitude lower at pH 7.5 compared with pH 6.5. The observed inhibition is consistent with a concept in which down regulation of the cytosolic Mg2+ activity is involved in (phyto)hormonal stress responses. PMID- 21247409 TI - A new principle of oligomerization of plant DEG7 protease based on interactions of degenerated protease domains. AB - Deg/HtrA proteases are a large group of ATP-independent serine endoproteases found in almost every organism. Their usual domain arrangement comprises a trypsin-type protease domain and one or more PDZ domains. All Deg/HtrA proteases form homo-oligomers with trimers as the basic unit, where the active protease domain mediates the interaction between individual monomers. Among the members of the Deg/HtrA protease family, the plant protease DEG7 is unique since it contains two protease domains (one active and one degenerated) and four PDZ domains. In the present study, we investigated the oligomerization behaviour of this unusual protease using yeast two-hybrid analysis in vivo and with recombinant protein in vitro. We show that DEG7 forms trimeric complexes, but in contrast with other known Deg/HtrA proteases, it shows a new principle of oligomerization, where trimerization is based on the interactions between degenerated protease domains. We propose that, during evolution, a duplicated active protease domain degenerated and specialized in protein-protein interaction and complex formation. PMID- 21247410 TI - Adult peripheral blood mononuclear cells transdifferentiate in vitro and integrate into the retina in vivo. AB - Adult peripheral blood-derived cells are able to differentiate into a variety of cell types, including nerve cells, liver-like cells and epithelial cells. However, their differentiation into retina-like cells is controversial. In the present study, transdifferentiation potential of human adult peripheral blood mononuclear cells into retina-like cells and integration into the retina of mice were investigated. Freshly isolated adult peripheral blood mononuclear cells were divided into two groups: cells in group I were cultured in neural stem cell medium, and cells in group II were exposed to conditioned medium from rat retinal tissue culture. After 5 days, several distinct cell morphologies were observed, including standard mononuclear, neurons with one or two axons and elongated glial like cells. Immunohistochemical analysis of neural stem cell, neuron and retina cell markers demonstrated that cells in both groups were nestin-, MAP2 (microtubule-associated protein)- and GFAP (glial fibrillary acidic protein) positive. Flow cytometry results suggested a significant increase in nestin-, MAP2- and CD16-positive cells in group I and nestin-, GFAP-, MAP2-, vimentin- and rhodopsin-positive cells in group II. To determine survival, migration and integration in vivo, cell suspensions (containing group I or group II cells) were injected into the vitreous or the peritoneum. Tissue specimens were obtained and immunostained 4 weeks after transplantation. We found that cells delivered by intravitreal injection integrated into the retina. Labelled cells were not detected in the retina of mice receiving differentiated cells by intraperitoneal injection, but cells (groups I and II) were detected in the liver and spleen. Our findings revealed that human adult peripheral blood mononuclear cells could be induced to transdifferentiate into neural precursor cells and retinal progenitor cells in vitro, and the differentiated peripheral blood mononuclear cells can migrate and integrate into the retina in vivo. PMID- 21247411 TI - RNA interference-mediated silencing of focal adhesion kinase inhibits growth of human malignant glioma xenograft in nude mice. AB - FAK (focal adhesion kinase), which plays a pivotal role in mediating cell proliferation, survival and migration, is frequently overexpressed in human malignant glioma. The expression of FAK increases with the advance of tumour grade and stage. Based on these observations, we hypothesized that attenuation of FAK expression may have inhibitory effects on the growth of malignant glioma. In the present study, human glioma cell line U251 was transfected with plasmids containing U6 promoter-driven shRNAs (small-hairpin RNAs) against human FAK using cationic liposome. The effects of FAK knockdown in U251 cells in vitro were analysed by using flow cytometry and PI (propidium iodide)-staining assays. Based on the encouraging in vitro results with FAK silencing, plasmids encoding FAK targeted shRNA were encapsulated by DOTAP (dioleoyltrimethylammonium propane):Chol (cholesterol) cationic liposome and injected via tail vein to evaluate its therapeutic efficiency on suppressing tumour growth in a human glioma xenograft model. PCNA (proliferating-cell nuclear antigen), CD34 immunostaining and TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay were used to assess the changes in tumour angiogenesis, apoptosis and proliferation respectively. The results indicated that DOTAP:Chol cationic liposome could deliver therapeutic plasmids systemically to tumour xenografts, resulting in suppression of tumour growth. Treatment with plasmid encoding FAK-targeted shRNA reduced mean tumour volume by approx. 70% compared with control groups (P<0.05), accompanied with angiogenesis inhibition (P<0.05), tumour cell proliferation suppression (P<0.05) and apoptosis induction (P<0.05). Taken together, our results demonstrated that shRNA-mediated silencing of FAK might be a potential therapeutic approach against human malignant glioma. PMID- 21247412 TI - SPECT/CT imaging of the lumbar spine in chronic low back pain: a case report. AB - Mechanical low back pain is a common indication for Nuclear Medicine imaging. Whole-body bone scan is a very sensitive but poorly specific study for the detection of metabolic bone abnormalities. The accurate localisation of metabolically active bone disease is often difficult in 2D imaging but single photon emission computed tomography/computed tomography (SPECT/CT) allows accurate diagnosis and anatomic localisation of osteoblastic and osteolytic lesions in 3D imaging. We present a clinical case of a patient referred for evaluation of chronic lower back pain with no history of trauma, spinal surgery, or cancer. Planar whole-body scan showed heterogeneous tracer uptake in the lumbar spine with intense localisation to the right lateral aspect of L3. Integrated SPECT/CT of the lumbar spine detected active bone metabolism in the right L3/L4 facet joint in the presence of minimal signs of degenerative osteoarthrosis on CT images, while a segment demonstrating more gross degenerative changes was more quiescent with only mild tracer uptake. The usefulness of integrated SPECT/CT for anatomical and functional assessment of back pain opens promising opportunities both for multi-disciplinary clinical assessment and treatment for manual therapists and for research into the effectiveness of manual therapies. PMID- 21247413 TI - Systematic review of clinical trials of cervical manipulation: control group procedures and pain outcomes. AB - OBJECTIVE: To characterize the types of control procedures used in controlled clinical trials of cervical spine manipulation and to evaluate the outcomes obtained by subjects in control groups so as to improve the quality of future clinical trials METHODS: A search of relevant clinical trials was performed in PubMed 1966-May 2010 with the following key words: "Chiropractic"[Mesh] OR "Manipulation, Spinal"[Mesh]) AND "Clinical Trial "[Publication Type]. Reference lists from these trials were searched for any additional trials. The reference lists of two prior studies, one review and one original study were also searched. Accepted reports were then rated for quality by 2 reviewers using the PEDro scale. Studies achieving a score of >50% were included for data extraction and analysis. Intra-group change scores on pain outcomes were obtained. For determining clinically important outcomes, a threshold of 20% improvement was used where continuous data were available; otherwise, an effect size of 0.30 was employed RESULTS: The PubMed search yielded 753 citations of which 13 were selected. Eight (8) other studies were identified by reviewing two systematic reviews and through reference searches. All studies scored >50% on the PEDro scale. There were 9 multi-session studies and 12 single-session studies. The most commonly used control procedure was "manual contact/no thrust". Four (4) studies used a placebo-control (patient blinded). For two of these studies with VAS data, the average change reported was 4.5 mm. For the other control procedures, variable results were obtained. No clinically important changes were reported in 57% of the paired comparisons, while, in 43% of these, changes which would be considered clinically important were obtained in the control groups. Only 15% of trials reported on post-intervention group registration. CONCLUSIONS: Most control procedures in cervical manipulation trials result in small clinical changes, although larger changes are observed in 47% of paired comparisons. The vast majority of studies do not result in subject blinding; the effect of unmasking of control subjects in these studies makes the interpretation of the existing clinical trials challenging. The greatest majority of trials do not report on post-intervention blinding. A small number of candidate procedures for effective control interventions exist. Much more research is required to improve this important aspect of clinical trial methodology in cervical manipulation studies. PMID- 21247414 TI - The journal 'chiropractic & osteopathy' changes its title to 'chiropractic & manual therapies'. a new name, a new era. AB - Chiropractic & Osteopathy changes its title to Chiropractic & Manual Therapies in January 2011. This change reflects the expanding base of submissions from clinical scientists interested in the discipline of manual therapy. It is also in accord with the findings of a review of the journal content and a joint venture between the original parent organisation the Chiropractic and Osteopathic College of Australasia and a new partner the European Academy of Chiropractic, which is a subsidiary body of the European Chiropractors' Union. The title change should encourage submissions from all professionals interested in manual therapy including chiropractors, osteopaths, physiotherapists, medical doctors and scientists interested in this field. PMID- 21247415 TI - Effects of cereal breakfasts on postprandial glucose, appetite regulation and voluntary energy intake at a subsequent standardized lunch; focusing on rye products. AB - BACKGROUND: Rye products have been demonstrated to lower the acute insulin demand, induce a low and prolonged blood glucose response (high Glycemic Profile, GP) and reduce subclinical inflammation. These products may therefore contribute to a lowered risk of obesity, type 2 diabetes and cardio vascular disease. The objective of the present paper was to evaluate the mechanism for a reduced postprandial insulin demand with rye products, and to explore possible appetite regulating properties. METHODS: 10 healthy subjects were served breakfast meals (50 g of available starch) with endosperm- or whole grain rye breads, with and without lactic acid, boiled whole grain rye- (RK) or wheat (WK) kernels, or white wheat bread reference (WWB) in random order in a cross-over design. Plasma concentrations of glucose, ghrelin, serum insulin, free fatty acids, adiponectin, breath hydrogen excretion (H(2)), and subjective satiety was evaluated during the postprandial phase. 270 min after the breakfast, an ad lib lunch buffet was served and the voluntary energy intake (EI) was registered. RESULTS: All rye products and WK induced lower insulinemic indices (II) than WWB. A lower incremental insulin peak following breakfast correlated with a lower EI at lunch (r = 0.38). A low II was related to improved satiety in the early postprandial phase (fullness AUC 0-60 min, r = -0.36). RK induced a higher GP compared to WWB and WK. A higher GP was related to a lowered desire to eat before lunch (AUC 210 270) and to a lower concentration of ghrelin in the late postprandial phase after breakfast (270 min), r = -0.29 and -0.29), which in turn was related to a lower voluntary EI (r = 0.43 and 0.33). The RK breakfast improved satiety in the early postprandial phase (0-60 min) compared to WWB, and induced a lower EI at lunch ( 16%). A high content of indigestible carbohydrates in the breakfast products was related to improved satiety (0-60 min, r = 0.68 for fullness), and a higher breath H(2) in the late postprandial phase (120-270 and 270-390 min, r = 0.46 and 0.70). High H(2) (AUC 120-270 min) also correlated with lower EI (r = -0.34). CONCLUSIONS: Rye products, rich in indigestible carbohydrates, induce colonic fermentation already post the breakfast meal, and lowers acute insulin responses. A high excretion of breath H(2) also correlated with a higher GP. Especially, rye kernels induced a high GP which was associated with a 16% lowering of energy intake at a subsequent lunch meal. The bulking effect of rye fiber, colonically derived fermentation metabolites, a high GP and a low insulin response possibly all contributes to the benefits on glucose- and appetite regulation seen in an acute and semi-acute perspective. PMID- 21247417 TI - Atrial fibrillation in healthy adolescents after highly caffeinated beverage consumption: two case reports. AB - INTRODUCTION: Energy drinks and highly caffeinated drinks comprise some of the fastest growing products of the beverage industry, often targeting teenagers and young adults. Cardiac arrhythmias in children related to high caffeine consumption have not been well described in the literature. This case series describes the possible association between the consumption of highly caffeinated drinks and the subsequent development of atrial fibrillation in the adolescent population. CASE PRESENTATIONS: We report the cases of two Caucasian adolescent boys of 14 and 16 years of age at the time of presentation, each without a significant cardiac history, who presented with palpitations or vague chest discomfort or both after a recent history of excessive caffeine consumption. Both were found to have atrial fibrillation on electrocardiogram; one patient required digoxin to restore a normal sinus rhythm, and the other self-converted after intravenous fluid administration. CONCLUSION: With the increasing popularity of energy drinks in the pediatric and adolescent population, physicians should be aware of the arrhythmogenic potential associated with highly caffeinated beverage consumption. It is important for pediatricians to understand the lack of regulation in the caffeine content and other ingredients of these high-energy beverages and their complications so that parents and children can be educated about the risk of cardiac arrhythmias with excessive energy drink consumption. PMID- 21247416 TI - Ubiquitin-proteasome genes as targets for modulation of cisplatin sensitivity in fission yeast. AB - BACKGROUND: The ubiquitin(Ub)-proteasome pathway is implicated in the regulation of a variety of cellular functions and plays a major role in stress response in eukaryotic cells, by targeting misfolded and damaged proteins for degradation. In addition, in the presence of DNA damage, the Ub-proteasome system regulates proteins involved in sensing, repairing, and/or tolerating the damage. Antitumor agents such as cisplatin can activate the pathway, but the role of specific pathway components in cell sensitivity/response to the drug is not known. Since platinum compounds represent clinically relevant antitumor agents and a major limitation to their use is the development of drug resistance, there is an urgent need for identifying targets for improving their efficacy. RESULTS: In the present study, we performed a genome-wide screening for sensitivity to cisplatin using non-essential haploid deletion mutants of the fission yeast Schizosaccharomyces pombe, belonging to a collection of haploid strains constructed through homologous recombination. Using this approach, we identified three Ub-proteasome mutants exhibiting hypersensitivity to cisplatin (ubp16, ubc13 and pmt3) and ten mutants (including ufd2, beta7 20S, rpt6/let1) resistant to the drug. In addition, the importance of lub1 gene emerged from the comparison between the present screening and gene expression profile data previously obtained in fission yeast. CONCLUSIONS: The factors identified in the present study allowed us to highlight most finely the close relationship between the Ub proteasome system and DNA damage response mechanisms, thus establishing a comprehensive framework of regulators likely relevant also in higher eukaryotes. Our results provide the proof of principle of the involvement of specific genes modulated by cisplatin treatment in cell response to the drug, suggesting their potential role as targets for modulating cisplatin sensitivity. In this regard, the prospective identification of novel targets for modulation of cisplatin sensitivity in an eukaryotic model organism appears particularly intriguing towards the discovery of strategies to overcome cisplatin resistance in human tumors. PMID- 21247418 TI - The European Society of Human Reproduction and Embryology guideline for the diagnosis and treatment of endometriosis: an electronic guideline implementability appraisal. AB - BACKGROUND: Clinical guidelines are intended to improve healthcare. However, even if guidelines are excellent, their implementation is not assured. In subfertility care, the European Society of Human Reproduction and Embryology (ESHRE) guidelines have been inventoried, and their methodological quality has been assessed. To improve the impact of the ESHRE guidelines and to improve European subfertility care, it is important to optimise the implementability of guidelines. We therefore investigated the implementation barriers of the ESHRE guideline with the best methodological quality and evaluated the used instrument for usability and feasibility. METHODS: We reviewed the ESHRE guideline for the diagnosis and treatment of endometriosis to assess its implementability. We used an electronic version of the guideline implementability appraisal (eGLIA) instrument. This eGLIA tool consists of 31 questions grouped into 10 dimensions. Seven items address the guideline as a whole, and 24 items assess the individual recommendations in the guideline. The eGLIA instrument identifies factors that influence the implementability of the guideline recommendations. These factors can be divided into facilitators that promote implementation and barriers that oppose implementation. A panel of 10 experts from three European countries appraised all 36 recommendations of the guideline. They discussed discrepancies in a teleconference and completed a questionnaire to evaluate the ease of use and overall utility of the eGLIA instrument. RESULTS: Two of the 36 guideline recommendations were straightforward to implement. Five recommendations were considered simply statements because they contained no actions. The remaining 29 recommendations were implementable with some adjustments. We found facilitators of the guideline implementability in the quality of decidability, presentation and formatting, apparent validity, and novelty or innovation of the recommendations. Vaguely defined actions, lack of facilities, immeasurable outcomes, and inflexibility within the recommendations formed barriers to implementation. The eGLIA instrument was generally useful and easy to use. However, assessment with the eGLIA instrument is very time-consuming. CONCLUSIONS: The ESHRE guideline for the diagnosis and treatment of endometriosis could be improved to facilitate its implementation in daily practice. The eGLIA instrument is a helpful tool for identifying obstacles to implementation of a guideline. However, we recommend a concise version of this instrument. PMID- 21247420 TI - A Normalized Tree Index for identification of correlated clinical parameters in microarray experiments. AB - BACKGROUND: Measurements on gene level are widely used to gain new insights in complex diseases e.g. cancer. A promising approach to understand basic biological mechanisms is to combine gene expression profiles and classical clinical parameters. However, the computation of a correlation coefficient between high dimensional data and such parameters is not covered by traditional statistical methods. METHODS: We propose a novel index, the Normalized Tree Index (NTI), to compute a correlation coefficient between the clustering result of high dimensional microarray data and nominal clinical parameters. The NTI detects correlations between hierarchically clustered microarray data and nominal clinical parameters (labels) and gives a measurement of significance in terms of an empiric p-value of the identified correlations. Therefore, the microarray data is clustered by hierarchical agglomerative clustering using standard settings. In a second step, the computed cluster tree is evaluated. For each label, a NTI is computed measuring the correlation between that label and the clustered microarray data. RESULTS: The NTI successfully identifies correlated clinical parameters at different levels of significance when applied on two real-world microarray breast cancer data sets. Some of the identified highly correlated labels confirm the actual state of knowledge whereas others help to identify new risk factors and provide a good basis to formulate new hypothesis. CONCLUSIONS: The NTI is a valuable tool in the domain of biomedical data analysis. It allows the identification of correlations between high-dimensional data and nominal labels, while at the same time a p-value measures the level of significance of the detected correlations. PMID- 21247419 TI - Rasd1 interacts with Ear2 (Nr2f6) to regulate renin transcription. AB - BACKGROUND: The Rasd1 protein is a dexamethasone induced monomeric Ras-like G protein that oscillates in the suprachiasmatic nucleus (SCN). Previous studies have shown that Rasd1 modulates multiple signaling cascades. However, it is still unclear exactly how Rasd1 carries out its function. Studying protein-protein interactions involving Rasd1 may provide insights into its biological functions in different contexts. RESULTS: To further explore the molecular function of Rasd1, we performed a yeast two-hybrid screen and identified Ear2, a negative regulator of renin transcription, as an interaction partner of Rasd1. We validated the interaction in vitro and in transfected COS-7 cells. We further confirmed the interaction of endogenous Rasd1 and Ear2 from HEK293T cell and mouse brain extract. Rasd1 inhibited transcriptional repression by Ear2 on a renin promoter-luciferase reporter construct both in the presence and absence of all-trans-retinoic acid. Moreover, real-time RT-PCR showed upregulation of endogenous renin transcription in As4.1 cells over-expressing Rasd1. We demonstrated that the ligand binding domain of Ear2 is required for physical and functional interaction between the two proteins. In addition, we demonstrated that shRNA-mediated knockdown of Rasd1 results in further repression of Ear2 mediated renin transcription, whereas induction of Rasd1 by dexamethasone counteracts the effects of shRNA-mediated Rasd1 knockdown. Finally, our study showed that Rasd1 missense mutations not only attenuate their physical interaction with Ear2 but also abolish their ability to counteract repression of renin transcription mediated by Ear2. CONCLUSIONS: Our study provides evidence for physical and functional interactions between Rasd1 and Ear2. The results suggest that their interactions are involved in renin transcriptional regulation. These findings not only reveal a novel role for Rasd1-medated signaling but also provide the basis for potential intervention of renin expression. PMID- 21247421 TI - Stochastic simulations of the tetracycline operon. AB - BACKGROUND: The tetracycline operon is a self-regulated system. It is found naturally in bacteria where it confers resistance to antibiotic tetracycline. Because of the performance of the molecular elements of the tetracycline operon, these elements are widely used as parts of synthetic gene networks where the protein production can be efficiently turned on and off in response to the presence or the absence of tetracycline. In this paper, we investigate the dynamics of the tetracycline operon. To this end, we develop a mathematical model guided by experimental findings. Our model consists of biochemical reactions that capture the biomolecular interactions of this intriguing system. Having in mind that small biological systems are subjects to stochasticity, we use a stochastic algorithm to simulate the tetracycline operon behavior. A sensitivity analysis of two critical parameters embodied this system is also performed providing a useful understanding of the function of this system. RESULTS: Simulations generate a timeline of biomolecular events that confer resistance to bacteria against tetracycline. We monitor the amounts of intracellular TetR2 and TetA proteins, the two important regulatory and resistance molecules, as a function of intrecellular tetracycline. We find that lack of one of the promoters of the tetracycline operon has no influence on the total behavior of this system inferring that this promoter is not essential for Escherichia coli. Sensitivity analysis with respect to the binding strength of tetracycline to repressor and of repressor to operators suggests that these two parameters play a predominant role in the behavior of the system. The results of the simulations agree well with experimental observations such as tight repression, fast gene expression, induction with tetracycline, and small intracellular TetR2 amounts. CONCLUSIONS: Computer simulations of the tetracycline operon afford augmented insight into the interplay between its molecular components. They provide useful explanations of how the components and their interactions have evolved to best serve bacteria carrying this operon. Therefore, simulations may assist in designing novel gene network architectures consisting of tetracycline operon components. PMID- 21247422 TI - In silico comparative analysis of SSR markers in plants. AB - BACKGROUND: The adverse environmental conditions impose extreme limitation to growth and plant development, restricting the genetic potential and reflecting on plant yield losses. The progress obtained by classic plant breeding methods aiming at increasing abiotic stress tolerances have not been enough to cope with increasing food demands. New target genes need to be identified to reach this goal, which requires extensive studies of the related biological mechanisms. Comparative analyses in ancestral plant groups can help to elucidate yet unclear biological processes. RESULTS: In this study, we surveyed the occurrence patterns of expressed sequence tag-derived microsatellite markers for model plants. A total of 13,133 SSR markers were discovered using the SSRLocator software in non redundant EST databases made for all eleven species chosen for this study. The dimer motifs are more frequent in lower plant species, such as green algae and mosses, and the trimer motifs are more frequent for the majority of higher plant groups, such as monocots and dicots. With this in silico study we confirm several microsatellite plant survey results made with available bioinformatics tools. CONCLUSIONS: The comparative studies of EST-SSR markers among all plant lineages is well suited for plant evolution studies as well as for future studies of transferability of molecular markers. PMID- 21247423 TI - Evidence for classification of c.1852_1853AA>GC in MLH1 as a neutral variant for Lynch syndrome. AB - BACKGROUND: Lynch syndrome (LS) is an autosomal dominant inherited cancer syndrome characterized by early onset cancers of the colorectum, endometrium and other tumours. A significant proportion of DNA variants in LS patients are unclassified. Reports on the pathogenicity of the c.1852_1853AA>GC (p.Lys618Ala) variant of the MLH1 gene are conflicting. In this study, we provide new evidence indicating that this variant has no significant implications for LS. METHODS: The following approach was used to assess the clinical significance of the p.Lys618Ala variant: frequency in a control population, case-control comparison, co-occurrence of the p.Lys618Ala variant with a pathogenic mutation, co segregation with the disease and microsatellite instability in tumours from carriers of the variant. We genotyped p.Lys618Ala in 1034 individuals (373 sporadic colorectal cancer [CRC] patients, 250 index subjects from families suspected of having LS [revised Bethesda guidelines] and 411 controls). Three well-characterized LS families that fulfilled the Amsterdam II Criteria and consisted of members with the p.Lys618Ala variant were included to assess co occurrence and co-segregation. A subset of colorectal tumour DNA samples from 17 patients carrying the p.Lys618Ala variant was screened for microsatellite instability using five mononucleotide markers. RESULTS: Twenty-seven individuals were heterozygous for the p.Lys618Ala variant; nine had sporadic CRC (2.41%), seven were suspected of having hereditary CRC (2.8%) and 11 were controls (2.68%). There were no significant associations in the case-control and case-case studies. The p.Lys618Ala variant was co-existent with pathogenic mutations in two unrelated LS families. In one family, the allele distribution of the pathogenic and unclassified variant was in trans, in the other family the pathogenic variant was detected in the MSH6 gene and only the deleterious variant co-segregated with the disease in both families. Only two positive cases of microsatellite instability (2/17, 11.8%) were detected in tumours from p.Lys618Ala carriers, indicating that this variant does not play a role in functional inactivation of MLH1 in CRC patients. CONCLUSIONS: The p.Lys618Ala variant should be considered a neutral variant for LS. These findings have implications for the clinical management of CRC probands and their relatives. PMID- 21247424 TI - Secretion of beta-human chorionic gonadotropin by non-small cell lung cancer: a case report. AB - INTRODUCTION: We describe a case of non-small cell lung cancer that was found to stain positive for beta-human chorionic gonadotropin on immunohistochemistry. Only a few case reports have described lung cancers that secrete beta-human chorionic gonadotropin. CASE PRESENTATION: A 68-year-old Caucasian man presented with symptoms of weakness, fatigue and weight loss for the past two months. On examination, he was found to have generalized lymphadenopathy, and radiologic workup revealed numerous metastases in the lungs, liver and kidneys. Biopsy of the supraclavicular lymph node revealed metastatic large cell lung cancer with beta-human chorionic gonadotropin hormone positivity. The serum beta-human chorionic gonadotropin level was 11,286 mIU/ml (upper limit of normal, 0.5 mIU/ml in non-pregnant females). He was diagnosed with stage 4 lung non-small cell lung cancer. The patient refused chemotherapy. He was discharged home with hospice care. CONCLUSION: The markedly elevated serum values of beta-human chorionic gonadotropin initially prompted the medical team to investigate germinal tumors. In the presence of a negative testicular ultrasound, workup was performed to find an extratesticular source of the tumor. Finally, the diagnosis was made with a tissue biopsy. This case illustrates that atypical markers can be seen in many cancers, emphasizing the role of immunohistochemistry and tissue biopsy in establishing the diagnosis. PMID- 21247425 TI - Systematic error detection in experimental high-throughput screening. AB - BACKGROUND: High-throughput screening (HTS) is a key part of the drug discovery process during which thousands of chemical compounds are screened and their activity levels measured in order to identify potential drug candidates (i.e., hits). Many technical, procedural or environmental factors can cause systematic measurement error or inequalities in the conditions in which the measurements are taken. Such systematic error has the potential to critically affect the hit selection process. Several error correction methods and software have been developed to address this issue in the context of experimental HTS 1234567. Despite their power to reduce the impact of systematic error when applied to error perturbed datasets, those methods also have one disadvantage - they introduce a bias when applied to data not containing any systematic error 6. Hence, we need first to assess the presence of systematic error in a given HTS assay and then carry out systematic error correction method if and only if the presence of systematic error has been confirmed by statistical tests. RESULTS: We tested three statistical procedures to assess the presence of systematic error in experimental HTS data, including the chi2 goodness-of-fit test, Student's t-test and Kolmogorov-Smirnov test 8 preceded by the Discrete Fourier Transform (DFT) method 9. We applied these procedures to raw HTS measurements, first, and to estimated hit distribution surfaces, second. The three competing tests were applied to analyse simulated datasets containing different types of systematic error, and to a real HTS dataset. Their accuracy was compared under various error conditions. CONCLUSIONS: A successful assessment of the presence of systematic error in experimental HTS assays is possible when the appropriate statistical methodology is used. Namely, the t-test should be carried out by researchers to determine whether systematic error is present in their HTS data prior to applying any error correction method. This important step can significantly improve the quality of selected hits. PMID- 21247426 TI - Posterior leukoencephalopathy following repair of an ileocecal anastomosis breakdown: a case report and review of the literature. AB - INTRODUCTION: Posterior reversible leukoencephalopathy syndrome refers to a constellation of neurologic symptoms related to temporary white matter changes. The disease typically presents in the context of an abrupt and drastic elevation in blood pressure (>180/110 mmHg). We report an unusual case of posterior reversible leukoencephalopathy syndrome in a post-operative setting, with a blood pressure parameter generally tolerated by most patients. CASE PRESENTATION: We report the case of a 22-year-old Caucasian man who suffered acute onset visual acuity loss four days after an ileocecal anastomosis. A head magnetic resonance imaging scan revealed findings typically associated with posterior reversible leukoencephalopathy syndrome. His symptoms developed in the context of blood pressure parameters that are typically well tolerated in a post-operative setting (150-160/80-90 mmHg). He did not have a history of renal failure or immunosuppression. His symptoms resolved with aggressive blood pressure management. CONCLUSIONS: Posterior reversible leukoencephalopathy syndrome can occur in a post-operative setting with blood pressure parameters typically well tolerated in most post-surgical patients. Timely diagnosis and treatment will minimize the risk of permanent neurologic injury. PMID- 21247427 TI - Age, season and spatio-temporal factors affecting the prevalence of Echinococcus multilocularis and Taenia taeniaeformis in Arvicola terrestris. AB - BACKGROUND: Taenia taeniaeformis and the related zoonotic cestode Echinococcus multilocularis both infect the water vole Arvicola terrestris. We investigated the effect of age, spatio-temporal and season-related factors on the prevalence of these parasites in their shared intermediate host. The absolute age of the voles was calculated based on their eye lens weights, and we included the mean day temperature and mean precipitation experienced by each individual as independent factors. RESULTS: Overall prevalences of E. multilocularis and T. taeniaeformis were 15.1% and 23.4%, respectively, in 856 A. terrestris trapped in the canton Zurich, Switzerland. Prevalences were lower in young (<= 3 months: E. multilocularis 7.6%, T. taeniaeformis 17.9%) than in older animals (>7 months: 32.6% and 34.8%). Only 12 of 129 E. multilocularis-infected voles harboured protoscoleces. Similar proportions of animals with several strobilocerci were found in T. taeniaeformis infected voles of <5 months and >=5 months of age (12.8% and 11.9%). Multivariate analyses revealed strong spatio-temporal variations in prevalences of E. multilocularis. In one trapping area, prevalences varied on an exceptional high level of 40.6-78.5% during the whole study period. Low temperatures significantly correlated with the infection rate whereas precipitation was of lower importance. Significant spatial variations in prevalences were also identified for Taenia taeniaeformis. Although the trapping period and the meteorological factors temperature and precipitation were included in the best models for explaining the infection risk, their effects were not significant for this parasite. CONCLUSIONS: Our results demonstrate that, besides temporal and spatial factors, low temperatures contribute to the risk of infection with E. multilocularis. This suggests that the enhanced survival of E. multilocularis eggs under cold weather conditions determines the level of infection pressure on the intermediate hosts and possibly also the infection risk for human alveolar echincoccosis (AE). Therefore, interventions against the zoonotic cestode E. multilocularis by deworming foxes may be most efficient if conducted just before and during winter. PMID- 21247428 TI - Low density lipoprotein cholesterol is inversely correlated with abdominal visceral fat area: a magnetic resonance imaging study. AB - BACKGROUND: Visceral Fat Area (VFA) is an independent predictor of coronary disease. While low density lipoprotein cholesterol (LDL-C) is used to determine risk and guide therapy, its accuracy fails in obese patients who may have low LDL C despite high VFA. OBJECTIVE: We sought to describe the relationship between VFA, LDL-C and to describe shifting cholesterol metabolism with increasing VFA. METHODS: 42 High-risk vascular patients not on lipid-lowering therapy provided a fasting lipid profile and underwent magnetic resonance imaging (MRI) to quantify VFA and subcutaneous fat area (SFA) at the L4-L5 disc. Comparisons: 1. Correlation between VFA, SFA, LDL-C and the standard lipid panel 2. Correlation between VFA, SFA and markers of cholesterol synthesis (desmosterol, lathosterol) and cholesterol absorption (cholestanol, sitosterol). RESULTS: VFA was inversely correlated with LDL-C (r = -0.348) indicating potential discordance between cardiovascular risk and LDL-C. However, VFA was appropriately correlated with other markers of increased risk: r = -0.361 with HDL-C, r = 0.503 with VLDL-C, r = 0.499 with TG (all p < 0.05). VFA did not correlate significantly with non-HDL C. VFA correlated positively with cholesterol synthesis markers (desmosterol, lathosterol) and negatively with an absorption marker (cholestanol). CONCLUSIONS: LDL-C is inversely correlated with VFA and this may explain the loss of the relationship between LDL-C and cardiovascular events in the obese. While Non-HDL C did not correlate positively with VFA, the absence of a negative correlation suggests that it may be a more appropriate lipid target in an increasingly obese world. PMID- 21247429 TI - Idiopathic giant abdominal lymph cyst: a case report. AB - INTRODUCTION: Giant lymph cysts are a relatively frequent complication after surgical procedures in the abdomen, often after kidney transplantation, but there are also cases after pelvic surgery such as lymphadenectomy and others. In the recent literature, there have been no reported cases of idiopathic giant lymphocyst. CASE PRESENTATION: We present the case of a 76-year-old Caucasian man who had a lymph cyst he had known of for more than 15 years. Laparoscopic treatment was necessary because of hydronephrosis of the left kidney. CONCLUSION: This case shows that laparoscopic drainage and partial resection of the lymph cyst is a safe and effective treatment. PMID- 21247430 TI - Stretching positions for the coracohumeral ligament: Strain measurement during passive motion using fresh/frozen cadaver shoulders. AB - BACKGROUND: Contracture of the coracohumeral ligament is reported to restrict external rotation of the shoulder with arm at the side and restrict posterior inferior shift of the humeral head. The contracture is supposed to restrict range of motion of the glenohumeral joint. METHODS: To obtain stretching position of the coracohumeral ligament, strain on the ligament was measured at the superficial fibers of the ligament using 9 fresh/frozen cadaver shoulders. By sequential measurement using a strain gauge, the ligament strain was measured from reference length (L0). Shoulder positions were determined using a 3 Space Tracker System. Through a combination of previously reported coracohumeral stretching positions and those observed in preliminary measurement, ligament strain were measured by passive external rotation from 10 degrees internal rotation, by adding each 10 degrees external rotation, to maximal external rotation. RESULTS: Stretching positions in which significantly larger strain were obtained compared to the L0 values were 0 degrees elevation in scapula plane with 40 degrees , 50 degrees and maximum external rotation (5.68%, 7.2%, 7.87%), 30 degrees extension with 50 degrees , maximum external rotation (4.20%, 4.79%), and 30 degrees extension + adduction with 30 degrees , 40 degrees , 50 degrees and maximum external rotation (4.09%, 4.67%, 4.78%, 5.05%)(P < 0.05). No positive strain on the coracohumeral ligament was observed for the previously reported stretching positions; ie, 90 degrees abduction with external rotation or flexion with external rotation. CONCLUSIONS: Significant strain of the coracohumeral ligament will be achieved by passive external rotation at lower shoulder elevations, extension, and extension with adduction. PMID- 21247431 TI - Effect of pentoxifylline on preventing acute kidney injury after cardiac surgery by measuring urinary neutrophil gelatinase - associated lipocalin. AB - BACKGROUND: Based on Acute Kidney Injury Network (AKIN) criteria, we considered acute kidney injury (AKI) as an absolute increase in the serum creatinine (sCr) level of more than or equal to 0.3 mg/dl or 50%. The introduction of Urinary neutrophil gelatinase-associated lipocalin (UNGAL) has conferred earlier diagnosis of AKI. Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor, can suppress the production of some factors of inflammatory response and presumably prevent AKI. We examined the PTX on the development of AKI in cardiac surgery patients by measuring the levels of UNGAL. MATERIALS AND METHODS: We performed a double blind randomized clinical trial, enrolling 28 consecutive patients undergoing elective coronary artery bypass graft (CABG) surgery. Patients were divided into two groups, one to receive PTX 5 mg/kg intravenous bolus injection, followed by 1.5 mg/kg/h continuous intravenous infusion until 3 hours after cessation of CPB and the other group received placebo. UNGAL was measured before, 3 and 24 hours after surgery. In addition serum creatinine was measured before and 24, 48, 72 and 96 hours after surgery and C-reactive protein (CRP) only 24 hours postoperatively. RESULTS: Both groups did not differ in demographic and baseline characteristics. 12 patients developed AKI 48 hours after surgery; 5 of them were in the intervention group and 7 in the control group (p= 0.445). There was an increase of UNGAL in both groups postoperatively, although not significant. Mean sCr was significantly increased in the control group at 24 and 48 hours after surgery (24-h mean: 0.79 +/- 0.18 mg/dl vs. 1.03 +/- 0.43 mg/dl, P value = 0.02; 48-h mean: 1.17 +/- 0.24 mg/dl vs. 0.98 +/- 0.20 mg/dl, P value = 0.03, respectively). PTX had a positive effect in preventing AKI reflecting in changes in sCr, and the increase of UNGAL was consistent with the emergence of AKI (Pearson's correlation = 0.30). CONCLUSION: Our study demonstrates a weak correlation between UNGAL and sCr after cardiac surgery. The rise of UNGAL in these patients may be reduced by administration of PTX although we did not show significance. PTX could reduce the occurrence of AKI as determined by attenuation of sCr rise without causing hemodynamic instability or increased bleeding. Overall, we suggest future studies with larger sample sizes to elucidate this effect and determine the different aspects of administrating PTX. TRIAL REGISTRATION: ISRCTN: IRCT138807302622N1. PMID- 21247432 TI - Cardiogenol C can induce Mouse Hair Bulge Progenitor Cells to Transdifferentiate into Cardiomyocyte-like Cells. AB - BACKGROUND: Hair bulge progenitor cells (HBPCs) are multipotent stem cells derived from the bulge region of mice vibrissal hairs. The purified HBPCs express CD34, K15 and K14 surface markers. It has been reported that HBPCs could be readily induced to transdifferentiate into adipocytes and osteocytes. However, the ability of HBPCs to transdifferentiate into cardiomyocytes has not yet been investigated. METHODOLOGY/PRINCIPAL FINDINGS: The cardiomyogenic potential of HBPCs was investigated using a small cell-permeable molecule called Cardiogenol C. We established that Cardiogenol C could induce HBPCs to express transcription factors GATA4, Nkx2.5 and Tbx5, which are early specific markers for pre cardiomyogenic cells. In prolonged cultures, the Cardiogenol C-treated HBPCs can also express muscle proteins, cardiac-specific troponin I and sarcomeric myosin heavy chain. However, we did not observe the ability of these cells to functionally contract. Hence, we called these cells cardiomyocyte-like cells rather than cardiomyocytes. We tried to remedy this deficiency by pre-treating HBPCs with Valproic acid first before exposing them to Cardiogenol C. This pretreatment inhibited, rather than improved, the effectiveness of Cardiogenol C in reprogramming the HBPCs. We used comparative proteomics to determine how Cardiogenol C worked by identifying proteins that were differentially expressed. We identified proteins that were involved in promoting cell differentiation, cardiomyocyte development and for the normal function of striated muscles. From those differentially expressed proteins, we further propose that Cardiogenol C might exert its effect by activating the Wnt signaling pathway through the suppression of Kremen1. In addition, by up-regulating the expression of chromatin remodeling proteins, SIK1 and Smarce1 would initiate cardiac differentiation. CONCLUSIONS/SIGNIFICANCE: In conclusion, our CD34+/K15+ HBPCs could be induced to transdifferentiate into cardiomyocyte-like cells using a small molecule called Cardiogenol C. The process involves activation of the Wnt signaling pathway and altered expression of several key chromatin remodeling proteins. The finding is clinically significant as HBPCs offer a readily accessible and autologous source of progenitor cells for cell-based therapy of heart disease, which is one of major killers in developed countries. PMID- 21247433 TI - Assessing the stroke-specific quality of life for outcome measurement in stroke rehabilitation: minimal detectable change and clinically important difference. AB - BACKGROUND: This study was conducted to establish the minimal detectable change (MDC) and clinically important differences (CIDs) of the physical category of the Stroke-Specific Quality of Life Scale in patients with stroke. METHODS: MDC and CIDs scores were calculated from the data of 74 participants enrolled in randomized controlled trials investigating the effects of two rehabilitation programs in patients with stroke. These participants received treatments for 3 weeks and underwent clinical assessment before and after treatment. To obtain test-retest reliability for calculating MDC, another 25 patients with chronic stroke were recruited. The MDC was calculated from the standard error of measurement (SEM) to indicate a real change with 95% confidence for individual patients (MDC95). Distribution-based and anchor-based methods were adopted to triangulate the ranges of minimal CIDs. The percentage of scale width was calculated by dividing the MDC and CIDs by the total score range of each physical category. The percentage of patients exceeding MDC95 and minimal CIDs was also reported. RESULTS: The MDC95 of the mobility, self-care, and upper extremity (UE) function subscales were 5.9, 4.0, and 5.3 respectively. The minimal CID ranges for these 3 subscales were 1.5 to 2.4, 1.2 to 1.9, and 1.2 to 1.8. The percentage of patients exceeding MDC95 and minimal CIDs of the mobility, self-care, and UE function subscales were 9.5% to 28.4%, 6.8% to 28.4%, and 12.2% to 33.8%, respectively. CONCLUSIONS: The change score of an individual patient has to reach 5.9, 4.0, and 5.3 on the 3 subscales to indicate a true change. The mean change scores of a group of patients with stroke on these subscales should reach the lower bound of CID ranges of 1.5 (6.3% scale width), 1.2 (6.0% scale width), and 1.2 (6.0% scale width) to be regarded as clinically important change. This information may facilitate interpretations of patient-reported outcomes after stroke rehabilitation. Future research is warranted to validate these findings. PMID- 21247434 TI - System in biology leading to cell pathology: stable protein-protein interactions after covalent modifications by small molecules or in transgenic cells. AB - BACKGROUND: The physiological processes in the cell are regulated by reversible, electrostatic protein-protein interactions. Apoptosis is such a regulated process, which is critically important in tissue homeostasis and development and leads to complete disintegration of the cell. Pathological apoptosis, a process similar to apoptosis, is associated with aging and infection. The current study shows that pathological apoptosis is a process caused by the covalent interactions between the signaling proteins, and a characteristic of this pathological network is the covalent binding of calmodulin to regulatory sequences. RESULTS: Small molecules able to bind covalently to the amino group of lysine, histidine, arginine, or glutamine modify the regulatory sequences of the proteins. The present study analyzed the interaction of calmodulin with the BH3 sequence of Bax, and the calmodulin-binding sequence of myristoylated alanine rich C-kinase substrate in the presence of xanthurenic acid in primary retinal epithelium cell cultures and murine epithelial fibroblast cell lines transformed with SV40 (wild type [WT], Bid knockout [Bid-/-], and Bax-/-/Bak-/- double knockout [DKO]). Cell death was observed to be associated with the covalent binding of calmodulin, in parallel, to the regulatory sequences of proteins. Xanthurenic acid is known to activate caspase-3 in primary cell cultures, and the results showed that this activation is also observed in WT and Bid-/- cells, but not in DKO cells. However, DKO cells were not protected against death, but high rates of cell death occurred by detachment. CONCLUSIONS: The results showed that small molecules modify the basic amino acids in the regulatory sequences of proteins leading to covalent interactions between the modified sequences (e.g., calmodulin to calmodulin-binding sites). The formation of these polymers (aggregates) leads to an unregulated and, consequently, pathological protein network. The results suggest a mechanism for the involvement of small molecules in disease development. In the knockout cells, incorrect interactions between proteins were observed without the protein modification by small molecules, indicating the abnormality of the protein network in the transgenic system. The irreversible protein-protein interactions lead to protein aggregation and cell degeneration, which are observed in all aging-associated diseases. PMID- 21247435 TI - Plasma lipoprotein-associated phospholipase A2 in patients with metabolic syndrome and carotid atherosclerosis. AB - BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a recently identified and potentially useful plasma biomarker for cardiovascular and atherosclerotic diseases. However, the correlation between the Lp-PLA2 activity and carotid atherosclerosis remains poorly investigated in patients with metabolic syndrome (MetS). The present study aimed to evaluate the potential role of Lp-PLA2 as a comprehensive marker of metabolic syndrome in individuals with and without carotid atherosclerosis. METHODS: We documented 118 consecutive patients with MetS and 70 age- and sex-matched healthy subjects served as controls. The patients were further divided into two groups: 39 with carotid plaques and 79 without carotid plaques to elucidate the influence of Lp-PLA2 on carotid atherosclerosis. The plasma Lp-PLA2 activity was measured by using ELISA method and carotid intimal-media thickness (IMT) was performed by ultrasound in all participants. RESULTS: Lp-PLA2 activity was significantly increased in MetS subgroups when compared with controls, and was higher in patients with carotid plaques than those without plaques (P < 0.05). Furthermore, we found that significant difference in Lp-PLA2 was obtained between patients with three and four disorders of metabolic syndrome (P < 0.01). Age (beta = 0.183, P = 0.029), LDL-cholesterol (beta = 0.401, P = 0.000) and waist-hip ratio (beta = 0.410, P = 0.000) emerged as significant and independent determinants of Lp-PLA2 activity. Multiple stepwise regression analysis revealed that LDL-cholesterol (beta = 0.309, P = 0.000), systolic blood pressure (beta = 0.322, P = 0.002) and age (beta = 0.235, P = 0.007) significantly correlated with max IMT, and Lp-PLA2 was not an independent predictor for carotid IMT. CONCLUSIONS: Lp-PLA2 may be a modulating factor for carotid IMT via age and LDL-cholesterol, not independent predictor in the pathophysiological process of carotid atherosclerosis in patients with MetS. PMID- 21247436 TI - The financial protection effect of Ghana National Health Insurance Scheme: evidence from a study in two rural districts. AB - BACKGROUND: One of the key functions of health insurance is to provide financial protection against high costs of health care, yet evidence of such protection from developing countries has been inconsistent. The current study uses the case of Ghana to contribute to the evidence pool about insurance's financial protection effects. It evaluates the impact of the country's National Health Insurance Scheme on households' out-of-pocket spending and catastrophic health expenditure. METHODS: We use data from a household survey conducted in two rural districts, Nkoranza and Offinso, in 2007, two years after the initiation of the Ghana National Health Insurance Scheme. To address the skewness of health expenditure data, the absolute amount of out-of-pocket spending is estimated using a two-part model. We also conduct a probit estimate of the likelihood of catastrophic health expenditures, defined at different thresholds relative to household income and non-food consumption expenditure. The analysis controls for chronic and self-assessed health conditions, which typically drive adverse selection in insurance. RESULTS: At the time of the survey, insurance coverage was 35 percent. Although the benefit package of insurance is generous, insured people still incurred out-of-pocket payment for care from informal sources and for uncovered drugs and tests at health facilities. Nevertheless, they paid significantly less than the uninsured. Insurance has been shown to have a protective effect against the financial burden of health care, reducing significantly the likelihood of incurring catastrophic payment. The effect is particularly remarkable among the poorest quintile of the sample. CONCLUSIONS: Findings from this study confirm the positive financial protection effect of health insurance in Ghana. The effect is stronger among the poor group than among general population. The results are encouraging for many low income countries who are considering a similar policy to expand social health insurance. Ghana's experience also shows that instituting insurance by itself is not adequate to remove fully the out-of-pocket payment for health. Further works are needed to address the supply side's incentives and quality of care, so that the insured can enjoy the full benefits of insurance. PMID- 21247437 TI - Construction of a potato consensus map and QTL meta-analysis offer new insights into the genetic architecture of late blight resistance and plant maturity traits. AB - BACKGROUND: Integrating QTL results from independent experiments performed on related species helps to survey the genetic diversity of loci/alleles underlying complex traits, and to highlight potential targets for breeding or QTL cloning. Potato (Solanum tuberosum L.) late blight resistance has been thoroughly studied, generating mapping data for many Rpi-genes (R-genes to Phytophthora infestans) and QTLs (quantitative trait loci). Moreover, late blight resistance was often associated with plant maturity. To get insight into the genomic organization of late blight resistance loci as compared to maturity QTLs, a QTL meta-analysis was performed for both traits. RESULTS: Nineteen QTL publications for late blight resistance were considered, seven of them reported maturity QTLs. Twenty-one QTL maps and eight reference maps were compiled to construct a 2,141-marker consensus map on which QTLs were projected and clustered into meta-QTLs. The whole-genome QTL meta-analysis reduced by six-fold late blight resistance QTLs (by clustering 144 QTLs into 24 meta-QTLs), by ca. five-fold maturity QTLs (by clustering 42 QTLs into eight meta-QTLs), and by ca. two-fold QTL confidence interval mean. Late blight resistance meta-QTLs were observed on every chromosome and maturity meta-QTLs on only six chromosomes. CONCLUSIONS: Meta-analysis helped to refine the genomic regions of interest frequently described, and provided the closest flanking markers. Meta-QTLs of late blight resistance and maturity juxtaposed along chromosomes IV, V and VIII, and overlapped on chromosomes VI and XI. The distribution of late blight resistance meta-QTLs is significantly independent from those of Rpi-genes, resistance gene analogs and defence-related loci. The anchorage of meta-QTLs to the potato genome sequence, recently publicly released, will especially improve the candidate gene selection to determine the genes underlying meta-QTLs. All mapping data are available from the Sol Genomics Network (SGN) database. PMID- 21247438 TI - Down regulation of the high-affinity IgE receptor associated with successful treatment of chronic idiopathic urticaria with omalizumab. AB - Chronic idiopathic urticaria is a condition that is often controllable with antihistamine therapy. However, some patients have disease burden that is difficult to manage, non-responsive to antihistamines and often requires immunosuppressive medications such as corticosteroids or cyclosporine. We present here a study that demonstrates the effectiveness of omalizumab in treating this condition and the temporal relationship between improvement and down regulation of the high affinity IgE receptor (FcepsilonRI). For this, blood samples were obtained from a symptomatic patient before each treatment and processed for flow cytometric analysis of FcepsilonRI levels on the surface of blood basophils. Down regulation of FcepsilonRI was observed in association with significant clinical improvement and discontinuation of immunosuppressive medications. PMID- 21247439 TI - Characteristics of chronic non-specific musculoskeletal pain in children and adolescents attending a rheumatology outpatients clinic: a cross-sectional study. AB - BACKGROUND: Chronic non-specific musculoskeletal pain (CNSMSP) may develop in childhood and adolescence, leading to disability and reduced quality of life that continues into adulthood. The purpose of the study was to build a biopsychosocial profile of children and adolescents with CNSMSP. METHODS: CNSMSP subjects (n = 30, 18 females, age 7-18) were compared with age matched pain free controls across a number of biopsychosocial domains. RESULTS: In the psychosocial domain CNSMSP subjects had increased levels of anxiety and depression, and had more somatic pain complaints. In the lifestyle domain CNSMSP subjects had lower physical activity levels, but no difference in television or computer use compared to pain free subjects. Physically, CNSMSP subjects tended to sit with a more slumped spinal posture, had reduced back muscle endurance, increased presence of joint hypermobility and poorer gross motor skills. CONCLUSION: These findings support the notion that CNSMSP is a multidimensional biopsychosocial disorder. Further research is needed to increase understanding of how the psychosocial, lifestyle and physical factors develop and interact in CNSMSP. PMID- 21247440 TI - Meta-analysis of haplotype-association studies: comparison of methods and empirical evaluation of the literature. AB - BACKGROUND: Meta-analysis is a popular methodology in several fields of medical research, including genetic association studies. However, the methods used for meta-analysis of association studies that report haplotypes have not been studied in detail. In this work, methods for performing meta-analysis of haplotype association studies are summarized, compared and presented in a unified framework along with an empirical evaluation of the literature. RESULTS: We present multivariate methods that use summary-based data as well as methods that use binary and count data in a generalized linear mixed model framework (logistic regression, multinomial regression and Poisson regression). The methods presented here avoid the inflation of the type I error rate that could be the result of the traditional approach of comparing a haplotype against the remaining ones, whereas, they can be fitted using standard software. Moreover, formal global tests are presented for assessing the statistical significance of the overall association. Although the methods presented here assume that the haplotypes are directly observed, they can be easily extended to allow for such an uncertainty by weighting the haplotypes by their probability. CONCLUSIONS: An empirical evaluation of the published literature and a comparison against the meta-analyses that use single nucleotide polymorphisms, suggests that the studies reporting meta-analysis of haplotypes contain approximately half of the included studies and produce significant results twice more often. We show that this excess of statistically significant results, stems from the sub-optimal method of analysis used and, in approximately half of the cases, the statistical significance is refuted if the data are properly re-analyzed. Illustrative examples of code are given in Stata and it is anticipated that the methods developed in this work will be widely applied in the meta-analysis of haplotype association studies. PMID- 21247441 TI - Comparative analysis of information contents relevant to recognition of introns in many species. AB - BACKGROUND: The basic process of RNA splicing is conserved among eukaryotic species. Three signals (5' and 3' splice sites and branch site) are commonly used to directly conduct splicing, while other features are also related to the recognition of an intron. Although there is experimental evidence pointing to the significant species specificities in the features of intron recognition, a quantitative evaluation of the divergence of these features among a wide variety of eukaryotes has yet to be conducted. RESULTS: To better understand the splicing process from the viewpoints of evolution and information theory, we collected introns from 61 diverse species of eukaryotes and analyzed the properties of the nucleotide sequences relevant to splicing. We found that trees individually constructed from the five features (the three signals, intron length, and nucleotide composition within an intron) roughly reflect the phylogenetic relationships among the species but sometimes extensively deviate from the species classification. The degree of topological deviation of each feature tree from the reference trees indicates the lowest discordance for the 5' splicing signal, followed by that for the 3' splicing signal, and a considerably greater discordance for the other three features. We also estimated the relative contributions of the five features to short intron recognition in each species. Again, moderate correlation was observed between the similarities in pattern of short intron recognition and the genealogical relationships among the species. When mammalian introns were categorized into three subtypes according to their terminal dinucleotide sequences, each subtype segregated into a nearly monophyletic group, regardless of the host species, with respect to the 5' and 3' splicing signals. It was also found that GC-AG introns are extraordinarily abundant in some species with high genomic G + C contents, and that the U12-type spliceosome might make a greater contribution than currently estimated in most species. CONCLUSIONS: Overall, the present study indicates that both splicing signals themselves and their relative contributions to short intron recognition are rather susceptible to evolutionary changes, while some poorly characterized properties seem to be preserved within the mammalian intron subtypes. Our findings may afford additional clues to understanding of evolution of splicing mechanisms. PMID- 21247442 TI - Effect of small interfering RNA 3'-end overhangs on chemosensitivity to thymidylate synthase inhibitors. AB - BACKGROUND: Small interfering RNAs (siRNAs) are double-stranded RNAs that effectively inhibit expression of its complimentary target mRNA. Standard siRNAs contain two nucleotide overhangs on their 3' end. While these overhangs are usually comprised of deoxythymidines (dT), it has been shown that any nucleotide can be used on the 3' end without affecting RNAi silencing. RESULTS: It was recently shown that extension of the 3' end to five or eight dT molecules allows siRNAs to be effectively complexed with linear polyethylenimine (PEI), leading to enhanced cellular uptake and intracellular release. Here, we provide further evidence that only extended or 'sticky' siRNAs complexed with PEI result in significant target knockdown. However, when investigating the potential effects of these extended siRNAs on growth of human colon cancer RKO cells, we observed a dose-dependent reversal of cytotoxicity of a thymidylate synthase-targeted siRNA. In contrast, siRNAs with uridine overhangs maintained their growth inhibitory effects. We further demonstrated that dT-containing siRNAs prevented the cytotoxic effects of thymidylate synthase (TS) inhibitor compounds, such as ZD1694 and 5'-fluoro-deoxyuridine, while having no deleterious effect on cisplatin toxicity. We show that this rescue effect results from the rapid degradation of the siRNA. CONCLUSIONS: Given that TS is an important enzyme for cell growth and proliferation and that its expression is controlled by multiple pathways, the rescue of its growth inhibitory effects may have unintended consequences. As siRNAs are being developed as therapeutic molecules, it will be important to avoid such off-target effects due to dT release. Hence, siRNAs should contain only uridine residues in their 3'-end overhangs. PMID- 21247443 TI - Identification of fusion genes in breast cancer by paired-end RNA-sequencing. AB - BACKGROUND: Until recently, chromosomal translocations and fusion genes have been an underappreciated class of mutations in solid tumors. Next-generation sequencing technologies provide an opportunity for systematic characterization of cancer cell transcriptomes, including the discovery of expressed fusion genes resulting from underlying genomic rearrangements. RESULTS: We applied paired-end RNA-seq to identify 24 novel and 3 previously known fusion genes in breast cancer cells. Supported by an improved bioinformatic approach, we had a 95% success rate of validating gene fusions initially detected by RNA-seq. Fusion partner genes were found to contribute promoters (5' UTR), coding sequences and 3' UTRs. Most fusion genes were associated with copy number transitions and were particularly common in high-level DNA amplifications. This suggests that fusion events may contribute to the selective advantage provided by DNA amplifications and deletions. Some of the fusion partner genes, such as GSDMB in the TATDN1-GSDMB fusion and IKZF3 in the VAPB-IKZF3 fusion, were only detected as a fusion transcript, indicating activation of a dormant gene by the fusion event. A number of fusion gene partners have either been previously observed in oncogenic gene fusions, mostly in leukemias, or otherwise reported to be oncogenic. RNA interference-mediated knock-down of the VAPB-IKZF3 fusion gene indicated that it may be necessary for cancer cell growth and survival. CONCLUSIONS: In summary, using RNA-sequencing and improved bioinformatic stratification, we have discovered a number of novel fusion genes in breast cancer, and identified VAPB IKZF3 as a potential fusion gene with importance for the growth and survival of breast cancer cells. PMID- 21247444 TI - Application and comparison of scoring indices to predict outcomes in patients with healthcare-associated pneumonia. AB - INTRODUCTION: Healthcare-associated pneumonia (HCAP) is a relatively new category of pneumonia. It refers to infections that occur prior to hospital admission in patients with specific risk factors following contact or exposure to a healthcare environment. There is currently no scoring index to predict the outcomes of HCAP patients. We applied and compared different community acquired pneumonia (CAP) scoring indices to predict 30-day mortality and 3-day and 14-day intensive care unit (ICU) admission in patients with HCAP. METHODS: We conducted a retrospective cohort study based on an inpatient database from six medical centers, recruiting a total of 444 patients with HCAP between 1 January 2007 and 31 December 2007. Pneumonia severity scoring indices including PSI (pneumonia severity index), CURB 65 (confusion, urea, respiratory rate, blood pressure, age 65), IDSA/ATS (Infectious Diseases Society of America/American Thoracic Society), modified ATS rule, SCAP (severe community acquired pneumonia), SMART-COP (systolic blood pressure, multilobar involvement, albumin, respiratory rate, tachycardia, confusion, oxygenation, pH), SMRT-CO (systolic blood pressure, multilobar involvement, respiratory rate, tachycardia, confusion, oxygenation), and SOAR (systolic blood pressure, oxygenation, age, respiratory rate) were calculated for each patient. Patient characteristics, co-morbidities, pneumonia pathogen culture results, length of hospital stay (LOS), and length of ICU stay were also recorded. RESULTS: PSI (>90) has the highest sensitivity in predicting mortality, followed by CURB-65 (>=2) and SCAP (>9) (SCAP score (area under the curve (AUC): 0.71), PSI (AUC: 0.70) and CURB-65 (AUC: 0.66)). Compared to PSI, modified ATS, IDSA/ATS, SCAP, and SMART-COP were easy to calculate. For predicting ICU admission (Day 3 and Day 14), modified ATS (AUC: 0.84, 0.82), SMART-COP (AUC: 0.84, 0.82), SCAP (AUC: 0.82, 0.80) and IDSA/ATS (AUC: 0.80, 0.79) performed better (statistically significant difference) than PSI, CURB-65, SOAR and SMRT CO. CONCLUSIONS: The utility of the scoring indices for risk assessment in patients with healthcare-associated pneumonia shows that the scoring indices originally designed for CAP can be applied to HCAP. PMID- 21247445 TI - Dropped head syndrome due to myogenic atrophy - a case report of surgical treatment. AB - We report a case of a 69-year-old man with dropped head syndrome associated with isolated neck extensor myopathy (INEM). Over a period of 2 years, he exhibited progressive inability to lift his chin off his chest, resulting in the dropped head position that impaired his activities of daily living. He had a disturbed gait with severe imbalance of spinal alignment. Computed tomography revealed osseous contracture of cervical vertebral bodies in flexed position. Anterior combined posterior reconstruction surgery yielded a successful outcome in his activities of daily living, including his walking balance of spinal alignment. Pathologic study confirmed myogenic atrophy in the cervical extensor muscles. We suggest that consideration for surgical management should be given to dropped head syndrome especially due to INEM. PMID- 21247446 TI - A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism. AB - BACKGROUND: Genome-wide Association Studies (GWAS) have proved invaluable for the identification of disease susceptibility genes. However, the prioritization of candidate genes and regions for follow-up studies often proves difficult due to false-positive associations caused by statistical noise and multiple-testing. In order to address this issue, we propose the novel GWAS noise reduction (GWAS-NR) method as a way to increase the power to detect true associations in GWAS, particularly in complex diseases such as autism. METHODS: GWAS-NR utilizes a linear filter to identify genomic regions demonstrating correlation among association signals in multiple datasets. We used computer simulations to assess the ability of GWAS-NR to detect association against the commonly used joint analysis and Fisher's methods. Furthermore, we applied GWAS-NR to a family-based autism GWAS of 597 families and a second existing autism GWAS of 696 families from the Autism Genetic Resource Exchange (AGRE) to arrive at a compendium of autism candidate genes. These genes were manually annotated and classified by a literature review and functional grouping in order to reveal biological pathways which might contribute to autism aetiology. RESULTS: Computer simulations indicate that GWAS-NR achieves a significantly higher classification rate for true positive association signals than either the joint analysis or Fisher's methods and that it can also achieve this when there is imperfect marker overlap across datasets or when the closest disease-related polymorphism is not directly typed. In two autism datasets, GWAS-NR analysis resulted in 1535 significant linkage disequilibrium (LD) blocks overlapping 431 unique reference sequencing (RefSeq) genes. Moreover, we identified the nearest RefSeq gene to the non-gene overlapping LD blocks, producing a final candidate set of 860 genes. Functional categorization of these implicated genes indicates that a significant proportion of them cooperate in a coherent pathway that regulates the directional protrusion of axons and dendrites to their appropriate synaptic targets. CONCLUSIONS: As statistical noise is likely to particularly affect studies of complex disorders, where genetic heterogeneity or interaction between genes may confound the ability to detect association, GWAS-NR offers a powerful method for prioritizing regions for follow-up studies. Applying this method to autism datasets, GWAS-NR analysis indicates that a large subset of genes involved in the outgrowth and guidance of axons and dendrites is implicated in the aetiology of autism. PMID- 21247448 TI - Relationships between heavy metal concentrations in three different body fluids and male reproductive parameters: a pilot study. AB - BACKGROUND: Animal studies have shown the reproductive toxicity of a number of heavy metals. Very few human observational studies have analyzed the relationship between male reproductive function and heavy metal concentrations in diverse biological fluids. METHODS: The current study assessed the associations between seminal and hormonal parameters and the concentration of the 3 most frequent heavy metal toxicants (lead, cadmium and mercury) in three different body fluids. Sixty one men attending infertility clinics that participated in a case-control study to explore the role of environmental toxins and lifestyles on male infertility were analyzed. Concentration of lead, cadmium and mercury were measured in blood and seminal plasma and whole blood using anodic stripping voltammetry and atomic absorption spectrophotometry. Serum samples were analyzed for follicle-stimulating hormone, luteinizing hormone and testosterone. Semen analyses were performed according to World Health Organization criteria. Mann Whitney test and Spearman's rank correlations were used for unadjusted analyses. Multiple linear regression models were performed controlling for age, body mass index and number of cigarettes per day. RESULTS: There were no significant differences between cases and controls in the concentrations of heavy metals in any of the three body fluids. In multivariate analyses using all subjects no significant associations were found between serum hormone levels and metal concentrations. However there was a significant positive association between the percentage of immotile sperms and seminal plasma levels of lead and cadmium. CONCLUSIONS: Our results suggest that the presence of lead and cadmium in the reproductive tract of men may be related to a moderate alteration of their seminal parameters. PMID- 21247447 TI - CYP2C19 and ABCB1 gene polymorphisms are differently distributed according to ethnicity in the Brazilian general population. AB - BACKGROUND: Recent studies have reported the clinical importance of CYP2C19 and ABCB1 polymorphisms in an individualized approach to clopidogrel treatment. The aims of this study were to evaluate the frequencies of CYP2C19 and ABCB1 polymorphisms and to identify the clopidogrel-predicted metabolic phenotypes according to ethnic groups in a sample of individuals representative of a highly admixtured population. METHODS: One hundred and eighty-three Amerindians and 1,029 subjects of the general population of 4 regions of the country were included. Genotypes for the ABCB1c.C3435T (rs1045642), CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*4 (rs28399504), CYP2C19*5 (rs56337013), and CYP2C19*17 (rs12248560) polymorphisms were detected by polymerase chain reaction followed by high resolution melting analysis. The CYP2C19*3, CYP2C19*4 and CYP2C19*5 variants were genotyped in a subsample of subjects (300 samples randomly selected). RESULTS: The CYP2C19*3 and CYP2C19*5 variant alleles were not detected and the CYP2C19*4 variant allele presented a frequency of 0.3%. The allelic frequencies for the ABCB1c.C3435T, CYP2C19*2 and CYP2C19*17 polymorphisms were differently distributed according to ethnicity: Amerindian (51.4%, 10.4%, 15.8%); Caucasian descent (43.2%, 16.9%, 18.0%); Mulatto (35.9%, 16.5%, 21.3%); and African descent (32.8%, 20.2%, 26.3%) individuals, respectively. As a result, self-referred ethnicity was able to predict significantly different clopidogrel predicted metabolic phenotypes prevalence even for a highly admixtured population. CONCLUSION: Our findings indicate the existence of inter-ethnic differences in the ABCB1 and CYP2C19 variant allele frequencies in the Brazilian general population plus Amerindians. This information could help in stratifying individuals from this population regarding clopidogrel-predicted metabolic phenotypes and design more cost-effective programs towards individualization of clopidogrel therapy. PMID- 21247449 TI - Peripheral artery disease assessed by ankle-brachial index in patients with established cardiovascular disease or at least one risk factor for atherothrombosis--CAREFUL study: a national, multi-center, cross-sectional observational study. AB - BACKGROUND: To investigate the presence of peripheral artery disease (PAD) via the ankle brachial index (ABI) in patients with known cardiovascular and/or cerebrovascular diseases or with at least one risk factor for atherothrombosis. METHODS: Patients with a history of atherothrombotic events, or aged 50-69 years with at least one cardiovascular risk factor, or > = 70 years of age were included in this multicenter, cross-sectional, non-interventional study (DIREGL04074). Demographics, medical history, physical examination findings, and physician awareness of PAD were analyzed. The number of patients with low ABI (< = 0.90) was analyzed. RESULTS: A total of 530 patients (mean age, 63.4 +/- 8.7 years; 50.2% female) were enrolled. Hypertension and dyslipidemia were present in 88.7% and 65.5% of patients, respectively. PAD-related symptoms were evident in about one-third of the patients, and at least one of the pedal pulses was negative in 6.5% of patients. The frequency of low ABI was 20.0% in the whole study population and 30% for patients older than 70 years. Older age, greater number of total risk factors, and presence of PAD-related physical findings were associated with increased likelihood of low ABI (p < 0.001). There was no gender difference in the prevalence of low ABI, PAD symptoms, or total number of risk factors. Exercise (33.6%) was the most common non-pharmacological option recommended by physicians, and acetylsalicylic acid (ASA) (45.4%) was the most frequently prescribed medication for PAD. CONCLUSION: Our results indicate that advanced age, greater number of total risk factors and presence of PAD-related physical findings were associated with increased likelihood of low ABI. These findings are similar to those reported in similar studies of different populations, and document a fairly high prevalence of PAD in a Mediterranean country. PMID- 21247450 TI - Phylogenetic group- and species-specific oligonucleotide probes for single-cell detection of lactic acid bacteria in oral biofilms. AB - BACKGROUND: The purpose of this study was to design and evaluate fluorescent in situ hybridization (FISH) probes for the single-cell detection and enumeration of lactic acid bacteria, in particular organisms belonging to the major phylogenetic groups and species of oral lactobacilli and to Abiotrophia/Granulicatella. RESULTS: As lactobacilli are known for notorious resistance to probe penetration, probe-specific assay protocols were experimentally developed to provide maximum cell wall permeability, probe accessibility, hybridization stringency, and fluorescence intensity. The new assays were then applied in a pilot study to three biofilm samples harvested from variably demineralized bovine enamel discs that had been carried in situ for 10 days by different volunteers. Best probe penetration and fluorescent labeling of reference strains were obtained after combined lysozyme and achromopeptidase treatment followed by exposure to lipase. Hybridization stringency had to be established strictly for each probe. Thereafter all probes showed the expected specificity with reference strains and labeled the anticipated morphotypes in dental plaques. Applied to in situ grown biofilms the set of probes detected only Lactobacillus fermentum and bacteria of the Lactobacillus casei group. The most cariogenic biofilm contained two orders of magnitude higher L. fermentum cell numbers than the other biofilms. Abiotrophia/Granulicatella and streptococci from the mitis group were found in all samples at high levels, whereas Streptococcus mutans was detected in only one sample in very low numbers. CONCLUSIONS: Application of these new group- and species-specific FISH probes to oral biofilm-forming lactic acid bacteria will allow a clearer understanding of the supragingival biome, its spatial architecture and of structure-function relationships implicated during plaque homeostasis and caries development. The probes should prove of value far beyond the field of oral microbiology, as many of them detect non-oral species and phylogenetic groups of importance in a variety of medical conditions and the food industry. PMID- 21247451 TI - Left atrial volume and exercise capacity in adult heart transplant recipients. PMID- 21247452 TI - Conserved generation of short products at piRNA loci. AB - BACKGROUND: The piRNA pathway operates in animal germ lines to ensure genome integrity through retrotransposon silencing. The Piwi protein-associated small RNAs (piRNAs) guide Piwi proteins to retrotransposon transcripts, which are degraded and thereby post-transcriptionally silenced through a ping-pong amplification process. Cleavage of the retrotransposon transcript defines at the same time the 5' end of a secondary piRNA that will in turn guide a Piwi protein to a primary piRNA precursor, thereby amplifying primary piRNAs. Although several studies provided evidence that this mechanism is conserved among metazoa, how the process is initiated and what enzymatic activities are responsible for generating the primary and secondary piRNAs are not entirely clear. RESULTS: Here we analyzed small RNAs from three mammalian species, seeking to gain further insight into the mechanisms responsible for the piRNA amplification loop. We found that in all these species piRNA-directed targeting is accompanied by the generation of short sequences that have a very precisely defined length, 19 nucleotides, and a specific spatial relationship with the guide piRNAs. CONCLUSIONS: This suggests that the processing of the 5' product of piRNA-guided cleavage occurs while the piRNA target is engaged by the Piwi protein. Although they are not stabilized through methylation of their 3' ends, the 19-mers are abundant not only in testes lysates but also in immunoprecipitates of Miwi and Mili proteins. They will enable more accurate identification of piRNA loci in deep sequencing data sets. PMID- 21247454 TI - First Honorary Medal of the Signal Transduction Society (STS) and 'CELL COMMUNICATION AND SIGNALING' awarded to Professor Anthony J. (Tony) Pawson. PMID- 21247453 TI - Identification of Schistosoma mansoni microRNAs. AB - BACKGROUND: MicroRNAs (miRNAs) constitute a class of single-stranded RNAs which play a crucial role in regulating development and controlling gene expression by targeting mRNAs and triggering either translation repression or messenger RNA (mRNA) degradation. miRNAs are widespread in eukaryotes and to date over 14,000 miRNAs have been identified by computational and experimental approaches. Several miRNAs are highly conserved across species. In Schistosoma, the full set of miRNAs and their expression patterns during development remain poorly understood. Here we report on the development and implementation of a homology-based detection strategy to search for miRNA genes in Schistosoma mansoni. In addition, we report results on the experimental detection of miRNAs by means of cDNA cloning and sequencing of size-fractionated RNA samples. RESULTS: Homology search using the high-throughput pipeline was performed with all known miRNAs in miRBase. A total of 6,211 mature miRNAs were used as reference sequences and 110 unique S. mansoni sequences were returned by BLASTn analysis. The existing mature miRNAs that produced these hits are reported, as well as the locations of the homologous sequences in the S. mansoni genome. All BLAST hits aligned with at least 95% of the miRNA sequence, resulting in alignment lengths of 19-24 nt. Following several filtering steps, 15 potential miRNA candidates were identified using this approach. By sequencing small RNA cDNA libraries from adult worm pairs, we identified 211 novel miRNA candidates in the S. mansoni genome. Northern blot analysis was used to detect the expression of the 30 most frequent sequenced miRNAs and to compare the expression level of these miRNAs between the lung stage schistosomula and adult worm stages. Expression of 11 novel miRNAs was confirmed by northern blot analysis and some presented a stage-regulated expression pattern. Three miRNAs previously identified from S. japonicum were also present in S. mansoni. CONCLUSION: Evidence for the presence of miRNAs in S. mansoni is presented. The number of miRNAs detected by homology-based computational methods in S. mansoni is limited due to the lack of close relatives in the miRNA repository. In spite of this, the computational approach described here can likely be applied to the identification of pre-miRNA hairpins in other organisms. Construction and analysis of a small RNA library led to the experimental identification of 14 novel miRNAs from S. mansoni through a combination of molecular cloning, DNA sequencing and expression studies. Our results significantly expand the set of known miRNAs in multicellular parasites and provide a basis for understanding the structural and functional evolution of miRNAs in these metazoan parasites. PMID- 21247455 TI - Effectiveness of an intercultural module added to the treatment guidelines for Moroccan and Turkish patients with depressive and anxiety disorders. AB - BACKGROUND: Since the sixties of the last century, many people from Morocco and Turkey have migrated into the Netherlands. In the last decade, Moroccan and Turkish patients have found their way to organizations for mental health care. However, they often drop out of treatment. Problems in the communication with therapists and different expectations regarding treatment seem to be causal factors for the early drop-out of therapy. In the Netherlands as in other countries courses have been developed for training cultural competence of therapists. Yet, up to now, the effectiveness of increased cultural competence of therapists in reducing drop-out of treatment has not been studied. METHODS/DESIGN: A randomized clinical trial was started in January 2010. Moroccan and Turkish adult patients who are referred to our outpatient clinics for mood and anxiety disorders are randomly assigned to mental health workers who are trained in a cultural module and to those who are not. The therapists have been trained in the Cultural Formulation and in techniques bridging the (cultural) gap between them and their Moroccan and Turkish patients. The target number of participants is 150 patients, 75 for each group. Drop-out of treatment is the primary outcome measure. Secondary outcome measures are no-show and patients' perspective of care. DISCUSSION: The study will give an answer to the question whether increasing cultural competence of therapists reduces drop-out of treatment in Moroccan and Turkish outpatients with depressive and anxiety disorders. PMID- 21247456 TI - Temporal trends in the initiation of glucose-lowering medications after a first time myocardial infarction - a nationwide study between 1997 and 2006. AB - BACKGROUND: Type 2 diabetes is a well-established risk factor for cardiovascular disease and is common among patients with acute myocardial infarction (MI). The extent to which patients with first-time MI develop diabetes requiring glucose lowering medications (GLM) is largely unknown. The aim of the study was to investigate temporal trends in the initiation of GLM among patients discharged after first-time MI. METHODS: All Danish residents aged >= 30 years without prior diabetes hospitalized with first-time MI between 1997 and 2006 were identified by individual-level-linkage of nationwide registers. Initiation of GLM during follow up was assessed by claimed prescriptions from pharmacies. Temporal trends in initiation of GLM were assessed by incidence rate calculations in the MI population as in the general population. Multivariable Cox proportional-hazard models were used to investigate the likelihood of initiating GLM within a year post-MI. RESULTS: The population comprised 66,788 patients. Among these patients 3962 patients initiated GLM, of whom 1567 started within one year post-MI. An increase in incidence rates of GLM initiation in the MI population from 19.6 per 1000 person years in 1997 to approximately 27.6 in 2001 was demonstrated. After 2001 the incidence rates stabilized. A similar trend was observed in the general population where the incidence rates increased from 2.8 in 1997 to 4.0 in 2004 and then stabilized. CONCLUSION: Our study demonstrated an increase in incidence rates of GLM initiation within the first year post- MI. A similar trend was observed in the general population suggesting that the increase in GLM among MI patients was primarily the effect of a general increased awareness of diabetes. From a public heath perspective, this study underscores a continuous need for diagnostic and therapeutic improvement in the care of MI patients that develop diabetes. PMID- 21247457 TI - Genetic variant of V825I in the ATP-binding cassette transporter A1 gene and serum lipid levels in the Guangxi Bai Ku Yao and Han populations. AB - BACKGROUND: Several genetic variants in the ATP-binding cassette transporter A1 (ABCA1) gene have associated with modifications of serum high-density lipoprotein cholesterol (HDL-C) levels and the susceptibility for coronary heart disease, but the findings are still controversial in diverse racial/ethnic groups. Bai Ku Yao is an isolated subgroup of the Yao minority in southern China. The present study was undertaken to detect the possible association of V825I (rs2066715) polymorphism in the ABCA1 gene and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. METHODS: A total of 677 subjects of Bai Ku Yao and 646 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Polymerase chain reaction and restriction fragment length polymorphism assay combined with gel electrophoresis were performed for the genotyping of V825I variant, and then confirmed by direct sequencing. RESULTS: The levels of serum total cholesterol (TC), HDL-C, apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P < 0.01 for all). The frequency of G and A alleles was 57.4% and 42.6% in Bai Ku Yao, and 57.7% and 42.3% in Han (P > 0.05); respectively. The frequency of GG, GA and AA genotypes was 33.7%, 47.4% and 18.9% in Bai Ku Yao, and 33.4%, 48.6% and 18.0% in Han (P > 0.05); respectively. There was no difference in the genotypic and allelic frequencies between males and females in the both ethnic groups. The subjects with AA genotype in Bai Ku Yao had higher serum TC levels than the subjects with GG and GA genotypes (P < 0.05). The participants with AA genotype in Han had lower serum HDL-C and ApoAI levels than the participants with GG and GA genotypes (P < 0.05 for each), but these results were found in males but not in females. Multivariate linear regression analysis showed that the levels of TC in Bai Ku Yao and HDL-C and ApoAI in male Han were correlated with genotypes (P < 0.05 for all). Serum lipid parameters were also correlated with sex, age, body mass index, alcohol consumption, and blood pressure in both ethnic groups (P < 0.05-0.001). CONCLUSION: The present study suggests that the V825I polymorphism in the ABCA1 gene is associated with male serum HDL-C and ApoAI levels in the Han, and serum TC levels in the Bai Ku Yao populations. The difference in the association of V825I polymorphism and serum lipid levels between the two ethnic groups might partly result from different ABCA1 gene environmental interactions. PMID- 21247458 TI - Analysis of the PDZ binding specificities of Influenza A virus NS1 proteins. AB - The Influenza A virus non-structural protein 1 (NS1) is a multifunctional virulence factor with several protein-protein interaction domains, involved in preventing apoptosis of the infected cell and in evading the interferon response. In addition, the majority of influenza A virus NS1 proteins have a class I PDZ binding motif at the C-terminus, and this itself has been shown to be a virulence determinant.In the majority of human influenza NS1 proteins the consensus motif is RSxV: in avian NS1 it is ESxV. Of the few human strains that have the avian motif, all were from very high mortality outbreaks of the disease. Previous work has shown that minor differences in PDZ-binding motifs can have major effects on the spectrum of cellular proteins targeted. In this study we analyse the effect of these differences upon the binding of Influenza A virus NS1 protein to a range of cellular proteins involved in polarity and signal transduction. PMID- 21247459 TI - A second generation genetic map of the bumblebee Bombus terrestris (Linnaeus, 1758) reveals slow genome and chromosome evolution in the Apidae. AB - BACKGROUND: The bumblebee Bombus terrestris is an ecologically and economically important pollinator and has become an important biological model system. To study fundamental evolutionary questions at the genomic level, a high resolution genetic linkage map is an essential tool for analyses ranging from quantitative trait loci (QTL) mapping to genome assembly and comparative genomics. We here present a saturated linkage map and match it with the Apis mellifera genome using homologous markers. This genome-wide comparison allows insights into structural conservations and rearrangements and thus the evolution on a chromosomal level. RESULTS: The high density linkage map covers ~ 93% of the B. terrestris genome on 18 linkage groups (LGs) and has a length of 2'047 cM with an average marker distance of 4.02 cM. Based on a genome size of ~ 430 Mb, the recombination rate estimate is 4.76 cM/Mb. Sequence homologies of 242 homologous markers allowed to match 15 B. terrestris with A. mellifera LGs, five of them as composites. Comparing marker orders between both genomes we detect over 14% of the genome to be organized in synteny and 21% in rearranged blocks on the same homologous LG. CONCLUSIONS: This study demonstrates that, despite the very high recombination rates of both A. mellifera and B. terrestris and a long divergence time of about 100 million years, the genomes' genetic architecture is highly conserved. This reflects a slow genome evolution in these bees. We show that data on genome organization and conserved molecular markers can be used as a powerful tool for comparative genomics and evolutionary studies, opening up new avenues of research in the Apidae. PMID- 21247461 TI - Delivering early care in diabetes evaluation (DECIDE): a protocol for a randomised controlled trial to assess hospital versus home management at diagnosis in childhood diabetes. AB - BACKGROUND: There is increased incidence of new cases of type 1 diabetes in children younger than 15 years. The debate concerning where best to manage newly diagnosed children continues. Some units routinely admit children to hospital whilst others routinely manage children at home. A Cochrane review identified the need for a large well-designed randomised controlled trial to investigate any significant differences in comprehensive short and long-term outcomes between the two approaches. The DECIDE study will address these knowledge gaps, providing high quality evidence to inform national and international policy and practice. METHODS/DESIGN: This is a multi-centre randomised controlled trial across eight UK paediatric diabetes centres. The study aims to recruit 240 children newly diagnosed with type 1 diabetes and their parents/carers. Eligible patients (aged 0-17 years) will be remotely randomised to either 'hospital' or 'home' management. Parents/carers of patients will also be recruited. Nursing management of participants and data collection will be co-ordinated by a project nurse at each centre. Data will be collected for 24 months after diagnosis; at follow up appointments at 3, 12 and 24 months and every 3-4 months at routine clinic visits.The primary outcome measure is patients' glycosylated haemoglobin (HbA1c) at 24 months after diagnosis. Additional measurements of HbA1c will be made at diagnosis and 3 and 12 months later. HbA1c concentrations will be analysed at a central laboratory.Secondary outcome measures include length of stay at diagnosis, growth, adverse events, quality of life, anxiety, coping with diabetes, diabetes knowledge, home/clinic visits, self-care activity, satisfaction and time off school/work. Questionnaires will be sent to participants at 1, 12 and 24 months and will include a questionnaire, developed and validated to measure impact of the diagnosis on social activity and independence. Additional qualitative outcome measures include the experience of both approaches by a subgroup of participants (n = 30) and health professionals. Total health service costs will be evaluated. A cost effectiveness analysis will assess direct and indirect health service costs against the primary outcome (HbA1c). DISCUSSION: This will be the first randomised controlled trial to evaluate hospital and home management of children newly diagnosed with type 1 diabetes and the findings should provide important evidence to inform practice and national guidelines. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN78114042. PMID- 21247460 TI - Comparative and functional genomics provide insights into the pathogenicity of dermatophytic fungi. AB - BACKGROUND: Millions of humans and animals suffer from superficial infections caused by a group of highly specialized filamentous fungi, the dermatophytes, which exclusively infect keratinized host structures. To provide broad insights into the molecular basis of the pathogenicity-associated traits, we report the first genome sequences of two closely phylogenetically related dermatophytes, Arthroderma benhamiae and Trichophyton verrucosum, both of which induce highly inflammatory infections in humans. RESULTS: 97% of the 22.5 megabase genome sequences of A. benhamiae and T. verrucosum are unambiguously alignable and collinear. To unravel dermatophyte-specific virulence-associated traits, we compared sets of potentially pathogenicity-associated proteins, such as secreted proteases and enzymes involved in secondary metabolite production, with those of closely related onygenales (Coccidioides species) and the mould Aspergillus fumigatus. The comparisons revealed expansion of several gene families in dermatophytes and disclosed the peculiarities of the dermatophyte secondary metabolite gene sets. Secretion of proteases and other hydrolytic enzymes by A. benhamiae was proven experimentally by a global secretome analysis during keratin degradation. Molecular insights into the interaction of A. benhamiae with human keratinocytes were obtained for the first time by global transcriptome profiling. Given that A. benhamiae is able to undergo mating, a detailed comparison of the genomes further unraveled the genetic basis of sexual reproduction in this species. CONCLUSIONS: Our results enlighten the genetic basis of fundamental and putatively virulence-related traits of dermatophytes, advancing future research on these medically important pathogens. PMID- 21247462 TI - A novel informatics concept for high-throughput shotgun lipidomics based on the molecular fragmentation query language. AB - Shotgun lipidome profiling relies on direct mass spectrometric analysis of total lipid extracts from cells, tissues or organisms and is a powerful tool to elucidate the molecular composition of lipidomes. We present a novel informatics concept of the molecular fragmentation query language implemented within the LipidXplorer open source software kit that supports accurate quantification of individual species of any ionizable lipid class in shotgun spectra acquired on any mass spectrometry platform. PMID- 21247463 TI - Microarray-based gene expression profiles of silkworm brains. AB - BACKGROUND: Molecular genetic studies of Bombyx mori have led to profound advances in our understanding of the regulation of development. Bombyx mori brain, as a main endocrine organ, plays important regulatory roles in various biological processes. Microarray technology will allow the genome-wide analysis of gene expression patterns in silkworm brains. RESULTS: We reported microarray based gene expression profiles in silkworm brains at four stages including V7, P1, P3 and P5. A total of 4,550 genes were transcribed in at least one selected stage. Of these, clustering algorithms separated the expressed genes into stably expressed genes and variably expressed genes. The results of the gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analysis of stably expressed genes showed that the ribosomal and oxidative phosphorylation pathways were principal pathways. Secondly, four clusters of genes with significantly different expression patterns were observed in the 1,175 variably expressed genes. Thirdly, thirty-two neuropeptide genes, six neuropeptide-like precursor genes, and 117 cuticular protein genes were expressed in selected developmental stages. CONCLUSION: Major characteristics of the transcriptional profiles in the brains of Bombyx mori at specific development stages were present in this study. Our data provided useful information for future research. PMID- 21247464 TI - In-vitro antiviral activity of Solanum nigrum against Hepatitis C Virus. AB - BACKGROUND: Hepatitis C is a major health problem causes liver cirrhosis, hepatocellular carcinoma and death. The current treatment of standard interferon in combination with ribavirin, has limited benefits due to emergence of resistant mutations during long-term treatment, adverse side effects and high cost. Hence, there is a need for the development of more effective, less toxic antiviral agents. RESULTS: The present study was designed to search anti-HCV plants from different areas of Pakistan. Ten medicinal plants were collected and tested for anti-HCV activity by infecting the liver cells with HCV 3a innoculum. Methanol and chloroform extracts of Solanum nigrum (SN) seeds exhibited 37% and more than 50% inhibition of HCV respectively at non toxic concentration. Moreover, antiviral effect of SN seeds extract was also analyzed against HCV NS3 protease by transfecting HCV NS3 protease plasmid into liver cells. The results demonstrated that chloroform extract of SN decreased the expression or function of HCV NS3 protease in a dose- dependent manner and GAPDH remained constant. CONCLUSION: These results suggest that SN extract contains potential antiviral agents against HCV and combination of SN extract with interferon will be better option to treat chronic HCV. PMID- 21247465 TI - Predicting functionally important SNP classes based on negative selection. AB - BACKGROUND: With the advent of cost-effective genotyping technologies, genome wide association studies allow researchers to examine hundreds of thousands of single nucleotide polymorphisms (SNPs) for association with human disease. Recently, many researchers applying this strategy have detected strong associations to disease with SNP markers that are either not in linkage disequilibrium with any nonsynonymous SNP or large distances from any annotated gene. In such cases, no well-established standard practice for effective SNP selection for follow-up studies exists. We aim to identify and prioritize groups of SNPs that are more likely to affect phenotypes in order to facilitate efficient SNP selection for follow-up studies. RESULTS: Based on the annotations available in the Ensembl database, we categorized SNPs in the human genome into classes related to regulatory attributes, such as epigenetic modifications and transcription factor binding sites, in addition to classes related to gene structure and cross-species conservation. Using the distribution of derived allele frequencies (DAF) within each class, we assessed the strength of natural selection for each class relative to the genome as a whole. We applied this DAF analysis to Perlegen resequenced SNPs genome-wide. Regulatory elements annotated by Ensembl such as specific histone methylation sites as well as classes defined by cross-species conservation showed negative selection in comparison to the genome as a whole. CONCLUSIONS: These results highlight which annotated classes are under purifying selection, have putative functional importance, and contain SNPs that are strong candidates for follow-up studies after genome-wide association. Such SNP annotation may also be useful in interpreting results of whole-genome sequencing studies. PMID- 21247466 TI - The association of remotely-sensed outdoor temperature with blood pressure levels in REGARDS: a cross-sectional study of a large, national cohort of African American and white participants. AB - BACKGROUND: Evidence is mounting regarding the clinically significant effect of temperature on blood pressure. METHODS: In this cross-sectional study the authors obtained minimum and maximum temperatures and their respective previous week variances at the geographic locations of the self-reported residences of 26,018 participants from a national cohort of blacks and whites, aged 45+. Linear regression of data from 20,623 participants was used in final multivariable models to determine if these temperature measures were associated with levels of systolic or diastolic blood pressure, and whether these relations were modified by stroke-risk region, race, education, income, sex hypertensive medication status, or age. RESULTS: After adjustment for confounders, same-day maximum temperatures 20 degrees F lower had significant associations with 1.4 mmHg (95% CI: 1.0, 1.9) higher systolic and 0.5 mmHg (95% CI: 0.3, 0.8) higher diastolic blood pressures. Same-day minimum temperatures 20 degrees F lower had a significant association with 0.7 mmHg (95% CI: 0.3, 1.0) higher systolic blood pressures but no significant association with diastolic blood pressure differences. Maximum and minimum previous-week temperature variabilities showed significant but weak relationships with blood pressures. Parameter estimates showed effect modification of negligible magnitude. CONCLUSIONS: This study found significant associations between outdoor temperature and blood pressure levels, which remained after adjustment for various confounders including season. This relationship showed negligible effect modification. PMID- 21247467 TI - Open access publishing: a girder in the success of the Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine. PMID- 21247468 TI - Evolutionary patterns of proteinase activity in attine ant fungus gardens. AB - BACKGROUND: Attine ants live in symbiosis with a basidiomycetous fungus that they rear on a substrate of plant material. This indirect herbivory implies that the symbiosis is likely to be nitrogen deprived, so that specific mechanisms may have evolved to enhance protein availability. We therefore hypothesized that fungal proteinase activity may have been under selection for efficiency and that different classes of proteinases might be involved. RESULTS: We determined proteinase activity profiles across a wide pH range for fungus gardens of 14 Panamanian species of fungus-growing ants, representing eight genera. We mapped these activity profiles on an independently obtained molecular phylogeny of the symbionts and show that total proteinase activity in lower attine symbionts peaks at ca. pH 6. The higher attine symbionts that have no known free-living relatives had much higher proteinase activities than the lower attine symbionts. Their total in vitro proteinase activity peaked at pH values around 5, which is close to the pH that the ants maintain in their fungus gardens, suggesting that the pH optimum of fungal proteinases may have changed after the irreversible domestication of evolutionary more derived fungal symbionts. This notion is also supported by buffering capacities of fungus gardens at pH 5.2 being remarkably high, and suggests that the fungal symbiont actively helps to maintain garden acidity at this specific level. Metalloproteinases dominated the activity profiles of lower attine gardens and may thus represent the ancestral type of proteinase production, whereas serine proteinase activity dominated the activity profiles of the higher attine gardens reared by Trachymyrmex and Sericomyrmex, suggesting that there may be trade-offs in the production of these enzyme classes. Remarkably, the single symbiont that is shared by species of the crown group of Atta and Acromyrmex leaf-cutting ants mostly showed metalloproteinase activity, suggesting that recurrent changes in enzyme production may have occurred throughout the domestication history of fungus-garden symbionts. CONCLUSIONS: Proteinase pH optima and buffering capacities of fungal symbionts appear to have evolved remarkable adaptations to living in obligate symbiosis with farming ants. Although the functional roles of serine and metalloproteinases in fungus gardens are unknown, the differential production of these classes of proteolytic enzymes suggest that substrate specificity may be important and that trade-offs may prevent the simultaneous upregulation of both classes of enzymes. PMID- 21247469 TI - DNA methylation-mediated control of learning and memory. AB - Animals constantly receive and respond to external or internal stimuli, and these experiences are learned and memorized in their brains. In animals, this is a crucial feature for survival, by making it possible for them to adapt their behavioral patterns to the ever-changing environment. For this learning and memory process, nerve cells in the brain undergo enormous molecular and cellular changes, not only in the input-output-related local subcellular compartments but also in the central nucleus. Interestingly, the DNA methylation pattern, which is normally stable in a terminally differentiated cell and defines the cell type identity, is emerging as an important regulatory mechanism of behavioral plasticity. The elucidation of how this covalent modification of DNA, which is known to be the most stable epigenetic mark, contributes to the complex orchestration of animal behavior is a fascinating new research area. We will overview the current understanding of the mechanism of modifying the methyl code on DNA and its impact on learning and memory. PMID- 21247470 TI - A systems biology approach to investigate the effect of pH-induced gene regulation on solvent production by Clostridium acetobutylicum in continuous culture. AB - BACKGROUND: Clostridium acetobutylicum is an anaerobic bacterium which is known for its solvent-producing capabilities, namely regarding the bulk chemicals acetone and butanol, the latter being a highly efficient biofuel. For butanol production by C. acetobutylicum to be optimized and exploited on an industrial scale, the effect of pH-induced gene regulation on solvent production by C. acetobutylicum in continuous culture must be understood as fully as possible. RESULTS: We present an ordinary differential equation model combining the metabolic network governing solvent production with regulation at the genetic level of the enzymes required for this process. Parameterizing the model with experimental data from continuous culture, we demonstrate the influence of pH upon fermentation products: at high pH (pH 5.7) acids are the dominant product while at low pH (pH 4.5) this switches to solvents. Through steady-state analyses of the model we focus our investigations on how alteration in gene expression of C. acetobutylicum could be exploited to increase butanol yield in a continuous culture fermentation. CONCLUSIONS: Incorporating gene regulation into the model of solvent production by C. acetobutylicum enables an accurate representation of the pH-induced switch to solvent production to be obtained and theoretical investigations of possible synthetic-biology approaches to be pursued. Steady state analyses suggest that, to increase butanol yield, alterations in the expression of single solvent-associated genes are insufficient; a more complex approach targeting two or more genes is required. PMID- 21247472 TI - Pulse pressure variation and stroke volume variation during increased intra abdominal pressure: an experimental study. AB - INTRODUCTION: The aim of this study was to evaluate dynamic indices of fluid responsiveness in a model of intra-abdominal hypertension. METHODS: Nine mechanically-ventilated pigs underwent increased intra-abdominal pressure (IAP) by abdominal banding up to 30 mmHg and then fluid loading (FL) at this IAP. The same protocol was carried out in the same animals made hypovolemic by blood withdrawal. In both volemic conditions, dynamic indices of preload dependence were measured at baseline IAP, at 30 mmHg of IAP, and after FL. Dynamic indices involved respiratory variations in stroke volume (SVV), pulse pressure (PPV), and systolic pressure (SPV, %SPV and Deltadown). Stroke volume (SV) was measured using an ultrasound transit-time flow probe placed around the aortic root. Pigs were considered to be fluid responders if their SV increased by 15% or more with FL. Indices of fluid responsiveness were compared with a Mann-Whitney U test. Then, receiver operating characteristic (ROC) curves were generated for these parameters, allowing determination of the cut-off values by using Youden's method. RESULTS: Five animals before blood withdrawal and all animals after blood withdrawal were fluid responders. Before FL, SVV (78 +/- 19 vs 42 +/- 17%), PPV (64 +/- 18 vs 37 +/- 15%), SPV (24 +/- 5 vs 18 +/- 3 mmHg), %SPV (24 +/- 4 vs 17 +/- 3%) and Deltadown (13 +/- 5 vs 6 +/- 4 mmHg) were higher in responders than in non-responders (P < 0.05). Areas under ROC curves were 0.93 (95% confidence interval: 0.80 to 1.06), 0.89 (0.70 to 1.07), 0.90 (0.74 to 1.05), 0.92 (0.78 to 1.06), and 0.86 (0.67 to 1.06), respectively. Threshold values discriminating responders and non-responders were 67% for SVV and 41% for PPV. CONCLUSIONS: In intra-abdominal hypertension, respiratory variations in stroke volume and arterial pressure remain indicative of fluid responsiveness, even if threshold values identifying responders and non-responders might be higher than during normal intra-abdominal pressure. Further studies are required in humans to determine these thresholds in intra-abdominal hypertension. PMID- 21247471 TI - Using an agent-based model to analyze the dynamic communication network of the immune response. AB - BACKGROUND: The immune system behaves like a complex, dynamic network with interacting elements including leukocytes, cytokines, and chemokines. While the immune system is broadly distributed, leukocytes must communicate effectively to respond to a pathological challenge. The Basic Immune Simulator 2010 contains agents representing leukocytes and tissue cells, signals representing cytokines, chemokines, and pathogens, and virtual spaces representing organ tissue, lymphoid tissue, and blood. Agents interact dynamically in the compartments in response to infection of the virtual tissue. Agent behavior is imposed by logical rules derived from the scientific literature. The model captured the agent-to-agent contact history, and from this the network topology and the interactions resulting in successful versus failed viral clearance were identified. This model served to integrate existing knowledge and allowed us to examine the immune response from a novel perspective directed at exploiting complex dynamics, ultimately for the design of therapeutic interventions. RESULTS: Analyzing the evolution of agent-agent interactions at incremental time points from identical initial conditions revealed novel features of immune communication associated with successful and failed outcomes. There were fewer contacts between agents for simulations ending in viral elimination (win) versus persistent infection (loss), due to the removal of infected agents. However, early cellular interactions preceded successful clearance of infection. Specifically, more Dendritic Agent interactions with TCell and BCell Agents, and more BCell Agent interactions with TCell Agents early in the simulation were associated with the immune win outcome. The Dendritic Agents greatly influenced the outcome, confirming them as hub agents of the immune network. In addition, unexpectedly high frequencies of Dendritic Agent-self interactions occurred in the lymphoid compartment late in the loss outcomes. CONCLUSIONS: An agent-based model capturing several key aspects of complex system dynamics was used to study the emergent properties of the immune response to viral infection. Specific patterns of interactions between leukocyte agents occurring early in the response significantly improved outcome. More interactions at later stages correlated with persistent inflammation and infection. These simulation experiments highlight the importance of commonly overlooked aspects of the immune response and provide insight into these processes at a resolution level exceeding the capabilities of current laboratory technologies. PMID- 21247473 TI - Early intervention to promote oral feeding in patients with intracerebral hemorrhage: a retrospective cohort study. AB - BACKGROUND: Stroke is a major cause of dysphagia, but little is known about when and how dysphagic patients should be fed and treated after an acute stroke. The purpose of this study is to establish the feasibility, risks and clinical outcomes of early intensive oral care and a new speech and language therapist/nurse led structured policy for oral feeding in patients with an acute intracerebral hemorrhage (ICH). METHODS: A total of 219 patients with spontaneous ICH who were admitted to our institution from 2004 to 2007 were retrospectively analyzed. An early intervention program for oral feeding, which consisted of intensive oral care and early behavioral interventions, was introduced from April 2005 and fully operational by January 2006. Outcomes were compared between an early intervention group of 129 patients recruited after January 2006 and a historical control group of 90 patients recruited between January 2004 and March 2005. A logistic regression technique was used to adjust for baseline differences between the groups. To analyze time to attain oral feeding, the Kaplan-Meier method and Cox proportional hazard model were used. RESULTS: The proportion of patients who could tolerate oral feeding was significantly higher in the early intervention group compared with the control group (112/129 (86.8%) vs. 61/90 (67.8%); odds ratio 3.13, 95% CI, 1.59-6.15; P < 0.001). After adjusting for baseline imbalances, the odds ratio was 4.42 (95% CI, 1.81-10.8; P = 0.001). The incidence of chest infection was lower in the early intervention group compared with the control group (27/129 (20.9%) vs. 32/90 (35.6%); odds ratio 0.48, 95% CI, 0.26-0.88; P = 0.016). A log-rank test found a significant difference in nutritional supplementation-free survival between the two groups (hazard ratio 1.94, 95% CI, 1.46-2.71; P < 0.001). CONCLUSIONS: Our data suggest that the techniques can be used safely and possibly with enough benefit to justify a randomized controlled trial. Further investigation is needed to solve the eating problems that are associated with patients recovering from a severe stroke. PMID- 21247475 TI - Effect of training and sudden detraining on the patellar tendon and its enthesis in rats. AB - BACKGROUND: Different conditions may alter tendon characteristics. Clinical evidence suggests that tendon injuries are more frequent in athletes that change type, intensity and duration of training. Aim of the study was the assessment of training and especially detraining on the patellar tendon (PT) and its enthesis. METHODS: 27 male adult Sprague-Dawley rats were divided into 3 groups: 20 rats were trained on a treadmill for 10 weeks. Of these, 10 rats were euthanized immediately after training (trained group), and 10 were caged without exercise for 4 weeks before being euthanized (de-trained group). The remaining 7 rats were used as controls (untrained rats). PT insertion, structure (collagen fiber organization and proteoglycan, PG, content), PT thickness, enthesis area, and subchondral bone volume at the enthesis were measured by histomorphometry and microtomography. RESULTS: Both PG content and collagen fiber organization were significantly lower in untrained and detrained animals than in trained ones (p < 0.05 and p < 0.0001). In the detrained group, fiber organization and PG content were worse than that of the untrained groups and the untrained group showed a significantly higher score than the detrained group (p < 0.05). In the trained group, the PT was significantly thicker than in untrained group (p < 0.05). No significant differences in the enthesis area and subchondral bone volume among the three groups were seen. CONCLUSIONS: Moderate exercise exerts a protective effect on the PT structure while sudden discontinuation of physical activity has a negative effect on tendons. The present results suggest that after a period of sudden de-training (such as after an injury) physical activity should be restarted with caution and with appropriate rehabilitation programs. PMID- 21247476 TI - Squamous cell carcinoma of the tonsillar remnant--clinical presentation and oncological outcome. AB - BACKGROUND: Squamous cell carcinoma (SCC) of the tonsil is the most common malignant tumour of the oropharynx. Paediatric tonsillectomy is one of the most commonly performed procedures in Otorhinolaryngology. SCC of the tonsil remnant (SCCTR) in a previously tonsillectomised patient is rare. METHODS: Retrospective review of patients with SCCTR presenting to the Otorhinolaryngology, Head and Neck Unit January 2000 to December 2007. RESULTS: Two hundred and fifty patients with tonsil SCC were identified. Ten (4%) of these had previously undergone tonsillectomy in childhood. Nine patients underwent radical treatment including surgery, radiotherapy and in four cases concomitant chemotherapy. Eight patients are alive with no signs of recurrence with follow-up of a minimum of 24 months. One has been lost from follow-up. CONCLUSIONS: Clinicians should be aware that SCC can arise from a tonsillar remnant. SCCTR has similar oncological outcomes as tonsillar tumours. PMID- 21247474 TI - Analysis of positional candidate genes in the AAA1 susceptibility locus for abdominal aortic aneurysms on chromosome 19. AB - BACKGROUND: Abdominal aortic aneurysm (AAA) is a complex disorder with multiple genetic risk factors. Using affected relative pair linkage analysis, we previously identified an AAA susceptibility locus on chromosome 19q13. This locus has been designated as the AAA1 susceptibility locus in the Online Mendelian Inheritance in Man (OMIM) database. METHODS: Nine candidate genes were selected from the AAA1 locus based on their function, as well as mRNA expression levels in the aorta. A sample of 394 cases and 419 controls was genotyped for 41 SNPs located in or around the selected nine candidate genes using the Illumina GoldenGate platform. Single marker and haplotype analyses were performed. Three genes (CEBPG, PEPD and CD22) were selected for DNA sequencing based on the association study results, and exonic regions were analyzed. Immunohistochemical staining of aortic tissue sections from AAA and control individuals was carried out for the CD22 and PEPD proteins with specific antibodies. RESULTS: Several SNPs were nominally associated with AAA (p < 0.05). The SNPs with most significant p-values were located near the CCAAT enhancer binding protein (CEBPG), peptidase D (PEPD), and CD22. Haplotype analysis found a nominally associated 5-SNP haplotype in the CEBPG/PEPD locus, as well as a nominally associated 2-SNP haplotype in the CD22 locus. DNA sequencing of the coding regions revealed no variation in CEBPG. Seven sequence variants were identified in PEPD, including three not present in the NCBI SNP (dbSNP) database. Sequencing of all 14 exons of CD22 identified 20 sequence variants, five of which were in the coding region and six were in the 3'-untranslated region. Five variants were not present in dbSNP. Immunohistochemical staining for CD22 revealed protein expression in lymphocytes present in the aneurysmal aortic wall only and no detectable expression in control aorta. PEPD protein was expressed in fibroblasts and myofibroblasts in the media-adventitia border in both aneurysmal and non aneurysmal tissue samples. CONCLUSIONS: Association testing of the functional positional candidate genes on the AAA1 locus on chromosome 19q13 demonstrated nominal association in three genes. PEPD and CD22 were considered the most promising candidate genes for altering AAA risk, based on gene function, association evidence, gene expression, and protein expression. PMID- 21247477 TI - Neurabin in the anterior cingulate cortex regulates anxiety-like behavior in adult mice. AB - Affective disorders, which include anxiety and depression, are highly prevalent and have overwhelming emotional and physical symptoms. Despite human brain imaging studies, which have implicated the prefrontal cortex including the anterior cingulate cortex (ACC), little is known about the ACC in anxiety disorders. Here we show that the ACC does modulate anxiety-like behavior in adult mice, and have identified a protein that is critical for this modulation. Absence of neurabin, a cytoskeletal protein, resulted in reduced anxiety-like behavior and increased depression-like behavior. Selective inhibition of neurabin in the ACC reproduced the anxiety but not the depression phenotype. Furthermore, loss of neurabin increased the presynaptic release of glutamate and cingulate neuronal excitability. These findings reveal novel roles of the ACC in anxiety disorders, and provide a new therapeutic target for the treatment of anxiety disorders. PMID- 21247478 TI - Elevated serum neutrophil elastase is related to prehypertension and airflow limitation in obese women. AB - BACKGROUND: Neutrophil elastase level/activity is elevated in a variety of diseases such as atherosclerosis, systolic hypertension and obstructive pulmonary disease. It is unknown whether obese individuals with prehypertension also have elevated neutrophil elastase, and if so, whether it has a deleterious effect on pulmonary function. OBJECTIVES: To determine neutrophil elastase levels in obese prehypertensive women and investigate correlations with pulmonary function tests. METHODS: Thirty obese prehypertensive women were compared with 30 obese normotensive subjects and 30 healthy controls. The study groups were matched for age. MEASUREMENTS: The following were determined: body mass index, waist circumference, blood pressure, lipid profile, high sensitivity C-reactive protein, serum neutrophil elastase, and pulmonary function tests including forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio. RESULTS: Serum neutrophil elastase concentration was significantly higher in both prehypertensive (405.8 +/- 111.6 ng/ml) and normotensive (336.5 +/- 81.5 ng/ml) obese women than in control non-obese women (243.9 +/- 23.9 ng/ml); the level was significantly higher in the prehypertensive than the normotensive obese women. FEV1, FVC and FEV1/FVC ratio in both prehypertensive and normotensive obese women were significantly lower than in normal controls, but there was no statistically significant difference between the prehypertensive and normotensive obese women. In prehypertensive obese women, there were significant positive correlations between neutrophil elastase and body mass index, waist circumference, systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, low density lipoprotein cholesterol, high sensitivity C-reactive protein and negative correlations with high density lipoprotein cholesterol, FEV1, FVC and FEV1/FVC. CONCLUSION: Neutrophil elastase concentration is elevated in obese prehypertensive women along with an increase in high sensitivity C-reactive protein which may account for dyslipidemia and airflow dysfunction in the present study population. PMID- 21247479 TI - Preclinical study of dimebon on beta-amyloid-mediated neuropathology in Alzheimer's disease. AB - BACKGROUND: Dimebon is a retired non-selective antihistamine drug currently being investigated as a therapeutic agent for the treatment of Alzheimer's disease (AD). Results from several completed clinical trials are mixed and contradictory. Proper interpretations of these clinical observations, as well as future development of dimebon in AD treatment are complicated by the lack of concrete information on the mechanisms by which dimebon might benefit AD. RESULTS: The present studies are designed specifically to assess whether dimebon might modulate beta-amyloid (Abeta)-mediated responses which are central to the development and progression of AD dementia. We found that dimebon is bioavailable in the brains of mice following oral administration. AD mice chronically treated with dimebon exhibited a trend of improvement in spatial memory function without affecting the levels of total Abeta as well as soluble oligomeric Abeta in the brain. The same trend of behavior improvement is also seen in wild type animals chronically treated with dimebon. CONCLUSION: Collectively, our preclinical studies using the TgCRND8 AD mouse model demonstrated that dimebon might have some beneficial effect in improving cognitive function independent of Alzheimer's disease-type Abeta-related mechanisms or global energy metabolism in the brain. Observations from our study and others suggesting dimebon might improve cognition in wild type mice and rats raises the possibility that dimebon might be able to benefit cognitive function in patients with other neurodegenerative disorders, such as Huntington's disease, or in the aging population. Additional studies will be necessary to clarify the mechanisms by which dimebon might directly or indirectly benefit cognitive function. PMID- 21247481 TI - Breastfeeding and transmission of cytomegalovirus to preterm infants. Case report and kinetic of CMV-DNA in breast milk. AB - BACKGROUND: Breastfeeding has a major impact on CMV epidemiology. Postnatal CMV reactivation's incidence during lactation is nearby the maternal seroprevalence. Although perinatal CMV infection has practically no consequences in term newborn, it may cause, in some cases, a severe symptomatic disease in preterm newborns. The aims of the present study are to evaluate the rate and clinical expression of CMV infection breast milk transmitted in preterm infants and to check the safety of the freezing treated breast milk. METHODS: The study included fifty-seven preterm infants and their CMV seropositive mothers. Fresh breast milk samples have been collected from 1(st) to 9(th) postpartum week. Both fresh breast milk and 72, 96, 120 hours frozen samples have been examined, checking the presence of CMV; urine samples have been tested too. RESULTS: 70.2% of tested mothers showed reactivation of the infection, and CMV-positive breast milk during the six weeks postpartum has been found. However, only one infant was infected by CMV, developing hepatic affection concomitantly with a multi-system involvement, as shown CMV DNA detection in urine, saliva, blood, gastric aspirate, and stools. CONCLUSION: Freezing breast milk at -20 degrees C and pasteurization may respectively reduce or eliminate the viral load. PMID- 21247480 TI - Trial Protocol: Communicating DNA-based risk assessments for Crohn's disease: a randomised controlled trial assessing impact upon stopping smoking. AB - BACKGROUND: Estimates of the risk of developing Crohn's disease (CD) can be made using DNA testing for mutations in the NOD2 (CARD15) gene, family history, and smoking status. Smoking doubles the risk of CD, a risk that is reduced by stopping. CD therefore serves as a timely and novel paradigm within which to assess the utility of predictive genetic testing to motivate behaviour change to reduce the risk of disease. The aim of the study is to describe the impact upon stopping smoking of communicating a risk of developing CD that incorporates DNA analysis. We will test the following main hypothesis:Smokers who are first degree relatives (FDRs) of CD probands are more likely to make smoking cessation attempts following communication of risk estimates of developing CD that incorporate DNA analysis, compared with an equivalent communication that does not incorporate DNA analysis. METHODS/DESIGN: A parallel groups randomised controlled trial in which smokers who are FDRs of probands with CD are randomly allocated in families to undergo one of two types of assessment of risk for developing CD based on either: i. DNA analysis, family history of CD and smoking status, or ii. Family history of CD and smoking status. The primary outcome is stopping smoking for 24 hours or longer in the six months following provision of risk information. The secondary outcomes are seven-day smoking abstinence at one week and six month follow-ups. Randomisation of 470 smoking FDRs of CD probands, with 400 followed up (85%), provides 80% power to detect a difference in the primary outcome of 14% between randomised arms, at the 5% significance level. DISCUSSION: This trial provides one of the strongest tests to date of the impact of communicating DNA based risk assessment on risk-reducing behaviour change. Specific issues regarding the choice of trial design are discussed. PMID- 21247483 TI - Excellence in Family Paediatricians: the FIMP-MCRN (Medicines for Children Research Network) becomes a member of ENPR-EMA (European Network of Paediatric Research at the European Medicines Agency). AB - One of the objectives of the Paediatric Regulation (EC) No 1901/2006, is to foster high quality ethical research on medicinal products to be used in children. To achieve this objective, the EMA is responsible for developing a European paediatric network of existing national and European networks and centres with specific expertise in research and clinical trials relating to paediatric medicines. The purpose of this article is to disseminate knowledge of the structure and goals of ENPR-EMA and to highlight the cultural and organizational difficulties for its implementation.Following the publication of research quality requirements, a set of recognition criteria, which have to be fulfilled to become a member of ENPR-EMA were agreed. So far, 32 networks and centres (of 62 identified networks) submitted self-assessment reports indicating whether or not they fulfill the agreed minimum criteria. Sixteen networks (26% of 62 identified networks) fulfilled all minimum criteria and became therefore members of ENPR-EMA. The Family Paediatricians Medicines for Children Research Network (FIMP-MCRN), established with the aim of developing competence, infrastructure, networking and education for paediatric clinical trials, became member of the ENPR-EMA responding satisfactorily to all the points of the self assessment report. PMID- 21247482 TI - Overexpression of sICAM-1 in the alveolar epithelial space results in an exaggerated inflammatory response and early death in Gram negative pneumonia. AB - BACKGROUND: A sizeable body of data demonstrates that membrane ICAM-1 (mICAM-1) plays a significant role in host defense in a site-specific fashion. On the pulmonary vascular endothelium, mICAM-1 is necessary for normal leukocyte recruitment during acute inflammation. On alveolar epithelial cells (AECs), we have shown previously that the presence of normal mICAM-1 is essential for optimal alveolar macrophage (AM) function. We have also shown that ICAM-1 is present in the alveolar space as a soluble protein that is likely produced through cleavage of mICAM-1. Soluble intercellular adhesion molecule-1 (sICAM-1) is abundantly present in the alveolar lining fluid of the normal lung and could be generated by proteolytic cleavage of mICAM-1, which is highly expressed on type I AECs. Although a growing body of data suggesting that intravascular sICAM 1 has functional effects, little is known about sICAM-1 in the alveolus. We hypothesized that sICAM-1 in the alveolar space modulates the innate immune response and alters the response to pulmonary infection. METHODS: Using the surfactant protein C (SPC) promoter, we developed a transgenic mouse (SPC-sICAM 1) that constitutively overexpresses sICAM-1 in the distal lung, and compared the responses of wild-type and SPC-sICAM-1 mice following intranasal inoculation with K. pneumoniae. RESULTS: SPC-sICAM-1 mice demonstrated increased mortality and increased systemic dissemination of organisms compared with wild-type mice. We also found that inflammatory responses were significantly increased in SPC-sICAM 1 mice compared with wild-type mice but there were no difference in lung CFU between groups. CONCLUSIONS: We conclude that alveolar sICAM-1 modulates pulmonary inflammation. Manipulating ICAM-1 interactions therapeutically may modulate the host response to Gram negative pulmonary infections. PMID- 21247484 TI - Anaemia in a phase 2 study of a blood stage falciparum malaria vaccine. AB - BACKGROUND: A Phase 1-2b study of the blood stage malaria vaccine AMA1 C1/Alhydrogel was conducted in 336 children in Doneguebougou and Bancoumana, Mali. In the Phase 2 portion of the study (n = 300), no impact on parasite density or clinical malaria was seen; however, children who received the study vaccine had a higher frequency of anaemia (defined as haemoglobin < 8.5 g/dL) compared to those who received the comparator vaccine (Hiberix). This effect was one of many tested and was not significant after adjusting for multiple comparisons. METHODS: To further investigate the possible impact of vaccination on anaemia, additional analyses were conducted including patients from the Phase 1 portion of the study and controlling for baseline haemoglobin, haemoglobin types S or C, alpha-thalassaemia, G6PD deficiency, and age. A multiplicative intensity model was used, which generalizes Cox regression to allow for multiple events. Frailty effects for each subject were used to account for correlation of multiple anaemia events within the same subject. Intensity rates were calculated with reference to calendar time instead of time after randomization in order to account for staggered enrollment and seasonal effects of malaria incidence. Associations of anaemia with anti-AMA1 antibody were further explored using a similar analysis. RESULTS: A strong effect of vaccine on the incidence of anaemia (risk ratio [AMA1-C1 to comparator (Hiberix)]= 2.01, 95% confidence interval [1.26,3.20]) was demonstrated even after adjusting for baseline haemoglobin, haemoglobinopathies, and age, and using more sophisticated statistical models. Anti-AMA1 antibody levels were not associated with this effect. CONCLUSIONS: While these additional analyses show a robust effect of vaccination on anaemia, this is an intensive exploration of secondary results and should, therefore, be interpreted with caution. Possible mechanisms of the apparent adverse effect on haemoglobin of vaccination with AMA1-C1/Alhydrogel and implications for blood stage vaccine development are discussed. The potential impact on malaria associated anaemia should be closely evaluated in clinical trials of AMA1 and other blood stage vaccines in malaria-exposed populations. PMID- 21247485 TI - Darkfield-confocal microscopy detection of nanoscale particle internalization by human lung cells. AB - BACKGROUND: Concerns over the health effects of nanomaterials in the environment have created a need for microscopy methods capable of examining the biological interactions of nanoparticles (NP). Unfortunately, NP are beyond the diffraction limit of resolution for conventional light microscopy (~200 nm). Fluorescence and electron microscopy techniques commonly used to examine NP interactions with biological substrates have drawbacks that limit their usefulness in toxicological investigation of NP. EM is labor intensive and slow, while fluorescence carries the risk of photobleaching the sample and has size resolution limits. In addition, many relevant particles lack intrinsic fluorescence and therefore can not be detected in this manner. To surmount these limitations, we evaluated the potential of a novel combination of darkfield and confocal laser scanning microscopy (DF-CLSM) for the efficient 3D detection of NP in human lung cells. The DF-CLSM approach utilizes the contrast enhancements of darkfield microscopy to detect objects below the diffraction limit of 200 nm based on their light scattering properties and interfaces it with the power of confocal microscopy to resolve objects in the z-plane. RESULTS: Validation of the DF-CLSM method using fluorescent polystyrene beads demonstrated spatial colocalization of particle fluorescence (Confocal) and scattered transmitted light (Darkfield) along the X, Y, and Z axes. DF-CLSM imaging was able to detect and provide reasonable spatial locations of 27 nm TiO2 particles in relation to the stained nuclei of exposed BEAS 2B cells. Statistical analysis of particle proximity to cellular nuclei determined a significant difference between 5 min and 2 hr particle exposures suggesting a time-dependent internalization process. CONCLUSIONS: DF-CLSM microscopy is an alternative to current conventional light and electron microscopy methods that does not rely on particle fluorescence or contrast in electron density. DF-CLSM is especially well suited to the task of establishing the spatial localization of nanoparticles within cells, a critical topic in nanotoxicology. This technique has advantages to 2D darkfield microscopy as it visualizes nanoparticles in 3D using confocal microscopy. Use of this technique should aid toxicological studies related to observation of NP interactions with biological endpoints at cellular and subcellular levels. PMID- 21247486 TI - Hybrid approach of ventricular assist device and autologous bone marrow stem cells implantation in end-stage ischemic heart failure enhances myocardial reperfusion. AB - We challenge the hypothesis of enhanced myocardial reperfusion after implanting a left ventricular assist device together with bone marrow mononuclear stem cells in patients with end-stage ischemic cardiomyopathy. Irreversible myocardial loss observed in ischemic cardiomyopathy leads to progressive cardiac remodelling and dysfunction through a complex neurohormonal cascade. New generation assist devices promote myocardial recovery only in patients with dilated or peripartum cardiomyopathy. In the setting of diffuse myocardial ischemia not amenable to revascularization, native myocardial recovery has not been observed after implantation of an assist device as destination therapy. The hybrid approach of implanting autologous bone marrow stem cells during assist device implantation may eventually improve native cardiac function, which may be associated with a better prognosis eventually ameliorating the need for subsequent heart transplantation. The aforementioned hypothesis has to be tested with well designed prospective multicentre studies. PMID- 21247488 TI - Use of a Western blot technique for the serodiagnosis of glanders. AB - BACKGROUND: The in vivo diagnosis of glanders relies on the highly sensitive complement fixation test (CFT). Frequently observed false positive results are troublesome for veterinary authorities and cause financial losses to animal owners. Consequently, there is an urgent need to develop a test with high specificity. Hence, a Western blot assay making use of a partly purified lipopolysaccaride (LPS) containing antigen of three Burkholderia mallei strains was developed. The test was validated investigating a comprehensive set of positive and negative sera obtained from horses and mules from endemic and non endemic areas. RESULTS: The developed Western blot assay showed a markedly higher diagnostic specificity when compared to the prescribed CFT and therefore can be used as a confirmatory test. However, the CFT remains the test of choice for routine testing of glanders due to its high sensitivity, its feasibility using standard laboratory equipment and its worldwide distribution in diagnostic laboratories. CONCLUSIONS: The CFT should be amended by the newly validated Western blot to increase the positive likelihood ratio of glanders serodiagnosis in non endemic areas or areas with low glanders prevalence. Its use for international trade of horses and mules should be implemented by the OIE. PMID- 21247487 TI - Bim and Mcl-1 exert key roles in regulating JAK2V617F cell survival. AB - BACKGROUND: The JAK2V617F mutation plays a major role in the pathogenesis of myeloproliferative neoplasms and is found in the vast majority of patients suffering from polycythemia vera and in roughly every second patient suffering from essential thrombocythemia or from primary myelofibrosis. The V617F mutation is thought to provide hematopoietic stem cells and myeloid progenitors with a survival and proliferation advantage. It has previously been shown that activated JAK2 promotes cell survival by upregulating the anti-apoptotic STAT5 target gene Bcl-xL. In this study, we have investigated the role of additional apoptotic players, the pro-apoptotic protein Bim as well as the anti-apoptotic protein Mcl 1. METHODS: Pharmacological inhibition of JAK2/STAT5 signaling in JAK2V617F mutant SET-2 and MB-02 cells was used to study effects on signaling, cell proliferation and apoptosis by Western blot analysis, WST-1 proliferation assays and flow cytometry. Cells were transfected with siRNA oligos to deplete candidate pro- and anti-apoptotic proteins. Co-immunoprecipitation assays were performed to assess the impact of JAK2 inhibition on complexes of pro- and anti-apoptotic proteins. RESULTS: Treatment of JAK2V617F mutant cell lines with a JAK2 inhibitor was found to trigger Bim activation. Furthermore, Bim depletion by RNAi suppressed JAK2 inhibitor-induced cell death. Bim activation following JAK2 inhibition led to enhanced sequestration of Mcl-1, besides Bcl-xL. Importantly, Mcl-1 depletion by RNAi was sufficient to compromise JAK2V617F mutant cell viability and sensitized the cells to JAK2 inhibition. CONCLUSIONS: We conclude that Bim and Mcl-1 have key opposing roles in regulating JAK2V617F cell survival and propose that inactivation of aberrant JAK2 signaling leads to changes in Bim complexes that trigger cell death. Thus, further preclinical evaluation of combinations of JAK2 inhibitors with Bcl-2 family antagonists that also tackle Mcl-1, besides Bcl-xL, is warranted to assess the therapeutic potential for the treatment of chronic myeloproliferative neoplasms. PMID- 21247489 TI - Reproductive protein evolution in two cryptic species of marine chordate. AB - BACKGROUND: Reproductive character displacement (RCD) is a common and taxonomically widespread pattern. In marine broadcast spawning organisms, behavioral and mechanical isolation are absent and prezygotic barriers between species often operate only during the fertilization process. Such barriers are usually a consequence of differences in the way in which sperm and egg proteins interact, so RCD can be manifest as faster evolution of these proteins between species in sympatry than allopatry. Rapid evolution of these proteins often appears to be a consequence of positive (directional) selection. Here, we identify a set of candidate gamete recognition proteins (GRPs) in the ascidian Ciona intestinalis and showed that these GRPs evolve more rapidly than control proteins (those not involved in gamete recognition). Choosing a subset of these gamete recognition proteins that show evidence of positive selection (CIPRO37.40.1, CIPRO60.5.1, CIPRO100.7.1), we then directly test the RCD hypothesis by comparing divergence (omega) and polymorphism (McDonald-Kreitman, Tajima's D, Fu and Li's D and F, Fay and Wu's H) statistics in sympatric and allopatric populations of two distinct forms of C. intestinalis (Types A and B) between which there are strong post-zygotic barriers. RESULTS: Candidate gamete recognition proteins from two lineages of C. intestinalis (Type A and B) are evolving more rapidly than control proteins, consistent with patterns seen in insects and mammals. However, omega (dN/dS) is not significantly different between the sympatric and allopatric populations, and none of the polymorphism statistics show significant differences between sympatric and allopatric populations. CONCLUSIONS: Enhanced prezygotic isolation in sympatry has become a well-known feature of gamete recognition proteins in marine broadcast spawners. But in most cases the evolutionary process or processes responsible for this pattern have not been identified. Although gamete recognition proteins in C. intestinalis do appear to evolve more rapidly, on average, than proteins with other functions, rates of evolution are not different in allopatric and sympatric populations of the two reproductively isolated forms. That sympatry is probably human-mediated, and therefore recent, may explain the absence of RCD. PMID- 21247490 TI - Non-invasive quantification of brain tumor-induced astrogliosis. AB - BACKGROUND: CNS injury including stroke, infection, and tumor growth lead to astrogliosis, a process that involves upregulation of glial fibrillary acidic protein (GFAP) in astrocytes. However, the kinetics of astrogliosis that is related to these insults (i.e. tumor) is largely unknown. RESULTS: Using transgenic mice expressing firefly luciferase under the regulation of the GFAP promoter (GFAP-luc), we developed a model system to monitor astrogliosis upon tumor growth in a rapid, non-invasive manner. A biphasic induction of astrogliosis was observed in our xenograft model in which an early phase of activation of GFAP was associated with inflammatory response followed by a secondary, long-term upregulation of GFAP. These animals reveal GFAP activation with kinetics that is in parallel with tumor growth. Furthermore, a strong correlation between astrogliosis and tumor size was observed. CONCLUSIONS: Our results suggest that non-invasive, quantitative bioluminescent imaging using GFAP luc reporter animal is a useful tool to monitor temporal-spatial kinetics of host mediated astrogliosis that is associated with glioma and metastatic brain tumor growth. PMID- 21247491 TI - Towards an organisation-wide process-oriented organisation of care: a literature review. AB - BACKGROUND: Many hospitals have taken actions to make care delivery for specific patient groups more process-oriented, but struggle with the question how to deal with process orientation at hospital level. The aim of this study is to report and discuss the experiences of hospitals with implementing process-oriented organisation designs in order to derive lessons for future transitions and research. METHODS: A literature review of English language articles on organisation-wide process-oriented redesigns, published between January 1998 and May 2009, was performed. RESULTS: Of 329 abstracts identified, 10 articles were included in the study. These articles described process-oriented redesigns of five hospitals. Four hospitals tried to become process-oriented by the implementation of coordination measures, and one by organisational restructuring. The adoption of the coordination mechanism approach was particularly constrained by the functional structure of hospitals. Other factors that hampered the redesigns in general were the limited applicability of and unfamiliarity with process improvement techniques. CONCLUSIONS: Due to the limitations of the evidence, it is not known which approach, implementation of coordination measures or organisational restructuring (with additional coordination measures), produces the best results in which situation. Therefore, more research is needed. For this research, the use of qualitative methods in addition to quantitative measures is recommended to contribute to a better understanding of preconditions and contingencies for an effective application of approaches to become process oriented. Hospitals are advised to take the factors for failure described into account and to take suitable actions to counteract these obstacles on their way to become process-oriented organisations. PMID- 21247492 TI - Transcriptome profiling of the rice blast fungus during invasive plant infection and in vitro stresses. AB - BACKGROUND: Rice blast is the most threatening disease to cultivated rice. Magnaporthe oryzae, its causal agent, is likely to encounter environmental challenges during invasive growth in its host plants that require shifts in gene expression to establish a compatible interaction. Here, we tested the hypothesis that gene expression patterns during in planta invasive growth are similar to in vitro stress conditions, such as nutrient limitation, temperature up shift and oxidative stress, and determined which condition most closely mimicked that of in planta invasive growth. Gene expression data were collected from these in vitro experiments and compared to fungal gene expression during the invasive growth phase at 72 hours post-inoculation in compatible interactions on two grass hosts, rice and barley. RESULTS: We identified 4,973 genes that were differentially expressed in at least one of the in planta and in vitro stress conditions when compared to fungal mycelia grown in complete medium, which was used as reference. From those genes, 1,909 showed similar expression patterns between at least one of the in vitro stresses and rice and/or barley. Hierarchical clustering of these 1,909 genes showed three major clusters in which in planta conditions closely grouped with the nutrient starvation conditions. Out of these 1,909 genes, 55 genes and 129 genes were induced and repressed in all treatments, respectively. Functional categorization of the 55 induced genes revealed that most were either related to carbon metabolism, membrane proteins, or were involved in oxidoreduction reactions. The 129 repressed genes showed putative roles in vesicle trafficking, signal transduction, nitrogen metabolism, or molecular transport. CONCLUSIONS: These findings suggest that M. oryzae is likely primarily coping with nutrient-limited environments at the invasive growth stage 72 hours post-inoculation, and not with oxidative or temperature stresses. PMID- 21247493 TI - Who seeks primary care for musculoskeletal disorders (MSDs) with physicians prescribing homeopathic and other complementary medicine? Results from the EPI3 LASER survey in France. AB - BACKGROUND: There is a paucity of information describing patients with musculoskeletal disorders (MSDs) using complementary and alternative medicines (CAMs) and almost none distinguishing homeopathy from other CAMs. The objective of this study was to describe and compare patients with MSDs who consulted primary care physicians, either certified homeopaths (Ho) or regular prescribers of CAMs in a mixed practice (Mx), to those consulting physicians who strictly practice conventional medicine (CM), with regard to the severity of their MSD expressed as chronicity, co-morbidity and quality of life (QOL). METHODS: The EPI3-LASER study was a nationwide observational survey of a representative sample of general practitioners and their patients in France. The sampling strategy ensured a sufficient number of GPs in each of the three groups to allow comparison of their patients. Patients completed a questionnaire on socio demographics, lifestyle and QOL using the Short Form 12 (SF-12) questionnaire. Chronicity of MSDs was defined as more than twelve weeks duration of the current episode. Diagnoses and co-morbidities were recorded by the physician. RESULTS: A total of 825 GPs included 1,692 MSD patients (predominantly back pain and osteoarthritis) were included, 21.6% in the CM group, 32.4% Ho and 45.9% Mx. Patients in the Ho group had more often a chronic MSD (62.1%) than the CM (48.6%) or Mx (50.3%) groups, a result that was statistically significant after controlling for patients' characteristics (Odds ratio = 1.43; 95% confidence interval (CI): 1.07 - 1.89). Patients seen by homeopaths or mixed practice physicians who were not the regular treating physician, had more often a chronic MSD than those seen in conventional medicine (Odds ratios were 1.75; 95% CI: 1.22 - 2.50 and 1.48; 95% CI: 1.06 - 2.12, respectively). Otherwise patients in the three groups did not differ for co-morbidities and QOL. CONCLUSION: MSD patients consulting primary care physicians who prescribed homeopathy and CAMs differed from those seen in conventional medicine. Chronic MSD patients represented a greater proportion of the clientele in physicians offering alternatives to conventional medicine. In addition, these physicians treated chronic patients as consulting rather than regular treating physicians, with potentially important impacts upon professional health care practices and organisation. PMID- 21247494 TI - Enhanced genetic maps from family-based disease studies: population-specific comparisons. AB - BACKGROUND: Accurate genetic maps are required for successful and efficient linkage mapping of disease genes. However, most available genome-wide genetic maps were built using only small collections of pedigrees, and therefore have large sampling errors. A large set of genetic studies genotyped by the NHLBI Mammalian Genotyping Service (MGS) provide appropriate data for generating more accurate maps. RESULTS: We collected a large sample of uncleaned genotype data for 461 markers generated by the MGS using the Weber screening sets 9 and 10. This collection includes genotypes for over 4,400 pedigrees containing over 17,000 genotyped individuals from different populations. We identified and cleaned numerous relationship and genotyping errors, as well as verified the marker orders. We used this dataset to test for population-specific genetic maps, and to re-estimate the genetic map distances with greater precision; standard errors for all intervals are provided. The map-interval sizes from the European (or European descent), Chinese, and Hispanic samples are in quite good agreement with each other. We found one map interval on chromosome 8p with a statistically significant size difference between the European and Chinese samples, and several map intervals with significant size differences between the African American and Chinese samples. When comparing Palauan with European samples, a statistically significant difference was detected at the telomeric region of chromosome 11p. Several significant differences were also identified between populations in chromosomal and genome lengths. CONCLUSIONS: Our new population-specific screening set maps can be used to improve the accuracy of disease-mapping studies. As a result of the large sample size, the average length of the 95% confidence interval (CI) for a 10 cM map interval is only 2.4 cM, which is considerably smaller than on previously published maps. PMID- 21247495 TI - Deletion of the thrombin cleavage domain of osteopontin mediates breast cancer cell adhesion, proteolytic activity, tumorgenicity, and metastasis. AB - BACKGROUND: Osteopontin (OPN) is a secreted phosphoprotein often overexpressed at high levels in the blood and primary tumors of breast cancer patients. OPN contains two integrin-binding sites and a thrombin cleavage domain located in close proximity to each other. METHODS: To study the role of the thrombin cleavage site of OPN, MDA-MB-468 human breast cancer cells were stably transfected with either wildtype OPN (468-OPN), mutant OPN lacking the thrombin cleavage domain (468-DeltaTC) or an empty vector (468-CON) and assessed for in vitro and in vivo functional differences in malignant/metastatic behavior. RESULTS: All three cell lines were found to equivalently express thrombin, tissue factor, CD44, alphavbeta5 integrin and beta1 integrin. Relative to 468-OPN and 468-CON cells, 468-DeltaTC cells expressing OPN with a deleted thrombin cleavage domain demonstrated decreased cell adhesion (p < 0.001), decreased mRNA expression of MCAM, maspin and TRAIL (p < 0.01), and increased uPA expression and activity (p < 0.01) in vitro. Furthermore, injection of 468-DeltaTC cells into the mammary fat pad of nude mice resulted in decreased primary tumor latency time (p < 0.01) and increased primary tumor growth and lymph node metastatic burden (p < 0.001) compared to 468-OPN and 468-CON cells. CONCLUSIONS: The results presented here suggest that expression of thrombin-uncleavable OPN imparts an early tumor formation advantage as well as a metastatic advantage for breast cancer cells, possibly due to increased proteolytic activity and decreased adhesion and apoptosis. Clarification of the mechanisms responsible for these observations and the translation of this knowledge into the clinic could ultimately provide new therapeutic opportunities for combating breast cancer. PMID- 21247496 TI - Persistence of decidual NK cells and KIR genotypes in healthy pregnant and preeclamptic women: a case-control study in the third trimester of gestation. AB - BACKGROUND: Natural Killer (NK) cells are the most abundant lymphocytes in the decidua during early gestation. The interactions of NK cells with the extravillous cytotrophoblast have been associated with a normal spiral artery remodeling process, an essential event for a successful pregnancy. Recent data indicate that alterations in the amount of decidual NK (dNK) cells contribute to the development of preeclampsia (PE). Moreover, genetic studies suggest that Killer Immunoglobulin-like Receptors (KIR) expressed in dNK cells influence the susceptibility to PE. Although dNK cells have been well characterized during early pregnancy, they have been scarcely studied in the third trimester of gestation. The aim of this work was to characterize dNK cells at the last trimester of gestation and to analyze the KIR genotype of healthy and PE women. METHODS: Decidual samples were obtained during Caesarean section from control (n = 10) and PE (n = 9) women. Flow cytometric analysis of CD3, CD56, CD16 and CD9 was used to characterize and quantify dNK cells in both groups. Cell surface markers from decidual leukocytes were compared with PBMC from healthy donors.KIR genotyping was performed in genomic DNA (control, n = 86; PE, n = 90) using PCR SSP. RESULTS: The results indicate that dNK cells persist throughout pregnancy. They represented 20% of total leukocytes in control and PE groups, and they expressed the same cell surface markers (CD3-, CD56+, CD16- and CD9+) as dNK in the first trimester of gestation. There were no significant differences in the percentage of dNK cells between control and PE groups. The analysis of KIR gene frequencies and genotypes was not statistically different between control and PE groups. The ratio of activating to inhibitory genes indicated that the overall inhibitory balance (0.2-0.5) was more frequent in the PE group (control, 31.3% vs PE, 45.5%), and the activating balance (0.6-1.1) was more frequent in the control group (control, 68.6% vs PE, 54.4%). However this difference was not significant. CONCLUSION: We demonstrated the persistence of dNK cells in PE and control women at the third trimester of pregnancy; these dNK cells had a similar phenotype to those found during early pregnancy. The predominance of a KIR inhibitory balance in the PE group could be associated to the physiopathology of PE. PMID- 21247497 TI - Osteoid osteoma near the intervertebral foramen may induce radiculopathy through tumorous inflammation. AB - Osteoid osteoma of the spine is a relatively rare bone-forming tumor. Pain that is worse at night and relieved by aspirin and muscle contracture are the most characteristic symptoms of spinal osteoid osteoma. Although radicular pain occasionally occurs in spinal osteoid osteoma, spinal cord and nerve root compression is absent in most cases. Although radicular pain appears to be associated with tumorous inflammation, there have been no presentations of histological findings of inflammation around the nerve root. We present here two rare cases of spinal osteoid osteoma causing radiculopathy and the first histological evidence of tumorous inflammation as a cause of radiculopathy in osteoid osteoma near the intervertebral foramen. PMID- 21247498 TI - Genetic variation of glucose transporter-1 (GLUT1) and albuminuria in 10,278 European Americans and African Americans: a case-control study in the Atherosclerosis Risk in Communities (ARIC) study. AB - BACKGROUND: Evidence suggests glucose transporter-1 (GLUT1) genetic variation affects diabetic nephropathy and albuminuria. Our aim was to evaluate associations with albuminuria of six GLUT1 single nucleotide polymorphisms(SNPs), particularly XbaI and the previously associated Enhancer-2 (Enh2) SNP. METHODS: A two-stage case-control study was nested in a prospective cohort study of 2156 African Americans and 8122 European Americans with urinary albumin-to-creatinine ratio (ACR). Cases comprised albuminuria (N = 825; >= 30 MUg/mg) and macroalbuminuria (N = 173; >= 300 MUg/mg). ACR < 30 MUg/mg classified controls (n = 9453). Logistic regression and odds ratios (OR) assessed associations. The evaluation phase (stage 1, n = 2938) tested associations of albuminuria (n = 305) with six GLUT1 SNPs: rs841839, rs3768043, rs2297977, Enh2(rs841847) XbaI (rs841853), and rs841858. Enh2 was examined separately in the replication phase (stage 2, n = 7340) and the total combined sample (n = 10,278), with all analyses stratified by race and type 2 diabetes. RESULTS: In European Americans, after adjusting for diabetes and other GLUT1 SNPs in stage 1, Enh2 risk genotype (TT) was more common in albuminuric cases (OR = 3.37, P = 0.090) whereas XbaI (OR = 0.94, p = 0.931) and remaining SNPs were not. In stage 1, the Enh2 association with albuminuria was significant among diabetic European Americans (OR = 2.36, P = 0.025). In African Americans, Enh2 homozygosity was rare (0.3%); XbaI was common (18.0% AA) and not associated with albuminuria. In stage 2 (n = 7,340), Enh2 risk genotype had increased but non-significant OR among diabetic European Americans (OR = 1.66, P = 0.192) and not non-diabetics (OR = 0.99, p = 0.953), not replicating stage 1. Combining stages 1 and 2, Enh2 was associated with albuminuria (OR 2.14 [1.20-3.80], P = 0.009) and macroalbuminuria (OR 2.69, [1.02 7.09], P = 0.045) in diabetic European Americans. The Enh2 association with macroalbuminuria among non-diabetic European Americans with fasting insulin (OR = 1.84, P = 0.210) was stronger at the highest insulin quartile (OR = 4.08, P = 0.040). CONCLUSIONS: As demonstrated with type 1 diabetic nephropathy, the GLUT1 Enh2 risk genotype, instead of XbaI, may be associated with type 2 diabetic albuminuria among European Americans, though an association is not conclusive. The association among diabetic European Americans found in stage 1 was not replicated in stage 2; however, this risk association was evident after combining all diabetic European Americans from both stages. Additionally, our results suggest this association may extend to non-diabetics with high insulin concentrations. Rarity of the Enh2 risk genotype among African Americans precludes any definitive conclusions, although data suggest a risk-enhancing role. PMID- 21247499 TI - Involvement of spinal NR2B-containing NMDA receptors in oxaliplatin-induced mechanical allodynia in rats. AB - BACKGROUND: Oxaliplatin is a platinum-based chemotherapy drug characterized by the development of acute and chronic peripheral neuropathies. The chronic neuropathy is a dose-limiting toxicity. We previously reported that repeated administration of oxaliplatin induced cold hyperalgesia in the early phase and mechanical allodynia in the late phase in rats. In the present study, we investigated the involvement of NR2B-containing N-methyl-D-aspartate (NMDA) receptors in oxaliplatin-induced mechanical allodynia in rats. RESULTS: Repeated administration of oxaliplatin (4 mg/kg, i.p., twice a week) caused mechanical allodynia in the fourth week, which was reversed by intrathecal injection of MK 801 (10 nmol) and memantine (1 MUmol), NMDA receptor antagonists. Similarly, selective NR2B antagonists Ro25-6981 (300 nmol, i.t.) and ifenprodil (50 mg/kg, p.o.) significantly attenuated the oxaliplatin-induced pain behavior. In addition, the expression of NR2B protein and mRNA in the rat spinal cord was increased by oxaliplatin on Day 25 (late phase) but not on Day 5 (early phase). Moreover, we examined the involvement of nitric oxide synthase (NOS) as a downstream target of NMDA receptor. L-NAME, a non-selective NOS inhibitor, and 7 nitroindazole, a neuronal NOS (nNOS) inhibitor, significantly suppressed the oxaliplatin-induced pain behavior. The intensity of NADPH diaphorase staining, a histochemical marker for NOS, in the superficial layer of spinal dorsal horn was obviously increased by oxaliplatin, and this increased intensity was reversed by intrathecal injection of Ro25-6981. CONCLUSION: These results indicated that spinal NR2B-containing NMDA receptors are involved in the oxaliplatin-induced mechanical allodynia. PMID- 21247500 TI - Conceptualising population health: from mechanistic thinking to complexity science. AB - The mechanistic interpretation of reality can be traced to the influential work by Rene Descartes and Sir Isaac Newton. Their theories were able to accurately predict most physical phenomena relating to motion, optics and gravity. This paradigm had at least three principles and approaches: reductionism, linearity and hierarchy. These ideas appear to have influenced social scientists and the discourse on population health. In contrast, Complexity Science takes a more holistic view of systems. It views natural systems as being 'open', with fuzzy borders, constantly adapting to cope with pressures from the environment. These are called Complex Adaptive Systems (CAS). The sub-systems within it lack stable hierarchies, and the roles of agency keep changing. The interactions with the environment and among sub-systems are non-linear interactions and lead to self organisation and emergent properties. Theoretical frameworks such as epi+demos+cracy and the ecosocial approach to health have implicitly used some of these concepts of interacting dynamic sub-systems. Using Complexity Science we can view population health outcomes as an emergent property of CAS, which has numerous dynamic non-linear interactions among its interconnected sub-systems or agents. In order to appreciate these sub-systems and determinants, one should acquire a basic knowledge of diverse disciplines and interact with experts from different disciplines. Strategies to improve health should be multi-pronged, and take into account the diversity of actors, determinants and contexts. The dynamic nature of the system requires that the interventions are constantly monitored to provide early feedback to a flexible system that takes quick corrections. PMID- 21247501 TI - Association of basal serum testosterone levels with ovarian response and in vitro fertilization outcome. AB - BACKGROUND: To evaluate basal testosterone (T) levels during follicular phase of the menstrual cycle as a predictor for ovarian response and in vitro fertilization (IVF) outcome. METHOD: We analyzed data retrospectively from hospital-based IVF center including one thousand two hundred and sixty Chinese Han women under their first IVF cycle reached the ovum pick-up stage, without polycystic ovary syndrome (PCOS) or endometriosis undergoing long IVF protocol. Patients were divided into 2 groups. Group 1: patients with diminished ovarian reserve (basal FSH >10 IU/L) (n = 187); Group 2: patients with normal ovarian reserve (basal FSH < = 10 IU/L) (n = 1073). We studied the association of basal T levels with ovarian response and IVF outcome in the two groups. Long luteal down regulation protocol was used in all patients, that is, the gonadotropin releasing hormone agonist was administered in the midluteal phase of the previous cycle and use of recombinant FSH was started when satisfactory pituitary desensitization was achieved. RESULTS: Basal T levels were markly different between pregnant and non-pregnant women in Group 1; whereas not in Group 2. A testosterone level of 47.85 ng/dl was shown to predict pregnancy outcome with a sensitivity of 52.8% and specificity of 65.3%; and the basal T was correlated with the numbers of large follicles (> 14 mm) on HCG day in Group 1. Significantly negative correlations were observed between basal T, days of stimulation and total dose of gonadotropins after adjusting for confounding factors in both groups. CONCLUSION: In women with diminished ovarian reserve, basal T level was a predictor for the number of large follicles on HCG day and pregnancy outcome; but could not in those with normal serum FSH. Basal T levels were associated with both days of stimulation and total dose of gonadotropins, indicating that lower level of T might relate with potential ovarian poor response. PMID- 21247502 TI - Fish consumption and the risk of gastric cancer: systematic review and meta analysis. AB - BACKGROUND: Gastric cancer is the fourth most frequently occurring malignancy after lung, breast, and colorectal cancer, and the second most common cause of death from cancer worldwide. Epidemiologic studies have examined the possible association between fish consumption and gastric cancer, but the results were inconclusive. We conducted a systematic review and meta-analysis to examine the association between fish intake and the risk of gastric cancer. METHODS: PubMed was searched for studies published in English-language journals from 1991 through 2009. We identified 17 epidemiologic studies (15 case-control and 2 cohort studies) that included relative risks (RRs) or odds ratios (ORs) estimates with 95% confidence intervals (CIs) of the relationship between gastric cancer and fish consumption. Data were extracted using standardized data forms. Summary RRs or ORs for the highest versus non/lowest fish consumption levels were calculated using random-effects model. Heterogeneity among studies was examined using Q and I2 statistics. RESULTS: In this study, 5,323 cases of gastric cancer and over 130,000 non-cases were included. The combined results from all studies indicated that the association between high fish consumption and reduced gastric cancer risk was not statistically insignificant (RR = 0.87, 95% CI = 0.71-1.07). CONCLUSIONS: Current evidence indicated that the association between fish consumption and risk of gastric cancer remains unclear. PMID- 21247503 TI - Differential effect of corn oil-based low trans structured fat on the plasma and hepatic lipid profile in an atherogenic mouse model: comparison to hydrogenated trans fat. AB - BACKGROUND: Trans fat are not desirable in many aspects on health maintenance. Low trans structured fats have been reported to be relatively more safe than trans fats. METHODS: We examined the effects of low trans structured fat from corn oil (LC), compared with high trans fat shortening, on cholesterol and fatty acid metabolism in apo E deficient mice which is an atherogenic animal model. The animals were fed a high trans fat (10% fat: commercial shortening (CS)) or a low trans fat (LC) diet for 12 weeks. RESULTS: LC decreased apo B and hepatic cholesterol and triglyceride concentration compared to the CS group but significantly increased plasma total cholesterol and triglyceride concentration and fecal lipids with a simultaneous increase in HDL-cholesterol level, apo A-I, and the ratio of HDL-cholesterol to total cholesterol (HTR). Reduction of hepatic lipid levels by inclusion of LC intake was observed alongside modulation of hepatic enzyme activities related to cholesterol esterification, fatty acid metabolism and fecal lipids level compared to the CS group. The differential effects of LC intake on the plasma and hepatic lipid profile seemed to be partly due to the fatty acid composition of LC which contains higher MUFA, PUFA and SFA content as well as lower content of trans fatty acids compared to CS. CONCLUSIONS: We suggest that LC may exert a dual effect on plasma and hepatic lipid metabolism in an atherogenic animal model. Accordingly, LC, supplemented at 10% in diet, had an anti-atherogenic effect on these apo E-/- mice, and increased fecal lipids, decreased hepatic steatosis, but elevated plasma lipids. Further studies are needed to verify the exact mode of action regarding the complex physiological changes and alteration in lipid metabolism caused by LC. PMID- 21247504 TI - Breast cancer and human papillomavirus infection: no evidence of HPV etiology of breast cancer in Indian women. AB - BACKGROUND: Two clinically relevant high-risk HPV (HR-HPV) types 16 and 18 are etiologically associated with the development of cervical carcinoma and are also reported to be present in many other carcinomas in extra-genital organ sites. Presence of HPV has been reported in breast carcinoma which is the second most common cancer in India and is showing a fast rising trend in urban population. The two early genes E6 and E7 of HPV type 16 have been shown to immortalize breast epithelial cells in vitro, but the role of HPV infection in breast carcinogenesis is highly controversial. Present study has therefore been undertaken to analyze the prevalence of HPV infection in both breast cancer tissues and blood samples from a large number of Indian women with breast cancer from different geographic regions. METHODS: The presence of all mucosal HPVs and the most common high-risk HPV types 16 and 18 DNA was detected by two different PCR methods - (i) conventional PCR assays using consensus primers (MY09/11, or GP5+/GP6+) or HPV16 E6/E7 primers and (ii) highly sensitive Real-Time PCR. A total of 228 biopsies and corresponding 142 blood samples collected prospectively from 252 patients from four different regions of India with significant socio cultural, ethnic and demographic variations were tested. RESULTS: All biopsies and blood samples of breast cancer patients tested by PCR methods did not show positivity for HPV DNA sequences in conventional PCRs either by MY09/11 or by GP5+/GP6+/HPV16 E6/E7 primers. Further testing of these samples by real time PCR also failed to detect HPV DNA sequences. CONCLUSIONS: Lack of detection of HPV DNA either in the tumor or in the blood DNA of breast cancer patients by both conventional and real time PCR does not support a role of genital HPV in the pathogenesis of breast cancer in Indian women. PMID- 21247505 TI - The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and the underlying mechanisms of its etiological role. AB - Streptococcus bovis (S. bovis) bacteria are associated with colorectal cancer and adenoma. S. bovis is currently named S. gallolyticus. 25 to 80% of patients with S. bovis/gallolyticus bacteremia have concomitant colorectal tumors. Colonic neoplasia may arise years after the presentation of bacteremia or infectious endocarditis of S. bovis/gallolyticus. The presence of S. bovis/gallolyticus bacteremia and/or endocarditis is also related to the presence of villous or tubular-villous adenomas in the large intestine. In addition, serological relationship of S. gallolyticus with colorectal tumors and direct colonization of S. gallolyticus in tissues of colorectal tumors were found. However, this association is still under controversy and has long been underestimated. Moreover, the etiological versus non-etiological nature of this associationis not settled yet. Therefore, by covering the most of up to date studies, this review attempts to clarify the nature and the core of S. bovis/gallolyicus association with colorectal tumors and analyze the possible underlying mechanisms. PMID- 21247507 TI - Cationized gelatin-HVJ envelope with sodium borocaptate improved the BNCT efficacy for liver tumors in vivo. AB - BACKGROUND: Boron neutron capture therapy (BNCT) is a cell-selective radiation therapy that uses the alpha particles and lithium nuclei produced by the boron neutron capture reaction. BNCT is a relatively safe tool for treating multiple or diffuse malignant tumors with little injury to normal tissue. The success or failure of BNCT depends upon the 10B compound accumulation within tumor cells and the proximity of the tumor cells to the body surface. To extend the therapeutic use of BNCT from surface tumors to visceral tumors will require 10B compounds that accumulate strongly in tumor cells without significant accumulation in normal cells, and an appropriate delivery method for deeper tissues.Hemagglutinating Virus of Japan Envelope (HVJ-E) is used as a vehicle for gene delivery because of its high ability to fuse with cells. However, its strong hemagglutination activity makes HVJ-E unsuitable for systemic administration.In this study, we developed a novel vector for 10B (sodium borocaptate: BSH) delivery using HVJ-E and cationized gelatin for treating multiple liver tumors with BNCT without severe adverse events. METHODS: We developed cationized gelatin conjugate HVJ-E combined with BSH (CG-HVJ-E-BSH), and evaluated its characteristics (toxicity, affinity for tumor cells, accumulation and retention in tumor cells, boron-carrying capacity to multiple liver tumors in vivo, and bio distribution) and effectiveness in BNCT therapy in a murine model of multiple liver tumors. RESULTS: CG-HVJ-E reduced hemagglutination activity by half and was significantly less toxic in mice than HVJ-E. Higher 10B concentrations in murine osteosarcoma cells (LM8G5) were achieved with CG-HVJ-E-BSH than with BSH. When administered into mice bearing multiple LM8G5 liver tumors, the tumor/normal liver ratios of CG-HVJ-E-BSH were significantly higher than those of BSH for the first 48 hours (p < 0.05). In suppressing the spread of tumor cells in mice, BNCT treatment was as effective with CG-HVJ-E-BSH as with BSH containing a 35-fold higher 10B dose. Furthermore, CG-HVJ-E-BSH significantly increased the survival time of tumor-bearing mice compared to BSH at a comparable dosage of 10B. CONCLUSION: CG-HVJ-E-BSH is a promising strategy for the BNCT treatment of visceral tumors without severe adverse events to surrounding normal tissues. PMID- 21247509 TI - Treatment with recombinant human activated protein C: one size does not fit all. AB - Protein C plays an important role in the coagulopathy associated with sepsis and probably also in the pathogenesis of sepsis-induced organ dysfunction. Plasma levels of protein C strongly correlate with clinical outcome in patients with severe sepsis. The RESPOND (Research Evaluating Serial Protein C Levels in Severe Sepsis Patients on Drotrecogin Alfa [Activated]) study shows that administration of recombinant human activated protein C in patients with severe sepsis with alternative dose regimens adjusted to plasma levels of protein C results in higher plasma levels of protein C. This may potentially translate to a better clinical outcome in patients with severe sepsis, although that was not directly shown in this trial. PMID- 21247508 TI - Distribution of high and low risk HPV types by cytological status: a population based study from Italy. AB - BACKGROUND: HPV type distribution by cytological status represents useful information to predict the impact of mass vaccination on screening programs. METHODS: women aged from 25 to 64 who attended cervical cancer screening in five different Italian regions were tested for HPV infection with Hybrid Capture II (HCII) low and high risk probes. Women repeating Pap-test upon unsatisfactory or positive results, or as a post-treatment and post-colposcopy follow-up analysis, were excluded from our study. High risk (HR) HPV positive samples were typed using GP5+/GP6+ primed PCR, followed by Reverse Line Blot for 18 high/intermediate risk HPV types, while low risk (LR) HPV positive samples were tested with type specific primers for HPV6 and HPV11. RESULTS: 3410 women had a valid HCII and Pap-test. The prevalence of HR and LR infections was 7.0% and 3.6%, 29.1% and 13.7%, 68.1% and 31.9%, 60.0% and 0.0%, 65.0% and 12.0%, for negative, ASC-US, L-SIL, ASC-H and H-SIL cytology, respectively. The fraction of ASC-US+ cytology due to HPV 16 and 18 ranged from 11.2 (HPV 16/18 alone) to 15.4% (including HPV 16/18 in co-infection with other virus strains), and that due to HPV 6 and 11 ranged from 0.2% (HPV 6/11 alone) to 0.7% (including HPV 6/11 in co infection with other LR virus strains). CONCLUSIONS: mass vaccination with bivalent or quadrivalent HPV vaccine would modestly impact on prevalence of abnormal Pap-test in screening. PMID- 21247510 TI - Integrating systems biology data to yield functional genomics insights. AB - A report of the recent EMBO Conference 'From Functional Genomics to Systems Biology' held at the EMBL Advanced Training Centre, Heidelberg, Germany, 13-16 November 2010. PMID- 21247511 TI - Kinetic-energy discrimination for atom probe tomography. AB - The benefits of using kinetic-energy information to aid ion discrimination in atom probe tomography (APT) are explored. Ion peak interferences in time-of flight (TOF) mass spectra are categorized by difficulty of discrimination using TOF and kinetic-energy information. Several of these categories, which are intractable interferences when only TOF information is available, may be discriminated when kinetic-energy information also is available. Furthermore, many opportunities for removing noise from composition determinations and three dimensional images are enabled. Modest kinetic-energy resolving powers (KRPs) of 10 or so should be sufficient to have a major impact on APT. With KRP of about 100, the energy deficits in voltage pulsing may be resolved to enable peak discrimination in straight-flight-path instruments. Real examples and simulated mass spectra are used to illustrate the benefits of kinetic-energy discrimination. Many of the conclusions are applicable generally in TOF spectroscopy. Current detectors do not provide the kinetic energy of incoming ions, but there are realistic prospects for building such detectors and these are discussed. A program to develop these detectors should be pursued. PMID- 21247506 TI - Animal products, diseases and drugs: a plea for better integration between agricultural sciences, human nutrition and human pharmacology. AB - Eicosanoids are major players in the pathogenesis of several common diseases, with either overproduction or imbalance (e.g. between thromboxanes and prostacyclins) often leading to worsening of disease symptoms. Both the total rate of eicosanoid production and the balance between eicosanoids with opposite effects are strongly dependent on dietary factors, such as the daily intakes of various eicosanoid precursor fatty acids, and also on the intakes of several antioxidant nutrients including selenium and sulphur amino acids. Even though the underlying biochemical mechanisms have been thoroughly studied for more than 30 years, neither the agricultural sector nor medical practitioners have shown much interest in making practical use of the abundant high-quality research data now available. In this article, we discuss some specific examples of the interactions between diet and drugs in the pathogenesis and therapy of various common diseases. We also discuss, using common pain conditions and cancer as specific examples, how a better integration between agricultural science, nutrition and pharmacology could lead to improved treatment for important diseases (with improved overall therapeutic effect at the same time as negative side effects and therapy costs can be strongly reduced). It is shown how an unnaturally high omega 6/omega-3 fatty acid concentration ratio in meat, offal and eggs (because the omega-6/omega-3 ratio of the animal diet is unnaturally high) directly leads to exacerbation of pain conditions, cardiovascular disease and probably most cancers. It should be technologically easy and fairly inexpensive to produce poultry and pork meat with much more long-chain omega-3 fatty acids and less arachidonic acid than now, at the same time as they could also have a similar selenium concentration as is common in marine fish. The health economic benefits of such products for society as a whole must be expected vastly to outweigh the direct costs for the farming sector. PMID- 21247512 TI - The 'healthy immigrant' effect: initial evidence for Ireland. AB - The period from 1996 to 2008 was one of rapid economic and social change in Ireland, with one of the most significant changes being the transition from a situation of net emigration to one of substantial net immigration. Although research on the impact of immigration on Irish society, as well as the labour market characteristics and experiences of immigrants in Ireland has increased in recent years, comparatively little is known about the health status of immigrants to Ireland. An extensive international literature has documented a 'healthy immigrant' effect for large immigrant-receiving countries such as the United States, Canada and Australia, whereby the health status of immigrants is better than comparable native-born individuals. There is also evidence to suggest that immigrants' health status deteriorates with time spent in the host country. However, the Irish immigration experience differs considerably from that of countries that have been the focus of research on the 'healthy immigrant' effect. Using microdata from a nationally representative survey of the population in 2007, this paper finds only limited evidence in favour of a 'healthy immigrant' effect for Ireland, although the distinctive features of the Irish immigrant population, and the nature of the data available, may partly explain the results. PMID- 21247513 TI - Comparison of BMI and anthropometric measures among South Asian Indians using standard and modified criteria. AB - OBJECTIVE: To compare the prevalence rates of obesity based on BMI/anthropometric measures, using WHO standard and ethnicity-specific criteria, the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and the International Diabetes Federation (IDF) definitions, among a migrant South Asian Indian population. DESIGN: Cross-sectional study conducted in October 2007. SUBJECTS: A total of 213 participants of South Asian descent over the age of 18 years. Measures included a questionnaire with basic demographic information and self-reported histories of diabetes, coronary artery disease and/or hypercholesterolaemia. Height, weight, waist and hip circumference and blood pressure measurements were obtained. SETTING: Houston and surrounding suburbs. RESULTS: WHO-modified (WHO-mod) BMI and IDF waist circumference (WC) criteria independently identified higher numbers of overweight/obese participants; however, when the WHO-mod BMI or IDF WC criteria were applied, nearly 75% of participants were categorized as overweight/obese--a proven risk factor for the future development of metabolic syndrome. CONCLUSIONS: Obesity is likely under diagnosed using the standard WHO and NCEP-ATPIII guidelines. Stressing the use of modified criteria more universally to classify obesity among South Asian Indians may be optimal to identify obesity and help appropriately risk stratify for intervention to prevent chronic diseases. PMID- 21247515 TI - The clinical effectiveness and cost-effectiveness of long-term weight management schemes for adults: a systematic review. AB - OBJECTIVE: To assess the long-term clinical effectiveness and cost-effectiveness of multicomponent weight management schemes for adults in terms of weight loss and maintenance of weight loss. DATA SOURCES: Bibliographic databases were searched from inception to December 2009, including the Cochrane Library, MEDLINE (Ovid), EMBASE (Ovid), and MEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were screened, key conferences and symposia were searched and experts were contacted to identify additional published and unpublished references. REVIEW METHODS: For the clinical effectiveness review, two reviewers independently screened titles and abstracts for eligibility. Inclusion criteria were applied to the full text of retrieved papers by one reviewer and checked by a second reviewer using a pre-piloted inclusion flow chart. The studies were long-term randomised controlled trials (RCTs) of adult participants who were classified by body mass index as overweight or obese. Interventions were multicomponent weight management programmes (including diet, physical activity and behaviour change strategies) that assessed weight measures. Programmes that involved the use of over-the-counter medicines licensed in the UK were also eligible. For the cost-effectiveness review two reviewers independently screened studies for inclusion. Cost-effectiveness, cost-utility, cost-benefit or cost-consequence analyses were eligible. Data were extracted using a standardised and pre-piloted data extraction form. The quality of included studies was assessed using standard criteria. Studies were synthesised through a narrative review with full tabulation of results. RESULTS: A total of 3358 references were identified, of which 12 were included in the clinical effectiveness review. Five RCTs compared multicomponent interventions with non-active comparator groups. In general, weight loss appeared to be greater in the intervention groups than in the comparator groups. Two RCTs compared multicomponent interventions that focused on the diet component. In these studies there were no statistically significant differences in weight loss between interventions. Four RCTs compared multicomponent interventions that focused on the physical activity component. There was little consistency in the pattern of results seen, in part owing to the differences in the interventions. In one RCT the intervention focused on the goal setting interval and it appeared that weight loss was greatest in those given daily goals compared with weekly goals. Overall, where measured, it appeared that most groups began to regain weight at further follow-up. Of the 419 studies identified in the cost-effectiveness searches, none met the full inclusion criteria. Two economic evaluations are described in our review; however, caution is required in their interpretation, as they did not meet all inclusion criteria. Lifetime chronic disease models were used in these studies and the models included the costs and benefits of avoiding chronic illness. Both studies found the interventions to be cost-effective, with estimates varying between -L473 and L7200 (US$12,640) per quality-adjusted life-year gained; methodological omissions from these studies were apparent and caution is therefore required in the interpretation of these results. CONCLUSIONS: Long-term multicomponent weight management interventions were generally shown to promote weight loss in overweight or obese adults. Weight changes were small however and weight regain was common. There were few similarities between the included studies; consequently an overall interpretation of the results was difficult to make. There is some evidence that weight management interventions are likely to be cost effective, although caution is required as there were some limitations in the two cost-evaluation studies described. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 21247516 TI - Management of clopidogrel hypersensitivity without drug interruption. AB - Clopidogrel hypersensitivity affects up to 6% of treated patients, often leading to discontinuation of the drug. Conventional desensitization protocols incorporate a washout period off medication that may be problematic after percutaneous coronary intervention because premature discontinuation of dual antiplatelet therapy is a major risk factor for stent thrombosis. The purpose of this study was to evaluate a strategy for treating clopidogrel hypersensitivity without drug interruption using corticosteroids and antihistamines to facilitate development of physiologic tolerance. The study population consisted of 25 consecutive patients who developed clopidogrel hypersensitivity after percutaneous coronary intervention and were managed with suppressive therapy using corticosteroids and antihistamines. Treatment success (resolution of hypersensitivity symptoms without interrupting clopidogrel) was assessed, in addition to duration of clopidogrel therapy and adverse cardiac events during late follow-up (mean 670 +/- 630 days). The cohort included 19 men and 6 women with a mean age of 62 +/- 9 years. Drug-eluting stents were used in 16 patients (64%). Clopidogrel hypersensitivity occurred 6 +/- 2 days after drug initiation. Treatment included corticosteroids (5 patients), antihistamines (5 patients), or corticosteroids and antihistamines (15 patients). Patients treated with corticosteroids received tapering courses for a mean of 10 +/- 8 days. Treatment was successful with sustained symptom resolution in 22 of 25 patients (88%). Clopidogrel therapy was continued in successfully desensitized patients for 417 +/- 369 days and in patients with drug-eluting stents for 529 +/- 376 days. There were no deaths, myocardial infarctions, or stent thrombosis during extended follow-up. In conclusion, clopidogrel hypersensitivity can be successfully treated using short-course corticosteroids and antihistamines without interrupting drug therapy. This technique enables long-term continuation of clopidogrel and confers a low risk of adverse cardiac events. PMID- 21247517 TI - Safety of ivabradine in patients with coronary artery disease and left ventricular systolic dysfunction (from the BEAUTIFUL Holter Substudy). AB - The BEAUTIFUL Holter substudy explored the cardiac safety of the I(f) inhibitor ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction receiving optimal background therapy. The Holter substudy included 840 patients (ivabradine 5 or 7.5 mg/day, n = 421; placebo, n = 419), and the safety set consisted of 807 patients (ivabradine, n = 408; placebo, n = 399). Ambulatory 24-hour electrocardiographic Holter monitoring was performed at baseline and after 1 month and 6 months. There were no relevant between-group differences in baseline characteristics; 93% were receiving concomitant beta blocker. Treatment with ivabradine was associated with a decrease in 24-hour heart rate of 6.3 +/- 9.5 beats/min at last assessment versus no change with placebo (0.4 +/- 7.2 beats/min, p <0.001, between-group difference), with a greater decrease in waking heart rate with ivabradine than during sleep (6.8 +/- 10.4 vs 5.2 +/- 8.9 beats/min, respectively, at last visit). Incidence of episodes of heart rate <30 beats/min during waking hours or during sleep was <=1% in the 2 groups. Although there were more patients with heart rates <40 or <50 beats/min with ivabradine than with placebo (awake 12% vs 4% for <40 beats/min and 68% vs 36% for <50 beats/min, respectively; asleep 22% vs 5% for <40 beats/min and 77% vs 50% for <50 beats/min, respectively), there was no between group difference in episode severity. There was no increase in incidence of conduction and rhythm disturbances. In conclusion, our results confirm that ivabradine significantly lowers heart rate without raising concern for cardiac safety. Our observations strongly support the safety of combining ivabradine with beta blockers in patients with coronary artery disease. PMID- 21247514 TI - Contribution of nonprimate animal models in understanding the etiology of schizophrenia. AB - Schizophrenia is a severe psychiatric disorder that is characterized by positive and negative symptoms and cognitive impairments. The etiology of the disorder is complex, and it is thought to follow a multifactorial threshold model of inheritance with genetic and neurodevelop mental contributions to risk. Human studies are particularly useful in capturing the richness of the phenotype, but they are often limited to the use of correlational approaches. By assessing behavioural abnormalities in both humans and rodents, nonprimate animal models of schizophrenia provide unique insight into the etiology and mechanisms of the disorder. This review discusses the phenomenology and etiology of schizophrenia and the contribution of current nonprimate animal models with an emphasis on how research with models of neuro transmitter dysregulation, environmental risk factors, neurodevelopmental disruption and genetic risk factors can complement the literature on schizophrenia in humans. PMID- 21247518 TI - Chronic kidney disease and CHADS(2) score independently predict cardiovascular events and mortality in patients with nonvalvular atrial fibrillation. AB - Chronic kidney disease is a risk factor for cardiovascular events, but how it relates to the prognosis associated with clinical risk factors for thromboembolism in patients with nonvalvular atrial fibrillation (AF) is not well known. Estimated glomerular filtration rate (eGFR), score for congestive heart failure, hypertension, age >=75 years, diabetes mellitus, and stroke/transient ischemic attack (CHADS(2)), and clinical outcomes of cardiovascular events were determined in 387 patients with nonvalvular AF (mean age 66 years, 289 men, mean follow-up 5.6 +/- 3.2 years). Decreased eGFR (<60 ml/min/1.73 m(2)) combined with CHADS(2) score >=2 was associated with higher all-cause (12.9% vs 1.4% per year, hazard ratio [HR] 6.9, p <0.001) and cardiovascular (6.5% vs 0.2% per year, HR 29.7, p <0.001) mortalities compared to preserved eGFR (>=60 ml/min/1.73 m(2)) combined with CHADS(2) score <2. This was also true for rates of cardiac events (cardiac death, nonfatal myocardial infarction, or hospitalization for worsening of heart failure, 10.4% vs 1.3% per year, HR 8.9, p <0.001), ischemic stroke (3.6% vs 0.2% per year, HR 11.0, p <0.001), and cardiovascular events (cardiac events and ischemic stroke, 13.6% vs 1.5% per year, HR 8.3, p <0.001). On multivariate analysis, CHADS(2) score >=2, decreased eGFR, and male gender independently predicted all-cause mortality. In conclusion, combined eGFR and CHADS(2) score could be an independent powerful predictor of cardiovascular events and mortality in patients with nonvalvular AF. Long-term mortality, cardiac events, and stroke risk were >8 times higher when decreased eGFR (<60 ml/min/1.73 m(2)) was present with higher CHADS(2) score (>=2). PMID- 21247519 TI - Incidence, predictors, and outcome of conduction disorders after transcatheter self-expandable aortic valve implantation. AB - The aims of the present study were to investigate the incidence and characteristics of conduction disorders (CDs) after transcatheter aortic valve implantation (TAVI), to analyze the predictors of permanent pacemaker (PPM) implantation, and to evaluate the outcomes of CDs over time. In particular, we sought to investigate whether the depth of deployment and other technical aspects of valve implantation might predict the need for PPM implantation after TAVI. TAVI has been reported to favor the onset or worsening of CDs often requiring PPM implantation. A total of 70 patients with aortic stenosis due to dystrophic calcification underwent TAVI with third-generation CoreValve Revalving System from May 2007 to April 2009. We collected electrocardiograms at baseline, during TAVI, during hospitalization and at the 1-, 3-, 6-, and 12-month follow-up visits thereafter. The clinical, anatomic, and procedural variables were tested to identify the predictors of PPM implantation. The PPM dependency at follow-up was analyzed. Six patients were excluded from the analysis because of a pre-existing PPM. Of the 64 patients, 32 (50%) had one or more atrioventricular intraventricular CDs at baseline. TAVI induced a worsening in the CDs in 49 (77%) of the 64 patients, with 25 (39%) requiring in-hospital PPM implantation. On multivariate analysis, the independent predictors of PPM implantation were the depth of the prosthesis implantation (p = 0.039) and the pre-existing right bundle branch block (p = 0.046). A trend in the recovery of the CDs over time was recorded, although 2 patients required PPM implantation 1 month after discharge for late complete atrioventricular block. In conclusion, TAVI often induces or worsens CDs, requiring PPM in more than one third of patients, although a trend in the recovery of CDs during the midterm was recorded. The independent predictors of PPM implantation were the depth of prosthesis implantation and pre existing right bundle branch block. PMID- 21247520 TI - Efficacy of fenofibric acid plus statins on multiple lipid parameters and its safety in women with mixed dyslipidemia. AB - The combination of fibrate and statin therapies may be a treatment option for women with multiple lipid abnormalities. We, therefore, initiated the present safety and efficacy analysis to address the paucity of such data in women with mixed dyslipidemia. A total of 1,393 women with mixed dyslipidemia (low-density lipoprotein [LDL] cholesterol >= 130 mg/dl, triglycerides [TG] >= 150 mg/dl, high density lipoprotein [HDL] cholesterol <50 mg/dl), who had enrolled in any 1 of 3 randomized clinical trials, were evaluated. The eligible women were randomized to receive fenofibric acid plus a low- or moderate-dose statin (combination treatment); or low-, moderate-, or high-dose statin monotherapy; or fenofibric acid monotherapy. With low-dose combination treatment, the baseline HDL cholesterol level increased 20% and TG decreased 46% compared to an 8% HDL cholesterol increase and 20% TG decrease with low-dose statins alone. With the moderate-dose combination, the baseline HDL cholesterol increased 21% and TG decreased 44% compared to an 8% HDL cholesterol increase and 26% TG decrease with moderate-dose statins alone. The reduction in baseline LDL cholesterol with low dose and moderate-dose combinations (37% and 39%, respectively) was comparable to the reduction with corresponding-dose statins (36% and 43%, respectively). High dose statins decreased the baseline LDL cholesterol 47%; however, the increase in HDL cholesterol (9%) and decrease in TG (25%) were similar to the changes observed with lower doses of statins. The safety profiles of the combinations were comparable to those of the component therapies. In conclusion, these data suggest that a combination of fenofibric acid and a statin could be considered safe and efficacious for treating women with mixed dyslipidemia. PMID- 21247521 TI - Comparison of central artery elasticity in swimmers, runners, and the sedentary. AB - Although swimming is one of the most popular, most practiced, and most recommended forms of physical activity, little information is available regarding the influence of regular swimming on vascular disease risks. Using a cross sectional study design, key measurements of vascular function were performed in middle-aged and older swimmers, runners, and sedentary controls. There were no group differences in age, height, dietary intake, and fasting plasma concentrations of glucose, total cholesterol, and low-density lipoprotein cholesterol. Runners and swimmers were not different in their weekly training volume. Brachial systolic blood pressure and pulse pressure were higher (p <0.05) in swimmers than in sedentary controls and runners. Runners and swimmers had lower (p <0.05) carotid systolic blood pressure and carotid pulse pressure than sedentary controls. Carotid arterial compliance was higher (p <0.05) and beta stiffness index was lower (p <0.05) in runners and swimmers than in sedentary controls. There were no significant group differences between runners and swimmers. Cardiovagal baroreflex sensitivity was greater (p <0.05) in runners than in sedentary controls and swimmers and baroreflex sensitivity tended to be higher in swimmers than in sedentary controls (p = 0.07). Brachial artery flow mediated dilation was significant greater (p <0.05) in runners compared with sedentary controls and swimmers. In conclusion, our present findings are consistent with the notion that habitual swimming exercise may be an effective endurance exercise for preventing loss in central arterial compliance. PMID- 21247522 TI - Prognosis based on creatine kinase isoenzyme MB, cardiac troponin I, and right ventricular size in stable patients with acute pulmonary embolism. AB - Prognosis of stable patients with acute pulmonary embolism (PE) has been assessed with cardiac troponin I (cTnI) and right ventricular (RV) function or size. Whether creatine kinase-MB isoenzyme (CK-MB) would add to the prognostic assessment is uncertain. We retrospectively assessed in-hospital mortality from PE in 392 stable patients to test the hypothesis that CK-MB would be of greater prognostic value than cTnI or RV size and we assessed whether combinations would increase prognostic value. CK-MB was high in 29 patients (7.4%); cTnI was high in 76 patients (19%) and intermediate in 78 patients (20%). The right ventricle was dilated in 128 patients (33%). Trends showed highest in-hospital mortality from PE in 4 of 29 (14%) with high CK-MB compared to 6 of 76 (7.9%) with high cTnI and 8 of 128 (6.3%) with RV dilatation (differences NS). High CK-MB and high cTnI provided added prognostic information only in patients with RV dilatation. Mortality with high CK-MB plus RV dilatation (4 of 19, 21%) tended to exceed mortality with high cTnI plus RV dilatation (5 of 39, 13%, NS). When CK-MB and cTnI were high and the right ventricle was dilated, PE mortality tended to be highest (4 of 14, 29%, NS). In conclusion, cardiac biomarkers contributed to prognosis only in patients with RV dilatation. CK-MB was the strongest predictor of death from PE but its prevalence was low, thus limiting its value as a single prognostic indicator. The combination of high CK-MB, high cTnI, and RV dilatation tended to indicate the highest mortality. PMID- 21247523 TI - Effect and clinical prediction of worsening renal function in acute decompensated heart failure. AB - We aimed to establish the prevalence and effect of worsening renal function (WRF) on survival among patients with acute decompensated heart failure. Furthermore, we sought to establish a risk score for the prediction of WRF and externally validate the previously established Forman risk score. A total of 657 consecutive patients with acute decompensated heart failure presenting to the emergency department and undergoing serial creatinine measurements were enrolled. The potential of the clinical parameters at admission to predict WRF was assessed as the primary end point. The secondary end point was all-cause mortality at 360 days. Of the 657 patients, 136 (21%) developed WRF, and 220 patients had died during the first year. WRF was more common in the nonsurvivors (30% vs 41%, p = 0.03). Multivariate regression analysis found WRF to independently predict mortality (hazard ratio 1.92, p <0.01). In a single parameter model, previously diagnosed chronic kidney disease was the only independent predictor of WRF and achieved an area under the receiver operating characteristic curve of 0.60. After the inclusion of the blood gas analysis parameters into the model history of chronic kidney disease (hazard ratio 2.13, p = 0.03), outpatient diuretics (hazard ratio 5.75, p <0.01), and bicarbonate (hazard ratio 0.91, p <0.01) were all predictive of WRF. A risk score was developed using these predictors. On receiver operating characteristic curve analysis, the Forman and Basel prediction rules achieved an area under the curve of 0.65 and 0.71, respectively. In conclusion, WRF was common in patients with acute decompensated heart failure and was linked to significantly worse outcomes. However, the clinical parameters failed to adequately predict its occurrence, making a tailored therapy approach impossible. PMID- 21247524 TI - Frequency of atrial flutter after adult lung transplantation. AB - Lung transplantation, which involves an anastomosis of the graft to the native left atrium, may increase the risk of left-side atrial flutter (AFL). Our aim was to evaluate the incidence, predisposing conditions, and course of AFL after lung transplantation in adults. Two hundred sixty-nine consecutive patients who underwent lung transplantation were studied retrospectively. All patients received a preoperative echocardiogram and postoperative electrocardiographic monitoring. All 12-lead electrocardiograms were reviewed. Typical or atypical AFL was diagnosed by 2 independent reviewers based on accepted criteria. Predictors of AFL were investigated separately using univariate and multivariate logistic regression analyses. AFL occurred in 35 of 269 patients (13%) over a mean of 12 days after transplantation. All patients who developed AFL had no previous atrial arrhythmia. Of these 35 patients, 24 (68.6%) had atypical AFL by electrocardiographic criteria. In multivariate logistic regression analysis, patients with idiopathic pulmonary fibrosis (IPF) were 2.9 times more likely to have AFL than those patients with lung transplant without IPF (p = 0.009). Other independent risk factors for AFL were advanced age and preoperative left atrial enlargement. Only 3 of 35 patients (8.6%) with AFL had persistent atrial arrhythmia and needed electrophysiologic study and ablation. In conclusion, AFL is common soon after lung transplantation. Those with IPF, advanced age, or left atrial enlargement are at increased risk. In most cases, AFL is a self-limited arrhythmia that resolves spontaneously with no need for ablation. PMID- 21247525 TI - Placental growth factor and B-type natriuretic peptide as independent predictors of risk from a multibiomarker panel in suspected acute coronary syndrome (Acute Risk and Related Outcomes Assessed With Cardiac Biomarkers [ARROW]) study. AB - Most patients presenting to the emergency department with possible cardiac symptoms have low cardiac troponin (cTn) concentrations. A combination of biomarkers that improves risk stratification in patients at very low risk for major adverse cardiovascular events (MACEs) would be beneficial. In this multicenter prospective cohort study, specimens from 598 subjects presenting to 5 emergency departments with suspected acute coronary syndromes were collected on arrival and serially for traditional and novel biomarkers. Subjects were evaluated for MACEs, defined as death, myocardial infarction, or revascularization at 30 and 365 days. Classification and regression tree analysis assessed biomarker and clinical factors associated with MACEs. The 1-year rate of MACE was 10.5% (47 of 449). Rates of death, myocardial infarction, and revascularization were 4.2%, 1.6%, and 4.7%, respectively. The combination of B type natriuretic peptide (BNP), placental growth factor (PlGF), and estimated glomerular filtration rate (eGFR) was the most accurate predictor of MACEs compared to any other biomarker or clinical factors including cTnI. If BNP was <= 65 ng/L and PlGF was <= 19.5 ng/L, the negative predictive value for 1-year MACEs was 99.1%. Conversely, BNP >150 ng/L and eGFR <= 68 ml/min/1.73 m(2) predicted a very high (36.5%) MACE rate. Prognostic values of BNP and PlGF were incremental (none increased, 2 of 212, 0.9%; only PlGF increased, 30 of 170, 17.6%; only BNP increased, 33 of 153, 21.6%; BNP and PlGF increased, 18 of 86, 20.9%). Considering only initial emergency department samples, 97% and 96% of patients with normal PlGF, BNP, and cTnI levels were event-free at 30 and 365 days, respectively. In conclusion, the combination of BNP, PlGF, and eGFR is the most accurate in risk-stratifying patients with suspected acute coronary syndrome. PMID- 21247526 TI - Achieving optimal lipid goals in patients with coronary artery disease. AB - Guidelines for lipid-lowering therapy recommend intensive low-density lipoprotein (LDL) cholesterol lowering for patients with coronary artery disease. Previous studies have found that many high-risk patients are not achieving their LDL cholesterol goals, and many patients, despite being treated with lipid-lowering therapy, also have elevated triglycerides or low levels of high-density lipoprotein (HDL) cholesterol. To evaluate lipid goals in a "real world" clinical setting, the electronic medical records of 10,040 patients with coronary artery disease from a large cardiology subspecialty practice from September 2008 to September 2009 were reviewed. Overall, 79% of patients achieved an LDL cholesterol goal of <100 mg/dl, while only 35% achieved the more aggressive goal of <70 mg/dl. Non-HDL cholesterol goals of <130 and <100 mg/dl were achieved in 79% and 44% of patients, respectively. Only 69% achieved normal triglyceride levels, and only 63% of men and 56% of women achieved normal levels of HDL cholesterol. Women and younger men were less likely to achieve their lipid goals. In conclusion, most patients with coronary artery disease achieve the minimal LDL cholesterol goal of 100 mg/dl, but few achieve the more aggressive goals of <70 mg/dl. Many high-risk patients have elevated levels of triglycerides or low levels of HDL cholesterol despite treatment. Combination lipid-lowering therapy is used infrequently in practice. There exists a significant opportunity for physicians to more aggressively treat lipids to achieve the levels recommended by clinical guidelines. PMID- 21247527 TI - Effect of concomitant use of clopidogrel and proton pump inhibitors after percutaneous coronary intervention. AB - The aim of the present study was to analyze the effect of drug exposure patterns of clopidogrel and proton pump inhibitors (PPIs) on the clinical outcomes after percutaneous coronary intervention (PCI). Previous analyses predominantly included discharge medications and did not explore the effect of the drug exposure patterns. We analyzed all-cause death, nonfatal myocardial infarction, repeat revascularization, and major adverse cardiovascular events (MACE) in a cohort of 23,200 post-PCI patients (January 2003 to December 2008) using a multivariate adjusted Cox model and propensity-matched case-control analysis. The adjusted hazard ratio for MACE on PPI according to the exposure patterns of clopidogrel after PCI for 6 years was 1.24 (95% confidence interval [CI] 1.11 to 1.38) and 1.12 (95% CI 1.03 to 1.22) for "continuous" (consistent clopidogrel with or without PPIs) and "switched" (clopidogrel with or without varying PPIs) respectively. However, the propensity score adjusted odds ratios for MACE on PPI use was 0.97 (95% CI 0.65 to 1.44) for "continuous" and 1.04 (95% CI 0.87 to 1.25) for "switched." Moreover, in the first year after PCI, the use of "rescue" (<=30 days before MACE) nitroglycerin was greater in the patients taking clopidogrel and PPIs than in those taking clopidogrel alone, as was the overall use of rescue PPIs (p <0.001). In conclusion, PPI use in clopidogrel-treated post PCI patients was not associated with an increased risk of MACE after controlling for the confounding effect of PPI use with propensity matching. A potential for the misdiagnosis of angina symptoms and rescue use of nitroglycerin and PPIs in post-PCI patients exists, a finding that might have confounded previous observational analyses. PMID- 21247528 TI - Cardiac magnetic resonance imaging and the assessment of ebstein anomaly in adults. AB - No published studies have evaluated the role of cardiac magnetic resonance (CMR) imaging for the assessment of Ebstein anomaly. Our objective was to evaluate the right heart characteristics in adults with unrepaired Ebstein anomaly using contemporary CMR imaging techniques. Consecutive patients with unrepaired Ebstein anomaly and complete CMR studies from 2004 to 2009 were identified (n = 32). Volumetric measurements were obtained from the short-axis and axial views, including assessment of the functional right ventricular (RV) end-diastolic volume (EDV) and end-systolic volume. The volume of the atrialized portion of the right ventricle in end-diastole was calculated as the difference between the total RVEDV and the functional RVEDV. The reproducibility of the measurements in the axial and short-axis views was determined within and between observers. The median value derived from the short-axis and axial views was 136 ml/m(2) (range 59 to 347) and 136 ml/m(2) (range 63 to 342) for the functional RVEDV, 153 ml/m(2) (range 64 to 441) and 154 ml/m(2) (range 67 to 436) for the total RVEDV, 49% (range 32% to 46%) and 50% (range 40% to 64%) for the functional RV ejection fraction, respectively. The axial measurements demonstrated lower intraobserver and interobserver variability than the short-axis approach for all values, with the exception of the intraobserver functional RVEDV and interobserver total RVEDV for which the limits of agreement and variance were not significantly different between the 2 views. In conclusion, measurements of right heart size and systolic function in patients with Ebstein anomaly can be reliably achieved using CMR imaging. Axial imaging appeared to provide more reproducible data than that obtained from the short-axis views. PMID- 21247529 TI - Effect of CC chemokine receptor 2 CCR2 blockade on serum C-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region. AB - CC chemokine receptor 2 (CCR2), expressed on the surface of circulating monocytes, and its ligand monocyte chemoattractant protein-1 (MCP-1; also known as CC-chemokine ligand 2) are present in atherosclerotic plaques and may have important roles in endothelial monocyte recruitment and activation. MLN1202 is a highly specific humanized monoclonal antibody that interacts with CCR2 and inhibits MCP-1 binding. The aim of this randomized, double-blind, placebo controlled study was to measure reductions in circulating levels of high sensitivity C-reactive protein, an established biomarker of inflammation associated with coronary artery disease, on MLN1202 treatment in patients at risk for atherosclerotic cardiovascular disease (>=2 risk factors for atherosclerotic cardiovascular disease and circulating high-sensitivity C-reactive protein >3 mg/L). Additionally, patients were genotyped for the 2518 A->G polymorphism in the promoter of the MCP-1 gene to investigate the correlation between this polymorphism and reduced C-reactive protein levels with MLN1202 treatment. Patients who received MLN1202 exhibited significant decreases in high-sensitivity C-reactive protein levels, beginning at 4 weeks and continuing through 12 weeks after dosing. Patients with A/G or G/G genotypes in the MCP-1 promoter had significantly greater reductions in high-sensitivity C-reactive protein levels than patients with the wild-type A/A genotype. In conclusion, MLN1202 treatment was well tolerated in this patient population and resulted in significant reductions in high-sensitivity C-reactive protein levels. PMID- 21247530 TI - Relation of soluble receptor for advanced glycation end products to predict mortality in patients with chronic heart failure independently of Seattle Heart Failure Score. AB - Knowledge of the role of the soluble receptor for advanced glycation end products (sRAGEs) in chronic heart failure (CHF) is very limited. In the present study, we measured plasma sRAGE levels in patients with CHF and examined whether plasma sRAGE predicts prognosis in patients with HF independently of validated scores as the Seattle Heart Failure Score (SHFS). We measured plasma sRAGE in 106 outpatients with CHF. Patients were prospectively followed during a median follow up period of 1.3 years with end points of cardiac death or rehospitalization. Plasma sRAGE level increased with advancing New York Heart Association functional class, SHFS, age, and ischemic cause. Plasma sRAGE level was also higher in patients with cardiac death and/or events than in event-free patients. In Cox multivariate proportional hazard analysis, SHFS, sRAGE, and N-terminal pro-B-type natriuretic peptide were independent risk factors for cardiac death (sRAGE hazard ratio 1.26, 95% confidence interval 1.09 to 1.45, p = 0.002) and/or cardiac events (sRAGE hazard ratio 1.07, 95% confidence interval 1.03 to 1.11, p = 0.002). Survival curves adjusted by Cox analysis clearly demonstrated that the high-sRAGE group (higher than median) had a significantly higher incidence of cardiac death than the low-sRAGE group (p = 0.001). In conclusion, sRAGE is a novel, highly sensitive, and specific prognostic marker in current optimally treated patients with CHF with an additive and independent value compared to the multimarker SHFS. PMID- 21247531 TI - Spontaneous rupture of atrioventricular valve tensor apparatus as late manifestation of anti-Ro/SSA antibody-mediated cardiac disease. AB - Atrioventricular (AV) block and endocardial fibroelastosis associated with dilated cardiomyopathy are the most common clinical manifestations of anti-Ro/SSA mediated fetal cardiac disease. Valvar dysfunction has not been a prominent feature of this disease; however, recent anecdotal cases have suggested an association between rupture of the AV valve tensor apparatus and maternal anti Ro/SSA antibodies. In the present study, we have described the clinical and laboratory findings and reviewed the published data for infants of anti-Ro/SSA positive pregnancies with AV valve insufficiency due to chordal rupture from the papillary muscles. The histopathologic features of the papillary muscle and ventricular free wall and septum biopsy specimens were examined and compared to the sections of AV leaflets from 6 autopsied fetuses with anti-Ro/SSA-mediated complete AV block without chordal disruption. Specific epitopes to the p200 region of Ro52, and Ro60 antibodies were evaluated in cases with chordal rupture. Severe AV valve insufficiency was detected prenatally (as early as 34 weeks of gestation) or postnatally (as late as 182 days) after areas of patchy echogenicity were noted in the papillary muscle at 19 to 22 weeks of gestation. Postnatally, urgent valve surgery was performed in 5 of 6 patients; 1 of 6 patients died preoperatively. All patients tested positive for Ro52. Valve leaflet tissue from the autopsy specimens was normal. The ventricular free wall and septum biopsy specimens from a patient with chordal rupture showed normal tissue; however, the papillary muscle biopsy specimens demonstrated severe atrophy with near total replacement of myocytes by fibrosis and dystrophic calcifications, and negative immunochemistry findings. In conclusion, these findings have defined an underappreciated complication of fetal antibody-mediated cardiac inflammation. PMID- 21247532 TI - Catheter aspiration in ST-elevation myocardial infarction and different extent of coronary thrombus. AB - Manual catheter aspiration appears to be a useful adjunct to primary percutaneous coronary intervention (PCI) in ST-elevation myocardial infarction. We investigated effects of catheter aspiration during primary PCI in patients with different extents of coronary thrombus. The study included 46 patients with no or possible thrombus (thrombus scale [TS] grades 0 to 1) and 135 patients with angiographic evidence of obvious thrombus (TS grades 2 to 5). Reference vessel diameter, which was significantly larger in the group with TS grades 2 to 5 (3.4 vs 3.2 mm, p = 0.004), was the only independent predictor of angiographically visible thrombus (odds ratio 3.3, 95% confidence interval 1.3 to 8.7, p = 0.015, per millimeter increase). Aspiration catheter was successfully advanced across the lesion in 89% of patients with TS grades 0 to 1 and 96% of those with TS grades 2 to 5 (p = 0.115). Number of aspirations varied from 1 to 5 and was significantly larger in patients with TS grades 2 to 5. Visually observable aspirate was obtained in 90% of patients with TS grades 2 to 5 and in 67% of patients with TS grades 0 to 1 (p <0.001) with more patients with TS grades 2 to 5 having aspirate >5 mm in length (49% vs 11%, p <0.001). Final Thrombolysis In Myocardial Infarction grade 3 flow (89% vs 92%), residual TS (0.2 vs 0.1), frequency of distal embolization (2% vs 6%), and early complete ST resolution (65% vs 70%) were comparable between groups with TS grades 0 to 1 and 2 to 5. In conclusion, although the amount of aspirate is larger in patients with angiographically obvious thrombus, visually observable aspirate can be obtained in most patients without definite signs of thrombus. Extent of coronary thrombus does not influence primary PCI result if manual aspiration is used. PMID- 21247533 TI - Usefulness of comprehensive cardiothoracic computed tomography in the evaluation of acute undifferentiated chest discomfort in the emergency department (CAPTURE). AB - Newer cardiac computed tomographic (CT) technology has permitted comprehensive cardiothoracic evaluations for coronary artery disease, pulmonary embolism, and aortic dissection within a single breath hold, independent of the heart rate. We conducted a randomized diagnostic trial to compare the efficiency of a comprehensive cardiothoracic CT examination in the evaluation of patients presenting to the emergency department with undifferentiated acute chest discomfort or dyspnea. We randomized the emergency department patients clinically scheduled to undergo a dedicated CT protocol to assess coronary artery disease, pulmonary embolism, or aortic dissection to either the planned dedicated CT protocol or a comprehensive cardiothoracic CT protocol. All CT examinations were performed using a 64-slice dual source CT scanner. The CT results were immediately communicated to the emergency department providers, who directed further management at their discretion. The subjects were then followed for the remainder of their hospitalization and for 30 days after hospitalization. Overall, 59 patients (mean age 51.2 +/- 11.4 years, 72.9% men) were randomized to either dedicated (n = 30) or comprehensive (n = 29) CT scanning. No significant difference was found in the median length of stay (7.6 vs 8.2 hours, p = 0.79), rate of hospital discharge without additional imaging (70% vs 69%, p = 0.99), median interval to exclusion of an acute event (5.2 vs 6.5 hours, p = 0.64), costs of care (p = 0.16), or the number of revisits (p = 0.13) between the dedicated and comprehensive arms, respectively. In addition, radiation exposure (11.3 mSv vs 12.8 mSv, p = 0.16) and the frequency of incidental findings requiring follow-up (24.1% vs 33.3%, p = 0.57) were similar between the 2 arms. Comprehensive cardiothoracic CT scanning was feasible, with a similar diagnostic yield to dedicated protocols. However, it did not reduce the length of stay, rate of subsequent testing, or costs. In conclusion, although this "triple rule out" protocol might be helpful in the evaluation of select patients, these findings suggest that it should not be used routinely with the expectation that it will improve efficiency or reduce resource use. PMID- 21247534 TI - Gender differences between the Minnesota code and Novacode electrocardiographic prognostication of coronary heart disease in the cardiovascular health study. AB - The Minnesota Code (MC) and Novacode (Nova) are the most widely used electrocardiographic (ECG) classification systems. The comparative strengths of their classifications for Q- and ST-T-wave abnormalities in predicting coronary heart disease (CHD) events and total mortality have not been evaluated separately by gender. We studied standard 12-lead electrocardiograms at rest from 4,988 participants in the Cardiovascular Health Study. Average age at baseline was 73 years, 60% of participants were women 85% were white, and 22% had a history of cardiovascular disease or presence of ECG myocardial infarction by MC or Nova. Starting in 1989 with an average 17-year follow-up, 65% of participants died and 33% had incident CHD in a cohort free of cardiovascular disease at baseline. Of these, electrocardiograms with major Q-wave or major ST-T abnormalities by MC or Nova predicted increased risk for CHD events and total mortality with no significant differences in predictability between men and women. The study also found that women had fewer major Q-wave changes but more major ST-T abnormalities than men. However, there were no gender differences in predicting CHD events and total mortality. In conclusion, ECG classification systems for myocardial infarction/ischemia abnormalities by MC or Nova are valuable and useful for men and women in clinical trials and epidemiologic studies. PMID- 21247535 TI - Value of early risk stratification using hemoglobin level and neutrophil-to lymphocyte ratio in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - Complete blood count is the most widely available laboratory datum in the early in-hospital period after ST-elevation myocardial infarction (STEMI). We assessed the clinical utility of the combined use of hemoglobin (Hb) level and neutrophil to-lymphocyte ratio (N/L) for early risk stratification in patients with STEMI. We analyzed 801 consecutive patients with STEMI treated with primary percutaneous coronary intervention (PCI) within 12 hours of onset of symptoms. Patients with cardiogenic shock or underlying malignancy were excluded, and 739 patients (63 +/ 13 years, 74% men) were included in the final analysis. Patients were categorized into 3 groups using the median value of N/L (3.86) and the presence of anemia (Hb <13 mg/dl in men and <12 mg/dl in women); group I had low N/L and no anemia (n = 272), group II had low N/L and anemia, or high N/L and no anemia (n = 331), and group III had high N/L and anemia (n = 136). There were significant differences on clinical outcomes during 6-month follow-up among the 3 groups. Prognostic discriminatory capacity of combined use of Hb level and N/L was also significant in high-risk subgroups such as patients with advanced age, diabetes mellitus, multivessel coronary disease, low ejection fraction, and even in those having higher mortality risk based on Thrombolysis In Myocardial Infarction risk score. In a Cox proportional hazards model, after adjusting for multiple covariates, group III had higher mortality at 6 months (hazard ratio 5.6, 95% confidence interval 1.1 to 27.9, p = 0.036) compared to group I. In conclusion, combined use of Hb level and N/L provides valuable timely information for early risk stratification in patients with STEMI undergoing primary PCI. PMID- 21247536 TI - Evidence of a "heart failure belt" in the southeastern United States. AB - The southeastern region of the United States is known as the "stroke belt" because of excess stroke mortality in this region compared to the rest of the country. However, whether a similar geographic variation in heart failure mortality exists is unknown. Using the Center for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research publicly available compressed mortality data files and 2000 United States population as the standard, we estimated age-adjusted heart failure and stroke mortality rates per 100,000 for patients of all ages, men and women, and all races during 1979 through 1998 in the United States and mapped rates at the state level. Age-adjusted heart failure mortality rate for the 6 contiguous southeastern states (Alabama, Arkansas, Mississippi, Oklahoma, Louisiana, and Georgia) was 31.0/100,000, which was 69% higher than the national rate of 18.3/100,000. This geographic disparity was similar in African-Americans (32.9/100,000 in the southeast vs 21.7/100,000 nationally) and whites (30.8/100,000 in the southeast vs 18.1/100,000 nationally). These findings suggest that, in addition to the stroke belt, the southeastern region of the United States may also be burdened by a "heart failure belt." To better understand the causes of excess stroke mortality in the stroke belt, the National Institutes of Health has funded the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study (n = 30,239, >1/2 from the southeastern region), which provides a unique opportunity to study the underlying causes of excess heart failure mortality in the heart failure belt. PMID- 21247537 TI - Relation of circulating osteoprotegerin levels on admission to microvascular obstruction after primary percutaneous coronary intervention. AB - Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, has recently been linked to atherosclerosis and development of postinfarction heart failure. This study was designed to assess the association between admission OPG levels and microvascular obstruction (MVO) in patients who underwent primary percutaneous coronary intervention (p-PCI). Plasma samples for OPG analysis were obtained <30 minutes after admission in 47 patients who underwent p-PCI. Angiographic no-reflow (Thrombolysis In Myocardial Infarction [TIMI] flow grade <3 or 3 with myocardial blush grade 0 or 1 after p-PCI) was assessed immediately after p-PCI. MVO was assessed and quantified by the intracoronary hemodynamic measure of index of microcirculatory resistance performed on day 4 or 5 after p-PCI. Patients with angiographic no-reflow had significantly higher OPG levels on admission. On multiple linear regression analysis, OPG (beta = 0.412, p = 0.001) and B-type natriuretic peptide (beta = 0.409, p = 0.001) levels were independently and directly associated with the index of microcirculatory resistance. In conclusion, plasma OPG levels on admission are strongly associated with MVO and significantly correlated with the degree of MVO after p-PCI. It remains to be established whether improvement of microvascular perfusion is feasible with therapeutic strategies aimed to decrease circulating OPG levels. PMID- 21247538 TI - Long-term (three-year) safety and efficacy of everolimus-eluting stents compared to paclitaxel-eluting stents (from the SPIRIT III Trial). AB - The safety and efficacy of the XIENCE V everolimus-eluting stent (EES) compared to the Taxus Express(2) paclitaxel-eluting stent (PES) has been demonstrated through 2 years in the SPIRIT II and III randomized clinical trials, but limited longer-term data have been reported. In the SPIRIT III trial, 1,002 patients with up to 2 lesions in 2 coronary arteries were randomized 2:1 to EESs versus PESs at 65 United States sites. At completion of 3-year follow-up, treatment with EES compared to PES resulted in a significant 30% decrease in the primary clinical end point of target vessel failure (cardiac death, myocardial infarction, or ischemic-driven target vessel revascularization, 13.5% vs 19.2%, hazard ratio 0.70, 95% confidence interval 0.50 to 0.96, p = 0.03) and a 43% decrease in major adverse cardiovascular events, cardiac death, myocardial infarction, or ischemic driven target lesion revascularization (9.1% vs 15.7%, hazard ratio 0.57, 95% confidence interval 0.39 to 0.83, p = 0.003). In a landmark analysis, major adverse cardiovascular events were decreased to a similar extent with EES compared to PES 0 through 1 year and 1 year through 3 years (hazard ratio 0.56, 95% confidence interval 0.35 to 0.90; hazard ratio 0.59, 95% confidence interval 0.31 to 1.11, respectively). In conclusion, patients treated with EES rather than PES in the SPIRIT III trial had significantly improved event-free survival at 3 years. From 1 year to 3 years hazard curves continued to diverge in favor of EES, consistent with an improving long-term safety and efficacy profile of EES compared to PES, with no evidence of late catchup. PMID- 21247539 TI - Mortality in individuals without known coronary artery disease but with discordance between the Framingham risk score and coronary artery calcium. AB - A risk-management approach based on the Framingham risk score (FRS), although useful in preventing future coronary artery disease (CAD) events, is unable to identify a considerable portion of patients with CAD who need aggressive medical management. Coronary artery calcium (CAC), an anatomic marker of atherosclerosis, correlates well with presence and extent of CAD. This study investigated mortality risk associated with CAC score and FRS in subjects classified as "low risk" versus "high risk" based on FRS. In total 730 veterans without known CAD (61 +/- 10 years old, 12.8% women) underwent measurement of their FRS and CAC. Subjects were classified as "discordant low risk" (DLR) if their FRS was <10% and CAC score was >= 100 (n = 108, 14.8%) or "discordant high risk" (DHR) if their FRS was >= 20% and CAC score was 0 (n = 104, 14.2%). Survival analysis was used to compare mortality rates associated with FRS and CAC in DLR versus DHR subjects. Mortality rate during the mean 48-month follow-up was 7.3% (n = 53) including 18.5% (n = 20) in the DLR group and 7.7% (n = 8) in the DHR group, respectively. Adjusted relative risks of mortality were 5.46 (95% confidence interval [CI] 2.44 to 12.20, p = 0.0001) in subjects with CAC score >= 100 compared to CAC score 0 and 1.35 (95% CI 1.01 to 4.32, p = 0.04) in subjects with FRS >= 20% compared to FRS <10%. Adjusted relative risk of mortality was 3.6 (95% CI 1.57 to 8.34, p = 0.003) for DLR compared to DHR. Areas under the receiver operator curve to predict mortality were 0.72 for FRS, 0.82 for CAC score, and 0.92 for the combination. In conclusion, the prognostic value of CAC to predict future mortality is superior to the FRS. Addition of CAC score to FRS significantly improves the identification and prognostication of patients without known CAD. PMID- 21247541 TI - Temporal trends (over 30 years), clinical characteristics, outcomes, and gender in patients <=50 years of age having percutaneous coronary intervention. AB - Little is known regarding temporal trends in characteristics and outcomes of young (<=50 years) patients who develop symptomatic premature coronary artery disease (CAD). The aim of this study was to describe temporal trends in clinical characteristics and outcomes and gender differences in patients with premature CAD undergoing percutaneous coronary intervention (PCI) over 3 decades. A retrospective analysis of 2,922 consecutive patients <=50 years of age undergoing PCI from 1980 through 2007 was conducted. Baseline characteristics and in hospital and long-term outcomes were compared by decade. Gender differences and predictors of mortality were analyzed in the most recent cohort. Although most patients were men (80%), there was an increasing proportion of women over time. An increasing prevalence of diabetes mellitus (10% in 1980 to 1989, 16% in 1990 to 1999, 20% in 2000 to 2007, p <0.001), hypertension (29%, 41%, 57%, p <0.001), and hyperlipidemia (39%, 55%, 73%, p <0.001) coincided with increasing body mass index (28.2 +/- 4.6, 29.9 +/- 5.8, 30.9 +/- 6.7 kg/m(2), p <0.001). The proportion of smokers decreased (84%, 76%, 74%, p <0.001). In-hospital mortality (1.0%, 0.8%, 0.9%, p = 0.93) and long-term mortality at 5 years (6%, 6%, 7%, p = 0.97) did not change over time. In contemporary PCI practice, women with premature CAD were more likely to have diabetes mellitus (25% vs 19%, p = 0.02), single-vessel disease (56% vs 41%, p <0.001), and a bleeding complication. In conclusion, there is an increasing burden of cardiovascular risk factors, related mostly to obesity, in patients with premature CAD requiring PCI. Long-term morbidity or mortality in these patients has not improved over the previous 3 decades. PMID- 21247540 TI - Sleep-disordered breathing in patients with the Brugada syndrome. AB - We investigated breathing patterns and the occurrence of arrhythmias and ST segment changes during sleep in patients with Brugada syndrome. Patients with Brugada syndrome are more likely to die from ventricular arrhythmias during sleep. ST-segment changes have been correlated with risk of sudden cardiac death. Whether sleep disturbances may contribute to arrhythmogenesis is unknown. Patients with Brugada syndrome underwent overnight polysomnography with simultaneous 12-lead electrocardiographic recording. A control group matched by age, gender, and body mass index (BMI) also underwent polysomnography. Twenty patients were included (50 +/- 15 years old, 75% men). Despite their normal BMI (24.7 +/- 2.7 kg/m(2)), 45% had sleep-disordered breathing (SDB), with a mean apnea-hypopnea index of 17.2 +/- 14 events/hour. In patients with a high risk of arrhythmias, 5 (63%) had SDB. In the control group, 27% had SDB. Atrial or ventricular arrhythmias were not observed. Spontaneous ST-segment changes occurred in 2 patients over 45 different time points. Most ST-segment changes were observed during rapid eye movement sleep (31%) or within 1 minute of arousals (44%). Regarding respiratory events, 25 (56%) of ST-segment changes were related to occurrence of apnea or hypopnea. In conclusion, patients with Brugada syndrome have a high prevalence of SDB even in the setting of normal BMI. The higher incidence of nocturnal death in patients with Brugada syndrome may be conceivably related to co-morbid SDB. Moreover, autonomic instability encountered in rapid eye movement sleep and arousals could potentiate the risk of arrhythmias. PMID- 21247542 TI - Usefulness of postexercise ankle-brachial index to predict all-cause mortality. AB - Peripheral arterial disease predicts future cardiovascular events and all-cause mortality. Conventional methods of assessment might underestimate its true prevalence. We sought to determine whether a postexercise ankle-brachial index (ABI), not only improved peripheral arterial disease detection, but also independently predicted death. This was an observational study of consecutive patients referred for ABI measurement before and after the fixed-grade treadmill or symptom-limited exercise component to a noninvasive vascular laboratory from January 1990 to December 2000. The subjects were classified into 2 groups. Group 1 included patients with an ABI of >=0.85 before and after exercise, and group 2 included patients with a normal ABI at rest but <0.85 after exercise. A total of 6,292 patients underwent ABI measurements with exercise during the study period. Propensity score matching of the groups was performed to minimize observational bias. Overall mortality, as determined using the United States Social Security death index, was the end point. The 10-year mortality rate of groups 1 and 2 was 32.7% and 41.2%, respectively. An abnormal postexercise ABI result independently predicted mortality (hazard ratio 1.3, 95% confidence interval 1.07 to 1.58, p = 0.008). Additional independent predictors of mortality were age, male gender, diabetes, and hypertension. After the exclusion of patients with a history of cardiovascular events, the predictive value of an abnormal postexercise ABI remained statistically significant (hazard ratio 1.67, 95% confidence interval 1.29 to 2.17, p <0.0001). In conclusion, our results have shown that the postexercise ABI is a powerful independent predictor of all-cause mortality and provides additional risk stratification beyond the ABI at rest. PMID- 21247543 TI - Relation of aortic valve weight to severity of aortic stenosis. AB - The purpose of this study was to analyze the relation of aortic valve weight to transvalvular gradient and area, with special regard to valve anatomy, size of calcific deposits, gender, and body size. Two hundred forty-two surgically excised stenotic aortic valves of patients (139 men, mean age 72 +/- 9 years) who had undergone preoperative cardiac catheterization and echocardiography were weighed and examined with respect to number of cusps (tricuspid vs bicuspid), size of calcium deposits (microaggregates vs nodular macroaggregates), and presence of cholesterol clefts. The relation among valve weight, gradient, and area was studied. Transvalvular gradient was independent of gender or valve anatomy and was linearly correlated with valve weight absolutely (r = 0.33, p <0.01) or normalized by body surface area (r = 0.40, p <0.01). No correlation was evident between valve area and weight. Calcium macroaggregates were mainly present in men (51%) and in bicuspid valves (67%) and were seen to be strong determinants of valve weight (2.84 +/- 1.03 g with macroaggregates vs 1.63 +/- 0.56 g with microaggregates, p <0.001) but not of transvalvular gradient. Calcium microaggregates characterized tricuspid valves (62%), where transvalvular gradient was determined by valve weight (p = 0.0026). In conclusion, the heavier the valve, the less frequent were hypercholesterolemia, valve cholesterol clefts, hypertension, and diabetes mellitus. PMID- 21247544 TI - Prevalence of severe (500 to 2,000 mg/dl) hypertriglyceridemia in United States adults. AB - A growing amount of evidence has supported an association between elevated triglyceride levels and cardiovascular disease. However, little information regarding co-morbidities, levels of other cholesterol types, or medication use among adults with severe hypertriglyceridemia (SHTG; (500 to 2,000 mg/dl) is available. We examined the data from 5,680 subjects, >= 20 years old, who had participated in the National Health and Nutrition Examination Survey from 2001 and 2006, to evaluate the epidemiology of adults with SHTG. Approximately 1.7% of the sample had SHTG, equating to roughly 3.4 million Americans. The participants with SHTG tended to be men (75.3%), non-Hispanic whites (70.1%), and aged 40 to 59 years (58.5%). More than 14% of those with SHTG reported having diabetes mellitus, and 31.3% reported having hypertension. Only 14% of the subjects with SHTG reported using statins, and 4.0% reported using fibrates. The factors significantly associated with having SHTG included high-density lipoprotein <40 mg/dl (odds ratio [OR) 11.45, 95% confidence interval [CI] 6.28 to 20.86), non high-density lipoprotein 160 to 189 mg/dl (OR 9.74, 95% CI 1.68 to 56.40) or non high-density lipoprotein >= 190 mg/dl (OR 24.99, 95% CI 3.90 to 160.31), diabetes mellitus (OR 3.04, 95% CI 1.45 to 6.37), and chronic renal disease (OR 7.32, 95% CI 1.45 to 36.94). In conclusion, SHTG is rare among adults in the United States and the use of pharmacologic intervention is low among those with SHTG. PMID- 21247545 TI - Comparison of angiographic findings in patients with acute anteroseptal versus anterior wall ST-elevation myocardial infarction. AB - Anteroseptal ST elevation myocardial infarction (AS-STEMI), in which ST elevation is limited to leads V(1) to V(3), is considered confined to the basal and mid anterior and septal segments, sparing the apex. In contrast, extensive anterior STEMI (EA-STEMI), in which ST elevation extends to leads V(4) to V(6), is considered to involve more apical segments. However, it has been reported that AS STEMI affects mainly the apex. Others have suggested that AS-STEMI may occur in patients with extensive anterior involvement if proximal occlusion of a wrapping left anterior descending coronary artery (LAD) results in cancelation of the basal-anterior and apical injury vectors. Therefore, the aim of this study was to identify, in 97 consecutive patients with STEMI, distinct coronary angiographic characteristics that could differentiate between cases of AS-STEMI (n = 39) and EA-STEMI (n = 58). Angiography was used to determine the length of the LAD, its site of occlusion, and whether there was an alternative blood supply to the apex. Patients with AS-STEMI were more likely than those with EA-STEMI to have >=1 branches that reached the apex (p = 0.0015) and to have proximal LAD occlusion combined with either a short LAD or >1 large side branch (35.9% vs 12.1%, p = 0.011). However, patients with AS-STEMI were also more likely to have proximal occlusion before the first septal branch of a long LAD (35.9% vs 10.3%, p = 0.005). In conclusion, AS-STEMI can occur when only the basal and mid portions of the anterior wall are infarcted, but it can also arise when the infarction extensively involves the basal anterior and the distal inferior and apical segments. PMID- 21247546 TI - Comparison of peripheral endothelial function in shift versus nonshift workers. AB - Shift working is related to increased cardiovascular morbidity. Peripheral endothelial dysfunction, an inherent feature of early atherosclerosis, has been suggested as a surrogate marker of cardiovascular risk. Whether shift working is associated with peripheral endothelial dysfunction has not been investigated to date. A total of 48 male shift workers (SWs) and 47 male nonshift workers (NSWs) (mean age 43 +/- 5 years) were recruited from a glass manufactory. The SWs and NSWs were matched according to age, body mass index, smoking habits, family history of premature coronary artery disease, prevalence of hypercholesterolemia and hypertension, and work place. Their sport habits were also documented. Peripheral endothelial function was assessed using the EndoPAT technique to determine the peripheral arterial tone (PAT) index. According to the study design, no difference was found in the risk factor profiles between the SWs and NSWs. Despite a greater percentage of regular physical activity among the SWs (16.7 vs 4.3%, p = 0.05), shift working was associated with a reduced PAT index compared to working only on the day shift (PAT index 1.73 +/- 0.4 vs 1.94 +/- 0.5, p = 0.03). In the NSW group, the participants with regular physical training (n = 16) had a greater PAT index than those without regular physical activity (n = 12; PAT index 2.28 +/- 0.45 vs 1.86 +/- 0.51, p = 0.03). No such difference was found in the SWs. In conclusion, SWs had a reduced PAT index compared with NSWs, suggesting endothelial dysfunction. Therefore, the known increased cardiovascular risk in those shift working might be related to endothelial dysfunction. PMID- 21247547 TI - Disappearance of angina pectoris by lipid-lowering in type III hyperlipoproteinemia. AB - Type III hyperlipoproteinemia is a rare familial disease characterized by marked elevations of serum cholesterol and triglyceride levels caused by an accumulation of remnant lipoproteins in apolipoprotein E2/E2 homozygotes. It is associated with an increased risk for premature atherosclerotic vascular disease. A 55-year old woman was diagnosed as having type III hyperlipoproteinemia on the basis of skin lesions, serum lipid levels, lipid electrophoresis, and apolipoprotein E genotyping and stable angina pectoris on the basis of typical symptoms and treadmill exercise electrocardiographic results. After 1 year of combination therapy with atorvastatin and fenofibrate, skin xanthomata disappeared, leaving minimal remnants. In addition, there was no exertional chest pain, and treadmill exercise electrocardiographic results were negative. This finding was confirmed by coronary computed tomographic angiography. This case suggests that proper medical therapy can induce the regression of uncomplicated coronary lesions in type III hyperlipoproteinemia. PMID- 21247548 TI - Subclinical and clinical correlates of left ventricular wall motion abnormalities in the community. AB - The prevalence and clinical correlates of left ventricular (LV) wall motion abnormalities (WMAs), associated with morbidity and mortality, have not been well characterized in the population. Framingham Heart Study Offspring Cohort participants (n = 1,794, 844 men, age 65 +/- 9 years) underwent cine cardiovascular magnetic resonance for evaluation of LV function. A subset (n = 1,009, 460 men) underwent cardiac multidetector computed tomography for analysis of coronary artery calcium. The presence of coronary heart disease and heart failure (CHD-HF) were assessed in relation to the presence of WMAs. WMAs were present in 117 participants (6.5%) and were associated with male gender, elevated hemoglobin A1c, LV mass, LV end-diastolic volume, and lower LV ejection fraction. Of the 1,637 participants without CHD-HF, 68 (4.2%) had WMAs. In this group, WMAs were associated with obesity, hypertension, and Framingham coronary heart disease risk score in the age- and gender-adjusted analyses and were associated with male gender and hypertension on multivariate analysis. Most subjects with WMAs were in the greatest coronary artery calcium groups. The presence of coronary artery calcium greater than the seventy-fifth percentile and Agatston score >100 were associated with a greater than twofold risk of WMAs in the age- and gender adjusted analysis but were no longer significant when additionally adjusted for CHD-HF. Previous Q-wave myocardial infarction was present in 29% of the 117 participants with WMAs. In conclusion, in the present longitudinally followed free-living population, 4.2% of the participants without CHD-HF had WMAs. WMAs were associated with the clinical parameters associated with cardiovascular disease risk. Aggressive risk factor modification may be prudent for subjects with WMAs, particularly those free of clinical CHD-HF. PMID- 21247549 TI - A Grimm situation. The patient, young and pregnant, had upper abdominal pain and a moveable mass. PMID- 21247550 TI - The risk of large for gestational age across increasing categories of pregnancy glycemia. AB - OBJECTIVE: We sought to estimate the risk of large for gestational age (LGA) across categories of glucose tolerance. STUDY DESIGN: In a cohort of 89,141 participants, women without gestational diabetes mellitus (GDM) were categorized by their screening and diagnostic test results; those with GDM were categorized as meeting the National Diabetes Data Group or only the American Diabetes Association (ADA) criteria. Multivariable logistic regression models estimated the risk of LGA; screening values 5.5-6.0 mmol/L comprised the referent. RESULTS: In women without GDM, the odds ratio for LGA was 1.89 (95% confidence interval [CI], 1.45-2.45) for fasting, 1.57 (95% CI, 1.31-1.89) for 1-hour, 1.60 (95% CI, 1.33-1.93) for 2-hour, and 1.62 (95% CI, 1.23-2.14) for 3-hour values meeting the ADA time point-specific thresholds. CONCLUSION: For GDM identified in a 2-step procedure, our findings support the use of isolated abnormal fasting values according to the ADA threshold in identifying women who could benefit from treatment. PMID- 21247551 TI - Evaluation of a screening tool for bleeding disorders in a US multisite cohort of women with menorrhagia. AB - OBJECTIVE: The purpose of this study was to determine the usefulness of a simple screening tool for bleeding disorders in a multisite population of women with menorrhagia. STUDY DESIGN: Women with menorrhagia between the ages of 18 and 50 years from 6 geographically diverse US centers underwent hemostatic testing for bleeding disorders, complete blood cell count, and ferritin. A questionnaire that contained all elements of the 8-question screening tool was administered. Sensitivity of the screening tool, a screening tool with a pictorial blood assessment chart (PBAC) score of >185, and a screening tool with serum ferritin were calculated for hemostatic disorders. RESULTS: Two hundred and seventeen women who were identified with a PBAC score of >=100 participated in the study. The sensitivity of the screening tool was 89% for hemostatic defects, and sensitivity increased to 93% and 95% with a serum ferritin level of <=20 ng/mL and a PBAC score of >185, respectively. CONCLUSION: This study confirms the usefulness of a short screening tool for the stratification of women with menorrhagia for hemostatic evaluation. PMID- 21247552 TI - Comparison of the prognostic significance of uterine factors and nodal status for endometrial cancer. AB - OBJECTIVE: We examined the prognostic significance of uterine risk factors (RF) compared to nodal metastases in endometrial cancer. STUDY DESIGN: Women with stage I-IIIC endometrioid cancer were stratified based on the presence of positive or negative lymph nodes. Each patient was characterized by the number of RF present: myoinvasion >=50%, cervical stromal involvement, and grade 3 histology. RESULTS: A total of 26,967 women were identified. In a multivariable model, uterine RF strongly influenced survival but nodal disease was a more important negative prognostic factor. Five-year overall survival was 68% (95% confidence interval [CI], 63-72%) for group 1 (node positive/no RF) vs 69% (95% CI, 66-72%) for group 5 (node negative/multiple RF). Five-year survival was lower for node-positive patients with RF (58%; 95% CI, 54-61%) than node-positive patients without RF (68%; 95% CI, 63-72%). CONCLUSION: Uterine RF strongly influenced survival both in the presence and absence of nodal metastasis. PMID- 21247553 TI - Passive smoke exposure and abnormal cervical cytology in a predominantly Hispanic population. AB - OBJECTIVE: We sought to evaluate the association between passive cigarette smoke exposure and cervical cytological abnormalities in a predominantly Hispanic sample. STUDY DESIGN: Data were collected as part of a larger, ongoing randomized clinical trial. Inclusion criteria were met by 4403 Hispanic (73%) and non Hispanic (27%) women between 18-55 years of age (mean = 30.14 +/- 8.7). Analysis of variance and multivariate logistic regression determined the association between passive smoke exposure and Pap abnormality. RESULTS: Passive smoke exposure was positively associated with having an abnormal Pap smear (odds ratio, 1.70; 95% confidence interval, 1.14-2.52) as was current active smoking (odds ratio 1.45; 95% confidence interval, 1.03-2.04). Neither effect was modified by ethnicity. Increasing hours per week of passive smoke exposure was associated with low-grade squamous intraepithelial lesion (P < .05). CONCLUSION: Passive smoke exposure is an important independent risk factor for cytological abnormalities in Hispanic and non-Hispanic women. This study adds to the growing body of evidence of the dangers of passive smoke exposure. PMID- 21247554 TI - Bilateral asymmetry of tooth formation is elevated in children with simple hypodontia. AB - OBJECTIVE: Tooth formation normally progresses symmetrically between sides; the goal in this study was to test the clinical impression that left-right asymmetry in tooth formation is elevated in children with simple hypodontia. MATERIALS AND METHODS: Data from panoramic X-rays of American white children (5-14 years of age) with simple hypodontia (n=158) were compared to a comparable group from the same practises with all teeth present (n=206). Children with hypodontia were otherwise phenotypically normal, with no cleft or recognized syndrome. Crown-root formation of each tooth (ignoring third molars) was scored using an 11-grade scheme. Analysis relied on chi-square goodness-of-fit tests and odds ratios. RESULTS: Hypodontia typically occurs unilaterally; it is more common in girls than boys; and it most frequently affects second premolars (omitting third molars). No evidence of a side preference was found as regards absence of the tooth or tooth formation. Tooth formation was decidedly more frequently asymmetric in those with hypodontia, though again the distribution by side was random in the sample. Summed over all tooth types, asymmetric formation occurred in 18.6% of cases with hypodontia compared to 11.9% in controls, and this is significant by chi-square (P=0.03), with an odds ratio of 1.43 (CL: 1.02, 2.04). All tooth types exhibit elevated developmental asymmetry in the hypodontic sample despite only one or a few teeth being agenic. CONCLUSIONS: Increased asymmetry suggests a breakdown in the rigour of developmental timing in cases with simple hypodontia. In concert with increased frequencies of other growth issues in such cases, such as side differences in size and morphology, hypodontia is best viewed as a symptom of an anatomically broad relaxation of developmental canalization between homologous structures, not an isolated dental feature. PMID- 21247555 TI - Presence of wax esters and squalene in human saliva. AB - OBJECTIVE: The purpose of this study was to determine the presence and relative composition of neutral lipids in human saliva. DESIGN: Whole unstimulated saliva was collected from 12 subjects ranging from 21 to 29 years old. Samples were lyophilized, and lipids were extracted using chloroform-methanol. Lipids were analysed by thin-layer chromatography. RESULTS: Human saliva contains cholesterol, fatty acids, triglycerides, wax esters, cholesterol esters and squalene. The mean total neutral lipid content was 12.1+/-6.3 MUg/ml. CONCLUSIONS: These lipids in human saliva closely resemble the lipids found on the skin surface. These salivary lipids are most likely produced by the sebaceous follicles in the oral mucosa and sebaceous glands associated with major salivary glands. PMID- 21247556 TI - Developmental trajectories of the corpus callosum in attention deficit/hyperactivity disorder. AB - BACKGROUND: It was recently found that the development of typical patterns of prefrontal, but not posterior, cortical asymmetry is disrupted in right-handed youth with attention-deficit/hyperactivity disorder (ADHD). Using longitudinal data, we tested the hypothesis that there would be a congruent disruption in the growth of the anterior corpus callosum, which contains white matter tracts connecting prefrontal cortical regions. METHODS: Areas of five subregions of the corpus callosum were quantified using a semiautomated method from 828 neuroanatomic magnetic resonance scans acquired from 236 children and adolescents with ADHD (429 scans) and 230 typically developing youth (399 scans), most of whom had repeated neuroimaging. Growth rates of each diagnostic group were defined using mixed-model linear regression. RESULTS: Right-handed participants with ADHD showed a significantly higher rate of growth in the anterior-most region of the corpus callosum (estimated annual increase in area of .97%, SEM .12%) than their typically developing peers (annual increase in area of .32% SEM .13%; t = 3.64, p = .0003). No significant diagnostic differences in growth rates were found in any other regions in right-handed participants, and no significant diagnostic differences were found in non-right-handed participants. CONCLUSIONS: As hypothesized, we found anomalous growth trajectories in the anterior corpus callosum in ADHD. This disrupted anterior callosal growth may reflect, or even drive, the previously reported disruption in the development of prefrontal cortex asymmetry. The finding documents the dynamic, age-dependent nature of callosal and congruent prefrontal cortical abnormalities characterizing ADHD. PMID- 21247557 TI - The effect of motion content in action naming by Parkinson's disease patients. AB - INTRODUCTION: The verb-specific impairment present in patients with motion related neurological diseases has been argued to support the hypothesis that the processing of words referring to motion depends on neural activity in regions involved in motor planning and execution. We presented a group of Parkinson's disease (PD) patients with an action-naming task in order to test whether the prevalence of motion-related semantic content in different verbs influences their accuracy. METHODS: Forty-nine PD patients and 19 healthy seniors participated in the study. All of PD participants underwent a neurological and neuropsychological assessment to rule out dementia. Subjective ratings of the motion content level of 100 verbs were obtained from 14 young voluntaries. Then, pictures corresponding to two subsets of 25 verbs with significantly different degrees of motor component were selected to be used in an action-naming task. Stimuli lists were matched on visual and psycholinguistic characteristics. RESULTS: ANOVA analysis reveals differences between groups. PD patients obtained poor results in response to pictures with high motor content compared to those with low motor association. Nevertheless, this effect did not appear on the control group. The general linear mixed model analytic approach was applied to explore the influence of the degree of motion-related semantic content of each verb in the accuracy scores of the participants. The performance of PD patients appeared to be negatively affected by the level of motion-related semantic content associated to each verb. CONCLUSIONS: Our results provide compelling evidence of the relevance of brain areas related to planning and execution of movements in the retrieval of motion-related semantic content. PMID- 21247558 TI - Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis. AB - OBJECTIVE: To quantify the magnitude and pattern of low-density lipoprotein (LDL) cholesterol and nonhigh-density lipoprotein (HDL) cholesterol levels in women with polycystic ovary syndrome (PCOS) versus control women. DESIGN: Systematic review and meta-analysis of lipid levels in published cross-sectional studies worldwide where PCOS women and controls were examined and sampled. MAIN OUTCOME MEASURE(S): Differences in plasma lipids (including triglycerides, HDL cholesterol, LDL-cholesterol, and nonHDL-cholesterol) in PCOS versus control subjects were calculated. Comparisons were made with and without body mass index (BMI) matching. RESULT(S): Triglyceride levels were 26 mg/dL (95% confidence interval [CI] 17-35) higher and HDL-cholesterol concentrations 6 mg/dL (95% CI 4 9) lower in women with PCOS. Also, LDL-cholesterol and nonHDL-cholesterol concentrations were higher in PCOS: by 12 mg/dL (95% CI 10-16) and 19 mg/dL (95% CI 16-22), respectively. With BMI matching, LDL-cholesterol and nonHDL cholesterol were still higher in PCOS: by 9 mg/dL (95% CI 6-12) and 16 mg/dL (95% CI 14-19), respectively. LDL-cholesterol and nonHDL-cholesterol differences were greater with National Institutes of Health criteria [15 mg/dL (95% CI 13-17) and 21 mg/dL (95% CI 16-25), respectively] versus Rotterdam criteria [8 mg/dL (95% CI 5-12) and 17 (95% CI 13-22), respectively]. CONCLUSION(S): Dyslipidemia is common in PCOS. Beyond known alterations in triglycerides and HDL-cholesterol, women with PCOS have higher LDL-cholesterol and nonHDL-cholesterol, regardless of BMI. We recommend that all women with PCOS be screened for dyslipidemia, including LDL cholesterol and nonHDL-cholesterol determinations, for effective cardiovascular risk prevention. PMID- 21247559 TI - Haemorrhage control in pelvic fractures--a survey of surgical capabilities. AB - BACKGROUND: In the emergency management of patients with pelvic fractures, there is ongoing debate about the roles of angiography and open pelvic packing. It is agreed that some form of haemorrhage control is required for patients who are haemo-dynamically unstable despite resuscitation. We set out to determine whether on-call general and orthopaedic surgeons would feel able to perform emergency surgical procedures for these patients and whether vascular radiology was available to them. METHODS: Surveys were sent to all 221 general and orthopaedic surgeons in Wales. Questions included: sub-speciality interest, geographical region, whether there is a pelvic binder in their hospital, availability of interventional radiology, and whether surgeons would perform a range of procedures to control haemorrhage in the emergency setting. RESULTS: There were 141 responses to the survey, giving a 64% response rate. Only 18% reported that their unit had a formal rota for interventional radiology out of hours. 16% did not know. 96% of orthopaedic surgeons would perform external fixation, although only 49% would use a C-clamp. 90% of general surgeons would be able to pack the pelvis from within the abdominal compartment and 84% would be prepared to cross clamp the aorta if the situation required. Despite being widely recommended in the literature as a method of haemorrhage control, our survey revealed only 45% would perform extra(pre)-peritoneal packing of the pelvis (58% of general surgeons; 34% of orthopaedic surgeons) and only 12% had received formal training in this procedure. CONCLUSIONS: With appropriately targeted training it is likely that the care of patients with pelvic fractures can be significantly improved. PMID- 21247560 TI - Knowledge of HPV infection and Pap testing among young women in Serbia. PMID- 21247561 TI - A comparative study of female sterilization via modified Uchida and silver clip techniques in rural China. AB - OBJECTIVE: To compare the specific effects of 2 female sterilization methods: the modified Uchida technique and the application of silver clips. METHODS: A total of 2198 women living in rural areas who were still of reproductive age but opting for sterilization were enrolled. The participants were randomly divided into 2 groups, and underwent sterilization by either modified Uchida technique or silver clips. Information on acceptability, operation conditions, effectiveness, adverse effects, and complaints was collected 3, 6, and 12 months after the procedure. RESULTS: No significant difference in effectiveness, adverse effects or chief complaints between the 2 procedures was found. Differences in operative outcome, bleeding volume during the procedure, and operation time were found. CONCLUSION: A shorter operation time and less bleeding for the silver clip method indicated that female sterilization by this technique was as safe as that by modified Uchida technique. PMID- 21247562 TI - A 10-year experience of laparoscopic surgery for adnexal masses during pregnancy. AB - OBJECTIVE: To assess the clinicopathologic outcomes of laparoscopic surgery for adnexal masses during pregnancy. METHODS: In a retrospective study, the medical records of 88 patients who underwent laparoscopic surgery for adnexal masses during pregnancy between 2000 and 2009 were reviewed. RESULTS: The mean age of the study population was 30.1 years (range 21-40 years), and the mean gestational age at surgery was 11.6 weeks (4.6-23.6 weeks). The mean diameter of the mass on sonography was 7.5 cm (1.8-18 cm). Pathologically, the most common tumor was a mature cystic teratoma (35.2%), and the prevalence of malignancy was 6.8%. Emergency surgery due to torsion was performed in 28 patients (31.8%). Two spontaneous abortions occurred, both after emergency surgery. The frequency of obstetric complications, such as low birth weight, preterm delivery, use of tocolytics for preterm labor, low Apgar score, and fetal anomaly, was acceptable. CONCLUSION: Laparoscopic surgery for adnexal masses during pregnancy provided tolerable outcomes for the fetus and the mother. In the future, larger prospective clinical trials are necessary to elucidate fully the impact on the fetus. PMID- 21247563 TI - Influence of employment status on menopausal symptoms. AB - OBJECTIVE: To evaluate the variation of climacteric symptoms among working and nonworking postmenopausal Turkish women. METHODS: This cross-sectional study enrolled a random sample of 132 women (66 employed, 66 not employed). Sociodemographic data were collected through a sociodemographic questionnaire. Menopause symptomatology was assessed using the Climacteric Complaint Tool. RESULTS: All women had a similar sociodemographic background. A significantly greater percentage of nonworking women suffered from hot flushes, difficulty in sleeping, headache, irritability, depressive mood, muscle and joint pain, and urinary problems. Multivariate logistic regression analysis showed that the employment status had a significant effect on the experience of climacteric symptoms even after adjustments for education status and income adequacy. CONCLUSIONS: The present study indicates that the employment status might contribute to significant variations in climacteric symptomatology. PMID- 21247564 TI - Intrauterine insemination in Jamaica as a low-cost subfertility treatment in a low-resource region. AB - OBJECTIVE: To determine the impact of intrauterine insemination on the management of subfertility in Jamaica. METHODS: The present study was a retrospective analysis of all intrauterine insemination cycles completed from May 1, 2002, to August 31, 2005, at the University of the West Indies, Mona, Jamaica. The cycle pregnancy rate (CPR), live-birth rate (LBR), and cumulative pregnancy rate were obtained and prognostic factors were reviewed. RESULTS: The CPR, LBR, and cumulative pregnancy rate were 10.1%, 8.8%, and 13.9%, respectively. Improved success was significantly associated with a shorter period of infertility (3.10 +/- 1.43 years vs 5.22 +/- 2.89 years; P = 0.01). Women younger than 40 years of age, men with increased post-preparation sperm counts, and couples undergoing 2-3 cycles had improved outcomes. CONCLUSION: Intrauterine insemination represents a safe and cost-effective option for mild male factor infertility or unexplained infertility, especially in resource-poor regions such as the Caribbean. Repeated failed cycles identify those who would probably benefit from early intervention with in vitro fertilization. PMID- 21247565 TI - Ethical dilemmas in women's health in under-resourced settings. AB - Ethical decision making in women's health presents a series of unique challenges that are exacerbated considerably in under-resourced settings. Severe constraints on both autonomy and resources highlight limitations of principle-based ethics for addressing ethical dilemmas. Other useful ethical "tools" are considered in the context of 2 cases that emphasize the challenges to ethical decision making in under-resourced settings. The cases confront traditional notions of patient autonomy, highlight pervasive issues with regard to allocation of resources, and demonstrate the difficulties encountered in the careful application of medical ethics. PMID- 21247566 TI - Polycystic ovary syndrome and increased polyp numbers as risk factors for malignant transformation of endometrial polyps in premenopausal women. AB - OBJECTIVE: To determine the pre-malignant and malignant potential of endometrial polyps and to assess whether different clinical parameters are associated with malignancy in the polyps of premenopausal women. METHODS: The clinical records of operative office hysteroscopic and resectoscopic procedures for endometrial polyps in 417 premenopausal women who attended Baskent University were examined over a retrospective period of 30 months. Only premenopausal patients were included in the study. RESULTS: In 97.8% of women, histology showed benign endometrial pathology. In 2.2% of women, pre-malignant or malignant conditions were found in the polyp. Polycystic ovary syndrome (PCOS) and the presence of 2 or more polyps were associated with significant pre-malignant or malignant changes. CONCLUSION: The presence of irregular vaginal bleeding was not a predictor of malignancy in the polyp. Premenopausal women with PCOS and those with 2 or more polyps had an increased prevalence of polyp malignancy. These groups of patients, whether symptomatic or not, should be evaluated by hysteroscopic resection of the polyps. PMID- 21247567 TI - Magnetic resonance imaging findings among women with tubercular tubo-ovarian masses. AB - OBJECTIVE: To assess the usefulness of magnetic resonance imaging (MRI) in women with tubercular tubo-ovarian masses. METHODS: Twenty-four women with a confirmed diagnosis of tubercular tubo-ovarian masses underwent MRI. The findings were compared with laparotomy/laparoscopy results wherever possible. RESULTS: The mean age was 30.7 years and the mean parity was 1.5. The main symptom in 37.5% of patients was infertility. The MRI findings included unilateral definitive tubo ovarian masses (n=4 [16.7%]); bilateral definitive tubo-ovarian masses (n=4 [16.7%]); unilateral hydrosalpinx (n=8 [33.3%]); bilateral hydrosalpinx (n=4 [16.7%]); unilateral adnexal cyst (n=4 [16.7%]), tuberculous deposits on the liver (n=1 [4.2%]); and cervical growth (n=1 [4.2%]). Other associated findings were endometriosis (n=2 [8.3%]), inclusion cyst (n=1 [4.2%]), subserous fibroid (n=1 [4.2%]), sacroiliac joint arthritis (n=1 [4.2%]), and enteritis (n=1 [4.2%]). CONCLUSION: MRI seems to be a useful modality for the diagnosis of tubercular tubo-ovarian masses. PMID- 21247568 TI - High prevalence of vitamin D deficiency in Pakistani mothers and their newborns. AB - OBJECTIVE: To determine the prevalence of vitamin D deficiency in Pakistani parturients and their newborns and to assess the correlation between maternal and newborn serum levels of the vitamin D metabolite 25-hydroxy vitamin D3. METHODS: A prospective study of parturients presenting to the labor suite with a singleton pregnancy. Maternal and cord blood were collected for estimation of serum 25 hydroxy vitamin D3. RESULTS: In total, 89% of the gravidae were deficient in vitamin D (serum 25-hydroxy vitamin D3 <30 ng/mL). There was a positive correlation between maternal and cord blood 25-hydroxy vitamin D3 levels(r = 0.68; P < 0.001). Inverse correlations were noted between cord blood 25-hydroxy vitamin D3 and a longer duration of gestation (r = -0.33; P = 0.003) and with the newborn's birth weight (r = -0.23; P = 0.048). Maternal 25-hydroxy vitamin D3 levels were inversely correlated with maternal mean arterial pressure (r = 0.029; P < 0.020). CONCLUSION: There was a high prevalence of vitamin D deficiency in the Pakistani parturients and their newborns. There was a correlation between higher maternal vitamin D levels and lower blood pressure in the mothers. PMID- 21247569 TI - Low-cost simulation models for teaching episiotomy/laceration repair and venous cutdown. PMID- 21247570 TI - Emergency contraception in the context of marriage in Upper Egypt. AB - OBJECTIVE: To explore the degree of knowledge, perception, and practice of emergency contraception (EC) within marital relations in Egypt. METHODS: The present study was a pilot cross-sectional survey. Eligible participants were randomly selected from 4 governorates in Upper Egypt. A questionnaire was designed by the investigators and administered to an unselected sample of healthcare providers and potential users of EC. The questionnaire collected information in 4 domains: demographics; knowledge about EC; attitudes toward EC; and practice of EC in Egypt. RESULTS: In total, 240 healthcare providers and 60 potential users of EC completed the questionnaire. Approximately 85% of healthcare providers and 30% of potential users had heard about EC. A similar proportion of study participants said that EC methods are needed. Only 32.7% of healthcare providers and very few potential users had actually used EC. CONCLUSION: There is a need for EC in Egypt. However, a big gap in knowledge leads to nonuse or incorrect use of EC and negative attitude toward it. If health service planners and policy makers could fill this gap, a considerable decline in the prevalence of unwanted pregnancy may be achieved by using EC. PMID- 21247571 TI - Evaluation of the incision angle of mediolateral episiotomy at 60 degrees. AB - OBJECTIVE: To study the angle of mediolateral episiotomy at the time of cut, after primary repair, and 6 months postpartum; and the incidence and severity of perineal pain and anal incontinence 6 months after delivery. METHODS: The study group comprised 60 consecutively recruited primiparous women who required episiotomy during delivery assisted by 2 obstetricians. The incision angle of episiotomy (defined as 60 degrees ) was measured before cutting, after primary repair, and after 6 months. At follow-up, perineal pain was evaluated by a verbal rating score; anal incontinence was assessed by St Mark's score. RESULTS: The angles differed significantly among the incision (60 degrees ), repair (45 degrees ), and 6-month (48 degrees ) measurements (P < 0.001). There was a poor correlation between the suture angle and the angle measured at 6 months postpartum. No severe perineal tear was diagnosed in the cohort. At 6 months postpartum, only 1 woman reported mild symptoms of de novo anal incontinence, whereas 7 women reported perineal pain related to episiotomy. CONCLUSION: An incision angle of mediolateral episiotomy of 60 degrees resulted in a low incidence of anal sphincter tearing, anal incontinence and perineal pain. A randomized controlled trial is needed to assess the outcome when different angles of episiotomy are used. PMID- 21247572 TI - Pregnancy outcome in patients treated with cervical conization for cervical intraepithelial neoplasia. AB - OBJECTIVE: To examine the causal contribution of conization to premature delivery. METHODS: This was a retrospective, case-control, multicenter study of women who underwent conization in 5 hospitals in the Basque Country (Spain) from 1998 to 2007. Three study groups were established: group A, post-conization infant deliveries; control group B, pre-conization infant deliveries; and control group C, infant deliveries without conization. RESULTS: Comparing group A with group C, there was a higher rate of preterm delivery before 35 weeks (5.3% versus 1.6%), a lower mean birth weight (3156.2g versus 3328.5 g), and a greater prevalence of infants under 2500 g (10.6% versus 3.7%). There were no significant differences between group A and group B: preterm delivery before 35 weeks (5.3% versus 4.8%), mean birth weight (3156.2g versus 3119.4 g), and prevalence of infants under 2500 g (10.6% versus 10.6%). CONCLUSION: Pregnancy in women post conization was associated with a risk of preterm delivery. However, there were no significant differences between women who underwent conization before and those who underwent conization after delivery. Cervical conization does not necessarily increase the risk of preterm delivery in subsequent pregnancy. Conization should be considered an indicator of such risk because it is associated with pregnancy complications arising from socio-epidemiologic factors present in women requiring conization that are also present in women who have premature delivery. PMID- 21247573 TI - Randomized study of vaginal and neonatal cleansing with 1% chlorhexidine. AB - OBJECTIVE: To determine the safety, acceptability, and antimicrobial effect of 1% chlorhexidine (CHX) vaginal washing of women in labor and their neonates. METHODS: Randomized controlled trial of 1% CHX vaginal and neonatal washing compared with no washing (usual care [UC]). The study included 502 women (334 CHX, 168 UC) who delivered 508 liveborn neonates (335 CHX, 173 UC). Main outcome measures were the incidence of maternal adverse effects, the incidence of neonatal skin rash, the axillary temparature before and after neonatal wiping, and vaginal culture results. RESULTS: Maternal demographics did not differ between the groups. No case of maternal rash occurred; 4% of women experienced vaginal burning. An axillary temperature drop of more than 1 degrees C after CHX cleansing occurred in 8 neonates; 2 neonates had a minor rash. In the subset of women with positive vaginal cultures as baseline, 1% CHX eliminated culture growth in 56% after 1 wash, and in 86% after 2 washes. CONCLUSIONS: Use of 1% CHX is safe for neonates, well tolerated by laboring mothers, and effective in treating vaginal infections during labor. A randomized controlled trial using 1% CHX and powered for a reduction in neonatal septic mortality is justified based on these data. PMID- 21247574 TI - Congenital fetal lymphangioma causing shoulder dystocia and uterine rupture. PMID- 21247575 TI - Pregnancy outcome in cases of intrahepatic cholestasis of pregnancy. PMID- 21247576 TI - Uptake of the H1N1 vaccine by maternity staff at a university hospital in the UK. PMID- 21247577 TI - Self-rated coping styles and registered sickness absence among nurses working in hospital care: a prospective 1-year cohort study. AB - BACKGROUND: Sickness absence is an important problem in healthcare that affects the quality of care. Sickness absence has been related to coping strategies. Problem-focused coping was shown to be associated with low sickness absence and emotion-focused coping with high sickness absence among postal workers. OBJECTIVES: This study investigated the relationship between coping styles and sickness absence in healthcare. DESIGN: Prospective study linking self-rated coping styles at baseline with the number of episodes of sickness absence during one year of follow-up. SETTING: Somatic hospital employing 1,153 persons. PARTICIPANTS: Convenience sample of 566 female nurses working in the hospital's clinical wards and outpatient clinic. Of these, 386 (68%) nurses had complete data for analysis. METHODS: The nurses completed a questionnaire at baseline with items on health, work, and coping styles. Three styles of coping were defined: problem-solving coping (i.e., looking for opportunities to solve a problem), social coping (i.e., seeking social support in solving a problem), and palliative avoidant coping (i.e., seeking distraction and avoiding problems). Sickness absence data were retrieved from the hospital's register in the following year. The association between the coping styles and the number of both short (1-7 days) and long (>7 days) episodes of sickness absence was assessed by Poisson regression analyses with age, work hours per week, general health, mental health, and effort-reward [ER] ratio as covariates. RESULTS: Problem-solving coping was negatively associated with the number of long episodes of sickness absence (rate ratio [RR] = 0.78, 95% confidence interval [CI] = 0.64-0.95). Social coping was negatively associated with the number of both short episodes (RR = 0.88, 95% CI = 0.79-0.97) and long episodes (RR = 0.79, 95% CI = 0.64-0.97) of sickness absence. After adjustment for the ER-ratio, the associations of coping with short episodes of sickness absence strengthened and associations with long episodes weakened, however, significance was lost for both types of sickness absence. Palliative avoidant coping was not associated with sickness absence among female hospital nurses. CONCLUSION: Problem-solving coping and social coping styles were associated with less sickness absence among female nurses working in hospital care. Nurse managers may use this knowledge and reduce sickness absence and understaffing by stimulating problem-solving strategies and social support within nursing teams. PMID- 21247578 TI - The impact of type of manual medication cart filling method on the frequency of medication administration errors: a prospective before and after study. AB - BACKGROUND: The medication cart can be filled using an automated system or a manual method and when using a manual method the medication can be arranged either by round time or by medication name. For the manual methods, it is hypothesized that the latter method would result in a lower frequency of medication administration errors because nurses are forced to read the medication labels, but evidence for this hypothesis is lacking. OBJECTIVES: The aim of this study was to compare the frequency of medication administration errors of two different manual medication cart filling methods, namely arranging medication by round time or by medication name. DESIGN: A prospective, observational study with a before-after design. PARTICIPANTS AND SETTINGS: Eighty-six patients who stayed on an orthopaedic ward in one university medical centre in the Netherlands were included. METHODS: Disguised observation was used to detect medication administration errors. The medication cart filling method in usual care was to fill the cart with medication arranged by round time. The intervention was the implementation of the second medication cart filling method, where the medication cart was filled by arranging medicines by their names. The primary outcome was the frequency of medication administrations with one or more error(s) after the intervention compared with before the intervention. The secondary outcome was the frequency of subtypes of medication administration errors. RESULTS: After the intervention 170 of 740 (23.0%) medication administrations with one or more medication administration error(s) were observed compared to 114 of 589 (19.4%) before the intervention (odds ratio 1.24 [95% confidence interval 0.95-1.62]). The distribution of subtypes of medication administration errors before and after the intervention was statistically significantly different (p<0.001). Analysis of subtypes revealed more omissions and wrong time errors after the intervention than before the intervention. Unauthorized medication errors were detected more frequently before the intervention than after the intervention. CONCLUSION: The frequency of medication administration errors with the medication cart filling method where the medication is arranged by name was not statistically significantly different compared to the medication cart filling method where the medication is arranged by round time. PMID- 21247579 TI - Macrophages exposed to hypoxia secrete proteoglycans for which LDL has higher affinity. AB - Macrophages are prominent in hypoxic areas of atherosclerotic lesions. Their secreted proteoglycans (PG) can modulate the retention of lipoproteins as well as the activity of enzymes, cytokines, and growth factors involved in atherogenesis. Versican appears to be one of the main extracellular matrix components binding LDL in the arterial intima. We have recently shown that hypoxia increases versican and perlecan expression in macrophages, and that this increase was regulated by the hypoxia inducible factor (HIF). Here we report effects of hypoxia on human monocyte-derived macrophage (HMDM) secreted glycosaminoglycans (GAG), and its interaction with LDL. After 24 h exposure to 0.5% O2 (hypoxia), metabolically labeled GAG of secreted PG had higher affinity for LDL compared to 21% O2 (control cells). GAG secreted by HMDM in hypoxia were found to be more sulfated and longer which might be responsible for the increased affinity of LDL for these GAG chains. These results indicate that hypoxia induced changes in macrophage GAG biosynthesis have important consequences for the interaction with LDL. If present in vivo, an augmented association of GAG with LDL might contribute to the development of atherosclerosis in hypoxic intima. PMID- 21247580 TI - Characterization of silver nanoparticles using flow-field flow fractionation interfaced to inductively coupled plasma mass spectrometry. AB - The ability to detect and identify the physiochemical form of contaminants in the environment is important for degradation, fate and transport, and toxicity studies. This is particularly true of nanomaterials that exist as discrete particles rather than dissolved or sorbed contaminant molecules in the environment. Nanoparticles will tend to agglomerate or dissolve, based on solution chemistry, which will drastically affect their environmental properties. The current study investigates the use of field flow fractionation (FFF) interfaced to inductively coupled plasma-mass spectrometry (ICP-MS) as a sensitive and selective method for detection and characterization of silver nanoparticles. Transmission electron microscopy (TEM) is used to verify the morphology and primary particle size and size distribution of precisely engineered silver nanoparticles. Subsequently, the hydrodynamic size measurements by FFF are compared to dynamic light scattering (DLS) to verify the accuracy of the size determination. Additionally, the sensitivity of the ICP-MS detector is demonstrated by fractionation of MUg/L concentrations of mixed silver nanoparticle standards. The technique has been applied to nanoparticle suspensions prior to use in toxicity studies, and post-exposure biological tissue analysis. Silver nanoparticles extracted from tissues of the sediment-dwelling, freshwater oligochaete Lumbriculus variegatus increased in size from approximately 31-46nm, indicating a significant change in the nanoparticle characteristics during exposure. PMID- 21247581 TI - Determination of chromatographic separation parameters of tryptophan enantiomers on a Chirosil-SCA chiral stationary phase by using the inverse method based on the initial guesses estimated from elution by characteristic point method. AB - An effective chiral stationary phase (CSP) for enantioseparation of amino acids was established previously by bonding (18-crown-6)-2, 3, 11, 12-tetracarboxylic acid to silica gel. This CSP has recently been commercialized under the name of Chirosil-SCA. As a first step for developing a Chirosil-SCA simulated moving bed chromatographic process for separation of tryptophan enantiomers, the adsorption isotherm and mass-transfer parameters of each tryptophan enantiomer on the Chirosil-SCA CSP were determined in this study while using only water as a mobile phase. For this task, inverse method (IM) was applied on the basis of the initial guesses estimated from elution by characteristic point (ECP) method, which was found to be more advantageous in the aspects of both accuracy and computational efficiency than the case of utilizing individually only IM or ECP method. The results revealed that the adsorption behavior of each tryptophan enantiomer on the Chirosil-SCA could be well described by the Langmuir-Freundlich isotherm. The model predictions based on the determined parameter values were in close agreement with the experimental chromatograms from a series of single-component or mixture pulse tests that were performed under various feed concentrations and flow rates. It was also found that the Langmuir-Freundlich isotherm parameters of each enantiomer were largely affected by temperature. Such a marked dependence of the parameters on temperature was investigated quantitatively. The results of such an investigation indicated that as the temperature decreases, the adsorption affinities of both enantiomers become higher and the heterogeneity of the Chirosil-SCA becomes more pronounced. PMID- 21247582 TI - Using the liquid nature of the stationary phase. VI. Theoretical study of multi dual mode countercurrent chromatography. AB - Countercurrent chromatography (CCC) is a separation technique using a biphasic liquid system and centrifugal forces to maintain a support-free liquid stationary phase. Either one of the two phases can be the liquid stationary phase. It is even possible to switch the phase role during the separation. The dual-mode method is revisited recalling its theoretical background. The multi-dual mode (MDM) CCC method was introduced to enhance the resolution power of a CCC column. The theoretical study of the MDM method is validated by modeling the separation of two solutes. The basic hypothesis is that the forward step (partial classical elution) is followed by a backward step that returns the less retained solute to the column head. The equations show that the most important parameter to maximize resolution is not the number of MDM steps but the total volume of liquid phases used to elute the solutes. The model is validated calculating correctly the peak position of previously published MDM experiments. PMID- 21247583 TI - A retrospective study of 586 tumours in Brazilian cattle. AB - Records from 6,706 necropsy examinations of cattle performed over a 45-year period were surveyed and 586 cases of neoplasia were identified. The organ system most frequently affected by neoplastic disease (n=139 cases) was the alimentary tract. This finding was attributed to a high incidence of squamous cell carcinoma of the upper alimentary tract associated with the chronic ingestion of bracken fern (Pteridium aquilinum). This carcinogenic plant was also associated with a relatively high incidence (n=35 cases) of urinary bladder tumours (enzootic haematuria). Tumours of the alimentary tract were followed, in decreasing order of frequency, by tumours of the skin and subcutis (n=129 cases), haemopoietic tissue (n=101 cases), the eye and periorbital tissues (n=88 cases), the urinary system (n=44 cases), the female reproductive system (n=21 cases), the endocrine system (n=16 cases), the liver and pancreas (n=12 cases), the nervous system (n=6 cases), the respiratory system (n=6 cases) and the mammary gland (n=1 case). The primary anatomical location of 16 tumours was undetermined. PMID- 21247584 TI - Post-mortem findings in Irish culled hounds. AB - Little is known of the common diseases of hunting dogs or of the reasons why they are culled. To address these questions, necropsy examinations were conducted on 52 hounds aged 1.5-12 years (mean 6.5 +/- 2.5 years) and culled from 10 Irish hunting kennels over a 3-year period. Progressive systemic disease was seen in six dogs only and encompassed individual cases of tuberculosis caused by Mycobacterium bovis, bronchioalveolar carcinoma with metastasis to regional lymph nodes, renal amyloidosis, suppurative pneumonia, extramedullary plasmacytoma in the atrial wall of the heart and foreign body-induced hepatitis with focal peritonitis. Single or multiple localized tumours were identified in five dogs and, apart from the aforementioned, included two cutaneous haemangiomas, a trichoepithelioma, a lipoma and a mammary ductal adenoma. Three dogs were culled for lameness; one of these dogs had torn musculature, another had cellulitis and the third had a healed fracture of the tibia and fibula. Chronic renal changes were present in 48% of the dogs and included focal proliferative, exudative or crescentic glomerulonephritis (33%) or low-grade interstitial inflammatory changes (50%). The most frequently diagnosed skin lesions reported in this study were mild healed decubitus ulcers (33%), scars (33%) and stereotypic dermatitis (13%). These findings indicate that hounds are likely to be culled for reasons other than the presence of disease in most cases. In addition, this survey highlights different disease patterns in hounds than are typically observed in pet dogs. PMID- 21247585 TI - Myoepithelial cell layer integrity in canine mammary carcinoma. AB - The aim of this study was to determine whether the myoepithelial (ME) cell marker calponin could be used to analyze the integrity of the ME cell layer as a means of identifying canine mammary carcinoma in situ. Tissue from 74 canine mammary lesions was evaluated (two dysplasia, eight benign tumours and 64 carcinomas including one carcinoma in situ). The 63 carcinomas included examples of histological grade 1 (n=32), grade 2 (n=23) and grade 3 (n=8). Expression of calponin was determined by immunohistochemistry. The percentage of proliferating cells surrounded by a single layer of calponin-positive cells formed the basis of classification as type I (>= 90%), type II (70-90%) and type III (<= 70%). Expression of Ki67 was used to determine the proliferation index (PI). The malignant tumours comprised of an approximately equal mixture of type I, II and III lesions. The two examples of dysplasia, the carcinoma in situ and two thirds of the benign tumours were classified as type I lesions. Some overlap in the level of calponin expression was observed between benign and malignant tumours. Positive correlations between the degree of calponin expression and the type of lesion (i.e. benign versus malignant; R=+0.3, P=0.08) and the histological grade of malignancy (R=+0.54, P=0.000001) were found. A negative correlation between the degree of calponin expression and PI (R=+0.027, P=0.016) was found. The ME cell marker calponin may be used as an aid in the identification of canine carcinoma in situ, but the study of the ME cell layer integrity is not definitive for the diagnosis of malignancy in canine mammary tumours. PMID- 21247586 TI - Immunohistochemical distribution of laminin-332 and collagen type IV in the basement membrane of normal horses and horses with induced laminitis. AB - The basement membrane (BM) is a thin layer of extracellular matrix that regulates cell functions as well as providing support to tissues of the body. Primary components of the BM of epithelial tissues are laminin-332 (Ln-332) and collagen type IV. Equine laminitis is a disease characterized by destruction and dislocation of the hoof lamellar BM. Immunohistochemistry was used to characterize the distribution of Ln-332 and collagen type IV in the organs of normal horses and these proteins were found to be widespread. Analysis of a panel of tissue samples from horses with experimentally-induced laminitis revealed that Ln-332 and collagen type IV degradation occurs in the skin and stomach in addition to the hoof lamellae. These findings suggest that BM degradation is common to many epithelial tissues during equine laminitis and suggests a role for systemic trigger factors in this disease. PMID- 21247587 TI - Gastritis in Alaskan racing sled dogs. AB - Alaskan racing sled dogs are a well-established model of exercise-induced gastric disease. The aim of this study was to define the temporal development of microscopical gastric lesions during long distance racing. Two groups of dogs were examined: group I comprised conditioned dogs that were exercising and group II were conditioned dogs not exercising. The gastric mucosa was examined endoscopically and sampled for routine histopathology and microscopical scoring, immunohistochemistry (IHC) and detection of apoptotic epithelial cells. Overall, group I dogs exhibited more significant epithelial lesions, including ulcers, compared with dogs in group II. Group II dogs exhibited the most severe mucosal inflammatory infiltrates. Although the intensity of inflammation differed, the nature of the inflammation was similar between groups, consisting of diffuse lymphocytic infiltration and a unique interface-type infiltrate that obscured the basement membrane zone and was accompanied by intraepithelial infiltration of lymphocytes. IHC confirmed the presence of CD3(+) T and CD79(+) B lymphocytes within the mucosal infiltrates; however, most of the intraepithelial and interface infiltrates were CD3(+) T cells. Spiral-shaped bacterial organisms were seen in the gastric tissues; however, their presence did not correlate with either the severity of epithelial lesions, inflammation or the pattern of interface inflammation. The number of apoptotic epithelial cells was widely variable and not significantly different between groups. These findings confirm previous observations that gastric ulcers develop in conditioned dogs under racing stress. The unique nature of the interface-type gastric inflammation is similar to that of human lymphocytic gastritis and may suggest an immune-mediated mechanism for the changes seen in Alaskan racing sled dogs. PMID- 21247588 TI - Intravascular lymphoma presenting as a longitudinally-extensive myelitis: diagnostic challenges and etiologic clues. AB - Intravascular lymphoma is a rare disorder that commonly involves the central nervous system. Neurologic involvement may be the presenting and only manifestation. Identifying intravascular lymphoma as the cause of neurologic disease is diagnostically challenging. We report an elderly woman presenting with subacute onset paraparesis due to spinal cord involvement by an intravascular lymphoma. Progressive worsening was associated with extension of a longitudinally extensive thoracic intramedullary spinal cord lesion. Extensive investigations failed to provide a diagnosis in life and repeated empiric therapeutic trials were unsuccessful. Diagnostic confirmation was postmortem. A longitudinally extensive spinal cord lesion has a broad differential diagnosis. Intravascular lymphoma should be considered particularly in older individuals. The presence of coexisting hematologic abnormalities should prompt consideration of a bone marrow biopsy. Early diagnosis may direct therapy and lead to a more favorable prognosis. PMID- 21247589 TI - Short- and long-term mortality associated with new-onset atrial fibrillation after coronary artery bypass grafting: a systematic review and meta-analysis. AB - OBJECTIVES: Our objectives were to evaluate short- and long-term mortality associated with new-onset atrial fibrillation after coronary artery bypass grafting and to identify preoperative and intraoperative patient characteristics associated with new-onset atrial fibrillation. METHODS: Three independent investigators comprehensively reviewed the literature using Medline from 1960, Web of Science from 1980, and Scopus from 1960. All searches were done through December 2009. Selected cohort studies were used to evaluate associations between new-onset atrial fibrillation after coronary artery bypass grafting or coronary bypass plus valve and short-term mortality (defined as 30-day or in-hospital mortality) and long-term mortality (defined as mortality >= 6 months). We excluded studies involving atrial flutter, off-pump coronary bypass, and isolated valve surgery. Heterogeneity among studies was accounted for by meta-analysis with random-effects models. RESULTS: Eleven studies (n = 40,112) met our inclusion criteria. New-onset atrial fibrillation was associated with higher short-term mortality (3.6% vs 1.9%; odds ratio [OR], 2.29; 95% confidence interval [CI], 1.74-3.01; P < .00001; heterogeneity of effects, P = .002). Mortality risks at 1 year and 4 years were 2.56 (95% CI, 2.14-3.08) and 2.19 (95% CI, 1.97-2.45; P < .0001), respectively. Older age, lower ejection fraction, history of hypertension, heart failure, prior stroke, peripheral arterial disease, and longer cardiopulmonary bypass and aortic clamp times were associated with new-onset atrial fibrillation. Preoperative use of beta-blockers reduced occurrence of new-onset atrial fibrillation (OR, 0.94 [95% CI, 0.88-1.01; P = .08]), whereas angiotensin-converting enzyme inhibitors increased it (OR, 1.20 [95% CI, 1.11-1.29], P < .00001). CONCLUSIONS: New-onset atrial fibrillation after coronary artery bypass grafting appears to increase short- and long-term mortality. Preoperative use of beta-blockers, avoidance of angiotensin-converting enzyme inhibitors, and shorter cardiopulmonary bypass and aortic clamp times potentially reduce occurrence of new-onset atrial fibrillation. PMID- 21247590 TI - Perventricular device closure of post-myocardial infarction ventricular septal defect on the beating heart. PMID- 21247591 TI - Percutaneous mitral valve repair as a bail-out strategy for patients with severe mitral regurgitation after cardiac surgery. PMID- 21247592 TI - Transthoracic occlusion for secundum atrial septal defects unsuitable for transcatheter occlusion approach. AB - OBJECTIVE: Transcatheter occlusion of secundum atrial septal defects is a safe and effective alternative to traditional surgical closure; however, it is associated with serious occasional complications and inapplicable to more than 20% of atrial septal defects. In 2000, transthoracic occlusion was pioneered at Xijing Hospital as a novel method of atrial septal defect closure. The purpose of this study is to report the early and mid-term results of the transthoracic occlusion procedure and to evaluate its safety and efficacy. METHODS: From April 2000 to April 2006, 268 patients with atrial septal defects were classified into 2 groups: group A (unsuitable for transcatheter occlusion, n = 126) and group B (n = 142). The transthoracic occlusion method used transesophageal echocardiographic-guided atrial septal defects occluder deployment via a right minithoracotomy without cardiopulmonary bypass or fluoroscopy. RESULTS: Device implantation was successful in 265 patients (98.9%), including 9 elliptical devices in group A. The average size of circular occluders in group A was 38.2 +/ 4.2 mm, which was larger than in group B (24.0 +/- 4.5 mm) (P < .001). The average procedure time was 37.2 +/- 9.2 minutes, the average intracardiac manipulation time was 5.8 +/- 3.0 minutes, and the average inpatient stay was 3.2 +/- 0.8 days. Twenty-five complications (9.3%) occurred in patients during the follow-up period. No large residual shunting, device embolization, or other severe complications resulted from transthoracic occlusion. CONCLUSIONS: Transthoracic occlusion is a new safe and effective method for atrial septal defect treatment, even for patients with partial atrial septal defects unsuitable for transcatheter occlusion. This hybrid method broadens the indications of atrial septal defect treatment with device occlusion. PMID- 21247593 TI - Influence of patient gender on mortality after aortic valve replacement for aortic stenosis. AB - OBJECTIVE: To assess the influence of gender on mortality after aortic valve replacement for aortic stenosis. METHODS: A retrospective analysis was performed on data prospectively collected from all patients undergoing aortic valve replacement for aortic stenosis. Multivariate regression analysis was performed to evaluate the effect of 22 preoperative and operative variables on early, late, and overall mortality. RESULTS: Aortic valve replacement was performed in 3343 patients with aortic stenosis between 1982 and 2003. The female patients were older, with a smaller body mass index. The women were less likely to have diabetes, chronic obstructive pulmonary disease, previous myocardial infarction, or left ventricular ejection fraction <35% but were more likely to have hypertension or a New York Heart Association III-IV classification. The female patients received a smaller prosthetic valve, with a smaller effective orifice area index (EOAI). The mean follow-up period was 6.18 +/- 4.96 years, with a total of 2066.142 years of follow-up. The independent predictors of early mortality for the male patients included age, concomitant surgical revascularization, congestive heart failure, and valve size of <=21 mm. The independent predictors of late mortality for the male patients included age, concomitant surgical revascularization, diabetes, renal failure, chronic obstructive pulmonary disease, congestive heart failure, and a bioprosthetic valve. The independent predictors of overall mortality for the male patients included age, concomitant surgical revascularization, diabetes, renal failure, heart failure, and valve size of <=21 mm. For the female patients, the risk factors for early mortality included body mass index <25 kg/m(2); for late mortality included age, concomitant surgical revascularization, New York Heart Association class III-IV, and diabetes; and for overall mortality included age, concomitant surgical revascularization, New York Heart Association class III-IV, and renal failure. Furthermore, male gender was an independent predictor of late (but not early or overall) mortality. CONCLUSIONS: The independent predictors of mortality after aortic valve replacement for aortic stenosis differed between the male and female patients. Male gender increased the risk of late mortality, and a valve size of <=21 mm increased the risk of early and overall mortality among the male patients only. These differences need to be taken into consideration preoperatively and require consideration during operative management. PMID- 21247594 TI - Anomalous left coronary artery arising from the pulmonary artery in hypoplastic left hearts: case series and review of literature. PMID- 21247595 TI - Ureteroarterial fistula treatment with open surgery versus endovascular management: long-term outcomes. AB - PURPOSE: Ureteroarterial fistulas can be treated with open vascular or percutaneous arterial stent placement. We compared the long-term outcomes of each treatment. MATERIALS AND METHODS: A single center, retrospective review of ureteroarterial fistulas (1996 to 2008) was performed. RESULTS: We identified 20 ureteroarterial fistulas in 19 patients. All patients had undergone extirpative surgery with pelvic radiation in 74% and long-term ureteral stents in 84%. At a mean followup of 15.5 months (range 1 to 99) survival was 53%. Of the 70% (14 of 20) treated with percutaneous endovascular iliac artery stenting or embolization, 2 patients later required open vascular graft and 12 were treated with long-term ureteral stenting. Of the 30% (6 of 20) of patients treated with open surgical repair or bypass 2 required bypass revision and/or thrombectomy, and 4 had concomitant ureteral ligation or nephrectomy. Despite undergoing anticoagulation 10 patients (53%) experienced lower extremity morbidity including ulceration, ischemia and amputation. In each treatment group 2 patients had recurrent hemorrhage requiring a secondary procedure, leading to death in 2 for an overall 10% acute mortality rate. Overall noncause specific mortality of ureteroarterial fistulas was 47% and 10% to 20% was related to the fistula or treatment complications. CONCLUSIONS: Endovascular stenting is increasingly used in lieu of open techniques due to the high operative risk and comorbidities in patients with ureteroarterial fistulas. This retrospective review fails to identify a clear advantage for endovascular or open vascular surgical management. Thus, endovascular stenting is preferred in most cases. Regardless of therapy, patients are at risk for recurrent bleeding, lower extremity complications and stent/graft complications. The use of antibiotics and long-term anticoagulant therapy appear prudent but not proved. PMID- 21247596 TI - National trends in the usage and success of sacral nerve test stimulation. AB - PURPOSE: Little is known about outcomes of sacral neuromodulation in the general community, with published reports to date limited to case series or randomized, controlled trials. The goal of this analysis was to identify the national sacral neuromodulation test phase success rate and patient factors that contribute to success. MATERIALS AND METHODS: Medical claims data were obtained from a 5% sample of Medicare beneficiaries (1997 to 2007) and from employees of 25 large (Fortune 500) companies (Ingenix(r), 2002 to 2007). Using billing codes for the sacral neuromodulation procedure, success was defined as progressing from test phase (percutaneous or staged) to battery implantation. The rate of success was compared based on age, race, gender and diagnosis. RESULTS: In the Medicare sample 358 patients received percutaneous test stimulation and 1,132 underwent 2 stage lead placement, of whom 45.8% and 35.4%, respectively, underwent subsequent battery implantation. In the privately insured sample there were 266 percutaneous procedures and 794, 2-stage procedures. Percutaneous procedures were followed by battery placement in 24.1% of cases, whereas 50.9% of staged procedures resulted in battery implantation. Gender was the only consistent predictor of success, with female patients demonstrating higher success rates in each data set. CONCLUSIONS: The sacral neuromodulation success rates in these data sets are inferior to those published in case series and small randomized, controlled trials. Women had significantly better results than men and privately insured individuals had better results than those with Medicare, indicating a potential age effect. PMID- 21247597 TI - Long-term outcome and surgical interventions after sacral neuromodulation implant for lower urinary tract symptoms: 14-year experience at 1 center. AB - PURPOSE: Few reports address the reoperation rate after sacral neuromodulation implants. We report our long-term results and reoperations during our 14-year experience with sacral neuromodulation at our center. MATERIALS AND METHODS: We retrospectively reviewed the patient database at our center to assess the long term outcome, incidence and cause of surgical re-intervention after InterStim(r) sacral neuromodulation implantation for lower urinary tract dysfunction between 1994 and 2008. RESULTS: A total of 96 sacral neuromodulation devices were implanted in 88 women and 8 men. Indications for implantation were bladder pain syndrome in 47.9% of cases, urgency urinary incontinence in 35.4% and idiopathic urinary retention in 16.7%. The explantation rate was 20.8% and median time to removal was 18.5 months. Reasons for explantation in all subgroups were poor result in 12 patients, painful stimulation in 6 and radiation of stimulation to the leg in 2. Median long-term followup was 50.7 months. The long-term success rate was 87.5%, 84.8% and 73% in patients with idiopathic urinary retention, urgency urinary incontinence and bladder pain syndrome, respectively. Overall 39% of patients needed revision of the sacral neuromodulation implant. The main reason for revision was loss of stimulation in 58.5% of cases. The revision rate decreased with the introduction of the tined lead technique from 50% using lead Model 3092 to 31% using lead Model 3893 (Medtronic, Minneapolis, Minnesota). The battery was changed in 8 patients. Mean battery life was 101.8 months. CONCLUSIONS: Sacral neuromodulation is a minimally invasive procedure with a good long-term outcome. The reoperation rate has improved with advances in surgical technique and equipment. PMID- 21247598 TI - Force of stream after sling therapy: safety and efficacy of rapid discharge care pathway based on subjective patient report. AB - PURPOSE: We evaluated the safety of a mid urethral sling postoperative care pathway using patient subjective reporting of force of stream to minimize length of stay and catheter placement. MATERIALS AND METHODS: Women undergoing solitary mid urethral sling surgery were prospectively enrolled in our study. Force of stream after the sling therapy protocol consisted of retrograde bladder filling with 300 ml fluid within 1 hour after surgery. Patients rated force of stream compared to baseline on a visual analog scale. Those with a force of stream of 50% or greater were immediately discharged home regardless of post-void residual urine volume. Only those unable to void and those rating force of stream less than 50% with post-void residual urine volume greater than 500 ml were discharged home with a catheter. Patients were telephoned within 1 week of surgery and seen 4 to 6 weeks postoperatively. The primary outcome was unexpected visits to the emergency room or office for voiding dysfunction or urinary retention. RESULTS: A total of 114 women were prospectively enrolled in our study, of whom 105 (92.1%) passed the protocol and were discharged home without a catheter. Of the patients 14 were discharged home with increased post-void residual urine volume (range 152 to 427 ml) but no catheter, representing those who would have been discharged with a catheter by many traditional voiding protocols. According to protocol 9 patients were discharged with a catheter. No patient presented to the emergency room or office in urinary retention or with voiding dysfunction before the scheduled visit. CONCLUSIONS: Patients who report a force of stream of 50% or greater can be safely and rapidly discharged home after an uncomplicated mid urethral sling procedure regardless of post-void residual urine volume. Scanned post-void residual urine volume does not add much value in those who can void. By following the force of stream after sling therapy protocol patients can be discharged home less than 3 hours after mid urethral sling surgery. PMID- 21247599 TI - Parameatal urethral cysts in prepubertal males. AB - PURPOSE: Parameatal urethral cyst in boys is an uncommon and often poorly understood condition. We describe the largest known series of 18 prepubertal boys with parameatal cysts. MATERIALS AND METHODS: We retrospectively reviewed the charts of all pediatric patients at our institution diagnosed with a penile cyst according to our office database between 1992 and 2010. Charts were reviewed to determine patient demographics, symptomatology, pathology, cyst characteristics and treatment. RESULTS: We identified 18 patients during the last 18 years who were diagnosed with a parameatal cyst. Most patients (66%) were asymptomatic. All cysts were less than 1 cm in diameter. Of the patients 50% were circumcised before presentation and 78% underwent surgical excision. There have been no recurrences in patients who underwent excision. One patient had spontaneous resolution of the cyst during the first few weeks of life. Pathology results were available for 6 patients. Three specimens contained a single type of epithelium and 3 contained a combination of transitional, cuboidal and/or columnar epithelia. The transitional and cuboidal epithelia were the most common components. There was no evidence of malignancy in any of the specimens and only 1 specimen contained an inflammatory infiltrate. CONCLUSIONS: Parameatal cysts are a benign, usually asymptomatic condition that may contain a variety of epithelial types. The cysts may resolve spontaneously in neonates but are also easily excised with minimal risk of recurrence. PMID- 21247600 TI - Successful repeat microdissection testicular sperm extraction in men with nonobstructive azoospermia. AB - PURPOSE: We studied factors that can predict successful repeat microdissection testicular sperm extraction in men with nonobstructive azoospermia. MATERIALS AND METHODS: We retrospectively analyzed the records of 126 men with nonobstructive azoospermia who underwent 1 successful microdissection testicular sperm extraction attempt. Clinical factors identifiable at the second procedure, including age, testicular volume, endocrinological data and histology, were analyzed. RESULTS: Overall testicular spermatozoa were successfully retrieved at 103 of 126 repeat attempts (82%). Men with a successful repeat attempt had lower follicle-stimulating hormone (mean+/-SD 23.1+/-12.4 vs 29.2+/-12.8, p=0.04) and larger testicular volume (mean 10+/-5 vs 7+/-4, p=0.0001) at the repeat procedure compared to men with a failed repeat attempt. Adjusted associations from a multiple logistic regression model showed that no factors predicted sperm retrieval during repeat microdissection testicular sperm extraction. An ROC curve showed a fair prediction model (AUC=0.71). CONCLUSIONS: The follicle-stimulating hormone level and testicular volume at the repeat attempt appear to have predictive value to determine the success of a second attempt. These observations are interesting since testicular volume and follicle-stimulating hormone in men with nonobstructive azoospermia do not predict sperm retrieval at a primary microdissection testicular sperm extraction attempt. PMID- 21247601 TI - The use of bilateral sacral nerve stimulation in patients with loss of unilateral treatment efficacy. AB - PURPOSE: We evaluated whether bilateral sacral nerve stimulation can be effective to restore treatment efficacy in patients in whom unilateral sacral neuromodulation fails. MATERIALS AND METHODS: Patients in whom unilateral sacral neuromodulation failed were included in analysis. The percutaneous nerve evaluation test was used to evaluate the effect of contralateral and bilateral stimulation. The stimulation electrode was placed in the contralateral S3 foramen and symptoms were self-recorded using a 3-day voiding diary. Clinical success was defined as more than 50% improvement in at least 1 relevant voiding diary parameter vs baseline. RESULTS: The 15 study patients underwent test stimulation with percutaneous nerve evaluation. In 3 patients lead migration was suspected and, thus, they were not included in analysis. Four of the remaining 12 patients had a successful response to percutaneous nerve evaluation, of whom 3 were eventually implanted with a contralateral lead. After 12 months of treatment 2 of the 3 patients had a successful outcome. CONCLUSIONS: In this pilot study only a select group of patients appeared to benefit from bilateral stimulation after unilateral therapy failure. Further investigation is needed to determine the predictive factors and cost-effectiveness of this treatment. PMID- 21247602 TI - Risk factors for conversion to hand assisted laparoscopy or open surgery during laparoscopic renal surgery. AB - PURPOSE: Risk factors for conversion to hand assisted laparoscopic or open surgery during laparoscopic renal surgery are incompletely defined. MATERIALS AND METHODS: We reviewed our institutional database of 759 standard laparoscopic and 833 hand assisted laparoscopic radical, simple, donor and partial nephrectomies, pyeloplasties and nephroureterectomies from June 1996 to February 2009, representing a total of 1,592 cases. We identified the incidence of and indications for conversion to hand assisted laparoscopic and open surgery, and determined risk factors for conversion. RESULTS: Of all 1,592 procedures 20 (1.3%) required conversion to open surgery. Of 759 standard laparoscopic procedures 21 (2.8%) were converted to hand assisted laparoscopic surgery and 1.7% were converted to open surgery for an overall standard laparoscopy conversion rate of 4.6%. Only 0.7% of hand assisted laparoscopic procedures were converted to open surgery. The rate of conversion to open surgery ranged from 0.3% for laparoscopic partial to 2.5% for laparoscopic simple nephrectomy. The rate of conversion to hand assisted laparoscopic surgery ranged from 0% for laparoscopic pyeloplasty to 6.5% for laparoscopic partial nephrectomy. Conversion to open surgery was most likely due to hemorrhage (50% of cases) or failure to progress (40%) while conversion to hand assisted laparoscopic surgery was most likely due to failure to progress (76%) and tumor anatomy (19%). Multivariate analysis revealed that the only significant risk factor for conversion to open surgery was greater American Society of Anesthesiologists score. Conversion to hand assisted laparoscopic surgery was associated with greater body mass index, American Society of Anesthesiologists score and partial nephrectomy. CONCLUSIONS: Conversion during laparoscopic renal surgery to open or hand assisted laparoscopic surgery is a rare but important event in laparoscopic surgery. The risk is influenced by the nature of the procedure and overall patient health. PMID- 21247603 TI - Is obesity a risk factor for failure and complications after surgery for incontinence and prolapse in women? AB - PURPOSE: Obese women (body mass index 30 kg/m2 or greater) are considered to be at risk for postoperative complications and failure after stress incontinence surgery. We compare the outcomes in this population with nonobese women (body mass index less than 30 kg/m2) undergoing rectus fascia, porcine dermis and polypropylene sling procedures. MATERIALS AND METHODS: We retrospectively identified 412 women with a body mass index less than 30 kg/m2 (94 autologous rectus fascia, 157 acellular porcine dermis, 161 transobturator polypropylene mid urethral sling) and 297 with a body mass index of 30 kg/m2 or greater (66 autologous rectus fascia, 114 acellular porcine dermis, 117 transobturator polypropylene mid urethral sling) who underwent sling procedures and other pelvic surgery. Evaluation included SEAPI assessment and quality of life questionnaires. Global cure equaled subjective SEAPI composite=0 and subjective satisfaction. Stress urinary incontinence cure equaled SEAPI (S)=0 and negative cough stress test. Chart review for perioperative data was conducted. Groups and outcomes were statistically compared. RESULTS: All women had a minimum followup of 12 months. After controlling for body mass index preoperative demographics, SEAPI scores and quality of life indices were not statistically different within each sling group. Global cure and stress urinary incontinence cure rates were significantly higher for nonobese women in each sling group. Statistically significant improvement in SEAPI scores and quality of life indices was achieved for all groups, and there were no statistical differences within each sling group. Overall obese women had no increase in complications compared with nonobese women. The incidence of obstructive sequelae was statistically higher in nonobese women undergoing autologous rectus fascia and transobturator polypropylene mid urethral sling procedures. CONCLUSIONS: Although cure rates are lower, obese women have significant improvements in quality of life after surgery for stress urinary incontinence. Obesity does not appear to be a risk factor for additional complications during sling and prolapse surgery. PMID- 21247604 TI - The association of adiposity and overactive bladder appears to differ by gender: results from the Boston Area Community Health survey. AB - PURPOSE: We investigate the association of different measures of adiposity (waist circumference, hip circumference, waist-to-hip ratio and body mass index) with overactive bladder (urinary frequency and urgency), whether the association varies by gender or age and whether it persists when models are adjusted for other confounders. MATERIALS AND METHODS: Data were from the Boston Area Community Health epidemiological survey, a random sample of 5,503 Boston, Massachusetts, residents 30 to 79 years old with equal representation from 3 racial/ethnic groups (black, Hispanic and white). Statistical analysis involved nonparametric loess models and multivariate logistic regression. RESULTS: We noted distinct patterns by gender for the association of various adiposity measures with overactive bladder. Waist-to-hip ratio was not significantly associated with overactive bladder in either gender. In women the prevalence of overactive bladder increased as waist (OR adjusted for other confounders 1.10/10 cm increase) or hip circumference (OR 1.12/10 cm increase) or body mass index (OR 1.03/kg/m2 increase) increased. In men the prevalence of overactive bladder decreased as adiposity increased (OR 0.65/10 cm increase in waist circumference, OR 0.71/10 cm increase in hip circumference and OR 0.87/kg/m2 in body mass index) but only to a certain point (waist circumference 100 cm, hip circumference 115 cm and body mass index 27.5 kg/m2, respectively). At that point the prevalence of overactive bladder increased with increasing adiposity (OR 1.19/10 cm increase in waist circumference, OR 1.16/10 cm increase in hip circumference and OR 1.08/kg/m2 in body mass index). CONCLUSIONS: The relationship between adiposity and overactive bladder varies by gender. PMID- 21247605 TI - The diagnostic efficacy of 3-dimensional ultrasound estimated bladder weight corrected for body surface area as an alternative nonurodynamic parameter of bladder outlet obstruction. AB - PURPOSE: We investigated the relationship between ultrasound estimated bladder weight/corrected ultrasound estimated bladder weight and the bladder outlet obstruction index derived from pressure flow study to evaluate its diagnostic efficacy to predict bladder outlet obstruction. MATERIALS AND METHODS: A total 193 men older than 50 years with lower urinary tract symptoms were enrolled in this study. Ultrasound estimated bladder weight measurements were made with a 3 dimensional ultrasound system. Corrected bladder weight was defined as ultrasound estimated bladder weight divided by body surface area on data analysis. The study population was classified into obstructed and unobstructed groups (bladder outlet obstruction index 40 or greater and less than 40, respectively). We evaluated the correlation between bladder outlet obstruction and clinical parameters, including bladder weight/corrected bladder weight and the diagnostic accuracy of bladder weight/corrected bladder weight for bladder outlet obstruction. RESULTS: A total of 50 (26%) and 143 patients (74%) were categorized as obstructed and nonobstructed, respectively. Corrected bladder weight, maximum urine flow and the bladder contraction index showed statistically significant differences between the groups. Bladder weight/corrected bladder weight positively correlated with the bladder outlet obstruction index and corrected bladder weight showed a stronger correlation. Corrected bladder weight was significantly increased depending on obstruction severity. When corrected bladder weight was used to diagnose obstruction, sensitivity, specificity, and positive and negative predictive values were 61.9%, 59.8%, 33.8% and 82.6%, respectively, at a 28 gm/m(2) cutoff. CONCLUSIONS: Ultrasound estimated bladder weight/corrected ultrasound estimated bladder weight is a statistically significant parameter correlating with bladder outlet obstruction. However, bladder weight/corrected bladder weight alone was insufficient to predict bladder outlet obstruction due to its weak correlation with and low accuracy for diagnosing obstruction. PMID- 21247606 TI - Imaging strategy for infants with urinary tract infection: a new algorithm. AB - PURPOSE: We analyzed clinical data for prediction of permanent renal damage in infants with first time urinary tract infection. MATERIALS AND METHODS: This population based, prospective, 3-year study included 161 male and 129 female consecutive infants with first time urinary tract infection. Ultrasonography and dimercapto-succinic acid scintigraphy were performed as acute investigations and voiding cystourethrography within 2 months. Late scintigraphy was performed after 1 year in infants with abnormality on the first dimercapto-succinic acid scan or recurrent febrile urinary tract infections. End point was renal damage on the late scan. RESULTS: A total of 270 patients had end point data available, of whom 70 had renal damage and 200 did not. Final kidney status was associated with C reactive protein, serum creatinine, temperature, leukocyturia, non-Escherichia coli bacteria, anteroposterior diameter on ultrasound and recurrent febrile urinary tract infections. In stepwise multiple regression analysis C-reactive protein, creatinine, leukocyturia, anteroposterior diameter and non-E.coli bacteria were independent predictors of permanent renal damage. C-reactive protein 70 mg/l or greater combined with anteroposterior diameter 10 mm or greater had sensitivity of 87% and specificity of 59% for renal damage. An algorithm for imaging of infants with first time urinary tract infection based on these results would have eliminated 126 acute dimercapto-succinic acid scans compared to our study protocol, while missing 9 patients with permanent renal damage. CONCLUSIONS: C-reactive protein can be used as a predictor of permanent renal damage in infants with urinary tract infection and together with anteroposterior diameter serves as a basis for an imaging algorithm. PMID- 21247607 TI - [Thoracic spine pseudarthrosis treated by transpleural corporectomy and bone morphogenic protein]. AB - BACKGROUND AND PURPOSE: Traumatic thoracic spine instability is a rare but difficult-to-treat entity, particularly above T5 where pedicle screwing is widely regarded as an unsatisfactory option and anterior surgery is considered difficult because of the anatomic relationship with the shoulder and large vessels. METHODS: A case of T4 and T5 pseudarthrosis after posterior fixation is reported. It was treated with transpleural corpectomy and fixation, with bone morphogenic protein used to obtain rapid arthrodesis between T3 and T6. No bracing or second posterior fixation was used. RESULT: At 45 days of follow-up, the patient was without pain and the neurologic examination was normal. The CT scan showed bony bridges across all fracture lines. Complete cure of this pseudarthrosis was achieved with a single surgery. At the 12-month follow-up, the clinical status was normal. CONCLUSIONS: The use of bone morphogenic proteins might be of great help in rare but challenging cases of spinal pseudarthrosis, with a quick return to normal activity after a single-stage surgery. PMID- 21247608 TI - The safety and efficacy of itraconazole for the treatment of patients with eumycetoma due to Madurella mycetomatis. AB - This prospective study aimed to determine the safety and efficacy of itraconazole for the treatment of patients with mycetoma due to Madurella mycetomatis. The study consisted of 13 patients with confirmed disease; all were treated with oral itraconazole in a dose of 400mg daily for three months after which the dose was reduced to 200mg daily for nine months. All patients showed good clinical response to 400mg itraconazole daily, but when the dose was reduced to 200mg daily, the clinical response was gradual and slow. Post-treatment surgical exploration showed that, in all patients, the lesions were well localized, encapsulated with thick capsule and they were easily removed surgically. In all these lesions, grains colonies were encountered and they were viable on culture. Post-operative biopsies showed no significant changes in the morphology of the grains. A constant finding was the presence of between 5-7 grains in a single cavity walled by fibrous tissue. The reaction surrounding the grains was a Type I tissue reaction characterized by a neutrophil zone around grains. Patients were followed up post-operatively for variable periods (range 18-36 months) and only one patient had recurrence. Initial pre-operative treatment with itraconazole may be recommended for eumycetoma patients to enhance lesions encapsulation and localization which can facilitate wide local excision to avoid unnecessary massive mutilating surgery and recurrence. PMID- 21247609 TI - Deconstructing laparoscopic competence in a virtual reality simulation environment. AB - BACKGROUND: Virtual reality (VR) simulators play a substantial role in modern medical education and have generated several performance parameters that are not always standardized and open to clear and easy interpretation. Consequently, our study objective was to investigate how these parameters contribute to the enhancement of key competencies in laparoscopic surgical skills. METHODS: We recruited 20 residents and 8 experienced surgeons to participate in this study. The residents were trained on 5 basic tasks (4 of them at two difficulty levels) using a commercially available VR simulator. Study participants also performed an additional 3 complex tasks before and after training for assessment purposes. The experienced surgeons served as controls and so only performed the assessment tasks. Performance parameters were grouped to reflect errors in dexterity, safety, and technical skill. These errors, as well as the parameters of time and instrument velocity, were analyzed during training and assessment. RESULTS: Performance for training tasks demonstrated notable learning curves for most of the parameters that were measured (ie, plateaus varied between the second and seventh VR training session). Velocity was influenced least by the training (3 of the 5 tasks), while time and dexterity were influenced most (all 5 tasks and for both difficulty levels). In the assessment tasks, technical skill was improved (P < .05) for some study participants, but this improvement was not demonstrated in all of the complex procedures tested (eg, bowel suturing). There was a significant improvement in safety (all 3 tasks; P < .05), and time to completion and dexterity (both of them in 2 tasks; P < .05). Experienced surgeons scored at a greater level than VR-trained residents in terms of time (all tasks; P < .05), safety and technical skill (bowel suturing; P < .05), as well as dexterity (adhesiolysis and bowel suturing; P < .05). CONCLUSION: VR simulation training contributed markedly to the enhancement of key surgical competencies of residents. The proposed mapping of the simulator parameters may help program directors and trainees evaluate important competency domains during VR-based surgical training. PMID- 21247610 TI - Consensus classifications of postoperative complications--are they really useful? PMID- 21247611 TI - Ischemic colitis: who will survive? AB - BACKGROUND: Operative treatment for acute ischemic colitis is associated with a high morbidity and mortality. These patients often have a prolonged postoperative stay in the intensive care unit with an uncertain outcome. In this study, we aimed to develop a predictive risk score for perioperative mortality and to examine long-term follow-up of patients with acute ischemic colitis. METHODS: All patients (n = 177) undergoing surgical treatment for acute ischemic colitis in our institution from 2002 to 2008 were prospectively included in this study. Independent predictors of perioperative mortality and poor long-term survival were assessed by uni- and multivariate analysis. RESULTS: A risk score including various perioperative variables (nonocclusive ischemic colitis, acute renal failure, extent of bowel ischemia, serum lactate, and duration of catecholamine therapy) was defined being highly predictive for postoperative mortality of patients having undergone an operation for acute ischemic colitis. Mesenteric atherosclerosis in the surgical specimen is an independent prognostic factor for poor long-term survival (52 vs 40 months with mesenteric atherosclerosis; P = .027). CONCLUSION: This study for the first time presents a risk score highly predictive of postoperative mortality of patients undergoing an operation for ischemic colitis. Our score may help to further select and modify therapeutic management in patients with acute ischemic colitis on the basis of validated data. Furthermore, we could demonstrate a significant influence of mesenteric atherosclerosis on long-term survival of patients with acute ischemic colitis. PMID- 21247612 TI - Stem cell-based anti-HIV gene therapy. AB - Human stem cell-based therapeutic intervention strategies for treating HIV infection have recently undergone a renaissance as a major focus of investigation. Unlike most conventional antiviral therapies, genetically engineered hematopoietic stem cells possess the capacity for prolonged self renewal that would continuously produce protected immune cells to fight against HIV. A successful strategy therefore has the potential to stably control and ultimately eradicate HIV from patients by a single or minimal treatment. Recent progress in the development of new technologies and clinical trials sets the stage for the current generation of gene therapy approaches to combat HIV infection. In this review, we will discuss two major approaches that are currently underway in the development of stem cell-based gene therapy to target HIV: one that focuses on the protection of cells from productive infection with HIV, and the other that focuses on targeting immune cells to directly combat HIV infection. PMID- 21247614 TI - The effects of dissolved organic matter and pH on sampling rates for polar organic chemical integrative samplers (POCIS). AB - The effect of solution pH and levels of dissolved organic matter (DOM) on the sampling rates for model pharmaceuticals and personal care products (PPCPs) and endocrine disrupting substance (EDS) by polar organic chemical integrative samplers (POCIS) was investigated in laboratory experiments. A commercially available POCIS configuration containing neutral Oasis HLB (hydrophilic lipophilic balance) resin (i.e. pharmaceutical POCIS) and two POCIS configurations prepared in-house containing MAX and MCX anion and cation exchange resins, respectively were tested for uptake of 21 model PPCPs and EDS, including acidic, phenolic, basic and neutral compounds. Laboratory experiments were conducted with dechlorinated tap water over a pH range of 3, 7 and 9. The effects of DOM were studied using natural water from an oligotrophic lake in Ontario, Canada (i.e. Plastic Lake) spiked with different amounts of DOM (the concentration of dissolved organic carbon ranged from 3 to 5mgL(-1) in uptake experiments). In experiments with the commercial (HLB) POCIS, the MCX-POCIS and the MAX-POCIS, the sampling rates generally increased with pH for basic compounds and declined with pH for acidic compounds. However, the sampling rates were relatively constant across the pH range for phenols with high pKa values (i.e. bisphenol A, estrone, estradiol, triclosan) and for the neutral pharmaceutical, carbamazepine. Thus, uptake was greatest when the amount of the neutral species in solution was maximized relative to the ionized species. Although the solution pH affected the uptake of some model ionic compounds, the effect was by less than a factor of 3. There was no significant effect of DOM on sampling rates from Plastic Lake. However, uptake rates in different aqueous matrixes declined in the order of deionized water>Plastic Lake water>dechlorinated tap water, so other parameters must affect uptake into POCIS, although this influence will be minor. MAX-POCIS and MCX-POCIS showed little advantage over the commercial POCIS configuration for monitoring in natural waters. PMID- 21247615 TI - Sorption and degradation of wastewater-associated non-steroidal anti-inflammatory drugs and antibiotics in soils. AB - Presence of pharmaceuticals at trace levels in recycled water is an emerging issue impacting the beneficial reuse of treated wastewater, including practices such as irrigation and groundwater recharge in arid and semi-arid regions. To assess the environmental risks of irrigation with recycled water containing such micropollutants, in this study we evaluated sorption and degradation of five pharmaceuticals that are antibiotic and anti-inflammatory drugs in two soils collected from arid regions. Naproxen and trimethoprim showed moderate to strong sorption, while the sorption of diclofenac, ibuprofen and sulfamethoxazole was negligible in both soils. Under aerobic conditions, the studied compounds were susceptible to microbial degradation with half-lives varying from 4.8 to 69.3d. Apart from sulfamethoxazole, the other compounds were relatively persistent under anaerobic conditions as indicated by a negligible loss over 84d of incubation or half-lives >50d. The degradation of the selected pharmaceuticals was influenced by microbial activities, oxygen status in the soil, soil type and compound characteristics. The poor sorption and relative persistence of diclofenac and ibuprofen under anaerobic conditions suggest that the two chemicals may pose a high leaching risk when using recycled for irrigation or groundwater replenishment. PMID- 21247613 TI - Cell-to-cell transmission of retroviruses: Innate immunity and interferon-induced restriction factors. AB - It has been known for some time that retroviruses can disseminate between immune cells either by conventional cell-free transmission or by directed cell-to-cell spread. Over the past few years there has been increasing interest in how retroviruses may use cell-to-cell spread to promote more rapid infection kinetics and circumvent humoral immunity. Effective humoral immune responses are intimately linked with innate immunity and the interplay between retroviruses and innate immunity is a rapidly expanding area of research that has been advanced considerably by the identification of cellular restriction factors that provide barriers to retroviral infection. The effect of innate immunity and restriction factors on retroviral cell-to-cell spread has been comparatively little studied; however recent work suggests this maybe changing. Here I will review some recent advances in what is a budding area of retroviral research. PMID- 21247616 TI - Osmoregulation of the resident estuarine fish Atherinella brasiliensis was still affected by an oil spill (Vicuna tanker, Paranagua Bay, Brazil), 7 months after the accident. AB - An oil tanker loaded with methanol and bunker oil has exploded in November 2004 in Paranagua Bay, in front of Paranagua Harbor, southern Brazil. In order to investigate the chronic effects of an oil spill on a resident estuarine fish, the Brazilian silverside Atherinella brasiliensis was sampled 1, 4, and 7 months after the spill, from 2 sites inside Paranagua Bay, and also from a reference site inside nearby Guaratuba Bay, non-affected by the spill. Increases in plasma osmolality (reaching ~525 mOsm/kg H2O, or ~70% above values in reference fish) and chloride (reaching 214 mM in site C, or ~51% above values in reference fish) were detected 4 months after the spill, in parallel with branchial carbonic anhydrase inhibition (to 56% of the activity measured in reference fish) in silversides obtained from the contaminated sites. Plasma cortisol concentration increased progressively in samples from fish obtained 4 (462 ng/mL) and 7 (564 650 ng/mL) months after the spill, when compared to values in reference fish (192 ng/mL). Osmoregulation of a resident estuarine fish is still affected by an oil spill, months after the accident. It is, thus, a sensitive tool for the evaluation of the chronic effects of oil spills inside tropical estuarine systems, and A. brasiliensis is proposed as an adequate sentinel species for monitoring protocols. PMID- 21247617 TI - Echocardiographic assessment of pulmonary arterial pressure in the follow-up of patients with pulmonary embolism. AB - BACKGROUND: Echocardiography remains a clinically useful screening test for chronic thromboembolic pulmonary hypertension (CTEPH) in patients with a history of pulmonary embolism (PE). To devise an effective screening strategy, the definition of a high-risk group is necessary. METHODS: We examined a total of 744 patients with acute symptomatic pulmonary embolism (PE) who were enrolled in a Spanish multicenter study. Patients were monitored every 6months during the first two years, and then once a year thereafter. Transthoracic echocardiography was used to screen patients with a clinical suspicion of CTEPH during follow-up. Pulmonary arterial hypertension was defined as an estimated pulmonary artery systolic pressure (PAP)>50mm Hg. The index thromboembolic episode was considered severe if: (a) the patient was immobilized for medical reasons; or (b) systolic blood pressure was less than 90mm Hg; or (c) troponin T values were above the reference range. RESULTS: The incidence of PAP>50mm Hg at 36months was 8.3% (95% confidence interval=4.6%-14.5%). Statistical analysis showed a highly significant association between a severe index thromboembolic episode and the subsequent detection of PAP>50mm Hg on echocardiography, with high positive likelihood ratio (2.40) and negative predictive value (>0.97). CONCLUSIONS: Patients with a severe index thromboembolic episode would constitute a high-risk group for the development of CTEPH. This group of patients should be subjected to a strict follow-up protocol. PMID- 21247618 TI - Increase in the incidence of gestational trophoblastic disease in The Netherlands. AB - OBJECTIVE: The objective of this study is to determine the incidence and time trends of gestational trophoblastic disease (GTD) in The Netherlands using population-based data. METHODS: Data on patients with a pathologically confirmed diagnosis of GTD from 1995 to 2008 were obtained from PALGA, a national archive containing all histopathology reports in The Netherlands. Data on number of deliveries were obtained from the Database of Statistics Netherlands. RESULTS: During the study period, 4249 GTD patients were registered. Overall incidence rates of hydatidiform mole (HM), choriocarcinoma and placental site trophoblastic tumor (PSTT) were 1.34 per 1000 deliveries, 3.1 per 100,000 deliveries, and 1.0 per 100,000 deliveries, respectively. Incidence rates of HM increased from 1.02 per 1000 deliveries in 1995 to 1.56 per 1000 in 2001, an increase of 0.091 per year (95% CI 0.081-0.101). After 2001 incidence rates remained constant (increase per year -0.010, 95% CI -0.045-0.024). Maternal age and ethnicity are known to influence the risk of HM. Highest incidences were observed in women under 20 and over 40years of age. The proportion of deliveries accounted for by women over 40years of age increased from 1.5% to 2.9%, whereas women under 20 accounted for 1.5% of deliveries. The proportion of live births of Asian descent increased from 2.6% to 3.7%. CONCLUSION: The incidence of GTD in The Netherlands increased significantly from 1995 to 2008. This can partially be explained by increased maternal age and increased proportion of live births of Asian descent. Part of the increase might result from improved diagnostic techniques. However, these factors do not seem to account for the total observed increase and part of the increase therefore remains unexplained. PMID- 21247620 TI - Lipid content and apoptosis of in vitro-produced bovine embryos as determinants of susceptibility to vitrification. AB - The objective was to evaluate supplementation of fetal calf serum (FCS) and phenazine ethosulfate (PES), a metabolic regulator that inhibits fatty acid synthesis, in culture media during in vitro production (IVP) of bovine embryos. Taking oocyte fertilization (n = 4,320) as Day 0, four concentrations of FCS (0, 2.5, 5, and 10%) and three periods of exposure to PES (without addition-CONTROL; after 60 h-PES Day 2.5 of embryo culture; and after 96 h-PES Day 4) were evaluated. Increasing FCS concentration in the culture media enhanced lipid accumulation (P < 0.05), increased apoptosis in fresh (2.5%: 19.1 +/- 1.8 vs 10%: 28.4 +/- 2.3, P < 0.05; mean +/- SEM) and vitrified (2.5%: 42.8 +/- 2.7 vs 10%: 69.2 +/- 3.4, P < 0.05) blastocysts, and reduced blastocoele re-expansion after vitrification (2.5%: 81.6 +/- 2.5 vs 10%: 67.3 +/- 3.5, P < 0.05). The addition of PES in culture media, either from Days 2.5 or 4, reduced lipid accumulation (P < 0.05) and increased blastocoele re-expansion after vitrification ( CONTROL: 72.0 +/- 3.0 vs PES Day 2.5: 79.9 +/- 2.8 or PES Day 4: 86.2 +/- 2.4, P < 0.05). However, just the use of PES from D4 reduced apoptosis in vitrified blastocysts ( CONTROL: 52.0 +/- 3.0 vs PES Day 4: 39.2 +/- 2.4, P < 0.05). Independent of FCS withdrawal or PES addition to culture media, the in vivo control group had lesser lipid accumulation, a lower apoptosis rate, and greater cryotolerance (P < 0.05). The increased lipid content was moderately correlated with apoptosis in vitrified blastocysts (r = 0.64, P = 0.01). In contrast, the increased apoptosis in fresh blastocysts was strongly correlated with apoptosis in vitrified blastocysts (r = 0.94, P < 0.0001). Therefore, using only 2.5% FCS and the addition of PES from Day 4, increased the survival of IVP embryos after vitrification. Moreover, embryo quality, represented by the fresh apoptosis rate, was better than lipid content for predicting embryo survival after vitrification. PMID- 21247619 TI - Adhesion of Streptococcus pneumoniae to human airway epithelial cells exposed to urban particulate matter. AB - BACKGROUND: Epidemiologic studies report an association between pneumonia and urban particulate matter (PM) less than 10 microns (MUm) in aerodynamic diameter (PM(10)). Streptococcus pneumoniae is a common cause of bacterial pneumonia worldwide. To date, the mechanism whereby urban PM enhances vulnerability to S pneumoniae infection is unclear. Adhesion of S pneumoniae to host cells is a prerequisite for infection. Host-expressed proteins, including the receptor for platelet-activating factor (PAFR), are co-opted by S pneumoniae to adhere to lower airway epithelial cells. OBJECTIVES: To define whether inhalable urban PM enhances the adhesion of S pneumoniae to airway epithelial cells. METHODS: A549 cells were cultured with PM(10) from Leicester (United Kingdom [UK]) and PM(10) and PM less than 2.5 MUm in aerodynamic diameter (PM(2.5)) from Accra (Ghana), then infected with S pneumoniae strain D39. Pneumococcal adhesion to human primary bronchial epithelial cells was also assessed. Bacterial adhesion was determined by quantitative culture and confocal microscopy. The role of oxidative stress was assessed by N-acetyl cysteine, and the role of PAFR was assessed by mRNA transcript level, receptor expression, and receptor blocking. RESULTS: PM(10) (UK) increased S pneumoniae adhesion to both A549 airway epithelial cells and human primary bronchial epithelial cells. PM(10) (Ghana) and PM(2.5) (Ghana) also increased adhesion. Culture of A549 cells by PM(10) (UK) increased PAFR mRNA transcript level and PAFR expression. PM(10) (UK)-stimulated adhesion to A549 cells was attenuated by a PAFR blocker and N-acetyl cysteine. CONCLUSION: Urban PM increases adhesion of S pneumoniae to human airway epithelial cells. PM stimulated adhesion is mediated by oxidative stress and PAFR. PMID- 21247621 TI - Comparison of progesterone-based protocols with gonadotropin-releasing hormone or estradiol benzoate for timed artificial insemination or embryo transfer in lactating dairy cows. AB - The objective was to compare two protocols for synchronizing ovulation in lactating Holstein cows submitted to timed AI (TAI) or timed ET (TET). Within each farm (n = 8), cows (n = 883; mean +/- SEM 166.24 +/- 3.27 d postpartum, yielding 36.8 +/- 0.34 kg of milk/d) were randomly assigned to receive either: 1) an intravaginal progesterone insert (CIDR(r)) with 1.9 g of progesterone + GnRH on Day -10, CIDR(r) withdrawal + PGF2alpha on Day -3, and 1 mg estradiol cypionate on Day -2 (treatment GP-P-E; n(TAI) = 180; n(TET) = 260); or 2) a CIDR(r) insert + 2 mg estradiol benzoate on Day -10, PGF2alpha on Day -3, CIDR(r) withdrawal + 1 mg estradiol cypionate on Day -2 (treatment EP-P-E; n(TAI) = 174; n(TET) = 269). Cows were subsequently randomly assigned to receive either TAI on Day 0 or TET on Day 7. Serum progesterone concentration on Day -3 was greater in GP-P-E than in EP-P-E (2.89 +/- 0.15 vs 2.29 +/- 0.15 ng/mL; P < 0.01), with no significant effect of group on serum progesterone on Day 7. Compared to cows submitted to TAI, those submitted to TET had greater pregnancy rates on Day 28 (44.0% [233/529] vs 29.7% [105/354]; P < 0.001) and on Day 60 (37.6% [199/529] vs 26.5 [94/354]; P < 0.001). However, there were no effects of treatments (GP-P-E vs EP-P-E; P > 0.10) on synchronization (87.0% [383/440] vs 85.3% [378/443]), conception (TAI: 35.3% [55/156] vs 33.8% [50/148]; TET: 50.7% [115/227] vs 51.3% [118/230]) and pregnancy rates on Days 28 (TAI: 30.5% [55/180] vs 28.7% [50/174]; TET: 44.2% [115/260] vs 43.9% [118/269]) and 60 (TAI: 27.2% [49/80] vs 25.9% [45/174]; TET: 38.8% [101/260] vs 36.4% [98/269]). In conclusion, GP-P-E increased serum progesterone concentrations on Day -3, but rates of synchronization, conception, and pregnancy were not significantly different between cows submitted to GP-P-E and EP-P-E protocols, regardless of whether they were inseminated or received an embryo. PMID- 21247622 TI - Comparison of prostaglandin- and progesterone-based protocols for timed artificial insemination in sheep. AB - The objective was to compare the reproductive performance of a new PGF(2alpha) based timed artificial insemination (TAI) protocol in sheep (Synchrovine(r): two doses of PGF(2alpha), 7 d apart) to a traditional progesterone-eCG (P4-eCG) protocol, considering the effects of seminal state, AI-times, and AI-pathway. Three experiments involving 1297 multiparous Australian Merino ewes were done during the physiologic breeding season (location 32 degrees S-57 degrees W). Reproductive performance was assessed as non-return rate to service 21 d after AI (NRR21d), based on detection with androgenized wethers, as well as Fertility (pregnant/inseminated ewes), Prolificacy (fetuses/pregnant ewe), and Fecundity (fetuses/inseminated ewe), which were based on transabdominal ultrasonography 50 d after TAI. In Experiment 1, Synchrovine(r) treated ewes TAI cervically with fresh semen at 42, 48, or 54 h had similar NRR21d (0.51, 0.46, 0.57), Fertility (0.27, 0.31, 0.26), and Fecundity (0.29, 0.32, 0.27), all of which were lower (P < 0.05) than in a control P4-eCG group inseminated at 54 h (0.61, 0.48, 0.52, NRR21d, Fertility and Fecundity respectively). In Experiment 2, using chilled semen and cervical TAI, Synchrovine(r) treated ewes inseminated at 42 h yielded lower (P < 0.05) NRR21d, Fertility and Fecundity (0.28, 0.06, 0.06) compared to 48 (0.43, 0.24, 0.24) and 54 h (0.44, 0.22, 0.23). In Experiment 3 with chilled semen, Synchrovine(r) treated ewes TAI into the cervix at 51 or 57 h were similar in NRR21d (0.16 vs 0.20), Fertility (0.12 vs 0.14), and Fecundity (0.12 vs 0.15), respectively; but lower (P < 0.05) than P4-eCG treated ewes TAI at 54 h (0.34, 0.28, and 0.33 for NRR21d, Fertility and Fecundity respectively). Synchrovine(r) treated ewes intrauterine TAI at 51 or 57 h yielded similar NRR21d (0.51 vs 0.58), Fertility (0.43 vs 0.51), and Fecundity (0.45 vs 0.56) respectively, but lower (P < 0.05) results compared to P4-eCG treated ewes (0.75, 0.71, and 0.88 for NRR21d, Fertility and Fecundity respectively). In conclusion, AI-time in Synchrovine(r) treated ewes with fresh semen might be extended (42 to 54 h after the second PGF(2alpha)), but should be delayed to 48-54 h with chilled semen and cervical AI. Independent of the seminal state, AI-time or AI-pathway, Synchrovine(r) yielded lower reproductive results than a conventional P4-eCG protocol. PMID- 21247623 TI - Effects of hypothermic storage on intracellular calcium, reactive oxygen species formation, mitochondrial function, motility, and plasma membrane integrity in striped bass (Morone saxatilis) sperm. AB - Experiments were conducted to determine the effect of hypothermic 24 h storage on striped bass sperm cell plasma membrane integrity, free intracellular Ca(2+) ([Ca(2+)](i)), mitochondrial membrane potential (DeltaPsi(m)), and reactive oxygen species (ROS) formation (oxidation of hydroethidine to ethidium) as determined by flow cytometry; motion activation and ATP concentration as determined by Luciferin-Luciferase bioluminescence assay. Semen was stored for 1 or 24 h at 4 degrees C in an O(2) atmosphere undiluted or diluted (one volume semen with 3 volumes diluent) with T350 (20 mM TRIS base-NaCl, 350 mOsm/mL, pH 8) or with seminal plasma in the presence of various treatments. Viability (% cells excluding propidium iodide) approached 100% after 1 h storage in undiluted or diluted semen. After 1 h of storage the [Ca(2+)](i) marker, Fluo-3, was detected in only 3% of sperm cells in undiluted or diluted semen. In contrast to storage for 1 h, after 24 h the incidence Fluo-3 fluorescence intensity was increased (P < 0.05) in > 50% of the viable cells in undiluted and diluted semen along with increased cell death; the presence of 1 mM ethylene glycol tetraacetic acid (EGTA) blocked CaCl(2)-induced Fluo-3 fluorescence and cell death. Activation of sperm motility was 82% after 1 h in T350 and decreased (P < 0.05) to 30% after 24 h. However, motility activation failed in the presence of EGTA at 1 or 24 h. During storage DeltaPsi(m) was not affected by storage time or treatment. In contrast, sperm ATP was greater (P < 0.05) at 1 h than at 24 h and was greater in sperm stored in diluted than undiluted form. While ROS formation was induced by menadione treatment, there was no evidence of storage-induced ROS formation in the absence of menadione. The increased [Ca(2+)](i) found after 24 h indicates a storage induced defect in the maintenance of cellular calcium homeostasis which may be detrimental to sperm activation. PMID- 21247624 TI - Detection of bovine herpesvirus 1 and 5 in semen from Brazilian bulls. AB - Bovine herpesvirus 1 (BoHV-1) and 5 (BoHV-5) are important pathogens of the respiratory and genital tract of cattle and may also affect the central nervous system and cause meningoencephalitis. Both virus types are estimated to be widely distributed in Southern Brazil. In the present study, BoHV-1 and/or BoHV-5 DNA were detected in bovine semen samples from two states of Brazil by two species specific nested polymerase chain reactions (nPCRs). These nPCRs were used to assay 53 samples of fresh semen and 23 samples of frozen semen from breeding bulls. Viral DNA was detected in all 76 semen samples: all were positive for BoHV 5, whereas 34 of these were positive for BoHV-1 as well. Moreover, in five fresh and in 13 frozen semen samples-of a total number of 40 samples suitable for virus isolation-infectious BoHV-1 and/or BoHV-5 virus were detected. In conclusion, that both BoHV-1 and BoHV-5 were detected in bovine semen in Brazil highlighted the importance of examining bull semen in search for both agents to reduce the risk of transmitting these viruses. PMID- 21247625 TI - Seasonal changes in ovarian steroid hormone concentrations in the large hairy armadillo (Chaetophractus villosus) and the crying armadillo (Chaetophractus vellerosus). AB - Knowledge of armadillo reproductive physiology is essential for developing ex situ and in situ assisted reproductive techniques for propagating and/or controlling populations of these animals. The present study included assessment of fecal sex steroids by radioimmunoassay, determining reproductive status via monitoring ovarian activity (in the wild) and therefore reproductive status, in wild females of the large hairy armadillo (Chaetophractus villosus) and the crying armadillo (Chaetophractus vellerosus) in the southern hemisphere. Plasma and fresh fecal progesterone concentrations were not significantly correlated in either species. However, in both species, there was a significant positive correlation between plasma progesterone and dry fecal progesterone concentrations (r = 0.82, P < 0.05 and r = 0.60, P < 0.05, respectively). Dry fecal progesterone and estradiol concentrations were measured in one captive C. villosus (average baseline progesterone and estradiol concentrations 28.72 +/- 11.75 ng/g dry feces and 3.04 +/- 0.80 ng/g dry feces, respectively) and one captive C. vellerosus (average baseline progesterone and estradiol concentrations 14.05 +/- 3.03 ng/g dry feces and 3.46 +/- 1.20 ng/g dry feces, respectively) to detect hormonal peaks over 1 y; these occurred from late fall to early summer. Feces from wild C. villosus and C. vellerosus were also collected over 1 y to determine progesterone peaks, which occurred in winter and spring in both species (with no peaks during the summer or fall). Accordingly, C. villosus and C. vellerosus had a seasonal reproductive pattern. The significant correlations between dry fecal and plasma progesterone concentrations validated this method for monitoring reproductive status in these species. PMID- 21247626 TI - Expression of matrix metalloproteinase (MMP)-2, MMP-14 and tissue inhibitor of matrix metalloproteinase (TIMP)-2 during bovine placentation and at term with or without placental retention. AB - Matrix metalloproteinases (MMPs) and counteracting tissue inhibitors of metalloproteinases (TIMPs) are balancing extracellular matrix (ECM) formation and degradation. The latter is believed to be an important aspect for the detachment of fetal membranes postpartum when loosening the feto-maternal connection which is a prerequisite to avoid placental retention a common disease in cows leading to considerable economic loss. Membrane-type (MT) MMPs have been suggested as potential activators controlling ECM remodelling. In particular, MT1-MMP (MMP-14) is able to degrade ECM substrates and activate MMP-2 through binding TIMP-2 at the cell surface. Since the connection between the trophoblast and the maternal caruncular epithelium is supported by integrin receptors bound to ECM, we hypothesize that impaired modulation of the ECM by TIMPs/MMPs participates in the aetiology of bovine retained fetal membranes. To analyse this involvement, placentomes were collected from cows after term parturition and timely release of fetal membranes (n = 4) and cows with retained fetal membranes after various treatments for the induction of parturition using progesterone antagonist (aglepristone), PGF(2alpha) analogue, glucocorticoid, and after elective caesarean sections (each group n = 3). The expression of MMP-14, MMP-2 and of TIMP-2 was examined by real-time-PCR, immunohistochemistry, Western blot and zymography. The relative mRNA expression levels of MMP-14 remained unchanged, while the expression levels of TIMP-2 and MMP-2 partly increased in animals with induced parturition and retention of fetal membranes compared to animals without placental retention. MMP-14 protein was expressed in cells of the uninucleated trophoblast, the fetal mesenchyme and maternal stroma. TIMP-2 was present exclusively in trophoblast giant cells, while MMP-2 could be detected in uninucleated trophoblast cells and the fetal mesenchyme. The presence of the activated enzyme was confirmed by zymography. In conclusion, MMP-14, MMP-2 and TIMP-2 are co-localized in the fetal compartment and therefore could influence the timely release of fetal membranes in cattle. PMID- 21247627 TI - Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. AB - BACKGROUND: Aromatase inhibitors improved disease-free survival compared with tamoxifen when given as an initial adjuvant treatment or after 2-3 years of tamoxifen to postmenopausal women with hormone-receptor-positive breast cancer. We therefore compared the long-term effects of exemestane monotherapy with sequential treatment (tamoxifen followed by exemestane). METHODS: The Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase 3 trial was conducted in hospitals in nine countries. Postmenopausal women (median age 64 years, range 35-96) with hormone-receptor-positive breast cancer were randomly assigned in a 1:1 ratio to open-label exemestane (25 mg once a day, orally) alone or following tamoxifen (20 mg once a day, orally) for 5 years. Randomisation was by use of a computer generated random permuted block method. The primary endpoint was disease-free survival (DFS) at 5 years. Main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, NCT00279448, NCT00032136, and NCT00036270; NTR 267; Ethics Commission Trial27/2001; and UMIN, C000000057. FINDINGS: 9779 patients were assigned to sequential treatment (n=4875) or exemestane alone (n=4904), and 4868 and 4898 were analysed by intention to treat, respectively. 4154 (85%) patients in the sequential group and 4186 (86%) in the exemestane alone group were disease free at 5 years (hazard ratio 0.97, 95% CI 0.88-1.08; p=0.60). In the safety analysis, sequential treatment was associated with a higher incidence of gynaecological symptoms (942 [20%] of 4814 vs 523 [11%] of 4852), venous thrombosis (99 [2%] vs 47 [1%]), and endometrial abnormalities (191 [4%] vs 19 [<1%]) than was exemestane alone. Musculoskeletal adverse events (2448 [50%] vs 2133 [44%]), hypertension (303 [6%] vs 219 [5%]), and hyperlipidaemia (230 [5%] vs 136 [3%]) were reported more frequently with exemestane alone. INTERPRETATION: Treatment regimens of exemestane alone or after tamoxifen might be judged to be appropriate options for postmenopausal women with hormone receptor-positive early breast cancer. FUNDING: Pfizer. PMID- 21247629 TI - Hydrogel network design using multifunctional macromers to coordinate tissue maturation in ovarian follicle culture. AB - Synthetic hydrogels with tunable properties are appealing for regenerative medicine. A critical limitation in hydrogel design at low solids concentration is the formation of defects, which increase gelation times and swelling, and reduce elasticity. Here, we report that trifunctional cross-linking peptides applied to 4-arm poly-(ethylene glycol) (PEG) hydrogels decreased swelling and gelation time relative to bi-functional crosslinkers. In contrast to bi-functional peptides, the third cross-linking site on the peptide created a branch point if an intramolecular cross-link formed, which prevented non-functional "dangling-ends" in the hydrogel network and enhanced the number of elastically active cross links. The improved network formation enabled mouse ovarian follicle encapsulation and maturation in vitro. Hydrogels with bi-functional crosslinkers resulted in cellular dehydration, likely due to osmosis during the prolonged gelation. For trifunctional crosslinkers, the hydrogels supported a 17-fold volumetric expansion of the tissue during culture, with expansion dependent on the ability of the follicle to rearrange its microenvironment, which is controlled through the sensitivity of the cross-linking peptide to the proteolytic activity of plasmin. The improved network design enabled ovarian follicle culture in a completely synthetic system, and can advance fertility preservation technology for women facing premature infertility from anticancer therapies. PMID- 21247630 TI - Optical imaging of intracellular reactive oxygen species for the assessment of the cytotoxicity of nanoparticles. AB - The generation of intracellular reactive oxygen species (ROS) was optically monitored using ROS-sensitive gold nanoprobes in response to an exposure of nanoparticles (NPs). Fluorescent dye-labeled hyaluronic acid was grafted onto the surface of gold nanoparticles (HF-AuNPs) for imaging intracellular ROS. The ultrasensitive detection of intracellular ROS was utilized as a powerful analytical tool to assess early cellular toxicities of monodisperse polystyrene (PS) particles with different sizes and different functional groups on the surface. The effect of PEGylation on the surface of PS NPs was also investigated by evaluating intracellular ROS generation. For various PS NPs, the extent of intracellular ROS was well correlated with cellular uptake, apoptosis inducing activity, and cytotoxic effect of NPs. In addition to the nanoparticles, commonly used polymeric gene carriers such as linear and branched polyethylenimine (PEI) were tested to analyze their extent of intracellular ROS generation related to cellular toxicity. This study demonstrated that sensitive and optical detection of intracellular ROS generation can provide a valuable toxicity index value for a wide range of NPs as an early indicator for cellular responses. PMID- 21247631 TI - Gene expression signature of lymphocyte in acute lymphoblastic leukemia patients immediately after total body irradiation. AB - Molecular mechanisms involved in TBI preconditioning before allogenetic transplantation remain unclear. To elucidate possible signaling pathway in it, gene expression profiles of peripheral lymphocytes were compared between samples 24h after each 4.5 Gy total body irradiation treatment (total 9 Gy) from 4 adult ALL patients. 478 significant expressed genes and three unique patterns were identified. Of these, a dominant progressively repressed expression of genes involved in ubiquitin-dependent process and repressed expression only at 9 Gy of genes involved in allograft rejection and graft-versus-host disease pathways were observed. The results suggest these pathways may play important roles for subsequent transplantation. PMID- 21247632 TI - The effect of cerebral spinal fluid replacement on acute myelopathy induced by intrathecal therapy of leukemia. PMID- 21247633 TI - A case of therapy-related acute lymphoblastic leukemia with t(9;22)(q34;q11.2) following treatment of breast cancer. PMID- 21247634 TI - Treating myelodysplastic syndrome improves an accompanying autoimmune disease along with a reduction in regulatory T-cells. PMID- 21247635 TI - Metallothionein cDNA cloning, metallothionein expression and heavy metals in Scapharca inaequivalvis along the Northern Adriatic coast of Italy. AB - The aims of this work were: (1) identification of the metallothionein (MT) gene coding sequence in order to prepare an MT probe in Scapharca inaequivalvis and (2) quantification of Cd, Zn, Cu, MT and MTmRNA expression in tissues of molluscs from three areas along the Northern Adriatic coast of Italy. By RT-PCR we cloned the MTcDNA of S. inaequivalvis using the RNA extracted from hepatopancreas of specimens exposed to Cd. The 61 amino acids sequence of MT was deduced and was 70% identical to S. brughtonii MT. Cd concentration in molluscs from the wild was significantly higher in gills from specimens sampled near Ravenna. Zn concentration in the same tissue was significantly higher in Ravenna with respect to Porto Garibaldi while no difference with respect to Cesenatico was detected. Cu levels showed significant differences among sites in gills and mantle whereas values in the hepatopancreas were similar in all sites. The low MT levels were indicative of a low metal exposure; few differences were found in MTmRNA concentrations, which resulted significantly higher in hepatopancreas of molluscs from Porto Garibaldi. PMID- 21247636 TI - Comorbidity and risk indicators for alcohol use disorders among persons with anxiety and/or depressive disorders: findings from the Netherlands Study of Depression and Anxiety (NESDA). AB - INTRODUCTION: This study examines comorbidity of alcohol abuse and alcohol dependence as well as its risk indicators among anxious and/or depressed persons, also considering temporal sequencing of disorders. METHODS: Baseline data from the Netherlands Study of Depression and Anxiety (NESDA) were used, including 2329 persons with lifetime DSM-IV anxiety (social phobia, generalized anxiety disorder, panic disorder, and agoraphobia) and/or depressive (major depressive disorder and dysthymia) disorders and 652 controls. Lifetime diagnoses of DSM-IV alcohol abuse and dependence were established, as well as information about socio demographic, vulnerability, addiction-related and anxiety/depression-related characteristics. Temporal sequencing of disorders was established retrospectively, using age of onset. RESULTS: Of persons with combined anxiety/depression 20.3% showed alcohol dependence versus 5.5% of controls. Prevalence of alcohol abuse was similar across groups (+/- 12%). Independent risk indicators for alcohol dependence among anxious and/or depressed persons were male gender, vulnerability factors (family history of alcohol dependence, family history of anxiety/depression, openness to experience, low conscientiousness, being single, and childhood trauma), addiction-related factors (smoking and illicit drug use) and early anxiety/depression onset. Persons with secondary alcohol dependence were more neurotic, more often single and lonelier, while persons with primary alcohol dependence were more often male and more extravert. DISCUSSION: Alcohol dependence, but not abuse, is more prevalent in anxious and/or depressed persons. Persons with comorbid alcohol dependence constitute a distinct subgroup of anxious and/or depressed persons, characterized by addiction related habits and vulnerability. However, considerable variation in characteristics exists depending on temporal sequencing of disorders. This knowledge may improve identification and treatment of those anxious and/or depressed patients who are additionally suffering from alcohol dependence. PMID- 21247637 TI - Dual purpose contraceptives: targeting fertility and sexually transmitted disease. AB - There have been no radically new forms of contraception since the pill was introduced 1960 and even this form of fertility regulation can be traced back to endocrine advances that were made in the 1920s. Whatever new forms of fertility control we introduce for the future, they should exploit the significant advances that have been made in our understanding of the reproductive system in recent years and be tailored to the needs of the 21st century. In this context, there is an urgent need to develop novel, safe, effective, dual-purpose contraceptive agents that combine the prevention of pregnancy with protection against sexually transmitted diseases (STDs). To achieve this aim we have researched a class of a topical contraceptive agent that selectively and instantaneously immobilizes millions of spermatozoa, while suppressing the infectivity of pathogenic microbes, such as Chlamydia, in the ejaculate. This approach is based upon the ability of small molecular mass organic compounds to selectively and covalently adduct key proteins in spermatozoa and pathogenic organisms and disrupt their biological function. We have also successfully developed strategies for the preparation of latent formulations that would only become activated on contact with seminal plasma. The further development and refinement of these molecules should permit a radical rethink in the way that safe, effective topical protection is provided to control both fertility and the world-wide spread of STDs. PMID- 21247638 TI - A latent class analysis of DSM-IV criteria for pathological gambling: Results from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - With rapid increases in gambling opportunities over the past decade, gambling has emerged as an important social and public health concern. The pending revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM) has prompted a flurry of empirical research evaluating the extant diagnostic classification scheme; however few studies have evaluated the pathological gambling criteria. This paper utilized latent class analysis (LCA) to empirically derive and validate a typology of gamblers. LCA was applied to the 10 DSM-IV pathological gambling criteria utilizing data from the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (n=11,104). LCA identified three latent classes which largely differed according to severity. The majority of respondents were assigned to the no gambling problems class (93.3%). Gamblers in the moderate gambling problems class (6.1%) primarily endorsed the preoccupation, tolerance, and chasing criteria. The pervasive gambling problems class (0.6%) endorsed the majority of the criteria. A number of significant differences between the classes emerged as a function of demographic, psychiatric and substance use disorders. The findings offer a heuristic and clinically useful typology of gamblers. Support for a continuum of gambling-related problems reiterate the need for assessment, prevention, and treatment strategies that reflect this more nuanced understanding of gambling. PMID- 21247639 TI - Urgent maxillectomy in infants for rare infantile maxillary tumors. AB - OBJECTIVE: The purpose of this study was to present our experience with definitive surgical management of infants with Melanotic neuroectodermal tumor of infant (MNTI) and epithelioid hemangioendothelioma (EHE). PATIENTS AND METHODS: This study included four male infants with histologically proven MNTI (three infants) and EHE (one infant). CT scan and MRI were for taken for the patients preoperatively. Surgical intervention was used in all infants. RESULTS: This study is a retrospective study that reflects our experience in the last 20 years in maxillectomy in infants. All infants were male with mean age 6 months (2-9 months). Complete resection of the tumor was achieved all infants with no residual or recurrence. Neither chemotherapy nor radiation was used in this study. CONCLUSIONS: MNTI and EHE are rare tumor of infant. They present as a slow painless hard swelling of the maxilla. Imaging is an essential before surgical treatment. Complete excision is curative. PMID- 21247640 TI - Peripartum and other cardiomyopathies in a Nigerian adult population. PMID- 21247641 TI - Viral and bacterial patterns induce TLR-mediated sustained inflammation and calcification in aortic valve interstitial cells. AB - BACKGROUND: Aortic stenosis shares some ethiopathological features with atherosclerosis and increasing evidence links Toll-like receptors (TLRs) to atherogenesis. METHODS: TLR-mediated inflammation and osteogenesis were investigated in human interstitial cells isolated from stenotic and non-stenotic aortic valves. TLR expression and signalling were evaluated by quantitative RT PCR, flow cytometry, Western blot analysis, ELISA, and cytokine arrays. Osteogenesis was evaluated by measuring alkaline phosphatase activity. RESULTS: Interstitial cells from control valves express most TLRs, being TLR4 the most abundant, whereas cells from stenotic valves express higher TLR4 and TLR2 and lower TLR5 and TLR9 transcript levels. When pro-inflammatory pathways were analyzed, we observed that TLR4, TLR2 and TLR3 ligands induced an early activation of NF-kappaB and p38 MAPK activation in cells from control and stenotic valves. Strikingly, when TLRs sensing viral patterns were studied, a sustained TLR3-mediated activation of NF-kappaB, a kappaB-independent induction of catalytically active cyclooxigenase (COX)-2 and ICAM-1 expression, and induction of expression of several chemokines were observed. TLR4, but not TLR2, engagement produced a similar but NF-kappaB-dependent effect. Moreover, TLR3 and TLR4 agonists induced alkaline phosphatase expression and activity. CONCLUSIONS: Exposure of aortic valve interstitial cells to viral and Gram-negative bacteria molecular patterns induces distinct and long-term TLR-mediated pro-inflammatory and pro-osteogenic responses that might be relevant to the pathogenesis of degenerative aortic stenosis. PMID- 21247642 TI - Hypolipidemic potential of Lepidogrammitis drymoglossoides in high-fat diet fed mice. PMID- 21247643 TI - Interval training does not decrease oxidative stress in the heart of mice. PMID- 21247644 TI - Tako-tsubo cardiomyopathy after administration of intravenous epinephrine during an anaphylactic reaction. PMID- 21247645 TI - Rosiglitazone suppresses lipopolysaccharide-induced matrix metalloproteinase-2 activity in rat aortic endothelial cells via Ras-MEK1/2 signaling. AB - OBJECTIVES: Matrix metalloproteinases (MMPs) play a key role in the pathogenesis of chronic inflammatory disease, such as atherosclerosis. Among MMPs, MMP-2 is regarded as a major proteinase in atherosclerotic plaque lesions. Peroxisome proliferator activated receptor-gamma (PPARgamma) ameliorates oxidative stress and the inflammatory response. The aim of the present study was to evaluate the effect of Rosiglitazone on lipopolysaccharide (LPS)-induced MMP-2 activation as well as its possible mechanism. METHODS: Primary culture of rat aortic endothelial cells (RAEC) was derived from male Sprague-Dawley rat. MMP-2 activity was assayed by gelatin zymography. Protein expressions were determined by Western Blotting. DNA binding activity of NF-kappaB was studied with electrophoretic mobility shift assay. RESULTS: LPS-induced MMP-2 activity was inhibited by Rosiglitazone (PPARgamma agonist) in the rat aortic endothelial cells (RAEC). LPS induced MMP-2 activation was diminished due to exposure to NF-kappaB Activation Inhibitor II (JSH-23) or Ras inhibitor, farnesylthiosalicylic acid (FTS). Further study shows that LPS-induced activation of Phospho-Ras homologue gene family, member A (Rho A) and Phospho-mitogen-activated protein kinase kinase 1/2 (MEK1/2) were significantly inhibited by Rosiglitazone. The activation of NF-kappaB p65 in the nuclear extract of cells was also significantly suppressed by Rosiglitazone, moreover, the expression of NF-kappaB p65 was partly activated by GW9662 (PPARgamma antagonist). NF-kappaB DNA binding activity was also demolished by Rosiglitazone. CONCLUSIONS: Our data shows that PPARgamma agonist, Rosiglitazone suppresses LPS-activated MMP-2 secretion via Ras-MEK1/2 signaling pathways and NF kappaB activation. PPARgamma agonist and Ras-MEK1/2 pathway may be another potential therapeutic target for the disease induced by chronic inflammation. PMID- 21247646 TI - Combined antiplatelet therapy and oral anticoagulation: is a balance between thromboembolism and bleeding possible? PMID- 21247647 TI - The anatomy of absenteeism. AB - Based on comprehensive administrative register data from Norway, we examine the determinants of sickness absence behavior; in terms of employee characteristics, workplace characteristics, panel doctor characteristics, and economic conditions. The analysis is based on a novel concept of a worker's steady state sickness absence propensity, computed from a multivariate hazard rate model designed to predict the incidence and duration of sickness absence for all workers. Key conclusions are that (i) most of the cross-sectional variation in absenteeism is caused by genuine employee heterogeneity; (ii) the identity of a person's panel doctor has a significant impact on absence propensity; (iii) sickness absence insurance is frequently certified for reasons other than sickness; and (iv) the recovery rate rises enormously just prior to the exhaustion of sickness insurance benefits. PMID- 21247648 TI - Health and income: a robust comparison of Canada and the US. AB - This paper uses sequential stochastic dominance procedures to compare the joint distribution of health and income across space and time. It is the first application of which we are aware of methods to compare multidimensional distributions of income and health using procedures that are robust to aggregation techniques. The paper's approach is more general than comparisons of health gradients and does not require the estimation of health equivalent incomes. We illustrate the approach by contrasting Canada and the US using comparable data. Canada dominates the US over the bottom part of the bi dimensional distribution of health and income, though not generally over the uni dimensional distributions of health or income. The paper also finds that welfare for both Canadians and Americans has not unambiguously improved during the last decade over the joint distribution of income and health, in spite of the fact that the uni-dimensional distributions of income have clearly improved during that period. PMID- 21247649 TI - Influence of light on food relevant fungi with emphasis on ochratoxin producing species. AB - The influence of light of varying wavelength on growth and ochratoxin A biosynthesis of Aspergillus carbonarius, A. niger, A. steynii and on Penicillium nordicum and P. verrucosum was analysed. For comparison the influence of light on various other food relevant fungi, including citrinin producers, was also tested. Generally the Aspergilli seem to be more resistant to light treatment than the Penicillia. Interestingly wavelengths from both sides of the spectrum, e. g. red (long wavelength, 627 nm) and blue (short wavelength 470-455 nm) had the strongest inhibitory effects on growth and ochratoxin A biosynthesis. Blue light generally had a stronger effect. Light of moderate wavelength, 590 to 530 nm, (yellow to green) had more a positive than a negative influence on growth or ochratoxin A biosynthesis compared to the control (dark incubation). The light effect on growth and ochratoxin A biosynthesis was dependent on the growth medium. In contrast to malt extract medium (MEA), YES medium, as an especially nutrient rich medium, had an attenuating effect on the reactivity against light. However the tendency of the response in both media was the same. Moreover, the light intensity strongly influences how the fungus reacts. Depending on the intensity and the resistance of the species a complete cessation of growth and/or inhibition of ochratoxin A biosynthesis could be achieved. Light irradiation has the opposite effect on ochratoxin A than citrinin, two mycotoxins which can be produced simultaneously in P. verrucosum. Citrinin was produced essentially under light conditions which inhibited ochratoxin A biosynthesis. The same was true for a derivative of ochratoxin, in particular a derivative of ochratoxin beta in A. carbonarius. A. carbonarius produced high amounts of the ochratoxin beta derivative under blue light when the production of ochratoxin A was ceased at the most inhibiting conditions used (MEA, royal blue light, 455 nm, 1700 lx). Light has a growth stalling but not inactivating effect on aerial mycelia. If a non growing colony under light is shifted to the dark it immediately grows normally. However on spores blue light has a deactivating effect. After incubation of spores of P. verrucosum for 24h under blue light up to 97% of the spores were no longer able to germinate. Again the spores of the Aspergilli were much more resistant. PMID- 21247650 TI - Molecular response of Saccharomyces cerevisiae wine and laboratory strains to high sugar stress conditions. AB - One of the stress conditions that can affect Saccharomyces cerevisiae cells during their growth is osmotic stress. Under particular environments (for instance, during the production of alcoholic beverages) yeasts have to cope with osmotic stress caused by high sugar concentrations. Although the molecular changes and pathways involved in the response to saline or sorbitol stress are widely understood, less is known about how cells respond to high sugar concentrations. In this work we present a comprehensive study of the response to this form of stress which indicates important transcriptomic changes, especially in terms of the genes involved in both stress response and respiration, and the implication of the HOG pathway. We also describe several genes of an unknown function which are more highly expressed under 20% (w/v) glucose than under 2% (w/v) glucose. In this work we focus on the YHR087w (RTC3) gene and its encoded protein. Proteomic analysis of the mutant deletion strain reveals lower levels of several yeast Hsp proteins, which establishes a link between this protein and the response to several forms of stress. The relevance of YHR087W for the response to high sugar and other stress conditions and the relationship of the encoded protein with several Hsp proteins suggest applications of this gene in biotechnological processes in which response to stress is important. PMID- 21247651 TI - Clinical evidence to demonstrate that simultaneous growth of epithelial and fibroblast cells is essential for deep wound healing. AB - OBJECTIVE: The aim of this study was to evaluate the chronic wound healing properties of tannin rich plant extracts. METHODS: The cell growth stimulating potential of 128 procyanidin rich plant extracts was evaluated in in vitro cell culture models. For clinical trial, a 3% solution of two plant extracts having synergistic effect on cell growth was prepared in glycerol and honey. Placebo test product contained only glycerol and honey. 93 adult patients with one or more lower extremity deep wounds were divided at randomly in two groups. 41 patients in the placebo (AS-22) and 52 in the active treatment (AS-21) groups having respectively 49 and 69 wounds of a mean surface area of 56.70 and 52.03 cm(2), and volume of 57.22 and 52.15 cm(3), were treated by applying the test products topically for a period of 6-weeks. RESULTS: A statistically significant difference was observed between the placebo and the AS-21 treated groups with respect to reduction in the wound surface area (33.37 vs 97.87%) and wound volume (29.45 vs 94.17%) after 6-weeks of treatment. Mean wound humidity and pain scores were also reduced. CONCLUSION: Tannin rich plant extracts are highly interesting for the treatment of chronic wounds. PMID- 21247652 TI - Development of blood glucose control for extremely premature infants. AB - Extremely premature neonates often experience hyperglycaemia, which has been linked to increased mortality and worsened outcomes. Insulin therapy can assist in controlling blood glucose levels and promoting needed growth. This study presents the development of a model-based stochastic targeted controller designed to adapt insulin infusion rates to match the unique and changing metabolic state and control parameters of the neonate. Long-term usage of targeted BG control requires successfully forecasting variations in neonatal metabolic state, accounting for differences in clinical practices between units, and demonstrating robustness to errors that can occur in everyday clinical usage. Simulation studies were used to evaluate controller ability to target several common BG ranges and evaluate controller sensitivity to missed BG measurements and delays in control interventions on a virtual patient cohort of 25 infants developed from retrospective data. Initial clinical pilot trials indicated model performance matched expected performance from simulations. Stochastic targeted glucose control developed using validated patient-specific virtual trials can yield effective protocols for this cohort. Long-term trials show fundamental success, however clinical interface design appears as a critical factor to ensuring good compliance and thus good control. PMID- 21247653 TI - Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: a mono-institutional experience. AB - BACKGROUND: Upfront tyrosine kinase inhibitor (TKI) has proved effective for selective advanced lung cancer patients in Taiwan. We hypothesized that early integration of radiotherapy during TKI treatment would decrease the chance of drug resistance and prolong progression-free survival (PFS). METHODS: This study included 25 patients with stage IIIb or IV non-squamous cell, non-small cell lung cancer (NSqCLC) who responded to upfront TKI treatment. Multi-target radiotherapy was administered during the TKI treatment course. Tomotherapy comprising a hypofractionated schedule with a dose of 40-50 Gy in 16-20 fractions was used for individual metastatic lesions. RESULTS: The patients' median follow-up duration was 30 months (range, 9-62 months). Of the 23 patients who had stage IV disease, 9 had oligometastases (<=5 gross target volumes) and 14 were in the more advanced stages of the disease. Twelve patients received more than 1 cycle of radiotherapy (median, 3; range, 2-6) with TKI being the only systemic treatment before they were salvaged with chemotherapy. The overall response rate after radiotherapy was 84.0%, and the median PFS was 16 months. The 3-year overall survival rate was 62.5% (95% confidence interval [CI], 39.1-85.8%). Toxicities were generally tolerated but it is necessary to prevent radiation-induced pneumonitis. CONCLUSION: We showed that combined first-line TKI therapy and early multi-target radiotherapy are very effective in selected patients that respond to TKI, when the status of mutations in the epidermal growth factor receptor (EGFR) are not known before the treatment. Our data may aid expansion of the effectiveness of TKI treatment through radiotherapy in Asian patients with stage IV NSqCLC. PMID- 21247654 TI - Immunization with cationized BSA inhibits progression of disease in ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis. AB - Immune responses against modified self-antigens generated by hypercholesterolemia play an important role in atherosclerosis identifying the immune system as a possible novel target for prevention and treatment of cardiovascular disease. It has recently been shown that these immune responses can be modulated by subcutaneous injection of adjuvant. In the present study we immunized 25-week old ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis with adjuvant and two different concentrations of the carrier molecule cationized BSA (cBSA). Plasma levels of Th2-induced apolipoprotein B (apoB)/IgG1 immune complexes were increased in the cBSA immunized groups verifying induction of immunity against a self-antigen. Mice were sacrificed at 36 weeks of age and atherosclerosis was monitored by en face Oil red O staining of the aorta. Immunization with 100 MUg cBSA inhibited plaque progression, whereas the lower dose (50 MUg) did not. In addition, the higher dose induced a more stable plaque phenotype, indicated by a higher content of collagen and less macrophages and T cells in the plaques. Moreover, there was an increased ratio of Foxp3+/Foxp3- T cells in the circulation suggesting activation of a regulatory T cell response. In conclusion, we show that immunization with cBSA induces an immune response against apoB as well as an activation of Treg cells. This was associated with development of a more stable plaque phenotype and reduced atherosclerosis progression. PMID- 21247655 TI - Salmonella enteritidis ghost vaccine induces effective protection against lethal challenge in specific-pathogen-free chicks. AB - Bacterial ghosts (BGs) are empty bacterial envelopes generated by expulsion of the bacterial genome and cytoplasmic contents from bacterial cells, and the process is mediated by lysis protein E encoded on bacteriophage PhiX174. BGs represent a new approach in vaccine development and have been applied to a variety of gram-negative bacterial vaccine candidates. In this study, a BG vaccine generated from Salmonella enteritidis (S. enteritidis) strain DH091 was prepared using the highly efficient plasmid, pBV-mE. The efficacy of the BG vaccine was tested using 75 chicks (Gallus gallus) kept under specific pathogen free (SPF) conditions. A comprehensive evaluation of the immune response, including humoral and cellular immune responses, interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) production, and histopathology of various tissues, was performed in BG-vaccinated animals subsequently challenged with S. enteritidis. The results were compared with animals that were immunized with the inactivated vaccine. S. enteritidis ghosts not only promoted the generation of high titer antibodies and IFN-gamma and IL-4 production but also stimulated a significant increase in CD8(+) and CD4(+) T lymphocytes. In particular, the dramatic increase in CD8(+) T cells indicated that the vaccine was able to induce clearance of intracellular Salmonella. The protective effects of BG vaccination in SPF chicks against 5*10(9) colony forming units of S. enteritidis were a result of the induction of a more effective immune response than that observed with the inactivated vaccine. These findings demonstrate the potential of S. enteritidis ghosts to be used as effective vaccines. PMID- 21247656 TI - Role of Abl and Src family kinases in actin-cytoskeletal rearrangements induced by the Helicobacter pylori CagA protein. AB - The clinical outcome of infections with Helicobacter pylori is determined by a complex interplay of host-pathogen interactions, and persistent infection with this pathogen is the major cause of developing chronic gastritis, peptic ulcers and gastric cancer. Highly virulent strains encode a so-called type IV secretion system which translocates the CagA effector protein into gastric epithelial target cells. Injected CagA becomes tyrosine-phosphorylated on EPIYA sequence motifs by Src and Abl family kinase members. CagA then binds to and activates/inactivates various signalling proteins in a phosphorylation-dependent and phosphorylation-independent manner. In this way injected CagA can act as a master key that evolved during evolution the ability to highjack multiple downstream signalling cascades. Here we review our knowledge on the tyrosine phosphorylation motifs in CagA, the recent advances in the interaction of CagA with Src and Abl tyrosine kinases and their role in signalling events leading to changes of the phosphorylation status of actin-binding proteins cortactin, ezrin and vinculin followed by actin-cytoskeletal rearrangements, cell scattering and elongation. Detailed investigation of these pathways will help to yield novel insights and to elucidate the mechanisms of H. pylori-induced pathogenesis. PMID- 21247657 TI - New insights into the mode of action of the actin ADP-ribosylating virulence factors Salmonella enterica SpvB and Clostridium botulinum C2 toxin. AB - The C2 toxin from Clostridium botulinum represents the prototype of the family of binary actin-ADP-ribosylating toxins. These toxins covalently transfer ADP-ribose from nicotinamide adenine dinucleotide (NAD(+)) onto arginine-177 of actin in the cytosol of eukaryotic cells resulting in depolymerization of actin filaments and cell rounding. The C2 toxin consists of two non-linked proteins, the enzyme component C2I and the binding and translocation component C2II, which delivers C2I into host cells. The ADP-ribosyltransferase SpvB from Salmonella enterica also modifies actin, but is delivered into the host cell cytosol from intracellular growing Salmonella, most likely via type-III-secretion. We characterized the mode of action of SpvB in comparison to C2 toxin in vitro and in intact cells. We identified arginine-177 as the target for SpvB-catalyzed mono ADP-ribosylation of actin. To compare the cellular responses following modification of actin by SpvB or by the binary toxins without the influence of other Salmonella virulence factors, we constructed a cell-permeable fusion toxin to deliver the catalytic domain of SpvB (C/SpvB) into the cytosol of target cells. This review summarizes recent findings of research on the actin ADP ribosylating toxins regarding their cellular uptake, molecular mode of action and the cellular consequences following ADP-ribosylation of actin. PMID- 21247658 TI - Pre-anthesis high-temperature acclimation alleviates damage to the flag leaf caused by post-anthesis heat stress in wheat. AB - The objective of this study was to investigate the effect of pre-anthesis high temperature acclimation on leaf physiology of winter wheat in response to post anthesis heat stress. The results showed that both pre- and post-anthesis heat stresses significantly depressed flag leaf photosynthesis and enhanced cell membrane peroxidation, as exemplified by increased O2-(.) production rate and reduction in activities of antioxiditave enzymes. However, under post-anthesis heat stress, plants with pre-anthesis high-temperature acclimation (HH) showed much higher photosynthetic rates than those without pre-anthesis high-temperature acclimation (CH). Leaves of HH plants exhibited a higher Chl a/b ratio and lower chlorophyll/carotenoid ratio and superoxide anion radical release rate compared with those of the CH plants. In addition, antioxidant enzyme activities in HH plants were significantly higher than in CH. Coincidently, expressions of photosythesis-responsive gene encoding Rubisco activase B (RcaB) and antioxidant enzyme-related genes encoding mitochondrial manganese superoxide dismutase (Mn SOD), chloroplastic Cu/Zn superoxide dismutase (Cu/Zn-SOD), catalase (CAT) and cytosolic glutathione reductase (GR) were all up-regulated under HH, whereas a gene encoding a major chlorophyll a/b-binding protein (Cab) was up-regulated by post-anthesis heat stress at 10 DAA, but was down-regulated at 13 DAA. The changes in the expression levels of the HH plants were more pronounced than those for the CH. Collectively, the results indicated that pre-anthesis high temperature acclimation could effectively alleviate the photosynthetic and oxidative damage caused by post-anthesis heat stress in wheat flag leaves, which was partially attributable to modifications in the expression of the photosythesis-responsive and antioxidant enzymes-related genes. PMID- 21247659 TI - Protein composition analysis of oil bodies from maize embryos during germination. AB - Seed oil bodies (OBs) are intracellular particles that store lipids. In maize embryos, the oil bodies are accumulated mainly in the scutellum. Oil bodies were purified from the scutellum of germinating maize seeds and the associated proteins were extracted and subjected to 2-DE analysis followed by LC-MS/MS for protein identification. In addition to the previously known oil body proteins oleosin, caleosin and steroleosin, new proteins were identified. PMID- 21247660 TI - The impact of cold on photosynthesis in genotypes of Coffea spp.--photosystem sensitivity, photoprotective mechanisms and gene expression. AB - Environmental constraints disturb plant metabolism and are often associated with photosynthetic impairments and yield reductions. Among them, low positive temperatures are of up most importance in tropical plant species, namely in Coffea spp. in which some acclimation ability has been reported. To further explain cold tolerance, the impacts on photosynthetic functioning and the expression of photosynthetic-related genes were analyzed. The experiments were carried out along a period of slow cold imposition (to allow acclimation), after chilling (4 degrees C) exposure and in the following rewarming period, using 1.5 year-old coffee seedlings of 5 genotypes with different cold sensitivity: Coffea canephora cv. Apoata, Coffea arabica cv. Catuai, Coffea dewevrei and 2 hybrids, Icatu (C. arabica*C. canephora) and Piata (C. dewevrei*C. arabica). All genotypes suffered a significant leaf area loss only after chilling exposure, with Icatu showing the lowest impact, a first indication of a higher cold tolerance, contrasting with Apoata and C. dewevrei. During cold exposure, net photosynthesis and Chl a fluorescence parameters were strongly affected in all genotypes, but stomatal limitations were not detected. However, the extent of mesophyll limitation, reflecting regulatory mechanisms and/or damage, was genotype dependent. Overnight retention of zeaxanthin was common to Coffea genotypes, but the accumulation of photoprotective pigments was highest in Icatu. That down regulated photochemical events but efficiently protected the photosynthetic structures, as shown, e.g., by the lowest impacts on A(max) and PSI activity and the strongest reinforcement of PSII activity, the latter possibly reflecting the presence of a photoprotective cycle around PSII in Icatu (and Catuai). Concomitant to these protection mechanisms, Icatu was the sole genotype to present simultaneous upregulation of caCP22, caPI and caCytf, related to, respectively, PSII, PSI and to the complex Cytb(6)/f, which could promote better repair ability, contributing to the maintenance of efficient thylakoid functioning. We conclude that Icatu showed the best acclimation ability among the studied genotypes, mostly due to a better upregulation of photoprotection and repair mechanisms. We confirmed the presence of important variability in Coffea spp. that could be exploited in breeding programs, which should be assisted by useful markers of cold tolerance, namely the upregulation of antioxidative molecules, the expression of selected genes and PSI sensitivity. PMID- 21247662 TI - A comparison of postprocedural wound care treatments: do antibiotic-based ointments improve outcomes? AB - BACKGROUND: Topical antibiotic ointments are commonly used for the postprocedural treatment of superficial wounds created during dermatologic procedures. We propose that antibiotics may not be necessary for healing these wounds, have the potential to cause allergic contact dermatitis, and may contribute to the development of antibiotic resistance. OBJECTIVE: We sought to compare the efficacy and safety of a nonantibiotic, petrolatum-based ointment (Aquaphor Healing Ointment [AHO], Beiersdorf Inc, Wilton, CT) and an antibiotic-based first aid ointment (Polysporin [Poly/Bac], Johnson & Johnson, New Brunswick, NJ) for the treatment of wounds created by removal of seborrheic keratoses. METHODS: In this double-blind study, 30 subjects each had two seborrheic keratoses removed from their trunk or abdomen; one wound was treated with AHO and one with Poly/Bac twice daily. Clinical grading of wound healing and subjective irritation was assessed at days 7, 14, and 28 postwounding. Adverse events were recorded. RESULTS: Clinical grading assessment showed no differences between wounds treated with AHO versus Poly/Bac for erythema, edema, epithelial confluence, crusting, and scabbing at any time point. Subjective irritation assessment showed wounds treated with Poly/Bac had a significant increase in burning at week 1, whereas no differences were seen between treatments for stinging, itching, tightness, tingling, or pain. One case of allergic contact dermatitis was reported after Poly/Bac treatment. LIMITATIONS: This was a relatively small study. CONCLUSIONS: This study demonstrated that the petrolatum-based skin protectant ointment AHO provided equivalent efficacy for wound healing as a combination antibiotic first aid ointment. Antibiotics may not be necessary to achieve satisfactory wound healing and may cause allergic contact dermatitis. PMID- 21247661 TI - Irritation and allergy patch test analysis of topical treatments commonly used in wound care: evaluation on normal and compromised skin. AB - BACKGROUND: Topical agents indicated for the treatment of superficial wounds have the potential to cause irritation or allergic contact dermatitis, particularly when applied to an impaired skin barrier. OBJECTIVE: We sought to compare the irritancy potential of 5 topical wound care products commonly used in dermatologic practice on normal and compromised skin. METHODS: Agents tested included Aquaphor Healing Ointment (AHO) (Beiersdorf Inc, Wilton, CT); bacitracin; Biafine Topical Emulsion (BTE) (OrthoNeutrogena, Los Angeles, CA); Neosporin (Poly/Bac/Neo) (Johnson & Johnson, New Brunswick, NJ); and Polysporin (Poly/Bac) (Johnson & Johnson). Study 1 assessed cumulative irritation using a modified human repeat insult patch test on normal back skin with an induction phase (test materials applied under occlusive patch 9 times at 48- to 72-hour intervals) and a challenge phase (test materials applied to original and naive sites for 48 hours, 12-24 days postinduction). Irritation was graded for erythema and type IV allergy skin responses. Study 2 assessed the acute irritation potential of agents on tape-stripped ("wounded") back skin. Test sites were graded for erythema, transepidermal water loss, and skin color (Chroma Meter a*) (Minolta, Osaka, Japan) at 48 and 72 hours poststripping. RESULTS: In study 1, cumulative irritation testing in 108 subjects classified AHO, bacitracin, Poly/Bac/Neo, and Poly/Bac as "mild," and BTE as "probably mild." In study 2 at 72 hours, mean clinical grading scores were significantly higher for BTE and Poly/Bac/Neo than AHO. Transepidermal water loss and colorimeter a* values were significantly lower for AHO and bacitracin compared with BTE. No allergic contact dermatitis was seen in either study. CONCLUSIONS: Patch test studies demonstrated that BTE showed the greatest irritancy potential in both normal and compromised skin whereas AHO showed the least. PMID- 21247663 TI - Postprocedural wound-healing efficacy following removal of dermatosis papulosa nigra lesions in an African American population: a comparison of a skin protectant ointment and a topical antibiotic. AB - BACKGROUND: Removal of dermatosis papulosa nigra (DPN) lesions results in superficial cutaneous wounds that are frequently treated with topical antibiotic ointments. We hypothesize that antibiotics are not necessary for effective and safe healing of such wounds. OBJECTIVE: This study compared the wound healing efficacy and safety of the skin protectant Aquaphor Healing Ointment (AHO) (Beiersdorf Inc, Wilton, CT) and Polysporin first-aid ointment (Poly/Bac) (polymyxin B sulfate/bacitracin zinc) (Johnson & Johnson, New Brunswick, NJ) after removal of DPN lesions. METHODS: This double-blind, split-face, pilot study removed two DPN lesions from each side of the face of 20 African American subjects. Wounds on opposite sides of the face were treated with AHO or Poly/Bac twice daily for 21 days. Wounds were evaluated for erythema, edema, crusting, scabbing, epithelial confluence, melanin confluence, general wound appearance, and subjective irritation on days 1, 3, 7, 10, 14, and 21 after surgery using 5 point scales. RESULTS: Wound healing parameter assessments showed no differences between wounds treated with AHO versus Poly/Bac in erythema, edema, epithelial confluence, crusting, scabbing, melanin confluence, or postinflammatory hyperpigmentation at any time point. Subjective irritation was similar between treatments for burning, stinging, itching, tightness, tingling, and pain. No adverse events were reported. LIMITATIONS: This was a small study in a homogenous population of African Americans. CONCLUSIONS: Postprocedural treatment with AHO and Poly/Bac demonstrated equivalent wound healing in an African American population. These results support the hypothesis that antibiotics are not necessary for safe and effective healing of facial wounds resulting from removal of DPN lesions. PMID- 21247664 TI - A comparison of wound healing between a skin protectant ointment and a medical device topical emulsion after laser resurfacing of the perioral area. AB - BACKGROUND: Currently, there is no standard of care for postlaser resurfacing treatment of the face. Ideally, treatment should speed re-epithelialization and reduce downtime, with minimal irritation. OBJECTIVE: This study compared the wound healing efficacy and safety of Aquaphor Healing Ointment (AHO) (Beiersdorf Inc, Wilton, CT) and Biafine Topical Emulsion (BTE) (OrthoNeutrogena, Los Angeles, CA) treatment after laser resurfacing of the perioral area. METHODS: In this double-blind, split-face study, 20 subjects with perioral rhytides received fractional carbon dioxide laser resurfacing. AHO and BTE were applied to opposite sides of the face 4 times daily after the resurfacing procedure. Clinical grading of erythema, edema, epithelial confluence, crusting/scabbing, subjective irritation, and general wound appearance were assessed using 5-point scales on days 2, 4, 7, and 14. Subjects ranked the two treatment sites daily as to which side of their face looked better. RESULTS: AHO resulted in significantly less erythema (days 2 and 7) and crusting/scabbing (days 2, 4, and 7) and higher epithelial confluence (day 4) than BTE (P <= .042). Subjective irritation assessments demonstrated significantly less stinging, itching, and tightness at day 2 and tightness at day 7 with AHO than with BTE (P <= .049). General wound appearance was graded significantly higher for AHO on days 2 and 7 (P <= .049). Significantly more subjects preferred AHO to BTE (P <= .046). LIMITATIONS: This was a small study in a homogenous population of white women. CONCLUSIONS: AHO exhibited superiority to BTE in several wound healing parameters and in overall wound condition. PMID- 21247666 TI - Wound care in the dermatology office: where are we in 2011? AB - Dermatologists perform several minor surgical procedures in their offices on a daily basis that result in superficial cutaneous wounds. Conventionally, the approach to postoperative care for these superficial wounds has been the application of a topical antibiotic ointment. In reality, this practice is based more on perception and habit, and not on sound scientific evidence, especially regarding reduction in postoperative infection rates and risk of adverse reactions. In addition, the routine use of a topical antibiotic in this scenario may contribute to the emergence of antibiotic-resistant bacterial strains, and has been shown to increase the risk of allergic contact dermatitis. With few new antibiotics in development and several worldwide initiatives to curb the increase in antibiotic resistance in progress, it is important that clinicians reevaluate the standard postoperative wound care that is used after superficial office-based dermatologic procedures. PMID- 21247665 TI - Treatment of minor wounds from dermatologic procedures: a comparison of three topical wound care ointments using a laser wound model. AB - BACKGROUND: Topical antibiotic ointments are commonly used for postoperative wound care after dermatologic procedures such as curettage, electrodessication, or shave removals. Antibiotics have the potential to cause allergic contact dermatitis and increase drug resistance and may not be necessary for the treatment of clean surgical wounds. OBJECTIVE: This study compared the wound healing properties of the topical wound care ointments Aquaphor Healing Ointment (AHO) (Beiersdorf Inc, Wilton, CT), Neosporin (Poly/Bac/Neo) (Johnson & Johnson, New Brunswick, NJ), and Polysporin (Poly/Bac) (Johnson & Johnson) using a laser wound model. METHODS: In this double-blind study, 4 uniform circular erbium/carbon dioxide laser wounds penetrating to the dermis were made in 20 subjects. Each wound was treated 3 times daily for 18 days with AHO, Poly/Bac/Neo, or Poly/Bac, with one wound left untreated (control). Efficacy and safety were assessed using clinical grading, transepidermal water loss, investigator grading of wound appearance, subjective ranking of wound appearance, and adverse event reporting. RESULTS: Significant improvements in erythema (days 7-18), edema (days 4 and 7), epithelial confluence (days 7-18), and general wound appearance (days 7-18) were observed with AHO compared with Poly/Bac/Neo and Poly/Bac (P <= .007). No differences were observed between Poly/Bac/Neo and Poly/Bac for any clinical parameters. The average transepidermal water loss value on day 4 was significantly less with AHO compared with the other treatments (P = .0006). Subjects ranked the treated sites as follows: AHO (best), Poly/Bac, and Poly/Bac/Neo. No adverse events were reported. LIMITATIONS: This was a small pilot study using a laser wound model to replicate minor wounds. CONCLUSIONS: AHO demonstrated fast and effective improvements in several wound healing parameters compared with antibiotic-containing treatments. PMID- 21247667 TI - Efficient microwave-assisted synthesis of novel 3-aminohexahydrocoumarin derivatives and evaluation on their cytotoxicity. AB - The efficient synthesis of novel 3-aminohexahydrocoumarin derivatives with high diastereoselectivity, wide applicability, short reaction time, high yields as well as operational simplicity was achieved via microwave-assisted reactions of dimedone or cyclohexane-1,3-dione with 4-arylidene-2-phenyloxazol-5(4H)-ones. Moreover, these novel compounds were subject to the test of in vitro cytotoxicity to carcinoma SW1116 and SGC7901 cells. Seven compounds showed stronger cytotoxicity to carcinoma SW1116 cells than doxorubicin hydrochloride at the concentration of 10 ug/mL. Nearly all the tested compounds exhibited strong or moderate cytotoxicity to SGC7901 cells with IC(50) values from 5.127 to 0.158 ug/mL. PMID- 21247668 TI - Exploring the impact of journal clubs: a systematic review. AB - There is a significant gap between the knowledge available about effective clinical practice and what is actually applied (Parkes et al., 2004, Seymour et al., 2003; Sherratt, 2005; McQueen et al., 2006). McMahon (1997) suggests that journal clubs are a particularly good method of exposing practitioners to current literature. Doubt has been cast on the transferability of thinking from classroom to practice (Soden and Halliday, 2000) and the lack of attention as to how knowledge expertise is transferred to problem solving (Soden and Pithers, 2001). The journal club is proposed as a means to address the theory-to-practice gap using the basic components involved in the process of evidence based medicine/practice [EBM (P)]. The literature search covered the period 1992 to 2009. Studies focusing upon outcomes of actual journal clubs that impacted upon participants in terms of increased research awareness, knowledge, skills and enhanced care delivery, were reviewed. Sixteen studies met review inclusion criteria. The review draws from the strengths of journal clubs to recommend the multidisciplinary work based journal club, as a cost effective way of enhancing practitioner capability. PMID- 21247669 TI - Predictors of academic performance of nursing and paramedic students in first year bioscience. AB - The expanding scope of practice of paramedics and nurses demands they possess a sophisticated knowledge of bioscience to enable them to think critically and make rational clinical decisions. It is well documented that nursing students struggle with bioscience but there are no studies examining the performance of paramedic students in this crucial subject. In this study, we compared the academic performance of first year nursing, paramedic and nursing/paramedic double degree students in a bioscience subject. Regression analyses were used to identify predictors of academic success. Data revealed a low success rate in bioscience for all three degree programs (63.2, 58.8, and 67.6% respectively) and a strong correlation between academic success in bioscience and non-bioscience subjects (r(2)=0.49). The best predictors of overall academic success were the University Admission Index score and mature entry into the course. Previous study of biology was associated with an increased bioscience and overall GPA but not with non bioscience grades. Discriminant analysis was used to develop a model that could predict overall academic success with an accuracy of 78.5%. These criteria may be useful during the admission process and for the early identification of students at risk of failure. PMID- 21247670 TI - Simulation gaming in nurse education; entertainment or learning? PMID- 21247671 TI - Pentoxifylline and tocopherol in the management of patients with osteoradionecrosis, the Portsmouth experience. AB - Osteoradionecrosis of the jaw remains the most problematic consequence of radiotherapy for the management of head and neck cancer. Treatment is often complex and multimodal. New theories on its pathophysiology have allowed the development of potential treatment modalities, including the use of pentoxifylline and tocopherol. In this retrospective case series we examined the outcomes of patients with ORN prescribed pentoxifylline and tocopherol. PMID- 21247672 TI - The buck stops here: midwives and maternity care in rural Scotland. AB - OBJECTIVE: To explore and understand what it means to provide midwifery care in remote and rural Scotland. DESIGN: Qualitative interviews with 72 staff from 10 maternity units, analysed via a case study approach. SETTING: Remote and rural areas of Scotland. PARTICIPANTS: Predominantly midwives, with some additional interviews with paramedics, general surgeons, anaesthetists and GPs. FINDINGS: Remote and rural maternity care includes a range of settings and models of care. However, the impact of rural geographies on decision-making and risk assessment is common to all settings. Making decisions and dealing with the implications of these decisions is, in many cases, done without onsite specialist support. This has implications for the skills and competencies that are needed to practice midwifery in remote and rural settings. Whereas most rural midwives reported that their skills in risk assessment and decisions to transfer were well developed and appropriate to practising in their particular settings, they perceived these decisions to be under scrutiny by urban-based colleagues and felt the need to stress their competence in the face of what they imagined to be stereotypes of rural incompetence. CONCLUSIONS: This study shows that skills in risk assessment and decision-making are central to high quality remote and rural midwifery care. However, linked to different perspectives on care, there is a risk that these skills can be undermined by contact with colleagues in large urban units, particularly when staff do not know each other well. There is a need to develop a professional understanding between midwives in different locations. IMPLICATIONS FOR PRACTICE: It is important for the good working relationships between urban and rural maternity units that all midwives understand the importance of contextual knowledge in both decisions to transfer from rural locations and the position of midwives in receiving units. Multiprofessional CPD courses have been effective in bringing together teams around obstetric emergencies; we suggest that a similar format may be required in considering issues of transfer. PMID- 21247673 TI - Factor structure, validity and reliability of the Spanish version of the Cambridge Worry Scale. AB - OBJECTIVE: To analyse the factor structure and reliability of the Cambridge Worry Scale (CWS) in the Spanish population. DESIGN: Prospective cross-sectional study using a postal questionnaire. SETTING: The study was conducted at a university hospital in Madrid between October 2007 and December 2008. PARTICIPANTS: 285 Spanish pregnant women. METHODS: Factor structure of a Spanish version (original 16 items test and reduced 13 items version) of the scale was analysed through exploratory factor analysis. FINDINGS: The Spanish version of the reduced 13 items version replicated the original factor structure. The internal consistency was good for the total scale (0.83) and for the subscales (0.70-0.79). Significant positive correlations between the CWS and its subscales with anxiety, depression and neuroticism were found. Similarly, acceptable to good reliability and convergent validity indexes were obtained for the original 16 items test. DISCUSSION: The present study confirmed the validity of the two Spanish versions of the CWS (16 item and reduced 13 item). Considering the performance of two of the three items eliminated from the original version and the universality in the use of the short version we recommend the use of the reduced 13 item scale. Practical implications of the use of the CWS in maternity care are discussed. PMID- 21247674 TI - The use of complementary and alternative medicine by pregnant women: a literature review. AB - BACKGROUND: The use of complementary and alternative medicine (CAM) has become increasingly prevalent in industrialised countries, with women being the most prolific users. Some women continue to consume these therapies when they become pregnant. AIM: To review the literature exploring prevalence and motivation for use of complementary and alternative medicine by pregnant women. METHOD: A search for relevant literature published from 2001 was undertaken using a range of databases and by examining relevant bibliographies. RESULTS: Although the estimates vary widely from 1% to 87%, the general trend indicates that a significant number of pregnant women use complementary and alternative medicine. Common modalities used include massage, vitamin and mineral supplements, herbal medicine, relaxation therapies and aromatherapy. Reasons for use are varied and include the belief that these therapies offer safe alternatives to pharmaceuticals, they allow greater choice and control over the childbearing experiences, and they are congruent with their holistic health beliefs. The influence of traditional cultural practices on the use of these therapies is unclear. Most expectant women rely on advice from family and friends, and many do not disclose their use to their pregnancy care providers. CONCLUSIONS: Many women use complementary and alternative medicine when they are pregnant. Further research is needed to gain a greater understanding of the true prevalence and expectant women's motivation for the use of complementary and alternative medicine. Health-care professionals are encouraged to ask women about their use of these treatments and seek out relevant information. PMID- 21247675 TI - Pilot survey of domestic abuse amongst pregnant women attending an antenatal clinic in a public hospital in Gauteng Province in South Africa. AB - BACKGROUND: Violence against women is a major contributor to the ill health of women. It can affect women and may lead to pregnancy complications or adverse birth outcomes. PURPOSE: To identify and outline domestic abuse amongst pregnant women, thereby providing preliminary data to justify the need for an abuse screening programme in the antenatal clinic. METHOD: A quantitative, descriptive cross-sectional survey. Data collection was undertaken through purposive sampling of pregnant mothers and the use of questionnaires in the form of structured interviews. FINDINGS: The overall prevalence of domestic abuse amongst pregnant women was 41%. When categorized by type of abuse, the prevalence rates were: emotional abuse, 26%; physical abuse, 17%; both physical and emotional abuse, 5%; and sexual abuse, 9%. CONCLUSIONS: There is a high prevalence of domestic abuse amongst pregnant women and there is a need for abuse assessment screening during antenatal care for all pregnant women. PMID- 21247676 TI - Spine stability: lessons from balancing a stick. AB - This paper introduces control concepts that are important for ensuring stability. To clarify these concepts, a series of experiments using a simple task of stick balancing will be performed. The lessons from these experiments will be applied to the spine system and illustrated with clinical examples. Insight into the following will be gained: what information is used to stabilize the spine, how does noise in control affect spine performance, how has the spine evolved to allow it to be stabilized and controlled in a metabolically efficient way, how do delays in control affect spine performance, and how do different goals (i.e., maximizing performance versus minimizing fatigue) affect the logic for controlling the spine? PMID- 21247677 TI - Muscle parameters for musculoskeletal modelling of the human neck. AB - BACKGROUND: To study normal or pathological neuromuscular control, a musculoskeletal model of the neck has great potential but a complete and consistent anatomical dataset which comprises the muscle geometry parameters to construct such a model is not yet available. METHODS: A dissection experiment was performed on the left side of one 50th percentile male embalmed specimen. Geometrical data including muscle attachment sites were digitized using an Optotrak measurement system and laser diffraction was used to determine muscle sarcomere lengths. Bony landmarks were recorded and joint centres of rotation between different vertebrae were estimated using literature data. FINDINGS: A total of 34 muscle parts of the neck were divided in 129 elements per body side. Muscle attachment sites, mass, physiological cross sectional area, fibre length, tendon length and optimal fibre length for each element are supplied as digital annexes to the paper. Results are coherent with other studies and new data are provided for several smaller muscles not reported elsewhere. INTERPRETATION: Implementation of this dataset into a neck model is likely to improve the estimation of muscle forces and thus increase the model validity; this makes future neck models more suitable for the use as clinical tools. PMID- 21247678 TI - Aggregation and ecotoxicity of CeO2 nanoparticles in synthetic and natural waters with variable pH, organic matter concentration and ionic strength. AB - The influence of pH (6.0-9.0), natural organic matter (NOM) (0-10 mg C/L) and ionic strength (IS) (1.7-40 mM) on 14 nm CeO2 NP aggregation and ecotoxicity towards the alga Pseudokirchneriella subcapitata was assessed following a central composite design. Mean NP aggregate sizes ranged between 200 and 10000 nm. Increasing pH and IS enhanced aggregation, while increasing NOM decreased mean aggregate sizes. The 48 h-E(r)C20s ranged between 4.7 and 395.8 mg CeO2/L. An equation for predicting the 48 h-E(r)C20 (48 h-E(r)C20 = -1626.4 * (pH) + 109.45 * (pH)2 + 116.49 * ([NOM]) - 14.317 * (pH) * ([NOM]) + 6007.2) was developed. In a validation study with natural waters the predicted 48 h-E(r)C20 was a factor 1.08-2.57 lower compared to the experimental values. PMID- 21247679 TI - Avoidance tests with Folsomia candida for the assessment of copper contamination in agricultural soils. AB - The feasibility of assessing copper accumulation in agricultural soils using avoidance tests with a Canadian strain of Folsomia candida was investigated under laboratory conditions. The avoidance response to nominal copper sulfate concentrations of 0, 200, 800, 1600 and 3200 mg kg-1 in OECD soil was inconsistent between trials with the standard plastic cup or a modified Petri dish method requiring less soil. However, combined results from three Petri dish trials decreased variability and provided a 75% avoidance level, close to the 80% criterion proposed for avoidance tests. A Copper avoidance EC50s of 18 mg kg-1 was obtained using the Petri dish method whether tests were conducted with or without light. While Petri dish tests have potential as a cheap tool to distinguish metal contaminated soils from uncontaminated soils they would be unsuitable for tracking or quantifying changes in metal concentrations. throughout remediation. Advantages and limitations of the method have been presented. PMID- 21247680 TI - Characteristics of the event mean concentration (EMC) from rainfall runoff on an urban highway. AB - The purpose of this study was to investigate the characterization of the event mean concentration (EMC) of runoff during heavy precipitation events on highways. Highway runoff quality data were collected from the 7th highway, in South Korea during 2007-2009. The samples were analyzed for runoff quantity and quality parameters such as COD(cr), TSS, TPHs, TKN, NO3, TP, PO4 and six heavy metals, e.g., As, Cu, Cd, Ni, Pb and Zn. Analysis of resulting hydrographs and pollutant graphs indicates that the peak of the pollutant concentrations in runoff occurs 20 min after the first rainfall runoff occurrence. The first flush effect depends on the preceding dry period and the rainfall intensity. The results of this study can be used as a reference for water quality management of urban highways. PMID- 21247681 TI - On airborne nano/micro-sized wear particles released from low-metallic automotive brakes. AB - The paper addresses the wear particles released from commercially available "low metallic" automotive brake pads subjected to brake dynamometer tests. Particle size distribution was measured in situ and the generated particles were collected. The collected fractions and the original bulk material were analyzed using several chemical and microscopic techniques. The experiments demonstrated that airborne wear particles with sizes between 10 nm and 20 MUm were released into the air. The numbers of nanoparticles (< 100 nm) were by three orders of magnitude larger when compared to the microparticles. A significant release of nanoparticles was measured when the average temperature of the rotor reached 300 degrees C, the combustion initiation temperature of organics present in brakes. In contrast to particle size distribution data, the microscopic analysis revealed the presence of nanoparticles, mostly in the form of agglomerates, in all captured fractions. The majority of elements present in the bulk material were also detected in the ultra-fine fraction of the wear particles. PMID- 21247682 TI - A critical account of the rise and spread of 'leadership': the case of U.K. healthcare. AB - This paper considers the rise of 'leadership' in discourses relating to the British health service, and the application of the term to increasingly heterogeneous actors. Analysing interviews with NHS chief executives from the late 1990s, and key policy documents published since, we highlight how leadership has become a term of choice among policymakers, with positive cultural valences which previously predominant terms such as 'management' now lack. We note in particular how leadership is increasingly conferred not only on those in positions of formal power but on frontline clinicians, patients and even the public, and how not just the implementation but the design of policy is now constructed as being led by these groups. Such constructions of the distribution of power in the health service, however, contradict the picture drawn by academic work. We suggest, therefore, that part of the purpose of leadership discourse is to align the subjectivities of health-service stakeholders with policy intentions, making their implementation not just everyone's responsibility, but part of everyone's sense of self. Given the realities of organizational life for many of the subjects of leadership discourse, however, the extent to which leadership retains its current positive associations and ubiquity remains to be seen. PMID- 21247684 TI - Radiorecurrent prostate cancer: an emerging and largely mismanaged epidemic. PMID- 21247685 TI - Evaluation of cerebral vasomotor reactivity in Parkinson's disease: is there any association with orthostatic hypotension? AB - OBJECTIVE: Our aim was to look for a probable relationship between cerebral vasomotor reactivity (VMR) and orthostatic hypotension (OH) in Parkinson's disease (PD). MATERIALS AND METHODS: This study was conducted on 44 patients with PD. Assessment of cerebral VMR was performed by means of transcranial Doppler (TCD) of middle cerebral artery (MCA) before and after a vasodilatory stimulus, carbon dioxide test. Moreover, orthostatic hypotension was evaluated. RESULTS: OH was presented in 12 (27.3%) Parkinson's patients. The average resting blood flow velocity (BFV) in the MCA was 30.20 (SD=9.58)cms(-1) which significantly increased to 46.25 (SD=16.23)cms(-1) after carbon dioxide test (P<0.001). Impaired VMR was observed in 15 (34.1%) of the subjects, while it was not associated with the presence of OH (P=0.770). CONCLUSION: Evaluation of VMR in patients affected by PD, could assist in early diagnosis of cerebral autonomic dysfunction and prevent its serious consequences prior and more valid to OH. PMID- 21247686 TI - Hippo signaling in oval cells and hepatocarcinogenesis. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies and the third leading cause of cancer mortality world wide. Despite continuing development of new therapies, the prognosis for patients with HCC remains extremely poor. In part, this may relate to molecular abnormalities that stimulate HCC tumorigenesis and also contribute to reduced sensitivity to standard treatment. Increasing evidence has revealed the importance of liver cancer stem cells in hepatocarcinogenesis. Although widely investigated, the signaling pathways important for liver cancer stem cells in liver tumor initiation and progression are poorly understood. The Hippo signaling pathway was identified in Drosophila as an essential regulator of cell proliferation and apoptosis. Recently, Hippo pathway has been implicated in multiple events during development and it has also been proposed to play a vital role in several tumor types, especially in hepatocellular carcinoma. Strong evidences also proved the significant role of the Hippo signaling pathway in oval cell activation. As suggested, hippo signaling has a dual regulation of Hippo in liver tumor suppression as well as transition of oval cells to fully differentiated hepatocytes. Delineation of the malfunction of Hippo signaling pathway in HCC may lead to better understanding of hepatocarcinogenesis, rational medical therapy for HCC and possible therapy for other tumors. Here, we provide a historical review of this potent growth-regulatory pathway in HCC and highlight outstanding questions that will likely be the focus of future investigation. PMID- 21247687 TI - Geochemical speciation and risk assessment of heavy metals in the river estuarine sediments--a case study: Mahanadi basin, India. AB - Sequential extraction technique was used to study the mobility and dynamics of operationally determined chemical forms of heavy metals in the sediments and their ecological risk on the biotic species. The results reveal that high environmental risk of Cd, Ni, Co and Pb, are due to their higher availability in the exchangeable fraction. Substantial amount of Cd, Co, Mn, Cu, Zn, Ni and Pb, is observed as carbonate bound, which may result due to their special affinity towards carbonate and their co-precipitation with its minerals. Colloids of Fe-Mn oxides act as efficient scavengers for the heavy metals like Zn, Pb, Cu, Cr, Co, and Ni. Toxic metals like Ni, Pb and Cd are of concern, which occasionally may be associated with adverse biological effects based on the comparison with sediment quality guidelines (SQGs). The risk assessment code (RAC) suggests that the highest mobility of Cd poses a higher environmental risk and also threat to the aquatic biota. Factor analysis reveals that the enrichment of heavy metals in bioavailable fraction is mostly contributed from anthropogenic sources. These contributing sources are highlighted by cluster analysis. PMID- 21247688 TI - Attribute based specification, comparison and selection of feed stock for anaerobic digestion using MADM approach. AB - Organic wastes are common in nature and generated at different sources which need to be treated before disposing into the environment. Anaerobic digestion (AD) process is a primary technique used for digestion and reduction of the ill effects of disposing the organic waste. Selection of appropriate feed stock for anaerobic digestion among the available options is a primary concern and the process efficiency and stability largely depend on this. The present paper describes a methodology for evaluation, comparison, ranking and optimum selection of a feed stock for anaerobic digestion. A 30 attribute coding scheme is proposed to evaluate the existing alternatives for feed stock of anaerobic digester. A three stage procedure which includes the elimination search is proposed to evaluate the available alternatives with the help of attributes quickly. Technique for order preference by similarity to ideal solution (TOPSIS) is a Multiple Attribute Decision Making (MADM) approach and graphical methods namely line graph and spider diagrams are used for optimum selection of feed stock among the available options. MATLAB code is written to execute the three stage procedure. The proposed methodology is explained through an illustrated example. PMID- 21247689 TI - Semi-dynamic leaching tests of nickel containing wastes stabilized/solidified with magnesium potassium phosphate cements. AB - Herein is presented a study on the long-term leaching behaviour of nickel containing wastes stabilized/solidified with magnesium potassium phosphate cements. Two different semi-dynamic leaching tests were carried out on monolithic materials: ANS 16.1 test with liquid-to-solid ratio (L/S) of 10 dm(3) kg(-1) and increasing renewal times, and ASTM C1308 test with liquid-to-solid ratio (L/S) of 100 dm(3) kg(-1) and constant renewal time of 1 day. ASTM C1308 provides a lower degree of saturation of the leachant with respect to the leached material. The effectiveness of magnesium potassium phosphate cements for the inertization of nickel was proved. XRD analyses showed the presence of bobierrite on the monolith's surface after the leaching test, which had not been detected prior to the leaching test. In addition, the calculated cumulative release of the main components of the stabilization matrix (Mg(2+), total P and K(+)) was represented versus time in logarithmic scale and it was determined if the leaching mechanism corresponds to diffusion. Potassium is released by diffusion, while total phosphorous and magnesium show dissolution. Magnesium release in ANS 16.1 is slowed down because of saturation of the leachant. Experimental results demonstrate the importance of L/S ratio and renewal times in semi-dynamic leaching tests. PMID- 21247690 TI - Procedural uncertainties of Proctor compaction tests applied on MSWI bottom ash. AB - MSWI bottom ash is a well-graded highly compactable material that can be used as a road material in unbound pavements. Achieving the compactness assumed in the design of the pavement is of primary concern to ensure long term structural stability. Regulations on road construction in a number of EU countries rely on standard tests originally developed for natural aggregates, which may not be appropriate to accurately assess MSWI bottom ash. This study is intended to assist in consistently assessing MSWI bottom ash compaction by means of the Proctor method. This test is routinely applied to address unbound road materials and suggests two methods. Compaction parameters show a marked procedural dependency due to the particle morphology and weak particle strength of ash. Re compacting a single batch sample to determine Proctor curves is a common practise that turns out to overvalue optimum moisture contents and maximum dry densities. This could result in wet-side compactions not meeting stiffness requirements. Inaccurate moisture content measurements during testing may also induce erroneous determinations of compaction parameters. The role of a number of physical properties of MSWI bottom ash in compaction is also investigated. PMID- 21247691 TI - Impact of soil particle size and bioaccessibility on children and adult lead exposure in peri-urban contaminated soils. AB - The impact of soil particle size and bioaccessibility on children and adult lead (Pb) exposure via the incidental soil ingestion pathway was assessed in 16 peri urban contaminated soils. A comparison of Pb distribution across 4 particle size fractions (<50 MUm, <100 MUm, <250 MUm and <2 mm) found increasing Pb concentrations associated with decreasing particle size fractions. Lead enrichment in the <50 MUm particle size fraction was up to 5 times the concentration observed in the bulk soil. When gastric phase Pb bioaccessibility was determined in the <50, <100 and <250 MUm particle size fractions using the SBRC assay, Pb bioaccessibility also increased with decreasing particle size fraction for 6 of the 16 soils tested. Assessment of children and adult Pb exposure indicated that particle size and bioaccessibility had a significant influence on the contribution of incidental soil ingestion to daily Pb intake values. Although the <250 MUm particle size fraction is recommended for incidental soil ingestion calculations, using this fraction has the potential to underestimate Pb exposure due to the preferential adhesion of smaller particles to hands with elevated Pb concentrations. PMID- 21247692 TI - Modelling the pH dependence of the kinetics of aerobic p-nitrophenol biodegradation. AB - There are a number of publications in the literature that might indicate a connection between pH and the kinetics of the aerobic p-nitrophenol (PNP) biodegradation. In this study two hypotheses were postulated to elucidate the kinetics dependence on pH: (i) the substrate inhibition does not depend on the pH value, therefore the half-saturation coefficient and the substrate inhibition constant will be the same at any pH and (ii) the substrate inhibition depends on the pH value, therefore the half-saturation coefficient and the substrate inhibition constant will have a different value depending on the pH. A PNP degrading activated sludge was used to carry out three batch respirometric experiments at different pH values: 6.5+/-0.1, 7.0+/-0.1, 8.0+/-0.1. The ability to describe the experimental results with the kinetic models derived from both postulated hypotheses was quantitatively evaluated through the norm of the prediction error array. The time course of specific oxygen uptake rate and PNP concentration was satisfactorily described by a Haldane kinetics that includes the pH effect, based on the PNP acid-base equilibrium, on the kinetic parameters. The results suggest that the nonionised form of PNP is the real substrate and also the inhibitor of the aerobic PNP biodegradation. PMID- 21247693 TI - Surface-modified Phanerochaete chrysosporium as a biosorbent for Cr(VI) contaminated wastewater. AB - To improve the removal efficiency of heavy metals from wastewater, the surface of a fungal biomass was modified to obtain a high-capacity biosorbent for Cr(VI) in wastewater. The effects of pH, initial concentration, and sorption time on Cr(VI) removal by polyethylenimine (PEI)-modified Phanerochaete chrysosporium were investigated. The biomass adsorption capacity was significantly dependent on the pH of the solution, and the optimum pH was approximately 3.0. The maximum removal for Cr(VI) was 344.8 mg/g as determined with the Langmuir adsorption isotherm. Pseudo-first-order Lagergren model is better than pseudo-second-order Lagergren model when simulating the kinetic experiment results. Furthermore, an amount of Cr(VI) was reduced to Cr(III), indicating that some reactions occurred on the surface of the biomass leading to the reduction of Cr(VI). The point of zero potential for the modified biomass increased from an initial pH of 3.0 to a much higher value of 10.8, indicating that the PEI-modified biomass is better than the pristine biomass for adsorption of anionic adsorbates. Results showed that the PEI-modified biosorbent presented high efficiency in treating Cr(VI)-contaminated wastewater. PMID- 21247694 TI - Capture of Co(II) from its aqueous EDTA-chelate by DTPA-modified silica gel and chitosan. AB - The adsorption of Co(II) by diethylenetriaminepentaacetic acid (DTPA)-modified silica gel and chitosan in the presence of EDTA and other interfering species was studied. Co(II) removal ranged from 93% to 96% from the solutions where Co(II) was totally chelated by EDTA. The amount of oxalate or Fe(II) did not affect the adsorption of Co(II) in the case of DTPA-chitosan. However, increasing the amount of oxalate enhanced the adsorption performance of DTPA-silica gel, probably due to the formation of new active sites on the silica gel surface. DTPA-chitosan was also effective in simulated decontamination solutions. For DTPA-silica gel, the rate of adsorption of free Co(II) was controlled by pore diffusion, but the rate of adsorption of Co(II)EDTA was controlled by the surface chelation reaction, which was attributed to the inhibited diffusion of Co(II)EDTA inside the silica gel mesopores. However, the macroporous structure of DTPA-chitosan enabled pore diffusion of both Co(II) and Co(II)EDTA. The equilibrium isotherms of DTPA-silica gel were best described by a BiLangmuir model, in which there are two different adsorption sites on the silica gel surface assigned to different speciations of DTPA. For DTPA-chitosan, the data fit best with a Sips model, which indicates system heterogeneity. Finally, measurements with capillary electrophoresis showed an increase in dissolved EDTA during adsorption, demonstrating the ability of DTPA-modified adsorbents to release Co(II) from its EDTA chelate. This promising result can provide a basis for applying the studied materials to the treatment of water effluents containing Co(II) chelated by EDTA by a simple one-step adsorption process. PMID- 21247695 TI - Thermal and catalytic degradation of polyethylene wastes in the presence of silica gel, 5A molecular sieve and activated carbon. AB - A comparative study of thermal and catalytic degradation of polyethylene wastes has been carried out with the aim of obtaining chemical compounds with potential use in the chemical industry and the energy production. Polyethylene wastes were obtained from polyethylene bags used in supermarkets. Catalysts utilized in the study were silica gel, 5A molecular sieve and activated carbon. The pyrolysis was performed in a batch reactor at 450, 500 and 700 degrees C during 2h for each catalyst. The ratio catalyst/PE was 10% w/w and the solid and gaseous products were analyzed by gas chromatography and mass spectrometry. The optimum operation temperature and the influence of the three catalysts are discussed with regards to the products formed. The best temperature for degradation with silica gel and activated carbon as catalysts was 450 degrees C and with 5A molecular sieve was 700 degrees C. Degradation products of PE (solid fraction and gas fraction) are depending on temperature and catalyst used. External surface and structure of catalysts were visualized by Scanning Electron Microscopy (SEM) and the contribution on product distribution is commented. All products from different degradations could be used as feed stocks in chemical industry or in energy production based on the value of heat of combustion for solid fraction (45000 J/g), similar to the heat of combustion of commercial fuels. PMID- 21247697 TI - Use of strong opioids among community-dwelling persons with and without Alzheimer's disease in Finland. AB - The objective of this study was to investigate the national pattern of strong opioid use among community-dwelling persons with and without Alzheimer's disease (AD) in Finland. All persons (n=28,093) with a diagnosis of AD in 2005 were identified by the Social Insurance Institution of Finland (SII). For each person with AD, the SII identified a comparison person individually matched in terms of age (+/-1year), sex, and region of residence. Records of all reimbursed drug purchases in 2005 were extracted from the Finnish National Prescription Register. Conditional logistic regression was used to calculate unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for reimbursed opioid use. The age of the persons with and without AD ranged from 42 to 101 (mean 80.0) years, with men comprising 32.2% (n=9048) of persons. The annual prevalence of reimbursed opioid use was 3.0% (n=273) and 3.8% (n=727) among men and women with AD, respectively. The use of all reimbursed opioids was lower among persons with AD compared with those without AD (adjusted OR 0.77, 95% CI 0.71 to 0.84). The use of strong opioids (adjusted OR 1.26, 95% CI 1.05 to 1.51) and fentanyl (adjusted OR 1.44, 95% CI 1.13 to 1.83) was higher among persons with AD. Our study did not assess the stage or severity of AD, nor the opioid doses prescribed. However, the results highlight the challenges associated with diagnosing and treating pain in this population, and the importance of balancing the risk of adverse drug reactions against the ease of transdermal administration. Use of opioid analgesics was lower among 28,089 persons with Alzheimer's disease (AD) compared with individually matched comparison persons without AD. However, use of strong opioids and transdermal fentanyl was more prevalent among persons with AD. PMID- 21247696 TI - Yoga for persistent pain: new findings and directions for an ancient practice. PMID- 21247698 TI - Shaping the lens of the atom probe: fabrication of site specific, oriented specimens and application to grain boundary analysis. AB - The random sampling provided by classical atom probe sample preparation methods is one of the major factors limiting the types of problems that can be addressed using this powerful technique. A focused ion beam enables not only site-specific preparation, but can also be used to give the specimen, which acts as the lens in an atom probe experiment, a specific shape. In this paper we present a technique that uses low accelerating voltages (10 and 5 kV) in the focused ion beam (FIB) to reproducibly produce specimens with selected grain boundaries <100 nm from the tip at any desired orientation. These tips have a high rate of successfully running in the atom probe and no Ga contamination within the region of interest. This technique is applied to the analysis of grain boundaries in a high purity iron wire and a strip-cast steel. Lattice resolution is achieved around the boundary in certain areas. Reconstruction of these datasets reveals the distribution of light and heavy elements around the boundary. Issues surrounding the uneven distribution of certain solute elements as a result of field-induced diffusion are discussed. PMID- 21247699 TI - Ordering and site occupancy of D03 ordered Fe3Al-5 at%Cr evaluated by means of atom probe tomography. AB - Addition of ternary elements to the D0(3) ordered Fe(3)Al intermetallic phase is a general approach to optimise its mechanical properties. To understand the physical influences of such additions the determination of the probability of site occupancies of these additions on the lattice site and ordering parameters is of high interest. Some common experimental techniques such as X-ray diffraction or Atom Location by Channelling Enhanced Microanalysis (ALCHEMI) are usually applied to explore this interplay. Unfortunately, certain published results are partly inconsistent, imprecise or even contradictory. In this study, these aspects are evaluated systematically by atom probe tomography (APT) and a special data analysis method. Additionally, to account for possible field evaporation effects that can falsify the estimation of site occupancy and induce misinterpretations, APT evaporation sequences were also simulated. As a result, chromium occupies most frequently the next nearest neighbour sites of Al atoms and local ordering parameters could be achieved. PMID- 21247700 TI - Methods of quantitative matrix analysis of Zircaloy-2. AB - The zirconium-based alloy Zircaloy-2 contains small amounts of iron, chromium and nickel dissolved in the matrix. Several attempts to measure these amounts have been made in the past, but the results are conflicting and inconclusive. The advent of wide angle, laser pulsed atom probe tomography motivates a new attempt to analyze the matrix. Large datasets are now easily obtained using laser pulsing but quantification is not straightforward due to rather complex mass spectra. Zircaloy-2 contains about 1 wt% tin, 0.1 wt% oxygen and trace amounts of Si, C and Al. Severe overlaps make quantification of any Fe(+), Cr(+) and Ni(+) ions impossible. Quantification of Fe, Cr and Ni therefore requires that they appear as doubly charged ions only, and consequently the field must be kept high enough. In addition, adsorbed CO(+) may appear at the main peak of Fe(2+). In the paper a method is reported, which gives what we believe an accurate quantitative analysis of at least iron and chromium in the matrix. PMID- 21247701 TI - Optimisation of specimen temperature and pulse fraction in atom probe microscopy experiments on a microalloyed steel. AB - This paper details the effects of systematic changes to the experimental parameters for atom probe microscopy of microalloyed steels. We have used assessments of the signal-to-noise ratio (SNR), compositional measurements and field desorption images to establish the optimal instrumental parameters. These corresponded to probing at the lowest possible temperature (down to 20K) with the highest possible pulse fraction (up to 30%). A steel containing a fine dispersion of solute atom clusters was used as an archetype to demonstrate the importance of running the atom probe at optimum conditions. PMID- 21247702 TI - Prevalence of IgG antibodies to Encephalitozoon cuniculi and Toxoplasma gondii in cats with and without chronic kidney disease from Virginia. AB - Kidney disease is a common and serious condition in domestic cats. There are numerous causes of kidney disease including parasitic infection. Encephalitozoon cuniculi is a microsporidian parasite that develops in the kidneys of rabbits and causes chronic renal disease. Little has been reported concerning E. cuniculi in cats and no serological studies on this parasite in cats have been conducted in the United States to date. The present study explored the possibility that E. cuniculi is an unrecognized contributor to the high prevalence of kidney disease observed in cats. A serological survey was conducted to determine the prevalence of IgG antibodies to spores of E. cuniculi in cats with and without a diagnosis of chronic kidney disease (CKD) according to the International Renal Interest Society (IRIS) staging system. Likewise, samples were examined for IgG antibodies to Toxoplasma gondii, a common well studied protozoan of cats. Plasma and sera were obtained from 232 feline patients at the Virginia-Maryland Regional College of Veterinary Medicine teaching hospital. With the investigators blinded to the renal status of test subjects, samples were screened via indirect immunofluorescent antibody assay (IFA). Thirty-six of the 232 cats met the IRIS staging system criteria for CKD. Antibodies to E. cuniculi were found in 15 of the 232 samples, which included 4 of the 36 cats with CKD. Sera from cats serologically positive to E. cuniculi did not react to spores of E. intestinalis or E. hellem when examined in the IFA. Antibodies to T. gondii were found in 63 of the 232 samples, which included 10 of the 36 cats with CKD. The prevalence of antibodies in cats with CKD to either protozoan was not significantly different (P>0.05) from the cats without CKD in the study. Collectively the results do not support the hypothesis that either E. cuniculi or T. gondii play a significant etiologic role in the occurrence or progression of CKD in cats. PMID- 21247703 TI - Occurrence of nematodes and anthelmintic management of ostrich farms from different Brazilian states: Libyostrongylus douglassii dominates mixed infections. AB - Ostriches were imported to Brazil in the early 1990s without appropriate parasite control leading to a co-importation of parasites. Libyostrongylus douglassii, Libyostrongylus dentatus and Codiostomum struthionis are nematodes of the ostriches that have been reported on some Brazilian farms but no national survey has been performed. Moreover, little is known about anthelmintic usage to control these parasites in Brazil. Therefore, the occurrence of L. douglassii, L. dentatus and C. struthionis and the anthelmintic management practices in Brazilian ostrich farms were studied. A questionnaire about management practices and information on how to collect, store and ship feces to the laboratory were sent to 17 farms located in 9 Brazilian states. Received fecal samples were submitted to fecal cultivation and larval harvested. Infective larvae were morphologically analyzed and quantified. The majority of the farms (88%) used an anthelmintic at least once a year. Ivermectin was the principal anthelmintic. Libyostrongylus sp. and C. struthionis were found in samples from 76 and 18% of the examined farms, respectively. The presence of L. douglassii (61-97%) was higher than L. dentatus (3-57%) and C. struthionis (2-30%). At the farm level, both species of Libyostrongylus were always found together. Sheath tail measurements of their infective larvae were crucial for morphological diagnosis. L. dentatus and L. douglassii are well adapted to Brazil and are widely distributed in the Brazilian territory, proving that this mixed infection in Brazilian ostrich's farms is common. PMID- 21247704 TI - Effects of dietary non-starch polysaccharides on establishment and fecundity of Heterakis gallinarum in grower layers. AB - It was hypothesized that the establishment and fecundity of Histomonas meleagridis free Heterakis gallinarum may be affected by dietary non-starch polysaccharides (NSPs). One-day-old female layer chicks (N=670) were fed ad libitum for 11wk one of the following diets in a three-times repeated experiment: basal diet (CON), basal diet plus pea bran rich in insoluble NSP (I-NSP), basal diet plus chicory root meal as a source of inulin rich soluble NSP (S-NSP). At the end of wk three, each feeding group was subdivided into an uninfected and an infected group of birds each being inoculated with a placebo or with 200 H. meleagridis free eggs of H. gallinarum. The birds were slaughtered 8wk post infection and their worm burdens, the nematode egg excretion, caeca sizes and weights as well as intracaecal pH and volatile fatty acid (VFA) concentrations were determined. The NSP supplemented diets and also infection led to reduced body weights (BWs) of birds and impaired the feed conversion rate (P<0.001). The NSP supplemented diets increased average length of caecum (P<0.001) with S-NSP exerting a stronger effect than I-NSP (P<0.05). Full caeca weight was increased by S-NSP (P<0.001). Feeding S-NSP lowered intracaecal pH and molar proportion of acetate and increased that of butyrate compared to CON and I-NSP (P<0.001). Caecal pool of VFA was increased with S-NSP (P<0.001). The NSP-diets elevated incidence of infection (P<0.01), average number of larvae (P<0.009) and total worm burden (P<0.001) compared to CON. The daily amount of faeces increased in NSP-fed birds (P<0.001). Number of eggs per gram of faeces (EPG), number of eggs excreted per worm population of a bird within 24h (EPD) and female worm fecundity (EPD/female worm) were elevated after feeding S-NSP (P<=0.002), whereas I-NSP led to lower EPG/female worm (P<0.05). The EPD increased in the sequence of CON= 7 mmol/L; or (4) glycosylated haemoglobin >= 6.2%. Logistic regressions were used to estimate odds ratios (OR [with 95% confidence intervals]) for diabetes, with stepwise adjustments for demographic, lifestyle, and clinical factors. RESULTS: Diabetes prevalence was positively associated with age groups 45-54 years (2.8 [1.4, 5.8]), 55-64 years (3.9 [1.9, 8.3]) and >= 65 years (4.0 [1.8, 8.9]), lowest income group (1.8 [1.0, 3.4]), ex-smoker (1.8 [1.2, 2.9]), lowest (3.2 [1.9, 5.5]) and middle (1.9 [1.1, 3.4]) alcohol tertiles, cardiovascular disease (1.9 [1.2, 2.8]), metabolic syndrome (4.0 [2.6, 6.1]), and lowest plasma total testosterone tertile (1.8 [1.1, 3.0]), but negatively associated with middle (0.5 [0.3, 0.8]) and highest (0.4 [0.3, 0.7]) sugar intake tertiles, arthritis (0.6 [0.3, 1.0]), and elevated LDL cholesterol (0.5 [0.3, 0.8]); ORs showed an inverted 'U' shape for middle and highest voiding lower urinary tract symptoms tertiles. Body composition, muscle strength, and cardio-metabolic factors partially explained the association between low plasma total testosterone and diabetes. CONCLUSIONS: Plasma total testosterone was inversely and independently associated with diabetes prevalence, that might have been partially explained by several modifiable risk factors. PMID- 21247711 TI - Uterine sarcomas--recent progress and future challenges. AB - Uterine sarcomas are a group of rare tumours that provide considerable challenges in their treatment. Radiological diagnosis prior to hysterectomy is difficult, with the diagnosis frequently made post-operatively. Current staging systems have been unsatisfactory, although a new FIGO staging system specifically for uterine sarcomas has now been introduced, and may allow better grouping of patients according to expected prognosis. While the mainstay of treatment of early disease is a total abdominal hysterectomy, it is less clear whether routine oophorectomy or lymphadenectomy is necessary. Adjuvant pelvic radiotherapy may improve local tumour control in high risk patients, but is not associated with an overall survival benefit. Similarly there is no good evidence for the routine use of adjuvant chemotherapy. For advanced leiomyosarcoma, newer chemotherapy agents including gemcitabine and docetaxel, and trabectedin, offer some promise, while hormonal therapies appear to be more useful in endometrial stromal sarcoma. Novel targeted agents are now being introduced for sarcomas, and uterine sarcomas, and show some indications of activity. Non-pharmacological treatments, including surgical metastatectomy, radiofrequency ablation, and CyberKnife((r)) radiotherapy, are important additions to systemic therapy for advanced metastatic disease. PMID- 21247712 TI - Imaging disease of the female pelvis. PMID- 21247713 TI - Hyperintensity on diffusion weighted image along ipsilateral cortical spinal tract after cerebral ischemic stroke: a diffusion tensor analysis. AB - PURPOSE: Hyperintensity along the ipsilateral cortical spinal tract (CST) on a diffusion weighted imaging (DWI) has been reported to may be associated with motor disability after brain infarction and can be misdiagnosed as a new infarction. However, the underlying patho-physiology related to this finding is not clear. The goal of our study was to analyze the diffusion tensor imaging (DTI) changes in patients with this hyperintensity. MATERIALS AND METHODS: Eight patients (50 +/- 10 years) who exhibited hyperintensity on DWI along ipsilateral CST from 3 to 21 days after stroke onset were reviewed as positive group, including 5 patients with serial DTI examinations. Twelve patients without hyperintensity during the matched examination time were classified as reference group. The apparent diffusion coefficient (ADC), fractional anisotropy (FA), and eigenvalues and their ratios (ipsilateral/contralateral value) in cerebral peduncle were measured, their correlation with motor function scale at eight months after stroke onset were evaluated. RESULTS: The serial examinations showed that hyperintensity could eventually disappear. Both the ipsilateral ADC and FA values were significantly decreased (p<0.05) compared to the contralateral side. The ipsilateral FA significantly correlated with motor function scale in both groups (r = 0.875, 0.738; p = 0.004, 0.006 respectively). CONCLUSIONS: The hyperintensity on DWI is a transient pathological process of Wallerian degeneration after ischemic stroke, its diffusion characteristics include concurrent significant decrease of ipsilateral ADC and FA. The ipsilateral FA value has the potential to predict neurological motor function outcome in such patients. PMID- 21247714 TI - Delineation of Stenotrophomonas spp. by multi-locus sequence analysis and MALDI TOF mass spectrometry. AB - The genus Stenotrophomonas is genetically and phenotypically heterogeneous. Of the nine species now accepted, only S. maltophilia is of clinical importance. Based on DNA-sequences of seven house keeping genes, it encompasses genogroups of DNA-similarity below 97% that predominantly comprise strains of environmental origin. Therefore, in order to unravel the uneven distribution of environmental isolates within genogroups and reveal genetic relationships within the genus, there is need for an easy and reliable approach for the identification and delineation of Stenotrophomonas spp. In this first study, a multi-locus sequence analysis (MLSA) with seven housekeeping genes (atpD, gapA, guaA, mutM, nuoD, ppsA and recA) was applied for analysis of 21 S. maltophilia of environmental origin, Stenotrophomonas spp. and related genera. The genotypic findings were compared with the results of matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS) analyses. Our MLSA provided reliable inter- and intra-species discrimination of all tested isolates that correlated with the MALDI-TOF mass spectrometry data. One distantly related genogroup of environmental S. maltophilia strains needs to be reclassified as S. rhizophila. However, there are still remaining delineated S. maltophilia genogroups of predominantly environmental origin. Our data provide further evidence that 'Pseudomonas'beteli is a heterotypic synonym of S. maltophilia. Based on MLSA and MALDI-TOF data, Stenotrophomonas sp. (DSM 2408) belongs to S. koreensis. PMID- 21247715 TI - Differentiation of species of the Streptococcus bovis/equinus-complex by MALDI TOF Mass Spectrometry in comparison to sodA sequence analyses. AB - The Streptococcus bovis/equinus complex is a heterogeneous group within the group D streptococci with important clinical relevance regarding infective endocarditis, sepsis and colon carcinoma. The taxonomic identification of species and sub-species of this complex, by the standard methods remains difficult. In the present study, we compared the cluster analysis of 88 strains of species of the S. bovis/equinus complex by sequence analysis of the manganese-dependent superoxide dismutase gene (sodA) and by Matrix Assisted Laser Desorption/Ionization-Time Of Flight Mass Spectrometry (MALDI-TOF MS). We observed a high congruence of strain grouping by MALDI-TOF MS in comparison with sodA sequence analyses, demonstrating the accuracy and reliability of MALDI-TOF MS in comparison to DNA sequence-based method. By generating mass spectra for each species and sub-species, we were able to discriminate all members of the S. bovis/equinus complex. Furthermore, we demonstrated reliable identifications to the species level by MALDI-TOF MS, independently of cultivation conditions. PMID- 21247716 TI - Rapid identification of Legionella spp. by MALDI-TOF MS based protein mass fingerprinting. AB - A set of reference strains representing 38 different Legionella species were submitted to Whole Cell Mass Spectrometry (WCMS) with MALDI-TOF. The dendrogram computed from strain mass spectral patterns obtained by WCMS was compared to the phylogenetic tree obtained from macrophage infectivity potentiator (mip) sequences. The trees inferred from these two methods revealed significant homologies. Using 453 Legionella isolates previously characterized by genotyping, it was possible to create species-specific SuperSpectra, using appropriate sets of spectral masses, allowing unambiguous differentiation and identification of the most frequently isolated Legionella species. These SuperSpectra were tested for their suitability to identify Legionella strains isolated from water samples, cooling towers, potting soils and patient specimens deposited at the Swiss National Reference Centre for Legionella and previously identified by molecular methods such as mip gene sequencing. 99.1% of the tested strains isolated from the environment could be correctly identified by comparison with the new SuperSpectra. The identification of Legionella spp. by MALDI-TOF MS is rapid, easy to perform and has the advantage of being time- and cost-saving, in comparison to sequence-based identification. PMID- 21247717 TI - Mapping of neural activity produced by thermal pain in the healthy human spinal cord and brain stem: a functional magnetic resonance imaging study. AB - Functional magnetic resonance imaging (fMRI) has greatly advanced our current understanding of pain, although most studies to date have focused on imaging of cortical structures. In the present study, we have used fMRI at 3 T to investigate the neural activity evoked by thermal sensation and pain (42 degrees C and 46 degrees C) throughout the entire lower neuroaxis from the first synapse in the spinal cord rostral to the thalamus in healthy subjects. The results demonstrate that noxious thermal stimulation (46 degrees C) produces consistent activity within various structures known to be involved in the pain matrix including the dorsal spinal cord, reticular formation, periaqueductal gray and rostral ventral medulla. However, additional areas of activity were evident that are not considered to be part of the pain matrix, including the olivary nucleus. Thermal stimulation (42 degrees C) reported as either not painful or mildly painful produced quantitative, but not qualitative, differences in neuronal activity depending on the order of experiments. Activity was greater in the spinal cord and brain stem in earlier experiments, compared with repeated experiments after the more noxious (46 degrees C) stimulus had been applied. This study provides significant insight into how the lower neuroaxis integrates and responds to pain in humans. PMID- 21247718 TI - Development of chiral liquid chromatography-tandem mass spectrometry isotope dilution methods for the determination of unconjugated and total S-equol in human plasma and urine. AB - Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for the determination of unconjugated and total (conjugated plus unconjugated) S-equol in human plasma and urine were developed and validated. The separation of R and S enantiomers was achieved with a Chiracel OJ-H column operated in a normal phase mode using ethanol/hexane mobile phase components. Ionization of S-equol by negative ion electrospray generated the [M-H](-) ion whose response was augmented by post-column addition of ammonium hydroxide. A triple stage quadrupole mass spectrometer was used to measure the ion current generated from the dissociative transitions m/z 241->m/z 121 (S-equol) and m/z 245->m/z 123 (equol-d(4)). The determination of total S-equol included an additional deconjugation step involving incubation of the sample with sulfatase and glucuronidase. Average recovery for both unconjugated and total S-equol was 85% with no observable matrix effects. Linearity was established for unconjugated S-equol from 0.025ng/mL to 10ng/mL (plasma) and 0.20ng/mL to 200ng/mL (urine). The average coefficient of variation and accuracy per occasion was within +/-15% of the theoretical concentration of S-equol. The method was used to measure the pharmacokinetics of S-equol in human plasma after an oral administration of a single 20mg dose of S-equol to three normal healthy volunteers. PMID- 21247719 TI - HPLC/MS/MS for quantification of two types of neurotransmitters in rat brain and application: myocardial ischemia and protection of Sheng-Mai-San. AB - Sheng-Mai-San (SMS), a traditional Chinese multiherbal formula, is widely used in clinic for the treatment of myocardial ischemia (MI) in China. Recently, it has been shown that the change of neurotransmitters in central nervous system is closely related to the pathogenesis of MI, whether SMS might affect the neurotransmitters at central nervous system in MI patients has not been studied yet. In this study, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of two types of neurotransmitters (neuropeptides and monoaminergic neurotransmitters) in rat brain tissue was developed. The instrument was operated under the multiple reaction monitoring (MRM) mode using electrospray ionization (ESI) in the positive ion mode. A good linear relationship with coefficients >=0.99 was achieved over the concentration ranges of 10-1000ngmL(-1) for 5-hydroxytryptamine (5-HT) and norepinephrine (NE); 2-250ngmL(-1) for methionine-enkephalin (M-ENK) and leucine-enkephalin (L-ENK). Quantification limit for 5-HT and NE was 4.0ngmL(-1); and 2.0ngmL(-1) for M-ENK and L-ENK. The intra- and inter-day precision was less than 15% and accuracy was within +/-15%. The analysis revealed significant reductions at the levels of 5-HT (p<0.01), NE (p<0.01), M-ENK (p<0.05) and L-ENK (p<0.01) in the MI group compared to the control group. These findings demonstrate that myocardial ischemia reduces the concentrations of 5-HT, NE, M-ENK and L-ENK in rat brains, while SMS shows protective effects on MI associated with reversing these four neurotransmitters to sham levels. PMID- 21247720 TI - Highly sensitive DNA detection with a combination of 2 DNA-intercalating dyes for microchip electrophoresis. AB - A highly sensitive DNA detection method using a combination of ethidium bromide (EtBr) and SYBR Green II (SG II) for microchip electrophoresis was developed. By use of the combination of these intercalating DNA-staining dyes for microchip electrophoresis with Hitachi SV1100 system, the fluorescence intensities corresponding to DNA fragments were obviously increased over those obtained with EtBr only, with accuracy of DNA sizing and quantification. The detection limit with EtBr and the combination of EtBr and SG II were 0.048 and 0.007ng/MUl, respectively. This highly sensitive DNA detection just using the combination of these dyes offering high resolution in a short time will be useful for various biological analyses. PMID- 21247721 TI - Simultaneous analysis of moisture, active component and cake structure of lyophilized powder for injection with diffuse reflectance FT-NIR chemometrics. AB - This paper establishes a novel method for the simultaneous analysis of moisture, active component and cake structure of lyophilized powder for injection using diffuse reflectance Fourier transform near infrared (FT-NIR) chemometrics. The experiment indicated that the back-propagation artificial neural network (BP-ANN) was suitable for the content predictions of moisture and active component; the root mean square errors of prediction (RMSEPs) were 0.1471 and 0.0082, the correlation coefficients (Rs) of prediction 0.9553 and 0.9891. And the self organizing map (SOM) was adapted to the discrimination of cake structures; the prediction accuracy was 100.0%. PMID- 21247722 TI - A fatal case of necrotizing Aeromonas schubertii fasciitis after penetrating injury. AB - Necrotizing fasciitis is an uncommon but life-threatening condition with a high associated mortality and morbidity. Most infections are polymicrobial, another distinct form of necrotizing fasciitis that occurred by penetrating freshwater trauma, such as fishing or wading in wet fields. Aeromonas species are responsible. The rapidity of the infectious process is similar to that of clostridial infection, but gas production is not a consistent feature. We report a patient who presented with fever, chills, and bullae on left forearm, despite antibiotics and wound debridement; the infection extend to mid humerus with a rapid onset of skin necrosis and progressive sepsis. Aeromonas schubertii fasciitis is particularly virulent. An apparent superficial cellulitis that fails to respond to standard therapy must raise suspicion of a more extensive underlying subcutaneous infection. Aggressive surgical debridement and antibiotic coverage for gram-negative rods are the essential features of treatment. Delay caused by a mistaken diagnosis of cellulitis and subsequent inadequate debridement would likely prove fatal. PMID- 21247723 TI - Cancer diagnosis and outcomes in Michigan EDs vs other settings. AB - OBJECTIVE: This study determined the proportion of incident colorectal and lung cancers with a diagnosis associated with an emergency department (ED) visit. The characteristics of these patients and the correlation between diagnosis near an ED visit and stage at diagnosis were also examined. METHODS: A population-based sample of all Michigan cancer cases diagnosed in all EDs and other health care settings was used to extract a sample of patients >65 years old, diagnosed with colorectal and lung cancers between January 1, 1996, and June 30, 2000 (n = 20 311). Logistic regressions were used for the statistical analysis. RESULTS: Patients with a colorectal cancer diagnosis associated with an ED visit were more likely insured by Medicaid before diagnosis (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.17-1.60), had an inpatient admission before diagnosis (OR, 1.29; 95% CI, 1.06-1.56), had 3 or more comorbidities (OR, 4.11; 95% CI, 3.53-4.79), were more likely to be female (OR, 1.18; 95% CI, 1.07-1.31), and were more likely to be aged 85 years and older (OR, 1.89; 95% CI, 1.57-2.27). Patients who had at least one primary care physician (PCP) visit before diagnosis were less likely to have a diagnosis associated with an ED visit (OR, 0.68; 95% CI, 0.61-0.76). Patients diagnosed with lung cancer in association with an ED visit were also more likely to have an inpatient admission before diagnosis (OR, 1.21; 95% CI, 1.02-1.43), a higher comorbidity burden (OR, 12.44; 95% CI, 10.18-15.20), be female (OR, 1.13; 95% CI, 1.02-1.25), African-American (OR, 1.42; 95% CI, 1.21 1.66), and older (80 years and older) (ages 80-84 years: OR, 1.33; 95% CI, 1.13 1.57; age 85 years and older: OR, 1.52; 95% CI, 1.25-1.85). Patients with an ED visit near a colorectal cancer (OR, 1.28; 95% CI, 1.15-1.42) or lung cancer diagnosis (OR, 1.65; 95% CI, 1.44-1.88) were more likely to be diagnosed at a later stage compared with patients diagnosed in other settings. CONCLUSIONS: An examination of patients' patterns of care leading to a cancer diagnosis in association with an ED visit lends insight to conditions precipitating a more immediate diagnosis and their associated outcomes. PMID- 21247724 TI - Comparison of acute nonthrombolytic and thrombolytic treatments in ischemic stroke patients 80 years or older. AB - OBJECTIVES: The aim of this study was to compare the clinical outcomes of acute ischemic stroke patients 80 years or older treated with intravenous recombinant tissue plasminogen activator (i.v. rt-PA), or endovascular intervention with or without i.v. rt-PA, or nonthrombolytic medical treatment. METHODS: This study was a retrospective, nonrandomized, observational study of patients, admitted within 9 hours of symptom onset, at 3 academic, university-affiliated hospitals. The main outcome measures were neurologic improvement, defined by improvement in National Institutes of Health Stroke Scale score at 7 days or discharge of 4 or more, or achieving a score of 0; symptomatic and asymptomatic intracerebral hemorrhage; favorable outcome (discharge modified Rankin score 0-2); and in hospital mortality. RESULTS: A total of 44 patients received i.v. rt-PA, 46 received endovascular intervention with or without i.v. rt-PA, and 66 received nonthrombolytic medical treatment. I.v. rt-PA-treated patients had a significantly clinically higher chance of favorable outcome (odds ratio [OR], 5.6; 95% confidence interval [CI], 1.8-17.5), when compared with nonthrombolytic medical treatment. A significantly higher rate of neurologic improvement was observed among the i.v. rt-PA (7.2; 95% CI, 2.7-19.5) and endovascularly treated patients (5.8; 95% CI, 2-16.8) when compared with nonthrombolytic medical treatment. CONCLUSIONS: A prominently higher rate of neurologic improvement and favorable clinical outcome was observed among acute ischemic stroke patients 80 years or older treated with i.v. rt-PA or endovascular intervention when compared with nonthrombolytic medical treatment, supporting the use of acute thrombolytic therapies in this patient population when contraindications are not present. PMID- 21247725 TI - Thymic abscess: unusual cause of fever in a child. PMID- 21247726 TI - Outcome of chest pain patients discharged from a French emergency department: a 60-day prospective study. AB - BACKGROUND: Chest pain (CP) is a common complaint among patients presenting to the emergency department (ED). Previous studies suggest that between 2% and 5% of ED patients who present with CP and are sent home develop an acute coronary syndrome within 30 days. In France, no prospective data are available concerning the outcome of CP patients discharged from the ED. OBJECTIVE: The objective of our study was to determine the rate of adverse cardiac events (ACE) within a period of 60 days after discharge from the ED. METHODS: From October 2007 to February 2008, consecutive patients aged 25 years or more who presented to the ED with CP were prospectively included. Patients discharged from the ED were contacted by phone at 60 days to determine their clinical course and the occurrence of an ACE. RESULTS: There were 322 CP patients enrolled, representing 3.9% of all medical admissions to the ED; 40.4% of these patients were hospitalized and 59.6% were discharged. Three patients (1.6%) could not be contacted for follow-up, leaving 189 patients eligible for the study. The rate of ACE was 3.7%: one ST-segment elevation myocardial infarction and six non-ST segment elevation myocardial infarctions. Follow-up revealed that 39.1% of patients saw a cardiologist and that 14.2% were readmitted for CP. CONCLUSION: We found that CP is a frequent complaint in patients who present to our ED, and that a small proportion (3.7%) is mistakenly discharged and presents with an ACE during the 60-day follow-up period. PMID- 21247727 TI - Methodological reflections on body-mind intervention studies with cancer patients. AB - OBJECTIVE: Methodological reflection on the content, results and limitations of three body-mind intervention studies with cancer patients (CPs) in order to improve the quality of studies on body-mind interventions and to raise the potential value for CPs. METHODS: A secondary analysis of a study on haptotherapy and two studies applying relaxing face massage, using a variety of well-being effect measures. Six methodological themes are discussed: (1) drop-out; (2) characteristics of participating patients, (3) participation of patients in other complementary interventions; (4) satisfaction of participants; (5) effects of the three interventions, and (6) role of response shift. RESULTS: The three interventions showed limited effects after controlling for relevant confounding factors. They are mainly the small sample sizes, the low intensity of the intervention, the possible inadequate measure moments and the use of other CAM that may be responsible for the absence of effects. CONCLUSIONS: Body-mind interventions require more methodological reflections to develop attractive and effective interventions for CPs. Attention needs to be paid to measuring short term effects, practically fitting research designs, and response shift. PRACTICE IMPLICATIONS: Interventions should be intensive, repeated and not too short. The implementation of interventions requires attention to several organizational factors in the health care. PMID- 21247728 TI - Endovascular exclusion of a saccular aortic aneurysm using a septal occluder device. AB - Endovascular repair of aneurysms involving the visceral segment of the abdominal aorta still remains a challenge. We report a patient with a large saccular aneurysm involving the visceral segment of the abdominal aorta that was ultimately excluded by endovascular deployment of an Amplatzer atrial septal occluder device (AGA Medical/St. Jude Medical, St Paul, Minn). PMID- 21247729 TI - Synchronous carotid artery stenting and open heart surgery. AB - BACKGROUND: The optimal management of the patients requiring cardiac surgery with concomitant severe carotid disease remains a controversy. The traditional approach involves staged or combined carotid endarterectomy and cardiac surgery. This study evaluated the feasibility and safety of angioplasty and stenting for the treatment of carotid stenoses concomitantly to cardiac operations to reduce the risk of perioperative stroke. METHODS: All patients scheduled for cardiac surgery were screened preoperatively by color duplex ultrasonography for carotid disease. Carotid stenoses >=60% in symptomatic patients and >=70% in asymptomatic patients were treated using carotid artery stenting (CAS) under local anesthesia immediately before the open heart surgery. Cerebral protection devices were used in all cases. Patients did not receive aspirin or clopidogrel before the procedure. In a prospective, nonrandomized study, we analyzed 90 consecutive patients requiring cardiac surgery with concomitant severe carotid artery disease who underwent one stage CAS and cardiac surgery. RESULTS: Despite the high baseline risk profile, our results were encouraging. Carotid stenting was successful in all patients. No neurologic complications occurred during the carotid stenting procedures. The 30-day death/stroke rate was 2.2% (one death, one contralateral stroke). No myocardial infarction occurred. The carotid restenosis rate was zero during the intermediate-term follow-up. CONCLUSIONS: In our experience, CAS followed immediately by cardiac surgery is safe and represents a reasonable option for selected patients presenting with severe carotid and coronary disease. PMID- 21247730 TI - A multicenter experience of the management of collapsed thoracic endografts. AB - OBJECTIVES: Thoracic endograft collapse after thoracic endovascular aortic repair (TEVAR) is a potentially devastating complication. This study evaluates the management of thoracic stent graft collapse. METHODS: A multicenter review of thoracic stent graft collapse was performed from 2005 to 2009. Diagnosis and preoperative planning was performed by computed tomography angiography (CTA). Outcome measures included success of endovascular salvage, postoperative complications, and conversion to open repair. RESULTS: Eleven patients (10 men) with thoracic endograft collapse were identified. Mean age was 41.2 years old (range, 21-66 years). Indications for the index TEVAR were traumatic aortic transections in 8 patients and acute type B dissections in 3 patients. All were initially treated with the TAG endoprosthesis (Gore and Associates, Flagstaff, Ariz). The median duration from initial repair to diagnosis of collapse was 9 days (range, 1 day-38 months). All collapses were initially treated by endovascular means using another TAG device in 7 patients, a Talent (Medtronic, Santa Rosa, Calif) thoracic stent graft in 3 patients, and a Palmaz (Cordis Endovascular, Warren, NJ) stent in 1 patient. In 1 patient, the secondary TAG did not resolve the collapse and required a Palmaz stent placement. Technical success rate was 91%, while re-expansion of the collapsed endograft was achieved in all patients. Early and late complications were observed in 3 patients. Delayed (>30 days) open conversion with device explantation was performed for an aortoesophageal fistula, physiological aortic coarctation, and prevention of a recurrent collapse in 1 patient each. There were no perioperative deaths or recurrent collapses. CONCLUSION: Endograft collapse can be successfully managed by endovascular techniques in most cases. Redo-TEVAR using high radial force devices should be considered the initial treatment of choice. Late endograft related complications after treatment of collapsed endografts are not uncommon and can be safely managed by open conversion. PMID- 21247732 TI - Roadside judgments in children with Developmental Co-ordination Disorder. AB - As pedestrians, the perceptual ability to accurately judge the relative rate of approaching vehicles and select a suitable crossing gap requires sensitivity to looming. It also requires that crossing judgments are synchronized with motoric capabilities. Previous research has suggested that children with Developmental Co ordination Disorder (DCD) may have deficits in visual processing, specifically in detecting visual motion. It is possible, therefore that this population are at greater risk at the roadside. In a series of motion prediction tasks, several component roadside skills were assessed in 15 children with DCD, or at risk of DCD, aged between 6 and 11 years along with 15 typically developing age and gender matched controls. First, threshold errors for relative approach rate judgments (looming) were measured when vehicle size (car or truck) varied. Second, thresholds for crossing gap selection were measured for vehicle approach speeds of 32, 48, 64 and 80 km/h (20-50 mph). These were related to the walking speeds of children of different ages and profiles. We found that children with DCD showed a deficit in making relative approach rate judgments, using looming, which suggests they may not discern that a vehicle is travelling faster than the urban speed limit. Children with DCD also left considerably longer temporal crossing gaps than controls perhaps reflecting a lack of confidence in their ability, these preferred gaps were over twice the average inter-car gaps that occurred on roads around their school. Our findings raise a number of issues concerning children with DCD and their competence and potential limitations as pedestrians. PMID- 21247731 TI - The inducible prostaglandin E synthase mPGES-1 regulates growth of endometrial tissues and angiogenesis in a mouse implantation model. AB - Endometriosis is one of the most common gynecological diseases in women of reproductive age. Although cyclooxygenase (COX)-2 inhibitors are effective in the treatment of endometriosis, the adverse cardiovascular effects associated with these inhibitors have limited their use. Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible enzyme downstream of COX-2 in prostaglandin E(2) biosynthesis. Previously, we developed mPGES-1 knockout mice (mPGES-1(-/-)) and have identified for the first time the roles of ectopic lesion- and host associated mPGES-1 in angiogenesis and the growth of endometrial tissues. When mPGES-1(-/-) endometrial fragments were implanted into wild type (WT) mice (mPGES 1(-/-)->WT), or WT fragments implanted into mPGES-1(-/-) mice (WT->mPGES-1(-/-)), the growth of the implants was suppressed at days 14 and 28 after implantation, compared toWT->WT transplantation. An even greater degree of suppression was observed in mPGES-1(-/-) endometrial fragments implanted into mPGES-1(-/-) mice (mPGES-1(-/-)->mPGES-1(-/-)). After WT-WT implantation, mPGES-1 expression was localized at the border of the implanted endometrial tissues. Microvessel density, determined by CD31 immunostaining, was markedly suppressed in the mPGES 1(-/-) endometrial fragments implanted into mPGES-1(-/-) mice, with some suppression also observed in the mPGES-1(-/-)->WT and WT->mPGES-1(-/-) groups. The expression of vascular endothelial growth factor (VEGF-A) was significantly reduced in mPGES-1(-/-) endometrial tissues implanted into mPGES-1(-/-) mice at days 14 and 28, in comparison to the WT->WT group. These results suggested that mPGES-1 enhanced angiogenesis and growth of the endometrial implant, and indicate that mPGES-1 may be a good therapeutic target for endometriosis. PMID- 21247733 TI - Cardiovascular risk factors and systolic and diastolic cardiac function: a tissue Doppler and speckle tracking echocardiographic study. AB - BACKGROUND: The aim of this study was to determine whether blood pressure, body mass index (BMI), serum lipids, glucose, and renal function are associated with left ventricular (LV) and right ventricular function in a low-risk population. METHODS: The associations of common risk factors with cardiac function were assessed, using multiple linear regression, in a random sample of 1,266 individuals free from hypertension, diabetes, and cardiovascular disease. A combination of conventional echocardiographic, speckle-tracking, and tissue Doppler methods was used to assess cardiac function. RESULTS: Older age and higher BMI, systolic and diastolic blood pressure, and non-high-density lipoprotein (HDL) cholesterol were associated with lower LV function. Thus, LV strain was reduced by approximately 5% per 5 kg/m(2) increase in BMI and by 4% per 10 mm Hg increase in diastolic blood pressure. Corresponding reductions in peak early diastolic mitral annular velocity were 7% for both BMI and diastolic blood pressure. Higher HDL cholesterol was associated with better LV function. In women, smoking was also associated with reduced LV function. LV function was lower also at low levels of diastolic pressure and BMI. Reduced right ventricular function was related to older age, smoking, higher diastolic blood pressure and non-HDL cholesterol, and lower HDL cholesterol. CONCLUSIONS: These findings suggest that conventional risk factors may predict cardiac function many years before clinical disease. The J-shaped associations related to diastolic blood pressure and BMI may suggest that in some individuals, low levels of these factors may indicate underlying but unknown disease. PMID- 21247734 TI - GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). AB - In the GRADE approach, randomized trials start as high-quality evidence and observational studies as low-quality evidence, but both can be rated down if most of the relevant evidence comes from studies that suffer from a high risk of bias. Well-established limitations of randomized trials include failure to conceal allocation, failure to blind, loss to follow-up, and failure to appropriately consider the intention-to-treat principle. More recently recognized limitations include stopping early for apparent benefit and selective reporting of outcomes according to the results. Key limitations of observational studies include use of inappropriate controls and failure to adequately adjust for prognostic imbalance. Risk of bias may vary across outcomes (e.g., loss to follow-up may be far less for all-cause mortality than for quality of life), a consideration that many systematic reviews ignore. In deciding whether to rate down for risk of bias- whether for randomized trials or observational studies--authors should not take an approach that averages across studies. Rather, for any individual outcome, when there are some studies with a high risk, and some with a low risk of bias, they should consider including only the studies with a lower risk of bias. PMID- 21247735 TI - A simple tool predicted probability of falling after aged care inpatient rehabilitation. AB - OBJECTIVE: To develop and internally validate a falls prediction tool for people being discharged from inpatient aged care rehabilitation. STUDY DESIGN AND SETTING: Prospective cohort study. Possible predictors of falls were collected for 442 aged care rehabilitation inpatients at two hospitals. RESULTS: One hundred fifty participants fell in the 3 months after discharge from rehabilitation (34% of 438 with follow-up data). Predictors of falls were male gender (odds ratio [OR] 2.32, 95% confidence interval [CI]=1.00-4.03), central nervous system medication prescription (OR 2.04, 95% CI=1.00-3.30), and increased postural sway (OR 1.93, 95% CI=1.00-3.26). This three-variable model was adapted for clinical use by unit weighting (i.e., a score of 1 for each predictor present). The area under the receiver operating characteristic curve (AUC) for this tool was 0.69 (95% CI=0.64-0.74, bootstrap-corrected AUC=0.69). There was no evidence of lack of fit between prediction and observation (Hosmer-Lemeshow P=0.158). CONCLUSION: After external validation, this simple tool could be used to quantify the probability with which an individual will fall in the 3 months after an aged care rehabilitation stay. It may assist in the discharge process by identifying high-risk individuals who may benefit from ongoing assistance or intervention. PMID- 21247736 TI - Orthognathic surgery for the Asian patient and the influence of the surgeon's background on treatment. AB - The aim of this study was to determine whether there are differences in esthetic preferences and orthognathic treatment for Asian patients between US- and Asian trained surgeons. Twenty-five Caucasian-American, 23 Asian-American, 24 Asian oral and maxillofacial surgeons (OMFS) completed an Institutional Review Board (IRB)-approved survey. They were asked to rate seven Asian male and female profiles from most attractive to least attractive and to choose maxillary advancement, mandibular setback, or no treatment for an Asian male and female patient with a maxillomandibular discrepancy. There was no statistical difference for the most and least attractive rankings among the OMFS. Variations in ranking for intermediate profiles showed a statistical difference between the Asian- and US-trained OMFS. These intermediate profile rankings appeared to explain the differences in surgical treatment. Treatment recommendations for the Asian male among the OMFS, regardless of ethnicity, preferred maxillary advancement. For the Asian female, all Asian-trained OMFS preferred mandibular setback, while nearly 40% of US-trained OMFS preferred maxillary advancement (p=0.003). Differences in surgical management of the Asian patient were dependent on whether the surgeon trained in the US or in Asia and the gender of the patient. There was concordance between the Asian-American and Caucasian-American surgeons. PMID- 21247737 TI - Callosotomy and subsequent surgery for children with refractory epilepsy. AB - Callosotomy has been considered as a palliative therapy for refractory epilepsy patients with non-focal onset seizures. Residual partial seizures and unilateral epileptiform discharges on electroencephalography (EEG) are sometimes observed after callosotomy. These findings suggest that some patients may be candidates for subsequent resective surgery. Of 149 children who received a callosotomy, resective/disconnective surgery was subsequently performed in 19 patients. Most patients had generalized seizures and epileptiform discharges on EEG before callosotomy. Two-third had normal neuroimaging studies at initial presurgical evaluation. After callosotomy, ictal symptoms evolved into asymmetric features suggesting partial onset seizures. Post-callosotomy EEG showed completely lateralized or localized epileptiform discharges responsible for residual partial seizures in 16 of 19 patients. Fifteen patients underwent resective surgery of the unilateral frontal lobe, and the remaining received hemispherotomy or posterior quadrantectomy. After subsequent surgery, favorable seizure outcomes were obtained in 11 patients (57.9%). Favorable seizure outcomes may be achieved with callosotomy and subsequent surgery in selected patients who are not candidates for a conventional resective surgery at initial presurgical evaluation. PMID- 21247738 TI - Structural alterations of the cutaneous vasculature in aged and in photoaged human skin in vivo. PMID- 21247739 TI - Silica particles coated with zwitterionic polymer brush: formation of colloidal crystals and anti-biofouling properties in aqueous medium. AB - Silica particles (SiP) were modified with 2-bromoisobutyryl group-carrying silane coupling reagent, and a polymer brush of carboxymethylbetaine, poly[1-carboxy-N,N dimethyl-N-(2'-methacryloyloxyethyl)methanaminium inner salt] (PolyCMB), was introduced onto surface of the particles using surface-initiated atom transfer radical polymerization (ATRP). After purification by simple ultrafiltration, the layer of the PolyCMB brush-carrying silica particle (SiP-PolyCMB) in aqueous medium showed a clear iridescence at the bottom of a quartz cell upon a slow sedimentation, indicating the formation of colloidal crystals due to both electrostatic and steric repulsion between the particles. The peak of the reflection spectra gradually shifted to a smaller wavelength region due to the formation of more densely packed ordered structure of the SiP-PolyCMB. Moreover, SiP-PolyCMBs dispersed in water showed neither salt- nor freeze-thaw cycle induced coagulation, and were resistant against the non-specific adsorption of proteins such as bovine serum albumin and egg white lysozyme, which is in contrast with the noticeable adsorption of the proteins to the bare silica particles. PMID- 21247740 TI - Antimicrobial and anti-adhesive potential of a biosurfactant Rufisan produced by Candida lipolytica UCP 0988. AB - In the last years, researches developed with biosurfactants for application in the medical area have been revealing the promising biological activities of these biomolecules. In this work the antimicrobial and anti-adhesive properties of a biosurfactant Rufisan isolated from the yeast Candida lipolytica UCP 0988, growth in a medium supplemented with ground nut refinery residue was determined against several microorganisms. The biosurfactant was able to reduce the water surface tension from 70 to 25.3 mN/m and showed a critical micelle concentration (CMC) of 0.03%. The biosurfactant was isolated after 72 h of fermentation and was tested in concentrations varying from 0.75 to 12 mg/l. The highest antimicrobial activities were observed against Streptococcus agalactiae, Streptococcus mutans, Streptococcus mutans NS, Streptococcus mutans HG, Streptococcus sanguis 12, Streptococcus oralis J22 at a concentration superior to the biosurfactant critical micelle concentration. Moreover, the biosurfactant showed anti-adhesive activity against most of the microorganisms tested. As far as we know, this is the first compilation of data on antimicrobial and anti-adhesive activities of a biosurfactant obtained from a Candida strain against such a broad group of microorganisms. The results obtained in this work showed that the biosurfactant from C. lipolytica is a potential antimicrobial and/or anti-adhesive agent for several biomedical applications. PMID- 21247741 TI - Molecular origin of Na(+)/Li(+) exchanger: Evidence against the involvement of major cloned erythrocyte transporters. AB - Numerous studies have demonstrated heightened Na(+)/Li(+) countertransport (NLCT) activity in erythrocytes of patients with essential hypertension or diabetic nephropathy. The same carrier also contributes to the therapeutic action of lithium salt, widely used in the treatment of psychiatric disorders. However, the molecular origin of NLCT remains unknown. This study examined the role of major ion transporters in NLCT by comparative analysis of its activity and that of ion transporters providing inwardly directed (86)Rb, (22)Na and (32)P fluxes. NLCT was below the detection limit in rat erythrocytes and ~50-fold higher in rabbits compared to humans. Unlike NLCT, the activities of Na(+),K(+)-ATPase, Na(+),K(+),2Cl(-) cotransporter and anion exchanger were somewhat similar in the erythrocytes of these species, whereas Na(+),P(i) cotransport was in 1:2:6 proportion in rats, humans and rabbits, respectively. Loading of erythrocytes with Li(+) for NLCT measurement did not affect the activity of Na(+),P(i) cotransporter. Keeping in mind that NLCT is much higher in rabbits vs humans and rats, we compared the set of membrane proteins in these species using 2 dimensional gel electrophoresis. This approach revealed 174 common spots, whereas 132 proteins were detected only in human and rabbit erythrocyte membranes. Among these proteins, we found 17 spots whose expression was higher by more than 5-fold in rabbit compared to human erythrocytes. Thus, our results argue against the involvement of major ion transporters in NLCT. They also show that comparative proteomics is a potent tool to identify the molecular origin of this carrier. PMID- 21247742 TI - Value of multiparametric prostate MRI of the peripheral zone. AB - RATIONALE AND OBJECTIVES: MRI of the prostate offers the possibility to localize and stage prostate cancer and may improve detection of disease. Currently, T2 weighted images and spectroscopy are the most commonly used MRI techniques. To assess the value of prostate MRI and its different modalities in the process of diagnosis, the currently available MRI techniques were compared. MATERIALS AND METHODS: 16 patients were examined on a 1.5 T MR system. All patients underwent the same MR protocol using an endorectal coil: T2-weighted triplanar turbo-spin echo (TSE), axial echo-planar diffusion-weighted imaging (DWI), 3D chemical-shift imaging MR spectroscopy (MRS) and axial dynamic-contrast-enhanced TurboFLASH (DCE). Parametric maps of the choline+creatine/citrate ratio (CC-CR), apparent diffusion coefficient (ADC) and plasma flow/mean transit time (PF/MTT) were calculated. Additionally, average time for reading and scanning were evaluated. As reference, biopsy results were used. RESULTS: Sensitivity/specificity were 50.0-85.7%/44.4-72.2% for the T2 weighted images, 78.6-100.0%/38.9-55.6% for the ADC maps, 71.4-85.7%/44.4-55.6% for the PF/MTT maps and 64.3-78.6%/50.0-77.8% for the CC-CR. Average scan and reading time were 8:46/1:54 min for T2, 1:28/3:17 min for DWI, 8:41/2:12 min for DCE and 11:36/3:47 for spectroscopy. CONCLUSION: We found no significant differences in accuracy between the modalities. We observed DWI to be advantageous in examination and reading compared to DCE and MRS, therefore it might be the preferred modality when a shortened protocol is needed. PMID- 21247743 TI - [Experimental investigation of the collection efficiency of a PTW Roos ionization chamber irradiated with pulsed beams at high pulse dose with different pulse lengths]. AB - In gas-filled ionization chambers as radiation detectors, the collection of the charge carriers is affected by the recombination effect. In dosimetry this effect must be accounted for by the saturation correction factor k(S). The physical description of the correction factor by Boag, Hochhauser and Balk for pulsed radiation is well established. However, this description is only accurate when the pulse length is short compared to the collection time of the ionization chamber. In this work experimental investigations of the saturation correction factor have been made for pulses of 4 MU s up to pulse doses of about 230 mGy, and the theory of Boag, Hochhauser and Balk was again confirmed. For longer pulses, however, the correction factor decreases and at a pulse duration of about 200MUs reaches 75% of the value valid for short pulses. This reduced influence of the ion recombination is interpreted by the reaction kinetics of ion recombination as a second-order reaction. This effect is negligible for PTW Roos chambers at clinical linear accelerators with 4 MU s pulse duration for pulse doses up to 120 mGy. PMID- 21247744 TI - Monte Carlo dose calculation on deforming anatomy. AB - This article presents the implementation and validation of a dose calculation approach for deforming anatomical objects. Deformation is represented by deformation vector fields leading to deformed voxel grids representing the different deformation scenarios. Particle transport in the resulting deformed voxels is handled through the approximation of voxel surfaces by triangles in the geometry implementation of the Swiss Monte Carlo Plan framework. The focus lies on the validation methodology which uses computational phantoms representing the same physical object through regular and irregular voxel grids. These phantoms are chosen such that the new implementation for a deformed voxel grid can be compared directly with an established dose calculation algorithm for regular grids. Furthermore, separate validation of the aspects voxel geometry and the density changes resulting from deformation is achieved through suitable design of the validation phantom. We show that equivalent results are obtained with the proposed method and that no statistically significant errors are introduced through the implementation for irregular voxel geometries. This enables the use of the presented and validated implementation for further investigations of dose calculation on deforming anatomy. PMID- 21247745 TI - The beta-1 adrenergic antagonist, atenolol, decreases acylation stimulating protein, exercise capacity and plasma free fatty acids in men with type 2 diabetes. AB - BACKGROUND AND AIMS: Atenolol is a beta-1 adrenergic antagonist commonly prescribed for the treatment of systemic hypertension or coronary artery disease yet its use in individuals with type 2 diabetes mellitus (T2DM) is controversial due to potentially negative side effects on insulin resistance. Non-esterified fatty acid (NEFA) metabolism is altered in T2DM especially under conditions of metabolic stress such as exercise or the postprandial state. We evaluated atenolol effects on circulating NEFA and related hormones in men with T2DM during acute cardiorespiratory exercise in both the fasting and postprandial state, including the adipokine acylation stimulating protein (ASP) which stimulates adipose tissue NEFA uptake. METHODS AND RESULTS: Ten men with T2DM underwent four 1-h exercise sessions at 60% of their maximal oxygen uptake (VO(2max)) under the following conditions: 1) fasting (F), and 2) 2 h postprandial (PP) without medication; and 3) fasting (F-Atenolol), and 4) 2 h postprandial (PP-Atenolol) after a one-week treatment with atenolol. Results were tested for the effects of atenolol via two-way ANOVA for the F vs F-Atenolol and PP vs PP-Atenolol states separately. Atenolol treatment decreased fasting and postprandial glycerol (p < 0.0001) and NEFA (p < 0.0001), postprandial epinephrine (p = 0.048), postprandial cortisol (p = 0.02), postprandial ASP (p = 0.04) and postprandial dopamine (p < 0.004). CONCLUSION: Atenolol alters fatty acid metabolism and associated metabolic hormones including ASP during exercise in men with T2DM and its effects are more apparent during conditions of stress such as the postprandial state, acute exercise and obesity. PMID- 21247746 TI - Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. AB - Despite its prevalence, clinical and prognostic impact, diabetic autonomic neuropathy, is widely under-diagnosed. The need for training and expertise to perform the cardiovascular tests (usually the task of diabetologists) is one possible reason. The availability of computer-assisted systems has allowed a wider diffusion of testing, but has also highlighted the need for an adequate knowledge of physiopathological backgrounds for their correct application and interpretation. The recommendations presented here were developed by the Neuropathy Study Group of the Italian Society of Diabetology and then endorsed by the Italian Association for the Study of Neurovegetative System, to promote the widespread adoption of good clinical practice in diabetic cardiovascular autonomic testing by outlining main evidence-based aspects, i.e. which tests, how to perform them, adequate interpretation of the results and their diagnostic use, confounding conditions that can impact on tests reliability. Therefore, these recommendations include the essential aspects of the physiopathological substrate of the tests, the controversial points in their analysis, their diagnostic characteristics, as well as safety. Detailed information is given on the physiological (age, weight, body position, resting heart rate and blood pressure, respiratory pattern, exercise, meals, acute blood glucose changes) and pathophysiological confounding factors, with emphasis on the effects of drugs. Instructions on how to perform the tests and interpret their results are also considered together with indications of candidate patients and periodicity of testing. A patient instruction sheet on why and how to perform the tests is included. Finally, the specific requirements for computerized systems to perform and evaluate cardiovascular tests are provided. PMID- 21247747 TI - Evidence for an instructive role of apoptosis during the metamorphosis of Hydractinia echinata (Hydrozoa). AB - Apoptosis is a highly conserved mechanism of cell deletion that destroys redundant, dysfunctional, damaged, and diseased cells. Furthermore, apoptotic cell death is essential during the development of multicellular organisms. However, there are only a few examples where the occurrence of apoptosis has been shown to be a direct prerequisite for developmental processes. As described previously by our group, the degradation of larval tissue during the first half of the metamorphosis of Hydractinia echinata involves extensive cell death. A large number of cells are removed, and we observed several cellular features of apoptotic cell death in the dying tissue, e.g., nucleosomal DNA fragmentation and nuclear condensation. Furthermore, we showed that metamorphosis in the basal cnidarian H. echinata depends on the activity of caspases, the central enzymes of apoptosis. In the present study, we build on these previous investigations of apoptosis in H. echinata by characterising a caspase-3 sequence in this species and placing it in an evolutionary context by performing phylogenetic analyses. Furthermore, we report the successful knockdown of a caspase by RNAi and show that apoptosis plays a role as an instructive mechanism in the metamorphosis of H. echinata. PMID- 21247748 TI - A mimic peroxidase biosensor based on calcined layered double hydroxide for detection of H2O2. AB - An enzymeless biosensor was explored from Cu-Mg-Al calcined layered double hydroxide (CLDH) modified electrode in this study. The Cu-Mg-Al CLDH greatly promotes the electron transfer between H(2)O(2) and GCE, and it is exemplified toward the non-enzymatic sensing of H(2)O(2). The results indicate that the Cu-Mg Al CLDH exhibits excellent electrocatalytic property, high sensitivity, good reproducibility, long-term stability, and fast amperometric response toward reduction of H(2)O(2), thus is promising for the future development of man-made mimics of enzyme in H(2)O(2) sensors. This work opens a way to utilize simply Cu Mg-Al CLDH as an electron mediator to fabricate an efficient H(2)O(2) biosensor, which exhibits great potential applications in varieties of simple, robust, and easy-to-make analytical approaches in the future. PMID- 21247749 TI - A novel system combining biocatalytic dephosphorylation of L-ascorbic acid 2 phosphate and electrochemical oxidation of resulting ascorbic acid. AB - An enzyme electrode was prepared with acid phosphatase (ACP) for development of a new electric power generation system using ascorbic acid 2-phosphate (AA2P) as a fuel. The properties of the electrode were investigated with respect to biocatalytic dephosphorylation of AA2P and electrochemical oxidation of resulting ascorbic acid (AA). The enzyme electrode was fabricated by immobilization of ACP through amide linkage onto a self-assembled monolayer of 3-mercaptopropionic acid on a gold electrode. AA2P was not oxidized on a bare gold electrode in the potential sweep range from -0.1 to +0.5 V vs. Ag/AgCl. However, the enzyme electrode gave an oxidation current in citric buffer solution of pH 5 containing 10 mM of AA2P. The oxidation current began to increase at +0.2V, and reached to 5.0 MUA cm(-2) at +0.5 V. The potential +0.2 V corresponded to the onset of oxidation of ascorbic acid (AA). These results suggest that the oxidation current observed with the enzyme electrode is due to AA resulting from dephosphorylation of AA2P. The oxidation current increased with increasing concentration of AA2P and almost leveled off at around the concentration of 5mM. Thus the enzyme electrode brought about biocatalytic conversion of AA2P to AA, followed by electrochemical oxidation of the AA. The oxidation current is likely to be controlled by the biocatalytic reaction. PMID- 21247750 TI - Impact of microbial transformation of food on health - from fermented foods to fermentation in the gastro-intestinal tract. AB - Fermentation of food components by microbes occurs both during certain food production processes and in the gastro-intestinal tract. In these processes specific compounds are produced that originate from either biotransformation reactions or biosynthesis, and that can affect the health of the consumer. In this review, we summarize recent advances highlighting the potential to improve the nutritional status of a fermented food by rational choice of food-fermenting microbes. The vast numbers of microbes residing in the human gut, the gut microbiota, also give rise to a broad array of health-active molecules. Diet and functional foods are important modulators of the gut microbiota activity that can be applied to improve host health. A truly multidisciplinary approach is required to increase our understanding of the molecular mechanisms underlying health beneficial effects that arise from the interaction of diet, microbes and the human body. PMID- 21247751 TI - Molecular design of the microbial cell surface toward the recovery of metal ions. AB - The genetic engineering of microorganisms to adsorb metal ions is an attractive method to facilitate the environmental cleanup of metal pollution and to enrich the recovery of metal ions such as rare metal ions. For the recovery of metal ions by microorganisms, cell surface design is an effective strategy for the molecular breeding of bioadsorbents as an alternative to intracellular accumulation. The cell surface display of known metal-binding proteins/peptides and the molecular design of novel metal-binding proteins/peptides have been performed using a cell surface engineering approach. The adsorption of specific metal ions is the important challenge for the practical recovery of metal ions. In this paper, we discuss the recent progress in surface-engineered bioadsorbents for the recovery of metal ions. PMID- 21247752 TI - Revealing the genetic basis of multiple sclerosis: are we there yet? AB - For more than 30 years the only genetic factor associated with susceptibility to multiple sclerosis (MS) was the human leukocyte antigen (HLA) region. Recent advancements in genotyping platforms and the development of more effective statistical methods resulted in the identification of 16 more genes by genome wide association studies (GWAS) in the last three years alone. While the effect of each of these genes is modest compared to that of HLA, this list is expected to grow significantly in the near future, thus defining a complex landscape in which susceptibility may be determined by a combination of allelic variants in different pathways according to ethnic background, disease sub-type, and specific environmental triggers. A considerable overlap of susceptibility genes among multiple autoimmune diseases is becoming evident and integration of these genetic variants with our current knowledge of affected biological pathways will greatly improve our understanding of mechanisms of general autoimmunity and of tissue specificity. PMID- 21247753 TI - Ultrastructural organization of presynaptic terminals. AB - In response to calcium influx, synaptic vesicles fuse very rapidly with the plasma membrane to release their neurotransmitter content. An important mechanism for sustained release includes the formation of new vesicles by local endocytosis. How synaptic vesicles are trafficked from the sites of endocytosis to the sites of release and how they are maintained at the release sites remain poorly understood. Recent studies using fast freezing immobilization and electron tomography have led to insights on the ultrastructural organization of presynaptic boutons and how these structural elements may maintain synaptic vesicles and organize their exocytosis at particular areas of the plasma membrane. PMID- 21247756 TI - Investment of palliative medicine in bridging the gap with academia: a call to action. AB - Palliative care and palliative medicine define a relatively new medical discipline that has arisen in response to the need for better approaches to caring for people with advanced life-limiting illnesses. For professional, managerial and cultural reasons, it has evolved largely outside of academic structures. As the discipline has matured, its needs for education, training, intellectual discourse, evidence development and new science have become more apparent. Traditional academia remains sceptical about the role of palliative medicine, and bastions of palliative medicine expertise in universities have been slow to develop. Yet the engagement of the academic sector in palliative medicine has distinct benefits: (1) promoting the exploration of the culture, humanities and science of the discipline; (2) generating evidence to support practice; (3) creating a legion of educators to train a palliative medicine workforce and to inform clinical colleagues of the role of palliative medicine; and (4) providing order and direction to the discipline's development. A roadmap leading to better engagement between palliative medicine and academia is needed. Examples of developments that could help bridge the two domains include: standardisation of terminology and clarification of boundaries of influence; focus on high-quality research that will generate robust evidence to support clinical decision-making; and clear definition of outcomes, with measures that are understandable across medical disciplines. PMID- 21247754 TI - Structural and dynamic mechanisms for the function and inhibition of the M2 proton channel from influenza A virus. AB - The M2 proton channel from influenza A virus, a prototype for a class of viral ion channels known as viroporins, conducts protons along a chain of water molecules and ionizable sidechains, including His37. Recent studies highlight a delicate interplay between protein folding, proton binding, and proton conduction through the channel. Drugs inhibit proton conduction by binding to an aqueous cavity adjacent to M2's proton-selective filter, thereby blocking access of proton to the filter, and altering the energetic landscape of the channel and the energetics of proton-binding to His37. PMID- 21247755 TI - Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas. AB - PURPOSE: Inhibition of epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) pathways may result in synergistic antitumour activity. We designed a phase I study to evaluate the combination of vandetanib, an investigational agent with activity against EGF receptor and VEGF receptor 2, and bevacizumab, a monoclonal antibody against VEGF. EXPERIMENTAL DESIGN: Patients with advanced solid tumours and lymphomas were enrolled. Objectives were to determine the safety and maximum tolerated dose of the combination, characterise pharmacokinetics, measure angiogenic marker changes in blood, and assess tumour blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Vandetanib was given orally once daily and bevacizumab intravenously once in every 3 weeks in 21-day cycles utilising a standard dose-escalation design. RESULTS: Fifteen patients were enrolled, and a total of 94 cycles of therapy were administered. No protocol-defined dose-limiting toxicities were observed; due to toxicities associated with chronic dosing, hypertension, proteinuria, diarrhoea and anorexia, dose escalation was stopped at the second dose level. We observed one partial response and one minor response; 9 patients experienced stable disease. There were significant changes in plasma VEGF and placental-derived growth factor levels, and decreases in K(trans) and k(ep) were observed by DCE MRI. CONCLUSION: In this trial, we safely combined two targeted agents that cause dual blockade of the VEGF pathway, demonstrated preliminary evidence of clinical activity, and conducted correlative studies demonstrating anti-angiogenic effect. The recommended phase II dose was established as vandetanib 200 mg daily and bevacizumab 7.5 mg/kg every 3 weeks. PMID- 21247757 TI - Reversible swelling of the cell wall of poplar biomass by ionic liquid at room temperature. AB - Time-resolved autofluorescence, Raman microspectroscopy, and scanning microprobe X-ray diffraction were combined in order to characterize lignocellulosic biomass from poplar trees and how it changes during treatment with the ionic liquid 1-n ethyl-3-methylimidazolium acetate (EMIMAC) at room temperature. The EMIMAC penetrates the cell wall from the lumen, swelling the cell wall by about a factor of two towards the empty lumen. However, the middle lamella remains unchanged, preventing the cell wall from swelling outwards. During this swelling, most of the cellulose microfibrils are solubilized but chain migration is restricted and a small percentage of microfibrils persist. When the EMIMAC is expelled, the cellulose recrystallizes as microfibrils of cellulose I. There is little change in the relative chemical composition of the cell wall after treatment. The action of EMIMAC on the poplar cell wall at room temperature would therefore appear to be a reversible swelling and a reversible decrystallization of the cell wall. PMID- 21247758 TI - Enzyme hydrolysis and ethanol fermentation of dilute ammonia pretreated energy cane. AB - This study is the first one ever to report on the use of high fiber sugarcane (a.k.a. energy cane) bagasse as feedstock for the production of cellulosic ethanol. Energy cane bagasse was pretreated with ammonium hydroxide (28% v/v solution), and water at a ratio of 1:0.5:8 at 160 degrees C for 1h under 0.9-1.1 MPa. Approximately, 55% lignin, 30% hemicellulose, 9% cellulose, and 6% other (e.g., ash, proteins) were removed during the process. The maximum glucan conversion of dilute ammonia treated energy cane bagasse by cellulases was 87% with an ethanol yield (glucose only) of 23 g ethanol/100g dry biomass. The enzymatic digestibility was related to the removal of lignin and hemicellulose, perhaps due to increased surface area and porosity resulting in the deformation and swelling of exposed fibers as shown in the SEM pictures. PMID- 21247759 TI - A pilot study on lignocelluloses to ethanol and fish feed using NMMO pretreatment and cultivation with zygomycetes in an air-lift reactor. AB - A complete process for the production of bioethanol and fungal biomass from spruce and birch was investigated. The process included milling, pretreatment with N-methylmorpholine-N-oxide (NMMO), washing of the pretreated wood, enzymatic hydrolysis, and cultivation of the zygomycetes fungi Mucor indicus. Investigated factors included wood chip size (0.5-16 mm), pretreatment time (1-5h), and scale of the process from bench-scale to 2m high air-lift reactor. Best hydrolysis yields were achieved from wood chips below 2mm after 5h of pretreatment. Ethanol yields (mg/g wood) of 195 and 128 for spruce, and 175 and 136 for birch were achieved from bench-scale and airlift, respectively. Fungal biomass yields (mg/g wood) of 103 and 70 for spruce, and 86 and 66 for birch from bench scale and airlift respectively were simultaneously achieved. NMMO pretreatment and cultivation with M. indicus appear to be a good alternative for ethanol production from birch and spruce. PMID- 21247760 TI - Biotechnological potential of inulin for bioprocesses. AB - Inulin consists of linear chains of beta-2,1-linked D-fructofuranose molecules terminated by a glucose residue through a sucrose-type linkage at the reducing end. In this review article, inulin and its applications in bioprocesses are overviewed. The tubers of many plants, such as Jerusalem artichoke, chicory, dahlia, and yacon contain a large amount of inulin. Inulin can be actively hydrolyzed by microbial inulinases to produce fructose, glucose and inulooligosaccharides (IOS). The fructose and glucose formed can be further transformed into ethanol, single-cell protein, single cell oil and other useful products by different microorganisms. IOS formed have many functions. Therefore, inulin can be widely used in food, feed, pharmaceutical, chemical and biofuels industries. PMID- 21247761 TI - Biodegradation of bromoamine acid using combined airlift loop reactor and biological activated carbon. AB - The biodegradation of bromoamine acid (BAA) in a combined airlift loop reactor (ALR) and biological activated carbon (BAC) system was investigated. The results showed that the ALR using Sphingomonas xenophaga as inoculum and granular activated carbon (GAC) as carrier, could run steadily for over 3 months at less than 950 mg L(-1) BAA. And the efficiencies of BAA decolorization and COD removal in ALR reached about 90% and 50% within 12h, respectively. When it was further aerated for another 12h, the ALR effluent gradually became yellow due to the auto oxidation of BAA decolorization products which were identified by HPLC-MS. Further biotreatment of the ALR effluent using BAC showed that the efficiency of TOC removal could reach 90%. Moreover, the release efficiencies of Br(-) and SO(4)(2-) were 73.5% and 67.4%, respectively. It indicated that BAC system was effective in the biodegradation of the auto-oxidative BAA decolorization products. PMID- 21247762 TI - Synthesis, modification, and evaluation of (R)-de-O-methyllasiodiplodin and analogs as nonsteroidal antagonists of mineralocorticoid receptor. AB - Macrolide (R)-de-O-methyllasiodiplodin (1), discovered to be a potent nonsteroidal antagonist of the mineralocorticoid receptor (MR), was synthesized via an efficient method and evaluated for MR antagonistic activity together with its analogs. Among all the tested compounds, compounds 18a, 18b and 18c, exhibited more potent antagonistic activity against MR with IC(50) values ranging from 0.58 to 1.11 MUM. Generally, it was obviously demonstrated that acetylation at phenolic hydroxyl groups and the ring size in analogs of 1 were very important for MR antagonist activity. PMID- 21247763 TI - Pyridylmethylthio derivatives as VEGF inhibitors: part 2. AB - Optimization of compounds 5 and 6 led to the discovery of VEGF inhibitor 10g which reduced CYP inhibition. It was highly active in vitro (VEGF induced HUVEC proliferation assay) and showed efficacies in three disease models in vivo (cancer, RA, and AMD). PMID- 21247764 TI - Sporadic centronuclear myopathy with muscle pseudohypertrophy, neutropenia, and necklace fibres due to a DNM2 mutation. PMID- 21247765 TI - Calculating gait kinematics using MR-based kinematic models. AB - Rescaling generic models is the most frequently applied approach in generating biomechanical models for inverse kinematics. Nevertheless it is well known that this procedure introduces errors in calculated gait kinematics due to: (1) errors associated with palpation of anatomical landmarks, (2) inaccuracies in the definition of joint coordinate systems. Based on magnetic resonance (MR) images, more accurate, subject-specific kinematic models can be built that are significantly less sensitive to both error types. We studied the difference between the two modelling techniques by quantifying differences in calculated hip and knee joint kinematics during gait. In a clinically relevant patient group of 7 pediatric cerebral palsy (CP) subjects with increased femoral anteversion, gait kinematic were calculated using (1) rescaled generic kinematic models and (2) subject-specific MR-based models. In addition, both sets of kinematics were compared to those obtained using the standard clinical data processing workflow. Inverse kinematics, calculated using rescaled generic models or the standard clinical workflow, differed largely compared to kinematics calculated using subject-specific MR-based kinematic models. The kinematic differences were most pronounced in the sagittal and transverse planes (hip and knee flexion, hip rotation). This study shows that MR-based kinematic models improve the reliability of gait kinematics, compared to generic models based on normal subjects. This is the case especially in CP subjects where bony deformations may alter the relative configuration of joint coordinate systems. Whilst high cost impedes the implementation of this modeling technique, our results demonstrate that efforts should be made to improve the level of subject-specific detail in the joint axes determination. PMID- 21247766 TI - Biomechanical and lifestyle risk factors for medial tibia stress syndrome in army recruits: a prospective study. AB - Medial tibial stress syndrome (MTSS) is a common injury in active populations and has been suggested to be a result of both biomechanical and lifestyle factors. The main aim of this study was to determine prospectively whether gait biomechanics and lifestyle factors can be used as a predictor of MTSS development. British infantry male recruits (n=468) were selected for the study. Plantar pressure variables, lifestyle factors comprising smoking habit and aerobic fitness as measured by a 1.5 mile timed-run were collected on the first day of training. Injury data were collected during the 26 week training period and incidence rate was 7.9% (n=37). A logistic regression model for membership of the MTSS and non-MTSS groups was developed. An imbalance in foot pressure with greater pressure on the medial side than on the lateral side was the primary risk factor. Low aerobic fitness, as deduced from a 1.5 mile timed-run and smoking habit were also important, but were additive risk factors for MTSS. In conclusion, "poor" biomechanics were the strongest predictors of MTSS development but lifestyle factors were also important. The logistic regression model combining all three risk factors was capable of predicting 96.9% of the non injured group and 67.5% of the MTSS group with an overall accuracy of 87.7%. While the model has yet to be validated against an external sample and limitations exist with regards to the quality of the data collected, it is nonetheless suggested that the combined analysis of biomechanical and lifestyle factors has the potential to improve the prediction of MTSS. PMID- 21247767 TI - The impact of molecular and clinical factors on patient outcome in oligodendroglioma from 20 years' experience at a single centre. AB - The increased chemosensitivity of oligodendroglial tumours has been associated with loss of heterozygosity (LOH) of the p arm of chromosome 1 and the q arm of chromosome 19 (LOH 1p/19q). Other clinical and molecular factors have also been identified as being prognostic and predictive of treatment outcome. We reviewed 105 patients with oligodendroglioma treated at a single centre over 20 years. Median survival in oligodendroglioma patients with LOH 1p/19q was significantly longer (10.9 vs. 2.0 years). In the anaplastic oligodendroglioma group, univariate analysis demonstrated decreased patient age, presentation with seizures, use of adjuvant chemotherapy and LOH 1p/19q as predictors of improved survival. Multivariate analysis confirmed LOH 1p/19q as a significant predictor of improved survival (hazard ratio, 3.4; p=0.015). Median survival in patients with anaplastic oligodendroglioma with LOH 1p/19q was 15.4 years vs. 1.2 years for those without LOH 1p/19q. This study confirms the utility of LOH 1p/19q as a prognostic marker in oligodendroglioma. PMID- 21247768 TI - Immediate development of a contralateral acute subdural hematoma following acute subdural hematoma evacuation. AB - Contralateral hematoma formation following acute subdural hematoma (ASDH) evacuation is a well-described complication. The most common type of contralateral hematoma is an epidural hematoma. Rarely, ASDH develops on the contralateral side. We report an elderly woman who presented with a post traumatic ASDH and underwent ipsilateral hematoma evacuation by craniotomy and subsequently developed a contralateral ASDH. Because of the potential consequences of a delayed ASDH, there should be a low threshold for early post operative imaging following ASDH evacuation, especially in elderly patients and those with additional associated intracranial injuries. PMID- 21247769 TI - Surgical treatment of parapontine epidermoid cysts presenting with trigeminal neuralgia. AB - We retrospectively reviewed the management of 49 patients with parapontine epidermoid cyst presenting with trigeminal neuralgia, emphasizing the importance of fully removing the tumor to relieve the trigeminal neuralgia. Clinical symptoms, MRI, the operative approach, and post-operative results were examined. Trigeminal neuralgia was noted in all patients. The mean duration from onset of symptoms to surgery was 18 months. Total removal was achieved in 23 patients, near-total removal in 21, and subtotal removal in five patients. However, all tumor capsule that adhered to the trigeminal nerve was completely removed. After the operation, 33 patients developed facial hypoesthesia, three complained of double vision, and two developed acute hydrocephalus. At six months of follow-up, all patients had recovered and returned to their normal lives. At 2 years of follow-up, one patient experienced pain recurrence and underwent another operation. Parapontine epidermoid cysts either encase cranial nerve (CN) V but with intact arachnoid between the capsule and the nerve, or compress and distort the nerve with tumor capsule adherent or attached to the nerve surface. Resecting the tumor capsule's attachment to CN V is critical in relieving pain, even though this method may damage the nerve. PMID- 21247770 TI - Central nervous system involvement in hepatocellular carcinoma: clinical characteristics and comparison of intracranial and spinal metastatic groups. AB - From January 1993 to December 2006 we analyzed the clinical characteristics of patients with hepatocellular carcinoma (HCC) with central nervous system (CNS) metastasis at the Kaohsiung Chang Gung Memorial Hospital, Taiwan. Forty-six patients with HCC and CNS metastasis were identified, of whom 36 had intracranial metastasis and 10 had spinal metastasis. The clinical presentations, laboratory data and imaging studies were collected and analyzed. The age at the time of HCC diagnosis ranged from 34 to 78 years; CNS metastasis occurred between 0 and 85 months after diagnosis and death followed between 0 and 93 months later. The Glasgow Coma Scale (GCS) score at the time of CNS metastasis ranged from 7 to 15 and the Child-Pugh score at diagnosis of HCC ranged from 5 to 15. Patients with spinal metastasis had a higher GCS score and lower Child-Pugh score at diagnosis. None of the serum biochemical studies showed unique abnormalities. From the data currently available, intracranial metastasis is the most common site of CNS metastasis of HCC. Advances in treating and diagnosing HCC have improved patient outcomes remarkably; however, CNS metastasis continues to have a grave prognosis. Without a specific biomarker for predicting CNS involvement in HCC, a high index of suspicion for the diagnosis should be maintained, particularly in HCC hyperendemic areas such as Taiwan. PMID- 21247771 TI - Abnormal mitochondrial cristae were experimentally generated by high doses of Apis mellifera venom in the rat adrenal cortex. AB - In the present study, Apis mellifera venom (AmV) was tested for its ability to cause ultrastructural changes in mitochondria of rat adrenal cortex in vivo. In order to achieve this goal, different AmV treatments were performed and the effects were quantified on transmission electron micrographs. In a first experimental group, AmV injected for 30 days in low daily doses (700 MUg/kg) generated important ultrastructural changes in zona fasciculata. The mitochondrial ultrastructure was not affected, but the diameters of mitochondrial cristae (MC) were reduced (57.066 +/- 7.795 nm) as compared to the MC diameters in the corresponding control groups (58.596 +/- 6.603 nm, and 58.503 +/- 5.708 nm). In adrenal glands collected from rats injected with a single, high dose of AmV (62 mg/kg), many ultrastructural changes were described. Mitochondria with normal, tubular MC (with diameter of 58.711 +/- 5.907 nm) were observed in many cells, very close to the values calculated for the corresponding control group (58.639 +/- 6.117 nm). However, the striking data reported herein concerned the ability of AmV high doses to promote dramatic alterations in the ultrastructure of these particular mitochondria, similar to those described in certain severe diseases. Thus, several types of abnormal mitochondria were observed, including mitochondria displaying lamellar and/or circular, concentric cristae and mitochondria devoid of cristae. The abnormal circular, concentric MC, with large inner (281.904 +/- 158.588 nm) and outer (432.076 +/- 230.372 nm) diameters, appeared to be the most stable form of MC in the adrenal cortex after the acute treatment with AmV. Among other ultrastructural aspects, these important changes indicated a high level of cytotoxicity of AmV in adrenocortical cells following in vivo experimental poisoning. PMID- 21247772 TI - Molecular cloning and biochemical characterization of a novel cystatin from Hevea rubber latex. AB - A novel cDNA encoding a cysteine proteinase inhibitor or phytocystatin was isolated from Hevea brasiliensis RRIM600 rubber latex cDNA library. The full length HbCPI obtained from rapid amplification of cDNA ends contains 588 bp. An open reading frame of 306 bp encodes for a protein of 101 amino acids with the typical inhibitory motifs of phytocystatin superfamily, namely the central signature motif QXVXG, a GG doublet and LARFAV-like motifs in the N-terminal part, and conserved A/PW residues in the C-terminal region. Sequence comparison showed that the deduced amino acid sequence was similar to that of cysteine protease inhibitor from Manihot esculenta (84% identity). The HbCPI was subcloned into expression vector pQE-40 and then overexpressed in Escherichia coli M15 strain (pREP4) as a His-tagged recombinant protein with molecular mass approximately 13 kDa. The purified HbCPI showed thermal stable property and efficiently inhibited the protease activity of papain by non-competitive inhibition with K(i) value of 15.4 nM. Beside latex, HbCPI also transcripted in leaf and young seed. The HbCPI message accumulation was induced by phytopathogenic fungi Phytophthora palmivora infection. These data suggest that HbCPI might play crucial roles in defense mechanism against biotic stimuli. PMID- 21247773 TI - Outcome after surgery for acute aortic dissection type A in patients over 70 years: data analysis from the German Registry for Acute Aortic Dissection Type A (GERAADA). AB - OBJECTIVE: The number of elderly patients undergoing emergency surgery for acute aortic dissection type A (AADA) is rising. Published results report a higher risk for these patients compared with younger patients. The aim of our study was to analyse the surgical outcome of these patients and to identify those at risk. METHODS: Between July 2006 and June 2009, 44 centres participating in the German Registry for Acute Aortic Dissection Type A (GERAADA) reported a total of 1558 patients. As many as 381 patients were between 70 and 80 years of age (septuagenarians), while 83 patients were 80 years and older (octogenarians). We compared the clinical features and events occurring 30 days after surgery. RESULTS: On admission, 23% (n=89) of septuagenarians had cardiac tamponade, compared with 31% (n=26) of those age >= 80 years (p=0.13). A little more than 13% (n=48) of septuagenarians were intubated at admission compared with 21% (n=17) of octogenarians (p=0.06). The septuagenarians' 30-day postoperative mortality was 16% (n=60), whereas that of patients aged over 80 years was 35% (n=29) (p<0.001). The mean hospital stay in the younger group was 18 days, of which 12 days were in the intensive care unit, compared with 18 and 13 days for octogenarians, respectively. CONCLUSIONS: Emergency surgery for septuagenarians with acute aortic dissection type A (AADA) resulted in acceptable mortality. Octogenarians revealed significantly higher 30-day mortality (odds ratio (OR)=3.23, confidence interval (CI)=(1.81-5.72)), although it was lower than the mortality among patients without surgical treatment. A surgical approach should be considered in all patients on an individual basis. PMID- 21247774 TI - Intracoronary levosimendan prevents myocardial ischemic damages and activates survival signaling through ATP-sensitive potassium channel and nitric oxide. AB - OBJECTIVE: Levosimendan has been reported to exert cardioprotection. In this study, we have examined the cardiac effects of different doses of intracoronary levosimendan on ischemia/reperfusion injuries, and the involvement of K(ATP) channels and nitric oxide (NO). METHODS: The experiments were performed in a total of 56 anesthetized pigs. In 21 pigs, 1.5, 5 and 12 MUg min(-1) levosimendan was infused over 15 min into the coronary artery at the onset of 1 h reperfusion following 2-h ischemia and the effects on cardiac function, infarcted area, and on apoptosis/autophagy were examined. In addition, the activation of Akt and extracellular receptor kinase (ERK) was analyzed. The findings were compared with those obtained in a further 14 pigs where the highest dose levosimendan was infused after glibenclamide and l-nitro-arginine methyl ester (l-NAME). RESULTS: Intracoronary 1.5, 5 and 12 MUg min(-1) levosimendan caused an increase of segmental shortening, dP/dt(max) and cardiac output of 7.8%, 22.6%, and 31.6%; 7.6%, 16.9%, and 21.6%; 2.8%, 5.9%, and 6.2%, respectively, from values measured at the end of ischemia. The beneficial effects elicited by levosimendan were still evident at the end of reperfusion when the increase of segmental shortening, dP/dt(max) and cardiac output caused by the three doses of levosimendan amounted to 3.7%, 13.3%, and 16.5%; 1.5%, 9.4%, and 11%; 1.4%, 2.7%, and 3.9%, respectively. When doses of 5 and 12 MUg min(-1) levosimendan were used, a reduction of infarcted area to about 69% and 67% of area at risk was observed, and was significantly different from that of about 79% measured in control animals. In addition, after intracoronary levosimendan, the inhibition of apoptosis and activation of autophagy and a dose-related increase of the level of phosphorylation of ERK and Akt were observed. These responses were completely prevented by glibenclamide and significantly reduced by l-NAME. CONCLUSIONS: The results of this study show that intracoronary levosimendan reduces cell death induced by ischemia/reperfusion in a dose-dependent manner and activates survival signaling through K(ATP) channel opening and NO. These findings support interesting implications for cardioprotection in interventional cardiology and cardiac surgery. PMID- 21247776 TI - Biophysical parameters influencing secondary oxidants activation in human serum exposed to singlet oxygen. AB - Singlet oxygen (1O2), produced during photodynamic therapy, deactivates during its interaction with tissues by producing reactive oxygen species (ROS) and peroxides as well as other degradation products. Here we investigated the role of parameters of light delivery, O(2), and temperature on the ROS and peroxides production, secondary to 1O2. A series of simple in vitro experiments has been performed with Rose Bengal (RB) as a 1O2 producer, human serum (HS) as a target and dichlorofluorescein (DCFH) as a nonspecific marker, becoming fluorescent when oxidized. The overall secondary production of ROS and peroxides in HS had also been compared to fetal calf serum (FCS) or mice sera. Increasing power but with a same delivered energy decreased secondary ROS and peroxides when increasing power with a same duration for light delivery increased them. Increasing delivered energy increased linearly secondary ROS or peroxides. Delivering O2 by bubbling before light delivery increased secondary ROS or peroxides, when Ar decreased them. Delivering gases after light delivery had no influence on secondary ROS or peroxides production. Increasing temperature from 20 to 40 degrees C increased secondary ROS or peroxides production but freezing after light delivery either before or after measurement had only a mild influence. Secondary ROS or peroxides production was 2 or 4 times lower in HS than in FCS or nude mice sera respectively. PDT seems to consist of two subsequent phases, both linked but developing independently. The intensity of photo-reactions varied with the model, human sera producing less secondary ROS than fetal calf or mouse sera. Search for new sensitizers should consider secondary ROS-induced pathways in addition to 1O2 production. PMID- 21247775 TI - Positive cultures from cardiopulmonary bypass: prevalence and relevance regarding postoperative infection. AB - OBJECTIVE: Postoperative infections due to cardiopulmonary bypass (CPB) are associated with high morbidity and mortality. The value of positive cultures taken from CPB priming fluid and CPB blood samples, however, is unclear. This study investigates the epidemiology of positive cultures from CPB and their relation to the occurrence of postoperative infection. METHODS: The study was conducted at the Maastricht University Medical Centre, a 715-bed teaching hospital with 900-1000 surgeries requiring CPB annually. From 1 January 1998 until 31 March 2010, all patients with positive CPB cultures drawn either from priming fluid or blood were retrospectively studied. Second, 335 patients with a positive CPB culture were compared with 335 randomly assigned patients who underwent cardiovascular surgery using CPB and had negative CPB cultures. Patients with active endocarditis were excluded. Demographic data and perioperative parameters were documented. Outcome measures were: a relevant infection (acute infectious valve endocarditis, wound infection, intravascular catheter-related infection, and bloodstream infection), occurrence of fever of unknown origin, and 30-day mortality. RESULTS: A total of 21840 cultures were analyzed, half being priming fluid and half CPB blood cultures. As many as 111 out of 10920 (1.0%) priming fluid cultures and 598 out of 10920 (5.6%) blood cultures tested positive. Gram-positive cocci predominated both priming fluid and blood cultures. Relevant postoperative infections within 30 days after surgery were seen in 47/663 (7.1%) of patients overall, in 27/330 in the CPB-culture positive group (8.2%) and 20/333 in the CPB-culture-negative group (6.0%), p=0.275. As many as 38 out of 363 patients (5.7%) were affected by fever of unknown origin (CPB-culture-positive group 4.5%, and CPB-culture-negative 6.9%; p=0.191). The 30-day mortality was 16/330 (4.8%) in the CPB-culture-positive group and 13/333 (3.9%) in the CPB-culture-negative group (p=0.552). CONCLUSIONS: Positive cultures from both CPB priming fluid and CPB blood samples were not a rarity and mainly involved skin bacteria, arguing that contamination may have played a role. The risk of postoperative infection within 30 days after surgery was not increased in CPB-culture-positive patients. Therefore, no evidence was found to support routine culturing of CPB samples in patients undergoing cardiothoracic surgery. PMID- 21247777 TI - Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice. AB - Cognitive impairment is frequently observed in epileptic patients. It has been seen that not only epilepsy but antiepileptic drugs also impair cognitive functions. The present study was undertaken to assess the effect of three anticonvulsants viz. lamotrigine (5mg/kg, p.o.), oxcarbazepine (15mg/kg, p.o.) and topiramate (10mg/kg, p.o.) on cognitive function and oxidative stress during pentylenetetrazole (PTZ)-kindling in mice. Kindling was induced by the administration of PTZ (25mg/kg, i.p.) on every alternate day till 5 weeks. Cognition was assessed after the development of kindling. Elevated plus maze (EPM) and passive avoidance response (PAR) tests were carried out after 24h and 48h of the last PTZ administration. After completion of behavioural tests malondialdehyde (MDA), glutathione levels, superoxide dismutase and catalase activity were measured as an indicator of oxidative stress. The results of the present study indicate that topiramate (10mg/kg) administration to kindled animals increased transfer latency and decreased step-down latency in EPM and PAR tests, respectively. However, lamotrigine and oxcarbazepine did not alter the two parameters. Topiramate administration to kindled as well as non-kindled animals has shown increase in MDA and decrease in glutathione levels. Lamotrigine and oxcarbazepine did not show significant alteration in oxidative stress parameters. To conclude, long term administration of topiramate impairs cognitive functions during experimental epilepsy while lamotrigine and oxcarbazepine are safer. PMID- 21247778 TI - Women in surgery residency programs: evolving trends from a national perspective. AB - BACKGROUND: Similar numbers of men and women are currently graduating from United States (US) medical schools; therefore, surgery residency programs need to attract graduates of both genders. This study compared gender distributions of allopathic US medical graduates (USMG) from academic years 1999-2000 through 2004 2005. In addition, the gender distributions of USMG and international medical graduates (IMG; analyzed separately) entering accredited general surgery (GS) programs and USMG entering other surgical specialty programs were compared across academic years 2000-2001 through 2005-2006. STUDY DESIGN: Data were extracted from the American College of Surgeons Resident Master File and the Association of American Medical Colleges FACTS Website and Data Warehouse. Chi-square statistics compared gender distributions across years for all USMG graduating and applying to GS programs each year between 1999-2000 and 2004-2005 and for USMG and IMG entering training between 2000-2001 and 2005-2006. RESULTS: During the study period, the proportion of women increased significantly (p < 0.001) among USMG (43% to 47%), USMG applying to GS programs (27% to 33%), and USMG entering GS residencies (32% to 40%); the percentages of women among IMG entering GS residencies ranged from 11% to 18%, with no apparent linear increase. Proportions of women among USMG entering training increased in most surgical specialties examined. CONCLUSIONS: The gender gap among USMG entering GS training appears to be closing, concurrent with that of USMG overall during the study period. Surgery programs must continue to recruit and retain women to attract the best and brightest trainees. PMID- 21247779 TI - First use of intravenous chemotherapy cancer treatment: rectifying the record. PMID- 21247780 TI - Development and validation of a bariatric surgery morbidity risk calculator using the prospective, multicenter NSQIP dataset. AB - BACKGROUND: Although a risk score estimating postoperative mortality for patients undergoing gastric bypass exists, there is none predicting postoperative morbidity. Our objective was to develop a validated risk calculator for 30-day postoperative morbidity of bariatric surgery patients. STUDY DESIGN: We used the American College of Surgeons' 2007 National Surgical Quality Improvement Program (NSQIP) dataset. Patients undergoing bariatric surgery for morbid obesity were studied. Multiple logistic regression analysis was performed and a risk calculator was created. The 2008 NSQIP dataset was used for its validation. RESULTS: In 11,023 patients, mean age was 44.6 years, 20% were male, 77% were Caucasian, and mean body mass index (BMI; calculated as kg/m(2)) was 48.9. Thirty day morbidity and mortality were 4.2% and 0.2%, respectively. Risk factors associated with increased risk of postoperative morbidity included recent MI/angina (odds ratio [OR] = 3.65; 95% CI 1.23 to 10.8), dependent functional status (OR = 3.48; 95% CI 1.78 to -6.80), stroke (OR = 2.89; 95% CI 1.09 to 7.67), bleeding disorder (OR = 2.23; 95% CI 1.47 to 3.38), hypertension (OR = 1.34; 95% CI 1.10 to 1.63), BMI, and type of bariatric surgery. Patients with BMI 35 to <45 and >60 had significantly higher adjusted OR compared with patients with BMI of 45 to 60 (p < 0.05 for all). These factors were used to create the risk calculator and subsequently validate it, with the model performance very similar between the 2007 training dataset and the 2008 validation dataset (c statistics: 0.69 and 0.66, respectively). CONCLUSIONS: NSQIP data can be used to develop and validate a risk calculator that predicts postoperative morbidity after various bariatric procedures. The risk calculator is anticipated to aid in surgical decision making, informed patient consent, and risk reduction. PMID- 21247781 TI - A new technique of ex vivo gene delivery of VEGF to wounds using genetically modified skin particles promotes wound angiogenesis. AB - BACKGROUND: Transplantation of genetically modified keratinocytes has been shown to accelerate wound healing. However, this method is labor-intensive and time consuming. We have developed a new technique of intraoperative gene delivery to wounds that involves transplantation of transfected minced skin particles (MSPs) derived from harvested partial-thickness skin. STUDY DESIGN: MSPs measuring 0.8 * 0.8 * 0.35 mm were created from a split-thickness skin graft of a pig. In vitro transfection was carried out with adenoviral LacZ (Ad-LacZ) for qualitative and adenoviral vascular endothelial growth factor (Ad-VEGF) for quantitative analysis. Transfected MSPs were transplanted to each of 2.5 * 2.5 cm full thickness wounds on the dorsum of the pig. Nontransfected MSPs served as controls. Wound chambers were applied and injected with saline to create a wet environment. RESULTS: LacZ expression was detected in migrating cells originating from MSPs both in vitro and in vivo. VEGF expression in the wound fluid of Ad VEGF-MSP-transplanted wounds on each of days 2 to 4 (mean +/- SEM 6.74 +/- 1.89 ng/mL, day 2; 9.88 +/- 2.27 ng/mL, day 3; 9.87 +/- 1.28 ng/mL, day 4) was significantly higher (p < 0.0001) compared with wounds transplanted with either untransfected MSPs, Ad-LacZ-MSPs, or untransplanted controls. In vitro VEGF expression was significantly higher (p < 0.0001) in Ad-VEGF 1 * 10(10) transfected MSPs compared with either Ad-VEGF 1 * 10(9) transfected MSPs or untransfected MSPs. Wounds transplanted with Ad-VEGF-MSPs showed significantly higher (p < 0.0001) numbers of newly formed blood vessels (12.6 +/- 0.9 vessels/high power field [HPF]) compared with wounds transplanted with either Ad LacZ-MSPs (4.4 +/- 0.5 vessels/HPF) or untransfected MSPs (5.2 +/- 0.7 vessels/HPF). All MSP-transplanted wounds (Ad-VEGF-MSPs, untransfected MSPs, Ad LacZ-MSPs) showed significantly higher re-epithelialization compared with untransplanted wounds on days 10 and 14 (p < 0.0001). CONCLUSIONS: We demonstrated successful transfection of MSPs that can be transplanted to wounds as a source of gene-expressing cells. This technique can be used to deliver growth-modulating genes in wound healing. PMID- 21247782 TI - Perioperative use of arginine-supplemented diets: a systematic review of the evidence. PMID- 21247783 TI - Comments regarding "A retrospective study of intravascular ultrasound use in patients undergoing endovascular aneurysm repair: its usefulness and a description of the procedure" The use of Contrast Enhanced Ultrasound for Intra procedural EVAR deployment completely eliminates the need for nephrotoxic iodinated intra-arterial contrast. PMID- 21247784 TI - The effects of including quality of life responses in models to predict walking performance of patients with intermittent claudication. AB - OBJECTIVES: To examine the accuracy of previously developed prediction models of treadmill walking performance in patients with intermittent claudication (IC) due to peripheral arterial disease (PAD); and to examine the accuracy of new prediction models. DESIGN: Analysis of data collected in a previous randomised clinical trial. MATERIALS: Ninety-three assessments of 28 patients diagnosed with IC due to PAD. METHODS: Patients undertook routine clinical assessments, quality of life (QOL) questionnaires and treadmill walking tests. Walking performance and estimates based on prediction models were compared via paired t-tests or Wilcoxon Rank Sum tests. Stepwise linear regression generated models to predict walking performance from clinical measures and QOL responses. Accuracy was determined as the absolute error between model estimates and patient results. RESULTS: Walking performance was significantly underestimated (35-71% error) by previously developed prediction models. Models developed in the current study identified QOL responses as the most significant predictors of current walking performance but these models still resulted in substantial errors (19-84%). CONCLUSIONS: Previously published predictors of walking performance significantly underestimated patient's ability in practise. Predictions based upon clinical measurements and QOL responses were developed however, their accuracy was also limited. Further research is needed regarding walking performance prediction to assist clinicians with assessment of PAD severity and treatment effectiveness. PMID- 21247785 TI - Oral and maxillofacial desmoid-type fibromatoses in an eastern Chinese population: a report of 20 cases. AB - OBJECTIVE: Primary desmoid-type fibromatoses arising from the oral and maxillofacial region are uncommon and hold the character of local invasion and regional recurrence. The purpose of this study was to analyze the clinicoepidemiologic characteristics of this rare disease in an eastern Chinese population. STUDY DESIGN: Epidemiological and clinicopathological data on 20 patients were reviewed from the hospital records and analyzed accordingly. RESULTS: Twelve males and 8 females with a ratio of 3:2 were involved. The mandible was the most common site of presentation. Suspected malignant change was found in 6 cases and an extremely high recurrence rate was also found in up to 53%. Abnormally high blood levels of alkaline phosphatase were found in 65% of patients, which had a close relation with tumor malignant change. CONCLUSION: Chinese people are more susceptible to desmoid-type fibromatoses and are at an extremely high risk of regional malignant change. Elevated serum alkaline phosphatase levels may be taken as an indicator for malignant transformation. PMID- 21247786 TI - Identification of potentially virulent strains of Haemophilus parasuis using a multiplex PCR for virulence-associated autotransporters (vtaA). AB - Haemophilus parasuis is the aetiological agent of Glasser's disease and is also a commensal of the upper respiratory tract of pigs. Trimeric autotransporter (vtaA) genes have been identified in H. parasuis and divided into three groups on the basis of the translocator domain sequence. In this study, group 3 vtaA genes were demonstrated by PCR in all 157 H. parasuis isolates tested. Group 1 vtaA genes were associated with virulent strains; 52/54 (96%) group 1 vtaA negative field isolates were isolated from the nasal passages of healthy animals, whereas no group 1 vtaA negative field isolates were isolated from cases of Glasser's disease. There was an association between absence of group 1 vtaA, sensitivity to phagocytosis and serum and classification of isolates into nasal cluster C by multilocus sequence typing. A multiplex PCR was developed for diagnosis of H. parasuis at the species level (group 3 vtaA positive) and to differentiate putative non-virulent strains (group 1 vtaA negative). When applied to field samples, the PCR confirmed a high prevalence of H. parasuis in conventionally farmed pigs and demonstrated that almost half of the animals carried potentially virulent strains. PMID- 21247787 TI - Determination of 1J(59Co-59Co) scalar coupling constants in the tetrahedral mixed metal cluster HFeCo3(CO)10(PCyH2)(PPh2[CH2C(O)Ph]) using COSY-type NMR experiments. AB - Two-dimensional 59Co correlation spectroscopy (COSY) and double-quantum-filtered (DQF) COSY NMR experiments are reported for the tetrahedral mixed-metal cluster HFeCo3(CO)10(PCyH2)(PPh2[CH2C(O)Ph]), which consists from the point of view of 59Co NMR spectroscopy, of an AMX system of three-spin S=7/2. Both 2D NMR spectra prove the existence of a J scalar coupling constant between non-equivalent 59Co nuclei. By contrast to what happens with the conventional 2D 59Co COSY NMR spectrum, it was possible to simulate the 2D 59Co DQF-COSY NMR spectrum by density matrix calculations in order to extract the values of the 1J(59Co-59Co) coupling constants. The comparison between experimental and theoretical 2D NMR spectra gives spin-couplings constants of several hundreds Hertz for this cluster. PMID- 21247788 TI - Extreme conditions during multibubble cavitation: Sonoluminescence as a spectroscopic probe. AB - We review recent work on the use of sonoluminescence (SL) to probe spectroscopically the conditions created during cavitation, both in clouds of collapsing bubbles (multibubble sonoluminescence, (MBSL)) and in single bubble events. The effective MBSL temperature can be controlled by the vapor pressure of the liquid or the thermal conductivity of the dissolved gas over a range from ~1600 to ~9000K. The effective pressure during MBSL is ~300bar, based on atomic line shifts. Given nanosecond emission times, this means that cooling rates are >10(12)K/s. In sulfuric and phosphoric acid, the low volatility and high solubility of any sonolysis products make bubble collapse more efficient and evidence for an optically opaque plasma core is found. PMID- 21247789 TI - A durable, low-cost electrogoniometer for dynamic measurement of joint trajectories. AB - This article introduces a method and step-by-step instructions for the design of a low-cost, flexible electrogoniometer, suitable for kinesiology, rehabilitation, and biometric applications. Two unidirectional flexible sensors are placed back to-back, and a multivariate linear regression model was used to combine measurements from the two sensors. Following a short calibration procedure, the electrogoniometer can be reliably used for measurement of flexion/extension angles of various hinge joints. The performance of the goniometer has been tested on a population of 21 healthy subjects performing flexion/extension of index finger, wrist and elbow. The proposed device achieves the quality of joint angle measurements comparable to that of commercial electrogoniometers, while having a significantly higher durability-to-cost ratio. PMID- 21247790 TI - Stroop test performance in impulsive and non impulsive patients with Parkinson's disease. AB - Impulsive personalities are considered to have a general impairment in cognitive flexibility and cortical inhibition. To examine this hypothesis we used a trial by trial Stroop task in impulsive and non impulsive patients with Parkinson's disease (PD) and recorded errors and reaction times (RT). We tested 28 impulsive PD (PD+ICB) and 24 non impulsive PD (PD-ICB) patients prior to and after dopaminergic medication. These results were compared with 24 age matched normal controls. We found an increased error rate in all PD patients prior to their usual medication which resolved after medication. Furthermore patients on medication showed enhanced cognitive flexibility and shorter RT. There was no difference between non impulsive and impulsive PD patients. This suggests that the impulsive behaviours may not affect response inhibition tasks and the response inhibition required in the Stroop test does not engage the same processes that differentiate impulsive and non-impulsive PD patients, which likely involve mesolimbic dopamine. PMID- 21247791 TI - Geranylgeraniol - a new potential therapeutic approach to bisphosphonate associated osteonecrosis of the jaw. AB - Bisphosphonate associated osteonecrosis of the jaw (BP-ONJ) is one of the main side effects of bisphosphonate therapy (BPT). To date, there is no effective therapy of the BP-ONJ. Nitrogen-containing bisphosphonates (N-BPs) are particularly able to inhibit pyrophosphate synthase (FPPS) in the mevalonate pathway (MVP). Consequent of decreased synthesis of the metabolite Geranylgeraniol (GGOH) is believed to largely account for the development of BP ONJ. Negative effect of N-BPs could be shown, resulting in decreased viability and migration capacity of different cell types of hard and soft tissues such as osteoblasts, fibroblast und endothelial cells. Aim of our in vitro study was to demonstrate that the mevalonate pathway metabolite GGOH could reverse the negative biological effect of N-BPs. Biological effect of GGOH on bisphosphonate treated human umbilicord vein endothelial cells (HUVEC), fibroblast and osteogenic cells was analyzed by a viability test and measuring the migration capacity in a scratch wound assay as well as a migration assay using Boyden chambers. The morphological cell architecture of the treated cells was analyzed by phallacidin staining. GGOH cell-treatment can rescue the negative effect of bisphosphonates. These results underline the hypothesis that systemic or local treatment with GGOH could lead to new therapeutic strategies for BP-ONJ. PMID- 21247792 TI - Synthesis, structure investigation, spectral characteristics and biological activities of some novel azodyes. AB - Four novel azo compounds were synthesized; o-phenylazo- (C(14)H(13)N(3)O(2)) (I), p-bromo-o-phenylazo- (C(14)H(13)BrN(3)O(2)) (II), p-methoxy-o-phenaylazo- (C(15)H(16)N(3)O(3)) (III) and p-nitro-o-phenylazo-p-acetamidophenol (C(14)H(13)N(4)O(4)) (IV). These compounds were carefully investigated using elemental analyses, UV-vis, FT-IR, (1)H NMR and mass spectra. Also, the effects of p-substituents such as bromo, methoxy and nitro groups on the mass fragmentation pathways of these dyes were studied using Hammet's effects. This research aimed chiefly to threw lights on the structures-stability relationship of four novel newly prepared azo derivatives of p-acetoamidophenol. The data obtained referred to the variation of mass fragmentation pathways with the variation of p-substituent of these dyes which can be used in industry for various dyeing purposes. This variation is also correlated and verified by molecular orbital calculations which were done on ionic forms of these dyes using semi empirical PM3 program. The biological activities of these dyes were also investigated and its structure relationship was correlated. PMID- 21247793 TI - First findings of monocrystalline aragonite inclusions in garnet from diamond grade UHPM rocks (Kokchetav Massif, Northern Kazakhstan). AB - The presence of aragonite inclusions in garnet from diamond-grade metamorphic rocks from the Kokchetav Massif, Northern Kazakhstan was identified for the first time by means of Raman analyses and mapping. Aragonite appears within the inclusions up to 50 MUm in size as a single crystal. These inclusions have rounded shape. The grain boundary between the host-garnet is smooth. No cracks occur around the aragonite inclusions. No significant shift in the main aragonite Raman band was measured. These observations indicate that residual pressure within the inclusion is minor. These findings imply either non-UHPM origin of the host garnet or significant plastic deformation of host minerals during retrograde stage. These features should be taken into account for recovery peak metamorphic conditions and modeling of exhumation processes of UHPM complexes. PMID- 21247794 TI - Absorption spectroscopic probe to investigate the interaction between Nd(III) and calf-thymus DNA. AB - The interaction between Nd(III) and Calf Thymus DNA (CT-DNA) in physiological buffer (pH 7.4) has been studied using absorption spectroscopy involving 4f-4f transition spectra in different aquated organic solvents. Complexation with CT DNA is indicated by the changes in absorption intensity following the subsequent changes in the oscillator strengths of different 4f-4f bands and Judd-Ofelt intensity (T(lambda)) parameters. The other spectral parameters namely Slator Condon (F(k)'s), nephelauxetic effect (beta), bonding (b(1/2)) and percent covalency (delta) parameters are computed to correlate with the binding of Nd(III) with DNA. The absorption spectra of Nd(III) exhibited hyperchromism and red shift in the presence of DNA. The binding constant, K(b) has been determined by absorption measurement. The relative viscosity of DNA decreased with the addition of Nd(III). Thermodynamic parameters have been calculated according to relevant absorption data and Van't Hoff equation. The characterisation of bonding mode has been studied in detail. The results suggested that the major interaction mode between Nd(III) and DNA was external electrostatic binding. PMID- 21247795 TI - Interaction of cinnamic acid derivatives with serum albumins: a fluorescence spectroscopic study. AB - Cinnamic acid (CA) derivatives are known to possess broad therapeutic applications including anti-tumor activity. The present study was designed to determine the underlying mechanism and thermodynamic parameters for the binding of two CA based intramolecular charge transfer (ICT) fluorescent probes, namely, 4-(dimethylamino) cinnamic acid (DMACA) and trans-ethyl p-(dimethylamino) cinnamate (EDAC), with albumins by fluorescence spectroscopy. Stern-Volmer analysis of the tryptophan fluorescence quenching data in presence of the added ligand reveals fluorescence quenching constant (kappa(q)), Stern-Volmer constant (K(SV)) and also the ligand-protein association constant (K(a)). The thermodynamic parameters like enthalpy (DeltaH) and entropy (DeltaS) change corresponding to the ligand binding process were also estimated. The results show that the ligands bind into the sub-domain IIA of the proteins in 1:1 stoichiometry with an apparent binding constant value in the range of 10(4) dm(3) mol(-1). In both the cases, the spontaneous ligand binding to the proteins occur through entropy driven mechanism, although the interaction of DMACA is relatively stronger in comparison with EDAC. The temperature dependence of the binding constant indicates the induced change in protein secondary structure. PMID- 21247796 TI - Quantum chemical computational studies on 5-(4-bromophenylamino)-2 methylsulfanylmethyl-2H-1,2,3-triazol-4-carboxylic acid ethyl ester. AB - The optimized molecular geometry, vibrational frequencies, and gauge including atomic orbital (GIAO) (1)H and (13)C NMR shift values of 5-(4-bromophenylamino)-2 methylsulfanylmethyl-2H-1,2,3-triazol-4-carboxylic acid ethyl ester have been calculated by using Hartree-Fock (HF) and density functional method (DFT/B3LYP) with 6-31G(d), 6-31G(d,p) and LANL2DZ basis sets. The optimized molecular geometric parameters were presented and compared with the data obtained from X ray diffraction. In order to fit the calculated harmonic wavenumbers to the experimentally observed ones, scaled quantum mechanics force field (SQM FF) methodology was proceeded. Correlation factors between the experimental and calculated (1)H chemical shift values of the title compound in vacuum and in CHCl(3) solution by using the conductor-like screening continuum solvation model (COSMO) were reported. The calculated results showed that the optimized geometry well reproduces the crystal structure. The theoretical vibrational frequencies and chemical shifts are in very good agreement with the experimental data. In solvent media the energetic behavior of the title compound was also examined by using the B3LYP method with the 6-31G(d) basis set, applying the COSMO model. The obtained results indicated that the total energy of the title compound decreases with increasing polarity of the solvent. Furthermore, molecular electrostatic potential (MEP), natural bond orbital (NBO) and frontier molecular orbitals (FMOs) of the title compound were performed by the B3LYP/LANL2DZ method, and also thermodynamic parameters for the title compound were calculated at all the HF and B3LYP levels. PMID- 21247797 TI - Behavioural differences between EEG-defined subgroups of children with Attention Deficit/Hyperactivity Disorder. AB - OBJECTIVE: This study investigated the presence and nature of EEG clusters within a clinically-referred sample of children with Attention-Deficit/Hyperactivity Disorder (AD/HD), and whether behavioural differences exist between clusters. METHOD: Participants were 155 boys with AD/HD and 109 age- and gender-matched controls. EEG was recorded during an eyes-closed resting condition and Fourier transformed to provide estimates for total power, and relative delta, theta, alpha, and beta. EEG data were grouped into 3 regions, and subjected to Cluster Analysis. Behavioural data for each cluster were compared against the remaining AD/HD subjects. RESULTS: Four EEG clusters were found. These were characterised by (a) elevated beta activity, (b) elevated theta with deficiencies of alpha and beta, (c) elevated slow wave with less fast wave activity, and (d) elevated alpha. An exploratory analysis of behavioural correlates with these EEG subtypes indicated the presence of interesting trends that need further investigation. CONCLUSIONS: This study found that the AD/HD EEG profiles reported in past studies are robust and not substantially affected by the inclusion of children with other comorbid conditions. The observed group differences in behavioural profiles indicated that different patterns of EEG activity have importance in determining behaviour. SIGNIFICANCE: This is the first study to link behavioural profiles of children with AD/HD to specific EEG abnormalities. PMID- 21247799 TI - Construction of a thiamine pyrophosphate high-producing strain of Aspergillus oryzae by overexpression of three genes involved in thiamine biosynthesis. AB - We have found a gene (thiP) encoding thiamine pyrophosphokinase (TPK) in the Aspergillus oryzae genome. No riboswitch-like region was found in the upstream region of thiP, although it was repressed probably by thiamine pyrophosphate (TPP) as well as thiA and nmtA, which are strictly regulated by TPP-riboswitch sequence. To improve the productivity of TPP in A. oryzae, we constructed the strain in which thiA, nmtA and thiP were overexpressed simultaneously. The resulting strain accumulated intracellular TPP 4-fold higher than did the control strain. PMID- 21247800 TI - Telemetric CPAP titration at home in patients with sleep apnea-hypopnea syndrome. AB - BACKGROUND: Home continuous positive airway pressure (CPAP) titration with automatic devices is not possible in a non-negligible percentage of patients with sleep apnea-hypopnea syndrome (SAHS). OBJECTIVES: To test the feasibility of a novel telemetric system for home CPAP titration. METHODS: One-night home CPAP titration was carried out on 20 SAHS patients (56+/-3 years; BMI=35+/-2 kg/m2). A telemetric unit, based on the conventional GPRS mobile phone network and connected to a commercial CPAP device, allowed the hospital technician to monitor flow, pressure and air leaks by remote control and titrate CPAP (elimination of apneas, hypopneas, flow limitation and snoring) in real time. After 1 week, a full hospital polysomnography was performed while the patient was subjected to the value of CPAP that was previously titrated at home via telemetry. RESULTS: The home-titrated CPAP systematically improved patients' breathing: the apnea hypopnea index and percentage of sleep time with arterial oxygen saturation below 90% were reduced from 58.1+/-5.1 to 3.8+/-0.6 events/h and from 19.8+/-1.1% to 4.4+/-0.7%, respectively. This CPAP value (9.15+/-0.47 cmH2O) was virtually the same as the pressure that optimized breathing during hospital polysomnography (9.20+/-0.41 cmH2O; mean difference: 0.02 cmH2O, limits of agreement:+/-1.00 cmH2O). CONCLUSIONS: This pilot study shows that a simple telemetric system, requiring neither a special telemedicine network nor any infrastructure in the patient's home, made it possible to perform effective remote CPAP titration on SAHS patients. PMID- 21247801 TI - Emergence and progression of Vibrio cholerae O1 El Tor variants and progenitor strains of Mozambique variants in Kolkata, India. AB - Analysis of 75 Vibrio cholerae O1 strains isolated from hospitalized patients in Kolkata from 1989 to 1994 revealed the existence of true El Tor along with El Tor variants that possessed the classical allele of ctxB (ctxB(cl)) in strains having an El Tor backbone. Based on the existence of different combinations of ctxB and rstR alleles and their localization sites in the genome, these strains were classified into multiple genetic groups. Of 75 clinical strains, 11 were identified as non-toxigenic. These 8 strains were also devoid of pTLC, which is uncommon among the O1 strains. However, Mozambique variants isolated in 2004 were typically negative for pTLC, but these strains possessed tandemly arranged CTX prophages with ctxB(cl) in the small chromosome. Genetic manipulation studies with laboratory-generated kanamycin-tagged pCTX-Kan (derived from tandemly arranged small chromosome-localized ctxB(cl) bearing CTX prophages of 1992 VC53, a progenitor strain of the Mozambique variant) demonstrated that integration specificity of the pCTX-Kan was somewhat towards small chromosome. Such integration could be the prime step towards generation of the Mozambique variant. Based on the existence of multiple alleles of CTXphi and their infections with non-toxigenic strains, we propose that the El Tor variant strains could have emerged following these genetic events. This study demonstrated existence of different 'intermediate strains' in a time frame that overlapped with a period of V. cholerae O139 emergence. Identification of these intermediate strains gave impetus to believe stepwise generation of the El Tor variants, and all these events profoundly influenced V. cholerae epidemiology in the following years. PMID- 21247802 TI - Design and validation of a portable, inexpensive and multi-beam timing light system using the Nintendo Wii hand controllers. AB - OBJECTIVES: Commercial timing light systems (CTLS) provide precise measurement of athletes running velocity, however they are often expensive and difficult to transport. In this study an inexpensive, wireless and portable timing light system was created using the infrared camera in Nintendo Wii hand controllers (NWHC). DESIGN: System creation with gold-standard validation. METHOD: A Windows based software program using NWHC to replicate a dual-beam timing gate was created. Firstly, data collected during 2m walking and running trials were validated against a 3D kinematic system. Secondly, data recorded during 5m running trials at various intensities from standing or flying starts were compared to a single beam CTLS and the independent and average scores of three handheld stopwatch (HS) operators. Intraclass correlation coefficient and Bland Altman plots were used to assess validity. Absolute error quartiles and percentage of trials in absolute error threshold ranges were used to determine accuracy. RESULTS: The NWHC system was valid when compared against the 3D kinematic system (ICC=0.99, median absolute error (MAR)=2.95%). For the flying 5m trials the NWHC system possessed excellent validity and precision (ICC=0.97, MAR<3%) when compared with the CTLS. In contrast, the NWHC system and the HS values during standing start trials possessed only modest validity (ICC<0.75) and accuracy (MAR>8%). CONCLUSIONS: A NWHC timing light system is inexpensive, portable and valid for assessing running velocity. Errors in the 5m standing start trials may have been due to erroneous event detection by either the commercial or NWHC-based timing light systems. PMID- 21247803 TI - Walking a fine line: an exploration of the experience of finding balance for older persons bereaved after caregiving for a spouse with advanced cancer. AB - PURPOSE OF THE RESEARCH: During the past decade, research regarding cancer patients has become more prevalent, however research regarding the needs of their family caregivers is limited. The purpose of this study was to explore the ways in which caregivers, who survive the loss of their spouse to cancer, find balance in their lives. METHODS AND SAMPLE: A constructivist grounded theory approach was undertaken which included the analysis of in depth interviews, journal entries and the researcher's field notes and memos. Interviews were conducted with 10 bereaved caregivers (7- females, 3-males) ranging in age from 66 to 83 years old. The data included 21 interviews and 8 journals. KEY RESULTS: For bereaved caregivers "walking a fine line" emerged as a major process, balancing between "deep grieving" and "moving forward" in order to successfully create a new life without their partner. The main concern of the participants was "losing control" of balance. The emergence of these processes reveals the importance of addressing the bereaved caregivers' need to find balance within their new lives. CONCLUSIONS: The findings of this study highlight the unique needs of bereaved caregivers who have lost a spouse to cancer, and provides a basis for ongoing research focused on assessment and intervention. Further research is needed to determine whether the process of finding balance is similar in other groups of caregivers who are bereaved. PMID- 21247805 TI - Heparinized polyvinyl alcohol to specifically adsorb low-density lipoprotein from plasma. AB - INTRODUCTION: A medical adsorbent for blood purification was developed to specifically adsorb low-density lipoprotein (LDL) from hypercholesterolemia patient's plasma by covalently immobilizing heparin onto the surface of polyvinyl alcohol (PVA) with the couplant toluence-2,4-diisocyanate (TDI). METHODS: We used IR to demonstrate the success of covalently immobilizing heparin onto the surface, and investigated its adsorption of LDL, and primarily evaluated its hemo compatibility using tests for platelet adhesion, the degree of platelet activation and a hemolysis test. RESULTS: (1) Heparin was successfully covalently immobilized onto the surface, the maximum amount of heparin immobilized on the surface of 1g PVA-1799 granules was about 5 MUg; (2) one optimal condition for adsorption of LDL from hyperlipidemia plasma was a pH within the range of 7.2~9.5, accordingly the adsorptive ratio (adsorbent/g: plasma/L=1:2) for LDL was about 70%; (3) it exhibited good hemo-compatibility. CONCLUSION: The adsorbent results in satisfactory adsorption of LDL with good hemo-compatibility; it could potentially be used as a blood purification material, and immobilization of heparin onto medical materials may be a way to develop an LDL-specific adsorbent for blood purification. PMID- 21247806 TI - Neurological complications of acute ischaemic stroke. AB - Complications after ischaemic stroke, including both neurological and medical complications, are a major cause of morbidity and mortality. Neurological complications, such as brain oedema or haemorrhagic transformation, occur earlier than do medical complications and can affect outcomes with potential serious short-term and long-term consequences. Some of these complications could be prevented or, when this is not possible, early detection and proper management could be effective in reducing the adverse effects. However, there is little evidence-based data to guide the management of these neurological complications. There is a clear need for improved surveillance and specific interventions for the prevention, early diagnosis, and proper management of neurological complications during the acute phase of stroke to reduce stroke morbidity and mortality. PMID- 21247804 TI - The TB Structural Genomics Consortium: a decade of progress. AB - The TB Structural Genomics Consortium is a worldwide organization of collaborators whose mission is the comprehensive structural determination and analyses of Mycobacterium tuberculosis proteins to ultimately aid in tuberculosis diagnosis and treatment. Congruent to the overall vision, Consortium members have additionally established an integrated facilities core to streamline M. tuberculosis structural biology and developed bioinformatics resources for data mining. This review aims to share the latest Consortium developments with the TB community, including recent structures of proteins that play significant roles within M. tuberculosis. Atomic resolution details may unravel mechanistic insights and reveal unique and novel protein features, as well as important protein-protein and protein-ligand interactions, which ultimately lead to a better understanding of M. tuberculosis biology and may be exploited for rational, structure-based therapeutics design. PMID- 21247807 TI - Peer support to promote physical activity after completion of centre-based cardiac rehabilitation: evaluation of access and effects. AB - BACKGROUND: Patients with heart disease receive little support for sustaining physical activity over the long-term. This study compared the characteristics of patients choosing to join a peer support program to promote use of physical activity and assessed its effects on physical activity. AIMS: To compare characteristics of those choosing to join the peer support (PS) program versus those who did not, and to assess the effect on physical activity patterns at 12 months of the PS program. METHODS: Based on health status from 225 people who completed centre-based cardiac rehabilitation, 109 patients with heart disease who had completed a program of hospital-based cardiac rehabilitation were suitable for the peer support program. Health status and characteristics of patients opting to join the program (n = 79) were compared to patients who did not wish to join (n = 30). A longitudinal study was then conducted to determine the objective effects on physical activity levels of program membership at 12 months as measured by self-report and pedometers. RESULTS: Patients who joined the peer support program tended to be older (p < 0.001), and female compared to those who were eligible but did not join (p = 0.04). Over the next 12 months, those who did not participate in the peer support program reported a decline of 211 min in the total amount of physical activity accumulated in an average week (1382.5 +/- 238.2 to 1171.5 +/- 220.1 min week(-1) p = 0.003), whereas program members sustained similar levels of physical activity as was recorded at the completion of cardiac rehabilitation (1021.1 +/- 141.9 to 1070 +/- 127.8 min week(-1)). Objective measures of physical activity indicated that groups increased moderately total step count per week (p = 0.68 and p = 0.25) and in their average steps per day (p = 0.68 and p = 0.25 respectively) from baseline to 12 months. CONCLUSION: Peer support programs have good potential to help people with heart disease maintain physical activity after cardiac rehabilitation. Importantly, they may offer particular benefits for older patients and females. PMID- 21247808 TI - Bioinformatic analysis of molecular network of glucosinolate biosynthesis. AB - Glucosinolates constitute a major group of secondary metabolites in Arabidopsis, which play an important role in plant interaction with pathogens and insects. Advances in glucosinolate research have defined the biosynthetic pathways. However, cross-talk and interaction between glucosinolate pathway and other molecular pathways are largely unknown. Here three bioinformatics tools were used to explore novel components and pathway connections in glucosinolate network. Although none of the software tools were prefect to predict glucosinolate genes, combination of results generated by all the tools led to successful prediction of all known glucosinolate genes. This approach was used to predict new genes in glucosinolate network. A total of 330 genes were found with high potential to relate to glucosinolate biosynthesis. Among them 64 genes were selected to construct glucosinolate network because their individual connection to at least one known glucosinolate gene was predicted by all the software tools. Microarray data of candidate gene mutants were used for validation of the results. The mutants of nine genes predicted by glucosinolate seed genes all exhibited changes in the expression of glucosinolate genes. Four of the genes have been well-known to functionally interact with glucosinolate biosynthesis. These results indicate that the approach we took provides a powerful way to reveal new players in glucosinolate networks. Creation of an in silico network of glucosinolate biosynthesis will allow the generation of many testable hypotheses and ultimately enable predictive biology. PMID- 21247809 TI - Immune system development during early childhood in tropical Latin America: evidence for the age-dependent down regulation of the innate immune response. AB - The immune response that develops in early childhood underlies the development of inflammatory diseases such as asthma and there are few data from tropical Latin America (LA). This study investigated the effects of age on the development of immunity during the first 5 years of life by comparing innate and adaptive immune responses in Ecuadorian children aged 6-9 months, 22-26 months, and 48-60 months. Percentages of naive CD4+ T cells declined with age while those of memory CD4(+) and CD8(+) T cells increased indicating active development of the immune system throughout the first five years. Young infants had greater innate immune responses to TLR agonists compared to older children while regulatory responses including SEB-induced IL-10 and percentages of FoxP3(+) T-regulatory cells decreased with age. Enhanced innate immunity in early life may be important for host defense against pathogens but may increase the risk of immunopathology. PMID- 21247810 TI - Place of mesh in vaginal surgery, including its removal and revision. AB - In this review, I aim to establish the place of vaginal pelvic organ prolapse surgery with mesh, drawing on personal experience. Physiopathologic justifications for the use of synthetic implants are described, and reasonable indications are highlighted. Major recommendations for the insertion are made. Possible complications, such as erosion, retraction, pain, failure and dysfunction are explained, and treatments, including secondary surgery are reviewed. The need for specific training is emphasised, including indications, standard techniques of insertion, follow up, and mesh-related symptoms of complications, their management, including indications, and techniques of revision or excision. Mesh surgery in pelvic organ prolapse aims to replace defective ligaments and fascias by a synthetic implant that provokes a foreign body reaction and fibrosis around it, recreating new connective support. Women indicated for this type of surgery include those at high risk of recurrence after autologous surgery resulting from defective connective tissue. Insertion techniques and the management of complications need specific training before using mesh in pelvic organ prolapse surgery. Revision and removal should be carried out in referral centres. PMID- 21247811 TI - Diabetes and obesity in pregnancy. AB - An epidemic of obesity is affecting growing numbers of women in their childbearing years increasing their risk of obstetric complications including diabetes, hypertension, pre-eclampsia, some malformations, macrosomia and the need for obstetric intervention. There is growing evidence that maternal obesity may increase the risk of obesity and diabetes in the offspring. Obesity and diabetes in pregnancy have independent and additive effects on obstetric complications, and both require management during pregnancy. Management of obesity including weight loss and physical activity prior to pregnancy is likely to be beneficial for mother and baby, although the benefits of bariatric surgery remain unclear at this time. Limiting gestational weight gain to 5-9 kg among pregnant obese women is likely to improve obstetric outcomes, but how to achieve this remains an active area of research. If gestational diabetes develops, there is good evidence that clinical management reduces the risk of adverse pregnancy outcomes. PMID- 21247812 TI - Characterisation of a refined rat model of respiratory infection with Pseudomonas aeruginosa and the effect of ciprofloxacin. AB - BACKGROUND: We sought to characterise a refined rat model of respiratory infection with P. aeruginosa over an acute time course and test the antibiotic ciprofloxacin. METHODS: Agar beads were prepared +/- SPAN((r))80. Rats were inoculated with sterile agar beads or those containing 10(5) colony forming units (cfu) P. aeruginosa via intra-tracheal dosing. Bacterial load and inflammatory parameters were measured. RESULTS: Differing concentrations of SPAN((r)) 80 modified median agar bead diameter and reduced particle size distribution. Beads prepared with 0.01% v/v SPAN((r))80 were evaluated in vivo. A stable lung infection up to 7 days post infection was achieved and induced BALF neutrophilia 2 and 5 days post infection. Ciprofloxacin (50mg/kg) significantly attenuated infection without affecting the inflammatory parameters measured. CONCLUSION: SPAN((r)) 80 can control the particle size and lung distribution of agar beads and P. aeruginosa-embedded beads prepared with 0.01%v/v SPAN((r))80 can induce infection and inflammation over 7 days. PMID- 21247813 TI - Urine metabolomics analysis for adrenal incidentaloma activity detection and biomarker discovery. AB - This study describes the development of a method suitable for the analysis of nineteen major urinary steroid metabolites in human urine. The analytes of interest were isolated from urine using solid phase extraction, subjected to enzymatic hydrolysis and again extracted applying solid phase extraction. After derivatization, methyloxime-trimethylsilyl ether derivatives of steroid hormones were identified by gas chromatography-mass spectrometry (GC/MS) and quantified by gas chromatography with flame ionization detector (GC/FID). The quantification method was validated for linearity, trueness, precision and selectivity. The limits of detection were between 6.2 and 7.2 ng/mL and limits of quantification were between 12.3 and 14.8 ng/mL. The established method was applied to analyze 28 urine samples from patients diagnosed with non-functioning adrenal incidentalomas (AIs) and 30 healthy subjects. Hierarchical cluster analysis (HCA) and principal component analysis (PCA) were employed to visualize the differences between metabolic profiles of patients and the control group and to determine possible markers of AIs activity. Both multivariate methods separated seven patients from the rest of the examined individuals. Five urinary metabolites including alpha-cortol, tetrahydrocorticosterone, tetrahydrocortisol, allo tetrahydrocortisol and etiocholanolone were identified as potential biomarkers of pathological adrenal function. The altered metabolites reflected pathological metabolism mainly of cortisol and cortisone. This research proved that metabolomics is a suitable tool for disease research. PMID- 21247814 TI - Identification of the potential active components of Abelmoschus manihot in rat blood and kidney tissue by microdialysis combined with ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - In this paper, microdialysis combining with ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was applied to simultaneously identify components in blood and kidney dialysis after oral administration of Abelmoschus manihot extract. Microdialysis probe was implanted in the jugular vein and the kidney medulla, respectively; microdialysis samples were collected continuously, transferred to microtubes and analyzed by UPLC-Q-TOF/MS. The components in microdialysis samples were separated by an UPLC HSS T3 column and eluted with acetonitrile and water (containing 0.1% formic acid) at a flow rate of 0.4 mL/min. The results showed that unbound constituents in blood circulation of the rat include hyperoside, isoquercitrin, quercetin monoglucuronide, quercetin-3'-O-glucoside, quercetin, myricetin, and hibifolin while unbound constituents in kidney are hyperoside, isoquercitrin, quercetin monoglucuronide, which might be the potential active components in vivo. The developed method was simple and reliable, and could be adopted to rapidly screen and identify potential active components contributing to pharmacological effects of TCM and to better clarify its action mechanism. PMID- 21247815 TI - [Potential risks of the adverse effects of thyrotropin suppression in differentiated thyroid carcinoma]. AB - In patients with differentiated thyroid carcinoma, long-term inhibition of thyrotropin (TSH) secretion through levothyroxine administration is required when there is evidence of persistent or recurrent disease. In these cases, levothyroxine doses should be monitored to achieve the objectives of inhibiting TSH and avoiding clinical hyperthyroidism. The possibility that suppressive therapy may produce deleterious effects is still controversial, mainly in elderly patients. There are many studies on the potential harmful effects of suppressive therapy on various organs and systems with discrepant results. However, there is no scientific evidence that the clinical impact of these effects is significant. PMID- 21247816 TI - [Septic arthritis due to Streptococcus pneumoniae]. PMID- 21247817 TI - Giant fibrolipoma with osseous metaplasia on the thigh. AB - Fibrolipomas are characterised by fat lobules embedded in perivascular oval fibrocytes and thick bundles of collagen. Actively growing superficial fibrolipomas rarely display a pedunculated protrusion and, thus, cosmetic and functional problems are uncommon. We present an exceptional case. While trauma and ischaemia can lead to fibrosis and dystrophic calcification in fibrolipomas as late sequelae, osseous and cartilaginous metaplasia can infrequently manifest after a long, chronic persistence. Further, depending on the chronic irritation, ulcerated wounds may develop on the surface, and these can be clinically confused with malignancy. In this article, we present a case of a pedunculated giant fibrolipoma manifesting metaplasic changes in its structure. PMID- 21247818 TI - [Efficacy and safety of lanthanum carbonate in chronic kidney disease patients with hyperphosphataemia]. AB - Hyperphosphataemia is a frequent complication in patients with chronic kidney disease and is associated with increased cardiovascular morbidity. Lanthanum carbonate is a calcium-free phosphate binder indicated in patients with chronic kidney disease. Its digestive absorption is minimal (<0,002%). This minimal quantity is rapidly excreted by the hepatobiliary system, but there is an initial accumulation in liver and bone, which reaches a plateau within a few weeks. Long term follow-up until six years did not show any bone or liver toxicity. Efficacy and safety of lanthanum carbonate have been assessed in randomized trials. The most common side effects reported were gastrointestinal and occurred with a similar incidence than with placebo and other phosphate binders. Hypercalcemia was less frequent than with calcium carbonate. This review highlights pharmacokinetic, pharmacodynamic and clinical (efficacy and safety) properties of lanthanum carbonate and discusses its place in the management of hyperphosphataemia in patients with chronic kidney disease. PMID- 21247819 TI - Mammographic density and hormone receptor expression in breast cancer: the Multiethnic Cohort Study. AB - BACKGROUND: It is unclear whether mammographic breast density, a strong risk factor for breast cancer, predicts subtypes of breast cancer defined by estrogen receptor (ER) and/or progesterone receptor (PR) expression. METHODS: In a nested case-control study, we compared the breast density of 667 controls and 607 breast cancer cases among women of Caucasian, Japanese, and Native Hawaiian ancestry in the Hawaii component of the Multiethnic Cohort Study. A reader blinded to disease status performed computer assisted density assessment on prediagnostic mammograms. Receptor status was obtained from the statewide Hawaii Tumor Registry. Tumors were classified into ER+PR+ (n=341), ER-PR- (n=50), ER+PR-/ER PR+ (n=64), and unstaged/unknown (n=152). Mean percent density values were computed for women with more than one mammogram. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) while adjusting for confounders. RESULTS: Mean percent density was significantly greater for ER+PR+ but not for ER-PR- tumors compared to controls after adjusting for age: 37.3%, 28.9% versus 29.4%, respectively. The overall OR per 10% increase in percent density were similar for ER+PR+ and ER+PR-/ER-PR+ tumors: 1.26 (95% CI 1.17-1.36) and 1.23 (95% CI 1.07-1.42), respectively. However, percent density was not found to be a predictor for ER-PR- tumors (OR 1.00, 95% CI 0.84-1.18). The results did not differ by ethnicity, nor by menopausal status, parity, or HRT use. CONCLUSIONS: Our findings indicate that within a multiethnic population, women with higher breast density have an increased risk for ER+PR+ but not ER-PR- tumors. PMID- 21247822 TI - Building capacity for pharmacist-provided patient care services. PMID- 21247820 TI - Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism. AB - BACKGROUND: Arsenic (As) occurs as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) in humans, and the methylation pattern demonstrates large interindividual differences. The fraction of urinary MMA is a marker for susceptibility to As-related diseases. OBJECTIVES: We evaluated the impact of polymorphisms in five methyltransferase genes on As metabolism in two populations, one in South America and one in Southeast Asia. The methyltransferase genes were arsenic(+III oxidation state) methyltransferase (AS3MT), DNA-methyltransferase 1a and 3b (DNMT1a and DNMT3b, respectively), phosphatidylethanolamine N-methyltransferase (PEMT), and betaine-homocysteine methyltransferase (BHMT). AS3MT expression was analyzed in peripheral blood. METHODS: Subjects were women exposed to As in drinking water in the Argentinean Andes [n = 172; median total urinary As (U-As), 200 ug/L] and in rural Bangladesh (n = 361; U-As, 100 ug/L; all in early pregnancy). Urinary As metabolites were measured by high-pressure liquid chromatography/inductively coupled plasma mass spectrometry. Polymorphisms (n = 22) were genotyped with Sequenom, and AS3MT expression was measured by quantitative real-time polymerase chain reaction using TaqMan expression assays. RESULTS: Six AS3MT polymorphisms were significantly associated with As metabolite patterns in both populations (p <= 0.01). The most frequent AS3MT haplotype in Bangladesh was associated with a higher percentage of MMA (%MMA), and the most frequent haplotype in Argentina was associated with a lower %MMA and a higher percentage of DMA. Four polymorphisms in the DNMT genes were associated with metabolite patterns in Bangladesh. Noncoding AS3MT polymorphisms affected gene expression of AS3MT in peripheral blood, demonstrating that one functional impact of AS3MT polymorphisms may be altered levels of gene expression. CONCLUSIONS: Polymorphisms in AS3MT significantly predicted As metabolism across these two very different populations, suggesting that AS3MT may have an impact on As metabolite patterns in populations worldwide. PMID- 21247823 TI - A brief history of the Journal of Pharmaceutical Science's first 50 years. PMID- 21247824 TI - Risks, benefits, and issues in creating a behind-the-counter category of medications. AB - OBJECTIVE: To examine the issues surrounding the development and implementation of a behind-the-counter (BTC) category of medications. DATA SOURCES: Testimony from organizations submitting comments to the Food and Drug Administration (FDA) panel hearings in November 2007, the 2009 final report of the U. S. General Accounting Office regarding a BTC drug category, literature review of research that has been conducted, experiences from other countries, and publically available information from agencies in charge of regulating medications similar to BTC. SUMMARY: Based on evidence attained from the current work, the following six recommendations regarding a BTC category of medications are provided. (1) Demonstration needs to occur that the risks and/or costs of BTC are outweighed by benefits, positive measurable outcomes, and financial savings to society. (2) Sufficient resources, including personnel, equipment, and facilities, need to be available for the appropriate provision of BTC services and to ensure ongoing monitoring and controls. (3) An appropriate compensation structure needs to be developed. (4) Encounters and outcomes should be documented in an electronic record, the information should be shared with other health care providers involved in patients' care, and interprofessional collaboration and communication should occur. (5) Criteria for designating candidates for transition, ongoing review for safety, and reverse transition must be developed. (6) Applicable lessons learned from other countries should be incorporated into BTC strategies. In addition to implementation recommendations, we also summarize additional evidence that needs to be gathered to optimize the BTC model. CONCLUSION: Based on the accumulated evidence, comments to FDA's request, and information from other countries, implementation of a BTC model probably is feasible in the United States. However, the optimal model remains uncertain and various aspects of a program need to be prioritized and rigorously tested. PMID- 21247825 TI - Clinical and economic outcomes of a pilot project examining pharmacist-focused collaborative care treatment for depression. AB - OBJECTIVE: To assess the clinical and economic impact of a pharmacist-focused health management program for patients with depression. DESIGN: Prospective, nonrandomized, proof-of-concept investigation. SETTING: Asheville, NC, from July 2006 through December 2007. PARTICIPANTS: Employees or adult dependents with depressive symptoms who agreed to enroll in an employer-sponsored treatment program conducted at two ambulatory clinics where consultative services were provided. Participants were included in the analysis if they participated in the program for at least 1 year and had two or more documented visits with a pharmacist. INTERVENTION: Outpatient-based pharmacists provided assessment, self management services follow-up, and treatment recommendations to primary care providers within a collaborative care management model. MAIN OUTCOME MEASURES: Changes in severity of depressive symptoms and impact on overall health care costs for employers and beneficiaries. RESULTS: Of the 151 beneficiaries referred to the program, 130 (82%) remained under pharmacist care for a minimum of 1 year and were included in the aggregate analysis. Statistically significant improvements were observed for Patient Health Questionnaire (PHQ)-9 scores from baseline to endpoint (11.5 +/- 6.6 to 5.3 +/- 4.7 [mean +/- SD], P < 0.0001). The clinical response rate was 68% with a 56% remission rate. In economic subgroup analysis (n = 48), annual medical costs decreased from an average of $6,351 per enrollee to $5,876, which was lower than the projected value ($7,195). Total health care costs to the employer increased from $7,935 per enrollee to $8,040, which was lower than the projected value ($9,023). CONCLUSION: Patients in the first year of the program had significant improvement in the PHQ-9 clinical indicator of depression severity. Total health care costs per patient per year were reduced compared with projected costs without the program. Employers expressed their appreciation for this collaborative care program and continued to offer this voluntary health benefit after the study's conclusion. PMID- 21247826 TI - Revealed preference for community and mail service pharmacy. AB - OBJECTIVE: To determine revealed pharmacy preference and predictors among patients enrolled in a pharmacy benefit that offered a 90-day supply of prescriptions via mail service and community pharmacy channels, with no differences in out-of-pocket costs. DESIGN: Retrospective cohort study. SETTING: United States in 2008-09. PATIENTS: 324,968 commercially insured participants enrolled in plans that required use of mail service pharmacy for maintenance medications. INTERVENTION: Implementation of a pharmacy benefit design with optional use of either mail service or community pharmacy for 90-day supply prescriptions. MAIN OUTCOME MEASURES: Selection rates of mail service and community pharmacy and adjusted odds ratios for predicting community pharmacy for selected characteristics. RESULTS: In the first 4 months of the benefit design, 31.8% of participants previously mandated to use mail service pharmacy elected to fill 90-day prescriptions at community pharmacies. Selection of community pharmacy ranged from a low of 23.7% (previous mail service pharmacy users) to 66.3% (previous community pharmacy users). Among those initiating therapy, 44.3% selected community pharmacy for their new prescriptions, and among those with no previous mail use, 68% selected community pharmacy for new prescriptions. Preference for community/mail service pharmacy was dependent on numerous characteristics, including age, gender, household income, region, driving distance (time), and concomitant medication use. CONCLUSION: Patient behavior indicates that certain patients prefer to access prescription medications via mail service and others through community pharmacy channels. Restrictive benefit designs that incentivize patients to use less preferable pharmacy channels may adversely affect patient convenience, which could have the unintended consequence of reducing medication use and adherence. PMID- 21247827 TI - Economic impact of pharmacist-reimbursed drug therapy modification. AB - OBJECTIVE: To determine (1) the frequency of the different types of drug therapy modification claims paid by a pharmacy benefits manager (PBM), (2) PBM cost savings and return on investment (ROI), and (3) patient savings from pharmacist reimbursed drug therapy modifications. DESIGN: Cross-sectional, retrospective, descriptive study. SETTING: Midwest United States in 2006. PATIENTS: Not applicable; 767 paid therapeutic interchange service claims from the PBM database were analyzed. INTERVENTION: Descriptive statistics for PBM costs and cost savings to the PBM and to patients were calculated using all prescription fills. MAIN OUTCOME MEASURE: ROI calculated by dividing net savings across all fills by net costs. RESULTS: Claims were paid to pharmacists for drug therapy modifications to allow tablet splitting, drug therapy changes, and switching noncovered drugs. Tablet splitting provided the largest cost savings to the PBM, accounting for slightly more than one-third of the claims and representing more than one-half of the prescription fills. Switching drugs not covered provided the largest cost savings to patients. Overall, the PBM saved a mean of $20.31 per prescription fill, and patients saved $14.76 per prescription fill. Mean overall ROI to the PBM was 3.55. CONCLUSION: Payment for pharmacist interventions can be an economic benefit for both patients and third-party payers. The cost savings for payers likely will dictate the endorsement of pharmacist-reimbursed programs and economic incentives offered to pharmacists and pharmacies. PMID- 21247829 TI - Effect of Medicare Part D and insurance type on Medicare beneficiary access to prescription medication and use of prescription cost-saving measures. AB - OBJECTIVES: To examine how prescription drug access and use of prescription cost saving measures changed after Medicare Part D was implemented and to determine their predictors in Medicare beneficiaries with different insurance types. DESIGN: Repeated cross-sectional study. SETTING: United States in 2005 and 2007. PATIENTS: Medicare beneficiaries aged 65 years or older (n = 1,220 in 2005 and n = 1,024 in 2007). INTERVENTION: Web-based surveys using nonprobability samples. MAIN OUTCOME MEASURES: Access to prescription drugs and use of seven costsaving measures. RESULTS: Significantly fewer participants stopped taking a prescription because of cost, applied to an assistance program, received free prescription samples, and had limited prescription access in 2007 compared with 2005. Use of cost-saving measures by Medicare Part D patients was more comparable with that by uninsured participants than patients with employer-based drug coverage. One-third of all participants and almost one-half of Medicare Part D participants had requested a less expensive prescription. Among those participants, 70% received a less expensive prescription and most thought it worked about the same as the more expensive prescription. CONCLUSION: Prescription drug access and use of cost saving measures improved somewhat following the implementation of Medicare Part D, but some access problems continued to exist for Part D participants. Requests for less expensive prescriptions were common and frequently resulted in satisfactory switches. PMID- 21247828 TI - Impact of antidepressant dispensing on health service use among veterans with stroke. AB - OBJECTIVE: To examine the association between dispensing of a selective serotonin reuptake inhibitor (SSRI) antidepressant medication and inpatient and outpatient service use in a cohort of veterans with confirmed acute stroke. DESIGN: Retrospective study. SETTING: Southeastern U. S. Veterans Health Administration (VHA) network, from October 1, 2000, to September 30, 2001. PATIENTS: 785 veterans with confirmed acute stroke. INTERVENTION: VHA and Medicare databases were used to obtain outcome information during the 12 months after the index stroke date. MAIN OUTCOME MEASURES: Number of inpatient admissions, length of inpatient stays, and number of outpatient clinic stops for all causes. RESULTS: Among the study cohort (n = 785), 12% had an SSRI dispensed 30 days or less poststroke, 19% had an SSRI dispensed between 31 and 365 days poststroke, and 69% were not dispensed an SSRI poststroke. After adjusting for risk factors, no significant association was found between time to first SSRI dispensing and inpatient use. However, patients with an early SSRI dispensing were more likely to have a greater number of all-cause outpatient stops compared with patients with later or no SSRI dispensing. Regardless of time to first dispensing, patients dispensed an SSRI had more outpatient clinic stops than patients without the medication. CONCLUSION: SSRI dispensing was not predictive of inpatient use but was a strong predictor of all-cause outpatient clinic stops. PMID- 21247830 TI - Community pharmacy and pharmacist staff call center: assessment of medication safety and effectiveness. AB - OBJECTIVE: To determine proof of concept for use of a network of pharmacists to evaluate the safety of medications. DESIGN: Pilot, comparative, prospective evaluation. SETTING: Community pharmacies and a pharmacist-staffed call center in Arizona during January through August 2006. PATIENTS: Patients filling prescriptions for ipratropium or tiotropium bromide at 1 of 55 Arizona pharmacies were encouraged to call a pharmacist-staffed call center. A total of 67 patients contacted the center and 41 participated. INTERVENTION: A network of community pharmacies and a call center were used to collect data on patients receiving one of two medications for the treatment of chronic obstructive pulmonary disease. Pharmacists in the community pharmacies recruited patients who presented with a prescription or requested a refill for one of the medications. The call center was used to collect patient data. Patients provided data on medication use, completed the chronic respiratory questionnaire (CRQ), and were encouraged to call the center to report health problems. After 30 days, patients were called to determine whether they experienced any adverse events while taking their medication and the CRQ was readministered. MAIN OUTCOME MEASURE: Knowledge gained on the feasibility of the model using pharmacists to assess drug safety. RESULTS: A total of 67 (6.7%) of a possible 995 patients contacted the call center about participating in the study. Approximately one-half (n = 28) of the 55 pharmacies had one or more patients contact the center about the study. A total of 41 patients met inclusion/exclusion criteria and were enrolled. Six (15%) patients reported an adverse effect, including one serious adverse event (acute glaucoma). CONCLUSION: This study provides limited evidence that community pharmacies and a pharmacist-staffed call center can be used to assess medication safety; however, a number of issues need to be examined to determine whether the approaches can be sufficiently effective. PMID- 21247831 TI - Selection of a validated scale for measuring medication adherence. AB - OBJECTIVE: To evaluate literature describing medication adherence surveys/scales to gauge patient behaviors at the point of care. DATA SOURCES: Literature was identified via PubMed and Ovid (1950 to June 2009) using the search terms medication adherence, medication compliance, and medication persistence and combined with the terms questionnaire, survey, scale, or self-report. STUDY SELECTION: All articles in English with adherence scales validated in two or more diseases and containing 30 or fewer questions were selected. DATA SYNTHESIS: Five adherence scales were identified and reviewed by evaluating positive characteristics (short length, internal consistency, reliability, barriers to adherence, literacy appropriate, and self-efficacy), sensitivity, specificity, and diseases in which they have been validated. The Medication Adherence Questionnaire (MAQ) is the shortest scale and easiest to score. MAQ identifies barriers to nonadherence but not self-efficacy. The Self-efficacy for Appropriate Medication Use Scale (SEAMS) is a 13-question scale, and the Brief Medication Questionnaire (BMQ) has three main question headings and multiple subquestions. Both assess barriers and self-efficacy; however, scoring is difficult. The Hill Bone Compliance Scale and Medication Adherence Rating Scale (MARS) address barriers and self-efficacy but are limited in their generalizability. The Hill Bone Compliance Scale focuses on hypertensive patients, while MARS is specific to psychiatric populations. CONCLUSION: No gold-standard medication adherence scale exists. MAQ is most adaptable at the point of care and across populations. MAQ is the quickest to administer and score and has been validated in the broadest range of diseases. SEAMS, BMQ, and the Hill-Bone Compliance Scale allow self-efficacy to be assessed and therefore may be useful in medication management clinics. MARS is specific to psychiatric populations. PMID- 21247832 TI - Description of a team-based job improvement process within a large geographically dispersed primary care clinical pharmacy service. AB - OBJECTIVE: To describe the team-based job improvement process that Primary Care Clinical Pharmacy Services (CPS) used to enhance teamwork and improve job satisfaction during a 4-year period. SETTING: Health maintenance organization in Colorado from 2005 through 2008. PRACTICE DESCRIPTION: Kaiser Permanente Colorado is a group model, not-forprofit health maintenance organization that provides health services to approximately 490,000 members. Highly integrated clinical pharmacy services are offered at each of its 17 primary care medical offices in the Denver-Boulder metropolitan area. PRACTICE INNOVATION: A written survey consisting of three open-ended questions specifically directed at perceived positive and negative job-related features within Primary Care CPS was administered to team members. Six areas of focus emerged that were addressed by Primary Care CPS members within small groups. MAIN OUTCOME MEASURES: Pre- and postsurvey results from six identified focus areas were measured to address any impact of the team-based job improvement process. RESULTS: Positive responses increased from baseline by 48% for communication, 42% for new employee orientation, 25% for teamwork, and 25% for Primary Care CPS meetings (P < 0.05; chi-square test). Positive responses related to clinical practice increased 22%; however, this did not reach statistical significance. Perceived satisfaction with the documentation system for tracking clinical interventions declined 11% from baseline. CONCLUSION: Based on the initial successes with surveys and small-group discussions, Primary Care CPS continues to use this team-based job improvement process to resolve concerns or share best practices. PMID- 21247833 TI - Organization and results of student pharmacist bone mineral density screenings in women. AB - OBJECTIVE: To describe the organization and results of student pharmacist-run screenings of bone mineral density (BMD) among women living in the community. SETTING: Iowa City from March 2008 to April 2009. PRACTICE DESCRIPTION: Student pharmacists operated a BMD screening service at several community-based screening events, including university-sponsored health fairs and community pharmacy events. Interested individuals were invited to have their BMD screened; however, only women aged 21 years or older were asked to participate in the data collection. A risk factor form was completed by consenting participants before BMD screening using a quantitative ultrasound densitometer. Upon screening completion, T- and Z-scores were recorded and participants were counseled on their results. PRACTICE INNOVATION: Student pharmacists worked to increase public awareness of bone health through the organization of BMD screenings. Working with faculty, a training process and screening-flow outline were developed to allow students to conduct the BMD screenings independently while adding to their education and increasing public health awareness in a community setting. MAIN OUTCOME MEASURES: T- and Z-scores from BMD screenings. RESULTS: Eight student pharmacist-organized BMD screenings were conducted during the course of 14 months. A total of 322 women participated in the screenings and data collection. The mean (+/-SD) T- and Z-scores for these participants were 0.03 +/- 1.30 and 0.52 +/- 1.13, respectively. A total of 62 (19.4%) women screened had an increased risk of fracture based on a T-score of -1 or less, whereas approximately two-thirds of all women had better-than-average BMD. CONCLUSION: Student pharmacists provided the community with free screenings that brought BMD scores to the attention of hundreds of women. Counseling sessions that accompanied the screenings contributed to the women learning more about their risks for osteoporosis. Based on these student pharmacist-run BMD screenings, we encourage other student pharmacist organizations to conduct similar screenings. PMID- 21247837 TI - 2010 pertussis outbreak and updated Tdap recommendations. PMID- 21247838 TI - New drugs: dabigatran etexilate mesylate, fingolimod hydrochloride, and ulipristal acetate. PMID- 21247840 TI - Serum dehydroepiandrosterone sulfate in the diagnosis of adrenal insufficiency: ready for prime time? PMID- 21247841 TI - Visual vignette. An acute adrenal crisis. PMID- 21247842 TI - Significance of elevated parathyroid hormone after parathyroidectomy for primary hyperparathyroidism. AB - OBJECTIVE: To provide a clinical update on persistent parathyroid hormone (PTH) elevation after surgical resection for primary hyperparathyroidism (PHPT) and to suggest a schedule for follow-up monitoring and strategies for future study. METHODS: We reviewed the literature targeting studies with detailed analysis of biochemical parameters before and after parathyroidectomy for PHPT. We focused on potential etiologies and currently available outcome data. RESULTS: PTH elevation with eucalcemia after parathyroidectomy for PHPT occurs in 12% to 43% of patients. Underlying etiology is probably multifactorial, and possible causes include bone hunger, vitamin D deficiency, inadequate calcium intake or absorption, reduced peripheral sensitivity to PTH, underlying chronic kidney disease, and/or a renal leak of calcium. No consensus exists on how to follow-up and treat these patients. CONCLUSIONS: Although most patients with PTH elevation after parathyroidectomy will have normalization of PTH levels with time and/or calcium and vitamin D supplementation, this finding may be an early indicator of autonomous parathyroid secretion in a small number of patients. Patients with persistent PTH elevation should be monitored over time for recurrence of PHPT and other possible complications. A standardized follow-up protocol is needed to better study and elucidate the clinical significance of elevated PTH after parathyroidectomy. PMID- 21247843 TI - Standardized glycemic management and perioperative glycemic outcomes in patients with diabetes mellitus who undergo same-day surgery. AB - OBJECTIVE: To assess the safety and effectiveness of a standardized glycemic management protocol in patients with diabetes mellitus who undergo same-day surgery. METHODS: The perioperative glycemic management protocol consisted of preoperative instructions and perioperative order sets for management of subcutaneous and intravenous insulin. Patients with known diabetes admitted to same-day surgery during a 10-month period were observed. Patient demographic information and all capillary blood glucose (CBG) values obtained during the same day surgery visit were collected. Hyperglycemia, defined as a CBG concentration of 200 mg/dL or greater, prompted notification of the attending anesthesiologist. While use of the perioperative order sets was encouraged, the attending anesthesiologist retained the prerogative to treat according to these order sets or their usual care. Physician compliance with the standardized order sets was determined by chart review in the patients who had a documented blood glucose value of 200 mg/dL or greater. RESULTS: Patients managed with the standardized order sets had greater reductions in CBG values (percentage change, 35 +/- 20.5% vs 18 +/- 24%, P<.001) and lower postoperative CBG values (186 +/- 53 mg/dL vs 208 +/- 63 mg/dL, P<.05) than patients who received usual care. No cases of intraoperative or postoperative hypoglycemia (CBG <70 mg/dL) were observed in either group. CONCLUSIONS: A systematic approach to glycemic management that includes instructions for preoperative adjustments to home diabetic medications and order sets for treatment of perioperative hyperglycemia is safe and can be more effective than usual care for ambulatory surgery patients with diabetes. PMID- 21247844 TI - Cost-effectiveness of parathyroidectomy for primary hyperparathyroidism. AB - OBJECTIVE: To review cost-effectiveness analyses of treatments for primary hyperparathyroidism (PHPT). METHODS: The PubMed database was searched with the keywords "cost effectiveness" and "primary hyperparathyroidism." The results of all studies identified were reviewed to ensure that the cost-effectiveness data were reported using incremental cost-effectiveness ratios, which are critical metrics for formal cost-effectiveness analysis. RESULTS: Six studies were identified that measured the cost-effectiveness of competing treatment strategies for PHPT with incremental cost-effectiveness ratios. Three studies were identified that compared surgical and medical treatment options for asymptomatic PHPT. Effectiveness was measured in quality-adjusted life years. In these studies, the strategy of medical observation was less effective than surgery. Surgery was less costly and more effective than pharmacologic therapy. Minimally invasive surgery was a cost-effective alternative to traditional surgical approaches. Parathyroidectomy was cost-effective for asymptomatic patients with a predicted life expectancy of 5 years (outpatient parathyroidectomy) or 6.5 years (inpatient parathyroidectomy). For patients with a shorter life expectancy, observation was the optimal strategy. One study examined the cost-effectiveness of 3 strategies for the surgical treatment of symptomatic PHPT. A minimally invasive treatment strategy had the lowest rate of surgical complications (5.3%), and when compared with bilateral neck exploration, produced an incremental cost effectiveness ratio of $28,439 per complication avoided. Two studies examined the cost effectiveness of adjunctive preoperative imaging in patients with PHPT. The results of both analyses favored preoperative imaging over immediate bilateral neck exploration. CONCLUSIONS: Parathyroidectomy has superior outcomes to observation, but it is more costly. Pharmacologic treatment strategies are quite costly, and offer limited benefits. The contemporary strategy of offering minimally invasive procedures with preoperative localization appears to be cost effective. PMID- 21247846 TI - Contemporary and practical uses of intraoperative parathyroid hormone monitoring. AB - OBJECTIVE: To describe the evolution and current applications of intraoperative parathyroid hormone (PTH) monitoring along with a detailed description of intraoperative protocol and assay methodology. METHODS: Review of the literature regarding the role of intraoperative PTH monitoring in parathyroidectomy, controversies associated with its use in the treatment of hyperparathyroidism, and outcomes using this operative approach. The technologies currently available for "quick" PTH measurement are summarized. RESULTS: Since its inception, intraoperative PTH monitoring has become an essential tool in the endocrine surgeon's armamentarium for treatment of sporadic primary hyperparathyroidism. Intraoperative PTH monitoring changed the operative approach to this disease from bilateral neck exploration with identification of all parathyroid glands and excision based on size, to a highly successful procedure achieved with a limited dissection and gland excision guided by hormone hypersecretion instead of morphologic characteristics. Intraoperative PTH monitoring accuracy is directly associated with the intraoperative criteria used. Although controversy exists regarding the best intraoperative PTH monitoring criteria to be used, most specialized centers have shown excellent results with this intraoperative guidance. Currently, most parathyroid surgeons use intraoperative PTH monitoring, selectively or routinely, during parathyroidectomy. CONCLUSION: Parathyroidectomy guided by intraoperative PTH monitoring to treat sporadic primary hyperparathyroidism is a highly successful and less-invasive approach associated with lower risks than bilateral neck exploration, and it has become the surgical treatment of choice for this disease. PMID- 21247847 TI - Panhypopituitarism secondary to a macroprolactinoma manifesting with pancytopenia: case report and literature review. AB - OBJECTIVE: To present a case of pancytopenia associated with hypopituitarism secondary to a macroprolactinoma. METHODS: We report the clinical features on presentation and results of laboratory investigation. Findings on magnetic resonance imaging are illustrated. The response to hormone replacement therapy is summarized. RESULTS: A 46-year-old man was referred with pancytopenia and secondary hypothyroidism. Laboratory investigation revealed hypopituitarism and a substantially increased prolactin level. Magnetic resonance imaging of the head demonstrated a macroprolactinoma. Hematologic investigation disclosed no other cause for the pancytopenia. Hormone replacement therapy was initiated with hydrocortisone, levothyroxine, and testosterone. Cabergoline was used to induce regression of the prolactinoma. A rapid improvement was seen in the cytopenias, with normalization of the blood cell counts after 8 months of treatment. This result has been sustained during 29 months of follow-up. CONCLUSION: Pancytopenia associated with hypopituitarism has been reported in the literature as a rare occurrence limited to isolated case reports, predominantly associated with Sheehan syndrome. To our knowledge, this is the first reported case of pancytopenia associated with a macroprolactinoma. This finding is noteworthy because prolactin alone has been reported to support hematopoiesis in animal studies. PMID- 21247845 TI - Hypothyroxinemia and pregnancy. AB - OBJECTIVE: To evaluate the peer-reviewed literature on iodine deficiency and hypothyroxinemia in pregnancy. METHODS: We review published studies on isolated hypothyroxinemia in pregnancy, methodology of free thyroxine (T4) assays, impact of iodine deficiency on free T4 levels, and status of ongoing prospective randomized trials of isolated hypothyroxinemia during pregnancy. RESULTS: Hypothyroxinemia during pregnancy is common. Studies have demonstrated the pivotal role exerted by maternal T4 on fetal brain development and the negative impact of hypothyroxinemia on neurobehavioral performance in offspring. Two intervention studies have demonstrated a positive effect on neurodevelopment in children of mothers promptly supplemented with iodine compared with the neurodevelopment in children of nonsupplemented mothers. Free T4 assays presently in clinical use have limitations. Preliminary results of the Controlled Antenatal Thyroid Study (CATS) are somewhat mixed, and the National Institutes of Health Maternal Fetal Medicine Thyrotropin Study (TSH Study) will be completed in 2015. Knowledge regarding the impact of isolated hypothyroxinemia has progressed, but major questions remain. An optimal diagnostic test for free T4 during pregnancy (accurate, inexpensive, and widely available) remains elusive. Trimester-specific normative data and normal ranges from different geographic regions do not exist. CONCLUSIONS: Data published to date are insufficient to recommend levothyroxine therapy in pregnant women with isolated hypothyroxinemia. Adequate iodine intake should be recommended before conception and early in pregnancy. PMID- 21247848 TI - Everolimus resolving hypoglycemia, producing hyperglycemia, and necessitating insulin use in a patient with diabetes and nonresectable malignant insulinoma. AB - OBJECTIVE: To present a case of management of refractory hypoglycemia due to malignant insulinoma with use of everolimus, resulting in recurrent insulin requiring diabetes. METHODS: This report describes a case of a nonresectable malignant insulinoma in a 78-year-old patient with long-standing type 2 diabetes mellitus. Endogenous hyperinsulinism was confirmed by a fasting test, which revealed a glucose level of 35 mg/dL and an insulin value of 23.7 MUIU/mL. Endoscopic ultrasonography, magnetic resonance imaging, and computed tomography identified a pancreatic mass, infiltration of the superior mesenteric vein, and metastatic lesions in the liver. RESULTS: After chemoembolization of the metastatic lesions, hypoglycemia recurred, despite combined treatment with somatostatin analogues, dexamethasone, and diazoxide. Everolimus, an orally administered mammalian target of rapamycin, was used at a daily dose of 5 mg. After 6 months, the hypoglycemia was controlled, and the patient presented with a C-peptide level of 0.2 ng/mL and secondary hyperglycemia that necessitated insulin treatment. CONCLUSION: The orally administered drug everolimus controlled hypoglycemia due to a malignant insulinoma in a patient with prior insulin requiring diabetes. Secondary hyperglycemia was an acceptable drug effect (to the patient and managing physicians), in light of the complex and often poorly tolerated treatments available for this rare condition. PMID- 21247849 TI - Lithium use and primary hyperparathyroidism. AB - OBJECTIVE: To review suspected causes of lithium-induced hyperparathyroidism, disease presentation, underlying pathology, and current recommendations and trends in medical and surgical treatment. METHODS: Relevant literature was reviewed. RESULTS: Lithium carbonate therapy has continued to be a mainstay of treatment for bipolar disease and schizoaffective disorder since its introduction into clinical use. Several metabolic consequences are associated with its long term use, including hypercalcemia and hyperparathyroidism. CONCLUSIONS: Until further data become available, the surgeon should remain vigilant for the presence of pathologically active glands that may manifest their function at different times during the disease course. PMID- 21247850 TI - Reliability of early iodine 123 uptake for treatment of Graves disease in children. AB - OBJECTIVE: To determine the reliability of early radioiodine uptake (RAIU) in calculation of the radioiodine ablation dose for pediatric patients with Graves disease. METHODS: This retrospective review of medical records involved 22 pediatric patients with Graves disease, who had undergone early (4 to 8 hours) and late (24 to 26 hours) RAIU studies and were treated with iodine 131 (131I). Quantitative data are reported as mean +/- standard error of the mean. Early and late RAIU and actual administered versus calculated 131I ablation doses were compared by using the paired t test. The correlation between early and late RAIU was assessed by curvilinear regression analysis. Significance was assessed at P<.05. RESULTS: Mean early RAIU was 57.1% +/- 18.2%, and mean late RAIU was 72.1% +/- 14.4% (P<.05). Curvilinear regression analysis showed the following: late RAIU = 7.13 + 1.71 * (early RAIU) - 0.01 x (early RAIU)2; r2 = 0.75. The mean ablation dose of 131I based on late RAIU was 9.3 +/- 2.0 mCi. The calculated radioiodine dose would have been, on average, 32% higher (12.3 +/- 3.8 mCi; P<.05) had early RAIU been used. CONCLUSION: In children, early RAIU can be much lower than late RAIU. This may be misleading for ablation dose calculations. Therefore, late RAIU should be used to avoid overtreatment in children with Graves disease. PMID- 21247851 TI - Outcome of Pregnancy After Exposure to Radioiodine In Utero. AB - OBJECTIVE: Radioiodine (131I) therapy is absolutely contraindicated in pregnancy yet reports of inadvertent exposure continue to appear in the literature. In this review, we discuss the risks of fetal exposure and prevention strategies in the light of current guidelines. METHODS: We performed a literature search on MEDLINE using the terms radioiodine, I-131, toxicity, complications and pregnancy and chose the most relevant studies for this review. RESULTS: Before implantation, the major concern is miscarriage and death of the embryo above a radiation threshold of 100mGy (10 rads). Exposure to 131I at this very early stage of pregnancy is unlikely to result in major malformations or thyroid dysfunction in surviving embryos. Exposure later in pregnancy i.e. during thyroidogenesis (from 10 weeks gestation) and organogenesis (from 2 weeks gestation) at similar radiation thresholds may result in fetal thyroid ablation, birth defects and in later life, growth retardation and reduction in IQ. In addition to these deterministic effects, radiation at any dose may increase the risk of cancer (stochastic effect) and recent evidence indicates an increased risk of thyroid cancer many years after in utero exposure. CONCLUSIONS: Clinicians treating women of child-bearing age with radioiodine need to be aware of the risks of fetal exposure to radioiodine and take all measures to avoid inadvertent exposure during pregnancy. PMID- 21247852 TI - Falsely elevated plasma parathyroid hormone level mimicking tertiary hyperparathyroidism. AB - OBJECTIVE: To report a case of misdiagnosed tertiary hyperparathyroidism attributable to heterophile antibody interference in a parathyroid hormone (PTH) assay. METHODS: We present clinical and laboratory data relative to this case and review the pertinent English-language literature. RESULTS: A 36-year-old woman with a functioning renal allograft, PTH excess (3,374 pg/mL) refractory to medical therapy, and a history of renal osteodystrophy presented for consideration of a third parathyroidectomy. Remedial parathyroidectomy was performed. The PTH levels did not decline postoperatively, but the patient developed severe hypocalcemia. Reanalysis of the patient's serum specimens was performed with (1) addition of heterophile blocking agents to the murine-based immunoassay and (2) use of a different, goat antibody-based immunoassay. The true PTH level was found to be 5 pg/mL with use of both methods. CONCLUSION: Previous administration of muromonab-CD3 (Orthoclone OKT3) for immunosuppression may have resulted in the development of human antimurine heterophile antibodies, causing a falsely elevated PTH result. PMID- 21247853 TI - Parathyroid carcinoma arising from four-gland hyperplasia. AB - OBJECTIVE: To report the use of immunohistochemical staining for parafibromin, APC, and galectin-3 to evaluate the malignant potential of a resected parathyroid specimen in a patient initially presenting with primary hyperparathyroidism attributable to 4-gland hyperplasia, who subsequently developed metastatic parathyroid carcinoma. METHODS: We describe a patient with primary hyperparathyroidism who underwent a 3-gland resection of hypercellular parathyroid glands, with postoperative normalization of her serum calcium and parathyroid hormone levels. She returned 4 years later with recurrent hypercalcemia and underwent partial resection of her remaining hypercellular parathyroid gland, without improvement of her hypercalcemia. Selective venous sampling localized the source as draining into her azygos vein, and metastatic parathyroid carcinoma was ultimately diagnosed. RESULTS: Immunohistochemical staining for parafibromin, APC, and galectin-3 suggested the malignant potential of the atypical adenoma removed during the patient's original operation, which is believed to be the source of her metastatic disease. Access to this information by the treating surgeon may have prompted a more extensive en bloc resection or more vigilant follow-up that could have altered the patient's clinical course. CONCLUSION: Immunohistochemical staining for parafibromin, APC, and galectin-3 can be used to help distinguish the source of metastatic disease in patients with parathyroid carcinoma. Selective venous sampling may help localize metastatic parathyroid carcinoma when the source is otherwise not apparent. PMID- 21247854 TI - Hyperandrogenism in a postmenopausal woman: diagnostic and therapeutic challenges. AB - OBJECTIVE: To describe a postmenopausal woman with severe hyperandrogenism who responded dramatically to a gonadotropin-releasing hormone (GnRH) agonist. METHODS: Detailed clinical and laboratory findings are presented, and the pertinent literature is reviewed. RESULTS: A 53-year-old postmenopausal woman with end-stage renal disease, who had undergone kidney transplantation, was referred because of high serum testosterone levels. She presented with worsening acne and hirsutism for the previous 2 years. Her medications included prednisone (7.5 mg every other day). On examination, mild facial acne and hirsutism but no virilizing features were noted. Laboratory results showed generous postmenopausal gonadotropin levels and markedly elevated total and free testosterone levels, which failed to suppress with a 2-day low-dose dexamethasone test. Transvaginal ultrasonography and a computed tomographic scan failed to identify an ovarian or adrenal abnormality. Administration of a GnRH agonist (Depo-Lupron) resulted in a dramatic decline in follicle-stimulating hormone, luteinizing hormone, and testosterone levels after 1 month, which persisted during the course of 11 months of therapy. The source of marked hyperandrogenism in postmenopausal women represents a diagnostic challenge. The absence of a tumor on diagnostic imaging and the inability to perform catheterization studies confound the problem. Androgen levels did not suppress with glucocorticoids. We reasoned that a clear response to a GnRH agonist would indicate a nontumorous ovarian source of hyperandrogenism. Regrettably, the literature has described cases of ovarian tumors and, rarely, adrenal adenomas that are responsive to gonadotropins. CONCLUSION: The striking improvement in a postmenopausal woman with severe hyperandrogenism by means of GnRH agonist therapy demonstrates its potential use in poor surgical candidates without necessarily delineating the source of androgen excess. PMID- 21247857 TI - [Differentiated thyroid cancer -- 2009]. AB - Three years ago continental guidelines were published referring management and follow-up of low risk thyroid cancer patients. The aim of this paper is to summarize the changes and new directions in this field. High risk patients require another protocol. Neck ultrasound plays important role in differential diagnosis and in detecting recurrences. Some new ultrasound techniques are discussed, too. FDG-PET can help to solve the problem of patients having negative scan and increased thyroglobulin level. In recent years there was an expansion of our knowledge about the pathomechanism of thyroid cancer. It appears that genetic alterations frequently play a key role in carcinogenesis. There are molecular methods that allow the detection of these genetic events in thyroid fine needle aspirations samples providing important information for diagnosis, management and prognosis. Instead of diagnostic whole body scanning the posttherapeutic scan became preferable but in high risk cases the diagnostic whole body scintigrams serve useful data. Primary therapy of thyroid cancer is an adequate surgery: total thyreoidectomy and, if necessary, lymph node dissection or limited surgery in selected cases. Nowadays radioguided surgery can help to improve the results. Radioiodine therapy (e.g. rest ablation) proved to be a safe and effective method to complete surgery. It can prevent relapses and results in longer survival. Thyroid hormone withdrawal or recombinant human thyrotropin stimulation can increase thyrotropin level before radioiodine treatment. These two methods have similar success rate of rest ablation but irradiation burden of blood is lower in the case of exogenous stimulation which avoids hypothyroid state and preserves quality of life. Since tumor cells fail to maintain the ability to perform physiological functions they undergo dedifferentiation. Therefore, an important aim is to reactivate some function of differentiated cells, e.g. iodine uptake, production of thyroperoxydase and thyroglobulin. Opportunities for this therapeutic effort are also mentioned. Restoration of iodine uptake enables radioisotope treatment. Until now there has been little interest in the development of new drugs for the treatment of thyroid cancer. However, advances in our understanding of tumor cell biology will lead to a paradigm shift in the therapy that is likely to benefit patients who have high risk disease and who do not almost have any therapeutic option. There are new drugs in clinical trials that appear to be more effective than earlier cytotoxic agents. Probably modern chemotherapy of advanced thyroid cancer will have significant results in the near future. PMID- 21247858 TI - [Physiologic effects of hypothermia]. AB - Therapeutic use of hypothermia has come to the frontline in the past decade again in the prevention and in mitigation of neurologic impairment. The application of hypothermia is considered as a successful therapeutic measure not just in neuro- or cardiac surgery, but also in states causing brain injury or damage. According to our present knowledge this is the only proven therapeutic tool, which improves the neurologic outcome after cardiac arrest, decreasing the oxygen demand of the brain. Besides influencing the nervous system, hypothermia influences the function of the whole organ system. Beside its beneficial effects, it has many side-effects, which may be harmful to the patient. Before using it for a therapeutic purpose, it is very important to be familiar with the physiology and complications of hypothermia, to know, how to prevent and treat its side-effects. The purpose of this article is to summarize the physiologic and pathophysiologic effects of hypothermia. PMID- 21247859 TI - [Nutrition and life style in the elderly - risk factors and recommendations]. AB - Demographic data appear to demonstrate an increase in the number and ratio of elderly world-wide. Authors give a short survey on physiological alterations occurring at older age, on methods suitable for assessing nutritional status and criticism thereof. Nutritional and life style habits are also discussed. Prevalence of obesity and undernutrition and their sequelae are likewise presented. Diagnosis of undernutrition by using questionnaire can significantly improve the efficiency of family doctors' activity. Authors provide recommendations for improving nutrition and life style in healthy persons with optimal body mass, and for obese and undernourished subjects. PMID- 21247860 TI - [Evaluation of patients' readiness for surgery when called from the waiting list for kidney transplantation: experience of the Budapest Centre]. AB - The aim of this study was to assess the impact of the establishment of waiting list committee on recipient evaluation for kidney transplantation. Studies on this issue have not been previously reported. METHODS: Data of 714 patients were collected between September 1, 2007 and April 20, 2010. Of the 714 patients 354 were transplanted. Data from the first 16 months period were compared to those obtained during the second 16 months period. RESULTS: During the first period 171 patients (47.9%) were unfit for transplantation [129 patients (36.1%) were refused after telephone information and 42 patients (11.8%) after clinical investigation]. During the second period 141 (39.5%) patients were found to be unsuitable [80 patients (22.4%) after telephone information and 61 patients (17.1)] after clinical examination. During the two periods of the study 44% of patients were unfit for transplantation. A considerable number of patients were refused because of cardiologic reasons. The percent of fit patients was 52.1% in the first period and 60.5% in the second period. In addition, the percent of unfit patients who were unsuitable for kidney transplantation after telephone information decreased from 36.1% to 22.4%, while the percent of unfit patients after clinical evaluation increased from 11.% to 17.1%. CONCLUSIONS: Authors conclude that waiting list committee made an effective work. PMID- 21247862 TI - Protected health information on social networking sites: ethical and legal considerations. AB - BACKGROUND: Social networking site use is increasingly common among emerging medical professionals, with medical schools even reporting disciplinary student expulsion. Medical professionals who use social networking sites have unique responsibilities since their postings could violate patient privacy. However, it is unknown whether students and residents portray protected health information and under what circumstances or contexts. OBJECTIVE: The objective of our study was to document and describe online portrayals of potential patient privacy violations in the Facebook profiles of medical students and residents. METHODS: A multidisciplinary team performed two cross-sectional analyses at the University of Florida in 2007 and 2009 of all medical students and residents to see who had Facebook profiles. For each identified profile, we manually scanned the entire profile for any textual or photographic representations of protected health information, such as portrayals of people, names, dates, or descriptions of procedures. RESULTS: Almost half of all eligible students and residents had Facebook profiles (49.8%, or n=1023 out of 2053). There were 12 instances of potential patient violations, in which students and residents posted photographs of care they provided to individuals. No resident or student posted any identifiable patient information or likeness in text form. Each instance occurred in developing countries on apparent medical mission trips. These portrayals increased over time (1 in the 2007 cohort; 11 in 2009; P = .03). Medical students were more likely to have these potential violations on their profiles than residents (11 vs 1, P = .04), and there was no difference by gender. Photographs included trainees interacting with identifiable patients, all children, or performing medical examinations or procedures such as vaccinations of children. CONCLUSIONS: While students and residents in this study are posting photographs that are potentially violations of patient privacy, they only seem to make this lapse in the setting of medical mission trips. Trainees need to learn to equate standards of patient privacy in all medical contexts using both legal and ethical arguments to maintain the highest professional principles. We propose three practical guidelines. First, there should be a legal resource for physicians traveling on medical mission trips such as an online list of local laws, or a telephone legal contact. Second, institutions that organize medical mission trips should plan an ethics seminar prior the departure on any trip since the legal and ethical implications may not be intuitive. Finally, at minimum, traveling physicians should apply the strictest legal precedent to any situation. PMID- 21247863 TI - Presenting evidence to patients online: what do web users think of consumer summaries of cochrane musculoskeletal reviews? AB - BACKGROUND: The Internet has the potential to be an effective medium for delivering health care knowledge to consumers. While computer usability research makes recommendations about how to present Web-based information generally, there remains no clear guidance on how to present specific forms of health care research evidence online in a way that facilitates understanding and good health care decision making. OBJECTIVE: The two goals of this study were to describe the Cochrane Musculoskeletal Group's (CMSG's) process for developing online patient focused summaries of systematic reviews and to evaluate the impressions of these summaries formed by users. METHODS: A process for summarizing the results of systematic reviews via consumer summaries has evolved over 15 years. An evaluation of this approach took the form of Internet surveys on the Arthritis Society of Canada website and surveys of members of the Canadian Arthritis Patient Alliance (CAPA). Respondents provided information on background, relationship to the decision, their satisfaction with and preparation for decision making, and suggestions for improvements to the summaries. Survey data were collected between August 1, 2005, and February 28, 2006. RESULTS: A total of 261 respondents completed the survey. The majority (226/261 or 87%) of respondents reported having an arthritis-related condition. The consumer summary approach was generally reviewed favorably by respondents, with most agreeing that the summary provided appropriate information (177/261 or 68%), would be useful to others (160/261 or 61%), was well laid out (159/261 or 61%), was easy to learn from (157/261 or 60%), and was useful to the reader (153/261 or 59%). Areas of potential improvement were indicated by relatively fewer respondents agreeing that they could easily find all the information they wanted (118/261 or 45%), by a substantial proportion being unable to judge whether the providers of the information are reliable (80/261 or 31%), and by a similar proportion being unable to determine whether the information presented was the best available (68/261 or 26%). CONCLUSIONS: The CMSG has developed an approach to summarizing the results of often-technical systematic reviews into public-friendly consumer summaries. Our online survey showed that this approach was generally well liked but identified specific areas for improvement. Feedback from this survey will help to reshape and improve the current template for consumer summaries used by the CMSG. PMID- 21247864 TI - Cancer survivorship in the age of YouTube and social media: a narrative analysis. AB - BACKGROUND: As evidenced by the increasing popularity of YouTube (www.youtube.com), personal narratives shared through social media are an area of rapid development in communication among cancer survivors. Identifying the thematic and linguistic characteristics of YouTube cancer stories can provide a better understanding of this naturally occurring communication channel and inform social media communication efforts aiming to use personal stories to reach individuals with serious illnesses. OBJECTIVE: The objective of our study was to provide an in-depth description of authentic personal cancer stories. Through a linguistically based narrative analysis of YouTube stories, the analysis explicates the common attributes of these narratives. METHODS: Informed by narrative theories, we conducted an iterative, bottom-up analysis of 35 YouTube videos identified by the search terms "cancer survivor" and "cancer stories". A list of shared thematic and linguistic characteristics was identified and analyzed. RESULTS: A subnarrative on the cancer diagnosis was present in 86% (30/35) of the stories under analysis. These diagnostic narratives were characterized by dramatic tension, emotional engagement, markers of the loss of agency or control, depersonalized reference to the medical personnel, and the unexpectedness of a cancer diagnosis. The analysis highlights the themes of story authenticity and emotional engagement in this online communication medium. CONCLUSIONS: Internet advances have enabled new and efficient exchange of personal stories, including the sharing of personal cancer experience among cancer survivors and their caregivers. The analytic results of this descriptive study point to the common characteristics of authentic cancer survivorship stories online. Furthermore, the results of this descriptive study may inform development of narrative-based communication, particularly in maintaining authenticity and emotional engagement. PMID- 21247865 TI - Health workforce in times of financial crisis. PMID- 21247866 TI - Public health genomics--public health goes personalized? PMID- 21247867 TI - Genome-based knowledge and public health: the vision of tomorrow and the challenge of today. PMID- 21247868 TI - Public health genomics and the challenges for epidemiology. PMID- 21247869 TI - A European view on the future of personalised medicine in the EU. PMID- 21247872 TI - Atomistic simulations reveal bubbles, kinks and wrinkles in supercoiled DNA. AB - Although DNA is frequently bent and supercoiled in the cell, much of the available information on DNA structure at the atomistic level is restricted to short linear sequences. We report atomistic molecular dynamics (MD) simulations of a series of DNA minicircles containing between 65 and 110 bp which we compare with a recent biochemical study of structural distortions in these tight DNA loops. We have observed a wealth of non-canonical DNA structures such as kinks, denaturation bubbles and wrinkled conformations that form in response to bending and torsional stress. The simulations show that bending alone is sufficient to induce the formation of kinks in circles containing only 65 bp, but we did not observe any defects in simulations of larger torsionally relaxed circles containing 110 bp over the same MD timescales. We also observed that under winding in minicircles ranging in size from 65 to 110 bp leads to the formation of single stranded bubbles and wrinkles. These calculations are used to assess the ability of atomistic MD simulations to determine the structure of bent and supercoiled DNA. PMID- 21247873 TI - A BEAF dependent chromatin domain boundary separates myoglianin and eyeless genes of Drosophila melanogaster. AB - Precise transcriptional control is dependent on specific interactions of a number of regulatory elements such as promoters, enhancers and silencers. Several studies indicate that the genome in higher eukaryotes is divided into chromatin domains with functional autonomy. Chromatin domain boundaries are a class of regulatory elements that restrict enhancers to interact with appropriate promoters and prevent misregulation of genes. While several boundary elements have been identified, a rational approach to search for such elements is lacking. With a view to identifying new chromatin domain boundary elements we analyzed genomic regions between closely spaced but differentially expressed genes of Drosophila melanogaster. We have identified a new boundary element between myoglianin and eyeless, ME boundary, that separates these two differentially expressed genes. ME boundary maps to a DNaseI hypersensitive site and acts as an enhancer blocker both in embryonic and adult stages in transgenic context. We also report that BEAF and GAF are the two major proteins responsible for the ME boundary function. Our studies demonstrate a rational approach to search for potential boundaries in genomic regions that are well annotated. PMID- 21247874 TI - Large-scale prediction of long non-coding RNA functions in a coding-non-coding gene co-expression network. AB - Although accumulating evidence has provided insight into the various functions of long-non-coding RNAs (lncRNAs), the exact functions of the majority of such transcripts are still unknown. Here, we report the first computational annotation of lncRNA functions based on public microarray expression profiles. A coding-non coding gene co-expression (CNC) network was constructed from re-annotated Affymetrix Mouse Genome Array data. Probable functions for altogether 340 lncRNAs were predicted based on topological or other network characteristics, such as module sharing, association with network hubs and combinations of co-expression and genomic adjacency. The functions annotated to the lncRNAs mainly involve organ or tissue development (e.g. neuron, eye and muscle development), cellular transport (e.g. neuronal transport and sodium ion, acid or lipid transport) or metabolic processes (e.g. involving macromolecules, phosphocreatine and tyrosine). PMID- 21247875 TI - The amino terminal end determines the stability and assembling capacity of eukaryotic ribosomal stalk proteins P1 and P2. AB - The eukaryotic ribosomal proteins P1 and P2 bind to protein P0 through their N terminal domain to form the essential ribosomal stalk. A mutational analysis points to amino acids at positions 2 and 3 as determinants for the drastic difference of Saccharomyces cerevisiae P1 and P2 half-life, and suggest different degradation mechanisms for each protein type. Moreover, the capacity to form P1/P2 heterodimers is drastically affected by mutations in the P2beta four initial amino acids, while these mutations have no effect on P1beta. Binding of P2beta and, to a lesser extent, P1beta to the ribosome is also seriously affected showing the high relevance of the amino acids in the first turn of the NTD alpha helix 1 for the stalk assembly. The negative effect of some mutations on ribosome binding can be reversed by the presence of the second P1/P2 couple in the ribosome, indicating a stabilizing structural influence between the two heterodimers. Unexpectedly, some mutations totally abolish heterodimer formation but allow significant ribosome binding and, therefore, a previous P1 and P2 association seems not to be an absolute requirement for stalk assembly. Homology modeling of the protein complexes suggests that the mutated residues can affect the overall protein conformation. PMID- 21247876 TI - Evidence that Lin28 stimulates translation by recruiting RNA helicase A to polysomes. AB - The stem cell protein Lin28 functions to inhibit the biogenesis of a group of miRNAs but also stimulates the expression of a subset of mRNAs at the post transcriptional level, the underlying mechanism of which is not yet understood. Here we report the characterization of the molecular interplay between Lin28 and RNA helicase A (RHA) known to play an important role in remodeling ribonucleoprotein particles during translation. We show that reducing Lin28 expression results in decreased RHA association with polysomes while increasing Lin28 expression leads to elevated RHA association. Further, the carboxyl terminus of Lin28 is necessary for interaction with both the amino and carboxyl termini of RHA. Importantly, a carboxyl terminal deletion mutant of Lin28 that retains RNA-binding activity fails to interact with RHA and exhibits dominant negative effects on Lin28-dependent stimulation of translation. Taken together, these results lead us to suggest that Lin28 may stimulate translation by actively recruiting RHA to polysomes. PMID- 21247877 TI - A piggyBac transposon-based mutagenesis system for the fission yeast Schizosaccharomyces pombe. AB - The TTAA-specific transposon piggyBac (PB), originally isolated from the cabbage looper moth, Trichoplusia ni, has been utilized as an insertional mutagenesis tool in various eukaryotic organisms. Here, we show that PB transposes in the fission yeast Schizosaccharomyces pombe and leaves almost no footprints. We developed a PB-based mutagenesis system for S. pombe by constructing a strain with a selectable transposon excision marker and an integrated transposase gene. PB transposition in this strain has low chromosomal distribution bias as shown by deep sequencing-based insertion site mapping. Using this system, we obtained loss of-function alleles of klp5 and klp6, and a gain-of-function allele of dam1 from a screen for mutants resistant to the microtubule-destabilizing drug thiabendazole. From another screen for cdc25-22 suppressors, we obtained multiple alleles of wee1 as expected. The success of these two screens demonstrated the usefulness of this PB-mediated mutagenesis tool for fission yeast. PMID- 21247878 TI - Identification of human miRNA precursors that resemble box C/D snoRNAs. AB - There are two main classes of small nucleolar RNAs (snoRNAs): the box C/D snoRNAs and the box H/ACA snoRNAs that function as guide RNAs to direct sequence-specific modification of rRNA precursors and other nucleolar RNA targets. A previous computational and biochemical analysis revealed a possible evolutionary relationship between miRNA precursors and some box H/ACA snoRNAs. Here, we investigate a similar evolutionary relationship between a subset of miRNA precursors and box C/D snoRNAs. Computational analyses identified 84 intronic miRNAs that are encoded within either box C/D snoRNAs, or in precursors showing similarity to box C/D snoRNAs. Predictions of the folded structures of these box C/D snoRNA-like miRNA precursors resemble the structures of known box C/D snoRNAs, with the boxes C and D often in close proximity in the folded molecule. All five box C/D snoRNA-like miRNA precursors tested (miR-27b, miR-16-1, mir-28, miR-31 and let-7g) bind to fibrillarin, a specific protein component of functional box C/D snoRNP complexes. The data suggest that a subset of small regulatory RNAs may have evolved from box C/D snoRNAs. PMID- 21247879 TI - Species-specific microRNA roles elucidated following astrocyte activation. AB - MicroRNAs (miRNAs) are short non-coding RNAs that play a central role in regulation of gene expression by binding to target genes. Many miRNAs were associated with the function of the central nervous system (CNS) in health and disease. Astrocytes are the CNS most abundant glia cells, providing support by maintaining homeostasis and by regulating neuronal signaling, survival and synaptic plasticity. Astrocytes play a key role in repair of brain insults, as part of local immune reactivity triggered by inflammatory or pathological conditions. Thus, astrocyte activation, or astrogliosis, is an important outcome of the innate immune response, which can be elicited by endotoxins such as lipopolysaccharide (LPS) and cytokines such as interferon-gamma (IFN-gamma). The involvement of miRNAs in inflammation and stress led us to hypothesize that astrogliosis is mediated by miRNA function. In this study, we compared the miRNA regulatory layer expressed in primary cultured astrocyte derived from rodents (mice) and primates (marmosets) brains upon exposure to LPS and IFN-gamma. We identified subsets of differentially expressed miRNAs some of which are shared with other immunological related systems while others, surprisingly, are mouse and rat specific. Of interest, these specific miRNAs regulate genes involved in the tumor necrosis factor-alpha (TNF-alpha) signaling pathway, indicating a miRNA based species-specific regulation. Our data suggests that miRNA function is more significant in the mechanisms governing astrocyte activation in rodents compared to primates. PMID- 21247880 TI - Identification of a novel epigenetic regulatory region within the pluripotency associated microRNA cluster, EEmiRC. AB - The miR-290 cluster is expressed in embryonic stem cells (ESCs) and is important for the maintenance of pluripotency, but little is known about the mechanisms regulating the early embryonic microRNA cluster (EEmiRC) expression. Here we report the identification of a 332-bp intragenic enhancer (IE) able to modulate the transcription of the mouse EEmiRC locus, presumably through binding of transcription modulators like Oct3/4, Sox2 and CTCF. This IE also contains a CpG island showing a differential pattern of DNA and histone methylation marks during differentiation of ESCs, which places EEmiRC in a novel regulatory feedback loop with DNA methylases. Deletion of IE significantly reduced the transcription of the EEmiRC, further proving the importance of this region in regulating the expression of EEmiRC. PMID- 21247881 TI - Mutant CAG repeats of Huntingtin transcript fold into hairpins, form nuclear foci and are targets for RNA interference. AB - The CAG repeat expansions that occur in translated regions of specific genes can cause human genetic disorders known as polyglutamine (poly-Q)-triggered diseases. Huntington's disease and spinobulbar muscular atrophy (SBMA) are examples of these diseases in which underlying mutations are localized near other trinucleotide repeats in the huntingtin (HTT) and androgen receptor (AR) genes, respectively. Mutant proteins that contain expanded polyglutamine tracts are well known triggers of pathogenesis in poly-Q diseases, but a toxic role for mutant transcripts has also been proposed. To gain insight into the structural features of complex triplet repeats of HTT and AR transcripts, we determined their structures in vitro and showed the contribution of neighboring repeats to CAG repeat hairpin formation. We also demonstrated that the expanded transcript is retained in the nucleus of human HD fibroblasts and is colocalized with the MBNL1 protein. This suggests that the CAG repeats in the HTT mRNA adopt ds-like RNA conformations in vivo. The intracellular structure of the CAG repeat region of mutant HTT transcripts was not sufficiently stable to be protected from cleavage by an siRNA targeting the repeats and the silencing efficiency was higher for the mutant transcript than for its normal counterpart. PMID- 21247882 TI - Genome-wide profiling of forum domains in Drosophila melanogaster. AB - Forum domains are stretches of chromosomal DNA that are excised from eukaryotic chromosomes during their spontaneous non-random fragmentation. Most forum domains are 50-200 kb in length. We mapped forum domain termini using FISH on polytene chromosomes and we performed genome-wide mapping using a Drosophila melanogaster genomic tiling microarray consisting of overlapping 3 kb fragments. We found that forum termini very often correspond to regions of intercalary heterochromatin and regions of late replication in polytene chromosomes. We found that forum domains contain clusters of several or many genes. The largest forum domains correspond to the main clusters of homeotic genes inside BX-C and ANTP-C, cluster of histone genes and clusters of piRNAs. PRE/TRE and transcription factor binding sites often reside inside domains and do not overlap with forum domain termini. We also found that about 20% of forum domain termini correspond to small chromosomal regions where Ago1, Ago2, small RNAs and repressive chromatin structures are detected. Our results indicate that forum domains correspond to big multi-gene chromosomal units, some of which could be coordinately expressed. The data on the global mapping of forum domains revealed a strong correlation between fragmentation sites in chromosomes, particular sets of mobile elements and regions of intercalary heterochromatin. PMID- 21247883 TI - Wide-ranging functions of E2F4 in transcriptional activation and repression revealed by genome-wide analysis. AB - The E2F family of transcription factors has important roles in cell cycle progression. E2F4 is an E2F family member that has been proposed to be primarily a repressor of transcription, but the scope of its binding activity and functions in transcriptional regulation is not fully known. We used ChIP sequencing (ChIP seq) to identify around 16,000 E2F4 binding sites which potentially regulate 7346 downstream target genes with wide-ranging functions in DNA repair, cell cycle regulation, apoptosis, and other processes. While half of all E2F4 binding sites (56%) occurred near transcription start sites (TSSs), ~20% of sites occurred more than 20 kb away from any annotated TSS. These distal sites showed histone modifications suggesting that E2F4 may function as a long-range regulator, which we confirmed by functional experimental assays on a subset. Overexpression of E2F4 and its transcriptional cofactors of the retinoblastoma (Rb) family and its binding partner DP-1 revealed that E2F4 acts as an activator as well as a repressor. E2F4 binding sites also occurred near regulatory elements for miRNAs such as let-7a and mir-17, suggestive of regulation of miRNAs by E2F4. Taken together, our genome-wide analysis provided evidence of versatile roles of E2F4 and insights into its functions. PMID- 21247884 TI - Net survival of perinatally and postnatally HIV-infected children: a pooled analysis of individual data from sub-Saharan Africa. AB - BACKGROUND: Previously, HIV epidemic models have used a double Weibull curve to represent high initial and late mortality of HIV-infected children, without distinguishing timing of infection (peri- or post-natally). With more data on timing of infection, which may be associated with disease progression, a separate representation of children infected early and late was proposed. METHODS: Paediatric survival post-HIV infection without anti-retroviral treatment was calculated using pooled data from 12 studies with known timing of HIV infection. Children were grouped into perinatally or post-natally infected. Net mortality was calculated using cause-deleted life tables to give survival as if HIV was the only competing cause of death. To extend the curve beyond the available data, children surviving beyond 2.5 years post infection were assumed to have the same survival as young adults. Double Weibull curves were fitted to both extended survival curves to represent survival of children infected perinatally or through breastfeeding. RESULTS: Those children infected perinatally had a much higher risk of dying than those infected through breastfeeding, even allowing for background mortality. The final-fitted double Weibull curves gave 75% survival at 5 months after infection for perinatally infected, and 1.1 years for post-natally infected children. An estimated 25% of the early infected children would still be alive at 10.6 years compared with 16.9 years for those infected through breastfeeding. CONCLUSIONS: The increase in available data has enabled separation of child mortality patterns by timing of infection allowing improvement and more flexibility in modelling of paediatric HIV infection and survival. PMID- 21247885 TI - Prenatal famine exposure and cognition at age 59 years. AB - BACKGROUND: Despite the perceived importance of early life nutrition for mental development, few studies have related gestational undernutrition to later-life cognitive functioning. We investigated the consequences of gestational exposure to the Dutch famine of 1944-45 for cognitive functioning at the age of 59 years. METHODS: We recruited men and women who were (i) born in birth clinics in Amsterdam, Rotterdam and Leiden, between January 1945 and March 1946, whose mothers experienced famine during or immediately preceding pregnancy (n = 354); (ii) born in the same three institutions during 1943 and 1947, whose mothers did not experience famine during this pregnancy (n = 292); or (iii) same-sex siblings of those in the first two categories (n = 311). We assessed cognitive performance at the age of 59 years by means of a comprehensive test battery. RESULTS: All cognitive functioning test scores were within normal ranges for this age group. There were no differences in cognitive performance at the age of 59 years between individuals exposed to gestational undernutrition and those without this exposure. For the general cognitive index, a summary measure across six functional domains (mean 100, standard deviation (SD) 15 points), famine exposure was associated with a decrease of 0.57 points [95% confidence interval (95% CI) 2.41 to 1.28] points. Individuals exposed to famine in gestational weeks 1-10 had a cognitive functioning index 4.36 (95% CI 8.04-0.67) points lower than those without this exposure. Within-sibling-pair analyses gave consistent results. CONCLUSION: We found no overall association between maternal exposure to acute famine in pregnancy and cognitive performance of the offspring at the age of 59 years, but cannot rule out an association specific to early pregnancy exposure. PMID- 21247886 TI - Epidemiology in a changing world: variation, causation and ubiquitous risk factors. AB - We are all living in the era of globalization and, like it or not, it is going to change the way we practise epidemiology, the kinds of questions we ask and the methods we use to answer them. However, the methods, and ways of thinking about the health of populations, that will be required for epidemiology in the 21st century are in some instances quite different from the standard epidemiological techniques that are taught in most textbooks and courses today. As we develop epidemiological methods for addressing the scientific and public health problems of the 21st century, it is important that we consider, once again, the distinction between the analysis of variance and the analysis of causes. This has primarily been considered with respect to genetic research, and also with regard to the problems of making comparisons between different populations and environments at the same point in time. It has not been considered in depth with regard to the issues of conducting epidemiological research in a world that is changing over time. In this article, I first consider the statistical and scientific issues involved in the distinction between the analysis of variance and the analysis of causes. I then discuss some examples of the implications of this distinction for the theory and practice of epidemiology in a changing world, particularly with regard to risk factors that become ubiquitous over time. Sometimes the most important causes of disease are invisible because they are everywhere. PMID- 21247887 TI - Progressive strength training in older patients after hip fracture: a randomised controlled trial. AB - OBJECTIVE: the aim of this study was to assess the effect of a 3-month strength training programme on functional performance and self-rated health in a group of home-dwelling older hip fracture patients. DESIGN: randomised, controlled; single blind parallel-group trial. SETTING: intervention at outpatient's clinic. SUBJECTS: one hundred and fifty patients with surgical fixation for a hip fracture. METHODS: strength training was integrated into all stages of the programme. The programme comprised four exercises, half of them in a standing position, performed at 80% of maximum. Measurements were taken after the 3-month intervention. The primary outcome measurement was the Berg Balance Scale (BBS). Secondary outcomes were results of the sit-to-stand test, Timed Up-and-Go test, maximal gait speed, 6-min walk test, Nottingham Extended Activities of Daily Living scale and the SF-12 health status questionnaire. RESULTS: at baseline, there were no significant between-group differences. At follow-up, the intervention group showed highly significant improvements both in the primary endpoint (BBS, mean difference 4.7 points) and in secondary endpoints of tapping strength, mobility and instrumental activities of daily living. CONCLUSION: home dwelling hip fracture patients can benefit from an extended supervised strength training programme in a rehabilitation setting. These patients are capable of high-intensity strength training, which should optimise gains in physical function, strength and balance. Resistance exercise training seems to influence functional performance adaptation. PMID- 21247888 TI - Proprotein convertases process Pmel17 during secretion. AB - Pmel17 is a melanocyte/melanoma-specific protein that traffics to melanosomes where it forms a fibrillar matrix on which melanin gets deposited. Before being cleaved into smaller fibrillogenic fragments the protein undergoes processing by proprotein convertases, a class of serine proteases that typically recognize the canonical motif RX(R/K)R?. The current model of Pmel17 maturation states that this processing step occurs in melanosomes, but in light of recent reports this issue has become controversial. We therefore addressed this question by thoroughly assessing the processing kinetics of either wild-type Pmel17 or a secreted soluble Pmel17 derivative. Our results demonstrate clearly that processing of Pmel17 occurs during secretion and that it does not require entry of the protein into the endocytic system. Strikingly, processing proceeds even in the presence of the secretion inhibitor monensin, suggesting that Pmel17 is an exceptionally good substrate. In line with this, we find that newly synthesized surface Pmel17 is already quantitatively cleaved. Moreover, we demonstrate that Pmel17 function is independent of the sequence identity of its unconventional proprotein convertase-cleavage motif that lacks arginine in P4 position. The data alter the current view of Pmel17 maturation and suggest that the multistep processing of Pmel17 begins with an early cleavage during secretion that primes the protein for later functional processing. PMID- 21247889 TI - The heat shock-binding protein (HspBP1) protects cells against the cytotoxic action of the Tag7-Hsp70 complex. AB - Heat shock-binding protein HspBP1 is a member of the Hsp70 co-chaperone family. The interaction between HspBP1 and the ATPase domain of the major heat shock protein Hsp70 up-regulates nucleotide exchange and reduces the affinity between Hsp70 and the peptide in its peptide-binding site. Previously we have shown that Tag7 (also known as peptidoglycan recognition protein PGRP-S), an innate immunity protein, interacts with Hsp70 to form a stable Tag7-Hsp70 complex with cytotoxic activity against some tumor cell lines. This complex can be produced in cytotoxic lymphocytes and released during interaction with tumor cells. Here the effect of HspBP1 on the cytotoxic activity of the Tag7-Hsp70 complex was examined. HspBP1 could bind not only to Hsp70, but also to Tag7. This interaction eliminated the cytotoxic activity of Tag7-Hsp70 complex and decreased the ATP concentration required to dissociate Tag7 from the peptide-binding site of Hsp70. Moreover, HspBP1 inhibited the cytotoxic activity of the Tag7-Hsp70 complex secreted by lymphocytes. HspBP1 was detected in cytotoxic CD8+ lymphocytes. This protein was released simultaneously with Tag7-Hsp70 during interaction of these lymphocytes with tumor cells. The simultaneous secretion of the cytotoxic complex with its inhibitor could be a mechanism protecting normal cells from the cytotoxic effect of this complex. PMID- 21247890 TI - Binding of Efb from Staphylococcus aureus to fibrinogen blocks neutrophil adherence. AB - In addition to its pivotal role in hemostasis, fibrinogen (Fg) and provisional fibrin matrices play important roles in inflammation and regulate innate immune responses by interacting with leukocytes. Efb (the extracellular fibrinogen binding protein) is a secreted Staphylococcus aureus protein that engages host Fg and complement C3. However, the molecular details underlying the Efb-Fg interaction and the biological relevance of this interaction have not been determined. In the present study, we characterize the interaction of Efb with Fg. We demonstrate that the Fg binding activity is located within the intrinsically disordered N-terminal half of Efb (Efb-N) and that the D fragment of Fg is the region that mediates Efb-N binding. More detailed studies of the Efb-N-Fg interactions using ELISA and surface plasmon resonance analyses revealed that Efb N exhibits a much higher affinity for Fg than typically observed with Fg-binding MSCRAMMs (microbial surface components recognizing adhesive matrix molecules), and data obtained from ELISA analyses using truncated Efb-N constructs demonstrate that Efb-N contains two binding sites located within residues 30-67 and 68-98, respectively. Efb-N inhibits neutrophil adhesion to immobilized Fg by binding to Fg and blocking the interaction of the protein with the leukocyte integrin receptor, alpha(M)beta(2). A motif in the Fg gamma chain previously shown to be central to the alpha(M)beta(2) interaction was shown to be functionally distinguishable from the Efb-N binding site, suggesting that the Fg Efb interaction indirectly impedes Fg engagement by alpha(M)beta(2). Taken together, these studies provide insights into how Efb interacts with Fg and suggest that Efb may support bacterial virulence at least in part by impeding Fg driven leukocyte adhesion events. PMID- 21247891 TI - G protein activation by serotonin type 4 receptor dimers: evidence that turning on two protomers is more efficient. AB - The discovery that class C G protein-coupled receptors (GPCRs) function as obligatory dimeric entities has generated major interest in GPCR oligomerization. Oligomerization now appears to be a common feature among all GPCR classes. However, the functional significance of this process remains unclear because, in vitro, some monomeric GPCRs, such as rhodopsin and beta(2)-adrenergic receptors, activate G proteins. By using wild type and mutant serotonin type 4 receptors (5 HT(4)Rs) (including a 5-HT(4)-RASSL) expressed in COS-7 cells as models of class A GPCRs, we show that activation of one protomer in a dimer was sufficient to stimulate G proteins. However, coupling efficiency was 2 times higher when both protomers were activated. Expression of combinations of 5-HT(4), in which both protomers were able to bind to agonists but only one could couple to G proteins, suggested that upon agonist occupancy, protomers did not independently couple to G proteins but rather that only one G protein was activated. Coupling of a single heterotrimeric G(s) protein to a receptor dimer was further confirmed in vitro, using the purified recombinant WT RASSL 5-HT(4)R obligatory heterodimer. These results, together with previous findings, demonstrate that, differently from class C GPCR dimers, class A GPCR dimers have pleiotropic activation mechanisms. PMID- 21247892 TI - Distinct protein kinase A anchoring proteins direct prostaglandin E2 modulation of Toll-like receptor signaling in alveolar macrophages. AB - Toll-like receptors (TLRs) direct a proinflammatory program in macrophages. One mediator whose generation is induced by TLR ligation is prostaglandin E(2) (PGE(2)), which is well known to increase intracellular cAMP upon G protein coupled receptor ligation. How PGE(2)/cAMP shapes the nascent TLR response and the mechanisms by which it acts remain poorly understood. Here we explored PGE(2)/cAMP regulation of NO production in primary rat alveolar macrophages stimulated with the TLR4 ligand LPS. Endogenous PGE(2) synthesis accounted for nearly half of the increment in NO production in response to LPS. The enhancing effect of PGE(2) on LPS-stimulated NO was mediated via cAMP, generated mainly upon ligation of the E prostanoid 2 receptor and acting via protein kinase A (PKA) rather than via the exchange protein activated by cAMP. Isoenzyme-selective cAMP agonists and peptide disruptors of protein kinase A anchoring proteins (AKAPs) implicated PKA regulatory subunit type I (RI) interacting with an AKAP in this process. Gene knockdown of potential RI-interacting AKAPs expressed in alveolar macrophages revealed that AKAP10 was required for PGE(2) potentiation of LPS-induced NO synthesis. AKAP10 also mediated PGE(2) potentiation of the expression of cytokines IL-10 and IL-6, whereas PGE(2) suppression of TNF-alpha was mediated by AKAP8-anchored PKA-RII. Our data illustrate the pleiotropic manner in which G protein-coupled receptor-derived cAMP signaling can influence TLR responses in primary macrophages and suggest that AKAP10 may coordinate increases in gene expression. PMID- 21247893 TI - The Aspergillus fumigatus sialidase is a 3-deoxy-D-glycero-D-galacto-2 nonulosonic acid hydrolase (KDNase): structural and mechanistic insights. AB - Aspergillus fumigatus is a filamentous fungus that can cause severe respiratory disease in immunocompromised individuals. A putative sialidase from A. fumigatus was recently cloned and shown to be relatively poor in cleaving N acetylneuraminic acid (Neu5Ac) in comparison with bacterial sialidases. Here we present the first crystal structure of a fungal sialidase. When the apo structure was compared with bacterial sialidase structures, the active site of the Aspergillus enzyme suggested that Neu5Ac would be a poor substrate because of a smaller pocket that normally accommodates the acetamido group of Neu5Ac in sialidases. A sialic acid with a hydroxyl in place of an acetamido group is 2 keto-3-deoxynononic acid (KDN). We show that KDN is the preferred substrate for the A. fumigatus sialidase and that A. fumigatus can utilize KDN as a sole carbon source. A 1.45-A resolution crystal structure of the enzyme in complex with KDN reveals KDN in the active site in a boat conformation and nearby a second binding site occupied by KDN in a chair conformation, suggesting that polyKDN may be a natural substrate. The enzyme is not inhibited by the sialidase transition state analog 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (Neu5Ac2en) but is inhibited by the related 2,3-didehydro-2,3-dideoxy-D-glycero-D-galacto-nonulosonic acid that we show bound to the enzyme in a 1.84-A resolution crystal structure. Using a fluorinated KDN substrate, we present a 1.5-A resolution structure of a covalently bound catalytic intermediate. The A. fumigatus sialidase is therefore a KDNase with a similar catalytic mechanism to Neu5Ac exosialidases, and this study represents the first structure of a KDNase. PMID- 21247894 TI - The X protein of hepatitis B virus inhibits apoptosis in hepatoma cells through enhancing the methionine adenosyltransferase 2A gene expression and reducing S adenosylmethionine production. AB - The X protein (HBx) of hepatitis B virus (HBV) is involved in the development of hepatocellular carcinoma (HCC), and methionine adenosyltransferase 2A (MAT2A) promotes the growth of liver cancer cells through altering S-adenosylmethionine homeostasis. Thus, we speculated that a link between HBx and MAT2A may contribute to HCC development. In this study, the effects of HBx on MAT2A expression and cell apoptosis were investigated, and the molecular mechanism by which HBx and MAT2A regulate tumorigenesis was evaluated. Results from immunohistochemistry analyses of 37 pairs of HBV-associated liver cancer tissues/corresponding peritumor tissues showed that HBx and MAT2A are highly expressed in most liver tumor tissues. Our in vitro results revealed that HBx activates MAT2A expression in a dose-dependent manner in hepatoma cells, and such regulation requires the cis-regulatory elements NF-kappaB and CREB on the MAT2A gene promoter. Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) further demonstrated that HBx facilitates the binding of NF-kappaB and CREB to MAT2A gene promoter. In addition, overexpression of HBx or MAT2A inhibits cell apoptosis, whereas knockdown of MAT2A expression stimulates apoptosis in hepatoma cells. Furthermore, we demonstrated that HBx reduces MAT1A expression and AdoMet production but enhances MAT2beta expression. Thus, we proposed that HBx activates MAT2A expression through NF-kappaB and CREB signaling pathways to reduce AdoMet production, inhibit hepatoma cell apoptosis, and perhaps enhance HCC development. These findings should provide new insights into our understanding how the molecular mechanisms underline the effects of HBV infection on the production of MAT2A and the development of HCC. PMID- 21247895 TI - Galactose recognition by a tetrameric C-type lectin, CEL-IV, containing the EPN carbohydrate recognition motif. AB - CEL-IV is a C-type lectin isolated from a sea cucumber, Cucumaria echinata. This lectin is composed of four identical C-type carbohydrate-recognition domains (CRDs). X-ray crystallographic analysis of CEL-IV revealed that its tetrameric structure was stabilized by multiple interchain disulfide bonds among the subunits. Although CEL-IV has the EPN motif in its carbohydrate-binding sites, which is known to be characteristic of mannose binding C-type CRDs, it showed preferential binding of galactose and N-acetylgalactosamine. Structural analyses of CEL-IV-melibiose and CEL-IV-raffinose complexes revealed that their galactose residues were recognized in an inverted orientation compared with mannose binding C-type CRDs containing the EPN motif, by the aid of a stacking interaction with the side chain of Trp-79. Changes in the environment of Trp-79 induced by binding to galactose were detected by changes in the intrinsic fluorescence and UV absorption spectra of WT CEL-IV and its site-directed mutants. The binding specificity of CEL-IV toward complex oligosaccharides was analyzed by frontal affinity chromatography using various pyridylamino sugars, and the results indicate preferential binding to oligosaccharides containing Galbeta1 3/4(Fucalpha1-3/4)GlcNAc structures. These findings suggest that the specificity for oligosaccharides may be largely affected by interactions with amino acid residues in the binding site other than those determining the monosaccharide specificity. PMID- 21247896 TI - The dynamics and mechanism of SUMO chain deconjugation by SUMO-specific proteases. AB - SUMOylation of proteins is a cyclic process that requires both conjugation and deconjugation of SUMO moieties. Besides modification by a single SUMO, SUMO chains have also been observed, yet the dynamics of SUMO conjugation/deconjugation remain poorly understood. Using a non-deconjugatable form of SUMO we demonstrate the underappreciated existence of SUMO chains in vivo, we highlight the importance of SUMO deconjugation, and we demonstrate the highly dynamic nature of the SUMO system. We show that SUMO-specific proteases (SENPs) play a crucial role in the dynamics of SUMO chains in vivo by constant deconjugation. Preventing deSUMOylation in Schizosaccharomyces pombe results in slow growth and a sensitivity to replication stress, highlighting the biological requirement for deSUMOylation dynamics. Furthermore, we present the mechanism of SUMO chain deconjugation by SENPs, which occurs via a stochastic mechanism, resulting in cleavage anywhere within a chain. Our results offer mechanistic insights into the workings of deSUMOylating proteases and highlight their importance in the homeostasis of (poly)SUMO-modified substrates. PMID- 21247897 TI - SCCRO (DCUN1D1) promotes nuclear translocation and assembly of the neddylation E3 complex. AB - SCCRO/DCUN1D1/DCN1 (squamous cell carcinoma-related oncogene/defective in cullin neddylation 1 domain containing 1/defective in cullin neddylation) serves as an accessory E3 in neddylation by binding to cullin and Ubc12 to allow efficient transfer of Nedd8. In this work we show that SCCRO has broader, pleiotropic effects that are essential for cullin neddylation in vivo. Reduced primary nuclear localization of Cul1 accompanying decreased neddylation and proliferation in SCCRO(-/-) mouse embryonic fibroblasts led us to investigate whether compartmentalization plays a regulatory role. Decreased nuclear localization, neddylation, and defective proliferation in SCCRO(-/-) mouse embryonic fibroblasts were rescued by transgenic expression of SCCRO. Expression of reciprocal SCCRO and Cul1-binding mutants confirmed the requirement for SCCRO in nuclear translocation and neddylation of cullins in vivo. Nuclear translocation of Cul1 by tagging with a nuclear localization sequence allowed neddylation independent of SCCRO, but at a lower level. We found that in the nucleus, SCCRO enhances recruitment of Ubc12 to Cul1 to promote neddylation. These findings suggest that SCCRO has an essential role in neddylation in vivo involving nuclear localization of neddylation components and recruitment and proper positioning of Ubc12. PMID- 21247898 TI - Neuregulin-1-human epidermal receptor-2 signaling is a central regulator of pulmonary epithelial permeability and acute lung injury. AB - The mechanisms behind the loss of epithelial barrier function leading to alveolar flooding in acute lung injury (ALI) are incompletely understood. We hypothesized that the tyrosine kinase receptor human epidermal growth factor receptor-2 (HER2) would be activated in an inflammatory setting and participate in ALI. Interleukin 1beta (IL-1beta) exposure resulted in HER2 activation in human epithelial cells and markedly increased conductance across a monolayer of airway epithelial cells. Upon HER2 blockade, conductance changes were significantly decreased. Mechanistic studies revealed that HER2 trans-activation by IL-1beta required a disintegrin and metalloprotease 17 (ADAM17)-dependent shedding of the ligand neuregulin-1 (NRG-1). In murine models of ALI, NRG-1-HER2 signaling was activated, and ADAM17 blockade resulted in decreased NRG-1 shedding, HER2 activation, and lung injury in vivo. Finally, NRG-1 was detectable and elevated in pulmonary edema fluid from patients with ALI. These results suggest that the ADAM17-NRG-1-HER2 axis modulates the alveolar epithelial barrier and contributes to the pathophysiology of ALI. PMID- 21247899 TI - Structural and functional studies of the Escherichia coli phenylacetyl-CoA monooxygenase complex. AB - The utilization of phenylacetic acid (PA) in Escherichia coli occurs through a hybrid pathway that shows features of both aerobic and anaerobic metabolism. Oxygenation of the aromatic ring is performed by a multisubunit phenylacetyl coenzyme A oxygenase complex that shares remote homology of two subunits to well studied bacterial multicomponent monooxygenases and was postulated to form a new bacterial multicomponent monooxygenase subfamily. We expressed the subunits PaaA, B, C, D, and E of the PA-CoA oxygenase and showed that PaaABC, PaaAC, and PaaBC form stable subcomplexes that can be purified. In vitro reconstitution of the oxygenase subunits showed that each of the PaaA, B, C, and E subunits are necessary for catalysis, whereas PaaD is not essential. We have determined the crystal structure of the PaaAC complex in a ligand-free form and with several CoA derivatives. We conclude that PaaAC forms a catalytic core with a monooxygenase fold with PaaA being the catalytic alpha subunit and PaaC, the structural beta subunit. PaaAC forms heterotetramers that are organized very differently from other known multisubunit monooxygenases and lacks their conservative network of hydrogen bonds between the di-iron center and protein surface, suggesting different association with the reductase and different mechanisms of electron transport. The PaaA structure shows adaptation of the common access route to the active site for binding a CoA-bound substrate. The enzyme-substrate complex shows the orientation of the aromatic ring, which is poised for oxygenation at the ortho-position, in accordance with the expected chemistry. The PA-CoA oxygenase complex serves as a paradigm for the new subfamily multicomponent monooxygenases comprising several hundred homologs. PMID- 21247900 TI - Exploring by pulsed EPR the electronic structure of ubisemiquinone bound at the QH site of cytochrome bo3 from Escherichia coli with in vivo 13C-labeled methyl and methoxy substituents. AB - The cytochrome bo(3) ubiquinol oxidase from Escherichia coli resides in the bacterial cytoplasmic membrane and catalyzes the two-electron oxidation of ubiquinol-8 and four-electron reduction of O(2) to water. The one-electron reduced semiquinone forms transiently during the reaction, and the enzyme has been demonstrated to stabilize the semiquinone. The semiquinone is also formed in the D75E mutant, where the mutation has little influence on the catalytic activity, and in the D75H mutant, which is virtually inactive. In this work, wild type cytochrome bo(3) as well as the D75E and D75H mutant proteins were prepared with ubiquinone-8 (13)C-labeled selectively at the methyl and two methoxy groups. This was accomplished by expressing the proteins in a methionine auxotroph in the presence of l-methionine with the side chain methyl group (13)C-labeled. The (13)C-labeled quinone isolated from cytochrome bo(3) was also used for the generation of model anion radicals in alcohol. Two-dimensional pulsed EPR and ENDOR were used for the study of the (13)C methyl and methoxy hyperfine couplings in the semiquinone generated in the three proteins indicated above and in the model system. The data were used to characterize the transferred unpaired spin densities on the methyl and methoxy substituents and the conformations of the methoxy groups. In the wild type and D75E mutant, the constraints on the configurations of the methoxy side chains are similar, but the D75H mutant appears to have altered methoxy configurations, which could be related to the perturbed electron distribution in the semiquinone and the loss of enzymatic activity. PMID- 21247901 TI - Histone deacetylases 9 and 10 are required for homologous recombination. AB - We tested the role of histone deacetylases (HDACs) in the homologous recombination process. A tissue-culture based homology-directed repair assay was used in which repair of a double-stranded break by homologous recombination results in gene conversion of an inactive GFP allele to an active GFP gene. Our rationale was that hyperacetylation caused by HDAC inhibitor treatment would increase chromatin accessibility to repair factors, thereby increasing homologous recombination. Contrary to expectation, treatment of cells with the inhibitors significantly reduced homologous recombination activity. Using RNA interference to deplete each HDAC, we found that depletion of either HDAC9 or HDAC10 specifically inhibited homologous recombination. By assaying for sensitivity of cells to the interstrand cross-linker mitomycin C, we found that treatment of cells with HDAC inhibitors or depletion of HDAC9 or HDAC10 resulted in increased sensitivity to mitomycin C. Our data reveal an unanticipated function of HDAC9 and HDAC10 in the homologous recombination process. PMID- 21247902 TI - Crystal structure of the human N-Myc downstream-regulated gene 2 protein provides insight into its role as a tumor suppressor. AB - Considerable attention has recently been paid to the N-Myc downstream-regulated gene (NDRG) family because of its potential as a tumor suppressor in many human cancers. Primary amino acid sequence information suggests that the NDRG family proteins may belong to the alpha/beta-hydrolase (ABH) superfamily; however, their functional role has not yet been determined. Here, we present the crystal structures of the human and mouse NDRG2 proteins determined at 2.0 and 1.7 A resolution, respectively. Both NDRG2 proteins show remarkable structural similarity to the ABH superfamily, despite limited sequence similarity. Structural analysis suggests that NDRG2 is a nonenzymatic member of the ABH superfamily, because it lacks the catalytic signature residues and has an occluded substrate-binding site. Several conserved structural features suggest NDRG may be involved in molecular interactions. Mutagenesis data based on the structural analysis support a crucial role for helix alpha6 in the suppression of TCF/beta-catenin signaling in the tumorigenesis of human colorectal cancer, via a molecular interaction. PMID- 21247903 TI - Structural basis for selective small molecule kinase inhibition of activated c Met. AB - The receptor tyrosine kinase c-Met is implicated in oncogenesis and is the target for several small molecule and biologic agents in clinical trials for the treatment of cancer. Binding of the hepatocyte growth factor to the cell surface receptor of c-Met induces activation via autophosphorylation of the kinase domain. Here we describe the structural basis of c-Met activation upon autophosphorylation and the selective small molecule inhibiton of autophosphorylated c-Met. MK-2461 is a potent c-Met inhibitor that is selective for the phosphorylated state of the enzyme. Compound 1 is an MK-2461 analog with a 20-fold enthalpy-driven preference for the autophosphorylated over unphosphorylated c-Met kinase domain. The crystal structure of the unbound kinase domain phosphorylated at Tyr-1234 and Tyr-1235 shows that activation loop phosphorylation leads to the ejection and disorder of the activation loop and rearrangement of helix alphaC and the G loop to generate a viable active site. Helix alphaC adopts a orientation different from that seen in activation loop mutants. The crystal structure of the complex formed by the autophosphorylated c Met kinase domain and compound 1 reveals a significant induced fit conformational change of the G loop and ordering of the activation loop, explaining the selectivity of compound 1 for the autophosphorylated state. The results highlight the role of structural plasticity within the kinase domain in imparting the specificity of ligand binding and provide the framework for structure-guided design of activated c-Met inhibitors. PMID- 21247904 TI - Myocyte enhancer factor-2 interacting transcriptional repressor (MITR) is a switch that promotes osteogenesis and inhibits adipogenesis of mesenchymal stem cells by inactivating peroxisome proliferator-activated receptor gamma-2. AB - EZH2, a catalytic subunit of Polycomb-repressive complex 2 (PRC2), is a histone lysine methyltransferase that methylates lysine 27 of histone H3, resulting in gene silencing. It has been shown that EZH2 plays a pivotal role in fostering self-renewal and inhibiting the differentiation of embryonic stem cells. Mesenchymal stem cells (MSCs) can be induced to differentiate into adipogenic and osteogenic lineages, which are mutually exclusive. However, it is not clear whether the molecular events of EZH2-mediated epigenetic silencing may coordinate differentiation between osteoblasts and adipocytes. Disruption of the balance between adipogenesis and osteogenesis is associated with many diseases; thus, identifying a switch that determines the fate of MSC is critical. In this study, we used EZH2-ChIP-on-chip assay to identify differential EZH2 targets in the two differentiation stages on a genome-wide scale. After validating the targets, we found that myocyte enhancer factor-2 interacting transcriptional repressor (MITR)/HDAC9c was expressed in osteoblasts and greatly decreased in adipocytes. We demonstrated that MITR plays a crucial role in the acceleration of MSC osteogenesis and attenuation of MSC adipogenesis through interaction with peroxisome proliferator-activated receptor (PPAR) gamma-2 in the nucleus of osteoblasts, which interrupts PPARgamma-2 activity and prevents adipogenesis. Together, our results demonstrated that MITR plays a master switch role to balance osteogenic and adipogenic differentiation of MSCs through regulation of PPARgamma-2 transcriptional activity. PMID- 21247906 TI - Effects of Seed Cryopreservation and Priming on Germination in Several Cultivars of Apium graveolens. AB - Seed germination of seven celery cultivars was studied after storage in liquid nitrogen for 1 or 30 d. Cryopreservation was also carried out on pelleted and primed seeds. None of the treatments applied reduced germination percentages. T(50) (time for germination to reach 50%) significantly decreased in Florida, Utah and Istar cultivars when priming, alone or in combination with cryopreservation, was used. PMID- 21247905 TI - A functional-structural model of rice linking quantitative genetic information with morphological development and physiological processes. AB - BACKGROUND AND AIMS: Although quantitative trait loci (QTL) analysis of yield related traits for rice has developed rapidly, crop models using genotype information have been proposed only relatively recently. As a first step towards a generic genotype-phenotype model, we present here a three-dimensional functional-structural plant model (FSPM) of rice, in which some model parameters are controlled by functions describing the effect of main-effect and epistatic QTLs. METHODS: The model simulates the growth and development of rice based on selected ecophysiological processes, such as photosynthesis (source process) and organ formation, growth and extension (sink processes). It was devised using GroIMP, an interactive modelling platform based on the Relational Growth Grammar formalism (RGG). RGG rules describe the course of organ initiation and extension resulting in final morphology. The link between the phenotype (as represented by the simulated rice plant) and the QTL genotype was implemented via a data interface between the rice FSPM and the QTLNetwork software, which computes predictions of QTLs from map data and measured trait data. KEY RESULTS: Using plant height and grain yield, it is shown how QTL information for a given trait can be used in an FSPM, computing and visualizing the phenotypes of different lines of a mapping population. Furthermore, we demonstrate how modification of a particular trait feeds back on the entire plant phenotype via the physiological processes considered. CONCLUSIONS: We linked a rice FSPM to a quantitative genetic model, thereby employing QTL information to refine model parameters and visualizing the dynamics of development of the entire phenotype as a result of ecophysiological processes, including the trait(s) for which genetic information is available. Possibilities for further extension of the model, for example for the purposes of ideotype breeding, are discussed. PMID- 21247907 TI - Stemflow: A Source of Nutrients in some Naturally Growing Epiphytic Orchids of the Sikkim Himalaya. AB - A study on five naturally growing epiphytic orchids viz., Bulbophyllum affine Lindl., Coelogyne ochracea Lindl., Otochilus porrecta Lindl., Cirrhopetalum cornutum Lindl. and C. cornutum (var.) was carried out in the subtropical belt of Sikkim Himalaya. Stemflow leachates formed the main source of ammonium-N and nitrate-N for uptake by these orchids. Phosphorus concentration in the tissues of these orchids was high. Phosphate-P from stemflow does not seem to be a regular source of phosphorus for these orchids. Absorption/desorption results indicate that organic-N from stemflow leachates is not utilized by these orchids. PMID- 21247908 TI - Integrating low water potential seed hydration with other treatments to improve cold tolerance. AB - Matriconditioning improved the performance of pepper, tomato, sweet corn, snap bean, table beet, sugar beet and watermelon seeds in early field plantings at suboptimal temperatures (averaged over 10 d after planting) ranging from 12 to 18 degrees C. Reduction in the time to 50% (T(50)) emergence in conditioned seeds ranged from 0.6 d in watermelon to 3.3 d in pepper and improvement in emergence from 10% in sugar beet to 30% in table beet. Further improvement in emergence occurred by inclusion of pesticides and/or gibberellin during conditioning. A 4 d conditioning of pepper at 25 degrees C was superior to 7 d conditioning at 15 degrees C in seeds germinated at 15 degrees C on filter paper, but 15 degrees C conditioning was superior in improving percentage emergence in early field plantings. Tomato seeds conditioned at 15 or 25 degrees C performed equally well in the field. A 2 d conditioning was superior to 1 d conditioning in improving the performance of supersweet sweet corn cultivars grown in a growth chamber at 10/20 degrees C. The water uptake rate in the presence of Micro-Cel E during matriconditioning of sweet corn seeds was slower than when the seeds were exposed to the same amount of water in absence of the carrier. Electrolyte leakage was greater in supersweet 'Challenger' sweet corn seeds carrying the sh(2) gene compared to the sugary type sweet corn 'More', and in both cases matriconditioning reduced the leakage. Lettuce seeds matriconditioned for 24 h had higher 1-aminocyclopropane-l-carboxylic acid (ACC) content, developed greater ACC oxidase activity and performed better at 10 degrees C (germinated earlier and had higher percentage germination) than the untreated seeds. Matriconditioning appears to bring about beneficial physical, physiological and biochemical changes that seemingly improve embryo growth potential and tolerance to low temperatures. PMID- 21247909 TI - Cadmium Tolerance in a Metal-contaminated Population of the Grassland Moss Rhytidiadelphus squarrosus. AB - Two populations of Rhytidiadelphus squarrosus, from metal-contaminated and uncontaminated habitats, differed in their intra- and extracellular Cd contents but had similar cellular levels of Cu. Moss shoots were supplied with a pulse of toxic metal by incubating in Cu or Cd nitrate solutions and effects on respiration, photosynthesis and intracellular K loss were monitored with time after initial exposure. Increasing intracellular Cu levels correlated most closely with a concurrent decline in intracellular K. Photosynthesis also declined in proportion to intracellular Cu; significant Cu-induced stimulation of respiration was observed. The most significant effect of Cd treatment was a decline in photosynthesis in proportion to the intracellular concentration of Cd. Apical segments from both populations showed similar sensitivity to Cu, whereas the metal-contaminated population showed increased resistance to Cd. Sensitivity to Cd increased in the more basal portions of moss gametophores, indicating that apparent resistance of Cd might reflect shoot vitality and age effects. After laboratory growth to eliminate differences in the physiological status of apical segments, it was confirmed that the metal-contaminated population of the moss was photosynthetically more tolerant to Cd at intracellular Cd concentrations found to cause considerable photosynthetic inhibition in the uncontaminated population. The metal-contaminated population of the moss that was tolerant to Cd was not co tolerant to Cu. PMID- 21247910 TI - In Vitro Development from Leaf Explants of Sugar Beet (Beta vulgaris L). Rhizogenesis and the Effect of Sequential Exposure to Auxin and Cytokinin. AB - Adventitious root development in lamina and midrib-petiole junction expiants of sugar beet cv. Primo was investigated using scanning electron microscopy and light microscopy. Primordia developed close to the vascular strands and areas of newly dividing cells (meristematic centres) were seen adjacent to the intrafascicular cambium after 2 d incubation on medium containing 30 mg 1(-1)1 naphthalene acetic acid. Clearly defined primordia were visible at 4 d and the first roots had emerged by 6 d. A minimum of 24 h exposure to NAA was necessary for root induction. Four days on NAA caused twice as many roots to be initiated but more prolonged exposure (5 and 10 d) inhibited root development. Root initiation continued after transfer to medium containing no plant growth regulators, new primordia appearing as the older ones extended as roots. Attempts were made to modify the development of primordia by sequential culture on cytokinin after induction by auxin. Incubation on N6-benzylaminopurine within 48 h of exposure to NAA disrupted the development of primordia and roots but did not induce shoot formation. PMID- 21247911 TI - Short- and Long-term Stomatal Responses to Fluctuations in Environment in Southern European Greenhouses. AB - Stomatal behaviour in cucumber (Cucumis sativus L.) was analysed and modelled as a function of different greenhouse environmental parameters, under variable summer conditions. Solar radiation was the main regulating factor. During the day, large atmospheric vapour pressure deficit increased transpiration which was followed by a reduction in stomatal aperture, suggesting the presence of a feedback response to water stress. However, stomatal behaviour was more sensitive to high atmospheric vapour pressure deficit when this was accompanied by a rapid decrease of solar radiation. The response to the difference between leaf and air temperature was also influenced by air vapour pressure deficit and duration of plant exposure to high evaporative demand. Calculation of the crop water stress index showed that the air vapour pressure deficit of 1 kPa used in the control treatment probably caused water stress and induced some hardening, a necessary condition for adaptation to summer climate in southern Europe. The importance of the interaction between climatic parameters and plant response in greenhouse environmental management is analysed. Classical models of stomatal resistance are also discussed. PMID- 21247912 TI - A functional relationship between leghaemoglobin and nitrogenase based on novel measurements of the two proteins in legume root nodules. AB - A combination of physiological and structural measurements made on nodulated cowpea and soybean plants cultured with roots in different pO(2) permitted the expression of data in various ways. Values of leghemoglobin concentration and nitrogenase activity from the two legumes were expressed conventionally either on a per plant or per gram nodule fresh weight basis, and where microscopy was done, on the basis of nitrogenase-containing, N(2)-fixing units (i.e. per bacteroid, per infected cell, or per gram infected tissue). In both legumes, acetylene reduction, N fixed and ureide content expressed on the basis of whole plants or per nitrogenase-containing units were very significantly correlated with values of leghaemoglobin concentrations expressed in a similar manner. The use of mathematical correlations in this study involving leghaemoglobin concentrations and various indices of N(2) fixation indicated a strong functional relationship between the two proteins in symbiotic legumes. These findings confirm previous suggestions that leghaemoglobin and the nitrogenase complex are two proteins closely associated with N(2)-fixing efficiency in legume root nodules. PMID- 21247913 TI - Competition for assimilates and fruit position affect fruit set in indeterminate greenhouse tomato. AB - Localization and characterization of fruit set in winter tomato crops was investigated to determine the main internal and external controlling factors and to establish a quantitative relationship between fruit set and competition for assimilates. Individual fruit growth and development was assessed on a beef tomato cultivar during the reproductive period (first nine inflorescences). A non destructive photograph technique was used to measure fruit growth from very early stages of their development and then calliper measurements were made on big fruits. From these measurements we determined the precise developmental stage at which fruit growth stopped. Fruit potential growth, which is defined as the growth achieved in non-limiting conditions for assimilate supply, was also assessed by this method on plants thinned to one flower per inflorescence. The latter was used to calculate the ratio between actual and potential growth, which was found to be a good index of the competition for assimilates. Time lags of fruit set were observed mainly on distal organs. When more than three flowers were left on each inflorescence, distal organs developed at the same time as proximal organs of the following inflorescence. Consequently they were submitted to a double competition within one inflorescence and among inflorescences. It was shown that, what is commonly named 'fruit set failure', is not an irreversible death of the organ and that a small fruit could resume growth after a delay of several weeks as soon as the first fruits ripened and thus ceased to compete for assimilates. In that case proximal fruits resumed growth before distal ones. The delayed fruits contained only few seeds but a germination test confirmed that fertilization took place before fruit set failed. Competition for assimilates was calculated during plant development by the ratio between actual and potential fruit growth. Potential growth of proximal fruits was strongly dependent on the position of the inflorescence on the stem, whereas potential growth of distal fruits was lower than or equal to that of proximal fruits of the same inflorescence and it was independent on the inflorescence position. We took into account both inflorescence and fruit positions to establish a quantitative relationship between fruit set of individual inflorescences and the ratio between actual and potential fruit growth. PMID- 21247914 TI - Characterization of maize lines differing in leaf abscisic Acid content in the field. 1 abscisic Acid physiology. AB - The inbred maize lines Poljl7 and F-2 have previously been shown to differ by up to three-fold in leaf abscisic acid (ABA) concentration in the field. Lines from the cross Poljl7 * F-2 differing in leaf ABA concentrations, and the parents, were studied in the field to characterize the differences amongst the lines in ABA concentrations during the season, during the day and in different parts of the plants. The water status of the plants was measured and leaves were heat girdled to get information on possible causes for the genetic variation amongst the lines in ABA concentration. Leaf ABA concentrations of the high-AB A lines increased markedly and consistently from flowering time onwards, whereas leaf ABA concentrations of the low-ABA lines gradually fell after flowering. Leaf water potentials of high-ABA and low-ABA lines were similar during this time. Leaf ABA concentrations varied little during the day, and heat girdling caused a rise in ABA concentrations, which was similar in both high-ABA and low-ABA lines, only after girdling for at least 4 h. ABA concentrations were highest in the leaves and it was only in the leaves and developing kernels that substantial differences in ABA concentrations were found between the high-ABA and low-ABA classes. Although aerial brace roots also had high ABA concentrations, other roots and stem internodes had ABA concentrations which were consistently low and the same for both ABA classes. Differences between the ABA classes were unlikely to be due to differences in leaf water status or in ABA export from the leaves. Other possible explanations for the genotypic differences in leaf ABA concentrations are discussed. PMID- 21247915 TI - Differing organic Acid exudation pattern explains calcifuge and acidifuge behaviour of plants. AB - Many vascular plant species are unable to colonize calcareous sites. Thus, the floristic composition of adjacent limestone and acid silicate soils differs greatly. The inability of calcifuge plants to establish in limestone sites seems related to a low capacity of such plants to solubilize and absorb Fe or phosphate from these soils. Until now, mechanisms regulating this differing ability of plants to colonize limestone sites have not been elucidated. We propose that contrasting exudation of low-molecular organic acids is a major mechanism involved and show that germinating seeds and young seedlings of limestone plants exude considerably more di- and tricarboxylic acids than calcifuges, which mainly exude monocarboxylic acids. The tricarboxylic citric acid is a powerful extractor of Fe, and the dicarboxylic oxalic acid a very effective extractor of phosphate from limestone soils. Monocarboxylic acids are very weak in these respects. The study is based on ten species from limestone soils and ten species from acid silicate soils. PMID- 21247916 TI - Complex dynamics in a carbon-nitrogen model of a grass-legume pasture. AB - A physiologically based model of a grass-legume pasture is used to study the dynamics of these competing species. In our model, we consider carbon and nitrogen pools and fluxes, incorporating competition for light and soil mineral nitrogen, and including the processes of nitrogen fixation, nitrogen losses and dry matter allocation. First, the steadystate responses of each species to nitrogen deposition, to leaching rate, and to other nitrogen losses are examined. We then consider the dynamic behaviour of these species when there is no time delay for nitrogen cycled through the soil organic matter pool. Next, the effects of various time delays associated with the soil organic matter nitrogen pool on the system dynamics are examined: the behaviour becomes complex, non-linear and exhibits lightly or heavily damped oscillations at two frequencies. The high sensitivity of the system both to the initial value of the soil organic matter nitrogen pool, and to any photosynthetic competitive advantage, is investigated. The implications of these results in relation to observations and experiments on grass-legume pastures are discussed. PMID- 21247917 TI - First Cytogenetic Investigation in Populations of Acacia heterophylla, Endemic from La Reunion Island, with Reference to A. melanoxylon. AB - Five populations of tetraploid Acacia heterophylla, endemic from La Reunion island, were compared together and with their Australian diploid relative A. melanoxylon for cytogenetic and DNA characteristics. A. melanoxylon (2n = 26) had 1.59 pg nuclear DNA; A. heterophylla (2n = 4x = 52) had double this value (3.19 pg), and there was no difference between populations within species. Both species had 39 % GC. Interchromosome connections were evident at metaphase and mitotic irregularities at anaphase were twice as frequent in A. heterophylla as in A. melanoxylon, again with no difference between populations within species. These results argue for a recent autotetraploid origin of A. heterophylla from A. melanoxylon. Yet, fluorochrome banding showed that in some A. heterophylla populations, GC-rich bands had slightly changed from the supposed ancestral pattern, probably by means of translocations involving parts of nuclear organizer areas. No clear relation was found between banding patterns and ecological factors. PMID- 21247918 TI - Hyponatraemia and vasopressin in heart failure: markers or mediators? PMID- 21247919 TI - Prognostic significance of different measures of the ventilation-carbon dioxide relation in patients with suspected heart failure. AB - AIMS: We studied the prognostic significance of the ventilatory equivalent of carbon dioxide production (VEqCO(2)) at different time-points of a maximal cardiopulmonary exercise test (CPET) in patients with suspected heart failure (HF). METHODS AND RESULTS: The VEqCO(2) was calculated at three different time points; VEqCO(2) (rest) was calculated following 30 s of resting data immediately prior to the start of exercise; VEqCO(2) (nadir) was the lowest 30-s average over the duration of the test; VEqCO(2) (peak) was calculated using the mean value of the final 30 s of exercise. We included a healthy control group who had no evidence of cardiorespiratory disease. Four hundred and twenty-three patients with suspected HF (mean age 63 +/- 12 years; 80% males; left ventricular ejection fraction 36 +/- 6 %; peak oxygen uptake 22.3 +/- 8.1 mL kg(-1) min(-1); VE/VCO(2) slope 34 +/- 8) were included in the study. Seventy-eight healthy participants (62% males; age 61 +/- 11 years) were recruited as controls. One hundred and eighteen patients died during follow-up with a median follow-up of 8.6 +/- 2.1 years in survivors. The strongest univariable predictors of all-cause mortality were VEqCO(2) (nadir) (chi(2) = 47.9), peak oxygen uptake (chi(2) = 53.0), and the VE/VCO(2) slope (chi(2) = 31.7). In a Cox multivariable proportional hazards model, VEqCO(2) (nadir) (chi(2) = 8.8), peak systolic blood pressure (chi(2) = 6.0), and age (chi(2) = 6.6) were the most potent independent predictors of all cause mortality. CONCLUSION: The VEqCO(2) (nadir) provides greater prognostic value than other related ventilatory variables in patients with suspected HF. Further work in other populations is required to confirm our conclusions. PMID- 21247920 TI - Intrafamilial medically assisted reproduction. AB - For different motives, couples in need of third party assisted reproduction sometimes prefer the help of a family member over an unrelated collaborator. Quantitative (frequency) and qualitative (experience) data about this practice are lacking or scarce. Forms of intrafamilial medically assisted reproduction (IMAR) are different with respect to (i) familial closeness between the collaborator and the person whose reproductive contribution he or she replaces and whether assistance would be intra- or intergenerational, (ii) the relationship between the collaborator and the fertile partner (this relationship may or may not be consanguineous) and (iii) with regard to the material (sperm and oocytes) that is donated and the services (surrogacy) that are offered. This document aims at providing guidance to the professional handling of requests for IMAR. It briefly sketches the background of this practice and discusses a variety of relevant normative aspects. PMID- 21247921 TI - A pilot study assessing art therapy as a mental health intervention for subfertile women. AB - BACKGROUND Subfertility is a common but hidden source of anxiety, depressive symptoms and hopelessness. Counselling reduces this emotional burden and may even enhance the likelihood of pregnancy. Art therapy may be a useful intervention, because it facilitates the expression of feelings, both visually and verbally, and may ease emotional distress. METHODS Weekly 2-h art therapy group courses were held for a total of 21 subfertile women. The impact of subfertile women's support systems and barriers to coping were all explored. The effectiveness of art therapy was assessed using Beck Hopelessness, Depression and Anxiety Inventories, administered before and after participation, as well as a qualitative exit questionnaire. RESULTS The mean age of participants was 35.7 (SD 2.1) years and duration of infertility was 64 (12.0) months. Mean Beck Hopelessness Scale fell from 6.1 (3.8) to 3.5 (3.1, P = 0.01) after therapy. Beck Depression Inventory-II Score fell from 19.8 (11.0) to 12.5 (10.2, P = 0.01) and Beck Anxiety Inventory Score changed from 12.4 (8.4) to 8.4 (5.2, P = 0.3). Based on the exit questionnaire, women felt the course was insightful, powerful and enjoyable. CONCLUSIONS Art therapy is an inexpensive, non-pharmacological intervention, which was associated with decreased levels of hopelessness and depressed mood in subfertile women. It also provides insight into the meaning and emotional implications of subfertility for patients and caregivers. This pilot study highlights the need for further research in this field. PMID- 21247922 TI - To continue or discontinue storage of cryopreserved embryos? Patients' decisions in view of their child wish. AB - OBJECTIVE Cryopreservation of supernumerary embryos resulting from IVF treatment offers extra chances to conceive. The objective of this study is to describe patients' decisions to continue or discontinue storage of their embryos after a minimum storage period of 2 years. METHODS Female patients who had embryos stored at the Infertility Centre of the Ghent University Hospital (Belgium) were sent a mail questionnaire to be completed anonymously. RESULTS The questionnaire had a response rate of 79% (326/412). After an embryo storage period of at least 2 years, 40% of the couples who were still together wished to continue storage of their embryos. Half of these had no concrete plans for a transfer and wanted to postpone the decision or keep all options open. For those who decided to discontinue storage (60%), the main reason was the completion of their families. Despite the fact that the patients' child wish was the main factor in their storage decision, two groups of patients with distinct profiles made decisions that were inconsistent with their child wish: those who wanted to continue storage while not wanting a(nother) child (7% of those with no child wish), and those who wanted a(nother) child but decided to discontinue storage (25% of those with a child wish). Overall, these patients more often expressed emotional difficulties regarding this decision. CONCLUSIONS This study demonstrates the importance of gaining more insight into patients' embryo storage decisions (along with their embryo disposition decisions) and into the emotional factors playing a role in patients' decision-making. PMID- 21247923 TI - Discharge from hospice: dead or alive? PMID- 21247924 TI - What is palliative medicine? motivations and skills. AB - Palliative care began in the UK hospice movement in the late 1960s and has rapidly developed in many countries since. In some, it has become a fully recognized specialty with comprehensive training programs and recognized expertise in areas such as pain and symptom control. It is important to examine the formative influences and characteristic clinical expertise in palliative medicine. This article considers some of the conceptual, practical, and administrative challenges that have been faced in an effort to establish palliative medicine as a discrete field of specialized practice from a US perspective. We also comment on current issues in regard to education and research, and development of comprehensive palliative care programs in the United States. PMID- 21247925 TI - Happy or unhappy christmas? PMID- 21247926 TI - Attention to language in a request for physician aid in dying. PMID- 21247927 TI - Novel procedure- and device-based strategies in the management of systemic hypertension. AB - Despite the considerable advances in the treatment of hypertension that have been made over the past few decades, adequate management and control of this condition remains poor, and efforts are ongoing to develop new strategies to improve related outcomes. Novel therapeutic approaches to the management of systemic hypertension fall into two major categories: (i) those that seek to improve blood pressure-lowering efficacy using new therapeutic strategies in addition to standard non-pharmacological and pharmacological approaches and (ii) novel ways to optimize and improve the efficacy and utility of existing therapies. Novel procedure- and device-based strategies to control hypertension include renal sympathetic denervation and baroreflex sensitization. These two techniques will be the focus of the present review. PMID- 21247928 TI - Mutations in the mitochondrial thioredoxin reductase gene TXNRD2 cause dilated cardiomyopathy. AB - AIMS: Cardiac energy requirement is met to a large extent by oxidative phosphorylation in mitochondria that are highly abundant in cardiac myocytes. Human mitochondrial thioredoxin reductase (TXNRD2) is a selenocysteine-containing enzyme essential for mitochondrial oxygen radical scavenging. Cardiac-specific deletion of Txnrd2 in mice results in dilated cardiomyopathy (DCM). The aim of this study was to investigate whether TXNRD2 mutations explain a fraction of monogenic DCM cases. METHODS AND RESULTS: Sequencing and subsequent genotyping of TXNRD2 in patients diagnosed with DCM (n = 227) and in DCM-free (n = 683) individuals from the general population sample KORA S4 was performed. The functional impact of observed mutations on Txnrd2 function was tested in mouse fibroblasts. We identified two novel amino acid residue-altering TXNRD2 mutations [175G > A (Ala59Thr) and 1124G > A (Gly375Arg)] in three heterozygous carriers among 227 patients that were not observed in the 683 DCM-free individuals. Both DCM-associated mutations result in amino acid substitutions of highly conserved residues in helices contributing to the flavin-adenine dinucleotide (FAD)-binding domain of TXNRD2. Functional analysis of both mutations in Txnrd2(-/-) mouse fibroblasts revealed that contrasting to wild-type (wt) Txnrd2, neither mutant did restore Txnrd2 function. Mutants even impaired the survival of Txnrd2 wt cells under oxidative stress by a dominant-negative mechanism. CONCLUSION: For the first time, we describe mutations in DCM patients in a gene involved in the regulation of cellular redox state. TXNRD2 mutations may explain a fraction of human DCM disease burden. PMID- 21247929 TI - A genotypic and phenotypic information source for marker-assisted selection of cereals: the CEREALAB database. AB - The CEREALAB database aims to store genotypic and phenotypic data obtained by the CEREALAB project and to integrate them with already existing data sources in order to create a tool for plant breeders and geneticists. The database can help them in unravelling the genetics of economically important phenotypic traits; in identifying and choosing molecular markers associated to key traits; and in choosing the desired parentals for breeding programs. The database is divided into three sub-schemas corresponding to the species of interest: wheat, barley and rice; each sub-schema is then divided into two sub-ontologies, regarding genotypic and phenotypic data, respectively. Database URL: http://www.cerealab.unimore.it/jws/cerealab.jnlp. PMID- 21247930 TI - Cerebral extracellular chemistry and outcome following traumatic brain injury: a microdialysis study of 223 patients. AB - Secondary insults can adversely influence outcome following severe traumatic brain injury. Monitoring of cerebral extracellular chemistry with microdialysis has the potential for early detection of metabolic derangements associated with such events. The objective of this study was to determine the relationship between the fundamental biochemical markers and neurological outcome in a large cohort of patients with traumatic brain injury. Prospectively collected observational neuromonitoring data from 223 patients were analysed. Monitoring modalities included digitally recorded intracranial pressure, cerebral perfusion pressure, cerebrovascular pressure reactivity index and microdialysis markers glucose, lactate, pyruvate, glutamate, glycerol and the lactate/pyruvate ratio. Outcome was assessed using the Glasgow Outcome Scale at 6 months post-injury. Patient-averaged values of parameters were used in statistical analysis, which included univariate non-parametric methods and multivariate logistic regression. Monitoring with microdialysis commenced on median (interquartile range) Day 1 (1 2) from injury and median (interquartile range) duration of monitoring was 4 (2 7) days. Averaged over the total monitoring period levels of glutamate (P = 0.048), lactate/pyruvate ratio (P = 0.044), intracranial pressure (P = 0.006) and cerebrovascular pressure reactivity index (P = 0.01) were significantly higher in patients who died. During the initial 72 h of monitoring, median glycerol levels were also higher in the mortality group (P = 0.014) and median lactate/pyruvate ratio (P = 0.026) and lactate (P = 0.033) levels were significantly lower in patients with favourable outcome. In a multivariate logistic regression model (P < 0.0001), which employed data averaged over the whole monitoring period, significant independent positive predictors of mortality were glucose (P = 0.024), lactate/pyruvate ratio (P = 0.016), intracranial pressure (P = 0.029), cerebrovascular pressure reactivity index (P = 0.036) and age (P = 0.003), while pyruvate was a significant independent negative predictor of mortality (P = 0.004). The results of this study suggest that extracellular metabolic markers are independently associated with outcome following traumatic brain injury. Whether treatment-related improvement in biochemistry translates into better outcome remains to be established. PMID- 21247931 TI - Pathogenesis of the immune reconstitution inflammatory syndrome affecting the central nervous system in patients infected with HIV. AB - Anti-retroviral therapy partially restores the immune function of patients infected with human immunodeficiency virus, thereby drastically reducing morbidity and mortality. However, the clinical condition of a subset of patients on anti-retroviral therapy secondarily deteriorates due to an inflammatory process termed immune reconstitution inflammatory syndrome. This condition results from the restoration of the immune system that upon activation can be detrimental to the host. Among the various clinical manifestations, central nervous system involvement is associated with greater morbidity and mortality. This review covers the pathogenesis of this novel neuroinflammatory disease, including the nature of the provoking pathogens and the composition and specificity of the evoked immune responses. Our current perception of this neuroinflammatory disease supports therapeutic strategies aimed at modulating immune aggression without dampening the life-saving restoration of the immune response. PMID- 21247932 TI - SCAN heads to kindergarten. PMID- 21247933 TI - Modelling of intercellular induction of apoptosis in oncogenic transformed cells and radiation effects on the phenomenon. AB - The removal of transformed cells via induction of apoptosis through intercellular signalling by surrounding cells is supposed to represent an important control mechanism limiting carcinogenesis. Low doses of radiation influence the efficiency of this anti-carcinogenesis process, indicating possible beneficial effects of low doses of radiation mediated by intercellular communication ('non targeted effects'). To quantitatively understand the signalling system involved and the effects of radiation and to assess the role of this phenomenon in radiation-induced carcinogenesis, multi-scale modelling studies have been started. The proposed kinetic model takes into account (i) triggering of the effector function in cells in the vicinity of transformed cells, (ii) intercellular signalling between effector and transformed cells and (iii) execution of apoptosis in attacked cells. The systems model without radiation perturbance is reviewed. First results accounting for radiation-induced modulations of the signalling schemes are presented. PMID- 21247934 TI - Helix 8 of the M1 muscarinic acetylcholine receptor: scanning mutagenesis delineates a G protein recognition site. AB - We have used alanine-scanning mutagenesis followed by functional expression and molecular modeling to analyze the roles of the 14 residues, Asn422 to Cys435, C terminal to transmembrane (TM) helix 7 of the M(1) muscarinic acetylcholine receptor. The results suggest that they form an eighth (H8) helix, associated with the cytoplasmic surface of the cell membrane in the active state of the receptor. We suggest that the amide side chain of Asn422 may act as a cap to the C terminus of TM7, stabilizing its junction with H8, whereas the side chain of Phe429 may restrict the relative movements of H8 and the C terminus of TM7 in the inactive ground state of the receptor. We have identified four residues, Phe425, Arg426, Thr428, and Leu432, which are important for G protein binding and signaling. These may form a docking site for the C-terminal helix of the G protein alpha subunit, and collaborate with G protein recognition residues elsewhere in the cytoplasmic domain of the receptor to form a coherent surface for G protein binding in the activated state of the receptor. PMID- 21247935 TI - Coupling to polymeric scaffolds stabilizes biofunctional peptides for intracellular applications. AB - Here, we demonstrate that coupling to N-hydroxypropyl methacrylamide (HPMA) copolymer greatly enhances the activity of apoptosis-inducing peptides inside cells. Peptides corresponding to the BH3 domain of Bid were coupled to a thioester-activated HPMA (28.5 kDa) via native chemical ligation in a simple one pot synthesis. Peptides and polymer conjugates were introduced into cells either by electroporation or by conjugation to the cell-penetrating peptide nona arginine. The molecular basis of the increased activity is elucidated in detail. Loading efficiency and intracellular residence time were assessed by confocal microscopy. Fluorescence correlation spectroscopy was used as a separation-free analytical technique to determine proteolytic degradation in crude cell lysates. HPMA conjugation strongly increased the half-life of the peptides in crude cell lysates and inside cells, revealing proteolytic protection as the basis for higher activity. PMID- 21247936 TI - Meniscectomy as a risk factor for knee osteoarthritis: a systematic review. AB - INTRODUCTION: This review defines the recognized risk factors responsible for the development of knee osteoarthritis after surgical management of meniscal tears. SOURCES OF DATA: We performed a literature search using Medline, Ovid, Cochrane and Google Scholar using the keywords: 'Meniscal tears', 'meniscectomy', 'osteoarthritis', 'complications' and 'risk factors'. Thirty-two published studies were identified. AREAS OF AGREEMENT: In the long term, osteoarthritis develops in the knee of patients undergoing surgery for meniscal tears. The Coleman methodology score showed great heterogeneity in terms of patient characteristics and outcome assessment. Amount of meniscus removed, duration of pre-operative symptoms and lateral meniscectomy show strong statistical association to onset of knee osteoarthritis. AREAS OF CONTROVERSY: We did not find univocal findings defining the risk factors responsible for the development of post-operative knee osteoarthritis. GROWING POINTS: There is a need for standardized clinical and imaging validated scale to improve definition of post operative knee osteoarthritis to allow easier and more reliable comparison of outcomes in different studies. AREAS TIMELY FOR DEVELOPING RESEARCH: Appropriately powered randomized controlled trials reporting clinical and imaging related outcomes in patients undergoing arthroscopic minimally invasive procedures and meniscal suturing should be performed. Comparing imaging findings of patients undergoing arthroscopic partial and open meniscectomy, a lower incidence of knee osteoarthritic evolution was detected after arthroscopy. The amount of removed meniscus is the most important predictor factor for the development of osteoarthritis. Minimally invasive procedures seem to reduce the incidence of long-term osteoarthritic changes of the knee compared with more invasive open and or arthroscopic procedures. PMID- 21247937 TI - Genome-wide association studies for detecting cancer susceptibility. AB - Genome-wide association (GWA) studies search for genetic variants, across the entire genome, which display differences in frequencies between cases and controls. Studies in PubMed using the keywords 'genomewide association' and 'cancer' are reported together with selected literature. Since 2007, GWA studies have successfully yielded risk loci for most common cancers. Findings have provided insights into the biological basis of cancer susceptibility implicating previously unsuspected genes in tumourogenesis. The variants identified typically account for only a small proportion of the familial risk of cancer and thus their application for individual risk prediction is poor. Furthermore, the genotyped variants are unlikely to be directly causal and identifying the causal basis is a major challenge. Methodological developments are desirable to fully utilize existing data sets and to enable more complex models of inherited predisposition to be investigated. Annotation of low frequency variation coupled with next generation sequencing is making the search for rare disease-causing variants a realistic prospect. PMID- 21247938 TI - Efficient simulation under a population genetics model of carcinogenesis. AB - MOTIVATION: Cancer is well known to be the end result of somatic mutations that disrupt normal cell division. The number of such mutations that have to be accumulated in a cell before cancer develops depends on the type of cancer. The waiting time T(m) until the appearance of m mutations in a cell is thus an important quantity in population genetics models of carcinogenesis. Such models are often difficult to analyze theoretically because of the complex interactions of mutation, drift and selection. They are also computationally expensive to simulate because of the large number of cells and the low mutation rate. RESULTS: We develop an efficient algorithm for simulating the waiting time T(m) until m mutations under a population genetics model of cancer development. We use an exact algorithm to simulate evolution of small cell populations and coarse grained tau-leaping approximation to handle large populations. We compared our hybrid simulation algorithm with the exact algorithm in small populations and with available asymptotic results for large populations. The comparison suggested that our algorithm is accurate and computationally efficient. We used the algorithm to study the waiting time for up to 20 mutations under a Moran model with variable population sizes. Our new algorithm may be useful for studying realistic models of carcinogenesis, which incorporates variable mutation rates and fitness effects. PMID- 21247939 TI - Condition- and parasite-dependent expression of a male-like trait in a female bird. AB - In many species, females display brightly coloured and elaborate traits similar to those that males use in intra- and inter-sexual selection processes. These female characters are sometimes related to fitness, and might function as secondary sexual characteristics that have evolved through sexual selection. Here, we used descriptive data from 674 females in 10 populations and an experimental removal of Trichostrongylus tenuis parasites in four populations, to examine the effects of season, age, condition, and parasites on the size of supra orbital combs displayed by female red grouse Lagopus lagopus scoticus. We found that comb size (i) was greater during the breeding than the non-breeding season, (ii) was greater in adult than in young females, (iii) was positively correlated with body condition, and (iv) negatively correlated with parasite abundance. Experimentally, we showed that comb size increased proportionally to the number of worms removed after parasite dosing. Our findings provide a better understanding of proximate mechanisms behind the expression of a male-like trait in females, and we discuss its possible function as a female ornament. PMID- 21247940 TI - Flexing the abdominals: do bigger muscles make better fighters? AB - Animal contests often involve the use of repeated signals, which are assumed to advertise stamina, and hence fighting ability. While an individual may be predicted to give up once it has crossed an energetic threshold, costs inflicted by its opponent may also contribute to the giving-up decision. Therefore, physical strength should be of key importance in contests, allowing high signal magnitude as well as potentially inflicting costs. We investigated this using hermit crab shell fights, which employ a 'hybrid signal' of shell rapping, which advertises stamina but also imposes potentially deleterious consequences for the receiver. We examined the links between contest outcomes and two proxies for strength; the protein content and relative mass of hermit crab abdominal muscles, the main muscle group used in shell rapping. Our results indicate that there was no difference in muscle protein between winners and losers, whereas winners had significantly greater muscle mass : body mass ratios. Thus, while stamina has been assumed by theory to be an important determinant of agonistic success, the present results demonstrate the importance of muscle size and thereby strength. PMID- 21247941 TI - Aphid-parasitoid community structure on genetically modified wheat. AB - Since the introduction of genetically modified (GM) plants, one of the main concerns has been their potential effect on non-target insects. Many studies have looked at GM plant effects on single non-target herbivore species or on simple herbivore-natural enemy food chains. Agro-ecosystems, however, are characterized by numerous insect species which are involved in complex interactions, forming food webs. In this study, we looked at transgenic disease-resistant wheat (Triticum aestivum) and its effect on aphid-parasitoid food webs. We hypothesized that the GM of the wheat lines directly or indirectly affect aphids and that these effects cascade up to change the structure of the associated food webs. Over 2 years, we studied different experimental wheat lines under semi-field conditions. We constructed quantitative food webs to compare their properties on GM lines with the properties on corresponding non-transgenic controls. We found significant effects of the different wheat lines on insect community structure up to the fourth trophic level. However, the observed effects were inconsistent between study years and the variation between wheat varieties was as big as between GM plants and their controls. This suggests that the impact of our powdery mildew-resistant GM wheat plants on food web structure may be negligible and potential ecological effects on non-target insects limited. PMID- 21247942 TI - Oxidative damage to DNA related to survivorship and carotenoid-based sexual ornamentation in the common yellowthroat. AB - Carotenoid-based sexual ornaments are hypothesized to be reliable signals of male quality, based on an allocation trade-off between the use of carotenoids as pigments and their use in antioxidant defence against reactive oxygen species. Carotenoids appear to be poor antioxidants in vivo, however, and it is not clear whether variation in ornament expression is correlated with measures of oxidative stress (OXS) under natural conditions. We used single-cell gel electrophoresis to assay oxidative damage to erythrocyte DNA in the common yellowthroat (Geothlypis trichas), a sexually dichromatic warbler in which sexual selection favours components of the males' yellow 'bib'. We found that the level of DNA damage sustained by males predicted their overwinter survivorship and was reflected in the quality of their plumage. Males with brighter yellow bibs showed lower levels of DNA damage, both during the year the plumage was sampled (such that yellow brightness signalled current OXS) and during the previous year (such that yellow brightness signalled past OXS). We suggest that carotenoid-based ornaments can convey information about OXS to prospective mates and that further work exploring the proximate mechanism(s) linking OXS to coloration is warranted. PMID- 21247943 TI - Patterns of variability in early-life traits of fishes depend on spatial scale of analysis. AB - Estimates of early-life traits of fishes (e.g. pelagic larval duration (PLD) and spawning date) are essential for investigating and assessing patterns of population connectivity. Such estimates are available for a large number of both tropical and temperate fish species, but few studies have assessed their variability in space, especially across multiple scales. The present study, where a Mediterranean fish (i.e. the white seabream Diplodus sargus sargus) was used as a model, shows that spawning date and PLD are spatially more variable at a scale of kilometres than at a scale of tens to hundreds of kilometres. This study indicates the importance of considering spatial variability of early-life traits of fishes in order to properly delineate connectivity patterns at larval stages (e.g. by means of Lagrangian simulations), thus providing strategically useful information on connectivity and relevant management goals (e.g. the creation of networks of marine reserves). PMID- 21247944 TI - Structural purity of magnetite nanoparticles in magnetotactic bacteria. AB - Magnetosome biomineralization and chain formation in magnetotactic bacteria are two processes that are highly controlled at the cellular level in order to form cellular magnetic dipoles. However, even if the magnetosome chains are well characterized, controversial results about the microstructure of magnetosomes were obtained and its possible influence in the formation of the magnetic dipole is to be specified. For the first time, the microstructure of intracellular magnetosomes was investigated using high-resolution synchrotron X-ray diffraction. Significant differences in the lattice parameter were found between intracellular magnetosomes from cultured magnetotactic bacteria and isolated ones. Through comparison with abiotic control materials of similar size, we show that this difference can be associated with different oxidation states and that the biogenic nanomagnetite is stoichiometric, i.e. structurally pure whereas isolated magnetosomes are slightly oxidized. The hierarchical structuring of the magnetosome chain thus starts with the formation of structurally pure magnetite nanoparticles that in turn might influence the magnetic property of the magnetosome chains. PMID- 21247945 TI - Determination of surface-induced platelet activation by applying time-dependency dissipation factor versus frequency using quartz crystal microbalance with dissipation. AB - Platelet adhesion and activation rates are frequently used to assess the thrombogenicity of biomaterials, which is a crucial step for the development of blood-contacting devices. Until now, electron and confocal microscopes have been used to investigate platelet activation but they failed to characterize this activation quantitatively and in real time. In order to overcome these limitations, quartz crystal microbalance with dissipation (QCM-D) was employed and an explicit time scale introduced in the dissipation versus frequency plots (Df-t) provided us with quantitative data at different stages of platelet activation. The QCM-D chips were coated with thrombogenic and non-thrombogenic model proteins to develop the methodology, further extended to investigate polymer thrombogenicity. Electron microscopy and immunofluorescence labelling were used to validate the QCM-D data and confirmed the relevance of Df-t plots to discriminate the activation rate among protein-modified surfaces. The responses showed the predominant role of surface hydrophobicity and roughness towards platelet activation and thereby towards polymer thrombogenicity. Modelling experimental data obtained with QCM-D with a Matlab code allowed us to define the rate at which mass change occurs (A/B), to obtain an A/B value for each polymer and correlate this value with polymer thrombogenicity. PMID- 21247946 TI - Collagen gel three-dimensional matrices combined with adhesive proteins stimulate neuronal differentiation of mesenchymal stem cells. AB - Three-dimensional gel matrices provide specialized microenvironments that mimic native tissues and enable stem cells to grow and differentiate into specific cell types. Here, we show that collagen three-dimensional gel matrices prepared in combination with adhesive proteins, such as fibronectin (FN) and laminin (LN), provide significant cues to the differentiation into neuronal lineage of mesenchymal stem cells (MSCs) derived from rat bone marrow. When cultured within either a three-dimensional collagen gel alone or one containing either FN or LN, and free of nerve growth factor (NGF), the MSCs showed the development of numerous neurite outgrowths. These were, however, not readily observed in two dimensional culture without the use of NGF. Immunofluorescence staining, western blot and fluorescence-activated cell sorting analyses demonstrated that a large population of cells was positive for NeuN and glial fibrillary acidic protein, which are specific to neuronal cells, when cultured in the three-dimensional collagen gel. The dependence of the neuronal differentiation of MSCs on the adhesive proteins containing three-dimensional gel matrices is considered to be closely related to focal adhesion kinase (FAK) activation through integrin receptor binding, as revealed by an experiment showing no neuronal outgrowth in the FAK-knockdown cells and stimulation of integrin beta1 gene. The results provided herein suggest the potential role of three-dimensional collagen-based gel matrices combined with adhesive proteins in the neuronal differentiation of MSCs, even without the use of chemical differentiation factors. Furthermore, these findings suggest that three-dimensional gel matrices might be useful as nerve-regenerative scaffolds. PMID- 21247947 TI - Dual-phase evolution in complex adaptive systems. AB - Understanding the origins of complexity is a key challenge in many sciences. Although networks are known to underlie most systems, showing how they contribute to well-known phenomena remains an issue. Here, we show that recurrent phase transitions in network connectivity underlie emergent phenomena in many systems. We identify properties that are typical of systems in different connectivity phases, as well as characteristics commonly associated with the phase transitions. We synthesize these common features into a common framework, which we term dual-phase evolution (DPE). Using this framework, we review the literature from several disciplines to show that recurrent connectivity phase transitions underlie the complex properties of many biological, physical and human systems. We argue that the DPE framework helps to explain many complex phenomena, including perpetual novelty, modularity, scale-free networks and criticality. Our review concludes with a discussion of the way DPE relates to other frameworks, in particular, self-organized criticality and the adaptive cycle. PMID- 21247948 TI - Nanometric depth resolution from multi-focal images in microscopy. AB - We describe a method for tracking the position of small features in three dimensions from images recorded on a standard microscope with an inexpensive attachment between the microscope and the camera. The depth-measurement accuracy of this method is tested experimentally on a wide-field, inverted microscope and is shown to give approximately 8 nm depth resolution, over a specimen depth of approximately 6 um, when using a 12-bit charge-coupled device (CCD) camera and very bright but unresolved particles. To assess low-flux limitations a theoretical model is used to derive an analytical expression for the minimum variance bound. The approximations used in the analytical treatment are tested using numerical simulations. It is concluded that approximately 14 nm depth resolution is achievable with flux levels available when tracking fluorescent sources in three dimensions in live-cell biology and that the method is suitable for three-dimensional photo-activated localization microscopy resolution. Sub nanometre resolution could be achieved with photon-counting techniques at high flux levels. PMID- 21247949 TI - Modelling the initial phase of an epidemic using incidence and infection network data: 2009 H1N1 pandemic in Israel as a case study. AB - This paper presents new computational and modelling tools for studying the dynamics of an epidemic in its initial stages that use both available incidence time series and data describing the population's infection network structure. The work is motivated by data collected at the beginning of the H1N1 pandemic outbreak in Israel in the summer of 2009. We formulated a new discrete-time stochastic epidemic SIR (susceptible-infected-recovered) model that explicitly takes into account the disease's specific generation-time distribution and the intrinsic demographic stochasticity inherent to the infection process. Moreover, in contrast with many other modelling approaches, the model allows direct analytical derivation of estimates for the effective reproductive number (R(e)) and of their credible intervals, by maximum likelihood and Bayesian methods. The basic model can be extended to include age-class structure, and a maximum likelihood methodology allows us to estimate the model's next-generation matrix by combining two types of data: (i) the incidence series of each age group, and (ii) infection network data that provide partial information of 'who-infected who'. Unlike other approaches for estimating the next-generation matrix, the method developed here does not require making a priori assumptions about the structure of the next-generation matrix. We show, using a simulation study, that even a relatively small amount of information about the infection network greatly improves the accuracy of estimation of the next-generation matrix. The method is applied in practice to estimate the next-generation matrix from the Israeli H1N1 pandemic data. The tools developed here should be of practical importance for future investigations of epidemics during their initial stages. However, they require the availability of data which represent a random sample of the real epidemic process. We discuss the conditions under which reporting rates may or may not influence our estimated quantities and the effects of bias. PMID- 21247950 TI - Multiplexed protein analysis using encoded antibody-conjugated microbeads. AB - We describe a method for multiplexed analysis of proteins using fluorescently encoded microbeads. The sensitivity of our method is comparable to the sensitivity obtained by enzyme-linked immunosorbent assay while only 5 ul sample volumes are needed. Streptavidin-coated, 1 um beads are encoded with a combination of fluorophores at different intensity levels. As a proof of concept, we demonstrate that 27 microbead populations can be readily encoded by affinity conjugation using three intensity levels for each of three different biotinylated fluorescent dyes. Four populations of encoded microbeads are further conjugated with biotinylated capture antibodies and then combined and immobilized in a microfluidic flow cell for multiplexed protein analysis. Using four uniquely encoded microbead populations, we show that a cancer biomarker and three cytokine proteins can be analysed quantitatively in the picogram per millilitre range by fluorescence microscopy in a single assay. Our method will allow for the fabrication of high density, bead-based antibody arrays for multiplexed protein analysis using integrated microfluidic devices and automated sample processing. PMID- 21247951 TI - Antibacterial burst-release from minimal Ag-containing plasma polymer coatings. AB - Biomaterials releasing silver (Ag) are of interest because of their ability to inhibit pathogenic bacteria including antibiotic-resistant strains. In order to investigate the potential of nanometre-thick Ag polymer (Ag/amino-hydrocarbon) nanocomposite plasma coatings, we studied a comprehensive range of factors such as the plasma deposition process and Ag cation release as well as the antibacterial and cytocompatible properties. The nanocomposite coatings released most bound Ag within the first day of immersion in water yielding an antibacterial burst. The release kinetics correlated with the inhibitory effects on the pathogens Pseudomonas aeruginosa or Staphylococcus aureus and on animal cells that were in contact with these coatings. We identified a unique range of Ag content that provided an effective antibacterial peak release, followed by cytocompatible conditions soon thereafter. The control of the in situ growth conditions for Ag nanoparticles in the polymer matrix offers the possibility to produce customized coatings that initially release sufficient quantities of Ag ions to produce a strong adjacent antibacterial effect, and at the same time exhibit a rapidly decaying Ag content to provide surface cytocompatibility within hours/days. This approach seems to be favourable with respect to implant surfaces and possible Ag-resistance/tolerance built-up. PMID- 21247952 TI - Probing neural circuitry and function with electrical microstimulation. AB - Since the discovery of the nervous system's electrical excitability more than 200 years ago, neuroscientists have used electrical stimulation to manipulate brain activity in order to study its function. Microstimulation has been a valuable technique for probing neural circuitry and identifying networks of neurons that underlie perception, movement and cognition. In this review, we focus on the use of stimulation in behaving primates, an experimental system that permits causal inferences to be made about the effect of stimulation-induced activity on the resulting behaviour or neural signals elsewhere in the brain. PMID- 21247954 TI - Bayesian phylogeography of the Arawak expansion in lowland South America. AB - Phylogenetic inference based on language is a vital tool for tracing the dynamics of human population expansions. The timescale of agriculture-based expansions around the world provides an informative amount of linguistic change ideal for reconstructing phylogeographies. Here we investigate the expansion of Arawak, one of the most widely dispersed language families in the Americas, scattered from the Antilles to Argentina. It has been suggested that Northwest Amazonia is the Arawak homeland based on the large number of diverse languages in the region. We generate language trees by coding cognates of basic vocabulary words for 60 Arawak languages and dialects to estimate the phylogenetic relationships among Arawak societies, while simultaneously implementing a relaxed random walk model to infer phylogeographic history. Estimates of the Arawak homeland exclude Northwest Amazonia and are bi-modal, with one potential homeland on the Atlantic seaboard and another more likely origin in Western Amazonia. Bayesian phylogeography better supports a Western Amazonian origin, and consequent dispersal to the Caribbean and across the lowlands. Importantly, the Arawak expansion carried with it not only language but also a number of cultural traits that contrast Arawak societies with other lowland cultures. PMID- 21247953 TI - Hormone levels predict individual differences in reproductive success in a passerine bird. AB - Hormones mediate major physiological and behavioural components of the reproductive phenotype of individuals. To understand basic evolutionary processes in the hormonal regulation of reproductive traits, we need to know whether, and during which reproductive phases, individual variation in hormone concentrations relates to fitness in natural populations. We related circulating concentrations of prolactin and corticosterone to parental behaviour and reproductive success during both the pre-breeding and the chick-rearing stages in both individuals of pairs of free-living house sparrows, Passer domesticus. Prolactin and baseline corticosterone concentrations in pre-breeding females, and prolactin concentrations in pre-breeding males, predicted total number of fledglings. When the strong effect of lay date on total fledgling number was corrected for, only pre-breeding baseline corticosterone, but not prolactin, was negatively correlated with the reproductive success of females. During the breeding season, nestling provisioning rates of both sexes were negatively correlated with stress induced corticosterone levels. Lastly, individuals of both sexes with low baseline corticosterone before and high baseline corticosterone during breeding raised the most offspring, suggesting that either the plasticity of this trait contributes to reproductive success or that high parental effort leads to increased hormone concentrations. Thus hormone concentrations both before and during breeding, as well as their seasonal dynamics, predict reproductive success, suggesting that individual variation in absolute concentrations and in plasticity is functionally significant, and, if heritable, may be a target of selection. PMID- 21247955 TI - Genetic differentiation and the evolution of cooperation in chimpanzees and humans. AB - It has been proposed that human cooperation is unique among animals for its scale and complexity, its altruistic nature and its occurrence among large groups of individuals that are not closely related or are even strangers. One potential solution to this puzzle is that the unique aspects of human cooperation evolved as a result of high levels of lethal competition (i.e. warfare) between genetically differentiated groups. Although between-group migration would seem to make this scenario unlikely, the plausibility of the between-group competition model has recently been supported by analyses using estimates of genetic differentiation derived from contemporary human groups hypothesized to be representative of those that existed during the time period when human cooperation evolved. Here, we examine levels of between-group genetic differentiation in a large sample of contemporary human groups selected to overcome some of the problems with earlier estimates, and compare them with those of chimpanzees. We find that our estimates of between-group genetic differentiation in contemporary humans are lower than those used in previous tests, and not higher than those of chimpanzees. Because levels of between-group competition in contemporary humans and chimpanzees are also similar, these findings suggest that the identification of other factors that differ between chimpanzees and humans may be needed to provide a compelling explanation of why humans, but not chimpanzees, display the unique features of human cooperation. PMID- 21247956 TI - Variability in selecting patients to manage in the community: a service evaluation of community matron's case-finding strategies. AB - BACKGROUND: Community-based case management of high-frequency health service users, also termed 'high-intensity users' may reduce the demand on secondary care. In the UK, experienced senior nurses 'community matrons' have been appointed to provide more care in the community and to case manage high-intensity users and prevent unnecessary hospital admission. Computerized scoring systems have been developed to help with case finding. OBJECTIVE: To evaluate how community matrons select their caseload, in particular the impact of a case finding tool, and access to computer-based systems. METHODS: We used direct observation and the think aloud protocol during case selection and a series of workshops. Analysis was based on the Framework Approach (familiarization, coding, charting, mapping and interpretation) using verbatim transcripts analysed by N Vivo software. RESULTS: Community matrons within the same locality have different and sub-optimal caseloads. Although common elements exist in case selection, processes are modified by individuals depending on the influence of their interpersonal relationships, accessibility of computer systems and personal experience and expertise. The supporting IT system often produced data too late and while predicting admission did not identify cases amenable to community intervention. CONCLUSIONS: Inter-professional networks, personal experience and training influence the patients identified for case management. The combination of an improved case finding tool and a better defined role for community matrons could lead to more standardized and equitable case selection. PMID- 21247957 TI - Symptom attribution and presentation in general practice after an extreme life event. AB - BACKGROUND: A serious life event is likely to shape attributions relating to symptoms experienced afterwards. While they may play an important role in prognosis and seeking care, such perceptions have hardly been studied among survivors of a disaster. OBJECTIVE: To investigate the association between self reported health problems that have been attributed to an extreme life event and the symptoms presented to GPs. METHODS: A two-wave longitudinal survey (2-3 weeks and 18 months) among survivors of a fireworks disaster was combined with a continuous morbidity surveillance in general practice. Symptoms attributed to the disaster reported in an open-ended question in the two waves were analysed using descriptive statistics. Differences in presented symptoms over time were analysed using logistic multilevel analysis. RESULTS: More than half of the respondents reported health problems, which were, in their opinion, related to the disaster. Psychological problems were most frequently reported in association with the disaster, and in contrast to physical attributed symptoms, presentation of these problems in general practice decreased over time. In the total sample, musculoskeletal symptoms were less frequently presented in the longer term. Survivors who attributed symptoms to the disaster at both waves or after 18 months only most often presented such symptoms to the GP. CONCLUSION: Survivors attributed psychological problems and physical symptoms to the disaster at short term and midterm post-disaster. Most of these survivors presented such symptoms to the GP. Attribution of symptoms to an extreme life event such as a disaster may therefore require special attention from the GP. PMID- 21247958 TI - Time to care: tackling health inequalities through primary care. PMID- 21247959 TI - Laparoscopic revisional hepaticojejunostomy for biliary stricture after open repair following common bile duct injury: a case report. AB - INTRODUCTION: Incidence of bile duct injury has been reported more frequently following laparoscopic cholecystectomy. CASE REPORT: A 43-year-old female with a past medical history of laparoscopic cholecystectomy that was converted to open because of a common bile duct injury now presents with a stenosis at the hepaticojejunostomy that is causing recurrent cholangitis episodes. After the lysis of adhesions and dissection of the anastomotic area, a stricture was identified. The authors exposed and redid the hepaticojejunostomy with 4-0 Monocryl sutures without tension. The follow-up period was unremarkable. No leaks were documented, and the patient was discharged home on postoperative day 3. CONCLUSION: After percutaneous or endoscopic procedure failure for the treatment of hepaticojejunostomy strictures, the laparoscopic redo anastomosis is safe and feasible when performed by surgeons who are strongly trained in advanced laparoscopic surgery. PMID- 21247960 TI - V-Loc, a new wound closure device for peritoneal closure--is it safe? A comparative study of different peritoneal closure systems. AB - BACKGROUND: Transabdominal laparoscopic hernia repair is a safe and commonly used procedure for groin hernias. Failure of peritoneal closure is rare but can lead to herniation and bowel obstruction. A new wound closure device named V-Loc was tested in this study. It consists of a barbed absorbable thread that is self anchoring and eliminates the need to tie a knot. The efficacy of this device in achieving secure peritoneal closure was investigated. METHODS: In 10 recently deceased patients, peritoneal incisions were set and closed with 5 different devices including V-Loc. Peritoneal thickness was measured prior to testing. A tensiometer was used to apply tensile loads on the peritoneal closure. Tensile loads were measured in Newton at the time of peritoneal rupture or failure of the suture or knot. RESULTS: Peritoneal thickness had a significant impact on the results (P < .0001). A mean tensile load of 7.41 N was tolerated when the peritoneal thickness was <=0.25 mm and 15.38 N when the peritoneal thickness was >0.25 mm. Peritoneal rupture was observed more often than failure of closure. The latter occurred more often at high tension and in experiments with tacking or stapling devices than with sutures. While testing V-Loc, peritoneal rupture occurred at 19.85 N, mean, showing significantly better results than AbsorbaTack, extracorporally knotted running suture, or Multifire Endo Hernia Stapler (P < .05). CONCLUSIONS: The new wound closure device V-Loc is a feasible and promising alternative to common peritoneal closure techniques but is yet to be evaluated in clinical studies. PMID- 21247961 TI - Role of chemoembolization as a rescue treatment for recurrence of resected hepatoblastoma in adult patients. AB - INTRODUCTION: Hepatoblastoma is the most common malignant liver tumor in children, but it is extremely rare in adults. MATERIALS AND METHODS: A 33-year old man was admitted with nausea, vomiting, weight loss, and right upper quadrant pain. A preoperative magnetic resonance imaging showed a nodular hepatic lesion infiltrating the lesser curvature of the stomach. A left hepatectomy and a subtotal gastrectomy were performed. The histological diagnosis was hepatoblastoma. A recurrence in the right lobe was seen. RESULTS: Three cycles of transcatheter arterial chemoembolization (TACE) were performed 40, 70, and 130 days after surgery. No sign of recurrence was present at the time of the second chemoembolization. CONCLUSION: The TACE was well tolerated by the patient and controlled the recurrence. The patient survived 11 months after recurrence of disease and died 1 year after the liver resection. The use of TACE to treat the hepatic recurrence was never described. PMID- 21247962 TI - Congenital bleeding disorders in Karachi, Pakistan. AB - OBJECTIVE: To determine the frequency of inherited bleeding disorders, its complications, and treatment modalities available for its treatment. DESIGN: Cross-sectional study. PATIENTS AND METHODS: Patients with a history of bleeding tendency were tested for confirmation of the diagnosis. History and clinical findings were recorded. Laboratory analysis included prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time (BT), and fibrinogen assay. Patients with prolonged APTT were tested for factors VIII (FVIII) and IX (FIX). If FVIII was low, von Willebrand factor: antigen (vWF:Ag) and von Willebrand factor:ristocetin cofactor (vWF:RCo) were performed. When PT and APTT both were prolonged, FV, FX, and FII were tested. Platelet aggregation studies were done when there was isolated prolonged BT. Urea clot solubility test was done when all coagulation tests were normal. All patients with hemophilia A and B were evaluated for inhibitors. RESULTS: Of the 376 patients, inherited bleeding disorder was diagnosed in 318 (85%) cases. Median age of patients was 16.4 years. Hemophilia A was the commonest inherited bleeding disorder that was observed in 140 (37.2%) followed by vWD 68 (18.0%), platelet function disorders 48 (12.8%), and hemophilia B in 33 (8.8%) cases. We also found rare congenital factor deficiencies in 13 (3.4%), low VWF in 11 (3.0%) participants and 5 (1.3%) in female hemophilia carriers. Hemarthrosis was the most frequent symptom in hemophilia A and B (79.7%) involving knee joint. Inhibitor was detected in 21 (15%) cases. Fresh frozen plasma/cryoprecipitate were the most common modality of treatment. In 58 patients, no abnormality was detected in coagulation profile. CONCLUSION: Hemophilia A and vWD are the most common congenital bleeding disorders in this study. Hemarthrosis involving knee joint was the most common complication. Inhibitor was detected in a significant number of patients. Plasma is still the most common modality of treatment. PMID- 21247963 TI - Minor change, major difference: divergent functions of highly conserved cis regulatory elements subsequent to whole genome duplication events. AB - Within the vertebrate lineage, a high proportion of duplicate genes have been retained after whole genome duplication (WGD) events. It has been proposed that many of these duplicate genes became indispensable because the ancestral gene function was divided between them. In addition, novel functions may have evolved, owing to changes in cis-regulatory elements. Functional analysis of the PAX2/5/8 gene subfamily appears to support at least the first part of this hypothesis. The collective role of these genes has been widely retained, but sub-functions have been differentially partitioned between the genes in different vertebrates. Conserved non-coding elements (CNEs) represent an interesting and readily identifiable class of putative cis-regulatory elements that have been conserved from fish to mammals, an evolutionary distance of 450 million years. Within the PAX2/5/8 gene subfamily, PAX2 is associated with the highest number of CNEs. An additional WGD experienced in the teleost lineage led to two copies of pax2, each of which retained a large proportion of these CNEs. Using a reporter gene assay in zebrafish embryos, we have exploited this rich collection of regulatory elements in order to determine whether duplicate CNEs have evolved different functions. Remarkably, we find that even highly conserved sequences exhibit more functional differences than similarities. We also discover that short flanking sequences can have a profound impact on CNE function. Therefore, if CNEs are to be used as candidate enhancers for transgenic studies or for multi-species comparative analyses, it is paramount that the CNEs are accurately delineated. PMID- 21247964 TI - Lack of the ventral anterior homeodomain transcription factor VAX1 leads to induction of a second pituitary. AB - The pituitary gland is an endocrine organ that is developmentally derived from a fold in the oral ectoderm and a juxtaposed fold in the neural ectoderm. Here, we show that the absence of Vax1, a homeodomain transcription factor known for its role in eye and optic chiasm development, causes the rostral oral ectoderm to form an ectopic fold that eventually develops into a separate second pituitary with all the pituitary cell types and neuronal fibers characteristic of the normal pituitary. The induction of the second pituitary is associated with a localized ectopic expression of Fgf10, a gene encoding a growth factor known to recruit oral ectodermal cells into the pituitary. Interestingly, there are rare cases of pituitary duplications in humans that are also associated with optic nerve dysplasia, suggesting that VAX1 might be involved in the pathogenesis of this disorder. PMID- 21247965 TI - Dynamic stage-specific changes in imprinted differentially methylated regions during early mammalian development and prevalence of non-CpG methylation in oocytes. AB - Mammalian imprinted genes are associated with differentially methylated regions (DMRs) that are CpG methylated on one of the two parental chromosomes. In mice, at least 21 DMRs acquire differential methylation in the germline and many of them act as imprint centres. We previously reported the physical extents of differential methylation at 15 DMRs in mouse embryos at 12.5 days postcoitum. To reveal the ontogeny of differential methylation, we determined and compared methylation patterns of the corresponding regions in sperm and oocytes. We found that the extent of the gametic DMRs differs significantly from that of the embryonic DMRs, especially in the case of paternal gametic DMRs. These results suggest that the gametic DMR sequences should be used to extract the features specifying methylation imprint establishment in the germline: from this analysis, we noted that the maternal gametic DMRs appear as unmethylated islands in male germ cells, which suggests a novel component in the mechanism of gamete-specific marking. Analysis of selected DMRs in blastocysts revealed dynamic changes in allelic methylation in early development, indicating that DMRs are not fully protected from the major epigenetic reprogramming events occurring during preimplantation development. Furthermore, we observed non-CpG methylation in oocytes, but not in sperm, which disappeared by the blastocyst stage. Non-CpG methylation was frequently found at maternally methylated DMRs as well as non-DMR regions, suggesting its prevalence in the oocyte genome. These results provide evidence for a unique methylation profile in oocytes and reveal the surprisingly dynamic nature of DMRs in the early embryo. PMID- 21247966 TI - EGFR gene copy number gain is related to high tumor SUV and frequent relapse after adjuvant chemotherapy in resected lung adenocarcinoma. AB - OBJECTIVE: The purpose of our study was to define the prognostic impact of increased copies of epidermal growth factor receptor (EGFR) gene in lung adenocarcinoma patients receiving adjuvant chemotherapy after surgery. METHODS: The study included 95 adenocarcinoma patients who received curative resection for non-small cell lung cancer. Patients received adjuvant chemotherapy composed of paclitaxel and carboplatin. We performed fluorescent in situ hybridization on tissue microarray in duplicate to detect EGFR copy number change. RESULTS: The EGFR fluorescent in situ hybridization result was available in 93 patients with a positive rate of 32.6%. EGFR copy number change did not correlate with age, gender or smoking history. However, EGFR copy number gain was related to high tumor standardized uptake value at diagnosis (P = 0.042). An increase in EGFR copy number was a negative prognostic factor in terms of disease-free survival (median disease-free survival not reached versus 23.6 months, P = 0.037) and overall survival (median overall survival 74.6 versus 43.5 months, P = 0.032). An increase in EGFR copy number was independently related to short disease-free survival in multivariate analysis (hazard ratio 2.039, P = 0.025). CONCLUSIONS: EGFR copy number gain is associated with aggressive tumor biology and is a poor prognostic factor for tumor relapse in resected lung adenocarcinoma patients receiving adjuvant chemotherapy of paclitaxel and carboplatin. PMID- 21247968 TI - Eleven cases of cardiac metastases from soft-tissue sarcomas. AB - OBJECTIVE: Cardiac metastasis is a highly life-threatening condition because it leads to cardiac failure. However, it is difficult to diagnose because its precise clinical features are unknown. Here, we report 11 cases of cardiac metastasis from soft-tissue sarcoma, and discuss its diagnosis and treatment. METHODS: Of 641 patients with soft-tissue sarcoma treated in our institute between 1996 and 2009, we retrospectively reviewed the medical records of 11 patients whose cardiac metastases were diagnosed while they were alive. RESULTS: The most common primary tumor was leiomyosarcoma (n= 5), followed by clear cell sarcoma (n= 2). In all cases, metastases to other organs, including lungs (n= 10), soft tissues (n= 5) and bones (n= 4) were found along with cardiac metastases. Cardiac metastasis was diagnosed by echocardiography in six cases and by computed tomography in four cases. In four patients, cardiac metastasis was not detected by chest computed tomography as follow-up to lung metastases and echocardiography was required to make the diagnosis. Although five patients complained of exertional dyspnea, four were asymptomatic. Seven cases were treated with radiotherapy. No patient had surgery for their cardiac metastasis. The median survival of patients who received radiation therapy was 10.5 months; that of those who did not was 3.5 months. CONCLUSIONS: Cardiac metastasis is often asymptomatic. Echocardiography is better than computed tomography for diagnosing cardiac metastasis, and should be considered in all patients presenting with soft-tissue metastases. Owing to the highly life-threatening nature of cardiac metastases and the possibility of soft-tissue dissemination, treatment with radiation therapy is recommended immediately on diagnosis. PMID- 21247967 TI - Melphalan-prednisolone and vincristine-doxorubicin-dexamethasone chemotherapy followed by prednisolone/interferon maintenance therapy for multiple myeloma: Japan Clinical Oncology Group Study, JCOG0112. AB - A multicenter phase III study for untreated multiple myeloma was conducted to investigate a switch-induction chemotherapy with melphalan-prednisolone and vincristine-doxorubicin-dexamethasone followed by randomization on maintenance therapy for patients achieving plateau. Between November 2002 and November 2005, 34 patients were registered. The study was closed early because of poor accrual. Thirty-three eligible patients, with a median age of 65 years (range: 47-77 years) were analyzed for the secondary purpose. For induction therapy, 16 patients were treated with vincristine-doxorubicin-dexamethasone and 17 with melphalan-prednisolone initially. In eight cases, induction therapy was switched because of a poor response. Both regimens were well tolerated, but neutropenia, anorexia, constipation and infection with neutropenia were more frequent for vincristine-doxorubicin-dexamethasone. Best response rates were 44% (95% confidence interval, 20-70) and 47% (95% confidence interval, 23-72), respectively, for vincristine-doxorubicin-dexamethasone and melphalan prednisolone. Vincristine-doxorubicin-dexamethasone/melphalan-prednisolone switch induction therapy might be feasible and effective for Japanese patients with multiple myeloma. PMID- 21247969 TI - Quantitative annular dark-field STEM images of a silicon crystal using a large angle convergent electron probe with a 300-kV cold field-emission gun. AB - Annular dark-field scanning transmission electron microscope (ADF-STEM) images of an Si (001) crystal were obtained by using an aberration-corrected electron microscope, at 30-mrad convergent probe and cold field-emission gun at 300 kV. The intensity of ADF-STEM images, that is, the number of scattered electrons relative to the incident electrons, obtained for specimen thickness from 10 to 50 nm was compared quantitatively with absorptive multi-slice simulation. The column and background intensities were analyzed by column-by-column two dimensional Gaussian fitting. These intensities were found to increase linearly with the sample thicknesses. However, the simulated image gave higher column intensity and lower background intensity for all the sample thickness. We found that experimental images were reproduced by the simulation with Gaussian convolution of 70 pm full-width at half-maximum for all the sample thicknesses from 10 to 50 nm. The possible factors accounted for this Gaussian convolution is discussed. PMID- 21247970 TI - Mortality and causes of death among homeless women and men in Stockholm. AB - AIM: To study the mortality and causes of death among homeless men and women in relation to the risk indicators, previous treatment for alcohol and drug abuse, previous treatment for mental disorders and non-Swedish citizenship. METHODS: The mortality was studied in a cohort comprising 1,757 men and 526 women compared with the general population and persons with inpatient treatment for alcohol- and drug-related disorders. The follow-up period was from 1995 to 1997 until the end of 2005. The causes of death were analyzed. RESULTS: 421 deaths occurred during the follow-up period. The relative risk of death was 3.1, with no difference in mortality between homeless men and homeless women. Previous treatment for alcohol and drug abuse disorders was related to excess mortality and previous treatment for mental disease to lower mortality. Homeless people with inpatient treatment for alcohol or drug use disorders had no higher mortality than the general population in Stockholm with a similar history. There was a dominance of alcohol- and drug-related causes of death. DISCUSSION: Compared with previous studies of homeless people in Stockholm the excess mortality among men found in this study is of the same magnitude. Mortality among women is lower. The mortality rate in homeless people with previous treatment for an alcohol and illicit drug use disorder did not differ from those treated for these disorders in the general population. CONCLUSIONS: The most important finding is that excess mortality among homeless men and women in Stockholm is entirely related to alcohol and drug abuse. PMID- 21247971 TI - Exercise for multiple sclerosis: a single-blind randomized trial comparing three exercise intensities. AB - BACKGROUND: The most effective exercise dose has yet to be established for multiple sclerosis (MS). OBJECTIVE: The aim of this study was to investigate the effect of different exercise intensities in people with MS. METHODS: We completed a randomized comparator study of three cycling exercise intensities, with blinded assessment, was carried out in Oxford. Sixty-one adults with MS who fulfilled inclusion criteria were randomized at entry into the study, using a computer generated list held by an exercise professional, into either: continuous (at 45% peak power, n=20), intermittent (30 sec on, 30 sec off at 90% peak power, n=21) or combined (10 min intermittent at 90% peak power then 10 min continuous at 45% peak power, n=20) exercise for 20 min twice a week for 12 weeks in a leisure facility. Groups were assessed at: baseline, halfway (6 weeks), end intervention (12 weeks) and follow-up (24 weeks). Primary outcome measure was 2 min walk. RESULTS: Fifty-five participants were included in the analysis (n=continuous 20, intermittent 18, combined 17). No differences were found between groups. After 6 weeks, considering all participants, 2 min walk distance increased by 6.96+/-2.56 m (95% CI: 1.81 to 12.10, effect size (es): 0.25, p<0.01). The continuous group increased by 4.71+/-4.24 m (95% CI: -3.80 to 13.22, es: 0.06), intermittent by 12.94+/-4.71 m (95% CI: 3.97 to 21.92, es: 0.28) and combined by 3.22+/-4.60 m (95% CI: -6.01 to 12.46, es: 0.04). Two minute walk did not significantly change between further assessments. Between 6 and 12 weeks there was a drop in attendance that seemed to be associated with the intermittent and combined groups; these groups also had a greater number of adverse events (leg pain during cycling most common) and dropouts (n=continuous 1, intermittent 5, combined 10). Considering all participants, 6 weeks of cycling exercise produced benefits in mobility that were maintained with further sessions. CONCLUSION: While no differences were found between groups, greater benefit may be associated with higher-intensity exercise, but this may be less well tolerated. CONSORT-trial registration number (ISRCTN89009719). PMID- 21247972 TI - The effects of extreme heat on human mortality and morbidity in Australia: implications for public health. AB - Most regions of Australia are exposed to hot summers and regular extreme heat events; and numerous studies have associated high ambient temperatures with adverse health outcomes in Australian cities. Extreme environmental heat can trigger the onset of acute conditions, including heat stroke and dehydration, as well as exacerbate a range of underlying illnesses. Consequently, in the absence of adaptation, the associated mortality and morbidity are expected to increase in a warming climate, particularly within the vulnerable populations of the elderly, children, those with chronic diseases, and people engaged in physical labour in noncooled environments. There is a need for further research to address the evidence needs of public health agencies in Australia. Building resilience to extreme heat events, especially for the most vulnerable groups, is a priority. Public health professionals and executives need to be aware of the very real and urgent need to act now. PMID- 21247973 TI - Residential environmental risk factors for childhood asthma prevalence in metropolitan and semirural cities in Korea. AB - To identify the association between residential environmental risk factors and the prevalence of childhood asthma, the authors surveyed the prevalence of asthma, the residential environmental risk factors of 1819 elementary school students, and air pollution in metropolitan (Seongbuk), and semirural (Andong) areas. Although there was no significant difference in the prevalence of self reported asthma (SA) between the 2 geographic areas (12.8% vs 13.6%), the prevalence of physician-diagnosed asthma (PDA) in Andong (15.0%) was significantly higher than that in Seongbuk (6.8%). After adjusting for confounding factors, logistic regression suggested that there were significant differences in size of the house (adjusted odds ratio [aOR] = 1.82), medical insurance (aOR = 2.59), and number of residents in the household (aOR = 1.54) between the SA and non-SA groups. There was a significant difference in the area of residence (aOR = 2.12) between the PDA and non-PDA groups. In conclusion, residential environmental risk factors and the area of residence affect the prevalence of childhood asthma. PMID- 21247974 TI - Effects of a tailored health promotion program to reduce cardiovascular disease risk factors among middle-aged and advanced-age bus drivers. AB - A tailored health promotion program was developed and applied to reduce cardiovascular disease risk factors among middle-aged and advanced-age bus drivers. The participants were 248 bus drivers from 2 transportation companies, in whom the authors surveyed health behaviors (physical activity, diet, smoking habit, and alcohol consumption), health status (body mass index, systolic blood pressure, triglycerides, total cholesterol, high-density lipoprotein, and low density lipoprotein), and job stress. The tailored health promotion program consisted of exercise, diet, temperance, and smoking cessation education; the program was developed to reduce cardiovascular disease risk factors and was administered for 6 months. After the program, health behaviors, such as physical activity, dietary habits, smoking habits, and alcohol consumption, and health status indicators, such as blood pressure, had significantly improved (P < .05). The authors did not find an association between job stress and health behavior and status. This suggests that a tailored health promotion program for middle aged and advanced-age bus drivers was effective. PMID- 21247975 TI - Association between infant feeding practices and first meaningful words at first year of life: a prospective cohort study of Thai children. AB - Feeding practices show many benefits for child and cognitive development. The objective was to investigate the association between infant feeding practices and the first meaningful words of Thai children. The participants enrolled in this longitudinal study were 4245 children born between July 2000 and June 2002. They resided in 3 rural and 2 urban areas of Thailand and were followed from birth to childhood. The outcome was time from birth to expression of first meaningful words. Outcome and feeding information were gathered using a diary method, with parents and caregivers recording daily development. Nonstatistically significant corresponding reduction in time to expression of first meaningful words was found among children who were breastfed, and this increased with duration of breastfeeding. Breastfeeding may reduce the time taken for expression of first meaningful words by about 2% (hazard ratio = 0.98; 95% confidence interval = 0.94 to 1.01). No association between infant feeding practices and the expression of first meaningful words was found. PMID- 21247976 TI - Association of sociodemographic factors with depression in women of reproductive age. AB - INTRODUCTION: . Women suffer disproportionately from depression, which has a high prevalence in developing countries. Sociodemographic factors are associated with depression, some of which may be modifiable and lead to better outcomes for depression among women. OBJECTIVES: . To determine sociodemographic factors associated with depression among women of reproductive age in Karachi. METHODS: . A case control study was conducted on 376 women in 2 hospitals in Karachi. Patients were diagnosed by psychiatrists and family physicians by Diagnostic and Statistical Manual of Mental Disorders (4th ed.) criteria and SRQ20. RESULTS: . The odds for women with depression being married for >5 years, being abused by in laws, spending <=3 hours per day with their spouses, and being just satisfied or not satisfied with their married life was more than that for controls. CONCLUSION: . The authors' findings highlight the important modifiable risk factors for depression, which if addressed will help decrease the burden of depression among women. PMID- 21247977 TI - A cross-sectional study on posttraumatic impact among Qiang women in Maoxian County 1 year after the Wenchuan Earthquake, China. AB - The authors sought to examine the posttraumatic impact among Qiang women aged 18 years or older in 2 villages of Maoxian county 1 year after the Wenchuan earthquake and determined the variables associated with mental health status and posttraumatic symptoms for further psychological interventions. They interviewed 270 Qiang women. Psychological health status was assessed using the Chinese Health Questionnaire (CHQ-12). Posttraumatic symptoms were assessed using the Impact of Event Scale-Revised (IES-R), Chinese version. The results showed that 141 (52.2%) of the participants had psychological problems. The widowed and those who witnessed casualty scored higher on the CHQ-12. Among those surveyed, 100 (37.0%) women's mean intrusion subscale scores were >=2; for 71 (26.3%) women, the mean avoidance score was >=2; and for 88 (32.6%), the mean hyperarousal score was >=2. Also, 23 (8.5%) women had scores >=2 on all the 3 subscales. Those who had no job, were injured, and had witnessed casualties scored higher on each subscale of the IES-R. PMID- 21247978 TI - Anthropometric surrogates for screening of low birth weight newborns: a community based study. AB - In developing countries, where about 75% of births occur at home or in the community, logistic problems prevent the weighing of every newborn child. This study compares various anthropometric surrogates for identification of low birth weight neonates. A longitudinal community based study was done in an urban resettlement colony and 283 singleton neonates within 7 days of birth were examined for the anthropometric measurements such as head, chest, mid upper arm circumference and foot length as a screening tool for low birth weight. Chest circumference measured within 7 days of birth appeared to be the most appropriate surrogate of low birth weight with highest sensitivity (75.4%), specificity (78.4%), and positive predictive value (48.9%) as compared with other anthropometric parameters. Low birth weight neonates in absence of weighing scales can be early identified by using simple anthropometric measurements for enhanced home-based care and timely referral. PMID- 21247979 TI - Role of WNT signalling in the determination of human mesenchymal stem cells into preadipocytes. AB - The development of obesity is characterised not only by increased storage of lipids in existing fat cells but also by the generation of new adipocytes from progenitor cells. This process, called adipogenesis, can be divided into two related steps. First, during determination, multipotent mesenchymal stem cells commit to preadipocytes. These cells exhibit similar morphology compared with stem cells; however, they are committed to the adipogenic lineage and are not longer able to transform into osteoblasts, myocytes or chondrocytes. Secondly, during differentiation, preadipocytes become mature fat cells. As in other developmental processes, adipogenesis is tightly regulated at a molecular level by several transcription factors. Within the last decade, it has also become clear how the activity of these transcription factors is coordinated by extracellular signals. In this respect, secreted WNT signalling molecules are particularly important. Several members of the WNT family have been shown to inhibit early steps of adipogenesis. Conversely, endogenous inhibitors of WNT signalling were found to promote generation of adipocytes, indicating a fundamental role of these bioactive peptides in adipogenesis. From a pathophysiological point of view, it is of interest that polymorphisms in genes of the WNT signalling system have been associated with the development of obesity and type 2 diabetes in humans. Moreover, recent findings indicate that certain WNT molecules are involved in the so-called low-grade inflammation of adipose tissue, which is crucial in the development of obesity-associated insulin resistance. These important findings in nutritional and metabolic medicine will be summarised in the present review. PMID- 21247980 TI - Pharmacological characterization of a nociceptin receptor from zebrafish (Danio rerio). AB - The nociceptin receptor (NOP) and its endogenous ligand, nociceptin/orphanin FQ (OFQ), are involved in a wide range of biological functions, such as pain, anxiety, learning, and memory. The zebrafish has been proposed as a candidate to study the in vivo effects of several drugs of abuse and to discover new pharmacological targets. We report the cloning, expression, and pharmacological characterization of a NOP receptor from zebrafish (drNOP). The full-length cDNA codes a protein of 363 residues, which shows high sequence similarity to other NOPs. Phylogenetic analysis indicates that NOPs are broadly conserved during vertebrate evolution, and that they stand for the most divergent clade of the opioid/OFQ receptor family. Expression studies have revealed that drNOP mRNA is highly expressed in the central nervous system, and low expression levels are also found in peripheral tissues such as gills, muscle, and liver. Pharmacological analysis indicates that drNOP displays specific and saturable binding for [Leucyl-3,4,5-(3)H]nociceptin, with a K(d)=0.20 +/- 0.02 nM and a B(max)=1703 +/- 81 fmol/mg protein. [(3)H]Nociceptin binding is displaced by several opioid ligands such as dynorphin A (DYN A), naloxone, bremazocine, or the kappa-selective antagonist nor-binaltorphimine. [(35)S]GTPgammaS stimulation studies showed that drNOP receptor is functional, as nociceptin is able to fully activate the receptor and DYN A behaves as a partial agonist (50% stimulation). Our results indicate that drNOP receptor displays mixed characteristics of both NOP and kappa opioid receptors. Hence, drNOP, which has retained more of the likely ancestral features, bridges the gap between nociceptin and opiate pharmacology. PMID- 21247981 TI - Crystal structure of the TSH receptor (TSHR) bound to a blocking-type TSHR autoantibody. AB - A complex of the TSH receptor extracellular domain (amino acids 22-260; TSHR260) bound to a blocking-type human monoclonal autoantibody (K1-70) was purified, crystallised and the structure solved at 1.9 A resolution. K1-70 Fab binds to the concave surface of the TSHR leucine-rich domain (LRD) forming a large interface (2565 A(2)) with an extensive network of ionic, polar and hydrophobic interactions. Mutation of TSHR or K1-70 residues showing strong interactions in the solved structure influenced the activity of K1-70, indicating that the binding detail observed in the complex reflects interactions of K1-70 with intact, functionally active TSHR. Unbound K1-70 Fab was prepared and crystallised to 2.22 A resolution. Virtually no movement was observed in the atoms of K1-70 residues on the binding interface compared with unbound K1-70, consistent with 'lock and key' binding. The binding arrangements in the TSHR260-K1-70 Fab complex are similar to previously observed for the TSHR260-M22 Fab complex; however, K1 70 clasps the concave surface of the TSHR LRD in approximately the opposite orientation (rotated 155 degrees ) to M22. The blocking autoantibody K1-70 binds more N-terminally on the TSHR concave surface than either the stimulating autoantibody M22 or the hormone TSH, and this may reflect its different functional activity. The structure of TSHR260 in the TSHR260-K1-70 and TSHR260 M22 complexes show a root mean square deviation on all C(alpha) atoms of only 0.51 A. These high-resolution crystal structures provide a foundation for developing new strategies to understand and control TSHR activation and the autoimmune response to the TSHR. PMID- 21247982 TI - Use of healthcare access models to inform the patient protection and affordable care act. AB - Health policy findings on access to care provide more substantive information if linked to a theory that provides meaningful structure and standard definitions. Three theories of access are reviewed here because they have been used to inform health policy: Penchansky's Model, The Institute of Medicine (IOM) Model of Access Monitoring, and The Behavioral Model of Health Services Use. Penchansky's model is useful when subjective experiences with health care access are needed to inform policy makers. The IOM model is used for monitoring quality of health care services provided. The Behavioral Model identifies explanatory/predictive factors associated with utilization of services. Each model uniquely evaluates different health policies. Given the passage of the Patient Protection and Affordable Care Act (PPACA) of 2010, researchers and policy makers must agree on the model that best monitors and evaluates these new policy initiatives. PMID- 21247984 TI - The effect of oxygenator choice on hypotension during cardiopulmonary bypass. AB - Cardiopulmonary bypass (CPB) exposes blood to artificial surfaces, which induces a systemic inflammatory activation.This may contribute to hypotension during CPB. A perceived difference between two membrane oxygenators was noted. Data were collected on 222 consecutive patients; four were excluded from the analysis due to having emergency operations. One hundred and twelve (51%) patients received the Apex oxygenator whilst 106 (49%) received the Quadrox. There was no difference between the two groups in the primary outcome; 90/112 patients (80%) in the Apex group and 77/106 (73%) in the Quadrox group (p=0.18, OR: 0.65; 95% CI: 0.34, 1.22) received meteraminol due to marked hypotension during CPB. There was also no difference in the secondary outcomes, length of stay in ICU (22.8 versus 22.7 hours, (OR 0.79, 95% CI: 0.42, 1.48, p=0.16) and length of stay in hospital (8.5 days versus 8.0 days (OR: 0.83, 95% CI: 0.48, 1.45; p=0.52). The choice of oxygenator between the Apex and Quadrox does not have an effect on hypotension in cardiac surgery. PMID- 21247983 TI - The prevalence of sexual assault against people who identify as gay, lesbian, or bisexual in the United States: a systematic review. AB - This article systematically reviews 75 studies that examine the prevalence of sexual assault victimization among gay or bisexual (GB) men, and lesbian or bisexual (LB) women, in the United States. All studies were published between 1989 and 2009 and report the results of quantitative research. The authors reviewed the reported prevalence of lifetime sexual assault victimization (LSA), and where available, childhood sexual assault (CSA), adult sexual assault (ASA), intimate partner sexual assault (IPSA), and hate crime-related sexual assault (HC). The studies were grouped into those that used a probability or census sampling technique (n=25) and those that used a non-probability or ''community based'' sampling technique (n=50). A total of 139,635 gay, lesbian, and bisexual (GLB) respondents participated in the underlying studies reviewed. Prevalence estimates of LSA ranged from 15.6-85.0% for LB women and 11.8-54.0% for GB men. Considering the median estimates derived from the collective set of studies reviewed, LB women were more likely to report CSA, ASA, LSA, and IPSA than GB men, whereas GB men were more likely to report HC than LB women. Across all studies, the highest estimates reported were for LSA of LB women (85.0%), CSA of LB women (76.0%), and CSA of GB men (59.2%). With some exceptions, studies using non-probability samples reported higher sexual assault prevalence rates than did population-based or census sample studies. The challenges of assessing sexual assault victimization with GLB populations are discussed, as well as the implications for practice, policy, and future research. PMID- 21247985 TI - Evaluation of two pediatric polymethyl pentene membrane oxygenators with pulsatile and non-pulsatile perfusion. AB - OBJECTIVES: This experiment sought to compare two polymethyl pentene (PMP) hollow fiber membrane oxygenators: the Medos HILITE 2400 LT and the Maquet Quadrox-iD Pediatric in terms of transmembrane pressure gradients and hemodynamic energy preservation under both pulsatile and non-pulsatile conditions. METHODS: A simulated pediatric extracorporeal life support (ECLS) circuit was used to test these two oxygenators. The circuit consisted of a roller pump, 1/4 inch tubing for both arterial and venous lines, an oxygenator, and a venous reservoir served as a pseudo-patient. Three pressure transducers were placed upstream and downstream of the oxygenator and the distal arterial line. The experimental system was primed with lactated Ringer's solution and packed human red blood cells to maintain a hematocrit of 40%.The total volume was 600 ml, including the 350 ml volume of the pseudo-patient.The tests were performed at six flow rates (250, 500, 750, 1000, 1250, 1500 ml/min) and three distal arterial line pressures (MAP) (60, 80, 100 mmHg), under both pulsatile and non-pulsatile perfusion modes.The temperature was kept constant at 37 degrees C for all tests. RESULTS: Both oxygenators had adequate performances in pressure drop and hemodynamic energy preservation. There were no significant differences between pre- and post oxygenators for mean pressure (MP), energy equivalent pressure (EEP) and total hemodynamic energy (THE). During the pulsatile perfusion mode, the HILITE 2400 LT retained a greater percentage of surplus hemodynamic energy (SHE) across the oxygenator. CONCLUSIONS: Both the Quadrox-iD Pediatric and HILITE 2400LT PMP membrane oxygenators are suitable for pediatric ECLS therapy under both non pulsatile and pulsatile perfusion. An optimized combination of flow rate and MAP should be achieved in order to deliver the maximal pulsatile energy in the extracorporeal circuit. PMID- 21247986 TI - Spontaneous retrograde dissection of ascending aorta from descending thoracic aorta--a case review. AB - A 56-year-old man with sudden onset chest pain, absent right lower limb pulses and ECG changes suggestive of inferior ST elevation MI underwent coronary angiogram through the right radial artery with a view to primary percutaneous coronary intervention (PCI). The left coronary angiogram demonstrated severe proximal stenotic disease in the left anterior descending and circumflex coronary arteries, but the right coronary artery could not be selectively cannulated. An ascending aortogram to visualise the right coronary artery not only failed to demonstrate it, but revealed, instead, a dissection flap in the ascending aorta, arch and descending thoracic aorta, with moderately severe aortic regurgitation. At operation, the patient was found to have an acute dissection of the ascending aorta, arch and descending aorta with an entry tear in the descending aorta below the left subclavian artery origin. Triple coronary artery bypass grafting with re suspension of the aortic valve, supracoronary replacement of the ascending aorta and hemiarch and transaortic repair of the descending aortic tear was performed. The patient made an uncomplicated recovery, with the re-appearance of right limb pulses. A postoperative magnetic resonance (MR) scan revealed complete thrombosis of the false channel in the residual arch and a considerably shrunken false channel in the descending aorta and no aortic regurgitation. Retrograde dissection of the ascending aorta from the descending aorta has been reported infrequently in the past. We believe the scale of the problem has been underestimated because of the failure to adopt open distal anastomosis routinely in the past and, hence, failure to inspect the arch and the descending aorta routinely, particularly when the intimal tear was not identified in the ascending aorta. Retrograde dissection of the ascending aorta from an intimal tear in the descending aorta, when identified as such, has been managed, either on the principle of exclusion of the tear in the descending aorta by various elephant trunk procedures and their variants or, alternatively, on the principle of excision of the tear by extended one-stage aortic replacement, usually combined with an elephant trunk procedure. Neither of these procedures is widely adopted, owing to procedural, institutional and outcome considerations. We describe a transaortic repair of the intimal tear in the descending aorta with supracoronary interposition graft replacement of the ascending aorta and hemiarch with excellent clinical and radiological result. We also review the diagnostic and therapeutic approaches to this incompletely understood lethal disease. PMID- 21247987 TI - The importance of the conus artery in patients with obstructive coronary artery disease. AB - It is well-known that collateral circulation is important in preserving ventricular functions, especially in coronary artery disease with total occlusion. The conus branch is distinct in having notable capacity of angiogenesis and arteriogenesis. We intend to emphasize the clinical importance of the conus branch by presenting two cases in which it supplied the distal regions of total occlusion. PMID- 21247988 TI - Sub-chronic lead exposure alters kidney proteome profiles. AB - The current study examined the impact of sub-chronic lead (Pb)-exposure upon global protein profile in rodent kidney (blood Pb levels ~50 MUg/dL; 5 weeks oral Pb-acetate exposure). Utilizing 2D SDS-PAGE for kidney protein separation, greater than 500 protein spots were analyzed by densitometry following background noise removal, spot alignment, and intensity filtering. Approximately 100 protein spots were identified by ESI-MS/MS with mitochondrial, chaperone, antioxidant, and Pb-binding proteins included. Forty-eight protein spots exhibited significant alterations in abundance (18 identified by ESI-MS/MS) including the increased protein abundance of ketohexokinase, enolase, protein disulfide-isomerase, lamda crystallin, lactamase, and glycerol-3-phosphate dehydrogenase. Decreased protein abundances were observed for alpha-2 microglobulin, glutamate cysteine ligase, prohibitin, homogentisate 1,2-dioxygenase, alpha-ETF, argininosuccinate synthetase and ATP synthase (H+ transporting). These data support the hypothesis that protein profiles in the kidney are altered following sub-chronic physiologically relevant Pb-exposure. PMID- 21247989 TI - Dual effects of erdosteine on hemostasis via its different metabolites in young rats. AB - AIM: In the study, we examined erdosteine's effects on platelet functions and coagulation. MATERIALS AND METHODS: A total 29 young albino Wistar rats were divided into four groups. Control rats (n = 6) were given saline; Group 1 rats (n = 7) were given 3 mg/kg erdosteine by oral gavage for 3 days; Group 2 rats (n = 7) were given 10 mg/kg erdosteine by oral gavage for 3 days; and Group 3 rats (n = 9) were given 30 mg/kg erdosteine for 3 days. Twenty-four hours after the final dose, blood samples were drawn from a portal vein. Prothrombin time (PT), activated partial thromboplastin time (aPTT) and international normalized ratio (INR) were measured, and platelet counts were examined in a peripheral blood smear by light microscopy. RESULTS: PT and INR values of Group 1 increased compared to the controls but did not change in Group 3. Hemostatic parameters were not measured in Group 2 because the blood samples in Group 2's tubes clotted rapidly. Platelet counts of the peripheral blood from Group 2 were low but were normal in other groups. CONCLUSION: We have concluded erdosteine may disrupt hemostasis parameters by its different metabolites in patients. Erdosteine has dual effects on hemostasis via its different metabolites, which occur in different doses. PMID- 21247990 TI - Impact of pesticides residue and heavy metals on lipids and fatty acids composition of some seafoods of Red Sea (KSA). AB - Seafood is considered by nutritionists to be a high source of omega 3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) which are involved in prevention of cardiovascular diseases. The aim of the present study is firstly to detect the presence of organochlorine pesticides and heavy metals in some fresh seafood of Red Sea commonly used in KSA in relation to its contents. It was found that the fatty acids 18:2n-6, 18:3n-6, 18:3n-9 was statistically significantly higher in fresh samples than frozen (p < 0.05), smoked (p < 0.01) and canned fishes (p < 0.05), respectively. Total lipids and cholesterol content of canned and smoked fishes were significantly higher than fresh and frozen samples (p < 0.01, <0.05 and p < 0.01, <0.05). Vitamin D was found to be lower in frozen samples than fresh, smoked and canned (p < 0.05 for each). While vitamin A was higher in fresh and smoked as compared with frozen and canned samples. No organochlorine tested were detected in either fresh or processed samples (smoked, frozen and canned). Among the heavy metals, the highest lead level was detected in fresh and smoked samples as compared with frozen and canned samples. No correlation was found between organochlorine compounds in fish and the corresponding levels in fatty acids. We concluded that, all fishes are safe for uses but it is preferable to use fresh samples due to its high content of PUFA and low lead level. PMID- 21247991 TI - Protective effect of Cassia fistula fruit extract on bromobenzene-induced nephrotoxicity in mice. AB - The efficacy of a crude hydro-alcoholic extract of Cassia fistula (golden shower tree) fruit to protect the kidney against bromobenzene-induced toxicity was studied. Negative control mice received normal saline; positive control mice were given 460 mg/kg of bromobenzene; Cassia fistula treated mice received 200, 400, 600 and 800 mg/kg of Cassia fistula fruit extract followed by 460 mg/kg bromobenzene (daily by oral gavage for 10 days). On the 11th day, the mice were sacrificed, blood samples were obtained to assess blood urea nitrogen (BUN) and creatinine levels, and kidneys were removed for histological examination. We found that bromobenzene induced significant nephrotoxicity reflected by an increase in levels of BUN and creatinine that was dose dependently prevented by the Cassia fistula fruit extract. The nephroprotective effect of the Cassia fistula fruit extract was confirmed by the histological examination of the kidneys. To the best of our knowledge, this is the first study to demonstrate the protective effect of Cassia fistula in nephrotoxicity. PMID- 21247992 TI - Loxosceles gaucho spider venom and its sphingomyelinase fraction trigger the main functions of human and rabbit platelets. AB - Loxosceles venoms can promote severe local and systemic damages. We have previously reported that Loxosceles gaucho spider venom causes a severe early thrombocytopenia in rabbits. Herein, we investigated the in vitro effects of this venom and its sphingomyelinase fraction on the main functions of platelets. Whole venom and its fraction induced aggregation of both human and rabbit platelets. Aggregation was dependent of plasma component(s) but independent of venom-induced lysophosphatidic acid generation. There was no increase in the levels of lactate dehydrogenase during platelet aggregation, ruling out the possibility of platelet lysis. The increased expression of ligand-induced binding site 1 (LIBS1) induced by L. gaucho venom and its sphingomyelinase fraction, as well as of P-selectin by the whole venom, evidenced the activation state of both human and rabbit platelets. Adhesion assays showed an irregular response when platelets were exposed to the whole venom, whereas the sphingomyelinase fraction induced a dose dependent increase in the platelet adhesion to collagen. These findings evidence that L. gaucho venom and its sphingomyelinase fraction trigger adhesion, activation, and aggregation of both human and rabbit platelets. Thus, this work justifies the use of rabbits to investigate Loxosceles venom-induced platelet disturbances, and it also supports research on the role of platelets in the pathogenesis of loxoscelism. PMID- 21247993 TI - Genotoxic effects of aluminum, iron and manganese in human cells and experimental systems: a review of the literature. AB - There is considerable evidence indicating an increase in neurodegenerative disorders in industrialized countries. The clinical symptoms and the possible mutagenic effects produced by acute poisoning and by chronic exposure to metals are of major interest. This study is a review of the data found concerning the genotoxic potential of three metals: aluminum (Al), iron (Fe) and manganese (Mn), with emphasis on their action on human cells. PMID- 21247994 TI - The mechanism of sertraline-induced [Ca2+]i rise in human OC2 oral cancer cells. AB - Effect of sertraline, an antidepressant, on cytosolic free Ca(2+) levels ([Ca(2+)](i)) in human cancer cells is unclear. This study examined if sertraline altered basal [Ca(2+)](i) levels in suspended OC2 human oral cancer by using fura 2 as a Ca(2+)-sensitive fluorescent probe. At concentrations of 10-100 MUM, sertraline induced a [Ca(2+)](i) rise in a concentration-dependent fashion. The Ca(2+) signal was reduced partly by removing extracellular Ca(2+) indicating that Ca(2+) entry and release both contributed to the [Ca(2+)](i) rise. Sertraline induced Mn(2+) influx, leading to quench of fura-2 fluorescence suggesting Ca(2+) influx. This Ca(2+) influx was inhibited by suppression of phospholipase A2, inhibition of store-operated Ca(2+) channels or by modulation of protein kinase C activity. In Ca(2+)-free medium, pretreatment with the endoplasmic reticulum Ca(2+) pump inhibitor thapsigargin or 2,5-di-(t-butyl)-1,4-hydroquinone (BHQ) nearly abolished sertraline-induced Ca(2+) release. Conversely, pretreatment with sertraline greatly reduced the inhibitor-induced [Ca(2+)](i) rise, suggesting that sertraline released Ca(2+) from the endoplasmic reticulum. Inhibition of phospholipase C did not change sertraline-induced [Ca(2+)](i) rise. Together, in human oral cancer cells, sertraline induced [Ca(2+)](i) rises by causing phospholipase C-independent Ca(2+) release from the endoplasmic reticulum and Ca(2+) influx via store-operated Ca(2+) channels. PMID- 21247995 TI - Therapeutic management of neonatal hemochromatosis: report of four cases and literature review. AB - Neonatal hemochromatosis (NH) is a rare disease of iron metabolism that starts at intrauterine period causing liver failure and extrahepatic siderozis. The etiology of NH has not been understood exactly, yet it is accepted that a maternofetal alloimmune disorder that leads to liver failure in fetus causes the illness. The prognosis of NH is generally bad and death is inevitable if left untreated. The efficiency of chelation-antioxidant coctail used in medical treatment is between 10% and 20% and these patients frequently need liver transplantation. In our study, we presented four newborn cases diagnosed as NH and treated medically. Of the four patients, one died of pulmonary hemorrhage and another died of multiorgan failure in the first week of hospitalization. The other two patients' clinical status and laboratory parameters recovered with medical treatment. However, since liver transplantation was not carried out, one of these patients died at the age of two and a half months and the other at eighth month due to sepsis. In this study, we would like to emphasize the importance of early liver transplantation in patients recovered with medical treatment. PMID- 21247996 TI - Levels of select organophosphates in human colostrum and mature milk samples in rural region of Faizabad district, Uttar Pradesh, India. AB - INTRODUCTION: Human colostrum and mature milk samples from rural mothers were separately screened for organophosphate pesticides (OPPs). The samples were assessed for the pollution load they are transmitting to the nursing infant to determine potential toxicity. The role of colostrum for toxicity monitoring was assessed in comparison to mature milk as it is the very first infant food. MATERIALS AND METHODS: The pesticides were quantified using a Gas Chromatograph equipped with Electron Capture Detector (GC-ECD) and the results were further validated on GC linked with Mass Spectrophotometer (GC-MS) and Fourier transform infrared (FTIR). RESULTS: A total of 33 samples were analyzed out of 40 samples collected. These samples were from 33 mothers. Out of these, 25 were colostrum samples and 8 were mature milk samples. Frequency percentage (N%) of organophosphates analyzed was highest for ethion (23.1% or 6/26) in colostrum and chlorpyrifos (50% or 4/8) in mature milk samples. Frequency percentage in colostrum was 19.2% (5/26) for chlorpyrifos and 3.8% (1/26) for dimethoate; 25.0% (2/8) mature milk samples carried dimethoate and 12.5% (1/8) carried ethion. Mean OPPs in colostrum: dimethoate (85.888 ng/g fat) > ethion (48.000 ng/g fat) > chlorpyrifos (4.003 ng/g fat); and mature milk: ethion (744.925 ng/g fat) > chlorpyrifos (37.274 ng/g fat) > dimethoate (26.752 ng/g fat). MS data revealed the presence of methyl parathion, which was not quantitated. None of the samples exceeded acceptable daily intake standards set by Joint Meeting on Pesticide Residues (JMPR). The study will pave way for further analysis on pesticide toxicology. PMID- 21247997 TI - Beta-ketothiolase deficiency brought with lethargy: case report. AB - Beta-ketothiolase deficiency is a rare autosomal recessive disorder of isoleucine and ketone body metabolism. This disorder is clinically characterized by ketoacidotic attacks. Ketoacidosis, vomiting, and dehydration, lethargy and coma may be seen during attacks. A 9-month-old girl was admitted to our hospital with acidosis and dehydration. The patient was lethargic. Ketoacidosis was suspected because of acetone odor on her breath. Her blood glucose level was 262 mg/dL and urine ketone was (++++). Branched chain amino acid levels were elevated in her blood sample. Organic acid analysis of urine revealed 2-methylacetoacetyl-CoA thiolase deficiency. This was reported because of rarity of the disease and we should consider it in the differential diagnosis of ketoacidotic episodes. PMID- 21247999 TI - French drug reps. Say no to seeing sales reps. PMID- 21248000 TI - The life imprisonment of Dr Binayak Sen. PMID- 21248001 TI - The BMJ is on the iPad. PMID- 21248002 TI - Too many referral forms?. Hail, universal referral form. PMID- 21247998 TI - Pharmacogenetic approach at the serotonin transporter gene as a method of reducing the severity of alcohol drinking. AB - OBJECTIVE: Severe drinking can cause serious morbidity and death. Because the serotonin transporter (5-HTT) is an important regulator of neuronal 5-HT function, allelic differences at that gene may modulate the severity of alcohol consumption and predict therapeutic response to the 5-HT(3) receptor antagonist, ondansetron. METHOD: The authors randomized 283 alcoholics by genotype in the 5' regulatory region of the 5-HTT gene (LL/LS/SS), with additional genotyping for another functional single-nucleotide polymorphism (T/G), rs1042173, in the 3' untranslated region, in a double-blind controlled trial. Participants received either ondansetron (4 MUg/kg twice daily) or placebo for 11 weeks, plus standardized cognitive-behavioral therapy. RESULTS: Individuals with the LL genotype who received ondansetron had a lower mean number of drinks per drinking day (-1.62) and a higher percentage of days abstinent (11.27%) than those who received placebo. Among ondansetron recipients, the number of drinks per drinking day was lower (-1.53) and the percentage of days abstinent higher (9.73%) in LL compared with LS/SS individuals. LL individuals in the ondansetron group also had a lower number of drinks per drinking day (-1.45) and a higher percentage of days abstinent (9.65%) than all other genotype and treatment groups combined. For both number of drinks per drinking day and percentage of days abstinent, 5'-HTTLPR and rs1042173 variants interacted significantly. LL/TT individuals in the ondansetron group had a lower number of drinks per drinking day (-2.63) and a higher percentage of days abstinent (16.99%) than all other genotype and treatment groups combined. CONCLUSIONS: The authors propose a new pharmacogenetic approach using ondansetron to treat severe drinking and improve abstinence in alcoholics. PMID- 21248003 TI - Denialism in public health. Beware SLEAZE tactics. PMID- 21248004 TI - Point of credulity. Professor McLachlan's fraud. PMID- 21248005 TI - Middle ear forceps. Likened to pike in German. PMID- 21248006 TI - A French king's head. Was it Henri IV's head? PMID- 21248007 TI - Phantom vibration syndrome. Sixty eight per cent of us hallucinate. PMID- 21248008 TI - Cycling and health. Pernicious use of surrogate markers. PMID- 21248009 TI - Thrombolysis in elderly people. Observational data insufficient to change treatment. PMID- 21248011 TI - Overweening on weaning. PMID- 21248012 TI - Doctor who received {pound}1.2m from patient's estate is struck off. PMID- 21248013 TI - Why do pharmacists sell homoeopathic remedies? PMID- 21248015 TI - Direct coupling through gap junctions is not involved in urethral neurotransmission. AB - Interstitial cells of Cajal (ICC) are believed to participate in urethral neurotransmission and it was proposed that direct coupling of ICC and smooth muscle cells (SMC) through gap junctions (GJ) is involved, although this still remains unclear. Hence, we investigated the distribution of different connexins (Cx 43, Cx40, and Cx37) in the sheep and rat urethra, as well as their possible role in neurotransmission. Conventional PCR confirmed that three Cxs are expressed in the urethra. Moreover, both Cx43 and Cx37-immunoreactivity (-ir) were present in SMC, ICC, and the urothelium, although Cx37-ir was significantly weaker and Cx40-ir was limited to the endothelium. While these results indicate that GJ intercellular communication could occur between SMC and ICC, neither the contractile (noradrenergic) nor the relaxant (nitrergic) responses of the rat and sheep urethra to electrical field stimulation were significantly modified by two different GJ inhibitors: 18alpha-glycyrrhetinic acid and a cocktail of Cx mimetic peptides ((Cx43)Gap 26, (Cx37, Cx43)Gap 27, and (Cx40)Gap 27). By contrast, contractions induced by high K(+) were effectively reduced by both blockers, evidence that they effectively inhibit intercellular communication. These results indicate that GJ are not implicated in urethral neurotransmission, although the question of whether ICC modulate neurotransmission through some other mechanism remains to be determined. PMID- 21248016 TI - A rare cause of thunderclap headache. PMID- 21248017 TI - Early detection of complications after laparoscopic surgery: summary of a safety report from the National Patient Safety Agency. PMID- 21248018 TI - Diagnosis and management of hereditary haemochromatosis. PMID- 21248020 TI - Is research safe in their hands? PMID- 21248023 TI - The effect of COPD health forecasting on hospitalisation and health care utilisation in patients with mild-to-moderate COPD. AB - Exacerbations are a major cause of morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD) as well as having a large impact on health care utilisation (HCU). They are more frequent during periods of cold weather with a corresponding increase in hospital admissions. It has been hypothesised that COPD exacerbations and admissions can be reduced by predicting periods of cold weather coupled with patients' alerts and education. Healthy Outlook((r)) service provided by the Meteorological Office, UK, was used in patients with mild-to-moderate COPD who consented to participate from three primary care practices. Outcome measures included data relating to hospital admissions for acute exacerbations as well as HCU for these patients during the intervention period (1 Nov 2008-31 Mar 2009) and compared for the same patients and same period 12 months earlier (1 Nov 2007-31 Mar 2008). A cost analysis comparing treatment cost per patient for the two periods was also conducted. A total of 157 (34% of target COPD population) patients took part in the project, with five weather alerts generated (first alert reached 150 patients; second reached 146; third reached 138 patients; fourth reached 137 patients; and the fifth reached 125 patients) during the intervention period. There was a non statistically-significant increase in hospital admissions per patient (0.07 0.076; p = 0.83). The number of general practice visits per patient dropped from 4.9 to 3.8 (p = 0.001), with drop in average number of visits to patients by out of-hours services from 0.52-0.14 (p = 0.013). The average number of home consultations provided by general practice increased from 0.05 to 0.92 (p = 0.001). Cost per patient increased by an average of L142 (95% CI -L128 to L412). This anticipatory care model was not associated with reduction in admissions from COPD exacerbations. Further research is required to fully understand its role in the management of patients with COPD. PMID- 21248024 TI - Are physical activity interventions equally effective in adolescents of low and high socio-economic status (SES): results from the European Teenage project. AB - The aim was to study whether physical activity (PA) interventions in European teenagers are equally effective in adolescents of low versus high socio-economic status (SES). Based on a systematic review (Project TEENAGE), three school-based studies for secondary analyses were selected. SES stratified analyses were run in: (i) a Belgian multi-component intervention, (ii) a French multi-component intervention and (iii) a Belgian computer-tailored education trial. Results of the secondary analyses showed that no overall significant differences between low and high SES groups were found, but some interesting specific effects were revealed. Results from the first study showed an increase in objective PA in the low SES group (P = 0.015) compared with no significant effects in the high SES group. In the second study, larger effects were found in adolescents of high SES (increase of 11 min day(-1) P < 0.001), compared with adolescents of lower SES (increase of 7 min day(-1), P = 0.02) at the longer term. The third study showed a positive effect on school-related PA in adolescents of high SES (P < 0.05) and on leisure time transportation in adolescents of low SES (P < 0.05). To conclude, we were not able to show a significant widening or narrowing of inequalities in European adolescents. PMID- 21248025 TI - Roles of interpersonal and media socialization agents in adolescent self-reported health literacy: a health socialization perspective. AB - This study proposes a health socialization model and applies it to examine direct, relative and mediating roles of interpersonal and media health socialization agents in predicting adolescent self-reported health literacy. We conducted a paper-and-pencil survey among 452 seventh graders in rural and urban school districts. Our regression analysis results show that both interpersonal and media socialization agents are significantly and positively related to adolescent health literacy. Media socialization agents seem to play a strong role in health literacy orientation, not much weaker than those of interpersonal socialization agents. The proposed health socialization model could contribute to the literature on how adolescents acquire health-related information and channels through which they are most receptive. PMID- 21248026 TI - Students' personal traits, violence exposure, family factors, school dynamics and the perpetration of violence in Taiwanese elementary schools. AB - School violence has become an international problem affecting the well-being of students. To date, few studies have examined how school variables mediate between personal and family factors and school violence in the context of elementary schools in Asian cultures. Using a nationally representative sample of 3122 elementary school students in Taiwan, this study examined a theoretical model proposing that negative personal traits, exposure to violence and parental monitoring knowledge have both direct influences as well as indirect influences mediated through school engagement, at-risk peers and poor student-teacher relationships on school violence committed by students against students and teachers. The results of a structural equation modeling analysis provided a good fit for the sample as a whole. The final model accounted for 32% of the variance for student violence against students and 21% for student violence against teachers. The overall findings support the theoretical model proposed in this study. Similar findings were obtained for both male and female students. The study indicated that to reduce school violence more effectively in the context of elementary schools, intervention may exclusively focus on improving students' within-school experiences and the quality of the students' relationships with teachers and school peers. PMID- 21248027 TI - Vitamin D and nutritional status are related to bone fractures in alcoholics. AB - BACKGROUND: Bone fractures are common in alcoholics. AIMS: To analyse which factors (ethanol consumption; liver function impairment; bone densitometry; hormone changes; nutritional status, and disrupted social links and altered eating habits) are related to bone fractures in 90 alcoholic men admitted to our hospitalization unit because of organic problems. METHODS: Bone homoeostasis related hormones were measured in patients and age- and sex-matched controls. Whole-body densitometry was performed by a Hologic QDR-2000 (Waltham, MA, USA) densitometer, recording bone mineral density (BMD) and fat and lean mass; nutritional status and liver function were assessed. The presence of prevalent fractures was assessed by anamnesis and chest X-ray film. RESULTS: Forty-nine patients presented at least one fracture. We failed to find differences between patients with and without fractures regarding BMD parameters. Differences regarding fat mass were absent, but lean mass was lower among patients with bone fracture. The presence of fracture was significantly associated with impaired subjective nutritional evaluation (chi2 = 5.79, P = 0.016), lower vitamin D levels (Z = 2.98, P = 0.003) and irregular eating habits (chi2 = 5.32, P = 0.02). Reduced lean mass and fat mass, and altered eating habits were more prevalent among patients with only rib fractures (n = 36) than in patients with multiple fractures and/or fractures affecting other bones (n = 13). These last were more closely related to decompensated liver disease. Serum vitamin D levels showed a significant relationship with handgrip strength (rho = 0.26, P = 0.023) and lean mass at different parts of the body, but not with fat mass. By logistic regression analysis, only vitamin D and subjective nutritional evaluation were significantly, independently related with fractures. CONCLUSION: Prevalent fractures are common among heavy alcoholics. Their presence is related more closely to nutritional status, lean mass and vitamin D levels than to BMD. Lean mass is more reduced, nutritional status is more impaired and there is a trend to more altered eating habits among patients with rib fractures, whereas multiple fractures depend more heavily on advanced liver disease. PMID- 21248028 TI - ALIX/AIP1 is required for NP incorporation into Mopeia virus Z-induced virus-like particles. AB - During virus particle assembly, the arenavirus nucleoprotein (NP) associates with the viral genome to form nucleocapsids, which ultimately become incorporated into new virions at the cell membrane. Virion release is facilitated by the viral matrix Z protein through its interaction with the cellular endosomal sorting complex required for transport (ESCRT) machinery. However, the mechanism of nucleocapsid incorporation into virions is not well understood. Here, we demonstrate that ALIX/AIP1, an ESCRT-associated host protein, is required for the incorporation of the NP of Mopeia virus, a close relative of Lassa virus, into Z induced virus-like particles (VLPs). Furthermore, we show that the Bro1 domain of ALIX/AIP1 interacts with the NP and Z proteins simultaneously, facilitating their interaction, and we identify residues 342 to 399 of NP as being necessary for its interaction with ALIX/AIP1. Our observations suggest a potential role for ALIX/AIP1 in linking Mopeia virus NP to Z and the budding apparatus, thereby promoting NP incorporation into virions. PMID- 21248029 TI - A herpesvirus virulence factor inhibits dendritic cell maturation through protein phosphatase 1 and Ikappa B kinase. AB - Dendritic cells are sentinels in innate and adaptive immunity. Upon virus infection, a complex program is in operation, which activates IkappaB kinase (IKK), a key regulator of inflammatory cytokines and costimulatory molecules. Here we show that the gamma(1)34.5 protein, a virulence factor of herpes simplex viruses, blocks Toll-like receptor-mediated dendritic cell maturation. While the wild-type virus inhibits the induction of major histocompatibility complex (MHC) class II, CD86, interleukin-6 (IL-6), and IL-12, the gamma(1)34.5-null mutant does not. Notably, gamma(1)34.5 works in the absence of any other viral proteins. When expressed in mammalian cells, including dendritic cells, gamma(1)34.5 associates with IKKalpha/beta and inhibits NF-kappaB activation. This is mirrored by the inhibition of IKKalpha/beta phosphorylation, p65/RelA phosphorylation, and nuclear translocation in response to lipopolysaccharide or poly(I:C) stimulation. Importantly, gamma(1)34.5 recruits both IKKalpha/beta and protein phosphatase 1, forming a complex that dephosphorylates two serine residues within the catalytic domains of IkappaB kinase. The amino-terminal domain of gamma(1)34.5 interacts with IKKalpha/beta, whereas the carboxyl-terminal domain binds to protein phosphatase 1. Deletions or mutations in either domain abolish the activity of gamma(1)34.5. These results suggest that the control of IkappaB kinase dephosphorylation by gamma(1)34.5 represents a critical viral mechanism to disrupt dendritic cell functions. PMID- 21248030 TI - Development of a cellular assay system to study the genome replication of high- and low-risk mucosal and cutaneous human papillomaviruses. AB - We found that recircularized high-risk (type 16 and 18) and low-risk mucosal (type 6b and 11) and cutaneous (type 5 and 8) human papillomavirus (HPV) genomes replicate readily when delivered into U2OS cells by electroporation. The replication efficiency is dependent on the amount of input HPV DNA and can be followed for more than 3 weeks in proliferating cell culture without selection. Cotransfection of recircularized HPV genomes with a linear G418 resistance marker plasmid has allowed subcloning of cell lines, which, in a majority of cases, carry multicopy episomal HPV DNA. Analysis of the HPV DNA status in these established cell lines showed that HPV genomes exist in these cells as stable extrachromosomal oligomers. When the cell lines were cultivated as confluent cultures, a 3- to 10-fold amplification of the HPV genomes per cell was induced. Two-dimensional (2D) agarose gel electrophoresis confirmed amplification of mono- and oligomeric HPV genomes in these confluent cell cultures. Amplification occurred as a result of the initiation of semiconservative two-dimensional replication from one active origin in the HPV oligomer. Our data suggest that the system described here might be a valuable, cost-effective, and efficient tool for use in HPV DNA replication studies, as well as for the design of cell-based assays to identify potential inhibitors of all stages of HPV genome replication. PMID- 21248031 TI - Cellular gene expression that correlates with EBER expression in Epstein-Barr Virus-infected lymphoblastoid cell lines. AB - Novel Epstein-Barr Virus (EBV) strains with deletion of either EBER1 or EBER2 and corresponding revertant viruses were constructed and used to infect B lymphocytes to make lymphoblastoid cell lines (LCLs). The LCLs were used in microarray expression profiling to identify genes whose expression correlates with the presence of EBER1 or EBER2. Functions of regulated genes identified in the microarray analysis include membrane signaling, regulation of apoptosis, and the interferon/antiviral response. Although most emphasis has previously been given to EBER1 because it is more abundant than EBER2, the differences in cell gene expression were greater with EBER2 deletion. In this system, deletion of EBER1 or EBER2 had little effect on the EBV transformation frequency of primary B cells or the growth of the resulting LCLs. Using the recombinant viruses and novel EBER expression vectors, the nuclear redistribution of rpL22 protein by EBER1 in 293 cells was confirmed, but in LCLs almost all of the cells had a predominantly cytoplasmic expression of this ribosomal protein, which was not detectably changed by EBER1. The changes in LCL gene expression identified here will provide a basis for identifying the mechanisms of action of EBER RNAs. PMID- 21248032 TI - Prion propagation in cells expressing PrP glycosylation mutants. AB - Infection by prions involves conversion of a host-encoded cell surface protein (PrP(C)) to a disease-related isoform (PrP(Sc)). PrP(C) carries two glycosylation sites variably occupied by complex N-glycans, which have been suggested by previous studies to influence the susceptibility to these diseases and to determine characteristics of prion strains. We used the Rov cell system, which is susceptible to sheep prions, to generate a series of PrP(C) glycosylation mutants with mutations at one or both attachment sites. We examined their subcellular trafficking and ability to convert into PrP(Sc) and to sustain stable prion propagation in the absence of wild-type PrP. The susceptibility to infection of mutants monoglycosylated at either site differed dramatically depending on the amino acid substitution. Aglycosylated double mutants showed overaccumulation in the Golgi compartment and failed to be infected. Introduction of an ectopic glycosylation site near the N terminus fully restored cell surface expression of PrP but not convertibility into PrP(Sc), while PrP(C) with three glycosylation sites conferred cell permissiveness to infection similarly to the wild type. In contrast, predominantly aglycosylated molecules with nonmutated N-glycosylation sequons, produced in cells expressing glycosylphosphatidylinositol-anchorless PrP(C), were able to form infectious PrP(Sc). Together our findings suggest that glycosylation is important for efficient trafficking of anchored PrP to the cell surface and sustained prion propagation. However, properly trafficked glycosylation mutants were not necessarily prone to conversion, thus making it difficult in such studies to discern whether the amino acid changes or glycan chain removal most influences the permissiveness to prion infection. PMID- 21248033 TI - Effect of B-cell depletion on coreceptor switching in R5 simian-human immunodeficiency virus infection of rhesus macaques. AB - We recently described a coreceptor switch in rapid progressor (RP) R5 simian human immunodeficiency virus SF162P3N (SHIV(SF162P3N))-infected rhesus macaques that had high virus replication and undetectable or weak and transient antiviral antibody response (S. H. Ho et al., J. Virol. 81:8621-8633, 2007; S. H. Ho, N. Trunova, A. Gettie, J. Blanchard, and C. Cheng-Mayer, J. Virol. 82:5653-5656, 2008; and W. Ren et al., J. Virol. 84:340-351, 2010). The lack of antibody selective pressure, together with the observation that the emerging X4 variants were neutralization sensitive, suggested that the absence or weakening of the virus-specific humoral immune response could be an environmental factor fostering coreceptor switching in vivo. To test this possibility, we treated four macaques with 50 mg/kg of body weight of the anti-CD20 antibody rituximab every 2 to 3 weeks starting from the week prior to intravenous infection with SHIV(SF162P3N) for a total of six infusions. Rituximab treatment successfully depleted peripheral and lymphoid CD20(+) cells for up to 25 weeks according to flow cytometry and immunohistochemical staining, with partial to full recovery in two of the four treated monkeys thereafter. Three of the four treated macaques failed to mount a detectable anti-SHIV antibody response, while the response was delayed in the remaining animal. The three seronegative macaques progressed to disease, but in none of them could the presence of X4 variants be demonstrated by V3 sequence and tropism analyses. Furthermore, viruses did not evolve early in these diseased macaques to be more soluble CD4 sensitive. These results demonstrate that the absence or diminution of humoral immune responses by itself is insufficient to drive the R5-to-X4 switch and the neutralization susceptibility of the evolving viruses. PMID- 21248034 TI - M062 is a host range factor essential for myxoma virus pathogenesis and functions as an antagonist of host SAMD9 in human cells. AB - Myxoma virus (MYXV) M062R is a functional homolog of the C7L family of host range genes from orthopoxviruses. We constructed a targeted M062R-knockout-MYXV (vMyxM062-KO) and characterized its properties in vitro and in vivo. In European rabbits, infection by vMyxM062-KO was completely asymptomatic. The surviving rabbits did not gain full protection against the subsequent lethal-dose challenge with wild-type MYXV. We also looked for cellular tropism defects in a variety of cultured cells. In all of the rabbit cells tested, vMyxM062-KO conducts an abortive infection, although it initiates viral DNA replication. In many, but not all, human cancer cells that are permissive for wild-type MYXV, vMyxM062-KO exhibited a profound replication defect. We categorized human cells tested into two groups: (i) type A, which support productive replication for wild-type MYXV but are unable to produce significant levels of progeny virus by vMyxM062-KO, and (ii) type B, which are permissive to infections by both wild-type MYXV and vMyxM062-KO. Furthermore, using proteomic strategies, we identified sterile alpha motif domain containing 9 (SAMD9), an interferon-regulated cellular protein implicated in human inflammatory disorders, as a unique host binding partner of M062 in human cells. Significantly, knocking down SAMD9 in type A human cancer cells led to a substantial rescue of vMyxM062-KO infection. In summary, M062 is a novel host range factor that controls productive MYXV replication in rabbit cells and in a wide variety of human cells. M062 also binds and antagonizes cellular SAMD9 in human cells, suggesting that SAMD9 is a novel innate antiviral factor against poxviruses. PMID- 21248036 TI - Human cytomegalovirus UL97 kinase and nonkinase functions mediate viral cytoplasmic secondary envelopment. AB - Previous studies have revealed critical roles for the human cytomegalovirus (HCMV) UL97 kinase in viral nuclear maturation events. We have shown recently that UL97 affects the morphology of the viral cytoplasmic assembly compartment (AC) (M. Azzeh, A. Honigman, A. Taraboulos, A. Rouvinski, and D. G. Wolf, Virology 354:69-79, 2006). Here, we employed a comprehensive ultrastructural analysis to dissect the impact of UL97 on cytoplasmic steps of HCMV assembly. Using UL97 deletion (DeltaUL97) and kinase-null (K355M) mutants, as well as the UL97 kinase inhibitor NGIC-I, we demonstrated that the loss of UL97 kinase activity resulted in a unique combination of cytoplasmic features: (i) the formation of pp65-rich aberrant cytoplasmic tegument aggregates, (ii) distorted intracytoplasmic membranes, which replaced the normal architecture of the AC, and (iv) a paucity of cytoplasmic tegumented capsids and dense bodies (DBs). We further showed that these abnormal assembly intermediates did not result from impaired nuclear capsid maturation and egress per se by using 2-bromo-5,6 dichloro-1-(beta-d-ribofuranosyl) benzimidizole (BDCRB) to induce the artificial inhibition of nuclear maturation and the nucleocytoplasmic translocation of capsids. The specific abrogation of UL97 kinase activity under low-multiplicity of-infection conditions resulted in the improved release of extracellular virus compared to that of DeltaUL97, despite similar rates of viral DNA accumulation and similar effects on nuclear capsid maturation and egress. The only ultrastructural correlate of the growth difference was a higher number of cytoplasmic DBs, tegumented capsids, and clustered viral particles observed upon the specific abrogation of UL97 kinase activity compared to that of DeltaUL97. These combined findings reveal a novel role for UL97 in HCMV cytoplasmic secondary envelopment steps, with a further distinction of kinase-mediated function in the formation of the virus-induced AC and a nonkinase function enhancing the efficacy of viral tegumentation and release. PMID- 21248037 TI - Processing and localization of the african swine fever virus CD2v transmembrane protein. AB - The African swine fever virus (ASFV)-encoded CD2v transmembrane protein is required for the hemadsorption of red blood cells around infected cells and is also required for the inhibition of bystander lymphocyte proliferation in response to mitogens. We studied the expression of CD2v by expressing the gene with a V5 tag downstream from the signal peptide near the N terminus and a hemagglutinin (HA) tag at the C terminus. In ASFV-infected cells, a full-length glycosylated form of the CD2v protein, which migrated mainly as a 89-kDa product, was detected, as well as an N-terminal glycosylated fragment of 63 kDa and a C terminal nonglycosylated fragment of 26 kDa. All of these forms of the protein were localized in the membrane fraction of cells. The 26-kDa C-terminal fragment was also produced in infected cells treated with brefeldin A. These data indicate that the CD2v protein is cleaved within the luminal domain and that this occurs in the endoplasmic reticulum or Golgi compartments. Confocal microscopy showed that most of the expressed CD2v protein was localized within cells rather than at the cell surface. Comparison of the localization of full-length CD2v with that of a deletion mutant lacking all of the cytoplasmic tail apart from the 12 membrane proximal amino acids indicated that signals within the cytoplasmic tail are responsible for the predominant localization of the full-length and C-terminal 26 kDa fragment within membranes around the virus factories, which contain markers for the Golgi compartment. Processing of the CD2v protein was not observed in uninfected cells, indicating that it is induced by ASFV infection. PMID- 21248035 TI - Antigen-specific T-cell responses to a recombinant fowlpox virus are dependent on MyD88 and interleukin-18 and independent of Toll-like receptor 7 (TLR7)- and TLR9 mediated innate immune recognition. AB - Fowlpox virus (FWPV) is a double-stranded DNA virus long used as a live attenuated vaccine against poultry diseases, but more recent interest has focused on its use as a mammalian vaccine vector. Here, in a mouse model system using FWPV encoding the nominal target antigen chicken ovalbumin (OVA) (FWPV(OVA)), we describe for the first time some of the fundamental processes by which FWPV engages both the innate and adaptive immune systems. We show that Toll-like receptor 7 (TLR7) and TLR9 are important for type I interferon secretion by dendritic cells, while TLR9 is solely required for proinflammatory cytokine secretion. Despite this functional role for TLR7 and TLR9 in vitro, only the adapter protein myeloid differentiation primary response gene 88 (MyD88) was shown to be essential for the formation of adaptive immunity to FWPV(OVA) in vivo. The dependence on MyD88 was confined only to the T-cell compartment and was not related to its contribution to TLR signaling, dendritic cell maturation, or the capture and presentation of FWPV-derived OVA antigen. We demonstrate that this is not by means of mediating T-cell-dependent interleukin-1 (IL-1) signaling, but rather, we suggest that MyD88 functions to support T-cell-specific IL-18 receptor signaling, which in turn is essential for the formation of adaptive immunity to FWPV-encoded OVA. PMID- 21248038 TI - The V1V2 domain and an N-linked glycosylation site in the V3 loop of the HIV-1 envelope glycoprotein modulate neutralization sensitivity to the human broadly neutralizing antibody 2G12. AB - The broadly neutralizing human monoclonal antibody 2G12 binds to a carbohydrate dependent epitope involving three major potential N-linked glycosylation sites (PNGS) of gp120 (N295, N332, and N392). Through analysis of the sensitivity to 2G12 of pseudotyped viruses carrying envelope proteins from HIV-1 clade B infected long-term nonprogressors, we selected two naturally occurring env clones with opposite sensitivities to 2G12, albeit harboring the 3 particular PNGS known to be essential for 2G12 binding (N295, N332, and N392). The resistant clone presented a long and potentially heavily glycosylated V1V2 loop and an additional PNGS (N302) in the V3 loop. The sensitive clone harbored a short V1V2 loop and lacked the PNGS at N302. We created chimeric envelope genes by swapping the V1V2 domains of the two env clones. The influence of N302 on 2G12 sensitivity was assessed by PCR-based site-directed mutagenesis. Both the exchange of the V1V2 domain and the introduction of the PNGS at N302 on the 2G12-sensitive clone induced a significant decrease in sensitivity to 2G12. In contrast, the reverse V1V2 exchange and the removal of the PNGS at N302 on the 2G12-resistant clone increased sensitivity to 2G12, confirming the influence of these regions on 2G12 sensitivity. Our results, supported by a molecular-modeling study, suggest that both the V1V2 loop and an additional PNGS in V3 might limit access to the 2G12 epitope. PMID- 21248039 TI - The herpes simplex virus immediate-early ubiquitin ligase ICP0 induces degradation of the ICP0 repressor protein E2FBP1. AB - E2FBP1/hDRIL1, a DNA-binding A/T-rich interaction domain (ARID) family transcription factor, is expressed ubiquitously in human tissues and plays an essential role in maintaining the proliferation potential of passage-limited human fibroblasts by dissociating promyelocytic leukemia nuclear bodies (PML NBs). This effect on PML-NBs is similar to that of viral immediate-early gene products, such as infected cellular protein 0 (ICP0) from human herpes simplex virus 1 (HSV-1), which also disrupts PML-NBs to override the intrinsic cellular defense. Here we report that E2FBP1 inhibits accumulation of ICP0 RNA and, at the same time, is degraded via ICP0's herpes ubiquitin ligase 2 (HUL-2) activity upon HSV-1 infection. These reciprocal regulatory roles of ICP0 and E2FBP1 are linked in an ARID-dependent fashion. Our results suggest that E2FBP1 functions as an intrinsic cellular defense factor in spite of its PML-NB dissociation function. PMID- 21248040 TI - Human cytomegalovirus disrupts the major histocompatibility complex class I peptide-loading complex and inhibits tapasin gene transcription. AB - Major histocompatibility complex class I (MHC I) molecules present antigenic peptides for CD8(+) T-cell recognition. Prior to cell surface expression, proper MHC I loading is conducted by the peptide-loading complex (PLC), composed of the MHC I heavy chain (HC) and beta(2)-microglobulin (beta(2)m), the peptide transporter TAP, and several chaperones, including tapasin. Tapasin connects peptide-receptive MHC I molecules to the PLC, thereby facilitating loading of high-affinity peptides onto MHC I. To cope with CD8(+) T-cell responses, human cytomegalovirus (HCMV) encodes several posttranslational strategies inhibiting peptide transport and MHC I biogenesis which have been studied extensively in transfected cells. Here we analyzed assembly of the PLC in naturally HCMV infected fibroblasts throughout the protracted replication cycle. MHC I incorporation into the PLC was absent early in HCMV infection. Subsequently, tapasin neosynthesis became strongly reduced, while tapasin steady-state levels diminished only slowly in infected cells, revealing a blocked synthesis rather than degradation. Tapasin mRNA levels were continuously downregulated during infection, while tapasin transcripts remained stable and long-lived. Taking advantage of a novel method by which de novo transcribed RNA is selectively labeled and analyzed, an immediate decline of tapasin transcription was seen, followed by downregulation of TAP2 and TAP1 gene expression. However, upon forced expression of tapasin in HCMV-infected cells, repair of MHC I incorporation into the PLC was relatively inefficient, suggesting an additional level of HCMV interference. The data presented here document a two-pronged coordinated attack on tapasin function by HCMV. PMID- 21248041 TI - Vital role for CD8+ cells in controlling retroviral infections. AB - Antiviral adaptive immune defenses consist of humoral and cell-mediated responses, which together eliminate extracellular and intracellular virus. As most retrovirus-infected individuals do not raise efficient protective antivirus immune responses, the relative importance of humoral and cell-mediated responses in restraining retroviral infection is not well understood. We utilized retrovirus-resistant I/LnJ mice, which control infection with mouse mammary tumor virus (MMTV) and murine leukemia virus (MuLV) via an adaptive immune mechanism, to assess the contribution of cellular responses and virus-neutralizing antibodies (Abs) to the control of retroviral infection. We found that in retrovirus-infected CD8-deficient I/LnJ mice, viral titers exceed the neutralizing capability of antiviral Abs, resulting in augmented virus spread and disease induction. Thus, even in the presence of robust neutralizing Ab responses, CD8-mediated responses are essential for full protection against retroviral infection. PMID- 21248042 TI - Src kinase mediates productive endocytic sorting of reovirus during cell entry. AB - Reovirus cell entry is initiated by viral attachment to cell surface glycans and junctional adhesion molecule A. Following receptor engagement, reovirus is internalized into cells by receptor-mediated endocytosis using a process dependent on beta1 integrin. Endocytosed virions undergo stepwise disassembly catalyzed by cathepsin proteases, followed by endosomal membrane penetration and delivery of transcriptionally active core particles into the cytoplasm. Cellular factors that mediate reovirus endocytosis are poorly defined. We found that both genistein, a broad-spectrum tyrosine kinase inhibitor, and PP2, a specific Src family kinase inhibitor, diminish reovirus infectivity by blocking a cell entry step. Although neither inhibitor impedes internalization of reovirus virions, both inhibitors target virions to lysosomes. Reovirus colocalizes with Src during cell entry, and reovirus infection induces phosphorylation of Src at the activation residue, tyrosine 416. Diminished Src expression by RNA interference reduces reovirus infectivity, suggesting that Src is required for efficient reovirus entry. Collectively, these data provide evidence that Src kinase is an important mediator of signaling events that regulate the appropriate sorting of reovirus particles in the endocytic pathway for disassembly and cell entry. PMID- 21248043 TI - Rotavirus VP2 core shell regions critical for viral polymerase activation. AB - The innermost VP2 core shell of the triple-layered, icosahedral rotavirus particle surrounds the viral genome and RNA processing enzymes, including the RNA dependent RNA polymerase (VP1). In addition to anchoring VP1 within the core, VP2 is also an essential cofactor that triggers the polymerase to initiate double stranded RNA (dsRNA) synthesis using packaged plus-strand RNA templates. The VP2 requirement effectively couples packaging with genome replication and ensures that VP1 makes dsRNA only within an assembling previrion particle. However, the mechanism by which the rotavirus core shell protein activates the viral polymerase remains very poorly understood. In the current study, we sought to elucidate VP2 regions critical for VP1-mediated in vitro dsRNA synthesis. By comparing the functions of proteins from several different rotaviruses, we found that polymerase activation by the core shell protein is specific. Through truncation and chimera mutagenesis, we demonstrate that the VP2 amino terminus, which forms a decameric, internal hub underneath each 5-fold axis, plays an important but nonspecific role in VP1 activation. Our results indicate that the VP2 residues correlating with polymerase activation specificity are located on the inner face of the core shell, distinct from the amino terminus. Based on these findings, we predict that several regions of VP2 engage the polymerase during the concerted processes of rotavirus core assembly and genome replication. PMID- 21248044 TI - Coevolution of the hepatitis C virus polyprotein sites in patients on combined pegylated interferon and ribavirin therapy. AB - Genotype-specific sensitivity of the hepatitis C virus (HCV) to interferon ribavirin (IFN-RBV) combination therapy and reduced HCV response to IFN-RBV as infection progresses from acute to chronic infection suggest that HCV genetic factors and intrahost HCV evolution play important roles in therapy outcomes. HCV polyprotein sequences (n = 40) from 10 patients with unsustainable response (UR) (breakthrough and relapse) and 10 patients with no response (NR) following therapy were identified through the Virahep-C study. Bayesian networks (BNs) were constructed to relate interrelationships among HCV polymorphic sites to UR/NR outcomes. All models showed an extensive interdependence of HCV sites and strong connections (P <= 0.003) to therapy response. Although all HCV proteins contributed to the networks, the topological properties of sites differed among proteins. E2 and NS5A together contributed ~40% of all sites and ~62% of all links to the polyprotein BN. The NS5A BN and E2 BN predicted UR/NR outcomes with 85% and 97.5% accuracy, respectively, in 10-fold cross-validation experiments. The NS5A model constructed using physicochemical properties of only five sites was shown to predict the UR/NR outcomes with 83.3% accuracy for 6 UR and 12 NR cases of the HALT-C study. Thus, HCV adaptation to IFN-RBV is a complex trait encoded in the interrelationships among many sites along the entire HCV polyprotein. E2 and NS5A generate broad epistatic connectivity across the HCV polyprotein and essentially shape intrahost HCV evolution toward the IFN-RBV resistance. Both proteins can be used to accurately predict the outcomes of IFN RBV therapy. PMID- 21248045 TI - Involvement of p32 and microtubules in alteration of mitochondrial functions by rubella virus. AB - The interaction of the rubella virus (RV) capsid (C) protein and the mitochondrial p32 protein is believed to participate in virus replication. In this study, the physiological significance of the association of RV with mitochondria was investigated by silencing p32 through RNA interference. It was demonstrated that downregulation of p32 interferes with microtubule-directed redistribution of mitochondria in RV-infected cells. However, the association of the viral C protein with mitochondria was not affected. When cell lines either pretreated with respiratory chain inhibitors or cultivated under (mild) hypoxic conditions were infected with RV, viral replication was reduced in a time dependent fashion. Additionally, RV infection induces increased activity of mitochondrial electron transport chain complex III, which was associated with an increase in the mitochondrial membrane potential. These effects are outstanding among the examples of mitochondrial alterations caused by viruses. In contrast to the preferential localization of p32 to the mitochondrial matrix in most cell lines, RV-permissive cell lines were characterized by an almost exclusive membrane association of p32. Conceivably, this contributes to p32 function(s) during RV replication. The data presented suggest that p32 fulfills an essential function for RV replication in directing trafficking of mitochondria near sites of viral replication to meet the energy demands of the virus. PMID- 21248046 TI - Expression of the human endogenous retrovirus (HERV) group HML-2/HERV-K does not depend on canonical promoter elements but is regulated by transcription factors Sp1 and Sp3. AB - After fixation in the human genome, human endogenous retroviruses (HERVs) are bona fide cellular genes despite their exogenous origin. To be able to spread within the germ line and the early embryo, the ancient retroviral promoters must have adapted to the requirements for expression in these cell types. We describe that in contrast to the case for current exogenous retroviruses, which replicate in specific somatic cells, the long terminal repeat (LTR) of the human endogenous retrovirus HERV-K acts as a TATA- and initiator element-independent promoter with a variable transcription start site. We present evidence that the HERV-K LTR is regulated by the transcription factors Sp1 and Sp3. Mutating specific GC boxes, which are binding sites for Sp proteins, and knocking down Sp1 and Sp3 by use of small interfering RNA (siRNA) significantly reduced the promoter activity. Binding of Sp1 and Sp3 to the promoter region was confirmed using electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP). Our data explain why certain HERV-K proviruses have lost promoter competence. Since vertebrate promoters lacking canonical core promoter elements are common but poorly studied, understanding the HERV-K promoter not only will provide insight into the regulation of endogenous retroviruses but also can serve as a paradigm for understanding the regulation of this class of cellular genes. PMID- 21248047 TI - Adenovirus virus-associated RNAs induce type I interferon expression through a RIG-I-mediated pathway. AB - The current study demonstrates that adenovirus virus-associated RNA (VA) is recognized by retinoic acid-inducible gene I (RIG-I), a cytosolic pattern recognition receptor, and activates RIG-I downstream signaling, leading to the induction of type I interferons (IFNs), similarly to Epstein-Barr virus-encoded small RNA. Further analysis revealed that adenovirus infection leads to biphasic type I IFN induction at 12 to 24 h and 48 to 60 h postinfection. The later induction coincided with VA expression and was reduced by virus UV inactivation or RIG-I silencing. These results suggest that VA-mediated RIG-I activation is involved in activating innate immune responses during adenovirus infection. PMID- 21248048 TI - Reappraisal of the relationship between the HIV-1-protective single-nucleotide polymorphism 35 kilobases upstream of the HLA-C gene and surface HLA-C expression. AB - Previous studies have found an association between a single-nucleotide polymorphism 35 kb upstream of the HLA-C locus (-35 SNP), HLA-C expression, and HIV-1 set point viral loads. We show that the difference in HLA-C expression across -35 SNP genotypes can be attributed primarily to the very low expression of a single allelic product, HLA-Cw7, which is a common HLA type. We suggest that association of the -35 SNP and HIV-1 load manifests as a result of linkage disequilibrium of this polymorphism with both favorable and unfavorable HLA-C and -B alleles. PMID- 21248050 TI - Effect of drilling fluid systems and temperature on oil mist and vapour levels generated from shale shaker. AB - Workers in the drilling section of the offshore petroleum industry are exposed to air pollutants generated by drilling fluids. Oil mist and oil vapour concentrations have been measured in the drilling fluid processing areas for decades; however, little work has been carried out to investigate exposure determinants such as drilling fluid viscosity and temperature. A study was undertaken to investigate the effect of two different oil-based drilling fluid systems and their temperature on oil mist, oil vapour, and total volatile organic compounds (TVOC) levels in a simulated shale shaker room at a purpose-built test centre. Oil mist and oil vapour concentrations were sampled simultaneously using a sampling arrangement consisting of a Millipore closed cassette loaded with glass fibre and cellulose acetate filters attached to a backup charcoal tube. TVOCs were measured by a PhoCheck photo-ionization detector direct reading instrument. Concentrations of oil mist, oil vapour, and TVOC in the atmosphere surrounding the shale shaker were assessed during three separate test periods. Two oil-based drilling fluids, denoted 'System 2.0' and 'System 3.5', containing base oils with a viscosity of 2.0 and 3.3-3.7 mm(2) s(-1) at 40 degrees C, respectively, were used at temperatures ranging from 40 to 75 degrees C. In general, the System 2.0 yielded low oil mist levels, but high oil vapour concentrations, while the opposite was found for the System 3.5. Statistical significant differences between the drilling fluid systems were found for oil mist (P = 0.025),vapour (P < 0.001), and TVOC (P = 0.011). Increasing temperature increased the oil mist, oil vapour, and TVOC levels. Oil vapour levels at the test facility exceeded the Norwegian oil vapour occupational exposure limit (OEL) of 30 mg m(-3) when the drilling fluid temperature was >=50 degrees C. The practice of testing compliance of oil vapour exposure from drilling fluids systems containing base oils with viscosity of <=2.0 mm(2) s(-1) at 40 degrees C against the Norwegian oil vapour OEL is questioned since these base oils are very similar to white spirit. To reduce exposures, relevant technical control measures in this area are to cool the drilling fluid <50 degrees C before it enters the shale shaker units, enclose shale shakers and related equipment, in addition to careful consideration of which fluid system to use. PMID- 21248049 TI - Requirement for the amino-terminal domain of sindbis virus nsP4 during virus infection. AB - The Sindbis virus RNA-dependent RNA polymerase nsP4 possesses an amino-terminal region that is unique to alphaviruses and is predicted to be disordered. To determine the importance of this region during alphavirus replication, 29 mutations were introduced, and resultant viruses were assessed for growth defects. Three small plaque mutants, D41A, G83L, and the triple mutant GPG((8 10))VAV, had defects in subgenome synthesis, minus-strand synthesis, and overall levels of viral RNA synthesis, respectively. Large plaque viruses were selected following passage in BHK-21 cells, and the genomes of these were sequenced. Suppressor mutations in nsP1, nsP2, and nsP3 that restored viral RNA synthesis were identified. An nsP2 change from M282 to L and an nsP3 change from H99 to N corrected the D41A-induced defect in subgenomic RNA synthesis. Three changes in nsP1, I351 to V, I388 to V, or the previously identified change, N374 to H (C. L. Fata, S. G. Sawicki, and D. L. Sawicki, J. Virol. 76:8641-8649, 2002), suppressed the minus-strand synthetic defect. A direct reversion back to G at position 8 reduced the RNA synthesis defect of the GPG((8-10))VAV virus. These results imply that nsP4's amino-terminal domain participates in distinct interactions with other nsPs in the context of differentially functioning RNA synthetic complexes, and flexibility in this domain is important for viral RNA synthesis. Additionally, the inability of the mutant viruses to efficiently inhibit host protein synthesis suggests a role for nsP4 in the regulation of host cell gene expression. PMID- 21248051 TI - Role of sulfhydryl-dependent dimerization of soluble guanylyl cyclase in relaxation of porcine coronary artery to nitric oxide. AB - AIMS: Soluble guanylyl cyclase (sGC) is a heterodimer. The dimerization of the enzyme is obligatory for its function in mediating actions caused by agents that elevate cyclic guanosine monophosphate (cGMP). The present study aimed to determine whether sGC dimerization is modulated by thiol-reducing agents and whether its dimerization influences relaxations in response to nitric oxide (NO). METHODS AND RESULTS: The dimers and monomers of sGC and cGMP-dependent protein kinase (PKG) were analysed by western blotting. The intracellular cGMP content was measured by enzyme-linked immunosorbent assay. Changes in isometric tension were determined in organ chambers. In isolated porcine coronary arteries, the protein levels of sGC dimer were decreased by the thiol reductants dithiothreitol, l-cysteine, reduced l-glutathione and tris(2-carboxyethyl) phosphine. The effect was associated with reduced cGMP elevation and attenuated relaxations in response to nitric oxide donors. The dimerization of sGC and activation of the enzyme were also decreased by dihydrolipoic acid, an endogenous thiol antioxidant. Dithiothreitol at concentrations markedly affecting the dimerization of sGC had no significant effect on the dimerization of PKG or relaxation in response to 8-Br-cGMP. Relaxation of the coronary artery in response to a NO donor was potentiated by hypoxia when sGC was partly inhibited, coincident with an increase in sGC dimer and enhanced cGMP production. These effects were prevented by dithiothreitol and tris(2-carboxyethyl) phosphine. CONCLUSION: These results demonstrate that the dimerization of sGC is exquisitely sensitive to thiol reductants compared with that of PKG, which may provide a novel mechanism for thiol-dependent modulation of NO-mediated vasodilatation in conditions such as hypoxia. PMID- 21248056 TI - Follow-up survey of children who received sulfadoxine-pyrimethamine for intermittent preventive antimalarial treatment in infants. AB - Recently, the World Health Organization emphasized the potential benefit of intermittent preventive treatment in infants (IPTi) to control malaria and officially recommended implementation of IPTi with sulfadoxine-pyrimethamine (SP) in areas with moderate and high transmission, where SP resistance is not high. As reported rebound effects make further observation mandatory, we performed a survey of participants of a former IPTi trial. Malariometric parameters were similar in the SP and the placebo group. In contrast, anti-Plasmodium falciparum lysate immunoglobulin G antibody levels, a proxy measure for preceding malaria episodes, remained lower in the SP arm. The most likely explanation is a lower overall exposure to parasitic antigens after IPTi. PMID- 21248057 TI - Reticulospinal neurons controlling forward and backward swimming in the lamprey. AB - Most vertebrates are capable of two forms of locomotion, forward and backward, strongly differing in the patterns of motor coordination. Basic mechanisms generating these patterns are located in the spinal cord; they are activated and regulated by supraspinal commands. In the lamprey, these commands are transmitted by reticulospinal (RS) neurons. The aim of this study was to reveal groups of RS neurons controlling different aspects of forward (FS) and backward (BS) swimming in the lamprey. Activity of individual larger RS neurons in intact lampreys was recorded during FS and BS by chronically implanted electrodes. It was found that among the neurons activated during locomotion, 27% were active only during FS, 3% only during BS, and 70% during both FS and BS. In a portion of RS neurons, their mean firing frequency was correlated with frequency of body undulations during FS (8%), during BS (34%), or during both FS and BS (22%), suggesting their involvement in control of locomotion intensity. RS activity was phasically modulated by the locomotor rhythm during FS (20% of neurons), during BS (29%), or during both FS and BS (16%). The majority of RS neurons responding to vestibular stimulation (and presumably involved in control of body orientation) were active mainly during FS. This explains the absence of stabilization of the body orientation observed during BS. We discuss possible functions of different groups of RS neurons, i.e., activation of the spinal locomotor CPG, inversion of the direction of propagation of locomotor waves, and postural control. PMID- 21248059 TI - Neocortical layer 4 as a pluripotent function linearizer. AB - A highly effective kernel-based strategy used in machine learning is to transform the input space into a new "feature" space where nonlinear problems become linear and more readily solvable with efficient linear techniques. We propose that a similar "problem-linearization" strategy is used by the neocortical input layer 4 to reduce the difficulty of learning nonlinear relations between the afferent inputs to a cortical column and its to-be-learned upper layer outputs. The key to this strategy is the presence of broadly tuned feed-forward inhibition in layer 4: it turns local layer 4 domains into functional analogs of radial basis function networks, which are known for their universal function approximation capabilities. With the use of a computational model of layer 4 with feed-forward inhibition and Hebbian afferent connections, self-organized on natural images to closely match structural and functional properties of layer 4 of the cat primary visual cortex, we show that such layer-4-like networks have a strong intrinsic tendency to perform input transforms that automatically linearize a broad repertoire of potential nonlinear functions over the afferent inputs. This capacity for pluripotent function linearization, which is highly robust to variations in network parameters, suggests that layer 4 might contribute importantly to sensory information processing as a pluripotent function linearizer, performing such a transform of afferent inputs to a cortical column that makes it possible for neurons in the upper layers of the column to learn and perform their complex functions using primarily linear operations. PMID- 21248058 TI - The timing of associative memory formation: frontal lobe and anterior medial temporal lobe activity at associative binding predicts memory. AB - The process of associating items encountered over time and across variable time delays is fundamental for creating memories in daily life, such as for stories and episodes. Forming associative memory for temporally discontiguous items involves medial temporal lobe structures and additional neocortical processing regions, including prefrontal cortex, parietal lobe, and lateral occipital regions. However, most prior memory studies, using concurrently presented stimuli, have failed to examine the temporal aspect of successful associative memory formation to identify when activity in these brain regions is predictive of associative memory formation. In the current study, functional MRI data were acquired while subjects were shown pairs of sequentially presented visual images with a fixed interitem delay within pairs. This design allowed the entire time course of the trial to be analyzed, starting from onset of the first item, across the 5.5-s delay period, and through offset of the second item. Subjects then completed a postscan recognition test for the items and associations they encoded during the scan and their confidence for each. After controlling for item-memory strength, we isolated brain regions selectively involved in associative encoding. Consistent with prior findings, increased regional activity predicting subsequent associative memory success was found in anterior medial temporal lobe regions of left perirhinal and entorhinal cortices and in left prefrontal cortex and lateral occipital regions. The temporal separation within each pair, however, allowed extension of these findings by isolating the timing of regional involvement, showing that increased response in these regions occurs during binding but not during maintenance. PMID- 21248060 TI - Adaptations in biceps brachii motor unit activity after repeated bouts of eccentric exercise in elbow flexor muscles. AB - The purpose of this study was to examine changes in motor unit activity in the biceps brachii muscle after an initial (Bout 1) and repeated (Bout 2) session of eccentric exercise separated by 1 wk. Eight subjects (aged 22 +/- 2 yr) participated in experimental assessments of neuromuscular function obtained before, immediately after, 24 h after, and 7 days after each exercise bout. Each experimental session involved assessments of elbow-flexor force and biceps and triceps brachii electromyography during maximum voluntary isometric contractions (MVCs) and constant-force isometric contractions at five contraction intensities (5-50% MVC), along with indicators of muscle damage (muscle pain and passive tension). In addition, motor unit recordings were obtained before exercise, 7 days after Bout 1, and 24 h after Bout 2 to assess motor unit synchronization and recruitment thresholds. Following a single eccentric exercise session that elicited significant indicators of muscle damage, we found a 57% increase in motor unit synchronization 7 days later compared with before exercise, despite the recovery of maximal strength, soreness, and relaxed elbow-joint angle at this time. Furthermore, a second bout of the same eccentric exercise resulted in reduced indicators of muscle damage and a decline in the strength of motor unit synchronization (24 h after Bout 2) toward levels observed before both exercise sessions. In contrast, no changes in motor unit recruitment thresholds were observed 7 days after Bout 1 or 24 h after Bout 2 compared with before exercise. The increased motor unit synchronization 7 days after a single eccentric exercise session provides new evidence of changes in motor unit activity during the putative repair and regeneration phase following eccentric muscle damage. PMID- 21248061 TI - Cell-derived vesicles exposing coagulant tissue factor in saliva. AB - On vascular damage, coagulation is initiated by extravascular tissue factor (TF). Intravascular TF, which is present on circulating cell-derived vesicles, is noncoagulant under physiologic conditions but prothrombotic under pathologic conditions. Human saliva triggers coagulation, but the mechanism and physiologic relevance are unknown. Because saliva is known to contain TF, we hypothesized that this TF may also be associated with cell-derived vesicles to facilitate coagulation when saliva directly contacts blood. The saliva-induced shortening of the clotting time of autologous plasma and whole blood from healthy subjects (n = 10) proved TF-dependent. This TF was associated with various types of cell derived vesicles, including microparticles and exosomes. The physiologic function was shown by adding saliva to human pericardial wound blood collected from patients undergoing cardiac surgery. Addition of saliva shortened the clotting time from 300 +/- 96 to 186 +/- 24 seconds (P = .03). Our results show that saliva triggers coagulation, thereby reducing blood loss and the risk of pathogens entering the blood. We postulate that our reflex to lick a wound may be a mechanism to enable TF-exposing vesicles, present in saliva, to aid in the coagulation process and thus protect the organism from entering pathogens. This unique compartmentalization may be highly conserved because also animals lick their wounds. PMID- 21248062 TI - Polyclonal fluctuation of lentiviral vector-transduced and expanded murine hematopoietic stem cells. AB - Gene therapy has proven its potential to cure diseases of the hematopoietic system. However, severe adverse events observed in clinical trials have demanded improved gene-transfer conditions. Whereas progress has been made to reduce the genotoxicity of integrating gene vectors, the role of pretransplantation cultivation is less well investigated. We observed that the STIF (stem cell factor [SCF], thrombopoietin [TPO], insulin-like growth factor-2 [IGF-2], and fibroblast growth factor-1 [FGF-1]) cytokine cocktail developed to effectively expand murine hematopoietic stem cells (HSCs) also supports the expansion of leukemia-initiating insertional mutants caused by gammaretroviral gene transfer. We compared 4 protocols to examine the impact of prestimulation and posttransduction culture in STIF in the context of lentiviral gene transfer. Observing 56 transplanted mice for up to 9.5 months, we found consistent engraftment and gene-marking rates after prolonged ex vivo expansion. Although a lentiviral vector with a validated insertional-mutagenic potential was used, longitudinal analysis identifying > 7000 integration sites revealed polyclonal fluctuations, especially in "expanded" groups, with de novo detection of clones even at late time points. Posttransduction expansion in STIF did not enrich clones with insertions in proto-oncogenes but rather increased clonal diversity. Our data indicate that lentiviral transduction in optimized media mediates intact polyclonal hematopoiesis without selection for growth-promoting hits by posttransduction expansion. PMID- 21248063 TI - Bcr-Abl ubiquitination and Usp9x inhibition block kinase signaling and promote CML cell apoptosis. AB - Although chronic myelogenous leukemia (CML) is effectively controlled by Bcr-Abl kinase inhibitors, resistance to inhibitors, progressive disease, and incomplete eradication of Bcr-Abl-expressing cells are concerns for the long-term control and suppression of this disease. We describe a novel approach to targeting key proteins in CML cells with a ubiquitin-cycle inhibitor, WP1130. Bcr-Abl is rapidly modified with K63-linked ubiquitin polymers in WP1130-treated CML cells, resulting in its accumulation in aggresomes, where is it unable to conduct signal transduction. Induction of apoptosis because of aggresomal compartmentalization of Bcr-Abl was observed in both imatinib-sensitive and -resistant cells. WP1130, but not Bcr-Abl kinase inhibitors, directly inhibits Usp9x deubiquitinase activity, resulting in the down-regulation of the prosurvival protein Mcl-1 and facilitating apoptosis. These results demonstrate that ubiquitin-cycle inhibition represents a novel and effective approach to blocking Bcr-Abl kinase signaling and reducing Mcl-1 levels to engage CML cell apoptosis. This approach may be a therapeutic option for kinase inhibitor-resistant CML patients. PMID- 21248064 TI - Visualization and identification of the structures formed during early stages of fibrin polymerization. AB - We determined the sequence of events and identified and quantitatively characterized the mobility of moving structures present during the early stages of fibrin-clot formation from the beginning of polymerization to the gel point. Three complementary techniques were used in parallel: spinning-disk confocal microscopy, transmission electron microscopy, and turbidity measurements. At the beginning of polymerization the major structures were monomers, whereas at the middle of the lag period there were monomers, oligomers, protofibrils (defined as structures that consisted of more than 8 monomers), and fibers. At the end of the lag period, there were primarily monomers and fibers, giving way to mainly fibers at the gel point. Diffusion rates were calculated from 2 different results, one based on sizes and another on the velocity of the observed structures, with similar results in the range of 3.8-0.1 MUm2/s. At the gel point, the diffusion coefficients corresponded to very large, slow-moving structures and individual protofibrils. The smallest moving structures visible by confocal microscopy during fibrin polymerization were identified as protofibrils with a length of approximately 0.5 MUm. The sequence of early events of clotting and the structures present are important for understanding hemostasis and thrombosis. PMID- 21248065 TI - Internet to boost patient accrual in oncology trials? A multiinstitutional AERIO study. PMID- 21248066 TI - Convalescent plasma treatment reduced mortality in patients with severe pandemic influenza A (H1N1) 2009 virus infection. AB - BACKGROUND: Experience from treating patients with Spanish influenza and influenza A(H5N1) suggested that convalescent plasma therapy might be beneficial. However, its efficacy in patients with severe pandemic influenza A(H1N1) 2009 virus (H1N1 2009) infection remained unknown. METHODS: During the period from 1 September 2009 through 30 June 2010, we conducted a prospective cohort study by recruiting patients aged >= 18 years with severe H1N1 2009 infection requiring intensive care. Patients were offered treatment with convalescent plasma with a neutralizing antibody titer of >= 1:160, harvested by apheresis from patients recovering from H1N1 2009 infection. Clinical outcome was compared with that of patients who declined plasma treatment as the untreated controls. RESULTS: Ninety three patients with severe H1N1 2009 infection requiring intensive care were recruited. Twenty patients (21.5%) received plasma treatment. The treatment and control groups were matched by age, sex, and disease severity scores. Mortality in the treatment group was significantly lower than in the nontreatment group (20.0% vs 54.8%; P = .01). Multivariate analysis showed that plasma treatment reduced mortality (odds ratio [OR], .20; 95% confidence interval [CI], .06-.69; P = .011), whereas complication of acute renal failure was independently associated with death (OR, 3.79; 95% CI, 1.15-12.4; P = .028). Subgroup analysis of 44 patients with serial respiratory tract viral load and cytokine level demonstrated that plasma treatment was associated with significantly lower day 3, 5, and 7 viral load, compared with the control group (P < .05). The corresponding temporal levels of interleukin 6, interleukin 10, and tumor necrosis factor alpha (P < .05) were also lower in the treatment group. CONCLUSIONS: Treatment of severe H1N1 2009 infection with convalescent plasma reduced respiratory tract viral load, serum cytokine response, and mortality. PMID- 21248067 TI - Carbon monoxide involved in modulating HCO3- secretion in rat duodenum. AB - We examined the effect of the tricarbonyl-dichlororuthenium (II) dimer (CORM-2), a carbon monoxide (CO) donor, on duodenal HCO(3)(-) secretion in rats and investigated whether endogenous CO produced by heme oxygenase (HO) is involved in the regulation of this secretion. Under urethane anesthesia, a duodenal loop was perfused with saline, and HCO(3)(-) secretion was measured at pH 7.0 using a pH stat method. CORM-2, biliverdin, FeCl(2), or ruthenium (III) chloride hydrate (RuCl(3)) was applied to the loop for 5 min. The mucosal application of CORM-2 dose-dependently increased HCO(3)(-) secretion, whereas neither RuCl(3), FeCl(2), nor biliverdin had an effect. The stimulatory effect was significantly attenuated by indomethacin but not N(G)-nitro-L-arginine methyl ester. The application of CORM-2 increased the mucosal prostaglandin (PG) E(2) content of the duodenum. The acid-induced HCO(3)(-) response was markedly inhibited by indomethacin and Sn(IV) protoporphyrin IX dichloride (SnPP; an inhibitor of HO) but not Cu(II) protoporphyrin dichloride, and the inhibitory effect of SnPP was significantly reversed by pretreatment with hemin, a substrate of HO. Perfusion of the duodenal loop with 100 mM HCl for 2 h caused a few hemorrhagic lesions in the mucosa, and this response was significantly worsened by the prior administration of SnPP and indomethacin. The expression of HO-1 but not HO-2 protein was up-regulated in the duodenum after the acid treatment. These results suggest that CO, generated endogenously or exogenously, stimulates HCO(3)(-) secretion in the duodenum, and this effect is mediated by endogenous PGs. It is assumed that HO/CO plays a role in maintaining the integrity of the duodenal mucosa. PMID- 21248068 TI - Increased presynaptic and postsynaptic alpha2-adrenoceptor activity in the spinal dorsal horn in painful diabetic neuropathy. AB - Diabetic neuropathy is a common cause of chronic pain that is not adequately relieved by conventional analgesics. The alpha(2)-adrenoceptors are involved in the regulation of glutamatergic input and nociceptive transmission in the spinal dorsal horn, but their functional changes in diabetic neuropathy are not clear. The purpose of the present study was to determine the plasticity of presynaptic and postsynaptic alpha(2)-adrenoceptors in the control of spinal glutamatergic synaptic transmission in painful diabetic neuropathy. Whole-cell voltage-clamp recordings of lamina II neurons were performed in spinal cord slices from streptozotocin-induced diabetic rats. The amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) evoked from the dorsal root and the frequency of spontaneous EPSCs (sEPSCs) were significantly higher in diabetic than vehicle control rats. The specific alpha(2)-adrenoceptor agonist 5-bromo-6-(2-imidazolin 2-ylamino)quinoxaline (UK-14304) (0.1-2 MUM) inhibited the frequency of sEPSCs more in diabetic than vehicle-treated rats. UK-14304 also inhibited the amplitude of evoked monosynaptic and polysynaptic EPSCs more in diabetic than control rats. Furthermore, the amplitude of postsynaptic G protein-coupled inwardly rectifying K(+) channel (GIRK) currents elicited by UK-14304 was significantly larger in the diabetic group than in the control group. In addition, intrathecal administration of UK-14304 increased the nociceptive threshold more in diabetic than vehicle control rats. Our findings suggest that diabetic neuropathy increases the activity of presynaptic and postsynaptic alpha(2)-adrenoceptors to attenuate glutamatergic transmission in the spinal dorsal horn, which accounts for the potentiated antinociceptive effect of alpha(2)-adrenoceptor activation in diabetic neuropathic pain. PMID- 21248069 TI - Intragenic rearrangement and altered RNA splicing of the androgen receptor in a cell-based model of prostate cancer progression. AB - Androgen depletion for advanced prostate cancer (PCa) targets activity of the androgen receptor (AR), a steroid receptor transcription factor required for PCa growth. The emergence of lethal castration-resistant PCa (CRPCa) is marked by aberrant reactivation of the AR despite ongoing androgen depletion. Recently, alternative splicing has been described as a mechanism giving rise to COOH terminally truncated, constitutively active AR isoforms that can support the CRPCa phenotype. However, the pathologic origin of these truncated AR isoforms is unknown. The goal of this study was to investigate alterations in AR expression arising in a cell-based model of PCa progression driven by truncated AR isoform activity. We show that stable, high-level expression of truncated AR isoforms in 22Rv1 CRPCa cells is associated with intragenic rearrangement of an approximately 35-kb AR genomic segment harboring a cluster of previously described alternative AR exons. Analysis of genomic data from clinical specimens indicated that related AR intragenic copy number alterations occurred in CRPCa in the context of AR amplification. Cloning of the break fusion junction in 22Rv1 cells revealed long interspersed nuclear elements (LINE-1) flanking the rearranged segment and a DNA repair signature consistent with microhomology-mediated, break-induced replication. This rearrangement served as a marker for the emergence of a rare subpopulation of CRPCa cells expressing high levels of truncated AR isoforms during PCa progression in vitro. Together, these data provide the first report of AR intragenic rearrangements in CRPCa and an association with pathologic expression of truncated AR isoforms in a cell-based model of PCa progression. PMID- 21248070 TI - Genome-wide analysis of alternative splicing in medulloblastoma identifies splicing patterns characteristic of normal cerebellar development. AB - Alternative splicing is an important mechanism for the generation of protein diversity at a post-transcriptional level. Modifications in the splicing patterns of several genes have been shown to contribute to the malignant transformation of different tissue types. In this study, we used the Affymetrix Exon arrays to investigate patterns of differential splicing between pediatric medulloblastomas and normal cerebellum on a genome-wide scale. Of the 1,262 genes identified as potentially generating tumor-associated splice forms, we selected 14 examples of differential splicing of known cassette exons and successfully validated 11 of them by reverse transcriptase PCR. The pattern of differential splicing of three validated events was characteristic for the molecular subset of sonic hedgehog (Shh)-driven medulloblastomas, suggesting that their unique gene signature includes the expression of distinctive transcript variants. Generally, we observed that tumor and normal fetal cerebellar samples shared significantly lower exon inclusion rates than normal adult cerebellum. We investigated whether tumor-associated splice forms were expressed in primary cultures of Shh-dependent mouse cerebellar granule cell precursors (GCP) and found that Shh caused a decrease in the cassette exon inclusion rate of five of the seven tested genes. Furthermore, we observed a significant increase in exon inclusion between postnatal days 7 and 14 of mouse cerebellar development, at the time when GCPs mature into postmitotic neurons. We conclude that inappropriate splicing frequently occurs in human medulloblastomas and may be linked to the activation of developmental signaling pathways and a failure of cerebellar precursor cells to differentiate. PMID- 21248071 TI - Zyxin is a critical regulator of the apoptotic HIPK2-p53 signaling axis. AB - HIPK2 activates the apoptotic arm of the DNA damage response by phosphorylating tumor suppressor p53 at serine 46. Unstressed cells keep HIPK2 levels low through targeted polyubiquitination and subsequent proteasomal degradation. Here we identify the LIM domain protein Zyxin as a novel regulator of the HIPK2-p53 signaling axis in response to DNA damage. Remarkably, depletion of endogenous Zyxin, which colocalizes with HIPK2 at the cytoskeleton and in the cell nucleus, stimulates proteasome-dependent HIPK2 degradation. In contrast, ectopic expression of Zyxin stabilizes HIPK2, even upon enforced expression of its ubiquitin ligase Siah-1. Consistently, Zyxin physically interacts with Siah-1, and knock-down of Siah-1 rescues HIPK2 expression in Zyxin-depleted cancer cells. Mechanistically, our data suggest that Zyxin regulates Siah-1 activity through interference with Siah-1 dimerization. Furthermore, we show that endogenous Zyxin coaccumulates with HIPK2 in response to DNA damage in cancer cells, and that depletion of endogenous Zyxin results in reduced HIPK2 protein levels and compromises DNA damage-induced p53 Ser46 phosphorylation and caspase activation. These findings suggest an unforeseen role for Zyxin in DNA damage-induced cell fate control through modulating the HIPK2-p53 signaling axis. PMID- 21248072 TI - Candidate reference measurement procedures for serum 25-hydroxyvitamin D3 and 25 hydroxyvitamin D2 by using isotope-dilution liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: 25-hydroxyvitamin D [25(OH)D] assays are characterized by poor between-assay comparability. This result emphasizes the need for reference measurement procedures (RMPs) to establish calibration traceability and assist in method validation. We aimed at developing candidate RMPs on the basis of isotope- dilution liquid chromatography-tandem mass spectrometry (ID-LC-MS/MS) for separate quantification of serum 25(OH)D2 and 25(OH)D3. METHODS: Hexa-deuterated 25(OH)D3/D2 was added to serum. This mixture was extracted with n-hexane and fractionated on Sephadex LH-20 before 2-dimensional LC-MS/MS. In the first dimension, both procedures used a C4 column; however, in the second dimension, the 25(OH)D2 procedure used a C18 and the 25(OH)D3 procedure used a Zorbax SB-CN column. Calibration was traceable to the NIST Standard Reference Material (SRM) 2972. Validation comprised assessment of interference and limit of quantification/detection. Imprecision and trueness were validated by analysis of the SRM 972 against specifications (CV<5% and bias<1.7%). The expanded uncertainty for quadruplicate measurements was estimated. RESULTS: Testing of potentially interfering substances was negative. Interference by 3-epi-25(OH)D3 was resolved by sufficient chromatographic resolution. The limits of quantification/detection were 1.1 nmol/L and 0.09 pmol/L for 25(OH)D3 and 1.2 nmol/L and 0.05 pmol/L for 25(OH)D(2). Mean total CVs and differences from the SRM 972 target (+/-1-sided 95% CI) were 2.1% and 1.1%+/-1.5% [25(OH)D3] and 3% and 1.3%+/-0.6% [25(OH)D2], respectively. The respective expanded uncertainties were 3.4% and 3.9%. CONCLUSIONS: From the validation data, we conclude that we achieved our objective of 2 state-of-the-art candidate RMPs for serum 25(OH)D3 and 25(OH)D2. PMID- 21248073 TI - Gene expression profiles in aldosterone-producing adenomas and adjacent adrenal glands. AB - BACKGROUND: Primary aldosteronism (PA) is the most common form of endocrine hypertension affecting ~8-10% of hypertensive subjects. Aldosterone production in PA occurs under low-renin conditions, and the mechanisms that maintain the production of aldosterone in PA remain unknown. Objective This study was designed to compare the transcript profiles between aldosterone-producing adenoma (APA) and their adjacent adrenal gland (AAG) from the same adrenal. METHODS: Total RNA was extracted from ten APA and ten AAG; and subsequently analyzed by microarray and real-time quantitative RT-PCR (qPCR). The microarray data were paired for each APA-AAG, and analyzed by GeneSpring GX 11 with paired t-test and fold change calculations for each transcript. Changes identified by microarray analysis were confirmed by qPCR. RESULTS: Microarray analysis indicated that 14 genes had significantly up-regulated expression in APA compared to AAG. Among the elevated genes were aldosterone synthase (CYP11B2) as well as novel transcription factors, calmodulin-binding proteins, and other genes that have not been previously studied in APA. Selective analysis of 11 steroidogenic enzymes using microarray demonstrated that only CYP11B2 showed a significantly higher transcript level in APA compared to AAG (P<0.001). In contrast, AKR1C3 (17beta-hydroxysteroid dehydrogenase type 5), CYP17 (17alpha-hydroxylase/17,20 lyase), and CYB5 (cytochrome b5) showed significantly lower transcript level in APA (P<0.05). CONCLUSION: The transcriptome analysis of APA compared with AAG showed several novel genes that are associated with APA phenotype. This gene list provides new candidates for the elucidation of the molecular mechanisms leading to PA. PMID- 21248074 TI - Coexpression-based clustering of Arabidopsis root genes predicts functional modules in early phosphate deficiency signaling. AB - Phosphate (Pi) deficiency triggers the differential expression of a large set of genes, which communally adapt the plant to low Pi bioavailability. To infer functional modules in early transcriptional responses to Pi deficiency, we conducted time-course microarray experiments and subsequent coexpression-based clustering of Pi-responsive genes by pairwise comparison of genes against a customized database. Three major clusters, enriched in genes putatively functioning in transcriptional regulation, root hair formation, and developmental adaptations, were predicted from this analysis. Validation of gene expression by quantitative reverse transcription-PCR revealed that transcripts from randomly selected genes were robustly induced within the first hour after transfer to Pi deplete medium. Pectin-related processes were among the earliest and most robust responses to Pi deficiency, indicating that cell wall alterations are critical in the early transcriptional response to Pi deficiency. Phenotypical analysis of homozygous mutants defective in the expression of genes from the root hair cluster revealed eight novel genes involved in Pi deficiency-induced root hair elongation. The plants responded rapidly to Pi deficiency by the induction of a subset of transcription factors, followed by a repression of genes involved in cell wall alterations. The combined results provide a novel, integrated view at a systems level of the root responses that acclimate Arabidopsis (Arabidopsis thaliana) to suboptimal Pi levels. PMID- 21248075 TI - Overexpression of sinapine esterase BnSCE3 in oilseed rape seeds triggers global changes in seed metabolism. AB - Sinapine (O-sinapoylcholine) is the predominant phenolic compound in a complex group of sinapate esters in seeds of oilseed rape (Brassica napus). Sinapine has antinutritive activity and prevents the use of seed protein for food and feed. A strategy was developed to lower its content in seeds by expressing an enzyme that hydrolyzes sinapine in developing rape seeds. During early stages of seedling development, a sinapine esterase (BnSCE3) hydrolyzes sinapine, releasing choline and sinapate. A portion of choline enters the phospholipid metabolism, and sinapate is routed via 1-O-sinapoyl-beta-glucose into sinapoylmalate. Transgenic oilseed rape lines were generated expressing BnSCE3 under the control of a seed specific promoter. Two distinct single-copy transgene insertion lines were isolated and propagated to generate homozygous lines, which were subjected to comprehensive phenotyping. Sinapine levels of transgenic seeds were less than 5% of wild-type levels, whereas choline levels were increased. Weight, size, and water content of transgenic seeds were significantly higher than those of wild type seeds. Seed quality parameters, such as fiber and glucosinolate levels, and agronomically important traits, such as oil and protein contents, differed only slightly, except that amounts of hemicellulose and cellulose were about 30% higher in transgenic compared with wild-type seeds. Electron microscopic examination revealed that a fraction of the transgenic seeds had morphological alterations, characterized by large cavities near the embryonic tissue. Transgenic seedlings were larger than wild-type seedlings, and young seedlings exhibited longer hypocotyls. Examination of metabolic profiles of transgenic seeds indicated that besides suppression of sinapine accumulation, there were other dramatic differences in primary and secondary metabolism. Mapping of these changes onto metabolic pathways revealed global effects of the transgenic BnSCE3 expression on seed metabolism. PMID- 21248076 TI - Photosynthesis-dependent but neochrome1-independent light positioning of chloroplasts and nuclei in the fern Adiantum capillus-veneris. AB - Chloroplasts change their positions in the cell depending on the light conditions. In the dark, chloroplasts in fern prothallia locate along the anticlinal wall (dark position). However, chloroplasts become relocated to the periclinal wall (light position) when the light shines perpendicularly to the prothallia. Red light is effective in inducing this relocation in Adiantum capillus-veneris, and neochrome1 (neo1) has been identified as the red light receptor regulating this movement. Nevertheless, we found here that chloroplasts in neo1 mutants still become relocated from the dark position to the light position under red light. We tested four neo1 mutant alleles (neo1-1, neo1-2, neo1-3, and neo1-4), and all of them showed the red-light-induced chloroplast relocation. Furthermore, chloroplast light positioning under red light occurred also in Pteris vittata, another fern species naturally lacking the neo1-dependent phenomenon. The light positioning of chloroplasts occurred independently of the direction of red light, a response different to that of the neo1-dependent movement. Photosynthesis inhibitors 3-(3,4 dichlorophenyl)-1,1-dimethylurea or 2,5-dibromo-3-isopropyl-6-methyl-p-benzoquinone blocked this movement. Addition of sucrose (Suc) or glucose to the culture medium induced migration of the chloroplasts to the periclinal wall in darkness. Furthermore, Suc could override the effects of 3-(3,4 dichlorophenyl)-1,1-dimethylurea. Interestingly, the same light positioning was evident for nuclei under red light in the neo1 mutant. The nuclear light positioning was also induced in darkness with the addition of Suc or glucose. These results indicate that photosynthesis-dependent nondirectional movement contributes to the light positioning of these organelles in addition to the neo1-dependent directional movement toward light. PMID- 21248077 TI - Temporal and spatial patterns of endogenous danger signal expression after wound healing and in response to lymphedema. AB - While acute tissue injury potently induces endogenous danger signal expression, the role of these molecules in chronic wound healing and lymphedema is undefined. The purpose of this study was to determine the spatial and temporal expression patterns of the endogenous danger signals high-mobility group box 1 (HMGB1) and heat shock protein (HSP)70 during wound healing and chronic lymphatic fluid stasis. In a surgical mouse tail model of tissue injury and lymphedema, HMGB1 and HSP70 expression occurred along a spatial gradient relative to the site of injury, with peak expression at the wound and greater than twofold reduced expression within 5 mm (P < 0.05). Expression primarily occurred in cells native to injured tissue. In particular, HMGB1 was highly expressed by lymphatic endothelial cells (>40% positivity; twofold increase in chronic inflammation, P < 0.001). We found similar findings using a peritoneal inflammation model. Interestingly, upregulation of HMGB1 (2.2-fold), HSP70 (1.4-fold), and nuclear factor (NF)-kappabeta activation persisted at least 6 wk postoperatively only in lymphedematous tissues. Similarly, we found upregulation of endogenous danger signals in soft tissue of the arm after axillary lymphadenectomy in a mouse model and in matched biopsy samples obtained from patients with secondary lymphedema comparing normal to lymphedematous arms (2.4-fold increased HMGB1, 1.9-fold increased HSP70; P < 0.01). Finally, HMGB1 blockade significantly reduced inflammatory lymphangiogenesis within inflamed draining lymph nodes (35% reduction, P < 0.01). In conclusion, HMGB1 and HSP70 are expressed along spatial gradients and upregulated in chronic lymphatic fluid stasis. Furthermore, acute expression of endogenous danger signals may play a role in inflammatory lymphangiogenesis. PMID- 21248078 TI - Wnt4 activates the canonical beta-catenin pathway and regulates negatively myostatin: functional implication in myogenesis. AB - Expression of Wnt proteins is known to be important for developmental processes such as embryonic pattern formation and determination of cell fate. Previous studies have shown that Wn4 was involved in the myogenic fate of somites, in the myogenic proliferation, and differentiation of skeletal muscle. However, the function of this factor in adult muscle homeostasis remains not well understood. Here, we focus on the roles of Wnt4 during C2C12 myoblasts and satellite cells differentiation. We analyzed its myogenic activity, its mechanism of action, and its interaction with the anti-myogenic factor myostatin during differentiation. Established expression profiles indicate clearly that both types of cells express a few Wnts, and among these, only Wnt4 was not or barely detected during proliferation and was strongly induced during differentiation. As attested by myogenic factors expression pattern analysis and fusion index determination, overexpression of Wnt4 protein caused a strong increase in satellite cells and C2C12 myoblast differentiation leading to hypertrophic myotubes. By contrast, exposure of satellite and C2C12 cells to small interfering RNA against Wnt4 strongly diminished this process, confirming the myogenic activity of Wnt4. Moreover, we reported that Wnt4, which is usually described as a noncanonical Wnt, activates the canonical beta-catenin pathway during myogenic differentiation in both cell types and that this factor regulates negatively the expression of myostatin and the regulating pathways associated with myostatin. Interestingly, we found that recombinant myostatin was sufficient to antagonize the differentiation-promoting activities of Wnt4. Reciprocally, we also found that the genetic deletion of myostatin renders the satellite cells refractory to the hypertrophic effect of Wnt4. These results suggest that the Wnt4-induced decrease of myostatin plays a functional role during hypertrophy. We propose that Wnt4 protein may be a key factor that regulates the extent of differentiation in satellite and C2C12 cells. PMID- 21248079 TI - Small GTPase Rab11b regulates degradation of surface membrane L-type Cav1.2 channels. AB - L-type Ca(2+) channels (LTCCs) play a critical role in Ca(2+)-dependent signaling processes in a variety of cell types. The number of functional LTCCs at the plasma membrane strongly influences the strength and duration of Ca(2+) signals. Recent studies demonstrated that endosomal trafficking provides a mechanism for dynamic changes in LTCC surface membrane density. The purpose of the current study was to determine whether the small GTPase Rab11b, a known regulator of endosomal recycling, impacts plasmalemmal expression of Ca(v)1.2 LTCCs. Disruption of endogenous Rab11b function with a dominant negative Rab11b S25N mutant led to a significant 64% increase in peak L-type Ba(2+) current (I(Ba,L)) in human embryonic kidney (HEK)293 cells. Short-hairpin RNA (shRNA)-mediated knockdown of Rab11b also significantly increased peak I(Ba,L) by 66% compared when with cells transfected with control shRNA, whereas knockdown of Rab11a did not impact I(Ba,L). Rab11b S25N led to a 1.7-fold increase in plasma membrane density of hemagglutinin epitope-tagged Ca(v)1.2 expressed in HEK293 cells. Cell surface biotinylation experiments demonstrated that Rab11b S25N does not significantly impact anterograde trafficking of LTCCs to the surface membrane but rather slows degradation of plasmalemmal Ca(v)1.2 channels. We further demonstrated Rab11b expression in ventricular myocardium and showed that Rab11b S25N significantly increases peak I(Ba,L) by 98% in neonatal mouse cardiac myocytes. These findings reveal a novel role for Rab11b in limiting, rather than promoting, the plasma membrane expression of Ca(v)1.2 LTCCs in contrast to its effects on other ion channels including human ether-a-go-go-related gene (hERG) K(+) channels and cystic fibrosis transmembrane conductance regulator. This suggests Rab11b differentially regulates the trafficking of distinct cargo and extends our understanding of how endosomal transport impacts the functional expression of LTCCs. PMID- 21248080 TI - Beyond translation: the renal phosphate census. Focus on "Large-scale phosphoproteomic analysis of membrane proteins in renal proximal and distal tubule". PMID- 21248081 TI - PHACES syndrome and ectopia cordis. AB - PHACES syndrome is a spectrum of anomalies, P, posterior fossa anomalies as Dandy Walker malformation; H, hemangioma; A, arterial lesions of the head and neck (the most commonly detected include dysplasia, aberrant origin or course, hypoplasia, and absence or agenesis); C, cardiac abnormalities as aortic coarctation; E, abnormalities of the eye and S, sternal defect, that may be present in up to 2% of children with facial hemangiomas and 20% of children with segmental facial hemangiomas. The constellation of PHACES syndrome symptoms may vary significantly between different patients. Major and minor criteria for PHACES syndrome have been recently described in order to improve their classification and management. We report the case of a newborn with PHACES syndrome, who had additional congenital defects including ectopia cordis as the most severe form of midline defect. Although the list and variety of published cardiac malformations in PHACES syndrome are extensive, ectopia cordis has not been previously reported. PMID- 21248082 TI - Enucleation of calcium core and in-situ valve replacement for massive posterior mitral annular calcification. AB - A 67-year-old female was admitted to our hospital for surgical treatment of the aortic and mitral valvular disease. She had chronic renal failure and dialysis was started 13 years previously. A diagnosis of severe aortic stenosis and regurgitation with severe mitral stenosis was made, and she underwent aortic valve and mitral valve replacement. Because mitral annular calcification had deeply invaded into the subvalvular region, enucleation of calcified core was performed using the ultrasonic aspiration system. The posterior mitral annulus was reconstructed using equine pericardium and aortic and mitral valve replacement was performed. The postoperative course was uneventful. PMID- 21248083 TI - Post-implantation syndrome following endovascular abdominal aortic aneurysm repair: preliminary data. AB - OBJECTIVES: Endovascular aneurysm repair (EVAR), may elicit an unexpected systemic inflammatory response, which has been named post-implantation syndrome (PIS). The aim of this study was to prospectively evaluate the association of PIS with clinical and laboratory parameters in patients who underwent EVAR for abdominal aortic aneurysms (AAA). METHODS: Forty consecutive patients who underwent EVAR for AAA were studied. Complete blood count, fibrinogen, high sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-1, tumor necrosis factor-alpha were determined before and after surgery. Several parameters regarding the operation, as well as the hospitalization days were recorded. RESULTS: PIS was diagnosed in 35% of the patients. Patients with PIS showed significant greater changes of inflammation marker levels, including hs-CRP and IL-6, as compared with the non-PIS group. PIS was associated with longer hospitalization. CONCLUSION: PIS is a relatively common complication of EVAR used to treat AAAs and it is associated with features of a systemic inflammatory response and prolongation of hospitalization. Further studies are necessary towards understanding the underlying pathophysiology and evaluating effective preventive strategies. PMID- 21248084 TI - Laboratory diagnosis, epidemiology, and clinical outcomes of pandemic influenza A and community respiratory viral infections in southern Brazil. AB - Community respiratory viruses (CRVs) are commonly associated with seasonal infections. They have been associated with higher morbidity and mortality among children, elderly individuals, and immunosuppressed patients. In April 2009, the circulation of a new influenza A virus (FLUA H1N1v) was responsible for the first influenza pandemic of this century. We report the clinical and epidemiological profiles of inpatients infected with CRVs or with FLUA H1N1v at a tertiary care hospital in southern Brazil. In addition, we used these profiles to evaluate survivor and nonsurvivor patients infected with FLUA H1N1v. Multiplex reverse transcription-PCR (RT-PCR) and real time RT-PCR were used to detect viruses in inpatients with respiratory infections. Record data from all patients were reviewed. A total of 171 patients were examined over a period of 16 weeks. Of these, 39% were positive for FLUA H1N1v, 36% were positive for CRVs, and 25% were negative. For the FLUA H1N1v- and CRV-infected patients, epidemiological data regarding median age (30 and 1.5 years), myalgia (44% and 13%), need for mechanical ventilation (44% and 9%), and mortality (35% and 9%) were statistically different. In a multivariate analysis comparing survivor and nonsurvivor patients infected with influenza A virus H1N1, median age and creatine phosphokinase levels were significantly associated with a severe outcome. Seasonal respiratory infections are a continuing concern. Our results highlight the importance of studies on the prevalence and severity of these infections and that investments in programs of clinical and laboratory monitoring are essential to detect the appearance of new infective agents. PMID- 21248085 TI - Molecular phylogenetic analysis of Enterobius vermicularis and development of an 18S ribosomal DNA-targeted diagnostic PCR. AB - We genetically characterized pinworms obtained from 37 children from different regions of Germany and established new species-specific molecular diagnostic tools. No ribosomal DNA diversity was found; the phylogenetic position of Enterobius vermicularis within the Oxyurida order and its close relationship to the Ascaridida and Spirurida orders was confirmed. PMID- 21248086 TI - Comparison of nine phenotypic methods for detection of extended-spectrum beta lactamase production by Enterobacteriaceae. AB - The detection of extended-spectrum beta-lactamase-producing (ESBL) bacteria is of importance for infection control and epidemiological surveillance. We aimed to compare phenotypic methods available in the routine laboratory and to evaluate two-step strategies using these methods for the detection of ESBL-positive Enterobacteriaceae. Two methods used for routine susceptibility testing (Vitek2 and disk diffusion methods) and seven methods designed for the detection of ESBL production (ESBL Etests, combination disks, double-disk synergy [DDS] methods on Mueller-Hinton [MH] agar and cloxacillin-containing MH agar, and the Cica-Beta test) were tested against 107 strains of Enterobacteriaceae not susceptible to extended-spectrum cephalosporins. All strains were screened for the presence of acquired ESBL-encoding genes by PCR, and the PCR result was considered the gold standard for evaluation of the other test methods. Among the 107 strains, 52 (49%) were ESBL positive. With Vitek2, sensitivities were the highest when using extended cards (73% to 79%), but 25% to 31% of the strains yielded indeterminate results. For the disk diffusion method, sensitivities were the highest (96%) when testing at least cefotaxime, cefepime, and a third compound (ceftazidime, cefpodoxime, or aztreonam). For the specific methods, specificities ranged from 62% (ceftazidime ESBL Etest) to 100% (DDS using a disk spacing of 20 mm). When a method designed for ESBL detection was used on strains considered ESBL negative or with an indeterminate result by a first routine susceptibility method, sensitivities reached 100% for a majority of combinations. In conclusion, two step strategies using phenotypic methods available in most clinical laboratories may reach a sensitivity of 100% for ESBL detection among a large panel of species, including AmpC producers, providing a sensible choice of tests. PMID- 21248087 TI - Outbreak of infections by hepatitis B virus genotype A and transmission of genetic drug resistance in patients coinfected with HIV-1 in Japan. AB - The major routes of hepatitis B virus (HBV) infection in Japan has been mother-to child transmission (MTCT) and blood transfusion. However, HBV cases transmitted through sexual contact are increasing, especially among HIV-1-seropositive patients. To understand the molecular epidemiology of HBV in HBV/HIV-1 coinfection, we analyzed HBV genotypes and HIV-1 subtypes in HBV/HIV-1-coinfected patients at Nagoya Medical Center from 2003 to 2007. Among 394 HIV-1-infected Japanese men having sex with men (MSM) who were newly diagnosed during the study period, 31 (7.9%) tested positive for the hepatitis B virus surface antigen. HBV sequence analyses were successful in 26 cases, with 21 (80.7%) and 5 (19.3%) cases determined as genotypes A and C, respectively. Our finding that HBV genotype A was dominant in HIV-1-seropositive patients alerts clinicians to an alternative outbreak of HBV genotype A in the HIV-1-infected MSM population and a shift in HBV genotype from C to A in Japan. The narrow genetic diversity in genotype A cases suggests that genotype A has been recently introduced into the MSM population and that sexual contacts among MSM were more active than speculated from HIV-1 tree analyses. In addition, we found a lamivudine resistance mutation in one naive case, suggesting a risk of drug-resistant HBV transmission. As genotype A infection has a higher risk than infection with other genotypes for individuals to become HBV carriers, prevention programs are urgently needed for the target population. PMID- 21248088 TI - Screening for urinary tract infection with the Sysmex UF-1000i urine flow cytometer. AB - The diagnosis of urinary tract infection (UTI) by urine culture is time-consuming and can produce up to 60 to 80% negative results. Fast screening methods that can reduce the necessity for urine cultures will have a large impact on overall turnaround time and laboratory economics. We have evaluated the detection of bacteria and leukocytes by a new urine analyzer, the UF-1000i, to identify negative urine samples that can be excluded from urine culture. In total, 1,577 urine samples were analyzed and compared to urine culture. Urine culture showed growth of >=10(3) CFU/ml in 939 samples (60%). Receiver operating characteristics (ROC) curves and ROC decision plots were been prepared at three different gold standard definitions of a negative urine culture: no growth, growth of bacteria at <10(4) CFU/ml, and growth of bacteria at <10(5) CFU/ml. Also, the reduction in urine cultures and the percentage of false negatives were calculated. At the most stringent gold standard definition of no growth, a chosen sensitivity of 95% resulted in a cutoff value of 26 bacteria/MUl, a specificity of 43% and a reduction in urine cultures of only 20%, of which 14% were false negatives. However, at a gold standard definition of <10(5) CFU/ml and a sensitivity of 95%, the UF-1000i cutoff value was 230 bacteria/MUl, the specificity was 80%, and the reduction in urine cultures was 52%, of which 0.3% were false negatives. The applicability of the UF-1000i to screen for negative urine samples strongly depends on population characteristics and the definition of a negative urine culture. In our setting, however, the low workload savings and the high percentage of false-negative results do not warrant the UF-1000i to be used as a screening analyzer. PMID- 21248089 TI - Relapse of Enterococcus hirae prosthetic valve endocarditis. AB - Enterococcus hirae, a gram-positive bacterium, is a rare isolate in clinical specimens. We report an unusual case of a relapse of prosthetic valve endocarditis due to E. hirae 6 months after the initial episode. Clonal relationship was proven by genomic analysis. PMID- 21248090 TI - Mistaken identity of Peptoniphilus asaccharolyticus. PMID- 21248091 TI - Nucleic Acid Amplification of the opa Gene for Detection of Neisseria gonorrhoeae: experience from a diagnostic laboratory. AB - We report results of Neisseria gonorrhoeae nucleic acid amplification testing (NAAT) with the Abbott m2000 PCR at a tertiary laboratory 6 months after its introduction. Of 5,475 specimens tested, 45 samples (0.82%) tested positive for N. gonorrhoeae. Eight were not cultured, but seven tested positive with a porA pseudogene NAAT. PMID- 21248092 TI - Direct genotyping of Toxoplasma gondii in ocular fluid samples from 20 patients with ocular toxoplasmosis: predominance of type II in France. AB - We report the direct genotyping analysis of Toxoplasma gondii in ocular samples collected from 20 patients, as well as associated clinical and epidemiological data. This work was aimed at better understanding the impact of genotypes of Toxoplasma gondii strains on toxoplasmic retinochoroiditis. For this purpose, we studied the aqueous humor (AH) or vitreous humor (VH) of 20 patients presenting with ocular toxoplasmosis (OT) in 2 hospitals in France. Genetic characterization was obtained with microsatellite markers in a multiplex PCR assay. In contrast to the results of previous studies, we found no association between atypical Toxoplasma gondii genotypes and the occurrence of OT. Considering the local epidemiological data, our OT patients seemed to be infected more frequently by ordinary type II strains found in the environment. In conclusion, direct genotyping of Toxoplasma gondii strains from aqueous or vitreous humor showed a predominance of the type II genotype in ocular toxoplasmosis; this may be due to a high exposure rate of this genotype in humans. PMID- 21248093 TI - Colorimetric-plate method for rapid disk diffusion susceptibility testing of Escherichia coli. AB - Here, we report a laboratory-developed colorimetric-plate method for rapid disk diffusion susceptibility testing of Escherichia coli. One hundred isolates were evaluated. Categorical agreement between the colorimetric plate and the standard disk diffusion method was 99%. Mean time to results was 7.07 h (95% confidence interval, 5.96 to 8.19). PMID- 21248094 TI - Detection of hepatitis C virus and antibodies in postmortem blood and bloodstains. AB - To evaluate the risk of accidental hepatitis C virus (HCV) infection, we examined whether anti-HCV antibodies and HCV RNA were detectable in HCV-infected blood samples from living donors, cadavers, and bloodstains. We showed that even after blood has left the body for several days, anti-HCV antibodies and HCV RNA may persist in it. PMID- 21248095 TI - Time-dependent sensitivity of a rapid antigen test in patients with 2009 H1N1 influenza. PMID- 21248096 TI - Analysis of emergence of quinolone-resistant gonococci in Greece by combined use of Neisseria gonorrhoeae multiantigen sequence typing and multilocus sequence typing. AB - The prevalence of quinolone-resistant Neisseria gonorrhoeae (QRNG) in Greece remained low from 1997 to 2003 but increased dramatically from 11% to 56% between 2004 and 2007. N. gonorrhoeae multiantigen sequence typing (NG-MAST) and multilocus sequence typing (MLST) were used to investigate trends in quinolone resistance from 1997 to 2007 and explore the origins of the recent increase in QRNG. We characterized 295 QRNG isolates from the study period and 233 quinolone susceptible (QS) gonococci from 2004 and 2005, when the rapid increase in QRNG occurred. From 1997 to 1999, an outbreak of QRNG was due to the dissemination of isolates of serovar Arst that belonged to two closely related genotypes. Few QRNG isolates, of diverse genotypes, were present between 2001 and 2003, whereas the sharp increase in QRNG from 2004 onwards was due to the appearance of serovar Bropyst isolates of several major NG-MAST sequence type (STs) that previously had not been identified in Greece. These isolates were shown by MLST to be variants of a single multiply antibiotic-resistant QRNG strain (ST1901) that appeared in Greece and rapidly diversified into 31 NG-MAST STs. There were no isolates of MLST ST1901 or any of the 31 NG-MAST STs among QS isolates from 2004 and 2005 or among 8 representatives of multiresistant but quinolone-susceptible serovar Bropyst isolates circulating in Greece during the 1990 s, supporting the view that the recent increase in QRNG was due to importation of a QRNG strain(s) of MLST ST1901 into Greece. Recently, multiresistant QRNG isolates of ST1901 with reduced susceptibility to the newer cephalosporins have appeared in Greece. PMID- 21248097 TI - Comparison of Aptima Trichomonas vaginalis transcription-mediated amplification assay and BD affirm VPIII for detection of T. vaginalis in symptomatic women: performance parameters and epidemiological implications. AB - Trichomonas vaginalis is an underestimated sexually transmitted infection (STI) associated with numerous clinical sequelae. The true prevalence and clinical impact of trichomoniasis are unknown, as current methods of detection exhibit poor sensitivity compared to molecular amplification methods. Limited data exist comparing the BD Affirm VPIII hybridization assay to the Gen-Probe Aptima T. vaginalis (ATV) transcription-mediated amplification (TMA) assay for detection of T. vaginalis. In this study, specimens from 766 patients were evaluated. Specimens were retrieved consecutively from patients with vaginal complaints and/or with histories suggestive of STI. Study inclusion was dependent upon the request for and collection of both a vaginal swab for Affirm and a specimen for Aptima Combo 2 by the health care provider during the same office visit. Affirm was performed using the specific collection swab and the transport provided for the test. The ATV assay was performed on remnant Aptima Combo 2 specimens. A second ATV TMA assay, utilizing an alternate T. vaginalis primer and probe set, was performed on all specimens positive by the initial TMA and/or the Affirm assay. Infected-patient status was defined as positive T. vaginalis test results by at least 2 assays. Overall, 5.1% of subjects were positive for T. vaginalis. T. vaginalis was most prevalent in women who were 36 to 45 (11.9%), 51 to 60 (7.7%), and 16 to 25 (4.2%) years of age. The ATV assay was statistically more sensitive than the Affirm assay (100% versus 63.4%, P < 0.0001), identifying 36.6% more positive patients. PMID- 21248098 TI - rapidSTRIPE H1N1 test for detection of the pandemic swine origin influenza A (H1N1) virus. AB - The rapidSTRIPE H1N1 test, based on a nucleic acid lateral-flow assay, has been developed for diagnosis of a swine-origin influenza A (H1N1) virus. This test is simple and cost-effective and allows specific detection of the S-OIV A (H1N1) virus from swab sampling to final detection on a lateral-flow stripe within 2 to 3 h. PMID- 21248099 TI - The rtxA toxin gene of Kingella kingae: a pertinent target for molecular diagnosis of osteoarticular infections. AB - Kingella kingae is an emerging osteoarticular pathogen in young children. Its isolation by traditional culture methods remains difficult, underscoring the need to implement other diagnostic methods for its detection and identification, such as nucleic acid amplification tests. Although the genome of this bacterium has not yet been sequenced, a toxin named RTX has been identified. The goal of this study was to develop sensitive, specific, and rapid molecular methods based on the rtxA toxin gene sequence to diagnose this infection. Two real-time PCR assays (SYBR green and TaqMan chemistries) targeting this gene are reported. Sensitivity and specificity were first evaluated successfully with 67 strains: 31 Kingella kingae isolates and 36 strains from other bacterial species. Then, 52 clinical specimens positive or negative by culture and/or PCR (16S rRNA and cpn60 genes) were tested with these assays. A nested PCR assay with subsequent sequencing was also developed to confirm the presence of Kingella kingae isolates in these clinical specimens. The results obtained demonstrate that these assays are accurate for the diagnosis of Kingella kingae infection. PMID- 21248100 TI - Ambiguous genitalia in a fertile, unilaterally cryptorchid male miniature schnauzer dog. AB - A 7-year-old male miniature schnauzer dog with unilateral cryptorchidism was presented for elective orchiectomy. Surgery to remove the cryptorchid testis revealed a fully formed uterus with horns attached to both testis and the body and cervix terminating at the prostate gland. The gross and microscopic diagnosis for the genital tract was persistent Mullerian duct syndrome with unilateral cryptorchidism. Additional associated lesions included cystic endometrial hyperplasia and a solitary, intratubular seminoma within the undescended testis. Persistent Mullerian duct syndrome is rare among domestic animals but is more common in miniature schnauzer dogs because of inheritance as an autosomal recessive trait. PMID- 21248101 TI - Spasmodic dysphonia: a laryngeal control disorder specific to speech. AB - Spasmodic dysphonia (SD) is a rare neurological disorder that emerges in middle age, is usually sporadic, and affects intrinsic laryngeal muscle control only during speech. Spasmodic bursts in particular laryngeal muscles disrupt voluntary control during vowel sounds in adductor SD and interfere with voice onset after voiceless consonants in abductor SD. Little is known about its origins; it is classified as a focal dystonia secondary to an unknown neurobiological mechanism that produces a chronic abnormality of laryngeal motor neuron regulation during speech. It develops primarily in females and does not interfere with breathing, crying, laughter, and shouting. Recent postmortem studies have implicated the accumulation of clusters in the parenchyma and perivascular regions with inflammatory changes in the brainstem in one to two cases. A few cases with single mutations in THAP1, a gene involved in transcription regulation, suggest that a weak genetic predisposition may contribute to mechanisms causing a nonprogressive abnormality in laryngeal motor neuron control for speech but not for vocal emotional expression. Research is needed to address the basic cellular and proteomic mechanisms that produce this disorder to provide intervention that could target the pathogenesis of the disorder rather than only providing temporary symptom relief. PMID- 21248102 TI - A novel signaling pathway that modulates inflammatory pain. PMID- 21248103 TI - Opposing gradients of ribbon size and AMPA receptor expression underlie sensitivity differences among cochlear-nerve/hair-cell synapses. AB - The auditory system transduces sound-evoked vibrations over a range of input sound pressure levels spanning six orders of magnitude. An important component of the system mediating this impressive dynamic range is established in the cochlear sensory epithelium, where functional subtypes of cochlear nerve fibers differ in threshold sensitivity, and spontaneous discharge rate (SR), by more than a factor of 1000 (Liberman, 1978), even though, regardless of type, each fiber contacts only a single hair cell via a single ribbon synapse. To study the mechanisms underlying this remarkable heterogeneity in threshold sensitivity among the 5-30 primary sensory fibers innervating a single inner hair cell, we quantified the sizes of presynaptic ribbons and postsynaptic AMPA receptor patches in >1200 synapses, using high-power confocal imaging of mouse cochleas immunostained for CtBP2 (C-terminal binding protein 2, a major ribbon protein) and GluR2/3 (glutamate receptors 2 and 3). We document complementary gradients, most striking in mid-cochlear regions, whereby synapses from the modiolar face and/or basal pole of the inner hair cell have larger ribbons and smaller receptor patches than synapses located in opposite regions of the cell. The AMPA receptor expression gradient likely contributes to the differences in cochlear nerve threshold and SR seen on the two sides of the hair cell in vivo (Liberman, 1982a); the differences in ribbon size may contribute to the heterogeneity of EPSC waveforms seen in vitro (Grant et al., 2010). PMID- 21248104 TI - MicroRNA miR-9 modifies motor neuron columns by a tuning regulation of FoxP1 levels in developing spinal cords. AB - The precise organization of motor neuron subtypes in a columnar pattern in developing spinal cords is controlled by cross-interactions of multiple transcription factors and segmental expressions of Hox genes and their accessory proteins. Accurate expression levels and domains of these regulators are essential for organizing spinal motor neuron columns and axonal projections to target muscles. Here, we show that microRNA miR-9 is transiently expressed in a motor neuron subtype and displays overlapping expression with its target gene FoxP1. Overexpression or knockdown of miR-9 alters motor neuron subtypes, switches columnar identities, and changes axonal innervations in developing chick spinal cords. miR-9 modifies spinal columnar organization by specifically regulating FoxP1 protein levels, which in turn determine distinct motor neuron subtypes. Our findings demonstrate that miR-9 is an essential regulator of motor neuron specification and columnar formation. Moreover, the overlapping expression of miR-9 and its target FoxP1 further illuminates the importance of fine-tuning regulation by microRNAs in motor neuron development. PMID- 21248105 TI - GluA2 (GluR2) regulates metabotropic glutamate receptor-dependent long-term depression through N-cadherin-dependent and cofilin-mediated actin reorganization. AB - The GluA2 (GluR2) subunit is critical for the regulation of AMPA receptor properties and synaptic plasticity, but the underlying mechanisms remain unclear. Here, we demonstrate that GluA2 regulates metabotropic glutamate receptor dependent long-term depression (mGluR-LTD) through a previously unknown mechanism involving N-cadherin-dependent and cofilin-mediated actin reorganization. We show that GluA2 is indispensable for mGluR-LTD in the hippocampus, and surprisingly this action of GluA2 is mediated by its extracellular domain interaction with N cadherin. Accordingly, we show that the function of N-cadherin is regulated by and required for mGluR-LTD. Furthermore, we show that the regulatory effect of GluA2/N-cadherin is mediated through activation of Rho GTPase Rac1 and its downstream actin regulator cofilin, and, importantly, the requirement for GluA2/N cadherin can be overcome by manipulating cofilin. These results provide compelling evidence that the extracellular domain of GluA2 regulates long-lasting synaptic plasticity through a signaling mechanism that is distinct from those used by the other domains of the receptor subunit. PMID- 21248106 TI - The suppressive effect of an intra-prefrontal cortical infusion of BDNF on cocaine-seeking is Trk receptor and extracellular signal-regulated protein kinase mitogen-activated protein kinase dependent. AB - Cocaine-mediated neuroadaptations in the prefrontal cortical-nucleus accumbens pathway underlie drug-seeking in animals with a cocaine self-administration (SA) history. Neuroplasticity in the cortico-accumbens pathway is regulated, in part, by the expression and availability of neurotrophic factors, such as BDNF. We have previously demonstrated that infusion of BDNF into the dorsomedial prefrontal cortex (dmPFC) immediately after the last of 10 cocaine SA sessions attenuates contextual, cue- and cocaine prime-induced reinstatement of cocaine-seeking (Berglind et al., 2007) and normalizes cocaine-induced disruption of glutamatergic transmission in the nucleus accumbens (Berglind et al., 2009). In the present study, the suppressive effect of intra-dmPFC BDNF on cocaine-seeking is shown to depend on Trk receptor-mediated activation of extracellular signal regulated kinase (ERK) signaling in the dmPFC. The tyrosine kinase inhibitor, K252a, and the mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor, U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2 aminophenylthio]butadiene), prevented BDNF's suppressive effects on cocaine seeking. Vehicle-infused rats with a cocaine SA history showed significant decreases in ERK and cyclic AMP response element binding protein (CREB), but not Akt, phosphorylation after the final cocaine SA session that were reversed by intra-dmPFC BDNF. Additionally, BDNF's ability to normalize cocaine-mediated decreases in ERK and CREB phosphorylation was blocked by U0126, demonstrating that ERK/MAPK activation mediated the behavioral effects. This study elucidates a mechanism whereby BDNF/TrkB (tropomyosin receptor kinase B) activates ERK regulated CREB phosphorylation in the dmPFC to counteract the neuroadaptations induced by cocaine SA and subsequent relapse to cocaine-seeking. PMID- 21248107 TI - The ERK2 mitogen-activated protein kinase regulates the timing of oligodendrocyte differentiation. AB - Oligodendrocyte development is tightly controlled by a variety of extracellular growth and differentiation factors. The mitogen-activated protein kinases (MAPKs), ERK1 and ERK2, are critical intracellular signaling molecules important for transducing these extracellular signals. The extracellular signal-regulated kinases (ERKs) are ubiquitously expressed, coordinately regulated, and highly similar, but Erk2 deletion in mice is embryonic lethal whereas Erk1 deletion is not. Several studies have suggested that MAPK signaling is important for oligodendrocyte differentiation, although specific roles for the two ERK isoforms have not been investigated. In this study, we deleted Erk2 in the developing mouse cortex from GFAP-expressing radial glia that generate neurons and oligodendrocytes. In vitro analysis revealed that loss of ERK2 resulted in fewer galactocerebroside-expressing mature oligodendrocytes in cortical cultures. In vivo, a delay in the expression of the myelin protein MBP was observed in the corpus callosum at postnatal day 10 (P10). In contrast, Erk1 deletion did not affect oligodendrocyte differentiation. By P21, MBP expression was restored to wild-type levels, demonstrating that the loss of ERK2 results in a delay but not a complete arrest in the appearance of differentiated oligodendrocytes in vivo. Importantly, both the proliferation and total number of oligodendrocyte progenitor cells (OPCs) appeared normal in the Erk2 conditional knock-out cortex, demonstrating that ERK2 plays a specific role in the timing of forebrain myelination but is not critical for the proliferation or survival of OPCs. Oligodendrocyte-specific deletion of Erk2 also resulted in decreased levels of MBP, indicating a cell-autonomous effect of ERK2 in the oligodendrocyte lineage. PMID- 21248108 TI - Changes in hippocampal neuronal activity during and after unilateral selective hippocampal ischemia in vivo. AB - The hippocampal formation is one of the brain regions most sensitive to ischemic damage. However, there are no studies about changes in hippocampal neuronal activity during and after a selective unilateral hippocampal ischemia. We developed a novel unilateral cerebrovascular ischemia model in mice that selectively shuts down blood supply to the ipsilateral hippocampal formation. Using a modified version of the photothrombotic method, we stereotaxically targeted the initial ascending part of the longitudinal hippocampal artery in urethane anesthetized and rose bengal-injected mice. To block blood flow in the targeted artery, we photoactivated the rose bengal by illuminating the longitudinal hippocampal artery through an optical fiber inserted into the brain. In vivo field potential recordings in the CA1 region of the hippocampus before, during and after the induction of ischemia demonstrated a high-frequency discharge (HFD) reaching frequencies of >300 Hz and lasting 7-24 s during the illumination consistent with a massive synchronous neuronal activity. The HFD was invariably followed by a DC voltage shift and a decreased activity at both low (30-57 Hz)- and high (63-119 Hz)-gamma frequencies. This decrease in gamma activity lasted for the entire duration of the recordings (~160 min) following ischemia. The contralateral hippocampus displayed HFDs but with different frequency spectra and without DC voltage shifts or long-lasting decreases in gamma oscillations. Our findings reveal for the first time the acute effects of unilateral hippocampal ischemia on ensemble hippocampal neuronal activities. PMID- 21248109 TI - Dynamic characterization of Drosophila antennal olfactory neurons indicates multiple opponent signaling pathways in odor discrimination. AB - Opponent signaling refers to processes in which antagonistic signals are produced by different, but closely related, stimuli. It allows enhanced discrimination and more accurate behavioral responses. We explored opponent signaling in the Drosophila melanogaster olfactory system by measuring frequency response functions between odorant concentrations and primary olfactory neuron responses. Random fluctuations in concentration of two aliphatic and two aromatic fruit odorants were used to modulate action potentials from basiconic antennal sensilla. We separated action potentials by two-dimensional cluster analysis using amplitude and cross-correlation with a median action-potential template. Frequency response functions were fitted with either bandpass or second-order low pass functions and then divided into two polarity groups, excitatory and inhibitory, by fitting the frequency response functions. Cluster analysis gave two, three, or four action potential clusters for each sensillum recording. Sensilla were then grouped by the patterns of response polarities of the individual neurons into four sensillum types, one with four neurons and three with two neurons. All four odorant compounds produced a mixture of excitatory, inhibitory, and null responses in different neurons. Statistical analysis of frequency response parameters for individual odorants gave only weak correlation between dynamics and some neuron types, even when comparing the dynamics of excitatory and inhibitory responses to the same odorant. However, response dynamics were significantly different between aliphatic and aromatic compounds, and between the two aliphatic compounds. Each odorant caused opposing excitatory and inhibitory signals to be sent to the antennal lobe along at least two pairs of axonal pathways. PMID- 21248110 TI - The GABAA receptor alpha+beta- interface: a novel target for subtype selective drugs. AB - GABA(A) receptors mediate the action of many clinically important drugs interacting with different binding sites. For some potential binding sites, no interacting drugs have yet been identified. Here, we established a steric hindrance procedure for the identification of drugs acting at the extracellular alpha1+beta3- interface, which is homologous to the benzodiazepine binding site at the alpha1+gamma2- interface. On screening of >100 benzodiazepine site ligands, the anxiolytic pyrazoloquinoline 2-p-methoxyphenylpyrazolo[4,3 c]quinolin-3(5H)-one (CGS 9895) was able to enhance GABA-induced currents at alpha1beta3 receptors from rat. CGS 9895 acts as an antagonist at the benzodiazepine binding site at nanomolar concentrations, but enhances GABA induced currents via a different site present at alpha1beta3gamma2 and alpha1beta3 receptors. By mutating pocket-forming amino acid residues at the alpha1+ and the beta3- side to cysteines, we demonstrated that covalent labeling of these cysteines by the methanethiosulfonate ethylamine reagent MTSEA-biotin was able to inhibit the effect of CGS 9895. The inhibition was not caused by a general inactivation of GABA(A) receptors, because the GABA-enhancing effect of ROD 188 or the steroid alpha-tetrahydrodeoxycorticosterone was not influenced by MTSEA-biotin. Other experiments indicated that the CGS 9895 effect was dependent on the alpha and beta subunit types forming the interface. CGS 9895 thus represents the first prototype of drugs mediating benzodiazepine-like modulatory effects via the alpha+beta- interface of GABA(A) receptors. Since such binding sites are present at alphabeta, alphabetagamma, and alphabetadelta receptors, such drugs will have a much broader action than benzodiazepines and might become clinical important for the treatment of epilepsy. PMID- 21248111 TI - Attentional modulation of alpha oscillations in macaque inferotemporal cortex. AB - Recent work reported the observation of alpha frequency oscillations (8-12 Hz) in several regions of macaque visual cortex, including V2, V4, and inferotemporal cortex (IT). While alpha-related physiology in V2 and V4 appears consistent with a role in attention-related suppression, in IT, alpha reactivity appears conflicted with such a role. We addressed this issue directly by analyzing laminar profiles of local field potentials and multiunit activities from the IT of macaque monkeys during performance of an intermodal selective attention task (visual versus auditory). We found that (1) before visual stimulus onset (-200 to 0 ms), attention to visual input increased ongoing alpha power in IT relative to attention to auditory input, and (2) in contrast to the prevailing view of alpha inhibition, the increased ongoing alpha activity is accompanied by increased concurrent multiunit firing and facilitates visual stimulus processing. These results suggest that ongoing alpha oscillations in IT play a different functional role than that in the occipital cortex and may be part of the neuronal mechanism representing task-relevant information. PMID- 21248112 TI - Gdf11 facilitates temporal progression of neurogenesis in the developing spinal cord. AB - Various types of neurons and glia are generated following a precise spatial and temporal order during neurogenesis. The mechanisms that control this sequential generation of neuronal and glial cell types from the same progenitor population are not well understood. Growth differentiation factor 11 (Gdf11) belongs to the TGF-beta family of proteins and is expressed transiently in newly born neurons adjacent to the progenitor domain in the developing spinal cord. We examined the phenotypes of Gdf11(-/-) mouse embryos and found that without Gdf11, neuronal differentiation in the spinal cord progresses at a slower rate. Higher progenitor proliferation rate, along with a delay in gliogenesis, is also observed in Gdf11( /-) spinal cord but only after the peak of Gdf11 expression, indicating that Gdf11 can cause long-lasting changes in progenitor properties. These changes can be preserved in vitro, as neurospheres derived from Gdf11(-/-) and wild-type littermates at a stage after, but not before the onset of Gdf11 expression, exhibit differences in proliferation and differentiation potential. Moreover, these changes in progenitor properties can be induced in vitro by the addition of Gdf11. We also demonstrate that the effects of Gdf11 on progenitor cells are associated with its ability to upregulate p57(Kip2) and p27(Kip1) while downregulating Pax6 expression. These results support a model in which Gdf11 secreted by newly born neurons in the developing spinal cord facilitates the temporal progression of neurogenesis by acting as a positive feedback signal on the progenitor cells to promote cell cycle exit and decrease proliferation ability, thus changing their differentiation potential. PMID- 21248113 TI - Spontaneous action representation in smokers when watching movie characters smoke. AB - Do smokers simulate smoking when they see someone else smoke? For regular smokers, smoking is such a highly practiced motor skill that it often occurs automatically, without conscious awareness. Research on the brain basis of action observation has delineated a frontoparietal network that is commonly recruited when people observe, plan, or imitate actions. Here, we investigated whether this action observation network would be preferentially recruited in smokers when viewing complex smoking cues, such as those occurring in motion pictures. Seventeen right-handed smokers and 17 nonsmokers watched a popular movie while undergoing functional magnetic resonance imaging. Using a natural stimulus, such as a movie, allowed us to keep both smoking and nonsmoking participants naive to the goals of the experiment. Brain activity evoked by movie scenes of smoking was contrasted with nonsmoking control scenes that were matched for frequency and duration. Compared with nonsmokers, smokers showed greater activity in left anterior intraparietal sulcus and inferior frontal gyrus, regions involved in the simulation of contralateral hand-based gestures, when viewing smoking versus control scenes. These results demonstrate that smokers spontaneously represent the action of smoking when viewing others smoke, the consequence of which may make it more difficult to abstain from smoking. PMID- 21248114 TI - A novel role for {gamma}-secretase: selective regulation of spontaneous neurotransmitter release from hippocampal neurons. AB - With a multitude of substrates, gamma-secretase is poised to control neuronal function through a variety of signaling pathways. Presenilin 1 (PS1) is an integral component of gamma-secretase and is also a protein closely linked to the etiology of Alzheimer's disease (AD). To better understand the roles of gamma secretase and PS1 in normal and pathological synaptic transmission, we examined evoked and spontaneous neurotransmitter release in cultured hippocampal neurons derived from PS1 knock-out (KO) mice. We found no changes in the size of evoked synaptic currents, short-term plasticity, or apparent calcium dependence of evoked release. The rate of spontaneous release from PS1 KO neurons was, however, approximately double that observed in wild-type (WT) neurons. This increase in spontaneous neurotransmission depended on calcium influx but did not require activation of voltage-gated calcium channels or presynaptic NMDA receptors or release of calcium from internal stores. The rate of spontaneous release from PS1 KO neurons was significantly reduced by lentivirus-mediated expression of WT PS1 or familial AD-linked M146V PS1, but not the D257A PS1 mutant that does not support gamma-secretase activity. Treatment of WT neuronal cultures with gamma secretase inhibitor mimicked the loss of PS1, leading to a selective increase in spontaneous release without any change in the size of evoked synaptic currents. Together, these results identify a novel role for gamma-secretase in the control of spontaneous neurotransmission through modulation of low-level tonic calcium influx into presynaptic axon terminals. PMID- 21248115 TI - A rat model of progressive nigral neurodegeneration induced by the Parkinson's disease-associated G2019S mutation in LRRK2. AB - The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is the most common genetic cause of Parkinson's disease (PD), accounting for a significant proportion of both autosomal dominant familial and sporadic PD cases. Our aim in the present study is to generate a mammalian model of mutant G2019S LRRK2 pathogenesis, which reproduces the robust nigral neurodegeneration characteristic of PD. We developed adenoviral vectors to drive neuron-specific expression of full-length wild-type or mutant G2019S human LRRK2 in the nigrostriatal system of adult rats. Wild-type LRRK2 did not induce any significant neuronal loss. In contrast, under the same conditions and levels of expression, G2019S mutant LRRK2 causes a progressive degeneration of nigral dopaminergic neurons. Our data provide a novel rat model of PD, based on a prevalent genetic cause, that reproduces a cardinal feature of the disease within a rapid time frame suitable for testing of neuroprotective strategies. PMID- 21248116 TI - Distinct representations of a perceptual decision and the associated oculomotor plan in the monkey lateral intraparietal area. AB - Perceptual decisions that are used to select particular actions can appear to be formed in an intentional framework, in which sensory evidence is converted directly into a plan to act. However, because the relationship between perceptual decision-making and action selection has been tested primarily under conditions in which the two could not be dissociated, it is not known whether this intentional framework plays a general role in forming perceptual decisions or only reflects certain task conditions. To dissociate decision and motor processing in the brain, we recorded from individual neurons in the lateral intraparietal area of monkeys performing a task that included a flexible association between a decision about the direction of random-dot motion and the direction of the appropriate eye-movement response. We targeted neurons that responded selectively in anticipation of a particular eye-movement response. We found that these neurons encoded the perceptual decision in a manner that was distinct from how they encoded the associated response. These decision-related signals were evident regardless of whether the appropriate decision-response association was indicated before, during, or after decision formation. The results suggest that perceptual decision-making and action selection are different brain processes that only appear to be inseparable under particular behavioral contexts. PMID- 21248117 TI - Hearing while blinking: multisensory attentional blink revisited. AB - It is well established that cognitive system overload is reflected in the attentional blink (AB), the failure to report a second target when it closely follows detection of a first target within a rapid series of stimuli. However, there is intense controversy concerning the effect of first-target detection in one modality on subsequent dynamics of attentional resources in other modalities. Mixed results were found using an audiovisual AB paradigm: depletion of resources in one modality either impaired performance in the other modality or had no effect. Here, we circumvent the need for task switching by measuring an event related potential, the mismatch negativity, which reflects implicit auditory change detection without requiring task engagement and is present even for background sounds that participants ignore. Surprisingly, we find that during the visual AB, auditory processing is enhanced rather than inhibited, as would be expected by system overload. We suggest that multimodal attentional resources may be freed rather than engaged during the visual AB. Suppression of irrelevant input may require active control by a central executive, which is preoccupied during the visual AB, and/or there may be no reason to suppress other-modal input since the visual system will miss its second target anyway. PMID- 21248118 TI - Adaptive allocation of vision under competing task demands. AB - Human behavior in natural tasks consists of an intricately coordinated dance of cognitive, perceptual, and motor activities. Although much research has progressed in understanding the nature of cognitive, perceptual, or motor processing in isolation or in highly constrained settings, few studies have sought to examine how these systems are coordinated in the context of executing complex behavior. Previous research has suggested that, in the course of visually guided reaching movements, the eye and hand are yoked, or linked in a nonadaptive manner. In this work, we report an experiment that manipulated the demands that a task placed on the motor and visual systems, and then examined in detail the resulting changes in visuomotor coordination. We develop an ideal actor model that predicts the optimal coordination of vision and motor control in our task. On the basis of the predictions of our model, we demonstrate that human performance in our experiment reflects an adaptive response to the varying costs imposed by our experimental manipulations. Our results stand in contrast to previous theories that have assumed a fixed control mechanism for coordinating vision and motor control in reaching behavior. PMID- 21248119 TI - Multipotent adult progenitor cells prevent macrophage-mediated axonal dieback and promote regrowth after spinal cord injury. AB - Macrophage-mediated axonal dieback presents an additional challenge to regenerating axons after spinal cord injury. Adult adherent stem cells are known to have immunomodulatory capabilities, but their potential to ameliorate this detrimental inflammation-related process has not been investigated. Using an in vitro model of axonal dieback as well as an adult rat dorsal column crush model of spinal cord injury, we found that multipotent adult progenitor cells (MAPCs) can affect both macrophages and dystrophic neurons simultaneously. MAPCs significantly decrease MMP-9 (matrix metalloproteinase-9) release from macrophages, effectively preventing induction of axonal dieback. MAPCs also induce a shift in macrophages from an M1, or "classically activated" proinflammatory state, to an M2, or "alternatively activated" antiinflammatory state. In addition to these effects on macrophages, MAPCs promote sensory neurite outgrowth, induce sprouting, and further enable axons to overcome the negative effects of macrophages as well as inhibitory proteoglycans in their environment by increasing their intrinsic growth capacity. Our results demonstrate that MAPCs have therapeutic benefits after spinal cord injury and provide specific evidence that adult stem cells exert positive immunomodulatory and neurotrophic influences. PMID- 21248120 TI - Disparity-tuned population responses from human visual cortex. AB - We used source imaging of visual evoked potentials to measure neural population responses over a wide range of horizontal disparities (0.5-64 arcmin). The stimulus was a central disk that moved back and forth across the fixation plane at 2 Hz, surrounded either by binocularly uncorrelated dots (disparity noise) or by correlated dots presented in the fixation plane. Both disk and surround were composed of dynamic random dots to remove coherent monocular information. Disparity tuning was measured in five visual regions of interest (ROIs) [V1, human middle temporal area (hMT+), V4, lateral occipital complex (LOC), and V3A], defined in separate functional magnetic resonance imaging scans. The disparity tuning functions peaked between 2 and 16 arcmin for both types of surround in each ROI. Disparity tuning in the V1 ROI was unaffected by the type of surround, but surround correlation altered both the amplitude and phase of the disparity responses in the other ROIs. Response amplitude increased when the disk was in front of the surround in the V3A and LOC ROIs, indicating that these areas encode figure-ground relationships and object convexity. The correlated surround produced a consistent phase lag at the second harmonic in the hMT+ and V4 ROIs without a change in amplitude, while in the V3A ROI, both phase and amplitude effects were observed. Sensitivity to disparity context is thus widespread in visual cortex, but the dynamics of these contextual interactions differ across regions. PMID- 21248121 TI - Axonal degeneration is mediated by the mitochondrial permeability transition pore. AB - Axonal degeneration is an active process that has been associated with neurodegenerative conditions triggered by mechanical, metabolic, infectious, toxic, hereditary and inflammatory stimuli. This degenerative process can cause permanent loss of function, so it represents a focus for neuroprotective strategies. Several signaling pathways are implicated in axonal degeneration, but identification of an integrative mechanism for this self-destructive process has remained elusive. Here, we show that rapid axonal degeneration triggered by distinct mechanical and toxic insults is dependent on the activation of the mitochondrial permeability transition pore (mPTP). Both pharmacological and genetic targeting of cyclophilin D, a functional component of the mPTP, protects severed axons and vincristine-treated neurons from axonal degeneration in ex vivo and in vitro mouse and rat model systems. These effects were observed in axons from both the peripheral and central nervous system. Our results suggest that the mPTP is a key effector of axonal degeneration, upon which several independent signaling pathways converge. Since axonal and synapse degeneration are increasingly considered early pathological events in neurodegeneration, our work identifies a potential target for therapeutic intervention in a wide variety of conditions that lead to loss of axons and subsequent functional impairment. PMID- 21248123 TI - Neural basis of superior performance of action videogame players in an attention demanding task. AB - Steady-state visual evoked potentials (SSVEPs) were recorded from action videogame players (VGPs) and from non-videogame players (NVGPs) during an attention-demanding task. Participants were presented with a multi-stimulus display consisting of rapid sequences of alphanumeric stimuli presented at rates of 8.6/12 Hz in the left/right peripheral visual fields, along with a central square at fixation flashing at 5.5 Hz and a letter sequence flashing at 15 Hz at an upper central location. Subjects were cued to attend to one of the peripheral or central stimulus sequences and detect occasional targets. Consistent with previous behavioral studies, VGPs detected targets with greater speed and accuracy than NVGPs. This behavioral advantage was associated with an increased suppression of SSVEP amplitudes to unattended peripheral sequences in VGPs relative to NVGPs, whereas the magnitude of the attended SSVEPs was equivalent in the two groups. Group differences were also observed in the event-related potentials to targets in the alphanumeric sequences, with the target-elicited P300 component being of larger amplitude in VGPS than NVGPs. These electrophysiological findings suggest that the superior target detection capabilities of the VGPs are attributable, at least in part, to enhanced suppression of distracting irrelevant information and more effective perceptual decision processes. PMID- 21248122 TI - Calcium-independent inhibitory G-protein signaling induces persistent presynaptic muting of hippocampal synapses. AB - Adaptive forms of synaptic plasticity that reduce excitatory synaptic transmission in response to prolonged increases in neuronal activity may prevent runaway positive feedback in neuronal circuits. In hippocampal neurons, for example, glutamatergic presynaptic terminals are selectively silenced, creating "mute" synapses, after periods of increased neuronal activity or sustained depolarization. Previous work suggests that cAMP-dependent and proteasome dependent mechanisms participate in silencing induction by depolarization, but upstream activators are unknown. We, therefore, tested the role of calcium and G protein signaling in silencing induction in cultured hippocampal neurons. We found that silencing induction by depolarization was not dependent on rises in intracellular calcium, from either extracellular or intracellular sources. Silencing was, however, pertussis toxin sensitive, which suggests that inhibitory G-proteins are recruited. Surprisingly, blocking four common inhibitory G-protein coupled receptors (GPCRs) (adenosine A(1) receptors, GABA(B) receptors, metabotropic glutamate receptors, and CB(1) cannabinoid receptors) and one ionotropic receptor with metabotropic properties (kainate receptors) failed to prevent depolarization-induced silencing. Activating a subset of these GPCRs (A(1) and GABA(B)) with agonist application induced silencing, however, which supports the hypothesis that G-protein activation is a critical step in silencing. Overall, our results suggest that depolarization activates silencing through an atypical GPCR or through receptor-independent G-protein activation. GPCR agonist-induced silencing exhibited dependence on the ubiquitin-proteasome system, as was shown previously for depolarization-induced silencing, implicating the degradation of vital synaptic proteins in silencing by GPCR activation. These data suggest that presynaptic muting in hippocampal neurons uses a G-protein dependent but calcium-independent mechanism to depress presynaptic vesicle release. PMID- 21248125 TI - A critical time window for the recruitment of bulbar newborn neurons by olfactory discrimination learning. AB - In the mammalian brain, the dentate gyrus and the olfactory bulb are regions where new neurons are continuously added. While the functional consequences of continuous hippocampal neurogenesis have been extensively studied, the role of olfactory adult-born neurons remains elusive. In particular, the involvement of these newborn neurons in odor processing is still a matter of debate. We demonstrate a critical impact of both the age of new neurons and the memory processes involved (learning vs recall) in the recruitment of newborn cells. Thus, odor stimulation preferentially recruited immature neurons over more mature ones (2 weeks old vs 5 and 9 weeks old), whereas associative learning based on odor discrimination preferentially recruited mature neurons (5-9 weeks old). Furthermore, while mature neurons were activated by this associative learning, they were not activated by long-term memory recall, indicating that the contribution of newborn neurons in olfactory functions depends also on the memory process involved. Our data thus show that newborn neurons are indeed involved in odor processing and that their recruitment is age- and memory process-dependent. PMID- 21248124 TI - Unusual pungency from extra-virgin olive oil is attributable to restricted spatial expression of the receptor of oleocanthal. AB - Oleocanthal, a major phenolic compound in extra-virgin olive oil with antiinflammatory properties, elicits an unusual oral pungency sensed almost exclusively in the throat. This contrasts with most other common oral irritants, such as cinnamaldehyde, capsaicin, and alcohol, which irritate mucus membranes throughout the oral cavity. Here, we show that this rare irritation pattern is a consequence of both the specificity of oleocanthal for a single sensory receptor and the anatomical restriction of this sensory receptor to the pharynx, within the oral cavity. We demonstrate, in vitro, that oleocanthal selectively activates the hTRPA1 channel in HEK 293 cells and that its ability to excite the trigeminal nervous system in rodents requires a functional TRPA1. Moreover, we similarly demonstrate that the over-the-counter analgesic, ibuprofen, which elicits the same restricted pharyngeal irritation as oleocanthal, also specifically excites rodent sensory neurons via TRPA1. Using human sensory psychophysical studies and immunohistochemical TRPA1 analyses of human oral and nasal tissues, we observe an overlap of the anatomical distribution of TRPA1 and the regions irritated by oleocanthal in humans. These results suggest that a TRPA1 (ANKTM1) gene product mediates the tissue sensitivity to oleocanthal within the oral cavity. Furthermore, we demonstrate that, despite the fact that oleocanthal possesses the classic electrophilic reactivity of many TRPA1 agonists, it does not use the previously identified activation mechanism via covalent cysteine modification. These findings provide an anatomical and molecular explanation for a distinct oral sensation that is elicited by oleocanthal and ibuprofen and that is commonly experienced around the world when consuming many extra-virgin olive oils. PMID- 21248127 TI - Noninvasive magnetic resonance imaging detection of cerebral amyloid angiopathy related microvascular alterations using superparamagnetic iron oxide particles in APP transgenic mouse models of Alzheimer's disease: application to passive Abeta immunotherapy. AB - Cerebral amyloid angiopathy (CAA) is a common feature of Alzheimer's disease (AD). More advanced stages are accompanied by microhemorrhages and vasculitis. Peripheral blood-borne macrophages are intimately linked to cerebrovascular pathology coincident with AD. Magnetic resonance imaging (MRI) was used to noninvasively study microvascular lesions in amyloid precursor protein transgenic mouse AD models. Foci of signal attenuation were detected in cortical and thalamic brain regions of aged APP23 mice. Their strength and number was considerably enhanced by intravenous administration of iron oxide nanoparticles, which are taken up by macrophages through absorptive endocytosis, 24 h before image acquisition. The number of cortical sites displaying signal attenuation increased with age. Histology at these sites demonstrated the presence of iron containing macrophages in the vicinity of CAA-affected blood vessels. A fraction of the sites additionally showed thickened vessel walls and vasculitis. Consistent with the visualization of CAA-associated lesions, MRI detected a much smaller number of attenuated signal sites in APP23xPS45 mice, for which a strong presenilin mutation caused a shift toward amyloid beta(42), thus reducing vascular amyloid. Similar results were obtained with APP24 and APP51 mice, which develop significantly less CAA and microvascular pathology than APP23. In a longitudinal study, we noninvasively demonstrated the reinforced formation of microvascular pathology during passive amyloid beta immunotherapy of APP23 mice. Histology confirmed that foci of signal attenuation reflected an increase in CAA related lesions. Our data demonstrate that MRI has the sensitivity to noninvasively monitor the development of vascular pathology and its possible enhancement by amyloid beta immunotherapy in transgenic mice modeling AD. PMID- 21248126 TI - Dendritic calcium activity precedes inspiratory bursts in preBotzinger complex neurons. AB - Medullary interneurons of the preBotzinger complex assemble excitatory networks that produce inspiratory-related neural rhythms, but the importance of somatodendritic conductances in rhythm generation is still incompletely understood. Synaptic input may cause Ca(2+) accumulation postsynaptically to evoke a Ca(2+)-activated inward current that contributes to inspiratory burst generation. We measured Ca(2+) transients by two-photon imaging dendrites while recording neuronal somata electrophysiologically. Dendritic Ca(2+) accumulation frequently precedes inspiratory bursts, particularly at recording sites 50-300 MUm distal from the soma. Preinspiratory Ca(2+) transients occur in hotspots, not ubiquitously, in dendrites. Ca(2+) activity propagates orthodromically toward the soma (and antidromically to more distal regions of the dendrite) at rapid rates (300-700 MUm/s). These high propagation rates suggest that dendritic Ca(2+) activates an inward current to electrotonically depolarize the soma, rather than propagate as a regenerative Ca(2+) wave. These data provide new evidence that respiratory rhythmogenesis may depend on dendritic burst-generating conductances activated in the context of network activity. PMID- 21248128 TI - Drosophila amyloid precursor protein-like is required for long-term memory. AB - The amyloid precursor protein (APP) plays an important role in Alzheimer's disease (AD), a progressive neurodegenerative pathology that first manifests as a decline of memory. While the main hypothesis for AD pathology centers on the proteolytic processing of APP, very little is known about the physiological function of the APP protein in the adult brain. Likewise, whether APP loss of function contributes to AD remains unclear. Drosophila has been used extensively as a model organism to study neuronal function and pathology. In addition, many of the molecular mechanisms underlying memory are thought to be conserved from flies to mammals, prompting us to study the function of APPL, the fly APP ortholog, during associative memory. It was previously shown that APPL expression is highly enriched in the mushroom bodies (MBs), a specialized brain structure involved in olfactory memory. We analyzed memory in flies in which APPL expression has been silenced specifically and transiently in the adult MBs. Our results show that in adult flies, APPL is not required for learning but is specifically involved in long-term memory, a long lasting memory whose formation requires de novo protein synthesis and is thought to require synaptic structural plasticity. These data support the hypothesis that disruption of normal APP function may contribute to early AD cognitive impairment. PMID- 21248130 TI - Functional magnetic resonance imaging blood oxygenation level-dependent signal and magnetoencephalography evoked responses yield different neural functionality in reading. AB - It is often implicitly assumed that the neural activation patterns revealed by hemodynamic methods, such as functional magnetic resonance imaging (fMRI), and electrophysiological methods, such as magnetoencephalography (MEG) and electroencephalography (EEG), are comparable. In early sensory processing that seems to be the case, but the assumption may not be correct in high-level cognitive tasks. For example, MEG and fMRI literature of single-word reading suggests differences in cortical activation, but direct comparisons are lacking. Here, while the same human participants performed the same reading task, analysis of MEG evoked responses and fMRI blood oxygenation level-dependent (BOLD) signals revealed marked functional and spatial differences in several cortical areas outside the visual cortex. Divergent patterns of activation were observed in the frontal and temporal cortex, in accordance with previous separate MEG and fMRI studies of reading. Furthermore, opposite stimulus effects in the MEG and fMRI measures were detected in the left occipitotemporal cortex: MEG evoked responses were stronger to letter than symbol strings, whereas the fMRI BOLD signal was stronger to symbol than letter strings. The EEG recorded simultaneously during MEG and fMRI did not indicate neurophysiological differences that could explain the observed functional discrepancies between the MEG and fMRI results. Acknowledgment of the complementary nature of hemodynamic and electrophysiological measures, as reported here in a cognitive task using evoked response analysis in MEG and BOLD signal analysis in fMRI, represents an essential step toward an informed use of multimodal imaging that reaches beyond mere combination of location and timing of neural activation. PMID- 21248129 TI - PSD-95 alters microtubule dynamics via an association with EB3. AB - Little is known about how the neuronal cytoskeleton is regulated when a dendrite decides whether to branch or not. Previously, we reported that postsynaptic density protein 95 (PSD-95) acts as a stop signal for dendrite branching. It is yet to be elucidated how PSD-95 affects the cytoskeleton and how this regulation relates to the dendritic arbor. Here, we show that the SH3 (src homology 3) domain of PSD-95 interacts with a proline-rich region within the microtubule end binding protein EB3. Overexpression of PSD-95 or mutant EB3 results in a decreased lifetime of EB3 comets in dendrites. In line with these data, transfected rat neurons show that overexpression of PSD-95 results in less organized microtubules at dendritic branch points and decreased dendritogensis. The interaction between PSD-95 and EB3 elucidates a function for a novel region of EB3 and provides a new and important mechanism for the regulation of microtubules in determining dendritic morphology. PMID- 21248131 TI - Multiple reference frames for saccadic planning in the human parietal cortex. AB - We apply functional magnetic resonance imaging and multivariate analysis methods to study the coordinate frame in which saccades are represented in the human cortex. Subjects performed a memory-guided saccade task in which equal-amplitude eye movements were executed from several starting points to various directions. Response patterns during the memory period for same-vector saccades were correlated in the frontal eye fields and the intraparietal sulcus (IPS), indicating a retinotopic representation. Interestingly, response patterns in the middle aspect of the IPS were also correlated for saccades made to the same destination point, even when their movement vector was different. Thus, this region also contains information about saccade destination in (at least) a head centered coordinate frame. This finding may explain behavioral and neuropsychological studies demonstrating that eye movements are also anchored to an egocentric or an allocentric representation of space rather than strictly to the retinal visual input and that parietal cortex is involved in maintaining these representations of space. PMID- 21248132 TI - Genetically induced adult oligodendrocyte cell death is associated with poor myelin clearance, reduced remyelination, and axonal damage. AB - Loss of oligodendrocytes is a feature of many demyelinating diseases including multiple sclerosis. Here, we have established and characterized a novel model of genetically induced adult oligodendrocyte death. Specific primary loss of adult oligodendrocytes leads to a well defined and highly reproducible course of disease development that can be followed longitudinally by magnetic resonance imaging. Histological and ultrastructural analyses revealed progressive myelin vacuolation, in parallel to disease development that includes motor deficits, tremor, and ataxia. Myelin damage and clearance were associated with induction of oligodendrocyte precursor cell proliferation, albeit with some regional differences. Remyelination was present in the mildly affected corpus callosum. Consequences of acutely induced cell death of adult oligodendrocytes included secondary axonal damage. Microglia were activated in affected areas but without significant influx of B-cells, T-helper cells, or T-cytotoxic cells. Analysis of the model on a RAG-1 (recombination activating gene-1)-deficient background, lacking functional lymphocytes, did not change the observed disease and pathology compared with immune-competent mice. We conclude that this model provides the opportunity to study the consequences of adult oligodendrocyte death in the absence of primary axonal injury and reactive cells of the adaptive immune system. Our results indicate that if the blood-brain barrier is not disrupted, myelin debris is not removed efficiently, remyelination is impaired, and axonal integrity is compromised, likely as the result of myelin detachment. This model will allow the evaluation of strategies aimed at improving remyelination to foster axon protection. PMID- 21248133 TI - HMGB1 acts on microglia Mac1 to mediate chronic neuroinflammation that drives progressive neurodegeneration. AB - What drives the gradual degeneration of dopamine neurons in Parkinson's disease (PD), the second most common neurodegenerative disease, remains elusive. Here, we demonstrated, for the first time, that persistent neuroinflammation was indispensible for such a neurodegenerative process. 1-Methyl-4-phenylpyridinium, lipopolysaccharide (LPS), and rotenone, three toxins often used to create PD models, produced acute but nonprogressive neurotoxicity in neuron-enriched cultures. In the presence of microglia (brain immune cells), these toxins induced progressive dopaminergic neurodegeneration. More importantly, such neurodegeneration was prevented by removing activated microglia. Collectively, chronic neuroinflammation may be a driving force of progressive dopaminergic neurodegeneration. Conversely, ongoing neurodegeneration sustained microglial activation. Microglial activation persisted only in the presence of neuronal damage in LPS-treated neuron-glia cultures but not in LPS-treated mixed-glia cultures. Thus, activated microglia and damaged neurons formed a vicious cycle mediating chronic, progressive neurodegeneration. Mechanistic studies indicated that HMGB1 (high-mobility group box 1), released from inflamed microglia and/or degenerating neurons, bound to microglial Mac1 (macrophage antigen complex 1) and activated nuclear factor-kappaB pathway and NADPH oxidase to stimulate production of multiple inflammatory and neurotoxic factors. The treatment of microglia with HMGB1 led to membrane translocation of p47(phox) (a cytosolic subunit of NADPH oxidase) and consequent superoxide release, which required the presence of Mac1. Neutralization of HMGB1 and genetic ablation of Mac1 and gp91(phox) (the catalytic submit of NADPH oxidase) blocked the progressive neurodegeneration. Our findings indicated that HMGB1-Mac1-NADPH oxidase signaling axis bridged chronic neuroinflammation and progressive dopaminergic neurodegeneration, thus identifying a mechanistic basis for chronic PD progression. PMID- 21248134 TI - Frequency-dependent modes of synaptic vesicle endocytosis and exocytosis at adult mouse neuromuscular junctions. AB - During locomotion, adult rodent lumbar motoneurons fire in high-frequency (80-100 Hz) 1-2 s bursts every several seconds, releasing between 10,000 and 20,000 vesicles per burst. The estimated total vesicle pool size indicates that all vesicles would be used within 30 s; thus, a mechanism for rapid endocytosis and vesicle recycling is necessary to maintain effective transmission and motor behavior. However, whether such rapid recycling exists at mouse neuromuscular junctions (NMJs) or how it is regulated has been unclear. Here, we show that much less FM1-43 dye is lost per stimulus with 100 Hz stimulation than with 10 Hz stimulation even when the same number of vesicles undergo exocytosis. Electrophysiological data using folimycin show this lesser amount of dye loss is caused in part by the rapid reuse of vesicles. We showed previously that a myosin light chain kinase (MLCK)-myosin II pathway was required for effective transmission at 100 Hz. Here, we confirm the activation of MLCK, based on increased nerve terminal phospho-MLC immunostaining, with 100 Hz but not with 10 Hz stimulation. We further demonstrate that activation of MLCK, by increased extracellular Ca(2+), by PKC (protein kinase C) activation, or by a MLCK agonist peptide, reduces the amount of dye lost even with 10 Hz stimulation. MLCK activation at 10 Hz also resulted in more vesicles being rapidly reused. Thus, MLCK activation by 100 Hz stimulation switches the mechanism of vesicle cycling to a rapid-reuse mode and is required to sustain effective transmission in adult mouse NMJs. PMID- 21248135 TI - Increased neurotransmitter release at the neuromuscular junction in a mouse model of polyglutamine disease. AB - In Huntington's disease (HD), the expansion of polyglutamine (polyQ) repeats at the N terminus of the ubiquitous protein huntingtin (htt) leads to neurodegeneration in specific brain areas. Neurons degenerating in HD develop synaptic dysfunctions. However, it is unknown whether mutant htt impacts synaptic function in general. To investigate that, we have focused on the nerve terminals of motor neurons that typically do not degenerate in HD. Here, we have studied synaptic transmission at the neuromuscular junction of transgenic mice expressing a mutant form of htt (R6/1 mice). We have found that the size and frequency of miniature endplate potentials are similar in R6/1 and control mice. In contrast, the amplitude of evoked endplate potentials in R6/1 mice is increased compared to controls. Consistent with a presynaptic increase of release probability, synaptic depression under high-frequency stimulation is higher in R6/1 mice. In addition, no changes were detected in the size and dynamics of the recycling synaptic vesicle pool. Moreover, we have found increased amounts of the synaptic vesicle proteins synaptobrevin 1,2/VAMP 1,2 and cysteine string protein-alpha, and the SNARE protein SNAP-25, concomitant with normal levels of other synaptic vesicle markers. Our results reveal that the transgenic expression of a mutant form of htt leads to an unexpected gain of synaptic function. That phenotype is likely not secondary to neurodegeneration and might be due to a primary deregulation in synaptic protein levels. Our findings could be relevant to understand synaptic toxic effects of proteins with abnormal polyQ repeats. PMID- 21248137 TI - Precision in visual working memory reaches a stable plateau when individual item limits are exceeded. AB - Multiple studies have demonstrated that resolution in working memory (WM) declines as the number of stored items increases. Discrete-resource models predict that this decline should reach a stable plateau at relatively small set sizes because item limits prevent additional information from being encoded into WM at larger set sizes. By contrast, flexible-resource models predict that the monotonic declines in precision will continue indefinitely as set size increases and resources are distributed without any fixed item limit. In the present work, we found that WM resolution exhibited monotonic declines until set size reached three items, after which resolution achieved a clear asymptote. Moreover, analyses of individual differences showed a strong correlation between each observer's item limit and the set size at which WM resolution achieved asymptote. These behavioral observations were corroborated by measurements of contralateral delay activity (CDA), an event-related potential waveform that tracks the number of items maintained during the delay period. CDA activity rose monotonically and achieved asymptote at a set size that predicted individual WM capacity. Moreover, this neural measure of on-line storage also predicted the set size at which mnemonic resolution reached a stable plateau for each observer. Thus, independent behavioral and neural measures of WM capacity support a clear prediction of discrete-resource models. Precision in visual WM reaches asymptote when individual item limits are exceeded. PMID- 21248136 TI - Mitochondrial reactive oxygen species are activated by mGluR5 through IP3 and activate ERK and PKA to increase excitability of amygdala neurons and pain behavior. AB - Reactive oxygen species (ROS) such as superoxide are emerging as important signaling molecules in physiological plasticity but also in peripheral and spinal cord pain pathology. Underlying mechanisms and pain-related ROS signaling in the brain remain to be determined. Neuroplasticity in the amygdala plays a key role in emotional-affective pain responses and depends on group I metabotropic glutamate receptors (mGluRs) and protein kinases. Using patch-clamp, live-cell imaging, and behavioral assays, we tested the hypothesis that mitochondrial ROS links group I mGluRs to protein kinase activation to increase neuronal excitability and pain behavior. Agonists for mGluR1/5 (DHPG) or mGluR5 (CHPG) increased neuronal excitability of neurons in the laterocapsular division of the central nucleus of the amygdala (CeLC). DHPG effects were inhibited by an mGluR5 antagonist (MTEP), IP(3) receptor blocker (xestospongin C), or ROS scavengers (PBN, tempol), but not by an mGluR1 antagonist (LY367385) or NO synthase inhibitor (l-NAME). Tempol inhibited the effects of IP(3) but not those of a PKC activator, indicating that ROS activation was IP(3) mediated. Live-cell imaging in CeLC-containing brain slices directly showed DHPG-induced and synaptically evoked mitochondrial superoxide production. DHPG also increased pain-related vocalizations and spinal reflexes through a mechanism that required mGluR5, IP(3), and ROS. Combined application of inhibitors of ERK (U0126) and PKA (KT5720) was necessary to block completely the excitatory effects of a ROS donor (tBOOH). A PKC inhibitor (GF109203X) had no effect. Antagonists and inhibitors alone did not affect neuronal excitability. The results suggest an important role for the novel mGluR5- IP(3)-ROS-ERK/PKA signaling pathway in amygdala pain mechanisms. PMID- 21248138 TI - Drosophila tao controls mushroom body development and ethanol-stimulated behavior through par-1. AB - In both mammalian and insect models of ethanol-induced behavior, low doses of ethanol stimulate locomotion. However, the mechanisms of the stimulant effects of ethanol on the CNS are mostly unknown. We have identified tao, encoding a serine threonine kinase of the Ste20 family, as a gene necessary for ethanol-induced locomotor hyperactivity in Drosophila. Mutations in tao also affect behavioral responses to cocaine and nicotine, making flies resistant to the effects of both drugs. We show that tao function is required during the development of the adult nervous system and that tao mutations cause defects in the development of central brain structures, including the mushroom body. Silencing of a subset of mushroom body neurons is sufficient to reduce ethanol-induced hyperactivity, revealing the mushroom body as an important locus mediating the stimulant effects of ethanol. We also show that mutations in par-1 suppress both the mushroom body morphology and behavioral phenotypes of tao mutations and that the phosphorylation state of the microtubule-binding protein Tau can be altered by RNA interference knockdown of tao, suggesting that tao and par-1 act in a pathway to control microtubule dynamics during neural development. PMID- 21248139 TI - Deletion of ERK1 and ERK2 in the CNS causes cortical abnormalities and neonatal lethality: Erk1 deficiency enhances the impairment of neurogenesis in Erk2 deficient mice. AB - Intracellular signaling through extracellular signal-regulated kinase (ERK) is important in regulating cellular functions in a variety of tissues including the CNS. Although ERK1 and ERK2 have a very similar substrate profile and amino acid sequences, there are strikingly different phenotypes between Erk1- and Erk2 deficient mice. Thus, the question arose as to whether these two proteins are functional homologs that compensate for each other, or whether they have distinct functions. Here, we generated double knock-out mice deficient for Erk2 in the CNS, with ubiquitous homozygous deletion of Erk1, and compared the phenotypes of these mice with those of monogenic Erk2-deficient mice. Although we did obtain double knock-out newborn pups, they survived for not >1 d. These pups appeared normal just after parturition. However, they had no milk in their stomachs even 6 7 h after birth. Intracerebral hemorrhages with varying location and severity were observed. The ventricular zones and corpus callosum of the double knock-out pups did not develop adequately. Neuronal size and nuclear morphology in some brain regions were markedly aberrant in the double knock-out pups compared with controls, while deficiency in Erk2 only caused a mild phenotype. These results suggest that total ERK1/2 activity governs cellular behaviors to ensure proper brain development. PMID- 21248140 TI - Stress potentiates early and attenuates late stages of visual processing. AB - Stress can fundamentally alter neural responses to incoming information. Recent research suggests that stress and anxiety shift the balance of attention away from a task-directed mode, governed by prefrontal cortex, to a sensory-vigilance mode, governed by the amygdala and other threat-sensitive regions. A key untested prediction of this framework is that stress exerts dissociable effects on different stages of information processing. This study exploited the temporal resolution afforded by event-related potentials to disentangle the impact of stress on vigilance, indexed by early perceptual activity, from its impact on task-directed cognition, indexed by later postperceptual activity in humans. Results indicated that threat of shock amplified stress, measured using retrospective ratings and concurrent facial electromyography. Stress also double dissociated early sensory-specific processing from later task-directed processing of emotionally neutral stimuli: stress amplified N1 (184-236 ms) and attenuated P3 (316-488 ms) activity. This demonstrates that stress can have strikingly different consequences at different processing stages. Consistent with recent suggestions, stress amplified earlier extrastriate activity in a manner consistent with vigilance for threat (N1), but disrupted later activity associated with the evaluation of task-relevant information (P3). These results provide a novel basis for understanding how stress can modulate information processing in everyday life and stress-sensitive disorders. PMID- 21248141 TI - Effect of animal facility construction on basal hypothalamic-pituitary-adrenal and renin-aldosterone activity in the rat. AB - Although loud noise and intense vibration are known to alter the behavior and phenotype of laboratory animals, little is known about the effects of nearby construction. We studied the effect of a nearby construction project on the classic stress hormones ACTH, corticosterone, renin, and aldosterone in rats residing in a barrier animal facility before, for the first 3 months of a construction project, and at 1 month after all construction was completed. During some of the construction, noise and vibrations were not obvious to investigators inside the animal rooms. Body weight matched for age was not altered by nearby construction. During nearby construction, plasma ACTH, corticosterone, and aldosterone were approximately doubled compared with those of pre- and postconstruction levels. Expression of CRH mRNA in the paraventricular nucleus of the hypothalamus, CRH receptor and POMC mRNA in the anterior pituitary, and most mRNAs for steroidogenic genes in the adrenal gland were not significantly changed during construction. We conclude that nearby construction can cause a stress response without long-term effects on hypothalamic-pituitary-adrenal axis gene expression and body weight. PMID- 21248142 TI - Sox3 functions in a cell-autonomous manner to regulate spermatogonial differentiation in mice. AB - The X-linked Sox3 gene encodes a member of the Sry high-mobility group box proteins, which play a role in many developmental processes including neurogenesis and testis development. This study further examined the role of Sox3 in spermatogenesis. Males without Sox3 expression exhibited a similar number of germ cell nuclear antigen-positive germ cells at 1, 5, and 10 d postpartum (dpp) compared to their wild-type littermates, but there was significant germ cell depletion by 20 dpp. However, spermatogenesis later resumed and postmeiotic germ cells were observed by 56 dpp. The VasaCre transgene was used to generate a germ cell-specific deletion of Sox3. The phenotype of the germ cell-specific Sox3 knockout was similar to the ubiquitous knockout, indicating an intrinsic role for Sox3 in germ cells. The residual germ cells in 20 dpp Sox3(-/Y) males were spermatogonia as indicated by their expression of neurogenin3 but not synaptonemal complex protein 3, which is expressed within cells undergoing meiosis. RNA expression analyses corroborated the histological analyses and revealed a gradual transition from relatively increased expression of spermatogonia genes at 20 dpp to near normal expression of genes characteristic of undifferentiated and meiotic germ cells by 84 dpp. Fluorescent-activated cell sorting of undifferentiated (ret tyrosine kinase receptor positive) and differentiated (kit receptor tyrosine kinase-positive) spermatogonia revealed depletion of differentiated spermatogonia in Sox3(-/Y) tubules. These results indicate that Sox3 functions in an intrinsic manner to promote differentiation of spermatogonia in prepubertal mice but it is not required for ongoing spermatogenesis in adults. The Sox3(-/Y) males provide a unique model for studying the mechanism of germ cell differentiation in prepubertal testes. PMID- 21248143 TI - G6PD up-regulation promotes pancreatic beta-cell dysfunction. AB - Increased reactive oxygen species (ROS) induce pancreatic beta-cell dysfunction during progressive type 2 diabetes. Glucose-6-phosphate dehydrogenase (G6PD) is a reduced nicotinamide adenine dinucleotide phosphate-producing enzyme that plays a key role in cellular reduction/oxidation regulation. We have investigated whether variations in G6PD contribute to beta-cell dysfunction through regulation of ROS accumulation and beta-cell gene expression. When the level of G6PD expression in pancreatic islets was examined in several diabetic animal models, such as db/db mice and OLEFT rats, G6PD expression was evidently up-regulated in pancreatic islets in diabetic animals. To investigate the effect of G6PD on beta-cell dysfunction, we assessed the levels of cellular ROS, glucose-stimulated insulin secretion and beta-cell apoptosis in G6PD-overexpressing pancreatic beta-cells. In INS-1 cells, G6PD overexpression augmented ROS accumulation associated with increased expression of prooxidative enzymes, such as inducible nitric oxide synthase and reduced nicotinamide adenine dinucleotide phosphate oxidase. G6PD up regulation also caused decrease in glucose-stimulated insulin secretion in INS-1 cells and primary pancreatic islets. Moreover, elevated G6PD expression led to beta-cell apoptosis, concomitant with the increase in proapoptotic gene expression. On the contrary, suppression of G6PD with small interference RNA attenuated palmitate-induced beta-cell apoptosis. Together, these data suggest that up-regulation of G6PD in pancreatic beta-cells would induce beta-cell dysregulation through ROS accumulation in the development of type 2 diabetes. PMID- 21248144 TI - Estrogens promote invasion of prostate cancer cells in a paracrine manner through up-regulation of matrix metalloproteinase 2 in prostatic stromal cells. AB - Accumulating evidence suggests an enhancing effect of estrogens on prostate cancer (PCa) progression. Matrix metalloproteinase 2 (MMP2), which plays an important role in prostate cancer invasion, is mainly expressed in prostatic stromal cells (PrSC). Here we show that estradiol (E(2)) treatment up-regulates MMP2 production in PrSC, which promotes PCa cell invasion in a paracrine manner. Conditioned medium (CM) was collected from E(2)-treated prostatic stromal cell line WPMY-1 and primary PrSC. The CM of E(2)-treated WPMY-1 and PrSC promoted invasion of PCa cells, as measured by Matrigel transwell assays. Treatment with E(2) and 1,3,5-Tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole, an estrogen receptor alpha (ERalpha) specific agonist, significantly up-regulated MMP2 expression in WPMY-1 and PrSC cells at both mRNA and protein levels. The CM treated with an anti-MMP2 antibody lost the stimulatory effect on invasion of PCa cells. The ER inhibitor ICI 182,780, as well as a TGFbeta1 neutralizing antibody and ERalpha specific small interfering RNA effectively suppressed E(2)-induced MMP2 expression in WPMY-1 cells. Mechanistic studies showed that E(2) up-regulated MMP2 in an indirect manner: E(2) induced TGFbeta1 expression via ERalpha; TGFbeta1 stimulated MMP2 expression in PrSC; the invasion of PCa cells were stimulated by elevated MMP2 expression induced by E(2) in a paracrine manner. Our data show that E(2) induces MMP2 expression in WPMY-1 and PrSC cells, which was mediated by TGFbeta1. The effect of E(2) on invasion of PCa cells is mediated by up-regulation of MMP2 in a paracrine mechanism. PMID- 21248145 TI - Impaired hypothalamic regulation of endocrine function and delayed counterregulatory response to hypoglycemia in Magel2-null mice. AB - Hypothalamic dysfunction may underlie endocrine abnormalities in Prader-Willi syndrome (PWS), a genetic disorder that features GH deficiency, obesity, and infertility. One of the genes typically inactivated in PWS, MAGEL2, is highly expressed in the hypothalamus. Mice deficient for Magel2 are obese with increased fat mass and decreased lean mass and have blunted circadian rhythm. Here, we demonstrate that Magel2-null mice have abnormalities of hypothalamic endocrine axes that recapitulate phenotypes in PWS. Magel2-null mice had elevated basal corticosterone levels, and although male Magel2-null mice had an intact corticosterone response to restraint and to insulin-induced hypoglycemia, female Magel2-null mice failed to respond to hypoglycemia with increased corticosterone. After insulin-induced hypoglycemia, Magel2-null mice of both sexes became more profoundly hypoglycemic, and female mice were slower to recover euglycemia, suggesting an impaired hypothalamic counterregulatory response. GH insufficiency can produce abnormal body composition, such as that seen in PWS and in Magel2 null mice. Male Magel2-null mice had Igf-I levels similar to control littermates. Female Magel2-null mice had low Igf-I levels and reduced GH release in response to stimulation with ghrelin. Female Magel2-null mice did respond to GHRH, suggesting that their GH deficiency has a hypothalamic rather than pituitary origin. Female Magel2-null mice also had higher serum adiponectin than expected, considering their increased fat mass, and thyroid (T(4)) levels were low. Together, these findings strongly suggest that loss of MAGEL2 contributes to endocrine dysfunction of hypothalamic origin in individuals with PWS. PMID- 21248147 TI - The rat NK cell receptors Ly49s4 and Ly49i4 recognize nonclassical MHC-I molecules on Listeria monocytogenes-infected macrophages. AB - Ly49 receptors in rodents, like KIRs in humans, regulate NK cell activity. Although inhibitory Ly49 receptors clearly recognize MHC-I molecules, ligands for the activating Ly49 receptors are less well defined. Here, we show that the activating Ly49s4 and the inhibitory Ly49i4 receptors recognize nonclassical MHC I molecules on the rat macrophage cell line R2 (RT1(d)). Listeria infection of R2 macrophages led to increased expression of classical and nonclassical MHC-I molecules. Coincubation of these infected cells with reporter cells expressing Ly49i4 or Ly49s4 increased the reporter cell responses. These responses were blocked by mAb OX18 (anti-MHC-I) and AAS1 (anti-nonclassical MHC-I). IFN-gamma treatment of normal R2 cells also increased the MHC-I expression and enhanced the reporter cell responses. These results suggest that activating and inhibitory Ly49 receptors monitor MHC-I expression on Listeria-infected cells. PMID- 21248146 TI - Minireview: roles of the forkhead transcription factor FOXL2 in granulosa cell biology and pathology. AB - The forkhead transcription factor (FOXL2) is an essential transcription factor in the ovary. It is important in ovarian development and a key factor in female sex determination. In addition, FOXL2 plays a significant role in the postnatal ovary and follicle maintenance. The diverse transcriptional activities of FOXL2 are likely attributable to posttranslational modifications and binding to other key proteins involved in granulosa cell function. Mutations of FOXL2 lead to disorders of ovarian function ranging from premature follicle depletion and ovarian failure to unregulated granulosa cell proliferation leading to tumor formation. Thus, FOXL2 is a key regulator of granulosa cell function and a master transcription factor in these cells. PMID- 21248148 TI - Differential internalization of hu14.18-IL2 immunocytokine by NK and tumor cell: impact on conjugation, cytotoxicity, and targeting. AB - The hu14.18-IL2 (EMD 273063) IC, consisting of a GD(2)-specific mAb genetically engineered to two molecules of IL-2, is in clinical trials for treatment of GD(2) expressing tumors. Anti-tumor activity of IC in vivo and in vitro involves NK cells. We studied the kinetics of retention of IC on the surface of human CD25(+)CD16(-) NK cell lines (NKL and RL12) and GD(2)(+) M21 melanoma after IC binding to the cells via IL-2R and GD(2), respectively. For NK cells, ~ 50% of IC was internalized by 3 h and ~ 90% by 24 h of cell culture. The decrease of surface IC levels on NK cells correlated with the loss of their ability to bind to tumor cells and mediate antibody-dependent cellular cytotoxicity in vitro. Unlike NK cells, M21 cells retained ~ 70% of IC on the surface following 24 h of culture and maintained the ability to become conjugated and lysed by NK cells. When NKL cells were injected into M21-bearing SCID mice, IT delivery of IC augmented NK cell migration into the tumor. These studies demonstrate that once IC binds to the tumor, it is present on the tumor surface for a prolonged time, inducing the recruitment of NK cells to the tumor site, followed by tumor cell killing. PMID- 21248149 TI - SerpinB1 protects the mature neutrophil reserve in the bone marrow. AB - SerpinB1 is among the most efficient inhibitors of neutrophil serine proteases- NE, CG, and PR-3--and we investigated here its role in neutrophil development and homeostasis. We found that serpinB1 is expressed in all human bone marrow leukocytes, including stem and progenitor cells. Expression levels were highest in the neutrophil lineage and peaked at the promyelocyte stage, coincident with the production and packaging of the target proteases. Neutrophil numbers were decreased substantially in the bone marrow of serpinB1(-/-) mice. This cellular deficit was associated with an increase in serum G-CSF levels. On induction of acute pulmonary injury, neutrophils were recruited to the lungs, causing the bone marrow reserve pool to be completely exhausted in serpinB1(-/-) mice. Numbers of myeloid progenitors were normal in serpinB1(-/-) bone marrow, coincident with the absence of target protease expression at these developmental stages. Maturation arrest of serpinB1(-/-) neutrophils was excluded by the normal CFU-G growth in vitro and the normal expression in mature neutrophils of early and late differentiation markers. Normal absolute numbers of proliferating neutrophils and pulse-chase kinetic studies in vivo showed that the bone marrow deficit in serpinB1(-/-) mice was largely restricted to mature, postmitotic neutrophils. Finally, upon overnight culture, apoptosis and necrosis were greater in purified bone marrow neutrophils from serpinB1(-/-) compared with WT mice. Collectively, these findings demonstrate that serpinB1 sustains a healthy neutrophil reserve that is required in acute immune responses. PMID- 21248150 TI - Spatiotemporal photolabeling of neutrophil trafficking during inflammation in live zebrafish. AB - How neutrophils traffic during inflammation in vivo remains elusive. To visualize the origin and fate of neutrophils during induction and resolution of inflammation, we established a genetically encoded photolabeling system by generating transgenic zebrafish that express a photoconvertible fluorescent reporter Dendra2 in neutrophils. Spatiotemporal photolabeling of neutrophils in vivo demonstrates that they emerge from the hematopoietic tissue in close proximity to injured tissue and repeat forward and reverse migration between the wound and the vasculature. Subsequently, neutrophils disperse throughout the body as wound-healing proceeds, contributing to local resolution at injured tissue and systemic dissemination of wound-sensitized neutrophils. Tissue damage also alters the fate of neutrophils in the caudal hematopoietic tissue and promotes caudorostral mobilization of neutrophils via the circulation to the cephalic mesenchyme. This work provides new insight into neutrophil behaviors during inflammation and resolution within a multicellular organism. PMID- 21248151 TI - The unexpected link between infection-induced apoptosis and a TH17 immune response. AB - Microbial pathogens can initiate MOMP in host cells and as such, initiate the mitochondrial pathway of apoptosis. Innate immune recognition of cells dying in this way by infection-induced apoptosis would involve recognition of ligands derived from the apoptotic host cell simultaneously with those derived from the infecting pathogen. The resultant signal transduction pathways engaged direct DCs to concomitantly synthesize TGF-beta and IL-6, two cytokines that subsequently favor the differentiation of naive CD4 T cells into T(h)17 cells. Citrobacter rodentium is one rodent pathogen that targets mitochondria and induces apoptosis, and blockade of apoptosis during enteric Citrobacter infection impairs the characteristic T(h)17 response in the intestinal LP. Here, we review these original findings. We discuss microbial infections other than Citrobacter that have been shown to induce T(h)17 responses, and we examine what is known about the ability of those pathogens to induce apoptosis. We also consider types of cell death other than apoptosis that can be triggered by microbial infection, and we highlight how little we know about the impact of various forms of cell death on the ensuing adaptive immune response. PMID- 21248152 TI - Obstacles and opportunities for understanding macrophage polarization. AB - Macrophages are now routinely categorized into phenotypic subtypes based on gene expression induced in response to cytokine and pathogen-derived stimulation. In the broadest division, macrophages are described as being CAMs (M1 macrophages) or AAMs (M2 macrophages) based on their exposure to TLR and IFN signals or Th2 cytokines, respectively. Despite the prolific use of this simple classification scheme, little is known about the precise functions of effector molecules produced by AAMs, especially how representative the CAM and AAM subtypes are of tissue macrophages in homeostasis, infection, or tissue repair and how plasticity in gene expression regulates macrophage function in vivo. Furthermore, correlations between mouse and human tissue macrophages and their representative subtypes are lacking and are a major barrier to understanding human immunity. Here, we briefly summarize current features of macrophage polarization and discuss the roles of various macrophage subpopulations and macrophage-associated genes in health and disease. PMID- 21248153 TI - Characterization of infecting strains and superantigen-neutralizing antibodies in Staphylococcus aureus bacteremia. AB - Staphylococcus aureus superantigens (SAgs) are highly potent T cell mitogens. Antibodies against non-enterotoxin gene cluster (non-egc) SAgs are common in healthy adults, whereas neutralizing antibodies against egc SAgs are rare. We investigated the infecting S. aureus strains and the anti-SAg antibody response during S. aureus bacteremia (SAB). This prospective clinical study (www.clinicaltrials.gov, NCT00548002) included 43 injection drug users (IDUs) and 44 group-matched nonaddicts with SAB. spa genotypes and SAg gene patterns (multiplex PCR) of the S. aureus isolates were determined. The neutralizing capacities of sera obtained at the acute phase and the convalescent phase of SAB were tested against the SAg cocktail of the respective infecting strain and a panel of recombinant SAgs. The lineages CC59 and CC30 were more prevalent among bacteremia strains from IDUs than among strains from nonaddicts. SAg gene patterns in isolates from IDUs and nonaddicts were similar. At the acute phase of bacteremia, IDUs had more neutralizing antibodies against non-egc SAgs than did nonaddicts. Antibody titers frequently increased during infection. In contrast, there were no neutralizing antibodies against egc SAgs at disease onset and such antibodies were not induced by SAB. SAB triggers an antibody response only against non-egc SAgs. Preimmunization in IDU patients is probably due to previous exposure to the infecting strain. PMID- 21248154 TI - Identification of human T-cell responses to Mycobacterium tuberculosis resuscitation-promoting factors in long-term latently infected individuals. AB - The Mycobacterium bovis BCG vaccine is the only tuberculosis (TB) vaccine available, yet it provides limited protection against pulmonary TB in adults and fails to protect against TB reactivation. We hypothesized that immunity against Mycobacterium tuberculosis "resuscitation-promoting factors" (Rpfs), which are small bacterial proteins that promote proliferation of dormant mycobacteria, may be relevant in the human immune response to M. tuberculosis. In previous unpublished work, we found that Rpfs Rv0867c and Rv2389c induced gamma interferon (IFN-gamma) production in the blood of TB patients' healthy household contacts in several different African populations. Here we examine these two dominant Rpf antigens in more detail and define the nature of the responding T-cell subsets. Multiparameter cytokine profiling showed that Rv2389c and, to a lesser extent, Rv0867c were recognized by mycobacterium-responsive healthy Dutch individuals; peptide-scanning revealed several epitopes, including a single immunodominant epitope in Rv2389c. Rv0867c and, to a lesser extent, Rv2389c Rpf-specific T-cell responses were maintained for decades in long-term M. tuberculosis nonprogressors. Prominent Rv0867c-specific double- and single-cytokine-producing CD8(+) T-cell subset responses were found, including a large population of CD8(+) effector memory and effector T-cell subsets. We conclude that M. tuberculosis Rpf antigens are important targets in the human immune response to M. tuberculosis and represent interesting TB vaccine candidate antigens. PMID- 21248155 TI - Evaluation of the immunogenicity and biological activity of the Citrobacter freundii Vi-CRM197 conjugate as a vaccine for Salmonella enterica serovar Typhi. AB - Typhoid fever remains a major health problem in developing countries. Young children are at high risk, and a vaccine effective for this age group is urgently needed. Purified capsular polysaccharide from Salmonella enterica serovar Typhi (Vi) is licensed as a vaccine, providing 50 to 70% protection in individuals older than 5 years. However, this vaccine is ineffective in infants. Vi conjugated to a carrier protein (i.e., an exoprotein A mutant from Pseudomonas aeruginosa [rEPA]) is highly immunogenic, provides long-term protection, and shows more than 90% protective efficacy in children 2 to 5 years old. Here, we describe an alternative glycoconjugate vaccine for S. Typhi, Vi-CRM(197), where Vi was obtained from Citrobacter freundii WR7011 and CRM(197), the mutant diphtheria toxin protein, was used as the carrier. We investigated the optimization of growth conditions for Vi production from C. freundii WR7011 and the immunogenicity of Vi-CRM(197) conjugates in mice. The optimal saccharide/protein ratio of the glycoconjugates was identified for the best antibody production. We also demonstrated the ability of this new vaccine to protect mice against challenge with Vi-positive Salmonella enterica serovar Typhimurium. PMID- 21248156 TI - Persistence of a positive (1,3)-beta-D-glucan test after clearance of candidemia in hematopoietic stem cell transplant recipients. AB - In 6 hematopoietic stem cell transplant (HSCT) recipients with candidemia, the (1,3)-beta-d-glucan (BG) test was positive a median of 2.5 days after a positive blood culture. Only in 1 patient did BG positivity precede positive blood cultures. BG concentrations decreased in patients with clinical response, but positive BG results persisted long after blood cultures became sterile (median, 48 days). PMID- 21248157 TI - Mucosal immunologic responses in cholera patients in Bangladesh. AB - Vibrio cholerae O1 causes dehydrating diarrhea with a high mortality rate if untreated. The infection also elicits long-term protective immunity. Since V. cholerae is noninvasive, mucosal immunity is likely important for protection. In this study, we compared humoral immune responses in the duodenal mucosa and blood of cholera patients at different time points after the onset of disease and compared them with those of healthy controls (HCs). Immune responses to lipopolysaccharide (LPS) and the recombinant cholera toxin B subunit (rCTB) were assessed by enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot (ELISPOT) assay. Significant increases in V. cholerae LPS-specific IgA and IgG antibody levels were seen in duodenal extracts on day 30, but the levels decreased to baseline by day 180; plasma V. cholerae LPS-specific IgA levels remained elevated longer. Levels of mucosal CTB antibodies also peaked on day 30, but the increase reached statistical significance only for IgG. A significant correlation was found between the CTB antibody-secreting cell (ASC) response in the circulatory system on day 7 and subsequent CTB-specific IgA levels in duodenal extracts on day 30 and the numbers of CTB-specific IgA ASCs in duodenal tissues on day 180. The proportion (0.07%) of mucosal V. cholerae LPS IgA ASCs peaked on day 30 and remained elevated through day 180 compared to that of HCs (P = 0.03). These results suggest that protective immunity against V. cholerae is not likely mediated by the constitutive secretion of antibodies at the mucosal surface; our results are consistent with those of other studies that suggest instead that anamnestic immune responses of mucosal lymphocytes may play a major role in protection against cholera. PMID- 21248158 TI - Human papillomavirus 16 (HPV 16) and HPV 18 antibody responses measured by pseudovirus neutralization and competitive Luminex assays in a two- versus three dose HPV vaccine trial. AB - Human papillomavirus 16 (HPV 16) and HPV 18 antibody responses in a 2- versus 3 dose HPV vaccine (Gardasil) trial were measured by a pseudovirus neutralizing antibody (PsV NAb) assay and by the Merck competitive Luminex immunoassay (cLIA). Eight hundred twenty-four female subjects assigned to three dosing regimens (group 1, 9 to 13 years old; 2 doses, months 0 and 6 [n = 259]; group 2, 9 to 13 years old; 3 doses, months 0, 2, and 6 [n = 260]; group 3, 16 to 26 years old; 3 doses, months 0, 2, and 6 [n = 305]) had postvaccine responses assessed 1 month after the last dose. Of 791 subjects with baseline and 7-month sera, 15 (1.9%) and 9 (1.1%) were baseline seropositive for HPV 16 and HPV 18, respectively. All baseline-seronegative vaccinees seroconverted to both HPV 16 and HPV 18. Mean anti-HPV 16 levels were similar for groups 1 and 2 (for PsV NAb, P = 0.675; for cLIA, P = 0.874), and levels for both groups 1 and 2 were approximately 2-fold higher than that for group 3 (for PsV NAb and cLIA, P < 0.001). Mean anti-HPV 18 levels were approximately 1.4-fold lower in group 1 than in group 2 (for PsV, NAb P = 0.013; for cLIA, P = 0.001), and levels for both groups 1 and 2 were approximately 2.0- to 2.5-fold higher than that for group 3 (for PsV NAb and cLIA, P < 0.001). Pearson correlation coefficients for the assays were 0.672 for HPV 16 and 0.905 for HPV 18. Most of the discordant results were observed at lower cLIA signals. These results suggest that the PsV NAb assay could be a suitable alternative to cLIA for the measurement of postvaccine antibody responses. PMID- 21248159 TI - Serum antibody kinetics following nasal or parenteral challenge with meningococcal polysaccharide in healthy adults. AB - Limited data are available on the kinetics of meningococcal serogroup C (MenC) specific antibody responses following parenteral or nasal challenge in those who have received prior MenC vaccination (polysaccharide or conjugate). Young adults who had previously received either meningococcal A/C polysaccharide (MACP) or MenC conjugate (MCC) vaccine or naive subjects were challenged with MACP via one of two routes, nasal or parenteral. Blood samples were taken prevaccination and on days 1 to 4 and day 10 postvaccination. MenC serum bactericidal antibody (SBA) and MenC-specific IgG were measured. Following parenteral challenge, MenC SBA and IgG responses were seen to occur between 4 and 7 days postchallenge. A lower proportion of subjects responded following nasal challenge, with naive subjects showing little change in SBA geometric mean titer (GMT) and IgG geometric mean concentration (GMC) over the 10 days following challenge. Increases in SBA GMTs were seen between 4 and 7 days after nasal challenge in those who had received prior MCC and between 7 and 10 days in those who had received prior MACP, and the responses in the prior-MACP group were of lower magnitude than the responses of the prior-MCC group. The data presented here indicate that, following MCC vaccination, memory has been induced at the mucosal level, and these subjects were able to respond with increases in SBA levels. These results demonstrate that the speed of response (primary or secondary) to challenge with MenC polysaccharide via the nasal or parenteral route does not differ and support concerns that immunological memory alone is too slow to provide protection. PMID- 21248160 TI - Improving the science and politics of quality improvement. PMID- 21248161 TI - A multifaceted intervention for quality improvement in a network of intensive care units: a cluster randomized trial. AB - CONTEXT: Evidence-based practices improve intensive care unit (ICU) outcomes, but eligible patients may not receive them. Community hospitals treat most critically ill patients but may have few resources dedicated to quality improvement. OBJECTIVE: To determine the effectiveness of a multicenter quality improvement program to increase delivery of 6 evidence-based ICU practices. DESIGN, SETTING, AND PARTICIPANTS: Pragmatic cluster-randomized trial among 15 community hospital ICUs in Ontario, Canada. A total of 9269 admissions occurred during the trial (November 2005 to October 2006) and 7141 admissions during a decay-monitoring period (December 2006 to August 2007). INTERVENTION: We implemented a videoconference-based forum including audit and feedback, expert-led educational sessions, and dissemination of algorithms to sequentially improve delivery of 6 practices. We randomized ICUs into 2 groups. Each group received this intervention, targeting a new practice every 4 months, while acting as control for the other group, in which a different practice was targeted in the same period. MAIN MEASURE OUTCOMES: The primary outcome was the summary ratio of odds ratios (ORs) for improvement in adoption (determined by daily data collection) of all 6 practices during the trial in intervention vs control ICUs. RESULTS: Overall, adoption of the targeted practices was greater in intervention ICUs than in controls (summary ratio of ORs, 2.79; 95% confidence interval [CI], 1.00 7.74). Improved delivery in intervention ICUs was greatest for semirecumbent positioning to prevent ventilator-associated pneumonia (90.0% of patient-days in last month vs 50.0% in first month; OR, 6.35; 95% CI, 1.85-21.79) and precautions to prevent catheter-related bloodstream infection (70.0% of patients receiving central lines vs 10.6%; OR, 30.06; 95% CI, 11.00-82.17). Adoption of other practices, many with high baseline adherence, changed little. CONCLUSION: In a collaborative network of community ICUs, a multifaceted quality improvement intervention improved adoption of care practices. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00332982. PMID- 21248163 TI - Type 1 diabetes: etiology, immunology, and therapeutic strategies. AB - Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D. PMID- 21248165 TI - Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. AB - The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and to electrolytes and water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to non self antigens. Zonulin is the only physiological modulator of intercellular tight junctions described so far that is involved in trafficking of macromolecules and, therefore, in tolerance/immune response balance. When the finely tuned zonulin pathway is deregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune, inflammatory, and neoplastic disorders can occur. This new paradigm subverts traditional theories underlying the development of these diseases and suggests that these processes can be arrested if the interplay between genes and environmental triggers is prevented by reestablishing the zonulin-dependent intestinal barrier function. This review is timely given the increased interest in the role of a "leaky gut" in the pathogenesis of several pathological conditions targeting both the intestine and extraintestinal organs. PMID- 21248164 TI - Role of Rab GTPases in membrane traffic and cell physiology. AB - Intracellular membrane traffic defines a complex network of pathways that connects many of the membrane-bound organelles of eukaryotic cells. Although each pathway is governed by its own set of factors, they all contain Rab GTPases that serve as master regulators. In this review, we discuss how Rabs can regulate virtually all steps of membrane traffic from the formation of the transport vesicle at the donor membrane to its fusion at the target membrane. Some of the many regulatory functions performed by Rabs include interacting with diverse effector proteins that select cargo, promoting vesicle movement, and verifying the correct site of fusion. We describe cascade mechanisms that may define directionality in traffic and ensure that different Rabs do not overlap in the pathways that they regulate. Throughout this review we highlight how Rab dysfunction leads to a variety of disease states ranging from infectious diseases to cancer. PMID- 21248166 TI - The WNKs: atypical protein kinases with pleiotropic actions. AB - WNKs are serine/threonine kinases that comprise a unique branch of the kinome. They are so-named owing to the unusual placement of an essential catalytic lysine. WNKs have now been identified in diverse organisms. In humans and other mammals, four genes encode WNKs. WNKs are widely expressed at the message level, although data on protein expression is more limited. Soon after the WNKs were identified, mutations in genes encoding WNK1 and -4 were determined to cause the human disease familial hyperkalemic hypertension (also known as pseudohypoaldosteronism II, or Gordon's Syndrome). For this reason, a major focus of investigation has been to dissect the role of WNK kinases in renal regulation of ion transport. More recently, a different mutation in WNK1 was identified as the cause of hereditary sensory and autonomic neuropathy type II, an early-onset autosomal disease of peripheral sensory nerves. Thus the WNKs represent an important family of potential targets for the treatment of human disease, and further elucidation of their physiological actions outside of the kidney and brain is necessary. In this review, we describe the gene structure and mechanisms regulating expression and activity of the WNKs. Subsequently, we outline substrates and targets of WNKs as well as effects of WNKs on cellular physiology, both in the kidney and elsewhere. Next, consequences of these effects on integrated physiological function are outlined. Finally, we discuss the known and putative pathophysiological relevance of the WNKs. PMID- 21248168 TI - Pathophysiological mechanisms of atrial fibrillation: a translational appraisal. AB - Atrial fibrillation (AF) is an arrhythmia that can occur as the result of numerous different pathophysiological processes in the atria. Some aspects of the morphological and electrophysiological alterations promoting AF have been studied extensively in animal models. Atrial tachycardia or AF itself shortens atrial refractoriness and causes loss of atrial contractility. Aging, neurohumoral activation, and chronic atrial stretch due to structural heart disease activate a variety of signaling pathways leading to histological changes in the atria including myocyte hypertrophy, fibroblast proliferation, and complex alterations of the extracellular matrix including tissue fibrosis. These changes in electrical, contractile, and structural properties of the atria have been called "atrial remodeling." The resulting electrophysiological substrate is characterized by shortening of atrial refractoriness and reentrant wavelength or by local conduction heterogeneities caused by disruption of electrical interconnections between muscle bundles. Under these conditions, ectopic activity originating from the pulmonary veins or other sites is more likely to occur and to trigger longer episodes of AF. Many of these alterations also occur in patients with or at risk for AF, although the direct demonstration of these mechanisms is sometimes challenging. The diversity of etiological factors and electrophysiological mechanisms promoting AF in humans hampers the development of more effective therapy of AF. This review aims to give a translational overview on the biological basis of atrial remodeling and the proarrhythmic mechanisms involved in the fibrillation process. We pay attention to translation of pathophysiological insights gained from in vitro experiments and animal models to patients. Also, suggestions for future research objectives and therapeutical implications are discussed. PMID- 21248162 TI - Regulation of blood pressure and salt homeostasis by endothelin. AB - Endothelin (ET) peptides and their receptors are intimately involved in the physiological control of systemic blood pressure and body Na homeostasis, exerting these effects through alterations in a host of circulating and local factors. Hormonal systems affected by ET include natriuretic peptides, aldosterone, catecholamines, and angiotensin. ET also directly regulates cardiac output, central and peripheral nervous system activity, renal Na and water excretion, systemic vascular resistance, and venous capacitance. ET regulation of these systems is often complex, sometimes involving opposing actions depending on which receptor isoform is activated, which cells are affected, and what other prevailing factors exist. A detailed understanding of this system is important; disordered regulation of the ET system is strongly associated with hypertension and dysregulated extracellular fluid volume homeostasis. In addition, ET receptor antagonists are being increasingly used for the treatment of a variety of diseases; while demonstrating benefit, these agents also have adverse effects on fluid retention that may substantially limit their clinical utility. This review provides a detailed analysis of how the ET system is involved in the control of blood pressure and Na homeostasis, focusing primarily on physiological regulation with some discussion of the role of the ET system in hypertension. PMID- 21248170 TI - Leucovorin-induced hypersensitivity reaction. AB - Leucovorin is a reduced form of folic acid, which has multiple uses.(1) In this case report, it is used in combination with fluorouracil in the treatment of colon cancer. We describe a 53-year-old male, who was started on FOLFOX 6 + bevacizumab who experienced a hypersensitivity reaction to leucovorin. There have been very few cases of leucovorin hypersensitivity reactions reported in the literature. In this case, symptoms include flushing, hives, body pain, headaches, elevated blood pressures, and general discomfort. Although leucovorin reactions are considered rare, one should be aware of the types of reactions that can occur with leucovorin. PMID- 21248171 TI - Adult Wilms' tumor: review of literature. AB - BACKGROUND: The most common renal tumors in adults is renal cell carcinoma. Wilms' tumor in subjects older than 16 years is rare; only 3% of Wilms' tumors are reported in adults, which explain the difficulties in diagnosis and treatment of this tumor entity in this age group. METHODS: Patient with stage IV adult nephroblastoma with favorable histology was described, current treatment modalities were discussed, and the literature was reviewed. RESULTS: Nineteen year old female patient is presented with renal mass, abdominal lymphadenopathy, and bilateral pulmonary deposits. Sonar guided biopsy from the renal mass was taken and pathology revealed nephroblastoma. Right nephrectomy was performed and the pathological examination revealed classic histology of nephroblastoma. The case diagnosed as stage IV adult Wilms' tumor with favorable histology. According to National Wilms' Tumor Study Group (NWTS-3), multimodal therapy was initiated immediately after surgery. The patient failed to respond to the first line therapy and died due to disease progression. CONCLUSION: Adult Wilms' tumor has no specific guidelines and this may lead to improper or incorrect treatment. PMID- 21248172 TI - Targeting macrophages in classical Hodgkin's lymphoma may seem rational, but is it safe? AB - A few reports have linked increased numbers of tissue macrophages with treatment failure and reduced lifespan in classical Hodgkin's lymphoma (HL) patients. Some investigators even suggested to target the macrophages in HL with biologic therapy, thus eliminating them from the tumor microenvironment. This review explores the risk: benefit equation of such approach as well as what the author believes is the driving force behind the 'great' migration of macrophages in HL. This article unravels the inflammatory pathways and immune alterations in classical HL that lead to a complex network consisting of T-cells, numerous cytokines, macrophages, and other cells. Macrophages are thought to play a crucial role in tumor antigen processing and presentation tasks, Reed-Sternberg (RS) cell phagocytosis, and antibody-dependent cellular cytotoxicity, therefore their extinction may be hazardous. The author believes RS cells should be targeted by the biologics, not the macrophages, and links his hopes with the existing investigational anti-CD30 therapies in relapsed/refractory classical HL. PMID- 21248173 TI - Newer developments in the therapeutics of the transitional cell carcinoma of renal pelvis. AB - Many of the risk factors and pathogenesis of urothelial carcinoma of the renal pelvis are similar to the ones of the more common urothelial bladder cancer. In addition, two endemic nephropathies and two inherited syndromes have been linked with the development of upper urologic cancer. Multiple synchronous or metachronous lesions throughout urinary tract are rather common and should always be sought in the management of this entity. Surgical resection is the treatment of choice in early-stage tumors. The role of adjuvant radiation and chemoradiation for carcinoma of the renal pelvis remains to be redefined, given the advent of conformal approaches and intensity modulation. In non-surgical candidates, chemotherapy remains the mainstay. Metastatic urothelial renal pelvic cancer is usually treated with combination platinum-based chemotherapy. Definitive radiation therapy should be considered in persons with locally advanced/unresectable disease, multiple comorbidities, and/or severely compromised performance status. Recently, the antifolate agent pemetrexed has demonstrated an overall response rate of circa 30% in urothelial carcinoma. New targeted agents, alone or in combination with cytotoxic drugs, are currently being tested in clinical trials and may lead to new and exciting avenues for the therapy of this disease. PMID- 21248174 TI - Is there a benefit to having a clinical oncology pharmacist on staff at a community oncology clinic? AB - BACKGROUND: The John Marsh Cancer Center is an ambulatory oncology clinic located in Hagerstown, MD. In 2004, a clinical oncology pharmacist was hired to help manage therapies and control cost. The objective was to evaluate clinical interventions, consultations and cost savings by the clinical oncology pharmacist. METHODS: This was a retrospective descriptive analysis of clinical interventions by the clinical oncology pharmacist from September 4, 2004 to October 27, 2006. Interventions were categorized as either drug-related or consultative. Drug-related interventions included medication reconciliation, dosing, and adverse effect management and prevention. Consultations incorporated drug information questions, patient visits, and patient education sessions. Information was extracted from an online documentation program linked to medical charts. RESULTS: A total of 583 clinical interventions were documented among 199 patients. Average time spent per intervention was 10 minutes. Drug-related and consultative interventions accounted for 35% and 65%, respectively. Included among the drug-related interventions were adverse events (131), medication reconciliation (52) and dosing (22). Consultation services consisted of patient education (143), patient visits (124) and drug information (25). The on-site pharmacist saved $210,000 by admixing chemotherapy. Patient and colleague surveys evaluated pharmacist services with positive ratings of 95% and 98%, respectively. CONCLUSION: Analysis of clinical interventions, cost-savings, and feedback from patients and colleagues confirmed beneficial services provided by a clinical pharmacist in this outpatient oncology center. PMID- 21248167 TI - Hyaluronan as an immune regulator in human diseases. AB - Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases. PMID- 21248175 TI - The cellular endosomal sorting complex required for transport pathway is not involved in avian metapneumovirus budding in a virus-like-particle expression system. AB - Avian metapneumovirus (AMPV) is a paramyxovirus that principally causes respiratory disease and egg production drops in turkeys and chickens. Together with its closely related human metapneumovirus (HMPV), they comprise the genus Metapneumovirus in the family Paramyxoviridae. Little is currently known about the mechanisms involved in the budding of metapneumovirus. By using AMPV as a model system, we showed that the matrix (M) protein by itself was insufficient to form virus-like-particles (VLPs). The incorporation of M into VLPs was shown to occur only when both the viral nucleoprotein (N) and the fusion (F) proteins were co-expressed. Furthermore, we provided evidence indicating that two YSKL and YAGL segments encoded within the M protein were not a functional late domain, and the endosomal sorting complex required for transport (ESCRT) machinery was not involved in metapneumovirus budding, consistent with a recent observation that human respiratory syncytial virus, closely related to HMPV, uses an ESCRT independent budding mechanism. Taken together, these results suggest that metapneumovirus budding is independent of the ESCRT pathway and the minimal budding machinery described here will aid our future understanding of metapneumovirus assembly and egress. PMID- 21248176 TI - Reassortant low-pathogenic avian influenza H5N2 viruses in African wild birds. AB - To investigate the presence and persistence of avian influenza virus in African birds, we monitored avian influenza in wild and domestic birds in two different regions in Nigeria. We found low-pathogenic avian influenza (LPAI) H5N2 viruses in three spur-winged geese (Plectropterus gambensis) in the Hadejia-Nguru wetlands. Phylogenetic analyses revealed that all of the genes, except the non structural (NS) genes, of the LPAI H5N2 viruses were more closely related to genes recently found in wild and domestic birds in Europe. The NS genes formed a sister group to South African and Zambian NS genes. This suggested that the Nigerian LPAI H5N2 viruses found in wild birds were reassortants exhibiting an NS gene that circulated for at least 7 years in African birds and is part of the African influenza gene pool, and genes that were more recently introduced into Africa from Eurasia, most probably by intercontinental migratory birds. Interestingly the haemagglutinin and neuraminidase genes formed a sister branch to highly pathogenic avian influenza (HPAI) H5N2 strains found in the same wild bird species in the same wetland only 1 year earlier. However, they were not the closest known relatives of each other, suggesting that their presence in the wetland resulted from two separate introductions. The presence of LPAI H5N2 in wild birds in the Hadejia-Nguru wetlands, where wild birds and poultry occasionally mix, provides ample opportunity for infection across species boundaries, with the potential risk of generating HPAI viruses after extensive circulation in poultry. PMID- 21248177 TI - Epstein-Barr virus latent gene sequences as geographical markers of viral origin: unique EBNA3 gene signatures identify Japanese viruses as distinct members of the Asian virus family. AB - Polymorphisms in Epstein-Barr virus (EBV) latent genes can identify virus strains from different human populations and individual strains within a population. An Asian EBV signature has been defined almost exclusively from Chinese viruses, with little information from other Asian countries. Here we sequenced polymorphic regions of the EBNA1, 2, 3A, 3B, 3C and LMP1 genes of 31 Japanese strains from control donors and EBV-associated T/NK-cell lymphoproliferative disease (T/NK LPD) patients. Though identical to Chinese strains in their dominant EBNA1 and LMP1 alleles, Japanese viruses were subtly different at other loci. Thus, while Chinese viruses mainly fall into two families with strongly linked 'Wu' or 'Li' alleles at EBNA2 and EBNA3A/B/C, Japanese viruses all have the consensus Wu EBNA2 allele but fall into two families at EBNA3A/B/C. One family has variant Li-like sequences at EBNA3A and 3B and the consensus Li sequence at EBNA3C; the other family has variant Wu-like sequences at EBNA3A, variants of a low frequency Chinese allele 'Sp' at EBNA3B and a consensus Sp sequence at EBNA3C. Thus, EBNA3A/B/C allelotypes clearly distinguish Japanese from Chinese strains. Interestingly, most Japanese viruses also lack those immune-escape mutations in the HLA-A11 epitope-encoding region of EBNA3B that are so characteristic of viruses from the highly A11-positive Chinese population. Control donor-derived and T/NK-LPD-derived strains were similarly distributed across allelotypes and, by using allelic polymorphisms to track virus strains in patients pre- and post haematopoietic stem-cell transplant, we show that a single strain can induce both T/NK-LPD and B-cell-lymphoproliferative disease in the same patient. PMID- 21248178 TI - Withdrawal of mechanical ventilation in the home: a case report and review of the literature. AB - Once it has been determined that aggressive medical treatment can no longer meet the goals of care for a ventilated patient, the process of withdrawing mechanical ventilation begins. This is a challenging clinical situation, drawing on the treating physician's skills including clinical decision making with consideration of the ethical and legal domains of practice, high level communication skills, intensive symptom control for the dying patient, and support for families throughout the episode, including bereavement. Central to the success of this process is recognition and respect for the needs and wishes of the patient and family. This case reports on the withdrawal of mechanical ventilation from a conscious patient in their own home, leading to death, following a prolonged hospital admission. PMID- 21248179 TI - What does the answer mean? A qualitative study of how palliative cancer patients interpret and respond to the Edmonton Symptom Assessment System. AB - The Edmonton Symptom Assessment System (ESAS) is a well-known self-reporting tool for symptom assessment in palliative care. Research has shown that patients experience difficulties in the scoring and interpretation, which may lead to suboptimal treatment. The aims were to examine how palliative care cancer patients interpreted and responded to the ESAS. Eleven patients (3 F/8 M), median age 65 (34-95) with mixed diagnoses were interviewed by means of cognitive interviewing, immediately after having completed the ESAS. The highest mean scores were found with tiredness (6.3) and oral dryness (5.7). The results showed that sources of error were related to interpretation of symptoms and differences in the understanding and use of the response format. The depression and anxiety symptoms were perceived as difficult to interpret, while the appetite item was particularly prone to misunderstandings. Contextual factors, such as mood and time of the day, influenced the answers. Lack of information and feedback from staff influenced the scores. Some patients stated that they scored at random because they did not understand why and how the ESAS was used. The patients' interpretation must be considered in order to minimize errors. The ESAS should always be reviewed with the patients after completion to improve symptom management, thereby strengthening the usability of the ESAS. PMID- 21248180 TI - Does place of death from cancer vary between ethnic groups in South East England? AB - There is growing evidence that the palliative care needs of certain people, such as those from minority ethnic groups, are not being met. The aim of this study was to investigate whether place of death from cancer differs between ethnic groups. A total of 101,516 patients resident in South East England and who died from lung, colorectal, breast or prostate cancer between 1998 and 2006 were extracted from the Thames Cancer Registry database. Ethnicity data were available for 68,804 patients (68%). The odds ratios (ORs) of death from cancer in a hospice, at home or in hospital were calculated. The results were adjusted for age at death, deprivation, cancer network of residence and time between diagnosis and death. Following adjustment, death in a hospice was significantly less likely for Pakistani patients (OR=0.47 95% CI [0.30-0.74]), Indian patients (0.68 [0.55 0.84]) and Bangladeshi patients (0.33 [0.19-0.56]). Death at home was significantly less likely in Black African patients (0.48 [0.36-0.65]), Black Caribbean patients (0.78 [0.67-0.90]) and Chinese patients (0.46 [0.28-0.76]). Pakistani, Indian, Bangladeshi, Black African, Black Caribbean and Chinese patients were all significantly more likely than White patients to die in hospital. The results were not substantially altered by recoding the unknown ethnicity group to White or using multiple imputation to assign those with a missing ethnicity an ethnic group. Place of death varies between ethnic groups. This may reflect differences in preferences for place of death or barriers to accessing specialist care in different settings. More detailed prospective qualitative studies are urgently required to determine reasons for this variation. PMID- 21248181 TI - Is levomepromazine stable over time? AB - Levomepromazine (methotrimeprazine) is an anti-psychotic used at low dose for the control of nausea and vomiting. When levomepromazine hydrochloride as Nozinan(r) is diluted with 0.9% sodium chloride at concentrations ranging from 0.13 to 6.25 mg/ml, and stored in polypropylene syringes, the drug is stable for at least 14 days. PMID- 21248182 TI - Return home at the end of life: Patients' vulnerability and risk factors. AB - Although most of the people in good health questioned about the subject said they would like to die at home, in the western world between 60 and 80% of deaths occur in hospital. Most authors consider that the indispensable conditions for a return home are the patient's desire and presence of the family and caregivers with the appropriate skills. The assessment of other factors predictive of a return home is inadequate. The aim of this study is to clarify how the return home is influenced by the vulnerability of the patient at the end of life, and by that of the family and caregivers. We carried out a multicentric, observational, prospective, exhaustive and longitudinal epidemiological study (three months follow-up), including 146 patients hospitalized at the end of their life and desiring to return home. For these patients the caregivers respected their freedom to choose to die at home in over half the cases (56%). Their overall vulnerability (personal, family context and caregivers) had a significant influence on the return home. This overall vulnerability was in fact identified as applying in 40% of the clinical situations, and made the possibility of a return home 50% less likely. PMID- 21248183 TI - Vitamin A supplementation modifies the association between mucosal innate and adaptive immune responses and resolution of enteric pathogen infections. AB - BACKGROUND: The efficacy of vitamin A supplementation on diarrheal disease morbidity may reflect the divergent effects that supplementation has on pathogen specific immune responses and pathogen-specific outcomes. OBJECTIVE: We examined how vitamin A supplementation modified associations between gut-cytokine immune responses and the resolution of different diarrheal pathogen infections. DESIGN: Stools collected from 127 Mexican children who were 5-15 mo old and enrolled in a randomized, placebo-controlled vitamin A supplementation trial were screened for enteropathogenic Escherichia coli (EPEC), enterotoxigenic E. coli (ETEC), and Giardia lamblia. Fecal concentrations of interleukin (IL)-6, IL-8, IL-4, IL-5, IL 10, monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-alpha (TNF alpha), and interferon-gamma (IFN-gamma) were measured by using an enzyme-linked immunosorbent assay. Hazard models that incorporated categorized cytokine variables (ie, nondetectable, less than the median of detectable concentrations, and at least the median of detectable concentrations) were fit to the length of pathogen infections stratified by treatment group. RESULTS: Vitamin A supplemented children with fecal MCP-1 or IL-8 concentrations less than the median of detectable concentrations and IL-10 concentrations of at least median concentrations had longer durations of EPEC infection than did children in the placebo group. In supplemented children, detectable fecal TNF-alpha or IL-6 concentrations were associated with shorter ETEC infection durations, whereas MCP 1 concentrations of at least the median were associated with longer infection durations. Children in this group who had IL-4, IL-5, or IFN-gamma concentrations of at least median detectable concentrations had shorter durations of G. lamblia infection. CONCLUSION: The effect of supplementation on associations between fecal cytokine concentrations and pathogen infection resolution depends on the role of inflammatory immune responses in resolving specific pathogen infections. PMID- 21248184 TI - Black and green tea consumption and the risk of coronary artery disease: a meta analysis. AB - BACKGROUND: Epidemiologic studies are inconsistent regarding the association between tea consumption and the risk of coronary artery disease (CAD). OBJECTIVE: The objective was to perform a meta-analysis to determine whether an association exists between tea consumption and total CAD endpoints in observational studies. DESIGN: We searched PUBMED and EMBASE databases for studies conducted from 1966 through November 2009. Study-specific risk estimates were combined by using a random-effects model. RESULTS: A total of 18 studies were included in the meta analysis: 13 studies on black tea and 5 studies on green tea. For black tea, no significant association was found through the meta-analysis [highest compared with lowest, summary relative risk (RR): 0.92; 95% CI: 0.82, 1.04; an increment of 1 cup/d, summary RR: 0.98; 95% CI: 0.94, 1.02]. For green tea, the summary RR indicated a significant association between the highest green tea consumption and reduced risk of CAD (summary RR: 0.72; 95% CI: 0.58, 0.89). Furthermore, an increase in green tea consumption of 1 cup/d was associated with a 10% decrease in the risk of developing CAD (summary RR: 0.90; 95% CI: 0.82, 0.99). CONCLUSIONS: Our data do not support a protective role of black tea against CAD. The limited data available on green tea support a tentative association of green tea consumption with a reduced risk of CAD. However, additional studies are needed to make a convincing case for this association. PMID- 21248186 TI - Is a trend to reduced sodium intake in the United States concealed by obesity? PMID- 21248187 TI - Body mass index, medical qualification status, and discharge during the first year of US Army service. AB - BACKGROUND: The high prevalence of overweight and obesity in military recruits and in the US population as a whole necessitates understanding the health effects of body composition and associated morbidity. OBJECTIVE: In this study, we examined the effect of body mass index (BMI; in kg/m(2)) and medical status on premature discharge from the US Army in a large cohort of first-time-enlisted, active-duty soldiers. DESIGN: We determined the odds ratios (ORs) associated with BMI and medical status at enlistment by using a retrospective cohort of first time, active-duty army recruits. RESULTS: ORs for BMI, calculated by using 24 24.9 as a reference, exhibited a U-shaped pattern. Soldiers with a BMI >34 had the highest ORs for all-cause (OR: 1.47; 95% CI: 1.32, 1.64) and medical (OR: 1.68; 95% CI: 1.46, 1.93) discharges. A BMI <17 was 1.35 times as likely (95% CI: 1.02, 1.80) to result in an all-cause discharge and 1.45 times as likely (95% CI: 1.01, 2.08) to result in a medical discharge. ORs for soldiers who required a medical reexamination did not vary when all-cause discharge (OR: 1.10; 95% CI: 1.06, 1.14) and medical discharge (OR: 1.10; 95% CI: 1.05, 1.15) were compared. The medical discharge OR for soldiers who required a medical waiver to enter the army (OR: 1.56; 95% CI: 1.48, 1.64) was higher than the OR for all-cause discharge (OR: 1.27; 95% CI: 1.22, 1.32). CONCLUSION: Enlistment BMI and medical qualification status play an important role in early discharge and may provide a valuable tool in the development of fitness, nutrition, and injury-prevention interventions in higher-risk groups. PMID- 21248185 TI - Obesity-susceptibility loci have a limited influence on birth weight: a meta analysis of up to 28,219 individuals. AB - BACKGROUND: High birth weight is associated with adult body mass index (BMI). We hypothesized that birth weight and BMI may partly share a common genetic background. OBJECTIVE: The objective was to examine the associations of 12 established BMI variants in or near the NEGR1, SEC16B, TMEM18, ETV5, GNPDA2, BDNF, MTCH2, BCDIN3D, SH2B1, FTO, MC4R, and KCTD15 genes and their additive score with birth weight. DESIGN: A meta-analysis was conducted with the use of 1) the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk, Hertfordshire, Fenland, and European Youth Heart Study cohorts (n(max) = 14,060); 2) data extracted from the Early Growth Genetics Consortium meta-analysis of 6 genome-wide association studies for birth weight (n(max) = 10,623); and 3) all published data (n(max) = 14,837). RESULTS: Only the MTCH2 and FTO loci showed a nominally significant association with birth weight. The BMI-increasing allele of the MTCH2 variant (rs10838738) was associated with a lower birth weight (beta +/- SE: -13 +/- 5 g/allele; P = 0.012; n = 23,680), and the BMI-increasing allele of the FTO variant (rs1121980) was associated with a higher birth weight (beta +/- SE: 11 +/- 4 g/allele; P = 0.013; n = 28,219). These results were not significant after correction for multiple testing. CONCLUSIONS: Obesity-susceptibility loci have a small or no effect on weight at birth. Some evidence of an association was found for the MTCH2 and FTO loci, ie, lower and higher birth weight, respectively. These findings may provide new insights into the underlying mechanisms by which these loci confer an increased risk of obesity. PMID- 21248169 TI - Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. AB - Vascular endothelial cells (ECs) are exposed to hemodynamic forces, which modulate EC functions and vascular biology/pathobiology in health and disease. The flow patterns and hemodynamic forces are not uniform in the vascular system. In straight parts of the arterial tree, blood flow is generally laminar and wall shear stress is high and directed; in branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress. Sustained laminar flow with high shear stress upregulates expressions of EC genes and proteins that are protective against atherosclerosis, whereas disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote atherogenesis. These findings have led to the concept that the disturbed flow pattern in branch points and curvatures causes the preferential localization of atherosclerotic lesions. Disturbed flow also results in postsurgical neointimal hyperplasia and contributes to pathophysiology of clinical conditions such as in-stent restenosis, vein bypass graft failure, and transplant vasculopathy, as well as aortic valve calcification. In the venous system, disturbed flow resulting from reflux, outflow obstruction, and/or stasis leads to venous inflammation and thrombosis, and hence the development of chronic venous diseases. Understanding of the effects of disturbed flow on ECs can provide mechanistic insights into the role of complex flow patterns in pathogenesis of vascular diseases and can help to elucidate the phenotypic and functional differences between quiescent (nonatherogenic/nonthrombogenic) and activated (atherogenic/thrombogenic) ECs. This review summarizes the current knowledge on the role of disturbed flow in EC physiology and pathophysiology, as well as its clinical implications. Such information can contribute to our understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions. PMID- 21248188 TI - Unexplained chronic cough and vitamin B-12 deficiency. AB - BACKGROUND: Chronic cough is characterized by sensory neuropathy. Vitamin B-12 (cobalamin) deficiency (Cbl-D) causes central and peripheral nervous system damage and has been implicated in sensory neuropathy and autonomic nervous system dysfunction. OBJECTIVE: We evaluated whether Cbl-D has a role in chronic, unexplained cough. DESIGN: Laryngeal threshold (histamine concentration that provokes a 25% decrease in the midinspiratory flow), bronchial threshold (histamine concentration that provokes a 20% decrease in the forced expiratory volume in 1 s), and cough threshold (histamine concentration that causes >=5 coughs) in response to an inhaled histamine were assessed in 42 patients with chronic, unexplained cough [27 Cbl-D patients and 15 patients without Cbl-D (Cbl N)] before and after intramuscular injections of cobalamin for 2 mo. Laryngeal, bronchial, and cough hyperresponsiveness was diagnosed when histamine concentration thresholds were <=8 mg/mL. Seven Clb-D and 3 Cbl-N patients underwent an oropharyngeal biopsy before treatment. RESULTS: Cbl-D patients had a higher prevalence of laryngeal hyperresponsiveness than did Cbl-N patients (92.6% compared with 66.7%; P = 0.03), a thinner oropharyngeal epithelium [133.7 MUm (95% CI: 95, 172 MUm) compared with 230.8 MUm (95% CI: 224, 237 MUm); P = 0.002], a lower number of myelinated nerve fibers [2.25/mm(2) (95% CI: 1.8, 2.7/mm(2)) compared with 3.44/mm(2) (95% CI: 3, 3.8/mm(2)); P = 0.05], and a higher immunoreactive score for nerve growth factor (NGF) [6.7 (95% CI: 6, 7.3) compared with 2.8 (95% CI: 2.5, 3.1); P = 0.02]. After cobalamin supplementation, symptoms and laryngeal, bronchial, and cough thresholds were significantly improved in Cbl D but not in Cbl-N patients. CONCLUSIONS: This study suggests that Cbl-D may contribute to chronic cough by favoring sensory neuropathy as indicated by laryngeal hyperresponsiveness and increased NGF expression in pharyngeal biopsies of Cbl-D patients. Cbl-D should be considered among factors that sustain chronic cough, particularly when cough triggers cannot be identified. PMID- 21248190 TI - Scaling of body composition to height: relevance to height-normalized indexes. AB - BACKGROUND: Body weight scales to height with a power of ~2, thus forming the basis of body mass index (weight/height(2)). The corresponding scaling of body composition to height has not been established in a representative sample of US adults. OBJECTIVE: The aim of the study was to examine the scaling of weight, fat, fat-free mass, and bone mineral content to height. DESIGN: Adult non Hispanic white (NHW), non-Hispanic black (NHB), and Mexican American National Health and Nutrition Examination Survey (NHANES) participants were included in allometric analyses if they had complete age, weight, height, and body composition data as measured by dual-energy X-ray absorptiometry. Powers of height in allometric regression models were developed for each measure and adjusted for age. RESULTS: The analyses included 13,183 subjects (6699 NHW, 3015 NHB, and 3469 Mexican American). The scaling of weight to height across sex-race groups provided powers (mean +/- SE) ranging from 1.85 +/- 0.12 in Mexican American women to 2.48 +/- 0.17 in Mexican American men. Powers of height for body composition similarly ranged widely and were often outside the 95% CI for a power of 2. Of the 3 body-composition measures, the mean age-adjusted powers of height rounded to 2 as the nearest integer in 16 of 18 sex-race groups. CONCLUSIONS: Adult weight and body composition scale to height with variable age adjusted powers that are sometimes outside the 95% CI for a power of 2 but frequently round to 2 as the nearest integer. These observations have implications for developing height-adjusted body-composition indexes. PMID- 21248191 TI - The paired deuterated retinol dilution technique can be used to estimate the daily vitamin A intake required to maintain a targeted whole body vitamin A pool size in men. AB - The estimated average requirement (EAR) for vitamin A (VA) of adult males is based on the amount of dietary VA required to maintain adequate function and provide a modest liver VA reserve (0.07 MUmol/g). In the present study, the paired-deuterated retinol dilution technique was used to estimate changes in VA pool size in Bangladeshi men from low-income, urban neighborhoods who had small initial VA pool sizes (0.059 +/- 0.032 mmol, or 0.047 +/- 0.025 MUmol/g liver; n = 16). The men were supplemented for 60 d with 1 of 8 different levels of dietary VA, ranging from 100 to 2300 MUg/d (2 men/dietary VA level). VA pool size was estimated before and after the supplementation period. The mean change (plus or minus) in VA pool size in the men was plotted against their corresponding levels of daily VA intake and a regression line was fit to the data. The level of intake at which the regression line crossed the x-axis (where estimates of VA pool size remained unchanged) was used as an estimate of the EAR. A VA intake of 254-400 MUg/d was sufficient to maintain a small VA pool size (0.059 +/- 0.032 mmol) in the Bangladeshi men, corresponding to a VA intake of 362-571 MUg/d for a 70-kg U.S. man, which is lower than their current EAR of 625 MUg/d. The data suggest that the paired-deuterated retinol dilution technique could be used for estimating the EAR for VA for population subgroups for which there are currently no direct estimates. PMID- 21248189 TI - Heritability of serum vitamin D concentrations: twin studies. PMID- 21248192 TI - Dietary calcium restriction affects mesenchymal stem cell activity and bone development in neonatal pigs. AB - The effects of dietary calcium (Ca) deficiency on skeletal integrity are well characterized in growing and mature mammals; however, less is known about Ca nutrition during the neonatal period. In this study, we examined the effects of neonatal Ca nutrition on bone integrity, endocrine hormones, and mesenchymal stem cell (MSC) activity. Neonatal pigs (24 +/- 6 h of age) received either a Ca adequate (1.2 g/100 g) or an ~40% Ca-deficient diet for 18 d. Ca deficiency reduced (P < 0.05) bone flexural strength and bone mineral density without major differences in plasma indicators of Ca status. There were no meaningful differences in plasma Ca, phosphate (PO(4)), parathyroid hormone, or 1,25 dihydroxycholecalciferol due to Ca nutrition throughout the study. Calcium deficiency also reduced (P < 0.05) the in vivo proliferation of MSC by ~50%. In vitro studies utilizing homologous sera demonstrated that MSC activity was affected (P < 0.05) by both the Ca status of the pig and the sera as well as by their interaction. The results indicate that neonatal Ca nutrition is crucial for bone integrity and suggest that early-life Ca restriction may have long-term effects on bone integrity via programming of MSC. PMID- 21248193 TI - The metabolic availability of threonine in common feedstuffs fed to adult sows is higher than published ileal digestibility estimates. AB - Amino acid (AA) requirements for sows during pregnancy are currently under review. However, requirement recommendations must be accompanied by an estimate of the bioavailability of AA from feeds to ensure adequate supply of AA and to minimize excess nitrogen excretion. Current ileal AA digestibility estimates are based on growing pig data; however, availability of AA in adult pigs may be different from that in growing pigs. The metabolic availability (MA) of threonine (Thr) in corn and barley was determined in 6 pregnant sows using the indicator AA oxidation method and L-[1-(13)C]phenylalanine as the tracer AA. Sows were fed reference diets formulated from 30 to 75% of the breakpoint derived in Expt. 1; all other nutrients were set at 120% of requirement. Test ingredients diets were formulated to supply Thr at 75% of the determined requirement. Tracer phenylalanine was given orally in 8 one-half-hourly meals and expired (13)CO(2) was quantified. The determined MA of Thr from corn and barley fed to pregnant sows was 88.0 and 89.3%, respectively. The determined MA was 7 and 9% greater than the published standard ileal digestibility estimates of Thr in corn (82%) and barley (81%), respectively. Mature animals have a greater capacity to digest and absorb nutrients from feed ingredients than previously assumed based on ileal digestibility studies. Sow diets formulated based on published ileal digestibility estimates are overformulated with respect to available protein and AA and thus increase excess nitrogen excretion and potential environmental concerns. PMID- 21248195 TI - Dietary intake of protein is positively associated with percent body fat in middle-aged and older adults. AB - Data on associations between dietary intake of macronutrients and body composition in the general population are sparse. This population-based, cross sectional study of 4478 middle-aged (47-49 y) and elderly (71-74 y) men and women from the Hordaland Health Study in western Norway was conducted using a validated FFQ and measurements by dual-energy X-ray absorptiometry. The relation between macronutrient intake [percentage of total energy intake (E%)] and percent body fat was investigated in the total population and in a subgroup with intermediate BMI and stable weight (BMI within the 25th-75th percentile and weight change <5% during the last 6 y; n = 975). In the total population, protein intake (E%) was associated with higher percent body fat (partial r = 0.11; P < 0.001) in multivariate linear regression analysis. In the subgroup with intermediate BMI and stable weight, there was no association between protein intake (E%) and percent body fat. Fat intake (E%) was positively associated (partial r = 0.07) whereas carbohydrate intake (E%) was inversely associated (partial r = -0.07) with percent body fat (P = 0.042 for both) in the subgroup with intermediate BMI and stable weight. Both in the total population and in the stable weight group, physical activity was inversely related to adiposity (partial r = -0.15 and 0.12, respectively; P < 0.001). Our results may explain some of the conflicting data on the effects of macronutrients in different populations and suggest the potential importance of protein intake as a factor in obesity. PMID- 21248194 TI - Urinary excretion of 3-hydroxyisovaleryl carnitine is an early and sensitive indicator of marginal biotin deficiency in humans. AB - Mounting evidence indicates that marginal biotin deficiency is not rare, contrary to previous assumptions. Accordingly, robust indicators of biotin status would be useful. In a study of 10 healthy adults, we recently provided evidence that abnormally increased plasma concentration of 3-hydroxyisovaleryl carnitine (3HIA carnitine) is a sensitive indicator of marginal biotin deficiency. We sought to determine whether urinary excretion of 3HIA-carnitine (expressed as the ratio to urinary creatinine) significantly increases in marginal biotin deficiency. Marginal, asymptomatic biotin deficiency was induced experimentally in the same 10 healthy adults (8 women) by feeding undenatured egg white with meals for 28 d. Biotin status was repleted by a mixed general diet plus biotin supplementation. Urinary excretion of 3HIA-carnitine was determined by liquid chromatography tandem MS on d 0, 14, and 28 (depletion) and on d 35 and 50 (repletion). Mean urinary 3HIA-carnitine concentration increased with depletion (P < 0.0001; d 0 vs. 28) and decreased with repletion (P = 0.0002; d 28 vs. 50). Urinary 3HIA carnitine excretion was greater than the upper limit of normal in 9 of 10 participants by d 14 and decreased to within normal limits by d 50 in all participants. This study provides evidence that urinary excretion of 3HIA carnitine is an early and sensitive indicator of marginal biotin deficiency. The ease of collection of untimed urine samples and application of a new analytical method with simplified sample preparation suggest that urinary 3HIA-carnitine is likely to be a useful indicator for large population studies. PMID- 21248197 TI - Breastfeeding in infancy is not associated with inflammatory status in healthy adolescents. AB - It has been suggested that breast-feeding (BF) may be associated with a decreased risk of cardiovascular disease in adulthood. A low-grade inflammation is associated with an increased risk of cardiovascular disease, even in apparently healthy children. The objective of this study was to assess the potential modulating effect of BF on the inflammatory status of healthy adolescents. Information on BF (duration) was obtained from parental records in 484 of 1040 healthy European urban adolescents (56.4% females) that had a blood sample obtained as part of the Healthy Lifestyle in Europe by Nutrition and Adolescence study. Blood serum inflammatory markers were measured, including high sensitivity C-reactive protein, complement factors 3 and 4, ceruloplasmin, adhesion molecules (L-selectin and soluble endothelial selectin, soluble vascular cell adhesion molecule 1, and intercellular adhesion molecule 1), cytokines, TGFbeta1, and white blood cells. After univariate analysis, a propensity score, including the potential confounding factors, was computed and used to assess the association between BF and selected inflammatory markers. BF was not significantly associated with any of the selected inflammatory markers after adjustment for gender and propensity score. In our study, BF was not associated with low-grade inflammatory status in healthy adolescents, suggesting that the potential cardiovascular benefits of BF are related to other mechanisms than modulation of inflammation or might become relevant at a later age. Groups at high risk for cardiovascular disease should be a target for further research concerning the effects of BF. PMID- 21248196 TI - Moderate zinc deficiency reduces testicular Zip6 and Zip10 abundance and impairs spermatogenesis in mice. AB - Male infertility accounts for ~40% of cases of failure to conceive. Testes have a strict zinc (Zn) requirement and severe Zn deficiency compromises spermatogenesis, sperm viability, and motility, compromising fertility in men. Despite the high prevalence of marginal Zn deficiency in humans, less emphasis has been placed on understanding the consequences on male reproduction. Swiss Webster mice were used to visualize Zip protein expression during spermatogenesis using immunohistochemistry. Data suggest Zip5 imports Zn into Sertoli cells and spermatocytes, augmented by Zip10 (primary spermatocytes) and Zip8 (secondary spermatocytes). Zip6, 8, and 10 expression was retained in round spermatids, although Zip8 and Zip10 expression disappears during spermatid maturation. Zip1 and Zip6 expression was detected in mature, elongated spermatids. Zip14 was detected in undifferentiated spermatogonia and Leydig cells. Mice fed diets (n = 10/group) reduced in Zn concentration [marginal-Zn diet (MZD), 10 mg Zn/kg; low Zn diet (ZD), 7 mg Zn/kg] for 30 d had >35% lower liver Zn concentrations than mice fed the control diet (C; 30 mg Zn/kg) (P < 0.05). Plasma Zn and testosterone concentrations and the testes Zn concentration and weight were not significantly lower than in controls. Plasma Zn was greater in the ZD group than in the C and MZD groups. Mice fed ZD had a reduced number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells (~50%; P < 0.05), compromised seminiferous tubule structure, and reduced Zip10 and Zip6 abundance (>50%; P < 0.5) compared with mice fed C. Our data provide compelling evidence that reduced Zn intake may be associated with infertility in men, perhaps independent of decreased levels of circulating Zn or testosterone, which warrants further investigation in human populations. PMID- 21248198 TI - Starch with high amylose and low in vitro digestibility increases short-chain fatty acid absorption, reduces peak insulin secretion, and modulates incretin secretion in pigs. AB - Diets containing different starch types affect peripheral glucose and insulin responses. However, the role of starch chemistry in kinetics of nutrient absorption and insulin and incretin secretion is poorly understood. Four portal vein-catheterized pigs (35.0 +/- 0.2 kg body weight) consumed 4 diets containing 70% purified starch [0-63.2% amylose content and 0.22 (slowly) to 1.06%/min (rapidly) maximum rate of in vitro digestion] for 7-d periods in a 4 * 4 Latin square. On d 7, blood was collected for 12 h postprandial with simultaneous blood flow measurement for determining the net portal appearance (NPA) of nutrients and hormones. The NPA of glucose, insulin, C-peptide, and glucose-dependent insulinotropic polypeptide (GIP) during 0-4 h postprandial were lower (P < 0.05) and those of butyrate and total SCFA were higher (P < 0.05) when pigs consumed the diet containing slowly digestible compared with rapidly digestible starch. The peak NPA of insulin occurred prior to that of glucose when pigs consumed diets containing rapidly digestible starch. The kinetics of insulin secretion had a linear positive relation with kinetics of NPA of glucose (R(2) = 0.50; P < 0.01). In conclusion, starch with high amylose and low in vitro digestibility decreases the kinetics of glucose absorption and insulin and GIP secretion and increases SCFA absorption and glucagon-like peptide-1 secretion. In conclusion, starch with high amylose content and a lower rate and extent of in vitro digestion decreased glucose absorption and insulin secretion and increased SCFA absorption. PMID- 21248199 TI - A diet high in meat protein and potential renal acid load increases fractional calcium absorption and urinary calcium excretion without affecting markers of bone resorption or formation in postmenopausal women. AB - Our objective in this study was to determine the effects of a high-protein and high-potential renal acid load (PRAL) diet on calcium (Ca) absorption and retention and markers of bone metabolism. In a randomized crossover design, 16 postmenopausal women consumed 2 diets: 1 with low protein and low PRAL (LPLP; total protein: 61 g/d; PRAL: -48 mEq/d) and 1 with high protein and high PRAL (HPHP; total protein: 118 g/d; PRAL: 33 mEq/d) for 7 wk each separated by a 1-wk break. Ca absorption was measured by whole body scintillation counting of radio labeled (47)Ca. Compared with the LPLP diet, the HPHP diet increased participants' serum IGF-I concentrations (P < 0.0001), decreased serum intact PTH concentrations (P < 0.001), and increased fractional (47)Ca absorption (mean +/- pooled SD: 22.3 vs. 26.5 +/- 5.4%; P < 0.05) and urinary Ca excretion (156 vs. 203 +/- 63 mg/d; P = 0.005). The net difference between the amount of Ca absorbed and excreted in urine did not differ between 2 diet periods (55 vs. 28 +/- 51 mg/d). The dietary treatments did not affect other markers of bone metabolism. In summary, a diet high in protein and PRAL increases the fractional absorption of dietary Ca, which partially compensates for increased urinary Ca, in postmenopausal women. The increased IGF-I and decreased PTH concentrations in serum, with no change in biomarkers of bone resorption or formation, indicate a high-protein diet has no adverse effects on bone health. PMID- 21248200 TI - Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis. AB - Mitoferrin 1 (Mfrn1; Slc25a37) and mitoferrin 2 (Mfrn2; Slc25a28) function as essential mitochondrial iron importers for heme and Fe/S cluster biogenesis. A genetic deficiency of Mfrn1 results in a profound hypochromic anemia in vertebrate species. To map the cis-regulatory modules (CRMs) that control expression of the Mfrn genes, we utilized genome-wide chromatin immunoprecipitation (ChIP) datasets for the major erythroid transcription factor GATA-1. We identified the CRMs that faithfully drive the expression of Mfrn1 during blood and heart development and Mfrn2 ubiquitously. Through in vivo analyses of the Mfrn-CRMs in zebrafish and mouse, we demonstrate their functional and evolutionary conservation. Using knockdowns with morpholinos and cell sorting analysis in transgenic zebrafish embryos, we show that GATA-1 directly regulates the expression of Mfrn1. Mutagenesis of individual GATA-1 binding cis elements (GBE) demonstrated that at least two of the three GBE within this CRM are functionally required for GATA-mediated transcription of Mfrn1. Furthermore, ChIP assays demonstrate switching from GATA-2 to GATA-1 at these elements during erythroid maturation. Our results provide new insights into the genetic regulation of mitochondrial function and iron homeostasis and, more generally, illustrate the utility of genome-wide ChIP analysis combined with zebrafish transgenesis for identifying long-range transcriptional enhancers that regulate tissue development. PMID- 21248201 TI - A novel mitochondrial outer membrane protein, MOMA-1, that affects cristae morphology in Caenorhabditis elegans. AB - Three proteins with similar effects on mitochondrial morphology were identified in an RNA interference (RNAi) screen for mitochondrial abnormalities in Caenorhabditis elegans. One of these is the novel mitochondrial outer membrane protein MOMA-1. The second is the CHCHD3 homologue, CHCH-3, a small intermembrane space protein that may act as a chaperone. The third is a mitofilin homologue, IMMT-1. Mitofilins are inner membrane proteins that control the shapes of cristae. RNAi or mutations in each of these genes change the relatively constant diameters of mitochondria into highly variable diameters, ranging from thin tubes to localized swellings. Neither growth nor brood size of the moma-1, chch-3, or immt-1 single mutants is affected, suggesting that their metabolic functions are normal. However, growth of moma-1 or immt-1 mutants on chch-3(RNAi) leads to withered gonads, a lack of mitochondrial staining, and a dramatic reduction in fecundity, while moma-1; immt-1 double mutants are indistinguishable from single mutants. Mutations in moma-1 and immt-1 also have similar effects on cristae morphology. We conclude that MOMA-1 and IMMT-1 act in the same pathway. It is likely that the observed effects on mitochondrial diameter are an indirect effect of disrupting cristae morphology. PMID- 21248203 TI - Shroom2 regulates contractility to control endothelial morphogenesis. AB - The intrinsic contractile, migratory, and adhesive properties of endothelial cells are central determinants in the formation of vascular networks seen in vertebrate organisms. Because Shroom2 (Shrm2) is expressed within the endothelium, is localized to cortical actin and cell-cell adhesions, and contains a conserved Rho kinase (Rock) binding domain, we hypothesized that Shrm2 may participate in the regulation of endothelial cell behavior during vascular morphogenesis. Consistent with this hypothesis, depletion of Shrm2 results in elevated branching and sprouting angiogenic behavior of endothelial cells. This is recapitulated in human umbilical vein endothelial cells and in a vasculogenesis assay in which differentiated embryonic stem cells depleted for Shrm2 form a more highly branched endothelial network. Further analyses indicate that the altered behavior observed following Shrm2 depletion is due to aberrant cell contractility, as evidenced by decreased stress fiber organization and collagen contraction with an increase in cellular migration. Because Shrm2 directly interacts with Rock, and Shrm2 knockdown results in the loss of Rock and activated myosin II from sites of cell-cell adhesion, we conclude that Shrm2 facilitates the formation of a contractile network within endothelial cells, the loss of which leads to an increase in endothelial sprouting, migration, and angiogenesis. PMID- 21248202 TI - Resurrection of a functional phosphatidylinositol transfer protein from a pseudo Sec14 scaffold by directed evolution. AB - Sec14-superfamily proteins integrate the lipid metabolome with phosphoinositide synthesis and signaling via primed presentation of phosphatidylinositol (PtdIns) to PtdIns kinases. Sec14 action as a PtdIns-presentation scaffold requires heterotypic exchange of phosphatidylcholine (PtdCho) for PtdIns, or vice versa, in a poorly understood progression of regulated conformational transitions. We identify mutations that confer Sec14-like activities to a functionally inert pseudo-Sec14 (Sfh1), which seemingly conserves all of the structural requirements for Sec14 function. Unexpectedly, the "activation" phenotype results from alteration of residues conserved between Sfh1 and Sec14. Using biochemical and biophysical, structural, and computational approaches, we find the activation mechanism reconfigures atomic interactions between amino acid side chains and internal water in an unusual hydrophilic microenvironment within the hydrophobic Sfh1 ligand-binding cavity. These altered dynamics reconstitute a functional "gating module" that propagates conformational energy from within the hydrophobic pocket to the helical unit that gates pocket access. The net effect is enhanced rates of phospholipid-cycling into and out of the Sfh1* hydrophobic pocket. Taken together, the directed evolution approach reveals an unexpectedly flexible functional engineering of a Sec14-like PtdIns transfer protein-an engineering invisible to standard bioinformatic, crystallographic, and rational mutagenesis approaches. PMID- 21248204 TI - Yeast homologues of lethal giant larvae and type V myosin cooperate in the regulation of Rab-dependent vesicle clustering and polarized exocytosis. AB - Lgl family members play an important role in the regulation of cell polarity in eukaryotic cells. The yeast homologues Sro7 and Sro77 are thought to act downstream of the Rab GTPase Sec4 to promote soluble N-ethylmaleimide-sensitive factor adaptor protein receptor (SNARE) function in post-Golgi transport. In this article, we characterize the interaction between Sro7 and the type V myosin Myo2 and show that this interaction is important for two distinct aspects of Sro7 function. First, we show that this interaction plays a positive role in promoting the polarized localization of Sro7 to sites of active growth. Second, we find evidence that Myo2 negatively regulates Sro7 function in vesicle clustering. Mutants in either Myo2 or Sro7 that are defective for this interaction show hypersensitivity to Sro7 overexpression, which results in Sec4-dependent accumulation of large groups of vesicles in the cytoplasm. This suggests that Myo2 serves a dual function, to both recruit Sro7 to secretory vesicles and inhibit its Rab-dependent tethering activity until vesicles reach the plasma membrane. Thus Sro7 appears to coordinate the spatial and temporal nature of both Rab-dependent tethering and SNARE-dependent membrane fusion of exocytic vesicles with the plasma membrane. PMID- 21248206 TI - Early effects of resident work-hour restrictions on patient safety: a systematic review and plea for improved studies. AB - BACKGROUND: since the inception of the eighty-hour work week, work hour restrictions have incited considerable debate. Work hour policies were designed to prevent medical errors and to reduce patient morbidity and mortality. It is unclear whether work hour restrictions have been helpful in medicine in general and in orthopaedic surgery specifically. This systematic review of the literature was designed to determine the success of these restrictions in terms of patient mortality, medical errors, and complications. METHODS: a systematic review of the literature was performed to determine if work hour rules have improved patient and systems-based outcomes and reduced physician errors as measured by mortality, medical errors, and complications. A random effects model was utilized to determine whether patient mortality rates were improved under the new rules. RESULTS: the odds of patient death before implementation of the work hour rules were 1.12 (95% confidence interval, 1.07 to 1.17) times those after implementation. These differences were consistent across disciplines. The data concerning medical or surgical complications before and after the institution of the work hour rules were mixed. There was little information in these studies concerning direct medical errors. The odds of death in nonteaching cohorts were not significantly different from that in teaching cohorts. CONCLUSIONS: there appears to be a decrease in mortality following the institution of work hour rules. The difference seen in teaching cohorts is not significantly different from that in nonteaching cohorts. It is unclear whether this difference would have been observed even without work hour restrictions. No study has shown a reduction in mortality for orthopaedic patients in teaching cohorts that was greater than that observed in nonteaching cohorts. Because of methodological concerns and the lack of current literature linking physician fatigue and physician underperformance with patient mortality, it is unclear whether the goals of the work hour reductions have been achieved. Furthermore, because of a lack of a so-called dose-response relationship between work hour reduction and patient mortality, it is uncertain whether further reductions would be beneficial. LEVEL OF EVIDENCE: therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence. PMID- 21248205 TI - Identification of an inhibitory budding signal that blocks the release of HIV particles and exosome/microvesicle proteins. AB - Animal cells bud exosomes and microvesicles (EMVs) from endosome and plasma membranes. The combination of higher-order oligomerization and plasma membrane binding is a positive budding signal that targets diverse proteins into EMVs and retrovirus particles. Here we describe an inhibitory budding signal (IBS) from the human immunodeficiency virus (HIV) Gag protein. This IBS was identified in the spacer peptide 2 (SP2) domain of Gag, is activated by C-terminal exposure of SP2, and mediates the severe budding defect of p6-deficient and PTAP-deficient strains of HIV. This IBS also impairs the budding of CD63 and several other viral and nonviral EMV proteins. The IBS does not prevent cargo delivery to the plasma membrane, a major site of EMV and virus budding. However, the IBS does inhibit an interaction between EMV cargo proteins and VPS4B, a component of the endosomal sorting complexes required for transport (ESCRT) machinery. Taken together, these results demonstrate that inhibitory signals can block protein and virus budding, raise the possibility that the ESCRT machinery plays a role in EMV biogenesis, and shed new light on the role of the p6 domain and PTAP motif in the biogenesis of HIV particles. PMID- 21248207 TI - A new model of health care that can be efficiently and inexpensively delivered to the community. PMID- 21248208 TI - Peritendinous adhesions that form after the repair of lacerated digital flexor tendons cause stiffness and functional impairment. PMID- 21248209 TI - Internet-based outpatient telerehabilitation for patients following total knee arthroplasty: a randomized controlled trial. AB - BACKGROUND: total knee arthroplasty is an effective means for relieving the symptoms associated with degenerative arthritis of the knee. Rehabilitation is a necessary adjunct to surgery and is important in regaining optimum function. Access to high-quality rehabilitation services is not always possible, especially for those who live in rural or remote areas. The aim of this study was to evaluate the equivalence of an Internet-based telerehabilitation program compared with conventional outpatient physical therapy for patients who have had a total knee arthroplasty. METHODS: this investigation was a single-blinded, prospective, randomized, controlled noninferiority trial. Sixty-five participants were randomized to receive a six-week program of outpatient physical therapy either in the conventional manner or by means of an Internet-based telerehabilitation program. The primary outcome measure was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) measured at baseline and six weeks by a blinded independent assessor. Secondary outcomes included the Patient-Specific Functional Scale, the timed up-and-go test, pain intensity, knee flexion and extension, quadriceps muscle strength, limb girth measurements, and an assessment of gait. Noninferiority was assessed through the comparison of group differences with a noninferiority margin and with linear mixed model statistics. RESULTS: baseline characteristics between groups were similar, and all participants had significant improvement on all outcome measures with the intervention (p < 0.01 for all). After the six-week intervention, participants in the telerehabilitation group achieved outcomes comparable to those of the conventional rehabilitation group with regard to flexion and extension range of motion, muscle strength, limb girth, pain, timed up-and-go test, quality of life, and clinical gait and WOMAC scores. Better outcomes for the Patient-Specific Functional Scale and the stiffness subscale of the WOMAC were found in the telerehabilitation group (p < 0.05). The telerehabilitation intervention was well received by participants, who reported a high level of satisfaction with this novel technology. CONCLUSIONS: the outcomes achieved via telerehabilitation at six weeks following total knee arthroplasty were comparable with those after conventional rehabilitation. LEVEL OF EVIDENCE: therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence. PMID- 21248210 TI - Trends and variation in incidence, surgical treatment, and repeat surgery of proximal humeral fractures in the elderly. AB - BACKGROUND: the treatment of proximal humeral fractures in the elderly remains controversial. Options include nonoperative treatment, open reduction with internal fixation (ORIF), and hemiarthroplasty. Locking plate technology has expanded the indications for ORIF for certain fracture types in osteoporotic bone. This study was performed to characterize the incidence, treatment, and revision surgery of proximal humeral fractures according to geographic region both before (1999 to 2000) and after (2004 to 2005) the introduction of locking plates. METHODS: we used a 20% sample of Medicare Part-B data and the Medicare denominator file for the years 1998 to 2006. Proximal humeral fractures were identified by Common Procedural Terminology codes for treatment, categorized as nonoperative, ORIF, or hemiarthroplasty. Geographic variation in treatment type was determined with use of 306 hospital referral regions. Odds ratios for revision surgery were calculated by the need for repeat surgery within one year of the index procedure. Rates were adjusted for age, sex, race, and comorbidities. RESULTS: there were 14,774 proximal humeral fractures in the 20% sample from 1999 to 2000 (an estimated total of 73,870 fractures) and 16,138 fractures in the sample from 2004 to 2005 (an estimated total of 80,690 fractures). The overall age, sex, and race-adjusted incidence of proximal humeral fractures was unchanged from 1999 to 2005 (2.47 vs. 2.48 per 1000 Medicare beneficiaries; p = 0.992). However, the absolute rate of surgically managed proximal humeral fractures rose 3.2 percentage points from 12.5% to 15.7%, a relative increase of 25.6% (p < 0.0001). The relative increase in the percentage of fractures treated with ORIF was 28.5% (p < 0.0001), while the percentage of fractures treated with hemiarthroplasty increased 19.6% (p < 0.0001). There were large regional variations in the proportion treated surgically (range, 0% to 68.18%). The rates of repeat surgery were significantly higher in 2004 to 2005 compared with 1999 to 2000 (odds ratio = 1.47, p = 0.043). CONCLUSIONS: although the incidence of proximal humeral fractures in the elderly did not change from 1999 to 2005, the rate of surgical treatment increased significantly. The marked regional variation in the rates of surgical treatment highlights the need for better consensus regarding optimal treatment of proximal humeral fractures. Additional research is needed to help to determine which fractures are best treated operatively in order to maximize outcome and minimize the need for revision surgery. LEVEL OF EVIDENCE: therapeutic Level II. See Instructions to Authors for a complete description of levels of evidence. PMID- 21248211 TI - Reduction of Peritendinous adhesions by hydrogel containing biocompatible phospholipid polymer MPC for tendon repair. AB - BACKGROUND: Peritendinous adhesions are serious complications after surgical repair of tendons. As an anti-adhesion material, we focused on 2 methacryloyloxyethyl phosphorylcholine (MPC) polymer, our original biocompatible polymer, and prepared an aqueous solution of MPC-containing polymer called poly(2 methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate-co-p vinylphenylboronic acid) (PMBV), which can be formed into hydrogel properties by mixture with another aqueous polymer, poly(vinyl alcohol) (PVA). The objective of the present study was to examine the possible application of the MPC hydrogel for the reduction of peritendinous adhesions. METHODS: the effects of the hydrogel on peritendinous adhesions and tendon healing were examined by means of histological and mechanical analyses in a rat Achilles tendon model and a rabbit flexor digitorum profundus tendon model. Cell migration and viability were examined with use of fibroblastic NIH3T3 cells cultured in a double chamber dish. RESULTS: among the concentrations examined, 2.5% and 5.0% PMBV formed hydrogel properties immediately after mixing with 2.5% PVA and maintained a honeycomb microstructure with nanometer-scaled pores for three weeks after implantation. In animal models, the hydrogel formed from 5.0% PMBV remained at the sutured site during the critical period up to three weeks and disappeared by six weeks. The MPC hydrogel reduced the peritendinous adhesions histologically and mechanically by >25% at three weeks, without impairing tendon healing as determined with mechanical analyses. In the cell culture, cell migration was reduced by the MPC hydrogel, although cell viability was unaffected, indicating physical prevention, rather than cytotoxicity, to be the anti-adhesion mechanism. CONCLUSIONS: the MPC hydrogel that was formed by a local injection and mixture of two aqueous solutions, 5.0% PMBV and 2.5% PVA, reduced peritendinous adhesions without impairing tendon healing. This effect may be due to its excellent biocompatibility without a foreign-body reaction and the formation of a microstructure that physically prevents passage of cells but allows cytokines and growth factors to pass for healing. CLINICAL RELEVANCE: this nanotechnology could potentially improve the quality of surgical repair of tendon, especially the zone II area of the digital flexor tendon. PMID- 21248212 TI - Reliability of physical examination in the measurement of hip flexion contracture and correlation with gait parameters in cerebral palsy. AB - BACKGROUND: this study was undertaken to determine the validity and reliability of the physical examination tests commonly used to measure hip flexion contracture in patients with cerebral palsy who are able to walk. METHODS: thirty six consecutive patients (twenty-two male and fourteen female patients), with a mean age (and standard deviation) of 9.8 +/- 3.9 years, who had cerebral palsy (level I, II, or III on the Gross Motor Function Classification System) and thirty-seven children without cerebral palsy (nineteen male and eighteen female subjects), with a mean age of 10.0 +/- 3.0 years, were enrolled prospectively for this study. Hip flexion contracture was determined by three physical examination tests: the Thomas test, the prone hip extension test (the Staheli test), and the hamstring shift test. Three-dimensional gait analysis was performed in all subjects. The interobserver reliabilities of the three physical examination tests were determined with use of three observers. Convergent validity was assessed by evaluating the relationships between the findings on physical examination and kinematic and kinetic gait variables (maximum hip extension during stance and hip flexor index) and three-dimensional modeled psoas lengths. RESULTS: the Thomas test showed the highest intraclass correlation coefficient (0.501 in patients and 0.207 in controls) and the smallest mean absolute difference (5.8 degrees in patients and 1.2 degrees in controls). The Staheli test was found to be the most valid method in the patient group (r = 0.568 with hip flexor index), whereas the Thomas test was the most valid in the control group (r = 0.526 with maximum hip extension in stance, and r = 0.532 with the hip flexor index). The hamstring shift test had the lowest intraclass correlation coefficient and the lowest convergent validity. CONCLUSIONS: while the Thomas test showed the highest intraclass correlation coefficient and the smallest mean absolute difference, the Staheli test was the most valid method for detecting hip flexion contractures in patients with cerebral palsy. Although the Staheli test cannot be used for intraoperative assessment, we recommend that this test be included in preoperative physical examinations to determine the role of a hip flexion contracture in the abnormal gait of patients with cerebral palsy. PMID- 21248213 TI - Locking intramedullary nails and locking plates in the treatment of two-part proximal humeral surgical neck fractures: a prospective randomized trial with a minimum of three years of follow-up. AB - BACKGROUND: locking intramedullary nails and locking plates specially designed for proximal humeral fractures are widely used. The purpose of our study was to compare the outcomes between these two types of implants in patients with a two part surgical neck fracture. The advantages and shortcomings of each method were analyzed. METHODS: a prospective randomized study was performed. Fifty-one consecutive patients with a fresh two-part surgical neck fracture were randomized to be treated with a locking intramedullary nail (n = 25) or a locking plate (n = 26). Clinical and radiographic assessments were conducted at one year and three years after the surgery. A visual analog scale (VAS) was used to assess shoulder pain. The American Shoulder and Elbow Surgeons (ASES) scores and Constant-Murley scores were recorded to evaluate shoulder function. RESULTS: fracture union was achieved in all patients within three months after the surgery. At one year postoperatively, a significant difference (p = 0.024) was found with regard to the complication rate between the locking plate group (31%) and the locking nail group (4%). The average ASES score, median VAS score, and average strength of the supraspinatus were significantly better in the locking plate group (90.8 compared with 83.6 points [p = 0.021], 1.0 compared with 0.5 point [p = 0.042], and 77.4% compared with 64.3% [p = 0.032]). At three years postoperatively, no significant difference could be found in terms of any parameter between the two groups. Significant improvement in the VAS pain scores, ASES scores, and Constant-Murley scores were found between the one-year and three-year follow-up examinations in each group. CONCLUSIONS: satisfactory results can be achieved with either implant in the treatment of two-part proximal humeral surgical neck fractures. There was no difference regarding the ASES scores between these two implants at the time of the final, three-year follow-up. The complication rate was lower in the locking intramedullary nail group, while fixation with a locking plate had the advantage of a better one-year outcome. LEVEL OF EVIDENCE: therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence. PMID- 21248214 TI - The mechanical axes of the wrist are oriented obliquely to the anatomical axes. AB - BACKGROUND: the complex motions of the wrist are described in terms of four anatomical directions that are accomplished through the multiple articulations of the carpus. With minimal tendinous insertions, the carpus is primarily a passive structure. This emphasizes the importance of its mechanical properties, which few studies have examined to date. The purpose of the present study was to determine the mechanical properties of the wrist in twenty-four different directions of wrist motion. METHODS: the moment-rotation mechanical behavior of six fresh frozen cadaver wrists was determined in four directions: flexion, extension, ulnar deviation, and radial deviation. Twenty other directions that were a combination of these anatomical directions were also studied. A custom-designed jig was interfaced with a standard materials testing system to apply unconstrained moments. Moments of +/- 2 Nm were applied, and the moment-rotation data were recorded and analyzed to determine the neutral zone, range of motion, and stiffness values as well as the orientation of the envelope of these values. RESULTS: the envelope of wrist range-of-motion values was ellipsoidal in shape and was oriented obliquely (p < 0.001) to the direction of pure flexion-extension by a mean (and standard deviation) of 26.6 degrees +/- 4.4 degrees . The largest wrist range of motion was a mean of 111.5 degrees +/- 10.2 degrees , in the direction of ulnar flexion, 30 degrees from pure flexion. The largest stiffness (mean, 0.4 Nm/deg) was in the direction of radial flexion, while the smallest stiffness (mean, 0.15 Nm/deg) was in the direction of ulnar flexion. CONCLUSIONS: the mechanical axes of the wrist are oriented obliquely to the anatomical axes. The primary mechanical direction is one of radial extension and ulnar flexion, a direction along a path of the dart thrower's wrist motion. CLINICAL RELEVANCE: understanding the mechanical function of the wrist can aid clinical treatment decisions, arthroplasty, and implant designs. The findings of this study provide new evidence that the mechanical axes of the wrist are not collinear with the anatomical axes. PMID- 21248215 TI - Cemented versus cementless total hip replacements in patients fifty-five years of age or older with rheumatoid arthritis. AB - BACKGROUND: results obtained from single-center studies indicate that a cemented total hip replacement is the treatment of choice for the management of patients over fifty-five years of age with rheumatoid arthritis. The aim of this study was to analyze population-based survival rates for cemented and cementless total hip replacements in patients aged fifty-five years or over with rheumatoid arthritis in Finland. METHODS: between 1980 and 2006, a total of 6000 primary total hip replacements performed for the management of rheumatoid arthritis in patients who were fifty-five years of age or older were entered in the Finnish Arthroplasty Registry. 4019 of them fulfilled our inclusion criteria and were subjected to analysis. The implants were classified into one of three possible groups: (1) a cementless group (a noncemented proximally porous-coated stem and a noncemented porous-coated press-fit cup), (2) a cemented group 1 (a cemented, loaded-taper stem combined with a cemented, all-polyethylene cup), or (3) a cemented group 2 (a cemented, composite-beam stem with a cemented, all-polyethylene cup). RESULTS: cementless stems and cups, analyzed separately, had a significantly lower risk of revision for aseptic loosening than cemented implants in patients who were fifty five years of age or older with rheumatoid arthritis. The fifteen-year survival rate of cementless total hip replacements (80%) was comparable with the rates of the cemented groups (86% in cemented group 1 and 79% in cemented group 2) when revisions for any reason were used as the end point. CONCLUSIONS: cementless and cemented total hip replacements produced comparable long-term results in patients who were fifty-five years of age or older with rheumatoid arthritis. LEVEL OF EVIDENCE: therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence. PMID- 21248216 TI - Development of a prognostic naive bayesian classifier for successful treatment of nonunions. AB - BACKGROUND: predictive models permitting individualized prognostication for patients with fracture nonunion are lacking. The objective of this study was to train, test, and cross-validate a Bayesian classifier for predicting fracture nonunion healing in a population treated with extracorporeal shock wave therapy. METHODS: prospectively collected data from 349 patients with delayed fracture union or a nonunion were utilized to develop a naive Bayesian belief network model to estimate site-specific fracture-nonunion healing in patients treated with extracorporeal shock wave therapy. Receiver operating characteristic curve analysis and tenfold cross-validation of the model were used to determine the clinical utility of the approach. RESULTS: predictors of fracture-healing at six months following shock wave treatment were the time between the fracture and the first shock wave treatment, the time between the fracture and the surgery, intramedullary stabilization, the number of bone-grafting procedures, the number of extracorporeal shock wave therapy treatments, work-related injury, and the bone involved (p < 0.05 for all comparisons). These variables were all included in the naive Bayesian belief network model. CONCLUSIONS: a clinically relevant Bayesian classifier was developed to predict the outcome after extracorporeal shock wave therapy for fracture nonunions. The time to treatment and the anatomic site of the fracture nonunion significantly impacted healing outcomes. Although this study population was restricted to patients treated with shock wave therapy, Bayesian-derived predictive models may be developed for application to other fracture populations at risk for nonunion. LEVEL OF EVIDENCE: prognostic Level II. See Instructions to Authors for a complete description of levels of evidence. PMID- 21248217 TI - Bilateral lipoma arborescens of the knee: a case report. PMID- 21248218 TI - Rapidly growing squamous-cell carcinoma of the hand in a renal transplant recipient: a case report. PMID- 21248219 TI - American academy of orthopaedic surgeons clinical practice guideline on: the treatment of glenohumeral joint osteoarthritis. PMID- 21248220 TI - Principles of biomechanics and biomaterials in orthopaedic surgery. PMID- 21248221 TI - What's New in Limb Lengthening and Deformity Correction. PMID- 21248222 TI - Infringing on freedom of speech. PMID- 21248224 TI - CD34+ hematopoietic precursors are present in human decidua and differentiate into natural killer cells upon interaction with stromal cells. AB - Natural killer (NK) cells are the main lymphoid population in the maternal decidua during the first trimester of pregnancy. Decidual NK (dNK) cells display a unique functional profile and play a key role in promoting tissue remodeling, neoangiogenesis, and immune modulation. However, little information exists on their origin and development. Here we discovered CD34(+) hematopoietic precursors in human decidua (dCD34(+)). We show that dCD34(+) cells differ from cord blood- or peripheral blood-derived CD34(+) precursors. The expression of IL-15/IL-2 receptor common beta-chain (CD122), IL-7 receptor alpha-chain (CD127), and mRNA for E4BP4 and ID2 transcription factors suggested that dCD34(+) cells are committed to the NK cell lineage. Moreover, they could undergo in vitro differentiation into functional (i.e., IL-8- and IL-22-producing) CD56(bright)CD16(-)KIR(+/-) NK cells in the presence of growth factors or even upon coculture with decidual stromal cells. Their NK cell commitment was further supported by the failure to undergo myeloid differentiation in the presence of GM CSF. Our findings strongly suggest that decidual NK cells may directly derive from CD34(+) cell precursors present in the decidua upon specific cellular interactions with components of the decidual microenvironment. PMID- 21248223 TI - Simultaneous shape repulsion and global assimilation in the perception of aspect ratio. AB - Although local interactions involving orientation and spatial frequency are well understood, less is known about spatial interactions involving higher level pattern features. We examined interactive coding of aspect ratio, a prevalent two dimensional feature. We measured perception of two simultaneously flashed ellipses by randomly post-cueing one of them and having observers indicate its aspect ratio. Aspect ratios interacted in two ways. One manifested as an aspect ratio-repulsion effect. For example, when a slightly tall ellipse and a taller ellipse were simultaneously flashed, the less tall ellipse appeared flatter and the taller ellipse appeared even taller. This repulsive interaction was long range, occurring even when the ellipses were presented in different visual hemifields. The other interaction manifested as a global assimilation effect. An ellipse appeared taller when it was a part of a global vertical organization than when it was a part of a global horizontal organization. The repulsion and assimilation effects temporally dissociated as the former slightly strengthened, and the latter disappeared when the ellipse-to-mask stimulus onset asynchrony was increased from 40 to 140 ms. These results are consistent with the idea that shape perception emerges from rapid lateral and hierarchical neural interactions. PMID- 21248225 TI - Mutant proteins as cancer-specific biomarkers. AB - Cancer biomarkers are currently the subject of intense research because of their potential utility for diagnosis, prognosis, and targeted therapy. In theory, the gene products resulting from somatic mutations are the ultimate protein biomarkers, being not simply associated with tumors but actually responsible for tumorigenesis. We show here that the altered protein products resulting from somatic mutations can be identified directly and quantified by mass spectrometry. The peptides expressed from normal and mutant alleles were detected by selected reaction monitoring (SRM) of their product ions using a triple-quadrupole mass spectrometer. As a prototypical example of this approach, we demonstrated that it is possible to quantify the number and fraction of mutant Ras protein present in cancer cell lines. There were an average of 1.3 million molecules of Ras protein per cell, and the ratio of mutant to normal Ras proteins ranged from 0.49 to 5.6. Similarly, we found that mutant Ras proteins could be detected and quantified in clinical specimens such as colorectal and pancreatic tumor tissues as well as in premalignant pancreatic cyst fluids. In addition to answering basic questions about the relative levels of genetically abnormal proteins in tumors, this approach could prove useful for diagnostic applications. PMID- 21248226 TI - Metaplasticity governs compartmentalization of synaptic tagging and capture through brain-derived neurotrophic factor (BDNF) and protein kinase Mzeta (PKMzeta). AB - Activity-dependent synaptic plasticity is widely accepted to be the cellular correlate of learning and memory. It is believed that associativity between different synaptic inputs can transform short-lasting forms of synaptic plasticity (<3 h) to long-lasting ones. Synaptic tagging and capture (STC) might be able to explain this heterosynaptic support, because it distinguishes between local mechanisms of synaptic tags and cell-wide mechanisms responsible for the synthesis of plasticity-related proteins (PRPs). STC initiate storage processes only when the strength of the synaptic tag and the local concentration of essential proteins are above a certain plasticity threshold. We present evidence that priming stimulation through the activation of metabotropic glutamate receptors substantially increases the "range of threshold" for functional plasticity by producing protein kinase Mzeta (PKMzeta) as a PRP through local protein synthesis. In addition, our results implicate BDNF as a PRP which is mandatory for establishing cross-capture between synaptic strengthening and weakening, whereas the newly generated PKMzeta specifically establishes synaptic tagging of long-term potentiation. Most intriguingly, we show here that STC are confined to specific dendritic compartments and that these compartments contain "synaptic clusters" with different plasticity thresholds. Our results suggest that within a dendritic compartment itself a homeostatic process exists to adjust plasticity thresholds. The range in which these clusters operate can be altered by processes of metaplasticity, which will operate on the cluster independently of other clusters at the same dendrite. These clusters will then prepare the synaptic network to form long-term memories. PMID- 21248227 TI - Action potentials drive body wall muscle contractions in Caenorhabditis elegans. AB - The sinusoidal locomotion exhibited by Caenorhabditis elegans predicts a tight regulation of contractions and relaxations of its body wall muscles. Vertebrate skeletal muscle contractions are driven by voltage-gated sodium channel-dependent action potentials. How coordinated motor outputs are regulated in C. elegans, which does not have voltage-gated sodium channels, remains unknown. Here, we show that C. elegans body wall muscles fire all-or-none, calcium-dependent action potentials that are driven by the L-type voltage-gated calcium and Kv1 voltage dependent potassium channels. We further demonstrate that the excitatory and inhibitory motoneuron activities regulate the frequency of action potentials to coordinate muscle contraction and relaxation, respectively. This study provides direct evidence for the dual-modulatory model of the C. elegans motor circuit; moreover, it reveals a mode of motor control in which muscle cells integrate graded inputs of the nervous system and respond with all-or-none electrical signals. PMID- 21248228 TI - Loss-of-function DNA sequence variant in the CLCNKA chloride channel implicates the cardio-renal axis in interindividual heart failure risk variation. AB - Common heart failure has a strong undefined heritable component. Two recent independent cardiovascular SNP array studies identified a common SNP at 1p36 in intron 2 of the HSPB7 gene as being associated with heart failure. HSPB7 resequencing identified other risk alleles but no functional gene variants. Here, we further show no effect of the HSPB7 SNP on cardiac HSPB7 mRNA levels or splicing, suggesting that the SNP marks the position of a functional variant in another gene. Accordingly, we used massively parallel platforms to resequence all coding exons of the adjacent CLCNKA gene, which encodes the K(a) renal chloride channel (ClC-K(a)). Of 51 exonic CLCNKA variants identified, one SNP (rs10927887, encoding Arg83Gly) was common, in linkage disequilibrium with the heart failure risk SNP in HSPB7, and associated with heart failure in two independent Caucasian referral populations (n = 2,606 and 1,168; combined P = 2.25 * 10(-6)). Individual genotyping of rs10927887 in the two study populations and a third independent heart failure cohort (combined n = 5,489) revealed an additive allele effect on heart failure risk that is independent of age, sex, and prior hypertension (odds ratio = 1.27 per allele copy; P = 8.3 * 10(-7)). Functional characterization of recombinant wild-type Arg83 and variant Gly83 ClC-K(a) chloride channel currents revealed ~ 50% loss-of-function of the variant channel. These findings identify a common, functionally significant genetic risk factor for Caucasian heart failure. The variant CLCNKA risk allele, telegraphed by linked variants in the adjacent HSPB7 gene, uncovers a previously overlooked genetic mechanism affecting the cardio-renal axis. PMID- 21248229 TI - Myxobacteria gliding motility requires cytoskeleton rotation powered by proton motive force. AB - Myxococcus xanthus is a Gram-negative bacterium that glides over surfaces without the aid of flagella. Two motility systems are used for locomotion: social motility, powered by the retraction of type IV pili, and adventurous (A) motility, powered by unknown mechanism(s). We have shown that AgmU, an A-motility protein, is part of a multiprotein complex that spans the inner membrane and periplasm of M. xanthus. In this paper, we present evidence that periplasmic AgmU decorates a looped continuous helix that rotates clockwise as cells glide forward, reversing its rotation when cells reverse polarity. Inhibitor studies showed that the AgmU helix rotation is driven by proton motive force (PMF) and depends on actin-like MreB cytoskeletal filaments. The AgmU motility complex was found to interact with MotAB homologs. Our data are consistent with a mechanochemical model in which PMF-driven motors, similar to bacterial flagella stator complexes, run along an endless looped helical track, driving rotation of the track; deformation of the cell surface by the AgmU-associated proteins creates pressure waves in the slime, pushing cells forward. PMID- 21248231 TI - The effect of abnormality-prevalence expectation on expert observer performance and visual search. AB - PURPOSE: To measure the effect of abnormality-prevalence expectation on experienced radiologists' performance during pulmonary nodular lesion detection on a chest radiograph. MATERIALS AND METHODS: A multiobserver receiver operating characteristic (ROC) and eye-position analysis study was performed to assess the effect of prevalence expectation on observer performance. Twenty-two experienced radiologists were divided into three groups and each was asked to interpret 30 (15 abnormal) identical posteroanterior chest images twice and decide if pulmonary lesions were present. Before each viewing, the radiologists were told that the images contained a specific number of abnormal images: group 1: 9 and 15; group 2: 15 and 22; and group 3: 15 and not told. RESULTS: ROC analysis demonstrated that no significant effect could be measured as a function of prevalence expectation (P > .05). However, eye-position analysis showed significant increases in eye movements at higher prevalence expectation rates in terms of the number of fixations per image (group 1: P = .0001; group 2: P = .0001; group 3: P = .001) and the total scrutiny time of each image (group 1: P = .0001; group 2: P = .0283; group 3: P = .028). CONCLUSION: Overall, findings of this study showed no evidence that the accuracy of expert radiologists is altered due to changing prevalence expectation rates. However, the time spent interpreting each image and the number of fixations increased at higher prevalence rates. Maintenance of diagnostic efficacy has been shown even when circumstances challenge normal observer behavior. PMID- 21248230 TI - Iron conservation by reduction of metalloenzyme inventories in the marine diazotroph Crocosphaera watsonii. AB - The marine nitrogen fixing microorganisms (diazotrophs) are a major source of nitrogen to open ocean ecosystems and are predicted to be limited by iron in most marine environments. Here we use global and targeted proteomic analyses on a key unicellular marine diazotroph Crocosphaera watsonii to reveal large scale diel changes in its proteome, including substantial variations in concentrations of iron metalloproteins involved in nitrogen fixation and photosynthesis, as well as nocturnal flavodoxin production. The daily synthesis and degradation of enzymes in coordination with their utilization results in a lowered cellular metalloenzyme inventory that requires ~40% less iron than if these enzymes were maintained throughout the diel cycle. This strategy is energetically expensive, but appears to serve as an important adaptation for confronting the iron scarcity of the open oceans. A global numerical model of ocean circulation, biogeochemistry and ecosystems suggests that Crocosphaera's ability to reduce its iron-metalloenzyme inventory provides two advantages: It allows Crocosphaera to inhabit regions lower in iron and allows the same iron supply to support higher Crocosphaera biomass and nitrogen fixation than if they did not have this reduced iron requirement. PMID- 21248232 TI - Evaluation of reader variability in the interpretation of follow-up CT scans at lung cancer screening. AB - PURPOSE: To measure reader agreement in determining whether lung nodules detected at baseline screening computed tomography (CT) had changed at subsequent screening examinations and to evaluate the variability in recommendations for further follow-up. MATERIALS AND METHODS: All subjects were enrolled in the National Lung Screening Trial (NLST), and each participant consented to the use of their de-identified images for research purposes. The authors randomly selected 100 cases of nodules measuring at least 4.0 mm at 1-year screening CT that were considered by the original screening CT reader to be present on baseline CT scans; nodules considered by the original reader to have changed were oversampled. Selected images from each case showing the entire nodule at both examinations were preloaded on a picture archiving and communication system workstation. Nine radiologists served as readers, and they evaluated whether the nodule was present at baseline and recorded the bidimensional measurements and nodule characteristics at each examination, presence or absence of change, results of screening CT, and follow-up recommendations (high-level follow-up, low level follow-up, no follow-up). RESULTS: On the basis of reviews during case selection, five nodules seen at follow-up were judged not to have been present at baseline; for 19 of the remaining 95 cases, at least one reader judged the nodule not to have been present at baseline. For the 76 nodules that were unanimously considered to have been present at baseline, 21%-47% (mean +/- standard deviation, 30% +/- 9) were judged to have grown. The kappa values were similar for growth (kappa = 0.55) and a positive screening result (kappa = 0.51) and were lower for a change in margins and attenuation (kappa = 0.27-0.31). The kappa value in the recommendation of high- versus low-level follow-up was high (kappa = 0.66). CONCLUSION: Reader agreement on nodule growth and screening result was moderate to substantial. Agreement on follow-up recommendations was lower. PMID- 21248233 TI - Quantification of hepatic steatosis with T1-independent, T2-corrected MR imaging with spectral modeling of fat: blinded comparison with MR spectroscopy. AB - PURPOSE: To prospectively compare an investigational version of a complex-based chemical shift-based fat fraction magnetic resonance (MR) imaging method with MR spectroscopy for the quantification of hepatic steatosis. MATERIALS AND METHODS: This study was approved by the institutional review board and was HIPAA compliant. Written informed consent was obtained before all studies. Fifty-five patients (31 women, 24 men; age range, 24-71 years) were prospectively imaged at 1.5 T with quantitative MR imaging and single-voxel MR spectroscopy, each within a single breath hold. The effects of T2 correction, spectral modeling of fat, and magnitude fitting for eddy current correction on fat quantification with MR imaging were investigated by reconstructing fat fraction images from the same source data with different combinations of error correction. Single-voxel T2 corrected MR spectroscopy was used to measure fat fraction and served as the reference standard. All MR spectroscopy data were postprocessed at a separate institution by an MR physicist who was blinded to MR imaging results. Fat fractions measured with MR imaging and MR spectroscopy were compared statistically to determine the correlation (r(2)), and the slope and intercept as measures of agreement between MR imaging and MR spectroscopy fat fraction measurements, to determine whether MR imaging can help quantify fat, and examine the importance of T2 correction, spectral modeling of fat, and eddy current correction. Two-sided t tests (significance level, P = .05) were used to determine whether estimated slopes and intercepts were significantly different from 1.0 and 0.0, respectively. Sensitivity and specificity for the classification of clinically significant steatosis were evaluated. RESULTS: Overall, there was excellent correlation between MR imaging and MR spectroscopy for all reconstruction combinations. However, agreement was only achieved when T2 correction, spectral modeling of fat, and magnitude fitting for eddy current correction were used (r(2) = 0.99; slope +/- standard deviation = 1.00 +/- 0.01, P = .77; intercept +/- standard deviation = 0.2% +/- 0.1, P = .19). CONCLUSION: T1-independent chemical shift-based water-fat separation MR imaging methods can accurately quantify fat over the entire liver, by using MR spectroscopy as the reference standard, when T2 correction, spectral modeling of fat, and eddy current correction methods are used. PMID- 21248234 TI - Staging hepatic fibrosis: comparison of gadoxetate disodium-enhanced and diffusion-weighted MR imaging--preliminary observations. AB - PURPOSE: To evaluate the utility of hepatocyte-phase gadoxetate disodium-enhanced magnetic resonance (MR) imaging in staging hepatic fibrosis and to compare it with diffusion-weighted imaging. MATERIALS AND METHODS: This retrospective study had institutional review board approval, and the requirement for informed consent was waived. Gadoxetate disodium-enhanced and diffusion-weighted MR images obtained in 114 consecutive patients (70 men, 44 women; age range, 37-91 years) were evaluated. Liver-to-muscle signal intensity (SI) ratio on hepatocyte-phase images (SI(post)), contrast enhancement index calculated as SI(post) /SI(pre), where SI(pre) is liver-to-muscle SI ratio on nonenhanced images, and apparent diffusion coefficient (ADC) of the liver were measured. Necroinflammatory activity grades and hepatic fibrosis stages were histopathologically determined in 99 patients. Multiple regressions of SI(post), contrast enhancement index, ADC, serum albumin concentration, serum total bilirubin level, prothrombin time, and Child-Pugh score were examined to determine correlation with hepatic necroinflammatory activity grades and fibrosis stages. RESULTS: Among the MR, hematologic, and clinical parameters, contrast enhancement index was most strongly correlated with fibrosis stage (r = -0.79, P < .001). Multiple regression analysis showed that the contrast enhancement index, ADC, and prothrombin time were significantly correlated (r(2) = 0.66, P < .05) with fibrosis stage and that the contrast enhancement index and serum total bilirubin level were weakly correlated (r(2) = 0.24, P < .05) with the necroinflammatory activity grade. CONCLUSION: Gadoxetate disodium-enhanced MR imaging is more reliable for staging hepatic fibrosis than are diffusion-weighted MR imaging, hematologic, and clinical parameters. PMID- 21248235 TI - Evaluation of the mean and entropy of apparent diffusion coefficient values in chronic hepatitis C: correlation with pathologic fibrosis stage and inflammatory activity grade. AB - PURPOSE: To determine whether mean and entropy apparent diffusion coefficient (ADC) values obtained at diffusion-weighted (DW) magnetic resonance (MR) imaging can help detect and stage histopathologic liver fibrosis and grade inflammation activity in patients with chronic hepatitis C. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and the requirement for informed consent was waived. The study included 55 patients with focal hepatic lesions and either chronic hepatitis C (n = 43) or normal hepatic function (control subjects) (n = 12). Mean and entropy of volume histograms were generated in four cubic regions of interest placed in the right hepatic lobe of ADC map images, which were obtained at echo-planar DW MR imaging (gradient factor b values of 0 and 1000 sec/mm(2)). These two parameters (mean and entropy ADC) were compared by using METAVIR histopathologic liver fibrosis and inflammatory activity scores. Statistical analysis was performed with the Kruskal-Wallis test and receiver operating characteristic curves. RESULTS: The mean ADC decreased with an increase in the fibrosis stage or inflammatory activity grade, and the entropy ADC increased with an increase in the fibrosis stage or inflammatory activity grade (P < .001 for all comparisons, Kruskal-Wallis test). The area under the receiver operating characteristic curve (A(z)) for the mean ADC was statistically significant in the differentiation of fibrosis stage or inflammatory activity grade (A(z), 0.807-0.926; P < .001 for all comparisons). Entropy of ADC was helpful for classifying normal from abnormal fibrosis stage or inflammatory activity grade (A(z) for both parameters, 0.937; P < .001). CONCLUSION: Assessment of a combination of mean ADC and entropy ADC in patients with chronic hepatitis C is more accurate for predicting pathologic hepatic fibrosis stage and inflammatory activity grade and helpful for detecting early fibrotic or inflammatory activity when compared with assessment of mean ADC alone. PMID- 21248236 TI - Tetralogy of Fallot: impact of the excursion of the interventricular septum on left ventricular systolic function and fibrosis after surgical repair. AB - PURPOSE: To quantify the excursion of interventricular septum (IVS) in patients after repair of tetralogy of Fallot (TOF), a marker of interventricular interaction, and assess its association with left ventricular (LV) ejection fraction, LV septal wall thickening, and LV fibrosis. MATERIALS AND METHODS: The HIPAA-compliant protocol received institutional board review approval. IVS excursion was measured at cardiovascular magnetic resonance (MR) imaging in 82 patients after repair of TOF and in 10 healthy volunteers. IVS excursion was correlated with LV ejection fraction, LV septal wall thickening, and LV delayed gadolinium enhancement. Independent predictors of reduced LV ejection fraction were identified, including significant univariable predictors with use of a multivariable logistic regression model. RESULTS: IVS excursion was greater in patients than in healthy volunteers (5.3 mm +/- 3.1 vs 1.2 mm +/- 0.4, P < .01). Patients (n = 68) with abnormal excursion of the IVS had reduced LV ejection fraction (57% +/- 7 vs 61% +/- 4, P < .01) and reduced LV septal wall thickening (24% +/- 10 vs 29% +/- 5, P = .01) compared with patients with normal IVS excursion. Maximal IVS excursion (odds ratio = 1.27 per millimeter, P = .03) and right ventricular (RV) ejection fraction (odds ratio = 0.92 per percentage, P = .031) were independent predictors of reduced LV ejection fraction (<55%). Among the 44 patients with delayed enhancement images, those with abnormal excursion of the IVS had higher LV delayed enhancement scores (median, 1.5 [interquartile range, 0-2] vs 0 [interquartile range, 0-0]; P < .01] than patients with normal IVS excursion. Notably, in all but one patient the delayed enhancement was located at the RV-LV hinge points. CONCLUSION: Abnormal IVS excursion after repair of TOF is associated with reduced global and septal LV systolic function and LV fibrosis at the RV-LV hinge points, suggesting a mechanism of adverse interventricular interaction. PMID- 21248237 TI - Assessment of adverse reaction rates during gadoteridol-enhanced MR imaging in 28,078 patients. AB - PURPOSE: To determine adverse reaction rates in a tertiary care clinical setting after adoption of gadoteridol as the institutional routine magnetic resonance (MR) imaging contrast agent. MATERIALS AND METHODS: With institutional review board approval, informed consent waiver, and HIPAA compliance, a prospective observational study of 28 078 patients who underwent intravenous gadoteridol enhanced MR imaging from July 2007 to December 2009 was performed. Reactions were recorded by technologists who noted types of reactions, method of injection, and treatment. Reactions were classified as mild, moderate, or severe per American College of Radiology definitions. Comparisons of reaction rates with dose and method of injection were analyzed with the Fisher exact and chi(2) tests. RESULTS: Overall reaction rate was 0.666% (187 patients), including 177 mild, six moderate, and four severe reactions. Treatment was given in 27 patients (14.4%). The most frequent reaction was nausea (and/or vomiting) in 149 patients (79.7% of patients with any adverse reaction, 0.530% of overall population). Method of injection did not affect reaction rate or severity. There was no difference in type or severity of reactions in comparison of patients receiving half the dose versus patients receiving the standard dose (P = .33-.75). CONCLUSION: The observed adverse reaction rate to gadoteridol was lower than previously reported. Specifically, the rate of nausea (0.530%) was less than half the rate (1.4%) in clinical trials of 1251 patients, leading to FDA approval in 1992. Rates of adverse reactions for this macrocyclic contrast agent are comparable to those published for linear gadolinium-based contrast agents. PMID- 21248238 TI - Classification of Alzheimer disease, mild cognitive impairment, and normal cognitive status with large-scale network analysis based on resting-state functional MR imaging. AB - PURPOSE: To use large-scale network (LSN) analysis to classify subjects with Alzheimer disease (AD), those with amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) subjects. MATERIALS AND METHODS: The study was conducted with institutional review board approval and was in compliance with HIPAA regulations. Written informed consent was obtained from each participant. Resting state functional magnetic resonance (MR) imaging was used to acquire the voxelwise time series in 55 subjects with clinically diagnosed AD (n = 20), aMCI (n =15), and normal cognitive function (n = 20). The brains were divided into 116 regions of interest (ROIs). The Pearson product moment correlation coefficients of pairwise ROIs were used to classify these subjects. Error estimation of the classifications was performed with the leave-one-out cross-validation method. Linear regression analysis was performed to analyze the relationship between changes in network connectivity strengths and behavioral scores. RESULTS: The area under the receiver operating characteristic curve (AUC) yielded 87% classification power, 85% sensitivity, and 80% specificity between the AD group and the non-AD group (subjects with aMCI and CN subjects) in the first-step classification. For differentiation between subjects with aMCI and CN subjects, AUC was 95%; sensitivity, 93%; and specificity, 90%. The decreased network indexes were significantly correlated with the Mini-Mental State Examination score in all tested subjects. Similarly, changes in network indexes significantly correlated with Rey Auditory Verbal Leaning Test delayed recall scores in subjects with aMCI and CN subjects. CONCLUSION: LSN analysis revealed that interconnectivity patterns of brain regions can be used to classify subjects with AD, those with aMCI, and CN subjects. In addition, the altered connectivity networks were significantly correlated with the results of cognitive tests. PMID- 21248239 TI - Neuronal FLT1 receptor and its selective ligand VEGF-B protect against retrograde degeneration of sensory neurons. AB - Even though VEGF-B is a homologue of the potent angiogenic factor VEGF, its angiogenic activities have been controversial. Intrigued by findings that VEGF-B may also affect neuronal cells, we assessed the neuroprotective and vasculoprotective effects of VEGF-B in the skin, in which vessels and nerves are functionally intertwined. Although VEGF-B and its FLT1 receptor were prominently expressed in dorsal root ganglion (DRG) neurons innervating the hindlimb skin, they were not essential for nerve function or vascularization of the skin. However, primary DRG cultures lacking VEGF-B or FLT1 exhibited increased neuronal stress and were more susceptible to paclitaxel-induced cell death. Concomitantly, mice lacking VEGF-B or a functional FLT1 developed more retrograde degeneration of sensory neurons in a model of distal neuropathy. On the other hand, the addition of the VEGF-B isoform, VEGF-B(186), to DRG cultures antagonized neuronal stress, maintained the mitochondrial membrane potential and stimulated neuronal survival. Mice overexpressing VEGF-B(186) or FLT1 selectively in neurons were protected against the distal neuropathy, whereas exogenous VEGF-B(186), either delivered by gene transfer or as a recombinant factor, was protective by directly affecting sensory neurons and not the surrounding vasculature. Overall, this indicates that VEGF-B, instead of acting as an angiogenic factor, exerts direct neuroprotective effects through FLT1. These findings also suggest a clinically relevant role for VEGF-B in preventing distal neuropathies. PMID- 21248240 TI - Carbon monoxide protects against oxidant-induced apoptosis via inhibition of Kv2.1. AB - Oxidative stress induces neuronal apoptosis and is implicated in cerebral ischemia, head trauma, and age-related neurodegenerative diseases. An early step in this process is the loss of intracellular K(+) via K(+) channels, and evidence indicates that K(v)2.1 is of particular importance in this regard, being rapidly inserted into the plasma membrane in response to apoptotic stimuli. An additional feature of neuronal oxidative stress is the up-regulation of the inducible enzyme heme oxygenase-1 (HO-1), which catabolizes heme to generate biliverdin, Fe(2+), and carbon monoxide (CO). CO provides neuronal protection against stresses such as stroke and excitotoxicity, although the underlying mechanisms are not yet elucidated. Here, we demonstrate that CO reversibly inhibits K(v)2.1. Channel inhibition by CO involves reactive oxygen species and protein kinase G activity. Overexpression of K(v)2.1 in HEK293 cells increases their vulnerability to oxidant-induced apoptosis, and this is reversed by CO. In hippocampal neurons, CO selectively inhibits K(v)2.1, reverses the dramatic oxidant-induced increase in K(+) current density, and provides marked protection against oxidant-induced apoptosis. Our results provide a novel mechanism to account for the neuroprotective effects of CO against oxidative apoptosis, which has potential for therapeutic exploitation to provide neuronal protection in situations of oxidative stress. PMID- 21248241 TI - Rescuing replication and osteogenesis of aged mesenchymal stem cells by exposure to a young extracellular matrix. AB - This study aimed to determine whether aging negatively affects MSC replication and osteogenesis and whether these features could be altered by exposure to an extracellular matrix (ECM) generated by marrow cells from young or old mice. A cell-free ECM was prepared from cultured femoral marrow cells from either 3- or 18-mo-old C57BL/6 mice (young-ECM or old-ECM, respectively). The replication and osteogenesis of young or old MSCs maintained on young-ECM vs. old-ECM as well as plastic were examined in vitro and in vivo. We found that the frequency of MSCs in marrow from old mice, measured by colony-forming cells, was only marginally lower than that of young mice. In contrast, defects in the self-renewal and bone formation capacity of old MSCs were remarkable. These defects were corrected by provision of a young-ECM but not old-ECM. In parallel cultures maintained on a young-ECM, the intracellular levels of reactive oxygen species from both old and young mice were reduced 30-50% compared to those maintained on old-ECM or plastic. We concluded that aging negatively affects the formation of an ECM that normally preserves MSC function, and aged MSCs can be rejuvenated by culture on a young-ECM. PMID- 21248242 TI - Microdomain organization and frequency-dependence of CREB-dependent transcriptional signaling in heart cells. AB - Voltage-gated Ca(v)1.2 calcium channels couple membrane depolarization to cAMP response-element-binding protein (CREB)-dependent transcriptional activation. To investigate the spatial and temporal organization of CREB-dependent transcriptional nuclear microdomains, we combined perforated patch-clamp technique and FRET microscopy for monitoring CREB and CREB-binding protein interaction in the nuclei of live cells. The experimental approach to the quantitative assessment of CREB-dependent transcriptional signaling evoked by cAMP- and Ca(v)1.2-dependent mechanisms was devised in COS1 cells expressing recombinant Ca(v)1.2 calcium channels. Using continuous 2-dimensional wavelet transform and time series analyses, we found that nuclear CREB-dependent transcriptional signaling is organized differentially in spatially and temporally separated microdomains of 4 distinct types. In rat neonatal cardiomyocytes, CREB dependent transcription is mediated by the cAMP-initiated CaMKII-sensitive and Ca(v)1.2-initiated CaMKII-insensitive mechanisms. The latter microdomains show a tendency to exhibit periodic behavior correlated with spontaneous contraction of myocytes suggestive of frequency-dependent CREB-dependent transcriptional regulation in the heart. PMID- 21248244 TI - Assessment of catheter tip contact force resulting in cardiac perforation in swine atria using force sensing technology. AB - BACKGROUND: Force sensing is a recently developed technology that allows the determination of the contact force (CF) at the tip of the catheter during electrophysiology procedures. Previous studies suggested that the optimal CF for adequate catheter contact ranges between 10 and 40 g. The aim of this study was to determine the CF needed to cause perforation in the swine atria. METHODS AND RESULTS: Pericardial access was obtained at the beginning of the study in a swine model to drain pericardial effusions. Electroanatomic maps of the right atrium (RA) and left atrium (LA) were constructed. Ablation was performed using an irrigated-tip radiofrequency catheter equipped with force-sensing technology (30 W, 30 mL/min, for 30 seconds). Perforations of the LA and RA wall were intentionally performed in different locations with and without radiofrequency ablation. CF values preceding each perforation were recorded. A total of 111 cardiac perforations were achieved in 7 pigs. The overall average CF resulting in perforation was 175.8+/-60.4 g (range, 77 to 376 g). This was significantly lower after 30 seconds of radiofrequency delivery: 151.8+/-49.9 g versus 197+/-61.3 g (P=0.00005). The average value of CF resulting in perforation was not statistically different between the RA and the LA (169.6+/-61.6 g versus 181.7+/ 59.3 g) (P=0.29). CONCLUSIONS: Perforation of the atrial wall in a swine model can occur over a wide range of CF values. Perforation can occur with a CF as low as 77 g. Ablation reduces the perforating force by 23%. PMID- 21248243 TI - Neurobiological effects of sphingosine 1-phosphate receptor modulation in the cuprizone model. AB - Fingolimod (FTY720) is a sphingosine 1-phosphate (S1P) receptor modulator that regulates lymphocyte trafficking and exerts pleiotropic actions on oligodendrocytes (OLGs) and other neural cells. The purpose of this study was to investigate the role of S1P receptors in a non-T-cell model of demyelination, the cuprizone (cupr) model in C57BL/6 mice. Treatment with FTY720 (1 mg/kg) led to attenuated injury to OLGs, myelin, and axons in the corpus callosum (percentage of myelinated fibers was 44.7% in cupr-water and 63% in cupr-FTY720). Reactive astrogliosis and microgliosis were ameliorated when FTY720 was given from d 1, but astrogliosis was augmented when FTY720 was given from wk 4-9. FTY720 did not promote remyelination in this model. The protective effect of FTY720 was associated with decreased interleukin-1beta and CCL2 transcripts in the corpus callosum, as well as altered S1P1 expression. Targeted deletion of S1P1 in OLG lineage cells did not lead to obvious clinical phenotype, but resulted in subtle abnormalities in myelin and an increased susceptibility to cupr-induced demyelination. We conclude that S1P receptors expressed by neuroglia are involved in regulating the response to injury, and CNS effects of FTY720 could contribute to its favorable therapeutic response in multiple sclerosis. PMID- 21248245 TI - The incidence and long-term clinical outcome of iatrogenic atrial septal defects secondary to transseptal catheterization with a 12F transseptal sheath. AB - BACKGROUND: Studies assessing the presence of a residual iatrogenic atrial septal defect (iASD) after transseptal catheterization with 8F transseptal sheaths have suggested that the majority of these iASDs close within 6 months. However, these studies have been limited by small patient numbers and short follow-up. Additionally, there are a number of novel catheter procedures in interventional cardiology and electrophysiology that use larger transseptal sheaths. The objective of this study was to assess the incidence of and complications associated with iASDs in a large cohort of patients undergoing transseptal catheterization with a 12F transseptal sheath. METHODS AND RESULTS: Patients (n=253) without a preexisting interatrial shunt undergoing WATCHMAN implantation as part of the PROTECT AF study were included in this current study. Patients underwent transesophageal echocardiography with echo-contrast immediately after the procedure and at 45 days and 6 months and 12 months. Eighty-seven percent of patients had an iASD immediately after the procedure, the majority of which sealed by 6 months (incidence of iASD, 34% at 45 days, 11% at 6 months, 7% at 12 months). Whereas the majority of iASDs were >3 mm in diameter immediately after the procedure, the minority of iASD were >3 mm during the follow-up period. Additionally, interatrial shunting was predominantly left-to-right when an iASD was present. There was no significant difference in the rate of stroke and/or systemic embolism during the follow-up period in patients with or without iASD. CONCLUSIONS: Transseptal catheterization procedures with a large-diameter transseptal sheath have a high spontaneous closure rate of iASDs that is not associated with an increased rate of stroke/systemic embolization during long term follow-up. PMID- 21248246 TI - Steerable versus nonsteerable sheath technology in atrial fibrillation ablation: a prospective, randomized study. AB - BACKGROUND: Steerable sheath technology is designed to facilitate catheter access, stability, and tissue contact in target sites of atrial fibrillation (AF) catheter ablation. We hypothesized that rhythm control after interventional AF treatment is more successful using a steerable as compared with a nonsteerable sheath access. METHODS AND RESULTS: One hundred thirty patients with paroxysmal or persistent drug-refractory AF undergoing their first ablation procedure were prospectively included in a randomized fashion in 2 centers. Ablation was performed by 10 operators with different levels of clinical experience. Treatment outcome was measured with serial 7-day Holter ECGs and additional symptom-based arrhythmia documentation. Single procedure success (freedom from AF and/or atrial macroreentrant tachycardia) was significantly higher in patients ablated with a steerable sheath (78% versus 55% after 3 months, P=0.005; 76% versus 53% after 6 months, P=0.008). Rate of pulmonary vein isolation, procedure duration, and radiofrequency application time did not differ significantly, whereas fluoroscopy time was lower in the steerable sheath group (33+/-14 minutes versus 45+/-17 minutes, P<0.001). Complication rates showed no significant difference (3.2% versus 5%, P=0.608). On multivariable analysis, steerable sheath usage remained the only powerful predictor for rhythm outcome after 6 months of follow-up (hazard ratio, 2.837 [1.197 to 6.723]). CONCLUSIONS: AF catheter ablation using a manually controlled, steerable sheath for catheter navigation resulted in a significantly higher clinical success rate, with comparable complication rates and with a reduction in periprocedural fluoroscopy time. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00469638. PMID- 21248247 TI - A proteomic focus on the alterations occurring at the human atherosclerotic coronary intima. AB - Coronary atherosclerosis still represents the major cause of mortality in western societies. Initiation of atherosclerosis occurs within the intima, where major histological and molecular changes are produced during pathogenesis. So far, proteomic analysis of the atherome plaque has been mainly tackled by the analysis of the entire tissue, which may be a challenging approach because of the great complexity of this sample in terms of layers and cell type composition. Based on this, we aimed to study the intimal proteome from the human atherosclerotic coronary artery. For this purpose, we analyzed the intimal layer from human atherosclerotic coronaries, which were isolated by laser microdissection, and compared with those from preatherosclerotic coronary and radial arteries, using a two-dimensional Differential-In-Gel-Electrophoresis (DIGE) approach. Results have pointed out 13 proteins to be altered (seven up-regulated and six down regulated), which are implicated in the migrative capacity of vascular smooth muscle cells, extracellular matrix composition, coagulation, apoptosis, heat shock response, and intraplaque hemorrhage deposition. Among these, three proteins (annexin 4, myosin regulatory light 2, smooth muscle isoform, and ferritin light chain) constitute novel atherosclerotic coronary intima proteins, because they were not previously identified at this human coronary layer. For this reason, these novel proteins were validated by immunohistochemistry, together with hemoglobin and vimentin, in an independent cohort of arteries. PMID- 21248248 TI - Absence of MyD88 results in enhanced TLR3-dependent phosphorylation of IRF3 and increased IFN-beta and RANTES production. AB - Toll-like receptors are a group of pattern-recognition receptors that play a crucial role in "danger" recognition and induction of the innate immune response against bacterial and viral infections. TLR3 has emerged as a key sensor of viral dsRNA, resulting in the induction of the anti-viral molecule, IFN-beta. Thus, a clearer understanding of the biological processes that modulate TLR3 signaling is essential. Previous studies have shown that the TLR adaptor, Mal/TIRAP, an activator of TLR4, inhibits TLR3-mediated IFN-beta induction through a mechanism involving IRF7. In this study, we sought to investigate whether the TLR adaptor, MyD88, an activator of all TLRs except TLR3, has the ability to modulate TLR3 signaling. Although MyD88 does not significantly affect TLR3 ligand-induced TNF alpha induction, MyD88 negatively regulates TLR3-, but not TLR4-, mediated IFN beta and RANTES production; this process is mechanistically distinct from that employed by Mal/TIRAP. We show that MyD88 inhibits IKKepsilon-, but not TBK1-, induced activation of IRF3. In doing so, MyD88 curtails TLR3 ligand-induced IFN beta induction. The present study shows that while MyD88 activates all TLRs except TLR3, MyD88 also functions as a negative regulator of TLR3. Thus, MyD88 is essential in restricting TLR3 signaling, thereby protecting the host from unwanted immunopathologies associated with the excessive production of IFN-beta. Our study offers a new role for MyD88 in restricting TLR3 signaling through a hitherto unknown mechanism whereby MyD88 specifically impairs IKKepsilon-mediated induction of IRF3 and concomitant IFN-beta and RANTES production. PMID- 21248249 TI - Visualizing the role of Cbl-b in control of islet-reactive CD4 T cells and susceptibility to type 1 diabetes. AB - The E3 ubiquitin ligase Cbl-b regulates T cell activation thresholds and has been associated with protecting against type 1 diabetes, but its in vivo role in the process of self-tolerance has not been examined at the level of potentially autoaggressive CD4(+) T cells. In this study, we visualize the consequences of Cbl-b deficiency on self-tolerance to lysozyme Ag expressed in transgenic mice under control of the insulin promoter (insHEL). By tracing the fate of pancreatic islet-reactive CD4(+) T cells in prediabetic 3A9-TCR * insHEL double-transgenic mice, we find that Cbl-b deficiency contrasts with AIRE or IL-2 deficiency, because it does not affect thymic negative selection of islet-reactive CD4(+) cells or the numbers of islet-specific CD4(+) or CD4(+)Foxp3(+) T cells in the periphery, although it decreased differentiation of inducible regulatory T cells from TGF-beta-treated 3A9-TCR cells in vitro. When removed from regulatory T cells and placed in culture, Cblb-deficient islet-reactive CD4(+) cells reveal a capacity to proliferate to HEL Ag that is repressed in wild-type cells. This latent failure of T cell anergy is, nevertheless, controlled in vivo in prediabetic mice so that islet-reactive CD4(+) cells in the spleen and the pancreatic lymph node of Cblb-deficient mice show no evidence of increased activation or proliferation in situ. Cblb deficiency subsequently precipitated diabetes in most TCR:insHEL animals by 15 wk of age. These results reveal a role for peripheral T cell anergy in organ-specific self-tolerance and illuminate the interplay between Cblb-dependent anergy and other mechanisms for preventing organ specific autoimmunity. PMID- 21248250 TI - Essential role of E3 ubiquitin ligase activity in Cbl-b-regulated T cell functions. AB - E3 ubiquitin ligases have been placed among the essential molecules involved in the regulation of T cell functions and T cell tolerance. However, it has never been experimentally proven in vivo whether these functions indeed depend on the catalytic E3 ligase activity. The Casitas B-cell lymphoma (Cbl) family protein Cbl-b was the first E3 ubiquitin ligase directly implicated in the activation and tolerance of the peripheral T cell. In this study, we report that selective genetic inactivation of Cbl-b E3 ligase activity phenocopies the T cell responses observed when total Cbl-b is ablated, resulting in T cell hyperactivation, spontaneous autoimmunity, and impaired induction of T cell anergy in vivo. Moreover, mice carrying a Cbl-b E3 ligase-defective mutation spontaneously reject tumor cells that express human papilloma virus Ags. These data demonstrate for the first time, to our knowledge, that the catalytic function of an E3 ligase, Cbl-b, is essential for negative regulation of T cells in vivo. Thus, modulation of the E3 ligase activity of Cbl-b might be a novel modality to control T cell immunity in vaccination, cancer biology, or autoimmunity. PMID- 21248251 TI - SLAP deficiency enhances number and function of regulatory T cells preventing chronic autoimmune arthritis in SKG mice. AB - To test if manipulating TCR complex-mediated signaling (TCR signaling) could treat autoimmune disease, we generated the double SKG Src-like adapter protein (SLAP) knockout (DSSKO) mouse model. The SKG mutation in ZAP70 and SLAP have opposing functions on the regulation of TCR signaling. The combination of these two mutations alters TCR signaling in the context of a defined genetic background, uniform environmental conditions, and a well-characterized signaling disruption. In contrast to SKG mice, DSSKO mice do not develop zymosan-induced chronic autoimmune arthritis. This arthritis prevention is not due to significant alterations in thymocyte development or repertoire selection but instead enhanced numbers of regulatory T cells (Tregs) and decreased numbers of Th17 cells skewing the ratio of Tregs to autoreactive effector T cells. Treg depletion and/or functional blockade led to the development of arthritis in DSSKO mice. In vitro suppression of effector T cell proliferation was also enhanced, demonstrating that DSSKO mice have increased numbers of Tregs with increased function. Understanding how TCR signals influence development, expansion, and function of Tregs in DSSKO mice could advance our ability to manipulate Treg biology to treat ultimately autoimmune disease. PMID- 21248252 TI - Cutting Edge: The murine high-affinity IgG receptor FcgammaRIV is sufficient for autoantibody-induced arthritis. AB - K/BxN serum-induced passive arthritis was reported to depend on the activation of mast cells, triggered by the activating IgG receptor FcgammaRIIIA, when engaged by IgG1 autoantibodies present in K/BxN serum. This view is challenged by the fact that FcgammaRIIIA-deficient mice still develop K/BxN arthritis and because FcgammaRIIIA is the only activating IgG receptor expressed by mast cells. We investigated the contribution of IgG receptors, IgG subclasses, and cells in K/BxN arthritis. We found that the activating IgG2 receptor FcgammaRIV, expressed only by monocytes/macrophages and neutrophils, was sufficient to induce disease. K/BxN arthritis occurred not only in mast cell-deficient W(sh) mice, but also in mice whose mast cells express no activating IgG receptors. We propose that at least two autoantibody isotypes, IgG1 and IgG2, and two activating IgG receptors, FcgammaRIIIA and FcgammaRIV, contribute to K/BxN arthritis, which requires at least two cell types other than mast cells, monocytes/macrophages, and neutrophils. PMID- 21248253 TI - A novel and divergent role of granzyme A and B in resistance to helminth infection. AB - Granzyme (gzm) A and B, proteases of NK cells and T killer cells, mediate cell death, but also cleave extracellular matrices, inactivate intracellular pathogens, and induce cytokines. Moreover, macrophages, Th2 cells, regulatory T cells, mast cells, and B cells can express gzms. We recently reported gzm induction in human filarial infection. In this study, we show that in rodent filarial infection with Litomosoides sigmodontis, worm loads were significantly reduced in gzmA * B and gzmB knockout mice during the whole course of infection, but enhanced only early in gzmA knockout compared with wild-type mice. GzmA/B deficiency was associated with a defense-promoting Th2 cytokine and Ab shift, enhanced early inflammatory gene expression, and a trend of reduced alternatively activated macrophage induction, whereas gzmA deficiency was linked with reduced inflammation and a trend toward increased alternatively activated macrophages. This suggests a novel and divergent role for gzms in helminth infection, with gzmA contributing to resistance and gzmB promoting susceptibility. PMID- 21248254 TI - Accelerated dendritic cell differentiation from migrating Ly6C(lo) bone marrow monocytes in early dermal West Nile virus infection. AB - No study has investigated the participation of Ly6C(+) monocytes in the earliest phase of skin infection with the mosquito-borne West Nile virus. In a novel murine model mimicking natural dermal infection, CCL2-dependent bone marrow (BM) derived monocyte migration, differentiation into Ly6C(+) dendritic cells (DC), and accumulation around dermal deposits of infected fibroblasts by day 1 postinfection were associated with increasing numbers of monocyte-derived TNF/inducible NO synthase-producing DC by day 2 postinfection in draining auricular lymph nodes (ALN). Adoptive transfer demonstrated simultaneous migration of bone marrow-derived Ly6C(lo) monocytes to virus-infected dermis and ALN, where they first become Ly6C(hi) DC within 24 h and then Ly6C(lo) DC by 72 h. DC migration from the infected dermis to the ALN derived exclusively from Ly6C(lo) BM monocytes. This demonstrates that Ly6C(hi) and Ly6C(lo) BM-derived monocytes have different fates in vivo and suggests that BM may be a reservoir of preinflammatory monocytes for rapid deployment as inflammatory DC during virus infection. PMID- 21248255 TI - The evolution and regulation of the mucosal immune complexity in the basal chordate amphioxus. AB - Both amphioxus and the sea urchin encode a complex innate immune gene repertoire in their genomes, but the composition and mechanisms of their innate immune systems, as well as the fundamental differences between two systems, remain largely unexplored. In this study, we dissect the mucosal immune complexity of amphioxus into different evolutionary-functional modes and regulatory patterns by integrating information from phylogenetic inferences, genome-wide digital expression profiles, time course expression dynamics, and functional analyses. With these rich data, we reconstruct several major immune subsystems in amphioxus and analyze their regulation during mucosal infection. These include the TNF/IL 1R network, TLR and NLR networks, complement system, apoptosis network, oxidative pathways, and other effector genes (e.g., peptidoglycan recognition proteins, Gram-negative binding proteins, and chitin-binding proteins). We show that beneath the superficial similarity to that of the sea urchin, the amphioxus innate system, despite preserving critical invertebrate components, is more similar to that of the vertebrates in terms of composition, expression regulation, and functional strategies. For example, major effectors in amphioxus gut mucous tissue are the well-developed complement and oxidative-burst systems, and the signaling network in amphioxus seems to emphasize signal transduction/modulation more than initiation. In conclusion, we suggest that the innate immune systems of amphioxus and the sea urchin are strategically different, possibly representing two successful cases among many expanded immune systems that arose at the age of the Cambrian explosion. We further suggest that the vertebrate innate immune system should be derived from one of these expanded systems, most likely from the same one that was shared by amphioxus. PMID- 21248256 TI - Mice lacking Ly49E show normal NK cell development and provide evidence for probabilistic expression of Ly49E in NK cells and T cells. AB - Ly49E is an unusual member of the Ly49 family that is expressed on fetal NK cells, epithelial T cells, and NKT cells, but not on resting adult NK cells. Ly49E(bgeo/bgeo) mice in which the Ly49E gene was disrupted by inserting a beta geo transgene were healthy, fertile, and had normal numbers of NK and T cells in all organs examined. Their NK cells displayed normal expression of Ly49 and other NK cell receptors, killed tumor and MHC class I-deficient cells efficiently, and produced normal levels of IFN-gamma. In heterozygous Ly49E(+/bgeo) mice, the proportion of epidermal T cells, NKT cells, and IL-2-activated NK cells that expressed Ly49E was about half that found in wild-type mice. Surprisingly, although splenic T cells rarely expressed Ly49E, IL-2-activated splenic T cells from Ly49E(bgeo/bgeo) mice were as resistant to growth in G418 as NK cells and expressed similar levels of beta-geo transcripts, suggesting that disruption of the Ly49E locus had increased its expression in these cells to the same level as that in NK cells. Importantly, however, the proportion of G418-resistant heterozygous Ly49E(+/bgeo) cells that expressed Ly49E from the wild-type allele was similar to that observed in control cells. Collectively, these findings demonstrate that Ly49E is not required for the development or homeostasis of NK and T cell populations or for the acquisition of functional competence in NK cells and provide compelling evidence that Ly49E is expressed in a probabilistic manner in adult NK cells and T cells. PMID- 21248257 TI - Pulmonary surfactant protein A enhances endolysosomal trafficking in alveolar macrophages through regulation of Rab7. AB - Surfactant protein A (SP-A), the most abundant pulmonary soluble collectin, modulates innate and adaptive immunity of the lung, partially via its direct effects on alveolar macrophages (AM), the most predominant intra-alveolar cells under physiological conditions. Enhanced phagocytosis and endocytosis are key functional consequences of AM/SP-A interaction, suggesting a SP-A-mediated modulation of small Rab (Ras related in brain) GTPases that are pivotal membrane organizers in both processes. In this article, we show that SP-A specifically and transiently enhances the protein expression of endogenous Rab7 and Rab7b, but not Rab5 and Rab11, in primary AM from rats and mice. SP-A-enhanced GTPases are functionally active as determined by increased interaction of Rab7 with its downstream effector Rab7 interacting lysosomal protein (RILP) and enhanced maturation of cathepsin-D, a function of Rab7b. In AM and RAW264.7 macrophages, the SP-A-enhanced lysosomal delivery of GFP-Escherichia coli is abolished by the inhibition of Rab7 and Rab7 small interfering RNA transfection, respectively. The constitutive expression of Rab7 in AM from SP-A(-/-) mice is significantly reduced compared with SP-A(+/+) mice and is restored by SP-A. Rab7 blocking peptides antagonize SP-A-rescued lysosomal delivery of GFP-E. coli in AM from SP A(-/-) mice. Activation of Rab7, but not Rab7b, by SP-A depends on the PI3K/Akt/protein kinase Czeta (PKCzeta) signal transduction pathway in AM and RAW264.7 macrophages. SP-A induces a Rab7/PKCzeta interaction in these cells, and the disruption of PKCzeta by small interfering RNA knockdown abolishes the effect of SP-A on Rab7. The data demonstrate a novel role for SP-A in modulating endolysosomal trafficking via Rab7 in primary AM and define biochemical pathways involved. PMID- 21248258 TI - Th17 cells expressing KIR3DL2+ and responsive to HLA-B27 homodimers are increased in ankylosing spondylitis. AB - CD4 Th cells producing the proinflammatory cytokine IL-17 (Th17) have been implicated in a number of inflammatory arthritides including the spondyloarthritides. Th17 development is promoted by IL-23. Ankylosing spondylitis, the most common spondyloarthritis (SpA), is genetically associated with both HLA-B27 (B27) and IL-23R polymorphisms; however, the link remains unexplained. We have previously shown that B27 can form H chain dimers (termed B27(2)), which, unlike classical HLA-B27, bind the killer-cell Ig-like receptor KIR3DL2. In this article, we show that B27(2)-expressing APCs stimulate the survival, proliferation, and IL-17 production of KIR3DL2(+) CD4 T cells. KIR3DL2(+) CD4 T cells are expanded and enriched for IL-17 production in the blood and synovial fluid of patients with SpA. Despite KIR3DL2(+) cells comprising a mean of just 15% of CD4 T in the peripheral blood of SpA patients, this subset accounted for 70% of the observed increase in Th17 numbers in SpA patients compared with control subjects. TCR-stimulated peripheral blood KIR3DL2(+) CD4 T cell lines from SpA patients secreted 4-fold more IL-17 than KIR3DL2(+) lines from controls or KIR3DL2(-) CD4 T cells. Strikingly, KIR3DL2(+) CD4 T cells account for the majority of peripheral blood CD4 T cell IL-23R expression and produce more IL-17 in the presence of IL-23. Our findings link HLA B27 with IL-17 production and suggest new therapeutic strategies in ankylosing spondylitis/SpA. PMID- 21248259 TI - B lymphocytes differentially influence acute and chronic allograft rejection in mice. AB - The relative contributions of B lymphocytes and plasma cells during allograft rejection remain unclear. Therefore, the effects of B cell depletion on acute cardiac rejection, chronic renal rejection, and skin graft rejection were compared using CD20 or CD19 mAbs. Both CD20 and CD19 mAbs effectively depleted mature B cells, and CD19 mAb treatment depleted plasmablasts and some plasma cells. B cell depletion did not affect acute cardiac allograft rejection, although CD19 mAb treatment prevented allograft-specific IgG production. Strikingly, CD19 mAb treatment significantly reduced renal allograft rejection and abrogated allograft-specific IgG development, whereas CD20 mAb treatment did not. By contrast, B cell depletion exacerbated skin allograft rejection and augmented the proliferation of adoptively transferred alloantigen-specific CD4(+) T cells, demonstrating that B cells can also negatively regulate allograft rejection. Thereby, B cells can either positively or negatively regulate allograft rejection depending on the nature of the allograft and the intensity of the rejection response. Moreover, CD19 mAb may represent a new approach for depleting both B cells and plasma cells to concomitantly impair T cell activation, inhibit the generation of new allograft-specific Abs, or reduce preexisting allograft-specific Ab levels in transplant patients. PMID- 21248260 TI - Metabolic stress boosts humoral responses in vivo independently of inflammasome and inflammatory reaction. AB - Adjuvant formulations boost humoral responses by acting through several, yet incompletely elucidated pathways. In this study, we show that oligomycin or 5 aminoimidazole-4-carboxamide-1-beta-D-ribonucleoside (AICAR) enhances Ab production when coinjected with T cell-dependent Ags. Oligomycin and AICAR lead to intracellular ATP reduction, suggesting that metabolic stress could be sensed by immune cells and leads to increased humoral responses. AICAR promotes IL-4 and IL-21 by naive Th cells but does not affect dendritic cell activation/maturation in vitro or in vivo. Accordingly, the adjuvant effect of AICAR or oligomycin does not require MyD88 or caspase-1 expression in vivo. Because AICAR is well tolerated in humans, this compound could represent a novel and safe adjuvant promoting humoral responses in vivo with a minimal reactogenicity. PMID- 21248261 TI - Suppressive effect of bacterial polysaccharides on BAFF system is responsible for their poor immunogenicity. AB - Capsular polysaccharides of encapsulated bacteria are weakly immunogenic T cell independent type 2 (TI-2) Ags. Recent findings suggest that BAFF system molecules have a critical role in the development of Ab responses against TI-2 Ags. In this study, we investigated the effect of bacterial polysaccharides on B cell responses to BAFF and a proliferation-inducing ligand (APRIL). We determined that B cells exposed to meningococcal type C polysaccharide (MCPS) or group B Streptococcus serotype V (GBS-V) were unresponsive to BAFF- and APRIL-induced Ig secretion. Moreover, MCPS and GBS-V strongly downregulated transmembrane activator and calcium-modulator and cyclophilin ligand interactor, the BAFF and APRIL receptor that is responsible for Ab development against TI-2 Ags. Interestingly, (4-hydroxy-3-nitrophenyl)acetyl-Ficoll (NP-Ficoll), a prototype TI 2 Ag, did not manifest a suppressive effect on B cells. Paradoxically, whereas GBS-V and MCPS inhibited IFN-gamma-induced BAFF production from dendritic cells, NP-Ficoll strongly increased BAFF secretion. TLR 9 agonist CpG deoxyoligonucleotide (ODN) was able to reverse the MCPS-mediated transmembrane activator and calcium-modulator and cyclophilin ligand interactor suppression but could not rescue the Ig secretion in BAFF- or APRIL-stimulated B cells. In support of these in vitro observations, it was observed that CpG ODN could help augment the Ab response against NP in mice immunized with a CpG ODN-containing NP Ficoll vaccine but exhibited only marginal adjuvant activity for MCPS vaccine. Collectively, these results suggest a mechanism for the weak immunogenicity of bacterial polysaccharides and explain the previously observed differences between bacterial polysaccharide and NP-Ficoll immunogenicity. PMID- 21248262 TI - The IL1RN promoter rs4251961 correlates with IL-1 receptor antagonist concentrations in human infection and is differentially regulated by GATA-1. AB - IL-1R antagonist (IL-1Ra) is required for adequate host defense in invasive pneumococcal disease (IPD). The minor allele of an IL1RN gene (C/T) promoter polymorphism (rs4251961) has been shown to be associated with decreased IL-1Ra production in healthy adults. We genotyped 299 children with IPD, and examined 19 IL1RN haplotype-tagging single-nucleotide polymorphisms. Human embryonic kidney HEK293(T) cells were transfected with the promoter reporter plasmid pGL3p containing either allelic variant C (pGL3pCC) or T (pGL3pTT) with or without cotransfection with an expression construct overexpressing the globin transcription factor GATA-1. Plasma IL-1Ra concentrations were significantly higher in nonsurvivors compared with survivors (p < 0.0005), and the C allele of rs4251961 was associated with a significant increase in plasma IL-1Ra concentrations (p = 0.01) during the acute illness of IPD. These findings were validated in a cohort of 276 treatment-naive HIV-infected adults, with borderline significance (p = 0.058). Functional analyses demonstrated that the activity of the promoter constructs containing the T allele increased ~6-fold as compared with basal activity, and that containing the C allele by ~9-fold (p < 0.001) in the presence of GATA-1. Our findings suggest that the IL-1Ra single-nucleotide polymorphism rs4251961 plays a key role in the pathophysiology of IPD and in other human infections. PMID- 21248263 TI - Evolution of the antigen-specific CD8+ TCR repertoire across the life span: evidence for clonal homogenization of the old TCR repertoire. AB - Defects in T cell responses against pathogens and reduced diversity of TCRs have been described at both extremes of the life span. Yet, we still lack information on how Ag-specific T cell populations are maintained and/or altered from birth to old age. In this study, for the first time to our knowledge, we provide insight into Ag-specific TCR repertoire changes over the life span at the single-cell level. We have examined the TCR diversity of the primary CD8(+) T cell response to the immunodominant HSV-1 epitope HSV glycoprotein B 495-502 (HSV gB(498-505); SSIEFARL) (gB-8p) in neonatal, adult, and old C57BL/6 mice. The global distinctive features of the gB-8p-specific TCR repertoire were preserved in mice of different ages. However, both old and especially neonatal mice exhibited significant decreases in TCR diversity compared with that of adult mice. Still, although the neonatal Ag-specific repertoire comprised expectedly shorter germline-biased CDR3beta lengths, the repertoire was surprisingly complex, and only a minority of responding cells lacked random nucleotide additions. Changes with aging included increased use of the already dominant TCRVbeta10 family, a trend for lower content of the TCR containing the germline WG motif in the CDR3, and a remarkable sharing of one dominant clonotype between individual old mice, implying operation of selective mechanisms. Implications for the rational design of vaccines for neonates and the elderly are discussed. PMID- 21248264 TI - HLA-G expression in human embryonic stem cells and preimplantation embryos. AB - Human leukocyte Ag-G, a tolerogenic molecule that acts on cells of both innate and adaptive immunity, plays an important role in tumor progression, transplantation, placentation, as well as the protection of the allogeneic fetus from the maternal immune system. We investigated HLA-G mRNA and protein expression in human embryonic stem cells (hESC) derived from the inner cell mass (ICM) of blastocysts. hESC self-renew indefinitely in culture while maintaining pluripotency, providing an unlimited source of cells for therapy. HLA-G mRNA was present in early and late passage hESC, as assessed by real time RT-PCR. Protein expression was demonstrated by flow cytometry, immunocytochemistry, and ELISA on an hESC extract. Binding of HLA-G with its ILT2 receptor demonstrated the functional active status. To verify this finding in a physiologically relevant setting, HLA-G protein expression was investigated during preimplantation development. We demonstrated HLA-G protein expression in oocytes, cleavage stage embryos, and blastocysts, where we find it in trophectoderms but also in ICM cells. During blastocyst development, a downregulation of HLA-G in the ICM cells was present. This data might be important for cell therapy and transplantation because undifferentiated hESC can contaminate the transplant of differentiated stem cells and develop into malignant cancer cells. PMID- 21248265 TI - Comment on "Type 1 diabetes in BioBreeding rats is critically linked to an imbalance between Th17 and regulatory T cells and an altered TCR repertoire". PMID- 21248266 TI - Comment on "Flagellin as an adjuvant: cellular mechanisms and potential". PMID- 21248267 TI - Receptor editing as a mechanism of B cell tolerance. PMID- 21248268 TI - Receptor editing: an approach by autoreactive B cells to escape tolerance. The Journal of Experimental Medicine. 1993. 177: 999-1008. PMID- 21248269 TI - Receptor editing in self-reactive bone marrow B cells. The Journal of Experimental Medicine. 1993. 177: 1009-1020. PMID- 21248271 TI - Genotype-phenotype associations in SCN1A-related epilepsies. AB - OBJECTIVE: Most mutations in SCN1A-related epilepsies are novel and when an infant presents with febrile seizures (FS) it is uncertain if they will have simple FS, FS+, or develop a severe epilepsy such as Dravet syndrome. Our objective was to examine whether the nature of a SCN1A mutation affects the epilepsy phenotype. METHODS: We retrospectively evaluated clinical and genetic data from 273 individuals with SCN1A mutations identified in our laboratory and reviewed data from 546 published cases. We examined whether the mutation class or distribution or nature of amino acid substitution correlated with the epilepsy phenotype, using the Grantham Score (GS) as a measure of physicochemical difference between amino acids. RESULTS: Compared to missense mutations, truncating mutations were associated with earlier mean onset of prolonged seizures (7.4 vs 8.8 months; p = 0.040), myoclonic seizures (16.4 vs 19.4 months; p = 0.041), and atypical absence seizures (19.1 vs 30.6 months; p = 0.001). The median GS was higher in patients with Dravet syndrome compared to polymorphisms (94 vs 58; p = 0.029) and orthologs (94 vs 45; p < 0.001). A high GS was correlated with early onset of seizures (r(s) = -0.235; p = 0.008). Missense mutations occurred most frequently in the voltage and ion-pore regions where changes in amino acid polarity were greater in the Dravet group compared to the genetic epilepsy with febrile seizures plus group (3.6 vs 2.7; p = 0.031). CONCLUSIONS: These findings help define the clinical significance of specific SCN1A mutations based on mutation class and amino acid property and location. PMID- 21248272 TI - Does genotype determine phenotype? Sodium channel mutations in Dravet syndrome and GEFS+. PMID- 21248270 TI - Recent developments in cancer vaccines. AB - The adoptive transfer of cancer Ag-specific effector T cells in patients can result in tumor rejection, thereby illustrating the immune system potential for cancer therapy. Ideally, one would like to directly induce efficient tumor specific effector and memory T cells through vaccination. Therapeutic vaccines have two objectives: priming Ag-specific T cells and reprogramming memory T cells (i.e., a transformation from one type of immunity to another, for example, regulatory to cytotoxic). Recent successful phase III clinical trials showing benefit to the patients revived cancer vaccines. Dendritic cells (DCs) are essential in generation of immune responses, and as such represent targets and vectors for vaccination. We have learned that different DC subsets elicit different T cells. Similarly, different activation methods result in DCs able to elicit distinct T cells. We contend that a careful manipulation of activated DCs will allow cancer immunotherapists to produce the next generation of highly efficient cancer vaccines. PMID- 21248273 TI - Increasing incidence of ischemic stroke in patients with HIV infection. AB - BACKGROUND: Large-scale epidemiologic data on stroke in HIV-infected persons are scarce, especially in an era of combination antiretroviral therapies, which have prolonged patient survival, but may boost stroke risk. We assessed trends in the proportion of HIV infection among patients with stroke in the United States. METHODS: Data were obtained from all states within the United States that contributed to the Nationwide Inpatient Sample. All patients admitted to hospitals between 1997 and 2006 with a primary discharge diagnosis of stroke (identified by the International Classification of Diseases, Ninth Revision procedure codes) were included. Time trends in the proportion of these patients with HIV diagnosis were computed, and independent predictors of comorbid HIV diagnosis evaluated using multivariable logistic regression. RESULTS: Of all (ischemic and hemorrhagic) stroke hospitalizations, patients with comorbid HIV infection constituted 0.09% in 1997 vs 0.15% in 2006 (p < 0.0001). Actual numbers of overall US stroke hospitalizations lessened 7% (998,739 to 926,997), while actual numbers of stroke hospitalizations with coexisting HIV infection rose 60% (888 to 1,425). Patients with comorbid HIV infection comprised 0.08% of ischemic strokes in 1997 vs 0.18% in 2006 (p < 0.0001), but their proportion of hemorrhagic strokes did not significantly change. Factors independently associated with higher odds of comorbid HIV diagnosis were Medicaid insurance, urban hospital type, dementia, liver disease, renal disease, and cancer. CONCLUSION: Over the last decade in the United States, there has been a substantial and significant rise in patients hospitalized for stroke with coexisting HIV infection. This has important public health and socioeconomic consequences. PMID- 21248275 TI - Postthrombolysis hemorrhage risk is affected by stroke assessment bias between hemispheres. AB - OBJECTIVE: Stroke symptoms in right hemispheric stroke tend to be underestimated in clinical assessment scales, resulting in greater infarct volumes in right as compared to left hemispheric strokes despite similar clinical stroke severity. We hypothesized that patients with right hemispheric nonlacunar stroke are at higher risk for secondary intracerebral hemorrhage after thrombolysis despite similar stroke severity. METHODS: We analyzed data of 2 stroke cohorts with CT-based and MRI-based imaging before thrombolysis. Initial stroke severity was measured with the NIH Stroke Scale (NIHSS). Lacunar strokes were excluded through either the presence of cortical symptoms (CT cohort) or restriction to patients with prestroke diffusion-weighted imaging (DWI) lesion size >3.75 mL (MRI cohort). Probabilities of having a parenchymal hematoma were determined using multivariate logistic regression. RESULTS: A total of 392 patients in the CT cohort and 400 patients in the MRI cohort were evaluated. Although NIHSS scores were similar in strokes of both hemispheres (median NIHSS: CT: 15 vs 13, MRI: 14 vs 16), the frequencies of parenchymal hematoma were higher in right hemispheric compared to left hemispheric strokes (CT: 12.4% vs 5.7%, MRI: 10.4% vs 6.8%). After adjustment for potential confounders (but not pretreatment lesion volume), the probability of parenchymal hematoma was higher in right hemispheric nonlacunar strokes (CT: odds ratio [OR] 2.3; 95% confidence interval [CI] 1.08-4.89; p = 0.032) and showed a borderline significant effect in the MRI cohort (OR 2.1; 95% CI 0.98-4.49; p = 0.057). Adjustment for pretreatment DWI lesion size eliminated hemispheric differences in hemorrhage risk. CONCLUSIONS: Higher hemorrhage rates in right hemispheric nonlacunar strokes despite similar stroke severity may be caused by clinical underestimation of the proportion of tissue at bleeding risk. PMID- 21248276 TI - Micronucleus frequencies in lymphocytes and buccal epithelial cells from patients having head and neck cancer and their first-degree relatives. AB - Head and neck squamous cell carcinoma is the fifth most common cancer type worldwide. Even though it is known that the most important environmental aetiological factors for head and neck cancer (HNC) development are tobacco and alcohol, genetic susceptibility is also thought to be important. The use of biomarkers of chromosomal damage due to genetic instability in order to predict risk of cancer as well as to identify high-risk individuals is imperative. We have investigated genetic damage in patients having HNC (n = 59) and their first degree relatives (FDRs) (n = 34) with a biomarker in two different tissues; the micronucleus (MN) test in peripheral blood lymphocytes and in exfoliated buccal cells. The mean (standard deviation) levels of MN frequencies (0/00) in lymphocytes of patients, relatives and controls were 27.10 (9.52), 14.09 (5.13) and 9.00 (6.87), respectively. The mean (standard deviation) levels of MN frequencies (0/00) in exfoliated buccal cells of patients, relatives and controls were 2.87 (1.16), 1.38 (0.85) and 1.23 (0.93), respectively. Our results indicated that spontaneous genetic damage in lymphocytes of patients having HNC was significantly higher than that of controls (P < 0.01) and thus genetic instability appeared to exist in lymphocytes of cancer patients. Similar findings were obtained for exfoliated buccal cell MN frequencies of cancer patients (P < 0.01). We observed that the FDRs of patients having HNC showed significantly higher chromosomal damage in terms of MN frequencies in lymphocytes when compared with those of controls (P < 0.05), thus reflecting an increased susceptibility to HNC in FDRs. However, for buccal cell MN frequencies, we could not demonstrate enhanced genetic instability in the FDRs of patients having HNC. PMID- 21248274 TI - Survival after neuroAIDS: association with antiretroviral CNS Penetration Effectiveness score. AB - OBJECTIVE: We examined if the CNS Penetration-Effectiveness (CPE) score of antiretroviral drugs was associated with survival after a diagnosis of HIV related encephalopathy, progressive multifocal leukoencephalopathy (PML), cerebral toxoplasmosis, or cryptococcal meningitis. METHODS: Using data from the FHDH-ANRS CO4, we compared the survival of 9,932 HIV-infected patients diagnosed with a first neurologic AIDS-defining event in the pre-combination antiretroviral therapy (cART) (1992-1995), early cART (1996-1998), or late cART (1999-2004) periods. Follow-up was subdivided (CPE < 1.5 and CPE >= 1.5), and relative rates (RR) of death were estimated using multivariable Poisson regression models. RESULTS: In the pre-cART and early cART periods, regimens with CPE >= 1.5 were associated with lower mortality after HIV-related encephalopathy (RR 0.64; 95% confidence interval [CI] 0.47-0.86 and RR 0.45; 95% CI 0.35-0.58) and after PML (RR 0.79; 95% CI 0.55-1.12 and RR 0.45; 95% CI 0.31-0.65), compared to regimens with CPE < 1.5, while in the late cART period there was no association between the CPE score and the mortality. A higher CPE score was also associated with a lower mortality in all periods after cerebral toxoplasmosis (RR 0.68, 95% CI 0.56 0.84) or cryptococcal meningitis (RR 0.50, 95% CI 0.34-0.74). Whatever the neurologic event, these associations were not maintained after adjustment on updated plasma HIV-RNA (missing, <500, >=500 copies/mL) with RR ranging from 0.82 (95% CI 0.36-1.91) to 1.02 (0.69-1.52). CONCLUSION: At the beginning of the cART era, the CPE score was of importance for survival after severe neurologic event, while in the late cART period, the additional effect of CPE score vanished with more powerful antiretroviral regimens associated with plasma viral load control. PMID- 21248277 TI - Predicting the occurrence, conviction, distress, and disruption of different delusional experiences in the daily life of people with schizophrenia. AB - Recent research has shown that negative emotional states of increased anxiety and sadness prospectively predict the occurrence of persecutory ideation, but it is not known whether these findings extend to other subtypes of delusions. The current study explored whether these negative emotional states, as well as hallucinations, biased reasoning style (ie, jumping to conclusions), and negative self-esteem prospectively predict the occurrence and various dimensions of delusions of control, reference, and grandiosity in real time, as they occur in daily life. One hundred and thirty community-dwelling participants with schizophrenia or schizoaffective disorder completed laboratory measures and momentary self-reports generated by a personal digital assistant multiple times per day, over 7 consecutive days. Analyses were time lagged allowing simultaneous examination of person-level and within-person time-varying relationships among the variables. Approximately, half of the participants reported having at least one delusional experience during the week, and approximately, a quarter of those individuals reported experiencing all 3 delusion subtypes. Hallucinations were a significant predictor of the occurrence of delusions of control and reference over the subsequent hours of the same day, but negative emotional states of anxiety and sadness were not. Negative self-esteem predicted the frequency of all 3 delusion subtypes during the week, and a reasoning style characterized by reduced information gathering was a significant predictor of the frequency of delusions of control. Delusional dimensions of conviction, distress, and disruption had different associations with the variables tested for each delusion subtype. PMID- 21248278 TI - Length does not matter: a new take on telomerase reverse transcriptase. PMID- 21248279 TI - Vascular calcification: it's all the RAGE! PMID- 21248280 TI - Endosomal ClC-3 and Nox1: moving marksmen of redox signaling? PMID- 21248281 TI - Close encounters of the third kind: progenitor cells land on the platelet enriched vascular surface. PMID- 21248283 TI - Crying that heals: concept evaluation. AB - Although much has been written about the healing power of tears, the research into this phenomenon has been fragmented, uncoordinated, and inconclusive. Nonetheless, a substantial amount of the literature across multiple disciplines has addressed the subject, both directly and indirectly. In this article, the authors submit crying that heals (CTH) as a concept of possible significance to health care and evaluate CTH using the criteria for concept evaluation proposed by Morse, Mitcham, Hupcey, and Tason (1996). Using these criteria, CTH is tentatively defined, and its characteristics, boundaries, preconditions, and outcomes are proposed and examined in the context of this definition. Suggestions for additional analysis and research are offered, and the potential importance of CTH to health care professions, especially nursing, is discussed. PMID- 21248284 TI - Peroxiredoxin 2 inhibits granulosa cell apoptosis during follicle atresia through the NFKB pathway in mice. AB - Peroxiredoxin 2 (PRDX2) has been known to act as an antioxidant enzyme whose main function is H(2)O(2) reduction in cells. We aimed to study the expression patterns of PRDX2 in mouse ovaries and explore the function of this protein in apoptosis of granulosa cells (GCs). We found that the expression of the PRDX2 protein in atretic follicle GCs was markedly higher than in healthy follicle GCs. In vitro, the transfection of siRNA targeting the Prdx2 gene inhibited the proliferation and induced the apoptosis of primary cultured GCs. Furthermore, suppression of PRDX2 resulted in the augmentation of endogenous H(2)O(2), and the ability to eliminate the exogenous H(2)O(2) was attenuated. The expression of PRDX2 and nuclear factor kappa-light-chain-enhancer of activated B cells (NFKB), whose activity was inhibited by binding to IKB, increased in GCs treated with various concentrations of H(2)O(2) for 30 min. However, no significant change in cytoplasmic IKB expression was observed. At 2 h after treatment with H(2)O(2), nuclear NFKB expression level was reduced, cytoplasmic IKB expression was increased, and PRDX2 expression was unchanged. Silencing of the Prdx2 gene caused early changes in NFKB and IKB expression in the primary cultured GCs compared to that in control cells. Taken together, these data suggest that PRDX2 plays an important role in inhibiting apoptosis in GCs and that PRDX2 actions may be related to the expression of NFKB and IKB. PMID- 21248286 TI - Resveratrol modulates the expression of PTGS2 and cellular proliferation in the normal rat endometrium in an AKT-dependent manner. AB - Resveratrol (trans-3,4N-trihydroxystilbene), a phytoalexin present in grapes and red wine is emerging as a natural compound with anticancer properties. However, the physiological and molecular effects of resveratrol on normal uterine cells are poorly understood. In the present study we evaluated the effects of resveratrol on normal uterine cells and the mechanisms involved in vivo. Healthy immature rats were treated s.c. with resveratrol (0, 0.5, 5, and 50 mg/kg body weight) for 7 consecutive days and euthanized on the eighth day. Uteri were collected and weighed, and endometrium was recovered for total protein extraction, followed by Western blot analysis. Estrogen receptor alpha 1 (ESR1) and beta 2 (ESR2) affinity and activation by resveratrol were also determined by in vitro ESR-binding assays. Immunohistochemistry (IHC) studies were performed to visualize the proliferation marker, proliferating cell nuclear antigen (PCNA), and immunofluorescence (IF) studies were done to study the localization of PTGS2. The results showed that resveratrol increased uterine wet weight and uterine body weight ratios significantly. This local cellular proliferation in terms of the thickening of the columnar epithelial cells and an increase in the number of glands was accompanied by an increase of AKT 16 phosphorylation and PTGS2 and XIAP protein expression. These results were further supported by IF and IHC analyses. Total AKT, ESR1, and ESR2 protein expression levels were not modulated by the treatment; however, resveratrol showed moderate estrogenicity for both ESR isoforms. Expression of progesterone receptor A (PGR) was induced in the presence of resveratrol. These data support the hypothesis that resveratrol can act in a prosurvival or antiapoptotic way through AKT, XIAP, and PTGS2 regulation in the endometrium and could positively affect the outcome of pregnancy and favor fertility. PMID- 21248285 TI - Cervical softening during pregnancy: regulated changes in collagen cross-linking and composition of matricellular proteins in the mouse. AB - A greater understanding of the parturition process is essential in the prevention of preterm birth, which occurs in 12.7% of infants born in the United States annually. Cervical remodeling is a critical component of this process. Beginning early in pregnancy, remodeling requires cumulative, progressive changes in the cervical extracellular matrix (ECM) that result in reorganization of collagen fibril structure with a gradual loss of tensile strength. In the current study, we undertook a detailed biochemical analysis of factors in the cervix that modulate collagen structure during early mouse pregnancy, including expression of proteins involved in processing of procollagen, assembly of collagen fibrils, cross-link formation, and deposition of collagen in the ECM. Changes in these factors correlated with changes in the types of collagen cross-links formed and packing of collagen fibrils as measured by electron microscopy. Early in pregnancy there is a decline in expression of two matricellular proteins, thrombospondin 2 and tenascin C, as well as a decline in expression of lysyl hydroxylase, which is involved in cross-link formation. These changes are accompanied by a decline in both HP and LP cross-links by gestation Days 12 and 14, respectively, as well as a progressive increase in collagen fibril diameter. In contrast, collagen abundance remains constant over the course of pregnancy. We conclude that early changes in tensile strength during cervical softening result in part from changes in the number and type of collagen cross-links and are associated with a decline in expression of two matricellular proteins thrombospondin 2 and tenascin C. PMID- 21248287 TI - Zebrafish germline chimeras produced by transplantation of ovarian germ cells into sterile host larvae. AB - High frequency production of zebrafish germline chimeras was achieved by transplanting ovarian germ cells into sterile Danio hybrid recipients. Ovarian germ cells were obtained from 3-mo-old adult Tg(vasa:DsRed2-vasa);Tg(bactin:EGFP) double transgenic zebrafish by discontinuous Percoll gradient centrifugation. An average of 755 +/- 108 DsRed-positive germ cells was recovered from each female. For transplantations, a total of approximately 620 +/- 242 EGFP-positive cells of which 12 +/- 4.7 were DsRed-positive germ cells were introduced into the abdominal cavity under the swim bladder of 2-wk-old sterile hybrid larvae. Six weeks after transplantation, a total of 10 recipients, obtained from 2 different transplantations, were examined, and 2 individuals (20%) were identified that possessed a large number of DsRed- and EGFP-positive cells in the gonadal region. The transplanted ovarian germ cells successfully colonized the gonads and differentiated into sperm in the male hybrid recipients. Of 67 adult recipients, 12 (18%) male chimeric fish reproduced and generated normal offspring when paired with wild-type zebrafish females. The fertilization efficiency ranged from 23% to 56%. Although the fertile male chimeras were generated by transplantation of ovarian germ cells, the F1 generation produced by the male chimeras contained both male and female progeny, indicating that male sex determination in zebrafish is not controlled by sex chromosome heterogamy. Our findings indicate that a population of ovarian germ cells that are present in the ovary of adult zebrafish can function as germline stem cells, able to proliferate and differentiate into testicular germ cells and functional sperm in male recipients. The high frequency of germline chimera formation achieved with the ovarian germ cells and the convenience of identifying the chimeras in the sterile host background should make this transplantation system useful for performing genetic manipulations in zebrafish. PMID- 21248288 TI - Regulating DNA supercoiling: sperm points the way. PMID- 21248290 TI - Ovarian steroid receptors and activated MAPK in the regional decidualization in rats. AB - Though the decidua serves a critical function in implantation, the hormonal regulated pathway in decidualization is still elusive. Here we describe in detail the regional distribution and the effects of progesterone receptors (PGR), estrogen receptors (ESR), and MAPK activation on decidualization. We showed an increase in PGR A, PGR B, ESR1, and phosphorylated MAPK3-1 proteins (p-MAPK3-1), but not in ESR2, in the decidual tissue up to Day 8 of pregnancy. PGR was predominantly found in the nuclei of mesometrial decidual cells and of undifferentiated stromal cells where it colocalizes with ESR2 and ESR1. In the antimesometrial decidua, all the receptors showed cytoplasmic localization. MAPK was activated exclusively in undifferentiated stromal cells of the junctional zone between the antimesometrial and mesometrial decidua and at the border of the antimesometrial decidua. Treatment with the progesterone antagonist onapristone and/or the estrogen antagonist faslodex reduced the extent of decidual tissue and downregulated the levels of PGR and ESR1. The expression level of ESR2 was affected only by the progesterone receptor antagonist, while neither the antiprogestin nor the antiestrogen significantly modified the p-MAPK3-1 level. The inhibition of MAPK3-1 phosphorylation by PD98059 impaired the extent of decidualization and the closure reaction of the implantation chamber, and significantly downregulated ESR1. These results confirm a role of both steroid receptors in the growth and differentiation of the different decidual regions and suggest a new function for p-MAPK3-1 in regulating expression levels of ESR1, thereby maintaining the proliferation capacity of stromal cells and limiting the differentiation process in specified regions of decidual tissues. PMID- 21248289 TI - GATA4 deficiency impairs ovarian function in adult mice. AB - Transcription factor GATA4 is expressed in granulosa cells and, to a lesser extent, in other ovarian cell types. Studies of mutant mice have shown that interactions between GATA4 and its cofactor, ZFPM2 (also termed FOG2), are required for proper development of the fetal ovary. The role of GATA4 in postnatal ovarian function, however, has remained unclear, in part because of prenatal lethality of homozygous mutations in the Gata4 gene in mice. To circumvent this limitation, we studied ovarian function in two genetically engineered mouse lines: C57BL/6 (B6) female mice heterozygous for a Gata4-null allele, and 129;B6 female mice in which Gata4 is deleted specifically in proliferating granulosa cells using the Cre-loxP recombination system and Amhr2 cre. Female B6 Gata4(+/-) mice had delayed puberty but normal estrous cycle lengths and litter size. Compared to wild-type mice, the ovaries of gonadotropin stimulated B6 Gata4(+/-) mice were significantly smaller, released fewer oocytes, produced less estrogen, and expressed less mRNA for the putative GATA4 target genes Star, Cyp11a1, and Cyp19. Gata4 conditional knockout (cKO) mice had a more severe phenotype, including impaired fertility and cystic ovarian changes. Like Gata4(+/-) mice, the ovaries of gonadotropin-stimulated cKO mice released fewer oocytes and expressed less Cyp19 than those of control mice. Our findings, coupled with those of other investigators, support the premise that GATA4 is a key transcriptional regulator of ovarian somatic cell function in both fetal and adult mice. PMID- 21248291 TI - Regulation of the expression of proto-oncogenes by autocrine embryotropins in the early mouse embryo. AB - Autocrine embryotropins act as survival signals for the preimplantation embryo. In this study we examined the role of Paf in the transcription of the key proto oncogenes Bcl2 and Fos. Transcripts were detected in oocytes and some cohorts of zygotes but not in cohorts of 2-cell, 8-cell, and blastocyst stage embryos. Immunolocalization of BCL2 and FOS showed little staining in oocytes and zygotes but increased staining in the embryo from the 2-cell to blastocyst stage. Paf (37 nM) treatment of 2-cell embryos caused an alpha-amanitin (26 MUM)-sensitive increase in Bcl2 and Fos transcripts 20 min after treatment that subsided by 40 min. This increase was blocked by inhibition of calcium (by BAPTA-AM) or phosphatidylinositol-3-kinase signaling (by LY294002). Paf challenge also caused increased staining of BCL2 and FOS. Increased staining of FOS required new protein synthesis that had a half-life of 2-4 h after Paf challenge. Only a small proportion (~12%) of individual 2-cell embryos collected from the reproductive tract had detectable Bcl2 and Fos. This dichotomous pattern of transcript expression is consistent with the known periodic actions of Paf (which has a periodicity of ~90 min) and the relatively short half-life of the resulting transcripts. A BCL2 antagonist (HA14-1) caused a dose-dependent decrease in the capacity of cultured zygotes to develop to morphological blastocysts, which was partially reversed by the simultaneous addition of Paf to medium. The results show that Paf induces periodic transient transcriptions of key proto-oncogenes that result in the persistent presence of the resulting proteins in the preimplantation phase of development. PMID- 21248292 TI - Loss of methylation at H19 DMD is associated with biallelic expression and reduced development in cattle derived by somatic cell nuclear transfer. AB - Although cloning of mammals has been achieved successfully, the percentage of live offspring is very low because of reduced fetal size and fewer implantation sites. Recent studies have attributed such pathological conditions to abnormal reprogramming of the donor cell used for cloning. The inability of the oocyte to fully restore the differentiated status of a somatic cell to its pluripotent and undifferentiated state is normally evidenced by aberrant DNA methylation patterns established throughout the genome during development to blastocyst. These aberrant methylation patterns are associated with abnormal expression of imprinted genes, which among other genes are essential for normal embryo development and gestation. We hypothesized that embryo loss and low implantation rates in cattle derived by somatic cell nuclear transfer (SCNT) are caused by abnormal epigenetic reprogramming of imprinted genes. To verify our hypothesis, we analyzed the parental expression and the differentially methylated domain (DMD) methylation status of the H19 gene. Using a parental-specific analysis, we confirmed for the first time that H19 biallelic expression is tightly associated with a severe demethylation of the paternal H19 DMD in SCNT embryos, suggesting that these epigenetic anomalies to the H19 locus could be directly responsible for the reduced size and low implantation rates of cloned embryos in cattle. PMID- 21248293 TI - Dialysis practice and patient outcome in the aftermath of the earthquake at L'Aquila, Italy, April 2009. AB - BACKGROUND: In the aftermath of large natural and manmade disasters, the need for continuing maintenance haemodialysis (HD) in end-stage renal disease patients of the disaster area and care including dialysis for patients suffering from acute kidney injury (AKI) due to crush syndrome are the two most important nephrological problems. METHODS: We report on how renal patients and renal care personnel faced emergency in the aftermath of the earthquake that struck the Italian town of L'Aquila and a surrounding district, on Monday 6 April 2009, causing 308 deaths, some 1500 injured and 66,000 people to be displaced. RESULTS: The Dialysis Centre in the town did not collapse but was seriously damaged and out of action, making it necessary to move 88 patients on regular dialysis treatment to the closest available facilities to continue treatment. This was all the more urgent in that 45 patients of the Monday-Wednesday-Friday batch were coming off the long interdialytic interval, with possible medical problems (i.e. high increase in weight gain, blood pressure, etc.). In spite of manifold difficulties (including road interruption and shortage of means of transportation, problems in establishing contact between patients and care personnel due to failure of phone and electronic communication and the limited number of available dialysis posts), no patient missed any scheduled HD session. This was obtained thanks to the transfer of patients to neighbouring functioning units, often with extra dialysis shifts. In 3 days, a provisional Dialysis Centre was set up in an inflatable military-style tent, enabling 780 dialysis sessions to be performed safely on patients who had opted to return to L'Aquila. The tent facility was replaced by a rigid modular structure, insulated as living accommodation, containing 13 dialysis machines (20 from 17 November) functioning in HD or on-line haemodiafiltration. Ten cases of crush-related AKI needing dialysis treatment were recorded, the ratio of dialysed victims to number of deaths (32.4: 10 cases/308 deaths, 1000*) being the highest value yet reported. Fasciotomy was performed in six patients but none of the patients had to be amputated. Intermittent HD was used in most cases as the single modality of renal replacement therapy. All patients survived and recovered renal function on discontinuing dialysis treatment. Serum creatinine returned to normal values upon discharge from hospital or during the follow-up period. CONCLUSIONS: Each earthquake is different and may pose issues that will require unanticipated response efforts. Advance planning and rescue coordination, flexibility and creativity in the emergency situation, as well as the hard work and dedication of the entire dialysis care community, contributed to the remarkably positive outcome of dialysis-needing patients in the aftermath of the Aquila earthquake. PMID- 21248294 TI - Correlates of insulin resistance in older individuals with and without kidney disease. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with insulin resistance (IR). Prior studies have found that in individuals with CKD, leptin is associated with fat mass but resistin is not and the associations with adiponectin are conflicting. This suggests that the mechanism and factors associated with IR in CKD may differ. METHODS: Of the 2418 individuals without reported diabetes at baseline, participating in the Health, Aging and Body Composition study, a study in older individuals aged 70-79 years, 15.6% had CKD defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) based on cystatin C. IR was defined as the upper quartile of the homeostasis model assessment. The association of visceral and subcutaneous abdominal fat, percent body fat, muscle fat, lipids, inflammatory markers and adiponectin were tested with logistic regression. Interactions were checked to assess whether the factors associated with IR were different in those with and without CKD. RESULTS: Individuals with IR had a lower eGFR (80.7 +/- 20.9 versus 75.6 +/- 19.6, P < 0.001). After multivariable adjustment, eGFR (odds ratio per 10 mL/min/1.73 m(2) 0.92, 95% confidence interval 0.87-0.98) and CKD (1.41, 1.04-1.92) remained independently associated with IR. In individuals with and without CKD, the significant predictors of IR were male sex, black race, higher visceral fat, abdominal subcutaneous fat and triglycerides. In individuals without CKD, IR was associated with lower high-density lipoprotein and current nonsmoking status in multivariate analysis. In contrast, among individuals with CKD, interleukin-6 (IL-6) was independently associated with IR. There was a significant interaction of eGFR with race and IL-6 with a trend for adionectin but no significant interactions with CKD (P > 0.1). In the fully adjusted model, there was a trend for an interaction with adiponectin for eGFR (P = 0.08) and significant for CKD (P = 0.04 ), where adiponectin was associated with IR in those without CKD but not in those with CKD. CONCLUSIONS: In mainly Stage 3 CKD, kidney function is associated with IR; except for adiponectin, the correlates of IR are similar in those with and without CKD. PMID- 21248295 TI - Associations of blood lead with estimated glomerular filtration rate using MDRD, CKD-EPI and serum cystatin C-based equations. AB - BACKGROUND: Low-level lead exposure is widespread and has been implicated as a chronic kidney disease (CKD) risk factor. However, studies evaluating associations of lead dose with newer, potentially more accurate, estimates of kidney function, in participants with a wide range of glomerular filtration rates (GFRs), are scarce. METHODS: We compared associations of blood lead and estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and cystatin C single variable, multivariable and combined creatinine/cystatin C equations in 3941 adults who participated in the 1999-2002 National Health and Nutrition Examination Survey cystatin C subsample. RESULTS: Geometric mean blood lead was 1.7 MUg/dL. After multivariable adjustment, differences [95% confidence interval (CI)] in mean eGFR for a doubling of blood lead were -1.9 (-3.2, -0.7), -1.7 ( 3.0, -0.5) and -1.4 (-2.3, -0.5) mL/min/1.73 m(2), using the cystatin C single variable, multivariable and combined creatinine/cystatin C equations, respectively, reflecting lower eGFR with increased blood lead. The corresponding differences (95% CI) were -0.9 (-1.9, 0.02) and -0.9 (-1.8, 0.01) using the creatinine-based MDRD and CKD-EPI equations, respectively. In participants aged >=60 years, differences in mean eGFR ranged from -3.0 to -4.5 mL/min/1.73 m(2), and odds of reduced eGFR (<60 mL/min/1.73 m(2)) were increased for all estimates of GFR. CONCLUSIONS: These results support the inclusion of cystatin C-based eGFR in future lead research and provide additional evidence for environmental lead exposure as a CKD risk factor. PMID- 21248296 TI - Serum phosphate but not pulse wave velocity predicts decline in renal function in patients with early chronic kidney disease. AB - BACKGROUND: The rate of decline in kidney function is a powerful predictor of cardiovascular risk in patients with chronic kidney disease (CKD). Serum phosphate and increased arterial stiffness are associated with elevated cardiovascular risk in CKD and the general population. We sought to determine whether serum phosphate and markers of arterial stiffness predict progression of renal dysfunction in patients with early CKD. METHODS: Two hundred and twenty five patients with Stage II-IV CKD were prospectively followed up at University Hospital Birmingham. Serum phosphate was measured at baseline and arterial stiffness was determined through measurement of aortic pulse wave velocity (PWV) and augmentation index (AIx). Progression of renal dysfunction was defined as the slope of estimated glomerular filtration rate (eGFR) against time. We determined the associations between possible predictors and rate of progression and also examined a combined end point of start of dialysis or >= 25% decline in eGFR. RESULTS: Mean baseline eGFR was 43 +/- 19 mL/min/1.73 m(2) and serum phosphate 1.22 +/- 0.27 mmol/L. Median follow-up was 924 days. Serum phosphate independently predicted a greater decline in eGFR; a 1 mmol/L increment in serum phosphate was associated with a 0.34 mL/min/month steeper decline (P = 0.02). Brachial and aortic systolic pressure independently predicted the rate of renal function decline but aortic PWV and AIx had no significant influence. Forty-one patients (18%) reached the combined end point; serum phosphate was significantly higher in this group (1.32 +/- 0.36 versus 1.19 +/- 0.24 mmol/L, P = 0.04) and was an independent predictor for the combined end point. CONCLUSIONS: Serum phosphate independently predicts decline in renal function in early CKD. Further studies are required to determine the mechanisms involved and to investigate the potential benefits of phosphate lowering on preserving kidney function. PMID- 21248297 TI - Overexpression of miR-200c induces chemoresistance in esophageal cancers mediated through activation of the Akt signaling pathway. AB - PURPOSE: To determine the relationship between resistance to chemotherapy and microRNA (miRNA) expression in esophageal cancer, we focused on miRNAs known to be associated with maintenance of stem cell function. EXPERIMENTAL DESIGN: Using 98 formalin-fixed, paraffin-embedded samples obtained from patients with esophageal cancer who had received preoperative chemotherapy followed by surgery, we measured expression levels of several miRNAs that are considered to be involved in the regulation of stem cell function (e.g., let-7a, let-7g, miR-21, miR-134, miR-145, miR-155, miR-200c, miR-203, and miR-296) by real-time reverse transcriptase PCR. Then, we examined the relationship between miRNA expression and prognosis or response to chemotherapy. To investigate the mechanism of miRNA induced chemoresistance, in vitro assays were carried out using esophageal cancer cells. RESULTS: Analyses of the 9 miRNAs expression showed that overexpression of miR-200c (P = 0.037), underexpression of miR-145 (P = 0.023), and overexpression of miR-21 (P = 0.048) correlated significantly with shortened overall duration of survival. In particular, miR-200c expression correlated significantly with response to chemotherapy (P = 0.009 for clinical response; P = 0.007 for pathologic response). In vitro assay showed significantly increased miR-200c expression in cisplatin-resistant cells compared with their parent cells (~1.7 fold). In anti-miR-200c-transfected cells, chemosensitivity to cisplatin and apoptosis after exposure to cisplatin was found to increase as compared with the negative control. Western blotting showed that knockdown of miR-200c expression was associated with increased expression of PPP2R1B, a subunit of protein phosphatase 2A, which resulted in reduced expression of phospho-Akt. CONCLUSIONS: Results of this study emphasized the involvement of miR-200c in resistance to chemotherapy among esophageal cancers and that this effect was mediated through the Akt pathway. PMID- 21248298 TI - Association of IFN-gamma signal transduction defects with impaired HLA class I antigen processing in melanoma cell lines. AB - PURPOSE: Abnormalities in the constitutive and IFN-gamma-inducible HLA class I surface antigen expression of tumor cells is often associated with an impaired expression of components of the antigen processing machinery (APM). Hence, we analyzed whether there exists a link between the IFN-gamma signaling pathway, constitutive HLA class I APM component expression, and IFN-gamma resistance. EXPERIMENTAL DESIGN: The basal and IFN-gamma-inducible expression profiles of HLA class I APM and IFN-gamma signal transduction cascade components were assessed in melanoma cells by real-time PCR (RT-PCR), Western blot analysis and/or flow cytometry, the integrity of the Janus activated kinase (JAK) 2 locus by comparative genomic hybridization. JAK2 was transiently overexpressed in JAK2(-) cells. The effect of IFN-gamma on the cell growth was assessed by XTT [2,3-bis(2 methoxy-4-nitro-S-sulfophenynl)-H-tetrazolium-5-carboxanilide inner salt] assay. RESULTS: The analysis of 8 melanoma cell lines linked the IFN-gamma unresponsiveness of Colo 857 cells determined by lack of inducibility of HLA class I surface expression on IFN-gamma treatment to a deletion of JAK2 on chromosome 9, whereas other IFN-gamma signaling pathway components were not affected. In addition, the constitutive HLA class I APM component expression levels were significantly reduced in JAK2(-) cells. Furthermore, JAK2-deficient cells were also resistant to the antiproliferative effect of IFN-gamma. Transfection of wild-type JAK2 into JAK2(-) Colo 857 not only increased the basal APM expression but also restored their IFN-gamma sensitivity. CONCLUSIONS: Impaired JAK2 expression in melanoma cells leads to reduced basal expression of MHC class I APM components and impairs their IFN-gamma inducibility, suggesting that malfunctional IFN-gamma signaling might cause HLA class I abnormalities. PMID- 21248299 TI - New strategies in HER2-overexpressing breast cancer: many combinations of targeted drugs available. AB - The anti-HER2 drugs trastuzumab and lapatinib are increasingly changing the natural history of early and metastatic HER2-overexpressing breast cancer. Many other agents targeted against the HER2 signaling network are in clinical development, and these are or will soon be combined with the currently approved anti-HER2 therapies. We review herein recent data in support of the early use of combinations of agents targeted to the HER2 network as the most rational approach against this subtype of breast cancer. We propose that the optimal combination or combinations of anti-HER2 agents delivered early in the natural history of HER2+ breast cancer should close to eliminate acquired drug resistance, shorten the duration of therapy, and potentially dispense with the need of concurrent chemotherapy. PMID- 21248300 TI - Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) mutation T790M is reported in approximately 50% of lung cancers with acquired resistance to EGFR inhibitors and is a potential prognostic and predictive biomarker. Its assessment can be challenging due to limited tissue availability and underdetection at low mutant allele levels. Here, we sought to determine the feasibility of tumor rebiopsy and to more accurately assess the prevalence of the T790M using a highly sensitive locked nucleic acid (LNA) PCR/sequencing assay. MET amplification was also analyzed. METHODS: Patients with acquired resistance were rebiopsied and samples were studied for sensitizing EGFR mutations. Positive cases were evaluated for T790M using standard PCR-based methods and a subset were re evaluated with an LNA-PCR/sequencing method with an analytical sensitivity of approximately 0.1%. MET amplification was assessed by FISH. RESULTS: Of 121 patients undergoing tissue sampling, 104 (86%) were successfully analyzed for sensitizing EGFR mutations. Most failures were related to low tumor content. All patients (61/61) with matched pretreatment and resistance specimens showed concordance for the original sensitizing EGFR mutation. Standard T790M mutation analysis on 99 patients detected 51(51%) mutants. Retesting of 30 negative patients by the LNA-based method detected 11 additional mutants for an estimated prevalence of 68%. MET was amplified in 11% of cases (4/37). CONCLUSIONS: The re biopsy of lung cancer patients with acquired resistance is feasible and provides sufficient material for mutation analysis in most patients. Using high sensitivity methods, the T790M is detected in up to 68% of these patients. PMID- 21248301 TI - Distinct p53 gene signatures are needed to predict prognosis and response to chemotherapy in ER-positive and ER-negative breast cancers. AB - PURPOSE: Estrogen receptor-positive (ER+) and -negative (ER) breast cancers are molecularly distinct diseases. We hypothesized that p53 mutations may lead to different transcriptional changes and carry different prognostic value in these two different types of cancers. EXPERIMENTAL DESIGN: We developed a 39-gene p53 signature derived from 213 ER+ and a separate 30-gene signature from 38 ER- cancers with known mutation status and tested their prognostic and chemotherapy response predictive values in ER+ and ER- cancers, respectively. RESULTS: External validation to predict p53 status (n = 103) showed sensitivity and specificity of 89% and 54% for the 39-gene signature, and 82% and 61% for the 30 gene signature. The 39-gene signature was predictive of worse distant metastasis free survival in ER+ cancers in two separate prognostic data sets (n = 255, HR: 2.3, P = 0.005 and n = 198, HR: 2.17, P = 0.09). It also predicted for poor prognosis even with adjuvant tamoxifen therapy (n = 277, HR = 2.43, P < 0.0001) but it was not prognostic in ER- cancers. It was also associated with higher chemotherapy sensitivity in ER+ but not in ER- cancers. The prognostic and predictive values remained significant in multivariate analysis. The 30-gene, ER , p53 signature showed no prognostic or predictive values in ER+ cancers but it was associated with better prognosis in ER- cancers. It also had no chemotherapy response predictive value in ER- or ER+ cancers. CONCLUSIONS: P53 dysfunction is prognostically most relevant in ER+ cancers and supports the hypothesis that different predictive or prognostic markers will be needed for different molecular subsets of breast cancer. PMID- 21248302 TI - Modulators of arginine metabolism do not impact on peripheral T-cell tolerance and disease progression in a model of spontaneous prostate cancer. AB - PURPOSE: Chronic inflammation, recruitment of myeloid-derived cells, and perturbation of the arginine metabolism have been all proposed as mechanisms favoring prostate carcinogenesis and tumor immunoescape. Objective of this study was to evaluate whether accumulation of CD11b(+)Gr1(+) cells, also defined myeloid-derived suppressor cells, occur in mice affected by transplantable or spontaneous prostate cancer (PC). We also investigated whether N(G) nitro-L arginine methyl ester (L-NAME) and sildenafil, both modulators of the arginine metabolism, restrain tumor growth and restore tumor-specific immunity. EXPERIMENTAL DESIGN: Wild-type C57BL/6 mice bearing TRAMP-C1 PC and transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were treated with vehicle, L NAME or sildenafil, and evaluated for CD11b(+) cells accumulation in the blood, several organs, and the tumor mass and for disease progression. RESULTS: CD11b(+)Gr1(high), CD11b(+)Gr1(int), and CD11b(+)Gr1(-) cells differently accumulated in different organs and especially in the tumor of the two mouse models. L-NAME and sildenafil impaired the immunosuppressive function of CD11b(+) cells in both models and restrained TRAMP-C1 growth, but they neither break tumor specific immune tolerance nor limit tumor progression in TRAMP mice. CONCLUSIONS: Collectively, our results emphasize substantial differences in tumor-induced alteration of myelopoiesis and sensitivity to modulators of the arginine metabolism between a transplantable and a spontaneous model of PC. They also suggest that perturbation of the arginine metabolism is dispensable for PC progression and the associated T-cell tolerance. PMID- 21248303 TI - Phase I/II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib. AB - PURPOSE: In patients with epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma, treatment with erlotinib or gefitinib is associated with a 75% radiographic response rate and progression-free survival of approximately 12 months. The most common mechanism of acquired resistance to erlotinib is development of a secondary mutation in EGFR, suggesting that these tumors continue to depend on EGFR signaling. We hypothesized that combined EGFR blockade would overcome acquired resistance to erlotinib in patients with lung adenocarcinoma. To evaluate the toxicity and efficacy of cetuximab and erlotinib in patients with acquired resistance to erlotinib, we conducted this phase I/II clinical trial. EXPERIMENTAL DESIGN: Patients with lung adenocarcinoma and clinically defined acquired resistance to erlotinib were treated with erlotinib 100 mg daily, along with cetuximab every 2 weeks in three escalating dose cohorts (250 mg/m(2), 375 mg/m(2), and 500 mg/m(2)). The recommended phase II dose was then evaluated in a two-stage trial, with a primary end point of objective response rate. RESULTS: A total of 19 patients were enrolled. The most common toxicities for the combination of cetuximab and erlotinib were rash, fatigue, and hypomagnesemia. The recommended phase II dose identified was cetuximab 500 mg/m(2) every 2 weeks and erlotinib 100 mg daily. At this dose and schedule, no radiographic responses were seen (0 of 13, 0%, 95% CI, 0-25). CONCLUSIONS: Combined EGFR inhibition, with cetuximab 500 mg/m(2) every 2 weeks and erlotinib 100 mg daily, had no significant activity in patients with acquired resistance to erlotinib. PMID- 21248304 TI - Immortalized neurons for the study of hypothalamic function. AB - The hypothalamus is a vital part of the central nervous system: it harbors control systems implicated in regulation of a wide range of homeostatic processes, including energy balance and reproduction. Structurally, the hypothalamus is a complex neuroendocrine tissue composed of a multitude of unique neuronal cell types that express a number of neuromodulators, including hormones, classical neurotransmitters, and specific neuropeptides that play a critical role in mediating hypothalamic function. However, neuropeptide and receptor gene expression, second messenger activation, and electrophysiological and secretory properties of these hypothalamic neurons are not yet fully defined, primarily because the heterogeneity and complex neuronal architecture of the neuroendocrine hypothalamus make such studies challenging to perform in vivo. To circumvent this problem, our research group recently generated embryonic- and adult-derived hypothalamic neuronal cell models by utilizing the novel molecular techniques of ciliary neurotrophic factor-induced neurogenesis and SV40 T antigen transfer to primary hypothalamic neuronal cell cultures. Significant research with these cell lines has demonstrated their value as a potential tool for use in molecular genetic analysis of hypothalamic neuronal function. Insights gained from hypothalamic immortalized cells used in conjunction with in vivo models will enhance our understanding of hypothalamic functions such as neurogenesis, neuronal plasticity, glucose sensing, energy homeostasis, circadian rhythms, and reproduction. This review discusses the generation and use of hypothalamic cell models to study mechanisms underlying the function of individual hypothalamic neurons and to gain a more complete understanding of the overall physiology of the hypothalamus. PMID- 21248305 TI - Shape of glucose, insulin, C-peptide curves during a 3-h oral glucose tolerance test: any relationship with the degree of glucose tolerance? AB - We aimed to analyze the shape of the glucose, insulin, and C-peptide curves during a 3-h oral glucose tolerance test (OGTT). Another aim was defining an index of shape taking into account the whole OGTT pattern. Five-hundred ninety two OGTT curves were analyzed, mainly from women with former gestational diabetes, with glycemic concentrations characterized by normal glucose tolerance (n = 411), impaired glucose metabolism (n = 134), and Type 2 diabetes (n = 47). Glucose curves were classified according to their shape (monophasic, biphasic, triphasic, and 4/5-phases), and the metabolic condition of the subjects, divided according to the glucose shape stratification, was analyzed. Indices of shape based on the discrete second-order derivative of the curve patterns were also defined. We found that the majority of the glucose curves were monophasic (n = 262). Complex shapes were less frequent but not rare (n = 37 for the 4/5-phases shape, i.e., three peaks). There was a tendency toward the amelioration of the metabolic condition for increasing complexity of the shape, as indicated by lower glucose concentrations, improved insulin sensitivity and beta-cell function. The shape index computed on C-peptide, WHOSH(CP) (WHole-Ogtt-SHape-index-C-peptide), showed a progressive increase [monophasic: 0.93 +/- 0.04 (dimensionless); 4/5 phases: 1.35 +/- 0.14], and it showed properties typical of beta-cell function indices. We also found that the type of glucose shape is often associated to similar insulin and C-peptide shape. In conclusion, OGTT curves can be characterized by high variability, and complex OGTT shape is associated with better glucose tolerance. WHOSH(CP) (WHole-Ogtt-SHape-index) may be a powerful index of beta-cell function much simpler than model-based indices. PMID- 21248306 TI - Factors that render the kidney susceptible to tissue hypoxia in hypoxemia. AB - To better understand what makes the kidney susceptible to tissue hypoxia, we compared, in the rabbit kidney and hindlimb, the ability of feedback mechanisms governing oxygen consumption (Vo(2)) and oxygen delivery (Do(2)) to attenuate tissue hypoxia during hypoxemia. In the kidney (cortex and medulla) and hindlimb (biceps femoris muscle), we determined responses of whole organ blood flow and Vo(2), and local perfusion and tissue Po(2), to reductions in Do(2) mediated by graded systemic hypoxemia. Progressive hypoxemia reduced tissue Po(2) similarly in the renal cortex, renal medulla, and biceps femoris. Falls in tissue Po(2) could be detected when arterial oxygen content was reduced by as little as 4-8%. Vo(2) remained stable during progressive hypoxemia, only tending to fall once arterial oxygen content was reduced by 55% for the kidney or 42% for the hindlimb. Even then, the fall in renal Vo(2) could be accounted for by reduced oxygen demand for sodium transport rather than limited oxygen availability. Hindlimb blood flow and local biceps femoris perfusion increased progressively during graded hypoxia. In contrast, neither total renal blood flow nor cortical or medullary perfusion was altered by hypoxemia. Our data suggest that the absence in the kidney of hyperemic responses to hypoxia, and the insensitivity of renal Vo(2) to limited oxygen availability, contribute to kidney hypoxia during hypoxemia. The susceptibility of the kidney to tissue hypoxia, even in relatively mild hypoxemia, may have important implications for the progression of kidney disease, particularly in patients at high altitude or with chronic obstructive pulmonary disease. PMID- 21248307 TI - House sparrows (Passer domesticus) increase protein catabolism in response to water restriction. AB - Birds primarily rely on fat for energy during fasting and to fuel energetically demanding activities. Proteins are catabolized supplemental to fat, the function of which in birds remains poorly understood. It has been proposed that birds may increase the catabolism of body protein under dehydrating conditions as a means to maintain water balance, because catabolism of wet protein yields more total metabolic and bound water (0.155.H(2)O(-1).kJ(-1)) than wet lipids (0.029 g.H(2)O(-1).kJ(-1)). On the other hand, protein sparing should be important to maintain function of muscles and organs. We used quantitative magnetic resonance body composition analysis and hygrometry to investigate the effect of water restriction on fat and lean mass catabolism during short-term fasting at rest and in response to a metabolic challenge (4-h shivering) in house sparrows (Passer domesticus). Water loss at rest and during shivering was compared with water gains from the catabolism of tissue. At rest, water-restricted birds had significantly greater lean mass loss, higher plasma uric acid concentration, and plasma osmolality than control birds. Endogenous water gains from lean mass catabolism offset losses over the resting period. Water restriction had no effect on lean mass catabolism during shivering, as water gains from fat oxidation appeared sufficient to maintain water balance. These data provide direct evidence supporting the hypothesis that water stress can increase protein catabolism at rest, possibly as a metabolic strategy to offset high rates of evaporative water loss. PMID- 21248308 TI - Maternal diabetes increases large conductance Ca2+-activated K+ outward currents that alter action potential properties but do not contribute to attenuated excitability of parasympathetic cardiac motoneurons in the nucleus ambiguus of neonatal mice. AB - Previously, we demonstrated that maternal diabetes reduced the excitability and increased small-conductance Ca(2+)-activated K(+) (SK) currents of parasympathetic cardiac motoneurons (PCMNs) in the nucleus ambiguus (NA). In addition, blockade of SK channels with apamin completely abolished this reduction. In the present study, we examined whether maternal diabetes affects large-conductance Ca(2+)-activated K(+) (BK) channels and whether BK channels contribute to the attenuation of PCMN excitability observed in neonates of diabetic mothers. Neonatal mice from OVE26 diabetic mothers (NMDM) and normal FVB mothers (control) were used. The pericardial sac of neonatal mice at postnatal days 7-9 was injected with the tracer X-rhodamine-5 (and 6)-isothiocyanate 2 days prior to the experiment to retrogradely label PCMNs in the NA. Whole cell current and voltage-clamps were used to measure spike frequency, action potential (AP) repolarization (half-width), afterhyperpolarization potential (AHP), transient outward currents, and afterhyperpolarization currents (I(AHP)). In whole cell voltage clamp mode, we confirmed that maternal diabetes increased transient outward currents and I(AHP) compared with normal cells. Using BK channel blockers charybdotoxin (CTx) and paxilline, we found that maternal diabetes increased CTx- and paxilline-sensitive transient outward currents but did not change CTx- and paxilline-sensitive I(AHP). In whole cell current-clamp mode, we confirmed that maternal diabetes increased AP half-width and AHP, and reduced excitability of PCMNs. Furthermore, we found that after blockade of BK channels with CTx or paxilline, maternal diabetes induced a greater increase of AP half-width but similarly decreased fast AHP without affecting medium AHP. Finally, blockade of BK channels decreased spike frequency in response to current injection in both control and NMDM without reducing the difference of spike frequency between the two groups. Therefore, we conclude that although BK transient outward currents, which may alter AP repolarization, are increased in NMDM, BK channels do not directly contribute to maternal diabetes-induced attenuation of PCMN excitability. In contrast, based on evidence from our previous and present studies, reduction of PCMN excitability in neonates of diabetic mothers is largely dependent on altered SK current associated with maternal diabetes. PMID- 21248309 TI - Metabolic and functional differences between brain and spinal cord mitochondria underlie different predisposition to pathology. AB - Mitochondrial dysfunctions contribute to neurodegeneration, the locations of which vary among neurodegenerative diseases. To begin to understand what mechanisms may underlie higher vulnerability of the spinal cord motor neurons in amyotrophic lateral sclerosis, compared with brain mitochondria, we studied three major functions of rat brain mitochondria (BM) and spinal cord mitochondria (SCM) mitochondria: oxidative phosphorylation, Ca(2+) sequestration, and production of reactive oxygen species (ROS), using a new metabolic paradigm (Panov et al., J. Biol. Chem. 284: 14448-14456, 2009). We present data that SCM share some unique metabolic properties of the BM. However, SCM also have several distinctions from the BM: 1) With the exception of succinate, SCM show significantly lower rates of respiration with all substrates studied; 2) immunoblotting analysis showed that this may be due to 30-40% lower contents of respiratory enzymes and porin; 3) compared with BM, SCM sequestered 40-50% less Ca(2+), and the total tissue calcium content was 8 times higher in the spinal cord; 4) normalization for mitochondria from 1 g of tissue showed that BM can sequester several times more Ca(2+) than was available in the brain tissue, whereas SCM had the capacity to sequester only 10-20% of the total tissue Ca(2+); and 5) with succinate and succinate-containing substrate mixtures, SCM showed significantly higher state 4 respiration than BM and generated more ROS associated with the reverse electron transport. We conclude that SCM have an intrinsically higher risk of oxidative damage and overload with calcium than BM, and thus spinal cord may be more vulnerable under some pathologic conditions. (250). PMID- 21248310 TI - Examining overweight and obesity as risk factors for common mental disorders using fat mass and obesity-associated (FTO) genotype-instrumented analysis: The Whitehall II Study, 1985-2004. AB - The Mendelian randomization approach exploits genetic variants to improve causal inference when using observational data. The authors examined the relation between long-term obesity and common mental disorders (CMD) by utilizing the known relation between fat mass and obesity-associated (FTO) genotype and body mass index (BMI; weight (kg)/height (m)(2)). Data collection in 2,981 men and 1,164 women (mean age at baseline = 44 years) from the Whitehall II Study (London, United Kingdom) included 4 repeated examinations of BMI and CMD over a 19-year follow-up period (1985-2004), plus an assessment of FTO polymorphism rs1421085. In men, there was an association of FTO genotype with all measures of adiposity (mean BMI, number of times obese, and, in nonobese persons, number of times overweight). FTO was also associated with CMD in men. This was independent of adiposity, thus potentially violating the exclusion restriction assumption. According to both conventional and FTO-instrumented regression analysis, measurement of obesity was associated with an increased occurrence of CMD. In the FTO-instrumented analysis only, higher BMI and overweight were also associated with CMD. In women, there was no link between FTO and adiposity. Mendelian randomization analyses supported the status of long-term obesity as a risk factor for CMD in men-a finding that should be interpreted cautiously because the function of the FTO gene is unknown. PMID- 21248312 TI - "Creating hope" and other incentives for drug development for children. AB - Enhancing drug development for pediatric disease is a priority and a public responsibility. The Creating Hope Act of 2010 is important new proposed legislation that adds drugs and biologics for treating rare diseases in children to those for neglected tropical diseases as eligible for a priority review voucher from the U.S. Food and Drug Administration. The Act enhances existing incentive programs through specific financial benefits to companies who seek a pediatric indication for a new drug to treat an orphan disease that occurs specifically in children. PMID- 21248311 TI - Serum 25-hydroxyvitamin D and risks of colon and rectal cancer in Finnish men. AB - Prospective investigations of circulating vitamin D concentrations suggest inverse associations with colorectal cancer risk, although inconsistencies remain and few studies have examined the impact of season. The authors conducted a prospective case-control study of 239 colon cancer cases and 192 rectal cancer cases (diagnosed in 1993-2005) and 428 controls matched on age and blood collection date within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, a cohort study of Finnish male smokers. Baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations were categorized using a priori defined cutpoints of <25, 25-<37.5, 37.5-<50, 50-<75, and >=75 nmol/L and by season-specific and season-standardized 25(OH)D quartiles. Conditional logistic regression models yielded multivariate-adjusted odds ratios for the predefined cutpoints of 0.63, 0.91, 0.73, 1.00 (referent), and 1.44 for colon cancer and 0.64, 0.58, 0.84, 1.00, and 0.76 for rectal cancer, respectively (all 95% confidence intervals included 1.00). Colon cancer risks were significantly elevated for the highest season-specific and season-standardized quartiles versus the lowest quartiles (OR = 2.11 (95% CI: 1.20, 3.69) and OR = 1.88 (95% CI: 1.07, 3.28), respectively), while rectal cancer risk estimates were null. These results provide no evidence to support an inverse association between vitamin D status and colon or rectal cancer risk; instead, they suggest a positive association for colon cancer. PMID- 21248314 TI - Leukotriene inflammatory mediators meet their match. AB - Leukotrienes are arachidonic acid-derived lipid mediators of inflammation. The initial catalytic step in the formation of leukotrienes is catalyzed by 5 lipoxygenase (5-LOX) in conjunction with its activating partner protein FLAP. The long-awaited crystal structure of 5-LOX--reported in a recent issue of Science- should lead to novel, purpose-designed inhibitors for the treatment of asthma and for probing leukotriene involvement in cardiovascular disease and cancer. PMID- 21248315 TI - Stromal endothelial cells directly influence cancer progression. AB - Cancer growth and metastasis are regulated in part by stromal cells such as fibroblasts and immune cells within the tumor microenvironment. Endothelial cells (ECs) are also ubiquitous within tumors because tumors are vascular, and yet, the impact of tumor-resident ECs is less well understood. Through paracrine regulation, ECs modulate a diverse spectrum of pathophysiologic processes in normal and hyperplastic tissues. We hypothesized that ECs offer similar paracrine regulatory control of cancer biology. Indeed, secretions from quiescent ECs muted the proliferative and invasive phenotype of lung and breast cancer cells in vitro and reduced cancer cell protumorigenic and proinflammatory signaling. EC perlecan silencing significantly changed this regulatory relationship, eliminating the ability of ECs to inhibit cancer cell invasiveness via increased interleukin-6 secretion. Moreover, implanting ECs embedded within porous matrices slowed adjacent xenograft tumor growth and prevented architectural degeneration, with a concomitant reduction in proliferative and tumorigenic markers. Finally, lung carcinoma cells pretreated with intact EC-conditioned media, but not media conditioned with perlecan-silenced ECs, exhibited reduced micrometastatic burden after tail vein injection. These findings add to an emerging appreciation of EC regulatory effects that transcend their structural roles and pave the way for improved characterization and control of EC-cancer cross-talk interactions for diagnosis, prognosis, and treatment of cancer. PMID- 21248316 TI - An aptamer-siRNA chimera suppresses HIV-1 viral loads and protects from helper CD4(+) T cell decline in humanized mice. AB - Therapeutic strategies designed to treat HIV infection with combinations of antiviral drugs have proven to be the best approach for slowing the progression to AIDS. Despite this progress, there are problems with viral drug resistance and toxicity, necessitating new approaches to combating HIV-1 infection. We have therefore developed a different combination approach for the treatment of HIV infection in which an RNA aptamer, with high binding affinity to the HIV-1 envelope (gp120) protein and virus neutralization properties, is attached to and delivers a small interfering RNA (siRNA) that triggers sequence-specific degradation of HIV RNAs. We have tested the antiviral activities of these chimeric RNAs in a humanized Rag2(-/-)gammac(-/-) (RAG-hu) mouse model with multilineage human hematopoiesis. In this animal model, HIV-1 replication and CD4(+) T cell depletion mimic the situation seen in human HIV-infected patients. Our results show that treatment with either the anti-gp120 aptamer or the aptamer siRNA chimera suppressed HIV-1 replication by several orders of magnitude and prevented the viral-induced helper CD4(+) T cell decline. In comparison to the aptamer alone, the aptamer-siRNA combination provided more extensive inhibition, resulting in a significantly longer antiviral effect that extended several weeks beyond the last injected dose. The aptamer thus acts as a broad-spectrum HIV neutralizing agent and an siRNA delivery vehicle. The combined aptamer-siRNA agent provides an attractive, nontoxic therapeutic approach for treatment of HIV infection. PMID- 21248317 TI - Multiple sclerosis prevalence in Ireland: relationship to vitamin D status and HLA genotype. AB - BACKGROUND: The relationship between prevalence of multiple sclerosis (MS) and latitude may be due to both genetic and environmental factors. The hypothesis that, in Ireland, MS prevalence is increasing and that north-south differences relate to variation in serum 25-hydroxyvitamin D (25(OH)D) levels was tested in this study. PATIENTS AND METHODS: Patients and matched control subjects were identified in counties Donegal, Wexford and South Dublin through multiple sources. Prevalence was determined. Blood samples were taken for serum 25(OH)D and serum intact parathyroid hormone measurement, and DNA was extracted. RESULTS: Prevalence in 2007 was significantly greater in Donegal (northwest) (290.3/105, 95% CI 262.3 to 321.7) compared with 2001 (184.6/105; 162 to 209.5). In Wexford (southeast), there was a non-significant increase in prevalence in 2007 compared with 2001. Prevalence was significantly higher in Donegal than in Wexford (144.8/105; 126.7 to 167.8, p<0.0001) and South Dublin (127.8/105; 111.3 to 148.2, p<0.0001). Overall, mean 25(OH)D levels were low and did not differ between patients (38.6 nmol/l) and controls (36.4 nmol/l) However, significantly more patients than controls had 25(OH)D levels <25 nmol/l (deficiency) (p=0.004). Levels of 25(OH)D (mean 50.74 nmol/l) were significantly higher in South Dublin (area with lowest prevalence) (p<0.0001) than in Donegal or Wexford. HLA DRB1*15 occurred most frequently in Donegal (greatest MS prevalence) and least frequently in South Dublin. CONCLUSION: Vitamin D deficiency is common in Ireland. Latitudinal variation in MS probably relates to an interaction between genetic factors and environment (25(OH)D levels), and MS risk may be modified by vitamin D in genetically susceptible individuals. PMID- 21248319 TI - Cytokeratin (CK7 and CK20) switching in the natural history of pulmonary small cell carcinoma: an interesting but unpublished phenomenon. PMID- 21248318 TI - Genotype-phenotype study of familial haemophagocytic lymphohistiocytosis type 3. AB - BACKGROUND: Mutations of UNC13D are causative for familial haemophagocytic lymphohistiocytosis type 3 (FHL3; OMIM 608898). OBJECTIVE: To carry out a genotype-phenotype study of patients with FHL3. METHODS: A consortium of three countries pooled data on presenting features and mutations from individual patients with biallelic UNC13D mutations in a common database. RESULTS: 84 patients with FHL3 (median age 4.1 months) were reported from Florence, Italy (n=54), Hamburg, Germany (n=18), Stockholm, Sweden (n=12). Their ethnic origin was Caucasian (n=57), Turkish (n=10), Asian (n=7), Hispanic (n=4), African (n=3) (not reported (n=3)). Thrombocytopenia was present in 94%, splenomegaly in 96%, fever in 89%. The central nervous system (CNS) was involved in 49/81 (60%) patients versus 36% in patients with FHL2 (p=0.001). A combination of fever, splenomegaly, thrombocytopenia and hyperferritinaemia was present in 71%. CD107a expression, NK activity and Munc 13-4 protein expression were absent or reduced in all but one of the evaluated patients. 54 different mutations were observed, including 15 new ones: 19 missense, 14 deletions or insertions, 12 nonsense, nine splice errors. None was specific for ethnic groups. Patients with two disruptive mutations were younger than patients with two missense mutations (p<0.001), but older than comparable patients with FHL2 (p=0.001). CONCLUSION: UNC13D mutations are scattered over the gene. Ethnic-specific mutations were not identified. CNS involvement is more common than in FHL2; in patients with FHL3 and disruptive mutations, age at diagnosis is significantly higher than in FHL2. The combination of fever, splenomegaly, thrombocytopenia and hyperferritinaemia appears to be the most easily and frequently recognised clinical pattern and their association with defective granule release assay may herald FHL3. PMID- 21248320 TI - Combined pulmonary fibrosis and emphysema syndrome associated with familial SFTPC mutation. PMID- 21248321 TI - Towards individualised treatment in COPD. PMID- 21248322 TI - Respiratory disease associated with solid biomass fuel exposure in rural women and children: systematic review and meta-analysis. AB - BACKGROUND: Numerous studies with varying associations between domestic use of solid biomass fuels (wood, dung, crop residue, charcoal) and respiratory diseases have been reported. OBJECTIVE: To present the current data systematically associating use of biomass fuels with respiratory outcomes in rural women and children. METHODS: Systematic searches were conducted in 13 electronic databases. Data were abstracted from original articles that satisfied selection criteria for meta-analyses. Publication bias and heterogeneity of samples were tested. Studies with common diagnoses were analysed using random-effect models. RESULTS: A total of 2717 studies were identified. Fifty-one studies were selected for data extraction and 25 studies were suitable for meta-analysis. The overall pooled ORs indicate significant associations with acute respiratory infection in children (OR 3.53, 95% CI 1.94 to 6.43), chronic bronchitis in women (OR 2.52, 95% CI 1.88 to 3.38) and chronic obstructive pulmonary disease in women (OR 2.40, 95% CI 1.47 to 3.93). In contrast, no significant association with asthma in children or women was noted. CONCLUSION: Biomass fuel exposure is associated with diverse respiratory diseases in rural populations. Concerted efforts in improving stove design and lowering exposure to smoke emission may reduce respiratory disease associated with biomass fuel exposure. PMID- 21248323 TI - Pathology peer review. PMID- 21248324 TI - Response to International recommendations for training future toxicologic pathologists participating in regulatory-type, nonclinical toxicity studies by Bolon et. al. PMID- 21248325 TI - Does access to open water affect the health of Pekin ducks (Anas platyrhynchos)? AB - Access to open water is considered good for the welfare of Pekin ducks. These studies investigated the effect that the type of water resource, provided over either straw bedding or a rubber mesh, had on measures of duck health. Pekin strain ducklings (n = 2,600) were managed in pens of 100 on straw over a solid concrete floor. In study 1, one of two water resources (nipple, n = 5 pens; wide lip bell drinker, n = 5 pens), was located directly over the straw. In study 2, one of three water resources (narrow-lip bell drinker, n = 6 pens; trough, n = 5 pens; and bath, n = 5 pens) was located over a rubber mesh. On d 16, 24, 29, 35, and 43, (study 1) or d 21, 29, 35, and 43 posthatch (study 2), 10 birds were selected from each pen and weighed, and then feather hygiene, footpad dermatitis, eye health, gait score, and nostril condition scores were taken. Treatment had no effect on BW in either study, but in study 2, ducks in the open water treatments had higher scores (P < 0.001) than those in the narrow-lip bell drinker treatment by d 43. In study 1, treatment had no effect on hygiene scores, but scores increased over time (P < 0.001). In study 2, ducks in the narrow-lip bell drinker treatment were dirtier than those in the bath treatment (P = 0.01), with those in the trough treatment being intermediate. In both studies, ducks with bell drinkers had worse gait scores than those in the other treatments (study 1, P < 0.01; study 2, P < 0.05). Treatment had no effect on eye health scores. However, ducks were less likely to have dirty nostrils when provided with more open water resources in both studies (P < 0.01), or were less likely to have blocked nostrils in the trough and bath treatments than in the narrow-lip bell drinker treatment in study 2 (P = 0.01). Provision of open water, particularly over a properly constructed drainage area, improved some aspects of duck health (improved feather hygiene and BW, and fewer dirty and blocked nostrils). However, further work is needed to investigate these treatments on a commercial scale. PMID- 21248326 TI - Physiological responses of broiler embryos to in ovo implantation of temperature transponders. AB - Previous techniques that have been used to monitor broiler embryonic temperature and metabolism during incubation either have been invasive to the embryo or have not directly determined internal egg temperature. Therefore, the current investigation was conducted to determine the earliest day of incubation on which temperature transponder implantation in the egg air cell could be performed with minimal invasiveness to broiler embryogenesis. Eggs from young broiler breeder hens (Ross 308; 27 wk of age) were weighed and set on 3 tray levels (approximately 120 eggs per tray level) of a single incubator. Randomly, on each tray level and on each day between d 10 and 14 of incubation, 4 embryonated eggs were assigned to an invasive control (IC) treatment (shell perforation only) and 4 other embryonated eggs were assigned to a transponder implantation (TI) treatment (shell perforation, followed by transponder implantation in the air cell). Four embryonated eggs per tray were also assigned to a noninvasive control treatment on d 10 of incubation. Percentage of embryo survivability through d 18 of incubation, and percentages of mean daily incubational egg weight loss between d 18 and each respective day of implantation were calculated. Furthermore, various internal organ and tissue parameters were examined on d 18 of incubation. Embryo survivability was reduced because of transponder implantation on d 10 and 11 of incubation; however, embryo survivability was not different between eggs in the noninvasive control and IC treatments and the eggs that received the TI treatment on d 12, 13, and 14 of incubation. In comparison with eggs in the IC treatment, those in the TI treatment had a higher percentage of embryo weight. Conversely, yolk sac moisture was significantly higher in IC-treated eggs than in TI-treated eggs. It was concluded that temperature transponders may be inserted into the air cells of broiler hatching eggs between d 12 and 14 of incubation without adversely affecting eggshell porosity or embryogenesis and without causing physiological stress to growing broiler embryos. PMID- 21248327 TI - Characterization of two Indian native chicken breeds for production, egg and semen quality, and welfare traits. AB - The present study was conducted to characterize 2 important native chicken breeds from India and compare them on growth, production, egg and semen quality, and welfare traits. The Aseel breed showed (P < 0.001) higher BW at different ages; higher shank, radius, and toe lengths at 40 wk of age; and greater egg weights at 28, 32, and 40 wk of age than did the Kadaknath breed. The Kadaknath breed reached sexual maturity at an early age, and it had higher 40-wk egg production (P < 0.001). Higher egg specific gravity (P < 0.05) and higher albumen (P < 0.001) and shell (P < 0.009) percentages in the Kadaknath were observed, whereas the Aseel breed had a higher yolk index (P < 0.004), higher yolk percentage (P < 0.001), and higher yolk-to-albumen ratio (P < 0.001). Concentration of sperm (P < 0.01), live sperm counts (P < 0.05), and semen appearance scores (P < 0.05) were higher in the Aseel breed than in the Kadaknath breed. The Aseel breed showed a greater incidence of feather-pecking behavior under floor rearing, and this was negligible or mild in the Kadaknath breed. Broodiness under cage rearing was observed (8.42%) in the Aseel breed. With regard to welfare traits, male Aseel birds had a significantly shorter (P < 0.05) duration of tonic immobility (TI) than did male Kadaknath birds. Furthermore, male Aseel birds had a shorter (P < 0.001) duration of TI than did female Aseel birds, whereas female Aseel birds had a longer (P < 0.05) duration of TI than did female and male Kadaknath birds. From this study, it was concluded that the breeds differed on various growth, production, egg and semen quality, and behavioral traits, but not on welfare traits, although female Aseel birds exhibited a greater fear response. PMID- 21248328 TI - Evaluation of limit feeding varying levels of distillers dried grains with solubles in non-feed-withdrawal molt programs for laying hens. AB - An experiment was conducted with 672 Hy-Line W-36 Single Comb White Leghorn hens (69 wk of age) to evaluate the effects of feeding varying levels of corn distillers dried grains with solubles (DDGS) with corn, wheat middlings, and soybean hulls on long-term laying hen postmolt performance. The control molt treatment consisted of a 47% corn:47% soybean hulls (C:SH) diet fed ad libitum for 28 d. Hens fed the other 7 treatments were limit fed 65 g/hen per day for 16 d, and then fed 55 g/hen per day for 12 d. Hens on treatments 2 and 3 were fed 49% C:35% wheat middlings (WM) or SH:10% DDGS diets (C:WM:10DDGS, C:SH:10DDGS). Hens on treatments 4 and 5 were fed 49% C:25% WM or SH:20% DDGS diets (C:WM:20DDGS, C:SH:20DDGS). Those on treatments 6 and 7 were fed 47% C:47% DDGS (C:DDGS) or 47% WM:47% DDGS (WM:DDGS) diets. Those on treatment 8 were fed a 94% DDGS diet. At 28 d, all hens were fed a corn-soybean meal layer diet (16% CP) and production performance was measured for 36 wk. None of the hens fed the molt diets went completely out of production, and only the C:SH and C:SH:10DDGS molt diets decreased hen-day egg production to below 5% by wk 4 of the molt period. Postmolt egg production was lowest (P < 0.05) for the C:WM:20DDGS treatment. No differences (P > 0.05) in egg weights were detected among treatments throughout the postmolt period. In addition, no consistent differences were observed among treatments for egg mass throughout the postmolt period. Overall results of this study indicated that limit feeding diets containing DDGS at levels of 65 or 55 g/hen per day during the molt period did not cause hens to totally cease egg production. PMID- 21248329 TI - Clinical and acquired immunologic responses to West Nile virus infection of domestic chickens (Gallus gallus domesticus). AB - Numerous bird species are highly susceptible to North American strains of West Nile virus (WNV), and although domestic chickens are relatively resistant to WNV associated disease, this species currently represents the most practical avian model for immune responses to WNV infection. Knowledge of the immunomodulation of susceptibility to WNV in birds is important for understanding taxonomic differences in infection outcomes. While focusing on immunophenotyping of CD3(+), CD4(+), CD8(+), and CD45(+) lymphocyte subpopulations, we compared lymphocyte subpopulations, blood chemistries, cloacal temperatures, IgM and IgG antibody titers, and differential whole-blood cell counts of WNV-infected and uninfected hens. Total blood calcium and lymphocyte numbers were lower in WNV-infected chickens compared with uninfected chickens. The heterophil-to-lymphocyte ratio increased over time from 2 to 22 d postinoculation (DPI) in uninfected chickens and from 2 to 8 DPI in WNV-infected chickens, although levels declined from 8 to 22 DPI in the latter group. No significant differences were found in the remaining immunological and hematological variables of the WNV-infected and uninfected groups. Our results reaffirm that chickens are resistant to WNV infection, and demonstrated that the heterophil-to-lymphocyte ratio differed between groups, allowing for sorting of infection status. Similar patterns in immune responses over time in both infected and uninfected hens may be related to age (i.e., 10 wk) and associated immune development. PMID- 21248330 TI - Effects of repeated intratracheally administered lipopolysaccharide on primary and secondary specific antibody responses and on body weight gain of broilers. AB - Earlier, we reported that pathogen-associated molecular patterns such as lipopolysaccharide (LPS), when administered intratracheally (i.t.), affected primary and secondary specific antibody responses to antigens administered concurrently, either i.t. or systemically, and also affected BW gain (BWG) of layers and broilers. In the present study, we evaluated the effects of repeated i.t. challenge with LPS concurrently with or before i.t. immunizations with the specific antigens human serum albumin (HuSA) and rabbit gamma globulin (RGG) on primary (HuSA, RGG) and secondary (HuSA) systemic antibody responses and (isotype) IgM and IgG responses at 2 different ages. Broilers were challenged via the trachea at 3 and 7 wk of age with various combinations of LPS, HuSA, and RGG. All treatments affected immune responses at several time points and also affected BWG, albeit temporarily for the latter. Lipopolysaccharide enhanced primary antibody responses to HuSA and to RGG, when challenged concurrently, but birds challenged solely with LPS at 3 wk of age also showed enhanced primary antibody responses to HuSA and RGG given at 7 wk of age. This was true for IgM as well as IgG isotype responses. Lipopolysaccharide challenge negatively affected BWG at 3 wk of age, whereas the negative effects of LPS after a secondary LPS challenge at 7 wk of age were most pronounced in the birds challenged with LPS at 3 wk of age. The present results indicated that LPS, when administered i.t. at a young age, may affect specific humoral immune responsiveness to antigens administered simultaneously and to BWG of broilers, but also when challenged 4 wk later with specific antigens, suggesting an enhanced status of immune reactivity or sensitivity. The hygienic status of broiler houses at a young age may thus influence BWG, immune responsiveness, and, consequently, the vaccine efficacy and disease resistance in broilers at later ages. The consequences of our findings are discussed. PMID- 21248331 TI - Sodium bentonite and monensin under chronic aflatoxicosis in broiler chickens. AB - Clay feed additives have been increasingly incorporated into animal diets to prevent aflatoxicosis. Due to the nonselective nature of the binding interaction, many important components of the diets could also be made unavailable because of these feed additives. The anticoccidial monensin (MON) could also be sequestered by these clays. The use of sodium bentonite (Na-B) from a mine in the province of Mendoza, Argentina, was investigated as a sequestering agent to prevent the effects of 100 ug/kg of dietary aflatoxin B(1) (AFB(1)). In vitro studies demonstrated that the above Na-B was a good candidate to prevent aflatoxicosis. They also showed that MON competes with AFB(1) for the adsorption sites on the clay surface and effectively displaces the toxin when it is in low concentration. Even though the levels of MON in diets, approximately 55 mg/kg, are high enough to not be significantly changed as a consequence of the adsorption, they can further affect the ability of the clays to bind low levels of AFB(1). An in vivo experiment carried out with poultry showed that 100 ug/kg of AFB(1) does not significantly change productive or biochemical parameters. However, liver histopathology not only confirmed the ability of this particular Na-B to prevent aflatoxicosis but also the decrease of this capacity in the presence of 55 mg/kg of MON. This is the first report stressing this fact and further research should be performed to check if this behavior is a characteristic of the assayed Na-B or of this type of clay. On the other hand, the presence of MON should also be taken into account when assaying the potential AFB(1) binding ability of a given bentonite. PMID- 21248332 TI - Effects of single and combined Mycoplasma gallisepticum vaccinations on blood electrolytes and acid-base balance in commercial egg-laying hens. AB - A previous study from our laboratory on F-strain Mycoplasma gallisepticum inoculated layers showed a significant increase in arterial partial pressure of oxygen (pO(2)), which is generally associated with an oxygen-dependent improvement in tissue oxygenation. The aim of this study was to determine whether a killed (bacterin) and live TS-11-strain M. gallisepticum (TS-11-MG) vaccine treatment combination could further enhance the arterial pO(2) levels in layer chickens. The experiment was conducted in 2 trials and arranged in a completely randomized experimental design with 4 treatments. The treatments consisted of a control M. gallisepticum, bacterin, TS-11-MG, and bacterin + TS-11-MG combined, with all treatments receiving the R low strain of MG at 30 wk of age (WOA). In each of the 2 trials, 160 one-day-old MG-free pullets were raised to 10 WOA and were transported to a poultry disease isolation facility. Sixteen isolation units were divided into 4 treatment groups, and each of the 4 treatment groups had 4 replication units, with 10 birds/unit (40 birds/treatment). Venous blood samples were collected at the termination of the study at 56 WOA. The TS-11-MG-vaccinated chickens had a higher (P <= 0.05) blood pO(2) and a lower (P <= 0.05) partial pressure of CO(2) when compared with the control and combined MG-vaccinated groups. However, no significant blood pO(2) differences were observed between the bacterin and TS-11-MG treatment groups. Hematocrit and blood concentrations of hemoglobin were not statistically different among treatments, but were numerically higher in the TS-11-MG treatment group. There was a significant (P <= 0.05) treatment effect on blood concentrations of Na(+), Ca(2+), and anion, but no significant effect on glucose, cholesterol, triglyceride, or osmolality. These data suggest that the inoculation of layers with TS-11-MG was more effective in elevating pO(2) than was inoculation with TS-11-MG + bacterin combined. PMID- 21248333 TI - Efficacy of allicin from garlic against Ascaridia galli infection in chickens. AB - The use of garlic as a treatment against helminth infections is increasing in organic layer farms in several European countries. Its efficacy against these parasites, however, has not been demonstrated thus far. Therefore, a study was conducted to determine the efficacy of a commercially available garlic product consisting of a high concentration of allicin (i.e., the main active component of garlic) against experimentally induced Ascaridia galli infection in chickens. In total, 450 Lohmann LSL-Classic cockerels were used. Group 1, the uninfected, untreated group, consisted of 50 chickens. Groups 2 to 5, each consisting of approximately 100 chickens, were inoculated with 300 embryonated A. galli eggs/chicken at 6 wk of age. Group 2 was not treated, whereas groups 3 through 5 were given daily individual oral treatments from 13 wk of age onward. Group 3 received the recommended dose of allicin for 2 wk, whereas group 4 received a 10 fold dose of allicin. Group 5 was given 10 mg of flubendazole/kg of BW for 1 wk. Necropsy of 20 birds of all groups was performed weekly between 13 and 16 wk of age to determine adult worm loads. Group 1 remained free of A. galli. The experimental infection in the other groups resulted in a mean adult worm load of approximately 16 worms/bird. No significant differences were observed in worm counts of the allicin-treated groups (groups 3 and 4) compared with the infected, untreated group (group 2) at any week (P > 0.05). In contrast, no worms were found in chickens after flubendazole treatment (group 5). It was concluded that allicin does not represent an alternative to flubendazole for the treatment of A. galli infections in chickens. PMID- 21248334 TI - Evaluation of corn distillers dried grains with solubles as an alternative ingredient for broilers. AB - The effects of graded levels of corn distillers dried grains with solubles (DDGS) were investigated as a partial replacement for sources of protein, energy, and other nutrients for broilers when the digestible amino acid balance was maintained. Zero, 8, 16, and 24% DDGS were incorporated into isonutritive diets at the expense of corn, soybean meal, and dl-Met. Poultry oil, l-Lys, and l-Thr additions increased with increasing levels of DDGS. Diets were each fed to 36 Cobb 500 straight-run broilers in 6 floor pens in 2 experiments. In experiment 1, broilers fed >=8% DDGS showed increased BW gain compared with those fed the control diet during the 0- to 18-d starter period (P = 0.0164) but were almost identical in BW at 42 d (P = 0.9395). The only difference at 42 d was in the carcass fat composition of female broilers: percentage of fat pad decreased with increasing DDGS level (P = 0.0133). Corn DDGS reduced the pellet durability index. However, the pellet durability index was not related to growth or feed utilization. In experiment 2 at 42 d, broilers fed all levels of DDGS showed increased BW gain compared with those fed the control diet. Broilers may perform well when fed properly balanced feeds containing up to 24% DDGS despite reduced pellet quality. PMID- 21248335 TI - Nutritional equivalency evaluation of transgenic maize grain from event DP-O9814O 6 and transgenic soybeans containing event DP-356O43-5: laying hen performance and egg quality measures. AB - The objective of this study was to compare the nutritional performance of laying hens fed maize grain from event DP-O9814O-6 (98140; gat4621 and zm-hra genes) and processed soybean meal from soybeans containing event DP-356O43-5 (356043; gat4601 and gm-hra genes), individually or in combination, with the performance of hens fed diets containing nontransgenic maize and soybean meal. Healthy pullets (n = 216) placed in cages (3 hens/cage) were randomly assigned to 9 dietary treatments (8 cages/treatment): nontransgenic controls 1, 2, and 3 (comparable genetic background controls for 98140, 356043, and 98140 + 356043, respectively); reference 1, reference 2, and reference 3 (commercially available nontransgenic maize-soybean meal sources); and 98140 (test 1), 356043 (test 2), and 98140 + 356043 (test 3). The experiment was divided into three 4-wk phases (24 to 28 wk, 28 to 32 wk, and 32 to 36 wk of age), during which time hens were fed mash diets. Performance (BW, feed intake, and egg production) and egg quality data were collected. Data were analyzed using a mixed model ANOVA; differences between the control and respective test group means were considered significant at P < 0.05. Data generated from the reference groups were used only in the estimation of experimental variability and in generating the tolerance interval. Body weight and BW gain, egg production, and production efficiency for hens fed the test diets were similar to the respective values for hens fed the corresponding control diets. Haugh unit measures and egg component weights were similar between the respective test and control groups, and no differences were observed in quality grades or crack measures. All observed values of the control and test groups were within the calculated tolerance intervals. This research indicates that the performance and egg quality of hens fed diets containing 98140 maize grain, 356043 soybean meal, or a combination of the 2 was comparable with that of hens fed diets formulated with nontransgenic maize grain or soybean meal control diets with comparable genetic backgrounds. PMID- 21248336 TI - Nutritional value of soybean meal produced from conventional, high-protein, or low-oligosaccharide varieties of soybeans and fed to broiler chicks. AB - Three experiments were conducted to determine the feeding value to broiler chicks of soybean meal (SBM) produced from high-protein (SBM-HP), low-oligosaccharide (SBM-LO), or conventional (SBM-CV) varieties of soybeans. The 3 SBM contained 54.9, 53.6, and 47.5% CP, respectively. The standardized digestibility (SDD) of amino acids (AA) in the 3 ingredients was measured using a precision-fed rooster assay with cecectomized Single Comb White Leghorn roosters. Results indicated that the SDD of AA was not different among the 3 sources of SBM, with the exception that the SDD of Lys in SBM-HP tended to be greater (P = 0.07) than that in SBM-CV. In the second experiment, a precision-fed rooster assay was used to measure the concentration of TME(n) in each source of SBM. Results indicated that the TME(n) in SBM-HP was greater (P < 0.001) than those in SBM-LO and SBM-CV (3,104 vs. 2,984 and 2,963 kcal/kg of DM). A 14-d growth performance experiment was also conducted using 120 Ross 308 male commercial broiler chicks (mean initial BW = 102.6 g) that were allotted to a completely randomized design. There were 5 chicks/pen and 8 replicate pens/diet. Three corn- and SBM-based diets were formulated based on the data for digestible AA and TME(n) that were measured in the previous experiments. Each source of SBM was used in 1 diet, but because of the greater concentrations of digestible AA in SBM-HP and SBM-LO than in SBM-CV, the inclusion of SBM-HP and SBM-LO were 31.21 and 32.60%, respectively, whereas an inclusion of 38.21% SBM-CV was used. There were no differences among the 3 diets for BW gain or feed efficiency, which indicated that the reduced inclusion rates of SBM-HP and SBM-LO compared with SBM-CV were not detrimental to broiler chick growth performance. It was concluded that, compared with SBM-CV, SBM-HP and SBM-LO are needed in lower concentrations in diets fed to broiler chicks because these 2 sources of SBM have a greater nutritional value than does SBM-CV. PMID- 21248337 TI - Development of a precision-fed ileal amino acid digestibility assay using 3-week old broiler chicks. AB - The objective of these studies was to develop a precision-fed ileal digestibility assay, primarily for amino acids (AA), using 3-wk-old broiler chicks. For all experiments, day-old Ross * Ross 708 broiler chicks were fed a standard corn soybean meal starter diet until 21 d of age. In experiment 1, feed was removed and excreta were collected at 2, 4, 6, 8, 10, 12, and 14 h after feed withdrawal. Results indicated that 8 h of feed withdrawal was sufficient to empty the ileum of feed residues. In a subsequent experiment, chicks were fasted overnight for 10 h and then tube-fed various amounts (from 6 to 15 g) of a corn-soybean meal mixture (60:40). Ileal digesta from Meckel's diverticulum to the ileo-cecal junction were then collected at various collection times between 3 and 7 h postfeeding. Results indicated that the amount of digesta in the distal ileum was generally maximized by 4 h postfeeding and by feed intakes of 9 g or greater. Based on the results of the previous study, apparent and standardized ileal digestibility values of AA in a corn-soybean meal chick starter diet were then determined at 2, 3, and 4 h postfeeding. Digestibility values were similar for the 3- and 4-h collection times, but were numerically or significantly (P <= 0.05) lower at the 2-h collection time. The results of this study indicate that ileal AA digestibility can easily be determined in 3-wk-old broiler chicks when using a precision-fed assay. For such an assay, it is recommended that the chicks be fasted for at least 8 h before tube-feeding, that they be precision-fed approximately 10 g of feed, and that the ileal contents be collected at approximately 4 h postfeeding. PMID- 21248338 TI - Effect of liver X receptor activation on the very low density lipoprotein secretion and messenger ribonucleic acid level of related genes in goose primary hepatocytes. AB - In this study, we investigated the role of liver X receptor (LXR) activation in hepatic assembly and in the secretion of very low density lipoprotein triglycerides in goose primary hepatocytes. Goose primary hepatocytes were isolated and treated with the LXR agonist T0901317. Total triglyceride accumulation, intracellular and extracellular triglyceride concentrations, extracellular very low density lipoprotein concentration, and gene expression levels of LXRalpha, microsomal triglyceride transfer protein, acyl coenzyme A:diacylglycerol acyltransferase (DGAT) 1, and DGAT2 were measured in primary hepatocytes. We found a dose-dependent upregulation of total and intracellular TG accumulation when using 0, 0.01, 0.1, 1, and 10 MUM T0901317, but the extracellular triglyceride and very low density lipoprotein concentrations were dose dependent only when the T0901317 concentration was below 1 MUM; as compared with 1 MUM T0901317, 10 MUM T0901317 had an inhibiting effect (P < 0.05). The mRNA levels of all the detected genes increased in the presence of T0901317. The change in LXRalpha and DGAT1 was dose dependent, and the mRNA levels of microsomal triglyceride transfer protein and DGAT2 increased with a T0901317 concentration up to 1 MUM, but decreased when treated with 10 MUM T0901317 (P < 0.05). In conclusion, the secretion of very low density lipoprotein plays a role in pharmacologically activating the LXR-induced development of hepatocellular steatosis in geese. PMID- 21248339 TI - The chick embryo yolk sac membrane expresses nutrient transporter and digestive enzyme genes. AB - The yolk sac membrane plays a major role in the transport of nutrients from the yolk contents to the chick embryo. We examined whether the yolk sac membrane expresses genes for nutrient digestion, enzymes, and nutrient transporters. We evaluated relative mRNA abundance of the digestive enzymes aminopeptidase N (APN) and sucrase-isomaltase (SI); the nutrient transporters oligopeptide transporter Pept1, cationic amino acid transporter CAT1, and sodium glucose transporter SGLT1; and the micronutrient transporters type IIb sodium phosphate cotransporter NPT2b, calcium transporter TRPV6, and zinc transporter ZnT-1 from embryonic d 11 (11E) to 21E (day of hatch) by real-time reverse-transcription PCR. The yolk sac membrane expressed all the examined genes, which exhibited several patterns of expression. Relative abundance of APN mRNA increased in the yolk sac membrane from 11E to 17E and decreased from 17E to 20E. Expression of PepT1 increased from 11E to 15E and decreased from 15E to 20E. In contrast, CAT1 expression decreased from 11E to 13E and increased from 15E to 17E. Expression of SGLT1 increased between 15E and 20E and decreased substantially between 20E and 21E. Expression of NPT2b increased during incubation and exhibited the highest relative expression of all the examined genes, particularly on 20E to 21E. Expression of TRPV6 decreased from 11E to 13E and increased substantially from 15E to 19E. No significant difference was found between the sampled days for ZnT-1 or SI expression, with the latter exhibiting the lowest relative expression of all the genes studied. These results present the first documentation of nutrient transporter and digestive enzyme gene-expression patterns in the yolk sac membrane, and provide a basis for future research on the capacity of the yolk sac membrane for nutrient digestion and transport. PMID- 21248340 TI - Expression of Toll-like receptors and avian beta-defensins and their changes in response to bacterial components in chicken sperm. AB - The aim of the present study was to examine whether chicken sperm express mRNA of Toll-like receptors (TLR) and avian beta-defensins (avBD), and whether the expression of avBD in the sperm are regulated by the interaction of TLR-2 and TLR 4 with their corresponding ligands. Total RNA was extracted from fresh sperm and mRNA expression for TLR and avBD were examined by reverse-transcription PCR. Changes in the expression of avBD-5, avBD-9, avBD-10, and avBD-12 in the sperm after incubation with lipopolysaccharide (LPS; TLR-4 ligand) or lipopeptide (Pam3CSK4; TLR-2 ligand) were examined by real-time PCR. Among 8 types of TLR, PCR products of 7 types, namely, TLR-2 to TLR-5, TLR-7, TLR-15, and TLR-21, were identified in the sperm. The sperm also expressed cluster of differentiation 14 (CD14), which is required for the binding of LPS to TLR-4. Out of 14 avBD types reported in the chicken, a total of 9 types, namely, avBD-1, avBD-3, avBD-5, and avBD-7 to avBD-12 were expressed by the sperm, whereas avBD-5, avBD-9, avBD-10, and avBD-12 showed dense signals on the gel. Expression levels of avBD-5, avBD-9, avBD-10, and avBD-12 were significantly increased in the sperm stimulated with LPS, and that of avBD-5 was also enhanced by Pam3CSK4. These results suggest that avian sperm have the ability of the innate host defense to protect themselves from infection in the male and female genital tracts. PMID- 21248341 TI - Influence of parent flock age on embryonic metabolism in modern turkey strains. AB - The metabolic response of some galliform embryos to embryonic heat production (EHP) and how incubation conditions have been adjusted to prevent overheating of embryos is well established in broiler breeders. However, the daily metabolic status of turkey embryos has not been studied or established in turkey embryos. The objectives of the current research were therefore to determine the respiratory (eggshell conductance, G) and metabolic status (EHP) of 2 modern turkey genetic strains [Hybrid (H) and Nicholas (N)] and 4 parent flock ages [young (Y, 30 wk), peak (P, 34 wk), mature (M, 55 wk), and old (O, 60 wk)] during incubation. To measure G, moisture loss from 15 eggs/genetic strain per flock age and saturated vapor pressure measured between the eggshell and its immediate environment were used. Daily embryonic O(2) consumption and CO(2) production rates were assessed 6 times each day from embryos of eggs (n = 11 eggs/genetic strain per flock age) incubated in individual metabolic chambers and were used to determined daily EHP. Data were analyzed using the mixed model procedure of SAS at P <= 0.05. The results showed that the G values (g/d per mmHg) were significantly different for the interaction between genetic strain and parent flock age (H * Y = 17.71, H * P = 17.53, H * M = 19.73, H * O = 26.46, N * Y = 16.70, N * P = 20.96; N * M = 25.47, N * O = 26.05; P = 0.0227). Daily EHP (mW) was higher in embryos from the O flock than in embryos from the Y flock during all days presented except at 8, 25, and 28 d of incubation (4 d: Y = 1.00, P = 0.93, M = 1.60, O = 1.75; 12 d: Y = 19.0, P = 20.0, M = 21.6, O = 23.4; 16 d: Y = 51.7, P = 60.5, M = 65.9, O = 70.8; 20 d: Y = 129, P = 146, M = 144, O = 155; 24 d: Y = 154, P = 188, M = 167, O = 180; 26 d: Y = 169, P = 199, M = 197, O = 230; and 27 d: Y = 231, P = 265, M = 288, O = 307; P < 0.05). The data showed that metabolic differences existed between embryos from flocks of different ages and that embryos from older flocks were metabolizing at a higher rate and could be subject to overheating, which requires further investigation. On the basis of the data, turkey eggs from flocks of different ages should be incubated separately for optimal physiological performance. PMID- 21248342 TI - Characterizing the glycocalyx of poultry spermatozoa: III. Semen cryopreservation methods alter the carbohydrate component of rooster sperm membrane glycoconjugates. AB - The carbohydrate-rich zone on the sperm surface is essential for inmunoprotection in the female tract and early gamete interactions. We recently have shown the glycocalyx of chicken sperm to be extensively sialylated and to contain residues of mannose, glucose, galactose, fucose, N-acetyl-galactosamine, N-acetyl glucosamine, and N-acetyl-lactosamine. Our objective here was to evaluate the effects of 3 different cryopreservation methods on the sperm glycocalyx. Semen from roosters was pooled, diluted, cooled to 5 degrees C, and aliquoted for cryopreservation using 6% dimethylacetamide (DMA), 11% dimethylsulfoxide (DMSO), or 11% glycerol (GOH). For the DMA method, semen was equilibrated for 1 min with cryoprotectant and rapidly frozen by dropping 25-uL aliquots into liquid nitrogen. For the other methods, semen was equilibrated for either 1 min (DMSO) or 20 min (GOH), loaded into straws, and frozen with a programmable freezer. Thawing rates mimicked the freezing rates (e.g., rapid for DMA; moderate for DMSO and GOH). Aliquots of thawed and fresh, unfrozen semen were incubated with 1 of 12 fluorescein isothiocyanate-conjugated lectins and counterstained with propidium iodide, and mean fluorescence intensity (MFI) was assessed by flow cytometry. For each lectin, the MFI of propidium iodide-negative (viable sperm) was compared among the fresh and frozen-thawed treatments (n = 5). For sperm frozen with GOH and DMA, the MFI of most lectins was similar (P > 0.05) to that of fresh sperm, whereas only 5 of 12 lectins were similar between fresh and DMSO frozen sperm. Sperm from all 3 methods had higher (P < 0.05) MFI for lectins specific for N-acetyl-glucosamine and beta-galactose than did fresh sperm. Fewer sperm were damaged (P < 0.001) with GOH than with DMA or DMSO, and membrane integrity was correlated with MFI for 9 of 12 lectins (P < 0.05). These data indicate that surface carbohydrates are altered during cryopreservation, and that cryoprotectant type and freezing-thawing rates affect the degree of modification. Although the glycoconjugates have not yet been identified, it is likely that these cryopreservation-induced changes contribute to the reduced fertility of frozen-thawed chicken semen. PMID- 21248343 TI - Effect of acute cold exposure, age, sex, and lairage on broiler breast meat quality. AB - The effect of acute cold exposure on bird physiology, muscle metabolites, and meat quality was assessed in 360 male and female broilers at 5 and 6 wk of age, exposed for 3 h to temperature ranges of -18 to -4 degrees C and a control of +20 degrees C, by using a simulated transport system followed by 0 or 2 h of lairage. Core body temperature (CBT) was recorded, and the microclimate temperature and RH surrounding individual birds were monitored. Birds were classified based on the temperature in their immediate surroundings. Exposure to temperatures below 0 degrees C resulted in a decrease (P < 0.05) in blood glucose and an increase in live shrink. During the 3 h of exposure to -8 degrees C or lower, CBT dropped substantially. Temperatures below -14 degrees C caused lower glycolytic potential and lactate concentrations. Five-week-old birds showed darker and redder breast meat with higher ultimate pH (pH(u)), less cook loss, and higher processing cook yield at temperatures below -8 degrees C compared with warmer temperatures and with 6-wk-old birds exposed to similar temperatures. No difference in meat quality was observed between the 2 ages at temperatures below -14 degrees C. Males had a greater decrease in CBT and had breast meat with higher pH(u) compared with females. The 2-h lairage resulted in darker breast meat with higher pH(u) at exposure temperatures below -14 degrees C and with higher water-binding capacity and processing cook yield at temperatures below -11 degrees C. A high (>57%) incidence of dark, firm, and dry breast meat [pH >6.1 and L* (lightness) <46] was observed at temperatures below -14 degrees C. A 2-h lairage resulted in an additional 20% increase in the incidence of dark, firm, and dry meat at temperatures below -8 degrees C. Results of this study showed that older birds coped better with extreme cold conditions compared with younger birds. Furthermore, it would be beneficial to limit the length of lairage before processing after exposure to acute cold to improve bird welfare and reduce meat quality defects. PMID- 21248344 TI - Impact of citric acid and calcium ions on acid solubilization of mechanically separated turkey meat: effect on lipid and pigment content. AB - Increased demand for poultry products has resulted in an increased availability of by-products, such as the neck, back, and frame, that can be processed into mechanically separated poultry meat. The major problems with mechanically separated poultry meat are its high lipid content, color instability, and high susceptibility to lipid oxidation. The present work was undertaken to determine the effect of different concentrations of citric acid and calcium ions on protein yield, color characteristics, and lipid removal from protein isolates prepared using an acid-aided extraction process. Six levels of citric acid (0, 2, 4, 6, 8, and 10 mmol/L) and 2 levels of calcium chloride (0 and 8 mmol/L) were examined. The entire experiment was replicated 3 times, resulting in 36 extractions (3 * 6 * 2). The highest (P < 0.05) protein yield was found for the treatment with 6 mmol/L of citric acid. In general, all the combinations removed an average of 90.8% of the total lipids from mechanically separated turkey meat, ranging from 86.2 to 94.7%. The lowest amount (1.14%) of total lipids obtained was for samples treated with 4 mmol/L of citric acid. Maximum removal of neutral lipids (96.5%) and polar lipids (96.4%) was attained with the addition of 6 and 2 mmol/L of citric acid, respectively. Polar lipid content was found to be significantly (P = 0.0045) affected by the presence of calcium chloride. The isolated proteins were less (P < 0.05) susceptible to lipid oxidation compared with raw mechanically separated turkey meat. The most efficient removal of total heme pigment was obtained with the addition of 6 or 8 mmol/L of citric acid. Addition of calcium chloride had a negative effect on total pigment content. The study revealed that acid extractions with the addition of citric acid resulted in substantial removal of lipids and pigments from mechanically separated turkey meat, improved stability of the recovered proteins against lipid oxidation, and appreciable protein recovery yields. PMID- 21248345 TI - Effects of chitosan coating and storage with dry ice on the freshness and quality of eggs. AB - To develop a method that can maintain egg freshness during practical storage conditions, eggs were coated with chitosan and stored with or without dry ice. The physicochemical and microbiological qualities of eggs were evaluated during 14 d of storage at 4 and 23 degrees C without dry ice and at 23 degrees C with dry ice. The combination of chitosan coating and dry ice significantly inhibited a Haugh unit decrease during storage at 23 degrees C. No difference in functional properties, such as foaming ability, foam stability, and viscosity, among treatments was observed, but chitosan coating and storage with dry ice decreased the rate of pH increase and moisture loss in albumen at d 7 and 14. The eggs treated with chitosan coating and storage with dry ice had a significantly lower number of Salmonella Typhimurium inoculated on the egg surface than did control eggs during storage at 23 degrees C. Results revealed that the combination of chitosan coating and storage with dry ice limited the moisture loss, CO(2) emission, and pH increase, which helped maintaining the freshness of eggs. Microbial growth was also inhibited during storage at 23 degrees C. PMID- 21248346 TI - Lipid oxidation stability of omega-3- and conjugated linoleic acid-enriched sous vide chicken meat. AB - Lipid oxidation is known to occur rather rapidly in cooked chicken meat containing relatively high amounts of polyunsaturated fatty acids. To assess the lipid oxidation stability of sous vide chicken meat enriched with n-3 and conjugated linoleic acid (CLA) fatty acids, 624 Cobb * Ross broilers were raised during a 6-wk feeding period. The birds were fed diets containing CLA (50% cis-9, trans-11 and 50% trans-10, cis-12 isomers), flaxseed oil (FSO), or menhaden fish oil (MFO), each supplemented with 42 or 200 mg/kg of vitamin E (dl-alpha tocopheryl acetate). Breast or thigh meat was vacuum-packed, cooked (74 degrees C), cooled in ice water, and stored at 4.4 degrees C for 0, 5, 10, 15, and 30 d. The lipid oxidation development of the meat was estimated by quantification of malonaldehyde (MDA) values, using the 2-thiobarbituric acid reactive substances analysis. Fatty acid, nonheme iron, moisture, and fat analyses were performed as well. Results showed that dietary CLA induced deposition of cis-9, trans-11 and trans-10, cis-12 CLA isomers, increased the proportion of saturated fatty acids, and decreased the proportions of monounsaturated and polyunsaturated fatty acids. Flaxseed oil induced higher deposition of C18:1, C18:2, C18:3, and C20:4 fatty acids, whereas MFO induced higher deposition of n-3 fatty acids, eicosapentaenoic acid (C20:5), and docosahexaenoic acid (C22:6; P < 0.05). Meat lipid oxidation stability was affected by the interaction of either dietary oil or vitamin E with storage day. Lower (P < 0.05) MDA values were found in the CLA treatment than in the MFO and FSO treatments. Lower (P < 0.05) MDA values were detected in meat samples from the 200 mg/kg of vitamin E than in meat samples from the 42 mg/kg of vitamin E. Nonheme iron values did not affect (P > 0.05) lipid oxidation development. In conclusion, dietary CLA, FSO, and MFO influenced the fatty acid composition of chicken muscle and the lipid oxidation stability of meat over the storage time. Supranutritional supplementation of vitamin E enhanced the lipid oxidation stability of sous vide chicken meat. PMID- 21248347 TI - The relationship between blood and muscle samples to monitor for residues of the antibiotic enrofloxacin in chickens. AB - In 2005, the US Food and Drug Administration withdrew approval for use of enrofloxacin in poultry, thus effectively imposing zero tolerance for residues of this antibiotic in poultry. Conventional residue monitoring for most antibiotics, including enrofloxacin, involves removing poultry carcasses from the processing line and collecting muscle tissues for analysis. Because of the loss of valuable edible products and the difficulties and expense of sampling all the carcasses, only a small portion of carcasses are tested for violative residues. Unlike muscle tissue, blood is readily available from all birds at the beginning of processing and may be used to screen for illegal residues in all poultry carcasses. It is unknown, however, if enrofloxacin concentrations in blood are predictive of muscle concentrations. In an effort to evaluate this relationship, 156 broiler chickens, 5 wk of age, were dosed with either 25 or 50 ug/mL of enrofloxacin for 3 or 7 d, respectively, in the drinking water. Blood and muscle samples were collected at 0, 1, 3, 6, 12, and 24 h (n = 6 birds/group) during the first dosing day, every 48 h during the dosing period, and every 12 h during the withdrawal period for up to 60 h after withdrawal. Enrofloxacin residues were determined in all blood and tissue samples during the dosing periods and in most of the withdrawal period for both doses. These results support the potential to use blood to screen for illegal enrofloxacin residues in edible poultry tissues in an effort to protect the human food supply. PMID- 21248348 TI - Electron microscopy of contractile bands and quality characteristics in high voltage electrical stimulation broiler breast meat. AB - In this study, 20 broilers were used to examine the effect of high-voltage electrical stimulation (HVES) on meat quality and the microstructure of the pectoralis muscle. After slaughter, carcasses were randomly distributed into 2 treatment groups (n = 10). In the first group, carcasses were electrically stimulated (500 V, 100 Hz) for 60 s. Carcasses in the second group (nonelectrical stimulation) were used as a control. Meat quality was evaluated by the rate of pH, water-holding capacity, cooking loss, color (L*, a*, b*), shear force, and sarcomere length. As a result, HVES increased the rate of muscle pH decline (P < 0.001). High-voltage electrical stimulation had no effect on water-holding capacity and cooking loss values. Only L* (lightness) values were improved during the storage time (P < 0.01). Tenderness (P < 0.001) and sarcomere length (P < 0.05) values were significantly increased at 2 and 5 d postmortem. In addition, microstructure examination demonstrated that the stimulated muscles had longer sarcomeres; however, the A-, I-, and Z-bands and the mitochondrial membrane structure were intact in HVES and nonelectrically stimulated carcasses. The results showed that HVES is a useful method for improving the tenderness of broiler breast meat. PMID- 21248349 TI - Effect of stomaching on numbers of bacteria recovered from chicken skin. AB - Stomaching of skin samples releases only slightly more bacteria than a single rinse. Successive rinses, however, continue to remove almost as many bacteria as the first rinse. One hypothesis to explain this observation is that relatively violent treatment of skin generates smaller pieces of skin, thus increasing the net surface area and effectively sequestering bacteria in a water film on the skin pieces so that numbers of bacteria suspended in the rinsate do not increase. An experiment was conducted to determine whether inoculated marker bacteria are removed from the rinse liquid as skin pieces are stomached and naturally occurring bacteria are released. In each of 4 replications, 5 prechill broiler carcasses were collected from a commercial processing plant. Two 5-g pieces (n = 40) of breast skin were removed from each carcass and placed in a stomacher bag. An inoculum of 30 mL of 0.85% saline solution containing approximately 10(4) of nalidixic acid-resistant Salmonella enterica serovar Typhimurium per milliliter was added to each sample. Skin samples were hand-massaged for 30 s to mix the inoculum, after which a 1-mL aliquot was removed for enumeration of bacteria. A similar sample was taken after 4 min of vigorous stomaching of the skin sample. Bacterial counts recovered from the 30-s hand-massage were 4.3, 2.7, 2.6, and 3.7 log(10) cfu/mL of rinsate for aerobic bacteria, coliforms, Escherichia coli, and Salmonella, respectively. After stomaching, counts were 4.3, 2.9, 2.8, and 3.8, respectively. There was no difference in aerobic plate counts, but mean coliform and E. coli counts were significantly higher (P < 0.05) after stomaching. Numbers of inoculated Salmonella did not decrease. Breaking up the skin into smaller pieces by stomaching did not reduce the number of inoculated bacteria suspended in the rinsate. PMID- 21248350 TI - Water administration of the medium-chain fatty acid caprylic acid produced variable efficacy against enteric Campylobacter colonization in broilers. AB - Campylobacter is one of the most common causes of foodborne illness, and poultry are considered a primary source of Campylobacter infections. Caprylic acid, an 8 carbon fatty acid, has been shown in previous studies to reduce enteric cecal Campylobacter concentrations in poultry when administered in the feed. For greater ease of application for producers, a water-soluble form of caprylic acid, sodium octanoate, was evaluated for efficacy against enteric Campylobacter. The first trial consisted of 70 birds in 7 groups (n = 10 chicks/group): an untreated control and 6 other groups that were challenged with Campylobacter at d 3 and that received 0, 0.175, 0.35, 0.7, 1.4, or 2.8% water-soluble caprylic acid in water 3 d before necropsy at d 14. The second trial consisted of 80 birds in 8 groups (n = 10 chicks/group): an untreated negative control and 7 other groups, all of which were challenged with Campylobacter at d 3 and received 0, 0.044, 0.088, 0.175, 0.35, 0.7, or 1.4% water-soluble caprylic acid for 3 d before necropsy at d 14. In trial 1, only the 0.175% dose caused a reduction in cecal Campylobacter counts in comparison with the positive control (approximately a 3 log reduction). In trial 2, no treatment reduced Campylobacter counts compared with the positive control. Unlike the efficacy of caprylic acid in feed, treatment with caprylic acid in water had an inconsistent effect on intestinal Campylobacter counts. PMID- 21248351 TI - Standardized data in the broiler value chain. AB - In the Dutch broiler chain, data are collected as a routine practice. However, there is wide variation in the content of data collected and in data collection systems. This variability hampers the use of field data in management information systems to support decisions. The objective of this study was to analyze the quality of data and to standardize the content of data sets in the broiler production chain. To evaluate the quality of data, data sets from 3 Dutch hatcheries, from 23,637 batches of eggs, were assessed. The quality of data was assessed intuitively based on 7 quality attributes. To standardize the content of the data set, a protocol was proposed and validated. The protocol was validated at 30 breeder farms, 3 hatcheries, and 104 broiler farms by using 3 quality attributes: consistency, uniformity, and completeness. Results of the data quality analysis of the 3 Dutch hatcheries showed that the data sets had some fields with inaccurate, incorrect, inconsistent, nonuniform, incomprehensible, missing relevant, or incomplete data. Results of the validation protocol were as follows: feedback was obtained from 23 (77%) breeder farms, 3 (100%) hatcheries, and 7 (7%) broiler farms. Of all the questions, on average 88% were answered on breeder farms; 57, 65, and 82% were answered at each of the 3 hatcheries, respectively; and 79% were answered on the broiler farms. Data collected at 2 hatcheries were more consistent than those collected at the third hatchery. Hatchery data were less consistent than breeder farm data, but the number of data entries at hatcheries far exceeded the number at the farm level. Data from the hatcheries, breeder farms, and broiler farms were not always uniform, possibly because of differences in management strategies. This protocol enables the listing of relevant and standard contents of a data set whereby information exchange along the chain can be simplified. However, it is recommended that the protocol be supplemented with some rules for data collection and management, for example, that variables must be recorded in the provided fields, and that a variable must have one and only one name or code, the same unit of measurement, and the same definition. PMID- 21248352 TI - Narushin-Takma models as flexible alternatives for describing economic traits in broiler breeder flocks. AB - Three Narushin-Takma (NT) models (NT1, NT2, and NT3) were examined for their ability to describe different curves obtained from broiler breeder flocks. The models NT1, NT2, and NT3 comprise 3 flexible mathematical functions (rational polynomial functions) with 5, 6, and 7 parameters, respectively. The characteristics fitted were BW, egg production, egg mass, egg weight, first- and second-grade eggs, hatchability, feed intake, and feed conversion ratio. To evaluate the ability of these NT models to fit the different curves, comparisons were made with more commonly fitted functions (Gompertz, modified compartmental, Richards, Adams-Bell, and Lokhorst). Comparisons revealed a higher accuracy of fit with the NT models, proving their general flexibility. This study likely represents the first time a generic model has been demonstrated to fit all these characteristics satisfactorily. Results showed that in most cases, NT3, because of its greater number of parameters, gave the highest accuracy of prediction. The NT models are likely to fit most curves and are therefore advocated for accurate prediction of other traits with a minimum of mathematical complexity. PMID- 21248353 TI - Energy partitioning during incubation and consequences for embryo temperature: a theoretical approach. AB - In practice, many hatchability and chick quality problems have been related to the control of embryo temperature (ET) during incubation. Within an incubator, set at a constant machine temperature (MT), ET can vary substantially. Embryo temperature is the result of the balance between heat transfer to and from the embryo and heat production (HP) of the embryo. We investigated which factors theoretically could account for the variation in ET within an incubator. First, the effects egg weight, MT, and oxygen availability on HP of embryos were quantified. Differences in HP could be due only to differences in the amount of energy utilized from the egg or to differences in the efficiency of the conversion of energy in the egg to energy in the chicken, indicated as E(YFB). Results of these analyses showed that differences in HP attributable to egg weight or oxygen availability were mainly a result of the amount of energy used from the egg constituents and not of a change in E(YFB). However, at a given MT, this variation in HP could account for a maximum increase in ET of only 1.21 degrees C, suggesting that other factors played a role because in practice within an incubator, larger differences in ET have been found. The most important factor was probably the difference in air velocity within an incubator, resulting in differences in heat transfer. Because of this variation, ET varied within an incubator and with increasing ET, E(YFB) decreased, resulting in an even higher HP and consequently ET. We concluded that this theoretical approach could explain the wide variation in ET, and consequently could explain the negative effects of high ET on hatchability and chick quality found in the literature. This indicates that, in both practice and in incubation experiments, it is of great importance to realize that any factor affecting HP or heat transfer influences ET. We strongly suggest that ET (or eggshell temperature) be controlled in any incubation experiment involving hatchability or energy utilization. PMID- 21248354 TI - Effects of eggshell calcium on productive performance, plasma calcium, bone mineralization, and gonadal characteristics in laying hens. AB - A study was conducted with Rhode Island Red females to determine the effects of replacing limestone in the diet with ground, sterilized eggshell. Productive performance, egg quality, plasma Ca, bone characteristics, and the morphology of the ovary and oviduct were evaluated. One hundred forty-four 25-wk-old hens were housed in floor pens, located in a conventional open-sided layer shed. The birds were randomly divided into 3 groups, with each group represented by 4 replicates consisting of 12 birds each. Group 1 (control) was provided with a layer ration that contained all the CaCO(3) as fine limestone, whereas groups 2 and 3 were placed on diets in which 50 and 100% of the limestone, respectively, were substituted with ground eggshell. The birds were given free access to food and water and exposed to a 16L:8D photoperiod daily. Throughout the entire 10 wk of the study, BW, feed intake, egg production, egg weight, and egg quality of the 3 bird groups were not significantly (P > 0.05) different. Percentage of eggshell, eggshell thickness, and egg specific gravity were not affected by the treatment diets. At the end of the trial, number of ovarian follicles, ovary weight, and oviduct weight and length did not differ among hens fed the different Ca sources. The hematocrit values and concentrations of plasma Ca and P were similar in all treatment groups. Results showed that tibia-breaking strength and ash content of the birds were comparable whatever the Ca source. In addition, weight and length of the humerus, tarsometatarsus, and keel did not differ among treatments. The results indicate that eggshells can be fully used as a Ca source in layer diets without detrimental effects on productive traits, egg and eggshell quality, plasma Ca balance, bone mineralization, and gonadal performance. PMID- 21248356 TI - Cleft lip with cleft palate, ankyloglossia, and hypodontia are associated with TBX22 mutations. AB - X-linked cleft palate and ankyloglossia (CPX) are caused by mutations in the TBX22 transcription factor. To investigate whether patients with ankyloglossia alone or in the presence of other craniofacial features including hypodontia or CLP might be caused by TBX22 mutations, we analyzed 45 Thai patients with isolated ankyloglossia, 2 unusual CPA families, and 282 non-syndromic Thai and UK patients with CLP. Five putative missense mutations were identified, including 3 located in the T-box binding domain (R120Q, R126W, and R151L) that affects DNA binding and/or transcriptional repression. The 2 novel C-terminal mutations, P389Q and S400Y, did not affect TBX22 activity. Mutations R120Q and P389Q were identified in patients with ankyloglossia only, while R126W and R151L were present in families that included CLP. Several individuals in these families were also found to have micro/hypodontia. This study has expanded the phenotypic spectrum of TBX22-related mutations to include dental anomalies and cleft lip. PMID- 21248355 TI - Murine TMJ loading causes increased proliferation and chondrocyte maturation. AB - The purpose of this study was to examine the effects of forced mouth opening on murine mandibular condylar head remodeling. We hypothesized that forced mouth opening would cause an anabolic response in the mandibular condylar cartilage. Six-week-old female C57BL/6 mice were divided into 3 groups: (1) control, (2) 0.25 N, and (3) 0.50 N of forced mouth opening. Gene expression, micro-CT, and proliferation were analyzed. 0.5 N of forced mouth opening caused a significant increase in mRNA expression of Pthrp, Sox9, and Collagen2a1, a significant increase in proliferation, and a significant increase in trabecular spacing in the subchondral bone, whereas 0.25 N of forced mouth opening did not cause any significant changes in any of the parameters examined. Forced mouth opening causes an increase in the expression of chondrocyte maturation markers and an increase in subchondral trabecular spacing. PMID- 21248357 TI - Cochrane reviews on the benefits/risks of fluoride toothpastes. AB - This concise review presents two Cochrane Reviews undertaken to determine: (1) the relative effectiveness of fluoride toothpastes of different concentrations in preventing dental caries in children and adolescents; and (2) the relationship between the use of topical fluorides in young children and their risk of developing dental fluorosis. To determine the relative effectiveness of fluoride toothpastes of different concentrations, we undertook a network meta-analysis utilizing both direct and indirect comparisons from randomized controlled trials (RCTs). The review examining fluorosis included evidence from experimental and observational studies. The findings of the reviews confirm the benefits of using fluoride toothpaste, when compared with placebo, in preventing caries in children and adolescents, but only significantly for fluoride concentrations of 1000 ppm and above. The relative caries-preventive effects of fluoride toothpastes of different concentrations increase with higher fluoride concentration. However, there is weak, unreliable evidence that starting the use of fluoride toothpaste in children under 12 months of age may be associated with an increased risk of fluorosis. The decision of what fluoride levels to use for children under 6 years should be balanced between the risk of developing dental caries and that of mild fluorosis. PMID- 21248358 TI - MEPE activated by furin promotes pulpal cell adhesion. AB - Matrix extracellular phosphoglycoprotein (MEPE) is predominantly expressed in osteoblasts, osteocytes, and odontoblasts and plays key biological roles in bone and dentin metabolism. Post-translational modifications are essential for its activation. This study tested the hypothesis that MEPE is activated through proteolytic processing by furin in dental pulp. MEPE was present in three sizes, 1 full-length and 2 cleaved fragments; the cleavage site was 146R?147. The proprotein convertase family, particularly furin, was a candidate enzyme. Introducing a substitution at the cleavage site inhibited hydrolysis, but there was no cleavage of MEPE expressed in furin-deficient LoVo cells. Therefore, furin is a strong candidate for the proteolytic cleavage of MEPE. The C-terminal cleavage product promoted cell adhesion via its RGD motif. These results indicate that proteolytic processing by furin may activate MEPE during its secretion from odontoblasts and may play important roles in dentinogenesis and pulpal homeostasis. ABBREVIATIONS: MEPE, matrix extracellular phosphoglycoprotein; PTM, post-translational modifications; OLC, odontoblast-lineage cells. PMID- 21248359 TI - Angiogenic biomarkers and healing of living cellular constructs. AB - The use of intra-oral soft-tissue-engineered devices has demonstrated potential for oral mucosa regeneration. The aim of this study was to investigate the temporal expression of angiogenic biomarkers during wound healing of soft tissue reconstructive procedures comparing living cellular constructs (LCC) with autogenous free gingival grafts. Forty-four human participants bilaterally lacking sufficient zones of attached keratinized gingiva were randomly assigned to soft tissue surgery plus either LCC or autograft. Wound fluid samples were collected at baseline and weeks 1, 2, 3, and 4 post-operatively and analyzed for a panel of angiogenic biomarkers: angiogenin (ANG), angiostatin (ANT), PDGF-BB, VEGF, FGF-2, IL-8, TIMP-1, TIMP-2, GM-CSF, and IP-10. Results demonstrated a significant increase in expression of ANT, PDGF-BB, VEGF, FGF-2, and IL-8 for the LCC group over the autograft group at the early stages of wound repair. Although angiogenic biomarkers were modestly elevated for the LCC group, no clinical correlation with wound healing was found. This human investigation demonstrates that, during early wound-healing events, expression of angiogenic-related biomarkers is up-regulated in sites treated with LCC compared with autogenous free gingival grafts, which may provide a safe and effective alternative for regenerating intra-oral soft tissues (ClinicalTrials.gov number, NCT01134081). PMID- 21248360 TI - Influence of experimental esophageal acidification on sleep bruxism: a randomized trial. AB - The aim of this cross-over, randomized, single-blinded trial was to examine whether intra-esophageal acidification induces sleep bruxism (SB). Polysomnography with electromyogram (EMG) of masseter muscle, audio-video recording, and esophageal pH monitoring were performed in a sleep laboratory. Twelve healthy adult males without SB participated. Intra-esophageal infusions of 5-mL acidic solution (0.1 N HCl) or saline were administered. The frequencies of EMG bursts, rhythmic masticatory muscle activity (RMMA) episodes, grinding noise, and the RMMA/microarousal ratio were significantly higher in the 20-minute period after acidic infusion than after saline infusion. RMMA episodes including SB were induced by esophageal acidification. This trial is registered with the UMIN Clinical Trials Registry, UMIN000002923. ABBREVIATIONS: ASDA, American Sleep Disorders Association; EMG, electromyogram; GER, gastroesophageal reflux; LES, lower esophageal sphincter; NREM, non-rapid eye movement; REM, rapid eye movement; RMMA, rhythmic masticatory muscle activity; SB, sleep bruxism; SD, standard deviation; UES, upper esophageal sphincter. PMID- 21248361 TI - Maternal oral health predicts their children's caries experience in adulthood. AB - The long-term effects of poor maternal oral health are unknown. We determined whether maternal oral health when children were young was a risk indicator for caries experience in adulthood, using oral examination and interview data from age-5 and age-32 assessments in the Dunedin Study, and maternal self-rated oral health data from the age-5 assessment. The main outcome measure was probands' caries status at age 32. Analyses involved 835 individuals (82.3% of the surviving cohort) dentally examined at both ages, whose mothers were interviewed at the age-5 assessment. There was a consistent gradient in age-32 caries experience across the categories of maternal self-rated oral health status (from the age-5 assessment): it was greatest among the probands whose mothers rated their oral health as "poor" or who were edentulous, and lowest among those whose mothers rated their oral health as "excellent". Unfavorable maternal self-rated oral health when children are young should be regarded as a risk indicator for poor oral health among offspring as they reach adulthood. PMID- 21248362 TI - Cysteine cathepsins in human carious dentin. AB - Matrix metalloproteinases (MMPs) are important in dentinal caries, and analysis of recent data demonstrates the presence of other collagen-degrading enzymes, cysteine cathepsins, in human dentin. This study aimed to examine the presence, source, and activity of cysteine cathepsins in human caries. Cathepsin B was detected with immunostaining. Saliva and dentin cysteine cathepsin and MMP activities on caries lesions were analyzed spectrofluorometrically. Immunostaining demonstrated stronger cathepsins B in carious than in healthy dentin. In carious dentin, cysteine cathepsin activity increased with increasing depth and age in chronic lesions, but decreased with age in active lesions. MMP activity decreased with age in both active and chronic lesions. Salivary MMP activities were higher in patients with active than chronic lesions and with increasing lesion depth, while cysteine cathepsin activities showed no differences. The results indicate that, along with MMPs, cysteine cathepsins are important, especially in active and deep caries. PMID- 21248363 TI - Dissecting the role of the S1P/S1PR axis in health and disease. AB - Sphingosine-1-phosphate (S1P) is a pleiotropic sphingophospholipid generated from the phosphorylation of sphingosine by sphingosine kinases (SPHKs). S1P has been experimentally demonstrated to modulate an array of cellular processes such as cell proliferation, cell survival, cell invasion, vascular maturation, and angiogenesis by binding with any of the five known G-protein-coupled sphingosine 1 phosphate receptors (S1P1-5) on the cell surface in an autocrine as well as a paracrine manner. Recent studies have shown that the S1P receptors (S1PRs) and SPHKs are the key targets for modulating the pathophysiological consequences of various debilitating diseases, such as cancer, sepsis, rheumatoid arthritis, ulcerative colitis, and other related illnesses. In this article, we recapitulate these novel discoveries relative to the S1P/S1PR axis, necessary for the proper maintenance of health, as well as the induction of tumorigenic, angiogenic, and inflammatory stimuli that are vital for the development of various diseases, and the novel therapeutic tools to modulate these responses in oral biology and medicine. PMID- 21248365 TI - Diverse functions of plant peptides: entering a new phase. PMID- 21248366 TI - Resistance to neuraminidase inhibitors. PMID- 21248364 TI - Infection, inflammation, and bone regeneration: a paradoxical relationship. AB - Various strategies have been developed to promote bone regeneration in the craniofacial region. Most of these interventions utilize implantable materials or devices. Infections resulting from colonization of these implants may result in local tissue destruction in a manner analogous to periodontitis. This destruction is mediated via the expression of various inflammatory mediators and tissue destructive enzymes. Given the well-documented association among microbial biofilms, inflammatory mediators, and tissue destruction, it seems reasonable to assume that inflammation may interfere with bone healing and regeneration. Paradoxically, recent evidence also suggests that the presence of certain pro inflammatory mediators is actually required for bone healing. Bone injury (e.g., subsequent to a fracture or surgical intervention) is followed by a choreographed cascade of events, some of which are dependent upon the presence of pro inflammatory mediators. If inflammation resolves promptly, then proper bone healing may occur. However, if inflammation persists (which might occur in the presence of an infected implant or graft material), then the continued inflammatory response may result in suboptimal bone formation. Thus, the effect of a given mediator is dependent upon the temporal context in which it is expressed. Better understanding of this temporal sequence may be used to optimize regenerative outcomes. PMID- 21248367 TI - HIV mono-infection is associated with FIB-4 - A noninvasive index of liver fibrosis - in women. AB - BACKGROUND: FIB-4 represents a noninvasive, composite index that is a validated measure of hepatic fibrosis, which is an important indicator of liver disease. To date, there are limited data regarding hepatic fibrosis in women. METHODS: FIB-4 was evaluated in a cohort of 1227 women, and associations were evaluated in univariate and multivariate regression models among 4 groups of subjects classified by their human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infection status. RESULTS: The median FIB-4 scores were 0.60 in HIV-/HCV- women, 0.83 in HIV-/HCV+ women, 0.86 in HIV+/HCV- women, and 1.30 in HIV+/HCV+ women. In the HIV/HCV co-infected group, multivariate analysis showed that CD4(+) cell count and albumin level were negatively associated with FIB-4 (P <.0001), whereas antiretroviral therapy (ART) was positively associated with FIB-4 score (P =.0008). For the HIV mono-infected group, multivariate analysis showed that CD4(+) cell count (P <.0001) and albumin level (P =.0019) were negatively correlated with FIB-4 score, ART was positively associated with FIB-4 score (P =.0008), and plasma HIV RNA level was marginally associated with FIB-4 score (P =.080). In 72 HIV mono-infected women who were also hepatitis B surface antigen negative, ART naive, and reported no recent alcohol intake, plasma HIV RNA level was associated with increased FIB-4 score (P =.030). CONCLUSIONS: HIV RNA level was associated with increased FIB-4 score in the absence of hepatitis B, hepatitis C, ART, or alcohol use, suggesting a potential relationship between HIV infection and hepatic fibrosis in vivo. A better understanding of the various demographic and virologic variables that contribute to hepatic fibrosis may lead to more effective treatment of HIV infection and its co-morbid conditions. PMID- 21248369 TI - Coalescent histories on phylogenetic networks and detection of hybridization despite incomplete lineage sorting. AB - Analyses of the increasingly available genomic data continue to reveal the extent of hybridization and its role in the evolutionary diversification of various groups of species. We show, through extensive coalescent-based simulations of multilocus data sets on phylogenetic networks, how divergence times before and after hybridization events can result in incomplete lineage sorting with gene tree incongruence signatures identical to those exhibited by hybridization. Evolutionary analysis of such data under the assumption of a species tree model can miss all hybridization events, whereas analysis under the assumption of a species network model would grossly overestimate hybridization events. These issues necessitate a paradigm shift in evolutionary analysis under these scenarios, from a model that assumes a priori a single source of gene tree incongruence to one that integrates multiple sources in a unifying framework. We propose a framework of coalescence within the branches of a phylogenetic network and show how this framework can be used to detect hybridization despite incomplete lineage sorting. We apply the model to simulated data and show that the signature of hybridization can be revealed as long as the interval between the divergence times of the species involved in hybridization is not too small. We reanalyze a data set of 106 loci from 7 in-group Saccharomyces species for which a species tree with no hybridization has been reported in the literature. Our analysis supports the hypothesis that hybridization occurred during the evolution of this group, explaining a large amount of the incongruence in the data. Our findings show that an integrative approach to gene tree incongruence and its reconciliation is needed. Our framework will help in systematically analyzing genomic data for the occurrence of hybridization and elucidating its evolutionary role. PMID- 21248368 TI - Frequency of drug-resistant viruses and virus shedding in pediatric influenza patients treated with neuraminidase inhibitors. AB - BACKGROUND: Although influenza virus resistance to the neuraminidase inhibitor zanamivir is reported less frequently than is resistance to the neuraminidase inhibitor oseltamivir in clinical settings, it is unknown whether this difference is due to the limited use of zanamivir or to an inherent property of the drug. We therefore compared the prevalence of drug-resistant viruses and virus shedding in seasonal influenza virus-infected children treated with either oseltamivir or zanamivir. METHODS: Clinical specimens (throat or nasal swab) were collected from a total of 144 pediatric influenza patients during the 2005-2006, 2006-2007, 2007 2008, and 2008-2009 influenza seasons. Neuraminidase inhibitor-resistant mutants were detected among the isolated viruses by sequencing the viral hemagglutinin and neuraminidase genes. Sensitivity of the viruses to neuraminidase inhibitors was tested by neuraminidase inhibition assay. RESULTS: In oseltamivir- or zanamivir-treated influenza patients who were statistically comparable in their age distribution, vaccination history, and type or subtype of virus isolates, the virus-shedding period in zanamivir-treated patients was significantly shorter than that in oseltamivir-treated patients. Furthermore, the frequency of zanamivir-resistant viruses was significantly lower than that of oseltamivir resistant viruses. CONCLUSION: In comparison with treatment with oseltamivir, treatment of pediatric patients with zanamivir resulted in the emergence of fewer drug-resistant influenza viruses and a shorter virus-shedding period. We conclude that zanamivir shows promise as a better therapy for pediatric influenza patients. PMID- 21248370 TI - An advanced environment for hybrid modeling of biological systems based on modelica. AB - Biological systems are often very complex so that an appropriate formalism is needed for modeling their behavior. Hybrid Petri Nets, consisting of time discrete Petri Net elements as well as continuous ones, have proven to be ideal for this task. Therefore, a new Petri Net library was implemented based on the object-oriented modeling language Modelica which allows the modeling of discrete, stochastic and continuous Petri Net elements by differential, algebraic and discrete equations. An appropriate Modelica-tool performs the hybrid simulation with discrete events and the solution of continuous differential equations. A special sub-library contains so-called wrappers for specific reactions to simplify the modeling process. The Modelica-models can be connected to Simulink models for parameter optimization, sensitivity analysis and stochastic simulation in Matlab. The present paper illustrates the implementation of the Petri Net component models, their usage within the modeling process and the coupling between the Modelica-tool Dymola and Matlab/Simulink. The application is demonstrated by modeling the metabolism of Chinese Hamster Ovary Cells. PMID- 21248371 TI - HIF-1alpha antagonizes p53-mediated apoptosis by triggering HIPK2 degradation. AB - Many human diseases are characterized by the development of tissue hypoxia. Hypoxia-inducible factor (HIF) is a transcription factor that regulates fundamental cellular processes in response to changes in oxygen concentration, such as angiogenesis, survival, and alterations in metabolism. The levels of HIF 1alpha subunit are increased in most solid tumors not only by low oxygen but also by growth factors and oncogenes and correlate with patient prognosis and treatment failure. The link between HIF-1alpha and apoptosis, a major determinant of cancer progression and treatment outcome, is poorly understood. Here we show that HIF-1alpha protects against drug-induced apoptosis by antagonizing the function of the tumor suppressor p53. HIF-1alpha upregulation induced proteasomal degradation of homeodomain-interacting protein kinase-2 (HIPK2), the p53 apoptotic activator. Inhibition of HIF-1alpha by siRNA, HIF-1alpha-dominant negative or by zinc re-established the HIPK2 levels and the p53-mediated chemosensitivity in tumor cells. Our findings identify a novel circuitry between HIF-1alpha and p53, and provide a paradigm for HIPK2 dictating cell response to antitumor therapies. PMID- 21248372 TI - SIRT3: Striking at the heart of aging. PMID- 21248373 TI - Be quiet and you'll keep young: does mTOR underlie p53 action in protecting against senescence by favoring quiescence? PMID- 21248374 TI - The role of glyoxalases for sugar stress and aging, with relevance for dyskinesia, anxiety, dementia and Parkinson's disease. PMID- 21248375 TI - Regulation of the mitochondrial transition pore: impact on mammalian aging. PMID- 21248376 TI - Sirt3 targets mPTP and prevents aging in the heart. PMID- 21248377 TI - Treating transgenic Alzheimer mice with a beta-secretase inhibitor, what have we learned? AB - beta-Secretase is an attractive target of amyloid-reduction therapy for Alzheimer's disease. Currently, no efficacy data is available from clinical trials of beta-secretase inhibitors. Treating young transgenic Tg2576 mice with a brain-penetrating beta-secretase inhibitor reduced brain amyloid-beta by about 50% and rescued the age-related cognitive decline. Implications from these model studies on the design of clinical trials are discussed herein. PMID- 21248378 TI - Automated spike sorting algorithm based on Laplacian eigenmaps and k-means clustering. AB - This study presents a new automatic spike sorting method based on feature extraction by Laplacian eigenmaps combined with k-means clustering. The performance of the proposed method was compared against previously reported algorithms such as principal component analysis (PCA) and amplitude-based feature extraction. Two types of classifier (namely k-means and classification expectation-maximization) were incorporated within the spike sorting algorithms, in order to find a suitable classifier for the feature sets. Simulated data sets and in-vivo tetrode multichannel recordings were employed to assess the performance of the spike sorting algorithms. The results show that the proposed algorithm yields significantly improved performance with mean sorting accuracy of 73% and sorting error of 10% compared to PCA which combined with k-means had a sorting accuracy of 58% and sorting error of 10%.A correction was made to this article on 22 February 2011. The spacing of the title was amended on the abstract page. No changes were made to the article PDF and the print version was unaffected. PMID- 21248380 TI - Nerve lesioning with direct current. AB - Spastic hypertonus (muscle over-activity due to exaggerated stretch reflexes) often develops in people with stroke, cerebral palsy, multiple sclerosis and spinal cord injury. Lesioning of nerves, e.g. with phenol or botulinum toxin is widely performed to reduce spastic hypertonus. We have explored the use of direct electrical current (DC) to lesion peripheral nerves. In a series of animal experiments, DC reduced muscle force by controlled amounts and the reduction could last several months. We conclude that in some cases controlled DC lesioning may provide an effective alternative to the less controllable molecular treatments available today. PMID- 21248379 TI - Multiple components of ganglion cell desensitization in response to prosthetic stimulation. AB - Retinal prostheses aim to restore functional vision to those blinded by outer retinal diseases using electric stimulation of surviving neurons. Previous work indicates that repetitive stimulation with stimuli that activate the synaptic network reduces the sensitivity of retinal neurons to further stimulation. Such desensitization may contribute to the fading of visual percepts over time reported by human subjects. Here, we show that desensitization may be more complex than previously considered. We recorded spike trains from rabbit retinal ganglion cells and found that desensitization persists in the presence of inhibitory blockers (strychnine and picrotoxin), indicating amacrine cell inhibition is not solely responsible for reducing sensitivity in response to electric stimulation. The threshold for direct activation of the ganglion cell changes little during the simultaneous desensitization of the synaptically mediated response, indicating that desensitization likely occurs upstream of the spike generator. In addition to rapid desensitization acting over hundreds of milliseconds (tau = 176.4 +/- 8.8 ms), we report the presence of slow acting desensitization with a time course of seconds (tau = 14.0 +/- 1.1 s). The time courses of the two components of desensitization that we found are similar to the two phases of brightness fading seen in human subjects. This suggests that the reduction in ganglion cell firing due to desensitization may be responsible for the fading of visual percepts over time in response to prosthetic stimulation. PMID- 21248381 TI - Detection of lapses in responsiveness from the EEG. AB - A system capable of reliably detecting lapses in responsiveness ('lapses') has the potential to increase safety in many occupations. We have developed an approach for detecting the state of lapsing with second-scale temporal resolution using data from 15 subjects performing a one-dimensional (1D) visuomotor tracking task for two 1 h sessions while their electroencephalogram (EEG), facial video, and tracking performances were recorded. Lapses identified using a combination of facial video and tracking behaviour were used to train the classification models. Linear discriminant analysis was used to form detection models based on individual subject data and stacked generalization was utilized to combine the outputs of multiple classifiers to obtain the final prediction. The performance of detectors estimating the lapse/not-lapse state at 1 Hz based on power spectral features, approximate entropy, fractal dimension, and Lempel-Ziv complexity of the EEG was compared. Best lapse state estimation performance was achieved using the detector model created using power spectral features with an area under the curve from receiver operating characteristic analysis of 0.86 +/- 0.03 (mean+/ SE) and an area under the precision-recall curve of 0.43 +/- 0.09. A novel technique was developed to provide improved estimation of accuracy of detection of variable-duration events. Via this approach, we were able to show that the detection of lapse events from spectral power features was of moderate accuracy (sensitivity = 73.5%, selectivity = 25.5%). PMID- 21248383 TI - Electrode alignment of transverse tripoles using a percutaneous triple-lead approach in spinal cord stimulation. AB - The aim of this modeling study is to determine the influence of electrode alignment of transverse tripoles on the paresthesia coverage of the pain area in spinal cord stimulation, using a percutaneous triple-lead approach. Transverse tripoles, comprising a central cathode and two lateral anodes, were modeled on the low-thoracic vertebral region (T10-T12) using percutaneous triple-lead configurations, with the center lead on the spinal cord midline. The triple leads were oriented both aligned and staggered. In the staggered configuration, the anodes were offset either caudally (caudally staggered) or rostrally (rostrally staggered) with respect to the midline cathode. The transverse tripolar field steering with the aligned and staggered configurations enabled the estimation of dorsal column fiber thresholds (I(DC)) and dorsal root fiber thresholds (I(DR)) at various anodal current ratios. I(DC) and I(DR) were considerably higher for the aligned transverse tripoles as compared to the staggered transverse tripoles. The aligned transverse tripoles facilitated deeper penetration into the medial dorsal columns (DCs). The staggered transverse tripoles always enabled broad and bilateral DC activation, at the expense of mediolateral steerability. The largest DC recruited area was obtained with the rostrally staggered transverse tripole. Transverse tripolar geometries, using percutaneous leads, allow for selective targeting of either medial or lateral DC fibers, if and only if the transverse tripole is aligned. Steering of anodal currents between the lateral leads of the staggered transverse tripoles cannot target medially confined populations of DC fibers in the spinal cord. An aligned transverse tripolar configuration is strongly recommended, because of its ability to provide more post-operative flexibility than other configurations. PMID- 21248382 TI - Mimicking muscle activity with electrical stimulation. AB - Functional electrical stimulation is a rehabilitation technology that can restore some degree of motor function in individuals who have sustained a spinal cord injury or stroke. One way to identify the spatio-temporal patterns of muscle stimulation needed to elicit complex upper limb movements is to use electromyographic (EMG) activity recorded from able-bodied subjects as a template for electrical stimulation. However, this requires a transfer function to convert the recorded (or predicted) EMG signals into an appropriate pattern of electrical stimulation. Here we develop a generalized transfer function that maps EMG activity into a stimulation pattern that modulates muscle output by varying both the pulse frequency and the pulse amplitude. We show that the stimulation patterns produced by this transfer function mimic the active state measured by EMG insofar as they reproduce with good fidelity the complex patterns of joint torque and joint displacement. PMID- 21248384 TI - The hidden-Markov brain: comparison and inference of white matter hyperintensities on magnetic resonance imaging (MRI). AB - Rating and quantification of cerebral white matter hyperintensities on magnetic resonance imaging (MRI) are important tasks in various clinical and scientific settings. As manual evaluation is time consuming and imprecise, much effort has been made to automate the quantification of white matter hyperintensities. There is rarely any report that attempts to study the similarity/dissimilarity of white matter hyperintensity patterns that have different sizes, shapes and spatial localizations on the MRI. This paper proposes an original computational neuroscience framework for such a conceptual study with a standpoint that the prior knowledge about white matter hyperintensities can be accumulated and utilized to enable a reliable inference of the rating of a new white matter hyperintensity observation. This computational approach for rating inference of white matter hyperintensities, which appears to be the first study, can be utilized as a computerized rating-assisting tool and can be very economical for diagnostic evaluation of brain tissue lesions. PMID- 21248386 TI - Quality control measurements for digital x-ray detectors. AB - This paper describes a digital radiography (DR) quality control protocol for DR detectors from the forthcoming report from the Institute of Physics and Engineering in Medicine (IPEM). The protocol was applied to a group of six identical caesium iodide (CsI) digital x-ray detectors to assess reproducibility of methods, while four further detectors were assessed to examine the wider applicability. Twelve images with minimal spatial frequency processing are required, from which the detector response, lag, modulation transfer function (MTF), normalized noise power spectrum (NNPS) and threshold contrast-detail (c-d) detectability are calculated. The x-ray spectrum used was 70 kV and 1 mm added copper filtration, with a target detector air kerma of 2.5 uGy for the NNPS and c d results. In order to compare detector performance with previous imaging technology, c-d data from four screen/film systems were also acquired, at a target optical density of 1.5 and an average detector air kerma of 2.56 uGy. The DR detector images were typically acquired in 20 min, with a further 45 min required for image transfer and analysis. The average spatial frequency for the 50% point of the MTF for six identical detectors was 1.29 mm(-1) +/- 0.05 (3.9% coefficient of variation (cov)). The air kerma set for the six systems was 2.57 uGy +/- 0.13 (5.0% cov) and the NNPS at this air kerma was 1.42 * 10(-5) mm(2) (6.5% cov). The detective quantum efficiency (DQE) measured for the six identical detectors was 0.60 at 0.5 mm(-1), with a maximum cov of 10% at 2.9 mm(-1), while the average DQE was 0.56 at 0.5 mm(-1) for three CsI detectors from three different manufacturers. Comparable c-d performance was found for these detectors (5.9% cov) with an average threshold contrast of 0.46% for 11 mm circular discs. The average threshold contrast for the S/F systems was 0.70% at 11 mm, indicating superior imaging performance for the digital systems. The protocol was found to be quick, reproducible and gave an in-depth assessment of performance for a range of digital x-ray detectors. PMID- 21248387 TI - A feasibility study of a molecular-based patient setup verification method using a parallel-plane PET system. AB - A feasibility study of a novel PET-based molecular image guided radiation therapy (m-IGRT) system was conducted by comparing PET-based digitally reconstructed planar image (PDRI) registration with radiographic registration. We selected a pair of opposing parallel-plane PET systems for the practical implementation of this system. Planar images along the in-plane and cross-plane directions were reconstructed from the parallel-plane PET data. The in-plane and cross-plane FWHM of the profile of 2 mm diameter sources was approximately 1.8 and 8.1 mm, respectively. Therefore, only the reconstructed in-plane image from the parallel plane PET data was used in the PDRI registration. In the image registration, five different sizes of (18)F cylindrical sources (diameter: 8, 12, 16, 24, 32 mm) were used to determine setup errors. The data acquisition times were 1, 3 and 5 min. Image registration was performed by five observers to determine the setup errors from PDRI registration and radiographic registration. The majority of the mean registration errors obtained from the PDRI registration were not significantly different from those obtained from the radiographic registration. Acquisition time did not appear to result in significant differences in the mean registration error. The mean registration error for the PDRI registration was found to be 0.93 +/- 0.33 mm. This is not statistically different from the radiographic registration which had a mean registration error of 0.92 +/- 0.27 mm. Our results suggest that m-IGRT image registration using PET-based reconstructed planar images along the in-plane direction is feasible for clinical use if PDRI registration is performed at two orthogonal gantry angles. PMID- 21248385 TI - Electric field strength and focality in electroconvulsive therapy and magnetic seizure therapy: a finite element simulation study. AB - We present the first computational study comparing the electric field induced by various electroconvulsive therapy (ECT) and magnetic seizure therapy (MST) paradigms. Four ECT electrode configurations (bilateral, bifrontal, right unilateral, and focal electrically administered seizure therapy) and three MST coil configurations (circular, cap, and double cone) were modeled. The model incorporated a modality-specific neural activation threshold. ECT (0.3 ms pulse width) and MST induced the maximum electric field of 2.1-2.5 V cm-1 and 1.1-2.2 V cm-1 in the brain, corresponding to 6.2-7.2 times and 1.2-2.3 times the neural activation threshold, respectively. The MST electric field is more confined to the superficial cortex compared to ECT. The brain volume stimulated was much larger with ECT (up to 100%) than with MST (up to 8.2%). MST with the double-cone coil was the most focal, and bilateral ECT was the least focal. Our results suggest a possible biophysical explanation of the reduced side effects of MST compared to ECT. Our results also indicate that the conventional ECT pulse amplitude (800-900 mA) is much higher than necessary for seizure induction. Reducing the ECT pulse amplitude should be explored as a potential means of diminishing side effects. PMID- 21248388 TI - Assessing algorithms for defining vascular architecture in subharmonic images of breast lesions. AB - The ability to accurately and non-invasively characterize breast lesions and their vasculature would greatly limit the number of unneeded biopsies performed annually. Subharmonic ultrasound imaging (SHI) allows exclusive imaging of vasculature in real time, while completely suppressing tissue signals. Previously, cumulative maximum intensity (CMI) projections of SHI data were shown to be useful for characterization, but lacked means of quantification. In this study we investigate three potential thinning algorithms for defining breast lesion architecture. Sequential thinning, parallel thinning, and distance transformation algorithms were compared using 40 in vitro test images. Sequential thinning was selected due to superior connectivity, minimal rotational variance, and sufficient data reduction. This algorithm was then applied to 16 CMI SHI images of breast lesions, out of which 13 were successfully skeletonized. Average bifurcations were 9.8 +/- 8.18 and 6.9 +/- 6.50 in malignant and benign lesions, respectively (p > 0.60). Average vessel-chain length was 88.9 +/- 79.10 pixels versus 63.2 +/- 45.65 pixels in malignant versus benign lesions (p > 0.40). While the sequential thinning algorithm was promising for quantifying breast vasculature, its ability to significantly differentiate between malignant and benign lesions in this study was limited by a high degree of variability and limited sample size. PMID- 21248389 TI - Simulation of a 6 MV Elekta Precise Linac photon beam using GATE/GEANT4. AB - The GEANT4-based GATE Monte Carlo (MC) platform was initially focused on PET and SPECT simulations. The new release v6.0 (February 2010) proposes new tools dedicated for radiation therapy simulations. In this work, we investigated some part of this extension and proposed a general methodology for Linac simulations. Details of the modeling of a 6 MV photon beam delivered by an Elekta Precise Linac, with radiation fields ranging from 5 * 5 to 30 * 30 cm(2) at the isocenter are presented. Comparisons were performed with measurements in water. The simulations were performed in two stages: first, the patient-independent part was simulated and a phase space (PhS) was built above the secondary collimator. Then, a multiple source model (MSM) derived from the PhS was proposed to simulate the photon fluence interacting with the patient-dependent part. The selective bremsstrahlung splitting (SBS) variance reduction technique proposed in GATE was used in order to speed up the accelerator head simulation. Further investigations showed that the SBS can be safely used without biasing the simulations. Additional comparisons with full simulations performed on the EGEE grid, in a single stage from the electron source to the water phantom, allowed the evaluation of the MSM. The proposed MSM allowed for calculating depth dose and transverse profiles in 48 hours on a single 2.8 GHz CPU, with a statistical uncertainty of 0.8% for a 10 * 10 cm(2) radiation field, using voxels of 5 * 5 * 5 mm(3). Good agreement between simulations and measurements in water was observed, with dose differences of about 1% and 2% for depth doses and dose profiles, respectively. Additional gamma index comparisons were performed; more than 90% of the points for all simulations passed the 3%/3 mm gamma criterion. To our knowledge, this feasibility study is the first one illustrating the potential of GATE for external radiotherapy applications. PMID- 21248390 TI - A note on computing the derivative at a constant direction. AB - The derivative at constant direction is frequently used in inversion of cone-beam data. Several algorithms for computing the derivative have been proposed in the literature. The best algorithm to date has been proposed recently by Noo et al (2007 Phys. Med. Biol. 52 5393-414). In this note we propose a new, simple and efficient formula for computing the derivative. Numerical experiments with helical CT show that our formula and the one of Noo et al provide fairly similar spatial resolution and noise stability, even though the new formula is more efficient and easier to implement. PMID- 21248391 TI - Bias in iterative reconstruction of low-statistics PET data: benefits of a resolution model. AB - Iterative image reconstruction methods such as ordered-subset expectation maximization (OSEM) are widely used in PET. Reconstructions via OSEM are however reported to be biased for low-count data. We investigated this and considered the impact for dynamic PET. Patient listmode data were acquired in [(11)C]DASB and [(15)O]H(2)O scans on the HRRT brain PET scanner. These data were subsampled to create many independent, low-count replicates. The data were reconstructed and the images from low-count data were compared to the high-count originals (from the same reconstruction method). This comparison enabled low-statistics bias to be calculated for the given reconstruction, as a function of the noise-equivalent counts (NEC). Two iterative reconstruction methods were tested, one with and one without an image-based resolution model (RM). Significant bias was observed when reconstructing data of low statistical quality, for both subsampled human and simulated data. For human data, this bias was substantially reduced by including a RM. For [(11)C]DASB the low-statistics bias in the caudate head at 1.7 M NEC (approx. 30 s) was -5.5% and -13% with and without RM, respectively. We predicted biases in the binding potential of -4% and -10%. For quantification of cerebral blood flow for the whole-brain grey- or white-matter, using [(15)O]H(2)O and the PET autoradiographic method, a low-statistics bias of <2.5% and <4% was predicted for reconstruction with and without the RM. The use of a resolution model reduces low-statistics bias and can hence be beneficial for quantitative dynamic PET. PMID- 21248392 TI - In vivo non-thermal irreversible electroporation impact on rat liver galvanic apparent internal resistance. AB - Non-thermal irreversible electroporation (NTIRE) is a biophysical phenomenon which involves application of electric field pulses to cells or tissues, causing certain rearrangements in the membrane structure leading to cell death. The treated tissue ac impedance changes induced by electroporation were shown to be the indicators for NTIRE efficiency. In a previous study we characterized in vitro tissue galvanic apparent internal resistance (GAIR) changes due to NTIRE. Here we describe an in vivo study in which we monitored the GAIR changes of a rat liver treated by NTIRE. Electrical pulses were delivered through the same Zn/Cu electrodes by which GAIR was measured. GAIR was measured before and for 3 h after the treatment at 15 min intervals. The results were compared to the established ac bioimpedance measurement method. A decrease of 33% was measured immediately after the NTIRE treatment and a 40% decrease was measured after 3 h in GAIR values; in the same time 40% and 47% decrease respectively were measured by ac bioimpedance analyses. The temperature increase due to the NTIRE was only 0.5 degrees C. The results open the way for an inexpensive, self-powered in vivo real time NTIRE effectiveness measurement. PMID- 21248393 TI - GATE V6: a major enhancement of the GATE simulation platform enabling modelling of CT and radiotherapy. AB - GATE (Geant4 Application for Emission Tomography) is a Monte Carlo simulation platform developed by the OpenGATE collaboration since 2001 and first publicly released in 2004. Dedicated to the modelling of planar scintigraphy, single photon emission computed tomography (SPECT) and positron emission tomography (PET) acquisitions, this platform is widely used to assist PET and SPECT research. A recent extension of this platform, released by the OpenGATE collaboration as GATE V6, now also enables modelling of x-ray computed tomography and radiation therapy experiments. This paper presents an overview of the main additions and improvements implemented in GATE since the publication of the initial GATE paper (Jan et al 2004 Phys. Med. Biol. 49 4543-61). This includes new models available in GATE to simulate optical and hadronic processes, novelties in modelling tracer, organ or detector motion, new options for speeding up GATE simulations, examples illustrating the use of GATE V6 in radiotherapy applications and CT simulations, and preliminary results regarding the validation of GATE V6 for radiation therapy applications. Upon completion of extensive validation studies, GATE is expected to become a valuable tool for simulations involving both radiotherapy and imaging. PMID- 21248395 TI - Can load carriage system weight, design and placement affect pain and discomfort? A systematic review. AB - PURPOSE: A systematic review of the literature was conducted to answer the following questions: 1. Does usage or weight of load carriage system cause pain, perceived exertion or discomfort? 2. Can load carriage system placement on the spine influence pain, perceived exertion or discomfort? 3. Can load carriage system design influence the amount of pain, perceived exertion or discomfort caused by their use? METHOD: Eight databases were searched. Each included study was analysed and quality appraised by two independent reviewers. RESULTS: Forty seven articles that addressed the research questions were included in the study. Significant variability in the study design and populations of the studies prevented data pooling and the evidence is conflicting. However, qualitative synthesis of the studies shows that carrying loads may provoke low back pain; and it may also trigger neck, thoracic and shoulder pain. Backpack weight can influence perceived pain, however other factors are involved. DISCUSSION: There is conflicting but positive evidence on the correlation between backpack load carrying and experiencing pain during different stages of life. The research to date is lacking with the most commonly identified methodological deficiencies being poor overall design, the lack of justification of sample size, providing training sessions for examiners, and not utilising calibrated, valid and reliable instruments for measurement. PMID- 21248396 TI - Trunk muscle fatigue in subjects with a history of low back pain and a group of healthy controls measured by similarity index. AB - BACKGROUND: Trunk muscle fatigue has high relevance in human performance. Most authors agree that the use of the median frequency is preferred as a fatigue indicator. Most work has to date, been done on dynamic fatigue measurements, using the similarity index (SI). OBJECTIVE: Repeated trunk flexion-extensions were measured using the B200 Isostation. Muscle activity was recorded by surface electromyography (EMG) in order to evaluate fatigue of trunk flexor and extensor muscles. Twenty male university students participated in this pilot study, including 6 apparently healthy subjects with a history of low back pain (LBP), and 14 healthy matched controls. All participants were instructed to perform repeated trunk flexion-extension against 50% of their back extensors maximal volutary contractions (MVCs) resistance until they could no longer perform the task. The SI was calculated from quantitative analysis of EMG data recording during dynamic trunk flexion extension task. Median frequency was also measured before and after fatiguing contractions. RESULTS: The results of this study revealed a significant decrease in the SI and median frequency measurements following fatigue in both groups (p< 0.05). CONCLUSION: The results of this study indicated that in both groups changes in SI measurements following fatigue are in agreement with the changes in median frequency measurements. PMID- 21248397 TI - Degeneration of the extensor muscle group in a surgical low back and leg pain population. AB - The spinal muscles have received great attention in low back pain (LBP) with suggestions of a de-conditioning syndrome. It is not known whether it is a long or short term consequence of LBP. This study explored the cross section area (CSA) and muscle quality of the spinal extensor group in LBP patients referred to a spinal clinic. MRI scans of 100 annoymised patients were retrospectively reviewed; sagittal and transverse (from levels L3-5) images were archived and analysed to determine CSA and levels of fat infiltration of the extensor muscle groups. Forty six patients had spinal stenosis (28 males, 18 females, mean age 66 +/- 14.2 years) and 54 had a disc prolapse (28 males, 26 females, mean age 50 +/- 12.9 years). CSA was significantly smaller in the stenotics at both L3/4 and L4/5. Patients presenting with leg pain and a disc herniation had a significantly smaller CSA (p < 0.01) at L3/4 and L4/5 levels. Fat infiltration was present in both groups but was significantly greater in the stenotic group (p < 0.01) and was present at a similar degree at all spinal levels. Multiple regression analysis confirmed that reduced CSA was linked to leg pain (p < 0.01) and age was linked with fat infiltration (p < 0.01). Future work should explore the extent of such changes in an age and sex matched control population with no current back pain or sciatica. PMID- 21248398 TI - Rapid analgesic onset of intra-articular hyaluronic acid with ketorolac in osteoarthritis of the knee. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy of intra articular ketorolac to improve intra-articular hyaluronic acid (HA) therapy in knee osteoarthritis with respect to the initiation of pain relief. METHODS: This study was designed as a single-blind study with a blinded observer and a 3-month follow-up. Forty-three patients with knee osteoarthritis were randomized to the ketorolac group (n=21) or the HA group (n=22). Ketorolac group members were given three weekly intra-articular injections of HA with ketorolac and then two weekly intra-articular injections of HA; and HA group members were given five weekly intra-articular HA injections. Visual analog scale (VAS), pain rating score (PRS) and adverse events were assessed at baseline and at 1st, 3rd, 5th, and 16th week after treatment commencement. RESULTS: Significant improvement regarding pain assessment tools was observed in the ketorolac group by the addition of ketorolac to HA as compared with the HA group within 16 weeks of follow-up (p < 0.05). In the ketorolac group, 5 of the 21 subjects developed focal post-injection knee pain for about 8 hours after injection. CONCLUSION: Intra-articular HA with ketorolac showed more rapid analgesic onset than intra-articular HA alone and did not induce any serious complications. PMID- 21248399 TI - Comparison of ultrasound and ketoprofen phonophoresis in the treatment of carpal tunnel syndrome. AB - OBJECTIVE: The aim of this study was to compare the efficacy of ultrasound (US) and ketoprofen phonophoresis (PH) in the treatment of carpal tunnel syndrome (CTS). DESIGN: This study was a prospective, randomised, controlled, double blinded clinical trial with follow-up at 8 weeks. Fiftyone patients (76 median nerves) with clinical and electrophysiologic evidence of mild or moderate CTS were included in the study. They were randomly assigned to one of three groups; group 1 received sham US and splinting, group 2 received US and splinting, and group 3 received ketoprofen phonophoresis and splinting. Patients were evaluated by use of electrophysiological variables such as median motor distal latency (mMDL), median sensory distal latency (mSDL), functional status scale (FSS), symptom severity scale (SSS) and visual analog scale (VAS). Electrophysiological variables and scales were evaluated at the beginning, end of therapy (2nd week) and 8th week. RESULTS: All the randomised patients were included in the intention to-treat (ITT) analysis. The per protocol (PP) analysis included only those patients who complied with the study protocol. After completing 2 weeks of treatment, seven out of 51 randomized patients did not finish the study protocol due to non-compliance to splinting, illness and lost to follow-up. Those patients were excluded from PP analysis. Participants were similar in all clinical, electrophysiological and demographic respects (p>0.05). An improvement was found in all parameters (VAS, FSS, SSS, mMDL and mSDL) for all groups at the end of the treatment and 8th week. It was found that pain score was significantly lower in group 3 compared to other treatment groups at 8th week according to ITT and PP analysis (p= 0.002, p=0.004 and p=0.001, p=0.001). CONCLUSION: Ketoprofen PH as adjuvant therapy on splinting is effective with respect to reduction of pain. Adding US therapy to the splinting is not superior to the splinting alone in patients with CTS. PMID- 21248400 TI - The impact of physically demanding work of basketball and volleyball players on the risk for patellar tendinopathy and on work limitations. AB - Patellar tendinopathy is a common injury in jumping athletes. Little is known about work-related etiological factors for patellar tendinopathy and related work limitations. The aim of this study was to identify work-related etiological factors for patellar tendinopathy and to determine the relation between patellar tendinopathy and work limitations. Basketball and volleyball players between 18 and 35 years were invited to complete an online-questionnaire concerning knee complaints, etiological risk factors for patellar tendinopathy and related work limitations. A total of 1505 subjects were included in the analysis. Risk factors for patellar tendinopathy were gender and heavy physically demanding work. The odds for having patellar tendinopathy were significantly higher for heavy physically demanding occupations compared to mentally demanding occupations. 30% of subjects with patellar tendinopathy with a physically demanding job reported to be impaired in their work and 17% reported to be less productive. Basketball and volleyball players with heavy physically demanding work seem to have an increased risk for developing patellar tendinopathy. This finding has important clinical relevance in the treatment of this injury. Working activities should be adjusted in order to reduce the total load on the patellar tendon and help prevention and recovery. PMID- 21248401 TI - The efficacy of balneotherapy and physical modalities on the pulmonary system of patients with fibromyalgia. AB - Effects of balneotherapy on Primary Fibromyalgia Syndrome (FMS) have been studied well, except for its effect on the respiratory symptoms of FMS. In this study we allocated 56 patients with FMS into three groups who matched according to age, gender and duration of illness. All three groups received the same three physical therapy modalities (PTM): transcutaneous electrical nerve stimulation (TENS), ultrasound (US) and infrared (IR). The first group received PTM plus balneotherapy (PTM+BT), the second group received PTM alone (PTM), whilst the third group received PTM plus hydrotherapy (PTM+HT). All groups were treated for three weeks and in the same season. All patients were assessed at four time points: (a) at baseline, (b) on the 7th day of therapy, (c) at the end of therapy (after 3 weeks) and (d) at 6 months after the end of therapy. The effectiveness of treatments in all groups were evaluated in three main categories (pain, depressive and respiratory symptoms). Tender point count, total algometric measurements and pain with visual analog scale for pain; Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS) for depression; dyspnea scale, and spirometric measurements for respiratory symptoms; plus quality of life with visual analog scale as a general measurement of effectiveness were taken at all four assessment time points.Both at the end of therapy and at the 6 months follow up significant improvements in dyspnea scale, and spirometric measurements, as well as in other measured parameters were observed in group PTM+BT. All groups achieved significant improvements in BDI and HDRS but scores of PTM and PTM+HT groups had overturned at 6 months follow up. Except second group which receieved PTM alone, pain evaluation assessments were improved at 6 month follow up in PTM+HT and PTM+BT groups. But PTM+BT group had more significant improvements at the end of therapy. PTM group had no significant change for dyspnea scale and spirometric measurements. PTM combined BT and HT groups achieved significant improvements at the end of therapies for dyspnea scale and spirometric measurements, but only PTM +BT group had significant improvements for dyspnea scale and spirometric measurements at six month follow up. The group of PTM+BT was significantly better than other groups. Our results suggest that supplementation of PTM with balneotherapy is effective on the respiratory and other symptoms of FMS and these effects were better than other protocols at 6 month follow up. PMID- 21248402 TI - Immunohistochemical and biomolecular identification of 5-HT7 receptor in rat vestibular nuclei. AB - The association between migraine and balance disorder morbidities has been a topic of interest for many years, and serotonin (5-HT) receptor is known to be closely related with migraine and also to be associated with vestibular symptoms. However, the mechanism underlying the pathogenesis of migrainous vertigo and its association with 5-HT has not been elucidated. Of the many 5-HT receptors, 5-HT7 receptor has recently attracted attention in the context of migraine treatment. The purpose of this study was to investigate the localization and expression of 5 HT7 receptor in the rat vestibular nuclei by immunohistochemical staining and reverse transcriptase-polymerase chain reaction (RT-PCR). The present study might provide additional insight into the role of 5-HT7 receptor in the pathogenesis of migraine-related vestibular symptoms. PMID- 21248403 TI - Short and long-term postural learning to withstand galvanic vestibular perturbations. AB - We investigated changes of postural responses to repeated bipolar galvanic vestibular stimulation on 5 consecutive days and once again after 3 months. Subjects consisted of 21 healthy volunteers. Except for the first day did the induced torque variance in response to galvanic vestibular stimulation not decrease within each test session, but there was a major reduction from day to day (p< 0.001) reflecting a continued processing of the postural experience gained during the stimulation. The decreased end level magnitude of postural responses after 5 days was retained after 3 months. The galvanic stimulation failed to induce larger torque variance compared to quiet stance toward the end of the 5 days as well as after 3 months, indicating a down-regulation of a repeated erroneous vestibular stimulation by the postural control system - i.e. sensory reweighting. This argues that a major adaptation effect to galvanic vestibular perturbation takes place after the exposure to the stimulation - similar to the concept of the consolidation process involved in motor learning. This should be considered when repeatedly assessing vestibular function both clinically and in studies. It implies that sensory training involved in rehabilitation from vestibular diseases/deficiencies should be executed with spaced intervals in order to procure more efficient learning processes and in the end, a better function. PMID- 21248404 TI - Measuring caloric response: comparison of different analysis techniques. AB - INTRODUCTION: Electronystagmography (ENG) testing has been supplanted by newer techniques of measuring eye movement with infrared cameras (VNG). Most techniques of quantifying caloric induced nystagmus measure the slow phase velocity in some manner. Although our analysis is carried out by very experienced assessors, some systems have computer algorithms that have been "taught" to locate and quantify maximum responses. We wondered what differences in measurement might show up when measuring calorics using different techniques and systems, the relevance of this being that if there was a change in slow phase velocity between ENG and VNG testing when measuring caloric response, then normative data would have to be changed. There are also some subjective but important aspects of ENG interpretation which comment on the nature of the response (e.g. responses which might be "sporadic" or "scant"). METHODS: Our experiment compared caloric responses in 100 patients analyzed four different ways. Each caloric was analyzed by our old ENG system, our new VNG system, an inexperienced assessor and the computer algorithm, and data was compared. CONCLUSIONS: All four systems made similar measurements but our inexperienced assessor failed to recognize responses as sporadic or scant, and we feel this is a limitation to be kept in mind in the rural setting, as it is an important aspect of assessment in complex patients. Assessment of complex VNGs should be left to an experienced assessor. PMID- 21248406 TI - Pathophysiology of lateral semicircular canal paroxysmal positional vertigo. AB - OBJECTIVE: To study the pathophysiology of lateral semicircular canal (LSC) paroxysmal positional vertigo (PPV). STUDY DESIGN: Retrospective study. METHODS: Between June 2004 and June 2005 we observed 471 patients with PPV. In the apogeotropic forms of LSC-PPV, we tried to transform the nystagmus into the geotropic form, either by diagnostic or therapeutic menoeuvres. If we failed, we advised barbecue rotations toward the healthy side and sleeping on the affected side. Patients were evaluated once a week until resolution. RESULTS: 91 patients suffered LSC involvement, in 61 cases in the geotropic form and in 30 cases in the apogeotropic form. Out of these, five transformed into the geotropic form during the first examination; in 5 patients we observed geotropic nystagmus at the follow-up visit; the last 20 never showed geotropic nystagmus before resolution. CONCLUSION: We hypothesize that in the geotropic form the debris is free floating in the posterior arm of the LSC (canalolithiasis). In the apogeotropic form the debris can be free floating in the anterior arm or attached to the cupula of the ampulla; if we observe transformation from the apogeotropic into the geotropic form this suggested a canalolithiasis, otherwise we have assumed a cupulolithiasis. PMID- 21248405 TI - Test-retest reliability of vibration-induced nystagmus in peripheral dizzy patients. AB - The purpose of this study was to analyze test-retest reliability of vibration induced nystagmus (VIN) in dizzy patients. Fifty-two consecutive patients with positive eye movements induced by vibration at all four different stimulation sites were enrolled. Evaluation of VIN was repeated in 2 separate sessions, 30 minutes apart. Maximum slow-phase eye velocities at different sites from the first and second sessions were assessed via the intraclass correlation coefficient (ICC) and the Pearson correlation coefficient. The incidence of directional changing of evoked nystagmus and the abnormal rates were also evaluated. Excellent reliability with ICC values ranging from 0.89-0.98 and substantial-to-excellent correlation was obtained for the maximum slow-phase eye velocities at different sites. The incidence of directional changes of evoked nystagmus was 0%-4% at each stimulation site. Forty-three patients (83%) had abnormal results in the first session and 41 patients (79%) had abnormal results in the second session. Overall, the direction and maximum slow-phase eye velocities of VIN for different stimulation sites had excellent test-retest reliability. The VIN test is a reliable test for detecting vestibular imbalance in evaluating a dizzy patient. PMID- 21248408 TI - Modeling hospital surgical delivery process design using system simulation: optimizing patient flow and bed capacity as an illustration. AB - OBJECTIVES: It is increasingly recognized that hospital operation is an intricate system with limited resources and many interacting sources of both positive and negative feedback. The purpose of this study is to design a surgical delivery process in a county hospital in the U.S where patient flow through a surgical ward is optimized. METHOD: The system simulation modeling is used to address questions of capacity planning, throughput management and interacting resources which constitute the constantly changing complexity that characterizes designing a contemporary surgical delivery process in a hospital. RESULTS: The steps in building a system simulation model is demonstrated using an example of building a county hospital in a small city in the US. It is used to illustrate a modular system simulation modeling of patient surgery process flows. CONCLUSIONS: The system simulation model development will enable planners and designers how they can build in overall efficiencies in a healthcare facility through optimal bed capacity for peak patient flow of emergency and routine patients. PMID- 21248407 TI - Attenuation of trunk acceleration during walking in patients with unilateral vestibular deficiencies. AB - OBJECTIVE: Head stability, central for balance control during locomotion, is associated with attenuation of trunk oscillations. The study aimed at exploring trunk attenuation in patients with unilateral vestibular disorder (UVD) assuming it was compromised, and to see if attenuation could be influenced by vestibular rehabilitation therapy. METHODS: Patients with UVD (N= 21), mean age (SD): 50.7 (11.5) years, women: 57%, were tested before and after intervention. Patients walked at different velocities with triaxial accelerometers over the lower and upper trunk. Normalization of data allowed comparison across patients over time. Self-reported symptoms and perception of handicap were registered. RESULTS: Acceleration was significantly higher at the lower compared to the upper trunk on both occasions. Increased accelerations at the lower and decreased accelerations at the upper trunk following intervention caused attenuation to increase along the antero-posterior (p=0.05) and medio-lateral axes (p< 0.01). Cadence was reduced (p=0.01), step-length increased (p= 0.01), and self-reported balance (p=0.05) and handicap (p<0.01) improved. CONCLUSION: More effective attenuation of trunk oscillations was found during walking following intervention. The observed increased stability of the upper trunk is compatible with improved head control, and this was associated with increased mobility of the lower trunk facilitating balance control during ambulation. Trunk accelerations may be useful for identification of balance control in UVD patients. PMID- 21248409 TI - The metabolic cost of passive walking during robotics-assisted treadmill exercise. AB - BACKGROUND: We are investigating the potential of robotics-assisted treadmill technology as a mode of exercise in people with spinal cord injury (SCI). People with incomplete SCI can actively contribute to this form of exercise, but in the clinical setting they often walk passively in the system. It is not known whether in doing so they are meeting the recommended guidelines for increasing cardiopulmonary fitness. OBJECTIVE: The aims of this study were twofold: to characterise the intensity of passive walking during robotics-assisted treadmill exercise (RATE) in incomplete SCI; and to determine if this intensity meets the recommended guidelines for cardiopulmonary training in this population. METHODS: 10 subjects with incomplete SCI twice performed an exercise test on a robotics assisted treadmill. The test comprised a period of passive walking and a ramp phase to the limit of tolerance. Oxygen uptake VO(2) heart rate (HR) were continuously measured. RESULTS: VO(2) during passive exercise was on average 1.4 times higher than resting VO(2R), but this was only 29% of peak VO(2) (VO(2 peak))(range 16-43%). Relative to rest, passive VO(2) (VO(2P) was only 12% of VO(2 peak). HR did not increase from rest to passive walking (81 +/- 10 bpm to 81 +/- 13 bpm respectively). The HR associated with passive walking was on average 50% of peak HR (HR(peak)) (161 +/- 13 bpm). Test-retest reliability was moderate for VO(2R) (R=0.62) and resting HR (HR(R)) (R=0.68), high for VO(2P) (R=0.81), passive HR (HR(P)) (R=0.87) and HR(peak) (R=0.88), and very high (R=0.95) for VO(2 peak). Only HR(p) differed significantly between tests (p=0.029). CONCLUSIONS: The intensity of passive walking during RATE is low and is insufficient to increase cardiopulmonary fitness in people with SCI. Subjects must actively contribute to the exercise in order to achieve the recommended training intensity. PMID- 21248410 TI - The impact of seating forces from a cementless femoral component in hip resurfacing arthroplasty on the femoral head--a cadaver study using MU-CT analysis. AB - Recent studies have assumed micro-fractures of the femoral head during hip resurfacing arthroplasty as a possible reason for fractures at the implant/neck junction. The purpose of this study was to analyze whether implantation of a cementless femoral hip resurfacing component which requires high seating forces, causes micro-fractures of the femoral head. A cementless hip resurfacing femoral component was installed on 20 human, cadaveric femoral heads with an impaction device that generated 4.5 kilonewton force in one group and by hand in the other. Before and after impaction, the specimens were scanned with a MU-CT-System. The CT datasets were segmented and registered for detection of small trabecular fractures. The average percentage of shared voxels was 80.29% (standard deviation 3.24%). Change in bone structure after impaction (19.71%) was found on the surfaces of all samples. No formation that was ascribed to fracture was found. No difference between the specimens that were impacted by hand or by impaction device was noted. No fractures of the cancellous femoral head during installation of a cementless femoral THR component occurred. Cementless hip resurfacing might not increase the risk of fracturing the cancellous femoral head during implantation in a cadaveric MU-CT study. PMID- 21248411 TI - Implementing evidential activity recognition in sensorised homes. AB - Automated recognition of activities of daily living such as preparing meals and grooming may be considered as one of the most desirable computational functions within a Smart Home for the elderly. In our current work we present a process framework with the capability of realising evidential ontology networks for recognising activities of daily living in a single-person occupied inhabitancy. The performance of this framework has been evaluated using a publicly available data set consisting of 28 days worth of sensor data which was recorded from a single person living in an apartment. Within the paper we show how evidential inference networks of activities of daily living can be generated from the smart home and subsequently used to represent sensor evidence and activity performance. Based on exposure to the data set considered within the study the model achieved an overall class accuracy of 83.4% and timeslice accuracy of 95.7%. Previously reported attempts to classify this data based on a probabilistic approach achieved rates in the region of 79.4% and 94.5% respectively. PMID- 21248413 TI - Bioreactors in tissue engineering. AB - A bioreactor can be defined as a device that uses mechanical means to influence biological processes. In tissue engineering bioreactors can be used to aid in the in vitro development of new tissue by providing biochemical and physical regulatory signals to cells and encouraging them to undergo differentiation and/or to produce extracellular matrix prior to in vivo implantation. This chapter discusses the necessity for bioreactors in tissue engineering, the numerous types of bioreactor that exist, the means by which they stimulate cells and how their functionality is governed by the requirements of the specific tissue being engineered and the cell type undergoing stimulation. PMID- 21248414 TI - Posttraumatic stress disorder and work. PMID- 21248415 TI - Return to work after 9/11. AB - This case study is a report of a rehabilitative employment program that used trauma focused group treatment with individuals who suffered from Posttraumatic Stress Disorder (PTSD) post 9/11. The program was developed in order to assist them to return to the work force. These Individuals lost their jobs because of the 9/11 terrorist attack and experienced financial difficulty, yet because of their PTSD symptoms, had difficulty seeking employment. Individuals were selected for group treatment based on the presence of PTSD symptoms as measured by The Posttraumatic Stress Diagnostic Scale, an external locus of control determined by the Internal and External Locus of Control Scale, low self-esteem as per the Self Efficacy Scale, and hopelessness, as assessed through the Hopelessness Scale. Additional assessments (Role Checklist, Psychiatric Rehabilitation Determination, Vocational Sentence Completion, Activity Record of the Occupational Questionnaire, and an interview that included a work history) were administered by an occupational therapist. Results of these assessments were used to inform group co-leaders (one social worker and one occupational therapist per group) of their members' symptoms, coping mechanisms, attitudes towards work, rehabilitation readiness, life roles and values, and use of time in order to plan appropriate group intervention. Groups met for once-a-week 90 minute sessions. Group leaders used restructuring and systematic prolonged exposure to encourage group members to describe their traumatic experiences in order to neutralize negative affect states, mange symptoms, and work through guilt and distorted perceptions. Members attended until they began gainful employment. Descriptive data revealed that during the first year of the program, 9/11/2001-9/11/2002, 262 of the 3,567 clients seen (13.6%) returned to the work force. PMID- 21248416 TI - U.S. Army combat operational stress control throughout the deployment cycle: a case study. AB - As military conflicts around the world persist, a comprehensive approach in managing behavioral health issues will continue to be a key component of military healthcare. Deployed military personnel frequently exposed to trauma are well known to be at high risk for developing behavioral health disorders, including combat stress reactions and posttraumatic stress disorder. In the U.S. Army, members of combat operational stress control (COSC) units have unique skills to assist soldiers and their families not only throughout all phases of a deployment, but also throughout a soldier's entire career. The purposes of this article are twofold, first to describe the role of COSC operations with an emphasis on interventions in a deployed environment. The second purpose is to present a case study from Operation Iraqi Freedom highlighting the efficacy of the COSC approach to meet a Soldier's behavioral health needs in a deployed environment. PMID- 21248417 TI - A study in contrasts: inscriptions of posttraumatic stress disorder (PTSD) in two works of fiction. AB - OBJECTIVE: This study investigates the depiction of Posttraumatic Stress Disorder (PTSD) in two works of fiction, The Bluest Eye, by Toni Morrison, and Ordinary People, by Judith Guest. PARTICIPANTS: In each text, the character struggling to mount a defense against the symptoms of PTSD is a child who must confront not only a single, precipitous event but also deleterious, ancillary conditions that threaten to impede the recovery process. METHODS: This is a study in contrast that utilizes a comparative case analysis of two fictional characters. RESULTS: One child reconstructs an integrated self while the other deteriorates mentally and emotionally. CONCLUSIONS: These results suggest factors such as social supports, economic status, race and aesthetic self-image may play critical roles in a child's resiliency to the symptoms of PTSD. PMID- 21248418 TI - Posttraumatic stress disorder and occupational performance: building resilience and fostering occupational adaptation. AB - Resilience and vulnerability refer to an individual's capacity to persevere in the face of adversity. Resiliency and vulnerability are distinctive personal characteristics influenced by environmental factors such as socio-cultural and institutional contexts. Resiliency and vulnerability are not absolute; they are psychosocial constructs of a phenomenological continuum. Hence, a resilient individual is not invincible to all life events but has the capacity to endure in most circumstances. Clients who sustain traumatic injuries or witness traumatic events have a greater vulnerability to stress disorders like posttraumatic stress disorder (PTSD). Occupational therapy practitioners should be cognizant of a client's resilient and adaptive capacities when providing services to a client who has endured a traumatic event. This paper explores resilience theory and its application to occupational therapy practice. PMID- 21248419 TI - Challenges of welfare-to-work programs. AB - Governmental expectations of placement outcomes were often high given the severity of work barriers that were present in disabled welfare recipients in the United States [11]. The purpose of this article is to identify challenges that were inherent in welfare-to-work programs and solutions to these challenges. Although rich with opportunity, welfare-to-work programs presented the challenge of employing large numbers of difficult-to-employ individuals before their public assistance benefits expired?cite{5}. Many clients also had symptoms of Posttraumatic Stress Disorder (PTSD) secondary to childhood physical or sexual abuse (59%) or severe domestic violence (55%) [8]. Few funds were available for work training and education. Instead, the employment-first model was expected even though most consumers did not have a high school diploma, had not worked in years, and were fearful and resistant about returning to work [3]. Performance based payment systems presented a challenge because the program's future depended on the compliance of its consumers. There was an impetus for substance abusers to return to work even if they were still using drugs, which contradicted the teachings of many recovery models. This paper presents possible solutions to each of these problems and reports outcomes of one particular welfare-to-work program. By examining the challenges of welfare-to-work programs, by identifying solutions, and by realizing that these solutions are inherent in the basic principles of rehabilitation, this article provides therapists with tools and motivation to make unique contributions to this area of practice. PMID- 21248420 TI - Return to work: a case of PTSD, dissociative identity disorder, and satanic ritual abuse. AB - This case study investigated an intervention that enabled an individual with Posttraumatic Stress Disorder (PTSD), Dissociative Identity Disorder (DID), and satanic ritual abuse to return to work after discharge from psychiatric inpatient treatment. The Occupational Questionnaire [88] revealed past difficulties in organization, awareness of time, communication, cooperation, frustration tolerance, competition, stress management, goal setting, and amnesia resulting in incomplete tasks and sporadic attendance at work. The Role Checklist [72] identified alters valuing work and employed in the past. The Modified Interest Checklist [70] identified running as an interest that 24 alters shared. Based on the initial evaluations, three times a week treadmill running was used as an intervention that built work skills (as measured by the Clerical Work Sample of the Valpar Component Work Sample Series [97]) necessary to sustain gainful employment upon discharge. After intervention, this individual improved in awareness of time, stress management, and goal setting abilities and was less amnestic as per the Occupational Questionnaire [88] and four additional alters expressed an interest in work according to the Modified Interest Checklist [70]. PMID- 21248421 TI - The influence of posttraumatic stress disorder, depression, and sensory processing patterns on occupational engagement: a case study. AB - The purpose of this article is to provide a brief overview of how Posttraumatic Stress Disorder (PTSD), Depression, and Sensory Processing patterns influence occupational engagement, including work performance. Interventions and outcomes of the Sensory Modulation Program and approaches from Cognitive Behavior Therapy (CBT) are reviewed through single case exploration with a 42 year-old woman in outpatient services. The marked increase in occupational engagement and improved work performance in this single case review demonstrates the need for more research on the use of the Sensory Modulation Program and approaches from CBT with populations with PTSD, Depression, and Sensory Processing disorder. PMID- 21248422 TI - Occupation as therapy for trauma recovery: a case study. AB - In this case study, a young women who has chronic verbal, emotional, and physical abuse and was exposed to repetitive adult acts of abuse as a child initially presented with Posttraumatic Stress Disorder (PTSD) marked by constriction and disconnection, which resulted in her feeling passive and tortured. As part of her occupational therapy intervention, based on the occupational adaptation, psychoanalytic, and recovery frames of reference, she was able to use her skills as a musician and lyricist to work through her trauma by performing heavy metal music. She used work to express emotions and tell and retell her story to audiences eager to hear her. Work helped her develop an identity that allowed her to be active in the world and reach out to others through her music. This case study focuses on the intervention - how music and occupation functioned as a foundation for relieving her PTSD. PMID- 21248423 TI - Expert witness evaluation of posttraumatic stress disorder (PTSD) and return to work. AB - This author was hired by a defendant's attorney as an expert witness in the evaluation of a plaintiff who filed a lawsuit for the loss of her job and concomitant income due to posttraumatic stress disorder (PTSD) symptoms acquired after sustaining a traumatic injury. This writer evaluated her symptoms, level of function, roles, and interests using a variety of assessments. This case study is a report of the evaluation. The results indicated that the plaintiff developed adequate coping mechanisms to manage her symptoms of PTSD in order to function in her diverse and chosen roles of worker, mother, care giver, wife, family member, volunteer, home maintainer, and religious participant even though she did not return to her prior place of employment. Because of these results, the case was settled out of court in the favor of the defendant. PMID- 21248424 TI - Pretraumatic stress prevention (PTSP) versus posttraumatic stress disorder (PTSD). PMID- 21248425 TI - The management of hepatocellular carcinoma in Asia: a guideline combining quantitative and qualitative evaluation. AB - Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related deaths around the world; Asian countries account for nearly 78% of the roughly 600,000 cases of HCC reported globally each year. Europe, the US, Asian-Pacific nations, South Korea, and Japan have published evidence-based guidelines for the management of HCC. The management of HCC in Japan has achieved remarkable results, which are attributed to a combination of quantitative and qualitative evaluation incorporated in the Japanese guidelines. However, many of the control methods and interventions in current HCC guidelines cannot be implemented in some Asian countries. The majority of HCC patients in Asia still present with advanced HCC and long-term outcomes following treatment are unsatisfactory because of a lack of effective adjuvant and systemic therapies. Asian countries should formulate evidence-based clinical practice guidelines and pay particularly close attention to combining quantitative and qualitative evaluation when drafting and implementing HCC guidelines. The guidelines should also be updated by incorporating new evidence. PMID- 21248426 TI - The role of hypoxia in mental development and in the treatment of mental disorders: a review. AB - The purpose of this review is to trace the trends in studying and applying hypoxia in the field of mental problems. A literature review was conducted using the PubMed database, with a time-frame extending to October 2010. According to the neurodevelopmental model of mental disorders, abnormalities in brain development during pre- and perinatal life lead to psychotic manifestation in adolescence or young adulthood. Studies show that hypoxia plays an important role in almost any risk factor related to brain development in early life: pre eclampsia, infection/inflammation, hypoxia/ischemia, preterm birth, and asphyxia at birth. The cited data show trends in using hypoxia, especially in the form of intermittent hypoxic training, for the treatment and prevention of mental disorders, and trends in using it for increasing mental capacity in animals. PMID- 21248427 TI - Chinese herbal medicines as adjuvant treatment during chemo- or radio-therapy for cancer. AB - Numerous studies have indicated that in cancer treatment Chinese herbal medicines in combination with chemo- or radio-therapy can be used to enhance the efficacy of and diminish the side effects and complications caused by chemo- and radio therapy. Therefore, an understanding of Chinese herbal medicines is needed by physicians and other health care providers. This review provides evidence for use of Chinese herbal medicines as adjuvant cancer treatment during chemo- or radio therapy. First, Chinese herbal medicines (e.g. Astragalus, Turmeric, Ginseng, TJ 41, PHY906, Huachansu injection, and Kanglaite injection) that are commonly used by cancer patients for treating the cancer and/or reducing the toxicity induced by chemo- or radio-therapy are discussed. Preclinical and clinical studies have shown that these Chinese herbal medicines possess great advantages in terms of suppressing tumor progression, increasing the sensitivity of chemo- and radio therapeutics, improving an organism's immune system function, and lessening the damage caused by chemo- and radio-therapeutics. Second, clinical trials of Chinese herbal medicines as adjuvant cancer treatment are reviewed. By reducing side effects and complications during chemo- and radio-therapy, these Chinese herbal medicines have a significant effect on reducing cancer-related fatigue and pain, improving respiratory tract infections and gastrointestinal side effects including diarrhea, nausea, and vomiting, protecting liver function, and even ameliorating the symptoms of cachexia. This review should contribute to an understanding of Chinese herbal medicines as adjuvant treatment for cancer and provide useful information for the development of more effective anti-cancer drugs. PMID- 21248428 TI - Preparation of asialo-agalacto-glycophorin A for screening of anti-Tn antibodies. AB - Oncogenic antigens such as Tn-antigen (GalNAcalpha-Ser/Thr) are involved in metastatic processes and are associated with a poor prognosis, thus representing excellent targets for cancer intervention. Available anti-Tn antibodies which can be applied for therapeutics or diagnostics are severely limited mostly because the Tn-antigen epitope by itself is too small to be antigenic in addition to the fact that many carbohydrates are self-antigens. To characterize anti-Tn monoclonal antibodies as well as to perform panning and screening for isolation of anti-Tn single chain variable fragments from phage-display libraries, a large quantity of inexpensive Tn-antigens are needed. In this study, thus, glycophorin A which is a highly glycosylated sialoglycoprotein with approximately 12 O glycans was sequentially treated with sialidase and beta-galactosidase to remove sialic acid and galactose residues. The resulted product was shown to be an asialo-agalacto-glycophorin A which is reactive to an anti-Tn-antigen antibody. The simple preparation procedures described here would greatly help production and characterization of potentially valuable anti-Tn-antigen antibodies, which can be readily developed for cancer therapeutics and diagnostics. PMID- 21248429 TI - Identification of mouse mutant cells exhibiting plastic mutant phenotype II; ionizing radiation-induced mutant phenotype plasticity is not dependent on DNA methylation of the hypoxanthine phosphoribosyl transferase gene in mouse FM3A cells. AB - As we previously reported, we isolated and examined mouse mutant cells exhibiting phenotypic plasticity. Approximately 10% of 6-thioguanine resistant (6TG(R)) cells derived from the irradiated cell population exhibited phenotypic plasticity and reverted to wild type HAT resistance (HAT(R)). Similar mutant cells were also identified in an un-irradiated wild type cell population, but at a lower frequency. Ionizing irradiation enhanced the frequency of the plastic mutation approximately 24 times in our experiments. Treatment with 5-aza-cytidine did not affect phenotypic plasticity. In this study, we further performed detailed molecular analysis of the promoter region of the hypoxanthine phosphoribosyl transferase (Hprt) gene. The analysis revealed that most cytidine residues were not methylated, even in 6TG(R) mutant cells, in which Hprt activity must be down regulated. These results suggested that DNA methylation was not involved in mutant phenotype plasticity, a new type of genomic instability induced by ionizing radiation. Plasticity in gene regulation may play an important role in radiation carcinogenesis, which is a multiple-stage process. PMID- 21248430 TI - Availability and use of emergency obstetric care services in public hospitals in Laos PDR: a systems analysis. AB - The maternal mortality ratio in Laos in 2005 was 660 per 100,000 lives birth which was the third highest in Asia-Pacific Region. The objective was to determine the availability and use of emergency obstetric care (EmOC) in provincial and district hospitals in Borikhamxay, Khammouane, and Savannakhet provinces using UN guidelines. A hospital-based cross sectional survey was conducted from January to March 2008. All district (30) and provincial hospitals (3) from three provinces were included. Analysis was based on hospital records reflecting 12 months of facility data. Data indicates that only 14 hospitals (42.4%) were providing EmOC services, i.e., 9 basic, 5 comprehensive services. The proportion of births in EmOC facilities was only 11.2%, the met need was a very low 14.5%, and the cesarean section rate was only 0.9%. The case fatality rate in Borikhanxay province was 2.8%; in Khammouane and in Savannakhet provinces it was less than 1%. Record keeping at hospitals was poor. Signal functions provided in the last three months showed only 48.5% of the facilities performed assisted vaginal delivery. This is the first study in Lao PDR to assess EmOC services. Almost all the indicators were below the UN recommendations. Health planners must take evidence-based decisions to rectify and improve the situation in the hospitals regarding EmOC services. These data can therefore help government to assign and allocate budgets appropriately, and help policymakers and planners to identify systemic bottlenecks and prioritize solutions and will help in improving maternal health. PMID- 21248431 TI - Association between circulating leptin and insulin resistance, the lipid profile, and metabolic risk factors in North Indian adult women. AB - Leptin plays an important role in the regulation of body weight and operates by inhibiting food intake and stimulating energy expenditure. The purpose of the present study was to ascertain the relationship between serum leptin levels and the lipid profile, insulin resistance, and metabolic risk factors in North Indian adult women. In a transactional case-control study of 390 women, subjects were 186 women with metabolic syndrome according to National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP) guidelines and 204 healthy control women without metabolic syndrome, all of whom were between 20-40 years of age. Circulating leptin levels were determined by sandwich enzyme-linked immunosorbent assay, insulin resistance was determined by homeostasis model assessment for insulin resistance (HOMA-IR), and the lipid profile was determined using an enzymatic method. Results indicated that circulating leptin (13.38 +/- 9.00 vs. 8.16 +/- 6.31 ng/mL, p < 0.001), HOMA-IR (2.68 +/- 2.05 vs. 1.72 +/- 1.20, p < 0.001), the lipid profile, and other metabolic risk factors (waist circumference, waist-to-hip ratio, body mass index, and fasting plasma insulin) were significantly higher in women with metabolic syndrome than in women without the syndrome (p < 0.001). Further, in women with metabolic syndrome serum leptin was significantly (p < 0.05 or p < 0.001) and positively correlated with HOMA-IR (p = 0.000) and other metabolic risk factors but negatively correlated with fasting plasma glucose, triglycerides, and high-density lipoprotein cholesterol. Circulating leptin was found to be significantly associated with hyperlipidemia, insulin resistance, and other metabolic risk factors in North Indian adult women. PMID- 21248432 TI - Frequencies of VKORC1 -1639 G>A, CYP2C9*2 and CYP2C9*3 genetic variants in the Northern Indian population. AB - Dose requirements for oral anticoagulants in thromboembolic events are influenced by polymorphisms in VKORC1 and CYP2C9 genes. The Indian population comprises multiple ethnic groups but no data is available on allele frequencies of these genes for North Indians. The present study aimed at establishing the allele and genotype frequencies of VKORC1 -1639 G>A, CYP2C9*2 and CYP2C9*3 alleles in the North Indian population. One hundred and two healthy subjects from the Northern Indian region were genotyped for VKORC1 -1639 G>A, CYP2C9*2 and CYP2C9*3 by polymerase chain reaction and restriction fragment length polymorphism. Allele frequencies were compared with that of the HapMap populations. The allele frequencies for VKORC1 -1639 A, CYP2C9*2 and CYP2C9*3 were found to be 14.22%, 4.90% and 3.92% respectively. This report also describes the inter-ethnic differences in the Northern Indian frequencies of VKORC1 -1639 G>A, CYP2C9*2 and CYP2C9*3 alleles with that of other populations and HapMap project data. VKORC1 1639 G>A allele is present at moderately high frequency in the Northern Indian population. The frequencies of CYP2C9*2 and CYP2C9*3 alleles are also found to be different from other populations. PMID- 21248433 TI - Loss-of-heterozygosity analysis of 6-thioguanine-resistant mutants induced by radon exposure in mouse FM3A cells. AB - Radon is an inert gas that can migrate from soils and rocks and accumulate in enclosed areas such as buildings and underground mines. The ubiquitous occurrence of radon in the environment is the primary cause of harmful radiation exposure to the public. To investigate the mutagenic effect of radon, mouse FM3A cells growing on soft agarose plates were exposed to alpha particles disintegrated from radon-222 and daughter elements. Mutation induction at the hypoxanthine phosphoribosyl transferase (Hprt) allele was examined at radon concentrations of 10, 230, 1,100, 6,500, 200,000, 1,000,000, and 10,000,000 Bq/m(3) for an exposure period of 1 week. A typical inverse dose-rate effect was observed in the frequencies of 6-thioguanine-resistant (6TG(R)) mutations, and lower mutation frequencies were exhibited at 230, 1,100, 6,500, and 200,000 Bq/m(3) than at 10, 1,000,000, and 10,000,000 Bq/m(3). Loss-of-heterozygosity (LOH) analysis at the Hprt locus revealed that deletion mutations were dominant at radon concentrations of 230, 1,100, 6,500, and 10,000,000 Bq/m(3), but not at 10, 200,000, and 1,000,000 Bq/m(3). These results suggested that alpha particles released from radon in the normal atmosphere did not exhibit the measured mutagenic effect in mouse FM3A cells, but that increased concentrations of radon led to a significant increase in the mutagenic effect of radon. At 6,500 Bq/m(3), radon exposure induced the least number of 6TG(R) mutants but all had LOH deletion mutations, which is the typically observed type of mutation in radiation carcinogenesis. Our results suggest that certain concentrations of environmental radon may have specific carcinogenic potential, and it should be avoided by proper ventilation wherever possible. PMID- 21248434 TI - No relation between folate and homocysteine levels and depression in early pregnant women. AB - The objective in this study was to evaluate the association between folate and homocysteine (Hcy) levels and depressive symptoms in early pregnancy. A cross sectional study was conducted with 86 pregnant women in the first trimester. A Japanese version of the Center for Epidemiologic Studies Depression (CES-D) scale was used to screen for depression. Non-fasting blood samples were collected from the women to measure folate and Hcy levels. Fifty-three (61.6%) women scored at or above a clinical cut-off of 16, and were classified with depression. In logistic regression analyses, no significant associations were observed between the incidence of depression in the first trimester and elevated Hcy and deficiencies of serum folate, folate intake, vitamin B6 intake and vitamin B12 intake. Folate and Hcy concentrations, and folate consumption, may not be protective against depression in early pregnancy. PMID- 21248435 TI - Second trimester pregnancy termination with 400 MUg vaginal misoprostol: efficacy and safety. AB - The present study was designed to evaluate the efficacy and safety of misoprostol (400 MUg) given intravaginally repeated at 6 hourly intervals for a maximum of 6 doses for second-trimester pregnancy terminations. The study was conducted on women who had to undergo pregnancy termination between 13 and 26 weeks of gestation for various indications but mainly intrauterine death over a period of 2 years. A standard regime of 400 MUg of misoprostol 6 hourly intravaginally was given until a maximum of 6 doses. Sixty women underwent second trimester terminations. The mean induction abortion interval was 11.8 h. The success rate at the end of 48 h was 96.6%. Side-effects were in the form of incomplete abortion, excessive blood loss, and fever. No patient had a uterus rupture. Intravaginal misoprostol 400 MUg given 6 hourly seems to be an effective, safe, and acceptable method for second trimester pregnancy terminations. PMID- 21248436 TI - Ruptured hepatic subcapsular hematoma following laparoscopic cholecystectomy: report of a case. AB - Laparoscopic cholecystectomy is now a standard procedure for cholecystolithiasis because of its minimally invasive nature compared to the conventional method. However, severe complications that have never been seen for open surgery have also been reported. Here, we report the case of a 28-year-old woman who underwent laparoscopic cholecystectomy and then developed a ruptured subcapsular hematoma. On postoperative day 1, she developed shock, and postoperative bleeding was suspected. During re-operation, a ruptured subcapsular hematoma of the whole right lobe of the liver with active bleeding was found, and hemostasis was achieved. In this case, it was assumed that the rupture of the subcapsular hematoma was due to compression of the liver by the clamp for retrieving the spilled gallstones during the first operation and perioperative administration of nonsteroidal anti-inflammatory drugs. PMID- 21248437 TI - A brief review of voice restoration following total laryngectomy. AB - Despite advances in conservative laryngeal surgery and radiotherapy, total laryngectomy still remains the procedure of choice for advanced-stage (UICC T3 and T4) laryngeal carcinoma, around the world. The functional rehabilitation of the laryngectomized patients has been a concern of head and neck surgeons and speech therapists. Significant developments in speech rehabilitation over the past three decades have led to substantial improvements in the quality of life of these patients. The tracheoesophageal (TE) voice prosthesis has become the gold standard in various centers for voice rehabilitation since its introduction in 1980. Successful tracheoesophageal voice restoration in laryngectomy patients can be very rewarding and patients no longer have to live in silence while they await the results of their cancer treatments. They can face the challenges of life with the knowledge that a near normal quality of life is very much possible.In this article, we present a brief review of voice restoration following laryngectomy. PMID- 21248438 TI - Helicobacter pylori infection in relation to gastric cancer progression. AB - Gastric cancer is a major cause of cancer death worldwide, especially in developing countries. The incidence of gastric cancer varies from country to country, probably as a result of genetic, epigenetic, and environmental factors. H. pylori infection is considered as a major risk factor in the development of gastric cancer. However, the scenario varies in Asian countries, exhibiting a higher rate of H. pylori infection and low incidence of gastric cancer, which could be attributed to strain-specific virulence factors and host genetic makeup. In this review, we discuss the various virulence factors expressed by this bacterium and their interaction with the host factors, to influence pathogenesis. PMID- 21248439 TI - Preoperative assessment and optimization in periampullary and pancreatic cancer. AB - Perioperative management of pancreatic and periampullary cancer poses a considerable challenge to the pancreatic surgeon, anesthesiologist, and the intensive care team. The preoperative surgical evaluation of a pancreatic lesion aims to define the nature of the lesion (malignant or benign), stage the tumor, and to determine resectability or other non-surgical treatment options. Patients are often elderly and may have significant comorbidities and malnutrition. Obstructive jaundice may lead to coagulopathy, infection, renal dysfunction, and adverse outcomes. Routine preoperative biliary drainage can result in higher complication rates, and metal stents may be preferred over plastic stents in selected patients with resectable disease. Judicious use of antibiotics and maintaining fluid volume preoperatively can reduce the incidence of infection and renal dysfunction, respectively. Perioperative fluid therapy with hemodynamic optimization using minimally invasive monitoring may help improve outcomes. Careful patient selection, appropriate preoperative evaluation and optimization can greatly contribute to a favorable outcome after major pancreatic resections. PMID- 21248440 TI - Outcome of combined modality treatment including neoadjuvant chemotherapy of 128 cases of locally advanced breast cancer: data from a tertiary cancer center in northern India. AB - BACKGROUND: Breast cancer is now the most common cancer in many parts of India and the incidence varies from 12 to 31/100,000, and is rising. Locally advanced breast cancer (LABC) accounts for 30-35% of all cases of breast cancers in India. LABC continues to present a challenge and imposes a major health impact in our country. MATERIALS AND METHODS: We carried out a analysis of our LABC patients who received neoadjuvant chemotherapy (NACT) at our hospital over a 10-year period, from January 1995 to December 2004. We analyzed the response to NACT, disease-free survival (DFS), and overall survival (OS). RESULTS: Patients with stages IIIA, IIIB, and IIIC were included. LABC comprised of 26.24% (609 patients) of new patients. One hundred and twenty-eight (31.1%) patients received NACT. Median age was 48 years and estrogen receptor was positive in 64%. Chemotherapy protocol was an FEC (5-Fluorouracil, Epirubicin, Cyclophosphamide) regimen in the following doses: Cyclophosphamide 600 mg/m2, 5-FU 600 mg/m2, and Epirubicin 75 mg/m2 given every three weeks, six doses, followed by modified radical mastectomy (MRM) and locoregional radiotherapy. The overall response rate (complete response (CR) + partial response (PR)) was 84.4%, clinical CR (cCR) was 13.3% and pathological CR (pCR) was 7.8%. Median DFS and OS were 33 and 101 months, respectively. The disease-free survival (DFS) and overall survival (OS) at five years were 41 and 58%, respectively. CONCLUSIONS: This study analyzes the outcome in patients who received NACT, in the largest number of LABC patients from a single center in India, and our results are comparable to the results reported from other centers. PMID- 21248441 TI - Evaluation of carbamate insecticides as chemotherapeutic agents for cancer. AB - BACKGROUND: Cancer chemotherapy has already been in practice by the use of toxins and some of the specific poisonous compounds of cyanide derivatives. Carbamate insecticides inhibit cellular metabolism including energy, protein, and nucleic acid metabolism, thereby, causing cell regression and death. AIM: Preliminary evaluation of three carbamate insecticides, namely, baygon, carbaryl, and carbofuran as chemotherapeutic agents for cancer is undertaken in the present study. MATERIALS AND METHODS: The toxicity of carbamates on squamous cell carcinoma was assessed in-vitro using dye binding tests. Cells were grown in microtitration ELISA plates, as adherent cultures, for six hours, and then exposed to the drugs for 2, 4, 8, and 12 hours, and finally stained with neutral red, to assess the viable cell number, and with methylene blue for the determination of protein in the monolayer. Optical density was read in an ELISA reader. STATISTICAL ANALYSIS: The data obtained during the experiment was subjected to statistical analysis by using the student 't' test. RESULTS: The results indicated that the percentage of the viable cell number reduced with an increase in the time of exposure of the drugs. Exposure of the tumor cells to the drugs for 12 hours detached them completely from the wells, and hence, all the cells were washed out. Exposure of the drugs prior to the establishment of the culture in-vitro resulted in the non-formation of the monolayer in the wells. CONCLUSIONS: Among the three drugs studied, the survival percent was least with carbaryl treatment followed by baygon, and with carbofuran treatment it was almost near to control group. PMID- 21248442 TI - Comparative study of the toxicity of 5-fluorouracil-adriamycin-cyclophosphamide versus adriamycin-cyclophosphamide followed by paclitaxel in carcinoma breast. AB - CONTEXT: When cure is possible treatment should be undertaken despite life threatening toxicities. Fluorouracil-Adriamycin-Cyclophosphamide (FAC) and Adriamycin-Cyclophosphamide (AC-P) are two popular regimens used in the treatment of carcinoma breast and the data regarding the toxicity profile of the AC-P regimen is scarce in the South Indian population. AIMS: To study the severity of different types of toxicities seen in patients on FAC and AC-P regimens, to grade the toxicity according to the World Health Organization (WHO) toxicity grading, and to compare the same. SETTINGS AND DESIGN: A prospective observational study, with 50 patients in each regimen, was conducted in the Department of Radiotherapy between February 2007 and July 2008. MATERIALS AND METHODS: The high risk patients received the AC-P regimen and the rest received the FAC regimen. The toxicities developed were graded according to the WHO guidelines. STATISTICAL ANALYSIS USED: The data was analyzed using the chi square test in SPSS 16. RESULTS: Anemia, hyperpigmentation, stomatitis, and diarrhea were significantly high (P < 0.05) in patients receiving the FAC regimen, whereas, leukopenia, myalgia, arthralgia and peripheral neuropathy were significantly high (P < 0.05) in patients receiving the AC-P regimen. The Karnofsky performance status was higher in patients receiving the AC-P regimen. CONCLUSIONS: Although both the regimens had different toxicity profiles the quality of life was better for patients on the AC-P regimen. PMID- 21248443 TI - Integrating the geographic information system into cancer research. AB - Cancer control researchers seek to reduce the burden of cancer by studying interventions, their impact on defined populations, and the means by which they can be better used. The first step in cancer control is identifying where the cancer burden is elevated, which suggests locations where interventions are needed. Geographic information systems (GIS) and other spatial analytic methods provide such a solution and thus can play a major role in cancer control. The purpose of this article is to examine the impact of GIS on the direction of cancer research. It will consider the application of GIS techniques to research in cancer etiology. PMID- 21248444 TI - Role of RT-PCR and FISH in diagnosis and monitoring of acute promyelocytic leukemia. AB - BACKGROUND: Patients with a presence of Promyelocytic Leukemia-Retinoic Acid Receptor Alpha (PML-RARA) genes rearrangement predict a favorable response to all trans retinoic acid (ATRA), and a significant improvement in survival. Therefore, establishing the presence of PML-RARA rearrangement is important for optimal patient management. AIM: The objective of this study is to compare and assess the role of fluorescent in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) in the diagnosis and long-term monitoring of Acute Promyelocytic Leukemia (APL). MATERIALS AND METHODS: We compared 145 samples received at different interval of times to analyze the sensitivity of RT PCR and FISH. RESULTS: The failure rate for RT-PCR was 4% at baseline, 13% at induction, and 0% at the end of consolidation. And for FISH it was 8% at baseline, 38% at induction, and 66% at the end of consolidation. The predictive values of relapse in the patients who were positive and negative by RT-PCR, at the end of induction, were 60% and 3%, respectively, and at end of consolidation it was 67% and 4%, respectively. On the other hand the predictive values of relapse in patients who were positive and negative by FISH at end of induction were 57% and 6%, respectively; while at end of consolidation it was 14% who were negative by FISH. CONCLUSION: Both RT-PCR and FISH are important for the diagnosis of APL cases, as both techniques complement each other in the absence or failure of any one of them. However, RT-PCR is more sensitive than FISH for the detection of minimal residual disease in the long-term monitoring of these patients. The present study shows that the predictive value of relapse is more associated with minimal residual disease (MRD) results by RT-PCR than that by FISH. PMID- 21248445 TI - Spirituality, distress, depression, anxiety, and quality of life in patients with advanced cancer. AB - OBJECTIVE: To study the influence of spiritual well being (Sp WB) on symptoms of distress, depression, and other dimensions of quality of life in advanced cancer patients receiving palliative care. MATERIALS AND METHODS: The study was cross sectional in nature. Fifty patients with advanced cancer from a hospice were assessed with the following instruments: the visual analog scale for pain (VAP), M.D. Anderson symptom inventory (MDASI), Hospital Anxiety Depression Scale (HADS), Functional assessment of cancer therapy-Palliative Care (FACT-pal), and Functional assessment of chronic illness therapy-spiritual well-being (FACIT-sp). We studied the correlations between spirituality and other variables on these scales. RESULTS: Depression and anxiety were negatively correlated with spiritual well-being (Sp WB). Sp WB was significantly correlated with fatigue (r = -0.423, P = 0.002), symptom distress (r = -0.717, P < 0.001), memory disturbance (r = 0.520, P < 0.001), loss of appetite (r = -0.399, P = 0.004), drowsiness (r = 0.400, P = 0.004), dry mouth (r = -0.381, P = 0.006), and sadness (r = -0.720, P < 0.001). Sp WB was positively correlated with all the other aspects of QOL measures. Predictors such as palliative care well-being (t = 2.840, P = 0.008), distress (t = -2.582, P = 0.015), sadness (t = -2.765, P = 0.010), mood (t = 2.440, P = 0.021), and enjoyment in life (t = -3.586, P = 0.001) were significantly correlated with Sp WB, after regression analysis. CONCLUSIONS: This study suggests that spiritual well being is an important component of the quality of life of advanced cancer patients, and is closely related to the physical and psychological symptoms of distress. It should be addressed appropriately and adequately in palliative care settings. PMID- 21248446 TI - Role of cetuximab and sorafenib in treatment of metastatic colorectal cancer. AB - BACKGROUND: The relationship of epidermal growth factor receptors (EGFR) pathway, such as PI3K, K-ras, and B-raf, with response to EGFR-targeted antibodies is less well studied. AIM: To assess sorafenib with cetuximab in treating metastatic colorectal cancer. SETTINGS AND DESIGN: Thirty-five patients with metastatic colorectal cancer were randomized to receive cetuximab with or without oral sorafenib. PATIENTS AND METHODS: Patients received cetuximab i.v. weekly for four weeks and oral sorafenib twice daily on days 1-28, with recycling every four weeks. The primary end point was the response rate (partial and complete), while the secondary end points were the adverse effects, time to progression and overall survival. STATISTICAL ANALYSIS: was made using the Statistical Product and Service Solutions, using SPSS 10.0, with estimation of both time to progression and overall survival time by the Kaplan-Meier method and comparing the two groups with the use of a log-rank test. RESULTS: Partial response was higher in cetuximab-sorafenib (EN), which constituted 33.3% compared to 17.6% in the cetuximab group (P = 0.44). Progression-free survival had a statistically higher significant difference in wild K-ras compared to mutant K-ras cases (P = .0001). Median overall survival was seven and five months in the (EN) and (E) groups respectively (P = 0.49). CONCLUSION: K-ras and B-raf was a predictor of response, so genotyping of tumors was needed for defining the patient population that was likely to benefit from the targeted therapy. A combination of therapy that simultaneously targets K-ras and B-raf could be a useful approach to increase the number of patients who may benefit from anti-EGFR therapy. PMID- 21248448 TI - Eight-year experience in esophageal cancer surgery. AB - AIM: Esophageal cancer remains a major and lethal health problem. In Nepal, not much has been explored about its management. The aim of this study was to conduct a retrospective review of esophageal cancer patients undergoing surgery or combined modality treatment at a cancer hospital in Nepal. MATERIALS AND METHODS: Resectable cases were treated primarily with surgery. Locally advanced cases with doubtful or obviously unresectability underwent preoperative chemo/radiation or chemoradiation followed by surgery. RESULTS: Among 900 patients, 103 were treated with curative intent. Mean age of patients was 54 years, and 100% of the patients presented with complaint of dysphagia. Surgery as a single modality of treatment was done in 57% of cases, and the remaining underwent combined modality treatment. Transthoracic and transhiatal approaches were used in 95% and 5% of cases, respectively. Nodal sampling, two-field (2-FD), and three-field lymphadenectomy (3-FD) were done in 18%, 59%, and 20% of cases, respectively. A majority of patients had pathological stage III disease (46.6%). In-hospitality mortality was 5%, and anastomotic leakage rate was 14%. In 87% of patients, R0 resection was achieved. Overall, 4-year survival was 20%. A R0 resection, early stage disease and 3-FD favored the survival advantage (P < 0.05). CONCLUSION: The mortality, complication, and survival results were in the acceptable range. R0 resection and radical nodal dissection should be standard practice. PMID- 21248447 TI - Correlates of cervical cancer screening among underserved women. AB - BACKGROUND AND OBJECTIVES: Substantial subgroups of Indian women, specifically those of ethnic minorities, had not been screened for cervical cancer or are not screened at regular intervals. We aim to find out the magnitude of cervical cancer and precancerous lesions among women in the age group 15-60 years, and to identify the various socio-demographic and reproductive correlates among those with the cervical lesions. PATIENTS AND METHODS: Nine hundred and sixty-eight adult women in the age group 15-60 years were selected by simple random sampling technique in a population based descriptive cross-sectional study in a cervical cancer screening camp in a primary health center at the East Sikkim, during 1st September to 30th November 2006. Main outcome measures were the extent and correlates of cervical cancer without any interventions. The data collection tool used for the study was a pre-tested questionnaire prepared prior to the study for ensuring feasibility, acceptability, time management, validity and reliability. Information on socio-demographic and reproductive variables was collected by interview method using this questionnaire. RESULTS: Out of 968 women in the study population, overwhelming majority 921 (95.15%) had no overt or pre-cancerous cervical lesion. Only 47 were found to have changes in their cervical epithelium. None of these 47 women was proved dyskaryotic on cytopathological screening of the cervical smear. No significant difference was noted among those with or without lesions among women below 30 years of age with those above, among illiterate women with literates, in per capita monthly family income difference, age at marriage and childbirth. Low-grade and high-grade squamous intraepithelial cervical lesions were associated with Hindu women only and were related with past history of abortion and still birth in women significantly. CONCLUSION: There was an imperative need for identifying prevalence of asymptomatic cervical dysplasia in all population. PMID- 21248449 TI - Tetany: possible adverse effect of bevacizumab. AB - BACKGROUND: Bevacizumab a recombinant humanized monoclonal antibody was approved in 2004 by US FDA for metastatic colorectal cancer. It is reported to cause potentially serious toxicities including severe hypertension, proteinuria, and congestive heart failure. AIM: To correlate adverse event tetany with the use of bevacizumab. MATERIALS AND METHODS: World Health Organization's Uppsala Monitoring Centre, Sweden, for reporting of adverse drug reactions from all over the world, identified 7 cases with tetany-related symptoms to bevacizumab from four different countries. These 7 patients reported to UMC database developed adverse events described as musculoskeletal stiffness (1), muscle spasm (1), muscle cramps (1), lock jaw or jaw stiffness (4), and hypertonia (1), with hypocalcaemia. RESULTS: After detailed study of the possible mechanism of actions of bevacizumab and factors causing tetany, it is proposed that there is a possibility of tetany by bevacizumab, which may occur by interfering with calcium metabolism. Resorption of bone through osteoclasts by affecting VEGF may interfere with calcium metabolism. Another possibility of tetany may be due to associated hypomagnesaemia, hypokalemia, or hyponatremia. CONCLUSIONS: Tetany should be considered as a one of the signs. Patient on bevacizumab should carefully watch for tetany-related symptoms and calcium and magnesium levels for their safety. PMID- 21248450 TI - Postoperative chemoradiation in patients with localized gastric adenocarcinoma: single center experience. AB - BACKGROUND: 5-Fluorouracil (FU)-based chemotherapy (CT) and concurrent 45 Gy radiotherapy (RT) is one of the standard postoperative approaches currently used in gastric carcinoma. The high toxicity rates of this treatment leads to interruption of treatment in the majority of patients. In our study, we investigated the rates of toxicity and treatment discontinuation observed during postoperative FU-based chemoradiotherapy (CRT); retrospectively evaluated the effect of CRT and the other prognostic factors on local and distant control and survival. PATIENTS AND METHODS: A total of 160 patients consisting of 97 total and 63 subtotal gastrectomy receiving postoperative CRT, have been studied retrospectively. RESULTS: Patients who had to discontinue the treatment for a median of 6 (range, 3-13) days experienced toxicity during treatment at a rate of 43%. During the 21 (range, 4-68) months of follow-up local recurrences were observed in 8 (5%) patients and distant recurrences were observed in 41 (25.6%) patients. While the 1-3 year overall survival (OS) rates were 75% and 42%, 13 year disease-free survival (DFS) rates were 63% and 42%, respectively. In the univariate analysis for OS and DFS demonstrated statistical significance for below those 60 years of age, D1-D2 dissection type, negative surgical margin, early treatment beginning, the absence of invasion, and early stage disease. D1D2 dissection type, early treatment beginning, age below 60 years and early stage disease significantly improve OS and DFS in multivariate analysis. CONCLUSIONS: Survival is worse in patients older than 60 years, had late treatment beginning, advanced stage and D0 dissection. PMID- 21248451 TI - [Evaluation of atrial conduction time by P wave dispersion and tissue Doppler echocardiography in prehypertensive patients]. AB - OBJECTIVES: Prehypertension is a predictor for the future development of hypertension and represents an increased risk for cardiovascular morbidity and mortality. Prolonged intra/interatrial conduction times demonstrated by P wave dispersion (PD) and tissue Doppler echocardiography (TDE) are related to the development of atrial fibrillation. The aim of this study was to evaluate atrial conduction time by PD and TDE in patients with prehypertension. STUDY DESIGN: In 46 prehypertensive patients (22 males, 24 females; mean age 56.5+/-12.3 years) and 39 normotensive healthy controls (19 males, 20 females; mean age 55.8+/-11.7 years), we measured P wave duration and dispersion on 12-lead electrocardiography, and atrial electromechanical coupling intervals (PA) by TDE. RESULTS: Maximum P wave duration (Pmax) and PD were prolonged in prehypertensives compared to controls (Pmax 110.1+/-13.8 vs. 91.4+/-7.7 msec, p<0.001; PD 55.7+/ 11.1 vs. 36.8+/-5.7 msec, p<0.001). Atrial PAs measured at the lateral and septal mitral annuluses were significantly delayed in the prehypertensive group (lateral PA 76.5+/-10.1 vs. 65.4+/-10.4 msec, p<0.001; septal PA 59.0+/-6.4 vs. 53.5+/-7.5 msec, p=0.002). Both interatrial (lateral PA-tricuspid PA) and intra-atrial (septal PA-tricuspid PA) conduction times were delayed in the prehypertensive group (25.8+/-9.3 vs. 17.0+/-9.5 msec, p<0.001; 9.2+/-3.7 vs. 6.7+/-3.0 msec, p=0.008, respectively). Correlation analysis showed that both Pmax and PD were correlated with interatrial (r=0.38, p<0.001 and r=0.40, p<0.001, respectively) and intra-atrial (r=0.31, p=0.01 and r=0.38, p<0.001, respectively) electromechanical delays. CONCLUSION: Our finding of significant prolongation of atrial electromechanical coupling and PD may indicate an increased risk for the development of atrial fibrillation in prehypertensive subjects. PMID- 21248452 TI - [Efficacy and outcome of primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction due to saphenous vein graft occlusion]. AB - OBJECTIVES: We evaluated the efficacy and outcome of primary percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) due to saphenous vein graft (SVG) occlusion. STUDY DESIGN: We reviewed 2,646 consecutive patients (mean age 56.6+/-11.8 years) who underwent primary PCI for STEMI between 2003 and 2009. All clinical and angiographic data and in-hospital and long-term (median 22 months) outcomes were retrospectively collected. The patients were classified into two groups based on the lesions treated with primary PCI, i.e., native vessels (n=2,625) and SVG (n=21). RESULTS: Compared to patients with occluded native vessels, patients with SVG occlusion had significantly higher rates of coronary bypass operation (100% vs. 2.3%, p<0.001), previous myocardial infarction (52.4% vs. 10.8%, p<0.001), and diabetes mellitus (52.4% vs. 25.1%, p=0.002), but lower frequency of anterior myocardial infarction (9.5% vs. 49.3%, p<0.001). Tirofiban use (71.4% vs. 48.2%, p=0.01) and three-vessel disease (81% vs. 25.6%, p<0.001) were significantly more common in the SVG group. The rate of successful primary PCI was lower in SVG occlusions compared to native vessels (61.9% vs. 84.7%, p=0.01). The two groups did not differ significantly with respect to in-hospital and long-term cardiovascular events and mortality (p>0.05). In multivariate logistic regression analysis, application of PCI to SVG was found to be an independent predictor for unsuccessful procedure (OR 6.76, 95% CI 2.05-22.21; p=0.002). CONCLUSION: Although the success rate of primary PCI in SVG lesions was lower compared to native vessels, this did not have an adverse effect on postprocedural cardiovascular events and mortality in patients presenting with STEMI. PMID- 21248453 TI - [The effects of thyroid hormones and interleukin-8 levels on prognosis after congenital heart surgery]. AB - OBJECTIVES: We evaluated the effects of thyroid hormone levels and interleukin-8 levels on prognosis in patients undergoing congenital heart surgery under cardiopulmonary bypass (CPB). STUDY DESIGN: The study included 41 consecutive children (19 boys, 22 girls; mean age 3.4 +/- 3.1 years; range 0.3 to 12 years). The patients were divided into two groups based on the presence or absence of postoperative low cardiac output state (LCOS). The definition of LCOS included oliguria, tachycardia, metabolic acidosis, and increased plasma lactate level. Plasma total (tT4) and free (fT4) thyroxine, total (tT3) and free (fT3) triiodothyronine, thyroid stimulating hormone (TSH), and interleukin-8 (IL-8) levels were measured preoperatively and at 48 hours postoperatively. RESULTS: Postoperatively, nine patients (22%) developed LCOS. While the two groups were similar with respect to preoperative levels of thyroid hormones, lactate, and IL 8, postoperative tT3 and fT3 levels were significantly lower, and lactate and IL 8 levels were significantly higher in the LCOS group (p<0.05). In correlation analysis, postoperative IL-8 level showed significant correlations with CPB time (r=0.66), duration of mechanical ventilation (r=0.68), and inotropic requirement (r=0.59) (for all p<0.001). On the other hand, LCOS was significantly correlated with the following: preoperative tT4 (r=-0.32, p=0.043) and postoperative fT3 (r= 0.44, p=0.004) levels, duration of mechanical ventilation (r=0.56, p<0.001), intensive care unit stay (r=0.45, p=0.003), and cross-clamp time (r=0.43, p=0.005). Regression analysis showed preoperative level of tT4 as the independent predictor of LCOS (t=-2.092, p=0.045). Mortality occurred in four patients (9.8%) in the early postoperative period, all of whom were in the LCOS group. CONCLUSION: Our findings suggest that the development of LCOS after congenital heart surgery is associated with decreased total and free T3, and increased IL-8 levels at 48 hours, and preoperative tT4 level is an independent predictor of LCOS. PMID- 21248454 TI - [Adherence to statin therapy and LDL cholesterol goal attainment in type 2 diabetics and secondary prevention patients: the role of education and knowledge]. AB - OBJECTIVES: Lipid levels of most patients receiving antilipidemic therapy are not under control as proposed by the guidelines. We evaluated adherence to statin therapy and LDL cholesterol goal attainment in type 2 diabetic and secondary prevention patients. STUDY DESIGN: A total of 194 patients (131 men, 63 women; mean age 57 +/- 11 years) who had been on statin therapy for at least a year for a target LDL cholesterol level of <100 mg/dl were administered a two-part questionnaire. The first part inquired demographic and clinical characteristics, duration of hyperlipidemia, referral to a dietician, risk factors and, if present, the reasons for drug discontinuation. The second part consisted of 23 questions (total score 30) inquiring the knowledge levels of patients about hypercholesterolemia. RESULTS: There were 61 primary (31.4%, diabetics) and 133 secondary (68.6%) prevention patients. The mean LDL level was 122.6 +/- 28.7 mg/dl. The incidence of attaining target LDL level was only 23.7% (n=46), being lower in diabetics compared to secondary prevention patients (6.6% vs. 31.6, p<0.0001). The mean knowledge score was 18.2 +/- 5. When the threshold score was taken as 18 (median), attainment of the target LDL level was significantly higher in patients having a score of >= 18 (32%) compared to those with a lower score (14.9%). There were 77 patients (40%) who sought dietician counseling. Patients with a high school or higher education and those with dietician counseling had higher knowledge scores compared to those with a lower education level and without dietician counseling (p<0.0001). Intermittent drug discontinuation was seen in 109 patients (56.2%), the most common reason being decrease in cholesterol levels to normal (35%). CONCLUSION: Target LDL level was achieved in only about 24%. As the knowledge on hypercholesterolemia accrues, the success rate of LDL cholesterol goal attainment increases. PMID- 21248455 TI - Incremental diagnostic value of color M-mode propagation velocity of the descending thoracic aorta to exercise electrocardiography. AB - OBJECTIVES: Exercise electrocardiography test (EET) has limited sensitivity and specificity. Recently, color M-mode-derived propagation velocity of the descending thoracic aorta (APV) has been shown to be associated with coronary artery disease (CAD). We evaluated the incremental value of APV for better prediction of CAD in EET-positive patients. STUDY DESIGN: Color M-mode APV was measured in 342 patients undergoing EET for chest pain and an intermediate likelihood of CAD. Coronary angiography was performed in 199 patients having a positive EET. RESULTS: The mean APV was 44.5 +/- 20.8 cm/sec in patients with a positive EET compared to 63.5 +/- 19.6 cm/sec in those with a normal test. Significant CAD was detected in 134 patients (67.3%), involving one vessel (n=41), two vessels (n=52), and three vessels (n=41). Patients with CAD had significantly lower APV values compared to patients with normal coronary arteries (33.8 +/- 13.2 vs. 66.6 +/- 15.6 cm/sec, p<0.001). An APV value of <= 41 cm/sec predicted CAD with 85.1% sensitivity and 93.8% specificity. An APV of >61 cm/sec had 94% specificity for the estimation of normal coronary arteries. A threshold of >41 cm/sec and a threshold of >61 cm/sec would have avoided unnecessary coronary angiography in 30.7% (61/199) and 21.6% (43/199) of patients with a positive EET but high APV values, with negative predictive values of 75.3% and 84.3%, respectively. In correlation analysis, APV was significantly correlated with Duke treadmill score (r=0.587, p<0.001) and the number of coronary vessels involved (r=-0.767, p<0.001), but not with any of the echocardiographic parameters. CONCLUSION: Measurement of APV may improve diagnostic value of EET and may be specifically valuable to exclude false positive EET results, leading the physician to other noninvasive tests for further evaluation of CAD probability. PMID- 21248456 TI - Accessory mitral papillary muscle causing severe aortic insufficiency. AB - Accessory mitral papillary muscle originating from the interventricular septum is a rare congenital anomaly. A 20-year-old male patient presented with a complaint of exertional dyspnea. On cardiac examination, a grade 3/4 diastolic murmur was heard over the right upper parasternal area, and the apical pulsations were easily palpable over the precordium. Transthoracic echocardiography showed severe aortic regurgitation, dilatation of the left ventricle, and an accessory papillary muscle with its chordae, extending from the interventricular septum to the anterior mitral leaflet in the left ventricular outflow tract (LVOT). There was no mitral regurgitation. Color Doppler imaging showed turbulence set up by the abnormal mitral attachment and an associated mild pressure gradient of 20 mmHg across the LVOT. At surgery for aortic valve replacement, degenerative changes in the aortic leaflets were noted. The accessory papillary muscle was spared to maintain mitral valve functions and an aortic bileaflet mechanical prosthetic valve was implanted. During eight months of follow-up, he was well without any signs of left ventricular systolic dysfunction and mitral regurgitation, with a functioning prosthetic valve. PMID- 21248457 TI - Late stent thrombosis after paclitaxel-eluting stent placement in a patient with essential thrombocytosis. AB - We report on a case of late stent thrombosis after drug-eluting stent placement in a patient with essential thrombocytosis. A 51-year-old male patient with a three-month history of paclitaxel-eluting stent placement to the left anterior descending artery presented with a complaint of severe retrosternal chest pain. A high platelet count (1,063,000/mm3) was detected two months prior to presentation, which was interpreted as essential thrombocytosis. He was on standard dual antiplatelet therapy (aspirin and clopidogrel). The electrocardiogram showed ST-segment elevation in leads V1-V6. Emergent coronary angiography revealed thrombotic total occlusion at the location of the paclitaxel eluting stent. Balloon angioplasty was performed yielding a satisfactory result and TIMI 3 flow. Following the procedure, there was no chest pain. His platelet count was 388,000/mm3. He was discharged on medical therapy following an uneventful hospital course. Patients with essential thrombocytosis may not be eligible for drug-eluting stent placement. PMID- 21248458 TI - Very late drug-eluting stent thrombosis in a patient with an INR of 4.4. AB - Duration of dual antiplatelet therapy after drug-eluting stent implantation is still an important issue awaiting a definite answer. A 50-year-old male patient was admitted with acute-onset chest pain and was diagnosed to have acute anterior myocardial infarction due to very late stent thrombosis. He had a 38-month history of two sirolimus-eluting stent implantation in the proximal left anterior descending (LAD) coronary artery. He had been on warfarin along with clopidogrel 75 mg/day until he decided to cease clopidogrel before a minor dental procedure 10 days before. Findings of physical examination and laboratory tests were normal except for an INR value of 4.4. After a loading dose of 300 mg clopidogrel, he was immediately taken to the catheterization laboratory. Angiography of the left system showed total occlusion of the proximal LAD with a thrombus at the level of the proximal stent. He was successfully revascularized without any complication and was discharged free of symptoms. PMID- 21248459 TI - Kearns-Sayre syndrome presenting as somatomedin C deficiency and complete heart block. AB - Kearns-Sayre syndrome (KSS) is a rare mitochondrial disease in which neuromuscular structures, endocrine glands, and cardiac conduction systems are most commonly involved. An 11-year-old boy was admitted with blurred consciousness, respiratory instability, and bradycardia of two-hour onset. He was immediately intubated. His medical history included growth retardation and myopic refractive defect for six years, therapy for somatomedin C deficiency for 15 months, and bilateral ptosis for three months. On physical examination, he was unconscious, had a peak heart rate of 40/min, blood pressure of 60/20 mmHg, and a weak pulse. Laboratory findings showed elevated blood lactate and blood pyruvate levels and an increased lactate/pyruvate ratio. The electrocardiogram showed complete atrioventricular block and echocardiography showed mitral valve prolapse. Following implantation of a temporary transvenous cardiac pacemaker, his heart rate and clinical condition improved. Further analysis with cranial magnetic resonance (MR) imaging demonstrated hyperintense signal changes in the subcortical white matter of the two cerebral hemispheres, bilateral thalamus, putamen, cerebral peduncles, dorsal medulla, and midbrain. The typical clinical and MR findings confirmed the initial diagnosis of KSS. A permanent cardiac pacemaker was implanted into the right ventricle. PMID- 21248460 TI - A case of myocarditis mimicking acute coronary syndrome associated with H1N1 influenza A virus infection. AB - Myocarditis due to H1N1 influenza infection has not been previously described. We report on a case of acute fulminant myocarditis caused by H1N1 influenza A virus infection that mimicked acute coronary syndrome. A 50-year-old man was admitted with dyspnea, fever, cough, vomiting, and atypical chest pain of three-day history. His body temperature, pulse rate, and blood pressure were 39.2 degrees C, 115 beats/min, and 80/40 mmHg, respectively. Electrocardiography showed sinus tachycardia, 1-mm ST-segment elevation, and absence of R wave progression in anterior leads, and ST depression in anterolateral leads. The chest radiogram revealed diffuse bilateral alveolar infiltrates. Cardiac enzymes were elevated. Despite treatment with aspirin, clopidogrel, low-molecular weight heparin, metoprolol, and an ACE inhibitor, he developed hemodynamic instability on the first day of admission. Echocardiographic examination showed anteroseptal, apical, and lateral wall hypokinesia, left ventricular diastolic dysfunction, and dilatation of all the chambers. There was no abnormal finding on coronary angiography. The diagnosis was considered to be myocarditis; thus, anticoagulant and antiaggregant therapies were discontinued, and empirical broad-spectrum antimicrobial treatment was initiated together with antiviral oseltamivir (2x75 mg/day). The patient's clinical condition significantly improved. Nasopharyngeal samples were positive for H1N1 influenza A virus. He was discharged on the 15th in good medical condition. PMID- 21248461 TI - [Arterial tortuosity syndrome in two cases]. AB - Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disease characterized by elongation, tortuosity, aneurysmatic formation, and stenotic lesions in large and medium-size arteries. We present two cases of ATS diagnosed during cardiac examination for murmurs. The first was an 11-year old boy who had an atypical facial appearance and hyperelasticity. He had a prior operation for inguinal hernia. Echocardiography showed aneurysmatic dilatation in the main pulmonary artery and peripheral stenotic lesions. Angiography and computed tomography angiography confirmed aneurysmatic formation in the main pulmonary artery and multiple stenotic lesions in peripheral arteries and showed elongation and tortuosity of the major branches of the aorta. Surgical reconstruction of the pulmonary arterial system was performed. The second was a 3 month-old girl with an atypical facial appearance, hyperelasticity, and marked hypotonia. The aortic arch could not be visualized during echocardiography. Angiographic examination showed mild bilateral stenosis of distal pulmonary arteries, elongation and tortuosity of the aortic arch and its main branches. PMID- 21248462 TI - [Evaluation of exercise capacity in pulmonary arterial hypertension]. AB - Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by increased pulmonary vascular resistance that leads to right ventricular failure. The most common clinical features of PAH are dyspnea and exercise intolerance. Measurement of exercise capacity is of considerable importance for the assessment of disease severity as well as routine monitoring of disease. Maximal, symptom-limited, cardiopulmonary exercise test (CPET) is the gold standard for the evaluation of exercise capacity, whereby functions of several systems involved in exercise can be assessed, including cardiovascular, respiratory, and metabolic systems. However, in order to derive the most useful diagnostic information on physiologic limitations to exercise, CPET requires maximal effort of the patient, which can be difficult and risky for some severely ill patients. Moreover, it requires specific exercise equipment and measurement systems, and experienced and trained personnel. Thus, routine clinical use of CPET to assess exercise capacity in patients with PAH may not always be feasible. A practical and simple alternative to CPET to determine exercise capacity is the 6-minute walk test (6MWT). It is simple to perform, safe, and reproducible. In contrast to CPET, the 6MWT reflects a submaximal level of exertion that is more consistent with the effort required for daily physical activities. This review focuses on the role of CPET and 6MWT in patients with PAH. PMID- 21248463 TI - Giant sclerosing hemangioma of the lung causing compression to the heart. PMID- 21248464 TI - Huge aortic aneurysm and dissection detected by the right parasternal echocardiographic window. PMID- 21248465 TI - [Case Images: pseudoaneurysm of the subclavian artery]. PMID- 21248466 TI - [Case Images: giant Eustachian valve mimicking cor triatriatum dexter]. PMID- 21248467 TI - [Case images: hydatid cyst of the interventricular septum]. PMID- 21248468 TI - Senescence-associated heterochromatin foci are dispensable for cellular senescence, occur in a cell type- and insult-dependent manner and follow expression of p16(ink4a). AB - Cellular senescence, an irreversible proliferation arrest evoked by stresses such as oncogene activation, telomere dysfunction, or diverse genotoxic insults, has been implicated in tumor suppression and aging. Primary human fibroblasts undergoing oncogene-induced or replicative senescence are known to form senescence-associated heterochromatin foci (SAHF), nuclear DNA domains stained densely by DAPI and enriched for histone modifications including lysine9 trimethylated histone H3. While cellular senescence occurs also in premalignant human lesions, it is unclear how universal is SAHF formation among various cell types, under diverse stresses, and whether SAHF occur in vivo. Here, we report that human primary fibroblasts (BJ and MRC-5) and primary keratinocytes undergoing replicative senescence, or premature senescence induced by oncogenic H Ras, diverse chemotherapeutics and bacterial cytolethal distending toxin, show differential capacity to form SAHF. Whereas all tested cell types formed SAHF in response to activated H-Ras, only MRC-5, but not BJ fibroblasts or keratinocytes, formed SAHF under senescence induced by etoposide, doxorubicin, hydroxyurea, bacterial intoxication or telomere attrition. In addition, DAPI-defined SAHF were detected on paraffin sections of Ras-transformed cultured fibroblasts, but not human lesions at various stages of tumorigenesis. Overall, our results indicate that unlike the widely present DNA damage response marker gammaH2AX, SAHF is not a common feature of cellular senescence. Whereas SAHF formation is shared by diverse cultured cell types under oncogenic stress, SAHF are cell-type-restricted under genotoxin-induced and replicative senescence. Furthermore, while the DNA/DAPI-defined SAHF formation in cultured cells parallels enhanced expression of p16(ink4a) , such 'prototypic' SAHF are not observed in tissues, including premalignant lesions, irrespective of enhanced p16(ink4a) and other features of cellular senescence. PMID- 21248469 TI - This message was inspected by Upf1: 3'UTR length sensing in mRNA quality control. PMID- 21248470 TI - Triggering of toll-like receptor-4 in human multiple myeloma cells promotes proliferation and alters cell responses to immune and chemotherapy drug attack. AB - Multiple myeloma (MM) is an incurable B-cell malignancy characterized by accumulation of malignant plasma cells in the bone marrow and by recurrent or persistent infections. Toll-like receptors (TLRs) are essential in the host defense against infections. The aim of this study was to investigate TLR initiated responses in MM cells including proliferation, anti-apoptosis and immune escape. Myeloma cell lines gene transcription, cell cycle and protein expression were detected by RT-PCR, real-time PCR, western blot, ELISA and flow cytometry analysis. 3H-thymidine was used for measuring cell proliferation, and Annexin V-PI flow cytometry for the detection of cell apoptosis. We show that human myeloma cell lines expressed TLRs,and LPS induced the proliferation and partially protected MM.1S and ARP-1 cells from adriamycin-induced apoptosis. LPS appears to induce proliferation via MyD88 and MAPKs signaling. In addition, LPS treatment upregulated myeloma cell secretion of cytokine IL-18 and expression of immunoregulatory factors B7-H1, B7-H2 and CD40 mRNA and helped myeloma cells to escape immune surveillance. Our results show that TLRs are functional on myeloma tumor cells, and the ligands to these TLRs have a functional role in affecting myeloma cell proliferation, survival, and response to chemotherapy and immune attacks. PMID- 21248471 TI - Introduction of hypoxia-targeting p53 fusion protein for the selective therapy of non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC), which accounts for ~85% of lung cancer, is the major cause of malignancy mortality around the world. TP53 dysfunction and hypoxia are the typical biological features of the diverse solid tumors, including NSCLC. To develop an effective and low cytotoxic biological agent for targeted therapy, a p53 fusion protein, which was conjugated with the minimum motif of oxygen-dependent degradation domain (ODD) and the basic domain of TAT of HIV-1 named as TAT-ODD-p53, was evaluated for the treatment of NSCLC established by grafting H1299 cell line in which TP53 is homozygously deleted. We provide the evidence that this p53 fusion protein could significantly induce the cell-cycle arrest and/or apoptosis to inhibit H1299 cells' growth via p53-dependent pathways, including up-regulation of p21 expression and activation of pro-caspase 3, especially under hypoxia in vitro. The results in vivo indicated that this protein could selectively accumulate in the low oxygen tension areas of solid tumor tissues, inhibiting tumor growth via a similar mechanism to that in vitro. No obvious side effects were observed. Therefore, this recombinant p53 protein is likely to become a good candidate for targeted therapy of NSCLC. PMID- 21248472 TI - Strigolactones as mediators of plant growth responses to environmental conditions. AB - Strigolactones (SLs) have been recently identified as a new group of plant hormones or their derivatives thereof, shown to play a role in plant development. Evolutionary forces have driven the development of mechanisms in plants that allow adaptive adjustments to a variety of different habitats by employing plasticity in shoot and root growth and development. The ability of SLs to regulate both shoot and root development suggests a role in the plant's response to its growth environment. To play this role, SL pathways need to be responsive to plant growth conditions, and affect plant growth toward increased adaptive adjustment. Here, the effects of SLs on shoot and root development are presented, and possible feedback loops between SLs and two environmental cues, light and nutrient status, are discussed; these might suggest a role for SLs in plants' adaptive adjustment to growth conditions. PMID- 21248473 TI - Photosynthesis-dependent anthocyanin pigmentation in Arabidopsis. AB - Light is the ultimate energy source for photo-autotrophs on earth. For green plants, however, it can also be toxic under certain stressful environmental conditions and at critical developmental stages. Anthocyanins, a class of flavonoids, act as an effective screening mechanism that allows plant survival and proliferation under occasional periods of harmful irradiation through modulation of light absorption. Apart from light-sensing through photoreceptors such as phytochrome and cryptochrome, plants use the photosynthetic electron transfer (PET) chain to integrate light information. The redox status of the plastoquinone (PQ) pool of the PET chain regulates anthocyanin biosynthesis genes, together with the plant hormone ethylene and plant hormone-like sugars. A complex signaling apparatus in acyanic cells appears to transduce information to cyanic cells to regulate anthocyanin production through an intercellular signaling pathway that remains largely uncharacterized. This review will highlight recent advances in this field and their implications for the regulation of anthocyanin pigmentation. PMID- 21248474 TI - Latest findings about the interplay of auxin, ethylene and nitric oxide in the regulation of Fe deficiency responses by Strategy I plants. AB - Under Fe deficiency, Strategy I (non-graminaceous) plants up-regulate the expression of many Fe acquisition genes and develop morphological changes in their roots. The regulation of these responses is not completely known, but since the 1980's different results suggest a role for auxin, ethylene and, more recently, nitric oxide. The up-regulation of the Fe acquisition genes does not depend solely on these hormones, that would act as activators, but also on some other signals, probably phloem Fe, that would act as an inhibitor. It is not known which of the hormones considered is the last activator of the Fe acquisition genes, but some results suggest that auxin acts upstream of ethylene and NO and that, perhaps, ethylene is the last activator. PMID- 21248475 TI - Cross-talk of calcium-dependent protein kinase and MAP kinase signaling. AB - Plants use different signalling pathways to acclimate to changing environmental conditions. Fast changes in the concentration of free Ca(2+) ions - so called Ca(2+) signals - are among the first responses to many stress situations. These signals are decoded by different types of calcium-dependent protein kinases, which - together with mitogen-activated protein kinases (MAPK) - present two major pathways that are widely used to adapt the cellular metabolism to a changing environment. Ca(2+)-dependent protein kinase (CDPK) and MAPK pathways are known to be involved in signalling of abiotic and biotic stress in animal, yeast and plant cells. In many cases both pathways are activated in response to the same stimuli leading to the question of a potential cross-talk between those pathways. Cross-talk between Ca(2+)-dependent and MAPK signalling pathways has been elaborately studied in animal cells, but it has hardly been investigated in plants. Early studies of CDPKs involved in the biotic stress response in tobacco indicated a cross-talk of CDPK and MAPK activities, whereas a recent study in Arabidopsis revealed that CDPKs and MAPKs act differentially in innate immune signalling and showed no direct cross-talk between CDPK and MAPK activities. Similar results were also reported for CDPK and MAPK activities in the salt stress response in Arabidopsis. Different modes of action are furthermore supported by the different subcellular localization of the involved kinases. In this review, we discuss recent findings on CDPK and MAPK signalling with respect to potential cross-talk and the subcellular localization of the involved components. PMID- 21248477 TI - Development of Casparian strip in rice cultivars. AB - The development of Casparian strips (CSs) on the endo- and exodermis and their chemical components in roots of three cultivars of rice (Oryza sativa) with different salt tolerance were compared using histochemistry and Fourier transform infrared (FTIR) spectroscopy. The development and deposition of suberin lamellae of CSs on the endo- and exodermis in the salt-tolerant cultivar Liaohan 109 was earlier than in the moderately tolerant cultivar Tianfeng 202 and the sensitive cultivar Nipponbare. The detection of chemical components indicated major contributions to the structure of the outer part from aliphatic suberin, lignin, and cell wall proteins and carbohydrates to the rhizodermis, exodermis, sclerenchyma, and one layer of cortical cells in series (OPR) and the endodermal Casparian strip. Moreover, the amounts of these major chemical components in the outer part of the Liaohan 109 root were higher than in Tianfeng 202 and Nipponbare, but there was no distinct difference in endodermal CSs among the three rice cultivars. The results suggest that the exodermis of the salt-tolerant cultivar Liaohan 109 functions as a barrier for resisting salt stress. PMID- 21248476 TI - The role of the Elongator complex in plants. AB - The multi-subunit complex Elongator interacts with elongating RNA polymerase II (RNAPII) and is thought to facilitate transcription through histone acetylation. Elongator is conserved in eukaryotes, yet functions in diverse kingdom-specific processes. In this mini-review, we discuss the known functions of Elongator in plants, including its roles in development and responses to biotic and abiotic stresses. We propose that Elongator functions in these processes by accelerating gene induction in response to changing cellular and environmental conditions. PMID- 21248478 TI - The SlMKK2 and SlMPK2 genes play a role in tomato disease resistance to Xanthomonas campestris pv. vesicatoria. AB - Xanthomonas campestris pv. vesicatoria (Xcv) is the causal agent of bacterial spot disease in tomato (Solanum lycopersicum) plants. We recently identified a MAPKKK gene, SlMAPKKKepsilon, which is required for tomato resistance to Xcv strains and encodes a positive regulator of cell death. We also provided evidence that the MEK2 MAPKK, and the WIPK and SIPK MAPKs act downstream to MAPKKKepsilon in Nicotiana benthamiana plants. Here, we used the virus-induced gene silencing technique to assess whether tomato homologs of MEK2 (SlMKK2), SIPK (SlMPK1 and SlMPK2), WIPK (SlMPK3), and other components of MAP kinase cascades (SlNPK1, SlMEK1 and SlNTF6), which were previously implicated in plant immunity, are involved in disease resistance to Xcv. Silencing of none of the tested genes caused the appearance of disease symptoms in tomato leaves challenged with an avirulent Xcv strain. However, bacterial populations were significantly higher in leaves of plants silenced for SlMKK2 and SlMPK2, as compared to control plants, suggesting that these two genes contribute to disease resistance to Xcv. It remains to be established whether SlMKK2 and SlMPK2 are activated by SlMAPKKKepsilon directly or through a distinct MAPKKK. PMID- 21248479 TI - Further characterization of an aluminum influx transporter in rice. AB - Nrat1 is a plasma membrane-localized aluminum transporter recently identified in rice, which is a member of Nramp family. Here, we further characterized this transporter in terms of transport substrate specificity. Heterologous assay in yeast showed that Al transport activity by Nrat1 was unaffected by the presence of high concentration of Ca, but significantly inhibited by trivalent ions including Yb and Ga, analogs of Al. Knockout of Nrat1 did not affect the uptake of Cd and Mn in rice. On the other hand, over-expression of Nrat1 led to enhanced Al uptake by rice roots compared with wild-type rice, but did not affect Cd uptake. These results provide further evidence that unlike other Nramp members, Nrat1 is an influx transporter for trivalent Al ion. PMID- 21248480 TI - Gene fusions find an ERG-way to tumor inflammation. PMID- 21248482 TI - CXCR4 and renal cancer: from lab to bedside. PMID- 21248481 TI - Cell size and growth rate are major determinants of replicative lifespan. AB - Yeast cells, like mammalian cells, enlarge steadily as they age. Unabated cell growth can promote cellular senescence; however, the significance of the relationship between size and cellular lifespan is not well understood. Herein, we report a genetic link between cell size, growth rate and lifespan. Mutations that increase cell size concomitantly increase growth rate and decrease lifespan. As a result, large cells grow, divide and age dramatically faster than small cells. Conversely, small cell mutants age slowly and are long-lived. Investigation of the mechanisms involved suggests that attainment of a maximal size modulates lifespan. Indeed, cumulative results revealed that life expectancy is size-dependent, and that the rate at which cells age is determined in large part by the amount of cell growth per generation. PMID- 21248483 TI - Research highlights on a notable retrovirus and a popular guardian gene. PMID- 21248485 TI - Cyclin E goes nuts: a cell cycle regulator affects male fertility. PMID- 21248484 TI - Linking Cdc7 with the replication checkpoint. PMID- 21248486 TI - When enough is enough: detrimental effects of excess histones. PMID- 21248487 TI - Skirmish between the mighty p53 protein and the complex retrovirus HIV-1. PMID- 21248488 TI - bZIP transcription factor RSG controls the feedback regulation of NtGA20ox1 via intracellular localization and epigenetic mechanism. AB - Gibberellins (GAs) are phytohormones that regulate growth and development throughout the life cycle of plants. Negative feedback contributes to homeostasis of GA levels. DELLA proteins are involved in this process. Since DELLA proteins do not have apparent DNA binding motifs, other DNA binding proteins might act as a mediator downstream of DELLA proteins in the GA feedback regulation. In this review, we highlight the mechanisms of GA feedback regulation, specifically the differential regulation of GA 20-oxidase (GA20ox) and GA 3-oxidase (GA3ox) by transcription factors. RSG (REPRESSION OF SHOOT GROWTH) is a tobacco (Nicotiana tabacum) transcriptional activator with a basic leucine zipper domain that controls the levels of endogenous GAs through the regulation of GA biosynthesis genes. Recently we reported that RSG not only regulates the expression of ent kaurene oxidase gene but is also involved in the negative feedback of NtGA20ox1 by GAs. RSG plays a role in the homeostasis of GAs through direct binding to the NtGA20ox1 promoter triggered by a decrease in GA levels in the cell. Furthermore, decreases in GA levels promote modifications of active histone marks on the NtGA20ox1 promoter. We have developed a hypothetical model to explain how RSG regulates dual target genes via epigenetic regulation. PMID- 21248489 TI - Interactions between abscisic acid and plastidial glycolysis in Arabidopsis. AB - The phytohormone abscisic acid (ABA) controls the development of plants and plays a crucial role in their response to adverse environmental conditions like salt and water stress. Complex interactions between ABA and sugar signal transduction pathways have been shown. However, the role played by glycolysis in these interactions is not known. In the associated study, we investigated the interactions between plastidial glycolytic glyceraldehyde-3-phosphate dehydrogenase (GAPCp) and ABA signal transduction in Arabidopsis. We followed physiological, genetic and genomic approaches to understand the processes and mechanisms underlying the ABA-glycolysis interactions. Our results indicated that GAPCp deficiency leads to ABA-insensitivity and impaired ABA signal transduction. The gene expression of the transcription factor ABI4, involved in both sugar and ABA signaling, was altered in gapcp double mutants (gapcp1gapcp2), suggesting that the ABA insensitivity of mutants is mediated, at least in part, through this transcriptional regulator. We also suggested that amino acid homeostasis and/or serine metabolism may also be important determinants in the connections of ABA with primary metabolism. These studies provide new insights into the links between plant primary metabolism and ABA signal transduction, and demonstrate the importance of plastidial glycolytic GAPCps in these interactions. PMID- 21248490 TI - Deepening into the proteome of maize cells habituated to the cellulose biosynthesis inhibitor dichlobenil. AB - Cellulose biosynthesis inhibitors, such as dichlobenil (DCB), have become a valuable tool for the analysis of structural and compositional plasticity of plant cell walls. By stepwise increasing the concentration of DCB in the culture medium, we obtained maize cells able to cope with DCB through the acquisition of a modified cell wall in which cellulose was partially replaced by a more extensive network of feruloylated arabinoxylans. Recently we demonstrated that the expression of several Cellulose Synthase and phenylpropanoid-related genes is altered in DCB-habituated cells. In addition, by using a proteomic approach we identified several proteins induced or repressed in DCB-habituated cells. After a more in-depth analysis, some new proteins induced (two inhibitors TAXI-IV, an alpha-1,4-glucan-protein synthase, and a pectinesterase inhibitor) or repressed (a chaperonin 60, a fructokinase-1 and a spermidine synthase 1) were identified, and their possible role in the context of DCB-habituation is discussed. PMID- 21248491 TI - Phospholipases in action during plant defense signaling. AB - Eukaryotic organisms rely on intricate signaling networks to connect recognition of microbes with the activation of efficient defense reactions. Accumulating evidence indicates that phospholipids are more than mere structural components of biological membranes. Indeed, phospholipid-based signal transduction is widely used in plant cells to relay perception of extracellular signals. Upon perception of the invading microbe, several phospholipid hydrolyzing enzymes are activated that contribute to the establishment of an appropriate defense response. Activation of phospholipases is at the origin of the production of important defense signaling molecules, such as oxylipins and jasmonates, as well as the potent second messenger phosphatidic acid (PA), which has been shown to modulate the activity of a variety of proteins involved in defense signaling. Here, we provide an overview of recent reports describing the different plant phospholipase pathways that are activated during the establishment of plant defense reactions in response to pathogen attack. PMID- 21248492 TI - Preventing unwanted breakups: using polygalacturonases to regulate cell separation. AB - Cell separation is an important biological process in plants that is precisely regulated both spatially and temporally. Key separation events include abscission of organs such as leaves and fruit and dehiscence events such as pod shatter in canola and other Brassicas. Polygalacturonases (PGs) are enzymes essential for the degradation of pectin, an important component of the adhesive material between cells. Although there are around 70 PG genes with overlapping expression domains, recent analysis has revealed the function of several PGs in specific aspects of Arabidopsis reproductive development. Upstream regulators that control the expression domain of some of these PGs during reproductive development have also been identified. This information provides new strategies to control unwanted cell separation events in various crops. PMID- 21248493 TI - A matter of fat: interaction between nitric oxide and sphingolipid signaling in plant cold response. AB - We recently evidenced that plant response to cold stress includes a rapid formation of nitric oxide (NO) that participates in the control of cold responsive gene expression. Unexpectedly we also shed light on a novel downstream element of NO signalling that is phosphosphingolipid (PS) metabolism. Indeed, two phosphosphingolipid species, phytosphingosine phosphate (PHS-P) and a ceramide phosphate (Cer-P) are specifically synthesized upon cold exposure. Manipulating NO levels by pharmacological or genetic means dramatically modified the cold triggered synthesis of PHS-P and Cer-P, but did not affect the cold-responsive formation of phosphatidic acid (PtdOH), a ubiquitous lipid signal derived from phospholipid degradation. So far no crosstalk between NO and PS signalling had been reported in plants. How NO might modulate PS formation and whether this regulation might be extended to other physiological processes are further discussed. PMID- 21248494 TI - Determination of factors affecting glutamate concentrations in the whole blood of healthy human volunteers. AB - BACKGROUND: Abnormally high concentrations of glutamate in brain fluids have been shown to be neurotoxic and correlate with a poor neurological outcome following traumatic brain injury (TBI). Since brain fluid glutamate can be reduced by scavenging blood glutamate, the purpose of this study was to investigate factors that may potentially influence levels of blood glutamate, glucose, and the enzymes glutamate-pyruvate transaminase (GPT) and glutamate-oxaloacetate transaminase (GOT) in healthy individuals. METHODS: Factors that were examined included age, gender, time of last meal or drink, and recent consumption of coffee. A total of 112 healthy volunteers between 18 and 70 years of age participated in the study. The average participant was 38 years old, and the sample consisted of 48 males and 64 females. Five milliliters of venous blood was collected from participants' cubital vein and blood glutamate, glucose, GOT and GPT levels were determined. Participants were then asked to complete a questionnaire addressing their gender, age, time of last meal, time of last drink, and whether coffee was consumed within the last 6 hours. RESULTS: Blood glutamate concentrations were significantly higher in males than in females (P < 0.001) and may be due to effects of estrogen and progesterone. Concentrations of GOT were significantly higher in males than in females (P < 0.01). Concentrations of GPT were significantly higher in males than in females (P < 0.01). There were no other significant differences demonstrated. CONCLUSIONS: Understanding the factors that affect blood glutamate levels may give new insight into mechanisms that protect the brain from excess glutamate and result in a better neurological outcome following TBI. PMID- 21248495 TI - Coupling between electroencephalography pattern and cyclic transcranial Doppler flow during aortic root surgery. PMID- 21248496 TI - Use of sugammadex for reversal of neuromuscular blockade in 2 patients requiring intraoperative neurophysiological monitoring. PMID- 21248497 TI - A minimalistic approach to a complex perioperative fluid therapy for diabetes insipidus: is what we perceive the actual reality. PMID- 21248498 TI - Is intraoperative cardiac arrest enough for cancellation of surgery in patients with neural tube defect? PMID- 21248499 TI - Tracheal stent-implanted patients who underwent nonrelated cervical surgery: endoprosthesis management when removed it is possible. PMID- 21248500 TI - Incidence, predictors, costs, and outcome of renal cell carcinoma after kidney transplantation: USRDS experience. AB - INTRODUCTION: We carried out an analysis of the United States Renal Data System to determine the incidence, risk factors, prognosis, and costs associated with the diagnosis of renal cell carcinoma (RCC) after kidney transplantation. METHODS: This is a retrospective cohort of 40,821 Medicare primary renal transplant recipients transplanted from January 1, 2000, to July 1, 2005, and followed up till December 31, 2005, excluding those with prior RCC or nephrectomy. Kaplan-Meier analysis was performed to determine the time of occurrence of RCC, and Cox regression was used to determine factors associated with RCC. RESULTS: Three hundred sixty-eight patients were diagnosed with RCC within 3 years after transplant (incidence of 3.16 per 1000 person years). The 3 year incidence of RCC posttransplant was 9.29 per 1000 person years (2.3%) for those with pretransplant cysts and 3.08 per 1000 person years (0.7%) without pretransplant cysts. RCC was diagnosed disproportionately early posttransplant in patients with cysts. Cysts were independently associated with increased risk of RCC, as was male gender, older recipient, donor age, African American recipient, increased time on dialysis and acute rejection within first year posttransplant. RCC was associated with increased risk of mortality with a higher risk with pretransplant cysts. Patients who developed RCC had higher cumulative median costs ($55,456 at 2 years) than those who did not develop RCC ($40,369). There was no "clustering" of RCC in individual states or centers more than would be expected by chance. CONCLUSION: RCC was diagnosed disproportionately early in patients with pretransplant renal cysts and was associated with a worse prognosis and increased costs. PMID- 21248514 TI - The role of albumin as a resuscitation fluid for patients with sepsis: a systematic review and meta-analysis. AB - OBJECTIVE: To assess whether resuscitation with albumin-containing solutions, compared with other fluids, is associated with lower mortality in patients with sepsis. DATA SOURCES: MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases, the metaRegister of Controlled Trials, and the Medical Editors Trial Amnesty Register. STUDY SELECTION: Prospective randomized clinical trials of fluid resuscitation with albumin-containing solutions compared with other fluid resuscitation regimens, which included a population or subgroup of participants with sepsis, were included. DATA EXTRACTION: Assessment of the validity of included studies and data extraction were conducted independently by two authors. DATA SYNTHESIS: For the primary analysis, the effect of albumin containing solutions on all-cause mortality was assessed by using a fixed-effect meta-analysis. RESULTS: Seventeen studies that randomized 1977 participants were included in the meta-analysis. There were eight studies that included only patients with sepsis and nine where patients with sepsis were a subgroup of the study population. There was no evidence of heterogeneity, I2 = 0%. The use of albumin for resuscitation of patients with sepsis was associated with a reduction in mortality with the pooled estimate of the odds ratio of 0.82 (95% confidence limits 0.67-1.0, p = .047). CONCLUSIONS: In this meta-analysis, the use of albumin-containing solutions for the resuscitation of patients with sepsis was associated with lower mortality compared with other fluid resuscitation regimens. Until the results of ongoing randomized controlled trials are known, clinicians should consider the use of albumin-containing solutions for the resuscitation of patients with sepsis. PMID- 21248515 TI - Caveats for comparing catheter-associated bloodstream infection rates. PMID- 21248516 TI - Optimizing sepsis care: target the process or the patient? PMID- 21248517 TI - Stop filling patients against central venous pressure, please! PMID- 21248518 TI - What is the evidence for glucose control in children undergoing cardiac surgery? PMID- 21248519 TI - Regional anticoagulation with citrate: expanding its indications. PMID- 21248520 TI - Resolving issues of consent and oversight: one step closer to terra firma in deceased organ donor research. PMID- 21248521 TI - Stroke volume variation: from applied physiology to improved outcomes. PMID- 21248522 TI - Stress and cardiopulmonary resuscitation performance. PMID- 21248523 TI - Blood urea nitrogen beyond estimation of renal function. PMID- 21248524 TI - The Frog Prince of calcium homeostasis. PMID- 21248525 TI - Translating the PIRO staging system concept into clinical practice: where do we go from here? PMID- 21248526 TI - Niacin as a novel therapy for septic shock? PMID- 21248527 TI - Ultrasound and abdominal compartment syndrome: can we cast the other tools aside yet? PMID- 21248528 TI - Matrix metalloproteinases: from tadpole tails to critical illness. PMID- 21248529 TI - ALI: Acute lung injury, or arginine-vasopressin limits inflammation, or both? PMID- 21248530 TI - Pushing the envelope. PMID- 21248531 TI - Is it time to replace L-arginine in severe sepsis? PMID- 21248532 TI - Does albumin fluid resuscitation in sepsis save lives? PMID- 21248533 TI - Prevalence and prognosis of shunting across patent foramen ovale during acute respiratory distress syndrome. PMID- 21248535 TI - Passive leg raising for monitoring volume status and predicting fluid responsiveness. PMID- 21248538 TI - Defining refractory myocardial infarction-associated cardiogenic shock: an ongoing elusive challenge. PMID- 21248539 TI - Mono- or combination antibiotic therapy for septic shock? An epistemological dilemma. PMID- 21248541 TI - When the buck fails to stop where it should. PMID- 21248542 TI - Implementation of diagnosis-related mental health programs: impact on health care providers. AB - Mental health services are in the midst of change in different countries. In Quebec (Canada), the government has adopted a Mental Health Action Plan (2005 2010). In this context, 2 psychiatric institutions have developed and implemented a mental health services organization model based on diagnosis-related mental health programs and support for frontline services. This article presents the impact on health care providers of implementation of diagnosis-related mental health programs in the context of transformation of mental health services. PMID- 21248543 TI - Demand study for advanced dental hygiene educational degrees: Part 1: Assessing the clinical changes of our population. AB - The debate over the addition of the midlevel provider position for dental hygienists currently rages on. The midlevel provider (similar to the physician's assistant) in dentistry exists in a handful of states but is hotly contested in many other states. This is a 2-part study to add to the current body of knowledge by addressing the changing clinical needs in our population and the associated demand study for additional educational degrees for dental hygienists to address these changing needs. Part 1 addresses a literature update on oral health and systemic correlations contributing to our populations' declining health conditions, whereas part 2 illustrates the results of the demand study. PMID- 21248544 TI - Quality of life of hemodialysis and renal transplantation patients. AB - The quality of life of patients with end-stage renal disease is an important indicator of disease burden. To achieve a better quality of life, some medical treatment might be replaced by other approaches. The aim of this study was to compare the quality of life of renal-transplanted and hemodialysis patients in Iran. Two hundred hemodialysis and 200 renal transplantation patients were recruited from 5 major hospitals and renal patients' support society in Tehran, Iran. The data were collected using the Persian versions of the Ferrans and Powers Quality of Life Index-Dialysis and Transplantation Version. The quality-of life mean scores of renal transplantation patients were significantly better compared with those of the hemodialysis patients (21.36 [SD, 4.06] vs 20.35 [SD, 5.14]; P = .03). The questionnaire demonstrated significant differences in health/functioning and familial subscale of quality of life between the transplanted and hemodialysis patients (p < .05). The better quality of life of transplant patients, in comparison with hemodialysis patients, is an important reason for advising kidney transplants in renal failure patients. To improve the patients' quality of life, kidney transplantation might be effective for the end stage renal disease. With regard to socioeconomic problem in most of the patients with renal failure, comprehensive insurance and referral to renal and transplanted patients' support society are suggested for those who have undergone different renal replacement therapies. PMID- 21248545 TI - Strengthening affective organizational commitment: the influence of fairness perceptions of management practices and underlying employee cynicism. AB - This study investigates the relationship between cynicism, the perceived fairness of change management and personnel practices, and affective organizational commitment. High levels of affective organizational commitment have been shown to reduce voluntary turnover in the nursing workforce. Previous research suggests that "unfair" management practices and employee cynicism lead to lower commitment. It is not clear, however, whether the perceived fairness of particular practices influences affective commitment beyond that accounted for by underlying employee cynicism. Data were obtained from a study involving 1104 registered nurses that formed part of a larger investigation of the general well being of nurses in Western Australia. Only nurses who were permanent or employed on fixed term or temporary contracts were included. Findings indicated that although higher levels of cynicism among nurses were associated with lower levels of affective commitment, their perception of the fairness of change management and personnel practices influenced their affective commitment over and above their cynicism. The perceived fairness of management practices is an important influence on nurses' affective commitment beyond that accounted for by cynicism. The implication for managers is that the affective organizational commitment of nurses is likely to be strengthened by addressing the perceived fairness of change management and personnel practices notwithstanding their beliefs about the integrity of the organization. PMID- 21248546 TI - Department manager's checklist: Absenteeism. PMID- 21248547 TI - Acquisition and allocation of human, financial, and physical resources in the health care system. AB - Based on the current financial status and forthcoming changes in the health care system, governing boards give chief executive officers the responsibility to manage human, financial, and physical resources. The role and degree of involvement of chief executive officers in managing resources--the resource allocation process, retention and recruitment, technology adaptation, reimbursement, and expansion of the outpatient program--are illustrated in this article. A new strategy for diverting resources to tap into the outpatient market is the appropriate direction to choose during days when the economy is down and people are not seeking inpatient treatment as in the past. Reimbursement in the future will depend on customer satisfaction scores; therefore, a dedicated and loyal staff is the most important resource for any service organization. PMID- 21248548 TI - Electronic health record implementations: applying the principles of monitoring and controlling to achieve success. AB - Electronic health record systems are being implemented in physicians' offices around the country at an outstanding rate. These implementations require great skill and collaboration. This article seeks to apply 2 fundamental principles of project management, monitoring and controlling, to electronic health record implementation. Issues such as project costs, project progress, schedule controls, quality management, and controlling risks are discussed. PMID- 21248550 TI - Factors impacting perceived threat of malpractice lawsuits by various medical specialists. AB - A study was undertaken to examine perceived threat of malpractice lawsuits affecting different physician specialties and to examine factors that impact such perceptions of those specialties. The study used data collected by the Center for Studying Health System Change's 2008 Health Tracking Physician (HTP) Survey. The 2008 HTP data set consisted of 4720 physicians belonging to the American Medical Association. Primary care physicians, medical specialists, surgical specialists, psychiatrists, and obstetricians/gynecologists (ObGyns) physicians participated in the 2008 HTP Survey. The order (from high to low) of perceived threat of malpractice lawsuits for various specialists is surgical specialists (3.87), ObGyns (3.81), medical specialists (3.60), primary care physicians (3.55), and psychiatrists (3.12). Regression results indicate that patient interaction, insufficient care quality, competition, medical school, age, and career satisfaction impacted perceived threat of malpractice lawsuits for most of the specialties. For ObGyns, white non-Hispanic was the only factor that impacted perceived threat of malpractice lawsuits. The perceived threat of malpractice lawsuits varies by specialists. Patient interaction, insufficient care quality, competition, medical school, and career satisfaction are major predictors of such threats for most physician specialties. PMID- 21248551 TI - Assessing your office for care of lesbian, gay, bisexual, and transgender patients. AB - Practitioners act as guide, protector, and confidant to their patients' most vulnerable health care concerns. Arguably, one of the most important times to consider the dynamics of a health care relationship is when treating culturally diverse populations such as lesbian, gay, bisexual, and transgender (LGBT) patients. This article outlines several recommendations for how physicians can begin the process of assessing their office and practice habits for supportive care of LGBT patients, including evaluating your belief systems, understanding risk factors associated with LGBT patients, modifying medical intake forms and interview practices, reviewing staff training and office procedures, and becoming familiar with available tools and resources. With several minor but effective changes, you can offer your LGBT patients a practitioner who is (1) knowledgeable of relevant LGBT health care and basic human sexuality, (2) mindful and sensitive to the needs of diverse sexual and gender identities, and (3) capable of making interpersonal and office-related adjustments for the purpose of providing them with the best possible medical care. PMID- 21248552 TI - Toward the adoption of complexity science in health care: implications for risk taking and decision-making activities. AB - This article explores the issues of risk taking and decision making in health care. An analysis of various sociocultural and psychological influences is provided for understanding of the dominant mind set in this industry. In tandem with this analysis, the evolution of system theories is described so as to promote understanding of the relative merits of the mechanistic and complexity philosophies. These philosophies are at odds with each other, conceptually and practically speaking; however, it seems that the complexity approach offers more promising strategies for the growth and development of health care. Recommendations for improving employee competencies and the organizational structure and culture in health care are offered in light of this analysis. These recommendations are relevant to activities that are clinical and administrative in nature. PMID- 21248553 TI - Leader communication styles and organizational health. AB - Communication is perhaps one of the greatest challenges facing managers and leaders today. Clearly articulating ideas and expectations to employees is vital to the productivity and the longevity of an organization. Furthermore, the style in which the communication is delivered has an influence on the satisfaction levels of employees. Research has discovered that there are many different styles in which a leader may communicate with employees. Research has provided several methods that aid in determining which style is the most appropriate for any given circumstance. Research has demonstrated how appropriate and effective communication is used to promote organizational health. Furthermore, research has demonstrated how inappropriate communication may decrease employee satisfaction. Finally, research has provided methods to aid in improving communication styles and delivery. PMID- 21248554 TI - Flexible fixation with locking plates. PMID- 21248555 TI - Flexible fixation and fracture healing: do locked plating 'internal fixators' resemble external fixators? AB - External and internal fixators use bone screws that are locked to a plate or bar to prevent periosteal compression and associated impairment of blood supply. Both osteosynthesis techniques rely on secondary bone healing with callus formation with the exception of compression plating of simple, noncomminuted fractures. External fixation uses external bars for stabilization, whereas internal fixation is realized by subcutaneous placement of locking plates. Both of these "biologic" osteosynthesis methods allow a minimally invasive approach and do not compromise fracture hematoma and periosteal blood supply. Despite these similarities, differences between the two fixation methods prevail. Locked plating "internal fixators" allow a combination of biomechanical principles such as buttressing and dynamic compression. Periarticular locking plates are anatomically contoured to facilitate fixation of articular fractures. They allow for subchondral stabilization using small-diameter angular stable screws as well as buttressing of the joint and the metaphyseal component of a fracture. Biomechanically, they can be far stiffer than external fixators, because subcutaneous plates are located much closer to the bone surface than external fixator bars. External fixators have the advantage of being less expensive, highly flexible, and technically less demanding. They remain an integral part of orthopaedic surgery for emergent stabilization, for pediatric fractures, for definitive osteosynthesis in certain indications such as distal radius fractures, and for callus distraction. PMID- 21248556 TI - Biomechanics of far cortical locking. AB - The development of far cortical locking (FCL) was motivated by a conundrum: locked plating constructs provide inherently rigid stabilization, yet they should facilitate biologic fixation and secondary bone healing that relies on flexible fixation to stimulate callus formation. Recent studies have confirmed that the high stiffness of standard locked plating constructs can suppress interfragmentary motion to a level that is insufficient to reliably promote secondary fracture healing by callus formation. Furthermore, rigid locking screws cause an uneven stress distribution that may lead to stress fracture at the end screw and stress shielding under the plate. This review summarizes four key features of FCL constructs that have been shown to enhance fixation and healing of fractures: flexible fixation, load distribution, progressive stiffening, and parallel interfragmentary motion. Specifically, flexible fixation provided by FCL reduces the stiffness of a locked plating construct by 80% to 88% to actively promote callus proliferation similar to an external fixator. Load is evenly distributed between FCL screws to mitigate stress risers at the end screw. Progressive stiffening occurs by near cortex support of FCL screws and provides additional support under elevated loading. Finally, parallel interfragmentary motion by the S-shaped flexion of FCL screws promotes symmetric callus formation. In combination, these features of FCL constructs have been shown to induce more callus and to yield significantly stronger and more consistent healing compared with standard locked plating constructs. As such, FCL constructs function as true internal fixators by replicating the biomechanical behavior and biologic healing response of external fixators. PMID- 21248557 TI - Far cortical locking enables flexible fixation with periarticular locking plates. AB - The high stiffness of periarticular locked plating constructs can suppress callus formation and fracture healing. Replacing standard locking screws with far cortical locking (FCL) screws can decrease construct stiffness and can improve fracture healing in diaphyseal plating constructs. However, FCL function has not been tested in conjunction with periarticular plating constructs in which FCL screws are confined to the diaphyseal segment. This biomechanical study evaluated if diaphyseal fixation of a periarticular locking plate with FCL screws reduces construct stiffness and induces parallel interfragmentary motion without decreasing construct strength. Periarticular locking plates were applied to stabilize distal femur fractures in 22 paired femurs using either a standard locked plating approach (LP group) or FCL for diaphyseal fixation (FCL group) using MotionLoc screws (Zimmer, Warsaw, IN). Each specimen was evaluated under quasiphysiological loading to assess construct stiffness, construct durability under dynamic loading, and residual strength after dynamic loading. FCL constructs had an 81% lower initial stiffness than LP constructs. They induced nearly five times more interfragmentary motion than LP constructs under one body weight loading (P < 0.001). FCL constructs generated parallel interfragmentary motion, whereas LP constructs exhibited 48% less motion at the near cortex than at the far cortex (P = 0.002). Seven LP constructs and eight FCL constructs survived 100,000 loading cycles. The residual strength of surviving constructs was 4.9 +/- 1.6 kN (LP group) and 5.3 +/- 1.1 kN (FCL group, P = 0.73). In summary, FCL screws reduce stiffness, generate parallel interfragmentary motion, and retain the strength of a periarticular locked plating construct. Therefore, FCL fixation may be advisable for stiffness reduction of periarticular plating constructs to promote fracture healing by callus formation. PMID- 21248558 TI - Effects of near cortical slotted holes in locking plate constructs. AB - The development of locked plating has led to substantial improvements in fracture fixation. This is particularly evident in periarticular fractures, in which conventional nonlocking plates are unable to support the articular surface from a single side. Initially, locked plating appeared to be the ideal solution for these situations and reduced the necessity for double plating and secondary bone grafting. However, with increasing use of locked plating, it became evident that the plate-bone interaction is rigid and may lead to impaired bone healing. The near cortical locking holes increased the construct stiffness and appeared to interfere with local healing. Slotted near cortical locking holes might improve this drawback. This review summarizes the current knowledge of the healing process associated with different types of near cortical locking options. PMID- 21248559 TI - Biomechanical principles and mechanobiologic aspects of flexible and locked plating. AB - The goal of minimally invasive surgery in extramedullary internal fixation has led to the development of flexible plates, bridging plates, and locked internal fixators. The change from conventional compression plates to these new implants, however, resulted in different biomechanics of fixation and different mechanobiologic processes for fracture healing. The aim of a flexible fixation is the stimulation of fracture healing by callus formation. Fracture healing follows mechanobiologic rules based mainly on interfragmentary strain, which is dependent on the stability of the fixation construct and the type of fracture. Knowledge of the mechanobiologic processes and the factors influencing the stability of fracture fixation are necessary for the surgeon to choose the correct technique for fracture fixation. Problems in the selection of the correct technique and limitations with the available implants as well as possible future developments are discussed. PMID- 21248560 TI - Locking plates for distal femur fractures: is there a problem with fracture healing? AB - OBJECTIVES: Fractures of the distal femur are severe injuries that present many clinical challenges. Nonunion, delayed union, implant failure, and the need for secondary procedures can reflect complications of healing. This article reviews the literature on distal femur fractures treated with locking plates to determine the reported rate of healing difficulties. DATA SOURCES: The PubMed database and the Orthopaedic Trauma Association and American Academy of Orthopedic Surgeons abstract archives were searched for studies including the key words distal femur fracture, supracondylar femur fracture, or locking plate from the year 2000 to the present. STUDY SELECTION: Reports were included when distal femur fractures were treated with locking plates and when the number of healed fractures was identified in the study. The reported healing rates and the rate of healing complications were determined from the studies. The time to implant failure was recorded. Those articles that included periprosthetic fractures were separated from those only including acute distal femur fractures. DATA SYNTHESIS: Fifteen full-length publications and three abstracts were included. The rate of complications related to healing ranged from 0% to 32% in these studies. Implant failures occurred late with 75% of the failures occurring after 3 months and 50% occurring after 6 months. CONCLUSIONS: Complications of healing including nonunion, delayed union, and implant failure are not infrequent and represent ongoing problems with distal femur fracture treatment. Further clinical research combined with innovation in surgical techniques and implant design will be necessary to improve the results of the last decade. PMID- 21248566 TI - Nightingale's teaching: still relevant. PMID- 21248567 TI - Seize the opportunity an externship offers. PMID- 21248572 TI - Create your own tracheostomy and laryngectomy teaching aids. PMID- 21248573 TI - Incidence of quality bundles across critical care and telemetry patients. PMID- 21248576 TI - Patient education series. Preventing falls. PMID- 21248578 TI - A race to the end. PMID- 21248579 TI - Relationship-based care: a new approach. PMID- 21248580 TI - Puzzling out disclosure programs: where do you fit into the picture? PMID- 21248581 TI - Vincent and Ludwig angina: two damaging oral infections. PMID- 21248582 TI - Your final assessment: determination of death. AB - After a long illness, a patient with a do-not-resuscitate (DNR) order took his last breath while surrounded by family at his hospital bed. His oncology nurse came into the room immediately to answer questions and offer support. She then explained that the house physician would come to pronounce their father. Sadly, 3 hours passed before this occurred due to other emergencies in the hospital. PMID- 21248583 TI - New thinking about fibromyalgia pain. PMID- 21248584 TI - Vital information about a vital sign: BP. PMID- 21248585 TI - Scoring patients for fire risk adds to safety. PMID- 21248586 TI - Online resources for patients with Alzheimer disease. PMID- 21248587 TI - Acute hyperglycemia. PMID- 21248588 TI - Wound infections after surgery for neuromuscular scoliosis: risk factors and treatment outcomes. AB - STUDY DESIGN: Retrospective, case-control study. OBJECTIVE: Determine risk factors for postoperative wound infections after surgery for neuromuscular scoliosis as well as the causative organisms and the results of treatment. SUMMARY OF BACKGROUND DATA: Wound infection after surgery for neuromuscular scoliosis is more common than that for idiopathic scoliosis. A variety of potential risk factors have been identified, but few have demonstrated statistical significance. METHODS: The Pediatric Orthopedic Spine Database identified 151 patients with neuromuscular scoliosis who underwent surgery and had a follow-up of minimum of 2 years. A total of eight patients (5.3% prevalence) developed a postoperative wound infection. Nine patients without an infection were matched by year and type of surgery, for each patient with an infection and selected as controls (n = 72). Preoperative, intraoperative, and postoperative factors were analyzed for an association with wound infection by using stepwise logistic regression. In addition, causative organisms as well as the methods and results of treatment were recorded for each patient. RESULTS.: The control group consisted of 32 males and 40 females with a mean age of 13.3 years (range, 7-21 years) and a mean follow-up of 4.6 years (range, 2.0-20.9 years) at surgery. The infection group (n = 8) consisted of four males and four females with a mean age of 12.5 years (range, 11-14 years) and a mean follow-up of 5.1 year (range, 2.0-12.3 years) at surgery. There were five early and three late wound infections. The presence of a ventriculoperitoneal shunt before surgery was the only factor statistically associated with an increased risk for wound infection (P < 0.01). In addition, infection was associated with pseudarthrosis (P < 0.01) and an increased length of hospitalization (P < 0.01). The most common causative species was staphylococcus and the majority (88%) of infections required surgical intervention with a mean of 2.1 debridements (range, 1-4 debridements). CONCLUSIONS: The presence of a ventriculoperitoneal shunt is a statistically significant risk factor for wound infection after corrective surgery for neuromuscular scoliosis. Wound infection is associated with pseudarthrosis and prolonged hospitalization. LEVEL OF EVIDENCE: III. PMID- 21248589 TI - Sagittal spinal balance after lumbar spinal fusion: the impact of anterior column support results from a randomized clinical trial with an eight- to thirteen-year radiographic follow-up. AB - STUDY DESIGN: Randomized clinical trial. OBJECTIVE: To analyze the long-term clinical impact of anterior column support on sagittal balance after lumbar spinal fusion. SUMMARY OF BACKGROUND DATA: Several investigators have stressed the importance of maintaining sagittal balance in relation to spinal fusion to avoid lumbar 'flat back,' accelerated adjacent segment degeneration, pain, and inferior functional outcome. Only limited evidence exists on how sagittal alignment affects clinical outcome. Anterior lumbar interbody fusion combined with posterolateral fusion has been proved superior to posterolateral fusion alone regarding outcome and cost-effectiveness. No randomized controlled trial has been published analyzing the effect of anterior support on radiographic measurements of sagittal balance. METHODS: Between 1996 and 1999, 148 patients with severe chronic low back pain were randomly selected for posterolateral lumbar fusion plus anterior support (PLF + ALIF) or posterolateral lumbar fusion. A total of 92 patients participated. Sagittal balance parameters were examined on full lateral radiographs of the spine: pelvic incidence (PI), pelvic tilt (PT), sacral slope, thoracic kyphosis, lumbar lordosis, and positioning of C7 plumb line. The type of lumbar lordosis was evaluated and outcome assessed by Oswestry Disability Index (ODI). RESULTS: Follow-up rate was 74%. Sagittal balance parameters were similar between randomization groups. None of the parameters differed significantly between patients with an ODI from 0 to 40 and patients with ODI over 40. Balanced patients had a significantly superior outcome as measured by ODI (P < 0.05) compared with unbalanced patients. CONCLUSION: No difference in the investigated sagittal balance parameters was seen between patients treated with PLF + ALIF or posterolateral fusion alone. Lumbar lordosis and type of lordosis correlated with outcome but could not explain the superior outcome in the group with anterior support. Whether sagittal balance and anterior support during fusion provide a protective effect on adjacent motion segments remains unclear. PMID- 21248590 TI - Interaction of 5-hydroxytryptamine and tumor necrosis factor-alpha to pain related behavior by nucleus pulposus applied on the nerve root in rats. AB - STUDY DESIGN: The effects of exogenous 5-hydroxytryptamine (5-HT), tumor necrosis factor(TNF)-alpha, 5-HT + TNF in combination, and autologous nucleus pulposus (NP) at dorsal root ganglion (DRG) were examined using rat models. OBJECTIVE: To examine the interaction of 5-HT with TNF for pain-related behavior in a rat lumbar disc herniation (LDH) model. SUMMARY OF BACKGROUND DATA: 5-HT and TNF have been shown to play roles in sciatica in lumbar disc herniation as chemical factors. METHODS: Adult female Sprague-Dawley rats were divided into six groups: 5-HT group, TNF group, 5-HT + TNF (combination) group, NP group, control group, and naive group. Von Frey tests were used for pain-related behavior testing. Expressions of activating transcription factor 3 and calcitonin gene-related peptide (CGRP) were evaluated immunohistochemically. Expressions of TNF, TNF receptor 1 (TNFR1), and 5-HT2A receptors in the left L5 DRG were examined using western blotting. Plasma levels of 5-hydroxyindole acetic acid, a metabolite of 5 HT, were measured. RESULTS: Mechanical withdrawal thresholds were significantly decreased in the 5-HT, TNF, combination, and NP groups compared with controls. Thresholds recovered after 14 days in the 5-HT and TNF groups, and after 28 days in the combination group. Exogenous 5-HT and TNF to the nerve root induced pain related behavior and lasted for a shorter period compared with combination and NP groups. Activating transcription factor 3- and calcitonin gene-related peptide immunoreactive DRG neurons were significantly increased only in the early phase in 5-HT, TNF, combination, and NP groups. TNF induced 5-HT2A receptor expressions in the DRG, while 5-HT induced TNF and TNF receptor 1 expressions. CONCLUSION: The present findings suggest that both 5-HT and TNF induce pain-related behavior and interact with each other to prolong pain-related behavior in a rat LDH model. PMID- 21248592 TI - Aortic abutment after direct vertebral rotation: plowing of pedicle screws. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To report the occurrence of pedicle screw plow after individual-level direct vertebral rotation (DVR) that resulted in critical screw proximity to the aorta, from three institutions over a four-year period (2004-2008). SUMMARY OF BACKGROUND DATA: Thoracic pedicle screws are generally accepted as safe implants that possess sufficient strength to correct the coronal, sagittal, and now transverse plane deformities associated with scoliosis. Structural failure of the bone resulting in translation of the screw in the transverse plane, defined as plow, can occur with individual-level DVR. METHODS: We performed a retrospective review of all pediatric patients who underwent posterior spinal fusion with pedicle screws for neuromuscular and idiopathic scoliosis and underwent postoperative computed tomographic scan. We identified all patients who required a secondary procedure for implant removal because of malposition of the screw. RESULTS: Six patients with lateral screw direction after a DVR maneuver required screw removal because of proximity to the aorta. All patients had intraoperative confirmation of adequate screw placement before introducing the rod and performing derotation. CONCLUSIONS.: The biologic limitations of vertebrae are approached as we strive to achieve further correction of the spine. Surgeons' experience and methods to assess proper screw placement may give a false sense of adequate final implant position after DVR. Vigilance to ensure proper pedicle screw position can avoid potential iatrogenic catastrophes. PMID- 21248591 TI - A Cochrane review of combined chiropractic interventions for low-back pain. AB - STUDY DESIGN: Cochrane systematic review of randomized controlled trials. OBJECTIVE: To determine the effects of combined chiropractic interventions on pain, disability, back-related function, overall improvement, and patient satisfaction in adults with low-back pain (LBP). SUMMARY OF BACKGROUND DATA: Chiropractors commonly use a combination of interventions to treat people with LBP, but little is known about the effects of this care. METHODS: We used a comprehensive search strategy. All randomized trials comparing combined chiropractic interventions (rather than spinal manipulation alone) with no treatment or other therapies were included. At least two authors selected studies, assessed bias risk, and extracted data. Descriptive synthesis and meta analyses were performed. RESULTS: We included 12 studies involving 2887 LBP participants. Three studies had low risk of bias. Included studies evaluated a range of chiropractic procedures in a variety of subpopulations with LBP. For acute and subacute LBP, chiropractic interventions improved short- and medium term pain (standardized mean difference [SMD] -0.25 [95% CI: -0.46 to -0.04] and MD -0.89 [95%CI: -1.60 to -0.18]) compared with other treatments, but there was no significant difference in long-term pain (MD -0.46 [95% CI -1.18 to 0.26]). Short-term improvement in disability was greater in the chiropractic group compared to other therapies (SMD -0.36 [95% CI: -0.70 to -0.02]). However, the effect was small and studies contributing to these results had high risk of bias. There was no difference in medium- and long-term disability. No difference was demonstrated for combined chiropractic interventions for chronic LBP and studies that had a mixed population of LBP. CONCLUSION: Combined chiropractic interventions slightly improved pain and disability in the short term and pain in the medium term for acute/subacute LBP. However, there is currently no evidence that supports or refutes that these interventions provide a clinically meaningful difference for pain or disability in people with LBP when compared to other interventions. PMID- 21248593 TI - Patient self-assessment of appearance is improved more by all pedicle screw than by hybrid constructs in surgical treatment of adolescent idiopathic scoliosis. AB - STUDY DESIGN: A multicenter prospective cohort study. OBJECTIVE: To compare the effect of all pedicle screw versus hybrid constructs on patient self-assessment of appearance after posterior spinal fusion with instrumentation for adolescent idiopathic scoliosis (AIS). This will contribute to future cost-effective analyses on surgical management of AIS. SUMMARY OF BACKGROUND DATA: For surgical management of AIS, the Spinal Appearance Questionnaire (SAQ) and the Scoliosis Research Society outcomes instrument (SRS-30) are reliable surveys of patient satisfaction, but neither tool has been used to assess outcome by implant type. METHODS: Patients received either all pedicle screws or hybrid instrumentation. Self-assessment of appearance pre- and after surgery was measured by SAQ and SRS 30. Statistical significance was evaluated through P values (P < 0.01 in the SAQ, P < 0.05 in the SRS-30) and effect sizes. RESULTS: There were 93 patients in the all pedicle screw cohort and 61 in the hybrid cohort. There were no significant preoperative differences between the cohorts in the SAQ or SRS-30. All pedicle screw patients tended to see more improvement in shoulder level than hybrid patients in 2 separate SAQ questions (P = 0.025, Cohen's D = 0.20; P = 0.013, D = 0.24). The screw patients also tended to have better scores than hybrid patients in the category, "looking better in clothes" (P = 0.017, V = 0.24) at 2 years postoperative. All pedicle screw patients self-reported significant greater improvement than hybrid patients in the SRS-30 Appearance and Mental domains (P = 0.016, ES = 0.038; P = 0.005, ES = 0.051). There were no significant differences between cohorts in age, gender, baseline curve, or major curve magnitude. CONCLUSION: All pedicle screw constructs lead to better self-assessment of appearance in operative treatment of AIS, as determined by SAQ and SRS-30. PMID- 21248595 TI - Perspective: Does medical education promote professional alexithymia? A call for attending to the emotions of patients and self in medical training. AB - Emotions--one's own and others'--play a large role in the lives of medical students. Students must deal with their emotional reactions to intellectual and physical stress, the demanding clinical situations to which they are witness, as well as patients' and patients' family members' often intense feelings. Yet, currently few components in formal medical training--in either direct curricular instruction or physician role modeling--focus on the emotional lives of students. In this article, the author examines patients', medical students', and physician role models' emotions in the clinical context, highlighting challenges in all three of these arenas. Next, the author asserts that the preponderance of medical education continues to address the emotional realm through ignoring, detaching from, and distancing from emotions. Finally, she presents not only possible theoretical and conceptual models for developing ways of understanding, attending to, and ultimately "working with" emotions in medical education but also examples of innovative curricular efforts to incorporate emotional awareness into medical student training. The author concludes with the hope that medical educators will consider making a concerted effort to acknowledge emotions and their importance in medicine and medical training. PMID- 21248596 TI - Humanism at heart: preserving empathy in third-year medical students. AB - PURPOSE: Research suggests that medical student empathy erodes during undergraduate medical education. The authors evaluated the Jefferson Scale of Physician Empathy Medical Student Version (JSPE-MS) scores of two consecutive medical school classes to assess the impact of an educational intervention on the preservation of empathy. METHOD: The authors conducted a before-and-after study of 209 Robert Wood Johnson Medical School (RWJMS) students enrolled in the classes of 2009 and 2010. Students' clerkships included a mandatory, longitudinal "Humanism and Professionalism" (H&P) component, which included blogging about clerkship experiences, debriefing after significant events, and discussing journal articles, fiction, and film. Students completed the JSPE-MS during their first and last clerkships. RESULTS: The results showed that (1) contrary to previous studies' findings, third-year students did not show significant decline in empathy as measured by the JSPE-MS (these students, from two consecutive RWJMS classes, experienced the H&P intervention), (2) students selected for the Gold Humanism Honor Society (GHHS) were significantly different from their peers in empathy scores as measured by JSPE-MS, and (3) knowledge of selection for the GHHS seems to positively influence students' JSPE-MS scores. CONCLUSIONS: Maintaining empathy during the third year of medical school is possible through educational intervention. A curriculum that includes safe, protected time for third-year students to discuss their reactions to patient care situations during clerkships may have contributed to the preservation of empathy. Programs designed to validate humanism in medicine (such as the GHHS) may reverse the decline in empathy as measured by the JSPE-MS. PMID- 21248597 TI - Perspective: Physician education: a promising strategy to prevent adolescent suicide. AB - Many young people who present to primary care providers (PCPs) have high levels of emotional distress and/or suicidal ideation. Therefore, PCPs are in an ideal position to recognize and respond to early symptoms and distress signals that accompany suicide warning signs, yet they underrecognize mood disorders and suicidality among youth. Medical school and residency programs typically provide inadequate training on pediatric mental health and adolescent suicide prevention. Thus, PCPs lack complete knowledge of risk factors and feel unprepared to handle mental health problems among youth. In this article, the authors provide an overview of the epidemiology of adolescent suicide and describe risk factors, protective factors, and warning signs. They propose that physician education represents a promising strategy to prevent adolescent suicide, and they establish the need for improved educational opportunities that would provide PCPs with the necessary skills and supports to identify and respond to psychosocial concerns that may increase suicide risk among youth. They recommend strategies, methods, and content areas for addressing educational gaps, as well as organizational approaches to support enhanced physician education. They also suggest areas for future research. PMID- 21248598 TI - Virtual humans versus standardized patients: which lead residents to more correct diagnoses? AB - PURPOSE: Medical educators frequently use standardized patient (SP) encounters to bridge the gap between didactic education and practical application. Typically, SPs are healthy adults with no consistent physical findings; however, highly immersive virtual humans (VHs) may enable the consistent presentation of abnormal physical findings to multiple learners across multiple repetitions. Thus, the authors conducted this study to compare how frequently junior anesthesiology residents suspected obstructive sleep apnea (OSA) in preoperative assessments of SPs versus a VH. METHOD: The authors presented a patient whose case included the historical features of OSA (snoring, daytime fatigue, observed apnea, hypertension, and obesity). Three SPs (in 2008) and one VH (in 2009) were necessary to run the residents through the assessment. The VH appeared morbidly obese and had a neck circumference of 40 cm [corrected]. An airway exam of the VH displayed an image of redundant soft tissue, prominent tongue, and tonsillar hypertrophy. The VH responded to natural speech by recognizing "triggers" in a human's voice. The 849 triggers and 259 VH responses were designed with a technique that collects information from user interactions. RESULTS: Five of 21 residents (23.8%) suspected OSA after interviewing the SPs, whereas 11 of 13 residents (84.6%) suspected OSA after interviewing the VH (odds ratio of 17.6; 95% CI of 2.9-107). CONCLUSIONS: Residents suspected OSA much more frequently after interviewing the VH than after interviewing the SPs. The VH provides a unique opportunity to display numerous abnormal physical findings as part of SP encounters. PMID- 21248599 TI - Which experiences in the hidden curriculum teach students about professionalism? AB - PURPOSE: To examine the relationship between learner experience in the "hidden curriculum" and student attribution of such experiences to professionalism categories. METHOD: Using the output of a thematic analysis of 272 consecutive narratives recorded by 135 students on a medical clerkship from June through November 2007, the authors describe the frequency of these experiences within and across student-designated Association of American Medical Colleges-National Board of Medical Examiners professionalism categories and employ logistic regression to link varieties of experience to specific professionalism categories. RESULTS: Thematic analysis uncovered two main domains of student experience: medical clinical interaction and teaching-and-learning experiences. From a student perspective the critical incident stories evoked all professionalism categories. Most frequently checked off categories were caring/compassion/communication (77%) and respect (69%). Logistic regression suggested that student experiences within the teaching-and-learning environment were associated with professionalism categories of excellence, leadership, and knowledge and skills, whereas those involving medical-clinical interactions were associated with respect, responsibility and accountability, altruism, and honor and integrity. Experiences of communicating and working within teams had the broadest association with learning about professionalism. CONCLUSIONS: Student narratives touched on all major professionalism categories as well as illuminating the contexts in which critical experiences emerged. Linked qualitative and quantitative analysis identified those experiences that were associated with learning about particular aspects of professionalism. Experiences of teamwork were especially relevant to student learning about professionalism in action. PMID- 21248600 TI - Online "spaced education progress-testing" of students to confront two upcoming challenges to medical schools. AB - PURPOSE: U.S. medical students will soon complete only one licensure examination sequence, given near the end of medical school. Thus, schools are challenged to identify poorly performing students before this high-stakes test and help them retain knowledge across the duration of medical school. The authors investigated whether online spaced education progress-testing (SEPT) could achieve both aims. METHOD: Participants were 2,648 students from four U.S. medical schools; 120 multiple-choice questions and explanations in preclinical and clinical domains were developed and validated. For 34 weeks, students randomized to longitudinal progress-testing alone (LPTA) received four new questions (with answers/ explanations) each week. Students randomized to SEPT received the identical four questions each week, plus two-week and six-week cycled reviews of the questions/explanations. During weeks 31-34, the initial 40 questions were re-sent to students to assess longer-term retention. RESULTS: Of the 1,067 students enrolled, the 120-question progress-test was completed by 446 (84%) and 392 (74%) of the LPTA and SEPT students, respectively. Cronbach alpha reliability was 0.87. Scores were 39.9%, 51.9%, 58.7%, and 58.8% for students in years 1-4, respectively. Performance correlated with Step 1 and Step 2 Clinical Knowledge scores (r = 0.52 and 0.57, respectively; P < .001) and prospectively identified students scoring below the mean on Step 1 with 75% sensitivity, 77% specificity, and 41% positive predictive value. Cycled reviews generated a 170% increase in learning retention relative to baseline (P < .001, effect size 0.95). CONCLUSIONS: SEPT can identify poorly performing students and improve their longer-term knowledge retention. PMID- 21248601 TI - The hidden and implicit curricula in cultural context: new insights from Doha and New York. AB - The authors report their longitudinal experience teaching a clerkship in clinical ethics and palliative care at the Weill Cornell Medical College campuses in New York and Doha. This course uses participant observation and reflective practice to counteract the hidden curriculum when learning about clinical ethics and end of-life care. The authors consider how this formal element of the curriculum is influenced by the implicit and hidden curricula in different cultural contexts and how these differing venues affect communication and information exchange, using the anthropological concept of high- and low-context societies. The authors' analysis provides additional information on Weill Cornell's educational efforts in the medical humanities, bioethics, and palliative care across the curriculum and across cultural settings. By contrasting high-context Doha, where much information is culturally embedded and seemingly hidden, with low-context New York, where information is made overt, the authors theorize that in each setting, the proportion of implicit and explicit curricular elements is determined by the extramural cultural environment. They argue that there are many hidden and implicit curricula and that each is dependent on modes of communication in any given setting. They assert that these variations can be seen not only across differing societies but also, for example, among individual U.S. medical schools because of local custom, history, or mission. Because these contextual factors influence the relative importance of what is implicit and explicit in the student's educational experience, medical educators need to be aware of their local cultural contexts in order to engage in effective pedagogy. PMID- 21248602 TI - What should we include in a cultural competence curriculum? An emerging formative evaluation process to foster curriculum development. AB - PURPOSE: To identify, prioritize, and organize components of a cultural competence curriculum to address disparities in cardiovascular disease. METHOD: In 2006, four separate nominal group technique sessions were conducted with medical students, residents, community physicians, and academic physicians to generate and prioritize a list of concepts (i.e., ideas) to include in a curriculum. Afterward, 45 educators and researchers organized and prioritized the concepts using a card-sorting exercise. Multidimensional scaling (MDS) and hierarchical cluster analysis produced homogeneous groupings of related concepts and generated a cognitive map. The main outcome measures were the number of cultural competence concepts, their relative ranks, and the cognitive map. RESULTS: Thirty participants generated 61 concepts; 29 were identified by at least two participants. The cognitive map organized concepts into four clusters, interpreted as (1) patient's cultural background (e.g., information on cultures, habits, values), (2) provider and health care (e.g., clinical skills, awareness of one's bias, patient centeredness, professionalism), communication skills (e.g., history, stereotype avoidance, health disparities epidemiology), (3) cross culture (e.g., idiomatic expressions, examples of effective communication), and (4) resources to manage cultural diversity (e.g., translator guides, instructions, community resources). The MDS two-dimensional solution demonstrated a good fit (stress = 0.07; R2 = 0.97). CONCLUSIONS: A novel, combined approach allowed stakeholders' inputs to identify and cognitively organize critical domains used to guide development of a cultural competence curriculum. Educators may use this approach to develop and organize educational content for their target audiences, especially in ill-defined areas like cultural competence. PMID- 21248603 TI - Managing conflicts of interest in clinical care: a national survey of policies at U.S. medical schools. AB - PURPOSE: Policy recommendations specify how academic medical centers should manage clinical conflicts of interest (CCOIs), including gifts and payments to physicians from pharmaceutical companies. However, no reliable data exist on the extent to which schools have policies to manage CCOIs. The authors sought to determine the extent and strength of medical schools' CCOI policies. METHOD: A survey asked compliance officers at 125 MD-granting medical schools in the United States to indicate whether their institutions had policies covering 11 areas of CCOI and to provide copies of relevant policies. Policies were scored as 0 (no policy), 1 (permissive), 2 (moderate), or 3 (stringent), based on published recommendations. Each school's scores were averaged to create a measure of overall policy strength. The authors also collected information on schools' public/private status, hospital ownership/affiliation, and NIH funding to determine whether these characteristics were associated with differences in policy strength. RESULTS: A representative sample of 77 of 125 (62%) medical schools responded between October 2007 and December 2008. Absence of policy was the most frequent finding in 7 of 11 CCOI areas. The mean score for overall policy strength was 1.2. Greater NIH funding was associated with stronger policies in 9 areas. CONCLUSIONS: This analysis provides a comprehensive overview of medical schools' CCOI policies. Wider adoption of CCOI policies is crucial to eliminate undue industry influence in clinical care and to preserve public trust in the medical profession. The authors close with a consideration of why so few medical schools have implemented strong policies. PMID- 21248604 TI - Physicians' empathy and clinical outcomes for diabetic patients. AB - PURPOSE: To test the hypothesis that physicians' empathy is associated with positive clinical outcomes for diabetic patients. METHOD: A correlational study design was used in a university-affiliated outpatient setting. Participants were 891 diabetic patients, treated between July 2006 and June 2009, by 29 family physicians. Results of the most recent hemoglobin A1c and LDL-C tests were extracted from the patients' electronic records. The results of hemoglobin A1c tests were categorized into good control (<7.0%) and poor control (>9.0%). Similarly, the results of the LDL-C tests were grouped into good control (<100) and poor control (>130). The physicians, who completed the Jefferson Scale of Empathy in 2009, were grouped into high, moderate, and low empathy scorers. Associations between physicians' level of empathy scores and patient outcomes were examined. RESULTS: Patients of physicians with high empathy scores were significantly more likely to have good control of hemoglobin A1c (56%) than were patients of physicians with low empathy scores (40%, P < .001). Similarly, the proportion of patients with good LDL-C control was significantly higher for physicians with high empathy scores (59%) than physicians with low scores (44%, P < .001). Logistic regression analyses indicated that physicians' empathy had a unique contribution to the prediction of optimal clinical outcomes after controlling for physicians' and patients' gender and age, and patients' health insurance. CONCLUSIONS: The hypothesis of a positive relationship between physicians' empathy and patients' clinical outcomes was confirmed, suggesting that physicians' empathy is an important factor associated with clinical competence and patient outcomes. PMID- 21248605 TI - Perspective: Medical professionalism and medical education should not involve commitments to political advocacy. AB - It is increasingly suggested that political advocacy is a core professional responsibility for physicians. The author argues that this is an error. Advocacy on behalf of societal goals, even those goals as unexceptionable as the betterment of human health, is inevitably political. Claims that political advocacy are a professional responsibility are mistaken, the author argues, because (1) civic virtues are outside the professional realm, (2) even if civic virtues were professionally obligatory, it is unclear that civic participation is necessary for such virtue, and (3) the profession of medicine ought not to require any particular political stance of its members. Claims that academic health centers should systematically foster advocacy are also deeply problematic. Although advocacy may coexist alongside the core university activities of research and education, insofar as it infects those activities, advocacy is likely to subvert them, as advocacy seeks change rather than knowledge. And official efforts on behalf of advocacy will undermine university aspirations to objectivity and neutrality.American society has conferred remarkable success and prosperity on its medical profession. Physicians are deserving of such success only insofar as they succeed in offering society excellence and dedication in professional work. Mandatory professional advocacy must displace such work but cannot substitute for it. The medical profession should steadfastly resist attempts to add advocacy to its essential professional commitments. PMID- 21248606 TI - Perspective: Malpractice in an academic medical center: a frequently overlooked aspect of professionalism education. AB - Understanding how medical malpractice occurs and is resolved is important to improving patient safety and preserving the viability of a physician's career in academic medicine. Every physician is likely to be sued by a patient, and how the physician responds can change his or her professional life. However, the principles of medical malpractice are rarely taught or addressed during residency training. In fact, many faculty at academic medical centers know little about malpractice.In this article, the authors propose that information about the inciting causes of malpractice claims and their resolution should be incorporated into residency professionalism curricula both to improve patient safety and to decrease physician anxiety about a crucial aspect of medicine that is not well understood. The authors provide information on national trends in malpractice litigation and residents' understanding of malpractice, then share the results of their in-depth review of surgical malpractice claims filed during 2001-2008 against their academic medical center. The authors incorporated those data into an evidence-driven curriculum for residents, which they propose as a model for helping residents better understand the events that lead to malpractice litigation, as well as its process and prevention. PMID- 21248607 TI - Perspective: The case for research justice: inclusion of patients with limited English proficiency in clinical research. AB - Persons with limited English proficiency (LEP) constitute a growing portion of the U.S. population, yet they are underrepresented in clinical research. This inherently limits the societal benefits of the research and its generalizability to ethnic populations living in the United States. To illustrate the complexity associated with including LEP participants in clinical research, the authors critically evaluated LEP consent requirements posted on the Web sites of 134 academic health centers in March 2008. They found wide variability with regard to consent policies and striking interinstitutional differences in posted IRB policies and attitudes toward consent of LEP patients in research. The authors argue this variation highlights competing concerns between autonomy and justice. Outcomes-based justice requires inclusion of LEP patients in the research, yet the consent process is often resource-intensive and complex. The authors suggest that more uniform and specific guidance from federal agencies for enrollment of LEP patients in clinical research be established and that this guidance explicitly recalibrate the current balance between autonomy and justice. Investigators and institutional review boards should also develop streamlined best practices to reduce unnecessary effort and expense associated with recruitment of LEP individuals. LEP individuals should have fair access to clinical research in order to fully realize individual and societal benefits of their participation and to ensure the generalizability of scientific discovery. PMID- 21248608 TI - Checklists to reduce diagnostic errors. AB - Diagnostic errors are common and can often be traced to physicians' cognitive biases and failed heuristics (mental shortcuts). A great deal is known about how these faulty thinking processes lead to error, but little is known about how to prevent them. Faulty thinking plagues other high-risk, high-reliability professions, such as airline pilots and nuclear plant operators, but these professions have reduced errors by using checklists. Recently, checklists have gained acceptance in medical settings, such as operating rooms and intensive care units. This article extends the checklist concept to diagnosis and describes three types of checklists: (1) a general checklist that prompts physicians to optimize their cognitive approach, (2) a differential diagnosis checklist to help physicians avoid the most common cause of diagnostic error--failure to consider the correct diagnosis as a possibility, and (3) a checklist of common pitfalls and cognitive forcing functions to improve evaluation of selected diseases. These checklists were developed informally and have not been subjected to rigorous evaluation. The purpose of this article is to argue for the further investigation and revision of these initial attempts to apply checklists to the diagnostic process. The basic idea behind checklists is to provide an alternative to reliance on intuition and memory in clinical problem solving. This kind of solution is demanded by the complexity of diagnostic reasoning, which often involves sense-making under conditions of great uncertainty and limited time. PMID- 21248609 TI - Building a departmental quality program: a patient-based and provider-led approach. AB - Quality improvement in health care today requires a comprehensive approach. Improvement efforts led by patients, payers, regulators, or health care providers face many barriers. Obstacles include selecting measures with clinical value, building physician acceptance, establishing routine and efficient measurement, and resolving competing clinical demands and work flow impediments. To meet these challenges, the Brigham and Women's Hospital Department of Medicine created a grassroots quality program guided by four main principles: improvement is led by frontline clinicians who select measures important to their patients, performance measurement is automated and accurate, appropriate resources are provided, and interventions are system based and without financial incentives for individual providers. The quality program has engaged the department's physicians from the start. Given the flexibility to define their own metrics according to their patients' needs, clinicians have selected measures related to prevention and wellness, which are often based on national standards. The central quality team facilitates measurement and reporting while providers focus on patient care. The subsequent production of meaningful, actionable data has been instrumental in building physician acceptance and in providing clinicians the opportunity to evaluate and monitor performance. The program's largest challenges have been in capturing meaningful data from electronic systems. The program's system-based focus encourages providers to develop solutions within the existing framework of clinic resources, primarily targeting work flows and processes, while minimizing large expenditures on additional staffing. PMID- 21248610 TI - Sharing facilities and administrative cost recovery to facilitate interdisciplinary research. AB - PURPOSE: Despite increasing interest in interdisciplinary research, researchers consistently cite institutional barriers as deterrents. Researchers, administrators, and others have suggested developing processes for sharing facilities and administrative (F&A) cost recovery as one way to support collaborative research. Therefore, the authors reviewed current policies for sharing F&A cost recovery and user satisfaction with them. METHOD: In 2010, through reviewing institutional Web sites and surveying researchers and grants administrators from a range of institutions, the authors identified different policies currently employed and assessed user satisfaction with them. RESULTS: Whereas most respondents (80.7%, 205/254) agreed that a standard policy for sharing F&A cost recovery would facilitate interdisciplinary collaboration, only 35.4% (90/254) reported that their institutions had such a policy. Among the 85 respondents who answered questions about their institution's policy, most (66 [77.6%]) reported that the policy applied to grants with multiple principal investigators or coinvestigators across departments or schools, and 68 (80.0%) reported satisfaction with the policy. Respondents from institutions with policies were significantly more likely to endorse the notion that policies are helpful compared with those who reported that their institutions did not have such policies or were unsure of their existence (89% versus 76%, P = .014). The authors detected no significant differences in satisfaction scores based on policy type, whether determined by investigator effort, space allocation, or other considerations (P = .29). CONCLUSIONS: These data support the need for institutions to establish formal policies for sharing F&A cost recovery as a way to promote interdisciplinary research collaboration. PMID- 21248611 TI - Perspective: Academic obstetrics-gynecology departments in the city of Philadelphia: are the wheels coming off? AB - Maternity care in Philadelphia is in an unprecedented and precarious situation, as all the community hospitals that once provided maternity care services have either closed completely or stopped providing maternity services. Six academic medical centers (AMCs) in the city of Philadelphia now provide care to a population of 1.5 million requiring increasingly complex and expensive maternity care, at the same time as insurance premiums and the malpractice crisis in Pennsylvania peaked. The AMCs are able to continue providing maternity care to this population that includes a large proportion of poor, minority, and un- or underinsured patients thanks to government subsidization of resident education, the services provided by resident physicians, and the influx of government and industry research funds, but the financial outlook of academic obstetrics gynecology departments in this city is dire. Obstetric academic medicine in Philadelphia has come to more closely resemble a "big wheel" tricycle than Flexner's "three-legged stool." Clinical medicine is the driver (the large front wheel and pedal) pulling along education and research, the two smaller wheels in the back. A maternity care alliance is needed in Philadelphia allowing area AMCs to pool and trade resources, reduce costs, improve quality and innovation, and share risks. Philadelphia may serve as an early warning for other cities and AMCs around the country and has the opportunity to serve as a model for how to overcome these serious challenges. PMID- 21248612 TI - Pharmacokinetic studies in women of 2 novel oral formulations of tranexamic acid therapy for heavy menstrual bleeding. AB - Two randomized, open-label clinical studies involving healthy female volunteers aged 18-45 years (study 1, N = 32; study 2, N = 40) are described, which characterize the pharmacokinetics and steady-state dosage regimen performance of 2 novel, modified-release tranexamic acid tablet formulations. The objective of these studies was to identify the optimum product formulation to advance into late-phase clinical trials for heavy menstrual bleeding. For study 1, participants received single 1.3-g doses (2 650-mg tablets) of tranexamic acid modified-immediate-release (MIR) and tranexamic acid delayed-release (DR) formulations under fasting conditions compared with nonfasting conditions (after breakfast). For study 2, participants received tranexamic acid MIR or tranexamic acid DR as a single 1.3-g dose followed by a dosage regimen of 1.3 g every 8 hours for 5 days. Plasma tranexamic acid concentrations reached minimum effective levels (>=5 MUg/mL) within 1.5 hours and within 3 hours after a 1.3-g tranexamic acid MIR and tranexamic acid DR dose, respectively. Food did not appreciably influence tranexamic acid MIR pharmacokinetics, whereas a high-fat meal significantly lowered the maximum concentration produced with tranexamic acid DR. Peak systemic exposure and maintenance of plasma tranexamic acid concentrations within the therapeutic range (5-15 MUg/mL) were optimally achieved with 1.3 g of the MIR formulation dosed every 8 hours. The MIR and DR formulations were well tolerated. Peak-to-trough steady-state performance of the tranexamic acid MIR 1.3 g product (dosed every 8 hours, or 3 times daily, for up to 5 days) supported its advancement to late-phase clinical trials in women with heavy menstrual bleeding. PMID- 21248613 TI - Thinking beyond the obvious: hepatotoxicity secondary to idiosyncratic depakote toxicity. AB - Depakote-induced hepatotoxicity has been well established as an adverse effect, and periodic monitoring of drug level is often required. Depakote-induced hepatotoxicity mostly occurs at supratherapeutic drug level. Rarely, an idiosyncratic response is triggered, and hepatotoxicity can occur at the therapeutic drug level mostly in chronic users. Here, we describe a rare case of idiosyncratic depakote-induced hepatotoxicity. A 25-year-old female with non insulin-dependent diabetes mellitus, hypothyroidism, seizure disorder, and Dandy Walker Syndrome presented with an unwitnessed seizure and altered mental status. The patient's medication list included zonisamide, depakote, and synthroid. She was noted to be lethargic, disoriented, nonverbal, but awake. An arterial blood gas examination showed severe anion gap metabolic acidosis. Blood work was consistent with hepatitis, hyperammonemia, thrombocytopenia, and coagulopathy. The Depakote level was therapeutic. Head computed tomography and liver ultrasound results were not significant. After ruling out all other causes and seeing improvement of parameters after the drug was discontinued, idiosyncratic depakote toxicity was diagnosed. Based on the patient's rapid improvement; idiosyncratic valproate toxicity was confirmed. This case signifies the importance of recognizing, diagnosing, and treating depakote toxicity in chronic users who have no other explanation for their symptomatology. PMID- 21248614 TI - Valproate-induced hyperammonemic encephalopathy: a case report and brief review of the literature. AB - Almost 50 years after its discovery, valproic acid remains a mainstay in the treatment of epilepsy, both alone and in combination with other anticonvulsants. It is also associated with a hyperammonemic encephalopathy, when used in combination with other drugs. We present a case of valproate-induced hyperammonemic encephalopathy in a patient on multiple anticonvulsant and psychotropic medications. The patient presented with altered mental status and became progressively more obtunded and finally began to experience seizures. Her symptoms resolved with the discontinuation of valproic acid and with supportive care. PMID- 21248615 TI - A case of palpable purpura and nephropathy: Occam's Razor or Hickam's Dictum. AB - Vasculitis causing palpable purpura, nephropathy, and hematologic abnormalities is a well-known entity. However, sometimes, vasculitis may not be the primary cause but is part of a systemic disease. Literature suggests that infections like HIV can induce nephropathy and antineutrophilic cytoplasmic antibody-positive vasculitis, which is different from the well-known entity of "antineutrophilic cytoplasmic antibody-associated vasculitis." We present a 46-year-old female patient with a history of intravenous drug abuse who reported with a rash, swelling, and palpable purpura of the lower extremities. Peripheral smear showed no evidence of disseminated intravascular coagulation or thrombotic thrombocytopenic purpura; metabolic profile showed acute kidney injury. She was found to be HIV- and hepatitis C-positive. Immunologic workup was positive for both MPO and PR3 antineutrophilic cytoplasmic antibodies and negative for cryoglobulins; complement levels were low. Skin biopsy showed leukocytoclastic vasculitis but kidney biopsy was negative for any immunologic involvement; it showed only glomerulosclerosis. Thus, it was thought that nephropathy and vasculitis, in this case, are two distinct pathologic processes, both induced by infection (HIV and/or hepatitis C). The patient responded to low-dose steroid therapy. She was later started on the definitive therapy, the highly active antiretroviral therapy regimen. This case illustrates the fact that low-dose steroids can still be a good alternative in acute situations in patients at risk from immunosuppression. PMID- 21248616 TI - Myths in the treatment of type 2 diabetes: an alternative viewpoint based on randomized controlled trials. AB - Numerous randomized control trials (RCTs) have now questioned the effectiveness and safety of several therapeutic interventions in type 2 diabetes (T2DM). Those RCTs that address several therapeutic interventions in T2DM were reviewed. Meta analysis and ad hoc analysis were excluded. The data from those trials involving self-monitoring of blood glucose, treating hyperglycemia, lowering triglycerides, aggressive treatment of hypertension, and antiplatelet therapy with aspirin are presented with emphasis on hard end points. The evidence shows that self monitoring of blood glucose, lowering blood glucose, reducing triglycerides, aggressive treatment of hypertension, and aspirin therapy are of questionable value in T2DM and may cause harm. Based on RCTs, most therapies in the treatment of T2DM are of questionable value. The medical community should reassess the usefulness of these therapies, which have become commonplace in the management of this condition. PMID- 21248617 TI - Diabetes mellitus in older adults. AB - The prevalence of diabetes mellitus increases with age and causes significant morbidity and poor quality of life in older adults. To review the current literature on the diagnosis and management of diabetes in the elderly, the relevant manuscripts were identified through a MEDLINE (2000-September 1, 2010) search of the English literature. The key phrase used was diabetes in older adults or diabetes in the elderly. The literature search was limited to core clinical journals that have accessible full texts. A total of 480 manuscripts were reviewed. Managing diabetes in older adults is a challenging task. Some features of the disease are unique to the older patient. Several new antidiabetic agents are now available for clinical use, and yet very few clinical trials have been carried out in this age group. For many older adults, maintaining independence is more important than adherence to published guidelines to prevent diabetes complications. The goals of diabetes care in older adults are to enhance quality of life without subjecting the residents to inappropriate interventions. PMID- 21248618 TI - Importance of pharmacokinetic considerations for selecting therapy in the treatment of invasive fungal infections. AB - Invasive fungal infections continue to be a significant cause of morbidity and mortality among at-risk patients. Over the last decade, the epidemiology of invasive mycoses has been defined by increasing rates of infection caused by azole-resistant yeast (Candida glabrata, Candida krusei), Aspergillus, and in some centers, non-Aspergillus moulds, such as Fusarium species, Scedosporium species, and Mucorales. Early and appropriate antifungal therapy is crucial for a favorable clinical outcome. When selecting antifungal therapy--especially during the initial acute phases of treatment--spectrum of activity and pharmacokinetic characteristics are key treatment considerations. Important pharmacokinetic considerations for selecting antifungal therapy in the treatment of invasive fungal infections include drug-drug interactions and variability in adsorption that may limit efficacy during the early phase of treatment, poor oral availability, and variable tissue distribution. A patient's underlying condition and pharmacogenetics also may affect the pharmacokinetics of antifungal drugs, resulting in interpatient pharmacokinetic differences. PMID- 21248619 TI - Protease-activated receptor-1 antagonists: focus on SCH 530348. AB - Currently available antiplatelet agents have shown improved short- and long-term clinical outcomes but are associated with increased bleeding risk, and the rates of recurrent ischemic events still remain high. Selective inhibition of protease activated receptor-1 for thrombin represents a potential novel strategy to reduce ischemic events without increasing the risk of bleeding. Two protease-activated receptor-1 antagonists are currently being evaluated in clinical trials: SCH 530348 and E5555. Results of phase II trials have shown that SCH 530348, when added to standard antiplatelet therapy, was well tolerated and not associated with increased bleeding risk. Two large-scale phase III trials assessing the efficacy of SCH 530348 in addition to the standard of care are currently ongoing. This review provides an outline of the current status of understanding on platelet thrombin-receptor antagonist SCH 530348, focusing on its pharmacologic properties and clinical development. PMID- 21248620 TI - A gargantuan acetaminophen level in an acidemic patient treated solely with intravenous N-acetylcysteine. AB - The objective of this report is to describe an acidemic patient with one of the largest recorded acetaminophen ingestions in a patient with acidemia who was treated with supportive care and intravenous (IV) N-acetylcysteine. A 59-year-old female with a history of depression was found comatose. In the Emergency Department, she was obtunded with agonal respirations and immediately intubated. Activated charcoal was given through a nasogastric tube. An initial acetaminophen serum level was 1141 mg/L. The patient was started on IV N-acetylcysteine. The acetaminophen level peaked 2 hours later at 1193 mg/L. She was continued on the IV N-acetylcysteine protocol. The next day her aspartate aminotransferase was 3150 U/L, alanine aminotransferase was 2780 U/L, and creatinine phosphokinase was 16,197 U/L. There was no elevation in bilirubin or international normalized ratio (INR). Transaminase levels decreased on day 3 and normalized by day 4 when she was transferred to a psychiatric unit. Few cases have been reported of strikingly elevated acetaminophen levels in poisoned patients who did not receive hemodialysis. These patients did have increased lactate levels, and some had normal liver function tests. All of these patients received N-acetylcysteine and survived the poisoning without sequelae. This patient in this report was unique in that she had the highest reported serum acetaminophen level with acidosis and was treated successfully with only IV N-acetylcysteine and supportive care. PMID- 21248622 TI - Severe Brochostenosis by Oral Propafenone Immediately After Commencing Treatment. AB - Propafenone is a membrane-stabilizing agent belonging to a subgroup of the Vaughan Williams class I antidysrhythmic agents, structurally resembling propranolol and characterized by weaker beta-blocking activity. Despite respiratory complications having been reported as examples of side effects, very few reports have been published in the literature.We describe the case of an elderly woman with a history of hypertension and allergy to Parietaria, grass, olive, mites, and with periodic asthmatic manifestations, for whom the administration of oral propafenone for recurrent supraventricular dysrhythmia was associated with the sudden onset of severe bronchostenosis.A 78-year-old woman was frequently admitted to the Emergency Department for a recurrent supraventricular tachycardia, which was treated initially with veramapil and thereafter with ivabradin. During her last visit to the cardiologist, she was prescribed propafenone (150 mg, 3 times a day) in place of ivabradin. After the administration of the second dose on the first day of the therapy, the patient began to complain of the onset of progressively severe dyspnea at rest. In the Emergency Department, respiratory auscultation showed diffuse rhonchi, wheezing, and rales; and arterial pressure was 200/100 mm Hg. Hemogasanalysis revealed hypoxemia, respiratory acidosis with 83% of O2-saturation. Emergency treatment with O2 therapy, methylprednisolone intravenous, furosemide, and then salbutamol was also started; the electrocardiogram only showed sinusal tachycardia. Results of laboratory examinations, including a white cell count and cardiac enzymes, were within the normal range. The patient achieved good respiratory function, after a period of 3 days.This report describes that even a relatively small dose of oral propafenone after commencing treatment can have a severe effect in exacerbating the obstruction of the airways in a susceptible subject. The likely mechanisms are an allergic reaction or a direct bronchospastic effect. Considering the recognized asthmogenicity of propafenone due to beta-blocker activity, we suggest that the cardiologist always refer to the patient's medical history before prescribing this drug, which is capable of producing notable side effects in predisposed individuals, beginning the eventual administration in the hospital setting. The use of bronchial provocation test allows the selection of inclined patients, thus reducing the risk of bronchospasm. PMID- 21248621 TI - Targeting the proteasome with bortezomib in multiple myeloma: update on therapeutic benefit as an upfront single agent, induction regimen for stem-cell transplantation and as maintenance therapy. AB - Bortezomib is the first therapeutic inhibitor of the proteasome that has demonstrated a significant clinical response in patients with otherwise refractory or rapidly advancing disease. Bortezomib has received US Federal Drug Administration approval for the treatment of the hematologic malignancies such as multiple myeloma and mantle cell lymphoma. Herein, the use of bortezomib as an upfront therapy, as an induction regimen before stem-cell transplantation and as maintenance therapy in the treatment of multiple myeloma is discussed. PMID- 21248623 TI - Pulmonary hypertension: a review of pathophysiology and anesthetic management. AB - Pulmonary hypertension is a condition that can result in serious complications in patients undergoing any type of anesthesia during the perioperative period. By definition, pulmonary artery hypertension is caused by a persistent rise in mean pulmonary artery pressure >=25 mm Hg with Pulmonary capillary wedge pressure <= 15 mm Hg or exercise mean pulmonary artery pressure >=35 mm Hg and pulmonary vascular resistance >= 3 wood unit's. The severity of the complications depends on the severity of the underlying condition, other comorbidities, and type of procedure, anesthetic technique, and anesthetic drugs. In this article, we briefly review the pulmonary vascular physiology, pathophysiology of the disease, clinical assessment and diagnosis, treatment options, and the anesthetic management of these patients. PMID- 21248627 TI - Re: risk-based selective referral for cancer surgery: a potential strategy to improve perioperative outcomes. PMID- 21248628 TI - Risk of perioperative transfusion in elective hepatectomy. PMID- 21248629 TI - Perioperative transfusion risk assessment with elective hepatectomy. PMID- 21248630 TI - Role of mechanical bowel preparation and anastomotic technique in low-anterior resection. PMID- 21248631 TI - Tubular epithelial injury and inflammation after ischemia and reperfusion in human kidney transplantation. AB - OBJECTIVE: To provide an integrated insight into the kinetics of tubular injury, inflammation, and oxidative stress after human kidney transplantation. BACKGROUND: Tissue injury due to ischemia and reperfusion is an inevitable consequence of kidney transplantation. Tubular epithelial injury, inflammation, and oxidative stress play major roles in the pathophysiology of acute kidney injury in small animals, but it remains to be established whether this paradigm holds true for human kidney transplantation. METHODS: Markers of tubular injury, inflammation, and oxidative stress were compared between recipients of kidneys from donors after cardiac death (DCD; N = 8) with prolonged ischemia and recipients of living donor kidneys with minimal ischemia (N = 8). RESULTS: In the early postoperative period, creatinine clearance and tubular sodium reabsorption were profoundly reduced in DCD kidneys, coinciding with significantly increased urinary concentrations of tubular injury markers (neutrophil gelatinase associated lipocalin, N-acetyl-beta--glucosaminidase, and cystatin C) and an 18 fold increase in renal production of cytokeratin-18, indicating extensive necrotic cell death. Tubular injury in DCD kidneys was followed by greater systemic inflammatory activity and oxidative stress in the postoperative period (measured with 17-plex cytokine arrays and as plasma F2-isoprostanes, respectively). In contrast, no evidence of oxidative damage to either of the 2 kidney types was found in the early reperfusion period. CONCLUSIONS: These findings establish the relevance of observations in animal models for human kidney transplantation and form the basis for development of novel therapies to improve early graft function and expand the use of donor kidneys with prolonged ischemia. PMID- 21248632 TI - Influence of margin status on outcomes in lobular carcinoma: experience of the European Institute of Oncology. AB - OBJECTIVE: We analyzed 382 patients with pure lobular carcinoma treated up to 2002 with sufficient follow-up to draw prognostic conclusions, all treated by conservative surgery. Our aim was to evaluate the influence of margin status on outcomes with a view assessing the appropriateness of conservative surgery in this breast cancer subtype. METHODS: We assessed locoregional relapse, distant metastasis, contralateral breast cancer, breast cancer-related event free survival, disease-free survival and overall survival according to margin status categorized as at least 10 mm versus less than 10 mm (usually considered negative). RESULTS: The proportions of patients with less than 10 mm margins varied significantly with age (P = 0.02), menopausal status (P = 0.006), and tumor size (P = 0.02) but no other characteristic was significantly related to margin status. As regards unfavorable events during follow-up, none differed significantly between at least 10 mm and less than 10 mm margin groups. In particular, there were 11 (3.7%) local relapses in the same quadrant in at least 10 mm margin group compared to 4 (4.6%) in the less than 10 mm margin group, and 7 (2.4%) ipsilateral breast cancers in the 10 mm or more margin group but none in the less than 10 mm group. These findings indicate that minimal residual disease as evidenced by margins less than 10 mm is eradicated by radiotherapy (backed up in selected cases by reexcision, which in this series was always conservative). The rate of contralateral breast cancer was low at 2.9% indicating that prophylactic contralateral mastectomy is not justified. CONCLUSIONS: We conclude that the surgical approach and criteria for adjuvant hormonal and systemic treatment in lobular carcinoma should be the same as for ductal carcinoma, provided that adequate preoperative investigations exclude extensive multifocal and contralateral disease. PMID- 21248633 TI - Pylorus ring resection reduces delayed gastric emptying in patients undergoing pancreatoduodenectomy: a prospective, randomized, controlled trial of pylorus resecting versus pylorus-preserving pancreatoduodenectomy. AB - OBJECTIVE: To determine in a prospective randomized controlled trial (RCT) whether pylorus-resecting pancreatoduodenectomy (PrPD) with preservation of nearly the entire stomach reduces the incidence of delayed gastric emptying (DGE) compared with pylorus-preserving pancreatoduodenectomy (PpPD). BACKGROUND: Several RCTs have compared PpPD and conventional pancreatoduodenectomy with antrectomy. However, no study has reported the difference between PrPD with preservation of nearly the entire stomach and PpPD. METHODS: One hundred thirty patients were randomized to preservation of the pylorus ring (PpPD) or to resection of the pylorus ring with preservation of nearly the entire stomach (PrPD). This RCT was registered at clinicaltrials.gov NCT00639314. RESULTS: The incidence of DGE was 4.5% in PrPD and 17.2% in PpPD, a significant difference. Delayed gastric emptying was classified into 3 categories proposed by the International Study Group of Pancreatic Surgery. The proposed clinical grading classified 11 cases of DGE in PpPD into grades A (n = 6), B (n = 5), and C (n = 0) and one case in PrPD into each of the 3 grades. The time to peak CO2 content in the C-acetate breath test at 1, 3, and 6 months postoperatively was significantly delayed in PpPD compared with PrPD (34.3 +/- 24.6 minutes versus 18.7 +/- 11.8 minutes, 26.5 +/- 21.1 minutes versus 17.3 +/- 11.7 minutes, 26.7 +/- 18.8 minutes versus 17.4 +/- 13.2 minutes, respectively). Pylorus-resecting pancreatoduodenectomy and PpPD had comparable outcomes for quality of life, weight loss, and nutritional status during a 6-month follow-up period. CONCLUSION: Pylorus-resecting pancreatoduodenectomy significantly reduces of the incidence of DGE compared with PpPD. PMID- 21248634 TI - Noninvasive tools to assess liver disease. AB - PURPOSE OF REVIEW: To improve understanding of recent developments in the noninvasive assessment of fibrosis and their potential clinical application to a range of chronic liver diseases. RECENT FINDINGS: Many noninvasive tests have evolved from their primary validation in chronic hepatitis C virus (HCV) infection to integration into clinical management algorithms for chronic liver disease of varying cause. Recent studies consider the use of these techniques in sequence or in combination, and compare the performance of serum and imaging based noninvasive techniques to identify patients with significant fibrosis, or those at most risk of clinical sequelae from advanced-stage disease. Methods developed in chronic hepatitis C have now been applied in different chronic liver diseases, including nonalcoholic fatty liver disease, alcoholic liver disease, HIV/HCV co-infection and primary biliary cirrhosis. A number of new management algorithms have been developed to facilitate the integration of noninvasive techniques into clinical practice. SUMMARY: Noninvasive tools to assess liver diseases continue to evolve. New imaging technologies have been developed. Existing biomarkers and imaging modalities have been better integrated into clinical practice algorithms, and applied to different chronic liver diseases. Noninvasive techniques will likely continue to be refined and play an important role in the future management of patients with chronic liver disease. PMID- 21248636 TI - Covered self-expandable metal stents for benign biliary tract diseases. AB - PURPOSE OF REVIEW: Benign biliary diseases are often managed endoscopically using plastic stents. Benign biliary strictures (BBS) respond to placement of multiple large-bore plastic stents, though requiring multiple procedures to place stents, and to exchange stents to prevent and/or treat stent occlusion. Bile leaks close using plastic stents, which divert bile away from the leak into the duodenum. Covered self-expandable metal stents (CSEMS), intended for palliation of malignant biliary obstruction, have been used to treat benign biliary diseases. Advantages include small predeployment and large postexpansion diameters. Lack of imbedding of the metal into the bile duct wall enables removability. RECENT FINDINGS: For strictures, one CSEMS is inserted without need for dilation and remains in place for up to 6 months. Successful removal has been reported in all cases. Long-term stricture resolution is achieved in up to 92%. Adverse events include migration and new stricture formation. For treatment of complex bile leaks, the covering and large diameter allow successful closure in nearly all cases. Other uses of CSEMS include treatment of postsphincterotomy bleeding and closure of perforations. SUMMARY: CSEMS show promise for treatment of BBS and complex biliary leaks. Successful resolution can be achieved in the majority of patients with the advantage of fewer procedures, which offsets their higher cost. PMID- 21248635 TI - Innate immunity in the small intestine. AB - PURPOSE OF REVIEW: In this article, we provide an update of the latest findings related to the innate immunity in the small intestine. In particular, we will focus on innate immune receptors and antimicrobial strategies that keep luminal bacteria and viral pathogens under control to avoid mucosal damage. These strategies include IgA secretion and antimicrobial peptides produced by Paneth cells, and downregulation or anergy of the innate immune receptors themselves. RECENT FINDINGS: Pattern-recognition receptors are the main target in the study of innate immunity in the intestinal mucosa due to their involvement in the regulation of host-commensal interactions. It has been shown that TLR5-deficient mice develop metabolic syndrome and have altered intestinal microbiota. On the contrary, NOD2 has been associated with the activation of autophagy and the inhibition of TLR4. Moreover, NOD2 has been described to be essential to keep a feedback loop in the host-commensal homeostasis, through the kinase Rip-2. SUMMARY: Innate immunity in the small intestine is mainly characterized by IgA secretion and Paneth cell antimicrobial function. In both cases pattern recognition receptors, Toll-like receptors and nucleotide-binding and oligomerization domain-like receptors, are involved. A better understanding of the innate immunity in the small intestine would provide valuable information to develop vaccines against pathogens. PMID- 21248637 TI - Live donor liver transplantation for primary sclerosing cholangitis: is disease recurrence increased? AB - PURPOSE OF REVIEW: There is convincing evidence that primary sclerosing cholangitis (PSC) recurs after deceased donor liver transplantation with an incidence of about 20% after 5 years. This review summarizes data regarding recurrent disease in the setting of live donor liver transplantation. RECENT FINDINGS: End-stage liver disease secondary to PSC accounts for less than 3% of all live donor liver transplantations worldwide. Therefore, there are only few data regarding recurrent disease in this setting available, mainly from Japanese transplant centers. Based on these studies, however, only including a small number of patients, recurrent disease was diagnosed in 25-67% of transplant recipients after a mean follow-up of 34 months following transplantation. Cytomegalovirus infection in the early postoperative phase and biologically related donors were found to be statistically significant risk factors for disease recurrence. More than one third of patients with recurrent disease either died or developed graft failure. SUMMARY: These data suggest that patients with PSC undergoing live donor liver transplantation, especially with biologically related donors, may have a higher risk to develop recurrent disease compared with the deceased donor setting. However, this fact has to be interpreted with great caution, primarily due to the rather small number of patients. Further studies analyzing pooled data of all transplant centers performing live donor liver transplantations are needed to confirm these findings. PMID- 21248638 TI - Ventilator-associated pneumonia management in critical illness. AB - PURPOSE OF REVIEW: Ventilator-associated pneumonia (VAP) is a frequent adverse event in the intensive care unit.We review recent publications about the management and prevention of VAP. RECENT FINDINGS: The latest care bundles introduced standard interventions to facilitate implementation of evidence-based clinical guidelines and to improve the outcome of patients. Recent studies find that prevention management of ventilated patients decreases the risk of VAP. Enteral feeding, considered a risk factor for VAP, currently has been recommended, with appropriate administration, for all critical ill patients if no contraindications exist. SUMMARY: In view of the recently available data, it can be concluded that the implementation of care bundles on the general management of ventilated patients in daily practice has reduced the VAP rates. The main pharmacological measures to prevent VAP are proper hands hygiene, high nurse-to patient ratio, avoid unnecessary transfer of ventilated patients, use of noninvasive mechanical ventilation, shortening weaning period, avoid the use of nasal intubation, prevent bio-film deposition in endotracheal tube, aspiration of subglottic secretions, maintenance of adequate pressure of endotracheal cuffs, avoid manipulation of ventilator circuits, semi-recumbent position and adequate enteral feeding.In addition, updated guidelines incorporate more comprehensive diagnostic protocols to the evidence-based management of VAP. PMID- 21248639 TI - Current status of behavioral medicine research and practice in developing countries. PMID- 21248640 TI - Role of expectations in health. AB - PURPOSE OF REVIEW: Considerable progress has been made in the neurobiological understanding of expectations in physiological and pathological processes. This article is aimed at presenting an overview of the role of expectations in producing health-related effects. We selected recent laboratory and clinical studies in the field of the placebo effect, with a particular focus on psychiatric disorders. RECENT FINDINGS: Recent scientific research indicates that expectations have the potential for relieving many symptoms. This research relies mostly on the study of placebo and nocebo phenomena which influence physiological and pathological functions. The findings from placebo and nocebo research have important implications for the design and interpretation of clinical trials and for clinical practice. SUMMARY: The studies of expectations in the field of psychiatry and in other fields of medicine suggest that placebo effects are likely to be an important aspect of any treatment. The application of research on health-related expectations has the potential for promoting wellness, improving health, and benefiting patient care. PMID- 21248641 TI - Brain-derived neurotrophic factor: findings in schizophrenia. AB - PURPOSE OF REVIEW: To review the role of brain-derived neurotrophic factor (BDNF) in neuroplasticity related to schizophrenia and the recent findings that have been reported on the status of BDNF in patients with schizophrenia and its association with the clinical measures. RECENT FINDINGS: Peripheral BDNF levels have been found altered in first-episode patients with psychosis and also in chronic schizophrenia patients. A few studies have reported changes in peripheral BDNF levels following antipsychotic treatment. The role of Val66Met polymorphism in BDNF has been shown to play an important role in structural and functional plasticity in schizophrenia. SUMMARY: Although peripheral BDNF levels hold promise for providing new perspectives for the development of novel therapeutic strategies for the treatment of schizophrenia, additional studies including efforts to prove its potential as a biomarker are warranted. PMID- 21248642 TI - Potential benefits from deeply inserted cochlear implant electrodes. AB - OBJECTIVES: This review examines evidence for potential benefits of using cochlear implant electrodes that extend into the apical regions of the cochlea. Most cochlear implant systems use electrode arrays that extend 1 to 1.5 turns from the basal cochleostomy, but one manufacturer (MED-EL GmbH) uses an electrode array that is considerably longer. The fundamental rationale for using electrodes extending toward the apex of the cochlea is to provide additional low-pitched auditory percepts and thereby increase the spectral information available to the user. Several experimental long arrays have also been produced by other manufacturers to assess potential benefits of this approach. DESIGN: In addition to assessing the effects of deeply inserted electrodes on performance, this review examines several underlying and associated issues, including cochlear anatomy, electrode design, surgical considerations (including insertion trauma), and pitch scaling trials. Where possible, the aim is to draw conclusions regarding the potential from apical electrodes in general, rather than relating to the performance of specific and current devices. RESULTS: Imaging studies indicate that currently available electrode arrays rarely extend more than two turns into the cochlea, the mean insertion angle for full insertions of the MED EL electrodes being about 630 degrees . This is considerably shorter than the total length of the cochlea and more closely approximates the length of the spiral ganglion. Anatomical considerations, and some modelling studies, suggest that fabrication of even longer electrodes is unlikely to provide additional spectral information. The issue of potential benefit from the most apical electrodes, therefore, is whether they are able to selectively stimulate discrete and tonotopically ordered neural populations near the apex of the spiral ganglion, where the ganglion cells are closely grouped. Pitch scaling studies, using the MED-EL and experimental long arrays, suggest that this is achieved in many cases, but that a significant number of individuals show evidence of pitch confusions or reversals among the most apical electrodes, presumably reducing potential performance benefit and presenting challenges for processor programming. CONCLUSIONS: Benefits in terms of speech recognition and other performance measures are less clear. Several studies have indicated that deactivation of apical electrodes results in poorer speech recognition performance, but these have been mostly acute studies where the subjects have been accustomed to the full complement of electrodes, thus making interpretation difficult. Some chronic studies have suggested that apical electrodes do provide additional performance benefit, but others have shown performance improvement after deactivating some of the apical electrodes. Whether or not deeply inserted electrodes can offer performance benefits, there is evidence that currently available designs tend to produce more intracochlear trauma than shorter arrays, in terms of loss of residual acoustic hearing and reduction of the neural substrate. This may have important long-term consequences for the user. Furthermore, as it is possible that subjects with better low-frequency residual hearing are more likely to benefit from the inclusion of apical electrodes, there may be a potential clinical dilemma as the same subjects are those most likely to benefit from bimodal electroacoustic stimulation, requiring a relatively shallow insertion. PMID- 21248644 TI - Nurses' perceptions of how rapid response teams affect the nurse, team, and system. AB - Rapid response teams (RRTs) continue to be implemented in hospitals to prevent unnecessary cardiac arrests and reduce patient mortality. Although studies suggest that RRTs improve patient care, research is lacking on the perspectives of nurses who use them. This focus group study elicited nurses' experiences with RRTs in a community hospital. Study findings provide insights into why nurses believe RRTs achieve their intended purpose. PMID- 21248643 TI - Perception of environmental sounds by experienced cochlear implant patients. AB - OBJECTIVES: Environmental sound perception serves an important ecological function by providing listeners with information about objects and events in their immediate environment. Environmental sounds such as car horns, baby cries, or chirping birds can alert listeners to imminent dangers as well as contribute to one's sense of awareness and well being. Perception of environmental sounds as acoustically and semantically complex stimuli may also involve some factors common to the processing of speech. However, very limited research has investigated the abilities of cochlear implant (CI) patients to identify common environmental sounds, despite patients' general enthusiasm about them. This project (1) investigated the ability of patients with modern-day CIs to perceive environmental sounds, (2) explored associations among speech, environmental sounds, and basic auditory abilities, and (3) examined acoustic factors that might be involved in environmental sound perception. DESIGN: Seventeen experienced postlingually deafened CI patients participated in the study. Environmental sound perception was assessed with a large-item test composed of 40 sound sources, each represented by four different tokens. The relationship between speech and environmental sound perception and the role of working memory and some basic auditory abilities were examined based on patient performance on a battery of speech tests (HINT, CNC, and individual consonant and vowel tests), tests of basic auditory abilities (audiometric thresholds, gap detection, temporal pattern, and temporal order for tones tests), and a backward digit recall test. RESULTS: The results indicated substantially reduced ability to identify common environmental sounds in CI patients (45.3%). Except for vowels, all speech test scores significantly correlated with the environmental sound test scores: r = 0.73 for HINT in quiet, r = 0.69 for HINT in noise, r = 0.70 for CNC, r = 0.64 for consonants, and r = 0.48 for vowels. HINT and CNC scores in quiet moderately correlated with the temporal order for tones. However, the correlation between speech and environmental sounds changed little after partialling out the variance due to other variables. CONCLUSIONS: Present findings indicate that environmental sound identification is difficult for CI patients. They further suggest that speech and environmental sounds may overlap considerably in their perceptual processing. Certain spectrotemproral processing abilities are separately associated with speech and environmental sound performance. However, they do not appear to mediate the relationship between speech and environmental sounds in CI patients. Environmental sound rehabilitation may be beneficial to some patients. Environmental sound testing may have potential diagnostic applications, especially with difficult-to-test populations and might also be predictive of speech performance for prelingually deafened patients with cochlear implants. PMID- 21248645 TI - Cross-sectional study of craniocerebral trauma in a tertiary hospital after 2008 Sichuan earthquake: a brief report of 242 cases and experiences from West China Hospital. AB - BACKGROUND: We aim to analyze clinical features of patients with craniocerebral trauma after 2008 Sichuan earthquake in China. METHODS: Medical records of patients with craniocerebral trauma admitted to Department of Neurosurgery in West China Hospital within 30 days after earthquake were retrospectively analyzed. Demographic data, clinical diagnosis, treatment, and prognosis were reviewed. Patients' data from peripheral hospitals were also analyzed. RESULTS: Two hundred forty-two patients with craniocerebral injuries were included in the study. The male to female ratio was 1.3:1, and more than half of the patients were between 20 and 60 years. Majority of patients suffered from mild to moderate injuries (88.4%). Scalp wound was the leading type, followed by skull fractures and brain contusion and laceration. Fifty patients (20.7%) underwent craniotomy. Overall mortality was 5.4% (n = 13). In survivors, 186 patients had good outcome (Glasgow Outcome Scale score >=4, 76.9%). Staphylococcus aureus (n = 74, 44.6%), Aerobacter cloacae (n = 37, 22.3%), and Staphylococcus epidermidis (n = 33, 19.9%) were most frequently isolated bacteria in wound smear. Over 85% (n=6) of patients with infectious wound (n=7) obtained delayed first stage healing. Mortality of patients in local hospitals ranged from 3.8% to 8.9%. CONCLUSIONS: Most patients admitted to tertiary hospitals are mildly or moderately injured. Cooperation among different departments is critical to shorten delay in emergency room. First stage wound healing or delayed first stage healing can be achieved in most patients after treatment. More than 76% of seismic injury patients in a tertiary medical center have good outcome. PMID- 21248646 TI - Ultra-small intravenous bolus of 7.5% NaCl/Mg2+ with adenosine and lidocaine improves early resuscitation outcome in the rat after severe hemorrhagic shock in vivo. AB - OBJECTIVE: Much controversy exists over the fluid composition for hypotensive resuscitation. We previously showed that addition of 6% Dextran-70 or hetastarch to 7.5% NaCl led to heart instability and mortality. Our aim was to examine the early resuscitative effects of 7.5% NaCl with adenosine, lidocaine, and magnesium (ALM) on hemodynamics and mortality in a rat model of severe hemorrhagic shock. METHODS: Male fed Sprague-Dawley rats (300-450 g, n = 48) were anesthetized and randomly assigned to one of six groups (n = 8): (1) Untreated, (2) 7.5% saline, (3) 7.5% NaCl/Mg2+, (4) 7.5% NaCl with adenosine/Mg2+, (5) 7.5% NaCl with lidocaine/Mg2+, and (6) 7.5% NaCl/ALM. Hemorrhagic shock was induced by phlebotomy until mean arterial pressure (MAP) was 35 mm Hg to 40 mm Hg and continued for 20 minutes (40% blood loss). Animals were left in shock for 60 minutes at 34 degrees C. 0.3 mL (~3.5% of shed blood) was injected as a 10-second bolus into the femoral vein. Lead II electrocardiography, arterial pressures, MAP, heart rate, and rate-pressure product were monitored. RESULTS: Untreated rats experienced severe arrhythmias and 38% mortality. There were no other deaths. 7.5% NaCl alone failed to maintain MAP after 5 minutes and was significantly improved with Mg2+. At 60 minutes, the MAP for 7.5% NaCl alone was 36 mm Hg compared with 48 mm Hg for the magnesium group. 7.5% NaCl/ALM led to a significantly higher MAP (57-60 mm Hg at 45-60 minutes). The higher MAP was associated with up to a 2-fold increase in arterial diastolic pressure. Both 7.5% NaCl with adenosine/Mg2+ and lidocaine/Mg2+ were mildly bradycardic but not when combined as ALM. A few arrhythmias occurred in 7.5% NaCl group with or without Mg, but no arrhythmias occurred in the other treatment groups. CONCLUSION: Ultra small intravenous bolus of 7.5% NaCl with ALM led to a significantly higher MAP, higher diastolic rescue, and higher rate-pressure product compared with other treatment groups. The possible clinical and military applications for permissive hypotensive resuscitation are discussed. PMID- 21248647 TI - Improved resuscitation from hemorrhagic shock with Ringer's lactate with increased viscosity in the hamster window chamber model. AB - BACKGROUND: Infusion of large volume of fluid is practiced in the treatment of hemorrhagic shock although resuscitation with small fluid volumes reduces the risks associated with fluid overload. We explored the hypothesis that reduced Ringer's lactate (RL) volume restoration in hemorrhage is significantly improved by increasing its viscosity, leading to improved microvascular conditions. METHODS: Awake hamsters were subjected to a hemorrhage of 50% of blood volume followed by a shock period of 1 hour. They were resuscitated with conventional RL (n = 6) or with RL whose viscosity was increased by the addition of 0.3% alginate (RL-HV) (n = 6). In both cases, the volume infused was 200% of shed blood. RESULTS: After resuscitation, blood and plasma viscosities were 1.9 cp +/- 0.18 cp and 1.0 cp +/- 0.03 cp in RL and 2.5 cp +/- 0.34 cp and 1.6 cp +/- 0.05 cp in RL-HV. Mean arterial pressure was lower than baseline in RL. Arteriolar diameter and arteriolar and venular flow were significantly higher in RL-HV. Functional capillary density was significantly higher in RL-HV than RL. After 90 minutes of resuscitation, functional capillary density was lower than baseline in RL, whereas it was maintained in RL-HV. Arteriolar PO2 was higher in RL-HV than RL. Microcirculation O2 delivery and tissue PO2 were significantly higher in RL-HV. CONCLUSIONS: Increasing blood and plasma viscosities in resuscitation from hemorrhagic shock with increased viscosity RL improves microvascular hemodynamics and oxygenation parameters. PMID- 21248648 TI - Validation of the "HAMP" mapping algorithm: a tool for long-term trauma research studies in the conversion of AIS 2005 to AIS 98. AB - BACKGROUND: There are significant changes in the abbreviated injury scale (AIS) 2005 system, which make it impractical to compare patients coded in AIS version 98 with patients coded in AIS version 2005. METHODS: Harborview Medical Center created a computer algorithm "Harborview AIS Mapping Program (HAMP)" to automatically convert AIS 2005 to AIS 98 injury codes. The mapping was validated using 6 months of double-coded patient injury records from a Level I Trauma Center. HAMP was used to determine how closely individual AIS and injury severity scores (ISS) were converted from AIS 2005 to AIS 98 versions. The kappa statistic was used to measure the agreement between manually determined codes and HAMP derived codes. RESULTS: Seven hundred forty-nine patient records were used for validation. For the conversion of AIS codes, the measure of agreement between HAMP and manually determined codes was [kappa] = 0.84 (95% confidence interval, 0.82-0.86). The algorithm errors were smaller in magnitude than the manually determined coding errors. For the conversion of ISS, the agreement between HAMP versus manually determined ISS was [kappa] = 0.81 (95% confidence interval, 0.78 0.84). CONCLUSION: The HAMP algorithm successfully converted injuries coded in AIS 2005 to AIS 98. This algorithm will be useful when comparing trauma patient clinical data across populations coded in different versions, especially for longitudinal studies. PMID- 21248649 TI - Radial head and neck fractures: functional results and predictors of outcome. AB - BACKGROUND: The purpose of this study was to determine the functional outcomes and predictive factors of radial head and neck fractures. METHODS: Over an 18 month period, we performed a prospective study of 237 consecutive patients with a radiographically confirmed proximal radial fracture (156 radial head and 81 radial neck). Follow-up was carried out over a 1-year period using clinical and radiologic assessment, including the Mayo Elbow Score (MES). Multivariate regression analysis was used to determine significant predictors of outcome according to the MES. RESULTS: Of the 237 patients enrolled in the study, 201 (84.8%) attended for review, with a mean age of 44 years (range, 16-83 years; standard deviation, 17.3). One hundred eighty-seven (93%) patients achieved excellent or good MESs. The mean MES for Mason type-I (n = 103) and type-II (n = 82) fractures was excellent, with only two patients undergoing surgical intervention. For Mason type-III (n = 11) and type-IV (n = 5) fractures, the flexion arc, forearm rotation arc, and MES in the nonoperatively treated patients were not significantly different (all p >= 0.05) from those managed operatively. Regression analysis revealed that increasing age, increasing fracture complexity according to the AO-OTA classification, increasing radiographic comminution, and operative treatment choice were independently significant predictors of a poorer outcome (all p < 0.05). CONCLUSIONS: A majority of radial head and neck fractures can be treated nonoperatively, achieving excellent or good results. Age, fracture classification, radiographic comminution, and treatment choice are important factors that determine recovery. PMID- 21248650 TI - The presence of nonthoracic distracting injuries does not affect the initial clinical examination of the cervical spine in evaluable blunt trauma patients: a prospective observational study. AB - BACKGROUND: A distracting injury mandates cervical spine (c-spine) imaging in the evaluable blunt trauma patient who demonstrates no pain or tenderness over the c spine. The purpose of this study was to examine which distracting injuries can negatively affect the sensitivity of the standard clinical examination of the c spine. METHODS: This is a prospective observational study conducted at a Level I Trauma Center from January 1, 2008, to December 31, 2009. After institutional review board approval, all evaluable (Glasgow Coma Scale score >=13) blunt trauma patients older than 16 years sustaining a c-spine injury were enrolled. A distracting injury was defined as any immediately evident bony or soft tissue injury or a complaint of non-c-spine pain whether or not an actual injury was subsequently diagnosed. Information regarding the initial clinical examination and the presence of a distracting injury was collected from the senior resident or attending trauma surgeon involved in the initial management. RESULTS: During the study period, 101 evaluable patients sustained a c-spine injury. Distracting injuries were present in 88 patients (87.1%). The most common was rib fracture (21.6%), followed by lower extremity fracture (20.5%) and upper extremity fracture (12.5%). Only four (4.0%) patients had no pain or tenderness on the initial examination of the c-spine. All four patients had bruising and tenderness to the upper anterior chest. None of these four patients developed neurologic sequelae or required a surgical stabilization or immobilization. CONCLUSION: C spine imaging may not be required in the evaluable blunt trauma patient despite distracting injuries in any body regions that do not involve the upper chest. Further definition of distracting injuries is mandated to avoid unnecessary utilization of resources and to reduce the imaging burden associated with the evaluation of the c-spine. PMID- 21248651 TI - Do locked compression intramedullary nails improve the biomechanical stability of distal femoral fractures? AB - BACKGROUND: A distal femur nail with fixed-angle locking screws intends to combine the advantages of angular stability and intramedullary stabilization in extraarticular distal femur fractures. The goal of this study was to analyze whether the locked compression distal femur nail (LCN) was biomechanically more stable than a conventional standard distal femur nail (CN). METHODS: Both nails were compared on a series of 10 matched pairs of human femora. After setting a distal femur defect fracture, the intramedullary stabilized femur was axially loaded starting from 100 N, increasing in steps of 100 N after every 200 cycles with a triangular frequency of 1 Hz, until a predefined point of failure was reached. RESULTS: The two types of nails showed no significant difference in terms of maximum tolerated load, maximum number of cycles repeated, or axial deformation of the bone-implant construct. The mean load at failure was 2,954 N for the CN and 2,483 N for the LCN. The mean axial deformation for the conventional (14.8 mm) and locked compression nail (15.3 mm) did not differ significantly. Mode of failure was a bony fracture in all specimens predominantly involving the proximal femur. CONCLUSIONS: No significant difference in stability between the two compared implants could be demonstrated. The LCN showed comparable characteristics under cyclic axial loading as the conventional distal femur nail. No migration into the articular space or implant failure was observed. PMID- 21248652 TI - Modified retrograde-locked nailing for aseptic femoral supracondylar nonunion with severe osteoporosis in elderly patients. AB - BACKGROUND: Femoral supracondylar nonunions in elderly patients are uncommon. To date, there is no convincing technique for managing this condition. When the nonunion is associated with severe osteoporosis, treatment becomes even more complicated. We developed a modified retrograde-locked nailing technique to treat this complex lesion. METHODS: Twenty-four aseptic femoral supracondylar nonunions with severe osteopenia in 24 elderly patients (aged >=65 years) were treated. A retrograde femoral-locked nail was inserted in the dynamic mode. Next, the medial 1/2 to 2/3 marrow cavity in the nonunion site was filled with bone cement, and the lateral 1/3 to 1/2 marrow cavity received a cancellous bone graft with or without a bone graft substitute. A cylindrical brace was applied for 3 weeks postoperation. Early ambulation with a walker or wheelchair was encouraged. RESULTS: Twenty patients were followed up for an average period of 2.5 years (range, 1.1-4.5 years), and 18 nonunions healed. The union rate was 90.0% with an average union period of 4.9 months (range, 4-7 months). No deep infection or malunion was found. The two patients with persistent nonunions were advised to use a walker whenever necessary. The satisfactory rate for knee function improved from 0% preoperatively to 80.0% at the latest follow-up. CONCLUSIONS: The described technique may concomitantly provide sufficient stability and initiate osteogenic potential, thus facilitating bone union. This technique is simple with a low complication rate and thus should be considered as a useful alternative for treating this complex lesion. PMID- 21248653 TI - Reducing pulmonary injury by hyperbaric oxygen preconditioning during simulated high altitude exposure in rats. AB - BACKGROUND: Hyperbaric oxygen preconditioning (HBO2P + HAE) has been found to be beneficial in preventing the occurrence of ischemic damage to brain, spinal cord, heart, and liver in several disease models. In addition, pulmonary inflammation and edema are associated with a marked reduction in the expression levels of both aquaporin (AQP) 1 and AQP5 in the lung. Here, the aims of this study are first to ascertain whether acute lung injury can be induced by simulated high altitude in rats and second to assess whether HBO2P + HAE is able to prevent the occurrence of the proposed high altitude-induced ALI. METHODS: Rats were randomly divided into the following three groups: the normobaric air (NBA; 21% O2 at 1 ATA) group, the HBO2P + high altitude exposure (HAE) group, and the NBA + HAE group. In HBO2P + HAE group, animals received 100% O2 at 2.0 ATA for 1 hour per day, for five consecutive days. In HAE groups, animals were exposed to a simulated HAE of 6,000 m in a hypobaric chamber for 24 hours. Right after being taken out to the ambient, animals were anesthetized generally and killed and thoroughly exsanguinated before their lungs were excised en bloc. The lungs were used for both histologic and molecular evaluation and analysis. RESULTS: In NBA + HAE group, the animals displayed higher scores of alveolar edema, neutrophil infiltration, and hemorrhage compared with those of NBA controls. In contrast, the levels of both AQP1 and AQP5 proteins and mRNA expression in the lung in the NBA + HAE group were significantly lower than those of NBA controls. However, the increased lung injury scores and the decreased levels of both AQP1 and AQP5 proteins and mRNA expression in the lung caused by HAE was significantly reduced by HBO2P + HAE. CONCLUSIONS: Our results suggest that high altitude pulmonary injury may be prevented by HBO2P + HAE in rats. PMID- 21248654 TI - Immediate splenectomy decreases mortality and improves cognitive function of rats after severe traumatic brain injury. AB - BACKGROUND: Traumatic brain injury (TBI) is a major health problem all over the world. It frequently causes a considerable social burden because of its high incidence of death and long-term disability, especially in the case of severe TBI. Recent studies revealed that the spleen might contribute to secondary brain injury after ischemia or intracerebral hemorrhage. The purpose of this study was to evaluate the significance of the spleen in traumatic brain edema after severe TBI. METHODS: We established a severe TBI model with rats and performed splenectomy to observe the mortality, brain water content, cognitive function (water maze), and cytokines levels, including interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha), IL-6, and IL-10, in the blood plasma (enzyme linked immunosorbent assay) and their mRNA expression levels in injured brain tissue (quantitative reverse transcriptase-polymerase chain reaction). RESULTS: The immediate splenectomy after TBI significantly decreased the death rate from 35.42% to 14.89% and eliminated the brain water content of the injured brain, especially at days 2 and 3. The Morris water maze assessment showed an improved spatial reference memory in rats that underwent both TBI and splenectomy when compared with those in the TBI group, 4 weeks later. Splenectomy reduced the IL 1beta, TNF-alpha, and IL-6 contents in the blood serum after TBI, and the mRNA expression levels of IL-1beta, TNF-alpha, and IL-6 in the ipsilateral brain tissue also decreased. CONCLUSIONS: Our study demonstrates that splenectomy has a protective effect on rats with severe TBI by inhibiting proinflammatory cytokines, including IL-1beta, TNF-alpha, and IL-6, both systematically and locally in the injured brain, hence leading to a decreased mortality and improved cognitive function. PMID- 21248655 TI - Outcome of urinary tract infections caused by extended spectrum beta-lactamase producing Enterobacteriaceae in children. AB - The outcome of patients with urinary tract infections caused by extended spectrum beta-lactamases (ESBL)-producing bacteria (cases) was compared with that of matched controls with urinary tract infections caused by non-extended spectrum beta-lactamases-producing isolates. Significantly, more case patients received inappropriate empiric therapy than controls. Nevertheless, clinical and microbiologic outcomes as well as formation of renal scars did not differ between the 2 groups. PMID- 21248656 TI - Frequency of human rhinovirus species in outpatient children with acute respiratory infections at primary care level in Brazil. AB - This study assessed the occurrence of human rhinovirus (HRV) species in outpatient children attending day-care in Sao Paulo, Brazil. HRV reverse transcriptase polymerase chain reaction and amplicon sequencing were done in 120 samples collected in 2008. HRV was detected in 27.5% of samples. HRV C was detected in 60.7% of wheezers, a frequency not different from that observed in nonwheezers (69.6%). PMID- 21248657 TI - Seasonal influenza vaccination status among children with laboratory evidence of pandemic H1N1 infection. AB - BACKGROUND: The 2009 pandemic H1N1 influenza virus emerged in March 2009 and spread rapidly, causing many thousands of deaths worldwide. A case-control study of 60 Mexican adults with H1N1 suggested that the seasonal influenza vaccine protected against H1N1 infection (odds ratio [OR], 0.27; 95% confidence interval [CI], 0.11-0.66), but subsequent studies have had varied results and few have addressed this question in children. The objective of this study was to evaluate the effect of 2008-2009 seasonal influenza vaccination on pandemic H1N1 infection in children. METHODS: Cases (n = 165) were Kaiser Permanente Colorado inpatients and outpatients aged between 18 months and 18 years, with laboratory-confirmed pandemic H1N1 infection from May to November 2009. Controls (n = 660) were pediatric Kaiser Permanente members without documented H1N1 infection who were matched by age and gender. Seasonal influenza vaccination status was recorded for all cases and controls; conditional logistic regression analyses were used to calculate matched odds ratios. RESULTS: Cases were more likely than controls to have underlying chronic health conditions (45% vs. 21%, P < 0.0001). Pandemic H1N1 cases were neither more nor less likely to have received the 2008-2009 seasonal influenza vaccine (OR, 1.31; 95% CI, 0.92-1.88). After adjustment for chronic medical conditions and health-seeking behavior, H1N1 cases were as likely as controls to have received the 2008-2009 seasonal influenza vaccine (OR, 1.08; 95% CI, 0.75-1.57). CONCLUSIONS: There was no overall association--either protection or risk--between seasonal influenza vaccination and medically attended pandemic H1N1 infection in children. These results have important implications for understanding influenza immunity and future public health efforts to prevent pandemic influenza. PMID- 21248658 TI - Antibody response to influenza vaccine in pediatric liver transplant recipients. AB - BACKGROUND: Data on the immunogenicity of the influenza vaccine in children after liver transplantation are sparse. Our study aims to evaluate the response of such patients to the trivalent influenza vaccine, administered by different protocols in 2 influenza seasons. METHODS: Children attending the Liver Transplantation Unit of a tertiary care medical center were prospectively recruited and immunized with the inactivated subvirion influenza vaccine during the influenza seasons of 2004/2005 (1 dose, n = 18) and 2005/2006 (2 doses 4-6 weeks apart, n = 32). Antibodies were measured by hemagglutination inhibition assay. Immunity was defined as a titer of >=1:40, and response was defined as a >=4-fold increase in antibody titer from baseline. RESULTS: In 2004/2005, the proportions of patients with protective antibodies were similar before and after 1 dose of vaccine. We found significant difference after the first dose for the A/H3N2 Wisconsin strain (43.2% vs. 70.3%, P = 0.003) and B/Malaysia strains (8.1% vs. 35.1%, P = 0.003) and for A/H1N1 New Caledonia strain (48.6% vs. 64.9% vs. 75%, P = 0.08, 0.005, respectively) after the second dose in 2005/2006 season. In 2004/2005, geometric mean titers rose significantly (P = 0.03) for the A/H3N2 New York strain; in 2005/2006, geometric mean titers for A/H3N2 New York and B/Malaysia increased after the first dose and for A/H1N1 New Caledonia after the second dose. Antibody titers were unrelated to age at transplantation, time from transplantation, and number of immunosuppressive drugs used. No serious vaccine-related events were documented. CONCLUSIONS: Liver-transplanted children respond to influenza vaccination. For some strains, the response is similar to that reported for healthy children. A second vaccine dose yielded no statistically significant benefit. PMID- 21248659 TI - World Kidney Day 2011: protect your kidneys, save your heart. PMID- 21248660 TI - Quantification of the islet product: presentation of a standardized current good manufacturing practices compliant system with minimal variability. AB - BACKGROUND: Accurate islet quantification has proven difficult to standardize in a good manufacturing practices (GMP) approved manner. METHODS: The influence of assessment variables from both manual and computer-assisted digital image analysis (DIA) methods were compared using calibrated, standardized microspheres or islets alone. Additionally, a mixture of microspheres and exocrine tissue was used to evaluate the variability of both the current, internationally recognized, manual method and a novel GMP-friendly purity- and volume-based method (PV) evaluated by DIA in a semiclosed, culture bag system. RESULTS: Computer-assisted DIA recorded known microsphere size distribution and quantities accurately. By using DIA to evaluate islets, the interindividual manually evaluated percent coefficients of variation (CV%; n=14) were reduced by almost half for both islet equivalents (IEs; 31% vs. 17%, P=0.002) and purity (20% vs. 13%, P=0.033). The microsphere pool mixed with exocrine tissue did not differ from expected IE with either method. However, manual IE resulted in a total CV% of 44.3% and a range spanning 258 k IE, whereas PV resulted in CV% of 10.7% and range of 60 k IE. Purity CV% for each method were similar approximating 10.5% and differed from expected by +7% for the manual method and +3% for PV. CONCLUSION: The variability of standard counting methods for islet samples and clinical quantities of microspheres mixed with exocrine tissue were reduced with DIA. They were reduced even further by use of a semiclosed bag system compared with standard manual counting, thereby facilitating the standardization of islet evaluation according to GMP standards. PMID- 21248661 TI - NAFLD recurrence in liver transplant recipients. AB - BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is a common indication for liver transplantation and can recur in the graft. To describe this recurrence, we performed a cohort study of individuals undergoing liver transplantation for NAFLD-related cirrhosis between 1993 and 2007. Predictors of NAFLD recurrence and outcomes in this cohort were also studied. METHODS: Eighty eight liver transplant recipients were included in this study. NAFLD recurrence was described by performing a blinded reevaluation of posttransplant liver biopsies and classified according to histologic activity (NAFLD activity score) and fibrosis. RESULTS: Recurrent NAFLD was seen in 34 (39%) recipients with isolated steatosis in 9 and steatohepatitis in 25 recipients. Severe recurrence was seen in 3 of 34 recipients (NAFLD activity score >= 5) and advanced fibrosis in 3 recipients. NAFLD recurrence correlated with higher pretransplant (P=0.001) and posttransplant body mass index (P<0.0001) and increased triglyceride levels posttransplantation. Serum triglyceride levels at 6 and 12 months were 280 +/- 129 and 324 +/- 265 mg/dL, respectively, in those with NAFLD recurrence versus 206 +/- 96 mg/dL at 6 months and 190 +/- 103 mg/dL in those without NAFLD recurrence (P=0.007 at 6 months and P=0.005 at 12 months). Average steroid dose at 6 months posttransplant was also higher in those with NALFD recurrence than those without (11 +/- 8.5 and 7.2 +/- 5.7 mg/day, P=0.04). Posttransplant survival did not differ between those with and without NAFLD recurrence during the entire follow-up period (P=0.78). Posttransplant cardiovascular disease was significantly and adversely correlated with posttransplant survival. CONCLUSIONS: NAFLD recurrence is common in the first 5 years postliver transplantation and is associated with features of the metabolic syndrome. Although NAFLD recurrence was not associated with higher mortality in our cohort, cardiovascular mortality and morbidity were common, suggesting that the metabolic syndrome is an important link to NAFLD recurrence and cardiovascular deaths posttransplantation. PMID- 21248662 TI - New organ transplant policies in Japan, including the family-oriented priority donation clause. AB - The revised Organ Transplant Law in Japan that took effect in July 2010 allows organ procurement from brain-dead individuals, including children, only with family consent. The amended law also allows individuals to prioritize family members to receive their donated organs after death. This policy differs from the prioritization policy in Israel, which provides incentives to individuals who agree to help each other in society and rectifies the problem of free riders, individuals who are willing to accept an organ but refuse to donate. Despite these differences, however, the Japanese and Israeli policies have revealed new ethical dilemmas, including the fear of compromising fairness in organ allocation. PMID- 21248663 TI - The discovery of small-molecule mimicking peptides through phage display. AB - Using peptides to achieve the functional and structural mimicry of small molecules, especially those with biological activity or clear biotechnological applications, has great potential in overcoming difficulties associated with synthesis, or unfavorable physical properties. Combinatorial techniques like phage display can aid in the discovery of these peptides even if their mechanism of mimicry is not rationally obvious.The major focus of this field has been limited to developing biotin and sugar mimetics. However, the full "mimicry" of these peptides has not yet been fully established as some bind to the target with a different mechanism than that of the natural ligand and some do not share all of the natural ligand's binding partners. In this article, mimicry of small molecules by phage display-discovered peptides is reviewed and their potential in biochemical and medical applications is analyzed. PMID- 21248664 TI - Phage display: selecting straws instead of a needle from a haystack. AB - An increasing number of peptides with specific binding affinity to various protein and even non-protein targets are being discovered from phage display libraries. The power of this method lies in its ability to efficiently and rapidly identify ligands with a desired target property from a large population of phage clones displaying diverse surface peptides. However, the search for the needle in the haystack does not always end successfully. False positive results may appear. Thus instead of specific binders phage with no actual affinity toward the target are recovered due to their propagation advantages or binding to other components of the screening system, such as the solid phase, capturing reagents, contaminants in the target sample or blocking agents, rather than the target. Biopanning experiments on different targets performed in our laboratory revealed some previously identified and many new target-unrelated peptide sequences, which have already been frequently described and published, but not yet recognized as target-unrelated. Distinguishing true binders from false positives is an important step toward phage display selections of greater integrity. This article thoroughly reviews and discusses already identified and new target-unrelated peptides and suggests strategies to avoid their isolation. PMID- 21248665 TI - Specific radioactivity of neutron induced radioisotopes: assessment methods and application for medically useful 177Lu production as a case. AB - The conventional reaction yield evaluation for radioisotope production is not sufficient to set up the optimal conditions for producing radionuclide products of the desired radiochemical quality. Alternatively, the specific radioactivity (SA) assessment, dealing with the relationship between the affecting factors and the inherent properties of the target and impurities, offers a way to optimally perform the irradiation for production of the best quality radioisotopes for various applications, especially for targeting radiopharmaceutical preparation. Neutron-capture characteristics, target impurity, side nuclear reactions, target burn-up and post-irradiation processing/cooling time are the main parameters affecting the SA of the radioisotope product. These parameters have been incorporated into the format of mathematical equations for the reaction yield and SA assessment. As a method demonstration, the SA assessment of 177Lu produced based on two different reactions, 176Lu (n,gamma)177Lu and 176Yb (n,gamma) 177Yb (beta- decay) 177Lu, were performed. The irradiation time required for achieving a maximum yield and maximum SA value was evaluated for production based on the 176Lu (n,gamma)177Lu reaction. The effect of several factors (such as elemental Lu and isotopic impurities) on the 177Lu SA degradation was evaluated for production based on the 176Yb (n,gamma) 177Yb (beta- decay) 177Lu reaction. The method of SA assessment of a mixture of several radioactive sources was developed for the radioisotope produced in a reactor from different targets. PMID- 21248666 TI - Enhancement of diepoxin zeta production by yeast extract and its fractions in liquid culture of Berkleasmium-like endophytic fungus Dzf12 from Dioscorea zingiberensis. AB - This study was to examine the effects of yeast extract (YE) and its fractions (YE1 and YE2) on the growth and diepoxin zeta (a spirobisnaphthalene with a diversity of bioactivities) production in liquid culture of Berkleasmium-like endophytic fungus Dzf12 from Dioscorea zingiberensis. When YE was applied to the liquid medium at 10 g/L on day 3 of culture, the diepoxin zeta production was most effectively enhanced 3.2-fold (378.70 mg/L versus 120.09 mg/L in control) after another 10 days culture. Feeding with 15 g/L of YE on day 9, the mycelia biomass reached 16.44 g/L, about 2.3-fold in comparison with the control (7.15 g/L). The polysaccharide fraction (YE1) was mainly responsible for stimulating diepoxin zeta accumulation, and the non-polysaccharide fraction (YE2) was mainly responsible for promoting mycelia growth. The results showed that the diepoxin zeta production in liquid culture of endophyte Dzf12 could be effectively enhanced by YE and its fractions. PMID- 21248667 TI - Porto-spleno-mesenteric venous thrombosis. AB - Porto-spleno-mesenteric (PSM) venous thrombosis is a rare clinical condition that, while being mostly unrecognized, is nonetheless often severe with a high morbidity and mortality. PSM venous thrombosis is the cause of as many as 5-10% of all abdominal ischemic events, and it presents with a highly variable and non specific pattern of abdominal symptoms. Such complex and non-specific presentation can delay diagnosis, determining the poor clinical outcome of this condition. This review article discusses the information available on the pathogenesis, clinical presentation, diagnosis and general management of PSM venous thrombosis, with a focus on a number of some clinical issues that remain unaddressed. In particular, the current understanding of the predisposing factors and the heterogeneous clinical manifestations of this condition are described in detail. The recent advances in imaging techniques, which are leading to an improved diagnostic accuracy and facilitate an early diagnosis are also presented. Further, the indications and limits of both pharmacological and surgical treatment options are discussed. PMID- 21248668 TI - Effect of immersion in CO2-enriched water on free radical release and total antioxidant status in peripheral arterial occlusive disease. AB - AIM: The aim of this paper was to investigate the release of oxygen free radicals in patients with peripheral occlusive arterial disease and the effects of immersion of the legs and feet in carbon dioxide (CO(2))-enriched water. METHODS: Twenty-five patients with peripheral occlusive arterial disease (Fontaine stage II) and 15 healthy controls were treated by immersing the lower legs in either CO(2)-enriched or normal spa water. Blood samples were collected in heparinized tubes and total antioxidant status (TAS) and reactive oxygen metabolites (ROMs) were measured after five treatments a week for two weeks. RESULTS: d-ROM plasma levels decreased in patients with peripheral occlusive disease after immersion in CO(2)-enriched water (P<0.001), and in healthy controls (P<0.01), in line with a significant increase in TAS (P<0.001). CONCLUSION: CO(2)-enriched water immersion had a positive effect, reducing free radical plasma levels and raising the levels of antioxidants, suggesting an improvement in the microcirculation. PMID- 21248669 TI - Cardiovascular risk and lupus disease. AB - AIM: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). The aim of this study was to evaluate subclinical atherosclerosis and to determine the prevalence of risk factors for CVD in SLE patients. METHODS: One hundred fifty-three patients (149 women and 4 men), aged (37+/-11.6) years with a definite diagnosis of SLE according to the revised criteria of the American College of Rheumatology (ACR), underwent physical examination, carotid and leg arteries B-mode ultrasound with a measure of ankle-brachial pressure index (ABPI); 94 patients had myocardial tomoscintigraphy. The laboratory check-up was: total cholesterol (TC), HDLc, LDLc, homocystein, glycemia, vascular cell adhesion molecules (VCAM-I). All patients had a normal renal function at the time of the study. RESULTS: The mean age is 37 years. Cardiovascular events were noticed in 15 patients (6 angina, 2 myocardial infarction and 7 strokes). Cardiovascular risk factors (CVRF) were: dyslipidemia (62.8%), moderate homocysteinemia (55%), BMI>25 (39%) and hypertension (35%) which is associated with a stroke (P<0.0006). The cumulative prednisone dose per patient was 45.5g. V.C.A.M-I level was high in 86.2 % of cases.95% of our patients had at least two CVRF. Myocardial perfusion stress scanning showed abnormalities in 21 patients (22.3%). Perfusion defects were linked with a stroke (P<0.01) and coronary events (P<0.02). Carotid atheroma was present in 32 patients (20.9%). Carotid plaques were associated with age (P<0.01), total cholesterol (TC)(P<0.05), and steroid dose (P<0.01). Intima-media thickness was correlated with age (P<0.0003), TC (P<0.0007), LDLc (P<0.002), and homocysteine (P<0.03). 70% patients had a mediacalcinosis in femoral and popliteal arteries. The ABPI was correlated with V.C.A.M-I (P<0.0005). CONCLUSION: In Algeria, as elsewhere, young women with SLE have subclinical atherosclerosis which must be detected and they are at high risk of a vascular event. PMID- 21248670 TI - Endogenous vascular endothelial growth factor and angiopoietin-2 expression in critical limb ischemia. AB - AIM: The aim of this paper was to contribute to a better understanding of the angiogenesis in peripheral arterial disease (PAD); we evaluated the expression of vascular endothelial growth factor (vegf) and angiopoietin-2 (Ang-2) in critical limb ischemia (CLI). METHODS: Skin and muscle biopsies were collected from 12 patients submitted to major amputation for CLI, proximal samples from amputation level and distal ones from the more ischemic region. Three controls were obtained from orthopedic patients. Capillary density was determined in random selected high-power fields. Expression pattern of VEGF and Ang-2 was studied by immunohistochemistry and quantification was performed by enzyme-linked immunosorbent assay. RESULTS: In skin, capillary density and levels of VEGF and Ang-2 were higher in distal samples when compared to proximal (capillary density, P=0.003, VEGF, P=0.008, Ang-2, P=0.041). Distal muscle had also elevated capillary number (P=0.005) and Ang-2 concentration (P=0.023). VEGF concentration in distal muscle was found to be similar to proximal muscle (P=1). Immunohistochemical expression of VEGF was clearly more evident in distal samples and was predominantly present in epidermis and skeletal myocytes. Ang-2 was essentially detected distally and only observed in endothelial cells. CONCLUSION: The capillary density is enhanced in distal samples, suggesting an effective angiogenic drive in CLI. In addition, the observed increase of VEGF expression in ischemic skin and Ang-2 in ischemic skin and muscle may contribute to clarify the potential role of VEGF and Ang-2 supplementation for therapeutic angiogenesis in CLI. PMID- 21248671 TI - Semapimod a new pretreatment modality of acute intestinal ischemia-reperfusion syndrome: experimental study in rabbits. AB - AIM: Semapimod is an experimental drug that strongly inhibits macrophages and stimulates the cholinergic anti-inflammatory pathway. The aim of this study was to evaluate the effect of semapimod on experimentally-induced acute intestinal ischemia-reperfusion syndrome in rabbits. METHODS: The experimental protocol included 16 adult male White New Zealand rabbits divided into two equal groups, A and B. Animals were subjected to 150 min of intestinal ischemia, followed by 30 min of reperfusion. At 30, 90 and 150 min after the onset of ischemia the animals in group A received i.v. placebo (2 mg/kg; Cytokine PharmaSciences Inc, PA, USA) and those of group B received i.v. semapimod (2 mg/kg; Cytokine PharmaSciences Inc, PA, USA). Blood samples were taken for plasma measurements of tumor necrosis factor-a (TNF-a), interleukin 1beta (IL-1beta) and interleukin 6 (IL-6) at 0, 60, 120 and 180 min after the onset of ischemia. At the same time points, wedge intestinal biopsies were taken for histopathological evaluation of mucosal injury. All data were analyzed by the non-parametric Mann-Whitney test as appropriate. The power effect of Semapimod was evaluated by mixed between-within Anova statistical analysis. RESULTS: Measurements of TNF-a and IL-1beta levels showed significant differences between groups A and B at 120 min (P=0.004 and P=0.003 respectively) and at 180 min (P=0.001 and p<0.005 respectively). IL-6 values were lower in animals of group B but the differences were not significant. Intestinal mucosal injuries were significantly milder in animals of group B at 120 and 180 min CONCLUSION: Semapimod minimized intestinal mucosa injury and reduced the systemic inflammatory response during acute intestinal ischemia reperfusion. Further studies are required to investigate the possible value of semapimod as a new pretreatment modality in acute vascular abdomen. PMID- 21248672 TI - ICU transfer after elective abdominal aortic aneurysm repair can be succesfully reduced with a modified protocol. A fourteen year experience from a University Hospital. AB - AIM: To compare different selective criteria for Internal Care Unit (ICU) admission in two different timeframes, after abdominal aortic aneurysm (AAA) repair. A retrospective audit of acquired data was performed. METHODS: During a period of fourteen years (1994-2008), 1152 patients underwent an elective open operation for infrarenal abdominal aortic aneurysm, in our department. Six hundred and two patients (Group A) were treated in the period January 1994 January 2003, and 550 patients (Group B) between January 2003 and August 2008. Postoperatively, all patients were transferred to postanesthesia unit (PAU). After a 2 hours period of close observation, they were transferred either to the ICU or to the surgical ward, according to certain selective criteria (SC). In group A we used SC-A, for admission to an ICU, and in group B we used new, stricter, criteria (SC-B). Thirty-day mortality and morbidity, elective admissions to ICU, rate of subsequent ICU admission, from ward to ICU, and the mean hospital and ICU length of stay, were compared between the two groups. RESULTS: The use of SC-B resulted in a significant reduction of elective admissions to ICU (3.1% vs 8.5%, P<0.001). Nevertheless, the portion of patients, which were transferred with a severe postoperative complication from the ward to ICU, remained similar between the two groups (1.1% vs 0,9%, in group A and B, respectively). All other endpoints were similar in both groups. CONCLUSION: Modifying the protocol of ICU transfer, after elective abdominal aortic aneurysm repair, we can reduce the number of patients requiring ICU, without compromising patients' safety. PMID- 21248673 TI - Screening for asymptomatic cardiovascular disease in Arab patients with diabetes. AB - AIM: Diabetes mellitus is a major risk factor for atherosclerosis and accordingly increased morbidity and mortality. This study aimed at screening high risk diabetic patients for atherosclerosis in different arterial territories. METHODS: All high risk asymptomatic patients attending the diabetic clinic, King Fahd Hospital of the University, Saudi Arabia were invited to be screened for peripheral arterial disease (PAD), extra-cranial cerebrovascular disease (CVD) and coronary artery disease (CAD) over one year. All participants underwent measurement of ankle brachial pressure index, carotid Duplex scan and exercise electrocardiography (ECG). All patients underwent evaluation of conventional risk factors for atherosclerosis RESULTS: One hundred and sixty nine patients were invited to be screened. Of these 138 (82%) completed all the screening tests. The mean age was 53.5+/-7.18 years. Seventy-five (55%) had evidence of subclinical atherosclerosis. In the atherosclerotic group, 24 patients had PAD, 47 had CVD and 30 had CAD. There were significant differences between the atherosclerotic and non-atherosclerotic groups with regard to most risk factors. In age, sex adjusted, the risk of developing atherosclerosis was significantly increased with all risk factors. Dyslipidemia had the highest association (OR 9.7, 95% CI 8.1 10.2) CONCLUSION: Participation and diagnostic yield of screening for atherosclerosis had satisfactory validity and reliability. Routine screening in high-risk diabetic patients can serve as an effective tool for diagnosis of sub clinical cardiovascular disease and provide strategies to optimize risk reduction. PMID- 21248674 TI - How to diagnose giant cell arteritis. AB - AIM: Current debate on how to diagnose giant cell arteritis (GCA) has strayed from the traditional approach of temporal artery biopsy and has instead explored the effectiveness of alternative imaging modalities. METHODS: We have reviewed the literature and pooled published results for temporal artery imaging including magnetic resonance imaging (MRI), Duplex ultrasound, positron emission tomography computed tomography (PET-CT) scan. RESULTS: The results of this review show that ultrasound and MRI both represent viable options for evaluation of GCA; however utilizing ultrasound first may be the best first option in diagnostic tools. In 1990 the American College of Rheumatology offered criteria for positive pathology in GCA. CONCLUSION: In this study, we propose a risk stratification criteria as well as an algorithm for the best diagnostic approach when GCA is suspected. PMID- 21248675 TI - Clinical signs in the diagnosis of deep vein thrombosis. AB - AIM: Deep vein thrombosis (DVT) is an insidious disease wherein more than 15 different clinical signs are described. The aim of this work was to focus on these clinical signs and to test them for their importance in making a diagnosis of DVT. METHODS: All patients treated with a tentative diagnosis of DVT in the emergency department were asked to take part in the study. Out of the 254 patients who were examined in order to exclude DVT, 204 patients agreed to participate in the study. The patients who agreed to take part were tested for fifteen clinical examination signs. The Wells score was then determined. RESULTS: Sixty-two were diagnosed with DVT. For 142 patients, DVT could be ruled out. The probability of DVT for 9 signs together is 88%, and for 3 signs is 78%. The negative predictive values are 91-95%. The combination of the clinical signs showed a specificity of 100%, independent if the patients were old, comorbid, and were diagnosed with the thrombosis in the lower limbs. The determination of the Wells score resulted in no convincing evidence for or against the diagnosis of DVT. CONCLUSION: We suggest a modified Wells score integrating missing clinical signs with more reliable predictive values. Even with the availability of ultrasound, clinical signs have not become superfluous. They are quick to carry out, safe, cheap and an important addition to the Wells score, particularly for multimorbid and elderly patients. PMID- 21248676 TI - The clinical importance in differentiating portal from mesenteric venous thrombosis. AB - AIM: To relate the extent of portomesenteric thrombosis to the risk of intestinal infarction, concomitant venous thromboembolism and underlying diseases. METHODS: Identification of patients with mesenteric (MVT) and portal vein thrombosis (PVT) at Malmo University Hospital from a clinical series from 2000 - 2006 as well as an autopsy cohort of 24000 consecutive autopsies from 1970 - 1982. RESULTS: In the clinical comparative study, MVT (n=51) was associated with more thrombophilic disorders (P=0.040) and intestinal infarctions (P=0.046), whereas patients with PVT without extension to the superior mesenteric vein (n=20) more often had liver disease (P<0.001). At autopsy, 270 patients with portomesenteric venous thrombosis were found; twenty-nine out of the 31 cases with MVT had intestinal infarction. None (0%) of the 239 patients with PVT without extension into the superior mesenteric vein had intestinal infarction. Portomesenteric venous thrombosis and intestinal infarction was associated with concomitant venous thromboembolism (O. R. 6.1 [95% CI 1.8-21]). CONCLUSION: MVT carries a high risk of developing intestinal infarction and is associated with concomitant venous thromboembolism, whereas PVT is associated with liver disease. PMID- 21248677 TI - Assessment of venous thrombus time of progression by gray-scale median analysis. AB - AIM: To determine if gray-scale median (GSM) analysis could differentiate acute and recent deep venous thrombosis (DVT). METHODS: Patients submitted to vascular ultrasound examination of lower extremities due to suspected DVT were evaluated. Patients with acute or recent femoropopliteal DVT were included, whereas those without DVT, with chronic or isolated calf DVT were excluded. Time of onset of DVT symptoms was recorded. A transverse image of the thrombosed vein and adjacent artery was obtained. Two sonographers determined a subjective impression of thrombus time of progression and classified it as acute or recent. Thrombus GSM was calculated with a software. ROC curve was used to determine GSM cut-off points. Fischer's exact and Student's t tests were also used. P<0.05 indicated statistical significance. RESULTS: 128 veins of 63 extremities were studied. Thrombus GSM correlated with time of onset of DVT symptoms (P=0.005) and with subjective evaluation of thrombus time of progression (P<0.001). When DVT symptoms had begun up to two weeks before and thrombus was classified as acute, GSM was lower. Area under ROC curve for thrombus GSM was 0.76 (P<0.001). GSM 17.90, 23.03, and 40.02 cut-off points differentiated between acute and recent thrombi with 35.59% sensitivity and 91.30% specificity, 59.32% sensitivity and 84.06% specificity, 91.53% sensitivity and 31.88% specificity, respectively. CONCLUSION: GSM was a reliable tool for objectively differentiating acute and recent DVT in most thrombus images. GSM 17.90 and 40.02 cut-off points showed high specificity and high sensitivity, respectively, for acute and recent DVT differentiation. In 17.90 to 40.02 interval, GSM cut-off point that best distinguished acute from recent DVT was 23.03. PMID- 21248678 TI - Neurological deficit after simultaneous open abdominal aortic surgery and thoracic aortic endovascular therapy. AB - We examined a total of 12 cases; 8 cases were identified by searching the literature on Pubmed (excluding case reports published prior to 2000) and 4 cases were ones we personally encountered. We examined age, sex, history of smoking, and preoperative risk factors as preoperative factors, the access route and coverage of the descending aorta as perioperative factors, and complications and survival time as postoperative factors. Mean coverage of the thoracic aorta was 90.8 mm. In terms of perioperative deaths, 8.3% (1 patient) were due to coagulopathy. Perioperative complications occurred in 16.7% of cases (coagulopathy in 1 patient and paralysis in another). No patients experienced complications or underwent additional treatment during a mean follow-up of 22.9 months. This study suggested that simultaneous open abdominal aortic repair and thoracic aortic endovascular therapy is feasible and also involves few postoperative complications. Paraplegia and paralysis tended to occur less frequently than with two-stage surgery, but further study is needed to explain why this is true. PMID- 21248679 TI - A fatal case of Behcet's disease. AB - We report the case of a 32-year-old man with new diagnosed Behcet's disease (BD) with cardiac, central nervous system and vascular involvement. Transthoracic echocardiography disclosed a thrombus in the right ventricle and another thrombus in the inferior vena cava (IVC). The color Doppler imaging was compatible with Budd-Chiari syndrome. Magnetic resonance imaging (MRI) of the brain revealed atrophy of brain stem and right hemisphere and a milimmetric lacunar infarct. Although therapy with urokinase, pulse methylprednisolone and cyclophosphamide was administered immediately, the patient died due to hepatic failure. BD should always be considered in the differential diagnosis of thromboses in the young and thrombotic events should be evaluated during the clinical course of BD. PMID- 21248680 TI - Self-reported influenza-like illness during the 2009 H1N1 influenza pandemic- United States, September 2009 - March 2010. AB - CDC identified the first case of 2009 H1N1 pandemic influenza on April 15, 2009. During the first 3 months of the outbreak, approximately 43,000 cases were reported to CDC. In June 2009, the World Health Organization declared the outbreak an influenza pandemic. Because no existing influenza surveillance system in the United States monitored influenza-like illness (ILI) among persons with ILI who did not seek health care, CDC initiated community-based surveillance of self-reported ILI (defined as the presence of fever with cough or sore throat) and health-care--seeking behavior through a supplementary module of the Behavioral Risk Factor Surveillance System (BRFSS). This report summarizes results from BRFSS surveys conducted during September 2009--March 2010. Among 216,431 adults and 43,511 children (aged <18 years), the average monthly percentage of respondents reporting ILI in the 30 days preceding the interview was 8.1% among adults (range: 5.5% for September interviews to 9.5% for November) and 28.4% among children (range: 20.4% for September interviews to 35.9% for November). Health care was sought by 40% of adults and 56% of children with self reported ILI. The results indicate that reported symptoms of ILI were widespread during the 2009--10 influenza season, with a substantial percentage of those reporting ILI seeking health care. PMID- 21248681 TI - CDC grand rounds: childhood obesity in the United States. AB - In the United States, childhood obesity affects approximately 12.5 million children and teens (17% of that population). Changes in obesity prevalence from the 1960s show a rapid increase in the 1980s and 1990s, when obesity prevalence among children and teens tripled, from nearly 5% to approximately 15% (Figure 1). During the past 10 years, the rapid increase in obesity has slowed and might have leveled. However, among the heaviest boys, a significant increase in obesity has been observed, with the heaviest getting even heavier. Moreover, substantial racial/ethnic disparities exist, with Hispanic boys and non-Hispanic black girls disproportionately affected by obesity (Figure 2). Also, older children and teens are more likely to be obese compared with preschoolers. PMID- 21248682 TI - Antiviral agents for the treatment and chemoprophylaxis of influenza --- recommendations of the Advisory Committee on Immunization Practices (ACIP). AB - This report updates previous recommendations by CDC's Advisory Committee on Immunization Practices (ACIP) regarding the use of antiviral agents for the prevention and treatment of influenza (CDC. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices [ACIP]. MMWR 2008;57[No. RR-7]).This report contains information on treatment and chemoprophylaxis of influenza virus infection and provides a summary of the effectiveness and safety of antiviral treatment medications. Highlights include recommendations for use of 1) early antiviral treatment of suspected or confirmed influenza among persons with severe influenza (e.g., those who have severe, complicated, or progressive illness or who require hospitalization); 2) early antiviral treatment of suspected or confirmed influenza among persons at higher risk for influenza complications; and 3) either oseltamivir or zanamivir for persons with influenza caused by 2009 H1N1 virus, influenza A (H3N2) virus, or influenza B virus or when the influenza virus type or influenza A virus subtype is unknown; 4) antiviral medications among children aged <1 year; 5) local influenza testing and influenza surveillance data, when available, to help guide treatment decisions; and 6) consideration of antiviral treatment for outpatients with confirmed or suspected influenza who do not have known risk factors for severe illness, if treatment can be initiated within 48 hours of illness onset. Additional information is available from CDC's influenza website at http://www.cdc.gov/flu, including any updates or supplements to these recommendations that might be required during the 2010-11 influenza season. Health-care providers should be alert to announcements of recommendation updates and should check the CDC influenza website periodically for additional information. Recommendations related to the use of vaccines for the prevention of influenza during the 2010-11 influenza season have been published previously (CDC. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices [ACIP], 2010. MMWR 2010;59[No. RR 8]). PMID- 21248683 TI - Genotypic inference of HIV-1 tropism using population-based sequencing of V3. AB - BACKGROUND: Prior to receiving a drug from CCR5-antagonist class in HIV therapy, a patient must undergo an HIV tropism test to confirm that his or her viral population uses the CCR5 coreceptor for cellular entry, and not an alternative coreceptor. One approach to tropism testing is to examine the sequence of the V3 region of the HIV envelope, which interacts with the coreceptor. METHODS: Viral RNA is extracted from blood plasma. The V3 region is amplified in triplicate with nested reverse transcriptase-PCR. The amplifications are then sequenced and analyzed using the software, RE_Call. Sequences are then submitted to a bioinformatic algorithm such as geno2pheno to infer viral tropism from the V3 region. Sequences are inferred to be non-R5 if their geno2pheno false positive rate falls below 5.75%. If any one of the three sequences from a sample is inferred to be non-R5, the patient is unlikely to respond to a CCR5-antagonist. PMID- 21248684 TI - Combining transcranial magnetic stimulation and FMRI to examine the default mode network. AB - The default mode network is a group of brain regions that are active when an individual is not focused on the outside world and the brain is at "wakeful rest." It is thought the default mode network corresponds to self-referential or "internal mentation". It has been hypothesized that, in humans, activity within the default mode network is correlated with certain pathologies (for instance, hyper-activation has been linked to schizophrenia and autism spectrum disorders whilst hypo-activation of the network has been linked to Alzheimer's and other neurodegenerative diseases. As such, noninvasive modulation of this network may represent a potential therapeutic intervention for a number of neurological and psychiatric pathologies linked to abnormal network activation. One possible tool to effect this modulation is Transcranial Magnetic Stimulation: a non-invasive neurostimulatory and neuromodulatory technique that can transiently or lastingly modulate cortical excitability (either increasing or decreasing it) via the application of localized magnetic field pulses. In order to explore the default mode network's propensity towards and tolerance of modulation, we will be combining TMS (to the left inferior parietal lobe) with functional magnetic resonance imaging (fMRI). Through this article, we will examine the protocol and considerations necessary to successfully combine these two neuroscientific tools. PMID- 21248685 TI - TMS: using the theta-burst protocol to explore mechanism of plasticity in individuals with Fragile X syndrome and autism. AB - Fragile X Syndrome (FXS), also known as Martin-Bell Syndrome, is a genetic abnormality found on the X chromosome. Individuals suffering from FXS display abnormalities in the expression of FMR1--a protein required for typical, healthy neural development. Recent data has suggested that the loss of this protein can cause the cortex to be hyperexcitable thereby affecting overall patterns of neural plasticity. In addition, Fragile X shows a strong comorbidity with autism: in fact, 30% of children with FXS are diagnosed with autism, and 2-5% of autistic children suffer from FXS. Transcranial Magnetic Stimulation (a non-invasive neurostimulatory and neuromodulatory technique that can transiently or lastingly modulate cortical excitability via the application of localized magnetic field pulses) represents a unique method of exploring plasticity and the manifestations of FXS within affected individuals. More specifically, Theta-Burst Stimulation (TBS), a specific stimulatory protocol shown to modulate cortical plasticity for a duration up to 30 minutes after stimulation cessation in healthy populations, has already proven an efficacious tool in the exploration of abnormal plasticity. Recent studies have shown the effects of TBS last considerably longer in individuals on the autistic spectrum--up to 90 minutes. This extended effect duration suggests an underlying abnormality in the brain's natural plasticity state in autistic individuals, similar to the hyperexcitability induced by Fragile X Syndrome. In this experiment, utilizing single-pulse motor-evoked potentials (MEPs) as our benchmark, we will explore the effects of both intermittent and continuous TBS on cortical plasticity in individuals suffering from FXS and individuals on the Autistic Spectrum. PMID- 21248686 TI - State-dependency effects on TMS: a look at motive phosphene behavior. AB - Transcranial magnetic stimulation (TMS) is a non-invasive neurostimulatory and neuromodulatory technique that can transiently or lastingly modulate cortical excitability (either increasing or decreasing it) via the application of localized magnetic field pulses. Within the field of TMS, the term state dependency refers to the initial, baseline condition of the particular neural region targeted for stimulation. As can be inferred, the effects of TMS can (and do) vary according to this primary susceptibility and responsiveness of the targeted cortical area. In this experiment, we will examine this concept of state dependency through the elicitation and subjective experience of motive phosphenes. Phosphenes are visually perceived flashes of small lights triggered by electromagnetic pulses to the visual cortex. These small lights can assume varied characteristics depending upon which type of visual cortex is being stimulated. In this particular study, we will be targeting motive phosphenes as elicited through the stimulation of V1/V2 and the V5/MT+ complex visual regions. PMID- 21248687 TI - Isolation of valvular endothelial cells. AB - Heart valves are solely responsible for maintaining unidirectional blood flow through the cardiovascular system. These thin, fibrous tissues are subjected to significant mechanical stresses as they open and close several billion times over a lifespan. The incredible endurance of these tissues is due to the resident valvular endothelial (VEC) and interstitial cells (VIC) that constantly repair and remodel in response to local mechanical and biological signals. Only recently have we begun to understand the unique behaviors of these cells, for which in vitro experimentation has played a key role. Particularly challenging is the isolation and culture of VEC. Special care must be used from the moment the tissue is removed from the host through final plating. Here we present protocols for direct isolation, side specific isolation, culture, and verification of pure populations of VEC. We use enzymatic digestion followed by a gentle swab scraping technique to dislodge only surface cells. These cells are then collected into a tube and centrifuged into a pellet. The pellet is then resuspended and plated into culture flasks pre-coated with collagen I matrix. VEC phenotype is confirmed by contact inhibited growth and the expression of endothelial specific markers such as PECAM1 (CD31), Von Willebrand Factor (vWF), and negative expression of alpha-smooth muscle actin (alpha-SMA). The functional characteristics of VEC are associated with high levels of acetylated LDL. Unlike vascular endothelial cells, VEC have the unique capacity to transform into mesenchyme, which normally occurs during embryonic valve formation. This can also occur during significantly prolonged post confluent in vitro culture, so care should be made to passage at or near confluence. After VEC isolation, pure populations of VIC can then be easily acquired. PMID- 21248688 TI - Testing protozoacidal activity of ligand-lytic peptides against termite gut protozoa in vitro (protozoa culture) and in vivo (microinjection into termite hindgut). AB - We are developing a novel approach to subterranean termite control that would lead to reduced reliance on the use of chemical pesticides. Subterranean termites are dependent on protozoa in the hindguts of workers to efficiently digest wood. Lytic peptides have been shown to kill a variety of protozoan parasites (Mutwiri et al. 2000) and also protozoa in the gut of the Formosan subterranean termite, Coptotermes formosanus (Husseneder and Collier 2009). Lytic peptides are part of the nonspecific immune system of eukaryotes, and destroy the membranes of microorganisms (Leuschner and Hansel 2004). Most lytic peptides are not likely to harm higher eukaryotes, because they do not affect the electrically neutral cholesterol-containing cell membranes of higher eukaryotes (Javadpour et al. 1996). Lytic peptide action can be targeted to specific cell types by the addition of a ligand. For example, Hansel et al. (2007) reported that lytic peptides conjugated with cancer cell membrane receptor ligands could be used to destroy breast cancer cells, while lytic peptides alone or conjugated with non specific peptides were not effective. Lytic peptides also have been conjugated to human hormones that bind to receptors on tumor cells for targeted destruction of prostate and testicular cancer cells (Leuschner and Hansel 2004). In this article we present techniques used to demonstrate the protozoacidal activity of a lytic peptide (Hecate) coupled to a heptapeptide ligand that binds to the surface membrane of protozoa from the gut of the Formosan subterranean termite. These techniques include extirpation of the gut from termite workers, anaerobic culture of gut protozoa (Pseudotrichonympha grassii, Holomastigotoides hartmanni,Spirotrichonympha leidyi), microscopic confirmation that the ligand marked with a fluorescent dye binds to the termite gut protozoa and other free living protozoa but not to bacteria or gut tissue. We also demonstrate that the same ligand coupled to a lytic peptide efficiently kills termite gut protozoa in vitro (protozoa culture) and in vivo (microinjection into hindgut of workers), but is less bacteriacidal than the lytic peptide alone. The loss of protozoa leads to the death of the termites in less than two weeks. In the future, we will genetically engineer microorganisms that can survive in the termite hindgut and spread through a termite colony as "Trojan Horses" to express ligand-lytic peptides that would kill the protozoa in the termite gut and subsequently kill the termites in the colony. Ligand-lytic peptides also could be useful for drug development against protozoan parasites. PMID- 21248689 TI - Bioassays for monitoring insecticide resistance. AB - Pest resistance to pesticides is an increasing problem because pesticides are an integral part of high-yielding production agriculture. When few products are labeled for an individual pest within a particular crop system, chemical control options are limited. Therefore, the same product(s) are used repeatedly and continual selection pressure is placed on the target pest. There are both financial and environmental costs associated with the development of resistant populations. The cost of pesticide resistance has been estimated at approximately $ 1.5 billion annually in the United States. This paper will describe protocols, currently used to monitor arthropod (specifically insects) populations for the development of resistance. The adult vial test is used to measure the toxicity to contact insecticides and a modification of this test is used for plant-systemic insecticides. In these bioassays, insects are exposed to technical grade insecticide and responses (mortality) recorded at a specific post-exposure interval. The mortality data are subjected to Log Dose probit analysis to generate estimates of a lethal concentration that provides mortality to 50% (LC(50) of the target populations and a series of confidence limits (CL's) as estimates of data variability. When these data are collected for a range of insecticide-susceptible populations, the LC(50) can be used as baseline data for future monitoring purposes. After populations have been exposed to products, the results can be compared to a previously determined LC(50) using the same methodology. PMID- 21248690 TI - Large scale zebrafish-based in vivo small molecule screen. AB - Given their small embryo size, rapid development, transparency, fecundity, and numerous molecular, morphological and physiological similarities to mammals, zebrafish has emerged as a powerful in vivo platform for phenotype-based drug screens and chemical genetic analysis. Here, we demonstrate a simple, practical method for large-scale screening of small molecules using zebrafish embryos. PMID- 21248691 TI - Facilitating the analysis of immunological data with visual analytic techniques. AB - Visual analytics (VA) has emerged as a new way to analyze large dataset through interactive visual display. We demonstrated the utility and the flexibility of a VA approach in the analysis of biological datasets. Examples of these datasets in immunology include flow cytometry, Luminex data, and genotyping (e.g., single nucleotide polymorphism) data. Contrary to the traditional information visualization approach, VA restores the analysis power in the hands of analyst by allowing the analyst to engage in real-time data exploration process. We selected the VA software called Tableau after evaluating several VA tools. Two types of analysis tasks analysis within and between datasets were demonstrated in the video presentation using an approach called paired analysis. Paired analysis, as defined in VA, is an analysis approach in which a VA tool expert works side-by side with a domain expert during the analysis. The domain expert is the one who understands the significance of the data, and asks the questions that the collected data might address. The tool expert then creates visualizations to help find patterns in the data that might answer these questions. The short lag-time between the hypothesis generation and the rapid visual display of the data is the main advantage of a VA approach. PMID- 21248692 TI - Protocol for production of a genetic cross of the rodent malaria parasites. AB - Variation in response to antimalarial drugs and in pathogenicity of malaria parasites is of biologic and medical importance. Linkage mapping has led to successful identification of genes or loci underlying various traits in malaria parasites of rodents and humans. The malaria parasite Plasmodium yoelii is one of many malaria species isolated from wild African rodents and has been adapted to grow in laboratories. This species reproduces many of the biologic characteristics of the human malaria parasites; genetic markers such as microsatellite and amplified fragment length polymorphism (AFLP) markers have also been developed for the parasite. Thus, genetic studies in rodent malaria parasites can be performed to complement research on Plasmodium falciparum. Here, we demonstrate the techniques for producing a genetic cross in P. yoelii that were first pioneered by Drs. David Walliker, Richard Carter, and colleagues at the University of Edinburgh. Genetic crosses in P. yoelii and other rodent malaria parasites are conducted by infecting mice Mus musculus with an inoculum containing gametocytes of two genetically distinct clones that differ in phenotypes of interest and by allowing mosquitoes to feed on the infected mice 4 days after infection. The presence of male and female gametocytes in the mouse blood is microscopically confirmed before feeding. Within 48 hrs after feeding, in the midgut of the mosquito, the haploid gametocytes differentiate into male and female gametes, fertilize, and form a diploid zygote (Fig. 1). During development of a zygote into an ookinete, meiosis appears to occur. If the zygote is derived through cross-fertilization between gametes of the two genetically distinct parasites, genetic exchanges (chromosomal reassortment and cross-overs between the non-sister chromatids of a pair of homologous chromosomes; Fig. 2) may occur, resulting in recombination of genetic material at homologous loci. Each zygote undergoes two successive nuclear divisions, leading to four haploid nuclei. An ookinete further develops into an oocyst. Once the oocyst matures, thousands of sporozoites (the progeny of the cross) are formed and released into mosquito hemoceal. Sporozoites are harvested from the salivary glands and injected into a new murine host, where pre-erythrocytic and erythrocytic stage development takes place. Erythrocytic forms are cloned and classified with regard to the characters distinguishing the parental lines prior to genetic linkage mapping. Control infections of individual parental clones are performed in the same way as the production of a genetic cross. PMID- 21248693 TI - Corneal confocal microscopy: a novel non-invasive technique to quantify small fibre pathology in peripheral neuropathies. AB - The accurate quantification of peripheral neuropathy is important to define at risk patients, anticipate deterioration, and assess new therapies. Conventional methods assess neurological deficits and electrophysiology and quantitative sensory testing quantifies functional alterations to detect neuropathy. However, the earliest damage appears to be to the small fibres and yet these tests primarily assess large fibre dysfunction and have a limited ability to demonstrate regeneration and repair. The only techniques which allow a direct examination of unmyelinated nerve fibre damage and repair are sural nerve biopsy with electron microscopy and skin-punch biopsy. However, both are invasive procedures and require lengthy laboratory procedures and considerable expertise. Corneal Confocal microscopy is a non-invasive clinical technique which provides in-vivo imaging of corneal nerve fibres. We have demonstrated early nerve damage, which precedes loss of intraepidermal nerve fibres in skin biopsies together with stratification of neuropathic severity and repair following pancreas transplantation in diabetic patients. We have also demonstrated nerve damage in idiopathic small fibre neuropathy and Fabry's disease. PMID- 21248694 TI - Tri-layered electrospinning to mimic native arterial architecture using polycaprolactone, elastin, and collagen: a preliminary study. AB - Throughout native artery, collagen and elastin play an important role, providing a mechanical backbone, preventing vessel rupture, and promoting recovery under pulsatile deformations. The goal of this study was to mimic the structure of native artery by fabricating a multi-layered electrospun conduit composed of poly(caprolactone) (PCL) with the addition of elastin and collagen with blends of 45-45-10, 55-35-10, and 65-25-10 PCL-ELAS-COL to demonstrate mechanical properties indicative of native arterial tissue, while remaining conducive to tissue regeneration. Whole grafts and individual layers were analyzed using uniaxial tensile testing, dynamic compliance, suture retention, and burst strength. Compliance results revealed that changes to the middle/medial layer changed overall graft behavior with whole graft compliance values ranging from 0.8 - 2.8 % / 100 mmHg, while uniaxial results demonstrated an average modulus range of 2.0 - 11.8 MPa. Both modulus and compliance data displayed values within the range of native artery. Mathematical modeling was implemented to show how changes in layer stiffness affect the overall circumferential wall stress, and as a design aid to achieve the best mechanical combination of materials. Overall, the results indicated that a graft can be designed to mimic a tri-layered structure by altering layer properties. PMID- 21248695 TI - Measurement of bioelectric current with a vibrating probe. AB - Electric fields, generated by active transport of ions, are present in many biological systems and often serve important functions in tissues and organs. For example, they play an important role in directing cell migration during wound healing. Here we describe the manufacture and use of ultrasensitive vibrating probes for measuring extracellular electric currents. The probe is an insulated, sharpened metal wire with a small platinum-black tip (30-35 MUm), which can detect ionic currents in the MUA/cm(2) range in physiological saline. The probe is vibrated at about 200 Hz by a piezoelectric bender. In the presence of an ionic current, the probe detects a voltage difference between the extremes of its movement. A lock-in amplifier filters out extraneous noise by locking on to the probe's frequency of vibration. Data are recorded onto computer. The probe is calibrated at the start and end of experiments in appropriate saline, using a chamber which applies a current of exactly 1.5 MUA/cm(2). We describe how to make the probes, set up the system and calibrate. We also demonstrate the technique of cornea measurement, and show some representative results from different specimens (cornea, skin, brain). PMID- 21248696 TI - Streamlined purification of plasmid DNA from prokaryotic cultures. AB - We describe the complete process of AcroPrep Advance Filter Plates for 96 plasmid preparations, starting from prokaryotic culture and ending with high purity DNA. Based on multi-well filtration for bacterial lysate clearance and DNA purification, this method creates a streamlined process for plasmid preparation. Filter plates containing silica-based media can easily be processed by vacuum filtration or centrifuge to yield appreciable quantities of plasmid DNA. Quantitative analyses determine the purified plasmid DNA is consistently of high quality with average OD(260/280;) ratios of 1.97. Overall, plasmid yields offer more pure DNA for downstream applications, such as sequencing and cloning. This streamlined method of using AcroPrep Advance Filter Plates allows for manual, semi-automated or fully-automated processing. PMID- 21248697 TI - Intra-operative behavioral tasks in awake humans undergoing deep brain stimulation surgery. AB - Deep brain stimulation (DBS) is a surgical procedure that directs chronic, high frequency electrical stimulation to specific targets in the brain through implanted electrodes. Deep brain stimulation was first implemented as a therapeutic modality by Benabid et al. in the late 1980s, when he used this technique to stimulate the ventral intermediate nucleus of the thalamus for the treatment of tremor. Currently, the procedure is used to treat patients who fail to respond adequately to medical management for diseases such as Parkinson's, dystonia, and essential tremor. The efficacy of this procedure for the treatment of Parkinson's disease has been demonstrated in well-powered, randomized controlled trials. Presently, the U.S. Food and Drug Administration has approved DBS as a treatment for patients with medically refractory essential tremor, Parkinson's disease, and dystonia. Additionally, DBS is currently being evaluated for the treatment of other psychiatric and neurological disorders, such as obsessive compulsive disorder, major depressive disorder, and epilepsy. DBS has not only been shown to help people by improving their quality of life, it also provides researchers with the unique opportunity to study and understand the human brain. Microelectrode recordings are routinely performed during DBS surgery in order to enhance the precision of anatomical targeting. Firing patterns of individual neurons can therefore be recorded while the subject performs a behavioral task. Early studies using these data focused on descriptive aspects, including firing and burst rates, and frequency modulation. More recent studies have focused on cognitive aspects of behavior in relation to neuronal activity. This article will provide a description of the intra-operative methods used to perform behavioral tasks and record neuronal data with awake patients during DBS cases. Our exposition of the process of acquiring electrophysiological data will illuminate the current scope and limitations of intra-operative human experiments. PMID- 21248698 TI - Modeling stroke in mice - middle cerebral artery occlusion with the filament model. AB - Stroke is among the most frequent causes of death and adult disability, especially in highly developed countries. However, treatment options to date are very limited. To meet the need for novel therapeutic approaches, experimental stroke research frequently employs rodent models of focal cerebral ischaemia. Most researchers use permanent or transient occlusion of the middle cerebral artery (MCA) in mice or rats. Proximal occlusion of the middle cerebral artery (MCA) via the intraluminal suture technique (so called filament or suture model) is probably the most frequently used model in experimental stroke research. The intraluminal MCAO model offers the advantage of inducing reproducible transient or permanent ischaemia of the MCA territory in a relatively non-invasive manner. Intraluminal approaches interrupt the blood flow of the entire territory of this artery. Filament occlusion thus arrests flow proximal to the lenticulo-striate arteries, which supply the basal ganglia. Filament occlusion of the MCA results in reproducible lesions in the cortex and striatum and can be either permanent or transient. In contrast, models inducing distal (to the branching of the lenticulo striate arteries) MCA occlusion typically spare the striatum and primarily involve the neocortex. In addition these models do require craniectomy. In the model demonstrated in this article, a silicon coated filament is introduced into the common carotid artery and advanced along the internal carotid artery into the Circle of Willis, where it blocks the origin of the middle cerebral artery. In patients, occlusions of the middle cerebral artery are among the most common causes of ischaemic stroke. Since varying ischemic intervals can be chosen freely in this model depending on the time point of reperfusion, ischaemic lesions with varying degrees of severity can be produced. Reperfusion by removal of the occluding filament at least partially models the restoration of blood flow after spontaneous or therapeutic (tPA) lysis of a thromboembolic clot in humans. In this video we will present the basic technique as well as the major pitfalls and confounders which may limit the predictive value of this model. PMID- 21248699 TI - A procedure for studying the footshock-induced reinstatement of cocaine seeking in laboratory rats. AB - The most insidious aspect of drug addiction is the high propensity for relapse. Animal models of relapse, known as reinstatement procedures, have been used extensively to study the neurobiology and phenomenology of relapse to drug use. Although procedural variations have emerged over the past several decades, the most conventional reinstatement procedures are based on the drug self administration (SA) model. In this model, an animal is trained to perform an operant response to obtain drug. Subsequently, the behavior is extinguished by withholding response-contingent reinforcement. Reinstatement of drug seeking is then triggered by a discrete event, such as an injection of the training drug, re exposure to drug-associated cues, or exposure to a stressor. Reinstatement procedures were originally developed to study the ability of acute non-contingent exposure to the training drug to reinstate drug seeking in rats and monkeys. Reinstatement procedures have since been modified to study the role of environmental stimuli, including drug-associated cues and exposure to various forms of stress, in relapse to drug seeking. Over the past 15 years, a major focus of the reinstatement literature has been on the role of stress in drug relapse. One of the most commonly used forms of stress for studying this relationship is acute exposures to mild, intermittent, electric footshocks. The ability of footshock stress to induce reinstatement of drug seeking was originally demonstrated by Shaham and colleagues (1995) in rats with a history of intravenous heroin SA(5). Subsequently, the effect was generalized to rats with histories of intravenous cocaine, methamphetamine, and nicotine SA, as well as oral ethanol SA. Although footshock-induced reinstatement of drug seeking can be achieved reliably and robustly, it is an effect that tends to be sensitive to certain parametrical variables. These include the arrangement of extinction and reinstatement test sessions, the intensity and duration of footshock stress, and the presence of drug-associated cues during extinction and testing for reinstatement. Here we present a protocol for footshock-induced reinstatement of cocaine seeking that we have used with consistent success to study the relationship between stress and cocaine seeking. PMID- 21248700 TI - Principles of rodent surgery for the new surgeon. AB - For both scientific and animal welfare reasons, training in basic surgical concepts and techniques should be undertaken before ever seeking to perform surgery on a rodent. Students, post-doctoral scholars, and others interested in performing surgery on rodents as part of a research protocol may not have had formal surgical training as part of their required coursework. Surgery itself is a technical skill, and one that will improve with practice. The principles of aseptic technique, however, often remain unexplained or untaught. For most new surgeons, this vital information is presented in piecemeal fashion or learned on the job, neither of which is ideal. It may also make learning how to perform a particular surgery difficult, as the new surgeon is learning both a surgical technique and the principles of asepsis at the same time. This article summarizes and makes recommendations for basic surgical skills and techniques necessary for successful rodent surgery. This article is designed to supplement hands-on training by the user's institution. PMID- 21248701 TI - Growth and differentiation of adult hippocampal arctic ground squirrel neural stem cells. AB - Arctic ground squirrels (Urocitellus parryii, AGS) are unique in their ability to hibernate with a core body temperature near or below freezing. These animals also resist ischemic injury to the brain in vivo and oxygen-glucose deprivation in vitro. These unique qualities provided the impetus to isolate AGS neurons to examine inherent neuronal characteristics that could account for the capacity of AGS neurons to resist injury and cell death caused by ischemia and extremely cold temperatures. Identifying proteins or gene targets that allow for the distinctive properties of these cells could aid in the discovery of effective therapies for a number of ischemic indications and for the study of cold tolerance. Adult AGS hippocampus contains neural stem cells that continue to proliferate, allowing for easy expansion of these stem cells in culture. We describe here methods by which researchers can utilize these stem cells and differentiated neurons for any number of purposes. By closely following these steps the AGS neural stem cells can be expanded through two passages or more and then differentiated to a culture high in TUJ1-positive neurons (~50%) without utilizing toxic chemicals to minimize the number of dividing cells. Ischemia induces neurogenesis and neurogenesis which proceeds via MEK/ERK and PI3K/Akt survival signaling pathways contributes to ischemia resistance in vivo and in vitro (Kelleher-Anderson, Drew et al., in preparation). Further characterization of these unique neural cells can advance on many fronts, using some or all of these methods. PMID- 21248702 TI - Direct delivery of MIF morpholinos into the zebrafish otocyst by injection and electroporation affects inner ear development. AB - In recent years, electroporation has become a popular technique for in vivo transfection of DNA, RNA, and morpholinos into various tissues, including the eye, brain, and somites of zebrafish. The advantage of electroporation over other methods of genetic manipulation is that specific tissues can be targeted, both spatially and temporally, for the introduction of macromolecules by the application of electrical current. Here we describe the use of electroporation for transfecting mif and mif-like morpholinos into the tissues of the developing inner ear of the zebrafish. In past studies, mif morpholino injected into embryos at the 1- to 8-cell stage resulted in widespread morphological changes in the nervous system and eye, as well as the ear. By targeting the tissues of the inner ear at later stages in development, we can determine the primary effects of MIF in the developing inner ear, as opposed to secondary effects that may result from the influence of other tissues. By using phalloidin and acetylated tubulin staining to study the morphology of neurons, neuronal processes, and hair cells associated with the posterior macula, we were able to assess the efficacy of electroporation as a method for targeted transfection in the zebrafish inner ear. The otic vesicles of 24hpf embryos were injected with morpholinos and electroporated and were then compared to embryos that had received no treatment or had been only injected or electroporated. Embryos that were injected and electroporated showed a decrease in hair cell numbers, decreased innervation by the statoacoustic ganglion (SAG) and fewer SAG neurons compared with control groups. Our results showed that direct delivery of morpholinos into otocysts at later stages avoids the non-specific nervous system and neural crest effects of morpholinos delivered at the 1-8 cell stage. It also allows examination of effects that are directed to the inner ear and not secondary effects on the ear from primary effects on the brain, neural crest or periotic mesenchyme. PMID- 21248703 TI - Patch clamp and perfusion techniques for studying ion channels expressed in Xenopus oocytes. AB - The protocol presented here is designed to study the activation of the large conductance, voltage- and Ca(2+)-activated K(+) (BK) channels. The protocol may also be used to study the structure-function relationship for other ion channels and neurotransmitter receptors. BK channels are widely expressed in different tissues and have been implicated in many physiological functions, including regulation of smooth muscle contraction, frequency tuning of inner hair cells and regulation of neurotransmitter release. BK channels are activated by membrane depolarization and by intracellular Ca(2+) and Mg(2+). Therefore, the protocol is designed to control both the membrane voltage and the intracellular solution. In this protocol, messenger RNA of BK channels is injected into Xenopus laevis oocytes (stage V-VI) followed by 2-5 days of incubation at 18 degrees C. Membrane patches that contain single or multiple BK channels are excised with the inside out configuration using patch clamp techniques. The intracellular side of the patch is perfused with desired solutions during recording so that the channel activation under different conditions can be examined. To summarize, the mRNA of BK channels is injected into Xenopus laevis oocytes to express channel proteins on the oocyte membrane; patch clamp techniques are used to record currents flowing through the channels under controlled voltage and intracellular solutions. PMID- 21248704 TI - Establishing embryonic mouse neural stem cell culture using the neurosphere assay. AB - In mammalians, stem cells acts as a source of undifferentiated cells to maintain cell genesis and renewal in different tissues and organs during the life span of the animal. They can potentially replace cells that are lost in the aging process or in the process of injury and disease. The existence of neural stem cells (NSCs) was first described by Reynolds and Weiss (1992) in the adult mammalian central nervous system (CNS) using a novel serum-free culture system, the neurosphere assay (NSA). Using this assay, it is also feasible to isolate and expand NSCs from different regions of the embryonic CNS. These in vitro expanded NSCs are multipotent and can give rise to the three major cell types of the CNS. While the NSA seems relatively simple to perform, attention to the procedures demonstrated here is required in order to achieve reliable and consistent results. This video practically demonstrates NSA to generate and expand NSCs from embryonic day 14-mouse brain tissue and provides technical details so one can achieve reproducible neurosphere cultures. The procedure includes harvesting E14 mouse embryos, brain microdissection to harvest the ganglionic eminences, dissociation of the harvested tissue in NSC medium to gain a single cell suspension, and finally plating cells in NSA culture. After 5-7 days in culture, the resulting primary neurospheres are passaged to further expand the number of the NSCs for future experiments. PMID- 21248705 TI - High-density EEG recordings of the freely moving mice using polyimide-based microelectrode. AB - Electroencephalogram (EEG) indicates the averaged electrical activity of the neuronal populations on a large-scale level. It is widely utilized as a noninvasive brain monitoring tool in cognitive neuroscience as well as a diagnostic tool for epilepsy and sleep disorders in neurology. However, the underlying mechanism of EEG rhythm generation is still under the veil. Recently introduced polyimide-based microelectrode (PBM-array) for high resolution mouse EEG is one of the trials to answer the neurophysiological questions on EEG signals based on a rich genetic resource that the mouse model contains for the analysis of complex EEG generation process. This application of nanofabricated PBM-array to mouse skull is an efficient tool for collecting large-scale brain activity of transgenic mice and accommodates to identify the neural correlates to certain EEG rhythms in conjunction with behavior. However its ultra-thin thickness and bifurcated structure cause a trouble in handling and implantation of PBM-array. In the presented video, the preparation and surgery steps for the implantation of PBM-array on a mouse skull are described step by step. Handling and surgery tips to help researchers succeed in implantation are also provided. PMID- 21248706 TI - An introduction to worm lab: from culturing worms to mutagenesis. AB - This protocol describes procedures to maintain nematodes in the laboratory and how to mutagenize them using two alternative methods: ethyl methane sulfonate (EMS) and 4, 5', 8-trimethylpsoralen combined with ultraviolet light (TMP/UV). Nematodes are powerful biological systems for genetics studies because of their simple body plan and mating system, which is composed of self-fertilizing hermaphrodites and males that can generate hundreds of progeny per animal. Nematodes are maintained in agar plates containing a lawn of bacteria and can be easily transferred from one plate to another using a pick. EMS is an alkylating agent commonly used to induce point mutations and small deletions, while TMP/UV mainly induces deletions. Depending on the species of nematode being used, concentrations of EMS and TMP will have to be optimized. To isolate recessive mutations of the nematode Pristionchus pacificus, animals of the F2 generation were visually screened for phenotypes. To illustrate these methods, we mutagenized worms and looked for Uncoordinated (Unc), Dumpy (Dpy) and Transformer (Tra) mutants. PMID- 21248707 TI - High-resolution fiber-optic microendoscopy for in situ cellular imaging. AB - Many biological and clinical studies require the longitudinal study and analysis of morphology and function with cellular level resolution. Traditionally, multiple experiments are run in parallel, with individual samples removed from the study at sequential time points for evaluation by light microscopy. Several intravital techniques have been developed, with confocal, multiphoton, and second harmonic microscopy all demonstrating their ability to be used for imaging in situ. With these systems, however, the required infrastructure is complex and expensive, involving scanning laser systems and complex light sources. Here we present a protocol for the design and assembly of a high-resolution microendoscope which can be built in a day using off-the-shelf components for under US$5,000. The platform offers flexibility in terms of image resolution, field-of-view, and operating wavelength, and we describe how these parameters can be easily modified to meet the specific needs of the end user. We and others have explored the use of the high-resolution microendoscope (HRME) in in vitro cell culture, in excised and living animal tissues, and in human tissues in vivo. Users have reported the use of several different fluorescent contrast agents, including proflavine, benzoporphyrin-derivative monoacid ring A (BPD-MA), and fluoroscein, all of which have received full, or investigational approval from the FDA for use in human subjects. High-resolution microendoscopy, in the form described here, may appeal to a wide range of researchers working in the basic and clinical sciences. The technique offers an effective and economical approach which complements traditional benchtop microscopy, by enabling the user to perform high-resolution, longitudinal imaging in situ. PMID- 21248708 TI - The production of C. elegans transgenes via recombineering with the galK selectable marker. AB - The creation of transgenic animals is widely utilized in C. elegans research including the use of GFP fusion proteins to study the regulation and expression pattern of genes of interest or generation of tandem affinity purification (TAP) tagged versions of specific genes to facilitate their purification. Typically transgenes are generated by placing a promoter upstream of a GFP reporter gene or cDNA of interest, and this often produces a representative expression pattern. However, critical elements of gene regulation, such as control elements in the 3' untranslated region or alternative promoters, could be missed by this approach. Further only a single splice variant can be usually studied by this means. In contrast, the use of worm genomic DNA carried by fosmid DNA clones likely includes most if not all elements involved in gene regulation in vivo which permits the greater ability to capture the genuine expression pattern and timing. To facilitate the generation of transgenes using fosmid DNA, we describe an E. coli based recombineering procedure to insert GFP, a TAP-tag, or other sequences of interest into any location in the gene. The procedure uses the galK gene as the selection marker for both the positive and negative selection steps in recombineering which results in obtaining the desired modification with high efficiency. Further, plasmids containing the galK gene flanked by homology arms to commonly used GFP and TAP fusion genes are available which reduce the cost of oligos by 50% when generating a GFP or TAP fusion protein. These plasmids use the R6K replication origin which precludes the need for extensive PCR product purification. Finally, we also demonstrate a technique to integrate the unc-119 marker on to the fosmid backbone which allows the fosmid to be directly injected or bombarded into worms to generate transgenic animals. This video demonstrates the procedures involved in generating a transgene via recombineering using this method. PMID- 21248709 TI - Microdissection of black widow spider silk-producing glands. AB - Modern spiders spin high-performance silk fibers with a broad range of biological functions, including locomotion, prey capture and protection of developing offspring. Spiders accomplish these tasks by spinning several distinct fiber types that have diverse mechanical properties. Such specialization of fiber types has occurred through the evolution of different silk-producing glands, which function as small biofactories. These biofactories manufacture and store large quantities of silk proteins for fiber production. Through a complex series of biochemical events, these silk proteins are converted from a liquid into a solid material upon extrusion. Mechanical studies have demonstrated that spider silks are stronger than high-tensile steel. Analyses to understand the relationship between the structure and function of spider silk threads have revealed that spider silk consists largely of proteins, or fibroins, that have block repeats within their protein sequences. Common molecular signatures that contribute to the incredible tensile strength and extensibility of spider silks are being unraveled through the analyses of translated silk cDNAs. Given the extraordinary material properties of spider silks, research labs across the globe are racing to understand and mimic the spinning process to produce synthetic silk fibers for commercial, military and industrial applications. One of the main challenges to spinning artificial spider silk in the research lab involves a complete understanding of the biochemical processes that occur during extrusion of the fibers from the silk-producing glands. Here we present a method for the isolation of the seven different silk-producing glands from the cobweaving black widow spider, which includes the major and minor ampullate glands [manufactures dragline and scaffolding silk], tubuliform [synthesizes egg case silk], flagelliform [unknown function in cob-weavers], aggregate [makes glue silk], aciniform [synthesizes prey wrapping and egg case threads] and pyriform [produces attachment disc silk]. This approach is based upon anesthetizing the spider with carbon dioxide gas, subsequent separation of the cephalothorax from the abdomen, and microdissection of the abdomen to obtain the silk-producing glands. Following the separation of the different silk-producing glands, these tissues can be used to retrieve different macromolecules for distinct biochemical analyses, including quantitative real-time PCR, northern- and western blotting, mass spectrometry (MS or MS/MS) analyses to identify new silk protein sequences, search for proteins that participate in the silk assembly pathway, or use the intact tissue for cell culture or histological experiments. PMID- 21248710 TI - An investigation of the effects of sports-related concussion in youth using functional magnetic resonance imaging and the head impact telemetry system. AB - One of the most commonly reported injuries in children who participate in sports is concussion or mild traumatic brain injury (mTBI). Children and youth involved in organized sports such as competitive hockey are nearly six times more likely to suffer a severe concussion compared to children involved in other leisure physical activities. While the most common cognitive sequelae of mTBI appear similar for children and adults, the recovery profile and breadth of consequences in children remains largely unknown, as does the influence of pre-injury characteristics (e.g. gender) and injury details (e.g. magnitude and direction of impact) on long-term outcomes. Competitive sports, such as hockey, allow the rare opportunity to utilize a pre-post design to obtain pre-injury data before concussion occurs on youth characteristics and functioning and to relate this to outcome following injury. Our primary goals are to refine pediatric concussion diagnosis and management based on research evidence that is specific to children and youth. To do this we use new, multi-modal and integrative approaches that will: 1. Evaluate the immediate effects of head trauma in youth. 2. Monitor the resolution of post-concussion symptoms (PCS) and cognitive performance during recovery. 3. Utilize new methods to verify brain injury and recovery. To achieve our goals, we have implemented the Head Impact Telemetry (HIT) System. (Simbex; Lebanon, NH, USA). This system equips commercially available Easton S9 hockey helmets (Easton-Bell Sports; Van Nuys, CA, USA) with single-axis accelerometers designed to measure real-time head accelerations during contact sport participation. By using telemetric technology, the magnitude of acceleration and location of all head impacts during sport participation can be objectively detected and recorded. We also use functional magnetic resonance imaging (fMRI) to localize and assess changes in neural activity specifically in the medial temporal and frontal lobes during the performance of cognitive tasks, since those are the cerebral regions most sensitive to concussive head injury. Finally, we are acquiring structural imaging data sensitive to damage in brain white matter. PMID- 21248711 TI - The canonical Wnt signaling pathway is not involved in renal cyst development in the kidneys of inv mutant mice. AB - Recent studies have identified several genes whose defects cause hereditary renal cystic diseases with most of the gene products located in the primary cilia. It has been suggested that primary cilia are involved in signaling pathways, defects of which result in abnormal cell proliferation and randomization of oriented cell division in the kidney leading to cyst formation. Mice with a mutation in the inv gene are a model for human nephronophthisis type 2 and develop multiple renal cysts. Inv protein (also called inversin) is located in the base of primary cilia and acts as a switch from canonical to non-canonical Wnt signaling. Here, we studied the orientation of cell division and proliferation in the kidneys of inv mutant mice, as its loss is thought to maintain activation of the canonical Wnt signaling. To establish if canonical signaling was involved in this process, we mated inv mutant with BATlacZ mice to measure canonical Wnt activity. Based on these reporter mice, nuclear localization and phosphorylation of beta-catenin, and responsiveness to Wnt ligands in inv mutant cells, we found that random oriented cell division is an initial event for renal tubule expansion and precedes cell proliferation. Thus, our results do not support the hypothesis that canonical Wnt signaling causes renal cyst development in these mice. PMID- 21248712 TI - The biocompatibility of neutral pH, low-GDP peritoneal dialysis solutions: benefit at bench, bedside, or both? AB - For patients on peritoneal dialysis (PD), the development of peritonitis, the decline of residual kidney function, and the loss of peritoneal membrane function are central events that affect both patient and technique survival. The use of glucose as the osmotic agent in conventional PD solutions may increase the susceptibility to each of these events. However, its use may also be associated with systemic metabolic perturbations and, in turn, an increase in cardiovascular morbidity. Both in vitro and in vivo evidence suggest that both the local peritoneal and systemic toxicity induced by the use of glucose may be in part mediated by the presence of glucose degradation products (GDPs) coupled with the hyperosmolarity, reduced pH, and use of lactate as the buffer in conventional PD solutions. Therefore, the use of neutral pH, low-GDP (NpHL(GDP)), bicarbonate buffered PD solutions may represent a promising strategy to attenuate some of these adverse effects. However, the impact of these novel solutions on clinical outcomes remains largely unknown. In this review, we will highlight evidence regarding the biocompatibility of NpHL(GDP) PD solutions, review the utility of current biomarkers in the evaluation of biocompatibility, and discuss the clinical outcome data with these solutions. PMID- 21248713 TI - Persistent proteinuria and dyslipidemia increase the risk of progressive chronic kidney disease in lupus erythematosus. AB - Advances in immunotherapy have improved survival of patients with systemic lupus erythematosus who now face an increasing burden of chronic diseases including that of the kidney. As systemic inflammation is also thought to contribute directly to the progression of chronic kidney disease (CKD), we assessed this risk in patients with lupus, with and without a diagnosis of nephritis, and also identified modifiable risk factors. Accordingly, we enrolled 631 patients (predominantly Caucasian), of whom 504 were diagnosed with lupus within the first year and followed them an average of 11 years. Despite the presence of a chronic inflammatory disease, the rate of decline in renal function of 238 patients without nephritis was similar to that described for non-lupus patient cohorts. Progressive loss of kidney function developed exclusively in patients with lupus nephritis who had persistent proteinuria and dyslipidemia, although only six required dialysis or transplantation. The mortality rate was 16% with half of the deaths attributable to sepsis or cancer. Thus, despite the presence of a systemic inflammatory disease, the risk of progressive CKD in this lupus cohort was relatively low in the absence of nephritis. Hence, as in idiopathic glomerular disease, persistent proteinuria and dyslipidemia (modifiable risks) are the major factors for CKD progression in lupus patients with renal involvement. PMID- 21248714 TI - The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice. AB - Aging is thought to be associated with a higher susceptibility to renal ischemia reperfusion injury (IRI). To study whether defective induction of hemeoxygenase-1 (HO-1, a protective and anti-inflammatory enzyme) might contribute to this, we found that while 12-month-old mice had similar baseline renal function and HO-1 expression, the induction of HO-1 usually seen in ischemia-reperfusion was reduced. This was also associated with worsened renal function and acute tubular necrosis in the aged compared with young mice. In the older mice, heme arginate (HA) induced HO-1 in the cortex and medulla, significantly improved renal function, and reduced tissue injury. Cellular HO-1 induction in the medulla in response to injury or HA treatment was found to be interstitial rather than epithelial, as evidenced by its colocalization with macrophage markers. In vitro, HA treatment of primary macrophages resulted in marked HO-1 induction without impairment of classical activation pathways. Macrophage depletion, caused by diphtheria toxin treatment of 12-month-old CD11b-DTR transgenic animals, resulted in the loss of interstitial HO-1-positive cells and reversal of the protective phenotype of HA treatment. Thus, failure of HO-1 induction following renal IRI worsens structural and functional injury in older mice and represents a therapeutic target in the elderly. Hence, HO-1-positive renal macrophages mediate HA-induced protection in IRI. PMID- 21248715 TI - Endogenous foxp3(+) T-regulatory cells suppress anti-glomerular basement membrane nephritis. AB - Foxp3(+) T-regulatory cells (Tregs) may suppress pathogenic inflammation; however, although transferred Tregs lessen glomerulonephritis in mice, the role of endogenous foxp3(+) cells is not known. To study this, we characterized endogenous foxp3(+) cells in accelerated anti-glomerular basement membrane (GBM) nephritis by using foxp3(GFP) reporter mice to track their responses in early and established disease. Further, diphtheria toxin was used to ablate foxp3(+) Tregs in foxp3(DTR) mice after establishing an immune response. In this model, mice were immunized with sheep globulin in adjuvant, and sheep anti-mouse GBM globulin was injected after 4 days to initiate progressive histological and functional injury. Intrarenal leukocytic infiltrates were increased by day 3 but intrarenal foxp3(+) Tregs, present in interstitial and periglomerular areas, were only increased at day 7. Ablation of foxp3(+) Tregs after injection of anti-GBM globulin increased renal injury and systemic T-cell responses, including increased interferon-gamma and interleukin-17A (IL-17A) production, but no change in antibody titers. Compared with foxp3(+) Tregs isolated from naive mice, those from immunized mice produced more IL-10 and more effectively regulated CD4(+)foxp3(-) responder T cells. Thus, endogenous foxp3(+) Tregs infiltrate the kidney in glomerulonephritis, and deleting foxp3(+) cells after the induction of immune responses upregulated T-cell reactions and enhanced disease. Hence, endogenous foxp3(+) cells have increased suppressive capacity after immune stimuli. PMID- 21248716 TI - Renal transplantation in HIV-infected patients: 2010 update. AB - The prognosis of human immunodeficiency virus (HIV) infection has improved in recent years with the introduction of antiretroviral treatment. While the frequency of AIDS-defining events has decreased as a cause of death, mortality from non-AIDS-related events including end-stage renal diseases has increased. The etiology of chronic kidney disease is multifactorial: immune-mediated glomerulonephritis, HIV-associated nephropathy, thrombotic microangiopathies, and so on. HIV infection is no longer a contraindication to transplantation and is becoming standard therapy in most developed countries. The HIV criteria used to select patients for renal transplantation are similar in Europe and North America. Current criteria state that prior opportunistic infections are not a strict exclusion criterion, but patients must have a CD4+ count above 200 cells/mm(3) and a HIV-1 RNA viral load suppressible with treatment. In recent years, more than 200 renal transplants have been performed in HIV-infected patients worldwide, and mid-term patient and graft survival rates have been similar to that of HIV-negative patients. The main issues in post-transplant period are pharmacokinetic interactions between antiretrovirals and immunosuppressants, a high rate of acute rejection, the management of hepatitis C virus coinfection, and the high cardiovascular risk after transplantation. More studies are needed to determine the most appropriate antiretroviral and immunosuppressive regimens and the long-term outcome of HIV infection and kidney graft. PMID- 21248717 TI - Low-protein diet supplemented with ketoacids reduces the severity of renal disease in 5/6 nephrectomized rats: a role for KLF15. AB - Dietary protein restriction is an important treatment for chronic kidney disease. Herein, we tested the effect of low-protein or low-protein plus ketoacids (KA) diet in a remnant kidney model. Rats with a remnant kidney were randomized to receive normal protein diet (22%), low-protein (6%) diet (LPD), or low-protein (5%) plus KA (1%) diet for 6 months. Protein restriction prevented proteinuria, decreased blood urea nitrogen levels, and renal lesions; however, the LPD retarded growth and decreased serum albumin levels. Supplementation with KA corrected these abnormalities and provided superior renal protection compared with protein restriction alone. The levels of Kruppel-like factor-15 (KLF15), a transcription factor shown to reduce cardiac fibrosis, were decreased in remnant kidneys. Protein restriction, which increased KLF15 levels in the normal kidney, partially recovered the levels of KLF15 in remnant kidney. The expression of KLF15 in mesangial cells was repressed by oxidative stress, transforming growth factor-beta, and tumor necrosis factor (TNF)-alpha. The suppressive effect of TNF alpha on KLF15 expression was mediated by TNF receptor-1 and nuclear factor kappaB. Overexpression of KLF15 in mesangial and HEK293 cells significantly decreased fibronectin and type IV collagen mRNA levels. Furthermore, KLF15 knockout mice developed glomerulosclerosis following uninephrectomy. Thus, KLF15 may be an antifibrotic factor in the kidney, and its decreased expression may contribute to the progression of kidney disease. PMID- 21248718 TI - Kidney preservation by bone marrow cell transplantation in hereditary nephropathy. AB - The prospect of cell-based therapy for kidney disease remains controversial despite its immense promise. We had previously shown that transplanting bone marrow and hematopoietic stem cells could generate renal cells and lead to the preservation of kidney function in a mouse model for cystinosis (Ctns(-/-)) that develops chronic kidney injury, 4 months post transplantation. Here, we determined the long-term effects of bone marrow stem cell transplantation on the kidney disease of Ctns(-/-) mice 7 to 15 months post transplantation. Transfer of bone marrow stem cells expressing a functional Ctns gene provided long-term protection to the kidney. Effective therapy, however, depended on achieving a relatively high level of donor-derived blood cell engraftment of Ctns-expressing cells, which was directly linked to the quantity of these cells within the kidney. In contrast, kidney preservation was dependent neither on renal cystine content nor on the age of the mice at the time of transplant. Most of the bone marrow-derived cells within the kidney were interstitial and not epithelial, suggesting that the mechanism involved an indirect protection of the tubules. Thus, our model may help in developing strategies to enhance the potential success of cell-based therapy for kidney injury and in understanding some of the discrepancies currently existing in the field. PMID- 21248719 TI - Selective deletion of a cell cycle checkpoint kinase (ATR) reduces neurogenesis and alters responses in rodent models of behavioral affect. AB - Hippocampal function has been implicated in mood and anxiety disorders, as well as in the response to antidepressant (AD) treatment. However, the significance of new neurons in the therapeutic mechanism of ADs remains unclear. In this study, the proliferation of new neurons was inhibited through conditional deletion of ataxia telangeictasia-mutated and rad-3 related (ATR), a cell cycle checkpoint kinase, and cellular and behavioral outcomes following AD exposure were evaluated. ATR was conditionally deleted by microinjecting a Cre recombinase expressing virus into the hippocampus of floxed-ATR mice. Behavioral assessment in multiple rodent models of affective state revealed anxiolytic-like behavior in the elevated zero maze, marble burying test, and novelty-induced hypophagia (NIH) test. The efficacy of chronic desipramine (DMI) treatment was evaluated in the NIH test, as this paradigm is thought to be sensitive to increases in neurogenesis by chronic AD exposure. Chronic exposure to DMI reduced hyponeophagia in the NIH test in control mice, whereas DMI had no behavioral effect in ATR-deleted mice. Although DMI did not alter cell proliferation in either group, it did produce a robust increase in dendritic spine density in control mice, indicative of enhanced neuronal plasticity. This effect of DMI on spine density was severely attenuated following ATR deletion. These findings demonstrate that reductions in basal neurogenesis produce an anxiolytic phenotype and reduce AD efficacy in behaviors requiring chronic exposure. Furthermore, attenuated capacity for synaptic remodeling may underlie these behaviors. ATR deletion may serve as a valuable model to study the various proposed roles of newborn neurons in the hippocampus. PMID- 21248721 TI - Discrete forebrain neuronal networks supporting noradrenergic regulation of sensorimotor gating. AB - Prepulse inhibition (PPI) refers to the reduction in the startle response when a startling stimulus is preceded by a weak prestimulus, and is an endophenotype of deficient sensorimotor gating in several neuropsychiatric disorders. Emerging evidence suggests that norepinephrine (NE) regulates PPI, however, the circuitry involved is unknown. We found recently that stimulation of the locus coeruleus (LC), the primary source of NE to the forebrain, induces a PPI deficit that is a result of downstream NE release. Hence, this study sought to identify LC innervated forebrain regions that mediate this effect. Separate groups of male Sprague-Dawley rats received a cocktail solution of the alpha1-NE receptor agonist phenylephrine plus the beta-receptor agonist isoproterenol (equal parts of each; 0, 3, 10, and 30 MUg) into subregions of the medial prefrontal cortex (mPFC), nucleus accumbens (NAcc), extended amygdala, mediodorsal thalamus (MD thalamus), or the dorsal hippocampus (DH) before PPI testing. NE agonist infusion into the posterior mPFC, NAcc shell, bed nucleus of the stria terminalis, basolateral amygdala, and the MD-thalamus disrupted PPI, with particularly strong effects in MD-thalamus. Sites in which NE receptor stimulation did not disrupt PPI (anterior mPFC, NAcc core, central amygdala, and DH) did support PPI disruptions with the dopamine D2 receptor agonist quinpirole (0, 10 MUg). This pattern reveals new pathways in the regulation of PPI, and suggests that NE transmission within distinct thalamocortical and ventral forebrain networks may subserve the sensorimotor gating deficits that are seen in disorders such as schizophrenia, Tourette syndrome, and post-traumatic stress disorder. PMID- 21248720 TI - In vivo ethanol experience increases D(2) autoinhibition in the ventral tegmental area. AB - Alcoholism is characterized by compulsive alcohol intake after a history of chronic consumption. A reduction in mesolimbic dopaminergic transmission observed during abstinence may contribute to the negative affective state that drives compulsive intake. Although previous in vivo recording studies in rodents have demonstrated profound decreases in the firing activity of ventral tegmental area (VTA) dopamine neurons after withdrawal from long-term ethanol exposure, the cellular mechanisms underlying this reduced activity are not well understood. Somatodendritic dopamine release within the VTA exerts powerful feedback inhibition of dopamine neuron activity via stimulation of D(2) autoreceptors and subsequent activation of G protein-gated inwardly rectifying K(+) (GIRK) channels. Here, by performing patch-clamp recordings from putative dopamine neurons in the VTA of mouse brain slices, we show that D(2) receptor/GIRK mediated inhibition becomes more potent and exhibits less desensitization after withdrawal from repeated in vivo ethanol exposure (2 g/kg, i.p., three times daily for 7 days). In contrast, GABA(B) receptor/GIRK-mediated inhibition and its desensitization are not affected. Chelating cytosolic Ca(2+) with BAPTA augments D(2) inhibition and suppresses its desensitization in control mice, while these effects of BAPTA are occluded in ethanol-treated mice. Furthermore, inositol 1,4,5-trisphosphate (IP(3))-induced intracellular Ca(2+) release and Ca(2+)/calmodulin-dependent protein kinase II are selectively involved in the desensitization of D(2), but not GABA(B), receptor signaling. Consistent with this, activation of metabotropic glutamate receptors that are coupled to IP(3) generation leads to cross-desensitization of D(2)/GIRK-mediated responses. We propose that enhancement of D(2) receptor-mediated autoinhibition via attenuation of a Ca(2+)-dependent desensitization mechanism may contribute to the hypodopaminergic state during ethanol withdrawal. PMID- 21248722 TI - Effects of stimulant medication, incentives, and event rate on reaction time variability in children with ADHD. AB - This study examined the effects of methylphenidate (MPH) on reaction time (RT) variability in children with attention deficit hyperactivity disorder (ADHD). Using a broad battery of computerized tasks, and both conventional and ex Gaussian indicators of RT variability, in addition to within-task manipulations of incentive and event rate (ER), this study comprehensively examined the breadth, specificity, and possible moderators of effects of MPH on RT variability. A total of 93 children with ADHD completed a 4-week within-subject, randomized, double-blind, placebo-controlled crossover trial of MPH to identify an optimal dosage. Children were then randomly assigned to receive either their optimal MPH dose or placebo after which they completed five neuropsychological tasks, each allowing trial-by-trial assessment of RTs. Stimulant effects on RT variability were observed on both measures of the total RT distribution (ie, coefficient of variation) as well as on an ex-Gaussian measure examining the exponential portion of the RT distribution (ie, tau). There was minimal, if any, effect of MPH on performance accuracy or RT speed. Within-task incentive and ER manipulations did not appreciably affect stimulant effects across the tasks. The pattern of significant and pervasive effects of MPH on RT variability, and few effects of MPH on accuracy and RT speed suggest that MPH primarily affects RT variability. Given the magnitude and breadth of effects of MPH on RT variability as well as the apparent specificity of these effects of MPH on RT variability indicators, future research should focus on neurophysiological correlates of effects of MPH on RT variability in an effort to better define MPH pharmacodynamics. PMID- 21248723 TI - Key questions to guide a better understanding of host-commensal microbiota interactions in intestinal inflammation. AB - Co-evolution with an extremely complex commensal enteric microbiota has helped shape mammalian mucosal immune responses. A yet incompletely defined subset of intestinal bacteria is required to stimulate chronic, immune-mediated intestinal inflammation, including human Crohn's disease, and intestinal microbiota composition is altered in a characteristic manner by the inflammatory response to create a dysbiotic relationship of protective vs. aggressive bacteria. We pose a number of questions regarding host interactions with the enteric microbiota, including influences of inflammation, host genetics, early environmental exposure, and diet on microbial composition and function, and conversely, the effect of bacterial metabolism, enteric fungi and viruses, and endogenous protective bacterial species on host immune and inflammatory responses. These questions are designed to stimulate research that will promote a better understanding of host-microbial interactions in the intestine and promote targeted novel therapeutic interventions. PMID- 21248724 TI - A complex relationship: the interaction among symbiotic microbes, invading pathogens, and their mammalian host. AB - Symbiosis between microbes and their mammalian host is vital to maintaining homeostasis. Symbiotic microbes within the gastrointestinal tract provide an array of benefits to the host, including promotion of host immunity. A coordinated effort of the host and symbiotic microbes deters the colonization and survival of many invading pathogens. However, pathogens have devised strategies to overcome these mechanisms. Furthermore, some pathogens can hijack host hormones and bacterial autoinducers to induce virulence traits. Intra- and inter species (bacteria/bacteria) and interkingdom (bacteria/host) communication orchestrates the complex relationship among symbiotic microbes, invading pathogens, and their mammalian host. Insight into this communication will provide a foundation for the development of targeted antimicrobial therapies. PMID- 21248725 TI - Epigenetic regulation of human beta-defensin 2 and CC chemokine ligand 20 expression in gingival epithelial cells in response to oral bacteria. AB - Gingival epithelia utilize multiple signaling pathways to regulate innate immune responses to various oral bacteria, but little is understood about how these bacteria alter epithelial epigenetic status. In this study we report that DNA methyltransferase (DNMT1) and histone deacetylase expression were decreased in gingival epithelial cells treated with oral pathogen Porphyromonas gingivalis and nonpathogen Fusobacterium nucleatum. Pretreatment with trichostatin A and sodium butyrate, which increase acetylation of chromatin histones, significantly enhanced the gene expression of antimicrobial proteins human beta-defensin 2 (hBD2) and CC chemokine ligand 20 (CCL20) in response to both bacterial challenges. Pretreatment with DNMT inhibitor 5'-azacytidine increased hBD2 and CCL20 expression in response to F. nucleatum, but not to P. gingivalis. Furthermore, we observed a differential pattern of protein levels of H3K4me3, which has been associated with chromatin remodeling and activation of gene transcription, in response to P. gingivalis vs. F. nucleatum. This study provides a new insight into the bacteria-specific innate immune responses via epigenetic regulation. PMID- 21248727 TI - CYP2D6 in the brain: impact on suicidality. PMID- 21248726 TI - The emerging role of electronic medical records in pharmacogenomics. AB - Health-care information technology and genotyping technology are both advancing rapidly, creating new opportunities for medical and scientific discovery. The convergence of these two technologies is now facilitating genetic association studies of unprecedented size within the context of routine clinical care. As a result, the medical community will soon be presented with a number of novel opportunities to bring functional genomics to the bedside in the area of pharmacotherapy. By linking biological material to comprehensive medical records, large multi-institutional biobanks are now poised to advance the field of pharmacogenomics through three distinct mechanisms: (i) retrospective assessment of previously known findings in a clinical practice-based setting, (ii) discovery of new associations in huge observational cohorts, and (iii) prospective application in a setting capable of providing real-time decision support. This review explores each of these translational mechanisms within a historical framework. PMID- 21248728 TI - The emerging therapeutic role of RNA interference in disorders of the central nervous system. PMID- 21248729 TI - Highlights: Are race and ethnicity playing a useful structural role in epidemiologic research? PMID- 21248730 TI - What is the best path length for aortic pulse wave velocity? Preliminary answer to a stiff question. PMID- 21248733 TI - Clinical utility gene card for: alpha-1-antitrypsin deficiency. PMID- 21248734 TI - Genome-wide analysis of genetic susceptibility to language impairment in an isolated Chilean population. AB - Specific language impairment (SLI) is an unexpected deficit in the acquisition of language skills and affects between 5 and 8% of pre-school children. Despite its prevalence and high heritability, our understanding of the aetiology of this disorder is only emerging. In this paper, we apply genome-wide techniques to investigate an isolated Chilean population who exhibit an increased frequency of SLI. Loss of heterozygosity (LOH) mapping and parametric and non-parametric linkage analyses indicate that complex genetic factors are likely to underlie susceptibility to SLI in this population. Across all analyses performed, the most consistently implicated locus was on chromosome 7q. This locus achieved highly significant linkage under all three non-parametric models (max NPL = 6.73, P = 4.0 * 10(-11)). In addition, it yielded a HLOD of 1.24 in the recessive parametric linkage analyses and contained a segment that was homozygous in two affected individuals. Further, investigation of this region identified a two-SNP haplotype that occurs at an increased frequency in language-impaired individuals (P = 0.008). We hypothesise that the linkage regions identified here, in particular that on chromosome 7, may contain variants that underlie the high prevalence of SLI observed in this isolated population and may be of relevance to other populations affected by language impairments. PMID- 21248735 TI - Clinical utility gene card for: Diamond Blackfan anemia. PMID- 21248736 TI - Beckwith-Wiedemann syndrome and uniparental disomy 11p: fine mapping of the recombination breakpoints and evaluation of several techniques. AB - Beckwith-Wiedemann syndrome (BWS) is a phenotypically and genotypically heterogeneous overgrowth syndrome characterized by somatic overgrowth, macroglossia and abdominal wall defects. Other usual findings are hemihyperplasia, embryonal tumours, adrenocortical cytomegaly, ear anomalies, visceromegaly, renal abnormalities, neonatal hypoglycaemia, cleft palate, polydactyly and a positive family history. BWS is a complex, multigenic disorder associated, in up to 90% of patients, with alteration in the expression or function of one or more genes in the 11p15.5 imprinted gene cluster. There are several molecular anomalies associated with BWS and the large proportion of cases, about 85%, is sporadic and karyotypically normal. One of the major categories of BWS molecular alteration (10-20% of cases) is represented by mosaic paternal uniparental disomy (pUPD), namely patients with two paternally derived copies of chromosome 11p15 and no maternal contribution for that. In these patients, in addition to the effects of IGF2 overexpression, a decreased level of the maternally expressed gene CDKN1C may contribute to the BWS phenotype. In this paper, we reviewed a series of nine patients with BWS because of pUPD using several methods with the aim to evaluate the percentage of mosaicism, the methylation status at both loci, the extension of the pUPD at the short arm and the breakpoints of recombination. Fine mapping of mitotic recombination breakpoints by single-nucleotide polymorphism-array in individuals with UPD and fine estimation of epigenetic defects will provide a basis for understanding the aetiology of BWS, allowing more accurate prognostic predictions and facilitating management and surveillance of individuals with this disorder. PMID- 21248737 TI - Relationship between the polymorphism of tumor necrosis factor-alpha-308 G>A and susceptibility to inflammatory bowel diseases and colorectal cancer: a meta analysis. AB - Inflammatory bowel disease (IBD) and colorectal cancer (CRC) are common health problems worldwide. Tumor necrosis factor (TNF) is a type of cytokine that induces inflammation and inhibits tumorigenesis. Several studies have assessed the relationship between the polymorphism of TNF-alpha-308 G>A and the susceptibility to IBD and CRC; however, the results have been controversial. In addition, the hypothesis whether the increased risk of CRC in IBD patients could be partly ascribed to the polymorphism of TNF-alpha-308 G>A was unclear. Therefore, we conducted this meta-analysis to confirm these associations. Pooled odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated on the basis of data from 14, 18, and 7 studies from a total of 27 studies for the associations between the polymorphism of TNF-alpha-308 G>A and ulcerative colitis, Crohn's disease (CD) and CRC. In Europeans, the AA genotype increased the risk of ulcerative colitis (UC) (OR, 2.041; 95% CI, 1.261-3.301) and CD (OR, 1.730; 95% CI, 1.168-2.564) significantly, without obvious heterogeneity and publication bias. Meanwhile, the GA genotype increased the risk of UC in Asians (OR, 2.360; 95% CI, 1.269-4.390) significantly. However, no significant association was observed for CRC in any ethnic population. The results of this meta-analysis suggested that the polymorphism of TNF-alpha-308 G>A participates in modifying the susceptibility to UC and CD in Europeans and Asians. The increased risk of CRC in IBD patients should be clarified as the combined effects of polymorphisms in TNF-alpha and other cytokines, and the interaction with environmental factors, in future studies. PMID- 21248738 TI - Clinical utility gene card for: malignant hyperthermia. PMID- 21248739 TI - ALK2 mutation in a patient with Down's syndrome and a congenital heart defect. AB - Down's syndrome (DS), resulting from an additional copy of chromosome 21 (trisomy 21), is frequently associated with congenital heart defects (CHDs). Although the increased dosage of chromosome 21 sequences is likely to be part of the etiology of cardiac defects, only a proportion of DS patients exhibit a congenital heart defect (birth prevalence 40-60%). Through a large-candidate gene-sequencing screen in patients with atrioventricular septal defects, substitutions were identified in bone morphogenetic protein (BMP) type I receptor ALK2 and two other genes in a patient with DS and a primum-type atrial septal defect. Structural modeling of the cytoplasmic domain of the ALK2 receptor suggests that H286 is in close proximity to the nucleotide-binding site of the kinase domain. We investigated whether this p.His286Asp substitution altered ALK2 function by using both in vitro as well as in vivo assays. The p.His286Asp variant demonstrated impaired functional activity as measured by BMP-specific transcriptional response assays. Furthermore, mild dominant-interfering activity was observed in vivo compared with wild-type ALK2 as determined by RNA injection into zebrafish embryos. These data indicate that in the context of a DS background, ALK2 mediated reduction of BMP signaling may contribute to CHDs. PMID- 21248741 TI - Three novel mutations in the ACTA2 gene in German patients with thoracic aortic aneurysms and dissections. AB - Mutations in the gene encoding smooth muscle cell alpha actin (ACTA2) have recently been shown to cause familial thoracic aortic aneurysms leading to type A dissections (TAAD) and predispose to premature stroke and coronary artery disease. In order to further explore the role of ACTA2 variations in the pathogenesis of TAAD, we sequenced the coding regions of this gene in 40 unrelated German patients with TAAD (with (n=21) or without (n=19) clinical features suggestive of Marfan syndrome). All patients had previously tested negative for mutations in the FBN1 and TGFBR2 genes. We identified three novel ACTA2 mutations and mapped them on a three-dimensional model of actin. Two mutations affect residues within (M49V) or adjacent to (R39C), the DNAse-I binding loop within subdomain 2 of alpha actin. They were observed in families with recurrent aortic aneurysm (R39C) or aortic dissection (M49V). The third mutation causes an exchange in the vicinity of the ATP-binding site (G304R) in a patient thought to have isolated TAAD. None of the affected individuals had clinical features typical for Marfan syndrome, and no case of premature stroke or coronary artery disease was reported from the affected families. In conclusion, we underscore the role of ACTA2 mutations in nonsyndromic TAAD and suggest that ACTA2 should be included in the genes routinely investigated for syndromic and nonsyndromic TAAD. Detailed clinical investigations of additional families are warranted to further explore the full range of phenotypic signs associated with the three novel mutations described here. PMID- 21248740 TI - Genome-wide association study confirms extant PD risk loci among the Dutch. AB - In view of the population-specific heterogeneity in reported genetic risk factors for Parkinson's disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514,799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P = 1.63 * 10(-5), OR = 1.325 and BST1, rs12502586: P = 1.63 * 10(-3), OR = 1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3' and 5' ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P = 1.22 * 10(-4), OR = 1.51; HLA, rs4248166: P = 4.39 * 10(-5), OR = 1.36; and MAPT, rs3785880: P = 1.9 * 10(-3), OR = 1.19). PMID- 21248742 TI - HTT haplotypes contribute to differences in Huntington disease prevalence between Europe and East Asia. AB - Huntington disease (HD) results from CAG expansion in the huntingtin (HTT) gene. Although HD occurs worldwide, there are large geographic differences in its prevalence. The prevalence in populations derived from Europe is 10-100 times greater than in East Asia. The European general population chromosomes can be grouped into three major haplogroups (group of similar haplotypes): A, B and C. The majority of HD chromosomes in Europe are found on haplogroup A. However, in the East-Asian populations of China and Japan, we find the majority of HD chromosomes are associated with haplogroup C. The highest risk HD haplotypes (A1 and A2), are absent from the general and HD populations of China and Japan, and therefore provide an explanation for why HD prevalence is low in East Asia. Interestingly, both East-Asian and European populations share a similar low level of HD on haplogroup C. Our data are consistent with the hypothesis that different HTT haplotypes have different mutation rates, and geographic differences in HTT haplotypes explain the difference in HD prevalence. Further, the bias for expansion on haplogroup C in the East-Asian population cannot be explained by a higher average CAG size, as haplogroup C has a lower average CAG size in the general East-Asian population compared with other haplogroups. This finding suggests that CAG-tract size is not the only factor important for CAG instability. Instead, the expansion bias may be because of genetic cis-elements within the haplotype that influence CAG instability in HTT, possibly through different mutational mechanisms for the different haplogroups. PMID- 21248743 TI - Homozygosity mapping in outbred families with mental retardation. AB - Autosomal recessive mental retardation (AR-MR) may account for up to 25% of genetic mental retardation (MR). So far, mapping of AR-MR genes in consanguineous families has resulted in six nonsyndromic genes, whereas more than 2000 genes might contribute to AR-MR. We propose to use outbred families with multiple affected siblings for AR-MR gene identification. Homozygosity mapping in ten outbred families with affected brother-sister pairs using a 250 K single nucleotide polymorphism array revealed on average 57 homozygous regions over 1 Mb in size per affected individual (range 20-74). Of these, 21 homozygous regions were shared between siblings on average (range 8-36). None of the shared regions of homozygosity (SROHs) overlapped with the nonsyndromic genes. A total of 13 SROHs had an overlap with previously reported loci for AR-MR, namely with MRT8, MRT9, MRT10 and MRT11. Among these was the longest observed SROH of 11.0 Mb in family ARMR1 on chromosome 19q13, which had 2.9 Mb (98 genes) in common with the 5.4 Mb MRT11 locus (195 genes). These data support that homozygosity mapping in outbred families may contribute to identification of novel AR-MR genes. PMID- 21248744 TI - Breast and ovarian cancer screening of non-carriers from BRCA1/2 mutation positive families: 2-year follow-up of cohorts from France and Quebec. AB - We described and compared breast and ovarian screening practices in the 2-year period following test result disclosure in female non-carriers from BRCA1/2 mutation-positive families living in two countries, France and Quebec, Canada, which provide universal health care. Four hundred and two (France n=293; Quebec n=109) unaffected female non-carriers from BRCA-proven mutation families provided information about the uptake of mammography, clinical breast examination, breast self-examination, and ovarian ultrasounds using self-administered questionnaires. The frequency of screening practices between study cohorts were compared using logistic regression. Annual mammography was conducted in 23 and 43% of French and Quebecer women participants <50 years of age, respectively (adjusted odds ratio (aOR)=2.72; 95% confidence interval (CI), 1.08-6.81). In women >= 50 years of age, mammography was conducted in 49 and 65% of French and Quebecer participants (aOR=1.77; 95% CI, 0.07-4.51). Overall, 33% of French women and 39% of Quebecer women underwent at least one ovarian ultrasound during the 2-year period following BRCA1/2 test result with no significant difference between cohorts of women < 50 years of age. Among older women, Quebecers reported more frequently than French women that they had undergone ultrasound once (aOR=3.00; 95% CI, 1.02 8.83). The frequency of cancer screening practices for female non-carriers from BRCA1/2 mutation-positive families in both France and Quebec exceeded those recommended for similarly aged women in the general population. Our findings highlight the need for clearcut recommendations on the follow-up of women from BRCA1/2 families who are not themselves carriers of a BRCA1/2 mutation. PMID- 21248745 TI - Craniosynostosis. AB - Craniosynostosis, defined as the premature fusion of the cranial sutures, presents many challenges in classification and treatment. At least 20% of cases are caused by specific single gene mutations or chromosome abnormalities. This article maps out approaches to clinical assessment of a child presenting with an unusual head shape, and illustrates how genetic analysis can contribute to diagnosis and management. PMID- 21248746 TI - Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene. AB - Mutation of the LARGE gene is the rarest of the six known genetic causes of alpha dystroglycanopathy. We report further a family with MDC1D due to a complex genomic rearrangement that was not apparent on standard sequencing of LARGE. Two sisters in a consanguineous family had moderate mental retardation and cerebellar malformations, together with dystrophic changes and markedly reduced alpha dystroglycan glycosylation staining on muscle biopsy. There was homozygous linkage to the LARGE locus but sequencing of LARGE coding regions was normal. Analysis of LARGE cDNA showed an abnormal sequence inserted between exons 10 and 11, in most of the transcripts, predicted to introduce a premature stop codon. The abnormal sequence mapped to a spliced EST (DA935254) of unknown function, normally located at 100 kb centromeric of LARGE on chromosome 22q12.3. Quantitative PCR analysis of the EST and adjacent regions showed twice the normal copy number in patients' genomic DNA samples, consistent with a large intra chromosomal duplication inserted into intron 10 of LARGE in a homozygous state. This insertion was associated with deletion of a central region of intron 10, but the exact break points of the deletion/duplication were not found, suggesting that an even more complex rearrangement may have occurred. The exact function of LARGE, a golgi protein, remains uncertain. POMT and POMGnT enzyme activities were normal in patients' lymphoblast cells, suggesting that defects in LARGE do not affect the initiation of O-mannosyl glycans. PMID- 21248747 TI - Association of a variant in the CHRNA5-A3-B4 gene cluster region to heavy smoking in the Italian population. AB - Large-scale population studies have established that genetic factors contribute to individual differences in smoking behavior. Linkage and genome-wide association studies have shown many chromosomal regions and genes associated with different smoking behaviors. One study was the association of single-nucleotide polymorphisms (SNPs) in the CHRNA5-A3-B4 gene cluster to nicotine addiction. Here, we report a replication of this association in the Italian population represented by three genetically isolated populations. One, the Val Borbera, is a genetic isolate from North-Western Italy; the Cilento population, is located in South-Western Italy; and the Carlantino village is located in South-Eastern Italy. Owing to their position and their isolation, the three populations have a different environment, different history and genetic structure. The variant A of the rs1051730 SNP was significantly associated with smoking quantity in two populations, Val Borbera and Cilento, no association was found in Carlantino population probably because difference in LD pattern in the variant region. PMID- 21248748 TI - The phenotype of recurrent 10q22q23 deletions and duplications. AB - The genomic architecture of the 10q22q23 region is characterised by two low-copy repeats (LCRs3 and 4), and deletions in this region appear to be rare. We report the clinical and molecular characterisation of eight novel deletions and six duplications within the 10q22.3q23.3 region. Five deletions and three duplications occur between LCRs3 and 4, whereas three deletions and three duplications have unique breakpoints. Most of the individuals with the LCR3-4 deletion had developmental delay, mainly affecting speech. In addition, macrocephaly, mild facial dysmorphisms, cerebellar anomalies, cardiac defects and congenital breast aplasia were observed. For congenital breast aplasia, the NRG3 gene, known to be involved in early mammary gland development in mice, is a putative candidate gene. For cardiac defects, BMPR1A and GRID1 are putative candidate genes because of their association with cardiac structure and function. Duplications between LCRs3 and 4 are associated with variable phenotypic penetrance. Probands had speech and/or motor delays and dysmorphisms including a broad forehead, deep-set eyes, upslanting palpebral fissures, a smooth philtrum and a thin upper lip. In conclusion, duplications between LCRs3 and 4 on 10q22.3q23.2 may lead to a distinct facial appearance and delays in speech and motor development. However, the phenotypic spectrum is broad, and duplications have also been found in healthy family members of a proband. Reciprocal deletions lead to speech and language delay, mild facial dysmorphisms and, in some individuals, to cerebellar, breast developmental and cardiac defects. PMID- 21248749 TI - Deletions flanked by breakpoints 3 and 4 on 15q13 may contribute to abnormal phenotypes. AB - Non-allelic homologous recombination (NAHR) between segmental duplications in proximal chromosome 15q breakpoint (BP) regions can lead to microdeletions and microduplications. Several individuals with deletions flanked by BP3 and BP4 on 15q13, immediately distal to, and not including the Prader-Willi/Angelman syndrome (PW/AS) critical region and proximal to the BP4-BP5 15q13.3 microdeletion syndrome region, have been reported; however, because the deletion has also been found in normal relatives, the significance of these alterations is unclear. We have identified six individuals with deletions limited to the BP3-BP4 interval and an additional four individuals with deletions of the BP3-BP5 interval from 34 046 samples submitted for clinical testing by microarray-based comparative genomic hybridization (aCGH). Of four individuals with BP3-BP4 deletions for whom parental testing was conducted, two were apparently de novo and two were maternally inherited. A comparison of clinical features, available for five individuals in our study (four with deletions within BP3-BP4 and one with a BP3-BP5 deletion), with those in the literature show common features of short stature and/or failure to thrive, microcephaly, hypotonia, and premature breast development in some individuals. Although the BP3-BP4 deletion does not yet demonstrate statistically significant enrichment in abnormal populations compared with control populations, the presence of common clinical features among probands and the presence of genes with roles in development and nervous system function in the deletion region suggest that this deletion may have a role in abnormal phenotypes in some individuals. PMID- 21248750 TI - Interferon-gamma links ultraviolet radiation to melanomagenesis in mice. AB - Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood. We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and aetiological criteria, but only when irradiated as neonatal pups with UVB, not UVA. However, the mechanisms underlying UVB-initiated, neonatal-specific melanomagenesis remain largely unknown. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody mediated systemic blockade of interferon-gamma (IFN-gamma), but not type-I interferons. IFN-gamma was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-gamma blockade abolished macrophage-enhanced melanoma growth and survival. IFN-gamma-producing macrophages were also identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-gamma in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients. PMID- 21248751 TI - Entanglement in a solid-state spin ensemble. AB - Entanglement is the quintessential quantum phenomenon. It is a necessary ingredient in most emerging quantum technologies, including quantum repeaters, quantum information processing and the strongest forms of quantum cryptography. Spin ensembles, such as those used in liquid-state nuclear magnetic resonance, have been important for the development of quantum control methods. However, these demonstrations contain no entanglement and ultimately constitute classical simulations of quantum algorithms. Here we report the on-demand generation of entanglement between an ensemble of electron and nuclear spins in isotopically engineered, phosphorus-doped silicon. We combined high-field (3.4 T), low temperature (2.9 K) electron spin resonance with hyperpolarization of the (31)P nuclear spin to obtain an initial state of sufficient purity to create a non classical, inseparable state. The state was verified using density matrix tomography based on geometric phase gates, and had a fidelity of 98% relative to the ideal state at this field and temperature. The entanglement operation was performed simultaneously, with high fidelity, on 10(10) spin pairs; this fulfils one of the essential requirements for a silicon-based quantum information processor. PMID- 21248752 TI - Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. AB - The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ~3,500 genes by PCR-based exon re sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology. PMID- 21248753 TI - Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription. AB - The ability to direct functional proteins to specific DNA sequences is a long sought goal in the study and engineering of biological processes. Transcription activator-like effectors (TALEs) from Xanthomonas sp. are site-specific DNA binding proteins that can be readily designed to target new sequences. Because TALEs contain a large number of repeat domains, it can be difficult to synthesize new variants. Here we describe a method that overcomes this problem. We leverage codon degeneracy and type IIs restriction enzymes to generate orthogonal ligation linkers between individual repeat monomers, thus allowing full-length, customized, repeat domains to be constructed by hierarchical ligation. We synthesized 17 TALEs that are customized to recognize specific DNA-binding sites, and demonstrate that they can specifically modulate transcription of endogenous genes (SOX2 and KLF4) in human cells. PMID- 21248754 TI - Role of mineralocorticoid receptor on atrial structural remodeling and inducibility of atrial fibrillation in hypertensive rats. AB - Hypertension is well known to increase atrial fibrillation (AF) and the development of AF is associated with atrial chamber remodeling. Although mineralocorticoid receptor (MR) inhibition provides cardiovascular protection, the role of MR on atrial structural remodeling and inducibility of AF in hypertension remains unclear. Here, we investigated roles of the MR on atrial structural remodeling and inducibility of AF in hypertensive rats by using MR antagonist eplerenone (EPL). Dahl salt-sensitive (DS) rats were fed a normal-salt or a high-salt (HS) diet from 7 weeks, and a non-antihypertensive dose of EPL or vehicle was administrated from 13 weeks, at which time myocytes hypertrophy, interstitial fibrosis in the atrium and AF inducibility had increased, until 20 weeks. There was no significant difference in systolic blood pressure between DS+HS (186 +/- 4 mm Hg) and DS+HS+EPL (184 +/- 5 mm Hg) at 20 weeks. Burst atrial pacing demonstrated decreased AF inducibility in DS+HS+EPL (0 of 10) compared with DS+HS (7 of 10). Fibrosis and myocytes hypertrophy in the atrium were decreased in DS+HS+EPL with the reduction of atrial inflammatory cytokines. These beneficial effects of EPL were associated with less atrial oxidative stress, as assessed by 4-hydroxy-2-nonenal staining, and reduced activation of the Rho GTPase Rac1 in the atrium. Thus, MR has important roles in atrial structural remodeling and AF inducibility in Dahl rats. The effects of MR are associated, at least in part, with activation of Rac1-oxidative stress/inflammatory axis. PMID- 21248755 TI - Association between human metapneumovirus seroprevalence and hypertension in elderly subjects in a long-term care facility. AB - Recently, relations between hypertension and infections caused by several pathogens have been reported. However, few studies have examined the relationship between human metapneumovirus (hMPV) and hypertension in elderly inpatients. To assess the association between anti-hMPV-immunoglobulin G (IgG) titer and the prevalence of hypertension, we conducted a case-control study in a Japanese long term care facility (LTCF). The participants included 84 hypertensive patients aged ?65 years, and 84 age- and sex-matched normotensive controls (38 males and 46 females in each group; cases, 79.9+/-8.4 (s.d.) years; controls, 80.1+/-8.3 years). Data on underling chronic clinical conditions were collected. Titers were measured using an immunofluorescence assay kit. The significance of risk factor differences was analyzed using univariate and multivariate comparisons of cases and controls. All serum samples were positive for hMPV, and IgG titers ranged from 40-fold to more than 5120-fold. There were no significant sex- or age related differences in log(2) (anti-hMPV-IgG titer/10) among the subjects. Compared with normotensive subjects, hypertensive patients presented significantly higher log(2) (anti-hMPV-IgG titer/10) values (P<0.001). After adjustment with multiple logistic analysis, the odds ratio for log(2) (anti-hMPV IgG titer/10) was 1.42 (95% confidence interval 1.16-1.75, P=0.001) relative to normotensive subjects. In all subjects, stepwise multiple regression analysis revealed that both hypertension and a poor nutritional state independently contributed to increased log(2) (anti-hMPV-IgG titer/10). These observations suggest that an increased anti-hMPV-IgG titer was closely related to hypertension in elderly subjects in a Japanese LTCF. PMID- 21248756 TI - The positive effect of an intervention program on the hypertension knowledge and lifestyles of rural residents over the age of 35 years in an area of China. AB - Hypertension (HTN) is a leading cause of cardiovascular and cerebrovascular diseases. Lifestyle modification may be the preferential approach to prevent and control HTN. The purpose of this study was to evaluate the effects of a community intervention program, which focused on improving the HTN knowledge, diets and lifestyles in a rural Chinese area. The study was carried out in a rural area of the Hubei Province from May 2003 to April 2006. A total of 1632 participants were recruited. Of the participants, 826 from the town of Xiaoxita and 806 from the town of Fenxiang were assigned to the intervention group (group I) and to the control group (group C), respectively. Group I participants underwent an intervention that included HTN education and dietary and lifestyle guidance. Group C participants were not subjected to an intervention. The outcome measures included HTN knowledge, dietary and lifestyle behaviors, and prevalence, awareness, treatment and control rates of HTN. Along with the changes in HTN education (P<0.05), the participants in group I exhibited a significantly greater improvement in dietary habits and lifestyle behaviors, including reducing salty food intake (13.6%), fat intake (22.9%) and alcohol consumption (9.6%), after 3 years in comparison with those in group C (21.7, 31.9 and 18%, respectively). The prevalence of HTN was significantly lower in group I (22.5%) than in group C (36%) after the intervention strategies. The study showed that the implementation of a community intervention program involving HTN education and lifestyle modifications for rural residents is a powerful approach to reduce HTN prevalence and improve long-term health outcomes. PMID- 21248757 TI - Hypertension augments cardiac Toll-like receptor 4 expression and activity. AB - Hypertension causes cardiac hypertrophy characterized by low-grade inflammation. Toll-like receptors (TLRs), members of the innate immune system, contribute to cardiac failure. We hypothesized that hypertension is accompanied by enhanced TLR4 expression and activity. Cardiac TLR4 expression was determined in untreated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY; 4, 8, 16 weeks). Besides, hearts of 8-week-old rats were stimulated with the endogenous TLR4 ligand heparansulfate (HS); the proinflammatory mRNA pattern was assessed (tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, monocyte chemotactic protein (MCP)-1). Additionally, we induced hypertension in WKY by L NAME (N(omega)-nitro-L-arginine-methylester hydrochloride). In both hypertension models the effect of ramipril on TLR4 density was assessed. Cardiac TLR4 distribution was investigated by fluorescence-activated cell sorting analysis. Blood pressure (BP) and heart weight/body weight ratio (HW/BW) were elevated in SHR. Constitutive TLR4 expression was augmented in adolescent and adult, but not young SHR compared with WKY. TLR4 staining was pronounced in cardiomyocytes. HS entailed an aggravated TNF-alpha and IL-6 mRNA response in cardiac tissue, which was significantly pronounced in SHR. Ramipril (10 mg kg(-1) per day) reduced BP, HW/BW and TLR4 expression in SHR. L-NAME also augmented TLR4 expression in WKY. Ramipril (1 mg kg(-1) per day) lowered BP but TLR4 expression remained unaffected. High-dose ramipril (10 mg kg(-1) per day) however decreased TLR4 expression. Starting from adolescence SHR demonstrated enhanced cardiac TLR4 expression. TLR4 was also upregulated in L-NAME induced hypertension. Thus, enhanced TLR4 expression might be linked to the development and maintenance of hypertension. Finally, the antihypertensive, anti-inflammatory action of angiotensin-converting-enzyme inhibition had no effect on TLR4 expression in therapeutic doses but in a high-dose model. PMID- 21248758 TI - Rosiglitazone attenuates myocardial remodeling in spontaneously hypertensive rats. AB - Rosiglitazone, an important peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, improves left ventricular (LV) hypertrophy in diet-induced hypercholesterolemic rats. However, the effects and underlying mechanisms of rosiglitazone on myocardial remodeling in spontaneous hypertension rats (SHRs) are unclear. Twenty male 8-week-old SHRs were randomly divided into two groups: one treated with oral saline (n=10) and the other treated with rosiglitazone (5 mgkg(-1)day(-1), n=10). Ten age-matched Wistar-Kyoto rats were selected as a normal control group. Echocardiography, immunohistochemistry, real-time reverse transcriptase-PCR and western blot analysis were performed to assess the effects of rosiglitazone. After 16 weeks of treatment, LV hypertrophy was significantly attenuated by rosiglitazone (LV weight/body weight, 2.35+/-0.11 vs. 2.56+/-0.14 mgg(-1)). According to the echocardiography results, thickening of the LV wall was reduced, and mid-wall fractional shortening was improved by rosiglitazone. Similarly, the excessive collagen deposition and upregulation of collagen I and collagen III seen in SHRs receiving saline were significantly attenuated in SHRs receiving rosiglitazone. In addition, rosiglitazone treatment increased the activity of matrix metalloproteinase-9 (MMP-9) and normalized the MMP-9/tissue inhibitor of metalloproteinase-1 ratio. Furthermore, activator protein-1 (AP-1) activation and nuclear factor-kappa B (NF-kappaB) expression were suppressed in the rosiglitazone-treated group. These results demonstrate that the PPAR-gamma agonist rosiglitazone had beneficial effects on myocardial remodeling in SHRs by way of decreasing AP-1 activation and NF-kappaB expression, which may help in further inhibiting transcription of the downstream genes involved in the pathogenesis of myocardial remodeling induced by hypertension. PMID- 21248759 TI - A 1-MUT extremely low-frequency electromagnetic field vs. sham control for mild to-moderate hypertension: a double-blind, randomized study. AB - The effects of extremely low-frequency electromagnetic fields (ELF-EMFs) on blood pressure (BP) are controversial. In this double-blind, randomized, sham controlled study, we examined the effects of repeated exposure to a 1-MUT ELF-EMF on BP in 20 humans with mild-to-moderate hypertension. Subjects were randomly assigned to either the ELF-EMF group or the sham group. Subjects in the ELF-EMF group were exposed to an ELF-EMF (6- and 8 Hz, respectively, peak magnetic field 1 MUT, peak electric field 10 Vm(-1)) for at least two 10- to 15-min sessions per week, over a period of 4 weeks. In the sham group, the EMF-generating apparatus was not active. We obtained systolic and diastolic BP (SBP and DBP, respectively) measurements at registration and before and after each ELF-EMF exposure session. Subjects in the ELF-EMF and sham groups had mean ages of 52.8 and 55.1 years, and were exposed to a mean of 9.9 and 9.0 sessions, respectively. There was a significant difference between the ELF-EMF and sham groups with respect to change in SBP value between baseline and the end of the exposure regimen (P=0.02), but not with respect to change in DBP (P=0.21). There were no adverse events other than mild paresthesia of the hands of two subjects in the ELF-EMF group. Our results suggest that repeated exposure to an ELF-EMF has a BP-lowering effect on humans with mild-to-moderate hypertension. PMID- 21248760 TI - Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women. AB - Diastolic dysfunction is more prevalent in individuals with hypertension, particularly postmenopausal women; however, the pathogenesis of diastolic dysfunction remains unknown. Pressure overload activates cardiac inflammation, which induces myocardial fibrosis and diastolic dysfunction in rats with a suprarenal aortic constriction (AC). Therefore, we examined the effects of bilateral ovariectomy (OVX) on left ventricle (LV) remodeling, diastolic dysfunction and cardiac inflammation in hypertensive female rats. Rats were randomized to OVX+AC, OVX and AC groups as well as a Control group receiving sham operations for both the procedures. Rats underwent OVX at 6 weeks and AC at 10 weeks (Day 0). At Day 28, OVX did not appear to affect arterial pressure, cardiac hypertrophy or LV fractional shortening in AC rats. However, OVX increased myocardial fibrosis, elevated LV end-diastolic pressure and reduced the transmitral Doppler spectra early to late filling velocity ratio in AC rats. AC induced transient myocardial monocyte chemoattractant protein-1 expression and macrophage infiltration, both of which peaked at Day 3 and were augmented and prolonged by OVX. At Day 28, dihydroethidium staining revealed superoxide generation in the intramyocardial arterioles in the OVX+AC group but not in the AC group. NOX1, a functional subunit of nicotinamide adenine dinucleotide phosphate oxidase, was upregulated only in the OVX+AC group at Day 28. Chronic 17beta-estradiol replacement prevented the increases in macrophage infiltration, NOX1 upregulation, myocardial fibrosis and diastolic dysfunction in OVX+AC rats. In conclusion, we suggest that estrogen deficiency augments cardiac inflammation and oxidative stress and thereby aggravates myocardial fibrosis and diastolic dysfunction in hypertensive female rats. The findings provide insight into the mechanism underlying diastolic dysfunction in hypertensive postmenopausal women. PMID- 21248761 TI - Genetic association studies: hypertension and beyond. PMID- 21248762 TI - Association of CARD8 with inflammatory bowel disease in Koreans. AB - Caspase recruitment domain (CARD)-containing protein 8 (CARD8) is a potential candidate risk gene for inflammatory bowel disease (IBD) because of its role as a component of the NALP3 inflammasome and as an inhibitor of nuclear factor-kappa B. Previous studies examining the association of a CARD8 single-nucleotide polymorphism (SNP) (rs2043211, p.Cys10X) with IBD yielded mixed results in Caucasians that may result from interaction with NALP3 or NOD2 (nucleotide binding oligomerization domain 2) variants. To understand the genetic association between CARD8/NALP3 and IBD in Koreans, we investigated seven CARD8, four NALP3 and four NOD2 SNPs in 650 Crohn's disease (CD), 660 ulcerative colitis (UC) patients and 688 controls from the Korean population. rs2043211 of CARD8 showed significant association with UC (P = 0.011; odds ratio = 1.50, 95% confidence intervals = 1.12-2.00, P = 0.006 under recessive model). In contrast, an SNP in intron 1, rs1972619, was associated with CD only (P = 0.033). None of the NALP3 or NOD2 SNPs was significantly associated with CD or UC in the Korean populations. The stop allele of rs2043211 was associated with higher serum interleukin-1beta levels only in female patients with UC (P = 0.027). Our data suggest that CARD8 variants might have roles in the pathogenesis of CD and UC in Koreans. PMID- 21248763 TI - KEAP1 gene mutations and NRF2 activation are common in pulmonary papillary adenocarcinoma. AB - Distinctive histological variants of lung cancer are increasingly recognized to have specific genetic changes that affect tumor biology and response to therapy. In this study, we evaluated true papillary adenocarcinoma of the lung, proposed as a distinct diagnostic category with relatively poor response to therapy, to determine whether these tumors also have specific molecular alterations that would affect sensitivity to chemotherapy. Specifically, we measured protein levels of P53, excision repair cross-complementation 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) by immunohistochemistry and evaluated the Kelch-like erythroid cell-derived protein with cap-n-collar homology (ECH)-associated protein 1 (KEAP1) gene for mutations, correlating mutations of this gene with total and nuclear expression of the nuclear factor erythroid-2-related factor 2 (NRF2). We found high levels of P53 in 23 of the 55 specimens (41.8%), similar to the rate of P53 gene mutations observed in general for pulmonary adenocarcinoma, and levels of ERCC1 and RRM1 also showed distributions similar to those reported generally for non-small lung cell cancer (NSCLC). However, KEAP1 alterations were observed at a significantly higher frequency in papillary adenocarcinoma tumors (60%) than what has been reported previously for NSCLC (3-19%). These mutations of KEAP1 were associated with increased nuclear accumulation of NRF2 in tumors, as expected for functional alterations. Thus, high rates of KEAP1 mutations and NRF2 overexpression in true papillary adenocarcinoma could be related to poor prognosis and chemotherapy resistance. Furthermore, this distinctive molecular characteristic supports the recognition of true papillary adenocarcinoma as a diagnostic entity. PMID- 21248764 TI - Use of self-delivery siRNAs to inhibit gene expression in an organotypic pachyonychia congenita model. AB - Although RNA interference offers therapeutic potential for treating skin disorders, delivery hurdles have hampered clinical translation. We have recently demonstrated that high pressure, resulting from intradermal injection of large liquid volumes, facilitated nucleic acid uptake by keratinocytes in mouse skin. Furthermore, similar intradermal injections of small interfering RNA (siRNA; TD101) into pachyonychia congenita (PC) patient foot lesions resulted in improvement. Unfortunately, the intense pain associated with hypodermic needle administration to PC lesions precludes this as a viable delivery option for this disorder. To investigate siRNA uptake by keratinocytes, an organotypic epidermal model, in which pre-existing endogenous gene or reporter gene expression can be readily monitored, was used to evaluate the effectiveness of "self-delivery" siRNA (i.e., siRNA chemically modified to enhance cellular uptake). In this model system, self-delivery siRNA treatment resulted in reduction of pre-existing fluorescent reporter gene expression under conditions in which unmodified controls had little or no effect. Additionally, treatment of PC epidermal equivalents with self-delivery "TD101" siRNA resulted in marked reduction of mutant keratin 6a mRNA with little or no effect on wild-type expression. These results indicate that chemical modification of siRNA may overcome certain limitations to transdermal delivery (specifically keratinocyte uptake) and may have clinical utility for inhibition of gene expression in the skin. PMID- 21248765 TI - Very severe psoriasis is associated with increased noncardiovascular mortality but not with increased cardiovascular risk. AB - It has been hypothesized that severe psoriasis is an independent risk factor for cardiovascular disease (CVD). We prospectively studied patients with severe psoriasis treated with psoralens and ultraviolet-A therapy (PUVA) who enrolled in a cohort study in 1975-1976. From 1977 to 2005, 617 of the 1,376 patients (45%) died. Compared with the general population, cohort death rates were significantly higher than expected (standard mortality ratio (SMR) = 1.1, 95% confidence interval (CI) = 1.02-1.20). The number of deaths due to CVD (SMR = 1.02, 95% CI = 0.9-1.6) was nearly identical to the expected number. Deaths due to liver disease were significantly elevated (SMR = 4.04, 95% CI = 2.76-5.70). Patients with exceptionally severe psoriasis at entry (>42% body surface area (BSA)) had a significantly increased risk of death compared with less severely affected cohort members (all-cause hazard ratio (HR) = 1.42, 95% CI = 1.18-1.69) as well as for deaths because of causes other than cancer or CVD (multivariate HR 1.56, 95% CI = 1.14-2.13). Only patients with exceptionally severe psoriasis had an increased mortality risk compared with both the general population and other cohort members with less extensive but still severe psoriasis. These increases were not significant for CVD. Our data do not support the hypothesis that severe psoriasis is an independent risk factor for CVD. However, exceptionally severe psoriasis is associated with increased all-cause mortality. PMID- 21248766 TI - ROS quenching potential of the epidermal cornified cell envelope. AB - The cornified cell envelope (CE) is a specialized structure assembled beneath the plasma membrane of keratinocytes in the outermost layers of the epidermis. It is essential for the physical and permeability properties of the barrier function of the skin. Our skin is continuously exposed to atmospheric oxygen and threatened by reactive oxygen species (ROS). Here, we identify the CE as a first line of antioxidant defense and show that the small proline-rich (SPRR) family of CE precursor proteins have a major role in ROS detoxification. Cysteine residues within these proteins are responsible for ROS quenching, resulting in inter- and intramolecular S-S bond formation, both in isolated proteins and purified CEs. The related keratinocyte proline-rich protein is also oxidized on several cysteine residues within the CE. Differences in antioxidant potential between various SPRR family members are likely determined by structural differences rather than by the amount of cysteine residues per protein. Loricrin, a major component of the CE with a higher cysteine content than SPRRs, is a weak ROS quencher and oxidized on a single cysteine residue within the CE. It is inferred that SPRR proteins provide the outermost layer of our skin with a highly adaptive and protective antioxidant shield. PMID- 21248767 TI - TRAIL-induced keratinocyte differentiation requires caspase activation and p63 expression. AB - Cornification, the terminal differentiation of keratinocytes, is a special form of programmed cell death in the skin. In this article, we report that tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce the expression of the keratinocyte differentiation markers involucrin and type 1 transglutaminase in normal human epidermal keratinocytes. The induction of differentiation occurs mainly under the activation of caspases 3 and 8, and apoptosis can also be triggered. Inhibition of these apoptotic caspases attenuates both apoptosis and differentiation of keratinocytes caused by TRAIL but barely affects the induction of differentiation caused by calcium and phorbol 12-myristate 13-acetate. Differential regulation of extracellular signal regulated kinase and p38 activation by TRAIL is also observed. Moreover, the degradation of p63 is induced by TRAIL-elicited caspase activation. However, the existence of p63 is essential for the initiation of keratinocyte differentiation by TRAIL because knockdown of DeltaNp63 decreases TRAIL-induced differentiation. Taken together, our results suggest that TRAIL can be an inducer of both differentiation and apoptosis in human keratinocytes, and that caspases critically mediate these processes. This study identifies a new role of apoptotic caspases for terminal differentiation of keratinocytes and further elucidates the molecular pathways involved in this unique model of cell death. PMID- 21248768 TI - Endocannabinoids modulate human epidermal keratinocyte proliferation and survival via the sequential engagement of cannabinoid receptor-1 and transient receptor potential vanilloid-1. AB - We have recently shown that lipid mediators of the emerging endocannabinoid system (ECS) are key players of growth control of the human pilosebaceous unit. In this study, we asked whether the prototypic endocannabinoid anandamide (N arachidonoylethanolamine, AEA) has a role in growth and survival of epidermal keratinocytes (KCs). Using human cultured KCs and skin organ-culture models, and by employing combined pharmacological and molecular approaches, we provide early evidence that AEA markedly suppresses KC proliferation and induces cell death, both in vitro and in situ. Moreover, we present that these cellular actions are mediated by a most probably constitutively active signaling mechanism that involves the activation of the metabotropic cannabinoid receptor CB(1) and a sequential engagement of the "ionotropic cannabinoid receptor" transient receptor potential vanilloid-1 (TRPV1). Finally, we demonstrate that the cellular effects of AEA are most probably due to a Ca(2+) influx via the non-selective, highly Ca(2+)-permeable ion channel TRPV1, and the concomitant elevation of intracellular Ca(2+) concentration. The data reported here may encourage one to explore whether the targeted manipulation of the above signaling pathway of the cutaneous ECS could become a useful adjunct treatment strategy for hyperproliferative human dermatoses such as psoriasis or KC-derived skin tumors. PMID- 21248769 TI - Evidence for non-allergic mast cell activation in pollen-associated inflammation. PMID- 21248770 TI - In vivo imaging of T-cell motility in the elicitation phase of contact hypersensitivity using two-photon microscopy. PMID- 21248771 TI - Photodynamic therapy-induced immunosuppression in humans is prevented by reducing the rate of light delivery. AB - Photodynamic therapy (PDT) of non-melanoma skin cancers currently carries failure rates of 10-40%. The optimal irradiation protocol is as yet unclear. Previous studies showed profound immunosuppression after PDT, which may compromise immune mediated clearance of these antigenic tumors. Slower irradiation prevents immunosuppression in mice, and may be at least as effective as high-fluence-rate PDT in preliminary clinical trials. The photosensitizers 5-aminolaevulinic acid and/or methyl aminolaevulinate were applied to discrete areas on the backs of healthy Mantoux-positive volunteers, followed by narrowband red light irradiation (632 nm) at varied doses and fluence rates. Delayed type hypersensitivity (Mantoux) reactions were elicited at test sites and control sites to determine immunosuppression. Human ex vivo skin received low- and high-fluence-rate PDT and was stained for oxidative DNA photolesions. PDT caused significant, dose responsive immunosuppression at high (75 mW cm(-2)) but not low (15 or 45 mW cm( 2)) fluence rates. DNA photolesions, which may be a trigger for immunosuppression, were observed after high-fluence-rate PDT but not when light was delivered more slowly. This study demonstrates that the current clinical PDT protocol (75 mW cm(-2)) is highly immunosuppressive. Simply reducing the rate of irradiation, while maintaining the same light dose, prevented immunosuppression and genetic damage and may have the potential to improve skin cancer outcomes. PMID- 21248772 TI - Loss of E2F7 expression is an early event in squamous differentiation and causes derepression of the key differentiation activator Sp1. AB - Squamous differentiation is controlled by key transcription factors such as Sp1 and E2F. We have previously shown that E2F1 can suppress transcription of the differentiation-specific gene, transglutaminase type 1 (TG1), by an indirect mechanism mediated by Sp1. Transient transfection of E2F1-E2F6 indicated that E2F mediated reduction of Sp1 transcription was not responsible for E2F-mediated suppression of squamous differentiation. However, we found that E2F4 and E2F7, but not E2Fs 1, 2, 3, 5, or 6, could suppress the activation of the Sp1 promoter in differentiated keratinocytes (KCs). E2F4-mediated suppression could not be antagonized by E2Fs 1, 2, 3, 5, or 6 and was localized to a region of the human Sp1 promoter spanning -139 to + 35 bp. Chromatin immunoprecipitation analysis, as well as transient overexpression and short hairpin RNA knockdown experiments indicate that E2F7 binds to a unique binding site located between -139 and -119 bp of the Sp1 promoter, and knockdown of E2F7 in proliferating KCs leads to a derepression of Sp1 expression and the induction of TG1. In contrast, E2F4 knockdown in proliferating KCs did not alter Sp1 expression. These data indicate that loss of E2F7 during the initiation of differentiation leads to the derepression of Sp1 and subsequent transcription of differentiation-specific genes such as TG1. PMID- 21248774 TI - Effect of amino acid substitutions in the human IFN-gammaR2 on IFN-gamma responsiveness. AB - Patients with interferon-gamma receptor (IFN-gammaR) null mutations have severe infections with poorly pathogenic Mycobacteria. The IFN-gammaR complex involves two IFN-gammaR1 and two IFN-gammaR2 chains, in which several amino acid substitutions, some linked to disease and some apparently naturally occurring, have been described. We developed a model system to study functional effects of genetic variations in IFN-gammaR2. We retrovirally transduced wild-type IFN gammaR2 and IFN-gammaR2 carrying presently known amino acid substitutions in various human cell lines, and next determined the IFN-gammaR2 expression pattern as well as IFN-gamma responsiveness. We determined that the T58R, Q64R, E147K and K182E variants of IFN-gammaR2 are fully functional, although the Q64R variant may be expressed higher on the cell membrane. The R114C, T168N and G227R variants were identified in patients that had disseminated infections with non-tuberculous Mycobacteria. Of these genetic variants, T168N was confirmed to be completely non functional, whereas the novel variant G227R, and the previously reported R114C, were partial functional. The impaired IFN-gamma responsiveness of R114C and G227R is mainly due to reduced receptor function, although expression on the cell membrane is reduced as well. We conclude that the T58R, Q64R, E147K and K182E variants are polymorphisms, whereas the R114C, T168N and G227R constitute mutations associated with disease. PMID- 21248773 TI - Transcriptional repression and DNA looping associated with a novel regulatory element in the final exon of the lymphotoxin-beta gene. AB - Transcriptional regulation has a critical role in the coordinate and context specific expression of a cluster of genes encoding members of the tumour necrosis factor (TNF) superfamily found at chromosome 6p21, comprising TNF, LTA (encoding lymphotoxin-alpha) and LTB (encoding lymphotoxin-beta). This is important, as dysregulated expression of these genes is implicated in susceptibility to many autoimmune, inflammatory and infectious diseases. We describe here a novel regulatory element in the fourth exon of LTB, which is highly conserved, localises to the only CpG island in the locus, and is associated with a DNase I hypersensitive site and specific histone modifications. We find evidence of binding by Yin Yang 1 (YY1), cyclic AMP response element (CRE)-binding protein (CREB) and CCCTC-binding factor (CTCF) to this region in Jurkat T cells, which is associated with transcriptional repression on reporter gene analysis. Chromatin conformation capture experiments show evidence of DNA looping, involving interaction of this element with the LTB promoter, LTA promoter and TNF 3' untranslated region (UTR). Small interfering RNA (siRNA) experiments demonstrate a functional role for YY1 and CREB in LTB expression. Our findings provide evidence of additional complexity in the transcriptional regulation of LTB with implications for coordinate expression of genes in this important genomic locus. PMID- 21248775 TI - Identification and characterization of a loss-of-function human MPYS variant. AB - MPYS, also known as STING and MITA, is an interferon (IFN)beta stimulator essential for host defense against RNA, DNA viruses and intracellular bacteria. MPYS also facilitates the adjuvant activity of DNA vaccines. Here, we report identification of a distinct human MPYS haplotype that contains three non synonymous single nucleotide polymorphisms (SNPs), R71H-G230A-R293Q (thus, named the HAQ haplotype). We estimate, in two cohorts (1,074 individuals), that ~3% of Americans are homozygous for this HAQ haplotype. HAQ MPYS exhibits a > 90% loss in the ability to stimulate IFNbeta production. Furthermore, fibroblasts and macrophage cells expressing HAQ are defective in Listeria monocytogenes infection induced IFNbeta production. Lastly, we find that the loss of IFNbeta activity is due primarily to the R71H and R293Q SNPs in HAQ. We hypothesize that individuals carrying HAQ may exhibit heightened susceptibility to viral infection and respond poorly to DNA vaccines. PMID- 21248776 TI - CIITA is not associated with risk of developing rheumatoid arthritis. AB - The major histocompatibility complex (MHC) class II transactivator gene (CIITA) encodes an important transcription factor regulating genes required for human leukocyte antigen (HLA) class II MHC-restricted antigen presentation. MHC genes, particularly HLA class II, are strongly associated with risk of developing rheumatoid arthritis (RA). Given the strong biological relationship between CIITA and HLA class II genes, a comprehensive investigation of CIITA variation in RA was conducted. This study tested 31 CIITA single-nucleotide polymorphisms in 2542 RA cases and 3690 controls (N=6232). All individuals were of European ancestry, as determined by ancestry informative genetic markers. No evidence for association between CIITA variation and RA was observed after a correction for multiple testing was applied. This is the largest study to fully characterize common genetic variation in CIITA, including an assessment of haplotypes. Results exclude even a modest role for common CIITA polymorphisms in susceptibility to RA. PMID- 21248777 TI - The trend of hypertension and its relationship to the weight status among Taiwanese young adolescents. AB - This study evaluates prevalence of hypertension in 1996 and 2006, and examines the relationship between hypertension and weight of Taiwanese young adolescents. Two cross-sectional surveys, administered in 1996 and 2006, to junior-high school in Taipei were included. Anthropometric and blood pressure were measured using standard methods, and structured questionnaire was used to collect personal history and lifestyle characteristics. Overweight and obesity are defined based on Taiwan's Department of Health criteria and bases pre-hypertension and hypertension on the 90th and 95th percentile distribution of blood pressure of the population of both surveys. The prevalence of pre-hypertension in Taiwan between 1996 and 2006 increased from 12.0 to 14.4% for boys and decreased from 9.5 to 9.4% for girls. Hypertension increased from 22.8-29.7% and 12.5-20.7% for both boys and girls, respectively. In 1996, compared with normal young adolescents, the risk of hypertension for overweight was 1.8 times higher for boys and 3.4 times for girls. However, the risk of hypertension for overweight in 2006 was 1.7 times higher for boys and 1.5 times higher for girls compared with normal. Every unit increment of body mass index and waist circumference was associated with 17-27% and 6-11% risk of hypertension in both genders in 1996, and was associated with 9-13% and 4% risk of hypertension among young adolescents in 2006, respectively. The prevalence of hypertension has increased significantly in young adolescents, especially for overweight. It is necessary to enrol young adolescents in weight management programs to prevent hypertension-related co morbidities. PMID- 21248778 TI - Serum 25-hydroxyvitamin D and parathyroid hormone levels in relation to blood pressure in a cross-sectional study in older Chinese men. AB - Vitamin D status, parathyroid hormone (PTH) level and their associations with blood pressure in Chinese population are unknown. This study examined these associations in older Chinese men. Blood pressure, serum 25-hydroxyvitamin D (25OHD) and PTH was measured in 939 community-dwelling Chinese men aged 65 years and older. Linear regression analyses were performed with adjustments for age, body mass index, education, season of measurement, medication use, self-reported history of stroke and Parkinson's disease, and other lifestyle factors. In either crude or adjusted models, serum 25OHD was not associated with blood pressure, whereas increasing PTH levels was associated with higher blood pressure. Men in the highest quartile of serum PTH level had a mean difference of 3.4 mm Hg and 2.8 mm Hg higher in as systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively, than men in the lowest quartile of serum PTH level (P(trend)=0.019 for SBP and <0.001 for DBP). In conclusion, the findings support an association between serum PTH and blood pressure, but not for serum 25OHD in older Chinese men whose vitamin D status is optimal. The lack of association between serum 25OHD and blood pressure may possibly because of the relatively high serum 25OHD levels of the study sample. PMID- 21248779 TI - Impact of blood pressure cuff inflation rates on flow-mediated dilatation and contralateral arm response. AB - Flow-mediated dilatation (FMD) is widely used as an index of nitric oxide mediated vasodilator function, yet its methodology has not been well established. Previous research indicates that a rapid inflation of a blood pressure cuff evokes systemic vasoconstriction, as it was observed even on non-occluded contralateral arm. This would potentially contribute to the variability of FMD readings and complicate the emerging evidence that non-occluded contralateral arm fingertip temperature responses during the FMD procedure may be an indicator of the presence of coronary artery disease. To test the hypotheses that rapid inflation of a blood pressure cuff could reduce FMD values and influence contralateral vasodilatory states, 33 apparently healthy adults (18 males and 15 females, 29+/-6 years) were studied in two randomized FMD trials. The blood flow occluding cuff was inflated rapidly (<1 s) in one trial or slowly over 10 s in the other trial. Arterial diameter, fingertip temperature and infrared thermography were obtained throughout each session. FMD values were not different between the rapid and slow cuff inflation trials (5.9+/-0.6 vs 5.9+/-0.4%). There were no differences in reactive hyperaemia (6.4+/-1.6 vs 6.2+/-1.7 AU), shear stress (80+/-20 vs 77+/-17 dyn cm(-2)) and fingertip temperature rebound (TR; 1.8+/-1.2 vs 1.9+/-1.0 degrees C) between the rapid and slow inflation. Changes in finger temperature on the contralateral (non-occluded) arm were positively associated with those on the occluded arm (r=0.26 to 0.61, P<0.05). We concluded that rates of inflating a blood pressure cuff do not affect FMD and TR response, and that neurovascular-induced vasodilatation of the contralateral arm was not observed regardless of cuff inflation rates. PMID- 21248780 TI - Impairment of skin blood flow during post-occlusive reactive hyperhemy assessed by laser Doppler flowmetry correlates with renal resistive index. AB - We lack non-invasive tools for evaluating the coronary and renal microcirculations. Since cutaneous Doppler laser exploration has evidenced impaired cutaneous microvascular responses in coronary artery disease and in impaired renal function, we wanted to find out if there was a link between the impairments in the cutaneous and renal microcirculations. To specify the significance of the rise in the renal resistive index (RI), which is still unclear, we also sought relations between RI and arterial stiffness. We conducted a cross-sectional controlled study in a heterogeneous population including hypertensive patients of various ages with or without a history of cardiovascular disease along with a healthy control group. The cutaneous microcirculation was evaluated by laser Doppler flowmetry of the post-occlusive reactive hyperhemy (PORH) and of the hyperhemy to heat. The renal microcirculation was evaluated by measurement of the RI. Arterial stiffness was evaluated from an ambulatory measurement of the corrected QKD(100-60) interval. We included 22 hypertensives and 11 controls of mean age 60.6 vs 40.8 years. In this population, there was a correlation between RI and basal zero to peak flow variation (BZ-PF) (r=-0.42; P=0.02) and a correlation between RI and rest flow to peak flow variation (RF-PF) (r=-0.44; P=0.01). There was also a significant correlation between RI and the corrected QKD(100-60) (r=-0.47; P=0.01). The significant correlation between PORH parameters and RI indicates that the functional modifications of the renal and cutaneous microcirculations tend to evolve in parallel during ageing or hypertension. The relation between RI and arterial stiffness shows that RI is a compound index of both renal microvascular impairment and the deterioration of macrovascular mechanics. PMID- 21248782 TI - N-terminal pro-atrial natriuretic peptide reflects cardiac remodelling in stage 1 hypertension. AB - Early detection of left ventricular hypertrophy (LVH) is beneficial, since treatment-induced regression of LVH has been unequivocally associated with a better prognosis. Our aim was to study the relation of cardiac remodelling and natriuretic peptides (NPs) in stage 1 hypertension. We studied 175 (46+/-7 years, 87 women and 88 men) apparently healthy middle-aged that had never been treated for hypertension. Left ventricular and atrial parameters were determined by magnetic resonance imaging. Systolic blood pressure (BP) correlated with left ventricular mass index (LVMI) (r=0.23, P<0.01) and ventricular septum thickness index (IVSI) (r=0.29, P<0.001). N-terminal pro-B-type NP (NT-proBNP) or N terminal pro-atrial NP (NT-proANP) did not correlate with BP, LVMI or IVSI. NT proANP correlated with left atrial area index (LAAI) (r=0.38, P<0.001), and subjects with LVH had higher LAAI than subjects with normal left ventricular geometry and no LVH (11.2+/-0.3 vs 10.0+/-0.2 cm(2) m(-2), P<0.001). In conclusion, measurement of NT-proBNP or NT-proANP does not appear to discriminate LVH in middle-aged, never treated and apparently healthy hypertensives. NT proANP, but not NT-proBNP, reflects early cardiac remodelling in hypertensive heart disease. PMID- 21248781 TI - Genetic admixture, social-behavioural factors and body composition are associated with blood pressure differently by racial-ethnic group among children. AB - Cardiovascular disease has a progressively earlier age of onset, and disproportionately affects African Americans (AAs) in the United States. It has been difficult to establish the extent to which group differences are due to physiological, genetic, social or behavioural factors. In this study, we examined the association between blood pressure and these factors among a sample of 294 children, identified as AA, European American or Hispanic American. We use body composition, behavioural (diet and physical activity) and survey-based measures (socio-economic status and perceived racial discrimination), as well as genetic admixture based on 142 ancestry informative markers (AIMs) to examine associations with systolic and diastolic blood pressure. We find that associations differ by ethnic/racial group. Notably, among AAs, physical activity and perceived racial discrimination, but not African genetic admixture, are associated with blood pressure, while the association between blood pressure and body fat is nearly absent. We find an association between blood pressure and an AIM near a marker identified by a recent genome-wide association study. Our findings shed light on the differences in risk factors for elevated blood pressure among ethnic/racial groups, and the importance of including social and behavioural measures to grasp the full genetic/environmental aetiology of disparities in blood pressure. PMID- 21248783 TI - Epistatic effects of ACE I/D and AGT gene variants on left ventricular mass in hypertensive patients: the HyperGEN study. AB - Identifying predictors of left ventricular hypertrophy has been an active study topic because of its association with cardiovascular morbidity and mortality. We examined the epistatic effect (gene-gene interaction) of two genes (angiotensin converting enzyme (ACE) insertion/deletion (I/D); angiotensinogen (AGT) -6G-A, M235T, -20A-C) in the renin-angiotensin system on left ventricular mass (LVM) among hypertensive participants in the Hypertension Genetic Epidemiology Network study. Included were 2156 participants aged 20-87 years (60% women, 63% African American). We employed mixed linear regression models to assess main effects of four genetic variants on echocardigraphically determined LVM (indexed for height), and ACE-by-AGT epistatic effects. There was evidence that AGT -6G-A was associated with LVM among white participants: adjusted mean LVM (gm(-2.7)) increased with 'G' allele copy number ('AA':41.2, 'AG':42.3, 'GG':44.0; P=0.03). There was also evidence of an ACE I/D-by-AGT -20A-C epistatic effect among white participants (interaction P=0.03): among ACE 'DD' participants, AGT -20A-C 'C' allele carriers had lower mean LVM than 'AA' homozygotes ('DD/CC':39.2, 'DD/AC':39.9, 'DD/AA':43.9), with no similar significant effect among ACE 'I' allele carriers ('ID/CC':47.2, 'ID/AC':43.4, 'ID/AA':42.6; 'II/CC': NA, 'II/AC':41.3, 'II/AA':43.1). These findings indicate that renin-angiotensin system variants in at least two genes may interact to modulate LVM. PMID- 21248784 TI - Common variation in the adiponectin gene has an effect on systolic blood pressure. AB - The genotype at the C-11377G single-nucleotide polymorphism (SNP) (rs266729) in the adiponectin gene promoter has been shown to affect the prevalence of coronary atherosclerosis and incidence of vascular events in men, and to affect carotid intima media thickness. We have examined the relationship between this polymorphism and blood pressure in a cohort ascertained to express variability in blood pressure measurements. We studied a cohort of 255 families comprising 1425 individuals ascertained via a hypertensive proband. Blood pressure was measured by ambulatory monitoring. The C-11377G SNP was genotyped using a TaqMan assay. There was evidence of association between this SNP and log systolic blood pressure (SBP), having adjusted for significant covariates including gender, age and drug treatment; P=0.009, 0.014 and 0.022, respectively, for daytime, night time and clinic measurements. Replacing C by G caused an increase of 1.63, 1.83 and 1.61%, respectively, per gene copy. There were smaller effects on diastolic blood pressure and waist-hip ratio, which were of borderline significance. Genotype at the C-11377G (rs266729) polymorphism has independent effects both on waist-hip ratio and SBP. This may help in understanding the complex role that the adiponectin gene has in atherosclerosis. PMID- 21248785 TI - 24-Hour ambulatory blood pressure control with triple-therapy amlodipine, valsartan and hydrochlorothiazide in patients with moderate to severe hypertension. AB - To determine the effectiveness and safety of once-daily combination therapy with amlodipine, valsartan and hydrochlorothiazide for reducing ambulatory blood pressure (ABP) in patients with moderate to severe hypertension, a multicenter, double-blind study was performed (N=2271) that included ABP monitoring in a 283 patient subset. After a single-blind, placebo run-in period, patients were randomized to receive amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg), valsartan/hydrochlorothiazide (320/25 mg), amlodipine/valsartan (10/320 mg) or amlodipine/hydrochlorothiazide (10/25 mg) each morning for 8 weeks. Efficacy assessments included change from baseline in 24-h, daytime and night time mean ambulatory systolic BP (SBP) and diastolic BP (DBP). Statistically significant and clinically relevant reductions from baseline in all these parameters occurred in all treatment groups (P<0.0001, all comparisons versus baseline). At week 8, least squares mean reductions from baseline in 24-h, daytime and night time mean ambulatory SBP/DBP were 30.3/19.7, 31.2/20.5 and 28.0/17.8 mm Hg, respectively, with amlodipine/valsartan/hydrochlorothiazide; corresponding reductions with dual therapies ranged from 18.8-24.1/11.7-15.5, 19.0-25.1/12.0-16.0 and 18.3-22.6/11.1 14.3 mm Hg (P<=0.01, all comparisons of triple versus dual therapy). Treatment with amlodipine/valsartan/hydrochlorothiazide maintained full 24-h effectiveness, including during the morning hours; all hourly mean ambulatory SBP and mean ambulatory DBP measurements were <=130/85 mm Hg at end point. Amlodipine/valsartan/hydrochlorothiazide combination therapy was well tolerated. Once-daily treatment with amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg) reduces ABP to a significantly greater extent than component-based dual therapy and maintains its effectiveness over the entire 24-h dosing period. PMID- 21248786 TI - Wilms' tumours: about tumour suppressor genes, an oncogene and a chameleon gene. AB - Genes identified as being mutated in Wilms' tumour include TP53, a classic tumour suppressor gene (TSG); CTNNB1 (encoding beta-catenin), a classic oncogene; WTX, which accumulating data indicate is a TSG; and WT1, which is inactivated in some Wilms' tumours, similar to a TSG. However, WT1 does not always conform to the TSG label, and some data indicate that WT1 enhances cell survival and proliferation, like an oncogene. Is WT1 a chameleon, functioning as either a TSG or an oncogene, depending on cellular context? Are these labels even appropriate for describing and understanding the function of WT1? PMID- 21248787 TI - The role of G protein-coupled receptors in the pathology of Alzheimer's disease. AB - G protein-coupled receptors (GPCRs) are involved in numerous key neurotransmitter systems in the brain that are disrupted in Alzheimer's disease (AD). GPCRs also directly influence the amyloid cascade through modulation of the alpha-, beta- and gamma-secretases, proteolysis of the amyloid precursor protein (APP), and regulation of amyloid-beta degradation. Additionally, amyloid-beta has been shown to perturb GPCR function. Emerging insights into the mechanistic link between GPCRs and AD highlight the potential of this class of receptors as a therapeutic target for AD. PMID- 21248790 TI - Production and purification of lentiviral vectors generated in 293T suspension cells with baculoviral vectors. AB - Lentivirus can be engineered to be a highly potent vector for gene therapy applications. However, generation of clinical grade vectors in enough quantities for therapeutic use is still troublesome and limits the preclinical and clinical experiments. As a first step to solve this unmet need we recently introduced a baculovirus-based production system for lentiviral vector (LV) production using adherent cells. Herein, we have adapted and optimized the production of these vectors to a suspension cell culture system using recombinant baculoviruses delivering all elements required for a safe latest generation LV preparation. High-titer LV stocks were achieved in 293T cells grown in suspension. Produced viruses were accurately characterized and the functionality was also tested in vivo. Produced viruses were compared with viruses produced by calcium phosphate transfection method in adherent cells and polyethylenimine transfection method in suspension cells. Furthermore, a scalable and cost-effective capture purification step was developed based on a diethylaminoethyl monolithic column capable of removing most of the baculoviruses from the LV pool with 65% recovery. PMID- 21248789 TI - The role of phase synchronization in memory processes. AB - In recent years, studies ranging from single-unit recordings in animals to electroencephalography and magnetoencephalography studies in humans have demonstrated the pivotal role of phase synchronization in memory processes. Phase synchronization - here referring to the synchronization of oscillatory phases between different brain regions - supports both working memory and long-term memory and acts by facilitating neural communication and by promoting neural plasticity. There is evidence that processes underlying working and long-term memory might interact in the medial temporal lobe. We propose that this is accomplished by neural operations involving phase-phase and phase-amplitude synchronization. A deeper understanding of how phase synchronization supports the flexibility of and interaction between memory systems may yield new insights into the functions of phase synchronization in general. PMID- 21248788 TI - The stem cell potential of glia: lessons from reactive gliosis. AB - Astrocyte-like cells, which act as stem cells in the adult brain, reside in a few restricted stem cell niches. However, following brain injury, glia outside these niches acquire or reactivate stem cell potential as part of reactive gliosis. Recent studies have begun to uncover the molecular pathways involved in this process. A comparison of molecular pathways activated after injury with those involved in the normal neural stem cell niches highlights strategies that could overcome the inhibition of neurogenesis outside the stem cell niche and instruct parenchymal glia towards a neurogenic fate. This new view on reactive glia therefore suggests a widespread endogenous source of cells with stem cell potential, which might potentially be harnessed for local repair strategies. PMID- 21248792 TI - Goodbye Tevatron. PMID- 21248791 TI - Modulation of in utero total body irradiation induced newborn mouse growth retardation by maternal manganese superoxide dismutase-plasmid liposome (MnSOD PL) gene therapy. AB - To determine the effects of manganese superoxide dismutase (MnSOD) plasmid liposome (PL) maternal radioprotection on fetal mice, timed pregnant female mice (E14 gestation) were irradiated to 3.0 Gy total body irradiation (TBI) dose, and the number, weight and growth and development over 6 months after birth of newborn mice was quantitated compared with irradiated controls. Maternal MnSOD-PL treatment at E13 improved pup survival at birth (5.4+/-0.9 per litter) compared with non-irradiated 3.0 Gy controls 4.9+/-1.1. There was no statistically significant difference in newborn abnormalities, male to female ratio in newborn litters, or other evidence of teratogenesis in surviving newborn mice from MnSOD PL treated compared with irradiated controls. However, E14 3 Gy irradiated pups from gene therapy-treated mothers showed a significant increase in both growth and overall survival over 6 months after birth (P=0.0022). To determine if transgene product crossed the placenta pregnant E13 mice were injected intravenously with hemagglutinin-epitope-tagged MnSOD (100 MUg plasmid in 100 MUl liposomes), then after 24 h, fetal mice, placentas and maternal tissues were removed and tested by both immunohistochemistry and reverse transcriptase-PCR for transgene and product. There was no evidence of transgene or product in placenta or any fetal tissue while maternal liver was positive by both assays. The data provide evidence for fetal radioprotection by maternal MnSOD-PL gene therapy before irradiation, which is mediated by an indirect bystander effect and is associated with a significant improvement in both survival at birth and growth and development of newborn mice. PMID- 21248793 TI - Smallpox should be saved. PMID- 21248794 TI - Natural wealth. PMID- 21248807 TI - Cholera vaccine plan splits experts. PMID- 21248795 TI - Day of reckoning for Ecuador's biodiversity. PMID- 21248808 TI - Race against time for raiders of the lost lake. PMID- 21248809 TI - Low-cost carbon-capture project sparks interest. PMID- 21248810 TI - France mulls embryo research reform. PMID- 21248812 TI - Missing part delays space mission. PMID- 21248811 TI - Cells snag top modelling job. PMID- 21248814 TI - High-energy physics: Down the petabyte highway. PMID- 21248815 TI - Vision science: Seeing without seeing. PMID- 21248816 TI - Peer review: Trial by Twitter. PMID- 21248817 TI - Get ready for the flood of fetal gene screening. PMID- 21248818 TI - A lesson in sharing. PMID- 21248824 TI - Bioethanol's dirty footprint in Brazil. PMID- 21248825 TI - Will foreign-aid pledges materialize? PMID- 21248826 TI - Innovation: venture capital is vital too. PMID- 21248827 TI - Cutting random funding decisions. PMID- 21248828 TI - John Fenn (1917-2010). PMID- 21248829 TI - Financial systems: Ecology and economics. PMID- 21248830 TI - Neuroscience: Seeing into the future. PMID- 21248831 TI - Astrophysics: How galaxies got their black holes. PMID- 21248832 TI - AIDS: Drugs that prevent HIV infection. PMID- 21248833 TI - Imaging: Spot the hotspot. PMID- 21248834 TI - Evolutionary biology: Farming writ small. PMID- 21248835 TI - Immunology: Peptide gets in shape for self-defence. PMID- 21248836 TI - Chemical biology: Catalytic detoxification. PMID- 21248837 TI - Frontiers in biology. PMID- 21248838 TI - Cells of origin in cancer. AB - Both solid tumours and leukaemias show considerable histological and functional heterogeneity. It is widely accepted that genetic lesions have a major role in determining tumour phenotype, but evidence is also accumulating that cancers of distinct subtypes within an organ may derive from different 'cells of origin'. These cells acquire the first genetic hit or hits that culminate in the initiation of cancer. The identification of these crucial target cell populations may allow earlier detection of malignancies and better prediction of tumour behaviour, and ultimately may lead to preventive therapies for individuals at high risk of developing cancer. PMID- 21248839 TI - Autophagy in immunity and inflammation. AB - Autophagy is an essential, homeostatic process by which cells break down their own components. Perhaps the most primordial function of this lysosomal degradation pathway is adaptation to nutrient deprivation. However, in complex multicellular organisms, the core molecular machinery of autophagy - the 'autophagy proteins' - orchestrates diverse aspects of cellular and organismal responses to other dangerous stimuli such as infection. Recent developments reveal a crucial role for the autophagy pathway and proteins in immunity and inflammation. They balance the beneficial and detrimental effects of immunity and inflammation, and thereby may protect against infectious, autoimmune and inflammatory diseases. PMID- 21248840 TI - Pervasive roles of microRNAs in cardiovascular biology. AB - First recognized as regulators of development in worms and fruitflies, microRNAs are emerging as pivotal modulators of mammalian cardiovascular development and disease. Individual microRNAs modulate the expression of collections of messenger RNA targets that often have related functions, thereby governing complex biological processes. The wideranging functions of microRNAs in the cardiovascular system have provided new perspectives on disease mechanisms and have revealed intriguing therapeutic targets, as well as diagnostics, for a variety of cardiovascular disorders. PMID- 21248841 TI - The Polycomb complex PRC2 and its mark in life. AB - Polycomb group proteins maintain the gene-expression pattern of different cells that is set during early development by regulating chromatin structure. In mammals, two main Polycomb group complexes exist - Polycomb repressive complex 1 (PRC1) and 2 (PRC2). PRC1 compacts chromatin and catalyses the monoubiquitylation of histone H2A. PRC2 also contributes to chromatin compaction, and catalyses the methylation of histone H3 at lysine 27. PRC2 is involved in various biological processes, including differentiation, maintaining cell identity and proliferation, and stem-cell plasticity. Recent studies of PRC2 have expanded our perspectives on its function and regulation, and uncovered a role for non-coding RNA in the recruitment of PRC2 to target genes. PMID- 21248842 TI - Systemic risk in banking ecosystems. AB - In the run-up to the recent financial crisis, an increasingly elaborate set of financial instruments emerged, intended to optimize returns to individual institutions with seemingly minimal risk. Essentially no attention was given to their possible effects on the stability of the system as a whole. Drawing analogies with the dynamics of ecological food webs and with networks within which infectious diseases spread, we explore the interplay between complexity and stability in deliberately simplified models of financial networks. We suggest some policy lessons that can be drawn from such models, with the explicit aim of minimizing systemic risk. PMID- 21248843 TI - Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells. AB - Many tumours are composed of genetically diverse cells; however, little is known about how diversity evolves or the impact that diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR-ABL1 lymphoblastic leukaemia, we demonstrate that genetic diversity occurs in functionally defined leukaemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct leukaemia initiating cell subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multi-clonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, whereas in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A and CDKN2B, and a trend towards poorer patient outcome. Our findings link clonal diversity with leukaemia-initiating-cell function and underscore the importance of developing therapies that eradicate all intratumoral subclones. PMID- 21248845 TI - Supermassive black holes do not correlate with galaxy disks or pseudobulges. AB - The masses of supermassive black holes are known to correlate with the properties of the bulge components of their host galaxies. In contrast, they seem not to correlate with galaxy disks. Disk-grown 'pseudobulges' are intermediate in properties between bulges and disks; it has been unclear whether they do or do not correlate with black holes in the same way that bulges do. At stake in this issue are conclusions about which parts of galaxies coevolve with black holes, possibly by being regulated by energy feedback from black holes. Here we report pseudobulge classifications for galaxies with dynamically detected black holes and combine them with recent measurements of velocity dispersions in the biggest bulgeless galaxies. These data confirm that black holes do not correlate with disks and show that they correlate little or not at all with pseudobulges. We suggest that there are two different modes of black-hole feeding. Black holes in bulges grow rapidly to high masses when mergers drive gas infall that feeds quasar-like events. In contrast, small black holes in bulgeless galaxies and in galaxies with pseudobulges grow as low-level Seyfert galaxies. Growth of the former is driven by global processes, so the biggest black holes coevolve with bulges, but growth of the latter is driven locally and stochastically, and they do not coevolve with disks and pseudobulges. PMID- 21248844 TI - Nascent transcript sequencing visualizes transcription at nucleotide resolution. AB - Recent studies of transcription have revealed a level of complexity not previously appreciated even a few years ago, both in the intricate use of post initiation control and the mass production of rapidly degraded transcripts. Dissection of these pathways requires strategies for precisely following transcripts as they are being produced. Here we present an approach (native elongating transcript sequencing, NET-seq), based on deep sequencing of 3' ends of nascent transcripts associated with RNA polymerase, to monitor transcription at nucleotide resolution. Application of NET-seq in Saccharomyces cerevisiae reveals that although promoters are generally capable of divergent transcription, the Rpd3S deacetylation complex enforces strong directionality to most promoters by suppressing antisense transcript initiation. Our studies also reveal pervasive polymerase pausing and backtracking throughout the body of transcripts. Average pause density shows prominent peaks at each of the first four nucleosomes, with the peak location occurring in good agreement with in vitro biophysical measurements. Thus, nucleosome-induced pausing represents a major barrier to transcriptional elongation in vivo. PMID- 21248846 TI - Supermassive black holes do not correlate with dark matter haloes of galaxies. AB - Supermassive black holes have been detected in all galaxies that contain bulge components when the galaxies observed were close enough that the searches were feasible. Together with the observation that bigger black holes live in bigger bulges, this has led to the belief that black-hole growth and bulge formation regulate each other. That is, black holes and bulges coevolve. Therefore, reports of a similar correlation between black holes and the dark matter haloes in which visible galaxies are embedded have profound implications. Dark matter is likely to be non-baryonic, so these reports suggest that unknown, exotic physics controls black-hole growth. Here we show, in part on the basis of recent measurements of bulgeless galaxies, that there is almost no correlation between dark matter and parameters that measure black holes unless the galaxy also contains a bulge. We conclude that black holes do not correlate directly with dark matter. They do not correlate with galaxy disks, either. Therefore, black holes coevolve only with bulges. This simplifies the puzzle of their coevolution by focusing attention on purely baryonic processes in the galaxy mergers that make bulges. PMID- 21248847 TI - Directed self-assembly of a colloidal kagome lattice. AB - A challenging goal in materials chemistry and physics is spontaneously to form intended superstructures from designed building blocks. In fields such as crystal engineering and the design of porous materials, this typically involves building blocks of organic molecules, sometimes operating together with metallic ions or clusters. The translation of such ideas to nanoparticles and colloidal-sized building blocks would potentially open doors to new materials and new properties, but the pathways to achieve this goal are still undetermined. Here we show how colloidal spheres can be induced to self-assemble into a complex predetermined colloidal crystal-in this case a colloidal kagome lattice-through decoration of their surfaces with a simple pattern of hydrophobic domains. The building blocks are simple micrometre-sized spheres with interactions (electrostatic repulsion in the middle, hydrophobic attraction at the poles, which we call 'triblock Janus') that are also simple, but the self-assembly of the spheres into an open kagome structure contrasts with previously known close-packed periodic arrangements of spheres. This open network is of interest for several theoretical reasons. With a view to possible enhanced functionality, the resulting lattice structure possesses two families of pores, one that is hydrophobic on the rims of the pores and another that is hydrophilic. This strategy of 'convergent' self-assembly from easily fabricated colloidal building blocks encodes the target supracolloidal architecture, not in localized attractive spots but instead in large redundantly attractive regions, and can be extended to form other supracolloidal networks. PMID- 21248848 TI - Probing the electromagnetic field of a 15-nanometre hotspot by single molecule imaging. AB - When light illuminates a rough metallic surface, hotspots can appear, where the light is concentrated on the nanometre scale, producing an intense electromagnetic field. This phenomenon, called the surface enhancement effect, has a broad range of potential applications, such as the detection of weak chemical signals. Hotspots are believed to be associated with localized electromagnetic modes, caused by the randomness of the surface texture. Probing the electromagnetic field of the hotspots would offer much insight towards uncovering the mechanism generating the enhancement; however, it requires a spatial resolution of 1-2 nm, which has been a long-standing challenge in optics. The resolution of an optical microscope is limited to about half the wavelength of the incident light, approximately 200-300 nm. Although current state-of-the art techniques, including near-field scanning optical microscopy, electron energy loss spectroscopy, cathode luminescence imaging and two-photon photoemission imaging have subwavelength resolution, they either introduce a non-negligible amount of perturbation, complicating interpretation of the data, or operate only in a vacuum. As a result, after more than 30 years since the discovery of the surface enhancement effect, how the local field is distributed remains unknown. Here we present a technique that uses Brownian motion of single molecules to probe the local field. It enables two-dimensional imaging of the fluorescence enhancement profile of single hotspots on the surfaces of aluminium thin films and silver nanoparticle clusters, with accuracy down to 1.2 nm. Strong fluorescence enhancements, up to 54 and 136 times respectively, are observed in those two systems. This strong enhancement indicates that the local field, which decays exponentially from the peak of a hotspot, dominates the fluorescence enhancement profile. PMID- 21248849 TI - Primitive agriculture in a social amoeba. AB - Agriculture has been a large part of the ecological success of humans. A handful of animals, notably the fungus-growing ants, termites and ambrosia beetles, have advanced agriculture that involves dispersal and seeding of food propagules, cultivation of the crop and sustainable harvesting. More primitive examples, which could be called husbandry because they involve fewer adaptations, include marine snails farming intertidal fungi and damselfish farming algae. Recent work has shown that microorganisms are surprisingly like animals in having sophisticated behaviours such as cooperation, communication and recognition, as well as many kinds of symbiosis. Here we show that the social amoeba Dictyostelium discoideum has a primitive farming symbiosis that includes dispersal and prudent harvesting of the crop. About one-third of wild-collected clones engage in husbandry of bacteria. Instead of consuming all bacteria in their patch, they stop feeding early and incorporate bacteria into their fruiting bodies. They then carry bacteria during spore dispersal and can seed a new food crop, which is a major advantage if edible bacteria are lacking at the new site. However, if they arrive at sites already containing appropriate bacteria, the costs of early feeding cessation are not compensated for, which may account for the dichotomous nature of this farming symbiosis. The striking convergent evolution between bacterial husbandry in social amoebas and fungus farming in social insects makes sense because multigenerational benefits of farming go to already established kin groups. PMID- 21248850 TI - Reduction of disulphide bonds unmasks potent antimicrobial activity of human beta defensin 1. AB - Human epithelia are permanently challenged by bacteria and fungi, including commensal and pathogenic microbiota. In the gut, the fraction of strict anaerobes increases from proximal to distal, reaching 99% of bacterial species in the colon. At colonic mucosa, oxygen partial pressure is below 25% of airborne oxygen content, moreover microbial metabolism causes reduction to a low redox potential of -200 mV to -300 mV in the colon. Defensins, characterized by three intramolecular disulphide-bridges, are key effector molecules of innate immunity that protect the host from infectious microbes and shape the composition of microbiota at mucosal surfaces. Human beta-defensin 1 (hBD-1) is one of the most prominent peptides of its class but despite ubiquitous expression by all human epithelia, comparison with other defensins suggested only minor antibiotic killing activity. Whereas much is known about the activity of antimicrobial peptides in aerobic environments, data about reducing environments are limited. Herein we show that after reduction of disulphide-bridges hBD-1 becomes a potent antimicrobial peptide against the opportunistic pathogenic fungus Candida albicans and against anaerobic, Gram-positive commensals of Bifidobacterium and Lactobacillus species. Reduced hBD-1 differs structurally from oxidized hBD-1 and free cysteines in the carboxy terminus seem important for the bactericidal effect. In vitro, the thioredoxin (TRX) system is able to reduce hBD-1 and TRX co localizes with reduced hBD-1 in human epithelia. Hence our study indicates that reduced hBD-1 shields the healthy epithelium against colonisation by commensal bacteria and opportunistic fungi. Accordingly, an intimate interplay between redox-regulation and innate immune defence seems crucial for an effective barrier protecting human epithelia. PMID- 21248851 TI - Atomic-level modelling of the HIV capsid. AB - The mature capsids of human immunodeficiency virus type 1 (HIV-1) and other retroviruses are fullerene shells, composed of the viral CA protein, that enclose the viral genome and facilitate its delivery into new host cells. Retroviral CA proteins contain independently folded amino (N)- and carboxy (C)-terminal domains (NTD and CTD) that are connected by a flexible linker. The NTD forms either hexameric or pentameric rings, whereas the CTD forms symmetric homodimers that connect the rings into a hexagonal lattice. We previously used a disulphide crosslinking strategy to enable isolation and crystallization of soluble HIV-1 CA hexamers. Here we use the same approach to solve the X-ray structure of the HIV-1 CA pentamer at 2.5 A resolution. Two mutant CA proteins with engineered disulphides at different positions (P17C/T19C and N21C/A22C) converged onto the same quaternary structure, indicating that the disulphide-crosslinked proteins recapitulate the structure of the native pentamer. Assembly of the quasi equivalent hexamers and pentamers requires remarkably subtle rearrangements in subunit interactions, and appears to be controlled by an electrostatic switch that favours hexamers over pentamers. This study completes the gallery of substructures describing the components of the HIV-1 capsid and enables atomic level modelling of the complete capsid. Rigid-body rotations around two assembly interfaces appear sufficient to generate the full range of continuously varying lattice curvature in the fullerene cone. PMID- 21248852 TI - X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel. AB - General anaesthetics have enjoyed long and widespread use but their molecular mechanism of action remains poorly understood. There is good evidence that their principal targets are pentameric ligand-gated ion channels (pLGICs) such as inhibitory GABA(A) (gamma-aminobutyric acid) receptors and excitatory nicotinic acetylcholine receptors, which are respectively potentiated and inhibited by general anaesthetics. The bacterial homologue from Gloeobacter violaceus (GLIC), whose X-ray structure was recently solved, is also sensitive to clinical concentrations of general anaesthetics. Here we describe the crystal structures of the complexes propofol/GLIC and desflurane/GLIC. These reveal a common general anaesthetic binding site, which pre-exists in the apo-structure in the upper part of the transmembrane domain of each protomer. Both molecules establish van der Waals interactions with the protein; propofol binds at the entrance of the cavity whereas the smaller, more flexible, desflurane binds deeper inside. Mutations of some amino acids lining the binding site profoundly alter the ionic response of GLIC to protons, and affect its general-anaesthetic pharmacology. Molecular dynamics simulations, performed on the wild type (WT) and two GLIC mutants, highlight differences in mobility of propofol in its binding site and help to explain these effects. These data provide a novel structural framework for the design of general anaesthetics and of allosteric modulators of brain pLGICs. PMID- 21248856 TI - DddY, a periplasmic dimethylsulfoniopropionate lyase found in taxonomically diverse species of Proteobacteria. AB - The abundant compatible solute dimethylsulfoniopropionate (DMSP) is made by many marine algae. Different marine bacteria catabolise DMSP by various mechanisms, some of which liberate the environmentally important gas dimethyl sulfide (DMS). We describe an enzyme, DddY, which cleaves DMSP into DMS plus acrylate and is located in the bacterial periplasm, unlike other DMSP lyases that catalyse this reaction. There are dddY-like genes in strains of Alcaligenes, Arcobacter and Shewanella, in the beta-, E- and gamma-proteobacteria, respectively. In Alcaligenes, dddY is in a cluster of ddd and acu genes that resemble, but also have significant differences to, those in other bacteria that catabolise both DMSP and acrylate. Although production of DMS and transcription of Alcaligenes dddY are both apparently inducible by pre-growth of cells with DMSP, this substrate must be catabolised to form acrylate, the bona fide coinducer. PMID- 21248857 TI - Marine integrons containing novel integrase genes, attachment sites, attI, and associated gene cassettes in polluted sediments from Suez and Tokyo Bays. AB - In order to understand the structure and biological significance of integrons and associated gene cassettes in marine polluted sediments, metagenomic DNAs were extracted from sites at Suez and Tokyo Bays. PCR amplicons containing new integrase genes, intI, linked with novel gene cassettes, were recovered and had sizes from 1.8 to 2.5 kb. This approach uncovered, for the first time, the structure and diversity of both marine integron attachment site, attI, and the first gene cassette, the most efficiently expressed integron-associated gene cassette. The recovered 13 and 20 intI phylotypes, from Suez and Tokyo Bay samples, respectively, showed a highly divergence, suggesting a difference in integron composition between the sampling sites. Some intI phylotypes showed similarity with that from Geobacter metallireducens, belonging to Deltaproteobacteria, the dominant class in both sampling sites, as determined by 16S rRNA gene analysis. Thirty distinct families of putative attI site, as determined by the presence of an attI-like simple site, were recovered. A total of 146 and 68 gene cassettes represented Suez and Tokyo Bay unsaturated cassette pools, respectively. Gene cassettes, including a first cassette, from both sampling sites encoded two novel families of glyoxalase/bleomycin antibiotic resistance protein. Gene cassettes from Suez Bay encoded proteins similar to haloacid dehalogenases, protein disulfide isomerases and death-on-curing and plasmid maintenance system killer proteins. First gene cassettes from Tokyo Bay encoded a xenobiotic-degrading protein, cardiolipin synthetase, esterase and WD40 like beta propeller protein. Many of the first gene cassettes encoded proteins with no ascribable function but some of them were duplicated and possessed signal functional sites, suggesting efficient adaptive functions to their bacterial sources. Thus, each sampling site had a specific profile of integrons and cassette types consistent with the hypothesis that the environment shapes the genome. PMID- 21248858 TI - Structure and functions of exopolysaccharide produced by gut commensal Lactobacillus reuteri 100-23. AB - Lactobacillus reuteri strain 100-23 together with a Lactobacillus-free mouse model, provides a system with which the molecular traits underpinning bacterial commensalism in vertebrates can be studied. A polysaccharide was extracted from sucrose-containing liquid cultures of strain 100-23. Chemical analysis showed that this exopolysaccharide was a levan (beta-2, 6-linked fructan). Mutation of the fructosyl transferase (ftf) gene resulted in loss of exopolysaccharide production. The ftf mutant was able to colonise the murine gastrointestinal tract in the absence of competition, but colonisation was impaired in competition with the wild type. Biofilm formation by the mutant on the forestomach epithelial surface was not impaired and the matrix between cells was indistinguishable from that of the wild type in electron micrographs. Colonisation of the mouse gut by the wild-type strain led to increased proportions of regulatory T cells (Foxp3+) in the spleen, whereas colonisation by the ftf mutant did not. Survival of the mutant in sucrose-containing medium was markedly reduced relative to the wild type. Comparison of the genomic ftf loci of strain 100-23 with other L. reuteri strains suggested that the ftf gene was acquired by lateral gene transfer early in the evolution of the species and subsequently diversified at accelerated rates. Levan production by L. reuteri 100-23 may represent a function acquired by the bacterial species for life in moderate to high-sucrose extra-gastrointestinal environments that has subsequently been diverted to novel uses, including immunomodulation, that aid in colonisation of the murine gut. PMID- 21248859 TI - Two new subfamilies of DNA mismatch repair proteins (MutS) specifically abundant in the marine environment. AB - MutS proteins are ubiquitous in cellular organisms and have important roles in DNA mismatch repair or recombination. In the virus world, the amoeba-infecting Mimivirus, as well as the recently sequenced Cafeteria roenbergensis virus are known to encode a MutS related to the homologs found in octocorals and E proteobacteria. To explore the presence of MutS proteins in other viral genomes, we performed a genomic survey of four giant viruses ('giruses') (Pyramimonas orientalis virus (PoV), Phaeocystis pouchetii virus (PpV), Chrysochromulina ericina virus (CeV) and Heterocapsa circularisquama DNA virus (HcDNAV)) that infect unicellular marine algae. Our analysis revealed the presence of a close homolog of Mimivirus MutS in all the analyzed giruses. These viral homologs possess a specific domain structure, including a C-terminal HNH-endonuclease domain, defining the new MutS7 subfamily. We confirmed the presence of conserved mismatch recognition residues in all members of the MutS7 subfamily, suggesting their role in DNA mismatch repair rather than DNA recombination. PoV and PpV were found to contain an additional type of MutS, which we propose to call MutS8. The MutS8 proteins in PoV and PpV were found to be closely related to homologs from 'Candidatus Amoebophilus asiaticus', an obligate intracellular amoeba-symbiont belonging to the Bacteroidetes. Furthermore, our analysis revealed that MutS7 and MutS8 are abundant in marine microbial metagenomes and that a vast majority of these environmental sequences are likely of girus origin. Giruses thus seem to represent a major source of the underexplored diversity of the MutS family in the microbial world. PMID- 21248860 TI - CO2 and vitamin B12 interactions determine bioactive trace metal requirements of a subarctic Pacific diatom. AB - Phytoplankton growth can be limited by numerous inorganic nutrients and organic growth factors. Using the subarctic diatom Attheya sp. in culture studies, we examined how the availability of vitamin B(12) and carbon dioxide partial pressure (pCO(2)) influences growth rate, primary productivity, cellular iron (Fe), cobalt (Co), zinc (Zn) and cadmium (Cd) quotas, and the net use efficiencies (NUEs) of these bioactive trace metals (mol C fixed per mol cellular trace metal per day). Under B(12)-replete conditions, cells grown at high pCO(2) had lower Fe, Zn and Cd quotas, and used those trace metals more efficiently in comparison with cells grown at low pCO(2). At high pCO(2), B(12)-limited cells had ~50% lower specific growth and carbon fixation rates, and used Fe ~15-fold less efficiently, and Zn and Cd ~3-fold less efficiently, in comparison with B(12)-replete cells. The observed higher Fe, Zn and Cd NUE under high pCO(2)/B(12)-replete conditions are consistent with predicted downregulation of carbon-concentrating mechanisms. Co quotas of B(12)-replete cells were ~5- to 14 fold higher in comparison with B(12)-limited cells, suggesting that >80% of cellular Co of B(12)-limited cells was likely from B(12). Our results demonstrate that CO(2) and vitamin B(12) interactively influence growth, carbon fixation, trace metal requirements and trace metal NUE of this diatom. This suggests the need to consider complex feedback interactions between multiple environmental factors for this biogeochemically critical group of phytoplankton in the last glacial maximum as well as the current and future changing ocean. PMID- 21248861 TI - General practice formularies: the way ahead? PMID- 21248862 TI - Beef in canadian diets. PMID- 21248863 TI - Survey of pharmaceutical promotion in a family medicine training program. AB - Some researchers have shown that advertising by the pharmaceutical industry has a significant impact on the prescribing habits of physicians. Promotional material invades the practice of physicians in many guises, including journal advertisements, drug samples, clinical symposia sponsored by drug manufacturers, and the ever-diligent detail person. The author analyzed the prevalence of drug advertising, and found that promotional material was present in all the offices and examining rooms of clinicians in a Canadian family practice teaching centre. On average, 10.5 promotional items were present in each individual patient care area and almost 750 items were found in each physician's office. PMID- 21248864 TI - [Not Available]. AB - The authors, both family physicians, report on a profile of fifty-eight (58) Montreal narcotic addicts admitted to a methadone treatment program in 1986. Their characteristic are similar to those published for addicts being treated in the United States. In particular, there is a high rate of involvement with crime, multiple drug abuse and family histories of violence. Certain characteristics are very helpful in the planning of future resources for the Montreal area and suggest possible avenues to primary prevention. The question is asked about which factors, if any, have prognostic significance. PMID- 21248865 TI - Prescribing to the elderly: a review of the english language canadian literature. AB - The elderly receive proportionately more prescriptions than any other age group in Canada. In a review of available English language studies in the Canadian literature, the author found that the most common groups of drugs prescribed for the elderly are psychotropic and cardiovascular drugs, principally digoxin and diuretics. Elderly women recieve the bulk of prescriptions for psychotropic agents. Some evidence indicates generalized overprescribing, as well as overprescribing of antihypertensive and psychotropic agents. The elderly seem to be the group most likely to suffer an adverse drug reaction. As the elderly proportion of the population continues to grow, it will become increasingly important to prescribe appropriately to them. PMID- 21248866 TI - Images of illness: blindness. PMID- 21248867 TI - Guidelines for return to activity after injury. AB - Complete and effective rehabilitation is dependent on many factors and may be identified and measured by eight objectives. Use of these objectives should help to prevent many of the common errors in rehabilitation. Of these eight objectives, the authors concentrate on development of specific sports-related biomechanical skill patterns, an objective that is frequently neglected. Analysis of the specific demands of each sport for each athlete is required to tailor rehabilitation protocols as well as to provide a standard to determine when the athlete can return. Progressive sports-specific activity will help to return the athlete safely to activity. PMID- 21248868 TI - Does physical therapy have a role in fitness? AB - The author discusses the role of the physical therapist in fitness along with the interplay and communication necessary between the physician and therapist to ensure optimum care. The increased scientific knowledge of the physical therapist is also discussed. PMID- 21248869 TI - Patellofemoral syndrome: therapeutic regimen based on biomechanics. AB - The clinician needs to rehabilitate the patient with the patellofemoral syndrome based on biomechanics and anatomy. If we understand the function of the patella and the forces acting upon it, we can educate our patients to ensure their compliance through both the treatment phase and future maintenance. PMID- 21248870 TI - Calf pain in athletes. AB - The authors reviewed the literature published in English during the past 10 years about injuries to the musculotendinous unit of the posterior aspect of the leg. They discuss the anatomy and function of the motor unit, the history and physical examination pertinent to the injury, the differential diagnosis, and the management of the injury. The controversy over surgical versus conservative treatment continues with no general consensus. PMID- 21248871 TI - Fitness and spinal cord injuries. AB - Activity for many disabled persons often begins as therapy, but the additional rewards derived from exercise must be appreciated. Public attitudes toward disabled persons have changed during the last few decades, recently focusing on abilities rather than on disabilities. The family physician of patients with spinal cord injuries will assist in managing acute medical problems and the association with loss of some degree of physical capacity. Physicians also can guide these individuals to choose a life that remains active and interesting over a "house-bound," but safe, existence. Sensitivity and timing play key roles in establishing exercise as an intergral part of a disabled individuals' altered lifestyle. The physician can advocate increased access to wheelchairs and other facilities that make life easier for disabled individuals. PMID- 21248872 TI - Examining the Prospective Scuba Diver: Which Exclusions are Proven? AB - Who can safely dive? All prospective divers in Canada must have a physician's approval to start training. Many review articles and typical check-list medical forms, however, imply exclusions that are not well proven. The author critically analyzes current diving and diving accident statistics and discusses the physiology of risk. He also discusses diving morbidity and mortality from pressure changes, illness caused by immersion only, hypothermia, and diving during pregnancy. PMID- 21248873 TI - Exercise during pregnancy: current state of the art. AB - Women should be encouraged to become fit before they become pregnant. During pregnancy, those who were accustomed to aerobic exercise before pregnancy can probably continue their sports involvement throughout pregnancy, at the same perceived level of exertion. Weight training and calisthenics are advisable during pregnancy, even for those who never practised them before. Pregnant women should avoid high intensity, prolonged duration, hyperthermia, dehydration, abdominal trauma, and low oxygen availability in exercise. PMID- 21248874 TI - Culture and disability. PMID- 21248875 TI - Problems with emergency departments. PMID- 21248876 TI - Managing dyspepsia: a comment. PMID- 21248877 TI - Author's Views His Own. PMID- 21248878 TI - Training FPs in Emergency Medicine. PMID- 21248879 TI - Papanicolaou testing by physicians in manitoba: who does them? AB - Pap testing is one of the few effective preventive health practices available to primary care physicians. Yet we know little about how well this procedure is being done. Using data from the province of Manitoba's universal health insurance plan for the years 1976, 1978 and 1982, we determined the proportion of all Pap tests of women over 25 years of age performed by the various physician specialties; the percentage of physicians in each specialty who performed tests; and the mean number of tests per specialty group. We also determined the mean number of tests by age and training of the physician. The number of physicians performing Pap tests increased from 749 in 1976 to 780 in 1982. About 2% of Pap tests performed in the province were done by internists, 5% by general surgeons, about 33% by obstetrician/gynecologists, 40% by urban general practitioners, and 22% by rural general practitioners. Other physicians accounted for less than 0.2% of all tests. The mean number of Pap tests performed increased with increasing physician age up to age 60 and declined thereafter. Manitoba-trained physicians performed the highest rate of Pap testing, and this pattern was maintained over time. In 1982, only 22% of internists, 29% of general surgeons, and 78% of family physicians/general practitioners were performing tests. These results raise the question of why a significant number of physicians are not carrying out this effective preventive health practice. PMID- 21248880 TI - Use of clinical and paraclinical data to diagnose appendicitis in a patient with abdominal epilepsy. AB - We report a case of acute appendicitis in a 36-year-old patient with recurrent abdominal pain diagnosed seven years previously as abdominal epilepsy. Prior to his reported presentation, he successfully managed his pain at home by self administration of phenobarbital, but on three previous occasions the patient required emergency-department treatment for severe pain. Our patient had been symptom free for several months prior to this presentation. This case raises several important questions regarding the approach to the diagnosis of acute appendicitis in the emergency department. The case illustrates the relative value of clinical and paraclinical data in establishing the diagnosis. We evaluate accepted clinical and paraclinical data used to diagnose acute appendicitis and advocate using likelihood ratios to increase diagnostic accuracy. PMID- 21248881 TI - Gastric cancer in primary care: how hard should you look? AB - This article addresses the question of how vigorously a physician should search for gastric cancer among dyspeptic patients. To address this subject, two major questions are posed: Which patients presenting with dyspepsia are at highest risk of having gastric cancer? Does early diagnosis of symptomatic gastric cancer affect outcome? Although early detection of gastric cancer has been increasingly reported since the advent of fiberoptic endoscopy, factors such as lead time bias and an unchanged case-fatality rate preclude a definitive conclusion of improved treatment outcomes resulting from early detection. At present, a policy of routine immediate investigation of dyspeptic patients has not been shown to reduce gastric cancer mortality. PMID- 21248882 TI - Multiculturalism, medicine and health part v: community considerations. AB - In this article the author examines multicultural health issues from a community perspective, dealing with relationships between cultural communities and health care systems in terms of: hospitals and health-care institutions, family and social supports, social norms, and community-health programs. PMID- 21248883 TI - Neuroleptic malignant syndrome in an octogenarian: a case report. AB - Neuroleptic malignant syndrome is a potentially fatal and frequently undiagnosed consequence of the use of neuroleptics. We present a case report of the syndrome in an octogenarian, the second such to appear in the literature. This syndrome is reviewed and its importance in diagnosis and treatment of the elderly is indicated. PMID- 21248884 TI - Anorexia nervosa or not? A case presentation. AB - The authors of this article present a case of diabetic gastroparesis, initially diagnosed as anorexia nervosa. They compare the symptoms and signs of diabetic gastroparesis with the diagnostic criteria for anorexia nervosa and discuss treatment with domperidone. PMID- 21248885 TI - Training family physicians in emergency medicine. PMID- 21248886 TI - Quadriplegia: urological complications. AB - Unlike the general public, quadriplegics are prone to various urological complications as a direct/indirect result of spinal cord lesions. These complications include neurogenic bladder, urinary tract infections, renal and bladder calculi, obstructive uropathy, renal failure, and bladder neoplasms. A significant portion of upper urinary tract disease, including pyelonephritis, hypernephrosis, and calculi are usually secondary to neurogenic bladder related to detrusor sphincter dysfunction. These complications will be discussed in some detail in the following report. PMID- 21248887 TI - Pulmonary rehabilitation in the community hospital. AB - Chronic obstructive lung disease (COLD) often has a devastating impact on a patient's social and physical well-being. Pulmonary rehabilitation can help patients with COLD to optimize their quality of life. It can be used successfully by means of the resources available in a small community hospital. This article summarizes one approach to rehabilitation for COLD patients and deals with the results and the benefits to the patients and their families. It also considers the advantages for the medical staff and the community. PMID- 21248888 TI - Problems in prosthetics. AB - In the ever-evolving scientific world of medicine, prostheses continue to fulfill a necessary function. Modern aggressive management of such diseases as diabetes, stroke, and peripheral vascular disease has been matched by new technology and attitudes in the world of prosthetics. The final common denominator continues to be the patient. The problems patients have continue to be the focus of the Rehabilitation physician. PMID- 21248889 TI - Management of chronic pain. AB - Chronic pain is a major personal, family, and community disaster. The sufferer usually has difficulties in every aspect of life. The key to successful treatment lies in a comprehensive and accurate assessment that must include family, marital, legal, behavioural, mental, and organic considerations. With comprehensive assessment, a logical plan of treatment can be constructed. Non compliance, substance abuse, doctor shopping and secondary gain, as well as complex psychodynamics, make management of such pain difficult and frustrating. The patients are frequently playing "games" in which they control the rules, and which the physician can never win. Success rates are poor even in specialized centres, and many patients are ultimately injured by inappropriate investigation or treatment. Physicians who have become over-involved with such patients may also be injured by the process, to the detriment of their general care of other patients and themselves. PMID- 21248890 TI - Learing disabilities and the primary care physician. AB - Approximately 10% of the population has learning disabilities (LD). Although the main manifestations occur in childhood, many of the primary and secondary manifestations of LD can continue into adult life. The high prevalence of LD and the current economic climate in Canada imply that the primary care physician must have a role in the identification, diagnosis, and management services for persons with LD. Information about the specific aspects of a particular person's LD should be incorporated into the evaluation and management of other health matters with which the primary care physician deals. PMID- 21248891 TI - Primary Medical Care and Children's Learning Problems. AB - The authors describe the major learning problems that confront the primary-care physician. They discuss why they believe that the primary-care physician has an important role in case finding, referral, case management, and advocacy for the child with learning problems and his or her family. PMID- 21248892 TI - Emotional care of the mentally handicapped. AB - Emotional care of the mentally handicapped is complex. The author of this paper addresses issues of development of handicapped persons, and how these persons differ from those of average intelligence. She considers the unique circumstances of the family of the handicapped person and reviews factors relevant to the assessment of an emotional problem in a person so handicapped. She also outlines treatment modalities found effective for handling emotional concerns in this population. The family physician is encouraged to use an eclectic approach. A creative and accepting attitude towards the mental handicap can be the physician's greatest asset in assisting with emotional care of this group of people. PMID- 21248893 TI - Sexuality in persons with severe physical disability: a guide to the physician. AB - Persons with disabilities, as a group, may have distinctly fewer options for functioning sexually according to their own needs and goals than have able persons. Physicians have three special roles in providing sexual health care: identifying problems that are sexual; assessing these problems; and providing in depth management. Assessment includes a review of the disabled person's sexual response abilities, fertility potential and capability to use birth control, and estimates of musculoskeletal functions for intimate physical contact and bowel and urinary continence. Other areas to assess include partnership capabilities, sexual self-esteem, and sexual interest levels. Management is a team effort. Psychological, medical, and surgical methods developed for sexually dysfunctional persons may be adapted for persons with disabling conditions. PMID- 21248894 TI - Caring for families with a handicapped member. AB - The family with a handicapped member experiences stress and faces a variety of potential problems. The response of the family unit will vary according to the timing of this experience in the family life cycle, the health of the family, and the nature of the handicapped member's disability. Awareness of the needs of the family unit will help the physician to ensure its members' proper education and support, and to identify those families that may require family assessment and therapy. Dealing with the handicapped may also have implications for the physician. PMID- 21248895 TI - Charcot-marie-tooth disease as a disabling disorder. AB - The author looks at Charcot-Marie-Tooth disease and the disabling effects that it can have on the patient. A course of action is outlined to help the patient cope more fully with this fairly common but little understood disorder. PMID- 21248896 TI - Dental care for the handicapped. AB - The family physician/pediatrician who sees the newborn handicapped infant is the health-care professional who can best influence the parent concerning the general health-care needs of the child. The realization that dental disease is preventable and need not further compromise the child's health is of major importance. Too often dental care is not considered important until an emergency arises, and then panic follows. This paper will delineate some of the basic principles involved in providing dental treatment for the disabled and the importance of an early referral so that a sound preventive program can be instituted. This approach will minimize the need for emergency visits and will help to establish a solid rapport with the parents/guardian and the handicapped child. PMID- 21248897 TI - Nutritional problems of native canadian mothers and children. AB - Nutritional deficiencies are still all too common in Native Canadian women and children. Protein-calorie malnutrition is rare, although the 1972 Nutrition Canada Survey found low intakes of these nutrients in many pregnant Native women, especially among the Inuit, who still have a high (8%) incidence of low-birth weight infants. Clinically, we still see a great deal of iron deficiency and, although it is less common, of vitamin D-deficiency rickets in infants and toddlers. Breastfeeding rates are 50% or less at six months, and prolonged use of the nursing bottle contributes to iron deficiency and dental caries. Fluoride is not present in the water supply of most Native communities and must be given to combat dental caries, which is rampant in some areas. In adolescents we begin to see signs of overnutrition, with noticeable obesity that is highly prevalent in adults. The ultimate solution to these problems is improved economic circumstances and education. In the meantime, however, physicians treating Native patients must become familiar with the local circumstances. PMID- 21248898 TI - Esthetic dentistry. AB - The author of this article discusses the development of means to attach biologically acceptable polymers to tooth enamel, as well as the ongoing development of suitable reinforced plastics to provide esthetic improvement of patients' teeth. She describes a variety of esthetic dental problems and discusses their treatment. PMID- 21248899 TI - Bulimia: a comment on an old case report by sir Thomas browne. AB - This paper offers a brief review of recent literature on the incidence and age of onset of bulimia in the light of a 17th century description of a female centenarian with bulimia, together with a brief account of the physician, Sir Thomas Browne (1605-1682), and the etymology and early usage of the term. PMID- 21248900 TI - To a safer place. PMID- 21248901 TI - Social conscience among family physicians. PMID- 21248902 TI - Patients in nursing homes. PMID- 21248903 TI - Injury and illness among deer hunters. AB - General practice and out-patient emergency records for a five-year period were reviewed for injuries and illnesses that occurred during the week of deer rifle hunting on Manitoulin Island. Of 65 hunters who were identified, most had lacerations secondary to knife injuries. There were two deaths (one shooting and one in a motor vehicle accident), and 19 persons required hospitalization. More than half of these serious accidents occurred on the weekends immediately preceding or following the hunting season. Incidence of injury or illness requiring medical attention was calculated to be 0.23% per hunter each week of the deer season. Spot checks for alcohol and improved hunter safety courses might prevent many of these injuries and illnesses. PMID- 21248904 TI - A comparison of two methods of assessing alcoholism. AB - The author examined Michigan Alcohol Screening Test (MAST) scores and selected laboratory results of 50 patients encountered in a family physician's office. The severity of alcohol-related problems (as reflected by the MAST) was compared to the toxic effects of alcohol (as measured by the SGOT, gamma-glutamyltransferase levels, and the mean cell volume). No association was found between the MAST scores and the cellular toxic effect of alcohol. Patients with extensive alcohol related problems were more likely to report prolonged sobriety. These results suggest that testing with both MAST and laboratory tests is required to discover the effects of alcohol abuse in ambulatory patients. PMID- 21248905 TI - Neonatal resuscitation: a pictorial review. AB - All medical personnel participating in obstetrical deliveries have the obligation to anticipate potential neonatal problems and to maintain competence in newborn resuscitation. This step-by-step demonstration of neonatal resuscitation is applicable to both community and teaching hospitals. PMID- 21248906 TI - Pulmonary function tests: are they really necessary? AB - Pulmonary function tests and clinical evaluation can complement one another, but neither can take the place of the other. The tests can provide objective, reproducible assessment of a patient's pulmonary status. Pulmonary function tests can support clinical diagnoses, quantify the severity and variability of the disorder, and can assist early intervention by indicating problems likely to arise later in the course of the disease. PMID- 21248907 TI - Helping patients to quit smoking. AB - Years ago, the tobacco leaf offered its users many social and ceremonial benefits. But today, throughout the world, the manufactured cigarette wreaks biological havoc. Clinically, physicians can make a small, but significant, contribution to their patients' stopping smoking. Family physicians who want to offer systematic aid to their smoking patients should assess the amount of time and energy they are willing to invest in patients' smoking and the probable rewards of such efforts. Behavioural change comprises four stages: a pre motivational phase, a motivational phase, a behavioural-change phase, and a maintenance phase. Anyone who has ever smoked belongs to one of these phases and should be treated accordingly. Paradoxically, the physician should support consonant smoking (the patient freely choosing to smoke) except when the smoker is actively engaged in changing behaviour. PMID- 21248908 TI - Out-patient management of bronchial asthma. AB - Asthma, seen primarily as an inflammatory disease with secondary airway hyper responsiveness, causes symptoms through contraction of the airway's smooth muscles. The management of chronic asthma relies on bronchodilators for symptomatic relief of bronchospasm, while primary therapy is used to either prevent or reverse the inflammatory component of the disease. Anti-inflammatory therapeutic strategies include environmental control (where relevant), sodium cromoglycate (where appropriate), and both inhaled and oral glucocorticosteroids. Management of acute severe asthma is similar; bronchodilators are used to "buy time" while systemic corticosteroids control the inflammatory process. PMID- 21248910 TI - Respiratory diseases in iron ore miners and millers. AB - Workers in iron mines are at risk of developing interstitial lung disease if the dust levels are above the threshold limit value. However, they more commonly develop the usual diseases that affect all workers. Some illnesses, such as chronic bronchitis, bronchial asthma, and the collagen vascular diseases that affect the lung, may be more severe because of the inhalation of dust. The most difficult problem is to differentiate asymptomatic sarcoidosis from pneumoconiosis. The family doctor who also acts as the company doctor must be aware of the potential conflict of interest. PMID- 21248909 TI - Avoiding asthma fatalities in family practice. AB - Epidemics of sudden death in patients with asthma are more likely to result from inadequate realization of severity and insufficient or inappropriate drug therapy than from toxic drug reactions. The authors review management in children and adults involving step-by-step addition of different classes of drugs according to the severity and persistence of the asthma. PMID- 21248911 TI - Out-patient management of patients with chronic obstructive lung disease. AB - The treatment of chronic obstructive lung disease is multifaceted. If the patient smokes, he or she must quit. Treatment includes bronchodilator therapy, glucocorticosteroids, antibiotics for acute exacerbations, oxygen therapy for patients with chronic hypoxemia (it can also help patients with nocturnal and exercise-induced hypoxemia), and respiratory rehabilitation for motivated patients. Inhaled beta-agonists and anticholinergic agents have additive effects in recommended doses, as do theophylline and beta-agonists. PMID- 21248913 TI - Medifacts tape: response. PMID- 21248912 TI - Sigmoidoscopy for all? PMID- 21248914 TI - Biased medifacts tape: comment. PMID- 21248915 TI - Management of asthma. PMID- 21248916 TI - Sigmoidoscopy in general practice. AB - The author performed 961 consecutive rigid sigmoidoscopic examinations in his private practice from 1977 to 1986. All procedures were evaluated according to indication (541 routine "case finding" vs. 420 diagnostic examinations), risk status for colorectal cancer, presence of occult blood, relation to other modes of polyp detection (barium enema or colonoscopy), and pathology. During the 541 routine examinations, 70 (12.9%) procedures revealed 89 polypoid lesions. About half of these lesions were neoplastic, and the remainder were hyperplastic. Two carcinomas in situ were discovered during routine examination. During the 420 diagnostic procedures, 35 neoplastic polyps were discovered, including two invasive carcinomas and one carcinoma in situ within reach of the sigmoidoscope. Other colorectal disorders, such as ulcerative proctitis, were readily diagnosed. PMID- 21248917 TI - Colon and rectum rigid and flexible endoscopy. AB - The authors examined results of 1046 of the 1268 endoscopic examinations performed from July 1982 to June 1986 in a family practice unit. A flexible sigmoidoscope of 60 cm or more was used for 77% of the examinations. Data were collected from patients' charts and analyzed by computer in collaboration with a research methodologist. Screening for colorectal cancer was the reason for the examination in 287 patients (27.4%). More than 60% of the examinations were performed on patients with digestive symptoms. Miscellaneous colorectal diseases were diagnosed; more than 12% of the patients had at least one polyp with a diameter of 5 mm or more. Nine patients (0.86%) had cancer, and one patient had two primary tumours. Three of the nine patients were asymptomatic, and four had blood in their stools. Six patients had cancers found at a very early stage of development. PMID- 21248919 TI - Occupational medicine: opportunities for family physicians. AB - Occupational medicine has grown recently in sophistication and strength. Occupational physicians with specialty certification focus their attention on toxicology and health hazards in the workplace, compliance with regulatory requirements, and preventive services. These physicians are often employed by organizations. Most occupational health care will continue to be provided by family physicians, who may also be the physicians closest to the workers and their families. There are many opportunities for family physicians to develop their skills in occupational health care and to incorporate occupational medicine into their practices. PMID- 21248918 TI - Assessment and management of the violent patient. AB - The author reviews various techniques for evaluating the relative risk of violent behaviour. Recognition of relevant patient-related factors is explored. Management techniques are presented to help the physician avert and deal with impending or manifestly violent behaviour. Specific management techniques include talking to the patient, pharmacological agents, and pharmacological restraint. PMID- 21248920 TI - Occupational medicine: new interface for family medicine? AB - Family physicians are naturally concerned with the work effects or causes of their patients' health problems. As occupational risk factors have become better understood, however, a new specialty of occupational medicine has been recognized by the Royal College of Physicians and Surgeons in 1984, two years after the Canadian Board of Occupational Medicine started its own certification. Occupational physicians are available to act as an extension of the family doctor's care and can provide trustworthy medical resources in the workplace. The family physician should be aware of some of the games poorly trained or ill informed personnel managers may play in the workplace if they have no medical consultant to rely on. New human rights legislation has given more opportunities to rehabilitate workers back to their jobs, and occupational physicians and family physicians can achieve a great deal in co-operation as a result. PMID- 21248921 TI - Medical consequences of stratospheric ozone depletion. AB - The absorption of ultraviolet (UV) light by stratospheric ozone is crucial to the provision of an environment suitable for terrestrial life. Ultraviolet radiation is the part of the solar spectrum with wavelengths between 240 and 400 nm. Photons at wavelengths below about 320 nm can produce photochemical damage to the cells of living organisms. Data suggesting a causative role for UV exposure in squamous cell carcinoma, basal cell carcinoma, melanoma, cataract formation, and (as yet) poorly defined immune suppression comes from epidemiologic studies and, in some cases, clinical observation and experimental work. The author concentrates on the direct health effects of UV radiation, although the factors that lead to stratospheric ozone depletion also exert other powerful influences on the biosphere that will have less predictable direct and indirect effects on human health. PMID- 21248922 TI - Pre-employment and Return to Work Examinations. AB - The occupational health examination can be a challenging and interesting part of family practice. The pre-employment examination is conducted to ensure that the prospective employee has the physical and mental capacity for the job's demands. It is important to know both the state of the employee's health and the actual work environment, best assessed by visiting the work site. Most difficult decisions can be resolved by good communication with the employee and, with the employee's permission, with the employer. PMID- 21248923 TI - Workers' compensation claims: hidden agendas. AB - Successful management of compensable occupational disorders requires an understanding of both the medical and social models of illness. In addition to the usual roles of medical diagnosis and treatment, the physician must assume a number of hidden roles, including assessing job hazards, arriving at an opinion of work-relatedness, identifying unrealistic expectations and factors that may delay recovery, and identifying as early as possible when vocational rehabilitation is necessary. As a central member of the claims management team, the practising physician can contribute meaningfully to the employee's successful return to the work-force. PMID- 21248924 TI - Rehabilitation of the injured worker. AB - The Workers' Compensation Board is mostly involved in secondary and tertiary prevention of work-related accidents and disease. Through its new Medical Rehabilitation Strategy, the board will help to ensure that optimal health care programs are available to injured workers. For workers who are left with restricted function, even after the best possible health care, vocational rehabilitation or tertiary prevention programs are offered. In both phases the primary care physician has a key function and must be familiar with the "state of the art" treatment of so-called minor trauma and activity-related disorders. Physicians also must recognize the importance of providing a reasonable prognosis as early as possible because it will drive the vocational rehabilitation planning process. PMID- 21248925 TI - High-risk workers: the eczematous hand. AB - The hand is the most commonly involved site in occupation - related skin disease, and contact eczema is the most common diagnosis. The identification of workers at high risk for this condition is possible and will help in their management and assessment. PMID- 21248926 TI - WHMIS-The Right to Know in Canada: Are Family Physicians Prepared? AB - The family physician is in a unique position to provide information on health hazards and to answer questions about the causes of a person's illness, yet family physicians may not be prepared for the massive flow of new information being released to the public about workplace hazards. The Workplace Hazardous Material Information System (WHMIS) is designed to give Canadians information and training on workplace hazards. It requires that 1) all chemicals be labelled as to the nature of their hazards; 2) Material Safety Data Sheets be made available, which include health effects as well as control information; and 3) all workers be trained on the nature of the chemicals and their safe use. This report suggests sources of help for family physicians. PMID- 21248927 TI - Assessing functional capacity in occupational health: relevance to family physicians. AB - The family physician is often called on to determine the work readiness of a patient after injury. This determination can be assisted by the use of a formal functional capacity evaluation, which is available as a service through private agencies and Workers' Compensation Boards. These programs can be best used with a clear understanding of the injury and return to work process, the programs available, and most importantly, the terminology used in functional capacity evaluation. The authors describe these matters, particularly as they relate to the interaction between the family physician and the Worker's Compensation Board. Increased familiarity with these concepts will promote better communication among all who attempt to reduce the disabilities of injured workers. PMID- 21248928 TI - Advice on Pre-natal Work and Employment. AB - Most pregnant women are now employed during pregnancy, and almost all pregnant women do physical work of some kind. The author reviews the four major considerations in the provision of good prenatal advice for the working woman: the woman and her health status, the pregnancy itself, the job, and the woman's circumstances. Particular features of the job, including physical, chemical, biological, and psychological factors, are noted. For further information on specific work exposures, the family physician can consult expert sources. The author outlines general features of prenatal information that can be provided for all women who work during pregnancy. PMID- 21248929 TI - Occupational hazards of farming. AB - A number of occupational hazards exist for the farmer and farm worker. They include the hazards of farm machinery, biologic and chemical hazards, and social and environmental stresses. Recognizing of these hazards will help the family physician care for farmers and their families. PMID- 21248930 TI - Occupational health problems of musicians. AB - Musicians, as well as other performing artists, may have their careers interrupted by, interfered with, or terminated by occupational health problems involving the neuro-musculoskeletal system. Adverse working conditions, organization, and activity may affect the health of musicians in all age groups and at all levels of performing ability. Instrument-specific health problems are related to excessive force, static loading, repetitive movement, and duration of musical performance. Important risk factors are 1) change in technique or instrument; 2) intense preparation for a performance; 3) preparation of a new and difficult repertoire; and 4) prolonged periods of performance without rest. Treatment protocols and health promotion or disease prevention programs are being developed in collaboration with the performing arts community. PMID- 21248931 TI - Breaking through the boundaries. PMID- 21248933 TI - Ingrown toenails. PMID- 21248932 TI - Emergency medicine training. PMID- 21248934 TI - Specializing in primary care. PMID- 21248935 TI - Observations from fifth business. PMID- 21248936 TI - Testicular self-examination: are primary care physicians teaching this preventive measure? AB - The author polled 118 family physicians about their screening procedures for testicular cancer in males at risk. Fewer physicians (63%) teach testicular self examination (TSE) than teach breast self-examination (100%) as part of a periodic health examination. Physicians who examine their own testes or breasts regularly are more likely to examine their patients' testes during a periodic examination and to teach TSE to males at risk. Female physicians are more likely (75%) than male physicians (24%) to teach TSE. PMID- 21248937 TI - Mammography screening practices among primary care physicians. AB - Mammography screening is controversial; consequently, physicians' compliance with established recommendations varies. This questionnaire showed that 55.2% of responding physicians have some form of schedule for mammographic screening, but only 7.5% follow the Canadian recommendations exactly. The main reasons for not screening are fears of radiation exposure, concerns about cost-effectiveness, and feelings that mammography does not improve the prognosis of breast cancer. Physicians were more likely to screen by mammography if they were in group practice, female, had completed a family practice residency, and had been in practice 15 or fewer years. PMID- 21248938 TI - Pain perception in the neonate. AB - Pain expression in both pre-term and term infants is a little understood phenomenon. Recent research has generated data documenting that the newborn can feel pain, can act to avoid the pain, and may form memory traces of the experience. "Nociceptive activity" or "noxious stimuli" are better terms to use when addressing aversive stimulation of the neonate because they encourage scrutiny of the behavioural and physiologic responses of the newborn without placing emphasis on the emotional and subjective associations of the word "pain". Many invasive procedures are performed on infants with little or no provision for adequate pain management. The general and specific responses of the neonate to pain must be recognized. Analgesia and anesthesia should be made available to all infants, pre-term or term, sick or well, on the same basis on which they are made available to older children and adults. PMID- 21248939 TI - Unusual Complication of ACE Inhibitor-Induced Cough. AB - A cough produced by the administration of the angiotensin-converting enzyme (ACE) inhibitor, captopril, resulted in a case of rectus abdominis hematoma. The author discusses the incidence and pathophysiology of ACE inhibitor-induced cough. PMID- 21248940 TI - Akathisia. AB - An elderly woman diagnosed as having inoperable adenocarcinoma of the lung with liver metastases complained of extreme agitation within one week of diagnosis and symptomatic treatment. It was difficult to distinguish at first between a possible side-effect of the medication prescribed and the anxiety likely to be associated with the diagnosis of cancer and with an unfavourable prognosis. PMID- 21248941 TI - The spectrum of grief: identification and management. AB - Loss is a common human experience, and grief is frequently seen in a physician's office. Grief occurs not only after a death, but also during chronic or serious illness, infertility, divorce, job changes, surgery, rape, and so forth. Some patients somatize distress, presenting with physical symptoms rather than acknowledging their grief. Bereavement increases the risk of both psychiatric and physical disease and can exacerbate pre-existing illness. In the majority, grief resolves normally, but in some the process becomes morbid. The family physician is in a unique position to identify, educate, assess, and intervene with the grieving patient and his family. PMID- 21248942 TI - Unnecessary delay in tricyclic antidepressant treatment of a patient with atrial fibrillation. AB - Atrial fibrillation and other cardiac conduction disturbances are not contraindications for the use of tricyclic antidepressants. A case in which physician unfamiliarity with these facts led to an unnecessary delay in the antidepressant treatment of a patient with depression and long-standing atrial fibrillation is presented. PMID- 21248943 TI - The misdiagnosis of "depression". AB - The author employs recent diagnostic criteria to distinguish between depressive illness (major depressive episode) and other conditions involving depressive mood that more commonly present to the family physician. Relative indications for antidepressant medication and for two types of psychotherapy are discussed. The potential results of routinely prescribing antidepressants to patients who complain of depressive mood are outlined. PMID- 21248944 TI - Patient with borderline personality disorder. AB - Every family practice includes people who are difficult to manage. Persons with a borderline personality disorder can be the most difficult of all. They will trust no one, and consequently few, if any, others will be able to tolerate their profoundly difficult interpersonal communication style. These patients will present to their family physician more and more often with a variety of somatic and emotional symptoms. They will demand, either verbally or silently, that these symptoms be relieved immediately. This increasing demand for immediate response may eventually cause the physician to reject the patient. An understanding of this condition and how it develops in infancy may enable the physician to help the patient. A family physician who can set appropriate limits to the patient's demands may slowly convince the patient that he can trust and not be hurt. PMID- 21248946 TI - The successful use of antidepressants. AB - Depression is the most common psychiatric problem presenting to the family physician. The prevalence of depression among family-practice patients is of the order of 10%. Most cases of depression are treated by family physicians. Thus it is essential for family physicians to be fully familiar with the effective use of antidepressants. This article outlines the key components necessary for the successful use of antidepressants. The author discusses appropriate indications, dosage, length of treatment, and the psychotherapeutic functions of the physician. PMID- 21248945 TI - Neuroleptic malignant syndrome: a review. AB - There has recently been interest in neuroleptic malignant syndrome (NMS) as the disorder has been better characterized. Nms is still poorly recognized, however, by most physicians. Hyperpyrexia, rigidity, altered consciousness, autonomic instability, and enzymatic evidence of muscle breakdown after drug intake are the cardinal features. The authors of this article review the proposed pathogenesis, complications, and treatment of NMS. PMID- 21248947 TI - Aggression: psychopharmacologic management. AB - Aggression may be part of a variety of psychiatric diagnoses. The appropriate treatment requires that the physician recognize the underlying cause. Pharmacologic agents may form part of the overall treatment of the patient. The number of possible drugs for treating aggression has expanded rapidly, and it is important that the physician be familiar with the various options avilable. PMID- 21248948 TI - Two techniques of supportive psychotherapy. AB - This paper describes two techniques of supportive psychotherapy - clarification and confrontation - which can be used by family physicians. Case examples are offered to illustrate the application of these techniques. The author discusses what supportive psychotherapy is, and what it is not. PMID- 21248949 TI - Psychological treatment of depression: cognitive behavioural therapy. AB - Psychotherapy is preferred over pharmacotherapy in many instances of depression, either because of side-effects or overdose concerns, or because of the patient's choice. Psychologists are most likely to provide a course of cognitive therapy for depressed individuals. This paper offers a brief description of treatment results, rationale for therapy, and the elements of therapy. PMID- 21248950 TI - Social phobias: behavioural and pharmacotherapy. AB - Five to 10% of the general population suffers from symptoms of an anxiety disorder. Social phobias, while less common than panic disorder, agoraphobia or simple phobias, are just as debilitating. Patients present with somatic, behavioural, mood and cognitive disturbances, of which unrecognized social isolation, depression, loss of employment, and drug and alcohol abuse can be the result. A symptomatic approach can be implemented through the use of education, insight, support, behaviour therapy, cognitive therapy, and pharmacological intervention. PMID- 21248951 TI - Reassurance does not always help. AB - Reassurance is the most commonly misused form of supportive intervention in medical practice. It is superficial in activity and transient in its effects. It does not appear to be a very powerful therapeutic technique. To be effective, it should be realistic, sincere, given at the right time, directed at the appropriate target, based on sound grounds, and provided by a proper authority. It must always be given judiciously. PMID- 21248952 TI - Recognition of problem drinkers. AB - General practitioners often see patients with problems related to drinking behaviour, but recognize only a small proportion of these problem drinkers. The authors discuss some mechanisms of this non-recognition phenomenon and suggest ways to enhance early recognition. PMID- 21248953 TI - Diet and coronary heart disease: does beef fit in? AB - Changes in the fat and cholesterol content of retail cuts of Canadian beef over the past 16 years indicate that it is not necessary to limit beef in diets designed to meet the guidelines recommended at the recent Canadian Consensus Conference on Cholesterol. Recent studies have shown that the retail cuts of beef available in Canada today contain 20% to 60% less fat than previously reported in the Canadian nutrient data file. Cuts from the loin and hip region of the carcass (e.g., sirloin steak, round steak, and rump roast) that are trimmed of all visible fat are similar in fat, energy, and cholesterol content to chicken and fish. PMID- 21248954 TI - Emergency lumbar puncture in adults. AB - Three patients who had lumbar punctures performed in the presence of undiagnosed intracranial space-occupying lesions are described. Neurologic deterioration was precipitated in one and continued in another; neurologic status was unchanged in the third patient. The use of lumbar puncture in adults in the emergency setting is discussed in light of the accepted indications and contra-indications, available data on complication rates, and regional availability of cranial computed tomography. We recommend that all patients undergo computed tomography or other brain imaging, such as magnetic resonance, prior to lumbar puncture in order to detect unsuspected intracranial mass lesions or other abnormalities (such as subarachnoid hemorrhage and hydrocephalus) that would preclude lumbar puncture. PMID- 21248956 TI - Rural medical care in ontario: problems and possible solutions in the next decade. PMID- 21248955 TI - Screening for bacteriuria in infants. PMID- 21248958 TI - Supervised residencies. PMID- 21248957 TI - Statement on midwifery: a comment. PMID- 21248959 TI - Malaria prophylaxis. PMID- 21248960 TI - Inappropriate diabetes screening. PMID- 21248961 TI - Ancient reports of bulimia. PMID- 21248962 TI - Refusing to keep the secret. PMID- 21248963 TI - Family medicine research update. PMID- 21248964 TI - Sorbitol in bactrim(r). PMID- 21248965 TI - Men and women choose different careers in medicine: causes and consequences. AB - WOMEN MEDICAL GRADUATES OF MCMASTER UNIVERSITY WERE DIVIDED INTO TWO GROUPS: those in the fields traditionally chosen by women (primary care, general internal medicine, pediatrics, psychiatry, and anesthesia), and those in nontraditional fields (surgery, subspecialties of medicine, and academic medicine). The careers of the two groups of women were then compared with matched groups of men physicians. More women choosing traditional careers worked in another field, frequently health-related, before deciding to enter medicine than women entering nontraditional careers. Fewer of the former had a university education in the natural sciences, and more of them were married at the start of post-graduate training. Both groups of women worked shorter hours than the comparison groups of men. More women in traditional careers had selected group practice than had the corresponding men. Influences on career choices showed more sex similarities than career-type similarities, with women influenced more by factors related to family responsibilities. Few in any group reported that their choices are not their preferences. The results suggest that complete convergence of the medical careers of men and women in the near future is unlikely. PMID- 21248966 TI - Office screening for urinary tract infections in infancy. AB - A retrospective report of the experience of nine years of simplified office screening for infantile urinary tract infection (UTI) is compared with the more invasive and stringent methodology widely considered necessary. Urine samples were obtained from 1313 infants of two years or less. In 27 of these infants UTI was diagnosed and the data analysed from 24 cases. Nine infants were completely asymptomatic, while the rest had non-specific symptoms. Radiological investigations were carried out in all the infants with UTI. Urine samples were obtained without any specific precleansing of the perineum, and the criteria for diagnosing UTI were two consecutive positive cultures. The results were statistically similar to studies in which there was pre-cleansing, and in which the criteria were three consecutive positive cultures. PMID- 21248967 TI - Pelvic inflammatory disease: a family practice perspective. AB - Most women with symptomatic acute pelvic inflammatory disease (PID) are now managed outside of hospital by private practitioners. Clinical diagnosis of PID is often inaccurate, but can be improved by knowledge of risk factors, use of simple investigations, and referral for laparoscopy when the physician is unsure. Prompt treatment with a recommended regimen that includes at least two antibiotics, careful consideration of when to hospitalize or refer, and an awareness of the need for compliance and follow up are important attributes of good management. In contrast, asymptomatic PID, which is a common antecedent of tubal factor infertility and ectopic pregnancy, can be prevented only by screening for and appropriate treatment of sexually transmitted infections. PMID- 21248968 TI - Vaginal infections. AB - Vaginal infections are among the most common complaints for which women see their physicians. The patient complains primarily of vaginal discharge or pruritus. Optimal management of these infections requires a careful history, physical examination, and laboratory assessment to determine the pathogen. Specific therapy is available for the three important causes of vaginal infection: yeast vulvovaginitis, trichomoniasis, and bacterial vaginosis. Concomitant sexually transmitted diseases should be excluded in women with complaints suggestive of vaginal infection. PMID- 21248969 TI - Sexually transmitted cervicitis. AB - Cervical infections with Neisseria gonorrhoeae, Chlamydia trachomatis, and Herpes simplex virus are some of the most common sexually transmitted infections. They are often asymptomatic, and therefore the patient is at risk of developing complications, such as pelvic inflammatory disease. It is important to recognize cervicitis, investigate it appropriately, and provide early treatment. Sexual partners must also be located and offered therapy to prevent re-infection in the index patient. PMID- 21248970 TI - Gynecologic pelvic pain. AB - The family physician dealing with gynecologic pelvic pain (acute or chronic) enters at the beginning of the problem as diagnostician, refers the patient to a specialist in the interim, and resumes care in the follow-up period. Patients with chronic pelvic pain (pelvic pain that has lasted for at least six months) can be difficult to treat because they often have a history of dysfunctional family life, sexual and marital problems, and often a hidden history of sexual molestation or incest. The family physician can best care for the patient with empathy, a long ventilated history, complete physical and pelvic examination, and pelvic ultrasonograpy if necessary. Laparoscopy normally shows pelvic adhesions in one third of these patients, minimal endometriosis in one third, and a normal pelvis in the final third. The family physician should specifically reassure patients with normal results that they do not have cancer. The ideal therapy combines both stimulation-produced analgesia and treatment of the psychological, emotional, sociological, and environmental aspects of the disease. PMID- 21248971 TI - Sexual dysfunction in women. AB - Sexual dysfunction takes place in the context of women's lives and affects their sexuality and self-esteem. Awareness of these influences are vital to the management of the dysfunction and the promotion of positive sexuality. The family physician's contribution to both the prevention and management of sexual concerns includes an awareness of societal influences and facilitation of a woman's sense of her own power and control over her life. PMID- 21248972 TI - Carcinoma of the cervix: an infectious disease. AB - Investigation of the viral types of sexually transmitted diseases has disclosed that they not only produce local infections but may also cause profound pathological changes. The authors of this article review several types of sexually transmitted viral infections and make suggestions for their investigation and management. Further research and development in this area of medicine would be valuable. PMID- 21248973 TI - Human papilloma virus infections. AB - Genital warts are believed to be caused by human papilloma viruses and to be sexually transmitted. The viruses are classified by DNA types, which appear to cause different types of disease. The choice of treatment, and usually its success rate, vary according to the type of disease and its location. PMID- 21248975 TI - Estrogen replacement therapy. AB - The present status of estrogen replacement therapy suggests that its benefits far outweigh the risks; it is hoped that the incapacity related to fractures, coronary artery disease, and urinary incontinence may be reduced or prevented. Estrogen replacement therapy should provide for a healthier elderly population, increase the number who can remain in their homes, and therefore reduce the number that require institutionalization. PMID- 21248974 TI - Screening for squamous cell carcinoma of the cervix. AB - The author reviews the origins of screening for squamous cell carcinoma of the cervix and the question of its value. Definitions of screening and case finding are given. The natural history of carcinoma of the cervix is explored. Barriers to screening and items that facilitate the process are described. A selection of the many recommendations which have been tabled since 1976 are documented. An appropriate screening plan for Canadian family physicians is suggested. PMID- 21248976 TI - Investigation of the infertile couple. AB - Although the exact incidence of infertility in Canada is unknown, mathematical models predict that approximately 10% to 15% of couples will fail to achieve a pregnancy after one year of unprotected intercourse. The diagnosis requires assessment of both male and female partners. During the initial visit, a comprehensive history should be elicited and a thorough physical examination performed. The couple should receive complete information about the proposed diagnostic evaluation, and any misinformation that may have been gained from friends and the media should be corrected. When the primary evaluation and treatment has failed to result in a pregnancy, the couple should be referred to a specialist. PMID- 21248978 TI - Obstetric service in rural areas. PMID- 21248979 TI - Episiotomies in Canada: a comment. PMID- 21248977 TI - Deja vu. PMID- 21248980 TI - Overcoming aversion to breastfeeding. PMID- 21248981 TI - HBV Screening during Pregnancy. PMID- 21248983 TI - Emergency medicine in family practice. PMID- 21248982 TI - Unsupervised residencies. PMID- 21248984 TI - Is it Safe to Visit Israel? PMID- 21248985 TI - Practice-generated questions: a method of formulating true learning needs of family physicians. AB - The importance of identifying true learning needs prior to planning and conducting educational programs is well documented. In this study a collection of 579 clinical questions forwarded by 87 family physicians in southern Alberta was reviewed and analysed to determine if the questions would cluster and, therefore, be useful as sources for planning continuing medical education (CME) conferences and newsletters. The nature of submitted questions was also examined to determine if particular groups of physicians, as identified by socio-demographic characteristics, significanly differed by type of questions submitted. The study findings indicate that the questions generated by the clinical practices of family practitioners did cluster into meaningful categories, and did vary significantly by identified physician groups. Questions relating to the genito urinary system; adverse drug effects, interactions and contraindications; and nervous system and sense organs were most frequently submitted. The nature of questions generated differed significantly by gender, size of practice setting, and year and place of medical graduation. When highly relevant and specific clinical questions, as contrasted with broadly expressed needs, serve as sources of identified learning needs for CME planners, the daily clinical problems faced by practitioners are better addressed. The learning needs identified by this approach provide an optimum framework for planned CME to influence physician behaviour or practice patterns. PMID- 21248986 TI - Comparing skin staples to sutures. AB - In a prospective randomized study, 52 lacerations requiring closure in the emergency department were either stapled or sutured. Six participating emergency physicians closed the wounds and recorded data about the laceration and the treatment provided. Patients visited their own family physicians for removal of the closures. Forty family physicians removed closures from 44 lacerations and reported follow-up data on discomfort levels, ease of closure removal, and cosmetic results. Lacerations were closed 2.7 times faster by the staple method (p<0.001), and there were no clinically significant differences between the two methods with respect to discomfort, infection rates, cosmetic result, or ease of removal. The staple device we used was more expensive than sutures. We concluded that the staple method of closure is safe, comfortable, and effective in the emergency department setting, and that the method's speed offsets its greater expense in some circumstances. PMID- 21248987 TI - Medical services program for the 1988 winter olympics. AB - The Medical Services Program for the 1988 winter Olympic games in Calgary involved detailed planning to co-ordinate facilities, equipment, supplies, transportaion, staff, and auxiliary support. The successful delivery of health care to athletes, Olympic officials, and spectators depended upon the efforts of medical volunteers, who enabled the Medical staff to provide adequate, timely service as required. PMID- 21248988 TI - Portrayal of abortion in three novels. PMID- 21248989 TI - Confidentiality of the CFPC Certification Examination Results. PMID- 21248990 TI - Multiculturalism, Medicine and Health: Part VI. AB - In this article, which concludes the series, the author presents an overview of the earlier parts, contending that physicians must be aware of, and respond to, cultural factors in our increasingly pluralistic society in order to provide optimum health care for a variety of patients. PMID- 21248991 TI - Spinal tuberculosis: a diagnostic problem. AB - Fourteen patients with spinal tuberculosis were treated in one orthopaedic practice in Vancouver between 1982 and 1987. There was a significant delay in diagnosis of over one year in almost two-thirds of patients. Diagnosis of spinal tuberculosis is often difficult. In this study, half the subjects had a history of TB, but a significant number had negatives skin tests, almost half had normal chest X-rays, and half of them had negative needle biopsies. PMID- 21248992 TI - Jogger's Fatigue: A Case of Unsuspected Pathology. AB - While many organic diseases classically produce symptoms of fatigue, other problems such as iatrogenic drug effects, normal physiological alterations, and strees, present with this symptom. In order to rule out the presence of organic dissease, an adequate history and physical examination, and appropriate laboratory investigations are mandatory. The authors describe a case of fatigue in a highly stressed jogger. PMID- 21248993 TI - Can we afford not to evaluate services for elderly persons with dementia? AB - With the increasing expenditure on health-care programs for seniors, there is an urgent need to evaluate such programs. The Measurement Iterative Loop is a tool that can provide both health administrators and health researchers with a method of evaluation of existing programs and identification of gaps in knowledge, and forms a rational basis for health-care policy decisions. In this article, the Loop is applied to one common problem of the elderly: dementia. PMID- 21248994 TI - Organizing family medicine geriatric care. AB - This article, written from the perceptive of a practising community physician, examines the servies available in the field of geriatric care at the present time. It suggests integration and co-ordination of existing facilities to maximize the current potential. It also considers the economic, geographical, and ethical concerns relating to geriatric care. It is a call for family physicians to co-ordinate their efforts in a multidisciplinary mode to ensure that our elderly are maintained in a comfortable caring atmosphere that encourages their maximum independence. PMID- 21248995 TI - The Family physician and the Terminally Ill Elderly. AB - Palliative care rests on the three pillars of symptom control, communication, and family support. As our patient population ages, we family doctors will be increasingly involved in the care of the terminally ill elderly at home. Terminal illnesses are much more common in the elderly, and often death can be predicted. Family doctors have a most important role in co-ordinating the home-support services, in providing comfort care, and in supporting the family members who are caring for the terminally ill elderly at home. PMID- 21248996 TI - The family physician and nursing-home care. AB - Nursing home patinets are becoming more numerous and now form a part of most family physicians' practices. Physicians wishing to do more nursing home care require guideliness for preventing unnecessary nursing home admissions, for scheduling visits, and for making transfers to hospital. Multi-disciplinary conferences and good basic documentation are valuable in the nursing home. Therapy with medication may be a problem, especially if changes in compliance and independence as a therapeutic end-point are not borne in mind. Serious ethical questions arise routinely in the care of nursing home patients, and a scheme for addressing these is presented, together with some of its limitations. Contrary to the current common wisdom, nursing home care may be challenging and rewarding. PMID- 21248997 TI - [Not Available]. AB - Planning services for the mentally impaired elderly requires prior assessment of their needs, to make optimum use of available social and medical resources. Needs resulting from impairment can be determined after identifying the causes of the dementia. Additional needs arise from disabilities and handicaps that limit the patient's ability to perform daily tasks and to communicate. Relatives and others can provide a natural support network central to the patient's ability to maintain some measure of autonomy. Any factors undermining this network's commmitment to provide care should be identified. Yet, most mentally impaired elderly persons are not known to the health care system. Screening and casefinding by a team of psychogeriatric specialists would make it possible to identify the needs of these hidden patients and to plan services while they are still able to live at home. PMID- 21248998 TI - Geriatric stepped care: an organized approach. AB - This paper deals with the issue of geriatric care and the medical, financial, social and political ramifications of the demographic chages that will be occurring in Canada over the next 40 years. Some suggestions for solutions to the problems arising from those changes are discussed, including an attempt to apply the philosophy of preventative medicine in dealing with the ageing population. A "stepped care" approach that will help to avoid the random accessing of unco ordinated and diverse support systems in the community is outlined. PMID- 21248999 TI - Cognitive impairment in the elderly. AB - This paper deals with the reasons that cognitive impairment may occur in older persons and the ways in which it may complicate their life. The author suggests approaches to the detection and measurement of cognitive impairment, and discusses and recommends the use of brief mental status screening tests to assist in these processes. PMID- 21249000 TI - Hearing loss in the elderly: an overview. AB - Loss of hearing is tragic, yet most of those afflicted can be helped. Surgery is sometimes appropriate, but for the majority a hearing aid is the best answer. This article reviews what happens in different hearing losses, and gives an overview of hearing aids for the physician who lacks an extensive technical background but wishes to understand these devices a little better. Simple tips for investigation of hearing-aid complaints are included, as well as some tips for communication with hard-of-hearing persons. PMID- 21249001 TI - Falls in the elderly: a practical approach. AB - Falls in the elderly constitute a major problem confronting physicians. Their cost to individual patients and to society in terms of incidence, morbidity, and mortality is enormous. This paper attempts to outline some of the common etiological factors related to falls and a practical approach to the diagnosis and management. Causes of falls are clssified as extrinsic and intrinsic factors. The latter include disorders of many organ systems, especially those resulting from neurological and cardiovascular diseases. The role of drugs and alcohol is stressed. Determining the cause of falls requires a thorough history and physical examination. In order to manage successfully an elderly person with multiple falls, a co-ordinated effort by a multi-disciplinary team is often essential. PMID- 21249002 TI - An approach to management of gas in the elderly. AB - In this article I shall review the physiology, clinical manifestations, and management of gaseousness in the elderly. While not an infrequent complaint, little scientific study has been done of the causes or management of this problem. The regualtion of bowel gas is surprisingly complex. When problems occur, it is usually either because of excessive swallowing of air or because of the intraluminal producation of gas by colonic bacteria. Patients present with excessive belching, abdominal pain and bloating, or excessive passage of flatus. Management is determined, in the main, by the results of the history and physical examination. Medications are usually not indicated. Once a malabsorptive state is ruled out, the mainstay of management usually involves either alterations in the patient's diet or avoidance of aerophagia. PMID- 21249003 TI - Anemia in the elderly. AB - Physicians disagree in defining the normal range for hemoglobin in the elderly patient. In order to understand this controversy and make rational decisions in patient management, it is important to understand the physiological factors that may give rise to variation from normal. Although the spectrum of disease seen in geriatrics may differ from that seen in children and young adults, the pathophysiology of anemia does not change and should be thought of in terms of microcytic, macrocytic, or normocytic. The variation from normal in the elderly is usually small and does not allow a physician to ascribe the difference to age alone. PMID- 21249004 TI - Dangers of NSAIDs in the elderly. AB - Nsaids are the most widely prescribed of all drugs when grouped by generic categories, and they are frequently given in the treatment of musculoskeletal disorders. These drugs are known to produce serious side-effects, particulary in the elderly. The author of this article lists various categories of typical side effects and cautions against the routine use of Nsaids, particularly in patients at risk for certain conditions and in combination with certain other types of medication. PMID- 21249005 TI - Depressive disorders in old age: an overview. AB - Severe depression is one of the most prevalent health problems of the elderly. Approximately 10% to 20% of the elderly population is affected. Unfortunately, major depression frequently presents in atypical forms among the elderly. Frequent presentations include masked depression, where multiple somatic complaints are prominent; pseudodementia, in which the depressed elderly person presents as a primary dementia; and delusional depression, in which paranoid delusions are prominent. Diagnosis is complicated by a multiplicity of other physical problems and polypharmacy for medical disorders. If adequately diagnosed, major depression can generally be treated successfully with antidepressants. Caution must be exercised in the use of antidepressants, as their sideeffects are in general more noxious in the elderly. PMID- 21249006 TI - Expectant fathers: changes and concerns. AB - The author conducted a compreshensive literature review on expectant fatherhood to determine the needs of men participating in the childbearing cycle. A sparse but growing body of knowledge exists about this population. A number of authors reported distinct changes and concerns. Most of the study subjects were participatns in prenatal classes, a factor which suggests that the findings may not reflect the needs of all expectant fathers. All partners were experiencing a normal pregnancy. This precluded the anxiety of a high-risk situation as a confounding variable. Most information given to expectant fathers was intended to assist them to support their partners. There was little evidence that men received much professional guidance to prepare them for fatherhood. PMID- 21249007 TI - A general practice experience in rural tasmania. PMID- 21249008 TI - In praise of the hawthorne effect. PMID- 21249009 TI - Facilitating a pleasant birth. PMID- 21249011 TI - Fear of midwives. PMID- 21249010 TI - Alternative birthing positions. PMID- 21249012 TI - Ingrown toe-nails: a comment. PMID- 21249013 TI - Ingrown toe-nails: a response. PMID- 21249015 TI - Myocardial infarction. PMID- 21249014 TI - Studying refugee health. PMID- 21249016 TI - Mental handicaps. PMID- 21249017 TI - Nasal medications. PMID- 21249018 TI - Immortality for men. PMID- 21249019 TI - Approaching "DNR" Issues with AIDS Patients. PMID- 21249020 TI - Development of the art of medicine. AB - This paper reflects upon the art of family medicine experienced by one resident during an eight-month period of her two-year family medicine residency. The "science" of medicine, as experienced in medical school, is contrasted with the "art" of medicine fostered throughout the family medicine residency. Patients in all age categories, from neonates to those older than 90 years, were examined. The average number of patient-initiated encounters during the eight-month period was 2.3 per female and 2.4 per male. The five most common reasons for presenting were related to the skin, ears, throat, back, and requests for general "check ups." According to McWhinney's taxonomy of patient behaviour, patient-initiated visits could be categorized into the following groups: 67.4% were limit of tolerance; 7.2% limit of anxiety; 8.2% underlying problems of living; 0.3% for purely administrative purposes; and 16.9% for preventive purposes. The experiences with four of the more memorable patients seen during the 12-month residency, presented here in personal vignettes, proved vital in moving the author toward her goal of becoming a well-rounded family physician. PMID- 21249021 TI - Psychosis: a case report. AB - Healing is born in the genuine warm, caring, understanding relationships we establish with our patients. This warmth and understanding is essential when working with patients with schizophrenia. In order to help them, we must meet them in our humanity. This paper is an account of the author's experience while working with a patient diagnosed to have schizophrenia. PMID- 21249022 TI - Screening for breast cancer: current attitudes and practice. AB - In a survey of selected Ontario physicians, 21% reported following the suggestion of the Canadian Task Force on the Periodic Health Examination that all women 50 to 59 years of age have annual mammographic and physical examination of the breast. Concern about screening continues to centre on the issue of effectiveness and cost-effectiveness of mammography. In comparison to previous studies, fewer physicians report concern about radiation risk. The only characteristic distinguishing between physicians who report regularly screening for breast cancer and those who do not is their agreement with the Task Force suggestion. PMID- 21249023 TI - An audit of adult tetanus immunity. AB - Many Canadian adults are not protected against tetanus. This study examined adult patients' knowledge of their tetanus immunization and its documentation in family practice charts at a downtown teaching community health centre. A date of previous immunization was recalled by 38% (49/129) of patients. Immunization was documented on 34% (44/129) of the "cumulative patient profiles." Of the 22 patients who provided a recall date and whose charts documented immunization, 82% (18/22) had accurate recall. Written immunization records were kept by 19% (25/129) of patients. The results indicate problems both with patients' knowledge of immune status and with chart documentation by physicians. Recommendations for improvement of the immunization process are outlined. PMID- 21249024 TI - Critical appraisal of medical literature. AB - This skill-testing exercise is intended to update the "Critical Appraisal Package: Therapy," published by the College of Family Physicians of Canada in 1986. The format follows the design of the original practical exercises of the package: clinical scenario, article, worksheet, and methodology notes. PMID- 21249025 TI - Repairing skin lacerations: does sterile technique matter? AB - Patients with uncomplicated skin lacerations who attended a rural family-practice clinic were randomly assigned to have their cut repaired using either full sterile technique or a surgically-clean technique. No significant differences were found in the rate of healing or in the incidence of complications. It was concluded that full sterile technique is not needed to repair simple skin lacerations, and that to suture the lacerations using a surgically clean technique would save both time and money. PMID- 21249026 TI - Delayed Treatment of Carbon Monoxide Poisoning by HbO(2). AB - This case report demonstrates the importance of hyperbaric treatment in managing cases of known or suspected carbon monoxide poisoning. Even when prolonged delays in initiating this treatment are unavoidable, it can be beneficial. Prolonged administration of normobaric oxygen is inadequate treatment. PMID- 21249027 TI - Perilymph fistula: rare but real. AB - Although perilymph fistula is a rare diagnosis, it is important that family physicians be aware of the signs and symptoms that suggest its presence. When a patient develops sudden loss of hearing and/or vestibular dysfunction after experiencing trauma to the head or ears, after barotrauma, or after performing a vigorous Valsalva manoeuvre, he should be referred promptly to an otolaryngologist for assessment and proper management of the condition. PMID- 21249028 TI - Family medicine: the challenge of maturity. AB - In this paper, adapted from the Keynote address to the 30th Annual Scientific Assembly of the College of Family Physicians of Canada, May 1988, in Montreal, Quebec, it is pointed out that family medicine has been successfully establishing itself as a distinct academic discipline since the early 1950s. Yet family doctors have not fully accepted and integrated its status. We continue to behave as if we don't believe in ourselves. Several reasons are suggested to explain why we have been slow to accept the remarkable progress of our discipline. A greater research effort is needed for family medicine to reach its potential. Family physicians in private practice and in community health centres must play a major role if this research effort is to succeed. Some practical examples of how private practitioners can be involved in research are presented. PMID- 21249029 TI - Resources for family-practice research: have faith! AB - In order to translate a clinical question into a research project, essential resources are required. In this article, Canadian resources for family practice research are reviewed under the headings "funding", "advice", "information and training", "time" and "help from support staff" (FAITH). PMID- 21249030 TI - NaReS: Your National Research System. AB - The purpose and future direction of the National Recording System was reviewed by a Working Group of the National Research Committee in March 1988. The system will continue to study questions important to family physicians and to develop methodologies specific to the needs of family medicine research. It will actively seek projects from NaReS participants, College members, universities, government, and outside agencies. The administrative structure, policies, and future directions are reviewed. PMID- 21249031 TI - Update from ASPN. AB - Patients suffering from common illnesses seek assistance from their family physicians and are referred to tertiary care specialists only if unusual complications develop. Tertiary care specialists have performed the bulk of training and research for primary care physicians. The result is that research and education are inappropriate for the illnesses most often encountered in family practice. The Ambulatory Sentinel Practice Network (ASPN) was formed to gather information about the disorders encountered in general practice that form the greatest part of human suffering and to disseminate that information among primary care practitioners. PMID- 21249032 TI - Family medicine resident research: how about an N of 1 trial? AB - Encouraging family-practice residents to undertake a research project should be a mandate of every Department of Family Medicine. In order to have an effective resident research program, time, expertise, funding and ideas are needed. An N of 1 randomized trial is one study design that may be attractive to family-medicine residents as a methodology from which to learn basic concepts of research. This paper provides a background description of single-patient trials and their use in resident research. PMID- 21249033 TI - Microcomputers in primary care research. AB - The author of this article specifically addresses those physicians with little computer experience who have not so far applied microcomputers effectively to the non-business aspects of medical practice. He discusses the place of the microcomputer in primary care research, dealing with the four chief components of research applications. PMID- 21249034 TI - Using a full-text data base in a community hospital. AB - The electronic storage of reference material is called a computer data base. Such systems can store, sort, and retrieve large volumes of information very rapidly. Some new services act as a large library for anyone with a computer and a telephone line. Recent improvements in these systems have made them easier to use and more comprehensive. The Medical Society of Penticton, B.C., has completed its first 14 months' use of one such data base. Despite some limitations, many physicians felt it sufficiently valuable that they plan to continue subscribing to the service. PMID- 21249035 TI - One approach to demystifying research in primary care. AB - "Research" means different things to different people. "Organized curiosity" has been proposed as a suitable description for family-practice research. Studies involving patients in community practices are becoming recognized as a unique type of research that contributes new understanding to matters relating to primary care. Such research, however, requires an infrastructure that makes a study as unobtrusive as possible in participating practices. One approach is the development of a primary care research unit (PCRU): a central co-ordinating communications office which can provide the human and technical resources needed to assist each community office with protocol and data-collection steps. The author of this article describes the functional components of a PCRU in five groupings: namely, technical, human, communication and support systems, a network of community physicians, and facilities. Finally, several important principles about funding primary care research are suggested. PMID- 21249036 TI - Nurturing research in a family medicine department. AB - In order to encourage research, one must maintain the initial enthusiasm of residents for exploring the questions that arise during their early experience. Once they begin to study these questions, an academic department can help further by teaching skills in literature review, data analysis, and presentation of data. Once established, these support programs can assist faculty members to carry on their own research as well. PMID- 21249037 TI - The evolution of family medicine resident projects at dalhousie university. AB - The Dalhousie Family Medicine Residency Program has always attempted to meet the research objectives of the College of Family Physicians of Canada. From a "Monitored Reading and Research" program, where projects were encouraged, the department developed a program which involved a mandatory project, preferably involving research, that is formally and objectively evaluated and supervised by faculty. The background, rationale, and problems encountered, as well as attempted solutions, are outlined. PMID- 21249038 TI - An eight-year experience of a required resident project. AB - The authors describe the resident-project component of the Family Practice Residency program at the University of Toronto. The goals of the project are to allow the residents an experience of critical appraisal, writing for a medical forum, and presenting in a style acceptable to the medical community. Over 305 projects have been completed, and 100% of the residents complete projects at this time. An analysis of the types of projects, the topics covered, and the effect on the residency program is presented. An appendix lists projects that have been published. PMID- 21249039 TI - Guidelines for writing patient-related research proposals. PMID- 21249040 TI - Malaria prophylaxis. AB - The authors of this paper provide an overview of the relative risk of malaria in various areas of the world. On the basis of the geographic information available, they discuss both chemoprophylaxis and treatment for this disease, and make recommendations for their use. PMID- 21249041 TI - Medication caries: another form of "snacking". AB - The use of fluoride, frequent brushing and flossing, regular dental examinations, and limiting the ingestion of sweet snacks between meals are of primary importance in preventing dental caries. Because many commonly used medications have high concentrations of sucrose, the child with a chronic illness who needs medication on a long-term basis is at higher risk both for caries formation and for compliations of tooth decay. To minimize this risk most medication should be considered equivalent to a sweet snack for the purpose of dental hygiene. Sucrose in medication should be replaced by less cariogenic sweeteners, and sucrose containing medications should be given with meals if this is possible. PMID- 21249042 TI - Orthodontics. AB - The authors of this article offer an introduction to the field of orthodontics. They present the latest advances in orthodontic appliances and some of the possible consequences of orthodontic treatment. They discuss a number of cases and offer examples of some of the more common problems that the orthodontist is asked to treat. Such cases include severe Class II, division 1 malocclusion, surgical orthodontics, "long-face" syndrome, adult orthodontics-TMJ-periodontics, late adult growth, and post-retention changes. Practical information useful to the physician who encounters patient with these disorders is balanced with good research data to support the various claims. PMID- 21249043 TI - The top one hundred. PMID- 21249044 TI - Gatekeeping. PMID- 21249045 TI - Canadian Content Missing from CFP? PMID- 21249046 TI - Mandatory research projects. PMID- 21249048 TI - Family physicians in hospitals. PMID- 21249047 TI - Midwifery task force replies. PMID- 21249049 TI - Emergency lumbar puncture. PMID- 21249050 TI - Statement on midwifery: continued discussion. PMID- 21249051 TI - Familial dysautonomia. PMID- 21249052 TI - Is there a resurgence of acute rheumatic Fever in Canada? AB - Recent reports of acute rheumatic fever (ARF) outbreaks in the continental United States have caused alarm. A survey of Canadian pediatric cardiologists was undertaken to determine whether they were aware of an increase in ARF or, more specifically, rheumatic carditis. Ninety per cent of active pediatric cardiologists responded. In 1987, 48 cardiologists reported having seen 48 patients with ARF. Seventy-five per cent of respondents had seen no cases or only one case in the 12 previous months. Seventy-six per cent of respondents had noticed no increase in the number of cases since 1983. The rate of ARF reported by the cardiologists increased from east to west (p = .003), with an overall Canadian rate of 0.19 cases per 100 000 population. Rheumatic carditis and rheumatic fever remain rare. There is no evidence of a Canadian outbreak, but close monitoring is warranted. PMID- 21249053 TI - Evaluation of TestPack Strep A for Rapid Identification of Group A Streptococci. AB - The performance of a 10-minute immunoassay, TestPack Strep A, was compared with culture for the detection of Group A beta-hemolytic streptococci (GABHS) from 298 throat swabs. When cultured, 17.4% of the samples grew GABHS. The values calculated for the test were sensitivity, 67.3%; specificity, 99.2%; positive predictive value, 94.6%; negative predictive value, 93.5%; positive likelihood ratio, 82.79; and negative likelihood ratio, 0.33. The sensitivity decreased with decreasing growth of GABHS in the culture. If cultures with only light GABHS growth were eliminated from the analysis, the sensitivity was increased to 74.4%. The test has the advantages of immediate results, available while the patient is still in the office; simplicity; easy-to-interpret end-points, high positive likelihood ratio; high specificity; and high predictive values, which make it a rather attractive supplement to sore throat management in a busy family practice. The cost of the kit, however, may diminish its attractiveness. PMID- 21249054 TI - Managing sore throat: theory versus practice. AB - The authors address the reliability of clinical impression in the management of sore throat. Five primary care family physicians in rural Ontario examined 222 patients with sore throats. The clinical impression of either Group A beta hemolytic streptococcal (GABHS) or non-GABHS pharyngitis was recorded and throat cultures were ordered in each case. The physicians predicted that 50% of the cultures would be positive for GABHS, whereas only 13.5% actually had positive results. The initial clinical diagnosis of "strep throat" was correct only one in five times. Without cultures, at least 112 patients would have been treated with antibiotics, 87 unnecessarily. The authors conclude that the clinical prediction of GABHS is inaccurate and can lead to unnecessary use of antibiotics. PMID- 21249055 TI - Referrals in primary care: is the family physician a "gatekeeper"? AB - The increasing financial restraints on the use of health care resources make it important to examine the appropriateness of present usage patterns. The authors studied referral patterns for a group of academic family physicians practising in a health service organization in Ontario. They found that for all consultant encounters, the family physician directly controlled 65% of these consultations, whereas 13% were continuing consultations with the specialist without direct family physician referral. The remainder were either unknown or referred from other sources, for example, emergency room or specialist-to-specialist referrals. The family physician made the exact same diagnosis as the consultant in 73.4% of cases for which data were available, and the patient was referred to an inappropriate specialist in only 2.7% of cases. PMID- 21249056 TI - [Not Available]. AB - The rate of non-compliance with the post-vasectomy semen examination procedure at the Centre Hospitalier de l'Universite Laval (CHUL) between October 1, 1985 and March 31, 1987 was 21%, one of the highest in the literature. The purpose of our study was to determine the causes of this situation. The socio-demographic profile obtained from the computerized files of 50 patients who did not comply with the procedure was comparable to that of the 183 patients who did comply. A telephone survey of 43 non-compliant patients was carried out. In 70% of the responses to an open question on the reasons for non-compliance, the subject cited on his own negligence. In response to the closed questions, the constraints involved in the semen examination procedure were cited most often (49%). In the responses to both open and closed questions, a lack of information was cited least often. There is not a distinctive profile among vasectomy patients at the CHUL that would make it possible to predict compliance. Despite the fact that it would be difficult to improve the factors associated with patient negligence, it might be possible to increase compliance by following up more closely and lessening the constraints. PMID- 21249057 TI - Continuous intravenous infusion of opioid analgesics for severe pain. AB - Severe continuous pain is frequently a complication of terminal malignancy and other disease or trauma states. Effective pain relief will be an important factor in the physical and psychological outcome for the patient. At times, the continuous intravenous infusion of opioid analgesics will be indicated. Indications and guidelines for this therapy are described, with an illustrative case study. PMID- 21249059 TI - Images of illness: death. PMID- 21249058 TI - Part I: the difficult patient: medical and legal approaches. AB - Difficult patients are defined as those who elicit strong negative emotions from their physicians. If not acknowledged and managed correctly, these feelings can lead to diagnostic errors, unpleasant confrontations, and troublesome complaints or legal claims. The author reviews common personalities and situations that are associated with difficult encounters in emergency departments and describes an approach stressing flexibility in communication and the early establishment of rapport. He discusses diagnostic possibilities in the agitated or confused, unco operative patient, reviews relevant laws governing restraint and competence to consent, and outlines techniques to reduce medicolegal risks. PMID- 21249060 TI - Essential hypertension: when and how to initiate treatment. AB - One of the most common problems family physicians encounter is also one of the most difficult to define clearly. The authors consider an epidemiologic approach to the definition of essential hypertension and review the recommendations for the accurate recording of human blood pressure measurements. The authors evaluate evidence for the treatment of essential hypertension. Both nonpharmacologic and pharmacologic treatment of hypertension are considered, emphasizing an individualized, stepped-care approach to management. PMID- 21249061 TI - Does Antihypertensive Therapy Need to be Life-Long? AB - The author reviews the evidence for and against decreasing or discontinuing antihypertensive therapy on known hypertensive patients once their blood pressure has been brought under control. The evidence supports a trial of decreasing and, in many cases, discontinuing antihypertensive medication. Although there are no established protocols for cessation of therapy, the author discusses suggestions in the literature. PMID- 21249062 TI - Management of chronic headache. AB - Chronic headache interrupts the lives of 10 million Americans and sends them to their physicians. The problem can be difficult to treat. Medications, for acute migraine attacks or for prevention, require careful monitoring to avoid iatrogenic headache. Most important is the history; physical examination usually shows no abnormalities. Migraine in one of its several forms accounts for two thirds of headaches seen in doctors' offices. The International Headache Society has recently undertaken a major reclassification of headache. Dietary control, relaxation therapy, and personalized long-term care underline the breadth of treatment needed and the appropriateness of family medicine in dealing with this widespread problem. PMID- 21249063 TI - The Red Ear-drum: To Treat or Not To Treat? AB - Acute otitis media is typified by the patient with fever, earache, and a "red" ear-drum. Suppurative otitis media, however, often presents without specific symptoms, and redness is the least reliable physical finding. Impaired tympanic membrane mobility on pneumatic otoscopy and bulging and opacification of the ear drum are more reliable and important physical signs. Review of placebo-controlled trials reveals that antimicrobial therapy produces more rapid relief of fever and earache in patients with the most symptoms. Effects on patients with fewer symptoms are more modest. Amoxicillin remains the standard first-line treatment. Reasonable indications for alternative therapy are reviewed. PMID- 21249064 TI - Urinary tract infections in female patients. AB - Urinary tract infections are a common problem in female patients. Twenty-five per cent of patients with an initial infection will develop recurrent infections, with reinfection of the urine some time after the urine has been sterilized being the most common situation. Most adult patients have no urinary tract abnormality, with the infecting organism coming from the rectum and colonizing the vagina before colonizing the bladder. In children with urinary tract infections, there is a higher incidence of urinary tract abnormalities. The author presents a plan of management for various clinical problems. PMID- 21249065 TI - Allergies: review of the evidence. AB - Recent changes in our perceptions of allergic IgE-mediated disease are based on evidence indicating a prominent role for both the early- and late-phase responses. The relative importance of the late-phase inflammatory reaction suggests the need for a critical re-evaluation of both diagnosis and therapy. Skin testing remains the gold standard of laboratory procedures despite new technology. Corticosteroids, acting primarily as potent anti-inflammatory agents affecting the late response, are now seen as primary therapy for allergic disease. Other drugs without anti-inflammatory properties will likely play a secondary role in future. The use of immunotherapy is also changing; this treatment may play a more prominent clinical role as a modulator of the immune response, particularly the latephase reaction. PMID- 21249066 TI - Prevention and early detection in family medicine: where are we? AB - During the past 10 years, there has been important progress in the development of prevention and early detection of diseases in family medicine. The key feature in this development has been the increasing availability of evidence-guided recommendations. More recently, attention has begun to focus, as well, on challenges of implementing actions of proven benefit, spurred by the recommendations of the Canadian Task Force on the Periodic Health Examination. The author evaluates the current situation and suggests some strategies for family physicians to implement effective preventive manoeuvres. PMID- 21249067 TI - Prevention and treatment of relationship distress. AB - Relationship distress is likely to be a pervasive problem among patients seen by the primary care physician. Further, it can influence the patient's mental and physical health and well-being. The physician should play a role in the prevention and the alleviation of relationship distress. The author suggests how the physician can help prevent relationship distress by providing anticipatory counselling. In addition, some guidelines for effective physician intervention in cases of mild distress and for successful referral in cases of significant distress are outlined. PMID- 21249068 TI - Enuresis: are we using the optimal treatment? AB - A multitude of treatments are currently being used for enuresis. This article reviews the scientific evidence supporting various treatments and indicating their effectiveness. Recent evidence demonstrating the significant improvement of psychological well-being as a result of treatment indicates that treatment should be started early. The literature shows that 48% of parents do not seek medical help for children with enuresis. They tend to use ineffective and sometimes damaging treatment, such as punishment. The authors conclude that the modern enuretic alarm is relatively safe, painless, easy to use, and is the most effective treatment available. PMID- 21249069 TI - Chronic low back pain: a personal approach. AB - Sooner or later, all family physicians will face patients with chronic low back pain. This disorder does not result from the same causes and does not respond to the same treatment as acute back pain. A thorough assessment is the key to efficient treatment and should include data about familial, social, and occupational environments. The treatment should be multimodal and tailored to the patient's type of personality and to the causes of the syndrome. PMID- 21249070 TI - The challenge of urinary incontinence in the elderly. AB - By 2021 Canada will have an enormous population older than 65 years of age. Before the wholesale introduction of programs for seniors with urinary incontinence, careful evaluation of present treatments and the extent to which they can usefully be applied in the community is necessary. We need more information about the diagnosis and treatment of urinary incontinence in the elderly and about both patient and caregiver compliance with treatment for urinary incontinence. There is a great need for research on the efficiency of programs targeted at the incontinent group and for community surveys to reassess the problem's long-term consequences. PMID- 21249072 TI - Diagnostic investigations in family practice. PMID- 21249071 TI - Exercise after myocardial infarction: appraisal of the literature. AB - The prescription of exercise programs for patients is becoming more common. A review of the literature indicates that supervised exercise programs for patients who have had a myocardial infarction are relatively safe. Exercising probably makes patients feel better, but there is no conclusive evidence that exercise programs lower either mortality or morbidity for those who continue in an exercise program. On the basis of the current literature, it is not justified to recommend special exercise programs of cardiac rehabilitation as a routine measure in the care of most patients who have had an infarction. Some patients, especially those with left ventricular dysfunction, may benefit from supervised exercise programs. PMID- 21249073 TI - Rural practitioners. PMID- 21249074 TI - Rural medical care. PMID- 21249075 TI - Nursing home patients: a response. PMID- 21249076 TI - Training Residents for HIV-Positive Patients. PMID- 21249077 TI - Fluoxetine in the elderly. PMID- 21249078 TI - Ontario walk-in clinics: a preliminary descriptive study. AB - Little has been reported about Canadian walk-in clinics. The authors identified and surveyed 34 Ontario walk-in clinics in a preliminary descriptive study. A walk-in clinic was operationally defined as "a clinic that is separate from a hospital, has extended hours, and normally accepts patients without an appointment or a referral." Results showed that most Ontario walk-in clinics are not identifiable by name, have increased in number dramatically in the past two years, have laboratory, X-ray, and electrocardiographic facilities, and have varied practice patterns. Implications for rising health care costs and changing views on family practice were noted and suggestions made for future research. PMID- 21249079 TI - Walk-in Clinics and Primary Care: Review of the Literature. AB - Walk-in clinics have proliferated rapidly in many areas of Canada and the United States. Patients who attend these clinics have illnesses that are similar to those seen in family physicians' offices, yet walk-in patients perceive their symptoms to be more urgent and present at a much earlier stage of their illness than patients who attend their family doctor. Research has not yet proven that the opening of walk-in facilities lowers the demand for traditional primary care services; therefore the cost-effectiveness of walk-in clinics needs further evaluation. PMID- 21249080 TI - Caesarean section, epidural, and forceps intervention rates for low-risk obstetric deliveries. AB - A retrospective chart audit of 237 consecutive deliveries at a community hospital identified 71.3% as "low risk" at admission for labour and delivery. For this low risk group, 94.7% were delivered vaginally. The epidural rate was 25.6% and the forceps rate was 20.0% for these vaginal deliveries. This study shows it is possible to identify patients as "low risk" at admission for labour and delivery who can be managed expectantly with a relatively low intervention outcome. The author recommends a consistent definition of low-risk deliveries in all studies of obstetric outcomes to allow for valid comparison. As well, the large differences in outcomes of primiparas and multiparas underline the importance of analyzing these groups separately when comparing results with those of other hospitals or studies. PMID- 21249081 TI - [Not Available]. AB - The couvade syndrome describes the various physical symptoms found in expectant fathers. In this descriptive study, we have attempted 1) to determine the extent to which this syndrome occurs among expectant fathers in Quebec, 2) to identify certain risk factors, and 3) to observe the repercussions of pregnancy on the social and family behaviour of the expectant father as well as on the use of health care services. Within four days of delivery, a group of thirty-one fathers completed a multiple-choice questionnaire during an individual interview. Sixty one per cent reported at least one of twenty-eight physical symptoms listed. It would also appear that the men's relationship with their own father before the age of 12 had an impact on the development of the syndrome. PMID- 21249082 TI - Medical teaching in sioux lookout: primary health care in a cross-cultural setting. AB - When participating in health care in northern Native communities, physician teachers are challenged to understand community development, treat diverse manifestations of illness and socio-cultural strain, and provide opportunities for students and residents to learn the skills, knowledge, and attitudes that will promote the health of Native people and that will develop the students' own education. The University of Toronto Sioux Lookout Program includes a teaching practice with the goals of service, teaching, and research that provides care and promotes health for 13 000 Ojibway- or Cree-speaking aboriginal Canadians in northwestern Ontario. Knowledge gained in this setting about broad determinants of health, communication skills, and clinical decision making can be generalized to other practices. PMID- 21249083 TI - Part II: The Difficult Patient Detecting Drug Seekers in Primary Care. AB - Prescription drug diversion is a growing problem facing practitioners, pharmacists, and law enforcement officers in Canada. Prescription drug diversion leads to excess morbidity and mortality. Prescription drug seekers waste the physician's time through unnecessary visits and-should they get caught-through court appearances. The physician's office remains the drug seekers' favourite place to obtain prescription drugs. This article outlines the categories of prescription drugs and the relevant federal laws governing their use. Drug seeking individuals are described, as are the diseases they feign and the ruses they use to obtain drugs. Finally, ways of circumventing drug seekers are described. PMID- 21249085 TI - Patterns of Hypertension and their Implications for Therapy. AB - IN GENERAL PRACTICE, THREE PATTERNS OF HYPERTENSIVE DISEASE REQUIRE SPECIAL CONSIDERATION: mild hypertension, hypertension in the elderly, and hypertensive patients with additional cardiovascular risk factors. The success of treatment must be balanced against its cost, which includes impaired quality of life. The aim should be to save lives without compromising lifestyles.Hypercholesterolemia is more often found in hypertensive than in normotensive patients. A diagnostic workup of the lipid status and, if hyperlipidemia is diagnosed, its aggressive treatment are as important as the treatment of hypertension itself. Recent evidence shows that smoking has a negative effect on cardiovascular complications of hypertension and can entirely eliminate potential beneficial effects of some forms of antihypertensive treatment. PMID- 21249084 TI - Chronic fatigue syndrome: review of the literature. AB - Chronic fatigue syndrome, previously known as chronic mononucleosis or post infectious fatigue, is a poorly understood illness characterized by chronic debilitating fatigue, recurrent flu-like symptoms, and few clinical or laboratory abnormalities. Attention was briefly focused on the Epstein-Barr virus (EBV) as a causal agent, but that hypothesis is now in serious doubt. While a significant incidence of psychiatric illness has been demonstrated among patients with the chronic fatigue syndrome, there is also evidence of subtle immune system abnormalities, leading some researchers to postulate a multi-factorial psycho immune cause. PMID- 21249086 TI - Personalized hypertension management. AB - Although the "stepped-care" approach to the management of hypertension has been useful, newer recommendations suggest that therapy for the hypertensive patient take into consideration the presence of other illness, race, compliance, cost, and the use of non-pharmacologic techniques. Thiazide diuretics and beta-blockers remain the backbone of drug therapy, but other drugs can be considered as second line choices or even monotherapy in certain situations. The authors review recent conferences held in the United States and Canada on the topic of individualizing antihypertensive therapy. PMID- 21249087 TI - Aspirin in heart disease, transient ischemic attacks, and stroke. AB - The link between acetylsalicylic acid and the reduction of incidence in myocardial infarction has generated a great deal of interest among physicians and the general public. The author reviews recent literature on the use of ASA and describes the complex pharmacologic mechanism that may be responsible for the beneficial effects of ASA in such diverse situations as toothaches and heart attacks. PMID- 21249088 TI - Primary and secondary drug treatment of myocardial infarction. AB - The management of myocardial infarction has been revolutionized during the last few years. Based on a better understanding of the physiopathology of infarction, aggressive intervention with drug therapy has made great reductions in both mortality and morbidity possible. Early reperfusion of the infarct-related artery with such thrombolytic agents as streptokinase or recombinant tissue plasminogen activator may decrease acute mortality by up to 50%. New uses for older drugs, such as acetylsalicylic acid and nitroglycerin, give them a primary role in acute myocardial infarction. beta-Blocking drugs, when given in the early and later phases of myocardial infarction, also clearly reduce mortality and morbidity. Combining early reperfusion and adjunctive therapy with ASA, nitrates, and beta blockers will surely become accepted as the most effective method of treating the pain, limiting the damage, and preventing the complications of myocardial infarction. PMID- 21249089 TI - Investigation and management of renal stones. AB - Renal stones are a major source of morbidity and health care expenditure. Stone forming patients may be grouped according to the etiological factors of their disease. Investigation begins with an appropriate history and physical examination, followed by selected laboratory tests aimed at discovering factors that may be contributing to stone formation and also at classifying the activity of the stone disease. Management depends on timely surgical procedures to deal with problematic stones and on advice concerning fluid intake, dietary modification, and in some cases, drug therapy to prevent further stone formation. PMID- 21249090 TI - Practical management of tremors. AB - Tremors occur in a significant percentage of the adult population. They are quite variable and can be best seen under special conditions. All tremors cease during sleep. Tremors may represent adverse effects of certain drugs, or they may indicate the presence of systemic disturbances or diseases affecting the central nervous system. Most tremors are amenable to treatment. The author outlines the types of tremor and their management. PMID- 21249091 TI - Current medical management of peptic ulcer disease. AB - Peptic ulceration occurs when the digestive action of gastric secretions overcomes gastroduodenal mucosal defences. The therapeutic strategy used to correct this imbalance uses drugs that either reduce gastric secretion or increase mucosal resistance. Traditional therapies of dietary manipulation and antacid administration no longer play major roles in peptic ulcer therapy. Uncomplicated peptic ulcers respond quite well to drug treatment, although recurrences are common and may require long-term maintenance therapy. Drug induced gastric ulcers have represented a challenging problem, for which effective therapy is now available. PMID- 21249092 TI - Control of influenza: when do I use amantadine? AB - Influenza causes significant morbidity and mortality in Canada yearly despite the availability of vaccine and the antiviral drug amantadine (Symmetrel(r)). Vaccine is prepared annually against specific subtypes of influenza A and B that are anticipated to predominate during the winter months. The vaccine should be given in early autumn to patients considered at high risk for the sequelae of influenza. Amantadine, which was first marketed for the treatment of influenza in the early 1960s, is effective in the prevention and early treatment of illness caused by influenza A and is ineffective against influenza B. The drug is available in oral form and should be used as an adjunct to immunization or as an alternative in those for whom immunization is contraindicated or ineffective. PMID- 21249093 TI - New perspectives in multiple sclerosis. AB - Multiple sclerosis, a potentially disabling disease of young adults, is caused by as yet unknown agents. Recent studies suggest a genetic susceptibility factor with a superimposed environmental triggering or causative agent. New methods of diagnosing and monitoring multiple sclerosis, such as magnetic resonance imaging, are providing new insights into pathogenesis. Important new classes of drugs on the horizon may well help to retard the disease process. PMID- 21249094 TI - Exchange transfusion in a case of severe Plasmodium falciparum infection: a case report. AB - A 45-year-old Canadian man, who had recently returned from Cameroon, complained of fever lasting eight days. He had 40% parasitemia with Plasmodium falciparum. In spite of oral therapy with chloroquine, quinine, and tetracycline, the patient's condition deteriorated. Although his clinical condition improved more slowly, the patient's parasitemia improved considerably after exchange transfusion and the institution of parenteral quinidine therapy. Exchange transfusion may be life-saving in falciparum malaria and should be instituted early in severe cases. PMID- 21249095 TI - Illness in returned travellers. AB - Intercontinental travel is more common now than it has ever been before, and so are travel-related diseases. A thorough history and physical examination provide many clues to possible pathogens, particularly when combined with knowledge of the geographic distribution of specific diseases. Prompt diagnosis and proper treatment are imperative. PMID- 21249096 TI - Drug treatment of infertility. AB - Diagnosis and treatment of infertility, once a purely empirical process, can now be based on rational exclusion of alternatives. The author reviews the drug treatment of infertility, emphasizing ovulation induction. He also discusses the endocrine treatment of men, drug treatment of endometriosis, and antibiotic treatment of infections. The author recommends referral to a specialist when more invasive drugs, such as gonadotrophins or gonadotrophin-releasing hormone or analogue, are indicated, if the couple continues to be infertile, or when the physician suspects endometriosis. PMID- 21249097 TI - Geriatric rehabilitation: a family practice approach. AB - Geriatric patients require rehabilitative measures that restore function and prevent further loss, with the goal of preserving independence. Assessment of functional ability and problems contributing to the disability (there are frequently more than one in elderly patients) help to make realistic goals for treatment. Functional scales provide rational evaluation of baseline status, progress made during treatment, and when remission has occurred. PMID- 21249098 TI - International health. PMID- 21249099 TI - The difficult patient: comment. PMID- 21249100 TI - Practice assessment program: comment. PMID- 21249101 TI - Public health and the environment. PMID- 21249102 TI - Needs of caregivers of elderly attending day hospital. AB - A mailed questionnaire was used to assess the time demands and relative stress burden of tasks performed by caregivers to patients attending a geriatric day hospital. Eighty per cent (43 of 54) of the questionnaires were completed. Most (84%) of caregivers were women, and 38% were older than 65 years of age. Fifty three per cent of care receivers were women; 54% were 80 years of age or older. Most care receivers were related to the caregiver, and 84% lived with them. Activities causing the most stress to caregivers were bathing, bladder control, walking about the home, and travelling outside the home. A significant number of caregivers did not have access to alternate caregivers for relief during the day (18%) or night (26%), or for a weekend (28%) or a week (40%). Sixty-eight per cent of caregivers felt some mental strain as a result of their caregiver role. PMID- 21249103 TI - Nutrition education practices and opinions of alberta family physicians. AB - A questionnaire was mailed to a random sample of 532 members of the Alberta Chapter of the College of Family Physicians in order to assess the role of physicians in providing nutrition education to their patients. Of the 255 respondents (53% response rate), over 97% agreed that "educating patients about nutrition is an important role for physicians." Physicians most often gave nutrition information on obesity, constipation, heart disease and hypertension, alcohol, coffee, infant feeding, osteoporosis, and prenatal nutrition. Female physicians gave nutrition information significantly more often than male physicians on four maternal and child health topics. Perceived barriers to nutrition education included lack of reimbursement for physicians (86%), lack of time (48%), and limited access to patient information (42%). Most physicians often informed patients on the seven most common nutrition topics despite these concerns. PMID- 21249104 TI - Effect of Devil's Club Tea on Blood Glucose Levels in Diabetes Mellitus. AB - Devil's club (Oplopanax horridum) is a popular medicinal plant used by Native Indian tribes in the Pacific Northwest. One reported indication for using this plant is in the treatment of diabetes mellitus. Several physicians have reported patients with diabetes who were able to maintain normal blood glucose levels while taking devil's club preparations. The authors performed a pilot study in which blood glucose levels were carefully monitored in an insulin-dependent diabetic patient, a newly diagnosed non-insulin-dependent diabetic, and two healthy adults while they drank devil's club tea. The limited data do not show any hypoglycemic effect of devil's club tea. PMID- 21249105 TI - Microcomputers for analysis of emergency department function. AB - The Halifax Infirmary Hospital developed a system in which patient data from the emergency department were transferred from the hospital's mainframe computer to a microcomputer, under the control of staff most involved with the patient. Codes were automatically assigned to the diagnoses recorded in free text, and the accuracy of the data was verified. Emergency department staff used this system to perform audits, quality assurance, and research that would be difficult or impossible to do manually. PMID- 21249106 TI - Sick or Sinner? An Ethical Dilemma that Changes with the Times. AB - The work of the family physician is occasionally enlivened by an unusual patient problem. The particular episode described and discussed in this case report called into question the moral and ethical standards of both medicine and society. Issues of responsibility for unacceptable behaviour by an individual are examined within an historical context, and the reader is left to ponder his or her own answer to the questions raised. PMID- 21249107 TI - Neonatal screening part 1. General principles. AB - Neonatal screening is a widely accepted, cost-effective method for early detection of a variety of inborn errors of metabolism. This early detection improves the outcome in affected children. This series of three articles will examine different aspects of neonatal screening. In this first article, the author discusses general principles, including criteria for test selection, sensitivity and specificity of tests, cost-benefit analyses, laboratory factors in screening, and the role neonatal screening plays in the spectrum of diagnostic techniques for genetic disease. The second article will describe the current status of screening in Canada, the diseases for which screening is currently applied, and the benefits of screening and treatment. In the final article, the author will assess the controversial topics that may form the future of screening. PMID- 21249108 TI - Maternal mortality: preventing the tragedy in developing countries. AB - Maternal mortality in childbirth has been, until recently, a neglected tragedy in most developing countries. Rates of maternal deaths range from 300 to 700/100 000 live births, from 50 to 100 times greater in developing than in developed countries. The major direct obstetric causes include illegal abortions, hemorrhage, sepsis, obstructed labour, ruptured uterus, and pregnancy-induced hypertension. During the past decade, increased recognition of this problem has led to the "Safe Motherhood Initiative" by the World Health Organization in 1987, which has been integrated into the goal of "Health for All by the Year 2000." The training of traditional birth attendants (who attend from 40% to 60% of births in developing countries) is seen as one of the most important ways to improve obstetric care in remote rural villages. PMID- 21249109 TI - Primary health care experiences in the developing world: lessons for Canada? AB - Primary health care, as practised in many developing countries, is a set of guidelines for designing health strategies that are both appropriate to the health needs of the population and to cultural and socio-economic contexts. Four aspects of primary health care experience in developing countries may be relevant to Canadian health care: the integration of health and development, participation of the community in problem identification and program planning, the role of the community-based worker, and the use of health information. Canadian physicians may draw on this experience to address present challenges in our health system: providing health services to marginal groups, viewing health in a broader perspective, the escalating costs of health services, and increasing community involvement in planning health services. PMID- 21249110 TI - Indian Reserves: Canada's Developing Nations. AB - Indian reserves are the most visible reminder of the separation of aboriginal people from the rest of Canada and other Canadians. Illness patterns and social conditions in Native communities closely parallel those in developing nations. While they continue to have a large burden of infectious diseases, these groups also have an increased incidence of chronic and lifestyle diseases as well as environment-related conditions. Similarities can be seen in urban areas between immigrants from abroad and people from reserves. Barriers impede full access to and benefit from the Canadian health care system. The author reviews the evidence behind these comparisons and lists some resources that can help physicians meet the challenge of cross-cultural care to aboriginal Canadians. PMID- 21249111 TI - Adolescent health care: can an international approach help? AB - Our growing appreciation that young people share many concerns and problems has increased our perception of the importance of adolescent health care throughout the world. The social context in which adolescents must be viewed opens the way to more creative interventions by practising clinicians. The authors put the field of adolescent health in an historical perspective, highlighting evolving concepts and international initiatives and their relevance to the primary care physician. PMID- 21249112 TI - The plight of immigrant physicians in Canada. AB - A large number of foreign medical graduates are striving to obtain their licence to practise in Canada. The obstacles created by the federal and provincial medical authorities are numerous and difficult to surmount. The authors define the foreign medical graduate, describe the options and strategies one faces, and present statistics about the Medical Council of Canada Evaluating Examination and postgraduate training positions. Their purpose is to present the plight of foreign medical graduates in Canada to Canadian physicians and to acquaint foreign medical graduates with restrictive licensing procedures. PMID- 21249113 TI - Folk healers: a different perspective. AB - Non-western folk healers and their methods are often dismissed by westerners who feel that only physicians who have been well schooled in the Hippocratic tradition at an established university can provide health care adequately. The author, however, asserts that folk healers have a valuable role in medicine. A large percentage of the world's population relies on these practitioners as primary health care providers, and thus their contribution to medicine is considerable on a global scale. Similarly, treatments and pharmaceutical agents discovered by tribal healers have, on occasion, been keenly adopted by the west. Acknowledging the significance of this contribution can stimulate further study of alternative treatment options and philosophies. PMID- 21249114 TI - Goals of international health care organizations and their relationships to Canada. AB - The author discusses the goals of one international health care organization, The World Organization of National Colleges, Academies, and Academic Associations of General Practitioners/Family Physicians (WONCA), focusing particularly on how the organization relates to Canada. For clarification of the subject, a brief history and description of the organization has been included. A number of Canadian family physicians have played an active part in the foundation, evolution, and activities of WONCA. PMID- 21249115 TI - Primary Health Care: Every Doctor's Business. AB - The goal of "Health for All" has not changed since it was orginally promoted in 1977, but the strategy for reaching this goal has been revised dramatically. Primary health care, through preventive measures, simple lifestyle improvements, human resource development, and health education, is now promoted as a means to attain "Health for All" by the year 2000. The authors report the results of a health care project in Kenya's western province. PMID- 21249116 TI - [Not Available]. AB - The author discusses the factors that led to the establishment of departments of family medicine in South Africa and presents relevant background information about the country. Family medicine is firmly established in South Africa and, in spite of resistance from traditional academic departments of medicine, there are departments of family medicine with varying degrees of autonomy at all of the medical schools in the country. The author believes that, in the near future, the right to practice general (family) medicine will require specific occupational training. PMID- 21249117 TI - [Not Available]. AB - Interest in alternative medicine is increasing. Family physicians, frequently asked by patients about the merits of these practices, must increase their knowledge in order to develop an enlightened, scientific approach to the subject. Homeopathy is one such system of medicine; it was founded by Dr. Samuel Hahnemann nearly 200 years ago. Clinical research in homeopathy is in the very early stages. To date, clinical trials to determine the efficacy of individual homeopathic remedies and the validity of homeopathic theory generally have been inconclusive. It is to be hoped that clinical research in homeopathy will continue so that we can increase our knowledge and provide our patients with better answers to their questions. PMID- 21249118 TI - Medicine, the arts, and society. PMID- 21249119 TI - Epigenetic-genetic chromosome dosage approach for fetal trisomy 21 detection using an autosomal genetic reference marker. AB - BACKGROUND: The putative promoter of the holocarboxylase synthetase (HLCS) gene on chromosome 21 is hypermethylated in placental tissues and could be detected as a fetal-specific DNA marker in maternal plasma. Detection of fetal trisomy 21 (T21) has been demonstrated by an epigenetic-genetic chromosome dosage approach where the amount of hypermethylated HLCS in maternal plasma is normalized using a fetal genetic marker on the Y chromosome as a chromosome dosage reference marker. We explore if this method can be applied on both male and female fetuses with the use of a paternally-inherited fetal single nucleotide polymorphism (SNP) allele on a reference chromosome for chromosome dosage normalization. METHODOLOGY: We quantified hypermethylated HLCS molecules using methylation-sensitive restriction endonuclease digestion followed by real-time or digital PCR analyses. For chromosome dosage analysis, we compared the amount of digestion-resistant HLCS to that of a SNP allele (rs6636, a C/G SNP) that the fetus has inherited from the father but absent in the pregnant mother. PRINCIPAL FINDINGS: Using a fetal specific SNP allele on a reference chromosome, we analyzed 20 euploid and nine T21 placental tissue samples. All samples with the fetal-specific C allele were correctly classified. One sample from each of the euploid and T21 groups were misclassified when the fetal-specific G allele was used as the reference marker. We then analyzed 33 euploid and 14 T21 maternal plasma samples. All but one sample from each of the euploid and T21 groups were correctly classified using the fetal-specific C allele, while correct classification was achieved for all samples using the fetal-specific G allele as the reference marker. CONCLUSIONS: As a proof-of-concept study, we have demonstrated that the epigenetic-genetic chromosome dosage approach can be applied to the prenatal diagnosis of trisomy 21 for both male and female fetuses. PMID- 21249120 TI - Mouse survival motor neuron alleles that mimic SMN2 splicing and are inducible rescue embryonic lethality early in development but not late. AB - Spinal muscular atrophy (SMA) is caused by low survival motor neuron (SMN) levels and patients represent a clinical spectrum due primarily to varying copies of the survival motor neuron-2 (SMN2) gene. Patient and animals studies show that disease severity is abrogated as SMN levels increase. Since therapies currently being pursued target the induction of SMN, it will be important to understand the dosage, timing and cellular requirements of SMN for disease etiology and potential therapeutic intervention. This requires new mouse models that can induce SMN temporally and/or spatially. Here we describe the generation of two hypomorphic Smn alleles, Smn(C-T-Neo) and Smn(2B-Neo). These alleles mimic SMN2 exon 7 splicing, titre Smn levels and are inducible. They were specifically designed so that up to three independent lines of mice could be generated, herein we describe two. In a homozygous state each allele results in embryonic lethality. Analysis of these mutants indicates that greater than 5% of Smn protein is required for normal development. The severe hypomorphic nature of these alleles is caused by inclusion of a loxP-flanked neomycin gene selection cassette in Smn intron 7, which can be removed with Cre recombinase. In vitro and in vivo experiments demonstrate these as inducible Smn alleles. When combined with an inducible Cre mouse, embryonic lethality caused by low Smn levels can be rescued early in gestation but not late. This provides direct genetic evidence that a therapeutic window for SMN inductive therapies may exist. Importantly, these lines fill a void for inducible Smn alleles. They also provide a base from which to generate a large repertoire of SMA models of varying disease severities when combined with other Smn alleles or SMN2-containing mice. PMID- 21249121 TI - The Aquaporin gene family of the yellow fever mosquito, Aedes aegypti. AB - BACKGROUND: The mosquito, Aedes aegypti, is the principal vector of the Dengue and yellow fever viruses. During feeding, an adult female can take up more than its own body weight in vertebrate blood. After a blood meal females excrete large amounts of urine through their excretion system, the Malpighian tubules (MT). Diuresis starts within seconds after the mosquito starts feeding. Aquaporins (AQPs) are a family of membrane transporters that regulate the flow of water, glycerol and other small molecules across cellular membranes in both prokaryotic and eukaryotic cells. Our aim was to identify aquaporins that function as water channels, mediating transcellular water transport in MTs of adult female Ae. aegypti. METHODOLOGY/PRINCIPAL FINDINGS: Using a bioinformatics approach we screened genome databases and identified six putative AQPs in the genome of Ae. aegypti. Phylogenetic analysis showed that five of the six Ae. aegypti AQPs have high similarity to classical water-transporting AQPs of vertebrates. Using microarray, reverse transcription and real time PCR analysis we found that all six AQPs are expressed in distinct patterns in mosquito tissues/body parts. AaAQP1, 4, and 5 are strongly expressed in the adult female MT. RNAi-mediated knockdown of the MT-expressed mosquito AQPs resulted in significantly reduced diuresis. CONCLUSIONS/SIGNIFICANCE: Our results support the notion that AQP1, 4, and 5 function as water transporters in the MTs of adult female Ae. aegypti mosquitoes. Our results demonstrate the importance of these AQPs for mosquito diuresis after blood ingestion and highlight their potential as targets for the development of novel vector control strategies. PMID- 21249122 TI - Crystal structure of Escherichia coli CusC, the outer membrane component of a heavy metal efflux pump. AB - BACKGROUND: While copper has essential functions as an enzymatic co-factor, excess copper ions are toxic for cells, necessitating mechanisms for regulating its levels. The cusCBFA operon of E. coli encodes a four-component efflux pump dedicated to the extrusion of Cu(I) and Ag(I) ions. METHODOLOGY/PRINCIPAL FINDINGS: We have solved the X-ray crystal structure of CusC, the outer membrane component of the Cus heavy metal efflux pump, to 2.3 A resolution. The structure has the largest extracellular opening of any outer membrane factor (OMF) protein and suggests, for the first time, the presence of a tri-acylated N-terminal lipid anchor. CONCLUSIONS/SIGNIFICANCE: The CusC protein does not have any obvious features that would make it specific for metal ions, suggesting that the narrow substrate specificity of the pump is provided by other components of the pump, most likely by the inner membrane component CusA. PMID- 21249123 TI - Hydrodynamic regulation of monocyte inflammatory response to an intracellular pathogen. AB - Systemic bacterial infections elicit inflammatory response that promotes acute or chronic complications such as sepsis, arthritis or atherosclerosis. Of interest, cells in circulation experience hydrodynamic shear forces, which have been shown to be a potent regulator of cellular function in the vasculature and play an important role in maintaining tissue homeostasis. In this study, we have examined the effect of shear forces due to blood flow in modulating the inflammatory response of cells to infection. Using an in vitro model, we analyzed the effects of physiological levels of shear stress on the inflammatory response of monocytes infected with chlamydia, an intracellular pathogen which causes bronchitis and is implicated in the development of atherosclerosis. We found that chlamydial infection alters the morphology of monocytes and trigger the release of pro inflammatory cytokines TNF-alpha, IL-8, IL-1beta and IL-6. We also found that the exposure of chlamydia-infected monocytes to short durations of arterial shear stress significantly enhances the secretion of cytokines in a time-dependent manner and the expression of surface adhesion molecule ICAM-1. As a functional consequence, infection and shear stress increased monocyte adhesion to endothelial cells under flow and in the activation and aggregation of platelets. Overall, our study demonstrates that shear stress enhances the inflammatory response of monocytes to infection, suggesting that mechanical forces may contribute to disease pathophysiology. These results provide a novel perspective on our understanding of systemic infection and inflammation. PMID- 21249124 TI - The inflammatory microenvironment in colorectal neoplasia. AB - Colorectal cancer (CRC) is a major cause of mortality and morbidity worldwide. Inflammatory activity within the stroma of invasive colorectal tumours is known to be a key predictor of disease activity with type, density and location of immune cells impacting on patient prognosis. To date, there has been no report of inflammatory phenotype within pre-malignant human colonic adenomas. Assessing the stromal microenvironment and particularly, inflammatory activity within colorectal neoplastic lesions is central to understanding early colorectal carcinogenesis. Inflammatory cell infiltrate was assessed by immunohistochemistry in paired colonic adenoma and adjacent normal colonic mucosa samples, and adenomas exhibiting increasing degrees of epithelial cell dysplasia. Macrophage phenotype was assessed using double stain immunohistochemistry incorporating expression of an intracellular enzyme of function. A targeted array of inflammatory cytokine and receptor genes, validated by RT-PCR, was used to assess inflammatory gene expression. Inflammatory cell infiltrates are a key feature of sporadic adenomatous colonic polyps with increased macrophage, neutrophil and T cell (specifically helper and activated subsets) infiltration in adenomatous colonic polyps, that increases in association with characteristics of high malignant potential, namely, increasing degree of cell dysplasia and adenoma size. Macrophages within adenomas express iNOS, suggestive of a pro-inflammatory phenotype. Several inflammatory cytokine genes (CXCL1, CXCL2, CXCL3, CCL20, IL8, CCL23, CCL19, CCL21, CCL5) are dysregulated in adenomas. This study has provided evidence of increased inflammation within pre-malignant colonic adenomas. This may allow potential mechanistic pathways in the initiation and promotion of early colorectal carcinogenesis to be identified. PMID- 21249125 TI - Macrophage activation and differentiation signals regulate schlafen-4 gene expression: evidence for Schlafen-4 as a modulator of myelopoiesis. AB - BACKGROUND: The ten mouse and six human members of the Schlafen (Slfn) gene family all contain an AAA domain. Little is known of their function, but previous studies suggest roles in immune cell development. In this report, we assessed Slfn regulation and function in macrophages, which are key cellular regulators of innate immunity. METHODOLOGY/PRINCIPAL FINDINGS: Multiple members of the Slfn family were up-regulated in mouse bone marrow-derived macrophages (BMM) by the Toll-like Receptor (TLR)4 agonist lipopolysaccharide (LPS), the TLR3 agonist Poly(I?C), and in disease-affected joints in the collagen-induced model of rheumatoid arthritis. Of these, the most inducible was Slfn4. TLR agonists that signal exclusively through the MyD88 adaptor protein had more modest effects on Slfn4 mRNA levels, thus implicating MyD88-independent signalling and autocrine interferon (IFN)-beta in inducible expression. This was supported by the substantial reduction in basal and LPS-induced Slfn4 mRNA expression in IFNAR-1-/ BMM. LPS causes growth arrest in macrophages, and other Slfn family genes have been implicated in growth control. Slfn4 mRNA levels were repressed during macrophage colony-stimulating factor (CSF-1)-mediated differentiation of bone marrow progenitors into BMM. To determine the role of Slfn4 in vivo, we over expressed the gene specifically in macrophages in mice using a csf1r promoter driven binary expression system. Transgenic over-expression of Slfn4 in myeloid cells did not alter macrophage colony formation or proliferation in vitro. Monocyte numbers, as well as inflammatory macrophages recruited to the peritoneal cavity, were reduced in transgenic mice that specifically over-expressed Slfn4, while macrophage numbers and hematopoietic activity were increased in the livers and spleens. CONCLUSIONS: Slfn4 mRNA levels were up-regulated during macrophage activation but down-regulated during differentiation. Constitutive Slfn4 expression in the myeloid lineage in vivo perturbs myelopoiesis. We hypothesise that the down-regulation of Slfn4 gene expression during macrophage differentiation is a necessary step in development of this lineage. PMID- 21249126 TI - The importance of conserving biodiversity outside of protected areas in mediterranean ecosystems. AB - Mediterranean-type ecosystems constitute one of the rarest terrestrial biomes and yet they are extraordinarily biodiverse. Home to over 250 million people, the five regions where these ecosystems are found have climate and coastal conditions that make them highly desirable human habitats. The current conservation landscape does not reflect the mediterranean biome's rarity and its importance for plant endemism. Habitat conversion will clearly outpace expansion of formal protected-area networks, and conservationists must augment this traditional strategy with new approaches to sustain the mediterranean biota. Using regional scale datasets, we determine the area of land in each of the five regions that is protected, converted (e.g., to urban or industrial), impacted (e.g., intensive, cultivated agriculture), or lands that we consider to have conservation potential. The latter are natural and semi-natural lands that are unprotected (e.g., private range lands) but sustain numerous native species and associated habitats. Chile has the greatest proportion of its land (75%) in this category and California-Mexico the least (48%). To illustrate the potential for achieving mediterranean biodiversity conservation on these lands, we use species-area curves generated from ecoregion scale data on native plant species richness and vertebrate species richness. For example, if biodiversity could be sustained on even 25% of existing unprotected, natural and semi-natural lands, we estimate that the habitat of more than 6,000 species could be represented. This analysis suggests that if unprotected natural and semi-natural lands are managed in a manner that allows for persistence of native species, we can realize significant additional biodiversity gains. Lasting biodiversity protection at the scale needed requires unprecedented collaboration among stakeholders to promote conservation both inside and outside of traditional protected areas, including on lands where people live and work. PMID- 21249127 TI - White matter changes and word finding failures with increasing age. AB - BACKGROUND: Increasing life expectancy necessitates the better understanding of the neurophysiological underpinnings of age-related cognitive changes. The majority of research examining structural-cognitive relationships in aging focuses on the role of age-related changes to grey matter integrity. In the current study, we examined the relationship between age-related changes in white matter and language production. More specifically, we concentrated on word finding failures, which increase with age. METHODOLOGY/PRINCIPAL FINDINGS: We used Diffusion tensor MRI (a technique used to image, in vivo, the diffusion of water molecules in brain tissue) to relate white matter integrity to measures of successful and unsuccessful picture naming. Diffusion tensor images were used to calculate Fractional Anisotropy (FA) images. FA is considered to be a measure of white matter organization/integrity. FA images were related to measures of successful picture naming and to word finding failures using voxel-based linear regression analyses. Successful naming rates correlated positively with white matter integrity across a broad range of regions implicated in language production. However, word finding failure rates correlated negatively with a more restricted region in the posterior aspect of superior longitudinal fasciculus. CONCLUSIONS/SIGNIFICANCE: The use of DTI-MRI provides evidence for the relationship between age-related white matter changes in specific language regions and word finding failures in old age. PMID- 21249128 TI - TWEAK appears as a modulator of endometrial IL-18 related cytotoxic activity of uterine natural killers. AB - BACKGROUND: TWEAK (Tumor necrosis factor like WEAK inducer of apoptosis) is highly expressed by different immune cells and triggers multiple cellular responses, including control of angiogenesis. Our objective was to investigate its role in the human endometrium during the implantation window, using an ex vivo endometrial microhistoculture model. Indeed, previous results suggested that basic TWEAK expression influences the IL-18 related uNK recruitment and local cytotoxicity. METHODOLOGY/PRINCIPAL FINDINGS: Endometrial biopsies were performed 7 to 9 days after the ovulation surge of women in monitored natural cycles. Biopsies were cut in micro-pieces and cultured on collagen sponge with appropriate medium. Morphology, functionality and cell death were analysed at different time of the culture. We used this ex vivo model to study mRNA expressions of NKp46 (a uNK cytotoxic receptor) and TGF-beta1 (protein which regulates uNK cytokine production) after adjunction of excess of recombinant IL 18 and either recombinant TWEAK or its antibody. NKp46 protein expression was also detailed by immunohistochemistry in selected patients with high basic mRNA level of IL-18 and either low or high mRNA level of TWEAK. The NKp46 immunostaining was stronger in patients with an IL-18 over-expression and a low TWEAK expression, when compared with patients with both IL-18 and TWEAK high expressions. We did not observe any difference for TWEAK expression when recombinant protein IL-18 or its antibody was added, or conversely, for IL-18 expression when TWEAK or its antibody was added in the culture medium. In a pro inflammatory environment (obtained by an excess of IL-18), inhibition of TWEAK was able to increase significantly NKp46 and TGF-beta1 mRNA expressions. CONCLUSIONS/SIGNIFICANCE: TWEAK doesn't act on IL-18 expression but seems to control IL-18 related cytotoxicity on uNK cells when IL-18 is over-expressed. Thus, TWEAK appears as a crucial physiological modulator to prevent endometrial uNK cytotoxicity in human. PMID- 21249129 TI - Equivalence of conventionally-derived and parthenote-derived human embryonic stem cells. AB - BACKGROUND: As human embryonic stem cell (hESC) lines can be derived via multiple means, it is important to determine particular characteristics of individual lines that may dictate the applications to which they are best suited. The objective of this work was to determine points of equivalence and differences between conventionally-derived hESC and parthenote-derived hESC lines (phESC) in the undifferentiated state and during neural differentiation. METHODOLOGY/PRINCIPAL FINDINGS: hESC and phESC were exposed to the same expansion conditions and subsequent neural and retinal pigmented epithelium (RPE) differentiation protocols. Growth rates and gross morphology were recorded during expansion. RTPCR for developmentally relevant genes and global DNA methylation profiling were used to compare gene expression and epigenetic characteristics. Parthenote lines proliferated more slowly than conventional hESC lines and yielded lower quantities of less mature differentiated cells in a neural progenitor cell (NPC) differentiation protocol. However, the cell lines performed similarly in a RPE differentiation protocol. The DNA methylation analysis showed similar general profiles, but the two cell types differed in methylation of imprinted genes. There were no major differences in gene expression between the lines before differentiation, but when differentiated into NPCs, the two cell types differed in expression of extracellular matrix (ECM) genes. CONCLUSIONS/SIGNIFICANCE: These data show that hESC and phESC are similar in the undifferentiated state, and both cell types are capable of differentiation along neural lineages. The differences between the cell types, in proliferation and extent of differentiation, may be linked, in part, to the observed differences in ECM synthesis and methylation of imprinted genes. PMID- 21249130 TI - Gadd45a is an RNA binding protein and is localized in nuclear speckles. AB - BACKGROUND: The Gadd45 proteins play important roles in growth control, maintenance of genomic stability, DNA repair, and apoptosis. Recently, Gadd45 proteins have also been implicated in epigenetic gene regulation by promoting active DNA demethylation. Gadd45 proteins have sequence homology with the L7Ae/L30e/S12e RNA binding superfamily of ribosomal proteins, which raises the question if they may interact directly with nucleic acids. PRINCIPAL FINDINGS: Here we show that Gadd45a binds RNA but not single- or double stranded DNA or methylated DNA in vitro. Sucrose density gradient centrifugation experiments demonstrate that Gadd45a is present in high molecular weight particles, which are RNase sensitive. Gadd45a displays RNase-sensitive colocalization in nuclear speckles with the RNA helicase p68 and the RNA binding protein SC35. A K45A point mutation defective in RNA binding was still active in DNA demethylation. This suggests that RNA binding is not absolutely essential for demethylation of an artificial substrate. A point mutation at G39 impared RNA binding, nuclear speckle localization and DNA demethylation, emphasizing its relevance for Gadd45a function. SIGNIFICANCE: The results implicate RNA in Gadd45a function and suggest that Gadd45a is associated with a ribonucleoprotein particle. PMID- 21249131 TI - Comprehensive analysis of MGMT promoter methylation: correlation with MGMT expression and clinical response in GBM. AB - O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation has been identified as a potential prognostic marker for glioblastoma patients. The relationship between the exact site of promoter methylation and its effect on gene silencing, and the patient's subsequent response to therapy, is still being defined. The aim of this study was to comprehensively characterize cytosine guanine (CpG) dinucleotide methylation across the entire MGMT promoter and to correlate individual CpG site methylation patterns to mRNA expression, protein expression, and progression-free survival. To best identify the specific MGMT promoter region most predictive of gene silencing and response to therapy, we determined the methylation status of all 97 CpG sites in the MGMT promoter in tumor samples from 70 GBM patients using quantitative bisulfite sequencing. We next identified the CpG site specific and regional methylation patterns most predictive of gene silencing and improved progression-free survival. Using this data, we propose a new classification scheme utilizing methylation data from across the entire promoter and show that an analysis based on this approach, which we call 3R classification, is predictive of progression-free survival (HR = 5.23, 95% CI [2.089-13.097], p<0.0001). To adapt this approach to the clinical setting, we used a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) test based on the 3R classification and show that this test is both feasible in the clinical setting and predictive of progression free survival (HR = 3.076, 95% CI [1.301-7.27], p = 0.007). We discuss the potential advantages of a test based on this promoter-wide analysis and compare it to the commonly used methylation-specific PCR test. Further prospective validation of these two methods in a large independent patient cohort will be needed to confirm the added value of promoter wide analysis of MGMT methylation in the clinical setting. PMID- 21249132 TI - Transcription profile analysis reveals that zygotic division results in uneven distribution of specific transcripts in apical/basal cells of tobacco. AB - BACKGROUND: Asymmetric zygotic division in higher plants results in the formation of an apical cell and a basal cell. These two embryonic cells possess distinct morphologies and cell developmental fates. It has been proposed that unevenly distributed cell fate determinants and/or distinct cell transcript profiles may be the underlying reason for their distinct fates. However, neither of these hypotheses has convincing support due to technical limitations. METHODOLOGY/PRINCIPAL FINDINGS: Using laser-controlled microdissection, we isolated apical and basal cells and constructed cell type-specific cDNA libraries. Transcript profile analysis revealed difference in transcript composition. PCR and qPCR analysis confirmed that transcripts of selected embryogenesis-related genes were cell-type preferentially distributed. Some of the transcripts that existed in zygotes were found distinctly existed in apical or basal cells. The cell type specific de novo transcription was also found after zygotic cell division. CONCLUSIONS/SIGNIFICANCE: Thus, we found that the transcript diversity occurs between apical and basal cells. Asymmetric zygotic division results in the uneven distribution of some embryogenesis related transcripts in the two-celled proembryos, suggesting that a differential distribution of some specific transcripts in the apical or basal cells may involve in guiding the two cell types to different developmental destinies. PMID- 21249133 TI - Histone variants and their post-translational modifications in primary human fat cells. AB - Epigenetic changes related to human disease cannot be fully addressed by studies of cells from cultures or from other mammals. We isolated human fat cells from subcutaneous abdominal fat tissue of female subjects and extracted histones from either purified nuclei or intact cells. Direct acid extraction of whole adipocytes was more efficient, yielding about 100 ug of protein with histone content of 60%-70% from 10 mL of fat cells. Differential proteolysis of the protein extracts by trypsin or ArgC-protease followed by nanoLC/MS/MS with alternating CID/ETD peptide sequencing identified 19 histone variants. Four variants were found at the protein level for the first time; particularly HIST2H4B was identified besides the only H4 isoform earlier known to be expressed in humans. Three of the found H2A potentially organize small nucleosomes in transcriptionally active chromatin, while two H2AFY variants inactivate X chromosome in female cells. HIST1H2BA and three of the identified H1 variants had earlier been described only as oocyte or testis specific histones. H2AFX and H2AFY revealed differential and variable N-terminal processing. Out of 78 histone modifications by acetylation/trimethylation, methylation, dimethylation, phosphorylation and ubiquitination, identified from six subjects, 68 were found for the first time. Only 23 of these modifications were detected in two or more subjects, while all the others were individual specific. The direct acid extraction of adipocytes allows for personal epigenetic analyses of human fat tissue, for profiling of histone modifications related to obesity, diabetes and metabolic syndrome, as well as for selection of individual medical treatments. PMID- 21249134 TI - Interactions between laminin receptor and the cytoskeleton during translation and cell motility. AB - Human laminin receptor acts as both a component of the 40S ribosomal subunit to mediate cellular translation and as a cell surface receptor that interacts with components of the extracellular matrix. Due to its role as the cell surface receptor for several viruses and its overexpression in several types of cancer, laminin receptor is a pathologically significant protein. Previous studies have determined that ribosomes are associated with components of the cytoskeleton, however the specific ribosomal component(s) responsible has not been determined. Our studies show that laminin receptor binds directly to tubulin. Through the use of siRNA and cytoskeletal inhibitors we demonstrate that laminin receptor acts as a tethering protein, holding the ribosome to tubulin, which is integral to cellular translation. Our studies also show that laminin receptor is capable of binding directly to actin. Through the use of siRNA and cytoskeletal inhibitors we have shown that this laminin receptor-actin interaction is critical for cell migration. These data indicate that interactions between laminin receptor and the cytoskeleton are vital in mediating two processes that are intimately linked to cancer, cellular translation and migration. PMID- 21249135 TI - High-performance capillary electrophoresis for determining HIV-1 Tat protein in neurons. AB - The HIV-1 protein, Tat has been implicated in AIDS pathogenesis however, the amount of circulating Tat is believed to be very low and its quantification has been difficult. We performed the quantification of Tat released from infected cells and taken up by neurons using high performance capillary electrophoresis. This is the first report to successfully measure the amount of Tat in neurons and places Tat as a key player involved in HIV-associated neurocognitive disorders. PMID- 21249136 TI - Unusual regulation of a leaderless operon involved in the catabolism of dimethylsulfoniopropionate in Rhodobacter sphaeroides. AB - Rhodobacter sphaeroides strain 2.4.1 is a widely studied bacterium that has recently been shown to cleave the abundant marine anti-stress molecule dimethylsulfoniopropionate (DMSP) into acrylate plus gaseous dimethyl sulfide. It does so by using a lyase encoded by dddL, the promoter-distal gene of a three gene operon, acuR-acuI-dddL. Transcription of the operon was enhanced when cells were pre-grown with the substrate DMSP, but this induction is indirect, and requires the conversion of DMSP to the product acrylate, the bona fide co inducer. This regulation is mediated by the product of the promoter-proximal gene acuR, a transcriptional regulator in the TetR family. AcuR represses the operon in the absence of acrylate, but this is relieved by the presence of the co inducer. Another unusual regulatory feature is that the acuR-acuI-dddL mRNA transcript is leaderless, such that acuR lacks a Shine-Dalgarno ribosomal binding site and 5'-UTR, and is translated at a lower level compared to the downstream genes. This regulatory unit may be quite widespread in bacteria, since several other taxonomically diverse lineages have adjacent acuR-like and acuI-like genes; these operons also have no 5' leader sequences or ribosomal binding sites and their predicted cis-acting regulatory sequences resemble those of R. sphaeroides acuR-acuI-dddL. PMID- 21249138 TI - Malnutrition in hospital: the clinical and economic implications. AB - BACKGROUND: Undernutrition and malnutrition are common in hospitalized patients. Their combined prevalence on admission is estimated at 25% and is rising. METHODS: Selective literature review with special consideration of current guidelines and meta-analyses. RESULTS: The nutritional state of every patient should be assessed on admission with simple, established parameters, and patients suffering from under- or malnutrition should be treated with a targeted nutritional intervention based on the established stepwise treatment algorithm. Under- and malnutrition are an independent risk and cost factor with a significant influence on mortality, morbidity, length of hospital stay, and quality of life. Their direct costs alone amount to some 9 billion Euros in Germany each year. Therapeutic trials and meta-analyses have clearly documented the therapeutic benefit and cost-effectiveness of oral nutritional supplements and tube feeds. Targeted nutritional intervention is an integral part of medical treatment and prevention. CONCLUSION: Undernutrition and malnutrition are common in hospitalized patients and are both medically and economically harmful. If they are detected early by targeted assessment and then treated appropriately according to the established stepwise treatment algorithm, better clinical outcomes and lower costs will result. PMID- 21249139 TI - Correspondence (letter to the editor): Is the treatment the problem? PMID- 21249137 TI - The treatment of upper limb fractures in children and adolescents. AB - BACKGROUND: The treatment of fractures in children and adolescents must be based on an adequate knowledge of the physiology of the growing skeleton. Treatment failures usually do not result from technical deficiencies, but rather from a misunderstanding of the special considerations applying to the treatment of fractures in this age group. METHODS: We selectively reviewed recent publications on the main types of long bone fracture occurring in the period of skeletal development. RESULTS: Alleviating pain is the first step in fracture management, and due attention must be paid to any evidence of child abuse. The goals of treatment are to bring about healing of the fracture and to preserve the function of the wounded limb. The growth that has yet to take place over the remaining period of skeletal development also has to be considered. Predicting the growth pattern of fractured bones is a basic task of the pediatric traumatologist. During the period of skeletal development, conservative and surgical treatments are used in complementary fashion. Particular expertise is needed to deal with fractures around the elbow, especially supracondylar humeral fractures, displaced fractures of the radial condyle of the humerus, radial neck fractures, and radial head dislocations (Monteggia lesions). These problems account for a large fraction of the avoidable cases of faulty fracture healing leading to functional impairment in children and adolescents. CONCLUSION: The main requirements for the proper treatment of fractures in children and adolescents are the immediate alleviation of pain and the provision of effective treatment (either in the hospital or on an outpatient basis) to ensure the best possible outcome, while the associated costs and effort is kept to a minimum. Further important goals are a rapid recovery of mobility and the avoidance of late complications, such as restriction of the range of motion or growth disorders of the fractured bone. To achieve these goals, the treating physician should have the necessary expertise in all of the applicable conservative and surgical treatment methods and should be able to apply them for the proper indications. PMID- 21249140 TI - Correspondence (letter to the editor): What about the dam break upstream? PMID- 21249142 TI - Correspondence (letter to the editor): Uncritical prescription. PMID- 21249143 TI - Murine cytomegalovirus infection of neural stem cells alters neurogenesis in the developing brain. AB - BACKGROUND: Congenital cytomegalovirus (CMV) brain infection causes serious neuro developmental sequelae including: mental retardation, cerebral palsy, and sensorineural hearing loss. But, the mechanisms of injury and pathogenesis to the fetal brain are not completely understood. The present study addresses potential pathogenic mechanisms by which this virus injures the CNS using a neonatal mouse model that mirrors congenital brain infection. This investigation focused on, analysis of cell types infected with mouse cytomegalovirus (MCMV) and the pattern of injury to the developing brain. METHODOLOGY/PRINCIPAL FINDINGS: We used our MCMV infection model and a multi-color flow cytometry approach to quantify the effect of viral infection on the developing brain, identifying specific target cells and the consequent effect on neurogenesis. In this study, we show that neural stem cells (NSCs) and neuronal precursor cells are the principal target cells for MCMV in the developing brain. In addition, viral infection was demonstrated to cause a loss of NSCs expressing CD133 and nestin. We also showed that infection of neonates leads to subsequent abnormal brain development as indicated by loss of CD24(hi) cells that incorporated BrdU. This neonatal brain infection was also associated with altered expression of Oct4, a multipotency marker; as well as down regulation of the neurotrophins BDNF and NT3, which are essential to regulate the birth and differentiation of neurons during normal brain development. Finally, we report decreased expression of doublecortin, a marker to identify young neurons, following viral brain infection. CONCLUSIONS: MCMV brain infection of newborn mice causes significant loss of NSCs, decreased proliferation of neuronal precursor cells, and marked loss of young neurons. PMID- 21249144 TI - Identification of genes that elicit disuse muscle atrophy via the transcription factors p50 and Bcl-3. AB - Skeletal muscle atrophy is a debilitating condition associated with weakness, fatigue, and reduced functional capacity. Nuclear factor-kappaB (NF-kappaB) transcription factors play a critical role in atrophy. Knockout of genes encoding p50 or the NF-kappaB co-transactivator, Bcl-3, abolish disuse atrophy and thus they are NF-kappaB factors required for disuse atrophy. We do not know however, the genes targeted by NF-kappaB that produce the atrophied phenotype. Here we identify the genes required to produce disuse atrophy using gene expression profiling in wild type compared to Nfkb1 (gene encodes p50) and Bcl-3 deficient mice. There were 185 and 240 genes upregulated in wild type mice due to unloading, that were not upregulated in Nfkb1-/- and Bcl-3-/- mice, respectively, and so these genes were considered direct or indirect targets of p50 and Bcl-3. All of the p50 gene targets were contained in the Bcl-3 gene target list. Most genes were involved with protein degradation, signaling, translation, transcription, and transport. To identify direct targets of p50 and Bcl-3 we performed chromatin immunoprecipitation of selected genes previously shown to have roles in atrophy. Trim63 (MuRF1), Fbxo32 (MAFbx), Ubc, Ctsl, Runx1, Tnfrsf12a (Tweak receptor), and Cxcl10 (IP-10) showed increased Bcl-3 binding to kappaB sites in unloaded muscle and thus were direct targets of Bcl-3. p50 binding to the same sites on these genes either did not change or increased, supporting the idea of p50:Bcl-3 binding complexes. p65 binding to kappaB sites showed decreased or no binding to these genes with unloading. Fbxo9, Psma6, Psmc4, Psmg4, Foxo3, Ankrd1 (CARP), and Eif4ebp1 did not show changes in p65, p50, or Bcl-3 binding to kappaB sites, and so were considered indirect targets of p50 and Bcl-3. This work represents the first study to use a global approach to identify genes required to produce the atrophied phenotype with disuse. PMID- 21249145 TI - Cryptococcus gattii virulence composite: candidate genes revealed by microarray analysis of high and less virulent Vancouver island outbreak strains. AB - Human and animal cryptococcosis due to an unusual molecular type of Cryptococcus gattii (VGII) emerged recently on Vancouver Island, Canada. Unlike C. neoformans, C. gattii causes disease mainly in immunocompetent hosts, despite producing a similar suite of virulence determinants. To investigate a potential relationship between the regulation of expression of a virulence gene composite and virulence, we took advantage of two subtypes of VGII (a and b), one highly virulent (R265) and one less virulent (R272), that were identified from the Vancouver outbreak. By expression microarray analysis, 202 genes showed at least a 2-fold difference in expression with 108 being up- and 94 being down-regulated in strain R265 compared with strain R272. Specifically, expression levels of genes encoding putative virulence factors (e.g. LAC1, LAC2, CAS3 and MPK1) and genes encoding proteins involved in cell wall assembly, carbohydrate and lipid metabolism were increased in strain R265, whereas genes involved in the regulation of mitosis and ergosterol biosynthesis were suppressed. In vitro phenotypic studies and transcription analysis confirmed the microarray results. Gene disruption of LAC1 and MPK1 revealed defects in melanin synthesis and cell wall integrity, respectively, where CAS3 was not essential for capsule production. Moreover, MPK1 also controls melanin and capsule production and causes a severe attenuation of the virulence in a murine inhalational model. Overall, this study provides the basis for further genetic studies to characterize the differences in the virulence composite of strains with minor evolutionary divergences in gene expression in the primary pathogen C. gattii, that have led to a major invasive fungal infection outbreak. PMID- 21249146 TI - Role of intestinal bacteria in gliadin-induced changes in intestinal mucosa: study in germ-free rats. AB - BACKGROUND AND AIMS: Celiac disease (CD) is a chronic inflammatory disorder of the small intestine that is induced by dietary wheat gluten proteins (gliadins) in genetically predisposed individuals. The overgrowth of potentially pathogenic bacteria and infections has been suggested to contribute to CD pathogenesis. We aimed to study the effects of gliadin and various intestinal bacterial strains on mucosal barrier integrity, gliadin translocation, and cytokine production. METHODOLOGY/PRINCIPAL FINDINGS: Changes in gut mucosa were assessed in the intestinal loops of inbred Wistar-AVN rats that were reared under germ-free conditions in the presence of various intestinal bacteria (enterobacteria and bifidobacteria isolated from CD patients and healthy children, respectively) and CD-triggering agents (gliadin and IFN-gamma) by histology, scanning electron microscopy, immunofluorescence, and a rat cytokine antibody array. Adhesion of the bacterial strains to the IEC-6 rat cell line was evaluated in vitro. Gliadin fragments alone or together with the proinflammatory cytokine interferon (IFN) gamma significantly decreased the number of goblet cells in the small intestine; this effect was more pronounced in the presence of Escherichia coli CBL2 and Shigella CBD8. Shigella CBD8 and IFN-gamma induced the highest mucin secretion and greatest impairment in tight junctions and, consequently, translocation of gliadin fragments into the lamina propria. Shigella CBD8 and E. coli CBL2 strongly adhered to IEC-6 epithelial cells. The number of goblet cells in small intestine increased by the simultaneous incubation of Bifidobacterium bifidum IATA-ES2 with gliadin, IFN-gamma and enterobacteria. B. bifidum IATA-ES2 also enhanced the production of chemotactic factors and inhibitors of metalloproteinases, which can contribute to gut mucosal protection. CONCLUSIONS: Our results suggest that the composition of the intestinal microbiota affects the permeability of the intestinal mucosa and, consequently, could be involved in the early stages of CD pathogenesis. PMID- 21249147 TI - Electrosensitive spatial vectors in elasmobranch fishes: implications for source localization. AB - The electrosense of sharks and rays is used to detect weak dipole-like bioelectric fields of prey, mates and predators, and several models propose a use for the detection of streaming ocean currents and swimming-induced fields for geomagnetic orientation. We assessed pore distributions, canal vectors, complementarity and possible evolutionary divergent functions for ampullary clusters in two sharks, the scalloped hammerhead (Sphyrna lewini) and the sandbar shark (Carcharhinus plumbeus), and the brown stingray (Dasyatis lata). Canal projections were determined from measured coordinates of each electrosensory pore and corresponding ampulla relative to the body axis. These species share three ampullary groups: the buccal (BUC), mandibular (MAN) and superficial ophthalmic (SO), which is subdivided into anterior (SOa) and posterior (SOp) in sharks. The stingray also has a hyoid (HYO) cluster. The SOp in both sharks contains the longest (most sensitive) canals with main projections in the posterior-lateral quadrants of the horizontal plane. In contrast, stingray SO canals are few and short with the posterior-lateral projections subsumed by the HYO. There was strong projection coincidence by BUC and SOp canals in the posterior lateral quadrant of the hammerhead shark, and laterally among the stingray BUC and HYO. The shark SOa and stingray SO and BUC contain short canals located anterior to the mouth for detection of prey at close distance. The MAN canals of all species project in anterior or posterior directions behind the mouth and likely coordinate prey capture. Vertical elevation was greatest in the BUC of the sandbar shark, restricted by the hammerhead cephalofoil and extremely limited in the dorsoventrally flattened stingray. These results are consistent with the functional subunit hypothesis that predicts specialized ampullary functions for processing of weak dipole and geomagnetic induced fields, and provides an anatomical basis for future experiments on central processing of different forms of relevant electric stimuli. PMID- 21249148 TI - The N-terminal tail of hERG contains an amphipathic alpha-helix that regulates channel deactivation. AB - The cytoplasmic N-terminal domain of the human ether-a-go-go related gene (hERG) K+ channel is critical for the slow deactivation kinetics of the channel. However, the mechanism(s) by which the N-terminal domain regulates deactivation remains to be determined. Here we show that the solution NMR structure of the N terminal 135 residues of hERG contains a previously described Per-Arnt-Sim (PAS) domain (residues 26-135) as well as an amphipathic alpha-helix (residues 13-23) and an initial unstructured segment (residues 2-9). Deletion of residues 2-25, only the unstructured segment (residues 2-9) or replacement of the alpha-helix with a flexible linker all result in enhanced rates of deactivation. Thus, both the initial flexible segment and the alpha-helix are required but neither is sufficient to confer slow deactivation kinetics. Alanine scanning mutagenesis identified R5 and G6 in the initial flexible segment as critical for slow deactivation. Alanine mutants in the helical region had less dramatic phenotypes. We propose that the PAS domain is bound close to the central core of the channel and that the N-terminal alpha-helix ensures that the flexible tail is correctly orientated for interaction with the activation gating machinery to stabilize the open state of the channel. PMID- 21249149 TI - The role of the BMP signaling antagonist noggin in the development of prostate cancer osteolytic bone metastasis. AB - Members of the BMP and Wnt protein families play a relevant role in physiologic and pathologic bone turnover. Extracellular antagonists are crucial for the modulation of their activity. Lack of expression of the BMP antagonist noggin by osteoinductive, carcinoma-derived cell lines is a determinant of the osteoblast response induced by their bone metastases. In contrast, osteolytic, carcinoma derived cell lines express noggin constitutively. We hypothesized that cancer cell-derived noggin may contribute to the pathogenesis of osteolytic bone metastasis of solid cancers by repressing bone formation. Intra-osseous xenografts of PC-3 prostate cancer cells induced osteolytic lesions characterized not only by enhanced osteoclast-mediated bone resorption, but also by decreased osteoblast-mediated bone formation. Therefore, in this model, uncoupling of the bone remodeling process contributes to osteolysis. Bone formation was preserved in the osteolytic lesions induced by noggin-silenced PC-3 cells, suggesting that cancer cell-derived noggin interferes with physiologic bone coupling. Furthermore, intra-osseous tumor growth of noggin-silenced PC-3 cells was limited, most probably as a result of the persisting osteoblast activity. This investigation provides new evidence for a model of osteolytic bone metastasis where constitutive secretion of noggin by cancer cells mediates inhibition of bone formation, thereby preventing repair of osteolytic lesions generated by an excess of osteoclast-mediated bone resorption. Therefore, noggin suppression may be a novel strategy for the treatment of osteolytic bone metastases. PMID- 21249150 TI - Cross-regulation between oncogenic BRAF(V600E) kinase and the MST1 pathway in papillary thyroid carcinoma. AB - BACKGROUND: The BRAF(V600E) mutation leading to constitutive signaling of MEK-ERK pathways causes papillary thyroid cancer (PTC). Ras association domain family 1A (RASSF1A), which is an important regulator of MST1 tumor suppressor pathways, is inactivated by hypermethylation of its promoter region in 20 to 32% of PTC. However, in PTC without RASSF1A methylation, the regulatory mechanisms of RASSF1A MST1 pathways remain to be elucidated, and the functional cooperation or cross regulation between BRAF(V600E) and MST1,which activates Foxo3,has not been investigated. METHODOLOGY/PRINCIPAL FINDINGS: The negative regulators of the cell cycle, p21 and p27, are strongly induced by transcriptional activation of FoxO3 in BRAF(V600E) positive thyroid cancer cells. The FoxO3 transactivation is augmented by RASSF1A and the MST1 signaling pathway. Interestingly, introduction of BRAF(V600E)markedly abolished FoxO3 transactivation and resulted in the suppression of p21 and p27 expression. The suppression of FoxO3 transactivation by BRAF(V600E)is strongly increased by coexpression of MST1 but it is not observed in the cells in which MST1, but not MST2,is silenced. Mechanistically, BRAF(V600E)was able to bind to the C-terminal region of MST1 and resulted in the suppression of MST1 kinase activities. The induction of the G1-checkpoint CDK inhibitors, p21 and p27,by the RASSF1A-MST1-FoxO3 pathway facilitates cellular apoptosis, whereas addition of BRAF(V600E) inhibits the apoptotic processes through the inactivation of MST1. Transgenic induction of BRAF(V600E)in the thyroid gland results in cancers resembling human papillary thyroid cancers. The development of BRAF(V600E)transgenic mice with the MST1 knockout background showed that these mice had abundant foci of poorly differentiated carcinomas and large areas without follicular architecture or colloid formation. CONCLUSIONS/SIGNIFICANCE: The results of this study revealed that the oncogenic effect of BRAF(V600E) is associated with the inhibition of MST1 tumor suppressor pathways, and that the activity of RASSF1A-MST1-FoxO3 pathways determines the phenotypes of BRAF(V600E) tumors. PMID- 21249151 TI - 110 years of Avipoxvirus in the Galapagos Islands. AB - The role of disease in regulating populations is controversial, partly owing to the absence of good disease records in historic wildlife populations. We examined birds collected in the Galapagos Islands between 1891 and 1906 that are currently held at the California Academy of Sciences and the Zoologisches Staatssammlung Muenchen, including 3973 specimens representing species from two well-studied families of endemic passerine birds: finches and mockingbirds. Beginning with samples collected in 1899, we observed cutaneous lesions consistent with Avipoxvirus on 226 (6.3%) specimens. Histopathology and viral genotyping of 59 candidate tissue samples from six islands showed that 21 (35.6%) were positive for Avipoxvirus, while alternative diagnoses for some of those testing negative by both methods were feather follicle cysts, non-specific dermatitis, or post mortem fungal colonization. Positive specimens were significantly nonrandomly distributed among islands both for mockingbirds (San Cristobal vs. Espanola, Santa Fe and Santa Cruz) and for finches (San Cristobal and Isabela vs. Santa Cruz and Floreana), and overall highly significantly distributed toward islands that were inhabited by humans (San Cristobal, Isabela, Floreana) vs. uninhabited at the time of collection (Santa Cruz, Santa Fe, Espanola), with only one positive individual on an uninhabited island. Eleven of the positive specimens sequenced successfully were identical at four diagnostic sites to the two canarypox variants previously described in contemporary Galapagos passerines. We conclude that this virus was introduced late in 1890's and was dispersed among islands by a variety of mechanisms, including regular human movements among colonized islands. At present, this disease represents an ongoing threat to the birds on the Galapagos Islands. PMID- 21249152 TI - Up-regulation of sonic hedgehog contributes to TGF-beta1-induced epithelial to mesenchymal transition in NSCLC cells. AB - BACKGROUND: Lung cancer, especially non-small cell lung cancer (NSCLC) is the major cause of cancer-related deaths in the United States. The aggressiveness of NSCLC has been shown to be associated with the acquisition of epithelial-to mesenchymal transition (EMT). The acquisition of EMT phenotype induced by TGF beta1in several cancer cells has been implicated in tumor aggressiveness and resistance to conventional therapeutics; however, the molecular mechanism of EMT and tumor aggressiveness in NSCLC remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: In this study we found for the first time that the induction of EMT by chronic exposure of A549 NSCLC cells to TGF-beta1 (A549-M cells) led to the up regulation of sonic hedgehog (Shh) both at the mRNA and protein levels causing activation of hedgehog signaling. These results were also reproduced in another NSCLC cell line (H2030). Induction of EMT was found to be consistent with aggressive characteristics such as increased clonogenic growth, cell motility and invasion. The aggressiveness of these cells was attenuated by the treatment of A549-M cells with pharmacological inhibitors of Hh signaling in addition to Shh knock-down by siRNA. The inhibition of Hh signaling by pharmacological inhibitors led to the reversal of EMT phenotype as confirmed by the reduction of mesenchymal markers such as ZEB1 and Fibronectin, and induction of epithelial marker E cadherin. In addition, knock-down of Shh by siRNA significantly attenuated EMT induction by TGF-beta1. CONCLUSIONS/SIGNIFICANCE: Our results show for the first time the transcriptional up-regulation of Shh by TGF-beta1, which is mechanistically associated with TGF-beta1 induced EMT phenotype and aggressive behavior of NSCLC cells. Thus the inhibitors of Shh signaling could be useful for the reversal of EMT phenotype, which would inhibit the metastatic potential of NSCLC cells and also make these tumors more sensitive to conventional therapeutics. PMID- 21249153 TI - Creatine transporter (CrT; Slc6a8) knockout mice as a model of human CrT deficiency. AB - Mutations in the creatine (Cr) transporter (CrT; Slc6a8) gene lead to absence of brain Cr and intellectual disabilities, loss of speech, and behavioral abnormalities. To date, no mouse model of CrT deficiency exists in which to understand and develop treatments for this condition. The purpose of this study was to generate a mouse model of human CrT deficiency. We created mice with exons 2-4 of Slc6a8 flanked by loxP sites and crossed these to Cre:CMV mice to create a line of ubiquitous CrT knockout expressing mice. Mice were tested for learning and memory deficits and assayed for Cr and neurotransmitter levels. Male CrT(-/y) (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes. CrT(-/y) mice showed increased path length during acquisition and reversal learning in the Morris water maze. During probe trials, CrT(-/y) mice showed increased average distance from the platform site. CrT(-/y) mice showed reduced novel object recognition and conditioned fear memory compared to CrT(+/y). CrT(-/y) mice had increased serotonin and 5 hydroxyindole acetic acid in the hippocampus and prefrontal cortex. Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder. PMID- 21249154 TI - Smoking and multiple sclerosis: an updated meta-analysis. AB - BACKGROUND: Multiple sclerosis (MS) is a leading cause of disability in young adults. Susceptibility to MS is determined by environmental exposure on the background of genetic risk factors. A previous meta-analysis suggested that smoking was an important risk factor for MS but many other studies have been published since then. METHODS/PRINCIPAL FINDINGS: We performed a Medline search to identify articles published that investigated MS risk following cigarette smoking. A total of 14 articles were included in this study. This represented data on 3,052 cases and 457,619 controls. We analysed these studies in both a conservative (limiting our analysis to only those where smoking behaviour was described prior to disease onset) and non-conservative manner. Our results show that smoking is associated with MS susceptibility (conservative: risk ratio (RR) 1.48, 95% confidence interval (CI) 1.35-1.63, p < 10-15; non-conservative: RR 1.52, 95% CI 1.39-1.66, p < 10-19). We also analysed 4 studies reporting risk of secondary progression in MS and found that this fell just short of statistical significance with considerable heterogeneity (RR 1.88, 95% CI 0.98-3.61, p = 0.06). DISCUSSION: Our results demonstrate that cigarette smoking is important in determining MS susceptibility but the effect on the progression of disease is less certain. Further work is needed to understand the mechanism behind this association and how smoking integrates with other established risk factors. PMID- 21249155 TI - K70Q adds high-level tenofovir resistance to "Q151M complex" HIV reverse transcriptase through the enhanced discrimination mechanism. AB - HIV-1 carrying the "Q151M complex" reverse transcriptase (RT) mutations (A62V/V75I/F77L/F116Y/Q151M, or Q151Mc) is resistant to many FDA-approved nucleoside RT inhibitors (NRTIs), but has been considered susceptible to tenofovir disoproxil fumarate (TFV-DF or TDF). We have isolated from a TFV-DF treated HIV patient a Q151Mc-containing clinical isolate with high phenotypic resistance to TFV-DF. Analysis of the genotypic and phenotypic testing over the course of this patient's therapy lead us to hypothesize that TFV-DF resistance emerged upon appearance of the previously unreported K70Q mutation in the Q151Mc background. Virological analysis showed that HIV with only K70Q was not significantly resistant to TFV-DF. However, addition of K70Q to the Q151Mc background significantly enhanced resistance to several approved NRTIs, and also resulted in high-level (10-fold) resistance to TFV-DF. Biochemical experiments established that the increased resistance to tenofovir is not the result of enhanced excision, as K70Q/Q151Mc RT exhibited diminished, rather than enhanced ATP-based primer unblocking activity. Pre-steady state kinetic analysis of the recombinant enzymes demonstrated that addition of the K70Q mutation selectively decreases the binding of tenofovir-diphosphate (TFV-DP), resulting in reduced incorporation of TFV into the nascent DNA chain. Molecular dynamics simulations suggest that changes in the hydrogen bonding pattern in the polymerase active site of K70Q/Q151Mc RT may contribute to the observed changes in binding and incorporation of TFV-DP. The novel pattern of TFV-resistance may help adjust therapeutic strategies for NRTI-experienced patients with multi-drug resistant (MDR) mutations. PMID- 21249156 TI - Directed evolution and in silico analysis of reaction centre proteins reveal molecular signatures of photosynthesis adaptation to radiation pressure. AB - Evolutionary mechanisms adopted by the photosynthetic apparatus to modifications in the Earth's atmosphere on a geological time-scale remain a focus of intense research. The photosynthetic machinery has had to cope with continuously changing environmental conditions and particularly with the complex ionizing radiation emitted by solar flares. The photosynthetic D1 protein, being the site of electron tunneling-mediated charge separation and solar energy transduction, is a hot spot for the generation of radiation-induced radical injuries. We explored the possibility to produce D1 variants tolerant to ionizing radiation in Chlamydomonas reinhardtii and clarified the effect of radiation-induced oxidative damage on the photosynthetic proteins evolution. In vitro directed evolution strategies targeted at the D1 protein were adopted to create libraries of chlamydomonas random mutants, subsequently selected by exposures to radical generating proton or neutron sources. The common trend observed in the D1 aminoacidic substitutions was the replacement of less polar by more polar amino acids. The applied selection pressure forced replacement of residues more sensitive to oxidative damage with less sensitive ones, suggesting that ionizing radiation may have been one of the driving forces in the evolution of the eukaryotic photosynthetic apparatus. A set of the identified aminoacidic substitutions, close to the secondary plastoquinone binding niche and oxygen evolving complex, were introduced by site-directed mutagenesis in un-transformed strains, and their sensitivity to free radicals attack analyzed. Mutants displayed reduced electron transport efficiency in physiological conditions, and increased photosynthetic performance stability and oxygen evolution capacity in stressful high-light conditions. Finally, comparative in silico analyses of D1 aminoacidic sequences of organisms differently located in the evolution chain, revealed a higher ratio of residues more sensitive to oxidative damage in the eukaryotic/cyanobacterial proteins compared to their bacterial orthologs. These results led us to hypothesize an archaean atmosphere less challenging in terms of ionizing radiation than the present one. PMID- 21249159 TI - Polyamines in foods: development of a food database. AB - BACKGROUND: Knowing the levels of polyamines (putrescine, spermidine, and spermine) in different foods is of interest due to the association of these bioactive nutrients to health and diseases. There is a lack of relevant information on their contents in foods. OBJECTIVE: To develop a food polyamine database from published data by which polyamine intake and food contribution to this intake can be estimated, and to determine the levels of polyamines in Swedish dairy products. DESIGN: Extensive literature search and laboratory analysis of selected Swedish dairy products. Polyamine contents in foods were collected using an extensive literature search of databases. Polyamines in different types of Swedish dairy products (milk with different fat percentages, yogurt, cheeses, and sour milk) were determined using high performance liquid chromatography (HPLC) equipped with a UV detector. RESULTS: Fruits and cheese were the highest sources of putrescine, while vegetables and meat products were found to be rich in spermidine and spermine, respectively. The content of polyamines in cheese varied considerably between studies. In analyzed Swedish dairy products, matured cheese had the highest total polyamine contents with values of 52.3, 1.2, and 2.6 mg/kg for putrescine, spermidine, and spermine, respectively. Low fat milk had higher putrescine and spermidine, 1.2 and 1.0 mg/kg, respectively, than the other types of milk. CONCLUSIONS: The database aids other researchers in their quest for information regarding polyamine intake from foods. Connecting the polyamine contents in food with the Swedish Food Database allows for estimation of polyamine contents per portion. PMID- 21249157 TI - Identification of lysine 37 of histone H2B as a novel site of methylation. AB - Recent technological advancements have allowed for highly-sophisticated mass spectrometry-based studies of the histone code, which predicts that combinations of post-translational modifications (PTMs) on histone proteins result in defined biological outcomes mediated by effector proteins that recognize such marks. While significant progress has been made in the identification and characterization of histone PTMs, a full appreciation of the complexity of the histone code will require a complete understanding of all the modifications that putatively contribute to it. Here, using the top-down mass spectrometry approach for identifying PTMs on full-length histones, we report that lysine 37 of histone H2B is dimethylated in the budding yeast Saccharomyces cerevisiae. By generating a modification-specific antibody and yeast strains that harbor mutations in the putative site of methylation, we provide evidence that this mark exist in vivo. Importantly, we show that this lysine residue is highly conserved through evolution, and provide evidence that this methylation event also occurs in higher eukaryotes. By identifying a novel site of histone methylation, this study adds to our overall understanding of the complex number of histone modifications that contribute to chromatin function. PMID- 21249158 TI - Multi-modal proteomic analysis of retinal protein expression alterations in a rat model of diabetic retinopathy. AB - BACKGROUND: As a leading cause of adult blindness, diabetic retinopathy is a prevalent and profound complication of diabetes. We have previously reported duration-dependent changes in retinal vascular permeability, apoptosis, and mRNA expression with diabetes in a rat model system. The aim of this study was to identify retinal proteomic alterations associated with functional dysregulation of the diabetic retina to better understand diabetic retinopathy pathogenesis and that could be used as surrogate endpoints in preclinical drug testing studies. METHODOLOGY/PRINCIPAL FINDINGS: A multi-modal proteomic approach of antibody (Luminex)-, electrophoresis (DIGE)-, and LC-MS (iTRAQ)-based quantitation methods was used to maximize coverage of the retinal proteome. Transcriptomic profiling through microarray analysis was included to identify additional targets and assess potential regulation of protein expression changes at the mRNA level. The proteomic approaches proved complementary, with limited overlap in proteomic coverage. Alterations in pro-inflammatory, signaling and crystallin family proteins were confirmed by orthogonal methods in multiple independent animal cohorts. In an independent experiment, insulin replacement therapy normalized the expression of some proteins (Dbi, Anxa5) while other proteins (Cp, Cryba3, Lgals3, Stat3) were only partially normalized and Fgf2 and Crybb2 expression remained elevated. CONCLUSIONS/SIGNIFICANCE: These results expand the understanding of the changes in retinal protein expression occurring with diabetes and their responsiveness to normalization of blood glucose through insulin therapy. These proteins, especially those not normalized by insulin therapy, may also be useful in preclinical drug development studies. PMID- 21249160 TI - Polyamines: total daily intake in adolescents compared to the intake estimated from the Swedish Nutrition Recommendations Objectified (SNO). AB - BACKGROUND: Dietary polyamines have been shown to give a significant contribution to the body pool of polyamines. Knowing the levels of polyamines (putrescine, spermidine, and spermine) in different foods and the contribution of daily food choice to polyamine intake is of interest, due to the association of these bioactive amines to health and disease. OBJECTIVE: To estimate polyamine intake and food contribution to this intake in adolescents compared to a diet fulfilling the Swedish Nutrition Recommendations. DESIGN: A cross-sectional study of dietary intake in adolescents and an 'ideal diet' (Swedish nutrition recommendations objectified [SNO]) list of foods was used to compute polyamine intake using a database of polyamine contents of foods. For polyamine intake estimation, 7-day weighed food records collected from 93 adolescents were entered into dietetic software (Dietist XP) including data on polyamine contents of foods. The content of polyamines in foods recommended according to SNO was entered in the same way. RESULTS: The adolescents' mean daily polyamine intake was 316+/-170 umol/day, while the calculated contribution according to SNO was considerably higher with an average polyamine intake of 541 umol/day. In both adolescent's intake and SNO, fruits contributed to almost half of the total polyamine intake. The reason why the intake among the adolescents was lower than the one calculated from SNO was mainly due to the low vegetable consumption in the adolescents group. CONCLUSIONS: The average daily total polyamine intake was similar to that previously reported in Europe. With an 'ideal' diet according to Swedish nutrition recommendations, the intake of this bioactive non-nutrient would be higher than that reported by our adolescents and also higher than that previously reported from Europe. PMID- 21249161 TI - Distribution of human papillomavirus genotypes in sardinian patients with oral squamous cell carcinoma. AB - Human papillomaviruses (HPVs) seem to play an important role in the pathogenesis of gynecological carcinomas and in head and neck carcinomas. The aim of this study was to detect and genotype HPVs in fresh oral squamous cell carcinoma (OSCC) from a Sardinian population, and to determine whether HPV presence was significantly associated with the development of OSCC.The oral mucosa tissues were obtained from 120 samples (68 OSCC and 52 control samples) taken from a Sardinian population seen at the Dental Clinic of the Department of Surgery and Odontostomatological Sciences, University of Cagliari (Italy) and the " Ospedale SS Trinita", Cagliari (A.S.L. 8) between 2007 and 2008. PCR was used for the detection of HPV DNA and the genotype was determined by DNA sequencing. The frequency of HPV infection was evaluated in relation to age, sex, smoking and alcohol use. Statistical analysis was performed using the SPSS 11.5 software.The results showed the presence of HPV-DNA in 60.3% of OSCC with HPV-16 (51.2%) being the most frequent genotype. In these Sardinian OSCC patients, HPV-DNA was detected more in males (65.8%) than in females (34.1%) while controls show a 0% of HPV presence. HPV positive was highly associated with OSCC among subjects with a history of heavy tobacco and alcohol use and among those with no such history.A greater frequency of high risk HPV presence was observed in patients with OSCC compared to health control patients. In addition these results suggested that oral HPV presence could be associated in OSCC subjects. Our results need more analyses to detect the HPV-DNA integration into tumoral cells. PMID- 21249162 TI - Significance of Elevated Blood Metal Ion Levels in Patients with Metal-on-Metal Prostheses: An Evaluation of Oxidative Stress Markers. AB - It is widely known that cobalt and chromium ions can enhance the production of reactive oxygen species, known to be damaging to cells by disturbing their redox status and then generating oxidative stress. The aim of the present study was to determine if increased metal ion levels induce a state of oxidative stress in patients with metal-on-metal (MM) hip arthroplasty. Results indicated that there was no significant difference in the concentration of oxidative stress markers (total antioxidants, peroxides, and nitrated proteins) in the patients with MM bearings compared to patients without prostheses. The activity antioxidant enzymes was stable (catalase and glutathione peroxidase) or slightly decreased (superoxide dismutase and heme oxygenase-1) over time. This work is the first to determine the biological effects of metal ions released from MM hip implants with regards to mid-term systemic oxidative stress and showed that the increased levels of Co and Cr ions are not associated with significant oxidative stress damage in the plasma of patients with these implants. PMID- 21249163 TI - Reactions of persons with dementia to caregivers singing in morning care situations. AB - 'Music therapeutic caregiving', when caregivers sing for or together with persons with severe dementia during care situations, has been suggested as a way to reduce problematic behaviors in dementia care. The present study implemented this technique as an intervention in dementia care. Six caregivers participated in group interviews about their experiences of morning care situations without and with'Music therapeutic caregiving'. Through a qualitative content analysis two themes emerged.'Being in a different reality' was based on'usual' morning care situations. The caregivers' experienced the persons with dementia as absent minded; communication and cooperation were difficult. The second theme,'Being present', was based on morning care situations with the intervention. The caregivers described communication as enhanced; the persons with dementia expressed themselves more appropriately, making cooperation possible. The results indicate that'Music therapeutic caregiving' might lead to a more positive experience of the person with dementia and seems to increase receptivity to caregiving. PMID- 21249165 TI - Haemostasis in Open Carpal Tunnel Release: Tourniquet vs Local Anaesthetic and Adrenaline. AB - Open carpal tunnel release is one of the commonest performed procedures in hand surgery. We performed a prospective randomised control trial to compare the efficacy and patient satisfaction of the traditional arm tourniquet versus infiltration of adrenaline and local anaesthetic solution to achieve haemostasis during the procedure. Using a combination of objective and subjective measures we concluded that infiltration of local anaesthetic and adrenaline not only provided adequate haemostasis but also provided a significantly more tolerable experience for the patient during the procedure. PMID- 21249164 TI - alpha7 Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer's Disease. AB - Accumulating evidence suggests that alpha7 nicotinic receptors (alpha7 nAChRs), a subtype of nAChRs, play a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer's disease (AD). A number of psychopharmacological and genetic studies shown that alpha7 nAChRs play an important role in the deficits of P50 auditory evoked potential in patients with schizophrenia, and that (alpha nAChR agonists would be potential therapeutic drugs for cognitive impairments associated with P50 deficits in schizophrenia. Furthermore, some studies have demonstrated that alpha7 nAChRs might play a key role in the amyloid-beta (Abeta)-mediated pathology of AD, and that alpha7 nAChR agonists would be potential therapeutic drugs for Abeta deposition in the brains of patients with AD. Interestingly, the altered expression of alpha7 nAChRs in the postmortem brain tissues from patients with schizophrenia and AD has been reported. Based on all these findings, selective alpha7 nAChR agonists can be considered potential therapeutic drugs for cognitive impairments in both schizophrenia and AD. In this article, we review the recent research into the role of alpha7 nAChRs in the pathophysiology of these diseases and into the potential use of novel alpha7 nAChR agonists as therapeutic drugs. PMID- 21249166 TI - Cost-effectiveness of image-guided spine surgery. AB - OBJECTIVE: To determine if image-guided spine surgery is cost effective. METHODS: A prospective case series of the first 100 patients undergoing thoracolumbar pedicle screw instrumentation under image-guidance was compared to a retrospective control group of the last 100 patients who underwent screw placement prior to the use of image-guidance. The image-guidance system was NaviVision (Vector Vision-BrainLAB) and Arcadis Orbic (Siemens). RESULTS: The rate of revision surgery was reduced from 3% to 0% with the use of image guidance (p=0.08). The cost savings of image guidance for the placement of pedicle screws was $71,286 per 100 cases. Time required for pedicle screw placement with image guidance was 20 minutes for 2 screws, 29 minutes for 4 screws, 38 minutes for 6 screws, and 50 min for 8 screws. Cost savings for the time required for placement of pedicle screws with image guidance can be estimated by subtracting the time required with currently used techniques without image guidance from the above averages, then multiplying by $93 per minute. The approximate costs of the navigation system is $475,000 ( $225,000 for Vector Vision-BrainLAB and $250,000 for Arcadis Orbic-Siemens). CONCLUSION: Image guidance for the placement of pedicle screws may be cost effective in spine practices with heavy volume, that perform surgery in difficult cases, and that require long surgical times for the placement of pedicle screws. PMID- 21249167 TI - A Single Amino Acid Substitution Makes WNK4 Susceptible to SB 203580 and SB 202190. AB - Regulation of the SLC12 family of membrane transporters including NCCT involves a scaffold of interacting proteins including the STE 20 kinase SPAK and the WNK kinases, WNK 1 and WNK 4, which are mutated in the hypertensive syndrome of pseudohypoaldosteronism type 2 (PHAII). WNK4 regulates NCCT by affecting forward trafficking to the surface membrane. Studies in Xenopus using kinase dead WNK4 site mutants have produced inconsistent results with regard to the necessity of kinase function for NCCT regulation. Dynamic inhibition of WNK4 by small molecules may bring clarity to this issue however WNK4 is naturally resistant to commercial MAP kinase inhibitors owing to steric constraints prohibiting entry of small molecules to the active site. Using an approach similar to that used in p38 and ERK, we show that a single substitution in WNK4 (T261G) dramatically enhances its susceptibility to the inhibitors SB 202190 and SB 203580. PMID- 21249168 TI - Consultation of orthopaedics cases using multimedia messaging services. AB - BACKGROUND: Frequently, radiological data is transferred verbally between the Emergency Department (ED) and orthopaedic registrar. Given the different language skills and medical experience of health staff, there is often a limit to the adequacy of the verbal description that could lead to suboptimal patient care. This study proposes that concurrent review of MMS teleradiology with traditional verbal reporting results in a significant therapeutic benefit. METHODS: Case notes of 40 patients who presented to ED were reviewed. Images were captured and sent to an Orthopaedic registrar along with a brief clinical synopsis. Information was collected on the diagnosis of the MMS radiograph, need for urgent admission and management plan outlined to ED. RESULTS: Correct diagnosis was made in 27 of 40 cases. Using the latest technology available, MMS teleradiology had 79% sensitivity, 83% specificity and an accuracy of 80%. 50% of paediatric fractures and 60% of undisplaced fractures were diagnosed successfully. CONCLUSION: MMS teleradiology is not suitable by itself as a remote diagnostic tool. However, when combined with existing clinical practice, it is effective in screening patients, enhances confidence in decision making and communication between doctors. PMID- 21249169 TI - Evolutionary reshaping of fungal mating pathway scaffold proteins. AB - Scaffold proteins play central roles in the function of many signaling pathways. Among the best-studied examples are the Ste5 and Far1 proteins of the yeast Saccharomyces cerevisiae. These proteins contain three conserved modules, the RING and PH domains, characteristic of some ubiquitin-ligating enzymes, and a vWA domain implicated in protein-protein interactions. In yeast, Ste5p regulates the mating pathway kinases while Far1p coordinates the cellular polarity machinery. Within the fungal lineage, the Basidiomycetes and the Pezizomycetes contain a single Far1-like protein, while several Saccharomycotina species, belonging to the CTG (Candida) clade, contain both a classic Far1-like protein and a Ste5-like protein that lacks the vWA domain. We analyzed the function of C. albicans Ste5p (Cst5p), a member of this class of structurally distinct Ste5 proteins. CST5 is essential for mating and still coordinates the mitogen-activated protein (MAP) kinase (MAPK) cascade elements in the absence of the vWA domain; Cst5p interacts with the MEK kinase (MEKK) C. albicans Ste11p (CaSte11p) and the MAPK Cek1 as well as with the MEK Hst7 in a vWA domain-independent manner. Cst5p can homodimerize, similar to Ste5p, but can also heterodimerize with Far1p, potentially forming heteromeric signaling scaffolds. We found direct binding between the MEKK CaSte11p and the MEK Hst7p that depends on a mobile acidic loop absent from S. cerevisiae Ste11p but related to the Ste7-binding region within the vWA domain of Ste5p. Thus, the fungal lineage has restructured specific scaffolding modules to coordinate the proteins required to direct the gene expression, polarity, and cell cycle regulation essential for mating. PMID- 21249170 TI - Cyclic diguanylate signaling proteins control intracellular growth of Legionella pneumophila. AB - Proteins that metabolize or bind the nucleotide second messenger cyclic diguanylate regulate a wide variety of important processes in bacteria. These processes include motility, biofilm formation, cell division, differentiation, and virulence. The role of cyclic diguanylate signaling in the lifestyle of Legionella pneumophila, the causative agent of Legionnaires' disease, has not previously been examined. The L. pneumophila genome encodes 22 predicted proteins containing domains related to cyclic diguanylate synthesis, hydrolysis, and recognition. We refer to these genes as cdgS (cyclic diguanylate signaling) genes. Strains of L. pneumophila containing deletions of all individual cdgS genes were created and did not exhibit any observable growth defect in growth medium or inside host cells. However, when overexpressed, several cdgS genes strongly decreased the ability of L. pneumophila to grow inside host cells. Expression of these cdgS genes did not affect the Dot/Icm type IVB secretion system, the major determinant of intracellular growth in L. pneumophila. L. pneumophila strains overexpressing these cdgS genes were less cytotoxic to THP-1 macrophages than wild-type L. pneumophila but retained the ability to resist grazing by amoebae. In many cases, the intracellular-growth inhibition caused by cdgS gene overexpression was independent of diguanylate cyclase or phosphodiesterase activities. Expression of the cdgS genes in a Salmonella enterica serovar Enteritidis strain that lacks all diguanylate cyclase activity indicated that several cdgS genes encode potential cyclases. These results indicate that components of the cyclic diguanylate signaling pathway play an important role in regulating the ability of L. pneumophila to grow in host cells. PMID- 21249172 TI - Better data for teachers, better data for learners, better patient care: college wide assessment at Michigan State University's College of Human Medicine. AB - When our school organized the curriculum around a core set of medical student competencies in 2004, it was clear that more numerous and more varied student assessments were needed. To oversee a systematic approach to the assessment of medical student competencies, the Office of College-wide Assessment was established, led by the Associate Dean of College-wide Assessment. The mission of the Office is to 'facilitate the development of a seamless assessment system that drives a nimble, competency-based curriculum across the spectrum of our educational enterprise.' The Associate Dean coordinates educational initiatives, developing partnerships to solve common problems, and enhancing synergy within the College. The Office also works to establish data collection and feedback loops to guide rational intervention and continuous curricular improvement. Aside from feedback, implementing a systems approach to assessment provides a means for identifying performance gaps, promotes continuity from undergraduate medical education to practice, and offers a rationale for some assessments to be located outside of courses and clerkships. Assessment system design, data analysis, and feedback require leadership, a cooperative faculty team with medical education expertise, and institutional support. The guiding principle is 'Better Data for Teachers, Better Data for Learners, Better Patient Care.' Better data empowers faculty to become change agents, learners to create evidence-based improvement plans and increases accountability to our most important stakeholders, our patients. PMID- 21249171 TI - Cellular SNF2H chromatin-remodeling factor promotes herpes simplex virus 1 immediate-early gene expression and replication. AB - Like other DNA viruses that replicate in the nucleus, herpes simplex virus 1 (HSV 1) regulates the association of histones with its genome to promote viral replication and gene expression. We previously demonstrated that SNF2H, a member of the ISWI family of chromatin-remodeling factors, is concentrated in HSV-1 replication compartments in the nuclei of infected cells, suggesting that this cellular enzyme plays a role in viral replication. We show here that small interfering RNA (siRNA)-mediated knockdown of SNF2H in HEp-2 cells resulted in an approximately 20-fold decrease in HSV-1 replication, arguing that SNF2H promotes efficient HSV-1 replication. Decreases in HSV-1 replication were observed with multiple SNF2H-specific siRNAs, and the extent of the replication decrease correlated with the amount of SNF2H knockdown, indicating that the phenotype resulted from decreased SNF2H levels rather than off-target effects of the siRNAs. We also observed a decrease in the accumulation of immediate-early (IE) gene products in HSV-1-infected cells in which SNF2H was knocked down. Histone H3 occupancy on viral promoters was increased in HSV-1-infected cells that were transfected with SNF2H-specific siRNAs, suggesting that SNF2H promotes removal of histones from viral promoters during infection. Furthermore, chromatin immunoprecipitation (ChIP) studies showed that SNF2H associated with the HSV-1 genome during infection, which suggests that SNF2H may directly remodel viral chromatin. We hypothesize that SNF2H is recruited to viral promoters during HSV-1 infection, where it can remodel the chromatin state of the viral genome, facilitate the transcription of immediate-early genes, and enhance viral replication. PMID- 21249173 TI - A report on the piloting of a novel computer-based medical case simulation for teaching and formative assessment of diagnostic laboratory testing. AB - OBJECTIVES: Insufficient attention has been given to how information from computer-based clinical case simulations is presented, collected, and scored. Research is needed on how best to design such simulations to acquire valid performance assessment data that can act as useful feedback for educational applications. This report describes a study of a new simulation format with design features aimed at improving both its formative assessment feedback and educational function. METHODS: Case simulation software (LabCAPS) was developed to target a highly focused and well-defined measurement goal with a response format that allowed objective scoring. Data from an eight-case computer-based performance assessment administered in a pilot study to 13 second-year medical students was analyzed using classical test theory and generalizability analysis. In addition, a similar analysis was conducted on an administration in a less controlled setting, but to a much large sample (n = 143), within a clinical course that utilized two random case subsets from a library of 18 cases. RESULTS: Classical test theory case-level item analysis of the pilot assessment yielded an average case discrimination of 0.37, and all eight cases were positively discriminating (range = 0.11-0.56). Classical test theory coefficient alpha and the decision study showed the eight-case performance assessment to have an observed reliability of sigma = G = 0.70. The decision study further demonstrated that a G = 0.80 could be attained with approximately 3 h and 15 min of testing. The less-controlled educational application within a large medical class produced a somewhat lower reliability for eight cases (G = 0.53). Students gave high ratings to the logic of the simulation interface, its educational value, and to the fidelity of the tasks. CONCLUSIONS: LabCAPS software shows the potential to provide formative assessment of medical students' skill at diagnostic test ordering and to provide valid feedback to learners. The perceived fidelity of the performance tasks and the statistical reliability findings support the validity of using the automated scores for formative assessment and learning. LabCAPS cases appear well designed for use as a scored assignment, for stimulating discussions in small group educational settings, for self-assessment, and for independent learning. Extension of the more highly controlled pilot assessment study with a larger sample will be needed to confirm its reliability in other assessment applications. PMID- 21249174 TI - Standardized patient outcomes trial (SPOT) in neurology. AB - BACKGROUND: The neurologic examination is a challenging component of the physical examination for medical students. In response, primarily based on expert consensus, medical schools have supplemented their curricula with standardized patient (SP) sessions that are focused on the neurologic examination. Hypothesis driven quantitative data are needed to justify the further use of this resource intensive educational modality, specifically regarding whether using SPs to teach the neurological examination effects a long-term benefit on the application of neurological examination skills. METHODS: This study is a cross-sectional analysis of prospectively collected data from medical students at Weill Cornell Medical College. The control group (n=129) received the standard curriculum. The intervention group (n=58) received the standard curriculum and an additional SP session focused on the neurologic examination during the second year of medical school. Student performance on the neurologic examination was assessed in the control and intervention groups via an OSCE administered during the fourth year of medical school. A Neurologic Physical Exam (NPE) score of 0.0 to 6.0 was calculated for each student based on a neurologic examination checklist completed by the SPs during the OSCE. Composite NPE scores in the control and intervention groups were compared with the unpaired t-test. RESULTS: In the fourth year OSCE, composite NPE scores in the intervention group (3.5+/-1.1) were statistically significantly greater than those in the control group (2.2+/-1.1) (p<0.0001). CONCLUSIONS: SP sessions are an effective tool for teaching the neurologic examination. We determined that a single, structured SP session conducted as an adjunct to our traditional lectures and small groups is associated with a statistically significant improvement in student performance measured 2 years after the session. PMID- 21249175 TI - Induction of a peptide with activity against a broad spectrum of pathogens in the Aedes aegypti salivary gland, following Infection with Dengue Virus. AB - The ultimate stage of the transmission of Dengue Virus (DENV) to man is strongly dependent on crosstalk between the virus and the immune system of its vector Aedes aegypti (Ae. aegypti). Infection of the mosquito's salivary glands by DENV is the final step prior to viral transmission. Therefore, in the present study, we have determined the modulatory effects of DENV infection on the immune response in this organ by carrying out a functional genomic analysis of uninfected salivary glands and salivary glands of female Ae. aegypti mosquitoes infected with DENV. We have shown that DENV infection of salivary glands strongly up-regulates the expression of genes that encode proteins involved in the vector's innate immune response, including the immune deficiency (IMD) and Toll signalling pathways, and that it induces the expression of the gene encoding a putative anti-bacterial, cecropin-like, peptide (AAEL000598). Both the chemically synthesized non-cleaved, signal peptide-containing gene product of AAEL000598, and the cleaved, mature form, were found to exert, in addition to antibacterial activity, anti-DENV and anti-Chikungunya viral activity. However, in contrast to the mature form, the immature cecropin peptide was far more effective against Chikungunya virus (CHIKV) and, furthermore, had strong anti-parasite activity as shown by its ability to kill Leishmania spp. Results from circular dichroism analysis showed that the immature form more readily adopts a helical conformation which would help it to cause membrane permeabilization, thus permitting its transfer across hydrophobic cell surfaces, which may explain the difference in the anti-pathogenic activity between the two forms. The present study underscores not only the importance of DENV-induced cecropin in the innate immune response of Ae. aegypti, but also emphasizes the broad-spectrum anti-pathogenic activity of the immature, signal peptide-containing form of this peptide. PMID- 21249176 TI - Identification and characterization of the host protein DNAJC14 as a broadly active flavivirus replication modulator. AB - Viruses in the Flavivirus genus of the Flaviviridae family are arthropod transmitted and contribute to staggering numbers of human infections and significant deaths annually across the globe. To identify cellular factors with antiviral activity against flaviviruses, we screened a cDNA library using an iterative approach. We identified a mammalian Hsp40 chaperone protein (DNAJC14) that when overexpressed was able to mediate protection from yellow fever virus (YFV)-induced cell death. Further studies revealed that DNAJC14 inhibits YFV at the step of viral RNA replication. Since replication of bovine viral diarrhea virus (BVDV), a member of the related Pestivirus genus, is also known to be modulated by DNAJC14, we tested the effect of this host factor on diverse Flaviviridae family members. Flaviviruses, including the pathogenic Asibi strain of YFV, Kunjin, and tick-borne Langat virus, as well as a Hepacivirus, hepatitis C virus (HCV), all were inhibited by overexpression of DNAJC14. Mutagenesis showed that both the J-domain and the C-terminal domain, which mediates self interaction, are required for anti-YFV activity. We found that DNAJC14 does not block YFV nor HCV NS2-3 cleavage, and using non-inhibitory mutants demonstrate that DNAJC14 is recruited to YFV replication complexes. Immunofluorescence analysis demonstrated that endogenous DNAJC14 rearranges during infection and is found in replication complexes identified by dsRNA staining. Interestingly, silencing of endogenous DNAJC14 results in impaired YFV replication suggesting a requirement for DNAJC14 in YFV replication complex assembly. Finally, the antiviral activity of overexpressed DNAJC14 occurs in a time- and dose-dependent manner. DNAJC14 overexpression may disrupt the proper stoichiometry resulting in inhibition, which can be overcome upon restoration of the optimal ratios due to the accumulation of viral nonstructural proteins. Our findings, together with previously published work, suggest that the members of the Flaviviridae family have evolved in unique and important ways to interact with this host Hsp40 chaperone molecule. PMID- 21249177 TI - Salivary gland NK cells are phenotypically and functionally unique. AB - Natural killer (NK) cells and CD8(+) T cells play vital roles in containing and eliminating systemic cytomegalovirus (CMV). However, CMV has a tropism for the salivary gland acinar epithelial cells and persists in this organ for several weeks after primary infection. Here we characterize a distinct NK cell population that resides in the salivary gland, uncommon to any described to date, expressing both mature and immature NK cell markers. Using RORgammat reporter mice and nude mice, we also show that the salivary gland NK cells are not lymphoid tissue inducer NK-like cells and are not thymic derived. During the course of murine cytomegalovirus (MCMV) infection, we found that salivary gland NK cells detect the infection and acquire activation markers, but have limited capacity to produce IFN-gamma and degranulate. Salivary gland NK cell effector functions are not regulated by iNKT or T(reg) cells, which are mostly absent in the salivary gland. Additionally, we demonstrate that peripheral NK cells are not recruited to this organ even after the systemic infection has been controlled. Altogether, these results indicate that viral persistence and latency in the salivary glands may be due in part to the presence of unfit NK cells and the lack of recruitment of peripheral NK cells. PMID- 21249178 TI - Aerosols transmit prions to immunocompetent and immunodeficient mice. AB - Prions, the agents causing transmissible spongiform encephalopathies, colonize the brain of hosts after oral, parenteral, intralingual, or even transdermal uptake. However, prions are not generally considered to be airborne. Here we report that inbred and crossbred wild-type mice, as well as tga20 transgenic mice overexpressing PrP(C), efficiently develop scrapie upon exposure to aerosolized prions. NSE-PrP transgenic mice, which express PrP(C) selectively in neurons, were also susceptible to airborne prions. Aerogenic infection occurred also in mice lacking B- and T-lymphocytes, NK-cells, follicular dendritic cells or complement components. Brains of diseased mice contained PrP(Sc) and transmitted scrapie when inoculated into further mice. We conclude that aerogenic exposure to prions is very efficacious and can lead to direct invasion of neural pathways without an obligatory replicative phase in lymphoid organs. This previously unappreciated risk for airborne prion transmission may warrant re-thinking on prion biosafety guidelines in research and diagnostic laboratories. PMID- 21249179 TI - Composite effects of polymorphisms near multiple regulatory elements create a major-effect QTL. AB - Many agriculturally, evolutionarily, and medically important characters vary in a quantitative fashion. Unfortunately, the genes and sequence variants accounting for this variation remain largely unknown due to a variety of biological and technical challenges. Drosophila melanogaster contains high levels of sequence variation and low linkage disequilibrium, allowing us to dissect the effects of many causative variants within a single locus. Here, we take advantage of these features to identify and characterize the sequence polymorphisms that comprise major effect QTL alleles segregating at the bric-a-brac locus. We show that natural bric-a-brac alleles with large effects on cuticular pigmentation reflect a cumulative impact of polymorphisms that affect three functional regions: a promoter, a tissue-specific enhancer, and a Polycomb response element. Analysis of allele-specific expression at the bric-a-brac locus confirms that these polymorphisms modulate transcription at the cis-regulatory level. Our results establish that a single QTL can act through a confluence of multiple molecular mechanisms and that sequence variation in regions flanking experimentally validated functional elements can have significant quantitative effects on transcriptional activity and phenotype. These findings have important design and conceptual implications for basic and medical genomics. PMID- 21249180 TI - Transcription initiation patterns indicate divergent strategies for gene regulation at the chromatin level. AB - The application of deep sequencing to map 5' capped transcripts has confirmed the existence of at least two distinct promoter classes in metazoans: "focused" promoters with transcription start sites (TSSs) that occur in a narrowly defined genomic span and "dispersed" promoters with TSSs that are spread over a larger window. Previous studies have explored the presence of genomic features, such as CpG islands and sequence motifs, in these promoter classes, but virtually no studies have directly investigated the relationship with chromatin features. Here, we show that promoter classes are significantly differentiated by nucleosome organization and chromatin structure. Dispersed promoters display higher associations with well-positioned nucleosomes downstream of the TSS and a more clearly defined nucleosome free region upstream, while focused promoters have a less organized nucleosome structure, yet higher presence of RNA polymerase II. These differences extend to histone variants (H2A.Z) and marks (H3K4 methylation), as well as insulator binding (such as CTCF), independent of the expression levels of affected genes. Notably, differences are conserved across mammals and flies, and they provide for a clearer separation of promoter architectures than the presence and absence of CpG islands or the occurrence of stalled RNA polymerase. Computational models support the stronger contribution of chromatin features to the definition of dispersed promoters compared to focused start sites. Our results show that promoter classes defined from 5' capped transcripts not only reflect differences in the initiation process at the core promoter but also are indicative of divergent transcriptional programs established within gene-proximal nucleosome organization. PMID- 21249181 TI - Friedreich's ataxia (GAA)n*(TTC)n repeats strongly stimulate mitotic crossovers in Saccharomyces cerevisae. AB - Expansions of trinucleotide GAA*TTC tracts are associated with the human disease Friedreich's ataxia, and long GAA*TTC tracts elevate genome instability in yeast. We show that tracts of (GAA)(230)*(TTC)(230) stimulate mitotic crossovers in yeast about 10,000-fold relative to a "normal" DNA sequence; (GAA)(n)*(TTC)(n) tracts, however, do not significantly elevate meiotic recombination. Most of the mitotic crossovers are associated with a region of non-reciprocal transfer of information (gene conversion). The major class of recombination events stimulated by (GAA)(n)*(TTC)(n) tracts is a tract-associated double-strand break (DSB) that occurs in unreplicated chromosomes, likely in G1 of the cell cycle. These findings indicate that (GAA)(n)*(TTC)(n) tracts can be a potent source of loss of heterozygosity in yeast. PMID- 21249182 TI - Zebrafish usp39 mutation leads to rb1 mRNA splicing defect and pituitary lineage expansion. AB - Loss of retinoblastoma (Rb) tumor suppressor function is associated with human malignancies. Molecular and genetic mechanisms responsible for tumorigenic Rb downregulation are not fully defined. Through a forward genetic screen and positional cloning, we identified and characterized a zebrafish ubiquitin specific peptidase 39 (usp39) mutation, the yeast and human homolog of which encodes a component of RNA splicing machinery. Zebrafish usp39 mutants exhibit microcephaly and adenohypophyseal cell lineage expansion without apparent changes in major hypothalamic hormonal and regulatory signals. Gene expression profiling of usp39 mutants revealed decreased rb1 and increased e2f4, rbl2 (p130), and cdkn1a (p21) expression. Rb1 mRNA overexpression, or antisense morpholino knockdown of e2f4, partially reversed embryonic pituitary expansion in usp39 mutants. Analysis of pre-mRNA splicing status of critical cell cycle regulators showed misspliced Rb1 pre-mRNA resulting in a premature stop codon. These studies unravel a novel mechanism for rb1 regulation by a neuronal mRNA splicing factor, usp39. Zebrafish usp39 regulates embryonic pituitary homeostasis by targeting rb1 and e2f4 expression, respectively, contributing to increased adenohypophyseal sensitivity to these altered cell cycle regulators. These results provide a mechanism for dysregulated rb1 and e2f4 pathways that may result in pituitary tumorigenesis. PMID- 21249185 TI - Costs of reproduction and terminal investment by females in a semelparous marsupial. AB - Evolutionary explanations for life history diversity are based on the idea of costs of reproduction, particularly on the concept of a trade-off between age specific reproduction and parental survival, and between expenditure on current and future offspring. Such trade-offs are often difficult to detect in population studies of wild mammals. Terminal investment theory predicts that reproductive effort by older parents should increase, because individual offspring become more valuable to parents as the conflict between current versus potential future offspring declines with age. In order to demonstrate this phenomenon in females, there must be an increase in maternal expenditure on offspring with age, imposing a fitness cost on the mother. Clear evidence of both the expenditure and fitness cost components has rarely been found. In this study, we quantify costs of reproduction throughout the lifespan of female antechinuses. Antechinuses are nocturnal, insectivorous, forest-dwelling small (20-40 g) marsupials, which nest in tree hollows. They have a single synchronized mating season of around three weeks, which occurs on predictable dates each year in a population. Females produce only one litter per year. Unlike almost all other mammals, all males, and in the smaller species, most females are semelparous. We show that increased allocation to current reproduction reduces maternal survival, and that offspring growth and survival in the first breeding season is traded-off with performance of the second litter in iteroparous females. In iteroparous females, increased allocation to second litters is associated with severe weight loss in late lactation and post-lactation death of mothers, but increased offspring growth in late lactation and survival to weaning. These findings are consistent with terminal investment. Iteroparity did not increase lifetime reproductive success, indicating that terminal investment in the first breeding season at the expense of maternal survival (i.e. semelparity) is likely to be advantageous for females. PMID- 21249183 TI - Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. AB - Genome-wide association studies (GWAS) have defined over 150 genomic regions unequivocally containing variation predisposing to immune-mediated disease. Inferring disease biology from these observations, however, hinges on our ability to discover the molecular processes being perturbed by these risk variants. It has previously been observed that different genes harboring causal mutations for the same Mendelian disease often physically interact. We sought to evaluate the degree to which this is true of genes within strongly associated loci in complex disease. Using sets of loci defined in rheumatoid arthritis (RA) and Crohn's disease (CD) GWAS, we build protein-protein interaction (PPI) networks for genes within associated loci and find abundant physical interactions between protein products of associated genes. We apply multiple permutation approaches to show that these networks are more densely connected than chance expectation. To confirm biological relevance, we show that the components of the networks tend to be expressed in similar tissues relevant to the phenotypes in question, suggesting the network indicates common underlying processes perturbed by risk loci. Furthermore, we show that the RA and CD networks have predictive power by demonstrating that proteins in these networks, not encoded in the confirmed list of disease associated loci, are significantly enriched for association to the phenotypes in question in extended GWAS analysis. Finally, we test our method in 3 non-immune traits to assess its applicability to complex traits in general. We find that genes in loci associated to height and lipid levels assemble into significantly connected networks but did not detect excess connectivity among Type 2 Diabetes (T2D) loci beyond chance. Taken together, our results constitute evidence that, for many of the complex diseases studied here, common genetic associations implicate regions encoding proteins that physically interact in a preferential manner, in line with observations in Mendelian disease. PMID- 21249184 TI - Histone H4 lysine 12 acetylation regulates telomeric heterochromatin plasticity in Saccharomyces cerevisiae. AB - Recent studies have established that the highly condensed and transcriptionally silent heterochromatic domains in budding yeast are virtually dynamic structures. The underlying mechanisms for heterochromatin dynamics, however, remain obscure. In this study, we show that histones are dynamically acetylated on H4K12 at telomeric heterochromatin, and this acetylation regulates several of the dynamic telomere properties. Using a de novo heterochromatin formation assay, we surprisingly found that acetylated H4K12 survived the formation of telomeric heterochromatin. Consistently, the histone acetyltransferase complex NuA4 bound to silenced telomeric regions and acetylated H4K12. H4K12 acetylation prevented the over-accumulation of Sir proteins at telomeric heterochromatin and elimination of this acetylation caused defects in multiple telomere-related processes, including transcription, telomere replication, and recombination. Together, these data shed light on a potential histone acetylation mark within telomeric heterochromatin that contributes to telomere plasticity. PMID- 21249186 TI - Figure text extraction in biomedical literature. AB - BACKGROUND: Figures are ubiquitous in biomedical full-text articles, and they represent important biomedical knowledge. However, the sheer volume of biomedical publications has made it necessary to develop computational approaches for accessing figures. Therefore, we are developing the Biomedical Figure Search engine (http://figuresearch.askHERMES.org) to allow bioscientists to access figures efficiently. Since text frequently appears in figures, automatically extracting such text may assist the task of mining information from figures. Little research, however, has been conducted exploring text extraction from biomedical figures. METHODOLOGY: We first evaluated an off-the-shelf Optical Character Recognition (OCR) tool on its ability to extract text from figures appearing in biomedical full-text articles. We then developed a Figure Text Extraction Tool (FigTExT) to improve the performance of the OCR tool for figure text extraction through the use of three innovative components: image preprocessing, character recognition, and text correction. We first developed image preprocessing to enhance image quality and to improve text localization. Then we adapted the off-the-shelf OCR tool on the improved text localization for character recognition. Finally, we developed and evaluated a novel text correction framework by taking advantage of figure-specific lexicons. RESULTS/CONCLUSIONS: The evaluation on 382 figures (9,643 figure texts in total) randomly selected from PubMed Central full-text articles shows that FigTExT performed with 84% precision, 98% recall, and 90% F1-score for text localization and with 62.5% precision, 51.0% recall and 56.2% F1-score for figure text extraction. When limiting figure texts to those judged by domain experts to be important content, FigTExT performed with 87.3% precision, 68.8% recall, and 77% F1-score. FigTExT significantly improved the performance of the off-the-shelf OCR tool we used, which on its own performed with 36.6% precision, 19.3% recall, and 25.3% F1-score for text extraction. In addition, our results show that FigTExT can extract texts that do not appear in figure captions or other associated text, further suggesting the potential utility of FigTExT for improving figure search. PMID- 21249187 TI - Accuracy of CNV Detection from GWAS Data. AB - Several computer programs are available for detecting copy number variants (CNVs) using genome-wide SNP arrays. We evaluated the performance of four CNV detection software suites--Birdsuite, Partek, HelixTree, and PennCNV-Affy--in the identification of both rare and common CNVs. Each program's performance was assessed in two ways. The first was its recovery rate, i.e., its ability to call 893 CNVs previously identified in eight HapMap samples by paired-end sequencing of whole-genome fosmid clones, and 51,440 CNVs identified by array Comparative Genome Hybridization (aCGH) followed by validation procedures, in 90 HapMap CEU samples. The second evaluation was program performance calling rare and common CNVs in the Bipolar Genome Study (BiGS) data set (1001 bipolar cases and 1033 controls, all of European ancestry) as measured by the Affymetrix SNP 6.0 array. Accuracy in calling rare CNVs was assessed by positive predictive value, based on the proportion of rare CNVs validated by quantitative real-time PCR (qPCR), while accuracy in calling common CNVs was assessed by false positive/false negative rates based on qPCR validation results from a subset of common CNVs. Birdsuite recovered the highest percentages of known HapMap CNVs containing >20 markers in two reference CNV datasets. The recovery rate increased with decreased CNV frequency. In the tested rare CNV data, Birdsuite and Partek had higher positive predictive values than the other software suites. In a test of three common CNVs in the BiGS dataset, Birdsuite's call was 98.8% consistent with qPCR quantification in one CNV region, but the other two regions showed an unacceptable degree of accuracy. We found relatively poor consistency between the two "gold standards," the sequence data of Kidd et al., and aCGH data of Conrad et al. Algorithms for calling CNVs especially common ones need substantial improvement, and a "gold standard" for detection of CNVs remains to be established. PMID- 21249188 TI - Auditing the management of vaccine-preventable disease outbreaks: the need for a tool. AB - Public health activities, especially infectious disease control, depend on effective teamwork. We present the results of a pilot audit questionnaire aimed at assessing the quality of public health services in the management of VPD outbreaks. Audit questionnaire with three main areas indicators (structure, process and results) was developed. Guidelines were set and each indicator was assessed by three auditors. Differences in indicator scores according to median size of outbreaks were determined by ANOVA (significance at p<=0.05). Of 154 outbreaks; eighteen indicators had a satisfactory mean score, indicator "updated guidelines" and "timely reporting" had a poor mean score (2.84+/-106 and 2.44+/ 1.67, respectively). Statistically significant differences were found according to outbreak size, in the indicators "availability of guidelines/protocol updated less than 3 years ago" (p = 0.03) and "days needed for outbreak control" (p = 0.04). Improving availability of updated guidelines, enhancing timely reporting and adequate recording of control procedures taken is needed to allow for management assessment and improvement. PMID- 21249189 TI - Taking multiple infections of cells and recombination into account leads to small within-host effective-population-size estimates of HIV-1. AB - Whether HIV-1 evolution in infected individuals is dominated by deterministic or stochastic effects remains unclear because current estimates of the effective population size of HIV-1 in vivo, N(e), are widely varying. Models assuming HIV-1 evolution to be neutral estimate N(e)~102-104, smaller than the inverse mutation rate of HIV-1 (~105), implying the predominance of stochastic forces. In contrast, a model that includes selection estimates N(e)>105, suggesting that deterministic forces would hold sway. The consequent uncertainty in the nature of HIV-1 evolution compromises our ability to describe disease progression and outcomes of therapy. We perform detailed bit-string simulations of viral evolution that consider large genome lengths and incorporate the key evolutionary processes underlying the genomic diversification of HIV-1 in infected individuals, namely, mutation, multiple infections of cells, recombination, selection, and epistatic interactions between multiple loci. Our simulations describe quantitatively the evolution of HIV-1 diversity and divergence in patients. From comparisons of our simulations with patient data, we estimate N(e)~103-104, implying predominantly stochastic evolution. Interestingly, we find that N(e) and the viral generation time are correlated with the disease progression time, presenting a route to a priori prediction of disease progression in patients. Further, we show that the previous estimate of N(e)>105 reduces as the frequencies of multiple infections of cells and recombination assumed increase. Our simulations with N(e)~103-104 may be employed to estimate markers of disease progression and outcomes of therapy that depend on the evolution of viral diversity and divergence. PMID- 21249190 TI - Breast cancer cells induce cancer-associated fibroblasts to secrete hepatocyte growth factor to enhance breast tumorigenesis. AB - It has been well documented that microenvironment consisting of stroma affects breast cancer progression. However, the mechanisms by which cancer cells and fibroblasts, the major cell type in stroma, interact with each other during tumor development remains to be elucidated. Here, we show that the human cancer associated fibroblasts (CAFs) had higher activity in enhancing breast tumorigenecity compared to the normal tissue-associated fibroblasts (NAFs) isolated from the same patients. The expression level of hepatocyte growth factor (HGF) in these fibroblasts was positively correlated with their ability to enhance breast tumorigenesis in mice. Deprivation of HGF using a neutralizing antibody reduced CAF-mediated colony formation of human breast cancer cells, indicating that CAFs enhanced cancer cell colony formation mainly through HGF secretion. Co-culture with human breast cancer MDA-MB-468 cells in a transwell system enhanced NAFs to secret HGF as well as promote tumorigenecity. The newly gained ability of these "educated" NAFs became irreversible after continuing this process till fourth passage. These results suggested that breast cancer cells could alter the nature of its surrounding fibroblasts to secrete HGF to support its own progression through paracrine signaling. PMID- 21249191 TI - Estimating surface area in early hominins. AB - Height and weight-based methods of estimating surface area have played an important role in the development of the current consensus regarding the role of thermoregulation in human evolution. However, such methods may not be reliable when applied to early hominins because their limb proportions differ markedly from those of humans. Here, we report a study in which this possibility was evaluated by comparing surface area estimates generated with the best-known height and weight-based method to estimates generated with a method that is sensitive to proportional differences. We found that the two methods yield indistinguishable estimates when applied to taxa whose limb proportions are similar to those of humans, but significantly different results when applied to taxa whose proportions differ from those of humans. We also found that the discrepancy between the estimates generated by the two methods is almost entirely attributable to inter-taxa differences in limb proportions. One corollary of these findings is that we need to reassess hypotheses about the role of thermoregulation in human evolution that have been developed with the aid of height and weight-based methods of estimating body surface area. Another is that we need to use other methods in future work on fossil hominin body surface areas. PMID- 21249192 TI - Structure-activity relationship of cinnamaldehyde analogs as inhibitors of AI-2 based quorum sensing and their effect on virulence of Vibrio spp. AB - BACKGROUND: Many bacteria, including Vibrio spp., regulate virulence gene expression in a cell-density dependent way through a communication process termed quorum sensing (QS). Hence, interfering with QS could be a valuable novel antipathogenic strategy. Cinnamaldehyde has previously been shown to inhibit QS regulated virulence by decreasing the DNA-binding ability of the QS response regulator LuxR. However, little is known about the structure-activity relationship of cinnamaldehyde analogs. METHODOLOGY/PRINCIPAL FINDINGS: By evaluating the QS inhibitory activity of a series of cinnamaldehyde analogs, structural elements critical for autoinducer-2 QS inhibition were identified. These include an alpha,beta unsaturated acyl group capable of reacting as Michael acceptor connected to a hydrophobic moiety and a partially negative charge. The most active cinnamaldehyde analogs were found to affect the starvation response, biofilm formation, pigment production and protease production in Vibrio spp in vitro, while exhibiting low cytotoxicity. In addition, these compounds significantly increased the survival of the nematode Caenorhabditis elegans infected with Vibrio anguillarum, Vibrio harveyi and Vibrio vulnificus. CONCLUSIONS/SIGNIFICANCE: Several new and more active cinnamaldehyde analogs were discovered and they were shown to affect Vibrio spp. virulence factor production in vitro and in vivo. Although ligands for LuxR have not been identified so far, the nature of different cinnamaldehyde analogs and their effect on the DNA binding ability of LuxR suggest that these compounds act as LuxR-ligands. PMID- 21249193 TI - Large proteins have a great tendency to aggregate but a low propensity to form amyloid fibrils. AB - The assembly of soluble proteins into ordered fibrillar aggregates with cross beta structure is an essential event of many human diseases. The polypeptides undergoing aggregation are generally small in size. To explore if the small size is a primary determinant for the formation of amyloids under pathological conditions we have created two databases of proteins, forming amyloid-related and non-amyloid deposits in human diseases, respectively. The size distributions of the two protein populations are well separated, with the systems forming non amyloid deposits appearing significantly larger. We have then investigated the propensity of the 486-residue hexokinase-B from Saccharomyces cerevisiae (YHKB) to form amyloid-like fibrils in vitro. This size is intermediate between the size distributions of amyloid and non-amyloid forming proteins. Aggregation was induced under conditions known to be most effective for amyloid formation by normally globular proteins: (i) low pH with salts, (ii) pH 5.5 with trifluoroethanol. In both situations YHKB aggregated very rapidly into species with significant beta-sheet structure, as detected using circular dichroism and X ray diffraction, but a weak Thioflavin T and Congo red binding. Moreover, atomic force microscopy indicated a morphology distinct from typical amyloid fibrils. Both types of aggregates were cytotoxic to human neuroblastoma cells, as indicated by the MTT assay. This analysis indicates that large proteins have a high tendency to form toxic aggregates, but low propensity to form regular amyloid in vivo and that such a behavior is intrinsically determined by the size of the protein, as suggested by the in vitro analysis of our sample protein. PMID- 21249194 TI - Regulation of cullin RING E3 ubiquitin ligases by CAND1 in vivo. AB - Cullin RING ligases are multi-subunit complexes consisting of a cullin protein which forms a scaffold onto which the RING protein Rbx1/2 and substrate receptor subunits assemble. CAND1, which binds to cullins that are not conjugated with Nedd8 and not associated with substrate receptors, has been shown to function as a positive regulator of Cullin ligases in vivo. Two models have been proposed to explain this requirement: (i) CAND1 sequesters cullin proteins and thus prevents autoubiquitination of substrate receptors, and (ii) CAND1 is required to promote the exchange of bound substrate receptors. Using mammalian cells, we show that CAND1 is predominantly cytoplasmically localized and that cullins are the major CAND1 interacting proteins. However, only small amounts of CAND1 bind to Cul1 in cells, despite low basal levels of Cul1 neddylation and approximately equal cytoplasmic endogenous protein concentrations of CAND1 and Cul1. Compared to F box protein substrate receptors, binding of CAND1 to Cul1 in vivo is weak. Furthermore, preventing binding of F-box substrate receptors to Cul1 does not increase CAND1 binding. In conclusion, our study suggests that CAND1 does not function by sequestering cullins in vivo to prevent substrate receptor autoubiquitination and is likely to regulate cullin RING ligase activity via alternative mechanisms. PMID- 21249196 TI - Measuring the strength of interaction between the Ebola fusion peptide and lipid rafts: implications for membrane fusion and virus infection. AB - The Ebola fusion peptide (EBO16) is a hydrophobic domain that belongs to the GP2 membrane fusion protein of the Ebola virus. It adopts a helical structure in the presence of mimetic membranes that is stabilized by the presence of an aromatic aromatic interaction established by Trp8 and Phe12. In spite of its infectious cycle becoming better understood recently, several steps still remain unclear, a lacuna that makes it difficult to develop strategies to block infection. In order to gain insight into the mechanism of membrane fusion, we probed the structure, function and energetics of EBO16 and its mutant W8A, in the absence or presence of different lipid membranes, including isolated domain-resistant membranes (DRM), a good experimental model for lipid rafts. The depletion of cholesterol from living mammalian cells reduced the ability of EBO16 to induce lipid mixing. On the other hand, EBO16 was structurally sensitive to interaction with lipid rafts (DRMs), but the same was not observed for W8A mutant. In agreement with these data, W8A showed a poor ability to promote membrane aggregation in comparison to EBO16. Single molecule AFM experiments showed a high affinity force pattern for the interaction of EBO16 and DRM, which seems to be a complex energetic event as observed by the calorimetric profile. Our study is the first to show a strong correlation between the initial step of Ebola virus infection and cholesterol, thus providing a rationale for Ebola virus proteins being co localized with lipid-raft domains. In all, the results show how small fusion peptide sequences have evolved to adopt highly specific and strong interactions with membrane domains. Such features suggest these processes are excellent targets for therapeutic and vaccine approaches to viral diseases. PMID- 21249195 TI - Capsaicin-induced changes in LTP in the lateral amygdala are mediated by TRPV1. AB - The transient receptor potential vanilloid type 1 (TRPV1) channel is a well recognized polymodal signal detector that is activated by painful stimuli such as capsaicin. Here, we show that TRPV1 is expressed in the lateral nucleus of the amygdala (LA). Despite the fact that the central amygdala displays the highest neuronal density, the highest density of TRPV1 labeled neurons was found within the nuclei of the basolateral complex of the amygdala. Capsaicin specifically changed the magnitude of long-term potentiation (LTP) in the LA in brain slices of mice depending on the anesthetic (ether, isoflurane) used before euthanasia. After ether anesthesia, capsaicin had a suppressive effect on LA-LTP both in patch clamp and in extracellular recordings. The capsaicin-induced reduction of LTP was completely blocked by the nitric oxide synthase (NOS) inhibitor L-NAME and was absent in neuronal NOS as well as in TRPV1 deficient mice. The specific antagonist of cannabinoid receptor type 1 (CB1), AM 251, was also able to reduce the inhibitory effect of capsaicin on LA-LTP, suggesting that stimulation of TRPV1 provokes the generation of anandamide in the brain which seems to inhibit NO synthesis. After isoflurane anesthesia before euthanasia capsaicin caused a TRPV1-mediated increase in the magnitude of LA-LTP. Therefore, our results also indicate that the appropriate choice of the anesthetics used is an important consideration when brain plasticity and the action of endovanilloids will be evaluated. In summary, our results demonstrate that TRPV1 may be involved in the amygdala control of learning mechanisms. PMID- 21249197 TI - A simple model for the influence of meiotic conversion tracts on GC content. AB - A strong correlation between GC content and recombination rate is observed in many eukaryotes, which is thought to be due to conversion events linked to the repair of meiotic double-strand breaks. In several organisms, the length of conversion tracts has been shown to decrease exponentially with increasing distance from the sites of meiotic double-strand breaks. I show here that this behavior leads to a simple analytical model for the evolution and the equilibrium state of the GC content of sequences devoid of meiotic double-strand break sites. In the yeast Saccharomyces cerevisiae, meiotic double-strand breaks are practically excluded from protein-coding sequences. A good fit was observed between the predictions of the model and the variations of the average GC content of the third codon position (GC3) of S. cerevisiae genes. Moreover, recombination parameters that can be extracted by fitting the data to the model coincide with experimentally determined values. These results thus indicate that meiotic recombination plays an important part in determining the fluctuations of GC content in yeast coding sequences. The model also accounted for the different patterns of GC variations observed in the genes of Candida species that exhibit a variety of sexual lifestyles, and hence a wide range of meiotic recombination rates. Finally, the variations of the average GC3 content of human and chicken coding sequences could also be fitted by the model. These results suggest the existence of a widespread pattern of GC variation in eukaryotic genes due to meiotic recombination, which would imply the generality of two features of meiotic recombination: its association with GC-biased gene conversion and the quasi-exclusion of meiotic double-strand breaks from coding sequences. Moreover, the model points out to specific constraints on protein fragments encoded by exon terminal sequences, which are the most affected by the GC bias. PMID- 21249198 TI - A self-propagating matrix metalloprotease-9 (MMP-9) dependent cycle of chronic neutrophilic inflammation. AB - BACKGROUND: Chronic neutrophilic inflammation is a poorly understood feature in a variety of diseases with notable worldwide morbidity and mortality. We have recently characterized N-acetyl Pro-Gly-Pro (Ac-PGP) as an important neutrophil (PMN) chemoattractant in chronic inflammation generated from the breakdown of collagen by the actions of MMP-9. MMP-9 is present in the granules of PMNs and is differentially released during inflammation but whether Ac-PGP contributes to this ongoing proteolytic activity in chronic neutrophilic inflammation is currently unknown. METHODOLOGY/PRINCIPAL FINDINGS: Utilizing isolated primary blood PMNs from human donors, we found that Ac-PGP induces significant release of MMP-9 and concurrently activates the ERK1/2 MAPK pathway. This MMP-9 release is attenuated by an inhibitor of ERK1/2 MAPK and upstream blockade of CXCR1 and CXCR2 receptors with repertaxin leads to decreased MMP-9 release and ERK 1/2 MAPK activation. Supernatants obtained from PMNs stimulated by Ac-PGP generate more Ac PGP when incubated with intact collagen ex vivo; this effect is inhibited by an ERK1/2 pathway inhibitor. Finally, clinical samples from individuals with CF demonstrate a notable correlation between Ac-PGP (as measured by liquid chromatography-tandem mass spectrometry) and MMP-9 levels even when accounting for total PMN burden. CONCLUSIONS/SIGNIFICANCE: These data indicate that ECM derived Ac-PGP could result in a feed-forward cycle by releasing MMP-9 from activated PMNs through the ligation of CXCR1 and CXCR2 and subsequent activation of the ERK1/2 MAPK, highlighting for the first time a matrix-derived chemokine (matrikine) augmenting its generation through a discrete receptor/intracellular signaling pathway. These findings have notable implications to the development unrelenting chronic PMN inflammation in human disease. PMID- 21249200 TI - A non-Levy random walk in chacma baboons: what does it mean? AB - The Levy walk is found from amoebas to humans and has been described as the optimal strategy for food research. Recent results, however, have generated controversy about this conclusion since animals also display alternatives to the Levy walk such as the Brownian walk or mental maps and because movement patterns found in some species only seem to depend on food patches distribution. Here I show that movement patterns of chacma baboons do not follow a Levy walk but a Brownian process. Moreover this Brownian walk is not the main process responsible for movement patterns of baboons. Findings about their speed and trajectories show that baboons use metal maps and memory to find resources. Thus the Brownian process found in this species appears to be more dependent on the environment or might be an alternative when known food patches are depleted and when animals have to find new resources. PMID- 21249199 TI - Profiling early lung immune responses in the mouse model of tuberculosis. AB - Tuberculosis (TB) is caused by the intracellular bacteria Mycobacterium tuberculosis, and kills more than 1.5 million people every year worldwide. Immunity to TB is associated with the accumulation of IFNgamma-producing T helper cell type 1 (Th1) in the lungs, activation of M.tuberculosis-infected macrophages and control of bacterial growth. However, very little is known regarding the early immune responses that mediate accumulation of activated Th1 cells in the M.tuberculosis-infected lungs. To define the induction of early immune mediators in the M.tuberculosis-infected lung, we performed mRNA profiling studies and characterized immune cells in M.tuberculosis-infected lungs at early stages of infection in the mouse model. Our data show that induction of mRNAs involved in the recognition of pathogens, expression of inflammatory cytokines, activation of APCs and generation of Th1 responses occurs between day 15 and day 21 post infection. The induction of these mRNAs coincides with cellular accumulation of Th1 cells and activation of myeloid cells in M.tuberculosis-infected lungs. Strikingly, we show the induction of mRNAs associated with Gr1+ cells, namely neutrophils and inflammatory monocytes, takes place on day 12 and coincides with cellular accumulation of Gr1+ cells in M.tuberculosis-infected lungs. Interestingly, in vivo depletion of Gr1+ neutrophils between days 10-15 results in decreased accumulation of Th1 cells on day 21 in M.tuberculosis-infected lungs without impacting overall protective outcomes. These data suggest that the recruitment of Gr1+ neutrophils is an early event that leads to production of chemokines that regulate the accumulation of Th1 cells in the M.tuberculosis infected lungs. PMID- 21249201 TI - Conspecific crop-weed introgression influences evolution of weedy rice (Oryza sativa f. spontanea) across a geographical range. AB - BACKGROUND: Introgression plays an important role in evolution of plant species via its influences on genetic diversity and differentiation. Outcrossing determines the level of introgression but little is known about the relationships of outcrossing rates, genetic diversity, and differentiation particularly in a weedy taxon that coexists with its conspecific crop. METHODOLOGY/PRINCIPAL FINDINGS: Eleven weedy rice (Oryza sativa f. spontanea) populations from China were analyzed using microsatellite (SSR) fingerprints to study outcrossing rate and its relationship with genetic variability and differentiation. To estimate outcrossing, six highly polymorphic SSR loci were used to analyze >5500 progeny from 216 weedy rice families, applying a mixed mating model; to estimate genetic diversity and differentiation, 22 SSR loci were analyzed based on 301 weedy individuals. Additionally, four weed-crop shared SSR loci were used to estimate the influence of introgression from rice cultivars on weedy rice differentiation. Outcrossing rates varied significantly (0.4~11.7%) among weedy rice populations showing relatively high overall Nei's genetic diversity (0.635). The observed heterozygosity was significantly correlated with outcrossing rates among populations (r2 = 0.783; P<0.001) although no obvious correlation between outcrossing rates and genetic diversity parameters was observed. Allelic introgression from rice cultivars to their coexisting weedy rice was detected. Weedy rice populations demonstrated considerable genetic differentiation that was correlated with their spatial distribution (r2 = 0.734; P<0.001), and possibly also influenced by the introgression from rice cultivars. CONCLUSIONS/SIGNIFICANCE: Outcrossing rates can significantly affect heterozygosity of populations, which may shape the evolutionary potential of weedy rice. Introgression from the conspecific crop rice can influence the genetic differentiation and possibly evolution of its coexisting weedy rice populations. PMID- 21249203 TI - Decline of birds in a human modified coastal dune forest landscape in South Africa. AB - Previous studies demonstrate that old-growth forest remnants and vegetation regenerating after anthropogenic disturbance provide habitat for birds in a human modified coastal dune forest landscape in northern KwaZulu-Natal, South Africa. However, occurrence does not ensure persistence. Based on a 13-year monitoring database we calculated population trends for 37 bird species and general trends in overall bird density in different vegetation types. We evaluated species' characteristics as covariates of population trend and assessed changes in rainfall and proportional area and survey coverage per vegetation type. 76% of species assessed have declined, 57% significantly so at an average rate of 13.9% per year. Overall, bird density has fallen at 12.2% per year across old-growth forest and woody regenerating vegetation types. Changes in proportional area and coverage per vegetation type may partly explain trends for a few species but are unlikely to account for most. Below average rainfall may have contributed to bird declines. However, other possibilities warrant further investigation. Species with larger range extents tended to decline more sharply than did others, and these species may be responding to environmental changes on a broader geographical scale. Our results cast doubt on the future persistence of birds in this human modified landscape. More research is needed to elucidate the mechanisms driving population decline in the study area and to investigate whether the declines identified here are more widespread across the region and perhaps the continent. PMID- 21249202 TI - Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. AB - BACKGROUND: PTEN-induced kinase 1 (PINK1) is linked to recessive Parkinsonism (EOPD). Pink1 deletion results in impaired dopamine (DA) release and decreased mitochondrial respiration in the striatum of mice. To reveal additional mechanisms of Pink1-related dopaminergic dysfunction, we studied Ca2+ vulnerability of purified brain mitochondria, DA levels and metabolism and whether signaling pathways implicated in Parkinson's disease (PD) display altered activity in the nigrostriatal system of Pink1-/- mice. METHODS AND FINDINGS: Purified brain mitochondria of Pink1-/- mice showed impaired Ca2+ storage capacity, resulting in increased Ca2+ induced mitochondrial permeability transition (mPT) that was rescued by cyclosporine A. A subpopulation of neurons in the substantia nigra of Pink1-/- mice accumulated phospho-c-Jun, showing that Jun N-terminal kinase (JNK) activity is increased. Pink1-/- mice 6 months and older displayed reduced DA levels associated with increased DA turnover. Moreover, Pink1-/- mice had increased levels of IL-1beta, IL-12 and IL-10 in the striatum after peripheral challenge with lipopolysaccharide (LPS), and Pink1-/- embryonic fibroblasts showed decreased basal and inflammatory cytokine-induced nuclear factor kappa-beta (NF-kappaB) activity. Quantitative transcriptional profiling in the striatum revealed that Pink1-/- mice differentially express genes that (i) are upregulated in animals with experimentally induced dopaminergic lesions, (ii) regulate innate immune responses and/or apoptosis and (iii) promote axonal regeneration and sprouting. CONCLUSIONS: Increased mitochondrial Ca2+ sensitivity and JNK activity are early defects in Pink1-/- mice that precede reduced DA levels and abnormal DA homeostasis and may contribute to neuronal dysfunction in familial PD. Differential gene expression in the nigrostriatal system of Pink1-/- mice supports early dopaminergic dysfunction and shows that Pink1 deletion causes aberrant expression of genes that regulate innate immune responses. While some differentially expressed genes may mitigate neurodegeneration, increased LPS-induced brain cytokine expression and impaired cytokine-induced NF-kappaB activation may predispose neurons of Pink1-/- mice to inflammation and injury-induced cell death. PMID- 21249204 TI - Generation of human melanocytes from induced pluripotent stem cells. AB - Epidermal melanocytes play an important role in protecting the skin from UV rays, and their functional impairment results in pigment disorders. Additionally, melanomas are considered to arise from mutations that accumulate in melanocyte stem cells. The mechanisms underlying melanocyte differentiation and the defining characteristics of melanocyte stem cells in humans are, however, largely unknown. In the present study, we set out to generate melanocytes from human iPS cells in vitro, leading to a preliminary investigation of the mechanisms of human melanocyte differentiation. We generated iPS cell lines from human dermal fibroblasts using the Yamanaka factors (SOX2, OCT3/4, and KLF4, with or without c MYC). These iPS cell lines were subsequently used to form embryoid bodies (EBs) and then differentiated into melanocytes via culture supplementation with Wnt3a, SCF, and ET-3. Seven weeks after inducing differentiation, pigmented cells expressing melanocyte markers such as MITF, tyrosinase, SILV, and TYRP1, were detected. Melanosomes were identified in these pigmented cells by electron microscopy, and global gene expression profiling of the pigmented cells showed a high similarity to that of human primary foreskin-derived melanocytes, suggesting the successful generation of melanocytes from iPS cells. This in vitro differentiation system should prove useful for understanding human melanocyte biology and revealing the mechanism of various pigment cell disorders, including melanoma. PMID- 21249205 TI - Pathways of carbon and energy metabolism of the epibiotic community associated with the deep-sea hydrothermal vent shrimp Rimicaris exoculata. AB - BACKGROUND: The shrimp Rimicaris exoculata dominates the faunal biomass at many deep-sea hydrothermal vent sites at the Mid-Atlantic Ridge. In its enlarged gill chamber it harbors a specialized epibiotic bacterial community for which a nutritional role has been proposed. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed specimens from the Snake Pit hydrothermal vent field on the Mid-Atlantic Ridge by complementing a 16S rRNA gene survey with the analysis of genes involved in carbon, sulfur and hydrogen metabolism. In addition to Epsilon- and Gammaproteobacteria, the epibiotic community unexpectedly also consists of Deltaproteobacteria of a single phylotype, closely related to the genus Desulfocapsa. The association of these phylogenetic groups with the shrimp was confirmed by fluorescence in situ hybridization. Based on functional gene analyses, we hypothesize that the Gamma- and Epsilonproteobacteria are capable of autotrophic growth by oxidizing reduced sulfur compounds, and that the Deltaproteobacteria are also involved in sulfur metabolism. In addition, the detection of proteobacterial hydrogenases indicates the potential for hydrogen oxidation in these communities. Interestingly, the frequency of these phylotypes in 16S rRNA gene clone libraries from the mouthparts differ from that of the inner lining of the gill chamber, indicating potential functional compartmentalization. CONCLUSIONS: Our data show the specific association of autotrophic bacteria with Rimicaris exoculata from the Snake Pit hydrothermal vent field, and suggest that autotrophic carbon fixation is contributing to the productivity of the epibiotic community with the reductive tricarboxylic acid cycle as one important carbon fixation pathway. This has not been considered in previous studies of carbon fixation and stable carbon isotope composition of the shrimp and its epibionts. Furthermore, the co-occurrence of sulfur-oxidizing and sulfur-reducing epibionts raises the possibility that both may be involved in the syntrophic exchange of sulfur compounds, which could increase the overall efficiency of this epibiotic community. PMID- 21249206 TI - Brucella abortus ornithine lipids are dispensable outer membrane components devoid of a marked pathogen-associated molecular pattern. AB - The brucellae are alpha-Proteobacteria facultative intracellular parasites that cause an important zoonosis. These bacteria escape early detection by innate immunity, an ability associated to the absence of marked pathogen-associated molecular patterns in the cell envelope lipopolysaccharide, lipoproteins and flagellin. We show here that, in contrast to the outer membrane ornithine lipids (OL) of other Gram negative bacteria, Brucella abortus OL lack a marked pathogen associated molecular pattern activity. We identified two OL genes (olsB and olsA) and by generating the corresponding mutants found that olsB deficient B. abortus did not synthesize OL or their lyso-OL precursors. Liposomes constructed with B. abortus OL did not trigger IL-6 or TNF-alpha release by macrophages whereas those constructed with Bordetella pertussis OL and the olsB mutant lipids as carriers were highly active. The OL deficiency in the olsB mutant did not promote proinflammatory responses or generated attenuation in mice. In addition, OL deficiency did not increase sensitivity to polymyxins, normal serum or complement consumption, or alter the permeability to antibiotics and dyes. Taken together, these observations indicate that OL have become dispensable in the extant brucellae and are consistent within the trend observed in alpha-Proteobacteria animal pathogens to reduce and eventually eliminate the envelope components susceptible of recognition by innate immunity. PMID- 21249207 TI - Nationwide molecular surveillance of pandemic H1N1 influenza A virus genomes: Canada, 2009. AB - BACKGROUND: In April 2009, a novel triple-reassortant swine influenza A H1N1 virus ("A/H1N1pdm"; also known as SOIV) was detected and spread globally as the first influenza pandemic of the 21(st) century. Sequencing has since been conducted at an unprecedented rate globally in order to monitor the diversification of this emergent virus and to track mutations that may affect virus behavior. METHODOLOGY/PRINCIPAL FINDINGS: By Sanger sequencing, we determined consensus whole-genome sequences for A/H1N1pdm viruses sampled nationwide in Canada over 33 weeks during the 2009 first and second pandemic waves. A total of 235 virus genomes sampled from unique subjects were analyzed, providing insight into the temporal and spatial trajectory of A/H1N1pdm lineages within Canada. Three clades (2, 3, and 7) were identifiable within the first two weeks of A/H1N1pdm appearance, with clades 5 and 6 appearing thereafter; further diversification was not apparent. Only two viral sites displayed evidence of adaptive evolution, located in hemagglutinin (HA) corresponding to D222 in the HA receptor-binding site, and to E374 at HA2-subunit position 47. Among the Canadian sampled viruses, we observed notable genetic diversity (1.47 x 10-3 amino acid substitutions per site) in the gene encoding PB1, particularly within the viral genomic RNA (vRNA)-binding domain (residues 493-757). This genome data set supports the conclusion that A/H1N1pdm is evolving but not excessively relative to other H1N1 influenza A viruses. Entropy analysis was used to investigate whether any mutated A/H1N1pdm protein residues were associated with infection severity; however no virus genotypes were observed to trend with infection severity. One virus that harboured heterozygote coding mutations, including PB2 D567D/G, was attributed to a severe and potentially mixed infection; yet the functional significance of this PB2 mutation remains unknown. CONCLUSIONS/SIGNIFICANCE: These findings contribute to enhanced understanding of Influenza A/H1N1pdm viral dynamics. PMID- 21249208 TI - Plant diversity surpasses plant functional groups and plant productivity as driver of soil biota in the long term. AB - BACKGROUND: One of the most significant consequences of contemporary global change is the rapid decline of biodiversity in many ecosystems. Knowledge of the consequences of biodiversity loss in terrestrial ecosystems is largely restricted to single ecosystem functions. Impacts of key plant functional groups on soil biota are considered to be more important than those of plant diversity; however, current knowledge mainly relies on short-term experiments. METHODOLOGY/PRINCIPAL FINDINGS: We studied changes in the impacts of plant diversity and presence of key functional groups on soil biota by investigating the performance of soil microorganisms and soil fauna two, four and six years after the establishment of model grasslands. The results indicate that temporal changes of plant community effects depend on the trophic affiliation of soil animals: plant diversity effects on decomposers only occurred after six years, changed little in herbivores, but occurred in predators after two years. The results suggest that plant diversity, in terms of species and functional group richness, is the most important plant community property affecting soil biota, exceeding the relevance of plant above- and belowground productivity and the presence of key plant functional groups, i.e. grasses and legumes, with the relevance of the latter decreasing in time. CONCLUSIONS/SIGNIFICANCE: Plant diversity effects on biota are not only due to the presence of key plant functional groups or plant productivity highlighting the importance of diverse and high-quality plant derived resources, and supporting the validity of the singular hypothesis for soil biota. Our results demonstrate that in the long term plant diversity essentially drives the performance of soil biota questioning the paradigm that belowground communities are not affected by plant diversity and reinforcing the importance of biodiversity for ecosystem functioning. PMID- 21249209 TI - Fisheries and marine animal populations: learning from the long term. PMID- 21249210 TI - Structure of urban movements: polycentric activity and entangled hierarchical flows. AB - The spatial arrangement of urban hubs and centers and how individuals interact with these centers is a crucial problem with many applications ranging from urban planning to epidemiology. We utilize here in an unprecedented manner the large scale, real-time 'Oyster' card database of individual person movements in the London subway to reveal the structure and organization of the city. We show that patterns of intraurban movement are strongly heterogeneous in terms of volume, but not in terms of distance travelled, and that there is a polycentric structure composed of large flows organized around a limited number of activity centers. For smaller flows, the pattern of connections becomes richer and more complex and is not strictly hierarchical since it mixes different levels consisting of different orders of magnitude. This new understanding can shed light on the impact of new urban projects on the evolution of the polycentric configuration of a city and the dense structure of its centers and it provides an initial approach to modeling flows in an urban system. PMID- 21249211 TI - Cyp26b1 regulates retinoic acid-dependent signals in T cells and its expression is inhibited by transforming growth factor-beta. AB - BACKGROUND: The vitamin A metabolite, retinoic acid (RA), plays important roles in the regulation of lymphocyte properties. Dendritic cells in gut-related lymphoid organs can produce RA, thereby imprinting gut-homing specificity on T cells and enhancing transforming growth factor (TGF)-beta-dependent induction of Foxp3+ regulatory T cells upon antigen presentation. In general, RA concentrations in cells and tissues are regulated by its degradation as well. However, it remained unclear if T cells could actively catabolize RA. METHODOLOGY/PRINCIPAL FINDINGS: We assessed the expression of known RA catabolizing enzymes in T cells from mouse lymphoid tissues. Antigen-experienced CD44+ T cells in gut-related lymphoid organs selectively expressed Cyp26b1, a member of the cytochrome P450 family 26. However, T cells in the spleen or skin draining lymph nodes did not significantly express Cyp26b1. Accordingly, physiological levels of RA (1-10 nM) could induce Cyp26b1 expression in naive T cells upon activation in vitro, but could not do so in the presence of TGF-beta. Overexpression of Cyp26b1 significantly suppressed the RA effect to induce expression of the gut-homing receptor CCR9 on T cells. On the other hand, knocking down Cyp26b1 gene expression with small interfering RNA or inhibiting CYP26 enzymatic activity led to enhancement of the RA-induced CCR9 expression. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a role for CYP26B1 in regulating RA-dependent signals in activated T cells but not during TGF-beta-dependent differentiation to Foxp3+ regulatory T cells. Aberrant expression of CYP26B1 may disturb T cell trafficking and differentiation in the gut and its related lymphoid organs. PMID- 21249212 TI - Dendritic cells transfected with scFv from Mab 7.B12 mimicking original antigen gp43 induces protection against experimental Paracoccidioidomycosis. AB - Paracoccidioidomycosis (PCM), endemic in Latin America, is a progressive systemic mycosis caused by Paracoccidioides brasiliensis (P. brasiliensis), which primarily attacks lung tissue. Dendritic cells (DCs) are able to initiate a response in naive T cells, and they also participate in Th-cell education. Furthermore, these cells have been used for therapy in several disease models. Here we transfected DCs with a plasmid (pMAC/PS-scFv) encoding a single chain variable fragment (scFv) of an anti-Id antibody that is capable of mimicking gp43, the main antigenic component of P. brasiliensis. First, Balb/c mice were immunized subcutaneously with pMAC/PS-scFv and, after seven days, scFv protein was presented to the regional lymph nodes cells. Moreover, we showed that the DCs transfected with scFv were capable of efficiently activating proliferation of total lymph node cells and inducing a decrease in lung infection. Therefore, our results suggested that the use of scFv-transfected DCs may be a promising therapy in the paracoccidioidomycosis (PCM) model. PMID- 21249213 TI - Intrinsic regulation of spatiotemporal organization within the suprachiasmatic nucleus. AB - The mammalian pacemaker in the suprachiasmatic nucleus (SCN) contains a population of neural oscillators capable of sustaining cell-autonomous rhythms in gene expression and electrical firing. A critical question for understanding pacemaker function is how SCN oscillators are organized into a coherent tissue capable of coordinating circadian rhythms in behavior and physiology. Here we undertake a comprehensive analysis of oscillatory function across the SCN of the adult PER2::LUC mouse by developing a novel approach involving multi-position bioluminescence imaging and unbiased computational analyses. We demonstrate that there is phase heterogeneity across all three dimensions of the SCN that is intrinsically regulated and extrinsically modulated by light in a region-specific manner. By investigating the mechanistic bases of SCN phase heterogeneity, we show for the first time that phase differences are not systematically related to regional differences in period, waveform, amplitude, or brightness. Furthermore, phase differences are not related to regional differences in the expression of arginine vasopressin and vasoactive intestinal polypeptide, two key neuropeptides characterizing functionally distinct subdivisions of the SCN. The consistency of SCN spatiotemporal organization across individuals and across planes of section suggests that the precise phasing of oscillators is a robust feature of the pacemaker important for its function. PMID- 21249214 TI - Reward-related behavioral paradigms for addiction research in the mouse: performance of common inbred strains. AB - The mouse has emerged as a uniquely valuable species for studying the molecular and genetic basis of complex behaviors and modeling neuropsychiatric disease states. While valid and reliable preclinical assays for reward-related behaviors are critical to understanding addiction-related processes, and various behavioral procedures have been developed and characterized in rats and primates, there have been relatively few studies using operant-based addiction-relevant behavioral paradigms in the mouse. Here we describe the performance of the C57BL/6J inbred mouse strain on three major reward-related paradigms, and replicate the same procedures in two other commonly used inbred strains (DBA/2J, BALB/cJ). We examined Pavlovian-instrumental transfer (PIT) by measuring the ability of an auditory cue associated with food reward to promote an instrumental (lever press) response. In a separate experiment, we assessed the acquisition and extinction of a simple stimulus-reward instrumental behavior on a touch screen based task. Reinstatement of this behavior was then examined following either continuous exposure to cues (conditioned reinforcers, CRs) associated with reward, brief reward and CR exposure, or brief reward exposure followed by continuous CR exposure. The third paradigm examined sensitivity of an instrumental (lever press) response to devaluation of food reward (a probe for outcome insensitive, habitual behavior) by repeated pairing with malaise. Results showed that C57BL/6J mice displayed robust PIT, as well as clear extinction and reinstatement, but were insensitive to reinforcer devaluation. DBA/2J mice showed good PIT and (rewarded) reinstatement, but were slow to extinguish and did not show reinforcer devaluation or significant CR-reinstatement. BALB/cJ mice also displayed good PIT, extinction and reinstatement, and retained instrumental responding following devaluation, but, unlike the other strains, demonstrated reduced Pavlovian approach behavior (food magazine head entries). Overall, these assays provide robust paradigms for future studies using the mouse to elucidate the neural, molecular and genetic factors underpinning reward-related behaviors relevant to addiction research. PMID- 21249215 TI - Characterization of novel and uncharacterized p53 SNPs in the Chinese population- intron 2 SNP co-segregates with the common codon 72 polymorphism. AB - Multiple single nucleotide polymorphisms (SNPs) have been identified in the tumor suppressor gene p53, though the relevance of many of them is unclear. Some of them are also differentially distributed in various ethnic populations, suggesting selective functionality. We have therefore sequenced all exons and flanking regions of p53 from the Singaporean Chinese population and report here the characterization of some novel and uncharacterized SNPs - four in intron 1 (nucleotide positions 8759/10361/10506/11130), three in intron 3 (11968/11969/11974) and two in the 3'UTR (19168/19514). Allelic frequencies were determined for all these and some known SNPs, and were compared in a limited scale to leukemia and lung cancer patient samples. Intron 2 (11827) and 7 (14181/14201) SNPs were found to have a high minor allele frequency of between 26 47%, in contrast to the lower frequencies found in the US population, but similar in trend to the codon 72 polymorphism (SNP12139) that shows a distribution pattern correlative with latitude. Several of the SNPs were linked, such as those in introns 1, 3 and 7. Most interestingly, we noticed the co-segregation of the intron 2 and the codon 72 SNPs, the latter which has been shown to be expressed in an allele-specific manner, suggesting possible regulatory cross-talk. Association analysis indicated that the T/G alleles in both the co-segregating intron 7 SNPs and a 4tagSNP haplotype was strongly associated increased susceptibility to lung cancer in non-smoker females [OR: 1.97 (1.32, 3.394)]. These data together demonstrate high SNP diversity in p53 gene between different populations, highlighting ethnicity-based differences, and their association with cancer risk. PMID- 21249216 TI - Coral reef fish rapidly learn to identify multiple unknown predators upon recruitment to the reef. AB - Organisms often undergo shifts in habitats as their requirements change with ontogeny.Upon entering a new environment, it is vitally important to be able to rapidly assess predation risk. Predation pressure should selectively promote mechanisms that enable the rapid identification of novel predators. Here we tested the ability of a juvenile marine fish to simultaneously learn the identity of multiple previously unknown predators. Individuals were conditioned with a 'cocktail' of novel odours (from two predators and two non-predators) paired with either a conspecific alarm cue or a saltwater control and then tested for recognition of the four odours individually and two novel odours (one predator and one non-predator) the following day. Individuals conditioned with the 'cocktail' and alarm cue responded to the individual 'cocktail' odours with an antipredator response compared to controls. These results demonstrate that individuals acquire recognition of novel odours and that the responses were not due to innate recognition of predators or due to a generalised response to novel odours. Upon entering an unfamiliar environment prey species are able to rapidly assess the risk of predation, enhancing their chances of survival, through the assessment of chemical stimuli. PMID- 21249217 TI - Uptake and metabolism of the novel peptide angiotensin-(1-12) by neonatal cardiac myocytes. AB - BACKGROUND: Angiotensin-(1-12) [Ang-(1-12)] functions as an endogenous substrate for the productions of Ang II and Ang-(1-7) by a non-renin dependent mechanism. This study evaluated whether Ang-(1-12) is incorporated by neonatal cardiac myocytes and the enzymatic pathways of 125I-Ang-(1-12) metabolism in the cardiac myocyte medium from WKY and SHR rats. METHODOLOGY/PRINCIPAL FINDINGS: The degradation of 125I-Ang-(1-12) (1 nmol/L) in the cultured medium of these cardiac myocytes was evaluated in the presence and absence of inhibitors for angiotensin converting enzymes 1 and 2, neprilysin and chymase. In both strains uptake of 125I-Ang-(1-12) by myocytes occurred in a time-dependent fashion. Uptake of intact Ang-(1-12) was significantly greater in cardiac myocytes of SHR as compared to WKY. In the absence of renin angiotensin system (RAS) enzymes inhibitors the hydrolysis of labeled Ang-(1-12) and the subsequent generation of smaller Ang peptides from Ang-(1-12) was significantly greater in SHR compared to WKY controls. 125I-Ang-(1-12) degradation into smaller Ang peptides fragments was significantly inhibited (90% in WKY and 71% in SHR) in the presence of all RAS enzymes inhibitors. Further analysis of peptide fractions generated through the incubation of Ang-(1-12) in the myocyte medium demonstrated a predominant hydrolytic effect of angiotensin converting enzyme and neprilysin in WKY and an additional role for chymase in SHR. CONCLUSIONS/SIGNIFICANCE: These studies demonstrate that neonatal myocytes sequester angiotensin-(1-12) and revealed the enzymes involved in the conversion of the dodecapeptide substrate to biologically active angiotensin peptides. PMID- 21249218 TI - Safety and feasibility of long-term intravenous sodium nitrite infusion in healthy volunteers. AB - BACKGROUND: Infusion of sodium nitrite could provide sustained therapeutic concentrations of nitric oxide (NO) for the treatment of a variety of vascular disorders. The study was developed to determine the safety and feasibility of prolonged sodium nitrite infusion. METHODOLOGY: Healthy volunteers, aged 21 to 60 years old, were candidates for the study performed at the National Institutes of Health (NIH; protocol 05-N-0075) between July 2007 and August 2008. All subjects provided written consent to participate. Twelve subjects (5 males, 7 females; mean age, 38.8+/-9.2 years (range, 21-56 years)) were intravenously infused with increasing doses of sodium nitrite for 48 hours (starting dose at 4.2 ug/kg/hr; maximal dose of 533.8 ug/kg/hr). Clinical, physiologic and laboratory data before, during and after infusion were analyzed. FINDINGS: The maximal tolerated dose for intravenous infusion of sodium nitrite was 267 ug/kg/hr. Dose limiting toxicity occurred at 446 ug/kg/hr. Toxicity included a transient asymptomatic decrease of mean arterial blood pressure (more than 15 mmHg) and/or an asymptomatic increase of methemoglobin level above 5%. Nitrite, nitrate, S nitrosothiols concentrations in plasma and whole blood increased in all subjects and returned to preinfusion baseline values within 12 hours after cessation of the infusion. The mean half-life of nitrite estimated at maximal tolerated dose was 45.3 minutes for plasma and 51.4 minutes for whole blood. CONCLUSION: Sodium nitrite can be safely infused intravenously at defined concentrations for prolonged intervals. These results should be valuable for developing studies to investigate new NO treatment paradigms for a variety of clinical disorders, including cerebral vasospasm after subarachnoid hemorrhage, and ischemia of the heart, liver, kidney and brain, as well as organ transplants, blood-brain barrier modulation and pulmonary hypertension. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov; NCT00103025. PMID- 21249219 TI - ePlant and the 3D data display initiative: integrative systems biology on the world wide web. AB - Visualization tools for biological data are often limited in their ability to interactively integrate data at multiple scales. These computational tools are also typically limited by two-dimensional displays and programmatic implementations that require separate configurations for each of the user's computing devices and recompilation for functional expansion. Towards overcoming these limitations we have developed "ePlant" (http://bar.utoronto.ca/eplant) - a suite of open-source world wide web-based tools for the visualization of large scale data sets from the model organism Arabidopsis thaliana. These tools display data spanning multiple biological scales on interactive three-dimensional models. Currently, ePlant consists of the following modules: a sequence conservation explorer that includes homology relationships and single nucleotide polymorphism data, a protein structure model explorer, a molecular interaction network explorer, a gene product subcellular localization explorer, and a gene expression pattern explorer. The ePlant's protein structure explorer module represents experimentally determined and theoretical structures covering >70% of the Arabidopsis proteome. The ePlant framework is accessed entirely through a web browser, and is therefore platform-independent. It can be applied to any model organism. To facilitate the development of three-dimensional displays of biological data on the world wide web we have established the "3D Data Display Initiative" (http://3ddi.org). PMID- 21249220 TI - Performance of serum C-reactive protein as a screening test for smear-negative tuberculosis in an ambulatory high HIV prevalence population. AB - BACKGROUND: Delayed diagnosis has contributed to the high mortality of sputum smear-negative tuberculosis (SNTB) in high HIV prevalence countries. New diagnostic strategies for SNTB are urgently needed. C-reactive protein (CRP) is a non-specific inflammatory protein that is usually elevated in patients with tuberculosis, but its role in the diagnosis of tuberculosis is uncertain. METHODOLOGY/PRINCIPAL FINDINGS: To determine the diagnostic utility of CRP we prospectively evaluated the performance of CRP as a screening test for SNTB in symptomatic ambulatory tuberculosis suspects followed up for 8 weeks in KwaZulu Natal, South Africa. Confirmed tuberculosis was defined as positive culture or acid-fast bacilli with granulomata on histology, and possible tuberculosis as documented response to antitubercular therapy. The CRP quotient was defined as a multiple of the upper limit of normal of the serum CRP result. Three hundred and sixty four participants fulfilled entry criteria: 135 (37%) with confirmed tuberculosis, 114 (39%) with possible tuberculosis, and 115 (24%) without tuberculosis. The median CRP quotient was 15.4 (IQR 7.2; 23.3) in the confirmed tuberculosis group, 5.8 (IQR 1.4; 16.0) in the group with possible tuberculosis, and 0.7 (IQR 0.2; 2.2) in the group without tuberculosis (p<0.0001). The CRP quotient above the upper limit of normal had sensitivity 0.98 (95% CI 0.94; 0.99), specificity 0.59 (95% CI 0.50; 0.68), positive predictive value 0.74 (95% CI 0.67; 0.80), negative predictive value 0.96 (95% CI 0.88; 0.99), and diagnostic odds ratio 63.7 (95% CI 19.1; 212.0) in the confirmed tuberculosis group compared with the group without tuberculosis. Higher CRP quotients improved specificity at the expense of sensitivity. SIGNIFICANCE: In high HIV prevalence settings a normal CRP could be a useful test in combination with clinical evaluation to rule out tuberculosis in ambulatory patients. Point-of-care CRP should be further evaluated in primary care clinics. PMID- 21249221 TI - Crowding alone cannot account for cosolute effect on amyloid aggregation. AB - Amyloid fiber formation is a specific form of protein aggregation, often resulting from the misfolding of native proteins. Aimed at modeling the crowded environment of the cell, recent experiments showed a reduction in fibrillation halftimes for amyloid-forming peptides in the presence of cosolutes that are preferentially excluded from proteins and peptides. The effect of excluded cosolutes has previously been attributed to the large volume excluded by such inert cellular solutes, sometimes termed "macromolecular crowding". Here, we studied a model peptide that can fold to a stable monomeric beta-hairpin conformation, but under certain solution conditions aggregates in the form of amyloid fibrils. Using Circular Dichroism spectroscopy (CD), we found that, in the presence of polyols and polyethylene glycols acting as excluded cosolutes, the monomeric beta-hairpin conformation was stabilized with respect to the unfolded state. Stabilization free energy was linear with cosolute concentration, and grew with molecular volume, as would also be predicted by crowding models. After initiating the aggregation process with a pH jump, fibrillation in the presence and absence of cosolutes was followed by ThT fluorescence, transmission electron microscopy, and CD spectroscopy. Polyols (glycerol and sorbitol) increased the lag time for fibril formation and elevated the amount of aggregated peptide at equilibrium, in a cosolute size and concentration dependent manner. However, fibrillation rates remained almost unaffected by a wide range of molecular weights of soluble polyethylene glycols. Our results highlight the importance of other forces beyond the excluded volume interactions responsible for crowding that may contribute to the cosolute effects acting on amyloid formation. PMID- 21249222 TI - Phenotypic plasticity and effects of selection on cell division symmetry in Escherichia coli. AB - Aging has been demonstrated in unicellular organisms and is presumably due to asymmetric distribution of damaged proteins and other components during cell division. Whether the asymmetry-induced aging is inevitable or an adaptive and adaptable response is debated. Although asymmetric division leads to aging and death of some cells, it increases the effective growth rate of the population as shown by theoretical and empirical studies. Mathematical models predict on the other hand, that if the cells divide symmetrically, cellular aging may be delayed or absent, growth rate will be reduced but growth yield will increase at optimum repair rates. Therefore in nutritionally dilute (oligotrophic) environments, where growth yield may be more critical for survival, symmetric division may get selected. These predictions have not been empirically tested so far. We report here that Escherichia coli grown in oligotrophic environments had greater morphological and functional symmetry in cell division. Both phenotypic plasticity and genetic selection appeared to shape cell division time asymmetry but plasticity was lost on prolonged selection. Lineages selected on high nutrient concentration showed greater frequency of presumably old or dead cells. Further, there was a negative correlation between cell division time asymmetry and growth yield but there was no significant correlation between asymmetry and growth rate. The results suggest that cellular aging driven by asymmetric division may not be hardwired but shows substantial plasticity as well as evolvability in response to the nutritional environment. PMID- 21249223 TI - Alpha-synuclein is a cellular ferrireductase. AB - alpha-synuclein (alphaS) is a cellular protein mostly known for the association of its aggregated forms with a variety of diseases that include Parkinson's disease and Dementia with Lewy Bodies. While the role of alphaS in disease is well documented there is currently no agreement on the physiological function of the normal isoform of the protein. Here we provide strong evidence that alphaS is a cellular ferrireductase, responsible for reducing iron (III) to bio available iron (II). The recombinant form of the protein has a V(Max) of 2.72 nmols/min/mg and K(m) 23 uM. This activity is also evident in lysates from neuronal cell lines overexpressing alphaS. This activity is dependent on copper bound to alphaS as a cofactor and NADH as an electron donor. Overexpression of alpha-synuclein by cells significantly increases the percentage of iron (II) in cells. The common disease mutations associated with increased susceptibility to PD show no [corrected] differences in activity or iron (II) levels. This discovery may well provide new therapeutic targets for PD and Lewy body dementias. PMID- 21249225 TI - Rates of anti-tuberculosis drug resistance in Kampala-Uganda are low and not associated with HIV infection. AB - BACKGROUND: Drug resistance among tuberculosis patients in sub-Saharan Africa is increasing, possibly due to association with HIV infection. We studied drug resistance and HIV infection in a representative sample of 533 smear-positive tuberculosis patients diagnosed in Kampala, Uganda. METHODS/PRINCIPAL FINDINGS: Among 473 new patients, multidrug resistance was found in 5 (1.1%, 95% CI 0.3 2.5) and resistance to any drug in 57 (12.1%, 9.3-15.3). Among 60 previously treated patients this was 7 (11.7%, 4.8-22.6) and 17 (28.3%; 17.5-41.4), respectively. Of 517 patients with HIV results, 165 (31.9%, 27.9-36.1) tested positive. Neither multidrug (adjusted odds ratio (OR(adj)) 0.7; 95% CI 0.19-2.6) nor any resistance (OR(adj) 0.7; 0.43-1.3) was associated with HIV status. Primary resistance to any drug was more common among patients who had worked in health care (OR(adj) 3.5; 1.0-12.0). CONCLUSION/SIGNIFICANCE: Anti-tuberculosis drug resistance rates in Kampala are low and not associated with HIV infection, but may be associated with exposure during health care. PMID- 21249224 TI - Recruitment of both the mirror and the mentalizing networks when observing social interactions depicted by point-lights: a neuroimaging study. AB - BACKGROUND: Understanding social interactions requires the ability to accurately interpret conspecifics' actions, sometimes only on the basis of subtle body language analysis. Here we address an important issue that has not yet received much attention in social neuroscience, that of an interaction between two agents. We attempted to isolate brain responses to two individuals interacting compared to two individuals acting independently. METHODOLOGY/PRINCIPAL FINDINGS: We used minimalistic point-light displays to depict the characters, as they provide the most straightforward way to isolate mechanisms used to extract information from motion per se without any interference with other visual information. Functional magnetic resonance imaging (fMRI) method was used to determine which brain regions were recruited during the observation of two interacting agents, mimicking everyday social scenes. While the mirror and mentalizing networks are rarely concurrently active, we found that both of them might be needed to catch the social intentions carried by whole-body motion. CONCLUSIONS/SIGNIFICANCE: These findings shed light on how motor cognition contributes to social cognition when social information is embedded in whole-body motion only. Finally, the approach described here provides a valuable and original tool for investigating the brain networks responsible for social understanding, in particular in psychiatric disorders. PMID- 21249226 TI - Hepatitis C virus infection may lead to slower emergence of P. falciparum in blood. AB - BACKGROUND: Areas endemic for Plasmodium falciparum, hepatitis B virus (HBV) and hepatitis C virus (HCV) overlap in many parts of sub-Saharan Africa. HBV and HCV infections develop in the liver, where takes place the first development stage of P. falciparum before its further spread in blood. The complex mechanisms involved in the development of hepatitis may potentially influence the development of the liver stage of malaria parasites. Understanding the molecular mechanisms of these interactions could provide new pathophysiological insights for treatment strategies in Malaria. METHODOLOGY: We studied a cohort of 319 individuals living in a village where the three infections are prevalent. The patients were initially given a curative antimalarial treatment and were then monitored for the emergence of asexual P. falciparum forms in blood, fortnightly for one year, by microscopy and polymerase chain reaction. PRINCIPAL FINDINGS: At inclusion, 65 (20.4%) subjects had detectable malaria parasites in blood, 36 (11.3%) were HBV chronic carriers, and 61 (18.9%) were HCV chronic carriers. During follow-up, asexual P. falciparum forms were detected in the blood of 203 patients. The median time to P. falciparum emergence in blood was respectively 140 and 120 days in HBV- and HBV+ individuals, and 135 and 224 days in HCV- and HCV+ individuals. HCV carriage was associated with delayed emergence of asexual P. falciparum forms in blood relative to patients without HCV infection. CONCLUSIONS: This pilot study represents first tentative evidence of a potential epidemiological interaction between HBV, HCV and P. falciparum infections. Age is an important confounding factor in this setting however multivariate analysis points to an interaction between P. falciparum and HCV at the hepatic level with a slower emergence of P. falciparum in HCV chronic carriers. More in depth analysis are necessary to unravel the basis of hepatic interactions between these two pathogens, which could help in identifying new therapeutic approaches against malaria. PMID- 21249227 TI - 14-3-3 sigma expression effects G2/M response to oxygen and correlates with ovarian cancer metastasis. AB - BACKGROUND: In vitro cell culture experiments with primary cells have reported that cell proliferation is retarded in the presence of ambient compared to physiological O2 levels. Cancer is primarily a disease of aberrant cell proliferation, therefore, studying cancer cells grown under ambient O2 may be undesirable. To understand better the impact of O2 on the propagation of cancer cells in vitro, we compared the growth potential of a panel of ovarian cancer cell lines under ambient (21%) or physiological (3%) O2. PRINCIPAL FINDINGS: Our observations demonstrate that similar to primary cells, many cancer cells maintain an inherent sensitivity to O2, but some display insensitivity to changes in O2 concentration. Further analysis revealed an association between defective G2/M cell cycle transition regulation and O2 insensitivity resultant from overexpression of 14-3-3 sigma. Targeting 14-3-3 sigma overexpression with RNAi restored O2 sensitivity in these cell lines. Additionally, we found that metastatic ovarian tumors frequently overexpress 14-3-3 sigma, which in conjunction with phosphorylated RB, results in poor prognosis. CONCLUSIONS: Cancer cells show differential proliferative sensitivity to changes in O2 concentration. Although a direct link between O2 insensitivity and metastasis was not determined, this investigation showed that an O2 insensitive phenotype in cancer cells to correlate with metastatic tumor progression. PMID- 21249228 TI - Predicting impacts of climate change on Fasciola hepatica risk. AB - Fasciola hepatica (liver fluke) is a physically and economically devastating parasitic trematode whose rise in recent years has been attributed to climate change. Climate has an impact on the free-living stages of the parasite and its intermediate host Lymnaea truncatula, with the interactions between rainfall and temperature having the greatest influence on transmission efficacy. There have been a number of short term climate driven forecasts developed to predict the following season's infection risk, with the Ollerenshaw index being the most widely used. Through the synthesis of a modified Ollerenshaw index with the UKCP09 fine scale climate projection data we have developed long term seasonal risk forecasts up to 2070 at a 25 km square resolution. Additionally UKCIP gridded datasets at 5 km square resolution from 1970-2006 were used to highlight the climate-driven increase to date. The maps show unprecedented levels of future fasciolosis risk in parts of the UK, with risk of serious epidemics in Wales by 2050. The seasonal risk maps demonstrate the possible change in the timing of disease outbreaks due to increased risk from overwintering larvae. Despite an overall long term increase in all regions of the UK, spatio-temporal variation in risk levels is expected. Infection risk will reduce in some areas and fluctuate greatly in others with a predicted decrease in summer infection for parts of the UK due to restricted water availability. This forecast is the first approximation of the potential impacts of climate change on fasciolosis risk in the UK. It can be used as a basis for indicating where active disease surveillance should be targeted and where the development of improved mitigation or adaptation measures is likely to bring the greatest benefits. PMID- 21249229 TI - Survivin mutant protects differentiated dopaminergic SK-N-SH cells against oxidative stress. AB - Oxidative stress is due to an imbalance of antioxidant/pro-oxidant homeostasis and is associated with the progression of several neurological diseases, including Parkinson's and Alzheimer's disease and amyotrophic lateral sclerosis. Furthermore, oxidative stress is responsible for the neuronal loss and dysfunction associated with disease pathogenesis. Survivin is a member of the inhibitors of the apoptosis (IAP) family of proteins, but its neuroprotective effects have not been studied. Here, we demonstrate that SurR9-C84A, a survivin mutant, has neuroprotective effects against H2O2-induced neurotoxicity. Our results show that H2O2 toxicity is associated with an increase in cell death, mitochondrial membrane depolarisation, and the expression of cyclin D1 and caspases 9 and 3. In addition, pre-treatment with SurR9-C84A reduces cell death by decreasing both the level of mitochondrial depolarisation and the expression of cyclin D1 and caspases 9 and 3. We further show that SurR9-C84A increases the antioxidant activity of GSH-peroxidase and catalase, and effectively counteracts oxidant activity following exposure to H2O2. These results suggest for the first time that SurR9-C84A is a promising treatment to protect neuronal cells against H2O2-induced neurotoxicity. PMID- 21249230 TI - Molecular basis for vulnerability to mitochondrial and oxidative stress in a neuroendocrine CRI-G1 cell line. AB - BACKGROUND: Many age-associated disorders (including diabetes, cancer, and neurodegenerative diseases) are linked to mitochondrial dysfunction, which leads to impaired cellular bioenergetics and increased oxidative stress. However, it is not known what genetic and molecular pathways underlie differential vulnerability to mitochondrial dysfunction observed among different cell types. METHODOLOGY/PRINCIPAL FINDINGS: Starting with an insulinoma cell line as a model for a neuronal/endocrine cell type, we isolated a novel subclonal line (named CRI G1-RS) that was more susceptible to cell death induced by mitochondrial respiratory chain inhibitors than the parental CRI-G1 line (renamed CRI-G1-RR for clarity). Compared to parental RR cells, RS cells were also more vulnerable to direct oxidative stress, but equally vulnerable to mitochondrial uncoupling and less vulnerable to protein kinase inhibition-induced apoptosis. Thus, differential vulnerability to mitochondrial toxins between these two cell types likely reflects differences in their ability to handle metabolically generated reactive oxygen species rather than differences in ATP production/utilization or in downstream apoptotic machinery. Genome-wide gene expression analysis and follow-up biochemical studies revealed that, in this experimental system, increased vulnerability to mitochondrial and oxidative stress was associated with (1) inhibition of ARE/Nrf2/Keap1 antioxidant pathway; (2) decreased expression of antioxidant and phase I/II conjugation enzymes, most of which are Nrf2 transcriptional targets; (3) increased expression of molecular chaperones, many of which are also considered Nrf2 transcriptional targets; (4) increased expression of beta cell-specific genes and transcription factors that specify/maintain beta cell fate; and (5) reconstitution of glucose-stimulated insulin secretion. CONCLUSIONS/SIGNIFICANCE: The molecular profile presented here will enable identification of individual genes or gene clusters that shape vulnerability to mitochondrial dysfunction and thus represent potential therapeutic targets for diabetes and neurodegenerative diseases. In addition, the newly identified CRI-G1-RS cell line represents a new experimental model for investigating how endogenous antioxidants affect glucose sensing and insulin release by pancreatic beta cells. PMID- 21249231 TI - Benchmarking ontologies: bigger or better? AB - A scientific ontology is a formal representation of knowledge within a domain, typically including central concepts, their properties, and relations. With the rise of computers and high-throughput data collection, ontologies have become essential to data mining and sharing across communities in the biomedical sciences. Powerful approaches exist for testing the internal consistency of an ontology, but not for assessing the fidelity of its domain representation. We introduce a family of metrics that describe the breadth and depth with which an ontology represents its knowledge domain. We then test these metrics using (1) four of the most common medical ontologies with respect to a corpus of medical documents and (2) seven of the most popular English thesauri with respect to three corpora that sample language from medicine, news, and novels. Here we show that our approach captures the quality of ontological representation and guides efforts to narrow the breach between ontology and collective discourse within a domain. Our results also demonstrate key features of medical ontologies, English thesauri, and discourse from different domains. Medical ontologies have a small intersection, as do English thesauri. Moreover, dialects characteristic of distinct domains vary strikingly as many of the same words are used quite differently in medicine, news, and novels. As ontologies are intended to mirror the state of knowledge, our methods to tighten the fit between ontology and domain will increase their relevance for new areas of biomedical science and improve the accuracy and power of inferences computed across them. PMID- 21249232 TI - Characteristics of the earliest cross-neutralizing antibody response to HIV-1. AB - Recent cross-sectional analyses of HIV-1+ plasmas have indicated that broadly cross-reactive neutralizing antibody responses are developed by 10%-30% of HIV-1+ subjects. The timing of the initial development of such anti-viral responses is unknown. It is also unknown whether the emergence of these responses coincides with the appearance of antibody specificities to a single or multiple regions of the viral envelope glycoprotein (Env). Here we analyzed the cross-neutralizing antibody responses in longitudinal plasmas collected soon after and up to seven years after HIV-1 infection. We find that anti-HIV-1 cross-neutralizing antibody responses first become evident on average at 2.5 years and, in rare cases, as early as 1 year following infection. If cross-neutralizing antibody responses do not develop during the first 2-3 years of infection, they most likely will not do so subsequently. Our results indicate a potential link between the development of cross-neutralizing antibody responses and specific activation markers on T cells, and with plasma viremia levels. The earliest cross-neutralizing antibody response targets a limited number of Env regions, primarily the CD4-binding site and epitopes that are not present on monomeric Env, but on the virion-associated trimeric Env form. In contrast, the neutralizing activities of plasmas from subjects that did not develop cross-neutralizing antibody responses target epitopes on monomeric gp120 other than the CD4-BS. Our study provides information that is not only relevant to better understanding the interaction of the human immune system with HIV but may guide the development of effective immunization protocols. Since antibodies to complex epitopes that are present on the virion associated envelope spike appear to be key components of earliest cross neutralizing activities of HIV-1+ plasmas, then emphasis should be made to elicit similar antibodies by vaccination. PMID- 21249234 TI - Dual-use research and technological diffusion: reconsidering the bioterrorism threat spectrum. PMID- 21249233 TI - HCMV spread and cell tropism are determined by distinct virus populations. AB - Human cytomegalovirus (HCMV) can infect many different cell types in vivo. Two gH/gL complexes are used for entry into cells. gH/gL/pUL(128,130,131A) shows no selectivity for its host cell, whereas formation of a gH/gL/gO complex only restricts the tropism mainly to fibroblasts. Here, we describe that depending on the cell type in which virus replication takes place, virus carrying the gH/gL/pUL(128,130,131A) complex is either released or retained cell-associated. We observed that virus spread in fibroblast cultures was predominantly supernatant-driven, whereas spread in endothelial cell (EC) cultures was predominantly focal. This was due to properties of virus released from fibroblasts and EC. Fibroblasts released virus which could infect both fibroblasts and EC. In contrast, EC released virus which readily infected fibroblasts, but was barely able to infect EC. The EC infection capacities of virus released from fibroblasts or EC correlated with respectively high or low amounts of gH/gL/pUL(128,130,131A) in virus particles. Moreover, we found that focal spread in EC cultures could be attributed to EC-tropic virus tightly associated with EC and not released into the supernatant. Preincubation of fibroblast-derived virus progeny with EC or beads coated with pUL131A-specific antibodies depleted the fraction that could infect EC, and left a fraction that could predominantly infect fibroblasts. These data strongly suggest that HCMV progeny is composed of distinct virus populations. EC specifically retain the EC tropic population, whereas fibroblasts release EC-tropic and non EC-tropic virus. Our findings offer completely new views on how HCMV spread may be controlled by its host cells. PMID- 21249236 TI - N-heterocyclic carbene (NHC) ligands annulated to free-base porphyrins: modulation of the electronic properties of the NHC upon protonation or metallation of the porphyrin. AB - NHC ligands annulated to free-base porphyrins can be reversibly switched between electron-poor and electron-rich states upon protonation and deprotonation of the inner nitrogen atoms of the porphyrin. Metallation of the macrocycle with nickel(II) locks the peripheral NHC ligand in its electron-rich state. PMID- 21249235 TI - Stevens rearrangement as a tool for the structural modification of polyaminopolycarboxylic ligands. AB - Polyaminopolycarboxylic acids are a well known class of ligands employed for metal ion complexation. Despite the large commercial availability, reports of their use as substrates for direct structural modifications are rare. Herein we report a simple and efficient protocol for the preparation of substituted polyaminopolycarboxylic ligands relying on a one-pot N-alkylation-Stevens rearrangement cascade. PMID- 21249237 TI - Mechanistic differences between methanol and dimethyl ether carbonylation in side pockets and large channels of mordenite. AB - The activity and selectivity towards carbonylation presented by Bronsted acid sites located inside the 8MR pockets or in the main 12MR channels of mordenite is studied by means of quantum-chemical calculations, and the mechanistic differences between methanol and DME carbonylation are investigated. The selectivity towards carbonylation is higher inside the 8MR pockets, where the competitive formation of DME and hydrocarbons that finally leads to catalyst deactivation is sterically impeded. Moreover, inclusion of dispersion interactions in the calculations leads to agreement between the calculated activation barriers for the rate determining step and the experimentally observed higher reactivity of methoxy groups located inside the 8MR channels. PMID- 21249238 TI - 3-Dimensional cell culture for on-chip differentiation of stem cells in embryoid body. AB - This paper proposes a microfluidic device for the on-chip differentiation of an embryoid body (EB) formed in a microwell via 3-dimensional cultures of mouse embryonic carcinoma (EC) cells. The device adjusted the size of the EB by fluid volume, differentiated the EB by chemical treatment, and evaluated its effects in EC cells by on-chip immunostaining. A microfluidic resistance network was designed to control the size of the embryoid body. The duration time and flow rate into each microwell regulated the initial number of trapped cells in order to adjust the size of the EB. The docked cells were aggregated and formed a spherical EB on the non-adherent surface of the culture chip for 3 days. The EC cells in the EB were then differentiated into diverse cell lineages without attachment for an additional 4 days; meanwhile, retinoic acid (RA) was applied without serum to direct the cells into early neuronal lineage. On-chip immunostaining of the EB in the microwell with a neuronal marker was conducted to assess the differentiation-inducing ability of RA. The effect of RA on neuronal differentiation was analyzed with confocal microscopic images of the TuJ1 marker. The RA-treated cells expressed more neuronal markers and appeared as mature neuronal cells with long neurites. The fluorescence intensity of the TuJ1 in the RA-treated EB was twice that observed in the non-treated EB on day 5. It was demonstrated that the pre-screening of inducing chemicals on the early neuronal differentiation of EC cells in a single microfluidic chip was indeed feasible. This chip is expected to constitute a useful tool for assessing the early differentiation of ES cells without attachment, and is also expected to prove useful as an anti-cancer drug test platform for the cytotoxicity assay with cellular spheroids. PMID- 21249239 TI - The origin of the enhanced oxygen storage capacity of Ce(1-x)(Pd/Pt)(x)O2. AB - Doping CeO(2) with Pd or Pt increases the oxygen storage capacity (OSC) and catalytic activity of this environmentally important material. To date, however, an understanding of the mechanism underlying this improvement has been lacking. We present a density functional theory analysis of Pd- and Pt-doped CeO(2), and demonstrate that the increased OSC is due to a large displacement of the dopant ions from the Ce lattice site. Pd(II)/Pt(II) (in a d(8) configuration) moves by ~1.2 A to adopt a square-planar coordination due to crystal field effects. This leaves three three-coordinate oxygen atoms that are easier to remove, and which are the source of the increased OSC. These results highlight the importance of rationalizing the preferred coordination environments of both dopants and host cations when choosing suitable dopants for next generation catalysts. PMID- 21249240 TI - Relativistic DFT calculations of the NMR properties and reactivity of transition metal methane sigma-complexes: insights on C-H bond activation. AB - Relativistic ZORA DFT methods have been employed to predict the NMR properties of methane and methyl hydride complexes of rhodium and iridium. Two of these compounds, the rhodium methane and the iridium methyl hydride complexes, have been recently characterized by NMR spectroscopy. Calculations reveal that relativistic effects are largely responsible of the high shielding observed for the proton and carbon resonances of the methane moiety. The key steps for the reaction mechanism of C-H cleavage catalyzed by both compounds have been investigated at the relativistic level. Although the structure of the intermediates and TSs for the Rh and Ir complexes is rather similar, subtle differences in the energetics are responsible of the different catalytic activity of the two complexes. PMID- 21249244 TI - Controlled electrodeposition of Cu-Ga from a deep eutectic solvent for low cost fabrication of CuGaSe2 thin film solar cells. AB - The electrochemical deposition of Ga and Cu-Ga alloys from the deep eutectic solvent choline chloride/urea (Reline) is investigated to prepare CuGaSe(2) (CGS) semiconductors for their use in thin film solar cells. Ga electrodeposition is difficult from aqueous solution due to its low standard potential and the interfering hydrogen evolution reaction (HER). Ionic liquid electrolytes offer a better thermal stability and larger potential window and thus eliminate the interference of solvent breakdown reactions during Ga deposition. We demonstrate that metallic Ga can be electrodeposited from Reline without HER interference with high plating efficiency on Mo and Cu electrodes. A new low cost synthetic route for the preparation of CuGaSe(2) absorber thin films is presented and involves the one-step electrodeposition of Cu-Ga precursors from Reline followed by thermal annealing. Rotating disk electrode (RDE) cyclic voltammetry (CV) is used in combination with viscosity measurements to determine the diffusion coefficients of gallium and copper ions in Reline. The composition of the codeposited Cu-Ga precursor layers can be controlled to form Cu/Ga thin films with precise stoichiometry, which is important for achieving good optoelectronic properties of the final CuGaSe(2) absorbers. The morphology, the chemical composition and the crystal structure of the deposited thin films are analysed by scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDX) and X ray diffraction (XRD). Annealing of the Cu-Ga films in a selenium atmosphere allowed the formation of high quality CuGaSe(2) absorber layers. Completed CGS solar cells achieved a 4.1% total area power conversion efficiency. PMID- 21249245 TI - Extended viologen as a source of electric oscillations. AB - A long organic molecule 1 with five bipyridinium functions separated by benzene rings (extended viologen) undergoes a reversible multi-step electron transfer. Here we show that this decacation accepts electrons at the heterogeneous interface with the occurrence of the periodically changing electric reduction currents. According to the applied bias voltage the observed current-time dependence changes from chaotic through periodic and irregular to sinusoidal and finally to monotonous. A careful choice of the controlling parameters yields the sustained periodic sinusoidal currents lasting for a prolonged time. Oscillations stem from a mutual interplay of the heterogeneous supply of electrons and the homogeneous redox reactions (disproportionation) between the transient redox forms. In difference to many other electrochemical oscillating systems the described oscillations do not require any additional external impedance. The principle of these oscillatory currents may serve as a model of a truly 'molecular oscillator'. PMID- 21249246 TI - Enhanced oxygen reduction at Pd catalytic nanoparticles dispersed onto heteropolytungstate-assembled poly(diallyldimethylammonium)-functionalized carbon nanotubes. AB - Both Keggin-type phosphotungstic acid (HPW) and Pd are not prominent catalysts towards the oxygen reduction (ORR), but their composite Pd-HPW catalyst produces a significantly higher electrochemical activity for the ORR in acidic media. The novel composite catalyst was synthesized by self-assembly of HPW on multi-walled carbon nanotubes (MWCNTs) via the electrostatic attraction between negatively charged HPW and positively charged poly(diallyldimethylammonium (PDDA)-wrapped MWCNTs, followed by dispersion of Pd nanoparticles onto the HPW-PDDA-MWCNT assembly. The as-prepared catalyst was characterized by transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, thermal gravimetric analysis (TGA), Raman spectroscopy, and X-ray photoelectron spectroscopy (XPS). TEM images show that Pd nanoparticles were uniformly dispersed on the surface of MWCNTs even when the Pd loading was increased to 60 wt%. Electrochemical activity of the catalysts for the ORR was evaluated by steady state polarization measurements using a rotating disk electrode. Compared with the acid treated MWCNTs, Pd nanoparticles supported on the HPW-assembled MWCNTs show a much higher ORR activity that is comparable to conventional Pt/C catalysts. The high electrocatalytic activities could be related to high dispersion of Pd nanoparticles as well as synergistic effects originating from the high proton conductivity of HPW. The Pd/HPW-PDDA-MWCNTs system as the cathode catalyst in proton exchange membrane fuel cells is demonstrated. PMID- 21249247 TI - On the solvatochromism of the n <-> pi* electronic transitions in ketones. AB - The solvatochromism of the n <-> pi* electronic transitions of acetone, which is determined in this work by means of absorption and emission spectroscopy, has been studied using the pure solvent scales for polarizability, dipolarity and acidity of the medium. From these analyses, the necessary reduction of the dipole moment and the increase of the polarizability for acetone on electronic excitation are evaluated using Abe's approach (Bull. Chem. Soc. Jpn. 1966, 39, 936). The influence that the increase of the aromatic structure (cf. acetophenone) and the lengthening of the size of the alkyl substituents R- (cf. R CO-R) cause on the solvatochromism of acetone is discussed. Also, we have shown that the photophysical model proposed by Pimentel (J. Am. Chem. Soc. 1957, 79, 3323), which is widely accepted for explaining the n -> pi* blue shift phenomenon for hydrogen-bonded complexes, is mistaken due to ignoring the acid-base changes undergone on electronic excitation; accordingly, a new photophysical model has been proposed. PMID- 21249248 TI - Amido analogues of zincocenes and cadmocenes. AB - The synthesis and characterisation of low-coordinate zinc and cadmium complexes of the sterically demanding 1,3,6,8-tetra-tert-butylcarbazol-9-yl ligand ((t)Bu(4)carb(-)) are reported. ((t)Bu(4)carb)(2)M (M = Zn 1; M = Cd 2) are the first examples of formally two-coordinate bis-carbazol-9-yl complexes of the Group 12 metals and 2 is the first crystallographically characterised two coordinate amido complex of cadmium. The structure and bonding within these complexes are explored via a combination of X-ray crystallography and DFT calculations. The solid state structures for these zinc and cadmium complexes differ greatly from each other; not only do the steric demands of the peripheral tert-butyl substituents in these systems act to inhibit solvent coordination, but they also influence the coordination geometry around the metal centres. PMID- 21249250 TI - The FTIR spectrum of prostate cancer cells allows the classification of anticancer drugs according to their mode of action. AB - The number of anticancer agents that fail in the clinic far outweighs those considered effective, suggesting that the selection procedure for progression of drug molecules into the clinic requires improvement. Traditionally, new drugs are evaluated for their potential to kill cancer cell lines. This approach is obviously not sufficient, and molecules with new modes of action are required. We suggest here that the infrared spectrum of cells exposed to anticancer drugs could offer an opportunity to obtain a fingerprint of the metabolic changes induced by the drugs. Because the infrared spectrum of cells yields a precise image of all the chemical bonds present in the sample, different drug targets are likely to yield different infrared fingerprints characteristic of the 'mode of action' of the therapeutic agent under investigation. In turn, drug-induced metabolic disorders should be amenable to classification in the same way that bacteria gender, species, and strains can be classified. We examined here a human prostate cancer PC-3 cell line exposed to 7 well described antimitotics. In a first step the IC(50) values were determined. For FTIR imaging, PC-3 cells were exposed to the IC(50) concentration of each drug for 48 h. About one hundred images of 4096 IR spectra at 8 cm(-1) spectral resolution were acquired. We show with a Student t-test that the different molecules tested induced different infrared spectral modifications. Furthermore, drugs known to induce similar types of metabolic disturbances appear to cluster when spectrum shapes are analyzed. Finally, supervised statistical methods allowed the building of an efficient and discriminant model. When the discriminant model was applied to a full infrared image a good sorting was generally obtained and misclassified spectra generally belonged to a small number of specific cells. Taken all together these data suggest that FTIR could be used for the classification of drug action. PMID- 21249249 TI - Multifactorial optimization of endothelial cell growth using modular synthetic extracellular matrices. AB - Extracellular matrices (ECMs) are complex materials, containing at least dozens of different macromolecules that are assembled together, thus complicating their optimization towards applications in 3D cell culture or tissue engineering. The natural complexity of ECMs has limited cell-matrix investigations predominantly to experiments where only one matrix component is adjusted at a time, making it difficult to uncover interactions between different matrix components or to efficiently determine optimal matrix compositions for specific desired biological responses. Here we have developed modular synthetic ECMs based on peptide self assembly whose incorporation of multiple different peptide ligands can be adjusted. The peptides can co-assemble in a wide range of combinations to form hydrogels of uniform morphology and consistent mechanical properties, but with precisely varied mixtures of peptide ligands. The modularity of this system in turn enabled multi-factorial experimental designs for investigating interactions between these ligands and for determining a multi-peptide matrix formulation that maximized endothelial cell growth. In cultures of HUVECs, we observed a previously unknown antagonistic interaction between the laminin-derived peptide YIGSR and RGDS-mediated cell attachment and growth. We also identified an optimized combination of self-assembled peptides bearing the ligands RGDS and IKVAV that led to endothelial cell growth equivalent to that on native full length fibronectin. Both of these findings would have been challenging to uncover using more traditional one-factor-at-a-time analyses. PMID- 21249251 TI - Observation of slow relaxation of the magnetization and hysteresis loop in an antiferromagnetic ordered phase of a 2D framework based on Co(II) magnetic chains. AB - Slow relaxation of the magnetization and hysteresis loop were observed in the antiferromagnetic ordered phase of a two-dimensional framework based on one dimensional Co(II) magnetic chains. PMID- 21249252 TI - Multicompartmentalized polymersomes for selective encapsulation of biomacromolecules. AB - Multicompartmentalized polymersomes are formed using block co-polymers PMOXA-PDMS PMOXA and PS-PIAT, and are subsequently proven to be capable of selective encapsulation of biomacromolecules. This architecture mimics the compartmentalization found in cells and may serve as a simple, albeit robust, model system. PMID- 21249253 TI - Hexametallic manganese clusters with bulky derivatised salicylaldoximes. AB - The reaction of Mn(ClO(4))(2).6H(2)O with Ph-saoH(2) (Ph-saoH(2) = 2 hydroxybenzophenone oxime) in MeCN in the presence of sodium propionate forms the complex [Mn(III)(6)O(2)(Ph-sao)(6)(prop)(2)(MeCN)(2)].5.27MeCN (1.5.27MeCN) (prop = propionate). Repeating the same reaction in EtOH produces the complex [Mn(III)(6)O(2)(Ph-sao)(6)(prop)(2)(EtOH)(4)] (2). Complexes 1 and 2 may be considered as structural isomers, since they display the same metallic core but different coordination modes of the propionate ligands; bridging in 1 and terminal in 2. Performing similar reactions and switching from sodium propionate to sodium adamantane-carboxylate (NaO(2)C-ada) and sodium pivalate (Napiv) in the presence of NEt(4)OH yields the complexes [Mn(III)(6)O(2)(Ph-sao)(6)(O(2)C ada)(2)(MeOH)(4)] (3) and [Mn(III)(6)O(2)(Ph-sao)(6)(piv)(2)(EtOH)(4)].0.5Et(2)O (4.0.5Et(2)O), respectively. All four complexes contain the same {Mn(III)(3)O(Ph sao)(3)} building block. Variable temperature magnetic susceptibility and magnetization studies show that all complexes possess an S = 4 ground-state. PMID- 21249254 TI - Metal-mediated aggregation of DNA comprising 2,2'-bipyridine nucleoside, an asymmetrically substituted chiral bidentate ligand. AB - The incorporation of an artificial 5-methyl-2,2'-bipyridine nucleoside at the 5' terminus of an otherwise self-complementary oligonucleotide sequence opens up the opportunity of metal-mediated aggregation of DNA double helices triggered by the addition of the respective metal ions. Interestingly, two-dimensional aggregates (DNA monolayers) are formed in the presence of nickel(ii), whereas copper(ii) leads to the formation of three-dimensional disc-shaped structures. With iron(ii), a coexistence of both types of aggregates had been observed previously. Models are proposed in which these observations are explained based on geometrical considerations. The artificial nucleoside itself represents a rare example for a C(1)-symmetric chiral derivative of 2,2'-bipyridine, enabling the formation of four isomeric octahedral complexes. PMID- 21249255 TI - The effects of shear stress on isolated receptor-ligand interactions of Staphylococcus epidermidis and human plasma fibrinogen using molecularly patterned microfluidics. AB - Staphylococcus epidermidis is an opportunistic pathogen that has been implicated in hospital-acquired infections, specifically related to implanted intravascular devices. S. epidermidis adhesion is a mechanism of colonization, leading to pathogenesis. Here we demonstrate an easily fabricated and robust parallel microfluidic platform to investigate the physiologically-relevant effects of fluid shear on S. epidermidis adhesion to human fibrinogen (hFg) with increased experimental throughput. In situ molecular patterning using fluid flow boundaries allows for isolation of the molecular interactions in highly defined shear stress environments, while keeping the device operation simple and reproducible. We characterize two modes of attachment of S. epidermidis to hFg coated surfaces. Single colonies adhere in high fractions at low shear stresses (~1 dyne cm(-2)) and adhesion decays with increasing shear. However, clusters of bacteria adhere the highest at median wall shear stress (up to 10 dyne cm(-2)), and adhesion subsequently decays above this critical shear stress. This initial characterization suggests a previously unobserved phenomenon of shear activated cell-cell adhesion in S. epidermidis, which acts to increase the overall attachment strength to hFg. Both of these modes of attachment are dependant upon the presence of intact hFg, indicating that adhesion is resultant from specific molecular recognition between the bacteria and human fibrinogen. This platform provides new insight into complex host-pathogen interactions, and will allow for further investigation of colonization and pathogenesis in more physiologically relevant conditions. PMID- 21249259 TI - Synthesis and reactivity of niobium complexes having a tripodal triaryloxide ligand in bidentate, tridentate, and tetradentate coordination modes. AB - The synthesis and reactivity of niobium complexes incorporating a tripodal triphenol (tris(3,5-tert-butyl-2-hydroxylphenyl)methane = H(3)[O(3)]) have been investigated. Addition of one equivalent of NbCl(5) in CH(3)CN to H(3)[O(3)] in toluene led to partial HCl elimination, giving [H(O(3))]NbCl(3)(CH(3)CN) (1) with a bidendtate bis(aryloxide) ligand and a pendant phenol arm. Treatment of 1 with THF afforded [H(O(3))]NbCl(3)(THF) (2). Deprotonation of 1 with NEt(3) in toluene promoted coordination of the pendant phenol group to generate (Et(3)NH)[(syn O(3))NbCl(3)] (3-syn). Prolonged heating of 3-syn resulted in clean conversion to the anti isomer (3-anti). Attempted deprotonation of 2 with PhCH(2)MgCl provided [H(O(3))]Nb(CH(2)Ph)(3) (4), in which alkylation took place at the metal center but the pendant phenol arm remained intact. When 3-syn was treated with PhCH(2)MgCl, [O(3)C]Nb(CH(2)Ph) (5) was produced via C-H activation of the methine C-H bond. The analogous reaction with 3-anti provided a benzylidene complex [anti-O(3)]Nb(CHPh)(THF) (6). During the course of the reaction, the anti ligand conformation is retained. Upon heating, 4 underwent methine C-H and phenol O-H activation, yielding the metalatrane 5. Complexes 1, 3-syn, 3-anti, 4, and 5 were characterized by X-ray diffraction. PMID- 21249260 TI - Stereochemically inactive lone pairs in phosphorus(III) compounds: the characterisation of some derivatives with the 2,5-(CF3)2C6H3 (Ar) substituent and their complexation behaviour towards Pt(II) species. AB - Some new phosphorus(III) derivatives Ar(2)PX (X = Br, Cl, F or H), ArPX(2) (X = Br or Cl), Ar(3)P and Ar(t)BuPCl, with the 2,5-bis(trifluoromethyl)phenyl (Ar) substituent on phosphorus, have been prepared, and characterised by (31)P and (19)F NMR solution-state spectroscopy. The complexing ability of Ar(2)PX, Ar(3)P and Ar(t)BuPCl towards the dimeric platinum(II) complexes [PtY(MU-Y)(PEt(3))](2) (Y = Cl or Br, the latter for X = Br only) has also been investigated. Single crystal X-ray diffraction studies at low temperature have been carried out for Ar(3)P, Ar(2)PCl and the hydrolysis or oxidation products Ar(2)P(H)OH and Ar(2)P(O)OH. The structures of Ar(3)P and Ar(2)PCl are particularly interesting as in each compound the geometry around P is approximately octahedral. In Ar(3)P there are three short contacts to fluorine as well as the three bonded C atoms for both of the independent molecules in the unit cell. For Ar(2)PCl there are two short P-F contacts, and the octahedron is completed by a weak P-P interaction to a neighbouring molecule. In both instances the lone pair on the P(III) centre appears to be stereochemically inactive, and does not play a significant role in the structure. PMID- 21249261 TI - Development of an in vitro method to estimate lung bioaccessibility of metals from atmospheric particles. AB - The research presented here was initiated to improve the current knowledge on easily released metals from atmospheric particles. The objectives of this paper were to develop an in vitro method to estimate lung bioaccessibility and to provide quantitative data on metals bioaccessibility. A large set of metals has been investigated (Ba, Cd, Ce, Co, Cu, La, Mn, Mo, Ni, Pb, Rb, Sb and Zn) using two distinct fluids (water and Gamble solution) on four reference materials representing different types of particle sources. Through this study, different parameters such as extraction-time, composition of the leaching solution and solid-to-liquid (S/L) ratios were investigated. The findings obtained for four SRMs suggest that the bioaccessibility is maximized after a 24 h extraction for a range of S/L ratios varying from 1/500 to 1/50,000. We clearly demonstrate that the higher bioaccessibility of metals is obtained with the Gamble solution. Moreover, our results imply that bioaccessibility is speciation and element dependent with percentages varying from 3.3% for Pb to 92.5% for Zn. An estimation of uncertainties of 11% to 30% was obtained for metals bioaccessibility in the four reference materials. In addition, the extraction procedure was validated by performing a mass balance on both soluble and insoluble fractions. This developed method may be used to evaluate the pulmonary bioaccessibility of trace elements present in the atmospheric particles without major artefacts. PMID- 21249262 TI - A novel alpha-isocyanoacetamide-based three-component reaction for the synthesis of dialkyl 2-acyl-5-aminofuran-3,4-dicarboxylates. AB - alpha-Isocyanoacetamides, acyl chlorides and dialkylacetylenedicarboxylates undergo a smooth multicomponent reaction to produce dialkyl 2-acyl-5-aminofuran 3,4-dicarboxylates in good yield. The scope and mechanism of this new multicomponent transformation are discussed. PMID- 21249263 TI - Synthesis of MUC1 Neoglycopeptides using efficient microwave-enhanced chaotrope assisted click chemistry. AB - The first synthesis of click neoglycopeptide analogues of the biologically relevant MUC1 sequence is reported. In the process, microwave-enhanced chaotrope assisted click reaction conditions that may be used on a routine basis for the synthesis of click peptide conjugates have been developed. The convergent route for the synthesis of neoglycopeptides using these reaction conditions enables the facile, rapid, and highly efficient preparation of focused neoglycopeptide libraries of defined chemical structure for biological evaluation. PMID- 21249264 TI - A lab-on-chip for biothreat detection using single-molecule DNA mapping. AB - Rapid, specific, and sensitive detection of airborne bacteria, viruses, and toxins is critical for biodefense, yet the diverse nature of the threats poses a challenge for integrated surveillance, as each class of pathogens typically requires different detection strategies. Here, we present a laboratory-on-a-chip microfluidic device (LOC-DLA) that integrates two unique assays for the detection of airborne pathogens: direct linear analysis (DLA) with unsurpassed specificity for bacterial threats and Digital DNA for toxins and viruses. The LOC-DLA device also prepares samples for analysis, incorporating upstream functions for concentrating and fractionating DNA. Both DLA and Digital DNA assays are single molecule detection technologies, therefore the assay sensitivities depend on the throughput of individual molecules. The microfluidic device and its accompanying operation protocols have been heavily optimized to maximize throughput and minimize the loss of analyzable DNA. We present here the design and operation of the LOC-DLA device, demonstrate multiplex detection of rare bacterial targets in the presence of 100-fold excess complex bacterial mixture, and demonstrate detection of picogram quantities of botulinum toxoid. PMID- 21249265 TI - Comparison of noninvasive techniques to measure blood pressure in newborns. AB - OBJECTIVE: To compare blood pressure measurements in newborn infants using the flush method, pulse oximetry and oscillometry according to Doppler findings. METHODS: Noninvasive blood pressure measurements were made using three techniques (flush method, pulse oximetry and oscillometry) in three groups of newborns: 15 normal term infants, 16 stable preterm infants, and 14 critically ill infants. All measurements were video recorded, edited separately, coded and analyzed independently by three neonatologists. RESULTS: Fifty-seven measurements were made using each method. The flush method and pulse oximetry had a better correlation with Doppler findings than oscillometry (correlation coefficients: 0.89, 0.85, 0.71; p < 0.01). The difference between measurement means, their standard deviations and the 95% confidence intervals when compared with Doppler findings were: -5.2 +/- 7.9 (-21.1:10.7) mmHg for the flush method; 0.4 +/- 8.9 ( 17.5:18.2) mmHg for pulse oximetry; and 6.4 +/- 16.1 (-25.8:8.6) mmHg for oscillometry. The flush method had a better agreement with Doppler findings for the diagnosis of hypotension than oximetry and oscillometry. CONCLUSIONS: The flush method and pulse oximetry seem to be useful techniques to measure systolic blood pressure in newborn infants; oscillometry had the poorest agreement with Doppler findings to detect hypotension. PMID- 21249275 TI - [A novel method for targeting and characterizing healthy older people]. AB - BACKGROUND: there is no established definition of healthy aging in clinical practice, although it is a World Health Organization goal. AIM: to develop a clinical protocol to identify healthy older people living in the community and study their clinical, laboratory and functional characteristics. MATERIAL AND METHODS: healthy people aged 60 years or older, were invited to participate in the study, by newspapers and radio, if they selfperceived as healthy, lived in the community, were functionally independent and had low disease burden. Potential participants were initially screened by telephone, and those who met the inclusion criteria were included. They had a comprehensive geriatric assessment which included clinical, anthropometric, laboratory and functional assessments. RESULTS: of 384 people who answered the call, 83 subjects aged 60 to 98 years (57% women) met the inclusion criteria of healthy older people. Seventy eight percent did not consume any medication, 100% were able to perform physical activities that required at least three metabolic equivalents (Mets). Basic laboratory showed that approximately 90% of subjects had normal values, using standard benchmarks established for an adult population. CONCLUSIONS: the protocol used in this work was able to identify healthy older people with low disease burden and good functionality. It also validated history and comprehensive geriatric assessment as reliable instruments to identify these subjects. PMID- 21249276 TI - [Generation and validation of a scale to measure physicians' wellbeing]. AB - BACKGROUND: the recent and ongoing changes in the structure and social organization of medicine have deeply transformed medical practice. AIM: to study the perception of these changes by physicians, the impact of these changes in their subjective wellbeing and their strategies of adjustment. MATERIAL AND METHODS: a scale, consisting of 54 items grouped in nine dimensions to measure physicians? subjective wellbeing was devised. It was applied to a random sample of 580 physicians residing in Metropolitan Santiago and affiliated to the Colegio Medico de Chile (the Chilean Medical Association). RESULTS: the internal consistency analysis in the instrument showed a global Cronbach's alpha of 90 percent. CONCLUSIONS: these results support our methodological approach based on an initial qualitative identification of relevant topics in our local context, which afterwards were included as items in the scale to measure specific components of subjective wellbeing. PMID- 21249277 TI - [Changes in household food and nutrient consumption in Metropolitan Santiago 1988 97 by income]. AB - BACKGROUND: the rise in the prevalence of obesity, diabetes, and other risk factors for cardiovascular diseases and cancer observed in Chile over the past decades may be related to changes in dietary patterns of the population. AIM: to report changes in household apparent food-nutrients consumption (HAFNC) for Metropolitan Santiago-Chile 1988-97. MATERIAL AND METHODS: the analysis is based on data from household expenditure surveys conducted by the Instituto Nacional de Estadisticas (INE) on a representative sample of the population to define changes in food prices. Information on food and drink purchases were grouped by specific items and expen-ditures standardized across the two surveys. HAFNC was determined based on unit consumed at home and out of home by the total group and by income quintile using national food composition tables. RESULTS: apparent energy consumption increased over the study period by 25%, this was mainly explained by increased consumption of meat and dairy (rich in saturated fats of animal origin) and of processed foods (fat spreads, sweets and pastries) and foods rich in added sugars (sugary drinks and juices). Dietary fiber derived from whole grains, legumes and cereals decreased. The HAFNC of items protective against nutrition related chronic diseases, such as vegetables, fruits and other fiber rich foods remained stable or frankly decreased (legumes and non-starchy vegetables) Fish and other marine foods rich in omega- 3 fats remained low. CONCLUSIONS: the changes in apparent food consumption patterns can be characterized by an increase in energy dense, fat and sugar rich foods with a low consumption of fi sh, whole grains, legumes, vegetables and fruits. PMID- 21249278 TI - [Admission hyperglycemia and mortality of ST segment elevation myocardial infarction]. AB - BACKGROUND: hyperglycemia at admission has been associated to an adverse prognosis in patients with ST-segment elevation acute myocardial infarction (STE MI). However, its impact over the results of reperfusion therapies in patients with STEMI is still a matter of controversy. AIM: to determine the impact of admission hyperglycemia on hospital and long term mortality, according to the method of reper-fusion utilized in patients with STEMI. MATERIAL AND METHODS: prospective registry of 1,634 consecutive patients aged 60 +/- 12 years (77% male), from 3 participating hospitals in the Chilean Registry of Myocardial Infarction (GEMI). We evaluated demographic, clinical and laboratory variables, reperfusion method used, hospital and long term mortality. The impact of hyperglycemia on hospital and long term mortality was evaluated by a logistic regression analysis and Cox risk, respectively, adjusted by Thrombolysis in Myocardial Infarction (TIMI) risk score. RESULTS: twenty four percent of patients were diabetics and in 45%, the infarct was located on the anterior wall. The mean TIMI risk score was 3.2 +/- 2.4. Hyperglycemia at entry was associated to a greater hospital and long term mortality, independently of the reperfusion strategy utilized. Primary angioplasty was associated to a greater benefit, compared to thrombolysis among hyperglycemic patients with an odds ratio: 2.9, 95% confi dence intervals: 1.0-8.0 and a hazard ratio of 2.9, 95% confi dence intervals: 1.44-5.88, independently of a previous history of diabetes mellitus and TIMI risk score. CONCLUSIONS: in patients with STEMI, admission hyperglycemia is associated with a worse prognosis which was significantly improved with primary angioplasty compared to thrombolysis, independently of the admission TIMI risk score. PMID- 21249279 TI - [Long term follow up of patients consulting in a Chest Pain Unit]. AB - BACKGROUND: chest pain (CT) constitutes an important cause of consultation and diagnostic dilemma in the emergency room, especially due to the possible presence of coronary disease. Its presentation, diagnosis and prognosis are different between men and women. AIM: to report a follow-up of patients attended at a Chest Pain Unit (CPU), evaluating gender differences. MATERIAL AND METHODS: prospective evaluation of patients that consulted for chest pain in a period of 4 years. Baseline characteristics and the final diagnosis from CPU or hospitalization were registered. Telephonic follow-up was performed for at least one year. Mortality was determined using the national mortality registry. RESULTS: a total of 1,168 patients aged 62 +/- 23 years, 69 % men, were followed for a mean of 28 +/- 20 months. A definitive diagnosis of coronary disease (CD) was done in 32 %. Mortality among women and men with CD was 28 and 14% respectively (p = 0,02). Predictor variables for mortality were the presence of a complete left branch block in the initial electrocardiogram, with an odds ratio (OR) of 12,5 (95% confi dence intervals (CI): 1,98-25,8), the presence of coronary disease with an OR of 3,98 (95% CI: 1,45-13,8) and elevated troponin I with an OR 2,12 (95% CI: 1,05-7,89). Female gender lost significance in the adjusted model. CONCLUSIONS: complete left branch block, elevated troponin I and coronary etiology of CP are indicators of bad prognosis among patients that consult for CP. Women have twice the mortality of men after 28 months of follow-up. PMID- 21249280 TI - [Reference values for the 6-minutes walking test in healthy subjects 20-80 years old]. AB - BACKGROUND: the six minute walking distance test (6MWD) is widely used to evaluate exercise capacity in several diseases due to its simplicity and low cost. AIM: to establish reference values for 6MWD in healthy Chilean individuals. MATERIAL AND METHODS: we studied 175 healthy volunteers aged 20-80 years (98 women) with normal spirometry and without history of respiratory, cardiovascular or other diseases that could impair walking capacity. The test was performed twice with an interval of 30 min. Heart rate, arterial oxygen saturation (with a pulse oxymeter) and dyspnea were measured before and after the test. RESULTS: walking distance was 576 +/- 87 m in women and 644 +/- 84 m in men (p < 0.0001). For each sex, a model including age, height and weight produced 6MWD prediction equations with a coefficient of determination (R2) of 0.63 for women and 0.55 for men. CONCLUSIONS: our results provide reference equations for 6MWD that are valid for healthy subjects between 20 and 80 years old. PMID- 21249281 TI - Neuroblastoma in an adult: case report. AB - Neuroblastoma is the most common extracranial solid malignancy in children but rarely described in adults, being 10% of all cases diagnosed after the first decade of life. We report a 23 year-old black woman with a mass at paravertebral region of T3-T5, multiple lesions in vertebral bodies and expanding skull-brain lesion at the right parietal region. Immunohistochemical analysis (negative for CD99, CD20, CD3 and desmin; and positive chromogranin, synaptophysin and NB84) confi rmed the diagnosis of neuroblastoma. The patient was submitted to 12 cycles of chemotherapy receiving VAC (vincristine/doxorubicin/cyclophosphamide) interspersed with ICE (ifosfamide/mesna/etoposide) and doxorubicin was replaced by actinomycin in the 7th cycle. She had good tolerance to this therapy, and has been clinically stable. PMID- 21249282 TI - [Peliosis hepatis: report of one case]. AB - Peliosis hepatis is a rare vascular condition of the liver characterized by the presence of cystic blood-fi lled cavities distributed randomly throughout the liver parenchyma. We report a 46 year old female, with dyspepsia. An abdominal Doppler ultrasound showed a hyper vascularized solid liver nodule of 5 cm diameter. Magnetic resonance imaging and CT scan showed the same hyper vascularized nodule. With the possible diagnoses of primary hepatocellular carcinoma or focal nodular hyperplasia, the patient was subjected to an excision of hepatic segment VI, where the nodule was located. The pathological diagnosis of the surgical piece was a peliosis hepatis. PMID- 21249283 TI - [Immune thrombocytopenic purpura associated to hepatitis C virus infection: report of one case]. AB - Hepatitis C Virus (HCV) is a cause of secondary chronic immune thrombocytopenic purpura (ITP). We report a 43 year old man with mild Hemophilia A, who received blood transfusions during childhood, that consulted for epistaxis and ecchymoses. The laboratory showed a platelet count of 23.000/mm3, positive HCV serology and elevated transaminases. Steroids administered in pulses followed by oral doses resulted in a partial response requiring a second pulse and association of azathioprine. A steroidal diabetes appeared. Given his refractoriness, splenectomy and liver biopsy were performed. He continued on azathioprine maintaining a platelet count near 50.000/mm3 but continued with bleeding episodes. Liver biopsy showed a chronic active hepatitis. PMID- 21249284 TI - [Secondary adrenal insufficiency presenting as hyponatremia: report of one case]. AB - Hyponatremia can be a marker of an underlying disease. We report a 52 years-old male with Diabetes Mellitus who consulted for an episode of nausea and vomiting lasting four days. His baseline serum sodium was 118 mEq/L. He had no neurological deficit. Hyponatremia was initially interpreted in context of gastrointestinal fluid loss but correction with saline solution was poor. His urine sodium was 105 mEq/L and his urine osmolality was 281 mOsm/L, so an Inappropriate Secretion of Antidiuretic Hormone Syndrome was suspected. Later, we found that the patient had a two year history of fatigue, weakness, anorexia, frequent nausea, vomiting and diarrhea, loss of libido and decreased axillary and pubic hair. Thyroid-Stimulating Hormone (TSH) was normal and serum Cortisol < 1 ug/dL. A CT scan showed a sellar mass compatible with a macroadenoma. There was also a moderately high serum prolactin and low testosterone, thyroxin and growth hormone levels. The visual fi eld exami-nation showed right temporal hemianopsia. The patient was treated with steroids with a very good clinical response and serum sodium normalization. Subsequently a transsphenoidal excision of the tumor was performed and replacement of the other hormones was started. Now the patient remains asymptomatic. PMID- 21249285 TI - [Development of a distance education program in the public health system in Chile, 2004-2009]. AB - This paper reports the gradual development and results achieved in the distance education program set up in the Public Health System in Chile in 2004. Up to date, more than 22,000 students from 29 different health divisions have been trained. This strategy was designed to provide more flexibility and diversity to the training programs of the Health System within the framework of a deep and complex organizational change promoted by Health Reform. The main results show that the integration of organizational, teaching, logistic and budgetary aspects has turned out to be a key element in its success, validating the relevance of the provided solutions. The access to training by means of e-learning or blended learning (electronic education that includes traditional and distance learning activities) allowed employees to choose more independently what, where and when to study. This fact accounts for the high demand for this program. Through this initiative, the National Health System, introduced a wider scope of responses to training needs, which will mean a better adaptation to the challenges associated to health care. PMID- 21249286 TI - [Application of a simple methodological approach to analyze health inequalities: the case of infant mortality in Chile]. AB - BACKGROUND: the infant mortality gradient by maternal education is a good indicator of the health impact of the social inequalities that prevail in Chile. AIM: to propose a systematic method of analysis, using simple epidemiological measures, for the comparison of differential health risks between social groups that change over time. MATERIAL AND METHODS: data and statistics on births and infant deaths, obtained from the Ministry of Health, were used. Five strata of maternal schooling were defined and various measures were calculated to compare infant mortality, according to maternal education in the periods 1998-2001 and 2001-2003. RESULTS: of particular interest is the distinction between a measure of effect, Relative Risk (RR), which indicates the size of the gap between socioeconomic extremes and the etiological strength of low maternal schooling on infant mortality, and a measure of global impact, the Population Attributable Risk (PAR%), which takes into account the whole socioeconomic distribution and permits comparisons over time independently of the variability in the proportions of the different social strata. The comparison of these measures in the two periods studied, reveals an increase in the infant mortality gap between maternal educational extremes measured by the RR, but a stabilization in the population impact of low maternal schooling. CONCLUSIONS: these results can be explained by a decline in the proportion of mothers in the lowest educational level and an increase in the proportion in the highest group. PMID- 21249287 TI - [Perioperative risk among patients with cirrhosis]. AB - Ten percent of cirrhotic patients with severely compromised liver function will require a surgical procedure. This article reviews the surgical risk associated with liver damage and surgery. The most important prognostic factor is the degree of functional impairment of the liver. It is evaluated using the Child-Pugh score, which has limitations that have been partially overcome by the Model for End Stage Liver Disease (MELD) score. Cardiac surgery has the highest risk, while extra-thoracic and extra-abdominal procedures have the lowest risk. The mortality for abdominal surgery fluctuates between 11 and 76%. Biliary surgery is associated with frequent complications and mortality, which seem to decrease when the procedures are laparoscopic. There are few series that evaluate risk in Child C patients. In liver resective surgery, liver function impairment and magnitude of the excision determine the risk. A high serum creatinine, cardiac failure and emergency surgery are independent risk factors. Although MELD score is useful to predict surgical risk, decision-making must be based on an individualized evaluation of each patient and careful planning of surgical procedures. PMID- 21249288 TI - [Review on periodontal disease and metabolic control of diabetes mellitus]. AB - There may be an interaction between periodontal disease and some systemic diseases such as diabetes mellitus. The objective of this review was to verify, by means of a review of clinical trials, if there is a positive association between periodontal disease and the glycemic control of type 2 diabetes mellitus (DM-2) patients. Eleven articles that fi t the study criteria were revised. It was concluded that periodontal disease may influence the metabolic control of DM 2. Additional studies with larger sample sizes and longer follow up are necessary for a better clarification of this issue. PMID- 21249289 TI - [Biomarkers for spondyloarthropathies. State of the art]. AB - Among rheumatic diseases and specifically spondyloarthropathies (SpA), the study of biomarkers, defined as molecules that reflect either biologic or specific pathological process, is an important and necessary area in basic and clinical research, being a consequence or the response of an intervention. Other markers provide information about the pathogenesis of this disease. Recently, HLA-B27 has been used as diagnostic criteria to detect SpA. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) are clinical scores used to assess disease activity. A new activity index, Ankylosing Spondylitis Disease Activity Score (ASDAS) considers erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as biomarkers. This review describes the state of the art of research on SpA biomarkers. There are promising new candidates as biomarkers such as metallopro-teinase 3, Type II collagen neoepitopes (C2C and C1-2C), C-propeptide of Type II collagen (CPII), aggrecan 846 epitope, macrophage colony stimulating factor, serum amyloid A protein and interleukin-6, among others. PMID- 21249290 TI - [Comparative analysis of A(H1N1) influenza epidemiological dynamics in Chile]. AB - In order to increase awareness of the pandemic and to streamline control measures before any new outbreak of influenza we analyze the behavior of the cases of Chile and from 9 countries with more cases in 2009. Reproductive numbers, doubling times and estimations of susceptible and infected at the end of the epidemic were estimated. Epidemic curves to the situation in Chile under different initial conditions were adjusted and simulations for different reproductive numbers and notification scenarios were performed. The reproductive numbers varied between 1.37 and 1.82, with doubling times of between 5 and 8 days at 30 days of the epidemic. According to this, the proportions of infected by the end of the epidemic vary between 58% and 78.5%. The transmission coefficient ranged from 2 to 132 new cases per day x 10(6) susceptible individuals. The adjustments showed that the onset of the epidemic probably had more cases than reported. All estimates suggest that there must have been a large number of susceptible and therefore can not be explained as small outbreaks in 2009. A large number of susceptible individuals may still exist who are at risk from a possible new outbreak. PMID- 21249291 TI - [Transparency in biomedical research: about the risks associated with the use of Avandia]. AB - The question of how and when to communicate potential risks associated with new drugs has remained an important focus of tension between the pharmaceutical industry and regulatory entities, such as the American Food and Drug Administration. Recently there has been widespread concern related to the cardiovascular risks associated with the use of Avandia, a rosiglitazone produced by Glaxo Smith Kline. In fact, several metaanalyses involving rosiglitazone provided a relatively consistent message that rosiglitazone increases the risk of myocardial ischemic events. In the present article, we review the controversy regarding the way the pharmaceutical company handled this issue, and we describe examples of inappropriate conduct regarding an industry-sponsored clinical trial with this drug. We raise several important ethical questions related to the way researchers handle conflicts of interest when they are employees of the pharmaceutical industry. Finally, we discuss the requirements to conduct biomedical research funded by the pharmaceutical industry in Chile. PMID- 21249292 TI - [A survey about the competences required by primary health physicians in Chile]. PMID- 21249296 TI - A tribute to Professor Gustavo Hoecker Salas. PMID- 21249297 TI - Vertical transmission of Trypanosoma cruzi in the Province of Choapa, IV Region, Chile: Preliminary Report (2005-2008). AB - Congenital Chagas disease acquired special importance in Chile after the certification of the control of Triatoma infestans and transmission by blood donors affected with Trypanosoma cruzi. In order to establish adequate protocols for intervention and control in infected mother-neonate pairs in endemic zones of Chagas disease, we present partial results (2005-2008) of a pilot project which is being carried out in the Province of Choapa, IV Region, Chile, whose objectives are: determine the current prevalence of the disease in pregnant women, estimate the incidence of vertical transmission of T. cruzi to newborns, determine the lineages of the parasite present in mothers who do and do not transmit the disease, determine the prevalence of Chagas disease in maternal grandmothers of neonates and study placental histopathology. Preliminary results indicated that in this study period, 3.7% of the women who gave birth in the Province have Chagas disease and 2.5% of their newborns were infected. The most frequent T. cruzi genotypes found in mothers studied during pregnancy were TCI and TCIId, either alone or in mixed infections. A high percentage (74.3%) of the grandmothers studied was infected with the parasite. In 29 placentas from mothers with Chagas disease we observed edema, necrosis, fibrinoid deposits and slight lymphoplasmocyte infiltration. In three placentas we found erythroblastosis and in one of them amastigote forms of T. cruzi; this was one of the cases of congenital infection. The evaluation of the diagnostic and control protocols generated will allow us to determine if it has been possible to modify the natural history of vertical transmission of T. cruzi in Chile. PMID- 21249298 TI - Model of chromosome associations in Mus domesticus spermatocytes. AB - Understanding the spatial organization of the chromosomes in meiotic nuclei is crucial to our knowledge of the genome's functional regulation, stability and evolution. This study examined the nuclear architecture of Mus domesticus 2n=40 pachytene spermatocytes, analyzing the associations among autosomal bivalents via their Centromere Telomere Complexes (CTC). The study developed a nuclear model in which each CTC was represented as a 3D computer object. The probability of a given combination of associations among CTC was estimated by simulating a random distribution of 19 indistinguishable CTC over n indistinguishable "cells" on the nuclear envelope. The estimated association frequencies resulting from this numerical approach were similar to those obtained by quantifying actual associations in pachytene spermatocyte spreads. The nuclear localization and associations of CTC through the meiotic prophase in well-preserved nuclei were also analyzed. We concluded that throughout the meiotic prophase: 1) the CTC of autosomal bivalents are not randomly distributed in the nuclear space; 2) the CTC associate amongst themselves, probably at random, over a small surface of the nuclear envelope, at the beginning of the meiotic prophase; 3) the initial aggregation of centromere regions occurring in lepto-zygotene likely resolves into several smaller aggregates according to patterns of preferential partitioning; 4) these smaller aggregates spread over the inner face of the nuclear envelope, remaining stable until advanced stages of the meiotic prophase or even until the first meiotic division. PMID- 21249299 TI - Comparative in vivo antiangiogenic effects of calreticulin from Trypanosoma cruzi and Homo sapiens sapiens. AB - Angiogenesis is a complex multi-step process of neovascularization arising from preexisting blood vessels whose generation is regulated by pro- and anti angiogenic factors. Both Trypanosoma cruzi calreticulin (TcCRT) and its human counterpart (HuCRT) are antiangiogenic. This is the first report where the TcCRT and HuCRT anti-angiogenic properties are compared in vivo. In the chick embryonic chorioallantoid membrane assay (CAM) and at equimolar concentrations, TcCRT displayed significantly higher antiangiogenic activities than its human counterpart. LPS had marginal effects at the concentrations present in the recombinant protein preparations and the TcCRT antiangiogenic effects were largely inhibited by specific polyclonal antibodies, thus, reinforcing the fact that the observed TcCRT effects can be attributed to the parasite-derived molecule and not to the endotoxin. The antiangiogenic TcCRT effects correlate with its anti-tumor in vivo effects, as recently shown in our laboratory. PMID- 21249300 TI - Immunohistochemical evidences showing the presence of thymulin containing cells located in involuted thymus and in peripheral lymphoid organs. AB - Thymulin is a well-characterized thymic hormone that exists as a nonapeptide coupled to equimolar amounts of Zn2+. Thymulin is known to have multiple biological roles, including T cell differentiation, immune regulation, and analgesic functions. It has been shown that thymulin is produced by the reticulo epithelial cells of the thymus, and it circulates in the blood from the moment of birth, maintain its serum level until puberty diminishing thereafter in life. To study the localization of this hormone, we prepared polyclonal and monoclonal antibodies against the commercial peptide and utilized immunocytochemical techniques for visualization. The results indicate that thymulin stains the thymic reticular cells, the outer layers of Hassall's corpuscles and a large round cellular type, which is keratin-negative and does not show affinity for the common leukocyte antigen (CD-45). In mice, this thymulin-positive cell remains in the thymus throughout life and even appears in relatively increased numbers in old involuted thymi. It also appears in thymus-dependent areas of the spleen and lymph nodes, demonstrating that at least one of the thymus cells containing this peptide can be found in peripheral lymphoid tissue. PMID- 21249301 TI - Omissions in the synthetic theory of evolution. AB - The Synthetic Theory of Evolution is the most unifying theory of life science. This theory has dominated scientific thought in explaining the mechanisms involved in speciation. However, there are some omissions that have delayed the understanding of some aspects of the mechanisms of organic evolution, principally: 1) the bridge between somatic and germinal cells, especially in some phylum of invertebrates and vertebrates; 2) horizontal genetic transferences and the importance of viruses in host adaptation and evolution; 3) the role of non coding DNA and non-transcriptional genes; 4) homeotic evolution and the limitations of gradual evolution; and 5) excessive emphasis on extrinsic barriers to animal speciation. This paper reviews each of these topics in an effort to contribute to a better comprehension of organic evolution. Molecular findings suggest the need for a new evolutionary synthesis. PMID- 21249302 TI - Infection and invasion mechanisms of Trypanosoma cruzi in the congenital transmission of Chagas' disease: a proposal. AB - Chagas' disease is produced by the haemophlagelated protozoan Trypanosoma cruzi and transmitted by haematophages insects such as Triatoma infestans (vinchuca). Due to vector control, congenital transmission gains importance and is responsible for the presence and expansion of this disease in non-endemic areas. The mechanisms of congenital infection are uncertain. It has been suggested that the parasite reaches the fetus through the bloodstream by crossing the placental barrier, and that congenital Chagas' disease is the result of complex interactions between the immune response, placental factors, and the parasite's characteristics. We review the cellular and molecular mechanisms of infection and invasion of the parasite and how immune and placental factors may modulate this process. Finally, we propose a possible model for the vertical transmission of Chagas' disease. PMID- 21249303 TI - Betamethasone inhibits tumor development, microvessel density and prolongs survival in mice with a multiresistant adenocarcinoma TA3. AB - Tumor resistance to traditional cancer treatments poses an important challenge to modern science. Thus, angiogenesis inhibition is an important emerging cancer treatment. Many drugs are tested and corticosteroids have shown interesting results. Herein we investigate the effect on microvessel density, survival time and tumoral volume of mice with TA3-MTX-R tumors. Twenty six mice were inoculated with l x l06 tumor cells; 4-5 days after injection, six mice were injected with PBS (group A) and twenty mice were treated with beta-met (group B). All animals from Group A died on day 22. Group B was divided into Bl (treated discontinued) and B2 (treated daily) and observed until day 88. All mice were processed for histo-immunohistochemical analysis and the blood vessels were counted. A decrease in microvessel density and tumoral volume and longer survival times were observed in the treated group. We propose that the antiangiogenic beta-met effect explains, at least partially, its tumor inhibitory properties. As an important perspective, we will experimentally combine these strategies with those recently described by us with regard to the important antiangiogenic-antitumor effects of Trypanosoma cruzi calreticulin. Since the molecular targets of these strategies are most likely different, additive or synergic effects are envisaged. PMID- 21249304 TI - Chagas disease: Present status of pathogenic mechanisms and chemotherapy. AB - There are approximately 7.8 million people in Latin America, including Chile, who suffer from Chagas disease and another 28 million who are at risk of contracting it. Chagas is caused by the flagellate protozoan Trypanosoma cruzi. It is a chronic disease, where 20%-30% of infected individuals develop severe cardiopathy, with heart failure and potentially fatal arrhythmias. Currently, Chagas disease treatment is more effective in the acute phase, but does not always produce complete parasite eradication during indeterminate and chronic phases. At present, only nifurtimox or benznidazole have been proven to be superior to new drugs being tested. Therefore, it is necessary to find alternative approaches to treatment of chronic Chagas. The current treatment may be rendered more effective by increasing the activity of anti-Chagasic drugs or by modifying the host's immune response. We have previously shown that glutathione synthesis inhibition increases nifurtimox and benznidazole activity. In addition, there is increasing evidence that cyclooxygenase inhibitors present an important effect on T. cruzi infection. Therefore, we found that aspirin reduced the intracellular infection in RAW 264.7 cells and, decreased myocarditis extension and mortality rates in mice. However, the long-term benefit of prostaglandin inhibition for Chagasic patients is still unknown. PMID- 21249305 TI - Cyclosporin A-treated dendritic cells may affect the outcome of organ transplantation by decreasing CD4+CD25+ regulatory T cell proliferation. AB - One of the mechanisms for generation of tolerance involves immature dendritic cells (DCs) and a subpopulation of regulatory CD4+ CD25+ T lymphocytes (T REG). The purpose of this work was to analyze how Cyclosporine A (CsA), a widely used immunosuppressive drug, may affect T REG proliferation. Purified and activated murine DCs obtained from bone marrow precursors differentiated with rGMCSF were co-cultured with purified CFSE-labeled T REG from OTII mice, and their phenotype and proliferation analyzed by flow cytometry. Our data indicate that DCs differentiated in the presence of CsA show an altered phenotype, with a lower expression of MHC-II and a lower activating capacity. Additionally, these CsA treated DCs show decreased production of IL-2 and IL-12 and increased IL-10 secretion when stimulated with LPS, indicating an effect on the polarization of the immune response. Interestingly, CsA-treated DCs show an anti-tolerogenic effect since they reduce the proliferation of T REG cells from 72 to 47%. Further inhibition to a 24% of T REG proliferation was obtained as a direct effect of CsA on T REG. In conclusion, the anti-tolerogenic effect of CsA should be considered in the planning of immunosuppression in the context of clinical transplantation. PMID- 21249306 TI - Histocompatibility and immunogenetics in cord blood transplantation. AB - This review of the immunogenetics of cord blood transplantation attempts to highlight the connections between classical studies and conclusions of the tissue transplantation field as a scholarly endeavor, exemplified by the work of Professor Hoecker, with the motivations and some recent and key results of clinical cord blood transplantation. The authors review the evolution of understanding of transplantation biology and find that the results of the application of cord blood stem cells to Transplantation Medicine are consistent with the careful experiments of the pioneers in the field, from the results of tumor and normal tissue transplants, histocompatibility immunogenetics, to cell and molecular biology. Recent results of the National Cord Blood Program of the New York Blood Center describe the functioning in cord blood transplantation of factors, well known in transplantation immunogenetics, like the Fl anti-parent effect and the tolerance-like status of donors produced by non-inherited maternal HLA antigens. Consideration of these factors in donor selection strategies can improve the prognosis of transplantation by characterizing "permissibility" in HLA-incompatible transplantation thereby increasing the probability of survival and reducing the likelihood of leukemic relapse. PMID- 21249307 TI - Sexual orientation, handedness, sex ratio and fetomaternal tolerance-rejection. AB - Fraternal birth order (FBO) appears as a prenatal cause of 15% of homosexual males (gays) through mnemonic maternal anti-male factors. Non-right-handed men seem to be protected from homosexuality. Four hypotheses are proposed: (1) androgenic factors of non-right-handedness neutralize anti-male factors; (2) non right-handedness and homosexuality are lethal or produce mental impairment; (3) non-right-handed male embryos are insensitive to anti-male factors; (4) mothers of non-right-handed fetuses do not produce anti-male factors. Studies of the sex ratio (SR) of older and younger siblings show: (1) a significant heterogeneity in the SR of siblings of right or non-right handed heterosexual men and women; (2) lesbians are born among siblings with high SR; (3) siblings of right-handed gays show a higher SR than non-right-handed gays that present a low SR. Based on our discovery of maternal tolerance-rejection processes, associated with genetic systems (ABO, Rh), where zygotes or embryos different from their mother induce better pregnancy and maternal tolerance than do those that share antigens with their mothers, I propose a new explanation for sexual relationships, sexual orientation, handedness and sibling SR. Lesbian embryos could induce tolerance from mothers with anti-female factors. Non-right-handedness could induce maternal tolerance, or change the maternal compatibility of "gay" embryos. Alternatively, gay embryos could be poor inducers of maternal tolerance towards male traits. PMID- 21249308 TI - Chronic toxicity bioassay with populations of the crustacean Artemia salina exposed to the organophosphate diazinon. AB - A chronic toxicity bioassay was conducted with the microcrustacean Artemia salina as the testing organism for the toxic organophosphate diazinon in order to determine if the species is an appropriate indicator of pollution in aquatic environments. Tests of animal exposure to different concentrations of the toxicant were performed for 24, 48 and 72 hours after larvae hatching. Registered mortality data was used to obtain the lethal dose 50 (LD50) of the organophosphate for each exposure time, considering the immobilization of A. salina larvae as the mortality parameter. The lethal concentration (LD50) in the same exposure times was calculated by evaluating morphological changes on the three initial stages of larval development. Both doses were determined by using probit statistical analysis. Results indicate greater dose-response exactitude after 24 hours of exposure to the toxicant. High sensitivity of the organism to the toxicant was determined, thus indicating that A. salina is an appropriate ecotoxicological bioindicator of aquatic environments polluted with pesticides, with the special consideration that this species is a natural resident of saline water bodies, and thus could be used to control pollution in these environments as a result of the unrestrained usage of such toxic substances. PMID- 21249309 TI - Cytoprotective and suicidal signaling in oxidative stress. AB - Oxidative stress is an imbalance between pro-oxidants and antioxidants in favor of the pro-oxidants, leading to different responses depending on the level of pro oxidants achieved and the duration of exposure. In this article, we discuss the cytoprotective or suicidal signaling mechanisms associated with oxidative stress by addressing: (i) the development of an acute and mild pro-oxidant state by thyroid hormone administration eliciting the redox upregulation of the expression of proteins affording cell protection as a preconditioning strategy against ischemia-reperfusion liver injury; and (ii) the role of prolonged and severe oxidative stress and insulin resistance as determinant factors in the pathogenesis of non-alcoholic fatty liver disease associated with obesity. PMID- 21249310 TI - Inhibitory action of Celastrol on hypoxia-mediated angiogenesis and metastasis via the HIF-1alpha pathway. AB - Celastrol, a natural biologically active compound isolated from Tripterygium wilfordii Hook F root extracts, has been shown to possess antitumor properties and therefore, is an interesting candidate for the development of novel chemotherapeutic cancer agents. In this study, we have demonstrated that Celastrol is a potent inhibitor of hypoxia-induced angiogenic and metastatic activity as shown by a decrease in the proliferation of both endothelial and cancer cells, blocking of migration as well as of tube formation of endothelial cells, and by inhibition of cancer cell invasion under hypoxic conditions. Moreover, Celastrol decreased hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA levels under both normoxia and hypoxia and inhibited hypoxia-induced accumulation of nuclear HIF-1alpha protein. Meanwhile, inhibition of nuclear HIF-1alpha protein levels were accompanied by a reduction in the transcriptional activity of HIF-1alpha target genes, including VEGF. In addition, the inhibitory effect of Celastrol on HIF-1alpha protein was partly due to its suppression of HSP90 activity. We conclude that Celastrol regulates HIF-1alpha at multiple levels that may together or individually contribute to its antitumor activity against hypoxia induced angiogenesis and metastasis. PMID- 21249311 TI - Enhancement of radiation sensitivity in lung cancer cells by celastrol is mediated by inhibition of Hsp90. AB - The radiosensitizing activity of celastrol, a quinone methide triterpene was examined. We found that celastrol treatment of the NCI-H460 lung cancer cell line increased radiation-induced cell killing. The increased radiosensitivity was correlated with decreased levels of Hsp90 clients, such as EGFR, ErbB2 and survivin as well as with increased p53 expression. Celastrol inhibited the ATP binding activity of Hsp90. Furthermore, celastrol treatment dissociated an Hsp90 client protein, EGFR, and this in turn resulted in degradation of the client protein. These results were not observed with another structurally similar triterpenoid, 6beta-acetonyl-22beta-hydroxytingenol (TG), suggesting that a specific structural feature of the triterpenoid is required for radiosensitization. Moreover celastrol treatment increased p53 levels by phosphorylating Ser15 and Ser20 residues as well as by inhibiting its proteasomal degradation. Celastrol may be considered an effective radiosensitizer acting as an inhibitor of Hsp90 and a p53 activator. The two activities could be applicable to a broad range of cancer cells with either wild-type or mutant p53 because either activity could be effective for the enhancement of radiation cell killing. Further analysis with other triterpenoids should identify the functional moiety of the structure and additional candidates for effective radiosensitizers, which can be used in combined radiotherapy. PMID- 21249312 TI - Role of tumor necrosis factor-alpha in the pathogenesis of indomethacin-induced small intestinal injury in mice. AB - The pathogenesis of small intestinal damage caused by non-steroidal anti inflammatory drugs (NSAIDs) such as indomethacin is still unclear. For this reason, there is currently no therapeutic strategy for ameliorating such damage. On the other hand, molecular treatment strategies targeting tumor necrosis factor (TNF)-alpha exert beneficial effects on intestinal lesions in patients with inflammatory bowel disease (IBD). To clarify the participation of TNF-alpha in NSAID-induced small intestinal damage, we investigated the effects of indomethacin administration in mice with targeted deletion of the TNF-alpha gene. Indomethacin (10 mg/kg) was administered subcutaneously to male C57BL/6 (wild type: WT) mice and TNF-alpha-deficient (TNF-alpha-/-) mice to induce small intestinal damage. The ulcer score, the tissue-associated myeloperoxidase (MPO) activity as an index of neutrophil infiltration, and the expression of keratinocyte chemoattractant (KC) mRNA in the small intestinal mucosa were measured. In addition, we performed a TUNEL assay to evaluate indomethacin induced apoptosis of intestinal epithelial cells and measured the expression of caspase-3 protein and Bcl-2 mRNA. The ulcer score, MPO activity, and expression of KC mRNA were significantly increased after indomethacin administration. These increases were significantly inhibited in TNF-alpha-/- mice compared with WT mice. Apoptotic cells were observed by the TUNEL assay in the area of the ulcerative lesion, and they were significantly fewer in TNF-alpha-/- mice compared with WT mice. The expression of cleaved caspase-3 protein was induced by indomethacin administration, and significantly inhibited in TNF-alpha-/- mice compared with that of WT mice. The expression level of Bcl-2 mRNA in indomethacin treated TNF-alpha-/- mice was significantly higher than that in WT mice. TNF alpha plays an important role in the pathogenesis of indomethacin-induced small intestinal damage. These results suggest that TNF-alpha could become a new therapeutic target for NSAID-induced small intestinal damage. PMID- 21249313 TI - Involvement of Cyr61 in the growth, invasiveness and adhesion of esophageal squamous cell carcinoma cells. AB - Cysteine-rich 61 (Cyr61), a secreted protein which belongs to the CCN family, has been found to be differentially expressed in many cancers and to be involved in tumor progression. The expression of Cyr61 in esophageal squamous cell carcinoma (ESCC) has only recently been described, but the roles of Cyr61 in ESCC cells still remained unclear. In this study, we have shown that there are high levels of Cyr61 in ESCC cell lines. Furthermore, using RNA interference (RNAi), we stably silenced the expression of Cyr61 in EC109 cells, an ESCC cell line. The colony formation, MTT, cell migration, cell invasiveness and cell adhesion assays were employed to address the roles of Cyr61 in the growth, migration and adhesion of ESCC cells. The results have shown that Cyr61 knockdown by RNAi leads to a significant reduction of colony formation and cell growth. The migration and invasiveness ability of EC109 cells were also suppressed with the Cyr61 down regulation. Furthermore, the adhesion of the EC109 cells was decreased in the Cyr61 knockdown cells compared to the control cells. Taken together, our data suggest that Cyr61 may play crucial roles in regulating neoplasm progression of ESCC. PMID- 21249314 TI - Vaccinia virus GLV-1h237 carrying a Walker A motif mutation of mouse Cdc6 protein enhances human breast tumor therapy in mouse xenografts. AB - Recently it was shown that recombinant vaccinia virus GLV-1h68 is a promising tool for treating different type of cancers in animal models. The goal of the present study was to enhance the oncolytic potential of GLV-1h68 without decreasing its safety. A derivative of GLV-1h68 containing the gene for a Walker A motif mutant of the essential cell cycle protein Cdc6, GLV-1h237, was engineered. The characteristics of GLV-1h237 and its efficiency in treating human breast cancer GI-101A cells were compared with that of GLV-1h236 (carrying the wild-type gene for Cdc6), GLV-1h71 (a derivative of GLV-1h68) and GLV-1h68, respectively. RT-PCR and immunoblot analyses revealed that Cdc6 is efficiently overexpressed in GLV-1h237-infected GI-101A cells. GLV-1h237 was found to have higher replication efficiency and enhanced cytotoxity than GLV-1h68 in cell culture. In the GI-101A tumor xenograft animal model, GLV-1h237 turned out to be the most potent oncolytic virus strain investigated. A single i.v. injection of GLV-1h237 resulted in enhanced anti-tumor activity compared to GLV-1h68 concomitant with a high tumor selectivity and a comparable safety profile. Thus, the strategy to combine oncolytic virotherapy with agents that interfere with host cell DNA synthesis is a promising approach for effective cancer therapy. PMID- 21249315 TI - Tumor-associated MUC5AC stimulates in vivo tumorigenicity of human pancreatic cancer. AB - MUC5AC, a high molecular weight glycoprotein, is overexpressed in the ductal region of human pancreatic cancer but is not detectable in the normal pancreas, suggesting its association with disease development. In the present study, we investigated the in vitro and in vivo effects of MUC5AC knockdown by short interfering RNA (siRNA) in the MUC5AC-overexpressing SW1990 and BxPC3 human pancreatic cancer cell lines in order to clarify its function. Significant decreases in the expression levels of MUC5AC mRNA and protein were observed in SW1990 and BxPC3 cells that had been stably transfected with a MUC5AC siRNA expression vector (SW1990/si-MUC5AC and BxPC3/si-MUC5AC cells) compared to those in cells transfected with an si-mock vector (SW1990/si-mock and BxPC3/si-mock cells). In in vitro studies, neither type of MUC5AC-knockdown cell showed any difference in cell survival, proliferation, or morphology from the si-mock cells or parental cells. However, in vivo xenograft studies demonstrated that MUC5AC knockdown significantly reduced the tumorigenicity and suppressed the tumor growth of si-MUC5AC cells compared to those of the si-mock cells. Immunohistochemical analysis revealed that CD45R/B220+ and Gr-1+ cells had infiltrated into the tumor tissue of the SW1990/si-MUC5AC cells. Furthermore, cancer-associated antigen specific antibodies were detected at high levels in the sera from the SW1990/si-MUC5AC cell-bearing mice. These results suggest that tumor-associated MUC5AC expressed on the surface of pancreatic cancer cells supports the escape of pancreatic cancer cells from immunosurveillance. The present findings highlight a new dimension of MUC5AC as a functional immunosuppressive agent and its important role in pancreatic cancer progression. PMID- 21249316 TI - Synergistic effects of imatinib and carboplatin on VEGF, PDGF and PDGF Ralpha/beta expression in squamous cell carcinoma of the head and neck in vitro. AB - Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy. The development of new treatment modalities in order to improve long term survival of patients with HNSCC is imperative. Numerous studies have demonstrated that carcinogenesis and tumor cell dissemination is influenced by the tumor microenvironment. The protein-kinase-receptors (PTKs) are essential elements of the intracellular signal transduction pathway and regulate cell growth, development and apoptosis. Cell proliferation, migration, induction of tumor vascularization and carcinogenesis, invasion is regulated by a variety of angiogenic factors, such as PDGF (platelet-derived growth factor), VEGF (vascular endothelial growth factor) and their respective tyrosine kinase receptors (PDGF-R and VEGF-R). They present promising targets for anti-cancer therapy through abrogation of impaired signaling pathways. Indeed, imatinib, a small molecule drug targeting these protein kinases, has antiproliferative effects in several cancer types. The purpose of this study was to investigate the potential synergism of imatinib and carboplatin on the expression of PDGF, PDGF-R alpha/beta and VEGF in different HNSCC cell lines. Several tumor cell lines were subjected to increasing concentrations of carboplatin (3 and 7.5 umol/l) and imatinib (18 and 30 umol/l) and ELISA, immunohistochemical methods and RQ-PRC after 48, 72, 120 and 240 h were used to assess their expression levels. While PDGF-Ralpha/beta expression was unimpaired at lower imatinib concentrations (18 umol/l), PDGF-Ralpha/beta expression was suppressed at 30 umol/l, and suppression was enhanced by the presence of carboplatin. By RQ-PCR, a significant reduction of PDGF-Ralpha/beta expression was detected (p<0.5). We observed explicit significant reduction in VEGF levels with increasing concentrations of imatinib and with the combination of the two chemotherapeutic drugs (p<0.5). We report for the first time evidence of synergism of imatinib and carboplatin in suppressing VEGF, PDGF and PDGF-Ralpha/beta expression in HNSCC. PMID- 21249317 TI - Intraperitoneal administration of an adenovirus vector carrying REIC/Dkk-3 suppresses peritoneal dissemination of scirrhous gastric carcinoma. AB - Expression levels of the novel tumor suppressor gene REIC/Dkk-3 are reduced in many human cancers. We have previously showed that an adenovirus vector carrying REIC/Dkk-3 (Ad-REIC) induced apoptosis of cancer cells selectively and exerted bystander antitumor effects via ER stress. We examined possible effects of Ad REIC in a peritoneal dissemination model of scirrhous gastric carcinoma (SGC). Among various types of gastric cancer, SGC continues to be associated with the worst prognosis due to a high incidence of metastases in the peritoneal cavity. We found that a single intraperitoneal injection of Ad-REIC suppressed tumor dissemination and disease progression. Immunomodulation by Ad-REIC led to recruitment of natural killer cells inside tumor nodules. We conclude that Ad REIC gene therapy may be a potential tool in combinatorial approaches to achieve curative effects in SGC. PMID- 21249318 TI - Hyperglycemia enhances the invasive and migratory activity of pancreatic cancer cells via hydrogen peroxide. AB - Diabetes mellitus and pancreatic cancer are intimately related. Hyperglycemia, a chronic abnormality in diabetes, has been proved to be an independent predictor of mortality from cancer of the pancreas. However, little is known regarding the effect of hyperglycemia on pancreatic cancer cells. The aim of the present study was to evaluate whether increases in glucose concentration modulate the invasive and migratory potential of cancer cells, contributing to their enhanced metastatic behavior. Human pancreatic cancer cells BxPC-3 and Panc-1 were cultured in 5.5, 25 or 55 mM glucose for 12, 24 or 48 h in the absence or presence of superoxide dismutase and catalase. The intracellular reactive oxygen species were determined using 2,7-dichlorodihydrofluorecein diacetate. Wound healing assay and transwell invasion assay were used to detect the migratory and invasive potential of cancer cells. The invasion-related factor, urokinase plasminogen activator, was measured by RT-PCR and Western blot analysis. The production of reactive oxygen species was increased by glucose in a concentration dependent manner. High glucose significantly enhanced the cell migration and invasion potential. Meanwhile, the expression of urokinase plasminogen activator was also increased. Superoxide dismutase-dependent production of hydrogen peroxide led to increased cell invasive and migratory ability and the expression of urokinase plasminogen activator. These increases were reversed by the hydrogen peroxide-detoxifying enzyme catalase. These results suggest that the association between hyperglycemia and poor prognosis in pancreatic cancer can be attributed to the alterations of the migratory and invasive ability of the cells through the production of hydrogen peroxide. PMID- 21249319 TI - Expression of TGFbeta1 and its receptors is associated with biological features of ovarian cancer and sensitivity to paclitaxel/carboplatin. AB - It has been suggested that expression of TGFbeta1 and its receptors [TGFbeta receptor type I (TbetaRI) and TGFbeta receptor type II (TbetaRII)] may play a key role in the proliferation and progression of epithelial ovarian cancer. We investigated the biological significance of TGFbeta1 and its receptors, as well as their association with the tumor response to paclitaxel (PTX) and carboplatin (CBDCA). We studied 24 patients with ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who had undergone surgery and chemotherapy with PTX and CBDCA. Tissues from the primary tumor were examined and the expression of TGFbeta1, TbetaRI, and TbetaRII mRNA was assessed by the RNase protection assay. It was found that TGFbeta1 mRNA expression was significantly lower in the tumors of patients who had optimal surgery than in the tumors of patients with suboptimal surgery. TGFbeta1 mRNA expression was also significantly lower in tumors with high sensitivity to PTX and CBDCA than in those with low sensitivity. TbetaRI mRNA expression was not associated with any clinicopathological factors. Expression of TbetaRII mRNA was significantly higher in clear cell adenocarcinoma and mucinous adenocarcinoma, while it was lower in serous adenocarcinoma and endometrioid adenocarcinoma. Moreover, it tended to be higher in early-stage tumors compared with advanced tumors. Among TGFbeta1, TbetaRI, and TbetaRII, expression of TGFbeta1 mRNA was most strongly associated with progression-free survival. When the prognosis of the patients with advanced cancer was compared on the basis of TGFbeta1 mRNA expression, those whose tumors showed low expression tended to have a better prognosis than those whose tumors showed high expression. It is suggested that TGFbeta1 mRNA expression is an indicator of tumor sensitivity to standard therapy with PTX and CBDCA, that it can identify biologically aggressive and highly malignant tumors and that it can predict the prognosis of patients with ovarian cancer. PMID- 21249320 TI - Zoledronic acid, a third-generation bisphosphonate, inhibits cellular growth and induces apoptosis in oral carcinoma cell lines. AB - Bisphosphonates (BPs) inhibit bone resorption by preventing osteoclast maturation and apoptosis induction. Recently, BPs have also been shown to have antitumor effects against various types of carcinomas in vitro and in vivo. In this study, we investigated the antitumor effect of zoledronic acid (ZOL), a third generation bisphosphonate, on proliferation, cell cycle and apoptosis of oral cancer cells. Direct antitumor effects of ZOL against four oral carcinoma cell lines (squamous cell carcinoma, HSC3, HSC4, SCCKN; salivary adenocarcinoma, HSY) were measured by WST assay. Apoptosis-related molecules were analyzed by Western blot analysis and cell cycle was analyzed by flow cytometry. ZOL had a dose-dependent antitumor effect in the four oral cancer cell lines. ZOL activated caspase-3, -8 and -9 and induced cellular apoptosis. Western blot analysis showed that ZOL increased cleaved anti-human poly(ADP-ribose) polymerase expression and decreased Bcl-2 and Bid expression. Treatment with ZOL increased the number of cells in apoptosis, sub G1 phase and S phase, and reduced the number of cells in the G0/G1 and G2/M phase in a concentration-dependent manner. ZOL inhibits cell proliferation and induces apoptosis of oral cancer cells in vitro. These findings suggest that ZOL might be beneficial in the treatment of oral carcinoma patients. PMID- 21249321 TI - Down-regulation of MMP-2 expression due to inhibition of receptor tyrosine kinases by imatinib and carboplatin in HNSCC. AB - Squamous cell carcinoma of the head and neck (HNSCC) is the most common neoplasm arising in the upper aerodigestive tract. Unfortunately, the survival for this type of cancer has not improved significantly in the past 25 years. To enhance the survival rate multimodal therapy regimens have been set up. In these regimens chemotherapy plays a pivotal role in the majority of advanced cases. Transmembrane protein- tyrosine kinases (PTK) are fundamental elements of the signal transduction. In consequence, they might be promising targets for cancer therapy. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukemia. But imatinib also has an inhibitory impact on the PTK receptor c-kit and on its PTK activity. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). The ECM is altered by matrix metalloproteinases (MMP). In this study, we incubated different HNSCC cell lines with rising concentrations of imatinib and/or carboplatin. After an incubation time of up to 10 days, we evaluated c-kit, MMP-2 and MMP-14 by ELISA techniques and immunohistochemical methods. Especially the combination of 7.5 MUmol carboplatin with 30 MUmol imatinib resulted in a significant decrease in MMP-2 expression in all observed cell lines (p<0.05). We did not demonstrate a significant alteration in c-kit expression by imatinib and carboplatin. We observed an increase in apoptosis in HNSCC cells by the combination of the two observed chemotherapeutic drugs. In all cell lines tested, expression of c-kit and MMP could be demonstrated. Our results indicate that MMP 2 expression was suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially one keeping in mind the moderate toxicity of imatinib. PMID- 21249322 TI - Lactate dehydrogenase, Gleason score and HER-2 overexpression are significant prognostic factors for M1b prostate cancer. AB - It has not been elucidated whether certain types of M1b prostate cancer (M1b PC) are associated with a poor outcome. The present study retrospectively identified predictive factors related to the outcome of M1b PC. The subjects were 104 patients who attended our hospital and received a diagnosis of M1b PC. The observation period ranged from 4 to 122 months (median, 43 months). The parameters investigated were: T classification, N classification, Gleason score (GS), pretreatment prostate-specific antigen (PSA) level, extent of disease (EOD) grade, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), calcium, and hemoglobin (Hb) levels, platelet count, and the status of HER-2 overexpression as determined with a Hercep Test(TM) Kit using initial needle biopsy specimens for diagnosis. Log-rank test and Cox univariate analysis identified the following factors with statistically significant differences: pretreatment PSA >= 192, N1, GS >= 8, EOD grade 3+4, high LDH, high ALP, low Hb, and HER-2 overexpression. Multivariate Cox proportional hazard analysis identified the factors GS >= 8, high LDH, and HER-2 overexpression with significant differences. The hazard ratio was 5.962, 2.465, and 2.907, respectively, and the probability value was P=0.0218, P=0.0207 and P=0.0090, respectively. When the subjects with GS >= 8, high LDH, and HER-2 over-expression were classified as the high-risk group, the 5 year cause-specific survival rate was 51.2, 29.6, and 20.0%, respectively. The present study showed that M1b PC patients with GS >= 8, high LDH, and HER-2 overexpression have a very poor outcome and thus, should be treated as a high risk group requiring close follow-up. PMID- 21249323 TI - Anti-protein-bound polysaccharide-K monoclonal antibody binds the active structure and neutralizes direct antitumor action of the compound. AB - Protein-bound polysaccharide K (PSK) is extracted and purified from Coriolus versicolor (CM101), and is used as an anti-cancer agent. In this study, focusing on the direct actions of PSK, we investigated whether PSK reaches tumor and immune tissues with its active structure remaining intact, and the direct action of PSK was evaluated by its antitumor effects against MethA fibrosarcomas implanted in immunodeficient NOD/SCID mice. The results obtained suggest that PSK reaches the tumor tissue in its active form and exhibits antitumor effects against MethA cells. PMID- 21249324 TI - [Optimal timing of operations to treat fractures of the femoral neck with endoprotheses : CRP as a parameter of postoperative immunologic reaction]. AB - BACKGROUND: The optimal time to perform endoprosthesis of hip fractures in the elderly is still under discussion. CRP as an objective marker of postoperative inflammatory reaction should give an indication if early or late surgery is favored. METHODS: CRP values from 122 patients with no complications after hip arthroplasty of femoral neck fractures were analyzed in context with the time between the trauma and the operation. RESULTS: In early surgery within 24 h after trauma the CRP values were significantly lower than in delayed surgery. CONCLUSION: The lower postoperative inflammatory reaction after early surgery of hip fractures provides a better outcome when treated with arthroplasty. PMID- 21249325 TI - [Open abdomen 2009. A national survey of open abdomen treatment in Germany]. AB - BACKGROUND: Open abdomen (OA) treatment has been established worldwide. This survey examines the current status of OA treatment in Germany. MATERIAL AND METHODS: A national survey was conducted between October 2008 and September 2009 by questionnaires sent to 1,219 surgical departments. Data were evaluated descriptively. RESULTS: The response rate was 38% overall and 69% for university departments. Open abdomen treatment is used by 94% of all respondents. Most commonly used are staged abdominal lavage (87%), a commercial abdominal dressing system (82%), planned ventral hernia (69%), and other intra-abdominal dressings (e.g. vacuum pack 15%, Bogota bag 5%). Nearly half of the respondents (46%) indicated a modification of their strategy towards vacuum techniques during the last 5 years. CONCLUSIONS: Open abdomen procedures are widely used in German surgical departments. This survey indicates a shift of treatment strategies towards vacuum techniques but even though predominant, the effectiveness and safety of these techniques must still be confirmed by prospective controlled trials. This survey helps to identify relevant clinical questions and enables focused trial networking. PMID- 21249326 TI - [Conventional vs pathogen-inactivated platelet concentrates for the treatment of perioperative coagulopathy. A prospective cohort study]. AB - BACKGROUND: The aim of the present study was to assess ex-vivo function of pathogen-inactivated versus conventional platelet concentrates (PC) in the perioperative setting. MATERIAL AND METHODS: A total of 30 patients who underwent cardiac surgery and who postoperatively depended on the transfusion of two platelet concentrates were enrolled into this study. Of the patients 15 received conventional buffy coat PC (conv. PC) and 15 received pathogen-inactivated PC (PI PC). Age, volume and platelet content of each PC were recorded. Before (T0) and 30 min after PC transfusion (T1), blood samples were taken and platelet function analyses (MEA) and conventional laboratory coagulation analyses were performed. The transfusion-associated increment of platelet concentration (increment) and the corrected count increment (CCI) were assessed at timepoint T1. RESULTS: There were no significant group differences between the groups in MEA analyses or conventional laboratory at T0 or T1. The platelet content per PC was significantly higher in the PI-PC group [3.3 (3.1/3.5)* 10(11) platelets per PI PC versus 3 (2.9/3)* 10(11) platelets per conv. PC, p<0.001]. Platelet increment (42+/-27*10(9)/l versus 69.4+/-29*10(9)/l, p=0.013) was significantly lower in the PI-PC group. CONCLUSION: Whereas ex-vivo analyses of platelet function did not show any group differences at T1, a significantly lower increment was seen in the pilot study after transfusion of PI-PC as compared to conventional PC. PMID- 21249327 TI - [Pathophysiological basis of surgery-linked sepsis]. AB - Infection or injury, including surgical procedures, induces an inflammatory response of the host organism. This immune response must be finely tuned and precisely regulated, because deficiencies or excesses of the inflammatory response cause morbidity and shorten the lifespan. Activated receptors of the innate immune system (pattern recognition receptors, PRRs), which recognize pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) including injured tissue-associated intracellular proteins (alarmins), lead to an exaggerated immune response. This is characterized by a complex interplay of cytokines, chemokines, complement and coagulation factors as well as inflammatory and immune regulatory cells. There is increasing recognition that the major pathophysiologic event in sepsis is the progression from the initial hyperinflammatory state to an immunosuppressive state in which the host is unable to eradicate invading pathogens and particularly prone to develop secondary nosocomial infections and organ damage. Surgical trauma-associated immune dysfunction per se predisposes the host to surgery-related sepsis. Immune suppression is mediated by massive apoptosis-induced depletion of lymphocytes and dendritic cells, decreased expression of the cell surface antigen complex HLA-DR and increased expression of negative costimulatory molecules. Besides increased numbers of regulatory T cells there is a shift from a phenotype of inflammatory Th1 cells to an antiinflammatory phenotype of Th2 cells characterized by the production of interleukin-10. Key mediators of sepsis are HMGB1, MIF and complement factor C5a. With the identification of central pathomechanistic events, e.g. amplification of the coagulation, complement and inflammation cascades, immune dysbalance and neuroimmunomodulation via the cholinergic anti inflammatory reflex, the opportunity now exists to apply these insights to the development of new and novel therapeutics aimed at modulating rather than inhibiting the systemic host response to infection. PMID- 21249328 TI - [The carotid artery as recipient vessel: troubleshooting for free jejunal transfer after esophagectomy in preradiated patients]. AB - BACKGROUND: In the treatment of esophageal cancer neoadjuvant radiotherapy often leads to vascular damage of the usual recipient arteries for free jejunal transfer. End-to-side anastomosis to the carotid artery could be a potential alternative. PATIENTS AND METHODS: A total of 70 patients with locally advanced carcinoma of the esophagus underwent esophagectomy after neoadjuvant radiochemotherapy. In all patients reconstruction was carried out with a free jejunal transfer. Smaller vessels could be used for anastomoses in 54 of these patients and in 16 cases the jejunal flap artery was attached to the carotid artery. RESULTS: Out of 54 patients 9 (17%) with microvascular anastomoses to the smaller vessels needed surgical intervention for ischemia. In 16 patients with anastomosis to the carotid artery no significant failure of perfusion occurred. CONCLUSION: The carotid artery as recipient vessel in free jejunal transfer seems to be a safe therapeutic option for intestinal reconstruction of preradiated esophageal cancer with good functional results. PMID- 21249329 TI - Regression and stabilization of advanced murine atherosclerotic lesions: a comparison of LDL lowering and HDL raising gene transfer strategies. AB - Both reductions in atherogenic lipoproteins and increases in high-density lipoprotein (HDL) levels may affect atherosclerosis regression. Here, the relative potential of low-density lipoprotein (LDL) lowering and HDL raising gene transfer strategies to induce regression of complex murine atherosclerotic lesions was directly compared. Male C57BL/6 LDL receptor (LDLr)(-/-) mice were fed an atherogenic diet (1.25% cholesterol and 10% coconut oil) to induce advanced atherosclerotic lesions. A baseline group was killed after 6 months and remaining mice were randomized into a control progression (Adnull or saline), an apolipoprotein (apo) A-I (AdA-I), an LDLr (AdLDLr), or a combined apo A-I/LDLr (AdA-I/AdLDLr) adenoviral gene transfer group and followed-up for another 12 weeks with continuation of the atherogenic diet. Gene transfer with AdLDLr decreased non-HDL cholesterol levels persistently by 95% (p < 0.001) compared with baseline. This drastic reduction of non-HDL cholesterol levels induced lesion regression by 28% (p < 0.001) in the aortic root and by 25% (p < 0.05) in the brachiocephalic artery at 12 weeks after transfer. Change in lesion size was accompanied by enhanced plaque stability, as evidenced by increased collagen content, reduced lesional macrophage content, a drastic reduction of necrotic core area, and decreased expression of inflammatory genes. Elevated HDL cholesterol following AdA-I transfer increased collagen content in lesions, but did not induce regression. Apo A-I gene transfer on top of AdLDLr transfer resulted in additive effects, particularly on inflammatory gene expression. In conclusion, drastic lipid lowering induced by a powerful gene transfer strategy leads to pronounced regression and stabilization of advanced murine atherosclerosis. PMID- 21249330 TI - [Clinical evaluation of subarachnoid hemorrhaging]. AB - The classical symptoms of subarachnoid hemorrhaging are acute severe headache, stiff neck, confusion and often vegetative symptoms up to severe cardiac functional disorders. The extent of confusion is variable and correlates with the severity of the disease. Clinical signs are often loss of feeling in cranial nerves which can be indicative not only of the localization of the aneurysm but also of increased brain pressure. Terson's syndrome of vitreous hemorrhaging is indicative of a poor prognosis.Neurological focal symptoms are indicative of intraparenchymal hemorrhage but accompanying cramp attacks often occur independently. Subarachnoid hemorrhaging can present as a transient neurological symptomatic without relevant headache particularly in elderly patients. Despite substantial research activity the prognosis remains as before dependent on the initial clinical symptomatic, as previously described by Hunt and Hess in 1968. Assessment of the severity is nowadays often made in combination with the Glasgow coma scale (GCS). PMID- 21249332 TI - Zoledronic acid results in better health-related quality of life following hip fracture: the HORIZON-Recurrent Fracture Trial. AB - This study evaluated the benefits of ZOL versus placebo on health-related quality of life (HRQoL) among patients from HORIZON-RFT. At month 24 and end of the study visit, ZOL significantly improved patients' overall health state compared to placebo as assessed by the EQ-5D VAS. INTRODUCTION: To evaluate the benefits of zoledronic acid (ZOL) versus placebo on health-related quality of life (HRQoL) among patients from The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Recurrent Fracture Trial (HORIZON-RFT). METHODS: In this randomized, double-blind, placebo-controlled trial, 2,127 patients were randomized to receive annual infusion of ZOL 5 mg (n = 1,065) or placebo (n = 1,062) within 90 days after surgical repair of low-trauma hip fracture. HRQoL was measured using EQ-5D Visual Analogue Scale (VAS) and utility scores (EuroQol instrument) at months 6, 12, 24, 36, and end of the study visit. Analysis of covariance model included baseline EQ-5D value, region, and treatment as explanatory variables. RESULTS: At baseline, patients (mean age 75 years; 24% men and 76% women) were well matched between treatment groups with mean EQ-5D VAS of 65.82 in ZOL and 65.70 in placebo group. At the end of the study, mean change from baseline in EQ-5D VAS was greater for ZOL vs. placebo in all patients (7.67 +/- 0.56 vs. 5.42 +/- 0.56), and in subgroups of patients experiencing clinical vertebral fractures (8.86 +/- 4.91 vs. -1.69 +/- 3.42), non-vertebral fractures (5.03 +/- 2.48 vs. -1.07 +/- 2.16), and clinical fractures (5.19 +/- 2.25 vs. 0.72 +/- 1.82) with treatment difference significantly in favor of ZOL. EQ-5D utility scores were comparable for ZOL and placebo groups, but more patients on placebo consistently had extreme difficulty in mobility (1.74% for ZOL vs. 2.13% for placebo; p = 0.6238), self-care (4.92% vs. 6.69%; p = 0.1013), and usual activities (10.28% vs. 12.91%; p = 0.0775). CONCLUSION: ZOL significantly improves HRQoL in patients with low-trauma hip fracture. PMID- 21249334 TI - Phylogenetics. AB - The recent rapid expansion in the DNA and protein databases, arising from large scale genomic and metagenomic sequence projects, has forced significant development in the field of phylogenetics: the study of the evolutionary relatedness of the planet's inhabitants. Advances in phylogenetic analysis have greatly transformed our view of the landscape of evolutionary biology, transcending the view of the tree of life that has shaped evolutionary theory since Darwinian times. Indeed, modern phylogenetic analysis no longer focuses on the restricted Darwinian-Mendelian model of vertical gene transfer, but must also consider the significant degree of lateral gene transfer, which connects and shapes almost all living things. Herein, I review the major tree-building methods, their strengths, weaknesses and future prospects. PMID- 21249333 TI - Hip fractures in a city in Northern Norway over 15 years: time trends, seasonal variation and mortality : the Harstad Injury Prevention Study. AB - In this open population-based study from Northern Norway, there was no increase in hip fracture incidence in women and men from 1994 to 2008. Age-adjusted hip fracture rates was lower compared to reported rates from the Norwegian capital Oslo, indicating regional differences within the country. INTRODUCTION: The aim of the present population-based study was to describe age- and sex-specific incidence of hip fractures in a Northern Norwegian city, compare rates with the Norwegian capital Oslo, describe time trends in hip fracture incidence, place of injury, seasonal variation and compare mortality after hip fracture between women and men. METHODS: Data on hip fractures from 1994 to 2008 in women and men aged 50 years and above were obtained from the Harstad Injury Registry. RESULTS: There were altogether 603 hip fractures in Harstad between 1994 and 2008. The annual incidenc rose exponentially from 5.8 to 349.2 per 10,000 in men, and from 8.7 to 582.2 per 10,000 in women from the age group 50-54 to 90+ years. The age-adjusted incidence rates were 101.0 and 37.4 in women and men, respectively, compared to 118.0 in women (p = 0.005) and 44.0 in men (p = 0.09) in Oslo. The age-adjusted incidence rates did not increase between 1994-1996 and 2006-2008. The majority of hip fractures occurred indoors and seasonal variation was significant in fractures occurring outdoors only. After adjusting for age at hip fracture, mortality after fracture was higher in men than in women 3, 6 and 12 months (p <= 0.002) after fracture. CONCLUSIONS: There are regional differences in hip fracture incidence that cannot be explained by a north-south gradient in Norway. Preventive strategies must be targeted to indoor areas throughout the year and to outdoor areas in winter. PMID- 21249335 TI - Validated method for the determination of ethylglucuronide and ethylsulfate in human urine. AB - Detection of the alcohol metabolites ethylglucuronide (EtG) and ethylsulfate (EtS) has become routine in many forensic laboratories over the last few years. Most previously published methods using liquid chromatography coupled with electrospray tandem mass spectrometry require a post-chromatographic addition of solvent and/or extensive sample preparation prior to analysis. The aim of the study was to develop a simplified method. To 20 MUL urine, internal standard containing EtG-d5 and EtS-d(5) was added and the mixture was treated with elution buffer internal standard. EtG and EtS were separated using a Shimadzu Prominence high performance liquid chromatography (HPLC) system with a C18 separation column (Restek Ultra Aqueous C18, 4.6 * 150 mm, 5 MUm), using isocratic elution with a mobile phase consisting of 10 mM ammonium acetate buffer pH 7 (total run time, 6 min). The compounds were detected using an Applied Biosystems API 5000 liquid chromatography tandem mass spectrometry system (atmospheric pressure chemical ionization, multiple-reaction monitoring mode). The method was fully validated according to international guidelines. The assay was found to be selective for the compounds of interest. It was linear from 0.1 to 10 mg/L for all analytes (R(2) > 0.99). Matrix effects studies showed the presence of a slight but consistent ion enhancement (n = 10 different urine samples) at low concentrations and no effects at higher concentrations. Accuracy data were between 0.75% and 8.1% bias for EtG and between -5.0% and -11.3% bias for EtS. Precision data were between 4.3% and 6.9% relative standard deviations (RSD) for EtG and between 6.0% and 7.5% RSD for EtS. No instability was observed after repeated freezing and thawing. This fast, reliable, and accurate method enables the detection and quantification of alcohol metabolites in urine. The method is easier to use and more sensitive than previously published methods. PMID- 21249336 TI - Plastic matters: an analytical procedure to evaluate the degradability of contemporary works of art. AB - The most significant results concerning a chemical study to evaluate the degradability of polymeric components in four contemporary works of art, partially or completely realized in plastics, are presented and discussed in this paper. The procedure applied is mainly based on the use of Fourier transform IR and UV-vis spectroscopies and pyrolysis-gas chromatography/mass spectrometry, and consists of the following steps: (1) compositional analysis of the artworks, with particular attention to components which may have a negative effect on the overall ageing; (2) evaluation of the actual state of conservation; (3) investigation of the accelerated ageing of reference polymer samples; and (4) monitoring of the natural ageing of the artworks. On such a basis, the following could be concluded. Stage Evidence by Loris Cecchini is made of poly(ether urethane) elastomer which contains a high amount of phthalates. Their exudation gives a sticky appearance to the artwork and their removal during ageing is the main cause of the loss of flexibility. The latex used by Andres Pinal for tailoring Traxe de Home is a natural polyisoprene, whose oxidative degradation accounts for the extensive deterioration and yellowing of the artwork. The plaster sculptures of 3D Bodyscans 1:9 by Karin Sander are coated with an aliphatic epoxy resin. Its oxidation with formation of amides is the cause of the surface yellowing. The adhesive used by Dario Villalba for Tierra, Ladrillo y Agua is a commercial poly(vinyl acetate). Simulated photoageing suggests a fast deterioration due to deacetylation and cross-linking, which possibly is the main reason for the actual detachment of debris from the support. PMID- 21249337 TI - Development and applications of whole cell biosensors for ecotoxicity testing. AB - Whole cell biosensors are the focus of considerable and increasing interest worldwide as methods for detecting and quantifying environmental toxicity, including biochemical oxygen demand (BOD), heavy metals, antibiotics, pesticides and herbicides. This review follows the development of whole cell biosensors from attempts to utilise changes in cellular metabolism to determine BOD and general toxicity, through the exploitation of unique metabolic pathways to detect specific toxicants, to the increasingly widespread use of genetic engineering to build new, and modify existing, sensing pathways. PMID- 21249338 TI - Metabolism studies of the Kratom alkaloid speciociliatine, a diastereomer of the main alkaloid mitragynine, in rat and human urine using liquid chromatography linear ion trap mass spectrometry. AB - Mitragyna speciosa (Kratom) is currently used as a drug of abuse. When monitoring its abuse in urine, several alkaloids and their metabolites must be considered. In former studies, mitragynine (MG), its diastereomer speciogynine (SG), and paynantheine and their metabolites could be identified in rat and human urine using LC-MS(n). In Kratom users' urines, besides MG and SG, further isomeric compounds were detected. To elucidate whether the MG and SG diastereomer speciociliatine (SC) and its metabolites represent further compounds, the phase I and II metabolites of SC were identified first in rat urine after the administration of the pure alkaloid. Then, the identified rat metabolites were screened for in the urine of Kratom users using the above-mentioned LC-MS(n) procedure. Considering the mass spectra and retention times, it could be confirmed that SC and its metabolites are so far the unidentified isomers in human urine. In conclusion, SC and its metabolites can be used as further markers for Kratom use, especially by consumption of raw material or products that contain a high amount of fruits of the Malaysian plant M. speciosa. PMID- 21249339 TI - Improvement of reproducibility and sensitivity of CE analysis by using the capillary coated dynamically with carboxymethyl chitosan. AB - Analysis reproducibility and detection sensitivity of capillary electrophoresis (CE) are often questioned by applied scientists, which has hindered its application as a routine method. To address these issues, a simple, precise, and reproducible dynamic coating method was developed by applying carboxymethyl chitosan (CMC) dynamic coating on fused silica capillary. The proposed coating was accomplished by simply rinsing the capillary with CMC solution for 1 min in between runs, with no regeneration procedure or buffer additives needed. Electroosmotic flow could be well controlled by adjusting the pH of background electrolyte, and the adsorption of analytes onto the capillary inner wall was effectively eliminated. The main parameters of the coating condition were optimized, and extensive applications of these CMC-dynamically coated capillaries in CE separations were then firmly confirmed. By using proteins, aristolochic acids, and inorganic anions as model analytes, the coating showed a good stability, high reproducibility, as well as improved sensitivity. Baseline separations could be obtained with high efficiency. The reduced adsorption was impressively effective for basic proteins, with an average plate number of 90,000/m for each protein, apart from the good resolution on the chromatogram. A high sensitive detection of alpha-lactalbumin was achieved with a limit of detection (S/N = 3) of 3.5 nM, and the number of theoretical plates was as high as 1,200,000/m. In addition, the combination of the CMC coating with nonaqueous CE and CE-mass spectrometry proved to be practical. All results showed that the CMC-dynamically coated capillary has special properties and obvious superiority over the uncoated ones for CE analysis. PMID- 21249340 TI - Predicting the partitioning of biological compounds between room-temperature ionic liquids and water by means of the solvation-parameter model. AB - The partition coefficients, P(IL/w), for different probe molecules as well as for compounds of biological interest between the room-temperature ionic liquids (RTILs) 1-butyl-3-methylimidazolium hexafluorophosphate, [BMIM][PF(6)], 1-hexyl-3 methylimidazolium hexafluorophosphate, [HMIM][PF(6)], 1-octyl-3-methylimidazolium tetrafluoroborate, [OMIM][BF(4)] and water were accurately measured. [BMIM][PF(6)] and [OMIM][BF(4)] were synthesized by adapting a procedure from the literature to a simpler, single-vessel and faster methodology, with a much lesser consumption of organic solvent. We employed the solvation-parameter model to elucidate the general chemical interactions involved in RTIL/water partitioning. With this purpose, we have selected different solute descriptor parameters that measure polarity, polarizability, hydrogen-bond-donor and hydrogen-bond-acceptor interactions, and cavity formation for a set of specifically selected probe molecules (the training set). The obtained multiparametric equations were used to predict the partition coefficients for compounds not present in the training set (the test set), most being of biological interest. Partial solubility of the ionic liquid in water (and water into the ionic liquid) was taken into account to explain the obtained results. This fact has not been deeply considered up to date. Solute descriptors were obtained from the literature, when available, or else calculated through commercial software. An excellent agreement between calculated and experimental log P(IL/w) values was obtained, which demonstrated that the resulting multiparametric equations are robust and allow predicting partitioning for any organic molecule in the biphasic systems studied. PMID- 21249341 TI - New marker of tumor cell death revealed by ATR-FTIR spectroscopy. AB - Fourier transform infrared spectroscopy in attenuated total reflection can be used to discriminate the necrotic from the apoptotic cell death in a tumoral T cell line irradiated by a UV source able to induce both apoptosis and necrosis. Using Jurkat cells as the model system, significant spectral differences in the irradiated cells vs. time were observed in the lipid-proteins ratio absorbance band at 1,397 cm(-1) and in lactic acid IR band at 1,122 cm(-1); these spectral features are inversely correlated with the percentage of apoptotic cells assessed by flow cytometry. From the analysis of second derivatives in the IR spectral region between 1,800 and 900 cm(-1), we have detected two significant spectral changes: the first centered at 1,621 cm(-1) by analyzing the components of the amide I band and the second centered at 1,069 cm(-1) due to C-O stretching vibration of the DNA backbone sensitive to the dehydrated state of DNA; these identified differences in the intracellular biomolecules have been allowed to monitor the necrotic process. The variations in the spectral data set have been identified by the Kruskal-Wallis test and confirmed by the hierarchical cluster analysis. PMID- 21249342 TI - Development of a liquid chromatography-mass spectrometry method for the determination of ursolic acid in rat plasma and tissue: application to the pharmacokinetic and tissue distribution study. AB - A fast and sensitive liquid chromatography-mass spectrometry method was developed for the determination of ursolic acid (UA) in rat plasma and tissues. Glycyrrhetinic acid was used as the internal standard (IS). Chromatographic separation was performed on a 3.5 MUm Zorbax SB-C18 column (30 mm * 2.1 mm) with a mobile phase consisting of methanol and aqueous 10 mM ammonium acetate using gradient elution. Quantification was performed by selected ion monitoring with (m/z)(-) 455 for UA and (m/z)(-) 469 for the IS. The method was validated in the concentration range of 2.5 - 1470 ng mL(-1) for plasma samples and 20 - 11760 ng g(-1) for tissue homogenates. The intra- and inter-day assay of precision in plasma and tissues ranged from 1.6% to 7.1% and 3.7% to 9.0%, respectively, and the intra- and inter-day assay accuracy was 84.2 - 106.9% and 82.1 - 108.1%, respectively. Recoveries in plasma and tissues ranged from 83.2% to 106.2%. The limits of detections were 0.5 ng mL(-1) or 4.0 ng g(-1). The recoveries for all samples were >90%, except for liver, which indicated that ursolic acid may metabolize in liver. The main pharmacokinetic parameters obtained were T(max) = 0.42 +/- 0.11 h, C(max) = 1.10 +/- 0.31 MUg mL(-1), AUC = 1.45 +/- 0.21 MUg h mL( 1) and K(a) = 5.64 +/- 1.89 h(-1). The concentrations of UA in rat lung, spleen, liver, heart, and cerebellum were studied for the first time. This method is validated and could be applicable to the investigation of the pharmacokinetics and tissue distribution of UA in rats. PMID- 21249343 TI - A quantitative chemiluminescent assay for analysis of peroxide-based explosives. AB - A quantitative chemiluminescent method, enabling indirect identification of the peroxide-based explosives TATP (triacetone triperoxide) and HMTD (hexamethylene triperoxide diamine) has been developed. Treatment of these compounds with acidic solutions produced peroxides, which were transformed into radical derivatives by horseradish peroxidase (HRP) and then quantified by measuring the light emitted during their oxidation of luminol. The method was first developed in the microplate format and later optimized for a portable luminometer, to enable rapid application of the assay directly on site. When the portable luminometer was used each analysis took only 5-10 min. The method had good selectivity, sensitivity, and reproducibility; in the microplate format the limits of detection (LOD) and quantification (LOQ) were 40 and 50 ng mL(-1), respectively, for both TATP and HMTD. When the portable luminometer was used the LOD and LOQ were 50 and 100 ng mL(-1), respectively, for both compounds. Introduction of light emission enhancing compounds did not improve the analytical performance of the assay. Imprecision (CV values) was always below 10%. Recovery varied rapidly with time, with an average value of 78% after 5 min. No false-positive result was detected on measurement of a variety of samples; this is an important feature for analysis on site. The method was applied both to contaminated materials and to fortified soil samples, simulating operational conditions. PMID- 21249344 TI - Quantum dot-based array for sensitive detection of Escherichia coli. AB - A fluorescent quantum dot-based antibody array, used in sandwich format, has been developed to detect Escherichia coli O157:H7. Numerous parameters such as solid support, optimal concentration of immunoreagents, blocking reagents, and assay time were optimized for array construction. Quantum dot-conjugated anti-IgG was used as the detecting system. The array allows the detection of E. coli O157:H7 at concentrations below 10 CFU mL(-1) without sample enrichment, exhibiting an increase of three orders of magnitude in the limit of detection compared to ELISA. The interference caused by Gram (+) and Gram (-) bacteria was negligible at low concentrations of bacteria. PMID- 21249345 TI - Use of polyethylenimine-modified magnetic nanoparticles for highly specific enrichment of phosphopeptides for mass spectrometric analysis. AB - Phosphopeptides have been isolated and concentrated by use of polyethyleneimine (PEI)-modified magnetic nanoparticles as an extremely specific affinity probe. The particles specifically captured phosphopeptides from a tryptic digest of a protein mixture that contained 0.07% (mole/mole) phosphoproteins, which is the highest specificity obtained to date. The time required for enrichment of the phosphopeptides was 1 min only. PEI-modified magnetic nanoparticles carry positive charges over a wide range of pH-between 3 and 11. This feature means the particles are effectively dispersed in solution during phosphopeptide capture. Mass spectrometric analysis revealed the very high efficiency of enrichment of phosphopeptides that contain both single and multiply-phosphorylated sites. The detection limit in the analysis of phosphopeptides obtained from both bovine alpha-casein and beta-casein by matrix-assisted laser desorption/ionization mass spectrometry was 5 fmol. This approach was also used to enrich the phosphopeptides in a protein digest obtained from non-fat milk. PMID- 21249346 TI - Effects of weak environmental magnetic fields on the spontaneous bioelectrical activity of snail neurons. AB - We examined the effects of 50-Hz magnetic fields in the range of flux densities relevant to our current environmental exposures on action potential (AP), after hyperpolarization potential (AHP) and neuronal excitability in neurons of land snails, Helix aspersa. It was shown that when the neurons were exposed to magnetic field at the various flux densities, marked changes in neuronal excitability, AP firing frequency and AHP amplitude were seen. These effects seemed to be related to the intensity, type (single and continuous or repeated and cumulative) and length of exposure (18 or 20 min). The extremely low frequency (ELF) magnetic field exposures affect the excitability of F1 neuronal cells in a nonmonotonic manner, disrupting their normal characteristic and synchronized firing patterns by interfering with the cell membrane electrophysiological properties. Our results could explain one of the mechanisms and sites of action of ELF magnetic fields. A possible explanation of the inhibitory effects of magnetic fields could be a decrease in Ca(2+) influx through inhibition of voltage-gated Ca(2+) channels. The detailed mechanism of effect, however, needs to be further studied under voltage-clamp conditions. PMID- 21249347 TI - Colchicine modulates oxidative stress in serum and leucocytes from remission patients with Family Mediterranean Fever through regulation of Ca2+ release and the antioxidant system. AB - We investigated the effects of colchicine on oxidative stress and Ca2+ release in serum and polymorphonuclear leucocytes (PMNs) of Familial Mediterranean Fever (FMF) patients with attack, remission and unremission periods. Eighteen FMF patients and six age-matched healthy subjects in four groups were used. The first group was a control. The second group included patients with active FMF. The third and fourth groups were patients with remission and unremission, respectively. Colchicine (1.5 mg/day) was given to the third and fourth groups for 1 month. PMN cells, serum lipid peroxidation and intracellular Ca2+-release levels in the attack and unremission groups were higher than in those in controls, although they were lower in the remission group than in the attack group. Serum vitamin E and beta-carotene concentrations were higher in the remission group than in the control and attack groups. However, PMN, serum lipid peroxidation and Ca2+-release levels were further increased in the unremission group compared to the attack group. Glutathione peroxidase, reduced glutathione and vitamin A values in the four groups did not change by FMF and colchicine. In conclusion, we observed that colchicine induced protective effects on oxidative stress by modulating vitamin E, beta-carotene and Ca2+-release levels in FMF patients with a remission period. PMID- 21249348 TI - Chronopotentiometric technique as a method for electrical characterization of bilayer lipid membranes. AB - The basic electrical parameters of bilayer lipid membranes are capacitance and resistance. This article describes the application of chronopotentiometry to the research of lipid bilayers. Membranes were made from egg yolk phosphatidylcholine. The chronopotentiometric characteristic of the membranes depends on the current value. For low current values, no electroporation takes place and the voltage rises exponentially to a constant value. Based on these kinds of chronopotentiometric curves, a method of the membrane capacitance and the membrane resistance calculations are presented. PMID- 21249349 TI - Autophagy in cardiac plasticity and disease. AB - The heart is a highly plastic organ. In response to the physiological stress of normal life, as well as the pathological stress of disease, the myocardium manifests robust and rapid changes in mass. In the context of disease-associated stress, this myocardial remodeling response can culminate in ventricular thinning, mechanical dysfunction, and a clinical syndrome of heart failure. Recently, autophagy, a process of cellular cannibalization, has been implicated in many of these remodeling reactions. In some settings, the autophagic response is beneficial and pro-survival; in other contexts, it is maladaptive and promotes disease progression. Together, these observations raise the intriguing prospect of targeting maladaptive autophagy and advancing cell survival-promoting, adaptive autophagy to benefit patients with heart disease. PMID- 21249351 TI - Whole-body MR angiography: initial experience in imaging pediatric vasculopathy. AB - Radiological assessment of vasculopathy in children is typically undertaken with ultrasonography, echocardiography, conventional angiography, computed tomography and, more recently, positron emission tomography. Drawbacks of these modalities include radiation exposure or, in the case of ultrasonography, the dependence on operator skills and sufficient acoustic windows. With advancements in MR technology, which have improved sensitivity and shortened scan times, whole-body magnetic resonance angiography (WB-MRA) lends itself as a potential "one-stop shop" for vascular imaging. Currently, WB-MRA is primarily used in adult patients with atherosclerosis or multifocal regional vasculopathy. WB-MRA has not been employed in the routine assessment of pediatric vascular disease. The purpose of this article is to describe and illustrate our WB-MRA imaging technique for evaluation of pediatric vasculopathy. PMID- 21249352 TI - Presence and diversity of Streptomyces in Dendroctonus and sympatric bark beetle galleries across North America. AB - Recent studies have revealed several examples of intimate associations between insects and Actinobacteria, including the Southern Pine Beetle Dendroctonus frontalis and the Spruce Beetle Dendroctonus rufipennis. Here, we surveyed Streptomyces Actinobacteria co-occurring with 10 species of Dendroctonus bark beetles across the United States, using both phylogenetic and community ecology approaches. From these 10 species, and 19 other scolytine beetles that occur in the same trees, we obtained 154 Streptomyces-like isolates and generated 16S sequences from 134 of those. Confirmed 16S sequences of Streptomyces were binned into 36 distinct strains using a threshold of 0.2% sequence divergence. The 16S rDNA phylogeny of all isolates does not correlate with the distribution of strains among beetle species, localities, or parts of the beetles or their galleries. However, we identified three Streptomyces strains occurring repeatedly on Dendroctonus beetles and in their galleries. Identity of these isolates was corroborated using a house-keeping gene sequence (efTu). These strains are not confined to a certain species of beetle, locality, or part of the beetle or their galleries. However, their role as residents in the woodboring insect niche is supported by the repeated association of their 16S and efTu from across the continent, and also having been reported in studies of other subcortical insects. PMID- 21249353 TI - Low concentration of copper inhibits colonization of soil by the arbuscular mycorrhizal fungus Glomus intraradices and changes the microbial community structure. AB - Common agricultural practices result in accumulation of copper in agricultural soils worldwide. The effect of bioavailable copper ([Cu](bio)) on colonization of soil by the AM fungus Glomus intraradices and other soil microorganisms was investigated in microcosms containing copper-amended soil. To avoid indirect effects through the plant, copper was only added to root-free microcosm compartments. [Cu](bio) was measured using a Pseudomonas fluorescens biosensor strain. In the range of 0-1.5 MUg g(-1) [Cu](bio), a log-log linear relationship between added copper and [Cu](bio) was found. Microbial colonization of the root free compartment was evaluated by whole-cell fatty acid analysis (WCFA) and amplified rDNA restriction analysis (ARDRA). The WCFA analysis showed that the AM fungus soil colonization was severely inhibited by Cu with a 50% reduction of mycorrhizal growth at 0.26 MUg g(-1) [Cu](bio). The growth of other main microbial groups was not significantly affected by copper. However, ARDRA analysis showed a very strong effect of copper on the bacterial community composition probably caused by an increased proportion of Cu-resistant bacteria. Our results suggest that problems with plant yield may arise when converting slightly copper-contaminated soils to land uses such as low-input and sustainable agriculture that are dependent on AM fungal symbiosis. PMID- 21249354 TI - Genomic screening by 454 pyrosequencing identifies a new human IGHV gene and sixteen other new IGHV allelic variants. AB - Complete and accurate knowledge of the genes and allelic variants of the human immunoglobulin gene loci is critical for studies of B cell repertoire development and somatic point mutation, but evidence from studies of VDJ rearrangements suggests that our knowledge of the available immunoglobulin gene repertoire is far from complete. The reported repertoire has changed little over the last 15 years. This is, in part, a consequence of the inefficiencies involved in searching for new members of large, multigenic gene families by cloning and sequencing. The advent of high-throughput sequencing provides a new avenue by which the germline repertoire can be explored. In this report, we describe pyrosequencing studies of the heavy chain IGHV1, IGHV3 and IGHV4 gene subgroups in ten Papua New Guineans. Thousands of 454 reads aligned with complete identity to 51 previously reported functional IGHV genes and allelic variants. A new gene, IGHV3-NL1*01, was identified, which differs from the nearest previously reported gene by 15 nucleotides. Sixteen new IGHV alleles were also identified, 15 of which varied from previously reported functional IGHV genes by between one and four nucleotides, while one sequence appears to be a functional variant of the pseudogene IGHV3-25. BLAST searches suggest that at least six of these new genes are carried within the relatively well-studied populations of North America, Europe or Asia. This study substantially expands the known immunoglobulin gene repertoire and demonstrates that genetic variation of immunoglobulin genes can now be efficiently explored in different human populations using high-throughput pyrosequencing. PMID- 21249355 TI - Improvement of the quality of wheat bread by addition of glycoside hydrolase family 10 xylanases. AB - Although many xylanases are widely used in the baking industry, only one glycoside hydrolase family 10 (GH 10) xylanase has previously been reported to be effective in baking. In this study, we compared the effectiveness of two GH 10 xylanases, psychrophilic XynA from Glaciecola mesophila and mesophilic EX1 from Trichoderma pseudokoningii, in bread making. The optimal dosages needed to improve wheat flour dough and bread quality were 270-U/kg flour for EX1 and 0.9 U/kg flour for XynA. At their optimal dosage, both XynA and EX1 had significant dough-softening ability, resulting in a 50% reduction in Brabender units. XynA was more effective than EX1 in reducing the time to reach maximum consistency. XynA and EX1 showed similar effects in improving the bread volume (~30% increase). EX1 was more effective in reducing the initial crumb firmness. Although both enzymes exhibited similar anti-staling effects on the bread, based on a decrease in the bread firmness, XynA had a greater effect on reducing the firming rate, and EX1 showed an enhanced reduction in the initial firmness. These results show that these two GH 10 xylanases have unique advantages in improving dough and bread quality and indicate their potential in bread making. PMID- 21249356 TI - Menetrier's disease diagnosed by enteroclysis CT: a case report and review of the literature. AB - This study reports a case of Menetrier's disease (MD) in an adult who presented with epigastric pain and peripheric edema. We focused in particular on the imaging and diagnostic aspects of the presenting case as well as clinical, histologic, and therapeutic aspects. Computed tomography (CT) enteroclysis is a new imaging technique which combines enteroclysis and spiral multislice CT. To the best of our knowledge this is the first report on a MD in an adult patient diagnosed by CT Enteroclysis. PMID- 21249357 TI - Pre-operative serum C-reactive protein as independent prognostic factor for survival but not infection in patients with high-grade osteosarcoma. AB - PURPOSE: The purpose of this study was to investigate (a) whether pre-operative serum CRP is a predictor of survival in patients with high-grade osteosarcoma, (b) whether post-operative infection is a predictor of survival in these patients and (c) whether CRP is a predictor of post-operative infection, and especially deep prosthetic infection. METHODS: In this retrospective single-centre study, pre-operative serum CRP levels in 79 patients (37 females, 42 males; average age, 18 years; mean follow-up, 46 months) undergoing resection of an osteosarcoma were correlated with clinical data and survival. RESULTS: The mean pre-operative serum CRP level of all 79 patients was 0.53 mg/dl (SD, 1.27 mg/dl). Patients dying of their underlying disease had significantly higher CRP levels compared to patients surviving throughout the follow-up period (1.09 mg/dl +/- 2.02 mg/dl versus 0.32 mg/dl +/- 0.75 mg/dl, respectively; p = 0.015). CRP levels were significantly correlated with survival (Pearson's correlation coefficient = -0.25; p = 0.026) and histological subtype (Pearson's correlation coefficient = -0.42; p < 0.001), but not with sex, age, histological response, tumour size or metastatic disease. In uni- and multivariate survival analysis, age, response to chemotherapy and serum CRP were associated with disease-specific survival. Patients with a CRP level over 1 mg/dl had a significantly lower disease-specific five-year survival of 36.7% compared to 73.8% in patients with normal CRP values (p = 0.020). Infection was not correlated with disease-specific survival. Pre-operative serum CRP levels were not correlated with post-operative infection or deep prosthetic infection. CONCLUSIONS: Pre-operative serum CRP seems to be an independent predictor of survival in patients with high-grade osteosarcoma. Further studies are needed to confirm these results on a large-scale basis. PMID- 21249358 TI - Over 25 years survival after Charnley's total hip arthroplasty. AB - BACKGROUND: Since 1962, the low friction arthroplasty (LFA) developed by Sir John Charnley has spread widely throughout the world. Many series have reported long term results. Polyethylene (PE) wear is well known. The average wear ratio is about 0.1 mm a year. Many factors may influence that wear process. PURPOSE: The authors describe two different series of patients operated upon with Charnley's total hip arthroplasty (THA) using the original cemented stem and a non modular 22.2-mm head, with a cemented full polyethylene acetabular socket. Outcomes confirm excellent patient function after 25 years. They emphasise the fact that PE is the weak point of total hip arthroplasty. Function may be excellent even though PE wear is significant. In several cases, no wear at the maximum follow-up was detectable. RESULTS: This study confirms different publications relating long term follow-up with LFA. During a Charnley meeting in Lyon, we published a survival curve of 85% after 25 years. Berry et al. published a 86.5% survival curve (J Bone Joint Surg Am 84:171-177, 2002). In 1995, Luc and Marcel Kerboul published a 77% survival rate after 20 years in young patients under 40 years old at the time of the surgery. In 2009, Callaghan et al. published a series of 35 years follow-up with a ratio of 78% survivorship (J Bone Joint Surg Br 91:2617 2621). CONCLUSION: Could the long-term results be improved? Through recent decades, many solutions have been introduced to improve the survivorship of THA including bearing surfaces such as alumina-on-alumina and metal-on-metal. Different problems have occurred with these solutions. LFA might be improved by working on the nature and the quality of the head. Improvements might also be obtained by working on the quality and the hardness of the acetabular socket. PMID- 21249359 TI - Emergency surgical care delivery in post-earthquake Haiti: Partners in Health and Zanmi Lasante experience. AB - BACKGROUND: The earthquake that struck Haiti on 12 January 2010 caused significant devastation to both the country and the existing healthcare infrastructure in both urban and rural areas. Most hospital and health care facilities in Port-au-Prince and the surrounding areas were significantly damaged or destroyed. Consequently, large groups of Haitians fled Port-au-Prince for rural areas to seek emergency medical and surgical care. In partnership with the Haitian Ministry of Health, Partners in Health (PIH) and Zanmi Lasante (ZL) have developed and maintained a network of regional and district hospitals in rural Haiti for over twenty-five years. This PIH/ZL system was ideally situated to accommodate the increased need for emergent surgical care in the immediate quake aftermath. The goal of the present study was to provide a cross-sectional assessment of surgical need and care delivery across PIH/ZL facilities after the earthquake in Haiti. METHODS: We conducted a retrospective review of hospital case logs and operative records over the course of three weeks immediately following the earthquake. RESULTS: Roughly 3,000 patients were seen at PIH/ZL sites by a combination of Haitian and international surgical teams. During that period 513 emergency surgical cases were logged. Other than wound debridement, the most commonly performed procedure was fixation of long bone fractures, which constituted approximately one third of all surgical procedures. CONCLUSIONS: There was a significant demand for emergent surgical care after the earthquake in Haiti. The PIH/ZL hospital system played a critical role in addressing this acutely increased burden of surgical disease, and it allowed for large numbers of Haitians to receive needed surgical services. Our experiences reinforce that access to essential surgery is an essential pillar in public health. PMID- 21249360 TI - Life, liberty, and the pursuit of quality-adjusted life-years after pancreatic cancer surgery. PMID- 21249362 TI - Early fetal development of the rotator interval region of the shoulder with special reference to topographical relationships among related tendons and ligaments. AB - PURPOSE: There is a little information on the early fetal development of the rotator interval region of the shoulder, particularly with regard to whether topographical relationships among the ligaments and tendons change during development. METHODS: We examined the histological sections (transverse or frontal) of right or left shoulder in 20 mid-term human fetuses (7-15 weeks of gestation). RESULTS: The biceps tendon had an accompanying bursa-like cavity before the joint cavitation. The bursa for the tendon remained open to the joint cavity until 12 weeks. When reaching the glenoid, the biceps tendon involved and carried mesenchymal tissue around the coracoid process (the future coracohumeral ligament) toward the infraspinatus tendon. Until 10 weeks, the primitive glenohumeral ligament was established as simple collateral ligaments on the inner or humeral side of the rotator cuff tendons and the biceps long tendon. However, the subscapularis tendon crossed, attached to, and reformed the upper structure of the superior glenohumeral ligament. CONCLUSIONS: The early development of the coracohumeral ligament suggests that it is a primitive and basic structure. However, we hypothesize that mechanical demands from the subscapularis tendon and biceps long tendon are likely to change the primitive form of the rotator interval to the adult morphology, including the superior glenohumeral ligament. The significant modification evident during early fetal development suggests that anatomical reconstruction after rotator cuff tears should not be based on the "ideal" anatomy, especially that of the superior glenohumeral ligament, but on individual requirements. PMID- 21249361 TI - The hypofunctional effect of P335L single nucleotide polymorphism on SSTR5 function. AB - BACKGROUND: Somatostatin receptor subtype 5 (SSTR5) mediates the inhibitory effect of somatostatin on insulin expression/secretion and cell proliferation. A number of single nucleotide polymorphisms (SNPs) of SSTR5 have been identified, including P335L, a nonsynonymous SNP located in the protein C-terminal region and encrypted by the codon CCG (proline) or the codon CTG (leucine). In the present study we sought to determine the distribution of the SSTR5 P335L SNP in a cohort of pancreatic cancer patients and whether the P335L SNP affected cellular function of SSTR5 in human pancreatic cancer. METHODS: The P335L germline genotype of 246 patients with pancreatic cancer (213 Caucasians, 16 Hispanics, and 17 African Americans) and 17 human pancreatic cell lines was determined with the TaqMan SNP Genotyping assay. Human SSTR5 leucine variant (L335) was generated by performing site-directed mutagenesis using SSTR5 proline variant (P335) as a template. Transient transfections were performed in HEK293, Mia PaCa-2, and beta TC-6 cells using Lipofectamine 2000. The expression of SSTR5 L335 was determined with a mouse monoclonal anti-SSTR5 L335 antibody generated in our laboratory. The cell proliferation rate was measured by performing MTS assays. Insulin concentration was measured by performing ELISA assays. RESULTS: Genotyping of the patients' blood indicated that the frequency of the T allele (CT and TT genotypes) in codon 335 of SSTR5 in Caucasians, Hispanics, and African Americans was 52, 69, and 35%, respectively, which was race-dependent. Statistical analysis indicated that association between the frequency of the T allele and the existence of pancreatic cancer in each race missed significance perhaps due to limited sample size. In 17 tested human pancreatic cancer cell lines, 5 (Capan-2, HPAF-II, Panc03.27, Panc-1, and -3) were homozygous (TT genotype) and 9, including Mia PaCa-2, were heterozygous (CT genotype). Overexpression of SSTR5 L335 in Mia PaCa-2 cells enhanced cell proliferation compared to overexpression of SSTR5 P335. Overexpression of SSTR5 P335 enhanced the inhibitory effect of SSTR5 agonist RPL-1980 on cell proliferation of Mia PaCa-2 cells and glucose stimulated insulin secretion from mouse insulinoma cells, while overexpression of SSTR5 L335 blocked the inhibitory effect of RPL-1980. Overexpression of SSTR5 L335 enhanced PDX-1 expression in Mia PaCa-2 cells. A specific monoclonal antibody was generated to detect SSTR5 P335L. CONCLUSION: SSTR5 P335L SNP widely exists in the human population, in patients with pancreatic cancer, and is race dependent. The SNP is also present in selected human pancreatic cancer cell lines. In contrast to SSTR5 P335, overexpression of the SSTR5 L335 variant resulted in cellular proliferation and PDX-1 overexpression in human pancreatic cancer cells. Its overexpression blocked the inhibitory effect of an SSTR5 specific analog on human pancreatic cancer cell proliferation and on glucose stimulated insulin secretion from mouse insulinoma cells. These data suggest that SSTR5 P335L is a hypofunctional protein with a potentially harmful effect on function, as well as potential latent effect, and therefore it could affect the clinical response to somatostatin analog therapy for patients with pancreatic cancer. PMID- 21249364 TI - Prolonged transendothelial migration of human haematopoietic stem and progenitor cells (HSPCs) towards hydrogel-released SDF1. AB - The therapeutic success of haematopoetic stem and progenitor cell (HSPC) transplantation is critically dependent on HSPC engraftment in the bone marrow. Gradients of stromal cell-derived factor 1 (SDF1) direct HSPC homing, both in vitro and in vivo. Potentially, regulating the delivery levels of exogenous SDF1 applied to the bone marrow could augment HSPC engraftment. Thus, the aim of the present study was to revise the ability of biocompatible hydrogels to direct HSPC migration in vitro. The delivery system of choice is based on heparin cross linked with collagen1. We confirm that hydrogel is capable of trapping and releasing SDF1 and using it to generate a protein gradient in transendothelial migration experiments. The use of SDF1-functionalised hydrogel to produce a chemokine gradient revealed, sustained and increased HSPC migration when compared to diffusible SDF1 controls. In conclusion, regulating SDF1 gradients with heparin-containing hydrogels may offer valuable options to direct site-specific migration of HSPC. PMID- 21249363 TI - Anatomic variations of arterial liver vascularization: an analysis by using MDCTA. AB - PURPOSE: The knowledge of celiac trunk vascularization and hepatic arteries' configuration is extremely important in several areas like hepato-biliary pancreatic surgery, as well as in interventional radiological treatment. Our purpose was to evaluate the incidence of anatomic variation of arterial liver vascularization by using MDCTA in a large, homogeneous population. METHODS: Between January 2004 and December 2009, 1,910 patients (1,156 men; mean age, 62.7 years) who underwent MDCT were retrospectively analyzed. Hepatic arterial configuration was classified according to Michels' classification. Image quality was graded according to an ordinal scale. RESULTS: Of the 1,910 examined patients, 281 (15, 67%) were excluded because of sub-optimal image quality. Of the remaining 1,629 patients (986 men; mean age, 61.1 years +/- 8 (SD); age range, 19-90 years), anatomic variations were detected in 631 patients (38.73%). CONCLUSIONS: MDCT was useful in analyzing arterial liver configuration and demonstrated the presence of a significant incidence of arterial variants (38.73%) in the examined population. PMID- 21249365 TI - Genetic and molecular analysis of a purple sheath somaclonal mutant in japonica rice. AB - Natural and artificially induced mutants have provided valuable resources for plant genetic studies and crop improvement. In this study, we investigated the genetic and molecular basis of the purple sheath trait in a somaclonal mutant Z418, which was regenerated from a green sheath rice variety C418 through tissue culture. The purple sheath trait in Z418 was heritable and stable based on our 10 years of evaluation. Genetic analysis revealed that the purple sheath trait of the mutant was controlled by a single dominant gene. To map the gene, we scored 89 polymorphic SSRs markers in a F(2) population of 232 plants derived from a cross between Z418 and HX-3, an indica variety with green sheath trait. The gene was initially mapped to the short arm of chromosome 6 between two SSR markers, RPM5 and RM402, with a genetic distance of 1.1 and 10.3 cM, respectively. Thirty one SSR and indel markers located within the target region were further used to fine-map the gene to a 153-kb interval between two SSR markers (RPM8 and RPM11). The OsC1 gene, which locates within the region and encodes a MYB family transcription factor, was chosen as the candidate gene controlling the purple sheath trait in Z418. Sequencing analysis revealed that OsC1 gene and its transcript in Z418 was 34 bp longer than that in C418. The possible mechanisms for the gene mutation, the developmental and tissue-specific expression of purple anthocyanin pigmentation in Z418, were finally discussed. PMID- 21249366 TI - Characterization of the mannan synthase promoter from guar (Cyamopsis tetragonoloba). AB - Guar seed gum, consisting primarily of a high molecular weight galactomannan, is the most cost effective natural thickener, having broad applications in the food, cosmetics, paper, pharmaceutical and petroleum industries. The properties of the polymer can potentially be enhanced by genetic modification. Development of suitable endosperm-specific promoters for use in guar is desirable for metabolic engineering of the seed gum. A ~1.6 kb guar mannan synthase (MS) promoter region has been isolated. The MS promoter sequence was fused with the GUS reporter gene and overexpressed in the heterologous species alfalfa (Medicago sativa). The potential strength and specificity of the MS promoter was compared with those of the constitutive 35S promoter and the seed specific beta-phaseolin promoter. Quantitative GUS assays revealed that the MS promoter directs GUS expression specifically in endosperm in transgenic alfalfa. Thus, the guar MS promoter could prove generally useful for directing endosperm-specific expression of transgenes in legume species. PMID- 21249367 TI - Comparative characterization, expression pattern and function analysis of the 12 oxo-phytodienoic acid reductase gene family in rice. AB - The 12-oxo-phytodienoic acid reductases (OPRs) belong to the old yellow enzyme family of flavoenzymes and form multiple subfamilies in angiosperm plants. In our previous study, a comparative genomic analysis showed that five OPR subfamilies (subs. I-V) occur in monocots, and two subfamilies (subs. I and II) in dicots. Here, a comparative study of five OsOPR genes, representing five subfamilies (I V) in rice, was performed to provide insights into OPR biochemical properties and physiological importance. Comparative analysis of the three-dimensional structure by homology modeling indicated all five OsOPR proteins contained a highly conserved backbone with (alpha/beta)(8)-barrels, while two middle variable regions (MVR i and ii) were also detected and defined. Analysis of enzymatic characteristics revealed that all five OsOPR fusion proteins exhibit distinct substrate specificity. Different catalytic activity was observed using racemic OPDA and trans-2-hexen-1-al as substrates, suggesting OsOPR family genes participate in two main branches of the octadecanoid pathway, including the allene oxide synthase and hydroperoxide lyase pathways which regulate various developmental processes and/or defense responses. The transcript profiles of five OsOPR genes exhibited strong tissue-specific and inducible expression patterns under abiotic stress, hormones and plant wounding treatments. Furthermore, the transcriptions of OsOPR04-1 (OsOPR11) and OsOPR08-1 (OsOPR7), representing subs. I and II, respectively, were observed in all six selected tissues and with all above-stress treatments. This suggests that these two subfamilies play an important role during different developmental stages and in response to stresses; while the expressions of OsOPR06-1 (OsOPR6), OsOPR01-1 (OsOPR10) and OsOPR02-1 (OsOPR8), representing subs. III, IV and V respectively, were strongly up regulated with abscisic acid (ABA) and indoleacetic acid (IAA) treatments in roots, suggesting these three subfamilies play an important role in responding to hormones especially ABA and IAA signals in roots. PMID- 21249368 TI - Towards the development of better crops by genetic transformation using engineered plant chromosomes. AB - Plant Biotechnology involves manipulation of genetic material to develop better crops. Keeping in view the challenges being faced by humanity in terms of shortage of food and other resources, we need to continuously upgrade the genomic technologies and fine tune the existing methods. For efficient genetic transformation, Agrobacterium-mediated as well as direct delivery methods have been used successfully. However, these methods suffer from many disadvantages especially in terms of transfer of large genes, gene complexes and gene silencing. To overcome these problems, recently, some efforts have been made to develop genetic transformation systems based on engineered plant chromosomes called minichromosomes or plant artificial chromosomes. Two approaches namely, "top-down" or "bottom-up" have been used for minichromosomes. The former involves engineering of the existing chromosomes within a cell and the latter de novo assembling of chromosomes from the basic constituents. While some success has been achieved using these chromosomes as vectors for genetic transformation in maize, however, more studies are needed to extend this technology to crop plants. The present review attempts to trace the genesis of minichromosomes and discusses their potential of development into plant artificial chromosome vectors. The use of these vectors in genetic transformation will greatly ameliorate the food problem and help to achieve the UN Millennium development goals. PMID- 21249369 TI - The potential impact of plant biotechnology on the Millennium Development Goals. AB - The eight Millennium Development Goals (MDGs) are international development targets for the year 2015 that aim to achieve relative improvements in the standards of health, socioeconomic status and education in the world's poorest countries. Many of the challenges addressed by the MDGs reflect the direct or indirect consequences of subsistence agriculture in the developing world, and hence, plant biotechnology has an important role to play in helping to achieve MDG targets. In this opinion article, we discuss each of the MDGs in turn, provide examples to show how plant biotechnology may be able to accelerate progress towards the stated MDG objectives, and offer our opinion on the likelihood of such technology being implemented. In combination with other strategies, plant biotechnology can make a contribution towards sustainable development in the future although the extent to which progress can be made in today's political climate depends on how we deal with current barriers to adoption. PMID- 21249370 TI - Metal artifact reduction by dual energy computed tomography using monoenergetic extrapolation. AB - OBJECTIVE: The aim of the study was to assess the performance and diagnostic value of a dual energy CT approach to reduce metal artefacts in subjects with metallic implants. METHODS: 31 patients were examined in the area of their metallic implants using a dual energy CT protocol (filtered 140 kVp and 100 kVp spectrum, tube current relation: 3:1). Specific post-processing was applied to generate energies of standard 120 and 140 kVp spectra as well as a filtered 140 kVp spectrum with mean photon energies of 64, 69 and 88 keV, respectively, and an optimized hard spectrum of 95-150 keV. Image quality and diagnostic value were subjectively and objectively determined. RESULTS: Image quality was rated superior to the standard image in 29/31 high energy reconstructions; the diagnostic value was rated superior in 27 patients. Image quality and diagnostic value scores improved significantly from 3.5 to 2.1 and from 3.6 to 1.9, respectively. In several exams decisive diagnostic features were only discernible in the high energy reconstructions. The density of the artefacts decreased from 882 to -341 HU. CONCLUSIONS: Dual Energy CT with specific postprocessing can reduce metal artefacts and may significantly enhance diagnostic value in the evaluation of metallic implants. PMID- 21249371 TI - Computed tomography--old ideas and new technology. AB - Several recently introduced 'new' techniques in computed tomography--iterative reconstruction, gated cardiac CT, multiple-source, and dual-energy CT--actually date back to the early days of CT. We review the historic origins and evolution of these techniques, which may provide some insight into the latest innovations in commercial CT systems. PMID- 21249373 TI - Neoadjuvant chemoradiation therapy followed by curative transanal endoscopic microsurgery (TEM) for rectal cancer complicated by major suture dehiscence: avoiding ileostomy through hyperbaric oxygen therapy. PMID- 21249372 TI - Concomitant carcinoma in situ as an independent prognostic parameter for recurrence and survival in upper tract urothelial carcinoma: a multicenter analysis of 772 patients. AB - PURPOSE: The purpose of this study is to assess the association of concomitant carcinoma in situ (CIS) with disease recurrence and cancer-related death in a multi-institutional series of patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). METHODS: We collected retrospectively the data of 772 patients treated with RNU and ipsilateral bladder cuff excision at 9 international institutions in Asia, Europe, and Northern America from 1987 to 2008. Surgical specimens were processed according to standard pathologic procedures at each institution. Univariable and multivariable Cox regression models addressed time to recurrence and cancer-specific mortality. RESULTS: Concomitant CIS was present in 88 patients (11.4%); it was associated with more advanced pathologic stage, higher tumor grade, and presence of lymphovascular invasion (all P-values < 0.05). The five-year recurrence-free (RFS) and cancer-specific survival (CSS) estimates were 74.4 and 76.3%, respectively, in the absence of CIS compared with 56.4 and 59.9%, respectively, in the presence of CIS (P-values < 0.0001 for RFS and 0.002 for CSS, respectively). On multivariable Cox regression analyses, concomitant CIS was an independent predictor of both RFS (hazard ratio (HR): 1.9; P = 0.007) and CSS (HR: 1.7, P = 0.048). Similar findings were reconfirmed in subgroups analyses limited to T2, organ confined, and N0/Nx UTUC, or patients who did not receive adjuvant chemotherapy. CONCLUSIONS: Presence of concomitant CIS is an independent predictor of both RFS and CSS in patients treated with RNU for UTUC. This information may be useful in risk stratification of UTUC patients for follow-up and additional therapy. PMID- 21249374 TI - Intraarticular lesions in calcifying tendinitis: incidence and association with the acromion index. AB - INTRODUCTION: Intraarticular pathologies are a common finding during arthroscopy for rotator cuff lesions. Both rotator cuff tears as well as cartilage lesions have been described as correlating with the acromion index. METHODS: In the current study, we aimed to determine the incidence of intraarticular lesions in calcifying tendinitis, to compare the incidence in patients with partial- and full-thickness tears of the rotator cuff, and to determine the acromion index in these groups. The incidence and type of accompanying intraarticular lesions were compared between three consecutive, age-matched groups of 64 patients each: those with calcifying tendinitis (group A), and those with partial- (group B) and full thickness rotator cuff tears (group C). Also, the acromion index was measured from plain radiographs and compared between the groups. RESULTS: The incidence of intraarticular pathology was 43% in group A, 41% in group B and 84% in group C. The differences between groups A and C as well as B and C were significant (p < 0.0001), but not between groups A and B (p = 0.858). Even though the acromion index was larger in group C than in the other two groups, the difference was not significant (A vs. B, p = 0.505; A vs. C, p = 0.180; and B vs. C p = 0.446). The incidence and type of intraarticular lesions in calcifying tendinitis are comparable to age-matched shoulders with partial- rather than full-thickness rotator cuff tears. CONCLUSION: The acromion index is not different between shoulders with calcifying tendinitis, and partial- or full-thickness rotator cuff tears. PMID- 21249375 TI - Reliability in arthroscopic grading of cartilage lesions: results of a prospective blinded study for evaluation of inter-observer reliability. AB - INTRODUCTION AND AIM: Arthroscopy is a well-established method for grading cartilage lesions. This study was undertaken to evaluate the inter-observer variance of grading cartilage lesions in a real life operation. MATERIALS AND METHODS: Four experienced arthroscopic surgeons used diagnostic arthroscopy, one after the other, to grade cartilage lesions in a total of 16 patients who had undergone knee arthroscopy. RESULTS: In summary, a total of 14 cartilage areas in 16 patients were graded (n = 224). The Cohens (Fleiss) Kappa Index for multiple investigators was kappa = 0.052 in the medial, kappa = 0.300 in the central, and kappa = 0.107 in the lateral surface of the patella. The indices were kappa = 0.292 in the medial, kappa = 0.0.255 in the central, and kappa = 0.234 in the lateral surface of the trochlea. The inter-observer variance was kappa = 0.193 in the MFC mean bearing zone, kappa = 0.116 in the margin of the MFC, kappa = 0.168 in the mean bearing zone of the TM, and kappa = 0.164 in the TM margin. In the lateral compartment, the kappa-Index was 0.309 in the LFC mean bearing zone, 0.111 in the margin of the LFC, 0.020 in the mean bearing zone of the TL, and 0.085 in the TL margin. CONCLUSIONS: The inter-observer reliability of the arthroscopic grading of cartilage lesions is poor. The major problem is the relatively large variability in differentiating between intact cartilage and lesions that consist of the softening of the cartilage and the differentiation between superficial and deep cartilage lesions. In the future, objective measurements should be developed to solve this problem. PMID- 21249376 TI - Metabolic syndrome is an independent risk factor for breast cancer. AB - OBJECTIVE: This study was aimed to assess the prevalence of metabolic syndrome in patients with breast cancer and the independent effect of metabolic syndrome on breast cancer risk. METHODS: Eighty-one women aged 40-80 years with breast cancer and 81 controls of similar age were screened for metabolic syndrome prevalence and breast cancer risk factors, including age at diagnosis, age at menarche, reproductive status, live births, breastfeeding, family history of breast cancer, physical activity, cigarette smoking, body mass index, and metabolic syndrome parameters. Each variable was first assessed for baseline comparisons using the univariate model, and significant variables were then added to the multivariate conditional logistic regression model. RESULTS: Prevalence of metabolic syndrome was 59.2% in breast cancer patients, and 37% in the control group (p < 0.005). A positive and independent association was observed between metabolic syndrome and breast cancer risk (odds ratio = 2.49; 95% confidence interval 1.17-5.30). CONCLUSION: Metabolic syndrome is more prevalent in breast cancer patients and is an independent risk factor for breast cancer. PMID- 21249377 TI - Validity and accuracy of subciliary endoscopic-aided repair of orbital floor fractures. AB - Several approaches are used to reconstruct orbital floor fractures and restore orbital position and function, but many have the drawback of incomplete visualization, especially of the posterior part of the orbit. The aim is to assess the validity and accuracy of endoscopically aided subciliary approach repair of orbital floor fractures, as regards functional and cosmetic outcomes. Nine patients with orbital floor fractures were treated with iliac crest bone graft under complete endoscopically aided visualization, through a subciliary approach graft that was placed over the defect under complete visual control using endoscopes, through the same incision, to reconstruct the defect and assess the correction of the posterior edge of orbital floor defect. Improvement was assessed 2 weeks postoperatively. All operated cases had satisfactory results, both functionally and cosmetically. No permanent drawbacks from the incision were observed at 6 months follow-up. In case of repair of orbital floor fractures via a transciliary approach, the use of endoscopic aid through the same incision, allows better visualization of the posterior edge of the orbital floor and facilitates confirmation that all orbital soft tissues have been accurately elevated from the fracture site and that the bone grafts are placed in proper position. LEVEL OF EVIDENCE: 1b (individual inception study with >80% F/U). PMID- 21249378 TI - Factors affecting the detection and quantification of mitochondrial point heteroplasmy using Sanger sequencing and SNaPshot minisequencing. AB - Mitochondrial DNA analysis plays an important role in forensic science as well as in the diagnosis of mitochondrial diseases. The occurrence of two different nucleotides at the same sequence position can be caused either by heteroplasmy or by a mix of samples. The detection of superimposed positions in forensic samples and their quantification can provide additional information and might also be useful to identify a mixed sample. Therefore, the detection and visualization of heteroplasmy has to be robust and sensitive at the same time to allow for reliable interpretation of results and to avoid a loss of information. In this study, different factors influencing the analysis of mitochondrial heteroplasmy (DNA polymerases, PCR and sequencing primers, nucleotide incorporation, and sequence context) were examined. BigDye Sanger sequencing and the SNaPshot minisequencing were compared as to the accuracy of detection using artificially created mitochondrial DNA mixtures. Both sequencing strategies showed to be robust, and the parameters tested showed to have a variable impact on the display of nucleotide ratios. However, experiments revealed a high correlation between the expected and the measured nucleotide ratios in cell mixtures. Compared to the SNaPshot minisequencing, Sanger sequencing proved to be the more robust and reliable method for quantification of nucleotide ratios but showed a lower detection sensitivity of minor cytosine components. PMID- 21249379 TI - Short- and long-term effects of small bowel resection: a unique histological study in a piglet model of short bowel syndrome. AB - If we are to develop successful interventions to improve clinical outcomes for short bowel syndrome patients we require (1) knowledge of changes within the epithelial population following small bowel resection (SBR) and (2) an idea of when these changes occur to inform on the timing of potential interventions aimed at enhancing the adaptive response. The aim of this study was to produce a temporal map of epithelial changes within the crypt and villus at early and late adaptation phases. Four-week-old piglets underwent a 75% SBR or sham operation and were studied at 2, 4 and 6 weeks post-operation to allow analysis of early and late adaptation responses. Piglets received polymeric infant formula (PIF). Immunohistochemistry with specific cell markers was used to quantitate intestinal cell types and the total cell numbers. Changes within the crypt were temporally dependent on an early significant increase in enterocytes and proliferative cells not sustained at 6 weeks. Goblet cell numbers were increased at all time points. Despite a significant increase in total villus cell numbers at 6 weeks there was no change in specific cell types. We observed two distinct phases of cellular change following SBR. An early increase in enterocytes and proliferative cells was not reflected in increased weight gain indicating the early increase represents immature enterocytes. Interventions aimed at increasing differentiation of the rapidly changing crypt population would allow for an earlier increase in absorption. PMID- 21249380 TI - Physiological consequences of military high-speed boat transits. AB - The purpose of this study was to investigate the consequences of a high-speed boat transit on physical performance. Twenty-four Royal Marines were randomly assigned to a control (CON) or transit (TRAN) group. The CON group sat onshore for 3 h whilst the TRAN group completed a 3-h transit in open-boats running side by-side, at 40 knots in moderate-to-rough seas, with boat deck and seat-pan acceleration recorded. Performance tests (exhaustive shuttle-run, handgrip, vertical-jump, push-up) were completed pre- and immediately post-transit/sit, with peak heart rate (HRpeak) and rating of perceived exertion (RPE) recorded. Serial blood samples (pre, 24, 36, 48, 72 h) were analyzed for creatine kinase (CK) activity. The transit was typified by frequent high shock impacts, but moderate mean heart rates (<45% HRpeak). The TRAN group post-transit run distance (-219 m, P < 0.01) and vertical-jump height (5%, P < 0.05) were reduced, the CON group showed no change. The TRAN group post-transit test RPE increased (P < 0.05), however, HRpeak was similar for each group (98%). Post-transit CK activity increased in the TRAN group up to 72 h (P < 0.01) and also, but less markedly, in the CON group (24 and 48 h, P < 0.05). Post-transit run and jump performances were reduced despite mean transit heart rates indicating low energy expenditure. The greater TRAN CK activity suggests muscle damage may have been a contributory factor. These findings have operational implications for Special Forces/naval/police/rescue services carrying out demanding, high-risk physical tasks during and immediately after high-speed boat transits. PMID- 21249381 TI - Pleuran (beta-glucan from Pleurotus ostreatus) supplementation, cellular immune response and respiratory tract infections in athletes. AB - Prolonged and exhausting physical activity causes numerous changes in immunity and sometimes transient increases the risk of upper respiratory tract infections (URTIs). Nutritional supplements as countermeasures to exercise-induced changes have increasingly been studied in the last decade. One of the most promising nutritional supplements is beta-glucan, a well-known immunomodulator with positive effects on the function of immunocompetent cells. In this double blind, placebo-controlled study, we investigated the effect of pleuran, an insoluble beta-(1,3/1,6) glucan from mushroom Pleurotus ostreatus, on selected cellular immune responses and incidence of URTI symptoms in athletes. Fifty athletes were randomized to pleuran or placebo group, taking pleuran (commercial name Imunoglukan((r))) or placebo supplements during 3 months. Venous whole blood was collected before and after 3 months of supplementation and additionally 3 months after supplementation period was completed. Incidence of URTI symptoms together with characterization of changes in phagocytosis and natural killer (NK) cell count was monitored during the study. We found that pleuran significantly reduced the incidence of URTI symptoms and increased the number of circulating NK cells. In addition, the phagocytosis process remained stable in pleuran group during the study in contrast to placebo group where significant reduction of phagocytosis was observed. These findings indicate that pleuran may serve as an effective nutritional supplement for athletes under heavy physical training. Additional research is needed to determine the mechanisms of pleuran function. PMID- 21249382 TI - Myocardial function and aerobic fitness in adolescent females. AB - A recent report indicated that variations in myocardial functional (systolic and diastolic) responses to exercise do not contribute to inter-individual differences in aerobic fitness (peak VO(2)) among young males. This study was designed to investigate the same question among adolescent females. Thirteen highly fit adolescent football (soccer) players (peak VO(2) 43.5 +/- 3.4 ml kg( 1) min(-1)) and nine untrained girls (peak VO(2) 36.0 +/- 5.1 ml kg(-1) min(-1)) matched for age underwent a progressive cycle exercise test to exhaustion. Cardiac variables were measured by standard echocardiographic techniques. Maximal stroke index was greater in the high-fit group (50 +/- 5 vs. 41 +/- 4 ml m(-2)), but no significant group differences were observed in maximal heart rate or arterial venous oxygen difference. Increases in markers of both systolic (ejection rate, tissue Doppler S') and diastolic (tissue Doppler E', mitral E velocity) myocardial functions at rest and during the acute bout of exercise were similar in the two groups. This study suggests that among healthy adolescent females, like young males, myocardial systolic and diastolic functional capacities do not contribute to inter-individual variability in physiologic aerobic fitness. PMID- 21249383 TI - Accuracy of a novel multi-sensor board for measuring physical activity and energy expenditure. AB - The ability to relate physical activity to health depends on accurate measurement. Yet, none of the available methods are fully satisfactory due to several factors. This study examined the accuracy of a multi-sensor board (MSB) that infers activity types (sitting, standing, walking, stair climbing, and running) and estimates energy expenditure in 57 adults (32 females) 39.2 +/- 13.5 years. In the laboratory, subjects walked and ran on a treadmill over a select range of speeds and grades for 3 min each (six stages in random order) while connected to a stationary calorimeter, preceded and followed by brief sitting and standing. On a different day, subjects completed scripted activities in the field connected to a portable calorimeter. The MSB was attached to a strap at the right hip. Subjects repeated one condition (randomly selected) on the third day. Accuracy of inferred activities compared with recorded activities (correctly identified activities/total activities * 100) was 97 and 84% in the laboratory and field, respectively. Absolute accuracy of energy expenditure [100 - absolute value (kilocalories MSB - kilocalories calorimeter/kilocalories calorimeter) * 100] was 89 and 76% in the laboratory and field, the later being different (P < 0.05) from the calorimeter. Test-retest reliability for energy expenditure was significant in both settings (P < 0.0001; r = 0.97). In general, the MSB provides accurate measures of activity type in laboratory and field settings and energy expenditure during treadmill walking and running although the device underestimates energy expenditure in the field. PMID- 21249384 TI - Potential impact of a 500-mL water bolus and body mass on plasma osmolality dilution. AB - A methodological discrepancy exists in the hydration assessment literature regarding the establishment of euhydration, as some investigations utilize a pre hydration technique, while others do not (overnight fluid/food fast). However, the degree that plasma osmolality (P (osm)) dilutes when using the pre-hydration method and how body mass/composition might influence the results is not known. Thirty subjects (22 M, 8 F; 20 +/- 2 years (mean +/- SD); 1.8 +/- 0.1 m; 75.8 +/- 13.5 kg) had P (osm) measured after an 8-h food and fluid fast (overnight fast) and 90 min after a 500-mL (4-9 mL/kg) water bolus (pre-hydration). From pre- to post-bolus, participants' P (osm) declined from 297 +/- 3.5 to 295 +/- 3.8 mmol/kg (p < 0.05; ? -1.7 +/- 3.5 mmol/kg). One-third of the sample diluted to more than -3 mmol/kg. The effect of body mass on P (osm) dilution was investigated by comparing dilution in the ten lightest (62.8 +/- 3.4 kg) and heaviest (92.0 +/- 9.8 kg) participants; however, the change between the light (? -1.9 +/- 3.8 mmol/kg) versus heavy groups (? -1.1 +/- 3.0 mmol/kg) was not different (p > 0.05). The correlation between body mass or total body water and change in P (osm) was weak (p > 0.05), as was the correlation between relative fluid intake based on mass and change in P (osm) (p > 0.05). The two methodologies appear to produce similar P (osm) values when measured in most individuals. However, the potential for significant dilution (>3 mmol/kg) should be considered when choosing the pre-hydration methodology. PMID- 21249385 TI - Creatine supplementation attenuates hemodynamic and arterial stiffness responses following an acute bout of isokinetic exercise. AB - Arterial stiffness and hemodynamics may be increased following a bout of resistance exercise. Oral creatine supplementation (Cr) may attenuate cardiovascular responses after exercise via improved anaerobic metabolism. This study was aimed to determine the effect of Cr on hemodynamic and arterial stiffness responses after acute isokinetic exercise. Sixteen healthy males (22.6 +/- 0.6 year) were randomly assigned to either placebo (Pl, n = 8) or Cr (n = 8) (2 * 5 g/day) for 3 weeks. Brachial systolic blood pressure (SBP), heart rate (HR), brachial-ankle pulse wave velocity (baPWV), and leg PWV were measured in the supine position at rest before and after the interventions. After the supplementation period, parameters were also measured 5 min (PE5) and 15 min (PE15) after two sets of leg isokinetic exercise. There was no difference between the groups in resting measurements before and after the supplementation. Compared with the Pl group, the Cr group had attenuated (P < 0.05) increases in SBP at PE5 (Pl 14.0 +/- 2.5, Cr 5.6 +/- 2.3 mmHg), HR at both P5 (Pl 28 +/- 4 vs. Cr 16 +/- 2 beats/min) and PE15 (Pl 21 +/- 3, Cr 11 +/- 2 beats/min) and rate pressure product at P5 (Pl 45.8 +/- 6.4, Cr 24.8 +/- 2.2) and P15 (Pl 34.2 +/- 5.0, Cr 15.9 +/- 6.0). Compared with the Pl group, the Cr group had suppressed increases in baPWV at PE5 (Pl 1.5 +/- 0.4, Cr -0.1 +/- 0.4 m/s) and PE15 (Pl 1.1 +/- 0.2, Cr -0.3 +/- 0.3 m/s) and returned SBP to pre-exercise values at PE15 (Pl 10.6 +/- 2.8, Cr 2.1 +/- 2.6 mmHg). PWV in the exercised leg decreased at PE5 in both groups. These findings suggest that Cr supplementation attenuates the hemodynamic and baPWV responses after acute isokinetic exercise. PMID- 21249386 TI - Changes in salivary antimicrobial peptides, immunoglobulin A and cortisol after prolonged strenuous exercise. AB - The aim of the present study was to examine whether amount of oral antimicrobial components, human beta-defensin-2 (HBD-2), cathelicidin (LL-37), and immunoglobulin A (IgA), might be affected by prolonged strenuous exercise. Ten young male volunteers either exercised on recumbent ergometer at 75% [Formula: see text] for 60 min (exercise session) or sat quietly (resting session). Saliva samples were obtained at 60-min intervals during sessions for measurements of saliva antimicrobial components (HBD-2, LL-37, and IgA), saliva cortisol and osmolality. Saliva flow rate was decreased and saliva osmolality was increased during the 60-min exercise. Saliva HBD-2 and LL-37 concentrations and secretion rates were increased during and after the exercise, whereas saliva IgA concentration and secretion rates were decreased after the exercise. Saliva cortisol was increased during and after the exercise. The areas under the curve of the time courses of saliva levels of HBD-2 and LL-37 were negatively correlated with those of cortisol levels in saliva. The present findings suggested that a single bout of prolonged strenuous exercise caused a transient increase in the oral HBD-2 and LL-37 levels. PMID- 21249387 TI - Exercise aggravates cardiovascular risks and mortality in rats with disrupted nitric oxide pathway and treated with recombinant human erythropoietin. AB - Chronic administration of recombinant human erythropoietin (rHuEPO) can generate serious cardiovascular side effects such as arterial hypertension (HTA) in clinical and sport fields. It is hypothesized that nitric oxide (NO) can protect from noxious cardiovascular effects induced by chronic administration of rHuEPO. On this base, we studied the cardiovascular effects of chronic administration of rHuEPO in exercise-trained rats treated with an inhibitor of NO synthesis (L NAME). Rats were treated or not with rHuEPO and/or L-NAME during 6 weeks. During the same period, rats were subjected to treadmill exercise. The blood pressure was measured weekly. Endothelial function of isolated aorta and small mesenteric arteries were studied and the morphology of the latter was investigated. L-NAME induced hypertension (197 +/- 6 mmHg, at the end of the protocol). Exercise prevented the rise in blood pressure induced by L-NAME (170 +/- 5 mmHg). However, exercise-trained rats treated with both rHuEPO and L-NAME developed severe hypertension (228 +/- 9 mmHg). Furthermore, in these exercise-trained rats treated with rHuEPO/L-NAME, the acetylcholine-induced relaxation was markedly impaired in isolated aorta (60% of maximal relaxation) and small mesenteric arteries (53%). L-NAME hypertension induced an internal remodeling of small mesenteric arteries that was not modified by exercise, rHuEPO or both. Vascular ET-1 production was not increased in rHuEPO/L-NAME/training hypertensive rats. Furthermore, we observed that rHuEPO/L-NAME/training hypertensive rats died during the exercise or the recovery period (mortality 51%). Our findings suggest that the use of rHuEPO in sport, in order to improve physical performance, represents a high and fatal risk factor, especially with pre-existing cardiovascular risk. PMID- 21249388 TI - Recognition of activities in children by two uniaxial accelerometers in free living conditions. AB - The aim of this study was to develop a classification procedure for accelerometer data to recognize the mode of children's physical activity (PA) in free-living conditions and to compare it with an established cutoff method. Hip and wrist accelerometer data with an epoch interval of 1 s were collected for 7 days from 24 girls (age: 10.7 +/- 1.7 years) and 17 boys (age: 10.6 +/- 1.6 years). Videos were recorded during the same 7 days at several points of time at school and during leisure time. Each second of video data was labeled as one of nine activity classes. A classification procedure based on pattern recognition algorithms was trained with the accelerometer data relating to respective video labels of half of the children and tested against the data from the other half of the children. The overall recognition rate of the classification procedure was 67%. The procedure was able to classify 90% of stationary activities, 83% of walking, 81% of running and 61% of jumping activities. The remaining activities could not be recognized by the main classifier. This study developed a classification procedure based on well-accepted accelerometers and video recordings to recognize children's PA in free-living conditions. It has been shown to be valid for the activities of being stationary, walking, running and jumping. In contrast to former measurement and analysis procedures, this method is able to determine the modes of specific activities among children. Consequently, the presented classification procedure provides additional information on the PA behavior in children registered by established accelerometers. PMID- 21249389 TI - Does cerebral oxygenation affect cognitive function during exercise? AB - This study tested whether cerebral oxygenation affects cognitive function during exercise. We measured reaction times (RT) of 12 participants while they performed a modified version of the Eriksen flanker task, at rest and while cycling. In the exercise condition, participants performed the cognitive task at rest and while cycling at three workloads [40, 60, and 80% of peak oxygen uptake ([Formula: see text])]. In the control condition, the workload was fixed at 20 W. RT was divided into premotor and motor components based on surface electromyographic recordings. The premotor component of RT (premotor time) was used to evaluate the effects of acute exercise on cognitive function. Cerebral oxygenation was monitored during the cognitive task over the right frontal cortex using near-infrared spectroscopy. In the exercise condition, we found that premotor time significantly decreased during exercise at 60% peak [Formula: see text] relative to rest. However, this improvement was not observed during exercise at 80% peak [Formula: see text]. In the control condition, premotor time did not change during exercise. Cerebral oxygenation during exercise at 60% peak [Formula: see text] was not significantly different from that at rest, while cerebral oxygenation substantially decreased during exercise at 80% peak [Formula: see text]. The present results suggest that an improvement in cognitive function occurs during moderate exercise, independent of cerebral oxygenation. PMID- 21249390 TI - Red grape leaf extract improves endurance capacity by facilitating fatty acid utilization in skeletal muscle in mice. AB - Improving endurance capacity leads to increased athletic performance and active lifestyles. The aim of this study was to investigate the effect of the intake of red grape leaf extract (RGLE), used as a traditional herbal medicine in the Mediterranean area, on endurance capacity in mice. Male BALB/c mice were divided into three experimental groups with similar swimming times and body weights; control group, 0.2% (w/w) and 0.5% RGLE group. Swimming times were measured for evaluation of endurance capacity once a week during the 10-week experimental period. Blood and tissues were collected from anesthetized mice immediately after 30 min of swimming exercise, and analyzed blood component and fatty acid oxidation enzyme activity, and gene expression in soleus muscle and mesenteric adipose tissue. Endurance capacity was improved by RGLE in a dose-related manner, and was significantly longer in the 0.5% RGLE group than in the control group at week 10. Plasma lactate levels after exercise in the 0.5% RGLE group were significantly lower than that in the control group. RGLE induced the upregulation of hormone-sensitive lipase mRNA in mesenteric adipose tissue, increased the plasma free fatty acid concentration after exercise, and enhanced fatty acid oxidation enzyme activity in the soleus muscle. Furthermore, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (Pgc1alpha) and its downstream target genes were also significantly upregulated in the soleus muscle in the 0.5% RGLE group. Intake of RGLE upregulated Pgc1alpha expression and facilitated fatty acid oxidation in skeletal muscle, and these effects contributed, in part, to improve endurance capacity. PMID- 21249391 TI - Short-term exercise provides left ventricular myocardial protection against intermittent hypoxia-induced apoptosis in rats. AB - We investigated whether exercise provides beneficial effects to attenuate intermittent hypoxia (IH)-induced myocardial apoptosis. Male Sprague-Dawley rats were randomly assigned to four groups: control (CON), IH, exercise (EXE) or IH interspersed with EXE (IHEXE). IH rats were exposed to repetitive hypoxia reoxygenation cycles (30 s of 5% O(2); 45 s of 21% O(2), 6 h day(-1)) during the light phase (1000-1600 h) for 12 consecutive days. EXE rats were habituated to treadmill running for 5 days, permitted 2 days of rest, followed by 5 exercise bouts (30 m min(-1) for 60 min on a 2% grade) on consecutive days during the dark phase (2000-2200 h). IHEXE rats were exposed to IH during the light phase interspersed with exercise programs during the dark phase on the same day. Apoptosis levels, cytochrome c (Cyt-c), cleaved caspase-3, oxidative stress and antioxidant capacity were determined in the left ventricular (LV) myocardium. IH rats showed higher myocardial levels of the apoptotic index, mitochondria released Cyt-c, cleaved caspase-3 and oxidative stress and lower catalase activity levels than CON rats (p < 0.05, for all). These changes were not observed in EXE rats (p > 0.05, for all) except that catalase activity increased (p < 0.05). IHEXE rats showed lower myocardial levels of apoptotic index, mitochondria-released Cyt-c, cleaved caspase-3 and oxidative stress and higher catalase activity levels (p < 0.05, for all) than IH rats. We conclude that short term exercise provides potent cardioprotective effects by attenuating IH-induced myocardial apoptosis. PMID- 21249392 TI - Endurance exercise training ameliorates insulin resistance and reticulum stress in adipose and hepatic tissue in obese rats. AB - Obesity-induced endoplasmatic reticulum (ER) stress has been demonstrated to underlie the induction of obesity-induced JNK and NF-kappaB activation inflammatory responses, and generation of peripheral insulin resistance. On the other hand, exercise has been used as a crucial tool in obese and diabetic patients, and may reduce inflammatory pathway stimulation. However, the ability of exercise training to reverse endoplasmatic reticulum stress in adipose and hepatic tissue in obesity has not been investigated in the literature. Here, we demonstrate that exercise training ameliorates ER stress and insulin resistance in DIO-induced rats. Rats were fed with standard rodent chow (3,948 kcal kg(-1)) or high-fat diet (5,358 kcal kg(-1)) for 2 months. After that rats were submitted to swimming training (1 h per day, 5 days for week with 5% overload of the body weight for 8 weeks). Samples from epididymal fat and liver were obtained and western blot analysis was performed. Our results showed that swimming protocol reduces pro-inflammatory molecules (JNK, IkappaB and NF-kappaB) in adipose and hepatic tissues. In addition, exercise leads to reduction in ER stress, by reducing PERK and eIF2alpha phosphorylation in these tissues. In parallel, an increase in insulin pathway signaling was observed, as confirmed by increases in IR, IRSs and Akt phosphorylation following exercise training in DIO rats. Thus, results suggest that exercise can reduce ER stress, improving insulin resistance in adipose and hepatic tissue. PMID- 21249393 TI - A novel mutation of LHX3 is associated with combined pituitary hormone deficiency including ACTH deficiency, sensorineural hearing loss, and short neck-a case report and review of the literature. AB - The LHX3 LIM-homeodomain transcription factor gene is required for normal pituitary and motoneuron development. LHX3 mutations are associated with growth hormone, prolactin, gonadotropin, and TSH deficiency; abnormal pituitary morphology; and may be accompanied with limited neck rotation and sensorineural hearing loss. We report on a boy, who presented with hypoglycemia in the newborn period. He is the second child of healthy unrelated parents. Short neck, growth hormone deficiency, and central hypothyroidism were diagnosed at a general pediatric hospital. Growth hormone and levothyroxine treatment were started, and blood sugar normalized with this treatment. On cerebral MRI, the anterior pituitary gland was hypoplastic. Sensorineural hearing loss was diagnosed by auditory testing. During follow-up, six repeatedly low morning cortisol levels (<1 MUg/dl) and low ACTH levels (<10 pg/ml) were documented, so ACTH deficiency had developed over time and therefore hydrocortisone replacement was started at 1.5 years of age. Mutation analysis of the LHX3 gene revealed a homozygous stop mutation in exon 2: c.229C>T (CGA > TGA), Arg77stop (R77X). A complete loss of function is assumed with this homozygous stop mutation. We report a novel LHX3 mutation, which is associated with combined pituitary hormone deficiency including ACTH deficiency, short neck, and sensorineural hearing loss. All patients with LHX3 defects should undergo longitudinal screening for ACTH deficiency, since corticotrope function may decline over time. All patients should have auditory testing to allow for regular speech development. PMID- 21249394 TI - Clinical practice: neonatal cholestasis. AB - Neonatal cholestasis is a serious condition which requires urgent further investigation. Delayed referral of cholestatic neonates, however, is still a significant problem. Every child presenting with jaundice beyond the age of 2 weeks should be evaluated with a fractionated bilirubin checked. In case of neonatal cholestasis, the first step should be the assessment of coagulation and urgent parenteral vitamin K administration in case of coagulopathy and the exclusion of life-threatening conditions or disorders requiring urgent specific treatment. Any child presenting with acholic stools should be referred to a paediatric hepatology unit in order to confirm or rule out biliary atresia, as prognosis after porto-enterostomy correlates with younger age at the time of surgery. Once these conditions have been excluded, a more individualised approach is used based on anamnestic, clinical and further diagnostic findings. Besides specific medical or surgical therapy for selected diseases, early supportive treatment aiming for optimal growth and development and prevention of complications is of uttermost importance. PMID- 21249395 TI - Body size, trophic level, and the use of fish as transmission routes by parasites. AB - Within food webs, trophically transmitted helminth parasites use predator-prey links for their own transfer from intermediate prey hosts, in which they occur as larval or juvenile stages, to predatory definitive hosts, in which they reach maturity. In large taxa that can be used as intermediate and/or definitive hosts, such as fish, a host species' position within a trophic network should determine whether its parasite fauna consists mostly of adult or larval helminths, since vulnerability to predation determines an animal's role in predator-prey links. Using a large database on the helminth parasites of 303 fish species, we tested whether the proportion of parasite species in a host that occur as larval or juvenile stages is best explained by their trophic level or by their body size. Independent of fish phylogeny or habitat, only fish body length emerged as a significant predictor of the proportion of parasites in a host that occur as larval stages from our multivariate analyses. On average, the proportion of larval helminth taxa in fish shorter than 20 cm was twice as high as that for fish over 100 cm in length. This is consistent with the prediction that small fishes, being more vulnerable to predation, make better hosts for larval parasites. However, trophic level and body length are strongly correlated among fish species, and they may have separate though confounded effects on the parasite fauna exploiting a given species. Helminths show varying levels of host specificity toward their intermediate host when the latter is the downstream host involved in trophic transmission toward an upstream definitive host. Given this broad physiological compatibility of many helminths with fish hosts, our results indicate that fish body length, as a proxy for vulnerability to predators, is a better predictor of their use by helminth larvae than their trophic level based on diet content. PMID- 21249396 TI - Clinical and laboratory features of Macedonian children with OCRL mutations. AB - OCRL mutations, which are a hallmark of Lowe syndrome, have recently been found in patients with isolated renal phenotype (Dent-2 disease). In this report, we describe clinical and laboratory features in five Macedonian children with mutations in the OCRL gene. Children with a clinical diagnosis of Lowe syndrome or Dent disease underwent complete neurological and ophthalmological examination, imaging of the kidney and urinary tract, assessment of renal tubular function, and mutation analysis of the OCRL gene. Two children (18 months and 11 years, respectively) were diagnosed with Lowe syndrome on the basis of congenital cataracts, severe psychomotor retardation, and renal dysfunction. Both children had low molecular weight proteinuria (LMWP) and hypercalciuria, but not Fanconi syndrome. The older one had bilateral nephrolithiasis due to associated hypocitraturia and mild hyperoxaluria. Three children with asymptomatic proteinuria were diagnosed with Dent-2 disease; none had cataracts or neurological deficit. One child showed mild mental retardation. All had LMWP, hypercalciuria, and elevated enzymes (creatine phosphokinase, lactic dehydrogenase). All three children had an abnormal Tc-99m DMSA scan revealing poor visualization of the kidneys with a high radionuclide content in the bladder; none had nephrolithiasis or nephrocalcinosis. In conclusion, children with OCRL mutations may present with very mild phenotype (asymptomatic proteinuria with/without mild mental retardation) or severe classic oculocerebrorenal syndrome of Lowe. Elevated enzymes and abnormal results on the Tc-99m DMSA scan may be useful indicators for Dent-2 disease. PMID- 21249397 TI - World Kidney Day 2011: protect your kidneys, save your heart. PMID- 21249398 TI - Rhabdomyolysis: pathogenesis of renal injury and management. PMID- 21249399 TI - Pediatric patients with a malignant bone tumor: when does functional assessment make sense? AB - PURPOSE: The diagnosis of a malignant bone tumor in the lower limb is a risk factor for physical disability, limiting physical performance. Walking ability especially, which is essential for most activities of daily living, is limited in those patients. In the present study, the extent of limitations during the course of treatment was investigated to determine when the assessment of functional parameters is meaningful in those patients. METHODS: In the present study, activity levels were determined in 20 patients with a malignant bone tumor in the lower limb who received endoprosthetic replacement of the affected bone and in 20 healthy individuals. A uniaxial accelerometer was used to investigate patients at five different time points after surgery. RESULTS: Patients performed significantly less amounts and intensities of activity than control individuals at all measurements. Significant increases in the volume of activity were observed after cessation of treatment. However, the intensity of activity only showed minor increases. Patients experiencing complications of surgery revealed greater restriction than those without even 18 months after surgery. CONCLUSIONS: After cessation of treatment for their disease, patients recovered markedly and showed great improvements in physical activity. However, some limitations appeared to persist. Comparisons with patients with longer follow-up revealed that meaningful functional assessment does not make sense within the first 12 months after surgery. More research is needed to show if longer follow-up periods reveal further improvements. Based on such information, it should be more promising to develop individually tailored activity recommendations and intervention programs. PMID- 21249400 TI - Lightwand: a useful aid in faciomaxillary trauma. AB - Airway management in patients of faciomaxillary injury is of great concern to the anesthesiologist. Bag and mask ventilation and orotracheal intubation may be difficult with these patients. Recently, a middle aged, obese female presented in the emergency department after sustaining a blast injury, with laceration of the upper chest and left submandibular region. Laceration of the submandibular region was communicating with the intraoral space and the airway was filled with blood. The airway was secured with nasotracheal intubation aided by a lightwand, after failure with the Macintosh laryngoscope. This case report highlights the importance of the lightwand in intubating a patient with a bleeding airway and when the bright light glow of the lightwand gives sufficient direction toward the glottis for successful tracheal intubation. PMID- 21249402 TI - Axonal regeneration effects of Wnt3a-secreting fibroblast transplantation in spinal cord-injured rats. AB - BACKGROUND: Axonal regeneration is a prerequisite for recovery from spinal cord injury. Here, we investigated whether Wnt3a-secreting fibroblasts exert a favorable effect on spinal cord regeneration in spinal cord-injured rats. METHODS: Spinal cord injury (SCI) was induced in rats (n = 21) using an NYU impactor. One week after SCI, rats were assigned to a Wnt3a-secreting fibroblast transplantation group (Wnt group, n = 7), a L929 fibroblast transplantation group (vehicle group, n = 7), and contusion only group (sham group, n = 7). Motor function was tested weekly for 6 weeks. Manganese-enhanced magnetic resonance imaging (ME-MRI) was performed twice, once before cell transplantation and again 5 weeks after cell transplantation. After ME-MRI, expression of the axonal regeneration marker GAP-43 was assessed by immunohistochemistry (IHC). RESULTS: In the Wnt group, the mean Basso-Beattie-Bresnahan score was higher than that of the vehicle and sham groups throughout the observation period. The Wnt group also exhibited stronger signal intensity on ME-MRI, and IHC revealed that GAP-43 was highly expressed in the injured spinal cord in the Wnt group. CONCLUSIONS: These results strongly suggest that transplanted Wnt3a secreting fibroblasts promote axonal regeneration and functional improvement after SCI. Although further investigation will be necessary to clarify the intracellular mechanism by which Wnt signaling promotes axonal regeneration and functional improvement, this approach could be a highly promising therapeutic strategy for SCI. PMID- 21249401 TI - Sugar-sweetened and diet beverage consumption is associated with cardiovascular risk factor profile in youth with type 1 diabetes. AB - The prevalence of cardiovascular disease (CVD) risk factors among youth with type 1 diabetes is high and associated with age, gender, and race/ethnicity. It has also been shown that youth with type 1 diabetes often do not follow dietary recommendations. The objective of this cross-sectional observational study was to explore the association of sugar-sweetened and diet beverage intake with A1c, plasma lipids, adiponectin, leptin, systolic, and diastolic blood pressure in youth with type 1 diabetes. We examined data from 1,806 youth age 10-22 years with type 1 diabetes, of which 22% were minority (10% Hispanic, 8% African Americans, 4% other races) and 48% were female. Sugar-sweetened beverage, diet beverage, and mineral water intake was assessed with a food frequency questionnaire. After adjustment for socio-demographic and clinical covariates, physical activity and total energy intake, high sugar-sweetened beverage intake (at least one serving per day vs. none), was associated with higher levels of total cholesterol, LDL cholesterol, and plasma triglycerides, but not with A1c. High diet beverage intake was associated with higher A1c, total cholesterol, LDL cholesterol, and triglycerides. These associations were partially confounded by body mass index, saturated fat and total fiber intake. High sugar-sweetened beverage intake may have an adverse effect on CVD risk in youth with type 1 diabetes. Diet beverage intake may be a marker of unhealthy lifestyle which, in turn, is associated with worse metabolic control and CVD risk profile in these youth. Youth with diabetes should be encouraged to minimize sugar-sweetened beverage intake. PMID- 21249403 TI - Hemicallotasis for correction of varus deformity of the proximal tibia using a unilateral external fixator. AB - BACKGROUND: Gradual correction of varus deformity of the proximal tibia is generally accepted and produces good results. However, most studies have used circular external fixators, which are complex and cause patient discomfort. This study was undertaken to determine the efficacy of hemicallotasis with a unilateral external fixator for correction of varus deformity of the proximal tibia. METHODS: Thirteen patients (21 legs, 8 bilateral) were included in this study: 6 with constitutional bowing, 3 with a malunion, 2 with Blount's disease, and 2 with Turner syndrome. There were 7 males and 6 females of mean age 21 years (range 13-40). With an oblique osteotomy on the proximal tibia, a unilateral external fixator was placed on the medial side. Using a distraction of 1 mm/day, the external fixator was removed after consolidation of the callus. RESULTS: Surgery corrected medial proximal tibia angle from a preoperative average of 75.1 degrees (64 degrees -81 degrees ) to 88.6 degrees (86 degrees -90 degrees ) at final follow-up. Average tibiofemoral angle improved from -7 degrees to 6.8 degrees . The duration of external fixation averaged 101.3 days and the external fixation index was 70 days/cm. No patient had a limited ambulation, and all recovered preoperative range of knee motion (mean 130.1 degrees ) at final follow up. Seven minor complications (pin tract infection, clamp loosening) and 1 major complication (uncorrected genu procurvatum) were observed. CONCLUSIONS: Hemicallotasis using a unilateral external fixator was found to be a safe and simple corrective procedure for varus deformity of the proximal tibia, with few complications. PMID- 21249404 TI - Squeaking sound in total hip arthroplasty using ceramic-on-ceramic bearing surfaces. AB - PURPOSE: To evaluate the causes and frequency of the squeaking sound in ceramic on-ceramic THA. MATERIALS AND METHODS: This study included 61 hips of 50 patients who underwent ceramic-on-ceramic THA in our hospital from March 1999 to April 2005. The average age at the time of operation was 57.6 years. The average duration of follow-up was 69.5 months. Three different acetabular components were used: Osteonics (Stryker, USA: 24 cases), Bicontact (Aesculap, Germany: 27 cases) and ABG (Howmedica, UK: 10 cases). RESULTS: Fourteen (22.9%) of the 61 cases had a squeaking sound, and this sound started a mean of 47.57 months after the operation. Except in one case, the squeaking sound remained until the last follow up. There was no difference in acetabular component position between the squeaking and nonsqueaking groups. The squeaking sound was found to be related to the BMI (body mass index) and cup design. It occurred frequently in patients with high BMI who had received a total hip arthroplasty using an Osteonics cup. Among 11 of the patients, squeaking occurred while squatting, and in 3 patients while walking. Six patients suffered from mild restrictions on their activities of daily living, and 8 had more than moderate restrictions with squeaking sounds. CONCLUSION: A squeaking sound in THA using ceramic-on-ceramic surfaces is not a rare complication, and often affects the patient's behavior. PMID- 21249405 TI - Intramedullary spinal cord metastasis following spontaneous malignant transformation from giant cell tumor of bone 16 years after pulmonary metastasis. PMID- 21249406 TI - Lipoma-like lipoblastoma arising from the femoral vein. PMID- 21249407 TI - Electroconvulsive therapy for psychotropic-refractory bipolar affective disorder and severe self-injury and aggression in an 11-year-old autistic boy. AB - We report the successful use of electroconvulsive therapy in a 11-year-old boy with autism and a 4-year history of psychotropic-resistant bipolar affective disorder associated with dangerous episodes of self-injurious and aggressive behaviors placing his caregivers and himself at significant safety risk. Extensive behavioral and medication interventions in both inpatient and outpatient settings had been ineffective, and the boy was at risk for acute physical injury and restrictive out-of-home placement. An acute course of eight bilateral electroconvulsive therapies resulted in significant mood stabilization and significant improvement of self-injury and aggression. Maintenance electroconvulsive therapy and psychotropic interventions were then pursued. PMID- 21249408 TI - Assessment of cervical pain and function in patients with rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is characterized by inflammation of the synovial membrane, which can lead to deformities and functional disability. Unlike the dorsal and lumbar spine, the cervical spine is often affected by RA. The objective of this paper is to assess cervical pain and function in patients with RA and correlate these variables with overall function, quality of life, and radiographic findings on the cervical spine. One hundred individuals aged 18 to 65 years were divided into study group (50 patients with rheumatoid arthritis) and control group (50 healthy individuals, paired for gender and age). Patients with prior surgery, prior trauma or other symptomatic cervical spine condition were excluded. The visual analogue pain scale (VAS), Neck Pain and Disability Scale (NPDS), SF-36, HAQ and X-rays were used for evaluation purposes. Mean disease duration was 11.1 years. The cervical VAS was 2.4 cm and 1.3 cm for the study and control groups, respectively (p = 0.074). Statistical differences were found in NPDS scores, mean = 26.7 and 6.9, and HAQ scores, mean = 1.1 and 0.1, for the study and control groups, respectively (p < 0.001). SF-36 scores were statistically worse in the study group, except for the vitality, social aspects and mental health subscales. There was a positive correlation between the NPDS and VAS (r = 0.54) and between the NPDS and HAQ (r = 0.67). There was a negative correlation between the NPDS and SF-36 functional capacity domain (r = -0.53) and physical limitation domain (r = -0.58). The radiographic findings revealed more prevalent anterior atlanto-axial subluxation (p = 0.030), listhesis in neutral posture (p = 0.037), listhesis in extension (p = 0.007), degenerative alteration of C4-C5 segment (p = 0.023), size of C2 spinal canal (p = 0.002) and C3 spinal canal (p = 0.029) in the study group. Patients with RA have poorer cervical function than healthy individuals, although there is no difference in cervical pain. PMID- 21249409 TI - Neutrophil CD64: diagnostic accuracy and prognostic value in patients presenting to the emergency department. AB - The purpose of this study was to evaluate the diagnostic accuracy and prognostic value of neutrophil CD64 expression for bacterial infection in febrile adult patients presenting to our hospital emergency department. We prospectively included 132 patients with fever >= 38oC (>= 100.4oF) during the last 24 hours and we measured CD64 expression on neutrophils the day after admission at the emergency department. We followed the patients until full recovery or death. There were 115 (87%) patients with bacterial infection and 108 (94%) of them survived. There were 17 (13%) patients without bacterial infection and 12 (71%) of them survived. Patients with bacterial infection and patients who survived showed a CD64 index higher when compared with patients without bacterial infection and patients who died, respectively (3.7 +/- 3.2 vs. 2.5 +/- 2.3; p = 0.03; and 3.7 +/- 3.1 vs. 1.7 +/- 0.6; p = 0.002; Mann-Whitney U test). The receiver operating characteristic (ROC) curve analysis for detecting bacterial infection and predicting survival with the CD64 index showed an area under curve (AUC) of 0.66 (95% CI, 0.52-0.8; p = 0.03) and 0.71 (95% CI, 0.57-0.85; p = 0.01), respectively. Diagnostic accuracy and prognostic value of CD64 expression was good in adult patients with fever. PMID- 21249410 TI - Evaluation of discrepancies between oxacillin and cefoxitin susceptibility in coagulase-negative staphylococci. AB - The Clinical and Laboratory Standards Institute (CLSI) recommends testing coagulase-negative staphylococci (CoNS) strains to determine resistance against oxacillin by testing for mecA, PBP2a, or with cefoxitin disk. However, discrepant results of resistance to oxacillin and susceptibility to cefoxitin were found. In this study, we aimed to investigate the oxacillin resistance and cefoxitin susceptibility of CoNS in Taiwan. Of 9,017 strains collected from 2005 to 2010, 131 (1.5%) of the isolates were oxacillin-resistant and cefoxitin-susceptible. Species identification was carried out using the Vitek 2 system or 16S ribosomal RNA sequencing. Oxacillin minimum inhibitory concentrations (MICs) were examined by the agar dilution method. The presence of mecA and the activity of beta lactamase were performed by polymerase chain reaction (PCR) and Cefinase disks, respectively. Overall, 33% (43/129) of the strains carried mecA and 43% (37/86) of mecA-negative isolates tested positive for beta-lactamase. The remaining 49 isolates were negative for both mecA and beta-lactamase, and were mainly Staphylococcus cohnii ssp. urealyticus and S. saprophyticus (oxacillin MICs 0.5-2 MUg/ml) obtained from bloodstream and urinary tract infections. Our study suggests that incorrect reporting can be found in CoNS using cefoxitin disk alone to determine the susceptibility to oxacillin, and the strains should be further tested for oxacillin MICs and detection of the mecA gene or beta-lactamase activity. PMID- 21249411 TI - Why is the coexistence of gastric cancer and duodenal ulcer rare? Examination of factors related to both gastric cancer and duodenal ulcer. AB - The coexistence of gastric cancer with duodenal ulcer has been found empirically to be rare, but why it is rare is difficult to explain satisfactorily. To elucidate this question, we carried out a literature review of the subject. The frequency with which the two diseases coexist is 0.1-1.7%, and the main factor associated with both gastric cancer and duodenal ulcer is Helicobacter pylori infection. However, there are marked differences between the disorders of hyperchlorhydria in duodenal ulcer, and hypochlorhydria in gastric cancer. The most acceptable view of the reason for the difference may be that the acquisition of H. pylori infection occurs mainly in childhood, so that the time of acquisition of atrophic gastritis may be the most important, and if atrophic gastritis is not acquired early, high levels of gastric acid may occur, and consequently acute antral gastritis and duodenal ulcer may occur in youth, whereas, in elderly individuals, persistent H. pylori infections and the early appearance of atrophic gastritis may be the causes of low gastric acid, and consequently gastric cancer may occur. In patients with duodenal ulcer, factors such as nonsteroidal anti-inflammatory drugs (NSAIDs) and dupA-H. pylori strains may contribute to preventing the early acquisition of atrophic gastritis, while acid-suppressive therapy and vascular endothelial growth factor and other entities may inhibit atrophic gastritis. In contrast, in gastric cancer, factors such as excessive salt intake, acid-suppressive therapy, polymorphisms of inflammatory cytokines, and the homB-H. pylori strain may contribute to the early acquisition of atrophic gastritis, while factors such as NSAIDs; fruits and vegetables; vitamins A, C, and E; and good nutrition may inhibit it. PMID- 21249412 TI - Transcatheter arterial chemoembolization with docetaxel-loaded microspheres controls heavily pretreated unresectable liver metastases from colorectal cancer: a case study. AB - This is the first case report describing transcatheter arterial chemoembolization (TACE) with docetaxel-loaded microspheres which was successful in controlling liver metastases. We report on a 50-year-old woman with unresectable liver metastases from colorectal cancer. Since November 2007, the patient had received 12 courses of mFOLFOX6 (LV/5-FU/L-OHP) as the 1st line therapy, 18 courses of LV/5-FU as the 2nd line therapy, 16 courses of FOLFIRI (LV/5-FU/CPT-11) + bevacizumab as the 3rd line therapy, and 32 courses of cetuximab as the 4th line therapy. All treatments had been conducted after confirmation of the disease progression. The patient experienced hepatic dysfunction, upper abdominal pain and malaise due to the growth of metastatic liver tumors. Since December 2009, the patient received 3 courses of TACE with docetaxel-loaded microspheres in combination with hepatic arterial infusion of 20 mg cisplatin (CDDP) in a palliative setting for the treatment of liver metastases, which resulted in a reduction or necrosis of liver metastases and improvement in hepatic function and symptoms. TACE with docetaxel-loaded microspheres may be a palliative therapy for patients with colorectal cancer who are refractory to the current standard systemic chemotherapy and have predominant liver metastases. PMID- 21249413 TI - A case of usual (basaloid)-type vulvar intraepithelial neoplasia that failed to respond to imiquimod cream: clinical implications. AB - The authors report a case of usual-type (basaloid-type) vulvar intraepithelial neoplasia (VIN) 3 that failed to respond to imiquimod cream. A 51-year-old Japanese woman visited her local gynecologist complaining of vulvar itching. Atypical cells were noted in cytology smears, but nine vulvar biopsy specimens showed benign proliferation of epithelial tissue. The patient was placed under careful observation for 8 months, when the vulvar smears once again showed atypical cells and biopsy specimens revealed VIN3. The patient was then referred to our hospital where she was given a diagnosis of VIN 3, basaloid type of usual type. The biopsy specimens were positive for p16 and the lesions were confirmed to be human papilloma virus (HPV)-related. We recommended simple vulvectomy but the patient requested conservative treatment with imiquimod cream. With her written informed consent, we prescribed imiquimod cream to be self-administered 3 times a week. Colposcopy and pap smear test were performed every 2 weeks. Four weeks after the start of treatment, a fingertip-sized papule was detected at the patient's vaginal introitus. By 6 weeks, the lesion had enlarged, and biopsy specimens revealed invasive squamous cell carcinoma. At 7 weeks, we performed simple vulvectomy. The surgical specimen showed stage pT1b keratinizing-type squamous cell carcinoma. HPV-16 DNA was detected in the specimen. PMID- 21249414 TI - Pulmonary nocardiosis caused by Nocardia exalbida complicating Pneumocystis pneumonia in an HIV-infected patient. AB - A 47-year-old man with optimally controlled type-2 diabetes mellitus and chronic hepatitis B was admitted to a local hospital because of a 1-week history of cough and high-grade fever. He was diagnosed with Pneumocystis pneumonia (PCP) and Klebsiella pneumonia from a chest radiograph and sputum. Simultaneously, he was found to have HIV infection with a CD4 count of 76/MUl. Despite alteration of treatment secondary to the development of allergic reaction to trimethoprim sulfamethoxazole (TMP-SMX), the patient was able to complete a 3-week therapy for PCP after being switched to pentamidine isetionate. After the treatment of PCP, he was referred to our hospital for the initiation of anti-HIV therapy. He presented with recurrent high-grade fever of a few days' duration prior to his initial visit, which subsequently led to his admission. Chest computed tomography (CT) showed the enlargement of a previously identified infiltrate in the left upper lung field, and the sputum culture upon admission was positive for Gram positive branching rods; the organism was later identified as Nocardia exalbida. Due to his allergy to sulfonamide, the patient was treated with imipenem (IMP) and amikacin (AMK) given intravenously for 17 days, followed by garenoxacin (GRNX) taken orally for 6 months, without any adverse effects. The chest infiltrate resolved completely, and he remains stable without relapse 8 months after the completion of the therapy. Pulmonary nocardiosis should be considered as a differential diagnosis of recurring pneumonia in immunocompromised patients, especially in HIV-infected individuals. Oral administration of GRNX following IMP and AMK can be used as an alternative to TMP-SMX therapy in cases of pulmonary nocardiosis caused by N. exalbida. PMID- 21249415 TI - Evaluation of short-term clinical efficacy of 3-day therapy with azithromycin in comparison with 5-day cefcapene-pivoxyl for acute streptococcal tonsillopharyngitis in primary care. AB - Group A streptococcal (GAS) tonsillopharyngitis is one of the few conditions for which antibiotics are advocated among common upper respiratory infections. Although a 3-day course of azithromycin is attracting attention as a treatment of choice for the condition, it is not clear if the efficacy of the treatment is comparable with that of treatment with cephalosporins. A prospective, randomized, comparative multicenter study was conducted to compare the efficacy of azithromycin (AZM) given once daily for 3 days with that of cefcapene-pivoxyl (CFPN-PI) divided into three daily doses for 5 days. 88 patients (male: 38, mean age: 16.5) were treated with AZM and 69 (male: 34, mean age: 16.9) with CFPN-PI. The symptoms of all but 5 (2 for AZM and 3 for CFPN-PI) of the patients were resolved by the 8th day of the treatment. By the 4th day of the treatment, criteria for clinical efficacy were fulfilled in 71 (80.7%) subjects who were treated with AZM and in 48 (67.6%) of those treated with CFPN-PI (p = 0.07). The same figures on the 8th day of the treatment were 86 (97.7%) and 68 (95.8%), respectively (p = 0.66), confirming there was no significant difference in clinical efficacy between the two treatments. Mild adverse reactions were reported by two patients treated with AZM and by none treated with CFPN-PI. The clinical efficacy of a 3-day course with AZM was comparable with that of a 5-day course of CFPN-PI for GAS tonsillopharyngitis. PMID- 21249416 TI - Environmental factors influencing the survival of chronic dialysis patients. AB - BACKGROUND: There have been few investigations into the effects of environmental factors on the outcome of end-stage renal disease. METHODS: We investigated factors influencing the survival of dialysis patients in each prefecture of Japan by analyzing data from the Japan Statistics Bureau and Japanese Society for Dialysis Therapy using univariate and multivariate regression analysis. RESULTS: Univariate analysis showed that the number of dialysis specialists (p = 0.028, r = 0.319), the density of dialysis centers (the number in relation to the area of each prefecture, p = 0.018, r = 0.344), the average annual temperature (p < 0.0001, r = 0.686), and the mortality rate of the general population with cerebrovascular disease (p = 0.014, r = -0.355) were correlated with the 1-year survival of new dialysis patients from 2005 to 2007. Multivariate regression analysis showed that the average annual temperatures were extracted as determinants of the 1-year survival rate of new dialysis patients (p < 0.0001, F = 40.11, R(2) = 0.471, R(2)' = 0.460). CONCLUSION: The average annual temperatures could have an influence on the survival of dialysis patients. Survival of new dialysis patients by prefecture in Japan may be influenced by environmental factors that cannot be controlled medically after the initiation of dialysis. PMID- 21249417 TI - Effectiveness of an educational and physical program in reducing accompanying symptoms in subjects with head and neck pain: a workplace controlled trial. AB - The objective of this study is to evaluate the effectiveness of an educational and physical program in reducing behavioral or somatic symptoms along with headache, neck and shoulder pain in a working community. A controlled, non randomized trial was carried out in a working community and 384 employees were enrolled and divided into a study group (Group 1) and a control group (Group 2). The Group 1 received a physical and educational intervention, consisting of relaxation and posture exercises and the use of visual feedback. After 6 months, the intervention was administered to the Group 2. Both groups were then followed for an additional 6 months until the end of the trial. The presence of accompanying symptoms was investigated with a semi-structured interview using a checklist of 20 items, along with headache, neck, and shoulder pain parameters and the prevalence of generalized anxiety disorder and depression, in three clinical examinations at baseline, after 6 months and after 12 months. For each symptom, as well as the presence of any type of symptom, the differences between groups in the prevalence at the clinical examinations following the baseline were evaluated by applying logistic models. After 6 months, the probability of the presence of any type of symptom was significantly lower in the Group 1 (OR 0.69, 95% CI 0.56-0.85) with respect to the Group 2. After 12 months, the pooled estimation did not show any significant difference of symptom prevalence between groups (OR 0.80, 95% CI 0.64-1.00). In conclusion, this is the first longitudinal study relative to accompanying symptoms. Its results suggest the effectiveness of this cognitive program in reducing the burden of physical and psychiatric complaints in a large, working population. PMID- 21249418 TI - Selective embryo abortion in a perennial tree-legume: a case for maternal advantage of reduced seed number per fruit. AB - In this study, I analyzed time-course of embryo abortion, positional bias in seed maturation and maternal costs of seed packaging in Cercis canadensis. While basal embryos experience similar rates of abortion as those in other positions during the first week of development, abortion rates peak during the second week. Head start in resource sequestration by stigmatic embryos may explain high rates of basal embryo abortion. Similar seed packaging costs and seed mass for single and multi-seeded pods suggests that maternal parent regulates pod size in accordance with seed numbers per pod investing equally in the surviving offspring. Competition during early developmental period results in the abortion of less competitive embryos allowing for optimal resource investment. PMID- 21249419 TI - Orion: a web-based application designed to monitor resident and fellow performance on-call. AB - Radiology residency and fellowship training provides a unique opportunity to evaluate trainee performance and determine the impact of various educational interventions. We have developed a simple software application (Orion) using open source tools to facilitate the identification and monitoring of resident and fellow discrepancies in on-call preliminary reports. Over a 6-month period, 19,200 on-call studies were interpreted by 20 radiology residents, and 13,953 on call studies were interpreted by 25 board-certified radiology fellows representing eight subspecialties. Using standard review macros during faculty interpretation, each of these reports was classified as "agreement", "minor discrepancy", and "major discrepancy" based on the potential to impact patient management or outcome. Major discrepancy rates were used to establish benchmarks for resident and fellow performance by year of training, modality, and subspecialty, and to identify residents and fellows demonstrating a significantly higher major discrepancy rate compared with their classmates. Trends in discrepancies were used to identify subspecialty-specific areas of increased major discrepancy rates in an effort to tailor the didactic and case-based curriculum. A series of missed-case conferences were developed based on trends in discrepancies, and the impact of these conferences is currently being evaluated. Orion is a powerful information technology tool that can be used by residency program directors, fellowship programs directors, residents, and fellows to improve radiology education and training. PMID- 21249422 TI - Enolases: storage compounds in seeds? Evidence from a proteomic comparison of zygotic and somatic embryos of Cyclamen persicum Mill. AB - Somatic embryogenesis is well established for the economic relevant ornamental crop Cyclamen and thus could supplement the elaborate propagation via seeds. However, the use of somatic embryogenesis for commercial large scale propagation is still limited due to physiological disorders and asynchronous development within emerged embryos. To overcome these problems, profound knowledge of the physiological processes in Cyclamen embryogenesis is essential. Thus, the proteomes of somatic and zygotic embryos were characterised in a comparative approach. Protein separation via two dimensional IEF-SDS PAGE led to a resolution of more than 1,000 protein spots/gel. Overall, 246 proteins were of differential abundance in the two tissues compared. Mass spectrometry analysis of the 300 most abundant protein spots resulted in the identification of 247 proteins, which represent 90 distinct protein species. Fifty-five percent of the 247 proteins belong to only three physiological categories: glycolysis, protein folding and stress response. The latter physiological process was especially predominant in the somatic embryos. Remarkably, the glycolytic enzyme enolase was the protein most frequently detected and thus is supposed to play an important role in Cyclamen embryogenesis. Data are presented that indicate involvement of "small enolases" as storage proteins in Cyclamen. A digital reference map was established via a novel software tool for the web-based presentation of proteome data linked to KEGG and ExPasy protein-databases and both were made publicly available online. PMID- 21249420 TI - Compatibility between 3T 1H SV-MRS data and automatic brain tumour diagnosis support systems based on databases of 1.5T 1H SV-MRS spectra. AB - OBJECT: This study demonstrates that 3T SV-MRS data can be used with the currently available automatic brain tumour diagnostic classifiers which were trained on databases of 1.5T spectra. This will allow the existing large databases of 1.5T MRS data to be used for diagnostic classification of 3T spectra, and perhaps also the combination of 1.5T and 3T databases. MATERIALS AND METHODS: Brain tumour classifiers trained with 154 1.5T spectra to discriminate among high grade malignant tumours and common grade II glial tumours were evaluated with a subsequently-acquired set of 155 1.5T and 37 3T spectra. A similarity study between spectra and main brain tumour metabolite ratios for both field strengths (1.5T and 3T) was also performed. RESULTS: Our results showed that classifiers trained with 1.5T samples had similar accuracy for both test datasets (0.87 +/- 0.03 for 1.5T and 0.88 +/- 0.03 for 3.0T). Moreover, non significant differences were observed with most metabolite ratios and spectral patterns. CONCLUSION: These results encourage the use of existing classifiers based on 1.5T datasets for diagnosis with 3T (1)H SV-MRS. The large 1.5T databases compiled throughout many years and the prediction models based on 1.5T acquisitions can therefore continue to be used with data from the new 3T instruments. PMID- 21249423 TI - Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. AB - The immune system regulates angiogenesis in cancer with both pro- and antiangiogenic activities. The induction of angiogenesis is mediated by tumor associated macrophages and myeloid-derived suppressor cells (MDSC) which produce proinflammatory cytokines, endothelial growth factors (VEGF, bFGF...), and protease (MMP9) implicated in neoangiogenesis. Some cytokines (IL-6, IL-17...) activated Stat3 which also led to the production of VEGF and bFGF. In contrast, other cytokines (IFN, IL-12, IL-21, and IL-27) display an antiangiogenic activity. Recently, it has been shown that some antiangiogenic molecules alleviates immunosuppression associated with cancer by decreasing immunosuppressive cells (MDSC, regulatory T cells), immunosuppressive cytokines (IL-10, TGFbeta), and inhibitory molecules on T cells (PD-1). Some of these broad effects may result from the ability of some antiangiogenic molecules, especially cytokines to inhibit the Stat3 transcription factor. The association often observed between angiogenesis and immunosuppression may be related to hypoxia which induces both neoangiogenesis via activation of HIF-1 and VEGF and favors the intratumor recruitment and differentiation of regulatory T cells and MDSC. Preliminary studies suggest that modulation of immune markers (intratumoral MDSC and IL-8, peripheral regulatory T cells...) may predict clinical response to antiangiogenic therapy. In preclinical models, a synergy has been observed between antiangiogenic molecules and immunotherapy which may be explained by an improvement of immune status in tumor-bearing mice after antiangiogenic therapy. In preclinical models, antiangiogenic molecules promoted intratumor trafficking of effector cells, enhance endogenous anti-tumor response, and synergyzed with immunotherapy protocols to cure established murine tumors. All these results warrant the development of clinical trials combining antiangiogenic drugs and immunotherapy. PMID- 21249424 TI - Improving cancer immunotherapy by targeting tumor-induced immune suppression. AB - The status of a host's immune response influences both the development and progression of a malignancy such that immune responses can have both pro- and anti-tumorigenic effects. Cancer immunotherapy is a form of treatment that aims to improve the ability of a cancer-bearing individual to reject the tumor immunologically. However, antitumor immunity elicited by the host or by immunotherapeutic strategies, can be actively attenuated by mechanisms that limit the strength and/or duration of immune responses, including the presence of immunoregulatory cell types or the production of immunosuppressive factors. As our knowledge of tumor-induced immune suppression increases, it has become obvious that these mechanisms are probably a major barrier to effective therapy. The identification of multiple mechanisms of tumor-induced immune suppression also provides a range of novel targets for new cancer therapies. Given the vital role that a host's immune response is known to play in cancer progression, therapies that target immune suppressive mechanisms have the potential to enhance anticancer immune responses thus leading to better immune surveillance and the limitation of tumor escape. In this review, mechanisms of tumor-associated immune suppression have been divided into four forms that we have designated as (1) regulatory cells; (2) cytokines/chemokines; (3) T cell tolerance/exhaustion and (4) metabolic. We discuss select mechanisms representing each of these forms of immunosuppression that have been shown to aid tumors in evading host immune surveillance and overview therapeutic strategies that have been recently devised to "suppress these suppressors." PMID- 21249425 TI - Molecular determinants of immunogenic cell death elicited by anticancer chemotherapy. AB - The success of some chemo- and radiotherapeutic regimens relies on the induction of immunogenic tumor cell death and on the induction of an anticancer immune response. Cells succumbing to immunogenic cell death undergo specific changes in their surface characteristics and release pro-immunogenic factors according to a defined spatiotemporal pattern. This stimulates antigen presenting cells such as dendritic cells to efficiently take up tumor antigens, process them, and cross prime cytotoxic T lymphocytes, thus eliciting a tumor-specific cognate immune response. Such a response can also target therapy-resistant tumor (stem) cells, thereby leading, at least in some instances, to tumor eradication. In this review, we shed some light on the molecular identity of the factors that are required for cell death to be perceived as immunogenic. We discuss the intriguing observations that the most abundant endoplasmic reticulum protein, calreticulin, the most abundant intracellular metabolite, ATP, and the most abundant non histone chromatin-binding protein, HMGB1, can determine whether cell death is immunogenic as they appear on the surface or in the microenvironment of dying cells. PMID- 21249426 TI - Tumor immunosurveillance in human cancers. AB - Until now, the anatomic extent of tumor (TNM classification) has been by far the most important factor to predict the prognosis of colorectal cancer patients. However, in recent years, data collected from large cohorts of human cancers demonstrated that the immune contexture of the primary tumors is an essential prognostic factor for patients' disease-free and overall survival. Tumoral and immunological markers predicted by systems biology methods are involved in the shaping of an efficient immune reaction and can serve as targets for novel therapeutic approaches. Global analysis of tumor microenvironment showed that the nature, the functional orientation, the density, and the location of adaptive immune cells within distinct tumor regions influence the risk of relapse events. The density and the immune cell location within the tumor have a prognostic value that is superior to the TNM classification, and tumor invasion is statistically dependent on the host-immune reaction. Thus, the strength of the immune reaction could advance our understanding of cancer evolution and have important consequences in clinical practice. PMID- 21249427 TI - Interaction of microtubules and actin with the N-terminus of betaPix-b(L) directs cellular pinocytosis. AB - betaPix is a Rac/Cdc42 guanine nucleotide exchange factor (GEF) that is known to be a regulator of actin cytoskeleton remodeling. Recently, a novel splicing isoform, betaPix-b(L), was identified as an alternative translational product of the betaPix-b mRNA with an extended N-terminus comprising a partial calponin homology (CH) domain and a serine-rich (SR) domain. However, the cellular function of betaPix-b(L) is largely unknown. In the current study, we analyzed the genomic DNA structure and cellular functions of betaPix-b(L). The results of this study demonstrate that betaPix is composed of 24 exons and 21 introns spanning around 100 kb. RT-PCR experiments revealed that there are two forms of betaPix mRNA with distinct 5' UTRs that are the result of alternative splicing of exon 1 and 2 from betaPix genomic DNA. In addition, affinity chromatography analysis and a pull-down assay with the N-terminal region of betaPix-b(L) revealed that betaPix-b(L) interacts with tubulin and actin via its N-terminal CH and SR domains, respectively. Interaction with tubulin enabled betaPix-b(L) to bundle the microtubule and form membrane protrusions. Furthermore, the N-terminus of betaPix-b(L) was also critical for its localization to cellular vesicles. Functionally, betaPix-b(L) induced pinocytosis through cooperative action of the CH and Dbl homology (DH) domains, demonstrating the role of betaPix-b(L) in the regulation of membrane dynamics. PMID- 21249428 TI - Impaired miR-146a expression links subclinical inflammation and insulin resistance in Type 2 diabetes. AB - Type 2 diabetes patients exhibit subclinical inflammation but the regulatory mechanisms are poorly understood. We sought to evaluate the role of miR-146a expression along with its downstream proinflammatory signals in relation to glycemic control and insulin resistance. Study subjects (n = 20 each) comprised of clinically well characterized Type 2 diabetes patients and control non diabetic subjects. miRNA and mRNA expression levels were probed in peripheral blood mononuclear cells (PBMC) by Real-time RT-PCR and plasma levels of TNFalpha and IL-6 were measured by ELISA. The miR-146a expression levels were significantly decreased in PBMCs from patients with Type 2 diabetes compared to control subjects. Among the target genes of miR-146a, TRAF-6 mRNA expression was significantly increased in patients with Type 2 diabetes while there was no significant difference in the mRNA levels of IRAK1 in the study groups. In contrast, there were significantly increased levels of NFkappaB expression in patients with Type 2 diabetes. There was an increased trend in the levels of TNFalpha and IL-6 mRNA in patients with type 2 diabetes. While SOCS-3 mRNA levels increased, plasma TNFalpha and IL-6 levels were also significantly higher in patients with type 2 diabetes. miR-146a expression was negatively correlated to glycated hemoglobin, insulin resistance, TRAF6, and NFkappaB mRNA levels and circulatory levels of TNFalpha and IL-6. Reduced miR-146a levels are associated with insulin resistance, poor glycemic control, and several proinflammatory cytokine genes and circulatory levels of TNFalpha and IL-6 in Asian Indian Type 2 diabetic patients. PMID- 21249429 TI - Endothelial-specific intron-derived miR-126 is down-regulated in human breast cancer and targets both VEGFA and PIK3R2. AB - Endothelial cells are the key components of vascular intima and play pivotal roles in vasculogenesis, angiogenesis, and tumor growth. Using Northern blot and real-time PCR, we confirmed that miR-126 and its host gene EGF-like domain 7 (EGFL7) were widely expressed in rat tissues but strictly expressed in endothelial cells. In mammals, miR-126 gene is embedded in intron7 of EGFL7. To explore the biogenesis of miR-126, plasmid EGFL7(126)-pEGFPc1 containing segment of exon7-intron7-exon8 of EGFL7 was constructed and expressed in 293T. Expression of spliced exon7-8 and excised mature miR-126 was detected by PCR and Northern blot. Knocking-down of endothelial endogenous miR-126 did not affect EGFL7 expression at mRNA or protein level. To investigate the possible roles of miR 126, PicTar, miRBase, miRanda, Bibiserv, and Targetscan were used to screen the targets. VEGFA and PIK3R2 were confirmed as the targets of miR-126 by luciferase reporter assay and Western blot. Interestingly, Northern blot and western blot showed that miR-126 was down-regulated in breast tumors where the VEGF/PI3K/AKT signaling pathway was activated. Introduction of miR-126 mimics into MCF-7 could effectively decrease VEGF/PI3K/AKT signaling activity. In summary, miR-126 was strictly expressed in endothelial cells and excised from EGFL7 pre-mRNA without affecting splicing and expression of its host gene. In addition, miR-126 could target both VEGFA and PIK3R2, and its expression was decreased in human breast cancer, implying that miR-126 may play a role in tumor genesis and growth by regulating the VEGF/PI3K/AKT signaling pathway. PMID- 21249430 TI - Differential expression of signaling pathways in odontogenic differentiation of ectomesenchymal cells isolated from the first branchial arch. AB - The aim of this study was to screen for differential expression of signaling pathways in odontogenic differentiation of ectomesenchymal cells isolated from the first branchial arch of embryonic day 10 (E10) mice by real time RT-PCR microarray. Observations of cellular morphology, immunocytochemistry, and RT-PCR were used to identify the cell source. A real time RT-PCR microarray was then used to detect the differential expression of signaling pathways in cells dissected from animals at two different developmental stages. These assays identified 25 up-regulated genes and 16 down-regulated genes involved in odontogenic differentiation of the ectomesenchymal cells of the first branchial arch. They represented the main members of Wnt, Hedgehog, TGF-beta, NF-kappaB, and LDL signaling pathways. This study determined that these signaling pathways are important for odontogenic differentiation of ectomesenchymal cells of the first branchial arch. PMID- 21249431 TI - The Abelson tyrosine kinase (c-Abl) expression on the mouse uterus and placenta during gestational period. AB - c-Abl is a protein tyrosine kinase which has very important roles in signal transduction, control of the cell cycle, cell motility, proliferation, and inhibition of apoptosis. We hypothesized that c-Abl may play an important role on uterine remodeling during pre-receptive, receptive and non-receptive endometrium. Our aim is to investigate the expression of c-Abl protein tyrosine kinase in uterine remodeling and placental development in mouse gestational stage. We performed c-Abl immunohistochemistry on mouse uterine tissue sections on days 1 9, 11, 13, and 15 of pregnancy. c-Abl was highly upregulated in the uterine luminal epithelium and other endometrial structures including glands and blood vessels in pre-receptive and receptive endometrium. Therefore these results demonstrate a role for c-Abl in uterine remodeling during decidualization, implantation, and placentation throughout gestation. PMID- 21249432 TI - Variation in herbivory-induced volatiles among cucumber (Cucumis sativus L.) varieties has consequences for the attraction of carnivorous natural enemies. AB - In response to herbivory by arthropods, plants emit herbivory-induced volatiles that attract carnivorous enemies of the inducing herbivores. Here, we compared the attractiveness of eight cucumber varieties (Cucumis sativus L.) to Phytoseiulus persimilis predatory mites after infestation of the plants with herbivorous spider mites (Tetranychus urticae) under greenhouse conditions. Attractiveness differed considerably, with the most attractive variety attracting twice as many predators as the least attractive variety. Chemical analysis of the volatiles released by the infested plants revealed significant differences among varieties, both in quantity and quality of the emitted blends. Comparison of the attractiveness of the varieties with the amounts of volatiles emitted indicated that the quality (composition) of the blend is more important for attraction than the amount of volatiles emitted. The amount of (E)-beta-ocimene, (E,E)-TMTT, and two other, yet unidentified compounds correlated positively with the attraction of predatory mites. Quantities of four compounds negatively correlated with carnivore attraction, among them methyl salicylate, which is known to attract the predatory mite P. persimilis. The emission of methyl salicylate correlated with an unknown compound that had a negative correlation with carnivore attraction and hence could be masking the attractiveness of methyl salicylate. The results imply that the foraging success of natural enemies of pests can be enhanced by breeding for crop varieties that release specific volatiles. PMID- 21249433 TI - Flow injection spectrofluorimetric determination of iron in industrial effluents based on fluorescence quenching of 1-naphthol-2- sulfonate. AB - A sensitive and selective spectrofluorimetric method has been developed for flow injection analysis (FIA) of iron(III) based on its fluorescence quenching effect on the water soluble 1-naphthol-2-sulfonate. The fluorescence emission spectra were collected with excitation at 283 nm. The emission peaks of the neutral and anionic forms of 1-naphthol-2-sulfonate as well as the band area were found to decrease linearly with iron(III) concentrations over the range 0.1-18 MUg ml(-1) and a detection limit of 3.4 ng ml(-1) (emission at 349 nm) with FIA. Possible interferences from different cations and anions, which could affect the analytical response, are evaluated and showed the high selectivity of the method. The effect of solution pH and 1-naphthol-2-sulfonate concentration were examined and the reaction conditions are optimized. The method is successfully applied to determine iron(III) in industrial effluents from different sources without any complications with recoveries of almost 100% with both manual and flow injection methods. Results were found to be very consistent with those obtained using atomic absorption spectrometry. PMID- 21249434 TI - A new strategy to identify and eliminate the inner filter effects by outer filter technique. AB - To identify and eliminate the inner filter effects (IFEs), prepositive and side cells containing absorbents are fixed beside the fluorescer contained cell. In this way, excitation and emission lights can be quenched by primary and secondary outer filter effects respectively, depending on absorbent concentration and cell length. Herein the quenching of emission fluorescence caused by IFEs can be equally reduced by outer filter effects (OFEs) and the interference of IFEs was eliminated. This approach was experimentally used for identifying the interaction mode and mechanism between BSA and nanoAg. Results showed that the quenching of BSA fluorescence and synchronous fluorescence mainly attributes to IFEs, instead of static/dynamic fluorescent quenching. In view of the above, the elimination of the interference of IFEs by the design of OFEs plays an important part in the precise application of fluorescence detector. PMID- 21249435 TI - Bioenergetic impact of tissue-specific regulation of iodothyronine deiodinases during nutritional imbalance. AB - The regulation of energy homeostasis by thyroid hormones is unquestionable, and iodothyronine deiodinases are enzymes involved in the metabolic activation or inactivation of these hormones at the cellular level. T3 is produced through the outer ring deiodination of the prohormone T4, which is catalyzed by types 1 and 2 iodothyronine deiodinases, D1 and D2. Conversely, type 3 iodothyronine deiodinase (D3) catalyzes the inner ring deiodination, leading to the inactivation of T4 into reverse triiodothyronine (rT3). Leptin acts as an important modulator of central and peripheral iodothyronine deiodinases, thus regulating cellular availability of T3. Decreased serum leptin during negative energy balance is involved in the down regulation of liver and kidney D1 and BAT D2 activities. Moreover, in high fat diet induced obesity, instead of increased serum T(3) and T(4) secondary to higher circulating leptin and thyrotropin levels, elevated serum rT3 is found, a mechanism that might impair the further increase in oxygen consumption. PMID- 21249437 TI - Predictive value of B-type natriuretic peptide levels in patients with paroxysmal and persistent atrial fibrillation undergoing pulmonary vein isolation. AB - BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia reducing the health-related quality of life. Radiofrequency catheter ablation (CA) became the therapy of choice in patients with drug-resistant AF with success rates between 30% and 86%. However, CA remains a challenging intervention with major complications in about 5% of cases. Therefore, stratification into high and low success patient groups would be helpful. The aim of this study was to investigate the predictive value of B-type natriuretic peptide (BNP) on the outcome of pulmonary vein isolation (PVI) in patients with paroxysmal (PAF) and persistent (Pers-AF) atrial fibrillation. MATERIALS AND METHODS: In 73 patients (median age 53 years, 77% men) undergoing PVI for drug-refractory PAF (n = 45) or Pers-AF (n = 28), the serum BNP concentration was measured before and 3 months after the ablation procedure to assess any association of pre- and post interventional BNP concentrations with therapeutic outcome. The patients had suffered from AF for a median of 40 months. No patient had structural heart disease or an impaired left-ventricular ejection fraction. RESULTS: A total of 54 patients (74%) had stable sinus rhythm 3 months after PVI. The median baseline BNP levels in both PAF and Pers-AF patients were significantly lower in patients with a 3-month successful PVI than those in which it was unsuccessful, 57.5 pg/ml (20.4-87.9) versus 159.0 pg/ml (124.1-177.5; p = 0.001) in PAF patients and 90.3 pg/ml (41.0-155.0) versus 176 pg/ml (89.6-297.4; p = 0.026) in patients with Pers AF, respectively. A multiple logistic regression analysis identified pre interventional BNP levels as the only independent predictor for 3-month PVI outcomes (p = 0.010). Nevertheless, in this study, the predictive value of BNP for PVI outcomes was not high enough to permit individual outcome prediction. After successful PVI, BNP levels were significantly lower in patients with PAF and Pers-AF (median changes -16.9 and -23.8 pg/ml; p = 0.010 and p = 0.022, respectively), but not in patients with AF in follow-up (median change 9.0 pg/ml and -29.6 pg/ml; p = 1.000 and p = 0.109, respectively). CONCLUSION: Pre-ablation BNP level seems to be an independent marker for successful PVI procedures in patients with paroxysmal and persistent AF; however, the observed level of association is moderate. PMID- 21249436 TI - Disruption of mitochondrial homeostasis in organic acidurias: insights from human and animal studies. AB - Organic acidurias or organic acidemias constitute a group of inherited disorders caused by deficient activity of specific enzymes of amino acids, carbohydrates or lipids catabolism, leading to large accumulation and excretion of one or more carboxylic (organic) acids. Affected patients usually present neurologic symptoms and abnormalities, sometimes accompanied by cardiac and skeletal muscle alterations, whose pathogenesis is poorly known. However, in recent years growing evidence has emerged indicating that mitochondrial dysfunction is directly or indirectly involved in the pathology of various organic acidemias. Mitochondrial impairment in some of these diseases are generally due to mutations in nuclear genes of the tricarboxylic acid cycle or oxidative phosphorylation, while in others it seems to result from toxic influences of the endogenous organic acids to the mitochondrion. In this minireview, we will briefly summarize the present knowledge obtained from human and animal studies showing that disruption of mitochondrial homeostasis may represent a relevant pathomechanism of tissue damage in selective organic acidemias. The discussion will focus on mitochondrial alterations found in patients affected by organic acidemias and by the deleterious effects of the accumulating organic acids on mitochondrial pathways that are crucial for ATP formation and transfer. The elucidation of the mechanisms of toxicity of these acidic compounds offers new perspectives for potential novel adjuvant therapeutic strategies in selected disorders of this group. PMID- 21249438 TI - Societal views of pacemaker reutilization for those with untreated symptomatic bradycardia in underserved nations. AB - PURPOSE: Significant healthcare disparities exist between the developed world and low and middle income countries (LMIC), specifically in the field of cardiac electrophysiology. As a result, pacemaker reutilization has been proposed as a viable option for those in LMIC and no other means of obtaining a device. Little data exist regarding the feasibility of establishing a reuse program in addition to understanding the views of society on device reutilization. This study investigated the views of funeral directors, patients with cardiac devices, and members of the general population regarding reutilization of previously implanted pacemakers. METHODS: Ninety funeral directors in Michigan were surveyed regarding current practice as well as preferences for post-mortem device disposal. One hundred and fourteen patients with devices and 1,009 members of the general population were surveyed regarding post-mortem device handling. RESULTS: Funeral directors had an average of 21 years of experience with an annual volume of 120 deceased persons per year, with a cremation rate of 35%. When asked about disposal methods of explanted devices, the majority of devices (84%) were discarded as medical waste or stored with no intended purpose, with a total of 171 devices currently in possession at the funeral homes. Eighty-nine percent of funeral directors expressed a desire to donate devices for reuse in LMIC and 10% acknowledged previous device donation. Eighty-seven percent of device patients and 71% of the general population also expressed a desire to donate devices. CONCLUSIONS: The results of our survey show that a large percentage of funeral directors, patients with implantable devices, and members of the general population support a pacemaker reutilization initiative. This study lends further evidence that collection of devices for reuse is feasible and that establishing a framework for regional pacemaker reutilization program is warranted. If successful, the feasibility of this model should be investigated in other parts of the country in order to alleviate the burden of untreated symptomatic bradycardia in our world. PMID- 21249439 TI - Particle formation and risk of embolization during transseptal catheterization: comparison of standard transseptal needles and a new radiofrequency transseptal needle. AB - OBJECTIVE: Anecdotally, the Brockenbrough transseptal needle generates plastic particles through a process of skiving (shaving off particles), when advanced through the dilator and sheath. This study was performed to assess particle creation by the Brockenbrough needle during transseptal catheterization. We explore strategies that may reduce this phenomenon, including use of the Brockenbrough stylet and a radiofrequency transseptal needle. METHOD: In vitro simulations of transseptal catheterization were performed using Brockenbrough transseptal needles and a new radiofrequency transseptal needle. Particles that were created during advancement of transseptal needles through the sheath and dilator were collected and analyzed. Particles in the visible range of 50 MUm to 4 mm were identified using a light microscope, whereas particles in the sub visible, yet clinically relevant range of 10 to 50 MUm, were counted using a light obscuration method. RESULTS: All simulated procedures using the Brockenbrough transseptal needles, with or without a stylet, generated visible particles. Simulated procedures with the radiofrequency transseptal needle generated no visible particles. A greater number of sub-visible particles were generated with the standard Brockenbrough transseptal needle (BKR-1) without stylet compared with the standard Brockenbrough needle (BRK-1) with stylet, the Brockenbrough extra sharp (BRK-1XS) needle with or without stylet, and the radiofrequency needle (NRG C1). CONCLUSION: Clinically relevant particles, both visible and sub-visible, with the potential for causing embolic complications, are generated by the BRK-1 needle without stylet. Use of a stylet in the BRK-1 needle, or the BRK-1XS needle with or without stylet, appears to reduce the size and amount of particles created. The NRG C1 needle appears to eliminate visible particles and is comparable to the BRK-1 with stylet and the BRK-1XS with or without stylet in generation of sub-visible particles. Important steps can be taken to minimize the creation of particles during the advancement of the BRK-1 through the transseptal sheath and dilator. PMID- 21249440 TI - Analysis of codon usage in Newcastle disease virus. AB - In this study, the relative synonymous codon usage (RSCU) values, effective number of codon (ENC) values, nucleotide contents, and dinucleotide were used to investigate codon usage pattern of each protein-coding gene and genome among 31 Newcastle disease virus (NDV) isolates. The result shows that the overall extent of codon usage bias in NDV is low (mean ENC = 56.15 > 40). The good correlation between the (C + G)(12)% and (G + C)(3)% suggests that the mutational pressure, rather than natural selection, is the main factor that determines the codon usage bias and base component in NDV. It is observed that synonymous codon usage pattern in NDV genes is gene function and geography specific, but not host specific. By contrasting synonymous codon usage patterns of different NDV isolates, we suggest that more than one genotype of NDV circulates in waterfowl in USA; and gene length has no significant effect on the variations of synonymous codon usage in these virus genes. CpG under-represented is a characteristic for NDV to fit in its host. These results not only provide an insight into the variation of codon usage pattern among the genomes of NDV, but also may help in understanding the processes governing the evolution of NDV. PMID- 21249441 TI - The proposed diagnosis of hypersexual disorder for inclusion in DSM-5: unnecessary and harmful. PMID- 21249442 TI - Nuclei of chicken neurons in tissues and three-dimensional cell cultures are organized into distinct radial zones. AB - We used chicken retinospheroids (RS) to study the nuclear architecture of vertebrate cells in a three-dimensional (3D) cell culture system. The results showed that the different neuronal cell types of RS displayed an extreme form of radial nuclear organization. Chromatin was arranged into distinct radial zones which became already visible after DAPI staining. The distinct zones were enriched in different chromatin modifications and in different types of chromosomes. Active isoforms of RNA polymerase II were depleted in the outermost zone. Also chromocenters and nucleoli were radially aligned in the nuclear interior. The splicing factor SC35 was enriched at the central zone and did not show the typical speckled pattern of distribution. Evaluation of neuronal and non neuronal chicken tissues showed that the highly ordered form of radial nuclear organization was also present in neuronal chicken tissues. Furthermore, the data revealed that the neuron-specific nuclear organization was remodeled when cells spread on a flat substrate. Monolayer cultures of a chicken cell line did not show this extreme form of radial organization. Rather, such monolayer cultures displayed features of nuclear organization which have been described before for many different types of monolayer cells. The finding that an extreme form radial nuclear organization, which has not been described before, is present in RS and tissues, but not in cells spread on a flat substrate, suggests that it would be important to complement studies on nuclear architecture performed with monolayer cells by studies on 3D cell culture systems and tissues. PMID- 21249443 TI - Aromatase inhibitor therapy: toxicities and management strategies in the treatment of postmenopausal women with hormone-sensitive early breast cancer. AB - Aromatase inhibitors (AIs) have been shown to reduce the risk of breast cancer recurrence and are widely used today as adjuvant therapy in women with early stage endocrine-responsive breast cancer. Aromatase inhibitors may be prescribed as initial hormonal therapy, sequentially following 2-3 years of tamoxifen, or as extended adjuvant therapy (following 5 years of tamoxifen). Aromatase inhibitors are generally well tolerated; however, certain side effects, particularly arthralgia/musculoskeletal symptoms and gynecologic effects, may result in poor adherence to treatment. Patients receiving adjuvant therapy with an AI should be counseled regarding possible side effects and the importance of completing treatment. Interventions to ameliorate side effects should be individualized based on symptoms, comorbid conditions, and pre-existing therapies. In addition, bone and cardiovascular health should be monitored during AI therapy. Prompt therapeutic management of common side effects associated with AIs may provide patients with the opportunity to receive the full benefit of their adjuvant hormonal treatment while minimizing toxicity. PMID- 21249444 TI - VEGF 936C>T polymorphism and breast cancer risk: evidence needed further clarification. PMID- 21249445 TI - Persistence of dicofol residues in cotton lint seed, and soil. AB - A supervised field trial was conducted at the CCS Haryana Agricultural University, Hisar to assess the residues of dicofol on cotton, during Kharif season, 2008. Dicofol (Kelthane 18.5EC) was applied at 500 g a.i./ha (T(1)) and 1,000 g a.i./ha T(2)) after 105 days of sowing of cotton crop (Varity Cotton/H 1226). Soil samples were collected on 0 (1 h after treatment), 3, 7, 10, 15, 30, and 60 days after spray and cotton samples were collected at harvest. Samples were processed and residues were quantified by GC-ECD system equipped with capillary column. Limit of detection and limit of quantification (LOQ) were 0.001 and 0.010 mg kg( -1), respectively, for soil and LOQ for cotton lint and seed was 0.020 mg kg( -1). Initial residues of 0.588 and 1.182 mg kg( -1) in soil reached below detectable level (BDL) of 0.010 mg kg( -1) in T(1) and to the level of BDL (0.010 mg kg( -1)) in T(2) at harvest (60 days after treatment). In 60 days, residues dissipated almost completely (100 and >99%) in both the treatments. Half life period was calculated as 8.57 days at single dose and 8.69 days at double dose in soil. Residues of dicofol were detected in cotton lint to the levels of 0.292 and 0.653 mg kg( -1) and in seed 0.051 and 0.090 mg kg( -1) in T(1) and T(2) doses, respectively at harvest. Residues in cotton seed were below MRL value of 0.01 mg kg( -1) in both the doses. PMID- 21249446 TI - Sediment grain size estimation using airborne remote sensing, field sampling, and robust statistic. AB - Remote sensing has been used since the 1980s to study parameters in relation with coastal zones. It was not until the beginning of the twenty-first century that it started to acquire imagery with good temporal and spectral resolution. This has encouraged the development of reliable imagery acquisition systems that consider remote sensing as a water management tool. Nevertheless, the spatial resolution that it provides is not adapted to carry out coastal studies. This article introduces a new methodology for estimating the most fundamental physical property of intertidal sediment, the grain size, in coastal zones. The study combines hyperspectral information (CASI-2 flight), robust statistic, and simultaneous field work (chemical and radiometric sampling), performed over Santander Bay, Spain. Field data acquisition was used to build a spectral library in order to study different atmospheric correction algorithms for CASI-2 data and to develop algorithms to estimate grain size in an estuary. Two robust estimation techniques (MVE and MCD multivariate M-estimators of location and scale) were applied to CASI-2 imagery, and the results showed that robust adjustments give acceptable and meaningful algorithms. These adjustments have given the following R(2) estimated results: 0.93 in the case of sandy loam contribution, 0.94 for the silty loam, and 0.67 for clay loam. The robust statistic is a powerful tool for large dataset. PMID- 21249447 TI - Expression, purification and characterization of yellow grouper Epinephelus awoara regulator of G protein signaling 16 protein. AB - Regulators of G-protein signaling (RGS) proteins are a family of proteins, which accelerate GTPase-activity intrinsic to the alpha subunits of heterotrimeric G proteins and play crucial roles in the physiological control of G-protein signaling. Here, yellow grouper RGS16 protein was expressed in Escherichia coli and purified by Ni-NTA affinity chromatography. The expression level of the fusion protein was up to 30% of the total cellular protein.Western blotting analysis showed that a band with the molecular mass of about 21 Kda was detected. The purified recombinant protein was used to prepare polyclonal antibody, and antiserum obtained was highly specific with the titer of over 1:32,000. Additionally, RGS16 protein was expressed in the Tn-5B1-4 insect cells. Western blotting analysis revealed that the expressed protein had immunoreactivity. PMID- 21249448 TI - Study on seroprevalence, risk factors, and economic impact of foot-and-mouth disease in Borena pastoral and agro-pastoral system, southern Ethiopia. AB - Cross-sectional serological study and questionnaire survey were conducted in Borana pastoral and agro-pastoral area to determine seroprevalence and risk factors associated with foot-and-mouth disease (FMD) infection and to assess community perceptions as to importance of the disease. A multistage random sampling was carried out to select cattle for seroprevalence and households for interviews. Totally, 768 sera were collected from 111 herds. The overall individual level seroprevalence of 23.0% (n = 177) and herd level seroprevalence of 58.6% (n = 65) were recorded using 3ABC ELISA test. The variation of individual level seroprevalence in districts were statistically significant (P < 0.05) which was 29.9% in Arero, 24.0% in Yabello, and 15.7% in Teltele. From multivariate logistic regression analysis, herd size and age were seen to be significantly (P < 0.05) associated with FMD seroprevalence. The result of the questionnaire survey based on 120 respondents indicated that, the daily milk yield of cows infected with FMD during outbreaks is reduced to an average of 0.5 L for 25.5 days while cows developing heat-intolerance syndrome after acute infection gave an average 0.67 L for 3.8 months and their calving interval prolonged about 12 months. The questionnaire survey in agro-pastoral area of Borena also indicated that FMD-infected oxen remained off-plough for one season when outbreaks occur in cropping time, whereas heat-intolerant oxen were no longer used for traction. These findings of the present study indicated that FMD is a highly prevalent and economically important disease in the Borana pastoral and agro-pastoral production systems which need effective control strategy for the disease. PMID- 21249449 TI - Henoch-schonlein purpura in an adult mimicking Crohn's disease and pyoderma gangrenosum. PMID- 21249451 TI - Fluid dynamics analysis of a novel micropatterned cell bioreactor. AB - Although flow-based bioreactor has been widely used to provide sufficient mass transportation and nutrient supply for cell proliferation, differentiation, and apoptosis, the underlying mechanism of cell responses to applied flow at single cell level remains unclear. This study has developed a novel bioreactor that combines flow bioreactor with microfabrication technique to isolate individual cells onto micropatterned substrate. A mechanical model has also been developed to quantify the flow field or the microenvironment around the single cell; flow dynamics has been analyzed on five geometrically different patterns of circle-, cube-, 1:2 ellipse-, 1:3 ellipse-, and rectangle-shaped "virtual cells." The results of this study have demonstrated that the flow field is highly pattern dependent, and all the hydrodynamic development length, cell spacing, and orientation of inlet velocity vector are crucial for maintaining a fully developed flow. This study has provided a theoretical basis for optimizing the design of micropatterned flow bioreactor and a novel approach to understand the cell mechanotransduction and cell-surface interaction at single cell level. PMID- 21249452 TI - Residential rurality and oral health disparities: influences of contextual and individual factors. AB - The purposes of the study were (a) to identify disparities between urban and rural adults in oral health and (b) to examine contextual (i.e., external environment and access to dental care) and individual (i.e., predisposing, enabling, and lifestyle behavioral) factors associated with oral health problems in a community population. Study data were derived from a two-stage, telephone mailed survey conducted in 2006. The subjects were 2,591 adults aged 18 years and older. Cochran-Mantel-Haenszel statistics for categorical variables were applied to explore conditional independence between both health access and individual factors and oral health problems after controlling for the urban or rural residence. Logistic regression was used to investigate the simultaneous associations of contextual and individual factors in both rural and urban areas. Approximately one quarter (24.1%) of the study population reported oral health problems. Participants residing in rural areas reported more oral health disparities. Oral health problems were significantly associated with delaying dental care. These problems also were more common among those who were less educated, were African American, skipped breakfast every day, and currently smoked. The study findings suggest that oral health disparities persist for people in rural areas, and improving oral health status is strongly related to better access to oral health care and improved lifestyles in both rural and urban areas. PMID- 21249454 TI - Does fever relieve autistic behavior by improving brain blood flow? PMID- 21249453 TI - Insomnia: Neurophysiological and neuropsychological approaches. AB - Insomnia is a symptom, a syndrome and a comorbid disorder. Its diagnosis relies on subjective reports from the afflicted individual and is defined as difficulties in initiating sleep, maintaining sleep, waking up too early or non restorative sleep. However, insomnia and especially, primary insomnia, has received much attention in insomnia research with the use of objective measures. Insomnia, its peculiarities, most frequent subtypes and two most prominent models will first be briefly introduced. Then, insomnia will be reviewed according to results obtained with the use of neurophysiological measures as basic/traditional as polysomnography to more sophisticated ones such as power spectral analysis, neuroimaging, cyclic alternating patterns and event-related potentials. In addition, a review of the discrepancies between subjective and objective reports of cognitive alterations through neuropsychological testing is offered. The need to combine measures is then highlighted in conclusion. PMID- 21249455 TI - Validation of the S classification of sentinel lymph node and microanatomic location of sentinel lymph node metastases to predict additional lymph node involvement and overall survival in breast cancer patients. AB - BACKGROUND: Most patients with a positive sentinel lymph node (SN) have no further metastases in the axillary lymph nodes and may therefore not benefit from axillary lymph node dissection. In patients with melanoma, evaluation of the centripetal depth of tumor invasion in the SN, also known as the S classification of SN, and microanatomic localization of SN metastases were shown to predict non SN involvement. This phenomenon has been less extensively studied in breast cancer. We sought to validate the S classification and microanatomic location of SN metastases in breast cancer patients with regard to their predictive value for non-SN involvement and overall survival (OS). METHODS: A total of 236 patients with positive SN followed by axillary lymph node dissection were reevaluated according to the S classification and the microanatomic location of SN (subcapsular, parenchymal, combined subcapsular and parenchymal, multifocal, extensive) metastases to predict the likelihood of non-SN metastases and OS. RESULTS: S classification and the microanatomic location of SN metastases were significantly correlated with non-SN status (P < 0.001). Especially patients with a maximum depth of invasion <=0.3 mm (stage I according to the S classification) and those with SN metastases only in subcapsular location had a low probability of further non-SN metastases (7.8 and 6.1%) and a good prognosis for OS. CONCLUSIONS: S classification and microanatomic location of SN metastases predicts the likelihood of non-SN involvement. Especially patients with subcapsular or S stage I metastases have a low probability of non-SN metastases and a good prognosis for OS. PMID- 21249456 TI - A tale of two provinces: regionalization of pancreatic surgery in Ontario and Quebec. PMID- 21249457 TI - Dominance of CTX-M group 1 beta-lactamase enzymes in ESBL producing E. coli from outpatient urines in neighboring regions of Austria and Italy. AB - The importance of extended spectrum beta-lactamases (ESBL) is increasing worldwide. ESBLs of the CTX-M type are on the rise in Europe, not only in the hospital environment but also in outpatients. Therefore we performed a comparative pilot study including ESBL producing Escherichia coli isolated from outpatients suffering from urinary tract infections, 28 from Innsbruck, Austria, and 34 from Bolzano, Italy. Using established PCR methods we detected in nearly 90% of ESBL producing E. coli isolates CTX-M group 1 enzymes and only a few group 2 or group 9 enzymes. bla (TEM), bla (OXA-1) and aminoacyltransferase aac(6')-lb were significantly more frequent in the Austrian region, where also bla (SHV )was found in one isolate. In 2009 the overall prevalence of ESBL in E. coli causing urinary tract infection in outpatient samples was 7.6% in a local laboratory in Innsbruck and 5% in Bolzano. Additionally, we investigated plasmid-mediated qnr genes which can contribute to quinolone resistance, qnrA was found in an AmpC producing E. coli from Innsbruck and qnrS in two ESBL producers from Bolzano. Data confirmed that ESBL-producing E. coli have emerged as important pathogens in urinary tract infections of outpatients in both regions. PMID- 21249458 TI - Impact of selected solution factors on arsenate and arsenite removal by nanoiron particles. AB - INTRODUCTION: The nano-scale zero-valent iron (NZVI) was used for the removal of arsenite (As(III)) and arsenate (As(V)) in aqueous solution. Batch experiments were conducted to investigate the effects of initial pH, initial arsenic concentration, dissolved oxygen (DO), and ratio of As(III)/As(V) on arsenic removal. MATERIALS AND METHODS: The NZVI synthesized by using NaBH4 and FeCl3 was put into use right after its synthesis. The arsenic treatment system of recirculation mode consists of a reactor with a liquid volume of 4.4 L, which provides dual function of reactants reaction and particles settling in one unit. RESULTS AND DISCUSSION: Consequently, the pseudo-first order rate equations can be used to describe the removal kinetics for As(V) at pH 4 and 7, while the pseudo-second order reaction was observed for As(V) at pH 9 and As(III) at all pH's studied. Arsenic removal rates of both As(V) and As(III) were lower in the system with lower DO. The rate of As(III) removal decreased with the increase of its initial concentration. In contrast, the removal rate of As(V) still remained significantly high as its initial concentration increased. CONCLUSIONS: This study reveals that low pH and high DO will favor arsenic removal. With the mixture of As(III) and As(V), the total arsenic was removed faster than solution containing As(III) or As(V) alone. In addition, the mixture with higher fraction of As(V) resulted in higher arsenic removal. PMID- 21249459 TI - Detection of naproxen and its metabolites in fish bile following intraperitoneal and aqueous exposure. AB - PURPOSE: The anti-inflammatory drug naproxen (NPX) has been found as a micropollutant in river water downstream the discharge points of wastewater treatment plants (WWTP). In this study, rainbow trout (Oncorhynchus mykiss) was exposed to NXP and the uptake and metabolism of the drug was studied. METHODS: Following exposure through intraperitoneal injection (i.p., 0.5 mg NPX/100 g fish biomass) and through water (1.6 MUg L(-1)), the bile was collected and analyzed with various LC-MS/MS methods. The identification of the formed metabolites in i.p. injected fish was based on the exact mass determinations by a time-of-flight mass analyzer (Q-TOF-MS) and on the studies of fragments and fragmentation patterns of precursor ions by an ion trap mass analyzer (IT-MS). RESULTS: No matter the exposure route, the main metabolites were found to be acyl glucuronides of NPX and of 6-O-desmethylnaproxen. Also, unmetabolized NPX was detected in the bile. The total bioconcentration factors (BCF(total-bile)) of NPX and the metabolites in the bile of fish exposed through water ranged from 500 to 2,300. CONCLUSION: The findings suggest that fish living downstream WWTPs may take up NPX and metabolize the compound. Consequently, NPX and its metabolites in bile can be used to monitor the exposure of fish to NPX. PMID- 21249460 TI - Quantitative digital assessment of MGMT immunohistochemical expression in glioblastoma tissue. AB - Recent reports have suggested an important clinical role for hypermethylation of the O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter in patients with glioblastomas. Whether MGMT protein expression is correlated with promoter hypermethylation and patient outcomes, however, has not been elucidated. Here we describe a quantitative digital method for assessment of MGMT-specific immunostaining, and analyze the relationship between expression levels and methylation status of the MGMT promoter. We investigated 46 tumors from patients who received a diagnosis of glioblastoma or gliosarcoma. Immunohistochemistry with anti-MGMT antibody and methylation-specific PCR using bisulfite-modified tumor DNA were performed. The digital assessment method used image-analysis software to determine a digital MGMT staining index, and the results were compared with those obtained via conventional visual assessments. The digital staining index clearly correlated with the methylation status of MGMT promoter. In addition, the index correlated with our observational results when nuclear and cytoplasmic staining were assessed in three different fields. Our digital assessment method enabled us to assess uncertain immunopositive samples objectively and quantitatively, which is an important consideration when examining heterogeneous cellular staining. We expect that this method will be useful for assessment of heterogeneous staining with any antibodies. PMID- 21249461 TI - Performance-based contracting within a state substance abuse treatment system: a preliminary exploration of differences in client access and client outcomes. AB - To explore whether the implementation of performance-based contracting (PBC) within the State of Maine's substance abuse treatment system resulted in improved performance, one descriptive and two empirical analyses were conducted. The first analysis examined utilization and payment structure. The second study was designed to examine whether timeliness of access to outpatient (OP) and intensive outpatient (IOP) substance abuse assessments and treatment, measures that only became available after the implementation of PBC, differed between PBC and non PBC agencies in the year following implementation of PBC. Using treatment admission records from the state treatment data system (N = 9,128), logistic regression models run using generalized equation estimation techniques found no significant difference between PBC agencies and other agencies on timeliness of access to assessments or treatment, for both OP and IOP services. The third analysis, conducted using discharge data from the years prior to and after the implementation of performance-based contracting (N = 6,740) for those agencies that became a part of the performance-based contracting system, was designed to assess differences in level of participation, retention, and completion of treatment. Regression models suggest that performance on OP client engagement and retention measures was significantly poorer the year after the implementation of PBC, but that temporal rather than a PBC effects were more significant. No differences were found between years for IOP level of participation or completion of treatment measures. PMID- 21249462 TI - Financial incentives for extended weight loss: a randomized, controlled trial. AB - BACKGROUND: Previous efforts to use incentives for weight loss have resulted in substantial weight regain after 16 weeks. OBJECTIVE: To evaluate a longer term weight loss intervention using financial incentives. DESIGN: A 32-week, three-arm randomized controlled trial of financial incentives for weight loss consisting of a 24-week weight loss phase during which all participants were given a weight loss goal of 1 pound per week, followed by an 8-week maintenance phase. PARTICIPANTS: Veterans who were patients at the Philadelphia Veterans Affairs Medical Center with BMIs of 30-40. INTERVENTION: Participants were randomly assigned to participate in either a weight-monitoring program involving a consultation with a dietician and monthly weigh-ins (control condition), or the same program with one of two financial incentive plans. Both incentive arms used deposit contracts (DC) in which participants put their own money at risk (matched 1:1), which they lost if they failed to lose weight. In one incentive arm participants were told that the period after 24 weeks was for weight-loss maintenance; in the other, no such distinction was made. MAIN MEASURE: Weight loss after 32 weeks. KEY RESULTS: Results were analyzed using intention-to-treat. There was no difference in weight loss between the incentive arms (P = 0.80). Incentive participants lost more weight than control participants [mean DC = 8.70 pounds, mean control = 1.17, P = 0.04, 95% CI of the difference in means (0.56, 14.50)]. Follow-up data 36 weeks after the 32-week intervention had ended indicated weight regain; the net weight loss between the incentive and control groups was no longer significant (mean DC = 1.2 pounds, 95% CI, -2.58-5.00; mean control = 0.27, 95% CI, -3.77-4.30, P = 0.76). CONCLUSIONS: Financial incentives produced significant weight loss over an 8-month intervention; however, participants regained weight post-intervention. PMID- 21249463 TI - Misuse of respiratory inhalers in hospitalized patients with asthma or COPD. AB - BACKGROUND: Patients are asked to assume greater responsibility for care, including use of medications, during transitions from hospital to home. Unfortunately, medications dispensed via respiratory inhalers to patients with asthma or chronic obstructive pulmonary disease (COPD) can be difficult to use. OBJECTIVES: To examine rates of inhaler misuse and to determine if patients with asthma or COPD differed in their ability to learn how to use inhalers correctly. DESIGN: A cross-sectional and pre/post intervention study at two urban academic hospitals. PARTICIPANTS: Hospitalized patients with asthma or COPD. INTERVENTION: A subset of participants received instruction about the correct use of respiratory inhalers. MAIN MEASURES: Use of metered dose inhaler (MDI) and Diskus devices was assessed using checklists. Misuse and mastery of each device were defined as <75% and 100% of steps correct, respectively. Insufficient vision was defined as worse than 20/50 in both eyes. Less-than adequate health literacy was defined as a score of <23/36 on The Short Test of Functional Health Literacy in Adults (S-TOFHLA). KEY RESULTS: One-hundred participants were enrolled (COPD n = 40; asthma n = 60). Overall, misuse was common (86% MDI, 71% Diskus), and rates of inhaler misuse for participants with COPD versus asthma were similar. Participants with COPD versus asthma were twice as likely to have insufficient vision (43% vs. 20%, p = 0.02) and three-times as likely to have less-than- adequate health literacy (61% vs. 19%, p = 0.001). Participants with insufficient vision were more likely to misuse Diskus devices (95% vs. 61%, p = 0.004). All participants (100%) were able to achieve mastery for both MDI and Diskus devices. CONCLUSIONS: Inhaler misuse is common, but correctable in hospitalized patients with COPD or asthma. Hospitals should implement a program to assess and teach appropriate inhaler technique that can overcome barriers to patient self management, including insufficient vision, during transitions from hospital to home. PMID- 21249464 TI - Triple-vessel mesenteric ischaemia presenting with gastric ulceration. AB - We present an unusual presentation of chronic mesenteric ischaemia in a patient with recurrent gastric ulceration that highlights both the importance of recognition of ischaemia as a possible aetiology in those refractory to conventional treatment and the success of percutaneous transluminal mesenteric angioplasty in these cases. PMID- 21249466 TI - Valosin-containing protein gene mutations: cellular phenotypes relevant to neurodegeneration. AB - Previously, we identified valosin-containing protein (VCP) as a mediator of ER stress-induced cell death. Mutations in the VCP gene including R93, R155, and R191 have been described that manifest clinically as hereditary inclusion body myopathy with Paget's disease of bone and frontotemporal dementia. In addition, other studies have demonstrated that as a consequence of a mutation generated in the second ATP binding domain of VCP (K524A), cells accumulated large cytoplasmic vacuoles and underwent programmed cell death. In order to better understand the biochemical and molecular consequences of the clinically relevant VCP mutations as well as the genetically engineered ATPase-inactive mutant K524A and any relationship these may have to ER stress-induced cell death, we introduced analogous mutations separately and together into the human VCP gene and evaluated their effect on proteasome activity, Huntingtin protein aggregation and ER stress induced cell death. Our results indicate that the VCP K524A mutant and the triple mutant VCP R93C-R155C-K524A block protein degradation, trigger Huntingtin aggregate formation, and render cells highly susceptible to ER stress-induced cell death as compared to VCPWT or other VCP mutants. PMID- 21249467 TI - Role of tumor necrosis factor-alpha (C-863A) polymorphism in pathogenesis of inflammatory bowel disease in Northern India. AB - OBJECTIVE: Inflammatory bowel diseases (IBDs), namely ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic and idiopathic inflammatory conditions of gastrointestinal tract that are immunologically mediated. Single nucleotide polymorphisms in cytokine genes have been reported to modulate inflammation. Therefore, we analyzed the association of pro/anti-inflammatory cytokine genes polymorphism with IBD susceptibility. METHODS: Genotyping of interleukin (IL)-4 repeat polymorphism in intron-3, IL-10 (G-1082A and C-819T), and tumor necrosis factor-alpha (TNF-A) (-1031 T>C, -863 C>A, and -857 C>T) was performed in 153 patients with IBD and in 207 controls. RESULTS: TNF-A -863 AA genotype was associated with enhanced IBD susceptibility (odds ratio (OR), 4.82; 95% confidence interval (CI), 2.60-8.96), more so for UC (OR, 5.79; 95% CI, 2.99 11.21), Crohn's disease [CD] (OR, 3.13; 95% CI, 1.16-8.47). TNF-A T/C/T (OR, 4.40; 95% CI, 1.64-11.81) and C/A/C (OR, 4.15; 95% CI, 2.48-6.96) haplotypes were associated with increased IBD risk. The frequency of IL-4, B2 carrier (B1/B2 + B2/B2) was significantly lower in left-sided UC (17.1%) than proctosigmoiditis (47.6%); p, 0.016. In contrast, TNF-A -863 AA genotype frequency was much higher in pancolitis (45.5) than in proctosigmoiditis (14.2); p, 0.037. Variant genotypes of IL-4 (B1/B2 + B2/B2) were absent in colonic type CD. IL-10 polymorphisms did not demonstrate any association with IBD. None of the polymorphisms were associated with steroid treatment and surgery. CONCLUSION: The present study depicts that high-producing genotype of TNF-A (-863 AA) was associated with increased risk of IBD more so with UC. Similarly, combined effect of TNF-A polymorphisms in haplotype analysis demonstrated additively increased risk of IBD. PMID- 21249469 TI - Cervical emphysema and a voice change following sigmoid polypectomy. PMID- 21249468 TI - IgE, mast cells, and eosinophils in atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease with specific immune and inflammatory mechanisms. Atopy is among the major features of the diagnosis criteria for AD but is not an essential feature. Thus, patients diagnosed with AD can be atopic or non-atopic. This review focuses on the role of IgE, mast cells, and eosinophils in the pathogenesis of AD. The known functions of IgE in allergic inflammation suggest that IgE and IgE-mediated mast cell and eosinophil activation contribute to AD, but direct evidence supporting this is scarce. The level of IgE (thus the degree of allergic sensitization) is associated with severity of AD and contributed by abnormality of skin barrier, a key feature of AD. The function of IgE in development of AD is supported by the beneficial effect of anti-IgE therapy in a number of clinical studies. The role of mast cells in AD is suggested by the increase in the mast cell number and mast cell activation in AD lesions and the association between mast cell activation and AD. It is further suggested by their role in mouse models of AD as well as by the effect of therapeutic agents for AD that can affect mast cells. The role of eosinophils in AD is suggested by the presence of eosinophilia in AD patients and eosinophil infiltrates in AD lesions. It is further supported by information that links AD to cytokines and chemokines associated with production, recruitment, and activation of eosinophils. PMID- 21249470 TI - Inflammatory and prothrombotic parameters in normotensive non-diabetic obese women: effect of weight loss obtained by gastric banding. AB - Hypertension and diabetes are known risk factors for obesity-related thrombosis, but several studies have shown that obesity is characterised by a potentially prothrombotic inflammatory state because of activated coagulation and impaired fibrinolysis. In order to verify if obese patients-unaffected by hypertension, diabetes, dyslipidemia, cigarette smoking or inflammatory diseases-show increased prothrombotic markers and whether the weight loss induced by gastric banding normalises such parameters. Plasma levels of C reactive protein (CRP), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (VWF) and factor VII (FVII) were measured in 25 women with isolated obesity prior to, as well as 3, 6 and 12 months subsequent to gastric banding. Twenty-five healthy women served as a baseline control group. The obese women had higher CRP (p = 0.0001), fibrinogen (p = 0.014), PAI-1 (p = 0.003), VWF (p = 0.004) and FVII levels (p = 0.0001) than the normal controls, and their body mass index (BMI) positively correlated with CRP (r = 0.462, p = 0.02), fibrinogen (r = 0.426, p = 0.04) and PAI-1 (r = 0.468, p = 0.02). Twelve months after gastric banding, the median BMI had decreased from 40.0 to 34.9 (p = 0.0001); CRP from 4.18 to 1.69 MUg/ml (p = 0.01); fibrinogen from 389 to 318 mg/dl (p = 0.0001); PAI-1 from 32.1 to 12.0 UI/ml (p = 0.003); VWF from 144 to 120% (p = 0.0001); and FVII from 134 to 112% (p = 0.002). Even in the absence of major cardiovascular risk factors, obese patients are characterised by a prothrombotic state. The weight loss induced by gastric banding decreases the parameters of inflammation, coagulation and impaired fibrinolysis, thus potentially reducing the thrombotic risk. PMID- 21249471 TI - Performance of PSI, CURB-65, and SCAP scores in predicting the outcome of patients with community-acquired and healthcare-associated pneumonia. AB - The objective was to compare three score systems, pneumonia severity index (PSI), the Confusion-Urea-Respiratory Rate-Blood pressure-65 (CURB-65), and severe community-acquired pneumonia (SCAP), for prediction of the outcomes in a cohort of patients with community-acquired (CAP) and healthcare-associated pneumonia (HCAP). Large multi-center, prospective, observational study was conducted in 55 hospitals. HCAP patients were included in the high classes of CURB-65, PSI and SCAP scores have a mortality rate higher than that of CAP patients. HCAP patients included in the low class of the three severity rules have a significantly higher incidence of adverse events, including development of septic shock, transfer into an ICU, and death (p < 0.01). At multivariate Cox regression analysis, inclusion in the severe classes of PSI, CURB-65, or SCAP scores and receipt of an empirical therapy not adherent to international guidelines prove to be risk factors independently associated with poor outcome. PSI, CURB-65, and SCAP score have a good performance in patients with CAP but are less useful in patients with HCAP, especially in patients classified in the low-risk classes. PMID- 21249472 TI - Prognostic value of C-reactive protein in chronic obstructive pulmonary disease. AB - To establish whether C-reactive protein (CRP) is an independent predictor of all cause mortality and hospitalization in chronic obstructive pulmonary disease (COPD), we followed 200 patients with COPD and 201 age- and gender -matched controls for a median time of 4.2 years (range, 0.2-5.1 years). Airflow obstruction was rated moderate if forced expiratory volume in one second (FEV(1)) was 50-69% of the predicted value, or severe if FEV(1) was <50%. The CRP level was categorized as low (<=3 mg/L) or high (>3 mg/L). The hazard of death was estimated by a proportional hazard regression model, using controls with low CRP as the reference category. Fifty subjects died: 41 (21%) among the COPD and 9 (4%) among the controls (p < 0.0001). The hazard of death in moderate COPD was not significantly higher than in the reference category, independently of the CRP level. In severe COPD with a low CRP, the hazard of death is 3.4 times higher than in the reference category (p = 0.008); in severe COPD and a high CRP it is 9.6 times higher (p < 0.0001). The rate of hospitalization in COPD patients with a high CRP is 1.9 times higher than in those with a low CRP [95% confidence interval (CI), 1.2-3.2]. In severe COPD, it is 6.9 times higher than in moderate COPD (95% CI, 3.8-12.7). A high CRP level is a significant amplifier of the risk of death only in severe COPD. The degree of airflow obstruction is a strong independent predictor of COPD-related outcomes. PMID- 21249473 TI - Atrial standstill disease progression documented after 13 years follow-up. PMID- 21249475 TI - Pulmonary involvement complicating plasma cell proliferative disorders: a case report and review of the literature. PMID- 21249474 TI - Regional short-term climate variations influence on the number of visits for renal colic in a large urban Emergency Department: results of a 7-year survey. AB - The pathogenesis of renal stones is an intricate process and varies widely depending on the composition of stones. There is also a marked geographic variability, strongly attributable to the mean annual temperature (MAT) and, to a lesser extent, on the seasons. Previous investigations report peaks in Emergency Department (ED) visits for renal colic during the summer. The aim of the present investigation is to assess the influence of day-by-day climate changes on the number of visits due to renal colic in our ED (city of Parma, located in the Po river valley, with a temperate continental climate). A total of 8,168 colic episodes were retrieved from our database during a period of 2,557 days (from 1 January 2002 to 31 December 2008). Over the same period 557,990 patients were admitted to our ED, renal colic visits representing 1.46% of the total. The linear regression analysis fitting the mean number of colic visits per day and the mean daily temperature displays a very high and significant correlation (R = 0.88, p < 0.0001). A multiple linear regression analysis between the mean temperature of each of the 30 days preceding the colic episode also shows strong correlations, being the strongest on the 5th-7th days (R = 0.80, p < 0.0001 on the 6th day before the colic episode), and a weaker but highly significant correlation on days 14 (R = 0.77, p < 0.0001) and 20 (R = 0.70, p < 0.0001) before the colic episode. Taken together, these findings suggest a kind of "acceleration" process of stone formation caused by the hot climate and, perhaps, by dietary variations during the summer. This process might trigger a sudden growth of the stone and, finally, the resulting clinical episode. PMID- 21249476 TI - Role of renal resistive index to assess renal perfusion in ICU patients. PMID- 21249478 TI - Enterobacterial microflora in infancy - a case study with enhanced enrichment. AB - OBJECTIVE: To validate PMEU (Portable Microbe Enrichment Unit) method for monitoring the composition and development of infantile intestinal enterobacterial microflora. METHODS: A case study of a boy with neonatal sepsis is presented. During the first 32 months, he was given 19 systemic antibiotic treatments representing seven different antibiotic classes. Seven fecal samples collected at ages from 3.4 to 31.6 months were studied for enterobacterial strains by a combination of enhanced enrichment culture in the PMEU and plate culture. The identification and phenotypic characterization of the isolates was performed by biochemical tests. RESULTS: 37/51 (73%) of the enterobacterial isolates were detected only after the PMEU enrichment. In most samples Escherichia coli strains were predominating, but also several Enterobacter, Klebsiella, Pantoea and Proteus strains could be isolated. It seemed that the antibiotic medications remarkably delayed the development of the intestinal microflora, because first enterobacterial strains were detected only after 6 months of age. CONCLUSIONS: The enrichment step turned out to essentially improve the characterization and monitoring of the intestinal enterobacterial microbiota of infants. Compared to plate culture the amount of isolates was 2.6-fold by the PMEU enrichment. This study gives an idea on the development and succession of microbial communities in the gastrointestinal tract and on the variation of the strains due to the intestinal environmental factors. PMID- 21249479 TI - COL1A1 mutation in an Indian child with Caffey disease. AB - Caffey disease or infantile cortical hyperostosis is a rare skeletal disorder with both sporadic and familial occurrence. The autosomal dominant familial form has been found to be a collagenopathy. The case being reported is a 7- month-old Indian boy with Caffey disease who was found to have the R1014C heterozygous mutation in the COL1A1 gene. This is the first mutation report of an Indian case with Caffey disease. PMID- 21249480 TI - A head-to-head comparison of risperidone and divalproex for treatment of pediatric bipolar disorder. PMID- 21249477 TI - Bone marrow mesenchymal stem cells: biological properties and their role in hematopoiesis and hematopoietic stem cell transplantation. AB - Mesenchymal stem cells (MSCs) are multipotent adult stem cells that are present in practically all tissues as a specialized population of mural cells/pericytes that lie on the abluminal side of blood vessels. Originally identified within the bone marrow (BM) stroma, not only do they provide microenvironmental support for hematopoietic stem cells (HSCs), but can also differentiate into various mesodermal lineages. MSCs can easily be isolated from the BM and subsequently expand in vitro and in addition they exhibit intriguing immunomodulatory properties, thereby emerging as attractive candidates for various therapeutic applications. This review addresses the concept of BM MSCs via a hematologist's point of view. In this context it discusses the stem cell properties that have been attributed to BM MSCs, as compared to those of the prototypic hematopoietic stem cell model and then gives a brief overview of the in vitro and vivo features of the former, emphasizing on their immunoregulatory properties and their hematopoiesis-supporting role. In addition, the qualitative and quantitative characteristics of BM MSCs within the context of a defective microenvironment, such as the one characterizing Myelodysplastic Syndromes are described and the potential involvement of these cells in the pathophysiology of the disease is discussed. Finally, emerging clinical applications of BM MSCs in the field of hematopoietic stem cell transplantation are reviewed and potential hazards from MSC use are outlined. PMID- 21249481 TI - Oral dysplasia: biomarkers, treatment, and follow-up. AB - Dysplasia affecting the oral mucosa has a malignant potential. The options for treatment of oral dysplasia are limited. Surgery remains the mainstay of management, with no strong evidence for medical treatments currently available. Histological grading alone does not accurately predict which dysplastic lesions will progress to cancer, which poses the clinician with difficult decisions regarding the most appropriate treatment and may lead to some patients being overtreated, with potentially unnecessary morbidity. The use of biomarkers may help to improve prediction of which cases are likely to transform. The efficacy of individual markers for prediction will be discussed in this paper. There is also a lack of consensus on the optimal frequency and duration of follow-up for patients with oral dysplasia. PMID- 21249482 TI - Post-cardiac arrest syndrome: update on brain injury management and prognostication. AB - OPINION STATEMENT: Treatment of cardiac arrest should focus on maximizing neurologic recovery as well as systemic recovery to ensure the best possible functional outcome. This article focuses on the neurologic care of patients after they have been resuscitated from cardiac arrest. Maximizing neurologic outcome after cardiac arrest requires attention to prevention of primary and secondary brain injury. Primary brain injury such as hypoperfusion and hypoxic injury should be avoided by optimizing hemodynamic goals to maximize cerebral perfusion and maintain normoxia and normocarbia. Secondary brain injury mediated by excitotoxicity and the inflammatory cascade may be mitigated by therapeutic hypothermia. Other strategies that may be beneficial include the treatment of seizures and maintaining normoglycemia. Finally, accurate and timely prognostication is crucial because it influences withdrawal of care and overall mortality. With the adoption of therapeutic hypothermia, the classic prognostic paradigm that was previously used needs to be reexamined. The application of our knowledge of risk factors for poor outcome, serial physical examinations, neurophysiological tests, neuroimaging, and biochemical markers may need to be delayed until after rewarming. We emphasize the importance of a shift in physicians' approach to the management of post-cardiac arrest syndrome, not only in prognostication, but also in the early and aggressive therapies that have been shown to improve survival and quality of life. PMID- 21249483 TI - Defining racial and ethnic disparities in pain management. AB - BACKGROUND: Substantial pain prevalence is as high as 40% in community populations. There is consistent evidence that racial/ethnic minority individuals are overrepresented among those who experience such pain and whose pain management is inadequate. QUESTIONS/PURPOSES: The objectives of this paper are to (1) define parameters of and summarize evidence pertinent to racial/ethnic minority disparities in pain management, (2) identify factors contributing to observed disparities, and (3) identify strategies to minimize the disparities. METHODS: Scientific literature was selectively reviewed addressing pain epidemiology, differences in pain management of non-Hispanic whites versus racial/ethnic minority groups, and patient and physician factors contributing to such differences. RESULTS: Racial/ethnic minorities consistently receive less adequate treatment for acute and chronic pain than non-Hispanic whites, even after controlling for age, gender, and pain intensity. Pain intensity underreporting appears to be a major contribution of minority individuals to pain management disparities. The major contribution by physicians to such disparities appears to reflect limited awareness of their own cultural beliefs and stereotypes regarding pain, minority individuals, and use of narcotic analgesics. CONCLUSIONS: Racial/ethnic minority patients with pain need to be empowered to accurately report pain intensity levels, and physicians who treat such patients need to acknowledge their own belief systems regarding pain and develop strategies to overcome unconscious, but potentially harmful, negative stereotyping of minority patients. PMID- 21249484 TI - Factors and consequences of waiting times for total hip arthroplasty. AB - BACKGROUND: Various priority criteria for waiting lists for THA have been proposed. These criteria, however, are not typically included in clinical practice, resulting in unclear management procedures. Further, the clinical effects of waiting times on subsequent pain control or function are unclear. QUESTIONS/PURPOSES: Therefore, we asked (1) what factors affect the waiting time for THA when no prioritization criteria are implemented, and (2) does waiting time influence pain and function after THA? PATIENT AND METHODS: We prospectively identified all 1495 patients on a waiting list for THA during a year. Of these patients, 991 fulfilled the inclusion criteria, and waiting times were available for 695, of whom 527 (76%) responded to a followup questionnaire. Variables included wait time, sociodemographic data, comorbidities, and WOMAC and SF-36 questionnaires, collected preoperatively and 6 months after surgery. RESULTS: The mean wait time was 5 months (SD, 3.0). Patients with lower levels of pain and better function on the WOMAC scale, or better physical function on the SF-36, had longer waiting times. The gains in function were smaller for patients who waited more than 6 months. The likelihood of perceiving a gain greater than the minimal clinically important difference was greater for patients waiting less than 3 months. CONCLUSION: Only pain and previous function were significant determinants of prioritizing patients on the waiting list. Suboptimal patient selection had clinical consequences in function gain that affect the quality of the clinical care. PMID- 21249487 TI - [Acoustic neuroma or vestibular schwannoma]. PMID- 21249485 TI - Prognostic significance of carbonic anhydrase IX (CA-IX), endoglin (CD105) and 8 hydroxy-2'-deoxyguanosine (8-OHdG) in breast cancer patients. AB - The aim of this study was to examine the prognostic significance of carbonic anhydrase IX (CA-IX), an endogenous marker for tumor hypoxia; endoglin (CD105), a proliferation-associated and hypoxia-inducible glycoprotein and 8-hydroxy-2' deoxyguanosine (8-OHdG), an oxidative DNA lesion, in breast cancer patients. Immunohistochemical expressions of CA-IX, CD105 and 8-OHdG, analyzed on paraffin embedded tumor tissues from forty female breast cancer patients, were used to assess their prognostic implication on overall survival (OS) and relapse-free survival (RFS). Patients with high CA-IX expression (above cut-off value) had a higher occurrence of relapse (P = = 0.002). High CA-IX expression was significantly associated with shorter RFS (P < 0.001, hazard ratio (HR) 0.21) and shorter OS (P < 0.001, HR 0.19). Lymph node negative patients with high CA-IX expression had worse RFS (P = 0.031, HR 0.14) and OS (P = 0.005, HR 0.05). Patients with grade I&II tumors and high CA-IX expression showed shorter RFS (P = 0.028, HR 0.28) and OS (P = 0.008, HR 0.20). Worse OS (P = 0.046, HR 0.28) was found in subgroup of patients with grade II tumors and high CA-IX expression. Among all three markers, only high CA-IX expression was strong independent prognostic indicator for shorter OS (HR 4.14, 95% CI 1.28-13.35, P = 0.018) and shorter RFS (HR 3.99, 95% CI 1.38-11.59, P = 0.011). Elevated expression of CA-IX was an independent prognostic factor for decreased RFS and OS and a significant marker for tumor aggressiveness. CD105 had week prognostic value; whereas, 8 OHdG, in this study, did not provide sufficient evidence as a prognostic indicator in breast cancer patients. PMID- 21249489 TI - The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant impairs glucose stimulated insulin response in 5,722 non-diabetic Danish individuals. AB - AIMS/HYPOTHESIS: A genome-wide association study in the Japanese population reported two genome-wide significant loci associated with type 2 diabetes of which the VPS13C/C2CD4A/C2CD4B locus was replicated in Europeans. We looked for potential associations between the diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 variant and diabetes-related intermediary traits. METHODS: We genotyped the rs7172432 variant in the population-based Inter99 cohort (n = 6,784) and analysed quantitative diabetes-related traits in 5,722 non-diabetic participants who all were examined by an OGTT. RESULTS: The diabetes-associated A allele was associated with 0.60 cm higher waist circumference (p = 0.004), 0.037 mmol/l higher fasting plasma glucose (p = 4 * 10(-5)) and 0.11 mmol/l higher plasma glucose at 30 min during an OGTT (p = 4 * 10(-4)). In analyses adjusted for concomitant insulin sensitivity levels the diabetogenic allele was associated with a lower acute glucose-stimulated insulin response (GSIR) as estimated by 30 min serum insulin (beta = -0.039, p = 2 * 10(-7)), insulinogenic index (beta = 0.057, p = 1 * 10(-8)) and BIGTT-acute insulin release (beta = -0.041, p = 9 * 10(-9)). As rs7172432 is situated in a region previously associated with glycaemic traits, we tested linkage disequilibrium (LD) with the reported regional lead single-nucleotide polymorphisms for fasting (rs11071657) and 2 h plasma glucose (rs17271305), and performed conditional analyses of rs7172432. Rs7172432 showed moderate LD with rs11071657 and rs17271305 (R (2) < 0.34) and we found strong association by almost unchanged effect sizes of rs7172432 with plasma glucose and estimates of GSIR in analyses conditional on rs11071657 and rs17271305. CONCLUSIONS/INTERPRETATION: The diabetogenic VPS13C/C2CD4A/C2CD4B rs7172432 A allele associates with GSIR in non-diabetic individuals from the general population, suggesting an impaired beta cell function as an intermediary diabetes-related trait. PMID- 21249490 TI - Risk stratification systems for diabetic foot ulcers: a systematic review. AB - AIMS/HYPOTHESIS: Several risk stratification systems have been proposed for predicting development of diabetic foot ulcer. However, little has been published that assesses their similarities and disparities, diagnostic accuracy and evidence level. Consequently, we conducted a systematic review of the existing stratification systems. METHODS: We searched the MEDLINE database for studies (published until April 2010) describing the creation and validation of risk stratification systems for prediction of diabetic foot ulcer development. RESULTS: We included 13 studies describing or evaluating the following different risk degree stratification systems: University of Texas; International Working Group on Diabetic Foot; Scottish Intercollegiate Guideline Network (SIGN); American Diabetes Association; and Boyko and colleagues. We confirmed that five variables were included in almost all the systems: diabetic neuropathy, peripheral vascular disease, foot deformity, and previous foot ulcer and amputation. The number of variables included ranged from four to eight and the number of risk groups from two to six. Only four studies reported or allowed the calculation of diagnostic accuracy measures. The SIGN system showed some higher diagnostic accuracy values, particularly positive likelihood ratio, while predictive ability was confirmed through external validation only in the system of Boyko et al. CONCLUSIONS/INTERPRETATION: Foot ulcer risk stratification systems are a much needed tool for screening patients with diabetes. The core variables of various systems are very similar, but the number of included variables in each model and risk groups varied greatly. Overall, the quality of evidence for these systems is low, as little validation of their predictive ability has been done. PMID- 21249491 TI - Infrared spectroscopic analysis of 5,248 urinary stones from Chinese patients presenting with the first stone episode. AB - A series of 5,248 urinary stones was analyzed by Fourier transform infrared spectroscopy between 1999 and 2008. This study evaluated the percentage of each stone type and the association with sex and age in Chinese stone formers presenting with the first stone episode. The overall sex ratio (male:female) was 2.34:1. Results showed that the preponderant type of stone was calcium oxalate, followed by carbapatite, anhydrous uric acid, struvite and cystine. Struvite stones in this study accounted for a relatively low rate compared to that reported by others. Of 5,248 stones, only 38.1% had one component, 42.5% consisted of two components, and 20.4% consisted of three components. Our results also showed the higher percentage of carbapatite stones in females than in males and the increment of anhydrous uric acid stones with age. In addition, the percentage of calcium oxalate stones decreased with increase in the percentage of carbapatite stones over the period. PMID- 21249492 TI - Giant renal calculus in a horseshoe kidney presenting as an abdominal lump. AB - We report a case of giant renal calculus of 14 * 10.5 * 9 cm in size and weighing 790 g, in a horseshoe kidney, along with two large calculi on the opposite side. Patient presented with unusual complaint of an abdominal lump only. Physical examination revealed a stony hard mass on the left side of the abdomen, extending from the subcostal region to just above the iliac crest. A giant renal calculus on the left and two large calculi on the right side of a horseshoe kidney were diagnosed on computed tomography (CT) scan. Percutaneous nephrolithotomy, followed after 5 days by open pyelolithotomy was done for the stones on the right and left side, respectively. Analysis revealed a calcium phosphate stone. This case is worth reporting as it was not only the 8th heaviest renal stone reported in the English literature, but also the first giant stone to be reported in a horseshoe kidney. PMID- 21249493 TI - Simulating calcium salt precipitation in the nephron using chemical speciation. AB - Theoretical modeling of urinary crystallization processes affords opportunities to create and investigate scenarios which would be extremely difficult or impossible to achieve in in vivo experiments. Researchers have previously hypothesized that calcium renal stone formation commences in the nephron. In the present study, concentrations of urinary components and pH ranges in different regions of the nephron were estimated from concentrations in blood combined with a knowledge of the renal handling of individual ions. These were used in the chemical speciation program JESS to determine the nature of the solution complexes in the different regions of the nephron and the saturation index (SI) of the stone-forming salts calcium oxalate (CaOx), brushite (Bru), hydroxyapatite (HAP) and octacalcium phosphate (OCP). The effect of independent precipitation of each of the latter on the SI values of other salts was also investigated. HAP was the only salt which was supersaturated throughout the nephron. All of the other salts were supersaturated only in the middle and distal regions of the collecting duct. Supersaturations were pH sensitive. When precipitation of CaOx, Bru and OCP was simulated in the distal part of the collecting duct, little or no effect on the SI values of the other stone forming salts was observed. However, simulation of HAP precipitation caused all other salts to become unsaturated. This suggests that if HAP precipitates, a pure stone comprising this component will ensue while if any of the other salts precipitates, a mixed CaOx/CaP stone will be formed. Application of Ostwald's Rule of Stages predicts that the mixed stone is likely to be CaOx and Bru. Our modelling demonstrates that precipitation of stone forming salts in the nephron is highly dependent on the delicate nature of the chemical equilibria which prevail and which are themselves highly dependent on pH and component concentrations. PMID- 21249494 TI - Internal motions of actin characterized by quasielastic neutron scattering. AB - Quasielastic neutron scattering (QENS) experiments were carried out on powders of F-actin and G-actin hydrated with D(2)O to characterize the internal dynamics on the picosecond time scale and the Angstrom length scale. To investigate the effects of hydration, the measurements were done on samples at hydration ratio (h) of 0.4 (mg D(2)O/mg protein), containing only the first layer of hydration water, and at h = 1.0, containing more layers of water. The QENS spectra, obtained from the measurements at two energy resolutions of 110 and 15 MUeV, indicated that the internal motions of both F-actin and G-actin have distributions of motions with distinct correlation times and amplitudes. Increasing hydration changes relative populations of these distinct motions. The effects of hydration were shown to be different between F-actin and G-actin. Elastic incoherent neutron scattering measurements provided the concerted results. The observed effects were interpreted in terms of the dynamical heterogeneity of the actin molecule: in G-actin, more surface loops become flexible and undergo diffusive motions of large amplitudes, whereas in F-actin the molecular interactions that keep the polymerized state suppress the large motions of the surface loops involved with polymerization so that the population of atoms undergoing large motions can increase only to a lesser degree. PMID- 21249495 TI - Features of the popliteal lymph nodes seen on musculoskeletal MRI in a Western population. AB - OBJECTIVE: To asses the features and explore the clinical relevance of popliteal lymph nodes (PLNs) detected on MRI examination for different pathologies of the knee. MATERIALS AND METHODS: A total of 150 knee MRIs, which were conducted for various indications, were retrospectively collected from the Picture Archiving and Communication System. Imaging planes in at least two orthogonal planes were mandatory, with a field of view extending 15 cm cranial from the joint space. The localization of the PLN was determined by measuring the distance of the lowest border of the PLN to the lowest border of the lateral femoral condyle. Clinical diagnosis was obtained from radiology reports and a statistician performed the statistical analysis. RESULTS: The patients were 70 males [mean age 36.6 years (range: 5-72 years)] and 80 females [mean age 41.1 years (range: 9-76 years)]. In 36.7% of the patients, a PLN was visible. The number of PLNs was negatively associated with age (p < 0.001). The mean number of PLNs was 0.5 PLN per patient. The mean length, height, and width were respectively: 0.57 cm (SD = 0.15), 0.84 cm (SD = 0.26), and 0.71 cm (SD = 0.23). The mean location was 5.8 cm (SD = 1.61). No association was found between the presence of PLNs and internal derangement, inflammation, or cancer (p = 0.368). CONCLUSIONS: PLNs appearance is age related, with a higher frequency at a young age. The presence of the PLNs showed no relation to a specific clinical situation. PMID- 21249496 TI - Massive localised lymphoedema: clinical presentation and MR imaging characteristics. AB - Three morbidly obese women were referred to us with suspected soft-tissue sarcomas. All lesions arose from the medial subcutaneous tissues of the thigh, and were shown to represent massive localised lymphoedema (MLL), a rare condition occurring in morbidly obese adults. MR imaging typically demonstrates a sharply demarcated, pedunculated mass consisting of fat partitioned by fibrous septae surrounded by a thickened dermis. There is oedema both within the mass and tracking along the subcutaneous septae in a "lace-like" fashion outwards from the pedicle, outlining large lobules of fat. Minimal enhancement is observed within the dermis of the lesion following intravenous gadolinium administration. Obesity is a growing problem that is likely to result in an increase in the prevalence of this condition; therefore, familiarity with the radiological appearance is important in establishing a correct diagnosis in this condition that may mimic a soft-tissue sarcoma. PMID- 21249497 TI - Pure ethiodized oil-based transcatheter ablative therapy in normal rabbit kidneys and kidneys inoculated with VX-2 carcinoma. AB - PURPOSE: To evaluate the efficacy of ablation with selective arterial injection of pure ethiodized oil followed by arterial occlusion with 9:1 ethanol-Ethiodol mixture (EEM) and coil placement in normal rabbit kidneys and kidneys inoculated with VX-2 carcinoma. MATERIALS AND METHODS: All experiments were conducted with Animal Care and Use Committee approval. In six rabbits (group 1), one kidney was embolized with pure Ethiodol until capillary stasis, followed by injection of 9:1 EEM until arterial stasis and then coil placement into the main renal artery. In 12 other rabbits, one kidney was inoculated with VX-2 tumor. Ethiodol and EEM embolization and coil placement followed 7 days later (group 2, n = 6) or 11-14 days later (group 3, n = 6). Kidneys were evaluated (angiography, computed tomography, macro- and microscopy) 7 days after treatment. RESULTS: Capillary stasis was achieved in groups 1, 2, and 3 with (mean +/- standard deviation) 0.47 +/- 0.03, 0.53 +/- 0.02, and 0.56 +/- 0.04 ml of pure Ethiodol, followed by 0.47 +/- 0.05, 0.42 +/- 0.03, and 0.38 +/- 0.04 ml of EEM, respectively, which caused complete arterial occlusion in 17 of 18 kidneys. In group 1, all but one kidney showed at least 95% generalized coagulative necrosis. In group 2, all six kidneys exhibited 100% coagulative necrosis, with no viable tumor present. In group 3, 100% coagulative necrosis was present in all kidneys, with a small viable tumor in one. CONCLUSION: In the rabbit, selective arterial injection of pure Ethiodol can cause complete renal parenchyma and tumor ablation when it is followed by prompt, contiguous, and permanent occlusion of the arterial compartment. PMID- 21249498 TI - Retrospective evaluation of 22 patients with Takayasu's arteritis. AB - Takayasu's arteritis (TA) is a rare, idiopathic, inflammatory, granulomatous vasculitis that affects the aorta and its primary branches. Clinical features and the pattern of arterial involvement show differences in different regions of the world according to ethnic influences. Our aim in this retrospective study was to evaluate the demographic, clinic, laboratory, and angiographic findings of 22 patients with TA followed by our clinic and also compare our results with series from the literature. The hospital files of the 22 patients followed by our clinic between 1998 and 2009 were retrospectively evaluated. We also compared our results with the series from the literature that we were able to reach by US National Library of Medicine, National Institute of Health. Gender distribution, age at diagnosis, and type of aortic involvement were similar with the study from Turkey. Different clinical manifestations of Takayasu's arteritis have been described in different ethnic groups. We also want to underline the coincidence of TA and other rheumatic diseases such as sarcoidosis, SLE, RA, and psoriatic arthritis, different from other published series. PMID- 21249499 TI - SAPHO syndrome presenting as widespread bony metastatic disease of unknown origin. AB - SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome represents an inflammatory spectrum ranging from an osteitis through to a spondyloarthropathy which may or may not be associated with dermatological manifestations. We present the case of a 52-year-old female who presented with non-specific back pain. Radiological imaging showed mixed lytic and sclerotic lesions of her lumbar spine and pelvis consistent with bony metastatic disease. She underwent CT-guided biopsy that confirmed histological findings in keeping with non-bacterial osteitis/chronic recurrent multifocal osteomyelitis. This case report and review of the literature highlights the importance of the SAPHO syndrome and its treatment. PMID- 21249500 TI - Identification, frequency, activation and function of CD4+ CD25(high)FoxP3+ regulatory T cells in children with juvenile idiopathic arthritis. AB - The aim of the study was to test the frequency of CD4+ CD25(high)FoxP3 regulatory T cells in JIA patients and to assess their activation status and functional activity. The study involved 12 children with JIA and 35 healthy control subjects. PBMC were stained with monoclonal antibodies (anti-CD25, anti-CD4, anti CD127, anti-CD69, anti-CD71, and anti-FoxP3). The samples were evaluated using flow cytometer. CD4+ CD25- and CD4+ CD25+ cells were isolated by negative and positive selection with magnetic microbeads. CD4+ CD25+ and CD4+ CD25- cells were cultured separately and co-cultured (1:1) with or without PHA. The percentage of Tregs in JIA patients was significantly decreased in comparison with controls (median, 3.2 vs. 4.6; P = 0.042). Relative fluorescence intensities of FoxP3 were higher in JIA patients than in controls (median, 9.1 vs. 6.8). The percentage of activated Tregs (CD71+) was significantly higher in JIA patients in comparison with controls (median, 6.5 vs. 2.8; P = 0.00043). CD4+ CD25+ cells derived from JIA patients and controls were anergic upon PHA stimulation, while CD4+ CD25- cells showed intensive proliferative response. The proliferation rate of CD4+ CD25- cells stimulated by PHA was decreased in co-cultures. In JIA patients, the inhibition of proliferation of CD4+ CD25- cells by CD4+ CD25+ cells was 37.9%, whereas in controls it was significantly lower (55.7%, P = 0.046). JIA patients had statistically lower percentage of Tregs in peripheral blood compared to controls. CD4+ CD25+ cells sorted from peripheral blood of JIA patients had statistically lower ability to suppress CD4+ CD25- cell proliferation in comparison with cells obtained from controls. PMID- 21249501 TI - Diminishing returns: the influence of experience and environment on time-memory extinction in honey bee foragers. AB - Classical experiments demonstrated that honey bee foragers trained to collect food at virtually any time of day will return to that food source on subsequent days with a remarkable degree of temporal accuracy. This versatile time-memory, based on an endogenous circadian clock, presumably enables foragers to schedule their reconnaissance flights to best take advantage of the daily rhythms of nectar and pollen availability in different species of flowers. It is commonly believed that the time-memory rapidly extinguishes if not reinforced daily, thus enabling foragers to switch quickly from relatively poor sources to more productive ones. On the other hand, it is also commonly thought that extinction of the time-memory is slow enough to permit foragers to 'remember' the food source over a day or two of bad weather. What exactly is the time-course of time memory extinction? In a series of field experiments, we determined that the level of food-anticipatory activity (FAA) directed at a food source is not rapidly extinguished and, furthermore, the time-course of extinction is dependent upon the amount of experience accumulated by the forager at that source. We also found that FAA is prolonged in response to inclement weather, indicating that time memory extinction is not a simple decay function but is responsive to environmental changes. These results provide insights into the adaptability of FAA under natural conditions. PMID- 21249502 TI - Low risk of contamination with human papilloma virus during treatment of condylomata acuminata with multilayer argon plasma coagulation and CO2 laser ablation. AB - Multilayer argon plasma coagulation (APC) is a new effective method for the treatment of genital warts. We assessed the generation of aerosols containing human papilloma virus (HPV) DNA during treatment of genital warts with multilayer APC and with CO2 laser ablation. Surveillance petri dishes, swabs from the glasses and nasolabial folds of the operating physician, and swabs taken from the suction units used during CO2 laser ablation were tested by HPV PCR. HPV DNA corresponding to patient derived HPV types of genital warts was not found in any of the petri dishes and swabs obtained during APC treatment. HPV DNA was detected in none of the petri dishes obtained during CO2 laser treatment, but in suction filters. In conclusion, both CO2 laser ablation with plume suction and APC treatment seem to have a low risk of HPV contamination of the operation room. PMID- 21249503 TI - Meningeal melanocytosis: a possibly useful treatment for a rare primary brain neoplasm. PMID- 21249505 TI - Species response curves of oak species along climatic gradients in Turkey. AB - The genus Quercus is one of the most important tree species in Turkey. However, little is known on the ecological preferences of Turkish oak species regarding climate. We analyzed species response curves using a HOF-model approach to describe the general pattern of oak distributions along climatic gradients and to identify the driving climatic factors for eight oak species in Turkey. While climate data were extracted from the free available worldclim dataset, occurrence data on oak species were assembled from the literature into a vegetation database (n = 1,104). From the analyzed species response curves, only fa ew (16%) showed unimodal responses, while most were linear (31%) or exhibited a threshold response (31%). The driving factors were seasonality of temperature and seasonality of precipitation, indicating that Turkish oak species can be characterized best by the preference of climatic stability. These findings have important implications for conservation and climate change research, which usually focuses on trends of the mean values of temperature or precipitation but less often on the seasonality. In this study, we further tested whether niche optima derived from raw mean values of occurrences could replace missing model optima due to non-responsiveness of HOF models of type I. However, we did not find this to be a satisfactory solution. Finally, we discuss the need for the construction of a national database based on phytosociological releves for Turkey. PMID- 21249504 TI - A potato skin SSH library yields new candidate genes for suberin biosynthesis and periderm formation. AB - Potato (Solanum tuberosum) tubers are underground storage organs covered by the skin or periderm, a suberized layer that protects inner flesh from dehydration and pathogens. Understanding the molecular processes associated with periderm formation is of great importance for a better knowledge of this protective tissue and for improving the storage life of tubers. Here, to isolate new candidate genes for potato periderm, a suppression subtractive hybridization library from potato skin was performed. This library yielded a comprehensive list of 108 candidate genes that were manually sorted in functional categories according to the main cellular and metabolic processes in periderm. As expected, the list contains Suberin and wax genes, including some genes with a demonstrated role in the biosynthesis of these cell wall aliphatic compounds. Moreover, Regulation and Stress and defence genes are highly abundant in the library in general agreement with previous potato skin proteomic studies. The putative function of the genes in periderm is discussed. PMID- 21249507 TI - A kinematic analysis of relative stability of the lower extremities between subjects with and without chronic low back pain. AB - Even though a number of studies have evaluated postural adjustments based on kinematic changes in subjects with low back pain (LBP), kinematic stability has not been examined for abnormal postural responses during the one leg standing test. The purpose of this study was to evaluate the relative kinematic stability of the lower extremities and standing duration in subjects with and without chronic LBP. In total, 54 subjects enrolled in the study, including 28 subjects without LBP and 26 subjects with LBP. The average age of the subjects was 37.8 +/ 12.6 years and ranged from 19 to 63 years. The outcome measures included normalized holding duration and relative kinematic stability. All participants were asked to maintain the test position without visual input (standing on one leg with his/her eyes closed and with the contra lateral hip flexed 90 degrees ) for 25 s. The age variable was used as a covariate to control confounding effects for the data analyses. The control group demonstrated significantly longer holding duration times (T = -2.78, p = 0.007) than the LBP group (24.6 +/- 4.2 s vs. 20.5 +/- 6.7 s). For the relative kinematic stability, there was a difference in dominance side (F = 9.91, p = 0.003). There was a group interaction between side and lower extremities (F = 11.79, p = 0.001) as well as an interaction between age and dominance side (F = 7.91, p = 0.007). The relative kinematic stability had a moderate negative relationship with age (r = -0.60, p = 0.007) in subjects without LBP. Clinicians need to understand the effects of age and relative stability, which decreased significantly in the single leg holding test, in subjects with LBP in order to develop effective rehabilitation strategies. PMID- 21249508 TI - The Michel Benoist and Robert Mulholland yearly European Spine Journal Review: a survey of the "surgical and research" articles in the European Spine Journal, 2010. PMID- 21249509 TI - A comparative evaluation of gutta-percha filled areas in curved root canals obturated with different techniques. AB - The aim of this study was to compare different obturation techniques in severely curved canals in terms of the percentage of gutta-percha filled area and voids. The obturation times and the incidence of extrusion of filling material were also compared. Curved root canals (curvature, 25-35 degrees ) of 48 extracted human teeth were enlarged with Mtwo rotary NiTi instruments and obturated as follows: Group A: 0.04/35 matched-single-cone; Group B: cold lateral compaction with 0.04/35 gutta-percha master cone; Group C: warm vertical compaction; Group D: lateral compaction with standardized gutta-percha master cone. In all groups AHPlus was used as sealer. The teeth were sectioned horizontally at 2, 3, 4, 6 and 8 mm from the apex. The total area of each canal segment was measured and the areas of gutta-percha, sealer and voids were converted to percentages of the total area. Data were subjected to the Kruskal-Wallis and post hoc Dunn test. Obturation times were compared using ANOVA and post hoc Student-Newman-Keuls test. The matched-single-cone obturation (group A) was significantly the fastest method while warm vertical compaction (group C) required significantly more time than all other techniques (p < 0.05). No significant differences were obtained between the groups in terms of percentage of voids at any level (p > 0.05). At all levels, groups B, C, and D produced significantly higher gutta-percha filled areas (p < 0.05) and lower sealer-filled areas (p < 0.05) than group A. No significant differences were found between groups B, C, and D (p > 0.05) regarding gutta-percha and sealer-filled areas. Within the limitations of the in vitro study, it can be concluded that lateral compaction of greater taper gutta percha cones is a fast and efficient method for obturation of curved canals. PMID- 21249511 TI - On or in the liver? Two cases with diffuse pseudomyxoma peritonei and synchronous hepatic pathology. AB - Pseudomyxoma peritonei (PMP) is a borderline malignancy, simulating carcinomatosis and generally arising from perforation of an appendiceal mucinous tumour. Some patients have coincidental dual pathology. Liver abnormalities in particular may be overlooked and/or misclassified. We report 2 cases of patients who had diffuse PMP with synchronous hepatic pathology to highlight the need for vigilance and appropriate assessment of coincidental liver lesions. An assessment and management strategy is outlined. PMID- 21249510 TI - Tool-use and instrumental learning in the Eurasian jay (Garrulus glandarius). AB - Recent research with Rooks has demonstrated impressive tool-using abilities in captivity despite this species' classification as a non-tool-user in the wild. Here, we explored whether another non-tool-using corvid, the Eurasian Jay, would be capable of similar feats and investigated the relative contributions of causal knowledge and instrumental conditioning to the birds' performance on the tasks. Five jays were tested on a variety of tasks involving water displacement. Two birds reliably interacted with the apparatuses. In these tasks, both birds showed a preference for inserting stones into a tube containing liquid over a tube containing a solid or a baited 'empty' tube and also for inserting sinkable items over non-sinkable items into a tube of water. To investigate the contribution of instrumental conditioning, subjects were then tested on a series of tasks in which different cues were made available. It was found that, in the absence of any apparent causal cues, these birds showed a clear preference for the rewarded tube when the food incrementally approached with every stone insertion, but not when it simply "appeared" after the correct number of stone insertions. However, it was found that subjects did not prefer to insert stones into a tube rewarded by the incremental approach of food if the available causal cues violated the expectations created by existing causal knowledge (i.e. were counter-intuitive). An analysis of the proportion of correct and incorrect stone insertions made in each trial across tasks offering different types of information revealed that subjects were substantially more successful in experiments in which causal cues were available, but that rate of learning was comparable in all experiments. We suggest that these results indicate that Eurasian jays use the incremental approach of the food reward as a conditioned reinforcer allowing them to solve tasks involving raising the water level and that this learning is facilitated by the presence of causal cues. PMID- 21249512 TI - Study of epileptiform activity in cerebral ganglion of mud crab Scylla serrata. AB - An attempt is made to induce in mud crab (Scylla serrata) epileptiform activities that resemble the generalized epileptic seizures. Cerebral ganglion of crab was exposed in situ, to a convulsant drug pentylenetetrazole (PTZ) 100 mM, for induction of seizures. Also, crabs were pretreated with antiepileptic drug viz sodium valproate (120 MUmol/l) to inhibit epileptiform activities. The surface electrical discharges of cerebral ganglion were recorded using Unkelscope (MIT, USA) in control as well as experimental animals. The cerebral ganglion of crab showed a pattern of high cerebral electrical discharges after PTZ treatment compared to control. The sodium valproate promoted sedative action in control and prevented PTZ-mediated epileptiform discharges. Glutamate and GABA contents in cerebral ganglion were assayed. Glutamate level increased (31.45%) during PTZ treatment with concomitant decrease (43.93%) in GABA. Sodium valproate had no effect on glutamate concentration, but it decreased GABA by 24.75%. The present study shows that epileptiform activities can be induced in crabs. PMID- 21249514 TI - Sorafenib versus cytotoxic chemotherapy for patients with advanced hepatocellular carcinoma: a retrospective, single-institution study. AB - BACKGROUND: Prior to the 2008 advent of sorafenib, traditional cytotoxic agents were the therapeutic mainstay for patients with advanced hepatocellular carcinoma (HCC). We thus undertook a clinical study of sorafinib and conventional cytotoxic therapy for HCC, comparing efficacy and safety. METHODS: From January, 2002 to December, 2009, 173 patients with unresectable HCC were reviewed retrospectively. Among them, 44 (25.4%) had been treated with sorafenib, and the remainder had received cytotoxic therapy (CTX). We evaluated objective response rate (ORR), progression free survival (PFS), overall survival (OS), and toxicity profiles. RESULTS: Median OS of sorafinib was 23.0 weeks (95% CI, 8.1-37.9) vs 43.6 weeks (95% CI, 34.0-53.2) for CTX. Likewise, median PFS was 11.1 weeks (95% CI, 6.5 15.8) vs 12.4 weeks (95% CI, 8.1-16.7) for sorafenib and CTX, respectively. Neither parameter differed significantly (OS, p = 0.105; PFS, p = 0.496). ORR and disease control rate for sorafenib were 2.3% and 52.3% vs 6.2% and 43.4% for CTX. CTX-treated patients experienced more Grade 3/4 neutropenia (19.7% vs 0% for sorafenib), while sorafenib therapy was more often linked to dermatologic toxicities (all grades), such as hand-foot skin reaction, rash, and pruritus. CONCLUSION: Although sorafenib has become the treatment of choice for advanced HCC, there are still unsettled issues regarding the optimal use of sorafenib. Our analysis indicates that conventional CTX can be another option of treatment for advanced HCC. To improve clinical outcomes, further prospective investigations which define the role of CTX are needed. PMID- 21249515 TI - Classification of speech dysfluencies using LPC based parameterization techniques. AB - The goal of this paper is to discuss and compare three feature extraction methods: Linear Predictive Coefficients (LPC), Linear Prediction Cepstral Coefficients (LPCC) and Weighted Linear Prediction Cepstral Coefficients (WLPCC) for recognizing the stuttered events. Speech samples from the University College London Archive of Stuttered Speech (UCLASS) were used for our analysis. The stuttered events were identified through manual segmentation and were used for feature extraction. Two simple classifiers namely, k-nearest neighbour (kNN) and Linear Discriminant Analysis (LDA) were employed for speech dysfluencies classification. Conventional validation method was used for testing the reliability of the classifier results. The study on the effect of different frame length, percentage of overlapping, value of a in a first order pre-emphasizer and different order p were discussed. The speech dysfluencies classification accuracy was found to be improved by applying statistical normalization before feature extraction. The experimental investigation elucidated LPC, LPCC and WLPCC features can be used for identifying the stuttered events and WLPCC features slightly outperforms LPCC features and LPC features. PMID- 21249516 TI - Automatic classification and robust identification of vestibulo-ocular reflex responses: from theory to practice: introducing GNL-HybELS. AB - The Vestibulo-Ocular Reflex (VOR) stabilizes images of the world on our retinae when our head moves. Basic daily activities are thus impaired if this reflex malfunctions. During the past few decades, scientists have modeled and identified this system mathematically to diagnose and treat VOR deficits. However, traditional methods do not analyze VOR data comprehensively because they disregard the switching nature of nystagmus; this can bias estimates of VOR dynamics. Here we propose, for the first time, an automated tool to analyze entire VOR responses (slow and fast phases), without a priori classification of nystagmus segments. We have developed GNL-HybELS (Generalized NonLinear Hybrid Extended Least Squares), an algorithmic tool to simultaneously classify and identify the responses of a multi-mode nonlinear system with delay, such as the horizontal VOR and its alternating slow and fast phases. This algorithm combines the procedures of Generalized Principle Component Analysis (GPCA) for classification, and Hybrid Extended Least Squares (HybELS) for identification, by minimizing a cost function in an optimization framework. It is validated here on clean and noisy VOR simulations and then applied to clinical VOR tests on controls and patients. Prediction errors were less than 1 deg for simulations and ranged from .69 deg to 2.1 deg for the clinical data. Nonlinearities, asymmetries, and dynamic parameters were detected in normal and patient data, in both fast and slow phases of the response. This objective approach to VOR analysis now allows the design of more complex protocols for the testing of oculomotor and other hybrid systems. PMID- 21249513 TI - Epigenetic aberrations during oncogenesis. AB - The aberrant epigenetic landscape of a cancer cell is characterized by global genomic hypomethylation, CpG island promoter hypermethylation of tumor suppressor genes, and changes in histone modification patterns, as well as altered expression profiles of chromatin-modifying enzymes. Recent advances in the field of epigenetics have revealed that microRNAs' expression is also under epigenetic regulation and that certain microRNAs control elements of the epigenetic machinery. The reversibility of epigenetic marks catalyzed the development of epigenetic-altering drugs. However, a better understanding of the intertwined relationship between genetics, epigenetics and microRNAs is necessary in order to resolve how gene expression aberrations that contribute to tumorigenesis can be therapeutically corrected. PMID- 21249517 TI - Developmental pathways to depressive symptoms in adolescence: a multi-wave prospective study of negative emotionality, stressors, and anxiety. AB - This study examined two potential developmental pathways through which the temperament risk factor of negative emotionality (NE) leads to prospective increases in depressive symptoms through the mediating role of stressors and anxious symptoms in a sample of early to middle adolescents (N = 350, 6th-10th graders). The primary hypothesized model was that baseline NE leads to increased stressors, which results in increases in anxious arousal, which culminates with elevated depressive symptoms. An alternate model hypothesized that baseline NE leads to increased anxious arousal, which results in increases in stressors, and this culminates in elevated depressive symptoms. Youth completed self-report measures of NE, stressors, anxious arousal, and depressive symptoms at four time points. Path analysis supported the primary model and showed that the mediating influence of stressors and anxious arousal explained 78% of the association between NE and prospective elevations in depressive symptoms. The alternate model was not supported. Neither gender nor age were moderators. PMID- 21249518 TI - How do students with dyslexia perform in extended matching questions, short answer questions and observed structured clinical examinations? AB - There are an increasing number of students with learning difficulties attending university, and currently much debate about the suitability and ability of students with dyslexia at both medical school and once they graduate into clinical practice. In this study we describe the performance of students with dyslexia compared to fellow students in extended matching questions (EMQ), short answer question (SAQ) and observed structured clinical examinations (OSCE) and discuss the implications of differences identified. End of year assessment results for 5 cohorts of medical students were analysed. Students with dyslexia did less well overall in all assessment types in year 1 but this difference was not evident in later years. Dyslexic students who were allowed extra time in written assessments did better than dyslexic students who did not have their assessment concessions in place. When station type within OSCE assessments was analysed students with dyslexia did less well in both examination skills and data interpretation stations in years 1, 2 & 3. In conclusion, differences in performance in written assessments are only evident early in training and may be partly due to delayed adjustment to medical school or implementation of assessment concessions. Performance in individual OSCE stations is dependent on station type. Why students with specific learning difficulties (SpLDs) perform less well in examination skills and data analysis OSCE stations requires further investigation. PMID- 21249519 TI - Community mental health allies: referral behavior among Asian American immigrant Christian clergy. AB - Asian American Christian faith leaders support and provide an array of services within their communities. However, little is known about their response to congregants' mental health concerns. This study examined correlates of mental health referral behavior among 103 Asian American Christian clergy in California who completed an anonymous mail survey. Using multiple regression analyses, we found that clergy's prior mental health education, knowledge of mental illness, education level, time spent providing individual counseling and referral to general practitioners were positively associated with making mental health referrals. Outreach efforts (including mental health education, and mental health referral information) to facilitate clergy's support of congregants with mental health needs are discussed. PMID- 21249520 TI - A pilot study addressing the impact of religious practice on quality of life of breast cancer patients during chemotherapy. AB - The aim of this preliminary study was to investigate whether religious practice can modify quality of life (QoL) in BC patients during chemotherapy. QoL and religion practice questionnaire (RPQ) scores were evaluated in a sample of BC patients in different moments. Before chemotherapy initiation, women with lower physical and social functional scores displayed higher RPQ scores. On the other hand, low RPQ patients worsened some QoL scores over time. Body image acceptance was positively correlated with religious practice and specifically praying activity. This preliminary study suggests the importance of religion in coping with cancer chemotherapy. PMID- 21249521 TI - The adolescent Religious Coping Questionnaire. Translation and cultural adaptation of Pargament's RCOPE Scale for Polish adolescents. AB - The paper presents the process of translation and cultural adaptation of the Religious Coping Questionnaire (the RCOPE) by Pargament et al. (2000) for Polish adolescents. The work was driven by the necessity to obtain a structural and measurement equivalence between the American and Polish versions of the instrument. The Polish version was created at the Department of Clinical Psychology of Children and Adolescents at The John Paul II Catholic University of Lublin, Poland. The exploratory factor analysis with the Oblimin oblique rotation was carried out. The principal components method was used as an extraction method of common factors. The results provided input for constructing the scales. The Adolescent Religious Coping Questionnaire consists of 105 items, grouped in 16 scales, which reflects positive and negative religious coping strategies. PMID- 21249522 TI - Discrimination, religious coping, and tobacco use among White, African American, and Mexican American vocational school students. AB - This study examined whether religious coping moderates the impact of racial/ethnic discrimination on current (past 30 day) cigarette and cigar/cigarillo use among a racially/ethnically diverse sample of 984 technical/vocational school students (47.1% women; mean age = 25 years). Results indicate that discrimination increased the likelihood of current cigarette use among African American students and current cigar/cigarillo use among white and African American students. Positive religious coping decreased the likelihood of cigarette and cigar/cigarillo smoking for white students only. Negative religious coping increased the likelihood of cigarette use for white students and cigar/cigarillo use for white and African American students. Two 2-way interactions indicate that positive and negative religious coping moderate the discrimination-cigarette smoking relationship for African American and Mexican American students, respectively. PMID- 21249523 TI - Patients' expectations of healthcare chaplaincy: a cross-sectional study in the German part of Switzerland. AB - Identifying patients' expectations of and need for healthcare chaplaincy is important in terms of appropriate intervention. Therefore, a sample of 612 patients from 32 general hospitals and psychiatric clinics in the German part of Switzerland was surveyed about their expectations of chaplaincy service. A principal component factor analysis of participants' ratings found that the survey items fell into three distinct categories. These were the need for (1) emotional support, (2) help to cope with illness/disease, and (3) religious/spiritual assistance. Among the expectations, the need for emotional support was rated most important, followed by help to cope and, lastly, religious/spiritual assistance. Gender, religious denomination, general religiosity, and subjective health status significantly influenced these expectations. The results showed that fulfilling patients' expectations increases their overall satisfaction with, and the importance they accord to the chaplain's visit, as well as their confidence in the chaplain. PMID- 21249524 TI - Health care behaviours and beliefs in Hasidic Jewish populations: a systematic review of the literature. AB - Cultural issues impact on health care, including individuals' health care behaviours and beliefs. Hasidic Jews, with their strict religious observance, emphasis on kabbalah, cultural insularity and spiritual leader, their Rebbe, comprise a distinct cultural group. The reviewed studies reveal that Hasidic Jews may seek spiritual healing and incorporate religion in their explanatory models of illness; illness attracts stigma; psychiatric patients' symptomatology may have religious content; social and cultural factors may challenge health care delivery. The extant research has implications for clinical practice. However, many studies exhibited methodological shortcomings with authors providing incomplete analyses of the extent to which findings are authentically Hasidic. High-quality research is required to better inform the provision of culturally competent care to Hasidic patients. PMID- 21249525 TI - [African silhouettes and field photography. M. Griaule's contribution to the Maussian "discovery" of body techniques]. AB - This essay focuses on the interaction between the new reproduction media and corresponding reconfiguration of research fields in anthropology using the case of the "techniques of the body" - a concept developed by Marcel Mauss (1872 1950). For Mauss, the initiator of this discipline in France, body skills constituted the most important anthropological entity resulting from the confrontation of technical images and his interest in walking techniques. Three scenarios are especially significant for Mauss's formulation of "body techniques" as a genuine concept: the front during the World War I, a New Yorke hospital in 1926, and an ethnographical field study conducted in Africa during the ate 1920s. Both, the photographic media as well as the Abyssinian expedition of his student Marcel Griaule, whose research publication Mauss co-authored (Silhouettes et graffiti abyssins) n 1933, take centre stage here. PMID- 21249526 TI - Spatial clustering of HIV prevalence in Atlanta, Georgia and population characteristics associated with case concentrations. AB - We assessed prevalent HIV cases in Atlanta to examine case distribution trends and population characteristics at the census tract level that may be associated with clustering effects. We calculated cluster characteristics (area and internal HIV prevalence) via Kuldorff's spatial scan method. Subsequent logistic regression analyses were performed to analyze sociodemographics associated with inclusion in a cluster. Organizations offering voluntary HIV testing and counseling services were identified and we assessed average travel time to access these services. One large cluster centralized in downtown Atlanta was identified that contains 60% of prevalent HIV cases. The prevalence rate within the cluster was 1.34% compared to 0.32% outside the cluster. Clustered tracts were associated with higher levels of poverty (OR = 1.19), lower density of multi-racial residents (OR = 1.85), injection drug use (OR = 1.99), men having sex with men (OR = 3.01), and men having sex with men and IV drug use (OR = 1.6). Forty-two percent (N = 11) of identified HIV service providers in Atlanta are located in the cluster with an average travel time of 13 minutes via car to access these services (SD = 9.24). The HIV epidemic in Atlanta is concentrated in one large cluster characterized by poverty, men who have sex with men (MSM), and IV drug usage. Prevention efforts targeted to the population living in this area as well as efforts to address the specific needs of these populations may be most beneficial in curtailing the epidemic within the identified cluster. PMID- 21249527 TI - Surgery for hilar cholangiocarcinoma: a multi-institutional update on practice and outcome by the AFC-HC study group. AB - INTRODUCTION: Surgical resection is the only option for long-term survival in patients with hilar cholangiocarcinoma (HC), but it is associated with high morbidity and mortality. The aim of the present study was to prospectively assess the perioperative management and short-term outcomes of surgical treatment of HC in a recent, multi-institutional study with a short inclusion period. METHODS: Between January and December 2008, a register prospectively collected data on patients operated on for HC (exploratory or curative surgery) in eight tertiary centers. The register focused on perioperative management, resectability, surgical procedures employed, morbidity, and mortality. The study cohort consisted of 56 patients (40 men and 16 women) with a median age of 63 years (range, 33-83 years). RESULTS: Among the 56 patients, 47 (84%) were jaundiced and 42 (75%) tumors were classified as Bismuth-Corlette type III-IV. Nine patients (16%) underwent staging laparoscopy and four (7%) received neoadjuvant chemotherapy. Preoperative biliary drainage (endoscopy, 42%) was performed in 38 (81%) jaundiced patients and portal vein embolization (right side, 83%) was performed prior to surgery in 18 patients (32%). Among these 56 patients, curative resection was achieved in 39 (70%). All underwent major liver resection (>3 segments), bile duct resection, and lymphadenectomy. Thirteen patients (36%) underwent portal vein resection, one of whom also required pancreaticoduodenectomy. Eighty-two percent of resected patients (n = 32) had no proof of malignancy prior to hepatectomy. Clear surgical margins were obtained in 77% (n = 30). The postoperative mortality was 8% and complications occurred in 72% of the resected patients. Seven (25%) patients required reoperation, and 15 (54%) patients required percutaneous drainage. In a univariate analysis, the risk factors for morbidity were intraoperative blood transfusion (p = 0.009) and vascular clamping (p = 0.006). The median length of hospitalization was 20 +/- 13 days. CONCLUSION: Curative resection for HC is associated with a high rate of R0 resection. However, surgery is associated with high levels of morbidity and mortality, despite intensive perioperative management. PMID- 21249528 TI - Surface cooling after cardiac arrest: effectiveness, skin safety, and adverse events in routine clinical practice. AB - BACKGROUND: Effectiveness of cooling and adverse events (AEs) involving skin have not been intensively evaluated in cardiac arrest survivors treated with therapeutic hypothermia (TH) when induced and maintained with a servomechanism regulated surface cooling system. METHODS: Retrospective review of sixty-nine cardiac arrest survivor-events admitted from April 2006-September 2008 who underwent TH using the Medivance Arctic Sun Temperature Management System. A TH database and medical records were reviewed, and nursing interviews conducted. Primary endpoint was time from initiation to target temperature (TT; 32-34 degrees C). Secondary endpoints were cooling rate, percentage of hypothermia maintenance phase at TT, effect of body-mass index (BMI) on rate of cooling, and AEs. RESULTS: Mean time to the target temperature (TT) was 2.78 h; 80% of patients achieved TT within 4 h; all did within 8 h. Patients were at TT for 96.7% of hypothermia maintenance; 17% of patients had >1 hourly temperature measurement outside TT range. Mean cooling rate during induction phase was 1.1 degrees C/h, and was not associated with BMI. Minor skin injury occurred in 14 (20%) patients; 4 (6%) were device-related. Skin injuries were associated with shock (P = 0.04), and decubitus ulcers were associated with left ventricular ejection fraction <45% (P = 0.004). AEs included shivering (94%), hypokalemia (81%), hyperglycemia (57%), pneumonia (23%), bleeding (22%), post-cooling fever (17%), and bacteremia (9%). CONCLUSIONS: The Arctic Sun Temperature Management System was an effective means of performing therapeutic hypothermia after cardiac arrest. Infrequent skin injuries were associated with vasopressor use and low ejection fraction. PMID- 21249529 TI - Electric versus manual tooth brushing among neuroscience ICU patients: is it safe? AB - BACKGROUND: Poor oral hygiene has been associated with ventilator-acquired pneumonia. Yet providing oral care for intubated patients is problematic. Furthermore, concerns that oral care could raise intracranial pressure (ICP) may cause nurses to use foam swabs to provide oral hygiene rather than tooth brushing as recommended by the American Association of Critical-Care Nurses. Evidence is needed to support the safety of toothbrushing during oral care. We therefore evaluated ICP and cerebral perfusion pressure (CPP) during oral care with a manual or electric toothbrush in intubated patients in a neuroscience intensive care unit (ICU). METHODS: As part of a larger 2-year, prospective, randomized clinical trial, 47 adult neuroscience ICU patients with an ICP monitor received oral care with a manual or electric toothbrush. ICP and CPP were recorded before, during, and after oral care over the first 72 h of admission. RESULTS: Groups did not differ significantly in age, gender, or severity of injury. Of 807 ICP and CPP measurements obtained before, during, and after oral care, there were no significant differences in ICP (P = 0.72) or CPP (P = 0.68) between toothbrush methods. Analysis of pooled data from both groups revealed a significant difference across the three time points (Wilks' lambda, 12.56; P < 0.001; partial eta(2), 0.36). ICP increased significantly (mean difference, 1.7 mm Hg) from before to during oral care (P = 0.001) and decreased significantly (mean difference, 2.1 mm Hg) from during to after oral care (P < 0.001). CONCLUSIONS: In the absence of preexisting intracranial hypertension during oral care, tooth brushing, regardless of method, was safely performed in intubated neuroscience ICU patients. PMID- 21249530 TI - The use of lacosamide in refractory status epilepticus. AB - BACKGROUND: Case reports suggest lacosamide may have a role in status epilepticus (SE). The purpose of this case series is to describe the use of lacosamide in refractory SE (RSE) at our institution. METHODS: Observational study of all patients admitted to the neurosciences intensive care unit with RSE who received at least one dose of lacosamide from October 2009 to September 2010. RESULTS: Nine patients received lacosamide after failure of at least two other agents. Lacosamide was started a median of 2 days (range: 0-14 days) after the onset of SE. The most frequently used dosing regimen was an initial intravenous dose of 200 mg followed by 200 mg every 12 h. Most patients had received 3 (range: 2-5) AEDs prior to lacosamide. Levetiracetam was used prior to lacosamide in all cases. No patients evaluated responded to lacosamide according to our predefined criteria. One patient developed angioedema after receiving two doses; another patient developed angioedema where timing in relation to the lacosamide was unclear. Care was withdrawn in three of the nine patients for reasons unrelated to lacosamide. Lacosamide was continued at discharge on all surviving patients except in one case of angioedema. CONCLUSIONS: This is the largest case series to date describing the use of lacosamide in patients with RSE. Despite the novel mechanism of action, we observed no evidence that lacosamide is effective in RSE; however, our sample size was small. Further study is needed to determine the role of lacosamide in SE, especially early in the treatment course. PMID- 21249532 TI - Unified framework for development, deployment and robust testing of neuroimaging algorithms. AB - Developing both graphical and command-line user interfaces for neuroimaging algorithms requires considerable effort. Neuroimaging algorithms can meet their potential only if they can be easily and frequently used by their intended users. Deployment of a large suite of such algorithms on multiple platforms requires consistency of user interface controls, consistent results across various platforms and thorough testing. We present the design and implementation of a novel object-oriented framework that allows for rapid development of complex image analysis algorithms with many reusable components and the ability to easily add graphical user interface controls. Our framework also allows for simplified yet robust nightly testing of the algorithms to ensure stability and cross platform interoperability. All of the functionality is encapsulated into a software object requiring no separate source code for user interfaces, testing or deployment. This formulation makes our framework ideal for developing novel, stable and easy-to-use algorithms for medical image analysis and computer assisted interventions. The framework has been both deployed at Yale and released for public use in the open source multi-platform image analysis software- BioImage Suite (bioimagesuite.org). PMID- 21249531 TI - The DIADEM data sets: representative light microscopy images of neuronal morphology to advance automation of digital reconstructions. AB - The comprehensive characterization of neuronal morphology requires tracing extensive axonal and dendritic arbors imaged with light microscopy into digital reconstructions. Considerable effort is ongoing to automate this greatly labor intensive and currently rate-determining process. Experimental data in the form of manually traced digital reconstructions and corresponding image stacks play a vital role in developing increasingly more powerful reconstruction algorithms. The DIADEM challenge (short for DIgital reconstruction of Axonal and DEndritic Morphology) successfully stimulated progress in this area by utilizing six data set collections from different animal species, brain regions, neuron types, and visualization methods. The original research projects that provided these data are representative of the diverse scientific questions addressed in this field. At the same time, these data provide a benchmark for the types of demands automated software must meet to achieve the quality of manual reconstructions while minimizing human involvement. The DIADEM data underwent extensive curation, including quality control, metadata annotation, and format standardization, to focus the challenge on the most substantial technical obstacles. This data set package is now freely released ( http://diademchallenge.org ) to train, test, and aid development of automated reconstruction algorithms. PMID- 21249533 TI - Management of renal artery stenosis: 2010. AB - OPINION STATEMENT: Renal artery stenosis (RAS) is a relatively common manifestation of atherosclerosis, although in a small percentage of cases it is due to fibromuscular dysplasia and less frequently may have other etiologies. RAS may be treated by revascularization, using either percutaneous or open surgical techniques. Currently, technical success with percutaneous revascularization utilizing angioplasty and stenting is achieved in 95% or more of cases in which it is attempted. Despite this, at least one third of patients undergoing renal artery stenting do not receive any measurable benefit. Furthermore, randomized trials of stenting for RAS have failed to demonstrate a benefit over medical management alone. Thus, the clinician is faced with a challenge when determining how to manage an individual patient with RAS. In the current era, all patients with RAS should receive "optimal medical therapy." This approach should use medicines to control blood pressure, and specifically utilize agents proven to reduce cardiovascular morbidity and mortality. Other components of "optimal medical therapy" include the use of anti-platelet drugs such as aspirin and statins to minimize progression of atherosclerosis. In addition to these strategies, consideration should be given to revascularization therapy. When deciding to revascularize RAS, the patient should have an appropriate clinical indication, in addition to a significant anatomic stenosis. Importantly, stents should not be placed due to the "oculostenotic reflex." Specifically, patients who continue to have uncontrolled blood pressure or worsening renal function despite an aggressive approach with medical therapy may be particularly good candidates for renal artery stenting. Despite the lack of benefit in randomized trials to date, there is likely still a role for renal artery stenting in RAS; however, careful patient selection is essential to maximize the potential benefit. PMID- 21249536 TI - LIM kinase-1 in the cerebral ganglion of Drosophila with genetic disturbances of kynurenine balance. PMID- 21249537 TI - Oxygen supply of rat liver under the conditions of isolated perfusion. PMID- 21249538 TI - Regulatory peptides protect brain neurons from hypoxia in vivo. PMID- 21249539 TI - The role of total cholesterol in restoration of estrous cycles in animals. PMID- 21249540 TI - Effects of exogenous heat shock protein 70 and quercetin on NMDA-induced seizures. PMID- 21249542 TI - On the tube microstructure of recent spirorbids (Annelida, Polychaeta). PMID- 21249541 TI - Persistent hypertension modifies glutamatergic and GABA-ergic synaptic transmission in the rat olfactory brain cortex in vitro. PMID- 21249543 TI - Multilevel bioindication in modern monitoring technology as exemplified by zoobenthos of the Kola Bay estuarine zone academician. PMID- 21249544 TI - Geographical variation of the marbled polecat Vormela peregusna (Carnivora: Mustelidae): molecular genetic study. PMID- 21249545 TI - Expression of aquaporin genes in the common ice plant during induction of the water-saving mechanism of CAM photosynthesis under salt stress conditions. PMID- 21249546 TI - Electric discharges of the African catfishes Clarias anguillaris and Heterobranchus longifilis. PMID- 21249547 TI - Genetic monomorphism of the second exon of the DRB1 gene in the major histocompatibility complex of the arctic fox of Mednyi Island (Alopex lagopus semenovi Ognev, 1931). PMID- 21249548 TI - Mobile forms of silicon in plants. PMID- 21249549 TI - Immunostimulating chemosignaling in animals with secondary immunodeficiency. PMID- 21249550 TI - Tonoplast ATPases in ontogeny. PMID- 21249551 TI - Daily activity of the mandarin vole (Lasiopodomys mandarinus) under laboratory conditions. PMID- 21249552 TI - The quataron hypothesis of the origin of life. PMID- 21249553 TI - The architectonics of the collagen stroma of the chicken (Gallus domesticus) skin. PMID- 21249554 TI - Development of aggression as a possible basis of "Professional" specialization in ants. PMID- 21249555 TI - Medicinal plants concentrating selenium: prospects of wider use. PMID- 21249556 TI - Quantitative tomography of mouse early embryo. PMID- 21249557 TI - Role of heterochronies in the morphogenesis of amphibian skull bones: an experimental study. PMID- 21249558 TI - Outline of the hydrochory theory for some coniferous species. PMID- 21249559 TI - Ultrastructural changes in the Meissner plexus of the suckling rabbit small intestine in experimental cholera. PMID- 21249580 TI - Jugular venous reflux could influence cerebral blood flow: a transcranial Doppler study. AB - PURPOSE: Studies have found significant associations between jugular venous reflux (JVR) and neurological disorders. However, there still lacks evidences that JVR could influence cerebral circulation. The aim of the present study is trying to provide evidences that the retrogradely-transmitted venous pressure of JVR could reach cerebral venous system and has an influence on cerebral blood flow (CBF). METHODS: We recruited 50 volunteers. Only 42 subjects' data (55.81 +/ 19.96, 23 - 85 years; 9 women) were analyzed due to poor temporal windows in eight subjects. JVR was determined by color-coded Duplex sonography. Transcranial Doppler study was used to examine the CBF changes during Valsalva maneuver (VM) in each subject. RESULTS: All JVRs were detected during VM. We divided subjects into people with right JVR (n=12), left JVR (n=13) and no JVR (n=21) and four had bilateral JVR. There was a more decrease in CBF during and immediately after VM in right-JVR group than no-JVR group, though the baseline characteristics and arterial blood pressure changes were similar. There were no demographic and hemodynamic differences between left-JVR group and no-JVR group. CONCLUSION: We are the first to provide evidences that right JVR during VM could influence CBF. However, whether left JVR with or without right JVR may have similar effect on CBF deserves further study. The definite mechanism underlying this finding needs further studies. PMID- 21249581 TI - Cost-utility analysis of Parkinson's disease. AB - Many expensive treatments have been developed for Parkinson's disease (PD), and a good cost-utility analysis is required. Quality-adjusted life-years (QALY) allows comparison of the cost-utility of different medical conditions. If a treatment strategy gives a patient an extra but unhealthy year, the QALY he obtained will be less than one. When a therapeutic strategy is more effective, but causes higher costs, it is mandatory to calculate the incremental cost-effectiveness ratio (ICER). In keeping with guidance from the UK National Institute for Health and Clinical Excellence (NICE), a therapy that deliver QALYs of L20,000 or less are likely to be approved. The threshold used by NICE for the maximum it is prepared to pay for a QALY, which lies between L20,000 and L30,000, will be reviewed case by case. Subthalamic deep brain stimulation (STN-DBS) is an effective therapy, which can improve the quality of life in PD patients immediately, but has not been approved by the Bureau of National Health Insurance here. It has been estimated that the ICER/QALY in STN-DBS patients was of 34,389C= , which is within appropriate limits to consider STNDBS as an efficient therapy. We expect that we can have a decision-making mechanism similar to that of NICE that, according to the ICER of each medical condition, medical resource can be redistributed openly and justly. PMID- 21249586 TI - The age correlation of the carotid intima-media thickness according to sex and side in asymptomatic subjects. AB - PURPOSE: Reports concerning carotid intima-media thickness (CIMT) and linear correlation to age in healthy subjects did not distinguish the side and sex of the subjects. The purpose of this investigation attempts to clarify these issues. METHODS: 2402 asymptomatic persons, age 35-64, are separated into men's left (Lt) and right (Rt) and women's Lt and Rt carotid arteries for difference of CIMT between them and analysis of CIMT vs. age. RESULTS: There are significant difference between men's CIMT of Lt(CIMTML) vs Rt (CIMTMR), women's Lt(CIMTWL) vs. Rt (CIMTWR), Lt side CIMT of men vs women, and Rt side CIMT of men vs. women. The regression equation of CIMT vs. age for all four groups is determinated. CONCLUSION: We found an excellent linear correlation of CIMT to age and CIMT is significantly higher in men than women, so as higher in Lt than Rt. Further grouping of data into about 5-year period showed more clearly stepwise increasing of CIMT, so as the ratios of Lt CIMT different than Rt. CIMT study is served as highly efficient examination in therapy, prevention, clinic, or research survey about atherosclerosis and risk of stroke. Future study design concerning CIMT in separation groups of men and women, so as Lt and Rt is highly recommended. PMID- 21249588 TI - Chronic progressive external ophthalmoplegia with T9957C mitochondrial DNA mutation in a Taiwanese patient. AB - PURPOSE: Mitochondrial T9957C mutations have been reported in patients with nonarteritic ischemic optic neuropathy and seizures and in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. However, thus far, this mutation has not been reported in patients with chronic progressive external ophthalmoplegia (CPEO). CASE REPORT: Here we report a female patient with CPEO and agenesis of the corpus callosum. Although no ragged-red fibers were found upon muscle biopsy, sequencing of the entire mitochondrial DNA genome was done. RESULTS: The molecular genetic study revealed a nonsynonymous mitochondrial T9957C mutation. a new genotype of CPEO was identified with varied clinical presentations. Although the effect of the nuclear genome remains unknown, we believe that the nonsynonymous mitochondrial DNA (mtDNA) T9957C mutation may have a role in the clinical manifestations of this patient. CONCLUSION: This study extends the phenotype of T9957C mtDNA mutation. PMID- 21249589 TI - Cerebellar bacterial brain abscess: report of eight cases. AB - PURPOSE: To analyze the clinical characteristics and therapeutic outcome of patients with solely cerebellar bacterial brain abscess (BBA). CASE REPORT: Eight patients with solely cerebellar BBA, collected during a period of 23 years from 210 BBA patients, were included in this study. The eight patients were five men and three women, aged 5-54 years (mean, 36.6 years). Six of them were adults, one was a child, and one was an adolescent. Six patients had underlying medical/surgical problems. Of the clinical presentations, dizziness was the most common (87.5%, 7/8), followed by headache (62.5%, 5/8), altered consciousness (62.5%, 5/8), fever (50%, 4/8), ataxia (25%, 2/8), hearing impairment (12.5%, 1/8), dysarthria (12.5%, 1/8), and hemiparesis (12.5%, 1/8). The Image Severity Index (ISI) scores of these eight patients ranged from 6 to 12 points. All eight patients received both medical and surgical treatment. One patient died owing to a complication in the neurosurgical procedure and the remaining patients survived. The therapeutic outcome was quantified one month after discharge by modified Rankin scale (mRS) and the result showed six of the seven survivors had good outcomes, while the other one had a poor outcome (ataxic gait). CONCLUSION: Cerebellar BBA accounted for 3.8% (8/210) of the overall BBA. In cerebellar BBA, dizziness is a frequent symptom. Early diagnosis and a combination of antimicrobial and neurosurgical intervention is important for its treatment. The small case number is a limitation of this study; therefore, further large-scale study of cerebellar BBA is needed for better delineation of the clinical characteristics, therapeutic outcome, and prognostic factors. PMID- 21249590 TI - Gaze-evoking monocular scintillation in orbital tumor. PMID- 21249591 TI - Reversible signal changes in MR diffusion-weighted imaging in a patient with status epilepticus. AB - BACKGROUND: Abnormality in diffusion-weighted magnetic resonance imaging representing early changes of acute ischemic lesions in human and animal models of focal status epilepticus has been reported to correlate with clinical outcome. CASE REPORT: We reported a 35 year-old woman with initial status epilepticus, probably related to previous head injury with traumatic intracerebral hemorrhage. The presenting MRI showed reversible hyperintensity lesions on DWI, which is probably corresponding to the epileptogenic lesion. Similar abnormalities in the splenium as a remote effect were demonstrated in this case. CONCLUSION: The atrophic changes in the splenium and right parietal lobe in the follow-up MRI scans were supposed to correlate with the following neurological sequelae. PMID- 21249592 TI - Assessments of the reliability of the Iranian version of the Berg Balance Scale in patients with multiple sclerosis. AB - PURPOSE: Because of the balance limitations in many patients, balance assessment is necessary for multiple sclerosis patients in rehabilitation settings. The aim of this study was to investigate the Interrater reliability and the internal consistency of the Iranian version of the Berg Balance Scale (BBS) when applied to patients with multiple sclerosis (MS) in Tehran. METHODS: Fifty MS patients (with mean age of 36.6+/-9.5 years) from Hospitals of the Iran University of Medical Sciences and MS Society of Iran were included. Interrater reliability was measured with the Kappa statistics and Intraclass Correlation Coefficients (ICCs). RESULTS: The mean values of the BBS scored by the 2 evaluators were 37.7 +/-12.9 and 38.l +/- 12.3, respectively. Kappa scores for BBS varied from 0.7 to 1.0 Intraclass correlation coefficient for the BBS's sum score was excellent (ICC=0.99 with 95% confidence interval, 0.98-0.99). An excellent internal consistency was found within the BBS's sum score (Cronbach Alpha =0.9). The item to -total correlations for all items were higher than 0.6. CONCLUSION: The Iranian version of the BBS has excellent interrater reliability and internal consistency for the assessment of MS patients when applied in clinics. PMID- 21249593 TI - Rhombencephalitis as an initial manifestation of primary Sjogren's syndrome: a case report and review of the literatures. AB - PURPOSE: We present a case report and a comprehensive review of the literature concerning aseptic meningoencephalitis and Sjogren's syndrome (SS). CASE REPORT: We report a 44-year-old woman of primary SS with initial presentation of aseptic meningoencephalitis and a reversible magnetic resonance image (MRI) lesion in the medulla. The diagnosis of primary SS based on ocular dryness, lacrimal hyposecretion, secretory and excretory dysfunction from sialocintigraphy, and positive anti-SS-A antibodies. Corticosteroid and cyclophosphamide therapies reversed the neurological deficits and the MRI lesion. CONCLUSION: Primary SS may have variable manifestations in the central nervous system which may precede the classic sicca symptoms. SS should be investigated in cases of aseptic meningoencephalitis even without clinical signs of xerostomia or xerophthalmia. MRI is useful in demonstrating brain lesions and in evaluating treatment efficacy of the SS. PMID- 21249594 TI - Diffusion tensor images and magnetic resonance spectroscopy in primary central nervous system T-cell lymphoma: a case report. AB - PURPOSE: Primary central nervous system lymphoma (PCNSL) is rare and usually B cell in origin. T-cell lymphoma constitutes only 1.8% to 4.6% of the PCNSL, and may present as solitary or multiple homogeneous enhanced lesions. There have been few reports showing unusual leukoencephalopathy in PCNSL, which may be confused with other white matter diseases including multiple sclerosis and acute disseminated encephalomyelitis. CASE REPORT: We reported a patient with T-cell PCNSL who presented a progressive dull response and extrapyramidal symptoms. Brain magnetic resonance imaging showed multiple focal leukoencephalopathy. Diffusion weighted imaging demonstrated hyper-intensity lesions and apparent diffusion coefficient images showed hypo-intensity lesions. Diffuse tensor images showed decreased fractional anisotropy. Pathology examination finally confirmed T cell lymphoma. CONCLUSION: Although recent development of neuro-imaging studies, the diagnosis of PCNSL still await further pathological confirmation in some occasions. PMID- 21249595 TI - [The journal impact factor--a stable currency?]. PMID- 21249596 TI - [Christmas prize puzzle of PPmP - the solution]. PMID- 21249598 TI - Gianni Franchini (1934-2010). PMID- 21249599 TI - Hormones, endocrine disorders, and hemostasis. PMID- 21249600 TI - The spectrum of coagulation abnormalities in thyroid disorders. AB - The hemostatic balance is a complex system where the delicate equilibrium is regulated by several factors including hormones. A variety of endocrine disorders have been reported to be associated with coagulation abnormalities, ranging from mild laboratory changes to clinically relevant thrombotic or bleeding manifestations. In this review, we summarize the current knowledge on the main abnormalities of the coagulation and fibrinolytic systems associated with thyroid dysfunctions. Overall, although mostly based on uncontrolled studies, data in the literature suggest that patients with hyperthyroidism or subclinical hypothyroidism have a hypercoagulative state, whereas patients with overt hypothyroidism have a bleeding tendency. PMID- 21249601 TI - Thyroid disorders and hypercoagulability. AB - Various abnormalities of coagulation and fibrinolysis, ranging from subclinical laboratory abnormalities to clinically significant disorders of hemostasis, but rarely major hemorrhage or thromboembolism, may occur in patients with thyroid diseases. This review discusses the relationships between thyroid dysfunction and the coagulation/fibrinolytic system. According to the recent literature, most of the coagulation/fibrinolytic abnormalities associated with thyroid dysfunction are the consequences of direct effects of thyroid hormones on the synthesis of various hemostatic parameters. Thyroid autoimmunity may also modify the processes of secondary hemostasis. Hyperthyroidism is generally associated with hypercoagulability and hypofibrinolysis, whereas the hemostatic profile in hypothyroidism depends on the severity of the disease. Both hypercoagulable and hypocoagulable states including increased fibrinolytic activity have been reported in hypothyroidism. Few data are available on hemostasis in subclinical thyroid diseases. In conclusion, adequate further prospective clinical studies of high quality including a larges series of patients are needed to explain the degree and type of coagulation/fibrinolytic abnormalities in patients with thyroid diseases. PMID- 21249602 TI - New insights into subclinical hypothyroidism and cardiovascular risk. AB - Subclinical hypothyroidism (SH) is a frequent condition affecting millions of people around the world. Defined by increased thyrotropin-stimulating hormone (TSH) and accompanied by normal thyroid hormone levels, SH reflects a mild tissue hypothyroidism that has been associated with metabolic derangements and-although this issue is still contentious-possibly with increased cardiovascular risk. Depending on the degree of TSH elevation, SH has accordingly been associated with hyperlipidemia, arterial hypertension, and cardiovascular disease (CVD), as well as, increasingly, newly emerging CVD risk factors such as serum C-reactive protein and retinol binding protein 4 levels. There have also been reports of abnormalities in glucose metabolism and of hemostatic parameters, mainly underscored by the increased activity of factor VII. This review discusses the results of the latest studies on the various parameters affected by SH while highlighting the need for timely treatment with levothyroxine. PMID- 21249603 TI - The influence of pituitary, adrenal, and parathyroid hormones on hemostasis and thrombosis. AB - Endocrine disorders can influence the hemostatic balance. Abnormal coagulation test results have been observed in patients with abnormal hormone levels. The present review updates the available evidence on the influence of pituitary, adrenal, and parathyroid hormones on the coagulation and the fibrinolytic system, and their possible clinical implications. The literature supports a possible relevant clinical effect of the imbalance between coagulation and fibrinolysis on thrombotic events in endogenous Cushing's syndrome. An effect on markers of coagulation and fibrinolysis has been shown for hyperprolactinemia, growth hormone excess or deficiency, exogenous hypercortisolism, pheochromocytoma, primary hyperaldosteronism, and hyperparathyroidism. However, the clinical relevance is still unproven. Until definitive evidence is available, clinicians should be aware of the possibility that endocrine disorders may be risk factors for thrombotic events. PMID- 21249604 TI - Hemostatic disorders in type 1 diabetes mellitus. AB - This review summarizes current knowledge of the adverse effects of type 1 diabetes mellitus on coagulation and fibrinolysis. Although further larger studies are needed to provide more definitive information, patients with type 1 diabetes exhibit a proinflammatory/procoagulant condition deriving from increased platelet adhesiveness, activation of the coagulation system, and decreased plasma fibrinolytic potential. This review also focuses on recent data from large prospective studies suggesting a strong association between procoagulant imbalance and development of chronic vascular complications in people with type 1 diabetes. It is likely that a greater appreciation of the intimate interactions between endothelial integrity, coagulation and fibrinolytic factors, and platelets in type 1 diabetes will provide a greater understanding of the risk of developing cardiovascular disease and microvascular complications such as nephropathy and retinopathy in this patient population. PMID- 21249605 TI - Hormonal influences on hemostasis in women. AB - Hemostasis in women is influenced by physiological changes in hormone status associated with the menstrual cycle, pregnancy and hormone-based contraceptives, and hormone replacement therapy (HRT) preparations. These hormonal influences can lead to an increase in the risk of venous thromboembolism (VTE) due to altered levels of clotting factors and an acquired resistance to the actions of activated protein C. This articles reviews recent evidence for these changes. During the menstrual cycle, changes are observed in levels of von Willebrand factor (VWF), fibrinogen, and activated factor VII. No such effect has been demonstrated in protein S or protein C levels or activated protein C resistance. Pregnancy is a procoagulant state with progressive increase in levels of factors VII, VIII, X, and XII, fibrinogen, and VWF, as well as increased resistance to activated protein C. Hormonal contraceptives and HRT are widely used and have undergone many changes over the years. Recent modifications to the preparations used in combined oral contraceptives (COC) aimed at improving side-effect profiles have also been shown to increase the risk of VTE for third- and fourth-generation COC compared with second-generation COC. This has been shown to be due to changes in activated protein C resistance. This risk of VTE represents a significant public health issue, but increased awareness and further research may allow development of safer future therapies leading to improvements in women's health. PMID- 21249606 TI - Testosterone, hemostasis, and cardiovascular diseases in men. AB - Men have a higher incidence of cardiovascular disease (CVD) than women, and adverse thrombotic events increase with age. Recent experimental cross-sectional, and case-control studies have shown that testosterone may affect the hemostatic/fibrinolytic system in men in several ways. It has been hypothesized that physiological doses of testosterone would have a beneficial effect on tissue factor-induced thrombin generation and the development of CVD. The search for eternal youth has created a market for testosterone treatment in aging men during the last few years. However, whether testosterone supplementation could be useful in the treatment of testosterone-deficient elderly men is still controversial. The present review focuses on the coagulation system and CVD from the perspective of testosterone. PMID- 21249607 TI - [Clinical treatment of diabetic macular edema]. PMID- 21249608 TI - [New development in oculoplastic surgery]. PMID- 21249609 TI - [The underestimated depth of tissue invasion of xanthelasma--a histological study]. AB - BACKGROUND: The depth of tissue invasion of xanthelasma is of major importance in selecting the most suitable surgical procedure. Intraoperative findings let one assume, that despite the common presumption, xanthelasma are not limited to the superior dermis but that they may penetrate the entire dermis and reach into the orbicularis muscle. In this study the depth of tissue invasion of xanthelasma was measured in histological specimens. MATERIALS AND METHODS: Between 1993 and 2006 100 xanthelasmata of 78 patients were surgically removed and analysed. Histological specimens were examined by light microscopy and the depth of tissue invasion by fat-containing macrophages was measured using the digital picture analysis system AnalySIS(r) of Soft Imaging System Inc. The distance from the epidermis/dermis junction to the deepest "xanthelasma" cell (fat-containing macrophage) was measured. In addition, we classified the cases into 3 categories: 1) invasion into the dermis, 2) invasion adjacent to and 3) invasion into the stratum musculare. RESULTS: The thickness of the xanthelasmata ranged between 502.9 um und 4429.5 um (m = 1443.6 um, M = 1333.6 um, SD 716.1). In 58 % of specimens lipid-containing macrophages infiltrated the dermis (m = 1275.9 um, SD 571.0), in 15 % of specimens they touched the stratum musculare (m = 1426.2 um, SD 534.8) and in 27 % of specimens they even infiltrated this layer (m = 1813.4 um, SD 937.6). CONCLUSIONS: This study confirms our hypothesis that a significant part, namely 42 % of the xanthelasmata, infiltrates the entire dermis and reaches the stratum musculare or even invades into this layer. These xanthelasmata should not be treated by superficial laser therapy but should be better excised surgically. PMID- 21249610 TI - [Chronic eyelid oedema and rosacea (Morbus Morbihan): diagnostic and therapeutic challenges]. AB - BACKGROUND: Morbus Morbihan is a rare complication of rosacea, consisting of a persistent lymphoedema of the upper part of the face. It has typically a chronic course, unspecific histopathological findings and an extreme refractoriness to therapy. PATIENTS AND METHODS: Between February 2008 and January 2010, 5 patients with Morbus Morbihan were observed at the Department of Ophthalmology of the University Medical Centre Mainz. In the present cohort study, we describe the clinical, laboratory and histological findings that led to the diagnosis. The course of the affection and the results of different therapeutic options are also reported. RESULTS: Each patient underwent a complete ophthalmological examination, as well as general and dermatological consultations. All patients showed facial skin alterations typical for rosacea. 4 out of 5 subjects underwent a lid biopsy to confirm the diagnosis of Morbus Morbihan, one patient refused it. Initial treatment consisted of various systemic and local medical therapies, however, with poor success. One patient had intravenous therapy with corticosteroids elsewhere with no effect. We treated 3 cases with intralesional triamcinolone injections with good results. 2 patients underwent upper lid blepharoplasty. Results of surgery remained stable also due to manual lymph drainage and intralesional injections of triamcinolon. No complications or side effects were seen in patients treated with triamcinolone. CONCLUSIONS: Morbus Morbihan can be diagnosed only after excluding other conditions leading to chronic lid swelling. In our series, good results were achieved with intralesional injection of triamcinolone. Surgery also led to relevant improvements for a long period (13 months), with some adjuvant therapy. The treatment of chronic eyelid oedema associated with rosacea remains a challenge for the ophthalmologist and the oculoplastic surgeon. PMID- 21249611 TI - [How to treat a festoon]. AB - In German there is no word for the term "festoon" but it can be used to describe folds due to gravity of the upper and the lower lid, sometimes accompanied by an oedema. The manuals of eyelid surgery (Neubauer or Heilman and Paton) recommend a direct excision, perhaps in combination with a shortening of the lid. But the postoperative result may show a poor scar and a persisting oedema. In cases of low grade festoon a temporary therapy using hyaluronic acid is possible. A combination of different surgical steps, such a subciliary incision, arcus marginalis release, a lift of the malar region, thinning out the subcutaneous oedematous skin region, skin excision and optionally a resurfacing may lead to a better cosmetic outcome. PMID- 21249612 TI - [Fasanella-Servat procedure for the surgical treatment of acquired ptosis of the upper eyelid]. AB - PURPOSE: The oculoplastic surgeon may choose between several surgical procedures to treat ptosis of the eyelid. One such potential therapeutic option is the Fasanella-Servat procedure. The purpose of our study was to evaluate the postoperative outcome of the Fasanella-Servat procedure in patients with ptosis of the eyelid with regard to objective and subjective criteria. METHODS: The postoperative success of 20 patients (23 eyelids), 11 female and 9 male, with acquired ptosis of the upper eyelid who underwent the Fasanella-Servat procedure between 1995 and 2004 in an eye tertiary care centre, was evaluated. With regard to the type of ptosis, the pre- and postoperative opening of the eyelid, the levator function, and the symmetry between both eyes were analysed statistically. The patients' subjective satisfaction with the functional and cosmetic postoperative outcome was evaluated by means of a nominal questionnaire (scale 1 5). The intraoperatively removed tissue was analysed histopathologically for accessory lacrimal glands or levator muscle. RESULTS: The mean preoperative opening of the eyelid was 7.1 mm (min. 4 mm, max. 10 mm) with a mean levator function of 12.6 mm. Postoperatively, the opening of the eyelid improved significantly to 9.3 mm (min. 7 mm; max. 14 mm), while the levator function remained stable. The preoperative asymmetry between both eyes was significantly decreased. 90 % of the patients were satisfied with the cosmetic and functional results. There were no early and late postoperative complications. No side effects were recorded following treatment. The intraoperatively removed tissue showed no evidence of tissue of accessory lacrimal gland or levator muscle. CONCLUSIONS: The Fasanella-Servat procedure remains an effective procedure in treating mild ptosis with few complications and good cosmetic and functional results. PMID- 21249613 TI - [Intraorbital cavernous hemangiomas: symptoms, diagnostics and surgical approaches]. AB - BACKGROUND: Cavernous hemangiomas are the most common benign neoplasms of the orbit. Options for surgical therapy are transnasal, transcranial, transantral and ophthalmological approaches. In this study we present consecutively treated hemangiomas that were resected via ophthalmological approaches in our clinic between the years 2005 and 2010. METHOD: A retrospective analysis of all patients with orbital cavernous hemangiomas of the Eye Department of Charite Campus Virchow Klinikum from 2005 to 2010. We present the surgical approach, pre- and postoperative visual acuity, eye motility, globe position and operative complications. RESULTS: From 5 / 2005 to 5 / 2010 10 histologically confirmed intraorbital hemangiomas were resected in our department.7 hemangiomas were intraconal, 3 tumours were extraconal. 4 tumours were resected via a lateral orbitotomy, and in 6 patients tumour removal was carried out via a swinging eyelid approach. In all patients, visual acuity, visual field and motility remained unchanged pre- and postoperatively. Preoperative exophthalmos resolved completely after surgery. CONCLUSION: The swinging eyelid and lateral orbitotomy techniques are appropriate surgical approaches for resection of orbital cavernous hemangiomas. The resection via these approaches can be considered as a low-risk procedure. PMID- 21249614 TI - [Jewish ophthalmologists during National Socialism--a memorial file]. PMID- 21249615 TI - Aldosterone producing adrenal adenomas are characterized by activation of calcium/calmodulin-dependent protein kinase (CaMK) dependent pathways. AB - Primary aldosteronism is the most prevalent cause of secondary hypertension. However, insights in pathophysiological mechanisms resulting in autonomous aldosterone secretion are limited. Although transcriptional regulators of aldosterone synthase (CYP11B2) including calcium-binding calmodulin kinase (CaMK) dependent pathways have been defined in vitro, it remains uncertain whether these mechanisms play a role in the context of dysregulated steroidogenesis in aldosterone producing adrenadenomas. Thus, we compared expression and activation of key components of CaMK pathways in aldosterone producing adenomas (APAs) with normal adrenals glands (NAGs). As expected, aldosterone synthase expression in APAs was significantly higher in comparison to NAGs, suggesting transcriptional activation as a contributing factor of aldosterone excess. Along the same line, CaMKI was significantly upregulated in APAs on the mRNA and protein level. Furthermore, immunohistochemistry revealed nuclear localization of CaMKI in these tumors. The phosphorylation of CREB, a target protein for CaMKI was increased, which could represent a further stimulation of aldosterone synthase transcription. In summary, this study provides indirect evidence for a causative involvement of the CaM kinase signaling pathway in human aldosterone producing adenomas. PMID- 21249616 TI - Skeletal muscle 11betaHSD1 activity of nondiabetic subjects is unaltered in central obesity-associated insulin resistance. AB - Local activation of glucocorticoids in insulin target tissues by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) has been implicated in the etiology of the metabolic syndrome. In obesity, adipose tissue 11betaHSD1 is upregulated, leading to the generation of higher tissue levels of cortisol, which may increase insulin resistance. However, skeletal muscle is the predominant site of insulin-mediated glucose disposal, which is known to be reduced in obesity. We aimed to determine if there is any relationship between skeletal muscle 11betaHSD1 and markers of central adiposity and insulin resistance in nondiabetic subjects. 20 nondiabetic volunteers (8 males and 12 females, mean age 55 +/- 13 years, body mass index 21.5-47.6, mean 30.4 +/- 1.6 kg/m (2)) underwent a single fasting blood sample followed by a muscle biopsy of vastus lateralis under local anesthetic. Fasting glucose, insulin and adiponectin were measured in serum. Skeletal muscle 11betaHSD1 oxoreductase activity was determined by measuring the conversion of radiolabelled (3)H-cortisone to cortisol by thin layer chromatography. When subjects were categorised according to abdominal obesity (waist circumference >= 102 cm in men, >= 88 cm in women), there was no difference between the groups in skeletal muscle 11betaHSD1 activity. There was no correlation between body mass index or waist circumference and 11betaHSD1 activity or between HOMA and 11betaHSD1 activity. Skeletal muscle 11betaHSD1 oxoreductase activity is not altered in nondiabetic subjects with central obesity associated insulin resistance. It is therefore unlikely that the in vivo insulin resistance observed in skeletal muscle of centrally obese subjects is mediated by alterations in 11betaHSD1. PMID- 21249617 TI - Changes of CCAAT enhancer-binding proteins (CEBPs) in the lung of streptozotocin induced diabetic rats. AB - CCAAT enhancer-binding proteins (CEBPs) play key roles in the metabolic regulation, cell transformation, and inflammation. However, the expression and/or functions of CEBPs in rats with hyperglycemia are still unclear. In the present study, we investigated the changes of CEBPs protein in lung of the diabetic rats. The levels of C/EBPbeta and C/EBPdelta protein were decreased in the lung isolated from streptozotocin-induced diabetic rats (STZ-diabetic rats) as compared with that of normal rats. Exogenous insulin at the dose sufficient to normalize the plasma glucose of STZ-diabetic rats reversed the protein levels of C/EBPbeta and C/EBPdelta in lung after a 4-day treatment. Similar results were also observed in STZ-diabetic rats that received the treatment of phlorizin to reverse the plasma glucose level for 4 days. Otherwise, the protein level of C/EBPalpha in lung of the STZ-diabetic rats was similar as the normal rats. Also, the level of C/EBPalpha protein in lung of the STZ-diabetic rat was not significantly changed by correction of plasma glucose by exogenous insulin or phlorizin. In addition, we also cultured human lung cells (A-549) and rat lung cells (L2) in varies concentration of D-glucose and L-glucose to identify the effect of glucose in expression of C/EBPs. The obtained results suggest that increase of plasma glucose is related to the lower expression of C/EBPbeta and C/EBPdelta proteins in the lung of STZ-diabetic rats. The changes of expression of C/EBPbeta and C/EBPdelta are not caused by changes of osmolarity but by D glucose itself. PMID- 21249618 TI - Effect of fear of litigation on obstetric care: a nationwide analysis on obstetric practice. AB - The aim of our study was to investigate the influence of malpractice premiums paid by obstetricians on obstetric care across the United States. We conducted a retrospective cross-sectional population-based study using patient-level data obtained from the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample on every woman who delivered in 2006. Mode of delivery was compared with the average state medical liability insurance premium paid by obstetricians (Medical Liability Monitor and the National Association of Insurance Commissioners) using a generalized estimating equation to calculate crude and adjusted odds ratios. Our cohort included 890,266 women who delivered across 37 states in 2006. Average state malpractice premium of over $100,000 was associated with higher incidences of total cesarean deliveries (odds ratio [OR] 1.17, 95% confidence interval [CI]: 1.02, 1.35); lower incidences of vaginal births after cesarean deliveries (OR 0.60, 95% CI: 0.37, 0.98); and lower rates of instrumental deliveries (OR 0.72, 95% CI: 0.63, 0.83) compared with when the average state malpractice premium was less than $50,000. Fear of litigation appears to have a marked effect on obstetric practice, particularly total cesarean delivery, vaginal birth after cesarean, and instrumental delivery, when malpractice premiums rise above $100,000 per annum. PMID- 21249619 TI - [Solitary pulmonary nodule and hemoptysis]. PMID- 21249620 TI - [26-year old patient with asthma like seizure. Vocal-cord-Dysfunction (VCD)]. PMID- 21249621 TI - [45-year-old man with stress induced chest tightness]. PMID- 21249622 TI - [Fingernail alterations in a 71-year-old man. Terry's Nails (Pseudoleukonychie)]. PMID- 21249623 TI - [Rapid thoracic swelling]. PMID- 21249624 TI - [The concept of "vegetative depression" (1949) by Rudolf Lemke--an obsolete concept?]. AB - OBJECTIVE: In 1949 East German psychiatrist Rudolf Lemke presented his concept of a vegetative, i. e., anxious depression due to a vegetative dysfunction, in which the mental symptoms are dominated and oppressed by somatic complaints. METHODS: The strengths and weaknesses of Lemke's concept will be analysed with particular reference to earlier, similar theories, such as those by Cimbal, Hempel, and Rosenfeld. RESULTS/CONCLUSIONS: The fact that, due to the dominance of physical symptoms, many patients suffering from this disease consult a general practitioner even today proves that Lemke dealt with a problem most significant both for psychiatry and general medicine. PMID- 21249625 TI - [Too fat, too thin?--bodily self-perception and eating habits of teenagers in Bremen]. AB - A study of about 600 eighth grade students by the Bremen Department of Health show that overweight and the risk of an eating disorder are widespread among teenagers in Bremen. In the school year 2008/2009 a quota sample of eighth graders was questioned in regard to their dietary habits, their bodily self perception and their eating behaviour, and they were weighed and measured. 21% of the students were overweight, 10% were even obese. Our studies showed that the share of overweight students had doubled between the beginning and the end of primary school and only increased marginally after that. The students' bodily self-perception frequently did not correspond to their actual body weight, not only among those who were overweight, but also among those with an objectively normal body weight. In one in 7 of the teenagers with normal body weight, furthermore, we found signs of disrupted eating behaviour. The actuality of the topic of eating disorders for the health of teenagers becomes apparent when taking into account further results of the study. If, moreover, we bring to mind the long-term consequences of overweight and the often massive adverse effects through illnesses like anorexia or bulimia, it becomes clear that the disruptions addressed here should be a central concern for prevention. The study presented here shows where interventions are most needed. PMID- 21249628 TI - Reconstruction of rat calvarial defects with human mesenchymal stem cells and osteoblast-like cells in poly-lactic-co-glycolic acid scaffolds. AB - Human mesenchymal stem cells (hMSCs) can be used for xenogenic transplantation due to their low immunogenicity, high proliferation rate, and multi differentiation potentials. Therefore, hMSCs are an ideal seeding source for tissue engineering. The present study evaluates the reconstruction effects of hMSCs and osteoblast-like cells differentiated from hMSCs in poly-lactic-co glycolic acid (PLGA) scaffolds on the calvarial defect of rats. Two bilateral full-thickness defects (5mm in diameter) were created in the calvarium of nonimmunosuppressed Sprague-Dawley rats. The defects were filled by PLGA scaffolds with hMSCs (hMSC Construct) or with osteoblast-like cells differentiated from hMSCs (Osteoblast Construct). The defects without any graft (Blank Defect) or filled with PLGA scaffold without any cells (Blank Scaffold) were used as controls. Evaluation was performed using macroscopic view, histology and immunohistochemical analysis respectively at 10 and 20 weeks after transplantation. In addition, fluorescent carbocyanine CM-Dil was used to track the implanted cells in vivo during transplantation. The results showed that while both hMSC Construct and Osteoblast Construct led to an effective reconstruction of critical-size calvarial defects, the bone reconstruction potential of hMSC Construct was superior to that of Osteoblast Construct in non-autogenous applications. Our findings verify the feasibility of the use of xenogenic MSCs for tissue engineering and demonstrate that undifferentiated hMSCs are more suitable for bone reconstruction in xenotransplantation models. PMID- 21249629 TI - Mesenchymal stem cells: a perspective from in vitro cultures to in vivo migration and niches. AB - Mesenchymal Stromal Progenitor/Stem Cells (MSCs) are a rare population of non hematopoietic stromal cells, present in the bone marrow and most connective tissues of the body. They are capable of differentiation into mesenchymal tissues such as bone, cartilage, adipose tissue and muscle. In the absence of specific markers, MSCs have been defined following isolation and culture expansion, by their expression of various molecules including CD90, CD105 and CD73 and absence of markers like CD34, CD45, and CD14. MSCs have extensive proliferative ability in culture in an uncommitted state while retaining their multilineage differentiation potential, which make them attractive candidates for biological cell-based tissue repair approaches. However, their identity in their tissues of origin is not clear and the niches in which they reside are not defined. This review addresses the current state of MSC research including the differentiation potency of culture expanded MSCs, expression of chemokines and their receptors in MSCs--both relevant issues for the advocated use of MSCs for tissue repair and their systemic delivery to the affected tissues. It also reviews current knowledge of MSC niches in their native tissues, addressing the relationship with pericytes. Finally, it provides a scientific basis for the requirement of a thorough characterisation of the endogenous MSC niches within their native tissues in vivo. The knowledge of MSC niches will instruct development of innovative therapeutic measures such as producing pharmacological substances that target endogenous MSCs and their niches in order to activate and guide intrinsic repair and to improve disease outcomes. PMID- 21249630 TI - [Not Available]. PMID- 21249631 TI - [Not Available]. PMID- 21249632 TI - [Not Available]. PMID- 21249633 TI - [Clinic-internal and -external factors of length of hospital stay]. AB - In the context of forthcoming initiation of Diagnosis Related Groups (DRG) in Switzerland, the objective of the study was to find factors having an impact on the inpatient's length of hospital stay. The study was performed on two general medical wards of the Kantonsspital Winterthur, where all admitted patients were included in the study over two months. The various periods of diagnostic and therapeutic management of the patients and all diagnostic and therapeutic measures plus the arrangements after hospitalization were recorded. The determinants influencing the length of hospital stay were classified in clinic internal or -external. 124 inpatients entered the study. 91 (73.4%) had a length of hospital stay without delay, whereas 33 (26.6%) patients had an extended length of hospital stay. The cumulative length of hospital stay of all patients was 1314 days, whereof 216 days (16.4%) were caused by delays. 67 days were caused by clinic-internal (5.1%) and 149 days by clinic-external factors (11.3%). Delays were substantially more generated by clinic-internal than -external factors. Clinic-internal factors were mainly weekends with interruption of the diagnostic and therapeutic procedures, dead times waiting for diagnostic results and waiting times for consultations. Clinic-external factors were caused by delayed transfer in nursing homes or rehabilitation institutions, waiting for family members for the backhaul and by indetermination of the patient. Also factors relating to the patients' characteristics had an influence on the length of hospital stay. Summing up, a substantial part of the length of hospital stay was caused by delays. However, the many different clinic-internal factors complicate solutions to lower the length of hospital stay. Moreover, factors that cannot be influenced such as waiting for microbiological results, contribute to extended length of hospital stay. Early scheduling of post-hospital arrangements may lower length of hospital stay. Moreover, when cantonal restriction falls away in 2012, patients may be transferred to rehabilitation institutions more rapidly. Also the insurance companies may possibly strengthen their organisation and thus may meet the costs more quickly. PMID- 21249634 TI - [Is COPD a Cardiovascular Risk Factor?]. AB - Chronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lungs mainly caused by smoking and characterized by chronic airflow limitation. COPD is the fifth leading cause of death worldwide and up to 50% of COPD patients die of a cardiovascular event. Cohort studies demonstrated that airflow limitation is a predictor of cardiovascular risk, even after adjusting for known risk factors such as smoking and cholesterol levels. Various mechanisms of vascular damage have been suggested in COPD including systemic inflammation, hypoxia, oxidative stress, activation of the sympathetic nervous system and changes of the vascular connective tissue. The evidence of a causal relationship between COPD and cardiovascular disease is yet insufficient. Data from controlled trials investigating the postulated pathomechanisms are awaited with interest. PMID- 21249635 TI - [Prostate cancer: a changing disease]. AB - Prostate cancer remains by far the most common malignant disease in male patients. Despite this fact, research in prostate cancer was limited for many years. Radical prostatectomy or external beam radiation for local treatment and androgen deprivation for advanced and metastatic treatment were perceived to be the only options. Over recent years however, knowledge about the disease has rapidly risen in many fields including epidemiology, prophylaxis, screening and treatment of localised and advanced disease. At the same time, obviously many new questions have arisen. The treatment of prostate cancer is currently undergoing great changes. This article summarises current treatment concepts and treatment possibilities for the near future. PMID- 21249636 TI - [Not Available]. PMID- 21249637 TI - [A rare cause of a cervical lymphadenopathy]. AB - We report on a 15-year-old female patient with a slow-growing, mildly painful swelling on her neck, without any signs of inflammation or any general symptoms. Sonographic findings included two enlarged lymph nodes with hilar markings evident. Based on the histology, Castleman's disease of the hyaline vascular type was ultimately diagnosed. The differential diagnosis of the swelling on the neck is described along with the clinical, diagnostic, pathogenic and therapeutic aspects of Castleman's disease. Castleman's disease is a rare differential diagnosis of non-infectious cervical lymphadenopathy. Unicentric Castleman's is treated by surgical resection. In patients with contraindications, radiotherapy should be discussed as an alternative. Multicentric forms manifest as systemic diseases with poor prognosis and must be managed by an interdisciplinary team. PMID- 21249638 TI - [Not Available]. PMID- 21249640 TI - [Not Available]. PMID- 21249639 TI - [Not Available]. PMID- 21249641 TI - [Not Available]. PMID- 21249642 TI - [Not Available]. PMID- 21249643 TI - [Not Available]. PMID- 21249644 TI - Acupuncture and related interventions for smoking cessation. AB - BACKGROUND: Acupuncture and related techniques are promoted as a treatment for smoking cessation in the belief that they may reduce nicotine withdrawal symptoms. OBJECTIVES: The objectives of this review are to determine the effectiveness of acupuncture and the related interventions of acupressure, laser therapy and electrostimulation in smoking cessation, in comparison with no intervention, sham treatment, or other interventions. SEARCH STRATEGY: We searched the Cochrane Tobacco Addiction Group specialized register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, BIOSIS Previews, PsycINFO, Science Citation Index, AMED, Acubriefs in November 2010; and four Chinese databases: Chinese Biomedical Database, China National Knowledge Infrastructure, Wanfang Data and VIP in November 2010. SELECTION CRITERIA: Randomized trials comparing a form of acupuncture, acupressure, laser therapy or electrostimulation with either no intervention, sham treatment or another intervention for smoking cessation. DATA COLLECTION AND ANALYSIS: We extracted data in duplicate on the type of smokers recruited, the nature of the intervention and control procedures, the outcome measures, method of randomization, and completeness of follow up.We assessed abstinence from smoking at the earliest time-point (before six weeks), and at the last measurement point between six months and one year. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Those lost to follow up were counted as continuing smokers. Where appropriate, we performed meta-analysis using a fixed-effect model. MAIN RESULTS: We included 33 reports of studies. Compared with sham acupuncture, the fixed-effect risk ratio (RR) for the short-term effect of acupuncture was 1.18 (95% confidence interval 1.03 to 1.34), and for the long-term effect was 1.05 (CI 0.82 to 1.35). The studies were not judged to be free from bias. Acupuncture was less effective than nicotine replacement therapy (NRT). There was no evidence that acupuncture is superior to waiting list, nor to psychological interventions in short- or long term. The evidence on acupressure and laser stimulation was insufficient and could not be combined. The evidence suggested that electrostimulation is not superior to sham electrostimulation. AUTHORS' CONCLUSIONS: There is no consistent, bias-free evidence that acupuncture, acupressure, laser therapy or electrostimulation are effective for smoking cessation, but lack of evidence and methodological problems mean that no firm conclusions can be drawn. Further, well designed research into acupuncture, acupressure and laser stimulation is justified since these are popular interventions and safe when correctly applied, though these interventions alone are likely to be less effective than evidence based interventions. PMID- 21249645 TI - Digoxin for preventing or treating neonatal respiratory distress syndrome. AB - BACKGROUND: Lendrum 1955 suggested that pulmonary edema secondary to congestive heart failure may contribute to neonatal respiratory distress syndrome (RDS). Based on this hypothesis, investigators began to use digitalis glycosides to improve myocardial contractility and decrease congestive heart failure. The first use of digitalis glycosides in infants with RDS was reported by Stahlman 1959. Stahlman reported a reduction in mortality in an uncontrolled trial of digitalis in infants with RDS. OBJECTIVES: To assess the effect of digoxin on mortality in premature infants at risk for or with RDS. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, Medline (MeSH terms: digoxin; limits: age groups, newborn infants; publication type, clinical trial), previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants, and journal handsearching in the English language.When updated in December 2008, the search was expanded to include Medline, CINHAL, and Embase (MeSH terms and text words: digoxin or digitalis; limits: age group, all infants; publication type: clinical trial). SELECTION CRITERIA: Randomized and quazi randomized controlled trials of digoxin in either the prevention or treatment of RDS are included in this overview. DATA COLLECTION AND ANALYSIS: Data regarding clinical outcomes were excerpted from the trial reports by one review author (RS) and checked by the second review author (EO). Data were analyzed according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: Two randomized controlled trials have studied the effects of digoxin in the prevention and treatment of RDS. No improvement in respiratory status or mortality was noted. Meta-analysis of the effect of digoxin given to infants at risk of or with RDS on mortality does not suggest any benefit of digoxin treatment (typical relative risk 1.27 95% CI 0.78 to 2.07; typical risk difference 0.06, 95% CI -0.06 to 0.17). AUTHORS' CONCLUSIONS: Although hemodynamic disturbances play a role in the overall pathogenesis of respiratory distress syndrome, the specific contribution of early congestive heart failure (unrelated to hemodynamically significant patent ductus arteriosus) does not appear to be a significant factor in RDS. Treatment with digoxin has no proven value in infants solely affected with RDS. PMID- 21249646 TI - Acellular vaccines for preventing whooping cough in children. AB - BACKGROUND: Routine use of whole-cell pertussis vaccines was suspended in some countries in the 1970s/1980s because of concerns about adverse effects. There was a resurgence of whooping cough. Acellular pertussis vaccines (containing purified or recombinant Bordetella pertussis antigens) were developed in the hope that they would be as effective but less reactogenic than the whole-cell vaccines. OBJECTIVES: To assess the efficacy and safety of acellular pertussis vaccines in children. SEARCH STRATEGY: We searched the Cochrane Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 2) which contains the Acute Respiratory Infections Group's Specialised Register; MEDLINE (1950 to April week 2 2009) and EMBASE (1974 to April 2009). SELECTION CRITERIA: Double-blind randomised efficacy and safety trials of acellular pertussis vaccines in children up to six years old, with active follow-up of participants and laboratory verification of pertussis cases. DATA COLLECTION AND ANALYSIS: Two review authors independently performed data extraction and study quality assessment. Differences in trial design precluded pooling of the efficacy data. The safety data from individual trials were pooled using the Cochrane statistical package Review Manager 5. MAIN RESULTS: Six efficacy trials and 52 safety trials were included. The efficacy of multi-component (>= 3) vaccines varied from 84% to 85% in preventing typical whooping cough, and from 71% to 78% in preventing mild pertussis disease. In contrast, the efficacy of one- and two-component vaccines varied from 59% to 75% against typical whooping cough, and from 13% to 54% against mild pertussis disease. Multi-component acellular vaccines is more effective than low-efficacy whole-cell vaccines, but may be less effective than the highest-efficacy whole-cell vaccines. Most systemic and local adverse events were significantly less common with acellular than with whole-cell pertussis vaccines for the primary series as well as for the booster dose. AUTHORS' CONCLUSIONS: Multi-component acellular pertussis vaccines are effective, and show less adverse effects than whole-cell pertussis vaccines for the primary series as well as for booster doses. PMID- 21249647 TI - Multiple risk factor interventions for primary prevention of coronary heart disease. AB - BACKGROUND: Multiple risk factor interventions using counselling and educational methods assumed to be efficacious and cost-effective in reducing coronary heart disease (CHD) mortality and morbidity and that they should be expanded. Trials examining risk factor changes have cast doubt on the effectiveness of these interventions. OBJECTIVES: To assess the effects of multiple risk factor interventions for reducing total mortality, fatal and non-fatal events from CHD and cardiovascular risk factors among adults assumed to be without prior clinical evidence CHD.. SEARCH STRATEGY: We updated the original search BY SEARCHING CENTRAL (2006, Issue 2), MEDLINE (2000 to June 2006) and EMBASE (1998 to June 2006), and checking bibliographies. SELECTION CRITERIA: Randomised controlled trials of more than six months duration using counselling or education to modify more than one cardiovascular risk factor in adults from general populations, occupational groups or specific risk factors (i.e. diabetes, hypertension, hyperlipidaemia, obesity). DATA COLLECTION AND ANALYSIS: Two authors extracted data independently. We expressed categorical variables as odds ratios (OR) with 95% confidence intervals (CI). Where studies published subsequent follow-up data on mortality and event rates, we updated these data. MAIN RESULTS: We found 55 trials (163,471 participants) with a median duration of 12 month follow up. Fourteen trials (139,256 participants) with reported clinical event endpoints, the pooled ORs for total and CHD mortality were 1.00 (95% CI 0.96 to 1.05) and 0.99 (95% CI 0.92 to 1.07), respectively. Total mortality and combined fatal and non-fatal cardiovascular events showed benefits from intervention when confined to trials involving people with hypertension (16 trials) and diabetes (5 trials): OR 0.78 (95% CI 0.68 to 0.89) and OR 0.71 (95% CI 0.61 to 0.83), respectively. Net changes (weighted mean differences) in systolic and diastolic blood pressure (53 trials) and blood cholesterol (50 trials) were -2.71 mmHg (95% CI -3.49 to 1.93), -2.13 mmHg (95% CI -2.67 to -1.58 ) and -0.24 mmol/l (95% CI -0.32 to 0.16), respectively. The OR for reduction in smoking prevalence (20 trials) was 0.87 (95% CI 0.75 to 1.00). Marked heterogeneity (I(2) > 85%) for all risk factor analyses was not explained by co-morbidities, allocation concealment, use of antihypertensive or cholesterol-lowering drugs, or by age of trial. AUTHORS' CONCLUSIONS: Interventions using counselling and education aimed at behaviour change do not reduce total or CHD mortality or clinical events in general populations but may be effective in reducing mortality in high-risk hypertensive and diabetic populations. Risk factor declines were modest but owing to marked unexplained heterogeneity between trials, the pooled estimates are of dubious validity. Evidence suggests that health promotion interventions have limited use in general populations. PMID- 21249648 TI - Traditional suburethral sling operations for urinary incontinence in women. AB - BACKGROUND: Traditional suburethral slings are surgical operations used to treat women with symptoms of stress urinary incontinence. OBJECTIVES: To determine the effects of traditional suburethral slings on stress or mixed incontinence in comparison with other management options. SEARCH STRATEGY: We searched the Cochrane Incontinence Group Specialised Register (searched 3 June 2010) and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi randomised trials that included traditional suburethral slings for the treatment of stress or mixed urinary incontinence. DATA COLLECTION AND ANALYSIS: At least three reviewers independently extracted data from included trials onto a standard form and assessed trial methodological quality. The data abstracted were relevant to predetermined outcome measures. Where appropriate, a summary statistic was calculated: a relative risk for dichotomous data and a weighted mean difference for continuous data. MAIN RESULTS: Twenty six trials involving 2284 women were included. The quality of evidence was moderate for most trials and there was generally short follow-up ranging from 6-24 months.One medium sized trial compared traditional suburethral sling operations with oxybutynin in the treatment of mixed urinary incontinence patients. Surgery appeared to be more effective than drugs in treating patient-reported incontinence (n = 75, Risk Ratio (RR) 0.18, 95% Confidence Interval (CI) 0.08 to 0.43).One trial found that traditional slings were more effective than transurethral injectable treatment (RR for clinician-assessed incontinence within a year 0.21; 95% CI 0.09 to 0.21), and also cheaper on average cost.Seven trials compared slings with open abdominal retropubic colposuspension. Patient-reported incontinence was lower with the slings after one year (RR 0.75; 95% CI 0.62 to 0.90), but not when assessed by clinicians. Colposuspension, however, was associated with fewer peri-operative complications, shorter duration of use of indwelling catheter and less long term voiding dysfunction. One study showed there was a 20% lower risk of bladder perforation with the sling procedure but a 50% increase in urinary tract infection with the sling procedure compared with colposuspension. Fewer women developed prolapse after slings (compared with after colposuspension) in two small trials but this did not reach statistical significance.Twelve trials addressed the comparison between traditional sling operations and minimally invasive sling operations.These seemed to be equally effective in the short term (RR for incontinence within first year 0.97; 95% CI 0.78 to 1.20) but minimally invasive slings had a shorter operating time, fewer peri-operative complications (other than bladder perforation) and some evidence of less post-operative voiding dysfunction and detrusor symptoms.Six trials compared one type of traditional sling with another. Materials included porcine dermis, lyophilised dura mater, fascia lata, vaginal wall, autologous dermis and rectus fascia. Patient-reported improvement rates within the first year favoured the traditional autologous material rectus fascia over other biological materials (RR 0.45; 95% CI 0.21 to 0.98). There were more complications with the use of non-absorbable Goretex in one trial.Data for comparison of bladder neck needle suspension with suburethral slings were inconclusive because they came from a single trial with a small specialised population.No trials compared traditional suburethral slings with anterior repair, laparoscopic retropubic colposuspension or artificial sphincters. Most trials did not distinguish between women having surgery for primary or recurrent incontinence when reporting patient characteristics.For most of the comparisons, clinically important differences could not be ruled out. AUTHORS' CONCLUSIONS: Traditional slings seem to be as effective as minimally invasive slings, but had higher rates of adverse effects. This should be interpreted with some caution however, as the quality of evidence for the studies was variable, follow-up short and populations small, particularly for identifying complication rates. Tradional sling procedures appeared to confer a similar cure rate in comparison to open retropubic colposuspension, but the long term adverse event profile is still unclear. Reliable evidence to clarify whether or not traditional suburethral slings may be better or worse than other surgical or conservative management options is lacking. PMID- 21249649 TI - Screening for breast cancer with mammography. AB - BACKGROUND: A variety of estimates of the benefits and harms of mammographic screening for breast cancer have been published and national policies vary. OBJECTIVES: To assess the effect of screening for breast cancer with mammography on mortality and morbidity. SEARCH STRATEGY: We searched PubMed (November 2008). SELECTION CRITERIA: Randomised trials comparing mammographic screening with no mammographic screening. DATA COLLECTION AND ANALYSIS: Both authors independently extracted data. Study authors were contacted for additional information. MAIN RESULTS: Eight eligible trials were identified. We excluded a biased trial and included 600,000 women in the analyses. Three trials with adequate randomisation did not show a significant reduction in breast cancer mortality at 13 years (relative risk (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02); four trials with suboptimal randomisation showed a significant reduction in breast cancer mortality with an RR of 0.75 (95% CI 0.67 to 0.83). The RR for all seven trials combined was 0.81 (95% CI 0.74 to 0.87). We found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly because of differential misclassification of cause of death. The trials with adequate randomisation did not find an effect of screening on cancer mortality, including breast cancer, after 10 years (RR 1.02, 95% CI 0.95 to 1.10) or on all-cause mortality after 13 years (RR 0.99, 95% CI 0.95 to 1.03).Numbers of lumpectomies and mastectomies were significantly larger in the screened groups (RR 1.31, 95% CI 1.22 to 1.42) for the two adequately randomised trials that measured this outcome; the use of radiotherapy was similarly increased. AUTHORS' CONCLUSIONS: Screening is likely to reduce breast cancer mortality. As the effect was lowest in the adequately randomised trials, a reasonable estimate is a 15% reduction corresponding to an absolute risk reduction of 0.05%. Screening led to 30% overdiagnosis and overtreatment, or an absolute risk increase of 0.5%. This means that for every 2000 women invited for screening throughout 10 years, one will have her life prolonged and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress for many months because of false positive findings. It is thus not clear whether screening does more good than harm. To help ensure that the women are fully informed of both benefits and harms before they decide whether or not to attend screening, we have written an evidence-based leaflet for lay people that is available in several languages on www.cochrane.dk. PMID- 21249650 TI - Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. AB - BACKGROUND: Concerns regarding the safety of transfused blood have led to the development of a range of interventions to minimise blood loss during major surgery. Anti-fibrinolytic drugs are widely used, particularly in cardiac surgery, and previous reviews have found them to be effective in reducing blood loss, the need for transfusion, and the need for re-operation due to continued or recurrent bleeding. In the last few years questions have been raised regarding the comparative performance of the drugs. The safety of the most popular agent, aprotinin, has been challenged, and it was withdrawn from world markets in May 2008 because of concerns that it increased the risk of cardiovascular complications and death. OBJECTIVES: To assess the comparative effects of the anti-fibrinolytic drugs aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA) on blood loss during surgery, the need for red blood cell (RBC) transfusion, and adverse events, particularly vascular occlusion, renal dysfunction, and death. SEARCH STRATEGY: We searched: the Cochrane Injuries Group's Specialised Register (July 2010), Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 3), MEDLINE (Ovid SP) 1950 to July 2010, EMBASE (Ovid SP) 1980 to July 2010. References in identified trials and review articles were checked and trial authors were contacted to identify any additional studies. The searches were last updated in July 2010. SELECTION CRITERIA: Randomised controlled trials (RCTs) of anti-fibrinolytic drugs in adults scheduled for non-urgent surgery. Eligible trials compared anti-fibrinolytic drugs with placebo (or no treatment), or with each other. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. MAIN RESULTS: This review summarises data from 252 RCTs that recruited over 25,000 participants. Data from the head-to-head trials suggest an advantage of aprotinin over the lysine analogues TXA and EACA in terms of reducing perioperative blood loss, but the differences were small. Compared to control, aprotinin reduced the probability of requiring RBC transfusion by a relative 34% (relative risk [RR] 0.66, 95% confidence interval [CI] 0.60 to 0.72). The RR for RBC transfusion with TXA was 0.61 (95% CI 0.53 to 0.70) and was 0.81 (95% CI 0.67 to 0.99) with EACA. When the pooled estimates from the head-to-head trials of the two lysine analogues were combined and compared to aprotinin alone, aprotinin appeared more effective in reducing the need for RBC transfusion (RR 0.90; 95% CI 0.81 to 0.99).Aprotinin reduced the need for re-operation due to bleeding by a relative 54% (RR 0.46, 95% CI 0.34 to 0.62). This translates into an absolute risk reduction of 2% and a number needed-to-treat (NNT) of 50 (95% CI 33 to 100). A similar trend was seen with EACA (RR 0.32, 95% CI 0.11 to 0.99) but not TXA (RR 0.80, 95% CI 0.55 to 1.17). The blood transfusion data were heterogeneous and funnel plots indicate that trials of aprotinin and the lysine analogues may be subject to publication bias.When compared with no treatment aprotinin did not increase the risk of myocardial infarction (RR 0.87, 95% CI 0.69 to 1.11), stroke (RR 0.82, 95% CI 0.44 to 1.52), renal dysfunction (RR 1.10, 95% CI 0.79 to 1.54) or overall mortality (RR 0.81, 95% CI 0.63 to 1.06). Similar trends were seen with the lysine analogues, but data were sparse. These data conflict with the results of recently published non-randomised studies, which found increased risk of cardiovascular complications and death with aprotinin. There are concerns about the adequacy of reporting of uncommon events in the small clinical trials included in this review.When aprotinin was compared directly with either, or both, of the two lysine analogues it resulted in a significant increase in the risk of death (RR 1.39, 95% CI 1.02, 1.89), and a non-significant increase in the risk of myocardial infarction (RR 1.11 95% CI 0.82, 1.50). Most of the data contributing to this added risk came from a single study - the BART trial (2008). AUTHORS' CONCLUSIONS: Anti-fibrinolytic drugs provide worthwhile reductions in blood loss and the receipt of allogeneic red cell transfusion. Aprotinin appears to be slightly more effective than the lysine analogues in reducing blood loss and the receipt of blood transfusion. However, head to head comparisons show a lower risk of death with lysine analogues when compared with aprotinin. The lysine analogues are effective in reducing blood loss during and after surgery, and appear to be free of serious adverse effects. PMID- 21249651 TI - Glucocorticoids for croup. AB - BACKGROUND: Since the initial publication of this systematic review in 1997, several randomized trials examining the benefit of glucocorticoids have been published. The objective of this review is to provide evidence to guide clinicians in their treatment of patients with croup by determining the effectiveness of glucocorticoids and to identify areas requiring future research. OBJECTIVES: To determine the effect of glucocorticoids for children with croup. SEARCH STRATEGY: We searched CENTRAL (2010, Issue 3), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to July week 2, 2010) and EMBASE.com (1974 to July 2010). We also contacted authors of identified croup trials published in the last 10 years to inquire about additional published or unpublished trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) that examine children with croup and objectively measure the effectiveness of glucocorticoids. DATA COLLECTION AND ANALYSIS: Two review authors identified studies for potential relevance based on the review of the title and abstract (when available). Two review authors independently reviewed studies for relevance using a priori inclusion criteria and assessed trial quality. Differences were resolved by consensus. One review author extracted data using a structured form and another review author checked the results for accuracy. We performed standard statistical analyses. MAIN RESULTS: Thirty-eight studies were included (n = 4299). Glucocorticoids were associated with an improved Westley score (maximum 17 points) at six hours with a mean difference of -1.2 (95% confidence interval (CI) -1.6 to -0.8) and at 12 hours -1.9 (95% CI 2.4 to -1.3); at 24 hours this improvement was no longer significant (-1.3, 95% CI -2.7 to 0.2). Fewer return visits and/or (re)admissions occurred in participants treated with glucocorticoids (risk ratio (RR) 0.5; 95% CI 0.3 to 0.7). Length of time spent in accident and emergency or hospital (mean difference 12 hours, five to 19 hours) was significantly decreased for participants treated with glucocorticoids. Use of epinephrine decreased for children treated with a glucocorticoid (risk difference 10%; 95% CI 1 to 20). AUTHORS' CONCLUSIONS: Dexamethasone and budesonide are effective in relieving the symptoms of croup as early as six hours after treatment. Fewer return visits and/or (re)admissions are required and the length of time spent in hospital is decreased. Research is required to examine the most beneficial method for disseminating croup practice guidelines and to increase the uptake of evidence. PMID- 21249652 TI - Treatments for symptomatic urinary tract infections during pregnancy. AB - BACKGROUND: Urinary tract infections, including pyelonephritis, are serious complications that may lead to significant maternal and neonatal morbidity and mortality. There is a large number of drugs, and combination of them, available to treat urinary tract infections, most of them tested in non-pregnant women. Attempts to define the optimal antibiotic regimen for pregnancy have, therefore, been problematic. OBJECTIVES: The objective of this review was to determine, from the best available evidence from randomised controlled trials, which agent is the most effective for the treatment of symptomatic urinary tract infections during pregnancy in terms of cure rates, recurrent infection, incidence of preterm delivery and premature rupture of membranes, admission to neonatal intensive care unit, need for change of antibiotic, and incidence of prolonged pyrexia. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (November 2009) and reference lists of articles. SELECTION CRITERIA: We considered all trials where the intention was to allocate participants randomly to one of at least two alternative treatments for any symptomatic urinary tract infection. DATA COLLECTION AND ANALYSIS: Both review authors assessed trial quality and extracted data. MAIN RESULTS: We included 10 studies, recruiting a total of 1125 pregnant women. In most of the comparisons there were no significant differences between the treatments under study with regard to cure rates, recurrent infection, incidence of preterm delivery, admission to neonatal intensive care unit, need for change of antibiotic and incidence of prolonged pyrexia. When cefuroxime and cephradine were compared, there were better cure rates (29/49 versus 41/52) and fewer recurrences (20/49 versus 11/52) in the cefuroxime group. There was only one other statistically significant difference when comparing outpatient versus inpatient treatment. Gestational age at birth was greater in women from the outpatient group (38.86 versus 37.21), while birthweight was on average greater in the inpatient group (3120 versus 2659). AUTHORS' CONCLUSIONS: Although antibiotic treatment is effective for the cure of urinary tract infections, there are insufficient data to recommend any specific drug regimen for treatment of symptomatic urinary tract infections during pregnancy. All the antibiotics studied were shown to be very effective in decreasing the incidence of the different outcomes. Complications were very rare. All included trials had very small sample sizes to reliably detect important differences between treatments. Future studies should evaluate the most promising antibiotics, in terms of class, timing, dose, acceptability, maternal and neonatal outcomes and costs. PMID- 21249653 TI - Laxatives or methylnaltrexone for the management of constipation in palliative care patients. AB - BACKGROUND: Constipation is common in palliative care; it can generate considerable suffering due to the unpleasant physical symptoms. In the first Cochrane Review on effectiveness of laxatives for the management of constipation in palliative care patients, published in 2006, no conclusions could be drawn because of the limited number of evaluations. This article describes the first update of this review. OBJECTIVES: To determine the effectiveness of laxatives or methylnaltrexone for the management of constipation in palliative care patients. SEARCH STRATEGY: We searched databases including MEDLINE and CENTRAL (The Cochrane Library) in 2005 and in the update to August 2010. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating laxatives for constipation in palliative care patients. In the update we also included RCTs on subcutaneous methylnaltrexone; an opioid-receptor antagonist that is now licensed for the treatment of opioid-induced constipation in palliative care when response to usual laxative therapy is insufficient. DATA COLLECTION AND ANALYSIS: Two authors assessed trial quality and extracted data. The appropriateness of combining data from the studies depended upon clinical and outcome measure homogeneity. MAIN RESULTS: We included seven studies involving 616 participants; all under-reported methodological features. In four studies the laxatives lactulose, senna, co danthramer, misrakasneham, and magnesium hydroxide with liquid paraffin were evaluated. In three methylnaltrexone.In studies comparing the different laxatives evidence was inconclusive. Evidence on subcutaneous methylnaltrexone was clearer; in combined analysis (287 participants) methylnaltrexone, in comparison with a placebo, significantly induced laxation at 4 hours (odds ratio 6.95; 95% confidence interval 3.83 to 12.61). In combined analyses there was no difference in the proportion experiencing side effects, although participants on methylnaltrexone suffered more flatulence and dizziness. No evidence of opioid withdrawal was found. In one study severe adverse events, commonly abdominal pain, were reported that were possibly related to methylnaltrexone. A serious adverse event considered to be related to the methylnaltrexone also occurred; this involved a participant having severe diarrhoea, subsequent dehydration and cardiovascular collapse. AUTHORS' CONCLUSIONS: The 2010 update found evidence on laxatives for management of constipation remains limited due to insufficient RCTs. However, the conclusions of this update have changed since the original review publication in that it now includes evidence on methylnaltrexone. Here it found that subcutaneous methylnaltrexone is effective in inducing laxation in palliative care patients with opioid-induced constipation and where conventional laxatives have failed. However, the safety of this product is not fully evaluated. Large, rigorous, independent trials are needed. PMID- 21249654 TI - Percutaneous needle aspiration, injection, and re-aspiration with or without benzimidazole coverage for uncomplicated hepatic hydatid cysts. AB - BACKGROUND: Hepatic hydatid cyst is an important public health problem in parts of the world where dogs are used for cattle breeding. Management of uncomplicated hepatic hydatid cysts is currently surgical. However, the puncture, aspiration, injection, and re-aspiration (PAIR) method with or without benzimidazole coverage has appeared as an alternative over the past decade. OBJECTIVES: To assess the benefits and harms of PAIR with or without benzimidazole coverage for patients with uncomplicated hepatic hydatid cyst in comparison with sham/no intervention, surgery, or medical treatment. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, DARE, and ACP Journal Club and full text searches were combined (all searched October 2010). Reference lists of pertinent studies and other identified literature were scanned. Researchers in the field were contacted. SELECTION CRITERIA: Only randomised clinical trials using the PAIR method with or without benzimidazole coverage as the experimental treatment of uncomplicated hepatic hydatid cyst (ie, hepatic hydatid cysts, which are not infected and do not have any communication with the biliary tree or other viscera) versus no intervention, sham puncture (ie, performing all steps for puncture, pretending PAIR being performed, but actually not performing the procedure), surgery, or chemotherapy were included. DATA COLLECTION AND ANALYSIS: Data were independently extracted, and the risk of bias in each trial was assessed by the authors. Principal authors of the trials were contacted to retrieve missing data. MAIN RESULTS: We found no randomised clinical trials comparing PAIR versus no or sham intervention. We identified only two randomised clinical trials, one comparing PAIR versus surgical treatment (n = 50 participants) and the other comparing PAIR (with or without albendazole) versus albendazole alone (n = 30 participants). Both trials were graded as 'adequate' for allocation concealment; however, generation of allocation sequence and blinding methods were 'unclear' in both. Compared to surgery, PAIR plus albendazole obtained similar cyst disappearance and mean cyst diameter with fewer adverse events (32% versus 84%, P < 0.001) and fewer days in hospital (mean + SD) ( 4.2 + 1.5 versus 12.7 + 6.5 days, P < 0.001). Compared to albendazole, PAIR with or without albendazole obtained significantly more (P < 0.01) cyst reduction and symptomatic relief. AUTHORS' CONCLUSIONS: PAIR seems promising, but there is insufficient evidence to support or refute PAIR with or without benzimidazole coverage for treating patients with uncomplicated hepatic hydatid cyst. Further well-designed randomised clinical trials are necessary to address the topic. PMID- 21249655 TI - Bile acids for primary sclerosing cholangitis. AB - BACKGROUND: Primary sclerosing cholangitis is a progressive chronic cholestatic liver disease that usually leads to the development of cirrhosis. Studies evaluating bile acids in the treatment of primary sclerosing cholangitis have shown a potential benefit of their use. However, no influence on patients survival and disease outcome has yet been proven. OBJECTIVES: To assess the beneficial and harmful effects of bile acids for patients with primary sclerosing cholangitis. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Library, MEDLINE, EMBASE and Science Citation Index Expanded generally from inception through to October 2010. SELECTION CRITERIA: Randomised clinical trials comparing any dose of bile acids or duration of treatment versus placebo, no intervention, or another intervention were included irrespective of blinding, language, or publication status. DATA COLLECTION AND ANALYSIS: Two authors extracted data independently. We evaluated the risk of bias of the trials using prespecified domains. We performed the meta analysis according to the intention-to-treat principle. We presented outcomes as relative risks (RR) or mean differences (MD), both with 95% confidence intervals (CI). MAIN RESULTS: Eight trials evaluated ursodeoxycholic acid versus placebo or no intervention (592 patients). The eight randomised clinical trials have a high risk of bias. Patients were treated for three months to six years (median three years). The dosage of ursodeoxycholic acid used in the trials ranged from low (10 mg/kg body weight/day) to high (28 to 30 mg/kg body weight/day). Ursodeoxycholic acid did not significantly reduce the risk of death (RR 1.00; 95% CI 0.46 to 2.20); treatment failure including liver transplantation, varices, ascites, and encephalopathy (RR 1.22; 95% CI 0.91 to 1.64); liver histological deterioration (RR 0.89; 95% CI 0.45 to 1.74); or liver cholangiographic deterioration (RR 0.60; 95% CI 0.23 to 1.57). Ursodeoxycholic acid significantly improved serum bilirubin (MD -14.6 umol/litre; 95% CI -18.7 to -10.6), alkaline phosphatases (MD -506 IU/litre; 95% CI -583 to -430), aspartate aminotransferase (MD -46 IU/litre; 95% CI -77 to -16), and gamma-glutamyltranspeptidase (MD -260 IU/litre; 95% CI -315 to -205), but not albumin (MD -0.20 g/litre; 95% CI -1.91 to 1.50). Ursodeoxycholic acid was safe and well tolerated by patients with primary sclerosing cholangitis. AUTHORS' CONCLUSIONS: We did not find enough evidence to support or refute the use of bile acids in the treatment of primary sclerosing cholangitis. However, bile acids seem to lead to a significant improvement in liver biochemistry. Therefore, more randomised trials are needed before any of the bile acids can be recommended for this indication. PMID- 21249656 TI - Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection. AB - BACKGROUND: Observational studies of pregnant women in sub-Saharan Africa have shown that low serum vitamin A levels are associated with an increased risk of mother-to-child transmission (MTCT) of HIV. Vitamin A is cheap and easily provided through existing health services in low-income settings. It is thus important to determine the effect of routine supplementation of HIV positive pregnant or breastfeeding women with this vitamin on the risk of MTCT of HIV, which currently results in more than 1000 new HIV infections each day world-wide. OBJECTIVES: We aimed to assess the effect of antenatal and or postpartum vitamin A supplementation on the risk of MTCT of HIV as well as infant and maternal mortality and morbidity. SEARCH STRATEGY: In June 2010 we searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, AIDS Education Global Information System, and WHO International Clinical Trials Registry Platform; and checked reference lists of identified articles for any studies published after the earlier version of this review was updated in 2008. SELECTION CRITERIA: We selected randomised controlled trials conducted in any setting that compared vitamin A supplementation with placebo in known HIV-infected pregnant or breastfeeding women. DATA COLLECTION AND ANALYSIS: At least two authors independently assessed trial eligibility and quality and extracted data. We calculated relative risks (RR) or mean differences (MD), with their 95% confidence intervals (CI) for each study. We conducted meta-analysis using a fixed-effects method (when there was no significant heterogeneity between study results, i.e. P>0.1) or the random-effects method (when there was significant heterogeneity), and report the Higgins' statistic for all pooled effect measures. MAIN RESULTS: Five randomised controlled trials which enrolled 7,528 HIV-infected women (either during pregnancy or the immediate postpartum period) met our inclusion criteria. These trials were conducted in Malawi, South Africa, Tanzania, and Zimbabwe between 1995 and 2005. We combined the results of these trials and found no evidence that vitamin A supplementation has an effect on the risk of MTCT of HIV (4 trials, 6517 women: RR 1.04, 95% CI 0.87 to 1.24; I(2)=68%). However, antenatal vitamin A supplementation significantly improved birth weight (3 trials, 1809 women: MD 89.78, 95%CI 84.73 to 94.83; I(2)=33.0%), but there was no evidence of an effect on preterm births (3 trials, 2110 women: RR 0.88, 95%CI 0.65 to 1.19; I(2)=58.1%), stillbirths (4 trials, 2855 women: RR 0.99, 95%CI 0.68 to 1.43; I(2)=0%), deaths by 24 months (2 trials, 1635 women: RR 1.03, 95%CI 0.88 to 1.20; I(2)=0%), postpartum CD4 levels (1 trial, 727 women: MD -4.00, 95% CI -51.06 to 43.06), and maternal death ( 1 trial, 728 women: RR 0.49, 95%CI 0.04 to 5.37). AUTHORS' CONCLUSIONS: Current best evidence shows that antenatal or postpartum vitamin A supplementation probably has little or no effect on mother-to-child transmission of HIV. According to the GRADE classification, the quality of this evidence is moderate; implying that the true effect of vitamin A supplementation on the risk of mother-to-child transmission of HIV is likely to be close to the findings of this review, but that there is also a possibility that it is substantially different. PMID- 21249657 TI - 20 ug versus >20 ug estrogen combined oral contraceptives for contraception. AB - BACKGROUND: Concern about estrogen-related adverse effects has led to progressive reductions in the estrogen dose in combination oral contraceptives (COCs). However, reducing the amount of estrogen to improve safety could result in decreased contraceptive effectiveness and unacceptable changes in bleeding patterns. OBJECTIVES: To test the hypothesis that COCs containing <= 20 MUg ethinyl estradiol (EE) perform similarly as those containing > 20 MUg in terms of contraceptive effectiveness, bleeding patterns, discontinuation, and side effects. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, EMBASE, POPLINE, ClinicalTrials.gov, and ICTRP, and examined references of eligible trials. Initially, we wrote to oral contraceptive manufacturers to identify trials. SELECTION CRITERIA: English-language reports of randomized controlled trials were eligible that compare a COC containing <= 20 MUg EE with a COC containing > 20 MUg EE. We excluded studies where the interventions were designed to be administered for less than three consecutive cycles or to be used primarily as treatment for non-contraceptive conditions. Trials had to report on contraceptive effectiveness, bleeding patterns, trial discontinuation due to bleeding-related reasons or other side effects, or side effects to be included in the review. DATA COLLECTION AND ANALYSIS: One author evaluated all titles and abstracts from literature searches to determine whether they met the inclusion criteria. Two authors independently extracted data from studies identified for inclusion. We wrote to the researchers when additional information was needed. Data were entered and analyzed with RevMan. MAIN RESULTS: No differences were found in contraceptive effectiveness for the 13 COC pairs for which this outcome was reported. Compared to the higher-estrogen pills, several COCs containing 20 MUg EE resulted in higher rates of early trial discontinuation (overall and due to adverse events such as irregular bleeding) as well as increased risk of bleeding disturbances (both amenorrhea or infrequent bleeding and irregular, prolonged, frequent bleeding, or breakthrough bleeding or spotting). AUTHORS' CONCLUSIONS: While COCs containing 20 MUg EE may be theoretically safer, this review did not focus on the rare events required to assess this hypothesis. Data from existing randomized controlled trials are inadequate to detect possible differences in contraceptive effectiveness. Low-dose estrogen COCs resulted in higher rates of bleeding pattern disruptions. However, most trials compared COCs containing different progestin types, and changes in bleeding patterns could be related to progestin type as well as estrogen dose. Higher follow-up rates are essential for meaningful interpretation of results. PMID- 21249658 TI - Non-antiepileptic drugs for trigeminal neuralgia. AB - BACKGROUND: Non-antiepileptic drugs have been used in the management of trigeminal neuralgia since the 1970s. OBJECTIVES: The objective was to systematically review the efficacy and tolerability of non-antiepileptic drugs for trigeminal neuralgia. SEARCH STRATEGY: For this updated review we searched the Cochrane Neuromuscular Disease Group Specialized Register (30 April 2010). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2), MEDLINE (January 1966 to April 2010), EMBASE (January 1980 to April 2010), LILACS (January 1982 to April 2010) and the Chinese Biomedical Retrieval System (1978 to April 2010). We handsearched 10 Chinese journals. SELECTION CRITERIA: We searched for double-blind randomized or quasi randomized controlled trials in which the active drug was used for at least two weeks. DATA COLLECTION AND ANALYSIS: Two authors decided which trials fitted the inclusion criteria and independently graded risk of bias. MAIN RESULTS: Four trials involving 139 participants were included. The primary outcome measure in each was pain relief. Three trials with an unclear risk of bias compared one of the non-antiepileptic drugs tizanidine, tocainide or pimozide with carbamazepine. In a trial of tizanidine involving 12 participants (one dropped out due to unrelated disease) one of five treated with tizanidine and four of six treated with carbamazepine improved, risk ratio 0.30 (95% CI 0.05 to 1.89). Few side effects were noted with tizanidine. In a study involving 12 participants there was an improvement in mean pain scores with tocainide similar to that with carbamazepine, but significant side effects limited its use. In the pimozide study more participants improved on pimozide (48/48) than with carbamazepine (27/48) (risk ratio 1.76, 95% CI 1.37 to 2.26). Up to 83% of participants reported adverse effects but these did not lead to withdrawal from the study. A trial with low risk of bias involving 47 participants compared 0.5% proparacaine hydrochloride eyedrops with placebo but did not show any significant benefits or side effects. AUTHORS' CONCLUSIONS: Of the four studies identified, one had low and three an unclear risk of bias. There is insufficient evidence from randomized controlled trials to show significant benefit from non-antiepileptic drugs in trigeminal neuralgia. More research is needed. PMID- 21249659 TI - Enteral tube feeding for amyotrophic lateral sclerosis/motor neuron disease. AB - BACKGROUND: Enteral feeding (tube feeding) is offered to many people with amyotrophic lateral sclerosis/motor neuron disease experiencing difficulty swallowing (dysphagia) and maintaining adequate nutritional intake leading to weight loss. OBJECTIVES: To examine the efficacy of percutaneous endoscopic gastrostomy placement or other tube feeding placement on: (1) survival;(2) nutritional status; (3) quality of life;(4) minor and major complications of percutaneous endoscopic gastrostomy. SEARCH STRATEGY: We searched the Cochrane Neuromuscular Disease Group Trials Register (24 November 2009), MEDLINE (from January 1966 to September 2009), and EMBASE (from January 1980 to September 2009) for all papers on enteral tube feeding in amyotrophic lateral sclerosis/motor neuron disease. The results were screened to identify randomised controlled trials and to identify non-randomized studies that might be worthy of review and discussion. We checked references in published articles and enlisted personal communications to identify any additional references. SELECTION CRITERIA: A priori selection criteria included randomised and quasi-randomized controlled trials evaluating the efficacy of percutaneous endoscopic gastrostomy or other feeding tube placement. Since no such trials were discovered, all prospective and retrospective controlled studies were reviewed in the 'Background' or 'Discussion' sections of the review. DATA COLLECTION AND ANALYSIS: We independently assessed study design and extracted data. We considered the following outcomes: (1) survival rate in months (of primary interest), (2) nutritional status measured by weight change, change in body mass index, or other quantitative index of nutritional status, (3) self-perceived quality of life and (4) safety of the procedure as indicated by minor and major complications of surgical or radiological guided PEG tube insertion. MAIN RESULTS: We found no randomised controlled trials comparing the efficacy of enteral tube feeding with those people who continued to eat orally, without enteral feeding. We summarized the results of retrospective and prospective studies in the 'Discussion' section. AUTHORS' CONCLUSIONS: There are no randomised controlled trials to indicate whether enteral tube feeding is beneficial compared to continuation of oral feeding for any of the outcome measures. The 'best' evidence to date suggests a survival advantage for some people with amyotrophic lateral sclerosis/motor neuron disease, but these conclusions are tentative. Evidence for improved nutrition is also incomplete but tentatively favorable. Quality of life has been addressed in studies and needs more attention. Based on a number of recent non randomized studies comparing surgical and radiographic approaches to feeding tube insertion these two procedures for PEG tube insertion appear to be equivalent. PMID- 21249661 TI - WITHDRAWN: Antibiotics for exacerbations of chronic obstructive pulmonary disease. AB - BACKGROUND: Most patients with an exacerbation of chronic obstructive pulmonary disease (COPD) are treated with antibiotics. However the value of their use remains uncertain. Some controlled trials of antibiotics have shown benefit (Berry 1960; Pines 1972) while others have not (Elmes 1965b; Nicotra 1982). OBJECTIVES: To conduct a systematic review of the literature estimating the value of antibiotics in the management of acute COPD exacerbations. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2005, issue 4) which contains the Acute Respiratory Infections Group's Specialized Register; MEDLINE (1966 to December 2005); EMBASE (1974 to December 2005); Web of Science (December 2005), and other electronically available databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) in patients with acute COPD exacerbations comparing antibiotic (for a minimum of five days) and placebo. DATA COLLECTION AND ANALYSIS: Data were analysed using Review Manager software. Continuous data were analysed using weighted mean differences (WMD) and 95% confidence intervals (CI). Relative risks (RR) (and 95% CI) were calculated for all dichotomous data. Where appropriate, number needed to treat to benefit (NNT) and 95% CI were calculated. MAIN RESULTS: Eleven trials with 917 patients were included. Ten trials used increased cough, sputum volume and purulence diagnostic criteria for COPD exacerbation. Eight-hundred and fifty seven patients provided data for outcomes including mortality, treatment failure, increased sputum volume, sputum purulence, PaCO(2), PaO(2), peak flow and adverse events. Antibiotic therapy regardless of antibiotic choice significantly reduced mortality (RR 0.23; 95% CI 0.10 to 0.52 with NNT of 8; 95% CI 6 to 17), treatment failure (RR 0.47; 95% CI 0.36 to 0.62 with NNT of 3; 95% CI 3 to 5) and sputum purulence (RR 0.56; 95% CI 0.41 to 0.77 with NNT of 8; 95% CI 6 to 17). There was a small increase in risk of diarrhoea with antibiotics (RR 2.86; 95% CI 1.06 to 7.76). Antibiotics did not improve arterial blood gases and peak flow. AUTHORS' CONCLUSIONS: This review shows that in COPD exacerbations with increased cough and sputum purulence antibiotics, regardless of choice, reduce the risk of short term mortality by 77%, decrease the risk of treatment failure by 53% and the risk of sputum purulence by 44%; with a small increase in the risk of diarrhoea. These results should be interpreted with caution due to the differences in patient selection, antibiotic choice, small number of included trials and lack of control for interventions that influence outcome, such as use of systemic corticosteroids and ventilatory support. Nevertheless, this review supports antibiotics for patients with COPD exacerbations with increased cough and sputum purulence who are moderately or severely ill. PMID- 21249660 TI - Vitamin supplementation for preventing miscarriage. AB - BACKGROUND: Miscarriage is a common complication of pregnancy that can be caused by a wide range of factors. Poor dietary intake of vitamins has been associated with an increased risk of miscarriage, therefore supplementing women with vitamins either prior to or in early pregnancy may help prevent miscarriage. OBJECTIVES: The objectives of this review are to determine the effectiveness and safety of any vitamin supplementation, on the risk of spontaneous miscarriage, maternal adverse outcomes and fetal and infant adverse outcomes. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (21 June 2010). SELECTION CRITERIA: All randomised and quasi-randomised trials comparing one or more vitamins with either placebo, other vitamins, no vitamins or other interventions, prior to conception, periconceptionally or in early pregnancy (less than 20 weeks' gestation). DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed trials for inclusion, extracted data and assessed trial quality. MAIN RESULTS: We identified 28 trials assessing supplementation with any vitamin(s) starting prior to 20 weeks' gestation and reporting at least one primary outcome that was eligible for the review. Overall, the included trials involved 96,674 women and 98,267 pregnancies. Three trials were cluster randomised and combined contributed data for 62,669 women and 64,210 pregnancies in total. No significant differences were seen between women taking any vitamins compared with controls for total fetal loss (relative risk (RR) 1.04, 95% confidence interval (CI) 0.95 to 1.14), early or late miscarriage (RR 1.09, 95% CI 0.95 to 1.25) or stillbirth (RR 0.86, 95% CI 0.65 to 1.13) and most of the other primary outcomes, using fixed-effect models. Compared with controls, women given any type of vitamin(s) pre or peri-conception were more likely to have a multiple pregnancy (RR 1.38, 95% CI 1.12 to 1.70, three trials, 20,986 women). AUTHORS' CONCLUSIONS: Taking any vitamin supplements prior to pregnancy or in early pregnancy does not prevent women experiencing miscarriage or stillbirth. However, women taking vitamin supplements may be more likely to have a multiple pregnancy. There is insufficient evidence to examine the effects of different combinations of vitamins on miscarriage, stillbirth or other maternal and infant outcomes. PMID- 21249662 TI - Preoperative intra aortic balloon pumps in patients undergoing coronary artery bypass grafting. AB - BACKGROUND: The intra aortic balloon pump (IABP) is a mechanical assist device which improves cardiac function. The device has a well-established place in algorithms for managing low cardiac output following cardiac surgery. There is increasing evidence that certain cardiac surgery patients benefit from a period of preoperative augmentation with the intra aortic balloon pump. OBJECTIVES: To determine the effect of the preoperative intra aortic balloon pump on mortality and morbidity in a number of different patients groups undergoing coronary artery bypass grafting. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 3, 2009), MEDLINE (2000 to August 2009), EMBASE (1998 to August 2009), BIOSIS previews (1969 to August 2009) and ISI Proceedings (1990 to August 2009) were searched. References and ongoing registers of studies were checked. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials (RCTs) of any size or length were included. DATA COLLECTION AND ANALYSIS: Papers were assessed for inclusion by two authors independently and differences were settled by consensus with a third author. Date are presented in the form of odds ratios (OR) and 95% confidence intervals (CI). MAIN RESULTS: Six trials were included (five on-pump and one off-pump). This update adds the results of one further trial. Data from a total of 255 patients were included in the meta-analysis of mortality outcomes; all on-pump. Generally, the patients were considered as "high risk" and 132 were treated preoperatively with IABP and 123 served as controls. There were four hospital deaths in the intervention arm and 23 in the non-intervention arm (OR 0.18, 95% CI 0.08 to 0.41; P<0.0001). In a subgroup analysis, low cardiac index (<2.0 L/min/m(2)) was noted in 21 out of 105 patients in the treatment arm and 59 patients out of 88 in the non-treatment arm (OR 0.14, 95% CI: 0.08 to 0.25; P<0.00001). An off-pump versus on-pump analysis was not possible due to the limited number of off-pump studies. However a single well-conducted RCT suggested favourable effect of the preoperative IABP in off-pump patients. AUTHORS' CONCLUSIONS: Evidence suggests that preoperative IABP may have a beneficial effect on mortality and morbidity in specific high risk patient groups undergoing coronary artery bypass grafting, however there are many problems with the quality, validity and generalisability of the trials. However, the available evidence is not robust enough to extend the use of IABP to truly elective, high risk patients. Defining more precisely which patient groups may benefit would be the challenge for the future. PMID- 21249664 TI - Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults. AB - BACKGROUND: Gastroesophageal reflux disease (GORD) is said to be the causative factor in up to 41% of adults with chronic cough. Treatment for GORD includes conservative measures (diet manipulation), pharmaceutical therapy (motility or prokinetic agents, H(2)-antagonist and proton pump inhibitors (PPI)) and fundoplication. OBJECTIVES: To evaluate the efficacy of GORD treatment on chronic cough in children and adults with GORD and prolonged cough that is not related to an underlying respiratory disease, i.e. non-specific chronic cough. SEARCH STRATEGY: We searched the Cochrane Airways Group Specialised Register, the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, review articles and reference lists of relevant articles. The date of last search was 8 April 2010. SELECTION CRITERIA: All randomised controlled trials (RCTs) on GORD treatment for cough in children and adults without primary lung disease. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We contacted study authors for further information. MAIN RESULTS: We included 19 studies (six paediatric, 13 adults). None of the paediatric studies could be combined for meta-analysis. A single RCT in infants found that PPI (compared to placebo) was not efficacious for cough outcomes (favouring placebo OR 1.61; 95% CI 0.57 to 4.55) but those on PPI had significantly increased adverse events (OR 5.56; 95% CI 1.18 to 26.25) (number needed to treat for harm in four weeks was 11 (95% CI 3 to 232)). In adults, analysis of H(2) antagonist, motility agents and conservative treatment for GORD was not possible (lack of data) and there were no controlled studies of fundoplication. We analysed nine adult studies comparing PPI (two to three months) to placebo for various outcomes in the meta-analysis. Using intention-to treat, pooled data from studies resulted in no significant difference between treatment and placebo in total resolution of cough (OR 0.46; 95% CI 0.19 to 1.15). Pooled data revealed no overall significant improvement in cough outcomes (end of trial or change in cough scores). We only found significant differences in sensitivity analyses. We found a significant improvement in change of cough scores at end of intervention (two to three months) in those receiving PPI (standardised mean difference -0.41; 95% CI -0.75 to -0.07) using generic inverse variance analysis on cross-over trials. Two studies reported improvement in cough after five days to two weeks of treatment. AUTHORS' CONCLUSIONS: PPI is not efficacious for cough associated with GORD symptoms in very young children (including infants) and should not be used for cough outcomes. There is insufficient data in older children to draw any valid conclusions. In adults, there is insufficient evidence to conclude definitely that GORD treatment with PPI is universally beneficial for cough associated with GORD. Clinicians should be cognisant of the period (natural resolution with time) and placebo effect in studies that utilise cough as an outcome measure. Future paediatric and adult studies should be double-blind, randomised controlled and parallel-design, using treatments for at least two months, with validated subjective and objective cough outcomes and include ascertainment of time to respond as well as assessment of acid and/or non-acid reflux. PMID- 21249663 TI - Statins for the primary prevention of cardiovascular disease. AB - BACKGROUND: Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD) events in people with and without a past history of coronary heart disease (CHD) is an important goal of pharmacotherapy. Statins are the first choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with coronary artery disease. The case for primary prevention, however, is less clear. OBJECTIVES: To assess the effects, both harms and benefits, of statins in people with no history of CVD. SEARCH STRATEGY: To avoid duplication of effort, we checked reference lists of previous systematic reviews. We searched the Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (2001 to March 2007) and EMBASE (2003 to March 2007). There were no language restrictions. SELECTION CRITERIA: Randomised controlled trials of statins with minimum duration of one year and follow-up of six months, in adults with no restrictions on their total low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol levels, and where 10% or less had a history of CVD, were included. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion and extracted data. Outcomes included all cause mortality, fatal and non-fatal CHD, CVD and stroke events, combined endpoints (fatal and non fatal CHD, CVD and stroke events), change in blood total cholesterol concentration, revascularisation, adverse events, quality of life and costs. Relative risk (RR) was calculated for dichotomous data, and for continuous data pooled weighted mean differences (with 95% confidence intervals) were calculated. MAIN RESULTS: Fourteen randomised control trials (16 trial arms; 34,272 participants) were included. Eleven trials recruited patients with specific conditions (raised lipids, diabetes, hypertension, microalbuminuria). All-cause mortality was reduced by statins (RR 0.83, 95% CI 0.73 to 0.95) as was combined fatal and non-fatal CVD endpoints (RR 0.70, 95% CI 0.61 to 0.79). Benefits were also seen in the reduction of revascularisation rates (RR 0.66, 95% CI 0.53 to 0.83). Total cholesterol and LDL cholesterol were reduced in all trials but there was evidence of heterogeneity of effects. There was no clear evidence of any significant harm caused by statin prescription or of effects on patient quality of life. AUTHORS' CONCLUSIONS: Although reductions in all-cause mortality, composite endpoints and revascularisations were found with no excess of adverse events, there was evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease. Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk. PMID- 21249665 TI - WITHDRAWN: Inhaled corticosteroids during acute bronchiolitis in the prevention of post-bronchiolitic wheezing. AB - BACKGROUND: Acute bronchiolitis in infants and young children is associated with long-term airway disease also known as post-bronchiolitic wheezing. Two major hypotheses have been proposed to explain the association between bronchiolitis and PBW. The first hypothesis considers bronchiolitis to be the first manifestation of recurrent wheezing in infants and children who are susceptible to obstructive airway disease. The second hypothesis suggests that the infection and concomitant inflammatory reaction in the acute phase leads to airway epithelium injury resulting in long-term obstructive airway disease. In line with the latter hypothesis, corticosteroids may have a beneficial effect on the prevention of post-bronchiolitic wheezing. OBJECTIVES: The objective of this review was to evaluate the effect of inhaled corticosteroids, started during the acute phase of bronchiolitis, on the prevention of post-bronchiolitic wheezing. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, issue 3) which contains the Cochrane Acute Respiratory Infections Group's trials register, MEDLINE (1966 to September 2006), EMBASE (1980 to September 2006) and Current Contents (September 2006). Abstracts and reports of congresses (ERS 1999 to September 2005, ATS 1999 to September 2005) were obtained. We contacted experts in the field and pharmaceutical companies for ongoing or unpublished studies. SELECTION CRITERIA: Randomised placebo-controlled trials studying the effect of inhaled corticosteroids in children younger than two years of age with the clinical diagnosis of acute bronchiolitis were included. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed trial quality using the Jadad 5-point scale. MAIN RESULTS: Five studies matched the inclusion criteria, with a median Jadad score of 4 (Inter Quartile Range 3 to 4), involving 374 infants. Pooling of the data was limited, due to the clinical diversity of the studies. However, no effect of inhaled corticosteroids in the prevention of wheezing (diary records or GP diagnosed), hospital re-admissions or use of corticosteroids or bronchodilators could be demonstrated. Duration of therapy, length of follow up or causative agent (respiratory syncytial virus or not) did not influence the pooled effect. In the three studies that also evaluated the adverse events, none were reported. AUTHORS' CONCLUSIONS: This review does not demonstrate an effect of inhaled corticosteroids given during the acute phase of bronchiolitis in the prevention of post-bronchiolitic wheezing. The small number of included participants and the inability to pool all clinical outcomes precludes us from making strong recommendations. PMID- 21249666 TI - Antifibrinolytic drugs for acute traumatic injury. AB - BACKGROUND: Uncontrolled bleeding is an important cause of death in trauma victims. Antifibrinolytic treatment has been shown to reduce blood loss following surgery and may also be effective in reducing blood loss following trauma. OBJECTIVES: To quantify the effect of antifibrinolytic drugs in reducing blood loss, transfusion requirement and mortality after acute traumatic injury. SEARCH STRATEGY: We searched the Cochrane Injuries Group's Specialised Register, CENTRAL, MEDLINE, PubMed, EMBASE, Science Citation Index, National Research Register, Zetoc, SIGLE, Global Health, LILACS, and Current Controlled Trials. The Cochrane Injuries Group Specialised Register, CENTRAL, MEDLINE and EMBASE searches were updated in July 2010. SELECTION CRITERIA: We included all randomised controlled trials of antifibrinolytic agents (aprotinin, tranexamic acid [TXA] and epsilon-aminocaproic acid) following acute traumatic injury. DATA COLLECTION AND ANALYSIS: The titles and abstracts identified in the electronic searches were screened by two independent authors to identify studies that had the potential to meet the inclusion criteria. The full reports of all such studies were obtained. From the results of the screened electronic searches, bibliographic searches, and contacts with experts, two authors independently selected trials meeting the inclusion criteria, with any disagreements resolved by consensus. MAIN RESULTS: Four trials met the inclusion criteria. Two trials with a combined total of 20,451 patients assessed the effects of TXA on mortality; TXA reduced the risk of death by 10% (RR=0.90, 95% CI 0.85 to 0.97; p=0.0035). Data from one trial involving 20,211 patients found that TXA reduced the risk of death due to bleeding by 15% (RR=0.85, 95% CI 0.76 to 0.96; p=0.0077). There was no evidence that TXA increased the risk of vascular occlusive events or need for surgical intervention. There was no substantial difference in the receipt of blood transfusion between the TXA and placebo groups. The two trials of aprotinin provided no reliable data. AUTHORS' CONCLUSIONS: TXA safely reduces mortality in bleeding trauma patients without increasing the risk of adverse events. Further trials are needed to determine the effects of TXA in patients with isolated traumatic brain injury. PMID- 21249667 TI - Single or double-level anterior interbody fusion techniques for cervical degenerative disc disease. AB - BACKGROUND: The number of surgical techniques for decompression and solid interbody fusion as treatment for cervical spondylosis has increased rapidly, but the rationale for the choice between different techniques remains unclear. OBJECTIVES: To determine which technique of anterior interbody fusion gives the best clinical and radiological outcomes in patients with single- or double-level degenerative disc disease of the cervical spine. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2009, issue 1), MEDLINE (1966 to May 2009), EMBASE (1980 to May 2009), BIOSIS (2004 to May 2009), and references of selected articles. SELECTION CRITERIA: Randomised comparative studies that compared anterior cervical decompression and interbody fusion techniques for participants with chronic degenerative disc disease. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias using the Cochrane Back Review Group criteria. Data on demographics, intervention details and outcome measures were extracted onto a pre-tested data extraction form. MAIN RESULTS: Thirty-three small studies ( 2267 patients) compared different fusion techniques. The major treatments were discectomy alone, addition of an interbody fusion procedure (autograft, allograft, cement, or cage), and addition of anterior plates. Eight studies had a low risk of bias. Few studies reported on pain, therefore, at best, there was very low quality evidence of little or no difference in pain relief between the different techniques. We found moderate quality evidence for these secondary outcomes: no statistically significant difference in Odom's criteria between iliac crest autograft and a metal cage (6 studies, RR 1.11 (95% CI 0.99 to1.24)); bone graft produced more effective fusion than discectomy alone (5 studies, RR 0.22 (95% CI 0.17 to 0.48)); no statistically significant difference in complication rates between discectomy alone and iliac crest autograft (7 studies, RR 1.56 (95% CI 0.71 to 3.43)); and low quality evidence that iliac crest autograft results in better fusion than a cage (5 studies, RR 1.87 (95% CI 1.10 to 3.17)); but more complications (7 studies, RR 0.33 (95% CI 0.12 to 0.92)). AUTHORS' CONCLUSIONS: When the working mechanism for pain relief and functional improvement is fusion of the motion segment, there is low quality evidence that iliac crest autograft appears to be the better technique. When ignoring fusion rates and looking at complication rates, a cage has a weak evidence base over iliac crest autograft, but not over discectomy alone. Future research should compare additional instrumentation such as screws, plates, and cages against discectomy with or without autograft. PMID- 21249668 TI - Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular disease. AB - BACKGROUND: Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease. Adding a second antiplatelet drug to aspirin may produce additional benefit for those at high risk and those with established cardiovascular disease. OBJECTIVES: To quantify the benefit and harm of adding clopidogrel to standard long-term aspirin therapy for preventing cardiovascular events in people at high risk of cardiovascular disease and those with established cardiovascular disease. SEARCH STRATEGY: The searches have been updated: CENTRAL (Issue 3 2009), MEDLINE (2002 to September 2009) and EMBASE (2002 to September 2009). SELECTION CRITERIA: All randomized controlled trials comparing long term use of aspirin plus clopidogrel with aspirin plus placebo or aspirin alone in patients with coronary disease, ischemic cerebrovascular disease, peripheral arterial disease, or at high risk of atherothrombotic disease were included. DATA COLLECTION AND ANALYSIS: Data on mortality, non-fatal myocardial infarction, non-fatal stroke, unstable angina, heart failure, revascularizations, major and minor bleeding, and all adverse events were collected. The overall treatment effect was estimated by the pooled odds ratio (OR) with 95% confidence interval (CI) using a fixed-effect model (Mantel Haenszel). MAIN RESULTS: No new studies were identified from the updated searches. A total of two RCTs were found: the CHARISMA and the CURE study. The CURE study enrolled only patients with a recent non-ST segment elevation acute coronary syndrome. The use of clopidogrel plus aspirin, compared with placebo plus aspirin, was associated with a lower risk of cardiovascular events (OR: 0.87, 95% CI 0.81 to 0.94; P<0.01) and a higher risk of major bleeding (OR 1.34, 95% CI 1.14 to 1.57; P<0.01). Overall, we would expect 13 cardiovascular events to be prevented for every 1000 patients treated with the combination, but 6 major bleeds would be caused. In the CURE trial, for every 1000 people treated, 23 events would be avoided and 10 major bleeds would be caused. In the CHARISMA trial, for every 1000 people treated, 5 cardiovascular events would be avoided and 3 major bleeds would be caused. AUTHORS' CONCLUSIONS: The available evidence demonstrates that the use of clopidogrel plus aspirin is associated with a reduction in the risk of cardiovascular events and an increased risk of bleeding compared with aspirin alone. Only in patients with acute non-ST coronary syndrome benefits outweigh harms. PMID- 21249669 TI - Medical methods for mid-trimester termination of pregnancy. AB - BACKGROUND: With the improvement of ultrasound technology, the likelihood of detection of major fetal structural anomalies in mid-pregnancy has increased considerably. Upon the detection of serious anomalies, women typically are offered the option of pregnancy termination. Additionally, there are still many reasons other than fetal anomalies why women seek abortion in the mid-trimester. OBJECTIVES: To compare different methods of second trimester medical termination of pregnancy for their efficacy and side-effects. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, Popline and reference lists of retrieved papers and other sources. SELECTION CRITERIA: All randomised controlled trials (RCTs) examining medical regimens for termination of pregnancy of a singleton living fetus between 12-28 weeks' gestation were analysed. The outcome measures were the induction to abortion interval, abortion rate within 24 hours, need for surgical evacuation, blood loss, uterine rupture, pain, and side-effects.Trials including >20% fetal death, multiple pregnancies, previous uterine scars and regimens which involved cervical preparation were excluded. DATA COLLECTION AND ANALYSIS: Two authors selected the trials and three authors extracted data. MAIN RESULTS: Fourty RCTs were included, addressing various agents for pregnancy termination and methods of administration. When used alone, misoprostol was an effective inductive agent, though it appeared to be more effective in combination with mifepristone. However, the evidence from RCTs is limited.Misoprostol was preferably administered vaginally, although among multiparous women sublingual administration appeared equally effective. A range of doses of vaginally administered misoprostol has been used. No randomised trials comparing doses of misoprostol were identified; however low doses of misoprostol appear to be associated with fewer side-effects while moderate doses appear to be more efficient in completing abortion. Four RCTs showed that the induction to abortion interval with 3-hourly vaginal administration of prostaglandins is shorter than 6 hourly administration without an increase in side-effects.Many studies reported the need for surgical evacuation. Indications for surgical evacuation include retained products of the placenta and heavy vaginal bleeding. Fewer women required surgical evacuation when misoprostol was administrated vaginally compared with women receiving intra-amniotical PGF(2a) . Mild, self-limiting diarrhoea was more common among women who received misoprostol compared to other agents. AUTHORS' CONCLUSIONS: Medical abortion in the second trimester using the combination of mifepristone and misoprostol appeared to have the highest efficacy and shortest abortion time interval. Where mifepristone is not available, misoprostol alone is a reasonable alternative. The optimal route for administering misoprostol is vaginally, preferably using tablets at 3-hourly intervals. Apart from pain, the side-effects of vaginal misoprostol are usually mild and self limiting. Conclusions from this review are limited by the gestational age ranges and variable medical regimens, including dosing, administrative routes and intervals of medication, of the included trials. PMID- 21249670 TI - Medical interventions for traumatic hyphema. AB - BACKGROUND: Traumatic hyphema is the entry of blood into the anterior chamber (the space between the cornea and iris) subsequent to a blow or a projectile striking the eye. Hyphema uncommonly causes permanent loss of vision. Associated trauma (e.g., corneal staining, traumatic cataract, angle recession glaucoma, optic atrophy, etc.) may seriously affect vision. Such complications may lead to permanent impairment of vision. Patients with sickle cell trait/disease may be particularly susceptible to increases of elevated intraocular pressure. If rebleeding occurs, the rates and severity of complications increase. OBJECTIVES: The objective of this review was to assess the effectiveness of various medical interventions in the management of traumatic hyphema. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2010, Issue 6), MEDLINE (January 1950 to June 2010), EMBASE (January 1980 to June 2010), the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com) and ClinicalTrials.gov (http://clinicaltrials.gov). We searched the reference lists of identified trial reports to find additional trials. We also searched the ISI Web of Science Social Sciences Citation Index (SSCI) to find studies that cited the identified trials. There were no language or date restrictions in the search for trials. The electronic databases were last searched on 25 June 2010. SELECTION CRITERIA: Two authors independently assessed the titles and abstracts of all reports identified by the electronic and manual searches. In this review, we included randomized and quasi-randomized trials that compared various medical interventions to other medical interventions or control groups for the treatment of traumatic hyphema following closed globe trauma. There were no restrictions regarding age, gender, severity of the closed globe trauma or level of visual acuity at the time of enrollment. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data for the primary and secondary outcomes. We entered and analyzed data using Review Manager (RevMan) 5. We performed meta-analyses using a fixed-effect model and reported dichotomous outcomes as odds ratios and continuous outcomes as mean differences. MAIN RESULTS: Nineteen randomized and seven quasi-randomized studies with 2,560 participants were included in this review. Interventions included antifibrinolytic agents (oral and systemic aminocaproic acid, tranexamic acid, and aminomethylbenzoic acid), corticosteroids (systemic and topical), cycloplegics, miotics, aspirin, conjugated estrogens, monocular versus bilateral patching, elevation of the head, and bed rest. No intervention had a significant effect on visual acuity whether measured at two weeks or less after the trauma or at longer time periods. The number of days for the primary hyphema to resolve appeared to be longer with the use of aminocaproic acid compared to no use, but was not altered by any other intervention.Systemic aminocaproic acid reduced the rate of recurrent hemorrhage (odds ratio (OR) 0.25, 95% confidence interval (CI) 0.11 to 0.5), but a sensitivity analysis omitting studies not using an intention to-treat (ITT) analysis reduced the strength of the evidence (OR 0.41, 95% CI 0.16 to 1.09). We obtained similar results for topical aminocaproic acid (OR 0.42, 95% CI 0.16 to 1.10). We found tranexamic acid had a significant effect in reducing the rate of secondary hemorrhage (OR 0.25, 95% CI 0.13 to 0.49), as did aminomethylbenzoic acid as reported in a single study (OR 0.07, 95% CI 0.01 to 0.32). The evidence to support an associated reduction in the risk of complications from secondary hemorrhage (i.e., corneal blood staining, peripheral anterior synechiae, elevated intraocular pressure, and development of optic atrophy) by antifibrinolytics was limited by the small number of these events. Use of aminocaproic acid was associated with increased nausea, vomiting, and other adverse events compares with placebo. We found no difference in the number of adverse events with the use of systemic versus topical aminocaproic acid or with standard versus lower drug dose. The available evidence on usage of corticosteroids, cycloplegics or aspirin in traumatic hyphema was limited due to the small numbers of participants and events in the trials.We found no difference in effect between a single versus binocular patch nor ambulation versus complete bed rest on the risk of secondary hemorrhage or time to rebleed. AUTHORS' CONCLUSIONS: Traumatic hyphema in the absence of other intraocular injuries, uncommonly leads to permanent loss of vision. Complications resulting from secondary hemorrhage could lead to permanent impairment of vision, especially in patients with sickle cell trait/disease. We found no evidence to show an effect on visual acuity by any of the interventions evaluated in this review. Although evidence is limited, it appears that patients with traumatic hyphema who receive aminocaproic acid or tranexamic acid are less likely to experience secondary hemorrhaging. However, hyphema in patients on aminocaproic acid take longer to clear.Other than the possible benefits of antifibrinolytic usage to reduce the rate of secondary hemorrhage, the decision to use corticosteroids, cycloplegics, or non-drug interventions (such as binocular patching, bed rest, or head elevation) should remain individualized because no solid scientific evidence supports a benefit. As these multiple interventions are rarely used in isolation, further research to assess the additive effect of these interventions might be of value. PMID- 21249672 TI - Analgesia in patients with acute abdominal pain. AB - BACKGROUND: For decades, the indication of analgesia in patients with Acute Abdominal Pain (AAP) has been deferred until the definitive diagnosis has been made, for fear of masking symptoms, generating a change in the physical exploration or obstructing the diagnosis of a disease requiring surgical treatment. This strategy has been questioned by some studies that have shown that the use of analgesia in the initial evaluation of patients with AAP leads to a significant reduction in pain without affecting diagnostic accuracy. OBJECTIVES: To determine whether the evidence available supports the use of opioid analgesics in the diagnostic process of patients with AAP. SEARCH STRATEGY: Trials were identified through searches in Cochrane Controlled Trials Register (CENTRAL) (The Cochrane Library, issue 2, 2009), MEDLINE (1966 to 2009) and EMBASE (1980 to 2009). A randomised controlled trial (RCT) filter for a MEDLINE search was applied (with appropriate modification for an EMBASE search). Trials also were identified through "related articles". The search was not limited by language or publication status. SELECTION CRITERIA: All published RCTs which included adult patients with AAP, without gender restriction, comparing any opioids analgesia regimen with the non-use of analgesic before any intervention and independent of the results. DATA COLLECTION AND ANALYSIS: Two independent reviewers assessed the studies identified via the electronic search. Articles that were relevant and pertinent to the aims of the study were selected and their respective full-text versions were collected for subsequent blinded evaluation. The allocation concealment was considered in particular as an option to diminish the biases.The data collected from the studies were reviewed qualitatively and quantitatively using the Cochrane Collaboration statistical software RevMan 5.0. After performing the meta-analysis, the chi-squared test for heterogeneity was applied. In situations of significant clinical heterogeneity, statistical analyses were not applied to the pool of results. In situations of heterogeneity, the random effect model was used to perform the meta-analysis of the results. A sensitivity analysis was also applied based on the evaluation to the methodological quality of the primary studies. MAIN RESULTS: Eight studies fulfilled the inclusion criteria. Differences with use of opioid analgesia were verified in variables: Change in the intensity of the pain, change in the patients comfort level. AUTHORS' CONCLUSIONS: The use of opioid analgesics in the therapeutic diagnosis of patients with AAP does not increase the risk of diagnosis error or the risk of error in making decisions regarding treatment. PMID- 21249671 TI - Carbamazepine for acute and chronic pain in adults. AB - BACKGROUND: Carbamazepine is used to treat chronic neuropathic pain. OBJECTIVES: Evaluation of analgesic efficacy and adverse effects of carbamazepine for acute and chronic pain management (except headaches). SEARCH STRATEGY: Randomised controlled trials (RCTs) of carbamazepine in acute, chronic or cancer pain were identified, searching MEDLINE, EMBASE, SIGLE and Cochrane CENTRAL to June 2010, reference lists of retrieved papers, and reviews. SELECTION CRITERIA: RCTs reporting the analgesic effects of carbamazepine. DATA COLLECTION AND ANALYSIS: Two authors independently extracted results and scored for quality. Numbers needed to treat to benefit (NNT) or harm (NNH) with 95% confidence intervals (CI) were calculated from dichotomous data for effectiveness, adverse effects and adverse event withdrawal. Issues of study quality, size, duration, and outcomes were examined. MAIN RESULTS: Fifteen included studies (12 cross-over design; three parallel-group) with 629 participants.Carbamazepine was less effective than prednisolone in preventing postherpetic neuralgia following acute herpes zoster (1 study, 40 participants). No studies examined acute postoperative pain.Fourteen studies investigated chronic neuropathic pain: two lasted eight weeks, others were four weeks or less (mean 3 weeks, median 2 weeks). Five had low reporting quality. Ten involved fewer than 50 participants; mean and median maximum treatment group sizes were 34 and 29. Outcome reporting was inconsistent.Most placebo controlled studies indicated that carbamazepine was better than placebo. Five studies with 298 participants provided dichotomous results; 70% improved with carbamazepine and 12% with placebo. Carbamazepine at any dose, using any definition of improvement was significantly better than placebo (70% versus 12% improved; 5 studies, 298 participants); relative benefit 6.1 (3.9 to 9.7), NNT 1.7 (1.5 to 2.0). Four studies (188 participants) reporting outcomes equivalent to 50% pain reduction or more over baseline had a similar NNT.With carbamazepine, 66% of participants experienced at least one adverse event, and 27% with placebo; relative risk 2.4 (1.9 to 3.1), NNH 2.6 (2.1 to 3.5). Adverse event withdrawals occurred in12 of 323 participants (4%) with carbamazepine and 0 of 310 with placebo. Serious adverse events were not reported consistently; rashes were associated with carbamazepine. Five deaths occurred in patients on carbamazepine, with no obvious drug association. AUTHORS' CONCLUSIONS: Carbamazepine is effective in chronic neuropathic pain, with caveats. No trial was longer than four weeks, of good reporting quality, using outcomes equivalent to at least moderate clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible. PMID- 21249673 TI - Steroids for traumatic optic neuropathy. AB - BACKGROUND: Traumatic optic neuropathy (TON) is an important cause of severe visual loss following blunt or penetrating head trauma. Following the initial injury, optic nerve swelling within the optic nerve canal can result in secondary retinal ganglion cell loss. Optic nerve decompression with steroids or surgical interventions or both has therefore been advocated as a means of improving visual prognosis in TON. OBJECTIVES: The aim of this review was to examine the effectiveness and safety of using steroids in TON. SEARCH STRATEGY: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2010, Issue 11), MEDLINE (January 1950 to November 2010), EMBASE (January 1980 to November 2010), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to November 2010), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (http://clinicaltrials.gov) and Web of Science Conference Proceedings Citation Index- Science (CPCI-S). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 23 November 2010. We also searched the reference lists of included studies, other reviews and book chapters on TON to find references to additional trials. The Science Citation Index was used to look for papers that cited the studies included in this review. We did not manually search any journals or conference proceedings. We contacted trial investigators and experts in the field to identify additional published and unpublished studies. SELECTION CRITERIA: We planned to include only randomised controlled trials (RCTs) of TON in which any steroid regime, either on its own or in combination with surgical optic nerve decompression, was compared to surgery alone or no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the titles and abstracts identified from the electronic searches. MAIN RESULTS: We included one study that met our selection criteria; a double-masked, placebo-controlled, randomised trial of high dose intravenous steroids in patients with indirect TON diagnosed within seven days of the initial injury. A total of 31 eligible participants were randomised to receive either high dose intravenous steroids (n = 16) or placebo (n = 15), and they were all followed-up for three months. Mean final best corrected visual acuity (BCVA) was 1.78+/-1.23 Logarithm of the Minimum Angle of Resolution (LogMAR) in the placebo group, and 1.11+/-1.14 LogMAR in the steroid group. The mean difference in BCVA between the placebo and steroid groups was 0.67 LogMAR (95% confidence interval -1.54 to 0.20), and this difference was not statistically significant (P = 0.13). At three months follow-up, an improvement in BCVA of 0.40 LogMAR occurred in eight eyes (8/15, 53.3%) in the placebo group, and in 11 eyes (11/16, 68.8%) in the treatment group. This difference was not statistically significant (P = 0.38). AUTHORS' CONCLUSIONS: There is a relatively high rate of spontaneous visual recovery in TON and there is no convincing data that steroids provide any additional visual benefit over observation alone. Recent evidence also suggests a possible detrimental effect of steroids in TON and further studies are urgently needed to clarify this important issue. Each case therefore needs to be assessed on an individual basis and proper informed consent is paramount. PMID- 21249674 TI - The psychological effects of the physical healthcare environment on healthcare personnel. AB - BACKGROUND: The physical healthcare environment is capable of affecting patients. This concept of 'healing environments' refers to the psychological impact of environmental stimuli through sensory perceptions. It excludes more physiological effects such as those produced by ergonomic (i.e. fall prevention) or facilitative (i.e. hygiene-related) variables. The importance of an atmosphere in the healthcare environment that promotes the health and well-being of patients is evident, but this environment should not negatively affect healthcare personnel. The physical healthcare environment is part of the personnel's 'workscape'. This can make the environment an important determinant of subjective work-related outcomes like job satisfaction and well-being, as well as of objective outcomes like absenteeism or quality of care. In order to effectively build or renovate healthcare facilities, it is necessary to pay attention to the needs of both patients and healthcare personnel. OBJECTIVES: To assess the psychological effects of the physical healthcare environment on healthcare personnel. SEARCH STRATEGY: We searched the Cochrane EPOC Group Specialised Register; Cochrane Central Register of Controlled Trials; Database of Abstracts and Reviews of Effects; MEDLINE; EMBASE; CINAHL; Civil Engineering Database and Compendex. We also searched the reference lists of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCT), controlled clinical trials (CCT), controlled before and after studies (CBA), and interrupted time series (ITS) of psychological effects of the physical healthcare environment interventions for healthcare staff. The outcomes included measures of job satisfaction, satisfaction with the physical healthcare environment, quality of life, and quality of care. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed studies for eligibility, extracted data, and assessed methodological quality. MAIN RESULTS: We identified one study, which adopted a CBA study design to investigate the simultaneous effects of multiple environmental stimuli. Staff mood improved in this study, while no effects were found on ward atmosphere or unscheduled absences. AUTHORS' CONCLUSIONS: One study was included in this review. This review therefore indicates that, at present, there is insufficient evidence to support or refute the impact of the physical healthcare environment on work-related outcomes of healthcare staff. Methodological shortcomings, particularly confounding with other variables and the lack of adequate control conditions, partially account for this lack of evidence. Given these methodological issues, the field is in need of well-conducted controlled trials. PMID- 21249675 TI - Cognition-based interventions for healthy older people and people with mild cognitive impairment. AB - BACKGROUND: Evidence from some, but not all non-randomised studies suggest the possibility that cognitive training may influence cognitive functioning in older people. Due to the differences among cognitive training interventions reported in the literature, giving a general overview of the current literature remains difficult. OBJECTIVES: To systematically review the literature and summarize the effect of cognitive training interventions on various domains of cognitive function (ie memory, executive function, attention and speed) in healthy older people and in people with mild cognitive impairment. SEARCH STRATEGY: The CDCIG Specialized Register was searched on 30 September 2007 for all years up to December 2005. The Cochrane Library, MEDLINE, EMBASE, PsycINFO and CINAHL were searched separately on 30 September 2007 to find trials with healthy people. These results were supplemented by searches from January 1970 to September 2007 in PsychInfo/Psyndex, ISI Web of Knowledge and PubMed. SELECTION CRITERIA: RCTs of interventions evaluating the effectiveness of cognitive training for healthy older people and people with mild cognitive impairment from 1970 to 2007 that met inclusion criteria were selected. DATA COLLECTION AND ANALYSIS: Authors independently extracted data and assessed trial quality. Meta-analysis was performed when appropriate. MAIN RESULTS: Only data on memory training could be pooled for analysis. Within this domain, training interventions were grouped according to several outcome variables. Results showed that for healthy older adults, immediate and delayed verbal recall improved significantly through training compared to a no-treatment control condition. We did not find any specific memory training effects though as the improvements observed did not exceed the improvement in the active control condition. For individuals with mild cognitive impairment, our analyses demonstrate the same pattern. Thus, there is currently little evidence on the effectiveness and specificity of memory interventions for healthy older adults and individuals with mild cognitive impairment. AUTHORS' CONCLUSIONS: There is evidence that cognitive interventions do lead to performance gains but none of the effects observed could be attributable specifically to cognitive training, as the improvements observed did not exceed the improvement in active control conditions. This does not mean that longer, more intense or different interventions might not be effective, but that those which have been reported thus far have only limited effect. We therefore suggest more standardized study protocols in order to maximize comparability of studies and to maximize the possibility of data pooling - also in other cognitive domains than memory. PMID- 21249676 TI - Steam inhalation or humidified oxygen for acute bronchiolitis in children up to three years of age. AB - BACKGROUND: Acute bronchiolitis is a common respiratory infection and a major cause of morbidity in young children. It is treated with bronchodilators (for example, salbutamol), corticosteroids or humidified air (steam inhalation or cool mist). Steam inhalation is preferred in low-income countries as it is inexpensive and easily available. It is thought to act as a secretolytic agent to lighten secretions in the respiratory tract and relieve respiratory distress. OBJECTIVES: To evaluate the effect of steam inhalation or humidified oxygen to relieve respiratory distress and to evaluate adverse events in children up to three years old with acute bronchiolitis. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 1) which contains the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1950 to February Week 4, 2010), EMBASE.com (1974 to March 2010), CINAHL (1981 to March 2010), AMED (1985 to March 2010), Web of Science (2000 to March 2010) and LILACS (1982 to March 2010). SELECTION CRITERIA: Randomised controlled trials involving children up to three years old with bronchiolitis comparing steam inhalation (or cool mist) or humidified oxygen against bronchodilators, corticosteroids or placebo; alone or in combination. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: Only one study (156 children aged between seven weeks and 24 months with signs and symptoms of bronchiolitis) met the eligibility criteria for inclusion. Participants were randomised into three groups: nebulised salbutamol, nebulised saline and mist in a tent. The results showed a significant decrease in respiratory distress symptom (RDS) score in the nebulised salbutamol group but no significant decrease in the RDS score in the mist in a tent or nebulised saline groups. The study did not report on adverse effects of the interventions. AUTHORS' CONCLUSIONS: Steam inhalation (or cool mist therapy) is commonly used to treat acute bronchiolitis in resource-constrained settings. One study was eligible for inclusion and found that nebulised salbutamol was an effective intervention for young children with bronchiolitis but mist in a tent did not lead to a significant decrease in RDS score. Since only one study was analysed it would be misleading to conclude that mist therapy is ineffective in children with bronchiolitis. We conclude that there is insufficient evidence to inform practice regarding using steam inhalation or mist therapy for acute bronchiolitis in children up to three years old. PMID- 21249677 TI - The use of the exit interview to reduce turnover amongst healthcare professionals. AB - BACKGROUND: Exit interviews are widely used in healthcare organisations to identify reasons for staff attrition, yet their usefulness in limiting turnover is unclear. OBJECTIVES: To determine the effectiveness of various exit interview strategies in decreasing turnover rates amongst healthcare professionals. SEARCH STRATEGY: We used a comprehensive search strategy including an electronic search of the following databases: DARE, CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, ERIC (search date: 7 September 2010) and EPOC Specialised Register (search date: 30 September 2009). We also screened the reference lists of included studies and relevant reviews. SELECTION CRITERIA: Randomised controlled trials, controlled clinical trials, controlled before and after studies and interrupted time series studies comparing turnover rates between healthcare professionals who had undergone one form of exit interview with another form of exit interview or with no interview. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: The search identified 1560 citations of which we considered 19 potentially relevant. The two authors independently reviewed the abstracts of these studies and retrieved the full texts of eight studies. We excluded all eight following independent assessment. They were either interviews, commentaries on how to do an exit interview or descriptive studies about reasons for leaving. We found no trials that matched our inclusion criteria. AUTHORS' CONCLUSIONS: Evidence about the effectiveness of exit interviews to reduce turnover is currently not available. However, exit interviews may provide useful information about the work environment which, in turn, may be useful in the development of interventions to reduce turnover. PMID- 21249679 TI - Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer. AB - BACKGROUND: One of the most important adverse effects of anthracyclines is cardiotoxicity. A well-informed decision on the use of anthracyclines in the treatment of childhood cancers should be based on evidence regarding both antitumour efficacy and cardiotoxicity. OBJECTIVES: To compare antitumour efficacy of treatment including or not including anthracyclines in children with childhood cancer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 2), MEDLINE (1966 to March 2010) and EMBASE (1980 to March 2010). In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trials databases. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing treatment of any type of childhood cancer with and without anthracyclines and reporting outcomes concerning antitumour efficacy. DATA COLLECTION AND ANALYSIS: Two reviewers independently performed the study selection, risk of bias assessment and data extraction. MAIN RESULTS: We identified RCTs for six types of tumour: acute lymphoblastic leukaemia (ALL) (three trials; 912 children), Wilms' tumour (one trial; 316 children), rhabdomyosarcoma/undifferentiated sarcoma (one trial; 413 children), Ewing's sarcoma (one trial; 94 children), non-Hodgkin lymphoma (one trial; 284 children) and hepatoblastoma (one trial; 255 children). All studies had methodological limitations. For ALL no evidence of a significant difference in antitumour efficacy was identified in the meta-analyses, but in most individual studies there was a suggestion of better antitumour efficacy in patients treated with anthracyclines. For both Wilms' tumour and Ewing's sarcoma a significant difference in event-free and overall survival in favour of treatment with anthracyclines was identified, although for Wilms' tumour the significant difference in overall survival disappears with long-term follow-up. For rhabdomyosarcoma/undifferentiated sarcoma, non-Hodgkin lymphoma and hepatoblastoma no difference in antitumour efficacy between the treatment groups was identified. Clinical cardiotoxicity was evaluated in three RCTs: no significant difference between both treatment groups was identified, but in all individual studies there was a suggestion of a lower rate of clinical cardiotoxicity in patients who did not receive anthracyclines. None of the studies evaluated asymptomatic cardiac dysfunction. For other childhood cancers no RCTs were identified. AUTHORS' CONCLUSIONS: At the moment no evidence from RCTs is available which underscores the use of anthracyclines in ALL. However, "no evidence of effect", as identified in this review, is not the same as "evidence of no effect". For Wilms' tumour, rhabdomyosarcoma/undifferentiated sarcoma, Ewing's sarcoma, non-Hodgkin lymphoma and hepatoblastoma only one RCT was available and, therefore, no definitive conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours. For other childhood cancers no RCTs were identified and therefore, no conclusions can be made about the antitumour efficacy of treatment with or without anthracyclines in these tumours. PMID- 21249678 TI - Risperidone versus other atypical antipsychotics for schizophrenia. AB - BACKGROUND: In many countries of the industrialised world second-generation ("atypical") antipsychotics (SGAs) have become the first line drug treatment for people with schizophrenia. The question as to whether and if so how much the effects of the various SGAs differ is a matter of debate. In this review we examined how the efficacy and tolerability of risperidone differs from that of other SGAs. OBJECTIVES: To evaluate the effects of risperidone compared with other atypical antipsychotics for people with schizophrenia and schizophrenia like psychosis. SEARCH STRATEGY: 1. Electronic searching We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO.2. Reference searching We inspected the references of all identified studies for more trials.3. Personal contact We contacted the first author of each included study for missing information.4. Drug companies We contacted the manufacturers of all atypical antipsychotics included for additional data. SELECTION CRITERIA: We included all randomised, blinded trials comparing oral risperidone with oral forms of amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia like psychosis. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated risk ratio (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated mean differences (MD), again based on a random effects model. MAIN RESULTS: The review currently includes 45 blinded RCTs with 7760 participants. The number of RCTs available for each comparison varied: four studies compared risperidone with amisulpride, two with aripiprazole, 11 with clozapine, 23 with olanzapine, eleven with quetiapine, two with sertindole, three with ziprasidone and none with zotepine. Attrition from these studies was high (46.9%), leaving the interpretation of results problematic. Furthermore, 60% were industry sponsored, which can be a source of bias.There were few significant differences in overall acceptability of treatment as measured by leaving the studies early. Risperidone was slightly less acceptable than olanzapine, and slightly more acceptable than ziprasidone in this regard.Risperidone improved the general mental state (PANSS total score) slightly less than olanzapine (15 RCTs, n = 2390, MD 1.94 CI 0.58 to 3.31), but slightly more than quetiapine (9 RCTs, n = 1953, MD -3.09 CI -5.16 to -1.01) and ziprasidone (3 RCTs, n = 1016, MD -3.91 CI -7.55 to -0.27). The comparisons with the other SGA drugs were equivocal. Risperidone was also less efficacious than olanzapine and clozapine in terms of leaving the studies early due to inefficacy, but more efficacious than ziprasidone in the same outcome.Risperidone produced somewhat more extrapyramidal side effects than a number of other SGAs (use of antiparkinson medication versus clozapine 6 RCTs, n = 304, RR 2.57 CI 1.47 to 4.48, NNH 6 CI 33 to 3; versus olanzapine 13 RCTs, n = 2599, RR 1.28 CI 1.06 to 1.55, NNH 17 CI 9 to 100; versus quetiapine 6 RCTs, n = 1715, RR 1.98 CI 1.16 to 3.39, NNH 20 CI 10 to 100; versus ziprasidone 2 RCTs, n = 822, RR 1.42 CI 1.03 to 1.96, NNH not estimable; parkinsonism versus sertindole 1 RCT, n = 321, RR 4.11 CI 1.44 to 11.73, NNH 14 CI 100 to 8). Risperidone also increased prolactin levels clearly more than all comparators, except for amisulpride and sertindole for which no data were available.Other adverse events were less consistently reported, but risperidone may well produce more weight gain and/or associated metabolic problems than amisulpride (weight gain: 3 RCTs, n = 585, MD 0.99 CI 0.37 to 1.61), aripiprazole (cholesterol increase: 1 RCT, n = 83, MD 22.30 CI 4.91 to 39.69) and ziprasidone (cholesterol increase 2 RCTs, n = 767, MD 8.58 CI 1.11 to 16.04) but less than clozapine (weight gain 3 RCTs n = 373, MD -3.30 CI -5.65 to -0.95), olanzapine (weight gain 13 RCTs, n = 2116, MD -2.61 CI -3.74 to -1.48), quetiapine (cholesterol increase: 5 RCTs, n = 1433, MD -8.49 CI -12. 23 to -4.75) and sertindole (weight gain: 2 RCTs, n = 328, MD -0.99 CI -1.86 to -0.12). It may be less sedating than clozapine and quetiapine, lengthen the QTc interval less than sertindole (QTc change: 2 RCTs, n = 495, MD -18.60 CI -22.37 to 14.83), produce fewer seizures than clozapine (2 RCTs, n = 354, RR 0.22 CI 0.07 to 0.70, NNT 14 CI 8 to 33) and less sexual dysfunction in men than sertindole (2 RCTs, n = 437, RR 0.34 CI 0.16 to 0.76, NNT 13 CI 8 to 33). AUTHORS' CONCLUSIONS: Risperidone seems to produce somewhat more extrapyramidal side effects and clearly more prolactin increase than most other SGAs. It may also differ from other compounds in efficacy and in the occurrence of other adverse effects such as weight gain, metabolic problems, cardiac effects, sedation and seizures. Nevertheless, the large proportion of participants leaving studies early and incomplete reporting of outcomes makes it difficult to draw firm conclusions. Further large trials, especially comparing risperidone with those other new drugs for which only a few RCTs are available, are needed. PMID- 21249680 TI - Parenteral anticoagulation in patients with cancer who have no therapeutic or prophylactic indication for anticoagulation. AB - BACKGROUND: Anticoagulation may improve survival in patients with cancer through an antitumor effect in addition to the perceived antithrombotic effect. OBJECTIVES: To evaluate the efficacy and safety of parenteral anticoagulants in patients with cancer with no therapeutic or prophylactic indication for anticoagulation. SEARCH STRATEGY: A comprehensive search included (1) an electronic search (February 2010) of the following databases: Cochrane Central Register of Controlled Trials (CENTRAL) Issue 1, 2010, MEDLINE, EMBASE and ISI the Web of Science; (2) handsearch of conference proceedings; (3) checking of references of included studies; and (4) use of the 'related citation' feature in PubMed. SELECTION CRITERIA: Randomized controlled trials (RCTs) assessing the benefits and harms of parenteral anticoagulation in patients with cancer but no therapeutic or prophylactic indication for anticoagulation. DATA COLLECTION AND ANALYSIS: Using a standardized form we extracted in duplicate data on methodological quality, participants, interventions and outcomes of interest including all-cause mortality, symptomatic thromboembolism, major bleeding, minor bleeding and quality of life (QoL). MAIN RESULTS: Of 8187 identified citations, nine RCTs enrolling 2857 patients fulfilled the inclusion criteria. In all included RCTs the intervention consisted of heparin (either unfractionated heparin or low molecular weight heparin). Overall, the effect of heparin therapy on mortality was not statistically significant at 12 months (risk ratio (RR) 0.93; 95% CI 0.85 to 1.02) but it was statistically significant at 24 months (RR 0.92; 95% CI 0.88 to 0.97). Heparin therapy was associated with a statistically and clinically important reduction in venous thromboembolism (RR 0.55; 95% CI 0.37 to 0.82). There were no statistically significant effects on major bleeding (RR 1.30; 95% CI 0.59 to 2.88), minor bleeding (RR 1.05; 95% 0.75 to 1.46) or QoL. The quality of evidence was high for symptomatic venous thromboembolism, moderate for mortality, major bleeding and minor bleeding, and low for QoL. AUTHORS' CONCLUSIONS: Heparin was associated with a significant reduction of death at 24 months but not 12 months. It was also associated with a reduction in venous thromboembolism but based on the RCTs in this review it had no significant effect on major bleeding, minor bleeding or QoL. Future research should further investigate the survival benefit of different types of anticoagulants in patients with different types and stages of cancer. The decision for a patient with cancer to start heparin therapy for survival benefit should balance the benefits and downsides and integrate the patient's values and preferences. PMID- 21249681 TI - Duration of intravenous antibiotic therapy in people with cystic fibrosis. AB - BACKGROUND: Respiratory disease is the major cause of mortality and morbidity in cystic fibrosis (CF). Life expectancy of people with CF has increased dramatically in the last 40 years. One of the major reasons for this increase is the mounting use of antibiotics to treat chest exacerbations caused by bacterial infections. The optimal duration of intravenous antibiotic therapy is not clearly defined. Individuals usually receive intravenous antibiotics for 14 days, but treatment may range from 10 to 21 days. A shorter duration of antibiotic treatment risks inadequate clearance of infection which could lead to further lung damage. Prolonged courses of intravenous antibiotics are expensive and inconvenient and the incidence of allergic reactions to antibiotics also increases with prolonged courses. The use of aminoglycosides requires frequent monitoring to avoid some of their side effects. However, some organisms which infect people with CF are known to be multi-resistant to antibiotics, and may require a longer course of treatment. OBJECTIVES: To assess the optimal duration of intravenous antibiotic therapy for treating chest exacerbations in people with cystic fibrosis. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals, abstract books and conference proceedings.Most recent search of the Group's Cystic Fibrosis Trials Register: 3 December 2010. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials comparing different durations of intravenous antibiotic courses for acute respiratory exacerbations in people with CF, either with the same drugs at the same dosage, the same drugs at a different dosage or frequency or different antibiotics altogether, including studies with additional therapeutic agents. DATA COLLECTION AND ANALYSIS: No eligible trials were identified. MAIN RESULTS: No eligible trials were identified. AUTHORS' CONCLUSIONS: There are no clear guidelines on the optimum duration of intravenous antibiotic treatment. Duration of treatment is currently based on unit policies and response to treatment. Shorter duration of treatment should improve quality of life and compliance; result in a reduced incidence of drug reactions; and be less costly. However, this may not be sufficient to clear a chest infection and may result in an early recurrence of an exacerbation. This systematic review identifies the need for a multicentre, randomised controlled trial comparing different durations of intravenous antibiotic treatment as it has important clinical and financial implications. PMID- 21249683 TI - Three dimensional versus two dimensional imaging for laparoscopic cholecystectomy. AB - BACKGROUND: The benefits and harms of three dimensional imaging versus traditional two dimensional imaging for laparoscopic cholecystectomy are not known. OBJECTIVES: To assess the benefits and harms of use of three dimensional systems versus two dimensional systems during laparoscopic cholecystectomy. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until October 2010 for randomised clinical trials. SELECTION CRITERIA: Only randomised clinical trials, irrespective of language, blinding, or publication status were considered for the review. DATA COLLECTION AND ANALYSIS: Two authors independently identified trials and independently extracted data. We intended to calculate the risk ratio (RR), mean difference (MD), or standardised mean difference (SMD) with 95% confidence intervals (CI) using both the fixed-effect and the random-effects models with RevMan 5 based on intention-to-treat analysis. MAIN RESULTS: One trial randomised 60 patients to three dimensional laparoscopic cholecystectomy (n = 30) versus standard two dimensional laparoscopic cholecystectomy (n = 30). This trial was of high risk of bias. There were no post operative complications or conversion to open cholecystectomy in either group. There was no significant difference in the operating time (MD -1.00 minute; 95% CI -17.77 to 15.77) or number of errors between the two groups. AUTHORS' CONCLUSIONS: Currently, there is no evidence that three dimensional image is superior to two dimensional image in laparoscopic cholecystectomy. PMID- 21249682 TI - Adjuvant radiotherapy and/or chemotherapy after surgery for uterine carcinosarcoma. AB - BACKGROUND: Uterine carcinosarcomas are uncommon with about 35% not confined to the uterus at diagnosis. The survival of patients with advanced uterine carcinosarcoma is poor with pattern of failure indicating greater likelihood of upper abdominal and distant metastatic recurrence. OBJECTIVES: To evaluate the effectiveness and safety of radiotherapy and/or systemic chemotherapy in the management of stage III-IV persistent or recurrent uterine carcinosarcoma. SEARCH STRATEGY: We searched the Cochrane Gynaecological Cancer Group Trials Register, CENTRAL, The Cochrane Library 2010, Issue 2, MEDLINE and EMBASE to May 2010. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials comparing adjuvant radiotherapy and/or chemotherapy in women with uterine carcinosarcoma. DATA COLLECTION AND ANALYSIS: We independently abstracted data and assessed risk of bias. We pooled hazard ratios (HRs) for overall and progression-free survival and risk ratios (RRs) comparing adverse events in women who received radiotherapy and/or chemotherapy in meta-analyses. MAIN RESULTS: Three trials (579 women, of whom all were assessed at the end of the trials) met the inclusion criteria. Two trials (373 women with stage III-IV persistent or recurrent disease) found that women who received combination therapy had a significantly lower risk of death and disease progression than women who received single agent ifosfamide. There was no statistically significant difference in all reported adverse events, with the exception of nausea and vomiting, which affected significantly more women in the combination therapy group than in the ifosamide group.One trial found no statistically significant difference in the risk of death and disease progression in women who received whole abdominal irradiation and chemotherapy, after adjustment for age and FIGO stage (HR = 0.71, 95% CI 0.48 to 1.05 and HR = 0.79, 95% CI 0.53 to 1.18 for overall survival and progression-free survival respectively). There was no statistically significant difference in all reported adverse events, with the exception of haematological and neuropathy morbidities, which affected significantly fewer women in the whole body irradiation group than in the chemotherapy group (RR = 0.02, 95% CI 0.00 to 0.16). AUTHORS' CONCLUSIONS: The results of this review are limited to two trials. In the primary treatment/ first line therapy of advanced stage metastatic uterine carcinosarcoma, as well as in recurrent disease, adjuvant combination chemotherapy with ifosfamide and paclitaxel should be considered. None of the included studies reported on quality of life. PMID- 21249684 TI - Laparoscopic versus Open surgery for small bowel Crohn's disease. AB - BACKGROUND: Crohn's disease (CD) is a chronic inflammatory bowel disease that most commonly involves the terminal ileum and colon (55 percent). Surgical treatment is required in approximately 70 percent of patients. Multiple procedures and repeat operations are required in 30 - 70 percent of all patients (Duepree 2002) but the disease remains incurable.Laparoscopy has gained wide acceptance in gastrointestinal surgery with potential advantages of faster return to normal activity and diet, reduced hospital stay, reduced postoperative pain, better cosmesis (Duepree 2002, Dunker 1998, Milsom 2001, Reissman 1996), improved social and sexual interaction (Albaz 2000) and its use is accepted in benign and malignant colorectal diseases. Laparoscopic surgery offers additional advantage of smaller abdominal fascial wounds, low incidence of hernias, and decreased rate of adhesive small-bowel obstruction (Albaz 2000) compared with conventional surgery reducing the need for non-disease-related surgical procedures in CD population.There are concerns about missing occult segments of disease and critical proximal strictures due to limited tactile ability, earlier recurrence due to possible reduced immune response induced by laparoscopy, technical difficulty due to fragile inflamed bowel and mesentery and the existence of adhesions, fistulas, and abscesses (Uchikoshi 2004). It is therefore important to evaluate the potential benefits and risks of laparoscopic surgery versus open surgery in patients with small bowel CD (Lowney 2005). OBJECTIVES: To determine if there is a difference in the perioperative outcomes and re-operation rates for disease recurrence following laparoscopic surgery compared to open surgery in small bowel CD. SEARCH STRATEGY: Published and unpublished randomised controlled trials were searched for in the following electronic databases: The Cochrane Central Register of Controlled Trials (CENTRAL) 2010 issue 2 The Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects (DARE) 2010 issue 2 The Cochrane Colorectal Cancer Group Controlled Trials Register Ovid MEDLINE (1990 to 2010) EMBASE (1990 to 2010) Health Technology Assessment (HTA) Database (1990 to 2010) SELECTION CRITERIA: Randomised controlled trials (RCT) comparing laparoscopic and open surgery for small bowel CD were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the studies and extracted data. RevMan 5.0 was used for statistical analysis. MAIN RESULTS: Two RCTs comparing laparoscopic and open surgery for small bowel CD were identified. Long term outcomes of the patients in both the trials were published separately and these were included in the review.Laparoscopic surgery appeared to be associated with reduced number of wound infections (1/61 vs 9/59), reoperation rates for non disease related complications (3/57 vs 7/54 ) but the difference was not statistically significant [p values were 0.23 and 0.19 respectively]. There was no statistically significant difference between any of the compared outcomes between laparoscopic and open surgery in the management of small bowel CD. AUTHORS' CONCLUSIONS: Laparoscopic surgery for small bowel CD may be as safe as the open operation. There was no significant difference in the perioperative outcomes and the long term reoperation rates for disease-related or non-disease related complications of CD. PMID- 21249685 TI - Cycled light in the intensive care unit for preterm and low birth weight infants. AB - BACKGROUND: The potential benefits and harms of different lighting in neonatal units have not been quantified. OBJECTIVES: To compare the effectiveness of cycled lighting (CL) (approximately 12 hours of light on and 12 hours of light off) with irregularly dimmed light or near darkness (ND) and with continuous bright light (CBL) on growth in preterm infants at three and six months of age. SEARCH STRATEGY: Electronic searches of the literature were conducted (in May 2010) of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, CINAHL and abstracts from Pediatric Academic Societies' annual meetings. SELECTION CRITERIA: Randomised or quasi-randomised trials of CL versus ND or CBL in preterm and low birth weight infants. DATA COLLECTION AND ANALYSIS: Data collection and analyses were performed according to the methods of the Cochrane Neonatal Review Group. MAIN RESULTS: Five studies enrolling 387 infants compared CL to ND. No study reported on weight at three or six months. In one study (n = 40) there was no statistically significant difference in weight at four months between the CL and the ND groups. In another study (n = 62) the ratio of day-night activity prior to discharge favoured the CL group (mean difference 0.18, 95% CI 0.17 to 0.19) indicating 18% more activity during day than night in the CL group compared to the ND group. Two studies (n = 189) reported on retinopathy of prematurity (stage >= 3). There was no statistically significant difference between the CL and ND groups (typical RR 0.53, 95% CI 0.25 to 1.11, I(2) = 0%; typical RD -0.09, 95% CI -0.19 to 0.01, I(2) = 0%).Two studies enrolling 82 infants compared CL to CBL. One study (n = 41) reported higher mean weight at three months corrected age in infants cared for in the CL nursery (P < 0.02) and lower mean number of hours spent awake in 24 hours at three months (P < 0.005). In one study (n = 41) days on a ventilator were reduced in the CL group (mean difference -18, 95% CI -31 to -5 days).For many outcomes the trends favoured CL versus ND as well as CL versus CBL. AUTHORS' CONCLUSIONS: Trials assessing the effect of CL have enrolled 469 infants. Trends for many outcomes favoured cycled light (CL) compared to near darkness (ND) and CL compared to continuous bright light (CBL) The studies may have lacked significance due to a lack of statistical power. Future research should focus on comparing CL to ND. PMID- 21249686 TI - Factor Xa inhibitors for acute coronary syndromes. AB - BACKGROUND: The activation of coagulation mechanisms plays a central role in the pathogenesis of acute coronary syndromes (ACS). Administration of unfractionated heparin (UFH) and low molecular weight heparins (LMWH), agents preventing the progression of thrombus formation, is a crucial therapeutic strategy. However, some limitations related to their use have recently stimulated the development of new synthetic agents. OBJECTIVES: To evaluate the clinical efficacy and safety of factor Xa inhibitors for treatment of ACS compared to UFH or LMWH. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) of the Cochrane Library (Issue 1, 2008), PubMed, EMBASE and LILACS as well as the publications from International Congresses and the reference lists of the selected studies in December 2008. SELECTION CRITERIA: We used randomized controlled trials (RCTs) comparing factor Xa inhibitors to UFH or LMWH during the course of ACS. Outcome measures included all-cause mortality, myocardial infarction, re-infarction, ischemia recurrence, and adverse events. DATA COLLECTION AND ANALYSIS: The selection, quality assessment and data extraction of the included trials were done independently by two authors and disagreements were resolved by consensus. Data were analysed by the use of risk ratio (RR) with 95% confidence interval (CI), and the numbers needed to treat (NNT) were reported as needed. MAIN RESULTS: A total of four RCTs involving 27,976 subjects were included. Fondaparinux was the only factor Xa inhibitor identified in our included RCTs. Fondaparinux appeared to be related to a lower risk in all-cause mortality at 90 to 180 days (RR 0.89; 95% CI 0.81 to 0.97), especially in the group where enoxaparin (a LMWH) was the control drug. Fondaparinux was also associated with a lower risk in major and minor bleeding at 30 days compared to enoxaparin (RR 0.63, 95% CI 0.55 to 0.73; RR 0.34, 95% CI 0.28 to 0.43, respectively), but not when compared to UFHs (RR 1.41; 95% CI 0.49 to 4.10; RR 0.70, 95% CI 0.14 to 3.39 respectively). AUTHORS' CONCLUSIONS: The therapeutic efficacy of factor Xa inhibitors in ACS seemed to be related to a reduced risk in all-cause mortality at 90 to 180 days, with a better safety profile than enoxaparin in terms of reduce incidence of major and minor bleeding. PMID- 21249687 TI - Anti-inflammatory medications for obstructive sleep apnea in children. AB - BACKGROUND: Obstructive sleep apnea (OSA) is characterized by partial or complete upper airway obstruction during sleep. Approximately 1% to 4% of children are affected by OSA, with adenotonsillar hypertrophy the most common underlying risk factor. Surgical removal of enlarged tonsils and adenoids is the most commonly used treatment for OSA. Given the perioperative risk of the intervention and an estimated recurrence rate of up to 20%, there has recently been an increased interest in non-surgical treatment modalities. As the enlarged adenoids and tonsils consist of hypertrophied lymphoid tissue, anti-inflammatory agents have been proposed as a useful non-invasive treatment option in children with OSA. OBJECTIVES: To assess the efficacy of anti-inflammatory drugs for the treatment of OSA in children. SEARCH STRATEGY: We identified trials using searches of the Cochrane Airways Group Specialized Register, MEDLINE (1950 to 2010), EMBASE (1988 to 2010), CINAHL (1982 to 2010), CENTRAL (1964 to 2010), Web of Science (1900 to 2010), LILACS (1982 to 2010) and International Pharmaceutical Abstracts (IPA) (1970 to 2010). SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing anti-inflammatory drugs against placebo, other anti-inflammatory drugs, or other treatment in children between one and 16 years with objectively diagnosed OSA (Apnea Hypopnea Index (AHI) >= 1/hour (h)). DATA COLLECTION AND ANALYSIS: Both authors independently performed data extraction and quality assessment. It was not possible to combine data from the included studies; we summarized data in a narrative fashion. MAIN RESULTS: We included three RCTs. The first study was a six-week parallel-group trial (25 participants, mean age 3.8 years, mean AHI 10.8/h) of intranasal fluticasone versus placebo showed a statistically significant effect of the drug on improving the AHI. The second study compared intranasal budesonide with placebo in a six-week cross-over trial (62 participants, mean age 8.2 years, mean AHI 3.7/h). The authors reported an advantage of the drug over placebo in reducing the AHI. However, the patients were not analyzed as randomized so the result must be interpreted with caution. No valid group comparisons were reported for the third trial (30 participants, oral montelukast versus placebo in a 12-week parallel-group trial), which has so far only been published as an abstract. AUTHORS' CONCLUSIONS: A single small study has found a short-term beneficial effect on the AHI in children with mild to moderate OSA. However, long-term safety and efficacy data are not available yet. Further RCTs are needed to evaluate anti-inflammatory drugs for OSA in children. PMID- 21249688 TI - Endonasal versus external dacryocystorhinostomy for nasolacrimal duct obstruction. AB - BACKGROUND: Dacryocystorhinostomy (DCR) procedures can be performed using external or endonasal approaches. The comparative success rates of these procedures are unknown. OBJECTIVES: To compare the success rates of external and endonasal approaches to DCR. SEARCH STRATEGY: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2010, Issue 11), MEDLINE (January 1950 to December 2010), EMBASE (January 1980 to December 2010), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to December 2010), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) (December 2010), ClinicalTrials.gov (www.clinicaltrials.gov) (December 2010) and Web of Science Conference Proceedings Citation Index- Science (CPCI-S) (January 1990 to December 2010). There were no language or date restrictions in the search for trials. The electronic databases were last searched on 7 December 2010. We requested or examined relevant conference proceedings for appropriate trials. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing external and endonasal dacryocystorhinostomies. DATA COLLECTION AND ANALYSIS: Two review authors independently performed data extraction and assessment of quality with a predefined form. We contacted investigators to clarify the methodological quality of the studies. MAIN RESULTS: We identified one trial that fulfilled the inclusion criteria. This trial compared 64 DCR procedures (32 external and 32 endonasal procedures). Endonasal DCR was four times more likely to fail compared to external DCR. This was statistically significant (95% confidence interval (CI) 1.25 to 12.84). AUTHORS' CONCLUSIONS: The only trial included in the review provides evidence that endonasal DCR has statistically higher risk of failure compared to external DCR. However, this conclusion is limited by paucity of RCTs, small number of participants and lack of clarity of the methodological process. Well conducted RCTs with sufficient power are required to answer the research question. PMID- 21249689 TI - Mechanical versus manual chest compressions for cardiac arrest. AB - BACKGROUND: Mechanical chest compression devices have been proposed to improve the effectiveness of cardiopulmonary resuscitation (CPR). OBJECTIVES: To assess the effectiveness of mechanical chest compressions versus standard manual chest compressions with respect to neurologically intact survival in patients who suffer cardiac arrest. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Studies (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, Science Citation abstracts, Biotechnology and Bioengineering abstracts and Clinicaltrials.gov in November 2009. No language restrictions were applied. Experts in the field of mechanical chest compression devices and manufacturers were contacted. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster RCTs and quasi-randomised studies comparing mechanical chest compressions to manual chest compressions during CPR for patients with atraumatic cardiac arrest. DATA COLLECTION AND ANALYSIS: Two authors (SCB and LJM) abstracted data independently. Disagreement between reviewers was resolved by consensus and a third author (BB) if consensus could not be reached. The methodologies of selected studies were evaluated for risk of bias by a single author (SCB). The primary outcome was survival to hospital discharge with good neurologic outcome. We used the DerSimonian & Laird method (random-effects model) to provide a pooled estimate for relative risk with 95% confidence intervals. MAIN RESULTS: Four trials, including data from 868 patients, were included in the review. The overall quality of included studies was poor and significant clinical heterogeneity was observed. Only one study (N = 767) reported survival to hospital discharge with good neurologic function (as defined as a Cerebral Performance Category score of 1 or 2), demonstrating reduced survival with mechanical chest compressions when compared with manual chest compressions (RR 0.41 (95% CI 0.21- 0.79). Data from other studies included in this review were used to calculate relative risks for having a return of spontaneous circulation (2 studies, N = 51, pooled RR 2.81, 95% CI 0.96 to 8.22) and survival to hospital admission (1 study, N = 17, RR 4.13, 95% CI 0.19 to 88.71) in patients who received mechanical chest compressions versus those who received manual chest compressions. AUTHORS' CONCLUSIONS: There is insufficient evidence from human RCTs to conclude that mechanical chest compressions during cardiopulmonary resuscitation for cardiac arrest is associated with benefit or harm. Widespread use of mechanical devices for chest compressions during cardiac is not supported by this review. More RCTs that measure and account for CPR process in both arms are needed to clarify the potential benefit from this intervention. PMID- 21249690 TI - Antioxidants for male subfertility. AB - BACKGROUND: Between 30% to 80% of male subfertility cases are considered to be due to the damaging effects of oxidative stress on sperm. Oral supplementation with antioxidants may improve sperm quality by reducing oxidative stress. OBJECTIVES: This Cochrane review aimed to evaluate the effect of oral supplementation with antioxidants for male partners of couples undergoing assisted reproduction techniques (ART). SEARCH STRATEGY: We searched the Cochrane Menstrual Disorders and Subfertility Group Register, CENTRAL (The Cochrane Library), MEDLINE, EMBASE, CINAHL, PsycINFO and AMED databases (from their inception until Febuary 2010), trial registers, sources of unpublished literature, reference lists and we asked experts in the field. SELECTION CRITERIA: We included randomised controlled trials comparing any type or dose of antioxidant supplement (single or combined) taken by the male partner of a couple seeking fertility assistance with placebo, no treatment or another antioxidant. The outcomes were live birth, pregnancy, miscarriage, stillbirth, sperm DNA damage, sperm motility, sperm concentration and adverse effects. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and trial quality, and extracted data. MAIN RESULTS: We included 34 trials with 2876 couples in total. Live birth: three trials reported live birth. Men taking oral antioxidants had an associated statistically significant increase in live birth rate (pooled odds ratio (OR) 4.85, 95% CI 1.92 to 12.24; P = 0.0008, I(2) = 0%) when compared with the men taking the control. This result was based on 20 live births from a total of 214 couples in only three studies.Pregnancy rate: there were 96 pregnancies in 15 trials including 964 couples. Antioxidant use was associated with a statistically significant increased pregnancy rate compared to control (pooled OR 4.18, 95% CI 2.65 to 6.59; P < 0.00001, I(2) = 0%).Side effects: no studies reported evidence of harmful side effects of the antioxidant therapy used. AUTHORS' CONCLUSIONS: The evidence suggests that antioxidant supplementation in subfertile males may improve the outcomes of live birth and pregnancy rate for subfertile couples undergoing ART cycles. Further head to head comparisons are necessary to identify the superiority of one antioxidant over another. PMID- 21249692 TI - Laparoscopy for the management of acute lower abdominal pain in women of childbearing age. AB - BACKGROUND: Acute lower abdominal pain is common and making a diagnosis is particularly challenging in premenopausal woman as ovulation and menstruation symptoms overlap with the symptoms of appendicitis and pelvic infection. A management strategy involving early laparoscopy could potentially provide a more accurate diagnosis, earlier treatment and reduced risk of complications. OBJECTIVES: To evaluate the effectiveness and harms of laparoscopy for the management of acute lower abdominal pain in women of childbearing age. SEARCH STRATEGY: The Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, PsycINFO, LILACS and CINHAL were searched (to April 2010). SELECTION CRITERIA: Randomised controlled trials (RCTs) that included women of childbearing age who presented with acute lower abdominal pain, nonspecific lower abdominal pain or suspected appendicitis were included. DATA COLLECTION AND ANALYSIS: Data from studies that met the inclusion criteria were independently extracted by two authors and the risk of bias assessed. MAIN RESULTS: Laparoscopy was compared with open appendicectomy in eight RCTs. Laparoscopy was associated with an increased rate of specific diagnoses (7 RCTs, 561 participants; OR 4.10, 95% CI 2.50 to 6.71; I(2) 18%) but there was no evidence of reduced rate for any adverse event (8 RCTs, 623 participants; OR 0.46, 95% CI 0.19 to 1.10; I(2) 0%).Laparoscopic diagnosis versus a 'wait and see' strategy was investigated in four RCTs. There was a significant difference favouring laparoscopy in the rate of specific diagnoses (4 RCTs, 395 participants; OR 6.07, 95% CI 1.85 to 29.88; I(2) 79%) but there was no evidence of a difference in the rates of adverse events (OR 0.87, 95% CI 0.45 to 1.67; I(2) 0%). AUTHORS' CONCLUSIONS: The advantages of laparoscopy in women with nonspecific abdominal pain and suspected appendicitis include a higher rate of specific diagnoses being made and a lower rate of removal of normal appendices compared to open appendicectomy only. Hospital stays were shorter. There was no evidence of an increase in adverse events with any of the strategies. PMID- 21249691 TI - Interventions to modify sexual risk behaviours for preventing HIV in homeless youth. AB - BACKGROUND: Homeless youth are at high risk for HIV infection as a consequence of risky sexual behaviour. Interventions for homeless youth are challenging. Assessment of the effectiveness of interventions to modify sexual risk behaviours for preventing HIV in homeless youth is needed. OBJECTIVES: To evaluate and summarize the effectiveness of interventions for modifying sexual risk behaviours and preventing transmission of HIV among homeless youth. SEARCH STRATEGY: We searched electronic databases (CENTRAL, MEDLINE, EMBASE, AIDSearch, Gateway, PsycInfo, LILACS), reference lists of eligible articles, international health agency publication lists, and clinical trial registries. The search was updated January 2010. We contacted authors of published reports and other key role players. SELECTION CRITERIA: Randomised studies of interventions to modify sexual risk behaviour (biological, self-reporting of sexual-risk behaviour or health seeking behaviour) in homeless youth (12-24 years). DATA COLLECTION AND ANALYSIS: Data from eligible studies were extracted by two reviewers. We assessed risk of bias per the Cochrane Collaborations tool. None of the eligible studies reported any primary biological outcomes for this review. Reports of self-reporting sexual risk behaviour outcomes varied across studies precluding calculation of summary measures of effect; we present the outcomes descriptively for each study. We contacted authors for missing or ambiguous data. MAIN RESULTS: We identified three eligible studies after screening a total of 255 unique records. All three were performed in the United States of America and recruited substance-abusing male and female adolescents (total N=615) through homeless shelters into randomised controlled trials of independent and non-overlapping behavioural interventions. The three trials differed in theoretical background, delivery method, dosage (number of sessions,) content and outcome assessments. Overall, the variability in delivery and outcomes precluded estimation of summary of effect measures. We assessed the risk of bias to be high for each of the studies. Whilst some effect of the interventions on outcome measures were reported, heterogeneity and lack of robustness in these studies necessitate caution in interpreting the effectiveness of these interventions. AUTHORS' CONCLUSIONS: The body of evidence does not permit conclusions on the impact of interventions to modify sexual risk behaviour in homeless youth; more research is required. While the psychosocial and contextual factors that fuel sexual risk behaviours among homeless youth challenge stringent methodologies of RCT's, novel ways for program delivery and trial retention are in need of development. Future trials should comply with rigorous methodology in design, delivery, outcome measurement and reporting. PMID- 21249693 TI - Tocolysis for management of retained placenta. AB - BACKGROUND: Retained placenta affects 0.5% to 3% of women following delivery, with considerable morbidity if left untreated. Use of tocolytics, either alone or in combination with uterotonics, may be of value to minimise the need for manual removal of the placenta in theatre under anaesthesia. OBJECTIVES: Evaluate the benefits and harms of tocolytics alone or in addition to uterotonics in the management of retained placenta in order to reduce the need for manual removal of placenta. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 October 2010) and contacted experts in the field. SELECTION CRITERIA: Any adequately randomised controlled trial (RCT) comparing the use of tocolytics, either alone or in combination with uterotonics, with no intervention or with other interventions in the management of retained placenta. All women having a vaginal delivery with a retained placenta, regardless of the management of the third stage of labour (expectant or active). We included all trials with haemodynamically stable women in whom the placenta was not delivered at least within 15 minutes after delivery of the baby. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Consultation of the third author was done if needed. MAIN RESULTS: We included one RCT (involving 24 women). It compared the use of nitroglycerin tablets versus placebo after the treatment with oxytocin failed. There was a statistically significant reduction in the need for manual removal of placenta (risk ratio (RR) 0.04, 95% confidence interval (CI) 0.00 to 0.66). There was also a statistically significant reduction in mean blood loss during the third stage of labour (mean difference (MD) -262.50 ml, 95% CI -364.95 to -160.05). Sublingual nitroglycerin caused some haemodynamic changes as it lowers the systolic blood pressure and diastolic blood pressure by a means of 6 and 5 mmHg respectively. Pulse rate increased by a mean of two beats per minute. AUTHORS' CONCLUSIONS: Sublingual nitroglycerin, given when oxytocin fails, seems to reduce both the need for manual removal of placenta and blood loss during the third stage of labour when compared to placebo. Further trials are needed to confirm its clinical role and safety. Its routine use cannot be recommended based on a single small study. There is no evidence available for other types of tocolytics. PMID- 21249694 TI - Acupuncture for cancer pain in adults. AB - BACKGROUND: Forty percent of individuals with early or intermediate stage cancer and 90% with advanced cancer have moderate to severe pain and up to 70% of patients with cancer pain do not receive adequate pain relief. It has been claimed that acupuncture has a role in management of cancer pain and guidelines exist for treatment of cancer pain with acupuncture. OBJECTIVES: To evaluate efficacy of acupuncture for relief of cancer-related pain in adults. SEARCH STRATEGY: CENTRAL, MEDLINE, EMBASE, PsycINFO, AMED, and SPORTDiscus were searched up to November 2010 including non-English language papers. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating any type of invasive acupuncture for pain directly related to cancer in adults of 18 years or over. DATA COLLECTION AND ANALYSIS: It was planned to pool data to provide an overall measure of effect and to calculate the number needed to treat to benefit, but this was not possible due to heterogeneity. Two review authors (CP, OT) independently extracted data adding it to data extraction sheets. Quality scores were given to studies. Data sheets were compared and discussed with a third review author (MJ) who acted as arbiter. Data analysis was conducted by CP, OT and MJ. MAIN RESULTS: Three RCTs (204 participants) were included. One high quality study investigated the effect of auricular acupuncture compared with auricular acupuncture at 'placebo' points and with non-invasive vaccaria ear seeds attached at 'placebo' points. Participants in two acupuncture groups were blinded but blinding wasn't possible in the ear seeds group because seeds were attached using tape. This may have biased results in favour of acupuncture groups. Participants in the real acupuncture group had lower pain scores at two month follow-up than either the placebo or ear seeds group.There was high risk of bias in two studies because of low methodological quality. One study comparing acupuncture with medication concluded that both methods were effective in controlling pain, although acupuncture was the most effective. The second study compared acupuncture, point-injection and medication in participants with stomach cancer. Long-term pain relief was reported for both acupuncture and point injection compared with medication during the last 10 days of treatment. Although both studies have positive results in favour of acupuncture they should be viewed with caution due to methodological limitations, small sample sizes, poor reporting and inadequate analysis. AUTHORS' CONCLUSIONS: There is insufficient evidence to judge whether acupuncture is effective in treating cancer pain in adults. PMID- 21249695 TI - Cisapride for intestinal constipation. AB - BACKGROUND: Cisapride is a propulsive agent, withdrawn from most of the world's health institutes because of its recorded fatalities in addition to serious side effects such as severe arrhythmias. However it is widely available in third world countries and can be easily purchased through the Internet. We did a systematic review to assess its efficacy and safety in relieving constipation. OBJECTIVES: The primary objective is to assess Cisapride's role and safety as a prokinetic drug in the management of constipation and constipation predominant Irritable bowel syndrome (C-IBS).The secondary objective is to assess Cisapride's efficacy in improving symptoms of constipation and IBS. SEARCH STRATEGY: Cochrane methodology was followed to find available RCTs that assessed the efficacy of cisapride. Electronic databases searched November 2009:Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library 2009 issue 4MEDLINE (from 1966)EMBASE (from 1980) SELECTION CRITERIA: All RCTs comparing cisapride to placebo or to active comparators were included. We included patients of all ages who had functional constipation or C-IBS. DATA COLLECTION AND ANALYSIS: Eight RCTs were included, comparing cisapride to a placebo on patients with constipation or C-IBS. The studies were pooled and analysed and a combined effect was calculated using meta-analysis. MAIN RESULTS: 8 trials included in the review for a total 424 patients who were randomised to Cisapride or placebo, of which 157 were children and 284 were female. Intervention duration was 8 to 12 weeks. Dosage of Cisapride in the adult and children trials were 5mg TDS and 0.2mg/kg/dose TDS respectively.Cisapride showed significant benefit in investigators' assessment of clinical improvement (OR: 0.45, P=0.03), likelihood of passing daily stools (OR: 0.22, P<0.001), passage of normal stools (OR: 0.06, P<0.001) and total gastrointestinal transit time (MD: -19.47, P<0.00001). However Cisapride showed no benefit in global improvement of symptoms (MD: 0.11, P=0.99), abdominal pain (MD: 1.94, P=0.56), stool frequency: weekly (MD: 3.36, P=0.11), visual analogue scale (MD: -0.23, P=0.66), stool consistency (MD: 0.32, P=0.50), bloating (MD: 3.93, P=0.44), persistent bloating(OR: 1.11, P=0.83), 'feeling of incomplete evacuation' (MD: -3.80, P=0.08), straining (MD -0.95, p=0.19). AUTHORS' CONCLUSIONS: No clear benefit can be demonstrated with cisapride. We do not feel that cisapride can be justifiably used for chronic constipation or irritable bowel disease given its side effects of arrhythmia and associated 175 recorded deaths. PMID- 21249696 TI - Heated CO(2) with or without humidification for minimally invasive abdominal surgery. AB - BACKGROUND: Intraoperative hypothermia during both open and laparoscopic abdominal surgery may be associated with adverse events. For laparoscopic abdominal surgery, the use of heated insufflation systems for establishing pneumoperitoneum has been described to prevent hypothermia. Humidification of the insufflated gas is also possible. Past studies have shown inconclusive results with regards to maintenance of core temperature and reduction of postoperative pain and recovery times. OBJECTIVES: To determine the effect of heated gas insufflation on patient outcomes following minimally invasive abdominal surgery. SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE (PubMed), EMBASE, International Pharmaceutical Abstracts (IPA), Web of Science, Scopus, www.clinicaltrials.gov and the National Research Register were searched (1956 to 14 June 2010). Grey literature and cross references were also searched. Searches were limited to human studies without language restriction. SELECTION CRITERIA: All included studies were randomized trials comparing heated (with or without humidification) gas insufflation with cold gas insufflation in adult and pediatric populations undergoing minimally invasive abdominal procedures. Study quality was assessed in regards to relevance, design, sequence generation, allocation concealment, blinding, possibility of incomplete data and selective reporting. The selection of studies for the review was done independently by two authors, with any disagreement resolved in consensus with a third co-author. DATA COLLECTION AND ANALYSIS: Screening of eligible studies, data extraction and methodological quality assessment of the trials were performed by the authors. Data from eligible studies were collected using data sheets. Results were presented using mean differences for continuous outcomes and relative risks with 95% confidence intervals for dichotomous outcomes. The estimated effects were calculated using the latest version of RevMan software. Publication bias was taken into consideration and funnel plots were compiled. MAIN RESULTS: Sixteen studies were included in the analysis. During laparoscopic abdominal surgery, no effect on postoperative pain nor changes in core temperature, morphine consumption, length of hospitalisation, lens fogging, length of operation or recovery room stay were associated with heated compared to cold gas insufflation with or without humidification. AUTHORS' CONCLUSIONS: The study offers evidence that during laparoscopic abdominal surgery, heated gas insufflation, with or without humidification, has minimal benefit on patient outcomes. PMID- 21249697 TI - Acupuncture for primary dysmenorrhoea. AB - BACKGROUND: This review examined the currently available evidence supporting the use of acupuncture to treat primary dysmenorrhoea. OBJECTIVES: To determine the efficacy and safety of acupuncture in the treatment of primary dysmenorrhoea when compared with a placebo, no treatment, or conventional medical treatment (for example oral contraceptives and non-steroidal anti-inflammatory medication (NSAIDs)). SEARCH STRATEGY: The following databases were searched (from inception until March 2010): the Cochrane Menstrual Disorders and Subfertillity Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), PubMed, CINAHL, PsycINFO, Chinese Biomedical Literature Database (CBM), Chinese Medical Current Content (CMCC), China National Knowledge Infrastructure (CNKI), VIP database, Dissertation Abstracts International, BIOSIS, AMED (The Allied and Complementary Medicine Database), Acubriefs, and Acubase. SELECTION CRITERIA: Inclusion criteria included all published and unpublished randomised controlled trials comparing acupuncture with placebo control, usual care, and pharmacological treatment. The following modes of treatment were included: acupuncture, electro-acupuncture, and acupressure. Participants were women of reproductive age with primary dysmenorrhoea during the majority of the menstrual cycles or for three consecutive menstrual cycles, and moderate to severe symptoms. DATA COLLECTION AND ANALYSIS: Meta-analyses were performed using odds ratios (OR) for dichotomous outcomes and mean differences or standard mean differences (SMD) for continuous outcomes, with 95% confidence intervals (CI). Primary outcomes were pain relief and improved menstrual symptoms, measured by self-rating scales. Other outcomes included use of analgesics, quality of life, and absence from school or work. MAIN RESULTS: Ten trials were included in the review with data reporting on 944 participants. Six trials reported on acupuncture (n = 673) and four trials (n = 271) reported on acupressure. There was an improvement in pain relief from acupuncture compared with a placebo control (OR 9.5, 95% CI 21.17 to 51.8), NSAIDs (SMD -0.70, 95% CI 1.08 to -0.32) and Chinese herbs (SMD -1.34, 95% CI -1.74 to -0.95). In two trials acupuncture reduced menstrual symptoms (for example nausea, back pain) compared with medication (OR 3.25, 95% CI 1.53 to 6.86); in one trial acupuncture reduced menstrual symptoms compared with Chinese herbs (OR 7.0, 95% CI 2.22, 22.06); and in one trial acupuncture improved quality of life compared with usual care.There was an improvement in pain relief from acupressure compared with a placebo control (SMD -0.99, 95% CI -1.48 to -0.49), and in one trial acupressure reduced menstrual symptoms compared with a placebo control (SMD -0.58, 95% CI 1.06 to -0.10). The risk of bias was low in 50% of trials. AUTHORS' CONCLUSIONS: Acupuncture may reduce period pain, however there is a need for further well designed randomised controlled trials. PMID- 21249698 TI - Surgical interventions for high grade vulval intraepithelial neoplasia. AB - BACKGROUND: Vulval intraepithelial neoplasia (VIN) is a pre-malignant condition of the vulval skin. This uncommon chronic skin condition of the vulva is associated with a high risk of recurrence and the potential to progress to vulval cancer. The condition is complicated by its' multicentric and multifocal nature. The incidence of this condition appears to be rising particularly in the younger age group.There is a lack of consensus on the optimal surgical treatment method. However, the rationale for surgical treatment of VIN has been to treat symptoms and exclude underlying malignancy with the continued aim of preservation of vulval anatomy and function. Repeated treatments affect local cosmesis and cause psychosexual morbidity thus impacting on the patients' quality of life. OBJECTIVES: To evaluate the effectiveness and safety of surgical interventions for high grade VIN. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 3, 2010, Cochrane Gynaecological Cancer Group Trials Register, MEDLINE and EMBASE up to September 2010. We also searched registers of clinical trials, abstracts of scientific meetings, reference lists of included studies and contacted experts in the field. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared surgical interventions, in adult women diagnosed with high grade vulval intraepithelial neoplasia. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted data and assessed risk of bias. MAIN RESULTS: We found only one RCT which included 30 women that met our inclusion criteria and this trial reported data on carbon dioxide laser (CO(2) laser) versus ultrasonic surgical aspiration (USA).There was no statistically significant difference in the risk of disease recurrence after one year follow-up, pain, presence of scarring, dysuria or burning, adhesions, infection, abnormal discharge and eschar between women who received CO(2) laser and those who received USA. The trial lacked statistical power due to the small number of women in each group and the low number of observed events, but was at low risk of bias. AUTHORS' CONCLUSIONS: The included trial lacked statistical power due to the small number of women in each group and the low number of observed events. Therefore in the absence of reliable evidence regarding the effectiveness and safety of the two surgical techniques for the management of vulval intraepithelial neoplasia precludes any definitive guidance or recommendations for clinical practice. PMID- 21249699 TI - Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles. AB - BACKGROUND: Gonadotropin-releasing hormone (GnRH) antagonist protocols for pituitary down regulation in in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI) allow the use of GnRH agonists for triggering final oocyte maturation. Currently, human chorionic gonadotropin (HCG) is still the standard medication for this purpose. The effectiveness of triggering with a GnRH agonist compared to HCG measured as pregnancy and ovarian hyperstimulation(OHSS) rates are unknown. OBJECTIVES: To compare the effectiveness of a GnRH agonist with HCG for triggering final oocyte maturation in IVF and ICSI patients undergoing controlled ovarian hyperstimulation in a GnRH antagonist protocol followed by embryo transfer. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE , EMBASE, the National Research Register, the Medical Research Council's Clinical Trials Register, and the NHS Centre for Reviews and Dissemination database. We also examined the reference lists of all known primary studies and review articles, citation lists of relevant publications and abstracts of major scientific meetings. SELECTION CRITERIA: All randomised controlled studies (RCTs) reporting data comparing clinical outcomes for women undergoing IVF and ICSI cycles and using a GnRH agonist in comparison with HCG for final oocyte maturation triggering. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. MAIN RESULTS: We identified 11 RCTs (n = 1055). Eight studies assessed fresh autologous cycles and three studies assessed donor-recipient cycles. In fresh autologous cycles, GnRH agonist was less effective than HCG in terms of the live birth rate per randomised woman (OR 0.44, 95% CI 0.29 to 0.68; 4 RCTs) and ongoing pregnancy rate per randomised woman (OR 0.45, 95% CI 0.31 to 0.65; 8 RCTs). For a group with a 30% live birth or ongoing pregnancy rate using HCG, the rate would be between 12% and 22% using an GnRH agonist. Moderate to severe ovarian hyperstimulation syndrome (OHSS) incidence per randomised woman was significantly lower in the GnRH agonist group compared to the HCG group (OR 0.10, 95% CI 0.01 to 0.82; 5 RCTs). For a group with a 3% OHSS rate using HCG the rate would be between 0% and 2.6% using GnRH agonist. In donor recipient cycles, there was no evidence of a statistical difference in the live birth rate per randomised woman (OR 0.92, 95% CI 0.53 to 1.61; 1 RCT). AUTHORS' CONCLUSIONS: We do not recommend that GnRH agonists be routinely used as a final oocyte maturation trigger in fresh autologous cycles because of lowered live birth rates and ongoing pregnancy rates. An exception could be made for women with high risk of OHSS, after appropriate counselling. PMID- 21249701 TI - Water-based exercises for improving activities of daily living after stroke. AB - BACKGROUND: Water-based exercises are used in rehabilitation and might help to reduce disability after stroke. OBJECTIVES: To investigate the effect of water based exercises for reducing disability after stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched August 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 4), MEDLINE (1966 to April 2010), EMBASE (1980 to April 2010), CINAHL (1982 to April 2010), AMED (1985 to April 2010), SPORTDiscus (1949 to April 2010), the Physiotherapy Evidence Database (PEDro, April 2010) and OT Seeker (1969 to April 2010). In an effort to identify further published, unpublished and ongoing trials we handsearched relevant journals and conference proceedings, searched trials and research registers, checked reference lists and contacted authors. SELECTION CRITERIA: We included studies using random assignment. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trial quality and extracted the data. The primary outcome was activities of daily living. MAIN RESULTS: We included four trials involving 94 participants in this review. There was a significant improvement in activity of daily living (mean difference (MD) 13.20 points on the 'Capacidad funcional' (functional capacity) subscale of the Brazilian-Portuguese version of the SF-36; 95% confidence interval (CI) 8.36 to 18.04; P < 0.00001) and on muscle strength (MD 1.01 Nm/kg; 95% CI 0.19 to 1.83; P = 0.02) but these results should be interpreted with caution because population numbers were small and the results are based on single studies. There was no significant improvement in ability to walk (MD 0.14 m/s; 95% CI -0.32 to 0.606; P = 0.55), postural balance (MD 3.05 points; 95% CI -3.41 to 9.52; P = 0.35) or fitness (MD 3.6 (VO(2max); 95% CI -0.53 to 7.73; P = 0.09) after water-based exercises treatment compared to control. Adverse effects were not reported. AUTHORS' CONCLUSIONS: The evidence from randomised controlled trials so far does not confirm or refute that water-based exercises after stroke might help to reduce disability after stroke. There is a lack of hard evidence for water-based exercises after stroke. Better and larger studies are therefore required. PMID- 21249700 TI - Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin. AB - BACKGROUND: Aspirin is widely used for secondary prevention after stroke. Cilostazol has shown promise as an alternative to aspirin in Asian people with stroke. OBJECTIVES: To determine the relative effectiveness and safety of cilostazol compared directly with aspirin in the prevention of stroke and other serious vascular events in patients at high vascular risk for subsequent stroke, those with previous transient ischaemic attack (TIA) or ischaemic stroke of arterial origin. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched September 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, Issue 4), MEDLINE (1950 to May 2010) and EMBASE (1980 to May 2010). In an effort to identify further published, ongoing and unpublished studies we searched journals, conference proceedings and ongoing trial registers, scanned reference lists from relevant studies and contacted trialists and Otsuka Pharmaceutical Co Ltd. SELECTION CRITERIA: We selected all randomised controlled trials (RCTs) comparing cilostazol with aspirin where participants were treated for at least one month and followed systematically for development of vascular events. DATA COLLECTION AND ANALYSIS: Data extracted from eligible studies included: (1) a composite outcome of vascular events (stroke, myocardial infarction or vascular death) during follow up (primary outcome); (2) separate outcomes of stroke (ischaemic or haemorrhagic, fatal or non-fatal), myocardial infarction (MI) (fatal or non fatal), vascular death and death from all causes; and (3) main outcomes of safety including any intracranial, extracranial or gastrointestinal (GI) haemorrhage and other outcomes during treatment follow up (secondary outcomes). We computed an estimate of treatment effect and performed a test for heterogeneity between trials. We analysed data on an intention-to-treat basis and assessed bias for all included studies. MAIN RESULTS: We included two RCTs with 3477 Asian participants. Compared with aspirin, cilostazol was associated with a significantly lower risk of composite outcome of vascular events (6.77% versus 9.39%, risk ratio (RR) 0.72, 95% confidence interval (CI) 0.57 to 0.91), and lower risk of haemorrhagic stroke (0.53% versus 2.01%, RR 0.26, 95% CI 0.13 to 0.55). In terms of outcome of safety compared with aspirin, cilostazol was significantly associated with minor adverse effects (8.22% versus 4.95%, RR 1.66, 95% CI 1.51 to 1.83). AUTHORS' CONCLUSIONS: Cilostazol is more effective than aspirin in the prevention of vascular events secondary to stroke. Cilostazol has more minor adverse effects, although there is evidence of fewer bleeds. PMID- 21249702 TI - Botulinum toxin injections for low-back pain and sciatica. AB - BACKGROUND: Adequate relief from low-back pain (LBP) is not always possible. Emerging evidence suggests a role for botulinum neurotoxin (BoNT) injections in treating pain disorders. Proponents of BoNT suggest its properties can decrease muscle spasms, ischemia and inflammatory markers, thereby reducing pain. OBJECTIVES: To determine the effects of botulinum toxin injections in adults with LBP. SEARCH STRATEGY: We searched CENTRAL (The Cochrane Library 2009, issue 3) and MEDLINE, EMBASE, and CINAHL to August 2009; screened references from included studies; consulted with content experts and Allergan. We included published and unpublished randomised controlled trials without language restrictions SELECTION CRITERIA: We included randomised trials that evaluated BoNT serotypes versus other treatments in patients with non-specific LBP of any duration. DATA COLLECTION AND ANALYSIS: Two review authors selected the studies, assessed the risk of bias using the Cochrane Back Review Group criteria, and extracted the data using standardized forms. We performed a qualitative analysis due to lack of data. MAIN RESULTS: We excluded evidence from nineteen studies due to non randomisation, incomplete or unpublished data. We included three randomised trials (N =123 patients). Only one study included patients with chronic non specific LBP; the other two examined unique subpopulations. Only one of the three trials had a low risk of bias and demonstrated that BoNT injections reduced pain at three and eight weeks and improved function at eight weeks better than saline injections. The second trial showed that BoNT injections were better than injections of corticosteroid plus lidocaine or placebo in patients with sciatica attributed to piriformis syndrome. The third trial concluded that BoNT injections were better than traditional acupuncture in patients with third lumbar transverse process syndrome. Both studies with high risk of bias had several key limitations. Heterogeneity of the studies prevented meta-analysis. There is low quality evidence that BoNT injections improved pain, function, or both better than saline injections and very low quality evidence that they were better than acupuncture or steroid injections. AUTHORS' CONCLUSIONS: We identified three studies that investigated the merits of BoNT for LBP, but only one had a low risk of bias and evaluated patients with non-specific LBP (N = 31). Further research is very likely to have an important impact on the estimate of effect and our confidence in it. Future trials should standardize patient populations, treatment protocols and comparison groups, enlist more participants and include long-term outcomes, cost-benefit analysis and clinical relevance of findings. PMID- 21249703 TI - Piggy-back graft for liver transplantation. AB - BACKGROUND: Piggy-back method of transplantation, which involves preservation of the recipient retrohepatic inferior vena cava, has been suggested as an alternative to the conventional method of liver transplantation, where the recipient retrohepatic inferior vena cava is resected. OBJECTIVES: To compare the benefits and harms of piggy-back technique versus conventional liver transplantation as well as of the different modifications of piggy-back technique during liver transplantation. SEARCH STRATEGY: We searched The Cochrane Hepato Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded until June 2010 for identifying randomised trials using search strategies. SELECTION CRITERIA: Only randomised clinical trials, irrespective of language, blinding, or publication status were considered for the review. DATA COLLECTION AND ANALYSIS: Two authors (KSG and VP) independently identified trials and independently extracted data. We calculated the mean difference (MD) or standardised mean difference (SMD) with 95% confidence intervals (CI) using both the fixed-effect and the random-effects models with RevMan 5 based on intention-to-treat analysis for continuous outcomes. For binary outcomes, we used the Fisher's exact test since none of the comparisons of binary outcomes included more than one trial. MAIN RESULTS: Two trials randomised in total 106 patients to piggy-back method (n = 53) versus conventional method with veno-venous bypass (n = 53). Both trials were at high risk of bias. There was no significant difference in post-operative mortality, primary graft non-function, vascular complications, renal failure, transfusion requirements, intensive therapy unit (ITU) stay, or hospital stay between the two groups. The warm ischaemic time was significantly shorter in the piggy-back method than the conventional method (MD -11.50 minutes; 95% CI -19.35 to -3.65; P < 0.01). The proportion of patients who developed chest complications were significantly higher in the the piggy-back method than the conventional method (75.8% versus 44.1%; P = 0.01).One trial randomised 80 patients to piggy-back with porto-caval bypass (n = 40) versus piggy-back without porto-caval bypass (n = 40). This trial was at high risk of bias. There was no significant difference in post-operative mortality, re-transplantation due to primary graft non-function, vascular complications, renal failure, or hospital stay between the two groups. Fewer patients required blood transfusion in the piggy-back with porto-caval bypass group (55%) than the piggy-back without porto-caval bypass group (75%) (P = 0.02). There was no significant difference in the mean amount of blood transfused between the groups (MD -1.00 unit; 95% CI -2.19 to 0.19; P = 0.10). The ITU stay was significantly shorter in the piggy-back with porto-caval bypass group (2.9 days) than the piggy-back without porto-caval bypass group (4.9 days; MD -2.00 days; 95% CI -3.82 to -0.18; P = 0.03).There were no trials comparing piggy-back method with conventional method without veno-venous bypass or different techniques of piggy-back method. AUTHORS' CONCLUSIONS: There is currently no evidence to recommend or refute the use of piggy-back method of liver transplantation. PMID- 21249704 TI - Felbamate as an add-on therapy for refractory epilepsy. AB - BACKGROUND: Epilepsy is a chronic and disabling neurologic disorder, affecting approximately one per cent of the population. Up to 30% of people with epilepsy have seizures that are resistant to currently available drugs. Felbamate is one of the second generation antiepileptic drugs and its effects as an add-on therapy to standard drugs are assessed in this review. OBJECTIVES: To evaluate the efficacy and tolerability of felbamate versus placebo when used as an add-on treatment for people with refractory partial-onset epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group Specialized Register (6 December 2010), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 6 December 2010), and PubMed (6 December 2010). There were no language restrictions. We reviewed the reference lists of retrieved studies to search for additional reports of relevant studies. We also contacted the manufacturers of felbamate and experts in the field for information about any unpublished or ongoing studies. SELECTION CRITERIA: Randomized placebo-controlled add-on studies of people of any age with refractory partial-onset seizures. The studies could be double-blind, single-blind or unblinded and could be of parallel or crossover design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion and extracted information. Disagreements were resolved by discussion. If disagreements persisted, the third review author arbitrated. The following outcomes were assessed: 50% or greater reduction in seizure frequency; absolute or percentage reduction in seizure frequency; treatment withdrawal; adverse effects; quality of life. MAIN RESULTS: Three randomized controlled trials were included. The first was a parallel design, the second was a two period crossover design, and the third was a three-period crossover design. Due to significant methodological heterogeneity, clinical heterogeneity and differences in outcome measures, it was not possible to perform a meta-analysis of the results. None of the three studies reported 50% or greater reduction in seizure frequency. Only one study reported absolute and percentage reduction in seizure frequency compared to placebo, P values were 0.046 and 0.018, respectively. Adverse effects rates were higher during the felbamate period than the placebo period, particularly headache, nausea and dizziness. AUTHORS' CONCLUSIONS: In view of the methodological deficiencies, limited number of individual studies and differences in outcome measure, we have found no reliable evidence to support the use of felbamate as an add-on therapy in patients with refractory partial-onset epilepsy. A large scale, randomized controlled trial conducted over a greater period of time is required to inform clinical practice. PMID- 21249705 TI - Strategies for improving adherence to antiepileptic drug treatment in patients with epilepsy. AB - BACKGROUND: Poor adherence to antiepileptic medications is associated with increased mortality and morbidity. In this review we focus on interventions designed to assist patients with adherence to antiepileptic medications. OBJECTIVES: To determine the effectiveness of interventions aimed at improving adherence to antiepileptic medications in adults and children with epilepsy. SEARCH STRATEGY: We searched the Epilepsy Group's Specialised Register (24 June 2010), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 2) and electronic databases: MEDLINE (OVID) (1950 to June 2010); EMBASE (OVID) (1980 to 2010 Week 24); CINAHL (1982 to June 2010) and PsycINFO (22 June 2010), and the reference lists of relevant articles. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials of adherence-enhancing interventions aimed at patients with clinical diagnosis of epilepsy (as defined in individual studies), of any age and of either gender, treated with antiepileptic drugs in a primary care, outpatient or other community setting. DATA COLLECTION AND ANALYSIS: We screened titles and abstracts for eligibility. Two review authors independently extracted data and assessed each study according to the Cochrane criteria. The studies differed widely according to intervention and measures of adherence, therefore combining data was not appropriate. MAIN RESULTS: Six trials met our inclusion criteria: five targeted adult epileptic patients with a combined patient number of 222 and one targeted parents of children with epilepsy (n = 51). Follow-up time was generally short: from one to six months. Two main types of intervention were examined: educational and behavioural modification. Each study compared treatment with no intervention 'usual care'. None compared one intervention with another. Due to heterogeneity between studies in terms of interventions and the methods used to measure adherence, we did not pool the results. Education and counselling of patients with epilepsy have shown mixed success. Behavioural interventions such as the use of intensive reminders and 'implementation intention' interventions provided more positive effects on adherence. AUTHORS' CONCLUSIONS: Intensive reminders and 'implementation intention' interventions appear promising in enhancing adherence to antiepileptic mediations, however we need more reliable evidence on their efficacy from carefully designed randomised controlled trials before a firm conclusion can be reached. PMID- 21249706 TI - The effectiveness of strategies to change organisational culture to improve healthcare performance. AB - BACKGROUND: Organisational culture is an anthropological metaphor used to inform research and consultancy and to explain organisational environments. Great emphasis has been placed during the last years on the need to change organisational culture in order to pursue effective improvement of healthcare performance. However, the precise nature of organisational culture in healthcare policy often remains underspecified and the desirability and feasibility of strategies to be adopted has been called into question. OBJECTIVES: To determine the effectiveness of strategies to change organisational culture in order to improve healthcare performance.To examine the effectiveness of these strategies according to different patterns of organisational culture. SEARCH STRATEGY: We searched the following electronic databases for primary studies: The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, Sociological Abstracts, Web of Knowledge, PsycINFO, Business and Management, EThOS, Index to Theses, Intute, HMIC, SIGLE, and Scopus until October 2009. The Database of Abstracts of Reviews of Effectiveness (DARE) was searched for related reviews. We also searched the reference lists of all papers and relevant reviews identified, and we contacted experts in the field for advice on further potential studies. SELECTION CRITERIA: We considered randomised controlled trials (RCTs) or well designed quasi-experimental studies, controlled clinical trials (CCTs), controlled before and after studies (CBAs) and interrupted time series analyses (ITS) meeting the quality criteria used by the Cochrane Effective Practice and Organisation of Care Group (EPOC). Studies should be set in any type of healthcare organisation in which strategies to change organisational culture in order to improve healthcare performance were applied. Our main outcomes were objective measures of professional performance and patient outcome. DATA COLLECTION AND ANALYSIS: At least two review authors independently applied the criteria for inclusion and exclusion criteria to scan titles and abstracts and then to screen the full reports of selected citations. At each stage results were compared and discrepancies solved through discussion. MAIN RESULTS: The search strategy yielded 4239 records. After the full text assessment, no studies met the quality criteria used by the EPOC Group and evaluated the effectiveness of strategies to change organisational culture to improve healthcare performance. AUTHORS' CONCLUSIONS: It is not possible to draw any conclusions about the effectiveness of strategies to change organisational culture because we found no studies that fulfilled the methodological criteria for this review. Research efforts should focus on strengthening the evidence about the effectiveness of methods to change organisational culture to improve health care performance. PMID- 21249707 TI - Foot orthoses for patellofemoral pain in adults. AB - BACKGROUND: Foot orthoses, which are specially moulded devices fitted into footwear, are one of the treatment options for patellofemoral or anterior knee pain. OBJECTIVES: To assess the effects of foot orthoses for managing patellofemoral pain in adults. SEARCH STRATEGY: We searched the Cochrane Bone, Joint and Muscle Trauma Group's Specialised Register (March 2010), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2010, Issue 1), MEDLINE (1950 to March 2010), EMBASE (1980 to 2010 Week 11), CINAHL (1937 to March 2010), trial registers, reference lists and grey literature. No language restriction was applied. SELECTION CRITERIA: We included randomised or quasi randomised clinical studies that compared foot orthoses with flat insoles or another physical therapy intervention. The primary outcomes were knee pain and knee function. DATA COLLECTION AND ANALYSIS: Two authors independently selected eligible trials, assessed methodological quality and performed data extraction. We calculated risk ratios and 95% confidence intervals for dichotomous variables, and mean differences with 95% confidence intervals for continuous variables. We pooled data using the fixed-effect model. MAIN RESULTS: Two trials with a total of 210 participants were included. Both trials were at some risk of performance bias. One trial had four intervention groups and the other had three. One trial found that foot orthoses when compared with flat insoles (control group) had better results at six weeks in knee pain (participants with global improvement: risk ratio 1.48, 95% confidence interval 1.11 to 1.99), but not at one year follow-up. Participants in the orthoses group reported significantly more minor adverse effects (e.g. rubbing, blistering) compared with the flat insole group (risk ratio 1.87, 95% confidence intervaI 1.21 to 2.91). Both trials in their comparisons of orthoses plus physiotherapy versus physiotherapy alone found no statistically significant differences between the two intervention groups in knee pain or function. Results for knee pain outcomes did not show significant differences between foot orthoses versus physiotherapy. Although participants in the physiotherapy group had consistently better results for the functional index questionnaire, the clinical relevance of these results is uncertain. AUTHORS' CONCLUSIONS: While not robust, the available evidence does not reveal any clear advantage of foot orthoses over simple insoles or physiotherapy for patellofemoral pain. While foot orthoses may help relieve knee pain over the short term, the benefit may be marginal. Patients treated with orthoses are more likely to complain of mild adverse effects and discomfort. PMID- 21249708 TI - Progesterone for acute traumatic brain injury. AB - BACKGROUND: Traumatic brain injury is a leading cause of death and disability. Progesterone is a potential neuroprotective drug to treat patients with traumatic brain injury. OBJECTIVES: To assess the effectiveness and safety of progesterone in people with acute traumatic brain injury (TBI). SEARCH STRATEGY: We searched: the Cochrane Injuries Group's Specialised Register (to April 2010), Cochrane Central Register of Controlled Trials 2010, Issue 1 (The Cochrane Library), MEDLINE (Ovid) (1950 to April week 1 2010), EMBASE (Ovid) (1980 to week 14 2010), LILACS (to 17 April 2010 ), Zetoc (to 21 April 2010), Clinicaltrials.gov (17 April 2010 ), Controlled-trials.com (17 April 2010). SELECTION CRITERIA: We included published and unpublished randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of acute TBI. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results to identify the full texts of potentially relevant studies for inclusion. From the results of the screened searches two authors independently selected trials meeting the inclusion criteria, with no disagreement. MAIN RESULTS: Three studies were included with 315 patients. All three studies reported the effects of progesterone on mortality. The pooled relative risk (RR) for mortality at end of follow-up is 0.61, 95% confidence interval (CI) 0.40 to 0.93. Three studies measured disability and found the RR of death or severe disability in patients treated with progesterone was 0.77, 95% confidence interval (CI) 0.62 to 0.96. Two studies presented data on intracranial pressure and adverse events. One study presented blood pressure and temperature data. There was no substantial evidence for the presence of heterogeneity. AUTHORS' CONCLUSIONS: Current clinical evidence from three small RCTs indicates progesterone may improve the neurologic outcome of patients suffering TBI. This evidence is still insufficient and further multicentre randomised controlled trials are required. PMID- 21249709 TI - Oral 5-aminosalicylic acid for maintenance of surgically-induced remission in Crohn's disease. AB - BACKGROUND: The use of 5-aminosalicylates (5-ASAs) in Crohn's disease (CD) is controversial. A recent Cochrane review found that 5-ASAs are not effective for the maintenance of medically-induced remission in CD, but their role in the maintenance of surgically-induced remission is unclear. OBJECTIVES: The objectives were to evaluate the efficacy and safety of 5-ASA agents for the maintenance of surgically-induced remission in CD. SEARCH STRATEGY: The search was standardised and not limited by language and included electronic searching (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Inflammatory Bowel Disease Group Specialized Trials Register), reference searching of all included studies, abstracts from major meetings, personal contacts and drug companies. SELECTION CRITERIA: Randomised controlled trials (RCTs) which compared 5-ASAs with either placebo or another intervention, with treatment durations of at least 6 months were considered for inclusion. Participants were patients of any age with CD in remission following surgery. Primary outcome measures were clinical relapse or endoscopic recurrence as defined by the primary studies. Secondary endpoints were the occurrence of adverse events. DATA COLLECTION AND ANALYSIS: Relevant papers were identified and the authors independently assessed the eligibility of trials. Methodological quality was assessed using the Cochrane risk of bias tool.The Cochrane RevMan software was used for analyses. Patients with final missing outcomes were assumed to have relapsed. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated based on the fixed effects model. The chi square and I(2) statistics were used to assess statistical heterogeneity. MAIN RESULTS: Nine RCTs were included in the review. Seven studies compared oral 5-ASA with placebo and two compared oral 5-ASA with purine antimetabolites (azathioprine or 6 mercaptopurine). 5-ASA was significantly more effective than placebo for preventing relapse (OR 0.68, 95% CI, 0.52 to 0.90). There was no statistically significant heterogeneity among the 8 trials comparing 5-ASA with placebo (P=0.47). No statistically significant difference in adverse events was found for 5-ASA versus placebo (OR 1.02, 95%CI, 0.60 to 1.76). No statistically significant difference was found between 5-ASA and purine antimetabolites for preventing relapses (OR 1.08 95% CI, 0.63 to 1.85). AUTHORS' CONCLUSIONS: The pooled analyses suggest that 5-ASA preparations may be superior to placebo for the maintenance of surgically-induced remission in patients with CD. The results of the pooled analyses should be interpreted with caution because adequately powered studies demonstrated no difference and publication bias (failure to publish negative studies) may be an issue. The potential benefit provided by 5-ASA drugs is modest with a number needed to treat of approximately 16 to 19 patients to avoid one relapse which raises issues about the cost-effectiveness of this therapy. However, 5-ASA drugs are safe and well tolerated. The incidence of adverse events was not different in patients receiving 5-ASA compared with those receiving placebo. There is insufficient evidence to allow any conclusions on how 5-ASA preparations compare with azathioprine or 6-mercaptopurine. PMID- 21249710 TI - Vitamin K supplementation for cystic fibrosis. AB - BACKGROUND: Cystic fibrosis is a genetic disorder which can lead to multiorgan dysfunction. Malabsorption of fat and fat-soluble vitamins (A, D, E, K) may occur and can cause subclinical deficiencies of some of these vitamins. Vitamin K is known to play an important role in both blood coagulation and bone formation. Supplementation with vitamin K appears to be one way of addressing the deficiency, but there is very limited agreement on the appropriate dose and frequency of use of these supplements. OBJECTIVES: To assess the effects of vitamin K supplementation in people with cystic fibrosis and to determine the optimal dose and route of administration of vitamin K for both routine and therapeutic use. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 15 April 2010. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of all preparations of vitamin K used as a supplement compared to either no supplementation (or placebo) at any dose or route and for any duration, in children or adults diagnosed with cystic fibrosis (by sweat test or genetic testing). DATA COLLECTION AND ANALYSIS: Two authors independently screened papers, extracted trial details and assessed their risk of bias. MAIN RESULTS: Two trials (total of 32 participants) were included in the review and were assessed as having a moderate risk of bias. One was a dose-ranging parallel group trial; and the other had a cross-over design, but no separate data were reported for the first intervention period. Neither of the trials addressed any of the primary outcomes (coagulation, bone formation and quality of life). Both trials reported the restoration of serum vitamin K and undercarboxylated osteocalcin levels to the normal range after one month of daily supplementation with 1 mg of vitamin K. AUTHORS' CONCLUSIONS: Evidence from randomised controlled trials on the benefits of routine vitamin K supplementation for people with CF is currently weak and limited to two small trials of short duration. However, no harm was found and until further evidence is available, the present recommendations should be adhered to. PMID- 21249711 TI - Sperm washing to prevent HIV transmission from HIV-infected men but allowing conception in sero-discordant couples. AB - BACKGROUND: Sperm washing is a term used to describe the process in which individual spermatozoa are separated from the seminal fluid. Sperm washing is used to prevent HIV transmission but allow conception in sero-discordant couples, where the male is HIV positive, but the female is HIV negative. This procedure is based on the observation that HIV cannot attach itself to spermatozoa, but it can be found in the fluid and cells surrounding spermatozoa. OBJECTIVES: To determine the benefits and harms of sperm washing of HIV-infected males when used to prevent the transmission of HIV but allowing conception in the HIV-negative female. SEARCH STRATEGY: We searched the Cochrane HIV/AIDS Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, SCORPUS, AIDsearch, AJOL, LILACS and INDEX MEDICUS. We also searched the following conference proceedings for relevant abstracts:The International AIDS Conference; The Conference on Retroviruses and Opportunistic Infections (CROI); The British HIV Association (BHIVA) Conference; The International Conference of Obstetricians and Gynecologists (FIGO); The American Academy of HIV Medicine Conference; The Australasian HIV/AIDS Conference; The American Society for Reproductive Medicine (ASRM) conferences and website; The European Society for Human Reproduction and Embryology (ESHRE) conferences and websites, and the British Fertility Society (BFS) conferences and website. We also conducted a search of the website: www.ClinicalTrials.gov. The date of the most recent Cochrane HIV/AIDS Group Controlled Trials Register search was on the 10th of November, 2010. SELECTION CRITERIA: We preferentially looked for randomised or quasi-randomised controlled trials on sperm washing, aimed at preventing HIV transmission from HIV infected men but allowing conception in sero-discordant couples, irrespective of publication status, year of publication, or language in the review. DATA COLLECTION AND ANALYSIS: No relevant trials were identified for inclusion in this review. MAIN RESULTS: Forty four studies were identified, but none of them were suitable for inclusion in this review. AUTHORS' CONCLUSIONS: Reports on the use of sperm washing to prevent HIV transmission from HIV infected men but allowing conception in sero-discordant couples is currently limited to observational studies. No randomised controlled trial has assessed the benefit or risk of sperm washing to prevent HIV transmission from HIV infected men but allow conception in sero-discordant couples. Thus, this systematic review identifies the need for a multicentre randomised controlled trial assessing the benefits and possible risks of sperm washing in preventing HIV transmission from HIV infected men but allow conception in sero-discordant couples. PMID- 21249712 TI - Baclofen for alcohol withdrawal. AB - BACKGROUND: The treatment of baclofen can rapidly reduce symptoms of severe alcohol withdrawal syndrome (AWS) in alcoholic patients, with a significant reduction in the cost. Baclofen is easily manageable, what's more, no patient treated with baclofen reported euphoria or other pleasant effects caused by the drug and no subject reported any degree of craving for the drug. OBJECTIVES: To assess the efficacy and safety of baclofen for patients with alcohol withdrawal syndrome. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (September 2010), MEDLINE (1966 to September 2010), EMBASE (1980 to September 2010), and CINAHL (1982 to September 2010). We also searched the following registers of ongoing trials, e.g. Clinicaltrials.gov, Controlled trials.com, EUDRACT, etc. At the same time, we handsearched the references quoted in the identified trials, contact researchers, pharmaceutical companies and relevant trial authors seeking information about unpublished or incomplete trials. All searches included non-English language literature. SELECTION CRITERIA: All randomised controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for patients with AWS. Uncontrolled, non randomised or quasi-randomised trials were excluded. Both parallel group and cross-over design were included. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed references retrieved for possible inclusion. All disagreements were resolved by an independent party. Study authors were contacted for additional information. Adverse effects information was collected from the trials. MAIN RESULTS: We identified a total of 82 references from all electronic databases searched excluding duplicate. After screening of titles and abstracts, full papers of 7 studies were obtained and assessed for eligibility. Finally, only one study met the inclusion criteria, with 37 participants. AUTHORS' CONCLUSIONS: The evidence of recommending baclofen for AWS is insufficient. More well designed RCTs are demanded to further prove its efficacy and safety. PMID- 21249713 TI - Intravenous immunoglobulins for epilepsy. AB - BACKGROUND: Epilepsy is a common neurological condition, with an estimated incidence of 50 per 100,000 persons. People with epilepsy may present with various types of immunological abnormalities, such as low serum IgA level, lack of IgG subclass and identification of certain types of antibodies. Intravenous immunoglobulin (IVIg) treatment may represent a valuable approach and its efficacy has important implications for epilepsy management. OBJECTIVES: To examine the effects of IVIg on the frequency and duration of seizures, quality of life and adverse effects, when used as monotherapy or as add-on treatment for people with epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group Specialized Register (14 June 2010), the Cochrane Central Register of Controlled Trials (Issue 2 of 4, The Cochrane Library, 2010), MEDLINE (1950 to June 2010), Web of Science (14 June 2010), Current Controlled Trials (11 June 2010), the National Research Register (NRR) archive (11 June 2010), the US National Institutes of Health (Clinicaltrials.gov) (11 June 2010) and reference lists of articles. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of IVIg as monotherapy or add-on treatment in people with epilepsy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the trials for inclusion and extracted data. We contacted study authors for additional information. Outcomes included percentage of people rendered seizure-free, 50% or greater reduction in seizure frequency, adverse effects, treatment withdrawal and quality of life. MAIN RESULTS: We included one study (61 patients). We found no randomized controlled trials that investigated the effects of IVIg monotherapy for epilepsy. The included study was a randomized, double-blind, placebo controlled, multi-center trial which compared the treatment efficacy of IVIg as an add-on with a placebo add-on in patients with refractory epilepsy. There was no significant difference between IVIg and placebo in 50% or greater reduction in seizure frequency. The study reported a statistically significant effect for global assessment in favor of IVIg. No adverse effects were demonstrated. AUTHORS' CONCLUSIONS: No reliable conclusions can be drawn regarding the efficacy of IVIg as a treatment for epilepsy. Further randomized controlled trials are needed. PMID- 21249714 TI - Comparison of protocols and registry entries to published reports for randomised controlled trials. AB - BACKGROUND: Publication of complete trial results is essential if people are to be able to make well-informed decisions about health care. Selective reporting of randomised controlled trials (RCTs) is a common problem. OBJECTIVES: To systematically review studies of cohorts of RCTs to compare the content of trial reports with the information contained in their protocols, or entries in a trial registry. SEARCH STRATEGY: We conducted electronic searches in Ovid MEDLINE (1950 to August 2010); Ovid EMBASE (1980 to August 2010); ISI Web of Science (1900 to August 2010) and the Cochrane Methodology Register (Issue 3, 2010), checked reference lists, and asked authors of eligible studies to identify further studies. Studies were not excluded based on language of publication or our assessment of their quality. SELECTION CRITERIA: Published or unpublished cohort studies comparing the content of protocols or trial registry entries with published trial reports. DATA COLLECTION AND ANALYSIS: Data were extracted by two authors independently. Risk of bias in the cohort studies was assessed in relation to follow up and selective reporting of outcomes. Results are presented separately for the comparison of published reports to protocols and trial registry entries. MAIN RESULTS: We included 16 studies assessing a median of 54 RCTs (range: 2 to 362). Twelve studies compared protocols to published reports and four compared trial registry entries to published reports. In two studies, eligibility criteria differed between the protocol and publication in 19% and 100% RCTs. In one study, 16% (9/58) of the reports included the same sample size calculation as the protocol. In one study, 6% (4/63) of protocol-report pairs gave conflicting information regarding the method of allocation concealment, and 67% (49/73) of blinded studies reported discrepant information on who was blinded. In one study unacknowledged discrepancies were found for methods of handling protocol deviations (44%; 19/43), missing data (80%; 39/49), primary outcome analyses (60%; 25/42) and adjusted analyses (82%; 23/28). One study found that of 13 protocols specifying subgroup analyses, 12 of these 13 trials reported only some, or none, of these. Two studies found that statistically significant outcomes had a higher odds of being fully reported compared to nonsignificant outcomes (range of odds ratios: 2.4 to 4.7). Across the studies, at least one primary outcome was changed, introduced, or omitted in 4-50% of trial reports. AUTHORS' CONCLUSIONS: Discrepancies between protocols or trial registry entries and trial reports were common, although reasons for these were not discussed in the reports. Full transparency will be possible only when protocols are made publicly available or the quality and extent of information included in trial registries is improved, and trialists explain substantial changes in their reports. PMID- 21249715 TI - [What is expected of psychiatrists in cancer therapy]. PMID- 21249716 TI - Clinical and basic science articles from Thrombosis and Haemostasis. PMID- 21249717 TI - Seeing health care as a human right in India. PMID- 21249718 TI - Endovascular and open revascularization for nonatherosclerotic renal artery disease. PMID- 21249719 TI - Stability of human growth hormone: influence of methionine oxidation on thermal folding. AB - Oxidation, particularly of methionine residues, is one of the major chemical degradations of proteins. In a previous publication we studied the conformation of recombinant human growth hormone (r-hGH) selectively oxidized at Met14 and Met125. Conformation of oxidized r-hGH was found not different from that of nonoxidized r-hGH. In this paper, the effect of methionine oxidation on the thermal stability of r-hGH folding was investigated. The thermally induced unfolding process of the oxidized and nonoxidized protein was measured by monitoring the circular dichroism signal at 220 nm. The melting temperatures (T(m)) of the oxidized and nonoxidized r-hGH forms were determined at different pHs and in the presence of salts often used in pharmaceutical formulations. The effect of the location of the oxidized Met residue in the protein and the percentage of oxidation were investigated. Our findings indicate that the monoxidation of the two most accessible methionine residues of r-hGH-Met14 and Met125 - has no effect on the protein conformation. However, oxidation of these residues to form sulfoxides does influence the thermal stability of the protein folding. The presence of the polar oxygen atom on the methionine sulfoxide group thermally destabilizes r-hGH folding. The effect (T(m)) depends upon pH, ionic strength, and the location of the oxidized methionine residues in the protein. The thermal melting of r-hGH and its oxidized products is a highly cooperative process. Methionine oxidation leads to a thermal destabilization of the whole protein folding and is not just a local destabilization. PMID- 21249720 TI - Flecainide acetate acetic acid solvates. AB - Flecainide acetate forms acetic acid solvates with 0.5 and 2 acetic acid molecules. Powder X-ray diffraction, differential thermal analysis/thermogravimetric, infrared, and potentiometric titration were used to determine the composition of solvates. Flecainide acetate hemisolvate with acetic acid decomposes to form a new crystalline form of flecainide acetate. This form is less stable than the already known polymorphic form at all temperatures, and it is formed due to kinetic reasons. Both flecainide acetate nonsolvated and flecainide acetate hemisolvate forms crystallize in monoclinic crystals, but flecainide triacetate forms triclinic crystals. Solvate formation was not observed when flecainide base was treated with formic acid, propanoic acid, and butanoic acid. Only nonsolvated flecainide salts were obtained in these experiments. PMID- 21249722 TI - China wrestles with lung cancer. PMID- 21249721 TI - MET inhibitors: translating from bench to bedside. PMID- 21249723 TI - NICE guidance on trastuzumab for the treatment of HER2-positive metastatic gastric cancer. PMID- 21249724 TI - [Genius is high aim and apower of its achievement (to the 200th anniversary from the date of N.I. Pirogov's birth)]. PMID- 21249725 TI - Biologic and surgical challenge of colorectal hepatic metastases. Seminar dedicated to Dr. Leslie Blumgart and Dr. Henri Bismuth. PMID- 21249726 TI - Influence of intravenous administration of growth hormone releasing peptide-2 (GHRP-2) on detection of growth hormone doping: growth hormone isoform profiles in Japanese male subjects. AB - Administration of exogenous 22 kDa recombinant human growth hormone (rhGH) suppresses the non-22 kDa pituitary growth hormone (GH) secretion by negative feedback; then, the elevated 22 kDa GH to non-22 kDa GH ratio (Rec/Pit ratio) can be utilized to detect doping with rhGH (isoform differential immunoassay). The influence of intravenous administration of growth hormone releasing peptide GHRP 2 on the isoform differential immunoassay for detecting rhGH doping has been investigated.In this study, a reference population (n=100) was used, with 0.04 mg/kg rhGH subcutaneous administration (n=5), 100 MUg of GHRP-2 intravenous administration (n=10) and 0.04 mg/kg rhGH combined with 100 MUg of GHRP-2 (n=10) in Japanese male subjects. The results indicated that the low dose (0.04 mg/kg) of rhGH led to significantly increased Rec/Pit ratio compared with the Japanese reference limit (P < 0.001). Because GHRP-2 dose led to increases in concentrations of both recombinant GH (recGH) and pituitary GH (pit GH), no significant change in the Rec/Pit ratio was observed (P > 0.05). In a combined administration study, after GHRP-2 dose the Rec/Pit ratios decreased to 39.9 43.9% compared with the elevated ratio caused by the rhGH dose.The results indicated that GHRP-2 administration cannot only be detected by the isoform differential immunoassay but also masks rhGH doping. The analysis of GHRP-2 was found to be suitable for compensating for the disadvantages of the isoform differential immunoassay because GHRP-2 and its metabolite (AA-3) in urine could be detected during the periods of masking of the Rec/Pit ratio by means of liquid chromatography/tandem mass spectrometry. PMID- 21249728 TI - Special issue in memoriam: Armand M. Karow Jr., Ph.D. (1941-2007). PMID- 21249729 TI - Trilogy of the cornea: past, present, and future. Proceedings of a symposium. March 20-21, 2010. Yamaguchi, Japan. PMID- 21249727 TI - Experience with anti-TNF-alpha therapy for orofacial granulomatosis. AB - BACKGROUND: Orofacial granulomatosis (OFG) can be challenging to treat and experience with anti-TNF-alpha therapy is limited. We report our experience with infliximab (IFX) and adalimumab (ADA) for OFG in 14 patients, the largest reported series to date. METHODS: A review of patients receiving induction and maintenance IFX for OFG +/- Crohn's disease (CD) for active oral disease failing other therapies was performed. Clinical response defined by global physician assessment, aided by oral disease activity scores, was assessed at 2 months, 1 and 2 years. ADA was considered for patients failing IFX. Adverse events were recorded. Predictors of need for anti-TNF-alpha therapy were determined by comparison with OFG patients not requiring anti-TNF-alpha from our overall OFG database (n = 207). RESULTS: Fourteen patients (9 men) were treated with IFX [OFG only (n = 7), OFG with CD (n = 7)]. Nine patients received concomitant immunosuppression. Median duration of treatment was 18 months. Shortterm response was achieved in 10/14 (71%) patients. Eight of 14 (57%) and 4/12 (33%) patients remained responsive at 1 and 2 years, respectively. Two patients who failed IFX responded to ADA. Factors predicting need for anti-TNF-alpha therapy were oral sulcal involvement, intestinal CD and a raised C-reactive protein (CRP). Oral sulcal involvement predicted response at 1 and 2 years. Intestinal CD did not predict response. The only significant adverse event was an IFX infusion reaction. CONCLUSION: IFX provided good short-term response for most OFG patients; however, a significant proportion lost response long term. Adverse events were uncommon. Patients failing IFX may respond to ADA. PMID- 21249730 TI - Perspectives on healthcare from the 2010 Edward J. III Excellence in Medicine honorees. PMID- 21249732 TI - Humana diversifies. Insurer pays $790 million for Concentra. PMID- 21249731 TI - Missing benefits? Rule on medical loss ratios has some worried. PMID- 21249733 TI - Whistle-blowing pays off. Fraud settlements bring in $2.5 billion for feds. PMID- 21249734 TI - Getting organized. HCA agreement gives way to more unions. PMID- 21249735 TI - HFMA sees smaller shortfall. Form 990 shows group cut losses thanks to investments. PMID- 21249736 TI - RNs are the Rx. Nurse execs must promote quality, continuing education and nursing careers. PMID- 21249737 TI - Not a glowing outlook. While vital isotopes needed for medical imaging are back in supply, another shortage could loom as the U.S. continues to lack adequate domestic sources. PMID- 21249738 TI - Heading for the exit. Turmoil hits long-term-care insurance companies. PMID- 21249739 TI - Cold comfort. Deficit report garners more support than expected. PMID- 21249740 TI - Legislation a relief? Not really, say docs, in response to one-month fix. PMID- 21249741 TI - On the rise. Reform could help curb soaring costs: study. PMID- 21249742 TI - Feuding over physicians. WakeMed seeks records on UNC Health Care's arrangements with docs. PMID- 21249743 TI - Do over in Pennsylvania. Ruling allows West Penn to proceed with lawsuit. PMID- 21249744 TI - What's wrong with this picture? It's time to get serious about the overconsumption of healthcare services. PMID- 21249745 TI - Certification clues. DSC process requires dedication, focus. PMID- 21249746 TI - Nurses in charge. Growing number of patient-safety and quality-improvement initiatives at hospitals are being spearheaded by nurse leaders. PMID- 21249747 TI - Largest patient-satisfaction measurement firms. Ranked by total number of engagements in 2009. PMID- 21249750 TI - New mask study supports CDC's updated guidance for seasonal flu prevention strategies. PMID- 21249751 TI - Health warnings for people who use heroin. PMID- 21249752 TI - Learning from others. PMID- 21249753 TI - Long-term outcomes in patients with multiple sclerosis. Introduction. PMID- 21250398 TI - Antiquated tests within the clinical pathology laboratory. AB - OBJECTIVE: To provide evidence supporting the discontinuation of laboratory tests that do not have clinical utility today. STUDY DESIGN: We selected 10 representative tests considered antiquated by most experts in the clinical laboratory medicine field: creatine kinase-MB, myoglobin, serum folate and red blood cell folate, amylase, lecithin/sphingomyelin ratio, qualitative serum human chorionic gonadotropin, prostatic acid phosphatase, bleeding time, and erythrocyte sedimentation rate. METHODS: Published literature was reviewed to provide evidence of the poor performance and/or limited clinical utility of these tests. When available, subscriptions to the Proficiency Testing Program of the College of American Pathologists were tracked from 1993 to 2008 as supporting evidence. Finally, when appropriate, alternative testing was suggested. RESULTS: The data show clearly that there is a national trend toward reduction or elimination of these 10 tests. CONCLUSION: Together with their clinical colleagues, clinical laboratorians should review their menu of tests and consider removing tests that do not provide clinical benefit. In most cases, alternative tests are already in clinical use. PMID- 21250399 TI - Magnitude and economic effect of overuse of antisecretory therapy in the ambulatory care setting. AB - OBJECTIVES: To determine the prevalence and economic effect of inappropriate proton pump inhibitor (PPI) use in an ambulatory care setting. STUDY DESIGN: Retrospective medical record review of random sample with subgroup analysis. METHODS: Patients were categorized according to appropriateness of pharmacotherapy based on documented upper gastrointestinal tract diagnoses, gastrointestinal or extraesophageal symptoms, or gastroprotection. Adverse events potentially associated with PPI use were identified. RESULTS: Of 946 patients in an ambulatory care setting, 35.4% were given PPI therapy for an appropriately documented upper gastrointestinal tract diagnosis, 10.1% received PPIs empirically for symptomatic treatment based on extraesophageal symptoms, 18.4% received PPIs for gastroprotection, and 36.1% had no documented appropriate indication for PPI therapy. In a subgroup analysis, 48.6% of patients across all 4 categories received PPIs without documentation of reevaluation of upper gastrointestinal tract symptoms, accounting for 1034 patient-years of PPI use. The total cost of inappropriate PPI use was $233,994 based on over-the-counter PPI costs and $1,566,252 based on average wholesale price costs. Potentially related adverse events in this cohort included Clostridium difficile-associated diarrhea (6 cases) and community-acquired pneumonia (1 case), but no cases of hip fracture or vitamin B12 deficiency were identified. CONCLUSIONS: Proton pump inhibitors are often overused in the ambulatory care setting without documented valid indications. Inappropriate use of PPIs is associated with substantial cost expenditure and with the potential for adverse events. PMID- 21250400 TI - Benefits and risks of live attenuated influenza vaccine in young children. AB - OBJECTIVE: To examine the benefit-risk profile of live attenuated influenza vaccine (LAIV) across a range of clinical scenarios in which we varied assumptions regarding both the percentage of children who would receive LAIV in lieu of trivalent inactivated influenza virus (TIV) and the extent of off-label use. STUDY DESIGN: Model of expected benefits and risks of immunization of young children against influenza. METHODS: We estimated expected numbers of cases of influenza illness (FLU), medically significant wheezing (MSW), and hospitalization in a single influenza season under alternative assumptions regarding use of LAIV in lieu of TIV, based on projections from a large phase III trial. RESULTS: Assuming no use of LAIV in nonindicated children (aged <24 months and those with history of recurrent wheezing or asthma), and 50% use in lieu of TIV among children in the indicated population, there would be 2099 fewer FLU cases per 100,000 children aged 12 to 59 months, and no change in MSW or hospitalization. If LAIV also were used in lieu of TIV among 20% of children aged 12 to 23 months and 20% of children aged 24 to 59 months with a history of recurrent wheezing or asthma, there would be a further reduction of 397 FLU cases and 12 hospitalizations per 100,000 children aged 12 to 59 months, but 51 additional MSW cases. CONCLUSIONS: Our study suggests that even if LAIV were sometimes used inadvertently in clinical practice in young children for whom it is not indicated, the overall balance of expected benefits and risks would remain favorable. PMID- 21250401 TI - [Isolated oligodontia: a case presentation and review of the literature]. AB - Tooth agenesis is a common developmental anomaly that appears in 2.2-10% of the general population (excluding agenesis of third molars). Congenital tooth agenesis can be either Hypodontia (agenesis of fewer than six teeth excluding third molars) or Oligodontia (agenesis of more than six teeth excluding third molars). Oligodontia can occur either as an isolated condition (non-syndromic oligodontia) or be associated with cleft lip?palate and other genetic syndromes (syndromatic oligodontia). The purpose of this article is to present an unusual case of non-syndromic oligodontia and describe the dental treatment for this condition. The patient was a 25 years old healthy male with a chief complaint of multiple teeth agenesis and TMJ dysfunction. The family history revealed that the mother, grandmother and siblings have also multiple teeth agenesis. Clinical examination revealed missing of nine teeth in the maxilla (12,13, 15,15, 17, 23, 24, 25, 27) and 10 teeth in the mandible (32, 33, 34, 35, 37, 42, 43, 44, 45, 47). The patient's dental treatment plan included preparing provisional over dentures, orthodontic treatment and dental implants (after extractions of the deciduous teeth). In the discussion of the article the pathology and the genetics of oligodontia are reviewed. PMID- 21250402 TI - [Molar incisor hypomineralization (MIH)--a literature review]. AB - MIH was defined by Weerheijm (2001) as "hypomineralisation of systemic origin of 1-4 permanent first molars, frequently associated with affected incisors". The prevalence of MIH varies between 2.8% and 25%, dependent upon the study. At their sixth congress in 2003, The European Association of pediatric dentistry defined criteria for diagnosis of the phenomena. It included the presence of demarcated opacity, posteruptive enamel breakdown, atypical restoration, extracted molar due to MIH and unerupted teeth. According to the teeth involved and to the time of the crown formation, researches focused on environmental and systemic conditions as possible reasons for MIH.The etiologies were divided into five groups: Exposure to environmental contaminants, pre/peri and neonatal problems, exposure to fluoride, common childhood illnesses and medically compromised children. The clinical implications include highly sensitive teeth, difficulty to achieve adequate anesthesia, behavioral problems and anxiety, rapid progression of caries and the esthetic implications. A six step approach to management was described suggested: risk identification, early diagnosis, remineralization and desensitization, prevention of caries and posteruption breakdown, restorations and extractions and finally maintenance. Restoring an affected molar can vary from adhesive intra coronal restorations (resin composite is the material of choice) to extra coronal restorations (e.g. preformed metal crown). Esthetic solutions to affected incisors may include microabrasion (that shows little improvement) and resin composite or porcelain veneer. The key for a successful treatment is early diagnosis, intense follow up and usage of remineralizating agents as soon as the teeth erupt. There is still need for further research to clarify the etiological factors and improve the durability of restoration in affected teeth. PMID- 21250404 TI - [Dental practitioners in Israel: past, present and future]. AB - Since 1980 various studies have been published in Israel dealing with dental manpower issues, utilizing several methods such as manpower to population ratio. The dental literature pointed out that dentistry in Israel has an over supply of dentists and that manpower to population ratio is one of the highest in the world 1:770. All studies were based on the information provided by the Ministry of Health which showed that Israel has over 9500 dentists. The Israel Central Bureau of Statistics figures showed a much smaller number which was 5700 active dentists. This enormous gap in between two sources of information, following strict examination of the data revealed that the Bureau of Statistics information is reliable and hence, the real manpower to population ratio in Israel in 2008 was 1:1271. Prediction of manpower is extremely important and the base line information is crucial for future evaluations. PMID- 21250403 TI - [Toothpastes: ingredients, brands, categories and their utilization]. AB - Toothpaste is one of the most widely used dental products, with the largest sales. Its use is one of the most popular oral hygiene behaviors in developed countries. In the last 30 years there has been a large variety of changes in toothpaste composition. One of the main changes is utilizing the toothpaste as a delivery system for therapeutic agents to the oral cavity. A large variety of toothpastes can be found on the market, for different purposes: caries prevention, gingivitis prevention, anti calculus formation, dentine hypersensitivity prevention and for teeth whitening. Toothpastes have a wide range of ingredients: abrasives, humectants, preservatives, thickening or binding agents, detergents, flavoring agents and therapeutic agents. This review provides details on the ingredients of dentifrices, the evidence about the different brands and categories, and questions about their utilization. PMID- 21250405 TI - [Adherence to oral hygiene and dental self-care]. AB - Nearly every person will be in need of dental treatment in his lifetime, whether purely for health causes or alternately for esthetic issues. Yet the main reasons of seeking dental treatment are in fact Caries, Gingivitis and Periodontitis. In spite of the fact that these pathologies occur due to the accumulation of Plaque around the oral cavity and teeth, they are fairly easy to prevent. Using simple techniques such as oral rinsing, flossing and brushing of the teeth, are normally sufficient for obtaining good oral health. If this is actually the case, than how is it that we are witnessing a massive spread of dental problems? How come there are so many incidents of people suffering from dental problems if the preventative care is that easy to manage? The answer lies in the concept of Adherence, referring to the cooperation of an individual with the demands of his treatment regime and the dental staff. The idea of promoting health adherence aims mainly for using medication, attending the periodic inspections and examination, and making lifestyle changes such as preventive care illustrated above. This article exemplifies how one of the current trends in Medical Psychology discipline is to enhance adherence by establishing a secure therapeutic alliance which is based upon a positive relationship between the patient and his doctor, increasing patient's confidence and sense of self efficacy, and recruiting family members and friends to the patient's process of change. A distinctive emphasis is put on expanding the patient's knowledge about his condition, and raising awareness to the linkage between his medical (to be more specific-dental) problem and its symptoms to the implications. The most modish and putative intervention nowadays is Patient Centered, where the guiding principles used are urging the patient to be responsible for implying the treatment regime, taking active participation, and make decisions regarding his current and future status. This article illustrates, through a comprehensive literature review of theories, models and researches, the contemporary methods for promoting adherence to oral hygiene, dental Self-Care and treatment. Using the combination of a survey from a select sample of specialists in the field of Dentistry, and the conclusions inferred from studies reviewed, I was able to determine how investment in the Bio-Psycho-Social approach would improve patient satisfaction from their doctors and outcomes of the treatment, shorten the duration of treatment, consume only little resources, improve dental health of patients and prevent repetitive visits to the dentists clinics. At the same time, despite the fact that dentistry practitioners acknowledge the importance of patient's adherence and take active measures such as talks, praises, guidance and providing information, most of them don't seem to comprehend interfusion of family members or friends as an integral part of the treatment. Moreover, their overall feeling is of incompetence when regarding dealing with un-adherent patients. Therefore, maybe there is room for providing dentists and staff with seminars, conventions etc. about the latest novelties on the subject. In conclusion, enhancing dental patient's adherence to health behavior is a domain mainly under the responsibility of the dentist, but also of his staff. As elaborated in the article, the measures for doing so are: 1. Information- the dentist should guide patients about the different methods for maintaining oral hygiene, explain how proper adherence benefits positive treatment outcome, and provide a broad and informative picture of the patient's specific problem. 2. Positive rapport - the need for establishing a good relationship between the doctor and his patients is crucial for attaining effective and satisfactory treatment outcomes. No doubt that this matter depends upon the personality and character of both the doctor and the patient, but using positive verbal reinforcements, symbolic incentives (such as free toothpaste samples), support throughout the treatment, sharing the rationale behind professional decisions with the patient, and proving several treatment options to choose from, are all methods for recruiting patients to the treatment process and the implementation of health behavior change. 3. Using reminders - the dentist can suggest different ideas for preventing slips and withdrawals in the patient's behavior, mainly through dental calendars or periodic phone calls to prompt patient's persistence in their actions. In addition, it is possible of course to use family and friends as a supportive auxiliary power. PMID- 21250406 TI - [The influence of the relationship between physicians and pharmaceutical companies on the patient from the point of view of policy-makers in Israel]. AB - BACKGROUND: The relationship between doctors and pharmaceutical companies is an integral part of the health system in Israel and the whole world. The mutual need for such a relationship requires us, as a society, to examine its influence on the individual and the system as a whole. AIM: This research examines the relationship from the points of view of the relevant parties within the health system and outside the health system (decision-makers). METHODS: The authors used in-depth interviews and qualitative research methods in order to examine and understand the various positions of decision-makers. FINDINGS AND CONCLUSION: The position of the decision-makers, regarding all the aspects of this relationship, expresses their wishes and depends on their point of view. The impact of the relationship between the doctors and the pharmaceutical companies was examined with regard to the prescription behavior of the doctor. All the government representatives, all the physicians' representatives and those of the health funds, believe that the physicians' prescription behavior is impacted by the relationship. There are those who perceive this to be a negative trend and some doctors believe it to be a positive trend. With regard to possible harm to the patient, the parties believe that the relationship does not harm the patient, whereas most of the government representatives identify harm to the patients, both on the economic and health levels. The authors believe that the "influence" which exists or could exist on the part of the pharmaceutical companies is the main stumbling block in this relationship, which is expressed in the decision makers' perspective. PMID- 21250407 TI - [Non-traumatic unintentional injuries and risk factors for hospitalization in children presenting to a pediatric emergency department]. AB - OBJECTIVE: Unintentional injuries are a major cause of morbidity and mortality in children. The authors present the results of a study in which data was collected regarding unintentional injuries presented to the Pediatrics Emergency Department (PED) at Ha'Emek Medical Center. The present study represents the first collection and analysis of such data gathered from the Pediatric Emergency Department in Northern Israel. METHODS: This was a prospective study in which data was collected regarding children who presented with non-traumatic unintentional injuries to the Pediatric Emergency Department (PED) between the years 2000 and 2002. The injuries presented included poisoning, aspiration and swallowing of foreign bodies, smoke inhalation and near drowning. Data collected included the type of injury, location and time of the accident, and data regarding the child and his family. The authors examined the association between variables in order to identify the risk factors for hospitalization. RESULTS: Of 412 children, 59% were males and 41% were females. Seventy-three percent of all accidents happened in the child's home or yard, and 36.5% occurred during the summer. Poisoning was the most common unintentional injury (61% of cases) and house cleaning material was the most common source of poisoning. The probability of hospitalization was higher for the following situations: aspiration of foreign bodies, injuries that occurred during the summer, children of Arab ethnicity and patients presenting to the hospital at night. IN CONCLUSION: This study presents initial data regarding these types of injuries from the Jezreel Valley. These data may help establish and target prevention programs. PMID- 21250408 TI - [The Hebrew dizziness handicap inventory]. AB - BACKGROUND: The dizziness handicap inventory (DHI) has become a well accepted method for specifically assessing the quality of life among dizzy patients and in evaluating the results of different types of therapy, especially of vestibular rehabilitation programs. OBJECTIVE: To assess the reliability of a translated Hebrew version of the DHI (HDHI) on a cohort of patients attending a tertiary dizziness clinic. METHODS: A double translation method was applied on the original DHI. Consecutive patients with symptoms of dizziness lasting at least six months were included. HDHI questionnaires were completed by patients on three occasions: while waiting to be examined, after the examination and one week later. Internal consistency reliability of each questionnaire and test- retest reliability between the questionnaires were analyzed on the total score and for each of the emotional, functional and physical subgroups of the questionnaires. RESULTS: Thirty-one patients completed all three questionnaires. Internal consistency reliability of the three subgroups of questions: physical, emotional and functional in each of the three questionnaires were all high (Cronbach's Alpha coefficient 0.83-0.96). The test- retest reliability, the correlation between the total DHI scores of the first and second questionnaire (same day) showed a correlation coefficient of 0.96, and between the first and third questionnaire (7 days apart) was 0.94, with P values of < 0.01. The correlation coefficient of the subgroups ranged from 0.93 to 0.97. CONCLUSION: The HDHI is a reliable test of dizzy patients' symptoms and may be applied in patient care and for reporting on their follow-up. PMID- 21250409 TI - [Gastric banding for extensive treatment of morbid obesity]. AB - BACKGROUND: Morbid obesity results in multiple comorbidities and an increased rate of mortality. Laparoscopic adjustable gastric banding (LAGB)--a restrictive operation, has been found to be a safe, effective and durable tool in the management of morbid obesity. OBJECTIVE: Through clinical observation, the authors evaluate whether the effect of LAGB on the adjustment of the patients to the new mode of food intake and their change in lifestyle while losing weight, is restrictive or beyond. METHOD: During the last decade, 5000 patients underwent LAGB and were followed up in our outpatient clinic by a single team. Careful observations and interviews contributed to our expending database. RESULTS: The data we collected during their visit is presented as a four phase eating habits model which describes the changes in quality and manner of life while reducing weight. CONCLUSIONS: The mechanism of LAGB for losing weight is beyond the restrictive effect of the band. PMID- 21250410 TI - [Surgical treatment of maxillary tumors]. AB - OBJECTIVES: Tumors originating in the maxillary sinus are relativeLy rare. The aim of this article is to review the indications, diagnosis and treatment of patients with maxillary tumors operated at Tel Aviv Sourasky Medical Center during the period 1999 - 2008. METHODS: A total of 174 patients underwent surgery due to neoplasms originating in the maxillary sinus: 118 patients (68%) had malignant and 54 (32%) had benign tumors. RESULTS: The most common malignancy was squamous cell carcinoma (40%), and the most common benign tumor was juvenile nasopharyngeal angiofibroma (36%). A total of 146 patients (84%) underwent partial maxillectomy and 28 (16%) total maxillectomy. In 9 cases, resection was extended to include the eye socket or base of skull, due to tumor invasion. Thirty-five patients had post-operative complications, with local wound infection being the most common complication (n = 12). Among patients with malignant tumors, 75 are alive without disease (67%), 12 (10%) are alive with disease and 31 (23%) died of disease or other causes. CONCLUSIONS: The surgical approach to malignancies of the maxilla is safe and effective. A multidisciplinary team approach is essential to deliver appropriate therapeutic means for these patients. PMID- 21250411 TI - [708 IMAJ 2009--toward the next decade]. PMID- 21250413 TI - [Nutritional deficiencies in bariatric surgery patients: prevention, diagnosis and treatment]. AB - The number of people suffering from surgery and obesity in the western world is constantly growing. In 1997 the World Health Organization (WHO) defined obesity as a plague and one of greatest public health hazards of our time. The National Institution of Health (NIH) declared that surgery is the only long-term solution for obesity. Today there are four different types of bariatric surgery. Each variation has different implications on the nutritional status of bariatric surgery patients. Bariatric surgery candidates are at risk of developing vitamin and mineral nutritional deficiencies in the post-operative stage, due to vomiting, decrease in food intake, food intolerance, diminution of gastric secretions and bypass of absorption area. It is easier and more efficient to treat nutritional deficiencies in the preoperative stage. Therefore, preoperative detection and correction are crucial. Blood tests before surgery to detect and treat nutritional deficiencies are crucial. In the postoperative period, blood tests should be conducted every 3 months in the first year after operation, every six months in the second year and annually thereafter. Multivitamin is recommended to prevent nutritional deficiencies in all bariatric surgery patients. Furthermore, iron, calcium, Vitamin D and B12 are additionally recommended for Roux-en-Y Gastric Bypass patients. Patients with Biliopancreatic diversion and Duodenal Switch should also take fat soluble vitamins. PMID- 21250412 TI - [Aspirin for primary prevention of cardiovascular diseases--lessons from recent studies]. AB - Aspirin is recommended as a primary prevention treatment of cardiovascular disease for the population at risk. The American Heart Association guidelines of 2002 recommended aspirin as primary prevention for patients with a cardiovascular risk of over 10% per decade (according to the Framingham study). Over the last few years, several double-blind controlled studies analyzed the affect of aspirin for primary prevention in several population groups. For example, while the effect of aspirin in men is mainly in lowering myocardial infarction risk, the effect in women is mainly in lowering the risk of cerebrovascular accident. In view of those studies, the U.S. Preventive Services Task Force (USPSTF) published a gender-based set of guidelines for the use of aspirin as primary prevention. Despite the studies and the USPSTF guidelines, controversy still persists regarding aspirin as a primary prevention therapy. The available use of other therapeutics as a measure for primary prevention and the different harm-benefit ratio scaling for the aspirin effect, all contribute to the controversy. These considerations have led some of the authors of articles in this edition to recommend against administering aspirin as primary prevention. Studies in diabetic patients have shown inferior results compared to the general population. CONCLUSION: Despite tens of thousands of patients over the years, controversy over aspirin as a primary prevention measure still prevails. Therefore, the physician who decides on aspirin for primary prevention has to base his decision on the unique characteristics of each specific patient. PMID- 21250414 TI - [Optic pathway gliomas--current position and future directions]. AB - Optic pathway gliomas (OPG) are the most common primary tumors of the visual pathways, and constitute 1% of all brain tumors and 5% of all brain tumors in children. Among Neurofibromatosis type 1 patients (a hereditary genetic disorder which is characterized by higher incidence of tumors from a neurocutaneous origin) it is the most frequent tumor and it constitutes between 15 to 20 percent of all nervous system tumors. These tumors are stable most of the time and remain indolent for many years after diagnosis, especially in patients suffering from Neurofibromatosis type 1. However, amongst some of the patients suffering from OPG, these tumors develop progressive characteristics and can cause visual disturbances, endocrine dysfunction, blindness and even death. Patients with aggressive tumors will need treatment, which can be either surgery, chemotherapy or radiation therapy. Today, the treating physicians face substantial difficulty in estimating the course the tumor will take, choosing the right candidates for oncological treatment and the type of therapy most suited to the case, due to lack of reliable information in the relevant literature. This article characterizes the tumors, presents updates from recent literature, as well as recommendations for treatment and follow-up. PMID- 21250415 TI - [Knee injury in cyclers]. AB - Cycling is currently one of the most popular recreational activities. Hence, there are increases in the numbers of injuries resulting from cycling. Most of the injuries are to the knee and are of non-contact nature and therefore, preventable. The majority of pain syndromes are non-traumatic and caused by overuse, inadequate preparation, inappropriate equipment, poor technique and lack of training. The treatment of non-traumatic knee injuries is regularly conservative, including: rest, ice, NSAID's training programs modification and adequate equipment. Delayed treatment can cause chronic injuries. PMID- 21250416 TI - [The feminization of obstetrics and gynecology]. AB - Contemporary data indicate female dominance of obstetrics and gynecology. The authors sought to look for the effects of this domination on the discipline and further understand the reasons for these effects as reflected from the relevant current literature. Data clearly show a worldwide "creeping" process of female domination in the field of obstetrics and gynecology. Gender bias is present in hiring policies both for residency and afterwards. Female physicians encounter specific gender problems such as pregnancy, maternity leave and the additional burden of taking care of their family. These tasks may interfere with academic medicine. Furthermore, personal characteristics of women, which favor them for patients, may affect their productivity within the framework of community medicine. None of the alleged problems, which were linked to female obstetrician gynecologists, is irresolvable, assuming professional establishment, as well as government acceptance and proper planning. PMID- 21250417 TI - [Facing health inequities: the Negev as a case study--Center for Health Policy Research in the Negev and the Department of Health Systems Management, Faculty of Health Sciences, Ben Gurion University, June 2010]. PMID- 21250418 TI - [Childhood obesity--11th International Congress on Obesity, Stockholm, Sweden, 2010]. PMID- 21250419 TI - [On literature and medicine]. PMID- 21250420 TI - [Innovation in surgery]. PMID- 21250421 TI - [Clinical pathway in traumatology, a fashion or need?]. AB - A clinical route is defined as a "set of methods and instruments to members of a multidisciplinary and Interprofessional team to agree on the tasks for a specific patient population. This is a program of care to ensure the provision of quality care and efficient realization". The University Hospital is not immune to this phenomenon. In the Department of the musculoskeletal system, a first project of this kind concerns the fracture of the proximal femur in the elderly. PMID- 21250422 TI - [Pit falls in the emergency walk in clinic: upper limb]. AB - Trauma to the upper extremity presents difficulties in diagnosis because of the complexity of the anatomy and of the structures involved. These injuries are common, representing more that 45% of all injuries coming to a walk-in emergency center. Commonly missed or misdiagnosed injuries are listed below with clinical examples. Posterior dislocation of the shoulder or perilunar dislocations of the carpus are still commonly missed today in spite of ample information in all medically oriented media. This series of articles is tended to warn emergency room practitioners of the these traps for the unwary. PMID- 21250423 TI - [Meticulous approach of the distal numeral epiphyseal fractures]. AB - Epiphyseal fractures of the distal humerus and their treatment are common, source of many complications that may be immediate but also delayed. If the families accept the possibility of trauma to their child as part of his leisure activities or sports at times intense, they are much more intolerant if their child does not return after injury and repair, optimal function and physical performance unchanged. This intolerance, faced with the trauma but not its consequences, requires us to be particularly careful in the information given to the patient but also in monitoring the first few weeks. The treatment of epiphyseal fractures remains difficult and must be performed by trained teams, aware of the subtleties of pathology. It is essential to organize close monitoring and critical to be able to correct errors or secondary displacement in the first 15 days. PMID- 21250424 TI - [Update on total hip arthroplasty]. AB - Total hip arthroplasty (THA) is one of the most common surgical procedures performed by orthopedic surgeons. Frequent indications for THA include osteoarthrosis of the hip joint that can be primary origin or secondary to dysplasia or traumatic origin, as well as fractures of the femoral neck in active patients. Other common indications include rheumatoid arthritis and osteonecrosis of the femoral head. It is a surgical intervention giving very good results giving patients pain relief and mobility with a success rate in more than 90% of cases. The point of this article is to inform the medical community on the actual situation of hip prosthetics in fields including epidemiology, clinical results, indications, contraindications, different types of prosthetic materials as well as surgical approaches. PMID- 21250425 TI - [What's new in forefoot surgery]. AB - New implants and instruments have recently emerged in foot surgery. However, an additional and important development is the technique of minimally invasive surgery. As a result of new surgical approaches some common foot deformities can be corrected in a percutaneous manner. The benefits include improved wound healing, less pain, faster recovery, and less need for outpatient care. The main indications for such a technique are hallux valgus, correction of the lesser metatarsals, hallux rigidus, and some diabetic foot deformities. PMID- 21250427 TI - [The number pi is like alternative medicine: irrational]. PMID- 21250426 TI - [The "anticancer" virtues of aspirin]. PMID- 21250428 TI - [Yes, you can say (and write) in French!]. PMID- 21250429 TI - [Benedict XVI and AIDS: the first mea culpa? (2)]. PMID- 21250430 TI - [Incongruous, ironic and curious]. PMID- 21250431 TI - [Distributions of dissolved and particulate amino compounds in atmospheric aerosols at Qingdao]. AB - Amino compounds is one class of organic nitrogen compounds that has been measured extensively in aerosols and rainwater. These compounds in atmospheric deposition might have a potential role in marine ecosystem since it can be directly utilizable sources of nitrogen for microorganisms and plants. 66 total suspended particles samples were collected at Qingdao from January to December in 2008. Concentrations of dissolved amino compounds (DAC) and particulate amino compounds (PAC) were analyzed using precolumn fluorescence derivatization with o phthaldialdehyde and N-isobutyryl-L-cysteine, combined with reverse-phase high performance liquid chromatography. Concentrations of DAC in Qingdao aerosols ranged from 2.4 to 40.9 nmol x m(-3), with highest values occurring in spring, followed in summer and lowest values in autumn and winter. PAC concentration were from 0.7 to 76.1 nmol x m(-3), presenting the seasonal trend of spring > winter > autumn > summer. Compositions of amino compounds in aerosols varied seasonally. By classifying air mass back trajectories during each sampling period, the aerosol samples in Qingdao were mainly influenced by northerly continental source, southerly continental source and marine source. Concentrations of DAC and PAC were found highest in the samples influenced by southerly continental source, followed by northerly continental source and lowest in the samples by marine source. Compositions of amino compounds were also influenced by the sources. Contributions of protein-type to total amino compounds were highest in the aerosols from marine source and lowest in the aerosols from southerly continental source. PMID- 21250432 TI - [Sulfuration character of individual particulates of PM10]. AB - SEM/EDX was used to analyze the component and sulfuration characteristics of individual mineral particulates of PM10, which were collected at different times in summer of Harbin. The results indicate that, the 29 species of mineral were identified in summer of Harbin, in which the proportion of clay minerals is over 40%; There are almost no changes in sulfuration in the noon-time period samples, however, the samples collected in the morning and evening show universal sulfuration. In all samples, clay minerals have the highest sulfuration incidence, the average ratio of S/Ca value is 1.0, which is 73 times of noon sample S/Ca value. The sulfuration degree of samples at different times and meteorological condition show different mechanism of sulfuration. According to different content of mineral elements, mineral grains could be divided into five types: "Si-rich", "Ca-rich", "S-rich", "Fe-rich", "Mg-rich", respectively, showing that the mineral particles mainly come from the crust source; The mineral particles at different times have homology, which indicates that the atmospheric secondary chemical reaction could be the only reason leading to the S rich in morning or evening periods samples, and rule gypsum particles was formed mainly by sulfuration of calcium carbonate mineral salt such as calcite minerals, etc. PMID- 21250433 TI - [Water-soluble anions of atmosphere on Tianwan nuclear power station]. AB - Three major water-soluble anions (Cl-, SO4(2-) and NO3-) in the atmosphere of the Tianwan nuclear power station in Lianyungang were determined by ion chromatography from June 2005 to May 2006. The results showed that the annual average concentration of Cl-, SO4(2-) and NO3- in the atmosphere of Tianwan nuclear power station was (33.12 +/- 53.63) microg x m(-3), (53.34 +/- 30.34) microg x m(-3) and (8.34 +/- 4.47) microg x m(-3), respectively. The concentrations of the three water-soluble anions showed evident trend of seasonal variation. The concentrations of Cl-, SO4(2-) reached the highest level in summer and the lowest level in winter, while the concentration of NO3- in autumn and winter was higher than those in summer and spring. Meteorological parameters such as wind direction, wind speed, temperature and relative humidity were studied and showed definite influence to the anions concentration of the atmosphere. This is the first simultaneous monitoring of corrosive anions in the atmosphere of Chinese coastal nuclear power plant, and it will provide basis for the prevention of marine atmospheric corrosion, which will ensure the safely operating of our nuclear power industry. PMID- 21250434 TI - [Variation of total ozone over Tibetain Plateau during 30 years monitored by remotely sensed data]. AB - This paper is study on the temporal and spatial dynamics characteristics of total ozone over Tibetain Plateau from 1979 using multi-resource remote sensing. The findings indicate that the total ozone over Tibetain Plateau is continuously decreasing. The decreasing rate is larger than the global and northern hemisphere average, and the average annual decreasing rates are about 0.23%, 0.19% and 0.12% for Tibetain Plateau, global and northern hemisphere average respectively. However, the decreasing rate is lessening after 2000. The decreasing rates each year are about 0.51%, 0.49% and 0.31% during the 3 stages of 1979-1989, 1990-1999 and 2000-2008. The days of total ozone over Tibetain Plateau lower than 240 DU is up to 34 d, and there is not largely lower ozone (lower than 240 DU) area after 2005; the seasonal variation of total ozone present sinusoidal, the largest and smallest value appear in March and October, the average values are about 304.59 and 265.45 DU respectively. But the smallest of daily value are often appears in November or December. The largest and smallest fluctuation of total ozone appear in February and September with the standard deviation of 17.28 and 5.88 DU respectively; the total ozone and altitude is inversely relationship, lower ozone appear over higher altitude areas, especially, over Tibetain Plateau region. Compare with the average total ozone over the same latitude, the total ozone over Tibetain Plateau is lower with about 19 DU, and give birth to an ozone valley. PMID- 21250435 TI - [Reaction of NO with metal oxides and urea supported on activated carbons at low temperature]. AB - The catalysts were prepared by activated carbon fiber (ACF) loaded different contents of NiO and NiO-CeO2, Urea was loaded on the prepared catalysts as reductant. The experiments of selective catalytic reductions (SCR) of NO were carried out from 30 to 120 degrees C. The experiments of SEM, BET and XRD of the samples were also carried out selectively to study the catalysts properties, respectively. The experimental results showed that the loaded mass fraction of NiO could greatly affect the catalytic activity of the catalysts. 10% NiO catalyst activity and activity stability were both higher than that of the others, and it could yield about 50% removal efficiency of NO at 90 degrees C. With the loaded mass increasing, the catalytic activity was obviously decreased. And furthermore, the catalyst of 5% NiO-5% CeO2/ACF had the best catalytic activities on SCR NO and stability among the prepared NiO-CeO2/ACF catalysts, and its NO removal efficiency was over 55% at 110 degrees C. When the loaded mass increased, the similar phenomenon was observed, which was due to the decreasing of specific surface area of the catalysts. The metal oxides, loaded on ACF, were the catalytic centers in this study. Moreover, 5% CeO2-5% NiO/ACF had the highest catalytic activity than 10% CeO2/ACF and 10% NiO/ ACF. Therefore, there should be synergistic effect between CeO2 and NiO. Finally, the catalytic mechanism of SCR on NO at low temperature was discussed. PMID- 21250436 TI - [Adsorption performances for sulfur dioxide using imidazole ionic liquids]. AB - To discover the SO2 adsorption laws of ionic liquids in simulating flue gas, the SO2 adsorbents 1-butyl-3-methylimidazolium chloride ([Bmim] Cl), 1-butyl-3 methylimidazolium nitrate ([Bmim] NO3), 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim] BF4) and 1-amyl-3-methylimidazolium chloride [C5 mim] Cl ionic liquids were synthesized. The performances were studied under different conditions and the general rules of regeneration were explored. And the diversification of [Bmim] Cl chemical structures, which were pre-desulfated, post desulfated and post-regenerated, were characterized by Fourier Transform Infrared Spectroscopy. The results illustrated that these ionic liquids all had the ability of SO2 adsorption, and the order of SO2 adsorption performances was [C5 mim] C1 > [Bmim] Cl > [Bmim] NO3 > [Bmim] BF4. The total SO2 adsorption amount of [C5 mim] Cl was 200. 8 mg/g, and the optimal adsorption temperature of [Bmim] Cl was 40 degrees C. The order of anions impacting adsorption performances of ionic liquids was Cl- > NO3- > BF4-. The sulfur capacity of ionic liquids decreased to 26.5 mg/g from 65.9 mg/g after desorption under the condition of heating (90 degrees C), vacuum (0.09 MPa) and 4.0 h. In addition, the chemical structures of ionic liquid had changed, and the forms of SO2 adsorbed by [Bmim] Cl were physico chemical processes. PMID- 21250437 TI - [Output characteristics of non-point nitrogen from a typical village region in Yangtze Delta under an individual rainfall event]. AB - In order to provide a scientific foundation for controlling non-point source pollution, we studied on output characteristics of non-point nitrogen under different land uses in a typical agricultural village in the Yangtze River Delta. The various species of nitrogen and output load under a typical individual rainfall runoff event were investigated. The results indicated that the event mean concentrations (EMC) of total nitrogen (TN) in monitoring sites ranged from 20.01 mg/L to 22.83 mg/L, and the main form was dissolved nitrogen (DN) in TN. The main form of the lost nitrogen in the studied area was DN which was mainly composed by dissolved organic nitrogen (DON). Coupled with the characteristics of nitrogen concentration and runoff, two peaks of non-point nitrogen output could be found, and appeared 4-55 min before the runoff peaks. The concentrations of TN, DN, and nitrate (NO3(-) -N) decreased with the rainfall time increasing. Nitrogen load was influenced by its concentration and runoff, and showed the same output characteristics of nitrogen concentration with a gentle variation. Form the cumulative load curve of nitrogen in a typical rainfall event, first-flush effect could be found for each nitrogen species in rural runoff. PMID- 21250438 TI - [Characteristics and loads of key sources of pollutions discharged into Beishi River, Changzhou City]. AB - Choosing the Beishi river, Changzhou City as the study area, the sewage generation, pollutants characteristics and sewage discharge in catchment area of Beishi river were conducted, detailed investigated and monitored. After using pollution coefficients, the yearly loads of all sources of pollutions were calculated to determine the highest sewage. The results showed that: except pH, the high concentration of SS, COD, BOD5, ammonia nitrogen, TN and TP discharged from MSW collecting houses, MSW transfer stations, public toilets and dining in Changzhou city far exceeded the "Integrated Wastewater Discharge Standard" (GB 8978-1996) and "Effluent Discharged into the City Sewer Water Quality Standards" (CJ 3082-1999). Among which: the highest concentration of COD discharged from MSW transfer stations was up to 51 700 mg/L, while the ammonia nitrogen and TN were as high as 1 616 mg/L and 2 044 mg/L in the toilet wastewater. In addition to this, the ratio of wastewater discharged directly into the river through storm water pipe network was higher from MSW houses, MSW transfer stations, public toilets, dining and other waste in Changzhou city. The 125.2 t/a of COD and 40.53 t/a of BOD5 were the two highest concentrations of various sources of pollution. The highest annual polluting loads discharged into Beishi river is dining, followed by the sanitation facilities. Therefore, cutting pollution control of food and sanitation facilities along the river is particularly urgent. PMID- 21250439 TI - [Study on ecoregion techniques of lake nutrients in Yunnan-Guizhou plateau Lake regions]. AB - The primary objective of this research is to present an ecoregion model based on the principle components analysis (PCA), the cluster analysis (CA), the discriminant analysis (DA) and the spatial autocorrelation analysis (SAA), which were applied to establish the ecorigion of lake nutrients in Yunnan-Guizhou Plateau Lakes. First, the principle components analysis method was used not only to reduce the dimensionality of the feature space, but also to deal with new indexes. The accumulation contribution ratio of the four new indexes achieved 93.69%, which had the full representation. These complementary indexes which reflect the conditions of lakes were helpful to establish the index system of ecorigion of lake nutrients in Yunnan-Guizhou Plateau Lakes. Second, initial classification of lake drainage area was accomplished by new indicator values and cluster analysis which contained five classes, and then the categories of non lake drainage area could be identified by the discriminant analysis. Finally, the cluster result was carried on the global statistics, Moran's I was 0.32 which was higher than 0, and the examination value Z was 68.28 which was higher than marginal value (remarkable level 1% correspond 2.58), it was indicated that the cluster result and the space position had the remarkable relativity, afterward spatial distribution pattern of the region was achieved by the quantificational analysis about over score of principle components and application of local spatial autocorrelation method. Then the ecorigion of lake nutrients was accomplished by the association and difference between different districts of the scattered regions' s spatial character. These results indicated that the ecoregion model initiated in the paper was appropriate and feasible to receive objective results and avoid artificial factors. Also it has provided a new method to explore the index system and techniques about the ecoregion of lake nutrients. Scientifically, the model was in favor of the foundation of lake nutrient criteria and eutrophication control standards in China. PMID- 21250441 TI - [Study on simulation of clarification for Vegetative Filter Strips by VFSMOD Model]. AB - The functions and mechanism of Vegetative Filter Strips Model (VFSMOD) had been introduced in this paper, and the applicability and performance ability of this model have been tested by plot experiment data. The results show that the relative deviations between simulated values and measured values of outflow quantity are within +/- 15%, while with the concentration of SS, the relative deviations are within +/- 20%, and the determination coefficients between simulated values and measured values for outflow and SS are 0.995 and 0.889 respectively. Therefore, the simulation precision of this model is satisfactory, the model can be used as a tool for the design of VFS. PMID- 21250440 TI - [Quantification study on the runoff and seepage distribution and N, P pollutants removal of the vegetated buffer strips]. AB - By using the constructed buffer strips test base and the runoff hydrometric devices, a research on stagnant runoff and nitrogen (N), phosphorous (P) pollutants removal capacity of the vegetated buffer strips was conducted. The results show that the vegetated buffer strips might reduce the speed of runoff significantly and improve the hydraulic permeability of soil. The runoff water output time of 19 m buffer strips planted with Cynodon dactylon, Festuca arundinacea and Trifolium repens are 2.46, 1.72 and 2.03 times higher than the control (no vegetation) respectively; The seepage water quantity of three vegetation buffer strips are 3.01, 2.16 and 2.45 times higher than the control respectively as well. Total removal efficiency of the three buffer strips increase about 237%, 268% and 274% comparing with the control respectively. The N, P removal capacity of seepage is significantly higher than that of the runoff, the larger seepage water quantity will cause higher N, P total removal efficiency and removal loads of unit area. With different vegetated buffer strips, the TN, NH4(+) -N, TP removal ratio of seepage and runoff are 2.79, 2.02 and 2.83 respectively. PMID- 21250442 TI - [Study on the potential pollution in river section based on PPI]. AB - A new method named river section potential pollution index (R-PPI), which could forecast the influence of the potential pollution in river section was developed and applied in the three typical watersheds in mountainous area in Beijing. Water pollution is one of the most important water environment problems, and the administration needs to clear main polluted river section, area and pollution source. Assessment methods of river water quality based on water quality monitoring is hard to clear main pollution source. Based on potential non-point pollution index (PNPI), 3 important improvements were made including extending land use types, matching land use types and dividing the soil permeability classes and the PPI and R-PPI was developed. The research on the application in three watersheds showed that R-PPI is a simple and comprehensive method. It needs less monitoring data and is easier to find main pollution source, which can offer scientific rule for watershed pollution control. PMID- 21250443 TI - [Application of automated identification and quantification system with a database (AIQS-DB) to screen organic pollutants in surface waters from Yellow River and Yangtze River]. AB - Approximately 1 000 chemicals were screened in surface waters from downstreams of Yellow River and Yangtze River using GC-MS coupled with Automated Identification and Quantification System with a Database (AIQS-DB). 95 pollutants were detected in water samples from Yellow River in Shandong Province and 121 in those from Yangtze River in Jiangsu Province. The pollutants involved n-alkanes, PAHs, phenols, nitro compounds, phthalates esters (PAEs), pesticides and pharmaceuticals, etc. The average concentrations of n-alkanes, 16 priority PAHs and 6 priority PAEs were 1 806 ng/L, 27 ng/L, 77 ng/L in water samples from Yellow River and 720 ng/L, 30 ng/L, 2 166 ng/L in water samples from Yangtze River respectively. Besides, 9 and 11 pesticides were detected in water samples from Yellow River and Yangtze River respectively. The levels of pollutants showed stronger site dependence in samples from Yellow River than those from Yangtze River. Combination of GC-MS and AIQS-DB shows high efficiency in regional pollutants survey. PMID- 21250444 TI - [Dynamics model analysis of pollutants removal in aerated vertical-flow wetland]. AB - Based on the dynamic model building of pollutants removal in aerated vertical flow constructed wetland, data of the wetland under different aeration conditions were analysed. Different aeration conditions' k values were calculated, which represented the pollutants removal kinetic constants. The results demonstrate that the efficiency of pollutants removal is higher with the increasing gas-water ratio. The most favorable designing gas-water ratio of the aerated vertical-flow constructed wetland was chosen as 2 : 1 through analysis of curve fits by regression with kinetic constants values and gas-water ratio values. The corresponding k values of BOD5 and NH4(+) -N are 3.8 d(-1) and 4.1 d(-1) respectively. PMID- 21250445 TI - [Bioremediation of micro-polluted source water by simulated river bioreactor with different carriers]. AB - Two simulated river bioreactors with elastic filler and AquaMats were applied to remediate micro-polluted source water. Under intermittent aeration and gradual increase of aeration intensity, the biofilm reactor with elastic filler was successful start-up within 50 days, and average removal efficiencies of permanganate index, NH4(+) -N were 78.2% and 93.5%, respectively, but the removal efficiencies of the reactor with AquaMats were more than 70% and 80% after two weeks. On the condition of aerobic to anoxic ratio of 3 h: 3 h and aeration intensity of 250 L x h(-1), elastic filler was more efficient for the removal of permanganate index, NH4(+) -N, TN and TP. The pollutant removal of AquaMats was strongly enhanced when the aerobic to anoxic ratio and aeration intensity changed to 2 h :4 h and 120 L x h(-1), which suggested its potential of energy saving. Microscopic observation revealed that the surface of elastic filler was fully surrounded with filamentous bacteria and more inorganic particulate matter after successful start-up of the reactor, and the biofilm attaching to AquaMats was of higher microbial population diversity. The results indicated that elastic filler with homogeneous biofilm had a strong retention capacity for its radial structure, and the AquaMats with microporous structure was more suitable for the enrichment of different functional microorganisms and enhanced the collaborative removal of multiple pollutants. PMID- 21250446 TI - [Effects of sediment dredging on benthos community structure and water quality in Zhushan Bay]. AB - We surveyed the changes of macro-benthos community composition and nutrients concentration in water in Zhushan Bay after it had been dredged 6 months, which aimed to remove the polluted surface sediments. The results showed that the main benthos in the dredged and un-dredged sediments were Limodrilus hoffmeisteri, Pelopia and Bellamya aeruginosa; compared to the un-dredged sediments, the bio diversity of dredged areas became lower. However, its biomass became higher than that in un-dredged areas. Concentration range changes of TN and TP in overlying water was 1.64-4.45 mg/L and 0.133-0.258 mg/L, respectively. The post-dredged sediments were still in a higher state of nutrients for the higher concentration nutrients in overlying water, macro-benthos were the species that lived in a serious polluted water environment. Using Shannon-Weaver, Simpson, and Goodnight benthic index to evaluate the results show that the dredged area is in the moderately polluted level, but un-dredged area is in the middle-heavily polluted level. According to the benthos fauna surveys and water quality monitoring results, the effective of sediment dredging could play its role only the strict control on the external pollution resources have been made and reduces the effects of polluted water on the sediments. PMID- 21250447 TI - [Environment effects of algae-caused black spots: impacts on Fe-Mn-S cycles in water-sediment interface]. AB - The driving effects of algal cells settlement in the water-sediment interface on Fe, Mn, S biogeochemistry in laboratory through static cultivation device. Results showed that dissolved oxygen would be exhausted by algae cells in 50 min after the cyanobacteria cells settled to the sediment surface. Soon the water sediment interface formed the severe anoxia and Fe-Mn oxides and sulfides were deoxidized quickly in the strong reducing environment. The Fe2+, Mn2+ content in interface increased to the summit at the 4th day and their concentrations were 4.40 mg/L and 2.35 mg/L, respectively. When it comes to the end of the experiment, the Fe2+ content had a little reduction and Mn2+ reduced quickly, their concentrations were 3.37 mg/L and 0.97 mg/L at the end of experiment. However, S2- concentration in interface reached the highest at the 2nd day and its content was 0.63 mg/L, and its concentration was only 0.12 mg/L at the end since it has been reduced. The ORP was--150 mV in the sediment surface and indicated that the sediment environment was a strong reducing environment. Phenomenon of algal cells induced black spots in water bodies was the main driving factors on Fe/Mn oxides and sulfides biogeochemistry cycle, and also the extreme anoxia environment would have great harm on the water body's ecology. PMID- 21250448 TI - [Effect of low phosphorus concentration on the growth of Scenedesmus obliquus and phosphorus removal]. AB - Effects of phosphorus of low concentrations on the growth and the phosphorus removal efficiency of Scenedesmus obliquus were investigated in this study. Results showed that Scenedesmus obliquus achieved a phosphorus removal efficiency of 100% within 22 h when the initial algal cell concentration was 1 x 10(5) /mL and the initial phosphorus concentration was 0.02-0.10 mg/L. With the initial phosphorus concentration increased from 0.02 mg/L to 0.10 mg/L, both growth velocity of Scenedesmus obliquus and maximum biomass increased obviously. Research found that phosphorus concentration had a significant influence on cell morphology of algal. In the external phosphorus sufficient conditions, most of algae cell present as four cells gather round form, then transformed into two cells side by side form in the absence of external phosphorus in culture medium, Finally in single as the main form of existence. PMID- 21250449 TI - [Effect of different type sediments on transformation of phosphorus forms and growth of Myriophyllum spicatum]. AB - The changes of the different phosphorus (P) forms in sediments, overlying water and the diversity of dry weight and root forms of Myriophyllum spicatum were studied using different type sediments under simulating condition. The characteristic of transformation of P forms and growth of submerged plant Myriophyllum spicatum were illustrated. The results indicated that the P release was promoted by adding the silver sand in sediment, and their P concentrations in the overlying water were increased. The chemical characteristic of the sediments were changed by adding NH4 Cl, which restrained the P release from their sediments and decreased the P concentration in their overlying water. About 49%, 107% of their plant, root dry weight and 19% root length of Myriophyllum spicatum from different treatments were raised by adding silver sand in sediments. The root growths of the Myriophyllum spicatum from different treatments were restrained and their agings were promoted by adding NH4 Cl in sediments. The P release from sediments were accelerated by the growth of Myriophyllum spicatum, and the early decay of Myriophyllum spicatum can increase the P accumulation in sediment. The changing trend of different P forms in the sediments decreased firstly, and then increased with the Myriophyllum spicatum growthing, their contents of Fe/Al-P form in sediments varied greatly (41%-57%). The P release and adsorption in sediments were mainly affected by their root length index of Myriophyllum spicatum from different treatments. The P release in sediment was accelerated through their changing penetrate capacity by root diameter increasing. PMID- 21250450 TI - [Kinetic analysis of laccase catalyze phenolic and aniline compounds and detecting catechol in wastewater]. AB - Phenolic or aniline compounds were important pollutants in the industrial wastewaters to seriously polluted water environment. This research developed a detecting method of phenolic and aniline compounds based on the kinetic parameters of the substrates of laccase. Catalytic reaction between laccase and phenolic and aniline compounds was characterized using spectrophotometic method, which resulted 0-10 mg/L substrate reaction rate and calibration curve of substrate concentration and reaction rate. And then the non-volatile phenols in three kinds of coking wastewater were screened and the contents were detected. The result showed that polyhydric phenol, multi-amine and aminophenol were the main substrates of laccase. The optimum pH of phenols was around 7.0 and anilines 4.5-5.0, K(m) values of each substrates was 0.4-10 mmol/L. The calibration curve performed good first order kinetics linear relationship except benzidine with correlation coefficients above 0.96. Using laccase method, the contents of catechol in three kinds of coking wastewater were respectively detected to be 190.5, 265.8 and 155.3 mg/L with recoveries ranged from 89.9% to 115.8%. PMID- 21250451 TI - [Analysis on the spatial characteristics of the light quantum yields in Lake Taihu in spring]. AB - Based on the primary productions and underwater irradiance in the head of the jetty in a station of the Lake Taihu ecology network of the Chinese academia, Zhihugang estuary area, the center of Lake Taihu and Xukou Bay at April 28, May 4, May 5, May 6 in 2009, the light quantum yields of algae and P-I curve were calculated. Then the spatial characteristics were analyzed. There was significant photoinhibition in the head of the jetty in a station of the Lake Taihu ecology network of the Chinese academia; there was not appreciable photoinhibition in Zhihugang estuary area and the center of Xukou Bay; and there was only light saturation phenomena in the center of Lake Taihu. The order of the light quantum yield per Chl-a was the center of Lake Taihu, the head of the jetty, Zhihugang estuary area and the center of Xukou Bay. PMID- 21250452 TI - [Optimization immobilizing activated carbon and bacteria by sodium alginate and its character of adsorption of Pb2+]. AB - Through the immobilized biosorption of activated carbon and Paenibacillus polymyxa GA1 by sodium alginate, this paper take advantage of the orthogonal experiment to investigate the adsorption characteristics of sodium alginate. According to the research, the optimal preparation conditions were as following: the mass fraction of sodium alginate was 2.5%; the amount of carbon and bacteria was 1:20 and 1:2, respectively; under the preparation condition, the adsorption rate could reach to 93.74%. The adsorption conditions of the immobilized beads were: pH 5, temperature 30 degrees C and Pb2+ with an initial concentration of 300 mg x L(-1). Moreover, the immobilized activated carbon and GA1 improved their application range of pH, temperature and the initial concentration of Pb2+. Based on the equilibrium curve, it showed that the adsorption of Pb2+ was a rapid process within 30 min and gradually reached leveling within 2 h. What's more, the equilibrium curve could be well described by Langmuir model and Freundlich model, which be consisted mainly of monolayer adsorption, and the maximum monolayer adsorption amount was 370.37 mg x g(-1). Finally, the desorption result showed that the immobilized beads could be recycled effectively. PMID- 21250453 TI - [Characterization of Cr (VI) removal and total Cr equilibrium adsorption by sulfate reducing granular sludge in stimulant wastewater]. AB - Sulfate reducing granular sludge (SRGS) cultivated in small scale EGSB reactor was used for Cr (VI) removing. Characterization of Cr (VI) removal and total Cr equilibrium adsorption was studied, and the adsorption isotherm was fitted. Results showed that removal of Cr (VI) was in connection with the structure and chemical composition of SRGS and several environmental factors. The Cr (VI) removal rate increased with the dosage of granular sludge; the increasing of oscillation speed and temperature could enhance Cr (VI) removal and total Cr adsorption, but while the oscillation speed reached 150 r x min(-1) or the temperature came to 40 degrees C, the physical structure of granular sludge would be affected and the granular sludge discrete, and total Cr equilibrium adsorption decreased; lower pH value caused higher Cr (VI) removal rate, however the sulfate on the surface of granular sludge was affected by lower pH value easily and would translate into H2S, then total Cr adsorption rate decreased. Cr (VI) removal would be influenced by physical, chemical and biological factors, and the process included reduction and adsorption mainly. The maximum adsorption of total Cr by granular sludge was 6.84 mg x g(-1), and the total Cr adsorbing process fitted in with Langmuir adsorption isotherm. PMID- 21250454 TI - [Thermodynamics adsorption and its influencing factors of chlorpyrifos and triazophos on the bentonite and humus]. AB - The adsorption of chlorpyrifos and triazophos on bentonite and humus was investigated by using the equilibrium oscillometry. The adsorption capacity of chlorpyrifos and triazophos on humus was great higher than bentonite at the same concentration. Equilibrium data of Langmuir, Freundlich isotherms showed significant relationship to the adsorption of chlorpyrifos and triazophos on humus (chlorpyrifos: R2 0.996 4, 0.996 3; triazophos: R2 0.998 9, 0.992 4). Langmuir isotherm was the best for chlorpyrifos and triazophos on bentonite (chlorpyrifos: R2 = 0.995 7, triazophos: R2 = 0.998 9). The pH value, adsorption equilibrium time and temperature were the main factors affecting adsorption of chlorpyrifos and triazophos on bentonite and humus. The adsorption equilibrium time on mixed adsorbent was 12h for chlorpyrifos and 6h for triazophos respectively. The mass ratio of humus and bentonite was 12% and 14% respectively, the adsorption of chlorpyrifos and triazophos was the stronglest and tended to saturation. At different temperatures by calculating the thermodynamic parameters deltaG, deltaH and deltaS, confirmed that the adsorption reaction was a spontaneous exothermic process theoretically. The adsorption was the best when the pH value was 6.0 and the temperature was 15 degrees C. PMID- 21250455 TI - [Oxidation buffer capacity of sewage sludge barrier for immobilization of heavy metals]. AB - Benefit from the microbial activities especially the anaerobic sulfate reduction processes, sewage sludge could be used as a barrier to immobilize the heavy metals leached from tailings. With respect to the redox reaction between sewage sludge and acid mine drainage (AMD), oxidation titration test was carried out to study the effect of oxidation buffer capacity (OBC) of sewage sludge on the immobilization of heavy metals. Test results showed that OBC of sludge suspensions was decreased slightly with the solid-liquid ratio of the suspensions, but increased with the anaerobic incubation time, and that more than 50% of OBC was contributed by the sludge existed in strongly-reduction conditions (Eh < or = - 150 mV). During oxidation titration test, Zn was released obviously when Eh > or = - 150 mV, while Cu and Pb released obviously when Eh > or = 150 mV. According to the test results, a mathematical model was established to predict the OBC consumption of the sludge barrier under AMD penetrating conditions. The simulation results showed that a sludge barrier with 2m thickness, even undergone 38 787-years oxidation by AMD under 10m water head, keep in a strongly-reduced condition and, therefore, promote an immobilization of heavy metals from AMD in the barrier. PMID- 21250456 TI - [Concentrations and distribution characteristic of PAHs, PCBs and OCPs in the surface sediments of Qingtao coastal area]. AB - PAHs were measured by gas chromatography-mass spectrometry (GC-MS) in the surface sediments collected from the southern Shandong Peninsula coastal area. Contents and distribution characterizations of PAHs, PCBs and OCPs in the area were discussed. The concentration of PAHs in the surface sediments decreased gradually from the inshore area to the offshore area. According to the ratio of P/A and Fl/Py, the release from combustion of fuel was one of the most major sources of PAHs in this area. The level of PCBs in the surface sediments was higher in the Jiaozhou Bay and southwest coast of Qingtao, and lower in the other area. The distribution of PCBs decreased gradually from the inshore to the offshore area. OCPs in surface sediments also decreased from the inshore to the offshore area. The HCHs data showed the area was polluted by agriculture and industry at the same time. There were only a few DDTs imported into the area in the recent years, and DDTs were decomposed by aerobic microbial degradation in surface sediment. The concentration of PAHs, PCBs and OCPs suggested that the potential risk of environmental pollution was low in the area. PMID- 21250457 TI - [Pesticide residual status in litchi orchard soils in Guangdong, China]. AB - Litchi is a famous tropical and subtropical fruit originated in South China. Guangdong is one of the most important litchi production areas in China. Two hundred and eight soil samples were collected in litchi orchards after harvesting the fruit, in which nine often-used pesticides including metalaxyl, mancozeb, carbendazim, deltamethrin, cypermethrin, cyhalothrin, dipterex, dimethoate and dichlorvos were detected. The results showed that the detectable rates of various pesticides were ranked cypermethrin (59.1%) > carbendazim (51.0%) > mancozeb (11.1%) > metalaxyl (6.7%) > cyhalothrin (3.4%). Dimethoate and dichlorvos were detectable in few soil samples, and deltamethrin and dipterex were undetectable in all samples. The percentages of soil samples where different pesticides could be detected in one sample followed the order: one pesticide detectable (40.4%) > two pesticides simultaneously detectable (31.3%) > pesticide undetectable (18.8%) > three pesticides simultaneously detectable (8.2%) > four pesticides simultaneously detectable (1.4%). The concentrations of mancozeb in detectable samples averaged 39.05 microg x kg(-1), and that of cypermethrin was 7.83 microg x kg(-1). The mean concentrations of the other five pesticides ranged from 0.19 microg x kg(-1) to 1.65 microg x kg(-1). Totally, the pesticide residue status in litchi orchards in Guangdong was venial. PMID- 21250458 TI - [Human hair mercury levels and the influencing factors of the residents living in Qianguo Irrigation Area]. AB - To understand the current mercury exposure level of the residents living within the Second Songhua River basin, 120 hair samples were collected from Qianguo Irrigation Area in the downstream of the basin. The total mercury contents in hair samples were determined and the influencing factors were analyzed. The results showed that the range of the total mercury contents was 0.15-1.01 mg/kg and the average value was 0.56 mg/kg. The average hair mercury content of male residents was 0.55 mg/kg while that of female residents was 0.60 mg/kg. The total hair mercury firstly increased and then gradually decreased with the increasing of age. The lowest mean hair mercury value(0.47 mg/kg) was detected in the residents with the age of 0-20 and the highest mean hair mercury value (0.73 mg/kg) was detected in the residents with the age of 40-50. Among the other factors influencing human hair mercury contents, the gender, height, body weight, fish consumption, smoking and wine-drinking showed no significant correlations with the hair mercury contents. Only one hair sample was detected with greater mercury content than the limitation (1.00 mg/kg) established by USEPA, suggesting low mercury exposure risks in the area. This investigation indicated the historical pollution of the Second Songhua River hadn't lead health risks to the residents of the region and the irrigation using water from the river after the building of the Hadashan Reservoir would cause low environmental risks. PMID- 21250459 TI - [Analysis of difference between ecosystem respirations of Leymus chinensis steppe and Stipa baicalensis steppe]. AB - Static opaque chamber-chromatographic technique was applied to measure the ecosystem respirations of Leymus chinensis steppe and Stipa baicalensis steppe. The affecting factors of ecosystem respiration were analyzed. The difference between ecosystem respirations of the two grasslands was compared and the reasons resulting in the difference were analyzed. Ecosystem respiration of Leymus chinensis steppe [averaged (12.03 +/- 2.10) mg x (m2 x min)(-1)] was significantly smaller than that of Stipa baicalensis steppe [averaged (20.09 +/- 4.41) mg x (m2 x min)(-1)], while aboveground biomass of Leymus chinensis steppe was significantly larger than that of Stipa baicalensis steppe (p < 0.001). CO2 fluxes of Leymus chinensis steppe and Stipa baicalensis steppe were significantly correlated with air temperature in chamber, soil temperature at 5 cm and 15 cm depth. The results of partial correlation analysis showed that there were no significantly correlation between CO2 flux and Eh, pH, biomass of litter when soil temperature was unchanged, while it shows some correlation with biomass of living plant. The apparent liner relationship between CO2 flux and Eh, pH may be caused by the change of soil temperature. The CO2 fluxes of the two grasslands can be well explained by exponential models based on temperatures. Soil temperature can explain more variations of ecosystem respirations (R2 0.568 0.639) than air temperature in chamber (R2 0.323-0.426). Soil temperature was the most important affecting factor of ecosystem respiration and it may had concealed the effect of aboveground biomass on CO2 flux. The contribution of soil respiration to ecosystem respiration was large in this region and its higher soil organic matter content led to higher CO2 flux of Stipa baicalensis steppe. PMID- 21250460 TI - [Effects of topographies and land uses on soil organic carbon in subsurface in hilly region of Loess Plateau]. AB - It is important to accurately assess soil carbon sequestration potential and the global carbon cycle to study effects of topographies and land uses on soil profile organic carbon in subsurface. In Yangou watershed of hilly region of Loess Plateau, based on three topographies (tableland, slopeland, gullyland) and seven land uses (farmland, orchard, secondary grassland, manmade and secondary shrubland and manmade and secondary woodland), 53 soil profiles (0-100 cm) in six soil depths up to 898 samples were collected to investigate effects of topographies and land uses on contents and spatial distribution of soil organic carbon in subsurface. Topographies, land uses, depths and interaction of them significantly (p < 0.01) affected spatial distribution of soil organic carbon in subsurface in Yangou watershed. SOC had different spatial distribution in topographies between subsurface (10-100 cm) and surface (0-10 cm). In 0-10 cm soil layer, the content of soil organic carbon of slopeland (10.7 g x kg(-1)) was the highest, followed by gullyland (8.9 g x kg(-1)), the content of SOC of tableland (4.4 g x kg(-1)) was the lowest. But the contents of SOC every layer in 10-100 cm expressed as gullyland > slopeland > tableland trends, the average contents of SOC were 5.6 g x kg(-1), 4.5 g x kg(-1) and 3.2 g x kg(-1). Land uses significantly (p < 0.05) affected spatial distribution of SOC in subsurface in Yangou watershed. Compared with farmland, the content of SOC of orchard in 0-40 cm decreased by 21%, yet increased by 13% in 80-100 cm. The content of SOC of manmade shrubland (2.6 g x kg(-1)) was 19% lower than that of farmland, while SOC content of manmade woodland (3.4 g x kg(-1)) was 6% higher than that of farmland. The content of SOC of secondary shrubland was higher than that of any other land uses in 20-100 cm, but it is significantly (p < 0.05) different form other land uses in 40-100 cm, the average contents was 5.3 g x kg(-1), which was 66% higher than that of farmland. The content of SOC of secondary woodland was higher than that of any other land uses in 0-20 cm, but it was less differences form other land uses in 40-100 cm. The storage of SOC of gullyland (5.04 kg x m(-2)) in subsurface (20-100 cm) was the highest, accounted for 71.4% in 1 m profile, the relative storage of SOC of slopeland and tableland accounted for 63.6% and 72.3% respectively. The storages of SOC of secondary shrubland in subsurface (20-100 cm) were the highest, it was 6.01 kg x m(-2) accounted for 64.7% in 1 m profile, while the relative storage of secondary woodland was the lowest, only accounted for 49.7%. The storages of SOC of farmland and orchard both accounted for more than 70% of 1 m profile. PMID- 21250462 TI - [Effects of different long-term fertilizations on community properties and functions of methanotrophs in dark brown soil]. AB - The microbial mechanisms of how different long-term fertilizations change methane oxidation of Chinese upland arable soil is unclear so far. In the present study, we attempted to investigate the "soil properties-community properties of methanotrophs-methane oxidation" relation of dark brown soil in Northeastern China under different long-term fertilization regimes. Community structure and abundance were monitored with PCR-DGGE and real time PCR, respectively. Methane oxidizing rate and soil properties were measured as well. The results show that combined use of mineral fertilizer and compost (MNP) reduce soil methane oxidation by 61.2%, whereas either mineral fertilizer (NP) or compost (M) shows no effect. Comparing with no fertilizer (CK), M and MNP increase the Shannon index of methanotrophs by 91.9% and 102.5%, respectively, whereas NP has no effect. Similarly, M ( M or MNP) significantly increases pmoA gene abundance by up to 12.7 folds compared with no M addition (CK or NP). Methane oxidizing rates are significantly correlated with community structure and specific activity of methanotrophs, with correlation coefficients of 0.363 and 0.684, respectively. However, methane oxidizing rates do not correlate with abundance and diversity of methanotrophs. In addition, community structures and specific activity of methanotrophs are significantly correlated with soil pH and content of total nitrogen and organic matter. Our results suggest that long-term different fertilizations may change soil properties (such as pH and content of total nitrogen and organic matter) and thereafter the community structure and specific activity of soil methanotrophs, by which long-term different fertilizations influence soil methane oxidizing rate. The opposite change of methane oxidation to methanotrophs diversity and abundance in MNP suggests that only parts of the methanotrophs are active, which needs further research. PMID- 21250461 TI - [Relationship between Fe, Al oxides and stable organic carbon, nitrogen in the yellow-brown soils]. AB - The stable organic carbon and nitrogen of the different particles were gained by oxidation of 6% NaOCl in the yellow-brown soils. The relationships between the contents of selective extractable Fe/Al and the stable organic carbon/nitrogen were investigated. It shown that amounts of dithionite-citrate-(Fe(d)) and oxalate-(Fe(o)) and pyrophosphate extractable (Fe(p)) were 6-60.8 g x kg(-1) and 0.13-4.8 g x kg(-1) and 0.03-0.47 g x kg(-1) in 2-250 microm particles, respectively; 43.1-170 g x kg(-1) and 5.9-14.0 g x kg(-1) and 0.28-0.78 g x kg( 1) in < 2 microm particles, respectively. The contents of oxalate-(Al(o)) and pyrophosphate extractable (Al(p)) were 0.08-1.34 g x kg(-10 and 0.11-0.47 g x kg( 1) in 2-250 microm particles, respectively; 2.96-6.20 g x kg(-1) and 0.38-0.78 g x kg(-1) in < 2 microm particles, respectively. And amounts of selective extractable Fe are generally higher in paddy yellow-brown soils than in arid yellow-brown soils, and that of selective extractable Al are lower in the former than in the latter. Amounts of the stable organic carbon and nitrogen, higher in paddy yellow-brown soils than in arid yellow-brown soils, were 0.93-6.0 g x kg( 1) and 0.05-0.36 g x kg(-1) in 2-250 microm particles, respectively; 6.05-19.3 g x kg(-1) and 0.61-2.1 g x kg(-1) in < 2 microm particles, respectively. The ratio of the stable organic carbon and nitrogen (C(stable)/N(stable)) were 9.50-22.0 in 2-250 microm particles and 7.43-11.54 in < 2 microm particles, respectively. The stabilization index (SI(C) and SI(N)) of the organic carbon and nitrogen were 14.3-50.0 and 11.9-55.6 in 2-250 microm particles, respectively; 53.72-88.80 and 40.64-70.0 in < 2 microm particles, respectively. According to SI, it is lower in arid yellow-brown soils than in paddy yellow-brown soils. The organic carbon and nitrogen are advantageously conserved in paddy yellow-brown soil. An extremely significant positive correlation of the stable organic carbon and nitrogen with selective extractable Fe/Al is observed. The most amounts between the stable organic carbon and nitrogen and selective extractable Fe/Al appear in clay particles, namely the clay particles could protect the soil organic carbon and nitrogen. PMID- 21250463 TI - [Screening and nitrogen transformation activity of ammonia-oxidizing molds during aerobic chicken manure composting]. AB - In order to explicit the existence and nitrogen transformation activity of ammonia-oxidizing molds during aerobic chicken manure composting, the medium of ammonia-oxidizing molds was used to screen them, and correlation analysis between mycelium biomass and nitrogen transformation indexes was conducted, then high effective ammonia-oxidizing strains were determined and added into aerobic compost. The results show that all tested strains are able to oxidize ammonium nitrogen to nitrite nitrogen and nitrate nitrogen, indicating that there are plenty of ammonia-oxidizing molds during aerobic chicken manure composting. Significantly positive correlations are detected between total contents of nitrite nitrogen and nitrate nitrogen, mycelium biomass and mycelium Kjeldahl nitrogen. When cultured in the medium of ammonia-oxidizing molds for 144 hours, two high-effective ammonia-oxidizing strains, named M25-22 (Penicillium sp.) and M40-4 (Aspergillus sp.), produce nitrate nitrogen by 1.1 x 10(-3) mg x mL(-1), 1.5 x 10(-3) mg x mL(-1), respectively, and decrease ammonium nitrogen by approximately 0.3 mg x mL(-1). Compared with the control treatment, the composting treatment with microbial agent M25-22 or M40-4 has lower ammonium nitrogen content, and higher contents of nitrate nitrogen and total nitrogen, indicating that they are of practical significance in reducing nitrogen loss during aerobic composting. PMID- 21250464 TI - [Integrating technologies for urban communities' municipal solid waste minimization]. AB - Municipal solid waste management of urban communities has difficulties of insufficient source separation and food waste's high moisture content, an integrating technology of manual separation, simple compression of food waste, reclaim of food waste and composting leachate was studied. Manual separating rate was 36.8 kg/h, and would increase when the worker became sophisticated. Community separated food waste had high organic matter content of 44.493%, nutrients N, P, K contents of 2.586%, 0.649% and 1.274%, C/N ratio of 17.427, but 0.07-0.82 times lower heavy metals contents compared to centralized separation of mixed municipal solid waste. Moisture content of food waste was still 78.7%, high enough to have negative impacts of composting processes. Composting leachate processing with biological stabilization and dilution showed a fertilizer efficiency, and dry weight of impatiens irrigated with composting leachate was 1.46-2.49 times of tap water irrigation. Integrating technology based on community's manual separation could decrease 52.6% municipal solid waste. PMID- 21250465 TI - [PCDD/Fs formation from pentachlorobenzene under the catalysis of CuO]. AB - The formation processes of PCDD/Fs from pentachlorobenzene catalyzed by CuO under heating conditions were investigated. The results showed that, the amount of the formed PCDD/Fs increased with the temperature from 200 degrees C to 350 degrees C, and then decreased with futher increase of temperature from 350 degrees C to 450 degrees C. PCDD/Fs homologue pattern varied significantly according to the reaction temperature. At the lower temperature (200-250 degrees C), the major PCDD/Fs products were highly chlorinated ones; but at the higher temperature (400 450 degrees C), the low chlorinated PCDD/Fs predominated in the PCDD/Fs products. The change of temperature did not cause a systematical variation in the isomer distributions in each PCDD/Fs homologue. By comparing the formation of PCDD/Fs from pentachlorobenzene with the dechlorination of OCDD/F both under the catalysis of CuO at 400 degrees C, the precursor mechanism of PCDD/ Fs formation from pentachlorobenzene was speculated. Low chlorinated PCDDs mainly came from the dechlorination of highly chlorinated PCDDs which were formed from the pentachlorobenzene, whereas PCDFs could be mainly formed by the direct condensation of dechlorination products of pentachlorobenzene. PMID- 21250466 TI - [Progress in research of urban greenhouse gas emission inventory]. AB - Urban areas carry main responsibility for consuming massive energy sources and make great contribution to global anthropogenic greenhouse gas emissions. City and local governments are seen to have a key role in climate mitigation. Hence,one of the important work concerns accounting for city greenhouse gas (GHG) emissions, because it plays significant role in setting reduction targets and evaluating success of local measures. However, open system architectures like city face many challenges for greenhouse gas accounting. Based on the review in details the methodology and case study, our study focuses on the difference and interconnection between country and city GHG accounts,and uncertainty of accounts. Further, we propose the valuable experience in order to improve domestic research on city GHG emission inventory. PMID- 21250467 TI - [Eco-efficiency of industry sectors for China]. AB - Industry is the main source of resource consumption and environmental emissions of China, and the analyzing of eco-efficiencies for industrial sectors may provide essential information for the restructure of industrial system and the improvement of environmental quality of China. The industry composition was analyzed and the relationship between the industry and its environment was established. The energy consumption and the main environmental emissions such as wastewater, solid waste, industry SO2, smog, dust were chosen as the environmental impact categories, the corresponding eco-efficiencies of industry were defined and estimated for China in 2007. The results are as follows: the energy efficiency is 615.5 x 10(4) yuan x ktce(-1), the wastewater and solid waste related eco-efficiencies are 54.3 x 10(4) yuan x kt(-1) and 1.9 x 10(4) yuan x t(-1), respectively; industry SO2, smog, dust related eco-efficiencies are 59.6 x 10(4), 169.2 x 10(4) and 184.6 x 10(4) yuan x t(-1), respectively. The eco efficiencies of 39 industry sectors were analyzed extensively and the results showed that, the distribution of industrial sectors in above eco-efficiencies is uneven, and the order of industrial sector in industry will vary with industry sector and eco-efficiency category. Meanwhile, for the same category of eco efficiency, the values for different industry sectors may change from centuplicate to several thousand folds, therefore a great possibility for the improvement of industry eco-efficiency is exist in the restructure of industry system. PMID- 21250468 TI - [Integrated evaluation of circular agriculture system: a life cycle perspective]. AB - For the point of view that recycling economy system is one of ways to achieve the low-carbon economy, we have made an evaluation on a typical circular agriculture duck industry in Hunan Province, China, through improving the framework of life cycle assessment (LCA). The analysis indicated that the consumption of non renewable resources, land and water were 48.629 MJ, 2.36 m2 and 1 321.41 kg, while the potential greenhouse gas (GHGs), acidification, eutrophication, human toxicity, freshwater ecotoxicity and terrestrial ecotoxicity were 11 543.26 g (CO2 eq), 52.36g (SO2eq), 25.83g (PO4eq), 1.26, 60.74 and 24.65 g (1,4-DCBeq), respectively. The potential damage of aquatic eutrophication, freshwater ecotoxicity and terrestrial ecotoxicity was more serious than that of GHGs. Main results were following: i. the circular agricultural chain promoted the principle of "moderate circulation", which based on the traditional production methods; ii. circular agriculture could not blindly pursue low carbon development. Instead, soil and biological carbon sequestration should be considered, in addition to reducing carbon emissions; iii. circular economy and circular agriculture should take other potential environmental impacts into account such as acidification, eutrophication and ecotoxicity,with the exception to carbon emissions,to developed integrated system assessment; iv. LCA could provide a comprehensive assessment of circular agriculture, and it was worth of further study. PMID- 21250469 TI - [Isolation and evaluation of exoelectrogenic bacteria in a baffled air-cathode microbial fuel cell]. AB - Facultative tube methods were adopted for isolation from biofilm in two compartments of a baffled air-cathode microbial fuel cell (BAFMFC). The separated strains were then putted into a sterile cubic MFC individually under the same condition in order to evaluate its electrogenic characteristic. Electrochemical impedance spectrometer (EIS) was employed for the internal resistance testing. It can be found that ohmic internal resistance was around 25omega, indicating the cell performance determined only by activity of the strain. Nineteen strains were obtained, seven of which had voltages over 200 mV under 1 000omega. The strain (A2), owned the highest electrogenic activity in compartment A, has a voltage of 328 mV with the maximum power density 165.1 mW/m2. The maximum power density of 214.4 mW/m2 was produced by the isolate B1 (the best exoelectrogenesis in compartment B), while the maximal voltage of 241 mV was achieved. Identification of fatty acids reveals that A2 belongs to Enterobacteriaceae, and B1 belongs to the genus Bacillus. PMID- 21250470 TI - [Power generation from glucose and nitrobenzene degradation using the microbial fuel cell]. AB - By constructing a dual-chamber microbial fuel cell (MFC), experiments were carried out using an initial glucose concentration of 1 000 mg/L with different nitrobenzene (NB) concentrations (0, 50, 150 and 250 mg/L) as the MFC's fuel. Results showed that with an external resistance of 1 000 omega, the initial glucose concentration of 1 000 mg/L and the initial NB concentrations of 0, 50, 150, 250 mg/L, the operation periods were 55.7, 51.6, 45.9 and 32.2 h, respectively, the maximum voltage outputs were 670, 597, 507, and 489 mV, the maximum volumetric power densities were 28.57, 20.42, 9.29, and 8.47 W/m3, and the electric charges were 65.10, 43.50, 35.48, and 30.32 C. The MFC could use the NB and glucose mixtures as fuel and generated stable electricity outputs. The degradation rates of NB in the MFC in all cases reached up to 100% and COD removals in the MFC were 87% - 98%. However, the electricity generation was negligible when using 250 mg/L NB as the sole fuel. Denaturing gradient gel electrophoresis (DGGE) profiles demonstrated that the presence of NB resulted in changes of the dominant bacterial species on the electrodes. PMID- 21250471 TI - [Fluoride adsorption form drinking water by granular lanthanum alginate]. AB - Granular lanthanum alginate was prepared by dripping solved sodium alginate into lanthanum chloride solution. After washed and dried, sorbent with 1-1.5 mm diameter, 25% (mass fraction) La content was made and applied for fluoride removal from drinking test. Adsorption performance such as adsorption rate, adsorption isotherm, pH and disturbing ions effects were tested in batch adsorption. The changes of adsorbent surface and the solution composition before and after adsorption were also studied. Results showed that the adsorption rate was fast, fluoride concentration trend to stable after 2h reaction, and the adsorption rate fit for pseudo second order equation. The adsorption was significantly affected by pH and some disturbing ions, optimum pH = 4, phosphate and carbonate reduced adsorption. Adsorption isotherm fitted Langmuir equation well; the max adsorption capacity was 197.2 mg x g(-1). SEM photographs of sorbent before and after adsorption showed significantly different surface morphology; EDX composition analysis of sorbent surface and solution concentration changes before and after adsorption showed that ion exchange take placed between solution F- and sorbent surface Cl- and OH-. PMID- 21250472 TI - [Effects of carbon sources changes on the property and morphology of 2,4-D degraded aerobic sludge granules]. AB - This study investigated the changes of the morphology, structure, and capability of removing the target contamination of the aerobic granules pre-cultured with mixed substrates of glucose and 2,4-dichlorophenoxyacetic acid (2,4-D) in a long time running sequence batch reactor (SBR), when the carbon source transformed into the sole carbon source of 2,4-D. Results showed that when the substrate turned to the sole carbon source of 2,4-D, the aerobic granules still maintained a strong degradation ability to the target contamination; a 2,4-D removal percentage of 99.2% -100% and an average COD removal rate of 85.6% were achieved at the initial 2,4-D concentration of 361-564 mg/L. Carbon source transformation caused certain damages to the original aerobic granule structure, made some parts of granules disintegrated, and led to granule size decline from 513 microm to 302 microm. However, those granules maintained the main body, re-aggregated and grew after a period of adaptation due to their strong resistance to toxicity. Aerobic granules capable of utilizing 2,4-D as the sole carbon source with a good settling ability (SYI 20-40 mL/g) and a mean diameter of 489 microm were finally obtained in this study. Scanning electron microscope (SEM) observation showed that the diversity of granule microbial species was declined when turned to the sole carbon source. PMID- 21250473 TI - [Molecularly imprinted technique-flow injection-chemoluminescence system analysis detect phenol in water]. AB - Using phenol as template, acrylamide as monomers, pentaerythritol triacrylate as crosslinking agent, azodiisobutyronitrile as initiating agent, acetomitrile as thinner, we synthesized MIPM in aquosity system with suspension polymerization, on which surface there are some holes. The adsorbance of MIPM to phenol will no longer increased after two hours, it means that it reaches the saturation which were 7.03 micromol x L(-1). The separate genes of MIPM were 1.66 and 1.99 with pyrocatechol and hydroquinone as competitors. The MIPM had the better effect of adsorption and selectivity. Using MIPM as molecule recognizates, we set up a new method which was molecularly imprinted technique-flow injection-chemoluminescence analysis to detect phenol. The result shows that the range of phenol concentration from 1 x 10(-3) microg x L(-1) to 100 microg x L(-1) with adsorbed by MIPM is linearly dependent, which relativity coefficient is 0.9996 and the relative standard deviation is 0.99%, the detection limit is 9 x 10(-4) microg x L(-1). Using the method to detecting phenol from the water samples, the recoveries of phenol is 99%-105%, the result is pretty good. PMID- 21250474 TI - [Terrestrial mollusks (Mollusca: Gastropoda) of Costa Rica: classification, distribution and conservation]. AB - Terrestrial mollusks are poorly known worldwide. The country has 183 reported species, 30% endemic and 7% are probably extinct. About 400 species are expected to inhabit the country. Biology, ecology, distribution, genetics and other areas of research are unknown for more than 95% of the species. The most diverse families are Spiraxidae, Orthalicidae and Subulinidae. However, the family that may have more species is Euconulidae. Euconulids inhabit the highlands, where less work has been done. The study of species of highlands will also rise the endemism rate. Future taxonomic, biological and ecological work should consider their low vagility, tendency to produce new taxa in sympatry, specific microhabitat requirements, hermaphroditism, high evolutionary rate (10% per million years), and divergence between species (2 to 30%). Urgent studies to protect the Costa Rican malacofauna include: distribution, abundance, effect of land use and climate changes on populations. PMID- 21250475 TI - [Analysis of diet composition and overlap in four species of the genus Diplectrum (Perciformes: Serranidae) in the Mexican Central Pacific]. AB - Analysis of diet composition and overlap in four species of the genus Diplectrum (Perciformes: Serranidae) in the Mexican Central Pacific. The information of trophic interactions among species is essential to understand ecosystem function. To assess this in four Diplectrum species, we analyzed the stomach contents of 397 individuals caught using shrimp trawling nets off the coasts of Jalisco and Colima, Mexico. Main food component of D. eumelum were fish of the Order Pleuronectiformes, followed by shrimps (Metapenaeopsis spp). D. euryplectrum feeds mainly on crustaceans, with stomatopods (Squilla mantoidea) as main food items followed by shrimps and brachyurans. Fish and polychaetes had a low representation in the diet of this species. D. labarum feeds mainly on crustaceans, mollusks and fish. The stomatopod Eurysquilla veleronis contributed to with a high diet percentage by weight, followed by shrimps (mostly Solenoceraflorae) and brachyurans, as well as the squid Lolliguncula diomedae. Fishes (Ophidion spp.) were also an important component of the diet of this species. The most common preys of D. rostrum were crustaceans, mollusks, polychaetes and fish. The squid Lolliguncula diomedae and fishes of genus Ophidion were also well represented in the diet. Diet breadth index yielded significant differences between species. The number of diet items varied from 16 in D. euryplectrum to 6 in D. eumelum. The average value of overlap (0.247) was not significantly different (p = 0.118) from the expected one for a null model (0.174). The observed variance of the overlap index (0.071) was significantly higher (V = 0.025, p = 0.0004) than the value expected for a null model. PMID- 21250476 TI - [Structure and injuries of octocoral communities (Octocorallia: Alcyonacea) of Ecological Reserve Siboney-Jutici, Santiago de Cuba, Cuba]. AB - In the spur-and-groove reefs of the Ecological Reserve Siboney-Jutici (Southeast Cuba) octocorals are one of the predominant components of the sessile fauna. Main objectives of the present paper are characterizing the composition, structure and conservation status of the octocoral communities and assessing on the prevailing environmental conditions in the study area. For data collection, six sampling sites were located every 2-3 km ranging from 12 m to 17 m depth along the spur and-groove reefs. In each site, 22-26 lm2 quadrants were zigzag arranged every 2 m. The density of colonies was determined per site. The severity degree and predictability of environmental conditions were inferred by using the Heterogeneity and Equitability indexes, respectively. Hydrodynamic stress and the Comparative Pollution Index were also assessed. Current affectations of the octocoral communities were also determined and classified into four main categories: mechanical damage, diseases, predation and invertebrate and macroalgae overgrowth. As a result, 25 species represented by 752 colonies were recorded and Eunicea flexuosa and Gorgonia ventalina were the most abundant. The occurrence of Eunicea succinea forma succinea constituted the first report for Eastern Cuba. Site densities ranged from 3.58 +/- 1.84 to 7.58 +/- 2.16 colonies/m2 and considered from moderate to low. The biggest densities were reported at both sides of the San Juan River mouth. Despite of the composition and structure of the octocoral communities, low to high hydrodynamic stress and low and moderate levels of contamination were inferred, it is likely that these indexes could have been overestimated due to the sensitivity of the indicator species to other factors such as sedimentation. The environmental conditions were mostly favorable and stable. In general, the number of dead colonies was low and mostly caused by the detachment of the substrate and overgrowth of Millepora alcicornis. Injuries were mainly brought about by mechanical damage, followed by coenenchyme loss, predation by Cyphoma gibbosum and macroalgae overgrowth. On the other hand, negative effects by Hermodice carunculata predation, bleaching, Red Band and Black Band Disease were not observed. Among sampled species, G. ventalina colonies were the most severely damaged within the community. As a whole, octocoral communities of spur-and-groove reefs in the Ecological Reserve Siboney-Jutici showed a good conservation status. PMID- 21250477 TI - [Feeding changes for three Sphoeroides species (Tetraodontiformes: Tetraodontidae) after Isidore hurricane impact in Carbonera Inlet, Southeastern Gulf of Mexico]. AB - The coexistence of ecologically similar species may occur because of resources distribution, such as prey and habitat type and segregation time, that minimizes the interspecific competition. The changes brought about by Hurricane Isidore in the distribution of food resources by three coexisting fish species of the family Tetraodontidae (Sphoeroides nephelus, S. spengleri and S testudineus), were analyzed at the Carbonera Inlet. Sphoeroides spp. based their food on benthic organisms; principally, they consume mussels (Brachidontes sp.), barnacles (Balanus sp.) and gastropods (Crepidula sp). Before hurricane impact, the three species share the available food resources in different proportions (bivalves, gastropods, barnacles and decapods), according to different strategies that enabled them to coexist and reduce interspecific competition. After the impact, the abundance of available prey decreased and the interespecific competition for food increased, leading to S. testudines and S. nephelus change their trophic spectrum (xiphosurans, amphipods, isopods and detritus) and displacing S. splengleri of the inlet. The distribution of food resources was conditioned by the abundance and diversity of prey, as well as the adaptive response of each species. PMID- 21250478 TI - [Presence and spatio-temporal habitat characterization of Dermatemys mawii (Testudines: Dermatemydidae) in the Grijalva-Usumacinta watershed, Tabasco, Mexico]. AB - The Central American River Turtle (Dermatemys mawii) is an endangered species that has been poorly studied. There are no reports on their population status, habitat condition, and the species distribution area is still unknown. This study analyzes the seasonal and spatial variations of their habitat and the presence/absence of D. mawii in three rivers within the Pantanos de Centla Biosphere Reserve (Tabasco, Mexico). For habitat characterization, natural segmentation of rivers was used and three sites per segment were identified, 9 in each rivers (Grijalva and Usumacinta) and 6 in Tabasquillo. Additionally, the evaluation of 11 environmental variables such as water hydrological, physicochemical characteristics and riparian and hydrophytic vegetation were carried out during two different seasons (dry and rainy). The presence/absence of species was assessed with eight fike nets that were set per segment, with a capture effort of 384 hours per trap. The capture per unit effort (CPUE) was used as an indicator of relative abundance. The results indicated spatio-temporal variations in habitat characteristics and the presence of environmental gradients. The principal components analysis (PCA) applied allowed us to determine that the first three components explained 67.8% of the environmental variability. The species presence was confirmed in all rivers, however significant differences exists in their relative abundance: the highest was registered in the Tabasquillo River where the species was present in both seasons and in all segments. Of the 11 environmental variables analyzed, the gradient, shelter and depth were the most indicative of species presence. The obtained results evidenced the importance of riparian vegetation as habitat for Dermatemys. This represents the first approach towards an action plan for a species and its habitat protection within the Pantanos de Centla Biosphere Reserve. PMID- 21250479 TI - [Population status of insects of Plecoptera order in Sierra Nevada National Park in Venezuela and its implications for conservation planning]. AB - Longitudinal distribution of Plecoptera species were examined along the Sierra Nevada National Park in the Andean region of Merida State, Venezuela. PNSN is one of the largest protected areas and consists of two major sub-basins. Quantitative samples were collected in 7 river tributaries along the PNSN from February to May of 2009, and a total of 135 individuals and 4 species of the genus Anacroneuria were collected. Only three rivers (Nuestra Senora, La Picon y Corcovada) found the presence of stoneflies, the principal component analysis show that the characterization of habitat, current velocity, dissolved oxygen and the absence of human disturbance sources of influence in a suitable habitat for populations. Stoneflies are endangered or have become extinct throughout much of its range due to human activities. Conservation plans must be implemented urgently, in order to avoid recreational areas and/or economic in vicinity thereof. PMID- 21250481 TI - [Mangrove dynamics in the Cispata lagoon system (Colombian Caribbean) during last 900 years]. AB - The lagoon complex of Cispata (old Sinu river delta) located at the Northwestern coast of the Colombian Caribbean, encloses one of the biggest mangrove areas in this region. This area has changed during the last 330 years because of several environmental and climatic causes, mainly changes in the position of the delta (Sinu River), which is the main freshwater source in this area, and sea level rise. We hypothesized that the climatic and geomorphologic dynamics has caused changes in the extension and composition of mangrove vegetation, especially during last 150 years. The dynamics of mangroves during the last 900 years was reconstructed based on the changes in the stratigraphy, pollen record, calcite concentrations (CaCO3) and C/N ratio, along two sediment cores from La Flotante and Navio lagoons, located in Cispata complex. The age model was built based on lineal interpolation of 210Pb ages and changes in granulometry. Establishment and expansion of mangrove forests during the last 900 years were related to fluviomarine dynamics in the area and the lagoon formation. During the period encompassed between 1064 and 1762 A.D., the Mestizos spit was formed when marine conditions predominated in the surroundings of La Flotante Lagoon. At the site of Navio, a river dominated lagoon, terrigenous conditions dominated since 1830. Although the colonization of herbaceous pioneer vegetation started between 1142 and 1331 A.D., mangrove colonization only took place since 1717 A.D. Mangrove colonization was a result of the delta progradation. In 1849 A.D. the Sinu river delta migrated to the Cispata bay. The eustatic sea level rise, the increase in river discharges and sedimentation rates produced the establishment of mangrove forests dominated by Rhizophora since 1849. Since 1900 a marine intrusion was recorded in both lagoons. In 1938, the migration of the delta toward its actual location in Tinajones gave place to the formation of the present lagoon system and to the expansion of mangrove forests, which reflects the balance between the high alluvial sediment input and the current sea level rise as has been recorded in similar ecosystems. PMID- 21250480 TI - [Intestinal parasites in white-faced capuchin monkeys Cebus capucinus (Primates: Cebidae) inhabiting a protected area in the Limon province of Northeastern Costa Rica]. AB - Deforestation of tropical forests is threatening monkey biodiversity and their health status, dependent of an ecologically undisturbed area. To asses this relationship, we analyzed parasite occurrence in their intestines. The study was conducted at the Estacion Biologica La Suerte (EBLS), Limon, Costa Rica. The group of white-faced capuchin monkeys (Cebus capucinus) was observed between March and December of 2006. A total of 75 feces samples were obtained. Once a sample was collected, the eaten plant type was identified to family and species level, and feces were processed in the laboratory to determine parasite incidence. Results showed that Moraceae was the most represented family in the samples. Among parasites, Strongyloides spp. and Acanthocephala were the most common. Positive prevalence of parasites was found similar and independent of sex and age of capuchin individuals. Microsporids were mainly reported in feces associated with Piperaceae. A low presence of these parasites was found in samples associated with Myrtaceae, with possible anti-parasite active components. The occurrence of parasites was relatively high in EBLS, when compared to other regions in Costa Rica. The higher occurrence of parasites observed in capuchins at EBLS may be due to the fact that this rain forest is surrounded by areas affected by human activities. We suggest the promotion of research in neotropical primates parasitology, for a better comprehension of the parasite-host relationship, and in a long term, being able to understand the ecosystems where they coexist, and consequently, preserve the biodiversity of the whole region. PMID- 21250482 TI - [Temporal comparison of the composition and zonation of rocky intertidal organisms at Cocos Island National Park, Pacific, Costa Rica]. AB - Several biological and physical factors change the rocky shore communities. The desiccation time and the tolerance of the intertidal species produce the vertical zonation. In many studies around the world, a temporal change in this zonation is presented.In Costa Rica, only studies that include temporal trends were carried out in Punta Mala and Montezuma, Pacific coast in 80's. The rocky intertidal of the Cocos Island National Park, Costa Rica were surveyed photographically. The Chatham bay was sampled in three expeditions (January 2007, October 2007 and April 2008). Photos corresponding to 25x25cm quadrats were taken with the goal to determine diversity and composition differences in rocky shore organisms between sampling dates. The Wafer bay was sampled in January and October 2007. The intertidal of Chatham consists of basaltic rock, while Wafer has basaltic and ignimbrite boulders. The main difference between sites were the higher algae cover (erect-frondose forms) and number of organism bands at Chatham bay. Temporal change was not found in the total cover of sessile fauna and autotrophs. The barnacle Tetraclita stalactifera, that occurs above the algal fringe (lower intertidal), was the invertebrate with the highest coverage. The mobile fauna biodiversity presented no significant trend between sampled months. However, the identity of species, their cover and their abundance showed a moderate temporal change. In October 2007, when the sea surface temperature was 23 degrees C the infralittoral zone had an increase in green algae cover. The red algae (crust and erect-frondose forms) were dominant in January and April. The pulmonate limpet, Siphonaria gigas and a bacterial biofilm at mid littoral showed a negative association. The snails of the high littoral and the supralittoral zone showed a temporal change in their abundance, but with contrasting patterns between sites. The temporal variation in the assemblages increased from the supralittoral to the infralittoral possibly due to changes in the water temperature and climatic conditions, that could influence the intertidal zone during the high and low tide, respectively. PMID- 21250483 TI - [Centrocestus formosanus (Opisthorchiida: Heterophyidae) as a cause of death in gray tilapia fry Oreochromis niloticus (Perciforme: Cichlidae) in the dry Pacific of Costa Rica]. AB - Centrocestusformosanus is a zoonotic trematode from Asia and has been mainly associated as cause of death of cultured fish. To identify pathogen trematode species in tilapia fry (Oreochromis niloticus) and to determine mollusks hosting these parasites, freshwater mollusks were collected from tilapia cultured ponds and experimental infections were carried out with tilapia fries and different mollusk species. A total of 907 freshwater mollusks were obtained from tilapia ponds and were identified to species level, four gastropods and one bivalve were determined: Melania tuberculata, Melanoides turricula, Pomacea flagellata, Haitia cubensis and Anodontiles luteola. For the first time, the presence of M. turricula and H. cubensis are reported in Costa Rica. Seven morphotypes of cercariae (Xifiodiocercaria, Equinostoma, Oftalmocercaria, Parapleurolofocercus, Cistocerca, Furcocercaria and Leptocercaria) parasitizing all five species of mollusks were found, all of distome type. Experimental exposure of tilapia fry to M. tuberculata demonstrated that the parapleurolofocercus morphotype found in the mollusk is in accordance with the finding of C. formosanus in tilapia fry. An abundance and mean intensity of 1018-1027 digeneans per gill in each exposed fish was determined. Centrocestus formosanus is reported for the first time in Costa Rica, for which the primary and secondary intermediate hosts were also determined. PMID- 21250484 TI - [Morphology, anatomy, ontogeny and chemical composition of inflorescences volatile secondary metabolites of Lippia alba (Verbenaceae) at three stages of development]. AB - There is an increased interest to know and scientifically validate traditional knowledge of medicinal plants. Lippia alba belongs to Verbenaceae family and has been of interest, not only because of its worldwide extensive distribution, but also for its variable use as antiviral, bactericide, citostatic, analgesic and sedative. To study this, the morphology and ontogeny of Lippia alba inflorescences and the chemical composition of its volatile secondary metabolites were analyzed during three different stages of development. Plants were collected at the experimental crop field in CENIVAM, Bucaramanga, Colombia. The inflorescence's morphology and ontogeny, and the chemical composition of volatile secondary metabolites were analyzed using a stereoscopic microscope and chromatographic and spectroscopic techniques. Fresh material corresponding to each stage was fixed in F.A.A (formol, acetic acid and alcohol), included in paraffin and cutted in transversal and longitudinal sections. Sections were stained with safranine-fastgreen, photographed and decribed. The chemical composition of volatile secondary metabolites at each ontogenic stage, was extracted by solid phase micro-extraction in the headspace mode and analyzed by gas chromatography coupled to mass spectrometry. Stage I showed a meristematic mass of cells in vegetative apex and bracts, with an outline of floral whorls. In Stage III. the stamens were adnate, epipetals and didynamous, bicarpelar and syncarpic gynoecium, with superior ovary and decurrent stigma. The main secondary metabolites detected were the bicyclosesquiphellandrene followed by carvone, limonene and trans-beta-farnesene, that constituted the 78% of the total relative amounts of compounds. Other metabolites such as beta-copaene, gamma-amorphene and cis-beta-guaiene, were reported for the first time in this study. When compared to other studies, morphological differences reported in this study are possibly related to adaptation to environmental conditions or pollinators, which let us suggest that there is no specific ontogenic pattern. Similarly, the qualitative and quantitative variations in the detected compounds could be explained because one or more of them are used as precursors of others. PMID- 21250485 TI - [Repellent activity of plant essential oils against bites of Lutzomyia migonei (Diptera: Psychodidae)]. AB - Natural repellents from plant extracts have demonstrated good efficacy against bites of some insect species. The present study evaluated the repellent effect of essential oils extracted from 8 plants species against bites of Lutzomyia migonei, the Leishmania vector. The essential oils were extracted by steam destillation in Clevenger chamber, from the following plants: Hyptis suaveolens, Pimenta racemosa, Piper marginatum, Monticalia imbricatifolia, Pseudognaphalium caeruleocanum, Espeletia shultzii, Plecthranthus amboinicus and Cinnamomun zeylanicum. Repellency tests were performed under laboratory conditions by the human hand method in cage assays, using female colonies of L. migonei. The more effective oils were tested at variable concentrations on different volunteers. The protection percentage and time were calculated. The results showed what oils of P. caeruleocanum and C. zeylanicum were the most effective. Although P. amboinicus oil also had repellent effect showed an irritant effect. The oils P. marginatum, H. suaveolens and P. racemosa showed no repellent effect, while the rest of oil extracts showed significant repellency in variable degrees. P. caeruleocanum and C. zeylanicum oils provided the 95% protection against bites of L. migonei for 3 h. The P. caeruleocanum oil showed the greatest protection time, with a mean over 4h and 3h at concentrations of 50% and 10% respectively. The results suggest that the P. caeruleocanum oil could represent a potential natural repellent against Leishmania vectors. PMID- 21250486 TI - [Apparent digestion coefficients for dry matter, protein and essential amino acids in terrestrial ingredients for Pacific shrimp Litopenaeus vannamei (Decapoda: Penaeidae)]. AB - Protein quality mainly depends on the essential amino acid (EAA) profile, but also on its bioavailability, because EAA digestibility is generally lower than the analyzed amounts. This information is needed in the aquaculture industry for aquafeed formulation. For this purpose, the apparent digestibility coefficients of dry matter, protein, and essential amino acids of eight feedstuffs of terrestrial origin were determined for the juvenile whiteleg shrimp Litopenaeus vannamei (15-19 g), using 1% chromic oxide as an inert marker. A reference diet was formulated and produced in the laboratory. Eight experimental diets were prepared each with 30% of one of the experimental ingredients added to the reference diet: casein, porcine byproduct meal poultry byproduct meal, corn meal, wheat gluten meal, soybean paste, sorghum meal, and wheat meal. The experiment consisted of a single-factor, completely randomized design with three replicates per treatment. Samples of ingredients, diets and feces were analyzed for nitrogen and amino acids. For amino acid assay, we used reverse-phase high performance liquid chromatography. To avoid partial loss of methionine and cystine, samples of ingredients, diets, and feces were oxidized with performic acid to methionine sulfone and cysteic acid prior to acid hydrolysis. The apparent dry matter and protein digestive utilization coefficients varied from 68% to 109% and from 70% to 103%, respectively. Apparent digestibility of protein for casein, soy paste, wheat meal and wheat gluten were very high (over 90%), corn gluten and poultry byproducts meal showed high protein digestibility (over 80%), but porcine byproducts meal and sorghum meal had low digestibility (76% and 70%, respectively). There was a reasonable, but not total, correspondence between apparent protein digestibility and average essential amino acid digestibility coefficients, except for arginine in corn gluten, phenylalanine and leucine in sorghum meal, phenylalanine in soy paste and lysine in wheat meal and poultry by product meal. The most digestible feed ingredients for whiteleg shrimp were: wheat gluten, wheat meal and soy paste; poultry byproduct meal and corn gluten were less digestible and the lowest digestibility occurred in porcine byproduct meal and sorghum meal. Feedstuffs exhibited great variability in dry matter, protein and amino acid digestive utilization coefficients, which should be considered when formulating shrimp feeds. PMID- 21250487 TI - [Autoimmune polyendocrine syndrome]. PMID- 21250488 TI - [Lymphoma-like course in aggressive adult multisystem Langerhans cell histiocytosis]. PMID- 21250489 TI - [A different view of acute upper gastrointestinal bleeding in liver cirrhosis patients]. AB - OBJECTIVES: The study focuses predominantly on non-varicose sources of acute upper gastrointestinal bleeding in liver cirrhosis patients and aims to determine its mortality. METHODS AND SUBJECTS: The prospective examination included 137 liver cirrhosis patients with acute upper GIT bleeding. All the patients underwent an endoscopic examination. In case of multiple findings, defining the bleeding source was based on the specialist's attitude presented as the conclusion of the endoscopic examination. RESULTS: The most frequent causes of acute bleeding included oesophagus varices (57.7%), followed by peptic gastric and duodenal ulcers (18.2%), then portal hypertension gastropathy (9.5%), gastric varices (5.1%), reflux oesophagitis (2.9%), Mallory-Weiss syndrome (2.9%) and erosive gastropathy (1.5%). The endoscopy of the upper digestive tract resulted in a negative diagnosis in not more than 2.2% of patients. The majority of examinations showed multiple findings in the upper digestive tract, each of which could have been a potential cause of bleeding. Mortality in all bleeding cirrhotic patients reached 14.6%, 18.6% of which were related to the varicose type of bleeding and 7.8% to the non-varicose type. CONCLUSION: Portal hypertension led to bleeding (caused by varices and portal hypertension gastropathy) in 72.3% of patients, 62.8% patients suffered from purely varicose bleeding, 37.2% patients from non-varicose bleeding. Mortality was statistically significantly higher on 0.1 level of significance in cases of varicose bleeding in comparison with non-varicose bleeding. An emphasis should be laid on an early and detailed endoscopic examination leading to an appropriate diagnosis and therapy. PMID- 21250490 TI - [Risk stratification by cardiac gated SPECT combined with coronary artery calcium score in patients with diabetes mellitus and/or renal failure]. AB - AIM: The aim of this study was to evaluate added value of coronary artery calcium score (CAC) measurement as an adjunct to cardiac gated SPECT for risk stratification in population of patients with diabetes mellitus (DM) and/or chronic renal failure on hemodialysis (CHRF-HD). METHODS: Retrospective analysis of 67 patients, who were referred for stress gated myocardial perfusion SPECT and CAC. Characteristics of study population: 40 men, mean age 59 +/- 12 years, DM (n = 28), CHRF-HD (n = 22), DM and CHRF-HD simultaneously (n = 17). Perfusion summed stress and different scores (SSS, SDS), the left ventricle ejection fraction (LVEF) and enddiastolic/endsystolic volumes (EDV/ESV) were automatically calculated using 4D-MSPECT software. The hard cardiac event was defined as sudden cardiac death or myocardial infarction (MI); angina or other symptoms requiring coronary revascularization were also calculated. RESULTS: During the average period of 18 +/- 10 months, we registered 8 cardiac deaths, 4 nonfatal MI and 7 patients underwent revascularization. In the subgroup of 19 patients with cardiac events, the observed parameters were significantly worse concerning perfusion (SSS 9 +/- 11 vs 2 +/- 3 and SDS 6 +/- 9 vs 1 +/- 2, P < 0.05), the left ventricle function (stress LVEF 53% +/- 13% vs 59% +/- 13%, rest LVEF 55% +/- 14% vs 59% +/- 12%, stress EDV/ESV 144 ml/71 ml vs 128 ml/59 ml, P < 0.05), and CAC score (1 965 +/- 1 772 vs 387 +/- 740, P < 0.05) in comparison with patients without cardiac event. In patients without a reversible perfusion abnormality (SDS < 2), we observed lower annual hard event rate (8% vs 19.6%, P < 0.05) and revascularization procedures (4% vs 19.6%, P < 0.05) in comparison with patients with SDS > or = 2. In patients with or without reversible defects, we registered significantly higher annual hard event rate in the setting of post-stress worsening of the LVEF > 5% and/or severe CAC score > or = 709 (23.8% vs 1.9% in patients with SDS < 2, and 26.7% vs 9.5% in patients with SDS > or = 2, P < 0.05). CONCLUSION: The findings of highly elevated CAC score as well as the post stress left ventricle stunning enable further risk stratification in patients with or without reversible perfusion abnormalities. PMID- 21250492 TI - [Osteoporosis in chronic obstructive pulmonary disease]. AB - Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of osteoporosis because of their age, limited physical activity, low body mass index, smoking, hypogonadism, malnutrition, and use of corticosteroids. Systemic inflammation represents an additional pathomechanism contributing to the development of osteoporosis in COPD patients. Males in their mid to late 60s with a smoking history of greater than 60 pack-years have a prevalence rate of vertebral fractures similar to, and possibly greater than, postmenopausal women greater than or equal to 65 years old: in patients with severe COPD, up to 50-70% have osteoporosis or osteopenia, and up to 24-30% have compression vertebral fractures. Correlates of osteoporosis in COPD are mainly measures of body composition, disease severity and the use of corticosteroids, although causality has not been proven. Systemic corticosteroids remain the most common cause of drug-related osteoporosis, and a meta-analysis concluded that the use of more than 6.25 mg prednisone daily led to decreased bone mineral density (BMD) and increased fracture risk. In contrast, the effects of the long-term use of inhaled corticosteroids on BMD remain debatable. Effects of treatment of osteoporosis have not been investigated in samples consisting of COPD patients only but the recommendations follow the general recommendations for the diagnosis and treatment of osteoporosis. Early recognition of BMD loss is essential, and assumes close interdisciplinary cooperation between respirologists and reumatologists. Longitudinal follow-up to assess determinants of osteoporosis in COPD and randomised placebo-controlled trials on the effects of treatment of osteoporosis in patients with COPD only are warranted. In the future, novel therapeutical strategies such as monoclonal antibodies against osteoclasts activators may prove their beneficial effects in the treatment of COPD-related osteoporosis. PMID- 21250491 TI - [Determination of the progression of prostate cancer using RT-PCR method]. AB - The aim of our study was to verify possible utilization of RT-PCR method (Reverse Transcriptase-Polymerase Chain Reaction) as a diagnostic and prognostic modality of the progression of prostate cancer. This approach is commonly used for the detection of circulating carcinomatous cells in peripheral blood of patients with malignant breast tumors, and our ambition was to adopt this method for patients with prostate cancer. The contribution of this method consists in its ability to detect early stages of the dispersion of carcinomatous cells, so called micrometastases, in the peripheral circulation of patients. The estimation of the progression of the disease is especially important for the selection of appropriate therapy for individual patients. Using this method we analyzed 50 men: 28 patients with clinically localized or locally advanced prostate cancer, 7 patients with clinically proven metastases, 8 patients with benign prostatic hyperplasia, and 7 healthy young men. PMID- 21250493 TI - [Guidelines for the diagnosis and treatment of chronic obstructive pulmonary disease (COPD)--stable phase]. PMID- 21250494 TI - [Metastatic involvement of the heart and pericardium--MR case reports]. AB - Secondary metastatic tumors of the heart and pericardium are in comparison with primary cardiac tumors more common, but their overall prognosis is very poor. Metastases can occur in every part of the heart and pericardium. The most common source are tumors--lung cancer, breast cancer, melanoma and lymphoma. In this case report we described two patients with metastatic involvement of the heart. We are pointing out the possibilities of diagnostic imaging of cardiac tumors using echocardiography and magnetic resonance. PMID- 21250495 TI - [Diffuse plane normolipemic xanthomatosis and necrobiotic xanthogranuloma associated with monoclonal gammopathy--determining the disease stage with PET-CT and treatment experience. Two case studies and literature review]. AB - Monoclonal gammopathy may manifest itself through a range of skin disorders, including plane normolipemic xanthoma and necrobiotic xanthogranuloma. The present paper describes two patients with these cutaneous symptoms. The first has extensive areas of skin affected by flat xanthomas, monoclonal gammopathy with > 10% infiltration of bone marrow with clonal plasmocytes and, according to PET-CT, unclear lymphadenopathy in the retroperitoneal area. The size of this lymphadenopathy (histologically no malignant infiltration and no confirmed infectious aetiology) has not changed significantly over a 4-year follow-up. Repeated PET-CT scans showed decrease in SUV value in this infiltration from 7.5 to 3.8. Four cycles of treatment with a combination of bortezomib, cyclophosphamide and dexamethasone brought neither reduction in monoclonal immunoglobulin nor change to skin morphology. We believe that the abdominal lymphadenopathy is associated with xanthomatosis but have been unable to confirm this unequivocally. The second patient is being followed up for more than 10 years, originally for MGUS, later for asymptomatic multiple myeloma. Last year, painful subcutaneous and cutaneous infiltrates, isolated on an upper limb and more frequent on lower limb, started to occur. These infiltrates are palpable. PET-CT imaging provided an excellent depiction of these infiltrates, showing no pathology on the head, chest and abdomen and no osteolytic foci on the skeleton. CT imaging showed clearly numerous infiltrates in the skin and subcutaneous tissue of lower limbs, particularly both shanks, reaching up to 2 cm in depth. The largest infiltrate, measuring 3.5 by 2 by 10 cm, was identified in the distal dorsal part of the right shank. PET imaging of lower limbs showed distinctly pathological accumulation in all infiltrates described above; the accumulation of glucose in the lower part of the right shank reached 10.0 SUV. CT images of lower limbs showed increased density saturated hypodermis even in the areas where there is no increased accumulation of 18 fluoroglucose. Following 40 Gy irradiation, the size of infiltrate in the radiated area decreased and their soreness ceased. CONCLUSION: PET-CT imaging offered information on extra-cutaneous signs of plane normolipemic xanthomas and provided excellent depiction of the areas of the skin and hypodermis affected by necrobiotic xanthogranuloma. Chemotherapy with cyclophosphamide, bortezomib and dexamethasone brought no reduction in monoclonal immunoglobulin concentration, and no reduction in plane normolipemic xanthomas. Radiotherapy targeted at large foci of xanthogranulomas led to partial regression and ceased infiltrate soreness. PMID- 21250496 TI - [Autoimmune polyendocrine syndrome type 2 associated with autoimmune hypophysitis and coeliac disease]. AB - Autoimmune polyendocrine syndromes (APS) are organ-specific autoimmune disorders affecting multiple endocrine glands; these are gradually destroyed by action of autoantibodies. Similarly to other autoimmune diseases, the presence of certain genetic predisposition is an essential prerequisite to the disease development; polymorphism of the main histocompatible system (HLA in humans) appears to play the most important role. APS are categorized into four types, based on what combination of endocrine glands is affected. APS type 1, characterised by hypoparathyreosis, mucocutaneous candidiasis and Addison's disease, is frequently seen in childhood. For a more common APS type 2 to be diagnosed, Addison's disease together with autoimmune thyroiditis (Schmidt's syndrome) and/or together with diabetes mellitus type I (Carpenter's syndrome) must be present. The third type of autoimmune polyendocrine syndromes (APS type 3) involves the same disorder of endocrine glands as type 2 but usually without any defect of adrenal cortex. If the autoimmune endocrine gland disorder does not fulfil the criteria of APS 1-3, the disease may be categorized as autoimmune polyendocrine syndrome type 4. The authors present a case of 33 years old APS type 2 patient who, over 20 years, developed a wide range of autoimmune endocrinopathies, including endocrinopathies that are less common, such as adenohypophysitis, and are associated with other organ-specific diseases (coeliac disease). The case is presented to demonstrate the fact that APS represent a dynamic process and that it is always important to keep in mind that, over time, a patient may develop other autoimmune diseases. To conclude, the authors emphasise the recommendation to test patients with monoglandular endocrinopathy for the presence of any secondary endocrine disorders. PMID- 21250497 TI - [Lymphoma-like course in aggressive adult multisystem Langerhans cell histiocytosis and the benefit of PET/CT imaging in evaluation of diffuse metabolic activity of lung parenchyma]. AB - The case report given here describes an unusual case of a 35-year-old otherwise healthy male diagnosed with aggressive form of Langerhans cell histiocytosis initially taking course under the form of lymphoma with expressed B symptoms (night sweats, fever and weight loss) and generalized peripheral lymphadenopathy. Also present were productive cough and perianal itching. The diagnosis was determined from lymph node and perianal skin biopsies. Furthermore, by a typical finding on HRCT (high-resolution computed tomography), pulmonary involvement was confirmed the gradual development of which we succeeded to document through a series of several HRCT and PET/CT scans from its initial florid phase characterized by disseminated nodularities up to the terminal phase with the decline of activity and development of cystic formations. After the collection of peripheral blood stem cells, the planned patient's therapy started which in all consisted of three monotherapy cycles with cladribine followed by three cycles of combined chemotherapy (cladribine + cyclophosphamide + methylprednisolone) and complemented with curative radiotherapy of the perianal area. This treatment put the disease into complete remission. However, in two months the initial B symptoms occurred again, along with the pulmonary symptomatology, perianal pruritus and newly also hip bone pains. The suspected LCH relapse was proved histologically by lymph node biopsy and confirmed at a restaging PET/CT examination which also showed disease dissemination into the hip bones. Consequently, an aggressive form of the disease with early relapse had been the case, which was indicated for administering 4 cycles of CHOEP (cyclophosphamide + doxorubicin + vincristine + etoposide + prednisone) as salvage regimen completed in March 2010 with autologous peripheral blood stem cell transplantation after high-dose BEAM (carmustine + etoposide + cytarabine + melphalan) chemotherapy. Thus, the generalized involvement of nodes doesn't always need to be malignant lymphoma or metastatic dissemination of a tumour but also LCH may be the case. The presence of B symptoms may very likely stand for an aggressive form of the disease course. Histological evaluation of the proliferative characteristic (given by Ki-67 immunohistochemical proliferative index marker and also morphologically by the number of mitosis) may draw attention to an aggressive form of this disease. However, therapy with cladribine (2-chlorodeoxyadenosine) which proves beneficial in classic forms of LCH, in cases of highly aggressive forms of LCH doesn't need to have the same effect as in LCH with low proliferative activity, which conforms to the present experience in the treatment of indolent and aggressive lymphomas. In our study, the hybrid PET/CT imaging proved high sensitivity in evaluating the activity of the disease, including its early relapse. We are presenting here a new method for description and evaluation of diffuse increased activity of pulmonary parenchyma by means of PET/CT examination and for using this method within the framework of monitoring the curative response. PMID- 21250498 TI - [Central hemiparesis as manifestation of systemic vasculitis]. AB - We present a case report of patient with systemic vasculitis with affection of heart, skin, gastrointestinal tract and rare involvement of central nervous system. Diagnosis of systemic vasculitis was based on clinical manifestations, blood hypereosinophilia and brain magnetic resonance imaging. Immunosuppressive therapy led to regression of symptoms including initially present neurologic manifestation. PMID- 21250499 TI - [Professor Frantisek Por MD and Professor Robert Klopstock MD, students at Budapest and Prague Faculties of Medicine]. AB - Professor Frantisek Por MD and Professor Robert Klopstock MD were contemporaries, both born in 1899, one in Zvolen, the other in Dombovar, at the time of Austro Hungarian Monarchy. Prof. Por attended the Faculty of Medicine in Budapest from 1918 to 1920, and Prof. Klopstock studied at the same place between 1917 and 1919. From 1920 until graduation on 6th February 1926, Prof. Por continued his studies at the German Faculty of Medicine, Charles University in Prague. Prof. Klopstock had to interrupt his studies in Budapest due to pulmonary tuberculosis; he received treatment at Tatranske Matliare where he befriended Franz Kafka. Later, upon Kafka's encouragement, he changed institutions and continued his studies at the German Faculty of Medicine, Charles University in Prague, where he graduated the first great go. It is very likely that, during their studies in Budapest and Prague, both professors met repeatedly, even though their life paths later separated. Following his graduation, Prof. Por practiced as an internist in Prague, later in Slovakia, and from 1945 in Kosice. In 1961, he was awarded the title of university professor of internal medicine at the Faculty of Medicine, Pavol Jozef Safarik University in Kosice, where he practiced until his death in 1980. Prof. Klopstock continued his studies in Kiel and Berlin. After his graduation in 1933, he practiced in Berlin as a surgeon and in 1938 left for USA. In 1962, he was awarded the title of university professor of pulmonary surgery in NewYork, where he died in 1972. PMID- 21250501 TI - [Freedom to wear religious symbols]. PMID- 21250502 TI - [The thematic issue on mouth diseases...]. PMID- 21250503 TI - [Scientific wrong-track?]. PMID- 21250504 TI - [Environmental chemistry: water supply network, 1900-40.]. PMID- 21250505 TI - [Turning the tap off on typhoid: epidemic, death, and the Tampere water issue.]. PMID- 21250507 TI - [The frontiers of identity: Baja Californian hunter-gatherers toward the end of the missionary era.]. PMID- 21250506 TI - [Race and ethnocentrism in Enlightenment aesthetics: what was beauty to European scholars?]. PMID- 21250508 TI - [Julio Guerrero: science and pessimism in Mexico in 1900.]. PMID- 21250509 TI - [Citadels of knowledge: the Kircher Museum and other Italian scientific collections of the 17th century.]. PMID- 21250510 TI - [Americans in Mexico: diverse and historical immigration.]. PMID- 21250512 TI - The landscapes of class negotiation on coffee plantations in the Blue Mountains of Jamaica: 1790-1850. PMID- 21250513 TI - Parish economies of welfare, 1650-1834. PMID- 21250514 TI - The inner mechanics of a South African racial massacre. PMID- 21250515 TI - Proceedings of the 7th China-Korea Symposium on Biomaterials and Nano Biotechnology. October 19-23, 2009. Nanjing and Suzhou, People's Republic of China. PMID- 21250516 TI - [Characteristics of the hemostasis system after long-duration space missions]. PMID- 21250517 TI - The Ottorino Rossi Award. PMID- 21250518 TI - Healthcare reform and New Jersey, perfect together? PMID- 21250519 TI - Health information technology can transform healthcare. PMID- 21250520 TI - Enabling the patient-centered medical home: the role of information technology. PMID- 21250521 TI - How the title of "disruptive physician" can ruin your career--and how to keep that from happening. PMID- 21250523 TI - Communication is key to hiring success. PMID- 21250522 TI - Chronic fatigue syndrome and fibromyalgia: a status report in 2010. PMID- 21250525 TI - The Research Colloquium of the Seton Hall University School of Health and Medical Sciences: a brief history and an overview of the 21st Annual Colloquium. PMID- 21250526 TI - Developments in medicine and technology. PMID- 21250527 TI - The next four years in New Jersey. PMID- 21250528 TI - Confidential litigation stress mentoring: thriving in the face of litigation. PMID- 21250529 TI - New Jersey law gives judges options regarding the mentally ill. PMID- 21250530 TI - Announcing the 2010 Edward J Ill Excellence in Medicine Awards. PMID- 21250531 TI - A cultural history of Fetal Alcohol Syndrome. PMID- 21250532 TI - Disclosure after an adverse event Part 2: common law duties. PMID- 21250533 TI - Prepare for change: it's all about branding. PMID- 21250534 TI - Why I am the right choice...for New Jersy and its doctors, nurses and public health professionals. PMID- 21250535 TI - Why I am the right choice: New Jersey deserves a governor focused on the entire healthcare delivery system. PMID- 21250536 TI - It will take an independent governor to change New Jersey for the better. PMID- 21250537 TI - Dangers abound for out-of-network providers who routinely waive coinsurance. PMID- 21250538 TI - Preparing for H1N1 influenza: New Jersey preparedness efforts ongoing for nearly a decade. PMID- 21250539 TI - Disclosure after an adverse event Part I: statutory duties. PMID- 21250540 TI - Healthcare information technology: a necessary step for healthcare reform. PMID- 21250541 TI - The challenge of change. PMID- 21250542 TI - Chromosomes in a hybrid zone of Israeli mole rars (Spalax, Rodentia). AB - Chromosomal novelties and the level of meiotic and mitotic abnormalities were studied in a hybrid zone between two chromosomally differentiated Spalax cytotypes of 2n = 58 and 2n = 52. These cytotypes differ by five Rb fusions, four centromeric shifts accompanied by heterochromatin deletion, one paracentric inversion, and the Y-chromosome reorganization. Among 149 specimens studied, 82 were hybrids with 64 different karyotypes ranging in diploid numbers from 2n = 50 to 2n = 60. Nine hybrid specimens were mosaics for the chromosome numbers due to occurrence of cell lines with different Robertsonian chromosome arrangements, and six specimens possessed variable number of B-chromosomes. Mosaicism of B chromosomes was found also in meiotic cells however chromatid breaks and abnormal chromosome pairing during meiosis occurred very rarely. All these results imply some local genomic instability resulting in the spontaneous process of reversible Rb fusions. PMID- 21250543 TI - The unique sex chromosome system in platypus and echidna. AB - A striking example of the power of chromosome painting has been the resolution of the male platypus karyotype and the pairing relationships of the chain often sex chromosomes. We have extended our analysis to the nine sex chromosomes of the male echidna. Cross-species painting with platypus shows that the first five chromosomes in the chain are identical in both, but the order of the remainder are different and, in each species, a different autosome replaces one of the five X chromosomes. As the therian X is homologous mainly to platypus autosome 6 and echidna 16, and as SRY is absent in both, the sex determination mechanism in monotremes is currently unknown. Several of the X and Y chromosomes contain genes orthologous to those in the avian Z but the significance of this is also unknown. It seems likely that a novel testis determinant is carried by a Y chromosome common to platypus and echidna. We have searched for candidates for this determinant among the many genes known to be involved in vertebrate sex differentiation. So far fourteen such genes have been mapped, eleven are autosomal in platypus, two map to the differential regions of X chromosomes, and one maps to a pairing segment and is likewise excluded. Search for the platypus testis-determining gene continues, and the extension of comparative mapping between platypus and birds and reptiles may shed light on the ancestral origin of monotreme sex chromosomes. PMID- 21250544 TI - Organization and evolution of heterochromatin in malaria mosquitoes. AB - The African malaria mosquito Anopheles gambiae was the first disease vector chosen for genome sequencing. Although its genome assembly has been facilitated by physical mapping, large gaps still pose a serious problem for accurate annotation and genome analysis. The majority of the gaps are located in regions of pericentromeric and intercalary heterochromatin. Genomic analysis has identified protein-coding genes and various classes of repetitive elements in the Anopheles heterochromatin. Molecular and cytogenetic studies have demonstrated that heterochromatin is a structurally heterogeneous and rapidly evolving part of the malaria mosquito genome. PMID- 21250545 TI - HP1 proteins--what is the essential interaction? AB - There are three mammalian HP1 genes, Cbx5 (encoding HP1alpha), Cbx1 (encoding HP1beta) and Cbx3 (encoding HP1gamma). Despite their high degree of sequence homology mutational analysis has revealed different phenotypes indicating that they possess different functions. Notably, the Cbx1 mutation is lethal in its homozygous condition. The Cbx1 null phenotype is therefore more severe than the Suv(3)9h1/h2 double-mutant mouse, indicating that the essential function of the Cbx1 gene product, HP1beta, is likely to lie outside its interaction with the heterochromatic H3K9me3 determinant of the "histone code" imposed by the Suv(3)9h1/h2 HMTases. Comparisons of HPI mutants in flies and fungi with corresponding mutations in Suv(3)9 genes show that HP1 mutations are invariably more severe than mutation in Suv(3)9 genes. The implications of these data for HP1 function are discussed. PMID- 21250546 TI - Induced cytomictic diversity in maize (Zea mays L.) inbred. AB - Mutation breeding has been used for improving oligogenic and polygenic characters, disease resistance and quantitative characters including yielding ability. The cytological stability of maize inbred lines is an important consideration in view of their extensive use in genetics and plant breeding research. Investigation in Zea mays L. confirms that the migration of chromosomes is a real event that cannot be misunderstood as an artifact produced by fixation or mechanical injuries. During present investigation, we found that out of six inbred lines of Zea mays L. viz. CM-135, CM-136, CM-137, CM-138, CM-142 and CM 213 at various treatment doses of gamma irradiations viz. 200, 400 and 600 Gy, some of the plants of inbred line CM- 138 at 200 Gy dose displayed characteristic cytoplasmic connections during all the stages of meiosis. Four plants from this treatment set were found to be engaged in a rare phenomenon reported as "Cytomixis". It elucidates that in inbred of Zea mays L., induced cytomixis through gamma rays treatment may be considered to be a possible source of production of aneuploid and polyploid gametes. This phenomenon may have several applications in Zea mays L. improvement in the sense of diversity and ever yield potential. PMID- 21250547 TI - Investigating the effects of vitreous humour (crude extract) on growth and differentiation of rat mesenchymal stem cells (rMSCs) and human NTERA2 cells. AB - Two main characteristics of all types of stem cells are their potency for differentiation and self renewal capacity. There is a lot of interest to find the conditions and factors, which govern these behaviours of stem cells. It is very well documented that retinoic acid (RA) reduces growth rate by induction of cell differentiation in certain conditions and cell lines. On the other hand, hyaluronic acid (HA) is known for its growth induction on cultured cells. A natural source of HA, rabbit vitreous humour (VH), was previously shown to promote wound repair in model animals. In search for its possible mechanisms, VH extract was tested on the cultured mesenchymal stem cells and NTERA2 as human embryonal carcinoma cells in the presence of RA. Changes in some cellular and molecular markers (A2B5, Oct4, Sox2) showed that VH and possibly HA interfere with differentiating effects of RA. Therefore, this reagent may affect cell proliferation and tissue regeneration by inhibition of cell differentiation. PMID- 21250548 TI - Complex cytogenetic and molecular-genetic analysis of males with spermatogenesis failure. AB - The chromosomal anomalies, microdeletions of AZF region of Y-chromosome and CFTR gene mutations have been studied among 80 infertile men with idiopathic spermatogenetic failure: 36 (45%) patients with aspermia, 19 (24%) patients with azoospermia and 25 (31%) patients with severe oligoasthenoteratozoospermia. In total 30% males with spermatogenetic failure genetic factor of infertility was observed. Karyotype anomalies were observed in 17.5% of infertile men, within 16.2% numerical and structural gonosomal anomalies and in 1.3%--Robertsonian translocation were revealed. In 11% males with spermatogenetic failure, Y chromosome AZF region microdeletions were detected. The frequency of CFTR major mutation F508del among infertile men was 6.25%. 5T allele of polymorphic locus IVS8polyT was detected in 7.5% of examined men. The results obtained indicate the high complexity of cytogenetic and molecular-genetic studies of male infertility. PMID- 21250550 TI - Epiglottis is not essential for successful swallowing in humans. AB - Controversy has continued for well over 100 years regarding the role of the epiglottis in deglutition. We describe the effect of isolated epiglottectomy on swallowing success in a case series of 3 adult human subjects with isolated epiglottectomy due to trauma, surgery, or cancerous erosion. The patients were 42, 51, and 70 years of age, and swallowing was analyzed objectively with videofluoroscopy. All subjects exhibited successful swallowing with all food types: thin liquid, puree, and solid food. Specifically, the patient with traumatic epiglottectomy exhibited rapid swallowing success, the patient with surgical epiglottectomy exhibited a short period of dysphagia due to postoperative edema, followed by swallowing success, and the patient with epiglottectomy due to cancerous erosion of the entire epiglottis exhibited long term adaptation, with successful swallowing maintained. We conclude that the epiglottis is not essential for successful swallowing in humans, because individuals can readily adapt to isolated epiglottectomy and avoid tracheal aspiration. PMID- 21250549 TI - Computed tomography and otosclerosis: a practical method to correlate the sites affected to hearing loss. AB - OBJECTIVES: We present a practical method for correlating computed tomography (CT) scans with hearing loss in otosclerosis. METHODS: We reviewed the CT scans of 18 patients (34 ears) with clinical otosclerosis who were seen between 2007 and 2008. The scans were reviewed by an otologist in a clinical office setting, followed by a blinded radiologist working at an imaging workstation. The 5 most commonly affected sites in otosclerosis were evaluated for evidence of otospongiosis and then correlated with the degree of air-bone gap and sensorineural hearing loss. RESULTS: Positive CT findings were noted in 70.5% of ears, with a 94% concordance between readings. The sites affected included the ante fenestram (21 ears), round window niche (12), cochlear promontory (4), cochlear apex (3), and posterior fenestram (2). The average air-bone gap increased with each additional site of involvement within an otic capsule (p = 0.004). The bone conduction threshold also increased, on average, with each additional affected site (p = 0.047). CONCLUSIONS: Most patients with clinical evidence of otosclerosis have evidence of otosclerosis on CT that is readily detected in the office setting. Ears with more affected sites have a significantly greater degree of air-bone gap and sensorineural hearing loss. PMID- 21250551 TI - Analysis of pepsin in tracheoesophageal puncture sites. AB - OBJECTIVES: Tracheoesophageal puncture (TEP) and prosthesis insertion is a well established method of voice rehabilitation after laryngectomy. Maintenance of the prosthesis and tract can be challenging, and reflux to the TEP site has been proposed as a cause. The sites of TEP were evaluated for the presence of pepsin in tissue biopsy specimens and tract secretions to explore this association. METHODS: Patients with TEP were interviewed for a history of symptoms related to reflux, medication use history, TEP voice quality, and incidence of TEP complications. Tissue biopsy specimens and tract secretions were obtained from TEP sites and analyzed for the presence of pepsin via sodium dodecyl sulfate polyacrylamide gel electrophoresis Western blot analysis. RESULTS: Twelve of 17 patients (47%) had some history of preoperative or postoperative symptoms of gastroesophageal reflux disease or laryngopharyngeal reflux. Pepsin was present within the TEP site in a total of 10 of 17 patients (58%; 7 of 17 tissue biopsy specimens and 6 of 7 secretion samples). There were no statistically significant associations between the presence of pepsin and sex, reflux history, use of acid suppressive medicine, or time since laryngectomy. CONCLUSIONS: Reflux with subsequent pepsin deposition into the TEP tract occurs in a majority of laryngectomy patients. Further studies on the effect of reflux on the health and function of the TEP tract are warranted. PMID- 21250552 TI - Clinical presentation and the presence of hearing impairment in branchio-oculo facial syndrome: a new mutation in the TFAP2A gene. AB - We report on the clinical presentation of branchio-oculo-facial (BOF) syndrome in 2 patients with mutations in the TFAP2A gene (OMIM 107580). This TFAP2A gene was recently shown to be involved in the causation of BOF syndrome. An overview of the literature on BOF syndrome is given based on clinical reports written in the period during which mutation analysis was not yet available for BOF syndrome. We also give descriptions of the mutations in the TFAP2A gene in our 2 new patients with BOF syndrome. Congenital conductive hearing impairments are described, including hearing rehabilitation and the results of ear surgery. PMID- 21250553 TI - Cochlear implantation in children with congenital X-linked deafness due to novel mutations in POU3F4 gene. AB - OBJECTIVES: We report novel mutations in the POU3F4 gene resulting in congenital X-linked deafness DFN3, and describe the results of cochlear implantation in 4 boys (3 siblings) followed for an average of 3.5 years. METHODS: The diagnosis of DFN3 was made in infant boys on the basis of the radiologic criteria of an underdeveloped modiolus, a wide cochlear fossette, and the presence of all cochlear turns. The POU3F4 gene was sequenced. A standard, transmastoid, facial recess approach was used for cochlear implantation. A lumbar drain was placed before the operation. RESULTS: The identified mutations in the POU3F4 gene were novel (p.R167X in the 3 siblings) or recently reported (p.S310del). A high-flow cerebrospinal fluid leak through the cochleostomy was encountered in each patient and was ultimately controlled. Although the implants functioned properly, the auditory perceptual abilities did not progress past sound detection in the 3 siblings, or past closed-set word identification in the non-sibling, who achieved better speech perception with contralateral amplification. Three boys (2 siblings) show signs of other learning disorders; 1 boy was too young for a complete assessment. CONCLUSIONS: Preoperative gene mutation analysis in DFN3 patients who are considering cochlear implantation may help in long-term counseling and in avoidance of postoperative complications. Limited auditory perception and language acquisition may result. Amplification may sometimes be a better alternative than cochlear implantation, despite the severity of the hearing loss. PMID- 21250554 TI - Effects of nerve-muscle pedicle on immobile rat vocal folds in the presence of partial innervation. AB - OBJECTIVES: We investigated whether implantation of an ansa cervicalis nerve (ACN)-muscle pedicle into the thyroarytenoid (TA) muscle is efficacious in the presence of partial recurrent laryngeal nerve (RLN) innervation. METHODS: We studied a total of 36 rats. Twelve of the rats served as positive and negative control animals. In the remaining 24 rats, the left RLN was transected, a 1-mm piece of nerve was removed, and the stumps were abutted in silicone tubes (STs), inducing partial RLN regeneration. Twelve of the ST-treated rats underwent this procedure alone, and the other 12 rats had a nerve-muscle pedicle (NMP) implanted into the left TA muscle 5 weeks after ST treatment. At 15 weeks, reinnervation was assessed by histologic evaluation of the TA muscle and by electromyography with stimulation of the RLNs and ACNs. RESULTS: The muscle area, the number of nerve terminals, the number of acetylcholine receptors, and the ratio of nerve terminals to acetylcholine receptors were significantly greater (p < 0.05) in the NMP group than in the ST group. Electromyography elicited TA muscle compound action potentials upon stimulation of the RLNs and ACNs. CONCLUSIONS: In rats, NMP implantation is efficacious for reducing atrophic changes in the TA muscle in the presence of partial RLN innervation. PMID- 21250555 TI - Mutations in TMC1 are a common cause of DFNB7/11 hearing loss in the Iranian population. AB - OBJECTIVES: We investigated the cause of autosomal recessive nonsyndromic hearing loss (ARNSHL) that segregated in 2 consanguineous Iranian families. METHODS: Otologic and audiometric examinations were performed on affected members of each family. Genome-wide parametric multipoint linkage mapping using a recessive model was performed with Affymetrix 50K GeneChips or short tandem repeat polymorphisms. Direct sequencing was used to confirm the causative mutation in each family. RESULTS: In 2 Iranian families, L-1651 and L-8600606, with ARNSHL that mapped to the DFNB7/11 locus, homozygosity for a reported splice site mutation (c.776+1G>A), and a novel deletion (c.1589_1590delCT; p.S530*) were identified in the TMC1 gene, respectively. CONCLUSIONS: Consistent with the previously reported phenotype in DFNB7/11 families, the 2 Iranian families had segregated congenital, profound hearing impairment. However, in family L-1651, one affected family member (IV:3) has milder hearing impairment than expected, suggesting a potential genetic modifier effect. These results indicate that DFNB7/11 is a common form of genetic hearing loss in Iran, because this population is the source of 6 of the 29 TMC1 mutations reported worldwide. PMID- 21250556 TI - Angioedema: a review of 367 episodes presenting to three tertiary care hospitals. AB - OBJECTIVES: We evaluated the clinical characteristics of patients treated for angioedema, and determined the factors associated with the clinical course. METHODS: We performed a chart review of 367 episodes presenting from 1997 through 2008. RESULTS: The mean (+/-SD) age was 51.8 +/- 20.1 years; 65.7% of the episodes occurred in female patients; 62.4% of the episodes were in African American patients. The patients were on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for 49.1% of the episodes, and an inciting factor (diet change, minor trauma, or exposure to fumes) was present for 21.5%. We found that 75.7% of the episodes were type 1 angioedema, 5.7% were type 2, 1.4% were type 3, and 17.2% involved multiple sites; 58% of the episodes required admission. For 3.3% of the episodes, the patients were intubated, and in 0.3% of the episodes, the patients required a tracheostomy. Logistic regression identified non-African American race, allergies, alcohol use, use of ACE inhibitors or ARBs, multiple sites, and age as associated with the need for admission. Bivariate analysis identified age, multiple affected sites, stridor, hoarseness, dysphagia, and drooling as associated with intubation or tracheostomy. CONCLUSIONS: The novel findings of this study are lower rates of airway intervention than reported previously and the fact that multiple affected sites were associated with admission and intubation or tracheostomy, particularly when the edema involved the larynx or hypopharynx. PMID- 21250557 TI - Influence of gender on pharyngeal airway length in obese adolescents. AB - OBJECTIVES: Although pharyngeal airway length has been implicated in an increased male predisposition for obstructive sleep apnea (OSA) in adults, data in obese children and adolescents are lacking. Our objective was to determine the influence of gender on pharyngeal airway length in obese adolescents, and to apply computational simulations to better understand the effect of pharyngeal airway length on the airway's predisposition to collapse in this select group. METHODS: Obese subjects without OSA were recruited from our Sleep Center. Their pharyngeal airway length was measured on midline sagittal magnetic resonance images as the distance between the hard palate and the base of the epiglottis. Computational fluid dynamics analysis was used to study the effect of pharyngeal airway length on airflow characteristics. The gender groups were compared for anthropometric measurements and pharyngeal airway length by an unpaired Student's t-test. RESULTS: Our study group included 18 female and 16 male obese adolescents with a mean (+/-SD) age of 14.7 +/- 2.3 years and a mean body mass index of 38.9 +/- 6.9 kg/m2. The groups did not differ in age, body weight, or normalized pharyngeal airway length (0.44 +/- 0.08 mm/cm in girls versus 0.44 +/- 0.11 mm/cm in boys; p = 0.9). The computational fluid dynamics simulation indicated that the 3-dimensional flow field and airway wall pressures were not significantly affected by pharyngeal airway lengthening of up to 10 mm. CONCLUSIONS: Our results indicate that in obese adolescents, there is no influence of gender on pharyngeal airway length, and pharyngeal airway length alone does not significantly affect the airway's predisposition to collapse. These findings suggest that pharyngeal airway length may not explain the increased male gender predisposition for OSA in this select group. PMID- 21250558 TI - Flipping ORs: does this common practice make business sense? PMID- 21250560 TI - Creating a culture shift for safety. PMID- 21250559 TI - Wrong-site errors as likely outside OR. PMID- 21250561 TI - Understanding tissue processing. PMID- 21250562 TI - How allograft tissue is regulated. PMID- 21250563 TI - AAMI advice on Class 6 indicators. AB - Class 6 emulating indicators may be used as internal chemical indicators and in PCDs to release nonimplant loads. Class 6 CIs could be used in BI PCDs for routine sterilizer efficacy monitoring and sterilizer qualification testing and along with BIs inside products undergoing product testing. In all applications, the Class 6 CIs/CI PCDs must be labeled for the specific cycle you are monitoring. Class 6 CIs and/or Class 6 CI PCDs are available from Getinge, Steris, SteriTec, and 3M. PMID- 21250564 TI - Onboarding: evaluating new RNs. PMID- 21250565 TI - Better compliance for preop BP meds. PMID- 21250566 TI - The evaluation of fluorescence changes after application of casein phosphopeptides (CPP) and amorphous calcium phosphate (ACP) on early carious lesions. AB - PURPOSE: To evaluate the effect of casein phosphopeptides (CPP) and amorphous calcium phosphate (ACP), as an adjunct to average oral hygiene, on the fluorescence of initial carious fissures and pits in vivo. METHODS: For this investigator-blind in vivo study 32 volunteers were recruited. Subjects with premolars and molars showing DIAGNOdent-values between 15 and 20 were randomly assigned to two treatment groups. During a wash-out period of 2 weeks and during the 3-week treatment period all subjects were instructed to use only standard fluoride toothpaste (1450 ppm F- as NaF) and to abstain from any oral hygiene products other than dental tape. During the treatment period, one group additionally applied a CPP-ACP containing cream on the respective fissures for 3 minutes, once per day. At Days 1, 8, 15, and 22, DIAGNOdent measurements and a visual assessment of the fissures were performed by two calibrated independent examiners. RESULTS: No significant changes of DIAGNOdent values were found in the control group during the study period. Fissures additionally treated with the CPP ACP containing cream showed significantly lower laser fluorescence values after Day 15 (P = 0.001) and Day 22 (P < 0.001) compared to the control group. No significant difference in the visual classification between the two groups could be found. PMID- 21250567 TI - Protective effect of NaF/triclosan/copolymer and MFP dentifrice on enamel erosion. AB - PURPOSE: To evaluate in situ the protective effect of sodium fluoride (NaF)/triclosan/copolymer dentifrice compared with monofluorphosphate (MFP) dentifrice on eroded enamel. METHODS: The specimens were subjected to erosion with cola soft drink for 60 seconds, four times a day, for 5 days, followed by treatment with the slurry of nonfluoridated, NaF (1450 ppm F/triclosan/copolymer) or MFP (1450 ppm F) dentifrices. Their effects were assessed by surface hardness loss. RESULTS: The dentifrice containing NaF/triclosan/copolymer was statistically more effective on reduction of enamel acid erosion than the non fluoride and the MFP dentifrice (P < 0.05). PMID- 21250568 TI - Effect of toothpaste containing d-limonene on natural extrinsic smoking stain: a 4-week clinical trial. AB - PURPOSE: To determine whether natural smoking stain could be removed/inhibited effectively by a toothpaste containing 5% d-limonene. For comparison and contrast, the effects of d-limonene on tea stain were also assessed. METHODS: The design was a randomized controlled double-blind trial with parallel groups. Toothpastes were: A: positive control with perlite whitening formulation; B: A+5% d-limonene; C: D + 5% d-limonene; D: negative control. The extrinsic stains were measured using Lobene Stain Index. Following baseline examination, all subjects were randomly assigned to one of the four toothpaste groups and instructed to brush with the assigned products twice daily. Subjects returned to the clinic after 4-week brushing for stain removal assessment, then all extrinsic stains, plaque and supragingival calculus were removed and use of assigned products was continued for another 4 weeks, and the stain scores were repeated for inhibition assessment. RESULTS: A total of 408 subjects, 201 with smoking stains and 207 with tea stains, participated in the trial. 5% d-limonene combined with Perlite whitening formulation significantly reduced stain scores both for smoking stain removal and inhibition (P < 0.05). Furthermore, 5% d-limonene alone (in negative formulation) exhibited an additional advantage for smoking stain inhibition (P < 0.05), but the advantage was not found for long-standing smoking stain removal (P > 0.05). The additional advantage of 5% d-limonene was shown neither for removal nor for inhibition in the tea stain study (P > 0.05). All test products were well tolerated over the study period. PMID- 21250569 TI - Polytetrafluoroethylene added to acrylic resin: surface properties and Candida albicans adherence. AB - PURPOSE: To evaluate the surface properties and Candida albicans adherence on two acrylic resins, one polymerized by long cycle and the other by short polymerization cycle, with added 2% PTFE (wt/wt) (experimental groups) or not added (control groups). METHODS: The specimens were divided into four groups (n = 10 per group): (1) acrylic resin polymerized by long cycle; (2) acrylic resin polymerized by long cycle with added 2% PTFE; (3) acrylic resin polymerized by short cycle; and (4) acrylic resin polymerized by short cycle with added 2% PTFE. After finishing and polishing, all specimens were assessed for their surface roughness (pm), contact angle (degree) and surface free energy (erg/cm 2) Saliva coated specimens were submitted to the adherence assay with C. albicans (ATCC 90028). Adhered cells were detached from the acrylic resin surface by ultrasonic waves at 7 watts for 30 seconds in phosphate buffered saline solution (PBS). This cell solution was serially diluted in PBS and plated on Sabouraud agar. The results were expressed in colony forming units per surface area (CFU/mm2). The data was analyzed by two-way ANOVA. The significance limit was set at 5%. RESULTS: No statistical differences were found for roughness, contact angle and surface free energy. There was a reduction trend in C. albicans adherence in PTFE added to resins, but it was not statistically significant. PMID- 21250570 TI - Effect of DPSS laser on the shear bond strength of orthodontic brackets. AB - PURPOSE: To test the bonding of orthodontic brackets to teeth using a diode pumped solid state (DPSS) laser. METHODS: A total of 60 extracted human teeth were divided randomly into four groups: Group 1 (control)--he brackets were bonded to teeth using the quartz-tungsten-halogen (QTH) light (800 mW/cm2) for 40 seconds; Groups 2-4--the brackets were bonded to teeth using the DPSS laser (500 mW/cm2) for 40 seconds, 20 seconds, and 10 seconds, respectively. The teeth were debonded using shear force in a universal testing machine, and the amount of residual adhesive remaining on each tooth was evaluated. Statistical analysis was carried out for the shear bond strength (SBS) and Adhesive Remnant Index (ARI). RESULTS: The brackets bonded using the DPSS laser for 40 seconds showed the highest mean SBS (13.1 +/- 1.2 MPa) among the groups. Furthermore, the DPSS laser with 10 seconds light-curing could achieve 83% of the mean SBS obtained using the QTH light for 40 seconds. The ARI scores showed no differences among all four groups suggesting a similar failure mode. PMID- 21250571 TI - Gloss and surface roughness produced by polishing kits on resin composites. AB - PURPOSE: To compare in vitro the surface roughness (Ra) and gloss (G) produced by three conventional and one experimental polishing kits on four resin composites. METHODS: 24 discs were prepared (d = 12 mm, t = 4 mm) for each resin composite: Filtek Supreme Plus Body/A2 (FSB), Yellow Translucent (FST), Heliomolar/A2 (HM), and EsthetX/A2 (EX) following the manufacturers' instructions. They were finished with 320 grit silicon carbide paper for 80 seconds each. Polishing systems: Sof Lex, Enhance-Pogo, Astropol and Experimental Discs/EXL-695, were applied following manufacturers' instructions. Each specimen was ultrasonically cleaned with distilled water and dried. Gloss and Ra were measured with a small area glossmeter (Novo-curve) and non-contact profilometer (Proscan 2000) following ISO 4288, respectively. The results were evaluated by two-way ANOVA followed by separate one-way ANOVA and Tukey/Kramer test (P = 0.05). RESULTS: There was a significant interaction of surface roughness and gloss between the composites and polishing systems (P < 0.05). The lowest surface roughness was recorded for FST polished with the Experimental kit. The highest gloss was obtained for FSB composite polished with the Experimental kit. The experimental polishing system produced smoothest surfaces (P < 0.05). The Enhance-Pogo and the experimental polishing kit produced highest gloss (P < 0.05). PMID- 21250572 TI - Bond strength of different veneering ceramics to zirconia and their susceptibility to thermocycling. AB - PURPOSE: To evaluate the bond strength of recently developed feldspathic veneering ceramics to zirconium-oxide ceramic core material (Y-TZP). In addition, the effect of thermocycling on the bond strength was investigated. METHODS: 90 square Lava framework Y-TZP specimens were randomly assigned to three groups (n = 30) and veneered with one of the three zirconia veneering ceramics Cerabien ZR (CZR), GC Initial (GCI), or Lava Ceram (LC). 30 additional metal-ceramic specimens served as the control (VO). 15 specimens per group were stored in a saline solution for 3 days. To test the durability of the bond, 15 specimens per group were thermocycled for 10,000 cycles between 5 degrees to 60 degrees C with a 15-second dwell time. Shear strength was tested with an Instron universal testing system. A two-way ANOVA model and Tukey's HSD were applied for statistical analyses (alpha = 0.05). RESULTS: The different material combinations revealed significantly different shear bond strength values (CZR > GCI > LC > VO). All veneering ceramic/zirconia combinations showed significantly higher bond strength than the metal-ceramic control VO. Bond strength values were not affected by thermocycling, except for CZR, which had significantly higher bond strength after thermocycling. Microscopic evaluation of failure modes revealed 100% cohesive failures in the veneering ceramic for all specimens. PMID- 21250573 TI - Effect of chlorhexidine concentrations on micro-shear bond strength of self-etch adhesive to normal and caries-affected dentin. AB - PURPOSE: To evaluate the effect of different chlorhexidine concentrations on bond strength of resin composite to normal and caries-affected dentin using a self etch primer adhesive. METHODS: Thirty carious human molars were ground to expose flat dentin surfaces containing caries-affected surrounded by normal dentin. The teeth were divided into three groups. One group received no chlorhexidine pretreatment (control). The second and third groups received 2% or 5% chlorhexidine pretreatments, respectively before applying the self-etch primer adhesive (Clearfil SE Bond). Resin composite was applied to caries-affected dentin and to normal dentin on the same tooth with the aid of polyethylene tubes (0.9 mm diameter and 0.7 mm height). For micro-shear bond strength testing, each tooth was secured in a specially designed attachment jig to hold the specimens to the universal testing machine. Load was applied by the testing machine through a wire loop adjusted to the bonded interface at a crosshead speed of 0.5 mm/minute. Micro-shear bond strength was calculated and mode of failure was examined with a x40 stereomicroscope. RESULTS: Statistical analysis revealed insignificant differences between control, 2% and 5% chlorhexidine pretreatment for normal as well as for caries-affected dentin groups. Also, there were insignificant differences in bond strength values between normal and caries-affected dentin for each treatment modality. Adhesive failure was the most common mode of failure. PMID- 21250574 TI - Temperature rises beneath resin composite restorations during curing. AB - PURPOSE: To compare the thermal conductivity of two different composite materials, with five light-cure units, in a series of different material thicknesses and light source distances. METHODS: Two commonly used resin composite restorative materials and three light emitting diodes (LED), one halogen, and one plasma arc lights were selected. The thermal conductivity of the composite materials with different light curing units (LCU) was measured and compared. A K-type thermocouple and digital thermometer were used to assess the thermal conductivity. Materials depths of 1 mm, 2 mm and 4 mm and curing distances of 0 mm, 3 mm and 6 mm were compared. Four-way ANOVA was used to analyze the Ln transformation of the maximal temperature and a Tukey test for multiple comparisons. RESULTS: Significant differences in temperature rise were observed between the two restorative materials. The thermal emission of the LED lights was higher than the other LCU's measured. An inverse ratio was found between material thickness and the measured thermal conductivity and the distance of the light tip from the restorative material. PMID- 21250575 TI - Comparison of fracture resistance of bonded glass fiber posts at different lengths. AB - PURPOSE: To evaluate in vitro the fracture resistance of quartz fiber posts for three different dowel lengths. METHODS: 30 single-rooted human premolars with similar root length and diameter were endodontically treated and randomly divided into three experimental groups (n = 10) according to the post space depth created: (1) 5 mm; (2) 7 mm; (3) 9 mm. Quartz fiber posts (Endo Light post) were cemented using a dual cured resin cement with its adhesive system (Prime & Bond NT + Fluorocore 2). After 24 hours, specimens were embedded in acrylic resin and loaded under continuous compressive force at the extruding coronal part of the post (45-degree angle) to the long tooth axis (crosshead speed: 0.75 mm/minute). Forces at fracture (Newtons) were recorded. One-way ANOVA and Tukey tests were used for the statistical analysis (P < 0.05). RESULTS: Mean strength values (SD) were: (1) 40.52 (3.14); (2) 41.68 (5.31); (3) 44.88 (6.77), respectively. No statistically significant differences were found among the groups. PMID- 21250576 TI - A 24-month randomized clinical trial of a two- and three-step etch-and-rinse technique. AB - PURPOSE: This 24-month randomized paired tooth clinical study evaluated the performance of All Bond 3 used in the simplified (2-step) and full (3-step) versions. METHODS: 33 patients, with at least two similar sized non-carious cervical lesions participated in this study. A total of 66 restorations were placed, half using the 2-step All Bond 3 (AB3-2) and the other half using 3-step All Bond 3 (AB3-3). The restorations were placed incrementally using the composite resin Aelite. The restorations were evaluated at baseline and after 6, 12 and 24 months following the modified USPHS criteria. Statistical differences between the adhesive were tested using with McNemar's test and clinical performance over time for each material with the Fisher's exact test (alpha = 0.05). RESULTS: After 24 months, six AB3-2 and four AB3-3 were rated as bravo for marginal discoloration but did not differ from each other significantly (P > 0.05). The retention rates at 24 months of AB3-2 and AB3-3 were 90.9% and 97.0%, respectively (P > 0.05). PMID- 21250577 TI - Universal vitamin A supplementation programme in India: the need for a re-look. PMID- 21250578 TI - Emerging carbapenem resistance in the context of a new metallo-beta-lactamase (NDM-1). PMID- 21250579 TI - Overweight and obesity among schoolchildren in Manipur, India. AB - BACKGROUND: The prevalence of overweight and obesity and their associated factors among schoolchildren in Manipur has not been studied. METHODS: We did a cross sectional study among 3356 schoolchildren of classes VIII to XII in Imphal West district, Manipur between September 2005 and August 2006. The characteristics of the respondents and related variables such as parental build, watching television, eating habits, playing of video/computer games and outdoor games, dietary pattern and knowledge of obesity were assessed using a questionnaire. Height, weight, waist circumference, hip circumference, fat percentage, fat mass and fat-free mass were measured. Body mass index (BMI) and waist-hip ratio for each student were calculated. RESULTS: The BMI of the sampled students was lower than the corresponding WHO and International Obesity Task Force standards. Using the WHO standard, the prevalence of overweight was 4.2% and of obesity 0.8%. Using multivariate logistic regression, mother being reported to be obese (OR 1.9, 95% CI 1.4-2.6), watching television for > 2 hours a day (OR 2.052, 95% CI 1.191-3.536), higher family income (OR 5.844, 95% CI 2.135-15.99), not eating other type of vegetables in the past 1 week (OR 2.338, 95% CI 1.04-5.24) and waist-hip ratio (OR 7.737, 95% CI 4.429-13.51) were found to be independent predictors of a higher BMI. Mother's literacy below class X (OR 0.6, 95% CI 0.378 0.997) and eating between major meals (OR 0.447, 95% CI 0.293-0.681) were significant predictors of a lower BMI. CONCLUSION: The prevalence of overweight and obesity among schoolchildren in the Imphal West district of Manipur is low. The possible reasons for this include a more traditional low-fat diet, less exposure to sedentary past-times and a greater time spent playing outdoors. PMID- 21250580 TI - Inequitable coverage of non-communicable diseases and injury interventions in India. AB - BACKGROUND: We examined the inequities in coverage of interventions for non communicable diseases (NCDs) and injuries in India. METHODS: Data collected by the WHO World Health Survey in 6 Indian states in 2003 were used to estimate the coverage of interventions for NCDs and injuries. Coverage was defined as the proportion of individuals who reported receiving the intervention among those in need of it. Multiple logistic regression analysis was used to assess inequities in coverage of interventions. Composite coverage was calculated for each state and assessed against expenditure on health. RESULTS: The composite coverage of interventions for NCDs and injuries for all states combined was 43.9% (95% CI 43.0%-44.8%), and was higher in urban than in rural areas. Lower wealth quintiles had higher odds of being in need of interventions but lower odds of being covered. Overall, the highest quintile had composite coverage of 54.5%, compared with 34.1% for the lowest quintile. The states with lower coverage of interventions had a higher proportion of households reporting selling items or borrowing money to cover health expenditure; this proportion was highest (58.8%) in Rajasthan state that had the lowest composite coverage (36.6%). CONCLUSION: The higher need for and lower coverage of interventions for NCDs and injuries in the poor, and the associated high risk of further adverse economic impact due to health spending, suggest that the public health system of India should improve access to these interventions at no cost for the economically disadvantaged. PMID- 21250581 TI - Rural cancer registry at Barshi, Maharashtra and its impact on cancer control. AB - BACKGROUND: The relevance of population-based cancer registries for planning and implementing cancer control programmes cannot be overemphasized. There are some urban registries in India but very few rural registries despite India being predominantly rural. There are several obstacles to setting up a rural registry including lack of cancer awareness in the rural population and inaccessibility of modern medical facilities. The first rural cancer registry was set up in 1987 at Barshi (population 0.4 million) in western Maharashtra by adopting a methodology suitable for rural areas. METHODS: The innovative methodology supplemented the usual registry methodology by regular interaction with the community to educate them on warning signals for cancer, raise cancer awareness and motivate suspected individuals to seek medical attention. Cancer detection clinics were held in villages. RESULTS: The reliability indices show that the registry is of an acceptable standard. The registry activity has increased cancer awareness in this population (p < 0.01), increased the frequency of early cervical cancers (stages I and IIa) by more than 2-fold during the past 16 years and significantly decreased the relative risk of death (hazard ratio 0.7 [0.5-0.9]). CONCLUSION: The innovative methodology has facilitated the process of cancer registration in rural areas. It has had a positive impact on cancer awareness, stage at presentation and survival of cervical cancers-the predominant cancer in the area. The registry has created a resource for epidemiological studies in a rural area where national and international studies are currently being undertaken. PMID- 21250582 TI - Household food security in urban Tamil Nadu: a survey in Vellore. AB - BACKGROUND: Food security has been a matter of concern in recent years due to the global food crisis and rising food prices. We aimed to study the level of food security in a densely populated urban area in southern India. METHODS: A door-to door survey of 130 households in an urban area in Vellore district, Tamil Nadu was done and information on food security status was collected using the United States Department of Agriculture Household Food Security Scale, on socioeconomic status using the modified Kuppuswamy scale and demographic details. RESULTS: Of the 130 households surveyed, food insecurity with hunger was present in 61.5% (95% CI 52.98%-70.02%), food insecurity without hunger in 13.1% (95% CI 7.2%-19%) and food security in 25.4% (95% CI 17.8%-33%) of the households. Prevalence of any form of food insecurity was present in three-fourths of the households (74.6%; 95% CI 67%-82.2%). Only 76 (58.5%) households used the public distribution system for buying rice-the staple food, and 63 (82.9%) households in the lower socioeconomic strata used the public distribution system for buying rice. CONCLUSIONS: Despite good penetration of the public distribution system in Tamil Nadu, the prevalence of food insecurity in urban areas is high. Nationwide and regional urban-rural food security data need to be studied to influence policy regarding the means to reduce food insecurity in India. PMID- 21250583 TI - Post-burn contracture neck with extreme microstomia and fibrosed obliterated nose: a unique airway challenge. PMID- 21250585 TI - Birth weight, early weight gain, and risk of type 1 diabetes. PMID- 21250586 TI - Exploring alternative health services for HIV screening of high risk individuals. PMID- 21250584 TI - Heart failure: epidemiology and prevention in India. AB - Reliable estimates of heart failure are lacking in India because of the absence of a surveillance programme to track incidence, prevalence, outcomes and key causes of heart failure. Nevertheless, we propose that the incidence and prevalence rates of heart failure are rising due to population, epidemiological and health transitions. Based on disease-specific estimates of prevalence and incidence rates of heart failure, we conservatively estimate the prevalence of heart failure in India due to coronary heart disease, hypertension, obesity, diabetes and rheumatic heart disease to range from 1.3 to 4.6 million, with an annual incidence of 491 600-1.8 million. The double burden of rising cardiovascular risk factors and persistent 'pre-transition' diseases such as rheumatic heart disease, limited healthcare infrastructure and social disparities contribute to these estimates. Staging of heart failure, introduced in 2005, provides a framework to target preventive strategies in patients at risk for heart failure (stage A), with structural disease alone (B), with heart failure symptoms (C) and with end-stage disease (D). Policy-level interventions, such as regulations to limit salt and tobacco consumption, are effective for primordial prevention and would have a wider impact on prevention of heart failure. Clinical preventive interventions and clinical quality improvement interventions, such as treatment of hypertension, atherosclerotic disease, diabetes and acute decompensated heart failure are effective for primary, secondary and even tertiary prevention. PMID- 21250587 TI - MRI contrast media: what clinicians need to know. AB - Magnetic resonance imaging (MRI) is an imaging modality that uses the differential spinning of protons (hydrogen) in the body when exposed to an external magnetic field, to produce cross-sectional images of the body. The advent of MRI is a boon to mankind as it does not involve ionizing radiation and provides superior soft tissue contrast even without administration of contrast media. The contrast media used in MRI were developed many years after MRI was already in use, the first being gadopentetate dimeglumine--a non-specific extracellular gadolinium chelate. Extracellular agents are the most widely used, although tissue-specific agents have been developed and are used as problem solving tools in specific conditions. Tolerance to gadolinium-based contrast agents is excellent. The tissue-specific agents do have some adverse effects, though none of them are life-threatening. However, identification of a condition called nephrogenic systemic fibrosis has forced a rethink about the liberal usage of MRI contrast agents. PMID- 21250588 TI - Needs and priorities of faculty development for medical teachers in India: a Delphi study. AB - BACKGROUND: The models of faculty development (FD) currently in use in India are not based on any needs assessment of teachers working in Indian medical schools. We did this study to identify pedagogic themes that should be included in FD programmes in India and to ascertain the relative importance of these themes as perceived by experienced teachers. METHODS: A questionnaire containing themes relating to FD was developed from a review of the literature and the content of current FD programmes in India. The themes to be included in the questionnaire were piloted with the help of 3 senior teachers. We then conducted a 3-round normative Delphi technique to identify which of these themes were considered the most important for FD programmes in India. RESULTS: Of 32 teachers from both clinical and non-clinical departments who agreed to rate the themes, 26 completed the entire process. There was a significant decrease in the standard deviation of the ratings in round 3 as compared to rounds 1 and 2. Themes related to instruction and assessment were rated the highest. Curriculum-related themes received lower priority. There was no significant difference in the ratings provided by clinical and non-clinical teachers. CONCLUSIONS: We prioritized the themes for FD programmes in India on the basis of the felt needs of teachers. These identified themes need to be given priority when planning FD programmes. PMID- 21250589 TI - Obesity. PMID- 21250590 TI - Slumdog's silent killer. PMID- 21250591 TI - Inhumanity in the autopsy room. PMID- 21250592 TI - An uncommon cause for bilateral peripheral facial nerve paralysis. PMID- 21250593 TI - Hand, foot and mouth disease (HFMD): a newly emerging infection in Orissa, India. PMID- 21250594 TI - Do journals acknowledge their past editors: an online survey of leading medicine journals. PMID- 21250595 TI - Glucose-6-phosphate dehydrogenase deficiency and haptoglobin polymorphism among Rajput and Brahmin children in Himachal Pradesh. PMID- 21250596 TI - Nurse tutors to teach basic clinical skills: an experience from Selcuk University, Turkey. PMID- 21250598 TI - Cloning and expression of chicken granulocyte-macrophage colony stimulating factor (GMCSF) gene. AB - Granulocyte-macrophage colony stimulating factor (GMCSF), a multifunctional cytokine can enhance immune responses when administered along with DNA vaccine. Aim of the present study was to clone and express the chicken GMCSF cytokine for use as 'genetic adjuvant'. Chicken GMCSF gene 435bp was amplified using specific primers in which restriction sites of BamHI and HindIII were at forward and reverse primers respectively. The PCR product was cloned into eukaryotic expression vector pcDNA 3.1(+) and clones were confirmed by restriction digestion and nucleotide sequencing. Functional activity of recombinant GMCSF was checked by expression of GMCSF specific mRNA in transfected Vero cells by RT-PCR of total RNA isolated from transfected Vero cells. The recombinant plasmid can be used as genetic adjuvant in chicken. PMID- 21250597 TI - Fluvastatin, a lipophilic statin, induces apoptosis in human hepatocellular carcinoma cells through mitochondria-operated pathway. AB - Fluvastatin, a lipophilic statin, was known to inhibit proliferation and induce apoptosis in many cancer cells. Its potential anticancer was evaluated in three hepatocellular carcinoma (HCC) cell lines (HepG2, SMMC-7721 and MHCC-97H). Cells were treated with fluvastatin in vitro and its effect on cell proliferation, cell cycle, invasion and apoptosis was determined. Mechanism of apoptosis induced by fluvastatin on HCC cell lines was also investigated through western blotting and mitochondrial membrane potential (MMP) analysis. It was observed that fluvastatin inhibited proliferation of HCC cells by inducing apoptosis and G2/M phase arrest in a dose-dependent manner. The results of cell invasion assay revealed that fluvastatin significantly decreased the invasion potency of HCC cells. A mitochondria-operated mechanism for fluvastatin induced apoptosis might be involved and was supported by Western blotting and MMP analysis. After fluvastatin treatment, expression of Bcl-2 and procaspase-9 were downregulated, cytochrome c (cytosolic extract), Bax and cleaved-caspase-3 protein expression were increased. Furthermore, a breakdown of MMP in HCC cells was observed. To conclude, these results have provided a rationale for clinical investigations of fluvastatin in future as a potential anticancer reagent for growth control of HCC. PMID- 21250599 TI - Immunogenicity of iron-regulated outer membrane proteins of Pasteurella multocida B:2 in mice model. AB - The present study was conducted to investigate the role of iron-regulated outer membrane proteins (IROMP) of Pasteurella multocida B:2 in mice as potential immunogens. Outer membrane proteins extracted from P. multocida B:2 grown under normal (OMP) and iron-deficient (IROMP) conditions were subjected to discontinuous SDS-PAGE. Nine polypeptides of MW ranging from 85.1 to 16.7 kDa from OMP preparations and two additional polypeptides of MW 95.4 and 89.1 kDa from IROMP preparations were observed with bands of MW 37.2 and 34.7 kDa as major proteins. Mice were immunized twice with OMP, IROMP-enriched fractions and whole cell lysate (WCL) via subcutaneous route at day 0 and 21. Antibody titers were determined from sera collected at weekly interval and protection was studied against challenge using 10(2) cfu of P. multocida two weeks after secondary immunization via intranasal and subcutaneous routes. IROMP and OMP immunized mice provoked significant antibody responses and IROMP induced higher antibody responses. IROMP and OMP immunized mice showed protection (100%) upon intranasal challenge and a protection (84%) following subcutaneous challenge as compared to high mortality (84%) in control mice. These results indicate that OMP enriched with IROMP fractions can be superior means of immunization. PMID- 21250600 TI - Vasoprotection by melatonin and quercetin in rats treated with cisplatin. AB - Cisplatin-based chemotherapy has a variety of vascular side effects. The aim of the present study was to evaluate the beneficial effect of melatonin and cisplatin on the alterations in vascular reactivity and structure of cisplatin treated rats. Phenylephrine (PHE) and KCl-caused concentration-dependent contractions of rat aorta. Pretreatment with cisplatin increased the sensitivity but not the max response to PHE and KCl. In rats treated with melatonin or quercetin before cisplatin, the EC50 values, but not the maximal response to both agents were significantly higher than cisplatin-treated group. Compared to the control group, cisplatin-treatment significantly reduced the luminal area of the aorta. In melatonin and quercetin-treated aortas the luminal area values were significantly higher than cisplatin-treated group. The results demonstrate for the first time that melatonin and quercetin treatment may protect the aorta in cisplatin-based chemotherapy. PMID- 21250601 TI - Eicosapentaenoic and docosahexaenoic acids enriched polyunsaturated fatty acids from the coastal marine fish of Bay of Bengal and their therapeutic value. AB - Eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) enriched polyunsaturated fatty acids (PUFA) significantly present in marine fish oil emerge as preventive agents for combating many health problems specially in chronic or metabolic disorders. The fish in the coastal area of Bay of Bengal has remained unexplored with respect to EPA/DHA enriched PUFA content in its oils, although it may be a potential source in harnessing the health benefit. In this study, seven varieties of the coastal fish were analysed for the content of EPA/DHA. The one locally known as lotte, (Harpadon nehereus) though has low content of total lipids, was found to have high EPA/DHA in its oil. The phospholipids rich fraction was extracted from the total fish oil. The EPA/DHA enriched PUFA was isolated to investigate the potential use for health benefits. EPA/DHA is found to act as protective agent against mercury poisoning studied in cell culture as well as in animal mode. It is found to be highly preventive in diabetes. The lotte is available in the coastal area of Bay of Bengal adjoining West Bengal, India in large scale and it is the first report showing EPA/DHA enriched PUFA in these fish oil that can be availed to harness in important health benefits. PMID- 21250602 TI - Oily fraction of Semecarpus anacardium Linn nuts involves protein kinase C activation for its pro-inflammatory response. AB - The oily fraction (non polar fraction-NPF) of S. anacardium (SA) significantly increased the expression of protein kinase C-delta (PKC-delta) in macrophages in concentration dependent manner, which was similar to phorbol myristate acetate (PMA) response. Further, H-7 (1-(5-isoquinolinesulphonyl)-2-methylpiperazine), an inhibitor of PKC significantly inhibited this NPF mediated response in a concentration dependent manner. In the post treatment kinetics, H-7 showed this inhibition only up to 6 min post NPF/PMA addition, but in similar condition, quercetin, a flavone with reported antioxidant property, showed this inhibition only up to 2 min. The results clearly suggest that oily fraction of SA nuts enhances the expression of PKC protein, which may be responsible for its reported pro-inflammatory property. PMID- 21250603 TI - In vitro free radical scavenging activity of wild edible mushroom, Pleurotus squarrosulus (Mont.) Singer. AB - Cellular damage caused by reactive oxygen species has been implicated in several diseases and hence antioxidants have significant importance in human health. Cold water, hot water and methanolic extract of Pleurotus squarrosulus were evaluated for antioxidant activity against hydroxyl radical, DPPH (1,1-Diphenyl-2 picrylhydrazyl) radical, superoxide radical, nitric oxide (NO) scavenging, reducing power, ferrous ion chelating ability and beta-carotenellinoleic acid assay. Total phenol, flavonoid, beta-carotene and lycopene content were also determined. Hot water extract showed significant antioxidant activity in all the test systems. Hydroxyl radical scavenging activity of all the extracts has been significant compared to positive control. Hot water extract has been found to have higher phenolic, total flavonoid, beta-carotene and lycopene content than cold water and methanolic extract of the mushroom. Results of this study showed that, hot water extract has maximum antioxidant property and may be utilized as a promising source of therapeutics. PMID- 21250604 TI - Screening of certain medicinal plants from India for their anti-quorum sensing activity. AB - Discovery of quorum sensing (QS) system to coordinate virulence and biofilm formation in bacterial pathogens has triggered search for safe, stable and non toxic anti-QS compounds from natural products. Ethanolic extracts of 24 Indian medicinal plants were tested by agar well and disc diffusion assay for anti-QS activity using Chromobacterium violaceum (CV12472 and CVO26) reporter strains. AHL from C. violaceum CV31532 was isolated and partially purified for its use in CVO26 based bioassay. Effect on swarming-motility of Pseudomonas aeruginosa (PAO1) was also recorded at sub-MIC concentrations of extracts. Of the 24 medicinal plants screened Hemidesmus indicus (L.) Schult (root), Holarrhena antidysenterica (Roth) A.DC. (bark), Mangifera indica L. (seed) Punica granatum L. (pericarp) and Psoralea corylifolia L. (seed) demonstrated varying level of inhibition of violacein production in the reporter strains. Moreover, a significant reduction in swarms was recorded over control. The inhibition of violacein production and swarming motility may be due to direct or indirect interference on QS by active constituents or the interactive effect of different phytocompounds present in the extracts. These plant extracts may be selected for activity guided fractionation to identify and characterize the active principle. PMID- 21250605 TI - Biological activity of sea anemone proteins: I. Toxicity and histopathology. AB - The crude as well as partially purified protein fractions from anemone species viz. Heteractis magnifica, Stichodactyla haddoni and Paracodylactis sinensis, collected from the Gulf of Mannar, south east coast of India were found to be toxic at different levels to mice. The mice showed behavioral changes such as loss of balance, opaque eyes, tonic convulsions, paralysis, micturiction, flexing of muscles, prodding (insensitive to stimulii), foaming from mouth and exophthalmia. The toxic proteins upon envenomation produced several chronic and lethal histopathological changes like formation of pycnotic nuclii and glial nodules in the brain; heamolysis, thrombosis and myocardial haemorrhage in the heart; granulomatous lesions, and damage to the hepatic cells in the liver and haemorrhage throughout the kidney parenchyma and shrinkage of glomerular tufts in the kidney. The toxins proved to be neurotoxic, cardiotoxic, nephrotoxic and hepatotoxic by their action on internal organ systems. The toxins were also thermostable till 60 degrees C and had considerable shelf life. PMID- 21250606 TI - Biological activity of sea anemone proteins: II. Cytolysis and cell line toxicity. AB - Potent cytolytic activity was exhibited by proteins extracted from three sea anemones viz. Heteractis magnifica, Stichodactyla haddoni and Paracodylactis sinensis by affecting the red blood corpuscles (RBC) and the mouse fibroblast cell line (L929) and leukemia cell line (P388). Crude toxin of all the three anemone species induced spontaneous hemolysis of chicken, goat and human erythrocytes. The crude toxin of H. magnifica (0.98 mg/ml) elicited hemolysis at levels of 4096, 512 and 4096 HU (hemolytic unit) in chicken, goat and human erythrocytes respectively. Subsequently, the crude toxin of S. haddoni (0.82 mg/ml) exhibited a hemolytic activity of 256, 128 and 512 HU and that of P. sinensis (0.60 mg/ml) had a hemolytic activity of 128, 4096 and 512 HU. Most of the partially purified proteins of these anemones also exhibited the activity against the three different erythrocytes. The viability of L929 and P388 was adversely affected on adding the crude toxins. The symptoms of toxicity shown by the cells were rounding, lysis and detachment from the substratum. These effects were the least in S. haddoni, as compared to those the crude toxins of the other two species. Inhibition of growth of L929 exhibited by the toxin of the three species ranged between 61.08 and 93.38%. Similarly, inhibition of the growth of P388 ranged between 51.32 and 86.16%. The present investigation reveal the cytotoxic nature of anemone toxins. PMID- 21250607 TI - Simultaneous removal of NO(x) and SO2 in exhausted gas through landfill leachate. AB - Simultaneous removal of NO(x) and SO2 from exhausted gas were investigated by studying co-culture of sulfate reducing bacteria and anaerobic denitrifying bacteria, separated from landfill leachate. When H2S, generated by sulfate reducing bacteria was chosen as the sole electron donor for anaerobic denitrifying bacteria, the co-culture system demonstrated a faster NO removal rate, higher stability and better permanence. When the feed gas flow rates of N2 and SO2 were maintained constant at 0.1 m3/h and 16 ml/min respectively, the maximum NO-removal rate could be achieved at over 92% with NO feed gas kept between 2-6 ml/min, while the SO2 removal rate was always above 95%. Long-term continuous removal of NO exhibited an evident periodicity of five days, however, the fluctuation range of NO-removal was decreasing. Moreover, the decrease of the gas flow rate and the increase in NO inlet concentration could contribute to a higher NO- removal rate. PMID- 21250608 TI - Visioning the future. PMID- 21250612 TI - Nursing Council expands scopes of practice and works on improving communication. PMID- 21250613 TI - How does dialysis treatment affect the lives of rural Maori patients? PMID- 21250614 TI - Upskilling ED clinical nurse specialists. PMID- 21250615 TI - Maintaining safety during blood transfusions. PMID- 21250616 TI - The case against more privatisation of health care--private care costs more. PMID- 21250617 TI - Report calls for major changes in aged care. PMID- 21250618 TI - Interprofessional postgraduate education: following the evidence for collaborative health professional practice. PMID- 21250619 TI - Harnessing technology to benefit nursing. PMID- 21250620 TI - Who needs learning reps in their workplace? PMID- 21250621 TI - Keeping abreast of the revolution in technology. PMID- 21250622 TI - Growing nursing's future leaders. PMID- 21250623 TI - Tariana Turia accepts taonga. PMID- 21250624 TI - QIPP. High impact for less pressure. PMID- 21250626 TI - Economic squeeze. Limited options. PMID- 21250625 TI - Legal. Passing on the baton. PMID- 21250627 TI - New skills. Building a future. PMID- 21250628 TI - Intermediate skills. A welcome workforce. PMID- 21250629 TI - Entry-level jobs. A foot in the door. PMID- 21250630 TI - Innovation. Keeping wisdom on the stocks. PMID- 21250631 TI - Turnaround. Being open to a second chance. PMID- 21250633 TI - Synthesis of monodisperse, rodlike silica colloids with tunable aspect ratio. AB - Although the experimental study of spherical colloids has been extensive, similar studies on rodlike particles are rare because suitable model systems are scarcely available. To fulfill this need, we present the synthesis of monodisperse rodlike silica colloids with tunable dimensions. Rods were produced with diameters of 200 nm and greater and lengths up to 10 MUm, resulting in aspect ratios from 1 to ~25. The growth mechanism of these rods involves emulsion droplets inside which silica condensation takes place. Due to an anisotropic supply of reactants, the nucleus grows to one side only, resulting in rod formation. In concentrated dispersions, these rods self-assemble in liquid crystal phases, which can be studied quantitatively on the single particle level in three-dimensional real space using confocal microscopy. Isotropic, paranematic, and smectic phases were observed for this system. PMID- 21250634 TI - Reactions of hydrosilanes with transition metal complexes and characterization of the products. PMID- 21250635 TI - Application of photonic crystal enhanced fluorescence to cancer biomarker microarrays. AB - We report on the use of photonic crystal surfaces as a high-sensitivity platform for detection of a panel of cancer biomarkers in a protein microarray format. The photonic crystal surface is designed to provide an optical resonance at the excitation wavelength of cyanine-5 (Cy5), thus providing an increase in fluorescent intensity for Cy5-labeled analytes measured with a confocal microarray scanner, compared to a glass surface. The sandwich enzyme-linked immunosorbent assay (ELISA) is undertaken on a microarray platform to undertake a simultaneous, multiplex analysis of 24 antigens on a single chip. Our results show that the resonant excitation effect increases the signal-to-noise ratio by 3.8- to 6.6-fold, resulting in a decrease in detection limits of 6-89%, with the exact enhancement dependent upon the antibody-antigen interaction. Dose-response characterization of the photonic crystal antibody microarrays shows the capability to detect common cancer biomarkers in the <2 pg/mL concentration range within a mixed sample. PMID- 21250636 TI - Linear/network poly(epsilon-caprolactone) blends exhibiting shape memory assisted self-healing (SMASH). AB - Self-healing (SH) polymers are responsive polymeric materials that can repair mechanical damage such as cracks in an autonomous fashion. In most SH polymers studies reported to date, crack closure was either unaddressed or achieved by manual intervention. Here, we report a new strategy that utilizes shape memory (SM) to prepare novel SH polymers that are capable of simultaneously closing and rebonding cracks with a simple thermal trigger. This strategy, termed "shape memory assisted self-healing (SMASH)", is demonstrated in a blend system consisting of cross-linked poly(epsilon-caprolactone) network (n-PCL) with linear poly(epsilon-caprolactone) (l-PCL) interpenetrating the network, and exhibits a combination of SM response from the network component and SH capacity from the linear component. Thermomechanical analysis revealed that the thermoset, n-PCL, demonstrates reversible plasticity -a form of shape memory where large plastic deformation at room temperature is fully recoverable upon heating. This SM action assists to close any cracks formed during deformation and/or damage while l-PCL chains tackify the crack surfaces by diffusion to the free surface and ultimately across the area of damage during the same heating step as used for SM. In our study, we investigated the controlled damage and SMASH healing of blends with varying composition using tensile testing of essential work of fracture film specimens. The healing component, l-PCL used had a high M(w) (M(w) ~65k g/mol) to enable re-entanglement after diffusion across the interface while the shape memory component, n-PCL was prepared from PCL telechelic diacrylates and a tetrathiol cross-linker, yielding excellent shape memory. We found excellent self healing of films by the SMASH mechanism, with near complete healing for l-PCL contents exceeding 25 wt %. Applications are envisioned in the area of self healing bladders, inflated structure membranes, and architectural building envelopes. PMID- 21250637 TI - Syntheses, structure, and luminescent properties of novel hydrated rare earth borates Ln2B6O10OH4*H2O (Ln = Pr, Nd, Sm, Eu, Gd, Dy, Ho, and Y). AB - Ln(2)B(6)O(10)(OH)(4)*H(2)O (Ln = Pr, Nd, Sm-Gd, Dy, Ho, and Y), a new series of hydrated rare earth borates, have been synthesized under hydrothermal conditions. A single crystal of Nd analogue was used for the structure determination by X-ray diffraction. It crystallizes in the monoclinic space group C2/c with lattice constants a = 21.756(4), b = 4.3671(9), c = 12.192(2) A, and beta = 108.29(3) degrees . The other compounds are isostructural to Nd(2)B(6)O(10)(OH)(4)*H(2)O. The fundamental building block (FBB) of the polyborate anion in this structure is a three-membered ring [B(3)O(6)(OH)(2)](5-). The FBBs are connected by sharing oxygen atoms forming an infinite [B(3)O(5)(OH)(2)](3-) chain, and the chains are linked by hydrogen bonds, establishing a two-dimensional (2-D) [B(6)O(10)(OH)(4)*H(2)O](6-) layer. The 2-D borate layers are thus interconnected by Ln(3+) ions to form the complex three-dimensional structure. Ln(2)B(6)O(10)(OH)(4)*H(2)O dehydrates stepwise, giving rise to two new intermediate compounds Ln(2)B(6)O(10)(OH)(4) and Ln(2)B(6)O(11)(OH)(2). The investigation on the luminescent properties of Gd(2 2x)Eu(2x)B(6)O(10)(OH)(4)*H(2)O (x = 0.01-1.00) shows a high efficiency of Eu(3+) f-f transitions and the existence of the energy transfer process from Gd(3+) to Eu(3+). Eu(2)B(6)O(10)(OH)(4)*H(2)O and its two dehydrated products, Eu(2)B(6)O(10)(OH)(4) and Eu(2)B(6)O(11)(OH)(2), present the strongest emission peak at 620 nm ((5)D(0) -> (7)F(2) transition), which may be potential red phosphors. PMID- 21250638 TI - Curcumin as the OO bidentate ligand in "2 + 1" complexes with the [M(CO)3]+ (M = Re, 99mTc) tricarbonyl core for radiodiagnostic applications. AB - The synthesis and characterization of "2 + 1" complexes of the [M(CO)(3)](+) (M = Re, (99m)Tc) core with the beta-diketones acetylacetone (complexes 2, 8) and curcumin (complexes 5, 10 and 6, 11) as bidentate OO ligands, and imidazole or isocyanocyclohexane as monodentate ligands is reported. The complexes were synthesized by reacting the [NEt(4)](2)[Re(CO)(3)Br(3)] precursor with the beta diketone to generate the intermediate aqua complex fac-Re(CO)(3)(OO)(H(2)O) that was isolated and characterized, followed by replacement of the labile water by the monodentate ligand. All complexes were characterized by mass spectrometry, NMR and IR spectroscopies, and elemental analysis. In the case of complex 2, bearing imidazole as the monodentate ligand, X-ray analysis was possible. The chemistry was successfully transferred at (99m)Tc tracer level. The curcumin complexes 5 and 6, as well as their intermediate aqua complex 4, that bear potential for radiopharmaceutical applications due to the wide spectrum of pharmacological activity of curcumin, were successfully tested for selective staining of beta-amyloid plaques of Alzheimer's disease. The fact that the complexes maintain the affinity of the mother compound curcumin for beta-amyloid plaques prompts for further exploration of their chemistry and biological properties as radioimaging probes. PMID- 21250639 TI - Tuning the electrochemistry of Re2(6+) species with divergent bicyclic guanidinate ligands and by modification of axial pi interactions. AB - Four Re(2)(6+) paddlewheel compounds with equatorial bicyclic guanidinate ligands and two monodentate anions in axial positions show a large change in the metal metal distance that depends on the bite angle of the ligands and whether there are pi interactions between the dimetal unit and the axial ligands. These processes are accompanied by significant changes in the redox behavior. The two pairs of compounds that have been synthesized are Re(2)(tbn)(4)Cl(2), 1, and Re(2)(tbn)(4)(SO(3)CF(3))(2), 2, as well as Re(2)(tbo)(4)Cl(2), 3, and Re(2)(tbo)(4)(SO(3)CF(3))(2), 4, where tbn is the anion of a bicyclic guanidinate with six- and five-membered rings (1,5,7-triazabicyclo[4.3.0]non-6-ene) and tbo is an analogous species with two five-membered rings (the anion of 1,4,6 triazabicyclo[3.3.0]oct-4-ene). For both 1 and 2 as well as for 3 and 4, the metal-metal distances are shorter for the triflate species than for the chloride analogues because of the pi interactions of the Cl with the pi bonds of the triply bonded Re(2)(6+) cores compounded by a small but symmetry allowed interaction between the antisymmetric combination of the filled sigmap orbitals of the chlorine atom and the empty sigma* orbital of the metal atoms. In addition there is a significant increase in the Re-Re distance from that in the six/five tbn-membered ring to the five/five-membered tbo species. Electrochemical measurements show two redox processes for each set of compounds corresponding to the uncommon Re(2)(6+) -> Re(2)(7+) and Re(2)(7+) -> Re(2)(8+) processes, which are strongly affected by the bite angle of the guanidinate ligand as well as the ability of the axial ligands to interact with the pi orbitals of the dirhenium unit. For 1 and 3, the first redox couples are at 0.146 and 0.487 V, respectively, while for 2 and 4 these are at 0.430 and 0.698 V, respectively. PMID- 21250640 TI - Binuclear methylborole iron carbonyls: iron-iron multiple bonds and perpendicular structures. AB - Methylborole iron tricarbonyl, (eta(5)-C(4)H(4)BCH(3))Fe(CO)(3), is known experimentally and is a potential source of binuclear (C(4)H(4)BCH(3))(2)Fe(2)(CO)(n) (n = 5, 4, 3, 2, 1) derivatives through reactions such as photolysis. In this connection the lowest energy (C(4)H(4)BCH(3))(2)Fe(2)(CO)(5) structures are predicted theoretically to have a single bridging carbonyl group and Fe-Fe distances consistent with formal single bonds. The lowest energy (C(4)H(4)BCH(3))(2)Fe(2)(CO)(4) structures have two bridging carbonyl groups and Fe?Fe distances suggesting formal double bonds. Analogously, the lowest energy (C(4)H(4)BCH(3))(2)Fe(2)(CO)(3) structures have three bridging carbonyl groups and very short Fe=Fe distances suggesting formal triple bonds. The tetracarbonyl (C(4)H(4)BCH(3))(2)Fe(2)(CO)(4) is predicted to be thermodynamically unstable toward disproportionation into (C(4)H(4)BCH(3))(2)Fe(2)(CO)(5) + (C(4)H(4)BCH(3))(2)Fe(2)(CO)(3), whereas the tricarbonyl is thermodynamically viable toward analogous disproportionation. The lowest energy structures of the more highly unsaturated methylborole iron carbonyls (C(4)H(4)BCH(3))(2)Fe(2)(CO)(n) (n = 2, 1) have hydrogen atoms bridging an iron-carbon bond. In addition, the lowest energy (C(4)H(4)BCH(3))(2)Fe(2)(CO) structures are "slipped perpendicular" structures with bridging methylborole ligands, a terminal carbonyl group, and agostic CH(3)->Fe interactions involving the methyl hydrogens. Thus, in these highly unsaturated systems the methyl substituent in the methylborole ligand chosen in this work is not an "innocent bystander" but instead participates in the metal-ligand bonding. PMID- 21250641 TI - Preparation of controllable core-shell gold nanoparticles and its application in detection of silver ions. AB - We report a novel shell technique to prepare controllable core-shell nanoparticles. In this technique, the shell is formed when the core reacts with metal ions and Na(2)S(2)O(3) and the size of the core and thickness of the shell can be controlled. Transmission electron microscopy and X-ray diffraction reveal that the shell consists of insoluble complex salts comprising Au(2)S, AuAgS, and Ag(3)AuS(2). The resulting core-shell nanoparticles obtained at different reaction stages demonstrate that the formation of Au(2)S, AuAgS, and Ag(3)AuS(2) shell proceeds from the outside. The morphological evolution of the particles changes significantly with reaction time demonstrating that formation of the shell results from diffusion in the solid shell. The core-shell nanoparticles produced by this technique can be used as nanosensors to detect Ag(+) in aqueous media with high selectivity and sensitivity. The excellent selectivity for Ag(+) is demonstrated by comparing the response to other metal ions. In addition, our evaluation indicates that gold nanorods offer higher sensitivity than gold nanospheres. PMID- 21250643 TI - Synthesis of beta-Mo(2)C thin films. AB - Thin films of stoichiometric beta-Mo(2)C were fabricated using a two-step synthesis process. Dense molybdenum oxide films were first deposited by plasma enhanced chemical vapor deposition using mixtures of MoF(6), H(2), and O(2). The dependence of operating parameters with respect to deposition rate and quality is reviewed. Oxide films 100-500 nm in thickness were then converted into molybdenum carbide using temperature-programmed reaction using mixtures of H(2) and CH(4). X ray diffraction confirmed that molybdenum oxide is completely transformed into the beta-Mo(2)C phase when heated to 700 degrees C in mixtures of 20% CH(4) in H(2). The films remained well-adhered to the underlying silicon substrate after carburization. X-ray photoelectron spectroscopy detected no impurities in the films, and Mo was found to exist in a single oxidation state. Microscopy revealed that the as-deposited oxide films were featureless, whereas the carbide films display a complex nanostructure. PMID- 21250642 TI - Nitric oxide-releasing electrospun polymer microfibers. AB - The preparation of electrospun polymer microfibers with nitric oxide (NO)-release capabilities is described. Polymer solutions containing disodium 1-[2 (carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO), a low-molecular weight NO donor, were electrospun to generate fibers ranging from 100-3000 nm in diameter capable of releasing NO upon immersion in aqueous solutions under physiological conditions (pH 7.4, 37 degrees C), with kinetics depending on polymer composition and fiber diameter. The NO release half-life for PROLI/NO doped electrospun fibers was 2-200 times longer than that of PROLI/NO alone. The influence of polymer concentration, applied voltage, capillary diameter, solution conductivity, flow rate, and additives on fiber properties are reported and discussed with respect to potential applications. PMID- 21250644 TI - Nanosized cation-deficient Fe-Ti spinel: a novel magnetic sorbent for elemental mercury capture from flue gas. AB - Nonstoichiometric Fe-Ti spinel (Fe(3-x)Ti(x))(1-delta)O(4) has a large amount of cation vacancies on the surface, which may provide active sites for pollutant adsorption. Meanwhile, its magnetic property makes it separable from the complex multiphase system for recycling, and for safe disposal of the adsorbed toxin. Therefore, (Fe(3-x)Ti(x))(1-delta)O(4) may be a promising sorbent in environmental applications. Herein, (Fe(3-x)Ti(x))(1-delta)O(4) is used as a magnetically separable sorbent for elemental mercury capture from the flue gas of coal-fired power plants. (Fe(2)Ti)(0.8)O(4) shows a moderate capacity (about 1.0 mg g(-1) at 250 degrees C) for elemental mercury capture in the presence of 1000 ppmv of SO(2). Meanwhile, the sorbent can be readily separated from the fly ash using magnetic separation, leaving the fly ash essentially free of sorbent and adsorbed mercury. PMID- 21250645 TI - Reflections on chemical biology. PMID- 21250649 TI - Fermenting next generation glycosylated therapeutics. AB - Mutants of glycosyltransferases and related sugar nucleotide biosynthetic enzymes have been essential for in vitro glycorandomization to create libraries of novel glycosylated natural products and derivatives. These diverse glycorandomized compounds can now be produced in vivo economically by fermenting engineered Escherichia coli cells that express enzyme mutants. PMID- 21250652 TI - Graphene growth by a metal-catalyzed solid-state transformation of amorphous carbon. AB - Single and few-layer graphene is grown by a solid-state transformation of amorphous carbon on a catalytically active metal. The process is carried out and monitored in situ in an electron microscope. It is observed that an amorphous carbon film is taken up by Fe, Co, or Ni crystals at temperatures above 600 degrees C. The nucleation and growth of graphene layers on the metal surfaces happen after the amorphous carbon film has been dissolved. It is shown that the transformation of the energetically less favorable amorphous carbon to the more favorable phase of graphene occurs by diffusion of carbon atoms through the catalytically active metal. PMID- 21250650 TI - Fluorescent-magnetic-biotargeting multifunctional nanobioprobes for detecting and isolating multiple types of tumor cells. AB - Fluorescent-magnetic-biotargeting multifunctional nanobioprobes (FMBMNs) have attracted great attention in recent years due to their increasing, important applications in biomedical research, clinical diagnosis, and biomedicine. We have previously developed such nanobioprobes for the detection and isolation of a single kind of tumor cells. Detection and isolation of multiple tumor markers or tumor cells from complex samples sensitively and with high efficiency is critical for the early diagnosis of tumors, especially malignant tumors or cancers, which will improve clinical diagnosis outcomes and help to select effective treatment approaches. Here, we expanded the application of the monoclonal antibody (mAb) coupled FMBMNs for multiplexed assays. Multiple types of cancer cells, such as leukemia cells and prostate cancer cells, were detected and collected from mixed samples within 25 min by using a magnet and an ordinary fluorescence microscope. The capture efficiencies of mAb-coupled FMBMNs for the above-mentioned two types of cells were 96% and 97%, respectively. Furthermore, by using the mAb-coupled FMBMNs, specific and sensitive detection and rapid separation of a small number of spiked leukemia cells and prostate cancer cells in a large population of cultured normal cells (about 0.01% were tumor cells) were achieved simply and inexpensively without any sample pretreatment before cell analysis. Therefore, mAb-coupled multicolor FMBMNs may be used for very sensitive detection and rapid isolation of multiple cancer cells in biomedical research and medical diagnostics. PMID- 21250651 TI - Decreased dissolution of ZnO by iron doping yields nanoparticles with reduced toxicity in the rodent lung and zebrafish embryos. AB - We have recently shown that the dissolution of ZnO nanoparticles and Zn(2+) shedding leads to a series of sublethal and lethal toxicological responses at the cellular level that can be alleviated by iron doping. Iron doping changes the particle matrix and slows the rate of particle dissolution. To determine whether iron doping of ZnO also leads to lesser toxic effects in vivo, toxicity studies were performed in rodent and zebrafish models. First, we synthesized a fresh batch of ZnO nanoparticles doped with 1-10 wt % of Fe. These particles were extensively characterized to confirm their doping status, reduced rate of dissolution in an exposure medium, and reduced toxicity in a cellular screen. Subsequent studies compared the effects of undoped to doped particles in the rat lung, mouse lung, and the zebrafish embryo. The zebrafish studies looked at embryo hatching and mortality rates as well as the generation of morphological defects, while the endpoints in the rodent lung included an assessment of inflammatory cell infiltrates, LDH release, and cytokine levels in the bronchoalveolar lavage fluid. Iron doping, similar to the effect of the metal chelator, DTPA, interfered in the inhibitory effects of Zn(2+) on zebrafish hatching. In the oropharyngeal aspiration model in the mouse, iron doping was associated with decreased polymorphonuclear cell counts and IL-6 mRNA production. Doped particles also elicited decreased heme oxygenase 1 expression in the murine lung. In the intratracheal instillation studies in the rat, Fe doping was associated with decreased polymorphonuclear cell counts, LDH, and albumin levels. All considered, the above data show that Fe doping is a possible safe design strategy for preventing ZnO toxicity in animals and the environment. PMID- 21250653 TI - Smart drug delivery through DNA/magnetic nanoparticle gates. AB - Mesoporous silica nanoparticles can be modified to perform on-demand stimuli responsive dosing of therapeutic molecules. The silica network was loaded with iron oxide superparamagnetic nanocrystals, providing the potential to perform targeting and magnetic resonance imaging. Single-stranded DNA was immobilized onto the material surface. The complementary DNA sequence was then attached to magnetic nanoparticles. The present work demonstrates that DNA/magnetic nanoparticle conjugates are able to cap the pores of the magnetic silica particles upon hybridization of both DNA strands. Progressive double-stranded DNA melting as a result of temperature increase gave rise to uncapping and the subsequent release of a mesopore-filled model drug, fluorescein. The reversibility of DNA linkage results in an "on-off" release mechanism. Moreover, the magnetic component of the whole system allows reaching hyperthermic temperatures (42-47 degrees C) under an alternating magnetic field. This feature leaves open the possibility of a remotely triggered drug delivery. Furthermore, due to its capacity to increase the temperature of the surrounding media, this multifunctional device could play an important role in the development of advanced drug delivery systems for thermochemotherapy against cancer. PMID- 21250654 TI - Fluorescence quantum yields of a series of red and near-infrared dyes emitting at 600-1000 nm. AB - The determination of the fluorescence quantum yields (QY, Phi(f)) of a series of fluorescent dyes that span the absorption/excitation and emission ranges of 520 900 and 600-1000 nm is reported. The dyes encompass commercially available rhodamine 101 (Rh-101, Phi(f) = 0.913), cresyl violet (0.578), oxazine 170 (0.579), oxazine 1 (0.141), cryptocyanine (0.012), HITCI (0.283), IR-125 (0.132), IR-140 (0.167), and four noncommercial cyanine dyes with specific spectroscopic features, all of them in dilute ethanol solution. The QYs have been measured relative to the National Institute of Standards and Technology's standard reference material (SRM) 936a (quinine sulfate, QS) on a traceably characterized fluorometer, employing a chain of transfer standard dyes that include coumarin 102 (Phi(f) = 0.764), coumarin 153 (0.544), and DCM (0.435) as links between QS and Rh-101. The QY of Rh-101 has also been verified in direct measurements against QS using two approaches that rely only on instrument correction. In addition, the effects of temperature and the presence of oxygen on the fluorescence quantum yield of Rh-101 have been assessed. PMID- 21250655 TI - Synthesis of 1,2,3-triazolo-linked octyl (1->6)-alpha-D-oligomannosides and their evaluation in mycobacterial mannosyltransferase assay. AB - The synthesis of conjugates consisting of two or three mannose units interconnected by a 1,2,3-triazole linker installed by the "click" reaction is reported. These conjugates were evaluated in mycobacterial mannosyltransferase (ManT) assay. Detailed analysis of the reaction products showed that these compounds with triazole linker between sugar moieties were tolerated by the enzyme, which elongated them by one or two sugar units with alpha-(1->6) linkage. The effectiveness of this transfer was reduced in comparison to that observed for the acceptor analogues containing a glycosidic linkage, but still, this is the first report on such unnatural compounds serving as substrates for mycobacterial ManT. The ability of the studied compounds to function as acceptors for the ManT suggests that the relative distance and spatial orientation of acceptor octyl hydrophobic aglycone (optimal length for the ManT) and free primary C-6 hydroxy group of the nonreducing terminal mannose unit (to which glycosyl residue is transferred by the mycobacterial ManT) are important for ManT activity, but at the same time, their variations are tolerated by the enzyme in a relatively wide range. PMID- 21250656 TI - Thermoresponsive heparin bioconjugate as novel aqueous antithrombogenic coating material. AB - A novel thermoresponsive aqueous antithrombogenic coating material comprising a heparin bioconjugate with a six-branched, star-shaped poly(2 (dimethylaminoethyl)methacrylate) (6B-PDMAEMA), which has both thermoresponsive and cationic characters, was developed to reduce the thrombogenic potential of blood-contacting materials such as synthetic polymers or tissue-engineered tissues in cardiovascular devices. 6B-PDMAEMA with M(n) of ca. 24 kDa was designed as a prototype compound by initiator-transfer agent-terminator (iniferter)-based living radical photopolymerization from hexakis(N,N diethyldithiocarbamylmethyl)benzene. Bioconjugation of heparin with 6B-PDMAEMA occurred as soon as both aqueous solutions were simply mixed to form particles. The particle size at 25 degrees C was less than several hundred nanometers in diameter under a heparin/6B-PDMAEMA mixing weight ratio of over 2.5. The particles were very stable because of the prevention of hydrolysis of 6B-PDMAEMA in its bioconjugated form. Because the lower critical solution temperature of the bioconjugate ranges from approximately 20 to 36 degrees C for the formation of microparticles, the coating could be done in an aqueous solution at low temperatures. The excellent adsorptivity and high durability of the coating above 37 degrees C was demonstrated on silicone and polyethylene films by surface chemical compositional analysis. Blood coagulation was significantly reduced on the bioconjugate-coated surfaces. Therefore, the thermoresponsive bioconjugate developed here appears to satisfy the initial requirements for a biocompatible aqueous coating material. PMID- 21250657 TI - Nitric oxide dioxygenation reaction in DevS and the initial response to nitric oxide in Mycobacterium tuberculosis. AB - DevS and DosT from Mycobacterium tuberculosis (MTB) are paralogous heme-based sensor kinases that respond to hypoxia and to low concentrations of nitric oxide (NO). Both proteins work with the response regulator DevR as a two-component regulatory system to induce the dormancy regulon in MTB. While DevS and DosT are inactive when dioxygen is bound to the heme Fe(II) at their sensor domain, autokinase activity is observed in their heme Fe(II)-NO counterparts. To date, the conversion between active and inactive states and the reactivity of the heme oxy complex toward NO have not been investigated. Here, we use stopped-flow UV vis spectroscopy and rapid freeze quench resonance Raman spectroscopy to probe these reactions in DevS. Our data reveal that the heme-O(2) complex of DevS reacts efficiently with NO to produce nitrate and the oxidized Fe(III) heme through an NO dioxygenation reaction that parallels the catalytic reactions of bacterial flavohemoglobin and truncated hemoglobins. Autophosphorylation activity assays show that the Fe(III) heme state of DevS remains inactive but exhibits a high affinity for NO and forms an Fe(III)-NO complex that is readily reduced by ascorbate, a mild reducing agent. On the basis of these results, we conclude that upon exposure to low NO concentrations, the inactive oxy-heme complex of DevS is rapidly converted to the Fe(II)-NO complex in the reducing environment of living cells and triggers the initiation of dormancy. PMID- 21250658 TI - Phosphoenolpyruvate: sugar phosphotransferase system from the hyperthermophilic Thermoanaerobacter tengcongensis. AB - Thermoanaerobacter tengcongensis is a thermophilic eubacterium that has a phosphoenolpyruvate (PEP) sugar phosphotransferase system (PTS) of 22 proteins. The general PTS proteins, enzyme I and HPr, and the transporters for N acetylglucosamine (EIICB(GlcNAc)) and fructose (EIIBC(Fru)) have thermal unfolding transitions at ~90 degrees C and a temperature optimum for in vitro sugar phosphotransferase activity of 65 degrees C. The phosphocysteine of a EIICB(GlcNAc) mutant is unusually stable at room temperature with a t(1/2) of 60 h. The PEP binding C-terminal domain of enzyme I (EIC) forms a metastable covalent adduct with PEP at 65 degrees C. Crystallization of this adduct afforded the 1.68 A resolution structure of EIC with a molecule of pyruvate in the active site. We also report the 1.83 A crystal structure of the EIC-PEP complex. The comparison of the two structures with the apo form and with full length EI shows differences between the active site side chain conformations of the PEP and pyruvate states but not between the pyruvate and apo states. In the presence of PEP, Arg465 forms a salt bridge with the phosphate moiety while Glu504 forms salt bridges with Arg186 and Arg195 of the N-terminal domain of enzyme I (EIN), which stabilizes a conformation appropriate for the in-line transfer of the phosphoryl moiety from PEP to His191. After transfer, Arg465 swings 4.8 A away to form an alternative salt bridge with the carboxylate of Glu504. Glu504 loses the grip of Arg186 and Arg195, and the EIN domain can swing away to hand on the phosphoryl group to the phosphoryl carrier protein HPr. PMID- 21250659 TI - Novel mechanism of the vascular protector prostacyclin: regulating microRNA expression. AB - Prostacyclin (PGI(2)) is a key vascular protector, metabolized from endogenous arachidonic acid (AA). Its actions are mediated through the PGI(2) receptor (IP) and nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARgamma). Here, we found that PGI(2) is involved in regulating cellular microRNA (miRNA) expression through its receptors in a mouse adipose tissue derived primary culture cell line expressing a novel hybrid enzyme gene (COX-1 10aa-PGIS), cyclooxygenase-1 (COX-1) and PGI(2) synthase (PGIS) linked with a 10 amino acid linker. The triple catalytic functions of the hybrid enzyme in these cells successfully redirected the endogenous AA metabolism toward a stable and dominant production of PGI(2). The miRNA microarray analysis of the cell line with upregulated PGI(2) revealed a significant upregulation (711, 148b, and 744) and downregulation of miRNAs of interest, which were reversed by antagonists of the IP and PPARgamma receptors. Furthermore, we also found that the insulin mediated lipid deposition was inhibited in the PGI(2)-upregulated adipocytes. The study also initiated a discussion that suggested that the endogenous PGI(2) inhibition of lipid deposition in adipocytes could involve miRNA-mediated inhibition of expression of the targeted genes. This indicated that PGI(2)-miRNA regulation could exist in broad pathophysiological processes involving PGI(2) (i.e., apoptosis, vascular inflammation, cancer, embryo implantation, and obesity). PMID- 21250660 TI - Escherichia coli class Ib ribonucleotide reductase contains a dimanganese(III) tyrosyl radical cofactor in vivo. AB - Escherichia coli class Ib ribonucleotide reductase (RNR) converts nucleoside 5' diphosphates to deoxynucleoside 5'-diphosphates in iron-limited and oxidative stress conditions. We have recently demonstrated in vitro that this RNR is active with both diferric-tyrosyl radical (Fe(III)(2)-Y(*)) and dimanganese(III)-Y(*) (Mn(III)(2)-Y(*)) cofactors in the beta2 subunit, NrdF [Cotruvo, J. A., Jr., and Stubbe, J. (2010) Biochemistry 49, 1297-1309]. Here we demonstrate, by purification of this protein from its endogenous levels in an E. coli strain deficient in its five known iron uptake pathways and grown under iron-limited conditions, that the Mn(III)(2)-Y(*) cofactor is assembled in vivo. This is the first definitive determination of the active cofactor of a class Ib RNR purified from its native organism without overexpression. From 88 g of cell paste, 150 MUg of NrdF was isolated with ~95% purity, with 0.2 Y(*)/beta2, 0.9 Mn/beta2, and a specific activity of 720 nmol min(-1) mg(-1). Under these conditions, the class Ib RNR is the primary active RNR in the cell. Our results strongly suggest that E. coli NrdF is an obligate manganese protein in vivo and that the Mn(III)(2) Y(*) cofactor assembly pathway we have identified in vitro involving the flavodoxin-like protein NrdI, present inside the cell at catalytic levels, is operative in vivo. PMID- 21250662 TI - Alteration of hydrogen bonding in the vicinity of histidine 48 disrupts millisecond motions in RNase A. AB - The motion of amino acid residues on the millisecond (ms) time scale is involved in the tight regulation of catalytic function in numerous enzyme systems. Using a combination of mutational, enzymological, and relaxation-compensated (15)N Carr Purcell-Meiboom-Gill (CPMG) methods, we have previously established the conformational significance of the distant His48 residue and the neighboring loop 1 in RNase A function. These studies suggested that RNase A relies on an intricate network of hydrogen bonding interactions involved in propagating functionally relevant, long-range ms motions to the catalytic site of the enzyme. To further investigate the dynamic importance of this H-bonding network, this study focuses on the individual replacement of Thr17 and Thr82 with alanine, effectively altering the key H-bonding interactions that connect loop 1 and His48 to the rest of the protein. (15)N CPMG dispersion studies, nuclear magnetic resonance (NMR) chemical shift analysis, and NMR line shape analysis of point mutants T17A and T82A demonstrate that the evolutionarily conserved single H-bond linking His48 to Thr82 is essential for propagating ms motions from His48 to the active site of RNase A on the time scale of catalytic turnover, whereas the T17A mutation increases the off rate and conformational exchange motions in loop 1. Accumulating evidence from our mutational studies indicates that residues experiencing conformational exchange in RNase A can be grouped into two separate clusters displaying distinct dynamical features, which appear to be independently affected by mutation. Overall, this study illuminates how tightly controlled and finely tuned ms motions are in RNase A, suggesting that designed modulation of protein motions may be possible. PMID- 21250661 TI - Genome mining in Streptomyces. Elucidation of the role of Baeyer-Villiger monooxygenases and non-heme iron-dependent dehydrogenase/oxygenases in the final steps of the biosynthesis of pentalenolactone and neopentalenolactone. AB - The pentalenolactone biosynthetic gene clusters have been cloned and sequenced from two known producers of the sesquiterpenoid antibiotic pentalenolactone, Streptomyces exfoliatus UC5319 and Streptomyces arenae TU469. The recombinant enzymes PenE and PntE, from S. exfoliatus and S. arenae, respectively, catalyze the flavin-dependent Baeyer-Villiger oxidation of 1-deoxy-11-oxopentalenic acid (7) to pentalenolactone D (8). Recombinant PenD, PntD, and PtlD, the latter from Streptomyces avermitilis, each catalyze the Fe(2+)-alpha-ketoglutarate-dependent oxidation of pentalenolactone D (8) to pentalenolactone E (15) and pentalenolactone F (16). Incubation of PenD, PntD, or PtlD with the isomeric neopentalenolactone D (9) gave PL308 (12) and a compound tentatively identified as neopentalenolactone E (14). These results are corroborated by analysis of the DeltapenD and DeltapntD mutants of S. exfoliatus and S. arenae, respectively, both of which accumulate pentalenolactone D but are blocked in production of pentalenolactone as well as the precursors pentalenolactones E and F. Finally, complementation of the previously described S. avermitilis DeltaptlE DeltaptlD deletion mutant with either penE or pntE gave pentalenolactone D (8), while complemention of the DeltaptlE DeltaptlD double mutant with pntE plus pntD or penE plus pntD gave pentalenolactone F (16). PMID- 21250663 TI - Enhanced base-pair opening in the adenine tract of a RNA double helix. AB - Proton exchange and nuclear magnetic resonance spectroscopy are being used to characterize the kinetics and energetics of base-pair opening in two nucleic acid double helices. One is the RNA duplex 5'-r(GCGAUAAAAAGGCC)-3'/5' r(GGCCUUUUUAUCGC)-3', which contains a central tract of five AU base pairs. The other is the homologous DNA duplex with a central tract of five AT base pairs. The rates and the equilibrium constants of the opening reaction of each base pair are measured from the dependence of the exchange rates of imino protons on ammonia concentration, at 10 degrees C. The results reveal that the tract of AU base pairs in the RNA duplex differs from the homologous tract of AT base pairs in DNA in several ways. The rates of opening of AU base pairs in RNA are high and increase progressively along the tract, reaching their largest values at the 3' end of the tract. In contrast, the opening rates of AT base pairs in DNA are much lower than those of AU base pairs. Within the tract, the largest opening rate is observed for the AT base pair at the 5'-end of the tract. These differences in opening kinetics are paralleled by differences in the stabilities of individual base pairs. All AU base pairs in the RNA are less stable than the AT base pairs in the DNA. The presence of the tract enhances these differences by increasing the stability of AT base pairs in DNA while decreasing the stability of AU base pairs in RNA. Due to these divergent trends, along the tracts, the AU base pairs become progressively less stable than AT base pairs. These findings demonstrate that tracts of AU base pairs in RNA have specific dynamic and energetic signatures that distinguish them from similar tracts of AT base pairs in DNA. PMID- 21250664 TI - Binding properties of the calcium-activated F2 isoform of Lethocerus troponin C. AB - While in most muscles contraction is triggered by calcium effluxes, insect flight muscles are also activated by mechanical stretch. We are interested in understanding the role that the troponin C protein, usually the calcium sensor, plays in stretch activation. In the flight muscles of Lethocerus, a giant water bug often used as a model system, there are two isoforms of TnC, F1 and F2, present in an approximately 10:1 ratio. F1 TnC is responsible for activating the muscle following a stretch, whereas F2 TnC produces a sustained contraction, the magnitude of which depends on the concentration of Ca(2+) in the fiber. We have previously shown that F1 TnC binds only one Ca(2+) ion in its C-terminal domain and that interaction with troponin H, the insect ortholog of troponin I, is insensitive to Ca(2+). Here, we have studied the effect of Ca(2+) and Mg(2+) on the affinities of the interaction of F2 TnC with troponin H peptides. We show that the presence of two Ca(2+) ions, one in each of the globular domains, increases the affinity for TnH by at least 1 order of magnitude. The N lobe has a lower affinity for Ca(2+), but it is also sensitive to Mg(2+). The C lobe is insensitive to Mg(2+) as previously demonstrated by mutations of the individual EF-hands. The interaction with TnH seems also to have significant structural differences from that observed for the F1 TnC isoform. We discuss how our findings could account for stretch activation. PMID- 21250665 TI - Binding of pentagalloyl glucose to two globular proteins occurs via multiple surface sites. AB - The interaction between pentagalloyl glucose (PGG) and two globular proteins, bovine serum albumin (BSA) and ribulose-1,5-bisphosphate carboxylase oxygenase (rubisco), was investigated by isothermal titration calorimetry (ITC). ITC data fit to a binding model consisting of two sets of multiple binding sites, which reveal similarities in the mode of binding of PGG to BSA and rubisco. In both cases, the interaction is characterized by a high number of binding sites, which suggests that binding occurs by a surface adsorption mechanism that leads to coating of the protein surface, which promotes aggregation and precipitation of the PGG-protein complex. This model was confirmed by turbidimetry analysis of the PGG-BSA interaction. Analysis of tryptophan fluorescence quenching during the interaction of PGG with BSA suggests that binding of PGG leads to some conformational changes that are energetically closer to the unfolded state of the BSA structure, because small red shifts in the resulting emission spectra were observed. PMID- 21250666 TI - Mechanisms of controlled release from silk fibroin films. AB - The controlled release of fluorescein-iso-thio-cyanate (FITC)-labeled dextrans from methanol-treated and untreated silk fibroin films was modeled to characterize the release kinetics and mechanisms. Silk films were prepared with FITC-dextrans of various molecular weights (4, 10, 20, 40 kDa). Methanol treatment was used to promote crystallinity. The release data were assessed with two different models, an empirical exponential equation commonly fit to release data and a mechanism-based semiempirical model derived from Fickian diffusion through a porous film. The FITC-dextran release kinetics were evaluated as a function of molecular weight and compared between the untreated- and methanol treated films. For the empirical model, the estimated values of the model parameters decreased with the molecular weight of the analyte and showed no significant difference between untreated- and methanol-treated films. For the diffusion-based model, the estimated diffusion coefficient was smaller for the methanol-treated films than for the untreated films. Also, the diffusion coefficient was observed to decrease linearly with increasing molecular weight of the analyte. The percent of FITC-dextran loading entrapped and not released was less for the methanol-treated films than for untreated films and linearly increased with molecular weight. A linear regression was fit to the relationship between molecular weight and the percent of entrapped FITC-dextran particles. Using these defined linear relationships, we present an updated version of the diffusion model for simulating release of FITC-dextran of varied molecular weights from methanol-treated and untreated silk films. PMID- 21250667 TI - Effects of CMC addition on bacterial cellulose production in a biofilm reactor and its paper sheets analysis. AB - Bacterial cellulose (BC) can be grown into any desired shape such as pellicles, pellets, and spherelike balls, depending on the cultivation method, additives, and cell population. In this study, Acetobacter xylinum (ATCC 700178) was grown in the production medium with different concentrations of carboxylmethylcellulose (CMC) and were evaluated for BC production by using a PCS biofilm reactor. The results demonstrated that BC production was enhanced to its maximum (~13 g/L) when 1.5% of CMC was applied, which was 1.7-fold higher than the result obtained from control culture. The major type of the produced BC was also switched from BC pellicle to small pellets. The ratio of BC pellets in suspension increased from 0 to 93%. Fourier transform infrared (FTIR) spectroscopy demonstrated that CMC was incorporated into BC during fermentation and resulted in the decreased crystallinity and crystal size. The X-ray diffraction (XRD) patterns indicated that CMC-BC exhibited both lower crystallinity (80%) and crystal size (4.2 nm) when compared with control samples (86% and 5.3 nm). The harvested BC was subjected to paper formation and its mechanical strength was determined. Dynamic mechanical analysis (DMA) results demonstrated that BC paper sheets exhibited higher tensile strength and Young's modulus when compared with regular paper. PMID- 21250668 TI - Cross-kingdom actions of phytohormones: a functional scaffold exploration. PMID- 21250669 TI - Phosphine-phosphinite and phosphine-phosphite ligands: preparation and applications in asymmetric catalysis. PMID- 21250670 TI - FI catalysts for olefin polymerization--a comprehensive treatment. PMID- 21250673 TI - Uranium isotope fractionation during adsorption to Mn-oxyhydroxides. AB - Previous work has shown uranium (U) isotope fractionation between natural ferromanganese crusts and seawater. Understanding the mechanism that causes (238)U/(235)U fractionation during adsorption to ferromanganese oxides is a critical step in the utilization of (238)U/(235)U as a tracer of U adsorption reactions in groundwater as well as a potential marine paleoredox proxy. We conducted U adsorption experiments using synthetic K-birnessite and U-bearing solutions. These experiments revealed a fractionation matching that observed between seawater and natural ferromanganese sediments: adsorbed U is isotopically lighter by ~0.20/00 (delta(238/235)U) than dissolved U. As the redox state of U does not change during adsorption, a difference in the coordination environment between dissolved and adsorbed U is likely responsible for this effect. To test this hypothesis, we analyzed U adsorbed to K-birnessite in our experimental study using extended X-ray absorption fine structure (EXAFS) spectroscopy, to obtain information about U coordination in the adsorbed complex. Comparison of our EXAFS spectra with those for aqueous U species reveals subtle, but important, differences in the U-O coordination shell between dissolved and adsorbed U. We hypothesize that these differences are responsible for the fractionation observed in our experiments as well as for some U isotope variations in nature. PMID- 21250675 TI - Deposition and leaching of sulfur, nitrogen and calcium in four forested catchments in China: implications for acidification. AB - Here we present the first detailed study on fluxes of sulfur (S), nitrogen (N), and major cations in Chinese subtropical forest catchments. Data are from four study sites, differing in inputs of atmospheric pollutants and sensitivity to acidification. Results show important differences from most sites in North America and Europe. Dry deposition of S, N, and calcium (Ca) is considerably larger than wet deposition in most cases causing deposition fluxes ranging from moderate to very high, both for acidifying compounds (S deposition 1.5-10.5 kiloequivalents per hectare and year (keq ha(-1) yr(-1)); N deposition 0.4 to 2.5 keq ha(-1) yr(-1)) and for alkaline compounds (Ca deposition 0.8 to 5.7 keq ha( 1) yr(-1)). More than half of the input of acidity is neutralized by alkalinity associated with Ca deposition. Furthermore, the retention of incoming S and N is small in the soil root zone, but considerable in the deeper soils or riparian zone. Drainage water from the root zone of the soils at the two sites with the highest deposition show pronounced acidification. For the two sites with moderate deposition inputs, the root zones are retaining some of the incoming S and buffer some of the incoming acidity. The subsoils and the riparian zonesare strong sinks for N, S, and Ca. This is associated with substantial acid neutralization at all sites. These features are of major importance for the understanding of the long term effects of acidification in China. PMID- 21250671 TI - Thiol-activated DNA damage by alpha-bromo-2-cyclopentenone. AB - Some biologically active chemicals are relatively stable in the extracellular environment but, upon entering the cell, undergo biotransformation into reactive intermediates that covalently modify DNA. The diverse chemical reactions involved in the bioactivation of DNA-damaging agents are both fundamentally interesting and of practical importance in medicinal chemistry and toxicology. The work described here examines the bioactivation of alpha-haloacrolyl-containing molecules. The alpha-haloacrolyl moiety is found in a variety of cytotoxic natural products including clionastatin B, bromovulone III, discorahabdins A, B, and C, and trichodenone C, in mutagens such as 2-bromoacrolein and 3-chloro-4 (dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), and in the anticancer drug candidates brostallicin and PNU-151807. Using alpha-bromo-2-cyclopentenone (1) as a model compound, the activation of alpha-haloacrolyl-containing molecules by biological thiols was explored. The results indicate that both low molecular weight and peptide thiols readily undergo conjugate addition to 1. The resulting products are consistent with a mechanism in which initial addition of thiols to 1 is followed by intramolecular displacement of bromide to yield a DNA-alkylating episulfonium ion intermediate. The reaction of thiol-activated 1 with DNA produces labile lesions at deoxyguanosine residues. The sequence specificity and salt dependence of this process is consistent with involvement of an episulfonium ion intermediate. The alkylated guanine residue resulting from the thiol triggered reaction of 1 with duplex DNA was characterized using mass spectrometry. The results provide new insight regarding the mechanisms by which thiols can bioactivate small molecules and offer a more complete understanding of the molecular mechanisms underlying the biological activity of cytotoxic, mutagenic, and medicinal compounds containing the alpha-haloacrolyl group. PMID- 21250674 TI - Self-organizing map analysis of toxicity-related cell signaling pathways for metal and metal oxide nanoparticles. AB - The response of a murine macrophage cell line exposed to a library of seven metal and metal oxide nanoparticles was evaluated via High Throughput Screening (HTS) assay employing luciferase-reporters for ten independent toxicity-related signaling pathways. Similarities of toxicity response among the nanoparticles were identified via Self-Organizing Map (SOM) analysis. This analysis, applied to the HTS data, quantified the significance of the signaling pathway responses (SPRs) of the cell population exposed to nanomaterials relative to a population of untreated cells, using the Strictly Standardized Mean Difference (SSMD). Given the high dimensionality of the data and relatively small data set, the validity of the SOM clusters was established via a consensus clustering technique. Analysis of the SPR signatures revealed two cluster groups corresponding to (i) sublethal pro-inflammatory responses to Al2O3, Au, Ag, SiO2 nanoparticles possibly related to ROS generation, and (ii) lethal genotoxic responses due to exposure to ZnO and Pt nanoparticles at a concentration range of 25-100 MUg/mL at 12 h exposure. In addition to identifying and visualizing clusters and quantifying similarity measures, the SOM approach can aid in developing predictive quantitative-structure relations; however, this would require significantly larger data sets generated from combinatorial libraries of engineered nanoparticles. PMID- 21250676 TI - Mercury isotopes link mercury in San Francisco Bay forage fish to surface sediments. AB - Identification of sources of biologically accessible Hg is necessary to fully evaluate Hg exposure in aquatic ecosystems. This study assesses the relationship between Hg in forage fish and Hg in surface sediments throughout San Francisco Bay (SF Bay) and evaluates processes influencing the incorporation of Hg into the aquatic food web. We measured the Hg stable isotope compositions of two nearshore fish species and compared them with previously reported analyses of colocated intertidal surface sediments. Fish delta(202)Hg values (mass-dependent fractionation) demonstrated a distinct spatial gradient within SF Bay that ranged from 0.600/00 in the south to -0.250/00 in the north. Fish delta(202)Hg values were consistently higher than sediment delta(202)Hg values by 0.730/00 (+/ 0.160/00, 1SD). Fish and sediment delta(202)Hg values in SF Bay proper were well correlated (r(2) = 0.83), suggesting that sediment is a primary source of Hg to the nearshore aquatic food web. Fish Delta(199)Hg values (mass-independent fractionation) ranged from 0.460/00 to 1.550/00, did not correlate with sediment values, and yielded a Delta(199)Hg/Delta(201)Hg ratio of 1.26 (+/-0.01, 1SD; r(2) = 0.99). This mass-independent fractionation is consistent with photodegradation of MeHg to varying degrees at each site prior to incorporation into the food web. PMID- 21250677 TI - Multiple pathways for benzyl alcohol oxidation by Ru(V)?O3+ and Ru(IV)?O2+. AB - Significant rate enhancements are found for benzyl alcohol oxidation by the Ru(V)?O(3+) form of the water oxidation catalyst [Ru(Mebimpy)(bpy)(OH(2))](2+) [Mebimpy = 2,6-bis(1-methylbenzimidazol-2-yl)pyridine; bpy = 2,2'-bipyridine] compared to Ru(IV)?O(2+) and for the Ru(IV)?O(2+) form with added bases due to a new pathway, concerted hydride proton transfer (HPT). PMID- 21250678 TI - Alkylamine-ligated H93G myoglobin cavity mutant: a model system for endogenous lysine and terminal amine ligation in heme proteins such as nitrite reductase and cytochrome f. AB - His93Gly sperm whale myoglobin (H93G Mb) has the proximal histidine ligand removed to create a cavity for exogenous ligand binding, providing a remarkably versatile template for the preparation of model heme complexes. The investigation of model heme adducts is an important way to probe the relationship between coordination structure and catalytic function in heme enzymes. In this study, we have successfully generated and spectroscopically characterized the H93G Mb cavity mutant ligated with less common alkylamine ligands (models for Lys or the amine group of N-terminal amino acids) in numerous heme iron states. All complexes have been characterized by electronic absorption and magnetic circular dichroism spectroscopy in comparison with data for parallel imidazole-ligated H93G heme iron moieties. This is the first systematic spectral study of models for alkylamine- or terminal amine-ligated heme centers in proteins. High-spin mono- and low-spin bis-amine-ligated ferrous and ferric H93G Mb adducts have been prepared together with mixed-ligand ferric heme complexes with alkylamine trans to nitrite or imidazole as heme coordination models for cytochrome c nitrite reductase or cytochrome f, respectively. Six-coordinate ferrous H93G Mb derivatives with CO, NO, and O(2) trans to the alkylamine have also been successfully formed, the latter for the first time. Finally, a novel high-valent ferryl species has been generated. The data in this study represent the first thorough investigation of the spectroscopic properties of alkylamine-ligated heme iron systems as models for naturally occurring heme proteins ligated by Lys or terminal amines. PMID- 21250679 TI - Diorganotin-based coordination polymers derived from sulfonate/phosphonate/phosphonocarboxylate ligands. AB - The reactions of diorganotin precursors [R(2)Sn(OR(1))(OSO(2)R(1))](n) [R = R(1) = Me (1); R = Me, R(1) = Et (2)] with an equimolar amount of t-butylphosphonic acid (RT, 8-10 h) in methanol result in the formation of identical products, of composition [(Me(2)Sn)(3)(O(3)PBu(t))(2)(O(2)P(OH)Bu(t))(2)](n) (3). On the other hand, a similar reaction of 2, when carried out in dichloromethane, affords [(Me(2)Sn)(3)(O(3)PBu(t))(2)(OSO(2)Et)(2).MeOH](n) (4). A plausible mechanism implicating the role of solvent in the formation of these compounds has been put forward. In addition, the synthesis of [(Me(2)Sn)(3)(O(3)PCH(2)CH(2)COOMe)(2)(OSO(2)Me)(2)](n) (5) and [R(2)Sn(O(2)P(OH)CH(2)CH(2)COOMe)(OSO(2)R(1))](n) [R = Et, R(1) = Me (6); R = (n)Bu, R(1) = Et (7)] has been achieved by reacting 1 and related diorganotin(alkoxy)alkanesulfonates with 3-phosphonopropionic acid in methanol. The formation of a methylpropionate functionality on the phosphorus center in these structural frameworks results from in situ esterification of the carboxylic group. X-ray crystallographic studies of 1-7 are presented. The structures of 1 and 2 represent one-dimensional (1D) coordination polymers composed of alternate [Sn-O](2) and [Sn-O-S-O](2) cyclic rings formed by MU(2)-alkoxo and sulfonate ligands, respectively. For 3-5 and 7, variable bonding modes of phosphonate and/or sulfonate ligands afford the construction of two- and three-dimensional self-assemblies that are comprised of trinuclear tin entities with an Sn(3)P(2)O(6) core as well as [Sn-O-P-O](2) and/or [Sn-O-S-O](2) rings. The formation of a 1D coordination polymer in 6 is unique in terms of repeating eight membered cyclic rings containing Sn, O, P, and S heteroatoms. The contribution from hydrogen-bonding interactions is also found to be significant in these structures. PMID- 21250680 TI - Atomic interactions in the p-type clathrate I Ba8Au5.3Ge40.7. AB - Single crystals of Ba(8)Au(5.3)Ge(40.7) [space group Pm(3)n (No. 223), a = 10.79891(8) A] were prepared by a Bridgman technique. The crystal structure refinement based on single-crystal X-ray diffraction data does not reveal any vacancies in the Au/Ge framework or in the cages. In addition to the ionic bonding between Ba and the anionic framework, a direct interaction between Ba and Au atoms was identified in Ba(8)Au(5.3)Ge(40.7) by applying the electron localizability indicator. As expected by the chemical-bonding picture, Ba(8)Au(5.3)Ge(40.7) is a diamagnet and shows p-type electrical conductivity with a hole carrier concentration of 7.14 * 10(19) cm(-3) at 300 K and very low lattice thermal conductivity of ~0.6 W m(-1) K(-1) at 500 K. The thermoelectric figure of merit ZT of single crystals of Ba(8)Au(5.3)Ge(40.7) attains 0.3 at 511 K and reaches 0.9 at 680 K in a polycrystalline sample of closely similar composition. This opens up an opportunity for tuning of the thermoelectric properties of materials in the Ba-Au-Ge clathrate system by changing the chemical composition. PMID- 21250681 TI - Novel pyridazine based scorpionate ligands in cobalt and nickel boratrane compounds. AB - Heating of 6-methylpyridazine-3-thione (HPn(Me)) and 6-tert-butylpyridazine-3 thione (HPn(tBu)) with potassium borohydride in diphenylmethane in a 3:1 ratio gave two new scorpionate ligands K[HB(Pn(Me))(3)] and K[HB(Pn(tBu))(3)]. Single crystal X-ray diffraction analysis of the methyl derivative K[HB(Pn(Me))(3)] revealed a dimeric species with one potassium atom coordinated by six sulfur atoms of two scorpionate ligands and a second potassium atom coordinated by three nitrogen atoms of one of the two ligands as well as by three water molecules. The reaction of K[HB(Pn(tBu))(3)] with nickel(II) chloride or cobalt(II) chloride in CH(2)Cl(2) led to the new boratrane compounds [M{B(Pn(tBu))(3)}Cl] (M = Ni 1, Co 3) where a formal reduction of the metal ions to Ni(I) and Co(I), respectively, and activation of the B-H bond occurred. Similar reactivity was observed by employing K[HB(Pn(R))(3)] (R = Me, tBu) and nickel(II) chloride in water. Reaction with cobalt(II) chloride in water also gave boratrane compounds [Co{B(Pn(R))(3)}(Pn(R))] (R = tBu 4, Ph 5), but instead of a chloride a bidentate pyridazinethionate ligand from a defragmentated scorpionate is found in the molecules. The molecular structures of all nickel and cobalt compounds were determined by single crystal X-ray diffraction analyses confirming the formation of boratranes in compounds 1-5. Magnetic measurements confirm the reduced oxidation states and the paramagnetic character of the Ni(I) and Co(I) complexes. Supportive DFT studies were carried out for a better understanding of the electronic nature of the metal-boron bond of the boratrane complexes. PMID- 21250683 TI - Synthesis, characterization, and structural studies of multimetallic ferrocenyl carbene complexes of group VII transition metals. AB - Fischer carbene complexes of the group VII transition metals (Mn and Re) containing at least two or three different transition metal substituents, all in electronic contact with the carbene carbon atom, were synthesized. The structural features and their relevance to bonding in the carbene multimetal compounds were investigated, as they represent indicators of possible reactivity sites in polymetallic carbene assemblies. For complexes of the type [ML(x){C(OR)R'}] (ML(x) = MnCp(CO)(2) or Re(2)(CO)(9)), ferrocenyl (Fc) was chosen as the R' substituent, while the OR substituent was systematically varied between an ethoxy or a titanoxy group, to yield the complexes 1a (ML(x) = MnCp(CO)(2), R = Et, R' = Fc), 2a (ML(x) = MnCp(CO)(2), R = TiCp(2)Cl, R' = Fc), 3a (ML(x) = Re(2)(CO)(9), R = Et, R' = Fc), and 4a (ML(x) = Re(2)(CO)(9), R = TiCp(2)Cl, R' = Fc). Direct lithiation of the ferrocene with n-BuLi/TMEDA at elevated temperatures, followed by the Fischer method of carbene preparation, resulted in formation of the novel biscarbene complexes with bridging ferrocen-1,1'-diyl (Fc') substituents [{pi Fe(C(5)H(4))(2)-C,C'}{C(OEt)ML(x)}(2)] (1b, ML(x) = MnCp(CO)(2); 3b, ML(x) = Re(2)(CO)(9)) or the unusual bimetallacyclic bridged biscarbene complexes [{pi TiCp(2)O(2)-O,O'}{pi-Fe(C(5)H(4))(2)-C,C'}{CML(x)}(2)] (2b, ML(x) = MnCp(CO)(2); 4b, ML(x) = Re(2)(CO)(9)). The target compounds that were isolated displayed a variety of different geometric isomers and conformations. The greater reactivity of the binary dirhenium acylates in solution, compared to that of the cyclopentadienyl manganese acylate, resulted in a complex reaction mixture. Although the stabilization of hydroxycarbene or hydrido-acyl intermediates of dirhenium carbonyls could not be achieved, their existence in solution was confirmed by the isolation of [(pi-H)(2)-(Re(CO)(4){C(O)Fc})(2)] (8), the unique dichloro-bridged biscarbene complex fac-[(pi-Cl)(2)-(Re(CO)(3){C(OEt)Fc})(2)] (6), the known hydrido complex [Re(3)(CO)(14)H] (5), the acyl complex [Re(CO)(5){C(O)Fc}] (7), and the aldehyde-functionalized eq [Re(2)(CO)(9){C(OTiCp(2)Cl)(Fc'CHO)}] (9). PMID- 21250682 TI - One octarepeate expansion to the human prion protein alters both the Zn2+ and Cu2+ coordination environments within the octarepeate domain. AB - The influence of a single octarepeat expansion on the Cu(II) and Zn(II) coordination environments within the octarepeat domain of the human prion protein is examined. Using X-ray absorption spectroscopy and diethyl pyrocarbonate labeling studies, we find that at low copper concentrations the "normal" octarepeat domain (four PHGGGWGQ repeats) coordinates Zn(II) in an (N/O)(6) coordination environment with two histidine residues and Cu(II) in a redox inactive (N/O)(4) coordination environment using one imidazole residue. Expansion of the octarepeat region by one repeat (five PHGGGWGQ repeats) yields a three histidine (N/O)(6) coordination environment for Zn(II) and a two-histidine (N/O)(4) coordination environment for Cu(II) at low copper concentrations. This Cu(II)[(N/O)(2)-histidine(2)] coordination motif is redox-active and capable of generating H(2)O(2) under reducing aerobic conditions. PMID- 21250684 TI - Rational assembly of soluble copper(II) phosphonates: synthesis, structure and magnetism of molecular tetranuclear copper(II) phosphonates. AB - The reactions of the dinuclear copper complexes [Cu(2)(L)(OAc)] [H(3)L = N,N'-(2 hydroxypropane-1,3-diyl)bis(salicylaldimine) or [Cu(2)(L')(OAc)] (H(3)L' = N,N' (2-hydroxypropane-1,3-diyl)bis(4,5-dimethylsalicylaldimine)] with various phosphonic acids, RPO(3)H(2) (R = t-Bu, Ph, c-C(5)H(9), c-C(6)H(11) or 2,4,6-i Pr(3)-C(6)H(2)), leads to the replacement of the acetate bridge affording tetranuclear copper(II) phosphonates, [Cu(4)(L)(2)(t BuPO(3))](CH(3)OH)(2)(C(6)H(6)) (1), [Cu(4)(L)(2)(PhPO(3))(H(2)O)(2)(NMe(2)CHO)](H(2)O)(2) (2), [Cu(4)(L')(2)(C(5)H(9)PO(3))](CH(3)OH)(2) (3), [Cu(4)(L')(2)(C(6)H(11)PO(3)](MeOH)(4)(H(2)O)(2) (4) and [Cu(4)(L')(2)(C(30)H(46)P(2)O(5))](PhCH(3)) (5). The molecular structures of 1-4 reveal that a [RPO(3)](2-) ligand is involved in holding the four copper atoms together by a 4.211 coordination mode. In 5, an in situ formed [(RPO(2))(2)O](4-) ligand bridges two pairs of the dinuclear subunits. Magnetic studies on these complexes reveal that the phosphonate ligand is an effective conduit for magnetic interaction among the four copper centers present; a predominantly antiferromagnetic interaction is observed at low temperatures. PMID- 21250685 TI - Solid state structure of thorium(IV) complexes with common aminopolycarboxylate ligands. AB - The crystal structures of the complexes formed by reaction of thorium(IV) nitrate with iminodiacetic acid (H(2)IDA), nitrilotriacetic acid (H(3)NTA), and ethylenediaminetetraacetic acid (H(4)EDTA) under hydrothermal conditions are reported. In [Th(HIDA)(2)(C(2)O(4))].H(2)O (1), the metal atom is chelated by two carboxylate groups from two HIDA(-) anions and by two oxalate ligands formed in situ; two additional oxygen atoms from two more HIDA(-) anions complete the ten coordinate environment of bicapped square antiprismatic geometry. The uncoordinated nitrogen atom is protonated and involved in hydrogen bonding. Two different ligands are present in [Th(NTA)(H(2)NTA)(H(2)O)].H(2)O (2), one of them being a O(3),N-chelating trianion which acts also as a bridge toward two neighboring metal ions, and the other being a bis-monodentate bridging species with an uncoordinated carboxylic arm and a central ammonium group. An aqua ligand completes the nine-coordinated, capped square antiprismatic metal environment. The EDTA(4-) anion in [Th(EDTA)(H(2)O)].2H(2)O (3) is chelating through one oxygen atom from each carboxylate group and the two nitrogen atoms, as in a previously reported molecular complex. Two carboxylate groups are bridging, which, with the addition of an aqua ligand, gives a capped square antiprismatic coordination polyhedron. Aminopolycarboxylate ligands have been much investigated in relation with actinide decorporation and nuclear wastes management studies, and the present results add to the structural information available on their complexes with thorium(IV), which has mainly been obtained up to now by extended X-ray absorption fine structure (EXAFS) spectroscopy. In particular, the bridging (non-chelating) coordination mode of H(2)NTA(-) is a novel feature in this context. All three complexes crystallize as two-dimensional assemblies and are thus novel examples of thorium-organic coordination polymers. PMID- 21250686 TI - Iron-mediated hydrazine reduction and the formation of iron-arylimide heterocubanes. AB - The reaction of Fe(N{SiMe(3)}(2))(2) (1) with 1 equiv of arylthiol (ArSH) results in material of notional composition Fe(SAr)(N{SiMe(3)}(2)) (2), from which crystalline Fe(2)(MU-SAr)(2)(N{SiMe(3)}(2))(2)(THF)(2) (Ar = Mes) can be isolated from tetrahydrofuran (THF) solvent. Treatment of 2 with 0.5 equiv of 1,2 diarylhydrazine (Ar'NH-NHAr', Ar' = Ph, p-Tol) yields ferric-imide-thiolate cubanes Fe(4)(MU(3)-NAr')(4)(SAr)(4) (3). The site-differentiated, 1-electron reduced iron-imide cubane derivative [Fe(THF)(6)][Fe(4)(MU(3)-N-p Tol)(4)(SDMP)(3)(N{SiMe(3)}(2))](2) ([Fe(THF)(6)][4](2); DMP = 2,6 dimethylphenyl) can be isolated by adjusting the reaction stoichiometry of 1/ArSH/Ar'NHNHAr' to 9:6:5. The isolated compounds were characterized by a combination of structural (X-ray diffraction), spectroscopic (NMR, UV-vis, Mossbauer, EPR), and magnetochemical methods. Reactions with a range of hydrazines reveal complex chemical behavior that includes not only N-N bond reduction for 1,2-di- and trisubstituted arylhydrazines, but also catalytic disproportionation for 1,2-diarylhydrazines, N-C bond cleavage for 1,2 diisopropylhydrazine, and no reaction for hindered and tetrasubstituted hydrazines. PMID- 21250687 TI - Palladium-catalyzed C-H aminations of anilides with N-fluorobenzenesulfonimide. AB - The first amide-directed, palladium-catalyzed, intermolecular, highly selective C H aminations with the non-nitrene-based nitrogen source N fluorobenzenesulfonimide have been developed. This methodology might provide a new pathway for directed metal-catalyzed aromatic C-H amination. PMID- 21250688 TI - Rh(I)-catalyzed formal [5 + 1]/[2 + 2 + 1] cycloaddition of 1-yne vinylcyclopropanes and two CO units: one-step construction of multifunctional angular tricyclic 5/5/6 compounds. AB - A novel Rh(I)-catalyzed formal [5 + 1]/[2 + 2 + 1] cycloaddition of 1-yne vinylcyclopropanes and two CO units for the construction of multifunctional angular tricyclic 5/5/6 skeletons with one or two adjacent bridgehead quaternary all-carbon stereocenters in one step has been developed. Preliminary density functional theory calculations have been carried out to investigate the reaction mechanism and the substituent effects. PMID- 21250689 TI - Single-molecule four-color FRET visualizes energy-transfer paths on DNA origami. AB - Fluorescence resonance energy transfer (FRET) represents a mechanism to transport light energy at the nanoscale, as exemplified by nature's light-harvesting complexes. Here we used DNA origami to arrange fluorophores that transport excited-state energy from an input dye to an output dye. We demonstrate that energy-transfer paths can be controlled on the single-molecule level by the presence of a "jumper" dye that directs the excited-state energy either to a red or to an IR output dye. We used single-molecule four-color FRET with alternating laser excitation to sort subpopulations and to visualize the control of energy transfer. PMID- 21250690 TI - Peptide conformational preferences in osmolyte solutions: transfer free energies of decaalanine. AB - The nature in which the protecting osmolyte trimethylamine N-oxide (TMAO) and the denaturing osmolyte urea affect protein stability is investigated, simulating a decaalanine peptide model in multiple conformations of the denatured ensemble. Binary solutions of both osmolytes and mixed osmolyte solutions at physiologically relevant concentrations of 2:1 (urea:TMAO) are studied using standard molecular dynamics simulations and solvation free energy calculations. Component analysis reveals the differences in the importance of the van der Waals (vdW) and electrostatic interactions for protecting and denaturing osmolytes. We find that urea denaturation governed by transfer free energy differences is dominated by vdW attractions, whereas TMAO exerts its effect by causing unfavorable electrostatic interactions both in the binary solution and mixed osmolyte solution. Analysis of the results showed no evidence in the ternary solution of disruption of the correlations among the peptide and osmolytes, nor of significant changes in the strength of the water hydrogen bond network. PMID- 21250691 TI - Cholesterol metabolism is modulated by quercetin in rats. AB - Quercetin has attracted much attention recently because of its antioxidant capacity and potential in the prevention of chronic degenerative diseases. However, its actions and the mechanisms involved are not completely understood. In this study, male Wistar rats were fed a diet containing 0.5% quercetin for 14 days. Serum samples were collected at the end of the experiment, and the overall serum metabolic profile was investigated by (1)H nuclear magnetic resonance (NMR) based metabolomic analysis. Remarkable changes in the serum metabolic profile were manifested with the relative increase in the levels of lactate and low density lipoprotein/very low-density lipoprotein (LDL/VLDL) and reduction in glucose, high-density lipoprotein (HDL), and some amino acids after quercetin exposure. Biochemical measurements confirmed that the serum low-density lipoprotein cholesterol (LDL-C) level was increased significantly after quercetin treatment. Our current findings indicate that quercetin can induce a remarkable change in cholesterol metabolism. Further studies are needed to investigate the molecular mechanisms and the possible links to the health effects or toxic actions of quercetin. PMID- 21250692 TI - Lipase-catalyzed esterification of ferulic Acid with oleyl alcohol in ionic liquid/isooctane binary systems. AB - Lipase-catalyzed synthesis of ferulic acid oleyl alcohol ester in an ionic liquid (IL)/isooctane system was investigated. Considerable bioconversion and volumetric productivity were achieved in inexpensive 1-hexyl-3-methylimidazolium hexafluorophosphate ([Hmim][PF(6)]) and 1-methyl-3-octylimidazolium hexafluorophosphate ([Omim][PF(6)]) mediated systems, and thus, the two types of ILs were selected for further optimization of variables. The results showed that, before reaching a maximum, the increase of ferulic acid concentration, temperature, or enzyme dosage led to an increase in volumetric productivity. Variations of the ratios of IL/isooctane and concentrations of oleyl alcohol also profoundly affected the volumetric productivity. To a higher extent, [Hmim][PF(6)]/isooctane and [Omim][PF(6)]/isooctane show similar reaction behaviors. Under the optimized reaction conditions (60 degrees C, 150 mg of Novozym 435 and 100 mg of molecular sieves), up to 48.50 mg/mL productivity of oleyl feruleate could be achieved for the [Hmim][PF(6)]/isooctane (0.5 mL/1.5 mL) system with a substrate concentration of ferulic acid of 0.08 mmol/mL and oleyl alcohol of 0.32 mmol; while an optimum volumetric productivity of 26.92 mg/mL was obtained for the [Omim][PF(6)]/ isooctane (0.5 mL/1.5 mL) system under a similar reaction condition other than the substrate concentrations of ferulic acid at 0.05 mmol/mL and oleyl alcohol at 0.20 mmol. PMID- 21250693 TI - Cyclic polyalcohols: fingerprints to identify the botanical origin of natural woods used in wine aging. AB - Cyclic polyalcohol composition of 80 natural wood samples from different botanical species, with the majority of them used in the oenology industry for aging purposes, has been studied by gas chromatography-mass spectrometry (GC-MS) after its conversion into their trimethylsilyloxime derivatives. Each botanical species showed a different and specific cyclic polyalcohol profile. Oak wood samples were characterized by the richness in deoxyinositols, especially proto quercitol. Meanwhile, other botanical species showed a very low content of cyclic polyalcohols. The qualitative and quantitative study of cyclic polyalcohols was a useful tool to characterize and differentiate woods of different botanical origin to guarantee the authenticity of chips used in the wine-aging process. Monosaccharide composition was also analyzed, showing some quantitative differences among species, but cyclic polyalcohols were the compounds that revealed the main differentiation power. PMID- 21250694 TI - Updating a synchronous fluorescence spectroscopic virgin olive oil adulteration calibration to a new geographical region. AB - Detecting and quantifying extra virgin olive adulteration is of great importance to the olive oil industry. Many spectroscopic methods in conjunction with multivariate analysis have been used to solve these issues. However, successes to date are limited as calibration models are built to a specific set of geographical regions, growing seasons, cultivars, and oil extraction methods (the composite primary condition). Samples from new geographical regions, growing seasons, etc. (secondary conditions) are not always correctly predicted by the primary model due to different olive oil and/or adulterant compositions stemming from secondary conditions not matching the primary conditions. Three Tikhonov regularization (TR) variants are used in this paper to allow adulterant (sunflower oil) concentration predictions in samples from geographical regions not part of the original primary calibration domain. Of the three TR variants, ridge regression with an additional 2-norm penalty provides the smallest validation sample prediction errors. Although the paper reports on using TR for model updating to predict adulterant oil concentration, the methods should also be applicable to updating models distinguishing adulterated samples from pure extra virgin olive oil. Additionally, the approaches are general and can be used with other spectroscopic methods and adulterants as well as with other agriculture products. PMID- 21250695 TI - Distribution of phenolic acids in different tissues of jujube and their antioxidant activity. AB - Free, esterified, glycosided, and insoluble-bound forms of eight phenolic acids in pulp, seed, and peel of jujube are separated and quantified by high performance liquid chromatography with electrochemical detection (HPLC-ECD). In the whole jujube, p-hydroxybenzoic and cinnamic acids are the most abundant phenolic acids. All quantified phenolic acids are mainly present in jujube peel. Phenolic acids in seed and peel are present in the insoluble-bound form, while, in pulp in the glycosided form, the glycosided and insoluble-bound phenolic acid fractions in jujube pulp represent the highest total phenolic content and the strongest antioxidant activity determined by DPPH and FRAP assays. Our results show that most phenolic compounds with antioxidant activity in different tissues of jujube are present as the glycosided and insoluble-bound forms. PMID- 21250696 TI - Quantification and partial characterization of the residual protein in fully and partially refined commercial soybean oils. AB - A method has been developed to determine residual protein in refined oils, a potential trigger of allergic reactions. High-pH bicarbonate or borate buffers were found to be the most effective extractants, residual oil protein comprising a mixture of proteins of M(r) 6000-100000. Extracted protein could be quantified with superior precision using 3-(4-carboxybenzoyl)quinolone-2-carboxaldehyde (CBQCA). Residual protein content determined in a set of oils using the borate extraction-CBQCA assay was positively correlated with contents determined using a bicarbonate-total amino acid analysis method. Oil refining substantially reduced the oil protein content determined by the borate-CBQCA assay with neutralized/refined, bleached, and deodorized (fully refined) oils containing 62 265 ng/g oil, whereas crude un-degummed oils contained 86000-87900 ng/g of protein. These analyses and published data on cumulative threshold doses for soybean suggest that even the most sensitive individuals would need to consume at least 50 g of highly refined oil to experience subjective symptoms. PMID- 21250697 TI - A multiscale simulation system for the prediction of drug-induced cardiotoxicity. AB - The preclinical assessment of drug-induced ventricular arrhythmia, a major concern for regulators, is typically based on experimental or computational models focused on the potassium channel hERG (human ether-a-go-go-related gene, K(v)11.1). Even if the role of this ion channel in the ventricular repolarization is of critical importance, the complexity of the events involved make the cardiac safety assessment based only on hERG has a high risk of producing either false positive or negative results. We introduce a multiscale simulation system aiming to produce a better cardiotoxicity assessment. At the molecular scale, the proposed system uses a combination of docking simulations on two potassium channels, hERG and KCNQ1, plus three-dimensional quantitative structure-activity relationship modeling for predicting how the tested compound will block the potassium currents IK(r) and IK(s). The obtained results have been introduced in electrophysiological models of the cardiomyocytes and the ventricular tissue, allowing the direct prediction of the drug effects on electrocardiogram simulations. The usefulness of the whole method is illustrated by predicting the cardiotoxic effect of several compounds, including some examples in which classic hERG-based models produce false positive or negative results, yielding correct predictions for all of them. These results can be considered a proof of concept, suggesting that multiscale prediction systems can be suitable for being used for preliminary screening in lead discovery, before the compound is physically available, or in early preclinical development when they can be fed with experimentally obtained data. PMID- 21250698 TI - Evaluation of quinazoline analogues as glucocerebrosidase inhibitors with chaperone activity. AB - Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC. PMID- 21250699 TI - Synthesis, characterization, and biological evaluation of novel diclofenac prodrugs. AB - Diclofenac ester pro drugs (4, 5, 6) were synthesized and evaluated in vitro and in vivo for their potential use for oral delivery, with the aim of obtaining enzymatically labile and less ulceration drugs than the parent drug diclofenac sodium (1a). Prodrugs 4, 5, 6 were found to be potent anti-inflammatory drugs with less ulcerogenic potential than the parent diclofenac sodium. Prodrugs 4, 5, 6 rapidly underwent enzymatic hydrolysis to release the parent drug diclofenac in 30-60 min in rat liver microsomes (RLM) and rat plasma (RP). Prodrugs were found to be more lipophilic when the partition coefficient was measured in 1-octanol and buffer system at pH 7.4 and 3.0. Diclofenac prodrugs 4, 5, 6 were found to be crystalline in nature (analyzed by PXRD). Prodrug 4 was found to be a superior candidate for the treatment of chronic inflammatory diseases. PMID- 21250700 TI - Cytotoxic and apoptosis-inducing activities of triterpene acids from Poria cocos. AB - Six lanostane-type triterpene acids (1a-6a), isolated from Poria cocos , and their methyl ester (1b-6b) and hydroxy derivatives (1c-6c) were prepared. Upon evaluation of the cytotoxic activity of these compounds against leukemia (HL60), lung (A549), melanoma (CRL1579), ovary (NIH:OVCAR-3), breast (SK-BR-3), prostate (DU145), stomach (AZ521), and pancreas (PANC-1) cancer cell lines, 11 compounds (5a, 6a, 2b-5b, 1c, and 3c-6c) exhibited activity with single-digit micromolar IC(50) values against one or more cell lines. Poricotriol A (1c), a hydroxy derivative of poricoic acid A (1a), exhibited potent cytotoxicities against six cell lines with IC(50) values of 1.2-5.5 MUM. Poricotriol A induced typical apoptotic cell death in HL60 and A549 cells on evaluation of the apoptosis inducing activity by flow cytometric analysis. Western blot analysis in HL60 cells showed that poricotriol A activated caspases-3, -8, and -9, while increasing the ratio of Bax/Bcl-2. This suggested that poricotriol A induced apoptosis via both mitochondrial and death receptor pathways in HL60. On the other hand, poricotriol A did not activate caspases-3, -8, and -9, but induced translocation of apoptosis-inducing factor (AIF) from mitochondria and increased the ratio of Bax/Bcl-2 in A549. This suggested that poricotriol A induced apoptosis via the mitochondrial pathway mostly by translocation of AIF, independent from the caspase pathway in A549. Furthermore, poricotriol A was shown to possess high selective toxicity in lung cancer cells since it exhibited only weak cytotoxicity against a normal lung cell line (WI-38). PMID- 21250701 TI - Stereoselective 6-exo radical cyclization using cis-vinyl sulfoxide: practical total synthesis of CTX3C. AB - Ciguatoxins, the principal causative toxins of ciguatera seafood poisoning, are large ladder-like polycyclic ethers. We report a highly stereoselective 6-exo radical cyclization/ring-closing olefin metathesis sequence to construct the syn/trans-fused polyether system. The new method was applied to the practical synthesis of ciguatoxin CTX3C. PMID- 21250702 TI - Structure, conformation, stereodynamics, and absolute configuration of the atropisomers of fluorenylidene derivatives. AB - The barrier for the interconversion of the conformational atropisomers of an aryl fluorenylidene derivative was determined by variable-temperature NMR technique. In the case of a more hindered compound the two atropisomers were isolated and the structure determined by X-ray diffraction. The absolute configuration was assigned by theoretical interpretation of the Electronic Circular Dichroism spectrum (ECD). PMID- 21250703 TI - Total synthesis of (+/-)-spiniferin-1 via a polyfluoroalkanosulfonyl fluoride induced homoallylic carbocation rearrangement reaction. AB - A facile total synthesis of marine natural product (+/-)-spiniferin-1 has been accomplished in eight steps with 28.9% overall yield, involving a rearrangement reaction initiated by polyfluoroalkanosulfonyl fluoride to construct the 1,6 methano[10]annulene core of the natural product as a key step. PMID- 21250704 TI - Diastereoselective synthesis of diketopiperazine bis-alpha,beta-epoxides. AB - Functionalized diketopiperazines (dioxopiperazines) are an important class of molecules in medicinal chemistry and material science. Herein we report a diastereoselective synthesis of diketopiperazine bis-alpha,beta-epoxides via the oxidation of exocyclic olefins. Although six diastereomers may be formed by this approach, only one or two of them were observed. PMID- 21250705 TI - Ligand-free copper-catalyzed arylation of amidines. AB - Copper-catalyzed cross-coupling reactions of amidine salts were utilized to synthesize monoarylated amidines in moderate to high yields with ligand-free conditions. DMF was the superior solvent for the N-arylation of benzamidines, while MeCN was used in the formation of N-aryl amidines in moderate to high yield. PMID- 21250706 TI - Mechanistic studies of Wacker-type intramolecular aerobic oxidative amination of alkenes catalyzed by Pd(OAc)2/pyridine. AB - Wacker-type oxidative cyclization reactions have been the subject of extensive research for several decades, but few systematic mechanistic studies of these reactions have been reported. The present study features experimental and DFT computational studies of Pd(OAc)(2)/pyridine-catalyzed intramolecular aerobic oxidative amination of alkenes. The data support a stepwise catalytic mechanism that consists of (1) steady-state formation of a Pd(II)-amidate-alkene chelate with release of 1 equiv of pyridine and AcOH from the catalyst center, (2) alkene insertion into a Pd-N bond, (3) reversible beta-hydride elimination, (4) irreversible reductive elimination of AcOH, and (5) aerobic oxidation of palladium(0) to regenerate the active trans-Pd(OAc)(2)(py)(2) catalyst. Evidence is obtained for two energetically viable pathways for the key C-N bond-forming step, featuring a pyridine-ligated and a pyridine-dissociated Pd(II) species. Analysis of natural charges and bond lengths of the alkene-insertion transition state suggest that this reaction is best described as an intramolecular nucleophilic attack of the amidate ligand on the coordinated alkene. PMID- 21250707 TI - Rapid nickel-catalyzed Suzuki-Miyaura cross-couplings of aryl carbamates and sulfamates utilizing microwave heating. AB - High-speed and scalable nickel-catalyzed cross-coupling of arylboronic acids with aryl carbamates and sulfamates is achieved by using sealed-vessel microwave processing. PMID- 21250708 TI - Synthesis of 2-keto-imidazoles utilizing N-arylamino-substituted N-heterocyclic carbenes. AB - A new method for the synthesis of 2-aroyl-, 2-heteroaroyl-, and 2-cinnamoyl substituted imidazoles in very good yields has been developed. The reaction employs novel nitrogen heterocyclic carbenes (NHCs), namely, N-arylamino substituted NHCs, formed in situ from the corresponding imidazolium salts, and subsequent reaction with aromatic, heteroaromatic, and cinnamic aldehydes without utilizing transition metals or expensive specialized catalysts. PMID- 21250709 TI - Electrochemical and H/D-labeling study of oxazolino[60]fullerene rearrangement. AB - Isomerization of an oxazoline cycle from a [6,6]- to [5,6]-junction on the C(60) sphere of dianionic [60]fullero-oxazoline (1(2-)) during a 1,4-addition is studied by electrochemistry and a stepwise addition of PhCH(2)Br and PhCD(2)Br. Cyclic voltammerty of the in situ generated 1(2-) shows a very unusual positive shift for the anodic peak corresponding to the oxidation of 1(2-), indicating that the C(60) cage of dianionic 1 bears only one unit negative charge due to the heterolytic cleavage of the C(60)-O bond. Further study with a stepwise addition of PhCH(2)Br and PhCD(2)Br, which are used to differentiate the aryl groups added at each step onto dianionic 1, shows explicitly there is an exclusive selectivity of the C-O bond for the ring-opening and ring-closure during the isomerization of the heterocycle. A reaction mechanism is proposed on the basis of the experimental results and computational calculations. PMID- 21250710 TI - Selective synthesis of gem-chlorofluorinated nitrogen-containing derivatives after superelectrophilic activation in superacid HF/SbF5. AB - The first direct selective synthesis of novel gem-chlorofluorinated nitrogen containing building blocks in superacid is reported. The dramatic role of the chlorine atom on the reaction is shown by in situ NMR experiments and allows the involvement of a novel original superelectrophilic activation process in superacid HF/SbF(5) to be postulated. PMID- 21250712 TI - The effect of proton donors on the facial stereoselectivity in SmI2 reduction of norcamphor. AB - The endo/exo product ratio in the reactions of SmI(2) with norcamphor in the presence of various proton donors was determined. The effect of MeOH, EtOH, trifluoroethanol (TFE), ethylene glycol (EG), and water was investigated at various concentrations of these proton donors. At low concentrations of EtOH, TFE, and EG, an endo/exo ratio near unit was found. This ratio increased as the concentration of the proton donor increased. However, MeOH and water gave a U type curve, in a plot of the endo/exo ratio vs proton donor concentration. The difference between the two groups of proton donors was shown not to result from differences in their acidities or polarity effects. It is suggested that at low MeOH and water concentrations, the second electron transfer takes place from the dimer of SmI(2) rather than from the monomer. This bulky electron donor approaches the radical anion preferentially from the exo direction giving rise to the high endo/exo ratio at the left arm of the U-shaped curve. Comparison of kinetic and product H/D isotope effects shows that protonation on carbon, the step that locks the stereochemistry, is a post rate determining step. PMID- 21250713 TI - Synthesis of and tautomerism in 3-acyltetramic acids. AB - The synthesis of 3-acyltetramic acids, the substructure of bioactive natural products, via O-acylation of tetramic acids with carboxylic acids followed by acyl migration, has been investigated. This acylation sequence is mediated by N,N'-dicyclohexylcarbodiimide (DCC) and 4-dimethylaminopyridine (DMAP) and is very sensitive to the nature of the nitrogen substituent (R(1)), the nature of the carboxylic acid (R(2)CO(2)H), and the amount of DMAP. Acylation of N-acyl tetramic acids with an alkyl carboxylic acid using 1.3 equiv of DMAP (with 1.1 equiv of DCC) unexpectedly gave the 3-acyltetramic acid directly as a result of acyl migration induced by excess amounts of DMAP. On the other hand, N unsubstituted, N-alkyl, and N-acyl tetramic acids with alkyl and aromatic carboxylic acids gave the O-acyl tetramic acids by using only 0.1 equiv of DMAP (with 1.1 equiv of DCC); these could be further rearranged to the acyl product by treatment with excess DMAP. The tautomeric equilibrium of these 3-acyltetramic acids in solution was found to strongly depend on the nitrogen substituent group (R(1)) rather than the 3-acyl group. PMID- 21250715 TI - Palladium(II)-catalyzed synthesis of functionalized indenes from o alkynylbenzylidene ketones. AB - An efficient method for the synthesis of functionalized indenes from o alkynylbenzylidene ketones under palladium(II) catalysis was developed. The reaction is initiated by trans-nucleopalladation of alkynes, followed by conjugate addition and quenched by protonolysis of the carbon-palladium bond. With acetate and halide ions as nucleophiles, 3-acetoxy- and 3-halogen substituted indenes could be obtained in high yields. PMID- 21250716 TI - A practical synthesis of renin inhibitor MK-1597 (ACT-178882) via catalytic enantioselective hydrogenation and epimerization of piperidine intermediate. AB - A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2. PMID- 21250717 TI - Palladium-catalyzed selective acyloxylation using sodium perborate as oxidant. AB - Sodium perborate (SPB), a principal component of washing powders, was employed as an inexpensive and eco-friendly oxidant in the palladium-catalyzed C-H acyloxylation of alkenes in excellent regio- and stereochemistry. The reactions used anhydrides as acyloxy sources. The method applies to both terminal and internal alkenes, and even benzylic C-H oxidation. PMID- 21250719 TI - Effect of electron-withdrawing substituents on the epoxide ring: an experimental and theoretical electron density analysis of a series of epoxide derivatives. AB - A series of acceptor-substituted epoxide derivatives is scrutinized by means of experimental and theoretical electron-density investigations. Due to the possibility of nucleophilic ring-opening, the epoxide ring is not only a very useful functional group in organic synthesis, but acceptor-substituted epoxides are valuable building blocks for the design of protease inhibitors. Therefore, the electron-density analysis in this work focuses on two main aspects that can contribute to rational drug design: (i) the quantification of the electron withdrawing substituent effects on the epoxide ring and (ii) the intermolecular interactions involving the epoxide ring in combination with different substituents. It can be shown that the electron-withdrawing properties of the substituents cause an elongation of the C-C bonds in the epoxide rings and the loss of electron density can be measured by an analysis of critical points, atomic charges, and the source function. The different strengths of the substituents are reflected in these properties. Covalent and electrostatic contributions to the intermolecular interactions and thus the lattice energies are depicted on different molecular surfaces. PMID- 21250718 TI - Synthesis-guided structure revision of the sarcodonin, sarcoviolin, and hydnellin natural product family. AB - A sweeping structural revision of the sarcodonin natural product family (published structures 1a-13a) is proposed after extensive studies aimed at their chemical synthesis. Key features of revised structure 1b include replacement of the N,N-dioxide moiety with an oxime, ring-opening of the central diketopiperazine, and transposition of the terphenyl wing from the 1beta-2beta position of 1a to the 2beta-3beta position of 1b. This structure revision arose from the serendipitous synthesis of a benzodioxane aminal (44) whose structure was unambiguously determined by X-ray crystallography and whose spectral properties bore considerable resemblance to the published data for the sarcodonins. A versatile new method for O-arylation of hydroxamic acids is also reported herein, as well as a manganese(III)-mediated alpha-oxidation of hydroxamic acids to aminals. PMID- 21250720 TI - Asymmetric aldol reaction organocatalyzed by (S)-proline-containing dipeptides: improved stereoinduction under solvent-free conditions. AB - The organocatalytic activity of the methyl ester of (S)-proline-(S) phenylalanine, (S,S)-2, in the asymmetric aldol reaction between cyclohexanone and acetone with various aromatic aldehydes under solvent-free conditions in a ball mill has been evaluated. alpha,alpha-Dipeptide (S,S)-2 catalyzed the stereoselective formation of the expected aldol products, with higher diastereo- and enantioselectivity relative to similar reactions in solution, up to 91:9 anti:syn diastereomeric ratio and up to 95% enantiomeric excess. PMID- 21250721 TI - A strategy for the late-stage divergent syntheses of scyphostatin analogues. AB - This account details the synthesis of two scyphostatin analogues exhibiting a reactive polar epoxycyclohexenone core and various amide side chains outfitted for late-stage chemical derivatization into the desirable lipophilic tails. Our efforts highlight a key ipso-dearomatization process and provide new insights regarding the incompatibility and orthogonal reactivity of scyphostatin's functional groups. We further showcase the utility of resorcinol derived 2,5 cyclohexadienones as synthetic platforms capable of participating in selective chemical reactivity, and we further demonstrate their potential for rapid elaboration into complex structural motifs. PMID- 21250722 TI - (N-heterocyclic carbene)-Pd-catalyzed anaerobic oxidation of secondary alcohols and domino oxidation-arylation reactions. AB - The use of commercially available (SIPr)Pd(cinnamyl)Cl (SIPr = 1,3-bis(2,6 diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene) as a precatalyst for the anaerobic oxidation of secondary alcohols is described. The use of this complex allows for a drastic reduction in the reaction times and catalyst loading when compared to the unsaturated counterpart. This catalytic system is compatible with the use of microwave dielectric heating, decreasing even further catalyst loading and reaction times. Domino Pd-catalyzed oxidation-arylation reactions of secondary alcohols are also presented. PMID- 21250723 TI - Forming spirocyclohexadienone-oxocarbenium cation species in the biomimetic synthesis of amomols. AB - The oxidation of appropriate 2-(4-hydroxyphenyl)ethyl ketones gives direct access to amomols by means of the formation of a transient spirocyclohexadienone oxocarbenium ion that is intermolecularly intercepted by an alcohol. Furthermore, homochiral amomols and other new analogues were synthesized for the first time and were biologically evaluated on Plasmodium falciparum. PMID- 21250724 TI - Facile synthesis of selenium/sulfur-substituted 3-oxa-bicyclo[4.2.0]octa-1(8),5 diene and tetrahydro-1H-isochromene via sequential three-component conjugate addition/condensation/elimination/[2 + 2] or [4 + 2] cyclization reactions. AB - An interesting sequential three-component reaction provides a facile synthesis of selenium/sulfur-substituted 3-oxabicyclo[4.2.0]octa-1(8),5-diene and tetrahydro 1H-isochromene from lithium alkylselenolates or alkylthiolates, 1 alkynylphosphine oxides, and aldehydes. The sequential reaction proceeds via a conjugate addition/condensation/elimination process to form the allene intermediate, which subsequently underwent [2 + 2] or [4 + 2] cyclization reaction to afford bicyclic frameworks. PMID- 21250725 TI - Direct synthesis of fused indoles by gold-catalyzed cascade cyclization of diynes. AB - A direct, concise, and atom-economical synthetic method for the generation of fused indoles, using a gold-catalyzed cascade cyclization of diynes, has been developed. The reaction gave various fused indoles, such as aryl annulated[a]carbazoles, dihydrobenzo[g]indoles, and azepino- or oxepinoindole derivatives in good to excellent yields, through an intramolecular cascade 5-endo dig hydroamination followed by a 6- or 7-endo-dig cycloisomerization, without producing theoretical byproduct. Three of the resulting indoles exhibited potent antifungal activities against T. mentagrophytes and T. rubrum, demonstrating the practical application of the described cascade reaction for drug discovery. PMID- 21250726 TI - Quantum chemical prediction of pathways and rate constants for reaction of cyanomethylene radical with NO. AB - High-level ab initio calculations have been performed to study the mechanism and kinetics of the reaction of the cyanomethylene radical (HCCN) with the NO. The species involved have been optimized at the B3LYP/6-311++G(3df,2p) level, and their corresponding single-point energies are improved by the CCSD(T)/aug-cc PVQZ//B3LYP/6-311++G(3df,2p) approach. From the calculated potential energy surface, we have predicted the favorable pathways for the formation of several isomers of a HCCN-NO complex. Barrierless formation of HCN + NCO (P1) is also possible. Formation of HCNO + CN (P3) is endoergic but may become significant at high temperatures. To rationalize the scenario of our calculated results, we also employ the Fukui functions and hard-and-soft acid-and-base (HSAB) theory to seek possible clues. The predicted total rate coefficient, k(total), at He pressure 760 Torr can be represented with the equation k(total) = 1.40 * 10(-7) T(-2.01) exp(3.15 kcal mol(-1)/RT) at T = 298-3000 K in units of cm(3) molecule(-1) s(-1). The predicted total rate coefficients at some available conditions (He pressures of 6, 18, and 30 Torr in the temperature of 298 K) are in reasonable agreement with experimental observation. In addition, the rate constants for key individual product channels are provided in different temperature and pressure conditions. PMID- 21250727 TI - Dipolar solute rotation in a supercritical polar fluid. AB - Fluorescence anisotropy measurements reveal a non-monotonic density dependence for average rotation time (tau(R)) of a polar solute, coumarin153 (C153) in polar supercritical fluoroform (CHF(3)). The conventional Stokes-Einstein-Debye model, relating tau(R) to the solvent viscosity, fails to explain the observed density dependence, because the experimental viscosity increases monotonously with density for a fluid, in general. Here, the density-dependent tau(R) is calculated by incorporating the wave vector-dependent viscosity of the solvent and the solute-solvent interaction. A molecular hydrodynamic description is used for the wave vector-dependent viscosity which is verified by molecular dynamics (MD) simulation. A justification for the applicability of the present prescription is provided by reproducing the experimental viscosity of supercritical (SC) CHF(3). Solute-solvent interaction has been included via the fluctuating torque acting on the rotating solute. Incorporation of wave vector-dependent viscosity leads to a qualitative description of the experimental density dependence of tau(R) which is further improved upon inclusion of solute-solvent interaction. PMID- 21250728 TI - Assessment of dispersion corrected atom centered pseudopotentials: application to energetic molecular crystals. AB - A comparative study of the structural features of molecular crystals 1,3,5,7 tetranitro-1,3,5,7-tetraazacyclooctane (HMX), cyclotrimethylenetrinitramine (RDX), 2,4,6-trinitro-1,3,5-benzenetriamine (TATB), and pentaerythritol tetranitrate (PETN) at ambient pressure were calculated using density functional theory (DFT) and dispersion corrected atom centered pseudopotentials (DCACPs). While the molecular structural parameters showed little dependence on the pseudopotential used, the overall volume and lattice vector lengths were substantially improved by the use of DCACPs. DCACP predictions of lattice vector lengths are within 1.3% of experiment, corresponding to an approximately 2% error in density. Conversely, DFT underestimates crystal densities by 5-10%. The results indicate that DCACPs substantially compensate for the inadequate description of van der Waals interactions in DFT. Additionally, comparison of DCACP predictions with analogous calculations using an alternate dispersion corrected DFT method indicate while both show an improvement over traditional DFT methods in describing van der Waals interactions for the molecular crystals in this study, the DCACP method is more accurate in predicting lattice vectors. PMID- 21250729 TI - Calculation of the molecular and atomic properties of selected anions in water. AB - The polarizability and other properties have been studied for F(-), Cl(-), Br(-), and HCOO(-) in water using a combined quantum chemical statistical mechanics simulation model that explicitly takes into account the Pauli repulsion as well as the electrostatic coupling between the QM system and the classical surroundings. It is shown that the surrounding molecules significantly reduce both the polarizability and the size of the anions. For the formate ions, local properties have been computed. PMID- 21250730 TI - Competitive adsorption of surfactants and polymers at the free water surface. A computer simulation study of the sodium dodecyl sulfate-poly(ethylene oxide) system. AB - Competitive adsorption of a neutral amphiphilic polymer, namely poly(ethylene oxide) (PEO) and an ionic surfactant, i.e., sodium dodecyl sulfate (SDS), is investigated at the free water surface by computer simulation methods at 298 K. The sampled equilibrium configurations are analyzed in terms of the novel identification of the truly interfacial molecules (ITIM) method, by which the intrinsic surface of the aqueous phase (i.e., its real surface corrugated by the capillary waves) instead of an ideally flat surface approximating its macroscopic surface plane, can be taken into account. In the simulations, the surface density of SDS is gradually increased from zero up to saturation, and the structural, dynamical, and energetic aspects of the gradual squeezing out of the PEO chains from the surface are analyzed in detail. The obtained results reveal that this squeezing out occurs in a rather intricate way. Thus, in the presence of a moderate amount of SDS the majority of the PEO monomer units, forming long bulk phase loops in the absence of SDS, are attracted to the surface of the solution. This synergistic effect of SDS of moderate surface density on the adsorption of PEO is explained by two factors, namely by the electrostatic attraction between the ionic groups of the surfactant and the moderately polar monomer units of the polymer, and by the increase of the conformational entropy of the polymer chain in the presence of the surfactant. This latter effect, thought to be the dominant one among the above two factors, also implies the formation of similar polymer/surfactant complexes at the interface than what are known to exist in the bulk phase of the solution. Finally, in the presence of a large amount of SDS the more surface active surfactant molecules gradually replace the PEO monomer units at the interfacial positions, and squeezing out the PEO molecules from the surface in a monomer unit by monomer unit manner. PMID- 21250731 TI - Delocalization-enhanced long-range energy transfer between cryptophyte algae PE545 antenna proteins. AB - We study the dynamics of interprotein energy transfer in a cluster, consisting of four units of phycoerythrin 545 (PE545) antenna proteins via a hybrid quantum classical approach. Long-range exciton transport is viewed as a random walk in which the hopping probabilities are determined from a quantum theory. We apply two different formulations of the exciton transport problem to obtain the hopping probabilities, and find that a theory that regards energy transfer as relaxations among the excitonic eigenstates mediated by the vibrational bath, predicts the fastest dynamics. Our results indicate that persistent exciton delocalization is an important implication of the quantum nature of energy transfer on a multiprotein length scale, and that a hybrid quantum-classical approach is a viable starting point in studies of long-range energy transfer in condensed phase biological systems. PMID- 21250732 TI - FRET-based ratiometric detection system for mercury ions in water with polymeric particles as scaffolds. AB - Mercury pollution is a global problem, and the development of stable and sensitive fluorescent probes for mercury ions in the water phase has long been sought. In this work, a novel fluorescence resonance energy transfer (FRET)-based ratiometric sensor for detecting Hg(2+) in pure water was demonstrated. Polymeric nanoparticles prepared by miniemulsion polymerization of methyl methacrylate and acrylic acid were used as the scaffold for the FRET-based sensor. A hydrophobic fluorescent dye nitrobenzoxadiazolyl derivative (NBD) was embedded in the nanoparticles during the polymerization and used as the donor. A spirolactam rhodamine derivative SRHB-NH(2) was synthesized and then covalently linked onto the particle surface and used as an ion recognition element. The presence of Hg(2+) in the water dispersion of nanoparticles induced the ring-opening reaction of the spirolactam rhodamine moieties and led to the occurrence of the FRET process, affording the nanoparticle system a ratiometric sensor for Hg(2+). The nanoparticle sensor can selectively detect the Hg(2+) in water with the detection limit of 100 nM (ca. 20 ppb). It has been found that the FRET-based system with smaller nanoparticles as the scaffold exhibited higher energy transfer efficiency and was more preferred for the accurate ratiometric detection. Moreover, the FRET based sensor was applicable in a relatively wide pH range (pH 4-8) in water; thus, this approach may provide a new strategy for ratiometric detection of analytes in environmental and biological applications. PMID- 21250733 TI - Using solvent binding and dielectric friction to interpret the hydration behavior of complex anions. AB - We investigate the hydration structure and water/ion dynamics about complex anions using a revised platinum group metal chloro-anion force field. Nanosecond atomistic molecular dynamics simulations were performed for the platinum group metal chloro-anion complexes. This investigation makes the first attempt at describing diffusion trends of polyatomic complex anions with counterions such as these using both hydrodynamic and dielectric friction properties of the anion solution. The transition metal anion complex diffusion rates are shown to be correlated to their first solvent shell radial distribution function peaks, their mean water residence times, and their solvation volumes as calculated by Voronoi tessellation of the simulation cell. The general trend is for slower diffusion rates to result from larger hydration shell volumes. This diffusion rate trend calculated from Stokes' law is best described using the solventberg approach with well-chosen effective solvated radii. However, to improve the diffusion constant estimates when they are compared with those calculated from computer simulations, the dielectric friction is required. PMID- 21250734 TI - Hybrid MC-DFT method for studying multidimensional entropic forces. AB - Entropic force has been a focus of many recent theoretical studies because of its fundamental importance in solution thermodynamics and its close relevance to a broad range of practical applications. Whereas previous investigations are mostly concerned with the potential energy as a one-dimensional function of the separation, here we propose a hybrid method for studying multidimensional systems by combining Monte Carlo simulation for the microscopic configurations of the solvent and the density functional theory for the free energy. We demonstrate that the hybrid method predicts the potential of mean force between a test particle and various concave objects in a hard-sphere solvent in excellent agreement with the results from alternative but more expensive computational methods. In particular, the hybrid method captures the entropic force between asymmetric particles and its dependence on the particle size and shape that underlies the "lock and key" interactions. Because the same molecular model is used for the theory and simulation, we expect that the hybrid method provides a new avenue to efficient computation of entropic forces in complex molecular systems. PMID- 21250735 TI - Ion extraction mechanism studied in a lyotropic lamellar phase. AB - In this paper we used a surfactant-stabilized lyotropic lamellar model system to study the interfacial behavior of an ion-extracting agent: N(1),N(3) dimethyl N(1),N(3)-dibutyl-2-tetradecylmalonamide (DMDBTDMA). An analysis of small-angle X ray scattering (SAXS) and polarized attenuated total reflectance-Fourier transform infrared (ATR-FTIR) data enabled us to describe the distribution of the malonamide extractant within the bilayers and its complexation state at the equilibrium. The lamellar phase was diluted with salt water containing varying amounts of complexing salt, and each structural state measured was described using a thermodynamic model based on three elementary equilibria: (i) partition of the extractant polar heads between the core and the polar shell of the bilayers, (ii) the complexation of ions by extractants at the bilayers surfaces, and (iii) the partition of bonded extractants between the core and interfaces of bilayers. This model enabled us to compare the energy cost of each step. PMID- 21250736 TI - Chemical behavior of methylpyranomalvidin-3-O-glucoside in aqueous solution studied by NMR and UV-visible spectroscopy. AB - In the present work, the proton-transfer reactions of the methylpyranomalvidin-3 O-glucoside pigment in water with different pH values was studied by NMR and UV visible spectroscopies. The results showed four equilibrium forms: the methylpyranomalvidin-3-O-glucoside cation, the neutral quinoidal base, the respective anionic quinoidal base, and a dianionic base unprotonated at the methyl group. According to the NMR data, it seems that for methylpyranomalvidin-3 O-glucoside besides the acid-base equilibrium between the pyranoflavylium cation and the neutral quinoidal base, a new species is formed at pD 4.88-6.10. This is corroborated by the appearance of a new set of signals in the NMR spectrum that may be assigned to the formation of hemiketal/cis-chalcone species to a small extent. The two ionization constants (pK(a1) and pK(a2)) obtained by both methods (NMR and UV-visible) for methylpyranomalvidin-3-O-glucoside are in agreement (pK(a1) = 5.17 +/- 0.03; pK(a2) = 8.85 +/- 0.08; and pK(a1) = 4.57 +/- 0.07; pK(a2) = 8.23 +/- 0.04 obtained by NMR and UV-visible spectroscopies, respectively). Moreover, the fully dianionic unprotonated form (at the methyl group) of the methylpyranomalvidin-3-O-glucoside is converted slowly into a new structure that displays a yellow color at basic pH. On the basis of the results obtained through LC-MS and NMR, the proposed structure was found to correspond to the flavonol syringetin-3-glucoside. PMID- 21250737 TI - Evidence of two distinct mechanisms driving photoinduced matter motion in thin films containing azobenzene derivatives. AB - Photoinduced matter motion in thin films containing azobenzene derivatives grafted to a polymer backbone is investigated by means of near-field probe microscopy. We evidence the existence of two different photomechanical processes which produce mass transport. One is governed by the light intensity pattern and the other by the light polarization pattern. The intensity-driven mechanism is found to critically depend on the polymer matrix while the polarization-driven mechanism occurs with almost the same efficiency in different materials. Depending on the relationship between the polarization and intensity patterns, the two processes may either compete or cooperate giving rise to a nontrivial directional mass transport process. PMID- 21250738 TI - Elucidation of the orientational order and the phase diagram of p-quinquephenyl. AB - The orientational order in the nematic phase of p-quinquephenyl, the pentamer of p-phenylene, has been determined by means of birefringence measurements and by wide-angle X-ray scattering (WAXS). The experimentally determined order parameters are compared with the temperature-dependent order parameter predicted by the Maier-Saupe theory. The order parameters derived from the birefringence at different temperatures in the nematic phase of p-quinquephenyl were in excellent agreement with the Maier-Saupe predictions. The values calculated from the azimuthal profiles derived from WAXS measurements were significantly lower than those determined by the birefringence measurements, especially at higher temperatures. For the birefringence measurements, alignment of the director is achieved by using polyimide alignment layers, whereas director alignment for the WAXS experiments was achieved by a magnetic field. We assign the low overall order parameters that were measured by WAXS to a lower macroscopic orientational order. In addition, upon reinvestigating the mesophase behavior of p-quinquephenyl, a monotropic smectic A phase has been observed upon cooling at 390 degrees C, just before the crystallization temperature is reached. PMID- 21250739 TI - Fouling behavior of microstructured hollow fiber membranes in dead-end filtrations: critical flux determination and NMR imaging of particle deposition. AB - The fouling behavior of microstructured hollow fibers was investigated in constant flux filtrations of colloidal silica and sodium alginate. It was observed that the fouling resistance increases faster with structured fibers than with round fibers. Reversibility of structured fibers' fouling was similar during silica filtrations and better in sodium alginate filtrations when compared with round fibers. The deposition of two different silica sols on the membranes was observed by NMR imaging. The sols had different particle size and solution ionic strength and showed different deposition behaviors. For the smaller particle sized sol in deionized solution (Ludox-TMA), there was more deposition within the grooves of the structured fibers and much less on the fins. For the alkali stabilized sol Bindzil 9950, which had larger particles, the deposition was homogeneous across the surface of the structured fiber, and the thickness of the deposit was similar to that on the round fiber. This difference between the deposition behavior of the two sols is explained by differences in the back diffusion, which creates concentration polarization layers with different resistances. The Ludox sol formed a thick polarization layer with very low resistance. The Bindzil sol formed a slightly thinner polarization layer; however, its resistance was much higher, of similar magnitude as the intrinsic membrane resistance. This high resistance of the polarization layer during the Bindzil sol filtration is considered to lead to quick flow regulation toward equalizing the resistance along the fiber surface. The Ludox particles were trapped at the bottom of the grooves as a result of reduced back diffusion. The fouling behavior in sodium alginate filtrations was explained by considering the size-dependent deposition within the broad alginate size distribution. The better reversibility of fouling in the structured fibers is thought to be the result of a looser deposit within the grooves, which is more easily removed than a compressed deposit on the round fibers. PMID- 21250740 TI - 1,10-Phenanthrolinium ionic liquid crystals. AB - The 1,10-phenanthrolinium cation is introduced as a new building block for the design of ionic liquid crystals. 1,10-Phenanthroline, 5-methyl-1,10 phenanthroline, 5-chloro-1,10-phenanthroline, and 4,7-diphenyl-1,10 phenanthroline were quaternized by reaction with 1,3-dibromopropane or 1,2 dibromoethane. The resulting cations were combined with dodecyl sulfate or dioctyl sulfosuccinate anions. The influence of both the cation and anion type on the thermal behavior was investigated. Several of the complexes exhibit mesomorphic behavior, with smectic E phases for the dodecyl sulfate salts and smectic A phases for the dioctyl sulfosuccinate salts. Structural models for the packing of the 1,10-phenanthrolinium and anionic moieties in the liquid crystalline phases are presented. The ionic compounds show fluorescence in the solid state and in solution. PMID- 21250741 TI - A convenient route to high area, nanoparticulate TiO2 photoelectrodes suitable for high-efficiency energy conversion in dye-sensitized solar cells. AB - Ethanol-soluble amphiphilic TiO(2) nanoparticles (NPs) of average diameter ~9 nm were synthesized, and an alpha-terpineol-based TiO(2) paste was readily prepared from them in comparatively few steps. When used for fabrication of photoelectrodes for dye-sensitized solar cells (DSSCs), the paste yielded highly transparent films and possessing greater-than-typical, thickness-normalized surface areas. These film properties enabled the corresponding DSSCs to produce high photocurrent densities (17.7 mA cm(-2)) and a comparatively high overall light-to-electrical energy conversion efficiency (9.6%) when deployed with the well-known ruthenium-based molecular dye, N719. These efficiencies are about ~1.4 times greater than those obtained from DSSCs containing photoelectrodes derived from a standard commercial source of TiO(2) paste. PMID- 21250742 TI - Long-lived antibubbles: stable antibubbles through Pickering stabilization. AB - Antibubbles, which are liquid droplets surrounded by a thin shell of gas in a liquid phase, have several promising applications, among which is encapsulation. A major hurdle toward these applications has hitherto been the inherent instability of antibubbles, leading to lifetimes of at most minutes. Here we show the production of antibubbles with a lifetime of at least tens of hours, with their stability stemming from the adsorption of colloidal particles at gas-water interfaces. Antibubbles were produced by coating aqueous droplets with hydrophobic colloidal particles, gelling the droplets, and then dropping them into an aqueous colloidal suspension. This resulted in the formation of antibubbles with a long lifetime, also after the melting of the gel. PMID- 21250743 TI - Ionization behavior of amino lipids for siRNA delivery: determination of ionization constants, SAR, and the impact of lipid pKa on cationic lipid biomembrane interactions. AB - Ionizable amino lipids are being pursued as an important class of materials for delivering small interfering RNA (siRNA) therapeutics, and research is being conducted to elucidate the structure-activity relationships (SAR) of these lipids. The pK(a) of cationic lipid headgroups is one of the critical physiochemical properties of interest due to the strong impact of lipid ionization on the assembly and performance of these lipids. This research focused on developing approaches that permit the rapid determination of the relevant pK(a) of the ionizable amino lipids. Two distinct approaches were investigated: (1) potentiometric titration of amino lipids dissolved in neutral surfactant micelles; and (2) pH-dependent partitioning of a fluorescent dye to cationic liposomes formulated from amino lipids. Using the approaches developed here, the pK(a) values of cationic lipids with distinct headgroups were measured and found to be significantly lower than calculated values. It was also found that lipid lipid interaction has a strong impact on the pK(a) values of lipids. Lysis of model biomembranes by cationic lipids was used to evaluate the impact of lipid pK(a) on the interaction between cationic lipids and cell membranes. It was found that cationic lipid-biomembrane interaction depends strongly on lipid pK(a) and solution pH, and this interaction is much stronger when amino lipids are highly charged. The presence of an optimal pK(a) range of ionizable amino lipids for siRNA delivery was suggested based on these results. The pK(a) methods reported here can be used to support the SAR screen of cationic lipids for siRNA delivery, and the information revealed through studying the impact of pK(a) on the interaction between cationic lipids and cell membranes will contribute significantly to the design of more efficient siRNA delivery vehicles. PMID- 21250744 TI - Obtaining charge distributions on geometrically generic nanostructures using scanning force microscopy. AB - We develop the self-consistent sum of dipoles (SCSD) theory for the purpose of recovering charge densities present on nanostructures using scanning force microscope (SFM) force-separation experiments. The dielectric probe is discretized into volume elements characterized by their atomic polarizabilities. Magnitudes of the induced dipole in each element are calculated based on discrete charges placed on the surfaces, dipole-dipole interactions, and dielectric and ionic properties of the surrounding medium. We perform two model-model comparisons, one with a macroscopic dielectric sphere and one with a nanocluster of silicon atoms. In both cases, using a single adjustable parameter, our SCSD theory agrees with the accepted theories to better than 99%. Force-separation curves between a silicon nitride probe and the basal plane of highly oriented pyrolytic graphite in nine ionic concentration and pH combinations were fit with a root-mean-square error of 3.6 pN, an improvement over the 12 pN error obtained using the Derjaguin approximation. These results suggest that the SCSD will be useful in modeling SFM force-separation data to obtain spatially varying charge densities on surfaces with complex geometries. PMID- 21250745 TI - Surface tension gradient driven spreading on aqueous mucin solutions: a possible route to enhanced pulmonary drug delivery. AB - Surface tension gradient driven, or "Marangoni", flow can be used to move exogenous fluid, either surfactant dispersions or drug carrying formulations, through the lung. In this paper, we investigate the spreading of aqueous solutions of water-soluble surfactants over entangled, aqueous mucin solutions that mimic the airway surface liquid of the lung. We measure the movement of the formulation by incorporating dyes into the formulation while we measure surface flows of the mucin solution subphase using tracer particles. Surface tension forces and/or Marangoni stresses initiate a convective spreading flow over this rheologically complex subphase. As expected, when the concentration of surfactant is reduced until its surface tension is above that of the mucin solution, the convective spreading does not occur. The convective spreading front moves ahead of the drop containing the formulation. Convective spreading ends with the solution confined to a well-defined static area which must be governed by a surface tension balance. Further motion of the spread solution progresses by much slower diffusive processes. Spreading behaviors are qualitatively similar for formulations based on anionic, cationic, or nonionic surfactants, containing either hydrophilic or hydrophobic dyes, on mucin as well as on other entangled aqueous polymer solution subphases. This independence of qualitative spreading behaviors from the chemistry of the surfactant and subphase indicates that there is little chemical interaction between the formulation and the subphase during the spreading process. The spreading and final solution distributions are controlled by capillary and hydrodynamic phenomena and not by specific chemical interactions among the components of the system. It is suggested that capillary forces and Marangoni flows driven by soluble surfactants may thereby enhance the uniformity of drug delivery to diseased lungs. PMID- 21250747 TI - Optomechanical transduction of an integrated silicon cantilever probe using a microdisk resonator. AB - Sensitive transduction of the motion of a microscale cantilever is central to many applications in mass, force, magnetic resonance, and displacement sensing. Reducing cantilever size to nanoscale dimensions can improve the bandwidth and sensitivity of techniques like atomic force microscopy, but current optical transduction methods suffer when the cantilever is small compared to the achievable spot size. Here, we demonstrate sensitive optical transduction in a monolithic cavity-optomechanical system in which a subpicogram silicon cantilever with a sharp probe tip is separated from a microdisk optical resonator by a nanoscale gap. High quality factor (Q ~ 10(5)) microdisk optical modes transduce the cantilever's megahertz frequency thermally driven vibrations with a displacement sensitivity of ~4.4 * 10(-16) m/(Hz)(1/2) and bandwidth >1 GHz, and a dynamic range >10(6) is estimated for a 1 s measurement. Optically induced stiffening due to the strong optomechanical interaction is observed, and engineering of probe dynamics through cantilever design and electrostatic actuation is illustrated. PMID- 21250746 TI - Suppression of melanoma growth and metastasis by DNA vaccination using an ultrasound-responsive and mannose-modified gene carrier. AB - DNA vaccination has attracted much attention as a promising therapy for the prevention of metastasis and relapse of malignant tumors, especially highly metastatic tumors such as melanoma. However, it is difficult to achieve a potent cancer vaccine effect by DNA vaccination, since the number of dendritic cells, which are the major targeted cells of DNA vaccination, is very few. Here, we developed a DNA vaccination for metastatic and relapsed melanoma by ultrasound (US)-responsive and antigen presenting cell (APC)-selective gene carriers reported previously, named Man-PEG2000 bubble lipoplexes. Following immunization using US exposure and Man-PEG(2000) bubble lipoplexes constructed with pUb-M, which expresses ubiquitylated melanoma-specific antigens (gp100 and TRP-2), the secretion of Th1 cytokines (IFN-gamma and TNF-alpha) and the activities of cytotoxic T lymphocytes (CTLs) were specifically enhanced in the presence of B16BL6 melanoma antigens. Moreover, we succeeded in obtaining potent and sustained DNA vaccine effects against solid and metastatic tumor derived from B16BL6 melanoma specifically. The findings obtained from this study suggest that the gene transfection method using Man-PEG2000 bubble lipoplexes and US exposure could be suitable for DNA vaccination aimed at the prevention of metastatic and relapsed cancer. PMID- 21250748 TI - Electrophilic carbocyclization of aryl propargylic alcohols: a facile synthesis of diiodinated carbocycles and heterocycles. AB - Diiodinated carbocycles and oxygen heterocycles can be readily synthesized by electrophilic carbocyclization of aryl propargylic alcohols in moderate to good yields under mild conditions. The resulting diiodide can be further exploited by subsequent oxidizing and coupling reactions. Both the iodine anion and cation generated from I(2) are used effectively. The presence of a trace amount of water is essential for this electrophilic cyclization. PMID- 21250749 TI - Enantioselective palladium-catalyzed carbozincation of cyclopropenes. AB - A highly enantioselective palladium-catalyzed carbozincation of cyclopropenes has been developed. The intermediate cyclopropylzinc species, after transmetalation with copper, were trapped with various electrophiles. This one-pot procedure furnished functionalizied cyclopropenes with excellent diastereo- and enantioselectivity. PMID- 21250750 TI - Palladium-catalyzed tandem fluorination and cyclization of enynes. AB - A novel palladium-catalyzed tandem fluorination and cyclization of enynes has been developed. A favorable cis-fluoropalladation is proposed as a key step to construct a vinyl-F bond, and the final C(sp3)-Pd bond is reduced by alcohol. This transformation represents an efficient road to synthesize fluorinated lactams. PMID- 21250751 TI - New thermally stable piezofluorochromic aggregation-induced emission compounds. AB - New piezofluorochromic compounds with high thermal stabilities and aggregation induced emission behavior were developed. The spectroscopic properties and morphological structures of these compounds were reversed upon pressing (or grinding)/annealing (or fuming). The switchable color change feature and aggregation-induced emission make the compounds promising candidates for optical recording, pressure-sensing, and light-emitting systems. PMID- 21250752 TI - Atropisomerism observed in indometacin derivatives. AB - To elucidate the active conformation of indometacin that differentiates between cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), the stereochemistry around the N-benzoylated indole moiety of indometacin was studied. Resolution of stable atropisomers as representative conformations was found to be possible by restricting rotation about the N-C7' and/or C7'-C1' bond. Only the aR-isomer showed specific inhibition of COX-1, and COX-2 was not inhibited by either atropisomer. PMID- 21250753 TI - Fast and flexible synthesis of pantothenic acid and CJ-15,801. AB - The fast and efficient syntheses of pantothenic acid and the antiparasitic agent CJ-15,801 have been achieved starting from a common imide unit through the selective manipulation of enamide intermediates. PMID- 21250754 TI - Endo-selective enyne ring-closing metathesis promoted by stereogenic-at-W mono pyrrolide complexes. AB - The utility of W-alkylidene complexes for enyne ring-closing metathesis is demonstrated in a direct comparison with Mo-based analogs. Tungsten complexes lead to less alkyne oligomerization and higher levels of endo-selectivity and enantioselectivity. PMID- 21250755 TI - Stereoselective synthesis of 2,6-cis- and 2,6-trans-piperidines through organocatalytic aza-Michael reactions: a facile synthesis of (+)-myrtine and (-) epimyrtine. AB - Both 2,6-cis- and 2,6-trans-piperidines were prepared from common substrates through organocatalytic aza-Michael reactions promoted by the gem-disubstituent effect in conjunction with dithiane coupling reactions. The organocatalytic aza Michael reaction enabled a facile synthesis of (+)-myrtine and (-)-epimyrtine from a common substrate. PMID- 21250756 TI - Improvement of the enediyne antitumor antibiotic C-1027 production by manipulating its biosynthetic pathway regulation in Streptomyces globisporus. AB - The production of C-1027 in Streptomyces globisporus was previously increased 2- to 3-fold by manipulating three pathway-specific activators, SgcR1, SgcR2, and SgcR3. In this study, we have further characterized two putative C-1027 regulatory genes, sgcE1 and sgcR, by in vivo inactivation. The HxlR family DNA binding protein SgcE1 was not essential for C-1027 biosynthesis, since inactivation of sgcE1 showed no effect on C-1027 production. In contrast, the proposed repressive role of the sgcR gene was confirmed by a 3-fold increase in C 1027 production in the DeltasgcR mutant S. globisporus SB1022 strain relative to the wild-type strain. Considering SgcR shows no significant similarity to any protein of known function, it may be representative of a new family of regulatory proteins. Finally, overexpression of the previously characterized activator sgcR1 in S. globisporus SB1022 increased the C-1027 yield to 37.5 +/- 7.7 mg/L, which is about 7-fold higher than the wild-type strain. PMID- 21250757 TI - N-rich salts of 2-methyl-5-nitraminotetrazole: secondary explosives with low sensitivities. AB - 2-Methyl-5-nitraminotetrazole (1) was formed by nitration of 2-methyl-5 aminotetrazole. 2-Methyl-5-aminotetrazole was obtained by an improved synthesis starting from sodium 5-aminotetrazolate, which is methylated with dimethyl sulfate in dimethyl formamide giving 2-methyl-5-aminotetrazole in 29% yield. Nitrogen-rich salts such as guanidinium (2), 1-aminoguanidinium (3), 1,3-diamino guanidinium (4), 1,3,5-triamino-guanidinium (5), azidoformamidinium (6), hydrazinium (7), diaminouronium 2-methyl-5-nitraminotetrazolate (8), as well as an urea adduct (9), were prepared by facile deprotonation or metathesis reactions. Diaminourea was synthesized by hydrazinolysis of dimethyl carbonate with hydrazine hydrate. All compounds were fully characterized by vibrational spectroscopy (IR and Raman), multinuclear NMR spectroscopy, elemental analysis, and differential scanning calorimetry (DSC) measurements. The crystal structures of 2-6, 8, and 9 could be determined using single crystal X-ray diffraction. The heats of formation of 2-9 were calculated using the atomization method based on CBS-4M enthalpies. With these values and the experimental (X-ray) densities several detonation parameters such as the detonation pressure, velocity, energy, and temperature were computed using the EXPLO5 code. In addition, the sensitivities toward impact, friction, and electrical discharge were tested using the BAM drop hammer, BAM friction tester, as well as a small scale electrical discharge device. PMID- 21250758 TI - Ca14Au46Sn5: a "colored" Gd14Ag51-type structure containing columns of well differentiated hexagonal gold stars. AB - A novel hexagonal phase discovered near the Ca(15)Au(60)Sn(25) quasicrystal and its cubic approximants (ACs) was synthesized by means of high-temperature solid state reactions. Single-crystal structural analyses show that this is a Gd(14)Ag(51) isotype with composition within the range Ca(14)Au(45.56(4) 46.67(4))Sn(5.14(3)-4.14(3)), space group P6/m (No. 175), and lattice parameters a = 12.763(3)-12.879(3) A and c = 9.326(3)-9.3815(4) A. In this phase, Sn mixes with Au in two of seven anionic sites to give a strong coloring that generates a narrow honeycomb-like Au/Sn template, in which sizable columns of hexagonal Au stars are confined. This phase transforms into the cubic 2/1 AC phase through a peritectic reaction at ~678 degrees C. The valence electron count per atom (e/a) of the present phase is in the range 1.41-1.45. However, it does not appear to follow a Hume-Rothery mechanism. PMID- 21250759 TI - Cost effectiveness of pneumococcal conjugate vaccination against acute otitis media in children: a review. AB - While pneumococcal conjugate vaccines have shown to be highly effective against invasive pneumococcal disease, their potential effectiveness against acute otitis media (AOM) might become a major economic driver for implementing these vaccines in national immunization programmes. However, the relationship between the costs and benefits of available vaccines remains a controversial topic. Our objective is to systematically review the literature on the cost effectiveness of pneumococcal conjugate vaccination against AOM in children. We searched PubMed, Cochrane and the Centre for Reviews and Dissemination databases (Database of Abstracts of Reviews of Effects [DARE], NHS Economic Evaluation Database [NHS EED] and Health Technology Assessment database [HTA]) from inception until 18 February 2010. We used the following keywords with their synonyms: 'otitis media', 'children', 'cost-effectiveness', 'costs' and 'vaccine'. Costs per AOM episode averted were calculated based on the information in this literature. A total of 21 studies evaluating the cost effectiveness of pneumococcal conjugate vaccines were included. The quality of the included studies was moderate to good. The cost per AOM episode averted varied from &U20AC;168 to &U20AC;4214, and assumed incidence rates varied from 20,952 to 118,000 per 100,000 children aged 0 10 years. Assumptions regarding direct and indirect costs varied between studies. The assumed vaccine efficacy of the 7-valent pneumococcal CRM197-conjugate vaccine was mainly adopted from two trials, which reported 6-8% efficacy. However, some studies assumed additional effects such as herd immunity or only took into account AOM episodes caused by serotypes included in the vaccine, which resulted in efficacy rates varying from 12% to 57%. Costs per AOM episode averted were inversely related to the assumed incidence rates of AOM and to the estimated costs per AOM episode. The median costs per AOM episode averted tended to be lower in industry-sponsored studies. Key assumptions regarding the incidence and costs of AOM episodes have major implications for the estimated cost effectiveness of pneumococcal conjugate vaccination against AOM. Uniform methods for estimating direct and indirect costs of AOM should be agreed upon to reliably compare the cost effectiveness of available and future pneumococcal vaccines against AOM. PMID- 21250761 TI - Extended cycles with the combined oral contraceptive chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg: pooled analysis of data from three large-scale, non interventional, observational studies. AB - BACKGROUND AND OBJECTIVE: The prescribing of extended regimens of oral contraceptives (OCs) is increasing in routine gynaecological practice as a means of reducing the number of annual menstrual bleeds. Typically, this involves taking one pill per day for, say, 84 days continuously (4*21 days), followed by a 7-day pill-free interval. Low-dose OCs are suitable for extended use, and many gynaecologists in Germany prescribe the combination of chlormadinone acetate 2 mg/ethinylestradiol 0.03 mg (CMA 2 mg/EE 0.03 mg). The aim of the current study was to assess the risks and benefits of CMA 2 mg/EE 0.03 mg in extended regimens, using pooled data from observational studies. METHODS: This pooled analysis of three large-scale, non-interventional, observational studies assessed the results in women receiving Belara(r) (CMA 2 mg/EE 0.03 mg) according to an extended regimen compared with conventional regimens documented in the summary of product characteristics. RESULTS: A total of 625 women were identified as extended regimen users (mean+/-SD age 24.9+/-9.0 years). Extended-cycle use was associated with decreases in skin problems, dysmenorrhoea symptoms (as shown by reductions in analgesic use; absence from school, university, or work; and restrictions in leisure and sporting activities), cycle-dependent symptoms (e.g. headache/migraine, breast tenderness), withdrawal bleeding, bleeding duration and reduced libido. Mean bodyweight remained almost constant over 6 months. Only nine adverse drug reactions, none severe, were reported in eight women (1.3%). CONCLUSION: This pooled analysis confirms that extended regimens of CMA 2 mg/EE 0.03 mg reduce cycle-related complaints and are very well tolerated. PMID- 21250760 TI - An appraisal of PCR-based technology in the detection of Mycobacterium tuberculosis. AB - Tuberculosis is an under-recognized yet catastrophic health problem, particularly in developing countries. The HIV pandemic has served to increase the number of susceptible individuals, and multidrug-resistance and poor socioeconomic conditions also augment the prevalence and the consequences of the disease. To control the disease and its spread, it is vital that tuberculosis diagnostics are accurate and rapid. Whereas microscopy and culture have several limitations (low sensitivity is a problem for the former, while the latter has a delayed turnaround time), PCR-based techniques targeting regions of the Mycobacterium tuberculosis genome such as IS6110 have proved to be useful. The purpose of this review is to assess the use of PCR-RFLP, nested PCR and real-time PCR protocols and the choice of target regions for the detection of M. tuberculosis. Real-time PCR for the detection of M. tuberculosis target genes in clinical specimens has contributed to improving diagnosis and epidemiologic surveillance in the past decade. However, targeting one genome sequence such as IS6110 may not by itself be sufficiently sensitive to reach 100% diagnosis, especially in the case of pulmonary tuberculosis. Additional testing for target genome sequences such as hsp65 seems encouraging. An interesting approach would be a multiplex real-time PCR targeting both IS6110 and hsp65 to achieve comprehensive and specific molecular diagnosis. This technology needs development and adequate field testing before it becomes the acceptable gold standard for diagnosis. PMID- 21250763 TI - Polypharmacy, aging and potential drug-drug interactions in outpatients in Taiwan: a retrospective computerized screening study. AB - BACKGROUND: Polypharmacy is common in outpatients and has been identified as a major risk factor for drug-drug interactions (DDIs), which are an important cause of adverse drug reactions. There has been a rapid increase in the number of elderly patients worldwide. However, there have been few studies quantifying the impact of both patient age and the number of concomitant drugs prescribed on the probability of potential DDIs per person in general outpatients. OBJECTIVE: To assess the extent to which polypharmacy and aging are associated with potential DDIs in outpatients at a medical centre in Taiwan. METHODS: The medications of 81,650 outpatients who visited a medical centre in Taiwan between January 2004 and March 2004 were retrospectively screened for potential DDIs using a computerized drug-interaction program. The main inclusion criteria were a minimum of two drug prescriptions and duration of use of 14 or more days. We also analysed the DDI pattern, which included severity, level of documentation and onset of potential DDIs, and assessed the impact of the number of drugs prescribed and of aging on the prevalence of potential DDIs per person. RESULTS: The prevalence of potential DDIs was 25.6% (20,902 of 81,650). The mean +/- SD age of the 20,902 patients with potential DDIs was 57.5 +/- 16.5 years, and 47.6% of these patients were male. The mean +/- SD number of prescribed drugs in patients with potential DDIs was 5.8 +/- 2.4, and 67.7% of these patients were prescribed more than four drugs. The majority (55.7%) of DDIs were of the C2 pattern (severity: moderate; documentation: probable). The prevalence of potential DDIs increased in a linear mode with increasing age (p < 0.001) and with the number of drugs prescribed (p < 0.001); furthermore, in addition to being independently associated with potential DDIs, these two factors interacted to increase the risk further. CONCLUSIONS: This study showed that approximately one-quarter of 81,650 outpatients who visited a medical centre in Taiwan over a period of 3 months in 2004 had potential DDIs. We observed independent increases in potential DDIs per person in association with aging and increasing number of prescribed drugs. Furthermore, a significant interaction between these two factors was observed: the effect of aging on the prevalence of potential DDIs increased as the number of prescribed drugs increased. Potential DDIs in outpatients can be reduced by minimizing the number of drugs prescribed following careful consideration of both their benefits and risks, particularly in the aging population. PMID- 21250762 TI - Effect of memantine on resting state default mode network activity in Alzheimer's disease. AB - BACKGROUND: Memantine is an approved symptomatic treatment for moderate to severe Alzheimer's disease that reduces the excitotoxic effects of hyperactive glutamatergic transmission. However, the exact mechanism of the effect of memantine in Alzheimer's disease patients is poorly understood. Importantly, the default mode network (DMN), which plays a key role in attention, is hypoactive in Alzheimer's disease and is under glutamatergic control. OBJECTIVE: To assess the effect of memantine on the activity of the DMN in moderate to severe Alzheimer's disease. METHODS: Functional magnetic resonance imaging (MRI) data from 15 patients with moderate to severe Alzheimer's disease, seven treated with memantine (mean +/- SD age 77 +/- 8 years, mean +/- SD Mini-Mental State Examination [MMSE] score 16 +/- 5) and eight with placebo (mean +/- SD age 76 +/- 6 years, mean +/- SD MMSE score 13 +/- 1), were acquired at baseline (T0) and after 6 months of treatment (T6). Resting state components were extracted after spatial normalization in individual patients with independent component analysis. The consistency of the components was assessed using ICASSO and the DMN was recognized through spatial correlation with a pre-defined template. Voxel-based statistical analyses were performed to study the change in DMN activity from T0 to T6 in the two groups. RESULTS: At T0, the two groups showed similar DMN activity except in the precuneus and cuneus, where the patients who started treatment with memantine had slightly greater activity (p < 0.05 corrected for familywise error [FWE]). The prospective comparison between T0 and T6 in the treated patients showed increased DMN activation mapping in the precuneus (p < 0.05, FWE corrected), while the prospective comparison in the untreated patients did not show significant changes. The treatment * time interaction term was significant at p < 0.05, FWE corrected. CONCLUSIONS: The results suggest a positive effect of memantine treatment in patients with moderate to severe Alzheimer's disease, resulting in an increased resting DMN activity in the precuneus region over 6 months. Future studies confirming the present findings are required to further demonstrate the beneficial effects of memantine on the DMN in Alzheimer's disease. PMID- 21250764 TI - Special care dentistry: Midazolam conscious sedation for patients with neurological diseases. AB - AIM: Midazolam is used very often to control the anxiety of patients for dental treatment, especially in patients with special needs. The objective of this study was to evaluate the efficiency of Midazolam in patients with neurological diseases referred for dental treatment. STUDY DESIGN: Descriptive study. MATERIALS AND METHODS: Forty consecutive patients with neurological disorders (encephalopathy, autism, and epilepsy) were referred to dental treatment, and 45 sedations were performed; all were sedated with Midazolam (intramuscular 0.2-0.3 mg/kg or intravenous 0.1mg/kg) and all were anesthetised with lidocaine 2% (0.5-2 mL). During the dental procedure, their behavior was analysed and classified into 3 categories: A (indifferent), B (reacted but allowed treatment), and C (did not allow treatment). Data were tabbed and statistically analysed. RESULTS: The final patients' classification was: A 22 (49%), B 18 (40%) and C 5 (11%); the patients with encephalopathy had the best results of sedation according to the proposed classification (p<0.05). CONCLUSION: Midazolam demonstrated to be effective in 89% of this sample for dental procedures in patients with neurological and behavioral disturbances, but it was less effective for patients with autism (p<0.05). PMID- 21250765 TI - Factors related to dental caries in adolescents in southeastern Brazil. AB - AIM: Identify the experience of dental caries among adolescents associated to work, self-care, social life and access to healthcare services. MATERIALS AND METHODS: This cross-sectional study was carried out with 60 adolescents aged 15 and 16 years in a city in southeastern Brazil. The data were collected through a structured interview and clinical exam for dental caries carried out by a single, duly calibrated examiner (Kappa=0.8 to 0.9). The relationships between the dependent variable (experience of dental caries) and independent variables (work, self-care, social life and access to healthcare services) was determined using bivariate (chi square test, p<0.10) and multivariate analysis (p<0.25). RESULTS: Eighty percent had two or more teeth with caries (95% CI: 70.0-90.0). Mean DMFT was 4.72 (+/- 3.55) and DMFS was 8.07 (+/- 7.46). When the experience of caries was related to the independent variables, only access to healthcare services achieved statistical significance. Individuals with greater access had a threefold greater chance of belonging to the group with a lesser experience with caries, PR=3.2 (90% CI 1.07-9.78). CONCLUSION: All interviewees reported seeking care in the private system when requiring dental assistance. Access to healthcare (declared as essentially private) was associated to dental caries. PMID- 21250766 TI - Growth indicators in orthodontic patients. Part 1: comparison of cervical vertebral maturation and hand-wrist skeletal maturation. AB - AIM: The purpose of this study was to predict the skeletal maturation status based on the assessment of cervical vertebrae from lateral cephalometric radiographs and to compare these findings with the skeletal maturity of the same individuals judged from the hand-wrist radiographs. MATERIALS AND METHODS: Lateral cephalometric and left hand-wrist radiographs of 393 Caucasian children from 8 to 18 years old were evaluated. On the hand-wrist radiographs the classification of Bjork [1972] and Grave and Brown [1976] was used to assess skeletal maturity (HWSS). Cervical vertebral maturation was also evaluated on lateral cephalometric radiographs using the improved CVMS method described by Baccetti, Franchi, and McNamara [2002]. These methods were correlated using the chi-square test. RESULTS: The chi-square test showed that skeletal maturational values obtained by the CVMS method were significantly correlated with the skeletal values obtained from the hand-wrist analysis for both genders (p<0.05). However, gender differentiation exists in CVMS method regarding the peak of growth spurt. CONCLUSION: The results of this study show that the CVMS method was compatible with a commonly used hand-wrist analysis method. The lateral cephalometric radiograph belonging to the standard set of records would be sufficient to evaluate skeletal maturity. PMID- 21250767 TI - Growth indicators in orthodontic patients. Part 2: comparison of cervical bone age to hand-wrist skeletal age. Relationship with chronological age. AB - AIM: The purpose of this study was to investigate the relationship between hand wrist skeletal age, chronological age and cervical skeletal age as assessed by lateral cephalometric radiograph. MATERIALS AND METHODS: Lateral cephalometric and left hand-wrist radiographs of 393 Caucasian children from 8 to 18 years old were evaluated. On the hand-wrist radiographs average values of the children's skeletal age as described by Schopf (1978), based on the classification of Bjork (1972), Grave and Brown (1976) were used. Cervical vertebral bone age also was depicted, using the method described by Mito, Sato, and Mitani. Pearson correlation coefficients (r) and regression analysis were calculated to assess the linear relationship between chronological, cervical bone and hand-wrist skeletal age. RESULTS: The cervical skeletal age correlated significantly with both the chronological and the hand-wrist skeletal age for each gender. However, the correlation coefficient between cervical skeletal age and hand-wrist skeletal age for both females (r 0.81) and males (0.76) is higher than that between cervical skeletal age and chronological age (females r 0.73; males r 0.72). In addition, regression analysis indicates that the relationship between cervical skeletal age and hand-wrist skeletal age is stronger than the relationship between cervical skeletal age and chronological age for both sexes. CONCLUSION: Cervical skeletal age reflects skeletal status because it can approximate hand wrist skeletal age, which is considered to be the most reliable method for measuring the degree of maturity. PMID- 21250768 TI - Early childhood caries and oral rehabilitation. A treatment quandary. AB - BACKGROUND: Early childhood caries (ECC) is a virulent form of dental caries that can destroy the primary dentition of toddlers and preschool children. It occurs worldwide, afflicting predominantly disadvantaged children. Although Streptococcus mutans is the most likely causative agent, diet also plays a critical role in the acquisition and clinical expression of this infection. Early acquisition of S. mutans via vertical or horizontal transmission is a key event in the natural history of the disease that coupled with caries promoting feeding behaviours results in accumulation of these organisms to levels exceeding 30% of the total cultivable plaque flora, which in turn leads to rapid demineralization of the tooth structure. Inflicted children may also have other associated health problems, ranging from local infections to oral pain that manifest as difficulty in eating and sleeping, reduced growth and altered behaviour. Oral rehabilitation usually consists of restoration or surgical removal of carious teeth along with recommendations regarding feeding habits. Although treatment can be instituted in the dental clinic, it becomes costly sometimes when cooperative capacity of babies and preschool children necessitates the use of general anaesthesia. Primary prevention of ECC has largely been restricted to counselling parents regarding proper feeding behaviour, oral hygiene measures and new strategies that address the infectious component through use of topical antimicrobial therapy in order to defeat this common oral affliction. PMID- 21250769 TI - Survey of mesiodens and its characteristics in 2500 children of Davangere city, India. AB - AIM: The aim of the present study is to report the prevalence of mesiodens and its characteristics and also to present 25 cases with 27 mesiodentes in 2500 children in Davangere city, India. MATERIALS AND METHODS: A survey of 2500 children examined in the Department of Paediatric Dentistry was conducted. Their ages ranged from 3 to 12 years. A total of 27 mesiodentes were diagnosed in 25 patients (1%). The patients' records and radiographs were evaluated and the following variables were studied: age and sex distribution, number, shape, position, eruption status, associated dentition and arch, associated complications and anomalies. RESULTS: In this study were enrolled 16 males and 9 females: 96.2% of the mesiodentes were seen in the maxillary arch while only one in the mandibular arch; 92.5% were observed in the permanent dentition. Most mesiodentes (92.5%) were conical in shape, and about 96.2% were placed vertical in position with only one mesiodens impacted and inverted. Of the 27 mesiodentes, 23 were u%% caused a midline diastema, 14.8% occlusal interference, 7.4% root resorption, and 3.7% had caused delayed eruption of permanent incisors. Rare anomalies like facial talon cusp were found in two mesiodentes (7.4%), and only one (3.7%) had a root anomaly. CONCLUSION: Mesiodens may occur as an isolated finding or can be associated with other odontogenic anomalies. PMID- 21250770 TI - Sleep-disordered breathing in a sample of 495 children in Southern Italy. AB - AIM: Our objective was to investigate the occurrence of sleep-related breathing disturbances in a large cohort of school-aged children in Southern Italy, and to evaluate the association with anthropometric data and clinical findings of oropharynx and nasal airways. STUDY DESIGN: A two-phase cross-sectional study was conducted with children from schools in Turi, Italy. MATERIALS AND METHODS: A screening phase aimed to identify symptomatic children and clinical data from a cohort of 495 children by a self-administered questionnaire, and an instrumental phase for the definition of sleep-related disorders and clinical analysis of oral status were performed. According to the answers, children were classified into 3 groups: habitual snorers, occasional snorers, and non-snorers. All habitual snoring children underwent a polysomnographic home evaluation, and those with oxygen desaturation index (ODI) > 2 were considered for nocturnal polygraphic monitoring (NPM). Children with apnoea/ hypopnea index (AHI) > 3 received a diagnosis of obstructive sleep apnoea syndrome (OSAS). Moreover, a complete oral examination was performed. RESULTS: A total of 436 questionnaires (response rate: 88.08%) were returned and scored (202 M, 234 F; Mean age +/- Standard deviation: 6.2 +/- 1.8); 18 children (4%) were identified as habitual snorers, 140 children (32%) were identified as occasional snorers, and 278 children (64%) were identified as non-snorers. The percentage of female children who were habitual snorers was higher than the percentage of male children (4.7% vs 3.6%). Habitual snorers had significantly more nighttime symptoms. OSAS was diagnosed in 2 children by NPM. A statistically significant association between snoring, cross bite, open-bite and increased over-jet was found. CONCLUSION: Habitual snoring and OSAS are significant problems for children and may be associated with diurnal symptoms. The presence of malocclusion increases the likelihood of sleep-related breathing disturbances. PMID- 21250771 TI - The relationship between aging and oral health inequalities assessed by the DMFT index. AB - AIM: A cross-sectional study to determine the caries experience characteristics and their relationship with aging. MATERIALS AND METHODS: Using stratified sampling method, 748 subjects divided into 3 age groups of 11-14, 14-17 and 17-20 year-olds (355 females and 393 males, aged 15.11 +/- 2.23 years) were examined in urban area of Isfahan (Iran). The DMFT scores (DT, MT, FT) were recorded. The Student t-test was used to assess any differences in the mean DMFT score between genders. Simple (DMFT >0), severe caries experience (DMFT >8), severe form of filling (FT>3), and decay (DT>6) were calculated. Chi-square tests were performed to assess any relationship between gender and DMFT variables. Binary logistic regression was used to estimate the predictive value of gender and age groups for the DMFT categories dichotomized into presence or absence of DMFT-related variable. Scatter plots and Spearman rank correlation coefficients were used to explore the relationships between the DMFT (DT, MT, FT) and participant's age. RESULTS: The mean DMFT values for the sample, 11-14, 14-17 and 17-20 year-olds were 4.94, 3.03, 5 and 6.66, respectively. Caries prevalence (DMFT >0) and active caries prevalence (DT >0) were 88.8% and 81.8%, respectively. Prevalence of active caries (DT) did not vary significantly between genders; however, prevalence of fillings (FT) was higher in females (OR 1.96, 95% CI, 1.45-2.67). The odds of experiencing caries (DMFT, DT, FT) increased with increase in participant's age. Prevalence of subjects with DT>6 was higher in males than in females (OR 1.50, 95% CI, 1.04-2.01). Prevalence of subjects with FT>3 was higher in females than in males (OR 1.74, 95% CI, 1.10-2.73). Significant positive correlations existed between the participant's age and DMFT (rho 0.40), DT (rho 0.34) and FT scores (rho 0.194), respectively. CONCLUSION: Caries experience was highly prevalent in our sample. With increase in age, there was an upward trend in caries prevalence and mean DMFT. PMID- 21250772 TI - Manual orthodontic vs. oscillating-rotating electric toothbrush in orthodontic patients: a randomised clinical trial. AB - AIM: To compare the efficacy of manual and oscillating-rotating electric toothbrushes in removing plaque and reducing gingivitis in patients with fixed orthodontic appliances. STUDY DESIGN: Randomised clinical trial. MATERIALS AND METHODS: 20 subjects aged 10 to 14 years (8 males; 12 females) scheduled for fixed orthodontic treatment were enrolled, randomly divided into two groups, A and B, and later assigned electric or manual toothbrushes, respectively. Three months after orthodontic appliance bonding (T1), and again after a further 4 (T2) and 8 (T3) weeks, plaque levels (PI), gingival bleeding (GBI) and hypertrophy were assessed. RESULTS: Between the two toothbrush types, statistically significant differences in PI were detected from T2 to T3 (P value 0.010), but not from T1 to T2. In contrast, the GBI was significantly different from T1 to T2 (P value 0.025), but not from T2 to T3. CONCLUSION: With respect to the manual orthodontic toothbrush, the electric oscillating-rotating toothbrush was found to better improve both PI and GBI. PMID- 21250773 TI - Parents' perceptions of oral health conditions depicted in photographs of anterior permanent teeth. AB - AIM: The aim of this study was to evaluate parents' perceptions of dental fluorosis and other oral health conditions depicted in photographs of anterior teeth. MATERIALS AND METHODS: The sample comprised 120 parents (average age 39.3 years) whose children were undergoing dental treatment at the School of Dentistry of the Federal University of Minas Gerais. Seven photographs were selected: P1, open bite; P2, dental fluorosis TF 1 associated with open bite; P3, dental fluorosis TF 1; P4, midline deviation and crowding; P5, dental hypoplasia; P6, teeth without oral problems; P7, dental fluorosis TF 3. All photographs were randomly shown to all the parents, who classified the conditions observed based on a numeric scale: 0-19 (very unsatisfactory), 20-39 (unsatisfactory), 40-59 (neutral), 60-79 satisfactory and 80-100 (very satisfactory). The reasons for dissatisfaction and the possible treatment choice were examined. RESULTS: P6 (normal teeth) was the most satisfactory photograph according to the parents (mean 61.2), and all photographs were statistically significantly different from one another (Mann-Whitney test, p <= 0.05), except the following pairs: P1 (mean 52.9) and P7 (mean 50.2) (p 0.537); P2 (mean 32.6) and P3 (mean 39.0) (p 0.073); and P5 (mean 18.9) and P4 (mean 18.4) (p 0.923). Alignment and crowding were considered the most prevalent problem in all cases (27.5 to 90.8% of parents) and orthodontic treatment was the most frequently cited option for treating all conditions (34.2 to 89.2% of parents). CONCLUSION: In general, parents were dissatisfied with the oral conditions depicted in all photographs. Midline deviation associated to crowding (P4) and dental hypoplasia (P5) were considered the most unsatisfactory conditions. The most frequently cited oral problems by the parents were alignment and crowding. Orthodontic treatment was considered the best option by the majority of parents. PMID- 21250774 TI - Effect on anterior temporalis surface EMG of eyes open-closed condition. AB - BACKGROUND: The use of rest surface EMG of jaw elevator muscles is still debated. The low voltage recorded in anterior temporalis muscle by electromyography (EMG) in rest position could be affected by electronic noise or by activity coming from other muscles. Our goal was to evaluate the physiological behaviour of the anterior temporalis by surface EMG at rest mandible position during open or closed eyes condition in healthy young subjects without both malocclusion and visual defect. MATERIALS AND METHODS: Surface EMG of anterior temporalis, masseter, digastric, sternomastoid muscle and mandible kinesiographic movement were recorded in 20 young, healthy individuals without both malocclusion and visual defect during open-closed eyes condition. RESULTS: No significant difference was found in surface EMG of anterior temporalis comparing eyes closed to eyes open condition. CONCLUSION: Physiology of open-closed eyes in healthy, young subjects without malocclusion or visual defect does not imply a change in surface EMG of anterior temporalis muscle. PMID- 21250775 TI - Auriculotemporal nerve syndrome in association with congenital haemangiopericytoma: a case report. AB - BACKGROUND: Auriculotemporal nerve syndrome is characterised by recurrent episodes of facial gustatory flushing and/or sweating along the cutaneous distribution of the auriculotemporal nerve. The condition is rare in children and is normally a sequel of perinatal birth trauma. We report a case of a sixteen month-old boy referred by paediatric oncology with recurrent, unilateral facial flushing of the left cheek which had been present for 2 months. The flushing only occurred during mastication. The patient had also received treatment for a rare vascular tumour, congenital haemangiopericytoma, of the left cheek and parotid region. The possible association between auriculotemporal nerve syndrome and congenital haemangiopericytoma is discussed. Knowledge of the presentation, aetiology and management of Auriculotemporal Nerve Syndrome can provide much needed reassurance to those suffering with this condition. PMID- 21250776 TI - Tooth replantation as an alternative to dental implantology in adolescent patients. AB - BACKGROUND: A 16-years old female patient was referred to our observation in July 2006, 14 days after an accident, with traumatic intrusive luxation of the right upper central incisor that caused the nasal floor and buccal cortical bone fracture. While the extraoral examination showed the traumatic lesions of the upper lip, the intraoral examination revealed intrusive luxation, pain and high mobility of the tooth, and bleeding of the adjacent oral tissue. The treatment protocol consisted in surgical buccal bone removal, tooth extraction, retrograde root-canal filling, and tooth repositioning in occlusion with a resilient splinting. After 8 weeks the splinting was removed, and clinical and radiological examinations were taken 3, 6, 9, 12, and 24 months after surgery. At the 24 months follow-up the root showed no radiographic signs of inflammation, resorption or ankylosis, and the function of the replanted tooth was fully maintained. Tooth replantation can be considered an effective alternative to dental implant, when the latter is contraindicated in young patient with incomplete skeletal development. The long-term success of the procedure will likely require a multidisciplinary approach. PMID- 21250777 TI - Neuroprotection of taurine against bilirubin-induced elevation of apoptosis and intracellular free calcium ion in vivo. AB - Previous work has shown that taurine protected neurons against unconjugated bilirubin (UCB)-induced neurotoxicity by preventing cell apoptosis and maintaining intracellular Ca2+ homeostasis in primary neuron culture. This study investigates the neurotoxicity of hyperbilirubinemia and neuroprotection of taurine in a clinically relevant murine model in vivo. A hyperbilirubinemia baby mice model was established by intraperitoneal injection with UCB. After 24 h, the neural apoptotic level, transcriptional activity of caspase-3, and iCa2+ concentration were detected. It was found that UCB injection significantly increased both intracellular free Ca2+ concentrations and the activities of proapoptosis protease caspase-3, which is related to the elevation of neural apoptosis level. When baby mice were pretreated with 7.5 or 15 mg/kg body weight (bw) taurine for 4 h and then exposed to UCB, apoptotic death was significantly attenuated through down-regulation of activity of caspase-3 and i[Ca2+] in the brain. From these observations, it was concluded that taurine limits bilirubin induced neural damage by inhibiting iCa2+ overload as well as decreasing activation of proapoptotic proteases caspase-3. This study might contribute to the development of taurine as a broad-spectrum agent for preventing and/or treating neural damage in neonatal jaundice. PMID- 21250778 TI - Soluble CD36- a marker of the (pathophysiological) role of CD36 in the metabolic syndrome? AB - CD36 is a class B scavenger receptor observed in many cell types and tissues throughout the body. Recent literature has implicated CD36 in the pathogenesis of metabolic dysregulation such as found in obesity, insulin resistance, and atherosclerosis. Genetic variation at the CD36 loci have been associated with obesity and lipid components of the metabolic syndrome, with risk of heart disease and type 2 diabetes. Recently, non-cell bound CD36 was identified in human plasma and was termed soluble CD36 (sCD36). In this review we will describe the functions of CD36 in tissues and address the role of sCD36 in the context of the metabolic syndrome. We will also highlight recent findings from human genetic studies looking at the CD36 locus in relation to metabolic profile in the general population. Finally, we present a model in which insulin resistance, oxLDL, low grade inflammation and liver steatosis may contribute to elevated levels of sCD36. PMID- 21250779 TI - Vanillic acid inhibits inflammatory mediators by suppressing NF-kappaB in lipopolysaccharide-stimulated mouse peritoneal macrophages. AB - Vanillic acid is a benzoic acid derivative that is used as a flavoring agent. It is an oxidized form of vanillin. At present, the mechanisms by which vanillic acid exerts its anti-inflammatory effects are incompletely understood. In this study, we attempted to determine the effects of vanillic acid on lipopolysaccharide (LPS)-induced inflammatory responses in mouse peritoneal macrophages. Our findings indicate that vanillic acid inhibits LPS-induced production of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6. During the inflammatory process, the levels of cyclooxygenase (COX)-2 and nitric oxide (NO) increased in mouse peritoneal macrophages, but vanillic acid suppressed both the enhanced levels of COX-2 and the production of prostaglandin E(2) and NO. Moreover, vanillic acid suppressed the activation of nuclear factor-kappa B (NF kappaB) and caspase-1. These results provide novel insights into the pharmacological actions of vanillic acid and are indicative of the potential use of this molecule in the treatment of inflammatory diseases. PMID- 21250782 TI - Probing bacterial pathogenesis with genetics, genomics, and chemical biology: past, present, and future approaches. AB - Classical genetic approaches for studying bacterial pathogenesis have provided a solid foundation for our current understanding of microbial physiology and the interactions between pathogen and host. During the past decade however, advances in several arenas have expanded the ways in which the biology of pathogens can be studied. This review discussed the impact of these advances on bacterial genetics, including the application of genomics and chemical biology to the study of pathogenesis. PMID- 21250783 TI - Bacterial phytochromes: more than meets the light. AB - Phytochromes are environmental sensors, historically thought of as red/far-red photoreceptors in plants. Their photoperception occurs through a covalently linked tetrapyrrole chromophore, which undergoes a light-dependent conformational change propagated through the protein to a variable output domain. The phytochrome composition is modular, typically consisting of a PAS-GAF-PHY architecture for the N-terminal photosensory core. A collection of three dimensional structures has uncovered key features, including an unusual figure-of eight knot, an extension reaching from the PHY domain to the chromophore-binding GAF domain, and a centrally located, long alpha-helix hypothesized to be crucial for intramolecular signaling. Continuing identification of phytochromes in microbial systems has expanded the assigned sensory abilities of this family out of the red and into the yellow, green, blue, and violet portions of the spectrum. Furthermore, phytochromes acting not as photoreceptors but as redox sensors have been recognized. In addition, architectures other than PAS-GAF-PHY are known, thus revealing phytochromes to be a varied group of sensory receptors evolved to utilize their modular design to perceive a signal and respond accordingly. This review focuses on the structures of bacterial phytochromes and implications for signal transmission. We also discuss the small but growing set of bacterial phytochromes for which a physiological function has been ascertained. PMID- 21250781 TI - Archaeal RNA polymerase and transcription regulation. AB - To elucidate the mechanism of transcription by cellular RNA polymerases (RNAPs), high-resolution X-ray crystal structures together with structure-guided biochemical, biophysical, and genetics studies are essential. The recently solved X-ray crystal structures of archaeal RNAP allow a structural comparison of the transcription machinery among all three domains of life. The archaea were once thought of closely related to bacteria, but they are now considered to be more closely related to the eukaryote at the molecular level than bacteria. According to these structures, the archaeal transcription apparatus, which includes RNAP and general transcription factors (GTFs), is similar to the eukaryotic transcription machinery. Yet, the transcription regulators, activators and repressors, encoded by archaeal genomes are closely related to bacterial factors. Therefore, archaeal transcription appears to possess an intriguing hybrid of eukaryotic-type transcription apparatus and bacterial-like regulatory mechanisms. Elucidating the transcription mechanism in archaea, which possesses a combination of bacterial and eukaryotic transcription mechanisms that are commonly regarded as separate and mutually exclusive, can provide data that will bring basic transcription mechanisms across all life forms. PMID- 21250784 TI - Schisandrin B elicits a glutathione antioxidant response and protects against apoptosis via the redox-sensitive ERK/Nrf2 pathway in AML12 hepatocytes. AB - Abstract This study examined the effects of (-)schisandrin B [(-)Sch B] on MAPK and Nrf2 activation and the subsequent induction of glutathione antioxidant response and cytoprotection against apoptosis in AML12 hepatocytes. Pharmacological tools, such as cytochrome P-450 (CYP) inhibitor, antioxidant, MAPK inhibitors and Nrf2 RNAi, were used to delineate the signalling pathway. ( )Sch B caused a time-dependent activation of MAPK in AML12 cells, particularly the ERK1/2. The MAPK activation was followed by an enhancement in Nrf2 nuclear translocation and the eliciting of a glutathione antioxidant response. Reactive oxygen species arising from a CYP-catalysed reaction with (-)Sch B seemed to be causally related to the activation of MAPK and Nrf2. ERK inhibition by U0126 or Nrf2 suppression by Nrf2 RNAi transfection almost completely abrogated the cytoprotection against menadione-induced apoptosis in (-)Sch B-pre-treated cells. (-)Sch B pre-treatment potentiated the menadione-induced ERK activation, whereas both p38 and JNK activations were suppressed. Under the condition of ERK inhibition, Sch B treatment did not protect against carbon tetrachloride hepatotoxicity in an in vivo mouse model. In conclusion, (-)Sch B triggers a redox-sensitive ERK/Nrf2 signalling, which then elicits a cellular glutathione antioxidant response and protects against oxidant-induced apoptosis in AML12 cells. PMID- 21250786 TI - Pharmacokinetic interaction between epsilon-acetamidocaproic acid (AACA) and cimetidine in indomethacin-induced acute gastric ulcer and control rats: inhibition of active renal secretion of AACA by cimetidine. AB - After both the intravenous and oral administration of zinc acexamate [ZAC; ion pairing between zinc and epsilon-acetamidocaproic acid (AACA)] and cimetidine together, the areas under the curve (AUCs) of AACA were significantly greater [by 28.2 and 98.9% after the intravenous and oral administration, respectively, for control rats and 13.5 and 16.9% for indomethacin-induced acute gastric ulcer (IAGU) rats, respectively] than those of ZAC alone due to the significantly slower renal clearance (CL(R)). The significantly greater AUCs of AACA after both the intravenous and oral administration of ZAC and cimetidine together in control and IAGU rats could have been due to the inhibition of active renal tubular secretion of AACA by cimetidine. After the intravenous and oral administration of both drugs together, the AUCs of cimetidine in control and IAGU rats were not different compared with those with cimetidine alone. PMID- 21250785 TI - Breast fine-needle aspiration malondialdehyde deoxyguanosine adduct in breast cancer. AB - This study has analysed the generation of 3-(2-deoxy-beta-D-erythro pentafuranosyl)pyrimido[1,2-alpha]purin-10(3H)-one deoxyguanosine adduct [M1dG], a biomarker of oxidative stress and lipid peroxidation, in breast fine-needle aspirate samples of 22 patients with breast cancer, at different clinical stages, in respect to 13 controls. The multivariate analysis show that M(1)dG adduct was higher in cases than in controls (Mean Ratio (MR) = 5.26, 95% CI = 3.16-8.77). Increased M1dG was observed in women with a tumour grade 3 and a pathological diameter 2 (MR = 7.61, 95% CI = 3.91-14.80 and MR = 5.75, 95% CI = 3.13-10.59, respectively). A trend with increasing tumour grade and pathological diameter was present (MR = 1.98, 95% CI = 1.57-2.50 and MR = 2.44, 95% CI = 1.71-3.48, respectively). Not significant effects of age and smoking habit were found (MR = 1.58, 95% CI = 0.92-2.72 and MR = 1.68, 95% CI 0.88-3.20, respectively). An increment over the background frequency of M1dG can contribute to breast cancer development. Increasing severity of breast tumour can influence DNA damage level. PMID- 21250787 TI - Periocular milia en plaque successfully treated by erbium:YAG laser ablation. AB - Milia en plaque in the periocular region represent a cosmetically disturbing skin condition of unknown origin characterized by numerous tiny milia grouped around the inner canthus and the medial aspect of both eyelids. While conservative treatment and manual expression often result in local recurrence, invasive approaches harbor the risk of mechanical or thermal injury of periocular skin and lid margins. A 32-year-old female patient with refractory periocular milia was treated with the erbium:YAG laser and followed-up for 12 months. Ablative laser treatment led to nearly complete resolution of the milia and an excellent clinical result. Importantly, no scarring, dyspigmentation or ocular complications were noted. This report demonstrates the efficacy and safety of erbium:YAG laser ablation of periocular milia. The precise control of tissue ablation with minimal thermal damage makes the erbium:YAG laser an ideal tool for the treatment of the delicate periocular region where even minimal scarring can result in ocular complications. PMID- 21250788 TI - A novel explanation for the healing effect of the Er:YAG laser during skin rejuvenation. AB - In the present short communication, we would like to suggest a possible mechanism for the healing effects exerted by the erbium:yttrium-aluminum-garnet (Er:YAG) laser with a wavelength of 2940 nm (which surprisingly is the exact vibrational OH stretch frequency of water). PMID- 21250789 TI - Topical application of growth factors after carbon dioxide fractional laser therapy: a randomized controlled split-face study. PMID- 21250790 TI - Concurrent structural fat grafting and carbon dioxide laser resurfacing for perioral and lower face rejuvenation. AB - OBJECTIVE: To quantitatively evaluate a dual-modality treatment that combines autologous structural fat grafting and carbon dioxide (CO(2)) laser resurfacing for perioral and lower face rejuvenation. METHOD: Retrospective review of patients undergoing rejuvenation by a single surgeon between 2005 and 2009. A blinded expert rated photographs on three scales, each with a range of 1 (no abnormality) to 5 (severe abnormality): (i) perioral fine rhytids; (ii) deep folds; and (iii) pigmentary or cutaneous abnormalities. Within-subject comparisons were generated. Results were correlated with skin type (Fitzpatrick) and baseline photodamage (Glogau). A test for effect of adjunctive procedures was performed. RESULTS: Seventeen patients were included (all female, mean age 61 years). Significant postoperative improvement was noted for perioral fine rhytids (3.1 to 1.7, p < 0.0001); deep folds (3.4 to 2.0, p < 0.00001); and pigmentation (2.5 to 1.9, p = 0.02). Fitzpatrick skin type was inversely correlated with improvement in pigmentation scores (r = -0.78), while the Glogau score correlated with improvement of fine rhytids (r = 0.76). No significant effect of adjunctive procedures was found. No complications occurred, though fat grafts resorbed in one patient. CONCLUSIONS: Concurrent structural fat grafting and CO(2) resurfacing result in quantifiable improvement of perioral and lower face aesthetics in relation to baseline characteristics and independent of adjunctive surgical procedures. PMID- 21250791 TI - 0.5% Liposome-encapsulated 5-aminolevulinic acid (ALA) photodynamic therapy for acne treatment. AB - BACKGROUND: Photodynamic therapy using topical 5-aminolevulinic acid (ALA) has been successful in treating acne vulgaris, but sun avoidance for at least 48 hours after treatment is necessary due to the risk of post-treatment photosensitivity. Recently, a lower concentration of liposome-encapsulated 5-ALA was introduced to minimize this risk. OBJECTIVES: To evaluate the efficacy and safety of liposome-encapsulated 0.5% 5-ALA in the photodynamic therapy of inflammatory acne and its effects on sebum secretion in Asian skin. METHODS: Thirteen Korean subjects with inflammatory acne were administered 0.5% ALA spray before photoradiation treatment. Photoradiation was performed at 3.5-6.0 J/cm(2) three times during each of two visits, performed 2 weeks apart. Improvement of acne was evaluated subjectively and objectively based on the Korean Acne Grading System. Sebum secretion was measured quantitatively at each visit. RESULTS: The mean reduction in acne grade at the end of the treatment was 43.2%. Of the patients, 69.2% reported improvements in subjective skin oiliness, but fewer showed objective reductions in sebum secretion as determined by the Sebumeter(r) SM10. No serious adverse events were observed. CONCLUSION: Photodynamic therapy using liposome-encapsulated 0.5% 5-ALA improved inflammatory acne with minimal side effects in Asians. PMID- 21250792 TI - Laser treatment of onychomycosis using a novel 0.65-millisecond pulsed Nd:YAG 1064-nm laser. AB - Onychomycosis is a common disorder of the nails. Treatment modalities include oral and topical antifungals, surgical treatment or a combination of these therapies. Cure rates remain low with relatively high relapse rates seen after successful treatment. The purpose of this study was to evaluate the treatment of onychomycosis using a novel 0.65-millisecond (ms) pulsed 1064-nm laser. Eight subjects were treated over two to three sessions spaced at least 3 weeks apart. Of the eight subjects evaluated, seven had negative post-treatment cultures after the second or third session. Treatments were well tolerated by all subjects. These data suggest that treatment of onychomycosis with a 0.65-ms pulsed Nd:YAG 1064-nm laser should be studied further to determine the long-term clinical and microbiologic effect. The optimal number of treatment sessions for each patient needs to be determined. PMID- 21250793 TI - The Pickering Syndrome--a pebble in the mosaic of the cardiorenal syndrome. PMID- 21250795 TI - Is well-being associated with lower urinary tract symptoms in patients with stroke? AB - OBJECTIVE: This study aimed to assess self-reported well-being in a clinical sample of stroke patients and to identify possible associations with prevalence, severity and bother of lower urinary tract symptoms (LUTS). MATERIAL AND METHODS: A cross-sectional, clinical survey was initiated whereby stroke patients were invited to complete The WHO-Five Well-Being Index (WHO-5) and a LUTS instrument, the Danish Prostatic Symptom Score (DAN-PSS-1) questionnaire. Of 519 stroke patients invited, 482 subjects were eligible and 407 (84%) respondents answered the questionnaires. RESULTS: Poor well-being (sum score <13) was reported by 22% of all stroke patients, for women 29% and for men 14%. Depression (sum score <8) was reported by 10%, for women 11% and for men 8%. Poor well-being was significantly (p < 0.01) associated with severity and bother of LUTS. Likewise, poor well-being was significantly (p < 0.001) associated with the prevalence of four different symptom groups of LUTS. CONCLUSIONS: The results indicate that poor well-being is present in stroke patients with LUTS, especially in women. Likewise, the data showed significant association between poor well-being and LUTS. Screening for well-being and LUTS in stroke patients is strongly recommended. PMID- 21250796 TI - Primary glioblastoma of the cerebellopontine angle in adults. AB - Gliomas are rare entities in the cerebellopontine angle (CPA) in adults. The authors present clinical, neuroradiological, serological, and neuropathological findings in a 60-year-old man with an extraaxial CPA glioblastoma arising from the proximal portion of cranial nerve VIII. The patient presented with progressive left-sided deafness and left-sided facial palsy lasting less than 2 months and progressive dysarthria and dysphagia lasting 2 weeks. Preoperative neuroimaging suggested the diagnosis of CPA meningioma with "dural-tail" sign and involvement of the internal auditory canal. Serological examination showed an increase in the malignant markers of ferritin and neuron-specific enolase, which suggested underlying malignancy. The tumor was subtotally removed, and it was confirmed to be completely separated from the brainstem and cerebellum. Cranial nerves VII and VIII were destroyed and sacrificed. Transient severe bradycardia occurred during surgery due to entrapment of the caudal cranial nerve complex by the tumor in such an infiltrative way. The neuropathological examination revealed a glioblastoma. The patient underwent no further treatment and died of cachexia 2 months postoperatively. To the authors' knowledge, this represents the first case of a primary glioblastoma in the CPA in an adult. A high index of suspicion along with reliance on clinical assessment, radiological findings, and serum detection of specific malignant markers is essential to diagnose such uncommon CPA lesions. PMID- 21250797 TI - Trigeminal neurinomas. PMID- 21250798 TI - Transfer of the teres minor motor branch for triceps reinnervation in tetraplegia. AB - In a case involving tetraplegia and paralysis of elbow extension, the authors transferred teres minor branches to the nerve of the triceps long head. Surgery was performed bilaterally 9 months after the patient sustained a spinal cord injury. Fourteen months postoperatively, elbow extension was complete (British Medical Research Council Score M4). Harvesting of the teres minor motor branch produced no deficits in shoulder function. In patients with tetraplegia, nerve transfer seems to be a promising new alternative for elbow extension reconstruction. PMID- 21250799 TI - Potential placebo effect in assessing idiopathic normal pressure hydrocephalus. AB - Although shunt placement constitutes the primary treatment for idiopathic normal pressure hydrocephalus (INPH), it has been challenging to decide which patients to refer for such an intervention. Procedures involving CSF removal, such as large-volume lumbar puncture (LP) and external lumbar drainage, are commonly used to predict a successful response to surgery, but their positive and negative predictive values have considerable shortcomings. The authors here report the case of a 76-year-old woman with possible INPH whose condition improved equally well after actual and sham large-volume LPs. The authors discuss the implications of this placebo response in the context of the diagnosis and management of INPH. The authors suggest that the clinical response to sham procedures for CSF removal might provide important information for better predicting which patient might respond to shunt surgery. PMID- 21250800 TI - Extent of resection and the long-term durability of vestibular schwannoma surgery. AB - OBJECT: With limited studies available, the correlation between the extent of resection and tumor recurrence in vestibular schwannomas (VSs) has not been definitively established. In this prospective study, the authors evaluated 772 patients who underwent microsurgical resection of VSs to analyze the association between total tumor resection and the tumor recurrence rate. METHODS: The authors selected all cases from a prospectively collected database of patients who underwent microsurgical resection as their initial treatment for a histopathologically confirmed VS. Recurrence-free survival was analyzed using Kaplan-Meier analysis. The authors studied the impact of possible confounders such as patient age and tumor size using stepwise Cox regression to calculate the proportional hazard ratio of recurrence while controlling for other cofounding variables. RESULTS: The authors analyzed data obtained in 571, 89, and 112 patients in whom gross-total, near-total, and subtotal resections, respectively, were performed. A gross-total resection was achieved in 74% of the patients, and the overall recurrence rate in these patients 8.8%. There was no significant relation between the extent of resection and the rate of tumor recurrence (p = 0.58). As expected, the extent of resection was highly correlated with patient age, tumor size, and surgical approach (p < 0.0001). Using Cox regression, the authors found that the approach used did not significantly affect tumor control when the extent of resection was controlled for. CONCLUSIONS: While complete tumor removal is ideal, the results presented here suggest that there is no significant relationship between the extent of resection and tumor recurrence. PMID- 21250801 TI - Variation of patient characteristics, management, and outcome with timing of surgery for aneurysmal subarachnoid hemorrhage. AB - OBJECT: The past 30 years have seen a shift in the timing of surgery for aneurysmal subarachnoid hemorrhage (SAH). Earlier practices of delayed surgery that were intended to avoid less favorable surgical conditions have been replaced by a trend toward early surgery to minimize the risks associated with rebleeding and vasospasm. Yet, a consensus as to the optimal timing of surgery has not been reached. The authors hypothesized that earlier surgery, performed using contemporary neurosurgical and neuroanesthesia techniques, would be associated with better outcomes when using contemporary management practices, and sought to define the optimal time interval between SAH and surgery. METHODS: Data collected as part of the Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) were analyzed to investigate the relationship between timing of surgery and outcome at 3 months post-SAH. The IHAST enrolled 1001 patients in 30 neurosurgical centers between February 2000 and April 2003. All patients had a radiographically confirmed SAH, were World Federation of Neurosurgical Societies Grades I-III at the time of surgery, and underwent surgical clipping of the presumed culprit aneurysm within 14 days of the date of hemorrhage. Patients were seen at 90-day follow-up visits. The primary outcome variable was a Glasgow Outcome Scale score of 1 (good outcome). Intergroup differences in baseline, intraoperative, and postoperative variables were compared using the Fisher exact tests. Variables reported as means were compared with ANOVA. Multiple logistic regression was used for multivariate analysis, adjusting for covariates. A p value of less than 0.05 was considered to be significant. RESULTS: Patients who underwent surgery on Days 1 or 2 (early) or Days 7-14 (late) (Day 0 = date of SAH) fared better than patients who underwent surgery on Days 3-6 (intermediate). Specifically, the worst outcomes were observed in patients who underwent surgery on Days 3 and 4. Patients who had hydrocephalus or Fisher Grade 3 or 4 on admission head CT scans had better outcomes with early surgery than with intermediate or late surgery. CONCLUSIONS: Early surgery, in good-grade patients within 48 hours of SAH, is associated with better outcomes than surgery performed in the 3- to 6-day posthemorrhage interval. Surgical treatment for aneurysmal SAH may be more hazardous during the 3- to 6-day interval, but this should be weighed against the risk of rebleeding. PMID- 21250802 TI - The natural history of intracranial meningiomas. AB - OBJECT: Despite the increased detection of incidental or small meningiomas, the lesion's natural history is largely unknown. METHODS: One year or longer of follow-up was conducted in 244 patients with 273 meningiomas managed conservatively by a single surgeon between 2003 and 2008. Data were stratified according to age, sex, tumor location, symptoms, initial tumor diameter, calcification, MR imaging intensity, and edema. Linear tumor growth was defined as a 2-mm or larger increase in the maximum diameter in any direction of the tumor. Volumetric analysis (ImageJ version 1.43) was also conducted in 154 of 273 meningiomas for which complete radiological data were available in the form of DICOM files throughout the follow-up period. A volume increase greater than 8.2% was regarded as significant because the preliminary volumetry based on 20 randomly selected meningiomas showed that the average SD was 4.1%. RESULTS: Linear growth was observed in 120 tumors (44.0%) with a mean follow-up of 3.8 years. Factors related to tumor growth were age of 60 or younger (p = 0.0004), absence of calcification (p = 0.027), MR imaging T2 signal hyperintensity (p = 0.021), and edema (p = 0.018). Kaplan-Meier analysis and Cox proportional hazards regression analysis revealed that age 60 or younger (hazard ratio [HR] 1.54, 95% CI 1.05-2.30, p = 0.026), initial tumor diameter greater than 25 mm (HR 2.23, 95% CI 1.44-3.38, p = 0.0004), and the absence of calcification (HR 4.57, 95% CI 2.69 8.20, p < 0.0001) were factors associated with a short time to progression. Volumetric growth was seen in 74.0% of the cases. Factors associated with a higher annual growth rate were male sex (p = 0.0002), initial tumor diameter greater than 25 mm (p < 0.0001), MR imaging T2 signal hyperintensity (p = 0.0001), presence of symptoms (p = 0.037), and edema (p < 0.0001). CONCLUSIONS: Although the authors could obtain variable results depending on the measurement method, the data demonstrate patients younger than 60 years of age and those with meningiomas characterized by hyperintensity on T2-weighted MR imaging, no calcification, diameter greater than 25 mm, and edema need to be observed more closely. Volumetry was more sensitive to detecting tumor growth than measuring the linear diameter. PMID- 21250803 TI - Normal pressure hydrocephalus. PMID- 21250804 TI - Association of the CC genotype of the regulatory BCL2 promoter polymorphism ( 938C>A) with better 2-year survival in patients with glioblastoma multiforme. AB - OBJECT: Bcl-2 plays a key role in the downregulation of apoptosis and proliferation and leads to increased chemoresistance in glioblastoma multiforme (GBM). The authors investigated the role of a common regulatory single-nucleotide polymorphism (-938C>A), which is located in the inhibitory P2 promoter of BCL2. METHODS: Data from 160 patients suffering from GBM were retrospectively evaluated. Study inclusion criteria consisted of available DNA and, in patients still alive, a follow-up of at least 24 months. Results were analyzed with respect to the basic clinical data, type of surgical intervention (gross-total resection [GTR] versus stereotactic biopsy [SB]), adjuvant therapy, MGMT promoter methylation, and survival at the 2-year follow-up. RESULTS: At the 2-year follow up, 127 (79.4%) of the 160 patients had died. Kaplan-Meier curves revealed a significantly higher rate of survival for homo- and heterozygous C-allele carriers (p = 0.031). In the GTR group, the survival rate was 47.1% for homozygous C-allele carriers, 32.0% for heterozygous C-allele carriers, and only 21.4% for homozygous A-allele carriers (p = 0.024). The SB group showed no genotype-dependent differences. Multivariable Cox regression revealed that the BCL2 (-938AA) genotype was an independent negative prognostic factor for 2-year survival in the GTR group according to the BCL2 (-938CC) genotype reference group (hazard ratio 2.50, 95% CI 1.14-5.48, p = 0.022). CONCLUSIONS: These results suggested that the (-938C>A) polymorphism is a survival prognosticator as well as a marker for a high-risk group among patients with GBM who underwent GTR. PMID- 21250805 TI - Parafalcine and midline arteriovenous malformations: surgical strategy, techniques, and outcomes. AB - OBJECT: Parafalcine arteriovenous malformations (AVMs) have a midline plane in common, but differ in their location (anterior, middle, or posterior) and depth (superficial or deep). Surgical management varies with AVM location and depth in terms of patient position, head position, craniotomy, and surgical approach. This study examined surgical strategies, patient outcomes, and regional factors influencing results. METHODS: Patients with AVMs located on the medial surface of the cerebral hemisphere were identified retrospectively from a consecutive, single-neurosurgeon series that is registered prospectively as part of the UCSF Brain Arteriovenous Malformation Study Project. During a 12-year period, 443 patients with AVMs were treated surgically. Of these 443 patients, 132 (30%) had parafalcine AVMs, which were distributed in zones as follows: superficial anterior, 25 (18.9%); superficial-middle, 26 (19.7%); superficial-posterior, 39 (29.5%); deep-anterior, 25 (18.9%); deep-posterior, 17 (12.9%). Five different surgical strategies were used depending on AVM zone. RESULTS: Complete AVM resection was achieved in 123 (93.2%) of 132 patients. Overall, neurological condition improved in 74 patients (56.1%) and remained unchanged in 41 patients (31.1%). Neurological condition deteriorated in 12 patients (9.1%), and 5 patients (3.8%) died. Patients with AVMs in the superficial-middle zone had the highest rate of neurological deterioration (26.9%). CONCLUSIONS: Parafalcine AVMs lie on a midline surface that, when exposed with a bilateral craniotomy across the superior sagittal sinus and a wide opening of the interhemispheric fissure, makes them superficial. However, unlike convexity AVMs, which are approached perpendicularly, parafalcine AVMs are approached tangentially. Gravity retraction is useful with deeply located AVMs (those in the deep-anterior and deep-posterior zones), because it widens the interhemispheric fissure and accesses deep arterial feeding vessels from the anterior and posterior cerebral arteries. Surgical risks were increased in the superficial-middle zone, which is likely explained by the proximity of sensorimotor cortex. The authors' regional classification of parafalcine AVMs may serve as a guide to surgical planning. PMID- 21250806 TI - Resection of vestibular schwannomas. PMID- 21250807 TI - Posterior epidural migration of herniated lumbar disc fragment. AB - OBJECT: Posterior epidural migration of a free disc fragment in the lumbar region is a very rare condition that has only been reported in isolated cases to date. Patients with this condition present with radiculopathy or major neurological deficits. Difficulties in diagnosis and the choice and timing of surgical treatment are important in these cases. In this clinical case series, features of cases with posterior epidural migration of free lumbar disc fragments accompanied by cauda equina syndrome are discussed. METHODS: Eight cases (0.27%) of posterior epidural migration of disc fragments were detected among 2880 patients surgically treated for lumbar disc herniation between 1995 and 2008. Seven of these patients had cauda equina syndrome. The mean duration of symptoms in the 8 cases was 4.2 days (range 1-10 days). The group included 6 men and 2 women, with a mean age of 48 years (range 34-72 years). The sequestered disc fragments were at the L3-4 level in 6 patients (75%) and the L4-5 level in 2 (25%). Magnetic resonance imaging showed tumor-like ring contrast enhancement around sequestered fragments in 5 patients. The patients' motor, sensory, sexual, and urological functions were evaluated postoperatively, and modified Odom criteria and a visual analog scale were used in the assessment of postoperative outcomes. RESULTS: A microsurgical approach was used in all cases. Sequestrectomy with minimal hemilaminotomy and removal of the free segments were performed. The patients were followed up for a mean period of 28.5 months. Three patients (37.5%) had excellent results, 3 (37.5%) had good results, 1 patient (12.5%) had fair results, and only 1 patient had poor results according to the Odom criteria. The main factors affecting the long-term outcomes were the presence of cauda equina syndrome and the time period between onset of symptoms and surgery. CONCLUSIONS: Patients with posterior migration of a disc fragment present with severe neurological deficits such as cauda equina syndrome. Because the radiological images of disc fragments may mimic those of other more common posterior epidural space-occupying lesions, definite diagnosis of posteriorly located disc fragments is difficult. All of these lesions can be completely removed with hemilaminotomy and sequestrectomy, and early surgical treatment is important as a first choice to prevent severe neurological deficits. PMID- 21250808 TI - Balloon kyphoplasty in the treatment of metastatic tumors of the upper thoracic spine. AB - OBJECT: Balloon kyphoplasty has recently been shown to be effective in providing rapid pain relief and enhancing health-related quality of life in patients with metastatic spinal tumors. When performed to treat lesions of the upper thoracic spine, kyphoplasty poses certain technical challenges because of the smaller size of the pedicle and vertebral bodies. Fluoroscopic visualization is also difficult due to interference of the shoulder. The authors' objective in the present study was to evaluate their approach and the results of balloon kyphoplasty in the upper thoracic spine in patients with metastatic spinal disease. METHODS: Fourteen patients underwent kyphoplasty via an extrapedicular approach to treat metastatic tumors in the upper (T1-5) thoracic spine. Electrodiagnostic monitoring (somatosensory and motor evoked potentials) was used in 5 cases. Three levels were treated in 7 cases, 2 levels in 2 cases, and 1 level in 5 cases. In 3 cases access was bilateral, whereas in 11 cases access was unilateral. The procedure took an average of 25 minutes per treated level, and the mean amount of cement applied was 3 ml per level. Four patients were discharged from the hospital on the day of the procedure, and 10 patients went home after 24 hours. RESULTS: All patients exhibited marked improvement in mean visual analog scale scores (preoperative score 79 vs postoperative score 30, respectively) and Oswestry Disability Index scores (83 vs 33, respectively). The mean kyphotic angle was 25.03 degrees preoperatively, whereas the mean postoperative angle was 22.65 degrees (p > 0.3). At latest follow-up, the mean kyphotic angle did not differ significantly from the postoperative kyphotic angle (26.3 degrees , p > 0.1). No neurological deficits or lung-related complications (pneumothorax or hemothorax) were encountered in any of the patients. Polymethylmethacrylate cement extravasations were observed in 3 (10%) of 30 treated vertebral bodies without any sequelae. By a mean follow-up of 16 months, no patients had experienced an adjacent-level fracture. CONCLUSIONS: Balloon kyphoplasty of the upper thoracic spine via an extrapedicular approach is an efficient and safe minimally invasive procedure that may provide immediate and long-term pain relief and improvement in functional ability. It is technically challenging and has the potential for serious complications. With a fundamental knowledge of anatomy, as well as an ability to interpret fluoroscopy images, one can feasibly and safely perform balloon kyphoplasty in the upper thoracic spine. PMID- 21250809 TI - Endoscopic resection of intrathoracic tumors: experience with and long-term results for 26 patients. AB - OBJECT: Thoracoscopy may be used in place of thoracotomy to resect intrathoracic neoplasms such as paraspinal neurogenic tumors. Although these tumors are rare, they account for the majority of tumors arising in the posterior mediastinum. METHODS: A database was maintained of all patients undergoing thoracoscopic surgery for tumors. The authors analyzed the presenting symptoms, pathological diagnoses, and outcomes of 26 patients (7 males and 19 females, mean age 37.2 years) who were treated for intrathoracic tumors via thoracoscopy between January 1995 and May 2009. Fourteen patients were diagnosed incidentally (54%). Five patients (19%) presented with dyspnea or shortness of breath, 4 (15%) with pain, 1 (4%) with pneumonia, 1 (4%) with hoarseness, and 1 (4%) with Horner syndrome. RESULTS: Pathology demonstrated schwannomas in 20 patients (77%). Other diagnoses included ganglioneurofibroma, paraganglioma, epithelioid angiosarcoma, benign hemangioma, benign granular cell tumor, and infectious granuloma. One patient required conversion to open thoracotomy due to pleural scarring to the tumor. One underwent initial laminectomy due to intraspinal extension of the tumor. Gross total resection was obtained in 25 cases (96%). The remaining patient underwent biopsy followed by radiation therapy. The mean surgical time was 2.5 hours, and the mean blood loss was 243 ml. The mean duration of chest tube insertion was 1.3 days, and the mean length of hospital stay was 3.0 days. Cases that were treated in the second half of the cohort were more often diagnosed incidentally, performed in less time, and had less blood loss than those in the first half of the cohort. There was 1 case of permanent treatment-related morbidity (mild Horner syndrome). All previously employed patients were able to return to work (mean clinical follow-up 43 months). There were no recurrences (mean imaging follow-up 54 months). CONCLUSIONS: Endoscopic transthoracic approaches can reduce approach-related soft-tissue morbidity and facilitate recovery by preserving the normal tissues of the chest wall, by avoiding rib retraction and muscle transection, and by reducing postoperative pain. This less invasive approach thus shortens hospital stay and recovery time. PMID- 21250811 TI - The role of flexion and extension computed tomography with reconstruction in clearing the cervical spine in trauma patients: a pilot study. AB - OBJECT: As a result of spinal trauma, approximately 12,000 individuals become quadriplegic or paraplegic each year in the US. The cervical spine is the most frequently injured part of the spinal column, and approximately 60% of spinal cord injuries involve the cervical region. The cervical collar remains the best method of prehospital spinal stabilization. Following trauma, difficulty securing an airway, the shielding of life-threatening injuries, and pressure ulcers are just a few of the serious problems that may be encountered in patients placed in cervical collars. The authors' goal was to develop an efficient method of clearing the cervical spine, by incorporating flexion and extension CT scanning with reconstruction (FECTR) into a trauma protocol. METHODS: This prospective study reviewed consecutive patients evaluated by the neurosurgery and trauma services who underwent FECTR. Imaging studies were reviewed using the Picture Activating and Communication System. The incidence of injury detection was recorded, and detection of otherwise-missed cervical spinal injuries using FECTR and CT scanning were also recorded. This technique was also applied, without causing any new neurological complications, for comatose patients if the original CT showed no suspicion of unstable injury. The study end point was determination of the presence of cervical spinal column injury that would pose a threat of instability or injury to the patient. RESULTS: Seventy-seven consecutive patients who underwent FECTR were identified. Far superior visualization of the cervicothoracic junction was achieved compared with flexion-extension cervical spine radiographs. In this case series, the sensitivity and specificity, respectively, of both FECTR and CT were 80% and 98.6% for all radiographic abnormalities. More importantly, for clinically unstable injuries, FECTR had a sensitivity of 100%. The use of FECTR added approximately 10-12 minutes to the time required for CT scanning. CONCLUSIONS: The authors' initial findings show FECTR to be a safe, effective, and efficient method of posttraumatic cervical spine clearance. In unconscious or obtunded patients, FECTR facilitates cervical spine clearance with a high degree of accuracy. A larger prospective study is needed to confirm these findings. PMID- 21250812 TI - Volumetric myelographic magnetic resonance imaging to localize difficult-to-find spinal dural arteriovenous fistulas. AB - Although more prevalent in males in the 6th and 7th decade of life, spinal dural arteriovenous fistulas (SDAVFs) are an uncommon cause of progressive myelopathy. Magnetic resonance imaging and more recently Gd bolus MR angiography have been used to diagnose, radiographically define, and preprocedurally localize the contributing lumbar artery. Three-dimensional myelographic MR imaging sequences have recently been developed for anatomical evaluation of the spinal canal. The authors describe 3 recent cases in which volumetric myelographic MR imaging with a 3D phase-cycled fast imaging employing steady state acquisition (PC-FIESTA) and a 3D constructive interference steady state (CISS) technique were particularly useful not only for documenting an SDAVF, but also for providing localization when CT angiography, MR imaging, MR angiography, and spinal angiography failed to localize the fistula. In a patient harboring an SDAVF at T-4, surgical exploration was performed based on the constellation of findings on the PC-FIESTA images as well as the fact that the spinal segments leading to T-4 were the only ones that the authors were unable to catheterize. In a second patient, who harbored an SDAVF at T-6, after 2 separate angiograms failed to demonstrate the fistula, careful assessment of the CISS images led the authors to focus a third angiogram on the left T-6 intercostal artery and to perform superselective microcatheterization. In a third patient with an SDAVF originating from the lateral sacral branch, the PC-FIESTA sequence demonstrated the arterialized vein extending into the S-1 foramen, leading to a second angiogram and superselective internal iliac injections. The authors concluded that myelographic MR imaging sequences can be useful not only as an aid to diagnosis but also for localization of an SDAVF in complex cases. PMID- 21250810 TI - "No performance in surgery more interesting and satisfactory": Harvey Cushing and his experience with spinal cord tumors at the Johns Hopkins Hospital. AB - Although Harvey Cushing was a neurosurgical pioneer, his work on the spine remains largely unknown. In fact, other than his own publications, Cushing's patients with pathological lesions of the spine who were treated while he was at the Johns Hopkins Hospital, including those with spinal cord tumors, have never been previously described. The authors report on 7 patients with spinal cord tumors that Cushing treated surgically between 1898 and 1911: 2 extradural, 3 intradural extramedullary, and 2 intramedullary tumors. The authors also describe 10 patients in whom Cushing performed an "exploratory laminectomy" expecting to find a tumor, but in whom no oncological pathological entity was found. Cushing's spine surgeries were limited by challenges in making the correct diagnosis, lack of surgical precedent, and difficulty in achieving adequate intraoperative hemostasis. Other than briefly mentioning 2 of the 4 adult patients in his landmark monograph on meningiomas, these cases-both those involving tumors and those in which he performed exploratory laminectomies--have never been published before. Moreover, these cases illustrate the evolution that Harvey Cushing underwent as a spine surgeon. PMID- 21250813 TI - In vitro comparison of the pullout strength of 3 anterior double-screw fixation techniques with different screw angulations. AB - OBJECT: The pullout resistance of double-screw fixation systems in anterior spine surgery has been shown to be dependent on screw length as well as on screw angulation. The objective of the study was to evaluate the pullout strength of anterior double-screw systems with different angulations. METHODS: The authors conducted a comparative pullout test of converging, parallel, and diverging angulations of double-screw systems in human cadavers. Twenty-four human vertebral bodies from T-11 to L-1 were harvested from 8 donors, dissected from surrounding tissue, and matched to 3 different fixation groups. Three systems were tested: VentroFix, with near parallel screw direction; the Hopf Anterior Fixation System (HAFS), with converging screw angulation; and the ART anterior system, with diverging screw angulation. RESULTS: The mean (+/- SD) pullout strength of the VentroFix system was 699 +/- 214 N, whereas the HAFS resisted to 591 +/- 372 N. The ART anterior system with diverging screws demonstrated a pullout resistance of 810 +/- 273 N. There was no significant difference amongst the pullout forces of the 3 groups (p > 0.05). In the HAFS and the ART anterior group, a weak correlation of pullout strength and bone mineral density measured by quantitative CT was found (r = 0.59 and r = 0.62, respectively), whereas the pullout force of the VentroFix system was not correlated with bone mineral density (r = 0.33). CONCLUSIONS: The in vitro pullout resistance of anterior double-screw systems does not appear to depend on screw angulation. PMID- 21250814 TI - Transplantation of mesenchymal stem cells and nucleus pulposus cells in a degenerative disc model in rabbits: a comparison of 2 cell types as potential candidates for disc regeneration. AB - OBJECT: The aim of this study was to compare transplanted mesenchymal stem cells (MSCs) with nucleus pulposus cells (NPCs) in a degenerative disc model in rabbits to determine the better candidate for disc cell therapy. METHODS: Mesenchymal stem cells and NPCs were transplanted in a rabbit model of disc degeneration. Changes in disc height, according to plain radiography, T2-weighted signal intensity on MR imaging, histology, sulfated glycosaminoglycan (sGAG)/DNA, and associated gene expression levels, were evaluated among healthy controls without surgery, sham-operated animals in which only disc degeneration was induced, MSC transplanted animals, and NPC-transplanted animals for a 16-week period. RESULTS: Sixteen weeks after cell transplantation, in the MSC- and NPC-transplanted groups, the decline in the disc height index was reduced and T2-weighted signal intensity increased compared with the sham-operated group. Safranin O staining showed a high GAG content, which was also supported by sGAG/DNA assessment. Disc regeneration was also confirmed at the gene expression level using real-time polymerase chain reaction. However, no significant differences in expression were found between the NPC- and MSC-transplanted groups. CONCLUSIONS: Study data showed that MSC transplantation is effective for the treatment of disc degeneration and seems to be an ideal substitute for NPCs. PMID- 21250815 TI - A simple method for making a hollow cylindrical polymethylmethacrylate strut for cervical spinal reconstruction. AB - OBJECT: The purpose of this study was to introduce a method for making a hollow cylindrical polymethylmethacrylate (PMMA) strut for perioperative anterior spinal reconstruction after discectomy and/or corpectomy. METHODS: For use after anterior cervical discectomy or corpectomy, the authors created a hollow cylindrical PMMA strut using 10- and 3-ml disposable plastic syringes filled with PMMA containing 10% BaSO(4) for anterior spinal reconstruction. RESULTS: With this method, the authors were able to make a PMMA strut that was approximately 50 mm in length with a 14-mm outer diameter and a 10-mm inner diameter. The PMMA strut could easily be cut with a saw to any desired length and molded with a cutting bur. The PMMA strut was used as a substitute for the cortical bone and was filled with bone graft for cervical spinal reconstruction after discectomy and/or corpectomy. The whole process of making the PMMA strut can be completed within 30 minutes, and it reduces costs by at least $1000 US (in 1-level discectomy), making the procedure cost effective. CONCLUSIONS: It is simple to make a hollow cylindrical PMMA strut with plastic syringes during a discectomy and/or corpectomy. The strut can provide adequate support at less cost than other methods. The hollow cylindrical strut is also of suitable size and length for anterior spinal reconstruction. It serves as an alternative for patients who cannot afford the expense of similar instruments or who cannot or do not want to take the risk of a human graft for anterior spinal reconstruction. PMID- 21250816 TI - "Fulfilling the chief of his duties as a physician": Harvey Cushing, selective dorsal rhizotomy and elective spine surgery for quality of life. AB - At the beginning of the 20th century, the development of safer anesthesia, antiseptic techniques, and meticulous surgical dissection led to a substantial decrease in operative risk. In turn, the scope of surgery expanded to include elective procedures performed with the intention of improving the quality of life of patients. Between 1908 and 1912, Harvey Cushing performed 3 dorsal rhizotomies to improve the quality of life of 3 patients with debilitating neuralgia: a 54 year-old man with "lightning" radicular pain from tabes dorsalis, a 12-year-old boy cutaneous hyperesthesia and spasticity in his hemiplegic arm, and a 61-year old man with postamputation neuropathic pain. Symptomatic improvement was seen postoperatively in the first 2 cases, although the third patient continued to have severe pain. Cushing also removed a prominent spinous process from each of 2 patients with debilitating headaches; both patients, however, experienced only minimal postoperative improvement. These cases, which have not been previously published, highlight Cushing's views on the role of surgery and illustrate the broader movement that occurred in surgery at the time, whereby elective procedures for quality of life became performed and accepted. PMID- 21250817 TI - Isolated intradural lumbosacral tailgut cyst with carcinoid features. AB - Tailgut cysts are developmental cysts that arise from remnants of the embryonic postanal gut and are typically located within the presacral, retrorectal space. Isolated cases of aberrant locations, including prerectal, perirenal, perianal, retrovesical, and subcutaneous locations, have been reported. Malignant transformations with the presence of adenocarcinomas or carcinoids have been recognized within these entities. It is well recognized that anterior sacrococcygeal abnormalities are present and are frequently caused by the slow growing nature of the tailgut cysts and related mass effect; however, the authors are aware of no reports in the literature of isolated tailgut cysts within the thecal sac in direct contact with neural elements, without extension into the peritoneal cavity. In this case, a 28-year-old woman presented with progressive back pain, frequent urinary tract infections, and bowel dysfunction. She was found to have a purely intradural tailgut cyst with malignant transformation consistent with carcinoid. No peritoneal extension of her disease was found. The authors hypothesize that this is a rare developmental aberration that has not been commonly recognized and potentially has implications for embryological development. PMID- 21250818 TI - Synthesis and evaluation of the antiproliferative activity of novel isoindolo[2,1 a]quinoxaline and indolo[1,2-a]quinoxaline derivatives. AB - A novel series of isoindolo[2,1-a]quinoxaline and indolo[1,2-a]quinoxaline derivatives was synthesized and evaluated in vitro against various human cancer cell lines for antiproliferative activity. These new compounds displayed activity against leukemia and breast cancer cell lines in the 3- to 18-uM concentration range. PMID- 21250819 TI - Synthesis, hydrolysis studies and phamacodynamic profiles of amide prodrugs of dexibuprofen with amino acids. AB - The present investigation deals with the synthesis of novel prodrugs of dexibuprofen with amino acids with an aim to achieve potent anti-inflammatory activity and less gastrointestinal toxicity. Structures of synthesized compounds were confirmed by spectral and elemental analyses. In vitro hydrolytic studies in simulated intestinal fluid, 80% plasma and rat faecal matter showed satisfactory release of dexibuprofen due to enzymatic cleavage. The synthesized prodrugs were evaluated for anti-inflammatory activity, analgesia, ulcerogenicity and histopathology. The anti-inflammatory activity of dexibuprofen was 43.3% whereas an improved value of 73.4, 77.3, 72.8 and 64.5% was observed for the synthesized prodrugs. The percentage analgesia of the prodrugs increased, whereas a decrease in the mean ulcer index values than dexibuprofen was observed. The histopathological studies revealed less ulceration in the gastric region when treated with prodrugs. Thus, the prodrugs were proved to be better in action as compared with the parent drug. PMID- 21250820 TI - Potentiation of the reductase activity of protein disulphide isomerase (PDI) by 19-nortestosterone, bacitracin, fluoxetine, and ammonium sulphate. AB - Protein disulphide isomerase (PDI) in the endoplasmic reticulum catalyzes the rearrangement of disulphide bridges during folding of secreted proteins. It binds various molecules that inhibit its activity. But here, we looked for molecules that would potentiate its activity. PDI reductase activity was measured in vitro using di-eosin-oxidized glutathione as substrate. Its classical inhibitor bacitracin was found to exert a biphasic effect: stimulatory at low concentrations (~10(-6) M) and inhibitory only at higher concentrations (~10(-4) 10(-3) M). The weak oestrogenic molecule bisphenol A was found to exert a weak inhibitory effect on PDI reductase activity relative to the strong oestrogens, ethynylestradiol, and diethylstilbestrol. Like 19-nortestosterone, fluoxetine was found to exert a potentiating effect on PDI reductase activity and their potentiating effects could be reversed by increasing concentrations of oestrogens. In conclusion, this paper provides the first identification of potentiators of PDI activity that are potential pharmaceuticals against pathologies affecting protein folding such as Alzheimer's disease. PMID- 21250821 TI - Synthesis of some thiazolyl aminobenzothiazole derivatives as potential antibacterial, antifungal and anthelmintic agents. AB - A series of 4-(6-substituted-1,3-benzothiazol-2-yl)amino-2-(4-substitutedphenyl)- amino-1,3-thiazoles, 9-24 have been synthesised from 2-chloro-N-(6-substituted 1,3-benzothiazol-2-yl)acetamides, 5-8. The structures of these compounds have been elucidated by spectral (IR, (1)H NMR, Mass) and elemental (C, H, N) analysis data. All the newly synthesised compounds (9-24) were screened for their antibacterial, antifungal and anthelmintic activities. Almost all of these compounds showed moderate to good antimicrobial activity against two gram negative bacteria (E. coli, P. aeruginosa), two gram positive bacteria (S. aureus, B. subtilis), pathogenic fungal strains (C. albicans, A. niger) and good anthelmintic activity against earthworm species (P. corethruses). Compounds 18 and 20 exhibited good antibacterial and antifungal activities, while compound 22 displayed the most significant anthelmintic activity. PMID- 21250822 TI - Synthesis and biological evaluation of novel N,N'-bis-methylenedioxybenzyl alkylenediamines as bivalent anti-Alzheimer disease ligands. AB - A novel series of N,N'-bis-methylenedioxybenzyl-alkylenediamines 5a-5g have been designed, synthesized and evaluated as bivalent anti-Alzheimer's disease ligands. The enzyme inhibition assay results indicated that compounds 5e-5g inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the micromolar range (IC(50), 2.76-4.24 uM for AChE and 3.02-5.14 uM for BuChE), which was in the same potential as the reference compound rivastigmine (IC(50), 5.50 uM for AChE and 1.60 uM for BuChE). It was found that compounds could bind simultaneously to the peripheral and catalytic sites of AChE. beta-Amyloid (Abeta) aggregation inhibition assay results showed that compound 5e exhibited highest self-mediated Abeta fibril aggregation inhibition activity (40.3%) with a similar potential as curcumin (41.6%). It was also found that 5e-5g did not affect neuroblastoma cell viability at the concentration of 50 MUM. PMID- 21250823 TI - Synthesis, QSAR and anti-HIV activity of new 5-benzylthio-1,3,4-oxadiazoles derived from alpha-amino acids. AB - 2-(1-[(4-Chloro/methylphenylsulfonylamino)alkyl]-5-thioxo-4,5-dihydro-1,3,4 oxadiazoles (4a-e) were synthesized, in four steps, via the sulfonyl derivatives of l-amino acids (l-alanine, l-methionine and l-phenylalanine) 1a-e, the esters 2a-e, the hydrazides 3a-e and finally the cyclization to 4a-e. Alkylation of 4a-e with 1.0 mole eq. of substituted benzyl halides furnished S-benzyl derivatives 5a t, while 1.1 mole eq. yielded major 5a-t and minor amount of 6a-d. Alternatively, treatment of 4a-e with 2.0 mole eq. of substituted benzyl halides furnished 6a-d only. The structures of 5b and 5l were further confirmed by single crystal X-ray analysis. Compounds 5a-t and 6a-d showed no selective inhibition against HIV-1 and HIV-2 replication in MT-4 cells. However, 5f and 5j-5q exhibited some inhibitory activity against both types with EC(50) values (>11.50 - >13.00 ug/mL). These results suggest that the structural modifications of these compounds might lead to the development of new antiviral agents. The quantum structure-activity relationship of these novel structural congeners is discussed. PMID- 21250824 TI - Synthesis, antimicrobial and antimycobacterial evaluation of [2-(substituted phenyl)-imidazol-1-yl]-pyridin-3-yl-methanones. AB - A series of [2-(substituted phenyl)-imidazol-1-yl]-pyridin-3-yl-methanones (1-11) were synthesized and screened for their antimicrobial and antimycobacterial activities. Further, a series of [2-(substituted phenyl)-benzimidazol-1-yl] pyridin-3-yl-methanones (12-20) reported in our earlier study was also screened for their antimycobacterial activity. The antimycobacterial activity results indicated that [2-(4-Nitro-phenyl)-imidazol-1-yl]-pyridin-3-yl-methanone (8, minimum inhibitory concentration [MIC] = 3.13 ug) was equipotent as standard drug ciprofloxacin and [2-(4-Nitro-phenyl)-benzimidazol-1-yl]-pyridin-3-yl-methanone (16, MIC = 1.56 ug) was equipotent as standard drug ethambutol. The results of antimicrobial screening demonstrated that 2-[1-(Pyridine-3-carbonyl)-1H-imidazol 2-yl]-benzoic acid (compound 11, MIC = 0.002 ug) was two times more effective than standard drug ciprofloxacin (MIC = 0.004 ug) against tested bacterial strains and [2-(2,5-Dimethyl-phenyl)-imidazol-1-yl]-pyridin-3-yl-methanone (compound 3, MIC = 0.005 ug) was equipotent to the reference compound, fluconazole against tested fungal strains. PMID- 21250825 TI - Inhibition of autophagy: a new strategy to enhance sensitivity of chronic myeloid leukemia stem cells to tyrosine kinase inhibitors. AB - Imatinib mesylate (IM) has become standard therapy for patients with chronic myeloid leukemia (CML), but CML stem cells are intrinsically resistant to IM and to second/third-generation tyrosine kinase inhibitors (TKIs), allowing the persistence of a 'reservoir' of BCR-ABL-expressing CML-initiating cells potentially responsible for disease progression. Although it is still controversial whether the 'insensitivity' of CML stem cells to treatment with TKIs is due to BCR-ABL-dependent or independent mechanisms, recent evidence indicates that treatment with IM suppresses BCR-ABL-dependent signaling in CML stem cells with no adverse effects on their survival. Treatment of CML cells with IM/TKIs induces autophagy, a genetically regulated process of adaptation to metabolic stress which may allow tumor cells to become metabolically inert, enabling their survival under conditions that may mimic growth factor/nutrient deprivation. Based on this hypothesis, TKI-induced autophagy may 'antagonize' TKI induced cell death and inhibition of autophagy may eliminate this survival mechanism by restoring 'sensitivity' of CML stem cells to treatment with IM/TKIs. Consistent with this, recent evidence indicates that phenotypically and functionally defined CML-enriched stem cells that are insensitive to treatment with TKIs are efficiently eliminated by the combination of TKI and chloroquine, an inhibitor of late stage autophagy. Thus, inhibition of autophagy may 'sensitize' CML stem cells to treatment with TKIs, thus preserving the high specificity of TKI-based therapies. PMID- 21250826 TI - Quality of life in patients with diffuse large B-cell lymphoma treated with dose dense chemotherapy is only affected temporarily. AB - (R)-CHOP-14 has substantially improved outcome in DLBCL, but may have increased morbidity and reduced quality of life (QoL). Our aim was to evaluate QoL during (R)-CHOP-14-based chemotherapy. Twenty-six patients participated (small single center study). EORTC QLQ-C30 was completed pre-treatment, mid-treatment, 14 days post-treatment, and 3 months post-treatment. Scores were compared to a reference population, and analyzed separately. Pre-treatment, global health status (p = 0.004), physical functioning (p = 0.036), role functioning (p = 0.017), and emotional functioning (p = 0.040) were reduced, and fatigue (p = 0.009) and appetite loss (p = 0.007) increased compared to the reference population. During treatment, physical functioning and role functioning decreased significantly, whereas emotional functioning, fatigue, and diarrhea increased. Three months post treatment, scores were generally equivalent to those of the reference population, and lower for nausea/vomiting (p < 0.001) and constipation (p < 0.001). Disease related symptoms were frequent in high-risk DLBCL. Treatment-related symptoms were normalized 3 months post-treatment. In conclusion, QoL is only temporarily affected during (R)-CHOP-14-based chemotherapy, and the treatment regimen is therefore feasible. PMID- 21250827 TI - Design and initial characterization of the SC-200 proteomics standard mixture. AB - High-throughput (HTP) proteomics studies generate large amounts of data. Interpretation of these data requires effective approaches to distinguish noise from biological signal, particularly as instrument and computational capacity increase and studies become more complex. Resolving this issue requires validated and reproducible methods and models, which in turn requires complex experimental and computational standards. The absence of appropriate standards and data sets for validating experimental and computational workflows hinders the development of HTP proteomics methods. Most protein standards are simple mixtures of proteins or peptides, or undercharacterized reference standards in which the identity and concentration of the constituent proteins is unknown. The Seattle Children's 200 (SC-200) proposed proteomics standard mixture is the next step toward developing realistic, fully characterized HTP proteomics standards. The SC-200 exhibits a unique modular design to extend its functionality, and consists of 200 proteins of known identities and molar concentrations from 6 microbial genomes, distributed into 10 molar concentration tiers spanning a 1,000-fold range. We describe the SC-200's design, potential uses, and initial characterization. We identified 84% of SC-200 proteins with an LTQ-Orbitrap and 65% with an LTQ-Velos (false discovery rate = 1% for both). There were obvious trends in success rate, sequence coverage, and spectral counts with protein concentration; however, protein identification, sequence coverage, and spectral counts vary greatly within concentration levels. PMID- 21250828 TI - Different regulation of N-cadherin and cadherin-11 in rat hippocampus. AB - Cadherin-mediated specific cell adhesion is an important process in brain development as well as in synaptic plasticity in the adult brain. In this study the authors quantified mRNA levels of N-cadherin and cadherin-11 in different brain regions for the first time. In hippocampus N-cadherin mRNA levels were very high at embryonic stages and decreased during further development, whereas cadherin-11 mRNA levels were highest at postnatal stages. However, N-cadherin protein level was not altered during hippocampal development and cadherin-11 protein was low at embryonic but high at postnatal and adult stages. In cultured hippocampal neurons both cadherins became colocalized and recruited to synaptic sites during ongoing differentiation, with especially high accumulation of cadherin-11 at synapses. These data hint at a critical role of N-cadherin at early embryonic stages and early synaptogenesis, whereas cadherin-11 might be more important for further stabilization of synapses in the postnatal period and adulthood. PMID- 21250829 TI - The design and implementation of a rescue terminal with vital signs telemonitoring based on Beidou 1 navigation satellite system. AB - This article presents the design and applications of a rescue terminal with positioning, vital signs sensing, and communicating function for special environment. The terminal provides three-dimensional positioning functionality via China's Beidou 1 Navigation Satellite (BD1) System and can collect users' vital signs with a set of wireless sensors. A controller of the terminal is in charge of processing data collected from the wireless sensors and communicating with the monitoring platform. With features such as small sizing, low power consumption, and accurate positioning, this terminal is very helpful in special circumstances such as disaster relief, dangerous outdoor sports and adventure monitoring, and antiterrorism activities. PMID- 21250830 TI - Successful periodontal ligament regeneration by periodontal progenitor preseeding on natural tooth root surfaces. AB - The regeneration of lost periodontal ligament (PDL) and alveolar bone is the purpose of periodontal tissue engineering. The goal of the present study was to assess the suitability of 3 odontogenic progenitor populations from dental pulp, PDL, and dental follicle for periodontal regeneration when exposed to natural and synthetic apatite surface topographies. We demonstrated that PDL progenitors featured higher levels of periostin and scleraxis expression, increased adipogenic and osteogenic differentiation potential, and pronounced elongated cell shapes on barren root chips when compared with dental pulp and dental follicle cells. When evaluating the effect of surface characteristics on PDL progenitors, natural root surfaces resulted in elongated PDL cell shapes, whereas PDL progenitors on synthetic apatite surfaces were rounded or polygonal. In addition, surface coatings affected PDL progenitor gene expression profiles: collagen I coatings enhanced alkaline phosphatase and osteocalcin expression levels and laminin-1 coatings increased epidermal growth factor (EGF), nestin, cadherin 1, and keratin 8 expression. PDL progenitors seeded on natural tooth root surfaces in organ culture formed new periodontal fibers after 3 weeks of culture. Finally, replantation of PDL progenitor-seeded tooth roots into rat alveolar bone sockets resulted in the complete formation of a new PDL and stable reattachment of teeth over a 6-month period. Together, these findings indicate that periodontal progenitor cell type as well as mineral surface topography and molecular environment play crucial roles in the regeneration of true periodontal anchorage. PMID- 21250831 TI - Death anxiety (Thanatophobia) among drug dependents in an Arabic psychiatric hospital. AB - AIM: The primary aim of this study was, for the first time to our knowledge, to examine the level of death anxiety (thanatophobia) in drug dependents attending the outpatient clinic in a psychiatric hospital and to examine the relationship of demographic variables to death anxiety. METHOD: Eighty-five patients were recruited from outpatient psychiatric attendees at the psychiatric hospital, Kingdom of Bahrain. The death anxiety scale was administered to assess death anxiety, and a clinical psychiatric interview was used to assess psychopathology. RESULTS: The mean age of the sample was 36.8 years (SD = 8.8). All subjects who participated in the study were Arabic males; the majority of them were primary school (i.e. first 5 years of education or schooling) educated (n = 57; 67%) and single (n = 48; 56.5%). The total mean of death anxiety score of the drug abusers was high (3.52+/-.95). One-way ANOVA showed that there was no significant difference among the scores the drug dependents received on the death anxiety scale related to different groups of age, education, type of the drug used, or the number of times of taking drugs per day. However, there was a significant difference in the level of control of use, marital status, duration of use, cigarettes smoking, and level of religiosity. CONCLUSION: The results of this study indicate that the level of death anxiety is high, in general, among drug abusers and that being divorced, not actively practicing a religious faith, having at least 1-10 years or more than 20 years history of drug abuse, and smoking at least 20 or more cigarettes per day significantly increases the level of death anxiety. PMID- 21250836 TI - Engineered pathways for correct disulfide bond oxidation. AB - Correct formation of disulfide bonds is critical for protein folding. We find that cells lacking protein disulfide isomerases (PDIs) can use alternative mechanisms for correct disulfide bond formation. By linking correct disulfide bond formation to antibiotic resistance, we selected mutants that catalyze correct disulfide formation in the absence of DsbC, Escherichia coli's PDI. Most of our mutants massively overproduce the disulfide oxidase DsbA and change its redox status. They enhance DsbA's ability to directly form the correct disulfides by increasing the level of mixed disulfides between DsbA and substrate proteins. One mutant operates via a different mechanism; it contains mutations in DsbB and CpxR that alter the redox environment of the periplasm and increases the level of the chaperone/protease DegP, allowing DsbA to gain disulfide isomerase ability in vivo. Thus, given the proper expression level, redox status, and chaperone assistance, the oxidase DsbA can readily function in vivo to catalyze the folding of proteins with complex disulfide bond connectivities. Our selection reveals versatile strategies for correct disulfide formation in vivo. Remarkably, our evolution of new pathways for correct disulfide bond formation in E. coli mimics eukaryotic PDI, a highly abundant partially reduced protein with chaperone activity. PMID- 21250838 TI - Increased BCMA expression in lupus marks activated B cells, and BCMA receptor engagement enhances the response to TLR9 stimulation. AB - B lymphocyte stimulator (BLyS) and APRoliferation inducing ligand (APRIL) are members of the TNF superfamily that regulate B-cell survival and autoreactivity. To further understand the significance of elevated BLyS and APRIL in systemic lupus erythematosus (SLE), we examined the expression profiles of their receptors (B-cell-activating factor (BAFF)-R, transmembrane activator and calcium modulator and cyclophilin ligand interactor, and B cell maturation antigen (BCMA)) on B cell subsets in SLE and also investigated the differential expression and function of BCMA in TLR9-induced B-cell activation. While BAFF-R expression on SLE B cells was significantly lower compared to healthy control B cells (p = 0.003), BCMA expression was substantially higher on SLE B cells (p = 0.038), especially on memory cells and plasmablasts. BCMA(+) cells had higher CD19 and CD86 expression, indicating a greater degree of activation in both healthy and lupus patients. CpG stimulation increased BCMA expression on B cells and induced the proliferation and maturation of BCMA(+) B cells. A BCMA agonistic antibody also enhanced CpG-induced proliferation, activation, and IgG secretion by B cells in both healthy controls and lupus patients. Furthermore, the agonistic BCMA antibody co-stimulated auto-antibody production by CpG-stimulated lupus B cells in vitro. Signaling through BCMA enhances B cell activation following exposure to TLR9 agonists, and increased expression in SLE may contribute to the production of IgG autoantibodies. PMID- 21250839 TI - Can MS fully exploit the benefits of fast chromatography? PMID- 21250840 TI - Supercritical fluid chromatography for bioanalysis: practical and theoretical considerations. PMID- 21250837 TI - Heterologous immunity: immunopathology, autoimmunity and protection during viral infections. AB - Heterologous immunity is a common phenomenon present in all infections. Most of the time it is beneficial, mediating protective immunity, but in some individuals that have the wrong crossreactive response it leads to a cascade of events that result in severe immunopathology. Infections have been associated with autoimmune diseases such as diabetes, multiple sclerosis and lupus erythematosis, but also with unusual autoimmune like pathologies where the immune system appears dysregulated, such as, sarcoidosis, colitis, panniculitis, bronchiolitis obliterans, infectious mononucleosis and even chronic fatigue syndrome. Here we review the evidence that to better understand these autoreactive pathologies it requires an evaluation of how T cells are regulated and evolve during sequential infections with different pathogens under the influence of heterologous immunity. PMID- 21250842 TI - Conference report: the 5th cell-based assay and bioanalytical method development conference. AB - Approximately 80 participants met at the Marriot Hotel, San Francisco, CA, USA, between the 4th and 6th October 2010 to share novel techniques and discuss the emerging approaches in the evolving field of cell-based assay and bioanalytical method development. This report highlights the discussion and summary of the meeting. PMID- 21250843 TI - Young investigator. AB - Supervisor's supporting comments Keyller B Borges carried out his MS and PhD studies in toxicology under my supervision. During the time he spent in my laboratory, he worked on the development of analytical methods and studied the biotransformation of several drugs by fungi. Characteristics such as dedication, ability, initiative and dynamism had been the basis for the success of his projects developed under my supervision, resulting in several publications in prestigious periodics of the area. Therefore, I consider Dr Keyller highly capable for the development of activities in the area of bioanalysis. PMID- 21250844 TI - Evaluation of blood microsampling techniques and sampling sites for the analysis of drugs by HPLC-MS. AB - BACKGROUND: the potential for whole blood sampling (20 ul) in toxicokinetic studies to reduce the sample volume was investigated. Blood microsamples were collected in three ways, either as a dried blood spot (DBS), a blood sample collected in a micropipette placed in a plastic tube and mixed with water or as plasma in the normal manner. RESULTS: blood samples on the DBS and the whole blood microtube (WBMT) were compared along with DBS and plasma to determine the toxicokinetic data equivalency. The DBS and WBMT comparison was shown to be equivalent, as demonstrated on a correlation plot with an R(2) value of 0.97 for an x = y plot. The plasma comparison with DBS also gave a good correlation. A correction factor (x(2)) was applied to the blood data to allow for the distribution of the compound between plasma and bloods, and therefore, a direct comparison could be made. The correlation plot derived from the sample data gave an R(2) value 0.98 (x = y plot), indicating dataset equivalency. Sampling sites were evaluated in a dog study. Blood was collected from the peripheral region, in this case the ear, and a venous region of the dog; and spotted onto DBS cards. Comparison of the mean area under the curve data for the sampling sites showed equivalent data: 5095 and 5175 ng.h/ml for the 25 mg/kg dose and 16695 ng.h/ml and 16000 ng.h/ml for the 50 mg/kg dose for the ear and the venous samples, respectively. CONCLUSION: the DBS cards were shown to be an equivalent microsampling process when compared with WBMT and conventional plasma analysis. With the added benefits of sample storage, shipment and ease of use for DBS, this technology could change the way samples are taken and then analyzed in bioanalysis in the future. PMID- 21250845 TI - Quantification of the anti-influenza drug zanamivir in plasma using high throughput HILIC-MS/MS. AB - BACKGROUND: parenteral zanamivir is a promising drug for the treatment of severe influenza. However, quantification of this polar drug in biological matrices has traditionally been difficult and the methods developed have been relatively insensitive. RESULTS: a high-throughput bioanalytical method for the analysis of zanamivir in human plasma using SPE in the 96-well plate format and LC coupled to positive MS/MS has been developed and validated according to US FDA guidelines. The method uses 50 microl of plasma and covers a large working range from 1-50, 000 ng/ml with a LOD of 0.50 ng/ml. CONCLUSION: this new LC-MS/MS assay is more sensitive than previous methods despite using a small plasma volume sample. It is particularly suitable for clinical studies on both parenteral and inhaled zanamivir. PMID- 21250846 TI - Effect of sample collection tubing type used in a clinical study on quantitation of pharmaceutical compounds in CSF by LC-MS/MS. AB - BACKGROUND: plasma/cerebrospinal fluid (CSF) ratio of compound K was determined to be lower than predicted during the conduct of clinical study. This triggered the evaluation of nonspecific binding of drug K and an additional ten compounds in CSF to collection tubing. Physiochemical properties such as pKa and log D values were correlated to the quantified results. RESULTS: mean recoveries of compound K quality controls sampled within 24 h, as compared with spiked quality control, were 12.9, 44.4 and 77.7% from silicone, Tygon and Pharmed collection tubing, respectively. Eight out of ten compounds showed significant loss into silicone and seven out of ten compounds showed no significant loss into Pharmed. CONCLUSION: silicone tubing is not recommended and Pharmed appears to be most appropriate. CSF sample collection tubing must be evaluated prior to starting clinical studies. PMID- 21250847 TI - LC-MS/MS-ESI method for simultaneous quantitation of three endocannabinoids and its application to rat pharmacokinetic studies. AB - An LC-MS/MS-ESI method has been validated for simultaneous estimation of the three endocannabinoids; N-arachidonoylethanolamine (AEA), N-oleoylethanolamine (OEA) and palmitoylethanolamide (PEA), in surrogate matrix using AEA-d (4) as an internal standard with highest sensitivity over the existing methods. Simple precipitation was used to extract analytes and these were subsequently analyzed on a monolithic column. Linear response function was established over the concentration range 12.3 to 1225 pg/ml for AEA (r > 0.994); 0.70 to 641 ng/ml for OEA (r > 0.999) and 0.54 to 321 ng/ml (r > 0.998) for PEA. The intra- and inter day precision values met the acceptance to criteria as per US FDA guidelines. Analytes were found to be stable in the battery of stability studies. The method was applied to quantify endogenous levels of analytes in rat plasma. PMID- 21250848 TI - Approaches for the rapid identification of drug metabolites in early clinical studies. AB - Understanding the metabolism of a novel drug candidate in drug discovery and drug development is as important today as it was 30 years ago. What has changed in this period is the technology available for proficient metabolite characterization from complex biological sources. High-efficiency chromatography, sensitive MS and information-rich NMR spectroscopy are approaches that are now commonplace in the modern laboratory. These advancements in analytical technology have led to unequivocal metabolite identification often being performed at the earliest opportunity, following the first dose to man. For this reason an alternative approach is to shift from predicting and extrapolating possible human metabolism from in silico and nonclinical sources, to actual characterization at steady state within early clinical trials. This review provides an overview of modern approaches for characterizing drug metabolites in these early clinical studies. Since much of this progress has come from technology development over the years, the review is concluded with a forward-looking perspective on how this progression may continue into the next decade. PMID- 21250849 TI - Plasma volume expanders: use in medicine and detecting misuse in sports. AB - Plasma volume expanders comprise a heterogeneous group of substances used in medicine that are intravenously administered in cases of great blood loss owing to surgery or medical emergency. These substances, however, can also be used to artificially enhance performance of healthy athletes in sport activities, and to mask the presence of others substances. These practices are considered doping, and are therefore prohibited by the International Olympic Committee and the World Antidoping Agency. Consequently, drug testing procedures are essential. The present work provides an overview of plasma volume expanders, assembling pertinent data such as chemical characteristics, physiological aspects, adverse effects, doping and analytical detection methods, which are currently dispersed in the literature. PMID- 21250850 TI - Isothermal DNA amplification in bioanalysis: strategies and applications. AB - Isothermal DNA amplification is an alternative to PCR-based amplification for point-of-care diagnosis. Since the early 1990s, the approach has been refined into a simple, rapid and cost-effective tool by means of several distinct strategies. Input signals have been diversified from DNA to RNA, protein or small organic molecules by translating these signals into input DNA before amplification, thus allowing assays on various classes of biomolecules. In situ detection of single biomolecules has been achieved using an isothermal method, leveraging localized signal amplification in an intact specimen. A few pioneering studies to develop a homogenous isothermal protein assay have successfully translated structure-switching of a probe upon target binding into input DNA for isothermal amplification. In addition to the detection of specific targets, isothermal methods have made whole-genome amplification of single cells possible owing to the unbiased, linear nature of the amplification process as well as the large size of amplified products given by phi29 DNA polymerase. These applications have been devised with the four isothermal amplification strategies covered in this review: strand-displacement amplification, rolling circle amplification, helicase-dependent amplification and recombinase polymerase amplification. PMID- 21250852 TI - A weight of evidence approach for selecting exposure biomarkers for biomonitoring. AB - CONTEXT: It is known that there are usually several biomarkers and/or medium combinations that can be applied to answer a specific exposure question. To help determine an appropriate combination for the specific question, we have developed a weight-of-evidence Framework that provides a relative appropriateness score for competing combinations. METHODS: The Framework is based on an expert assessor's evaluation of the relevance and suitability of the biomarker and medium for the question based on a set of criteria. We provide a computer based modeling tool to guide the researcher through the process. RESULTS: We present an example with six biomarkers of benzene exposure in one matrix; the six are either the most commonly used biomarkers and/or have recent widespread usage. The example clearly demonstrates the usefulness of the Framework for scoring the choices, as well as the transparency of the method that provides the basis for discussion. CONCLUSIONS: The Framework provides for the first time a method to transparently document the rationale behind selecting, from among a set of alternatives, the most scientifically supportable exposure biomarker to address a specific biomonitoring question, thus providing a reproducible account of expert opinions on the suitability of a biomarker. PMID- 21250859 TI - Inflammatory response is associated with increased cathepsin B and decreased cathepsin S concentrations in the circulation. AB - OBJECTIVE: Extracellular matrix remodeling by cathepsins play an important role in many conditions associated with inflammation. The aim of this study was to study the effect of inflammation on circulating levels of human cathepsin B and S. MATERIALS AND METHODS: Blood sampling was carried out prior to surgery and 4 and 30 days after surgery, respectively. Two patient groups were included: (1) patients undergoing orthopedic surgery (n = 29) and coronary bypass patients (n = 21). Serum cathepsin B and S levels were measured using sandwich ELISAs. C reactive protein (CRP) was analysed by turbidimetry. RESULTS: Serum cathepsin B showed significantly higher values 4 days after surgery in comparison with samples collected prior to surgery. Serum cathepsin S instead showed significantly lower values 4 days after surgery. Similar results were found in both patient groups. CONCLUSIONS: Inflammation has different effects on circulating levels of cathepsin B and S. PMID- 21250860 TI - The safety and efficacy of alcaftadine 0.25% ophthalmic solution for the prevention of itching associated with allergic conjunctivitis. AB - OBJECTIVE: The purpose of this study was to evaluate the safety and clinical efficacy of alcaftadine 0.25% ophthalmic solution, a new topical anti-allergic agent for the prevention of the signs and symptoms of allergic conjunctivitis induced by conjunctival allergen challenge (CAC). STUDY DESIGN AND METHODS: This two-arm, double-masked, multi-center, placebo-controlled Phase III study (NCT00889330) enrolled healthy volunteers (N = 58) with a history of allergic conjunctivitis. Subjects >=10 years of age with a reproducible, positive reaction to a CAC were randomized to receive either one drop of alcaftadine 0.25% ophthalmic solution bilaterally or vehicle bilaterally. After 16 hours (Visit 3) and 15 minutes (Visit 4), a CAC was performed and ocular and nasal symptoms of allergy were graded over a 20-minute period. Clinical and statistical significance were evaluated. MAIN OUTCOME MEASURES: The primary endpoints were ocular itching and conjunctival redness. The secondary endpoints were all other signs and symptoms of allergic conjunctivitis. Visual acuity, slit lamp biomicroscopy and adverse event reporting were the predetermined safety measures. RESULTS: Alcaftadine was effective in the prevention of ocular itching based on both clinically relevant and statistically significant differences compared with vehicle (placebo). Alcaftadine significantly reduced conjunctival redness, and almost all other allergic signs and symptoms at both 15 minutes and 16 hours after drug administration. No significant safety issues were reported. Between group differences in ocular itching were higher 16 hours after drug administration than at 15 minutes after drug administration. CONCLUSIONS: With an onset of action within 3 minutes and a duration of action of at least 16 hours, the statistically and clinically significant effect of alcaftadine 0.25% on itching make it an important addition to therapy for ocular allergy. Additional studies are warranted to better understand the mechanisms affording a fast onset and prolonged duration of action. PMID- 21250861 TI - Assessment of quality of life in patients with type 2 diabetes mellitus before and after starting biphasic insulin aspart 30 (BIAsp 30) therapy: IMPROVE study in Japan. AB - AIMS: To evaluate treatment satisfaction before and after starting biphasic insulin aspart 30 (BIAsp 30) therapy in patients with type 2 diabetes mellitus (T2D) in the IMPROVE study Japan using the Diabetes Medication Satisfaction (DiabMedSat) questionnaire. METHODS: The DiabMedSat questionnaire assesses overall satisfaction with drug therapy for diabetes treatment in three domains: burden, efficacy and symptoms. Patients previously treated by oral anti-diabetic drugs in the IMPROVE study Japan answered the DiabMedSat questionnaires at baseline (week 0) and week 26 after starting BIAsp 30 treatment. RESULTS: The mean scores for each domain at weeks 0 and 26, respectively, were: burden, 64.5 and 67.5 (p = 0.041); efficacy, 55.0 and 61.5 (p < 0.001); and symptoms, 70.9 and 68.1 (p = 0.049). The overall scores were 63.4 and 65.6, respectively (p = 0.079). With regard to burden, bothersome aspects were significantly improved with BIAsp 30 treatment at week 26, compared with treatment with oral anti diabetic drugs at week 0. Major hypoglycemic episodes were very rare; most hypoglycemic events were minor and occurred during the daytime. CONCLUSIONS: The study results indicate that BIAsp 30 does not adversely affect QOL in Japanese patients at insulin initiation. PMID- 21250862 TI - The single Z-plasty for cleft palate repair: a preliminary report. AB - OBJECTIVE: To introduce a surgical technique for the repair of cleft palate with the single and full-thickness Z-plasty method. PATIENTS AND METHODS: The procedure was performed from 1999 to 2006 in 34 patients with cleft palate with a median age of 6.0 years (range, 2.0 to 21 years). In these patients, in order to push the soft palate back farther, a single and full-thickness Z-plasty, designed on the soft palate across the defect, was applied to the von Langenbeck procedure. The full thickness of the soft palate was incised after the hard palate was closed by suturing the two mucoperiosteal flaps, and two Z-plasty flaps were formed. The two flaps were then transposed and closed by interrupted suturing of three layers of the palate in proper order, from nasal mucosa, levator muscle to oral mucosa. The patients were followed for 6 months to 3 years, velopharyngeal closure was examined by nasopharyngeal fiberscope and/or x ray radiography, and a clinical speech evaluation was performed. RESULTS: In all patients, no problem of flap viability was encountered and all healed well. The postoperative results were satisfactory without any complications such as dehiscence, perforation, or palatal fistula. The clinical speech evaluation was satisfactory, and the effects of the operation were stable. CONCLUSIONS: The technique presented has been effective, having the advantages of palatal closure without tension and with sufficient lengthening of the soft palate. PMID- 21250863 TI - Growth/differentiation factor-5 modulates the synthesis and expression of extracellular matrix and cell-adhesion-related molecules of rat Achilles tendon fibroblasts. AB - This study was designed to examine the cellular and molecular response of tendon fibroblasts to growth/differentiation factor-5 (GDF-5). Rat Achilles tendon fibroblasts (ATFs) were treated in culture with varying concentrations of GDF-5 (0-1000 ng/ml) over varying periods of time (0-12 days). Cell proliferation, evaluated through use of a standard MTT colorimetric assay, confirmed that GDF-5 stimulates ATF proliferation in a concentration- and time-dependent fashion. Temporal and concentration analysis revealed that GDF-5 increases total DNA, glycosaminoglycan (GAG), and hydroxyproline (HYP) content. Ratios of HYP/DNA and GAG/DNA increased with increasing concentrations of GDF-5 (0-1000 ng/ml). Expression of the following 12 extracellular matrix (ECM) and cell-adhesion related genes was assessed using real-time reverse transcriptase polymerase chain reaction (RT-PCR): collagen I (col I), collagen III (col III), matrix metalloproteinases (MMP)-3 and -13, aggrecan, tissue inhibitor of matrix metalloproteinase (TIMP)-2, syndecan-4, N-cadherin, tenascin-C, biglycan, versican, and decorin. RT-PCR data revealed an increase in the expression of col I, col III, MMP-3, MMP-13, TIMP-2, syndecan-4, N-cadherin, tenascin-C, and aggrecan genes by day 6. A statistically significant decrease in TIMP-2 and MMP 13 was observed on day 12. Decorin expression was depressed at all time points in cells treated with GDF-5. There was no significant change in biglycan expression in ATFs supplemented with GDF-5. These findings suggest that GDF-5 induces cellular proliferation and ECM synthesis as well as expression of ECM and cell adhesion-related genes in ATFs. This study further defines the influence of GDF-5 on rat ATFs through its action on the expression of genes that are associated with tendon ECM. PMID- 21250864 TI - Uptake of antigens from modified vaccinia Ankara virus-infected leukocytes enhances the immunostimulatory capacity of dendritic cells. AB - BACKGROUND AIMS: Modified vaccinia Ankara (MVA) is a promising vaccine vector for infectious diseases and malignancies. It is fundamental to ascertain its tropism in human leukocyte populations and immunostimulatory mechanisms for application in immunotherapy. METHODS: Human peripheral blood mononuclear cells (PBMC) and leukocyte subpopulations [monocyte-derived dendritic cells (DC), monocytes and B cells] were infected with MVA in order to evaluate their infection rate, changes in surface markers, cytokine expression and apoptosis. RESULTS: Monocytes, DC and B cells were most susceptible to MVA infection, followed by natural killer (NK) cells. Monocytes were activated strongly, with upregulation of co-stimulatory molecules, major histocompatibility complex (MHC) molecules and chemokine (C-C motif) receptor (CCR7), while immature DC showed partial activation and B cells were inhibited. Furthermore, expression of chemokine (C-X-C motif) ligand (CXCL10), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12p70 was enhanced but IL-1beta and IL-10 were stable or even downregulated. MVA induced a high apoptosis rate of antigen-presenting cells (APC). Nevertheless, incubation of MVA-infected leukocytes with uninfected immature DC (iDC) led to complete maturation of the DC. Subsequently, the matured DC were able to stimulate cytomegalovirus (CMV)-immediate early protein (IE1)-specific T cells. CONCLUSIONS: MVA induces a T-helper (Th)-1-polarizing cytokine expression in APC. Furthermore, incubation of MVA-infected leukocytes with uninfected iDC leads to complete maturation of the DC and may be the basis for cross-presentation of MVA encoded antigens. Thus this approach seems to be an ideal model for further studies with MVA-encoded viral antigens regarding immunotherapy and vaccination strategies. PMID- 21250866 TI - Dermatan sulfate and bone marrow mononuclear cells used as a new therapeutic strategy after arterial injury in mice. AB - BACKGROUND AIMS: Previously, we have demonstrated that administration of dermatan sulfate (DS) suppresses neointima formation in the mouse carotid artery by activating heparin co-factor II. A similar suppressive effect was observed by increasing the number of progenitor cells in circulation. In this study, we investigated the combination of DS and bone marrow mononuclear cells (MNC), which includes potential endothelial progenitors, in neointima formation after arterial injury. METHODS: Arterial injury was induced by mechanical dilation of the left common carotid artery. We analyzed the extension of endothelial lesion, thrombus formation, P-selectin expression and CD45(+) cell accumulation 1 and 3 days post injury, and neointima formation 21 days post-injury. Animals were injected with MNC with or without DS during the first 48 h after injury. RESULTS: The extension of endothelial lesion was similar in all groups 1 day after surgery; however, in injured animals treated with MNC and DS the endothelium recovery seemed to be more efficient 21 days after lesion. Treatment with DS inhibited thrombosis, decreased CD45(+) cell accumulation and P-selectin expression at the site of injury, and reduced the neointimal area by 56%. Treatment with MNC reduced the neointimal area by 54%. The combination of DS and MNC reduced neointima formation by more than 91%. In addition, DS promoted a greater accumulation of MNC at the site of injury. CONCLUSIONS: DS inhibits the initial thrombotic and inflammatory processes after arterial injury and promotes migration of MNC to the site of the lesion, where they may assist in the recovery of the injured endothelium. PMID- 21250865 TI - Global transcriptome analysis of human bone marrow stromal cells (BMSC) reveals proliferative, mobile and interactive cells that produce abundant extracellular matrix proteins, some of which may affect BMSC potency. AB - BACKGROUND AIMS: Bone marrow stromal cells (BMSC) are being used for immune modulatory, anti-inflammatory and tissue engineering applications, but the properties responsible for these effects are not completely understood. Human BMSC were characterized to identify factors that might be responsible for their clinical effects and biomarkers for assessing their quality. METHODS: Early passage BMSC prepared from marrow aspirates of seven healthy subjects were compared with three human embryonic stem cell (hESC) samples, CD34(+) cells from three healthy subjects and three fibroblast cell lines. The cells were analyzed with oligonucleotide expression microarrays with more than 35 000 probes. RESULTS: BMSC gene expression signatures of BMSC differed from those of hematopoietic stem cells (HSC), hESC and fibroblasts. Genes upregulated in BMSC were involved with cell movement, cell-to-cell signaling and interaction and proliferation. The upregulated genes most probably belonged to pathways for integrin signaling, integrin-linked kinase (ILK) signaling, NF-E2-related factor 2 (NFR2)-mediated oxidative stress response, regulation of actin-based motility by Rho, actin cytoskeletal signaling, caveolar-mediated endocytosis, clathrin mediated endocytosis and Wingless-type MMTV integration site (Wnt/beta catenin signaling. Among the most highly upregulated genes were structural extracellular matrix (ECM) proteins (alpha5 and beta5 integrin chains, fibronectin and collagen type IIIalpha1 and Valpha1) and functional EMC proteins [connective tissue growth factor (CTGF), transforming growth factor beta-induced protein (TGFBI) and A disintegrin and metalloproteinase (ADAM12)]. CONCLUSIONS: Global analysis of human BMSC suggests that they are mobile, metabolically active, proliferative and interactive cells that make use of integrins and integrin signaling. They produce abundant ECM proteins that may contribute to their clinical immune modulatory and anti-inflammatory effects. PMID- 21250868 TI - Falls efficacy among stroke survivors living in the community. AB - PURPOSE: The study focused on the falls efficacy of stroke survivors in the community and its association with the related factors. METHOD: The study was conducted through a cross-sectional design in the community setting. One hundred seven stroke survivors were recruited. Falls efficacy was measured by the 7-item Falls Efficacy Scale International version, where the higher mean score showed more concern about falling in daily life. RESULTS: Activities of daily living (ADL) dependency levels, including mild, moderate and severe, contributed to 33.5% of the explained variance. Women were over 7.5 times more likely to have high falls efficacy than men. Moderate and severe ADL dependency participants were 10.8 and 13.6 times more likely to have high falls efficacy than ADL independent participants. Single fall participants were also nearly 13 times more likely to have high falls efficacy than others who had either recurrent falls or no falls. CONCLUSIONS: Female gender, strong ADL dependency, and single falls were associated with high falls efficacy. The levels of ADL dependency were the most correlated with falls efficacy than with other related factors. Rehabilitation interventions should also be incorporated to minimise ADL dependency, and to improve falls efficacy for stroke survivors. PMID- 21250869 TI - Interferon in the treatment of chronic hepatitis C: a drug caught between past and future. AB - INTRODUCTION: Chronic hepatitis C affects 2.2 - 3% of the world population (130 million - 170 million). Pegylated IFN-alpha in combination with ribavirin, the currently approved therapy, leads to viral eradication in about 50% of treated patients, nevertheless it is associated with not negligible adverse events. Continuous efforts are being applied to improve the efficacy by means of new interferon molecules. Consensus IFN-alpha is currently available for use, while albumin-interferon, IFN-lambda and IFN-omega are under investigation. Research is focussed on the directly acting antivirals, such as telaprevir and boceprevir, which are anticipated to enter the drug market during the next few years. AREAS COVERED: This paper reviews the classification of interferons, mechanism of action, pegylated IFN-alpha molecules and their differences, current chronic hepatitis C treatment regimen and new drugs for HCV treatment. EXPERT OPINION: Pegylated IFN-alpha will remain the basis of anti-HCV therapy during the next decade, since new IFN formulation are not proven to be superior or are in early stages of development and directly acting antivirals show limited antiviral activity as monotherapy. PMID- 21250867 TI - Human umbilical cord blood plasma can replace fetal bovine serum for in vitro expansion of functional human endothelial colony-forming cells. AB - BACKGROUND AIMS: A hierarchy of endothelial colony-forming cells (ECFC) with different levels of proliferative potential has been identified in human circulating blood and blood vessels. ECFC has recently become an attractive target for new vascular regenerative therapies; however, in vitro expansion of ECFC typically depends on the presence of fetal bovine serum (FBS) or fetal calf serum (FCS) in the culture medium, which is not appropriate for its therapeutic application. METHODS: To identify optimal conditions for in vitro expansion of ECFC, the effects of human endothelial serum-free medium (SFM) supplemented with six pro-angiogenic cytokines and human umbilical cord blood plasma (HCP) were investigated. The in vitro morphology, proliferation, surface antigen expression and in vivo vessel-forming ability were utilized for examining the effects of medium on ECFC. RESULTS: This novel formulation of endothelial cell culture medium allows us, for the first time, to isolate and expand human ECFC efficiently in vitro with a low concentration of HCP (1.5%) and without bovine serum additives. In this serum-reduced medium (SRM), human ECFC colony yields remained quantitatively similar to those cultured in a high concentration (10%) of bovine serum-supplemented medium. SRM-cultured ECFC displayed a robust clonal proliferative ability in vitro and human vessel-forming capacity in vivo. CONCLUSIONS: The present study provides a novel method for the expansion of human ECFC in vitro and will help to advance approaches for using the cells in human therapeutic trials. PMID- 21250870 TI - The use of reversible addition fragmentation chain transfer polymerization for drug delivery systems. AB - INTRODUCTION: Reversible Addition Fragmentation Chain Transfer (RAFT) polymerisation is now an established tool for polymer chemists to create various polymer architectures with precise control over the molecular weight, and to install a variety of different moieties onto the polymer chain ends. Recently, there seems to be a trend of moving polymer science away from the traditional academic focussed research, to instead identifying real-world problems and how these can be solved with the aid of macromolecules. AREAS COVERED: This article has two themes; the synthesis of polymers for polymer therapeutics; and the design of polymer carriers for the physical encapsulation of drugs and genes, which can either be micelles, gels or other core-shell particles. The first part summarizes the avenues polymer chemists have developed by using RAFT polymerization to attach active compounds (such as drugs or proteins) to polymer chains. The second part gives an overview of the possibilities of using polymer nanocarriers (such as micelles, other core-shell nanoparticles, hydrogels and cationic polymers) for drug delivery. EXPERT OPINION: RAFT polymerisation seems to have endless possibilities in terms of macromolecular design, that is once the pitfalls of the process have been considered, which are based on the radical nature of the mechanism. Polymer chemists have explored many synthetic pathways in order to generate a myriad of structures, and to provide proof of concept for their ideas. However, considering the length of time it takes to get a polymer into a clinical trial, attention should be focussed on detailing the biological evaluation of these well-defined structures. PMID- 21250872 TI - Advances in human papilloma virus vaccines: a patent review. AB - INTRODUCTION: Human papilloma virus (HPV) infection is the main factor associated with the development of cervical cancer. The currently available HPV vaccines, Gardasil and Cervarix, can prevent infection by certain HPV types, but not all. At present, research efforts are being devoted to developing more broad spectrum preventative vaccines, as well as therapeutic vaccines. AREAS COVERED: Recent advances in HPV vaccine development are reviewed in this paper, with a focus on worldwide patents and patent applications. In principle, patents that have been granted since 2002 are covered. Exceptions are the patents pending at PCT stage and recent patent applications since 2009. Readers will gain insights into the cutting-edge technologies being used in the development and production of vaccines, as well as adjuvant systems. EXPERT OPINION: In the future, the use of mosaic virus-like particles (VLPs,) comprising at least one L1 protein of each HPV type, may be able to prevent infection by all HPV types while patented codon optimization techniques and the use of edible or DNA-based vaccines may be good places to start for reducing costs. Future vaccines should ideally have both preventive and therapeutic efficacies. Enhanced immunogenicity could be achieved by the use of more effective adjuvants, such as nanoparticle-based delivery systems, or new classes of adjuvants. PMID- 21250871 TI - Expert opinion on pharmacotherapy of kidney disease in HIV-infected patients. AB - INTRODUCTION: Human immunodeficiency virus (HIV) infection is associated with the development of a wide spectrum of kidney diseases. HIV-associated nephropathy (HIVAN) is the most common cause of chronic kidney disease (CKD) in HIV-infected individuals and predominantly affects patients of African ancestry. HIVAN is a leading cause of end-stage renal disease (ESRD) among African-Americans. AREAS COVERED: An overview of the spectrum of kidney disease in patients with HIV is given. Current pharmacologic interventions to treat kidney disease in HIV are discussed. This review will enhance knowledge regarding the most common causes of kidney disease in HIV-infected patients. An understanding of the principles related to pharmacotherapy in HIV-infected patients with kidney disease will also be gained. EXPERT OPINION: Kidney disease is an important cause of morbidity and mortality in HIV-infected patients. The most common cause of chronic kidney disease in this population is HIV-associated nephropathy, which is caused by viral infection of the renal epithelium. Several medications that are commonly used in HIV-infected patients can have adverse effects on the kidneys and the doses of many antiretroviral medications need to be adjusted in patients with impaired renal function. PMID- 21250873 TI - Blood coagulation factor Xa as an emerging drug target. AB - INTRODUCTION: Factor (F)Xa is well-known as an important player in the coagulation cascade responsible for thrombin generation. More recently, FXa emerged as an essential player in cell biology via activation of protease activated receptors (PAR)-1 and -2. This pleiotropic role of FXa forms the basis for its potential contribution to the pathogenesis of several diseases. AREAS COVERED: The role of FXa in pathophysiology is reviewed with special emphasis on its signal transduction properties. To this end, we first discuss the important role of FXa in the coagulation cascade, we continue with recent data on FXa induced signaling in pathophysiology with special emphasis on tissue remodeling and fibrosis and discuss the potential of FXa as an emerging drug target. EXPERT OPINION: FXa is more than a passive intermediate in the coagulation cascade and FXa may in fact orchestrate fundamental processes during pathophysiology. Targeting FXa may be an exciting new therapeutic strategy in the treatment of (fibro)proliferative diseases for which current treatment options are limited. PMID- 21250874 TI - The case for therapeutic proteostasis modulators. AB - A functional ubiquitin proteasome pathway (UPP) is vital for all eukaryotic cellular systems and therefore any alteration in this critical component of proteostasis machinery has rpotential pathological consequences. A proteostasis imbalance can be induced by environmental pollutants, age or genetic factors. Though the exact underlying mechanisms are unclear, a decrease in proteasome activity weakens the homeostatic cellular capacity to remove proteins that are either misfolded or need to be replenished, which favors the development of neurodegenerative, cardiac and other conformational diseases. In contrast, induction of proteasome activity is an attribute of many diseases including muscle wasting, sepsis, cachexia and uraemia. In the case of misfolded protein disorders, higher degradation of a single protein leads to the pathophysiological consequences due to the absence of functional protein. Therefore, selective proteostasis inhibition is a potential treatment strategy for misfolded protein disorders, while broad-spectrum proteasome inhibitor drugs are designed to target tumor metastasis. In contrast, for muscle wasting and neurodegeneration, the use of proteostasis-activating or modulating compounds could be more effective. PMID- 21250875 TI - An appropriate test for diagnosis of gestational diabetes mellitus. AB - Early diagnosis of GDM is necessary to reduce maternal and fetal morbidity and mortality. As all approaches to diagnosis of GDM are costly and difficult, we meant to find an appropriate and simple way to perform this test. One-thousand six-hundred and fifty-three pregnant women were screened for GDM at 24-28 weeks of gestation. Initial screening was done by a glucose challenge test with 50 g glucose. If the 1-h blood glucose level exceeded 130 mg/dl, then a 3-h oral glucose tolerance test (OGTT) with 100 g glucose was performed, and diagnosis was established according to ADA criteria. For determining which plasma glucose level is the best test for diagnosis of GDM, we used receiver operative characteristic cures (ROC) by plotting sensitivity versus one minus specificity at different times of plasma glucose levels in OGTT. In 732 pregnant women with a positive GCT, a 2-h plasma glucose level above 150 mg/dl was the most powerful test for detecting GDM, which revealed a sensitivity and specificity of 0.84 (0.81-0.86) and 0.94 (CI: 0.92-0.96), respectively. The results of this study suggest that 2 h 100 g OGTT could be an appropriate approach to diagnose GDM, which is cost effective and could reduce laboratory workload. PMID- 21250876 TI - Hb S-beta-thalassemia: molecular, hematological and clinical comparisons. AB - Clinical and hematological features are presented for 261 patients with identified beta-thalassemia (beta-thal) mutations. Mutations causing Hb S [beta6(A3)Glu->Val]-beta(0)-thal were IVS-II-849 (A>G) in 44%, frameshift codon (FSC) 6 (-A) in 14%, Hb Monroe [beta30(B12)Arg->Thr] in 14%, and IVS-II-1 (G>A) in 10%. Mutations causing Hb S-beta(+)-thal with 14-25% Hb A (type III) were -29 (A>G) mutation in 60%, -88 (C>T) in 22% and the polyadenylation signal site (polyA) (T>C) mutation in 14%, and in Hb S-beta(+)-thal with 1-7% Hb A (type I), all had the IVS-I-5 (G>C) mutation. Hematologically, only minor differences occurred between the four Hb S-beta(0)-thal mutations, but among the three mutations causing Hb S-beta(+)-thal type III, levels of Hb A(2), Hb F, hemoglobin (Hb), MCV and MCH were highest in the -88 and lowest in the polyA mutations. Clinically, Hb S-beta(0)-thal and Hb S-beta(+)-thal type I were generally severe, and Hb S-beta(+)-thal type III disease with the -88 mutation was milder than that caused by the polyA mutation. PMID- 21250877 TI - Fetal hemoglobin response to hydroxyurea in Yemeni sickle cell disease patients. AB - To assess the Hb F response to hydroxyurea (HU) in Yemeni sickle cell disease, 86 patients attending hospitals in Sana'a City, Yemen, were studied. Group I (short term follow-up, n = 21) were treated with 500 mg/day HU for 3-6 months; group II (long-term, n = 26) were treated with 500 mg/day HU for 8-48 months; group III were untreated (n = 39). Hb F levels were monitored using cation exchange high performance liquid chromatography (HPLC). Group I showed significant increase in Hb F level after treatment (10.0 +/- 5.8 to 13.8 +/- 5.9%). Hb F level increased significantly with treatment in group II when compared to group III. The increase in Hb F level was associated with increased hemoglobin (Hb) levels. Hydroxyurea, even at a low dose, appears to be effective in raising Hb F levels in Yemeni sickle cell disease patients without any association of major side effects. Further study is required to investigate its maximum tolerated dose and its effects on increase in Hb F, frequency of acute crisis and any long-term toxicity. PMID- 21250878 TI - Hb Nebraska [beta86(F2)Ala->Ile (HBB:c.259G>A;260C>T)]: a unique high oxygen affinity hemoglobin variant with a double nucleotide substitution within the same codon. AB - A new high oxygen affinity hemoglobin (Hb) variant, Hb Nebraska [beta86(F2)Ala >Ile, GCC>ATC; HGVS: HBB: c.259G>A;260C>T] is reported. This variant was not identified by routine methods and was only suspected due to erythrocytosis and an abnormal p50 value. The variant was analyzed by DNA sequencing and mass spectrometry (MS). The beta chain variant is unusual in that it has two nucleotide substitutions occurring at the same codon. PMID- 21250879 TI - Molecular spectrum of alpha- and beta-globin gene mutations detected in the population of Guangxi Zhuang Autonomous Region, People's Republic of China. AB - We studied 6,023 individuals diagnosed with anemia on the basis of hematological examinations. The study showed that the frequency of alpha-thalassemia (alpha thal) carriers was 26.9% and beta-thal carriers comprised 19.9% of the population of Guangxi Zhuang Autonomous Region, People's Republic of China (PCR). The diagnosed alpha-thal anomalies were related to six gene mutations and 16 genotypes, whereas the beta-thal were related to 10 gene mutations and 65 genotypes. The four most common mutations [codons 41/42 (-TTCT), codon 17 (A>T), 28 (A>G) and IVS-II-654 (C>T)] accounted for 86.38% of the beta-globin gene mutations. Risk analysis of mutation alleles in thalassemia cases identified four mutations (-alpha(3.7), -alpha(4.2), alphaalpha(Westmead) and alphaalpha(CS)) that were associated with alpha-thal intermedia, with an odds ratio (OR) of 62.41 32.68. Four high-risk mutations, namely, codon 26 (G>A), -28, codons 41/42 and codon 17, were associated with beta-thal major (beta-TM), with an OR of 3.93 2.20. The present study provides important genetic information on thalassemia in this population. PMID- 21250880 TI - Genotype-phenotype correlation in Iranian patients with Hb H disease. AB - Thalassemia is the most common genetic disorder in Iran. Some alpha-globin genotypes leading to Hb H disease may cause severe anemia and dependence on regular blood transfusions. In this study, 40 patients were analyzed for the molecular basis and the genotype-phenotype correlation of Hb H disease in Iran. alpha-Globin molecular analysis was performed by polymerase chain reaction (PCR) followed by agarose gel electrophoresis, reverse hybridization test strips or DNA sequencing. The most frequently observed alpha-globin genotypes were -alpha(3.7)/ -(MED) in 10 patients (25%), - -(20.5)/alpha(-5nt)alpha in six patients (15%) and - -(20.5)/-alpha(3.7) in four patients (10%). A subset of the identified Hb H genotypes, including - -(MED)/alpha(CS)alpha, - -(MED)/alpha(PolyA2)alpha and alpha(CS)alpha/alpha(CS)alpha, was associated with a need for regular or irregular blood transfusions. Our findings provide a basis for predicting phenotype severity by identifying the Hb H genotype and making more selective decisions for prenatal diagnosis. PMID- 21250881 TI - Prenatal diagnosis of beta-thalassemia and other hemoglobinopathies in southwestern Turkey. AB - Our aim was to evaluate the prenatal diagnosis of beta-thalassemia (beta-thal) and other hemoglobinopathies in a region with high frequency. After detection by premarital or antenatal screening, 312 patients underwent 420 prenatal diagnostic procedures for 407 fetuses in a 10-year period. Fetal samples were collected by chorionic villi sampling (CVS) in the first trimester and amniocentesis and cordocentesis in the second trimester. Mutation analyses of beta-globin and cytogenetic analyses were performed and the most common mutations detected were: IVS-I-110 (G>A), IVS-II-1 (G>A), IVS-I-6 (T>C) and IVS-II-745 (C>G). Hb S [beta6(A3)Glu->Val, GAG>GTG)] was the most common hemoglobin (Hb) variant with a frequency of 6.3%. Among 407 fetuses, 105 (25.8%) were diagnosed as affected, while 201 (49.4%) were carriers and 101 (24.8%) were normal. Cytogenetic analyses revealed nine fetuses (2.3%) with numerical chromosomal abnormalities as regular or mosaicism. Prenatal diagnosis of common hemoglobinopathies is safe and effective. Performing cytogenetic analysis in excess fetal material is an acceptable option. PMID- 21250882 TI - Novel and known microsatellite markers within the beta-globin cluster to support robust preimplantation genetic diagnosis of beta-thalassemia and sickle cell syndromes. AB - Preimplantation genetic diagnosis (PGD) for beta hemoglobinopathies has become the most common application among monogenic disorders. We present the identification of microsatellite markers [short tandem repeats (STRs)] closely linked to the beta-globin gene for incorporation within PGD protocols, with the aim of increasing the number of transferable embryos. Nine candidate STRs were identified in-silico, of which three were selected based on rate-of heterozygosity, polymerase chain reaction (PCR) efficiency and size. The multiplex reaction (beta-globin gene and selected STRs, all within <0.4 Mb from the beta gene) was optimized in single lymphocytes, and subsequently applied in 38 PGD cycles in couples at-risk for transmitting beta hemoglobinopathies. In conclusion, incorporation of closely linked polymorphic microsatellite markers <0.4 Mb from the beta-globin gene, facilitates robust assignment of beta hemoglobinopathy genotypes, increasing the number of transferrable embryos otherwise rejected due to allele-drop-out (ADO), at the mutation-specific locus, compared to results based on disease-mutation genotyping alone (p < 0.001). PMID- 21250883 TI - Increased oxidative stress and iron overload in Jordanian beta-thalassemic children. AB - beta-Thalassemia (beta-thal) is associated with abnormal synthesis of hemoglobin (Hb). Repeated blood transfusions in patients with beta-thal major (beta-TM) leads to an enhanced generation of reactive oxygen species (ROS), and subjects patients to peroxidative injury. We studied the antioxidant status and oxidative damage to children with beta-thal in Jordan. Samples from 40 children with beta thal and 40 healthy controls were used. All children were under 13 years of age. Our results showed that plasma thiobarbituric acid reactive substances (TBARS) were elevated in beta-thalassemic children compared to controls together with compensatory increase in superoxide dismutase (SOD) activity and decrease in catalase (CAT) activity. Elevated serum ferritin showed positive correlation with elevated liver enzyme levels except gamma glutamyl transferase (GGT), confirming liver involvement due to iron overload. Serum ferritin also showed a positive correlation with elevated TBARS and SOD, suggesting that iron overload is involved in the oxidative stress shown in cells. PMID- 21250884 TI - Characterization of the 5' and 3' breakpoints of the Spanish (deltabeta)0 thalassemia deletion in Mexican patients. AB - We studied five unrelated Mexican carriers of the Spanish (deltabeta)(0) thalassemia [(deltabeta)(0)-thal] mutation to characterize the size of the deletion, the 5' and 3' breakpoints and the 5' beta-globin haplotype. Sequence analysis revealed the presence of an 89,548 bp deletion. The delta- and beta globin genes, two olfactory receptor genes (OR51V1 and OR52A1) and two pseudogenes (OR52Z1P and OR51A1P) were deleted. The 5' breakpoint was located at the same position as previously reported, and the 3' breakpoint was situated 7.0 kb downstream of OR52A1 and 11.7 kb upstream of OR52A5. The Spanish (deltabeta)(0)-thal allele was associated with the 5' haplotype 2 [- + + - +] in the studied patients. Because this mutation is relatively frequent in Spain, and the Mexican population contains a high level of Spanish genetic background, we propose that the mutation in both populations share a common ancestral origin. PMID- 21250885 TI - beta+-Thalassemia trait due to a novel mutation in the beta-globin gene promoter: -26 (A>C) [HBB c.-76A>C]. AB - We report the case of a woman with beta(+)-thalassemia (beta(+)-thal) trait, in which there were two sequence variants within the beta-globin gene promoter: -54 (G>A) [HBB c.-104G>A] and -26 (A>C) [HBB c.-76A>C]. Data from other patients indicate that the -54 substitution is a non pathogenic sequence variant. Therefore, the beta-thal phenotype is most likely due to the -26 mutation that is adjacent to the conserved ATAA box. PMID- 21250886 TI - Screening for Hb Constant Spring in the Guangdong Province, South China, using the Sebia capillary electrophoresis system. AB - Hb Constant Spring [Hb CS; alpha142, Term->Gln (TAA>CAA in alpha2)] is a nondeletional alpha-thalassemia (alpha-thal) defect difficult to detect on conventional electrophoresis because of its small amount in heterozygotes. We have found that individuals with an Hb CS trait could efficiently be detected using the Sebia capillarys 2 system. In the present study, we have confirmed this method in a cohort of 23,842 individuals from Guangdong Province (South China). Hb CS was detected in 71 (0.3%) of the cases. The levels of Hb CS in heterozygotes ranged from 0.1-1.0% with an average of 0.6%. We propose the reported 0.3% as a realistic figure for the prevalence of Hb CS in South China. PMID- 21250887 TI - First report of Hb A2-NYU (HBD:c.39T>A) in the Hellenic population. AB - We report the first heterozygous case of Hb A(2)-NYU (HBD:c.39T>A) in the Hellenic population. The proband, an adult female from the island of Crete, Greece, was identified during routine family screening. DEAE chromatography of the index case revealed a minor hemoglobin (Hb) fraction preceding the elution of the wild-type Hb A(2). DNA sequencing of the entire HBD gene coding regions indicated that the index case was heterozygous for the rare variant Hb A(2)-NYU. Family studies indicated that this Hb variant was inherited from the mother. This finding underlines the vast genetic heterogeneity of the HBD gene in the Hellenic population. PMID- 21250888 TI - Motivators and barriers to a healthy postpartum lifestyle in women at increased cardiovascular and metabolic risk: a focus-group study. AB - OBJECTIVE: To describe the motivators and barriers to the adoption of a healthy postpartum lifestyle after a pregnancy complicated by preeclampsia, intrauterine growth restriction, and/or gestational diabetes. METHODS: Thirty-six women with complicated pregnancies participated in six focus-group interviews that aimed to explore the perceptions of modifiable determinants of postpartum lifestyle. RESULTS: Although women expressed that they intended to live a healthy postpartum lifestyle, it was generally not achieved. The motivators included improving their own current health condition as well as modeling a healthy lifestyle for their children. Important barriers were reported to be lack of knowledge, poor recovery, and lack of professional support after delivery. CONCLUSIONS: The reported motivators and barriers can be used to develop a postpartum lifestyle intervention. PMID- 21250889 TI - Changes in maternal serum thioredoxin (TRX) levels after delivery in preeclamptic and normotensive pregnant women. AB - OBJECTIVE: To investigate changes of maternal plasma thioredoxin (TRX) levels after delivery in preeclamptic and normotensive pregnant women. METHODS: Ten normotensive women (group A) were compared to 17 women with severe preeclampsia (group B). TRX levels were assessed in maternal plasma, immediately after delivery and 12-16 weeks postpartum. RESULTS: There were no differences in plasma TRX levels between the two groups immediately antepartum (p = 0.095). A significant reduction in plasma TRX levels was found immediately following delivery only in normotensive group (117.76 +/- 37.19 ng/mL vs. 43.45 +/- 21.11 ng/mL, p = 0.002), but not in women with preeclampsia (80.42 +/- 59.95 ng/mL vs. 53.82 +/- 44.34 ng/mL, p = 0.12). Plasma TRX levels remained unchanged in women with preeclampsia (80.42 +/- 59.95 ng/mL vs. 55.37 +/- 52.23 ng/mL, p = 0.2) at 12-14 weeks postpartum. PMID- 21250890 TI - Elevated serum-soluble Fas in preeclampsia: correlation with clinical, laboratory, and Doppler parameters. AB - OBJECTIVES: (i) To compare the levels of soluble Fas (sFas) in the sera of patients with variable degrees of preeclampsia and in healthy gravidas; and (ii) to correlate sFas with clinical, laboratory, and Doppler parameters in preeclampsia. METHODS: Fifty patients with mild preeclampsia, 50 patients with severe preeclampsia, and 50 healthy normotensive pregnant women (control group) were selected from those admitted to the delivery unit. All were nearly of the same maternal and gestational ages. Patients and controls were subjected to (i) history taking; (ii) general, abdominal, and pelvic examination; (iii) laboratory investigations including serum sFas, total bilirubin, aspartate transaminase, alanine transaminase, creatinine, uric acid, hematocrit value, platelet count, and 24 urinary proteins; (iv) obstetric ultrasound and biophysical profile; (v) Doppler cerebroplacental ratio; and (vi) neonatal assessment after delivery. RESULTS: Serum sFas was significantly higher (p < 0.001) in patients with mild and severe preeclampsia than in normal controls, and in patients with severe preeclampsia than in those with mild disease. In preeclampsia group, sFas correlated positively with systolic (r = 0.386; p < 0.001) and diastolic (r = 0.347; p = 0.001) blood pressures, serum uric acid (r = 0.452; p < 0.001), and urinary protein (r = 0.416; p < 0.001); and correlated negatively with biophysical profile (r = -0.371; p < 0.001), cerebroplacental ratio (r = -0.527; p < 0.001), and birth weight (r = -0.458; p < 0.001). CONCLUSION: Serum sFas is significantly elevated in preeclampsia and is correlated with some important clinical, laboratory, and Doppler parameters. Further longitudinal studies are recommended to investigate the possible value of sFas as an early predictor of preeclampsia and its severity. PMID- 21250891 TI - The evaluation of the oxidative state of low-density lipoproteins in intrauterine growth restriction and preeclampsia. AB - OBJECTIVE: To evaluate the oxidative state of lipoproteins in pregnancies complicated by intrauterine growth restriction (IUGR) in comparison to preeclampsia (PE) and healthy pregnant control subjects (CN). METHODS: Maternal serum of 20 PE, 29 IUGR, and 29 gestational age-matched CN were analyzed. Total cholesterol (TC), low-density lipoprotein (LDL)-bound cholesterol (LDL-C), and oxidized LDL (oxLDL) concentration were measured once between 25 and 34 weeks of gestation. Statistical estimates were performed by Student's t-test. RESULTS: Serum concentrations of LDL-C and TC were significantly reduced in IUGR [LDL-C: CN - mean = 146 mg/dL, SD = +/- 40.1; IUGR - mean = 102 mg/dL, SD = +/- 27.3 (p < 0.0001); PE - mean = 130 mg/dL, SD = 38.8 mg/dL; TC: CN - mean = 259/dL, SD = +/- 46.8; IUGR - mean = 218 mg/dL, SD = +/- 35.0 (p < 0.001); PE - mean = 244 mg/dL, SD = 48.2]. There was no significant difference in oxLDL/LDL-C ratio within the three groups (CN: mean = 0.76, SD = 0.24; IUGR: mean = 0.74, SD = 0.12; PE: mean = 0.77, SD = 0.22). CONCLUSION: Our results show a lower maternal LDL-C and TC concentration in IUGR pregnancies. These data contribute to the hypothesis of a decreased cholesterol supply to the fetus in IUGR. However, we could not confirm the hypothesis of an altered oxidative state in neither IUGR nor PE. PMID- 21250892 TI - The role of oxytocin in mother-infant relations: a systematic review of human studies. AB - BACKGROUND: Oxytocin is associated with the establishment and quality of maternal behavior in animal models. Parallel investigations in humans are now under way. This article reviews the current research examining the role of oxytocin in mother-infant relations, attachment, and bonding in humans. METHODS: A systematic search was made of three electronic databases and other bibliographic sources for published research studies that examined oxytocin and mother-infant relations in humans, including attachment, maternal behavior, parenting, and mother-infant relations. RESULTS: Eight studies were identified, all of which were unique in their methodologies, populations studied, and measures used. Seven studies found significant and strong associations between levels or patterns of oxytocin and aspects of mother-infant relations or attachment. CONCLUSIONS: Oxytocin appears to be of crucial importance for understanding mother-infant relationships. The findings of this review suggest that the pioneering, but preliminary, research undertaken to date is promising and that replication with larger samples is needed. Research that draws on more robust measures of attachment and bonding, as well as improved measures of oxytocin that include both central and peripheral levels, will elucidate the role of oxytocin in human mother-infant relationships. As the production of oxytocin is by no means restricted to mothers, the extension of the oxytocin studies to fathering, as well as to alloparental caregiving, would be an intriguing next step. PMID- 21250893 TI - Psychiatric outcomes in young children with a history of institutionalization. AB - Children raised in institutions, considered an extreme example of social deprivation, are one group through which we can better understand the impact of neglect on child health and development. The Bucharest Early Intervention Project (BEIP) is the first randomized, controlled trial of foster care as an intervention for institutionalized children. In this review we describe the mental health outcomes from the BEIP. Specifically, we report findings on attachment styles, attachment disorders, emotional reactivity, and psychiatric symptomatology for children in the BEIP. We describe the impact of the foster care intervention on these outcomes and also describe how outcomes differ by gender and by length of time spent in the institution. In addition, we explore the influence of genetic variation on individual outcomes and recovery from early severe social deprivation, as well as the role of differences in brain development in mediating later psychiatric morbidity. The results from the BEIP confirm and extend the previous findings on the negative sequelae of early institutional care on mental health. The results also underscore the benefit of early family placement for children living in institutions. PMID- 21250894 TI - The predictive value of risk categorization in schizophrenia. AB - BACKGROUND: Risk assessment is increasingly used to inform decisions regarding the psychiatric treatment of patients with schizophrenia and other serious mental disorders. AIMS: To examine the theoretical limits of risk assessment and risk categorization as applied to a range of harms known to be associated with schizophrenia. METHODS: Using known rates of suicide, homicide, self-harm, and violence in schizophrenia, a hypothetical tool with an unrealistically high level of accuracy was used to calculate the proportion of true- and false-positive risk categorizations. RESULTS: Risk categorization incorrectly classified a large proportion of patients as being at high risk of violence toward themselves and others. CONCLUSION: Risk assessment and categorization have severe limitations. A large proportion of patients classified as being at high risk will not, in fact, cause or suffer any harm. Unintended consequences of inaccurate risk categorization include unwarranted detention for some patients, failure to treat others, misallocation of scarce health resources, and the stigma arising from patients' being labeled as dangerous. PMID- 21250895 TI - Mental health implications of music: insight from neuroscientific and clinical studies. AB - Neuroscientific and clinical studies of music over the past two decades have substantially increased our understanding of its use as a means of therapy. The authors briefly review current literature related to music's effect on people with different mental illnesses, and examine several neurobiological theories that may explain its effectiveness or lack thereof in treating psychiatric disorders. Neuroscientific studies have shown music to be an agent capable of influencing complex neurobiological processes in the brain and suggest that it can potentially play an important role in treatment. Clinical studies provide some evidence that music therapy can be used as an alternative therapy in treating depression, autism, schizophrenia, and dementia, as well as problems of agitation, anxiety, sleeplessness, and substance misuse, though whether it can actually replace other modes of treatment remains undetermined. Future research should include translational studies involving both neuroscience and clinical medicine that investigate the long-term effects of music intervention and that lead to the development of new strategies for music therapy. PMID- 21250896 TI - Levetiracetam, seizures, and suicidality. PMID- 21250898 TI - Prospects for radiofrequency hyperthermia applicator research. I--Pre-optimised prototypes of endocavitary applicators with matching interfaces for prostate hyperplasia and cancer treatments. AB - Inconsistency is observed in comparing assessment data of applicators for endocavitary hyperthermia (EHT) with microwaves (MW) and radiofrequency (RF) obtained using the standard method of inserting bare applicators in phantom tissues. MW antennae exhibit overall average penetration depths of approximately 6 mm, excluding hot spots. RF radiators exhibit penetration depths of not more than approximately 3 mm, a value too low considering the superior penetration of the RF plane wave radiation. Assuming that a mismatch at the RF radiator-tissue interface is causing the poor energy transfer of RF energy, we developed new RF radiators with controlled dielectric matching interfaces for evaluating the potential of RF radiation in EHT and in interstitial hyperthermia (IHT) treatments. We designed, developed and assessed 27.12 MHz, 8 mm OD inductive and capacitive devices of novel and existing designs, each provided an optimised bi layer matching interface. The assessment results reveal features such as customisable length and shape, independence of insertion depth, uncritical air gap, longitudinal heating uniformity, outstanding penetration depths (19-20 mm) and high SAR gradients at both radiator ends--i.e. prostatic urethra ends--for added safety. These data clear the way for the development of pre-optimised EHT inductive and capacitive RF applicators. Evidence of positive effects of high near-fields density in cavity microenvironments is given. Such devices show potential for more effective prostatic hyperplasia treatments and for improving the feasibility of more adequate treatment planning and thermal dosimetry of interstitial and transurethral hyperthermia treatments of prostate carcinoma. PMID- 21250900 TI - Influence of debittered, defatted fenugreek seed powder and flaxseed powder on the rheological characteristics of dough and quality of cookies. AB - A functional ingredient mix (FIM) comprising debittered and defatted fenugreek seed powder (70%) and flaxseed powder (30%) was used in cookies. Ash, fat and protein, dough development time, resistance to extension and peak viscosity values increased as the level of FIM increased from 10 to 30% in the blend. Beyond 20% of FIM substitution, the quality characteristics of cookies were adversely affected. Use of soya lecithin produced a significant improvement in the overall quality of the cookies with 20% FIM. Linolenic acid and total dietary fiber content of the cookies with 20% FIM and lecithin contained four times the amount of linolenic acid (2.3%) and double the amount of dietary fiber (13.04%) when compared with the control cookies (0.5% and 6.22%) respectively. Surface scanning electron microscopy of cookies with different levels of FIM from 10 to 30% showed that there was a disruption in the matrix. PMID- 21250901 TI - Effects of vitamin D supplementation on 25-hydroxyvitamin D, high-density lipoprotein cholesterol, and other cardiovascular disease risk markers in subjects with elevated waist circumference. AB - The objective of the present trial was to assess the effects of vitamin D supplementation on serum 25-hydroxyvitamin D [25(OH)D] and high-density lipoprotein cholesterol (HDL-C) in subjects with high waist circumference. Subjects were randomly assigned a daily multivitamin and mineral (MVM) supplement or a MVM supplement plus vitamin D 1,200 IU/day (MVM+D) for 8 weeks. There was a significant difference in mean change for 25(OH)D between the MVM and MVM+D treatment groups ( - 1.2 +/- 2.5 nmol/l vs. 11.7 +/- 3.0 nmol/l, respectively; P = 0.003). Vitamin D 1,200 IU/day did not increase 25(OH)D to a desirable level ( >= 75 nmol/l) in 61% of participants. There were no significant changes in cardiovascular disease risk markers. Thus, vitamin D supplementation with 1,200 IU/day was insufficient to achieve desirable serum 25(OH)D in most participants and did not affect cardiovascular disease risk markers. PMID- 21250902 TI - Chemical compositions and glycemic responses to banana varieties. AB - Chemical compositions and glycemic indices of four varieties of banana (Musa spp.) (kolikuttu-Silk AAB, embul-Mysore AAB, anamalu-Gros Michel AAA, seeni kesel Pisang Awak ABB) were determined. Silk, Gros Michel, Pisang Awak and Mysore contained the highest percentages of starch (14%), sucrose (38%), free glucose (29%) and fructose (58%) as a percentage of the total available carbohydrate content respectively. Total dietary fiber contents of four varieties ranged from 2.7 to 5.3%. Glycemic indices of Silk, Mysore, Gros Michel and Pisang Awak were 61 +/- 5, 61 +/- 6, 67 +/- 7, 69 +/- 9 and can be categorized as low against white bread as the standard. A single banana of the four varieties elicited a low glycemic load. Thus, consumption of a banana from any of these varieties can be recommended as a snack for healthy or diabetic patients who are under dietary management or pharmacological drugs to regulate blood glucose responses in between meals. PMID- 21250903 TI - Customized cooking method improves total antioxidant activity in selected vegetables. AB - The present study compares water-soluble phenolic content (WPC) and antioxidant activities in Chinese long bean (Vigna unguiculata), bitter gourd (Momordica charantia), water convolvulus (Ipomoea aquatica) and broccoli (Brassica olearacea) prior to and after subjecting to boiling, microwaving and pressure cooking. The total antioxidant activity was increased in cooked water convolvulus, broccoli and bitter gourd, estimated based on the ferric reducing antioxidant power, the Trolox equivalent antioxidant capacity and 2,2-diphenyl-1 picryl-hydrazyl radical scavenging activity. Pressure cooking did not cause any significant decline in the antioxidant property. Boiling generally improved the overall antioxidant activity in all the vegetables. Correlation analysis suggests that WPC contributed to significant antioxidant activities in these vegetables. Thus, prudence in selecting an appropriate cooking method for different vegetables may improve or preserve their nutritional value. PMID- 21250904 TI - No high-risk human papillomavirus infection in prostate cancer tissues. PMID- 21250906 TI - Still births--eight years experience at Aga Khan University Hospital Karachi, Pakistan. AB - OBJECTIVES: To examine the possible etiological causes of still births during 8 years of clinical experience at a tertiary referral center, The Aga Khan University Hospital Karachi Pakistan. In addition, to compare demographic and medical risk factors along with analysis of cause of fetal death in different groups. MATERIAL AND METHODS: This was a retrospective cohort study, conducted at the Aga Khan University Karachi, Pakistan over a period of 8-year period between January 2000 and January 2008. We reviewed 287 medical records of all women who had intrauterine fetal demise during study time period. RESULTS: The prevalence of still births at our institution was 6.6 +/- 2.1 per 1000 total births. Congenital anomalies, maternal hypertension, and fetal growth restrictions were the three main causes of still births. About half of still births were among unbooked pregnant women. More than 90% of occurred during the ante natal period while 10% were intrapartum. Majority of stillborns were in macerated state when delivered. CONCLUSION: Most of still births were due to known causes such as hypertension, congenital anomalies, and fetal growth restriction. Improvement in the management of hypertension and diagnosis of congenital anomalies is necessary. Results of the analysis urge on the need for antenatal care and compliance for follow-ups. PMID- 21250907 TI - Prenatal diagnosis of Kniest dysplasia with three-dimensional helical computed tomography. AB - OBJECTIVE: Fetal three-dimensional helical computed tomography (3D-CT) has attracted attention in the diagnosis of fetal skeletal dysplasias because of limited diagnostic capabilities of standard ultrasonography to delineate the skeleton. Here we report the first instance of diagnosing Kniest dysplasia with 3D-CT. METHODS: Fetal 3D-CT was performed for a fetus at 28 weeks' gestation after ultrasonography at 24 weeks had shown moderate shortening of the limbs, mild narrow thorax, and polyhydramnios. The imaging parameters were set so as to reduce estimated fetal irradiation dose to 12.39 mGy of the CT dose index volume and 442 of the dose length product. RESULTS: Fetal 3D-CT revealed dumbbell-shaped femora and platyspondyly with coronal cleft of the lumbar vertebral body. This warranted a diagnosis of Kniest dysplasia and corresponded well with postnatal radiographic findings. In retrospect, however, spinal deformation was somewhat underestimated due to image smoothing associated with image processing in 3D-CT. Genetic testing for COL2A1 confirmed Kniest dysplasia; i.e., a de novo mutation of A-C transversion at the splice acceptor site of the 3' end of intron 16. CONCLUSIONS: The combined use of 3D-CT with ultrasonography is a power tool for the prenatal diagnosis of congenital skeletal dysplasias. PMID- 21250908 TI - Maternal and fetal angiotensin-converting enzyme gene insertion/deletion polymorphism not associated with pregnancy-induced hypertension in Chinese women. AB - OBJECTIVE: The study aimed to investigate whether maternal and fetal angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphisms and the incompatibility of maternal and fetal ACE genotype are associated with the risk of pregnancy-induced hypertension (PIH) in Chinese Han women. METHODS: Using a case-control mother-baby dyads study, a total of 226 maternal/offspring pairs were selected at Anyang Maternal and Child Health Hospital from January 2008 to December 2009. Maternal venous and cord bloods were obtained for DNA extraction. A polymerase chain reaction was performed on the genomic DNA samples to obtain the ACE gene I/D polymorphism. RESULTS: In the present sample, there is no difference in maternal and fetal ACE genotype or allele frequency between PIH patients and control group (p > 0.05). Furthermore, no significant association was found between the genotype incompatibility of fetal and maternal ACE gene and the risk of PIH (p > 0.05). CONCLUSION: We did not find fetus ACE gene I/D polymorphism to be associated with the risk of PIH. Nor is there any evidence that the incompatibility of fetal and maternal ACE genotype is associated with PIH in the studied population. PMID- 21250909 TI - Basal, endogenous leptin is metabolically active in newborn rat pups. AB - OBJECTIVE: The adipocyte-derived hormone leptin regulates food intake and body weight via the activation of JAK-STAT pathway in mammalian adult hypothalamic neurons. To investigate whether endogenous leptin is metabolically active in newborn rat pups, the JAK-STAT leptin signaling pathway was analyzed following leptin antagonist challenge. METHODS: One day old male control pups were injected with either (i) saline, (ii) leptin (10 MUg/g, s.c; n=4), (iii) pegylated leptin antagonist (PEG-MLA, 20 MUg/g, s.c, n=4), or (iv) leptin plus PEG-MLA. Hypothalamus was dissected from individual pups at 30, 45, and 60 min. Protein expression of ObR, STAT3, pSTAT3, and SOCS3 was analyzed by Western blot. RESULTS: Leptin, but not PEG-MLA, produced a significant increase in hypothalamic pSTAT3 relative to saline treatment. Systemically administered PEG-MLA effectively blocks leptin signal induction of hypothalamic JAK-STAT signaling. The presence of PEG-MLA in combination with leptin attenuated the leptin-induced increase in pSTAT3. CONCLUSIONS: Thus, basal leptin levels are metabolically active in the newborn rats. These results brings new insights in considering the importance of endogenous leptin at birth, especially in low birth weight offspring who may be predisposed to altered neurogenesis and later obesity, and provide potential therapeutic strategies for programmed or diet-induced obesity. PMID- 21250910 TI - Cerebral blood flow autoregulation and congenital heart disease: possible causes of abnormal prenatal neurologic development. AB - OBJECTIVE: To determine whether the major congenital heart diseases (CHDs) can modify the cerebrovascular flow dynamics and the biometrical parameters in fetuses at third trimester of pregnancy. METHODS: We studied 60 fetuses with CHD. Data included prenatal versus postnatal cardiac diagnosis, cerebral and umbilical artery doppler, fetal biometrical parameters, fetal weight, and gestational age. The pulsatility index (PI) was used to determine blood flow velocities in the umbilical artery (UA) and middle cerebral artery (MCA), while the cerebro/placental ratio (CPR) was assessed as a measure of cerebral autoregulation. Fetuses with CHD were compared to normal controls and then analyzed after being divided into groups based on specific defects. RESULTS: Compared with control fetuses, those with CHD showed a decrease of resistance blood flow in the middle cerebral artery (1.76 vs 1.92 PI) especially considering the CPR (1.66 vs 2.03 PI) (p < 0.01). Furthermore, fetuses with CHD also had smaller head circumferences (30.6 cm vs 31.5 cm p < 0.01) and head/abdominal (HC/AC) ratio (1 vs 1.05 p < 0.01). When stratified for single cardiac diseases, fetuses with hypoplasic left heart syndrome showed a lower CPR and HC/AC ratio. CONCLUSIONS: Cerebrovascular resistance is significantly lower in fetuses with CHD, especially in cases of left side obstruction. The cerebro/placental hemodynamic changes are similar to that described in fetuses with placental insufficiency and may contribute to their abnormal neurologic development. PMID- 21250911 TI - Heart stroke volume, cardiac output, and ejection fraction in 265 normal fetus in the second half of gestation assessed by 4D ultrasound using spatio-temporal image correlation. AB - OBJECTIVES: The aim of this study was to establish nomograms for fetal stroke volume (SV), cardiac output (CO), and ejection fraction (EF) using four dimensional ultrasound with spatio-temporal image correlation (STIC) modality. METHODS: The fetal heart was scanned using STIC modality, starting with classic four-chamber view plane, during fetal quiescence with abdomen uppermost, at an angle of 20-30 degrees , without color Doppler flow mapping. In post-processing virtual organ, computer-aided analysis technique was used to obtain a sequence of six sections of each ventricular volume in end-systolic volume (ESV) and end diastolic volume (EDV). The SV (SV = EDV-ESV), CO (CO = SV * fetal heart rate), and EF (EF = SV/EDV) for each ventricle were then calculated. Intra- and interobserver agreement were then calculated. RESULTS: Two hundred sixty-five fetuses, ranging in gestational age (GA) from 20 to 34(+6) weeks, were included in the study. The left and right SV and CO increased exponentially with gestation and EF remained fairly stable through gestational. Mean left and right SV increased from 0.211 ml and 0.220 ml at 20 weeks to 1.925 ml and 2.043 ml, respectively, at 34 weeks. Mean left and right CO increased from 30.25 ml/min and 31.52 ml/min at 20 weeks to 268.49 ml/min and 287.80 ml/min, respectively, at 34 weeks. Both left and right mean EF remained constant at around 0.63 with advancing GA. Nomograms were created for LSV, RSV, LCO, RCO, LEF, and REF vs. gestational age. Intra- and interobserver agreement reached 95%. CONCLUSIONS: Four-dimensional ultrasound using STIC represents a simple and reproducible method for estimating fetal cardiac function. STIC seems to overcome many of the pitfalls of conventional ultrasound methods and has the potential to become the method of choice. PMID- 21250912 TI - Artificial neural network for normal, hypertensive, and preeclamptic pregnancy classification using maternal heart rate variability indexes. AB - OBJECTIVE: A model construction for classification of women with normal, hypertensive and preeclamptic pregnancy in different gestational ages using maternal heart rate variability (HRV) indexes. METHOD AND PATIENTS: In the present work, we applied the artificial neural network for the classification problem, using the signal composed by the time intervals between consecutive RR peaks (RR) (n = 568) obtained from ECG records. Beside the HRV indexes, we also considered other factors like maternal history and blood pressure measurements. RESULTS AND CONCLUSIONS: The obtained result reveals sensitivity for preeclampsia around 80% that increases for hypertensive and normal pregnancy groups. On the other hand, specificity is around 85-90%. These results indicate that the combination of HRV indexes with artificial neural networks (ANN) could be helpful for pregnancy study and characterization. PMID- 21250913 TI - Early erythropoietin influences both transfusion and ventilation need in very low birth weight infants. AB - OBJECTIVE: The primary outcome measure of this study was the ability of rHuEPOalpha therapy to reduce transfusion needs, whereas secondary outcome measures were NICU-LOS and ventilation need. METHODS: All babies with BW <1250 g and GA <30 were eligible. Thirty premature neonates were enrolled in the study (10 treated, 20 controls). rHuEPOalpha was administered as 300 IU/kg/dose 3 times/week subcutaneously. Iron, folic acid and Vitamin E supplementation were administered in both groups. Hematologic variables and blood sampling were recorded during the study. RESULTS: In rHuEPO group, only four (40%) premature infants required a transfusion, averaging 0.4 +/- 0.52 transfusions/pts. A total of 23 transfusions were administered to controls; 11 (55%) infants received one transfusion at least, 55% required multiple transfusions. The average number of transfusions/pts was statistically different (1.15 +/- 1.46 vs. 0.4 +/- 0.52; p = 0.02), as the cumulative number of transfused patients (55% vs. 40%; p<0.001). NICU stay was not statistically different, whereas ventilation-free days were increased in EPO group (p<0.05). CONCLUSIONS: R-Hu-EPO treatment in first post natal weeks markedly enhanced erythropoiesis in severely premature infants compared with matched controls, with a significant impact on transfusion needs. EPO group experienced also a reduction of ventilation time and, possibly, a decreased occurrence of clinical BPD. PMID- 21250914 TI - The impact of obesity on maternal morbidity and feto-infant outcomes among macrosomic infants. AB - OBJECTIVE: To estimate the contribution of obesity to maternal complications, neonatal morbidity and mortality among macrosomic births. DESIGN: A population based retrospective cohort design using State of Missouri maternally linked birth cohort files. METHODS: Using pre-gravid body mass index (BMI), we categorized mothers of 116,976 singleton macrosomic live births as non-obese (BMI < 30) or obese (BMI >= 30). We used logistic regression models to generate adjusted odd ratios for pregnancy and neonatal complications. We also estimated the proportion of potentially preventable excess maternal and neonatal complications that could be eliminated among obese women with infant macrosomia at various levels of pre pregnancy obesity reduction. RESULT: Obese mothers with macrosomic infants were at elevated risk for chronic hypertension (odds ratio (OR) = 6.78 [95% confidence interval (CI): 5.82-7.88]), insulin-dependent diabetes mellitus, (OR = 2.60 [CI: 2.34-2.88]) other types of diabetes mellitus (OR = 2.83 [CI: 2.65-3.02]) and preeclampsia (OR = 2.49 [CI: 2.33-2.67]). Macrosomic infants of obese mothers were at greater risk for hyaline membrane disease (OR = 2.14 [CI: 1.73-2.66]), extended assisted ventilation (OR = 1.71 [CI: 1.44-2.04]), birth injury (OR = 1.58 [CI: 1.37-1.84]) and meconium aspiration syndrome (OR = 1.42 [CI: 1.09 1.87]). The proportion of preventable excess maternal morbidity was 60%, 45%, 30% and 15%, assuming an effective pre-conception intervention that could reduce obesity down to 0%, 25%, 50% and 75% of its current level, respectively. The corresponding proportion of preventable excess neonatal complications would be 40%, 30%, 20% and 10%, respectively. CONCLUSION: Among obese mothers with macrosomic births, a substantial proportion of maternal and neonatal morbidity could be averted through effective pre-conception interventions. PMID- 21250915 TI - First experiences with the use of intraoperative 3D-RX for wrist surgery. AB - With the use of conventional C-arm fluoroscopy for hand surgery, suboptimal positioning of implants, K-wires, insufficient reconstructions and joint incongruities frequently remain unrevealed We prospectively compared the performance of the surgeon interpreted from conventional methods (2D fluoroscopy and direct visual and physical inspection) versus 3D imaging as well as the occurrence of revision surgeries based on post-op radiological findings. Twenty four intraoperative findings based on 2D fluoroscopy and findings on direct visual and physical inspections were compared with intraoperatively acquired 3D RX scans by means of a questionnaire. Moreover, record was kept of revision surgery (minimal three months follow up) for all patients treated with the aid of 3D-RX. A clear difference in findings was observed between the performance based on fluoroscopy and direct visual and physical inspection and that based on intraoperative 3D-RX for hand surgery (p < 0.05). Post-operative radiological examinations revealed that none of the 56 patients treated with the aid of 3D-RX needed revision surgery. Intraoperative 3D-RX provides information for the hand surgeon that is additional to the information acquired with conventional fluoroscopy. Intraoperative 3D-RX provides well defined images of the positioning of osteosynthesis material, of the spatial orientation of carpals, and of reconstruction of the wrist joint. PMID- 21250916 TI - Intracanal pressure in compressive spinal cord injury: reduction with hypothermia. AB - Most cases of human spinal cord injury (SCI) are accompanied by continuing cord compression. Experimentally, compression results in rapid neurological decline over hours, suggesting a rise in intracanal pressure local to the site of injury. The aim of this study was to measure the rise in local intracanal pressure accompanying progressive canal occlusion and to determine the relationship between raised intracanal pressure and neurological outcome. We also aimed to establish whether hypothermia was able to reduce raised intracanal pressure. We demonstrate that, following SCI in F344 rats, local intracanal pressure remains near normal until canal occlusion exceeds 30% of diameter, whereupon a rapid increase in pressure occurs. Intracanal pressure appears to be an important determinant of neurological recovery, with poor long-term behavioural and histological outcomes in animals subject to 8 h of 45% canal occlusion, in which intracanal pressure is significantly elevated. In contrast, good neurological recovery occurs in animals with near normal intracanal pressure (animals undergoing 8 h of 30% canal occlusion or those undergoing immediate decompression). We further demonstrate that hypothermia is an effective therapy to control raised intracanal pressure, rapidly reducing elevated intracanal pressure accompanying critical (45%) canal occlusion to near normal. Overall these data indicate that following SCI only limited canal narrowing is tolerated before local intracanal pressure rapidly rises, inducing a sharp decline in neurological outcome. Raised intracanal pressure can be controlled with hypothermia, which may be a useful therapy to emergently decompress the spinal cord prior to surgical decompression. PMID- 21250917 TI - Diffusion tensor imaging of incentive effects in prospective memory after pediatric traumatic brain injury. AB - Few studies exist investigating the brain-behavior relations of event-based prospective memory (EB-PM) impairments following traumatic brain injury (TBI). To address this, children with moderate-to-severe TBI performed an EB-PM test with two motivational enhancement conditions and underwent concurrent diffusion tensor imaging (DTI) at 3 months post-injury. Children with orthopedic injuries (OI; n=37) or moderate-to-severe TBI (n=40) were contrasted. Significant group differences were found for fractional anisotropy (FA) and apparent diffusion coefficient for orbitofrontal white matter (WM), cingulum bundles, and uncinate fasciculi. The FA of these WM structures in children with TBI significantly correlated with EB-PM performance in the high, but not the low motivation condition. Regression analyses within the TBI group indicated that the FA of the left cingulum bundle (p=0.003), left orbitofrontal WM (p<0.02), and left (p<0.02) and right (p<0.008) uncinate fasciculi significantly predicted EB-PM performance in the high motivation condition. We infer that the cingulum bundles, orbitofrontal WM, and uncinate fasciculi are important WM structures mediating motivation-based EB-PM responses following moderate-to-severe TBI in children. PMID- 21250919 TI - Down-regulation of glial fibrillary acidic protein and vimentin by RNA interference improves acute urinary dysfunction associated with spinal cord injury in rats. AB - In spinal cord injury, glial scarring, a result of overexpressed intermediate filament (IF) proteins including glial fibrillary acidic protein (GFAP) and vimentin, is one of the largest obstacles in axonal regeneration. We postulated that specific suppression of IF proteins in the injured CNS might inhibit the excessive reactivity of astrocytes and thereby suppress glial scarring. siRNAs targeting GFAP and vimentin were transfected separately into C6 glioma cells and rat hippocampal astrocytes. These siRNAs suppressed both biphasic elements of each IF proteins: the ordinarily expressed elements having slow turnover and the immediately inducible elements stimulated by tumor necrosis factor-a (TNF-alpha). Moreover, adenovirus vectors expressing GFAP or vimentin siRNAs suppressed the proliferation of C6 glioma cells on days 3-9 after infection. Finally, each siRNA mixed with atelocollagen was applied together to the contused thoracic spines of spinal cord injury (SCI) model rats. The introduction of GFAP and vimentin siRNAs prevented the overexpression of IF proteins in the injured lesion (namely, in the white matter surrounding the long tract where the lateral funiculus exists and in the gray matter near the anterior horn neurons). Furthermore, the starting date of spontaneous voiding was significantly accelerated by application of GFAP and vimentin siRNAs. The inhibition of undesirable glial activity surrounding micturition-related pathways improved acute urinary dysfunction due to neurogenic bladder. In conclusion, the down-regulation of IF proteins by RNAi suppresses the overproliferation of reactive astrocytes and thereby might be an effective treatment for spinal cord injury. PMID- 21250918 TI - Cyclosporin A preserves mitochondrial function after traumatic brain injury in the immature rat and piglet. AB - Cyclosporin A (CsA) has been shown to be neuroprotective in mature animal models of traumatic brain injury (TBI), but its effects on immature animal models of TBI are unknown. In mature animal models, CsA inhibits the opening of the mitochondrial permeability transition pore (MPTP), thereby maintaining mitochondrial homeostasis following injury by inhibiting calcium influx and preserving mitochondrial membrane potential. The aim of the present study was to evaluate CsA's ability to preserve mitochondrial bioenergetic function following TBI (as measured by mitochondrial respiration and cerebral microdialysis), in two immature models (focal and diffuse), and in two different species (rat and piglet). Three groups were studied: injured+CsA, injured+saline vehicle, and uninjured shams. In addition, we evaluated CsA's effects on cerebral hemodynamics as measured by a novel thermal diffusion probe. The results demonstrate that post injury administration of CsA ameliorates mitochondrial dysfunction, preserves cerebral blood flow (CBF), and limits neuropathology in immature animals 24 h post-TBI. Mitochondria were isolated 24 h after controlled cortical impact (CCI) in rats and rapid non-impact rotational injury (RNR) in piglets, and CsA ameliorated cerebral bioenergetic crisis with preservation of the respiratory control ratio (RCR) to sham levels. Results were more dramatic in RNR piglets than in CCI rats. In piglets, CsA also preserved lactate pyruvate ratios (LPR), as measured by cerebral microdialysis and CBF at sham levels 24 h after injury, in contrast to the significant alterations seen in injured piglets compared to shams (p<0.01). The administration of CsA to piglets following RNR promoted a 42% decrease in injured brain volume (p<0.01). We conclude that CsA exhibits significant neuroprotective activity in immature models of focal and diffuse TBI, and has exciting translational potential as a therapeutic agent for neuroprotection in children. PMID- 21250920 TI - Assessment of the effectiveness of light-emitting diode and diode laser hybrid light sources to intensify dental bleaching treatment. AB - OBJECTIVE: To evaluate the effectiveness of the color change of hybrid light emitting diode (LED) and low-intensity infrared diode laser devices for activating dental bleaching and to verify the occurrence of a color regression with time. MATERIAL AND METHODS: A total of 180 specimens obtained from human premolars were immersed in a coffee solution for 15 days for darkening and then divided into eight experimental groups (n = 20 in each) as follows: G1, bleaching without light; G2, bleaching with halogen light; G3, bleaching with a blue LED (1000 mW/470 nm) and a laser device (120 mW/795 nm) simultaneously; G4, bleaching with an LED emitting blue light (1000 mW/470 nm); G5, bleaching with a blue LED (800 mW/470 nm) and a laser device (500 mW/830 nm) simultaneously; G6, bleaching with a blue LED device (800 mW); G7, bleaching with a green LED (600 mW/530 nm) and a laser device (120 mW/795 nm) simultaneously; and G8, bleaching with a green LED (600 mW). Three measurements were performed (at baseline and 14 days and 12 months after bleaching) using a Vita Easyshade spectrophotometer. The data were submitted to two-way ANOVA and a Tukey test. RESULTS: All groups showed significantly higher DeltaE values than Group G1, with the exception of Group G8. Variations in the DeltaE values at 14 days were significant when compared with those obtained at baseline and after 12 months. CONCLUSIONS: Light activation of the bleaching gel provided faster and more intense bleaching than use of the bleaching gel without light activation. Combinations of low-intensity diode lasers are ineffective as a bleaching gel activator. Color regression was observed after 12 months of storage. PMID- 21250922 TI - Controversies in ocular toxoplasmosis. AB - Toxoplasmosis, a major cause of infectious uveitis, was elected by the editors of Ocular Immunology and Inflammation as the disease of the year for 2011. The aim of the present review was to report on the results of a survey of leading uveitis experts, in which the authors asked participants to address some of the most important issues related to diagnosis, pathophysiology, and treatment of ocular toxoplasmosis. The survey revealed generally good consensus regarding clinical signs of typical and atypical toxoplasmic retinochoroiditis. In contrast, views regarding diagnostic approach, possible epidemiological influences, transmission of disease, and trigger factors seemed less clearly defined. Responses revealed a large number of drug regimens in use for both congenital and acquired disease. Finally, recurrence prophylaxis was not regularly recommended by the majority of experts. PMID- 21250923 TI - Genetics in ocular inflammation--basic principles. AB - The ability to identify individuals at risk of ocular disease, or to determine the potential severity of disease or response to therapy is the current focus of much research. These studies are being led by genetic analysis of individuals to determine associations with alterations in gens that may explain manifestations of particular diseases. In this review we consider the basic principles behind genetic studies in general and of ocular disease in particular. We address the methodologies being utilised, and the results derived so far. The potential and pitfalls of such studies are relevant to the concept of personalised medicine and better defined clinical trials. PMID- 21250924 TI - Spectral domain optical coherence tomography findings in acute posterior multifocal placoid pigment epitheliopathy. AB - PURPOSE: To report spectral domain optical coherence tomography (SD OCT) findings in acute posterior multifocal placoid pigment epitheliopathy (APMPPE). DESIGN: Prospective, observational case report. METHODS: Complete ophthalmologic examination, including fluorescein angiography and SD OCT. RESULTS: A 31-year-old female with APMPPE presented with large intraretinal cysts in the outer nuclear layer consistent with intraretinal edema on SD OCT. Spontaneous normalization of the gross anatomy of the fovea with disruption of the inner/outer photoreceptor segment junction was observed in both eyes. CONCLUSION: The findings show that massive intraretinal edema may occur in the early stages of APMPPE. PMID- 21250925 TI - Role of high-resolution computerized tomography (HRCT) of the chest in granulomatous uveitis: a tertiary uveitis clinic experience from India. AB - AIM: To evaluate the role of high-resolution computerized tomography (HRCT) of the chest as a diagnostic tool in granulomatous uveitis. DESIGN: Observational case series. METHODS: Fifty-eight consecutive patients were evaluated with chest HRCT based on clinical diagnosis of granulomatous uveitis, which was further classified using SUN classification as anterior, intermediate, posterior, and panuveitis. Clinical profile, laboratory findings, chest radiographs, and chest HRCT scans were analyzed. RESULTS: Of 58 patients, 35 were males and 23 females with mean age of 43.5 years. Forty-seven patients had bilateral and 11 had unilateral involvement. Eighty-one percent of patients referred for chest HRCT demonstrated signs suggestive of tuberculosis, 8.6% patients showed signs suggestive of sarcoidosis, and 10.3% patients showed normal chest HRCT. CONCLUSION: Chest HRCT was found to be a useful tool in the diagnosis of granulomatous uveitis, especially tuberculosis associated uveitis, and can aid in therapeutic decisions. PMID- 21250927 TI - Radiation therapy did not alleviate complete paralysis due to metastasis of lung adenocarcinoma to thoracic vertebrae until four months later. PMID- 21250928 TI - The frequency and consequences of cardiopulmonary resuscitation performed by bystanders on patients who are not in cardiac arrest. AB - BACKGROUND: The American Heart Association encourages trained and untrained bystanders to perform, at a minimum, chest compressions on anyone who suddenly collapses. It is possible that people who are not in cardiac arrest may receive bystander cardiopulmonary resuscitation (CPR), from which the potential for injury is unknown. OBJECTIVES: To determine the number of victims who received bystander CPR but were not in cardiac arrest and to identify any injuries resulting from receiving bystander CPR. METHODS: Retrospective review of patient care records from a countywide emergency medical services (EMS) database. All patients treated by EMS between March 2003 and February 2009 who received bystander CPR were queried. Victims who were determined not to be in cardiac arrest upon EMS personnel assessment were identified as likely not in cardiac arrest. Hospital medical records for transported patients were reviewed for injuries possibly related to CPR. Patient demographics were collected and descriptive statistics were used for analysis. RESULTS: Six hundred seventy-two incidents of bystander CPR occurred, with 77 (11.5%) cases not being identified as cardiac arrests by EMS. Twenty-three percent of the patients were less than 19 years of age. Emergency medical services arrived in less than 6 minutes for 68% of patients. Seventy-two patients were evaluable for injury; of those, 53% were admitted to the intensive care unit. One patient (1.4%) had an injury that was documented in the medical record as possibly CPR-related: rhabdomyolysis. CONCLUSIONS: Bystanders provide CPR for patients who are not in cardiac arrest at a relatively low frequency. Short-duration bystander CPR caused injury in less than 2% of victims. Our results suggest that the benefits of bystander CPR for adults who suddenly collapse outweigh the risk of injury for those not in cardiac arrest. PMID- 21250930 TI - Enhanced transplantability of a cell line from a murine ovary granulosa cell tumour in syngeneic B6C3F(1) mice continuously irradiated with low dose-rate gamma-rays. AB - PURPOSE: To understand the mechanisms of life-shortening due to early neoplastic death caused by chronic low dose-rate (LDR; 20 mGy/22 h/day) radiation which accumulates to a high dose (HD; 8 Gy) (LDR/HD) as reported previously. MATERIALS AND METHODS: Female B6C3F(1) mice were continuously exposed to LDR/HD gamma-rays under specific-pathogen-free (SPF) conditions for 400 days. OV3121 cells, which were derived from an ovarian granulosa cell tumour that arose in irradiated B6C3F(1) mice, were inoculated into LDR/HD irradiated and age-matched non irradiated control mice. The transplantability of tumour cells as well as T cell subsets and the proliferative activities of T cells were compared between irradiated and non-irradiated mice. RESULTS: We found that tumour formation of subcutaneously inoculated tumour cells occurred earlier in irradiated mice than in non-irradiated mice. Proliferative activity of draining lymph node lymphocytes against transplanted tumour cells as well as allogeneic mixed lymphocyte reactions were significantly reduced in irradiated mice compared to non irradiated mice. CONCLUSIONS: These results suggest that decreased tumour specific immune response due to LDR/HD irradiation may enhance tumorigenesis resulting in life-shortening of mice after chronic LDR/HD irradiation. PMID- 21250929 TI - Meta-analysis of non-tumour doses for radiation-induced cancer on the basis of dose-rate. AB - PURPOSE: Quantitative analysis of cancer risk of ionising radiation as a function of dose-rate. MATERIALS AND METHODS: Non-tumour dose, D(nt), defined as the highest dose of radiation at which no statistically significant tumour increase was observed above the control level, was analysed as a function of dose-rate of radiation. RESULTS: An inverse correlation was found between D(nt) and dose-rate of the radiation. D(nt) increased 20-fold with decreasing dose-rate from 1-10(-8) Gy/min for whole body irradiation with low linear energy transfer (LET) radiation. Partial body radiation also showed a dose-rate dependence with a 5- to 10-fold larger D(nt) as dose rate decreased. The dose-rate effect was also found for high LET radiation but at 10-fold lower D(nt) levels. CONCLUSIONS: The cancer risk of ionising radiation varies 1000-fold depending on the dose-rate of radiation and exposure conditions. This analysis explains the discrepancy of cancer risk between A-bomb survivors and radium dial painters. PMID- 21250931 TI - Sensitivity of porcine peripheral blood leukocytes to gamma irradiation in vivo, in vitro and ex vivo. AB - PURPOSE: The large white pig is a useful experimental model to compare in vivo, in vitro and ex vivo sensitivity of peripheral blood leukocytes to ionising radiation. Such studies are impossible to perform in humans and laboratory rodents due to ethical reasons and body size, respectively. We analysed dose- and time-dependent changes of lymphocyte and granulocyte absolute numbers in porcine peripheral blood after either whole-body irradiation (in vivo and ex vivo experiments) or exposure of porcine whole blood to gamma-irradiation (in vitro experiments). MATERIALS AND METHODS: CytoCountTM absolute counting beads and light scatter analysis using a flow cytometer were used to determine major leukocyte subpopulation numbers in blood samples after red cell removal. RESULTS: Similar to other species, lymphocyte numbers significantly decreased in pigs both in vivo and in vitro in a dose-dependent manner. Most importantly, our data clearly show that reduction of lymphocyte numbers after irradiation in vivo proceeds much faster than after irradiation in vitro and that granulocyte changes depend only on the time of analysis after irradiation. CONCLUSIONS: All three tested experimental arrangements demonstrated the radiosensitivity of lymphocytes and the radioresistance of peripheral blood granulocytes. These in vivo and in vitro approaches, as well as the newly introduced ex vivo observations, appear to be relevant to biodosimetry. PMID- 21250932 TI - Acute renal failure in severe pancreatitis: A population-based study. AB - INTRODUCTION: Acute pancreatitis (AP) is a common illness with varied mortality and morbidity. Patients with AP complicated with acute renal failure (ARF) have higher mortality than patients with AP alone. Although ARF has been proposed as a leading mortality cause for AP patients admitted to the ICU, few studies have directly analyzed the relationship between AP and ARF. METHODS: We performed a retrospective study using the population-based database from the Taiwan National Health Insurance Research Database (NHIRD). In the period from 1 January 2005 to 31 December 2005, every patient with AP admitted to the ICU was included and assessed for the presence of ARF and mortality risk. RESULTS: In year 2005, there were a total of 221,101 admissions to the ICU. There were 1,734 patients with AP, of which 261 (15.05%) patients also had a diagnosis of ARF. Compared to sepsis and other critical illness, patients with AP had a higher risk of having a diagnosis of ARF, and patients with both diagnoses had a higher mortality rate in the same ICU hospitalization. CONCLUSION: AP is associated with a higher risk of ARF, and, when both conditions exist, a higher risk of mortality is present. PMID- 21250933 TI - Haloperidol alters circadian clock gene product expression in the mouse brain. AB - OBJECTIVES: Circadian rhythms are patterns in behavioural and physiological measures that recur on a daily basis and are driven by an endogenous circadian timekeeping system whose molecular machinery consists of a number of clock genes. The typical anti-psychotic haloperidol has previously been shown to induce significant deficiencies in circadian timing in patients. In this study we examined the impact of haloperidol treatment on molecular components of the circadian clock in the mouse brain. METHODS: We examined how haloperidol treatment, either acute (both at day and night) or chronically over 14 days, alters the expression of three clock gene protein products (PER1, PER2, BMAL1) across the mouse brain by means of immunohistochemistry. RESULTS: Chronic haloperidol treatment significantly decreases the expression levels of PER1 in a number of brain areas, including the hippocampus, the prefrontal and cingulate cerebral cortex and the paraventricular nucleus of the hypothalamus. PER2 expression was only altered in the dentate gyrus and the CA3, and BMAL1 expression was only altered in the paraventricular nucleus of the hypothalamus. CONCLUSION: These data indicate that haloperidol has the potential to alter circadian rhythms via modulation of circadian clock gene expression. PMID- 21250934 TI - Increased density of GAD65/67 immunoreactive neurons in the posterior subiculum and parahippocampal gyrus in treated patients with chronic schizophrenia. AB - OBJECTIVES: Alterations of glutamic acid decarboxylase (GAD) play a crucial role in schizophrenic pathology. While GAD has been studied in several brain regions, its expression in the posterior hippocampus formation has not been investigated in schizophrenia. METHODS: We studied the brains of 17 patients with chronic schizophrenia and 15 controls. Using the optical dissector method we counted GAD65/67 immunoreactive neurons and pyramidal cells in the posterior hippocampus, subiculum, and parahippocampal gyrus, and measured the cortical thickness in posterior subiculum and parahippocampal gyrus. Patients had received typical neuroleptics for the mean of 20.8 years. RESULTS: In the patients we observed a significant increase of GAD immunoreactive neurons in the subiculum (left/right P = 0.004) and the parahippocampal gyrus (left P = 0.001, right P = 0.006). The hippocampus showed no or only subtle trends towards higher GAD densities. The density of pyramidal neurons and cortical thickness did not differ between the groups. A significant association between GAD density and the duration of illness was found in women with schizophrenia. CONCLUSIONS: The current data on GAD65/67 indicates a dysregulation of the GABAergic system in schizophrenia patients that may be associated with cognitive decline. However, a long term effect of neuroleptics on the GABAergic system cannot be excluded. PMID- 21250935 TI - Newer avenues for the treatment of leptomeningeal carcinomatosis. AB - Leptomeningeal Carcinomatosis (LC) refers to diffuse seeding of the leptomeninges by tumor metastases and is a rare presentation of solid tumors, particularly breast cancer, lung cancer and malignant melanoma in adults and hematogenous malignancies and primitive neuroectodermal tumor (PNET) in children. Recently, the incidence of LC has been reported to be increasing due to a longer overall survival obtained in patients treated with novel antineoplastic agents. The usual clinical presentation is a multifocal involvement of the neuraxis, with headache and radicular pain being the most common initial symptoms. The most frequent signs are motor deficits, altered mental status and cranial nerve involvement. The treatment of LC remains controversial and no straightforward guidelines exist in the literature. It has a bad prognosis and inevitably fatal outcome despite aggressive therapy. PMID- 21250936 TI - Neurogenic drugs and compounds to treat CNS diseases and disorders. AB - Neurological diseases and related conditions affect an estimated 1 billion of individuals worldwide [1]. There is still no cure for neurological diseases and disorders, barely a few treatments more or less efficient. This mandates the design and development of novel paradigms and strategies, to discover and develop new treatments and cures for these diseases. Neurogenesis occurs in the adult brain of mammals primarily in two regions, the dentate gyrus (DG) of the hippocampus and the subventricular zone, in various species including in humans. Neural progenitor and stem cells have been isolated, propagated and characterized in vitro from the adult brain of mammals, including humans. The confirmation that neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside in the adult central nervous system (CNS) of mammals, opens new avenues and opportunities for treating neurological diseases and injuries [2]. PMID- 21250937 TI - Elderly patients with migraine: an open-label study on prophylaxis therapy with levetiracetam. AB - In the last years, the hypothesis that cortical hyperexcitability may play a role in the physiopathology of migraine led to the therapeutic use of some antiepileptic drugs. To evaluate the efficacy of levetiracetam as prophylactic treatment for migraine without aura in elderly patients. We performed a small open-label trial treating 13 elderly patients(8F 5M) mean age 64.7 years (SD 3.4), range 60-72 years affected by migraine without aura (ICDH '04 criteria). The mean age of disease was 21.3 years (SD13.4) range 2-45 years. At baseline: the frequency of attacks was 12.2/month (SD 5.9), range 6-25; the mean number of drugs for acute attacks was 12.6 (SD 6.5) tablets/month. All patients took concomitant medication for other chronic diseases. After recruitment Levetiracetam 500 mg/die was administered for 1 week and 1000 mg/die for six months. The basal frequency of attack was 12,2 (SD 5.9) and 8,3 (SD 4.9), 4,1 (SD2.6), 1,3 (SD1.4) after 1, 3 and 6 months respectively [P=0.079; P<0.0001; P<0.0001].The basal value of intaking drugs for acute attacks was 12,6 (SD 6.5) and 6,7 (SD 4.3), 2,8 (SD 2.2), 1,4 (SD1.7) after 1, 3 and six months respectively [P=0.012; P<0.0001; P<0.0001](T-test analysis). Levetiracetam was well tolerated (7 patients complained somnolence, lack of concentration and gastralgia but none patient withdrew the study). In our study levetiracetam showed a good efficacy in frequency and intensity reduction of headache attack and showed a very good tolerability despite all elderly patients took drugs for concomitant diseases. PMID- 21250938 TI - The ongoing effort to increase awareness of novel scientific findings worldwide and the scientific issues amongst scientists and non-scientists alike is essential to restore independent science to each and every one that follows. PMID- 21250940 TI - HID-1 is a novel player in the regulation of neuropeptide sorting. AB - Peptide hormones and neuropeptides are packaged and stored in a specialized intracellular organelle called the dense core vesicle. It remains elusive how peptide cargoes are correctly sorted. In the present study, we show that a highly conserved Golgi-localized protein named HID-1 acts to prevent mis-sorting of peptide cargoes to lysosomes for degradation via a PtdIns3P-dependent trafficking pathway. Epistasis analysis suggests that rab-2 is epistatic to hid-1. PMID- 21250939 TI - Transcriptional regulation of the Zrg17 zinc transporter of the yeast secretory pathway. AB - The Msc2 and Zrg17 proteins of Saccharomyces cerevisiae are members of the cation diffusion facilitator family of zinc transporters. These proteins form heteromeric complexes that transport zinc into the ER (endoplasmic reticulum). Previous studies suggested that the ZRG17 gene is regulated in response to zinc status by the Zap1 transcription factor. Zap1 activates the expression of many genes in zinc-deficient cells. In the present study, we assessed whether ZRG17 is a direct Zap1 target gene. We showed that ZRG17 mRNA levels were elevated in zinc limited cells in a Zap1-dependent manner and were also elevated in zinc-replete cells expressing a constitutively active allele of Zap1. Furthermore, Zrg17 protein levels correlated closely with mRNA levels. A candidate Zap1-binding site [ZRE (zinc-responsive element)] in the ZRG17 promoter was required for this induction. Using electrophoretic mobility-shift assays and chromatin immunoprecipitation, we demonstrated that Zap1 binds specifically to the ZRG17 ZRE both in vitro and in vivo. By using a chromosomal ZRG17 mutant with a non functional ZRE, we found that Zap1 induction of ZRG17 is required for ER function as indicated by elevated ER stress under zinc-limited conditions. Together, these results establish that ZRG17 is a direct Zap1 target gene and its regulation has biological importance in maintaining ER function. PMID- 21250941 TI - IEX-1 suppresses apoptotic damage in human intestinal epithelial Caco-2 cells induced by co-culturing with macrophage-like THP-1 cells. AB - We have reported previously that apoptosis of intestinal epithelial Caco-2 cells is induced by co-culturing with human macrophage-like THP-1 cells, mainly via the action of TNFalpha (tumour necrosis factor alpha) secreted from THP-1 cells [Satsu, Ishimoto, Nakano, Mochizuki, Iwanaga and Shimizu (2006) Exp. Cell Res. 312, 3909-3919]. Our recent DNA microarray analysis of co-cultured Caco-2 cells showed that IEX-1 (immediate early-response gene X-1) is the most significantly increased gene during co-culture [Ishimoto, Nakai, Satsu, Totsuka and Shimizu (2010) Biosci. Biotechnol. Biochem. 74, 437-439]. Hence, we investigated the role of IEX-1 in the co-culture-induced damage of Caco-2 cells. We showed that IEX-1 expression induced in Caco-2 cells was suppressed by anti-TNFalpha antibody treatment. Experiments using IEX-1-overexpressing and -knockdown Caco-2 cells suggested that IEX-1 was involved in the suppression of Caco-2 cell damage. Increases in caspase 3 activity and TNFR1 (TNF receptor 1) mRNA expression were shown in IEX-1-knockdown Caco-2 cells, suggesting that IEX-1 plays a role in the suppression of apoptosis and protects cells by controlling sensitivity to TNFalpha under both normal and inflammatory conditions. PMID- 21250942 TI - Dysregulation of axonal transport and motorneuron diseases. AB - MNDs (motorneuron diseases) are neurodegenerative disorders in which motorneurons located in the motor cortex, in the brainstem and in the spinal cord are affected. These diseases in their inherited or sporadic forms are mainly characterized by motor dysfunctions, occasionally associated with cognitive and behavioural alterations. Although these diseases show high variability in onset, progression and clinical symptoms, they share common pathological features, and motorneuronal loss invariably leads to muscle weakness and atrophy. One of the most relevant aspect of these disorders is the occurrence of defects in axonal transport, which have been postulated to be either a direct cause, or a consequence, of motorneuron degeneration. In fact, due to their peculiar morphology and high energetic metabolism, motorneurons deeply rely on efficient axonal transport processes. Dysfunction of axonal transport is known to adversely affect motorneuronal metabolism, inducing progressive degeneration and cell death. In this regard, the understanding of the fine mechanisms at the basis of the axonal transport process and of their possible alterations may help shed light on MND pathological processes. In the present review, we will summarize what is currently known about the alterations of axonal transport found to be either causative or a consequence of MNDs. PMID- 21250943 TI - TBC proteins: GAPs for mammalian small GTPase Rab? AB - The TBC (Tre-2/Bub2/Cdc16) domain was originally identified as a conserved domain among the tre-2 oncogene product and the yeast cell cycle regulators Bub2 and Cdc16, and it is now widely recognized as a conserved protein motif that consists of approx. 200 amino acids in all eukaryotes. Since the TBC domain of yeast Gyps [GAP (GTPase-activating protein) for Ypt proteins] has been shown to function as a GAP domain for small GTPase Ypt/Rab, TBC domain-containing proteins (TBC proteins) in other species are also expected to function as a certain Rab-GAP. More than 40 different TBC proteins are present in humans and mice, and recent accumulating evidence has indicated that certain mammalian TBC proteins actually function as a specific Rab-GAP. Some mammalian TBC proteins {e.g. TBC1D1 [TBC (Tre-2/Bub2/Cdc16) domain family, member 1] and TBC1D4/AS160 (Akt substrate of 160 kDa)} play an important role in homoeostasis in mammals, and defects in them are directly associated with mouse and human diseases (e.g. leanness in mice and insulin resistance in humans). The present study reviews the structure and function of mammalian TBC proteins, especially in relation to Rab small GTPases. PMID- 21250944 TI - Cell-cycle-dependent telomere elongation by telomerase in budding yeast. AB - Telomeres are essential for the stability and complete replication of linear chromosomes. Telomere elongation by telomerase counteracts the telomere shortening due to the incomplete replication of chromosome ends by DNA polymerase. Telomere elongation is cell-cycle-regulated and coupled to DNA replication during S-phase. However, the molecular mechanisms that underlie such cell-cycle-dependent telomere elongation by telomerase remain largely unknown. Several aspects of telomere replication in budding yeast, including the modulation of telomere chromatin structure, telomere end processing, recruitment of telomere-binding proteins and telomerase complex to telomere as well as the coupling of DNA replication to telomere elongation during cell cycle progression will be discussed, and the potential roles of Cdk (cyclin-dependent kinase) in these processes will be illustrated. PMID- 21250945 TI - Polyploid tumour cells elicit paradiploid progeny through depolyploidizing divisions and regulated autophagic degradation. AB - 'Neosis' describes the process whereby p53 function-deficient tumour cells undergo self-renewal after genotoxic damage apparently via senescing ETCs (endopolyploid tumour cells). We previously reported that autophagic digestion and extrusion of DNA occurs in ETC and subsequently revealed that self-renewal transcription factors are also activated under these conditions. Here, we further studied this phenomenon in a range of cell lines after genotoxic damage induced by gamma irradiation, ETO (etoposide) or PXT (paclitaxel) treatment. These experiments revealed that chromatin degradation by autophagy was compatible with continuing mitotic activity in ETC. While the actively polyploidizing primary ETC produced early after genotoxic insult activated self-renewal factors throughout the polygenome, the secondary ETC restored after failed multipolar mitosis underwent subnuclei differentiation. As such, only a subset of subnuclei continued to express OCT4 and NANOG, while those lacking these factors stopped DNA replication and underwent degradation and elimination through autophagy. The surviving subnuclei sequestered nascent cytoplasm to form subcells, while being retained within the confines of the old ETC. Finally, the preformed paradiploid subcells became released from their linking chromosome bridges through autophagy and subsequently began cell divisions. These data show that 'neotic' ETC resulting from genotoxically damaged p53 function-deficient tumour cells develop through a heteronuclear system differentiating the polyploid genome into rejuvenated 'viable' subcells (which provide mitotically propagating paradiploid descendents) and subnuclei, which become degraded and eliminated by autophagy. The whole process reduces aneuploidy in descendants of ETC. PMID- 21250946 TI - Time delay between symptom and surgery in patients with carotid artery stenosis. AB - OBJECTIVES: Many severe strokes are preceded by warning signs such as a transient ischemic attack or stroke with minor deficits. Carotid endarterectomy (CEA) of a symptomatic carotid artery stenosis can prevent future strokes, but should be performed within 2 weeks after the initial symptom to maximize the benefit. The aim of this study was to determine the time delays between symptom and CEA. METHODS: We performed a single center observational retrospective study at a tertiary stroke center. A total of 142 carotids in 139 patients with symptomatic stenoses between 2002 and 2006 were included. The main outcome measure was time between qualifying cerebrovascular symptom and CEA. RESULTS: The median time between symptom and CEA was 26 days. The longest delays were between the last diagnostic examination and carotid conference, and between carotid conference and surgery. The median time was shorter for those who received emergency medical care (median 21 days) and for those who were admitted immediately to hospital (median 20 days). CONCLUSIONS: The time between symptom and surgery is often longer than desirable. There are several measures to improve the chain of procedures for patients with carotid artery stenosis. These may include omitting the formal carotid conference for uncomplicated cases and minimizing waiting time for surgery. PMID- 21250947 TI - In this issue - January/February 2011. PMID- 21250948 TI - Ernest Arthur Kendall: his life in peace and war. AB - Ernest Arthur Kendall (1876-1938), whose father founded the first veterinary school in Australia, qualified as a veterinary surgeon, as did three of his brothers. He was commissioned in the Australian Army Veterinary Corps and fought with distinction in both the Boer War and World War I. He established an Australian Veterinary Hospital near Calais, France, in 1917. The Purple Cross Society of Victoria paid for the fit-out and necessary material for the running of the hospital, which treated 24,300 animals before it closed in 1919. In that year, Colonel Kendall resumed his career in the Department of Agriculture Victoria, where he was appointed Chief Veterinary Officer in 1926 and Chairman of the Milk Board in 1934. He worked toward a pure milk supply, enabled the establishment of a laboratory to test milk samples, and looked forward to a well planned campaign for the eradication of bovine tuberculosis. PMID- 21250949 TI - Sequential opportunistic infections in two German Shepherd dogs. AB - Two German Shepherd dogs with sequential opportunistic infections are described. The first was a 2-year-old male with cryptococcal rhinitis that spread to involve the optic nerves and brain. It was successfully treated with combination therapy utilising amphotericin B administered for 2 years, but the dog developed a disseminated Aspergillus deflectus infection 5 years later and was euthanased. The second case was a 4-year-old male that presented for a severe, deep-seated infection of the right antebrachium, with gradual extension to contiguous tissues. Neosartorya fischeri (anamorph; Aspergillus fischerianus) was isolated in pure culture and detected in histological sections. The infection was refractory to itraconazole, but resolved after amputation of the affected limb. Five months later, the dog developed a localised cutaneous lesion on the proximal pelvic limb, from which Pythium insidiosum was isolated and then visualised in tissue sections, together with a structure thought to be grass seed. This lesion was treated by wide surgical resection, although it was reported that the dog died of disseminated disease some months later. These cases provide further circumstantial evidence that young adult German Shepherd dogs have a predilection to developing invasive infections with fungi and other saprophytic pathogens. PMID- 21250951 TI - Small intestinal ganglioneuromatosis in a dog. AB - A 6-week-old Staffordshire Bull Terrier cross was presented with a 4-week history of vomiting and small bowel diarrhoea. Abdominal ultrasound showed thickening of the distal jejunum and ileum. The dog underwent two exploratory laparotomies, during which grossly abnormal sections of intestine were resected. The patient developed septic peritonitis 48 h after the second surgery, caused by dehiscence of an intestinal anastomosis, and was euthanased. All intestinal tissue samples were examined histopathologically and a diagnosis of gastrointestinal ganglioneuromatosis was made. Intestinal ganglioneuromatosis is rare and this case represents a novel occurrence in the small intestine of a dog. PMID- 21250952 TI - Assessment of the short-term systemic effect of and acute phase response to mulesing and other options for controlling breech flystrike in Merino lambs. AB - BACKGROUND: Mulesing is an important method of preventing flystrike of Merino sheep in Australia, but because there are important short-term welfare issues associated with mulesing, alternative methods of removing the skin folds for breech flystrike prevention are being investigated. OBJECTIVE: To examine the short-term systemic effects of mulesing and two proposed alternatives, compared with two control methods, for controlling breech flystrike. METHOD: The five treatment groups comprised 10 lambs each: (1) mulesing, (2) intradermal-cetrimide treatment, (3) clip application, (4) tail docking only and (5) no treatment. Changes in body weight, haematological and biochemical profiles, and concentrations of fibrinogen, haptoglobin and serum amyloid A were measured repeatedly for 29 days post treatment. RESULTS: The mulesing and intradermal cetrimide groups were the only treatment groups to lose weight during the first week, with greater weight loss in the mulesing group. The mulesing group had the most marked increases in all three acute-phase protein concentrations, closely followed by the intradermal-cetrimide group, with a mild increase observed for the clip group and even less for the tail-docked group. The mulesing group was the only group to develop mild anaemia, transient hyperglycaemia and a persistent decreased albumin : globulin ratio. The neutrophil : lymphocyte ratio was above the upper reference limit for both the mulesing and intradermal-cetrimide groups. CONCLUSION: Mulesing had the greatest systemic effect in terms of the magnitude and duration of increased acute-phase protein concentrations and haematological, biochemical and body weight changes. The clips had a significantly reduced systemic effect compared with mulesing, with the intradermal-cetrimide treatment in between the two. Tail docking had a minimal systemic effect. PMID- 21250953 TI - Wound healing after mulesing and other options for controlling breech flystrike in Merino lambs: observations on gross and microscopic wound healing. AB - BACKGROUND: The mulesing procedure is the main procedure used to control breech flystrike of sheep in Australia, but other permanent methods of altering breech conformation are currently being investigated and wound healing is an important component of that comparative assessment. OBJECTIVE: To qualitatively assess the gross and microscopic tissue damage and wound healing that occurs in the immediate post-treatment period after mulesing, intradermal-cetrimide treatment and clip application. METHOD: The study group of 30 mulesed, 30 cetrimide treated, 30 control and 10 clip-treated sheep were humanely killed at six time points during the 3-47 days post treatment. Treatment sites and wound beds were examined grossly and microscopically. RESULTS: Mulesing wounds healed rapidly in a predictable manner, producing long linear scars on either side of the breech and tail by 32-47 days post treatment. Although the time course for healing post cetrimide-treatment was similar to that for mulesing, complications occurred and included inadequate wound healing because of persistence of adherent necrotic tissue, poor skin tightening around the tail, and patchy or deep penetration of the cetrimide resulting in necrosis of adjacent skin and deeper structures. The clips resulted in skin tightening around the ventrolateral breech and tail, although the formation of skin tags and clip slippage were of concern in some sheep. CONCLUSION: Wounds healed rapidly after mulesing with minimal complications. The intradermal-cetrimide treatment appeared to produce imperfect and sometimes delayed wound healing compared with mulesing. The clips resulted in comparable wound healing to mulesing, but further field trials are required to assess their effectiveness in flystrike prevention. PMID- 21250954 TI - Effect of unvaccinated Merino wether lambs on shedding of Mycobacterium avium subspecies paratuberculosis in flocks vaccinating for ovine Johne's disease. AB - OBJECTIVE: To determine the prevalence of Mycobacterium avium subspecies paratuberculosis (Mptb) shedding by unvaccinated wethers compared with vaccinated ewes. METHODS: Six self-replacing, ovine Johne's disease (OJD)-infected Merino flocks that had been vaccinating lambs with Gudair(TM) for at least 5 years, but had not vaccinated their last two drops of wethers were studied. Faecal samples were collected in pools of 50 from 350 vaccinated ewes (1-2 years old) and from 350 unvaccinated wethers of the same age and were cultured to determine the presence of viable Mptb. RESULTS: The estimated prevalence of shedding sheep among the unvaccinated wethers was 6-fold greater than among the vaccinated female siblings (0.21% vs 1.27%), with faecal pools collected from unvaccinated wethers being 19-fold more likely to be positive than those from the vaccinated ewes. CONCLUSION: Leaving wethers unvaccinated is likely to considerably increase pasture contamination with Mptb and potentially jeopardise disease control. PMID- 21250955 TI - Subclinical mastitis and associated risk factors on dairy farms in New South Wales. AB - OBJECTIVE: To determine the current prevalence of subclinical mastitis (SCM) and associated risk factors on dairy farms in New South Wales. METHODOLOGY: A survey was sent to 382 dairy farmers to acquire information on the relevant risk factors associated with SCM. RESULTS: The average herd prevalence of SCM among the 189 respondents (response rate 49.5%) was 29%. Farmers who had herds with a low prevalence (<20% cows with individual somatic cell count (ISCC) >2 * 105 cells/mL) more frequently wore gloves during milking (26% vs 62%), used individual paper towels for udder preparation (16% vs 62%), fed cows directly after milking (47% vs 87%) and more frequently treated cows with high ISCC (69% vs 80%) than farmers who had herds with a high prevalence of SCM (>30% cows with ISCC >2 * 105 cells/mL). The latter more often used selective dry cow therapy (52% vs 24%), compared with low prevalence herds. CONCLUSION: The prevalence of SCM in this cross-sectional study is comparable or lower than reported in other studies from North America and the European Union. The outcome provides a benchmark for the current focus of the NSW dairy industry on the management practices associated with a low prevalence of SCM, such as wearing gloves, using paper towels and feeding cows directly after milking. PMID- 21250956 TI - Neuroangiostrongyliasis and other parasites in tawny frogmouths (Podargus strigoides) in south-eastern Queensland. AB - The neurological, clinical and pathological findings and endoparasites in 10 wild tawny frogmouths (Podargus strigoides) presented to the Australian Wildlife Hospital in Beerwah, Queensland during a 28-day period in May 2009 are reported. Affected birds had a history of being found in poor body condition on the ground and unable to fly. Clinical examination revealed paresis with variable but generally weakened deep pain responses, withdrawal reflexes and an inability to perch. Severely affected birds that failed to respond to anti-inflammatory, antibiotic and anthelmintic treatments all had larval Angiostrongylus cantonensis in the brain and or spinal cord, with occasional larvae found in the visceral organs. Other parasites detected included the liver fluke, Brachylecithum podargi, the intestinal nematode, Allodapa suctoria, an unidentified species of Trichostrongylus and unidentified cestodes. Gametocytes of Leucocytozoon sp. were found in peripheral blood smears and low numbers of microfilariae were found in histological sections of various blood vessels of several birds. However, no adult filarioids were recovered. Unidentified subcutaneous mites were identified in the connective tissue of the thoracic inlet. Attempts to treat two birds with ivermectin or oxfendazole-praziquantel were unsuccessful, but a third bird treated with a combination of steroidal and non-steroidal anti-inflammatory therapy followed by moxidectin steadily recovered, such that by 6 weeks post presentation its ability to perch, grasp, fly and judge distances was considered normal and it was subsequently released. PMID- 21250957 TI - Congenital peritoneopericardial diaphragmatic hernia in an alpaca. AB - An adult alpaca was presented because of abdominal pain and was diagnosed with an intestinal obstruction. The putative diagnosis at surgery was an intestinal obstruction caused by peritonitis and intra-abdominal adhesions. The cause of the inflammation was not determined at that time. The alpaca died soon after surgery from post-surgical complications and a peritoneopericardial diaphragmatic hernia that was not diagnosed until necropsy. PMID- 21250958 TI - Gammaherpesvirus infection in a free-ranging eastern grey kangaroo (Macropus giganteus). AB - A gammaherpesvirus was detected by polymerase chain reaction (PCR) in ocular, nasal and oropharyngeal swab samples collected from an adult free-ranging male eastern grey kangaroo (Macropus giganteus) with clinical signs of severe respiratory disease. This is the first time a gammaherpesvirus has been detected in a free-ranging macropod in Australia. The nucleotide sequence of a conserved region of the DNA polymerase gene of the detected virus showed a high degree of identity to a gammaherpesvirus recently detected in a zoological collection of eastern grey kangaroos in North America. The detection of this gammaherpesvirus in a free-ranging, native eastern grey kangaroo provides evidence that this species is a natural host. PMID- 21250960 TI - Tumour necrosis factor-alpha blockers in the treatment of psoriasis. PMID- 21250961 TI - Advice on the safe introduction and continued use of isotretinoin in acne in the U.K. 2010. PMID- 21250964 TI - Does HLA-G prevent tissue destruction in psoriasis? PMID- 21250962 TI - Histopathological characterization of primary cutaneous melanoma using infrared microimaging: a proof-of-concept study. AB - BACKGROUND: The diagnosis of malignant melanoma is based upon the histological evaluation of the lesion. As such, the morphological interpretation relies on the expertise of a dermatopathologist. Infrared microimaging is emerging as a new powerful tool to investigate tissue biochemistry. Infrared spectra probe the biochemical constitution of the sample and are real tissue-specific spectroscopic fingerprints. OBJECTIVES: To assess the potential of infrared microimaging to aid in the analysis of tissue sections from primary cutaneous melanomas. METHODS: Ten samples of melanoma sections from the main histological subtypes were investigated using infrared microimaging combined with multivariate statistical analyses. RESULTS: This methodology yielded highly contrasted colour-coded images that permitted to highlight tissue architecture without any staining. It was possible to discriminate tumour areas from normal epidermis automatically, and intratumoral heterogeneity as revealed by our approach was correlated with the aggressiveness of the tumour. CONCLUSIONS: This proof-of-concept study shows that infrared microimaging could help in the diagnosis of primary cutaneous melanoma. PMID- 21250965 TI - Preliminary evidence for involvement of the tumour suppressor gene CHD5 in a family with cutaneous melanoma. AB - BACKGROUND: Cutaneous melanoma is rapidly increasing in incidence worldwide and approximately 5% of melanomas are hereditary. Deletions in chromosome 1p36 have been detected in melanoma but no candidate melanoma tumour suppressor gene has yet been found in this area. Recently, strong evidence has been reported that CHD5 is a tumour suppressor gene in this region. OBJECTIVES: To investigate CHD5 involvement in familial melanoma. METHODS: Peripheral blood DNA from 47 melanoma families who do not carry mutations in any of the three currently recognized melanoma genes, 398 patients with sporadic melanoma and 398 geographically matched nonmelanoma-bearing controls were studied. Linkage investigation, single nucleotide polymorphism (SNP) genotyping and mutation screening studies were carried out on the CHD5 locus. RESULTS: The CHD5 gene was not excluded by linkage analysis in any of the families. On SNP genotyping, the CHD5 rs7513548 SNP was found to be significantly associated with sporadic melanoma (odds ratio 1.53, 95% confidence interval 1.13-2.06). The AG genotype was found in 208 cases and 169 controls (cf. 141 and 175 cases and controls, respectively, for the AA genotype). On CHD5 mutation screening, a total of 50 single-base substitutions were detected. Of these, 39 were intronic and 11 were exonic. While 32 were previously recognized variants, 18 were newly identified. Three, in exons 4, 31 and 32, led to nonsynonymous substitutions. A p.Met1576Ile substitution was identified in a mother and daughter, both with invasive cutaneous melanoma. CONCLUSIONS: This study appears to be the first report of CHD5 variants in familial cutaneous melanoma. Such CHD5 variants could block or alter the ability of CHD5 to regulate the cell cycle pathway and to effect cellular control. As only one of the 47 families studied has this variant, it appears to be a rare event and further screening of melanoma families is required to confirm whether or not CHD5 is involved in melanoma pathogenesis. PMID- 21250966 TI - Hidradenitis suppurativa: a disease of the absent sebaceous gland? Sebaceous gland number and volume are significantly reduced in uninvolved hair follicles from patients with hidradenitis suppurativa. AB - BACKGROUND: The pathogenesis of hidradenitis suppurativa (HS) is not clearly understood. The nomenclature suggests an important role for the apocrine glands but recent evidence implicates the pilosebaceous unit as a more likely candidate to play a central role in the pathogenesis. OBJECTIVES: Our aim was to estimate the volume of the follicular epithelium, the follicular lumen and the sebaceous glands of patients with HS and healthy controls by means of stereology. METHODS: Four-millimetre punch biopsies were taken from 21 patients with HS and nine healthy controls, fixed in formalin, embedded in paraffin and stained with haematoxylin and eosin prior to volume estimation using the Cavalieri principle. RESULTS: Sebaceous gland tissue could be visualized in only 10 of 15 suitable hair follicle biopsies from patients with HS but was present in all biopsies from healthy controls (P = 0.05) and the mean sebaceous gland volume per follicle was one-seventh of that of healthy controls (P = 0.03). There was no significant difference between patients with HS and healthy controls with regard to follicular epithelium and follicle lumen volume. CONCLUSIONS: Our results suggest that the absence or reduced volume of the sebaceous gland may play a role in the pathogenesis of HS. The presence of fibrosis suggests that sebaceous glands are obliterated early in the pathogenesis of HS. PMID- 21250967 TI - Immediate pigment darkening and persistent pigment darkening as means of measuring the ultraviolet A protection factor in vivo: a comparative study. AB - BACKGROUND: Persistent pigment darkening (PPD) is a widely used in vivo method for measurement of ultraviolet (UV) A protection factor (UVAPF). However, with increased emphasis on UVA protection and sunscreen products with higher UVAPF gaining popularity, the immediate pigment darkening (IPD) method is drawing attention again. Furthermore, only about a quarter of the recommended quantity of sunscreen is used during daily activities. However, there is as yet no clearly defined relationship between the UVAPF and the amount of sunscreen applied. OBJECTIVES: To analyse the differences between the IPD and PPD methods, and to establish a relationship between the quantity of sunscreen application and the UVAPF. METHODS: Different doses of sunscreen were applied on the back of 15 healthy volunteers, and the UVAPF was measured using both the IPD and the PPD methods. RESULTS: Both methods proved to be effective for measuring the UVAPF. However, all the UVAPF values determined by the PPD method were lower than those determined by the IPD method. Additionally, an exponential relationship between the amount of sunscreen applied and the UVAPF was observed. CONCLUSIONS: The IPD method can also be used as an appropriate endpoint in the determination of UVA protection. It is time saving, and thus considerably lowers the risk of UV exposure, particularly when testing sunscreen products with higher UVAPF. We further state that in order to achieve the desired protective effect of the sunscreen, the quantity of application is also very important. PMID- 21250968 TI - Evaluation of mutations in the isocitrate dehydrogenase genes in therapy-related and secondary acute myeloid leukaemia identifies a patient with clonal evolution to IDH2 R172K homozygosity due to uniparental disomy. PMID- 21250969 TI - Personal practice: how we manage the risk of bleeding and thrombosis in children and young adults with acute lymphoblastic leukaemia. AB - Bleeding and thrombosis are not infrequent problems in children receiving treatment for acute lymphoblastic leukaemia (ALL). The exact frequency varies with age, co-morbidity and treatment schedule, but the risk is highest in the first few weeks of treatment when disease and treatment-related haemostatic abnormalities prevail. Recommendations for prevention and management are lacking due to a weak evidence base, resulting in considerable variation in practice. This article describes our personal practice in this area with reference to the available literature on the subject. PMID- 21250970 TI - Minimal residual disease assessment in childhood acute lymphoblastic leukaemia: a Swedish multi-centre study comparing real-time polymerase chain reaction and multicolour flow cytometry. AB - Minimal residual disease (MRD) assessment is a powerful prognostic factor for determining the risk of relapse in childhood acute lymphoblastic leukaemia (ALL). In this Swedish multi-centre study of childhood ALL diagnosed between 2002 and 2006, the MRD levels were analysed in 726 follow-up samples in 228 children using real-time quantitative polymerase chain reaction (RQ-PCR) of rearranged immunoglobulin/T-cell receptor genes and multicolour flow cytometry (FCM). Using an MRD threshold of 0.1%, which was the sensitivity level reached in all analyses, the concordance between RQ-PCR and FCM MRD values at day 29 was 84%. In B-cell precursor ALL, an MRD level of >=0.1% at day 29 predicted a higher risk of bone marrow relapse (BMR) with both methods, although FCM was a better discriminator. However, considering the higher median MRD values achieved with RQ PCR, a higher MRD cut-off (>=0.2%) improved the predictive capacity of RQ-PCR. In T-ALL, RQ-PCR was notably superior to FCM in predicting risk of BMR. That notwithstanding, MRD levels of >=0.1%, detected by either method at day 29, could not predict isolated extramedullary relapse. In conclusion, the concordance between RQ-PCR and FCM was high and hence both methods are valuable clinical tools for identifying childhood ALL cases with increased risk of BMR. PMID- 21250971 TI - Optimal management of beta thalassaemia intermedia. AB - Our understanding of the molecular and pathophysiological mechanisms underlying the disease process in patients with beta thalassaemia intermedia (TI) has substantially increased over the past decade. The hallmark of disease process in patients with TI includes ineffective erythropoiesis, chronic haemolytic anaemia, and iron overload. There are a number of options currently available for managing patients with TI including splenectomy, transfusion therapy, iron chelation therapy, modulation of fetal haemoglobin production, and several other agents targeting specific clinical complications. Limited studies assessed the efficacy and safety of these modalities; hence, there are currently no clear guidelines for managing patients with TI. Until solid evidence-based guidelines are available, individualised treatment should be entertained. PMID- 21250972 TI - A pooled analysis of three studies evaluating genetic variation in innate immunity genes and non-Hodgkin lymphoma risk. AB - Genetic variation in immune-related genes may play a role in the development of non-Hodgkin lymphoma (NHL). To test the hypothesis that innate immunity polymorphisms may be associated with NHL risk, we genotyped 144 tag single nucleotide polymorphisms (tagSNPs) capturing common genetic variation within 12 innate immunity gene regions in three independent population-based case-control studies (1946 cases and 1808 controls). Gene-based analyses found IL1RN to be associated with NHL risk (minP = 0.03); specifically, IL1RN rs2637988 was associated with an increased risk of NHL (per-allele odds ratio = 1.15, 95% confidence interval = 1.05-1.27; P(trend) = 0.003), which was consistent across study, subtype, and gender. FCGR2A was also associated with a decreased risk of the follicular lymphoma NHL subtype (minP = 0.03). Our findings suggest that genetic variation in IL1RN and FCGR2A may play a role in lymphomagenesis. Given that conflicting results have been reported regarding the association between IL1RN SNPs and NHL risk, a larger number of innate immunity genes with sufficient genomic coverage should be evaluated systematically across many studies. PMID- 21250973 TI - Revaccination of children after completion of standard chemotherapy for acute lymphoblastic leukaemia: a pilot study comparing different schedules. AB - Given that a significant proportion of children with acute lymphoblastic leukaemia (ALL) lose immune protection to tetanus, diphtheria, and poliomyelitis, revaccination is indicated after chemotherapy. Our randomized pilot study comparing different revaccination schedules suggests that children with ALL might be revaccinated with non-live vaccines as early as 3 months after chemotherapy. PMID- 21250974 TI - Effects on fibrin network porosity of anticoagulants with different modes of action and reversal by activated coagulation factor concentrate. AB - Orally available direct thrombin inhibitors (DTI) and direct activated factor X inhibitors (DFXaI) may replace vitamin K antagonists in patients needing long term anticoagulant treatment. We investigated the influence on the fibrin network of anticoagulants with different modes of action: AR-H067637 (DTI), the active metabolite of AZD0837, apixaban (DFXaI), fondaparinux (indirect FXaI) and warfarin. Counteraction of the anticoagulant effect by FEIBA((r)) (Factor Eight Inhibitor Bypass Activity) was also investigated. Tissue factor, phospholipids and calcium were used to initiate coagulation in human platelet poor plasma. The permeability constant (Ks), reflecting the amount of buffer passing through the coagulum, was calculated and the fibrin network was visualized by 3D confocal microscopy. Warfarin (International Normalized Ratio 2-3) increased Ks in plasma by 28-50% compared with control. 'Therapeutic' plasma concentrations of AR H067637 (0.3-0.6 MUmol/l), apixaban (0.2-0.4 MUmol/l) and fondaparinux (0.1-0.3 MUmol/l) increased Ks by 72-91%, 58-76% and 36-53% respectively. Addition of FEIBA((r)) totally reversed the warfarin effect but only partially reversed effects of the other anticoagulants at concentrations that increased Ks by 50% or more. Fibrin network observed with 3D confocal microscopy agreed well with the permeability results. In conclusion, all examined anticoagulants rendered the fibrin network more porous. FEIBA((r)) reversed the increased permeability in warfarin plasma but had only partial effects on the other anticoagulants. PMID- 21250975 TI - Metformin restores endothelial function in aorta of diabetic rats. AB - BACKGROUND AND PURPOSE: The effects of metformin, an antidiabetic agent that improves insulin sensitivity, on endothelial function have not been fully elucidated. This study was designed to assess the effect of metformin on impaired endothelial function, oxidative stress, inflammation and advanced glycation end products formation in type 2 diabetes mellitus. EXPERIMENTAL APPROACH: Goto Kakizaki (GK) rats, an animal model of nonobese type 2 diabetes, fed with normal and high-fat diet during 4 months were treated with metformin for 4 weeks before evaluation. Systemic oxidative stress, endothelial function, insulin resistance, nitric oxide (NO) bioavailability, glycation and vascular oxidative stress were determined in the aortic rings of the different groups. A pro-inflammatory biomarker the chemokine CCL2 (monocyte chemoattractant protein-1) was also evaluated. KEY RESULTS: High-fat fed GK rats with hyperlipidaemia showed increased vascular and systemic oxidative stress and impaired endothelial dependent vasodilatation. Metformin treatment significantly improved glycation, oxidative stress, CCL2 levels, NO bioavailability and insulin resistance and normalized endothelial function in aorta. CONCLUSION AND IMPLICATIONS: Metformin restores endothelial function and significantly improves NO bioavailability, glycation and oxidative stress in normal and high-fat fed GK rats. This supports the concept of the central role of metformin as a first-line therapeutic to treat diabetic patients in order to protect against endothelial dysfunction associated with type 2 diabetes mellitus. PMID- 21250976 TI - Nicorandil ameliorates ischaemia-reperfusion injury in the rat kidney. AB - BACKGROUND AND PURPOSE: Nicorandil, an ATP-sensitive potassium (K(ATP) ) channel opener and nitric oxide donor, is used in the treatment of angina and acute heart failure. Here we investigated the effects of two K(ATP) channel openers, nicorandil and cromakalim on ischaemia reperfusion (I-R) injury in the kidney. EXPERIMENTAL APPROACH: Right nephrectomy was performed in 8-week-old male Sprague Dawley rats and they were then divided into six groups: control group; I-R, including 30 min of left renal ischaemia followed by 24 h of reperfusion; I-R groups plus nicorandil 3 or 10 mg.kg-1 i.p.; and I-R groups plus cromakalim 100 or 300 ug.kg-1 i.p. After reperfusion, renal function was estimated by serum creatinine (SCr), urinary albumin:creatinine ratio (ACR) and urinary beta2 microglobulin (beta2-MG). Levels of K(ATP) channel subtypes were investigated by Western blot. Kidney sections were stained for 4-hydroxy-2-nonenal and 8-hydroxy 2'-deoxyguanosine. KEY RESULTS: Renal I-R induced significant increases in SCr, ACR and beta2-MG levels compared with the control animals. Treatment with K(ATP) channel openers reduced urinary beta2-MG levels, raised by I-R. Both K(IR) 6.1 and K(IR) 6.2 channels were expressed. Expression of K(IR) 6.2 channels in the I R group was lower than in the control group, which was restored to normal by treatment with K(ATP) channel openers. Histologically, severe acute tubular damage was observed in the I-R kidney and this damage was ameliorated by K(ATP) channel openers, dose-dependently. CONCLUSIONS AND IMPLICATIONS: ATP-sensitive potassium channel openers protected against proximal tubule damage after I-R injury. Nicorandil could represent a powerful additional component in the treatment of patients undergoing partial nephrectomy or renal transplantation. PMID- 21250977 TI - CCAAT/ enhancer-binding protein beta activation by capsaicin contributes to the regulation of CYP1A1 expression, mediated by the aryl hydrocarbon receptor. AB - BACKGROUND AND PURPOSE: Capsaicin, a constituent of peppers, has been linked to the suppression of tumorigenesis and carcinogenesis. The influence of capsaicin on cytochrome P450 (CYP) 1A1, which is involved in metabolism of carcinogens, and the underlying mechanisms remain unclear. Here, we examined the effect of capsaicin on CYP1A1 expression in mouse hepatoma cells. EXPERIMENTAL APPROACH: Murine hepatoma Hepa-1c1c7 cells were incubated with capsaicin and/or 3 methylcholanthrene (3-MC). Effects of capsaicin on CYP1A1 levels were determined by analysing mRNA expression, transcription activity and protein expression. Regulation of CYP1A1 was investigated by determining transcriptional factor expression, activation and binding activity with cotreatment with target signal antagonists. KEY RESULTS: Capsaicin alone slightly induced CYP1A1 activity, mRNA expression, protein level and promoter activity. Treatment with transient receptor potential vanilloid type-1 receptor (TRPV1) or aryl hydrocarbon receptor (AhR) antagonist decreased induction of CYP1A1 expression by capsaicin. Additionally, capsaicin significantly inhibited 3-MC-induced CYP1A1 mRNA and protein level and xenobiotic response element-luciferase activity. Capsaicin also inhibited 3-MC-induced AhR transactivation and nuclear localization of AhRs. Moreover, capsaicin increased Ca(2+) /calmodulin (CaM)-dependent protein kinase (CaMK) and CCAAT/ enhancer-binding protein beta (C/EBPbeta) activation, downstream of TRPV1 receptors. Capsaicin-induced C/EBPbeta activation inhibited induction of CYP1A1 mRNA and protein by 3-MC. CONCLUSIONS AND IMPLICATIONS: Capsaicin alone weakly induced CYP1A1 expression, and 3-MC-induced CYP1A1 levels were suppressed by capsaicin. Activation of C/EBPbeta and inhibition of 3-MC induced AhR transactivation by capsaicin contributed to the suppression of CYP1A1 expression. Capsaicin has a potential chemopreventive effect through inhibiting induction of CYP1A1 by poly aryl hydrocarbons. PMID- 21250978 TI - The anti-tumour compound, RH1, causes mitochondria-mediated apoptosis by activating c-Jun N-terminal kinase. AB - BACKGROUND AND PURPOSE: 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4 benzoquinone (RH1) is a bioreductive agent that is activated by the two-electron reductase NAD(P)H quinone oxidoreductase 1 (NQO1). Although the cytotoxic efficacy of RH1 against tumours has been studied extensively, the molecular mechanisms underlying this anti-cancer activity have not yet been fully elucidated. EXPERIMENTAL APPROACH: 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl 1,4-benzoquinone-induced apoptosis and related signalling pathways in NQO1 negative and NQO1-overexpressing cells were evaluated. The role of p53 in RH1 induced cell death was investigated using parental and p53-deficient RKO human colorectal cancer cells by assaying clonogenic cell survival. Specific inhibitors and siRNAs targeting factors involved in RH1-induced apoptosis were used to clarify the roles played by such factors in RH1-activated apoptotic signalling pathways. KEY RESULTS: 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4 benzoquinone induced apoptosis and clonogenic death, dependent on NQO1 and p53. Treatment of NQO1-overexpressing cells with RH1 caused rapid disruption of mitochondrial membrane potential, nuclear translocation of apoptosis-inducing factor (AIF) and endonuclease G (Endo G) from mitochondria, and subsequent caspase-independent apoptotic cell death. siRNA targeting AIF and Endo G effectively attenuated RH1-induced apoptotic cell death. Moreover, RH1 induced cleavage of Bax, which targets mitochondria. RH1 significantly activated the c Jun N-terminal kinase (JNK) pathway, and inhibition of this pathway suppressed RH1-induced mitochondria-mediated apoptosis. RH1-induced generation and mitochondrial translocation of cleaved Bax were blocked by the JNK inhibitor, SP600125. Inhibition of JNK with SP600125 attenuated the mitochondrial translocation of JNK. CONCLUSIONS AND IMPLICATIONS: 2,5-diaziridinyl-3 (hydroxymethyl)-6-methyl-1,4-benzoquinone activated JNK, resulting in mitochondria-mediated apoptotic cell death that was NQO1-dependent. PMID- 21250979 TI - delta-Opioid receptors stimulate GLUT1-mediated glucose uptake through Src- and IGF-1 receptor-dependent activation of PI3-kinase signalling in CHO cells. AB - BACKGROUND AND PURPOSE: Although opioids have been reported to affect glucose homeostasis, relatively little is known on the role of delta-opioid receptors. We have investigated the regulation of glucose transport by human delta-opioid receptors expressed in Chinese hamster ovary cells. EXPERIMENTAL APPROACH: The uptake of [(3)H]-2-deoxy-D-glucose and 3-O-[methyl-[(3)H]]-D-glucose in response to delta-opioid receptor ligands and the expression of GLUT1, GLUT3 and GLUT4 glucose transporters were examined. Moreover, the effects of intracellular signal transduction inhibitors on delta-opioid receptor-regulated [(3)H]-2-deoxy-D glucose uptake and protein phosphorylation were investigated. KEY RESULTS: Activation of delta-opioid receptors rapidly stimulated [(3)H]-2-deoxy-D-glucose and 3-O-[methyl-[(3)H]]-D-glucose uptakes, which were blocked by the GLUT inhibitors cytochalasin B and phloretin. The stimulation of [(3)H]-2-deoxy-D glucose uptake that occurred without a change in plasma membrane GLUT1 - required the coupling to G(i) /G(o) proteins - was independent of cAMP and extracellular signal-regulated protein kinases, and was suppressed by blockade of Src and insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinases. Inhibition of phosphatidylinositol 3-kinase (PI3K) by wortmannin or LY294002 and by PI3Kalpha, but not gamma, isoform-selective inhibitors greatly reduced the delta-opioid receptor stimulation of glucose uptake. Moreover, the response was attenuated by overexpressing a dominant-negative kinase-deficient Akt form and by chemical inhibition of Akt. Stimulation of delta-opioid receptors increased protein kinase Czeta/lambda (PKCzeta/lambda) phosphorylation and a selective PKCzeta/lambda inhibitor slightly reduced opioid stimulation of glucose uptake. CONCLUSIONS AND IMPLICATIONS: delta-Opioid receptors stimulated glucose transport probably by enhancing GLUT1 intrinsic activity through a signalling cascade involving G(i)/G(o), Src, IGF-1R, PI3Kalpha, Akt and, to a minor extent, PKCzeta/lambda. This effect may contribute to the opioid regulation of glucose homeostasis in physio-pathological conditions. PMID- 21250980 TI - G protein-coupled oestrogen receptor 1 (GPER1)/GPR30: a new player in cardiovascular and metabolic oestrogenic signalling. AB - Oestrogens are important sex hormones central to health and disease in both genders that have protective effects on the cardiovascular and metabolic systems. These hormones act in complex ways via both genomic and non-genomic mechanisms. The genomic mechanisms are relatively well characterized, whereas the non-genomic ones are only beginning to be explored. Two oestrogen receptors (ER), ERalpha and ERbeta, have been described that act as nuclear transcription factors but can also associate with the plasma membrane and influence cytosolic signalling. ERalpha has been shown to mediate both anti-atherogenic effects and pro-survival effects in pancreatic beta-cells. In recent years, a third membrane-bound ER has emerged, G protein-coupled receptor 30 or G protein-coupled oestrogen receptor 1 (GPER1), which mediates oestrogenic responses in cardiovascular and metabolic regulation. Both GPER1 knock-out models and pharmacological agents are now available to study GPER1 function. These tools have revealed that GPER1 activation may have several beneficial effects in the cardiovascular system including vasorelaxation, inhibition of smooth muscle cell proliferation, and protection of the myocardium against ischaemia/reperfusion injury, and in the metabolic system including stimulation of insulin release and protection against pancreatic beta-cell apoptosis. Thus, GPER1 is emerging as a candidate therapeutic target in both cardiovascular and metabolic disease. PMID- 21250982 TI - Altered distribution of caveolin-1 in early liver steatosis. AB - BACKGROUND: Caveolin-1, the main structural protein of caveolae, is involved in cholesterol homoeostasis, transcytosis, endocytosis and signal transduction and thought to play an important role in lipidogenesis. Little is known about the pathophysiological role of caveolin-1 in nonalcoholic fatty liver disease (NAFLD), a condition frequently associated with the metabolic syndrome and characterized by abnormal accumulation of intrahepatic triglycerides with a potentially harmful risk of evolution to liver fibrosis, cirrhosis and hepatocellular carcinoma. MATERIALS AND METHODS: Liver steatosis (micro/macrovesicular) was induced in adult rats fed a choline-deficient diet for 14days and compared with a control normal diet. The expression and subcellular distribution of caveolin-1 was assessed using light and electron microscopy by immunohistochemical and immunocytochemical techniques and by Western blotting. RESULTS: Caveolin-1 was mainly associated with the hepatocyte basolateral plasma membrane. Fatty hepatocytes were characterized by a significant increase in the expression of caveolin-1 around and within the lipid droplets as well as in the inner membrane of mitochondria. CONCLUSIONS: Our data suggest the involvement of caveolin-1 in the case of abnormal lipogenesis and mitochondrial function typical of steatotic hepatocytes in NAFLD. Addressing the role played by caveolin-1 in liver membranes in NAFLD may help future therapeutic choices in a frequent metabolic liver disease. PMID- 21250981 TI - Inhaled innate immune ligands to prevent pneumonia. AB - Epithelial surfaces throughout the body continuously sample and respond to environmental stimuli. The accessibility of lung epithelium to inhaled therapies makes it possible to stimulate local antimicrobial defences with aerosolized innate immune ligands. This strategy has been shown to be effective in preclinical models, as delivery of innate immune ligands to the lungs of laboratory animals results in protection from subsequent challenge with microbial pathogens. Survival of the animal host in this setting correlates directly with killing of pathogens within the lungs, indicating the induction of a resistance mechanism. Resistance appears to be mediated primarily by activated epithelial cells rather than recruited leucocytes. Resistance reaches a peak within hours and persists for several days. Innate immune ligands can interact synergistically under some circumstances, and synergistic combinations of innate ligands delivered by aerosol are capable of inducing a high level of broad host resistance to bacteria, fungi and viruses. The induction of innate antimicrobial resistance within the lungs could have clinical applications in the prevention of lower respiratory tract infection in subjects transiently at high risk. These include cancer patients undergoing myeloablative chemotherapy, intubated patients being mechanically ventilated, vulnerable individuals during seasonal influenza epidemics, asthmatic subjects experiencing a respiratory viral infection, and healthy subjects exposed to virulent pathogens from a bioterror attack or emergent pandemic. In summary, stimulation of the lung epithelium to induce localized resistance to infection is a novel strategy whose clinical utility will be assessed in the near future. PMID- 21250983 TI - Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers decrease the incidence of atrial fibrillation: a meta-analysis. AB - BACKGROUND: There is not a general agreement regarding antiarrhythmic effects on atrial fibrillation (AF) of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). This study was to assess whether ACEIs and ARBs could decrease the incidence of AF. MATERIALS AND METHODS: Medline, Embase and Cochrane Library databases were searched for trials reported from 1950 to May 2009. Search terms included 'randomized controlled trial (RCT), controlled clinical trials, random allocation' and medical subject headings that included all spellings of ACEIs and ARBs agents, 'atrial fibrillation' and 'atrial flutter'. Randomized, controlled human trials of ACEIs or ARBs reporting AF were included. Data were extracted independently by two reviewers using a predefined data extraction sheet, including study quality indicators. Meta-analysis and subgroup analyses were carried out with a random effects model. RESULTS: Twenty one trials including 91,381 patients and 5730 AF events were identified. Overall, ACEIs/ARBs reduced the relative risk (c) of AF by 25%. In primary and secondary prevention, ACEIs/ARBs decreased the incidence of AF by 24% and 27%, respectively. Patients with hypertension (RR: 0.71, 95%CI: 0.54-0.92), patients with chronic heart failure (RR: 0.58, 95%CI: 0.39-0.87) and those with AF (RR: 0.71, 95%CI: 0.52-0.96) benefited from ACEIs/ARBs treatment. CONCLUSIONS: ACEIs/ARBs are effective for primary prevention and secondary prevention of AF. They decrease the incidence of AF especially in patients with hypertension, patients with chronic heart failure and those with AF. PMID- 21250984 TI - Oxidative stress and autonomic nervous system functions in restless legs syndrome. AB - BACKGROUND: Oxidative stress has been implicated in over 100 disorders in recent years; however, the situation in restless legs syndrome (RLS) has not been studied yet. METHODS: Fifty patients with RLS not medicated for RLS and 50 sex- and age-matched, healthy controls and controls with no pathology except mild iron deficiency or iron deficiency anaemia were enrolled. Patients with secondary RLS other than iron deficiency were excluded. Total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), arylesterase (ARE), paraoxonase (PON), stimulated paraoxonase (stim-PON), lipid hydroperoxides (LOOHs), acetyl cholinesterase (AChE) and butyryl cholinesterase (BuChE) were measured. Heart rate variability (HRV) analysis was performed. RESULTS: TOS, ARE and AChE were increased (P = 0.018, P < 0.001 and P < 0.001, respectively), whereas LOOHs were decreased (P < 0.001) in RLS group. TAS, OSI, PON and stim-PON were comparable. Erythrocyte sedimentation rate (ESR) and mean platelet volume (MPV) were increased (P = 0.021 and P = 0.037, respectively) in RLS group. HRV triangular index (HRVi) was lower (P = 0.012) in RLS group. Other HRV parameters were similar. CONCLUSIONS: Increased AChE and decreased LOOHs, which were influenced by increased PON1, were considered as indicators of efforts towards the protection of dopaminergic activity in central nervous system in RLS group. Increased ESR, MPV and low HRVi indicate elevated sympathetic activity in RLS group. Elevated sympathetic activity might be beneficial in relieving RLS symptoms, also causing increases in TOS. The evidence we found regarding oxidative stress and autonomic nervous system might be seminal in RLS treatment. PMID- 21250985 TI - The association of serum potassium level with left ventricular mass in patients with primary aldosteronism. AB - BACKGROUND: Primary aldosteronism (PA) is associated a worse cardiovascular outcome than essential hypertension. Hypokalemia, which is one major characteristic of PA, can affect both cardiac structure and function. The goal of this study is to evaluate the influence of serum potassium level on left ventricular (LV) mass and function in PA patients. MATERIALS AND METHODS: We prospectively analysed 85 PA patients from October 2006 to September 2008 and 27 essential hypertension patients as the control group (group 1). Thirty-two patients with serum potassium < 3.5 mmol L(-1) were defined as hypokalemia (group 2), and 53 patients with serum potassium >= 3.5 mmol L(-1) were defined as normokalemia (group 3). Echocardiography including tissue Doppler image (TDI) recordings was performed in all patients. RESULTS: Group 2 patients had significant higher systolic and diastolic blood pressure (DBP), log-transformed plasma aldosterone concentration, log-transformed aldosterone-to-renin ratio and lower serum potassium level than groups 1 and 3. In echocardiographic measurement, group 2 patients had higher LV mass index (LVMI) than groups 1 and 3. In multivariate analysis for factors affecting LVMI in PA patients, only serum potassium level (P = 0.001), use of spironolactone (P = 0.004) and DBP (P = 0.005) were independent factors. In the TDI study, both groups 2 and 3 had lower e' and E/e' values than group 1. CONCLUSIONS: Serum potassium level is significantly associated with LVMI in PA patients. Compared with essential hypertensive patients, PA patients had a greater impairment of cardiac diastolic function. PMID- 21250986 TI - Homocysteine levels are associated with hippocampus volume in type 2 diabetic patients. AB - BACKGROUND: Elevated total plasma homocysteine (tHcy) levels are associated with cognitive dysfunction, in which changes in the hippocampus plausibly play a pivotal role. We tested the hypothesis that elevated tHcy levels are correlated with hippocampus volume and insulin resistance in nondementia patients with type 2 diabetes. MATERIALS AND METHODS: The study included 43 nondementia patients with type 2 diabetes, who were divided into two groups: a high tHcy group (age: 65 +/- 8 years, mean +/- standard deviation, n = 16) and a normal tHcy group (64 +/- 9 years, n = 27). Hippocampus volume was quantified with a computer-assisted analysis using a magnetic resonance imaging (MRI) voxel-based specific regional analysis system developed for the study of Alzheimer's disease (VSRAD), which yields a Z-score as the end point for the assessment of hippocampal volume. Results The Z-score was higher in the high tHcy group compared to the normal tHcy group (P < 0.0001). The fasting plasma glucose (P < 0.01) and insulin (P < 0.0001) concentrations and the homoeostasis model assessment (HOMA) index (P < 0.0001) were higher in the high tHcy group than in the normal tHcy group. Multiple regression analysis showed that the main factors that influenced tHcy levels may be the Z-score and the HOMA index. CONCLUSIONS: Our results indicate that the elevated levels of tHcy in Japanese nondementia patients with type 2 diabetes are characterised by hippocampal atrophy and insulin resistance and that the Z-score and HOMA index may be the primary factors that influence tHcy levels. PMID- 21250987 TI - Stereological estimation of the total number of myelinated callosal fibers in human subjects. AB - Using the fractionator principle, the total number, density and diameter size of myelinated callosal fibers were estimated in the corpus callosum (CC) of 10 Danish males between 39 and 60years of age. All sampled brains had been used in previous quantitative studies, for example, studies of neocortical neuron number, and were selected to determine whether the variability in the neocortical neuron number correlated with the total number of myelinated callosal fibers. Middle aged males had an average of 138*10(6) (coefficient of variance; CV=0.19) myelinated fibers, but did not show any correlation with the neocortical neuron number (r=0.25; P=0.49). The mean area of the CC was estimated to be 7.2cm(2) (CV=0.17), and showed a significant correlation with the number of callosal fibers (r=0.69, P=0.041). Additionally, an overall density decline from the anterior to the posterior region of the CC was observed, with an inverse relationship between the distribution of large and small fibers along the callosal axis. This study suggests that many mechanisms are involved in the development and determination of axonal projections across the CC that cannot simply be explained by the neocortical neuron number. Further, a positive correlation between callosal fibers and the CC area verifies that callosal fibers are the factor responsible for CC size. Finally, the number of callosal fibers and their diameters are distributed along the CC in a specific pattern that reflects interactions with different brain regions. PMID- 21250989 TI - The decoupling of abundance and species richness in lizard communities. AB - 1. Patterns of species richness often correlate strongly with measures of energy. The more individuals hypothesis (MIH) proposes that this relationship is facilitated by greater resources supporting larger populations, which are less likely to become extinct. Hence, the MIH predicts that community abundance and species richness will be positively related. 2. Recently, Buckley & Jetz (2010, Journal of Animal Ecology, 79, 358-365) documented a decoupling of community abundance and species richness in lizard communities in south-west United States, such that richer communities did not contain more individuals. They predicted, as a consequence of the mechanisms driving the decoupling, a more even distribution of species abundances in species-rich communities, evidenced by a positive relationship between species evenness and species richness. 3. We found a similar decoupling of the relationship between abundance and species richness for lizard communities in semi-arid south-eastern Australia. However, we note that a positive relationship between evenness and richness is expected because of the nature of the indices used. We illustrate this mathematically and empirically using data from both sets of lizard communities. When we used a measure of evenness, which is robust to species richness, there was no relationship between evenness and richness in either data set. 4. For lizard communities in both Australia and the United States, species dominance decreased as species richness increased. Further, with the iterative removal of the first, second and third most dominant species from each community, the relationship between abundance and species richness became increasingly more positive. 5. Our data support the contention that species richness in lizard communities is not directly related to the number of individuals an environment can support. We propose an alternative hypothesis regarding how the decoupling of abundance and richness is accommodated; namely, an inverse relationship between species dominance and species richness, possibly because of ecological release. PMID- 21250988 TI - Glutamate and ATP signalling in white matter pathology. AB - Excessive signalling by excitatory neurotransmitters like glutamate and ATP can be deleterious to neurons and oligodendroglia, and cause disease. In particular, sustained activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate and N-methyl-d-aspartate (NMDA) receptors damages oligodendrocytes, a feature that depends entirely on Ca(2+) overload of the cytoplasm and that can be initiated by disruption of glutamate homeostasis. Thus, inhibition of glutamate uptake by activated microglia can compromise glutamate homeostasis and induce oligodendrocyte excitotoxicity. Moreover, non-lethal, brief activation of kainate receptors in oligodendrocytes rapidly sensitizes these cells to complement attack as a consequence of oxidative stress. In addition to glutamate, ATP signalling can directly trigger oligodendrocyte excitotoxicity via activation of Ca(2+) -permeable P2X7 purinergic receptors, which mediates ischaemic damage to white matter (WM) and causes lesions that are reminiscent of multiple sclerosis (MS) plaques. Conversely, blockade of P2X7 receptors attenuates post-ischaemic injury to WM and ameliorates chronic experimental autoimmune encephalomyelitis, a model of MS. Importantly, P2X7 expression is elevated in normal-appearing WM in patients with MS, suggesting that signalling through this receptor in oligodendrocytes may be enhanced in this disease. Altogether, these observations reveal novel mechanisms by which altered glutamate and ATP homeostasis can trigger oligodendrocyte death. This review aims at summarizing current knowledge about the mechanisms leading to WM damage as a consequence of altered neurotransmitter signalling, and their relevance to disease. This knowledge will generate new therapeutic avenues to treat more efficiently acute and chronic WM pathology. PMID- 21250990 TI - Food chain length and omnivory determine the stability of a marine subtidal food web. AB - 1. Using a subtidal marine food web as a model system, we examined how food chain length (predators present or absent) and the prevalence of omnivory influenced temporal stability (and its components) of herbivores and plants. We held the density of top predators constant but manipulated their identity to generate a gradient in omnivory prevalence. 2. We measured temporal stability as the inverse of the coefficient of variation of abundance over time. Predators and omnivory could influence temporal stability through effects on abundance (the 'abundance' effect), summed variance across taxa (the 'portfolio effect') or summed covariances among taxa (the 'covariance effect'). 3. We found that increasing food chain length by predator addition destabilized aggregate herbivore abundance through their cascading effects on abundances. Thus, predators destabilized herbivores through the overyielding effect. We also found that the stability of herbivore abundance and microalgae declined with increasing prevalence of omnivory among top predators. Aggregate macroalgae was not affected, but the stability of one algal taxon increased with the prevalence of omnivory. 4. Our results suggest that herbivores are more sensitive than plants to changes in food web structure because of predator additions by invasion or deletions such as might occur via harvesting and habitat loss. PMID- 21250991 TI - Are numbers enough? Colonizer phenotype and abundance interact to affect population dynamics. AB - 1. Ecologists have long recognized that the number of colonizers entering a population can be a major driver of population dynamics, but still struggle to explain why the importance of colonizer supply varies so dramatically. While there are indications that differences in the phenotype among dispersing individuals could also be important to populations, the role of phenotypic variation relative to the number of individuals, and the extent to which they interact, remains unknown. 2. We simultaneously manipulated the phenotype (dispersal duration) and abundance of settlers of a marine bryozoan and measured subsequent population structure in the field. 3. Increases in the number of colonizing individuals increased the subsequent recruitment and biomass of populations, regardless of colonizer phenotype. However, the relationship between colonizer abundance and the subsequent reproductive yield of the population was strongly reduced in populations containing individuals that had long dispersal durations. 4. The interactive effects of colonizer phenotype and abundance on the reproductive yield of populations occurred because longer dispersal durations decreased the proportion of individuals that reproduced. In fact, populations established from a few individuals with short dispersal durations had similar reproductive yield to populations c. 30 times larger established from individuals with long dispersal durations. 5. Interactions between colonizer phenotype and abundance have important implications for predicting population dynamics beyond those previously provided by numerical abundance or recruit phenotype alone. PMID- 21250992 TI - Risk and protective factors for nicotine dependence in adolescence. AB - BACKGROUND: We investigated the role of psychosocial and proximal contextual factors on nicotine dependence in adolescence. METHODS: Data on a multiethnic cohort of 6th to 10th graders from the Chicago public schools were obtained from four household interviews conducted with adolescents over two years and one interview with mothers. Structural equation models were estimated on 660 youths who had smoked cigarettes by the first interview. RESULTS: Pleasant initial sensitivity to tobacco use, parental nicotine dependence (ND), adolescent ND and extensiveness of smoking at the initial interview had the strongest total effects on adolescent ND two years later. Perceived peer smoking and adolescent conduct problems were of lesser importance. Parental ND directly impacted adolescent ND two years later and had indirect effects through pleasant initial sensitivity and initial extensiveness of smoking. Parental depression affected initial adolescent dependence and depression but adolescent depression had no effect on ND. The model had greater explanatory power for males than females due partly to the stronger effect of conduct problems on dependence for males than females. CONCLUSIONS: The findings underscore the importance of the initial drug experience and familial factors on adolescent nicotine dependence and highlight the factors to be the focus of efforts targeted toward preventing ND among adolescents. PMID- 21250993 TI - Training anxious children to disengage attention from threat: a randomized controlled trial. AB - BACKGROUND: Threat-related attention biases have been implicated in the etiology and maintenance of anxiety disorders. As a result, attention bias modification (ABM) protocols have been employed as treatments for anxious adults. However, they have yet to emerge for children. A randomized, double-blind placebo controlled trial was conducted to examine the efficacy of an ABM protocol designed to facilitate attention disengagement from threats, thereby reducing anxiety and stress vulnerability in children. METHODS: Participants were 34 chronically high-anxious 10-year-olds. An emotional attention spatial cueing task was used. In the ABM condition (n=18), threat faces never cued the targets' locations, such that the valid-invalid ratio was 0%/100%, respectively. The valid invalid ratio on neutral cue trials was 25%/75%, respectively. In the control condition, the valid-invalid ratio was 25%/75% for both neutral and threat faces. Anxiety and depression were measured pre- and post-training and pre- and post stress induction. RESULTS: ABM facilitated attention disengagement from threat. In response to the stressor task, children in the ABM condition reported less state anxiety relative to controls. CONCLUSION: Computerized attention training procedures may be beneficial for reducing stress vulnerability in anxious children. PMID- 21250994 TI - Annual Research Review: Prenatal stress and the origins of psychopathology: an evolutionary perspective. AB - If a mother is stressed or anxious while pregnant her child is more likely to show a range of symptoms such as those of attention deficit hyperactivity disorder, conduct disorder, aggression or anxiety. While there remains some debate about what proportion of these effects are due to the prenatal or the postnatal environment, and the role of genetics, there is good evidence that prenatal stress exposure can increase the risk for later psychopathology. Why should this be? In our evolutionary history it is possible that some increase in these characteristics in some individuals was adaptive in a stressful environment, and that this type of fetal programming prepared the child or group for the environment in which they were going to find themselves. Anxiety may have been associated with increased vigilance, distractible attention with more perception of danger, impulsivity with more exploration, conduct disorder with a willingness to break rules, and aggression with the ability to fight intruders or predators. This adaptation for a future dangerous environment may explain why stress and anxiety, rather than depression, seem to have these programming effects; why there is a dose-response relationship with prenatal stress from moderate to severe and it is not only toxic stress that has consequences; why not all children are affected and why individual children are affected in different ways; and why the outcomes affected can depend on the sex of the offspring. An evolutionary perspective may give a different understanding of children in our society with these symptoms, and suggest new directions for research. For example, there is some evidence that the type of cognitive deficits observed after prenatal stress have specific characteristics; these may be those which were adaptive in a past environment. PMID- 21250995 TI - Development of an automated MODS plate reader to detect early growth of Mycobacterium tuberculosis. AB - In this work, an automated microscopic observation drug susceptibility (MODS) plate reader has been developed. The reader automatically handles MODS plates and after autofocussing digital images are acquired of the characteristic microscopic cording structures of Mycobacterium tuberculosis, which are the identification method utilized in the MODS technique to detect tuberculosis and multidrug resistant tuberculosis. In conventional MODS, trained technicians manually move the MODS plate on the stage of an inverted microscope while trying to locate and focus upon the characteristic microscopic cording colonies. In centres with high tuberculosis diagnostic demand, sufficient time may not be available to adequately examine all cultures. An automated reader would reduce labour time and the handling of M. tuberculosis cultures by laboratory personnel. Two hundred MODS culture images (100 from tuberculosis positive and 100 from tuberculosis negative sputum samples confirmed by a standard MODS reading using a commercial microscope) were acquired randomly using the automated MODS plate reader. A specialist analysed these digital images with the help of a personal computer and designated them as M. tuberculosis present or absent. The specialist considered four images insufficiently clear to permit a definitive reading. The readings from the 196 valid images resulted in a 100% agreement with the conventional nonautomated standard reading. The automated MODS plate reader combined with open source MODS pattern recognition software provides a novel platform for high throughput automated tuberculosis diagnosis. PMID- 21250996 TI - Transmission electron microscopy with a liquid flow cell. AB - The imaging of microscopic structures at nanometre-scale spatial resolution in a liquid environment is of interest for a wide range of studies. Recently, a liquid flow transmission electron microscopy (TEM) holder equipped with a microfluidic cell has been developed and shown to exhibit flow of nanoparticles through an electron transparent viewing window. Here we demonstrate the application of the flow cell system for both scanning and conventional transmission electron microscopy imaging of immobilized nanoparticles with a resolution of a few nanometres in liquid water of micrometre thickness. The spatial resolution of conventional TEM bright field imaging is shown to be limited by chromatic aberration due to multiple inelastic scattering in the water, and we demonstrate that the liquid in the cell can be displaced by a gas phase that forms under intense electron irradiation. Our data suggest that under appropriate conditions, TEM imaging with a liquid flow cell is a promising method for understanding the in situ behaviour of nanoscale structures in a prescribed and dynamically changing chemical environment. PMID- 21250997 TI - Brain region-specific deficit in mitochondrial electron transport chain complexes in children with autism. AB - Mitochondria play important roles in generation of free radicals, ATP formation, and in apoptosis. We studied the levels of mitochondrial electron transport chain (ETC) complexes, that is, complexes I, II, III, IV, and V, in brain tissue samples from the cerebellum and the frontal, parietal, occipital, and temporal cortices of subjects with autism and age-matched control subjects. The subjects were divided into two groups according to their ages: Group A (children, ages 4 10 years) and Group B (adults, ages 14-39 years). In Group A, we observed significantly lower levels of complexes III and V in the cerebellum (p<0.05), of complex I in the frontal cortex (p<0.05), and of complexes II (p<0.01), III (p<0.01), and V (p<0.05) in the temporal cortex of children with autism as compared to age-matched control subjects, while none of the five ETC complexes was affected in the parietal and occipital cortices in subjects with autism. In the cerebellum and temporal cortex, no overlap was observed in the levels of these ETC complexes between subjects with autism and control subjects. In the frontal cortex of Group A, a lower level of ETC complexes was observed in a subset of autism cases, that is, 60% (3/5) for complexes I, II, and V, and 40% (2/5) for complexes III and IV. A striking observation was that the levels of ETC complexes were similar in adult subjects with autism and control subjects (Group B). A significant increase in the levels of lipid hydroperoxides, an oxidative stress marker, was also observed in the cerebellum and temporal cortex in the children with autism. These results suggest that the expression of ETC complexes is decreased in the cerebellum and the frontal and temporal regions of the brain in children with autism, which may lead to abnormal energy metabolism and oxidative stress. The deficits observed in the levels of ETC complexes in children with autism may readjust to normal levels by adulthood. PMID- 21250998 TI - Tetraspanin, CD151, is required for maintenance of trigeminal placode identity. AB - The trigeminal ganglion is the largest of the cranial ganglia and responsible for transmitting sensory information for much of the face. The cell surface glycoprotein CD151 is an early marker of the trigeminal placode, the precursor to the ganglion. Here, we investigate the role of CD151 during specification of trigeminal placode cells in the developing chicken embryo. Expression of the transcription factor Pax3, the earliest known marker of the trigeminal placode, briefly precedes that of CD151, but they then subsequently overlap in the trigeminal placode. Loss of CD151 protein dramatically decreases the number of Pax3+ placode cells in Stage 13-14 embryos, leading to loss of ophthalmic trigeminal neurons by Stages 16 and 17. Although the initial size of the Pax3 population is similar to that in controls, the number of Pax3+ cells decreases with time without alterations in cell death or proliferation. This suggests a role for CD151 in maintenance of the specification state in the trigeminal placode, uncovering the first known role for a tetraspanin in a developmental system. PMID- 21250999 TI - Drought alters carbon fluxes in alpine snowbed ecosystems through contrasting impacts on graminoids and forbs. AB - * Climate change is predicted to increase the frequency of drought events in alpine ecosystems with the potential to affect carbon turnover. * We removed intact turfs from a Nardus stricta alpine snowbed community and subjected half of them to two drought events of 8 d duration under controlled conditions. Leachate dissolved organic carbon (DOC) was measured throughout the 6 wk study period, and a (13)CO(2) pulse enabled quantification of fluxes of recent assimilate into shoots, roots and leachate and ecosystem CO(2) exchange. * The amount of DOC in leachate from droughted cores was 62% less than in controls. Drought reduced graminoid biomass, increased forb biomass, had no effect on bryophytes, and led to an overall decrease in total above-ground biomass compared with controls. Net CO(2) exchange, gross photosynthesis and the amount of (13)CO(2) fixed were all significantly less in droughted turfs. These turfs also retained proportionally more (13)C in shoots, allocated less (13)C to roots, and the amount of dissolved organic (13)C recovered in leachate was 57% less than in controls. * Our data show that drought events can have significant impacts on ecosystem carbon fluxes, and that the principal mechanism behind this is probably changes in the relative abundance of forbs and grasses. PMID- 21251000 TI - Modelling photo-modulated internode elongation in growing glasshouse cucumber canopies. AB - * Growing glasshouse plant canopies are exposed to natural fluctuations in light quantity, and the dynamically changing canopy architecture induces local variations in light quality. This modelling study aimed to analyse the importance of both light signals for an accurate prediction of individual internode lengths. * We conceptualized two model approaches for estimating final internode lengths (FILs). The first one is only photosynthetically active radiation (PAR)-sensitive and ignores canopy architecture, whereas the second approach uses a functional structural growth model for considering variations in both PAR and red : far-red (R : FR) ratio (L-Cucumber). Internode lengths measured in three experiments were used for model parameterization and evaluation. * The overall trends for the simulated FILs using the exclusively PAR-sensitive model approach were already in line with the measured FILs, but they underestimated FILs at higher ranks. L Cucumber provided considerably better FIL predictions under various light conditions and canopy architectures. * Both light signals are needed for an accurate estimation of the FILs, and only L-Cucumber is able to consider R : FR signals from the growing canopy. Yet this study highlights the significance of the PAR signal for predicting FILs as neighbour effects increase, which indicates a potential role of photosynthate signalling in internode elongation. PMID- 21251001 TI - Selective lignin downregulation leads to constitutive defense response expression in alfalfa (Medicago sativa L.). AB - * Downregulation of hydroxycinnamoyl CoA: shikimate hydroxycinnamoyl transferase (HCT) in alfalfa (Medicago sativa) reduces lignin levels and improves forage quality and saccharification efficiency for bioethanol production. However, the plants have reduced stature. It was previously reported that HCT-down-regulated Arabidopsis have impaired auxin transport, but this has recently been disproved. * To address the basis for the phenotypes of lignin-modified alfalfa, we measured auxin transport, profiled a range of metabolites including flavonoids and hormones, and performed in depth transcriptome analyses. * Auxin transport is unaffected in HCT antisense alfalfa despite increased flavonoid biosynthesis. The plants show increased cytokinin and reduced auxin levels, and gibberellin levels and sensitivity are both reduced. Levels of salicylic, jasmonic and abscisic acids are elevated, associated with massive upregulation of pathogenesis and abiotic stress-related genes and enhanced tolerance to fungal infection and drought. * We suggest that HCT downregulated alfalfa plants exhibit constitutive activation of defense responses, triggered by release of bioactive cell wall fragments and production of hydrogen peroxide as a result of impaired secondary cell wall integrity. PMID- 21251002 TI - Contribution to safety of immunoglobulin and albumin from virus partitioning and inactivation by cold ethanol fractionation: a data collection from Plasma Protein Therapeutics Association member companies. AB - BACKGROUND: Virus removal by partitioning into different fractions during cold ethanol fractionation has been described by several authors, demonstrating that cold ethanol fractionation can provide significant contribution to virus removal, even in those cases where virus removal is limited and must be supported by additional measures for virus inactivation during further processing. STUDY DESIGN AND METHODS: Plasma Protein Therapeutics Association (PPTA) member companies collected and evaluated 615 studies on virus removal by the steps of the cold ethanol fractionation process. The studies describe the precipitation and separation of Fraction (F)III or FI/III in the immunoglobulin fractionation process and precipitation and separation of FII/III, FI/II/III, and FIV/IV in the albumin fractionation process. RESULTS: The data indicate a significant contribution of cold ethanol fractionation to the overall clearance of a broad spectrum of viruses, at varied process variables such as pH, temperature, and alcohol concentration and demonstrate the robustness of virus removal by the cold ethanol fractionation process. CONCLUSIONS: The data presented here support the importance of the partitioning steps for virus safety for immunoglobulins and albumin. However, virus removal by cold ethanol fractionation alone cannot provide viral safety of human albumin and immunoglobulins and therefore must be completed by other virus inactivation and removal procedures. PMID- 21251004 TI - Rejuvenation capacity of red blood cells in additive solutions over long-term storage. AB - BACKGROUND: Red blood cells (RBCs) are Food and Drug Administration (FDA) approved for 42-day storage with the use of additive solutions (ASs). However, adenosine triphosphate (ATP) and 2,3-diphosphoglycerate (2,3-DPG) levels in the RBCs decline over this time. These constituents may be restored by treatment with rejuvenation (REJ) solutions. This study was done to assess the response capability of RBCs from 30 to 120 days of storage in three FDA-licensed RBC storage solutions after incubation with a rejuvenating solution of pyruvate, inosine, phosphate, and adenine. STUDY DESIGN AND METHODS: Three units each of RBCs in approved AS (AS-1 [Adsol, Fenwal, Inc.], AS-3 [Nutricel, Medsep Corp.], and AS-5 [Optisol, Terumo Corp.]) were stored under standard conditions at 1 to 6 degrees C for up to 120 days. Aliquots (4 mL) on Days 30, 42, 60, 80, 100, and 120 (+/- 2 days) were REJ by incubating with Rejuvesol (Encyte Corp.). Control untreated and REJ aliquots were extracted using perchloric acid and stored at -80 degrees C until assayed for 2,3-DPG and ATP. RESULTS: RBCs responded to REJ by increasing DPG and ATP contents. The response declined linearly at 0.070 +/- 0.008 umol DPG/g hemoglobin (Hb)/day and 0.035 +/- 0.004 umol ATP/g Hb/day with no differences between ASs. CONCLUSION: We conclude that Rejuvesol is able to restore ATP and 2,3-DPG levels in RBCs stored up to 120 days in AS. The response diminishes as storage time increases. This rejuvenation (REJ) capability does not seem useful for routine assessment of RBC anabolic capacity in research programs, but may be useful to the investigator when studying unique and novel treatment methods. PMID- 21251003 TI - A shear-based assay for assessing plasma ADAMTS13 activity and inhibitors in patients with thrombotic thrombocytopenic purpura. AB - BACKGROUND: Severe deficiency of plasma ADAMTS13 activity is a frequent finding in patients with hereditary and acquired thrombotic thrombocytopenic purpura (TTP). To date, plasma ADAMTS13 activity is determined by cleavage of either predenatured von Willebrand factor (VWF) or small peptides derived from the VWF A2 domain. The physiologic relevance of the assay results is uncertain. STUDY DESIGN AND METHODS: We sought to develop a novel shear-based assay to assess plasma ADAMTS13 activity and inhibitors. We also compared this assay with a fluorogenic peptide assay. RESULTS: We found that an incubation of purified plasma VWF with 0.5 to 1.0 uL of citrated plasma under constant vortexing at 2500 rpm for 60 minutes in the presence of 5 mmol/L CaCl(2) and 1.7 umol/L ZnCl(2) and low concentration of NaCl resulted in the maximal cleavage of VWF. The cleavage product could be separated by a 2.5% agarose gel and detected by Western blotting. The assay revealed that plasma and recombinant ADAMTS13 are highly sensitive to inhibition by zinc and chloride ions. Under the optimal conditions, the shear-based assay appeared to be more sensitive than the guanidine denaturization assay for determining plasma ADAMTS13 activity. CONCLUSIONS: Our fluid shear-based assay may be useful for investigating basic biologic function and regulation of ADAMTS13 metalloprotease. It may also be applicable for assessing plasma ADAMTS13 activity and inhibitors in TTP patients. PMID- 21251005 TI - Occult hepatitis B virus infection in Thai blood donors. AB - BACKGROUND: An evaluation by the National Blood Center, the Thai Red Cross Society, of two commercial multiplex nucleic acid tests (NATs; the Chiron PROCLEIX ULTRIO test and the Roche Cobas TaqScreen MPX test) for screening Thai blood donors for hepatitis B virus (HBV), hepatitis C virus, and human immunodeficiency virus Type 1 identified 175 HBV NAT-reactive/hepatitis B surface antigen (HBsAg)-negative donors. The classification of the HBV infection of these donors was confirmed by follow-up testing. STUDY DESIGN AND METHODS: Index samples were tested for HBV serologic markers and HBV viral loads were determined. Donors were followed for up to 13 months and samples were tested with both NAT assays and for all HBV serological markers. RESULTS: Of 175 HBV NAT yield donors, 72 (41%) were followed. Based on the follow-up results, the majority of donors who were followed had an occult HBV infection (66.7%), followed by donors with a primary, acute infection (26.4%). The majority of donors in this latter group (20.8%) were in the window period. Three donors (4.2%), who were anti-HBs positive, had a reinfection or breakthrough infection. CONCLUSION: The majority of donors detected during routine screening, who were HBsAg negative and NAT reactive, had an occult HBV infection, thus validating the decision to introduce NAT for blood donations in Thailand. PMID- 21251006 TI - Current problems and future directions of transfusion-induced alloimmunization: summary of an NHLBI working group. AB - In April 2010, a working group sponsored by the National Heart, Lung, and Blood Institute was assembled to identify research strategies to improve our understanding of alloimmunization caused by the transfusion of allogeneic blood components and to evaluate potential approaches to both reduce its occurrence and manage its effects. Significant sequelae of alloimmunization were discussed and identified, including difficulties in maintaining chronic transfusion of red blood cells and platelets, hemolytic disease of the newborn, neonatal alloimmune thrombocytopenia, and rejection of transplanted cells and tissues. The discussions resulted in a consensus that identified key areas of future research and developmental areas, including genetic and epigenetic recipient factors that regulate alloimmunization, biochemical specifics of transfused products that affect alloimmunization, and novel technologies for high-throughput genotyping to facilitate extensive and efficient antigen matching between donor and recipient. Additional areas of importance included analysis of unappreciated medical sequelae of alloimmunization, such as cellular immunity and its effect upon transplant and autoimmunity. In addition, support for research infrastructure was discussed, with an emphasis on encouraging collaboration and synergy of animal models biology and human clinical research. Finally, training future investigators was identified as an area of importance. In aggregate, this communication provides a synopsis of the opinions of the working group on the above issues and presents both a list of suggested priorities and the rationale for the topics of focus. The areas of research identified in this report represent potential fertile ground for the medical advancement of preventing and managing alloimmunization in its different forms and mitigating the clinical problems it presents to multiple patient populations. PMID- 21251007 TI - The effects of long-term storage of human red blood cells on the glutathione synthesis rate and steady-state concentration. AB - BACKGROUND: Banked red blood cells (RBCs) undergo changes that reduce their viability after transfusion. Dysfunction of the glutathione (GSH) antioxidant system may be implicated. We measured the rate of GSH synthesis in stored RBCs and applied a model of GSH metabolism to identify storage-dependent changes that may affect GSH production. STUDY DESIGN AND METHODS: RBC units (n = 6) in saline adenine-glucose-mannitol (SAGM) solution were each divided into four transfusion bags and separate treatments were applied: 1) SAGM (control), 2) GSH precursor amino acids, 3) aminoguanidine, and 4) glyoxal. RBCs were sampled during 6 weeks of storage. Rejuvenated RBCs were also analyzed. RESULTS: After 6 weeks, the ATP concentration declined to 50 +/- 5.5% (p < 0.05) of that in the fresh RBCs. For control RBCs, the GSH concentration decreased by 27 +/- 6.5% (p < 0.05) and the rate of GSH synthesis by 45 +/- 8% (p < 0.05). The rate of GSH synthesis in rejuvenated and amino acid-treated RBCs was unchanged after 6 weeks. Modeling identified that the decline in GSH synthesis was due to decreased intracellular substrate concentrations and reduced amino acid transport, secondary to decreased ATP concentration. CONCLUSION: This study has uniquely shown that the glutathione synthesis rate decreased significantly after 6 weeks in stored RBCs. Our results have identified potential opportunities for improvement of banked blood storage. PMID- 21251009 TI - The descent of memory T cells. AB - Our T cell repertoire is shaped by antigen encounter. From a naive T cell pool that contains millions of different T cells with unknown specificities, pathogen infection leads to selection of those T cells that can detect pathogen-derived antigens. Following clearance of infection, a population of memory T cells remains and protects the individual from severe reinfection. A central question in the field has been how the generation of long-lived memory T cells, versus short-lived ("terminally differentiated") T cells, is controlled. In this review we discuss the models that have been put forward to explain the generation of memory T cells after infection and the experimental evidence supporting these hypotheses. Based on the available data we propose a new model that stipulates that during immune responses T cells do not acquire different fates that determine their subsequent long-term survival but rather T cells assume different states that simply reflect the likelihood of future survival, states that can still be modulated by external signals. PMID- 21251008 TI - Structural basis of influenza virus neutralization. AB - Although seasonal influenza vaccines play a valuable role in reducing the spread of virus at the population level, ongoing viral evolution to evade immune responses remains problematic. No current vaccines elicit enduring protection in the face of emerging and re-emerging influenza viruses that are rapidly undergoing antigenic drift. Eliciting broadly cross-neutralizing antibody (nAb) responses against influenza virus is a crucial goal for seasonal and pandemic influenza vaccine preparation. Recent three-dimensional structure information obtained from crystallization of influenza antigens in complex with nAbs has provided a framework for interpreting antibody-based viral neutralization that should aid in the design of vaccine immunogens. Here, we will review current knowledge of the structure-based mechanisms contributing to the neutralization and neutralization escape of influenza viruses. We will also explore the potential for this structure-based approach to overcome the obstacles in developing the highly desired "universal" influenza vaccine. PMID- 21251010 TI - Epigenetics in lupus. AB - Accumulating epidemiological, clinical, and experimental evidence supports the conclusion of a critical role of epigenetic factors in immune programming. This understanding provides the basis for elucidating how the intricate interactions of the genome, epigenome, and transcriptome shape immune responses and maintain immune tolerance to self-antigens. Deciphering the precise contribution of epigenetic factors to autoimmunity, and in particular to lupus, has become an active research area. On one hand, it is well established that environmental factors have an impact on the epigenome and, therefore, on the transcriptional and translational machinery of specific cell types; on the other, the environment also plays an important role in the severity of lupus and other autoimmunity diseases. Determining how epigenetics "connects" the environment to cell biology and to autoreactivity will be key for advancing our understanding in this field and, possibly, for developing novel preventive strategies. PMID- 21251011 TI - Social neuroscience: challenges and opportunities in the study of complex behavior. AB - Social species are so characterized because they form organizations that extend beyond the individual. The goal of social neuroscience is to investigate the biological mechanisms that underlie these social structures, processes, and behavior and the influences between social and neural structures and processes. Such an endeavor is challenging because it necessitates the integration of multiple levels. Mapping across systems and levels (from genome to social groups and cultures) requires interdisciplinary expertise, comparative studies, innovative methods, and integrative conceptual analysis. Examples of how social neuroscience is contributing to our understanding of the functions of the brain and nervous system are described, and societal implications of social neuroscience are considered. PMID- 21251014 TI - The human connectome: a complex network. AB - The human brain is a complex network. An important first step toward understanding the function of such a network is to map its elements and connections, to create a comprehensive structural description of the network architecture. This paper reviews current empirical efforts toward generating a network map of the human brain, the human connectome, and explores how the connectome can provide new insights into the organization of the brain's structural connections and their role in shaping functional dynamics. Network studies of structural connectivity obtained from noninvasive neuroimaging have revealed a number of highly nonrandom network attributes, including high clustering and modularity combined with high efficiency and short path length. The combination of these attributes simultaneously promotes high specialization and high integration within a modular small-world architecture. Structural and functional networks share some of the same characteristics, although their relationship is complex and nonlinear. Future studies of the human connectome will greatly expand our knowledge of network topology and dynamics in the healthy, developing, aging, and diseased brain. PMID- 21251015 TI - Dendritic cells and airway epithelial cells at the interface between innate and adaptive immune responses. AB - Because they can recognize and sample inhaled allergens, dendritic cells (DC) have been shown to be responsible for the initiation and maintenance of adaptive Th2 responses in asthma. It is increasingly clear that DC functions are strongly influenced by a crosstalk with neighboring cells like epithelial cells. Whereas the epithelium was initially considered only as a barrier, it is now seen as a central player in controlling the function of lung DCs through release of innate cytokines-promoting Th2 responses. Clinically relevant allergens, as well as known environmental and genetic risk factors for allergy and asthma, often interfere directly or indirectly with the innate immune functions of airway epithelial cells and DC. A better understanding of these interactions might lead to a better prevention and ultimately to new treatments for asthma. PMID- 21251012 TI - B cell receptor editing in tolerance and autoimmunity. AB - Receptor editing is the process of ongoing antibody gene rearrangement in a lymphocyte that already has a functional antigen receptor. The expression of a functional antigen receptor will normally terminate further rearrangement (allelic exclusion). However, lymphocytes with autoreactive receptors have a chance at escaping negative regulation by "editing" the specificities of their receptors with additional antibody gene rearrangements. As such, editing complicates the Clonal Selection Hypothesis because edited cells are not simply endowed for life with a single, invariant antigen receptor. Furthermore, if the initial immunoglobulin gene is not inactivated during the editing process, allelic exclusion is violated and the B cell can exhibit two specificities. Here, we describe the discovery of editing, the pathways of receptor editing at the heavy (H) and light (L) chain loci, and current evidence regarding how and where editing happens and what effects it has on the antibody repertoire. PMID- 21251013 TI - Hematopoietic progenitor migration to the adult thymus. AB - Although most hematopoietic lineages develop in the bone marrow (BM), T cells uniquely complete their development in the specialized environment of the thymus. Hematopoietic stem cells with long-term self-renewal capacity are not present in the thymus. As a result, continuous T cell development requires that BM-derived progenitors be imported into the thymus throughout adult life. The process of thymic homing begins with the mobilization of progenitors out of the BM, continues with their circulation in the bloodstream, and concludes with their settling in the thymus. This review will discuss each of these steps as they occur in the unirradiated and postirradiation scenarios, focusing on the molecular mechanisms of regulation. Improved knowledge about these early steps in T cell generation may accelerate the development of new therapeutic options in patients with impaired T cell number or function. PMID- 21251016 TI - Immunological mechanisms of sublingual allergen-specific immunotherapy. AB - Within the last 100 years of allergen-specific immunotherapy, many clinical and scientific efforts have been made to establish alternative noninvasive allergen application strategies. Thus, intra-oral allergen delivery to the sublingual mucosa has been proven to be safe and effective. As a consequence, to date, sublingual immunotherapy (SLIT) is widely accepted by most allergists as an alternative to conventional subcutaneous immunotherapy. Although immunological mechanisms remain to be elucidated in detail, several studies in mice and humans within recent years provided deeper insights into local as well as systemic immunological features in response to SLIT. First of all, it was shown that the target organ, the oral mucosa, harbours a sophisticated immunological network as an important prerequisite for SLIT, which contains among other cells, local antigen-presenting cells (APC), such as dendritic cells (DCs), with a constitutive disposition to enforce tolerogenic mechanisms. Further on, basic research on local DCs within the oral mucosa gave rise to possible alternative strategies to deliver the allergens to other mucosal regions than sublingual tissue, such as the vestibulum oris. Moreover, characterization of oral DCs led to the identification of target structures for both allergens as well as adjuvants, which could be applied during SLIT. Altogether, SLIT came a long way since its very beginning in the last century and some, but not all questions about SLIT could be answered so far. However, recent research efforts as well as clinical approaches paved the way for another exciting 100 years of SLIT. PMID- 21251017 TI - A bicistronic, Ubiquitin-10 promoter-based vector cassette for transient transformation and functional analysis of membrane transport demonstrates the utility of quantitative voltage clamp studies on intact Arabidopsis root epidermis. AB - To date the use of fluorescent reporter constructs in analysing membrane transport has been limited primarily to cell lines expressing stably either the tagged transporter protein(s) or markers to identify lineages of interest. Strategies for transient expression have yet to be exploited in transport analysis, despite their wide application in cellular imaging studies. Here we describe a Gateway-compatible, bicistronic vector, incorporating the constitutive Ubiqutin-10 gene promoter of Arabidopsis that gives prolonged expression after transient transformation and enables fluorescence marking of cells without a fusion construct. We show that Arabidopsis root epidermal cells are readily transformed by co-cultivation with Agrobacterium and are tractable for quantitative electrophysiological analysis. As a proof of principle, we transiently transformed Arabidopsis with the bicistronic vector carrying GFP as the fluorescent marker and, separately, the integral plasma membrane protein SYP121 essential for the inward K+ channel current. We demonstrate that transient expression of SYP121 in syp121 mutant plants is sufficient to rescue the K+ current in vivo. The combination of transient expression and use of the bicistronic vector promises significant advantages for studies of membrane transport and nutrient acquisition in roots. PMID- 21251018 TI - Using tunable diode laser spectroscopy to measure carbon isotope discrimination and mesophyll conductance to CO2 diffusion dynamically at different CO2 concentrations. AB - In C3 leaves, the mesophyll conductance to CO2 diffusion, g(m) , determines the drawdown in CO2 concentration from intercellular airspace to the chloroplast stroma. Both g(m) and stomatal conductance limit photosynthetic rate and vary in response to the environment. We investigated the response of g(m) to changes in CO2 in two Arabidopsis genotypes (including a mutant with open stomata, ost1), tobacco and wheat. We combined measurements of gas exchange with carbon isotope discrimination using tunable diode laser absorption spectroscopy with a CO2 calibration system specially designed for a range of CO2 and O2 concentrations. CO2 was initially increased from 200 to 1000 ppm and then decreased stepwise to 200 ppm and increased stepwise back to 1000 ppm, or the sequence was reversed. In 2% O2 a step increase from 200 to 1000 ppm significantly decreased g(m) by 26-40% in all three species, whereas following a step decrease from 1000 to 200 ppm, the 26-38% increase in g(m) was not statistically significant. The response of g(m) to CO2 was less in 21% O2. Comparing wild type against the ost1 revealed that mesophyll and stomatal conductance varied independently in response to CO2. We discuss the effects of isotope fractionation factors on estimating g(m) . PMID- 21251019 TI - Comparative ionomics and metabolomics in extremophile and glycophytic Lotus species under salt stress challenge the metabolic pre-adaptation hypothesis. AB - The legume genus Lotus includes glycophytic forage crops and other species adapted to extreme environments, such as saline soils. Understanding salt tolerance mechanisms will contribute to the discovery of new traits which may enhance the breeding efforts towards improved performance of legumes in marginal agricultural environments. Here, we used a combination of ionomic and gas chromatography-mass spectrometry (GC-MS)-based metabolite profilings of complete shoots (pooling leaves, petioles and stems) to compare the extremophile Lotus creticus, adapted to highly saline coastal regions, and two cultivated glycophytic grassland forage species, Lotus corniculatus and Lotus tenuis. L. creticus exhibited better survival after exposure to long-term lethal salinity and was more efficient at excluding Cl- from the shoots than the glycophytes. In contrast, Na+ levels were higher in the extremophile under both control and salt stress, a trait often observed in halophytes. Ionomics demonstrated a differential rearrangement of shoot nutrient levels in the extremophile upon salt exposure. Metabolite profiling showed that responses to NaCl in L. creticus shoots were globally similar to those of the glycophytes, providing little evidence for metabolic pre-adaptation to salinity. This study is the first comparing salt acclimation responses between extremophile and non-extremophile legumes, and challenges the generalization of the metabolic salt pre-adaptation hypothesis. PMID- 21251020 TI - Distinct responses of the mitochondrial respiratory chain to long- and short-term high-light environments in Arabidopsis thaliana. AB - In order to ensure the cooperative function with the photosynthetic system, the mitochondrial respiratory chain needs to flexibly acclimate to a fluctuating light environment. The non-phosphorylating alternative oxidase (AOX) is a notable respiratory component that may support a cellular redox homeostasis under high light (HL) conditions. Here we report the distinct acclimatory manner of the respiratory chain to long- and short-term HL conditions and the crucial function of AOX in Arabidopsis thaliana leaves. Plants grown under HL conditions (HL plants) possessed a larger ubiquinone (UQ) pool and a higher amount of cytochrome c oxidase than plants grown under low light conditions (LL plants). These responses in HL plants may be functional for efficient ATP production and sustain the fast plant growth. When LL plants were exposed to short-term HL stress (sHL), the UQ reduction level was transiently elevated. In the wild-type plant, the UQ pool was re-oxidized concomitantly with an up-regulation of AOX. On the other hand, the UQ reduction level of the AOX-deficient aox1a mutant remained high. Furthermore, the plastoquinone pool was also more reduced in the aox1a mutant under such conditions. These results suggest that AOX plays an important role in rapid acclimation of the respiratory chain to sHL, which may support efficient photosynthetic performance. PMID- 21251021 TI - Detraditionalisation, gender and alternative and complementary medicines. AB - This article is premised on the importance of locating the appeal and meaning of alternative and complementary medicines in the context of gendered identities. I argue that the discourse of wellbeing--captured in many alternative and complementary health practices--is congruent with culturally prevalent ideals of self-fulfilling, authentic, unique and self-responsible subjectivity. The discourse of wellbeing places the self at the centre, thus providing a contrast with traditional ideas of other-directed and caring femininity. As such, involvement in alternative and complementary medicines is entwined with a negotiation of shifting femininities in detraditionalising societies. Simultaneously, many alternative and complementary health practices readily tap into and reproduce traditional representations of caring femininity. It is through an emphasis on emotional honesty and intimacy that the discourse of wellbeing also captures a challenge to traditional ideas of masculinity. Expectations and experiences relating to gender add a further level of complexity to the meaningfulness and therapeutic value of alternative and complementary medicines and underlie the gender difference in the utilisation of holistic health practices. I draw on data from a qualitative study with 44, primarily white, middle-class users and practitioners of varied alternative and complementary medicines in the UK. PMID- 21251022 TI - Songs from a distant time. PMID- 21251023 TI - ICD problems--is the device to blame? PMID- 21251024 TI - Differential diagnosis of supraventricular tachycardia with ventriculoatrial dissociation during ventricular overdrive pacing. PMID- 21251025 TI - Ventricular fibrillation following successful DC cardioversion for atrial fibrillation. AB - Cardioversion remains an important therapy in the management of atrial fibrillation. Here, we report a case where direct current cardioversion resulted in a sudden dramatic change of heart rate that was associated with multiple ventricular fibrillation arrests in a manner akin to that previously observed post-atrioventricular node ablation. PMID- 21251026 TI - Early recurrences after paroxysmal atrial fibrillation ablation: when is the proper timing for reablation? AB - BACKGROUND: Early recurrences (ERs) within 1 month after paroxysmal atrial fibrillation (AF) ablation are common and may subside in a considerable proportion of patients. Although late reablation after 3 months is recommended, the proper timing for reablation remains undetermined. METHODS AND RESULTS: One hundred and seventeen (31.2%) from the pool of 375 patients experienced ERs at 7.5 +/- 5.5 days postablation. They were allocated into two groups randomly: early reablation group (ERe+) (n = 57) and nonearly reablation group (ERe-) (n = 60). Forty patients (70.2%) in ERe+ group underwent early reablation at 28.1 +/- 2.7 days postablation. Forty patients (66.7%) in ERe- group underwent late reablation at 98.2 +/- 5.2 days postablation. The proportion of reablation was comparable (P = 0.68). ERs subsided in 17 (29.8%) in ERe+ group and in 20 (33.3%) in ERe- group. In ERe+ group, PV reconnection in 36 (80.0%), non-PV foci in six (10.5%), and right or left atrial flutter in five (8.8%) was abolished by ablation. In ERe- group, pulmonary vein (PV) reconnection in 29 (72.5%), non-PV foci in eight (13.3%), and right or left atrial flutter in eight (13.3%) was ablated successfully. The proportion of PV reconnection, nonfoci, and atrial flutter was comparable, P = 0.45, 0.64, and 0.56, respectively. At the end of 16.5 +/- 2.0 (ERe+ group) and 15.2 +/- 2.6 (ERe- group) months' follow-up, 47 (82.5%) in ERe+ group and 51 (85%) in ERe- group were free of atrial tachyarrhythmias, P = 0.70. CONCLUSIONS: Compared with reablation 2 months later after initial ablation, early reablation at ~1 month had similar clinical effectiveness. The proper timing for reablation can be set at ~1 month after initial paroxysmal AF ablation. PMID- 21251027 TI - Insects as alternative hosts for phytopathogenic bacteria. AB - Phytopathogens have evolved specialized pathogenicity determinants that enable them to colonize their specific plant hosts and cause disease, but their intimate associations with plants also predispose them to frequent encounters with herbivorous insects, providing these phytopathogens with ample opportunity to colonize and eventually evolve alternative associations with insects. Decades of research have revealed that these associations have resulted in the formation of bacterial-vector relationships, in which the insect mediates dissemination of the plant pathogen. Emerging research, however, has highlighted the ability of plant pathogenic bacteria to use insects as alternative hosts, exploiting them as they would their primary plant host. The identification of specific bacterial genetic determinants that mediate the interaction between bacterium and insect suggests that these interactions are not incidental, but have likely arisen following the repeated association of microorganisms with particular insects over evolutionary time. This review will address the biology and ecology of phytopathogenic bacteria that interact with insects, including the traditional role of insects as vectors, as well as the newly emerging paradigm of insects serving as alternative primary hosts. Also discussed is one case where an insect serves as both host and vector, which may represent a transitionary stage in the evolution of insect phytopathogen associations. PMID- 21251028 TI - Prevalence of yeast-like fungi and evaluation of several virulence factors from feral pigeons in Seoul, Korea. AB - AIMS: Studies of pigeon-borne yeasts have tended to focus on species, such as Cryptococcus neoformans and Candida albicans, with scant attention to feral pigeons in Korea. We studied the prevalence of yeasts from faecal samples of feral pigeons obtained in various public places in Seoul, Korea, and assessed their potential capacity as human pathogens. METHODS AND RESULTS: Three hundred and six pigeon faeces samples were collected at city squares and parks in 21 localities in Seoul and Seoul Grand Park and analysed for yeast with conventional methods. Of the 306 samples, 126 (41.2%) were positive for yeast. Seventeen species of yeast were identified. The most frequent species were Candida glabrata (34.1%), Candida famata (12.7%), Cryptococcus albidus (14.3%) and Cryptococcus laurentii (7.9%). The yeast isolates were tested for virulence. Of the 116 isolates (ten isolates missing), 70.7% (n = 82) grew at 37 degrees C. All the Cryptococcus spp. isolates possessed a capsule, 16.4% (n = 19) produced melanin, and 33.6% (n = 39) produced proteinase. Two Ca. glabrata, a Ca. famata and Ca. albicans as well as three C. neoformans, a C. laurentii and Ca. albicans isolates had three virulence factors. Accordingly, 29.3% (n = 34) isolates possessed more than two virulence factors except capsule formation. CONCLUSIONS: These results of this study indicate that feral pigeons harbour a variety of yeasts and are a reservoir of human pathogenic fungi. SIGNIFICANCE AND IMPACT OF THE STUDY: This study is the first time about the microflora (fungi) presents in faecal samples collected from a variety of public areas throughout Seoul, Korea. PMID- 21251029 TI - Risk of tuberculosis in a large sample of patients with coeliac disease--a nationwide cohort study. AB - BACKGROUND: Research suggests a positive association between coeliac disease and tuberculosis (TB), but that research has often been limited to in-patients and small sample size. We examined the relationship between TB and coeliac disease. AIM: To examine the association of TB and coeliac disease. METHODS: We collected biopsy data from all pathology departments in Sweden (n=28) to identify individuals who were diagnosed with coeliac disease between 1969 and 2007 (Marsh 3: villous atrophy; n=29,026 unique individuals). Population-based sex- and age matched controls were selected from the Total Population Register. Using Cox regression, we calculated hazard ratios (HRs) for TB from data in the Swedish national health registers. RESULTS: Individuals with coeliac disease were at increased risk of TB (HR=2.0; 95% CI=1.3-3.0) (during follow-up, 31 individuals with coeliac disease and 74 reference individuals had a diagnosis of TB). The absolute risk of TB in patients with coeliac disease was 10/100,000 person-years with an excess risk of 5/100,000. Risk estimates were the highest in the first year. Restricting our outcome to a diagnosis of TB confirmed by (I) a record of TB medication (HR=2.9; 95% CI=1.0-8.3), (II) data in the National Surveillance System for Infectious Diseases in Sweden (HR=2.6; 95% CI=1.3-5.2) or (III) positive TB cultivation (HR=3.3; 95% CI=1.6-6.8) increased risk estimates. The positive association between coeliac disease and TB was also observed before the coeliac disease diagnosis (odds ratio=1.6; 95% CI=1.2-2.1). CONCLUSION: We found a moderately increased risk of tuberculosis in patients with coeliac disease. PMID- 21251030 TI - Meta-analysis: the effects of gut flora modulation using prebiotics, probiotics and synbiotics on minimal hepatic encephalopathy. AB - BACKGROUND: Minimal hepatic encephalopathy (MHE) is characterised by subtle neurocognitive deficits without overt clinical manifestations. Although several trials have individually evaluated the role of prebiotics, probiotics and synbiotics, there is yet no consensus on the management of MHE. AIM: To estimate the efficacy of prebiotics, probiotics and synbiotics in MHE in randomised controlled trials. METHODS: MEDLINE, EMBASE, CINAHL and the Cochrane Database of Systematic Reviews were searched for published studies in all languages. Inclusion and exclusion criteria were defined a priori. Pooled relative risk and heterogeneity were estimated as the measures of association. RESULTS: Nine studies met our inclusion criteria. Use of prebiotics, probiotics and synbiotics significantly reduced the pooled relative risk (RR) of no improvement of MHE (RR 0.40, 95% CI 0.32-0.50; P<0.001). Upon subgroup analysis, five studies with lactulose showed significant reduction of risk of no improvement of MHE (RR 0.34, 95% CI 0.24-0.47; P<0.0001) with no inter-trial heterogeneity. In two trials each of probiotics and synbiotics, their use was associated with significant beneficial effects (RR 0.41, 95% CI 0.26-0.65; P<0.0001 and RR of 0.51, 95% CI 0.32-0.80; P=0.004 respectively). There were no major adverse events though probiotics and synbiotics were better tolerated than lactulose. CONCLUSIONS: The use of prebiotics, probiotics and synbiotics was associated with significant improvement in minimal hepatic encephalopathy. Among individual agents, lactulose appears to have the most beneficial effect, followed closely by probiotics and synbiotics. PMID- 21251031 TI - Effect of rimonabant on oesophageal motor function in man. AB - BACKGROUND: Cannabinoid type 1 (CB1) receptors are implicated in the control of transient lower oesophageal sphincter relaxations (TLESRs) in animals. In man, it is unclear whether CB1 receptors are involved in the control of oesophageal function. AIM: To study the effects of the CB1 receptor antagonist rimonabant on fasting and postprandial LES function in healthy subjects. METHODS: Twelve healthy volunteers underwent two oesophageal manometry studies with administration of wet swallows and a meal after 3 days' premedication with placebo or rimonabant 20 mg. RESULTS: Rimonabant did not significantly alter preprandial LES pressure (21.1+/-4.0 vs. 17.3+/-3.0 mmHg, N.S.), but postprandial LES pressures were significantly enhanced (9.9+/-1.9 vs.17.1+/-2.7 mmHg in the first and 10.0+/-1.4 vs. 19.3+/-3.6 mmHg in the second postprandial hour, both P<0.05). Swallow-induced relaxations and amplitude of peristaltic contractions were not altered, but rimonabant significantly increased the duration of peristaltic contractions at all time points (e.g. 5.0+/-0.3 vs. 8.0+/-0.3s preprandially and 5.0+/-0.2 vs. 8.2+/-0.3s at 60 min postprandially, both P<0.01). The number of postprandial TLESRs (3.1+/-0.5 vs. 1.2+/-0.5, P<0.05) and acid reflux episodes (1.4+/-0.2 vs. 0.3+/-0.1, P<0.05) were significantly lower after rimonabant. CONCLUSION: The CB1 receptor antagonist rimonabant enhances postprandial LES pressure and decreases TLESRs in healthy subjects. PMID- 21251032 TI - The use of azathioprine in Crohn's disease during pregnancy and in the post operative setting: a worldwide survey of experts. AB - BACKGROUND: Although thiopurines are considered safe in humans, they are still pregnancy FDA category D drugs. Prevention of post-operative recurrence is a challenge in clinical practice in Crohn's disease. The European Crohn's and Colitis Organisation consensus states that thiopurines should be considered in high-risk patients. AIM: To perform a worldwide survey for evaluating the extent to which gastroenterologists who are experts in the field of IBD are utilising thiopurines during pregnancy and in the post-operative setting in Crohn's disease. METHODS: This was a Web-based cross-sectional, statement-based survey, which was conducted among experts who have published at least once in the field of thiopurines in IBD. RESULTS: Between 20 December 2009 and 9 April 2010, 175 questionnaires were received. The median number of IBD patients per physician per year was 400 (IQR 25-75th, 188-600) and the total number of IBD patients followed by all responders was 82,379. In a pregnant woman with a history of severe Crohn's disease in clinical remission after 1 year on azathioprine, 89% of experts usually continue azathioprine until delivery and 9% of physicians never administer azathioprine during pregnancy. After ileocecal resection for Crohn's disease, 39% of physicians initiate azathioprine only in high-risk patients, 28% of practitioners prescribe azathioprine according to endoscopic evaluation, 20% of gastroenterologists systematically initiate azathioprine and 13% have a different attitude. CONCLUSIONS: Almost 9 of 10 physicians continue azathioprine throughout pregnancy. About 7 of 10 physicians prescribe azathioprine in the post operative setting according to the European Crohn's and Colitis Organisation recommendations, whereas one-fifth of practitioners systematically initiate azathioprine after surgery. PMID- 21251033 TI - Systematic review: association of polycystic ovary syndrome with metabolic syndrome and non-alcoholic fatty liver disease. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is a common disorder for women of child-bearing age and is associated with metabolic syndrome (MS). AIM: To assess the literature for associations between polycystic ovary syndrome and non alcoholic fatty liver disease (NAFLD). METHODS: We performed a systematic review using PubMed-search for peer-reviewed articles related to polycystic ovary syndrome and NAFLD. Articles were summarised and grouped according to different sections defining interactions of polycystic ovary syndrome with metabolic syndrome and non-alcoholic fatty liver disease as well as risk factors, pathogenic pathways and treatment options. RESULTS: Obesity is a common factor involved in both polycystic ovary syndrome and non-alcoholic fatty liver disease. Obesity causes non-alcoholic fatty liver disease and aggravates hirsutism and menstrual disorders in polycystic ovary syndrome. Insulin resistance, a hallmark of metabolic syndrome is observed in 50-80% of women with polycystic ovary syndrome and patients with non-alcoholic fatty liver disease. Recent findings suggest that women with polycystic ovary syndrome may be at risk for developing non-alcoholic fatty liver disease and conversely, non-alcoholic fatty liver disease may be a risk for polycystic ovary syndrome. Based on the association of polycystic ovary syndrome and other metabolic abnormalities, such as insulin resistance, hyperandrogenism, obesity and non-alcoholic fatty liver disease, the candidate genes have been speculated for polycystic ovary syndrome. Closer scrutiny of these genes placed most of their proteins at the crossroads of three highly inter-related conditions: metabolic syndrome, obesity and non-alcoholic fatty liver disease. In most studies, the prevalence of both polycystic ovary syndrome and non-alcoholic fatty liver disease rises proportionally to the degree of insulin resistance and increases in the mass of adipose tissue. CONCLUSIONS: Non-alcoholic fatty liver disease is considered as the hepatic manifestation of metabolic syndrome. Similarly, it seems appropriate to consider polycystic ovary syndrome as the ovarian manifestation of metabolic syndrome. Both these conditions can co-exist and may respond to similar therapeutic strategies. PMID- 21251034 TI - Experiences of working with induced abortion: focus group discussions with gynaecologists and midwives/nurses. AB - BACKGROUND: While there exists an extensive amount of research regarding the medical aspects of abortion, there is a great lack of studies investigating staff's views and experiences of working in abortion services. AIMS: To elucidate gynaecologists' and midwives'/nurses' experiences, perceptions and interactions working in abortion services, their experiences of medical abortions and abortions performed at the woman's home. An additional aim was to illustrate gynaecologists', midwives' and nurses' visions of their future professional roles within the abortion services. METHOD: Three focus group discussions within each profession were carried out in 1-hour sessions with a total of 25 gynaecologists and 15 midwives/nurses from three different hospitals. RESULTS: The content analysis reflected that gynaecologists and midwives/nurses had no doubts about participating in abortions despite the fact that they had experienced complex and difficult situations, such as repeat and late-term abortions. They experienced their work as paradoxical and frustrating but also as challenging and rewarding. However, they were rarely offered ongoing guidance and continuously professional development education. For gynaecologists, as well as midwives/nurses, their experiences and perceptions were strongly linked to the concurrent development of abortion methods. The interaction between the professions was found to be based on great trust in each other's skills. CONCLUSIONS: In order to promote women's health, gynaecologists' and midwives'/nurses' need for a forum for reflection and ongoing guidance should be acted on. With a higher number of abortions done medically and a higher proportion of home abortions, midwives/nurses will get increased, responsibilities in the abortion services in the future. PMID- 21251035 TI - Secondary syphilis with an interstitial granuloma annulare-like histopathologic pattern. AB - A granulomatous tissue response may be observed in untreated, long-standing lesions of secondary syphilis. In addition to poorly defined granulomatous inflammation, leprosy-like sarcoidal and palisaded granulomatous inflammation has been documented in literature reports of lues. Herein, we report a 47-year-old man who presented with a 3-month history of a generalized non-pruritic macular and papular rash located on the trunk and extremities. Histopathologically, there was an interstitial arrangement of histiocytes with occasional multinucleated giant cells positioned among collagen bundles without associated necrosis, thereby closely mimicking interstitial granuloma annulare. A clue to the diagnosis was the presence of admixed plasma cells. To the best of our knowledge, this is the first reported case of secondary syphilis showing an interstitial granulomatous pattern mimicking interstitial granuloma annulare. PMID- 21251036 TI - A case of sebaceous carcinoma diagnosed in an adolescent male. AB - Sebaceous carcinoma is an uncommon and potentially aggressive malignancy that exhibits sebaceous differentiation. Approximately 75% of cases arise in the periocular region. Sebaceous carcinoma is rare in the pediatric population and its presentation in this age group is not well documented in the dermatopathology literature. We report the case of a 15-year-old male with sebaceous carcinoma who was first seen with a nodular lesion involving the skin of the left orbit/temporal area. A shave biopsy was performed which showed an infiltrative proliferation of basaloid cells that focally exhibited sebaceous differentiation, including the formation of incipient sebocytes. Immunohistochemically, the tumor cells expressed epithelial membrane antigen (EMA) and CK5/6, while a lack of Ber EP4 was observed. Based upon these attributes, the diagnosis of sebaceous carcinoma was rendered. Subsequent immunohistochemical analysis for a possible DNA mismatch repair enzyme defect revealed that all four mismatch repair gene products showed retained expression, thereby providing no support for the presence of underlying Muir-Torre syndrome. Sebaceous carcinomas are exceptional in the pediatric age group and are rarely documented in the dermatopathology literature. Knowledge that this adult carcinoma can occur mostly in the pediatric age group may aid in the recognition of this uncommon malignancy. PMID- 21251037 TI - Viral-associated trichodysplasia spinulosa: a case with electron microscopic and molecular detection of the trichodysplasia spinulosa-associated human polyomavirus. AB - Trichodysplasia spinulosa (TS) is a folliculocentric and clinically papular dermatological disorder occurring in the setting of immunosuppression typically in association with solid organ transplantation or hematolymphoid malignancies. We report the occurrence of TS in a 7-year-old girl with Down syndrome and pre-B acute lymphoblastic leukemia who was completing chemotherapy at onset. The patient's affected follicles were dilated by an expansion of a dystrophic follicular inner root sheath cell population displaying enlarged trichohyaline cytoplasmic granules and progressing centrally to keratotic and parakeratotic debris, and superficially demonstrating some diminutive hair shaft-like material within the keratotic spicules. Electron microscopic studies of a follicular lesion showed extracellular viral particles suggestive of a polyomavirus within the central follicular keratotic debris. DNA polymerase chain reaction (PCR) and gene sequencing studies, performed on the tissue of the microscopic slide and paraffin block, for the recently identified TS-associated polyomavirus (TSPyV) resulted as positive for TSPyV. PCR for the Merkel cell polyomavirus was negative. To date, this case is unique in representing the first case of TS confirmed by electron microscopy in which a related viral pathogen has been molecularly identified. An additional 19 reported cases classifiable as TS are tabulated and reviewed. PMID- 21251038 TI - Fluorescence in situ hybridization for distinguishing cellular blue nevi from blue nevus-like melanoma. AB - BACKGROUND: Blue nevus-like melanomas are melanomas that arise in association with blue nevi or closely simulate the histopathologic appearance of a blue nevus, usually a cellular blue nevus (CBN). Although the majority of CBN can be readily distinguished from blue nevus-like melanoma by conventional microscopy, there are a subset of cases where this distinction may be exceedingly difficult or impossible. METHODS: In this study, we evaluated the ability of a fluorescence in situ hybridization (FISH) assay targeting 6p25 (RREB1), 6q23 (MYB), 11q13 (CCND1) and the centromere of chromosome 6 (Cep6) to distinguish between CBN and blue nevus-like melanoma. We identified five cases of blue nevus-like melanoma and 12 cases of CBN. RESULTS: The FISH assay was performed with 100% sensitivity and 100% specificity. Three of five cases met the 6p25/Cep6 criteria, all five met the 6p25 gain criteria and three of five met the 6q23/Cep6 loss criteria. None of the cases met criteria for gains in 11q13. None of the 12 CBN met any criteria for melanoma. CONCLUSIONS: A combined analysis of clinical aspects, histopathologic changes and FISH analysis could potentially contribute significantly to the ability of pathologists to discriminate between blue nevus like melanoma and blue nevi in challenging cases. PMID- 21251039 TI - Cytokeratin 15 expression in central, centrifugal, cicatricial alopecia: new observations in normal and diseased hair follicles. AB - BACKGROUND: Cytokeratin 15 (CK15) is a useful marker for the bulge zone (BZ) and has been used to examine follicles in cicatricial alopecia. We studied the expression of CK15 in hair follicles of patients with central, centrifugal, cicatricial alopecia (CCCA) in an attempt to define BZ integrity. METHODS: A commercially available antibody to CK15 was used on formalin-fixed, paraffin embedded tissue from clinically and histologically 'normal' scalps, clinically diseased scalps from patients with CCCA and clinically 'normal' scalps from patients with CCCA. RESULTS: In both normal and diseased follicles, CK15 expression was closely linked to anatomical zone cellular morphology. Normal and abnormal inner root sheath (IRS) desquamation occurred in concert with predictable cellular morphological changes and CK15 expression. In most abnormal follicles, once the IRS desquamated, the morphology of BZ epithelium changed and CK15 expression disappeared. CONCLUSIONS: CK15 highlights BZ cells in normal human follicles, but may be unreliable for this purpose in diseased follicles. CK15 should not be the sole marker for studying stem cells in cicatricial alopecia because any disease-induced structural changes could alter CK15 expression. More sophisticated studies of stem cells will be required to reliably define their role in the pathogenesis of cicatricial alopecia. PMID- 21251040 TI - The HoVert technique: a novel method for the sectioning of alopecia biopsies. AB - BACKGROUND: Cicatricial forms of alopecia, including lichen planopilaris (LPP) and discoid lupus erythematosus (DLE), may present with overlapping clinical features. In such cases, histopathological examination may provide key information for resolving the differential diagnosis. Optimally, microscopical analysis for alopecia requires both vertical and horizontal sections, and this may necessitate multiple samples. Here, we present what we term the "HoVert" technique, which produces horizontal and vertical sections from a single biopsy. We hypothesize that the HoVert technique should be useful for differentiating DLE from LPP. METHODS: A formalin-fixed 4 mm punch scalp biopsy is transected approximately 1 mm below the skin surface to create an epidermal disc and a lower portion. The epidermal disc is bisected and embedded in conventional fashion to obtain vertical sections. The lower portion is serially sectioned and embedded to obtain horizontal sections. RESULTS: The HoVert technique yields vertical sections permitting visualization of the epidermis, the dermal-epidermal junction and perijunctional inflammation. The technique also provides horizontal sections that permit analysis of follicle number, follicle type, perifollicular inflammation and scarring. Evaluation of both vertical and horizontal sections from a single scalp biopsy maximizes the histopathological information obtained and enhances the diagnosis of LPP or DLE in specific cases. CONCLUSIONS: We believe that the HoVert technique represents a simple and diagnostically effective tool in differentiating LPP from DLE. It may also be applicable to the assessment of other forms of alopecia. PMID- 21251042 TI - Stem cell markers can help identify adnexal tumor differentiation when evaluated in the context of morphology: methodology matters. AB - Modern medicine is increasingly being influenced by the concepts of stem cell biology. In dermatopathology, one of the most intriguing yet unresolved questions is the lineage of adnexal neoplasms. With an expanding arsenal of stem cell markers, we have the tools available to address this question. The application of stem cell markers in dermatopathology requires intimate familiarity with the underlying basic science in order to avoid misinterpretation of their staining pattern. At the same time, the basic science itself can be misleading when immunohistochemical staining patterns for adnexal tumors are under consideration. The markers critically reviewed in this manuscript include B-lymphocyte-induced maturation protein 1 (Blimp-1), nestin, CD34, p63, cytokeratins 15 and 19 and the most recent ones appearing on the horizon: pleckstrin homology-like domain, family A, member 1 (PHLDA1) (TDAG51) and CD200. Of those, cytokeratin 15, PHLDA1 (TDAG51) and CD200 offer the most promise. A combined approach of modern morphology with basic science holds potential to advance one important aspect of our field further with the final goal of logically classifying adnexal tumors based on stem cell biology. PMID- 21251041 TI - Expression of embryonic stem cell markers SOX2 and nestin in dermatofibrosarcoma protuberans and dermatofibroma. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) was recently proposed to originate from a nestin-positive stem cell. In postnatal skin, nestin and another embryonic stem cell marker, SOX2, display a similar expression pattern with immunoreactivity in the hair follicle papilla and scattered cells of the perifollicular connective tissue sheath. The distribution pattern differs only in early embryogenesis, when nestin but not SOX2 is also expressed throughout the entire interfollicular dermis. We speculated that DFSP would not only be nestin positive but also SOX2-positive. METHODS: With appropriately reacting external and internal controls, we examined 24 examples of DFSP for SOX2 and nestin. For comparison, we included 10 dermatofibromas (DFs). RESULTS: All 24 cases of DFSP were immunoreactive for nestin but negative for SOX2. The DFs were both nestin negative and SOX2-negative. CONCLUSIONS: The observed staining pattern may indicate that DFSP derives from a subtype of nestin-immunoreactive mesenchymal stem cell that is different from the nestin- and SOX2-positive cell population of the perifollicular mesenchyme. Alternatively, nestin expression in DFSP may represent a recapitulation of the staining pattern in early embryogenesis without necessarily indicating that the nestin-positive cells represent stem cells. Also, DFSP may derive from hair follicle-associated mesenchymal stem cells that have lost their SOX2 expression. PMID- 21251043 TI - Regulatory relationship between tactile sensation at the vermilion of the lips and lip-closing force. AB - The objectives of this study were to identify the regulatory relationship between tactile sensation at the vermilion of the lips and the output of pursing-like lip closing force (LCF), as measured by a multidirectional LCF measurement system. Thirty-six healthy subjects were divided into Anaesthesia and Vaseline groups. The tactile detection threshold (TDT) at six sites on the vermilion and the maximum voluntary LCFs in eight directions were recorded before and during partial or whole application of the agent and 6 h after whole application (Recovery). Five per cent lidocaine gel and Vaseline was applied to the vermilion in the Anaesthesia and Vaseline groups, respectively. These agents were applied to either the right part of the vermilion of the lower lip (Partial) or the whole vermilion (Whole). Partial application of 5% lidocaine gel significantly decreased the magnitudes of six of eight directional LCFs, while it only increased the TDT at one site. The subsequent whole application of 5% lidocaine gel did not affect the magnitude of the LCFs in five of these six directions although its application increased the TDTs at all sites. These reductions in LCF were reversed after recovery from surface anaesthesia. Vaseline application did not affect either TDT or LCF in any conditions. We concluded that tactile sensation at the vermilion of the lips is related to the output of LCF, without any particular directional specificity. The present results suggest the presence of a common synaptic drive ordering the pursing of the relevant muscles. PMID- 21251044 TI - RNA integrity in post mortem human variant Creutzfeldt-Jakob disease (vCJD) and control brain tissue. AB - AIMS: To determine premortem and post mortem factors affecting quality and yield of RNA isolated from the unique archived brain material in the UK National Creutzfeldt-Jakob Disease Surveillance Unit Brain and Tissue Bank and to compare this to control brain tissue with no neurological disease. METHODS: In parallel and in replicate, RNA was prepared from the frontal parasagittal or subfrontal cortex of samples dissected from half brains (frozen intact) or from brain samples snap frozen or placed in RNALater. A total of 350 RNA samples from 78 human autopsy cases, 21 variant Creutzfeldt-Jakob disease, 26 other neurological diseases and 31 non-neurological diseases were studied. RESULTS: There was no difference in the quality or yield of RNA isolated from variant Creutzfeldt-Jakob disease, other neurological disease and non-neurological disease brains. RNA preparations from archived frozen half brains or snap frozen autopsy samples were generally of poor quality (RNA integrity number<5). There was a highly significant negative correlation between the number of times frozen half brains had been sampled and the quality of RNA. Samples stored in RNALater provided higher-quality RNA (RNA integrity number>5). Age at death, gender, post mortem interval and freezer storage time had no effect on RNA quality. CONCLUSION: Reasonable-quality RNA can be isolated from samples dissected from archived frozen human half brains but repeated sampling results in RNA degradation. Better quality RNA is obtained from samples placed in RNALater than from snap frozen samples. The quality and yield of RNA are not affected by age at death, gender, post mortem interval of >6 h or freezer storage time. PMID- 21251045 TI - A new index of agonal state for neurological disease. PMID- 21251046 TI - Hydrogen resuscitation, a new cytoprotective approach. AB - 1. Hydrogen is a colourless, odourless, tasteless and flammable gas. Hydrogen is considered a physiologically inert gas and is often used in deep sea diving medicine. In mammals, endogenous hydrogen is produced as a result of the fermentation of non-digestible carbohydrates by intestinal bacteria and it is absorbed into the systemic circulation. 2. Recent evidence indicates that hydrogen is a potent anti-oxidative, anti-apoptotic and anti-inflammatory agent and so may have potential medical application. The present review evaluates the concept of 'hydrogen resuscitation', based on knowledge that hydrogen treatment effectively protects cells, tissues and organs against oxidative injury and helps them recover from dysfunction. 3. Hydrogen therapy can be delivered by inhalation, the administration of hydrogen-enriched fluid or by approaches that affect endogenous hydrogen production. 4. Studies have shown that hydrogen resuscitation has cytoprotective effects in different cell types and disease models, including ischaemia-reperfusion injury, inflammation, toxicity, trauma and metabolic disease. The underlying mechanism may be the selective elimination of hydroxyl radicals, although other mechanisms may also be involved (e.g. hydrogen functioning as a gaseous signalling molecule). 5. Hydrogen resuscitation may have several potential advantages over current pharmacological therapies for oxidative injuries. However, more work is needed to identify the precise mechanism underlying the actions of hydrogen and to validate its therapeutic potential in the clinical setting. PMID- 21251047 TI - Optical imaging of propofol-induced central respiratory depression in medulla spinal cord preparations from newborn rats. AB - 1. Propofol (2,6-diisopropylphenol) is an intravenous anaesthetic used for the induction and maintenance of general anaesthesia; it also potently and dose dependently depresses respiration. The aim of the present study was to analyse propofol-induced changes in spatiotemporal patterns of inspiratory-related neural activity and to investigate the involvement of the GABAA receptor by using an optical imaging technique. 2. The brain stems and spinal cords of 0-1-day-old Wistar rats were isolated and stained using a fluorescent voltage-sensitive dye. Neuronal activity in the preparation was detected using an optical recording apparatus containing a charge-coupled device (CCD)-based camera. 3. Bath-applied propofol (7.5 MUmol/L) decreased the C4 burst rate to 45.9% of baseline. Although optical signals corresponding to membrane depolarization during the pre inspiratory phase in the parafacial region of the ventral medulla decreased to 28.7% of baseline following propofol application, those during the inspiratory phase in the caudal part of the rostral ventrolateral medulla did not. 4. The inhibitory effect of bath-applied propofol was reversed by 2 MUmol/L bicuculline. 5. Changes in optical signals corresponding to the population activity of pre inspiratory neurons were parallel to changes in the C4 burst rate. 6. The results suggest that propofol decreases the inspiratory burst rate by reducing the activity of pre-inspiratory neurons and that GABAA receptor activation plays a role in propofol-induced central respiratory depression. These results are consistent with those of previous electrophysiological studies. PMID- 21251048 TI - Effect of exercise training on renal function and renal aquaporin-2 expression in rats with chronic heart failure. AB - 1. Chronic heart failure (CHF) is often accompanied by renal dysfunction. Exercise training may relieve the symptomatic burden and improve the overall prognosis of CHF. In the present study, the effects of exercise training on renal function and renal aquaporin (AQP)-2 expression in CHF rats were examined to determine whether exercise training could relieve renal dysfunction in CHF rats. 2. Male Sprague-Dawley rats were divided into three groups: sham, sedentary CHF (Sed-CHF) and exercise training CHF (Ex-CHF) groups. Cardiorenal function was assessed in each group by haemodynamic measurement and ultraviolet spectrophotometry. Pathological changes in cardiac and renal tissues were evaluated histologically and the collagen volume fraction (CVF) was calculated. The expressions of AQP-2 and beta-tubulin were determined by western blotting and immunohistochemistry. 3. The Sed-CHF rats were found to have increased left ventricular end-diastolic pressure (LVEDP) and CVF in the heart compared with sham rats. Exercise training decreased LVEDP and CVF values in Ex-CHF rats. The Sed-CHF rats were found to have increased serum levels of creatinine (sCr), blood urea nitrogen (BUN) and arginine vasopressin (AVP), as well as increased CVF in the kidney, compared with sham rats. Exercise training decreased levels of sCr, BUN, AVP and CVF in Ex-CHF rats. Moreover, exercise training decreased AQP-2 and beta-tubulin protein expression in the kidney of CHF rats. 4. The results suggest that exercise training can significantly improve the renal dysfunction in CHF rats and that the underlying mechanism may be related to water reabsorption and preventing changes to the cytoskeleton. PMID- 21251050 TI - Recombinant human hepatocyte growth factor (HGF), but not rat HGF, elicits glomerular injury and albuminuria in normal rats via an immune complex-dependent mechanism. AB - 1. Hepatocyte growth factor (HGF) has the therapeutic potential to improve renal fibrosis and proteinuria in rodents with chronic kidney disease. In contrast, long-term administration of human HGF to normal rats reportedly elicits proteinuria. Thus, the role of HGF during proteinuria remains contentious. The aim of the present study was to demonstrate that human HGF is antigenic to rodents and that immune complex formation causes proteinuria. 2. We administered either human or rat HGF to normal rats for 28 days. Albuminuria was evaluated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The renal phenotypes of the two HGF treatments were examined using histological techniques. 3. Administration of human HGF (1 mg/kg per day, i.v.) to rats led to severe albuminuria and glomerular hypertrophy in association with increased blood levels of anti-human HGF IgG and IgG deposition in mesangial areas. Furthermore, an immune complex between human HGF and anti-human HGF IgG stimulated the production of proteinuric cytokines (including transforming growth factor-beta) in rat cultured mesangial cells. In contrast, treatment of healthy rats with rat HGF for 4 weeks caused neither mesangial IgG deposition nor elevated anti-HGF IgG in the blood. Overall, rat HGF did not provoke albuminuria. 4. We conclude that human HGF produces pseudotoxic effects in normal rat kidneys via an immune complex mediated pathway, whereas syngenic HGF is safe due to less deposition of glomerular IgG. Our results affirm the safety of the repeated use of syngenic HGF for the treatment of chronic organ diseases, such as renal fibrosis and liver cirrhosis. PMID- 21251049 TI - Renal inflammation, autoimmunity and salt-sensitive hypertension. AB - 1. The present article reviews the role of immune-competent cells infiltrating the kidney and their association with oxidative stress and renal angiotensin activity in the development of salt-sensitive hypertension. 2. We discuss changes in the pressure-natriuresis relationship resulting from renal inflammation and its improvement resulting from immunosuppressive treatment. 3. The potential role of T-cell-driven reactivity in sustaining the renal inflammation is examined in the light of accumulating evidence of autoimmune mechanisms in experimental and clinical hypertension. PMID- 21251051 TI - Medical students learning intimate examinations without valid consent: a multicentre study. AB - OBJECTIVES: This study aimed to explore medical students' explanations of their behaviour when instructed to observe or perform intimate examinations or procedures without valid patient consent. METHODS: We used a qualitative design employing individual and group interviews to elicit narratives of dilemmas associated with professionalism. Qualitative thematic analyses of narratives were followed by a qualitative and quantitative analysis using a validated coding scheme of students' explanations of their behaviours within dilemmas involving intimate examinations carried out without valid consent. Participants (n=200) were medical students drawn from each academic year of three medical schools, representing two 5-year undergraduate programmes and one 4-year graduate-entry programme in England, Wales and Australia. RESULTS: Of 833 narratives collected, 112 involved dilemmas associated with intimate examinations. Of these, 63% (n=71) described dilemmas which came about because students were instructed to observe or perform intimate examinations or procedures without valid consent. A total of 82% (n=58) involved students complying with instructions and contained 349 distinct explanations. Thirteen narratives described cases in which students had refused to comply and contained 84 explanations. A high proportion of explanations of compliance included statements by students that they 'had to' observe or perform the examination or procedure. Explanations of compliance behaviours significantly downplayed the intentionality of actions, whereas explanations of refusal emphasised intentionality (chi(2)=14.225, d.f.=2, p=0.001). CONCLUSIONS: Despite clear policies at each school, students in all schools observed or performed intimate examinations or procedures without having gained valid consent from the patient. Faculty development initiatives are clearly essential to help clinical teachers put intimate examination policy into practice. PMID- 21251052 TI - Novel wine-mediated FLO11 flocculation phenotype of commercial Saccharomyces cerevisiae wine yeast strains with modified FLO gene expression. AB - Depending on the genetic background of Saccharomyces strains, a wide range of phenotypic adhesion identities can be directly attributed to the FLO11-encoded glycoprotein, which includes asexual flocculation, invasive growth and pseudohyphal formation, flor formation and adhesion to biotic and abiotic surfaces. In a previous study, we reported that HSP30-mediated stationary-phase expression of the native chromosomal FLO11 ORF in two nonflocculent commercial Saccharomyces cerevisiae wine yeast strains, BM45 or VIN13 did not generate a flocculent phenotype under either standard laboratory media or synthetic MS300 must fermentation conditions. In the present study, the BM45- and VIN13-derived HSP30p-FLO11 wine yeast transformants were observed to be exclusively and strongly flocculent under authentic red wine-making conditions, thus suggesting that this specific fermentation environment specifically contributes to the development of a flocculent phenotype, which is insensitive to either glucose or mannose. Furthermore, irrespective of the strain involved this phenotype displayed both Ca(2+)-dependent and Ca(2+)-independent flocculation characteristics. A distinct advantage of this unique FLO11-based phenotype was highlighted in its ability to dramatically promote faster lees settling rates. Moreover, wines produced by BM45-F11H and VIN13-F11H transformants were significantly less turbid than those produced by their wild-type parental strains. PMID- 21251053 TI - Zoocin A facilitates the entry of antisense constructs into Streptococcus mutans. AB - The use of antisense oligodeoxyribonucleotides (asODNs) to inhibit gene function has proven to be an extremely powerful tool for establishing gene-function relationships. Diffusion limitations imposed by the thick peptidoglycan layer of Gram-positive bacteria have proven difficult to overcome for permeability of asODNs. Typically, introduction of the asODN is achieved by cloning the antisense sequence into a vector downstream of an inducible promoter and transforming this construct into the cell of interest. In this study, we report that the use of the streptococcolytic enzyme zoocin A facilitated entry of phosphorothioate oligodeoxyribonucleotides (PS-ODNs) into Streptococcus mutans, such that the degree of phenotypic response (cell growth inhibition) observed was sequence specific and correlated with the amount of zoocin A (R(2) =0.9919) or PS-ODN (R(2) =0.9928) used. Quantitative reverse transcriptase PCR was used to demonstrate that only the expression of the target gene against which the PS-ODN was designed was affected. We believe that the use of an appropriate bacteriolytic enzyme to facilitate entry of asODNs into bacterial cells provides a method that will be generally useful in the study of gene regulation in Gram positive bacteria. PMID- 21251054 TI - The phylogeny of Sodalis-like symbionts as reconstructed using surface-encoding loci. AB - Phylogenetic analyses of 16S rRNA support close relationships between the Gammaproteobacteria Sodalis glossinidius, a tsetse (Diptera: Glossinidae) symbiont, and bacteria infecting diverse insect orders. To further examine the evolutionary relationships of these Sodalis-like symbionts, phylogenetic trees were constructed for a subset of putative surface-encoding genes (i.e. ompA, spr, slyB, rcsF, ycfM, and ompC). The ompA and ompC loci were used toward examining the intra- and interspecific diversity of Sodalis within tsetse, respectively. Intraspecific analyses of ompA support elevated nonsynonymous (dN) polymorphism with an excess of singletons, indicating diversifying selection, specifically within the tsetse Glossina morsitans. Additionally, interspecific ompC comparisons between Sodalis and Escherichia coli demonstrate deviation from neutrality, with higher fixed dN observed at sites associated with extracellular loops. Surface-encoding genes varied in their phylogenetic resolution of Sodalis and related bacteria, suggesting conserved vs. host-specific roles. Moreover, Sodalis and its close relatives exhibit genetic divergence at the rcsF, ompA, and ompC loci, indicative of initial molecular divergence. The application of outer membrane genes as markers for further delineating the systematics of recently diverged bacteria is discussed. These results increase our understanding of insect symbiont evolution, while also identifying early genome alterations occurring upon integration of microorganisms with eukaryotic hosts. PMID- 21251055 TI - Spatial divergence in the proportions of genes encoding toxic peptide synthesis among populations of the cyanobacterium Planktothrix in European lakes. AB - It has been frequently reported that seasonal changes in toxin production by cyanobacteria are due to changes in the proportion of toxic/nontoxic genotypes in parallel to increases or decreases in population density during the seasonal cycle of bloom formation. In order to find out whether there is a relationship between the proportion of genes encoding toxic peptide synthesis and population density of Planktothrix spp. we compared the proportion of three gene regions that are indicative of the synthesis of the toxic heptapeptide microcystin (mcyB), and the bioactive peptides aeruginoside (aerB) and anabaenopeptin (apnC) in samples from 23 lakes of five European countries (n=153). The mcyB, aerB, and apnC genes occurred in 99%, 99%, and 97% of the samples, respectively, and on average comprised 60 +/- 3%, 22 +/- 2%, and 54 +/- 4% of the total population, respectively. Although the populations differed widely in abundance (10(-3)-10(3) mm(3) L(-1)) no dependence of the proportion of the mcyB, aerB, and apnC genes on the density of the total population was found. In contrast populations differed significantly in their average mcyB, aerB, and apnC gene proportions, with no change between prebloom and bloom conditions. These results emphasize stable population-specific differences in mcyB, aerB, and apnC proportions that are independent from seasonal influences. PMID- 21251056 TI - Serum concentrations of Anti-Mullerian Hormone (AMH) in 95 patients with Klinefelter syndrome with or without cryptorchidism. AB - AIM: Anti-Mullerian hormone (AMH) is produced by foetal Sertoli cells at the time of sexual differentiation and is responsible for the regression of the Mullerian ducts in the male foetus. AMH is a testis-specific marker of diagnostic value in infants with ambiguous genitalia or with bilateral cryptorchidism. However, little is known about AMH in boys and adult men with normal or abnormal gonadal function. We therefore aimed at determining circulating AMH concentrations in patients with 47,XXY Klinefelter syndrome (KS) with or without cryptorchidism. METHODS: AMH was determined in 95 47,XXY patients aged 0.2-64.5 years, of which 12 patients had a history of cryptorchidism. RESULTS: AMH was within the normal range in boys with Klinefelter syndrome until puberty. The pubertal decline was delayed, especially in patients with a history of cryptorchidism. AMH was below 2 SD in 85% of adult KS. CONCLUSION: AMH secretion in patients with 47,XXY KS was within normal limits during mini-puberty and until puberty. Thereafter, AMH declined to subnormal levels in all patients. We hypothesize that this decline was a result of the hyalinization of seminiferous tubules in relation to puberty, rather than caused by disrupted regulatory mechanisms at the level of the pituitary-gonadal axis. PMID- 21251057 TI - Effect of position on oxygen saturation and requirement in convalescent preterm infants. AB - AIMS: To document the effect of position on oxygen saturation and changes in oxygen requirement in convalescent preterm infants. METHODS: Twelve infants born >=24 and <=32 weeks gestation, extubated and without congenital anomaly were studied using nap polysomnography in prone and supine, twice weekly until discharge. Mean oxygen saturation (SpO(2)), minimum SpO(2) , mean minimum SpO(2) and time with SpO(2) < 90% were measured in active sleep. RESULTS: Eight male and four female infants [median gestation 28 (24-31) weeks and median birthweight 1059 (715-1840) g] had 39 studies. For 21 of 39 studies, the infant was on respiratory support. Four infants had chronic lung disease (CLD). SpO(2) varied with postmenstrual age (PMA) (p = 0.003) but not with position (p = 0.36), and PMA did not influence the effect of position on SpO(2) (p = 0.19). SpO(2) was lower for those with CLD (p < 0.0001) and those on respiratory support (p < 0.001), but there was no effect of position (p = 0.97 and p = 0.67, respectively). From 36 weeks PMA, a change to supine did not increase oxygen requirement. CONCLUSION: In preterm infants, PMA and residual respiratory disease have greater effects on oxygenation than position. A supine sleep position is not disadvantageous for preterm infants at discharge. PMID- 21251058 TI - Acute pancreatitis in children. AB - AIM: To identify clinical, laboratory, and imaging characteristics associated with severe acute pancreatitis in children. METHODS: This was a retrospective study of children under 18 years of age with acute pancreatitis between September 1993 and August 2008. Severity of pancreatitis was graded according to established criteria. Clinical, laboratory and radiological data for mild and severe pancreatitis were collected for analysis. RESULTS: There were 180 cases of pancreatitis; 51 (28.3%) met criteria for severe disease. Severe pancreatitis was most commonly associated with systemic disease (22 of 51; 43.1%) and trauma (13 of 51; 25.4%). Patients with severe pancreatitis had significantly higher body weight, higher frequency of dyspnoea and pleural effusion, and lower serum calcium and albumin levels. Ten patients with systemic disease died; four of them had systemic lupus erythematosus (SLE). Computed tomography (CT) was more accurate than ultrasound in evaluation of the severity of pancreatitis. CONCLUSIONS: Acute pancreatitis in children is associated with significant morbidity and mortality. The severity of paediatric pancreatitis may be influenced by aetiology. CT is recommended for evaluation of severity of pancreatitis. PMID- 21251059 TI - Insulin resistance and metabolic syndrome in prepubertal boys with Klinefelter syndrome. AB - AIMS: To investigate risk factors for metabolic syndrome in prepubertal boys with Klinefelter syndrome. METHODS: Eighty-nine boys with Klinefelter syndrome, ages 4 12.9 years, and 34 age-matched control boys had height, weight, waist circumference and blood pressure measured and their parents completed a questionnaire about physical activity. The boys with Klinefelter syndrome also had measurement of lipids, fasting glucose and insulin. Insulin-glucose homeostasis model assessment was calculated, and the boys were evaluated for childhood metabolic syndrome. RESULTS: The Klinefelter syndrome and control groups were similar ages (7.5 +/- 2.4 vs. 8.1 +/- 2.3 years). Body mass index measurements were similar, but waist circumference was >90 percentile in 30% of boys with Klinefelter syndrome versus 21% of controls. The mean daily time spent running was 42 min less in the Klinefelter syndrome versus control groups (p < 0.01). About 37% of the boys with Klinefelter syndrome had elevated LDL cholesterol, 24% had insulin resistance, and 7% met the three criteria for diagnosis of metabolic syndrome. CONCLUSIONS: Truncal obesity, insulin resistance and metabolic syndrome are present in boys as young as 4-12 years with Klinefelter syndrome, and these occur in association with reduced running-type activity. PMID- 21251060 TI - High-intensity phototherapy for the treatment of severe nonhaemolytic neonatal hyperbilirubinemia. AB - AIM: To describe the clinical approach to term and near-term newborn infants with severe hyperbilirubinaemia and to analyse the effect of high-intensity phototherapy on total serum bilirubin (TSB) levels. METHODS: We analysed a cohort of 116 newborn infants with severe nonhaemolytic hyperbilirubinaemia (TSB >=20 mg/dL/342 MUmol/L). All patients were treated with high-intensity phototherapy. The main outcomes were reduction in TSB levels in the first 24 h of phototherapy, incidence of exchange transfusion, pathological brainstem auditory evoked responses and pathological findings on neurological examination at discharge. RESULTS: The mean birth weight and gestational age were 3161+/-466 g and 37.8+/ 1.6 weeks. Mean initial TSB concentration was 22.4+/-2.4 mg/dL. Per cent decreases in TSB after 2, 4, 6, 12, 18 and 24 h of phototherapy were 9.4%, 16%, 23%, 40%, 44% and 50%, respectively. No infant was treated with exchange transfusion. Brainstem evoked response audiometry (BAER) was performed in 100% of the patients, and in three of them, this examination was altered. However, when repeated 3 months later, these BAER examinations were normal. Neurological examination was normal in all patients. CONCLUSIONS: High-intensity phototherapy significantly reduces TSB in nonhaemolytic severe hyperbilirubinaemia and decreases the need for exchange transfusion. PMID- 21251061 TI - Initial experience from the transgastric endoscopic peritoneoscopy and biopsy: a stepwise approach from the laboratory to clinical application. AB - BACKGROUND AND AIM: Natural-orifice translumenal endoscopic surgery (NOTES) is a newly minimally invasive technique that gives access to the abdominal cavity via transgastric, transcolonic, transvaginal or transvesical routes. The aim of the present study was to evaluate the safety and feasibility of transgastric endoscopic peritoneoscopy and biopsy from laboratory to clinical application. METHODS: With the animals under general anesthesia, a sterile esophageal overtube was placed and a gastric antibiotic lavage was performed. Subsequently, a needle knife and through-the-scope dilating balloon were used to make an anterior gastric wall incision through which a therapeutic gastroscope was advanced into the peritoneal cavity. After 2 weeks, another transgastric endoscopic exploration was performed in a different location of the stomach. The peritoneal cavity was examined before the gastric incision was closed. After 4 weeks of observation, necropsy was performed. In the clinical application, after gastric lavage, the first step was the creation of the gastrotomy under general anesthesia, sometime under direct vision of the laparoscopic scope. Then the endoscope can be maneuvered in the peritoneal cavity. And peritoneoscopy and biopsy were performed. Biopsies can be obtained from any suspicious areas using punch biopsy forceps. The gastrotomy was then closed with clips. The gastroscopy was examined after one week. RESULTS: Twenty-eight transgastric endoscopic peritoneoscopies and biopsies in pigs and a total of five transgastric human endoscopic peritoneoscopies and biopsies have been performed. All procedures were completed satisfactorily in the pig model and all patients. There were no intraoperative or postoperative complications. CONCLUSIONS: The advantages of peritoneoscopy and biopsy appeared to be enhanced by this approach. Patients had minor postoperative pain and minimal scarring. It is safe and feasible for us to use transgastric endoscopic peritoneoscopy and biopsy in humans. PMID- 21251062 TI - Therapeutic effects of cytokine modulator Y-40138 in the rat alcoholic liver disease model. AB - BACKGROUND AND AIM: Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), induce liver injury in the rat alcoholic liver disease (ALD) model. Y-40138 is known to suppress the pro inflammatory cytokines and augment the anti-inflammatory cytokines. We investigated whether or not Y-40138 may be effective as a novel immunotherapy in the rat ALD model. METHODS: Male Wistar rats were fed Lieber-DeCarli ethanol liquid diet. The effects of Y-40138 treatment in the ALD models were assessed by analyzing the serum and the liver tissues. RESULTS: The serum levels of alanine aminotransferase (ALT), TNF-alpha, and IFN-gamma, and the liver levels of TNF alpha and IFN-gamma were significantly higher in the ethanol-fed group than in the pair-fed group. The immunohistochemistry of the liver TNF-alpha and 4 hydroxynonenal (4HNE), and the expressions of TNF-alpha and IFN-gamma mRNA were increased, too. The gene expressions of interleukin-10 (IL-10) in the ethanol-fed group were suppressed as compared with the pair-fed group. The serum triglyceride (TG) and liver TG were increased, and Oil Red O and alpha-smooth muscle actin (alpha-SMA) staining showed greater expression by ethanol-fed feeding. After administration of Y-40138, enzyme linked immunosorbent assay and real-time polymerase chain reaction of the liver showed that the increased TNF-alpha and IFN-gamma were suppressed, and that IL-10 was augmented. Moreover, ethanol induced lipid accumulation in the liver was suppressed by administering Y-40138. CONCLUSIONS: Y-40138 decreased the inflammation, fibrosis, oxidative stress, and lipid synthesis, and augmented the anti-inflammatory cytokines of the liver. These results indicate that the multiple cytokine production modulator, Y-40138, is a promising novel therapy for ALD. PMID- 21251063 TI - Focal nodular hyperplasia or focal nodular hyperplasia-like lesions of the liver: a special emphasis on diagnosis. AB - BACKGROUND AND AIM: Focal nodular hyperplasia (FNH) and FNH-like lesions are hypervascular masses that can mimic hepatocellular carcinoma (HCC). We have investigated the clinical, radiological and pathological features of FNH and FNH like lesions of the liver, with particular focus on the aspect of diagnosis. METHODS: A total of 84 patients, 77 with pathologically-proven FNH and seven with FNH-like lesions of the liver, were analyzed retrospectively. RESULTS: Of the 84 patients, seven had underlying liver cirrhosis, including two with Budd-Chiari syndrome and one with cardiac cirrhosis. These cases were therefore classified as having FNH-like lesions. Two of the remaining 77 patients without underlying liver cirrhosis were positive for hepatitis B surface antigen. Seven of 50 (14.0%) patients evaluated by four-phase computed tomography (CT) showed portal or delayed washout, and three of 28 (10.7%) patients analyzed by three-phase CT showed washout on the portal phase. Collectively, three of nine (33.3%) patients with risk factors for HCC could have been wrongly diagnosed with HCC based on the non-invasive diagnostic criteria for HCC. A central scar was observed in 30 patients (35.7%) radiologically. Among 62 patients who underwent percutaneous needle biopsy, four patients (6.5%) were misdiagnosed as having HCC and two patients (3.2%) had inconclusive results by a first needle biopsy. CONCLUSIONS: The presence of a hepatic lesion with arterial hypervascularity and/or portal/delayed washout is not necessarily diagnostic of HCC, particularly in patients without risk factors for HCC. These radiological findings can also occur in cirrhotic patients with FNH-like lesions, including those with hepatic outflow obstruction. PMID- 21251064 TI - Sequential therapy in clarithromycin-sensitive and -resistant Helicobacter pylori based on polymerase chain reaction molecular test. AB - BACKGROUND AND AIM: The present study was designed to determine the eradication rate of 10 day sequential therapy in genotypic clarithromycin-resistant Helicobacter pylori group identified by molecular polymerase chain reaction (PCR) detection in Thai patients. METHODS: Between May 2007 and June 2010, patients who had undergone gastroscopic examination at the King Chulalongkorn Memorial Hospital, for dyspeptic symptoms were recruited. Two biopsy samples from gastric antrum were obtained, one for rapid urease test and another for PCR. PCR sequencing was performed to determine point mutations in 23S rRNA gene. Patients received 10 day sequential therapy consisting of lanzoprazole 30 mg and amoxicillin 1 g twice daily for 5 days followed by lanzoprazole 30 mg, clarithromycin 500 mg and nitroimidazole 500 mg twice daily for the remaining 5 days. Urea breath test (UBT) was performed to assess eradication therapy. RESULTS: A total of 151 patients (mean age 52.7 years, 75 males and 76 females) were recruited in this study. All patients completed sequential therapy without significant side effects. Point mutations at A2143G and A2142G were detected in 17 patients (11.3%). Overall eradication rate was 94%. The eradication rate in the group with point mutation was significantly lower than the eradication rate in the group without point mutation (64.7% vs 97.8%; odds ratio = 19.6 and 95% confidence interval = 4.3-88.8; P < 0.0001). CONCLUSION: Genotypic clarithromycin resistance was detected in only 11.3% of H. pylori infections in Thailand. Sequential therapy is highly effective in clarithromycin-sensitive but is less effective in clarithromycin-resistant H. pylori. PCR-molecular test could be a useful tool to identify antimicrobial resistance for optimizing an eradication regimen. PMID- 21251065 TI - Effect of ligustrazine on mice model of hepatic veno-occlusive disease induced by Gynura segetum. AB - BACKGROUND AND AIM: To investigate the therapeutic effect of ligustrazine on hepatic veno-occlusive disease (HVOD) induced by Gynura segetum and the possible mechanism of it. METHODS: Female Kunming mice (115) were randomly divided into four groups, gavaged with 30 g/kg per day Gynura segetum (group A), 30 g/kg per day Gynura segetum + 100 mg/kg per day ligustrazine (group B), 30 g/kg per day Gynura segetum + 200 mg/kg per day ligustrazine (group C) or 30 mL/kg per day phosphate-buffered saline (PBS) (group D). Thirty days later, all of the mice were killed. Blood samples and livers were harvested. Histological changes were evaluated by light microscopy. Liver function was measured, and the expression of tissue factor (TF), early growth response factor-1 (Egr-1) and nuclear factor KBp65 (NF-KBp65) were determined by reverse transcription-polymerase chain reaction and Western blot. RESULTS: A total of 24 mice in group A developed HVOD. Compared with the controls, they had increased liver ratio, serum total bilirubin (TBIL), direct bilirubin (DBIL), transaminase and decreased albumin (ALB) (P < 0.05). Administration of ligustrazine improved the clinical signs and biochemistry parameters in a dose-dependent manner. Compared with group A, the expression of TF, Egr-1 and NF-KB p65 decreased in groups B and C (P < 0.05). CONCLUSION: Ligustrazine has a therapeutic effect on HVOD, improving clinical manifestations and liver function. The possible mechanism may be that ligustrazine could reduce the expression of TF by downregulating the expression of transcription factors: Egr-1 and NF-KB p65. PMID- 21251066 TI - Association of cytotoxic T lymphocyte associated antigen-4 gene (rs60872763) polymorphism with Crohn's disease and high levels of serum sCTLA-4 in Crohn's disease. AB - BACKGROUND AND AIM: Our aim was to evaluate cytotoxic T lymphocyte associated antigen-4 (CTLA-4) gene polymorphisms in Crohn's disease (CD) and explore soluble CTLA-4 (sCTLA-4) levels in serum of CD patients in central China. METHODS: A total of 126 Chinese CD patients and 300 healthy controls were enrolled in this study. CTLA-4 (AT)n repeat polymorphism was genotyped by a semiautomatic fluorescently labeled polymerase chain reaction (PCR) method, and CTLA-4 -1661A/G and -1722T/C polymorphisms were genotyped by DNA sequencing. Serum sCTLA-4 and C reactive protein (CRP) levels were determined by enzyme linked immunosorbent assay (ELISA) and immunonephelometry, respectively. RESULTS: The frequency of 84 bp allele of CTLA-4 (AT)n repeats was lower in CD patients than in the healthy controls (22.2% vs 33.2%, P = 0.001, odds ratio = 0.58, 95% confidence interval: 0.41-0.81). The 84 bp allele carriers of (AT)n repeats were associated with non stricturing and non-penetrating disease behavior in CD patients (P = 0.007). Serum sCTLA-4 levels were more elevated in CD patients than in the healthy controls (P < 0.001). Among CD patients, serum sCTLA-4 levels were increased in active disease compared with inactive disease (P = 0.015), and were correlated with CRP levels (r = 0.524, P < 0.001). Serum sCTLA-4 levels were higher in CD patients with stricturing disease behavior than in patients with other disease behaviors (P = 0.009). CONCLUSIONS: 84 bp allele of CTLA-4 (AT)n repeat polymorphism was associated with CD in central China. sCTLA-4 levels were highly expressed in CD, especially in active disease, and were correlated with CRP levels and disease behavior in CD patients. PMID- 21251067 TI - Predictors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt in cirrhotic patients: a systematic review. AB - BACKGROUND AND AIM: Hepatic encephalopathy (HE) is a very common complication in patients after transjugular intrahepatic portosystemic shunt (TIPS). The purpose of this study is to determine the most robust predictors of post-TIPS HE by performing a systematic review of studies that identified the risk factors for patients with post-TIPS HE. METHODS: A PUBMED search was performed using the predefined rule. Studies were selected for analysis based on certain inclusion and exclusion criteria. Data were extracted from each study on the basis of predefined items. Meta-analyses were executed to verify the relevant risk factors. RESULTS: Thirty studies were included in this systematic review. In the 30 studies, the numbers of variables evaluated by univariate and multivariate analyses were 60 and 32, respectively. The numbers of variables found to be significant in univariate and multivariate analyses were 18 and 14, respectively. According to the accumulated number of studies that identified these variables as significant, the three most vigorous predictors of post-TIPS HE were age, prior HE and Child-Pugh class/score in both univariate analysis and multivariate analysis. Our meta-analysis showed that patients with HE before TIPS or higher Child-Pugh class/score had increased risk of post-TIPS HE. CONCLUSIONS: Increased age, prior HE and higher Child-Pugh class/score were the most robust predictors for post-TIPS HE. PMID- 21251068 TI - Metformin associated with lower mortality in diabetic patients with early stage hepatocellular carcinoma after radiofrequency ablation. AB - BACKGROUND AND AIM: Type 2 diabetes increases the risk of cancer development and mortality. However, antidiabetic treatment with metformin can reduce the risk of cancer. We studied whether metformin users among diabetic patients with early hepatocellular carcinoma (HCC) undergoing radiofrequency ablation (RFA) would have a favorable survival compared with those without metformin treatment. METHODS: A total of 135 patients with early stage HCC having 162 tumors underwent RFA. Among them, 53 patients were diabetic, including 21 metformin users and 32 patients without metformin treatment. RESULTS: Diabetic patients had an inferior survival rate compared with nondiabetic patients (1 year, 82.8% vs 93.9%; 3 years, 55.1% vs 80.2%; 5 years, 41.3% vs 64.7%; P = 0.004). With regards to antidiabetic treatments, metformin users had better survival outcome (adjusted hazard ratio [HR] 0.24; 95% confidence interval [CI], 0.07-0.80; P = 0.020) compared to patients without metformin treatment after adjustments for potential confounders. Sulfonylureas and insulin exposures did not achieve significant conclusions. For the whole studied population including nondiabetic and diabetic patients, the multivariate analysis revealed that maximum tumor size more than 2.5 cm (HR, 3.49; 95% CI, 1.74-6.99; P < 0.001) and diabetic patients without metformin treatment (HR, 3.34; 95% CI, 1.67-6.71, P = 0.001) were independent explanatory variables associated with unfavorable survival. CONCLUSIONS: Metformin users among diabetic patients with HCC undergoing RFA had a favorable overall survival compared with patients without metformin treatment. PMID- 21251070 TI - Refocusing the debate about advocacy. PMID- 21251071 TI - Effects of harvesting flowers from shrubs on the persistence and abundance of wild shrub populations at multiple spatial extents. AB - Wildflower harvesting is an economically important activity of which the ecological effects are poorly understood. We assessed how harvesting of flowers affects shrub persistence and abundance at multiple spatial extents. To this end, we built a process-based model to examine the mean persistence and abundance of wild shrubs whose flowers are subject to harvest (serotinous Proteaceae in the South African Cape Floristic Region). First, we conducted a general sensitivity analysis of how harvesting affects persistence and abundance at nested spatial extents. For most spatial extents and combinations of demographic parameters, persistence and abundance of flowering shrubs decreased abruptly once harvesting rate exceeded a certain threshold. At larger extents, metapopulations supported higher harvesting rates before their persistence and abundance decreased, but persistence and abundance also decreased more abruptly due to harvesting than at smaller extents. This threshold rate of harvest varied with species' dispersal ability, maximum reproductive rate, adult mortality, probability of extirpation or local extinction, strength of Allee effects, and carrying capacity. Moreover, spatial extent interacted with Allee effects and probability of extirpation because both these demographic properties affected the response of local populations to harvesting more strongly than they affected the response of metapopulations. Subsequently, we simulated the effects of harvesting on three Cape Floristic Region Proteaceae species and found that these species reacted differently to harvesting, but their persistence and abundance decreased at low rates of harvest. Our estimates of harvesting rates at maximum sustainable yield differed from those of previous investigations, perhaps because researchers used different estimates of demographic parameters, models of population dynamics, and spatial extent than we did. Good demographic knowledge and careful identification of the spatial extent of interest increases confidence in assessments and monitoring of the effects of harvesting. Our general sensitivity analysis improved understanding of harvesting effects on metapopulation dynamics and allowed qualitative assessment of the probability of extirpation of poorly studied species. PMID- 21251072 TI - Citation rate and perceived subject bias in the amphibian-decline literature. AB - As a result of global declines in amphibian populations, interest in the conservation of amphibians has grown. This growth has been fueled partially by the recent discovery of other potential causes of declines, including chytridiomycosis (the amphibian chytrid, an infectious disease) and climate change. It has been proposed that researchers have shifted their focus to these novel stressors and that other threats to amphibians, such as habitat loss, are not being studied in proportion to their potential effects. We tested the validity of this proposal by reviewing the literature on amphibian declines, categorizing the primary topic of articles within this literature (e.g., habitat loss or UV-B radiation) and comparing citation rates among articles on these topics and impact factors of journals in which the articles were published. From 1990 to 2009, the proportion of papers on habitat loss remained fairly constant, and although the number of papers on chytridiomycosis increased after the disease was described in 1998, the number of published papers on amphibian declines also increased. Nevertheless, papers on chytridiomycosis were more highly cited than papers not on chytridiomycosis and were published in journals with higher impact factors on average, which may indicate this research topic is more popular in the literature. Our results were not consistent with a shift in the research agenda on amphibians. We believe the perception of such a shift has been supported by the higher citation rates of papers on chytridiomycosis. PMID- 21251073 TI - Vascular endothelial growth factor genetic polymorphisms and haplotypes in female patients with bisphosphonate-related osteonecrosis of the jaws. AB - OBJECTIVE: To investigate the polymorphisms of the vascular endothelial growth factor (VEGF) gene in relation to female patients who developed bisphosphonate related osteonecrosis of the jaws (BRONJ). METHODS: Test subjects were 30 Italian female patients with BRONJ (Group A). Control subjects were 30 female patients with a history of intravenous bisphosphonate use without any evidence of osteonecrosis (Group B) and 125 unrelated healthy volunteers (Group C). Three single-nucleotide polymorphisms were investigated: -634 G>C, occurring in 5' untranslated region (UTR); +936 C>T, occurring in 3' UTR; and -2578 C>A of the promoter region. RESULTS: The frequency of the VEGF CAC (+936/-2578/-634) haplotype was increased in patients with BRONJ, compared with female disease negative controls [odds ratio (OR) = 2.76, 95% CI = 1.09-4.94, P = 0.039; corrected P value: P(c) = 0.117], and was also increased compared with female healthy controls (OR = 2.11, 95% CI = 1.14-3.89, P = 0.024; corrected P value: P(c) = 0.072). The CC homozygotes of -634G>C of VEGF gene and AA homozygotes of 2578C>A have also been significantly correlated in female patients who developed BRONJ compared with healthy controls (OR = 2.04, 95% CI = 1.12-3.70, P = 0.008; corrected P value: P(c) = 0.024). CONCLUSIONS: These results suggest a possible haplotype effect of VEGF polymorphisms expression in BRONJ Italian female patients. Studies with different and larger populations possibly using TagSNP to represent all haplotypes within the VEGF gene are needed to further delineate the genetic contribution of this gene to BRONJ. PMID- 21251074 TI - Dynamics of gas-phase trichloramine (NCl3) in chlorinated, indoor swimming pool facilities. AB - Trichloramine (NCl(3)) is recognized as an irritant of the human respiratory system and other tissues. Processes that lead to volatilization from the liquid phase allow for human exposure to gas-phase NCl(3) in swimming pool settings. The dynamics of these processes are not well defined. A N,N-diethyl-p phenylenediamine/potassium iodide (DPD/KI)-based wet-chemistry method for measuring gas-phase NCl(3) concentration was verified and applied in chlorinated, indoor swimming pool facilities. Other gas-phase oxidants in the air of indoor pools provided interference of 15% or less. The DPD/KI method was applied for the measurement of gas-phase NCl(3) in four chlorinated, indoor swimming pool facilities. All results showed a correlation between bather loading and gas-phase NCl(3) concentration. The nature of swimmer activities also influenced air quality, presumably because of the effects of these activities on mixing near the gas-liquid interface. PRACTICAL IMPLICATIONS: The activities of swimmers promote transfer of volatile compounds from water to the surrounding air. For chlorinated, indoor pool facilities, this can lead to exposure to gas-phase chemicals that can cause irritation of the respiratory system and other tissues. The focus of this study was on NCl(3), a common disinfection by-product (DBP) in chlorinated pools. However, the conditions that promote NCl(3) transfer are likely to promote transfer of other volatile chemicals from water to air. As such, it is possible that other DBPs formed in pools may also contribute to diminished air quality. PMID- 21251075 TI - Intermittent parathyroid hormone fails to stimulate osseointegration in diabetic rats. AB - OBJECTIVES: Diabetes is considered a risk factor in the osseointegration of dental implants, which suggests that these patients might benefit from anabolic therapies. Preclinical studies, including investigations by this research group, revealed that intermittent administration of parathyroid hormone (PTH) stimulates bone formation on the surface of titanium implants under physiological conditions. However, the anabolic effect of PTH on osseointegration under the hyperglycemic condition of diabetes is unknown. METHODS: The ability of PTH to stimulate osseointegration was investigated in 40 female Wistar rats that were randomly divided into the following treatment groups: diabetes, diabetes plus PTH, control, and control plus PTH. Diabetes was induced by intraperitoneal injection of streptozotocin (45 mg/kg) at 1 week before implantation. Rats received PTH at a dose of 60 MUg/kg or a vehicle by subcutaneous injection starting at the day of implant insertion into the tibia. Histomorphometric analysis was performed after 4 weeks. RESULTS: The medullary peri-implant bone area significantly increased in rats receiving PTH in comparison with the control group (41+/-12% to 20+/-12%; P<0.01). Moreover, there was an increased bone-to implant contact (BIC) area in animals treated with PTH (47+/-18% to 27+/-16%; P<0.05). In contrast, diabetic rats failed to benefit from the anabolic treatment. A similar peri-implant bone area occurred in the diabetes group, independent of treatment with PTH (13+/-9% to 15+/-6%; P>0.05). Moreover, PTH did not affect the BIC area under hyperglycemic conditions (16+/-12% to 16+/-8%; P>0.05). No significant changes were observed in the cortical compartment of all groups. CONCLUSION: These results demonstrate that the metabolic characteristics of the diabetic rats produced a condition that was unable to respond to PTH treatment. These findings led us to hypothesize that metabolic control of diabetes might be a critical determinant when diabetic patients are undergoing anabolic therapy to enhance osseointegration. PMID- 21251076 TI - Anti-infective treatment of peri-implant mucositis: a randomised controlled clinical trial. AB - AIM: To compare the effectiveness of two anti-infective protocols for the treatment of peri-implant mucositis. MATERIALS AND METHODS: Twenty-nine patients with one implant diagnosed with peri-implant mucositis (bleeding on probing [BOP] with no loss of supporting bone) were randomly assigned to a control or test group. Following an assessment of baseline parameters (probing depth, BOP, suppuration, presence of plaque), all patients received non-surgical mechanical debridement at the implant sites and were instructed to brush around the implant twice daily using a gel provided for a period of 4 weeks. The test group (15 patients) received a chlorhexidine gel (0.5%), and the control group (14 patients) received a placebo gel. The study was performed double blind. After 4 weeks, patients were instructed to discontinue using the gel and to continue with routine oral hygiene at the implant sites. Baseline parameters were repeated at 1 and 3 months. RESULTS: At 1 month, there was a statistically significant reduction in the mean number of sites with BOP and mean probing depth measurements at implants in both groups. There were also some statistically significant changes in these parameters from 1 to 3 months. However, there were no statistically significant differences between test and control groups. One month following treatment, 76% of implants had a reduction in BOP. Complete resolution of BOP at 3 months was achieved in 38% of the treated implants. The presence of a submucosal restoration margin resulted in significantly lower reductions in probing depth following treatment. CONCLUSIONS: Non-surgical debridement and oral hygiene were effective in reducing peri-implant mucositis, but did not always result in complete resolution of inflammation. Adjunctive chlorhexidine gel application did not enhance the results compared with mechanical cleansing alone. Implants with supramucosal restoration margins showed greater therapeutic improvement compared with those with submucosal restoration margins. PMID- 21251077 TI - Morse taper connection implants supporting "planned" maxillary and mandibular bar retained overdentures: a 5-year prospective multicenter study. AB - OBJECTIVES: In contrast to the excellent long-term outcomes described for implant supported mandibular overdentures, less favorable long-term survival and success rates have been reported for maxillary implants supporting overdentures. The aim of this study was to evaluate the treatment outcome of "planned" bar-retained maxillary and mandibular overdentures supported by Morse taper connection implants, investigating implant survival, peri-implant tissue health, marginal bone resorption and prosthetic complications. MATERIAL AND METHODS: Over a 2-year period, 60 patients were enrolled in this study, in four different clinical centers. The overdentures (maxilla 38, mandible 34) were planned with support from four implants anchored on a bar. A total of 288 Morse taper connection implants (Leone Implant System((r))) were inserted (152 maxilla, 136 mandible). Implants were evaluated 5 years after insertion. Success criteria included the absence of pain, suppuration or clinical mobility, the distance between implant shoulder and first crestal bone-implant contact (DIB) <2 mm and no exudate history. RESULTS: The overall 5-year implant survival rate was 98% (maxilla 97.4%, mandible 98.6%), with 282 implants still in function. Among these surviving implants, 278 (98.6%) were classified in the success group. At the 5 year examination, the mean DIB was 0.7 mm (+/-0.53). Few prosthetic complications were reported. CONCLUSIONS: With "planned" bar-retained maxillary and mandibular overdentures supported by Morse taper connection implants, satisfactory survival and success rate can be achieved. PMID- 21251078 TI - Analysis of the association of IL1B(C-511T) polymorphism with dental implant loss and the clusterization phenomenon. AB - OBJECTIVES: Endosteous dental implants consist in the treatment of choice to replace tooth loss. The knowledge that implant loss tends to cluster in subsets of individuals may indicate that host immune-inflammatory response is influenced by genetic factors. Interleukin-1 (IL-1) is a key mediator of inflammatory processes and functional polymorphisms in IL1 gene could be candidate genetic risk factors to study susceptibility to implant failure. The objective of this study was to investigate the association between IL1B (C-511T) genetic polymorphism and dental implant loss in a Brazilian population and its influence in the clusterization phenomenon. MATERIAL AND METHODS: The sample composed of 277 unrelated, both gender, mean age 53.63 +/- 11.14 years individuals, divided into test group - 92 subjects with implant loss, and control group - 185 subjects with no implant loss. Patients' socioeconomic profile and clinical variables were investigated. Genomic DNA from oral mucosa was analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: There was significant difference between the groups in medical treatment (P=0.040), edentulism (P=0.019), and mean number of placed implants (P=0.001). There was difference between groups with and without implant loss neither considering genotypes (P=0.279) nor alleles (P=0.168) for IL1B (C-511T) polymorphism. When individuals showing up to one implant failure (n=254) were investigated vs. patients presenting multiple implant loss (n=23), no difference was either observed between groups for genotype (P=0.083) and allele (P=0.838) frequencies. CONCLUSIONS: The borderline association of the study polymorphism with implant loss suggests further IL1 haplotype analysis to elucidate the global involvement of IL-1 proteins in the modulation of the osseointegration process. PMID- 21251079 TI - Titanium allergy: could it affect dental implant integration? AB - PURPOSE: Degradation products of metallic biomaterials including titanium may result in metal hypersensitivity reaction. Hypersensitivity to biomaterials is often described in terms of vague pain, skin rashes, fatigue and malaise and in some cases implant loss. Recently, titanium hypersensitivity has been suggested as one of the factors responsible for implant failure. Although titanium hypersensitivity is a growing concern, epidemiological data on incidence of titanium-related allergic reactions are still lacking. MATERIALS AND METHODS: A computer search of electronic databases primarily MEDLINE and PUBMED was performed with the following key words: 'titanium hypersensitivity', 'titanium allergy', 'titanium release' without any language restriction. Manual searches of the bibliographies of all the retrieved articles were also performed. In addition, a complementary hand search was also conducted to identify recent articles and case reports. RESULTS: Most of the literature comprised case reports and prospective in vivo/in vitro trials. One hundred and twenty-seven publications were selected for full text reading. The bulk of the literature originated from the orthopaedic discipline, reporting wear debris following knee/hip arthroplasties. The rest comprised osteosynthesis (plates/screws), oral implant/dental materials, dermatology/cardiac-pacemaker, pathology/cancer, biomaterials and general reports. CONCLUSION: This review of the literature indicates that titanium can induce hypersensitivity in susceptible patients and could play a critical role in implant failure. Furthermore, this review supports the need for long-term clinical and radiographic follow-up of all implant patients who are sensitive to metals. At present, we know little about titanium hypersensitivity, but it cannot be excluded as a reason for implant failure. PMID- 21251080 TI - The effect of zirconia and titanium implant abutments on light reflection of the supporting soft tissues. AB - OBJECTIVES: To determine the difference in light reflection of oral mucosa covering titanium (Ti) or zirconia (ZrO(2)) abutments as it relates to the thickness of the covering mucosa. MATERIAL AND METHODS: Fifteen anterior implants (Astra Osseo speed((r))) in 11 patients were fitted with a Ti or a ZrO(2) abutment (cross-over, within-subject comparison). Hyper-spectral images were taken with a camera fitted on a surgical microscope. High-resolution images with 70 nm interval between 440 and 720 nm were obtained within 30 s (1392 * 1024 pixels). Black- and white-point reference was used for spatial and spectral normalization as well as correction for motion during exposure. Reflection spectra were extracted from the image on a line mid-buccal of the implant, starting 1 mm above the soft tissue continuing up to 3 mm apically. RESULTS: Median soft tissue height is 2.3 mm (min: 1.2 mm and max: 3.1 mm). The buccal mucosa rapidly increases in the thickness, when moving apically. At 2.2 mm, thickness is 3 mm. No perceivable difference between the Ti and ZrO(2) abutment can be observed when the thickness of the mucosa is 2+/-0.1 mm (95% confidence interval) or more. CONCLUSION: It is expected that the difference in light reflection of soft tissue covering Ti or ZrO(2) abutments is no longer noticeable for the human eye when the mucosa thickness exceeds 2 mm. Haemoglobin peaks in the reflection spectrum can be observed and make hyper-spectral imaging a practical and useful tool for measuring soft tissue health. PMID- 21251081 TI - Vertical ridge augmentation of atrophic posterior mandible using an inlay technique with a xenograft without miniscrews and miniplates: case series. AB - BACKGROUND: Rehabilitation of partially or totally edentulous posterior mandible with implant-supported prosthesis has become a common practice in the last few decades, with reliable long-term results. The use of miniscrews and miniplates have been reported to increase the risk of fracture of the osteotomy segments. The purpose of this case series was to use an inlay technique, without the use of miniscrews and miniplates for stabilization of the transported bone fragments. MATERIALS AND METHODS: Nine consecutive patients (six men and three women) aged between 26 and 51 years (mean 44 years) were enrolled in this study. A horizontal osteotomy was performed 2-3 mm above the mandibular canal, and two oblique cuts were made using a piezosurgery device. The final phase of the osteotomy was performed with chisels. The osteotomized segment was then raised in the coronal direction, sparing the lingual periosteum. Two miniblocks of xenograft without miniscrews and miniplates were inserted mesially and distally between the cranial osteotomized segment and the mandibular basal bone. The residual space was filled with particles of cortico-cancellous porcine bone. Four months after surgery, a panoramic X-ray was taken before implant insertion. A bone trephine with an internal diameter of 2 mm was used as the second dental drill to take a bone core biopsy during preparation of the #35 and #37 or #45 and #47 implant sites. RESULTS: The postoperative course was uneventful in seven of the nine patients. No dehiscence of the mucosa was observed at the marginal ridge of the mobilized fragment. Newly formed bone was present near the osteotomized segments, and was observed in the bottom half of the specimens and was identified by its higher affinity toward the staining. Newly formed bone was observed to be in close contact with the particles of biomaterials. No gaps or connective tissue were present at the bone-biomaterial interface. Histomorphometry demonstrated that 44+/-2.1% of the specimens was composed by newly formed bone, 18+/-0.8% by marrow spaces, and 33+/-2.4% by the residual grafted biomaterial. CONCLUSION: The rigidity of the equine collagenated block allowed to eliminate the use of miniscrews and miniplates and simplified the technique. Moreover, the rigidity of the block allowed maintenance of the space. PMID- 21251082 TI - Bone remodelling after regenerative procedures around implants placed in fresh extraction sockets: an experimental study in Beagle dogs. AB - INTRODUCTION: After a tooth extraction, the height of the buccal wall tends to decrease. The literature indicates that regenerative techniques (guided bone regenerative [GBR] techniques) have succeeded in improving the bone levels. Therefore, this experiment set out to compare the physiological bone remodelling in Beagle dog models after implant placement in a fresh extraction socket, with and without the application of regenerative procedure. MATERIALS AND METHODS: Five dogs were used in this study. Test and control sites were randomly selected. The experimental teeth (fourth pre-molar and first molar) were hemi-sected removing the distal roots and placing implants. Porcine bone was placed to fill the gap around the implant on the test sites and a reabsorbable membrane was used to cover the area. The dogs were put down at different times (2 weeks, 1 month and 3 months). The measurements were taken immediately and at 2, 4, 12 weeks after implant placement. Student's test for paired data was used to compare the means of the clinical measurements. RESULTS: At 2 weeks: On the control sites, few signs of resorption were detected at the first molar only, while at the test sites bone levels were placed at the implant shoulder or above. At 4 weeks: On the control site, slight bone remodelling was observed, while on the test site minor signs of resorption or an increase of bone levels were detected. At 12 weeks: The alveolar crest on the control sites showed various degrees of remodelling. On the test sites stable bone levels or an increase of bone crest was observed. CONCLUSION: With the limits of this study, the findings showed that GBR techniques were able to limit resorption of the alveolar crest after tooth extraction. A pattern of bone remodelling after tooth extraction and implant placement was observed in the control sites (no GBR) as well as in test sites (GBR), and although the exact cause of this is unclear, surgical trauma could play a role. Further studies are necessary to confirm these results and to clarify the precise causes of bone remodelling in fresh extraction sockets. PMID- 21251083 TI - Heat shocks enhance procollagen type I and III expression in fibroblasts in ex vivo human skin. AB - BACKGROUND: The well-known characteristics of aging skin are the development of fine lines and wrinkles, but changes in skin tone, skin texture, thickness and moisture content are also aspects of aging. Rejuvenation of the skin aims at reversing the signs of aging and can be established in the epidermis as well as in the dermis. Aged dermis, in fact, has a degenerated collagen matrix. To regenerate this matrix, fibroblasts need to be stimulated into synthesizing new collagen. AIMS: In this study, the effects of heat shocks of different temperatures on human dermal fibroblasts in ex vivo skin on the expression of procollagen 1, procollagen 3, heat shock protein (hsp)27, hsp47, and hsp70 are investigated. MATERIALS AND METHODS: The heat shocks were applied on ex vivo skin samples by immersing the samples in heated phosphate-buffered saline of 45 degrees C or 60 degrees C. Metabolic activity was measured and at similar time points propidium-iodide-calceine staining was performed to establish cell viability. Quantitative polymerase chain reaction (qPCR) was performed after the heat shock to determine gene expression levels relative to the reference temperature. Furthermore, PicroSirius Red and hematoxylin stainings were performed to visualize the collagen network and the cells. RESULTS: The skin samples were shown to be viable and metabolically active. Histology indicated that the heat shocks did not influence the structure of the collagen network or cell appearance. qPCR results showed that in contrast to the 45 degrees C heat shock the 60 degrees C heat shock resulted in significant upregulations of procollagen type I and III, hsp70 and hsp47. CONCLUSION: A 60 degrees C, heat shock stimulates the human dermal fibroblasts in ex vivo skin to upregulate their procollagen type I and type III expression. PMID- 21251084 TI - Is there any barrier impairment in sensitive skin?: a quantitative analysis of sensitive skin by mathematical modeling of transepidermal water loss desorption curves. AB - BACKGROUND/PURPOSE: Sensitive skin is a vague, subjective and difficult to characterize affliction. It affects a large part of the population and is accompanied with great interest by the cosmetic industry. Some studies have suggested that sensitive skin is the result of impaired barrier function, which leads to the exposure of immune system cells and sensitive nerves, resulting in marked cutaneous responses to otherwise harmless stimuli. This study aimed to investigate the cutaneous barrier integrity of individuals with sensitive skin by a novel approach: a plastic occlusion stress test followed by measurement of transepidermal water loss (TEWL) desorption curves. METHODS: The study was conducted in volunteers with sensitive skin in the hands and a control group with no sensitivity complaints. A previously developed mathematical model was adjusted to the TEWL data points and two parameters were calculated: dynamic water mass and the evaporation half-life period. RESULTS: Statistically significant differences have been detected in the parameters obtained in the sensitive skin group, which supports the thesis that individuals with an increased skin susceptibility have impaired barrier function. CONCLUSION: Whereas in the studies based in basal TEWL measurements only discrete differences were reported, the dynamic approach followed in this study provided unequivocal evidence of barrier impairment. The methodology enabled a more objective characterization of sensitive skin and can potentially be applied to the diagnosis/prediction of sensitivity; as well as the efficacy assessment of cosmetic products that are specifically designed to fulfill the needs of consumers with this skin condition. PMID- 21251085 TI - Skin colorimetric parameters involved in skin age perception. AB - BACKGROUND/PURPOSE: Age perception is based on a number of facial attributes such as wrinkles, skin gravity effects, feature lines, and skin optical appearance. The colorimetric and optical diffusion properties of skin have been compared with the consumer interpretation of 'skin age' of cheek area pictures without wrinkles or feature lines. METHODS: Controlled lighting images of skin were taken with the Visia CR. Skin sections from the cheek area were selected without eye region wrinkles or naso-labial lines for consumer interpretation. These same skin sections were analyzed for optical roughness and colorimetric parameters in the LCH color space, by distinguishing several roughness parameters according to their physical scale. RESULTS: Three main optical parameters of skin were found to influence the consumer's interpretation of skin 'visual age': the chroma (color saturation), lightness, and the local light-diffusing ability of skin. For the chroma and lightness, mainly large-scale inhomogeneities in the 0.8-2 cm(-1) range are taken into account by the consumer. Surprisingly, variations in the skin hue show a total absence of correlation with the consumer grading. PMID- 21251086 TI - Thermal sensory and pain thresholds in the tongue and chin change with age, but are not altered in burning mouth syndrome. AB - BACKGROUND: Burning mouth syndrome (BMS) is a chronic orofacial pain syndrome that occurs in middle-aged and postmenopausal women and poses a therapeutic challenge to dermatologists and dentists. It has been suggested previously that BMS is a small-fiber neuropathy. AIMS: This study was designed to examine thermal sensory and pain thresholds in the oral mucosa and chin, both innervated by the trigeminal nerve, in patients with BMS, as well as in healthy controls. In addition, the study proposed to examine whether there are any differences in oral thermal and pain sensations between the advanced age group, where BMS is prevalent and a younger group. RESULTS: Thermal and pain thresholds of BMS patients did not differ significantly from those of healthy subjects. An increased threshold to thermal warmth and a decreased threshold for cold sensation for the tongue and chin were noted in the group over 50 years in comparison with younger subjects, indicating a decreased sensitivity to thermal stimuli. The group over 50 years of age displayed an increased sensitivity to cold pain and a decreased sensitivity to hot pain in the tongue (compared with the chin). CONCLUSION: BMS patients do not demonstrate alterations in thermal and pain detection, thus failing to support a true small nerve neuropathy in this condition. PMID- 21251087 TI - Comparative diagnostic accuracy in virtual dermatopathology. AB - BACKGROUND: Virtual microscopy can be used to teach histology and pathology and for in-training and certification examinations. A few online consultation websites already utilize virtual microscopy, thereby expanding the role of telemedicine in dermatopathology. There are, however, relatively few studies comparing the diagnostic accuracy and acceptability of virtual slides compared to traditional glass slides. METHODS: Ten Nordic dermatopathologists and pathologists were given a randomized combination of 20 virtual and glass slides and asked to identify the diagnoses. They were then asked to give their impressions about the virtual images. Descriptive data analysis and comparison of groups using Fisher's exact test were performed. OBJECTIVE: To compare the diagnostic ability of dermatopathologists and pathologists in two image formats: the traditional (glass) microscopic slides, and whole mount digitized images, and to elucidate their assessment of virtual microscopy in dermatopathology. RESULTS: Dermatopathologists and pathologists performed similarly in diagnosing dermatopathological disorders using virtual slides vs. glass slides, virtual 0.85 and glass 0.81, P=0.286. The order of administration of virtual or glass slides did not affect the percentage of questions answered correctly. Seven of nine participants completing the questionnaire, felt virtual microscopy is useful for both learning and testing. CONCLUSION: There was no significant difference in the participants' diagnostic ability using virtual slides compared with glass slides. Most participants agreed that virtual microscopy is a useful tool for learning and testing. PMID- 21251088 TI - Targeted 307 nm UVB-excimer light vs. topical dithranol in psoriasis. PMID- 21251089 TI - Antibody response to the extracellular adherence protein (Eap) of Staphylococcus aureus in healthy and infected individuals. AB - The extracellular adherence protein (Eap) from Staphylococcus aureus has been suggested as a vaccine candidate and for therapeutic use due to its immunomodulating and antiangiogenic properties; however, little is known about anti-Eap antibodies in humans. We determined anti-Eap antibody titers by enzyme linked immunosorbent assay and Western blot and measured serum samples from 92 patients with proven S. aureus infections and 93 healthy controls. The functionality of antibodies was assessed by a phagocytosis assay using Eap-coated fluorescent microspheres. Antibodies were detected in all human samples, but not in mice. Patients showed significantly higher titers than controls [immunoglobulin M (IgM), P=0.007; IgG, P<0.0001]. Patients with deep or severe infections showed higher titers than those with superficial or mild disease. Eap alone was sufficient to promote phagocytosis by peripheral blood mononuclear cell and granulocytes that was moderately enhanced in the presence of human serum, but no correlation was found with the levels of anti-Eap antibodies. Anti-Eap antibodies are prevalent in all tested humans and correlate with the severity of S. aureus infection; however, they do not seem to provide protection against invasive infections. Before considering Eap for therapy or as a vaccine candidate, further studies are warranted to assess the impact of the interference between Eap and its specific antibodies. PMID- 21251090 TI - Impact of the unfolded protein response on the pathogenicity of the necrotrophic fungus Alternaria brassicicola. AB - The unfolded protein response (UPR) is an important stress signalling pathway involved in the cellular development and environmental adaptation of fungi. We investigated the importance of the UPR pathway in the pathogenicity of the plant necrotrophic fungus Alternaria brassicicola, which causes black spot disease on a wide range of Brassicaceae. We identified the AbHacA gene encoding the major UPR transcription regulator in A. brassicicola. Deletion of AbHacA prevented induction of the UPR in response to endoplasmic reticulum stress. Loss of UPR in mutants resulted in a complete loss of virulence and was also associated with a cell wall defect and a reduced capacity for secretion. In addition, our results showed that the UPR was triggered by treatment of mycelia with camalexin, i.e. the major Arabidopsis thaliana phytoalexin, and that strains lacking functional AbHacA exhibited increased in vitro susceptibility to antimicrobial plant metabolites. We hypothesize that the UPR plays a major role in fungal virulence by altering cell protection against host metabolites and by reducing the ability of the fungus to assimilate nutrients required for growth in the host environment. This study suggests that targeting the UPR pathway would be an effective plant disease control strategy. PMID- 21251091 TI - 1H-MRS in spinal cord injury: acute and chronic metabolite alterations in rat brain and lumbar spinal cord. AB - A variety of tests of sensorimotor function are used to characterize outcome after experimental spinal cord injury (SCI). These tests typically do not provide information about chemical and metabolic processes in the injured CNS. Here, we used (1) H-magnetic resonance spectroscopy (MRS) to monitor long-term and short term chemical changes in the CNS in vivo following SCI. The investigated areas were cortex, thalamus/striatum and the spinal cord distal to injury. In cortex, glutamate (Glu) decreased 1 day after SCI and slowly returned towards normal levels. The combined glutamine (Gln) and Glu signal was similarly decreased in cortex, but increased in the distal spinal cord, suggesting opposite changes of the Glu/Gln metabolites in cortex and distal spinal cord. In lumbar spinal cord, a marked increase of myo-inositol was found 3 days, 14 days and 4 months after SCI. Changes in metabolite concentrations in the spinal cord were also found for choline and N-acetylaspartate. No significant changes in metabolite concentrations were found in thalamus/striatum. Multivariate data analysis allowed separation between rats with SCI and controls for spectra acquired in cortex and spinal cord, but not in thalamus/striatum. Our findings suggest MRS could become a helpful tool to monitor spatial and temporal alterations of metabolic conditions in vivo in the brain and spinal cord after SCI. We provide evidence for dynamic temporal changes at both ends of the neuraxis, cortex cerebri and distal spinal cord, while deep brain areas appear less affected. PMID- 21251092 TI - Notch/neurogenin 3 signalling is involved in the neuritogenic actions of oestradiol in developing hippocampal neurones. AB - The ovarian hormone oestradiol promotes neuritic outgrowth in different neuronal types, by mechanisms that remain elusive. Recent studies have shown that the Notch-regulated transcription factor neurogenin 3 controls neuritogenesis. In the present study, we assessed whether oestradiol regulates neurogenin 3 in primary hippocampal neurones. As expected, neuritogenesis was increased in the cultures treated with oestradiol. However, the neuritogenic action of oestradiol was not prevented by ICI 182,780, an antagonist of classical oestrogen receptors (ERs). Oestradiol decreased the expression of Hairy and Enhancer of Split-1, a Notch regulated gene that negatively controls the expression on neurogenin 3. Furthermore, oestradiol increased the expression of neurogenin 3 and regulated its distribution between the neuronal cell nucleus and the cytoplasm. The effect of oestradiol on neurogenin 3 expression was not blocked by antagonists of classical nuclear ER-mediated transcription and was not imitated by selective agonists of nuclear ERs. By contrast, G1, a ligand of G protein receptor 30/G protein-coupled ER, fully reproduced the effect of oestradiol on neuritogenesis, neurogenin 3 expression and neurogenin 3 subcellular localisation. Moreover, knockdown of neurogenin 3 in neurones by transfection with small interference RNA for neurogenin 3 completely abrogated the neuritogenic actions of oestradiol and G1. These results suggest that oestradiol regulates neurogenin 3 in primary hippocampal neurones by a nonclassical steroid signalling mechanism, which involves the down-regulation of Notch activity and the activation of G protein receptor 30/G protein-coupled ER or of other unknown G1 targets. In addition, our findings indicate that neurogenin 3 participates in the neuritogenic mechanisms of oestradiol in hippocampal neurones. PMID- 21251093 TI - Peptide YY 3-36 and pancreatic polypeptide differentially regulate hypothalamic neuronal activity in mice in vivo as measured by manganese-enhanced magnetic resonance imaging. AB - Peptide YY (PYY) and pancreatic polypeptide (PP) are two appetite suppressing hormones, released post-prandially from the ileum and pancreas, respectively. PYY(3-36) , the major circulating form of the peptide, is considered to reduce food intake in humans and rodents via high affinity binding to the auto inhibitory neuropeptide Y receptor Y2R, whereas PP is considered to act through the Y4R. Current evidence indicates the anorexigenic effects of both peptides occur via signalling in the brainstem and arcuate nucleus (ARC) of the hypothalamus. Manganese-enhanced magnetic resonance imaging (MEMRI) has previously been used to track hypothalamic neuronal activity in vivo in response to both nutritional interventions and gut hormone treatment. In the present study, we used MEMRI to demonstrate that s.c. administration of PP results in a significant reduction in signal intensity (SI) in the ARC, ventromedial hypothalamus and paraventricular nucleus of fasted mice. Subcutaneous delivery of PYY(3-36) resulted in a nonsignificant trend towards decreased SI in the hypothalamus of fasted mice. We found no SI change in the area postrema of the brainstem after s.c. injection of either peptide. These differences in hypothalamic SI profile between PP and PYY(3-36) occurred despite both peptides producing a comparable reduction in food intake. These results suggest that separate central pathways control the anorexigenic response for PP and PYY(3-36) , possibly via a differential effect of Y4 receptor versus Y2 receptor signalling. In addition, we performed a series of MEMRI scans at 0-2, 2-4 and 4-6 h post-injection of PYY(3-36) and a potent analogue of the peptide; PYY(3-36) (LT). We recorded a significant reduction in the ARC SI 2-4 h after PYY(3-36) (LT) injection compared to both saline and PYY(3-36) in fasted mice. The physiological differences between PYY(3-36) and its analogue were also observed in the long-term effects on food intake, with PYY(3-36) (LT) producing a more sustained anorexigenic effect. These data suggest that MEMRI can be used to investigate the long-term effects of gut peptide delivery on activity within the hypothalamus and brainstem. PMID- 21251094 TI - Maternal and paternal transmission of type 2 diabetes: influence of diet, lifestyle and adiposity. AB - OBJECTIVE: Transmission of family history of type 2 diabetes to the next generation is stronger for maternal than paternal diabetes in some populations. The aim of the present study was to investigate whether this difference is explained by diet, lifestyle factors and/or adiposity. METHODS: We analysed 35174 participants from the Dutch contribution to the European Prospective Investigation into Cancer and Nutrition, a prospective population-based cohort (aged 20-70 years) with a median follow-up of 10.2 years. Parental history of diabetes was self-reported. Occurrence of diabetes was mainly identified by self report and verified by medical records. RESULTS: Amongst 35174 participants, 799 incident cases of diabetes were observed. In age- and sex-adjusted analyses, hazard ratio (HR) and 95% confidence intervals (CIs) for diabetes by maternal and paternal diabetes were 2.66 (2.26-3.14) and 2.40 (1.91-3.02), respectively. Maternal transmission of risk of diabetes was explained by diet (9.4%), lifestyle factors including smoking, alcohol consumption, physical activity and educational level (7.8%) and by adiposity, i.e. body mass index and waist and hip circumference (23.5%). For paternal transmission, the corresponding values were 2.9%, 0.0% and 9.6%. After adjustment for diet, lifestyle factors and adiposity, the HRs for maternal (2.20; 95% CI, 1.87-2.60) and paternal (2.23; 95% CI, 1.77 2.80) transmission of diabetes were comparable. CONCLUSIONS: Both maternal and paternal diabetes are associated with increased risk of type 2 diabetes, independently of diet, lifestyle and adiposity. The slightly higher risk conferred by maternal compared to paternal diabetes was explained by a larger contribution of diet, lifestyle factors and adiposity. PMID- 21251095 TI - Risk of hip fracture in Addison's disease: a population-based cohort study. AB - OBJECTIVES: The results of studies of bone mineral density in Addison's disease (AD) are inconsistent. There are no published data on hip fracture risk in patients with AD. In this study, we compare hip fracture risk in adults with and without AD. DESIGN: A population-based cohort study. METHODS: Through the Swedish National Patient Register and the Total Population Register, we identified 3219 patients without prior hip fracture who were diagnosed with AD at the age of >=30 years during the period 1964-2006 and 31 557 age- and sex-matched controls. Time to hip fracture was measured. RESULTS: We observed 221 hip fractures (6.9%) in patients with AD and 846 (2.7%) in the controls. Patients with AD had a higher risk of hip fracture [hazard ratio (HR) = 1.8; 95% confidence interval (CI), 1.6 2.1; P < 0.001]. This risk increase was independent of sex and age at or calendar period of diagnosis. Risk estimates did not change with adjustment for type 1 diabetes, autoimmune thyroid disease, rheumatoid arthritis or coeliac disease. Women diagnosed with AD <=50 years old had the highest risk of hip fracture (HR = 2.7; 95 % CI, 1.6-4.5). We found a positive association between hip fracture and undiagnosed AD [odds ratio (OR) = 2.4; 95 % CI, 2.1-3.0] with the highest risk estimates in the last year before AD diagnosis (OR = 2.8; 95 % CI, 1.8-4.2). CONCLUSION: Both clinically undiagnosed and diagnosed AD was associated with hip fractures, with the highest relative risk seen in women diagnosed with AD <=50 years of age. PMID- 21251096 TI - Fine needle aspiration cytology of ectopic meningioma presenting as a neck mass: a case report and a review of the literature. PMID- 21251097 TI - Pruritus: an overview of current concepts. AB - Pruritus is an integral part of the patient's symptoms in numerous dermatological and systemic diseases in humans and animals. Comparable to chronic pain, pruritus can have a dramatic impact on the quality of life of the patient. In recent years, pruritus has been defined as an autonomous, pain-independent sensation, and itch-specific neurons, mediators, spinal neurons and cortical areas have been identified. These observations have not only improved our understanding of the neurobiology of itch but will also lead to improved diagnosis and to the development of new and more efficient therapeutic options. This article reviews the role of itch fibres and their response to various mediators of pruritus including histamine, vasoactive intestinal peptide (VIP), calcitonin gene-related peptide (CGRP), and substance P (SP), and opioids. Substances that may be involved in the induction or modulation of itch may be termed pruritogenic mediators and examples discussed include proteases, lipid mediators, neuropeptides, opioids and various cytokines. There is no single, generally accepted clinical classification of chronic pruritus. In the past pruritus has been classified on the basis of the neuroanatomical origin and on the potential underlying disease. Therapeutic options for the management of pruritus are discussed including topical and systemic therapies, assuming that trigger factors have been eliminated where possible. Topical agents may include capsaicin, the calcineurin inhibitors tacrolimus and pimecrolimus, and cannabinoid agonists such as N-palmitoyl ethanolamine. Systemic therapies may include antihistamines, anticonvulsants, opiate receptor antagonist or agonists, antidepressants, ciclosporin, and UV light. PMID- 21251098 TI - Role of the environment in the development of canine atopic dermatitis in Labrador and golden retrievers. AB - Canine and human atopic dermatitis are multifaceted diseases whose clinical development may be influenced by several factors, such as genetic background, environment, secondary infections, food and psychological effects. The role of the environment has been extensively examined in humans but remains unclear in dogs. The aim of this study was to examine environmental factors in two genetically close breeds, Labrador and golden retrievers. Using standard criteria, atopic dogs in Switzerland and Germany were selected and compared with healthy individuals. Information on environmental factors was collected using a 46-question survey encompassing date and place of birth, way of life at the breeder's and owner's home, food and treatments. Univariate and multivariate logistic regression were used to assess the association between potential risk factors and disease status. The following parameters were associated with an increased risk of disease development: living in a shed during puppyhood, adoption at the age of 8-12 weeks and washing the dog regularly. In contrast, the following factors were associated with a lower risk: living in a rural environment, living in a household with other animals and walking in a forest. These associations do not prove causality but support the primary hypothesis that certain environmental factors may influence the development of canine atopic dermatitis. Further studies are warranted to confirm these results and conclusions. PMID- 21251099 TI - Use of ciclosporin in a dog with canine juvenile sterile granulomatous dermatitis and lymphadenitis. PMID- 21251100 TI - Differential contributions of ribosomal protein genes to Arabidopsis thaliana leaf development. AB - In Arabidopsis thaliana, mutations in genes encoding ribosomal proteins (r proteins) perturb various developmental processes. Whether these perturbations are caused by overall ribosome insufficiency or partial dysfunction of the ribosome caused by deficiency of a particular ribosomal protein is not known. To distinguish these possibilities, a comparative study using several r-protein mutants was required. Here, we identified mutations in 11 r-protein genes from previously isolated denticulata and pointed-leaves mutants. Most of these mutations were associated with pointed leaves, with reduced growth due to a decrease in the number or size of palisade mesophyll and pavement cells. In addition, leaf abaxialization was usually observed when these r-protein mutations were combined with asymmetric leaves1 (as1) and as2 mutations. These results suggest that the establishment of leaf polarity is highly sensitive to ribosome functionality in general. However, several r-protein mutants showed a preference towards a specific developmental defect. For example, rpl4d mutations did not affect cell proliferation but caused strong abaxialization of leaves in the as1 and as2 backgrounds. On the other hand, rps28b enhanced leaf abaxialization of as2 to a weaker extent than expected on the basis of its negative effect on cell proliferation. In addition, hypomorphic rps6a alleles had the strongest effects on most of the phenotypes examined. These findings suggest that deficiencies in these three r-protein genes lead to production of dysfunctional ribosomes. Depending on their structural abnormalities, dysfunctional ribosomes may affect translation of specific transcripts involved in the regulation of some leaf developmental processes. PMID- 21251101 TI - A RESTORER OF FERTILITY-like PPR gene is required for 5'-end processing of the nad4 mRNA in mitochondria of Arabidopsis thaliana. AB - Processing of 5'-ends is a frequently observed step during maturation of plant mitochondrial mRNAs. Up to now, very little is known about the biochemistry of this process and the proteins involved in the removal of 5' leader sequences. Based on natural genetic variation we have used linkage mapping and complementation studies to identify a nuclear gene required for the efficient generation of a 5'-end 228 nucleotides upstream of the mitochondrial nad4 gene encoding subunit 4 of the NADH dehydrogenase complex. This nuclear gene, At1g12700, that we designate RNA PROCESSING FACTOR 1 (RPF1), encodes a pentatricopeptide repeat (PPR) protein of the P-class containing canonical PPR repeats. RPF1 belongs to a subgroup of PPR proteins, which includes the RESTORER OF FERTILITY (RF) gene products restoring cytoplasmic male sterility (CMS) in various plant species. CMS is a mitochondrially inherited trait caused by the expression of aberrant, chimeric genes, which has not been observed in the predominantly inbreeding species Arabidopsis thaliana. The here reported results are a further step towards the characterization of the plant mitochondrial RNA processing machinery and provide additional insights into the function of RF-like PPR proteins. PMID- 21251102 TI - Cross-genome map based dissection of a nitrogen use efficiency ortho-metaQTL in bread wheat unravels concerted cereal genome evolution. AB - Monitoring nitrogen use efficiency (NUE) in plants is becoming essential to maintain yield while reducing fertilizer usage. Optimized NUE application in major crops is essential for long-term sustainability of agriculture production. Here, we report the precise identification of 11 major chromosomal regions controlling NUE in wheat that co-localise with key developmental genes such as Ppd (photoperiod sensitivity), Vrn (vernalization requirement), Rht (reduced height) and can be considered as robust markers from a molecular breeding perspective. Physical mapping, sequencing, annotation and candidate gene validation of an NUE metaQTL on wheat chromosome 3B allowed us to propose that a glutamate synthase (GoGAT) gene that is conserved structurally and functionally at orthologous positions in rice, sorghum and maize genomes may contribute to NUE in wheat and other cereals. We propose an evolutionary model for the NUE locus in cereals from a common ancestral region, involving species specific shuffling events such as gene deletion, inversion, transposition and the invasion of repetitive elements. PMID- 21251103 TI - Rice interspecies hybrids show precocious or delayed developmental transitions in the endosperm without change to the rate of syncytial nuclear division. AB - In angiosperms, interspecific crosses often display hybrid incompatibilities that are manifested as under-proliferation or over-proliferation of endosperm. Recent analyses using crosses between Arabidopsis thaliana and its related species with different ploidy levels have shown that interspecific hybridization causes delayed developmental transition and increased mitotic activity in the endosperm. In this study, we investigated endosperm development in interspecific crosses between diploid Oryza species. In a cross between female O. sativa and male O. punctata, we found that the hybrid endosperm was reduced in size and this cross was associated with precocious developmental transition. By contrast, the cross between O. sativa and O. longistaminata generated enlarged hybrid endosperm at the mid-point of seed development and this cross was associated with delayed developmental transition. Subsequently, the hybrid endosperm displayed a shriveled appearance at the seed maturation stage. We found that the accumulation of storage products and the expression patterns of several marker genes were also altered in the hybrid endosperm. By contrast, the rate of syncytial mitotic nuclear divisions was not significantly affected. The gene OsMADS87 showed a maternal origin-specific expression pattern in rice endosperm, in contrast to its Arabidopsis homologue PHERES1, which shows paternal origin-specific expression. OsMADS87 expression was decreased or increased depending on the type of developmental transition change in the hybrid rice endosperm. Our results indicate that one of the interspecies hybridization barriers in Oryza endosperm is mediated by precocious or delayed developmental alterations and de-regulation of OsMADS87, without change to the rate of syncytial mitotic nuclear division in the hybrid endosperm. PMID- 21251104 TI - Small RNAs from MITE-derived stem-loop precursors regulate abscisic acid signaling and abiotic stress responses in rice. AB - Small silencing RNAs (sRNAs) are non-coding RNA regulators that negatively regulate gene expression by guiding mRNA degradation, translation repression or chromatin modification. Plant sRNAs play crucial roles in various developmental processes, hormone signaling, immune responses and adaptation to a variety of abiotic stresses. miR441 and miR446 were previously annotated as microRNAs (miRNAs) because their precursors can form typical stem-loop structures, but are not considered as real miRNAs because of inconsistency with some ancillary criteria of the recent guidelines for annotation of plant miRNAs. We tentatively rename them small interfering (si)R441 and siR446, respectively, in this study. It has recently been shown that the precursors of siR441 and siR446 might originate from the miniature inverted-repeat transposable element (MITE) Stowaway1. In this report, we show that, in contrast with Dicer-like (DCL)3- and RNA-dependent RNA polymerase (RDR)2-dependent MITE-derived ra-siRNAs, siR441 and siR446 are processed by OsDCL3a but independent of OsRDR2, indicating that siR441 and siR446 are generated from single-stranded stem-loop precursors. We also show that abscisic acid (ABA) and abiotic stresses downregulate the expression of siR441 and siR446 but, surprisingly, increase the accumulation of their precursors in rice plants, implying that processing of siRNA precursors is inhibited. We provide evidence to show that this defective processing is due to increased precursor accumulation per se, possibly by intermolecular self-pairing of the processing intermediate sequences, thus hindering their normal processing. Functional examinations indicate that siR441 and siR446 are positive regulators of rice ABA signaling and tolerance to abiotic stress, possibly by regulating MAIF1 expression. PMID- 21251105 TI - Multiple cytosolic and transmembrane determinants are required for the trafficking of SCAMP1 via an ER-Golgi-TGN-PM pathway. AB - How polytopic plasma membrane (PM) proteins reach their destination in plant cells remains elusive. Using transgenic tobacco BY-2 cells, we previously showed that the rice secretory carrier membrane protein 1 (SCAMP1), an integral membrane protein with four transmembrane domains (TMDs), is localized to the PM and trans Golgi network (TGN). Here, we study the transport pathway and sorting signals of SCAMP1 by following its transient expression in tobacco BY-2 protoplasts and show that SCAMP1 reaches the PM via an endoplasmic reticulum (ER)-Golgi-TGN-PM pathway. Loss-of-function and gain-of-function analysis of various green fluorescent protein (GFP) fusions with SCAMP1 mutations further demonstrates that: (i) the cytosolic N-terminus of SCAMP1 contains an ER export signal; (ii) the transmembrane domain 2 (TMD2) and TMD3 of SCAMP1 are essential for Golgi export; (iii) SCAMP1 TMD1 is essential for TGN-to-PM targeting; (iv) the predicted topology of SCAMP1 and its various mutants remain identical as demonstrated by protease protection assay. Therefore, both the cytosolic N terminus and TMD sequences of SCAMP1 play integral roles in mediating its transport to the PM via an ER-Golgi-TGN pathway. PMID- 21251106 TI - TFL2/LHP1 is involved in auxin biosynthesis through positive regulation of YUCCA genes. AB - TERMINAL FLOWER2 (TFL2) is the plant homologue of metazoan HETEROCHROMATIN PROTEIN1 (HP1) protein family. It is known that, unlike most HP1 proteins, TFL2 does not primarily localize to heterochromatin; instead it functions in regulation of specific genes in euchromatic regions. We show that the tfl2 mutant has a lower rate of auxin biosynthesis, resulting in low levels of auxin. In line with this, tfl2 mutants have lower levels of expression of auxin response genes and retain an auxin response. The reduced rate of auxin biosynthesis in tfl2 is correlated to the down-regulation of specific genes in the tryptophan-dependent auxin biosynthesis pathway, a sub-set of the YUCCA genes. In vivo, TFL2 is targeted to a number of the YUCCA genes in an auxin-dependent fashion revealing a role of TFL2 in auxin regulation, probably as a component of protein complexes affecting transcriptional control. PMID- 21251107 TI - Cyclobutane pyrimidine dimer (CPD) photolyase repairs ultraviolet-B-induced CPDs in rice chloroplast and mitochondrial DNA. AB - Plants use sunlight as energy for photosynthesis; however, plant DNA is exposed to the harmful effects of ultraviolet-B (UV-B) radiation (280-320 nm) in the process. UV-B radiation damages nuclear, chloroplast and mitochondrial DNA by the formation of cyclobutane pyrimidine dimers (CPDs), which are the primary UV-B induced DNA lesions, and are a principal cause of UV-B-induced growth inhibition in plants. Repair of CPDs is therefore essential for plant survival while exposed to UV-B-containing sunlight. Nuclear repair of the UV-B-induced CPDs involves the photoreversal of CPDs, photoreactivation, which is mediated by CPD photolyase that monomerizes the CPDs in DNA by using the energy of near-UV and visible light (300-500 nm). To date, the CPD repair processes in plant chloroplasts and mitochondria remain poorly understood. Here, we report the photoreactivation of CPDs in chloroplast and mitochondrial DNA in rice. Biochemical and subcellular localization analyses using rice strains with different levels of CPD photolyase activity and transgenic rice strains showed that full-length CPD photolyase is encoded by a single gene, not a splice variant, and is expressed and targeted not only to nuclei but also to chloroplasts and mitochondria. The results indicate that rice may have evolved a CPD photolyase that functions in chloroplasts, mitochondria and nuclei, and that contains DNA to protect cells from the harmful effects of UV-B radiation. PMID- 21251108 TI - Arabidopsis genes IRREGULAR XYLEM (IRX15) and IRX15L encode DUF579-containing proteins that are essential for normal xylan deposition in the secondary cell wall. AB - There are 10 genes in the Arabidopsis genome that contain a domain described in the Pfam database as domain of unknown function 579 (DUF579). Although DUF579 is widely distributed in eukaryotic species, there is no direct experimental evidence to assign a function to it. Five of the 10 Arabidopsis DUF579 family members are co-expressed with marker genes for secondary cell wall formation. Plants in which two closely related members of the DUF579 family have been disrupted by T-DNA insertions contain less xylose in the secondary cell wall as a result of decreased xylan content, and exhibit mildly distorted xylem vessels. Consequently we have named these genes IRREGULAR XYLEM 15 (IRX15) and IRX15L. These mutant plants exhibit many features of previously described xylan synthesis mutants, such as the replacement of glucuronic acid side chains with methylglucuronic acid side chains. By contrast, immunostaining of xylan and transmission electron microscopy (TEM) reveals that the walls of these irx15 irx15l double mutants are disorganized, compared with the wild type or other previously described xylan mutants, and exhibit dramatic increases in the quantity of sugar released in cell wall digestibility assays. Furthermore, localization studies using fluorescent fusion proteins label both the Golgi and also an unknown intracellular compartment. These data are consistent with irx15 and irx15l defining a new class of genes involved in xylan biosynthesis. How these genes function during xylan biosynthesis and deposition is discussed. PMID- 21251109 TI - A multifaceted genomics approach allows the isolation of the rice Pia-blast resistance gene consisting of two adjacent NBS-LRR protein genes. AB - The Oryza sativa (rice) resistance gene Pia confers resistance to the blast fungus Magnaporthe oryzae carrying the AVR-Pia avirulence gene. To clone Pia, we employed a multifaceted genomics approach. First, we selected 12 R-gene analog (RGA) genes encoding nucleotide binding site-leucine rich repeats (NBS-LRRs) proteins from a region on chromosome 11 that shows linkage to Pia. By using seven rice accessions, we examined the association between Pia phenotypes and DNA polymorphisms in the 10 genes, which revealed three genes (Os11gRGA3-Os11gRGA5) exhibiting a perfect association with the Pia phenotypes. We also screened ethyl methane sulfonate (EMS)-treated mutant lines of the rice cultivar 'Sasanishiki' harboring Pia, and isolated two mutants that lost the Pia phenotype. DNA sequencing of Os11gRGA3-Os11gRGA5 from the two mutant lines identified independent mutations of major effects in Os11gRGA4. The wild-type 'Sasanishiki' allele of Os11gRGA4 (SasRGA4) complemented Pia function in both mutants, suggesting that SasRGA4 is necessary for Pia function. However, when the rice cultivar 'Himenomochi' lacking Pia was transfected with SasRGA4, the Pia phenotype was not recovered. An additional complementation study revealed that the two NBS-LRR-type R genes, SasRGA4 and SasRGA5, that are located next to each other and oriented in the opposite direction are necessary for Pia function. A population genetics analysis of SasRGA4 and SasRGA5 suggests that the two genes are under long-term balancing selection. PMID- 21251110 TI - Arabidopsis homologues of the histone chaperone ASF1 are crucial for chromatin replication and cell proliferation in plant development. AB - Anti-silencing function1 (ASF1) is an evolutionarily conserved histone chaperone. Studies in yeast and animals indicate that ASF1 proteins play important roles in various chromatin-based processes, including gene transcription, DNA replication and repair. While two genes encoding ASF1 homologues, AtASF1A and AtASF1B, are found in the Arabidopsis genome, their function has not been studied. Here we report that both AtASF1A and AtASF1B proteins bind histone H3, and are localized in the cytoplasm and the nucleus. Loss-of-function of either AtASF1A or AtASF1B did not show obvious defects, whereas simultaneous knockdown of both genes in the double mutant Atasf1ab drastically inhibited plant growth and caused abnormal vegetative and reproductive organ development. The Atasf1ab mutant plants exhibit cell number reduction, S-phase delay/arrest, and reduced polyploidy levels. Selective up-regulation of expression of a subset of genes, including those involved in S-phase checkpoints and the CYCB1;1 gene at the G2-to-M transition, was observed in Atasf1ab. Furthermore, the Atasf1ab-triggered replication fork stalling constitutively activates the DNA damage checkpoint and repair genes, including ATM, ATR, PARP1 and PARP2 as well as several genes of the homologous recombination (HR) pathway but not genes of the non-homologous end joining (NHEJ) pathway. In spite of the activation of repair genes, an increased level of DNA damage was detected in Atasf1ab, suggesting that defects in the mutant largely exceed the available capacity of the repair machinery. Taken together, our study establishes crucial roles for the AtASF1A and AtASF1B genes in chromatin replication, maintenance of genome integrity and cell proliferation during plant development. PMID- 21251111 TI - Rapid formation of distinct hybrid lineages after secondary contact of two fish species (Cottus sp.). AB - Homoploid hybridization after secondary contact between related species can lead to mixtures of genotypes which have the potential for rapid adaptation to new environmental conditions. Here, we focus on a case where anthropogenic changes within the past 200 years have allowed the hybridization between two fish species (Cottus rhenanus and Cottus perifretum) in the Netherlands. Specifically, we address the question of the dynamics of the emergence of these hybrids and invasion of the river systems. Using a set of 81 mostly ancestry-informative SNP markers, as well as broad sample coverage in and around the area of the initial contact, we find a structured hybrid swarm with at least three distinct hybrid lineages that have emerged out of this secondary contact situation. We show that genetically coherent groups can occur at geographically distant locations, while geographically adjacent groups can be genetically different, indicating that some form of reproductive isolation between the lineages is already effective. Using a newly developed modelling approach, we test the relative influence of founding admixture, drift and migration on the allele compositions of the sampling sites. We find that the allele frequency distributions can best be explained if continued gene flow between the parental species and the hybrid lineages is invoked. Genome mapping of the invasive lineage in the Rhine shows that major chromosomal rearrangements were not involved in creating this distinct lineage. Our results show that hybridization after secondary contact can quickly lead to multiple independent new lineages that have the capacity to form hybrid species. PMID- 21251112 TI - Significant genetic boundaries and spatial dynamics of giant pandas occupying fragmented habitat across southwest China. AB - Understanding population history and genetic structure are key drivers of ecological research. Here, we studied two highly fragmented and isolated populations (Xiaoxiangling and Daxiangling) of giant pandas (Ailuropoda melanoleuca) at the extreme southwestern edge of their distribution. This area also contains the Dadu River, national road 108 and various human infrastructure and development, providing an ideal region in which we can identify the effects of different barriers on animal movements. We used partial mitochondrial control region (mtDNA) and nine microsatellite loci (nuclear DNA) data derived from 192 faecal and one blood sample collected from the wild. We found 136 genotypes corresponding to 53 unique multilocus genotypes and eight unique control region haplotypes (653 bp). Significant genetic boundaries correlated spatially with the Dadu River (K = 2). We estimate that a major divergence took place between these populations 26,000 years bp, at around the similar time the rock surface of valley bottom formed in Dadu River. The national road has resulted in further recent population differentiation (Pairwise F(S) on mtDNA and nuclear DNA) so that in effect, four smaller sub-populations now exist. Promisingly, we identified two possible first-generation migrants and their migration paths, and recommended the immediate construction of a number of corridors. Fortunately, the Chinese government has accepted our advice and is now planning corridor construction. PMID- 21251113 TI - Broad-scale latitudinal patterns of genetic diversity among native European and introduced house sparrow (Passer domesticus) populations. AB - Introduced species offer unique opportunities to study evolution in new environments, and some provide opportunities for understanding the mechanisms underlying macroecological patterns. We sought to determine how introduction history impacted genetic diversity and differentiation of the house sparrow (Passer domesticus), one of the most broadly distributed bird species. We screened eight microsatellite loci in 316 individuals from 16 locations in the native and introduced ranges. Significant population structure occurred between native than introduced house sparrows. Introduced house sparrows were distinguished into one North American group and a highly differentiated Kenyan group. Genetic differentiation estimates identified a high magnitude of differentiation between Kenya and all other populations, but demonstrated that European and North American samples were differentiated too. Our results support previous claims that introduced North American populations likely had few source populations, and indicate house sparrows established populations after introduction. Genetic diversity also differed among native, introduced North American, and Kenyan populations with Kenyan birds being least diverse. In some cases, house sparrow populations appeared to maintain or recover genetic diversity relatively rapidly after range expansion (<50 years; Mexico and Panama), but in others (Kenya) the effect of introduction persisted over the same period. In both native and introduced populations, genetic diversity exhibited large-scale geographic patterns, increasing towards the equator. Such patterns of genetic diversity are concordant with two previously described models of genetic diversity, the latitudinal model and the species diversity model. PMID- 21251114 TI - Integrated genomic profiling identifies loss of chromosome 11p impacting transcriptomic activity in aggressive pituitary PRL tumors. AB - Integrative genomics approaches associating DNA structure and transcriptomic analysis should allow the identification of cascades of events relating to tumor aggressiveness. While different genome alterations have been identified in pituitary tumors, none have ever been correlated with the aggressiveness. This study focused on one subtype of pituitary tumor, the prolactin (PRL) pituitary tumors, to identify molecular events associated with the aggressive and malignant phenotypes. We combined a comparative genomic hybridization and transcriptomic analysis of 13 PRL tumors classified as nonaggressive or aggressive. Allelic loss within the p arm region of chromosome 11 was detected in five of the aggressive tumors. Allelic loss in the 11q arm was observed in three of these five tumors, all three of which were considered as malignant based on the occurrence of metastases. Comparison of genomic and transcriptomic data showed that allelic loss impacted upon the expression of genes located in the imbalanced region. Data filtering allowed us to highlight five deregulated genes (DGKZ, CD44, TSG101, GTF2H1, HTATIP2), within the missing 11p region, potentially responsible for triggering the aggressive and malignant phenotypes of PRL tumors. Our combined genomic and transcriptomic analysis underlines the importance of chromosome allelic loss in determining the aggressiveness and malignancy of tumors. PMID- 21251115 TI - Cannabinoid receptor and N-acyl phosphatidylethanolamine phospholipase D- evidence for altered expression in multiple sclerosis. AB - Cannabinoids have been shown to have a beneficial effect in both animal models of multiple sclerosis (MS) and human disease, although the mechanisms of action are unclear. We examined expression of the major cannabinoid receptors [(CBRs) cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2)] and a key enzyme involved in synthesis of the endocannabinoid anandamide [N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD)] in autopsy brain samples from patients with MS. CB1 was expressed in neurons, injured axons, oligodendrocytes, macrophages/microglia, some astrocytes, endothelial cells, smooth muscle cells and pericytes. CB2 and NAPE-PLD were localized to cerebral endothelial cells, pericytes, smooth muscle cells, astrocytes and macrophages/microglia. NAPE-PLD immunoreactivity was also seen in neurons. Endothelial CB2 expression was greatest in chronic inactive plaques, and in areas was seen in segments of endothelium where the endothelial expression of adhesion molecules (VCAM-1 and ICAM-1) was focally undetectable, and was often expressed in areas of blood-brain barrier damage. Vascular density was increased in chronic active plaques and normal-appearing white matter compared with controls. These data support findings from animal models which suggest a role for the endocannabinoid system in the MS, particularly in the regulation of endothelial leukocyte adhesion and the cellular response to injury. PMID- 21251116 TI - A most dignified ceremony. PMID- 21251117 TI - Biomechanical evaluation of tooth- and implant-supported fixed dental prostheses with various nonrigid connector positions: a finite element analysis. AB - PURPOSE: In the tooth- and implant-supported fixed dental prosthesis (FDP), rigid and nonrigid connector (NRC) designs have been preferred by clinicians for many years. The aim of this study was to analyze the stress distribution on the connecting areas of the superstructure and supporting structure of the tooth- and implant-supported FDP designs under both static vertical and oblique occlusal loads. MATERIALS AND METHODS: Four 2D finite element analysis (FEA) models were prepared presuming that the first and second molars were missing, and that the implant (3.80-mm diameter * 13-mm length) was placed in the second molar NRC design and patrix-matrix position supported by teeth/implants. Nonlinear contact elements were used to simulate a realistic interface fixation within the implant system and the sliding function of the NRC. Supporting periodontal ligament and alveolar bone (cortical and trabecular) were also modeled. Linear static analysis was performed on the prepared 2D solid models with a total masticatory force of 250 N (50 N for premolar, 100 N for first molar, 100 N for second molar), 0 degrees (at a right angle) and 30 degrees to the long axis of the supports. The maximum equivalent Von Mises (VM(Max)) was analyzed around the supporting teeth/implant and connector areas on tooth- and implant-supported FDP. RESULTS: The simulated results indicated that the highest level of VM(Max) (400.377 MPa) was observed on the NRC with the matrix positioned on the implant site of tooth- and implant-supported FDP under vertical occlusal load. The highest level of VM(Max) (392.8 MPa) under oblique occlusal load was also observed on the same model; however, the lowest VM(Max) value around implants was observed with the NRC when the patrix was positioned on the implant site of the FDP. Under vertical occlusal loads, in designs where the NRC was placed on the implant site, the stress formed around the implant decreased when compared to the designs where the NRCs were positioned on the tooth site. CONCLUSIONS: The efficiency of the NRC exhibited varying behavior depending on the direction of the load applied. The use of the patrix part of the NRC on the implant site may be more efficient in reducing the stress formation around the implant. PMID- 21251120 TI - Breast reconstruction in women under 30: a 10-year experience. PMID- 21251121 TI - Improvement in DCIS detection rates by MRI over time in a high-risk breast screening study. AB - Although magnetic resonance imaging (MRI) is much more sensitive than mammography for detecting early invasive breast cancer, in many high-risk screening studies MRI was less sensitive than mammography for detecting ductal carcinoma in situ (DCIS). We reviewed our experience detecting DCIS in our single center study of annual MRI, mammography, ultrasound and clinical breast examination (CBE) for screening very high-risk women. All cases of DCIS+/-microinvasion and invasive cancer were compared in two time frames: before (period A) and after (period B) July 2001-when we acquired expertise in the detection of DCIS with MRI-with respect to patient demographics, method of detection, and rates of detection of invasive cancer and DCIS. In period A there were 15 cases (3.1% of 486 screens) in 223 women, of which 2 (13%) were DCIS-one with microinvasion-neither detected by MRI. In period B there were 29 cases (3.3% of 877 screens) in 391 women, of which 10 (34%) were DCIS+/-microinvasion (p=0.04), all 10 detected by MRI but only one by mammography. No DCIS cases were detected by ultrasound or CBE. Specificity was lower in period B than in period A but acceptable. The ability to detect DCIS with screening MRI improves significantly with experience. MRI-guided biopsy capability is essential for a high-risk screening program. In experienced centers the increased sensitivity of MRI relative to mammography is at least as high for DCIS as it is for invasive breast cancer. PMID- 21251122 TI - Age <40Years is an independent prognostic factor predicting inferior overall survival in patients treated with breast conservative therapy. AB - To evaluate the effect of age at diagnosis on the treatment outcome after breast conservative therapy (BCT), retrospective analysis was done for 378 patients undergoing BCT for early breast cancer. Patients were divided into two groups according to their age: 'younger' (<40years, n=108) and 'older' (>=40years, n=270). Multivariate analysis was performed on the variables including tumor characteristics, the use of systemic therapy, and age to assess risk factors for local-regional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), and overall survival rates (OS). The median follow-up duration was 94months. The 8-year LRRFS, DMFS, and OS for younger and older groups were 88.1% and 96.5% (p=0.0022); 85.7% and 93.7% (p=0.0310); 89.2% and 95.9% (p=0.0205), respectively. On multivariate analysis, younger age was the only significant predictor of poor LRRFS (p=0.0022). Younger age and ER negativity showed borderline significance for DMFS (p=0.0828 and 0.0618, respectively). Younger age had trend toward inferior OS (p=0.0702). In conclusion, age younger than 40years was associated with inferior LRRFS in early breast cancer patients treated with BCT. There was also a trend for inferior DMFS and OS in younger patients. Age at diagnosis should be considered for individualized patient management. PMID- 21251123 TI - Breast necrosis following coronary artery bypass grafting. AB - We present a case of left breast necrosis following coronary artery bypass grafting which was misdiagnosed as a breast cancer. Breast necrosis after myocardial revascularization is an extremely rare complication of the surgical procedure using the most conventional graft which is the left internal mammary artery. The left internal mammary artery is the main blood supplying artery of the left breast. PMID- 21251124 TI - Cutaneous schistosomiasis mimicking Paget's disease of the breast. PMID- 21251125 TI - Management of phyllodes breast tumors. AB - Phyllodes tumors are a rare distinctive fibroepithelial tumors of the breast and their management continues to be questioned. The aim of our study was to examine the treatment and outcome of 165 patients with phyllodes tumors and to review the options for surgical management. This is a retrospective study of 165 patients who presented to the Institut Curie between January 1994 and November 2008 for benign, borderline or malignant phyllodes tumors. The median follow-up was 12.65 months [range 0-149.8]. The median age at diagnosis was 44 years [range 17-79]. One hundred and sixty patients (97%) had breast-conserving treatment, of whom 3 patients (1.8%) had oncoplastic breast surgery. Younger women had a significantly higher chance of having a benign phyllodes tumor (p = 0.0001) or a tumor of small size (p < 0.0001). Histologic examination showed 114 benign (69%), 37 borderline (22%) and 14 malignant tumors (9%). The median tumor size was 30 mm [range 5 150]. The tumor margins were considered incomplete (< 10 mm) in 46 out of 165 cases (28%) with 52% revision surgery. Only the tumor grade was a significant risk factor for incomplete tumor margins (p = 0.005). Fifteen patients developed local recurrence (10%) and two, metastases. In univariate analysis, the histologic grade (p = 0.008), and tumor size (p = 0.02) were significative risk factors for local recurrence with an accentuated risk for "borderline" tumors and tumors of large size.).Similar results were obtained using multivariate analysis (p = 0.07). The mainstay of treatment for phyllodes tumors remains excision with a safe surgical margin, taking advantage breast conserving surgery where amenable. For borderline or malignant phyllodes tumors or in cases of local tumor recurrence, mastectomy, and immediate breast reconstruction may become the preferred option. Genetic analysis will potentially supplement classical histologic examination in order to improve our management of these tumors. The role of adjuvant treatments is unproven and must be considered on a case-by-case basis. PMID- 21251126 TI - Hydatid cyst of the breast. PMID- 21251127 TI - The ins and the outs of cardiac dyssynchrony. PMID- 21251128 TI - A novel method for patient-specific QTc--modeling QT-RR hysteresis. AB - BACKGROUND: Cardiac repolarization adaptation to cycle length change is patient dependent and results in complex QT-RR hysteresis. We hypothesize that accurate patient-specific QT-RR curves and rate corrected QT values (QTc) can be derived through patient-specific modeling of hysteresis. METHOD AND RESULTS: Model development was supported by QT-RR observations from 1959 treadmill tests, allowing extensive exploration of the influences of autonomic function on QT adaptation to rate changes. The methodology quantifies and then removes patient specific repolarization adaptation rates. The estimated average 95% QT confidence limit was approximately 1 msec for the studied population. The model was validated by comparing QT-RR curves derived from a submaximal exercise protocol with rapid exercise and recovery phases, characterized by high hysteresis, with QT-RR values derived from an incremental stepped protocol that held heart rate constant for 5 minutes at each stage of exercise and recovery. CONCLUSIONS: The underlying physiologic changes affecting QT dynamics during the transitions from rest to exercise to recovery are quite complex. Nevertheless, a simple patient specific model, comprising only three parameters and based solely on the preceding history of RR intervals and trend, is sufficient to accurately model QT hysteresis over an entire exercise test for a diverse population. A brief recording of a resting ECG, combined with a short period of submaximal exercise and recovery, provides sufficient information to derive an accurate patient specific QT-RR curve, eliminating QTc bias inherent in population-based correction formulas. PMID- 21251129 TI - Highly automated QT measurement techniques in 7 thorough QT studies implemented under ICH E14 guidelines. AB - Thorough QT (TQT) studies are designed to evaluate potential effect of a novel drug on the ventricular repolarization process of the heart using QTc prolongation as a surrogate marker for torsades de pointes. The current process to measure the QT intervals from the thousands of electrocardiograms is lengthy and expensive. In this study, we propose a validation of a highly automatic-QT interval measurement (HA-QT) method. We applied a HA-QT method to the data from 7 TQT studies. We investigated both the placebo and baseline-adjusted QTc interval prolongation induced by moxifloxacin (positive control drug) at the time of expected peak concentration. The comparative analysis evaluated the time course of moxifloxacin-induced QTc prolongation in one study as well. The absolute HA-QT data were longer than the FDA-approved QTc data. This trend was not different between ECGs from the moxifloxacin and placebo arms: 9.6 +/- 24 ms on drug and 9.8 +/- 25 ms on placebo. The difference between methods vanished when comparing the placebo-baseline-adjusted QTc prolongation (1.4 +/- 2.8 ms, P = 0.4). The differences in precision between the HA-QT and the FDA-approved measurements were not statistically different from zero: 0.1 +/- 0.1 ms (P = 0.7). Also, the time course of the moxifloxacin-induced QTc prolongation adjusted for placebo was not statistically different between measurements methods. PMID- 21251130 TI - Utility of combined indexes of electrocardiography and echocardiography in the diagnosis of biopsy proven primary cardiac amyloidosis. AB - OBJECTIVE: Primary cardiac amyloidosis (CA) is associated with poor prognosis. However, the noninvasive diagnostic tools are limited. The aim of the study is to assess the utility of combined indexes of electrocardiography (ECG) and echocardiography (ECHO) in the diagnosis of primary CA. METHODS: A total of 20 consecutive patients (7 men, mean age 50 +/- 12 years) referred for endomyocardial biopsy (EMB) were included. Eleven of these patients (55%) confirmed primary CA, the rest of 9 patients were EMB negative and used for the control. RESULTS: The voltage of S(V1) + R(V6) < 1.2 mV has a sensitivity of 91% and specificity of 89% for the identification of primary CA, yields the positive and negative predictive values of 91% and 89%, respectively. Among ECHO parameters, there were no significant differences between the 2 groups, except for left ventricular ejection fraction (47 +/- 12% in primary CA vs 67 +/- 11% in the control, P < 0.001). However, the combined indexes of ECG and ECHO parameters, including the ratio of R(I) /LVPW as well as R(V5) /LVPW and R(V6) /LVPW, were significantly lower in the patients with primary CA than the control. The ratio of R(I) /LVPW < 0.4 has the sensitivity of 91% and specificity of 100%, yields the positive and negative predictive values of 100% and 91%, respectively. The ratios of R(V5(6)) /LVPW < 0.7 have the sensitivity of 91% and specificity of 89%, yield the positive and negative predictive values of 91% and 89%, respectively. CONCLUSION: Patients with clinically suspected primary CA, combined indexes of ECGs and ECHOs could be used as the noninvasive diagnostic tools. PMID- 21251131 TI - Electrocardiographic abnormalities in patients with severe versus mild or moderate chronic obstructive pulmonary disease followed in an academic outpatient pulmonary clinic. AB - BACKGROUND: The prevalence of some electrocardiographic (ECG) abnormalities in severe versus mild or moderate chronic obstructive pulmonary disease (COPD) has been reported. METHODS: ECGs were interpreted blindly in 63 patients with severe COPD (group 1) versus 83 patients with mild or moderate COPD (group 2). RESULTS: Right atrial enlargement (RAE) occurred in 44% of group 1 and 15% of group 2 patients (P < 0.001). Right ventricular hypertrophy (RVH) occurred in 29% of group 1 and 4% of group 2 patients (P < 0.001). Right bundle branch block (RBBB) occurred in 29% of group 1 and 11% of group 2 patients (P < 0.01). Marked clockwise rotation of heart occurred in 40% of group 1 and 18% of group 2 patients (P < 0.005). Low voltage in limb leads occurred in 24% of group 1 and 11% of group 2 patients (P < 0.05). A QS pattern in leads III and aVF occurred in 16% of group 1 and 4% of group 2 patients (P < 0.01). Left axis deviation (LAD) occurred in 16% of group 1 and 4% of group 2 patients (P < 0.01). Premature atrial complexes (PACs) occurred in 19% of group 1 and 7% of group 2 patients (P < 0.05). Supraventricular tachyarrhythmias (SVTs) occurred in 16% of group 1 and 5% of group 2 patients (P < 0.025). CONCLUSIONS: RAE, RVH, RBBB, marked clockwise rotation of heart, a QS pattern in leads III and aVF, LAD, PACs, and SVTs were significantly more prevalent in patients with severe COPD than in patients with mild or moderate COPD. PMID- 21251132 TI - Electrocardiographic changes in workers occupationally exposed to lead. AB - BACKGROUND: The significance of heavy metals in pathogenesis of the circulatory system diseases remains unresolved. The aim of the study was to evaluate electrocardiographic changes in workers occupationally exposed to lead without clinical presentation of cardiac involvement. METHODS: A group of 60 smelters and refiners and 45 healthy men, as a control group, were enrolled. Twelve-lead electrocardiogram (ECG) and 24-hour Holter monitoring were performed. Further analysis included heart rate variability (HRV) in time and frequency domains and heart rate turbulence (HRT). RESULTS: Analysis of 12-lead ECG recordings revealed various pathologies in 27 out of 60 men occupationally exposed to lead. Twenty four-hour ECG Holter monitoring showed the higher mean heart rate in copper smelters than in healthy subjects (85.8 +/- 14.1 bpm vs 72.6 +/- 9.2 bpm; P < 0.05) and more premature supraventricular and ventricular contractions (298 +/- 235 vs 27 +/- 45; P < 0.05 and 152 +/- 138 vs 18 +/- 18; P < 0.05, respectively). The majority of time domain and frequency domain HRV parameters were significantly lower, and the LF:HF ratio was higher when compared with the control group. Turbulence onset was abnormal in six copper smelters and turbulence slope in five men exposed to lead. CONCLUSIONS: Electrocardiographic evaluation showed that various heart rhythm disorders were more frequent in metallurgists, as compared to the control group, and the decreased HRV and abnormal parameters of HRT were observed. Noninvasive electrocardiographic evaluation could be a valuable method of the early prediction of cardiovascular disorders in men occupationally exposed to lead. PMID- 21251133 TI - Correlation between electrocardiographic features and mechanical dyssynchrony in heart failure patients with left bundle branch block. AB - BACKGROUND: Few electrocardiographic parameters beyond the QRS duration were studied with regard to the correlation with mechanical dyssynchrony. This study aims to analyze the correlation between electrocardiographic parameters and mechanical dyssynchrony in patients with symptomatic heart failure (HF) and left bundle branch block (LBBB). METHODS: Patients with HF, ejection fraction <= 35%, and QRS interval >= 120 ms with a LBBB were prospectively studied. We analyzed the correlation between electrocardiographic parameters (QRS duration, R voltage in limb leads, S voltage in precordial leads, Sokolow and Cornell indexes, QRS axis deviation, and QRS notches in lateral and inferior leads) and mechanical dyssynchrony measured by tissue Doppler imaging (TDI). RESULTS: A group of 50 patients were studied, 60% male, 78% with nonischemic cardiomyopathy, NYHA Class III-IV (86%), and ejection fraction of 0.22 +/- 0.6. Intra- and interventricular dyssynchrony occurred in 68% and 74% of patients, respectively. The S amplitude in precordial leads and the Sokolow and Cornel indexes show a weak correlation with the degree of dyssynchrony. In the patients with QRS notching in the lateral and inferior leads, we observed significantly greater prevalence of intraventricular dyssynchrony, with sensitivity and specificity of 85% and 56%, respectively, for notches in lateral leads. The QRS duration presents moderate correlation with the degree of both intraventricular (r = 0.48) and interventricular dyssynchrony (r = 0.46). CONCLUSION: The following electrocardiographic parameters were related to the degree of mechanical dyssynchrony: QRS duration and notches in QRS. In addition, the patients tend to have highest S amplitude in precordial leads. PMID- 21251134 TI - Clinical determinants of electrocardiographic and spatial vectorcardiographic descriptors of ventricular repolarization in healthy children. AB - BACKGROUND: Although the association of repolarization alterations to the development of life-threatening ventricular arrhythmias has received considerable research attention, there is paucity of data regarding what may be considered as normal, especially in children. METHODS: To define electrocardiographic (ECG) and vectorcardiographic (VCG) descriptors of ventricular repolarization in healthy school-age children, 12-lead digital ECGs were obtained from 646 children (348 males/298 females, mean age 8.54 +/- 1.86 years). All QT intervals were measured manually using the digitally stored ECGs. Orthogonal X, Y, and Z leads were reconstructed from the standard 12-lead ECGs and the maximal amplitudes of the spatial QRS and T vectors were calculated, as well as the spatial QRS-T angle. RESULTS: The mean heart rate was 95.3 +/- 15.8 bpm and the QRS duration was 83.4 +/- 9.3 ms. Mean QT interval was 334.1 +/- 24.2 ms and the corrected QT interval was 436.5 +/- 23.8 ms (Bazzet) and 404.3 +/- 19.4 ms (Fridericia). Although the uncorrected maximum and mean QT intervals were significantly higher in boys (P values 0.011 and 0.009, respectively), there was no difference in the rate corrected QT interval. The spatial QRS and T-vector amplitudes were 1512.0 +/- 365.7 MUV and 478.8 +/- 149.3 MUV, respectively. The spatial QRS-T angle was 14.1 +/- 8.0 degrees. Although the mean QT interval showed significant increase with age (P = 0.014), all VCG parameters did not show significant variance with age. CONCLUSIONS: A range of ECG and VCG descriptors of ventricular repolarization was determined in a large sample of healthy school-age children to provide a data basis of normal values for future reference. PMID- 21251135 TI - Prognostic value of standard electrocardiographic parameters for predicting major adverse cardiac events after acute myocardial infarction. AB - BACKGROUND: The prognostic value of electrocardiographic (ECG) variables in predicting major adverse cardiac events (MACEs) after acute myocardial infarction (AMI) in the era of modern therapy is unclear. This study was conducted to evaluate the prognostic significance of ECG parameters in predicting 1-year MACEs for AMI patients. METHODS: Between January 2006 and January 2008, 529 AMI patients were included. ECG variables were analyzed from the ECG taken on discharge day. The 1-year MACEs were defined as death, nonfatal MI, and revascularization including repeat percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Mean follow-up duration was 360 +/- 119 days. RESULTS: Of these patients, 497 (94%) patients provided complete follow-up data (355 males; 67 +/- 12 years old). The rate of 1-year MACEs was 16%. In univariate analysis, heart rate, corrected QT interval, left ventricular (LV) hypertrophy, voltage (SV(1) + RV(5) ), lateral ST-depression (V(5-6) or I, aVL), pathologic Q wave (V(1-4) , V(5-6) ), ST-elevation (V(1-4) , V(5-6) or I, aVL), and T-wave inversion (V(1-4) , V(5-6) , or I, aVL) had a significant association with 1-year MACEs. In the Cox regression hazard model, lateral ST-depression (hazard ratio [HR] 2.260, 95% confidence interval [CI] 1.204 to 4.241, P = 0.011) and corrected QT interval (HR 1.007, 95% CI 1.002 to 1.011, P = 0.004) were independent predictors of 1-year MACEs. After adjustment for all risk variables, lateral ST-depression (HR 3.781, 95% CI 1.047 to 13.656, P = 0.042) was the only ECG variable that independently predicted 1-year MACEs. CONCLUSION: Lateral ST depression on discharge day ECG is an independent predictor of 1-year MACEs after AMI. PMID- 21251136 TI - ST elevation and inverted T wave as another normal variant mimicking acute myocardial infarction: the prevalence, age, gender, and racial distribution. AB - BACKGROUND: Early repolarization (ERP) as a normal variant is a well-recognized ECG entity. There is another normal variant of ST elevation (STTNV) in the midprecordial leads, which is distinctively different from ERP in that the T waves are inverted in these leads while they are upright and tall in ERP. These findings can be easily mistaken for acute myocardial infarction or pericarditis. The purpose of this study is to publicize this entity and to determine its prevalence, age, gender, and racial distributions. METHODS: All ECGs taken in adults at a Minneapolis hospital in 2007 were reviewed and individuals with the following ECG findings were identified: 1-3 mm ST elevation ending in an inverted T wave in midprecordial leads with preserved R waves. RESULTS: A total of 11,424 patients (5997 men, 5427 women) had one or more ECGs in 2007. STTNV was seen in 101 patients, 97 (96%) of whom were black. Seventy-seven of 2084 (3.7%) black men and 20 of 2020 (1%) black women had STTNV. It was rare in other races (0 to 0.7%), particularly in white patients (1 of 5099 patients). It seems to be evenly distributed throughout the age. The ECG findings normalized in all 6 patients who underwent a treadmill stress test. CONCLUSIONS: This entity is seen almost exclusively in blacks (3.7% of men, 1% of women), and is more or less evenly distributed throughout the age. Whether this variant is more often associated with malignant ventricular arrhythmias remains to be determined. PMID- 21251137 TI - Diagnostic utility of signal-averaged electrocardiography for detection of cardiac sarcoidosis. AB - INTRODUCTION: Cardiac sarcoidosis (CS) occurs in up to 25% of patients with pulmonary involvement. Early diagnosis is critical because sudden death from ventricular arrhythmias can be the initial presentation. We sought to evaluate the diagnostic utility of signal-averaged ECG (SAECG) for detection of cardiac involvement of sarcoidosis. METHODS: Subjects with biopsy proven sarcoidosis and symptoms suggestive of possible cardiac involvement were included in the cohort. Standard criteria for SAECG were used. Subjects were considered to have CS if they met criteria established by the Japanese Ministry of Health and Welfare modified to include cardiac MRI. RESULTS: Of the 88 patients in the cohort 27 had evidence of CS independent of the SAECG results. The SAECG was abnormal in 14 of these 27 patients and 11 of the 61 of the subjects without cardiac involvement (P < 0.01). The sensitivity of SAECG detection of CS was 52% with a specificity of 82%. For the entire cohort, SAECG had a positive predictive value (PPV) of 0.56 and a negative predictive value (NPV) of 0.79. Within a subgroup of 67 patients with an unfiltered QRS duration of <100 ms, the specificity for diagnosing cardiac sarcoidosis improves to 100% with a reduced sensitivity of 36.8. Of the SAECG parameters, LAS40 was significantly associated with the diagnosis of cardiac sarcoidosis for the entire cohort (P < 0.01) and among the subgroup of patients with an unfiltered QRS duration of <100 ms (P < 0.01). CONCLUSIONS: SAECG is a useful screening tool in the evaluation of sarcoidosis for detection of cardiac involvement. PMID- 21251138 TI - Do physicians' attitudes toward implantable cardioverter defibrillator therapy vary by patient age, gender, or race? AB - BACKGROUND: Implantable cardioverter defibrillator (ICD) therapy improves survival of patients with systolic heart failure. We assessed whether physicians' recommendation for ICD therapy varies as a function of patient age, gender, race, and physician's specialty. METHODS: We surveyed a random sample (n = 9969) of U.S. physicians who are active members of the American College of Cardiology (ACC). We asked participants about their likelihood to recommend ICD therapy in 4 clinical scenarios that randomly varied patient age, gender, race, and ICD indication (guideline Class I, Class IIa, Class III, and Class I in a noncompliant patient). RESULTS: Responses were received from 1210 physicians (response rate 12%), of whom 1127 met the study inclusion criteria. Responders and nonresponders had similar demographics. In responding to hypothetical clinical scenarios, physicians were less likely to recommend an ICD to older patients (>=80 vs 50 years) (P < 0.01) but were unaffected by gender or race for all class indications. Compared with non-electrophysiologists (EPs), EPs were significantly more likely to recommend an ICD for a Class I indication (92.4% vs 81.4%; P < 0.01), but they were not more likely to offer an ICD for a Class III indication (0.4% vs 0.6%; P = 0.95). CONCLUSIONS: Based on survey responses, physicians were equally willing to offer an ICD to men and women and to whites and blacks, but were less likely to offer an ICD to an older patient even when indicated by practice guidelines. Electrophysiologists (EPs) more often adhered to practice guideline recommendations on ICD therapy compared with non-EPs. PMID- 21251139 TI - EGC diagnosis of paroxysmal supraventricular tachycardias in patients without preexcitation. AB - This review is aimed at discussing the diagnostic value of the different electrocardiographic criteria so far described in the differential diagnosis of the major forms of paroxysmal supraventricular tachycardias (PSVTs). The predictive value of different combinations of these independent electrocardiographic (ECG) signs in distinguishing atrioventricular reentrant tachycardias (AVRTs) through a concealed accessory pathway (AP) versus atrioventricular nodal reentrant tachycardias (AVNRTs) are discussed in detail. In addition, the adjunctive diagnostic value of simple, bedside clinical variables and their combinations to the ECG interpretation in differentiating both tachycardia mechanisms is also reviewed. PMID- 21251140 TI - A young patient with exercise-induced polymorphic ventricular tachycardia. PMID- 21251141 TI - Successful therapeutic hypothermia in patients with congenital long QT syndrome. AB - Therapeutic hypothermia has been shown to improve neurological outcomes in patients who remain comatose following resuscitation from cardiac arrest. While there are numerous reports of patients who have had a successful course after induction of therapeutic hypothermia, such therapeutic intervention has not been described in patients with congenital long QT syndrome (LQTS). We report outcomes in two patients with LQTS who had therapeutic hypothermia following a ventricular fibrillation arrest. Careful and routine monitoring of the QT interval in this patient population is necessary due to the potential for worsening electrical instability during induced hypothermia. PMID- 21251142 TI - Persistent abnormal value of late potential in Brugada syndrome associated with hypokalemia. AB - Hypokalemia accentuates the electrocardiographic (ECG) pattern of Brugada syndrome. We report two patients with Brugada syndrome and hypokalemia-induced lethal events. Despite concealing the typical ECG pattern with normalization of serum potassium levels, late potentials were persistently detected by signal averaged ECG, even at the 18-month follow-up. An implantable cardioverter defibrillator was inserted to prevent sudden cardiac death. PMID- 21251143 TI - A statement on ethics from the HEART group. PMID- 21251144 TI - What happens when things go wrong? AB - When a patient is injured or dies during anesthesia care, both the family of the patient and the health care providers suffer. The family needs to know what happened. The family can benefit from personal contact with the involved physicians. Apology to the injured is very important. The health care providers must report adverse events. Systematic review of adverse events can provide improved patient safety. Mechanisms exist to support the health care providers recovering from these potentially devastating experiences, but useful support is often not immediately available. PMID- 21251145 TI - Pain management in 100 episodes of severe mucositis in children. AB - OBJECTIVE: We aimed to review the pain management in 100 episodes of severe mucositis in children and determine the incidence of associated side effects. BACKGROUND: Mucositis is a painful, debilitating condition affecting the alimentary mucosa and occurs following many anticancer treatments. Severe pain associated with mucositis may necessitate reductions, delays or termination of anticancer therapy and so intravenous morphine, preferably by patient-controlled analgesia (PCA) is the treatment of choice. METHODS: Retrospective review of consecutive episodes of mucositis in children requiring intravenous opioid analgesia over a 3-year period (May 2006-April 2009). RESULTS: In 24/92 (26%) of cases, morphine PCA provided insufficient pain relief and children required adjuvant ketamine therapy. These children had rapidly increasing morphine requirements approaching 1000 mcg/kg/day by day 2 (more than double compared with children on morphine alone), were more likely to be female, and tended to be older (median [IQR] age 12 [6-12] years vs 7 [3-14] years). The addition of ketamine to the morphine PCA appears to be associated with reduced morphine consumption, improved pain scores, causing minimal side effects and no hallucinations. CONCLUSIONS: Children with severe mucositis who have escalating morphine requirements may benefit from the addition of ketamine to their morphine PCA. PMID- 21251146 TI - Correlations between global clotting function tests, duration of operation, and postoperative chest tube drainage in pediatric cardiac surgery. AB - BACKGROUND: Systemic coagulation disorders after cardiac surgery represent serious postoperative complications. There have been few reports, however, identifying preoperative coagulation tests that predict postoperative bleeding. The aim of the present study was to investigate the relationship between postoperative hemorrhage and coagulation parameters determined by global coagulation assays, to define potential predictive markers. METHODS: Twenty-one pediatric patients were enrolled. Blood samples were collected before and 24 h after cardiac surgery. Laboratory investigations included platelet count, hematocrit, classical coagulation tests [prothrombin time, activated partial thromboplastin time, thrombin-antithrombin complex (TAT)], rotation thromboelastometry (ROTEM), and the thrombin generation test (TGT). The duration of the surgical procedure was recorded. Chest tube drainage was monitored for 24 h after operation as an index of postoperative hemorrhage. RESULTS: Comparisons between preoperative and postoperative results indicated that TAT increased significantly after operation, whereas ROTEM parameters did not show a hypercoagulable pattern. Preoperative endogenous thrombin potential (ETP) measured in the TGT and clot formation time (CFT) in the ROTEM correlated with chest tube drainage. The classical coagulation tests were not informative. Postoperatively, peak height and ETP in TGT, all ROTEM parameters, and duration of surgery were correlated with chest tube drainage. Duration of surgery was correlated with postoperative ROTEM parameters but not with TGT. Postoperative maximum clot firmness and AUC were correlated with platelet count decrease ratio. CONCLUSIONS: The preoperative CFT and ETP provide useful indices for predicting postoperative chest tube drainage volume. In addition, the duration of surgery also correlated with chest tube drainage and affected ROTEM parameters. PMID- 21251147 TI - Anidulafungin for the treatment of invasive candidiasis. AB - Candidaemia/invasive candidiasis (C/IC) is the most frequently occurring invasive fungal infection worldwide, with a particularly strong impact and high incidence in the intensive-care unit, where there is a need for new treatment options and strategies. The echinocandin anidulafungin has broad in vitro activity against a wide range of Candida species, along with favourable pharmacokinetics that allow administration in hepatic and renal impairment and with any comedication without the need for dose adjustments. The efficacy and safety of anidulafungin for the treatment of C/IC were demonstrated in a number of clinical studies and by some limited data from clinical practice. In a randomized comparative trial for the treatment of C/IC in adults, 76% of patients receiving anidulafungin and 60% of those given fluconazole were treated successfully (95% CI for difference: 4-27; p 0.01). Post hoc analyses suggest that anidulafungin is significantly more effective than standard-dose fluconazole for the treatment of candidaemia in critically ill patients. Anidulafungin is generally well tolerated, with commonly reported side effects including headache, hypokalaemia, gastrointestinal symptoms, abnormal liver function test results, and rash. In pharmaco-economic analyses, anidulafungin compared favourably with fluconazole (in terms of overall costs and hospital resource use) as well as with other echinocandins. Echinocandins, including anidulafungin, are now generally recommended as first line therapy in moderately to severely ill patients, those with prior azole exposure, and patients with C/IC caused by Candida glabrata or Candida krusei. PMID- 21251148 TI - Using self-efficacy theory to educate a patient with chronic obstructive pulmonary disease: A case study of 1-year follow-up. AB - Self-efficacy is important in determining which activities or situations an individual will perform or avoid. This is a case study report to explore the utility of structured education programme on strengthening self-efficacy in an older adult with chronic obstructive pulmonary disease (COPD). To comprehensively evaluate this intervention, a combined qualitative and quantitative approach was used. Although qualitative data were collected following the interview guide, quantitative data were collected by the demographic data form and the COPD Self Efficacy Scale (CSES) at the preprogramme and postprogramme stage. The patient's self-efficacy scores improved after 8 weeks of the structured education programme and remained relatively constant on all the repeated measurements after education. Qualitative data were identified as 'difficulties' and 'facilities'. This study indicates that, by applying a self-efficacy theory, a planned education programme could be useful in improving both short-term and long-term self-efficacy in patients with COPD. PMID- 21251149 TI - Developing a holistic approach to obesity management. AB - The aim of this paper is to discuss the theoretical background and relevance of a holistic approach to obesity management by nurses. There is a global rise in the number of people with obesity, such that it now represents one of the major health challenges. However, nurses are often influenced by physical and dietetic focused approaches and could fail to acknowledge a range of other factors that can impact on weight management. As part of the development of a holistic approach to obesity a literature search was undertaken to establish relevant theoretical perspectives that underpin practice in physical, psychological and social aspects of care (focused on the period 1995-2005). In addition, experiences of working in a secondary care weight management clinic were also drawn upon. Psychobiological, attribution and social support theories were identified that could contribute to a better understanding of obesity. If these theoretical perspectives and supporting evidence can be integrated in a holistic approach to care and management it might be possible to promote better health and well-being in those with obesity. Creating a greater understanding of the range of theoretical perspectives and supporting evidence related to obesity could, it is argued, provide enhanced care and management. PMID- 21251150 TI - The changes in health-related quality of life and related factors during the process of total hip arthroplasty. AB - This study was carried out to measure changes in health-related quality of life (HRQOL) in patients (n=100) undergoing total hip arthoplasty. The Sickness Impact Profile was used to measure patients' dysfunctions in 12 different categories post surgery. Improvement was observed in each category and dimension already at 3 months and at 6 months. Preoperative pain showed a statistically significant although declining correlation both with total, and with Physical and the Psychosocial dimensions of HRQOL. The greatest improvements were found in the categories Body Care and Movement, Ambulation, Alertness Behaviour, Social Interaction, Recreation and Pastimes and in Sleep and Rest. Patients' pain decreased, and 72% reported no pain at 6 months post the surgery. Patients' perceptions of their pain should be gathered carefully when deciding the need and timing for the surgery in order to minimize impairments into HRQOL. PMID- 21251151 TI - Lifestyle and health promoting behaviours in Jordanian subjects without prior history of coronary heart disease. AB - Modern styles of living and the accelerated pace of life could direct people to adopt unhealthy lifestyles. Globally, literature indicates that the percentages of people who adopt healthy lifestyle behaviour (HLB) are disappointing. This study aimed to identify the level of adoption of HLB in Jordanian subjects and to compare the sociodemographic and self-reported clinical history based on the HLB adoption level. Cross-section descriptive study was conducted and Health Promotion Lifestyle Profile-II was used to reflect subjects' adoption of HLB. Through convenience sampling 260 subjects were enrolled; 50% had excess weight, 30% were current smokers, 53% had never had their cholesterol assessed. Findings revealed that subjects were not adopting HLB regularly. Women, married, educated, young subjects and having higher income subjects had higher HLB adoption level. Health-promotion programmes are urgently needed for this community and sociodemographic variables have to be considered throughout preparation, implementation and evaluation phases of such programmes. PMID- 21251152 TI - Living a meaningful life with chronic pain from a nursing perspective. Narrative approach to a case story. AB - This paper is a case story discussing the experience of chronic pain from the perspective of the sufferer and suggests ways of improving the use of this perspective in nursing care. A narrative approach is adopted and the analysis was based on content analysis. A condensation of meaning-units revealed a variation in subthemes: the body in pain, striving to preserve self and self-fulfilment. The extent to which living a meaningful life is possible seems to depend on several complex factors, including a person's belief system, life experiences, personal resources, the meaning of pain and the extent to which nurses understand the overall situation. This story might indicate that nociceptive pain can be less important than pain that reduces long-term life quality. A better understanding of living with chronic pain based on cognitive-behavioural techniques could be linked to the information drawn from the narrative and used to improve nursing practice. PMID- 21251153 TI - Healthy lifestyle behaviour in university students and influential factors in eastern Turkey. AB - This research was carried out to determine the healthy lifestyle behaviour of university students receiving education in central Erzincan. The population of this descriptive and cross-sectional research included a total of 4506 students receiving education at Erzincan University in the city centre, and the sampling included 981 students selected by a simple random sampling method from these schools. Data were collected between April and May 2008 by using an identification form and the Health Promotion Life-Style Profile (HPLP) Scale. Healthy lifestyle behaviour point averages of students were detected to be at medium level (118.41+/-20.90). It was established that student's grade, educational level of parents, economic status of the family and the student, the place where the student stays and smoking status of the student resulted in a significant difference in HPLP Scale total score average and the mean score of the majority of subscales. PMID- 21251154 TI - Conducting randomized controlled trials with older people with dementia in long term care: Challenges and lessons learnt. AB - The characteristics of older people with dementia and the long-term care environment can make conducting research a challenge and, as such, this population and setting are often understudied, particularly in terms of clinical or randomized controlled trials. This paper provides a critical discussion of some of the difficulties faced whilst implementing a randomized controlled trial exploring the effect of a live music programme on the behaviour of older people with dementia in long-term care. A discussion of how these challenges were addressed is presented to aid investigators planning the design of similar research and help encourage a proactive approach in dealing with research-related challenges right from project conception. The article is structured according to the three principles of a randomized controlled trial in order to keep experimental rigour at the forefront of this research area. PMID- 21251155 TI - Analysis of falls incidents: Nurse and patient preventive behaviours. AB - Nurses play an important role in preventing and managing falls in acute hospitals. We analysed 577 hospital falls incidents and found 77% unwitnessed and most resulted in no patient harm (85%). Further qualitative analysis of 40 incidents highlighted a high proportion of falls being related to transferring near the bed unit. Simple messages for nurses working in acute care settings are recommended including 'high risk activity (transferring, mobilizing) and high risk area (bed unit, toilet/bathroom) is a high risk situation'. A balanced approach emphasizing patient and family education and the use of alarm devices where supervision is not available are suggested. Postfall management by nurses might be contributing to the low occurrence of injury reported in these findings and requires further research. PMID- 21251156 TI - Evaluation of patient education provided by clinical nurses in Turkey. AB - The purpose of this study was to determine the practices of patient education provided by nurses in hospital clinics. The data were collected using a questionnaire form developed by the researcher in the light of relevant literature. The questionnaire form included questions to help determine descriptive characteristics of nurses and practices of patient education. Statistical analysis was performed using percentages. Most of the nurses (82.4%) did not define a certain place or time for patient education, almost all of the nurses (98.9%) did not record the education process, and patients' family/relatives were not included in the education (82.4%). The results of this study have shown that clinical nurses do not adequately implement the phases of patient education. During nursing education, nurses' knowledge and skills in patient education should be developed, and they should be made to fully internalize their educational role. PMID- 21251157 TI - A descriptive qualitative review of the barriers relating to breast-feeding counselling. AB - The purpose of this review was to describe barriers in breast-feeding counselling considering it from the viewpoint of health professionals. CINAHL, MEDLINE and Cochrane databases were searched from 1950 to 2008. In total, 40 scientific research articles in English, Swedish or Finnish related to breast-feeding counselling were included and analysed using thematic analysis. The quality of the studies was also assessed. The main barriers were deficits in knowledge, resources, counselling skills and the counsellor's negative attitude. Conflicting advice, lack of guidelines, sufficiency of counselling and perceiving of the personal education needs were examples of the indicated barriers. The most commonly described barriers in breast-feeding counselling were limitations in breast-feeding knowledge. Developing of the measurements to assess the barriers in breast-feeding counselling is needed. PMID- 21251158 TI - Anxiety and quality of recovery in day surgery: A questionnaire study using Hospital Anxiety and Depression Scale and Quality of Recovery Score. AB - The aims of this study were (i) to examine the association between preoperative and postoperative anxiety, and (ii) to examine the association between preoperative anxiety and postoperative recovery, following day surgery under general anaesthesia. Day surgery has become more commonplace owing to advances in pharmacology, anaesthetic and surgical techniques, as it has recognized benefits, such as lower costs and reduced incidence of infection. Recent years have seen increased complexity of day surgery undertaken on a broader range of patients, but with reduced pre-surgery contact with the hospital environment. These recent service changes might have had an effect on the preparation of patients for day surgery, and this in turn might have affected their postoperative recovery. This pilot study used survey methods to examine potential associations between preoperative and postoperative anxiety, and between preoperative anxiety and postoperative recovery. Data were collected in 2008 from a convenience sample of 54 day surgery patients. The instruments used were the Hospital Anxiety and Depression Scale (HADS) and the Quality of Recovery Score (QoR-40). There was a statistically significant relationship between preoperative and postoperative anxiety (chi(2) =11.899, d.f.=1, P=0.001). The T-test showed a statistically significant difference in the mean scores for QoR-40 score for gender, and for the postoperative anxiety and QoR-40. A relationship between preoperative anxiety and postoperative recovery was not shown. Although challenging to implement in view of restricted timescales, appraisal and revision of pre-assessment processes to incorporate an anxiety measurement tool, such as the HADS, should be considered. PMID- 21251159 TI - Swaziland rural maternal care: Ethnography of the interface of custom and biomedicine. AB - A retrospective ethnographic enquiry was used to examine the values and beliefs that underpin Swazi women's birth practices during pregnancy, labour, birth and the postnatal period. An unstructured interview guide was used to conduct 15 one to-one audio-taped interviews in the field. Results revealed that although Swazi women embraced modern biomedical practices, they also largely adhered to customary practices, including use of traditional model of causation of illness, and the use of traditional medicines during childbirth. Recommendations include parallel antenatal education, which gives credence to the customs within the context of scientific modernity. In addition, changes are needed to public health policy that allows parallel systems of care to be delivered within the context of community midwifery practice. PMID- 21251160 TI - SPA-1 controls the invasion and metastasis of human prostate cancer. AB - Recent studies suggest that SIPA1 encoding a Rap GTPase-activating protein SPA-1 is a candidate metastasis efficiency-modifying gene in human breast cancer. In this study, we investigated the expression and function of SPA-1 in human prostate cancer (CaP). Immunohistochemical studies of tumor specimens from CaP patients revealed a positive correlation of SPA-1 expression with disease progression and metastasis. The correlation was recapitulated in human CaP cell lines; LNCaP that rarely showed metastasis in SCID mice expressed an undetectable level of SPA-1, whereas highly metastatic PC3 showed abundant SPA-1 expression. Moreover, SIPA1 transduction in LNCaP caused prominent abdominal lymph node metastasis without affecting primary tumor size, whereas shRNA-mediated SIPA1 knockdown or expression of a dominant-active Rap1 mutant (Rap1V12) in PC3 suppressed metastasis. LNCaP transduced with SPA-1 (LNCaP/SPA-1) showed attenuated adhesion to the precoated extracellular matrices (ECM) including collagens and fibronectin, due to defective ECM-medicated Rap1 activation. In addition, LNCaP/SPA-1 showed a diminished level of nuclear Brd4, which is known to bind SPA-1, resulting in reduced expression of a series of ECM-related genes. These results suggest that SPA-1 plays an important role in controlling metastasis efficiency of human CaP by regulating the expression of and interaction with ECM in the primary sites. PMID- 21251161 TI - B7-H3 expression in gastric cancer: a novel molecular blood marker for detecting circulating tumor cells. AB - The clinical significance of B7-H3 expression in gastric cancer remains unclear, although the B7 ligand family plays a critical role in the T cell-mediated immune response. We therefore investigated B7-H3 expression as a blood marker of circulating tumor cells and determined correlations with tumor progression in patients with gastric cancer. B7-H3 expression in gastric cell lines was initially evaluated by immunocytochemistry. Furthermore, we used quantitative RT PCR to assess B7-H3 mRNA expression in four cell lines and in 95 blood specimens from patients with gastric cancer, as well as in 21 samples of peripheral blood lymphocytes from healthy volunteers. B7-H3 expression in cell lines was identified by immunocytochemistry and quantitative RT-PCR. Blood specimens from patients with gastric cancer contained significantly more copies of B7-H3 mRNA than those from healthy volunteers without cancer (P < 0.0001). Levels of B7-H3 expression significantly correlated with overall stage (P = 0.013). The 5-year survival rate was significantly lower in patients with high B7-H3 expression than with low expression (P = 0.02). Multivariate analysis demonstrated that B7-H3 expression was an independent prognostic factor (P = 0.046). Our results indicate that B7-H3 appears to be a useful blood marker for predicting tumor progression in gastric cancer. PMID- 21251162 TI - Prevalence and type distribution of human papillomavirus in healthy Japanese women aged 20 to 25 years old enrolled in a clinical study. AB - Efficacy, immunogenicity and tolerability of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine were evaluated in Japanese women aged 20-25 years, for which results have been reported previously. We analyzed the baseline data from that study and report the prevalence rates of HPV infection in young healthy Japanese women. One thousand and the forty Japanese women aged 20-25 years were enrolled in a phase II, double-blind, controlled, randomized, multicenter study. At study entry, cervical specimens were collected from the women and tested by line probe assay for 25 HPV-types and by HPV-16/18-specific polymerase chain reaction. The most frequently detected HPV-type in baseline cervical specimens was HPV-52 (8.1%), followed by HPV-16 (6.5%), HPV-51 (4.5%), HPV-18 (4.0%) and HPV-31 (3.8%). The proportion of HPV DNA-positive women increased with severity of cytological abnormalities: 26.1% (237/908) in normal cytology, 93.3% (70/75) in low-grade squamous intraepithelial lesion and 100% (7/7) in high-grade squamous intraepithelial lesion. The relative contribution of HPV-16 and HPV-18 was 4.1 and 3.0% for normal cytology cases, and 20.0 and 16.0% in low-grade squamous intraepithelial lesion, respectively. HPV-16 was found in four of seven high-grade squamous intraepithelial lesion cases (57.1%) and five of the six cervical intraepithelial neoplasia 2+ cases (83.3%). Multiple and single HPV infections were observed in 13.5% (140/1039) and 20.7% (215/1039) of all women, respectively. The HPV prevalence rates in Japanese women aged 20-25 years underline the importance of HPV vaccination at a young age and this report should be useful for monitoring changes in HPV prevalence after widespread HPV vaccination in Japanese women. PMID- 21251163 TI - APOE epsilon4 allele is associated with an increased risk of bulbar-onset amyotrophic lateral sclerosis in men. AB - OBJECTIVE: Several association studies have identified possible susceptibility factors for sporadic amyotrophic lateral sclerosis (SALS). Studies on the APOE gene provided conflicting results, especially about the effect on bulbar onset. We assessed the possible role of APOE gene in a large cohort of patients with ALS and matched controls. METHODS: The APOE alleles were determined in 1482 patients with SALS and 955 controls and analysed by univariate and multivariate statistics, taking into account gender, site-of-onset and age-at-onset. RESULTS: Patients with bulbar onset were more likely to be women [odds ratio (OR)=2.17; 95% CI: 1.74-2.72] and to be older (OR=3.47; 95% CI: 2.58-4.67). The epsilon4 carriers were more frequent in the bulbar-onset group than in the limb-onset group (OR=1.39 bulbar onset versus limb onset; 95% CI: 1.08-1.80) but this association was observed amongst men (OR=1.78; 95% CI: 1.25-2.53) and not women (OR=1.09; 95% CI: 0.75-1.59). CONCLUSION: Our study provides evidence for a contribution of the epsilon4 allele in the occurrence of bulbar-onset ALS amongst men. We propose that men are normally protected by androgens against bulbar onset and that the epsilon4 allele inhibits this protection, perhaps by interfering with the androgen pathway. PMID- 21251164 TI - Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. AB - The Keap1-Nrf2 regulatory pathway plays a central role in the protection of cells against oxidative and xenobiotic damage. Under unstressed conditions, Nrf2 is constantly ubiquitinated by the Cul3-Keap1 ubiquitin E3 ligase complex and rapidly degraded in proteasomes. Upon exposure to electrophilic and oxidative stresses, reactive cysteine residues of Keap1 become modified, leading to a decline in the E3 ligase activity, stabilization of Nrf2 and robust induction of a battery of cytoprotective genes. Biochemical and structural analyses have revealed that the intact Keap1 homodimer forms a cherry-bob structure in which one molecule of Nrf2 associates with two molecules of Keap1 by using two binding sites within the Neh2 domain of Nrf2. This two-site binding appears critical for Nrf2 ubiquitination. In many human cancers, missense mutations in KEAP1 and NRF2 genes have been identified. These mutations disrupt the Keap1-Nrf2 complex activity involved in ubiquitination and degradation of Nrf2 and result in constitutive activation of Nrf2. Elevated expression of Nrf2 target genes confers advantages in terms of stress resistance and cell proliferation in normal and cancer cells. Discovery and development of selective Nrf2 inhibitors should make a critical contribution to improved cancer therapy. PMID- 21251165 TI - Nuclear and cytoplasmic effects of human CRM1 on HIV-1 production in rat cells. AB - The human immunodeficiency virus type 1 (HIV-1) regulatory protein, Rev, mediates the nuclear export of unspliced gag and singly spliced env mRNAs by bridging viral RNA and the export receptor, CRM1. Recently, rat CRM1 was found to be less efficient than human CRM1 in supporting Rev function in rats. In this study, to understand the role of CRM1 in HIV propagation, the mechanism underlying the function of human and rat CRM1 in HIV-1 replication was investigated in rat cells. The production of viral particles, represented by the p24 Gag protein, was greatly enhanced by hCRM1 expression in rat cells; however, this effect was not simply because of the enhanced export of gag mRNA. The translation initiation rate of gag mRNA was not increased, nor was the Gag protein stabilized in the presence of hCRM1. However, the processing of the p55 Gag precursor and the release of viral particles were facilitated. These results indicated that hCRM1 exports gag mRNA to the cytoplasm, not only more efficiently than rCRM1 but also correctly, leading to efficient processing of Gag proteins and particle formation. PMID- 21251166 TI - Anal cancer. Position statement of the Association of Coloproctology of Great Britain and Ireland introduction. PMID- 21251167 TI - Guidelines for management of anal intraepithelial neoplasia. PMID- 21251168 TI - Anal cancer: pathology, staging and evidence-based minimum data set. PMID- 21251169 TI - Initial management through the anal cancer multidisciplinary team meeting. PMID- 21251170 TI - Staging and management of inguinal nodes. PMID- 21251171 TI - Chemoradiotherapy in anal cancer. PMID- 21251172 TI - Follow up. PMID- 21251173 TI - Management of local disease relapse. PMID- 21251174 TI - Potential beneficial properties of bacteriocin-producing lactic acid bacteria isolated from smoked salmon. AB - AIMS: To evaluate the probiotic properties of strains isolated from smoked salmon and previously identified as bacteriocin producers. METHODS AND RESULTS: Strains Lactobacillus curvatus ET06, ET30 and ET31, Lactobacillus fermentum ET35, Lactobacillus delbrueckii ET32, Pediococcus acidilactici ET34 and Enterococcus faecium ET05, ET12 and ET88 survived conditions simulating the gastrointestinal tract (GIT) and produced bacteriocins active against several strains of Listeria monocytogenes, but presented very low activity against other lactic acid bacteria (LAB). Cell-free supernatants containing bacteriocins, added to 3-h-old cultures of L. monocytogenes 603, suppressed growth over 12 h. Auto-aggregation was strain specific, and values ranged from 7.2% for ET35 to 12.1% for ET05. Various degrees of co-aggregation with L. monocytogenes 603, Lactobacillus sakei ATCC 15521 and Enterococcus faecalis ATCC 19443 were observed. Adherence of the bacteriocinogenic strains to Caco-2 cells was within the range reported for Lactobacillus rhamnosus GG, a well-known probiotic. The highest levels of hydrophobicity were recorded for Lact. curvatus (61.9-64.6%), Lact. fermentum (78.9%), Lact. delbrueckii (43.7%) and Ped. acidilactici (51.3%), which are higher than the one recorded for Lact. rhamnosus GG (53.3%). These strains were highly sensitive to several antibiotics and affected by several drugs from different generic groups in a strain-dependent manner. CONCLUSIONS: Smoked salmon is a rich source of probiotic LAB. All strains survived conditions simulating the GIT and produced bacteriocins active against various pathogens. Adherence to Caco 2 cells was within the range reported for Lact. rhamnosus GG, a well-known probiotic. In addition, the high hydrophobicity readings recorded define the strains as good probiotics. PMID- 21251175 TI - Spread of North American wind-dispersed trees in future environments. AB - Despite ample research, understanding plant spread and predicting their ability to track projected climate changes remain a formidable challenge to be confronted. We modelled the spread of North American wind-dispersed trees in current and future (c. 2060) conditions, accounting for variation in 10 key dispersal, demographic and environmental factors affecting population spread. Predicted spread rates vary substantially among 12 study species, primarily due to inter-specific variation in maturation age, fecundity and seed terminal velocity. Future spread is predicted to be faster if atmospheric CO(2) enrichment would increase fecundity and advance maturation, irrespective of the projected changes in mean surface windspeed. Yet, for only a few species, predicted wind driven spread will match future climate changes, conditioned on seed abscission occurring only in strong winds and environmental conditions favouring high survival of the farthest-dispersed seeds. Because such conditions are unlikely, North American wind-dispersed trees are expected to lag behind the projected climate range shift. PMID- 21251176 TI - Extracellular polymeric substances from Shewanella sp. HRCR-1 biofilms: characterization by infrared spectroscopy and proteomics. AB - The composition of extracellular polymeric substances (EPS) from Shewanella sp. HRCR-1 biofilms was investigated using infrared spectroscopy and proteomics to provide insight into potential ecophysiological functions and redox activity of the EPS. Both bound and loosely associated EPS were extracted from Shewanella sp. HRCR-1 biofilms prepared using a hollow-fibre membrane biofilm reactor. Fourier transform infrared spectra revealed the presence of proteins, polysaccharides, nucleic acids, membrane lipids and fatty acids in the EPS fractions. Using a global proteomic approach, a total of 58 extracellular and outer membrane proteins were identified in the EPS. These included homologues of multiple Shewanella oneidensis MR-1 proteins that potentially contribute to key physiological biofilm processes, such as biofilm-promoting protein BpfA, surface associated serine protease, nucleotidases (CpdB and UshA), an extracellular lipase, and oligopeptidases (PtrB and a M13 family oligopeptidase lipoprotein). In addition, 20 redox proteins were found in extracted EPS. Among the detected redox proteins were the homologues of two S. oneidensis MR-1 c-type cytochromes, MtrC and OmcA, which have been implicated in extracellular electron transfer. Given their detection in the EPS of Shewanella sp. HRCR-1 biofilms, c-type cytochromes may contribute to the possible redox activity of the biofilm matrix and play important roles in extracellular electron transfer reactions. PMID- 21251177 TI - Iron uptake and toxin synthesis in the bloom-forming Microcystis aeruginosa under iron limitation. AB - Toxin production during cyanobacterial blooms poses a significant public health threat in water bodies globally and requires the development of effective bloom management strategies. Previously, synthesis of the hepatotoxin microcystin has been proposed to be regulated by iron availability, but the contribution of the toxin to the adaptation of cyanobacteria to environmental stresses, such as changing light intensity and nutrient limitation, remains unclear. The aim of this study was to compare the iron stress response in toxic and non-toxic strains of Microcystis aeruginosa subjected to moderate and severe iron limitation. The transcription of a number of genes involved in iron uptake, oxidative stress response, toxin synthesis and transcriptional control of these processes was accessed by quantitative real-time PCR (qRT-PCR). The process of adaptation of M. aeruginosa to iron stress was found to be highly dynamic and strain-specific. Toxin production in PCC 7806 increased in an iron-dependent manner and appeared to be regulated by FurA. The inability to produce microcystin, either due to natural mutations in the mcy gene cluster or due to insertional inactivation of mcyH, affected the remodelling of the photosynthetic machinery in iron-stressed cells, the transport of Fe(II) and transcription of the Fur family of transcriptional regulators. The presence of the toxin appears to give an advantage to microcystin-producing cyanobacteria in the early stages of exposure to severe iron stress and may protect the cell from reactive oxygen species induced damage. PMID- 21251179 TI - LY2189265, a long-acting glucagon-like peptide-1 analogue, showed a dose dependent effect on insulin secretion in healthy subjects. AB - AIM: To assess the safety, tolerability, pharmacokinetics, pharmacodynamics and potential immunogenicity of single, escalating subcutaneous injections of a once weekly glucagon-like peptide-1 analogue in healthy subjects. METHODS: This phase 1, three-period, crossover, double-blind, placebo-controlled study investigated single, escalating subcutaneous doses of LY2189265 (LY) ranging from 0.1 to 12 mg; approximately six subjects were randomized to each dose. Parameters of safety, including adverse events, were assessed. The pharmacokinetic profile was assessed over 14 days. Pharmacodynamic parameters (glucose and insulin concentrations) were measured following a step-glucose infusion (day 3) and as part of an oral glucose tolerance test (OGTT) (day 5). RESULTS: LY was generally well tolerated with some increase in gastrointestinal symptoms with escalating doses. There were small dose-dependent increases in pulse rate with doses >=1.0 mg and diastolic blood pressure with doses >=3.0 mg. The half-life of LY was approximately 90 h, with C(max) occurring between 24 and 48 h in most subjects. Evidence of increase in glucose-dependent insulin secretion and suppression of serum glucose excursions were observed during an OGTT at all doses compared to placebo; no episodes of hypoglycaemia occurred. No subjects developed antibodies to LY2189265. CONCLUSIONS: LY showed an acceptable safety profile and exhibited the expected glucagon-like peptide-1 pharmacological effects on glucose suppression and insulin secretion with a half-life that supports once-weekly dosing. PMID- 21251178 TI - A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes. AB - AIM: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of LY2189265 (LY), a novel, long-acting glucagen-like peptide-1 analogue, administered once weekly to subjects with type 2 diabetes. METHODS: This was a placebo-controlled, parallel-group, subject- and investigator-blind study of LY in subjects (N = 43) with type 2 diabetes mellitus controlled with diet and exercise alone or with a single oral antidiabetic medication. Subjects taking metformin or thiazolidinediones continued on their therapy. Subjects receiving sulfonylurea, acarbose, repaglinide or nateglinide were switched to metformin prior to enrollment. Subjects received five once-weekly doses of 0.05, 0.3, 1, 3, 5 or 8 mg. Effects on glucose, insulin and C-peptide concentrations were determined during fasting and following standard test meals. The pharmacokinetics of LY and its effects on HBA1c, glucagon, body weight, gastric emptying and safety parameters were assessed. RESULTS: Once-weekly administration of LY significantly reduced (p < 0.01) fasting plasma glucose, 2-h post-test meal postprandial glucose and area under the curve (AUC) of glucose after test meals at doses >=1 mg. These effects were seen after the first dose and were sustained through the weekly dosing cycle. Most doses produced statistically significant increases in insulin and C-peptide AUC when normalized for glucose AUC. Statistically significant reductions in HBA1c were observed for all dose groups except 0.3 mg. The most commonly reported adverse effects (AEs) were nausea (35 events), headache (20 events), vomiting (18 events) and diarrhoea (8 events). CONCLUSIONS: LY showed improvement in fasting and postprandial glycaemic parameters when administered once weekly in subjects with type 2 diabetes. The pharmacokinetics and safety profiles also support further investigation of this novel agent. PMID- 21251180 TI - The effects of LY2189265, a long-acting glucagon-like peptide-1 analogue, in a randomized, placebo-controlled, double-blind study of overweight/obese patients with type 2 diabetes: the EGO study. AB - AIM: To evaluate the efficacy and tolerability of once-weekly LY2189265 (LY), a novel glucagon-like peptide-1 (GLP-1) IgG4-Fc fusion protein, in patients with type 2 diabetes failing oral antihyperglycaemic medications (OAMs). METHODS: Placebo-controlled, double-blind study in 262 patients (mean age 57 +/- 12 years; BMI 33.9 +/- 4.1 kg/m(2); and glycosylated haemoglobin A1c (A1c) 8.24 +/- 0.93%) receiving two OAMs. Patients were randomized to once-weekly subcutaneous injections of placebo or LY 0.5 mg for 4 weeks, then 1.0 mg for 12 weeks (LY 0.5/1.0); 1.0 mg for 16 weeks (LY 1.0/1.0); or 1.0 mg for 4 weeks, then 2.0 mg for 12 weeks (LY 1.0/2.0). RESULTS: At week 16, A1c changes (least-squares mean +/- standard error) were -0.24 +/- 0.12, -1.38 +/- 0.12, -1.32 +/- 0.12 and -1.59 +/- 0.12%, in the placebo, LY 0.5/1.0, LY 1.0/1.0 and LY 1.0/2.0 arms, respectively (all p < 0.001 vs. placebo). Both fasting (p < 0.001) and postprandial (p < 0.05) blood glucose decreased significantly compared to placebo at all LY doses. Weight loss was dose dependent and ranged from -1.34 +/- 0.39 to -2.55 +/- 0.40 kg at 16 weeks (all p < 0.05 vs. placebo). At the highest LY dosage, the most common adverse events were nausea (13.8%), diarrhoea (13.8%) and abdominal distension (13.8%). Hypoglycaemia was uncommon overall (<=0.8 episodes/patient/30 days) but more common with LY than placebo through the initial 4 weeks (p < 0.05). No differences in cardiovascular events or blood pressure were shown between treatments. CONCLUSIONS: LY2189265, given to overweight/obese patients with type 2 diabetes for 16 weeks in combination with OAMs, was relatively well tolerated and significantly reduced A1c, blood glucose and body weight. PMID- 21251181 TI - Management of resistant mucocutaneous herpes simplex infections in AIDS patients: a clinical and virological challenge. AB - BACKGROUND: The use of highly active antiretroviral therapy (HAART) has been associated with a marked decrease in the prevalence of opportunistic infections in HIV-infected patients. However, chronic mucocutaneous herpes simplex virus (HSV) infection remains a difficult clinical challenge. OBJECTIVE: The aim of the study was to optimize the diagnosis and follow-up of chronic HSV-2 infection in HIV-infected patients and to correlate clinical data with CD4 cell count, in vitro HSV virological resistance and histology. METHODS: A retrospective case series was collected from a specialist out-patient clinic providing consultations to patients with infectious skin diseases. Clinical, biological, virological and histological data were analysed. RESULTS: Seven HIV-infected patients with genital and perianal herpes simplex infection were followed over 10 years. Ulcerative and pseudo-tumoral forms were observed. Lesions occurred at various stages of immune suppression (CD4 counts from 1 to 449 cells/MUL). Clinical resistance to conventional anti-herpetic drugs was correlated with the in vitro resistance of HSV in 70% of cases. CONCLUSIONS: Chronic mucocutaneous HSV infection in AIDS patients remains a rare but regularly observed infection in very immunosuppressed patients or those with unstable immunity during HAART. Virological results obtained from mucocutaneous samples were in most cases found to be correlated with clinical evolution and should therefore be used in making decisions on treatment. Despite efficient antiviral therapy, mucocutaneous healing is slow in the majority of cases. PMID- 21251182 TI - Clinical relevance of cytomegalovirus viraemia(*,?). AB - BACKGROUND: Using new sensitive quantitative polymerase chain reaction (PCR) assays, cytomegalovirus (CMV) DNA is often detectable in the plasma of immunosuppressed patients. We investigated the prognostic value of a positive CMV DNA test for the development of CMV end-organ disease, other AIDS-defining events and mortality. METHODS: A survival analysis was performed, using the Kaplan-Meier method and Cox proportional hazards models, for patients prospectively followed in the Swiss HIV Cohort Study, from January 1996 to December 2007, who were CMV seropositive, had a CD4 count of <= 100 cells/MUL, and had a plasma sample available for the measurement of baseline CMV DNA with an ultrasensitive PCR. The outcome analysed was an AIDS-defining event, including CMV end-organ disease, or death. Variables analysed at the time of CMV measurement were demographic variables, CD4 cell counts, HIV-1 RNA loads, and use and type of highly active antiretroviral therapy (HAART). RESULTS: Of 1128 patients, 208 (18%) presented an AIDS-defining event and 246 (22%) died. A total of 368 patients (34% of samples) had detectable CMV DNA at baseline, with DNA concentrations of up to 38 800 copies/mL. In the multivariate analysis, CMV DNA predicted evolution not only towards CMV end-organ disease [hazard ratio (HR) 12.6; 95% confidence interval (CI) 4.27-37.41], but also towards other AIDS-defining events (HR 2.6; 95% CI 1.60-4.33) and death (HR 1.9; 95% CI 1.10-3.34). CONCLUSION: Quantitative CMV DNA detected in the plasma of HIV-infected patients with CD4 counts <= 100 cells/MUL is a predictor for HIV disease progression, CMV disease and death. A single low value of 80 copies/mL identifies patients at low but significantly increased risk during the following months, after the measurement. PMID- 21251183 TI - Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the D:A:D study(*). AB - OBJECTIVES: The aim of the study was to estimate the rates of cardiovascular disease (CVD) events after stopping smoking in patients with HIV infection. METHODS: Patients who reported smoking status and no previous CVD prior to enrolment in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study were included in this study. Smoking status is collected at each visit as current smoker (yes/no) and ever smoker (yes/no). Time since stopping smoking was calculated for persons who had reported current smoking during follow-up and no current smoking subsequently. Endpoints were: myocardial infarction (MI); coronary heart disease (CHD: MI plus invasive coronary artery procedure or death from other CHD); CVD (CHD plus carotid artery endarterectomy or stroke); and all cause mortality. Event rates were calculated for never, previous and current smokers, and smokers who stopped during follow-up. Incidence rate ratios (IRRs) were determined using Poisson regression adjusted for age, sex, cohort, calendar year, family history of CVD, diabetes, lipids, blood pressure and antiretroviral treatment. RESULTS: A total of 27 136 patients had smoking status reported, with totals of 432, 600, 746 and 1902 MI, CHD, CVD and mortality events, respectively. The adjusted IRR of CVD in patients who stopped smoking during follow-up decreased from 2.32 within the first year of stopping to 1.49 after >3 years compared with those who never smoked. Similar trends were observed for the MI and CHD endpoints. Reductions in risk were less pronounced for all-cause mortality. CONCLUSION: The risk of CVD events in HIV-positive patients decreased with increasing time since stopping smoking. Smoking cessation efforts should be a priority in the management of HIV-positive patients. PMID- 21251184 TI - Use of neonatal post-exposure prophylaxis for prevention of mother-to-child HIV transmission in the UK and Ireland, 2001-2008. AB - OBJECTIVES: To investigate changing clinical practice with regard to antiretroviral post-exposure prophylaxis (PEP) and factors associated with the use of combination prophylaxis in infants born to HIV-infected women in the UK and Ireland. METHODS: Surveillance of obstetric and paediatric HIV infection in the UK and Ireland is conducted through the National Study of HIV in Pregnancy and Childhood. Infants born to HIV-infected women between 2001 and 2008 were included in the study. RESULTS: Ninety-nine per cent of infants (8155 of 8205) received antiretroviral prophylaxis; 86% of those with information on type of prophylaxis (n=8050) received single, 3% dual and 11% triple drug prophylaxis. Among those who received prophylaxis, use of triple prophylaxis increased significantly between 2001-2004 and 2005-2008, from 9% (297 of 3243) to 13% (624 of 4807) overall (P<0.001); from 43% (41 of 95) to 71% (45 of 63) in infants born to untreated women; and from 13% (114 of 883) to 32% (344 of 1088) where mothers were viraemic despite highly active antiretroviral therapy (HAART) in pregnancy. In multivariable analysis, factors associated with receipt of triple prophylaxis included later time period, shorter duration or lack of antenatal antiretroviral therapy, receipt of antiretroviral drugs during labour, detectable maternal viral load, CD4 count<200 cells/MUL in pregnancy, preterm delivery (<37 weeks) and unplanned (emergency caesarean or vaginal) delivery. CONCLUSION: Between 2001 and 2008, almost all infants born to HIV-infected women in the UK and Ireland received antiretroviral PEP, mostly with one drug. Use of triple PEP increased over time, particularly for infants whose mothers were untreated or viraemic despite HAART, in line with current guidelines. PMID- 21251185 TI - A study of fatty acid binding protein 4 in HIV-1 infection and in combination antiretroviral therapy-related metabolic disturbances and lipodystrophy. AB - OBJECTIVE: The aim of the study was to determine circulating levels of fatty acid binding protein 4 (FABP-4) in a cohort of HIV-1-infected patients treated with combination antiretroviral therapy (cART) and to investigate the relationships between FABP-4 levels and insulin resistance, dyslipidaemia, lipodystrophy and levels of proinflammatory adipocytokines in these patients. METHODS: A total of 282 HIV-1-infected patients treated with stable cART for at least 1 year (132 with lipodystrophy and 150 without) and 185 uninfected controls (UCs) were included in the study. Anthropometric parameters were determined. Plasma levels of FABP-4, soluble tumour necrosis factor receptors 1 and 2 (sTNF-R1 and sTNF R2), interleukin-18 (IL-18), IL-6, adiponectin and leptin were also analysed. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR). Subcutaneous adipose tissue mRNA expression of proinflammatory cytokines was assessed in 38 patients (25 with lipodystrophy and 13 without) by real-time polymerase chain reaction (PCR). RESULTS: The plasma FABP-4 concentration was significantly higher in patients with lipodystrophy than in those without (P=0.012). FABP-4 concentration was positively correlated with body mass index (BMI), HOMA-IR, and the concentrations of insulin, total cholesterol, triglycerides, sTNF-R1, leptin and IL-18, but showed a negative correlation with high-density lipoprotein (HDL) cholesterol and adiponectin concentrations. After adjusting for age, sex and BMI, the odds ratio (OR) for risk of lipodystrophy was found to be significantly increased for those with the highest levels of FABP-4 [OR 0.838, 95% confidence interval (CI) 0.435-1.616 for medium FABP-4 vs. OR 2.281, 95% CI 1.163-4.475 for high FABP-4]. In a stepwise regression model, FABP-4 was independently associated with HOMA-IR after controlling for clinical and inflammatory parameters (P=0.004). Moreover, a positive relationship was observed in patients with lipodystrophy between subcutaneous adipose tissue CD68 expression and FABP-4 plasma levels (r=0.525; P=0.031). CONCLUSIONS: cART-treated HIV-1-infected patients with lipodystrophy have a systemic overproduction of FABP-4, which is closely linked to insulin resistance and inflammatory markers in subcutaneous adipose tissue. PMID- 21251187 TI - Safety and efficacy of ultrasonography as an adjunct to fluoroscopy for renal access in percutaneous nephrolithotomy (PCNL). AB - OBJECTIVE: * To evaluate the safety and efficacy of ultrasonography (US)-guided renal access in percutaneous nephrolithotomy (PCNL), as compared with conventional fluoroscopy-guided renal access in a prospective randomized trial. PATIENTS AND METHODS: * From January 2008 to October 2009, 224 patients with renal calculi undergoing PCNL were randomized into two groups. * Group 1 (112 patients) underwent PCNL using only fluoroscopy-guided renal access; while in group 2 (112 patients), US guidance for puncture was used in addition to fluoroscopy. * The inclusion criteria were: normal renal functions, American Society of Anesthesiology scores 1 or 2, absence of congenital abnormalities, aged 15-70 years, and anticipated single-tract procedure. The patients in both groups were matched for age, sex, and stone characteristics. * The Student t-test was used for statistical analysis with an allowable error of 5%. RESULTS: * The mean time to successful puncture was 3.2 min and 1.8 min in group 1 and group 2, respectively (P < 0.01). * The mean duration of radiation exposure to successful puncture was 28.6 s in group 1 and 14.4 s in group 2 (P < 0.01). * The mean numbers of attempts for successful puncture in the desired calyx was 3.3 in group 1 as compared with 1.5 in group 2 (P < 0.01). * The meantime taken for tract formation in group 1 was 7.4 min with radiation exposure of 82 s, while in group 2 it took 4.8 min with radiation exposure of 58 s (P < 0.01). * Successful access was achieved in all patients. All patients were stone-free at the end of the operation. The hospital stay (2-3 days) was same in both groups. There was no incidence of significant bleeding requiring transfusion during or after surgery. All the patients were followed-up for a >= 6 months. CONCLUSION: * US-guided puncture in PCNL helps in increasing accuracy of puncture and decreasing radiation exposure for the surgical team and the patients. PMID- 21251186 TI - Fatty liver disease is associated with underlying cardiovascular disease in HIV infected persons(*). AB - BACKGROUND: Cardiovascular disease is an increasing concern among HIV-infected persons and their providers. We determined if fatty liver disease is a marker for underlying coronary atherosclerosis among HIV-infected persons. METHODS: We performed a cross-sectional study in HIV-infected adults to evaluate the prevalence of and factors, including fatty liver disease, associated with subclinical coronary atherosclerosis. All participants underwent computed tomography for determination of coronary artery calcium (CAC; positive defined as a score >0) and fatty liver disease (defined as a liver-to-spleen ratio <1.0). Factors associated with CAC were determined using multivariate logistic regression models. RESULTS: We included in the study 223 HIV-infected adults with a median age of 43 years [interquartile range (IQR) 36-50 years]; 96% were male and 49% were Caucasian. The median CD4 count was 586 cells/MUL and 83% were receiving antiretroviral medications. Seventy-five (34%) had a positive CAC score and 29 (13%) subjects had fatty liver disease. Among those with CAC scores of 0, 1-100 and >100, the percentage with concurrent fatty liver disease was 8, 18 and 41%, respectively (P=0.001). In the multivariate model, CAC was associated with increasing age [odds ratio (OR) 4.3 per 10 years; P<0.01], hypertension (OR 2.6; P<0.01) and fatty liver disease (OR 3.8; P<0.01). CONCLUSIONS: Coronary atherosclerosis as detected using CAC is prevalent among young HIV-infected persons. The detection of fatty liver disease among HIV-infected adults should prompt consideration of assessment for underlying cardiovascular disease and risk factor reduction. PMID- 21251188 TI - Adverse events from targeted therapies in advanced renal cell carcinoma: the impact on long-term use. AB - What's known on the subject? and What does the study add? The side-effect of targeted agents is known. The clinician should be aware of the side-effects of targeted agents and how to prevent/diminish them, particularly in sequential and combination therapies. The aim of this review is to help physicians tailor targeted treatments for advanced renal cell carcinoma to suit patient needs and ensure maximum overall duration of response to therapy by providing a summary of the frequency and time of onset of adverse events (AEs) and by raising awareness of AE profiles. A PubMed literature search was performed, and papers on targeted therapy-related AEs were reviewed. The frequency, severity and management of targeted therapy-related AEs are discussed. Manageable AEs commonly reported with all the approved targeted agents include: fatigue, gastrointestinal disorders (diarrhoea, nausea, vomiting), hypertension, skin and subcutaneous tissue disorders. Life-threatening AEs are less common than manageable AEs and are usually class specific. Data suggest that long-term treatment with well established targeted agents does not result in increased or unexpected AEs. Caution is required with regard to the long-term use of newer targeted agents for which there are no long-term tolerability data or clinical experience. Studies have reported that the type and frequency of observed AEs associated with sequential tyrosine kinase inhibitor (TKI) use are similar to those reported in the literature for TKI monotherapy. Having an awareness of the AE profiles of targeted agents allows the development of effective management strategies. Generally, more extensive clinical experience has accumulated, and AE profiles are more predictable, for well-established targeted agents. PMID- 21251189 TI - Biology of the sauropod dinosaurs: the evolution of gigantism. AB - The herbivorous sauropod dinosaurs of the Jurassic and Cretaceous periods were the largest terrestrial animals ever, surpassing the largest herbivorous mammals by an order of magnitude in body mass. Several evolutionary lineages among Sauropoda produced giants with body masses in excess of 50 metric tonnes by conservative estimates. With body mass increase driven by the selective advantages of large body size, animal lineages will increase in body size until they reach the limit determined by the interplay of bauplan, biology, and resource availability. There is no evidence, however, that resource availability and global physicochemical parameters were different enough in the Mesozoic to have led to sauropod gigantism. We review the biology of sauropod dinosaurs in detail and posit that sauropod gigantism was made possible by a specific combination of plesiomorphic characters (phylogenetic heritage) and evolutionary innovations at different levels which triggered a remarkable evolutionary cascade. Of these key innovations, the most important probably was the very long neck, the most conspicuous feature of the sauropod bauplan. Compared to other herbivores, the long neck allowed more efficient food uptake than in other large herbivores by covering a much larger feeding envelope and making food accessible that was out of the reach of other herbivores. Sauropods thus must have been able to take up more energy from their environment than other herbivores. The long neck, in turn, could only evolve because of the small head and the extensive pneumatization of the sauropod axial skeleton, lightening the neck. The small head was possible because food was ingested without mastication. Both mastication and a gastric mill would have limited food uptake rate. Scaling relationships between gastrointestinal tract size and basal metabolic rate (BMR) suggest that sauropods compensated for the lack of particle reduction with long retention times, even at high uptake rates. The extensive pneumatization of the axial skeleton resulted from the evolution of an avian-style respiratory system, presumably at the base of Saurischia. An avian-style respiratory system would also have lowered the cost of breathing, reduced specific gravity, and may have been important in removing excess body heat. Another crucial innovation inherited from basal dinosaurs was a high BMR. This is required for fueling the high growth rate necessary for a multi-tonne animal to survive to reproductive maturity. The retention of the plesiomorphic oviparous mode of reproduction appears to have been critical as well, allowing much faster population recovery than in megaherbivore mammals. Sauropods produced numerous but small offspring each season while land mammals show a negative correlation of reproductive output to body size. This permitted lower population densities in sauropods than in megaherbivore mammals but larger individuals. Our work on sauropod dinosaurs thus informs us about evolutionary limits to body size in other groups of herbivorous terrestrial tetrapods. Ectothermic reptiles are strongly limited by their low BMR, remaining small. Mammals are limited by their extensive mastication and their vivipary, while ornithsichian dinosaurs were only limited by their extensive mastication, having greater average body sizes than mammals. PMID- 21251191 TI - Use of the BioHoleTM device for the creation of tunnel tracks for buttonhole cannulation of fistula for hemodialysis. AB - Buttonhole cannulation is a method of cannulation of native arteriovenous fistulae traditionally practiced by self-cannulators. At St Michael's Hospital, this method has been modified to allow its use in problematic fistulae by multiple cannulators. In a busy dialysis unit, the need for a few specific cannulators to establish the tunnel tracks in combination with the variable dialysis schedules creates logistical challenges. A new method of creating tunnel tracks with the use of the BioHoleTM device was evaluated. Buttonhole tracks were created in 12 patients using a peg of polycarbonated material with a holder (BioHoleTM kit). The peg was inserted into the path left by the hemodialysis sharp needle following the index cannulation. Four of the 12 patients had an alternate access. Buttonhole tracks were successfully created in all the patients, albeit in 2 patients, the initial attempt to establish buttonhole tracks was aborted due to complications and the procedure was rescheduled. Compared with the modified buttonhole technique, pain on cannulation following track creation was significantly less in the BioHoleTM group (P < 0.001). Ease of cannulation was significantly improved in the BioHoleTM group (P<0.05) when compared with that in thrice-weekly patients using the modified buttonhole technique. Hemostasis postdialysis did not differ between the study groups. The use of the BioHoleTM device is effective in the creation of tunnel tracks for buttonhole cannulation, is associated with less pain, and simplifies the logistics of arranging patient and nurses' schedules. PMID- 21251192 TI - Fifty per cent of patients with pulmonary embolism can be treated as outpatients. PMID- 21251193 TI - The expanding menagerie: animal models of hemophilia A. PMID- 21251190 TI - The vaginal microbiome: new information about genital tract flora using molecular based techniques. AB - Vaginal microbiome studies provide information that may change the way we define vaginal flora. Normal flora appears dominated by one or two species of Lactobacillus. Significant numbers of healthy women lack appreciable numbers of vaginal lactobacilli. Bacterial vaginosis (BV) is not a single entity, but instead consists of different bacterial communities or profiles of greater microbial diversity than is evident from cultivation-dependent studies. BV should be considered a syndrome of variable composition that results in different symptoms, phenotypical outcomes, and responses to different antibiotic regimens. This information may help to elucidate the link between BV and infection-related adverse outcomes of pregnancy. PMID- 21251194 TI - Go6976 abrogates GPVI-mediated platelet functional responses in human platelets through inhibition of Syk. PMID- 21251195 TI - Efficient phagocytosis of periodontopathogens by neutrophils requires plasma factors, platelets and TLR2. AB - BACKGROUND: Periodontitis represents a chronic infection of supportive dental tissues by distinct gram-negative bacteria. It is characterized by chronic and local inflammation as well as transient bacteremia with frequently occurring infections at distant sites. OBJECTIVES: The present work aimed to clarify the role of platelets and plasma factors in neutrophil interactions with the periodontopathogens A. actinomycetemcomitans and P. gingivalis. METHODS: Phagocytosis, cell-cell interactions and activation of platelets and neutrophils in response to periodontopathogens were analyzed by flow cytometry, confocal microscopy and bacteria survival assay. Plasma factors, platelet signaling pathways and receptors involved in platelet-neutrophil-bacteria interactions were determined. The role of platelet and neutrophil TLR2 in phagocytosis was further evaluated in a murine TLR2 knockout model. RESULTS: In the presence of plasma neutrophil-mediated clearance of periodontopathogens is doubled due to opsonisation of bacteria. Platelets, which become activated by periodontopathogens, further enhance clearance of bacteria by 20%, via direct interaction with neutrophils. Plasma factors (e.g. CD14) are required for platelet activation, which is mainly TLR2 dependent and results in PI3K/Akt activation. In a murine TLR2 knockout model we prove that platelet TLR2 is important for formation of platelet-neutrophil aggregates and enhanced phagocytosis of periodontopathogens. In contrast, neutrophil TLR2 is not involved in platelet-neutrophil aggregate formation but is required for efficient phagocytosis. CONCLUSIONS: These data indicate that efficient elimination of periodontopathogens by neutrophils involves a complex interplay of plasma factors as well as platelets and requires functional TLR2. By enhancing neutrophil activation platelets contribute to immune defense but may also foster inflammation. PMID- 21251196 TI - Release of sphingosine-1-phosphate from human platelets is dependent on thromboxane formation. AB - BACKGROUND: Platelets release the immune-modulating lipid sphingosine-1-phosphate (S1P). However, the mechanisms of platelet S1P secretion are not fully understood. OBJECTIVES: The present study investigates the function of thromboxane (TX) for platelet S1P secretion during platelet activation and the consequences for monocyte chemotaxis. METHODS: S1P was detected using thin-layer chromatography in [(3)H]sphingosine-labeled platelets and by mass spectrometry. Monocyte migration was measured in modified Boyden chamber chemotaxis assays. RESULTS: Release of S1P from platelets was stimulated with protease-activated receptor-1-activating peptide (PAR-1-AP, 100 MUM). Acetylsalicylic acid (ASA) and two structurally unrelated reversible cyclooxygenase inhibitors diclofenac and ibuprofen suppressed S1P release. Oral ASA (500-mg single dose or 100 mg over 3 days) attenuated S1P release from platelets in healthy human volunteers ex vivo. This was paralleled by inhibition of TX formation. S1P release was increased by the TX receptor (TP) agonist U-46619, and inhibited by the TP antagonist ramatroban and by inhibitors of ABC-transport. Furthermore, thrombin-induced release of S1P was attenuated in platelets from TP-deficient mice. Supernatants from PAR-1-AP-stimulated human platelets increased the chemotactic capacity of human peripheral monocytes in a S1P-dependent manner via S1P receptors-1 and -3. These effects were inhibited by ASA-pretreatment of platelets. CONCLUSIONS: TX synthesis and TP activation mediate S1P release after thrombin receptor activation. Inhibition of this pathway may contribute to the anti-inflammatory actions of ASA, for example by affecting activity of monocytes at sites of vascular injury. PMID- 21251198 TI - Protein C inhibitor inhibits factor VIIa when bound to tissue factor. PMID- 21251197 TI - Enhancement of fibrinolysis by inhibiting enzymatic cleavage of precursor alpha2 antiplasmin. AB - BACKGROUND AND OBJECTIVE: Resistance of thrombi to plasmin digestion depends primarily on the amount of alpha(2)-antiplasmin (alpha(2)AP) incorporated within fibrin. Circulating prolyl-specific serine proteinase, antiplasmin-cleaving enzyme (APCE), a homologue of fibroblast activation protein (FAP), cleaves precursor Met-alpha(2)AP between -Pro12-Asn13- to yield Asn-alpha(2)AP, which is crosslinked to fibrin approximately 13* more rapidly than Met-alpha(2)AP and confers resistance to plasmin. We reasoned that an APCE inhibitor might decrease conversion of Met-alpha(2)AP to Asn-alpha(2)AP and thereby enhance endogenous fibrinolysis. METHODS AND RESULTS: We designed and synthesized several APCE inhibitors and assessed each vs. plasma dipeptidyl peptidase IV (DPPIV) and prolyl oligopeptidase (POP), which have amino acid sequence similarity with APCE. Acetyl-Arg-(8-amino-3,6-dioxaoctanoic acid)-D-Ala-L-boroPro selectively inhibited APCE vs. DPPIV, with an apparent K(i) of 5.7 nm vs. 6.1 MUm, indicating that an approximately 1000-fold greater inhibitor concentration is required for DPPIV than for APCE. An apparent K(i) of 7.4 nm was found for POP inhibition, which is similar to 5.7 nm for APCE; however, the potential problem of overlapping FAP/APCE and POP inhibition was negated by our finding that normal human plasma lacks POP activity. The inhibitor construct caused a dose-dependent decrease of APCE-mediated Met-alpha(2)AP cleavage, which ultimately shortened plasminogen activator-induced plasma clot lysis times. Incubation of the inhibitor with human plasma for 22 h did not lessen its APCE inhibitory activity, with its IC(50) value in plasma remaining comparable to that in phosphate buffer. CONCLUSION: These data establish that inhibition of APCE might represent a therapeutic approach for enhancing thrombolytic activity. PMID- 21251199 TI - Anti-beta2glycoprotein I antibodies from leprosy patients do not show thrombogenic effects in an in vivo animal model. PMID- 21251200 TI - Association between atopic diseases and venous thromboembolism: a case-control study in patients aged 45 years or less. PMID- 21251201 TI - Endogenous protein C inhibits activation of coagulation and transiently lowers bacterial outgrowth in murine Escherichia coli peritonitis. PMID- 21251202 TI - Bortezomib delays the onset of factor VIII inhibitors in experimental hemophilia A, but fails to eliminate established anti-factor VIII IgG-producing cells. AB - BACKGROUND: Replacement therapy with exogenous factor VIII to treat hemorrhages induces inhibitory anti-FVIII antibodies in up to 30% of patients with hemophilia A. Current approaches to eradicate FVIII inhibitors using high-dose FVIII injection protocols (immune tolerance induction) or anti-CD20 depleting antibodies (Rituximab) demonstrate limited efficacy; they are extremely expensive and/or require stringent compliance from the patients. OBJECTIVES: To investigate whether the proteasome inhibitor bortezomib, which depletes plasmocytes, modulates the anti-FVIII immune response in FVIII-deficient mice. METHODS AND RESULTS: Preventive 4-week treatment of naive mice with bortezomib at the time of FVIII administration delayed the development of inhibitory anti-FVIII IgG, and depleted plasma cells as well as different lymphoid cell subsets. Conversely, curative treatment of inhibitor-positive mice for 10 weeks, along with FVIII administration, failed to eradicate FVIII inhibitors to extents that would be clinically relevant if achieved in patients. Accordingly, bortezomib did not eradicate anti-FVIII IgG-secreting plasmocytes that had homed to survival niches in the bone marrow, despite significant elimination of total plasma cells. CONCLUSIONS: The data suggest that strategies for the efficient reduction of anti FVIII IgG titers in patients with hemophilia A should rely on competition for survival niches for plasmocytes in the bone marrow rather than the mere use of proteasome inhibitors. PMID- 21251203 TI - Increased tissue factor expression in diabetes mellitus type 2 monocytes caused by insulin resistance. PMID- 21251204 TI - T-cell responses in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site. AB - BACKGROUND: Development of neutralizing anti-factor (F)VIII antibodies ('inhibitors') is a serious clinical problem in hemophilia A. Increased inhibitor risk has been associated with certain FVIII missense substitutions, including R593C in the A2 domain. OBJECTIVES: The aim of the present study was to identify T-cell epitopes in FVIII and characterize T-cell responses in two unrelated hemophilia A subjects sharing F8-R593C and HLA-DRB1*1101 genotypes. We hypothesized that the hemophilic substitution site coincides with an important T cell epitope. PATIENTS/METHODS: The binding affinities of peptides for recombinant HLA-DR proteins were measured and compared with epitope prediction results. CD4+ T cells were stimulated using peptides and stained with fluorescent, peptide-loaded tetramers. RESULTS: The inhibitor subjects, but not HLA-matched controls, had high-avidity HLA-DRB1*1101-restricted T-cell responses against FVIII(589-608), which contains the hemophilic missense site. Antigen specific T cells secreted Th1 and Th2 cytokines and proliferated in response to FVIII and FVIII(592-603). FVIII(589-608) bound with physiologically relevant (micromolar) IC(50) values to recombinant DR0101, DR1101 and DR1501 proteins. CONCLUSIONS: Hemophilia A patients with R593C missense substitutions and these HLA haplotypes had an increased incidence of inhibitors in our cohorts, supporting a paradigm in which presentation of FVIII epitopes containing the wild type R593 influences inhibitor risk in this hemophilia A sub-population. PMID- 21251206 TI - The study of the effect of splicing mutations in von Willebrand factor using RNA isolated from patients' platelets and leukocytes. AB - BACKGROUND: In von Willebrand factor (VWF) the effect of mutations potentially affecting mRNA processing or splicing is less predictable than that of other mutations (e.g. nonsense or missense substitutions). Bioinformatic tools can provide a valuable means to determine the consequences of potential splice site mutations (PSSM), but functional studies are mandatory to elucidate the true effect of the variation detected. OBJECTIVES, PATIENTS AND METHODS: After identification of PSSM in VWD patients, we began a systematic study of their in vivo effect in RNA extracted from the patients' platelets and leukocytes. RESULTS AND CONCLUSIONS: Thirteen pairs of primers were designed for full amplification of VWF mRNA by RT-PCR that, after sequencing of aberrant products, enabled elucidation of the PSSM consequences for mRNA processing. This procedure was used to study seven different PSSM identified in four patients demonstrating diverse molecular mechanisms such as exon skipping (c.533-2A>G and c.8155+3G>C) and the activation of a cryptic splice site (c.7730-1G>C). No visible effect was evident for c.1533+15G>A and c.5170+10C>T and the consequence of c.[546G>A;7082-2A>G] was hidden by nonsense-mediated mRNA decay (NMD). Results were compared with in silico predictions of four splice-site analysis tools. We demonstrate selective degradation of VWF mRNA bearing PSSM by NMD for several mutations, which suggests that NMD represents a general mechanism for truncating mutations in VWF. Furthermore, because NMD efficiency varies between cell types, use of RNA from both platelets and leukocytes for in vivo study of VWF PSSM offers complementary results, particularly in cases in which NMD occurs in the allele carrying the mutation. PMID- 21251207 TI - Factor V Leiden pseudo-homozygotes have a more pronounced hypercoagulable state than factor V Leiden homozygotes. PMID- 21251205 TI - Hindered dissolution of fibrin formed under mechanical stress. AB - BACKGROUND: Recent data indicate that stretching forces cause a dramatic decrease in clot volume accompanied by gross conformational changes of fibrin structure. OBJECTIVE: The present study attempts to characterize the lytic susceptibility of fibrin exposed to mechanical stress as a model for fibrin structures observed in vivo. METHODS AND RESULTS: The relevance of stretched fibrin models was substantiated by scanning electron microscopic (SEM) evaluation of human thrombi removed during surgery, where surface fibrin fibers were observed to be oriented in the direction of shear forces, whereas interior fibers formed a random spatial meshwork. These structural variations were modeled in vitro with fibrin exposed to adjustable mechanical stress. After two- and three-fold longitudinal stretching (2 * S, 3 * S) the median fiber diameter and pore area in SEM images of fibrin decreased two- to three-fold. Application of tissue plasminogen activator (tPA) to the surface of model clots, which contained plasminogen, resulted in plasmin generation which was measured in the fluid phase. After 30 min activation 12.6 +/- 0.46 pmol mm(-2) plasmin was released from the non stretched clot (NS), 5.5 +/- 1.11 pmol mm(-2) from 2 * S and 2.3 +/- 0.36 pmol mm(-2) from 3 * S clot and this hampered plasmin generation was accompanied by decreased release of fibrin degradation products from stretched fibrins. Confocal microscopic images showed that a green fluorescent protein-fusion variant of tPA accumulated in the superficial layer of NS, but not in stretched fibrin. CONCLUSION: Mechanical stress confers proteolytic resistance to fibrin, which is a result of impaired plasminogen activation coupled to lower plasmin sensitivity of the denser fibrin network. PMID- 21251208 TI - Ribosomal DNA sequence polymorphism and the delineation of two ascosporic yeast species: Metschnikowia agaves and Starmerella bombicola. AB - The relationship between mating success and sequence divergence in the internal transcribed spacer (ITS)/5.8S-D1/D2 rDNA region was examined in isolates tentatively assigned to Metschnikowia agaves and Starmerella bombicola. Both species are haplontic and heterothallic, such that the formation of mature asci can be used as a measure of genetic compatibility. Parsimony haplotype network analysis and mating success confirmed that all known isolates of M. agaves are conspecific. The previously reported D1/D2 polymorphism of five substitutions was not corroborated; the maximum divergence observed between any two strains was three substitutions, four with ITS. Of 39 putative S. bombicola strains, 36 formed an ITS-D1/D2 haplotype network using the 95% criterion. Thirty-five strains could mate with one or more compatible partner. The excluded strains did not mate. Mature asci arose from crosses between individuals differing by as many as five, but not six or seven substitutions in the D1/D2 domain. All strains capable of mating formed mature asci with at least one partner and all network members could be linked to another member by three or fewer substitutions. These results support the use of sequence divergence as a criterion for species delineation, but caution against describing poorly sampled species solely on the basis of that criterion. PMID- 21251209 TI - Batch and continuous culture-based selection strategies for acetic acid tolerance in xylose-fermenting Saccharomyces cerevisiae. AB - Acetic acid tolerance of Saccharomyces cerevisiae is crucial for the production of bioethanol and other bulk chemicals from lignocellulosic plant-biomass hydrolysates, especially at a low pH. This study explores two evolutionary engineering strategies for the improvement of acetic acid tolerance of the xylose fermenting S. cerevisiae RWB218, whose anaerobic growth on xylose at pH 4 is inhibited at acetic acid concentrations >1 g L(-1) : (1) sequential anaerobic, batch cultivation (pH 4) at increasing acetic acid concentrations and (2) prolonged anaerobic continuous cultivation without pH control, in which acidification by ammonium assimilation generates selective pressure for acetic acid tolerance. After c. 400 generations, the sequential-batch and continuous selection cultures grew on xylose at pH<=4 with 6 and 5 g L(-1) acetic acid, respectively. In the continuous cultures, the specific xylose-consumption rate had increased by 75% to 1.7 g xylose g(-1) biomass h(-1) . After storage of samples from both selection experiments at -80 degrees C and cultivation without acetic acid, they failed to grow on xylose at pH 4 in the presence of 5 g L(-1) acetic acid. Characterization in chemostat cultures with linear acetic acid gradients demonstrated an acetate-inducible acetic acid tolerance in samples from the continuous selection protocol. PMID- 21251210 TI - Identification of protein targets underlying dietary nitrate-induced protection against doxorubicin cardiotoxicity. AB - We recently demonstrated protective effect of chronic oral nitrate supplementation against cardiomyopathy caused by doxorubicin (DOX), a highly effective anticancer drug. The present study was designed to identify novel protein targets related to nitrate-induced cardioprotection. Adult male CF-1 mice received cardioprotective regimen of nitrate (1 g NaNO(3) per litre of drinking water) for 7 days before DOX injection (15 mg/kg, i.p.) and continued for 5 days after DOX treatment. Subsequently the heart samples were collected for proteomic analysis with two-dimensional differential in-gel electrophoresis with 3 CyDye labelling. Using 1.5 cut-off ratio, we identified 36 proteins that were up regulated by DOX in which 32 were completely reversed by nitrate supplementation (89%). Among 19 proteins down-regulated by DOX, 9 were fully normalized by nitrate (47%). The protein spots were further identified with Matrix Assisted Laser Desorption/Ionization-Time-of-Flight (MALDI-TOF)/TOF tandem mass spectrometry. Three mitochondrial antioxidant enzymes were altered by DOX, i.e. up-regulation of manganese superoxide dismutase and peroxiredoxin 3 (Prx3), and down-regulation of Prx5, which were reversed by nitrate. These results were further confirmed by Western blots. Nitrate supplementation also significantly improved animal survival rate from 80% in DOX alone group to 93% in Nitrate + DOX group 5 days after the DOX treatment. In conclusion, the proteomic analysis has identified novel protein targets underlying nitrate-induced cardioprotection. Up regulation of Prx5 by nitrate may explain the observed enhancement of cardiac antioxidant defence by nitrate supplementation. PMID- 21251212 TI - Intracerebral transplantation of foetal neural stem cells improves brain dysfunction induced by intracerebral haemorrhage stroke in mice. AB - Intracerebral haemorrhage (ICH) can lead to secondary insults and severe neurological deficits. Transplantation of neural stem cells (NSCs) was suggested as an alternative to improve ICH-induced neurological dysfunction. The present study aimed at investigating the therapeutic role and long-term survival of foetal NSCs and potential role of foetal NSCs-produced factors in ICH. Our results demonstrated that foetal NSCs could differentiate into neural axons and dendrites and astrocytes in both in vitro and in vivo conditions, demonstrated by positive double or triple staining with Hoechst, neuronal specific nuclear protein, neurofilaments and glial fibrillary acidic protein. Intracerebral transplantation of foetal NSCs 3 days after ICH induction by intrastriatal administration of bacterial collagenase could improve the functional performance in the limb-placing test and shorten the duration of the recovery from ICH induced neural disorders. The foetal NSCs may also produce neurotrophic and/or neuroprotective factors during culture, because the culture medium alone could partially improve functional performance. Thus, our data suggest that the foetal NSCs may be one of the therapeutic candidates for ICH. PMID- 21251213 TI - Evaluation of exon-skipping strategies for Duchenne muscular dystrophy utilizing dystrophin-deficient zebrafish. AB - Duchenne muscular dystophy (DMD) is a severe muscle wasting disease caused by mutations in the dystrophin gene. By utilizing antisense oligonucleotides, splicing of the dystrophin transcript can be altered so that exons harbouring a mutation are excluded from the mature mRNA. Although this approach has been shown to be effective to restore partially functional dystrophin protein, the level of dystrophin protein that is necessary to rescue a severe muscle pathology has not been addressed. As zebrafish dystrophin mutants (dmd) resemble the severe muscle pathology of human patients, we have utilized this model to evaluate exon skipping. Novel dmd mutations were identified to enable the design of phenotype rescue studies via morpholino administration. Correlation of induced exon skipping efficiency and the level of phenotype rescue suggest that relatively robust levels of exon skipping are required to achieve significant therapeutic ameliorations and that pre-screening analysis of exon-skipping drugs in zebrafish may help to more accurately predict clinical trials for therapies of DMD. PMID- 21251211 TI - Why is the partial oxygen pressure of human tissues a crucial parameter? Small molecules and hypoxia. AB - Oxygen supply and diffusion into tissues are necessary for survival. The oxygen partial pressure (pO(2)), which is a key component of the physiological state of an organ, results from the balance between oxygen delivery and its consumption. In mammals, oxygen is transported by red blood cells circulating in a well organized vasculature. Oxygen delivery is dependent on the metabolic requirements and functional status of each organ. Consequently, in a physiological condition, organ and tissue are characterized by their own unique 'tissue normoxia' or 'physioxia' status. Tissue oxygenation is severely disturbed during pathological conditions such as cancer, diabetes, coronary heart disease, stroke, etc., which are associated with decrease in pO(2), i.e. 'hypoxia'. In this review, we present an array of methods currently used for assessing tissue oxygenation. We show that hypoxia is marked during tumour development and has strong consequences for oxygenation and its influence upon chemotherapy efficiency. Then we compare this to physiological pO(2) values of human organs. Finally we evaluate consequences of physioxia on cell activity and its molecular modulations. More importantly we emphasize the discrepancy between in vivo and in vitro tissue and cells oxygen status which can have detrimental effects on experimental outcome. It appears that the values corresponding to the physioxia are ranging between 11% and 1% O(2) whereas current in vitro experimentations are usually performed in 19.95% O(2), an artificial context as far as oxygen balance is concerned. It is important to realize that most of the experiments performed in so-called normoxia might be dangerously misleading. PMID- 21251214 TI - Special interest section on mouse ultrasonic vocalizations. PMID- 21251215 TI - Nox2 and Nox4 mediate tumour necrosis factor-alpha-induced ventricular remodelling in mice. AB - Reactive oxygen species (ROS) and pro-inflammatory cytokines are crucial in ventricular remodelling, such as inflammation-associated myocarditis. We previously reported that tumour necrosis factor-alpha (TNF-alpha)-induced ROS in human aortic smooth muscle cells is mediated by NADPH oxidase subunit Nox4. In this study, we investigated whether TNF-alpha-induced ventricular remodelling was mediated by Nox2 and/or Nox4. An intravenous injection of murine TNF-alpha was administered to a group of mice and saline injection was administered to controls. Echocardiography was performed on days 1, 7 and 28 post-injection. Ventricular tissue was used to determine gene and protein expression of Nox2, Nox4, ANP, interleukin (IL)-1beta, IL-2, IL-6, TNF-alpha and to measure ROS. Nox2 and Nox4 siRNA were used to determine whether or not Nox2 and Nox4 mediated TNF alpha-induced ROS and upregulation of IL-1beta and IL-6 in adult human cardiomyocytes. Echocardiography showed a significant increase in left ventricular end-diastolic and left ventricular end-systolic diameters, and a significant decrease in the ejection fraction and fractional shortening in mice 7 and 28 days after TNF-alpha injection. These two groups of mice showed a significant increase in ventricular ROS, ANP, IL-1beta, IL-2, IL-6 and TNF-alpha proteins. Nox2 and Nox4 mRNA and protein levels were also sequentially increased. ROS was significantly decreased by inhibitors of NADPH oxidase, but not by inhibitors of other ROS production systems. Nox2 and Nox4 siRNA significantly attenuated TNF-alpha-induced ROS and upregulation of IL-1beta and IL-6 in cardiomyocytes. Our study highlights a novel TNF-alpha-induced chronic ventricular remodelling mechanism mediated by sequential regulation of Nox2 and Nox4 subunits. PMID- 21251216 TI - Characterization of upper lamina propria interstitial cells in bladders from patients with neurogenic detrusor overactivity and bladder pain syndrome. AB - The upper lamina propria (ULP) area of interstitial cells (IC) in bladder has been studied for more than a decade in several species including human beings. Nevertheless there is still lack of uniformity in terminology of this cell layer. The aim of the present study was to add new data to the morphological and immunohistochemical phenotype of these cells and to find out whether this phenotype is changed in bladders from patients with neurogenic detrusor overactivity (NDO) and bladder pain syndrome (BPS). Bladder tissue was obtained from a control group and from patients with NDO and BPS. Samples were processed for morphology, electron microscopy and immunohistochemistry. A morphological and immunohistochemical phenotype for the ULP IC was assessed and changes in this phenotype were looked for in samples from patients with NDO and BPS. The ULP IC were characterized ultrastructurally by the presence of actin filaments with densifications, many caveolae and abundant rough endoplasmic reticulum (RER); on immunohistochemistry ULP IC were immunoreactive for alpha-sma, vimentin, CD10 and podoplanin and categorized as interstitial Cajal-like cells (ICLC). In NDO and BPS bladders we found a phenotypical shift towards a fibroblastic phenotype which was even more pronounced in the NDO group. In both groups there was also an increased presence in ULP lymphocytes. The ULP area in the human bladder contains a population of ICLC with distinct ultrastructural morphology and immunohistochemical phenotype. Their unique alpha-sma(+) /desmin(-) /CD34(-) phenotype allows studying this population in various bladder disorders. In bladders form patients with BPS and NDO, we observed these ULP ICLC to shift towards a fibroblast phenotype. PMID- 21251217 TI - Cyclic ADP ribose is a novel regulator of intracellular Ca2+ oscillations in human bone marrow mesenchymal stem cells. AB - Bone marrow mesenchymal stem cells (MSCs) are a promising cell source for regenerative medicine. However, the cellular biology of these cells is not fully understood. The present study characterizes the cyclic ADP-ribose (cADPR) mediated Ca(2+) signals in human MSCs and finds that externally applied cADPR can increase the frequency of spontaneous intracellular Ca(2+) (Ca(2+) (i) ) oscillations. The increase was abrogated by a specific cADPR antagonist or an inositol trisphosphate receptor (IP3R) inhibitor, but not by ryanodine. In addition, the cADPR-induced increase of Ca(2+) (i) oscillation frequency was prevented by inhibitors of nucleoside transporter or by inhibitors of the transient receptor potential cation melastatin-2 (TRPM2) channel. RT-PCR revealed mRNAs for the nucleoside transporters, concentrative nucleoside transporters 1/2 and equilibrative nucleoside transporters 1/3, IP3R1/2/3 and the TRPM2 channel, but not those for ryanodine receptors and CD38 in human MSCs. Knockdown of the TRPM2 channel by specific short interference RNA abolished the effect of cADPR on the Ca(2+) (i) oscillation frequency, and prevented the stimulation of proliferation by cADPR. Moreover, cADPR remarkably increased phosphorylated extracellular-signal-regulated kinases 1/2 (ERK1/2), but not Akt or p38 mitogen activated protein kinase (MAPK). However, cADPR had no effect on adipogenesis or osteogenesis in human MSCs. Our results indicate that cADPR is a novel regulator of Ca(2+) (i) oscillations in human MSCs. It permeates the cell membrane through the nucleoside transporters and increases Ca(2+) oscillation via activation of the TRPM2 channel, resulting in enhanced phosphorylation of ERK1/2 and, thereby, stimulation of human MSC proliferation. This study delineates an alternate signalling pathway of cADPR that is distinct from its well-established role of serving as a Ca(2+) messenger for mobilizing the internal Ca(2+) stores. Whether cADPR can be used clinically for stimulating marrow function in patients with marrow disorders remains to be further studied. PMID- 21251218 TI - Calcitonin receptor-mediated CFTR activation in human intestinal epithelial cells. AB - High levels of calcitonin (CT) observed in medullary thyroid carcinoma and other CT-secreting tumours cause severe diarrhoea. Previous studies have suggested that CT induces active chloride secretion. However, the involvement of CT receptor (CTR) and the molecular mechanisms underlying the modulation of intestinal electrolyte secreting intestinal epithelial cells have not been investigated. Therefore, current studies were undertaken to investigate the direct effects of CT on ion transport in intestinal epithelial cells. Real time quantitative RT-PCR and Western blot analysis demonstrated the expression of CTR in intestinal epithelial T84 cells. Exposure of T84 cells to CT from the basolateral but not from apical side significantly increased short circuit current (I(SC) ) in a dose dependent manner that was blocked by 1 MUM of CTR antagonist, CT8-32. CT-induced I(SC) was blocked by replacing chloride in the bath solutions with equimolar gluconate and was significantly inhibited by the specific cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor, CFTR(127inh). Further, biotinylation studies showed that CT increased CFTR levels on the apical membrane. The presence of either the Ca(2+) chelator, bis(2-aminophenoxy)ethane tetraacetic acid-acetoxymethyl (BAPTA-AM) ester or the protein kinase A (PKA) inhibitor, H89, significantly inhibited I(SC) induced by CT (~32-58% reduction). Response to CT was retained after permeabilization of the basolateral or the apical membranes of T84 cells with nystatin. In conclusion, the activation of CTR by CT induced chloride secretion across T84 monolayers via CFTR channel and the involvement of PKA- and Ca(2+) -dependent signalling pathways. These data elucidate the molecular mechanisms underlying CT-induced diarrhoea. PMID- 21251219 TI - Bone regeneration: stem cell therapies and clinical studies in orthopaedics and traumatology. AB - Regenerative medicine seeks to repair or replace damaged tissues or organs, with the goal to fully restore structure and function without the formation of scar tissue. Cell based therapies are promising new therapeutic approaches in regenerative medicine. By using mesenchymal stem cells, good results have been reported for bone engineering in a number of clinical studies, most of them investigator initiated trials with limited scope with respect to controls and outcome. With the implementation of a new regulatory framework for advanced therapeutic medicinal products, the stage is set to improve both the characterization of the cells and combination products, and pave the way for improved controlled and well-designed clinical trials. The incorporation of more personalized medicine approaches, including the use of biomarkers to identify the proper patients and the responders to treatment, will be contributing to progress in the field. Both translational and clinical research will move the boundaries in the field of regenerative medicine, and a coordinated effort will provide the clinical breakthroughs, particularly in the many applications of bone engineering. PMID- 21251220 TI - Epithelial-to-mesenchymal transformation alters electrical conductivity of human epicardial cells. AB - The myocardium of the developing heart tube is covered by epicardium. These epicardial cells undergo a process of epithelial-to-mesenchymal transformation (EMT) and develop into epicardium-derived cells (EPDCs). The ingrowing EPDCs differentiate into several celltypes of which the cardiac fibroblasts form the main group. Disturbance of EMT of the epicardium leads to serious hypoplasia of the myocardium, abnormal coronary artery differentiation and Purkinje fibre paucity. Interestingly, the electrophysiological properties of epicardial cells and whether EMT influences electrical conductivity of epicardial cells is not yet known. We studied the electrophysiological aspects of epicardial cells before and after EMT in a dedicated in vitro model, using micro-electrode arrays to investigate electrical conduction across epicardial cells. Therefore, human adult epicardial cells were placed between two neonatal rat cardiomyocyte populations. Before EMT the epicardial cells have a cobblestone (epithelium-like) phenotype that was confirmed by staining for the cell-adhesion molecule beta-catenin. After spontaneous EMT in vitro the EPDCs acquired a spindle-shaped morphology confirmed by vimentin staining. When comparing both types we observed that the electrical conduction is influenced by EMT, resulting in significantly reduced conductivity of spindle-shaped EPDCs, associated with a conduction block. Furthermore, the expression of both gap junction (connexins 40, Cx43 and Cx45) and ion channel proteins (SCN5a, CACNA1C and Kir2.1) was down-regulated after EMT. This study shows for the first time the conduction differences between epicardial cells before and after EMT. These differences may be of relevance for the role of EPDCs in cardiac development, and in EMT-related cardiac dysfunction. PMID- 21251222 TI - Should one size fit all? An overview and critique of the VULCAN study on silver dressings. PMID- 21251221 TI - Imprinted Rasgrf1 expression in neonatal mice affects olfactory learning and memory. AB - Rasgrf1 is genomically imprinted; only the paternally inherited allele is expressed in the neonatal mouse brain until weaning, at which time expression becomes biallelic. Whereas Rasgrf1 has been implicated in learning and memory via knockout studies in adult mice, the effect of its normal imprinted expression on these phenotypes has not yet been examined. Neonatal mice with experimentally manipulated patterns of imprinted Rasgrf1 expression were assessed on an associative olfactory task. Neonates lacking the normally expressed wild-type paternal allele exhibited significant impairment in olfactory associative memory. Adult animals in which neonatal imprinting had been manipulated were also behaviorally assessed; while neonatal imprinting significantly affects body weight even into adulthood, no learning and memory phenotype attributable to imprinting was observed in adults. Additional analyses of neonates showed imprinted Rasgrf1 transcript selective to olfactory bulb even in mice that were null for Rasgrf1 in the rest of the brain and showed that Rasgrf1 affects Ras and Rac activation in the brain. Taken together, these results indicate that Rasgrf1 expression from the wild-type paternal allele contributes to learning and memory in neonatal mice. PMID- 21251225 TI - Use and wear of anti-embolism stockings: a clinical audit of surgical patients. AB - The objective of this study was to determine if anti-embolism stockings are fitted and worn according to evidence-based guidelines in surgical patients. The methodology is that an observational study was undertaken during January and February, 2010. An audit tool was constructed for the recording of information on a variety of parameters relating to the correct fitting and wearing of anti embolism stockings. The results show that eighty surgical patients were audited with a mean age of 66 years. Of these, 72.5% were ambulatory; 38.75% of patients had incorrect presentation of their stockings; 29% were fitted with the incorrect size for limb measurement and 70% of patients reported not receiving any information regarding the reason for anti-embolism stocking use. Written information was not received by 100% of participants. For 82.5% of participants deep vein thrombosis (DVT) risk was not recorded. The garment size fitted (and/or limb measurement) was not recorded for 100% of patients. Daily routine skin inspection was noted for 29%. The findings of this study showed that anti embolism stockings were not fitted and worn according to evidence-based guidelines. The author recommends a new recording tool be developed to ensure consistency of assessment and documentation regarding risk assessment, contraindications identification, and education and monitoring of patients wearing anti-embolism stockings. PMID- 21251227 TI - New developments in fluorescence diagnostics. AB - In the last decade, significant advances have been achieved in the direct viewing of the skin. Non-invasive analysis of various skin diseases in vivo has become possible by special skin display devices, allowing the physician to view the structure and properties of the skin in greater detail than can be achieved by simple visual examination. We review the last 100 years of fluorescence imaging development from clinical observation to advanced spectral imaging, addressing the role of fluorescence diagnostics (FD) in modern dermatology as well as the detection of autofluorescence. PMID- 21251228 TI - Lichen planus pigmentosus over superficial leg veins. PMID- 21251229 TI - Research in practice: IL-22 and IL-20: significance for epithelial homeostasis and psoriasis pathogenesis. AB - Psoriasis vulgaris is a frequent, chronically relapsing, immune-mediated, systemic disease with characteristic skin changes. Despite the importance of this disease there are currently limited therapeutic options indicating a need for effective, long-lasting treatment strategies with few side effects. The most recent discoveries regarding psoriasis pathogenesis, particularly our results regarding two cytokines - IL-22 and IL-20 - could prove to be the foundation for such therapies. Whereas IL-22 is mainly produced by activated T-cell sub populations (Th22, Th1, Th17), monocytes, dendritic cells and keratinocytes produce IL-20. Blood and lesional skin samples from psoriasis patients demonstrate high levels of IL-22 and IL-20. Interestingly, both cytokines act principally on keratinocytes and do not impact the immune system. Similar to the changes in the psoriasis epidermis these cytokines inhibit the terminal differentiation of keratinocytes although they simultaneously increase their innate defense, mobility, and the production of some chemokines. Some IL-22 effects are amplified by TNF-alpha, IL-17, and IFN-alpha. IL-22/IL-20 lends the reconstructed epidermis a psoriasis-like appearance with acanthosis, hypogranularity, and hyperkeratosis. In addition, mice that constitutively express high levels of IL-22 or IL-20 demonstrate a psoriasis-like appearance. A therapy counteracting IL-22 and IL-20 would be an innovative treatment with the potential for few side effects that would act on the final phase of psoriasis pathogenesis. PMID- 21251230 TI - 2-amino-nonyl-6-methoxyl-tetralin muriate activity against Candida albicans augments endogenous reactive oxygen species production --a microarray analysis study. AB - Candida infections have become an increasingly significant problem, mainly because of the widespread nature of Candida and drug resistance. There is an urgent need to develop new classes of drugs for the treatment of opportunistic Candida infections, especially in medically complex patients. Previous studies have confirmed that 2-amino-nonyl-6-methoxyl-tetralin muriate (10b) possesses powerful antifungal activity in vitro against Candia albicans. To clarify the underlying action mechanism, an oligonucleotide microarray study was performed in C. albicans SC5314 without and with 10b treatment. The analytical results showed that energy metabolism-related genes, including glycolysis-related genes (PFK1, CDC19 and HXK2), fermentation-related genes (PDC11, ALD5 and ADH1) and respiratory electron transport chain-related genes (CBP3, COR1 and QCR8), were downregulated significantly. Functional analysis revealed that 10b treatment increased the generation of endogenous reactive oxygen species, and decreased mitochondrial membrane potential, ubiquinone-cytochrome c reductase (complex III) activity and intracellular ATP levels in C. albicans SC5314. Also, addition of the antioxidant ascorbic acid reduced the antifungal activity of 10b significantly. These results suggest that mitochondrial aerobic respiration shift and endogenous reactive oxygen species augmentation might contribute to the antifungal activity of 10b against C. albicans. This information may prove to be useful for the development of new strategies to treat Candida infections. PMID- 21251232 TI - Synthesis of novel indolyl-1,2,4-triazoles as potent and selective anticancer agents. AB - A diverse series of 22 indolyl-1,2,4-triazole congeners (6 and 7) have been synthesized from the reaction of indole-3-carbonitrile (4) or (5) with appropriate acid hydrazides in the presence of potassium carbonate. Synthesized compounds were evaluated for their cytotoxicity against six human cancer cell lines, and some of the compounds displayed promising activity. In particular, 3 (3',4',5'-trimethoxyphenyl)-5-(N-methyl-3'-indolyl)-1,2,4-triazole (7i) and 3-(4' piperidinyl)-5-(N-methyl-3'-indolyl)-1,2,4-triazole (7n) were the most promising and broadly active compounds against the tested cell lines. It was interesting to note that the trimethoxyphenyl analog 7i showed twofold selective cytotoxicity against PaCa2 cell line (IC(50) 0.8 MUm), whereas piperidinyl analog 7n was found to be selectively cytotoxic against MCF7 cell line (IC(50) 1.6 MUm). Notably, the 4-fluorophenyl derivative 7c exhibited selective cytotoxicity against PC3 cell line (IC(50) 4 MUm). The structure-activity relationship study revealed that substituents including 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 4-benzyloxy-3 methoxyphenyl, 4-piperidinyl, 4-fluorophenyl and N-methylindole are beneficial for the activity of indolyl-1,2,4-triazoles (6 and 7). PMID- 21251231 TI - Factor-inhibiting hypoxia-inducible factor (FIH) catalyses the post-translational hydroxylation of histidinyl residues within ankyrin repeat domains. AB - Factor-inhibiting hypoxia-inducible factor (FIH) is an Fe(II)/2-oxoglutarate dependent dioxygenase that acts as a negative regulator of the hypoxia-inducible factor (HIF) by catalysing beta-hydroxylation of an asparaginyl residue in its C terminal transcriptional activation domain (CAD). In addition to the hypoxia inducible factor C-terminal transcriptional activation domain (HIF-CAD), FIH also catalyses asparaginyl hydroxylation of many ankyrin repeat domain-containing proteins, revealing a broad sequence selectivity. However, there are few reports on the selectivity of FIH for the hydroxylation of specific residues. Here, we report that histidinyl residues within the ankyrin repeat domain of tankyrase-2 can be hydroxylated by FIH. NMR and crystallographic analyses show that the histidinyl hydroxylation occurs at the beta-position. The results further expand the scope of FIH-catalysed hydroxylations. PMID- 21251233 TI - Synthesis of 2-hydrazolyl-4-thiazolidinones based on multicomponent reactions and biological evaluation against Trypanosoma Cruzi. AB - A series of 18 novel 2-hydrazolyl-4-thiazolidinones-5-carboxylic acids, amides and 5,6-alpha,beta-unsaturated esters were synthesized, and their in vitro activity on cruzipain and T. cruzi epimastigotes was determined. Some agents show activity at 37 MUm concentration in the enzyme assay. Computational tools and docking were used to correlate the biological response with the physicochemical parameters of the compounds and their cruzipain inhibitory effects. PMID- 21251234 TI - Ligand-based 3D-QSAR studies of diaryl acyl-sulfonamide analogues as human umbilical vein endothelial cells inhibitors stimulated by VEGF. AB - Diaryl acylsulfonamide derivatives were reported as Human Umbilical Vein Endothelial cell (HUVEC) inhibitors, stimulated by Vascular Endothelial Growth Factor (VEGF). VEGF has angiogenic property to cause colorectal cancer. A ligand based 3D-QSAR technique was carried out on diaryl acylsulfonamide derivatives by using Comparative Molecular Field Analysis (CoMFA) studies to find relations between biological activities of inhibitors and their structures. In absence of binding mechanism for the ligand with VEGF receptor, current study hopes to shed some light on the inhibition mechanism of the ligands with HUVEC. 3D-QSAR technique was applied to a set of fifty ligands in order to facilitate the design of more potent inhibitors. However, the maximum cross-validated correlation coefficient value was found to be 0.417. The value is relatively low when compared to the usual acceptable cross-validated correlation coefficient, but no further improvements were observed by applying different available options. Therefore, the final model was used for further analysis. Additionally, the resulted CoMFA model was validated by an external set of 10 compounds yielding surprisingly, a satisfactory correlation coefficient value (r(2) (pred) ) 0.80. Moreover, the analysis of the individual generated 3D contours helped in understanding the possible structural modifications of molecules to improve the inhibitory potency. PMID- 21251235 TI - No effect of metabolic acidosis on nitric oxide production in hypoxic and hyperoxic lung regions in pigs. AB - AIM: In the severely ill intensive care patients metabolic acidosis and hypoxia often co-exist. We studied the effects of metabolic acidosis on nitric oxide synthase (NOS) dependent and NOS independent nitric oxide (NO) production in hypoxic and hyperoxic lung (HL) regions in a pig model. METHODS: Eighteen healthy anaesthetized pigs were separately ventilated with hypoxic gas to the left lower lobe (LLL) and hyperoxic gas to the rest of the lung. Six pigs received HCl infusion (HCl group), six pigs received the non-specific NOS inhibitor N(omega) -nitro-l-arginine methyl ester (l-NAME) and HCl infusions (l NAME + HCl group) and six pigs received buffered Ringer's solution (control group). NO concentration in exhaled air (ENO), NOS activity in lung tissue, and regional pulmonary blood flow were measured. RESULTS: Metabolic acidosis, induced by infusion of HCl, decreased the relative perfusion to the hypoxic LLL from 7 (3) [mean (SD)] to 3 (1) % in the HCl group (P < 0.01), and from 4 (1) to 1 (1) % in the l-NAME + HCl group (P < 0.05), without any measurable significant changes in ENO from hypoxic or HL regions There were no significant differences between the HCl and control groups for Ca(2+) -dependent (cNOS) or Ca(2+) -independent NOS (iNOS) activity in hypoxic or HL regions. CONCLUSIONS: Metabolic acidosis augmented the hypoxic pulmonary vasoconstriction, without any changes in pulmonary NOS dependent or NOS independent NO production. When acidosis was induced during ongoing NOS blockade, the perfusion of hypoxic lung regions was almost abolished, indicating acidosis-induced pulmonary vasoconstriction was not NO dependent. PMID- 21251236 TI - SGK1-dependent salt appetite in pregnant mice. AB - AIM: Pregnancy is typically paralleled by substantial increase in maternal extracellular fluid volume, requiring net accumulation of water and NaCl. The positive water and salt balance is accomplished at least in part by increased uptake of salt secondary to enhanced salt appetite. Little is known about the underlying cellular mechanisms. Stimulation of salt appetite by mineralocorticoids, however, is known to be dependent on the serum- and glucocorticoid-inducible kinase SGK1. METHODS: To test for a role of SGK1 in the stimulation of salt appetite during pregnancy, fluid intake was recorded in pregnant SGK1 knockout mice (sgk1(-/-) ) and their wild type littermates (sgk1(+/+) ). The mice were offered two bottles, one with plain water and the other with isotonic saline. RESULTS: In early pregnancy, i.e. up to 10 days prior to parturition, the sgk1(+/+) mice displayed a significant preference for saline, whereas the sgk1(-/-) mice preferred water. Accordingly, the water intake was significantly smaller and saline intake was significantly larger in sgk1(+/+) mice than in sgk1(-/-) mice and the preference for water was significantly stronger in sgk1(-/-) mice than in sgk1(+/+) mice. Plasma aldosterone levels were higher in sgk1(-/-) mice than in sgk1(+/+) mice, a difference contrasting the enhanced salt appetite of sgk1(+/+) mice. CONCLUSIONS: SGK1 participates in the stimulation of salt appetite during pregnancy. PMID- 21251237 TI - Survival in extreme environments - on the current knowledge of adaptations in tardigrades. AB - Tardigrades are microscopic animals found worldwide in aquatic as well as terrestrial ecosystems. They belong to the invertebrate superclade Ecdysozoa, as do the two major invertebrate model organisms: Caenorhabditis elegans and Drosophila melanogaster. We present a brief description of the tardigrades and highlight species that are currently used as models for physiological and molecular investigations. Tardigrades are uniquely adapted to a range of environmental extremes. Cryptobiosis, currently referred to as a reversible ametabolic state induced by e.g. desiccation, is common especially among limno terrestrial species. It has been shown that the entry and exit of cryptobiosis may involve synthesis of bioprotectants in the form of selective carbohydrates and proteins as well as high levels of antioxidant enzymes and other free radical scavengers. However, at present a general scheme of mechanisms explaining this phenomenon is lacking. Importantly, recent research has shown that tardigrades even in their active states may be extremely tolerant to environmental stress, handling extreme levels of ionizing radiation, large fluctuation in external salinity and avoiding freezing by supercooling to below -20 degrees C, presumably relying on efficient DNA repair mechanisms and osmoregulation. This review summarizes the current knowledge on adaptations found among tardigrades, and presents new data on tardigrade cell numbers and osmoregulation. PMID- 21251238 TI - Anion secretion by a model epithelium: more lessons from Calu-3. AB - Anion transport drives fluid into the airways and is essential for humidifying inspired air and supplying surface liquid for mucociliary transport. Despite the importance of airway secretion in diseases such as cystic fibrosis, the cellular mechanisms remain poorly understood, in part due to the small size and complicated structure of the submucosal glands that produce most of the fluid. The Calu-3 human lung adenocarcinoma cell line has become a popular model for studying airway secretion because it can be cultured as a flat sheet, expresses the cystic fibrosis transmembrane conductance regulator and several acinar cell markers, forms polarized monolayers with tight junctions, has robust cAMP stimulated anion transport, and responds to secretagogues that regulate the glands in vivo. However, some properties of Calu-3 cells are less consistent with those of native tissue. In particular, Calu-3 monolayers do not secrete chloride when stimulated by forskolin under short-circuit conditions. Bicarbonate ions are thought to carry the short-circuit current (I(sc)) and the drive secretion of alkaline fluid, in contrast to the neutral pH secretions that are produced by submucosal glands. Calu-3 cells also have abnormal chromosomes and characteristics of both serous and mucus cells. In this article, we discuss Calu 3 as a model in light of our ongoing studies, which suggest that Calu-3 monolayers resemble submucosal glands more closely than was previously thought. For example, we find that net HCO(3)(-) flux fully accounts for I(sc) as previously suggested but Cl(-) is the main anion transported under physiological conditions. A novel, HCO(3)(-) -dependent mechanism of Cl(-) transport is emerging which may explain secretion by Calu-3 and perhaps other epithelial cells. PMID- 21251239 TI - Lack of downstream insulin-mimetic effects of visfatin/eNAMPT on glucose and fatty acid metabolism in skeletal muscles. AB - AIM: Recent studies regarding downstream effects of visfatin/eNAMPT in skeletal muscles have attracted much attention as the previous reports suggested this adipokine may exert insulin-mimetic effects. However, studies in vivo present conflicting data and are still controversial. In this present work, we sought to investigate whether visfatin/eNAMPT is able to reproduce insulin effects on glucose transport and lipid metabolism. METHODS: We have used isolated skeletal muscles with different fibre type composition (Soleus and EDL) to examine glucose transport, GLUT-4 translocation, phosphorylation of insulin signalling pathway proteins, as well as the key parameters for fatty acid metabolism. RESULTS: We found that, in vitro exposure to visfatin/eNAMPT increased skeletal muscle glucose transport but only in EDL (+20%) and not in Soleus muscle (+5%). Interestingly, classical insulin signalling pathways were not significantly involved in this process. Concomitantly, visfatin/eNAMPT exerted no significant effects on muscle's fatty acids (FA) metabolism as no change in either palmitate oxidation or esterification was observed. Importantly, combined insulin and visfatin effects were not found, suggesting non-additivity. CONCLUSION: Our data suggest that visfatin/eNAMPT plays a rather limited role in regulating skeletal muscle glucose transport and FA metabolism. PMID- 21251240 TI - Usefulness of thyrogastric immune features as predictors of pernicious anaemia that lacks intrinsic factor antibody. AB - INTRODUCTION: The study aims to evaluate the diagnostic utility of thyrogastric immune features in the identification of intrinsic factor antibody negative (IFA ve) pernicious anaemia (PA) patients. METHODS: Clinico-pathological features of 'intrinsic factor antibody positive (IFA +ve) PA' and 'IFA -ve presumed PA' Chinese patients in a single hospital (2001-2009) were studied. Coefficients of independent variables identified were used as weighted scores. The result was validated by patients (1994-2000) with Schilling test done. RESULTS: Comparison of 127 'IFA +ve PA' and 130 'IFA -ve presumed PA' patients showed four independent variables, namely (+) gastric parietal cell (GPC) antibody (OR, 2.907, 95%; CI, 2.346-3.468; P < 0.001), (+) antithyroid antibodies (OR, 3.098, 95%; CI, 2.496-3.70; P < 0.001), (+) gastric atrophy (OR, 3.827, 95%; CI, 3.041 4.64; P = 0.001), and (-) Helicobacter pylori (HP) organisms (OR, 0.134, 95%; CI, -1.60-1.869; P = 0.023). The respective scores were 1.067, 1.131, 1.342 and 2.012. Total scores for each patient ranged from 3.54 to -2.012. When the cut-off score 1.528 was applied to the validation sample (n = 75), the specificity of identifying IFA -ve PA was 100%, sensitivity 53%, positive predictive value 100%, and negative predictive value 36%. CONCLUSION: Patients with two out of three features, GPC, antithyroid antibodies, gastric atrophy, but without HP organisms; or three features with HP organisms, can be predicted to have PA. PMID- 21251241 TI - Effect of the duration of immunomodulatory therapy on the clinical features of recurrent episodes in Vogt--Koyanagi--Harada disease. AB - PURPOSE: To evaluate the duration of immunomodulatory therapy (corticosteroids, immunosuppressive drugs) with regard to the rate of relapses and clinical features (exudative retinal detachment or anterior uveitis) in inflammatory episodes of Vogt--Koyanagi--Harada disease. METHODS: Data of all 42 patients diagnosed with acute uveitis associated with VKH disease during the period of January 2005 to December 2008 at the Pitie-Salpetriere Hospital or at the Lariboisiere Hospital in Paris, France were extracted by chart review. RESULTS: There were 31 patients (73.8%) with episodes of recurrence and were included in the study. At the first recurrence, 81% (13 patients) of exudative retinal detachments (ERD) were associated with an initial immunomodulatory treatment conducted <=6 months (3.76 months +/- 2.67). Conversely, an initial treatment duration of >6 months was associated with anterior uveitis signs for 66% of patients (eight patients) with anterior first recurrence (p = 0.0061). On second episode of recurrence, 75% of patients (three patients) who developed exudative retinal detachment had been managed by immunomodulatory therapy for <=6 months with the total duration of immunomodulatory treatment <=6 months during previous inflammatory episodes. Conversely, all 16 patients who presented anterior uveitis with additional manifestations (optic disc oedema, macular oedema, vitritis and/or 'Sunset glow' fundus) have been treated for more than 6 months or treated during the initial occurrence lasting more than 9 months (p = 0.0035). CONCLUSIONS: The duration of systemic corticosteroids (and/or immunosuppressive drug therapy) for <=6 months at first and second recurrence was associated with features of further exudative retinal detachment instead of anterior uveitis in VKH disease. PMID- 21251242 TI - Retinal nerve fibre layer attenuation: clinical indicator for vigabatrin toxicity. AB - PURPOSE: To investigate whether persistent visual field defects among patients exposed once to the antiepileptic drug vigabatrin (VGB) were associated with peripapillary retinal nerve fibre layer thickness (RNFLT) attenuation. METHODS: Nine individuals with partial epilepsy and VGB-attributed visual field loss (group 1; 18 eyes) and seven age- and gender-matched individuals with epilepsy and no previous VGB exposure (group 2; 14 eyes) were included in the study. Full field 120 point screening perimetry out to 60 degrees from central fixation using the Humphrey Field Analyzer was performed. RNFLT was quantified by optical coherence tomography (OCT) using Fast RNFLT protocol, Stratus OCT (3.0) after pupillary dilation. The results from the right eye are presented in this article. RESULTS: Among the patients with VGB-attributed visual field loss, five patients had only peripheral field defect (group 1a) and the remaining four had advanced field defects both in the periphery and within 30 degrees from central fixation (group 1b). None of the patients in the control group had manifest visual field loss. The mean RNFLT among the patients with VGB-attributed visual field loss was significantly attenuated compared to the controls [mean total RNFLT: group 1: 75.6 +/- 12.7 MUm, group 2: 103.5 +/- 9.7 MUm, mean difference 27.9 MUm, (CI 15.9 39.9; p < 0.001)]. RNFLT values classified as borderline according to normative database (Stratus OCT) occurred more frequently among individuals with VGB attributed visual field loss than in controls (frequency in group 1: 6/9; group 2: 0/7, p = 0.011). The nasal, superior and inferior quadrants of RNFLT in individuals with VGB-attributed visual field loss were significantly attenuated, while no difference was detected in temporal quadrants compared to controls. Both individuals with peripheral and those with advanced visual field losses in the VGB group had attenuated mean total RNFLT compared to controls (p = 0.006, p = 0.002, respectively). Occurrence of borderline classification of total RNFLT <=5th percentile was more frequent among individuals with advanced visual field loss than among controls (p = 0.048). CONCLUSION: Persistent visual field loss attributed to VGB is associated with reduced peripapillary RNFLT and was detected both among patients with advanced and among patients with only peripheral visual field defects. Measurements of RNFLT with OCT might be considered as a diagnostic supplement in the follow-up of patients exposed to vigabatrin. PMID- 21251243 TI - Analysis of trends and seasonal variation in primary cutaneous melanoma: an Irish study. AB - A seasonal variation in the presentation of cutaneous melanoma has been documented in several studies. We performed a retrospective review of primary cutaneous melanomas (n = 263) from our institution to examine whether the seasonal patterns of presentation noted in the literature would be similar in Ireland, a climate with low ambient sunshine. A summer : winter ratio was determined for age, gender, subtype, location and Breslow thickness. We found an increase in total numbers of melanomas, particularly in men. The summer : winter ratio was 2.39 for all patients (95% CI 1.60-3.57, P < 0.001), with seasonal variations noted for location, thickness and subtype (excluding lentigo). Melanomas presenting over the summer tended towards a greater Breslow thickness than did those presenting in winter. This subclassification of primary cutaneous melanoma with summer : winter ratios based on patient and tumour characteristics gave remarkably similar results to previously published reports, notwithstanding the low levels of annual ambient sunshine in Ireland. PMID- 21251244 TI - An algorithm for efficient constrained mate selection. AB - BACKGROUND: Mate selection can be used as a framework to balance key technical, cost and logistical issues while implementing a breeding program at a tactical level. The resulting mating lists accommodate optimal contributions of parents to future generations, in conjunction with other factors such as progeny inbreeding, connection between herds, use of reproductive technologies, management of the genetic distribution of nominated traits, and management of allele/genotype frequencies for nominated QTL/markers. METHODS: This paper describes a mate selection algorithm that is widely used and presents an extension that makes it possible to apply constraints on certain matings, as dictated through a group mating permission matrix. RESULTS: This full algorithm leads to simpler applications, and to computing speed for the scenario tested, which is several hundred times faster than the previous strategy of penalising solutions that break constraints. CONCLUSIONS: The much higher speed of the method presented here extends the use of mate selection and enables implementation in relatively large programs across breeding units. PMID- 21251245 TI - The discovery of potential acetylcholinesterase inhibitors: a combination of pharmacophore modeling, virtual screening, and molecular docking studies. AB - BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia characterized by progressive cognitive impairment in the elderly people. The most dramatic abnormalities are those of the cholinergic system. Acetylcholinesterase (AChE) plays a key role in the regulation of the cholinergic system, and hence, inhibition of AChE has emerged as one of the most promising strategies for the treatment of AD. METHODS: In this study, we suggest a workflow for the identification and prioritization of potential compounds targeted against AChE. In order to elucidate the essential structural features for AChE, three dimensional pharmacophore models were constructed using Discovery Studio 2.5.5 (DS 2.5.5) program based on a set of known AChE inhibitors. RESULTS: The best five-features pharmacophore model, which includes one hydrogen bond donor and four hydrophobic features, was generated from a training set of 62 compounds that yielded a correlation coefficient of R = 0.851 and a high prediction of fit values for a set of 26 test molecules with a correlation of R2 = 0.830. Our pharmacophore model also has a high Guner-Henry score and enrichment factor. Virtual screening performed on the NCI database obtained new inhibitors which have the potential to inhibit AChE and to protect neurons from Abeta toxicity. The hit compounds were subsequently subjected to molecular docking and evaluated by consensus scoring function, which resulted in 9 compounds with high pharmacophore fit values and predicted biological activity scores. These compounds showed interactions with important residues at the active site. CONCLUSIONS: The information gained from this study may assist in the discovery of potential AChE inhibitors that are highly selective for its dual binding sites. PMID- 21251246 TI - Lack of cathepsin activities alter or prevent the development of lung granulomas in a mouse model of sarcoidosis. AB - BACKGROUND: Remodeling of lung tissues during the process of granuloma formation requires significant restructuring of the extra-cellular matrix and cathepsins K, L and S are among the strongest extra-cellular matrix degrading enzymes. Cathepsin K is highly expressed in various pathological granulomatous infiltrates and all three enzymes in their active form are detected in bronchoalveolar lavage fluids from patients with sarcoidosis. Granulomatous inflammation is driven by T cell response and cathepsins S and L are actively involved in the regulation of antigen presentation and T-cell selection. Here, we show that the disruption of the activities of cathepsins K, L, or S affects the development of lung granulomas in a mouse model of sarcoidosis. METHODS: Apolipoprotein E-deficient mice lacking cathepsin K or L were fed Paigen diet for 16 weeks and lungs were analyzed and compared with their cathepsin-expressing littermates. The role of cathepsin S in the development of granulomas was evaluated using mice treated for 8 weeks with a potent and selective cathepsin S inhibitor. RESULTS: When compared to wild-type litters, more cathepsin K-deficient mice had lung granulomas, but individually affected mice developed smaller granulomas that were present in lower numbers. The absence of cathepsin K increased the number of multinucleated giant cells and the collagen content in granulomas. Cathepsin L deficiency resulted in decreased size and number of lung granulomas. Apoe-/- mice treated with a selective cathepsin S inhibitor did not develop lung granulomas and only individual epithelioid cells were observed. CONCLUSIONS: Cathepsin K deficiency affected mostly the occurrence and composition of lung granulomas, whereas cathepsin L deficiency significantly reduced their number and cathepsin S inhibition prevented the formation of granulomas. PMID- 21251247 TI - Nogo-B regulates migration and contraction of airway smooth muscle cells by decreasing ARPC 2/3 and increasing MYL-9 expression. AB - BACKGROUND: Abnormal proliferation, apoptosis, migration and contraction of airway smooth muscle (ASM) cells in airway remodeling in asthma are basically excessive repair responses to a network of inflammatory mediators such as PDGF, but the mechanisms of such responses remain unclear. Nogo-B, a member of the reticulum family 4(RTN4), is known to play a key role in arteriogenesis and tissue repair. Further studies are needed to elucidate the role of Nogo-B in airway smooth muscle abnormalities. METHODS: A mouse model of chronic asthma was established by repeated OVA inhalation and subjected to Nogo-B expression analysis using immunohistochemistry and Western Blotting. Then, primary human bronchial smooth muscle cells (HBSMCs) were cultured in vitro and a siRNA interference was performed to knockdown the expression of Nogo-B in the cells. The effects of Nogo-B inhibition on PDGF-induced HBSMCs proliferation, migration and contraction were evaluated. Finally, a proteomic analysis was conducted to unveil the underlying mechanisms responsible for the function of Nogo-B. RESULTS: Total Nogo-B expression was approximately 3.08-fold lower in chronic asthmatic mice compared to naive mice, which was obvious in the smooth muscle layer of the airways. Interference of Nogo-B expression by siRNA resulted nearly 96% reduction in mRNA in cultured HBSMCs. In addition, knockdown of Nogo-B using specific siRNA significantly decreased PDGF-induced migration of HBSMCs by 2.3-fold, and increased the cellular contraction by 16% compared to negative controls, but had limited effects on PDGF-induced proliferation. Furthermore, using proteomic analysis, we demonstrate that the expression of actin related protein 2/3 complex subunit 5 (ARPC 2/3) decreased and, myosin regulatory light chain 9 isoform a (MYL-9) increased after Nogo-B knockdown. CONCLUSIONS: These data define a novel role for Nogo-B in airway remodeling in chronic asthma. Endogenous Nogo-B, which may exert its effects through ARPC 2/3 and MYL-9, is necessary for the migration and contraction of airway smooth muscle cells. PMID- 21251248 TI - CODA (crossover distribution analyzer): quantitative characterization of crossover position patterns along chromosomes. AB - BACKGROUND: During meiosis, homologous chromosomes exchange segments via the formation of crossovers. This phenomenon is highly regulated; in particular, crossovers are distributed heterogeneously along the physical map and rarely arise in close proximity, a property referred to as "interference". Crossover positions form patterns that give clues about how crossovers are formed. In several organisms including yeast, tomato, Arabidopsis, and mouse, it is believed that crossovers form via at least two pathways, one interfering, the other not. RESULTS: We have developed a software package--"CODA", for CrossOver Distribution Analyzer--which allows one to quantitatively characterize crossover patterns by fitting interference models to experimental data. Two families of interfering models are provided: the "gamma" model and the "beam-film" model. The user can specify single or two-pathways modeling, and the software package infers the model's parameters and their confidence intervals. CODA can handle data produced from measurements on bivalents or gametes, in the form of continuous crossover positions or marker genotyping. We illustrate the possibilities on data from Wheat, corn and mouse. CONCLUSIONS: CODA extends the kind of crossover data that could be analyzed so far to include gametic data (rather than only bivalents/tetrads) when using two-pathways modeling. It will also enable users to perform analyses based on the beam-film model. CODA implements that model's complex physics and mathematics, and uses a summary statistic to overcomes the lack of a computable likelihood which has hampered its use till now. PMID- 21251249 TI - Experimental evolution of sperm competitiveness in a mammal. AB - BACKGROUND: When females mate with multiple partners, sperm from rival males compete to fertilize the ova. Studies of experimental evolution have proven the selective action of sperm competition on male reproductive traits. However, while reproductive traits may evolve in response to sperm competition, this does not necessarily provide evidence that sperm competitive ability responds to selection. Indeed, a study of Drosophila failed to observe divergence in sperm competitive ability of males in lines selected for enhanced sperm offence and defence. RESULTS: Adopting the naturally polygamous house mouse (Mus domesticus) as our vertebrate model, we performed an experimental evolution study and observed genetic divergence in sperm quality; males from the polygamous selection lines produced ejaculates with increased sperm numbers and greater sperm motility compared to males from the monogamous lines. Here, after 12 generations of experimental evolution, we conducted competitive matings between males from lineages evolving under sperm competition and males from lineages subject to relaxed selection. We reduced variation in paternity arising from embryo mortality by genotyping embryos in utero at 14 days gestation. Our microsatellite data revealed a significant paternity bias toward males that evolved under the selective regime of sperm competition. CONCLUSION: We provide evidence that the sperm competitiveness phenotype can respond to selection, and show that improved sperm quality translates to greater competitive fertilisation success in house mice. PMID- 21251250 TI - Structural correlations in bacterial metabolic networks. AB - BACKGROUND: Evolution of metabolism occurs through the acquisition and loss of genes whose products acts as enzymes in metabolic reactions, and from a presumably simple primordial metabolism the organisms living today have evolved complex and highly variable metabolisms. We have studied this phenomenon by comparing the metabolic networks of 134 bacterial species with known phylogenetic relationships, and by studying a neutral model of metabolic network evolution. RESULTS: We consider the 'union-network' of 134 bacterial metabolisms, and also the union of two smaller subsets of closely related species. Each reaction-node is tagged with the number of organisms it belongs to, which we denote organism degree (OD), a key concept in our study. Network analysis shows that common reactions are found at the centre of the network and that the average OD decreases as we move to the periphery. Nodes of the same OD are also more likely to be connected to each other compared to a random OD relabelling based on their occurrence in the real data. This trend persists up to a distance of around five reactions. A simple growth model of metabolic networks is used to investigate the biochemical constraints put on metabolic-network evolution. Despite this seemingly drastic simplification, a 'union-network' of a collection of unrelated model networks, free of any selective pressure, still exhibit similar structural features as their bacterial counterpart. CONCLUSIONS: The OD distribution quantifies topological properties of the evolutionary history of bacterial metabolic networks, and lends additional support to the importance of horizontal gene transfer during bacterial metabolic evolution where new reactions are attached at the periphery of the network. The neutral model of metabolic network growth can reproduce the main features of real networks, but we observe that the real networks contain a smaller common core, while they are more similar at the periphery of the network. This suggests that natural selection and biochemical correlations can act both to diversify and to narrow down metabolic evolution. PMID- 21251251 TI - Evolutionary changes in the notochord genetic toolkit: a comparative analysis of notochord genes in the ascidian Ciona and the larvacean Oikopleura. AB - BACKGROUND: The notochord is a defining feature of the chordate clade, and invertebrate chordates, such as tunicates, are uniquely suited for studies of this structure. Here we used a well-characterized set of 50 notochord genes known to be targets of the notochord-specific Brachyury transcription factor in one tunicate, Ciona intestinalis (Class Ascidiacea), to begin determining whether the same genetic toolkit is employed to build the notochord in another tunicate, Oikopleura dioica (Class Larvacea). We identified Oikopleura orthologs of the Ciona notochord genes, as well as lineage-specific duplicates for which we determined the phylogenetic relationships with related genes from other chordates, and we analyzed their expression patterns in Oikopleura embryos. RESULTS: Of the 50 Ciona notochord genes that were used as a reference, only 26 had clearly identifiable orthologs in Oikopleura. Two of these conserved genes appeared to have undergone Oikopleura- and/or tunicate-specific duplications, and one was present in three copies in Oikopleura, thus bringing the number of genes to test to 30. We were able to clone and test 28 of these genes. Thirteen of the 28 Oikopleura orthologs of Ciona notochord genes showed clear expression in all or in part of the Oikopleura notochord, seven were diffusely expressed throughout the tail, six were expressed in tissues other than the notochord, while two probes did not provide a detectable signal at any of the stages analyzed. One of the notochord genes identified, Oikopleura netrin, was found to be unevenly expressed in notochord cells, in a pattern reminiscent of that previously observed for one of the Oikopleura Hox genes. CONCLUSIONS: A surprisingly high number of Ciona notochord genes do not have apparent counterparts in Oikopleura, and only a fraction of the evolutionarily conserved genes show clear notochord expression. This suggests that Ciona and Oikopleura, despite the morphological similarities of their notochords, have developed rather divergent sets of notochord genes after their split from a common tunicate ancestor. This study demonstrates that comparisons between divergent tunicates can lead to insights into the basic complement of genes sufficient for notochord development, and elucidate the constraints that control its composition. PMID- 21251252 TI - An empirical evaluation of imputation accuracy for association statistics reveals increased type-I error rates in genome-wide associations. AB - BACKGROUND: Genome wide association studies (GWAS) are becoming the approach of choice to identify genetic determinants of complex phenotypes and common diseases. The astonishing amount of generated data and the use of distinct genotyping platforms with variable genomic coverage are still analytical challenges. Imputation algorithms combine directly genotyped markers information with haplotypic structure for the population of interest for the inference of a badly genotyped or missing marker and are considered a near zero cost approach to allow the comparison and combination of data generated in different studies. Several reports stated that imputed markers have an overall acceptable accuracy but no published report has performed a pair wise comparison of imputed and empiric association statistics of a complete set of GWAS markers. RESULTS: In this report we identified a total of 73 imputed markers that yielded a nominally statistically significant association at P < 10 -5 for type 2 Diabetes Mellitus and compared them with results obtained based on empirical allelic frequencies. Interestingly, despite their overall high correlation, association statistics based on imputed frequencies were discordant in 35 of the 73 (47%) associated markers, considerably inflating the type I error rate of imputed markers. We comprehensively tested several quality thresholds, the haplotypic structure underlying imputed markers and the use of flanking markers as predictors of inaccurate association statistics derived from imputed markers. CONCLUSIONS: Our results suggest that association statistics from imputed markers showing specific MAF (Minor Allele Frequencies) range, located in weak linkage disequilibrium blocks or strongly deviating from local patterns of association are prone to have inflated false positive association signals. The present study highlights the potential of imputation procedures and proposes simple procedures for selecting the best imputed markers for follow-up genotyping studies. PMID- 21251253 TI - Comparative population genetics of mimetic Heliconius butterflies in an endangered habitat; Brazil's Atlantic Forest. AB - BACKGROUND: Brazil's Atlantic Forest is a biodiversity hotspot endangered by severe habitat degradation and fragmentation. Habitat fragmentation is expected to reduce dispersal among habitat patches resulting in increased genetic differentiation among populations. Here we examined genetic diversity and differentiation among populations of two Heliconius butterfly species in the northern portion of Brazil's Atlantic Forest to estimate the potential impact of habitat fragmentation on population connectivity in butterflies with home-range behavior. RESULTS: We generated microsatellite, AFLP and mtDNA sequence data for 136 Heliconius erato specimens from eight collecting locations and 146 H. melpomene specimens from seven locations. Population genetic analyses of the data revealed high levels of genetic diversity in H. erato relative to H. melpomene, widespread genetic differentiation among populations of both species, and no evidence for isolation-by-distance. CONCLUSIONS: These results are consistent with the hypothesis that the extensive habitat fragmentation along Brazil's Atlantic Forest has reduced dispersal of Heliconius butterflies among neighboring habitat patches. The results also lend support to the observation that fine-scale population genetic structure may be common in Heliconius. If such population structure also exists independent of human activity, and has been common over the evolutionary history of Heliconius butterflies, it may have contributed to the evolution of wing pattern diversity in the genus. PMID- 21251254 TI - False negative rates in Drosophila cell-based RNAi screens: a case study. AB - BACKGROUND: High-throughput screening using RNAi is a powerful gene discovery method but is often complicated by false positive and false negative results. Whereas false positive results associated with RNAi reagents has been a matter of extensive study, the issue of false negatives has received less attention. RESULTS: We performed a meta-analysis of several genome-wide, cell-based Drosophila RNAi screens, together with a more focused RNAi screen, and conclude that the rate of false negative results is at least 8%. Further, we demonstrate how knowledge of the cell transcriptome can be used to resolve ambiguous results and how the number of false negative results can be reduced by using multiple, independently-tested RNAi reagents per gene. CONCLUSIONS: RNAi reagents that target the same gene do not always yield consistent results due to false positives and weak or ineffective reagents. False positive results can be partially minimized by filtering with transcriptome data. RNAi libraries with multiple reagents per gene also reduce false positive and false negative outcomes when inconsistent results are disambiguated carefully. PMID- 21251255 TI - Deep sequencing-based analysis of the anaerobic stimulon in Neisseria gonorrhoeae. AB - BACKGROUND: Maintenance of an anaerobic denitrification system in the obligate human pathogen, Neisseria gonorrhoeae, suggests that an anaerobic lifestyle may be important during the course of infection. Furthermore, mounting evidence suggests that reduction of host-produced nitric oxide has several immunomodulary effects on the host. However, at this point there have been no studies analyzing the complete gonococcal transcriptome response to anaerobiosis. Here we performed deep sequencing to compare the gonococcal transcriptomes of aerobically and anaerobically grown cells. Using the information derived from this sequencing, we discuss the implications of the robust transcriptional response to anaerobic growth. RESULTS: We determined that 198 chromosomal genes were differentially expressed (~10% of the genome) in response to anaerobic conditions. We also observed a large induction of genes encoded within the cryptic plasmid, pJD1. Validation of RNA-seq data using translational-lacZ fusions or RT-PCR demonstrated the RNA-seq results to be very reproducible. Surprisingly, many genes of prophage origin were induced anaerobically, as well as several transcriptional regulators previously unknown to be involved in anaerobic growth. We also confirmed expression and regulation of a small RNA, likely a functional equivalent of fnrS in the Enterobacteriaceae family. We also determined that many genes found to be responsive to anaerobiosis have also been shown to be responsive to iron and/or oxidative stress. CONCLUSIONS: Gonococci will be subject to many forms of environmental stress, including oxygen-limitation, during the course of infection. Here we determined that the anaerobic stimulon in gonococci was larger than previous studies would suggest. Many new targets for future research have been uncovered, and the results derived from this study may have helped to elucidate factors or mechanisms of virulence that may have otherwise been overlooked. PMID- 21251256 TI - Persistence of virus-specific immune responses in the central nervous system of mice after West Nile virus infection. AB - BACKGROUND: West Nile virus (WNV) persists in humans and several animal models. We previously demonstrated that WNV persists in the central nervous system (CNS) of mice for up to 6 months post-inoculation. We hypothesized that the CNS immune response is ineffective in clearing the virus. RESULTS: Immunocompetent, adult mice were inoculated subcutaneously with WNV, and the CNS immune response was examined at 1, 2, 4, 8, 12 and 16 weeks post-inoculation (wpi). Characterization of lymphocyte phenotypes in the CNS revealed elevation of CD19+ B cells for 4 wpi, CD138 plasma cells at 12 wpi, and CD4+ and CD8+ T cells for at least 12 wpi. T cells recruited to the brain were activated, and regulatory T cells (Tregs) were present for at least 12 wpi. WNV-specific antibody secreting cells were detected in the brain from 2 to 16 wpi, and virus-specific CD8+ T cells directed against an immunodominant WNV epitope were detected in the brain from 1 to 16 wpi. Furthermore, these WNV-specific immune responses occurred in mice with and without acute clinical disease. CONCLUSIONS: Virus-specific immune cells persist in the CNS of mice after WNV infection for up to 16 wpi. PMID- 21251257 TI - Autoreactive marginal zone B cells enter the follicles and interact with CD4+ T cells in lupus-prone mice. AB - BACKGROUND: Marginal zone B cells have been implicated in the production of autoantibodies in murine models of lupus. It has been suggested that they contribute to lupus immunopathogenesis through their enhanced effector functions and their repertoire that is biased toward autoreactive specificities. In the B6.NZM2410.Sle.Sle2.Sle3 (B6.TC) model of lupus, the majority of marginal zone B cells are located outside the marginal zone and inside the follicles. Genetic alterations of this strain have shown a correlation between autoimmune pathogenesis and the presence of intrafollicular marginal zone B cells. This study was designed first to strengthen our original observations and to determine how the marginal zone B cells from the lupus-prone mice respond to stimulations and interact with T cells. RESULTS: The intrafollicular location of B6.TC MZB cells starts before disease manifestations and puts MZB cells in direct contact with CD4+ T cells. Two different autoreactive B cell receptor (BCR) transgenic models showed that the expression of the Sle susceptibility loci enhances the presence of MZB cells inside the follicles. In vitro, B6.TC MZB cells were better effectors than B6 MZB cells with enhanced proliferation and antibody (Ab) production, including anti-DNA Ab, in response to stimulation with TLR ligands, immune complexes or anti-CD40. Furthermore, B6.TC MZB and CD4+ T cells showed a reciprocally enhanced activation, which indicated that their contacts inside B6.TC follicles have functional consequences that suggest an amplification loop between these two cell types. CONCLUSIONS: These results showed that the NZM2410 susceptibility loci induce MZB cells to locate into the follicles, and that this breach of follicular exclusion occurs early in the development of the autoimmune pathogenesis. The enhanced responses to stimulation and increased effector functions of MZB cells from lupus-prone mice as compare to non-autoimmune MZB cells provide a mechanism by which the failure of MZB cell follicular exclusion contributes to the autoimmune process. PMID- 21251258 TI - Induction kinetics of the Staphylococcus aureus cell wall stress stimulon in response to different cell wall active antibiotics. AB - BACKGROUND: Staphylococcus aureus activates a protective cell wall stress stimulon (CWSS) in response to the inhibition of cell wall synthesis or cell envelope damage caused by several structurally and functionally different antibiotics. CWSS induction is coordinated by the VraSR two-component system, which senses an unknown signal triggered by diverse cell wall active agents. RESULTS: We have constructed a highly sensitive luciferase reporter gene system, using the promoter of sas016 (S. aureus N315), which detects very subtle differences in expression as well as measuring > 4 log-fold changes in CWSS activity, to compare the concentration dependence of CWSS induction kinetics of antibiotics with different cell envelope targets. We compared the effects of subinhibitory up to suprainhibitory concentrations of fosfomycin, D-cycloserine, tunicamycin, bacitracin, flavomycin, vancomycin, teicoplanin, oxacillin, lysostaphin and daptomycin. Induction kinetics were both strongly antibiotic- and concentration-dependent. Most antibiotics triggered an immediate response with induction beginning within 10 min, except for tunicamycin, D-cycloserine and fosfomycin which showed lags of up to one generation before induction commenced. Induction characteristics, such as the rate of CWSS induction once initiated and maximal induction reached, were strongly antibiotic dependent. We observed a clear correlation between the inhibitory effects of specific antibiotic concentrations on growth and corresponding increases in CWSS induction kinetics. Inactivation of VraR increased susceptibility to the antibiotics tested from 2- to 16-fold, with the exceptions of oxacillin and D-cycloserine, where no differences were detected in the methicillin susceptible S. aureus strain background analysed. There was no apparent correlation between the induction capacity of the various antibiotics and the relative importance of the CWSS for the corresponding resistance phenotypes. CONCLUSION: CWSS induction profiles were unique for each antibiotic. Differences observed in optimal induction conditions for specific antibiotics should be determined and taken into account when designing and interpreting CWSS induction studies. PMID- 21251259 TI - Patterns and regulation of ribosomal RNA transcription in Borrelia burgdorferi. AB - BACKGROUND: Borrelia burgdorferi contains one 16S and two tandem sets of 23S-5S ribosomal (r) RNA genes whose patterns of transcription and regulation are unknown but are likely to be critical for survival and persistence in its hosts. RESULTS: RT-PCR of B. burgdorferi N40 and B31 revealed three rRNA region transcripts: 16S rRNA-alanine transfer RNA (tRNA Ala); tRNA Ile; and both sets of 23S-5S rRNA. At 34 degrees C, there were no differences in growth rate or in accumulation of total protein, DNA and RNA in B31 cultured in Barbour-Stoenner Kelly (BSK)-H whether rabbit serum was present or not. At 23 degrees C, B31 grew more slowly in serum-containing BSK-H than at 34 degrees C. DNA per cell was higher in cells in exponential as compared to stationary phase at either temperature; protein per cell was similar at both temperatures in both phases. Similar amounts of rRNA were produced in exponential phase at both temperatures, and rRNA was down-regulated in stationary phase at either temperature. Interestingly, a rel Bbu deletion mutant unable to generate (p)ppGpp did not down regulate rRNA at transition to stationary phase in serum-containing BSK-H at 34 degrees C, similar to the relaxed phenotype of E. coli relA mutants. CONCLUSIONS: We conclude that rRNA transcription in B. burgdorferi is complex and regulated both by growth phase and by the stringent response but not by temperature modulated growth rate. PMID- 21251260 TI - Amygdalar glutamatergic neuronal systems play a key role on the hibernating state of hamsters. AB - BACKGROUND: Excitatory transmitting mechanisms are proving to play a critical role on neuronal homeostasis conditions of facultative hibernators such as the Syrian golden hamster. Indeed works have shown that the glutamatergic system of the main olfactory brain station (amygdala) is capable of controlling thermoregulatory responses, which are considered vital for the different hibernating states. In the present study the role of amygdalar glutamatergic circuits on non-hibernating (NHIB) and hibernating (HIB) hamsters were assessed on drinking stimuli and subsequently compared to expression variations of some glutamatergic subtype mRNA levels in limbic areas. For this study the two major glutamatergic antagonists and namely that of N-methyl-D-aspartate receptor (NMDAR), 3-(+)-2-carboxypiperazin-4-yl-propyl-1-phosphonate (CPP) plus that of the acid alpha-amine-3-hydroxy-5-methyl-4-isoxazol-propionic receptor (AMPAR) site, cyano-7-nitro-quinoxaline-2,3-dione (CNQX) were infused into the basolateral amygdala nucleus. Attempts were made to establish the type of effects evoked by amygdalar glutamatergic cross-talking processes during drinking stimuli, a response that may corroborate their major role at least during some stages of this physiological activity in hibernators. RESULTS: From the behavioral results it appears that the two glutamatergic compounds exerted distinct effects. In the first case local infusion of basolateral complexes (BLA) with NMDAR antagonist caused very great (p < 0.001) drinking rhythms while moderately increased feeding (p < 0.05) responses during arousal with respect to moderately increased drinking levels in euthermics. Conversely, treatment with CNQX did not modify drinking rhythms and so animals spent more time executing exploratory behaviors. These same antagonists accounted for altered glutamatergic transcription activities as displayed by greatly reduced GluR1, NR1 and GluR2 levels in hippocampus, ventromedial hypothalamic nucleus (VMN) and amygdala, respectively, plus a great (p < 0.01) up-regulation of GluR2 in VMN of hibernators. CONCLUSION: We conclude that predominant drinking events evoked by glutamatergic mechanisms, in the presence of prevalently down regulated levels of NR1/2A of some telencephalic and hypothalamic areas appear to constitute an important neuronal switch at least during arousal stage of hibernation. The establishment of the type of glutamatergic subtypes that are linked to successful hibernating states, via drinking stimuli, may have useful bearings toward sleeping disorders. PMID- 21251261 TI - Macrophage presence is essential for the regeneration of ascending afferent fibres following a conditioning sciatic nerve lesion in adult rats. AB - BACKGROUND: Injury to the peripheral branch of dorsal root ganglia (DRG) neurons prior to injury to the central nervous system (CNS) DRG branch results in the regeneration of the central branch. The exact mechanism mediating this regenerative trigger is not fully understood. It has been proposed that following peripheral injury, the intraganglionic inflammatory response by macrophage cells plays an important role in the pre-conditioning of injured CNS neurons to regenerate. In this study, we investigated whether the presence of macrophage cells is crucial for this type of regeneration to occur. We used a clodronate liposome technique to selectively and temporarily deplete these cells during the conditioning phase of DRG neurons. RESULTS: Retrograde and anterograde tracing results indicated that in macrophage-depleted animals, the regenerative trigger characteristic of pre-conditioned DRG neurons was abolished as compared to injury matched-control animals. In addition, depletion of macrophage cells led to: (i) a reduction in macrophage infiltration into the CNS compartment even after cellular repopulation, (ii) astrocyte up-regulation at rostral regions and down-regulation in brain derived neurotrophic factor (BDNF) concentration in the serum. CONCLUSION: Activation of macrophage cells in response to the peripheral nerve injury is essential for the enhanced regeneration of ascending sensory neurons. PMID- 21251262 TI - Axonal outgrowth is associated with increased ERK 1/2 activation but decreased caspase 3 linked cell death in Schwann cells after immediate nerve repair in rats. AB - BACKGROUND: Extracellular-signal regulated kinase (ERK1/2) is activated by nerve damage and its activation precedes survival and proliferation of Schwann cells. In contrast, activation of caspase 3, a cysteine protease, is considered as a marker for apoptosis in Schwann cells. In the present study, axonal outgrowth, activation of ERK1/2 by phosphorylation (p-ERK 1/2 ) and immunoreactivity of cleaved caspase 3 were examined after immediate, delayed, or no repair of transected rat sciatic nerves. RESULTS: Axonal outgrowth, detected by neurofilament staining, was longer after immediate repair than after either the delayed or no repair conditions. Immediate repair also showed a higher expression of p-ERK 1/2 and a lower number of cleaved caspase 3 stained Schwann cells than after delayed nerve repair. If the transected nerve was not repaired a lower level of p-ERK 1/2 was found than in either the immediate or delayed repair conditions. Axonal outgrowth correlated to p-ERK 1/2, but not clearly with cleaved caspase 3. Contact with regenerating axons affected Schwann cells with respect to p-ERK 1/2 and cleaved caspase 3 after immediate nerve repair only. CONCLUSION: The decreased regenerative capacity that has historically been observed after delayed nerve repair may be related to impaired activation of Schwann cells and increased Schwann cell death. Outgrowing axons influence ERK 1/2 activation and apoptosis of Schwann cells. PMID- 21251263 TI - Development of genic-SSR markers by deep transcriptome sequencing in pigeonpea [Cajanus cajan (L.) Millspaugh]. AB - BACKGROUND: Pigeonpea [Cajanus cajan (L.) Millspaugh], one of the most important food legumes of semi-arid tropical and subtropical regions, has limited genomic resources, particularly expressed sequence based (genic) markers. We report a comprehensive set of validated genic simple sequence repeat (SSR) markers using deep transcriptome sequencing, and its application in genetic diversity analysis and mapping. RESULTS: In this study, 43,324 transcriptome shotgun assembly unigene contigs were assembled from 1.696 million 454 GS-FLX sequence reads of separate pooled cDNA libraries prepared from leaf, root, stem and immature seed of two pigeonpea varieties, Asha and UPAS 120. A total of 3,771 genic-SSR loci, excluding homopolymeric and compound repeats, were identified; of which 2,877 PCR primer pairs were designed for marker development. Dinucleotide was the most common repeat motif with a frequency of 60.41%, followed by tri- (34.52%), hexa- (2.62%), tetra- (1.67%) and pentanucleotide (0.76%) repeat motifs. Primers were synthesized and tested for 772 of these loci with repeat lengths of >= 18 bp. Of these, 550 markers were validated for consistent amplification in eight diverse pigeonpea varieties; 71 were found to be polymorphic on agarose gel electrophoresis. Genetic diversity analysis was done on 22 pigeonpea varieties and eight wild species using 20 highly polymorphic genic-SSR markers. The number of alleles at these loci ranged from 4-10 and the polymorphism information content values ranged from 0.46 to 0.72. Neighbor-joining dendrogram showed distinct separation of the different groups of pigeonpea cultivars and wild species. Deep transcriptome sequencing of the two parental lines helped in silico identification of polymorphic genic-SSR loci to facilitate the rapid development of an intra-species reference genetic map, a subset of which was validated for expected allelic segregation in the reference mapping population. CONCLUSION: We developed 550 validated genic-SSR markers in pigeonpea using deep transcriptome sequencing. From these, 20 highly polymorphic markers were used to evaluate the genetic relationship among species of the genus Cajanus. A comprehensive set of genic-SSR markers was developed as an important genomic resource for diversity analysis and genetic mapping in pigeonpea. PMID- 21251264 TI - Computational prediction and experimental validation associating FABP-1 and pancreatic adenocarcinoma with diabetes. AB - BACKGROUND: Pancreatic cancer, composed principally of pancreatic adenocarcinoma (PaC), is the fourth leading cause of cancer death in the United States. PaC associated diabetes may be a marker of early disease. We sought to identify molecules associated with PaC and PaC with diabetes (PaC-DM) using a novel translational bioinformatics approach. We identified fatty acid binding protein-1 (FABP-1) as one of several candidates. The primary aim of this pilot study was to experimentally validate the predicted association between FABP-1 with PaC and PaC with diabetes. METHODS: We searched public microarray measurements for genes that were specifically highly expressed in PaC. We then filtered for proteins with known involvement in diabetes. Validation of FABP-1 was performed via antibody immunohistochemistry on formalin-fixed paraffin embedded pancreatic tissue microarrays (FFPE TMA). FFPE TMA were constructed using 148 cores of pancreatic tissue from 134 patients collected between 1995 and 2002 from patients who underwent pancreatic surgery. Primary analysis was performed on 21 normal and 60 pancreatic adenocarcinoma samples, stratified for diabetes. Clinical data on samples was obtained via retrospective chart review. Serial sections were cut per standard protocol. Antibody staining was graded by an experienced pathologist on a scale of 0-3. Bivariate and multivariate analyses were conducted to assess FABP 1 staining and clinical characteristics. RESULTS: Normal samples were significantly more likely to come from younger patients. PaC samples were significantly more likely to stain for FABP-1, when FABP-1 staining was considered a binary variable. Compared to normals, there was significantly increased staining in diabetic PaC samples (p = 0.004) and there was a trend towards increased staining in the non-diabetic PaC group (p = 0.07). In logistic regression modeling, FABP-1 staining was significantly associated with diagnosis of PaC (OR 8.6 95% CI 1.1-68, p = 0.04), though age was a confounder. CONCLUSIONS: Compared to normal controls, there was a significant positive association between FABP-1 staining and PaC on FFPE-TMA, strengthened by the presence of diabetes. Further studies with closely phenotyped patient samples are required to understand the true relationship between FABP-1, PaC and PaC associated diabetes. A translational bioinformatics approach has potential to identify novel disease associations and potential biomarkers in gastroenterology. PMID- 21251266 TI - A case of septicaemic anthrax in an intravenous drug user. AB - BACKGROUND: In 2000, Ringertz et al described the first case of systemic anthrax caused by injecting heroin contaminated with anthrax. In 2008, there were 574 drug related deaths in Scotland, of which 336 were associated with heroin and or morphine. We report a rare case of septicaemic anthrax caused by injecting heroin contaminated with anthrax in Scotland. CASE PRESENTATION: A 32 year old intravenous drug user (IVDU), presented with a 12 hour history of increasing purulent discharge from a chronic sinus in his left groin. He had a tachycardia, pyrexia, leukocytosis and an elevated C-reactive protein (CRP). He was treated with Vancomycin, Clindamycin, Ciprofloxacin, Gentamicin and Metronidazole. Blood cultures grew Bacillus anthracis within 24 hours of presentation. He had a computed tomography (CT) scan and magnetic resonance imagining (MRI) of his abdomen, pelvis and thighs performed. These showed inflammatory change relating to the iliopsoas and an area of necrosis in the adductor magnus.He underwent an exploration of his left thigh. This revealed chronically indurated subcutaneous tissues with no evidence of a collection or necrotic muscle. Treatment with Vancomycin, Ciprofloxacin and Clindamycin continued for 14 days. Negative Pressure Wound Therapy (NPWT) device was applied utilising the VenturiTM wound sealing kit. Following 4 weeks of treatment, the wound dimensions had reduced by 77%. CONCLUSIONS: Although systemic anthrax infection is rare, it should be considered when faced with severe cutaneous infection in IVDU patients. This case shows that patients with significant bacteraemia may present with no signs of haemodynamic compromise. Prompt recognition and treatment with high dose IV antimicrobial therapy increases the likelihood of survival. The use of simple wound therapy adjuncts such as NPWT can give excellent wound healing results. PMID- 21251265 TI - Genital warts and infection with human immunodeficiency virus in high-risk women in Burkina Faso: a longitudinal study. AB - BACKGROUND: Human papillomaviruses are the most common sexually transmitted infections, and genital warts, caused by HPV-6 and 11, entail considerable morbidity and cost. The natural history of genital warts in relation to HIV-1 infection has not been described in African women. We examined risk factors for genital warts in a cohort of high-risk women in Burkina Faso, in order to further describe their epidemiology. METHODS: A prospective study of 765 high-risk women who were followed at 4-monthly intervals for 27 months in Burkina Faso. Logistic and Cox regression were used to identify factors associated with prevalent, incident and persistent genital warts, including HIV-1 serostatus, CD4+ count, and concurrent sexually transmitted infections. In a subset of 306 women, cervical HPV DNA was tested at enrollment. RESULTS: Genital wart prevalence at baseline was 1.6% (8/492) among HIV-uninfected and 7.0% (19/273) among HIV-1 seropositive women. Forty women (5.2%) experienced at least one incident GW episode. Incidence was 1.1 per 100 person-years among HIV-uninfected women, 7.4 per 100 person-years among HIV-1 seropositive women with a nadir CD4+ count >200 cells/MUL and 14.6 per 100 person-years among HIV-1 seropositive women with a nadir CD4+ count <= 200 cells/MUL. Incident genital warts were also associated with concurrent bacterial vaginosis, and genital ulceration. Antiretroviral therapy was not protective against incident or persistent genital warts. Detection of HPV-6 DNA and abnormal cervical cytology were strongly associated with incident genital warts. CONCLUSIONS: Genital warts occur much more frequently among HIV-1 infected women in Africa, particularly among those with low CD4+ counts. Antiretroviral therapy did not reduce the incidence or persistence of genital warts in this population. PMID- 21251267 TI - Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with intellectual disability. AB - BACKGROUND: Intellectual disability (ID) is frequently associated with sleep disorders. Treatment with melatonin demonstrated efficacy, suggesting that, at least in a subgroup of patients, the endogenous melatonin level may not be sufficient to adequately set the sleep-wake cycles. Mutations in ASMT gene, coding the last enzyme of the melatonin pathway have been reported as a risk factor for autism spectrum disorders (ASD), which are often comorbid with ID. Thus the aim of the study was to ascertain the genetic variability of ASMT in a large cohort of patients with ID and controls. METHODS: Here, we sequenced all exons of ASMT in a sample of 361 patients with ID and 440 controls. We then measured the ASMT activity in B lymphoblastoid cell lines (BLCL) of patients with ID carrying an ASMT variant and compared it to controls. RESULTS: We could identify eleven variations modifying the protein sequence of ASMT (ID only: N13H, N17K, V171M, E288D; controls only: E61Q, D210G, K219R, P243L, C273S, R291Q; ID and controls: L298F) and two deleterious splice site mutations (IVS5+2T>C and IVS7+1G>T) only observed in patients with ID. We then ascertained ASMT activity in B lymphoblastoid cell lines from patients carrying the mutations and showed significantly lower enzyme activity in patients carrying mutations compared to controls (p = 0.004). CONCLUSIONS: We could identify patients with deleterious ASMT mutations as well as decreased ASMT activity. However, this study does not support ASMT as a causative gene for ID since we observed no significant enrichment in the frequency of ASMT variants in ID compared to controls. Nevertheless, given the impact of sleep difficulties in patients with ID, melatonin supplementation might be of great benefit for a subgroup of patients with low melatonin synthesis. PMID- 21251269 TI - Effect of high parity on occurrence of anemia in pregnancy: a cohort study. AB - BACKGROUND: Studies that explore the controversial association between parity and anaemia-in-pregnancy (AIP) were often hampered by not distinguishing incident cases caused by pregnancy from prevalent cases complicated by pregnancy. The authors' aim in conducting this study was to overcome this methodological concern. METHODS: A retrospective cohort study was conducted in Oman on 1939 pregnancies among 479 parous female participants with available pregnancy records in a community trial. We collected information from participants, the community trial, and health records of each pregnancy. Throughout the follow-up period, we enumerated 684 AIP cases of which 289 (42.2%) were incident cases. High parity (HP, >= 5 pregnancies) accounted for 48.7% of total pregnancies. Two sets of regression analyses were conducted: the first restricted to incident cases only, and the second inclusive of all cases. The relation with parity as a dichotomy and as multiple categories was examined for each set; multi-level logistic regression (MLLR) was employed to produce adjusted models. RESULTS: In the fully adjusted MLLR models that were restricted to incident cases, women with HP pregnancies had a higher risk of AIP compared to those who had had fewer pregnancies (Risk Ratio, RR = 2.92; 95% CI 2.02, 4.59); the AIP risk increased in a dose-response fashion over multiple categories of parity. In the fully adjusted MLLR models that included all cases, the association disappeared (RR = 1.11; 95% CI 0.91, 1.18) and the dose-response pattern flattened. CONCLUSIONS: This study shows the importance of specifying which cases of AIP are incident and provides supportive evidence for a causal relation between parity and occurrence of incidental AIP. PMID- 21251268 TI - A cost-consequences analysis of the effect of pregabalin in the treatment of peripheral neuropathic pain in routine medical practice in primary care settings. AB - BACKGROUND: Neuropathic pain (NeP) is a common symptom of a group of a variety of conditions, including diabetic neuropathy, trigeminal neuralgia, or postherpetic neuralgia. Prevalence of NeP has been estimated to range between 5-7.5%, and produces up to 25% of pain clinics consultations. Due to its severity, chronic evolution, and associated co-morbidities, NeP has an important individual and social impact. The objective was to analyze the effect of pregabalin (PGB) on pain alleviation and longitudinal health and non-health resources utilization and derived costs in peripheral refractory NeP in routine medical practice in primary care settings (PCS) in Spain. METHODS: Subjects from PCS were older than 18 years, with peripheral NeP (diabetic neuropathy, post-herpetic neuralgia or trigeminal neuralgia), refractory to at least one previous analgesic, and included in a prospective, real world, and 12-week two-visit cost-of-illness study. Measurement of resources utilization included both direct healthcare and indirect expenditures. Pain severity was measured by the Short Form-McGill Pain Questionnaire (SF-MPQ). RESULTS: One-thousand-three-hundred-fifty-four PGB-naive patients [58.8% women, 59.5 (12.7) years old] were found eligible for this secondary analysis: 598 (44%) switched from previous therapy to PGB given in monotherapy (PGBm), 589 (44%) received PGB as add-on therapy (PGB add-on), and 167 (12%) patients changed previous treatments to others different than PGB (non PGB). Reductions of pain severity were higher in both PGBm and PGB add-on groups (54% and 51%, respectively) than in non-PGB group (34%), p < 0.001. Incremental drug costs, particularly in PGB subgroups [? 34.6 (80.3), ? 160.7 (123.9) and ? 154.5 (133.0), for non-PGB, PGBm and PGBadd-on, respectively (p < 0.001)], were off-set by higher significant reductions in all other components of health costs yielding to a greater total cost reductions: -? 1,045.3 (1,989.6),-? 1,312.9 (1,543.0), and -? 1,565.5 (2,004.1), for the three groups respectively (p = 0.03). CONCLUSION: In Spanish primary care settings, PGB given either add-on or in monotherapy in routine medical practice was associated with pain alleviation leading to significant longitudinal reductions in resource use and total costs during the 12-week period of the study compared with non-PGB-therapy of patients with chronic NeP of peripheral origin. The use of non-appropriate analgesic therapies for neuropathic pain in a portion of subjects in non-PGB group could explain partially such findings. PMID- 21251270 TI - Epidemiology and trends for Caesarean section births in New South Wales, Australia: a population-based study. AB - BACKGROUND: Caesarean section (CS) rates around the world have been increasing and in Australia have reached 30% of all births. Robson's Ten-Group Classification System (10-group classification) provides a clinically relevant classification of CS rates that provides a useful basis for international comparisons and trend analyses. This study aimed to investigate trends in CS rates in New South Wales (NSW), including trends in the components of the 10 group classification. METHODS: We undertook a cross-sectional study using data from the Midwives Data Collection, a state-wide surveillance system that monitors patterns of pregnancy care, services and pregnancy outcomes in New South Wales, Australia. The study population included all women giving birth between 1st January 1998 and 31st December 2008. Descriptive statistics are presented including age-standardised CS rates, annual percentage change as well as regression analyses. RESULTS: From 1998 to 2008 the CS rate in NSW increased from 19.1 to 29.5 per 100 births. There was a significant average annual increase in primary 4.3% (95%CI 3.0-5.7%) and repeat 4.8% (95% CI 3.9-5.7%) CS rates from 1998 to 2008. After adjusting for maternal and pregnancy factors, the increase in CS delivery over time was maintained. When examining CS rates classified according to the 10-group classification, the greatest contributors to the overall CS rate and the largest annual increases occurred among nulliparae at term having elective CS and multipara having elective repeat CS. CONCLUSIONS: Given that the increased CS rate cannot be explained by known and collected maternal or pregnancy characteristics, the increase may be related to differences in clinical decision making or maternal request. Future efforts to reduce the overall CS rate should be focussed on reducing the primary CS rate. PMID- 21251272 TI - The Farsi version of the Hypomania Check-List 32 (HCL-32): applicability and indication of a four-factorial solution. AB - BACKGROUND: Data from the Iranian population for hypomania core symptom clusters are lacking. The aim of the present study was therefore to apply the Farsi version of the Hypomania-Check-List 32 (HCL-32), and to explore its factorial structure. METHODS: A total of 163 Iranian out-patients took part in the study; 61 suffered from Major Depressive Disorder (MDD), and 102 suffered from Bipolar Disorders (BP). Participants completed the Mood Disorder Questionnaire (MDQ) and the Hypomania Checklist (HCL-32). Exploratory factor analyses were used to examine the properties of the HCL-32. A ROC-curve analysis was performed to calculate sensitivity and specificity. RESULTS: The HCL-32 differentiated between patients with MDD and with BP. Psychometric properties were satisfactory: sensitivity: 73%; specificity: 91%. MDQ and HCL-32 did correlate highly. No differences were found between patients suffering from BP I and BP II. DISCUSSION: Instead of the two-factorial structure of the HCL-32 reported previously, the present pattern of factorial results suggest a distinction between four factors: two broadly positive dimensions of hypomania ("physically and mentally active"; "positive social interactions") and two rather negative dimensions ("risky behavior and substance use"; "difficulties in social interaction and impatience"). CONCLUSION: The Farsi version of the HCL-32 proved to be applicable, and therefore easy to introduce within a clinical context. The pattern of results suggests a four factorial solution. PMID- 21251271 TI - Antiangiogenic effects of pazopanib in xenograft hepatocellular carcinoma models: evaluation by quantitative contrast-enhanced ultrasonography. AB - BACKGROUND: Antiangiogenesis is a promising therapy for advanced hepatocellular carcinoma (HCC), but the effects are difficult to be evaluated. Pazopanib (GW786034B) is a pan-vascular endothelial growth factor receptor inhibitor, the antitumor effects or antiangiogenic effects haven't been investigated in HCC. METHODS: In vitro direct effects of pazopanib on human HCC cell lines and endothelial cells were evaluated. In vivo antitumor effects were evaluated in three xenograft nude mice models. In the subcutaneous HCCLM3 model, intratumoral blood perfusion was detected by contrast-enhanced ultrasonography (CEUS), and serial quantitative parameters were profiled from the time-intensity curves of ultrasonograms. RESULTS: In vitro proliferation of various HCC cell lines were not inhibited by pazopanib. Pazopanib inhibited migration and invasion and induced apoptosis significantly in two HCC cell lines, HCCLM3 and PLC/PRF/5. Proliferation, migration, and tubule formation of human umbilical vein endothelial cells were inhibited by pazopanib in a dose-dependent manner. In vivo tumor growth was significantly inhibited by pazopanib in HCCLM3, HepG2, and PLC/PRF/5 xenograft models. Various intratumoral perfusion parameters changed over time, and the signal intensity was significantly impaired in the treated tumors before the treatment efficacy on tumor size could be observed. Mean transit time of the contrast media in hotspot areas of the tumors was reversely correlated with intratumoral microvessel density. CONCLUSIONS: Antitumor effects of pazopanib in HCC xenografts may owe to its antiangiogenic effects, and the in vivo antiangiogenic effects could be evaluated by quantitative CEUS. PMID- 21251274 TI - Breast cancer care compared with clinical Guidelines: an observational study in France. AB - BACKGROUND: Great variability in breast cancer (BC) treatment practices according to patient, tumour or organisation of care characteristics has been reported but the relation between these factors is not well known. In two French regions, we measured compliance with Clinical Practice Guidelines for non-metastatic BC care management and identified factors associated with non-compliance at clinical and organisational levels. METHODS: Eligible patients had invasive unilateral BC without distant metastases and at least two contacts with one of the two regional healthcare systems (2003-2004) in the first year after diagnosis. Medical data were collected from patient medical records in all public and private hospitals (99 hospitals).The care process was defined by 20 criteria: clinical decisions for treatment and therapeutic procedures. Each criterion was classified according to level of compliance ("Compliant", "Justifiable" and "Not Compliant") and factors of non-compliance were identified (mixed effect logistic regression). RESULTS: 926 women were included. Non-compliance with clinical decisions for treatment was associated with older patient age (OR 2.1; 95%CI: 1.3-3.6) and region (OR 3.0; 95%CI: 1.2-7.4). Non-compliance with clinical decisions for radiotherapy was associated with lymph node involvement or the presence of peritumoural vascular invasion (OR 1.5; 95%CI: 1.01-2.3) and non-compliance with overall treatment (clinical decisions for treatment + therapeutic procedures) was associated with the presence of positive lymph nodes (OR 2.0; 95%CI: 1.2-3.3), grade III versus grade I (OR 2.9; 95%CI: 1.4-6.2), and one region of care versus another (OR 3.5; 95%CI: 1.7-7.1). Finally, heterogeneity of compliance in overall treatment sequence was identified between local cancer units (p < 0.05). CONCLUSION: This study provides interesting insights into factors of non compliance in non-metastatic BC management and could lead to quality care improvements. PMID- 21251275 TI - Adherence with tobramycin inhaled solution and health care utilization. AB - BACKGROUND: Adherence with tobramycin inhalation solution (TIS) during routine cystic fibrosis (CF) care may differ from recommended guidelines and affect health care utilization. METHODS: We analyzed 2001-2006 healthcare claims data from 45 large employers. Study subjects had diagnoses of CF and at least 1 prescription for TIS. We measured adherence as the number of TIS therapy cycles completed during the year and categorized overall adherence as: low <= 2 cycles, medium >2 to <4 cycles, and high >= 4 cycles per year. Interquartile ranges (IQR) were created for health care utilization and logistic regression analysis of hospitalization risk was conducted by TIS adherence categories. RESULTS: Among 804 individuals identified with CF and a prescription for TIS, only 7% (n = 54) received >= 4 cycles of TIS per year. High adherence with TIS was associated with a decreased risk of hospitalization when compared to individuals receiving <= 2 cycles (adjusted odds ratio 0.40; 95% confidence interval 0.19-0.84). High adherence with TIS was also associated with lower outpatient service costs (IQR: $2,159-$8444 vs. $2,410-$14,423) and higher outpatient prescription drug costs (IQR: $35,125-$60,969 vs. $10,353-$46,768). CONCLUSIONS: Use of TIS did not reflect recommended guidelines and may impact other health care utilization. PMID- 21251276 TI - Quantification of HLA class I molecules on renal cell carcinoma using Edman degradation. AB - BACKGROUND: Unimpaired HLA class I antigen presentation is a prerequisite for the recognition of tumor cells by cytotoxic T lymphocytes and thus essential for the success of anticancer immunotherapeutic concepts. Several approaches have been taken in the immunotherapy of metastatic renal cell carcinoma (RCC), however of limited success. HLA loss or down-regulation have often been reported and might interfere with immunotherapeutic approaches aimed at the recognition of HLA presented peptides. METHODS: We employed a quantitative method of molecular analysis for the comparison of HLA amounts on primary tumor, normal kidney and metastases of RCC, using Edman degradation. We analyzed a series of 47 RCC samples including corresponding renal parenchyma, local lymph node metastases and distant metastases. RESULTS: Results of quantitative Edman degradation revealed significantly higher HLA yields on primary tumor and metastases compared to normal kidney tissue. This effect was shown not to result from infiltrating immune cells, since tumor-infiltrating lymphocytes had no influence on the overall HLA recovery from tumor tissue. Unexpectedly, we found a higher amount of HLA class I molecules on distant metastases compared to local lymph node metastases. CONCLUSION: Edman degradation allows the direct quantitative comparison of HLA class I protein expression by tumor or normal tissue and metastases of RCC patients. Our results raise hopes for improving the success and effectiveness of future immunotherapeutic concepts for metastatic RCC. PMID- 21251277 TI - Oxygen limitation and tissue metabolic potential of the African fish Barbus neumayeri: roles of native habitat and acclimatization. AB - BACKGROUND: Oxygen availability in aquatic habitats is a major environmental factor influencing the ecology, behaviour, and physiology of fishes. This study evaluates the contribution of source population and hypoxic acclimatization of the African fish, Barbus neumayeri, in determining growth and tissue metabolic enzyme activities. Individuals were collected from two sites differing dramatically in concentration of dissolved oxygen (DO), Rwembaita Swamp (annual average DO 1.35 mgO2 L(-1)) and Inlet Stream West (annual average DO 5.58 mgO2 L( 1)) in Kibale National Park, Uganda, and reciprocally transplanted using a cage experiment in the field, allowing us to maintain individuals under natural conditions of oxygen, food availability, and flow. Fish were maintained under these conditions for four weeks and sampled for growth rate and the activities of phosphofructokinase (PFK), lactate dehydrogenase (LDH), citrate synthase (CS), and cytochrome c oxidase (CCO) in four tissues, liver, heart, brain, and skeletal muscle. RESULTS: Acclimatization to the low DO site resulted in lower growth rates, lower activities of the aerobic enzyme CCO in heart, and higher activities of the glycolytic enzyme PFK in heart and skeletal muscle. The activity of LDH in liver tissue was correlated with site of origin, being higher in fish collected from a hypoxic habitat, regardless of acclimatization treatment. CONCLUSIONS: Our results suggest that the influence of site of origin and hypoxic acclimatization in determining enzyme activity differs among enzymes and tissues, but both factors contribute to higher glycolytic capacity and lower aerobic capacity in B. neumayeri under naturally-occurring conditions of oxygen limitation. PMID- 21251278 TI - Adverse outcomes after colposcopy. AB - BACKGROUND: Colposcopy is an essential part of the National Health Service Cervical Screening Programme (NHSCSP). It is used for both diagnosis and treatment of pre-cancerous cells of the cervix. Despite colposcopy being a commonly performed and relatively invasive procedure, very little research has explored the potential long-term impacts of colposcopic examination upon patient quality of life.The aim of this study is to investigate and quantify any potential reduction in women's quality of life following a colposcopy procedure. More specifically, the degree of female sexual dysfunction and the excess risk of adverse events in those undergoing colposcopy will be explored. If such risks are identified, these can be communicated to women before undergoing colposcopy. It will also assist in identifying whether there are particular sub-groups at greater risk and if so, this may lead to a re-evaluation of current recommendations concerning colposcopically directed treatments. METHODS/DESIGN: Cohort study using postal surveys to assess sexual function and quality of life in women who have attended for colposcopy (cases), compared with those who have not attended colposcopy (controls). The prevalence and excess risk of female sexual dysfunction will be determined. Logistic regression will identify the predictors of adverse outcomes. DISCUSSION: There are more than 400,000 colposcopy appointments each year in England, of which 134,000 are new referrals. There is some evidence that there may be long-term implications for women treated under colposcopy with respect to adverse obstetric outcomes, persisting anxiety, increased rates of sexual dysfunction and reduced quality of life. Reliably establishing whether such adverse outcomes exist and the excess risk of adverse events will facilitate informed decision-making and patient choice. PMID- 21251279 TI - Potent alpha-amylase inhibitory activity of Indian Ayurvedic medicinal plants. AB - BACKGROUND: Indian medicinal plants used in the Ayurvedic traditional system to treat diabetes are a valuable source of novel anti-diabetic agents. Pancreatic alpha-amylase inhibitors offer an effective strategy to lower the levels of post prandial hyperglycemia via control of starch breakdown. In this study, seventeen Indian medicinal plants with known hypoglycemic properties were subjected to sequential solvent extraction and tested for alpha-amylase inhibition, in order to assess and evaluate their inhibitory potential on PPA (porcine pancreatic alpha-amylase). Preliminary phytochemical analysis of the lead extracts was performed in order to determine the probable constituents. METHODS: Analysis of the 126 extracts, obtained from 17 plants (Aloe vera (L.) Burm.f., Adansonia digitata L., Allium sativum L., Casia fistula L., Catharanthus roseus (L.) G. Don., Cinnamomum verum Persl., Coccinia grandis (L.) Voigt., Linum usitatisumum L., Mangifera indica L., Morus alba L., Nerium oleander L., Ocimum tenuiflorum L., Piper nigrum L., Terminalia chebula Retz., Tinospora cordifolia (Willd.) Miers., Trigonella foenum-graceum L., Zingiber officinale Rosc.) for PPA inhibition was initially performed qualitatively by starch-iodine colour assay. The lead extracts were further quantified with respect to PPA inhibition using the chromogenic DNSA (3, 5-dinitrosalicylic acid) method. Phytochemical constituents of the extracts exhibiting>= 50% inhibition were analysed qualitatively as well as by GC-MS (Gas chromatography-Mass spectrometry). RESULTS: Of the 126 extracts obtained from 17 plants, 17 extracts exhibited PPA inhibitory potential to varying degrees (10%-60.5%) while 4 extracts showed low inhibition (< 10%). However, strong porcine pancreatic amylase inhibitory activity (> 50%) was obtained with 3 isopropanol extracts. All these 3 extracts exhibited concentration dependent inhibition with IC50 values, viz., seeds of Linum usitatisumum (540 MUgml-1), leaves of Morus alba (1440 MUgml-1) and Ocimum tenuiflorum (8.9 MUgml-1). Acarbose as the standard inhibitor exhibited an IC50 (half maximal inhibitory concentration)value of 10.2 MUgml-1. Phytochemical analysis revealed the presence of alkaloids, tannins, cardiac glycosides, flavonoids, saponins and steroids with the major phytoconstituents being identified by GC-MS. CONCLUSIONS: This study endorses the use of these plants for further studies to determine their potential for type 2 diabetes management. Results suggests that extracts of Linum usitatisumum, Morus alba and Ocimum tenuiflorum act effectively as PPA inhibitors leading to a reduction in starch hydrolysis and hence eventually to lowered glucose levels. PMID- 21251280 TI - Glucagon-like peptide-1 enhances cardiac L-type Ca2+ currents via activation of the cAMP-dependent protein kinase A pathway. AB - BACKGROUND: Glucagon-like peptide-1 (GLP-1) is a hormone predominately synthesized and secreted by intestinal L-cells. GLP-1 modulates multiple cellular functions and its receptor agonists are now used clinically for diabetic treatment. Interestingly, preclinical and clinical evidence suggests that GLP-1 agonists produce beneficial effects on dysfunctional hearts via acting on myocardial GLP-1 receptors. As the effects of GLP-1 on myocyte electrophysiology are largely unknown, this study was to assess if GLP-1 could affect the cardiac voltage-gated L-type Ca2+ current (I(Ca)). METHODS: The whole-cell patch clamp method was used to record I(Ca) and action potentials in enzymatically isolated cardiomyocytes from adult canine left ventricles. RESULTS: Extracellular perfusion of GLP-1 (7-36 amide) at 5 nM increased I(Ca) by 23 +/- 8% (p < 0.05, n = 7). Simultaneous bath perfusion of 5 nM GLP-1 plus 100 nM Exendin (9-39), a GLP 1 receptor antagonist, was unable to block the GLP-1-induced increase in I(Ca); however, the increase in I(Ca) was abolished if Exendin (9-39) was pre-applied 5 min prior to GLP-1 administration. Intracellular dialysis with a protein kinase A inhibitor also blocked the GLP-1-enhanced I(Ca). In addition, GLP-1 at 5 nM prolonged the durations of the action potentials by 128 +/- 36 ms (p < 0.01) and 199 +/- 76 ms (p < 0.05) at 50% and 90% repolarization (n = 6), respectively. CONCLUSIONS: Our data demonstrate that GLP-1 enhances I(Ca) in canine cardiomyocytes. The enhancement of I(Ca) is likely via the cAMP-dependent protein kinase A mechanism and may contribute, at least partially, to the prolongation of the action potential duration. PMID- 21251281 TI - Effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor alpha/gamma agonist on glycemic and lipid parameters in a primate model of the metabolic syndrome. AB - BACKGROUND: Glycemic control and management of dyslipidemia to reduce cardiovascular risk are major therapeutic goals in individuals with type 2 diabetes mellitus (T2DM). This study was performed to evaluate the effects of aleglitazar, a balanced dual peroxisome proliferator-activated receptor alpha/gamma (PPARalpha/gamma) agonist, on both lipid and glycemic parameters in obese, hypertriglyceridemic, insulin-resistant rhesus monkeys. METHODS: A 135-day efficacy study was performed in six rhesus monkeys. After a 28-day baseline assessment (vehicle only), monkeys received oral aleglitazar 0.03 mg/kg per day for 42 days, followed by a 63-day washout period. Plasma levels of markers of glycemic and lipid regulation were measured at baseline, at the end of the dosing period, and at the end of the washout period. RESULTS: Compared with baseline values, aleglitazar 0.03 mg/kg per day reduced triglyceride levels by an average of 89% (328 to 36 mg/dL; P = 0.0035 when normalized for baseline levels) and increased high-density lipoprotein cholesterol levels by 125% (46 to 102 mg/dL; P = 0.0007). Furthermore, aleglitazar reduced low-density lipoprotein cholesterol levels (41%) and increased levels of apolipoprotein A-I (17%) and A-II (17%). Aleglitazar also improved insulin sensitivity by 60% (P = 0.001). Mean body weight was reduced by 5.9% from baseline values with aleglitazar at this dose (P = 0.043). CONCLUSIONS: Aleglitazar, a dual PPARalpha/gamma agonist, has beneficial effects on both lipid and glucose parameters and may have a therapeutic role in modifying cardiovascular risk factors and improving glycemic control in patients with T2DM. PMID- 21251282 TI - Novel adiponectin-resistin (AR) and insulin resistance (IRAR) indexes are useful integrated diagnostic biomarkers for insulin resistance, type 2 diabetes and metabolic syndrome: a case control study. AB - BACKGROUND: Adiponectin and resistin are adipokines which modulate insulin action, energy, glucose and lipid homeostasis. Meta-analyses showed that hypoadiponectinemia and hyperresistinemia are strongly associated with increased risk of insulin resistance, type 2 diabetes (T2DM), metabolic syndrome (MS) and cardiovascular disease. The aim of this study was to propose a novel adiponectin resistin (AR) index by taking into account both adiponectin and resistin levels to provide a better indicator of the metabolic homeostasis and metabolic disorders. In addition, a novel insulin resistance (IRAR) index was proposed by integration of the AR index into an existing insulin resistance index to provide an improved diagnostic biomarker of insulin sensitivity. METHODS: In this case control study, anthropometric clinical and metabolic parameters including fasting serum total adiponectin and resistin levels were determined in 809 Malaysian men (208 controls, 174 MS without T2DM, 171 T2DM without MS, 256 T2DM with MS) whose ages ranged between 40-70 years old. Significant differences in continuous variables among subject groups were confirmed by ANCOVA or MANCOVA test using 1,000 stratified bootstrap samples with bias corrected and accelerated (BCa) 95% CI. Spearman's rho rank correlation test was used to test the correlation between two variables. RESULTS: The AR index was formulated as 1+log10(R0)-log10(A0). The AR index was more strongly associated with increased risk of T2DM and MS than hypoadiponectinemia and hyperresistinemia alone. The AR index was more strongly correlated with the insulin resistance indexes and key metabolic endpoints of T2DM and MS than adiponectin and resistin levels alone. The AR index was also correlated with a higher number of MS components than adiponectin and resistin levels alone. The IRAR index was formulated as log10(I0G0)+log10(I0G0)log10(R0/A0). The normal reference range of the IRAR index for insulin sensitive individuals was between 3.265 and 3.538. The minimum cut off values of the IRAR index for insulin resistance assessment were between 3.538 and 3.955. CONCLUSIONS: The novel AR and IRAR indexes are cost-effective, precise, reproducible and reliable integrated diagnostic biomarkers of insulin sensitivity for screening subjects with increased risk of future development of T2DM and MS. PMID- 21251283 TI - Improvements in vascular health by a low-fat diet, but not a high-fat diet, are mediated by changes in adipocyte biology. AB - BACKGROUND: Low-fat (LF) and high-fat (HF) weight loss diets improve brachial artery flow-mediated dilation (FMD) in obese individuals, although results are conflicting. Moreover, the role that adipose tissue plays in mediating these diet related effects are unknown. OBJECTIVE: This study examined how modulations in FMD by HF and LF diets relate to changes in adipocyte parameters. DESIGN: Obese subjects (n = 17) were randomized to a HF diet (60% kcal as fat) or a LF diet (25% kcal as fat) for 6 weeks. Both groups were restricted by 25% of energy needs. RESULTS: Body weight decreased (P <0.05) in both groups (HF: -6.6 +/- 0.5 kg, LF: -4.7 +/- 0.6 kg). Fat mass and waist circumference were reduced (P <0.05) in the LF group only (-4.4 +/- 0.3 kg; -3.6 +/- 0.8 cm, respectively). FMD improved (P <0.05) in the LF group (7.4 +/- 0.8% to 9.8 +/- 0.8; 32% increase) and was impaired in the HF group (8.5 +/- 0.6% to 6.9 +/- 0.7; 19% reduction). Increases in plasma adiponectin (P <0.05, 16 +/- 5%), and decreases in resistin (P <0.05, -26 +/- 11%), were shown by the LF diet only. Greater decreases in leptin were observed with LF (-48 +/- 9%) versus HF (-28 +/- 12%) (P <0.05, diet * time). Increased FMD by the LF diet was associated with increased adiponectin, and decreased fat mass, waist circumference, leptin, and resistin. CONCLUSION: Beneficial modulations in vascular health by LF diets may be mediated by improvements in adipocyte parameters. PMID- 21251284 TI - A 3D freehand ultrasound system for multi-view reconstructions from sparse 2D scanning planes. AB - BACKGROUND: A significant limitation of existing 3D ultrasound systems comes from the fact that the majority of them work with fixed acquisition geometries. As a result, the users have very limited control over the geometry of the 2D scanning planes. METHODS: We present a low-cost and flexible ultrasound imaging system that integrates several image processing components to allow for 3D reconstructions from limited numbers of 2D image planes and multiple acoustic views. Our approach is based on a 3D freehand ultrasound system that allows users to control the 2D acquisition imaging using conventional 2D probes.For reliable performance, we develop new methods for image segmentation and robust multi-view registration. We first present a new hybrid geometric level-set approach that provides reliable segmentation performance with relatively simple initializations and minimum edge leakage. Optimization of the segmentation model parameters and its effect on performance is carefully discussed. Second, using the segmented images, a new coarse to fine automatic multi-view registration method is introduced. The approach uses a 3D Hotelling transform to initialize an optimization search. Then, the fine scale feature-based registration is performed using a robust, non-linear least squares algorithm. The robustness of the multi view registration system allows for accurate 3D reconstructions from sparse 2D image planes. RESULTS: Volume measurements from multi-view 3D reconstructions are found to be consistently and significantly more accurate than measurements from single view reconstructions. The volume error of multi-view reconstruction is measured to be less than 5% of the true volume. We show that volume reconstruction accuracy is a function of the total number of 2D image planes and the number of views for calibrated phantom. In clinical in-vivo cardiac experiments, we show that volume estimates of the left ventricle from multi-view reconstructions are found to be in better agreement with clinical measures than measures from single view reconstructions. CONCLUSIONS: Multi-view 3D reconstruction from sparse 2D freehand B-mode images leads to more accurate volume quantification compared to single view systems. The flexibility and low cost of the proposed system allow for fine control of the image acquisition planes for optimal 3D reconstructions from multiple views. PMID- 21251285 TI - Fungal exposure in homes of patients with sarcoidosis - an environmental exposure study. AB - BACKGROUND: There is increasing evidence that exposure to moulds (fungi) may influence the development of sarcoidosis. To assess the influence of the environmental exposure, a study was undertaken to determine the exposure to fungi in homes of subjects with sarcoidosis. METHODS: Subjects were patients with clinically established sarcoidosis recruited during the period September 2007 till June 2010. Of these 55 were newly diagnosed and currently under treatment for less than one year, 25 had been treated and had no recurrence and 27 had been treated but had recurrence of the disease. Controls were healthy subjects without any respiratory symptoms (n = 30). Samples of air (about 2.5 m3) were taken in the bedroom of the subjects using a portable pump and cellulose ester filters. The filters were analysed for the content of the enzyme N-acetylhexosaminidase (NAHA) as a marker of fungal cell biomass, using a specific substrate and a fluorescent technique and expressed as NAHA units (U)/m3. RESULTS: Compared to controls, subjects undergoing treatment of the disease (newly diagnosed or with recurrence) had significantly higher activities of NAHA in their homes than controls (33.6 and 39.9 vs 10.0 U/m3, p < 0.001 and <0.001). Among controls only 5 out of 30 subjects had levels of NAHA above the second quartile value (14 U/m3). In homes of subjects with newly diagnosed disease with treatment less than one year, values above 14 NAHA U/m3 were found among 35 out of 55 and among those with recurrent disease among 18 out of 27. CONCLUSIONS: The higher activities of NAHA enzyme found in homes of subjects with active and recurrent sarcoidosis suggest that exposure to fungi is related to the risk of sarcoidosis. Further environmental studies to assess the importance of this exposure for subjects with sarcoidosis are warranted. The results suggest that remedial actions in homes with high levels of fungi may be justified. PMID- 21251286 TI - Modelling the variation of land surface temperature as determinant of risk of heat-related health events. AB - BACKGROUND: The evaluation of exposure to ambient temperatures in epidemiological studies has generally been based on records from meteorological stations which may not adequately represent local temperature variability. Here we propose a spatially explicit model to estimate local exposure to temperatures of large populations under various meteorological conditions based on satellite and meteorological data. METHODS: A general linear model was used to estimate surface temperatures using 15 LANDSAT 5 and LANDSAT 7 images for Quebec Province, Canada between 1987 and 2002 and spanning the months of June to August. The images encompassed both rural and urban landscapes and predictors included: meteorological records of temperature and wind speed, distance to major water bodies, Normalized Differential Vegetation Index (NDVI), land cover (built and bare land, water, or vegetation), latitude, longitude, and week of the year. RESULTS: The model explained 77% of the variance in surface temperature, accounting for both temporal and spatial variations. The standard error of estimates was 1.42 degrees C. Land cover and NDVI were strong predictors of surface temperature. CONCLUSIONS: This study suggests that a statistical approach to estimating surface temperature incorporating both spatially explicit satellite data and time-varying meteorological data may be relevant to assessing exposure to heat during the warm season in the Quebec. By allowing the estimation of space and time-specific surface temperatures, this model may also be used to assess the possible impacts of land use changes under various meteorological conditions. It can be applied to assess heat exposure within a large population and at relatively fine-grained scale. It may be used to evaluate the acute health effect of heat exposure over long time frames. The method proposed here could be replicated in other areas around the globe for which satellite data and meteorological data is available. PMID- 21251287 TI - The impact of plasma triglyceride and apolipoproteins concentrations on high density lipoprotein subclasses distribution. AB - OBJECTIVE: To investigate the effect of triglyceride (TG) integrates with plasma major components of apolipoproteins in HDL subclasses distribution and further elicited the TG-apolipoproteins (apos) interaction in the processes of high density lipoprotein (HDL) mature metabolic and atherosclerosis related diseases. METHODS: Contents of plasma HDL subclasses were quantities by two-dimensional gel electrophoresis associated with immunodetection in 500 Chinese subjects. RESULTS: Contents of prebeta1-HDL, HDL3a, and apoB-100 level along with apoB-100/A-I ratio were significantly increased, whereas there was a significant reduction in the contents of HDL2, apoA-I level as well as apoC-III/C-II ratio with increased TG concentration. Moreover, prebeta1-HDL contents is elevated about 9 mg/L and HDL2b contents can be reduced 21 mg/L for 0.5 mmol/L increment in TG concentration. Moreover, with increase of apoA-I levels, HDL2b contents were marginally elevated in any TG concentration group. Furthermore, despite of in the apoB-100/A-I < 0.9 group, the contents of prebeta1-HDL increased, and those of HDL2b decreased significantly for subjects in both high and very high TG levels compared to that in normal TG levels. Similarly, in the apoB-100/A-I >= 0.9 group, the distribution of HDL subclasses also showed abnormality for subjects with normal TG levels. CONCLUSIONS: The particle size of HDL subclasses tend to small with TG levels increased which indicated that HDL maturation might be impeded and efficiency of reverse cholesterol transport(RCT) might be weakened. These data suggest that TG levels were not only significantly associated with but liner with the contents of prebeta1-HDL and HDL2b. They also raise the possibility that the TG levels effect on HDL maturation metabolism are subjected to plasma apolipoproteins and apolipoproteins ratios. PMID- 21251288 TI - Synthesis of three-dimensional calcium carbonate nanofibrous structure from eggshell using femtosecond laser ablation. AB - BACKGROUND: Natural biomaterials from bone-like minerals derived from avian eggshells have been considered as promising bone substitutes owing to their biodegradability, abundance, and lower price in comparison with synthetic biomaterials. However, cell adhesion to bulk biomaterials is poor and surface modifications are required to improve biomaterial-cell interaction. Three dimensional (3D) nanostructures are preferred to act as growth support platforms for bone and stem cells. Although there have been several studies on generating nanoparticles from eggshells, no research has been reported on synthesizing 3D nanofibrous structures. RESULTS: In this study, we propose a novel technique to synthesize 3D calcium carbonate interwoven nanofibrous platforms from eggshells using high repetition femtosecond laser irradiation. The eggshell waste is value engineered to calcium carbonate nanofibrous layer in a single step under ambient conditions. Our striking results demonstrate that by controlling the laser pulse repetition, nanostructures with different nanofiber density can be achieved. This approach presents an important step towards synthesizing 3D interwoven nanofibrous platforms from natural biomaterials. CONCLUSION: The synthesized 3D nanofibrous structures can promote biomaterial interfacial properties to improve cell-platform surface interaction and develop new functional biomaterials for a variety of biomedical applications. PMID- 21251289 TI - Analysis of the proteome of human airway epithelial secretions. AB - BACKGROUND: Airway surface liquid, often referred to as mucus, is a thin layer of fluid covering the luminal surface that plays an important defensive role against foreign particles and chemicals entering the lungs. Airway mucus contains various macromolecules, the most abundant being mucin glycoproteins, which contribute to its defensive function. Airway epithelial cells cultured in vitro secrete mucins and nonmucin proteins from their apical surface that mimics mucus production in vivo. The current study was undertaken to identify the polypeptide constituents of human airway epithelial cell secretions to gain a better understanding of the protein composition of respiratory mucus. RESULTS: Fifty-five proteins were identified in the high molecular weight fraction of apical secretions collected from in vitro cultures of well-differentiated primary human airway epithelial cells and isolated under physiological conditions. Among these were MUC1, MUC4, MUC5B, and MUC16 mucins. By proteomic analysis, the nonmucin proteins could be classified as inflammatory, anti-inflammatory, anti-oxidative, and/or anti microbial. CONCLUSIONS: Because the majority of the nonmucin proteins possess molecular weights less than that selected for analysis, it is theoretically possible that they may associate with the high molecular weight and negatively charged mucins to form a highly ordered structural organization that is likely to be important for maintaining the proper defensive function of airway mucus. PMID- 21251290 TI - Changes in time-use and drug use by young adults in poor neighbourhoods of Greater Buenos Aires, Argentina, after the political transitions of 2001-2002: Results of a survey. AB - BACKGROUND: In some countries, "Big Events" like crises and transitions have been followed by large increases in drug use, drug injection and HIV/AIDS. Argentina experienced an economic crisis and political transition in 2001/2002 that affected how people use their time. This paper studies how time use changes between years 2001 and 2004, subsequent to these events, were associated with drug consumption in poor neighbourhoods of Greater Buenos Aires. METHODS: In 2003 2004, 68 current injecting drug users (IDUs) and 235 young non-IDUs, aged 21-35, who lived in impoverished drug-impacted neighbourhoods in Greater Buenos Aires, were asked about time use then and in 2001. Data on weekly hours spent working or looking for work, doing housework/childcare, consuming drugs, being with friends, and hanging out in the neighbourhood, were studied in relation to time spent using drugs. Field observations and focus groups were also conducted. RESULTS: After 2001, among both IDUs and non-IDUs, mean weekly time spent working declined significantly (especially among IDUs); time spent looking for work increased, and time spent with friends and hanging out in the neighbourhood decreased.We found no increase in injecting or non-injecting drug consumption after 2001. Subjects most affected by the way the crises led to decreased work time and/or to increased time looking for work--and by the associated increase in time spent in one's neighbourhood--were most likely to increase their time using drugs. CONCLUSIONS: Time use methods are useful to study changes in drug use and their relationships to every day life activities. In these previously-drug-impacted neighbourhoods, the Argentinean crisis did not lead to an increase in drug use, which somewhat contradicts our initial expectations. Nevertheless, those for whom the crises led to decreased work time, increased time looking for work, and increased time spent in indoor or outdoor neighbourhood environments, were likely to spend more time using drugs. These data suggest that young adults in traditionally less-impoverished neighbourhoods may be more vulnerable to Big Events than those in previously drug-impacted impoverished neighbourhoods. Since Big Events will continue to occur, research on the pathways that determine their sequelae is needed. PMID- 21251291 TI - The effect of time of onset on community preferences for health states: an exploratory study. AB - BACKGROUND: Health state descriptions used to describe hypothetical scenarios in community-perspective utility surveys commonly omit detail on the time of onset of a condition, despite our knowledge that among patients who have a condition, experience affects the value assigned to that condition. The debate regarding whose values to use in cost utility analysis is based in part on this observed difference between values depending on the perspective from which they are measured. This research explores the effect on community preferences for hypothetical health states of including the time of onset of a health condition in the health state description, to investigate whether this information induces community respondents to provide values closer to those of patients with experience with a condition. The goal of the research is to bridge the gap between patient and community preferences. METHODS: A survey of community perspective preferences for hypothetical health states was conducted among a convenience sample of healthy adults recruited from a hospital consortium's research volunteer pool. Standard gambles for three hypothetical health states of varying severity were compared across three frames describing time of onset: six months prior onset, current onset, and no onset specified in the description. Results were compared within health state across times of onset, controlling for respondent characteristics known to affect utility scores. Sub-analyses were conducted to confirm results on values meeting inclusion criteria indicating a minimum level of understanding and compliance with the valuation task. RESULTS: Standard gamble scores from 368 completed surveys were not significantly different across times of onset described in the health state descriptions regardless of health condition severity and controlling for respondent characteristics. Similar results were found in the subset of 292 responses that excluded illogical and invariant responses. CONCLUSIONS: The inclusion of information on the time of onset of a health condition in community-perspective utility survey health state descriptions may not be salient to or may not induce expression of preferences related to disease onset among respondents. Further research is required to understand community preferences regarding condition onset, and how such information might be integrated into health state descriptions to optimize the validity of utility data. Improved understanding of how the design and presentation of health state descriptions affect responses will be useful to eliciting valid preferences for incorporation into decision making. PMID- 21251292 TI - Examination of relaxin and its receptors expression in pig gametes and embryos. AB - BACKGROUND: Relaxin is a small peptide also known as pregnancy hormone in many mammals. It is synthesized by both male and female tissues, and its secretions are found in various body fluids such as plasma serum, ovarian follicular fluid, utero-oviduct secretions, and seminal plasma of many mammals, including pigs. However, the presence and effects of relaxin in porcine gametes and embryos are still not well-known. The purpose of this study was to assess the presence of relaxin and its receptors RXFP1 and RXFP2 in pig gametes and embryos. METHODS: Immature cumulus-oocyte complexes (COCs) were aspirated from sows' ovaries collected at the abattoir. After in vitro-maturation, COCs were in vitro fertilized and cultured. For studies, immature and mature COCs were separately collected, and oocytes were freed from their surrounding cumulus cells. Denuded oocytes, cumulus cells, mature boar spermatozoa, zygotes, and embryos (cleaved and blastocysts) were harvested for temporal and spatial gene expression studies. Sections of ovary, granulosa and neonatal porcine uterine cells were also collected to use as controls. RESULTS: Using both semi-quantitative and quantitative PCRs, relaxin transcripts were not detected in all tested samples, while RXFP1 and RXFP2 mRNA were present. Both receptor gene products were found at higher levels in oocytes compared to cumulus cells, irrespective of the maturation time. Cleaved-embryos contained higher levels of RXFP2 mRNA, whereas, blastocysts were characterized by a higher RXFP1 mRNA content. Using western immunoblotting or in situ immunofluorescence, relaxin and its receptor proteins were detected in all samples. Their fluorescence intensities were consistently more important in mature oocytes than immature ones. The RXFP1 and RXFP2 signal intensities were mostly located in the plasma membrane region, while the relaxin ones appeared homogeneously distributed within the oocytes and embryonic cells. Furthermore, spermatozoa displayed stronger RXFP2 signal than RXFP1 after western immunoblotting. CONCLUSION: All together, our findings suggest potential roles of relaxin and its receptors during oocyte maturation, early embryo development, and beyond. PMID- 21251293 TI - Reflections on the ethics of recruiting foreign-trained human resources for health. AB - BACKGROUND: Developed countries' gains in health human resources (HHR) from developing countries with significantly lower ratios of health workers have raised questions about the ethics or fairness of recruitment from such countries. By attracting and/or facilitating migration for foreign-trained HHR, notably those from poorer, less well-resourced nations, recruitment practices and policies may be compromising the ability of developing countries to meet the health care needs of their own populations. Little is known, however, about actual recruitment practices. In this study we focus on Canada (a country with a long reliance on internationally trained HHR) and recruiters working for Canadian health authorities. METHODS: We conducted interviews with health human resources recruiters employed by Canadian health authorities to describe their recruitment practices and perspectives and to determine whether and how they reflect ethical considerations. RESULTS AND DISCUSSION: We describe the methods that recruiters used to recruit foreign-trained health professionals and the systemic challenges and policies that form the working context for recruiters and recruits. HHR recruiters' reflections on the global flow of health workers from poorer to richer countries mirror much of the content of global-level discourse with regard to HHR recruitment. A predominant market discourse related to shortages of HHR outweighed discussions of human rights and ethical approaches to recruitment policy and action that consider global health impacts. CONCLUSIONS: We suggest that the concept of corporate social responsibility may provide a useful approach at the local organizational level for developing policies on ethical recruitment. Such local policies and subsequent practices may inform public debate on the health equity implications of the HHR flows from poorer to richer countries inherent in the global health worker labour market, which in turn could influence political choices at all government and health system levels. PMID- 21251294 TI - The economic impact of chronic fatigue syndrome in Georgia: direct and indirect costs. AB - BACKGROUND: Chronic fatigue syndrome (CFS) is a debilitating chronic illness affecting at least 4 million people in the United States. Understanding its cost improves decisions regarding resource allocation that may be directed towards treatment and cure, and guides the evaluation of clinical and community interventions designed to reduce the burden of disease. METHODS: This research estimated direct and indirect costs of CFS and the impact on educational attainment using a population-based, case-control study between September 2004 and July 2005, Georgia, USA. Participants completed a clinical evaluation to confirm CFS, identify other illnesses, and report on socioeconomic factors. We estimated the effect of CFS on direct medical costs (inpatient hospitalizations, provider visits, prescription medication spending, other medical supplies and services) and loss in productivity (employment and earnings) with a stratified sample (n = 500) from metropolitan, urban, and rural Georgia. We adjusted medical costs and earnings for confounders (age, sex, race/ethnicity, education, and geographic strata) using econometric models and weighted estimates to reflect response-rate adjusted sampling rates. RESULTS: Individuals with CFS had mean annual direct medical costs of $5,683. After adjusting for confounding factors, CFS accounted for $3,286 of these costs (p < 0.01), which were driven by increased provider visits and prescription medication use. Nearly one-quarter of these expenses were paid directly out-of pocket by those with CFS. Individuals with CFS reported mean annual household income of $23,076. After adjustment, CFS accounted for $8,554 annually in lost household earnings (p < 0.01). Lower educational attainment accounted for 19% of the reduction in earnings associated with CFS. CONCLUSIONS: Study results indicate that chronic fatigue syndrome may lead to substantial increases in healthcare costs and decreases in individual earnings. Studies have estimated up to 2.5% of non-elderly adults may suffer from CFS. In Georgia, a state with roughly 5.5 million people age 18-59, illness could account for $452 million in total healthcare expenditures and $1.2 billion of lost productivity. PMID- 21251295 TI - Prevalence of exercise and non-exercise physical activity in Chinese adolescents. AB - Non-exercise physical activity (NEPA) is an important part of energy expenditure. This study aimed to investigate the prevalence of exercise and NEPA among adolescents. In the HKSOS project 2006-2007, the proportions of Hong Kong Chinese adolescents (N=32,005) achieving 60-minute exercise and 60-minute NEPA per day were analyzed. Exercise was defined as structured and planned physical activities, and NEPA was defined as unstructured and unplanned physical activities including walking for transportation and climbing stairs. The prevalence of exercise was higher in boys than girls (after school: 63.8% vs 39.6%; holidays: 78.7% vs 60.0%), but the prevalence of NEPA in boys was similar to that in girls (after school: 72.2% vs 68.0%; holidays: 80.3% vs 79.4%). In general, the prevalence of both exercise and NEPA decreased with age in boys and girls, but was more marked for exercise than NEPA. In conclusion, the prevalence of exercise was lower in adolescent girls than boys, and decreased more rapidly with age than NEPA. NEPA seems to be easier to accumulate than exercise among adolescents regardless of sex and age. PMID- 21251298 TI - Tunicates push the limits of animal evo-devo. AB - The phylum to which humans belong, Chordata, takes its name from one of the major shared derived features of the group, the notochord. All chordates have a notochord, at least during embryogenesis, and there is little doubt about notochord homology at the morphological level. A study in BMC Evolutionary Biology now shows that there is greater variability in the molecular genetics underlying notochord development than previously appreciated. PMID- 21251299 TI - Design of a series visco-elastic actuator for multi-purpose rehabilitation haptic device. AB - BACKGROUND: Variable structure parallel mechanisms, actuated with low-cost motors with serially added elasticity (series elastic actuator--SEA), has considerable potential in rehabilitation robotics. However, reflected masses of a SEA and variable structure parallel mechanism linked with a compliant actuator result in a potentially unstable coupled mechanical oscillator, which has not been addressed in previous studies. METHODS: The aim of this paper was to investigate through simulation, experimentation and theoretical analysis the necessary conditions that guarantee stability and passivity of a haptic device (based on a variable structure parallel mechanism driven by SEA actuators) when in contact with a human. We have analyzed an equivalent mechanical system where a dissipative element, a mechanical damper was placed in parallel to a spring in SEA. RESULTS: The theoretical analysis yielded necessary conditions relating the damping coefficient, spring stiffness, both reflected masses, controller's gain and desired virtual impedance that needs to be fulfilled in order to obtain stable and passive behavior of the device when in contact with a human. The validity of the derived passivity conditions were confirmed in simulations and experimentally. CONCLUSIONS: These results show that by properly designing variable structure parallel mechanisms actuated with SEA, versatile and affordable rehabilitation robotic devices can be conceived, which may facilitate their wide spread use in clinical and home environments. PMID- 21251296 TI - Etiopathology of chronic tubular, glomerular and renovascular nephropathies: clinical implications. AB - Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e. no functional alterations are evident), continue through renal dysfunction and ends up in renal failure. At this point, kidney transplant or dialysis (renal replacement therapy, RRT) becomes necessary to prevent death derived from the inability of the kidneys to cleanse the blood and achieve hydroelectrolytic balance. Worldwide, nearly 1.5 million people need RRT, and the incidence of CKD has increased significantly over the last decades. Diabetes and hypertension are among the leading causes of end stage renal disease, although autoimmunity, renal atherosclerosis, certain infections, drugs and toxins, obstruction of the urinary tract, genetic alterations, and other insults may initiate the disease by damaging the glomerular, tubular, vascular or interstitial compartments of the kidneys. In all cases, CKD eventually compromises all these structures and gives rise to a similar phenotype regardless of etiology. This review describes with an integrative approach the pathophysiological process of tubulointerstitial, glomerular and renovascular diseases, and makes emphasis on the key cellular and molecular events involved. It further analyses the key mechanisms leading to a merging phenotype and pathophysiological scenario as etiologically distinct diseases progress. Finally clinical implications and future experimental and therapeutic perspectives are discussed. PMID- 21251297 TI - Repaired tetralogy of Fallot: the roles of cardiovascular magnetic resonance in evaluating pathophysiology and for pulmonary valve replacement decision support. AB - Surgical management of tetralogy of Fallot (TOF) results in anatomic and functional abnormalities in the majority of patients. Although right ventricular volume load due to severe pulmonary regurgitation can be tolerated for many years, there is now evidence that the compensatory mechanisms of the right ventricular myocardium ultimately fail and that if the volume load is not eliminated or reduced by pulmonary valve replacement the dysfunction might be irreversible. Cardiovascular magnetic resonance (CMR) has evolved during the last 2 decades as the reference standard imaging modality to assess the anatomic and functional sequelae in patients with repaired TOF. This article reviews the pathophysiology of chronic right ventricular volume load after TOF repair and the risks and benefits of pulmonary valve replacement. The CMR techniques used to comprehensively evaluate the patient with repaired TOF are reviewed and the role of CMR in supporting clinical decisions regarding pulmonary valve replacement is discussed. PMID- 21251300 TI - Inhibition of lung serine proteases in mice: a potentially new approach to control influenza infection. AB - BACKGROUND: Host serine proteases are essential for the influenza virus life cycle because the viral haemagglutinin is synthesized as a precursor which requires proteolytic maturation. Therefore, we studied the activity and expression of serine proteases in lungs from mice infected with influenza and evaluated the effect of serine protease inhibitors on virus replication both in cell culture and in infected mice. RESULTS: Two different inbred mouse strains were investigated: DBA/2J as a highly susceptible and C57Bl/6J as a more resistant strain to influenza virus infection. The serine proteases from lung homogenates of mice exhibited pH optima of 10.00. Using the substrate Bz-Val-Gly Arg-p-nitroanilide or in zymograms, the intensities of proteolysis increased in homogenates from both mouse strains with time post infection (p.i.) with the mouse-adapted influenza virus A/Puerto Rico/8/34 (H1N1; PR8). In zymograms at day 7 p.i., proteolytic bands were stronger and numerous in lung homogenates from DBA/2J than C57Bl/6J mice. Real-time PCR results confirmed differential expression of several lung proteases before and after infecting mice with the H1N1 virus. The most strongly up-regulated proteases were Gzma, Tmprss4, Elane, Ctrl, Gzmc and Gzmb. Pretreatment of mouse and human lung cell lines with the serine protease inhibitors AEBSF or pAB or a cocktail of both prior to infection with the H1N1 or the A/Seal/Massachusetts/1/80 (H7N7; SC35M) virus resulted in a decrease in virus replication. Pretreatment of C57Bl/6J mice with either AEBSF or a cocktail of AEBSF and pAB prior to infection with the H1N1 virus significantly reduced weight loss and led to a faster recovery of treated versus untreated mice while pAB alone exerted a very poor effect. After infection with the H7N7 virus, the most significant reduction of weight loss was obtained upon pretreatment with either the protease inhibitor cocktail or pAB. Furthermore, pretreatment of C57BL/6J mice with AEBSF prior to infection resulted in a significant reduction in the levels of both the H1N1 and H7N7 nucleoproteins in mice lungs and also a significant reduction in the levels of the HA transcript in the lungs of the H1N1 -but not the H7N7-infected mice. CONCLUSION: Multiple serine protease activities might be implicated in mediating influenza infection. Blocking influenza A virus infection in cultured lung epithelia and in mice by the used serine protease inhibitors may provide an alternative approach for treatment of influenza infection. PMID- 21251301 TI - Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis B to interferon alfa. AB - In order to examine whether variation in interleukin-10 promoter polymorphism would predict the likelihood of sustain response of chronic hepatitis B to treatment with interferon alfa (IFN-alpha), the inheritance of 3 biallelic polymorphisms in the IL-10 gene promoter in patients with 52 chronic hepatitis B were determined by polymerase chain reaction (PCR)-bared techniques, restriction enzyme digestion or direct sequencing. The relationship to the outcome of antiviral therapy for chronic HBV infection was studied in 24 patients who had a virologically sustained response(SR) and in 28 non-responder(NR) to interferon alfa-2b and several IL-10 variants were more frequent among SR compared with NR. Carriage of the -592A allele, -592A/A genotype and -1082/-1819/-592 ATA haplotype was associated with SR. Our findings indicate that heterogeneity in the promoter region of the IL-10 gene has a role in determining the initial response of chronic hepatitis B to IFN-alpha therapy. PMID- 21251302 TI - A reporter system for assaying influenza virus RNP functionality based on secreted Gaussia luciferase activity. AB - BACKGROUND: Influenza A virus can infect a wide variety of animal species including humans, pigs, birds and other species. Viral ribonucleoprotein (vRNP) was involved in genome replication, transcription and host adaptation. Currently, firefly luciferase (Fluc) reporter system was used in vRNP functional assay. However, its limitation for the testing by virus infection resulted in an increased need for rapid, sensitive, and biosafe techniques. Here, an influenza A virus UTR-driven gene reporter for vRNP assay based on secreted Gaussia luciferase (Gluc) activity was evaluated. RESULTS: By measuring Gluc levels in supernatants, reporter gene activity could be detected and quantitated after either reconstitution of influenza A virus polymerase complex or viral infection of 293T and A549 cells, respectively. As compared with Fluc reporter, Gluc-based reporter was heat-tolerant (65 degrees C for 30 min) and produced 50-fold higher bioluminescent activity at 24 h posttransfection. Signals generated by Gluc reporter gene could be detected as early as 6 h post-infection and accumulated with time. Testing by viral infection, stronger signals were detected by Gluc reporter at a MOI of 0.001 than that of 1 and the effects of PB2-627K/E or amantadine on influenza vRNP activity were elucidated more effectively by the Gluc reporter system. CONCLUSIONS: This approach provided a rapid, sensitive, and biosafe assay of influenza vRNP function, particularly for the highly pathogenic avian influenza viruses. PMID- 21251303 TI - Hepatitis G virus associated aplastic anemia: a recent case from Pakistan. AB - BACKGROUND: Aplastic anemia (AA) is a serious and rare disorder characterized by a hypocellular bone marrow. Hepatitis associated aplastic anemia (HAAA) is a variant of aplastic anemia in which aplastic anemia follows an acute attack of hepatitis. Several reports have noted an association between HGV and hepatitis associated aplastic anemia besides other hepatitis causing viruses. CASE PRESENTATION: A female girl of age 11 year with a history of loose motion for one month, vomiting for last 15 days and poor oral intake for last few days is reported here. The physical examination presents fever, pallor whereas bleeding, hepatomegaly, Splenomegaly and bruising were absent, abdominal ultrasonography confirmed the absence of hepatomegaly, Splenomegaly and lymphodenopathy. The laboratory investigation parameters were: haemoglobin 6.2 g/L, total leucocytes count 1.51, neutrophils 0.47%, absolute reticulocyte count 0.5%, Monocytes 0.16%, red cell count 3.2 mil/uL, Picked cell volume (PCV) 30.13%, Mean Corpuscular Volume (MCV) 78 fL, Mean Corpuscular Hemoglobin (MCH) 26.3 pg. The liver enzymes were alanine aminotransferease (ALT) 98 IU/L, aspartate aminotransferase (AST) 114 IU/L. Serologic and molecular tests for hepatitis A, B, C, D, E, TTV, B19 were negative, whereas HGV RNA PCR test was found positive for hepatitis G virus. The bone marrow aspirate and trephine biopsy examination revealed hypo- cellularity, erythropoiesis, myelopoiesis and megakaryopoiesis. CONCLUSION: HAAA is an uncommon but severe condition, which may occur following idiopathic cases of acute hepatitis. Our finding suggests the involvement of HGV in the development of aplastic anemia. In patients presenting with pancytopenia after an episode of acute hepatitis, the definitive diagnosis should be considered and confirmed by RT-PCR and if possible by bone marrow biopsy. PMID- 21251304 TI - Circulating interleukin-18: A specific biomarker for atherosclerosis-prone patients with metabolic syndrome. AB - BACKGROUND: Metabolic syndrome (MetS) is associated with an increased risk of the development of atherosclerotic cardiovascular disease (CVD). Interleukin-18 (IL 18), which is a pleiotropic proinflammatory cytokine with important regulatory functions in the innate immune response system, plays a crucial role in vascular pathologies. IL-18 is also a predictor of cardiovascular death in patients with CVD and is involved in atherosclerotic plaque destabilization. RESULTS: In order to determine if circulating levels of IL-18 can serve as a specific biomarker for distinguishing MetS patients from pre-MetS subjects, we studied 78 patients with visceral fat deposition and 14 age-matched control subjects. Increased levels of IL-18 were observed more frequently in patients with MetS than in pre-MetS subjects and were positively associated with waist circumference. Serum levels of IL-18 were significantly reduced by a change in weight caused by lifestyle modifications. There was a significant interaction between waist circumference and serum IL-18 concentration. Weight loss of at least 5% of the body weight caused by lifestyle modification decreased IL-18 circulating levels relative to the reduction in waist circumference and blood pressure, suggesting that this degree of weight loss benefits the cardiovascular system. CONCLUSION: IL-18 may be a useful biomarker of the clinical manifestations of MetS and for the management of the risk factors of CVD. PMID- 21251305 TI - Guidelines for rating Global Assessment of Functioning (GAF). AB - BACKGROUND: Global Assessment of Functioning (GAF) is a scoring system for the severity of illness in psychiatry. It is used clinically in many countries, as well as in research, but studies have shown several problems with GAF, for example concerning its validity and reliability. Guidelines for rating are important. The present study aimed to identify the current status of guidelines for rating GAF, and relevant factors and gaps in knowledge for the development of improved guidelines. METHODS: A thorough literature search was conducted. RESULTS: Few studies of existing guidelines have been conducted; existing guidelines are short; and rating has a subjective element. Seven main categories were identified as being important in relation to further development of guidelines: (1) general points about guidelines for rating GAF; (2) introduction to guidelines, with ground rules; (3) starting scoring at the top, middle or bottom level of the scale; (4) scoring for different time periods and of different values (highest, lowest or average); (5) the finer grading of the scale; (6) different guidelines for different conditions; and (7) different languages and cultures. Little information is available about how rules for rating are understood by different raters: the final score may be affected by whether the rater starts at the top, middle or bottom of the scale; there is little data on which value/combination of GAF values to record; guidelines for scoring within 10-point intervals are limited; there is little empirical information concerning the suitability of existing guidelines for different conditions and patient characteristics; and little is known about the effects of translation into different languages or of different cultural understanding. CONCLUSIONS: Few studies have dealt specifically with guidelines for rating GAF. Current guidelines for rating GAF are not comprehensive, and relevant points for new guidelines are presented. Theoretical and empirical studies, and international expert panels would be valuable, as well as production of a manual with more information about scoring. Computerised assessment may well be the future. PMID- 21251306 TI - Effects on patients of their healthcare practitioner's or institution's participation in clinical trials: a systematic review. AB - BACKGROUND: Systematic reviews have shown uncertainty about the size or direction of any 'trial effect' for patients in trials compared to those treated outside trials. We are not aware of any systematic review of whether there is a 'trial effect' related to being treated by healthcare practitioners or institutions that take part in research. METHODS: We searched the Cochrane Methodology Register and MEDLINE (most recently in January 2009) for studies in which patients were allocated to treatment in one or other setting, and cohort studies reporting the outcomes of patients from different settings. We independently assessed study quality, including the control of bias in the generation of the comparison groups, and extracted data. RESULTS: We retrieved and checked more than 15,000 records. Thirteen articles were eligible: five practitioner studies and eight institution studies. Meta-analyses were not possible because of heterogeneity. Two practitioner studies were judged to be 'controlled' or better. A Canadian study among nurses found that use of research evidence was higher for those who took part in research working groups and a Danish study on general practitioners found that trial doctors were more likely to prescribe in accordance with research evidence and guidelines. Five institution studies were 'controlled' but provided mixed results. A study of North American patients at hospitals that had taken part in trials for myocardial infarction found no statistically significant difference in treatment for patients in trial and non-trial hospitals. A Canadian study of myocardial infarction patients found that trial participants had better survival than patients in the same hospitals who were not in trials or those in non-trial hospitals. A study of general practices in Denmark did not detect differences in guideline adherence between trial and non-trial practices but found that trial practices were more likely to prescribe the trial sponsor's drugs. The other two 'controlled' studies of institutions found lower mortality in trial than non-trial hospitals. CONCLUSIONS: The available findings from existing research suggest that there might be a 'trial effect' of better outcomes, greater adherence to guidelines and more use of evidence by practitioners and institutions that take part in trials. However, the consequences for patient health are uncertain and the most robust conclusion may be that there is no apparent evidence that patients treated by practitioners or in institutions that take part in trials do worse than those treated elsewhere. PMID- 21251307 TI - Does treatment of subsyndromal depression improve depression and diabetes related outcomes: protocol for a randomised controlled comparison of psycho-education, physical exercise and treatment as usual. AB - BACKGROUND: The prevalence of mood difficulties in persons with diabetes is approximately twice that in the general population, affecting the health outcomes and patients' quality of life in an undesirable way. Although subsyndromal depression is an important predictor of a more serious clinical depression, it is often overlooked. This study aims to compare the effects of two non pharmacological interventions for subsyndromal depression, psychoeducation and physical exercise, with diabetes treatment as usual on mood- and diabetes-related outcomes. METHODS AND DESIGN: Type 2 diabetic patients aged 18-65 yrs. who report mood difficulties and the related need for help in a mail survey will be potential participants. After giving informed consent, they will be randomly assigned to one of the three groups (psychoeducation, physical activity, treatment as usual). Depressive symptoms, diabetes distress, health-related quality of life and diabetes self-care activities will be assessed at baseline, at 6 weeks, 6 months and 12 months. A structured clinical interview for DSM-IV Axis I Disorders (SCID-I) will be performed at baseline and at one-year follow-up in order to determine the clinical significance of the patients' depressive symptoms. Disease-related data will be collected from patients' files and from additional physical examinations and laboratory tests.The two interventions will be comparable in terms of format (small group work), duration (six sessions) and approach (interactive learning; supporting the participants' active roles). The group treated as usual will be informed about their screening results and about the importance of treating depression. They will be provided with brief re education on diabetes and written self-help instructions to cope with mood difficulties.Primary outcomes will be depressive symptoms. Secondary outcomes will be glycaemic control, diabetes-related distress, self-management of diabetes and health-related quality of life. Tertiary outcomes will be biochemical markers reflecting common pathophysiological processes of insulin resistance, inflammation and oxidative damage that are assumed to be intertwined in both diabetes and depression. The mixed-effect linear model will be used to compare the outcome variables.Power analysis has indicated that the two intervention groups and the control group should comprise 59 patients to enable detection of clinically meaningful differences in depressive symptoms with a power of 80% and alpha = 0.05. Outcomes will be analysed on an intention-to-treat basis. TRIAL REGISTRATION: ISRCTN: ISRCTN05673017. PMID- 21251308 TI - Defined plant extracts can protect human cells against combined xenobiotic effects. AB - BACKGROUND: Pollutants representative of common environmental contaminants induce intracellular toxicity in human cells, which is generally amplified in combinations. We wanted to test the common pathways of intoxication and detoxification in human embryonic and liver cell lines. We used various pollutants such as Roundup residues, Bisphenol-A and Atrazine, and five precise medicinal plant extracts called Circ1, Dig1, Dig2, Sp1, and Uro1 in order to understand whether specific molecular actions took place or not. METHODS: Kidney and liver are major detoxification organs. We have studied embryonic kidney and hepatic human cell lines E293 and HepG2. The intoxication was induced on the one hand by a formulation of one of the most common herbicides worldwide, Roundup 450 GT+ (glyphosate and specific adjuvants), and on the other hand by a mixture of Bisphenol-A and Atrazine, all found in surface waters, feed and food. The prevention and curative effects of plant extracts were also measured on mitochondrial succinate dehydrogenase activity, on the entry of radiolabelled glyphosate (in Roundup) in cells, and on cytochromes P450 1A2 and 3A4 as well as glutathione-S-transferase. RESULTS: Clear toxicities of pollutants were observed on both cell lines at very low sub-agricultural dilutions. The prevention of such phenomena took place within 48 h with the plant extracts tested, with success rates ranging between 25-34% for the E293 intoxicated by Roundup, and surprisingly up to 71% for the HepG2. By contrast, after intoxication, no plant extract was capable of restoring E293 viability within 48 h, however, two medicinal plant combinations did restore the Bisphenol-A/Atrazine intoxicated HepG2 up to 24-28%. The analysis of underlying mechanisms revealed that plant extracts were not capable of preventing radiolabelled glyphosate from entering cells; however Dig2 did restore the CYP1A2 activity disrupted by Roundup, and had only a mild preventive effect on the CYP3A4, and no effect on the glutathione S transferase. CONCLUSIONS: Environmental pollutants have intracellular effects that can be prevented, or cured in part, by precise medicinal plant extracts in two human cell lines. This appears to be mediated at least in part by the cytochromes P450 modulation. PMID- 21251309 TI - Polymorphisms in Tunisian patients with N-acetylgalactosamine-6-sulfate sulfatase gene deficiency: implication in Morquio A disease. AB - Mucopolysaccharidosis type IVA or Morquio A syndrome is characterized by the lack of N-acetylgalactosamine-6-sulfate-sulfatase and the accumulation of keratan sulfate and chondroitin-6-sulfate in the lysosomes. At least, 148 mutations and 16 polymorphisms were identified in the GALNS gene.The aim of this study was the screening of polymorphisms within 7 patients recruited from many regions of Tunisia in order to determine the haplotypes and their association with the mutations previously reported. PATIENTS AND METHODS: We have used the PCR sequencing to analyse the different haplotypes and to identify the polymorphisms within 7 affected MPS IVA patients. RESULTS: Nine GALNS polymorphisms were detected in the 7 studied patients. Five of these polymorphisms are within the GALNS gene exons. Six polymorphisms have been previously described and used for linkage analysis in MPS IVA patients and determination of haplotypes. We have identified two novel heterozygous polymorphisms in intron 13 and intron 3 CONCLUSION: Polymorphisms may be useful for carrier detection and prenatal diagnosis in informative families whose specific mutations have not been identified. The determination of haplotypes can also determine the origin of some mutations in a population. PMID- 21251310 TI - The value of shoe size for prediction of the timing of the pubertal growth spurt. AB - BACKGROUND: Knowing the timing of the pubertal growth spurt of the spine, represented by sitting height, is essential for the prognosis and therapy of adolescent idiopathic scoliosis. There are several indicators that reflect growth or remaining growth of the patient. For example, distal body parts have their growth spurt earlier in adolescence, and therefore the growth of the foot can be an early indicator for the growth spurt of sitting height. Shoe size is a good alternative for foot length, since patients can remember when they bought new shoes and what size these shoes were. Therefore the clinician already has access to some longitudinal data at the first visit of the patient to the outpatient clinic.The aim of this study was to describe the increase in shoe size during adolescence and to determine whether the timing of the peak increase could be an early indicator for the timing of the peak growth velocity of sitting height. METHODS: Data concerning shoe sizes of girls and boys were acquired from two large shoe shops from 1991 to 2008. The longitudinal series of 242 girls and 104 boys were analysed for the age of the "peak increase" in shoe size, as well as the age of cessation of foot growth based on shoe size. RESULTS: The average peak increase in shoe size occurred at 10.4 years (SD 1.1) in girls and 11.5 years (SD 1.5) in boys. This was on average 1.3 years earlier than the average peak growth velocity of sitting height in girls, and 2.5 years earlier in boys. The increase in shoe size diminishes when the average peak growth velocity of sitting height takes place at respectively 12.0 (SD 0.8) years in girls, and 13.7 (SD 1.0) years in boys. CONCLUSIONS: Present data suggest that the course of the shoe size of children visiting the outpatient clinic can be a useful first tool for predicting the timing of the pubertal growth spurt of sitting height, as a representative for spinal length.This claim needs verification by direct comparison of individual shoe size and sitting height data and than a step forward can be made in clinical decision making regarding adolescent idiopathic scoliosis. PMID- 21251311 TI - Case Report: Successful non-operative management of spontaneous splenic rupture in a patient with babesiosis. AB - BACKGROUND: Babesiosis is a zoonotic disease transmitted by the Ixodes tick species. Infection often results in sub-clinical manifestations; however, patients with this disease can become critically ill. Splenic rupture has been a previously reported complication of babesiosis, but treatment has always led to splenectomy. Asplenia places a patient at greater risk for overwhelming post splenectomy infection from encapsulated bacteria, Lyme disease, Ehrlichia as well as Babesia microti. Therefore, avoiding splenectomy in these patients must be considered by the physician; particularly, if the patient is at risk for re infection by living in an endemic area. CASE PRESENTATION: A 54 year-old male from the northeast United States presented with left upper quadrant abdominal pain associated with fever, chills, night sweats and nausea. A full evaluation revealed active infection with Babesia microti and multiple splenic lacerations. This patient was successfully treated with appropriate pharmacological therapy and non-operative observation for the splenic injury. CONCLUSION: Patients diagnosed with Babesia microti infection are becoming more common, especially in endemic areas. Although clinical manifestations are usually minimal, this infection can present with significant injuries leading to critical illness. We present the successful non-operative treatment of a patient with splenic rupture due to babesiosis infection. PMID- 21251312 TI - Perception of Deqi by Chinese and American acupuncturists: a pilot survey. AB - BACKGROUND: In acupuncture, deqi is the sensory experience related to clinical efficacy. As the first study taking into account cultural differences on deqi sensation, this pilot survey aims to corroborate the acupuncturists' general experience in clinical practice with functional magnetic resonance imaging (fMRI) findings. METHODS: Questionnaires were distributed to acupuncturists of TCM (traditional Chinese medicine)hospitals and acupuncturists attending workshops and seminars in the United States and China. Questions covered clinical significance of deqi, patient attitude and the nature of some pain-related sensations elicited by manual needling. RESULTS: 47 out of a total of 86 acupuncturists agreed that dull pain was deqi and over half regarded it beneficial, while sharp pain was non-deqi and harmful instead. The patients' attitude toward deqi sensation showed a difference between US and China. There was no other dimension showing a difference. CONCLUSION: Results of this pilot survey indicate that the acupuncturists' perception is consistent with our previous fMRI findings. Results showed almost complete agreement that dull pain is considered deqi and beneficial to treatment, while sharp pain is not deqi and harmful. Particularly, dull pain was deqi and was beneficial to treatment whereas sharp pain was not. Patients in China liked the deqi experience whereas those in the US did not. PMID- 21251313 TI - Peripheral muscarinic receptors mediate the anti-inflammatory effects of auricular acupuncture. AB - BACKGROUND: The cholinergic and opioid systems play important roles in modulating inflammation. This study tests whether auricular acupuncture (AA) produces anti inflammatory effects via opioid and peripheral cholinergic receptors in a rat model. METHODS: Rats were anesthetized with chloral hydrate and inflammation was induced by intraplantar injection of carrageenan. Electroacupuncture was performed at auricular points bilaterally. The severity of inflammation was assessed using changes in paw volume and thermal and mechanical pain thresholds of the rats during recovery from anesthesia. RESULTS: Electroacupuncture at selected auricular acupoints significantly reduced paw edema and mechanical hyperalgesia, with no significant effect on thermal hyperalgesia. The anti edematous and analgesic effects of AA were abolished by blockade of peripheral cholinergic muscarinic receptors with methyl atropine. Blockade of local muscarinic receptors at the inflamed site with a small dose of atropine also antagonized the anti-edematous effect of AA. By contrast, systemic opioid receptor blockade with naloxone did not antagonize the anti-inflammatory effects of AA. CONCLUSION: This study discovers a role of peripheral muscarinic receptors in mediating the anti-inflammatory effects of AA. The cholinergic muscarinic mechanism appears to be more important than the opioid mechanism in the anti inflammatory action of AA. PMID- 21251314 TI - Noise regulation by quorum sensing in low mRNA copy number systems. AB - BACKGROUND: Cells must face the ubiquitous presence of noise at the level of signaling molecules. The latter constitutes a major challenge for the regulation of cellular functions including communication processes. In the context of prokaryotic communication, the so-called quorum sensing (QS) mechanism relies on small diffusive molecules that are produced and detected by cells. This poses the intriguing question of how bacteria cope with the fluctuations for setting up a reliable information exchange. RESULTS: We present a stochastic model of gene expression that accounts for the main biochemical processes that describe the QS mechanism close to its activation threshold. Within that framework we study, both numerically and analytically, the role that diffusion plays in the regulation of the dynamics and the fluctuations of signaling molecules. In addition, we unveil the contribution of different sources of noise, intrinsic and transcriptional, in the QS mechanism. CONCLUSIONS: The interplay between noisy sources and the communication process produces a repertoire of dynamics that depends on the diffusion rate. Importantly, the total noise shows a non-monotonic behavior as a function of the diffusion rate. QS systems seems to avoid values of the diffusion that maximize the total noise. These results point towards the direction that bacteria have adapted their communication mechanisms in order to improve the signal-to-noise ratio. PMID- 21251316 TI - Unusual cardiovascular complications of brucellosis presenting in two men: two case reports and a review of the literature. AB - INTRODUCTION: Brucellosis is a zoonosis with worldwide distribution, which is particularly endemic in many countries of the Mediterranean basin. Cardiovascular complications of this disease, such as endocarditis, myocarditis and pericarditis, are very rare, with even fewer cases of myocarditis or asymptomatic pericardial effusion in the absence of concomitant endocarditis being reported. CASE PRESENTATION: We report two cases of brucellosis in two Caucasian men, aged 17 and 34 years old, with myocarditis and asymptomatic pericardial effusion, respectively. Of note, neither patient had concomitant endocarditis. The disease was confirmed serologically and by blood cultures. Both patients recovered completely after receiving appropriate antibiotic treatment without any sign of relapse during a follow-up of 12 months. CONCLUSION: These two cases emphasize that in endemic areas Brucella can be considered as a potentially causative agent of idiopathic pericardial effusion or myocarditis, even in the absence of concomitant endocarditis. This possibility could be taken into account particularly in cases where contraction of brucellosis is possible, such as occupational exposure or consumption of unpasteurized dairy products. PMID- 21251315 TI - Genome-scale reconstruction of metabolic network for a halophilic extremophile, Chromohalobacter salexigens DSM 3043. AB - BACKGROUND: Chromohalobacter salexigens (formerly Halomonas elongata DSM 3043) is a halophilic extremophile with a very broad salinity range and is used as a model organism to elucidate prokaryotic osmoadaptation due to its strong euryhaline phenotype. RESULTS: C. salexigens DSM 3043's metabolism was reconstructed based on genomic, biochemical and physiological information via a non-automated but iterative process. This manually-curated reconstruction accounts for 584 genes, 1386 reactions, and 1411 metabolites. By using flux balance analysis, the model was extensively validated against literature data on the C. salexigens phenotypic features, the transport and use of different substrates for growth as well as against experimental observations on the uptake and accumulation of industrially important organic osmolytes, ectoine, betaine, and its precursor choline, which play important roles in the adaptive response to osmotic stress. CONCLUSIONS: This work presents the first comprehensive genome-scale metabolic model of a halophilic bacterium. Being a useful guide for identification and filling of knowledge gaps, the reconstructed metabolic network iOA584 will accelerate the research on halophilic bacteria towards application of systems biology approaches and design of metabolic engineering strategies. PMID- 21251317 TI - An unusual case of metastasis to the left side of the heart: a case report. AB - INTRODUCTION: Cardiac metastases are found in six to 20% of autopsies of patients with malignant neoplasm. The most common neoplasms that metastasize to the heart are malignant melanoma, lymphoma, and leukemia, but the relative numbers are greater with breast and lung cancers, reflecting the most common incidence of these cancers. CASE PRESENTATION: A 60-year-old Hispanic man presented to our hospital after being transferred from an outside hospital for workup and evaluation of an adrenal mass of the abdomen and pelvis, found on computed tomography. His chief complaint upon admission was altered mental status. Physical examination was unremarkable. He was alert and oriented and had a dry and non-erythematous oropharynx, and bilateral diffuse wheezing on lung examination. Computed tomography of the chest showed multiple hypodense lesions in the left ventricular myocardium, suggestive of metastases. There were also tiny sub-centimeter nodular densities in the right upper and lower lobes. Adrenal glands contained hypodense lesions, which showed characteristic adenocarcinomatous malignant cells. CONCLUSION: Cancers which have metastasized to the heart are found in six to 20% of patients with malignant neoplasms. The right side of the heart is more commonly involved in metastasis. This study is unusual in that a tumor of an unknown primary origin had metastasized to the left side of the heart. PMID- 21251318 TI - Progressive multifocal cerebral infarction from intravascular large B cell lymphoma presenting in a man: a case report. AB - INTRODUCTION: Intravascular lymphoma is rare, and may present as ischemic stroke. Diagnosis is difficult due to the non-specific presentation and lack of lymphadenopathy, thus leading to frequent instances of autopsy-proven diagnosis. To the best of our knowledge, this is the first report of progressive stroke from intravascular lymphoma diagnosed antemortem by random skin biopsy. CASE PRESENTATION: A 42-year-old Thai man presented to our hospital with progressive multifocal cerebral infarction. Despite taking aspirin (300 mg/day), his neurological symptoms worsened. During admission, he developed an unexplained fever and hypoxemia. Magnetic resonance angiography clearly showed patency of all cerebral arteries including the internal carotid and vertebrobasilar arteries. Echocardiography, an antiphospholipid antibody test, cerebrospinal fluid cytology and a bone marrow study were normal. Other laboratory test results showed an elevated lactate dehydrogenase level, nephrotic range proteinuria (3.91 g/day), hypoalbuminemia (1.9 g/dL), a very low high-density lipoprotein level (7 mg/dL) and hypertriglyceridemia (353 mg/dL). Because of suspected vasculitis, pulse methylprednisolone was given with transiently minimal improvement. A random skin biopsy from both thighs revealed intravascular large B cell lymphoma. Chemotherapy was not given due to our patient having ventilator associated pneumonia. He died 10 days after the definite diagnosis was established. CONCLUSION: One etiology of stroke is intravascular lymphoma, in which random skin biopsy can be helpful for antemortem diagnosis. PMID- 21251319 TI - Unusual computed tomography findings of radionecrosis after chemoradiation of stage IV hypopharyngeal cancer: a case report. AB - INTRODUCTION: Radionecrosis (post-radiotherapy laryngeal submucosal inflammation and necrosis) is a complication of (chemo) radiotherapy for hypopharyngeal cancer that is difficult to differentiate from tumor recurrence. CASE PRESENTATION: A 67 year-old Japanese man presented with a condition extremely difficult to diagnose differentially as radionecrosis or tumor recurrence after radiotherapy for hypopharyngeal cancer. Although tumor recurrence was suspected from clinical conditions and computed tomography findings, pathologic analysis revealed no evidence of tumor recurrence, and successful therapy with steroids and antibiotics reduced the mucosal edema. CONCLUSION: Our findings emphasize the wide spectrum of radiographic presentation of radionecrosis after chemoradiation of stage IV hypopharyngeal cancer. PMID- 21251320 TI - Hemobilia caused by a ruptured hepatic cyst: a case report. AB - INTRODUCTION: Hemobilia is a rare cause of upper gastrointestinal bleeding. More than 50% of hemobilia cases are related to iatrogenic trauma from hepatobiliary procedures, and needle biopsy of the liver represents the most common cause. A minority of hemobilia cases are due to hepatobiliary disorders such as cholangitis, hepatobiliary cancers, choledocholithiasis, and vascular abnormalities in the liver. The classic presentation of hemobilia is the triad of right upper quadrant (biliary) pain, obstructive jaundice, and upper gastrointestinal bleeding. We report a rare case of hemobilia caused by a spontaneous hepatic cyst rupture, where our patient presented without the classical symptoms, in the absence of therapeutic or pathological coagulopathy, and in the absence of spontaneous or iatrogenic trauma. CASE PRESENTATION: A 91 year-old African-American woman was referred to our out-patient gastroenterology clinic for evaluation of mild epigastric pain and intermittent melena. An abdominal computed tomography scan was remarkable for multiple hepatic cysts. Esophagogastroduodenoscopy revealed multiple blood clots at the ampulla of Vater. Endoscopic retrograde cholangiopancreatography showed a single 18 mm-sized filling defect in the common hepatic duct wall at the junction of the right and left hepatic duct, adjacent to one of the hepatic cysts. The ruptured hepatic cyst communicated to the bile ducts and was the cause of hemobilia with an atypical clinical presentation. CONCLUSION: Hemobilia is an infrequent cause of upper gastrointestinal bleeding and rarely occurs due to hepatic cyst rupture. To the best of our knowledge, this is only the second case report in the literature that describes hemobilia due to hepatic cyst rupture. However, it is the first case in the literature of hemobilia due to hepatic cyst rupture in the absence of iatrogenic or spontaneous trauma, and in the absence of a spontaneous or pathological coagulopathy. PMID- 21251321 TI - Treatment course and outcomes following drug and alcohol-related traumatic injuries. AB - BACKGROUND: Alcohol and drug use is known to be a major factor affecting the incidence of traumatic injury. However, the ways in which immediate pre-injury substance use affects patients' clinical care and outcomes remains unclear. The goal of the present study is to determine the associations between pre-injury use of alcohol or drugs and patient injury severity, hospital course, and clinical outcome. MATERIALS AND METHODS: This study used more than 200,000 records from the National Trauma Data Bank (NTDB), which is the largest trauma registry in the United States. Incidents in the NTDB were placed into one of four classes: alcohol related, drug related, alcohol-and-drug related, and substance negative. Logistic regression models were used to determine comorbid conditions or treatment complications that were significantly associated with pre-injury substance use. Hospital charges were associated with the presence or absence of drugs and alcohol, and patient outcomes were assessed using discharge disposition as delimited by the NTDB. RESULTS: The rates of complications arising during treatment were 8.3, 10.9, 9.9 and 8.6 per one hundred incidents in the alcohol related, drug related, alcohol-and-drug related, and substance-negative classes, respectively. Regression models suggested that pre-injury alcohol use is associated with a 15% higher risk of infection, whereas pre-injury drug use is associated with a 30% higher risk of infection. Pre-injury substance use did not appear to significantly impact clinical outcomes following treatment for traumatic injury, however. CONCLUSION: This study suggests that pre-injury drug use is associated with a significantly higher complication rate. In particular, infection during hospitalization is a significant risk for both alcohol and drug related trauma visits, and drug-related trauma incidents are associated with increased risk for additional circulatory complications. Although drug and alcohol related trauma incidents are not associated with appreciably worse clinical outcomes, patients experiencing such complications are associated with significantly greater length of stay and higher hospitalization costs. Therefore significant benefits to trauma patients could be gained with enhanced surveillance for pre-injury substance use upon admission to the ED, and closer monitoring for infection or circulatory complications during their period of hospitalization. PMID- 21251322 TI - Evidence-based genomic diagnosis characterized chromosomal and cryptic imbalances in 30 elderly patients with myelodysplastic syndrome and acute myeloid leukemia. AB - BACKGROUND: To evaluate the clinical validity of genome-wide oligonucleotide array comparative genomic hybridization (aCGH) for detecting somatic abnormalities, we have applied this genomic analysis to 30 cases (13 MDS and 17 AML) with clonal chromosomal abnormalities detected in more than 50% of analyzed metaphase cells. RESULTS: The aCGH detected all numerical chromosomal gains and losses from the mainline clones and 113 copy number alterations (CNAs) ranging from 0.257 to 102.519 megabases (Mb). Clinically significant recurrent deletions of 5q (involving the RPS14 gene), 12p12.3 (ETV6 gene), 17p13 (TP53 gene), 17q11.2 (NF1 gene) and 20q, double minutes containing the MYC gene and segmental amplification involving the MLL gene were further characterized with defined breakpoints and gene contents. Genomic features of microdeletions at 17q11.2 were confirmed by FISH using targeted BAC clones. The aCGH also defined break points in a derivative chromosome 6, der(6)t(3;6)(q21.3;p22.2), and an isodicentric X chromosome. However, chromosomally observed sideline clonal abnormalities in five cases were not detected by aCGH. CONCLUSIONS: Our data indicated that an integrated cytogenomic analysis will be a better diagnostic scheme to delineate genomic contents of chromosomal and cryptic abnormalities in patients with MDS and AML. An evidence-based approach to interpret somatic genomic findings was proposed. PMID- 21251324 TI - Distribution of allele frequencies at TTN g.231054C > T, RPL27A g.3109537C > T and AKIRIN2 c.*188G > A between Japanese Black and four other cattle breeds with differing historical selection for marbling. AB - BACKGROUND: Marbling defined by the amount and distribution of intramuscular fat, so-called Shimofuri, is an economically important trait of beef cattle in Japan. Our previous study detected 3 single nucleotide polymorphisms (SNPs), g.231054C > T, g.3109537C > T and c.*188G > A, respectively, in the 5' flanking region of the titin (TTN), the 5' flanking region of the ribosomal protein L27a (RPL27A) and the 3' untranslated region of the akirin 2 genes (AKIRIN2), which have been considered as positional functional candidates for the genes responsible for marbling, and showed association of these SNPs with marbling in Japanese Black beef cattle. In the present study, we investigated the allele frequency distribution of the 3 SNPs among the 5 cattle breeds, Japanese Black, Japanese Brown, Japanese Shorthorn, Holstein and Brown Swiss breeds. FINDINGS: We genotyped the TTN g.231054C > T, RPL27A g.3109537C > T and AKIRIN2 c.*188G > A SNPs by polymerase chain reaction-restriction fragment length polymorphism method, using 101 sires and 1,705 paternal half sib progeny steers from 8 sires for Japanese Black, 86 sires and 27 paternal half sib progeny steers from 3 sires for Japanese Brown, 79 sires and 264 paternal half sib progeny steers from 14 sires for Japanese Shorthorn, 119 unrelated cows for Holstein, and 118 unrelated cows for Brown Swiss breeds. As compared to the frequencies of the g.231054C > T T, g.3109537C > T T and c.*188G > A A alleles, associated with high marbling, in Japanese Black breed that has been subjected to a strong selection for high marbling, those in the breeds, Japanese Shorthorn, Holstein and Brown Swiss breeds, that have not been selected for high marbling were null or lower. The Japanese Brown breed selected slightly for high marbling showed lower frequency than Japanese Black breed in the g.3109537C > T T allele, whereas no differences were detected between the 2 breeds in the frequencies of the g.231054C > T T and c.*188G > A A alleles. CONCLUSIONS: Based on this finding, we hypothesized that the pressure of the strong selection for high marbling in Japanese Black breed has increased the frequencies of the T, T and A alleles at the TTN g.231054C > T, RPL27A g.3109537C > T and AKIRIN2 c.*188G > A SNPs, respectively. This study, together with the previous association studies, suggested that the 3 SNPs may be useful for effective marker-assisted selection to increase the levels of marbling. PMID- 21251323 TI - EMT is the dominant program in human colon cancer. AB - BACKGROUND: Colon cancer has been classically described by clinicopathologic features that permit the prediction of outcome only after surgical resection and staging. METHODS: We performed an unsupervised analysis of microarray data from 326 colon cancers to identify the first principal component (PC1) of the most variable set of genes. PC1 deciphered two primary, intrinsic molecular subtypes of colon cancer that predicted disease progression and recurrence. RESULTS: Here we report that the most dominant pattern of intrinsic gene expression in colon cancer (PC1) was tightly correlated (Pearson R = 0.92, P < 10(-135)) with the EMT signature-- both in gene identity and directionality. In a global micro-RNA screen, we further identified the most anti-correlated microRNA with PC1 as MiR200, known to regulate EMT. CONCLUSIONS: These data demonstrate that the biology underpinning the native, molecular classification of human colon cancer- previously thought to be highly heterogeneous-- was clarified through the lens of comprehensive transcriptome analysis. PMID- 21251325 TI - Musical beauty and information compression: Complex to the ear but simple to the mind? AB - BACKGROUND: The biological origin of music, its universal appeal across human cultures and the cause of its beauty remain mysteries. For example, why is Ludwig Van Beethoven considered a musical genius but Kylie Minogue is not? Possible answers to these questions will be framed in the context of Information Theory. PRESENTATION OF THE HYPOTHESIS: The entire life-long sensory data stream of a human is enormous. The adaptive solution to this problem of scale is information compression, thought to have evolved to better handle, interpret and store sensory data. In modern humans highly sophisticated information compression is clearly manifest in philosophical, mathematical and scientific insights. For example, the Laws of Physics explain apparently complex observations with simple rules. Deep cognitive insights are reported as intrinsically satisfying, implying that at some point in evolution, the practice of successful information compression became linked to the physiological reward system. I hypothesise that the establishment of this "compression and pleasure" connection paved the way for musical appreciation, which subsequently became free (perhaps even inevitable) to emerge once audio compression had become intrinsically pleasurable in its own right. TESTING THE HYPOTHESIS: For a range of compositions, empirically determine the relationship between the listener's pleasure and "lossless" audio compression. I hypothesise that enduring musical masterpieces will possess an interesting objective property: despite apparent complexity, they will also exhibit high compressibility. IMPLICATIONS OF THE HYPOTHESIS: Artistic masterpieces and deep Scientific insights share the common process of data compression. Musical appreciation is a parasite on a much deeper information processing capacity. The coalescence of mathematical and musical talent in exceptional individuals has a parsimonious explanation. Musical geniuses are skilled in composing music that appears highly complex to the ear yet transpires to be highly simple to the mind. The listener's pleasure is influenced by the extent to which the auditory data can be resolved in the simplest terms possible. PMID- 21251326 TI - Management of lercanidipine overdose with hyperinsulinaemic euglycaemia therapy: case report. AB - This case report describes the first reported overdose of the dihydropyridine calcium channel blocker (CCB) lercanidipine. A 49 yr old male presented to the Emergency Department 3 hrs after the ingestion of 560 mg of lercanidipine. In the department he had a witnessed seizure within 15 minutes of arrival attributed to the overdose. Following immediate recovery of consciousness after the seizure, he had refractory hypotension and bradycardia which failed to respond to fluid resuscitation, glucagon therapy, and intravenous calcium. He went on to require vasopressor support with noradrenaline and was treated with high dose insulin therapy which was successful in achieving cardiovascular stability. Vasopressor therapy was no longer required within one half life of lercanidipine, and the total stay on intensive care was one day before transfer to a ward.Calcium channel blocker overdose is an uncommon but life-threatening overdose. Treatment for severe toxicity is similar to b-blocker overdose. Hypotension is treated with intravenous fluid therapy, intravenous calcium and possibly glucagon with vasopressor or inotropic support as required. Atropine is used to attempt reversal of bradycardia. High doses of intravenous insulin with intravenous dextrose as required (hyperinsulinaemic euglycaemia or HIET), has also been successfully reported. Experimental animal data suggests that HIET is of benefit and potentially superior to fluid therapy, calcium, glucagon and potentially vasopressor therapy. HIET effectively and sustainably reverses hypotension, bradycardia and improves myocardial contractility and metabolism. Current advice in calcium channel blocker overdose is to begin therapy early in toxicity, starting with a 1.0 IU/kg insulin bolus followed by an infusion of 0.5 IU/kg/hr of insulin and dextrose as required titrated to clinical response. PMID- 21251327 TI - Quality of data collection in a large HIV observational clinic database in sub Saharan Africa: implications for clinical research and audit of care. AB - BACKGROUND: Observational HIV clinic databases are now widely used to answer key questions related to HIV care and treatment, but there has been no systematic evaluation of their quality of data. Our objective was to evaluate the completeness and accuracy of recording of key data HIV items in a large routine observational HIV clinic database. METHODS: We looked at the number and rate of opportunistic infections (OIs) per 100 person years at risk in the 24 months following antiretroviral therapy (ART) initiation in 559 patients who initiated ART in 2004-2005 and enrolled into a research cohort. We compared this with data in a routine clinic database for the same 559 patients, and a further 1233 patients who initiated ART in the same period. The Research Cohort database was considered as the reference "gold standard" for the assessment of data accuracy. A crude percentage of underreporting of OIs in the clinic database was calculated based on the difference between the OI rates reported in both databases.We reviewed 100 clinic patient medical records to assess the accuracy of recording of key data items of OIs, ART toxicities and ART regimen changes. RESULTS: The overall incidence rate per 100 person years at risk for the initial OI in the 559 patients in the research cohort and clinic databases was 24.1 (95% CI: 20.5-28.2) and 13.2 (95% CI: 10.8-16.2) respectively, and 10.4 (95% CI: 9.1-11.9) for the 1233 clinic patients. This represents a 1.8- and 2.3-fold higher rate of events in the research cohort database compared with the same 599 patients and 1233 patients in the routine clinic database, or a 45.1% and 56.8% rate of underreporting, respectively. The combined error rate of missing and incorrect items from the medical records' review was 67% for OIs, 52% for ART-related toxicities, and 83% and 58% for ART discontinuation and modification, respectively. CONCLUSIONS: There is a high rate of underreporting of OIs in a routine HIV clinic database. This has important implications for the use and interpretation of routine observational databases for research and audit, and highlights the need for regular data validation of these databases. PMID- 21251328 TI - What was lost in translation in the DHA trial is whom you should intend to treat. AB - The results of a randomized double-blind placebocontrolled trial with docosahexaenoic acid (DHA) supplementation in mild to moderate Alzheimer's disease (AD) published by Quinn and colleagues in JAMA argues against overall efficacy of DHA in slowing progression. However, certain caveats in the results caution against discarding DHA altogether, raising questions about oxidation, dosage, pharmacogenomics and stage of intervention.One potential misconception is that what works for prevention will slow progression in AD subjects.Preclinical studies with DHA supported the rationale for early stage intervention; and three epidemiological studies indicated DHA intake was associated with reduced risk in non-apolipoprotein E4 (ApoE4) carriers. Putative drugs are initially tested for impact on progression because prevention approaches are problematic. However, should a drug be discarded for prevention if it fails to modify progression? Consistent with epidemiology, DHA significantly benefited two measures of cognition in mild to moderate non-ApoE4 carriers. Although the results of this trial were overall negative, failing to modify other outcomes, this commentary discusses important questions raised by them. Should future trials pursue DHA in non-ApoE4 carriers for slowing progression? Since in vivo oxidation of DHA may have adverse effects, particularly in ApoE4 patients, should preclinical and clinical studies be performed to optimize dose and mitigate oxidation before pursuing intervention or prevention trials with DHA? And finally, should DHA be tested now for mild cognitive impairment or prevention? PMID- 21251329 TI - p53 mutant breast cancer patients expressing p53gamma have as good a prognosis as wild-type p53 breast cancer patients. AB - INTRODUCTION: Normal function of the p53 network is lost in most cancers, often through p53 mutation. The clinical impact of p53 mutations in breast cancer remains uncertain, especially where p53 isoforms may modify the effects of these p53 mutations. METHODS: Expression of p53beta and p53gamma isoforms, the isoforms identified in normal breast tissue, was detected by reverse transcription polymerase chain reaction from a cohort of 127 primary breast tumours. Expression of p53beta and p53gamma isoforms was analysed in relation to clinical markers and clinical outcomes (5 years) by binary logistic regression, Cox proportional hazards regression and Kaplan-Meier survival analyses. RESULTS: p53beta and p53gamma were not randomly expressed in breast cancer. p53beta was associated with tumour oestrogen receptor (ER) expression, and p53gamma was associated with mutation of the p53 gene. The patient group with the mutant p53 breast tumour expressing p53gamma isoform had low cancer recurrence and an overall survival as good as that of patients with wild-type p53 breast cancer. Conversely, patients expressing only mutant p53, without p53gamma isoform expression, had a particularly poor prognosis. CONCLUSIONS: The determination of p53gamma expression may allow the identification, independently of the ER status, of two subpopulations of mutant p53 breast cancer patients, one expressing p53gamma with a prognosis as good as the wild-type p53 breast cancer patients and a second one not expressing p53gamma with a particularly poor prognosis. The p53gamma isoform may provide an explanation of the hitherto inconsistent relationship between p53 mutation, treatment response and outcome in breast cancer. PMID- 21251330 TI - Association of functional polymorphisms in CYP19A1 with aromatase inhibitor associated arthralgia in breast cancer survivors. AB - INTRODUCTION: Aromatase inhibitor-associated arthralgia (AIAA) is a common and often debilitating symptom in breast cancer survivors. Since joint symptoms have been related to estrogen deprivation through the menopausal transition, we hypothesized that genetic polymorphisms in CYP19A1, the final enzyme in estrogen synthesis, may be associated with the occurrence of AIAA. METHODS: We performed a cross-sectional study of postmenopausal women with stage 0 to III breast cancer receiving adjuvant aromatase inhibitor (AI) therapy. Patient-reported AIAA was the primary outcome. DNA was genotyped for candidate CYP19A1 polymorphisms. Serum estrogen levels were evaluated by radioimmunoassay. Multivariate analyses were performed to examine associations between AIAA and genetic variants controlling for possible confounders. RESULTS: Among 390 Caucasian participants, 50.8% reported AIAA. Women carrying at least one 8-repeat allele had lower odds of AIAA (adjusted odds ratio (AOR) 0.41, 95% confidence interval (CI) 0.21 to 0.79, P = 0.008) after adjusting for demographic and clinical covariates. Estradiol and estrone were detectable in 47% and 86% of subjects on AIs, respectively. Although these post-AI levels were associated with multiple genotypes, they were not associated with AIAA. In multivariate analyses, women with more recent transition into menopause (less than five years) were significantly more likely to report AIAA than those greater than ten years post-menopause (AOR 3.31, 95% CI 1.72 to 6.39, P < 0.001). CONCLUSIONS: Functional polymorphism in CYP19A1 and time since menopause are associated with patient-reported AIAA, supporting the hypothesis that the host hormonal environment contributes to the pathophysiology of AAIA. Prospective investigation is needed to further delineate relationships between host genetics, changing estrogen levels and AIAA. PMID- 21251331 TI - Medical pre-hospital management reduces mortality in severe blunt trauma: a prospective epidemiological study. AB - INTRODUCTION: Severe blunt trauma is a leading cause of premature death and handicap. However, the benefit for the patient of pre-hospital management by emergency physicians remains controversial because it may delay admission to hospital. This study aimed to compare the impact of medical pre-hospital management performed by SMUR (Service Mobile d'Urgences et de Reanimation) with non-medical pre-hospital management provided by fire brigades (non-SMUR) on 30 day mortality. METHODS: The FIRST (French Intensive care Recorded in Severe Trauma) study is a multicenter cohort study on consecutive patients with severe blunt trauma requiring admission to university hospital intensive care units within the first 72 hours. Initial clinical status, pre-hospital life-sustaining treatments and Injury Severity Scores (ISS) were recorded. The main endpoint was 30-day mortality. RESULTS: Among 2,703 patients, 2,513 received medical pre hospital management from SMUR, and 190 received basic pre-hospital management provided by fire brigades. SMUR patients presented a poorer initial clinical status and higher ISS and were admitted to hospital after a longer delay than non SMUR patients. The crude 30-day mortality rate was comparable for SMUR and non SMUR patients (17% and 15% respectively; P = 0.61). After adjustment for initial clinical status and ISS, SMUR care significantly reduced the risk of 30-day mortality (odds ratio (OR): 0.55, 95% CI: 0.32 to 0.94, P = 0.03). Further adjustments for the delay to hospital admission only marginally affected these results. CONCLUSIONS: This study suggests that SMUR management is associated with a significant reduction in 30-day mortality. The role of careful medical assessment and intensive pre-hospital life-sustaining treatments needs to be assessed in further studies. PMID- 21251332 TI - DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines. AB - BACKGROUND: DNA methylation is an essential epigenetic mechanism involved in gene regulation and disease, but little is known about the mechanisms underlying inter individual variation in methylation profiles. Here we measured methylation levels at 22,290 CpG dinucleotides in lymphoblastoid cell lines from 77 HapMap Yoruba individuals, for which genome-wide gene expression and genotype data were also available. RESULTS: Association analyses of methylation levels with more than three million common single nucleotide polymorphisms (SNPs) identified 180 CpG sites in 173 genes that were associated with nearby SNPs (putatively in cis, usually within 5 kb) at a false discovery rate of 10%. The most intriguing trans signal was obtained for SNP rs10876043 in the disco-interacting protein 2 homolog B gene (DIP2B, previously postulated to play a role in DNA methylation), that had a genome-wide significant association with the first principal component of patterns of methylation; however, we found only modest signal of trans-acting associations overall. As expected, we found significant negative correlations between promoter methylation and gene expression levels measured by RNA sequencing across genes. Finally, there was a significant overlap of SNPs that were associated with both methylation and gene expression levels. CONCLUSIONS: Our results demonstrate a strong genetic component to inter-individual variation in DNA methylation profiles. Furthermore, there was an enrichment of SNPs that affect both methylation and gene expression, providing evidence for shared mechanisms in a fraction of genes. PMID- 21251334 TI - Characterization of the radioresponse of human apical papilla-derived cells. AB - BACKGROUND: The purpose of this study was to characterize the radiobiological properties of stem/progenitor cells derived from apical papilla-derived cells (APDCs) compared to bulk APDCs. METHODS: APDCs were isolated from freshly extracted human third molars with immature apices. Multipotent spheres, which are thought to contain an enriched population of stem/progenitor cells, were formed from the APDCs, using a neurosphere culture technique. After gamma-irradiation, papillary sphere-forming cells (PSFCs) and bulk APDCs were subjected to radiosensitivity and hard tissue-forming assays. RESULTS: Compared to bulk APDCs, the PSFCs exhibited a radioresistant phenotype and a higher capacity for DNA double strand break repair. Irradiation induced a significant increase in a senescence-like phenotype in both cell types. Neither type of cells exhibited a significant induction of apoptotic changes after 8 Gy of irradiation. Ability to form hard tissue in vivo was significantly decreased in PSFCs, but not in APDCs following 4 Gy of irradiation. CONCLUSIONS: We demonstrated for the first time that stem/progenitor cells derived from APDCs exhibit a radioresistant phenotype; however, the hard tissue forming ability in vivo, but not bulk APDCs, was significantly reduced after irradiation. PMID- 21251333 TI - Coding potential of the products of alternative splicing in human. AB - BACKGROUND: Analysis of the human genome has revealed that as much as an order of magnitude more of the genomic sequence is transcribed than accounted for by the predicted and characterized genes. A number of these transcripts are alternatively spliced forms of known protein coding genes; however, it is becoming clear that many of them do not necessarily correspond to a functional protein. RESULTS: In this study we analyze alternative splicing isoforms of human gene products that are unambiguously identified by mass spectrometry and compare their properties with those of isoforms of the same genes for which no peptide was found in publicly available mass spectrometry datasets. We analyze them in detail for the presence of uninterrupted functional domains, active sites as well as the plausibility of their predicted structure. We report how well each of these strategies and their combination can correctly identify translated isoforms and derive a lower limit for their specificity, that is, their ability to correctly identify non-translated products. CONCLUSIONS: The most effective strategy for correctly identifying translated products relies on the conservation of active sites, but it can only be applied to a small fraction of isoforms, while a reasonably high coverage, sensitivity and specificity can be achieved by analyzing the presence of non-truncated functional domains. Combining the latter with an assessment of the plausibility of the modeled structure of the isoform increases both coverage and specificity with a moderate cost in terms of sensitivity. PMID- 21251335 TI - The effects of laminarin derived from Laminaria digitata on measurements of gut health: selected bacterial populations, intestinal fermentation, mucin gene expression and cytokine gene expression in the pig. AB - The aim of the present study was to establish the optimum inclusion level of laminarin derived from Laminaria digitata on selected microbial populations, intestinal fermentation, cytokine and mucin gene expression in the porcine ileum and colon. A total of twenty-one pigs (mean body weight 17.9 kg) were randomly assigned to one of three dietary treatments: T1 - basal (control) diet, T2 and T3 - basal diets supplemented with laminarin included at 300 and 600 parts per million (ppm), respectively. Selected intestinal bacterial populations and volatile fatty acid (VFA) concentrations were measured in the ileum and colon. Relative gene expression levels for specific cytokine and mucin genes were investigated in ileal and colonic tissue in the absence and presence of a lipopolysaccharide (LPS) challenge. There was an up-regulation of MUC2 gene expression at the 300 ppm inclusion level in the ileum. In the colon, there was a significant reduction in the enterobacteriaceae population at the 300 ppm inclusion level (P = 0.0421). Dietary supplementation of 600 ppm laminarin led to a significant increase in MUC2 (P = 0.0365) and MUC4 (P = 0.0401) expression in the colon, and in the total VFA concentration in the caecum (P = 0.0489). A significant increase was also recorded in IL-6 (P = 0.0289) and IL-8 gene expression (P = 0.0245) in LPS-challenged colonic tissue at both laminarin inclusion levels. In conclusion, dietary inclusion of 300 ppm laminarin appears to be the optimum dose in the present study due to the reduction in the enterobacteriaceae populations and enhanced IL-6 and IL-8 cytokine expression in response to an ex vivo LPS challenge. PMID- 21251336 TI - Folate supplementation differently affects uracil content in DNA in the mouse colon and liver. AB - High folate intake may increase the risk of cancer, especially in the elderly. The present study examined the effects of ageing and dietary folate on uracil misincorporation into DNA, which has a mutagenic effect, in the mouse colon and liver. Old (18 months; n 42) and young (4 months; n 42) male C57BL/6 mice were pair-fed with four different amino acid-defined diets for 20 weeks: folate deplete (0 mg/kg diet); folate replete (2 mg/kg diet); folate supplemented (8 mg/kg diet); folate deplete (0 mg/kg diet) with thymidine supplementation (1.8 g/kg diet). Thymidylate synthesis from uracil requires folate, but synthesis from thymidine is folate independent. Liver folate concentrations were determined by the Lactobacillus casei assay. Uracil misincorporation into DNA was measured by a GC/MS method. Liver folate concentrations demonstrated a stepwise increase across the spectrum of dietary folate levels in both old (P = 0.003) and young (P < 0.001) mice. Uracil content in colonic DNA was paradoxically increased in parallel with increasing dietary folate among the young mice (P trend = 0.033), but differences were not observed in the old mice. The mean values of uracil in liver DNA, in contrast, decreased with increasing dietary folate among the old mice, but it did not reach a statistically significant level (P < 0.1). Compared with the folate-deplete group, thymidine supplementation reduced uracil misincorporation into the liver DNA of aged mice (P = 0.026). The present study suggests that the effects of folate and thymidine supplementation on uracil misincorporation into DNA differ depending on age and tissue. Further studies are needed to clarify the significance of increased uracil misincorporation into colonic DNA of folate-supplemented young mice. PMID- 21251337 TI - Associations between dietary patterns, physical activity (leisure-time and occupational) and television viewing in middle-aged French adults. AB - Diet and physical activity are considered to be major components of a healthy lifestyle. However, few studies have examined in detail the relationships between specific types of physical activity, sedentary behaviour and diet in adults. The objective of the present study was to assess differential relationships between dietary patterns, leisure-time and occupational physical activities and time spent watching television (TV), as an indicator of sedentary behaviour, in middle aged French subjects. We performed a cross-sectional analysis using data from 1359 participants in the SUpplementation en VItamines et Mineraux AntioXydants study, who completed a detailed physical activity questionnaire and at least six 24 h dietary records. Sex-specific dietary patterns were derived using factor analysis; their relationships with leisure-time and occupational physical activities and TV viewing were assessed using ANCOVA, after adjustment for age, educational level and smoking status. Three dietary patterns were identified in each sex. After adjustment for potential confounders, leisure-time physical activity was positively associated with a 'healthy' food pattern in both men (P for trend < 0.01) and women (P for trend < 0.03) and negatively associated with an 'alcohol/meat' pattern in men (P for trend < 0.01). TV viewing was positively associated with a 'convenience' pattern in men and with a 'alcohol-appetiser' pattern in women. In conclusion, identification of relationships between dietary patterns, physical activity and sedentary behaviour can enable identification of different types of lifestyle and should help to target at-risk groups in nutrition prevention programmes. PMID- 21251338 TI - Different kinds of vegetable oils in relation to individual cardiovascular risk factors among Iranian women. AB - Detrimental effects of trans-fats on lipid profiles, blood pressure and plasma glucose levels have been documented by short-term clinical trials with high doses of trans-fats, but limited observational studies have considered habitual consumption of partially hydrogenated vegetable oil (PHVO) and these outcome variables, particularly hypertension. We aimed to evaluate the association of PHVO and non-hydrogenated vegetable oils (non-HVO) intake with individual cardiovascular risk factors. In a cross-sectional study of 486 Iranian adult women, usual dietary intakes were assessed, and fasting plasma glucose (FPG), lipid profiles and blood pressure were measured. PHVO (commonly used for cooking in Iran) were considered as the PHVO category. Sunflower oil, maize oil, rapeseed oil, soyabean oil and olive oil were defined as the non-HVO category. Diabetes (FPG >= 1260 mg/l), dyslipidaemia (based on Adult Treatment Panel III) and hypertension (based on Joint National Committee VI) were defined. The presence of 'at least one risk factor' and 'at least two risk factors' of the three major risk factors for CVD (hypertension, dyslipidaemia and diabetes) was also evaluated. After controlling for age and other potential confounders, a high consumption of HVO was associated with a greater risk of having dyslipidaemia (OR for top v. bottom quintile 5.04; 95 % CI 2.70, 9.36), hypertension (OR for top v. bottom quintile 3.03; 95 % CI 1.55, 6.10), at least one (OR for top v. bottom quintile 8.52; 95 % CI 4.41, 16.41) and at least two risk factors (OR for top v. bottom quintile 3.60; 95 % CI 1.64, 7.74), while those in the top quintile of non HVO consumption had lower odds for all these conditions. Further adjustment for dietary intakes had little impact on these associations. Even after additional adjustment for BMI, the positive association of HVO and the inverse association of non-HVO with the above-mentioned cardiovascular risk factors remained significant, except for the association between non-HVO and hypertension that became marginally significant. No overall significant associations were found between the consumption of HVO and non-HVO and diabetes. Higher intakes of PHVO were associated with a greater risk of individual cardiovascular risk factors, while those of non-HVO were associated with a reduced risk. PMID- 21251339 TI - Young women partition fatty acids towards ketone body production rather than VLDL TAG synthesis, compared with young men. AB - Before the menopause, women are relatively protected against CVD compared with men. The reasons for this sex difference are not completely understood, but hepatic fatty acid metabolism may play a role. The present study aimed to investigate the utilisation of plasma NEFA by the liver and to determine whether they are partitioned differently into ketone bodies and VLDL-TAG in healthy, lean young men and women. Volunteers were studied during a prolonged overnight fast (12-19 h) using an intravenous infusion of [U-13C]palmitate. After 12 h fasting, the women had a more advantageous metabolic profile with lower plasma glucose (P < 0.05) and TAG (P < 0.05) but higher plasma NEFA (P < 0.05) concentrations. Plasma 3-hydroxybutyrate (3-OHB) concentrations rose more in women than in men, and the transfer of 13C from [U-13C]palmitate to plasma [13C]3-OHB reached a plateau 6-7 h after the start of the infusion in women but was still increasing at 6 h in men. This implies a slower 3-OHB production rate and/or dilution by other precursor pools in men. In women, the high isotopic enrichment of plasma 3 OHB suggested that systemic plasma fatty acids were the major source of 3-OHB production. However, in men, this was not observed during the course of the study (P < 0.01). There were no sex differences for the incorporation of 13C into VLDL1 or VLDL2-TAG. The ability of young women to partition fatty acids towards ketone body production rather than VLDL-TAG may contribute to their more advantageous metabolic profile compared with young men. PMID- 21251340 TI - The effect of within-crop habitat manipulations on the conservation biological control of aphids in field-grown lettuce. AB - Within-crop habitat manipulations have the potential to increase the biological control of pests in horticultural field crops. Wildflower strips have been shown to increase the abundance of natural enemies, but there is little evidence to date of an impact on pest populations. The aim of this study was to determine whether within-crop wildflower strips can increase the natural regulation of pests in horticultural field crops. Aphid numbers in plots of lettuce grown adjacent to wildflower strips were compared with those in plots grown in the absence of wildflowers. The presence of wildflower strips led to a decrease in aphid numbers on adjacent lettuce plants during June and July, but had less impact in August and September. The decrease in aphid numbers was greatest close to the wildflower strips and, the decrease in aphid numbers declined with increasing distance from the wildflower strips, with little effect at a distance of ten metres. The main natural enemies found in the crop were those that dispersed aerially, which is consistent with data from previous studies on cereal crops. Analysis and interpretation of natural enemy numbers was difficult due to low recovery of natural enemies, and the numbers appeared to follow changes in aphid abundance rather than being directly linked to the presence of wildflower strips. Cutting the wildflower strips, to remove floral resources, had no impact on the reduction in aphid numbers achieved during June and July, but decreased the effect of the wildflower strips during August and September. The results suggest that wildflower strips can lead to increased natural regulation of pest aphids in outdoor lettuce crops, but more research is required to determine how this is mediated by natural enemies and how the impact of wildflower strips on natural pest regulation changes during the growing season. PMID- 21251341 TI - Longevity of Zygocotyle lunata in Balb/c mice and long-term survival of digeneans in vertebrate hosts. AB - This study used Balb/c mice to examine the longevity of Zygocotyle lunata in a murine host. Of 11 mice, each exposed to 20 Z. lunata cysts, six were infected with a total of 12 worms from 11 to 24 weeks postinfection (PI). Live worms recovered at 24 weeks PI had a mean body area of about 25 mm2. These worms produced viable eggs with well-developed miracidia following embryonation in artificial spring water for 2 weeks at 28 degrees C. The Balb/c mouse is a useful model to study longevity of this paramphistomid trematode for at least 6 months PI. An additional aspect of this article is a review of the pertinent literature published from 1937 to 2007 on ageing and longevity of digeneans. PMID- 21251342 TI - Endoparasite fauna of five Gadiformes fish species from the coast of Chile: host ecology versus phylogeny. AB - The aims of the present study were to compare, using multivariate analyses, the degree of similarity of the endoparasite fauna of five fish species belonging to the order Gadiformes: Merluccius gayi, Merluccius australis, Macruronus magellanicus (Gadoidei) and Micromesistius australis and Nezumia pulchella (Macrouroidei), from the southern and central Chilean coast, and to evaluate whether the composition of the endoparasite fauna was determined by phylogenetic or ecological relationships. We employed our database of Merluccius australis, M. magellanicus and Micromesistius australis, which was complemented with published information for M. magellanicus, Merluccius australis, Micromesistius australis, M. gayi and N. pulchella. A higher number of endoparasite species was recorded for Merluccius australis, Micromesistius australis and M. magellanicus, namely Anisakis sp. and Hepatoxylon trichiuri, which is the most prevalent parasite among these hosts. Aporocotyle wilhelmi and Hysterothylacium sp. were detected only in M. gayi, whereas Lepidapedon sp. was found exclusively in N. pulchella. These results suggest that fish ecology rather than host phylogeny was the most important factor for the determination of similarity in parasite composition. This result could be explained by the similar trophic patterns of hosts and by the predominance of generalist larval species among these fish parasite communities. PMID- 21251343 TI - An abattoir-based study of hydatidosis in the dromedary (Camelus dromedarius) in Mashhad, Iran. AB - A 6-year retrospective study based on abattoir records was carried out to determine the prevalence of hydatidosis in dromedaries in Khorasan province in north-eastern Iran. Between 20 March 2004 and 19 March 2010, 25,255 dromedaries were slaughtered in the study area and the livers of 2791 (11.1%) and the lungs of 3289 dromedaries (13.2%) were discarded due to hydatidosis. The annual prevalence of liver condemnations due to hydatidosis decreased from 24.1% in 2004 2005 to 13.3% in 2009, and finally to 6.8% in 2010. The corresponding features for lung condemnation due to hydatidosis were relatively higher than liver, declining from 28.7% in 2004-2005 to 14.9% in 2009, and finally to 7.1% in 2010. Liver and lung condemnations due to hydatidosis were significantly higher in the spring. This could be attributed to various factors such as sources of slaughtered animals, changes in management practice and ecological factors. The present survey provides baseline data for the future monitoring of this potentially important parasitic disease in the region. PMID- 21251344 TI - Neuroendocrine markers of high risk for psychosis: salivary testosterone in adolescent boys with prodromal symptoms. AB - BACKGROUND: The peak in age of onset of psychotic disorders such as schizophrenia during puberty and early adulthood suggests a relationship between the expression of psychopathology and the changes in the brain and body that take place during this dynamic maturational period, including a dramatic increase in circulating oestrogens and androgens. This study examined levels of salivary testosterone and oestradiol in adolescents with prepsychotic, prodromal symptoms, as this may mediate risk for psychosis by having an impact on brain development. METHOD: In 21 male adolescents with prodromal symptoms and 21 male non-clinical controls levels of testosterone and oestradiol were measured in saliva. Tanner pubertal stage and prodromal symptoms were also assessed. RESULTS: Levels of testosterone were significantly lower in adolescents with prodromal symptoms as compared with non-clinical controls. No group differences in oestradiol were found. In the total sample, level of testosterone was significantly correlated with age and Tanner pubertal stage. CONCLUSIONS: Our observations are in line with current hypotheses stressing the role of neuroendocrine factors during adolescence in the expression of psychotic symptoms. From a developmental perspective, susceptibility to psychotic disorders increases during adolescence. Our data suggest that testosterone might, in part, mediate this increased vulnerability. Further research is needed to assess the mediating, neural, mechanisms through which testosterone may have an impact on the development of psychotic symptoms. In the search for early risk markers for psychosis, studying neuroendocrine factors might increase our understanding of 'at-risk' developmental pathways. PMID- 21251345 TI - Sex differences and developmental stability in genetic and environmental influences on psychoactive substance consumption from early adolescence to young adulthood. AB - BACKGROUND: Genetic and environmental factors are important in the etiology of substance use. However, little is known about the stability of these factors across development. We aimed to answer three crucial questions about this etiology that have never been addressed in a single study: (1) Is there a general vulnerability to substance consumption from early adolescence to young adulthood? (2) If so, do the genetic and environmental influences on this vulnerability change across development? (3) Do these developmental processes differ in males and females? METHOD: Subjects included 1480 twin pairs from the Swedish Twin Study of Child and Adolescent Development who have been followed since 1994. Prospective, self-reported regular smoking, alcohol intoxication and illicit drug use were assessed at ages 13-14, 16-17 and 19-20 years. Structural modeling was performed with the program Mx. RESULTS: An underlying common factor accounted for the association between smoking, alcohol and illicit drug consumption for the three age groups. Common genetic and shared environmental effects showed substantial continuity. In general, as participants aged, the influence of the shared environment decreased, and genetic effects became more substance specific in their effect. CONCLUSIONS: The current report answers three important questions in the etiology of substance use. The genetic and environmental risk for substance consumption is partly mediated through a common factor and is partly substance specific. Developmentally, evidence was strongest for stability of common genetic effects, with less evidence for genetic innovation. These processes seem to be the same in males and females. PMID- 21251346 TI - Microbiological and epidemiological investigation of the Neisseria meningitidis serogroup A epidemic in Niger in 2009: last wave before the introduction of the serogroup A meningococcal conjugate vaccine? AB - The 2009 meningitis season in Niger was characterized by an early onset, beginning in the very first weeks of the year and peaking from the 12th to the 15th week with 5655 clinical cases over the 4 weeks. From 1 January 2009 to 28 June 2009 (week 26), a total of 13,733 clinical cases of meningitis were reported to the national epidemiological surveillance system with a case-fatality rate of 4.2%. During the season 25 of the 42 health districts reached the epidemic threshold and 11 the alert threshold. Reactive mass vaccination campaigns involving a total of 5 166,741 doses of the polysaccharide meningococcal bivalent (A+C) vaccine progressively controlled the outbreak in most parts of the country. A total of 3755 cerebrospinal fluid samples representing 28.1% of the suspected meningitis cases were analysed. Serogroup A meningococci were the causative agent in 97.5% of the meningococcal cases. Multi-locus sequence typing of 26 meningococal serogroup A strains showed 25 sequence type (ST)7 and one ST2859, both sequence types belonging to the ST5 clonal complex (CC5) of subgroup III. This is the largest epidemic observed in Niger since those of 1995-1996 (59,948 notified cases) and 2000 (14,633 notified cases). PMID- 21251348 TI - Measuring antibody levels in bulk-tank milk as an epidemiological tool to search for the status of Coxiella burnetii in dairy sheep. AB - Pooling samples may provide a valuable alternative to individual testing for pathogen surveillance purposes. We studied the reliability of measuring the level of antibodies against Coxiella burnetii in bulk-tank milk (BTM) to estimate the seroprevalence of C. burnetii in dairy sheep in 34 flocks. We then estimated the seroprevalence of C. burnetii in 154 dairy sheep flocks according to the level of antibodies in BTM. We tested for the accuracy of our estimation at the population level by comparing predicted mean C. burnetii flock seroprevalence with that obtained in another survey performed on the same population. Our findings showed that testing BTM by ELISA is a cost-effective and relatively good index of the seroprevalence of C. burnetii in dairy sheep and may be a useful tool for epidemiological surveillance at the population level. PMID- 21251347 TI - Increased influenza-related healthcare utilization by residents of an urban aboriginal community. AB - Most studies describing high rates of acute respiratory illness in aboriginals have focused on rural or remote communities. Hypothesized causes include socioeconomic deprivation, limited access to healthcare, and a high prevalence of chronic disease. To assess influenza rates in an aboriginal community while accounting for healthcare access, deprivation and chronic disease prevalence, we compared rates of influenza-related outpatient and emergency-department visits in an urban Mohawk reserve (Kahnawa:ke) to rates in neighbouring regions with comparable living conditions and then restricted the analysis to a sub-population with a low chronic disease prevalence, i.e. those aged <20 years. Using medical billing claims from 1996 to 2006 we estimated age-sex standardized rate ratios. The rate in Kahnawa:ke was 58% greater than neighbouring regions and 98% greater in the analysis of those aged <20 years. Despite relatively favourable socioeconomic conditions and healthcare access, rates of influenza-related visits in Kahnawa:ke were elevated, particularly in the younger age groups. PMID- 21251350 TI - The Cognitive Assessment Battery (CAB): a rapid test of cognitive domains. AB - BACKGROUND: The study aimed to evaluate the Cognitive Assessment Battery (CAB) in a specialist clinic setting in order to find out if it if it could be a supplement to the Mini-mental State Examination (MMSE) and distinguish between normal aging, mild cognitive impairment (MCI) and dementia, as well as MCI of different severities. METHODS: CAB consists of six short tests covering the cognitive domains of speed/attention, episodic memory, visuospatial functions, language and executive functions. It takes about 20 minutes to carry out and provides a quick overview of the patient's cognitive profile. Three groups were compared: healthy controls (N = 41), MCI (N = 83) and mild dementia (N = 28). RESULTS: CAB distinguished very clearly between controls and MCI as well as MCI and dementia. On further analysis CAB also distinguished between MCI of different severities. It also showed to have good sensitivity and specificity for identifying more severe MCI. CONCLUSIONS: CAB seems to be a useful supplement to MMSE and a screening instrument for MCI and dementia with good sensitivity and specificity. PMID- 21251349 TI - Waterborne norovirus outbreak in a municipal drinking-water supply in Sweden. AB - During Easter 2009, almost 200 people resident in a small Swedish village fell ill with gastrointestinal symptoms. We conducted a retrospective cohort study and a molecular investigation in order to identify the source of the outbreak. Residents living in households connected to the public water network were at an increased risk of developing disease (relative risk 4.80, 95% confidence interval 1.68-13.73) compared to those with no connection to the public network. Norovirus genotype GI.3 was identified in stool samples from six patients and in a sample from the public water network. Contamination of one of the wells supplying the public water network was thought to be the source of the outbreak. This is a description of a norovirus outbreak linked to a municipal drinking-water supply in Sweden. Information from epidemiological and molecular investigations is of utmost importance to guide outbreak control measures and to prevent future outbreaks. PMID- 21251351 TI - Norms and associated factors of the STAI-Y State anxiety inventory in older adults: results from the PAQUID study. AB - BACKGROUND: The latest version of the State-Trait Anxiety Inventory (STAI-Y) is commonly used in older adults, even though this anxiety scale was developed in and for young adults. Norms and associated factors of the STAI-Y are lacking for older adults in the general population. The objectives of the present study were to produce norms on the STAI-Y State scale for older adults using a large sample of older adults selected from a general population and to examine the sociodemographic and health-related factors associated with the STAI-Y State score. METHODS: 993 community-dwelling individuals aged 66 years and over from the PAQUID study were evaluated at home by a psychologist for the following variables: age, education, marital status, proximity of relatives, self assessment of income sufficiency, occupation during active life, depressive symptomatology, objective and subjective health, objective and subjective cognitive functioning, adverse life events, activities of daily living, drug use, and cigarette consumption. RESULTS: Norms were stratified for age, sex, and education and were produced separately for older adults with and without depressive symptomatology. Multivariate analyses revealed that younger age (66-79 years), female sex, lower education, perception of income insufficiency, depressive symptomatology, poor subjective health, subjective cognitive complaints, psychotropic drugs use, and recent adverse life events were independently associated with higher STAI-Y State score. CONCLUSIONS: This study provides norms for the STAI-Y State anxiety inventory in a general population of older adults and indicates the specific factors linked with state anxiety. Such factors should be taken into account by clinicians in order to better understand state anxiety in older adults. PMID- 21251352 TI - Awareness of olfactory deficits in healthy aging, amnestic mild cognitive impairment and Alzheimer's disease. AB - BACKGROUND: Olfactory dysfunction is present in early Alzheimer's disease (AD), and has now been reported in people with amnestic mild cognitive impairment (aMCI). Recent evidence suggests that unawareness of an olfactory deficit may predict which MCI patients will subsequently meet AD criteria. However, important methodological limitations challenge this suggestion. While addressing some of the limitations of previous research, this preliminary study explores unawareness of olfactory deficits as a predictive factor of future AD among people with aMCI. METHODS: Twenty-five participants with aMCI, 25 AD patients, and 22 healthy elderly participants underwent testing of olfactory identification. Subjective reports regarding perceived decline in olfactory detection and olfactory identification were also obtained. A subset of participants was reassessed 12 months later. RESULTS: Control participants performed better than both aMCI and AD patients on olfactory identification. Almost uniformly, participants did not report decline in either olfactory detection or identification. Prediction of olfactory identification scores from subjective reports of olfactory function was poor, and awareness of olfactory decline bore no relationship to the likelihood of aMCI patients progressing to AD by the 12-month review. CONCLUSIONS: Treating awareness of olfactory function as a unitary construct can be misleading, and there is a poor relationship between subjective and objective measures of olfactory ability. Our preliminary data suggest that unawareness of olfactory decline does not improve the identification of patients with MCI who are more likely to be in the prodromal phase of AD. Replication in a larger cohort is needed to support these findings. PMID- 21251353 TI - Neuropsychiatric and cognitive profile of patients with DSM-IV delirium referred to an old age psychiatry consultation-liaison service. AB - BACKGROUND: The phenomenology of delirium is understudied, including how the symptom profile varies across populations. The aim of this study was to explore phenomenology occurring in patients with delirium referred to an old age psychiatry consultation-liaison setting and compare with delirium occurring in palliative care patients. METHODS: Consecutive cases of DSM-IV delirium were assessed with the Delirium Rating scale Revised-98 (DRS-R98) and Cognitive Test for Delirium (CTD). RESULTS: Eighty patients (mean age 79.3 +/- 7.7 years; mean DRS-R98 total score 21.7 +/- 4.9 and total CTD score 10.2 +/- 6.3) were included. Forty patients (50%) with comorbid dementia were older, had a longer duration of symptoms at referral, and more severe delirium due to greater cognitive impairments. Inattention (100%) was the most prominent cognitive disturbance, while sleep-wake cycle disturbance (98%), altered motor activity (97%), and thought process abnormality (96%) were the most frequent DRS-R98 non-cognitive features. Inattention was associated with severity of other cognitive disturbances on both the DRS-R98 and CTD, but not with DRS-R98 non-cognitive items. The phenomenological profile was similar to palliative care but with more severe delirium due to greater cognitive and non-cognitive disturbance. CONCLUSION: Delirium is a complex neuropsychiatric syndrome with generalized cognitive impairment and disproportionate inattention. Sleep-wake cycle and motor activity disturbances are also common. Comorbid dementia results in a similar phenomenological pattern but with greater cognitive impairment and later referral. PMID- 21251356 TI - [Explore innovations at intersections of related disciplines]. PMID- 21251357 TI - [To ponder certain problems concerning lower respiratory infection]. PMID- 21251358 TI - [The influence of high positive end-expiratory pressure ventilation combined with low tidal volume on prognosis of patients with acute lung injury/acute respiratory distress syndrome: a Meta-analysis]. AB - OBJECTIVE: To compare the effects of high and low positive end-expiratory pressure (PEEP) levels on prognosis of patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS). METHODS: The data in PubMed, EMbase, Cochrane Library, CBM and CNKI were retrieved. All randomized controlled trials (RCTs) of treatment of ALI/ARDS with PEEP with high or low level were included. Study selection and assessment, data collection and analyses were undertaken by two independent reviewers. Meta-analyses were done using Cochrane Collaboration's RevMan 5.0 software. RESULTS: Six RCTs, involving a total of 2 484 patients of ALI/ARDS were included in the review. According to ventilation strategy, all trials were divided into subgroup A (high PEEP+low tidal volume of 6 ml/kg vs. low PEEP+low tidal volume) and subgroup B (high PEEP+low tidal volume vs. low PEEP+traditional tidal volume). In subgroup B, there were three RCTs, and high PEEP was found to be associated with a lower 28-day mortality [odds ratio (OR)=0.40, 95% confidence interval (95%CI) 0.22-0.72, P=0.003] and a lower barotraumas (OR=0.20, 95%CI 0.05-0.82, P=0.02) in patients with ALI/ARDS. In subgroup A, there were three RCTs, and it was found that the differences in 28 day mortality (OR=0.86, 95%CI 0.72-1.02, P=0.08) and barotraumas (OR=1.19, 95%CI 0.89-1.58, P=0.25) were not significant . CONCLUSION: As compared with conventional ventilation, high PEEP and low tidal volume ventilation are associated with improved survival and a lower rate of barotrauma in patients with ALI/ARDS. It is necessary to further confirm the role of high PEEP only in the ventilation strategy in patients with ALI/ARDS. PMID- 21251359 TI - [CCERW: a new rule to predict treatment failure in patients with community acquired pneumonia in middle aged and elderly people]. AB - OBJECTIVE: To develop and validate a clinical rule to predict treatment failure in middle-aged and elderly patients suffering from community-acquired pneumonia (CAP) in China, and to compare it with other prognostic rules. METHODS: Data of 58 variables affiliated to 6 aspects, including demographics, underlaying diseases, previous status, complications, symptoms, signs and laboratory examination results from the CAP patients aged>=45 years admitted to the respiratory departments in three university affiliated hospitals between December 17, 2006 and December 22, 2008 were enrolled prospectively and then validated in two groups to create a derivation cohort with 75% of the patients for rule development and an internal validation cohort with the other 25% for internal test. An external validation cohort was formed at the same time with patients admitted to the other university affiliated hospital for external test. The single outcome was treatment failure at the time of 14 days after admitted or at discharge from hospital. Univariate analysis, multivariate analysis and receiver operating characteristics (ROC) curve were used for the rule establishment, assessment and comparison among the pneumonia severity index (PSI), CURB65 [confusion, blood urea nitrogen>6.8 mmol/L, respiratory rate (RR)>=30 breaths per minute, systolic blood pressure (SBP)<90 mm Hg (1 mm Hg=0.133 kPa) or diastolic blood pressure (DBP)<=60 mm Hg, age>=65 years] and CRB65 (confusion, RR>=30 breaths per minute, SBP<90 mm Hg or DBP <=60 mm Hg, age>=65 years). RESULTS: The data of a total of 539 patients in three hospitals were enrolled for analysis. Of those, 400 and 139 patients were randomly allocated into the derivation cohort or internal validation cohort respectively. Meanwhile, 159 patients were enrolled in the external validation cohort. Analyzing the data from 400 patients in the derivation cohort, 33 variables of 6 aspects had significant difference between cure and treatment failure outcome in the univariate analysis. Then, in the multivariate analyses, five independent predictive factors showed significant difference, including confusion (C), creatinine<60 MUmol/L, electrolyte disturbances (E), respiratory failure (R), white blood cell (WBC)>7.5*10(9)/L. A clinical prediction rule CCERW based on these variables showed that the treatment failure outcome increased directly with increasing scores: 5.5%-9.1%, 12.8%-20.0% and 31.0%-40.5% for scores of 0-1, 2 and 3-6, respectively. ROC curve analysis yielded an area under the curve (AUC) for CCERW of 0.709 [95% confidence intervals (95%CI) 0.638-0.780], 0.725 (95%CI 0.613-0.838) and 0.686 (95%CI 0.590 0.782) in the derivation, internal and external validation cohorts respectively; and in the same manner, of 0.710 (95%CI 0.659-0.761) for total 698 patients, which was better than PSI, CURB65 and CRB65, at 0.667 (95%CI 0.614-0.719), 0.648 (95%CI 0.592-0.705), and 0.584 (95%CI 0.530-0.638), respectively. CONCLUSION: CCERW can help physicians to distinguish high and low risk leading to treatment failure in middle-aged and elder patients with CAP, and has better predictable capability than PSI, CURB65 and CRB65. We prudent recommend the simple rule can be used in the middle-aged and elder patients with CAP of Han race people in China. PMID- 21251360 TI - [The effect of bone marrow mesenchymal stem cells engraftment on lung tissue at early stage of smoke inhalation injury in rabbits]. AB - OBJECTIVE: To explore the effect of bone marrow mesenchymal stem cells (MSCs) engraftment on lung tissue at early stage of smoke inhalation injury in rabbits. METHODS: MSCs were proliferated by the method of whole marrow culture and identified by flow cytometry. Forty-eight rabbits were randomly divided into smoke inhalation group (S group) and MSCs group (M group) after reproduction of rabbit smoke inhalation injury model. 10 ml of phosphate buffer saline (PBS) containing 1*10(7)/ml MSCs was intravenously injected in M group, meanwhile 10 ml PBS was injected intravenously in S group. Eight rabbits were sacrificed at 2, 6 and 24 hours after intervention, and the lung tissue was harvested for morphological and pathological observation, and lung injury score was used to evaluate smoke inhalation injury. RESULTS: Cultured cells were confirmed to be MSCs with flow cytometry. Lung injury in rabbits of M group was less serious in morphology and histopathology than that in S group. Though there was no significance in lung injury score between M group and S group at 2 hours after injury (4.0+/-0.7 vs. 4.5+/-0.6, P>0.05), the lung injury scores in M group at 6 hours and 24 hours after injury were significantly lower than those in S group (6 hours: 6.1+/-0.9 vs. 8.2+/-0.9, 24 hours: 4.6+/-0.9 vs. 10.4+/-0.8, both P<0.01). CONCLUSION: Intravenous engraftment of MSCs could ameliorate lung injury induced by smoke inhalation, and improve lung injury score significantly. PMID- 21251361 TI - [Effect of bone marrow mesenchymal stem cells engraftment on secretion of inflammatory cytokine in the early stages of smoke inhalation injury in rabbits]. AB - OBJECTIVE: To explore the effect of bone marrow mesenchymal stem cells (MSCs) engraftment on secretion of tumor necrosis factor-alpha (TNF-alpha), interleukins (IL-1beta, IL-6, IL-10) in peripheral blood and lung homogenates in the early stages of smoke inhalation injury. METHODS: MSCs were proliferated by the method of whole marrow culture and identified by flow cytometry. Fifty-six healthy New Zealand rabbits were randomly divided into control group (C group, n=8), smoke inhalation injury group (S group, n=24) and smoke inhalation injury+MSCs engraftment group (M group, n=24). The latter two groups were subdivided into 2, 4, 6 hours after injury subgroups, with 8 rabbits in each group. The levels of TNF-alpha, IL-1beta, IL-6 and IL-10 in peripheral blood and lung homogenates were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with C group, concent of pro-inflammatory and anti-inflammatory cytokines in peripheral blood at each time point in S group were increased significantly. The concent of pro-inflammatory cytokines in lung homogenate at each time point in S group was significantly higher than those in C group, and that of anti-inflammatory cytokines showed no significant changes. Compared with the S group, concent of pro-inflammatory cytokines in peripheral blood in M group was decreased significantly, and that of anti-inflammatory cytokines was increased significantly [6 hours TNF-alpha (MUg/L): 1.7+/-1.7 vs. 4.1+/-1.6, IL-1beta (ng/L): 9.9+/-1.7 vs. 21.2+/-2.6, IL-6 (MUg/L): 1.0+/-0.3 vs. 1.3+/-0.2, IL-10 (ng/L): 15.2+/-4.4 vs. 7.9+/-3.5, all P<0.05]. Concent of pro-inflammatory cytokines at each time point in M group was decreased significantly when compared with S group in lung homogenate, while only anti-inflammatory cytokine at 4 hours and 6 hours was increased significantly [6 hours TNF-alpha (ng/L): 503.0+/-156.4 vs. 587.7+/-171.2, IL-1beta (ng/L): 0.4+/-0.2 vs. 0.6+/-0.2, IL-6 (ng/L): 155.2+/ 13.7 vs. 350.2+/-20.3, IL-10 (ng/L): 23.3+/-5.4 vs. 11.0+/-5.6, all P<0.05]. CONCLUSION: MSCs engraftment could decrease pro-inflammatory cytokines and increase anti-inflammatory cytokines in the early stages of smoke inhalation injury, thus ameliorates inflammatory response, which confers protective effect on smoke inhalation injury. PMID- 21251362 TI - [Clinical and laboratory criteria for identification of early-onset stroke associated pneumonia: a prospective trial]. AB - OBJECTIVE: To investigate the significance of first determined contents of procalcitonin (PCT), C-reactive protein (CRP), soluble triggering receptor expressed on myeloid cell-1 (sTREM-1) and the clinical pulmonary infection score (CPIS) in the detection of early-onset pneumonia (EOP) developed in patients suffering from stroke. METHODS: From June 2009 to June 2010, 244 stroke patients admitted to the emergency intensive care unit (EICU) in Shanghai Fifth People's Hospital were included in this prospective study. Patients were excluded if they were discharged or died in 24 hours of admission, or pneumonia was diagnosed at the admission. The serum levels of PCT, CRP and sTREM-1 were determined, and the CPIS was calculated in all patients on the day of admission. RESULTS: Among all 244 stroke patients, EOP was diagnosed in 105 of them, and 74 developed severe EOP. The serum levels of PCT, CRP, sTREM-1 and the CPIS in patients with EOP were significantly higher than those in patients who did not develop EOP [PCT (MUg/L): 4.20 (0.83,7.75) vs. 0.19 (0.12,0.41); CRP (mg/L): 56.0 (18.5,105.5) vs. 9.0 (7.0,15.0) ; sTREM-1 (ng/L): 56.0 (24.5,111.5) vs. 10.0 (8.0,16.0); CRIS: 4.0 (2.5,4.0) vs. 2.0 (1.0,2.0), all P<0.01], and the levels of PCT, CRP, sTREM-1 and the CPIS in patients with severe EOP were significantly higher than those in patients with mild EOP [PCT (MUg/L): 6.10 (3.40,8.83) vs. 0.61 (0.42,1.67); CRP (mg/L): 80.5 (31.5,113.0) vs. 21.0 (12.0,43.0); sTREM-1 (ng/L): 89.0 (53.8,132.8) vs. 21.0 (14.0,43.0); CPIS: 4.0 (3.0,5.0) vs. 2.0 (2.0,3.0), all P<0.01]. The cutoff point, sensitivity and specificity of each indicator to predict EOP were 89.5% and 79.1% in PCT>0.43 MUg/L, 78.1% and 78.4% in CRP>16 mg/L, 81.9% and 84.9% in sTREM-1>19 ng/L, 75.2% and 79.9% in CPIS>2. Using PCT>0.43 MUg/L combined with CPIS>3 to predict EOP, the sensitivity and specificity reached 81.9% and 92.1% respectively. The cutoff point, sensitivity and specificity of indicators to identify severe EOP were 87.8% and 83.9% in PCT>2.15 MUg/L, 70.3% and 77.4% in CRP>43 mg/L, 81.1% and 90.3% in sTREM-1>51 ng/L, 67.6% and 83.9% in CPIS>3. Using PCT>2.15 MUg/L combined with sTREM-1>56 ng/L to predict severe EOP, the sensitivity and specificity reached 82.4% and 100.0% respectively. CONCLUSION: The first PCT is an effective indicator to predict EOP. The first CPIS is an index for screening EOP. PCT combined with CPIS may improve the specificity to predict EOP. The first sTREM-1 is a good indicator to identify severe EOP. Combination of first PCT and sTREM-1 may greatly improve the specificity to predict severe EOP. PMID- 21251363 TI - [Effects of high positive end-expiratory pressure combined with recruitment maneuvers in patients with acute respiratory distress syndrome]. AB - OBJECTIVE: To investigate the clinical effects and safety degree of high positive end-expiratory pressure (PEEP) combined with lung recruitment maneuver (RM) in patients with acute respiratory distress syndrome (ARDS). METHODS: Thirty-eight patients in medical intensive care unit (MICU) of Affiliated Hospital of Guiyang Medical College suffering from ARDS admitted from June 2008 to May 2010 were enrolled in the study. With the envelope method they were randomized into RM group and non-RM group, with n=19 in each group. All patients received protective ventilation: pressure support ventilation (PSV) with plateau pressure limited at 30 cm H(2)O (1 cm H(2)O=0.098 kPa) or lower. PEEP was set at the minimum level with fraction of inspired oxygen (FiO(2)) <0.60 and partial pressure of arterial oxygen (PaO(2)) kept between 60 and 80 mm Hg (1 mm Hg=0.133 kPa). RM was conducted by regulating FiO(2) to 1.00, support pressure to 0, PEEP increased to 40 cm H(2)O and maintained for 30 seconds before lowering, and this maneuver was repeated every 8 hours for a total of 5 days. Base status, ventilation parameters, blood gas analysis and vital signs were obtained at baseline and for the next 5 days. Oxygenation status and lung injury indexes were compared between RM group and non-RM group, the adverse effects of RM and incidence of barotrauma were recorded. RESULTS: 1 There were no significant differences of base status and ventilation parameters between RM group and non-RM group. 2PaO(2) and oxygenation index (PaO(2)/FiO(2)) were both increased in RM group and non-RM group, but the values were higher in RM group [PaO(2)(mm Hg) 2 days: 85.8+/-21.3 vs. 73.5+/-18.7, 3 days: 88.6+/-22.8 vs. 74.3+/-19.8, 4 days: 98.8+/-30.7 vs. 79.3+/-19.3, 5 days: 105.5+/-29.4 vs. 84.4+/-13.8; PaO(2)/FiO(2) (mm Hg) 4 days: 221.8+/-103.5 vs. 160.3+/-51.4, 5 days: 239.6+/-69.0 vs. 176.8+/-45.5, all P<0.05]. 3 Hydrogen peroxide (H(2)O(2)) and interleukin-6 (IL-6) concentration in exhaled breath condensate (EBC) decreased in both groups but lower in RM group with significant difference [5 days H(2)O(2) (MUmol/L): 0.04+/-0.02 vs. 0.10+/ 0.03; IL-6 (ng/L): 4.12+/-2.09 vs. 9.26+/-3.47, both P<0.05]. (4) Barotrauma and arrhythmia did not occur in both groups. No significant changes in heart rate were found during RM. Central venous pressure and mean arterial pressure remained unchanged after RM. CONCLUSION: High level PEEP combined with RM can improve gas exchange and oxygenation, decrease ventilator associated lung injury (VALI). RM was safe and had good tolerance, no hypoxemia, barotrauma and hemodynamic instability were observed. PMID- 21251364 TI - [Effect of sulfonic tanshinone sodium injection on the expression and activity of aquaporin-5 of human alveolar epithelial cells after seawater exposure]. AB - OBJECTIVE: To explore the effects of tanshinone IIA on the activity of aquaporin 5 (AQP5) in human alveolar epithelial cells (A549) after seawater exposure and its possible mechanism. METHODS: Routinely cultured A549 cells were divided into different groups according to different content of seawater: blank control group, 15%, 25%, 50%, 75%, 100% seawater groups; they were divided into different groups according to the duration of exposure to 25% seawater: blank control group, 1, 4, 8 hours groups; they were also divided into different groups according to concentration of tanshinone IIA and exposed to seawater for 4 hours: blank control group, 25% seawater group, 25, 50, 75, 100 MUg/ml tanshinone IIA intervention groups. The expressions of AQP5 were respectively assayed by Western blotting and immunohistochemistry. RESULTS: The results of Western blotting showed that the expressions of AQP5 were remarkably higher at 8 hours of exposure to seawater in 25% and 50% seawater groups than those in blank control group (1.053+/-0.231, 1.116+/-0.316 vs. 0.101+/-0.081, both P<0.05); the expression of AQP5 in 1-hour group showed a slight increase compared with blank control group (0.306+/-0.125 vs. 0.288+/-0.098, P>0.05), that in 4-hour group was increased significantly (1.423+/-0.377, P<0.01), and in 8-hour group (1.507+/-0.461) it was slightly higher than that in 4-hour group without statistical significance. The AQP5 expression was significantly lower in tanshinone IIA 25 MUg/ml and 50 MUg/ml intervention groups than that in 25% seawater group (0.580+/-0.186, 0.499+/-0.172 vs. 1.013+/-0.287, both P<0.05). Immuno-histochemistry showed that the expression of AQP5 was markedly up-regulated after A549 cells were stimulated with 25% seawater for 4 hours as compared with blank control group (7.21+/-0.78 vs. 0.41+/ 0.07, P<0.01), but intervention of tanshinone IIA significantly inhibited the up regulation of AQP5 expression (3.02+/-0.23) induced by 25% seawater (P<0.05). CONCLUSION: The experimental results showed that tanshinone IIA is innocuous to A549 at a dosage of 25 MUg/ml, and it can decrease the overexpression of AQP5 induced by seawater. PMID- 21251365 TI - [Comparative study of recruitment maneuver guided by pressure-volume curve on respiratory physiology and lung morphology between acute respiratory distress syndrome of pulmonary and extrapulmonary origin in canine models]. AB - OBJECTIVE: To determine effects of recruitment maneuver (RM) guided by pressure volume (P-V) curve on respiratory physiology and lung morphology in canine models of acute respiratory distress syndrome of pulmonary or extrapulmonary origin (ARDSp and ARDSexp). METHODS: Twenty-four healthy dogs were randomly divided into two groups with 12 dogs each: ARDSexp and ARDSp. Each dog in ARDSexp group was injected with oleic acid 0.1 ml/kg through femoral vein, and each dog in ARDSp group received hydrochloric acid 2 ml/kg via trachea. Subsequently, dogs with both models were randomly subdivided into lung protective ventilation strategy (LPVS) group and LPVS+RM group, respectively. Dogs in LPVS group were given LPVS only without RM. RM guided by P-V curve was performed in LPVS+RM group followed by LPVS and pressure controlled ventilation (PCV) mode was selected. Phigh was set at upper inflection point (UIP) of the P-V curve, positive end-expiratory pressure (PEEP) was set at lower inflection point (LIP)+2 cm H(2)O (1 cm H(2)O=0.098 kPa), and the duration of RM was 60 seconds. The duration of mechanical ventilation (MV) in both subgroups was 4 hours. The oxygenation index (PaO(2)/FiO(2)), relative lung mechanical indexes were measured in two ARDS models before establishment of ARDS model, and before and after RM. The UIP and LIP were calculated with P-V curve. The percentage of different volume in ventilation of lung accounting for total lung volume was compared by CT scan. RESULTS: The PaO(2)/FiO(2), UIP and LIP did not showed significant differences among all groups before ARDS and before RM. PaO(2)/FiO(2) and respiratory system compliance (Crs) were significantly elevated in LPVS+RM group of both models 4 hours after RM compared with corresponding LPVS group [PaO(2)/FiO(2) (mm Hg, 1 mm Hg=0.133 kPa) of ARDSexp model: 263.9+/-69.2 vs. 182.8+/-42.8, Crs (ml/cm H(2)O) of ARDSexp model: 11.3+/-4.2 vs. 9.7+/-3.7; PaO(2)/FiO(2) (mm Hg) of ARDSp model: 193.4+/-33.5 vs. 176.4+/-40.2, Crs (ml/cm H(2)O) of ARDSp model: 10.1+/-3.9 vs. 9.0+/-3.9, P<0.05 or P<0.01], and the airway pressure was significantly declined compared with corresponding LPVS group [peak inspiratory pressure (PIP), cm H(2)O ] of ARDSexp model: 24.1+/-7.4 vs. 30.2+/-8.5, plateau pressure (Pplat, cm H(2)O) of ARDSexp model: 19.1+/-7.3 vs. 25.6+/-7.7; PIP (cm H(2)O) of ARDSp model: 26.6+/-8.4 vs. 29.6+/-10.3, Pplat (cm H(2)O) of ARDSp model: 21.9+/-7.3 vs. 25.1+/-8.4, P<0.05 or P<0.01]. Moreover, PaO(2)/FiO(2), Crs, PIP and Pplat were improved better in ARDSexp model than ARDSp model (P<0.05 orP<0.01). Compared with LPVS maneuver, RM plus LPVS maneuver could significantly decrease the proportion of closure and hypoventilation region, and increase the proportion of normal ventilation region in both models [closure region of ARDSexp model: (9.9+/ 3.1)% vs. (16.3+/-5.2)%, hypoventilation region of ARDSexp model: (10.2+/-4.2)% vs. (23.4+/-6.7)%, normal ventilation region of ARDSexp model: (76.2+/-12.3)% vs. (57.5+/-10.1)%; closure region of ARDSp model: (14.3+/-4.8)% vs. (18.2+/-5.1)%, hypoventilation region of ARDSp model: (17.4+/-6.3)% vs. (24.1+/-5.9)%, normal ventilation region of ARDSp model: (63.2+/-10.7)% vs. (54.6+/-11.3)%, P<0.05 or P<0.01]. All of the ventilation regions were better improved with ARDSexp model than ARDSp model (all P<0.05). CONCLUSION: RM guided by P-V curve could help obtain better oxygenation, improve pulmonary compliance and lung ventilation in ARDSexp and ARDSp, and better treatment effects are seen in ARDSexp dogs than ARDSp dogs. PMID- 21251366 TI - [Recognition of early risky factors in patients suffering from critical influenza A H1N1]. AB - OBJECTIVE: To investigate clinical risky factors and improve the ability to discover critically ill patients suffering from influenza A H1N1 in emergency department. METHODS: A retrospective study of 65 cases with severe influenza A H1N1 was conducted. Univariate analysis and multivariate Logistic regression analysis were used to identify independent predictors of critically ill cases. Goodness of Fit test was performed on an established clinical predicting scoring (prediction of critically ill with influenza score, PCIS) system. RESULTS: Univariate analysis showed that significant difference between critically ill and severe group consisted of eight factors including age distribution, more than one comorbidity, chronic cardiovascular disease, oncologic diseases, sputum, myalgia/arthralgia, dyspnea and oxygen saturation at admission. A multivariate Logistic regression showed an association between development of critical illness and more than one comorbidity [odds ratio (OR)=7.611, 95% confidence interval (95%CI) 1.635-35.429], myalgia/arthralgia (OR=7.523, 95%CI 1.462-38.716), dyspnea (OR=11.090, 95%CI 1.373-89.565), and oxygen saturation<0.95 at admission (OR=8.088, 95%CI 1.019-84.969, all P<0.05). The prognostic criteria had a good discriminative ability [area under receiver operating characteristic curve (AUC) was 0.922, 95%CI 0.860-0.985, P=0.000]. The PCIS scoring system was established according to the level of four high risk factors. Low risk (PCIS 0-1), intermediate risk (PCIS 2), high risk (PCIS 3), and very high risk (PCIS>=4) were categorized for predicting the occurrence of critical illness, and the Goodness of Fit test was good (R(2)=0.940 6, P=0.030 1). CONCLUSION: Emergency physician can predict the development of critical condition in patients with influenza A H1N1 by using clinical characteristics including comorbidity, myalgia/arthralgia, dyspnea, and oxygen saturation at admission, and it is helpful in making clinical decision. PMID- 21251367 TI - [Combined traditional and western medicine in the treatment of 100 elderly patients suffering from severe pneumonia: an analysis of clinical results]. PMID- 21251368 TI - [Treatment in 50 cases of pulmonary embolism]. PMID- 21251369 TI - [Effects of high dose ulinastatin treatment in patients with severe pneumonia complicating influenza A H1N1 infection]. PMID- 21251370 TI - [Unilateral lung ventilation in the treatment of unilateral pneumothorax complicated with reexpansion pulmonary edema: report of one case]. PMID- 21251371 TI - [Advancement in treatment of acute lung injury with stem cells]. PMID- 21251372 TI - [Anticoagulant therapy: a new idea in the treatment of acute lung injury and acute respiratory distress syndrome]. PMID- 21251373 TI - [The effect of aerosolized antibiotic therapy on ventilator associated pneumonia]. PMID- 21251376 TI - Do intra-operative fluids influence the need for post-operative cardiotropic support after a PDA ligation? AB - OBJECTIVE: To investigate the effect of intra-operative intravenous fluids on post-operative hemodynamic stability. METHODS: We performed a retrospective cohort study of 98 preterm infants who underwent a patent ductus arteriosus (PDA) ligation in one NICU between 2001 and 2007. The primary outcome was the need for cardiotropic support within 24 hrs of ligation. RESULTS: Twenty-seven infants (28%) required post-operative cardiotropic support. The amount of intra-operative fluids varied between 0 and 50.4 mL/kg (median: 10.2 mL/kg). No intra-operative fluid was recorded in 26 patients. Fluids were not associated with the need for post-operative cardiotropic support (P=0.10). Using a multivariate logistic regression model, age at ligation, weight at ligation and pre-operative FiO2 were significant predictors of post-operative cardiotropic support. CONCLUSIONS: Intra operative fluids do not appear to be associated with the need for post-operative cardiotropic support. A prospective cohort study may help identify modifiable risk factors and improve outcomes in this population. PMID- 21251377 TI - [Role of hypoxia-inducible factor-1alpha endothelin-1 and inducible nitric oxide synthase in the pathogenesis of hypoxia-induced pulmonary hypertension of the newborn]. AB - OBJECTIVE: To investigate the roles of hypoxia-inducible factor-1alpha (HIF 1alpha), endothelin-1 (ET-1) and inducible nitric oxide synthase (iNOS) in the pathogenesis of hypoxia-induced pulmonary hypertension (HPH) of the newborn. METHODS: Seventy-five term hospitalized neonates with HPH (mild 29 cases, moderate 25 cases, severe 21 cases) and 22 term hospitalized neonates without HPH (control group) were enrolled between June 2006 and November 2009. Serum levels of HIF-1alpha, iNOS and ET-1 were measured using ELASA 1, 3 and 7 days after birth. RESULTS: Serum concentrations of HIF-1alpha and ET-1 in the mild, moderate and severe HPH groups were significantly higher than those in the control group (P<0.01) 1 day after birth, and were related to the severity of HPH. The serum iNOS concentrations in the moderate and severe HPH groups were also significantly higher than those in the control group (P<0.01). By 3 days after birth, serum ET 1 concentration in the moderate HPH group and serum concentrations of HIF-1alpha, ET-1 and iNOS in the severe HPH group reminded significantly higher than those in the control group (P<0.05). At 7 days after birth, serum ET-1 concentration in the severe HPH group still remained higher than that in the control group (P<0.05). CONCLUSIONS: Serum levels of HIF-1alpha, ET-1 and iNOS increase in neonates with HPH, resulting in an imbalance of ET-1 and NO. This may be of importance in the pathogenesis of neonatal HPH. PMID- 21251378 TI - [Longitudinal study of the physical catch-up growth in 84 preterm appropriate for gestational age infants]. AB - OBJECTIVE: To study the growth rhythm of preterm appropriate for gestational age (AGA) infants by investigating their physical catch-up growth characteristics. METHODS: Eighty-four preterm AGA newborns (44 males and 40 females) with gestational ages between 28-36 weeks were enrolled. The weight, length and head circumference were evaluated by Z score according to the criterions of actual and corrected ages. RESULTS: The preterm infants had the catch-up growth in weight, length and head circumference in the first year of life. The growth velocity within the first three months was the highest. The velocity in the weight catch up was higher than that in the length. CONCLUSIONS: The fastest growing period is the early three month of life in preterm AGA infants. The catch-up growth in weight and length is unbalanced. PMID- 21251379 TI - [Nasal carriage of community-acquired methicillin-resistant Staphylococcus aureus in healthy children from Chengdu]. AB - OBJECTIVE: To evaluate the prevalence of nasal carriage of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) in healthy children from Chengdu. METHODS: Strains of Staphylococcus aureus were isolated from nasal swabs of healthy children from five kindergartens in Chengdu from September, 2005 to December, 2005 and questionnaires were obtained. Antibiotic susceptibility test was performed with agar disk diffusion and Bauer-Kirby on Mueller-Hinton medium method to determine CA-MRSA. mecA and PVL genes were detected with PCR in all of the CA-MRSA isolates. RESULTS: A total of 801 children were enrolled. Overall 147 children (18.4%) were carried with Staphylococcus aureus and 9 (1.1%) were carried with CA-MRSA. All CA-MRSA isolates were positive for mecA gene, and 5 CA MRSA isolates were positive for PVL gene. Of the 9 CA-MRSA isolates, 6 were multiresistant. CONCLUSIONS: CA-MRSA nasal colonization is present among Chengdu healthy children. The CA-MRSA isolates are multiresistant and parts of CA-MRSA isolates carry PVL gene. The nasal carriage of CA-MRSA in healthy children should be a concerned issue. PMID- 21251380 TI - [Antibiotic resistance of gram-negative Bacillis isolated from children with bronchopneumonia]. AB - OBJECTIVE: To study the distribution and antibiotic resistance of gram-negative pathogens isolated from children with bronchopneumonia. METHODS: The distribution and the results of susceptibility tests of 272 strains of gram-negative Bacillis isolated from children with bronchopneumonia during 2009 were analyzed. RESULTS: Among the isolates, the common pathogens were Klebsiella pneumoniae and Escherichia coli. The extended-spectrum beta-lactamase (ESBLs) production rate was 52.9%. Compared with the non-ESBLs producing strains, ESBLs-producing strains had a significantly higher drug resistance rate to many antibiotics except amikacin and meropenem (P<0.05). The lowest resistance to ESBLs producing gram negative strains was found for meropenem (0.7%), followed by imipenem, amikacin and cefoperazone/sulbactam. CONCLUSIONS: More attentions should be paid to the high rate of drug-resistance of ESBLs producing strains in children. Antimicrobial therapy should be based on the results of drug resistance surveillance. PMID- 21251381 TI - [Condition of Epstein Barr virus infection in hospitalized children from Wuhan region]. AB - OBJECTIVE: To study the condition and clinical characteristics of Epstein Barr virus (EBV) infection in hospitalized children from Wuhan region. METHODS: A total of 14 840 hospitalized children were classified into five age groups: less than 6 months old, 6 months to 1 year old, 1 to 3 years old, 3 to 7 years old and 7 to 15 years old. The antibodies IgM and IgG to EBV capsid antigen (VCA) were detected using ELISA. RESULTS: In the 14 840 hospitalized children, 7 899 were positive for EBV antibodies, with an infection rate of 53.23%. The positive rate of VCA-IgM was 4.05% (601/14 840) and that of VCA-IgG was 49.18% (7 298/14 840). The lowest positive rate of VCA-IgM (0.11%) was found in the group of less than 6 months old and the highest positive rate of VCA-IgG (79.83%) was found in the group of 7 to 15 years old. Of the 601 children with positive VCA-IgM, 429 (71.4%) suffered from respiratory tract infection. CONCLUSIONS: EBV infection is very common in hospitalized children in Wuhan. Respiratory tract infection is a leading disease in children with positive EBV antibodies. The infection rate of EBV in different age groups is different. PMID- 21251382 TI - [Comparisons of efficacy and safety of tolterodine and oxybutynin in children with idiopathic overactive bladder]. AB - OBJECTIVE: To compare the efficacy and safety of tolterodine and oxybutynin in the treatment of idiopathic overactive bladder in children. METHODS: A total of 204 children with idiopathic overactive bladder were randomly divided into three groups (n=68 each): placebo, tolterodine-treated and oxybutynin-treated. The efficacy and safety were evaluated two weeks after treatment. RESULTS: The effective rate was 25% in the placebo group, 89% in the tolterodine-treated group, and 92% in the oxybutynin-treated group. The effective rate in the two treatment groups was significantly higher than that in the placebo group (P<0.05). There was a similar efficacy between the two treatment groups. The incidence of adverse events in the tolterodine-treated group (28%) was significantly lower than that in the oxybutnin-treated group (57%) (P<0.05). CONCLUSIONS: Tolterodine has a similar efficacy to oxybutynin in the treatment of idiopathic overactive bladder in children, with better safety in pharmacotherapy. PMID- 21251383 TI - [Application of laryngeal mask airway anaesthesia combined with sacral canal block in pediatric anaesthesia]. AB - OBJECTIVE: To compare the advantages and disadvantages between laryngeal mask airway anaesthesia combined with sacral canal block and single tracheal tube anaesthesia in pediatric surgery. METHODS: Sixty 2-12-year-old children for lower limb or lower abdominal surgery were randomly assigned into two groups: a group that was given laryngeal mask airway anaesthesia combined with sacral canal block and a group was given single tracheal tube anaesthesia (n=30 each). Mean arterial pressure (MAP), SpO2 and heart rate (HR) were recorded before induction of anaesthesia, before and after insertion of laryngeal mask airway (LMA) or tracheal tube (TT) and after removal of LMA or TT. The waking-up time, VAS pain scores and the frequency of mania were recorded after surgery. RESULTS: There were no significant differences in MAP, SpO2 and HR between the combined and single anaesthesia groups before anaesthesia and insertion of LMA or TT, while the MAP and HR in the combined anaesthesia group were significantly lower than those in the single anaesthesia group after insertion and removal of LMA or TT (P<0.05). The VAS pain scores were significantly lower and the waking-up time was significantly shorter in the combined anaesthesia group than those in the single anaesthesia group (P<0.05) after surgery. The frequency of mania after surgery in the combined anaesthesia group was significantly lower than that in the single anaesthesia group (P<0.05). CONCLUSIONS: The hemodynamics is more stable in children during the induction and the waking-time of laryngeal mask anesthesia combined with sacral canal block. The anesthesia may relieve postoperative pain, shorten the waking-up time and decrease the frequency of mania. PMID- 21251384 TI - [Influence of near-work and outdoor activities on myopia progression in school children]. AB - OBJECTIVE: To study the influence of near-work and outdoor activities on myopia progression in school children. METHODS: Eighty 7-11-year-old school children with myopia were randomly assigned into an intervention group (n=41) and a control group (n=39). The children in the intervention group did near- and middle vision activities less than 30 hrs per week and more outdoor activities than 14 15 hrs per week. Myopia progression was observed regularly over 2 years after which ophthalmologists administered questionnaires regarding near-vision work (reading, writing and using computer), middle-vision work (watching TV and extracurricular learning activities), outdoor activities, using nature light, wearing glasses, etc. RESULTS: The annual mean myopia progression (0.38 +/- 0.15 D) in the intervention group was significantly lower than that in the control group (0.52 +/- 0.19 D; P<0.01). The children in the two groups spent similar amounts of time in near-vision activities, but the children in the intervention group spent less time in middle-vision activities (P<0.01) and more outdoor activities (13.7 +/- 2.4 vs 6.2 +/- 1.6 hrs/wk; P<0.01). When considering all children in the study, there were 4 factors that significantly correlated with less myopia progression: more outdoor activities, more time spent wearing glasses, more time spent in natural light and less time using a computer. When analyzing the intervention group separately, more outdoor activity was inversely correlated with myopia progression (t=-2.510, P<0.05). Separate analysis of the control group indicated that more time wearing glasses was correlated with less myopia progression (t=-3.115, P<0.05). CONCLUSIONS: Myopia progression in school children may be slowed by more outdoor activities, more time spent in natural light and more time wearing corrective glasses. PMID- 21251385 TI - [Effects of TGF-beta1 on gene expression of connective tissue growth factor in lung fibroblasts]. AB - OBJECTIVE: To study the effects of transforming growth factor-beta1 (TGF-beta1) on the gene expression of connective tissue growth factor (CTGF) in cultured lung fibroblasts of embryonic rats in vitro. METHODS: Wistar rats of embryonic 19 days were used for primary culture of lung fibroblasts (LFs). The cells in the experimental group were treated by different concentrations (1, 5 or 10 ng/mL) and different durations (12, 24 or 48 hrs) of TGF-beta1 to stimulate the LFs. The cells in the control group were cultured in serum-free medium. RT-PCR method was applied to detect CTGF mRNA expression in LFs. RESULTS: Compared with the control group, the levels of CTGF mRNA in LFs in the experimental group increased significantly (P<0.05). CTGF mRNA expression gradually increased with increasing concentration and duration of TGF-beta1 treatment (P<0.05). CONCLUSIONS: TGF beta1 can stimulate CTGF gene expression in LFs and increase CTGF gene expression in a dose-and time-dependent manner. PMID- 21251386 TI - [Effect of oxymatrine on the distribution of dendritic cells in lung and spleen tissues of asthmatic mice]. AB - OBJECTIVE: To study the effect of oxymatrine (Oxy) on airway inflammation and the distribution of dendritic cells (DC) in lung and spleen tissues of asthmatic mice. METHODS: Fifty BALB/c mice were assigned into five groups (n=10): an asthma model group, a dexamethasone (Dex) treatment group and three Oxy treatment groups (Oxy dose: 20, 40 and 80 mg/kg respectively). The histological changes of lung tissues were observed by hematoxylin and eosin staining. The expression of 33D1 antigen (a marker of DC) in lung and spleen tissues were detected by immunohistochemical staining. RESULTS: The inflammatory reactions of the lung tissues in the Dex or Oxy treatment groups were less severe than those in the asthma model group. 33D1 antigen was remarkably expressed in the lung and spleen tissues of the asthma model group. After Dex treatment, the expression of 33D1 antigen in the lung and spleen tissues decreased significantly (P<0.01). 33D1 antigen expression in the lung tissues was significantly reduced in all of the three Oxy treatment groups in a dose-dependent manner compared with that in the asthma model group (P<0.01). The treatment with Oxy of 40 and 80 mg/kg decreased significantly the 33D1 antigen expression in the spleen tissues (P<0.01). CONCLUSIONS: Oxy can alleviate airway inflammation and reduce the number of DC in lung and spleen tissues of asthma mice, which may be contributed to the mechanism of Oxy for treatment of asthma. PMID- 21251387 TI - [Effects of W-7 on the expression of GRP78 and neuronal apoptosis in immature rat hippocampus after status convulsion]. AB - OBJECTIVE: To investigate the effects of the calmodulin inhibitor W-7 on the expression of the key marker of ERS GRP78 and neuronal apoptosis in the immature rat hippocampus after status convulsion (SC). METHODS: One hundred and seventeen male Sprague-Dawley rats aged 19-21 days were randomly divided into three groups: normal saline control (control), SC with and without W-7 pretreatment. Each of the 3 groups was further subdivided into subgroups sacrificed at 4, 24 and 48 hrs. SC model was prepared using lithium-pilocarpine. GRP78 mRNA expression in the hippocampus was detected by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). GRP78 protein was ascertained by immunohistochemistry. Neuronal apoptosis was observed with TdT-mediated dUTP nick end labeling (TUNEL). RESULTS: The expression of GRP78 mRNA was significantly increased in the non pretreated SC group compared with the control group 24 hrs after injection of saline or lithium-pilocarpine (P<0.01), and the expression of GRP78 protein also increased markedly in the seizure group compared with the control group 24 and 48 hrs after the injection (P<0.01). The expression of GRP78 mRNA and protein in the W-7 pretreatment group was significantly higher than both the control and the non pretreated seizure groups 24 and 48 hrs after injection. The TUNEL positive cells in the hippocampus CA1 in the non-pretreated SC group 24 and 48 hrs after injection (21.0 +/- 2.5 and 29.4 +/- 2.8, respectively) were increased compared to the control group (7.1 +/- 1.4 and 7.3 +/- 1.6, respectively; P<0.01). W-7 pretreatment decreased TUNEL positive cells to 15.0 +/- 2.5 and 20.0 +/- 2.9 at 24 and 48 hrs after injection compared to the non-pretreated seizure group (P<0.01), but the number of TUNEL positive cells in the W-7 pretreatment group remained significantly greater than in the control group (P<0.01). CONCLUSIONS: W 7 may up-regulate the expression of GRP78 and reduce the number of apoptotic neurons, thus provides a neuroprotective effect against brain damage following SC. PMID- 21251388 TI - [Effects of recombinant human erythropoietin on serum levels of neuron-specific enolase, S-100beta protein and myelin basic protein in rats following status epilepticus]. AB - OBJECTIVE: This study examined the effect of recombinant human erythropoietin (r HuEPO) on the serum levels of neuron-specific enolase (NSE), S-100beta protein and myelin basic protein (MBP) in young rats 24 hrs after lithium-pilocarpine induced status epilepticus (SE) in order to study the potential role of r-HuEPO in epileptic brain damage. METHODS: Forty 19-21-day-old male Sprague-Dawley (SD) rats were randomly divided into four groups (n=10): normal control group, SE, r HuEPO pretreated-SE and r-HuEPO. SE was induced by lithium-pilocarpine. R-HuEPO (500 IU/kg) was intraperitoneally injected in the r-HuEPO pretreated-SE and r HuEPO groups 4 hrs before SE. Serum levels of NSE, S-100beta and MBP were determined 24 hrs after the SE event. RESULTS: Serum levels of NSE, S-100beta and MBP in the SE group increased significantly compared with those in the normal control and the r-HuEPO groups (P<0.05). The r-HuEPO pretreated-SE group showed significantly decreased serum levels of NSE, S-100beta and MBP compared with the SE group (P<0.05). CONCLUSIONS: r-HuEPO may reduce the expression of NSE, S 100beta and MBP and thus might provide an early protective effect against epileptic brain injury. PMID- 21251389 TI - [Effects of diallyl disulfide on apoptosis of human leukemia K562 cells and expression of Fas, FasL and caspase-8]. AB - OBJECTIVE: To study the effects of diallyl disulfide (DADS) on apoptosis of human leukemia K562 cells and possible mechanisms. METHODS: The morphologic changes of leukemia K562 cells after DADS treatment were observed by Hoechst 33258 staining. Cell apoptosis rates after different concentrations and different durations of DADS treatment were determined by flow cytometry. Fas, FasL and caspase-8 mRNA expression was estimated by reverse transcription-polymerase chain reaction (RT PCR) 48 hrs after DADS treatment. RESULTS: The characteristics of apoptosis in K562 cells induced by DADS were observed. After 24 hrs of DADS treatment, the apoptosis rate of K562 cells increased from (11.60 +/- 0.83)% at the concentration of 10 mg/L to (37.94 +/- 0.87)% at the concentration of 40 mg/L. The apoptosis rate of K562 cells increased after 40 mg/L DADS with the increasing time from (37.94 +/- 0.87)% (24 hrs) to (47.02 +/- 0.66)% (72 hrs). Expression of Fas and caspase-8 mRNA increased, while FasL mRNA expression decreased significantly 48 hrs after DADS treatment compared with the control group (P<0.05). CONCLUSIONS: DADS can induce apoptosis of human leukemia K562 cells in a time- and concentration-dependent manner, possibly through increasing Fas and caspase-8 expression and decreasing FasL expression. PMID- 21251390 TI - [Clinical features and follow-up analysis of 88 cases of incomplete Kawasaki disease]. PMID- 21251391 TI - [Long term follow-up study on Kawasaki disease complicated by coronary arterial aneurysm by coronary angiography and echocardiography in children]. PMID- 21251392 TI - [Clinical analysis of 110 cases of childhood influenza A (H1N1)]. PMID- 21251393 TI - [Pathogens and antimicrobial resistance in children with urinary tract infection]. PMID- 21251394 TI - [A case report of allergic bronchopulmonary aspergillosis]. PMID- 21251395 TI - [Malignant hyperthermia after the operation under general anesthesia: a case report]. PMID- 21251396 TI - [A case report of MN incompatibility hemolytic disease]. PMID- 21251397 TI - [Neurological assessment of neonatal brain development: a review on methods]. PMID- 21251398 TI - [Research progress on neonatal refractory seizures]. PMID- 21251399 TI - [Experimental study on lung cancer-targeted oncostatin M gene therapy induced by ionizing radiation]. AB - BACKGROUND: To improve the efficacy and selectivity of gene therapy for lung cancer through inducing oncostatin M (OSM) gene expression by radiation via the early growth response gene-1 (Egr-1) promoter. METHODS: The radio-inducible OSM gene was constructed by insertion of Egr-1 promoter into upstream of the OSM gene. The expression of OSM in lung adenocarcinoma cell line A549 which was transfected with pEO and exposed to different doses of gamma-ray irradiation was analyzed, and the relative survival fraction of cells and cell survival curve were observed. To examine the efficacy of this pEO gene therapy in vivo, the tumor supression effects were investigated in 40 nude mice bearing lung tumors. RESULTS: Expression of OSM gene in A549 cells transfected with pEO plasmids was markedly upregulated in a radiation dose-dependent manner. A gene therapy experiment in vitro showed that pEO transfected A549 cells became highly sensitive to ionizing radiation. pEO transfected tumors regressed significantly after a combination therapy with irradiation in all mice (n=10), and three tumors disappeared in 3 weeks without any side effect. CONCLUSIONS: The results indicate that tumor targeted expression of OSM gene under the control of a radio-inducible promoter represents a novel strategy for safe and effective gene therapy for lung cancer and might be widely applied in the future. PMID- 21251400 TI - [Effects of transfection of nm23-H1 gene on beta-catenin expression in human high metastatic large cell lung cancer cell line L9981]. AB - BACKGROUND: To explore the effects of transfection of nm23-H1 gene on expression of beta-catenin and phospho-beta-catenin in human high-metastatic large cell lung cancer line L9981, and to provide evidence to elucidate the molecular mechanism of nm23-H1 mediated tumor metastatic suppression. METHODS: To determine whether nm23-H1 contributes to cytoplasm and nuclear beta-catenin and phospho-beta catenin expression, the expression level of beta-catenin and phospho-beta-catenin in cytoplasm and nucleus was detected in human high-metastatic large cell lung carcinoma cell lines including primary cell line L9981 with nm23-H1 gene deletion, L9981-nm23-H1 transfected with nm23-H1 gene, and L9981-pLXSN transfected with vector by Western blot. RESULTS: (1)beta-catenin expression in L9981-nm23-H1 cytoplasm (IOD) (3 649+/-118) was significantly higher than that in L9981 (1 401+/-31) and L9981-pLXSN (1 350+/-55) cell lines (P < 0.001);(2)There was no statistical diffe-rence of the beta-catenin expression in nucleus among L9981-nm23-H1 (2 945+/-68), L9981 (2 604+/-23) and L9981-pLXSN (2 652+/-53) cell lines (P > 0.05);(3)Phospho-beta-cetenin expression of cytoplasm in L9981-nm23-H1 cell line (3 123+/-102) was significantly lower than that in L9981 (4 362+/-131) and L9981-pLXSN ( 4 500 +/-117) cell lines (P < 0.001);(4)Phospho-beta-catenin expression of nucleus in L9981-nm23-H1 (5 136+/-112) was significantly higher than that in L9981 (2 666+/-116) and L9981-pLXSN (2 661+/-66) cell lines (P < 0.001);(5)There was no statistical difference of beta-catenin or phospho-beta catenin expression in cytoplasm and nucleus between L9981 and L9981-pLXSN cell lines (P > 0.05). CONCLUSIONS: (1)nm23-H1 gene transfection can remarkably upregulates the expression of cytoplasm beta-catenin in human high-metastatic large cell lung cancer cell line L9981, but do not induce the nucleus accumulation of beta-catenin; (2)Transfection of nm23-H1 gene can significantly upregulate the expression of phospho-beta-catenin in nucleus and remarkably downregulate the expression of phospho-beta-catenin in cytoplasm of L9981; (3)Regulation of the expression of the key modecule, beta-catenin, in Wnt signal pathway might be the important melecular mechanisms which nm23-H1 gene controls "Lung Cancer Metastatic Suppresive Cascade" and reverves cancer metastasis in L9981. PMID- 21251401 TI - [Cloning of human telomerase catalytic subunit gene promoter and studying on its specific transcriptional activities in human lung cancer cells]. AB - BACKGROUND: To clone DNA sequence of human telomerase reverse transcriptase (hTERT) promoter, and study its transcriptional activities in various human lung cancer cells and normal lung cell. METHODS: hTERT promoter of 1.1 kb was amplified with polymerase chain reaction (PCR) method, utilizing DNA of 293 cell as template. After DNA sequencing with correct result, the hTERT promoter was inserted into luci-ferase reporter vectors (pGL3-Basic) to reconstruct a recombinant plasmid named pGL3-hTERTp. Then the reconstructed plasmid was transiently transfected into lung cancer cell lines A549, SPC-A-1, LTEPa-2, NCI H446, YTMLC, GLC-82, A2 and human embryonic pulmonary fibroblast cell line MRC-5. The transcriptional activities of hTERT promoter in various cells were determined by measuring the luciferase activities after 48 hours of transfection. RESULTS: Electrophoresis demonstrated that cloned hTERT promoter was about 1.1 kb, and DNA sequencing showed a same sequence as registered in GenBank. The cloned hTERT promoter was located between 1 126 bp and 43 bp in upstream of the transcription start site ATG and the length was 1 086 bp. The recombinant plasmid pGL3-hTERTp was confirmed by double digestion and PCR method with correct results. Luciferase assay showed there were different transcriptional activities of hTERTp in various lung cancer cell lines, but not in the MRC-5 cell line. CONCLUSIONS: The hTERT promoter cloned in this study has transcriptional activities in various lung cancer cell lines but not in normal cell. It may act as control element in tumor targeting gene therapy with hTERT. PMID- 21251402 TI - [Experimental study on the chemosensitivity of peripheral blood lymphocytes and tumor cells of lung cancer in vitro]. AB - BACKGROUND: To study chemosensitivity of anticancer drugs in the peripheral blood lymphocytes(PBL) of lung cancer patients and evaluate the correlation of chemosensitivity of tumor cells and peripheral blood lymphocytes in vitro. METHODS: The sensitive rate of 15 kinds of anticancer drugs in the peripheral blood lymphocytes and the tumor cells of 74 cases of lung cancer in vitro were tested by the MTT method. RESULTS: There was no significant difference in the sensitivity of 12 anticancer drugs between PBL and tumor cells of patients with lung cancer (P > 0.05). CONCLUSIONS: The chemosensitive test of the peripheral blood lymphocytes is valuable for reference of selecting anti-cancer drugs in clinic for lung cancer. PMID- 21251403 TI - [The clinical significance of thymosin beta4 expression in human non-small cell lung cancer]. AB - BACKGROUND: To study the relationship between human thymosin beta4 (Tbeta4 )expression and biological factors regarding invasion, metastasis and prognosis of human non-small cell lung cancer (NSCLC). METHODS: Tbeta4 expression was detected in samples of 76 paraffin-embedded specimens with the neighboring noncancerous tissue using anti-Tbeta4 IgY antibody (primary antibody) by immunohistochemical staining. The relationship between Tbeta4 expression and the clinicopthological factors was analyzed by Chi-square test, multivariate analysis and Kaplan-Meier method. RESULTS: In immunoreactive cells, staining was mainly located in cytoplasma. Human Tbeta4 expression was high positive in lung cancer tissues (76.3%, 58/76) while low positive in normal lung tissues. Tbeta4 expression was positively associated with TNM stage (r=0.239, P=0.032), lymphatic metastasis (r=0.243, P=0.029) and venous metastasis (r=0.224, P=0.045).A negative correlation was found between Tbeta4 expression and cell differentiation (r= 0.368, P=0.002). Patients with high Tbeta4 expression had a worse prognosis than those with low Tbeta4 expression (P < 0.05) CONCLUSIONS: Lung cancer has overexpression of Tbeta4, which is closely related to TNM stages, cell differentiation, metastasis of the cancer and prognosis of the patients with lung cancer. Detection of Tbeta4 expression in lung cancer tissues might be helpful to predict prognosis of patients with lung cancer. PMID- 21251404 TI - [Expression of vascular endothelial growth factor C and its receptor VEGF-R3 and their significance in non-small cell lung cancer]. AB - BACKGROUND: To determine the relationship between VEGF-C/VEGF-R3 expression and clinicopathologic factors and prognosis of patients with non-small cell lung cancer (NSCLC). METHODS: VEGF-C and VEGF-R3 expression was detected in 84 patients with NSCLC by immunohistochemical staining. The significance of VEGF-C and VEGF-R3 expression was analyzed statistically. RESULTS: In the immunoreactive cells, staining was mainly located in cytoplasm and membrane. VEGF-C and VEGF-R3 were highly expressed in lung cancer tissues (55.9% and 59.5%, respectively) while negative in the normal lung tissues. The expression of VEGF-C significantly correlated with histology (P=0.013). VEGF-R3 expression was associated with lymph node metastasis (P=0.002) and TNM stage (P=0.020). Multivariate analysis showed that VEGF-R3 (P < 0.001) and histology (P=0.020) were independent prognostic factors. CONCLUSIONS: Detection of VEGF-R3 in lung cancer tissues might be helpful to predict prognosis of patients with lung cancer. PMID- 21251405 TI - [Expression of Skp2 and its correlation with c-myc in non-small cell lung cancer]. AB - BACKGROUND: To study the expression of Skp2 and c-myc in non-small cell lung cancer (NSCLC) and to investigate their relationship and clinical significance. METHODS: The expression of Skp2 and c-myc was detected in 42 NSCLC, 10 pulmonary benign disease and 8 epithelial dysplasia tissues by immuno-histochemistry. RESULTS: The positive rate of Skp2 stain was 24.83%+/-13.64% in NSCLC tissues, which was significantly higher than that in pulmonary benign disease tissues (3.07%+/-1.32%)(P < 0.001) and that in dysplasia tissues (13.89%+/-3.95%)(P < 0.05). The expression level of Skp2 was closely related to cell differentiation (P < 0.001), TNM stages (P < 0.01) and lymph node metastasis (P < 0.05), but not to pathological type of NSCLC. There was a positive correlation between Skp2 and c-myc expression (r=0.448, P=0.003). The concurrent high expression rate of Skp2 and c-myc was 38.1% (16/42), which was closely rela- ted to TNM stage (P < 0.05), but not to cell differentiation, pathological type or lymph node metastasis. CONCLUSIONS: Overexpression of Skp2 may play important roles in carcinogenesis and development of NSCLC, and it may cooperate with c-myc protein. PMID- 21251407 TI - [Study of COX-2 expression and angiogenesis in non-small cell lung cancer]. AB - BACKGROUND: In this study the expression of COX-2 both in lung cancer tissues and tissues of benign disease of the lung is compared to explore the effect of COX-2 on occurrence and development of non-small cell lung cancer (NSCLC), and the relationship between COX-2 expression and clinical characteristics of patients with NSCLC. METHODS: The COX-2 expression, vascular endothelial growth factor (VEGF) expression and microvessel density (MVD) were detected in 78 NSCLC lung cancer tissues and 14 benign tissues of the lung by immunohistochemical method. RESULTS: Expression of COX-2 protein was significantly higher in cancer tissues (69.2%, 54/78) than paired noncancerous tissues (14.3%, 2/14)(Chi-square=15.044, P < 0.01). There was significant difference of MVD between COX-2 positive lung cancers (19.41+/-8.56) and negative ones(12.00+/-5.37)(t=3.906, P < 0.01). There was no significant relationship between COX-2 protein expression and patients' age, sex, TNM stages and smoking status (P > 0.05); for different pathological types, COX-2 protein expression was remarkably higher in adenocarcinoma (88.9%, 32/36) than that in squamous cell carcinoma (50.0%, 20/40) (Chi-square=13.262, P < 0.01); and for squamous cell carcimoma it was significantly higher in low differentiated ones (81.0%, 17/21) than that in high differentiated ones (15.8%, 3/19) (Chi-square=16.942,P < 0.01); for adenocarcinoma it was also remarkably higher in low differentiated ones (100.0%, 18/18) than that in high differentiated ones ( 77.8% , 14/18) (Chi-square=6.046, P < 0.05).The expressions of COX-2 and VEGF in NSCLC were significantly positively correlated (r=0.509, P < 0.01), so were the expressions of VEGF and MVD (r=0.324, P < 0.01), and the expressions of COX-2 and MVD (r=0.477, P < 0.01). Controlling for VEGF, there still was significant correlation between COX-2 and MVD (r=0.383, P < 0.01). CONCLUSIONS: The present study suggests that there is overexpression of COX-2 in lung cancer, which is closely related to angiogenesis of lung cancer. Further studies, therefore, are needed to find the exact mechanisms. PMID- 21251406 TI - [Expression of MMP-2, MMP-9, TIMP-1 and their relationship with prognosis in NSCLC]. AB - BACKGROUND: To study the expression of MMP-2, MMP-9, TIMP-1 proteins and mRNA in NSCLC and to analyse their relations with prognosis. METHODS: Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to detect the expression of MMP-2, MMP-9, TIMP-1 proteins and mRNA in pa-raffin-embedded NSCLC specimens. RESULTS: There were no significant differences among the MMP-2, MMP-9, TIMP-1 expression and age, sex, histological type and differentiation. There was statistical relationship between expression of MMP-2, MMP-9, TIMP-1 and lymph node metastasis. Multivariate Cox model analysis suggested that the survival time was significantly related to lymph node metastasis, expression of MMP-2 and MMP-9. The results of IHC and ISH suggested that the concordant rates of MMP-2, MMP-9, TIMP-1 proteins and mRNA were of statistical significance (P < 0.01,P < 0.005,P < 0.025). CONCLUSIONS: MMP-2 and MMP-9 are independent factors that affect prognosis, TIMP-1 is an useful parameter to the prognosis of NSCLC. PMID- 21251408 TI - [Efficacy of MVP chemotherapy combined with concurrent radiotherapy for advanced non-small cell lung cancer]. AB - BACKGROUND: To observe the effects of MVP chemotherapy combined with concurrent radiotherapy for stage IIIB-IV non-small cell lung cancer. METHODS: Sixty-two patients with stage IIIB-IV non-small cell lung cancer were randomized into two groups, concurrent radiochemotherapy group and MVP che-motherapy group. All patients in two groups were treated with MVP regimen (mitomycin C 6 mg/m2 on day 1, vindesine 2 mg/m2 on days 1, 8, and cisplatin 80-100 mg/m2). Patients in concurrent radiochemotherapy group received concurrent radiotherapy (46-56 Gy in 5-6 weeks). RESULTS: All patients received 2-4 cycles of MVP chemotherapy. The response rate was 48.4% and 19.4% in concurrent radiochemotherapy group and MVP group respectively (P < 0.05), the 1-year survival rate was 54.8% and 22.6% respectively (P < 0.05), median time to progression was 8 months and 4 months respectively (P < 0.05), and median survival duration was 10 months and 6 months respectively (P < 0.05). Incidence of grade II-III leukopenia in concurrent radiochemotherapy group was remarkably higher than those in MVP group.. CONCLUSIONS: The results show that efficacy of MVP chemotherapy combined with concurrent radiotherapy is significantly higher than that of MVP chemotherapy alone for advanced non-small cell lung cancer. PMID- 21251409 TI - [Clinical analysis on characteristics of lymph node metastasis in lung cancer]. AB - BACKGROUND: To investigate the characteristics and patterns of lymph node metastasis in lung cancer, and to provide evidence for determining range of lymph node dissection. METHODS: One hundred and five patients with lung cancer received complete resection combined with systematic lymph node dissection according to the mapping system developed by Naruke. RESULTS: A total of 801 lymph nodes were dissected from 105 lung cancer patients. The positive ratios of N1 and N2 were 15.9% and 14.9%, respectively. Twelve patients were found with skipping N2. These skipping N2 were located in 2, 4, 5, 6, 7 groups respectively. There was no significant relationship between size of primary tumor and lymph node metastasis. Small cell lung cancer showed the highest risk of lymph node metastasis. The metastatic rate of lymph node in adenocarcinoma was markedly higher than that in squamous cell carcinoma. Skipping mediastinal lymphatic metastasis was found more frequently in lower lobar tumors than that in upper lobar ones. CONCLUSIONS: Lymph node metastasis of lung cancer may occur in multiple groups and multiple regions, even in a skipping pattern. Systematic lymph node dissection should be routinely performed in pulmonary resection for lung cancer. PMID- 21251410 TI - [Clinical analysis of 99 young patients with lung cancer in different nationalities in Xinjiang]. AB - BACKGROUND: To study clinicopathological characteristics and national distribution of lung cancer in patients who were younger than 40 years of age in Xinjiang. METHODS: The records of 99 patients who were younger than 40 years of age with lung cancer who were diagnosed in our hospital from September, 1989 to July, 2001 were reviewed. Analyses as to gender, nationalities, misdiagnosis and pathological types were performed. RESULTS: The female had higher prevalence than the male did, the ratio of male to female was 1.75 to 1. The Han race had higher prevalence than other races did. Most of the patients had clinical manifestations (97.0%). Adenocarcinoma and small cell lung cancer were predominant histologic types, which accounted for about 71.1%. The misdiagnostic rate was 61.6%. CONCLUSIONS: In young patients with lung cancer, the diffe-rence of incidence between different genders is smaller than that in senile patients. The prevalence of lung can-cer in young people varies in different races in Xinjiang and Han race has the highest prevalence. The malignancy of lung cancer in young patients is high, and most cases are in advanced stage. The misdiagnostic rate is high. PMID- 21251411 TI - [Diagnosis and treatment of pulmonary sclerosing hemangioma]. AB - BACKGROUND: To investigate the diagnosis and treatment of pulmonary sclerosing hemangioma (PSH). METHODS: The clinical features, radiographic manifestations and treatment of 21 patients with PSH were reviewed. RESULTS: None of the 21 patients was diagnosed as PSH preoperatively. There were 18 females and 3 males, and the average age was 48.0 years in this group. Twelve patients were symptom free. The plain chest roentgenograms showed a well defined, homogeneous, round or oval nodulous shadow in most cases. All patients received operation. There was no postoperative morbidity and mortality. Postoperative follow-up showed a good prognosis. CONCLUSIONS: Preoperative diagnosis of PSH is quite difficult. PSH should be suspected in middle to old aged female patients who show a well defined, homogeneous, round or oval shadow in plain chest roentgenograms. PSH has a good prognosis if it is treated surgically. PMID- 21251412 TI - [Clinical study of navelbine combined with cisplatin in the treatment of advanced non-small cell lung cancer]. AB - BACKGROUND: To evaluate the efficacy and toxicity of combination chemotherapy with navelbine (NVB) and cisplatin (DDP) in the treatment of advanced non-small cell lung cancer (NSCLC). METHODS: From 1998 to 2003, 46 patients with advanced NSCLC were treated with NVB plus DDP. NVB was given at a dose of 25 mg/m2 on day 1 and 8, DDP at a dose of 65-80 mg/m2 on day 1 or days 1-3. Twenty-one days was one cycle, each patient was treated at least for two cycles. RESULTS: The overall response rate (RR) was 47.8% (22/46), 51.6% (16/31) for the first treated cases and 40.0% (6/15) for the retreated cases. RR of stage IIIB and IV was 54.5% (12/22) and 41.7% (10/24) respectively. RR for adenocarcinoma and squamous cell carcinoma was 50.0% (14/28) and 44.4% (8/18) respectively. The median survival time was 9.5 months. One-year survival rate was 39.1%. The common toxicities were myelosuppression, nausea/vomiting and phlebitis. Neutropenia accounted for 95.7% (grade III+IV was 28.3%), nausea/vomiting for 47.8% (grade III+IV was 8.7%) and phlebitis for 19.6%, but the last one were mild. CONCLUSIONS: Combination chemotherapy with NVB and DDP is an effective regimen to treat advanced NSCLC, and the toxicities are tolerable. PMID- 21251413 TI - Dynamic enhanced multi-slice spiral CT in evaluation of blood flow patterns of solitary pulmonary nodules with enhancement. AB - BACKGROUND: To investigate the methods of dynamic enhanced multi-slice spiral CT in evaluation of blood flow patterns of solitary pulmonary nodules (SPNs) with enhancement. METHODS: Seventy-eight patients with SPNs (<=4 cm) with strong enhancement underwent dynamic multi-slice spiral CT (Marconi Mx8000) scan before and after contrast enhancement by injecting contrast material with a rate of 4 mL/s. For the 40 patients in protocol one, one scan was obtained every 2 seconds during 15-45 and 75-105 seconds after injection, while for the 38 patients in protocol two, one scan was obtained every 2 seconds during 11-41 and 71-101 seconds. For all the patients, one scan was obtained every 30 seconds during 2-9 minutes. The section thickness was 2.5 mm for lesions <=3 cm and 5 mm for lesions > 3 cm. Standard algorithm was used in the image reconstruction. Precontrast and postcontrast attenuation on every scan was recorded. The perfusion, peak height, ratio of peak height of the SPN to that of the aorta and mean transit time were calculated. RESULTS: The peak height, perfusion, ratio of peak height of the SPN to that of the aorta and mean transit time in malignant SPNs were 34.85 Hu+/ 10.87 Hu, 30.37 ml/(min*100 g)+/-11.14 ml/(min*100 g), 13.78%+/- 3.96% , 14.19 s+/-6.19 s respectively in protocol one, while those in protocol two were 36.62 Hu+/-10.75 Hu, 30.01 ml/(min*100 g)+/-8.10 ml/(min*100 g), 14.70 %+/-4.71%, 13.91 s+/-4.82 s respectively. No statistically significant differences were found between the peak height (t= 0.673, P=0.503), perfusion (t= 0.152 , P=0.880), ratio of peak height of the SPN to that of the aorta (t= 0.861, P=0.393) and mean transit time (t= 0.199, P=0.843) in malignant SPNs measured in protocol one and those measured in protocol two. All mean transit time in protocol two (36/36) were obtained, but only part of them (25/32) were obtained in protocol one. CONCLUSIONS: Dynamic enhanced multi-slice spiral CT is a non-invasive method for quantitative evaluation of blood flow patterns of SPNs with enhancement and scans beginning at 11 seconds after injection of contrast material is suggested. PMID- 21251414 TI - Early results of a Canadian laparoscopic sleeve gastrectomy experience. AB - BACKGROUND: Sleeve gastrectomy (SG) is a relatively new bariatric procedure with a number of advantages compared with Roux-en-Y gastric bypass. However, SG also has a number of disadvantages and associated risks. We sought to examine perioperative complications and outcomes of laparoscopic SG (LSG) in a single major Canadian bariatric surgery centre (Victoria, BC). METHODS: Since June 2008, LSG has been performed at our centre and we reviewed the cases of all patients. We conducted a retrospective chart review in April 2010. RESULTS: Thirty-four patients had LSG, and none was lost to follow-up. Indications for LSG over other bariatric procedures were patient preference (n=28), severe obesity with a body mass index (BMI) greater than 60 kg/m(2) (n=5) and severe upper abdominal adhesions (n=1). All but 1 of the cohort were women, and the average age was 48 (standard deviation [SD] 11) years. Preoperatively, the average BMI was 50.3 (SD 7.7) kg/m(2). Preoperative obesity-related comorbidity rates were 56% (n=19) for type 2 diabetes mellitus (T2DM), 50% (n=17) for hypertension, 32% (n=11) for dys lipidemia, 62% (n=21) for obstructive sleep apnea (OSA), 62% (n=21) for knee and/or hip pain and 44% (n=15) for depression and/or anxiety. The mean duration of surgery was 74 (SD 21) minutes. There were 2 major perioperative complications: 1 staple line leak and 1 staple line hemorrhage. The median stay in hospital was 1 day. Postoperative upper gastrointestinal imaging studies were conducted in 11 patients; 1 was positive for staple line leak. Histopathology on the excised gastric segments revealed chronic helicobacter pylori gastritis in 2 patients and small gastrointestinal stromal tumours in 1 patient. The mean postoperative follow-up interval was 10 months. Weight loss averaged 27.4 (SD 9.0) kg. Overall weight loss was 3.3 (SD 1.8) kg/month. Resolution occurred in 74% of patients with T2DM, 53% with hypertension, 45% with dyslipidemia, 76% with OSA, 38% with joint pain and 20% with depression/anxiety. Overall satisfaction was rated as excellent by 68% of patients, good by 29% and poor by 3% of patients. CONCLUSION: Preliminary analysis of our experience with LSG indicates that this is an effective and safe procedure for the treatment of obesity. PMID- 21251415 TI - Value of an objective assessment tool in the operating room. AB - BACKGROUND: Concerns about the achievement of surgical proficiency during residency are increasing. To objectify surgical skills, the Objective Structured Assessment of Technical Skills (OSATS) was developed and proven valid, feasible and reliable for use in laboratory settings. This study aimed to evaluate the value of this tool for intraoperative use. METHODS: Residents were assessed with an OSATS after every procedure they performed as the primary surgeon during a 3 month clinical rotation in gynecological surgery. We mapped individual learning curves (OSATS scores plotted against experience) and established the average procedure-specific learning curve. We used linear mixed models to assess the relation between performance and experience. RESULTS: Nine residents were recruited and 319 OSATS analyzed. Individual learning curves revealed progression beyond 24 of 30 OSATS points for 7 residents. Performance on the average procedure improved with experience, and the OSATS score increased by an average of 1.10 points per assessed procedure (p=0.008, 95% confidence interval 0.44 1.77). Median OSATS scores ranged from 18 to 30 among the 21 assessors. CONCLUSION: Intraoperative implementation of OSATS seems to offer important advantages: structured feedback is facilitated, and learning curves enable insight into individual progression. However, doubts have been raised about the objectivity of the tool. Therefore, caution is warranted in using it for graduation and certification. PMID- 21251416 TI - Uncrossmatched blood transfusions for trauma patients in the emergency department: incidence, outcomes and recommendations. AB - BACKGROUND: Early transfusion of blood products for severely injured patients can improve volume depletion, acidosis, dilution and coagulopathy. There is concern that some patients are unnecessarily exposed to the risks of emergent transfusion with uncrossmatched red blood cell products (URBC) in the emergency department (ED). The goal of this study was to evaluate the transfusion practices in our ED among all patients who received URBC. METHODS: We analyzed all injured patients transfused at least 1 URBC in the ED at a level-1 trauma centre between Jan. 15, 2007, and Jan. 14, 2008. Demographics, injuries and outcomes were reported. We used standard statistical methodology. RESULTS: At least 1 URBC product was transfused into 153 patients (5% of all patients, mean 2.6 products) in the ED (median Injury Severity Score [ISS] 28; hemodynamic instability 94%). Sixty-four percent of patients proceeded to an emergent operation and 17% required massive transfusion. The overall mortality rate was 45%, which increased to 52% and 100% in patients who received 4 and 5 or more URBC products, respectively. Nonsurvivors had a higher median ISS (p=0.017), received more URBC in the ED (p=0.006) and possessed more major vascular injuries (p<0.001). Among nonsurvivors, 67% died of uncontrollable hemorrhage. Unnecessary URBC transfusions in the ED occurred in 7% of patients. CONCLUSION: Overtransfusion was minimal based on clinical acumen triggers. Early transfer of patients receiving URBC products in the ED to the operating room, intensive care unit or angiography suite for ongoing resuscitation and definitive hemorrhage control must be strongly considered. PMID- 21251417 TI - Surgeons' and residents' double-gloving practices at 2 teaching hospitals in Ontario. AB - BACKGROUND: Surgeons and residents are at increased risk of exposure to blood borne pathogens owing to percutaneous injury (PI) and contamination. One method known to reduce risk is double-gloving (DG) during surgery. METHODS: All surgeons and residents affiliated with the University of Western Ontario (UWO) and McMaster University in 2005 were asked to participate in a Web-based survey. The survey asked respondents their specialty, the number of operations they participated in per week, their age and sex, the proportion of surgeries in which they double-gloved (DG in >=75% surgeries was considered to be routine), and the average number of PIs they sustained per year and whether or not they reported them to an employee health service. RESULTS: In total, 155 of 331 (47%) eligible surgeons and residents responded; response rates for UWO and McMaster surgeons were 50% and 39%, respectively, and for UWO and McMaster residents, they were 52% and 47%, respectively. A total of 43% of surgeons and residents reported routine DG; 50% from McMaster and 36% from UWO. Using logistic regression to simultaneously adjust for participant characteristics, we confirmed that DG was more frequent at McMaster than at UWO, with an odds ratio of 3.32 (95% confidence interval 1.35-8.17). Surgeons and residents reported an average of 3.3 surgical PIs per year (2.2 among McMaster participants and 4.5 among UWO participants). Of the 77% who reported at least 1 injury/year, 67% stated that they had not reported it to an employee health service. CONCLUSION: Percutaneous injuries occur frequently during surgery, yet routine DG, an effective means of reducing risk, was carried out by less than half of the surgeons and residents participating in this study. This highlights the need for a more concerted and broad-based approach to increase the use of a measure that is effective, inexpensive and easily carried out. PMID- 21251419 TI - Ambulatory treatment of chronic pilonidal sinuses with lateral incision and primary suture. AB - BACKGROUND: Outpatient management is appropriate for chronic pilonidal sinuses. Even though there are different surgical treatments for pilonidal sinuses, the outcome may not be uniformly satisfactory. The aim of this paper was to examine the ambulatory treatment of chronic pilonidal sinuses with lateral incision and primary suture. METHODS: We present our experience with outpatient management of asymptomatic chronic pilonidal disease. We prospectively studied patients presenting with pilonidal disease from Mar. 20, 2005, to Mar. 20, 2008. All were managed as outpatients. We reviewed presentation, treatment, healing, time off work and recurrences. RESULTS: In all, 150 patients (131 men and 19 women) with chronic pilonidal sinuses underwent ambulatory plain lateral excision and primary repair during the study period. The mean age of patients was 22.1 years. The mean duration of surgery was 18.4 minutes. No general complications occurred. Local complications consisted of 3 wound infections and 4 wound hematomas. No sinus recurrence occurred. The healing rate was fast in all patients. CONCLUSION: Advantages of ambulatory plain lateral excision and primary repair include immediate treatment, minimal pain and a quick return to normal activities. This method is a simple and effective procedure in the treatment of uncomplicated pilonidal sinuses. PMID- 21251418 TI - Foxp3+ regulatory T cells and the formation of portal vein tumour thrombus in patients with hepatocellular carcinoma. AB - BACKGROUND: Most patients with hepatocellular carcinoma (HCC) have advanced-stage disease at diagnosis. The prognosis for patients with HCC is very poor, especially for those with portal vein tumour thrombi (PVTT). The purpose of our study was to observe the prognostic value of PVTT and tumour-infiltrating regulatory T cells (Tregs) and the correlation between them. METHODS: We examined 76 HCC specimens by immunohistochemistry for CD4+, CD8+ T cells and Foxp3+ Tregs. The survival of patients was prospectively followed up. Patients with HCC were grouped according to the formation of PVTT or Treg infiltration status. We performed a Kaplan-Meier survival analysis to observe the difference in prognosis between the groups. We analyzed the correlation of Treg expression with clinical and pathologic features. RESULTS: Survival analysis revealed that both the disease-free survival rate and total survival rate after hepatic resection were significantly lower in patients in the PVTT group than those in the non-PVTT group (p=0.026 and p=0.022, respectively). Likewise, both the disease-free survival rate and the total survival rate were significantly lower in patients in the high Treg group than those in the low Treg group (p=0.012 and p=0.023, respectively). We found that intratumoural Tregs were associated with PVTT formation (p=0.001) and that patients with high Treg infiltration had a higher percentage of PVTT formation. CONCLUSION: Patients with PVTT formation or high intratumoural Treg infiltration tended to have a poor prognosis. Intratumoural Treg was associated with formation of PVTT in patients with HCC. PMID- 21251420 TI - Impact of gastrografin in clinical practice in the management of adhesive small bowel obstruction. AB - BACKGROUND: Gastrografin (GG) has been shown to accelerate the resolution of adhesive small bowel obstruction (ASBO) and decrease length of stay (LOS) in hospital. Consequently, we instituted a protocol recommending the routine use of GG in patients with ASBO. This study reviews patient outcomes after protocol implementation. METHODS: We conducted a retrospective review of all patients with ASBO from January 1997 to December 2007. Data were categorized by admission date and use of GG. The outcomes reviewed were protocol uptake, median LOS in hospital and operative rate. Results were analyzed using the Mann-Whitney U test and the 2 tailed Fisher exact test. RESULTS: There were 710 patients with ASBO overall. Sixteen of 376 (4.3%) patients received GG before institution of the protocol (period 1), whereas 195 of 334 (58.4%) received GG thereafter (period 2). In period 2, use of GG was limited to between 58% and 69% of all potentially eligible patients per year. Fifty-seven of 710 (8%) patients required surgery. In period 1, there were no significant differences in median LOS in hospital (p=0.29) and operative rate (p=0.65) between patients who received GG and those who were managed without GG. In period 2, patients receiving GG had a greater median LOS in hospital (3 [range 2-5] v. 2 [range 1-5] d, p=0.048) but significantly lower operative rates (5.1% v. 12.9%, p=0.018). Overall, the median LOS decreased over time (period 1: 4 [2-7] d v. period 2: 2 [1-5] d, p=0.010). The operative rate did not vary substantially between periods (7.7% v. 8.4%, p=0.42). CONCLUSION: The introduction of a protocol has increased the proportion of eligible patients receiving GG. However, protocol nonadherence and factors other than GG usage have influenced LOS in hospital and operative rates. Demonstrated benefits from previously published clinical trials have thus not been replicated within our setting. PMID- 21251421 TI - Incidental thyroid "PETomas": clinical significance and novel description of the self-resolving variant of focal FDG-PET thyroid uptake. AB - BACKGROUND: Recent series of incidental thyroid activity on fluorodeoxyglucose positron emission tomography (FDG-PET) in patients evaluated for nonthyroidal malignancy, which we refer to as a "PEToma," have suggested that such lesions are associated with a significant incidence of primary thyroid cancer. METHODS: We retrospectively reviewed 6457 FDG-PET scans performed on 4726 patients from May 2004 to March 2007. We reviewed the cases of patients whose PET or computed tomography (CT) radiology reports described PET uptake within the thyroid to identify incidence and malignant potential of PETomas and evaluate their clinical and histopathologic features. RESULTS: We found that 160 patients (3.4%) had incidental, abnormal FDG uptake in the thyroid gland, 103 of whom had focal uptake (the PEToma group). Of these patients, 50 (48%) underwent further investigations, including ultrasonography in 48, fine-needle aspiration cytology in 38 and computed tomography in 3. Ten patients underwent surgery, and papillary thyroid cancer was identified in 9. The remaining 53 patients with PETomas underwent no further investigation. Interestingly, 5 patients who had focal uptake within the thyroid showed either spontaneous resolution on repeat FDG-PET (self-resolving) or no focal lesion on subsequent ultrasonography (false positive). CONCLUSION: The incidence of papillary thyroid cancer in the present series is similar to that in the literature. Although some patients will show self-resolving or false-positive focal thyroid uptake on FDG-PET, we believe that, if the patient's clinical status permits, the evaluation of patients with incidental thyroid PEToma should include ultrasonographic confirmation and fine needle aspiration cytology. PMID- 21251422 TI - Laparoscopic colostomy reversal after a Hartmann procedure: a prospective series, literature review and an argument against laparotomy as the primary approach. AB - BACKGROUND: Open restoration of bowel continuity after a Hartmann procedure has been associated with significant morbidity, including anastomotic leak, incisional hernia, wound infections and inability to re-establish intestinal continuity. Few studies have examined the role of laparoscopy in performing a Hartmann reversal. The aim of this study was to review our laparoscopic Hartmann reversal (LHR) experience with an emphasis on intra- and postoperative adverse events. METHODS: A prospectively collected laparoscopic colorectal database involving 3 surgeons in 4 academic centres between 1991 and 2008 was reviewed. Factors evaluated were patient demographics, diagnosis, duration of surgery, intra- and postoperative complications, recovery of bowel function and length of stay in hospital. RESULTS: Twenty-eight consecutive patients (13 men, 15 women) with a mean age of 61.1 (standard deviation [SD] 15.3) years and a mean weight of 72.3 (SD 20.1) kg underwent LHR. The diagnosis at initial surgery was complicated diverticulitis in 19 patients (67.9%), cancer in 6 patients (21.4%) and "other" in 3 patients (10.7%). The median duration of surgery was 166.2 (SD 74.4) minutes. There were no conversions. There was 1 major intraoperative complication (bleeding; 3.6%). There were 3 postoperative complications (10.7%): 1 abscess, 1 prolonged ileus and 1 wound hematoma. Only 1 patient with an abscess required readmission. There were no observed clinical anastomotic leaks. All patients underwent successful reanastomosis. The median time to return of bowel function was 4 (interquartile range [IQR] 3-4) days. The median length of stay in hospital was 5 (IQR 3-6) days. There was no mortality. CONCLUSION: Laparoscopic colostomy reversal after a Hartmann procedure is safe and feasible in experienced hands. It is associated with low morbidity, quick return of bowel function and short stay in hospital. PMID- 21251423 TI - The consensus statement on mixed martial arts: emotion, not evidence-based. PMID- 21251424 TI - Breslow thickness and nodular tumour type. PMID- 21251425 TI - Staff surgeon competence. PMID- 21251426 TI - Drills and exercises: the way to disaster preparedness. PMID- 21251427 TI - Disaster preparedness of Canadian trauma centres: the perspective of medical directors of trauma. AB - BACKGROUND: Owing to their constant readiness to treat injured patients, trauma centres are essential to regional responses to mass casualty incidents (MCIs). Reviews of recent MCIs suggest that trauma centre preparedness has frequently been limited. We set out to evaluate Canadian trauma centre preparedness and the extent of their integration into a regional response to MCIs. METHODS: We conducted a survey of Canadian level-1 trauma centres (n = 29) to characterize their existing disaster-response plans and to identify areas where preparedness could be improved. The survey was directed to the medical director of trauma at each centre. Descriptive statistics were used to analyze responses. RESULTS: Twenty-three (79%) trauma centres in 5 provinces responded. Whereas most (83%) reported the presence of a committee dedicated to disaster preparedness, only half of the medical directors of trauma were members of these committees. Almost half (43%) the institutions had not run any disaster drill in the previous 2 years. Only 70% of trauma centres used communications assets designed to function during MCIs. Additionally, more than half of the trauma directors (59%) did not know if their institutions had the ability to sustain operations for at least 72 hours during MCIs. CONCLUSION: The results of this study suggest important opportunities to better prepare Canadian trauma centers to respond to an MCI. The main areas identified for potential improvement include the need for the standardization of MCI planning and response at a regional level and the implementation of strategies such as stockpiling of resources and novel communication strategies to avoid functional collapse during an MCI. PMID- 21251428 TI - Surgical site infection in abdominal trauma patients: risk prediction and performance of the NNIS and SENIC indexes. AB - BACKGROUND: The National Nosocomial Infections Surveillance (NNIS) and Efficacy of Nosocomial Infection Control (SENIC) indexes are designed to develop control strategies and to reduce morbidity and mortality rates resulting from infections in surgical patients. We sought to assess the application of these indexes in patients undergoing surgery for abdominal trauma and to develop an alternative model to predict surgical site infections (SSIs). METHODS: We conducted a prospective cohort study between November 2000 and March 2002. The main outcome measure was SSIs. We evaluated the variables included in the NNIS and SENIC indexes and some preoperative, intraoperative and postoperative variables that could be risk factors related to the development of SSIs. We performed multivariate analyses using a forward logistic regression method. Finally, we assessed infection risk prediction, comparing the estimated probabilities with actual occurrence using the areas under the receiver operating characteristic (ROC) curves. RESULTS: Overall, 614 patients underwent an exploratory laparotomy. Of these, 85 (13.8%) experienced deep incisional and organ/intra-abdominal SSIs. The independent variables associated with this complication were an Abdominal Trauma Index score greater than 24, abdominal contamination and admission to the intensive care unit. We proposed a model for predicting deep incisional and organ/intra-abdominal SSIs using these variables (alternative model). The areas under the ROC curves were compared using the estimated probabilities for this alternative model and for the NNIS and SENIC scores. The analysis revealed a greater area under the ROC curve for the alternative model. The NNIS and SENIC scores did not perform as well as the alternative model in patients with abdominal trauma. CONCLUSION: The NNIS and SENIC indexes were inferior to the proposed alternative model for predicting SSIs in patients undergoing surgery for abdominal trauma. PMID- 21251429 TI - Quality of life and educational benefit among orthopedic surgery residents: a prospective, multicentre comparison of the night float and the standard call systems. AB - BACKGROUND: Given recent evolving guidelines regarding postcall clinical relief of residents and emphasis on quality of life, novel strategies are required for implementing call schedules. The night float system has been used by some institutions as a strategy to decrease the burden of call on resident quality of life in level-1 trauma centres. The purpose of this study was to determine whether there are differences in quality of life, work-related stressors and educational experience between orthopedic surgery residents in the night float and standard call systems at 2 level-1 trauma centres. METHODS: We conducted a prospective cohort study at 2 level-1 trauma hospitals comprising a standard call (1 night in 4) group and a night float (5 14-hour shifts [5 pm-7 am] from Monday to Friday) group for each hospital. Over the course of a 6-month rotation, each resident completed 3 weeks of night float. The remainder of the time on the trauma service consists of clinical duties from 6:30 am to 5:30 pm on a daily basis and intermittent coverage of weekend call only. Residents completed the Short Form-36 (SF-36) general quality-of-life questionnaire, as well as questionnaires on stress level and educational experience before the rotation (baseline) and at 2, 4 and 6 months. We performed an analysis of covariance to compare between-group differences using the baseline scores as covariates and Wilcoxon signed-rank tests (nonparametric) to determine if the residents' SF-36 scores were different from the age- and sex-matched Canadian norms. We analyzed predictors of resident quality of life using multivariable mixed models. RESULTS: Seven residents were in the standard call group and 9 in the night float group, for a total of 16 residents (all men, mean age 35.1 yr). Controlling for between group differences at baseline, residents on the night float rotation had significantly lower role physical, bodily pain, social function and physical component scale scores over the 6-month observation period. Compared with the Canadian normative population, the night float group had significantly lower SF 36 scores in all subscales except for bodily pain. There were no differences noted between the standard call group and Canadian norms at 6 months. No differences in educational benefits and stress level were measured between the 2 groups. Lack of time for physical activity was only significant in the night float group. Regression analysis demonstrated that the increased number of hours in hospital correlated with significantly lower SF-36 scores in almost all domains. CONCLUSION: Our study suggests that the residents in the standard call group had better health-related quality of life compared with those in the night float group. No differences existed in subjective educational benefits and stress level between the groups. PMID- 21251430 TI - Timing of femoral prosthesis insertion during cemented arthroplasty: cement curing and static mechanical strength in an in vivo model. AB - BACKGROUND: Modern cementing techniques aim to fix the implanted femoral prosthesis in the medullary cavity to minimize long-term complications such as aseptic loosening. The cure stage of bone cement into which the femoral component is being inserted is an important variable that is decided at the time of surgery. Late-cure cement is more viscous than early-cure cement and requires greater force on the part of the surgeon to insert the femoral prosthesis. We compared 2 cementing techniques, femoral component insertion into early-cure cement and insertion into late-cure cement, using an in vivo model to identify if cement cure stage affects the strength of the bone-cement interface. METHODS: We performed bilateral hemiarthroplasties using only the femoral component in vivo on paired porcine femora. The femora were harvested and cross-sectioned in preparation for strength testing. We measured bond strength by peak load required to push the femoral prosthesis and surrounding cement mantle free of the cancellous bone. RESULTS: All radiographs showed good cement interdigitation with no evidence of radiolucent lines at the bone-cement interface. We could not differentiate the early-cure and late-cure groups on postoperative radiographs. The mean failure load for the late-cure arthroplasties was 908 N (standard deviation [SD] 420 N), whereas the mean failure load for the conjugate early-cure arthroplasties was 503 N (SD 342 N). CONCLUSION: Femoral component insertion into late-cure cement required significantly higher loads for push-out than femoral component insertion into early-cure cement. PMID- 21251431 TI - A pediatric surgeon's 35-year experience with pilonidal disease in a Canadian children's hospital. AB - BACKGROUND: There is an ongoing debate regarding the optimal surgical management for pilonidal disease in the pediatric population. The purpose of this study was to evaluate a pediatric surgeon's experience at a Canadian children's hospital over 35 years. METHODS: We performed a retrospective review of the charts of patients seen and treated from July 1969 to December 2003, inclusive. All patients were evaluated for age, sex, clinical diagnosis, infection, treatment, healing time, complications and results. RESULTS: In all, 121 adolescents with pilonidal disease (64 boys, 57 girls) with a mean age of 15 (range 12-19) years were evaluated at the same children's hospital. The 107 (88%) patients with infection (46% acute) underwent surgery. At operation, all 107 pilonidal cysts were either excised and packed open, marsupialized or excised and closed primarily without drainage under general anesthesia; the operation performed was arbitrarily chosen. Vacuum-assisted closure was not used. All patients received antibiotics. The time for healing after the initial operation in the group whose cysts were excised and packed open was at least twice as long (75 d) as in the other 2 groups (p = 0.031). Disease recurred in 24 (22%) patients, 6 (25%) of whom experienced 2 recurrences. Among the 90 patients in the excised and packed open group, 20 (22%) experienced recurrences and 5 (25%) experienced 2 recurrences. Among the 13 patients in the marsupialized group, 3 (23%) experienced recurrences and 1 (33%) experienced 2 recurrences. Among the 4 patients in the excised and closed primarily without drainage group, 1 (25%) experienced a recurrence and none experienced 2 recurrences (p = 0.12). Each recurrence was smaller than the original. All wounds eventually healed. There were no other complications and no deaths. A multivariable logistic regression analysis revealed that the type of surgical approach was not predictive of recurrence after controlling for age and sex. CONCLUSION: Age, sex and surgical approach were not predictive of recurrence. From our experience, excision and packing open the wound produced a longer morbidity but offered the same results compared with marsupialization or excision and primary closure without drainage. PMID- 21251433 TI - Management of pancreatic adenocarcinoma in Ontario, Canada: a population-based study using novel case ascertainment. AB - BACKGROUND: Pancreatic adenocarcinoma (PA) is largely incurable, although recent progress has been made in the safety of surgery for PA and in adjuvant and palliative chemotherapy. The purpose of this study was to describe the management of PA in Ontario, Canada. METHODS: The Pathology Information Management System (PIMS), which uses electronic pathology reporting (E-path), was used to rapidly identify and recruit patients based on a pathologic diagnosis of PA between 2003 and 2006. Patients were mailed questionnaires for additional data. RESULTS: The patient participation rate was 26% (351 of 1325). Nonresponders were more likely to be older than 70 years (43% v. 28%, p < 0.001) and to have received treatment in nonacademic centres (53% v. 34%, p < 0.001). Fifty-four percent of responders underwent a potentially curative operation, and most (77%) were 70 years or younger (p = 0.03). Completed resections were documented in 83% of patients who underwent exploratory surgery with curative intent; 17% of patients had unresectable and/or metastatic disease at laparotomy. Of the completed resections, 24% were performed in nonacademic centres with a 32% positive margin rate; 76% were performed in academic centres with a 29% positive margin rate (p = 0.84). Resections with curative intent were less frequently aborted in academic centres (10% v. 33%, p < 0.001). Of the patients who responded to our questionnaire, 43% received chemotherapy and 7% participated in clinical trials. CONCLUSION: Despite using PIMS and E-path, the response rate for this study was low (< 30%). Nonresponders were older and more commonly treated in nonacademic centres. Patients undergoing surgery in academic centres had higher resection rates. The rate of adjuvant and palliative chemotherapy was stage-dependent and low. PMID- 21251432 TI - Impact of computed tomography of the abdomen on clinical outcomes in patients with acute right lower quadrant pain: a meta-analysis. AB - BACKGROUND: Clinical evaluation alone is still considered adequate by many clinicians who treat patients with appendicitis. The impact of computed tomography (CT) on clinical outcomes remains unclear, and there is no consensus regarding the appropriate use of CT in these patients. We sought to evaluate the impact of abdominal CT on the clinical outcomes of patients presenting with suspected appendicitis. METHODS: We conducted a systematic review of the literature to identify studies that examined clinical outcomes related to the use of abdominal CT in the diagnosis of acute appendicitis. Inclusion criteria were studies of adult patients with suspected appendicitis that evaluated the impact of abdominal CT on negative appendectomy rates, perforation rates or time to surgery. Two independent investigators reviewed all titles and abstracts and extracted data from 28 full-text articles. Statistical analysis was conducted using Review Manager 5.0.10 software. RESULTS: The negative appendectomy rate was 8.7% when using CT compared with 16.7% when using clinical evaluation alone (p < 0.001). There was also a significantly lower negative appendectomy rate during the CT era compared with the pre-CT era (10.0% v. 21.5%, p < 0.001). Time to surgery was evaluated in 10 of the 28 studies, 5 of which demonstrated a significant increase in the time to surgery with the use of CT. Appendiceal perforation rates were unchanged by the use of CT (23.4% in the CT group v. 16.7% in the clinical evaluation group, p = 0.15). Similarly, the perforation rate during the CT era was not significantly different than that during the pre-CT era (20.0% v. 19.6%, p = 0.74). CONCLUSION: This meta-analysis supports the hypothesis that the use of preoperative abdominal CT is associated with lower negative appendectomy rates. The use of CT in the absence of an expedited imaging protocol may delay surgery, but this delay is not associated with increased appendiceal perforation rates. Routine CT in all patients presenting with suspected appendicitis could reduce the rate of unnecessary surgery without increasing morbidity. PMID- 21251434 TI - Complications associated with adjustable gastric banding for morbid obesity: a surgeon's guides. AB - Laparoscopic adjustable gastric banding (LAGB) is considered to be a safe and effective method of weight loss and reduction of comorbidities associated with obesity. Despite its improved early safety profile compared with Roux-en-Y gastric bypass, patients with LAGB can manifest unique complications that must be recognized and managed appropriately to achieve good outcomes. This review will prepare the general surgeon to identify, diagnose and manage the common complications encountered in patients presenting following LAGB. PMID- 21251436 TI - Harmony in dermatology and venereology successfully approached. PMID- 21251435 TI - CAGS and ACS evidence based reviews in surgery. 36. Effect of high perioperative oxygen fraction on surgical site infection. PMID- 21251437 TI - Milestones in the history of Croatian dermatology and venereology: an outsider's insight. AB - While the first traces of interest in skin diseases date back to the 14(th) century recipes from Glagolitic manuscripts, the scientific beginnings of dermatovenereology might be associated with the beginning of the 19(th) century, when in the Rijeka region a 'new disease', called after the village of Skrljevo, was studied by Giovanni Battista Cambieri. This, however, has not been the only disease named after a Croatian toponym; in 1826, Luca Stulli of Dubrovnik was the first to describe the 'mal de Meleda', nowadays recognized as a form of hereditary palmoplantar keratoderma. In 1876, Carl Heizmann, a Croatian from Vinkovci by birth, was one of the founders of the American Dermatological Association. In 1894, the first department for dermatologic and venereologic patients was opened at Sestre milosrdnice (Sisters of Charity) Hospital in Zagreb. The beginning of the 20(th) century brought an accelerated development to Croatian dermatovenereology; in 1910, while still in its experimental phase, the drug Salvarsan was used in Zagreb for the treatment of syphilis. In 1921, the chair of dermatovenereology was established at Zagreb School of Medicine, and in 1927, Franjo Kogoj was the first to describe the spongiform pustule. In 1950, Ante Vukas from Rijeka developed a special method of epidermotectoscopy. If one remembers that the first history of AIDS was written by the Croatian Mirko Drazen Grmek, it would be allowed to concur that the history of dermatology and venereology on the Croatian soil has been characterized by a fascinating profusion and dynamism. PMID- 21251438 TI - Syphilis and Scherlievo in Dalmatia. AB - The authors describe the emergence of syphilis in Dalmatia, the coastal part of Croatia, at the very end of the 15(th) and the beginning of the 16(th) century, its presence up to the 20(th) century, making reference to the most important physicians that tried to cure the new disease. The archives of Dalmatian towns, their statutes, some literary works, travel writers, physician books, and articles by historians of medicine contain data on syphilis in Dalmatia. Syphilis was first observed in Zadar (1500), Trogir (1501) and Dubrovnik (1502). Among the first physicians who treated patients in Dubrovnik were Mariano Santo and Amatus Lusitanus. The latter was the first to make prosthesis for the palate defect to cure tertiary syphilis lesions. According to the statutes of Dalmatia towns, each had one or more paid physicians and pharmacists. The Ottoman travel writer Evlija Celebi gave an account of syphilis in Dalmatia in the 17(th) century. At the end of the 18(th) century and during the 19(th) century, endemic syphilis known as morbus de Scherlievo and morbus Brenensis appeared in Dalmatia. Because of the numerous cases observed in the region, new hospitals were opened in Dalmatian towns and the patients were hospitalized. Among the physicians who were engaged in the fight against syphilis in the 19th century, mention should be made of Giovanni Battista Cambieri, Nikola Selak and Bozo Pericic. They all treated the affected patients and described syphilis and 'Scherlievo disease'in Croatian as well as in other languages. Syphilis was present in Dalmatia towns during the 15(th)-20(th) century, remaining a challenge and arousing the interest of current dermatovenereologists as well as other specialists. PMID- 21251439 TI - Impairment quality of life in families of children with atopic dermatitis. AB - Atopic dermatitis (AD) not only changes the life of the affected child but also affects the physical, social and emotional functioning of parents. The aim of the study was to assess the quality of life of parents of children with AD and to correlate it with the disease severity. It was a cross sectional, self administered questionnaire study performed in parents of children with AD attending dermatology clinics affiliated to the College of Medicine, Qassim University, Saudi Arabia. The parents were asked to complete the validated Arabic version of the Dermatitis Family Impact (DFI) questionnaire. The severity of AD was evaluated by using the objective SCORAD index. Atopic dermatitis was considered mild when the score was <15, moderate at 15-40 and severe at >40. Out of a total of 774 children, 283 (36.6%) had mild, 259 (33.4%) moderate and 232 (30%) severe AD. The mean DFI score was 13.86+/-4.23. The DFI score of parents of children with severe AD (18.13+/-1.97) was significantly higher (P<0.001) as compared to mild (9.62+/-2.76) and moderate (14.68+/-2.26) AD. Family history of atopy in children and social class of parents had significant effect on the mean DFI scores. The highest scoring DFI domains were expenditure (mean score 1.74), sleep disturbance (mean score 1.73), food preparation (mean score 1.67) and emotional distress in parents (mean score 1.6). Tiredness and exhaustion in parents and housework were moderately affected, while the least affected areas were family leisure activity, treatment difficulties, time for shopping and relationship between family members. The severity of child's AD directly affects the quality of life of parents. The DFI is of value to guide appropriate management of children with AD and can be used as an added parameter in clinical trials concerning the management of children with AD. PMID- 21251440 TI - Biopsy proven morphea treated with tacalcitol ointment: case report. AB - A 43-year-old woman presented with a widespread morphea, which had its onset three months before. The patient had several plaques of active, pigmented, lilac halo disease on the trunk, arms and thighs. A biopsy confirmed that the patient was suffering from morphea. Therapy with clobetasol propionate ointment 0.05% was introduced, applied twice a day, 5 days a week. After a month, the ointment failed to significantly improve the lesions. Then the patient was treated with clobetasol ointment in the morning and tacalcitol ointment 4 mcg/g in the evening. This combination resulted in marked improvement of the disease after 20 days of therapy, and we decided to stop topical steroid. After three months of treatment with topical tacalcitol once a day, the plaques regressed considerably and only a very slight pigmentation remained. Therapy was further reduced to one evening, every other day for six months more, and then was suspended completely. No side effects were observed and there was no recurrence at 24-month follow up. PMID- 21251441 TI - Spitzoid melanoma: dermoscopic report and diagnostic discussion. AB - We present a case of a 16-year-old young man who came for a dermatologic appointment due to acne. He presented a pigmented asymptomatic lesion on the back of his right thigh. Dermoscopic examination revealed uncommon aspects, highly suspect of nodular melanoma, in particular a blue-whitish veil, striae and asymmetric globules. The lesion was promptly removed and the material referred for histopathologic examination. Microscopic findings showed an atypical spitzoid tumor, compatible with spitzoid melanoma. In this report, the importance of dermoscopy as an auxiliary method in the early diagnosis of cutaneous melanomas is emphasized. Its daily use by the dermatologist is an important tool in the decision-making process in cases of urgent removal of suspect lesions. PMID- 21251442 TI - Focal porokeratosis of nuchae: case report. AB - Porokeratosis is the common name of several diseases of unknown pathogenesis, which are similar in clinical appearance. It was first described in 1893 and was thought to be a disorder of sweat glands, hence the name porokeratosis. The lesion that can be found in all cases is annular, with atrophic center, and hyperkeratotic outer ring. Cases of porokeratosis have been linked with genetic heritage, excessive ultraviolet exposure, kidney failure, and state of immunosuppression, but no definitive link has been established. As a rare condition, its main feature is that the correct diagnosis can be delayed for a significant period of time. Porokeratotic lesions have a high incidence of malignant transformation and are considered premalignant. We present a case where a porokeratotic lesion was unsuccessfully treated as a psoriatic lesion for more than a year in a patient with previously diagnosed psoriasis. A skin biopsy was performed at our department, which revealed classic cornoid lamella and thus led to the correct diagnosis. The lesion was excised. Additional diagnostic tests revealed normal kidney function and intact immune system. A follow-up protocol was established for the patient, ensuring timely diagnosis of any future porokeratotic lesions. Porokeratosis, especially when there are only few lesions, is not difficult to manage - once it is diagnosed. A diagnosis of porokeratosis may also aid in identifying a serious systemic disease such as kidney failure. Importantly, a misdiagnosis of porokeratosis may lead to development of skin cancer. PMID- 21251443 TI - Initial presentation of hereditary angioedema as abdominal pain and ascites in puerperium: case report. AB - Hereditary angioedema is a rare genetic disorder resulting from an inherited deficiency or dysfunction of the C1 inhibitor. It is characterized by recurrent, circumscribed, and self-limiting episodes of cutaneous and mucous membrane swelling involving different organs. Hereditary angioedema may present with diverse clinical pictures, even within families with the same mutation. We present a first reported case of type 1 hereditary angioedema in a young woman presenting as recurrent abdominal pain associated with ascites without any other clinical features of hereditary angioedema, with initial presentation in puerperium. The recognition or awareness of hereditary angioedema as a cause of acute and/or recurrent abdominal pain associated with ascites is important, and may avoid unnecessary invasive procedures and facilitate appropriate treatment. PMID- 21251444 TI - Erythema annulare centrifugum in a patient operated on for breast carcinoma. AB - A 73-year-old Caucasian female patient presented for three annular erythematous lesions on the left leg and buttock, persisting for two months, clinically interpreted as erythema annulare centrifugum. Routine laboratory findings were within the normal ranges, Borrelia serology and wet mount microscopy for mycosis were negative. Histologic examination confirmed the diagnosis of superficial erythema annulare centrifugum. Since no association of erythema annulare centrifugum with concomitant bacterial or viral infections, or active systemic disease was found in our patient, we considered the possible activation of her previous breast cancer operated on in October 2000. PMID- 21251445 TI - Childhood acute generalized exanthematous pustulosis induced by oral ketoconazole. AB - Acute generalized exanthematous pustulosis is a rare disorder characterized by an acute onset of generalized, nonfollicular, pustular eruption associated with fever. It is usually drug-induced and is uncommon in children. We report a 12 year-old girl with acute generalized exanthematous pustulosis induced by oral ketoconazole. To our knowledge, in spite of its relatively frequent use, acute generalized exanthematous pustulosis due to ketoconazole has not been previously reported. PMID- 21251446 TI - Multiple angiokeratomas of the vulva: case report and literature review. AB - Angiokeratomas of the vulva are relatively rare finding and a limited number of cases have been reported in the literature. Clinically, angiokeratomas of the vulva are benign vascular lesions usually occurring in middle-aged or older women. Microscopically these lesions are characterized by epidermal hyperkeratosis, papillomatosis, acanthosis, and marked dilatation of the papillary dermal vessels. In most patients, genital lesions are asymptomatic; however, bleeding, dyspareunia and other symptoms have been described. We report a case of a 45-year-old woman with numerous blue-to-red, scaly papules that spread over the entire area of both labia majora. The patient reported occasional pruritus and burning sensations, discomfort during the intercourse, and significant psychological burden. Histopathologic analysis of the lesion confirmed the diagnosis of angiokeratoma, and all lesions were electrocauterized under local anesthesia. The results of the treatment were very satisfactory, with no side effects or complications. During one-year follow-up, no relapses were noted and the patient remained asymptomatic. Therefore, dermatovenereologists should be aware of angiokeratomas and respective therapeutic options when examining a patient with pruritic, painful, or bleeding lesions in the genital region. PMID- 21251447 TI - Early syphilis and syphilitic hepatitis following unprotected insertive oral sexual intercourse: case report. AB - We present a case of early syphilis in a HIV negative bisexual man after an oral insertive intercourse with clinical overlap of primary and secondary stages, and laboratory and other criteria for syphilitic hepatitis. Moreover, we herein stress the importance of awareness of the high-risk behaviors and report syphilitic hepatitis without jaundice, a usually unrecognized clinical condition, emphasizing the clinical and therapeutic importance of its occurrence among syphilitic cases. PMID- 21251448 TI - Melanoma staging and sentinel lymph node biopsy. AB - Tumor staging of melanoma is a crucial step for estimating patient prognosis, deciding on therapy approach, and efficient collection, analysis, comparison and communication of scientific data across borders and research groups. Recently, the Melanoma Staging Committee of the American Joint Committee on Cancer (AJCC) has proposed a revision of the widely used melanoma staging system, using an evidence-based approach, to reflect the improved understanding of this disease. Important adjustments were made related to the role of mitotic rate as a prognostic factor, definition of N category and classification of all microscopic nodal metastases, regardless of the extent of tumor burden, and specifically including micrometastases detected by immunohistochemistry as stage III. These revisions are to be implemented by early 2010 and are likely to be adopted and incorporated in international guidelines. Within the updated AJCC staging system, sentinel lymph node biopsy (SLNB) remains a standard-of-care diagnostic procedure, widely accepted as an important prognostic tool. According to current recommendations, SLNB is routinely offered as a staging procedure in patients with tumors more than 1 mm in thickness. Beyond its prognostic value, the therapeutic benefit of this procedure in improving overall survival yet remains to be proven. This article reviews and discusses the new aspects and challenges of the current staging recommendations for melanoma. PMID- 21251449 TI - Itch in atopic dermatitis - pathophysiology and treatment. AB - Pruritus is an essential feature of atopic dermatitis with a high impact on the quality of life. Although the pathophysiology of atopic dermatitis itch is not fully understood, recent studies have demonstrated that a variety of mechanisms contribute to the induction and maintenance of the symptom. For example, an increased number of cutaneous nerve fibers and neuropeptides were identified in atopic dermatitis skin. Histamine and histamine 4 receptor as well as interleukin 31 are novel key players identified in itch induction, in addition to inflammatory cells such as mast cells, eosinophils and lymphocytes. The new findings suggest that target-specific therapies are most likely to control atopic dermatitis itch. To date, only few therapies are available and controlled studies are pending. PMID- 21251450 TI - Metabolic comorbidities and psoriasis. AB - Psoriasis is a chronic inflammatory, immune-mediated skin disease, which affects 2%-3% of the population worldwide. Chronic plaque psoriasis is frequently associated with metabolic diseases including diabetes, obesity, dyslipidemia, metabolic syndrome and nonalcoholic fatty liver disease. Although the causal relationship between metabolic comorbidities and psoriasis has not yet been completely proven, it appears that shared genetic links, common environmental factors and/or common inflammatory pathways may underlie the development of psoriasis and comorbidities. The presence of comorbidities has important implications in the global approach to patients with psoriasis. Traditional systemic anti-psoriatic agents could negatively affect cardio-metabolic comorbidities, and may have important interactions with drugs commonly used by psoriatic patients. In contrast, the recent findings that the risk of myocardial infarction is reduced in patients with rheumatoid arthritis who respond to anti TNF-alpha therapy compared to non-responders, supports the hypothesis that the anti-inflammatory effect of TNF-alpha blockers might reduce the cardiovascular risk potentially also in psoriasis patients. Finally, patients with moderate to severe psoriasis should be treated promptly and effectively, and should be encouraged to drastically correct their modifiable cardiovascular risk factors, in particular obesity and smoking habit. PMID- 21251451 TI - Sexually transmitted infections and adolescence. AB - Sexually transmitted infections (STIs) remain a public health problem of major significance in most of the world. Adolescents make up about 20% of the world population, of whom 85% live in developing countries. They are at a greater risk of STIs because they frequently have unprotected intercourse, biologically may be more susceptible to infection, often are engaged in multiple monogamous relationships of limited duration, and face multiple obstacles in accessing confidential health care services. Young people who begin to have sexual intercourse in early or middle adolescence are more likely to develop an STI than those who postpone intercourse until later adolescence or adulthood. The most common STIs among adolescents are chlamydia, gonorrhea, human papillomavirus infection, and trichomoniasis. Unfortunately, lately the incidence of HIV/AIDS and syphilis among adolescents is growing. Comprehensive sex education programs in schools can increase STI knowledge and prevent risky sexual behaviors. Health care providers can promote STI prevention methods, including counseling about safe sex. PMID- 21251452 TI - Patient-based medicine and psoriasis. PMID- 21251453 TI - The First International Congress 'Current State in Corrective Dermatology: Lasers and Fillers' Zagreb, October 1-2, 2010. PMID- 21251455 TI - Transfusion considerations concerning patients with anti-hrB and confounding co morbid conditions: pregnancy and coagulopathy. PMID- 21251456 TI - Informed consent for cord blood donation. A theoretical and empirical study. AB - BACKGROUND AND OBJECTIVES: Umbilical cord blood (CB) banking and therapeutic use raise several ethical issues: medical indications, legal framework, public versus private biobanks, autologous versus allogeneic use, ownership, commercialisation, quality assurance and many others. Surrogate informed consent is one of the most notable controversial ethical issues. The aim of this study was to analyse and compare informed consent forms for CB collection, storage and use in the 18 accredited biobanks of the Italian Network. MATERIAL AND METHODS: The first part of the article gives a brief overview of the scientific framework, the comparison of allogeneic and autologous use and Italian regulations. In the second part the contents of the consent forms from the 18 Italian biobanks are compared with the "NetCord-FACT International Standards for Cord Blood Collection, Banking, and Release for Administration". RESULTS: Most of the Italian consent forms differ significantly from the NetCord-FACT Standards, with regards both to formal and substantial aspects. CONCLUSION: Italian forms for CB collection, storage and use need standardisation to meet international criteria. PMID- 21251457 TI - Congenital dyserythropoietic anaemias: new acquisitions. PMID- 21251458 TI - Pathophysiology and therapeutic options in primary immune thrombocytopenia. PMID- 21251459 TI - Increased detection of clinically significant antibodies and decreased incidence of delayed haemolytic transfusion reaction with the indirect antiglobulin test potentiated by polyethylene glycol compared to albumin: a Japanese study. AB - BACKGROUND: The indirect antiglobulin test (IAT) can be potentiated by agents such as polyethylene glycol (PEG-IAT) and albumin (Alb-IAT). PEG-IAT is generally regarded as superior to Alb-IAT for the detection of clinically significant red blood cell (RBC) antibodies. However, supporting data come from Caucasian dominant populations. Non-Caucasian populations should be investigated as well. MATERIAL AND METHODS: In this single-centre, retrospective, sequential study, Alb IAT was used from 1989 to 1996 (8 years) and PEG-IAT from 1997 to 2008 (12 years). Pre-transfusion RBC alloantibody detection rates and specificity, post transfusion alloantibody production, and the incidence of delayed haemolytic transfusion reaction were assessed and compared for the two periods. RESULTS: Although overall RBC alloantibody detection rates were comparable, PEG-IAT more frequently detected clinically significant antibodies such as anti-E, anti-Fy(b), and anti-Jk(a), and less frequently detected insignificant antibodies such as anti-Le(b) and anti-P(1). New alloantibodies emerged comparably during the two periods. Delayed haemolytic transfusion reaction was less frequent during the PEG IAT period (0.30% versus 0.12%, p<0.05). CONCLUSION: PEG-IAT was superior in the detection of clinically significant antibodies, reduced the detection of insignificant antibodies, and prevented delayed haemolytic transfusion reaction better than Alb-IAT among Japanese transfusion recipients in this retrospective survey of limited power. PMID- 21251460 TI - Effectiveness of recombinant activated factor VII in haemorragic cancer-related disseminated intravascular coagulation: a case report. PMID- 21251461 TI - Immunohaematological and apheretic aspects of the first kidney transplant from a living, ABO-incompatible donor carried out in Italy. PMID- 21251462 TI - Immunological testing for malaria and blood donor deferral: the experience of the Ca' Granda Polyclinic Hospital in Milan. AB - BACKGROUND: Current European regulations require a deferral period of 6 months or 3 years, depending on the risk of exposure, for prospective blood donors at risk of malaria. This period may be reduced to 4 months if an immunological or molecular genomic test is negative at each donation, but Italian regulations have not adopted this provision. As cases of transfusion-transmitted malaria have been recorded in medical literature in blood donors deferred for 3 years and not tested, the Immunohematology and Transfusion Centre of the Ca' Grande Polyclinic Hospital in Milan decided to introduce immunological testing for all donors at risk of malaria. MATERIALS AND METHODS: Four hundred and twelve blood donors at risk of malaria, who had lived in a malarial area during the first 5 years of life or for more than 6 consecutive months, were tested for malarial antibodies using an enzyme immunoassay kit. The kit (Malaria EIA, Newmarket, UK) uses four recombinant antigens specific for P. falciparum and P. vivax and with cross reactivity for P. ovale and P. malariae. The kit detects total immunoglobulin antibodies against P. falciparum and P. vivax and shows 80% cross-reactivity with P. ovale and 67% with P. malariae. Antibody-positive samples were further checked by an immunochromatographic test for P. falciparum, P. vivax, P. ovale and P. malariae antigens and by haemoscopy (thin film and thick smear). RESULTS: Italian citizens accounted for 16.8% (69/412) of the whole group of donors examined. We found that 8.7% of the donors who were classified as being at risk of malaria were positive for total immunoglobulin antibodies. Only one Italian citizen resulted positive for the test. The positive candidates were deferred from blood donation. None of the antibody-positive donors was confirmed positive by the immunochromatographic test and by haemoscopy. CONCLUSION: The introduction of a malarial screening test in the assessment of blood donor eligibility may increase the safety of blood donations, but could further reduce blood availability. If immunological testing were to be accepted nationally as a valid method of assessing the risk of malaria, more than 90% of the donors who are currently deferred for 3 years could be accepted 4 months after their last visit to an endemic area, thus increasing the availability of blood. PMID- 21251463 TI - The use of banked skin in the Burns Centre of Verona. AB - BACKGROUND: The use of glycerol and subsequent research enabling the conservation of tissues over time have led to the establishment and development of tissue banks, first in the USA and then in Europe. The Verona Tissue Bank was instituted in 2003 as the Regional Centre for the storage of skin and bone, adding to the already existing Italian banks at Turin, Milan, Cesena and Siena. This retrospective study analyses the use of banked skin (autologous and allogeneic grafts) from April 2003 (date of starting activity) to December 2007, in 171 patients with burns and four with necrotising fasciitis at the Burns Centre of Verona. MATERIALS AND METHODS: Homologous skin was used for superficial and deep skin burns to protect the residual structures, thus facilitating healing by spontaneous re-epithelialisation, and for deep burns after eschar removal to clean and prepare the base of the lesion for the definitive autologous graft. The placement of a homologous graft alone led to spontaneous healing of lesions in 65 patients (36 aged >15 years and 29 aged <15 years) with superficial skin burns, while the remaining 106 patients (84 aged >15 years and 22 aged <15 years) with deeper burns underwent surgery. CONCLUSIONS: The results obtained confirm the essential role of banked skin in covering superficial burns in order to protect important underlying structures and in deep burns by guaranteeing a good preparation of the base of the lesion for the subsequent definitive autologous graft. PMID- 21251464 TI - Improved traceability and transfusion safety with a new portable computerised system in a hospital with intermediate transfusion activity. AB - BACKGROUND: A retrospective study carried out on medical records of transfused patients in our hospital in 2002 revealed that manual identification procedures were insufficient to offer satisfactory traceability. The aim of this study was to assess adequacy of transfusion traceability and compliance with proper identification procedures after introducing an electronic identification system (EIS) for transfusion safety. MATERIALS AND METHODS: The chosen EIS (Gricode((r))) was set up. Traceability was calculated as the percentage of empty blood units used returned to the Transfusion Service, compared to the number of supplied units. Compliance in the Transfusion Service was calculated as the percentage of electronic controls from dispatch of blood components/transfusion request performed, compared to the total number of transfused units. Compliance in the ward was calculated as the percentage of electronic controls from sample collection/transfusion performed, compared to the total number of samples collected. RESULTS: This retrospective study showed that only 48.0% of the medical records were free of inaccuracies. After the implementation of the EIS (2005-2008), traceability was always above 99%. Percentage of monthly compliance from 2006 to 2008 was always above 93%, showing a significant trend to increase (p<0.05). The mean compliance in this period was higher in the Transfusion Service (97.8 +/- 0.7 SD) than in the ward (94.9 +/- 2.4 SD; p<0.001). Compliance in the ward was lowest when the system was first implemented (87.9% in April 2006) after which it progressively increased. No errors in ABO transfusions were registered. CONCLUSION: After implementation of the EIS, traceability and compliance reached very high levels, linked to an improvement in transfusion safety. PMID- 21251465 TI - Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. AB - BACKGROUND: Intracranial haemorrhage is a serious and potentially fatal complication of oral anticoagulant therapy. Prothrombin complex concentrates can substantially shorten the time needed to reverse the effects of oral anticoagulants. The aim of this study was to determine the efficacy and safety of a prothrombin complex concentrate for rapid reversal of oral anticoagulant therapy in patients with intracranial haemorrhage. METHODS: Patients receiving oral anticoagulant therapy and suffering from acute intracranial haemorrhage were eligible for this prospective cohort study if their International Normalised Ratio (INR) was higher than or equal to 2.0. The prothrombin complex concentrate was infused at doses of 35-50 IU/kg, stratified according to the initial INR. RESULTS: Forty-six patients (25 males; mean age: 75 years; range 38-92 years) were enrolled. The median INR at presentation was 3.5 (range, 2-9). At 30 minutes after administration of the prothrombin complex concentrate, the median INR was 1.3 (range, 0.9-3), and the INR then declined to less than or equal to 1.5 in 75% of patients. The benefit of the prothrombin complex concentrate was maintained for a long time, since the median INR remained lower than or equal to 1.5 (median, 1.16; range, 0.9-2.2) at 96% of all post-infusion time-points up to 96 hours. No thrombotic complications or significant adverse events were observed during hospitalisation; six patients (13%) died, but none of these deaths was judged to be related to administration of the prothrombin complex concentrate. CONCLUSIONS: Prothrombin complex concentrates are an effective, rapid and safe treatment for the urgent reversal of oral anticoagulation in patients with intracranial haemorrhage. Broader use of prothrombin complex concentrates in this clinical setting appears to be appropriate. PMID- 21251466 TI - Three or four factor prothrombin complex concentrate for emergency anticoagulation reversal? PMID- 21251467 TI - Idiopathic thrombocytopenia and Helicobacter pylori infection: platelet count increase and early eradication therapy. PMID- 21251468 TI - Intra-operative cell salvage: a fresh look at the indications and contraindications. PMID- 21251470 TI - Hereditary red cell membrane defects: diagnostic and clinical aspects. PMID- 21251469 TI - Allele-specific oligonucleotide polymerase chain reaction for the determination of Rh C/c and Rh E/e antigens in thalassaemic patients. AB - BACKGROUND: Thalassaemia is a genetic disease in which there is a relative or complete lack of alpha or beta globin chains. Patients with moderate to severe forms of thalassaemia need transfusions from the early years of life. Antibody production against blood group antigens may cause many problems in preparing compatible blood units for transfusion. The identification of definite blood group phenotypes by the haemagglutination method can be difficult because of the mixed population of red blood cells from the donor and recipient. MATERIALS AND METHODS: Forty multiply transfused thalassaemic patients and ten healthy controls with no history of blood transfusion were enrolled in this study. Allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) and haemagglutination methods were used to determine the presence of Rhesus (Rh) C, c, E and e antigens. RESULTS: In this study four primer sets were used for ASO-PCR amplification of RhC/c and RhE/e. Although PCR assays for RhC/c and RHE/e genotyping have been described previously, in this study we used a new condition for PCR by decreasing the annealing temperature from 63 degrees C to 58 degrees C in order to amplify all four genes in the same condition. In order to evaluate this single run molecular method, we used the haemagglutination test as the standard method and compared the results from the two methods. We found discrepancies between phenotype and genotype results among patients with beta thalassaemia, but complete agreement between phenotype and genotype in the control group. CONCLUSIONS: The advantage of this new ASO-PCR method compared to a restriction fragment length polymorphism (RFLP) PCR method is that with the former all four genes can be amplified at the same time by PCR, and electrophoresis can be performed immediately to determine individual antigen profiles. The simplicity of the ASO-PCR method makes it suitable for routine use in medical centres and it is also cheaper than RFLP-PCR. Furthermore, as shown by previous studies, the results of haemagglutination and PCR tests often differ because the existence of donor red blood cells in the patient's circulation can interfere with the interpretation of the haemagglutination test. PMID- 21251471 TI - An unusual case of a potentially clinically significant anti-M antibody in a healthy male blood donor without any history of blood transfusion. PMID- 21251472 TI - Quality of life and patient satisfaction after artificial urinary sphincter. AB - BACKGROUND: We assessed satisfaction and quality of life (QOL) in men with artificial urinary sphincter (AUS) placement. METHODS: We identified 39 men who had AUS placement. A retrospective chart review was conducted. Validated questionnaires, including the International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF), Post-Operative Patient Global Impression of Improvement (PGI-I), Incontinence Impact Questionnaire-Short Form (IIQ-SF), and Urogenital Distress Index (UDI-SF), were used to measure patient-reported outcome. Global satisfaction was also assessed. RESULTS: At chart review, 34 of 39 questionnaires were assessed for QOL, satisfaction and surgical outcome. Follow-up ranged from 7 to 60 months (median = 24 months). Surgical revisions were required in 6 (17.6%) patients due to infection (1), erosion (1), combined infection and erosion (1), device failure (1) and second cuff placement (2). Quality of life was assessed using the IIQ-SF and UDI-SF, with mean scores of 15.4 and 24.8, respectively; these scores indicated a low negative impact on QOL. The ICIQ-SF mean score was 8.2, well below the worst possible score. The number of men using more than 1 pad per day dropped from 27 preoperatively to 10 postoperatively. Most patients (31/34) described their urinary condition as better, 2 had no change and 1 was worse. Most patients (31/34, 91.2%) would be willing to undergo the procedure again, 2 were undecided, and 1 would not. Similarly, 28 patients (82.4%) would recommend the procedure to a friend, 3 respondents would "with reservation," 1 respondent was undecided, and 2 would not recommend the AUS placement. CONCLUSION: Treatment of urinary incontinence with the AUS has a positive effect on QOL with high patient satisfaction and reasonably low complication rates. PMID- 21251473 TI - Screening and identification of specific markers for bladder transitional cell carcinoma from urine urothelial cells with suppressive subtractive hybridization and cDNA microarray. AB - OBJECTIVE: The objective of this study was to screen and identify differentially expressed genes in invasive bladder transitional cell carcinoma (BTCC). METHODS: Voided urine samples were collected from consecutive patients with BTCC and patients under surveillance for bladder cancer recurrence; voided urine samples from patients with non-malignant diseases served as control. We identified the differentially expressed genes by comparing urine samples of bladder carcinoma to that of the control group with suppressive subtractive hybridization (SSH) and cDNA microarray. The differentially expressed genes were verified by quantitative real-time polymerase chain reaction (QPCR). RESULTS: From the 762 white colonies, a total of 449 positive clones were obtained in which 112 were found to be upregulated in BTCC. Sequencing and homology analysis were performed for these 112 clonies. The detection rates of some known genes (including IGF-1, human telomerase reverse transcriptase [hTERT], bladder cancer specific nuclear matrix protein 4 [BLCA-4] and homeobox A13 [HOXA13]) for BTCC at the Ta, T1 and >T1 stages were 48%, 90% and 100%, respectively, with a specificity of 85%. The test specificity was 80% for the 30 control patients with urinary tract infections. The combination of BLCA-4 and HOXA13 could distinguish between low- and high grade tumours, with specificity and sensitivity of 80%. CONCLUSION: We successfully constructed a reliable SSH library of BTCC and found that combination detection insulin-like growth factor 1 (IGF-1), hTERT, BLCA-4 and HOXA13 genes could help to evaluate BTCC at different stages. PMID- 21251475 TI - Shaping the future of the Portuguese Journal of Pulmonology. PMID- 21251474 TI - The pattern of prostate cancer local recurrence after radiation and salvage cryoablation. AB - OBJECTIVE: We assessed the pattern of local recurrence after salvage cryoablation of the prostate, and the impact of local recurrence on intermediate-term outcome. METHODS: One hundred twenty-two patients who underwent salvage cryoablation were studied after a mean follow-up of 56 months. Serial prostate biopsy was carried out after cryoablation. The histopathology of prostate biopsies before and after cryoablation were compared. The prognostic value of post-cryoablation biopsy was assessed with the Cox regression method. RESULTS: 23.1% of patients had a positive biopsy for prostate cancer following salvage cryoablation. Most cancer recurrences occurred in the apex (51.5%), base (21.2%) and seminal vesicles (18.2%). The presence of cancer at the base of the prostate was found to be a prognostic factor for eventual biochemical failure. Overall 5-year biochemical disease-free survival (bDFS) was 28%, however patients with cancer at the base of the prostate had a 5-year bDFS of 0%. CONCLUSION: Cancer recurrences occurred in areas where aggressive freezing was avoided as it might result in serious problems (e.g., urethro-rectal fistula and incontinence). Post-cryoablation biopsies and the location of persistent disease are of prognostic value. PMID- 21251477 TI - Every year is the year of the lung! PMID- 21251476 TI - Involuntary exposure to tobacco smoke in children. Smoking in young people. PMID- 21251478 TI - Hemoptysis--etiology, evaluation and treatment in a university hospital. AB - OBJECTIVE: Evaluate patients admitted for hemoptysis, its etiology, use of diagnostic tests, treatment and outcome. METHODS: A retrospective analysis was done, checking clinical files of patients admitted for hemoptysis, between 1st January 2004 and 31st December 2008. RESULTS: Two hundred and thirty seven patients were included in this study, with a mean age of 57.9 years. In patients under 18 years, the most frequent diagnoses were Bronchiectasis and Congenital Cardiopathy. In adults, Pulmonary Tuberculosis Sequelae and Bronchiectasis were the dominant diagnoses (22.2 % and 15.8 %, respectively), followed by Lung Cancer. Active infection was responsible for bleeding in 51 patients, especially Pulmonary Tuberculosis, Pneumonia and Tracheobronchitis. The etiology of hemoptysis was not established in 6.3 %. All patients performed chest X-Ray. Chest CT was performed in 81.4 % of patients and Fiberoptic bronchoscopy in 52.7 %, the latter locating the source of bleeding in 38.4 % and establishing a final diagnosis in 17.6 %. In most patients, effective control of bleeding was achieved by medical treatment (90.7 %). During these 5 years, arterial embolization was performed in 11.8 % of patients. The main reason for embolization was recurrence prevention. There were 14 deaths (5.9 %), being identified as poor prognostic factors, hemodynamic instability and malignancy. CONCLUSION: Hemoptysis is still a frequent symptom, being chronic infection sequelae and lung cancer their main causes. In this study, factors associated with a worse prognosis were hemodynamic instability and malignancy. PMID- 21251479 TI - HLA class II alleles as markers of tuberculosis susceptibility and resistance. AB - BACKGROUND: Not every individual exposed to Mycobacterium tuberculosis becomes infected. One host genetic factor, involved in modulating the immune response that has been studied in many ethnic groups is the association of human leukocyte antigens (HLA) with susceptibility to tuberculosis (TB). OBJECTIVE: To investigate the association between TB, HLA-DRB1 and HLA-DQB1 alleles in a Portuguese population. METHODS: HLA-DRB1 and HLA-DQB1 gene polymorphisms were analyzed by PCR-SSP in 92 TB patients, and 82 healthcare professionals without TB but exposed on a daily basis to infectious patients for more than two years (healthy exposed - HE). Tuberculin skin test reaction (TST), was positive in 69 individuals (all over 15 mm) in the HE group (HE+) and negative in thirteen (HE ). RESULTS: HLA-DRB1*14 frequency is higher in the TB patients group (7 % vs. 0; p = 0.038) than in HE+. CONCLUSIONS: No genetic marker clearly indicative of disease susceptibility or resistance was identified in this study. However, HLA DRB1*14 was more frequent in TB patients suggesting that it may be involved in the evolution infection towards active TB in our population. PMID- 21251480 TI - Environmental tobacco smoke (ETS) exposure and respiratory morbidity in school age children. AB - INTRODUCTION: Tobacco smoke is a risk factor for Chronic Obstructive Pulmonary Disease and a major public health problem. Prenatal maternal smoking and post natal environmental tobacco smoke (ETS) lead to dose-dependent decrease in lung function and respiratory morbidity. Influence of different socioeconomic indicators and ETS in the home has also been suggested. METHODS: Data on 313 children (52 % male) from 4 public schools in Lisbon was analyzed [1st (46 %) and 4th graders]. ETS assessment and respiratory symptoms were based on a self answered questionnaire. All children performed standard spirometry in the school setting and 54 % were acceptable according to ATS/ERS criteria. Descriptive and bivariate analysis of the most relevant variables was done, followed by multiple logistic regression analysis adjusted to the variables with clinical/statistical relevance. RESULTS: ETS in the home was found in 41 % (maternal smoking during pregnancy 18 %, smoking mother 32 %, smoking father 38 %). Smoking fathers had lower education and less qualified occupation. Cough was more frequent in children with a smoking mother (adjusted OR = 2.1 95CI 1.1-4.0) and wheezing in children with maternal smoking during pregnancy and smoking parents. All differences were significant (p < 0.05). No association was found between parental education and cough/wheeze or ETS and respiratory infections/asthma/decreased spirometric values. CONCLUSIONS: Children in Lisbon are frequently exposed to ETS which results in significant respiratory morbidity. Targeted interventions must have social conditions in consideration. In this study, field spirometry was not helpful in early detection of lung function disability in children associated with ETS. PMID- 21251481 TI - Social representations of smoking behaviour in 13-year-old adolescents. AB - OBJECTIVE: The purpose of this study was to identify adolescents' social representations on smoking using a qualitative approach. METHODS: Thirty semi structured interviews were conducted by trained interviewers. The interviews were recorded with participant's permission after our comprehensive explanation of the interview process. After transcript the content of each interview, information was synthesised under each of main question, and a conceptual content analysis was undertaken. The analysis was performed by two of the authors, and the conflicts were resolved by a third person. RESULTS: Adolescents suggested different explanations for general people and adolescent smoking behaviour. While in general people smoking behaviour was mostly related to dependence, in adolescence it is referred to be associated with status improving among peers and to keep up social relations. We realised that adolescents are aware of the serious health implications of smoking, but they only referred it as a long-term effect in adulthood and no consequences during adolescence were for seen. We also noted the difficulties in giving preventive measures targeted on adolescents. CONCLUSION: This study points out the importance of peers as agents of socialization in tobacco consumption, and shows the importance of anti-smoking campaigns among this age group with emphasis on smoking consequences in adolescence. PMID- 21251482 TI - Bronchiectasis: do we need aetiological investigation? AB - Bronchiectasis (BE) is characterized by irreversible dilation and damage to the bronchial walls. It is a morphological expression of a large variety of pathologies. The true prevalence of BE is unknown. It is known, however, that in Third World countries it is common due to lung infections. Its current prevalence in developed countries is rather significant due to a greater capacity for diagnosis, its association with highly prevalent diseases and to a greater chronicity of some of the underlying pathologies. Over the last few decades there has been little interest in the investigation of BE, unless it is associated with cystic fibrosis. One of the reasons is the presupposition that treatment is the same for all patients diagnosed with BE, regardless of the underlying aetiology. Several works carried out over the last decade show that a diagnosis based on aetiology changes both the approach and the treatment of BE within a relevant percentage of patients, with a consequent change in the prognosis. Currently, systematic investigation into the aetiology of BE is recommended, particularly in those disorders that respond to specific treatment. PMID- 21251483 TI - Severe malaria--clinical case. AB - We report a clinical case of severe malaria, where the rate of initial parasitaemia by Plasmodium falciparum was 43 %. Multiple organ dysfunction, including ARDS, forced admission in a close surveillance unit, with survival of the same. A brief review of the subject is made, focusing on severity and general conduct, alerting and awareness for this entity, whose expression, among us, could take on increasing importance. PMID- 21251484 TI - Primary pleomorphic sarcoma of lung--11 year survival. AB - Primary sarcomas of the lung are uncommon, potentially aggressive neoplasms that need to be distinguished from other malignant pulmonary tumors and whose biological behavior is as yet not fully understood. Primary undifferentiated pleomorphic sarcoma was diagnosed in the right lung of a 66 year-old man, who has survived over 11 years after treatment with endobronchial tumor debulking by laser therapy and radiotherapy. PMID- 21251485 TI - For a good cause a strong image. PMID- 21251486 TI - Effectiveness of the 2009 seasonal influenza vaccine against pandemic influenza A(H1N1)2009 in healthcare workers in New Zealand, June-August 2009. AB - There is uncertainty whether the 2009 seasonal influenza vaccination influences the risk of infection with the 2009 pandemic influenza A(H1N1) virus. This issue was investigated in 548 healthcare workers from Capital and Coast District Health Board, Wellington, New Zealand, presenting with influenza-like illness during the influenza pandemic between June and August 2009. All workers completed an assessment sheet and had a nasopharyngeal swab tested by real-time RT-PCR. The risk of pandemic influenza A(H1N1) infection associated with the 2009 seasonal inactivated trivalent influenza vaccine was determined by logistic regression, with adjustment for potential confounding variables. In 96 workers pandemic influenza A(H1N1) RNA was detected and 452 tested negative. The multivariate analysis did not show any effect of vaccination on PCR-confirmed influenza A(H1N1)2009 infection (odds ratio 1.2, 95% confidence interval 0.7-1.9, p=0.48). We conclude that 2009 seasonal influenza vaccination had no protective effect against influenza A(H1N1)2009 infection amongst healthcare workers. To protect against further waves of the current pandemic influenza or future pandemics in which the influenza virus is antigenically distinct from contemporary seasonal influenza viruses, it would be necessary to vaccinate with a specific pandemic influenza vaccine, or a seasonal influenza vaccine that includes the pandemic influenza serotype. PMID- 21251487 TI - Effectiveness of pandemic and seasonal influenza vaccine in preventing pandemic influenza A(H1N1)2009 infection in England and Scotland 2009-2010. AB - Following the global spread of pandemic influenza A(H1N1)2009, several pandemic vaccines have been rapidly developed. The United Kingdom and many other countries in the northern hemisphere implemented seasonal and pandemic influenza vaccine programmes in October 2009. We present the results of a case-control study to estimate effectiveness of such vaccines in preventing confirmed pandemic influenza infection. Some 5,982 individuals with influenza-like illness seen in general practices between November 2009 and January 2010 were enrolled. Those testing positive on PCR for pandemic influenza were assigned as cases and those testing negative as controls. Vaccine effectiveness was estimated as the relative reduction in odds of confirmed infection between vaccinated and unvaccinated individuals. Fourteen or more days after immunisation with the pandemic vaccine, adjusted vaccine effectiveness (VE) was 72% (95% confidence interval (CI): 21% to 90%). If protection was assumed to start after seven or more days, the adjusted VE was 71% (95% CI: 37% to 87%). Pandemic influenza vaccine was highly effective in preventing confirmed infection with pandemic influenza A(H1N1)2009 from one week after vaccination. No evidence of effectiveness against pandemic influenza A(H1N1)2009 was found for the 2009/10 trivalent seasonal influenza vaccine (adjusted VE of -30% (95% CI: -89% to 11%)). PMID- 21251488 TI - Measles among healthcare workers: a potential for nosocomial outbreaks. AB - We report here 14 cases of measles among healthcare workers (HCWs) in Public Hospitals of Marseilles, France that occurred between April and November 2010. All cases but one were under 30 years of age. Following the identification of these cases, we checked the immune status among 154 HCWs who volunteered to take part in the study and showed that 93% and 88% were immune against measles and mumps respectively. HCWs non-immunised against measles were all under 30 years of age. PMID- 21251489 TI - Outbreak of West Nile virus infection in humans, Romania, July to October 2010. AB - A total of 57 cases of West Nile virus infection (54 with neuroinvasive infection and three with fever) were identified in Romania between July and October 2010.The median age of the cases was 53.4 years, with the highest incidence in the age group 60-69 years.The case fatality rate was 8.8%. Cases were distributed in 19 districts in the southern, western, central and eastern parts of the country. Molecular investigation revealed lineage 2 West Nile virus, related to the Volgograd 2007 strain. PMID- 21251490 TI - Descemet stripping automated endothelial keratoplasty under failed penetrating keratoplasty: how to avoid complications. PMID- 21251491 TI - Femtosecond laser-assisted keratoplasty. PMID- 21251492 TI - Diabetic retinopathy in the developing world: how to approach identifying and treating underserved populations. PMID- 21251493 TI - Vision-specific quality-of-life research: a need to improve the quality. PMID- 21251495 TI - Yellow-tinted intraocular lenses on short-wavelength automated perimetry. PMID- 21251496 TI - Amniotic membrane grafting in the management of acute toxic epidermal necrolysis/Stevens Johnson syndrome. PMID- 21251498 TI - Graft failure after penetrating keratoplasty in eyes with Ahmed valves. PMID- 21251500 TI - The effect of image quality on retinal nerve fiber layer measurement in Stratus OCT. PMID- 21251502 TI - Laser in situ keratomileusis-induced monovision. PMID- 21251504 TI - Preoperative subpterygeal injection versus intraoperative mitomycin C for pterygium removal: comparison of results and complications. PMID- 21251506 TI - Retinal ganglion cells: development, function, and disease. PMID- 21251507 TI - Preface: Kidney diseases and renal replacement therapies. PMID- 21251508 TI - Acute kidney injury in dogs and cats. AB - The term acute kidney injury (AKI) has replaced the historical term acute renal failure for renal damage occurring over a short period of time (hours to days) because it is thought to better describe the pathophysiologic changes and duration of the different phases of injury. There are many potential causes of AKI in dogs and cats, and the prognosis has been shown to vary with the cause as well as with therapy. This article reviews current concepts of the pathophysiology, causes, clinical presentation, approach to diagnosis, and medical management of AKI in dogs and cats. PMID- 21251509 TI - Chronic kidney disease in small animals. AB - Chronic kidney disease (CKD) affects multiple body systems and presents with a wide variety of clinical manifestations. Proper application of conservative medical management can profoundly affect the clinical course of CKD. Diagnosis and management is facilitated by staging CKD and applying therapies that are appropriate for the patient's stage of CKD. Therapy and follow-up of CKD are described, with emphasis on stage-based therapy to ameliorate clinical signs and slow progression. PMID- 21251510 TI - Protein-losing nephropathy in small animals. AB - Genetic and acquired defects of glomerular permselectivity may lead to proteinuria and protein-losing nephropathy (PLN). Morbidity and mortality from complications of PLN may be severe even before progression to azotemia and renal failure. Leakage of plasma proteins into the glomerular filtrate can damage tubular cells and the function of the entire nephron. Detection, localization, and treatment of proteinuria are important to decrease the clinical signs and complications of PLN and the likelihood of progression to renal failure. Thorough diagnostic work-ups help to identify subsets of glomerular disease and their response to specific treatment protocols. PMID- 21251511 TI - Hypertension in small animal kidney disease. AB - Kidney disease is commonly associated with hypertension in dogs, cats and other species. There are multiple mechanisms underlying the development of renal hypertension including sodium retention, activation of the renin-angiotensin system and sympathetic nerve stimulation. The relative importance of these and other mechanisms may vary both between species and according to the type of kidney disease that is present. Consideration of underlying disease mechanisms may aid in the rational choice of therapy in hypertensive patients. PMID- 21251512 TI - Peritoneal dialysis in veterinary medicine. AB - Peritoneal dialysis is a modality of renal replacement therapy that is commonly used in human medicine for treatment of chronic kidney disease and end-stage kidney failure. Peritoneal dialysis uses the peritoneum as a membrane across which fluids and uremic solutes are exchanged. In this process, dialysate is instilled into the peritoneal cavity and, through the process of diffusion and osmosis, water, toxins, electrolytes, and other small molecules, are allowed to equilibrate. PMID- 21251513 TI - Intermittent hemodialysis for small animals. AB - Hemodialysis is a life-saving medical modality that cleanses the blood using an artificial kidney, called a dialyzer. Hemodialysis uses contact between the patient's blood and the semipermeable membrane of the extracorporeal dialyzer to remove compounds such as blood urea nitrogen, creatinine, electrolytes, minerals, anions, cations, certain drugs and toxins, and excess fluid from the bloodstream. The extracorporeal dialyzer distinguishes hemodialysis from peritoneal dialysis, which uses a patient's peritoneum as the dialysis membrane. There are 2 main types of hemodialysis: intermittent hemodialysis and continuous renal replacement therapy. This article focuses on intermittent hemodialysis for acute and chronic kidney injury. PMID- 21251514 TI - Continuous renal replacement therapy in dogs and cats. AB - Continuous renal replacement therapy (CRRT) is a relatively new extracorporeal blood purification modality that is rapidly gaining acceptance for the treatment of acute kidney injury in cats and dogs. The author has used CRRT for the treatment of leptospirosis, tumor lysis syndrome, heatstroke, pre- and postsurgical support of ureteral obstructions, as well as aminoglycoside and melamine toxicities. As the name implies, CRRT is a slow gradual process, and once treatment begins, patients continue therapy until their renal function returns, they are transitioned to intermittent hemodialysis (IHD), or they are euthanized. Unlike IHD, which is a primarily diffusive therapy, CRRT uses diffusion as well as convection. Because of its efficient use of fluids, CRRT units use prepackaged fluids, eliminating the need for costly water purification systems that are needed for IHD. PMID- 21251515 TI - Vascular access for extracorporeal renal replacement therapy in veterinary patients. AB - Vascular access is the first and most basic requirement for successful extracorporeal renal replacement therapy (ERRT). Dual-lumen catheters are the most commonly used method of vascular access for ERRT in veterinary patients. An adequately functioning dialysis catheter allows for smooth and efficient patient management, whereas a poorly functioning catheter frustrates the technician, doctor, and patient. These catheters are fairly quick to place but require meticulous care for optimal function. The most common complications are thrombosis and infection. Monitoring catheter performance should be a routine part of dialysis patient care. PMID- 21251516 TI - Anticoagulation in intermittent hemodialysis: pathways, protocols, and pitfalls. AB - Several methods to prevent extracorporeal circuit clotting during hemodialysis have been used in human medicine. Unfractionated (UF) heparin remains the mainstay of anticoagulant therapy in both human and veterinary intermittent hemodialysis. Different UF heparin regimes may be used depending on the bleeding risk of the patient. In patients with active bleeding or with a recent history of surgery or hemorrhagic episodes, hemodialysis may be performed without any anticoagulation or with regional anticoagulation. PMID- 21251517 TI - Equipment commonly used in veterinary renal replacement therapy. AB - Hemodialysis is a highly technical procedure that requires specialized equipment that is not used in other areas of veterinary medicine. Certain hemodialysis specific monitoring equipment is also employed. PMID- 21251518 TI - Urea kinetics and intermittent dialysis prescription in small animals. AB - Hemodialysis improves survival for animals with acute kidney injury beyond what would be expected with conventional management of the same animals. Clinical evidence and experience in human patients suggest a role for earlier intervention with renal replacement to avoid the morbidity of uremia and to promote better metabolic stability and recovery. For a large population of animal patients, it is the advanced standard for the management of acute and chronic uremia, life threatening poisoning, and fluid overload for which there is no alternative therapy. PMID- 21251519 TI - Extracorporeal removal of drugs and toxins. AB - Renal replacement therapies (RRT) are increasingly used for the treatment of acute and chronic kidney diseases as well as intoxications and accidental drug overdoses. These therapies offer a mechanism for the removal of toxic substances from the patient's blood and supplement the standard detoxification protocols. If instituted early, RRT can have a significant effect on the course of the toxicity; however, this process is not selective for the removal of only harmful products and can also result in the clearance of medications intended for therapeutic use. PMID- 21251520 TI - Nutritional considerations for the dialytic patient. AB - Nutritional therapy has a key role in the conservative management of renal disease. This role is even more vital with the advent of advanced renal replacement therapies to support patients with life threatening severe oliguric or anuric acute uremia or the International Renal Interest Society stage IV chronic kidney disease. Nutritional assessment and institution of nutritional support is crucial because dialysis only partially alleviates uremic anorexia. Dialytic patients have a higher risk of protein calorie, iron, zinc, vitamin B6, vitamin C, folic acid, 1,25-dihydroxycholecalciferol, and carnitine malnutritions. PMID- 21251521 TI - Emptying the corridors of shame: organizational lessons from England's 4-hour emergency throughput target. AB - STUDY OBJECTIVE: Since 2005, 98% of patients treated in England's emergency departments (EDs) must be discharged or placed in a hospital bed within 4 hours of arrival. Using a qualitative approach, we describe lessons learned from implementing the 4-hour emergency throughput target. METHODS: This was a qualitative study of EDs in England, purposively sampled for a range of size and performance on the target. Leadership of EDs at 9 Acute Trusts (hospitals) were interviewed between June and August 2008. Using content analysis, we analyzed semistructured interviews to identify salient themes. RESULTS: Twenty-seven interviews were coded. Respondents agreed on the following themes. (1) Interdependency: Even with extensive ED process re-engineering, widespread Trust involvement was essential to meeting the target. Additionally, lack of recognition that it was a "Trust target" contributed to conflicts between staff, concerns for patient safety, and lost opportunity for organizational improvement. (2) Contrasting change management strategies: ED leadership used collaborative strategies, whereas change in the rest of the hospital required a top-down approach. (3) Burden and benefit for staff: Nursing perceived the greatest burden from the target but also acquired enhanced authority, skills, and roles. (4) COSTS: Although most EDs are now within range of the target, consistent performance while balancing patient safety remains tenuous. CONCLUSION: Achieving the 4-hour target requires hospital-wide support. Lack of organizational ownership contributes to negative effects on staff, incomplete process improvement, and risk to patients. These lessons have widespread implications for all targets and may help explain why some health care targets fail to achieve their aims. PMID- 21251522 TI - Cutaneous cryptococcal infection as a manifestation of disseminated disease. Cryptococcus neoformans. PMID- 21251523 TI - A survey of past participants in the Annals of Emergency Medicine editorial board fellowship program. AB - Annals of Emergency Medicine established the Resident Editorial Fellow program for senior residents in 1998. As of 2009, 14 residents had completed the 1-year program. We survey the literature on training of medical editors, describe the structure of the fellowship, and present the results of a survey of all past participants, documenting their subsequent professional positions and the perceived influence of the fellowship on their careers. The response rate was 100%. PMID- 21251524 TI - Citations to Web pages in scientific articles: the permanence of archived references. AB - STUDY OBJECTIVE: We validate the use of archiving Internet references by comparing the accessibility of published uniform resource locators (URLs) with corresponding archived URLs over time. METHODS: We scanned the "Articles in Press" section in Annals of Emergency Medicine from March 2009 through June 2010 for Internet references in research articles. If an Internet reference produced the authors' expected content, the Web page was archived with WebCite (http://www.webcitation.org). Because the archived Web page does not change, we compared it with the original URL to determine whether the original Web page had changed. We attempted to access each original URL and archived Web site URL at 3 month intervals from the time of online publication during an 18-month study period. Once a URL no longer existed or failed to contain the original authors' expected content, it was excluded from further study. The number of original URLs and archived URLs that remained accessible over time was totaled and compared. RESULTS: A total of 121 articles were reviewed and 144 Internet references were found within 55 articles. Of the original URLs, 15% (21/144; 95% confidence interval [CI] 9% to 21%) were inaccessible at publication. During the 18-month observation period, there was no loss of archived URLs (apart from the 4% [5/123; 95% CI 2% to 9%] that could not be archived), whereas 35% (49/139) of the original URLs were lost (46% loss; 95% CI 33% to 61% by the Kaplan-Meier method; difference between curves P<.0001, log rank test). CONCLUSION: Archiving a referenced Web page at publication can help preserve the authors' expected information. PMID- 21251525 TI - Commentary: making a difference in emergency medical services. PMID- 21251526 TI - Personal experience and reflections on providing health care for detainees in support of Operation Iraqi Freedom. PMID- 21251527 TI - Change of shift. Surrogate child. PMID- 21251528 TI - Does "not different" equal "the same"? Answers to the september 2010 journal club questions. PMID- 21251529 TI - Woman with right-sided flank pain. Obstructing midureteral calculus with moderate hydronephrosis. PMID- 21251532 TI - Randomized controlled trials, antibiotics, and cutaneous abscesses: has lack of statistical power prevented recognition of an effective therapy? PMID- 21251530 TI - To treat or not to treat: adjunctive antibiotics for uncomplicated abscesses. PMID- 21251533 TI - Improving patient treatment capacity through placing physician orders at triage. PMID- 21251535 TI - Intoxication from smoking "spice". PMID- 21251536 TI - Quiz page February 2011: acute kidney injury, graft pain, and subtherapeutic levels of tacrolimus. PMID- 21251537 TI - The quality pyramid: the 2010 National Kidney Foundation presidential address. PMID- 21251538 TI - Drug-eluting coronary stents in patients with kidney disease. PMID- 21251539 TI - Hemoglobin variability as a predictor of mortality: What's a practitioner to do? PMID- 21251540 TI - Association of dietary patterns with albuminuria and kidney function decline in older white women: a subgroup analysis from the Nurses' Health Study. AB - BACKGROUND: Dietary patterns have been linked to such chronic diseases as cardiovascular disease, but sparse data currently are available for associations between dietary patterns and microalbuminuria or kidney function decline. STUDY DESIGN: Subgroup analysis from a prospective observational cohort study. SETTING & PARTICIPANTS: Female participants in the Nurses' Health Study who had dietary pattern data from food frequency questionnaires returned in 1984, 1986, 1990, 1994, and 1998 and urinary albumin-creatinine ratios from 2000 (n = 3,121); estimated glomerular filtration rate (eGFR) change between 1989 and 2000 was available for 3,071. PREDICTOR: Prudent (higher intake of fruits, vegetables, legumes, fish, poultry, and whole grains), Western (higher intake of red and processed meats, saturated fats, and sweets), and Dietary Approach to Stop Hypertension (DASH)-style dietary patterns (also greater intake of vegetables, fruits, and whole grains). OUTCOMES & MEASUREMENTS: Microalbuminuria (albumin creatinine ratio, 25-354 MUg/mg) in 2000 and change in kidney function using eGFR between 1989 and 2000. RESULTS: After multivariable adjustment, the highest quartile of Western pattern score compared with the lowest quartile was associated directly with microalbuminuria (OR, 2.17; 95% CI, 1.18-3.66; P for trend = 0.01) and rapid eGFR decline >=3 mL/min/1.73 m(2)/y (OR, 1.77; 95% CI, 1.03-3.03). Women in the top quartile of the DASH score had decreased risk of rapid eGFR decline (OR, 0.55; 95% CI, 0.38-0.80), but no association with microalbuminuria. These associations did not vary by diabetes status. The prudent dietary pattern was not associated with microalbuminuria or eGFR decline. LIMITATIONS: Study cohort included primarily older white women and generalizability of results would benefit from validation in nonwhites and men. CONCLUSIONS: A Western dietary pattern is associated with a significantly increased odds of microalbuminuria and rapid kidney function decrease, whereas a DASH-style dietary pattern may be protective against rapid eGFR decline. PMID- 21251541 TI - Facility-level interpatient hemoglobin variability in hemodialysis centers participating in the Dialysis Outcomes and Practice Patterns Study (DOPPS): Associations with mortality, patient characteristics, and facility practices. AB - BACKGROUND: Hemodialysis patients with larger hemoglobin level fluctuations have higher mortality rates. We describe facility-level interpatient hemoglobin variability, its relation to patient mortality, and factors associated with facility-level hemoglobin variability or achieving hemoglobin levels of 10.5-12.0 g/dL. Facility-level hemoglobin variability may reflect within-patient hemoglobin variability and facility-level anemia-control practices. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Data from the Dialysis Outcomes and Practice Patterns Study (DOPPS; 26,510 hemodialysis patients, 930 facilities, 12 countries, 1996-2008) and from the Centers for Medicare & Medicaid Services (CMS; 193,291 hemodialysis patients, 3,741 US facilities, 2002). PREDICTORS: Standard deviation (SD) in single-measurement hemoglobin levels in hemodialysis patients in facility cross-sections (facility-level hemoglobin SD); patient characteristics; facility practices. OUTCOMES: Patient-level mortality; additionally, facility practices correlated with facility-level hemoglobin SD or patient hemoglobin levels of 10.5-12.0 g/dL. RESULTS: Facility-level hemoglobin SD varied more than 5-fold across DOPPS facilities (range, 0.5-2.7 g/dL; mean, 1.3 g/dL) and by country (range, 1.1 in Japan-DOPPS [2005/2006] to 1.7 g/dL in Spain-DOPPS [1998/1999]), with substantial decreases seen in many countries from 1998 to 2007. Facility-level hemoglobin SD was related inversely to patient age, but was associated minimally with more than 30 other patient characteristics and facility mean hemoglobin levels. Several anemia management practices were associated strongly with facility-level hemoglobin SD and having a hemoglobin level of 10.5-12.0 g/dL. When examined in CMS data, facility-level hemoglobin SD was positively associated with within-patient hemoglobin SD during the prior 6 months. Patient mortality rates were higher with greater facility-level hemoglobin SD (DOPPS: HR, 1.08 per 0.5-g/dL greater facility-level hemoglobin SD [95% CI, 1.02-1.15; P = 0.006]; CMS: HR, 1.16 per 0.5-g/dL greater facility-level hemoglobin SD [95% CI, 1.11-1.21; P < 0. 001]). LIMITATIONS: Residual confounding. CONCLUSIONS: Facility-level hemoglobin SD was associated strongly and positively with patient mortality, not tightly linked to numerous patient characteristics, but related strongly to facility anemia management practices. Facility-level hemoglobin variability may be modifiable and its optimization may improve hemodialysis patient survival. PMID- 21251542 TI - Acute kidney injury due to osmotic nephrosis following intraoperative placement of an intraperitoneal antiadhesive barrier. AB - In recent years, a common strategy for the prevention of postsurgical intra abdominal adhesions has been intrasurgical placement of adhesion barriers into the peritoneal cavity. Osmotic agents, such as various polysaccharides, frequently are used as antiadhesive materials. The effects of these materials on kidney function have not yet been studied. We report a case of an individual with pre-existing chronic kidney disease who developed acute kidney injury after surgical placement of an antiadhesive barrier of macromolecular polysaccharides. A kidney biopsy, performed because of persistent kidney failure, showed tubular cell lesions compatible with osmotic nephrosis lesions. This case suggests that use of polysaccharide-containing antiadhesive barriers can induce severe kidney damage. Such barriers should be used with caution in patients with abnormal kidney function to prevent irreversible damage. PMID- 21251543 TI - Hypertension after kidney transplant. AB - Hypertension in kidney transplant recipients is a major "traditional" risk factor for atherosclerotic cardiovascular disease. Importantly, atherosclerotic cardiovascular disease is the leading cause of premature death and a major factor in death-censored graft failure in transplant recipients. The blood pressure achieved after transplant is related inversely to postoperative glomerular filtration rate (GFR), with many patients experiencing a significant improvement in blood pressure control with fewer medications within months of surgery. However, the benefits of improved GFR and fluid status may be affected by the immunosuppression regimen. Immunosuppressive agents affect hypertension through a variety of mechanisms, including catechol- and endothelin-induced vasoconstriction, abrogation of nitric oxide-induced vasodilatation, and sodium retention. Most notable is the role of calcineurin inhibitors in promoting hypertension, cyclosporine more so than tacrolimus. Additionally, the combination of calcineurin- and mammalian target of rapamycin (mTOR)-inhibitor therapy is synergistically nephrotoxic and promotes hypertension, whereas steroid withdrawal and minimization strategies seem to have little or no impact on hypertension. Other important causes of hypertension after transplant, beyond a progressive decrease in GFR, include transplant renal artery stenosis and sequelae of antibody-mediated rejection. Calcium channel blockers may be the most useful medication for mitigating calcineurin inhibitor-induced vasoconstriction, and use of such agents may be associated with improvements in GFR. Use of inhibitors of the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, remains an attractive strategy for many transplant recipients, although some recipients may have significant adverse effects associated with these medications, including decreased GFR, hyperkalemia, and anemia. In conclusion, hypertension control affects both patient and long term transplant survival, and its best management requires careful analysis of causes and close monitoring of therapies. PMID- 21251544 TI - Polyunsaturated fatty acids and kidney disease. PMID- 21251545 TI - Omega-3 polyunsaturated fatty acids and clinical trials. PMID- 21251547 TI - Effects of organ donor age on alloresponse. PMID- 21251548 TI - Altered bioavailability of tacrolimus following intravenous administration of tigecycline. PMID- 21251549 TI - Pseudohyperkalemia in chronic lymphocytic leukemia: phlebotomy sites and pneumatic tubes. PMID- 21251550 TI - A sweet cause of polyuria. PMID- 21251551 TI - Obstruction of a peritoneal dialysis catheter by an ovarian fimbria in a 2-year old girl. PMID- 21251552 TI - Sevelamer prescriptions after reporting of the Dialysis Clinical Outcomes Revisited (DCOR) trial findings: An analysis of 5,495 patients receiving maintenance dialysis in Ontario, Canada. PMID- 21251553 TI - Molecular analysis of Streptococcus pyogenes strains isolated from Chinese children with pharyngitis. AB - Streptococcus pyogenes is an important gram-positive bacterial pathogen that causes various human diseases, of which streptococcal pharyngitis is the most common. In this work, a total of 185 S. pyogenes isolated from Chinese children with pharyngitis was analyzed by superantigen (SAg) genes, emm genotyping, and pulsed-field gel electrophoresis (PFGE). Fifty-eight (31.4%) isolates were also typed by multilocus sequence typing (MLST). The results indicate that most of the emm1 isolates possessed speA (88.5%) and speJ (83.6%), and few isolates possessed speI gene (13.1%). In contrast, none of the emm12-type isolates possessed speJ; few isolates possessed speA (5.2%); and most of the isolates possessed speI (91.7%). PFGE analysis revealed 25 different clusters, and MLST was performed for 2 predominant emm-type isolates; emm12 isolates belonged to ST36 while emm1 isolates belonged to ST28. As far as this collection is concerned, emm1 and emm12 are the prevalent genotypes among S. pyogenes strains associated with children's pharyngitis in China. Most of the pharyngitis strains can be covered by a 26 valent vaccine. A strong correspondence is found only in the direction of emm type for both SAg profiles and PFGE types but not in the reverse direction. PMID- 21251554 TI - Phenotypic and molecular characterization of recent and archived Erysipelothrix spp. isolated from Brazilian swine. AB - One hundred fifty-one Erysipelothrix spp. isolates from Brazilian swine were characterized by serotyping, determination of antimicrobial susceptibility, amplified fragment length polymorphism (AFLP), and pulsed-field gel electrophoresis (PFGE). Among all isolates, 139 were classified in 18 different serotypes and serotype 2b was the most frequent. The susceptibility profiles of the isolates were very similar among each other, which did not permit subtyping Erysipelothrix spp. isolates by the antimicrobial susceptibility testing. Despite the fact that AFLP and PFGE provided the same discriminatory index (0.98), PFGE was more discriminatory than AFLP, given the types of groups it generates. Regardless the technique employed (AFLP or PFGE), no discrimination between recent and historical isolates was established, neither a fixed epidemiologic pattern for their grouping was observed. Nevertheless, AFLP could be an interesting alternative for discriminating the Erysipelothrix species, while PFGE could be an indication for discerning this bacterium according to the serotypes. PMID- 21251555 TI - UF-1000i flow cytometry is an effective screening method for urine specimens. AB - This study was undertaken to evaluate the UF-1000iTM (UF) flow cytometer to count urine constituents including bacteria. The objective was to screen urine samples and determine what white blood cell (WBC) and/or bacteria screening criteria would minimize the number of specimens cultured yet ensuring that all true positives were cultured. UF screening and culture on CHROMagarTM Orientation (CO) medium were performed on 2496 specimens. Various combinations of WBC/bacterial counts were assessed as screening criteria and correlated with significant growth on CO medium. A bacterial count of >=20 from UF gave an overall screening sensitivity of 92.6%, allowing 35% of specimens to be screened out and not cultured. The sensitivity was 99.2% and 85.0% for Gram-negative and Gram-positive organisms, respectively, using the same bacterial count. Our study indicated that UF was a simple, rapid, and reliable method for urine screening when the bacterial count of >=20 was used as the sole screening criterion. PMID- 21251556 TI - Development and clinical validation of a loop-mediated isothermal amplification method for the rapid detection of Neisseria meningitidis. AB - Loop-mediated isothermal amplification (LAMP) is an innovative technique that allows the rapid detection of target nucleic acid sequences under isothermal conditions without the need for complex instrumentation. The development, optimization, and clinical validation of a LAMP assay targeting the ctrA gene for the rapid detection of capsular Neisseria meningitidis were described. Highly specific detection of capsular N. meningitidis type strains and clinical isolates was demonstrated, with no cross-reactivity with other Neisseria spp. or with a comprehensive panel of other common human pathogens. The lower limit of detection was 6 ctrA gene copies detectable in 48 min, with positive reactions readily identifiable visually via a simple color change. Higher copy numbers could be detected in as little as 16 min. When applied to a total of 394 clinical specimens, the LAMP assay in comparison to a conventional TaqMan(r) based real time polymerase chain reaction system demonstrated a sensitivity of 100% and a specificity of 98.9% with a kappa coefficient of 0.942. The LAMP method represents a rapid, sensitive, and highly specific technique for the detection of N. meningitidis and has the potential to be used as a point-of-care molecular test and in resource-poor settings. PMID- 21251557 TI - Pneumocystis jirovecii testing by real-time polymerase chain reaction and direct examination among immunocompetent and immunosuppressed patient groups and correlation to disease specificity. AB - We used real-time polymerase chain reaction (PCR) targeting the cdc2 gene and direct fluorescent microscopy examination (DFME) to evaluate the prevalence of Pneumocystis jirovecii among immunocompetent patients without clinical pulmonary infection and immunosuppressed patients evaluated for opportunistic pulmonary infections. Among 102 bronchoalveolar lavage samples collected from immunocompetent patients without infection, none tested positive for P. jirovecii by either DFME or real-time PCR despite the presence of other comorbidities. Among patients with suspected pulmonary infection and tested with either assay, real-time PCR produced a higher number of positive results compared to DFME and increased P. jirovecii detection by 7% when added to DFME-negative samples. Real time PCR may have increased sensitivity for P. jirovecii detection over DFME and decrease the risk of sample contamination compared to conventional and nested PCR. The use of single-copy gene targets (e.g., cdc2) may lower the rate of "colonization" detection and confer a high predictive value for Pneumocystis pneumonia. PMID- 21251558 TI - Diagnostic accuracy of a 16S ribosomal DNA gene-based molecular technique (RT PCR, microarray, and sequencing) for bacterial meningitis, early-onset neonatal sepsis, and spontaneous bacterial peritonitis. AB - The diagnostic accuracy of a 16S ribosomal DNA (rDNA) gene-based molecular technique for bacterial meningitis (BM), early-onset neonatal sepsis (EONS), and spontaneous bacterial peritonitis (SBP) is evaluated. The molecular approach gave better results for BM diagnosis: sensitivity (S) was 90.6% compared to 78.1% for the bacterial culture. Percentages of cases correctly diagnosed (CCD) were 91.7% and 80.6%, respectively. For EONS diagnosis, S was 60.0% for the molecular approach and 70.0% for the bacterial culture; and CCD was 95.2% and 96.4%, respectively. For SPB diagnosis, the molecular approach gave notably poorer results than the bacterial cultures. S and CCD were 48.4% and 56.4% for the molecular approach and 80.6% and 89.1% for bacterial cultures. Nevertheless, bacterial DNA was detected in 53.3% of culture-negative samples. Accuracy of the 16S rDNA PCR approach differs depending on the sample, the microorganisms involved, the expected bacterial load, and the presence of bacterial DNA other than that from the pathogen implied in the infectious disease. PMID- 21251559 TI - Comparison of 2 highly automated nucleic acid extraction systems for quantitation of human cytomegalovirus in whole blood. AB - The aim of the study was to evaluate analytical performances of the COBAS Ampliprep and to compare extraction from whole blood on the COBAS Ampliprep and on the MagNA Pure instruments (Roche Diagnostics, Mannheim, Germany) for quantifying human cytomegalovirus (HCMV) DNA with real-time polymerase chain reaction (PCR). The limit of detection using the COBAS Ampliprep was 10 copies/run (150 copies/mL, i.e., 2.20 log(10) copies/mL). Quantitation of HCMV DNA was linear from 3.0 to 6.0 log(10) copies/mL. The intra-assay variations ranged from 11.1 % to 0.4 % and interassay variation was 11.3 %. A total of 107 samples were tested using both extraction systems. Only 3 samples gave discrepant results. Correlation between HCMV virus loads was good (r = 0.73) (P < 0.001). Mean virus load was lower (-0.49 log(10) copies/mL) with COBAS Ampliprep than with MagNA Pure extraction system. Both MagNA Pure and COBAS Ampliprep provide reliable and high-throughput platforms for real-time PCR HCMV quantitation of DNA extracted from whole blood. PMID- 21251560 TI - Analytical and clinical validation of novel real-time reverse transcriptase polymerase chain reaction assays for the clinical detection of swine-origin H1N1 influenza viruses. AB - During the early stages of the 2009/2010 swine-origin H1N1 influenza A (S-OIV H1N1 FluA) outbreak, the development and validation of sensitive and specific detection methods were a priority for rapid and accurate diagnosis. Between May and June 2009, 2 real-time reverse transcriptase-polymerase chain reaction (rRT PCR) assays targeting the hemagglutinin and neuraminidase genes of the S-OIV H1N1 FluA virus were developed. These assays are highly specific, showing no cross reactivity against a panel of respiratory viruses and can differentiate S-OIV H1N1 from seasonal FluA viruses. Analytical sensitivities of the 2 assays were found to be 10(-1) tissue culture infectious dose, 50%/ml. Clinical testing showed 99.2% sensitivity and 94.6-98.1% specificity. A large prospective analysis showed that 94.8-95.5% of S-OIV positive specimens were negative by seasonal H1/H3 subtyping. The large-scale validation data presented in this report indicate that these novel assays provide an accurate and efficient method for the rapid detection of S-OIV H1N1 FluA viruses. PMID- 21251561 TI - Prospective evaluation of nonstructural 1 enzyme-linked immunosorbent assay and rapid immunochromatographic tests to detect dengue virus in patients with acute febrile illness. AB - We prospectively evaluated the Bio-Rad nonstructural 1 (NS1) enzyme-linked immunosorbent assay (ELISA) and lateral flow immunochromatographic assay (LFIA) in comparison to an in-place reverse transcription-polymerase chain reaction for dengue diagnosis. Among 537 consecutive samples from patients with acute febrile disease, 264 (49.2%) tested positive in reverse transcription-polymerase chain reaction (RT-PCR), 156 (29.1%) in NS1-antigen (Ag) ELISA, and 125 (23.3%) in NS1 Ag LFIA. Compared to the RT-PCR status, the specificity was 100% for the NS1-Ag ELISA and LFIA, but their respective sensitivities were 61.2% [95% confidence interval (CI), 55.2-67.2] and 49.4% (95% CI, 43.2-55.6), with nadirs of 37.9% and 24.1% on day 6 of illness. The NS1-Ag ELISA and LFIA were positive, respectively, for 48.0% and 40.7% of the secondary infections versus 85.0% and 66.7% of the primary infections. For patients <5 years old, NS1-Ag ELISA and LFIA reached respective sensitivities of 100% and 90.5%. Reports of results of dengue NS1-Ag assays should specify that negativity does not preclude DENV infection, and require further investigations in the case of severe disease. PMID- 21251563 TI - Detection of Blastomyces dermatitidis antigen in patients with newly diagnosed blastomycosis. AB - Blastomycosis is a serious and potentially fatal infection, and diagnosis can be difficult at times. We evaluated the diagnostic utility of a commercially available assay for detection of Blastomyces dermatitidis antigen, recently modified to permit quantitation, in subjects with newly diagnosed blastomycosis. Twenty-three of 27 (85.1%) subjects had detectable B. dermatitidis antigenuria. In 2 of these 23, positive results were obtained after concentration of the urine specimen. Nine of 11 (81.8%) subjects had detectable B. dermatitidis antigen in serum, including 3 subjects with negative results before treatment of serum with ethylenediaminetetraacetic acid (EDTA) and positive results after EDTA treatment. B. dermatitidis antigen was not detected in specimens from 50 control subjects but was detected in 15 patients with histoplasmosis. B. dermatitidis antigen was detected in most of the patients with blastomycosis and can be a useful tool for timely diagnosis. PMID- 21251562 TI - Reverse transcription polymerase chain reaction and electrospray ionization mass spectrometry for identifying acute viral upper respiratory tract infections. AB - Diagnosis of respiratory viruses traditionally relies on culture or antigen detection. We aimed to demonstrate capacity of the reverse transcription polymerase chain reaction/electrospray ionization mass spectrometry (RT-PCR/ESI MS) platform to identify clinical relevant respiratory viruses in nasopharyngeal aspirate (NPA) samples and compare the diagnostic performance characteristics relative to conventional culture- and antigen-based methods. An RT-PCR/ESI-MS respiratory virus surveillance kit designed to detect respiratory syncytial virus, influenza A and B, parainfluenza types 1-4, Adenoviridae types A-F, Coronaviridae, human bocavirus, and human metapneumovirus was evaluated using both mock-ups and frozen archived NPA (N = 280), 95 of which were positive by clinical virology methods. RT-PCR/ESI-MS detected 74/95 (77.9%) known positive samples and identified an additional 13/185 (7%) from culture-negative samples. Viruses that are nondetectable with conventional methods were also identified. Viral load was semiquantifiable and ranged from 2400 to >320 000 copies/mL. Time to results was 8 h. RT-PCR/ESI-MS showed promise in rapid detection of respiratory viruses and merits further evaluation for use in clinical settings. PMID- 21251564 TI - Fusobacterium necrophorum endocarditis Case report and review of the literature. AB - Fusobacterium necrophorum is a gram-negative anaerobic bacillus that can cause serious systemic infections typically in previously healthy young adults. Lemierre's syndrome, also known as post-anginal sepsis or necrobacillosis, is the infection most usually associated with F. necrophorum. However, F. necrophorum is also a very rare cause of anaerobic endocarditis. Mortality and rates of thromboembolism are high with F. necrophorum endocarditis. In this article, we describe a case of F. necrophorum native valve infective endocarditis. The patient was treated with penicillin plus clindamycin followed by penicillin alone for 6 weeks resulting in complete resolution of infection. PMID- 21251565 TI - Kaposi sarcoma and paracoccidioidomycosis in the same fragment of oral mucosa biopsy: a rare association in human immunodeficiency virus-positive patient. A case report. AB - The immunossuppression caused by HIV infection makes the affected individuals more susceptible to some diseases including infections, neoplasms, or even the association between them. Kaposi sarcoma (KS) is the most common AIDS-related neoplasm, featured as an angioproliferative disorder. Its cause seems to be related to the human herpesvirus type 8 and it is usually associated with lower CD4+ T cell count. Oral involvement is frequent, presenting red to blue-purplish plaques, maculaes, and nodules. On the other hand, paracoccidioidomycosis (PCM) is a systemic mycosis, endemic in Latin America, caused by Paracoccidioides brasiliensis. This mycosis is not commonly related to human immunodeficiency virus (HIV) infection, although PCM can be present in immunosuppression cases. Oral lesions, as granulomatous ulcers, are often identified in seropositive patients with PCM. A rare case, in which a male HIV-positive patient presented simultaneously Kaposi sarcoma and PCM in the same fragment of oral mucosa biopsy, is described. To the best of our knowledge, this concomitant association had not been previously described. PMID- 21251566 TI - Nontypeable Streptococcus pneumoniae as an otopathogen. AB - Among 34 Streptococcus pneumoniae (Spn) sequential isolates from middle ear fluid, we found a case of a nontypeable S. pneumoniae (NT-Spn) in a child with acute otitis media (AOM). The strain was pneumolysin PCR positive and capsule gene PCR negative. Virulence of the NT-Spn was confirmed in a chinchilla model of AOM. PMID- 21251567 TI - Rapid and sensitive detection of human African trypanosomiasis by loop-mediated isothermal amplification combined with a lateral-flow dipstick. AB - A combined loop-mediated isothermal amplification lateral flow dipstick (LAMP LFD) format was evaluated in the detection of human infective trypanosome DNA from clinical samples. The LAMP-LFD showed analytical sensitivity equivalent to 0.01 tryps/mL, levels that were identical to using gel electrophoresis and SYBR Green I dye. The LAMP-LFD showed superior specificity to SYBR Green I when supernatant prepared from boiled human biological samples was used as template. These results indicate that the use of nonspecific DNA intercalators may produce false positives when partially processed templates are used. The LAMP-LFD format presented here is simple, rapid, and has future potential use in diagnosis of sleeping sickness. PMID- 21251568 TI - Disseminated intravascular coagulation as the laboratory hallmark of acute Q fever. AB - A 37-y-old white male presented with high fever, constitutional symptoms, mild meningeal and pulmonary involvement. Laboratory investigation revealed thrombocytopenia and excessive prolongation of coagulation times (International normalized ratio-INR- up to 6) requiring transfusion with 14 units of fresh frozen plasma. Serology established acute Coxiella burnetti infection. Patient recovered on levofloxacin. PMID- 21251569 TI - Molecular characterization of hospital-acquired methicillin-resistant Staphylococcus aureus strains in pediatric outbreaks using variable tandem repeat analysis with spa and ClfB typing. AB - To analyze 67 clinical methicillin-resistant Staphylococcus aureus (MRSA) isolated from pediatric hospital infections, we used multilocus variable-number tandem-repeat DNA sequence-based techniques, targeting the protein A polymorphic X region and the clumping factor B complete R domain. We define a "clfB similarity score" and then compare the double loci analysis of closely related MRSA isolates with pulsed-field gel electrophoresis (PFGE). We found an endemic clone (MLST-ST8, spa-t008, SCCmecIV, ClfB lineage 1) able to originate 3 possible outbreaks and a second clone (MLST-ST152, spa-t355, SCCmecV, ClfB lineage 4) responsible for limited cases of MRSA infections, indicating that the combination of spa and clfB-lineage typing is useful to trace MRSA pediatric outbreaks. PMID- 21251570 TI - Tn2008 is a major vehicle carrying bla(OXA-23) in Acinetobacter baumannii from China. AB - bla(OXA-23) and bla(OXA-66) were detected in 49 Acinetobacter baumannii isolates. These isolates were assigned to 7 subtypes by enterobacterial repetitive intergenic consensus polymerase chain reaction and 7 representative isolates were of ST92 or ST75. In most cases, the ISAba1-bla(OXA-23)-ATPaseDelta structure was identical to Tn2008. The 16-bp sequence at the left end of Tn2008 resembled the inverted repeat of ISAba1, suggesting that ISAba1 might have utilized an alternative boundary to mobilize bla(OXA-23). PMID- 21251571 TI - Tigecycline activity tested against multidrug-resistant Enterobacteriaceae and Acinetobacter spp. isolated in US medical centers (2005-2009). AB - We evaluated the activity of tigecycline against Enterobacteriaceae (9563 isolates) and Acinetobacter spp. (835) with various resistance phenotypes collected from 31 US medical centers in 2005-2009. The isolates were tested for susceptibility by the reference broth microdilution method against tigecycline and various comparators. Among Escherichia coli and Klebsiella spp., 6.8% and 15.4% exhibited an extended-spectrum beta-lactamase (ESBL) phenotype, respectively; and 22.2% of Enterobacter spp. strains were ceftazidime-resistant. Tigecycline was active against E. coli [minimum inhibitory concentration (MIC(50/90)), 0.12/0.25 MUg/mL; 100.0% susceptible] independent of ESBL phenotype or resistance to other antimicrobials. Among Klebsiella spp., 97.9% of ESBL producing Klebsiella spp. and 98.2% of imipenem-non-susceptible strains were susceptible to tigecycline (MIC(50/90), 0.5/1 MUg/mL for both subsets). Tigecycline was active against Enterobacter spp. (MIC(50/90), 0.25/1 MUg/mL; 98.4% susceptible), including ceftazidime-resistant strains (MIC(50/90), 0.5/2 MUg/mL; 97.1% susceptible). Tigecycline inhibited 94.4% of Acinetobacter spp. overall (MIC(50/90), 0.5/2 MUg/mL) and 86.2% of imipenem-non-susceptible (MIC(50/90), 1/4 MUg/mL) strains at <=2 MUg/mL. No trend toward decreased tigecycline activity overtime was observed for any of the organisms or resistant subsets during the study period. These results indicate that tigecycline has sustained potent in vitro activity and a broad spectrum against these clinically important Gram-negative pathogens causing infections in US medical centers, including multidrug-resistant organism subsets. PMID- 21251572 TI - bla(CTX-M)-carrying Escherichia coli of the O25b ST131 clonal group have emerged in China. AB - Six Escherichia coli O25b ST131 isolates, which were mostly hospital-acquired but from various types of samples, were found to carry bla(CTX-M-3a,)bla(CTX-M-14), or bla(CTX-M-65) genes, demonstrating that such isolates have emerged in China. The bla(CTX-M) genes were mostly carried by IncFII-related conjugative plasmids. All isolates were also resistant to ciprofloxacin and gentamicin and had substitutions in GyrA and carried an aac(3)-II gene. PMID- 21251573 TI - Co-emergence of linezolid-resistant Staphylococcus aureus and Enterococcus faecium in a patient with methicillin-resistant S. aureus pneumonic sepsis. PMID- 21251574 TI - Emergence of KPC-producing Klebsiella pneumoniae in Texas. PMID- 21251575 TI - New genetic environments of aac(6')-Ib-cr gene in a multiresistant Klebsiella oxytoca strain causing an outbreak in a pediatric intensive care unit. PMID- 21251576 TI - Images in cardiology. Heavy breathing hits the heart. PMID- 21251577 TI - Microribonucleic acids for prevention of plaque rupture and in-stent restenosis: "a finger in the dam". AB - Vascular smooth muscle cells (VSMCs), which make up the arterial medial layer, possess a phenotype switching capability. This modulation of VSMCs is important in the development of atherosclerotic vascular disease. It has been recognized that VSMCs may also have a stabilizing role in advanced atherosclerotic plaques. Moreover, reduction of the proliferative capacity of these cells may be of benefit in reducing neointimal hyperplasia following therapeutic percutaneous intervention. The biology of microribonucleic acids (miRNAs) and their ability to modify smooth muscle biology has recently emerged in a number of investigations. These studies elucidated the key role of miRNAs, miR-143 and miR-145, in particular, in the regulation of SMC homeostasis in vitro, in murine models of targeted gene deletion, and also in human vascular pathology. This review places this burgeoning knowledge within the wider context of atherosclerosis and restenosis and explores the therapeutic potential of miRNAs to change the fate of VSMCs within the plaque. PMID- 21251578 TI - Coronary responses and differential mechanisms of late stent thrombosis attributed to first-generation sirolimus- and paclitaxel-eluting stents. AB - OBJECTIVES: The purpose of this study was to assess the mechanism(s) of late stent thrombosis (LST) and vascular healing responses in first-generation polymeric drug-eluting stents (DES). BACKGROUND: Recent clinical trials have reported variations in late lumen loss between first-generation sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES). Little is known, however, about the vascular responses, time course of healing, and underlying mechanism(s) of complications of LST between platforms in human coronary implants. METHODS: The overall analysis included 174 cases (230 DES lesions) from the CVPath Institute's stent registry. Histomorphometry was performed on coronary stents from 127 patients (171 lesions) who died >= 30 days after receiving stent implants in which fibrin deposition, endothelial strut coverage, inflammatory response, and mechanism(s) of in-stent thrombosis were assessed. RESULTS: Both platforms demonstrated increased neointimal thickness over time where values were greater in PES (mean 0.13 mm; range 0.03 to 0.20 mm) than SES (mean 0.10 mm; range 0.04 to 0.15 mm; p = 0.04). The percentage of uncovered struts was similar between SES and PES including stents with LST (SES = 21% vs. PES = 27%; p = 0.47). The underlying mechanism(s) of LST, however, was strikingly different between platforms; localized strut hypersensitivity was exclusive to SES, whereas malapposition secondary to excessive fibrin deposition was the underlying cause in PES. Moreover, although both PES and SES showed nearly complete strut coverage after 12 months for on-label use, the majority of stents placed for off-label indications remained unhealed after 12 months in both types of DES. CONCLUSIONS: Differential mechanisms of LST involving either hypersensitivity or excessive fibrin were identified between first-generation DES in which overall stent healing was further delayed in DES placed for off-label indications. PMID- 21251579 TI - Cardiovascular mortality in chronic kidney disease patients undergoing percutaneous coronary intervention is mainly related to impaired P2Y12 inhibition by clopidogrel. AB - OBJECTIVES: We sought to determine whether low platelet response to the P2Y(12) receptor antagonist clopidogrel as assessed by vasodilator-stimulated phosphoprotein flow cytometry test (VASP-FCT) differentially affects outcomes in patients with or without chronic kidney disease (CKD) undergoing percutaneous coronary intervention (PCI). BACKGROUND: Although both CKD and impaired platelet responsiveness to clopidogrel are strong predictors of unfavorable outcome after PCI, the impact of their association is unknown. The platelet VASP-FCT assay is specific for the P2Y(12) ADP receptor pathway. In this test, platelet activation is expressed as the platelet reactivity index (PRI). METHODS: Four-hundred forty unselected patients (CKD: 126, estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m(2)), no-CKD: 314 eGFR >60 ml/min/1.73 m(2)) undergoing urgent (n = 336) or planned (n = 104) PCI were prospectively enrolled. In each subgroup, patients were classified as low-responders (LR: PRI >= 61%) or responders (R: PRI <61%) to clopidogrel. RESULTS: At a mean follow-up of 9 +/- 2 months, all-cause mortality, cardiac death, and possible stent thrombosis were higher in CKD than in no-CKD patients. Within the CKD group, the LR status was associated with higher rates of all-cause mortality (25.5% vs. 2.8%, p < 0.001), cardiac death (23.5% vs. 2.8%, p < 0.001), all stent thrombosis (19.6% vs. 2.7%, p = 0.003), and MACE (33.3% vs. 12.3%, p = 0.007). Conversely, in no-CKD patients, the LR status did not affect outcomes. Multivariate analysis identified Killip class >= 3, drug-eluting stent implantation, and the interaction between LR and CKD (hazard ratio: 11.96, 95% confidence interval: 1.22 to 116.82; p = 0.033) as independent predictors of cardiac death. CONCLUSIONS: In CKD patients, the presence of low platelet response to clopidogrel is associated with worse outcomes after PCI. PMID- 21251580 TI - Calcium-channel blockers do not alter the clinical efficacy of clopidogrel after myocardial infarction: a nationwide cohort study. AB - OBJECTIVES: The purpose of this study was to determine the risk of adverse cardiovascular events associated with concomitant use of clopidogrel and calcium channel blockers (CCBs) in patients with myocardial infarction (MI). BACKGROUND: CCBs inhibit a variety of cytochrome P-450 enzymes, some of which contribute to clopidogrel metabolic activation. This interaction may diminish the efficacy of clopidogrel. METHODS: All patients surviving 30 days after a first-time MI in the period 2000 to 2006 in Denmark were identified by individual-level linkage of nationwide administrative registers. The cohort was divided into patients treated with and without clopidogrel and followed for 1 year after discharge. The risk of a composite of cardiovascular death, MI, or stroke and the risk of the individual components of the composite end point and all-cause death associated with CCBs were analyzed with multivariable Cox proportional hazard models and in univariate propensity score-matched models. RESULTS: A total of 56,800 patients were included, of whom 24,923 were treated with clopidogrel and 13,380 with CCBs. In the Cox analyses, the risk of the composite end point associated with CCBs was increased in both patients treated and not treated with clopidogrel, with a hazard ratio of 1.15 (95% confidence interval [CI]: 1.07 to 1.24) and 1.05 (95% CI: 1.01 to 1.11), respectively. The increased risk was independent of clopidogrel use; the hazard rate ratio was 1.08 (95% CI: 0.99 to 1.18). Analyses of all additional adverse end points and propensity score-matched models provided similar results. CONCLUSIONS: The clinical efficacy of clopidogrel in patients with a recent MI is not modified by concomitant CCB treatment. This potential drug interaction is unlikely to have clinical significance. PMID- 21251581 TI - Worsening depressive symptoms are associated with adverse clinical outcomes in patients with heart failure. AB - OBJECTIVES: The purpose of this study was to assess the impact of changes in symptoms of depression over a 1-year period on subsequent clinical outcomes in heart failure (HF) patients. BACKGROUND: Emerging evidence shows that clinical depression, which is prevalent among patients with HF, is associated with a poor prognosis. However, it is uncertain how changes in depression symptoms over time may relate to clinical outcomes. METHODS: One-hundred forty-seven HF outpatients with ejection fraction of less than 40% were assessed for depressive symptoms using the Beck Depression Inventory (BDI) at baseline and again 1 year later. Cox proportional hazards regression analyses, controlling for established risk factors, were used to evaluate how changes in depressive symptoms were related to a combined primary end point of death or cardiovascular hospitalization over a median follow-up period of 5 years (with a range of 4 to 7 years and no losses to follow-up). RESULTS: The 1-year change in symptoms of depression, as indicated by higher BDI scores over a 1-year interval (1-point BDI change hazard ratio [HR]: 1.07, 95% confidence interval [CI]: 1.02 to 1.12, p = 0.007), was associated with death or cardiovascular hospitalization after controlling for baseline depression (baseline BDI HR: 1.1, 95% CI: 1.06 to 1.14, p < 0.001) and established risk factors, including HF cause, age, ejection fraction, plasma N-terminal pro-B-type natriuretic peptide level, and prior hospitalizations. CONCLUSIONS: Worsening symptoms of depression are associated with a poorer prognosis in HF patients. Routine assessment of symptoms of depression in HF patients may help to guide appropriate medical management of these patients who are at increased risk for adverse clinical outcomes. PMID- 21251582 TI - Assessment of depression in heart failure patients: what is the role for cardiology? PMID- 21251583 TI - Alcohol consumption and risk of atrial fibrillation: a meta-analysis. AB - OBJECTIVES: The purpose of this meta-analysis is to summarize the estimated risk of atrial fibrillation (AF) related to alcohol consumption. BACKGROUND: Results from observational studies examining the relationship between alcohol consumption and AF are inconsistent. METHODS: A systematic electronic search of Medline (January 1966 to December 2009) and Embase (January 1974 to December 2009) databases was conducted for studies using key words related to alcohol and AF. Studies were included if data on effect measures for AF associated with habitual alcohol intake were reported or could be calculated. The effect measures for AF for the highest versus lowest alcohol intake in individual studies were pooled with a variance-based method. Linear and spline regression analyses were conducted to quantify the relationship between alcohol intake and AF risk. RESULTS: Fourteen eligible studies were included in this meta-analysis. The pooled estimate of AF for the highest versus the lowest alcohol intake was 1.51 (95% confidence interval: 1.31 to 1.74). A linear regression model showed that the pooled estimate for an increment of 10 g per day alcohol intake was 1.08 (95% confidence interval: 1.05 to 1.10; R(2) = 0.43, p < 0.001). A spline regression model also indicated that the AF risk increased with increasing levels of alcohol consumption. CONCLUSIONS: Results of this meta-analysis suggest that not consuming alcohol is most favorable in terms of AF risk reduction. PMID- 21251584 TI - Dynamic 3-dimensional stress cardiac magnetic resonance perfusion imaging: detection of coronary artery disease and volumetry of myocardial hypoenhancement before and after coronary stenting. AB - OBJECTIVES: The aim of this study was to establish a new, dynamic 3-dimensional cardiac magnetic resonance (3D-CMR) perfusion scan technique exploiting data correlation in k-space and time with sensitivity-encoding and to determine its value for the detection of coronary artery disease (CAD) and volumetry of myocardial hypoenhancement (VOLUME(hypo)) before and after percutaneous coronary stenting. BACKGROUND: Dynamic 3D-CMR perfusion imaging might improve detection of myocardial perfusion deficits and could facilitate direct volumetry of myocardial hypoenhancement. METHODS: In 146 patients with known or suspected CAD, a 3.0-T CMR examination was performed including cine imaging, 3D-CMR perfusion under adenosine stress and at rest followed by delayed enhancement imaging. Quantitative invasive coronary angiography defined significant CAD (>= 50% luminal narrowing). Forty-eight patients underwent an identical repeat CMR examination after percutaneous stenting of at least 1 coronary lesion. The 3D-CMR perfusion scans were visually classified as pathologic if >= 1 segment showed an inducible perfusion deficit in the absence of delayed enhancement. The VOLUME(hypo) was measured by segmentation of the area of inducible hypoenhancement and normalized to left-ventricular myocardial volume (%VOLUME(hypo)). RESULTS: The 3D-CMR perfusion resulted in a sensitivity, specificity, and diagnostic accuracy of 91.7%, 74.3%, and 82.9%, respectively. Before and after coronary stenting, %VOLUME(hypo) averaged to 14.2 +/- 9.5% and 3.2 +/- 5.2%, respectively, with a relative VOLUME(hypo) reduction of 79.4 +/- 25.4%. Intrareader and inter-reader reproducibility of VOLUME(hypo) measurements was high (Lin's concordance correlation coefficient, 0.96 and 0.96, respectively). CONCLUSIONS: The 3D-CMR stress perfusion provided high image quality and high diagnostic accuracy for the detection of significant CAD. The VOLUME(hypo) measurements were highly reproducible and allowed for the assessment of the treatment effect achievable by percutaneous coronary stenting. PMID- 21251585 TI - Long-term cardiovascular mortality after radiotherapy for breast cancer. AB - OBJECTIVES: This study sought to investigate long-term cardiovascular mortality and its relationship to the use of radiotherapy for breast cancer. BACKGROUND: Cardiovascular diseases are among the main long-term complications of radiotherapy, but knowledge is limited regarding long-term risks because published studies have, on average, <20 years of follow-up. METHODS: A total of 4,456 women who survived at least 5 years after treatment of a breast cancer at the Institut Gustave Roussy between 1954 and 1984 were followed up for mortality until the end of 2003, for over 28 years on average. RESULTS: A total of 421 deaths due to cardiovascular diseases were observed, of which 236 were due to cardiac disease. Women who had received radiotherapy had a 1.76-fold (95% confidence interval [CI]: 1.34 to 2.31) higher risk of dying of cardiac disease and a 1.33-fold (95% CI: 0.99 to 1.80) higher risk of dying of vascular disease than those who had not received radiotherapy. Among women who had received radiotherapy, those who had been treated for a left-sided breast cancer had a 1.56-fold (95% CI: 1.27 to 1.90) higher risk of dying of cardiac disease than those treated for a right-sided breast cancer. This relative risk increased with time since the breast cancer diagnosis (p = 0.05). CONCLUSIONS: This study confirmed that radiotherapy, as delivered until the mid-1980s, increased the long term risk of dying of cardiovascular diseases. The long-term risk of dying of cardiac disease is a particular concern for women treated for a left-sided breast cancer with contemporary tangential breast or chest wall radiotherapy. This risk may increase with a longer follow-up, even after 20 years following radiotherapy. PMID- 21251586 TI - Radiation therapy for breast cancer: buyer beware. PMID- 21251587 TI - Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction. AB - OBJECTIVES: The purpose of this study was to test the safety and efficacy of direct injection of cardiosphere-derived cells (CDCs) and their 3-dimensional precursors, cardiospheres, for cellular cardiomyoplasty in a mini-pig model of heart failure after myocardial infarction. BACKGROUND: Intracoronary administration of CDCs has been demonstrated to reduce infarct size and improve hemodynamic indexes in the mini-pig model, but intramyocardial injection of CDCs or cardiospheres has not been assessed in large animals. METHODS: Autologous cardiospheres or CDCs grown from endomyocardial biopsies were injected through thoracotomy 4 weeks after anteroseptal myocardial infarction. Engraftment optimization with luciferase-labeled CDCs guided the choice of cell dose (0.5 million cells/site) and target tissue (20 peri-infarct sites). Pigs were randomly allocated to placebo (n = 11), cardiospheres (n = 8), or CDCs (n = 10). Functional data were acquired before injection and again 8 weeks later, after which organs were harvested for histopathology. RESULTS: Beyond the immediate perioperative period, all animals survived to protocol completion. Ejection fraction was equivalent at baseline, but at 8 weeks was higher than placebo in both of the cell-treated groups (placebo vs. CDC, p = 0.01; placebo vs. cardiospheres, p = 0.01). Echocardiographic and hemodynamic indexes of efficacy improved disproportionately with cardiospheres; likewise, adverse remodeling was more attenuated with cardiospheres than with CDCs. Provocative electrophysiologic testing showed no differences among groups, and no tumors were found. CONCLUSIONS: Dosage-optimized direct injection of cardiospheres or CDCs is safe and effective in preserving ventricular function in porcine ischemic cardiomyopathy. Although CDCs and cardiospheres have equivalent effects on left ventricular ejection fraction, cardiospheres are superior in improving hemodynamics and regional function, and in attenuating ventricular remodeling. PMID- 21251588 TI - Cell therapy for heart disease: where are we in 2011? PMID- 21251589 TI - Overexpression of CaMKIIdeltac in RyR2R4496C+/- knock-in mice leads to altered intracellular Ca2+ handling and increased mortality. AB - OBJECTIVES: We investigated whether increased Ca(2+)/calmodulin-dependent kinase II (CaMKII) activity aggravates defective excitation-contraction coupling and proarrhythmic activity in mice expressing R4496C mutated cardiac ryanodine receptors (RyR2). BACKGROUND: RyR2 dysfunction is associated with arrhythmic events in inherited and acquired cardiac disease. METHODS: CaMKIIdeltac transgenic mice were crossbred with RyR2(R4496C+/-) knock-in mice. RESULTS: Heart weight-to-body weight ratio in CaMKIIdeltac/RyR2(R4496C) and CaMKIIdeltac mice was similarly increased approximately 3-fold versus wild-type mice (p < 0.05). Echocardiographic data showed comparable cardiac dilation and impaired contractility in CaMKIIdeltac/RyR2(R4496C) and CaMKIIdeltac mice. Sarcoplasmic reticulum Ca(2+) content in isolated myocytes was decreased to a similar extent in CaMKIIdeltac/RyR2(R4496C) and CaMKIIdeltac mice. However, relaxation parameters and Ca(2+) decay at 1 Hz were prolonged significantly in CaMKIIdeltac mice versus CaMKIIdeltac/RyR2(R4496C) mice. Sarcoplasmic reticulum Ca(2+) spark frequency and characteristics indicated increased sarcoplasmic reticulum Ca(2+) leak in CaMKIIdeltac/RyR2(R4496C) versus CaMKIIdeltac myocytes (p < 0.05), most likely because of increased RyR2 phosphorylation. Delayed afterdepolarizations were significantly more frequent with increased amplitudes in CaMKIIdeltac/RyR2(R4496C) versus CaMKIIdeltac mice. Increased arrhythmias in vivo (67% vs. 25%; p < 0.05) may explain the increased mortality in CaMKIIdeltac/RyR2(R4496C) mice, which died prematurely with only 30% alive (vs. 60% for CaMKIIdeltac, p < 0.05) after 14 weeks. CONCLUSIONS: CaMKIIdeltac overexpression in RyR2(R4496C+/-) knock-in mice increases the propensity toward triggered arrhythmias, which may impair survival. CaMKII contributes to further destabilization of a mutated RyR2 receptor. PMID- 21251590 TI - Highlights of the year in JACC 2010. PMID- 21251591 TI - Images in cardiology. Chloroquine-induced transition from dilated to restrictive cardiomyopathy. PMID- 21251592 TI - Effect of granulocyte-colony stimulating factor on systolic function of oncology patients. PMID- 21251594 TI - TGFBR2 gene mutational spectrum in aortic pathology. PMID- 21251593 TI - Aortic elastic properties in patients with bicuspid aortic valve. PMID- 21251596 TI - Secondary traumatic stress in nurses: a systematic review. AB - BACKGROUND: Is there a "cost of caring" for health care providers of traumatized patients? OBJECTIVES: The aim of this study is to review the literature on secondary traumatic stress in nurses in order to answer the following questions: What studies have been conducted on secondary traumatic stress in nurses in all clinical specialties? What instruments were used to measure secondary traumatic stress in nurses and what psychometric properties were reported? DESIGN: A systematic review. DATA SOURCES: CINAHL, PubMed, and PsycINFO databases were searched for the years 1981 to the present. Keywords used in the database searches included secondary traumatic stress, compassion fatigue, vicarious traumatization, secondary trauma, PTSD, and nurses. REVIEW METHODS: Research studies were reviewed for the following inclusion criteria: the sample included nurses, the secondary traumatic stress symptoms were measured, and the language was English. RESULTS: Seven studies were found in which researchers examined secondary traumatic stress in nurses. The samples in five of these studies consisted of all nurses, whereas in the remaining two studies, nurses were included in the samples but the results were not specifically reported for the subgroup of nurses. Presence of secondary traumatic stress was reported in forensic nurses, emergency department nurses, oncology nurses, pediatric nurses, and hospice nurses. Three instruments were identified that measured secondary traumatic stress in practitioners who care for traumatized populations: Secondary Traumatic Stress Scale, Compassion Fatigue Self Test for Helpers, and the Compassion Fatigue Scale-Revised. CONCLUSIONS: Presence of secondary traumatic stress in nurses was reported in all of the studies included in this literature review. The use of small samples and a number of different instruments to measure secondary traumatic stress symptoms, however, hindered the ability to make comparisons across studies and to draw conclusions. None of the studies conducted to date have focused on secondary traumatic stress in psychiatric nurses. Suggestions for future research and clinical implications for what can be done to protect nurses from secondary traumatic stress are addressed. PMID- 21251597 TI - The Resilience Scale: psychometric properties and clinical applicability in older adults. AB - Resilience is described as the ability to achieve, retain, or regain a level of physical or emotional health after illness or loss. The Resilience Scale was specifically developed to measure personality characteristics of resilience in older adults. The purposes of this article are to provide additional support for the psychometric properties of the Resilience Scale and to consider the clinical applicability of this tool. Data from two independent samples of older adults were used. Most of the participants were Caucasian women, between 80 and 90 years of age, widowed, single, or divorced, and they had on average approximately three comorbid medical problems. Psychometric testing included confirmatory factor analysis, Rasch analysis, and test criterion relationships for validity testing, and internal consistency and estimates of R(2) for reliability testing. Although there was some support for the reliability and validity of the 25-item Resilience Scale, there was a poor fit of Items 3-6, 9, 11, 20, and 22 in the 25-item measure. Overall, participants in both samples scored high in resilience, and item mapping indicated that additional items are needed on the measure to differentiate those who are particularly resilient. Although revisions are recommended, use of the Resilience Scale can help identify older adults low in resilience and expose these individuals to interventions to improve resilience and facilitate successful aging. PMID- 21251598 TI - Regulatory oversight: do psychiatric patients have the right to refuse active treatment? AB - A psychiatric patient's right to refuse active treatment is currently under question due to the current regulatory requirements from the Centers for Medicare and Medicaid Services. Legislation that was originally intended to promote active treatment is now rigidly interpreted, and today's acute care psychiatric hospitals are forced to override their patient's autonomous decisions in fear of legislation penalties. This article will briefly discuss the moral complexities faced by psychiatric nurses when attempting to balance their patients' right to autonomy versus the regulatory demands of the federal government. PMID- 21251600 TI - Depressive symptoms among HIV-positive postpartum women in Thailand. AB - Depressive symptoms have been linked to faster progression to AIDS in HIV positive individuals. The purpose of this correlational, cross-sectional study was to examine the prevalence and predictors of depressive symptoms among postpartum women in Thailand who are HIV-positive. Data were collected at postpartum outpatient units in four hospitals in Thailand from June 2005 to December 2007. Eighty-five HIV-positive postpartum women completed questionnaires on depressive symptoms, self-esteem, emotional support, physical symptoms, infant health status, and demographics. Results showed that 74.1% of the participants reported depressive symptoms. Self-esteem, infant health status, and education were negatively associated with depressive symptoms. Because of the high rates of depression in our study, all HIV-positive postpartum women in Thailand should be screened for depressive symptoms. PMID- 21251599 TI - Symptom management of affective and cognitive disturbance with a group of cancer survivors. AB - Cancer survivors 65 years of age and older experience treatment-induced memory impairments. However, clinicians do not intervene for these cognitive problems. This article describes the findings from a pilot study of a memory versus health training intervention and its adaptability for cancer survivors for symptom management. DESIGN AND METHODS: A convenience sample of older adults was enrolled in a longitudinal study of a memory and health training intervention and tested on five occasions for 2 years postintervention. The memory training was designed to increase cognitive performance, reduce anxiety, decrease negative attributions, promote health, and increase memory self-efficacy. In this analysis, we included change over time for the first four of the five data collection points. We calculated means and standard deviations on the memory measures for cancer survivors in the intervention (n = 8) and comparison (n = 14) groups. The analysis consisted of a mixed design analysis of variance comparing the two intervention groups across four periods for 12 months. RESULTS: The typical cancer survivor in the sample was a 74-year-old Caucasian female; 14% were minorities. Because of the small sample, some of the effects were not statistically significant. Moderate to large effects were revealed in everyday and verbal memory performance scores, memory self-efficacy, strategy use, and memory complaints. There were also moderate effects for group-by-time interactions on the visual memory performance measure, the memory self-efficacy measure, the depression, the trait anxiety measure, and the complaints subscale. The memory intervention group tended to improve more than the health training group, although this was not always consistent. The results suggested that the participants benefited from the memory training intervention. IMPLICATIONS: Clinicians are often at a loss on how to intervene with cancer survivors who are experiencing cognitive problems following chemotherapy treatment. Evidenced-based interventions for this aspect of symptom management are almost nonexistent. The Cognitive Behavioral Model of Everyday Memory (CBMEM), derived from Self-Efficacy theory provides an evidence-based intervention for symptom management. PMID- 21251601 TI - Smoking cessation in women with severe mental illness: exploring the role of exercise as an adjunct treatment. AB - OBJECTIVE: The aim of this study was to investigate the potential role of exercise in smoking cessation in women with severe mental illness (SMI). METHODS: Semistructured interviews with 12 women diagnosed with SMI receiving smoking cessation treatment were conducted. RESULTS: Participants perceived three roles for exercise in assisting smoking cessation--addressing fears with preexisting chronic health conditions, emotion management and distraction, and weight management. Most participants identified health care providers (HCPs) as needing to play a supportive role in integrating exercise into smoking cessation attempts. CONCLUSION: Findings support a potential role for exercise in facilitating smoking cessation among women with SMI. PRACTICE IMPLICATIONS: HCPs should consider developing referral links with exercise specialists to facilitate smoking cessation in women with SMI. PMID- 21251602 TI - Reliability and validity of the Chinese Version of the Mood Disorder Questionnaire. AB - The purpose of this study was to examine the reliability, validity, sensitivity, and specificity of the Chinese Version of the Mood Disorder Questionnaire (MDQ C). A total of 170 patients were administered the Mini International Neuropsychological Interview and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision as criterion standard by on-site psychiatrists. The Cronbach's alpha, test-retest reliability, and the content validity index of the MDQ-C were .83, .76, and .80, respectively. Factor analysis revealed that two factors, elevated mood overactivity and irritable behavior, explained 40.89% of the variance. On the basis of the sensitivity and specificity results, the optimal cutoff point was 6. The MDQ-C is an effective short and comprehensive tool with robust psychometric properties for diagnosis of bipolar disorders, specifically for patients with bipolar I. PMID- 21251603 TI - Factors associated with glycemic control and diabetes self-care among outpatients with schizophrenia and type 2 diabetes. AB - We investigated the influence of the severity of schizophrenia on diabetes self care and glycemic control among outpatients with schizophrenia and diabetes. We conducted interviews with 38 participants and reviewed their clinical charts. The mean hemoglobin A1c (HbA1c) level in the full study population was 7.65%. There was no difference in the HbA1c level between two groups of subjects classified by the severity of schizophrenia. Some diabetes self-care indicators were significantly lower in patients with high Brief Psychiatric Rating Scale scores (P < .05). Although psychotic symptoms do not appear to affect glycemic control, psychotic symptoms might affect diabetes self-care behaviors in people with schizophrenia. PMID- 21251604 TI - Refining story inquiry as a method for research. PMID- 21251605 TI - HIV never ceases to surprise: Innovative methods in the quest for a cure. PMID- 21251607 TI - Polarization of tumor-associated macrophages: a novel strategy for vascular normalization and antitumor immunity. AB - Vascular normalization is an emerging concept in cancer treatment. In this issue of Cancer Cell, Rolny et al. show that histidine-rich glycoprotein normalizes tumor vessels and promotes antitumor immunity by polarizing tumor-associated macrophages, leading to decreased tumor growth and metastasis. Placental Growth Factor deletion in macrophages phenocopies many of these effects. PMID- 21251608 TI - Hard times for oncogenic BRAF-expressing melanoma cells. AB - In this issue of Cancer Cell, Arozarena et al. describe that the oncogenic BRAF Val600Glu mutant, which occurs in about half of melanomas, downregulates the cGMP hydrolysing phosphodiesterase PDE5A in melanoma cells through the ERK-MAPK cascade coupled to the POU-domain transcription factor BRN2, thereby increasing intracellular cGMP levels and promoting invasiveness. PMID- 21251609 TI - Keratin 15-positive stem cells give rise to basal cell carcinomas in irradiated Ptch1(+/-) mice. AB - The cell of origin for basal cell carcinoma (BCC) remains controversial. In this issue of Cancer Cell, Wang et al. provide strong evidence that BCC arise from hair follicle stem cells. PMID- 21251610 TI - Metastatic colon cancer cells negotiate the intravasation Notch. AB - In this issue of Cancer Cell, Sonoshita et al. report that Aes/Grg5 prevents metastasis of colorectal cancer cells by sequestering and inactivating Notch transcriptional effectors in distinct nuclear foci. Loss of Aes/Grg5 in invasive cancer cells where Notch is activated by stroma-expressed ligands promotes invasion, transendothelial migration, intravasation, and metastasis. PMID- 21251611 TI - Human acute myelogenous leukemia stem cells revisited: there's more than meets the eye. AB - In this issue of Cancer Cell, Goardon et al. revise earlier conclusions regarding acute myelogenous leukemia (AML) stem cells by demonstrating that in the majority of patients, they reside in two hierarchically related populations most similar to normal hematopoietic progenitors. These findings have implications for therapeutic targeting of these cells. PMID- 21251612 TI - Mutant BRAF melanomas--dependence and resistance. AB - RAF inhibitors have the unique property of transactivating RAS-dependent RAF dimers in most cells but inhibit RAF/MEK/ERK signaling in cells expressing mutant BRAF, in which RAS activity is too low to support this process. These drugs thus selectively inhibit ERK signaling in tumors with BRAF mutation. RAF inhibitors have remarkable clinical activity in melanomas with BRAFV600E mutations; however, resistance invariably develops. Three recent papers reveal that acquired resistance may be due to mechanisms that cause ERK signaling to become insensitive to RAF inhibitors, or that reduce the dependence of the tumor on ERK signaling through activation of other pathways. PMID- 21251613 TI - Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha ketoglutarate-dependent dioxygenases. AB - IDH1 and IDH2 mutations occur frequently in gliomas and acute myeloid leukemia, leading to simultaneous loss and gain of activities in the production of alpha ketoglutarate (alpha-KG) and 2-hydroxyglutarate (2-HG), respectively. Here we demonstrate that 2-HG is a competitive inhibitor of multiple alpha-KG-dependent dioxygenases, including histone demethylases and the TET family of 5 methlycytosine (5mC) hydroxylases. 2-HG occupies the same space as alpha-KG does in the active site of histone demethylases. Ectopic expression of tumor-derived IDH1 and IDH2 mutants inhibits histone demethylation and 5mC hydroxylation. In glioma, IDH1 mutations are associated with increased histone methylation and decreased 5-hydroxylmethylcytosine (5hmC). Hence, tumor-derived IDH1 and IDH2 mutations reduce alpha-KG and accumulate an alpha-KG antagonist, 2-HG, leading to genome-wide histone and DNA methylation alterations. PMID- 21251614 TI - Endogenous T cell responses to antigens expressed in lung adenocarcinomas delay malignant tumor progression. AB - Neoantigens derived from somatic mutations in tumors may provide a critical link between the adaptive immune system and cancer. Here, we describe a system to introduce exogenous antigens into genetically engineered mouse lung cancers to mimic tumor neoantigens. We show that endogenous T cells respond to and infiltrate tumors, significantly delaying malignant progression. Despite continued antigen expression, T cell infiltration does not persist and tumors ultimately escape immune attack. Transplantation of cell lines derived from these lung tumors or prophylactic vaccination against the autochthonous tumors, however, results in rapid tumor eradication or selection of tumors that lose antigen expression. These results provide insight into the dynamic nature of the immune response to naturally arising tumors. PMID- 21251615 TI - An Fcgamma receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells. AB - Antibodies to cell-surface antigens trigger activatory Fcgamma receptor (FcgammaR)-mediated retrograde signals in leukocytes to control immune effector functions. Here, we uncover an FcgammaR mechanism that drives antibody-dependent forward signaling in target cells. Agonistic antibodies to death receptor 5 (DR5) induce cancer-cell apoptosis and are in clinical trials; however, their mechanism of action in vivo is not fully defined. Interaction of the DR5-agonistic antibody drozitumab with leukocyte FcgammaRs promoted DR5-mediated tumor-cell apoptosis. Whereas the anti-CD20 antibody rituximab required activatory FcgammaRs for tumoricidal function, drozitumab was effective in the context of either activatory or inhibitory FcgammaRs. A CD40-agonistic antibody required similar FcgammaR interactions to stimulate nuclear factor-kappaB activity in B cells. Thus, FcgammaRs can drive antibody-mediated receptor signaling in target cells. PMID- 21251616 TI - Suppression of colon cancer metastasis by Aes through inhibition of Notch signaling. AB - Metastasis is responsible for most cancer deaths. Here, we show that Aes (or Grg5) gene functions as an endogenous metastasis suppressor. Expression of Aes was decreased in liver metastases compared with primary colon tumors in both mice and humans. Aes inhibited Notch signaling by converting active Rbpj transcription complexes into repression complexes on insoluble nuclear matrix. In tumor cells, Notch signaling was triggered by ligands on adjoining blood vessels, and stimulated transendothelial migration. Genetic depletion of Aes in Apc(Delta716) intestinal polyposis mice caused marked tumor invasion and intravasation that were suppressed by Notch signaling inhibition. These results suggest that inhibition of Notch signaling can be a promising strategy for prevention and treatment of colon cancer metastasis. PMID- 21251617 TI - Coexistence of LMPP-like and GMP-like leukemia stem cells in acute myeloid leukemia. AB - The relationships between normal and leukemic stem/progenitor cells are unclear. We show that in ~80% of primary human CD34+ acute myeloid leukemia (AML), two expanded populations with hemopoietic progenitor immunophenotype coexist in most patients. Both populations have leukemic stem cell (LSC) activity and are hierarchically ordered; one LSC population gives rise to the other. Global gene expression profiling shows the LSC populations are molecularly distinct and resemble normal progenitors but not stem cells. The more mature LSC population most closely mirrors normal granulocyte-macrophage progenitors (GMP) and the immature LSC population a previously uncharacterized progenitor functionally similar to lymphoid-primed multipotential progenitors (LMPPs). This suggests that in most cases primary CD34+ AML is a progenitor disease where LSCs acquire abnormal self-renewal potential. PMID- 21251618 TI - Point: Vaginal brachytherapy should be a standard adjuvant treatment for intermediate-risk endometrial cancer. PMID- 21251619 TI - Counterpoint: The role of adjuvant radiation in endometrial cancer. Inside, outside, or not at all? PMID- 21251622 TI - One-step customized transurethral resection of the prostate and permanent implant brachytherapy for selected prostate cancer patients: technically feasible but too toxic. AB - INTRODUCTION: Patients with prominent median lobe hyperplasia and/or high International Prostate Symptom Score (IPSS) are often contraindicated for prostate brachytherapy, mainly because of the risk of post-implant urinary retention. We evaluated an approach combining in the same operative step a limited transurethral resection (TURP) of the median lobe, immediately followed by permanent implant-free seed brachytherapy. METHODS AND MATERIALS: From January 2007 to November 2008, 22 patients underwent a customized limited TURP of their median lobe immediately before brachytherapy. All patients fulfilled our criteria for permanent implant brachytherapy, but presented with a more or less prominent median lobe and/or a high IPSS. RESULTS: The procedure appeared to be technically feasible, with only 0.3% of migrating seeds, a mean post-implant D90 of 173.4 Gy and a mean post-implant V100 of 96.6%. However, 5 patients (23%) experienced a urinary retention, with two patients having to undergo a complementary post implant TURP. Moreover, urinary toxicity was more pronounced than in our current experience, with high IPSS at 2 months (mean 19.2) and 6 months (mean 15.8). CONCLUSION: Although technically feasible, with relatively few migrating seeds and satisfactory post-implant dosimetric parameters, one-step TURP and brachytherapy was found to be poorly tolerated, with higher than usual urinary retention and urinary toxicity rates. Considering those results, our group is presently evaluating a two-step procedure, with a customized TURP followed after 4-6 months by brachytherapy. PMID- 21251623 TI - Percutaneous transcatheter mitral valve repair: a classification of the technology. AB - Surgical treatment of mitral regurgitation (MR) has evolved from mitral valve replacement (MVR) to repair (MVR(e)), because MVR(e) produces superior long-term outcomes. In addition, MVR(e) can be achieved through minimally invasive approaches. This desire for less invasive approaches coupled with the fact that a significant proportion of patients--especially elderly persons or those with significant comorbidities or severe left ventricular (LV) dysfunction, are not referred for surgery, has driven the field of percutaneous MVR(e). Various technologies have emerged and are at different stages of investigation. A classification of percutaneous MVR(e) technologies on the basis of functional anatomy is proposed that groups the devices into those targeting the leaflets (percutaneous leaflet plication, percutaneous leaflet coaptation, percutaneous leaflet ablation), the annulus (indirect: coronary sinus approach or an asymmetrical approach; direct: true percutaneous or a hybrid approach), the chordae (percutaneous chordal implantation), or the LV (percutaneous LV remodeling). The percutaneous edge-to-edge repair technology has been shown to be noninferior to open repair in a randomized clinical trial (EVEREST II [Endovascular Valve Edge-to-Edge REpair Study]). Several other technologies employing the concepts of direct and indirect annuloplasty and LV remodeling have achieved first-in-man results. Most likely a combination of these technologies will be required for satisfactory MVR(e). However, MVR(e) is not possible for many patients, and MVR will be required. Surgical MVR is the standard of care in such patients, although percutaneous options are under development. PMID- 21251624 TI - Four-year follow-up of TYPHOON (trial to assess the use of the CYPHer sirolimus eluting coronary stent in acute myocardial infarction treated with BallOON angioplasty). AB - OBJECTIVES: The aim of this study was to assess the long-term safety and efficacy of the CYPHER (Cordis, Johnson and Johnson, Bridgewater, New Jersey) sirolimus eluting coronary stent (SES) in percutaneous coronary intervention (PCI) for ST segment elevation myocardial infarction (STEMI). BACKGROUND: Concern over the safety of drug-eluting stents implanted during PCI for STEMI remains, and long term follow-up from randomized trials are necessary. TYPHOON (Trial to assess the use of the cYPHer sirolimus-eluting stent in acute myocardial infarction treated with ballOON angioplasty) randomized 712 patients with STEMI treated by primary PCI to receive either SES (n = 355) or bare-metal stents (BMS) (n = 357). The primary end point, target vessel failure at 1 year, was significantly lower in the SES group than in the BMS group (7.3% vs. 14.3%, p = 0.004) with no increase in adverse events. METHODS: A 4-year follow-up was performed. Complete data were available in 501 patients (70%), and the survival status is known in 580 patients (81%). RESULTS: Freedom from target lesion revascularization (TLR) at 4 years was significantly better in the SES group (92.4% vs. 85.1%; p = 0.002); there were no significant differences in freedom from cardiac death (97.6% and 95.9%; p = 0.37) or freedom from repeat myocardial infarction (94.8% and 95.6%; p = 0.85) between the SES and BMS groups. No difference in definite/probable stent thrombosis was noted at 4 years (SES: 4.4%, BMS: 4.8%, p = 0.83). In the 580 patients with known survival status at 4 years, the all-cause death rate was 5.8% in the SES and 7.0% in the BMS group (p = 0.61). CONCLUSIONS: In the 70% of patients with complete follow-up at 4 years, SES demonstrated sustained efficacy to reduce TLR with no difference in death, repeat myocardial infarction or stent thrombosis. (The Study to Assess AMI Treated With Balloon Angioplasty [TYPHOON]; NCT00232830). PMID- 21251625 TI - 5-year follow-up after primary percutaneous coronary intervention with a paclitaxel-eluting stent versus a bare-metal stent in acute ST-segment elevation myocardial infarction: a follow-up study of the PASSION (Paclitaxel-Eluting Versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation) trial. AB - OBJECTIVES: The purpose of this study was to evaluate the long-term outcomes of the PASSION (Paclitaxel-Eluting Versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation) trial. BACKGROUND: In primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction (STEMI), the use of drug-eluting stents (DES) is still controversial. Several randomized controlled trials of DES, compared with bare-metal stents (BMS), with short-term follow-up showed a reduction in target lesion revascularization (TLR), but no differences in rates of cardiac death or recurrent myocardial infarction. Moreover, the occurrence of (very) late stent thrombosis (ST) continues to be of major concern, and, therefore, long-term follow-up results are needed. METHODS: We randomly assigned 619 patients presenting with STEMI to a paclitaxel-eluting stent (PES) or the similar BMS. The primary end point was the composite of cardiac death, recurrent myocardial infarction, or TLR. We performed clinical follow-up at 5 years. RESULTS: At 5 years, the occurrence of the composite of cardiac death, recurrent myocardial infarction, or TLR was comparable at 18.6% versus 21.8% in PES and BMS, respectively (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.58 to 1.18, p = 0.28). The incidence of definite or probable ST was 12 (4.2%) in the PES group and 10 (3.4%) in the BMS group (HR: 1.19, 95% CI: 0.51 to 276, p = 0.68). CONCLUSIONS: In the present analysis of PES compared with BMS in primary percutaneous coronary intervention for STEMI, no significant difference in major adverse cardiac events was observed. In addition, no difference in the incidence of definite or probable ST was seen, although very late ST was almost exclusively seen after the use of PES. (Paclitaxel-Eluting Versus Conventional Stent in Myocardial Infarction with ST-Segment Elevation [PASSION]; ISRCTN65027270). PMID- 21251626 TI - Very late stent thrombosis after primary percutaneous coronary intervention with bare-metal and drug-eluting stents for ST-segment elevation myocardial infarction: a 15-year single-center experience. AB - OBJECTIVES: The purpose of this study was to assess the frequency of very late stent thrombosis (VLST) after stenting with bare-metal stents (BMS) and drug eluting stents (DES) for ST-segment elevation myocardial infarction (STEMI). BACKGROUND: Stent thrombosis occurs more frequently after stenting for STEMI than after elective stenting, but there are little data regarding VLST. METHODS: Consecutive patients (n = 1,463) who underwent stenting for STEMI were prospectively enrolled in our database. BMS were implanted exclusively from 1995 to 2002, and DES and BMS were implanted from 2003 to 2009. Follow-up was obtained at 1 to 15 years. RESULTS: BMS patients (n = 1,095) were older and had more shock, whereas DES patients (n = 368) had more diabetes and smaller vessels. Stent thrombosis occurred in 107 patients, of which 42 were VLST (>1 year). Stent thrombosis continued to increase to at least 11 years with BMS and to at least 4.5 years with DES. Stent thrombosis rates with BMS versus DES were similar at 1 year (5.1% and 4.0%, respectively) but increased more with DES after the first year (1.9%/year vs. 0.6%/year, respectively). Landmark analysis (>1 year) found DES had a higher frequency of VLST (p < 0.001) and reinfarction (p = 0.003). DES was the only significant independent predictor of VLST (hazard ratio: 3.79, 95% confidence interval: 1.64 to 8.79, p = 0.002). CONCLUSIONS: VLST after primary PCI for STEMI occurs with relatively high frequency to at least 11 years with BMS and to at least 4.5 years with DES. Very late stent thrombosis and reinfarction (>1 year) were more frequent with DES. New strategies are needed to manage this problem. PMID- 21251627 TI - Long-term follow-up of drug-eluting stents placed in the setting of ST-segment elevation myocardial infarction. PMID- 21251628 TI - Survival of patients undergoing rescue percutaneous coronary intervention: development and validation of a predictive tool. AB - OBJECTIVES: This study sought to develop a tool for predicting an individual's risk of mortality following rescue percutaneous coronary intervention (PCI). BACKGROUND: Although fibrinolytic therapy is appropriate and improves survival for certain ST-segment elevation myocardial infarction patients, a substantial proportion suffer ongoing myocardial ischemia, a class I indication for emergent percutaneous coronary intervention (rescue PCI). METHODS: Using the National Cardiovascular Data Registry (NCDR), rescue PCI was defined as nonelective PCI following failed fibrinolysis in patients with continuing or recurrent myocardial ischemia. Multivariable logistic regression was used to determine mortality predictors and the C-statistic for model discrimination. The NCDR-RESCUE (Real World Estimator of Survival in Catheterized STEMI Patients Following Unsuccessful Earlier Fibrinolysis) score was developed using a shortened list of 6 pre angiographic variables and 70% of the cohort; performance was subsequently validated against the remaining 30%. RESULTS: Among 166,516 PCI procedures on patients with an admission diagnosis of ST-segment elevation myocardial infarction, 8,007 (4.8%) represented rescue PCI. In-hospital mortality occurred in 464 (5.8%). Factors in the final model were age, glomerular filtration rate, history of congestive heart failure, insulin-treated diabetes, cardiogenic shock, and salvage status. The NCDR-RESCUE score effectively segregated individuals into 6 clinically meaningful risk categories, with 0.4% (0.0% to 1.3%), 1.6% (0.9% to 2.4%), 7.6% (5.3% to10.4%), 27.5% (20.7% to 35.1%), 64.2% (49.8% to 76.9%), or 100% (59.0% to 100.0%) risk, respectively, of in-hospital mortality (mean +/- 95% confidence interval, C-index = 0.88, Hosmer-Lemeshow p = 0.898). CONCLUSIONS: In hospital mortality risk among individuals undergoing rescue PCI varies from minimal to extreme and can be easily calculated using the NCDR-RESCUE score. This information can be of value in counseling patients, families, and referring caregivers. PMID- 21251629 TI - Persistent coronary no flow after wire insertion is an early and readily available mortality risk factor despite successful mechanical intervention in acute myocardial infarction: a pooled analysis from the STRATEGY (Single High Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) trials. AB - OBJECTIVES: These studies sought to investigate the impact on mortality of coronary flow after passage of the wire through the culprit vessel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing mechanical reperfusion. BACKGROUND: Reduced spontaneous coronary flow before percutaneous coronary intervention influences mortality in patients with STEMI. Response to vessel wiring in patients with an occluded coronary artery before intervention might further discriminate outcomes irrespective of pre- and post-intervention coronary flow. METHODS: Data from the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare-Metal Stent in Acute Myocardial Infarction Study) trials were pooled: of 919 index procedures, 902 films (98%) were technically adequate for core laboratory TIMI (Thrombolysis In Myocardial Infarction) flow determination. RESULTS: TIMI flow grade 0 was present before percutaneous coronary intervention in 59% of infarct vessels, TIMI flow grade 1 to 2 was found in 21%, whereas the remainder of infarct arteries presented with TIMI flow grade 3. In 49% of patients who showed persistent TIMI flow grade 0 after wire insertion (AWI), mortality was higher at 30 days (5.3%) and 1 year (9.4%) compared with patients in whom TIMI flow grade before percutaneous coronary intervention was either >0 (0.8%; p < 0.003 and 3.6%, p < 0.008) or improved from 0 AWI (1.5%, p < 0.04 and 3.6%, p < 0.02). After correcting for multiple imbalances, including baseline and final flow, persistent TIMI flow grade 0 AWI remained associated at 30 days to 2-fold (risk ratio [RR]: 2.1, 95% confidence interval [CI]: 1.08 to 5.00; p = 0.038) and at 1 year to almost 3-fold increases of mortality (RR: 2.7, 95% CI: 1.3 to 5.6; p = 0.008). CONCLUSIONS: STEMI patients displaying persistent no-flow AWI have a lower survival rate despite an apparently successful mechanical intervention. As an early marker for high residual mortality risk, persistent no-flow AWI may qualify STEMI patients for dedicated pharmacomechanical treatment strategies. PMID- 21251630 TI - Does angiographic response to wiring of totally occluded vessels predict outcomes in ST-segment elevation myocardial infarction? PMID- 21251631 TI - Prediction of 1-year clinical outcomes using the SYNTAX score in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a substudy of the STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study) trials. AB - OBJECTIVES: This study sought to evaluate the impact of SYNTAX score (SXscore), and compare its performance in isolation and combination with the PAMI (The Primary Angioplasty in Myocardial Infarction Study) score, for the prediction of 1-year clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention. BACKGROUND: Patients with STEMI were excluded from the original SYNTAX score (SXscore) algorithm. Therefore, the utility of using the SXscore in this patient group remains undefined. METHODS: SXscore was calculated retrospectively in 807 patients with STEMI enrolled in the randomized STRATEGY (Single High-Dose Bolus Tirofiban and Sirolimus-Eluting Stent Versus Abciximab and Bare-Metal Stent in Acute Myocardial Infarction) and MULTISTRATEGY (Multicenter Evaluation of Single High-Dose Bolus Tirofiban Versus Abciximab With Sirolimus-Eluting Stent or Bare Metal Stent in Acute Myocardial Infarction Study) clinical trials. Clinical outcomes of all-cause death, reinfarction, and clinically driven target vessel revascularization were subsequently stratified according to SXscore tertiles: SX(LOW) <= 9 (n = 311), 9 < SX(MID) <= 16 (n = 234), SX(HIGH) >16 (n = 262). RESULTS: At 1-year follow-up, all clinical outcomes including mortality, mortality/reinfarction, major adverse cardiac events (MACE) (a composite of all cause death, reinfarction and target vessel revascularization), and definite, definite/probable, and any stent thrombosis were all significantly higher in patients in the highest SXscore tertile. SXscore was identified as an independent predictor of mortality, MACE, and stent thrombosis out to 1-year follow-up. The combination SYNTAX-PAMI score led to a net reclassification improvement of 15.7% and 4.6% for mortality and MACE, respectively. The C-statistics for the SXscore, PAMI score, and the combined SYNTAX-PAMI score were 0.65, 0.81, and 0.73 for 1 year mortality, and 0.68, 0.64, and 0.69 for 1-year MACE, respectively. CONCLUSIONS: SXscore does have a role in the risk stratification of patients with STEMI having primary percutaneous coronary intervention; however, this ability can be improved through a combination with clinical variables. (Multicentre 2*2 Factorial Randomised Study Comparing Tirofiban Versus Abciximab and SES Versus BMS in AMI; NCT00229515). PMID- 21251632 TI - Difference of culprit lesion morphologies between ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome: an optical coherence tomography study. AB - OBJECTIVES: The aim of this study was to investigate the difference of culprit lesion morphologies assessed by optical coherence tomography (OCT) between ST segment elevation myocardial infarction (STEMI) and non-ST-segment elevation acute coronary syndrome (NSTEACS). BACKGROUND: Autopsy studies have reported that rupture of a thin-cap fibroatheroma and subsequent thrombus formation is the most important mechanism leading to acute coronary syndrome (ACS). Optical coherence tomography is a high-resolution imaging modality that is capable of investigating detailed coronary plaque morphology in vivo. METHODS: We examined the culprit lesion morphologies by OCT in 89 consecutive patients with acute coronary syndrome (STEMI = 40; NSTEACS = 49). RESULTS: The incidence of plaque rupture, thin-cap fibroatheroma, and red thrombus was significantly higher in STEMI compared with NSTEACS (70% vs. 47%, p = 0.033, 78% vs. 49%, p = 0.008, and 78% vs. 27%, p < 0.001, respectively). Although the lumen area at the site of plaque rupture was similar in the both groups (2.44 +/- 1.34 mm(2) vs. 2.96 +/- 1.91 mm(2), p = 0.250), the area of ruptured cavity was significantly larger in STEMI compared with NSTEACS (2.52 +/- 1.36 mm(2) vs. 1.67 +/- 1.37 mm(2), p = 0.034). Furthermore, the ruptured plaque of which aperture was open-wide against the direction of coronary flow was more often seen in STEMI compared with NSTEACS (46% vs. 17%, p = 0.036). CONCLUSIONS: The present OCT study demonstrated the differences of the culprit lesion morphologies between STEMI and NSTEACS. The morphological feature of plaque rupture and the intracoronary thrombus could relate to the clinical presentation in patients with acute coronary disease. PMID- 21251633 TI - New morphological insights on coronary plaque rupture: bridging the gap from anatomy to clinical presentation? PMID- 21251634 TI - Incidence, predictors, management, immediate and long-term outcomes following grade III coronary perforation. AB - OBJECTIVES: The aim of this study was to evaluate the incidence, predictors, management, and clinical outcomes in patients with grade III coronary perforation during percutaneous coronary intervention. BACKGROUND: Grade III coronary perforation is a rare but recognized complication associated with high morbidity and mortality. METHODS: From 24,465 patients undergoing percutaneous coronary intervention from May 1993 to December 2009, 56 patients had grade III coronary perforation. RESULTS: Most lesions were complex: 44.6% type B2, 51.8% type C, and 28.6% chronic total occlusions, and within a small vessel (<= 2.5 mm) in 32.1%. Glycoprotein IIb/IIIa inhibitors were administered in 17.9% of patients. The device causing perforation was intracoronary balloon in 50%: 53.6% compliant, 46.4% noncompliant; intracoronary guidewire in 17.9%; rotablation in 3.6%; and directional atherectomy in 3.6%. Following perforation, immediate treatment and success rates, respectively, were prolonged balloon inflation 58.9%, 54.5%; covered stent implantation 46.4%, 84.6%; coronary artery bypass graft surgery (CABG) and surgical repair 16.0%, 44.4%; and coil embolization 1.8%, 100%. Multiple methods were required in 39.3%. During the procedure (n = 56), 19.6% required cardiopulmonary resuscitation and 3.6% died. In-hospital (n = 54), 3.7% required CABG, 14.8% died. The combined procedural and in-hospital myocardial infarction rate was 42.9%, and major adverse cardiac event rate was 55.4%. At clinical follow-up (n = 46) (median: 38.1 months, range 7.6 to 122.8), 4.3% had a myocardial infarction, 4.3% required CABG, and 15.2% died. The target lesion revascularization rate was 13%, with target vessel revascularization in 19.6%, and major adverse cardiac events in 41.3%. CONCLUSIONS: Grade III coronary perforation is associated with complex lesions and high acute and long-term major adverse cardiac event rates. PMID- 21251635 TI - Coronary perforation: an inconvenient complication. PMID- 21251636 TI - Drug-eluting introducer sheath prevents local peripheral complications: pre clinical evaluation of nitric oxide-coated sheath. AB - OBJECTIVES: This study evaluated the protective effect of nitric oxide-coating of introducer sheath on the local complications in juvenile porcine femoral arteries with similar size to human radial arteries. BACKGROUND: Insertion of an introducer sheath induces vasospasm and transient or permanent vessel occlusion of radial arteries. METHODS: Nitric oxide-coated or control introducer sheaths with or without spasmolytic cocktail (control + C-sheath) were inserted into porcine femoral arteries, followed by percutaneous coronary intervention (PCI). The diameter of the femoral artery at the puncture site, distally and proximally, was measured by quantitative angiography. Histopathological and histomorphometric parameters of the femoral arteries were analyzed 1 h or 1 week after PCI. RESULTS: Insertion of femoral sheath led to mild or severe spasms, with significantly higher vessel diameter at the access site (2.69 +/- 0.81 mm vs. 1.77 +/- 0.77 mm and 1.85 +/- 0.66 mm, p < 0.001), and proximal and distal to it, during PCI in the nitric oxide-sheath group versus the control-sheath and control + C-sheath groups, respectively. Immediately following PCI, significantly less luminal thrombosis (12% vs. 33% and 31% of all analyzed segments, p < 0.001) was observed in the nitric oxide-sheath arteries. At 1 week, lower intimal inflammation score (0.43 +/- 11 vs. 1.03 +/- 0.35 and 1.04 +/- 0.32, p < 0.05), less luminal thrombosis (8% vs. 21% and 30% p < 0.05), and smaller intimal hyperplasia (0.31 +/- 0.31 mm(2) vs. 0.47 +/- 1.00 mm(2) and 0.86 +/- 0.82 mm(2), p < 0.05) were observed in NO-sheath arteries at the injury site. CONCLUSIONS: Nitric oxide coating on the introducer sheath prevents local complications during PCI and results in less vascular thrombosis and inflammation at the access site, contributing to patency of the access vessel with similar size to the radial artery. PMID- 21251637 TI - Description and assessment of a common reference method for fluoroscopic and transesophageal echocardiographic localization and guidance of mitral periprosthetic transcatheter leak reduction. AB - OBJECTIVES: This study sought to describe and compare a novel fluoroscopic method and a 2-dimensional transesophageal echocardiographic (TEE) method to localize mitral periprosthetic leaks (PPLs) for transcatheter reduction. BACKGROUND: Transcatheter reduction of significant regurgitation represents a modern and attractive alternative to surgery for the treatment of mitral PPL in high-risk patients. Accurate localization and precise communication between the echocardiographer and the interventional cardiologist are essential for procedural success. METHODS: We analyzed TEE and fluoroscopic studies of patients with mitral PPL who underwent multiplane 2-dimensional TEE-guided transcatheter reduction in our institution. Periprosthetic leaks were routinely localized using the "surgeon's-view" time-clock method during periprocedural TEE assessments. The 2-dimensional TEE examinations were later retrospectively reviewed by an echocardiographer blinded to procedural TEE findings. A corresponding surgeon's view time-clock method was plotted for fluoroscopic PPL localization. Using this fluoroscopic method, offline fluoroscopic images were reviewed by an independent interventional cardiologist blinded to TEE results. Agreement between methods was evaluated. RESULTS: Complete imaging data were available for analysis in 20 patients who, between 2002 and 2009, underwent transcatheter reduction in which the defect was successfully crossed. There was excellent agreement between procedural TEE and retrospective TEE review for PPL localization (100%; p < 0.0001) and between fluoroscopic and procedural TEE localization (90%; 95% confidence interval [CI]: 77% to 100%; p = 0.0003). In the 2 cases where there was disagreement, fluoroscopic PPL localization was adjacent to TEE localization. CONCLUSIONS: The surgeon's-view time-clock method of localizing PPL using 2 dimensional TEE is highly reproducible and allows fluoroscopic localization using the same reference system with very good agreement. PMID- 21251638 TI - Transcatheter implantation of the MONARC coronary sinus device for mitral regurgitation: 1-year results from the EVOLUTION phase I study (Clinical Evaluation of the Edwards Lifesciences Percutaneous Mitral Annuloplasty System for the Treatment of Mitral Regurgitation). AB - OBJECTIVES: This study sought to assess the safety and efficacy of transcatheter valve annuloplasty in patients with mitral regurgitation (MR). BACKGROUND: Mitral regurgitation is associated with a worsened prognosis in patients with dilated cardiomyopathy. Surgical mitral annuloplasty reduces the septal-lateral dimension of the mitral annulus resulting in improved leaflet coaptation with a reduction in regurgitation. Percutaneous annuloplasty with the MONARC device (Edwards Lifesciences, Irvine, California) implanted within the coronary sinus is designed to reduce mitral regurgitation through a similar mechanism. METHODS: A total of 72 patients with MR grade >= 2 were enrolled at 8 participating centers in 4 countries. Clinical evaluation and transthoracic echocardiography were performed at baseline and at 3, 6, and 12 months. Multislice cardiac computed tomography and coronary angiography were performed at baseline and 3 months. RESULTS: The MONARC device was implanted in 59 of 72 patients (82%). The primary safety end point (freedom from death, tamponade, or myocardial infarction at 30 days) was met in 91% of patients at 30 days and in 82% at 1 year. Computed tomography imaging documented passage of the great cardiac vein over an obtuse marginal artery in 55% of patients and was associated with angiographic coronary artery compression in 15 patients and myocardial infarction in 2 patients (3.4%). At 12 months, a reduction in MR by >= 1 grade was observed in 50.0% of 22 implanted patients with matched echocardiograms and in 85.7% of 7 patients with baseline MR grade >= 3. CONCLUSIONS: Implantation of the MONARC device in the coronary sinus is feasible and may reduce MR. However, coronary artery compression may occur in patients in whom the great cardiac vein passes over a coronary artery, necessitating strategies in future studies to avoid this occurrence. PMID- 21251639 TI - Late restenosis following sirolimus-eluting stent implantation. AB - OBJECTIVES: This serial angiographic study evaluated the incidence and predictors of late restenosis after sirolimus-eluting stent (SES) implantation. BACKGROUND: Previous studies showed late restenosis (i.e., late catch-up phenomenon) after implantation of 7-hexanoyltaxol-eluting stents and nonpolymeric, paclitaxel eluting stents. METHODS: Between August 2004 and December 2006, SES implantation was performed in 1,393 patients with 2,008 lesions, in whom 8-month and 2-year follow-up coronary angiography were planned. RESULTS: Of 2,008 lesions, 1,659 (83%) underwent 8-month follow-up angiography (8.3 +/- 2.2 months). Restenosis was observed in 122 lesions (7.4%). Coronary angiography 2 years (1.9 +/- 0.4 years) after SES deployment was performed in 1,168 lesions (74% of lesions without restenosis at 8-month follow-up angiography). Late restenosis was observed in 83 lesions (7.1%). There was significant decrease in minimum luminal diameter (MLD) between 8-month and 2-year follow-up (2.56 +/- 0.56 mm vs. 2.35 +/ 0.71 mm, p < 0.001). Multivariate analysis showed in-stent restenosis before SES implantation and MLD at 8-month follow-up as independent predictors of late restenosis. CONCLUSIONS: Between 8-month and 2-year follow-up after SES implantation, MLD decreases, which results in late restenosis in some lesions. In stent restenosis before SES implantation and MLD at 8-month follow-up are independent predictors of late restenosis. PMID- 21251640 TI - Images in intervention. Intramural hematoma appearing as a new lesion after coronary stenting. PMID- 21251641 TI - Dawn out of the darkness. PMID- 21251642 TI - Transcatheter aortic valve implantation: lessons from the PARTNER (Placement of Aortic Transcatheter Valves) trial. PMID- 21251643 TI - Don't be negative on negative trials. PMID- 21251644 TI - Perspective on fluid and solid dynamics in different pars plana vitrectomy systems. AB - PURPOSE: To summarize current concepts and recent data from the literature about different vitrectomy machines and small-gauge systems based on physical laws. DESIGN: Interpretive essay. METHODS: Review and synthesis of selected recent literature with interpretation and perspective. RESULTS: Pars plana vitrectomy can be performed with a wide variety of treatment strategies, for multiple diseases, and with different materials (solids and fluids). We discuss a variety of machines and system settings (peristaltic pump, duty cycle, aspiration, and infusion controls) targeting safer and the most effective surgery with detailed explanations of the physical properties. CONCLUSIONS: Effective management of new surgical strategies is based on recognizing and addressing various physical characteristics in disease and ocular settings. Although the properties of machine are expanding, the long-term efficacy and safety of most new approaches have yet to be established in controlled clinical trials. PMID- 21251645 TI - Activation of thalamocortical networks by the N-methyl-D-aspartate receptor antagonist phencyclidine: reversal by clozapine. AB - BACKGROUND: Noncompetitive N-methyl-D-aspartate receptor antagonists are widely used as pharmacological models of schizophrenia. Their neurobiological actions are still poorly understood, although the prefrontal cortex (PFC) appears as a key target area. METHODS: We examined the effect of phencyclidine (PCP) on neuronal activity of the mediodorsal (MD) and centromedial (CM) thalamic nuclei, reciprocally connected with the PFC, using extracellular recordings (n = 50 neurons from 35 Wistar rats) and c-fos expression. RESULTS: Phencyclidine (.25 mg/kg intravenous [IV]) markedly disorganized the activity of MD/CM neurons, increasing (424%) and decreasing (41%) the activity of 57% and 20% of the recorded neurons, respectively (23% remained unaffected). Phencyclidine reduced delta oscillations (.15-4 Hz) as assessed by recording local field potentials. The subsequent clozapine administration (1 mg/kg IV) reversed PCP effects on neuronal discharge and delta oscillations. Double in situ hybridization experiments revealed that PCP (10 mg/kg intraperitoneal [IP]) markedly increased c-fos expression in glutamatergic neurons of several cortical areas (prefrontal, somatosensory, retrosplenial, entorhinal) and in thalamic nuclei, including MD/CM. Phencyclidine also increased c-fos expression in the amygdala; yet, it had a small effect in the hippocampus. Phencyclidine did not increase c-fos expression in gamma-aminobutyric acidergic cells except in hippocampus, amygdala, somatosensory, and retrosplenial cortices. Clozapine (5 mg/kg IP) had no effect by itself but significantly prevented PCP-induced c-fos expression. CONCLUSIONS: Phencyclidine likely exerts its psychotomimetic action by increasing excitatory neurotransmission in thalamo-cortico-thalamic networks involving, among others, PFC, retrosplenial, and somatosensory cortices. The antipsychotic action of clozapine includes, among other actions, an attenuation of the neuronal hyperactivity in thalamocortical networks. PMID- 21251648 TI - WITHDRAWN: Synthesis, characterization, and antifungal activity of N,O-(acyl)-N (trimethyl) chitosan ammonium chloride. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21251647 TI - The role of norepinephrine in differential response to stress in an animal model of posttraumatic stress disorder. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder precipitated by exposure to extreme traumatic stress. Yet, most individuals exposed to traumatic stress do not develop PTSD and may be considered psychologically resilient. The neural circuits involved in susceptibility or resiliency to PTSD remain unclear, but clinical evidence implicates changes in the noradrenergic system. METHODS: An animal model of PTSD called Traumatic Experience with Reminders of Stress (TERS) was developed by exposing C57BL/6 mice to a single shock (2 mA, 10 sec) followed by exposure to six contextual 1-minute reminders of the shock over a 25-day period. Acoustic startle response (ASR) testing before the shock and after the last reminder allowed experimenters to separate the shocked mice into two cohorts: mice that developed a greatly increased ASR (TERS-susceptible mice) and mice that did not (TERS-resilient mice). RESULTS: Aggressive and social behavioral correlates of PTSD increased in TERS-susceptible mice but not in TERS-resilient mice or control mice. Characterization of c-Fos expression in stress-related brain regions revealed that TERS-susceptible and TERS-resilient mice displayed divergent brain activation following swim stress compared with control mice. Pharmacological activation of noradrenergic inhibitory autoreceptors or blockade of postsynaptic alpha(1)-adrenoreceptors normalized ASR, aggression, and social interaction in TERS-susceptible mice. The TERS-resilient, but not TERS-susceptible, mice showed a trend toward decreased behavioral responsiveness to noradrenergic autoreceptor blockade compared with control mice. CONCLUSIONS: These data implicate the noradrenergic system as a possible site of pathological and perhaps also adaptive plasticity in response to traumatic stress. PMID- 21251646 TI - Reduced interhemispheric resting state functional connectivity in cocaine addiction. AB - BACKGROUND: Models of cocaine addiction emphasize the role of disrupted frontal circuitry supporting cognitive control processes. However, addiction-related alterations in functional interactions among brain regions, especially between the cerebral hemispheres, are rarely examined directly. Resting-state functional magnetic resonance imaging (fMRI) approaches, which reveal patterns of coherent spontaneous fluctuations in the fMRI signal, offer a means to quantify directly functional interactions between the hemispheres. We examined interhemispheric resting-state functional connectivity (RSFC) in cocaine dependence using a recently validated approach, voxel-mirrored homotopic connectivity. METHODS: We compared interhemispheric RSFC between 25 adults (aged 35.0 +/- 8.8) meeting DSM IV criteria for cocaine dependence within the past 12 months but currently abstaining (>2 weeks) from cocaine and 24 healthy comparisons (35.1 +/- 7.5), group-matched on age, sex, education, and employment status. RESULTS: We observed reduced prefrontal interhemispheric RSFC in cocaine-dependent participants relative to control subjects. Further analyses demonstrated a striking cocaine dependence-related reduction in interhemispheric RSFC among nodes of the dorsal attention network, comprising bilateral lateral frontal, medial premotor, and posterior parietal areas. Further, within the cocaine-dependent group, RSFC within the dorsal attention network was associated with self-reported attentional lapses. CONCLUSIONS: Our findings provide further evidence of an association between chronic exposure to cocaine and disruptions within large-scale brain circuitry supporting cognitive control. We did not detect group differences in diffusion tensor imaging measures, suggesting that alterations in the brain's functional architecture associated with cocaine exposure can be observed in the absence of detectable abnormalities in the white matter microstructure supporting that architecture. PMID- 21251649 TI - Clinico-anatomical correlation in gliomas: a new frontier in clinical neuroscience? PMID- 21251650 TI - Predictive control for voltage collapse avoidance using a modified discrete multi valued PSO algorithm. AB - Voltage stability is one of the most challenging concerns that power utilities are confronted with, and this paper proposes a voltage control scheme based on Model Predictive Control (MPC) to overcome this kind of instability. Voltage instability has a close relation with the adequacy of reactive power and the response of Under Load Tap Changers (ULTCs) to the voltage drop after the occurrence of a contingency. Therefore, the proposed method utilizes reactive power injection and tap changing to avoid voltage collapse. Considering discrete nature of the changes in the tap ratio and also in the reactive power injected by capacitor banks, the search area for the optimizer of MPC will be an integer area; consequently, a modified discrete multi-valued Particle Swarm Optimization (PSO) is considered to perform this optimization. Simulation results of applying the proposed control scheme to a 4-bus system confirm its capability to prevent voltage collapse. PMID- 21251651 TI - Variance sensitive adaptive threshold-based PCA method for fault detection with experimental application. AB - Principal Component Analysis (PCA) is a statistical process monitoring technique that has been widely used in industrial applications. PCA methods for Fault Detection (FD) use data collected from a steady-state process to monitor T(2) and Q statistics with a fixed threshold. For the systems where transient values of the processes must be taken into account, the usage of a fixed threshold in PCA method causes false alarms and missing data that significantly compromise the reliability of the monitoring systems. In the present article, a new PCA method based on variance sensitive adaptive threshold (T(vsa)) is proposed to overcome false alarms which occur in the transient states according to changing process conditions and the missing data problem. The proposed method is implemented and validated experimentally on an electromechanical system. The method is compared with the conventional monitoring methods. Experimental tests and tabulated results confirm the fact that the proposed method is applicable and effective for both the steady-state and transient operations and gives early warning to operators. PMID- 21251652 TI - Incidental durotomy during spine surgery: incidence, management and complications. A retrospective review. AB - STUDY DESIGN: Retrospective review of a series of patients who underwent spinal surgery at a single spine unit during a 1 year period. OBJECTIVES: To assess the incidence, treatment, clinical consequence, complications of incidental durotomy during spine surgery and results of 37 months clinical follow-up. SUMMARY OF BACKGROUND DATA: Incidental durotomy is an underestimated and relatively adverse event during spinal surgery. Several consequences of inadequately treated dural tears have been reported. METHODS: A retrospective review was conducted on 1326 consecutive patients who underwent spinal surgery performed in one French spine unit from January 2005 to December 2005. We excluded from this study patients treated for emergency spine cases. RESULTS: Fifty-one dural tears were identified (3.84%). Incidental durotomies were associated with anterior cervical approach in 1 case, with posterior cervical approach in 1 case, with anterior retroperitoneal approach in 1 case and with posterior thoracolumbar approach in 48 cases. In addition, any clinically significant durotomy unrecognised during surgical procedure were included. Thirteen patients presented postoperative complications including 7 cerebrospinal fluid leaks, 2 wound infections, 2 postoperative haematomas, and 2 pseudomeningoceles. Nine of these 13 patients required a revision procedure. A mean follow-up of 37 months showed good long-term clinical results. CONCLUSIONS: Incidental durotomy is a common complication of spine surgery. All incidental durotomies must be repaired primarily. Dural tears that were immediately recognised and treated accordingly did not lead to any significant sequelae at a mean follow-up of 37 months. However, long-term follow up studies will be needed to confirm this finding. The risks associated with dural tears and cerebrospinal fluid leaks are serious and should be discussed with any patients undergoing spine surgery. PMID- 21251653 TI - Enoxaparin versus unfractionated heparin in the management of recurrent abortion secondary to antiphospholipid syndrome. AB - OBJECTIVE: To determine whether low molecular weight heparin (LMWH) plus low-dose aspirin (LDA) is comparable in efficacy and safety to unfractionated heparin (UFH) plus LDA in the management of pregnant women with a history of recurrent spontaneous abortion secondary to antiphospholipid syndrome (APS). METHODS: In a randomized prospective study, 60 women with a history of 3 or more consecutive spontaneous abortions and positive antiphospholipid antibodies were assigned in equal numbers to receive either UFH (5000 units, twice daily) plus LDA, or LMWH (enoxaparin 40 mg, once daily) plus LDA as soon as pregnancy was diagnosed. RESULTS: Twenty-four women in the LMWH group (80%) and 20 women in the UFH group (66.67%) delivered a viable infant (P = 0.243). There were no significant differences in pregnancy complications or neonatal morbidity between the 2 groups. There were no incidences of excessive bleeding, thrombocytopenia, or osteoporotic fractures in either group. CONCLUSION: LMWH plus LDA was successfully used as an alternative to UFH plus LDA in the management of recurrent abortion secondary to APS. The results highlight the need for a larger randomized controlled trial to determine whether LMWH plus LDA should be the treatment of choice for recurrent abortion secondary to APS. Clinicaltrials.gov NCT01051778. PMID- 21251654 TI - Rapid intrapartum or postpartum HIV testing at a midwife obstetric unit and a district hospital in South Africa. AB - OBJECTIVE: To compare the prepartum and postpartum feasibility and acceptance of voluntary counseling and rapid testing (VCT) among women with unknown HIV status in South Africa. METHODS: Eligible women were randomized according to the calendar week of presentation to receive VCT either while in labor or after delivery. RESULTS: Of 7238 women approached, 542 (7.5%) were eligible, 343 (63%) were enrolled, and 45 (13%) were found to be HIV infected. The proportions of eligible women who accepted VCT were 66.8% (161 of 241) in the intrapartum arm and 60.5% (182 of 301) in the postpartum arm, and the difference of 6.3% (95% CI, -1.8% to 14.5%) was not significant. The median times (44 and 45 minutes) required to conduct VCT were also similar in the 2 arms. In the intrapartum arm, all women in true labor received their test results before delivery and all those found to be HIV positive accepted prophylaxis with nevirapine before delivery. CONCLUSIONS: Rapid testing in labor wards for women with an unknown HIV status is feasible and well accepted, and allows for a more timely antiretroviral prophylaxis than postpartum testing. PMID- 21251655 TI - Coronary artery calcium score improves cardiovascular risk prediction in persons without indication for statin therapy. AB - BACKGROUND: Recent revision to the Canadian Cardiovascular Society (CCS) guidelines on cardiovascular disease (CVD) risk stratification provides expanded recommendations for statin therapy. If CVD risk in the remaining individuals can further be stratified and discriminated by additional risk assessment using coronary artery calcium (CAC) scoring is unknown. METHODS AND RESULTS: In a retrospectively analyzed subgroup comprising 1934 participants from the Heinz Nixdorf Recall study, who did not meet criteria for statin therapy based on current CCS guidelines, traditional CVD risk variables and CAC were measured. Between 2000 and 2008, incident CVD events, i.e. coronary deaths, non-fatal myocardial infarction, coronary revascularization, stroke and CV death were determined. Those 43 participants who experienced 55 CVD events (5-year risk to first event: 2.2% (1.6-3.0%)) had higher CAC scores than those who did not (p<0.0001). In multiple Cox regression analysis including age, sex, total-/HDL cholesterol ratio, and antihypertensive medication, log2(CAC+1) remained an independent predictor of CVD events (HR=1.21 (1.09-1.33), p<0.001). Measures of discrimination improved with the addition of CAC into the model: the incremental discrimination improvement was 0.0167, p=0.014. Net reclassification improvement using risk categories of 0-<3%, 3-10% and >10% was 25.1%, p=0.01, largely driven by a 32.6% correct up-classification in persons with events. Yet, only 38 (2%) of participants were identified being at high risk using CAC imaging in addition to traditional risk factor assessment. CONCLUSION: Adding CAC to traditional risk assessment in persons without indication for statin therapy improves discrimination. However, reclassification to the high risk category and overall event rates seem too low to justify liberal CAC testing in all these individuals. PMID- 21251657 TI - TGF-beta1 diminishes collagen production during long-term cyclic stretching of engineered connective tissue: implication of decreased ERK signaling. AB - Cyclic stretching and growth factors like TGF-beta have been used to enhance extracellular matrix (ECM) production by cells in engineered tissue to achieve requisite mechanical properties. In this study, the effects of TGF-beta1 were evaluated during long-term cyclic stretching of fibrin-based tubular constructs seeded with neonatal human dermal fibroblasts. Samples were evaluated at 2, 5, and 7 weeks for tensile mechanical properties and ECM deposition. At 2 weeks, +TGF-beta1 samples had 101% higher collagen concentration but no difference in ultimate tensile strength (UTS) or modulus compared to -TGF-beta1 samples. However, at weeks 5 and 7, -TGF-beta1 samples had higher UTS/modulus and collagen concentration, but lower elastin concentration compared to +TGF-beta1 samples. The collagen was better organized in -TGF-beta1 samples based on picrosirius red staining. Western blot analysis at weeks 5 and 7 showed increased phosphorylation of ERK in -TGF-beta1 samples, which correlated with higher collagen deposition. The TGF-beta1 effects were further evaluated by western blot for alphaSMA and SMAD2/3 expression, which were 16-fold and 10-fold higher in +TGF-beta1 samples, respectively. The role of TGF-beta1 activated p38 in inhibiting phosphorylation of ERK was evaluated by treating samples with SB203580, an inhibitor of p38 activation. SB203580-treated cells showed increased phosphorylation of ERK after 1 hour of stretching and increased collagen production after 1 week of stretching, demonstrating an inhibitory role of activated p38 via TGF-beta1 signaling during cyclic stretching. One advantage of TGF-beta1 treatment was the 4-fold higher elastin deposition in samples at 7 weeks. Further cyclic stretching experiments were thus conducted with constructs cultured for 5 weeks without TGF beta1 to obtain improved tensile properties followed by TGF-beta1 supplementation for 2 weeks to obtain increased elastin content, which correlated with a reduction in loss of pre-stress during preconditioning for tensile testing, indicating functional elastin. This study shows that a sequential stimulus approach - cyclic stretching with delayed TGF-beta1 supplementation - can be used to engineer tissue with desirable tensile and elastic properties. PMID- 21251658 TI - Reversed phase monolithic analytical columns for the determination of HA1 subunit of influenza virus haemagglutinin. AB - Monoliths are chromatographic stationary phases, which were specially designed for efficient purification of large biomolecules, like proteins, viruses and DNA. In this work, the small scale monolithic butyl (C4) and styrene-divinyl benzene (SDVB) columns were applied for reversed phase analyses of various degraded influenza viruses. The binding of the HA1 subunit of haemagglutinin to the monolithic columns was confirmed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and the Western blot. The working linear range was determined as 1.60*10(10) viral particles/mL to at least 1.64*10(11) viral particles/mL, the limit of detection was found to be 2.56*10(9) virus particles/mL and the limit of quantification was 5.12*10(9) virus particles/mL. The analytical HPLC method developed with the H1N1 virus was also applicable for the analytics of the HA1 subunit of H3N2 influenza virus and the influenza B virus. PMID- 21251656 TI - Porphyromonas gingivalis accelerates inflammatory atherosclerosis in the innominate artery of ApoE deficient mice. AB - OBJECTIVE: Studies in humans support a role for the oral pathogen Porphyromonas gingivalis in the development of inflammatory atherosclerosis. The goal of this study was to determine if P. gingivalis infection accelerates inflammation and atherosclerosis in the innominate artery of mice, an artery which has been reported to exhibit many features of human atherosclerotic disease, including plaque rupture. METHODS AND RESULTS: Apolipoprotein E-deficient (ApoE-/-) mice were orally infected with P. gingivalis, and magnetic resonance imaging (MRI) was used to monitor the progression of atherosclerosis in live mice. P. gingivalis infected mice exhibited a statistically significant increase in atherosclerotic plaque in the innominate artery as compared to uninfected mice. Polarized light microscopy and immunohistochemistry revealed that the innominate arteries of infected mice had increased lipids, macrophages and T cells as compared to uninfected mice. Increases in plaque, total cholesterol esters and cholesterol monohydrate crystals, macrophages, and T cells were prevented by immunization with heat-killed P. gingivalis prior to pathogen exposure. CONCLUSIONS: These are the first studies to demonstrate progression of inflammatory plaque accumulation in the innominate arteries by in vivo MRI analysis following pathogen exposure, and to document protection from plaque progression in the innominate artery via immunization. PMID- 21251659 TI - Novel molecularly imprinted polymer using 1-(alpha-methyl acrylate)-3 methylimidazolium bromide as functional monomer for simultaneous extraction and determination of water-soluble acid dyes in wastewater and soft drink by solid phase extraction and high performance liquid chromatography. AB - Novel water-compatible molecularly imprinted polymers were synthesized in methanol-water systems with Tratarzine as template and 1-(alpha-methyl acrylate) 3-methylimidazolium bromide (1-MA-3MI-Br) as functional monomer, which has pi-pi hydrophobic, hydrogen-bonding and electrostatic interactions with template molecule. 1-MA-3MI-Br molecularly imprinted polymers (1-MA-3MI-Br-MIPs) were used as selective sorbents for the solid-phase extraction (SPE) of water-soluble acid dyes from wastewater and soft drink. The good linearity of the method was obtained in a range of 5.0-2000 MUg/L with the correlation coefficient of > 0.999. The detection limits were in a range of 0.13-0.51 MUg/L for the water soluble acid dyes in wastewater and 0.095-0.84 MUg/L for those in soft drink. The mean recoveries for the acid dyes are from 89.1% to 101.0% in spiked wastewater and 91.0-101.3% in spiked soft drink. Compared with strongly anion exchange solid phase extraction (SAX-SPE), mixture anion exchange solid phase extraction (MAX SPE), and 1-MA-3MI-Br non-imprinted solid phase extraction (1-MA-3MI-Br-NISPE), almost all of the matrix interferences were removed by 1-MA-3MI-Br-MISPE, exhibiting higher selectivity, recovery and enrichment ability for the acid dyes and better baselines in the results of HPLC analysis. PMID- 21251660 TI - Design of an imprinted clean-up method for mycophenolic acid in maize. AB - In the present work, the development of imprinted polymers selective towards mycophenolic acid and their application in food analysis are reported for the first time. To synthesize the molecularly imprinted polymer (MIP) 4-vinylpyridine and ethyleneglycol dimethacrylate were applied as functional monomer and cross linker, respectively. Besides the toxin itself, the implementation of structural analogues as templates was evaluated. A molecularly imprinted solid-phase extraction (MISPE) procedure was designed for the selective clean-up of maize extracts. Binding experiments and Scatchard analysis indicated the presence of specific binding sites in the imprinted polymers. The imprinting effect varied along with the selected template. The dissociation constant (K(D)) of the higher affinity binding sites ranged from 0.8 MUmol/l to 15.6 MUmol/l, while the K(D) of the lower affinity binding sites was in the range of 138.5-519.3 MUmol/l. The performance of the MIPs throughout the clean-up of spiked maize sample extracts was evaluated and compared with the results obtained when applying a non imprinted polymer. Depending on the polymers and the spiked concentration, recoveries after MISPE and non-imprinted solid-phase extraction varied respectively from 49% to 84% and from 28% to 31%. The imprinted polymers were superior regarding matrix effect, limit of detection (LOD) and limit of quantification (LOQ). LOD ranged from 0.17 MUg/kg to 0.25 MUg/kg and LOQ varied from 0.57 MUg/kg to 0.82 MUg/kg. Analysis of 15 maize samples by liquid chromatography tandem mass spectrometry revealed that the MIPs could be excellent sorbents for clean-up of contaminated food samples. PMID- 21251661 TI - Performance of a non-grafted monolithic support for purification of supercoiled plasmid DNA. AB - The use of therapeutics based on plasmid DNA (pDNA) relies on procedures that efficiently produce and purify the supercoiled (sc) plasmid isoform. Several chromatographic methods have been applied for the sc plasmid purification, but with most of them it is not possible to obtain the required purity degree and the majority of the supports used present low capacity to bind the plasmid molecules. However, the chromatographic monolithic supports are an interesting alternative to conventional supports due to their excellent mass transfer properties and their high binding capacity for pDNA. The separation of pDNA isoforms, using short non-grafted monolithic column with CarbonylDiImidazole (CDI) functional groups, is described in the current work. The effect of different flow rates on plasmid isoforms separation was also verified. Several breakthrough experiments were designed to study the effect of different parameters such as pDNA topology and concentration as well as flow rate on the monolithic support binding capacity. One of the most striking results is related to the specific recognition of the sc isoform by this CDI monolith, without flow rate dependence. Additionally, the binding capacity has been found to be significantly higher for sc plasmid, probably because of its compact structure, being also improved when using feedstock with increased plasmid concentrations and decreased linear velocity. In fact, this new monolithic support arises as a powerful instrument on the sc pDNA purification for further clinical applications. PMID- 21251662 TI - Open tubular capillary columns with basic templates made by the generalized preparation protocol in capillary electrochromatography chiral separation and template structural effects on chiral separation capability. AB - Some open tubular (OT) molecule imprinted polymer (MIP) silica capillary columns have been prepared using atenolol, sulpiride, methyl benzylamine (MBA) and (1 naphthyl)-ethylamine (NEA) as templates by the pre-established generalized preparation protocol. The four MIP thin layers of different templates showed quite different morphologies. The racemic selectivity of each MIP column for the template enantiomers was optimized by changing eluent composition and pH. The template structural effects on chiral separation performance have been examined. This work verifies the versatility of the generalized preparation protocol for OT MIP silica capillary columns by extending its boundary toward templates with basic functional group moieties. This study is the very first report to demonstrate a generalized MIP preparation protocol that is valid for both acidic and basic templates. The chiral separation performances of atenolol and sulpiride by the MIPs of this study were found better than or comparable to those of atenolol and sulpiride obtained by non-MIP separation techniques and those of some basic template enantiomers obtained by MIP based techniques. PMID- 21251663 TI - Distribution of metoprolol, tramadol, and midazolam in human autopsy material. AB - In this study it was possible to measure the distribution of metoprolol, tramadol, and midazolam in human directly in several compartments. In the legal medicine autopsy material is normally investigated to find out the cause of death. But the results of corresponding toxicology measurements often involve more information. With screening methods drugs were detected without connection to the cause of death. The deceased had either a continual therapeutic treatment, a treatment during an operation, or an unsuccessful urgent therapy. A liquid/liquid extraction and a LC/MS/MS method were developed for the determination of the drug concentrations. Different autopsy materials of about 120 cases were investigated. Most frequently the drugs metoprolol, tramadol, and midazolam could be proved and determined simultaneously. Metoprolol was found in seven cases, tramadol in seven cases and midazolam in thirteen cases. The dosage of the drugs was unknown. Therefore and because of the low number of cases statistic calculations were not meaningful and an individual case study was necessary. In all cases with oral metoprolol application the patients probably took a normal customary continuous dosage. The concentrations of tramadol in blood were in the toxic range in three cases. The distribution of tramadol in the compartments was independent of the dosage. The time between oral intake of metoprolol or tramadol and death was unknown. With the distribution pattern of metoprolol in the compartments it was possible to estimate the duration between drug intake and death. In most cases midazolam was given intravenously during an operation or an unsuccessful urgent therapy. Sometimes the time between dosage and death was documented. The duration between application of the drug and death played the crucial role for the distribution of midazolam in the compartments. Measurements of drug concentrations in human autopsy material deepen the knowledge of the respective drugs' pharmacokinetics. PMID- 21251664 TI - Separation of inorganic anions using a series of sulfobetaine exchangers. AB - A set of five new sulfobetaine exchangers with inner quaternary amines and outer sulfonic acids have been prepared. A series of zwitterionic precursors was attached to highly porous divinylbenzene polymer using a grafting reaction, which allows a flexible adjustment of the degree of functionalisation. The resulting materials have identical spacers to the polymeric backbone and differ only in chain length between the charged functional groups. Capacities of the stationary phases were analysed by two different methods based on elemental analysis and the results obtained were found to correlate. The application of combustion elemental analysis proved an identical molar content of sulfur and nitrogen. The distance between the charged functional groups is varied from one to five methylene groups for a better understanding of the retention behaviour of inorganic anions on zwitterionic stationary phases. Inorganic anions were separated using sodium acetate eluents with varying ionic strength and pH and the behaviour of all columns has been compared to each other and to ZIC-HILIC and ZIC-pHILIC columns from Merck SeQuant. The exchangers with two and five methylene groups between the charges showed the highest retention factors. Polarity and accessibility of the anion exchange sites are dependent on the distance between the charged groups and the flexibility of the chains. These properties have a strong influence on anion separations. The exchanger with two methylene groups between the charged functional groups showed the biggest difference as compared to the commercially available ZIC-HILIC and ZIC-pHILIC exchangers. PMID- 21251665 TI - Size controlled synthesis of Li2MnSiO4 nanoparticles: effect of calcination temperature and carbon content for high performance lithium batteries. AB - Size controlled, nanoparticulate Li(2)MnSiO(4) cathodes were successfully prepared by sol-gel route. Effects of calcination temperature and carbon content (adipic acid) were studied during synthesis process. EPR study was conducted to ensure the formation of phase through oxidation state of manganese. Microscopic pictures indicate spherical shape morphology of the synthesized Li(2)MnSiO(4) nanoparticles. Transmission electron microscopic pictures confirmed the presence of carbon coating on the surface of the particles. Further, the optimization has been performed based on phase purity and its battery performance. From the optimization, 700 degrees C and 0.2 mol adipic acid (against total metal ion present in the compound) were found better conditions to achieve high performance material. The Li(2)MnSiO(4) nanoparticles prepared in the aforementioned conditions exhibited an initial discharge capacity of ~113 mAh g(-1) at room temperature in Li/1M LiPF(6) in EC:DMC/Li(2)MnSiO(4) cell configuration. All the Li(2)MnSiO(4) nanoparticles prepared at various conditions experienced the capacity fade during cycling. PMID- 21251666 TI - Mesoporous Fe2O3-doped TiO2 nanostructured fibers with higher photocatalytic activity. AB - Mesoporous Fe(2)O(3)-doped TiO(2) nanostructured fibers were fabricated through electrospinning the relevant gel precursor. The prepared fibers were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), X-ray diffraction (XRD), X ray photoelectron spectroscopy (XPS), and surface analysis, respectively. The photocatalytic activity of these mesoporous composite fibers was evaluated by photocatalytic degradation of methylene blue (MB) in water under UV irradiation. Compared with different types of photocatalysts, the 1% Fe(2)O(3)-doped TiO(2) fibers exhibited super photocatalytic activity. PMID- 21251667 TI - Synthesis and swelling behavior of temperature responsive kappa-carrageenan nanogels. AB - Crosslinked kappa-carrageenan hydrogel nanoparticles (nanogels) with an average size smaller than 100 nm were prepared using reverse microemulsions combined with thermally induced gelation. The size of the nanogels varied with biopolymer concentration at a constant water/surfactant concentration ratio. The nanogels were found to be thermo-sensitive in a temperature range acceptable for living cells (37-45 degrees C) undergoing reversible volume transitions in response to thermal stimuli. This opens the possibility to explore the application of these nanogels in smart therapeutics such as thermo-sensitive drug carriers. As such, the sustained release of methylene blue from the nanogels was evaluated in in vitro conditions as proof of concept experiments and the release rate was found to be controlled with temperature. PMID- 21251669 TI - Epithelioid haemangiosarcoma in the ocular tissue of horses. AB - Haemangiosarcomas (HSAs) are malignant tumours of endothelial cell origin. Epithelioid HSA is a variant of the histologically conventional HSA that has little or no morphological evidence of a vascular origin and has been reported rarely in domestic animals. The following report documents six cases of equine epithelioid HSA occurring in the ocular tissues of horses with a mean age of 19.8 years at the time of diagnosis. Microscopically, all of the lesions consisted of solid sheets or cords of epithelioid cells with rare narrow clefts or small spaces containing erythrocytes that were often the only feature indicating a vascular origin. On immunohistochemistry, the neoplastic cells expressed vimentin, CD31 and factor VIII-related antigen, but not cytokeratin, indicating an endothelial nature. PMID- 21251668 TI - Predicting word decoding and word spelling development in children with Specific Language Impairment. AB - This longitudinal investigation on Dutch children with Specific Language Impairment (SLI) aimed at determining the predictive value of statistically uncorrelated language proficiencies on later reading and spelling skills in Dutch. Language abilities, tested with an extensive test battery at the onset of formal reading instruction, were represented by four statistically uncorrelated factors: lexical-semantic abilities, auditory perception, verbal-sequential processing, and speech production. All factors contributed significantly to the prediction of word reading and spelling development seven months later. Verbal sequential processing was the strongest predictor for both word decoding and spelling. Furthermore, autoregression effects of word decoding and spelling were strong and verbal-sequential processing had predictive value on word spelling nineteen months later when pre-existing spelling abilities were accounted for. Children with SLI and normal literacy skills performed better on most of the language and language-related measures than children with SLI and poor literacy skills. LEARNING OUTCOMES: As a result of this activity, readers will describe four language domains that are related to later literacy skills in children with Specific Language Impairment (SLI). As a result of this activity, readers will recognize the predictive value of each of these language domains and the important role of verbal-sequential processing in learning to decode and writing words for children with SLI. As a result of this activity, readers will recall the differences in language proficiencies between children with SLI who develop normal literacy skills and those who encounter literacy problems. PMID- 21251670 TI - Thoracic emphysematous lymphadenitis in a foal. AB - Emphysema of lymph nodes is a rare finding that has been described in different anatomical locations and related to specific diseases in different animal species. Herein is described a foal with Rhodococcus equi infection that presented with emphysema and granulomatous inflammation of the bronchial and mediastinal lymph nodes. This is the first report of emphysematous lymphadenitis in a horse. PMID- 21251671 TI - Accounting for disease modifying therapy in models of clinical progression in multiple sclerosis. AB - Identifying predictors of clinical progression in patients with relapsing remitting multiple sclerosis (RRMS) is complicated in the era of disease modifying therapy (DMT) because patients follow many different DMT regimens. To investigate predictors of progression in a treated RRMS sample, a cohort of RRMS patients was prospectively followed in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB). Enrollment criteria were exposure to either interferon-beta (IFN-beta, n=164) or glatiramer acetate (GA, n=114) for at least 6 months prior to study entry. Baseline demographic and clinical features were used as candidate predictors of longitudinal clinical change on the Expanded Disability Status Scale (EDSS). We compared three approaches to account for DMT effects in statistical modeling. In all approaches, we analyzed all patients together and stratified based on baseline DMT. Model 1 used all available longitudinal EDSS scores, even those after on-study DMT changes. Model 2 used only clinical observations prior to changing DMT. Model 3 used causal statistical models to identify predictors of clinical change. When all patients were considered using Model 1, patients with a motor symptom as the first relapse had significantly larger change in EDSS scores during follow-up (p=0.04); none of the other clinical or demographic variables significantly predicted change. In Models 2 and 3, results were generally unchanged. DMT modeling choice had a modest impact on the variables classified as predictors of EDSS score change. Importantly, however, interpretation of these predictors is dependent upon modeling choice. PMID- 21251672 TI - Detection of absorptive hypercalciuria type I without the oral calcium load test. AB - PURPOSE: We retrospectively analyzed the validity of a simple method of detecting absorptive hypercalciuria type I, a common stone forming condition with hypercalciuria that is believed to be due to high intestinal calcium absorption. The method is based on urinary calcium derived from 24-hour urine collections while on random and restricted diets rather than on a calciuric response to an oral calcium load. MATERIALS AND METHODS: A group of 916 well characterized patients with idiopathic calcium oxalate urolithiasis comprised the study group. We also analyzed a subgroup of 695 patients, excluding 221 with dietary abuse, defined as urinary sodium greater than 150 mEq daily and/or sulfate greater than 35 mmol daily, to eliminate potential confounding dietary factors affecting the diagnosis. In each group absorptive hypercalciuria type I was detected by the old criteria, requiring an exaggerated calciuric response to an oral calcium load test, and by the new criteria, based on 24-hour urinary calcium 200 mg or greater daily while on random and restricted diets. RESULTS: Using the old criteria as the gold standard the positive and negative predictive values, sensitivity and specificity of the new criteria were 80.1%, 95.9%, 90.8% and 90.5%, respectively. When excluding patients with dietary abuse the values were 85.9%, 97.2%, 92.4% and 94.5%, respectively. CONCLUSIONS: Absorptive hypercalciuria type I may be reliably detected by a simple method based on high 24-hour urinary calcium while on random and restricted diets, especially when excluding patients with evidence of dietary abuse during the restricted diet. PMID- 21251673 TI - Most bothersome symptom and symptom specific goal achievement in patients with benign prostatic obstruction: a prospective open label study. AB - PURPOSE: We evaluated symptom specific goal achievement, and the correlations between goal achievement and traditional outcome measures after pharmacological therapy in patients with benign prostatic obstruction. MATERIALS AND METHODS: Men 50 years old or older with lower urinary tract symptoms secondary to benign prostatic obstruction and International Prostate Symptom Score 8 or greater were enrolled and treated with 10 mg alfuzosin XL for 12 months. Before treatment, face-to-face interviews were conducted to identify the single most bothersome symptoms and to set treatment goals for the symptoms in individual patients. After treatment, patients described perceptions of goal achievement using a 5 point Likert scale. Changes in International Prostate Symptom Score/quality of life score, International Continence Society male short form questionnaire, 3-day voiding diary and uroflowmetry parameters were analyzed to evaluate the correlations between goal achievement and traditional outcome measures. RESULTS: Of 108 most bothersome symptoms slow stream (26.9%) was the most frequently reported followed by increased daytime frequency (21.3%) and nocturia (19.4%). After treatment the median score of goal achievement was 3 points with no significant difference among most bothersome symptoms. Changes in quality of life score (correlation coefficient -0.247, p=0.020) and maximal flow rate (correlation coefficient 0.254, p=0.021) were correlated with goal achievement. For men with most bothersome symptoms of storage, changes in the number of micturition and urgency episodes per 24 hours were correlated with goal achievement. For men with most bothersome symptoms of voiding the International Prostate Symptom Score voiding score was correlated with goal achievement. CONCLUSIONS: Assessing goal achievement for most bothersome symptoms can be a useful outcome measure in patients with benign prostatic obstruction with heterogeneous symptoms or goals reflecting change in quality of life. PMID- 21251674 TI - Editorial comment. PMID- 21251675 TI - Prevalence of nocturia in United States men: results from the National Health and Nutrition Examination Survey. AB - PURPOSE: We estimated the prevalence of nocturia in the United States male population and identified associated factors. MATERIALS AND METHODS: Data were analyzed for 5,297 men (20 years old or older) who participated in the 2005-2006 and 2007-2008 cycles of the NHANES, a cross-sectional survey of the United States noninstitutionalized population. Getting up 2 or more times at night to urinate was coded as nocturia. Potential factors included age, race/ethnicity, education, waist circumference, self-reported health status, chronic diseases, and prior diagnosis of benign prostatic enlargement and/or prostate cancer (men 40 years old or older). Prevalence and prevalence odds ratios were estimated from a multivariable logistic regression analysis using appropriate sampling weights. RESULTS: The prevalence of nocturia was 21% (weighted 95% CI 19.3-23.0). Nocturia increased in prevalence with age (p<0.001) from 8.2% (CI 6.7-10.2) in men 20 to 34 years old up to 55.8% (CI 51.3-60.2) in men 75 years old or older. More nonHispanic black men had nocturia (30.2%, CI 26.7-34.1) than other racial/ethnic groups (20.1%, CI 18.1-22.1, p<0.001). Significant factors included 10-year increase in age (POR 1.5, CI 1.5-1.6), nonHispanic black race/ethnicity (POR 2.0, CI 1.6-2.7), fair/poor self-rated health (POR 1.5, CI 1.2-1.9), major depression (POR 2.5, CI 1.6-3.9), hypertension (POR 1.4, CI 1.0-1.9) and arthritis (POR 1.3, CI 1.0-1.7). Among men 40 years old or older benign prostatic enlargement (POR 1.4, CI 1.1-1.8) and prostate cancer (POR 1.6, CI 1.0-2.4) were associated with nocturia. CONCLUSIONS: After adjusting for age and race norms nocturia was common among United States men. NonHispanic black men had greater odds of nocturia even when controlling for other factors. PMID- 21251676 TI - Intermediate term outcomes associated with the surveillance of ureteropelvic junction obstruction in adults. AB - PURPOSE: We determined the outcome of minimally symptomatic adult ureteropelvic junction obstruction in a group of patients treated conservatively with an active surveillance regimen. MATERIALS AND METHODS: A total of 27 patients with asymptomatic or minimally symptomatic ureteropelvic junction obstruction were treated conservatively. All patients were evaluated with diuretic renograms. Ureteropelvic junction obstruction was defined by an obstructive pattern of the clearance curve and/or T1/2 greater than 20 minutes. Followup consisted of an office visit and renogram every 6 to 12 months. Cases of greater than 10% loss of relative renal function of the affected kidney, development of pyelonephritis and/or more than 1 episode of acute pain were considered active surveillance failures, and treatment was recommended. RESULTS: Of the 27 patients 6 were lost to followup, leaving 21 (median age 47 years) with sufficient followup for analysis. In the 4 patients (19%) who initially presented with mild pain that led to the diagnosis of ureteropelvic junction obstruction, the pain completely resolved. Ipsilateral relative renal function decreased significantly in 2 patients (9.5%, mean reduction 14%). Pain worsened in 3 patients (14.3%) and de novo pain occurred in 1 (4.7%). Surgical intervention for ureteropelvic junction obstruction was required in 6 patients (29%) at an average of 34 months. In total 15 patients (71%) remained on surveillance with a mean followup of 48 months. CONCLUSIONS: Active surveillance seems to be a reasonable initial option for asymptomatic or mildly symptomatic adult patients with ureteropelvic junction obstruction because only approximately 30% have progression to surgical intervention within 4 years of diagnosis. This strategy offers the advantage of individualizing therapy according to symptoms and renographic findings. PMID- 21251677 TI - Laparoscopic nephrectomy for nonfunctioning kidneys is feasible after previous ipsilateral renal surgery: a prospective cohort trial. AB - PURPOSE: Previous renal surgery is a relative contraindication to laparoscopic nephrectomy because adhesion formation makes surgical dissection difficult. We determined whether previous surgery at the same anatomical site would affected the surgical outcome in patients who underwent transperitoneal laparoscopic nephrectomy. MATERIALS AND METHODS: During the study period 79 consecutive patients who underwent transperitoneal laparoscopic nephrectomy were evaluated prospectively. All patients had symptomatic nonfunctioning small or hydronephrotic kidneys. Patients were divided into 29 with and 50 without prior surgery at the same anatomical site. Previous surgery included open nephrolithotomy in 16 patients, percutaneous nephrolithotomy in 8, open and percutaneous nephrolithotomy in 3, pyelolithotomy in 1 and pyeloplasty in 1. RESULTS: Patients who underwent prior surgery were older than patients who did not (average age 46.6 vs 34.9 years, p=0.008). Other patient characteristics, including gender ratio, body mass index and side of surgery, did not differ significantly between the 2 groups. Mean operative time was longer in patients with previous surgery than in the other group (98.6 vs 62.3 minutes, p=0.03). Other operative data, including blood loss, intraoperative and postoperative complications, open conversion and hospital stay, were similar in the groups. One case per group was converted to open surgery due to difficult pedicle dissection. CONCLUSIONS: Transperitoneal laparoscopic nephrectomy in patients with a history of ipsilateral renal surgery can be done safely in timely fashion. Although mean operative time was longer, there was no significant increase in the operative complication rate in patients with prior surgery. PMID- 21251679 TI - Outcome of hand assisted laparoscopic bilateral native nephrectomy in transplant recipients. AB - PURPOSE: We explored the safety and reproducibility of hand assisted laparoscopic bilateral native nephrectomy. We also present our improvements to the surgical technique. MATERIALS AND METHODS: We retrospectively reviewed the charts of 36 patients who underwent hand assisted laparoscopic bilateral nephrectomy at our institution between 2003 and 2010. In all cases the 2 kidneys were removed transperitoneally via a hand assisted laparoscopic technique. RESULTS: Mean operative time was 222 minutes. Pathological kidney size was 20 to 34 cm. Mean hospital stay was 3 days (range 1 to 13). Average estimated blood loss was 175 cc (range 50 to 200). No patient required intraoperative blood transfusion. There were no intraoperative complications and no conversions to open surgery. Postoperatively complications developed in 8 patients (22%), including temporary adrenal insufficiency and pulmonary embolism in 1 each, and myocardial infarction, superficial wound infection and loss of arteriovenous fistula function in 2 each. According to the Clavien-Dindo classification complications were grades 1, 2, 3 and 4a in 2, 3, 1 and 2 patients, respectively. A total of 18 patients with kidney transplants continued to have normal graft function after surgery. CONCLUSIONS: Simultaneous hand assisted bilateral nephrectomies are safe and reproducible. The complication rate is low and postoperative hospital stay is short compared to those in published open surgery series. Graft function was preserved in patients who underwent renal transplantation before native kidney removal. PMID- 21251678 TI - Kidney stones and subclinical atherosclerosis in young adults: the CARDIA study. AB - PURPOSE: Recent reports suggest that nephrolithiasis and atherosclerosis share a number of risk factors. To our knowledge there has been no previous examination of the relationship between kidney stones and subclinical atherosclerotic disease. We studied the relationship between nephrolithiasis, and carotid wall thickness and carotid stenosis assessed by B-mode ultrasound in the general community using data from the CARDIA study. MATERIALS AND METHODS: The CARDIA study is a United States, population based, observational study of 5,115 white and African-American men and women between the ages of 18 and 30 years at recruitment in 1985 to 1986. RESULTS: By the year 20 examination 200 (3.9%) CARDIA participants had reported ever having kidney stones. Symptomatic kidney stones were associated with greater carotid wall thickness measured at the year 20 examination, particularly of the internal carotid/bulb region. Using a composite dichotomous end point of carotid stenosis and/or the upper quartile of internal carotid/bulb wall thickness, the association of kidney stones with carotid atherosclerosis was significant (OR 1.6, 95% CI 1.1-2.3, p=0.01), even after adjusting for major atherosclerotic risk factors. CONCLUSIONS: The association between a history of kidney stones and subclinical carotid atherosclerosis in young adults adds further support to the notion that nephrolithiasis and atherosclerosis share common systemic risk factors and/or pathophysiology. PMID- 21251680 TI - River discharge reduces reef coral diversity in Palau. AB - Coral community structure is often governed by a suite of processes that are becoming increasingly influenced by land-use changes and related terrestrial discharges. We studied sites along a watershed gradient to examine both the physical environment and the associated biological communities. Transplanted corals showed no differences in growth rates and mortality along the watershed gradient. However, coral cover, coral richness, and coral colony density increased with increasing distance from the mouth of the bay. There was a negative relationship between coral cover and mean suspended solids concentration. Negative relationships were also found between terrigenous sedimentation rates and the richness of adult and juvenile corals. These results have major implications not only for Pacific islands but for all countries with reef systems downstream of rivers. Land development very often leads to increases in river runoff and suspended solids concentrations that reduce coral cover and coral diversity on adjacent reefs. PMID- 21251681 TI - Vessel biofouling as an inadvertent vector of benthic invertebrates occurring in Brazil. AB - This article reviews the literature involving benthic invertebrates that are cited in association with hull fouling, reporting the species that occur on the Brazilian coast and evaluating the importance of this vector for the introduction of nonindigenous and cryptogenic invertebrates in Brazil. It discusses some of the strategies that were used by the species that allowed for their overseas transport and made it easier to cross natural barriers that otherwise would have been obstacles to their dispersion. The compiled data list 343 species (65% nonindigenous and 35% cryptogenic), mainly from the northwestern Atlantic Ocean. The traveling fauna, composed mostly of cosmopolitan species (70.3%), is primarily euryhaline and marine stenohaline, with sessile and sedentary habits. After delineating the shipborne species' ecological profiles and traveling strategies and evaluating their overlapping vectors, we concluded that hull vessels were the main vector of introduction to the Brazilian coast for 89.8% of the compiled species. PMID- 21251682 TI - Assessment of health safety from ingestion of natural radionuclides in seafoods from a tropical coast, India. AB - The activities of 210Po and 210Pb were determined in commonly consumed seafoods to evaluate the internal exposure and risk to humans residing Kudankulam coast where a mega nuclear power plant is under construction. The concentration of 210Po in seafoods ranged from 1.2 +/- 0.7 to 248 +/- 8.1 Bq kg-1. Meanwhile, 210Pb ranged between 1.1 +/- 0.05 and 14.8 +/- 1.6 Bq kg-1. The committed effective dose (CED) due to 210Po and 210Pb varied from 11.04 to 515.6 and 3.93 to 23.5 MUSv yr-1, respectively. The lifetime cancer risk for the public due to 210Po was in the range of 3.47 * 10-5- 1.62 * 10-3 and it was 4.03 * 10-5 - 1.96 * 10-4 due to 210Pb. The activity intake, effective dose and cancer risk was found lesser than international guidelines and the seafood intake was considered to be safe for human consumption. PMID- 21251683 TI - Comparison of CHOP treatment with specific short-intensive chemotherapy in AIDS related Burkitt's lymphoma or leukemia. AB - BACKGROUND AND OBJECTIVE: AIDS-related Burkitt's lymphoma or leukemia (BLL) is increasingly treated with specific and intensive multiagent schedules. This retrospective study aimed to compare the results of CHOP with those from two protocols (PETHEMA-LAL3/97 and BURKIMAB) of specific therapy in Spain. PATIENTS AND METHODS: Patients from Group A (n=31) received 6 standard CHOP cycles every 3 weeks. Patients from group B (n=44) received six multiagent cycles including high dose methotrexate and high-dose cytarabine. The response to therapy, disease-free survival and overall survival (OS) were compared in the two groups. RESULTS: Both groups were comparable for the main clinical and biological parameters at diagnosis except for risk activity, previous HAART, bone marrow involvement, bulky disease and extranodal involved sites. Complete remission (CR) was achieved in 10 out of 31 (32%) patients in group A and 28 out of 44 (67%) patients in group B (P=.005). After a median (range) follow-up of 70 (26-139) and 17 (1-134) months, the 5-year (95% CI) DFS probability was 87% (64%-100%) for group A and 70% (51%-89%) for group B (P=.374), and the 5-year (95% CI) OS was 27% (10%-43%) for Group A and 57% (40%-74%) for group B (P=.028). Multivariate analyses showed that specific therapy was associated with an improved CR and OS. CONCLUSIONS: In AIDS-related BLL short intensive specific chemotherapy is feasible, with higher remission rate and improved survival than that obtained with CHOP-based regimens. PMID- 21251684 TI - Insulin resistance: an independent risk factor for lung cancer? AB - Insulin resistance is closely associated with numerous metabolic disorders. Although studies have supported the importance of insulin resistance in carcinogenesis, the existing data have not established its relevance in the context of lung cancer. The aim of the present case-control study was to evaluate the association between insulin resistance and lung cancer after adjusting for possible confounders. Homeostasis model assessment of insulin resistance (HOMA IR) and serum leptin and adiponectin levels were determined in 81 lung cancer cases and 162 age- and sex-matched controls; anthropometric and lifestyle variables were recorded. Mean HOMA-IR in the cases was more than 2-fold higher compared with the mean value of controls (P < .001). Among controls, HOMA-IR correlated positively with serum leptin (r = 0.16; P = .04), body mass index (r = 0.43; P = .0001), and waist-to-hip ratio (r = 0.21; P = .01) but negatively with serum adiponectin (r = -0.29; P = .0002). As expected, smoking was associated with an approximately 10-fold increase in lung cancer risk in multiple logistic regression models. A positive association between HOMA-IR, treated as continuous variable, and lung cancer (odds ratio [OR] = 1.52, 95% confidence interval [CI]: 1.16-1.99, P = .002, model 1) was demonstrated, which persisted after adjustment for somatometric and lifestyle variables (OR = 2.36, 95% CI: 1.00-5.55, P = .05, model 2). When serum adiponectin was also taken into account, the association seemed fairly robust (OR = 2.58, 95% CI: 1.11-6.01, P = .03, model 3); on the contrary, when serum leptin was added, the association remained positive, but lost its statistical significance (OR = 1.76, 95% CI: 0.78-3.98, P = .17, model 4). In the fully adjusted model, HOMA-IR was still positively, but only marginally, associated with lung cancer risk (OR = 2.02, 95% CI: 0.88-4.65, P = .10, model 5). Insulin resistance may represent a meaningful risk factor for lung cancer. PMID- 21251686 TI - Serum osteoprotegerin and tumor necrosis factor related apoptosis inducing-ligand (TRAIL) are elevated in type 2 diabetic patients with albuminuria and serum osteoprotegerin is independently associated with the severity of diabetic nephropathy. AB - Osteoprotegerin (OPG) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have recently been reported to be associated with diabetic nephropathy in an in vitro study. However, the literature regarding serum OPG and TRAIL in type 2 diabetes mellitus patients is scarce. To investigate the role of OPG/TRAIL in diabetic nephropathy, we measured the serum concentrations of OPG and TRAIL in type 2 diabetes mellitus patients with different stages of nephropathy by enzyme linked immunosorbent assay. One hundred seventy-nine subjects with type 2 diabetes mellitus were studied and stratified according to urinary microalbumin and serum creatinine measurements. The serum concentrations of OPG and TRAIL were significantly elevated in patients with microalbuminuria (OPG, 2154.2 +/- 922.1 pg/mL; TRAIL, 80.2 +/- 24.1 pg/mL) and macroalbuminuria (OPG, 2251.5 +/- 925.7 pg/mL; TRAIL, 88.1 +/- 23.8 pg/mL) as compared with patients with normoalbuminuria (OPG, 1690.1 +/- 627.2 pg/mL; TRAIL, 70.7 +/- 23.3 pg/mL). Serum OPG and TRAIL levels were increased in parallel and were significantly associated with each other. Using multivariate stepwise regression analysis, serum OPG was found to be an independent factor associated with the severity of diabetic nephropathy. Our results suggested that serum OPG may be a marker for the severity of diabetic nephropathy. Further studies are necessary to investigate the role of elevated serum OPG in the pathogenesis of diabetic nephropathy. PMID- 21251685 TI - Short-term hyperglycemia increases arterial superoxide production and iron dysregulation in atherosclerotic monkeys. AB - The incidence and severity of atherosclerotic vascular disease are increased in diabetic patients, in part because of increased production of reactive oxygen species (ROS). Previously, we found both increased atherosclerosis and arterial protein oxidation 6 months after streptozotocin-induced diabetes in monkeys fed an atherogenic diet, the pattern of which was indicative of redox-active transition metal involvement. The goal of this study was to determine if short term (1 month) hyperglycemia increases oxidative stress and dysregulates iron metabolism before differences in atherosclerosis. Cynomolgus monkeys with preexisting atherosclerosis were stratified by dietary history and plasma lipids and received either streptozotocin (STZ-DM; n = 10) or vehicle (control; n = 10). One month after diabetes induction, blood and artery samples were collected. There were no differences in plasma lipoprotein cholesterol, arterial cholesterol, and atherosclerosis between control and STZ-DM. However, plasma lipid peroxides were elevated 137% (P < .01); arterial superoxide was increased 47% (P < .05); plasma ferritin, an indicator of whole-body iron stores, was 46% higher (P < .05); and iron deposition within aortic atherosclerotic lesions was more prevalent in STZ-DM compared with controls. Arterial levels of the antioxidant enzymes, superoxide dismutase, catalase, and heme oxygenase-1 were not higher in STZ-DM, although superoxide was higher, suggesting impaired antioxidant response. The increase in ROS before differences in atherosclerosis supports ROS as an initiating event in diabetic vascular disease. Further studies are needed to determine if increases in iron stores and arterial iron deposition promote hydroxyl radical formation from superoxide and accelerate diabetic vascular damage. PMID- 21251687 TI - [Giant thoracolumbar synovial cyst: case report]. AB - METHODS: A case report of a giant thoracolumbar synovial cyst is presented. RESULTS: A 74-year-old woman presented with a chronic lumbar pain associated with pain in the left leg. MR imaging showed a voluminous extradural cyst extending from T12 to L2. The cyst was surgically removed entirely. Microscopic examination revealed a synovial cyst. CONCLUSIONS: In spite of a careful review of the literature, no other description of a giant thoracolumbar synovial cyst developed on three metameric levels was found. The diagnosis was made with a MRI scan combined with microscopic examination. The pathogenesis and therapeutic strategy are discussed. PMID- 21251688 TI - Characterization of species C human adenovirus serotype 6 (Ad6). AB - Adenovirus serotype (Ad5) is the most studied Ad. Ad1, 2, and 6 are also members of species C Ad and are presumed to have biologies similar to Ad5. In this work, we have compared the ability of Ad1, 2, 5, and 6 to infect liver and muscle after intravenous and intramuscular injection. We found that Ad6 was surprisingly the most potent at liver gene delivery and that Ad1 and Ad2 were markedly weaker than Ad5 and 6. To understand these differences, we sequenced the Ad6 genome. This revealed that the Ad6 fiber protein is surprisingly three shaft repeats shorter than the others which may explain differences in virus infectivity in vitro, but not in the liver. Comparison of hexon hypervariable regions (HVRs) suggests that the higher transduction by Ad5 and 6 as compared to Ad1 and 2 may be related to differences in charge and length. PMID- 21251689 TI - Dynamic control of endogenous retroviruses during development. AB - Close to half of the human genome encompasses mobile genetic elements, most of which are retrotransposons. These genetic invaders are formidable evolutionary forces that have shaped the architecture of the genomes of higher organisms, with some conserving the ability to induce new integrants within their hosts' genome. Expectedly, the control of endogenous retroviruses is tight and multi-pronged. It is most crucially established in the germ line and during the first steps of embryogenesis, primarily through transcriptional mechanisms that have likely evolved under their very pressure, but are now engaged in controlling gene expression at large, notably during early development. PMID- 21251691 TI - Differential host gene responses in mice infected with two highly pathogenic avian influenza viruses of subtype H5N1 isolated from wild birds in Thailand. AB - In Thailand, highly pathogenic avian influenza (HPAI) viruses of subtype H5N1 had been isolated from various wild birds during the HPAI outbreak in poultries. In this study, we examined the pathogenicity of two wild bird isolates (A/Pigeon/Thailand/VSMU-7-NPT/2004; Pigeon04 and A/Tree sparrow/Ratchaburi/VSMU 16-RBR/2005; T.sparrow05) in mice. They showed similar replication in several organs and lethal outcome. However, on day 3 post-infection, Pigeon04 induced mRNA expression of proinflammatory cytokines (IL6 and TNFalpha) and MIP-2, neutrophil chemoattractant, in the lungs, resulting in severe pneumonia that was accompanied by neutrophil infiltration. In contrast, on day 7 post-infection, T.sparrow05 induced the expression of several cytokines to a greater extent than Pigeon04; it also potently induced mRNA expression of several cytokines in brains of the infected mice that triggered frequent inflammatory events. In sum, our study demonstrated that two HPAI viruses induced different host responses, despite having similar replications, resulting in lethal outcome in mice. PMID- 21251692 TI - Oxidation of 2,4-dichlorophenol and 3,4-dichlorophenol by means of Fe(III) homogeneous photocatalysis and algal toxicity assessment of the treated solutions. AB - Chlorophenols are used worldwide as broad-spectrum biocides and fungicides. They have half-life times in water from 0.6 to 550 h and in sediments up to 1700 h and, due to their numerous origins, they can be found in wastewaters, groundwaters or soils. Moreover, chlorophenols are not readily biodegradable. Recently, classic Advanced Oxidation Processes (AOP) have been proposed for their abatement in an aqueous solution. This paper investigates the oxidation of 2,4 dichlorophenol and 3,4-dichlorophenol, at starting concentrations of 6.1 . 10(-5) mol L(-1), in aqueous solutions through Fe(III)/O(2) homogeneous photocatalysis under UV light (303 / 366 nm). The Fe(III)/O(2) homogeneous photocatalysis is less expensive than using H(2)O(2) due to the capability of Fe(III) to produce OH radicals, if irradiated with an UVA radiation, and of oxygen to re-oxidize ferrous ions to ferric ones when dissolved in solution. The results show that the best working conditions, for both compounds, are found for pH=3.0 and initial Fe(III) concentration equal to 1.5 . 10(-4) mol L(-1) although the investigated oxidizing system can be used even at pH close to 4.0 but with slower abatement kinetics. Toxicity assessment on algae indicates that treated solutions of 2,4 dichlorophenol are less toxic on algae Pseudokirchneriella subcapitata if compared to not treated solutions whereas in the case of 3,4-dichlorophenol only the samples collected during the runs at 20 and 60 min are capable of inhibiting the growth of the adopted organism. The values of the kinetic constant for the photochemical re-oxidation of iron (II) to iron (III) and for HO attack to intermediates are evaluated by a mathematical model for pH range of 2.0-3.0 and initial Fe(III) concentrations range of 1.5 . 10(-5)-5.2 . 10(-4) mol L(-1). PMID- 21251693 TI - Histopathological and biochemical alterations of the earthworm (Lumbricus Terrestris) as biomarker of soil pollution along Porsuk River Basin (Turkey). AB - This study investigated biomarker responses of the earthworm Lumbricus terrestris in order to evaluate the soil pollution along Porsuk River Basin. Samples consisted of animals from six sites that are agricultural regions and a forested control. Histopathological and biochemical alterations were examined. Significant histopathological alterations were observed in animals from three of the sampling sites. There was an enlargement of epithelial cell lining, mucus cell hyperplasia and increase in mucus secretion. Circular and longitudinal muscles lost their structural integrity. Chloragogenous tissue was dilated and vocuolized. Necrosis was observed in the cells and tissues of some affected worms. A load of heavy metals in tissues of animals was determined. Heavy metals were found to be accumulated particularly in longitudinal muscles of animals. CAT activity was found to be increased in animals from three of the experimental sites. GST activity was also increased in five sites while it was stable in one site. The results have shown that animals from locations particularly that are close to urbanized and industrialized regions were seriously affected from the soil pollution around the basin. These results are reflecting the biological effects of soil pollution around Porsuk River Basin on the indicator organism L. terrestris and constitute an early warning of ecological change in relation to human health. PMID- 21251694 TI - PTR-MS measurements and analysis of models for the calculation of Henry's law constants of monosulfides and disulfides. AB - Sulfides are known for their strong odor impact even at very low concentrations. Here, we report Henry's law constants (HLCs) measured at the nanomolar concentration range in water for monosulfides (dimethylsulfide, ethylmethylsulfide, diethylsulfide, allylmethylsulfide) and disulfides (dimethyldisulfide, diethylsulfide, dipropylsulfide) using a dynamic stripping technique coupled to Proton Transfer Reaction-Mass Spectrometry (PTR-MS). The experimental data were compared with literature values and to vapor/solubility calculations and their consistency was confirmed employing the extra thermodynamic enthalpy-entropy compensation effect. Our experimental data are compatible with reported literature values, and they are typically lower than averaged experimental literature values by about 10%. Critical comparison with other freely available models (modeled vapor/solubility; group and bond additivity methods; Linear Solvation Energy Relationship; SPARC) was performed to validate their applicability to monosulfides and disulfides. Evaluation of theoretical models reveals a large deviation from our measured values by up to four times (in units of Matm(-1)). Two group contribution models were adjusted in view of the new data, and HLCs for a list of sulfur compounds were calculated. Based on our findings we recommend the evaluation and adaption of theoretical models for monosulfides and disulfides to lower values of solubility and higher values of fugacity. PMID- 21251690 TI - Enterovirus infections of the central nervous system. AB - Enteroviruses (EV) frequently infect the central nervous system (CNS) and induce neurological diseases. Although the CNS is composed of many different cell types, the spectrum of tropism for each EV is considerable. These viruses have the ability to completely shut down host translational machinery and are considered highly cytolytic, thereby causing cytopathic effects. Hence, CNS dysfunction following EV infection of neuronal or glial cells might be expected. Perhaps unexpectedly given their cytolytic nature, EVs may establish a persistent infection within the CNS, and the lasting effects on the host might be significant with unanticipated consequences. This review will describe the clinical aspects of EV-mediated disease, mechanisms of disease, determinants of tropism, immune activation within the CNS, and potential treatment regimes. PMID- 21251695 TI - Rapid determination of dichlorodiphenyltrichloroethane and its main metabolites in aqueous samples by one-step microwave-assisted headspace controlled temperature liquid-phase microextraction and gas chromatography with electron capture detection. AB - A rapid and sensitive analytical method for the determination of dichlorodiphenyltrichloroethane (DDT) and its main metabolites in environmental aqueous samples has been developed using one-step microwave-assisted headspace controlled-temperature liquid-phase micro-extraction (MA-HS-CT-LPME) technique coupled with gas chromatography-electron-capture detection (GC-ECD). In this study, the one-step extraction of DDT and its main metabolites was achieved by using microwave heating to accelerate the evaporation of analytes into the controlled-temperature headspace to form a cloudy mist vapor zone for LPME sampling. Parameters influencing extraction efficiency were thoroughly optimized, and the best extraction for DDT and its main metabolites from 10-mL aqueous sample at pH 6.0 was achieved by using 1-octanol (4-MUL) as the LPME solvent, sampling at 34 degrees C for 6.5 min under 249W of microwave irradiation. Under optimum conditions, excellent linear relationship was obtained in the range of 0.05-1.0 MUg/L for 1-dichloro-2,2-bis-(p'-chlorophenyl)ethylene (p,p'-DDE), 0.1 2.0 MUg/L for o,p'-DDT, 0.15-3.0 MUg/L for 1,1-dichloro-2,2-bis-(p' chlorophenyl)ethane (p,p'-DDD) and p,p'-DDT, with detection limits of 20 ng/L for p,p'-DDE, and 30 ng/L for o,p'-DDT, p,p'-DDD and p,p'-DDT. Precision was in the range of 3.2-11.3% RSD. The proposed method was validated with environmental water samples. The spiked recovery was between 95.5% and 101.3% for agricultural field water, between 94% and 99.7% for sea water and between 93.5% and 98% for river water. Thus the established method has been proved to be a simple, rapid, sensitive, inexpensive and eco-friendly procedure for the determination of DDT and its main metabolites in environmental water samples. PMID- 21251696 TI - Dissolution of beryllium in artificial lung alveolar macrophage phagolysosomal fluid. AB - Dissolution of a lung burden of poorly soluble beryllium particles is hypothesized to be necessary for development of chronic beryllium lung disease (CBD) in humans. As such, particle dissolution rate must be sufficient to activate the lung immune response and dissolution lifetime sufficient to maintain chronic inflammation for months to years to support development of disease. The purpose of this research was to investigate the hypothesis that poorly soluble beryllium compounds release ions via dissolution in lung fluid. Dissolution kinetics of 17 poorly soluble particulate beryllium materials that span extraction through ceramics machining (ores, hydroxide, metal, copper-beryllium [CuBe] fume, oxides) and three CuBe alloy reference materials (chips, solid block) were measured over 31 d using artificial lung alveolar macrophage phagolysosomal fluid (pH 4.5). Differences in beryllium-containing particle physicochemical properties translated into differences in dissolution rates and lifetimes in artificial phagolysosomal fluid. Among all materials, dissolution rate constant values ranged from 10(-5) to 10(-10)gcm(-2)d(-1) and half-times ranged from tens to thousands of days. The presence of magnesium trisilicate in some beryllium oxide materials may have slowed dissolution rates. Materials associated with elevated prevalence of CBD had faster beryllium dissolution rates [10(-7)-10(-8)gcm(-2)d(-1)] than materials not associated with elevated prevalence (p<0.05). PMID- 21251697 TI - Nonlinear associations between blood lead in children, age of child, and quantity of soil lead in metropolitan New Orleans. AB - Previous studies identified a curvilinear association between aggregated blood lead (BL) and soil lead (SL) data in New Orleans census tracts. In this study we investigate the relationships between SL (mg/kg), age of child, and BL (MUg/dL) of 55,551 children in 280 census tracts in metropolitan New Orleans, 2000 to 2005. Analyses include random effects regression models predicting BL levels of children (MUg/dL) and random effects logistic regression models predicting the odds of BL in children exceeding 15, 10, 7, 5, and 3 MUg/dL as a function of age and SL exposure. Economic benefits of SL reduction scenarios are estimated. A unit raise in median SL0.5 significantly increases the BL level in children (b=0.214 p= or <0.01), and a unit change in Age0.5 significantly increases child BL (b=0.401, p= or <0.01). A unit change in Age0.5 increases the odds of a child BL exceeding 10 MUg/dL by a multiplicative factor of 1.23 (95% CI 1.21 to 1.25), and a unit (mg/kg) addition of SL increases the odds of child BL> 10 MUg/dL by a factor of 1.13 (95% CI 1.12 to 1.14). Extrapolating from regression results, we find that a shift in SL regulatory standard from 400 to 100 mg/kg provides each child with an economic benefit ranging from $4710 to $12,624 ($US 2000). Children's BL is a curvilinear function of both age and level of exposure to neighborhood SL. Therefore, a change in SL regulatory standard from 400 to 100mg/kg provides children with substantial economic benefit. PMID- 21251698 TI - The polyphenol-rich extract from grape seeds suppresses toxicity of homocysteine and its thiolactone on the fibrinolytic system. PMID- 21251699 TI - Impact of sex hormones, insulin, growth factors and peptides on cartilage health and disease. AB - Sex hormones contribute to the pathogenesis of osteoarthritis (OA) in both sexes. OA is normally not seen in pre-menopausal women, whereas men may develop the disease as early as the 30th year of life. OA also shows increased incidence in association with diseases such as diabetes mellitus. Recent years have seen characterization of essential components of a functional endocrinal network in the articular cartilage comprising not only sex hormones but apparently insulin, growth factors and various peptides as well. In this review, we summarize the latest information regarding the influence of sex hormones, insulin, growth factors and some peptides on healthy cartilage and their involvement in osteoarthritis. Both animal and human research data were considered. The results are presented in an information matrix that identifies what is known, with supporting references, and identifies areas for further investigation. PMID- 21251700 TI - DNA ploidy, nuclear size, proliferation index and DNA-hypomethylation in ovarian cancer. AB - OBJECTIVE: The present study was undertaken to analyze the impact of epigenetic alterations with a main focus on nuclear area, aneuploidy, hyperploidy, and proliferation in 70 ovarian cancer specimens. METHODS: Morphometric changes and somatic chromosomal ploidy status were assessed by Feulgen spectrophotometry. DNA hypomethylation of LINE1 repeats was analyzed by means of MethyLight PCR, and methylation levels of satellite 2 (Sat2) and satellite alpha (Satalpha) DNA sequences in chromosome 1 were measured by Southern blot analysis. These parameters were analyzed with regard to correlations as well as to recurrence and survival. RESULTS: We identified a significant association between LINE1 DNA hypomethylation and patient age (p=0.029). Furthermore, LINE1 DNA-hypomethylation was positively correlated with the nuclear area (r=0.47; p<0.001) and the proliferation index (r=0.36; p<0.001). Univariate survival analysis showed that the nuclear area and LINE1 DNA-hypomethylation were prognostic factors for overall (p=0.015 and =0.006, respectively) and progression-free survival (p=0.020 and p=0.001 respectively), the percentage of aneuploidy only for overall survival (p=0.031). Subgroup survival analyses revealed that the prognostic value of these factors is strictly confined to mucinous cancers. In serous cancers no prognostic value could be pointed out for any analyzed parameter. Multivariate analysis of the entire cohort showed that the percentage of hyperploidy was an independent prognostic parameter for overall survival (p=0.003) and LINE1 DNA-hypomethylation for progression-free survival (p=0.03). In mucinous cancers nuclear area and LINE1 DNA-hypomethylation were found to be independent predictors of progression free and overall survival. CONCLUSIONS: In this study we identified the correlations between early cancer-associated genome DNA-hypomethylation, nuclear morphometric changes, somatic chromosomal ploidy status and the proliferation index. Prognostic relevance of nuclear area and LINE1 DNA-hypomethylation was revealed exclusively in mucinous ovarian cancers. PMID- 21251701 TI - Birch pollen-related food allergy: clinical aspects and the role of allergen specific IgE and IgG4 antibodies. AB - BACKGROUND: Patients with birch pollen allergy often develop allergic reactions to plant foods. OBJECTIVE: To evaluate the prevalence, main symptoms, and triggers of birch pollen-related food allergy and the role of food-specific IgG(4) antibodies in food tolerance. METHODS: Food-induced symptoms were evaluated in 225 individuals with birch pollen allergy by using a standardized questionnaire. IgE and IgG(4) levels specific for the major birch pollen allergen Bet v 1 and birch profilin Bet v 2 and the Bet v 1 homologs in apple (Mal d 1) and hazelnut (Cor a 1) were quantified by ImmunoCAP. Mock-treated and IgG depleted sera from patients tolerating hazelnuts in food challenges were compared for their inhibitory activity for binding of Cor a 1-IgE complexes to B cells. RESULTS: In total, 73% of the study population experienced food allergy, which was perennial in 86% of the affected individuals. The oral allergy syndrome was the main clinical manifestation. However, more than 58% of the patients also experienced food-induced rhinoconjunctivitis. Apples and hazelnuts were identified as the most frequent triggers. Food allergy correlated with IgE reactivity to Bet v 1 but not to Bet v 2. Mal d 1-specific and Cor a 1-specific IgG(4)/IgE ratios were significantly higher in food-tolerant individuals than individuals with food allergy. Sera from IgG(4)-positive food-tolerant patients possessed IgG-dependent IgE-inhibitory activity. CONCLUSION: Birch pollen-related food allergy is highly prevalent and often perennial. High food allergen-specific IgG(4)/IgE ratios seem associated with food tolerance, potentially because specific IgG(4) blocks IgE binding to food allergens. Thus, the presence of food allergen-specific IgG(4) antibodies is no diagnostic marker for birch pollen related food allergy. PMID- 21251702 TI - The advent of recombinant allergens and allergen cloning. AB - When the allergen nomenclature system was adopted in 1986, allergens were identified by their behavior on electrophoresis and chromatography and by reactivity to shared antisera. Not only was this unsatisfactory for standardization, but the processes of allergic sensitization and immunotherapy could not be studied in the framework of antigen processing and B- and T-cell epitopes. Recombinant technologies developed in the 1980s for cloning cDNA from low-abundance mRNA permitted the cloning of allergens, beginning with the major house dust mite allergen Der p 1 and hornet allergen Dol m 5. After this, a wave of cloning with IgE immunoscreening resulted in the cloning of Der p 2, Der p 5, Bet v 1, Bet v 2, and Dac g 2 along with Fel d 1 cloned after amino acid sequencing. Recombinant allergens have now been used to define the important allergens for a wide range of allergies and to develop new types of immunotherapy, some of which have shown efficacy in human trials. The clonally pure allergens have been used to solve the tertiary structures of allergens and from this how allergens might activate innate immunity. Proprietary recombinant allergens are now being used in improved diagnostic tests. PMID- 21251703 TI - Comparison of three diagnostic methods to identify subclinical endometritis in mares. AB - The objective of this study was to compare the accuracy of a uterine swab (US), a cytological brush (CB) and an endometrial biopsy (EB) to detect subclinical endometritis in mares. Cytological and bacteriological results of all three techniques were related to histological occurrence of polymorphonuclear neutrophils (PMNs) in the stratum compactum, commonly known as 'best standard'; to diagnose endometritis. Samples were taken from 55 mares of different breeds without clinical signs of endometritis. Samples for US, CB and EB were collected, smeared on a microscopic slide and cultured for bacterial growth. Endometrial biopsy samples were additionally stored in 4% formaldehyde for histological analysis. Bacteriological cultures and cytological samples of all techniques were classified as negative (no uterine pathogens in monoculture; < 2% PMNs) or positive (uterine pathogens in > 90% of the grown colonies; > 2% PMNs) for endometritis. Uterine pathogens were diagnosed in 20.0% of the mares. Isolation of pathogens was not associated with positive cytological findings (r = -0.23; P = 0.87). None of the six mares with an Escherichia coli infection (10.9%) showed a positive cytological result. In contrast, two of five mares infected with Streptococcus zooepidemicus had a positive cytological result. Histologically, the presence of PMNs in the stratum compactum was regarded as positive for endometritis when the mare was in diestrus at time of sampling. Compared to the 'best standard', sensitivity for cytology of CB, US and EB was 0.17, 0.00 and 0.25, respectively. Specificity for cytology of CB, US and EB was 0.83, 0.93 and 0.85, respectively. Sensitivity of uterine culture was 0.25, 0.33 and 0.25 for CB, US and EB, respectively. Specificity for culture of CB, US and EB was 0.80, 0.83 and 0.95, respectively. In conclusion, cytological or bacteriological examinations alone provide a high incidence of false negative results. Sensitivity of cytology combined with bacteriology of CB was 0.42. A combination of a bacteriological and a cytological examination of a CB sample improved the diagnostic performance in subfertile mares. Based on these results, we can recommend the CB to improve the diagnosis of subclinical endometritis in the mare compared to the US alone as currently used routine method. PMID- 21251704 TI - An intervention program focused on self-understanding and interpersonal interactions to prevent psychosocial distress among Japanese university students. AB - This study evaluated the impact of a preventive intervention program focused on self-understanding and interpersonal interactions to prevent psychosocial distress among Japanese university students. Two hundred and twenty-two undergraduate students were divided into a treatment group and a control group to complete Time 1 and Time 2 surveys. The intervention program included eleven weekly sessions covering self-understanding, self-control, interpersonal relationships, problem solving, conflict resolution, and stress management. Both female and male students in the treatment group reported a significant increase in social self-efficacy in interpersonal relationships from Time 1 to Time 2, but no significant changes were noted in the control group. Anxiety significantly decreased from Time 1 to Time 2, and no difference in depression was noted in the female treatment group, although anxiety and depression significantly increased in the female control group. The intervention program effectively prevented some aspects of psychosocial distress. PMID- 21251706 TI - Augmented CPR: rescue after the ResQ trial. PMID- 21251705 TI - Standard cardiopulmonary resuscitation versus active compression-decompression cardiopulmonary resuscitation with augmentation of negative intrathoracic pressure for out-of-hospital cardiac arrest: a randomised trial. AB - BACKGROUND: Active compression-decompression cardiopulmonary resuscitation (CPR) with decreased intrathoracic pressure in the decompression phase can lead to improved haemodynamics compared with standard CPR. We aimed to assess effectiveness and safety of this intervention on survival with favourable neurological function after out-of-hospital cardiac arrest. METHODS: In our randomised trial of 46 emergency medical service agencies (serving 2.3 million people) in urban, suburban, and rural areas of the USA, we assessed outcomes for patients with out-of-hospital cardiac arrest according to Utstein guidelines. We provisionally enrolled patients to receive standard CPR or active compression decompression CPR with augmented negative intrathoracic pressure (via an impedance-threshold device) with a computer-generated block randomisation weekly schedule in a one-to-one ratio. Adults (presumed age or age >=18 years) who had a non-traumatic arrest of presumed cardiac cause and met initial and final selection criteria received designated CPR and were included in the final analyses. The primary endpoint was survival to hospital discharge with favourable neurological function (modified Rankin scale score of <=3). All investigators apart from initial rescuers were masked to treatment group assignment. This trial is registered with ClinicalTrials.gov, number NCT00189423. FINDINGS: 2470 provisionally enrolled patients were randomly allocated to treatment groups. 813 (68%) of 1201 patients assigned to the standard CPR group (controls) and 840 (66%) of 1269 assigned to intervention CPR received designated CPR and were included in the final analyses. 47 (6%) of 813 controls survived to hospital discharge with favourable neurological function compared with 75 (9%) of 840 patients in the intervention group (odds ratio 1.58, 95% CI 1.07-2.36; p=0.019]. 74 (9%) of 840 patients survived to 1 year in the intervention group compared with 48 (6%) of 813 controls (p=0.03), with equivalent cognitive skills, disability ratings, and emotional-psychological statuses in both groups. The overall major adverse event rate did not differ between groups, but more patients had pulmonary oedema in the intervention group (94 [11%] of 840) than did controls (62 [7%] of 813; p=0.015). INTERPRETATION: On the basis of our findings showing increased effectiveness and generalisability of the study intervention, active compression-decompression CPR with augmentation of negative intrathoracic pressure should be considered as an alternative to standard CPR to increase long term survival after cardiac arrest. FUNDING: US National Institutes of Health grant R44-HL065851-03, Advanced Circulatory Systems. PMID- 21251707 TI - An assessment of the risks of carcinogenicity associated with polyhydroxyalkanoates through an analysis of DNA aneuploid and telomerase activity. AB - Polyhydroxyalkanoates (PHA) are aliphatic polyesters synthesized by many bacteria. Because of their flexible mechanical strengths, superior elastic property, biodegradability and biocompatibility, PHA have been developed for applications as medical implants, drug delivery matrices, and devices to support cell growth. Lots of studies showed that PHA matrices improved cell proliferation and tissue regeneration. However, the possibility of whether rapid cell proliferation on PHA matrices will induce tumor formation is unclear. Here we confirmed that proliferating rat osteoblasts grown on films of various PHA including PHB, PHBV, P3HB4HB, PHBHHx and PHBVHHx did not lead to cancer induction at least for p8th. Cell proliferation was evaluated by the incorporation of 5 bromodeoxyuridine (BrdU), the transcript expression of cancer related genes Ki67, p53 and c-Fos was monitored by quantitative Real-time PCR, the results showed the cells proliferating on the PHA films were under normal cell cycle regulation. Moreover, DNA aneuploid and telomerase activity were only detected in the positive control UMR-108 cells; compared with cells grown on films, UMR-108 cells had longer telomeres, further demonstrated the normal status of cells proliferating on the PHA films. It indicated that the above PHA family members could be used to support cell growth without indication of susceptibility to tumor induction. These results will be important for promoting the application of PHA as new members of biomaterials. PMID- 21251708 TI - Cultivation and recovery of vascular endothelial cells in microchannels of a separable micro-chemical chip. AB - Various micro cell culture systems have recently been developed. However, it is extremely difficult to recover cultured cells from a microchannel because the upper and lower substrates of a microchip are permanently combined. Therefore, we developed a cell culture and recovery system that uses a separable microchip with reversible combining that allows separation between closed and open channels. To realize this system, two problems related to microfluidic control-prevention of leakage and non-invasive recovery of cultured cells from the substrate-must be overcome. In the present study, we used surface chemistry modification to solve both problems. First, octadecyltrimethoxysilane (ODTMS) was utilized to control the Laplace pressure at the liquid/vapor phase interface, such that it was directed toward the microchannels, which suppressed leakage from the slight gap between two substrates. Second, a thermoresponsive polymer poly(N-isopropyl acrylamide) (PNIPAAm) was used to coat the surface of the ODTMS-modified microchannel by UV-mediated photopolymerization. PNIPAAm substrates are well known for controlled cell adhesion/detachment by alteration of temperature. Finally, the ODTMS- and PNIPAAm-modified separable microchips were subjected to patterning, and human arterial endothelial cells (HAECs) were cultured in the resulting microchannels with no leakage. After 96 h of the culture, the HAECs were detached from the microchips by decreasing the temperature and were then recovered from the microchannels. This study is the first to demonstrate the recovery of living cells cultured in a microchannel, and may be useful as a fundamental technique for vascular tissue engineering. PMID- 21251709 TI - Silk fibroin in ocular tissue reconstruction. AB - The silk structural protein fibroin displays potential for use in tissue engineering. We present here our opinion of its value as a biomaterial for reconstructing tissues of clinical significance within the human eye. We review the strengths and weaknesses of using fibroin in those parts of the eye that we believe are most amenable to cellular reconstruction, namely the corneoscleral limbus, corneal stroma, corneal endothelium and outer blood-retinal barrier (Ruysch's complex). In these areas we find that by employing the range of manufacturing products afforded by fibroin, relevant structural assemblies can be made for cells expanded ex vivo. Significant questions now need to be answered concerning the effect of this biomaterial on the phenotype of key cell types and the biocompatibility of fibroin within the eye. We conclude that fibroin's strength, structural versatility and potential for modification, combined with the relative simplicity of associated manufacturing processes, make fibroin a worthy candidate for further exploration. PMID- 21251710 TI - Modulation of biological processes in the nucleus by delivery of DNA oligonucleotides conjugated with gold nanoparticles. AB - The development of a method that can efficiently deliver nucleic acids into the nucleus of living systems remains one of the key challenges for experimental and therapeutic use of nonbiological gene delivery agents. In the current study, we demonstrate a functionalized gold nanoparticle (AuNP) that can serve as a universal carrier for the delivery of DNA oligonucleotides (oligos) into the nucleus. We designed various types of DNA oligos to redirect alternative splicing of pre-mRNAs, such as MCL-1 and BCL-6, and to sequester transcriptional factors, including estrogen receptor alpha and p53. We successfully delivered the oligos into the nucleus, resulting in the targeted effects. In addition, injection of the antisense DNAs into a xenograft tumor in a mouse model system resulted in inhibited development of the tumor by redirecting the alternative splicing of the pre-mRNA. Our findings show that these nanoconjugates efficiently load and deliver antisense DNAs to redirect gene splicing or double-stranded DNAs to decoy gene transcription by transcriptional factors into mammalian cells and in vivo animals. Therefore, our lego-like AuNP gene delivery system can be used universally to control different biological processes by modulating nuclear gene expression events in living systems. PMID- 21251711 TI - Intracellularly monitoring/imaging the release of doxorubicin from pH-responsive nanoparticles using Forster resonance energy transfer. AB - Stimuli-responsive nanoparticles (NPs) have been receiving much attention as a drug-delivery vehicle for therapeutic applications; once internalized into cells, the intracellular fate of NPs and their drug release behavior in response to local stimuli must be understood for efficient delivery of therapeutics. In this study, we prepared pH-responsive doxorubicin (DOX)-loaded NPs, made of N palmitoyl chitosan bearing a Cy5 moiety (Cy5-NPCS), as an anticancer delivery device. The results of our molecular dynamic simulations showed that the ability of Cy5-NPCS to self-associate offered the close proximity between the donor (DOX) and the acceptor (Cy5) required for Forster resonance energy transfer (FRET), while the pH-driven structure transition prescribed the on-to-off switch of the energy transfer. The caveolae-mediated pathway played a major role in the internalization of NPCS NPs. Using the concept of FRET, we found that the DOX fluorescence in the cytosol was first seen when NPCS NPs were present in the slightly acidic early endosomes. Following NPCS NPs trafficking into a more acidic organelle (late endosomes/lysosomes), a more evident release of DOX into the cytosol was observed; the released DOX was then gradually accumulated in the cell nuclei, leading to a significant cytotoxicity. Understanding the fate of NPs with respect to their intracellular localization and drug release behavior is crucial for the rational design of drug carriers. PMID- 21251712 TI - Review: Preclinical studies on placenta-derived cells and amniotic membrane: an update. AB - Recent years have seen considerable advances in our knowledge of the biology and properties of stem/progenitor cells isolated from placental tissues. This has encouraged researchers to address the potential effects of these cells in animal models of different diseases, resulting in increasing expectations regarding their possible utility for cell-based therapeutic applications. This rapidly evolving research field is also enriched by studies aimed at expanding the use of the whole amniotic membrane (AM), a well-known surgical material, for pathological conditions other than those tested so far and for which clinical applications already exist. In this review, we provide an update on studies that have been performed with placenta-derived cells and fragments of the entire AM to validate their potential clinical applications in a variety of diseases, in particular those associated with degenerative processes induced by inflammatory and fibrotic mechanisms. We also offer, as far as possible, insight into the interpretation and suggested mechanisms to explain the most important outcomes achieved to date. PMID- 21251713 TI - Sea urchin eggs in the acid reign. AB - Sea urchin eggs have been an indispensable model system for studying egg activation and ionic signalling for at least a century. Instrumental in the discovery of two Ca(2+)-mobilizing second messengers, cyclic ADP-ribose and NAADP, the sea urchin has revolutionized cell biology for all phyla. This review attempts to summarize what we currently know about egg acidic vesicles in the context of Ca(2+) signalling. The dynamics of Ca(2+) storage, Ca(2+) mobilization, proton fluxes and two-pore channels will be discussed. PMID- 21251714 TI - Effects of copper, zinc and dragonfly kairomone on growth rate and induced morphology of Bufo arabicus tadpoles. AB - It is well documented that many amphibian species can detect chemical signals from predatory invertebrates and subsequently develop alternate phenotypes that are protective against predation. The effects of metallic pollutants on the development of predator-induced morphology have not previously been reported. Tadpoles of the Arabian toad Bufo arabicus were exposed for 20 days to copper (0, 10 or 100 MUg/L), zinc (0, 10 or 100 MUg/L) and kairomones of larval dragonflies (Crocothemis erythrea 1 dragonfly/12 L) in a fully crossed design. The effects of these treatments of growth and body shape were measured. Measured copper concentrations after 24 h were 4.25 MUg/L+/-1.30 (10 MUg/L nominal) and 34.9 MUg/L+/-2.15 (100 MUg/L nominal). Measured zinc concentrations were 3.04 MUg/L+/ 0.1 (10 MUg/L nominal) and 26.3 MUg/L+/-12.3 (100 MUg/L nominal). Tadpoles exposed to 34.9 MUg/L copper were significantly lighter and had a shorter body length than other groups. There was no direct effect of zinc on growth or tadpole shape. Tadpoles exposed to dragonfly kairomones were heavier, wider and had deeper bodies when viewed laterally and had longer tails but overall length was not affected. At 4.25 MUg/L copper differences between the control and predator exposed phenotypes increased but at 34.9 MUg/L the phenotypes converged, indicating that copper may inhibit the induced response. PMID- 21251715 TI - Physiological and chemical response of lichens transplanted in and around an industrial area of south Italy: relationship with the lichen diversity. AB - The lichen Evernia prunastri (L.) Ach. has been exposed for 3 months in and around an industrial area of Mediterranean Italy for monitoring physiological (photosynthetic efficiency, membrane lipids peroxidation and cell membrane integrity) and chemical (bioaccumulation of the heavy metals Cr, Ni, Pb, V and Zn) effects and investigate the consistency with the environmental quality status depicted by the diversity of epiphytic lichens (index of lichen diversity (ILD)). The results showed that thalli transplanted close to the industrial area exhibited early stress symptoms, as revealed by the increase in electrical conductivity indicating a damage endured by lichen cell membranes. The electrical conductivity was inversely correlated with the diversity of epiphytic lichens recorded at the same sites. The ILD negatively correlated also with membrane lipid peroxidation and the rate of accumulation of Pb, V and Zn. Reciprocal correlations found among trace elements pinpointed vehicular traffic and metal processing in the industrial area as main sources. The damage endured by cell membranes was the best physiological indicator consistent with the air quality status depicted by the diversity of epiphytic lichens. PMID- 21251716 TI - Modification in growth, biomass and yield of radish under supplemental UV-B at different NPK levels. AB - Growth, biomass, yield and quality characteristics of radish (Raphanus sativus L. var. Pusa Himani) were investigated under supplemental UV-B (sUV-B; 280-320 nm; +7.2 kJ m(-2) d(-1)) radiation at varying levels of soil NPK. Combinations of NPK were recommended, 1.5 times NPK, 1.5 times N and 1.5 times K. sUV-B radiation negatively affected the growth and economic yield with more reductions at 1.5 times recommended NPK, N and K compared to recommended NPK. Total biomass remained unaffected in plants at recommended NPK under sUV-B radiation. At 1.5 times NPK and N more partitioning of biomass to shoot led to reduction in root shoot ratio and consequently yield under sUV-B. Nutrients in edible part declined maximally at 1.5 times recommended K under sUV-B. The study suggests that higher than recommended NPK makes radish plants more sensitive to sUV-B in terms of yield by allocating less photosynthates towards roots compared to shoots. PMID- 21251717 TI - HSP90 is crucial for regulation of LAT expression in activated T cells. AB - T cell response initiated by engagement of T cell receptor (TCR) is dependent on signal transduction events composed of protein kinases and adaptor proteins. However, the molecular mechanism for gene expression of these proteins is not entirely understood. Here we identified Heat Shock Protein 90 (HSP90) as an essential regulator for gene expression of Linker for activation of T cells (LAT) in primarily activated human T cells. Primarily activated T cells continuously synthesized LAT protein and treatment of cells with 17-AAG, a pharmacological inhibitor of HSP90, decreased LAT protein level following reduction of LAT mRNA. Furthermore, promoter activity of LAT gene was dramatically inhibited by 17-AAG. These results reveal a novel role of HSP90 as a positive regulator for expression of LAT gene in activated T cells. PMID- 21251718 TI - Suicidal ideation among individuals whose parents have divorced: findings from a representative Canadian community survey. AB - This study used a large, nationally representative sample to examine the gender specific association between parental divorce and the cumulative lifetime incidence of suicidal ideation. Known risk factors for suicidal ideation, such as childhood stressors, socioeconomic factors, adult health behaviors and stressors, marital status, and any history of mood and/or anxiety disorders were controlled. Gender-specific analyses revealed that for men, the parental divorce-suicidal ideation relationship remained statistically significant even when the above listed cluster of risk factors were included in the analyses (odds ratio (OR)=2.36, 95% confidence interval (CI)=1.56, 3.58). For women, the association between parental divorce and suicidal ideation was reduced to non-significance when other adverse childhood experiences were included in the analyses (full adjustment OR=1.04, 95% CI=0.72, 1.50). These findings indicate a need for screening of suicidal ideation among individuals, particularly men and those with mood and/or anxiety disorders, who have experienced parental divorce. Future research should focus on the mechanisms linking parental divorce and suicidal ideation. PMID- 21251719 TI - Predictors of entry to the nursing home: does length of follow-up matter? AB - This study examined the extent to which predictors of nursing home entry vary in their salience as a function of length of follow-up. Participants were 201 persons attending five senior day care centers. The impact of baseline assessment on nursing home entry was examined at one, two, and three-year follow-up periods. Analysis revealed that MMSE, IADL, physical non-aggressive agitated behavior, and 4 indicators of caregiver burden had significantly changing impacts on time to nursing home entry. Only depressed affect and age remained significant predictors at all three follow-up periods in the multivariate analysis. Physical and verbal aggressive agitation and declining caregiver health were significant predictors in the short term. Socializing and ethnicity became predictors at year three. We have demonstrated that while some predictors of nursing home placement are robust over varying follow-up times, the predictive value of others changes with length of the follow-up period. Length of follow-up needs to be taken into account in clarifying the processes that predict nursing home entry. PMID- 21251720 TI - Impact of increased transmitral gradients after undersized annuloplasty for chronic ischemic mitral regurgitation. AB - BACKGROUND: Recent studies have demonstrated that undersized ring mitral annuloplasty (URMA) for chronic ischemic mitral regurgitation (CIMR) can induce iatrogenic mitral stenosis. The impact of this functional mitral stenosis on clinical and echocardiographic results is not well established. METHODS: 125 consecutive URMA for CIMR were dichotomized according to postoperative mean trans mitral gradient (Deltap) into Group A (61 patients, >5 mm Hg) and Group B (64 patients, <=5 mm Hg). Echocardiographic, clinical and functional outcomes were prospectively recorded and compared. RESULTS: There were no hospital deaths. Intensive-care and hospital length of stay were comparable in the 2 groups (p=N.S.). Twenty-three months of actuarial survival was 73.2 +/- 8.0%, without inter-group differences (log-rank p=0.627), actuarial freedom from congestive heart failure was 71.4 +/- 5.6%, freedom from hospitalization was 59.8 +/- 7.7%, without inter-group differences (p=0.497 and 0.393 respectively), and actuarial freedom from recurrent CIMR was 62.7 +/- 10.4%, without group-difference (p=0.259), respectively. Both groups showed progressive improvement of NYHA (Time p=0.0001), with reduced diuretics (p=0.0001), and without inter-group differences (Group Time p=0.894 and 0.397 respectively). Both groups showed a constant improvement of left ventricular end-systolic diameters, ejection fraction, CIMR grade, tricuspid insufficiency grading, indexed left ventricular mass, systolic pulmonary arterial pressure, and tricuspid annular plane systolic excursion (Time p=0.0001 for all), without intergroup differences (p=N.S. for all). However, left ventricular end-diastolic diameters were better remodeled in Group A (Group Time p=0.037), together with a higher mean trans-mitral Deltap and a lower coaptation depth (Group Time p=0.0001 and 0.05 respectively). Left atrial diameter was ameliorated in Group B, but remained unchanged in Group A (p=0.168). CONCLUSIONS: URMA cures CIMR. The induction of mild mitral stenosis did not affect clinical, functional and echocardiographic outcomes. PMID- 21251721 TI - Is danshen (Salvia miltiorrhiza) dripping pill more effective than isosorbide dinitrate in treating angina pectoris? A systematic review of randomized controlled trials. AB - BACKGROUND: Danshen dripping pill (DSP) is a popular Chinese medicinal product and often compared with isosorbide dinitrate (ISDN) in treating coronary heart disease angina pectoris. Over 100 randomized controlled trials (RCT) have been published in Chinese language but have not been evaluated according to the PRISMA systematic review standard. This study aims to provide a comprehensive and PRISMA compliant systematic review with sensitivity and subgroup analyses. METHODS: RCTs published between 1994 and 2009 on DSP versus ISDN in treating angina pectoris for 4 or more weeks were retrieved from major databases, including PubMed, Chinese National Knowledge Infrastructure, and WanFang Data. Meta-analysis was performed on the overall effects on symptomatic and electrocardiography (ECG) improvements. Sensitivity analysis was conducted on the study quality of RCTs based on a refined Jadad scale and different efficacy definitions. RESULTS: Sixty RCTs with 6931 participants were included. Summary odds ratios for comparing DSP and ISDN were 2.49 (95% CI 2.03-3.05) by symptoms (n=60) and 2.14 (95% CI 1.82 2.52) by ECG (n=53) according to the basic efficacy definitions and were 1.67 (95% CI 1.45-1.91) by symptoms (n=56) and 1.75 (95% CI 1.51-2.04) by ECG (n=45) according to the stringent efficacy criteria. CONCLUSION: The 60 eligible RCTs indicate that DSP is apparently more effective than ISDN in treating angina pectoris. However, further RCTs of larger scale, multi-centre/country, longer follow-up periods, and higher quality are still required to verify the efficacy of DSP over all anti-anginal therapies. PMID- 21251722 TI - Physician division of labor and patient selection for outpatient procedures. AB - Little is known about the ability of incentives to influence decisions by physicians regarding choices of settings for care delivery. In the context of outpatient procedural care, the emergence of freestanding ambulatory surgery centers (ASCs) as alternatives to hospital-based outpatient departments (HOPDs) creates a unique opportunity to study this question. We advance a model where physicians' division of labor between ASCs and HOPDs affects the medical complexity of patients treated in low-acuity settings (i.e. ASCs). Analyses of outpatient surgical procedure data show that physicians working exclusively in low-acuity settings (i.e. ASCs) treat patients of significantly higher medical complexity in these settings than do physicians who also practice in higher acuity settings (i.e. HOPDs). This discrepancy shrinks with increasing procedural risk and with increasing distance between ASCs and acute care hospitals. PMID- 21251724 TI - Sensitivity of Penicillium expansum field isolates to tebuconazole, iprodione, fludioxonil and cyprodinil and characterization of fitness parameters and patulin production. AB - A total of 236 Penicillium expansum field isolates from decayed apple fruit collected from packinghouses and processing industries located in the region of Imathia, Northern Greece were tested for their sensitivity to tebuconazole, fludioxonil, iprodione and cyprodinil. Preliminary fungitoxicity tests on the response of the isolates showed several phenotypes, distinguished according to their sensitivity to fungicides tested. The EC(50) values ranged from 0.64 to 5 (average = 0.98) MUg/ml for iprodione, 0.9 to 7.3 (average = 2.66) MUg/ml for tebuconazole, 0.008 to 1.28 (average = 0.55) MUg/ml for cyprodinil and from 0.013 to 0.47 (average = 0.08) MUg/ml for fludioxonil. A bimodal distribution of the EC(50) values of isolates with distinct sensitive and resistant populations to fludioxonil and tebuconazole were observed. In the case of cyprodinil, a much broader, hundred-fold, range of sensitivity was found, probably indicating that some isolates are relatively insensitive to cyprodinil compared to the most sensitive ones. Isolates exhibiting simultaneously reduced sensitivity to tebuconazole and fludioxonil or tebuconazole and iprodione or to tebuconazole and cyprodinil were also observed at low frequencies. A small portion of the population (7.5%) showed multiple resistance to tebuconazole, fludioxonil and iprodione. Study of fitness determining parameters showed that the resistance to tebuconazole, fludioxonil and iprodione had a significant adverse effect on mycelial growth rate and pathogenicity. Contrary to that, these fitness parameters were not affected in the isolates showing reduced sensitivity to cyprodinil. Analysis of patulin production on YES-agar growth medium and on artificially inoculated apple fruit showed that all isolates were mycotoxigenic. Most of the cyprodinil-insensitive isolates produced patulin at concentrations similar to or relatively higher (up to 1.5-fold on growth medium) than the sensitive ones. In contrast, a significant reduction (up to 98% of multiple resistant isolates) in patulin production was observed in all other phenotypes, indicating an adverse effect of fitness penalties on the mycotoxigenic ability of resistant isolates. The above mentioned data clearly show a considerable risk for the selection of P. expansum isolates resistant to fludioxonil, iprodione, tebuconazole and cyprodinil. The potential risk of increased patulin contamination of apples and their byproducts by the appearance and predominance of highly mycotoxigenic isolates of P. expansum resistant to the anilinopyrimidines is discussed. PMID- 21251723 TI - Design and application of genetically encoded biosensors. AB - In the past 5-10 years, the power of the green fluorescent protein (GFP) and its numerous derivatives has been harnessed toward the development of genetically encoded fluorescent biosensors. These sensors are incorporated into cells or organisms as plasmid DNA, which leads the transcriptional and translational machinery of the cell to express a functional sensor. To date, over 100 different genetically encoded biosensors have been developed for targets as diverse as ions, molecules and enzymes. Such sensors are instrumental in providing a window into the real-time biochemistry of living cells and whole organisms, and are providing unprecedented insight into the inner workings of a cell. PMID- 21251725 TI - Effects of hypoglycemia on health-related quality of life, treatment satisfaction and healthcare resource utilization in patients with type 2 diabetes mellitus. AB - AIMS: To quantify patient-reported rates of hypoglycemia and its association with health-related quality of life (HRQL), treatment satisfaction, and healthcare resource utilization. METHODS: Data were collected from 2006 to 2008 US National Health and Wellness Survey and the Ailment Panel of Lightspeed Online Research, an internet-based questionnaire. Adults (>= 18 years) with type 2 diabetes taking >= 1 oral antidiabetic agent (OAD), but not insulin, were included (n=2074). Multivariate analyses included logistic regression and generalized linear models. RESULTS: Overall, patients who reported experiencing hypoglycemia symptoms (n=286; 13.78%) were significantly more likely to have a lower HRQL on several parameters including: increased limitations on mobility (b=0.66, OR=1.93, p<0.0001) and usual activities (b=0.58, OR=1.78, p<0.0001), increased pain/discomfort (b=0.69, OR=2.00, p<0.0001) and anxiety/depression (b=0.84, OR=2.31, p<0.0001). They also had a lower total treatment satisfaction score as measured by the DiabMedSat tool (b=-7.66, p<0.0001). Self-reported rates of diabetes-related emergency room (b=0.98, p=0.004) and physician visits (b=0.30, p<0.0001) were also higher among these patients. CONCLUSION: Among OAD-treated type 2 diabetes patients, symptoms of hypoglycemia tend to be correlated with significantly lower HRQL, lower treatment satisfaction and higher levels of healthcare resource utilization. PMID- 21251726 TI - International noninterventional study of acarbose treatment in patients with type 2 diabetes mellitus. AB - AIM: To obtain data on efficacy, safety and tolerability of acarbose monotherapy or combination therapy during daily-life treatment. METHODS: This prospective, non-controlled, observational study enrolled patients with type 2 diabetes, whose physician decided that acarbose treatment was appropriate, from China, Middle East, Indonesia, Morocco, Pakistan, Philippines, Poland and Taiwan. The observation period included an initial visit and up to three follow-up visits; an extension of 2 years was realized in Pakistan and Poland. RESULTS: Of 14,574 patients enrolled, 14,418 comprised the intent-to-treat population. At the initial visit, 74.1% of patients had been treated with a glucose-lowering agent. Fasting blood glucose was reduced from 175.2mg/dL at the initial visit to 133.7 mg/dL at the last visit (mean of 11.3 weeks after initial visit; P<0.0001). Mean 2-h postprandial blood glucose decreased from 244.7 mg/dL to 172.4 mg/dL (P<0.0001). HbA1c reduced from 8.4% to 7.4% (P<0.0001). Glycemic efficacy was maintained over the 2-year extension period. There were 432 adverse events in 293 patients (2.03%), mainly gastrointestinal. Physicians assessed efficacy as "very good"/"good" in 85.1% of patients, and were "very satisfied"/"satisfied" with acarbose therapy in 94.3% of cases. CONCLUSION: Acarbose therapy was efficacious and well tolerated in daily life in patients with type 2 diabetes. PMID- 21251728 TI - [Conjunctival nevi: clinical presentations]. PMID- 21251729 TI - Performance evaluation of a noninvasive hemoglobin monitoring device. AB - STUDY OBJECTIVE: Hemoglobin measurement is a routine procedure, and a noninvasive point-of-care device may increase the quality of care. The aim of the present study is to compare hemoglobin concentration values obtained with a portable totally noninvasive device, the Masimo Labs Radical-7 Pulse CO-Oximeter, with the results obtained by the ADVIA 2120 in the laboratory. METHODS: This was a prospective monocentric open trial enrolling patients consulting in the emergency department of a university hospital from June 16 to December 17, 2009. The main outcome measure was the agreement between both methods and evaluation of the percentage of potential decision error for transfusion. RESULTS: Samples from 300 consecutive patients were assessed. Hemoglobin concentration could not be obtained with the new device for 24 patients. In others, the mean bias, the lower and the upper limits of agreement between the 2 methods, was 1.8 g/dL (95% estimated confidence interval [CI] 1.5 to 2.1 g/dL), -3.3 g/dL (95% CI -3.8 to 2.8 g/dL), and 6.9 g/dL (95% CI 6.4 to 7.4 g/dL), respectively. The intraclass correlation coefficient was 0.53 (estimated 95% CI 0.10 to 0.74). The number of potential errors about transfusion decision was 38 (13% of patients). The peripheral oxygen saturation and the true value of hemoglobin concentration were independently associated with the bias. CONCLUSION: Results from this widely available noninvasive point-of-care hemoglobin monitoring device were systematically biased and too unreliable to guide transfusion decisions. PMID- 21251730 TI - [Monitoring activities and improvement in the use of antibiotics in Spanish hospitals: results of a national survey]. AB - OBJECTIVES: To describe: 1) the main features of antimicrobial stewardship activities (ASA) in Spanish hospitals and 2) the perceptions of the Spanish Infectious Diseases (ID) community on ASA. METHODS: An online survey was designed and distributed through the e-mailing lists of several working groups of the Spanish Clinical Microbiology and Infectious Diseases Society. RESULTS: Between September 15 and November 23, 2009, surveys representing 78 hospitals were received. Most of the respondents were either ID physicians (30%) or microbiologists (29%), and 31/78 hospitals (40%) had ongoing ASA. These hospitals were concentrated in 4 of the 17 regions, particularly in Catalonia. Professionals belonging to 26/31 centres with ASA completed the survey. The most frequent principles of antibiotic (ABX) stewardship implemented in these programs were: 1) ABX streamlining (22/26) and 2) intravenous to oral switch (22/26) followed by 3) strategic monitoring of ABX (21/26). In 22/26 (86%) of the centres with ASA any physician could initially prescribe any of the antimicrobials included in the formulary. The most frequent activity carried out was ABX restriction, 69% (18/26) followed by conferences 61% (16/26) and therapeutic audit and feed-back 54% (14/26). When asked which antimicrobials that should be closely monitored, carbapenems were considered by all respondents in centres with ongoing ASA. CONCLUSIONS: 1) A minority (40%) of the surveyed hospitals in Spain has an ongoing ASA and large geographical variations were observed. 2) ASA were most commonly structured in the form of an integrated part-time multidisciplinary team of ID physicians and Pharmacists, and 3) Carbapenems were considered the ABX most required to be monitored. PMID- 21251731 TI - Optimization and in vitro toxicity evaluation of G4 PAMAM dendrimer-risperidone complexes. AB - Risperidone is an approved antipsychotic drug belonging to the chemical class of benzisoxazole. This drug has low solubility in aqueous medium and poor bioavailability due to extensive first-pass metabolism and high protein binding (>90%). As new strategies to improve treatments efficiency are needed, we have studied cationic G4 PAMAM dendrimers' performance to act as efficient nanocarriers for this therapeutic drug. In this respect, we explored dendrimer risperidone complexation dependence on solvent, temperature, pH and salt concentration, as well as in vitro cytotoxicity measured on L929 cell line and human red blood cells. The best dendrimer-risperidone incorporation was achieved when a mixture of 70:30 and 90:10 v/v chloroform:methanol was used, obtaining 17 and 32 risperidone molecules per dendrimer, respectively. No cytotoxicity on L929 cells was found when dendrimer concentration was below 3 * 10(-2) MUM and risperidone concentration below 5.1 MUM. Also, no significant hemolysis or morphological changes were observed on human red blood cells. Finally, attempting to obtain an efficient drug delivery system for risperidone, incorporation in G4 PAMAM dendrimers was optimized, improving drug solubility with low cytotoxicity. PMID- 21251732 TI - Clinical practice guidelines from the French Health High Authority: nutritional support strategy in protein-energy malnutrition in the elderly. AB - These guidelines were produced at the request of the General Directorate of Health within the scope of the French Nutrition and Health Program (PNNS). They concern the management of malnutrition in elderly persons living at home, in institutional care, or in hospital. They belong to a recent series of studies published by ANAES(1) or HAS. Preceding studies concerned the "Diagnostic assessment of protein-energy malnutrition in hospitalized adults" (ANAES, September 2003) and the work conducted by the Committee for the Assessment of Devices and Health Technologies (CEPP) on "Reimbursement procedures for dietary foods for special medical purposes for nutritional supplementation and home enteral nutrition" (HAS, September 2006). The objective of these guidelines is to develop a tool for identifying and managing elderly subjects who are malnourished or at risk of malnutrition. PMID- 21251733 TI - Monte Carlo based calibration of scintillation detectors for laboratory and in situ gamma ray measurements. AB - The calibration of scintillation detectors for gamma radiation in a well characterized setup can be transferred to other geometries using Monte Carlo simulations to account for the differences between the calibration and the other geometry. In this study a calibration facility was used that is constructed from bricks of well-known activity concentrations of 40K and of radionuclides from the 238U- and 232Th-series. Transfer of the calibration was attempted to a Marinelli beaker geometry with the detector inside a lead shield and to an in situ application with the detector positioned on a sand bed. In general this resulted in good correspondence (within 5-10%) between the activity concentrations derived using the transferred calibration and activities that were derived by independent measurements. Some discrepancies were identified that were attributed to coincident summing in the natural decay series and interference of radon. PMID- 21251734 TI - Between life and death: women's experiences of coming close to death, and surviving a severe postpartum haemorrhage and emergency hysterectomy. AB - OBJECTIVE: to describe women's experiences of having an emergency hysterectomy following a severe postpartum haemorrhage. DESIGN: a qualitative research approach was used to guide this study. Data were collected through semi structured, tape recorded face to face, email internet and telephone interviews. SETTING: three States in Australia: New South Wales, Victoria and Western Australia. PARTICIPANTS: twenty-one Australian women who experienced a severe post partum followed by an emergency hysterectomy participated in the study. The median age of participants at time of interview was 42 years and the median time since having the hysterectomy was four years. FINDINGS: a process of inductive analysis revealed the major theme, 'between life and death' and three sub-themes, 'being close to death: bleeding and fear', 'having a hysterectomy: devastation and realisation' and 'reliving the trauma: flashbacks and memories'. CONCLUSION: formulating a plan of care for women identifiably at risk of PPH and ensuring appropriate follow-up counselling is made, is key to help reduce the emotional and psychological symptoms experienced by these women in the aftermath of severe postpartum haemorrhage and hysterectomy. PMID- 21251735 TI - Health service utilisation by pregnant women over a seven-year period. AB - OBJECTIVE: to examine the use of complementary and alternative medicine during pregnancy using data from a longitudinal cohort study. DESIGN AND SETTING: the research was conducted as part of the Australian Longitudinal Study on Women's Health which was designed to investigate multiple factors affecting the health and well-being of women over a 20-year period. PARTICIPANTS: the younger cohort of the Australian Longitudinal Study on Women's Health who had completed four surveys in 1996, 2000, 2003 and 2006. FINDINGS: the data reveal an increase both in consumption of complementary and alternative medicine and in consultations with general practitioners/specialists during pregnancy. Women utilised complementary and alternative medicine as a supplement for conventional maternity care. IMPLICATIONS FOR PRACTICE: given the potential risks of some complementary and alternative medicine for pregnant women and their unborn child, it is essential that maternity care providers are adequately informed about these treatments and that further research investigates the details of such concurrent use. PMID- 21251736 TI - Care and environment in midwife-led and obstetric-led units: a comparison of mothers' and birth partners' perceptions. AB - BACKGROUND: Health-care design recognises the importance of people-environment interactions, and maternity units have responded by encouraging 'homely' environments. Birthing women and birth partners have been separately surveyed about their experiences of the maternity environment and midwifery care, but not to date as dyads. METHOD(S): Postal return survey of mothers and birth partners from nine maternity units (six midwife-led; three obstetric-led) in England, at eight days postnatally in 2004-5. Questions concerned participants' general and specific impressions of the unit environment and of the care given. A repeated measures analysis of variance was used to explore interactions between mothers and partners and different types of unit. The Wilcoxon signed rank test was used for skewed satisfaction scores. Loglinear models were used to analyse mothers' and partners' cited comments, factoring in types of unit. FINDINGS: 515 Dyads responded (response rate 50%). Mothers and partners were generally positive, but *mothers were more so. They rated the birth surroundings (Z = -8.083; p < 0.001) and the midwifery care (Z = -7.177; p < 0.001) more highly than their partners; these findings were significant in both types of unit. Loglinear analysis found that mothers especially were more likely to find midwife-led units 'homely' (Z = 2.496; p = 0.013), 'calming' (Z = 9.61; p < 0.001): and 'clean' (Z = 4.08, p < 0.001). Obstetric-led units were more likely to be thought 'stuffy' (Z = -3.51, p < 0.001). Partners were more likely to agree that there was a lack of privacy (Z = 3.401; p = 0.001), and that there was a lack of facilities for them, particularly within obstetric-led units. CONCLUSIONS: Although generally positive, birth partners were significantly less positive than the birthing mothers about a range of environmental and care variables. The primary focus is and should be the birthing woman, but the partner nevertheless has an interactive role to play, and improving his experience may assist this function. PMID- 21251737 TI - The effects of creep and recovery on the in vitro biomechanical characteristics of human multi-level thoracolumbar spinal segments. AB - BACKGROUND: Several physiological and pathological conditions in daily life cause sustained static bending or torsion loads on the spine resulting in creep of spinal segments. The objective of this study was to determine the effects of creep and recovery on the range of motion, neutral zone, and neutral zone stiffness of thoracolumbar multi-level spinal segments in flexion, extension, lateral bending and axial rotation. METHODS: Six human cadaveric spines (age at time of death 55-84 years) were sectioned in T1-T4, T5-T8, T9-T12, and L1-L4 segments and prepared for testing. Moments were applied of +4 to -4 N m in flexion-extension, lateral bending, and axial rotation. This was repeated after 30 min of creep loading at 2 N m in the tested direction and after 30 min of recovery. Displacement of individual motion segments was measured using a 3D optical movement registration system. The range of motion, neutral zone, and neutral zone stiffness of the middle motion segments were calculated from the moment-angular displacement data. FINDINGS: The range of motion increased significantly after creep in extension, lateral bending and axial rotation (P<0.05). The range of motion after flexion creep showed an increasing trend as well, and the neutral zone after flexion creep increased by on average 36% (P<0.01). The neutral zone stiffness was significantly lower after creep in axial rotation (P<0.05). INTERPRETATION: The overall flexibility of the spinal segments was in general larger after 30 min of creep loading. This higher flexibility of the spinal segments may be a risk factor for potential spinal instability or injury. PMID- 21251739 TI - Conducting model ecosystem studies in tropical climate zones: lessons learned from Thailand and way forward. AB - Little research has been done so far into the environmental fate and side effects of pesticides in the tropics. In addition, those studies conducted in tropical regions have focused almost exclusively on single species laboratory tests. Hence, fate and effects of pesticides on higher-tier levels have barely been studied under tropical conditions. To address this lack of knowledge, four outdoor aquatic model ecosystem experiments using two different test systems were conducted in Thailand evaluating the insecticide chlorpyrifos, the herbicide linuron and the fungicide carbendazim. Results of these experiments and comparisons of recorded fate and effects with temperate studies have been published previously. The present paper discusses the pros and cons of the methodologies applied and provides indications for i) possible improvements; ii) important aspects that should be considered when performing model ecosystem experiments in the tropics; iii) future research. PMID- 21251738 TI - Relationships between muscle contributions to walking subtasks and functional walking status in persons with post-stroke hemiparesis. AB - BACKGROUND: Persons with post-stroke hemiparesis usually walk slowly and asymmetrically. Stroke severity and functional walking status are commonly predicted by post-stroke walking speed. The mechanisms that limit walking speed, and by extension functional walking status, need to be understood to improve post stroke rehabilitation methods. METHODS: Three-dimensional forward dynamics walking simulations of hemiparetic subjects (and speed-matched controls) with different levels of functional walking status were developed to investigate the relationships between muscle contributions to walking subtasks and functional walking status. Muscle contributions to forward propulsion, swing initiation and power generation were analyzed during the pre-swing phase of the gait cycle and compared between groups. FINDINGS: Contributions from the paretic leg muscles (i.e., soleus, gastrocnemius and gluteus medius) to forward propulsion increased with improved functional walking status, with the non-paretic leg muscles (i.e., rectus femoris and vastii) compensating for reduced paretic leg propulsion in the limited community walker. Contributions to swing initiation from both paretic (i.e., gastrocnemius, iliacus and psoas) and non-paretic leg muscles (i.e., hamstrings) also increased as functional walking status improved. Power generation was also an important indicator of functional walking status, with reduced paretic leg power generation limiting the paretic leg contribution to forward propulsion and leg swing initiation. INTERPRETATION: These results suggest that deficits in muscle contributions to the walking subtasks of forward propulsion, swing initiation and power generation are directly related to functional walking status and that improving output in these muscle groups may be an effective rehabilitation strategy for improving post-stroke hemiparetic walking. PMID- 21251740 TI - Direct and indirect impact of sewage sludge compost spreading on Quercus coccifera monoterpene emissions in a Mediterranean shrubland. AB - Monoterpene emissions of Quercus coccifera L. were repeatedly measured during the two years following the spreading of a sewage sludge compost at rates of 50 Mg ha 1 and 100 Mg ha-1, in a twelve-year-old post-fire Mediterranean shrubland. We also monitored the patterns of change in soil and leaf nutrient content, plant water potential, chlorophyll fluorescence, and plant growth. Compost spreading resulted in weak changes in leaf nutrient content and plant water status, and therefore no significant effect on monoterpene emissions at leaf scale, except during one summer sampling, probably related to advanced leaf maturity with the highest compost rate. However, compost increased plant growth, particularly the leaf biomass. The results suggest that compost spreading in Mediterranean shrublands has no strong short-term effect on Q. coccifera monoterpene emissions at leaf level, but may indirectly increase volatile organic compound fluxes at the stand scale, which may contribute to regional ozone pollution. PMID- 21251741 TI - Processes and factors controlling N2O production in an intensively managed low carbon calcareous soil under sub-humid monsoon conditions. AB - An automated system for continuous measurement of N2O fluxes on an hourly basis was employed to study N2O emissions in an intensively managed low carbon calcareous soil under sub-humid temperate monsoon conditions. N2O emissions occurred mainly within two weeks of application of NH4(+) based fertilizer and total N2O emissions in wheat (average 0.35 or 0.21 kg N ha-1 season-1) and maize (average 1.47 or 0.49 kg N ha-1 season-1) under conventional and optimum N fertilization (300 and 50-122 kg N ha-1, respectively) were lower than previously reported from low frequency measurements. Results from closed static chamber showed that N2O was produced mainly from nitrification of NH4(+)-based fertilizer, with little denitrification occurring due to limited readily oxidizable carbon and low soil moisture despite consistently high soil nitrate-N concentrations. Significant reductions in N2O emissions can be achieved by optimizing fertilizer N rates, using nitrification inhibitors, or changing from NH4(+)- to NO3(-)-based fertilizers. PMID- 21251742 TI - Source, concentration, and distribution of elemental mercury in the atmosphere in Toronto, Canada. AB - Atmospheric gaseous elemental mercury [GEM] at 1.8, 4, and 59 m above ground, in parking lots, and in indoor and outdoor air was measured in Toronto City, Canada from May 2008-July 2009. The average GEM value at 1.8 m was 1.89 +/- 0.62 ng m( 3). The GEM values increased with elevation. The average GEM in underground parking lots ranged from 1.37 to 7.86 ng m(-3) and was higher than those observed from the surface parking lots. The GEM in the indoor air ranged from 1.21 to 28.50 ng m(-3), was higher in the laboratories than in the offices, and was much higher than that in the outdoor air. All these indicate that buildings serve as sources of mercury to the urban atmosphere. More studies are needed to estimate the contribution of urban areas to the atmospheric mercury budget and the impact of indoor air on outdoor air quality and human health. PMID- 21251743 TI - Neighborhood social capital and individual health. AB - Neighborhood social capital is increasingly considered to be an important determinant of an individual's health. Using data from the Netherlands we investigate the influence of neighborhood social capital on an individual's self reported health, while accounting for other conditions of health on both the level of the neighborhood and the individual. We use national representative data ('The Housing and Living Survey', 2006) on the Netherlands with 61,235 respondents in 3273 neighborhoods. The cross-sectional data were combined with information provided by Statistics Netherlands on neighborhoods, i.e., the percentage of residents in the highest income quintile per neighborhood and the municipality's degree of urbanity. The association of neighborhood social capital with individual health was assessed by multilevel logistic regression analysis. Our results show that neighborhood social capital is positively associated with health. Interestingly, residents in urban neighborhoods benefit particularly from their neighborhood social capital. PMID- 21251744 TI - Age-related differences in attentional networks of alerting and executive control in young, middle-aged, and older Chinese adults. AB - Previous studies suggest that aging is associated with impairment of attention. However, it is not known whether this represents a global attentional deficit or relates to a specific attentional network. We used the attention network test to examine three groups of younger, middle-aged, and older participants with respect to the efficiency of three anatomically defined attentional networks: alerting network, orienting network, and executive control network. Age-related change was found to have the greatest effect on the executive network and the least effect on the alerting network as well as on overall mean response time. Impairment of the orienting network was found to be insignificant. Age-related deterioration of the prefrontal lobe, the dopaminergic system, and function of specific genes may explain the age-related changes in executive attention, which occur after the fourth decade of life. PMID- 21251745 TI - [LLL plasty: simple procedure for coverage of cutaneous defects]. AB - Skin defects may be due to several causes: trauma, surgical excision of malignant or benign, even malformative pathologies. The aim of this work is to report the interest of the LLL flap (L for Lozenge) (Dufourmental flap) in the coverage of the skin defects that sometimes may reach high dimensions or being located in areas of lower skin extensibility. We report a study involving 26 patients who all benefited from this technique having skin defects due to different causes and serving in different locations. LLL plasty allowed a first closure in all patients. The cosmetic result was good and no recovery was necessary. LL plasty was first described in 1962 to cover limited skin defects. However, it requires some precision in its execution. This is a simple and reproducible procedure with considerable interest for its potential in the coverage of cutaneous defects in the face and that can reach up than 8cm. The scar would be reduced if we took care to match the areas of sutures with the shaded areas of the face (groove...). While allowing a better distribution of tension, this technique has demonstrated its superiority compared to direct suture, which the indication is limited by the size of the defect and its location (peri-orificial...) and other techniques that are similar as the Limberg flap. PMID- 21251746 TI - Effects of timing and duration of hypothermia on survival in an experimental gerbil model of global ischaemia. AB - PURPOSE: Despite the use of animal models to study post-cardiac-arrest resuscitation, the effects of hypothermia on physiological circulatory parameters are still not fully understood. In this study, using a gerbil model of global ischaemia/reperfusion, we aimed to assess the effects of hypothermia on physiological parameters and evaluated the optimal timing for the induction of hypothermia to achieve a better survival rate. METHODS: Survival rates at 72 h after reperfusion were evaluated by varying the degree of hypothermia and/or duration of ischaemia, and then examined by varying induction timing and/or extending the duration of ischaemia. Physiological parameters were measured using an intravital microscopy system. RESULTS: Under normothermic cerebral ischaemia, the survival rate was dramatically decreased by the induction of 15-20 min of ischaemia. Induction of hypothermia significantly improved the survival rate only when it occurred less than 10 min after ischaemic onset. In the hypothermia treated groups, post-ischaemic hyperperfusion was significantly suppressed, and post-ischaemic vasoconstriction of the pial arteriole was prevented. CONCLUSIONS: Hypothermia-induced suppression of post-ischaemic hyperperfusion and the prevention of vasoconstriction of the pial arteriole play an important role in improving the survival rate after global ischaemia/reperfusion, but the time window for induction of hypothermia remains relatively narrow. PMID- 21251747 TI - Familiarity with first-aid rules by attendees at rock-music festivals in Poland. PMID- 21251748 TI - Difference in expression of collagen type I and matrix metalloproteinase-1 in uterosacral ligaments of women with and without pelvic organ prolapse. AB - OBJECTIVE: To compare the expression of collagen type I and matrix metalloproteinase-1 (MMP-1) in uterosacral ligament biopsies from women with and without pelvic organ prolapse (POP). STUDY DESIGN: Uterosacral ligament biopsies were obtained from women with POP (n=46) and control subjects (n=49). Immunohistochemistry for collagen type I and MMP-1 was performed on formalin fixed and paraffin-embedded sections. The two groups were matched for age, body mass index, parity and postmenopausal status. Statistical Package for the Social Sciences Version 13.0 was used for statistical analysis. RESULTS: The expression of collagen type I (p=0.034) and MMP-1 (p=0.038) differed between women with POP and control subjects. There was increased expression of MMP-1 and decreased expression of collagen type 1 in uterosacral ligaments of women with POP compared with control subjects. CONCLUSIONS: This difference indicates a possible relationship between POP and the immunohistochemical expression of collagen type I and MMP-1 in uterosacral ligaments. PMID- 21251749 TI - Association between endometriosis and polymorphisms in insulin-like growth factors (IGFs) and IGF-I receptor genes in Korean women. AB - OBJECTIVES: To evaluate the relationship between endometriosis and polymorphisms in insulin-like growth factors (IGFs) and IGF-I receptor genes. STUDY DESIGN: In a case-control study, 128 women with endometriosis and 108 control women were recruited at the Department of Obstetrics and Gynecology in Seoul National University Hospital. Determinations of -969(CA) block, -603A>T, and -553T>C single nucleotide polymorphism (SNP)s in the IGF-I gene, c.517C>T, c.540G>T and 820G>A SNPs in the IGF-II gene, and c.3129G>A SNP in the IGF-I receptor gene were performed to evaluate the prevalence of IGFs and IGF-I receptor genotypes or alleles. RESULTS: Among studied SNPs, the IGF-II 820G>A polymorphism was associated with endometriosis. Women with endometriosis were observed 1.99 times more frequently in the GG genotype of the IGF-II 820G>A polymorphism compared with non-GG genotype (95% confidence level: 1.18-3.35). The similar finding was observed only in early stage endometriosis (stages I and II). CONCLUSIONS: The IGF-II 820G>A polymorphism is a genetic factor which may be associated with the development of endometriosis in Korean women. PMID- 21251750 TI - EIA application in China's expressway infrastructure: clarifying the decision making hierarchy. AB - China's EIA Law came into effect in 2003 and formally requires road transport infrastructure development actions to be subject to Environmental Impact Assessment (EIA). EIAs (including project EIA and plan EIA, or strategic environmental impact assessment, SEA) have been being widely applied in the expressway infrastructure planning field. Among those applications, SEA is applied to provincial level expressway network (PLEI) plans, and project EIA is applied to expressway infrastructure development 'projects' under PLEI plans. Three case studies (one expressway project EIA and two PLEI plan SEAs) were examined to understand currently how EIAs are applied to expressway infrastructure development planning. Through the studies, a number of problems that significantly influence the quality of EIA application in the field were identified. The reasons causing those problems are analyzed and possible solutions are suggested aimed at enhancing EIA practice, helping deliver better decision-making and ultimately improving the environmental performance of expressway infrastructure. PMID- 21251751 TI - Use and users of municipal commonage around three small towns in the Eastern Cape, South Africa. AB - Municipal commonages surround many small towns throughout South Africa, and are an integral component of the national land reform programme. But little is known about their extent, use or value, and most appear to have limited or no management or investment. This paper reports on a survey of randomly selected households in three small towns in the Eastern Cape to ascertain the extent and purpose of use of municipal commonages. Between 27% and 70% of urban households used commonage depending on site. Key resources used were fuelwood, medicinal plants, and grazing of livestock. Typically, commonage using households were poorer and less educated than other urban residents, although the profile of users is unique for each town. Given the extensive use of commonage resources, and their contribution to the livelihoods of the poor, local municipalities need to develop and implement sound management strategies that account for all users of commonages, rather than the oft encountered focus on livestock owners and production. PMID- 21251752 TI - Peripheral blood smear technique for detecting neuroacanthocytosis: a comment. PMID- 21251753 TI - Copper distribution in water-dispersible colloids of swine manure and its transport through quartz sand. AB - To demonstrate the potential risks associated with the application of solid agricultural wastes, we investigated Cu distribution in water-dispersible colloids derived from swine manure and its transport through quartz sand. Samples were sequentially centrifuged to obtain five colloid suspensions (<10, <1, <0.45, <0.2, and <0.02 MUm) and four colloid subsamples (1-10, 0.45-1, 0.2-0.45, and 0.02-0.2 MUm). We observed that 2% of Cu in the swine manure was found in the 0.02-10 MUm colloid fractions, while 18% was observed in the <0.02 MUm colloid suspension. The highest accumulation of Cu was found in the 0.02-0.2 MUm fraction of colloids, in which organic carbon was the major component. The Cu in the 1-10 MUm colloid fraction existed in both inorganic compounds and organic associations, whereas it mainly existed as organic complexes in colloids <1 MUm (<0.53 MUm, specifically). Furthermore, large colloids (1-10 MUm) of swine manure were partially filtered out as they passed through the sand particles, and fine colloids facilitated the transport of Cu. The formation of organic complexes was hypothesized to enhance the mobility of Cu. Further research is needed to incorporate our experimental findings into a realistic model of particle mobilization and transport through soil or groundwater aquifers. PMID- 21251754 TI - A new method of comprehensive utilization of rice husk. AB - Rice husk is an abundant agricultural byproduct. The research on comprehensive utilization of rice husk to prepare xylose, activated carbon and silica was carried out. The hydrolysis conditions of xylan in rice husk to produce xylose were as follows: the concentration of H(2)SO(4) was 3.6% (wt.%), the temperature was 100 degrees C, the ratio of rice husk mass (g) to H(2)SO(4) solution (ml) was 1:5 and the time was 3 h. The hydrolysis degree of xylan reached 95.6%. The resulting residues were used to prepare activated carbons with the BET surface area of 1763 m(2)/g when 50% H(3)PO(4) was impregnated with rice husk with the ratio of 5:1 at 500 degrees C for 0.5 h. The produced carbons had effective adsorption capability to purify the xylose solution. Furthermore, they exhibited good electrochemical performance. After adsorption, activated carbons were calcined to produce silica with the diameter of 30 nm. PMID- 21251755 TI - MnCl2 and MgCl2 for the removal of reactive dye Levafix Brilliant Blue EBRA from synthetic textile wastewaters: an adsorption/aggregation mechanism. AB - Two divalent cation-based coagulants, magnesium chloride and manganese chloride, were used to treat synthetic textile wastewaters containing the azo-dye pigment Levafix Brilliant Blue EBRA. The jar-tests were performed in the presence or absence of auxiliary dyeing chemicals. They proved that (i) both divalent cation based coagulants were effective in the treatment of those alkaline effluents, (ii) better performances in terms of color removal, residual turbidity, and settled volume, were achieved with manganese chloride, and (iii) the presence of dyeing auxiliaries significantly increases the required coagulant demand for treating the textile effluent. The dye removal mechanisms were investigated by combining observations of freeze-dried sediments with transmission electron microscopy coupled with energy-dispersive X-ray spectroscopy and selected area electron diffraction, Fourier transform infrared spectroscopy, adsorption experiments, and aggregates size measurements with a laser sizer under cyclic shear conditions. The results show that brucite (Mg(OH)(2)) particles are formed when applying MgCl(2) to the textile wastewaters, whereas a mixture of feitknechite (beta-MnOOH) and hausmannite (Mn(3)O(4)) is obtained when using MnCl(2). More poorly crystallized particles are formed in presence of auxiliary dyeing chemicals. The adsorption experiments suggested that the azo-dye pigment adsorbs onto the surface of precipitating phases, whereas the aggregation dynamics indicated that a charge-neutralization mechanism underlies the formation of aggregates. The dye removal is then consistent with a precipitation/adsorption mechanism. PMID- 21251756 TI - Acceptance-based interventions for the treatment of chronic pain: a systematic review and meta-analysis. AB - Acceptance-based interventions such as mindfulness-based stress reduction program and acceptance and commitment therapy are alternative therapies for cognitive behavioral therapy for treating chronic pain patients. To assess the effects of acceptance-based interventions on patients with chronic pain, we conducted a systematic review and meta-analysis of controlled and noncontrolled studies reporting effects on mental and physical health of pain patients. All studies were rated for quality. Primary outcome measures were pain intensity and depression. Secondary outcomes were anxiety, physical wellbeing, and quality of life. Twenty-two studies (9 randomized controlled studies, 5 clinical controlled studies [without randomization] and 8 noncontrolled studies) were included, totaling 1235 patients with chronic pain. An effect size on pain of 0.37 was found for the controlled studies. The effect on depression was 0.32. The quality of the studies was not found to moderate the effects of acceptance-based interventions. The results suggest that at present mindfulness-based stress reduction program and acceptance and commitment therapy are not superior to cognitive behavioral therapy but can be good alternatives. More high-quality studies are needed. It is recommended to focus on therapies that integrate mindfulness and behavioral therapy. Acceptance-based therapies have small to medium effects on physical and mental health in chronic pain patients. These effects are comparable to those of cognitive behavioral therapy. PMID- 21251757 TI - Relationship between physical activity and disability in low back pain: a systematic review and meta-analysis. AB - It is often assumed that patients with pain-related disability due to low back pain (LBP) will have reduced physical activity levels, but recent studies have provided results that challenge this assumption. The aim of our systematic review was to examine the relationship between physical activity and disability in LBP. The literature search included 6 electronic databases and the reference list of relevant systematic reviews and studies to May 2010. To be included, studies had to measure both disability (eg, with the Roland Morris Disability Questionnaire) and physical activity (eg, by accelerometry) in patients with non-specific LBP. Two independent reviewers screened search results and extracted data, and authors were contacted for additional data. Correlation coefficients were pooled using the random-effects model. The search identified 3213 records and 18 studies were eligible for inclusion. The pooled results showed a weak relationship between physical activity and disability in acute or subacute (<3months) LBP (r=-0.08, 95% confidence interval=-0.17 to 0.002), and a moderate and negative relationship in chronic (>3months) LBP (r=-0.33, 95% confidence interval=-0.51 to -0.15). That is, persons with acute or subacute LBP appear to vary in the levels of physical activity independent of their pain-related disability. Persons with chronic LBP with high levels of disability are also likely to have low levels of physical activity. Persons with acute or subacute back pain appear to vary in the levels of physical activity independent of disability. Persons with chronic back pain with high levels of disability will likely have low levels of physical activity. PMID- 21251758 TI - Recombinant S3Pvac-phage anticysticercosis vaccine: Simultaneous protection against cysticercosis and hydatid disease in rural pigs. AB - This paper provides macroscopic and histological evidence on the statistically significant protective effects of S3Pvac-phage vaccination against porcine cysticercosis and hydatidosis. The study included 391 rustically bred pigs (187 vaccinated and 204 controls). Vaccination significantly reduced the prevalence of cysticercosis by 61.7%. Vaccination also significantly reduced by 56.1% the prevalence of hydatidosis caused by Echinococcus granulosus in pigs. The presence of the vaccine epitopes in both cestodes is probably involved in the cross protection observed. Increased inflammation was found in 5% of cysticerci recovered from controls, versus 24% from vaccinated pigs (P<0.01). Hydatid cysts were non-inflammatory in either group. Vaccination was effective to prevent one single disease, but it failed to prevent the simultaneous infections with both parasites in a same pig. The widening of the S3Pvac-phage vaccine protective repertoire to include hydatidosis is a convenient feature that should reduce the prevalence of two frequent zoonoses that affect rustic porcine breading with a single action. Thus, the costs of two different vaccination programs would be reduced to a single one with significant reduction in both zoonoses. PMID- 21251759 TI - Molecular cloning and genetic polymorphism of Babesia capreoli gene Bcp37/41, an ortholog of Babesia divergens merozoite surface antigen Bd37. AB - Babesia divergens and Babesia capreoli are closely related species with distinct host ranges, a zoonotic feature being described only for B. divergens. The two species are 99.8% similar in the 18S rDNA gene sequence and indistinguishable by morphological or serological means, leading to confusion as to their species status. The phylogenetic relatedness between the two species, and the frequent involvement of surface components in serological cross-reactions led us to postulate that an ortholog of Bd37, the merozoite surface antigen described for B. divergens, could also exist in B. capreoli. We were able to amplify a single partial PCR product from B. capreoli genomic DNA using primers specific for the B. divergens merozoite surface protein coding gene Bd37, and sequencing confirmed the presence of a Bd37 ortholog in B. capreoli, named Bcp37/41. The full sequences of the Bcp37/41 genes and their intron-exon structures were obtained for two cloned lines of B. capreoli. They suggest functional homologies between Bd37 and Bcp37/41 such as their surface localization, their role in immune escape mechanism and in the initial non-specific attachment to the erythrocyte. Restriction fragment length polymorphism (RFLP) analysis of the amplicons and partial sequencing revealed an extreme polymorphism within B. capreoli, greater than the one observed for its ortholog Bd37. Such a marker could thus be useful in epidemiological as well as phylogenetic studies. PMID- 21251760 TI - Evaluation of immune responses in sheep induced by DNA immunization with genes encoding GRA1, GRA4, GRA6 and GRA7 antigens of Toxoplasma gondii. AB - The dense granule proteins of Toxoplasma gondii are investigated as possible vaccine candidates against the parasite. The aim of this research was to evaluate the immune responses of sheep injected twice, intramuscularly, with DNA plasmids encoding T. gondii dense granule antigens GRA1, GRA4, GRA6 and GRA7 formulated into liposomes. Control sheep were injected with an empty vector or received no injections. The injection of sheep with DNA plasmids encoding for GRA1, GRA4, GRA6 or GRA7 elicited an immune response after the first and the second injections as indicated by the moderate to high antibody responses. The injection of pGRA7 induced a significant level of anti-GRA7 IgG2 antibody and IFN-gamma responses indicating a Th1-like immune response whereas injection with pGRA1, pGRA4 and pGRA6 stimulated a IgG1 type antibody response with a limited, if any, IFN-gamma response. The results demonstrate that the intramuscular injection of sheep with a DNA liposome formulated plasmid coding for GRA proteins is an effective system that induces a significant immune response against T. gondii. PMID- 21251761 TI - Socio-economic and clinical factors predictive of paediatric quality of life post burn. AB - Burns represent the second most common cause of non-intentional death in children under the age of five. Burns are amongst the most traumatic injuries and may impose significant psychological, educational, social and future occupational limitations to the young child. This cross-sectional study aimed to determine the socio-economic and clinical factors which predict quality of life in children with burn in a burns unit in South Africa. The Paediatric Quality of Life Inventory (PedsQL) and the Household Economic and Social Status Index (HESSI) questionnaires were administered to children and their caregivers one week and three months post discharge from the Johnson and Johnson Paediatric Burns Unit, Chris Hani Baragwanath Hospital, Soweto. The improvement in the PedsQL scores suggests that the quality of life for children three months after discharge is good despite being burnt. The severity of the burn was found to be a significant predictor of quality of life (p=0.00). Poor socio-economic status was clearly evident in demographic data of the subjects. The findings from this study are particularly important in identifying areas for further research that would be beneficial to developing countries. Furthermore, the results are important in the move towards more holistic care for paediatric burn survivors. PMID- 21251762 TI - Altered levels of circulating insulin and other neuroendocrine hormones associated with the onset of schizophrenia. AB - Recently, we showed that the circulating levels of insulin-related peptides and the secretory granule protein chromogranin A were increased in small cohorts of first onset schizophrenia patients. Assuming that this effect was associated with impaired insulin signalling, we investigated the possibility that secretion of other hormones is also affected in schizophrenia. Multiplex immunoassay analysis of 21 hormones and hormone-related molecules was carried out using sera from 236 first and recent onset schizophrenia patients and 230 matched controls. Serum concentrations of insulin and chromogranin A were increased in schizophrenia subjects, consistent with our previous study. In addition, we found elevated concentrations of pancreatic polypeptide, prolactin, progesterone and cortisol, and decreased levels of growth hormone. We also found that growth hormone levels were decreased in post-mortem pituitaries obtained from chronic schizophrenia patients. It will be important to determine whether any of these molecules are involved in the pathosphysiology of schizophrenia or if they reflect the associated insulin resistance. We conclude that function of multiple components of the hypothalamic-pituitary-adrenal-gonadal axis may be affected in schizophrenia. This could have important implications for future biomarker discovery efforts and personalized medicine strategies based on patient stratification for the treatment of this debilitating disorder. PMID- 21251763 TI - Therapeutic cloning by xenotransplanted oocytes, supplemented with species specific reprogramming factors. AB - For therapeutic medication, a lot of work has been done regarding human embryonic stem (ES) cell lines derivation, but immunorejection is a major dilemma of this cell based therapy. Since long time, derivation of patient matched stem cells have been hoped to overcome this problem. Oocytes after nuclear transfer are the most reliable source for patient matched ES cells derivation, for therapeutic use. In humans, utilization of oocytes for stem cell research raises sensitive logistical and ethical questions; primarily surrounding participation of women as oocyte donors. It has been claimed that therapeutic cloning would lead to commercial exploitation of poor women. On the other hand, the therapeutic promise of embryonic stem cell is so huge that there is a strong incentive to find some alternate sources of human oocytes. Here we propose to utilize the cross species oocytes supplemented with human ES cellular extracts to establish patient specific ES cell lines. PMID- 21251764 TI - Milk signalling in the pathogenesis of type 2 diabetes. AB - The presented hypothesis identifies milk consumption as an environmental risk factor of Western diet promoting type 2 diabetes (T2D). Milk, commonly regarded as a valuable nutrient, exerts important endocrine functions as an insulinotropic, anabolic and mitogenic signalling system supporting neonatal growth and development. The presented hypothesis substantiates milk's physiological role as a signalling system for pancreatic beta-cell proliferation by milk's ability to increase prolactin-, growth hormone and incretin-signalling. The proposed mechanism of milk-induced postnatal beta-cell mass expansion mimics the adaptive prolactin-dependent proliferative changes observed in pregnancy. Milk signalling down-regulates the key transcription factor FoxO1 leading to up regulation of insulin promoter factor-1 which stimulates beta-cell proliferation, insulin secretion as well as coexpression of islet amyloid polypeptide (IAPP). The recent finding that adult rodent beta-cells only proliferate by self duplication is of crucial importance, because permanent milk consumption beyond the weaning period may continuously over-stimulate beta-cell replication thereby accelerating the onset of replicative beta-cell senescence. The long-term use of milk may thus increase endoplasmic reticulum (ER) stress and toxic IAPP oligomer formation by overloading the ER with cytotoxic IAPPs thereby promoting beta-cell apoptosis. Both increased beta-cell proliferation and beta-cell apoptosis are hallmarks of T2D. This hypothesis gets support from clinical states of hyperprolactinaemia and progeria syndromes with early onset of cell senescence which are both associated with an increased incidence of T2D and share common features of milk signalling. Furthermore, the presented milk hypothesis of T2D is compatible with the concept of high ER stress in T2D and the toxic oligomer hypothesis of T2D and may explain the high association of T2D and Alzheimer disease. PMID- 21251765 TI - Efficacy of washing meat surfaces with 2% levulinic, acetic, or lactic acid for pathogen decontamination and residual growth inhibition. AB - We compared spray washing at 55.4 degrees C with 2% levulinic acid to that with lactic or acetic acid for decontamination of pathogenic bacteria inoculated onto meat surfaces, and their residual protection against later growth of pathogenic bacteria. The model systems included Escherichia coli O157:H7 on beef plate, Salmonella on chicken skin and pork belly, and Listeria monocytogenes on turkey roll. In the decontamination studies, acid washes lowered recoverable numbers of pathogens by 0.6 to 1 log/cm(2) as compared to no-wash controls, and only lactic acid lowered the number of pathogens recovered as compared to the water wash. Washing with levulinic acid at 68.3 or 76.7 degrees C did not result in additional decontamination of E. coli. Acetic acid prevented residual growth of E. coli and L. monocytogenes, and it reduced numbers of Salmonella on chicken skin to below recoverable levels. Overall, levulinic acid did not provide as effective decontamination as lactic acid nor residual protection as acetic acid. PMID- 21251766 TI - Comparison of heating methods and the use of different tissues for sensory assessment of abnormal odours (boar taint) in pig meat. AB - Five heating methods (microwave, hotwire, boiling at 25 degrees C and 75 degrees C and melting) were used to generate cooking odours from backfat of entire male pigs and a 'composite' sample consisting of fat and muscle from the head along with salivary glands. The methods elicited significantly different scores for odours from 4 groups of 10 samples differing in their concentrations and ratios of skatole and androstenone. The odours (pork odour, abnormal odour, skatole odour and androstenone odour) were assessed by 3 experienced assessors. Correlations between skatole and androstenone concentrations and abnormal odour score in backfat were higher for skatole, suggesting it is the more important boar taint compound. In the composite sample, androstenone concentration was much higher than in backfat and androstenone was a more important contributor to boar taint. The microwave, hotwire and boiling (75 degrees C) methods produced the clearest separation between samples and the microwave method was considered the most suitable for on-line use. PMID- 21251767 TI - Toxicity and patterns of failure of adaptive/ablative proton therapy for early stage, medically inoperable non-small cell lung cancer. AB - PURPOSE: To analyze the toxicity and patterns of failure of proton therapy given in ablative doses for medically inoperable early-stage non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Eighteen patients with medically inoperable T1N0M0 (central location) or T2-3N0M0 (any location) NSCLC were treated with proton therapy at 87.5 Gy (relative biological effectiveness) at 2.5 Gy /fraction in this Phase I/II study. All patients underwent treatment simulation with four dimensional CT; internal gross tumor volumes were delineated on maximal intensity projection images and modified by visual verification of the target volume in 10 breathing phases. The internal gross tumor volumes with maximal intensity projection density was used to design compensators and apertures to account for tumor motion. Therapy consisted of passively scattered protons. All patients underwent repeat four-dimensional CT simulations during treatment to assess the need for adaptive replanning. RESULTS: At a median follow-up time of 16.3 months (range, 4.8-36.3 months), no patient had experienced Grade 4 or 5 toxicity. The most common adverse effect was dermatitis (Grade 2, 67%; Grade 3, 17%), followed by Grade 2 fatigue (44%), Grade 2 pneumonitis (11%), Grade 2 esophagitis (6%), and Grade 2 chest wall pain (6%). Rates of local control were 88.9%, regional lymph node failure 11.1%, and distant metastasis 27.8%. Twelve patients (67%) were still alive at the last follow-up; five had died of metastatic disease and one of preexisting cardiac disease. CONCLUSIONS: Proton therapy to ablative doses is well tolerated and produces promising local control rates for medically inoperable early-stage NSCLC. PMID- 21251769 TI - Invasive candidiasis in neonates and children. AB - Invasive candidiasis is associated with high morbidity and mortality in neonates and children. The incidence of invasive candidiasis is greater in children than in adults and is particularly high in neonates. Main risk factors are multiple antibiotics, central venous catheters, parenteral nutrition, immunodepression, low birth weight, fungal colonization, and necrotizing enterocolitis. Successful management of IFIs relies on early recognition and rapid initiation of effective treatment. PMID- 21251768 TI - Recent advances in prevention of sepsis in the premature neonates in NICU. AB - Sepsis-related morbidity and mortality are major problems in NICU. Preterm neonates display clinical characteristics that make them prone to infections. Due to the high frequency of severe neurodevelopmental sequelae in survivors, the best possible strategy to manage sepsis in NICU is to prevent them. Hygiene, cohorting, stewardship on use of H2-blockers, steroids and broad-spectrum antibiotic are mandatory, as well as proper management of central venous accesses and surgical devices. In addition, clinical research offers the opportunity of adopting pharmacological preventative strategies such as use of palivizumab to prevent RSV infection, use of fluconazole to prevent fungal sepsis, use of probiotics and lactoferrin to enhance the innate immunity, and use of pagibaximab to prevent staphylococcal sepsis. PMID- 21251770 TI - Antifungal prophylaxis in neonates. AB - Fungal-related morbidity and mortality is a major concern for most neonatal intensive care units (NICUs) worldwide. Incidence rates are increasing and might be higher than reported due to the challenges associated with diagnosing fungal infections. As preterm neonates display clinical characteristics that make them prone to Candida spp infections, and there is a high frequency of severe neurodevelopmental sequelae in those who survive neonatal fungal infections, specific prevention--rather than empiric or pre-emptive treatment--should be the optimal strategy. Besides stewardship of drug use and efforts to minimize invasive cares, pharmacological prevention with use of fluconazole has proved highly effective in decreasing the rates of fungal sepsis in very low birth weight (VLBW) neonates. Alternative options needing further and more conclusive assessments include use of nystatin, bovine lactoferrin or probiotics. PMID- 21251771 TI - New cardiopulmonary resuscitation guidelines 2010: managing the newly born in delivery room. AB - Most newborns are born vigorous and do not require neonatal resuscitation. However, about 10% of newborns require some type of resuscitative assistance at birth. Although the vast majority will require just assisted lung aeration, about 1% requires major interventions such as intubation, chest compressions, or medications. Recently, new evidence has prompted modifications in the international cardiopulmonary resuscitation (CPR) guidelines for both neonatal, paediatric and adult patients. Perinatal and neonatal health care providers must be aware of these changes in order to provide the most appropriate and evidence based emergency interventions for newborns in the delivery room. The aim of this article is to provide an overview of the main recommended changes in neonatal resuscitation at birth, according to the publication of the international Liaison Committee on Resuscitation (ILCOR) in the CoSTR document (based on evidence of sciences) and the new 2010 guidelines released by the European Resuscitation Council (ERC), the American Heart Association (AHA), and the American Academy of Pediatrics (AAP). PMID- 21251772 TI - Metabolic syndrome, fractures and gender. AB - The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors which has been suggested to have a possible effect on bone mass. Somewhat paradoxically, it is not clear whether this effect is protective or detrimental. Some of its components (e.g., obesity) seem to have the first type of effect and others (e.g., glucose metabolism changes) the second one. The epidemiological studies are not conclusive. Five out of six cross-sectional studies show no differences in the rate of fractures between subjects with or without MetS. In the sixth, fewer fractures were observed in patients with the syndrome. Two of three prospective studies also found fewer fractures, but the third more. Regarding the relationship of each individual component of MetS with fractures, the results - apart from obesity - are scarce or inconsistent. The relationship between MetS and bone mineral density (BMD) or bone turnover markers (BTMs) has also been addressed. Without adjusting for BMI, six out of nine studies have shown higher BMD values in MetS patients and the rest no differences. This positive effect on BMD is mainly driven by BMI, and therefore disappears after adjusting for it. The fasting plasma glucose level has been shown in general to be positively associated with BMD. Hypertension and hypertriglyceridemia showed variable results, while BTMs are decreased in MetS. Finally, there is no definite evidence about the existence of gender differences in the effect of MetS on bone. In conclusion, MetS tends to be positively associated with BMD and negatively with BTMs. No clear-cut data about fractures are available. PMID- 21251773 TI - An assessment of the accuracy of discriminant function equations for sex determination of the femur and tibia from a South African population. AB - The purpose of this study is to test the accuracy of seven discriminant function equations that have been derived by Steyn and Iscan for sex determination using measurements of the femur and tibia of South Africans of European descent (SAED). While the validity of some of the discriminant functions has been assessed by the authors who derived them, no previous independent study has been carried out to assess the accuracy of these equations. These equations have not been tested on skeletons located outside of the Gauteng province. A suite of measurements were taken on 272 femora and 256 tibiae obtained from four South African skeletal collections. The validity of each of the previously published equations for the femur was confirmed. However, two functions of the tibia showed low accuracy rates, most likely due to difficulties in recording the distal epiphyseal breadth measurement, and thus were found to be poor assessors of sex. PMID- 21251774 TI - Analysis of active ricin and castor bean proteins in a ricin preparation, castor bean extract, and surface swabs from a public health investigation. AB - In late February 2008, law enforcement officials in Las Vegas, Nevada, discovered in a hotel room, a copy of The Anarchist Cookbook, suspected castor beans and a "white powder" thought to be a preparation of ricin. Ricin is a deadly toxin from the seed of the castor bean plant (Ricinus communis). The United States regulates the possession, use, and transfer of ricin and it is the only substance considered a warfare agent in both the Chemical and the Biological Weapons Conventions. Six samples obtained from the hotel room were analyzed by laboratories at the Centers for Disease Control and Prevention using a panel of biological and mass spectrometric assays. The biological assays (real time-PCR, time resolved fluorescence and cytotoxicity) provided presumptive evidence of active ricin in each of the samples. This initial screen was followed by an in depth analysis using a novel, state-of-the-art mass spectrometry-based ricin functional assay and high sensitivity tandem mass spectrometry for protein identification. Mass spectrometric analysis positively identified ricin and confirmed that in each of the samples it was enzymatically active. The tandem mass spectrometry analysis used here is the most selective method available to detect ricin toxin. In each sample, ricin was unequivocally identified along with other R. communis plant proteins, including the highly homologous protein RCA120. Although database searches using tandem mass spectra acquired from the samples indicated that additional controlled substances were not present in these samples, the mass spectrometric results did provide extensive detail about the sample contents. To the best of our knowledge following a review of the available literature, this report describes the most detailed analysis of a white powder for a public health or forensic investigation involving ricin. PMID- 21251775 TI - Accuracy of 3.0 Tesla magnetic resonance imaging in the diagnosis of intracochlear schwannoma. AB - Intracochlear schwannomas (ICSs) are rare tumors. The diagnosis of ICS is based on high-resolution magnetic resonance imaging (MRI), which should be used for the accurate determination of the location of tumors. Recent advancements in imaging technologies and software enable the precise regional diagnosis of ICS. We experienced a case of intracochlear schwannoma with a diagnosis of progressive hearing loss and tinnitus. Audiometry revealed severe hearing loss in the right ear with remaining low-frequency hearing. MRI showed an abnormal lesion in the cochlea. Three-dimensional real inversion recovery (3D rIR) and constructive interference in steady state (CISS) MRI revealed the size and shape of the tumor via identification of the cochlear nerve and cochlear fluid space. CISS and 3D rIR sequences provide useful information regarding the boundaries of tumors and the tissues that surround them. PMID- 21251776 TI - Diagnostic criteria of eosinophilic otitis media, a newly recognized middle ear disease. AB - OBJECTIVE: Eosinophilic otitis media (EOM) is a newly recognized intractable middle ear disease, characterised by the accumulation of eosinophils in middle ear effusion and middle ear mucosa. Since EOM patients show gradual or sudden deterioration of hearing, it is important to properly diagnose EOM and to start adequate treatment for EOM. We aimed to investigate the clinical risk factors of EOM and to establish the diagnostic criteria of EOM. PATIENTS AND METHODS: We reviewed 138 patients with EOM and 134 age-matched patients with the common type of otitis media with effusion or chronic otitis media as controls. We analyzed the incidence of the following clinical variables in both groups: bilaterality of otitis media, viscosity of middle ear effusion, formation of granulation tissue in the middle ear, response to the treatment for otitis media, deterioration of bone conduction hearing level, and association with other diseases such as bronchial asthma, chronic rhinosinusitis, nasal polyposis, and allergic rhinitis. RESULTS: A high odds ratio was obtained from an association with bronchial asthma (584.5), resistance to conventional treatment for otitis media (232.2), viscous middle ear effusion (201.6), association with nasal polyposis (42.17), association with chronic rhinosinusitis (26.49), bilaterality (12.93), and granulation tissue formation (12.62). The percentage of patients with EOM who were positive for two or more among the highest four items was 98.55%. CONCLUSION: A patient who shows otitis media with effusion or chronic otitis media with eosinophil-dominant effusion (major criterion) and with two or more among the highest four items (minor criteria), can be diagnosed as having EOM. Patients with ear symptoms should have the proper diagnosis of EOM using the proposed diagnostic criteria, and then can receive adequate treatment, resulting in prevention of deterioration of hearing and quality of life. PMID- 21251777 TI - Effects of sequential and discrete rapid naming on reading in Japanese children with reading difficulty. AB - To clarify whether rapid naming ability itself is a main underpinning factor of rapid automatized naming tests (RAN) and how deep an influence the discrete decoding process has on reading, we performed discrete naming tasks and discrete hiragana reading tasks as well as sequential naming tasks and sequential hiragana reading tasks with 38 Japanese schoolchildren with reading difficulty. There were high correlations between both discrete and sequential hiragana reading and sentence reading, suggesting that some mechanism which automatizes hiragana reading makes sentence reading fluent. In object and color tasks, there were moderate correlations between sentence reading and sequential naming, and between sequential naming and discrete naming. But no correlation was found between reading tasks and discrete naming tasks. The influence of rapid naming ability of objects and colors upon reading seemed relatively small, and multi-item processing may work in relation to these. In contrast, in the digit naming task there was moderate correlation between sentence reading and discrete naming, while no correlation was seen between sequential naming and discrete naming. There was moderate correlation between reading tasks and sequential digit naming tasks. Digit rapid naming ability has more direct effect on reading while its effect on RAN is relatively limited. The ratio of how rapid naming ability influences RAN and reading seems to vary according to kind of the stimuli used. An assumption about components in RAN which influence reading is discussed in the context of both sequential processing and discrete naming speed. PMID- 21251778 TI - [There is room for different languages in public health journals]. PMID- 21251779 TI - [Critical analysis of French DRG based information system (PMSI) databases for the epidemiology of cancer: a longitudinal approach becomes possible]. AB - BACKGROUND: Use of French Diagnosis Related Groups (DRGs) program databases, apart from financial purposes, has recently been improved since a unique anonymous patient identification number has been created for each inpatient in administrative case mix database. Based on the work of the group for cancer epidemiological observation in the Rhone-Alpes area, (ONC-EPI group), we review the remaining difficulties in the use of DRG data for epidemiological purposes and we consider a longitudinal approach based on analysis of database over several years. We also discuss limitations of this approach. DIFFICULTIES: The main problems are related to a lack of quality of administrative data, especially coding of diagnoses. These errors come from missing or inappropriate codes, or not being in accordance with prioritization rules (causing an over- or under reporting or inconsistencies in coding over time). One difficulty, partly due to the hierarchy of coding and the type of cancer, is the choice of an extraction algorithm. In two studies designed to estimate the incidence of cancer cared in hospitals (breast, colon-rectum, kidney, ovaries), a first algorithm, including a code of cancer as principal diagnosis with a selection of surgical procedures less performed than the second one including a code of cancer as principal diagnosis only, for which the number of hospitalizations per patient ratio was stable across time and space. The chaining over several years allows, by tracing the trajectory of the patient, to detect and correct inaccuracies, errors and missing values, and for incidence studies, to correct incident cases by removing prevalent cases. DISCUSSION: However, linkage, complete only since 2007, does not correct data in all cases. Ways of future improvement certainly pass through improved algorithms for case identification and especially by linking DRG data with other databases. PMID- 21251780 TI - [Perception of health care quality by patients with chronic conditions]. AB - BACKGROUND: Patient opinion is becoming ever more important when considering healthcare quality and the reforms required to improve healthcare quality. The main aim of this study was to explore factors determining perceived healthcare quality among patients with chronic diseases. METHODS: Data are drawn from the survey carried out in 2008 by the Commonwealth Fund, in partnership with the French Superior Health Authority (Haute Autorite de sante). The prospective telephone survey targeted adults in eight countries who had serious health problems (chronic or severe disease, declared poor state of health, hospital admission or major surgery). Of the 1202 French respondents, 851 had at least one diagnosed chronic disease. A multinomial logistic model was used to identify the relationship between perceived healthcare quality and patients' recent experience with the healthcare system. RESULTS: People with chronic disease in general perceived that healthcare quality was excellent (45%) or good (44%). Only 11% of respondents judged it to be average or poor. There was a hint of "could do better", for example when considering podology and ophthalmology follow-up in diabetes or the management of multiple medications. The explanatory model revealed a positive correlation between excellent perceived healthcare quality and a strong doctor-patient relationship, taking into account both the length of this relationship and the ability of the doctor to involve the patient at all stages of decision-making concerning therapeutic management. There was no major link between the perceived quality of care and objective care quality, the quality of procedures, the cost of care to the patient or how frequently patients access the healthcare system. CONCLUSION: The quality of the relationship between the patient and his/her doctor is a determining factor in the patient's judgement of the quality of healthcare he/she receives. PMID- 21251781 TI - [Assessing the wearing of jewellery by French healthcare professionals]. AB - OBJECTIVE: A prospective observation study was undertaken in seven medical centers, in the French region Alpes-Maritime, to assess nail hygiene of healthcare professionals and how often they wear hand jewellery. METHOD: Seven hundred and six healthcare workers in seven medical centers were interviewed from March to April 2008. RESULTS: Among the 706 professionals, 306 (43%) were wearing one or several pieces of jewellery. The nails of 81 (11.5%) were non-standard according to guidelines. Three hundred and forty-four health care professionals (49%) were wearing one or several pieces of jewellery and/or presented with non standard nails. In univariate analysis, the wearing of jewellery was linked to the medical centre (P<0.001), to the professional category (p<0.001), to the number of times people washed their hands or used hand gel per day (ABHR) by categories (<10 times per day or >=10 times per day) (P<0.017). In the multivariate analysis, the risk factors linked to the wearing of jewellery were the medical centers, the professional category, and the age. CONCLUSION: There are still too many healthcare professionals who do not comply to French recommendations on hand hygiene concerning the wearing of jewellery and nail hygiene standards. PMID- 21251782 TI - [Public health surveillance and assessment of emerging infectious threats: method and criteria for risk analysis]. AB - One of the objectives of the surveillance systems implemented by the French National Institute for Public Health Surveillance is to detect communicable diseases and to reduce their impact. For emerging infections, the detection and risk analysis pose specific challenges due to lack of documented criteria for the event. The surveillance systems detect a variety of events, or "signals" which represent a potential risk, such as a novel germ, a pathogen which may disseminate in a non-endemic area, or an abnormal number of cases for a well known disease. These signals are first verified and analyzed, then classified as: potential public health threat, event to follow-up, or absence of threat. Through various examples, we illustrate the method and criteria which are used to analyze and classify these events considered to be emerging. The examples highlight the importance of host characteristics and exposure in groups at particular risk, such as professionals in veterinarian services, health care workers, travelers, immunodepressed patients, etc. The described method should allow us to identify future needs in terms of surveillance and to improve timeliness, quality of expertise, and feedback information regarding the public health risk posed by events which are insufficiently documented. PMID- 21251783 TI - [Duration of antibiotic therapy in bone infection and biological or radiological data]. AB - Modalities of bone infection therapeutic follow-up are controversial, notably for biological and radiological parameters. We have proposed six weeks of antibiotic therapy for all patients presenting with bone infection, since July 2005. Therefore, biological and radiological exams performed during the treatment were not taken into account when determining the duration of antibiotherapy. This protocol allows determining the usefulness of these biological and radiological parameters. METHODS: All patients presenting with bone infection, from July 2005 to July 2008, were included. Inflammatory biological parameters such as C reactive protein (CRP) and sedimentation rate were analyzed, and values were considered as normal when less than 10 mg/L and less than 15 mm respectively. All available CT- and MR imaging were analyzed by the same referent radiologist. RESULTS: Eighty-seven patients presenting with bone infection received antibiotic therapy for a mean [SD] 42 +/- 0.3 days. Cure was reported in 82 patients (94%) with a mean follow-up after antibiotic therapy of 36 +/- 9 months, five patients relapsed. CRP was available in 66 cases by the end of antibiotic therapy, it was normal in 40/64 of patients with favorable outcome (62%) and in one case of unfavorable outcome. The sedimentation rate was available in 22 cases, and normal in seven cases of favorable outcome (32%). By the end of antibiotic therapy, CT scan showed active bone infection for 15/23 of patients with favorable outcome (65%), while MR imaging suggested the same diagnosis in 8/14 cases (57%). CONCLUSION: Biological parameters and radiological findings are inadequate to determine the duration of antibiotic therapy in bone infection. PMID- 21251784 TI - The negative predictive value of breast Magnetic Resonance Imaging in noncalcified BIRADS 3 lesions. AB - PURPOSE: The purpose of this study is to determine whether breast MRI can provide a sufficient NPV to safely rule out malignancy in mammographic BIRADS 3 lesions. MATERIALS AND METHODS: In a 3-year consecutive mammographic examination study 176 out of 4391 patients had a lesion classified as BIRADS 3. 76 out of 176 patients underwent breast MRI as diagnostic work-up. Lesions which MRI classified as BIRADS 1 or 2 were considered negative for malignancy. Sensitivity, specificity, PPV and NPV were calculated. RESULTS: In 27 out of 76 (35.5%) patients MRI showed no enhancement and was classified as BIRADS 1. In 25 (32.9%) patients MRI showed focal or mass enhancement classified as BIRADS 2. In these 52 (68.4%) patients no malignancy was found during at least 2 years study follow-up. The other 24 (31.6%) patients had a lesion classified as BIRADS >= 3. Thirteen of these 24 lesions were malignant by pathology. MRI had a sensitivity of 100% (95% CI: 75 100%), specificity of 82.5% (95% CI: 71-91%), PPV of 54.2% (95% CI: 33-74%) and NPV of 100% (95% CI: 93-100%). CONCLUSION: Breast MRI should be used in a diagnostic strategy for the work-up of noncalcified BIRADS 3 lesions. Malignancy is ruled out with a very high level of confidence in the majority of patients (68%), herewith avoiding invasive diagnostic procedures. PMID- 21251785 TI - Liver metastases on quantitative color mapping of the arterial enhancement fraction from multiphasic CT scans: evaluation of the hemodynamic features and correlation with the chemotherapy response. AB - PURPOSE: To demonstrate the hemodynamic features of liver metastases using quantitative color mapping of the arterial enhancement fraction (AEF) and to investigate the feasibility of using the AEF to predict the chemotherapy response. MATERIALS AND METHODS: Seventy-two patients with liver metastases (metastasis group) and 18 cancer-matched patients without liver metastases (non metastasis group) were included. A quantitative AEF color map was created from multiphasic CT images using prototypic software. The AEF of tumor, tumor-adjacent parenchyma, and tumor-free parenchyma in the metastasis group; and the AEF of tumor-free parenchyma in the non-metastasis group were measured. In addition, in 28 patients with colorectal cancer for whom follow-up CT scans were available, the AEF on baseline CT scans was compared according to the initial response to chemotherapy in the response (n=11) vs. the non-response group (n=17). RESULT: In the metastasis group, the AEF of metastases (58.9+/-15.8) was significantly higher than that of tumor-adjacent parenchyma (35.5+/-15.4) (P<0.0001). In addition, tumor-adjacent parenchyma had a higher AEF than tumor-free parenchyma (26.4+/-7.5) (P<0.0001). The AEF of tumor-free parenchyma in the metastasis group and that in the non-metastasis group (25.4+/-3.7) did not show a significant difference. Of the patients with colorectal liver metastases, the response group demonstrated a significantly higher AEF of metastases (65.5+/-9.6) than the non response group (51.3+/-13.2) (P<0.01). CONCLUSION: Adding AEF mapping to multiphasic CT images can improve the demonstration of the hemodynamic features of liver metastases and may be helpful for predicting the tumor response in limited groups of patients with colorectal liver metastases. PMID- 21251786 TI - Hypersensitivity reactions and contrast medium injection: are they always related? AB - BACKGROUND: Hypersensitivity (allergic or non-allergic) reactions that occur after contrast medium (CM) injection are usually related to the CM. Recent studies, and case reports lack the analysis of alternate causes that could be also responsible in individual cases. PATIENTS AND METHODS: We investigated the individual relevant factor/causative agent of adult patients with hypersensitivity reactions that occurred in radiological units during CM-enhanced procedures (CT, angiography, urography, or MR-examinations). Both immediate and non-immediate (delayed) reactions were included. To find out the relevant agent a detailed patients' history was carefully analyzed. In addition, the records were retrospectively reviewed, and if indicated and possible laboratory (e.g. basophil activation test) and skin tests (e.g. prick) and/or provocations with CM injections under routine conditions were performed. RESULTS: 38 patients (men n=21) suspected for CM-hypersensitivity reactions were identified. These reactions were in most cases mild (n=21), moderate reactions occurred in 13 cases, and four patients had severe reactions. In 28 patients the reactions were induced by the CM (iodinated CM in 25 cases). Four patients had reactions that were not CM-related (latex allergy, adenosine reaction, vasovagal reaction, unknown cause) and in six cases the reaction was partly CM-related (immunological activation was present due to the patients' diseases). CONCLUSION: Our data support the hypothesis that in CM-enhanced procedures not only contrast materials but also a broad range of other factors may also induce hypersensitivity reactions. Therefore, the number of CM-induced hypersensitivity is smaller than initially suspected. The knowledge of the cause of a reaction is essential to effectively prevent its recurrence and to improve safety aspects in patients undergoing CM-injection. Larger trials should be performed to more specifically assess alternate causes in patients who acquire hypersensitivity reactions in CM enhanced diagnostic procedures. PMID- 21251787 TI - Rational use of stacking principles for signal enhancement in capillary electrophoretic separations of poliovirus samples. AB - The use of an earlier developed capillary electrophoresis (CE) method, either to investigate poliovirus (PV) samples with a low viral-purity level or to study the less abundant sub-viral particles, revealed the necessity for an intra-column signal enhancement strategy. Although intra-column signal enhancement is a very popular approach to assay small molecules, it is less straightforward for the analysis of biological macromolecules or particles. A reason could be that, for a proper signal enhancement approach, these samples have to be thoroughly studied to understand the factors affecting the separation process. For the investigated PV samples, a screening design revealed that injecting larger sample plugs significantly enhanced the analytical signal, but also significantly decreased the separation efficiency. A subsequently executed central composite design determined the largest sample plug that can be injected without compromising the separation. Finally, the sample dilution and the length of the injected plug were used for tuning the intensity of the analytical response. Two combinations of sample dilution and injected plug size, at extreme values, were investigated in detail to define the best procedure for PV analysis using CE. In both situations, PV was effectively separated and quantified in rather complex samples, showing a good repeatability, an acceptable linearity for the PV particles and a decreased limit of detection in comparison with the existing method. In conclusion, intra column signal enhancement can be successfully applied for viral suspensions, extending the applicability of CE methods to samples with lower virus concentrations, and/or allowing a significant reduction in the minimum required volume of sample. For PV samples, 5MUl of sample is necessary instead of the previous 20MUl, while the analytical signal was enhanced up to 14 times. The results of this study can provide a basis for the development of routine CE methods for viral particle analysis, especially when rational and reproducible signal enhancement is required. PMID- 21251788 TI - Health literacy and decision making styles for complex antithrombotic therapy among older multimorbid adults. AB - OBJECTIVES: To evaluate the effect of functional health literacy (FHL) on preferences for decision-making; and among those initially preferring a passive decision-making role, to explore how preferences change if their physician actively encourages their involvement. METHODS: Consecutive older adults with cardiovascular disease receiving complex antithrombotic therapy completed a comprehensive assessment including measures of FHL and preferences for shared decision making. RESULTS: Half of all participants had inadequate or marginal FHL. Those with inadequate FHL were more likely (P=0.01) to prefer passive rather than active decision making styles even after controlling for age, education, and numeracy. However, 40% of patients preferring passive styles had adequate FHL and these patients were significantly more likely to change their preference to more active styles (odds ratio=7.17, P<.01) if their physician "was more supportive or encouraged participation". CONCLUSIONS: Screening FHL can provide insight into patients' preferences for active participation in decision making. Clinicians' encouragement of participation can increase engagement by patients with adequate FHL. PRACTICE IMPLICATIONS: We propose an algorithm for screening FHL and preferences for participating in decisions about complex medication regimens. PMID- 21251789 TI - Patients' perception of communication with clinicians during screening and discussion of cancer supportive care needs. AB - OBJECTIVE: Effective communication between patients and clinicians is an essential aspect of supportive care for cancer patients, however many patients find this communication is inadequate. This study examined cancer patients' perception of communication with their clinician during a supportive care screening and discussion process and the ways in which this process assisted communication. METHODS: One hundred and fifty-four patients undertaking treatment for cancer in chemotherapy, radiotherapy and surgical units in six hospitals in Australia participated in a formal supportive care screening, discussion and referral process and were interviewed about their experiences. RESULTS: The majority of patients interviewed felt that the process enhanced communication by encouraging them to reflect on their needs, assisting them to initiate a discussion with the clinician, validating their needs, encouraging them to seek help and support and focusing clinician attention on unmet needs. CONCLUSION: Patients perceived the formal process of supportive care improved communication between themselves and their clinicians. PRACTICE IMPLICATIONS: Undertaking a patient-centred process of supportive care can assist clinicians to meet the unmet needs of patients with cancer and can increase patient satisfaction. PMID- 21251790 TI - Sentinel lymph node biopsy in primary breast cancer: trust the radiolabeled colloid method and avoid unnecessary procedures. AB - BACKGROUND: With regard to the sentinel lymph node (SLN) procedure in breast cancer, the study analyzed the impact of discrepancies between the number of clinically and histologically identified SLN, the impact of removing additional non-hot/non-blue but clinically conspicuous lymph nodes (LN), and whether the application of blue dye for mapping is necessary. METHODS: We analyzed 391 SLN procedures in which 928 SLN were removed. In all cases, radiolabeled colloid and blue dye were used for SLN mapping. RESULTS: In 60 cases (15.3%), additional LN that were not identified by the surgeon were found by histological examination. In 22 cases (5.3%), tissue which clinically resembled an SLN but was histologically connective tissue, was removed. In 76 cases (19.4%), 133 non hot/non-blue but clinically conspicuous LN were removed. These additionally removed LN, however, did not alter the axillary staging. In 50.8% of the cases (n = 471), the SLN were marked only by radiolabeled colloid. In 27 cases (2.9%), the surgeon identified the LN through blue coloration alone; however, in all of the latter cases, these SLN were not deciding for axillary staging. CONCLUSION: The mapping agents may accumulate in axillary tissue and mimic the existence of an SLN. The radiolabeled colloid method alone gives excellent mapping results. The additional application of blue dye is avoidable. Exact surgical preparation enables removal of the SLN only and avoids removal of LN-containing adjacent tissue. The removal of further clinically identifiable enlarged non-hot LN should only be done if there is strong suspicion of metastatic involvement. PMID- 21251791 TI - [Pandemic influenza A (H1N1 virus) on Futuna Island in the Pacific, from August to September 2009]. AB - OBJECTIVE: The aim of this study is to report the observation of the pandemic of influenza A (H1N1 virus) from August to September 2009 on the island of Futuna, in a context of isolated island that may mimic an environment closed. METHOD: We conducted a prospective observational study of influenza-like illness, from the first confirmed case of influenza A on the island until the end of the epidemic wave. RESULTS: From August 15 to September 20, 2009, 1536 cases of influenza syndrome were identified. The estimate of the overall clinical attack rate was 36 %. The evolution of the epidemic shows an explosion of new cases of influenza A and subsequently a rapid decline of the epidemic. The spread of the infection was made by contiguity, jumping from one city to another. The cumulative number of cases by age group shows that the majority of cases were children and young adults under the age of 20 years. The most frequent symptoms were cough, rhinorrhea, headache, myalgia or asthenia, and fever. CONCLUSION: This study, despite these limitations, shows an explosive epidemic of influenza A, which can be explained by the circulation of virus that has been fostered by gatherings of public and closed environment. Age group classification shows that majority of cases were young, in contrast to seasonal influenza, but the symptoms were alike. This study highlights the difficulties to manage an epidemic surveillance system at high level and given the quick spread of the disease. PMID- 21251792 TI - [Scrotal sarcoidosis]. PMID- 21251793 TI - [Bullous secondary syphilis]. PMID- 21251794 TI - [Should aqueous eosin continue to be used in therapeutics?]. PMID- 21251795 TI - Facial affect processing in patients receiving opioid treatment in palliative care: preferential processing of threat in pain catastrophizers. AB - CONTEXT: As a multidimensional phenomenon, pain is influenced by various psychological factors. One such factor is catastrophizing, which is associated with higher pain intensity and emotional distress in cancer and noncancer pain. One possibility is that catastrophizing represents a general cognitive style that preferentially supports the processing of negative affective stimuli. Such preferential processing of threat--toward negative facial expressions, for example--is seen in emotional disorders and is sensitive to pharmacological treatment. Whether pharmacological (analgesic) treatment might also influence the processing of threat in pain patients is currently unclear. OBJECTIVES: This study investigates the effects catastrophizing on processing of facial affect in those receiving an acute opioid dose. METHODS: In a double-blind crossover design, the performance of 20 palliative care patients after their usual dose of immediate-release opioid was compared with their performance following matched placebo administration on a facial affect recognition (i.e., speed and accuracy) and threat-pain estimation task (i.e., ratings of pain intensity). The influence of catastrophizing was examined by splitting the sample according to their score on the Pain Catastrophizing Scale (PCS). RESULTS: Opioid administration had no effect on facial affect processing compared with placebo. However, the main finding was that enhanced processing of fear, sadness, and disgust was found only in patients who scored highly on the PCS. There was no difference in performance between the two PCS groups on the other emotions (i.e., happiness, surprise, and anger). CONCLUSION: These findings suggest that catastrophizing is associated with an affective information-processing bias in patients with severe pain conditions. PMID- 21251796 TI - Psychostimulants for the management of cancer-related fatigue: a systematic review and meta-analysis. AB - CONTEXT: Cancer-related fatigue (CRF) is a common and distressing symptom affecting patients with cancer. There is an increasing number of drug trials examining potential treatments for CRF. Methylphenidate represents one of the most researched drugs in this area, and an up-to-date assessment of the evidence for its use is needed. OBJECTIVES: To assess and summarize the increasing evidence for the use of psychostimulants, particularly methylphenidate, in the treatment of CRF. METHODS: A systematic review of electronic databases was conducted from inception to the start of October 2009, together with cross referencing of cited abstracts and hand searching of relevant cancer journals. RESULTS: A meta-analysis was conducted on five psychostimulant trials (n=426 participants). The overall standardized mean difference was -0.28 (95% confidence interval [CI] -0.48, -0.09; P=0.005), although several trials failed to find any benefit over placebo. There were no differences in the frequency of adverse events between methylphenidate and placebo: combined odds ratio 1.24 (95% CI 0.42, 3.62). CONCLUSION: There is preliminary evidence for the use of psychostimulants to treat CRF. The absolute numbers still remain small, and further confirmation is needed before firm recommendations on their usage and safety can be made in the treatment of CRF. PMID- 21251797 TI - Intraocular lens power calculation after intrastromal femtosecond laser treatment for presbyopia: Theoretic approach. AB - PURPOSE: To evaluate the accuracy of intraocular lens (IOL) power calculation after an intrastromal femtosecond laser procedure to treat presbyopia using a theoretic approach. SETTING: International Vision Correction Research Centre, Department of Ophthalmology, University of Heidelberg, Heidelberg, Germany. DESIGN: Nonrandomized clinical trial. METHODS: Preoperatively and 12 months after intrastromal femtosecond laser treatment (IntraCor) of presbyopia, biometry was performed by partial coherence interferometry (PCI) (IOLMaster). The postoperative keratometry (K) values and IOL power calculation formulas (Holladay I, Haigis, SRK/T, Hoffer Q) were compared with results derived from the clinical history method, taking the manifest refraction change into account. RESULTS: The study enrolled 25 patients (median age 54 years). Three eyes were excluded for age-related lens changes. The median spherical equivalent change in the other 22 eyes was -0.38 diopter (D). The median difference in K values between the clinical history method and PCI was -0.21 D, resulting in a median IOL power difference between -0.23 D (SRK/T) and -0.29 D (Haigis) (range -1.58 to +1.00 D). The IOL power was underestimated in 59.1% of cases with the Hoffer Q and 63.6% of cases with the Holladay I, Haigis, and SRK/T. There was a difference of +/-0.75 D in 72.7% of eyes using the Holladay I, Haigis, and Hoffer Q and in 86.4% of eyes using the SRK/T. Neither K values nor IOL power differences were statistically significant (P > .17). CONCLUSION: Intraocular lens power calculation using modern standard formulas incorporated in a PCI biometry device after intrastromal femtosecond presbyopia treatment was reliable, with minimum underestimation on average. PMID- 21251799 TI - Enhanced K-complex: an EEG features supporting the concept of system epilepsy (Comment to: Si et al.). PMID- 21251798 TI - Clinicopathological factors are predictors of distant metastasis from major salivary gland carcinomas. AB - The risk of distant metastasis of salivary gland cancers has usually been associated with histological type, tumour size, and site. The aim of this study was to evaluate a series of patients with major salivary gland carcinomas in order to identify potential risk factors associated with distant metastasis. 255 patients treated for major salivary gland carcinoma in Brazil from 1953 to 2004 were reviewed. Clinical and treatment data were obtained from the medical records and histological features reviewed. 57 (22%) of 255 patients had distant metastasis. The lungs were the most common metastatic site (40 cases, 65%) and adenoid cystic carcinoma the most frequent histological type involved (27 cases, 47%). The percentage of tumours in the submandibular, parotid, and sublingual glands that presented distant metastasis was 42%, 20%, and 17%, respectively. These results provide evidences that clinicopathological factors (tumour site and histology) are significant predictors of distant metastasis in patients with major salivary gland carcinomas. PMID- 21251800 TI - rAAV2-mediated restoration of LEKTI in LEKTI-deficient cells from Netherton patients. AB - BACKGROUND: Netherton syndrome (NS, MIM 256500) is a potential live threatening autosomal-recessive skin disorder clinically characterized by the trias of congenital erythroderma, hair shaft anomalies and atopic diathesis. It is caused by mutations in the gene SPINK5 resulting in a deficiency of its processed protein named lympho-epithelial Kazal-type related inhibitor (LEKTI). LEKTI controls the activity of several serine proteases in the skin that are involved in terminal differentiation. Loss of LEKTI results in protease hyperactivity, increased degradation of intercellular junctions, reduced stratum corneum adhesion and impaired skin barrier function. Today NS can only be treated symptomatically. OBJECTIVE: Does gene transfer offer a therapeutic option for NS in the future? METHODS: A recombinant adeno-associated virus type 2 vector was constructed containing the full length cDNA (rAAV2/C-SPINK5) of functional human LEKTI. Infectious virus particles were used for transfection of LEKTI-deficient keratinocytes of NS patients in vitro. RESULTS: Gene transfer of SPINK5 in NS keratinocytes led to a five-fold increase in mRNA expression of SPINK5 reaching almost 75% of normal value. The functionality of the expressed LEKTI was proven in a hydrolytic activity assay demonstrating that the activity of LEKTI after gene transfer increased closely to the level seen in keratinocytes of healthy individuals. CONCLUSION: The results provide first evidence that gene transfer of SPINK5 results in increased LEKTI activity in NS-keratinocytes, thus offering a rational to further pursue such a gene therapy approach for NS. PMID- 21251801 TI - Gadolinium-based cancer therapeutic liposomes for chemotherapeutics and diagnostics. AB - Gadolinium (Gd)-based cancer therapeutic liposomes can be used for chemotherapeutics and diagnostics. In this study, dual functional liposomes co encapsulating doxorubicin (Dox) and Gd were prepared by Dox-transition metal complexation. Preparation conditions were optimized to obtain liposomes containing high concentrations of Dox and Gd. The optimized liposomes Gd250 co encapsulated 3.6 mM of Dox and 1.9 mM of Gd. The magnetic resonance (MR) properties of Gd250 liposomes were determined using a 4.7 T MR system. Cellular uptake of Dox was determined using a flow cytometer and a confocal microscopy and that of Gd was measured using an inductively coupled plasma-atomic emission spectrometer. Although encapsulated Gd exhibited lower relaxivity than MRbester(r), which is widely used for clinical diagnosis, because of limited diffusion across the liposome membrane, Gd250 liposomes showed much higher cellular uptake than that of MRbester(r). In Gd250 liposomes, Gd was highly accumulated in B16F10 cells, which could provide improved contrast sensitivity for molecular imaging. Additionally, in Gd250 liposomes, Dox was highly internalized, which could enhance its cancer therapeutic effects. Consequently, we suggest that dual functional liposomes can be used as therapeutic and diagnostic carriers. PMID- 21251802 TI - Peptide-modified inverted colloidal crystal scaffolds with bone marrow stromal cells in the treatment for spinal cord injury. AB - Inverted colloidal crystal (ICC) scaffolds grafted with two defined peptides, CSRARKQAASIKVAVSADR and CDPGYIGSR, and bone marrow stromal cells (BMSCs) were applied to the treatment for spinal cord injury (SCI) of model rats. The results revealed that the neuronal survival, characterized by the Nissl staining, in the injured thoracic spine at T10 decreased drastically after SCI without treatment over 4 weeks. The neuronal survival was enhanced by the present treatments. The order in the neuronal survival was BMSCs in peptide-modified ICC construct>BMSCs in peptide-free ICC construct>direct injection of BMSCs. Based on the nestin and neurofilament-H staining, the effect of therapeutic method on the quantity of neuronal precursor cells and axonal growth followed the same order as the neuronal survival. When treated with peptide-modified ICC construct, the expression of glial fibrillary acidic protein and tumor necrosis factor-alpha significantly reduced, indicating the inhibition of the formation of glial scar tissue and inflammatory cytokine. The ICC topography with the surface peptides can guide the differentiation of BMSCs toward neurons for nerve regeneration and enhance the SCI treatment. PMID- 21251803 TI - [Three cases of Hutchinson-Gilford progeria syndrome]. AB - Progeria, or Hutchinson-Gilford syndrome, is a rare genetic disease, characterized by several clinical features that develop in childhood, in particular, an accelerated aging aspect. Its incidence is 1-4 per 8 million newborns. Children with progeria syndrome usually appear normal at birth and in early infancy. Profound failure to thrive occurs during the 1st year. Characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, stiffness of joints, bone changes, and abnormal tightness of the skin over the abdomen and upper thighs usually become apparent during the 2nd to 3rd years. Motor and mental development is normal. Patients develop severe atherosclerosis. Death occurs as a result of complications of cardiac or cerebrovascular disease (heart attack or stroke) generally between ages 6 and 20 years. The diagnosis of Hutchinson-Gilford progeria syndrome (HGPS) is based on recognition of common clinical features and the detection of the recurrent p.Gly608Gly mutation in exon 11 of the LMNA gene, which is present in almost all individuals with HGPS. We present here 3 patients aged 5, 11, and 12 years referred to genetic consultation for dysmorphic facies and failure to thrive. After careful clinical examination and paraclinical assessment, the diagnosis of progeria syndrome was raised. We performed molecular analysis for the 3 patients by searching for the recurrent mutation c.1824C>T (p.Gly608Gly) of the LMNA gene, which was found only in 1 patient. We discuss the geneticist's role in the diagnosis of rare dysmorphic syndromes and their genetic counseling. We also analyze the clinical spectrum of HGPS by comparing the 3 patients. PMID- 21251805 TI - LTB4 increases nasal neutrophil activity and conditions neutrophils to exert antiviral effects. AB - BACKGROUND: Leukotriene B4 (LTB4) recruits and activates neutrophils. Accordingly, this leukotriene is involved in innate defense actions. OBJECTIVE: To examine if nasal LTB4 can produce neutrophil activity and to explore whether or not LTB4 can condition neutrophils to exert virucidal effects in vitro and in vivo. METHODS: 1. Twenty-three healthy subjects received nasal LTB4 in a randomized and sham-controlled design. Symptoms were scored and nasal lavages carried out. Myeloperoxidase (MPO) and alpha-defensins were monitored as indices of neutrophil activity. IL-8, eosinophil cationic protein (ECP) and alpha(2) macroglobulin were measured as indices of pro-inflammatory cytokine production, eosinophil activity, and plasma exudation. 2. Supernatants from neutrophils activated by LTB4 in vitro were assayed for virucidal activity against respiratory viruses. 3. In 38 healthy individuals, nasal inoculation with human rhinovirus-16 (HRV-16) was performed. In a preliminary study, intervention with LTB4 was given in a randomized and controlled design. Symptoms, virus replication, and antibody-titres were monitored. RESULTS: 1. LTB4 produced statistically significant increases in MPO and alpha-defensins, whereas IL-8, ECP, and alpha(2)-macroglobulin were unaffected. 2. The supernatants efficiently killed human coronavirus, respiratory syncytial virus, and influenza B virus. 3. HRV-16 replication was lower in subjects receiving LTB4, but this difference failed to reach statistical significance. Common cold symptoms and incidence of seroconversion were unaffected. CONCLUSION: Nasal LTB4 induces a selective recruitment/activation of neutrophils. LTB4 can condition neutrophils to exert virucidal effects in vitro and may reduce virus replication in vivo. We suggest that the condition induced by LTB4 reflects an enhanced state of innate defense. PMID- 21251806 TI - Resting handgrip force and impaired cardiac function at rest and during exercise in COPD patients. AB - BACKGROUND: Cardiac function measured as the oxygen pulse (O(2) pulse) is impaired during exercise (CPET) in patients with COPD. We investigated the relationship between handgrip force and O(2) pulse in COPD and controls. METHODS: We measured anthropometrics, lung function, respiratory muscle force, handgrip (HG) force and fat free mass (FFM) at rest in 18 men with COPD (FEV(1)%=45+/-20) and 15 controls. We then performed a symptom limited cardiopulmonary exercise test (CPET) with similar load and used heart rate, and oxygen pulse (VO(2)/HR) to express cardiac function at rest and during exercise. We corrected the O(2) pulse by FFM. RESULTS: Patients and controls were similar in BMI and FFM. COPD patients had lower handgrip (37.8+/-7 vs. 55+/-2) kg. O(2) pulse and HG were associated (r=0.665). At rest, COPD patients had faster heart rate (76+/-11 vs. 61+/-5) and lower oxygen pulse. COPD patients had lower oxygen pulse mL/beat at exercise isotime (10.6+/-3.7 vs. 14.3+/-2.7), even adjusted by muscle mass. CONCLUSION: Handgrip is associated with impaired heart function at rest and during exercise in COPD patients even adjusting for muscle mass differences. Lower handgrip may be a marker of impaired cardiac function in COPD patients. PMID- 21251804 TI - PET based volume segmentation with emphasis on the iterative TrueX algorithm. AB - PURPOSE: To assess the influence of reconstruction algorithms for positron emission tomography (PET) based volume quantification. The specifically detected activity in the threshold defined volume was investigated for different reconstruction algorithms as a function of volume size and signal to background ratio (SBR), especially for volumes smaller than 1ml. Special attention was given to the Siemens specific iterative reconstruction algorithm TrueX. METHODS: Measurements were performed with a modified in-house produced IEC body phantom on a Siemens Biograph 64 True Point PET/CT scanner (Siemens, Medical Systems) for six different SBRs (2.1, 3.8, 4.9, 6.7, 8.9, 9.4 and without active background (BG)). The phantom consisted of a water-filled cavity with built-in plastic spheres (0.27, 0.52, 1.15, 2.57, 5.58 and 11.49ml). The following reconstruction algorithms available on the Siemens Syngo workstation were evaluated: Iterative OSEM (OSEM) (4 iterations, 21 subsets), iterative TrueX (TrueX) (4 iterations, 21 subsets) and filtered backprojection (FBP). For the threshold based volume segmentation the software Rover (ABX, Dresden) was used. RESULTS: For spheres larger than 2.5ml a constant threshold (standard deviation (SD) 10%) level was found for a given SBR and reconstruction algorithm and therefore a mean threshold for the largest three spheres was calculated. This threshold could be approximated by a function inversely proportional to the SBR. The threshold decreased with increasing SBR for all sphere sizes. For the OSEM algorithm the threshold for small spheres with 0.27, 0.52 and 1.15ml varied between 17% and 44% (depending on sphere size). The threshold for the TrueX algorithm was substantially lower (up to 17%) than for the OSEM algorithm for all sphere sizes. The maximum activity in a specific volume yielded the true activity for the OSEM algorithm when using a SBR independent correction factor C, which depended on sphere size. For the largest three volumes a constant factor C=1.10+/-0.03 was found. For smaller volumes, C increased exponentially due to the partial volume effect. For the TrueX algorithm the maximum activity overestimated the true activity. CONCLUSION: The threshold values for PET based target volume segmentation increased with increasing sphere size for all tested algorithms. True activity values of spheres in the phantom could be extracted using experimentally determined correction factors C. The TrueX algorithm has to be used carefully for quantitative comparison (e.g. follow-up) and multicenter studies. PMID- 21251807 TI - Rapid measurement of the yield stress of anaerobically-digested solid waste using slump tests. AB - The anaerobic digestion of solid waste is usually performed using dry or semi-dry technology. Incoming waste and fermenting digestate are pasty media and thus, at the industrial scale, their suitability for pumping and mixing is a prerequisite at the industrial scale. However, their rheology has been poorly characterised in the literature because there is no suitable experimental system for analysing heterogeneous media composed of coarse particles. We have developed a practical rheometrical test, a "slump test", for the analysis of actual digested solid waste. It makes it possible to estimate yield stress from the final slump height. From the slump behavior, we conclude that digestates behave as visco-elastic materials. The yield stress of different digested waste was measured between 200 and 800Pa. We show that the media containing smaller particles or with higher moisture content are characterised by smaller yield stresses. This study thus demonstrates the impact of the origin of the digestate on the yield stress. PMID- 21251808 TI - Do foot orthoses replicate the static longitudinal arch angle during midstance in walking? AB - INTRODUCTION: In a normal clinical environment, foot function and treatment efficacy is evaluated using static foot posture assessment. Whilst there are several methods of static assessment, the longitudinal arch angle (LAA) has been validated as a repeatable and reliable static measure that represents foot posture during midstance whilst walking and running. The main aim of this study was to assess if static LAA is representative of dynamic LAA with the use of orthoses. METHOD: 17 male subjects with a mean age of 33.4 (SD 12.3) years, mean height of 169.88 (SD 9.2) mm and a mean weight of 72.71 (SD 11.36)kg, who provided an informed consent were included in the study. Orthotic prescription was produced using measurements from a weightbearing goniometer. An optoelectronic movement analysis system was employed to record and analyse the LAA in barefoot, shoe and shoe with orthoses conditions. This data was collected in a static standing condition and then repeated whilst walking. RESULTS: No significant differences were observed between right static and right dynamic barefoot condition t=1.329 (p=0.05). Same results were observed for right static and right dynamic orthotic condition t=-.233 (p=0.05). Similarly, no significant differences were recorded for left static and left dynamic barefoot condition and orthotic condition t=.303 (p=0.05) and t=.049 (p=0.05) respectively. However, differences were observed within the shoe only condition. CONCLUSION: LAA is been shown to be a good static measure for dynamic foot function and can reliably be implemented in a normal clinical environment to evaluate and assess the efficacy of the prescribed foot orthoses. PMID- 21251810 TI - Switching TGFbeta from a tumor suppressor to a tumor promoter. AB - TGFbeta acts as a potent tumor suppressor and tumor promoter in a context dependent manner. Tumor suppressive functions include inhibition of cell proliferation, induction of apoptosis and regulation of autophagy. As tumors develop they switch their response to TGFbeta and utilise this factor as a potent promoter of cell motility, invasion, metastasis and tumor stem cell maintenance. These multifactorial tumor influencing actions of TGFbeta involve regulation of an increasing number of signal transduction pathways employing a diverse range of signaling molecules. Understanding the molecular mechanisms of how tumor cells respond to TGFbeta and switch their response to this cytokine during disease progression is vital for both the development and the informed use of potentially powerful TGFbeta targeted therapeutics. PMID- 21251809 TI - We have got you 'covered': how the meninges control brain development. AB - The meninges have traditionally been viewed as specialized membranes surrounding and protecting the adult brain from injury. However, there is increasing evidence that the fetal meninges play important roles during brain development. Through the release of diffusible factors, the meninges influence the proliferative and migratory behaviors of neural progenitors and neurons in the forebrain and hindbrain. Meningeal cells also secrete and organize the pial basement membrane (BM), a critical anchor point for the radially oriented fibers of neuroepithelial stem cells. With its emerging role in brain development, the potential that defects in meningeal development may underlie certain congenital brain abnormalities in humans should be considered. In this review, we will discuss what is known about assembly of the fetal meninges and review the role of meningeal-derived proteins in mouse and human brain development. PMID- 21251812 TI - Sociodemographic factors and incidence of melanoma in the Netherlands, 1994-2005. AB - BACKGROUND: Time-space incidence maps of the Netherlands indicated differences in incidence of cutaneous melanoma (melanoma) over the country, which might be related to sociodemographic characteristics of living environment and socioeconomic status (SES) of the patients. The goal of this study was to refine the current approaches to prevention and early detection of melanoma by revealing relationships between sociodemographic factors and incidence of melanoma in the Netherlands. METHODS: Age-adjusted incidence rates were calculated from the Netherlands Cancer Registry. Data on sociodemographic factors were obtained from Statistics Netherlands. Logistic regression analysis was performed to investigate determinants of variation in incidence at the ecological level. At the individual level tumour characteristics were linked to SES based on postal code at the time of diagnosis. RESULTS: The lowest SES-group had a significantly lower incidence than the highest SES-group; 10.2 (95% confidence intervals (CI): 9.1-11.3) and 14.3 (95% CI: 12.9-15.8), respectively. Increased risk of melanoma was seen in municipalities with high population density, few people living on social security and many people with high income. Patients living in low SES neighbourhoods were diagnosed more often with higher stage disease (13% (95% CI: 12.3-13.8) diagnosed with pT4) than those living in high SES neighbourhoods (9% (95% CI: 8.5-9.8) diagnosed with pT4) (p<0.001) and with higher Breslow thickness (p<0.001). CONCLUSIONS: Awareness of the risks of UV radiation (UVR) is important and in the higher SES-groups primary prevention should remain the focus. However, if the incidence rates for the higher SES-groups are illustrative for the lower SES groups, then the focus should be on both primary and secondary prevention in the low SES-groups. PMID- 21251811 TI - Genetic modifiers of neurological disease. AB - Genetic modifiers make an important contribution to neurological disease phenotypes. Significant progress has been made by studying genetic modifiers in model organisms. The ability to study complex genetic interactions in model systems contributes to our understanding of the genetic factors that influence neurological disease. This will lead to the development of novel therapeutic strategies and personalized treatment based on genetic risk. PMID- 21251813 TI - Weekly docetaxel in metastatic breast cancer patients: no superior benefits compared to three-weekly docetaxel. AB - BACKGROUND: In anthracycline-pretreated metastatic breast cancer (MBC) patients, it is unknown whether weekly single-agent docetaxel is preferable to 3-weekly docetaxel regarding its toxicity and efficacy profile. PATIENTS AND METHODS: In this multicenter, randomised, open-label phase III trial, 162 patients were randomised to weekly docetaxel (group A) or 3-weekly docetaxel (group B). The primary end-point was tolerability; secondary end-points were efficacy and quality of life (QoL). RESULTS: Group A (weekly docetaxel, n=79) experienced less haematological toxicity, with just 1.3% versus 16.9% febrile neutropenia in group B (3-weekly docetaxel, n=77) (p=0.001). Not this difference, but fatigue and general malaise foremost led to more patient withdrawals in group A (24 versus 12 patients, p=0.032), less patients completing treatment (29 versus 43 patients, p=0.014) and reduced dose-intensity (15.6 versus 26mg/m(2)/week, 58% versus 70% of projected dose, p=0.017). As a result, 3-weekly docetaxel was related to better overall survival in multivariate analysis (hazard ratio 0.70, p=0.036), although in univariate analysis efficacy was similar in both groups. Reported QoL was similar in both groups, but less effective treatment with more general toxicity led to less completed QoL forms in group A (65.4% versus 50%, p=0.049). CONCLUSION: Weekly docetaxel is less well tolerated than a 3-weekly schedule, due to more non-haematological toxicity, despite less febrile neutropenia. Also, no efficacy benefits can be demonstrated for weekly docetaxel, which may even be inferior based on multivariate analysis. Therefore, a 3-weekly schedule should be preferred in the setting of MBC. PMID- 21251814 TI - Feasibility of metronomic oral cyclophosphamide plus prednisolone in elderly patients with inoperable or metastatic soft tissue sarcoma. AB - BACKGROUND: The number of elderly people with soft tissue sarcoma (STS) is increasing. A sizeable population of elderly patients with STS is unfit for conventional doxorubicin- or ifosfamide-based chemotherapy. We assessed the feasibility of metronomic oral cyclophosphamide (CPM) in this population. PATIENTS AND METHODS: Patients aged 65 years or older with unresectable STS received CPM 100mg twice daily plus prednisolone 20mg daily, the first week of a 2-week cycle in the outpatient setting. Main evaluation criterion was safety. Secondary evaluation criteria were objective response rate and progression-free survival. RESULTS: Twenty-six patients (median age: 72, range 66-88) received a total of 330 cycles (median per patient: 10, range 2-41) as first (n=19) or second-line chemotherapy (n=7). The most frequent histological subtypes were poorly differentiated sarcoma (n=8), leiomyosarcoma and liposarcoma (n = 5 each) and angiosarcoma (n=3). Grade >=3 lymphopenia was observed in 81% of pts but no opportunist infection occurred. Grade 3 anaemia and thrombocytopenia occurred in 2 pts (8%) each. No other grade 3-4 toxicity was seen. The response rate was 26.9% (95%CI: 9.9-44.0) and the disease control rate (responses and stable disease >12 weeks) was 69.2% (95%CI: 51.5-87.0). One complete (hepatic epithelioid haemangio-endothelioma) and 6 partial responses (including 5pts with radiation-induced sarcomas) were seen. Progression-free survival ranged from 0 to 20.6 months (median: 6.8 months) and was significantly longer in patients with radiation-induced sarcomas (median: 7.8 versus 5.2 months, p=0.02). CONCLUSION: Metronomic CPM showed good safety results for this frail population, with promising activity in patients with radiation-induced sarcoma. Toxicity profile was favourable, allowing prolonged home staying and rare treatment discontinuations. A larger prospective study is warranted to confirm these encouraging results in elderly with STS. PMID- 21251815 TI - Primary pancreatic cystic neoplasms revisited: part II. Mucinous cystic neoplasms. AB - Mucinous cystic neoplasms (MCNs) of the pancreas represent one of the most common primary pancreatic cystic neoplasms, accounting for approximately half of these cases. MCNs are observed almost exclusively in women, and most commonly are located in the body/tail of the pancreas. In contrast to SCNs, MCNs have malignant potential. Proliferative changes (hyperplasia with or without atypia, borderline changes, non-invasive or carcinomas in-situ, and invasive carcinomas) can often be observed within the same neoplasm. Several risk factors for the presence of underlying malignancy within an MCN have recently been recognized. Cross-sectional imaging is of key importance for the diagnostic evaluation of patients with a cystic pancreatic lesion. Cyst fluid examination (cytology, biochemical/genetic analysis) is possible by using fine needle aspiration of the MCN, usually under endoscopic guidance, and may provide useful information for the differential diagnosis. Since MCNs have malignant potential, surgical resection is the treatment of choice. PMID- 21251816 TI - Ethanol production from acid hydrolysates based on the construction and demolition wood waste using Pichia stipitis. AB - The feasibility of ethanol production from the construction and demolition (C&D) wood waste acid hydrolysates was investigated. The chemical compositions of the classified C&D wood waste were analyzed. Concentrated sulfuric acid hydrolysis was used to obtain the saccharide hydrolysates and the inhibitors in the hydrolysates were also analyzed. The C&D wood waste composed of lumber, plywood, particleboard, and medium density fiberboard (MDF) had polysaccharide (cellulose, xylan, and glucomannan) fractions of 60.7-67.9%. The sugar composition (glucose, xylose, and mannose) of the C&D wood wastes varied according to the type of wood. The additives used in the wood processing did not appear to be released into the saccharide solution under acid hydrolysis. Although some fermentation inhibitors were detected in the hydrolysates, they did not affect the ethanol production by Pichia stipitis. The hexose sugar-based ethanol yield and ethanol yield efficiency were 0.42-0.46 g ethanol/g substrate and 84.7-90.7%, respectively. Therefore, the C&D wood wastes dumped in landfill sites could be used as a raw material feedstock for the production of bioethanol. PMID- 21251817 TI - Simultaneous Congo red decolorization and electricity generation in air-cathode single-chamber microbial fuel cell with different microfiltration, ultrafiltration and proton exchange membranes. AB - Different microfiltration membrane (MFM), proton exchange membrane (PEM) and ultrafiltration membranes (UFMs) with different molecular cutoff weights of 1K (UFM-1K), 5K (UFM-5K) and 10K (UFM-10K) were incorporated into air-cathode single chamber microbial fuel cells (MFCs) which were explored for simultaneous azo dye decolorization and electricity generation to investigate the effect of membrane on the performance of the MFC. Batch test results showed that the MFC with an UFM 1K produced the highest power density of 324 mW/m(2) coupled with an enhanced coulombic efficiency compared to MFM. The MFC with UMF-10K achieved the fastest decolorization rate (4.77 mg/L h), followed by MFM (3.61 mg/L h), UFM-5K (2.38 mg/L h), UFM-1K (2.02 mg/Lh) and PEM (1.72 mg/Lh). These results demonstrated the possibility of using various membranes in the system described here, and showed that UFM-1K was the best one based on the consideration of both cost and performance. PMID- 21251818 TI - The influenced of PAC, zeolite, and Moringa oleifera as biofouling reducer (BFR) on hybrid membrane bioreactor of palm oil mill effluent (POME). AB - The main objective of this work was to determine the effectiveness of various biofouling reducers (BFRs) to operational condition in hybrid membrane bioreactor (MBR) of palm oil mill effluent (POME). A series of tests involving three bench scale (100 L) hybrid MBR were operated at sludge retention times (SRTs) of 30 days with biofouling reducer (BFR). Three different biofouling reducers (BFRs) were powdered actived carbon (PAC), zeolite (Ze), and Moringa oleifera (Mo) with doses of 4, 8 and 12 g L(-1) respectively were used. Short-term filtration trials and critical flux tests were conducted. Results showed that, all BFRs successfully removed soluble microbial products (SMP), for PAC, Ze, and Mo at 58%, 42%, and 48%, respectively. At their optimum dosages, PAC provided above 70% reductions and 85% in fouling rates during the short-term filtration and critical flux tests. PMID- 21251819 TI - Effects of heat treatment on hydrogen production potential and microbial community of thermophilic compost enrichment cultures. AB - Cellulosic plant and waste materials are potential resources for fermentative hydrogen production. In this study, hydrogen producing, cellulolytic cultures were enriched from compost material at 52, 60 and 70 degrees C. Highest cellulose degradation and highest H(2) yield were 57% and 1.4 mol-H(2) mol-hexose(-1) (2.4 mol-H(2) mol-hexose-degraded(-1)), respectively, obtained at 52 degrees C with the heat-treated (80 degrees C for 20 min) enrichment culture. Heat-treatments as well as the sequential enrichments decreased the diversity of microbial communities. The enrichments contained mainly bacteria from families Thermoanaerobacteriaceae and Clostridiaceae, from which a bacterium closely related to Thermoanaerobium thermosaccharolyticum was mainly responsible for hydrogen production and bacteria closely related to Clostridium cellulosi and Clostridium stercorarium were responsible for cellulose degradation. PMID- 21251820 TI - Synthesis and evaluation of new iRGD peptide analogs for tumor optical imaging. AB - Recently, a disulfide-based cyclic RGD peptide called iRGD, that is, c(CRGDKGPDC), has been reported to interact with both integrin and neuropilin-1 receptors for cellular and deep tissue penetration to improve the imaging sensitivity and therapeutic efficacy. In this study, two new near-infrared fluorescent iRGD conjugates, that is, Ac-Cys(IRDye(r)800CW)-iRGD (1), and its dual labeling analog DOTA-Cys(IRDye(r)800CW)-iRGD (2) were synthesized via the specific mercapto-maleimide reaction for tumor imaging. Both 1 and 2 showed significant tumor localization in optical imaging of MDA-MB-435 tumor-bearing mice. The potential of such iRGD compounds in tumor-targeted imaging and drug delivery deserves further exploration. PMID- 21251821 TI - Analysis of beta-amino alcohols as inhibitors of the potential anti-tubercular target N-acetyltransferase. AB - The synthesis and inhibitory potencies of a novel series of beta-amino alcohols, based on the hit-compound 3-[3'-(4''-cyclopent-2'''-en-1'''-ylphenoxy)-2' hydroxypropyl]-5,5 dimethylimidazolidine-2,4-dione as specific inhibitors of mycobacterial N-acetyltransferase (NAT) enzymes are reported. Effects of synthesised compounds on growth of Mycobacterium tuberculosis have been determined. PMID- 21251822 TI - Non-oxime inhibitors of B-Raf(V600E) kinase. AB - The development of inhibitors of B-Raf(V600E) serine-threonine kinase is described. Various head-groups were examined to optimize inhibitor activity and ADME properties. Several of the head-groups explored, including naphthol, phenol and hydroxyamidine, possessed good activity but had poor pharmacokinetic exposure in mice. Exposure was improved by incorporating more metabolically stable groups such as indazole and tricyclic pyrazole, while indazole could also be optimized for good cellular activity. PMID- 21251823 TI - Synthesis and biological evaluation of 2-aminoimidazole/carbamate hybrid anti biofilm and anti-microbial agents. AB - The successful marriage of structural features from our 2-aminoimidazole and menthyl carbamate classes of anti-biofilm agents has resulted in the development of a novel hybrid scaffold of biofilm modulators. The compounds were evaluated against a panel of four bacterial strains for anti-biofilm and anti-microbial activity. PMID- 21251824 TI - Potent and selective cyclohexyl-derived imidazopyrazine insulin-like growth factor 1 receptor inhibitors with in vivo efficacy. AB - Preclinical and emerging clinical evidence suggests that inhibiting insulin-like growth factor 1 receptor (IGF-1R) signaling may offer a promising therapeutic strategy for the treatment of several types of cancer. This Letter describes the medicinal chemistry effort towards a series of 8-amino-imidazo[1,5-a]pyrazine derived inhibitors of IGF-1R which features a substituted quinoline moiety at the C1 position and a cyclohexyl linking moiety at the C3 position. Lead optimization efforts which included the optimization of structure-activity relationships and drug metabolism and pharmacokinetic properties led to the identification of compound 9m, a potent, selective and orally bioavailable inhibitor of IGF-1R with in vivo efficacy in an IGF-driven mouse xenograft model. PMID- 21251825 TI - Orally bioavailable imidazoazepanes as calcitonin gene-related peptide (CGRP) receptor antagonists: discovery of MK-2918. AB - In our ongoing efforts to develop CGRP receptor antagonists for the treatment of migraine, we aimed to improve upon telecagepant by targeting a compound with a lower projected clinical dose. Imidazoazepanes were identified as potent caprolactam replacements and SAR of the imidazole yielded the tertiary methyl ether as an optimal substituent for potency and hERG selectivity. Combination with the azabenzoxazinone spiropiperidine ultimately led to preclinical candidate 30 (MK-2918). PMID- 21251826 TI - Potent radiosensitizing agents: 5-methylselenyl- and 5-phenylselenyl-methyl-2' deoxyuridine. AB - This Letter describes the novel radiosensitizing agents based on nucleoside base modification. In addition to the known 5-phenylselenide derivative, 5 methylselenide modified thymidine, which has a van der Waals radius smaller than the phenyl group, was newly synthesized. The similar monomer activity of 5 methylselenide derivative under oxidation condition was confirmed by NMR experiments. The cytotoxicity tests and radiosensitizing experiments of both compounds were carried out using the H460 lung cancer cell line. Both the 5 phenylselenide and the 5-methylselenide derivatives showed a relatively low toxicity to the cells. However, in combination with gamma-radiolysis, both exerted good radiosensitizing effects to the lung cancer cell lines in vitro. This result confirms that 5-methylselenide modified thymidine could be a useful candidate as a potential radiosensitizing agent in vivo. PMID- 21251827 TI - A unique and rapid approach toward the efficient development of novel protein tyrosine phosphatase (PTP) inhibitors based on 'clicked' pseudo-glycopeptides. AB - There has been considerable interest in the development of protein tyrosine phosphatase (PTP) inhibitors since many of the PTP members are tightly associated with major human diseases including autoimmune disorders, diabetes and cancer. We report here a unique and rapid approach toward the development of novel PTP inhibitor entities based on triazolyl pseudo-glycopeptides. By employing microwave-accelerated Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC or 'click reaction'), a series of triazole-linked serinyl, threoninyl, phenylalaninyl and tyrosinyl 1-O-gluco- or galactosides have been efficiently synthesized in high yields within only ~30 min. Successive biological assay identified these glycopeptidotriazoles as favorable PTP1B and CDC25B inhibitors with selectivity over TCPTP, LAR, SHP-1 and SHP-2. Both the structural diversity of the amino acid (Ser, Thr, Phe and Tyr) introduced and the epimeric identity (Glc or Gal) on monosaccharide scaffold were determined to impact the corresponding inhibitory activity and selectivity. In addition, the benzylated sugar scaffold was demonstrated to act as a crucial role for enhancing the binding affinity of the inhibitors with the targeted PTP. Docking simulation was eventually conducted to propose plausible binding modes of this compound series with PTP1B and CDC25B. Our approach readily realized from naturally abundant raw materials (sugar and amino acid) and via facile, regioselective and expeditious synthetic method (microwave-assisted click reaction) might provide new insights toward the 'click' fabrication of structurally diverse PTP inhibitors. PMID- 21251828 TI - Optimisation of 6-substituted isoquinolin-1-amine based ROCK-I inhibitors. AB - Rho kinase is an important target implicated in a variety of cardiovascular diseases. Herein, we report the optimisation of the fragment derived ATP competitive ROCK inhibitors 1 and 2 into lead compound 14A. The initial goal of improving ROCK-I potency relative to 1, whilst maintaining a good PK profile, was achieved through removal of the aminoisoquinoline basic centre. Lead 14A was equipotent against both ROCK-I and ROCK-II, showed good in vivo efficacy in the spontaneous hypertensive rat model, and was further optimised to demonstrate the scope for improving selectivity over PKA versus hydroxy Fasudil 3. PMID- 21251829 TI - Surgery for breast cancer in the elderly--how relevant? AB - Studies suggest that elderly women receive less aggressive treatment, experience higher disease progression and mortality from breast cancer. We report on an experience of 256 consecutive cases of symptomatic breast cancer in a population of over 75 years of age. 142/256 patients underwent surgical intervention in the form of breast conserving surgery or mastectomy, 114/256 did not. Mean follow up was 6.4 years. Our results show a statistically significant association between surgery and survival (p = 0.05, CI 0.00046-0.19641) and a strong statistically significant association between surgery and disease progression/recurrence (p = 0.001, CI 0.08713-0.03145). Women treated conservatively are significantly less fit hence suffering high cancer unrelated mortality; as a consequence they suffer higher disease related progression and mortality. In our study surgical treatment with adjuvant endocrine and/or radiotherapy was associated with a statistically significant advantage in terms of disease related mortality and local disease control. PMID- 21251830 TI - Self-esteem in patients with diabetes mellitus and foot ulcers. AB - AIM: To evaluate self-esteem in individuals with diabetes mellitus (DM) and foot ulcers. METHODS: This was a controlled, cross-sectional, analytical study. We selected 50 individuals with DM and foot ulcers (study group), as well as 50 with DM and without foot ulcers (control group). Self-esteem was evaluated using the Federal University of Sao Paulo/Paulista School of Medicine Portuguese-language version of the Rosenberg Self-Esteem Scale, on which scores range from 0 to 30, higher scores indicating lower self-esteem. RESULTS: Of the individuals evaluated, 27 (54%) of those in the study group and 31 (62%) of those in the control group were classified as being of low socioeconomic status (monthly income at or above, but less than double, the national minimum wage). In addition, 27 (54%) of the study group patients had type 2 DM, compared with 29 (58%) of those in the control group. Hypertension was observed in 31 (62%) of the study group patients and 29 (58%) of the control group patients. Of the patients in the study group, 33 (66%) had been diagnosed with heart disease, compared with 23 (46%) of those in the control group. High Rosenberg Self-Esteem Scale scores (21-30) were more common in the study group, being observed in 30 (60%) of the patients, whereas 33 (66%) of the control group patients had low scores (0-10). CONCLUSION: Foot ulcers appear to have a negative impact on the self-esteem of patients with DM. PMID- 21251831 TI - Effects of vertical center of mass redistribution on body sway parameters during quiet standing. AB - Body sway is usually described by center of foot pressure (COP)-derived parameters. Their sensitivity to vertical center of mass (COM) redistribution below its natural position has not yet been examined during quiet stance tasks. We examined the effects of both lowering and raising the COM on the following body sway parameters: cumulative, medial-lateral and anterior-posterior COP average velocity, amplitude and frequency. For this purpose, 13 healthy male subjects performed a quiet stance balance task with feet positioned in parallel stance (PS) at hip width apart and with hands holding a stick across the rear part of the shoulders. Each subject carried out five different modifications of the PS task in a randomized order: no additional load, an additional load of 10 kg and 30 kg suspended from the waist at mid-lower leg height, and an additional load of 10 kg and 30 kg across the rear of the shoulders. The studied body sway parameters proved to be sensitive to these manipulations. Specifically, lowering and raising the COM was mirrored in a systematic decrease/increase of the velocity, amplitude, and frequency parameters, indicating a larger effect in the anterior-posterior direction. These results suggest that the elevation of the body COM from a lower to a higher position systematically decreases the postural control during quiet standing, and consequently, increases the intensity of the balancing task. Thus, this type of physical manipulation could provide the basis for a simple progression in functional resistance training for persons with compromised balance. PMID- 21251832 TI - Break dance significantly increases static balance in 9 years-old soccer players. AB - Static balance in young athletes is an important ability that has a relevant influence on their present and future sport performances, as well as on the reduction in risk of injury. The present study reports data collected on three homogeneous groups of 9 years-old athletes (n=10 for each group), whose static balance was monitored every two months during an overall period of six months. At the beginning of the study, all of the children in each of the three groups were performing soccer activity with a frequency (three times a week) that was kept constant during the observation period. During the six months, group 1 maintained only the soccer activity, group 2 also performed swimming activity (twice a week) in parallel with the soccer activity, while group 3 started, at month 2, to perform soccer activity with a break dance course (twice a week). Double leg stance (with eyes open and closed) and single leg stance (on dominant and non dominant leg) tests were performed using a force platform, and the COP area calculated for each trial. Results show a clear decrease in the "soccer+break dance" players COP area values during the six months, suggesting an improvement in their static balance. The difference was significantly greater with respect to that of soccer players and "soccer+swimming" players. This was evident in all the tests performed starting from two months after the break dance activity began. PMID- 21251833 TI - Lifespan changes in multi-tasking: concurrent walking and memory search in children, young, and older adults. AB - We investigated dual-task performance of cognitive (semantic fluency) and sensorimotor tasks (walking) in 120 children and adults from four age groups (9 year olds, M=9.52 years; 11-year olds, M=11.51 years; young adults, M=25.34 years; older adults, M=64.28 years; N=30 per group). Distances walked during 90 s and numbers of category exemplars generated in the semantic fluency task showed an inverted U-shape function with age. In line with general resource models proportional dual-task costs in walking also showed a U-shaped relation as a function of age with pronounced decrements in the youngest and oldest groups. Only 9-year olds showed significant costs in the cognitive task. Individual differences in single-task performance accounted for more than half of the variance in dual-task performance. Reliable age-related residual variance implicated additional factors particularly in children's developing multi-tasking performances. PMID- 21251834 TI - Body of evidence supporting the clinical use of 3D multisegment foot models: a systematic review. AB - BACKGROUND: A critical component in the characterization of foot mechanics during clinical gait analysis is the quantitative measurement of foot kinematics. Currently, the use of 3D multisegment foot models (3DMFMs) is popular in gait laboratories as it would seem to be an adequate tool for the in vivo analysis of dynamic foot kinematics. This systematic review identifies and evaluates current evidence for the use of 3DMFMs in clinical gait analysis. METHODS: A targeted search strategy traced full papers that fulfilled the inclusion and exclusion criteria. The papers were classified and evaluated for quality using a custom made quality appraisal form. FINDINGS: Forty-one manuscripts were included yielding a total number of fifteen 3DMFMs. Generally, study procedures and sample selection were adequately described; however, the methodological quality varied widely. Evidence regarding the repeatability of the identified models also varied widely. Models facing the highest level of scientific credibility were characterized by adequate repeatability indices obtained from between-trial, between-day and between and within assessor studies. Generally, the highest reliability indices were found for the sagittal plane kinematics. Within-subject variability was found to be the lowest, contrarily, between-subject and between day variabilities were found to be highest. INTERPRETATION: Reported repeatability indices such as the coefficient of multiple correlation, standard deviation and standard error of measurement provide evidence for the continued use of 3DMFMs. While a number of published models exist, there is no adequate evidence available to support their clinical use. More reliability and validity studies are needed to confirm adequate measurement properties of 3DMFMs. PMID- 21251835 TI - Lower limb joint kinetics in walking: the role of industry recommended footwear. AB - The effects of current athletic footwear on lower extremity biomechanics are unknown. The aim of this study was to examine the changes, if any, that occur in peak lower extremity net joint moments while walking in industry recommended athletic footwear. Sixty-eight healthy young adults underwent kinetic evaluation of lower extremity extrinsic joint moments while walking barefoot and while walking in current standard athletic footwear matched to the foot mechanics of each subject while controlling for speed. A secondary analysis was performed comparing peak knee joint extrinsic moments during barefoot walking to those while walking in three different standard footwear types: stability, motion control, and cushion. 3-D motion capture data were collected in synchrony with ground reaction force data collected from an instrumented treadmill. The shod condition was associated with a 9.7% increase in the first peak knee varus moment, and increases in the hip flexion and extension moments. These increases may be largely related to a 6.5% increase in stride length with shoes associated with increases in the ground reaction forces in all three axes. The changes from barefoot walking observed in the peak knee joint moments were similar when subjects walked in all three footwear types. It is unclear to what extent these increased joint moments may be clinically relevant, or potentially adverse. Nonetheless, these differences should be considered in the recommendation as well as the design of footwear in the future. PMID- 21251836 TI - Notch1 expression is upregulated in glioma and is associated with tumor progression. AB - Notch signaling plays a complex role in human malignancies. It can affect cell proliferation, differentiation and apoptosis either positively or negatively, depending on cell type. In the present study we measured the expression of Notch1 in clinical glioma specimens and investigated a possible association between Notch1 expression and World Health Organization grade. Ninety-eight gliomas plus adjacent normal tissue and 26 specimens of normal control tissue were collected, and expression of Notch1 mRNA and protein were assessed using quantitative real time polymerase chain reaction, western blot and immunohistochemical analysis. We found that Notch1 mRNA and protein were expressed at higher levels in gliomas than in the adjacent tissue or in control brain tissue (p<0.05). Moreover, expression of Notch1 was closely associated with glioma progression, since expression levels increased from grade I to grade IV disease (p<0.05). Notch1 expression was also significantly associated with Karnofsky performance scale (KPS) score: Notch1 expression was significantly higher in patients with a lower KPS score (p<0.05). These findings confirm that Notch1 expression is upregulated in glioma and suggest it is related to tumor progression. If Notch1 plays an important oncogenic role in glioma progression, it may be a potential diagnostic and therapeutic target. PMID- 21251837 TI - A meta-analysis of 99mTc-MIBI SPECT for detection of recurrent glioma after radiation therapy. AB - We performed a meta-analysis of the diagnostic accuracy of technetium-99m methoxyisobutylisonitrile ((99m)Tc-MIBI) single photon emission computed tomography (SPECT) for assessment of glioma recurrence in patients after radiation therapy. The "PubMed" database was searched for relevant papers. Two reviewers extracted the data on study characteristics and examination results independently, and assessed the methodological quality of each included study. Pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curve were obtained. Six investigations met inclusion criteria. The sensitivity ranged from 0.733 to 0.984, and the specificity ranged from 0.750 to 0.955. The pooled sensitivity and specificity were 0.898 and 0.919. The positive likelihood ratio (LR+) ranged from 3.800 to 19.381, the negative likelihood ratio (LR-) ranged from 0.017 to 0.311, and the DOR ranged from 16.500 to 567.00. The pooled LR+, LR- and DOR were 10.913, 0.115 and 94.062, respectively. The area under the SROC curve was 0.9650. Our results indicate that (99m)Tc-MIBI SPECT is a highly sensitive and specific modality in assessing patients with suspected glioma recurrence after radiation therapy. PMID- 21251838 TI - A multidetector CT angiography study of variations in the circle of Willis in a Chinese population. AB - The circle of Willis is a major collateral circulation that has an important role in ischemic events. The purpose of our study was to investigate the collateral circulation in a Chinese population with 64-section multidetector CT angiography (CTA). A total of 170 patients who underwent 64-section CT angiography at The First Affiliated Hospital of Chongqing Medical University were included in our study. The morphological variations in the anterior and posterior circle of Willis were assessed in each patient. A total of 160 patients were included in the final analysis, of whom 126 (79%) demonstrated a complete anterior circle of Willis, and 50 (31%) had a complete posterior circle of Willis. A complete circle of Willis was seen in 43 of 160 participants (27%). A fetal-type posterior circle of Willis was seen in 15 (9.4%) patients. This is the first report of a CTA study of collateral circulation in a Chinese population. A higher prevalence of compromised posterior collaterals was observed in this Chinese population compared to Western and Japanese populations. PMID- 21251839 TI - The Twin Peg Oxford partial knee replacement: the first 100 cases. AB - We present the clinical results of the first 100 patients who received the Twin Peg Oxford partial knee replacement which has a 15 degrees extra femoral surface for contact in deep flexion, and has two pegs for more secure fixation. We measured the clinical outcome 2 years after the medial unicompartmental arthroplasty using patient and surgeon derived outcome measures. The results showed a mean Oxford Knee Score of 41, a mean American Knee Society Objective Score of 93 and a Functional Score of 84, a mean range of motion of 130 degrees and a high satisfaction rate. Results were significantly better in male patients. There were no deaths, infections, dislocations, fractures or revisions. There were no pathological radiolucencies suggestive of early loosening. We conclude that the Twin Peg Oxford partial knee replacement shows excellent clinical and radiological results at 2 years. For surgeons who have concern over the risk of femoral loosening with the single peg Oxford knee, or seek an improved surface area of contact in full flexion, this implant offers an excellent alternative. PMID- 21251840 TI - Synthesis of egonol derivatives and their antimicrobial activities. AB - Eighteen derivatives of egonol (A-R) were synthesized and evaluated for their antimicrobial activities against Staphylococcus aureus ATCC 29213, Bacillus subtilis ATCC 6633, Candida albicans ATCC 10231 and Escherichia coli ATCC 8739 microorganisms comparing with egonol. The obtained data reported that compound B exhibited improved activities against all tested bacteria than egonol, others have shown different range of activities. PMID- 21251841 TI - A new beta-carbonic anhydrase from Brucella suis, its cloning, characterization, and inhibition with sulfonamides and sulfamates, leading to impaired pathogen growth. AB - A beta-carbonic anhydrase (CA, EC 4.2.1.1) from the bacterial pathogen Brucella suis, bsCA II, has been cloned, purified, and characterized kinetically. bsCA II showed high catalytic activity for the hydration of CO(2) to bicarbonate, with a k(cat) of 1.1*10(6), and k(cat)/K(m) of 8.9*10(7)M(-1)s(-1). A panel of sulfonamides and sulfamates have been investigated for inhibition of this enzyme. All types of activities, from the low nanomolar to the micromolar, have been detected for these derivatives, which showed inhibition constants in the range of 7.3nM-8.56MUM. The best bsCA II inhibitors were some glycosylated sulfanilamides, aliphatic sulfamates, and halogenated sulfanilamides, with inhibition constants of 7.3-87nM. Some of these dual inhibitors of bsCA I and II, also inhibited bacterial growth in vitro, in liquid cultures. These promising data on live bacteria allow us to propose bacterial beta-CA inhibition as an approach for obtaining anti-infective agents with a new mechanism of action compared to classical antibiotics. PMID- 21251842 TI - Feasibility of photoelectron sources with sharp lines of stable energy between 20 and 80 keV. AB - Photo-absorption of gamma-rays in thin Al, Co, Ti, and Mo convertors was examined with the aim to produce quasi monoenergetic photoelectrons having an energy spread of 0.5-4.7eV about mean kinetic energies at discrete values between 18632 and 80321eV. The photoelectron rates were estimated for commercial photon sources of (241)Am, (119m)Sn, (125m)Te and (109)Cd with activities of 0.55-3.7GBq. Photoelectrons ejected by (241)Am gamma- and X-rays from Co convertors were measured with two different electron spectrometers and obtained energy spectra were compared with Monte Carlo predictions. PMID- 21251843 TI - Nicotinamide metabolism in ferns: formation of nicotinic acid glucoside. AB - The metabolic fate of [carbonyl-(14)C]nicotinamide was investigated in 9 fern species, Psilotum nudum, Angiopteris evecta, Lygodium japonicum, Acrostichum aureum, Asplenium antiquum, Diplazium subsinuatum, Thelypteris acuminate, Blechnum orientale and Crytomium fortune. All fern species produce a large quantity of nicotinic acid glucoside from [(14)C]nicotinamide, but trigonelline formation is very low. Increases in the release of (14)CO(2) with incubation time was accompanied by decreases in [carboxyl-(14)C]nicotinic acid glucoside. There was slight stimulation of nicotinic acid glucoside formation by 250 mM NaCl in mature leaves of the mangrove fern, Acrostichum aureum, but it is unlikely that this compound acts as a compatible solute. Nicotinamide and nicotinic acid salvage for pyridine nucleotide synthesis was detected in all fern species, although this activity was always less than nicotinic acid glucoside synthesis. Predominant formation of nicotinic acid glucoside is characteristic of nicotinic acid metabolism in ferns. This reaction appears to act as a detoxication mechanism, removing excess nicotinic acid. PMID- 21251844 TI - Jatropha curcas oil body proteome and oleosins: L-form JcOle3 as a potential phylogenetic marker. AB - The seed oil of Jatropha curcas has been proposed as a source of biodiesel. In plants, seed oil is stored in subcellular organelles called oil bodies (OBs), which are stabilized by proteins. Proteome composition of the J. curcas OBs revealed oleosins as the major component and additional proteins similar to those in other oil seed plants. Three J. curcas oleosins were isolated and characterized at the gene, transcript and protein level. They all contained the characteristic proline knot domain and were each present as a single copy in the genome. The smallest, L-form JcOle3 contained an intron. Isolation of its promoter revealed seed-specific cis-regulatory motifs among others. Spatio temporal transcript expression of J. curcas oleosins was largely similar to that in other oil seed plants. Immunoassay with antibodies against an Arabidopsis oleosin or against JcOle3, on seed proteins extracted by different approaches, revealed JcOle3 oligomers. Alleles of JcOle3 and single nucleotide polymorphisms (SNPs) in its intron were identified in J. curcas accessions, species and hybrids. Identified alleles and SNPs could serve as markers in phylogenetic or breeding studies. PMID- 21251845 TI - Tricuspid valved stent implantation: novel stent with a self-expandable super absorbent polymer. AB - OBJECTIVE: Trans-catheter aortic and pulmonary valve replacement procedures can result in favorable outcomes in selected patients. The aim of this study was to investigate the functioning of a novel self-expanding valved stent with super absorbent polymer (SAP) for minimally invasive replacement of the tricuspid valve. METHODS: A newly designed nitinol stent with SAP was specially designed for the tricuspid annulus. This device was composed of right atrial anchoring elements, a left ventricular tubular stent, and a trileaflet bovine pericardial valve. The stent was coated with a waterproof material, and a pouch containing SAP for minimizing paravalvular leakage was placed beneath the atrial element. Seven pigs underwent minimally invasive off-pump tricuspid valved stent implantation. This was performed through a lower ministernotomy using a transventricular approach under transesophageal echocardiographic guidance. After 1 and 6h, a complete echocardiographic evaluation and hemodynamics (Swan-Ganz catheter) were performed. RESULTS: Six of seven pigs exhibited normal hemodynamics immediately after tricuspid valved stent implantation and maintained stability for the entire period of monitoring. In one pig, a part of the atrial stent elements was deployed into the right ventricle, leading to significant paravalvular leakage, and died very soon. All subsequent animals survived with good results in the observation period. Accurate positioning of the valved stent was documented in six of seven pigs. SAP expanded and filled the gap between the stent and the native annulus in all animals. Mild paravalvular leakage was found in two of the six animals. Nevertheless, the observed leakage decreased to trace levels 6h after implantation. In the additional four pigs, only trace tricuspid regurgitation was revealed. No right ventricular outflow tract obstruction was detected. CONCLUSIONS: Trans-apical off-pump tricuspid valved stent implantation is feasible in an acute experimental setting, and SAP may help to reduce paravalvular leakages. PMID- 21251846 TI - An unusual wound problem following cardiac surgery. PMID- 21251847 TI - UV-prepared salep-based nanoporous hydrogel for controlled release of tetracycline hydrochloride in colon. AB - A highly swelling nanoporous hydrogel (NPH) was synthesized via UV-irradiation graft copolymerization of acrylic acid (AA) onto salep backbone and its application as a carrier matrix for colonic delivery of tetracycline hydrochloride (TH) was investigated. Optimized synthesis of the hydrogel was performed by the classic method. The swelling behavior of optimum hydrogel was measured in different media. The hydrogel formation was confirmed by Fourier transform infrared spectroscopy (FTIR) and thermo-gravimetric analysis (TGA/DTG/DTA). The study of the surface morphology of hydrogels using SEM showed a nanoporous (average pore size: about 350nm) structure for the sample obtained under optimized conditions. The drug delivery results demonstrated that this NPH could successfully deliver a drug to the colon without losing the drug in the stomach, and could be a good candidate as an orally administrated drug delivery system. PMID- 21251848 TI - The effect of rFVIIa on pro- and anti-inflammatory cytokines in serum and cerebrospinal fluid in a swine model of traumatic brain injury. AB - Traumatic brain injury (TBI) is associated with significant infectious and inflammatory complications. Though increasing evidence suggests that rFVIIa administration may be efficacious for the pre-hospital treatment of TBI, the FVIIa-tissue factor complex has been shown to be immunologically active. To date the cytokine response to rFVIIa administration for the treatment of TBI has not been evaluated. Twenty anesthetized immature Yorkshire swine underwent fluid percussion TBI. At 15 min following injury, animals were randomized to receive either 90 MUg/kg rFVIIa (rFVIIa) or nothing. Animals were observed for 6 h and then euthanized. Plasma and cerebrospinal (CSF) samples were collected at 0 min and 360 min, and ELISA analysis of TNF-alpha, IL-1beta and IL-10 was performed. Survival in both groups was 100%. Baseline cytokine concentrations were not statistically different between rFVIIa and control animals in plasma or CSF. Animals in both groups did not have significant changes in plasma cytokine concentrations following TBI. Control animals did not demonstrate significant changes from baseline of CSF cytokine concentrations following TBI. The administration of rFVIIa however, resulted in significant increases in CSF TNF alpha concentration (232.0 pg/ml +/- 75.9 vs 36.4 pg/ml +/- 10.4, p = 0.036) and IL-10 concentration (10.7 pg/ml +/- 0.6 vs 8.8 pg/ml +/- 0.1, p = 0.015). IL 1beta concentrations were not significantly changed over the experimental time course. These results suggest that rFVIIa administration for the treatment of TBI is not immunologically inert, and is associated with increased CSF concentrations of TNF-alpha and IL-10. PMID- 21251849 TI - Kinetic and electromyographic analysis of single repetition constant and variable resistance leg press actions. AB - During a multi-joint leg press action, maximal force capabilities increase with increasing knee angle. In typical resistance exercises, constant resistance is used, which does not stress the neuromuscular system at large knee angles. The purpose of this study was to compare constant and variable resistance settings using a range of contraction loads and velocities. Nine healthy, untrained males performed single contractions using four different resistance settings (constant resistance, two settings that increased resistance at large knee angles and one setting that reduced resistance at large knee angles). Single contractions using 40%, 60%, and 80% of one repetition maximum with both steady-paced and explosive contractions were assessed. Concentric force, velocity, power, and EMG (from the vastus lateralis, vastus medialis, rectus femoris, and biceps femoris muscles) were assessed at 20 degrees segments throughout the leg press range of motion (~60-180 degrees ). Results showed that force and rmsEMG activity was greater (P<0.05) by increasing resistance during steady-paced contractions. During explosive contractions, higher velocities were producible (P<0.05) when resistance was reduced at large knee angles. The results of this study show that different resistance settings affect kinetic and electromyographic characteristics, which may lead to specific long term training-induced adaptations. PMID- 21251850 TI - Sedation and analgesia in the cardiac electrophysiology laboratory: a national survey of electrophysiologists investigating the who, how, and why? AB - OBJECTIVE: To investigate sedation and anesthesia trends and practice patterns for procedures in the cardiac electrophysiology laboratory (EPL). DESIGN: A survey distributed by e-mail. SETTING: US teaching hospitals with a training program in cardiac electrophysiology. PARTICIPANTS: Cardiologists involved in procedures in the electrophysiology laboratory of academic electrophysiology programs. INTERVENTIONS: A survey was e-mailed to the selected programs. The survey questions included the use of anesthesia professional (MD/CRNA) and nonanesthesia professional (RN) services, medications administered, commonly performed airway interventions, satisfaction with anesthesia services, and reasons that anesthesia professionals are not used when RNs administer sedation. MEASUREMENTS AND MAIN RESULTS: Of the 95 academic electrophysiology programs surveyed, there were 38 responses (40%). The majority (71%) of respondents used a combined model of care with both anesthesia professional care and nonanesthesia professional (RN) sedation, although there were EPLs that had exclusively anesthesia professional (n = 6) and exclusively nonanesthesia professional coverage (n = 5); 26.3% of respondents answered that care by an anesthesia professional was warranted most (>50%) of the time regardless of their current care model. The main reasons cited for having RN-administered sedation were the lack of availability of anesthesia professionals, difficulty with scheduling, and increased operating room suite turnover times. Programs using exclusively RN sedation (13%) reported all levels of anesthesia including general anesthesia (patient unarousable to repeated deep stimulation). CONCLUSIONS: This survey suggested that sedation for EPL procedures was sometimes allowed to progress to deep sedation and general anesthesia and that selection of anesthesia provider frequently was made based on availability, operating room efficiency, and economic reasons before patient safety issues. The implications of the survey must be explored further in a larger-scale sample population before more definitive statements can be made, but results suggested that sedation in the EPL is an area that would benefit from updated guidelines specific to the current practice as well as attention from the anesthesia community to address the deficiency in provision of anesthesia care. PMID- 21251851 TI - Predictors of duration of unconsciousness in patients with coma after cardiac surgery. AB - OBJECTIVES: To describe clinical and brain imaging characteristics of patients who recovered and did not recover consciousness from a coma after cardiac surgery and to investigate predictors of the duration of unconsciousness in those patients who ultimately recovered consciousness. DESIGN: A retrospective analysis from a cohort of patients who developed coma after cardiac surgery. SETTING: A single university hospital. PARTICIPANTS: One hundred twelve patients with postoperative stroke, encephalopathy, and/or seizures who remained in coma longer than 24 hours after cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The authors analyzed the patients' perioperative and intraoperative characteristics, laboratory values, noncontrast head computed tomography (CT) scans, and outcomes. Patients who did not recover consciousness (n = 16) were more likely to have been classified preoperatively as New York Heart Association class III/IV (p = 0.037). In patients who recovered consciousness (n = 96), only increased preoperative serum creatinine was an independent predictor of a longer duration of unconsciousness (p = 0.011). In patients who eventually recovered consciousness and had no acute findings on brain imaging, preoperative creatinine (p = 0.014), the lowest postoperative hemoglobin (p = 0.039), and surgical emergency (p = 0.045) were independent predictors of the duration of unconsciousness (p = 0.002). In patients who regained consciousness but had acute findings on brain imaging, cardiogenic shock (p = 0.012) and the insertion of an intra-aortic balloon pump before or during surgery (p = 0.025) predicted longer durations of unconsciousness (p < 0.001). CONCLUSIONS: In patients who ultimately recovered consciousness after being in a coma for at least 24 hours after cardiac surgery and have no abnormality on a brain CT scan, elevated preoperative serum creatinine, urgent cardiac surgery, and lower postoperative hemoglobin were correlated with an increased duration of unconsciousness. PMID- 21251852 TI - Lest we forget: heparin-induced hyperkalemia. PMID- 21251853 TI - Effects of ownership expressed by the first-person possessive pronoun. AB - The present study examined the behavioral effects of the first-person possessive pronoun. In each trial, a noun (e.g. cup or bread) was presented to participants after visual presentation of a possessive pronoun "wo de" (Chinese for "my") or "ta de" (Chinese for "his"), which formed ownership. Half participants were assigned to contextual encoding (CE) condition in which they were required to judge whether they liked the item expressed by a noun from the first or third person perspective. The rest were assigned to perceptual encoding (PE) condition in which they were asked to judge what color the noun was. A subsequent recall test was performed. The results showed that there were significant memory and response advantages for nouns in "my" ownership under both conditions. The results were discussed with reference to self-specificity and other effects in the current study. PMID- 21251854 TI - Bilateral temporal lobe epilepsy confirmed with intracranial EEG in chorea acanthocytosis. AB - Chorea-acanthocytosis (ChAc) is an uncommon basal ganglia disorder, in which the movement disorder element may be obscured by the predominance of seizures. We report a pertinent case of a patient who had undergone extensive evaluation for epilepsy, including intracranial EEG before finally the diagnosis of ChAc was made and confirmed by Western blot. We suggest that in patients with epilepsy, particularly of temporal lobe origin and with onset in the third decade with inconclusive findings on clinical examination and neuroimaging such as dyskinesias, dystonia and basal ganglia involvement, ChAc should be considered. PMID- 21251855 TI - Histology versus microbiology for accuracy in identification of osteomyelitis in the diabetic foot. AB - It is important to accurately diagnose osteomyelitis, and bone biopsy is currently considered by many to be the gold standard diagnostic test for its identification. Microbiologic studies, namely culture and sensitivity tests, are also used to identify osteomyelitis. To our knowledge, no published reports exist that compare the diagnostic characteristics of bone biopsy to microbiology with regard to making the diagnosis of osteomyelitis. For these reasons, we undertook a matched case control study to test the null hypothesis that claimed there is no difference between histology and microbiology with regard to making the diagnosis of pedal osteomyelitis in diabetic patients. The sample population consisted of consecutive diabetic patients from a tertiary care hospital who were surgically treated for foot infection with suspected osteomyelitis. Each bone specimen was hemisected, and one half sent for microbiologic testing and the other half sent for histopathologic inspection. McNemar's test for correlated proportions was used to identify whether or not a statistically significant difference existed between the diagnostic methods. A total of 44 specimens were analyzed, and our results showed that a positive microbiologic and negative histologic result was just as likely as a negative microbiologic and positive histologic result (P > .05). In conclusion, based on the results of this investigation, microbiologic testing performed as well as did histopathologic testing when it came to identifying the presence of pedal osteomyelitis in the diabetic foot. PMID- 21251857 TI - Just when we thought we knew all the answers, someone changed the questions! PMID- 21251858 TI - Assessment of the impact of collection temperature and sampler design on the measurement of exhaled breath condensate pH in healthy horses. AB - The pH measurement of exhaled breath condensate (EBC) may provide a non-invasive method of assessing the lower airways of horses but the methodology used may influence findings. The aim of this study was to investigate the effect of two sampling devices and three methods of condensation surface cooling (ethanol slush, -100 degrees C; dry ice, -75 degrees C; water ice, 0 degrees C) on EBC pH. Each method was tested 30 times using six healthy ponies. Sample pH was determined before and after de-aeration with argon for 10 min. Sampler design was found to significantly affect pH. Samples collected as a liquid had a significantly higher pH than samples frozen during collection (P<0.05). De aeration resulted in significantly higher pH (P<0.05) with less variation. This study has shown that device design and condensation surface temperature will influence EBC pH, which will prevent a direct comparison of results when different methodologies are used. PMID- 21251856 TI - Using a tailored web-based intervention to set goals to reduce unnecessary recall. AB - RATIONALE AND OBJECTIVES: To examine whether an intervention strategy consisting of a tailored web-based intervention, which provides individualized audit data with peer comparisons and other data that can affect recall, can assist radiologists in setting goals for reducing unnecessary recall. MATERIALS AND METHODS: In a multisite randomized controlled study, we used a tailored web-based intervention to assess radiologists' ability to set goals to improve interpretive performance. The intervention provided peer comparison audit data, profiled breast cancer risk in each radiologist's respective patient populations, and evaluated the possible impact of medical malpractice concerns. We calculated the percentage of radiologists who would consider changing their recall rates, and examined the specific goals they set to reduce recall rates. We describe characteristics of radiologists who developed realistic goals to reduce their recall rates, and their reactions to the importance of patient risk factors and medical malpractice concerns. RESULTS: Forty-one of 46 radiologists (89.1%) who started the intervention completed it. Thirty-one (72.1%) indicated they would like to change their recall rates and 30 (69.8%) entered a text response about changing their rates. Sixteen of the 30 (53.3%) radiologists who included a text response set realistic goals that would likely result in reducing unnecessary recall. The actual recall rates of those who set realistic goals were not statistically different from those who did not (13.8% vs. 15.1%, respectively). The majority of selected goals involved re-reviewing cases initially interpreted as Breast Imaging Reporting and Data System category 0. More than half of radiologists who commented on the influence of patient risk (56.3%) indicated that radiologists planned to pay more attention to risk factors, and 100% of participants commented on concerns radiologists have about malpractice with the primary concern (37.5%) being fear of lawsuits. CONCLUSIONS: Interventions designed to reduce unnecessary recall can succeed in assisting radiologists to develop goals that may ultimately reduce unnecessary recall. PMID- 21251859 TI - Expression of 14-3-3 sigma protein in normal and neoplastic canine mammary gland. AB - 14-3-3 sigma protein is a negative cell cycle regulator, with both reduced and elevated levels associated with cancer in humans. This study assessed the expression of this protein in canine mammary tissues using immunohistochemistry and Western blotting. 14-3-3 sigma was detected in 97% of the mammary tissue samples examined and was found in both myoepithelial (MECs) and epithelial (ECs) cells. Expression levels were elevated and reduced in neoplastic ECs and MECs, respectively (P<0.001). Intense expression of 14-3-3 sigma was detected in neoplastic ECs infiltrating blood vessels and lymph nodes and suggests a possible role for this protein in the malignant transformation of mammary neoplasms. Moreover, double immunostaining for 14-3-3 sigma and the MEC-specific marker p63, confirmed that 14-3-3 sigma is a highly sensitive marker of MECs since all p63 positive cells were also positive for 14-3-3 sigma. However, this protein is not exclusive to MECs as ECs also labelled positively. PMID- 21251860 TI - Multi-centre European study of breakthrough cancer pain: pain characteristics and patient perceptions of current and potential management strategies. AB - This study involved 320 cancer patients from four Northern European countries. Patients with breakthrough pain were questioned about the characteristics of their pain, the current management of their pain, and the acceptability/utility of alternative routes of administration. The median number of episodes was 3/day. Forty-four percent patients reported incident-type pain, 39% spontaneous-type pain, and 17% a combination of these pains. The median duration was 60 min, and the median time to peak intensity was 15 min. Three percent patients reported "mild" pain, 37% "moderate" pain, and 60% "severe" pain. Ninety percent patients stated that the pain interfered with their daily activities. All patients were using opioids as rescue medication (mainly oral morphine/oxycodone), whilst 28% patients were using non-opioids, and 50% patients were using non-pharmacological interventions. Only 55% patients took rescue medication every time they experienced breakthrough pain. Sixty-five percent patients would definitely consider using an oral transmucosal product; patients from Denmark were less likely to answer positively, and a positive response was associated with previous use of the route for breakthrough pain. Seventy-three percent patients reported regular oral problems. Forty-two percent patients would definitely consider using an intranasal product, with 26% patients stating they would definitely not use such a preparation; patients from Denmark and Sweden were less likely to answer positively, and a positive response was associated with male gender, and previous use of the route. Forty-four percent patients reported regular nasal problems. Sixty percent patients would definitely consider using a subcutaneous product, and 44% patients would definitely consider using an intrapulmonary product. PMID- 21251861 TI - Lack of circulating bioactive and immunoreactive IGF-I changes despite improved fitness in chronic kidney disease patients following 48 weeks of physical training. AB - OBJECTIVE: As known abnormalities exist in the insulin-like growth factor (IGF) system in chronic kidney disease (CKD) patients, the measurement of bioactive IGF I may provide further insight into the therapeutic potential of long-term exercise training. DESIGN: Patients (N=21) with stages 3 and 4 CKD were recruited from a local nephrology practice in Springfield, MA and randomized into matched treatment and control groups. The treatment group participated in 48 weeks of supervised, progressive exercise training and dietary counseling, while the control group received only usual care. Treadmill testing, anthropometric measurements, and blood samples for analysis of immunoreactive IGF-I, IGF-II, IGFBP-1 and -2, and bioactive IGF-I were taken at baseline, 24 weeks, and 48 weeks. RESULTS: There were no significant differences in any of the components of the IGF system (all p-values>0.05). Immunoreactive IGF-I levels correlated significantly with bioactive IGF-I at baseline (r=0.50, p=0.02) and at 48 weeks (r=0.64, p=0.01). There was a significant interaction between group and time for both VO(2peak) (p=0.03) and total treadmill time (TT) (p<0.01). CONCLUSIONS: Despite improvements in physical performance, a 48-week training program did not affect any of the circulating IGF system measurements. Disparities between these findings and those of other researchers reporting a biphasic response to long term training may be explained by differences in study groups and exercise programs. PMID- 21251862 TI - Dosimetric parameters of the new design (103)Pd brachytherapy source based on Monte Carlo study. AB - In this study version 5 of the MCNP photon transport simulation was used to calculate the dosimetric parameters for new palladium brachytherapy source design following AAPM Task Group No. 43U1 report. The internal source components include four resin beads of 0.6 mm diameters with (103)Pd uniformly absorbed inside and one cylindrical copper marker with 1.5 mm length. The resin beads and marker are then encapsulated within 0.8 mm in diameter and 4.5 mm long cylindrical capsule of titanium. The dose rate constant, Lambda, line and point-source radial dose function, g(L)(r) and g(P)(r), and the anisotropy function, F(r,theta) of the IR01-(103)Pd seed have been calculated at distances from 0.25 to 5 cm. All the results are in good agreement with previously published thermoluminescence dosimeter measured values [3] for the source. The dosimetric parameters calculated in this work showed that in dosimetry point of view, the IR01-(103)Pd seed is suitable for use in brachytherapy of prostate cancer. PMID- 21251863 TI - Role for interferon-gamma release assays in latent tuberculosis screening before TNF-alpha antagonist therapy. AB - TNF-alpha antagonist therapy is associated with a risk of severe, extrapulmonary, disseminated tuberculosis, which is fatal in 10% of cases. The risk of tuberculosis is increased four-fold in patients on TNF-alpha antagonist therapy. The main risk factors are a history of untreated or inadequately treated primary tuberculosis, recent contact with a tuberculosis patient, and residence in or travel to a high-endemicity region. Infection surveillance agencies throughout the world have issued recommendations to ensure the detection and treatment of latent tuberculosis before TNF-alpha antagonist initiation. These recommendations have returned the incidence of tuberculosis to the level seen before the introduction of TNF-alpha antagonists. Nevertheless, there is still room for improvement. Recommendations about latent tuberculosis screening include the use of tuberculin skin tests. However, these tests are positive in individuals vaccinated with the BCG vaccine, which leads to overuse of tuberculosis chemoprophylaxis and, therefore, to unnecessary patient exposure to hepatotoxic effects. Furthermore, tuberculin skin tests may be falsely negative in immunosuppressed patients, leading to underuse of tuberculosis prophylaxis. These shortcomings of tuberculin skin tests have generated interest in interferon-gamma release assays (IGRAs). In patients with overt tuberculosis, IGRAs are more sensitive and more specific than tuberculin skin tests. However, the accuracy of IGRAs for diagnosing latent tuberculosis remains unknown, because no reference standard is available. In addition, patients taking immunosuppressant agents to treat systemic disease may exhibit anergia, which complicates the interpretation of IGRAs. Until additional data become available, caution requires that IGRAs be used only when a positive or negative result, as assessed on a case-by-case basis, will help to decide whether tuberculosis chemoprophylaxis is in order. PMID- 21251864 TI - Sonochemical replication of chloroplast with titania for light harvesting. AB - Hierarchy structure of granum in chloroplast was replicated onto titania using a simple and tactical sonochemical method and calcination. The structures of TiO(2) replicas were characterized by XRD, FE-SEM and TEM and the pore structures were characterized by N(2) adsorption/desorption. As a comparison, the preparation without sonication by using impregnation then calcination method was conducted, which shows the efficiency of the ultrasound on the exact replication of granum from micrometers down to nanometers. The optical properties of the TiO(2) replica, the chloroplast and the commercial pure TiO(2) powder together with the compared replica were measured by absorbance spectroscopy. It was found that the absorbance intensity of the TiO(2) replica made by ultrasonication is much better than the soaked one, and is twice of that of the pure TiO(2) powder in ultraviolet - visible light range. The excellent light harvesting performance of the TiO(2) is attributed to the combination of the functionality from the inorganic oxide and the fine hierarchical biological structures. PMID- 21251865 TI - Effect of different labor forces on fetal skull molding. AB - Fetal head molding is important for adapting the fetal head to the birth canal during vaginal delivery; however, excessive deformation of fetal head may lead to severe complications. Although labor force is one of the major factors which cause deformation of the fetal head, its effect on fetal head molding has not been quantitatively investigated yet. We examined this effect by using a finite element modeling approach. Firstly, a geometric model was created by scanning a polyethylene replica of fetal skull model with a white light three-dimensional scanner. Secondly, a nonlinear finite element model was proposed based on the geometric model. Next, the simulation results of the proposed model were verified against the experimental data reported in other literatures and they showed good agreement with the experimental observations. After this validation, the proposed model was used to simulate the fetal skull deformations under different labor forces. Simulation results illustrated that the fetal skull diameters and modified molding index (MMI) increased when the labor force was increased. Parietal bone around bregma and frontal bone around coronal suture undertook more stress, and parietal and frontal bones around coronal suture undertook more spatial and rotational displacement under larger labor force. The suboccipito bregmatic diameter (SOBD) was more sensitive to the changes of labor force than other fetal skull diameters. The simulation results revealed the quantitative relationship between the labor force and fetal skull molding during delivery. In the future, if the degree of fetal skull molding is directly related to that of the head injury, the relationship investigated in this study may be used to predict the head injury by measuring the labor force during delivery. PMID- 21251866 TI - Application of non-destructive impedance-based monitoring technique for cyclic fatigue evaluation of endodontic nickel-titanium rotary instruments. AB - This study investigates the application of non-destructive testing based on the impedance theory in the cyclic fatigue evaluation of endodontic Ni-Ti rotary instruments. Fifty Ni-Ti ProTaper instruments were divided into five groups (n=10 in Groups A to E). Groups A to D were subjected to cyclic fatigue within an artificial canal (Group E was the control group). The mean value of the total life limit (TLL), defined as the instrument being rotated until fracture occurred was found to be 104 s in Group A. Each rotary instrument in Groups B, C and D were rotated until the tested instruments reached 80% (84 s), 60% (62 s) and 40% (42 s) of the TLL. After fatigue testing, each rotary instrument was mounted onto a custom-developed non-destructive testing device to give the tip of the instrument a progressive sideways bend in four mutually perpendicular directions to measure the corresponding impedance value (including the resistance and the reactance). The results indicated that the impedance value showed the same trend as the resistance, implying that the impedance was primarily affected by the resistance. The impedance value for the instruments in the 80% and 60% TLL groups increased by about 6 mOmega (about 7.5%) more than that of the instruments in the intact and 40% TLL groups. The SEM analysis result showed that crack striations were only found at the tip of the thread on the cracked surface of the instrument, consistent with the impedance measurements that found the impedance value of the cracked surface to be significantly different from those in other surfaces. These findings indicate that the impedance value may represent an effective parameter for evaluating the micro-structural status of Ni-Ti rotary instruments subjected to fatigue loading. PMID- 21251867 TI - The impact of Masters education in manual and manipulative therapy and the 'knowledge acquisition model'. AB - This study aimed to explore the professional and personal impact that a clinical Masters program of manipulative therapy education had on the lives of individuals who had undertaken the course and was a follow-on study of participants' career pathways following Masters education (Green et al., 2008). Seven graduates from the program took part in a focus group. The narrative data obtained was independently verified prior to two researchers conducting a systematic, thematic content analysis. Three key themes were identified and the 'knowledge acquisition model' developed. Findings revealed that studying at Master's level is a 'life changing' and rewarding experience that develops individuals in three key domains; professionally, personally and intellectually. During Masters education students described a journey of multi-compartmental development whereby their knowledge-base was challenged and their existing cognitive framework deconstructed. Progression through the program resulted in the development of a new, clearer framework for thinking and understanding that extended, universally, into all aspects of their lives; clinically, managerially, emotionally, politically and intellectually. Participants also described two cultures for career progression in the UK National Health Service (NHS). Findings could help students considering undertaking Masters level education, employers and clinical mentors of these practitioners and academic educators. PMID- 21251868 TI - Mechanical diagnosis and therapy (MDT) approach for assessment and identification of serious pathology. PMID- 21251869 TI - Swimmer's shoulder in young athlete: rehabilitation with emphasis on manual therapy and stabilization of shoulder complex. PMID- 21251871 TI - Drug transporters of platinum-based anticancer agents and their clinical significance. AB - Platinum-based drugs are among the most active anticancer agents and are successfully used in a wide variety of human malignancies. However, acquired and/or intrinsic resistance still represent a major limitation. Lately, in particular mechanisms leading to impaired uptake and/or decreased cellular accumulation of platinum compounds have attracted attention. In this review, we focus on the role of active platinum uptake and efflux systems as determinants of platinum sensitivity and -resistance and their contribution to platinum pharmacokinetics (PK) and pharmacodynamics (PD). First, the three mostly used platinum-based anticancer agents as well as the most promising novel platinum compounds in development are put into clinical perspective. Next, we describe the presently known potential platinum transporters--with special emphasis on organic cation transporters (OCTs)--and discuss their role on clinical outcome (i.e. efficacy and adverse events) of platinum-based chemotherapy. In addition, transporter-mediated tumour resistance, the impact of potential platinum transporter-mediated drug-drug interactions, and the role of drug transporters in the renal elimination of platinum compounds are discussed. PMID- 21251872 TI - Vibrational spectroscopic study on 2-[2-(4-dipropylamino-phenyl)-vinyl]-1,3,3 trimethyl-3H-indolium chloride. AB - A new styryl dye were prepared, 2-[2-(4-dipropylamino-phenyl)-vinyl]-1,3,3 trimethyl-3H-indolium chloride (DPPTVI) chloride. Its infrared and Raman were measured. Quantum chemical calculations were computed for both the isolated and the solute cation. Optimized geometry, atomic net charges were calculated. The calculated vibrational frequencies were scaled to the experimental ones. Only 12 scale factors were used for the scaling of 174 vibrational modes. Based on these results, normal coordinate analysis were carried out for both the isolated and the solute cations. Infrared and Raman spectra were simulated. The results for the isolated and the solute cations were compared. PMID- 21251870 TI - Does cytokine signaling link sphingolipid metabolism to host defense and immunity against virus infections? AB - Sphingosine 1-phosphate (S1P)-metabolizing enzymes regulate the level of bioactive sphingolipids that have curative potential. Recently, S1P-metabolizing enzymes such as sphingosine kinase 1 and S1P lyase were shown to regulate influenza virus replication and the virus-induced cytopathogenicity. The mechanism appeared to employ a JAK/STAT type I interferon signaling pathway that induces anti-viral status. Further, sphingosine analogs altered cytokine responses upon influenza virus infection. This article focuses on recent discoveries about the sphingolipid system that influences on host protection from viral virulence and the involvement of cytokine signaling in its underlying mechanisms. Deciphering the steps of this pathway could help us envision how the modulation of sphingolipid metabolism can be applied as a therapeutic approach to overcome infectious diseases. PMID- 21251873 TI - Neuraminidase-inhibitor resistance testing for pandemic influenza A (H1N1) 2009 in Ontario, Canada. AB - BACKGROUND: Oseltamivir resistance-associated H275Y mutation in the neuraminidase (NA) gene of pandemic influenza A (H1N1) 2009 was occasionally reported worldwide during the 2009-2010 influenza season. A significant proportion of those were found in immunocompromised or severely ill persons. This phenomenon remains infrequent and clear recommendations for resistance testing are lacking. OBJECTIVES: Present the suggested clinical selection criteria for antiviral susceptibility testing for influenza in Canada and to describe the Ontarian experience during the 2009-2010 influenza season. STUDY DESIGN: Using a defined algorithm, we prospectively screened for OsR with pyrosequencing and phenotypic testing during the 2009-2010 influenza season. Zanamivir resistance was screened using phenotypic and sequencing technique on selected occasions. Clinical data was gathered for the resistant cases. RESULTS: A total of 804 clinical H1N1 (2009) positive samples from Ontario were screened for oseltamivir resistance between June 2009 and March 2010. We identified oseltamivir resistance in 5 (0.6%) distinct patients aged 9-62 years. All the resistant strains bore the H275Y mutation. Susceptibility to zanamivir was maintained in all of them. Three patients harboring oseltamivir resistant strain were intensive care unit patients and four were immunocompromised. All were tested for susceptibility because of a repeat positive result for influenza A PCR. CONCLUSION: Oseltamivir resistance was not frequent during the 2009-2010 influenza season but was identified with a systematic and prospective approach to resistance testing. In order to be as sensitive as possible in the detection of those few cases, we report the suggested indications for antiviral susceptibility testing in Canada. PMID- 21251874 TI - Symptom trajectories during chemotherapy in outpatients with lung cancer colorectal cancer, or lymphoma. AB - PURPOSE: Pain, depression, distress, fatigue, and sleep disturbance are common symptoms in oncology patients, but little data are available that examine the trajectories of these symptoms during chemotherapy (CTX). The purposes of this study were to examine the trajectories of these symptoms during the first six cycles of CTX and to determine whether individual characteristics predicted the trajectories of these symptoms. METHODS: Oncology outpatients (n = 118) with newly diagnosed lung cancer, colorectal cancer, or lymphoma rated symptoms using an electronic patient care monitor system. Pain, fatigue, and sleep disturbance were rated on 0-10 numeric rating scales; depression and distress were evaluated using scales converted to normalized T scores. Latent growth curve analyses (LGCA) examined for intra- and inter-individual differences in the trajectories of these five symptoms during the six cycles of CTX. RESULTS: Symptoms were present at the initiation of CTX (p < 0.0001) for all symptoms (p < 0.05). Distress (p = 0.03) and pain (p = 0.02) intensity decreased significantly over the six cycles of CTX. Advanced disease and a higher number of comorbidities predicted higher fatigue at baseline (p = 0.02 and 0.01 respectively). A diagnosis of lung cancer predicted an increasing intensity of fatigue during CTX (p = 0.04). Concurrent radiation therapy predicted more intense pain over time (p = 0.03). CONCLUSIONS: While symptom trajectories were highly variable in patients undergoing initial CTX, the majority of the symptom intensity scores decreased over time. However, patients with lung cancer, those with a higher number of comorbidities, and those with advanced disease experienced more intense fatigue and sleep disturbance over time. PMID- 21251875 TI - Prevalence of depression, anxiety, and adjustment disorder in oncological, haematological, and palliative-care settings: a meta-analysis of 94 interview based studies. AB - BACKGROUND: Substantial uncertainty exists about prevalence of mood disorders in patients with cancer, including those in oncological, haematological, and palliative-care settings. We aimed to quantitatively summarise the prevalence of depression, anxiety, and adjustments disorders in these settings. METHODS: We searched Medline, PsycINFO, Embase, and Web of Knowledge for studies that examined well-defined depression, anxiety, and adjustment disorder in adults with cancer in oncological, haematological, and palliative-care settings. We restricted studies to those using psychiatric interviews. Studies were reviewed in accordance with PRISMA guidelines and a proportion meta-analysis was done. FINDINGS: We identified 24 studies with 4007 individuals across seven countries in palliative-care settings. Meta-analytical pooled prevalence of depression defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM) or International Classification of Diseases (ICD) criteria was 16.5% (95% CI 13.1 20.3), 14.3% (11.1-17.9) for DSM-defined major depression, and 9.6% (3.6-18.1) for DSM-defined minor depression. Prevalence of adjustment disorder alone was 15.4% (10.1-21.6) and of anxiety disorders 9.8% (6.8-13.2). Prevalence of all types of depression combined was of 24.6% (17.5-32.4), depression or adjustment disorder 24.7% (20.8-28.8), and all types of mood disorder 29.0% (10.1-52.9). We identified 70 studies with 10,071 individuals across 14 countries in oncological and haematological settings. Prevalence of depression by DSM or ICD criteria was 16.3% (13.4-19.5); for DSM-defined major depression it was 14.9% (12.2-17.7) and for DSM-defined minor depression 19.2% (9.1-31.9). Prevalence of adjustment disorder was 19.4% (14.5-24.8), anxiety 10.3% (5.1-17.0), and dysthymia 2.7% (1.7 4.0). Combination diagnoses were common; all types of depression occurred in 20.7% (12.9-29.8) of patients, depression or adjustment disorder in 31.6% (25.0 38.7), and any mood disorder in 38.2% (28.4-48.6). There were few consistent correlates of depression: there was no effect of age, sex, or clinical setting and inadequate data to examine cancer type and illness duration. INTERPRETATION: Interview-defined depression and anxiety is less common in patients with cancer than previously thought, although some combination of mood disorders occurs in 30 40% of patients in hospital settings without a significant difference between palliative-care and non-palliative-care settings. Clinicians should remain vigilant for mood complications, not just depression. FUNDING: None. PMID- 21251877 TI - EAE: imperfect but useful models of multiple sclerosis. AB - The high failure rate of immunotherapies in multiple sclerosis (MS) clinical trials demonstrates problems in translating new treatment concepts from animal models to the patient. One main reason for this 'immunotherapy gap' is the usage of immunologically immature, microbiologically clean and genetically homogeneous rodent strains. Another reason is the artificial nature of the experimental autoimmune encephalomyelitis model, which favors CD4+ T cell driven autoimmune mechanisms, whereas CD8+ T cells are prevalent in MS lesions. In this paper, we discuss preclinical models in humanized rodents and non-human primates that are genetically closer to MS. We also discuss models that best reproduce specific aspects of MS pathology and how these can potentially improve preclinical selection of promising therapies from the discovery pipeline. PMID- 21251876 TI - The ever-expanding function of NOD2: autophagy, viral recognition, and T cell activation. AB - The identification of several families of innate pattern recognition receptors has greatly enhanced our understanding of the host innate immune response against a variety of pathogens. One such family of innate receptors is the nucleotide binding domain and leucine rich repeat containing receptors (NLRs). NOD2 has been characterized as a cytosolic sensor of bacteria peptidoglycan (PGN). For almost 10 years, NOD2 was assigned with the function of mediating the RICK- and nuclear factor-kappaB induced proinflammatory response triggered by PGN. Recent studies have extended the biological activity of NOD2 to include the induction of autophagy and antiviral responses, as well as mediating direct T cell activation. Here, we highlight and discuss these new findings in the context of immune activation and pathogen detection. PMID- 21251878 TI - RET in breast cancer: functional and therapeutic implications. AB - Recent studies demonstrate that the receptor tyrosine kinase RET is overexpressed in a subset of ER-positive breast cancers and that crosstalk between RET and ER is important in responses to endocrine therapy. The development of small molecular inhibitors that target RET allows the opportunity to consider combination therapies as a strategy to improve response to treatment and to prevent and combat endocrine resistance. This review discusses: (i) the current knowledge about RET, its co-receptors and ligands in breast cancer; (ii) the breast cancer clinical trials involving agents that target RET; and (iii) the challenges that remain in terms of specificity of available inhibitors and in understanding the complex molecular mechanisms that underlie the resistance to endocrine therapy. PMID- 21251880 TI - Techniques of laparoscopic myomectomy. AB - Myomectomy is one of the commonest gynaecological operations. Laparoscopic myomectomy has emerged over the last two decades as a possible alternative to the traditional laparotomy. Most studies have revealed that the laparoscopic procedure is at least as safe as the open procedure as to the rate of complications and may retain relevant advantages in terms of shorter admission and recovery times. Currently laparoscopic myomectomy is still a challenging operation that requires a well-trained surgical team, adequate instrumentation and accurate patient selection; the increasing slant of gynaecologists towards laparoscopic techniques, along with the advances in surgical instrumentation and suturing materials, will hopefully contribute to keep laparoscopic myomectomy no longer confined to tertiary care centres. PMID- 21251881 TI - Tuberculosis in prisons in sub-Saharan Africa--the need for improved health services, surveillance and control. AB - Prisons have long been associated with rapid transmission of infectious diseases. The HIV/AIDS epidemic in sub-Saharan Africa (SSA) has fuelled the spread of TB and HIV in prisons. The poor living conditions and ineffective health services in prisons in SSA are a major breeding ground of Mycobacterium tuberculosis (Mtb). The spread of TB between prisoners, prison staff and visitors and the emergence of drug-resistant TB in prisons now poses a threat to control efforts of national TB programmes in SSA. Accurate data required to develop appropriate interventions to tackle the ominous problem of TB in African prisons are scanty and unreliable. The health of prisoners is by default a neglected political issue. This article reviews the available literature on TB and drug-resistant TB in prisons from SSA countries, discusses the risk factors for acquiring TB and highlights the priorities for further translational research in prisons. Ethical issues pertaining to research on captive African populations are discussed. Scientific, political and funder attention is required urgently to improve prison health services. PMID- 21251882 TI - Enhanced expression of recX in Mycobacterium tuberculosis owing to a promoter internal to recA. AB - RecX is a small protein that interacts with, and modulates the activity of, RecA protein. In mycobacteria the recX gene is located immediately downstream of the recA gene, and the coding regions overlap. It has previously been shown that these two genes are co-transcribed in Mycobacterium smegmatis. In this study we examine the expression of recX in Mycobacterium tuberculosis. In addition to being co-transcribed with recA from the DNA-damage inducible recA promoters, we identify a constitutive recX promoter located within the recA coding sequence that is strong enough to make a significant contribution to the expression level of recX in the absence of DNA damage. Intriguingly, this promoter is inactivated in M. smegmatis by a critical base change in the -10 promoter motif, which probably accounts for the lower level of expression of recX relative to recA that we observed in that species. It is possible that this difference in relative expression influences RecA functions including the response to DNA damage of LexA regulated genes. PMID- 21251883 TI - CCL2, CCL18 and sIL-4R in renal, meningeal and pulmonary TB; a 2 year study of patients and contacts. AB - The role of Th2 cytokines and Th2-associated chemokines in tuberculosis (TB) remains controversial, though in Mexico a polymorphism causing increased production of CCL2 is a risk factor. We studied levels of the Th2-associated chemokines CCL2 and CCL18, circulating soluble IL-4 receptors (sIL-4R), IL-4 and the inhibitory splice variant of IL-4 (IL-4delta2) in a cohort of patients with pulmonary TB and their healthy contacts. These were followed for 2 years during which time 10 contacts developed pulmonary TB. Results were compared with measurements made in renal and meningeal TB, and in disease controls with bacterial pneumonias or Dengue fever that have large Th2 components. In these disease controls both chemokines were significantly raised. They were also very significantly raised in all forms of TB, irrespective of age or disease site. Levels of CCL18 were raised least in meningeal TB, and most in pulmonary patients with long histories, when levels were similar to those in disease controls. Levels of CCL2, although also raised in all three forms of TB, were negatively correlated with CCL18. We found that levels of sIL-4R were strikingly reduced in all forms of TB, particularly meningeal. Contacts who progressed could not be distinguished from contacts who remained healthy at 2 years in terms of IL-4, sIL 4R, CCL2 or CCL18. However contacts had raised expression of IL-4delta2 as previously found. These results indicate vigorous and previously unrecorded activity within the Th2 axis, and further investigation is warranted. PMID- 21251884 TI - Protein stability of previously frozen plasma, riboflavin and UV light-treated, refrozen and stored for up to 2 years at -30 degrees C. AB - BACKGROUND: The Mirasol pathogen reduction technology system for plasma is based on a riboflavin and UV light treatment process resulting in pathogen inactivation due to irreversible, photochemically induced damage of nucleic acids. The objective of this study was to evaluate the in vitro protein quality of previously frozen FFP, thawed, Mirasol-treated and refrozen for a final storage period of up to 2 years at -30 degrees C. MATERIALS AND METHODS: All plasma products were held at 4 +/- 2 degrees C, and frozen within 8h after the start of collection. FFP was stored frozen at -30 degrees C for eight time intervals before riboflavin and UV light treatment and refrozen to -30 degrees C and stored for varying time intervals for a total storage period of up to 2 years at 30 degrees C. Results were compared to paired, untreated units thawed and stored for the same time intervals. RESULTS: The overall mean values for all time points in riboflavin and UV light treated plasma samples indicates that all proteins were well preserved following a period of frozen storage for 2 years at -30 degrees C. Factors V, VII and XI, retained 70%, 65% and 53% activity, respectively. All other protein factors, anticoagulant and inhibitor proteins demonstrated retention between 74% and 100%. CONCLUSION: Riboflavin and UV light treated FFP maintained both coagulant and anticoagulant in vitro protein quality after double freeze/thaw storage at -30 degrees C for up to 2 years, a finding that may offer processing flexibility to blood centers. PMID- 21251885 TI - Preliminary study on changes in coagulation function and component transfusion time in patients with massive hemorrhage. AB - INTRODUCTION: To investigate the changes in coagulation function and component transfusion time in patients with massive hemorrhage. METHODS: Sixty-two patients with massive hemorrhage were enrolled in the study. Blood samples were collected from each patient when the blood loss reached 1000, 1500, 1700 and 2000 ml. The parameters FIB, PT, APTT, HGB, HCT, PLT and MAP were recorded for all patients. RESULTS: Sixty-two, 30, 20 and 8 patients showed blood loss exceeding 1000, 1500, 1700 and 2000 ml, respectively. Blood samples were successfully collected from all patients when the volume of blood lost reached 1000, 1500, 1700 and 2000 ml. However, at this time point, FIB, MAP, HGB, HCT and PLT were significantly lower than the baseline/preoperative values. These indices decreased progressively with increasing blood loss. PT and APTT were significantly higher than at baseline and increased progressively with increased blood loss. FIB, HCT and HGB were below the normal reference range when blood loss was 1500 ml. During surgery, FIB, MAP, HCT, HGB and PLT decreased substantially, whereas APTT and PT increased when blood loss exceeded 1500 ml. PT and MAP were beyond the normal range when blood loss reached 2000 ml. There was a correlation between FIB, HCT and HGB with intraoperative blood loss; the correlation coefficient was greatest between and FIB and blood loss. CONCLUSION: There were marked correlations between FIB, HCT and HGB with intraoperative blood loss, and the correlation was greatest with FIB. PMID- 21251886 TI - Oral hypoglycaemic agents during pregnancy: The evidence for effectiveness and safety. AB - With the increase in obesity and sedentary lifestyles, the incidence of diabetes among reproductive-aged women is rising globally. Providers are expected to care for a growing number of women with gestational diabetes (GDM) in the coming decades. Traditionally, insulin has been considered the standard for management of GDM, when diet and exercise fail to achieve tight maternal glucose control without the risk of transfer of insulin across the placenta. Understanding the effectiveness and safety of the use of oral diabetes agents during pregnancy for both maternal and neonatal outcomes as an alternative management option is essential to the care of women with GDM and their offspring. In this review, our objectives were to (1) summarise the available evidence on the efficacy these medications, (2) review available data on adverse effect, (3) discuss current gaps in research, outlining limitations in current study designs that deserve attention and (4) summarise key points for the practicing clinician. PMID- 21251887 TI - Complex pattern of convulsive syncope in glossopharyngeal neuralgia: video/EEG report and short review. AB - A 65-year-old woman presented with three "convulsive" events that were preceded by stabbing pain extending from the left submandible zone to the neck and ipsilateral ear. Video-electroencephalography captured a typical attack, where electrocardiography showed bradycardia for 17 seconds and asystole for at least 9 seconds. The patient lost consciousness while her head/gaze turned right. She then manifested tonic extension of her left limbs followed by adduction of her left limb and flexion of her right upper limb. Her gaze deviated upward and her left upper limb manifested swimming-like automatisms. The full episode lasted about 70 seconds, and the EEG showed progressive diffuse high-amplitude slowing. A diagnosis of convulsive syncope resulting from classic glossopharyngeal neuralgia was made. Carbamazepine led to steady remission. Glossopharyngeal neuralgia is a rare condition (incidence of 0.7/100.000/year), whereas the occurrence of syncope is about 20%, and that of convulsive syncope is about 5%. PMID- 21251888 TI - Determination of picropodophyllin and its isomer podophyllotoxin in human serum samples with electrospray ionization of hexylamine adducts by liquid chromatography-tandem mass spectrometry. AB - A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determination of the new anticancer agent picropodophyllin (AXL1717) and its isomer podophyllotoxin levels in human serum has been developed. Monitoring of hexylamine adducts rather than proton adducts was used to optimize sensitivity. The chromatography system was an Acquity BEH C18, 2.1 mm * 50 mm 1.7 MUm column with gradient elution (mobile phase A: 2.5 mM hexylamine and 5 mM formic acid in Milli-Q water and mobile phase B: methanol). The retention times were 1.4 min for picropodophyllin, 1.5 min for podophyllotoxin and 1.9 min for internal standard deoxypodophyllotoxin. The isomers were base-line separated. The analytes were detected after electrospray ionization in positive mode with selected reaction monitoring (SRM) with ion transitions m/z 516->102 for picropodophyllin and podophyllotoxin and m/z 500->102 for internal standard. The sample preparation was protein precipitation with acetonitrile (1:3) containing internal standard followed by dilution of the supernatant with mobile phase A (1:1). The limit of quantification (LOQ) was 0.01 MUmol/L for picropodophyllin and podophyllotoxin. The limit of detection (LOD) at 3 times the signal to noise (S/N) was estimated below 0.001 MUmol/L for picropodophyllin and podophyllotoxin. The quantification range of the method was between 0.01 MUmol/L and 5 MUmol/L for both isomers. The accuracy was within +/-15% of the theoretical value for both picropodophyllin and podophyllotoxin and inter-assay precision did not exceed +/-15%, except for the 0.016 MUmol/L level of podophyllotoxin, which was 18%. The selectivity of the method was verified by analysis of two different product ions for each analyte and by analysis for interference of seven different batches of blank human serum. The combined recovery and matrix effects were about 83% for picropodophyllin and podophyllotoxin. The new LC-MS/MS method showed sufficient sensitivity and selectivity for determination of picropodophyllin and its isomer podophyllotoxin levels in human serum from subjects receiving therapeutic doses of AXL1717. PMID- 21251889 TI - Determination of sulphasalazine and its main metabolite sulphapyridine and 5 aminosalicylic acid in human plasma by liquid chromatography/tandem mass spectrometry and its application to a pharmacokinetic study. AB - A simple and sensitive liquid chromatography/positive-ion electrospray ionization mass spectrometry (LC-ESI-MS/MS) method has been developed for the simultaneous determination of sulphasalazine (SASP) and its main metabolite sulphapyridine (SP) and 5-aminosalicylic acid (5-ASA) with 100 MUL of human plasma using dimenhydrinate as the internal standard (I.S.). The API-3000 LC-MS/MS was operated under the multiple reaction-monitoring mode (MRM) using the electrospray ionization technique. Protein precipitation process was used to extract SASP, SP, 5-ASA and I.S. from human plasma. The total run time was 9.0 min and the elution of SASP, SP and 5-ASA was at 4.8 min, 2.5 min and 2.0 min, respectively. The separation was achieved with a mobile phase consisting of 0.2% formic acid, 2 mM ammonium acetate in water (mobile phase A) and 0.2% formic acid, 2 mM ammonium acetate in methanol (mobile phase B) by using gradient elution on a XBP Phenyl column (100 mm * 2.1 mm, 5 MUm). The developed method was validated in human plasma with a lower limit of quantitation of 10 ng/mL for SASP, SP and 5-ASA, respectively. A linear response function was established for the range of concentrations 10-10,000 ng/mL (r>0.99) for SASP and 10-1000 ng/mL (r>0.99) for SP and 5-ASA. The intra and inter-day precision values for SASP, SP and 5-ASA met the acceptance as per FDA guidelines. SASP, SP and 5-ASA were stable during stability studies, i.e., long term, auto-sampler and freeze/thaw cycles. The method was successfully applied for the evaluation of pharmacokinetics of SASP, SP and 5-ASA after single oral doses of 250 mg SASP to 10 healthy volunteers. PMID- 21251890 TI - One less ulcer, one extra pylorus. PMID- 21251892 TI - The pseudomeningocoele that wasn't: case report of an adult who presented with a late infection of an implant. AB - This case report describes an unusual case of a 55-year-old male, who presented with what appeared to be a pseudomeningocoele. The patient suffered a skull fracture secondary to a direct blow almost 30 years prior, and had been repaired with a calvarial implant at that time. He had been symptom free for most of that time, until he presented to our institution with a bulging cyst in his left frontal region. Computed tomography revealed a calvarial defect at the site of the cyst and a presumptive diagnosis of pseudomeningocoele was made. As part of his treatment, the patient underwent a lumbar puncture and lumbar peritoneal shunt. These procedures, although temporarily beneficial, ultimately proved unsuccessful in permanently decreasing the size of the cyst. After all conservative measures were exhausted, the team surgically explored the patient: while no communication between the cerebrospinal fluid and cyst could be found, which would be expected in a pseudomeningocoele, there was fibrinous exudates on the implant surface. Tissue cultures showed Staphylococcus epidermidis. This case emphasises the importance of surgical exploration to make a correct diagnosis, as in this case of a sub-clinical calvarial implant infection 30 years after insertion of the implant. PMID- 21251891 TI - Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis. AB - BACKGROUND: Primary sclerosing cholangitis results in elevated but fluctuating serum alkaline phosphatase levels that occasionally return to normal. AIMS: To investigate the frequency of normalization of alkaline phosphatase in newly diagnosed primary sclerosing cholangitis patients and the subsequent clinical outcomes. METHODS: Records of newly diagnosed primary sclerosing cholangitis patients were examined retrospectively for laboratory values and clinical end points (cholangiocarcinoma, liver transplantation and death) within 10 years of diagnosis. Data from a recent prospective ursodeoxycholic acid treatment trial were also studied. RESULTS: Eighty-seven patients met the inclusion criteria. Normalization of alkaline phosphatase was seen in 35 (40%) patients. Five (14%) patients with normalization reached an end point whereas 17 (33%) of the patients with persistent elevation reached an end point (P = 0.02). Ursodeoxycholic acid was used similarly by both groups. When the investigative criteria were applied to a prospective trial, there was again a significant relationship between normalization of alkaline phosphatase and survival in patients receiving ursodeoxycholic acid (P < 0.01) and the placebo group (P = 0.02). CONCLUSIONS: Serum alkaline phosphatase was found to normalize in a high proportion of newly diagnosed primary sclerosing cholangitis patients. This was significantly associated with a better prognosis in a retrospective cohort and when data from a prospective treatment trial was evaluated. PMID- 21251893 TI - The EOS imaging system for understanding a patellofemoral disorder following THR. AB - An aspect of patellofemoral syndrome secondary to total hip replacement (THR) is mainly suggestive of a problem of femoral implant torsion. We here present the first reported case of patellofemoral syndrome secondary to THR relating to limb length discrepancy, with no abnormality of femoral torsion. The pelvis adapted to the length inequality by axial rotation rather than frontal tilt, and this went undetected on standard X-ray and CT-scan. 3D imaging in upright posture on the EOS system enabled the situation to be clearly described and analyzed, and adapted surgical correction to be indicated. PMID- 21251894 TI - CD40 is overexpressed by HPV16/18-E6 positive cervical carcinoma and correlated with clinical parameters and vascular density. AB - CD40 is expressed in many tumor cells, however, its role in tumor biology is yet to be demonstrated. In the present study, we investigated the role of CD40 in cervical carcinoma. In vivo, we evaluated CD40 expression in 56 cervical carcinoma tissues, 43 cervicitis and 38 normal cervix, and investigated the relationship between CD40 and HPV antigen, histopathological parameters, vascular density, and vascular endothelial growth factor (VEGF) expressions. The results clearly demonstrated that CD40 expression, including membranous and cytoplasmic staining, was significantly higher in cervical carcinoma than in the cervicitis and normal cervix. The expression of CD40 was significantly correlated with HPV and VEGF expressions and microvessel density (MVD). These observations provide evidence that CD40 may be involved in neovascularization of cervical carcinoma, they also suggest that CD40 and VEGF may be useful biomarkers for evaluating the risk of developing cervical carcinoma, and may also be used as a target for therapy. PMID- 21251895 TI - Unusual form of cutaneous leishmaniasis: erysipeloid form. AB - We report the epidemiological and clinical characteristics of the erysipeloid form of cutaneous leishmaniasis as well as its diagnostic and therapeutic challenges. CASE REPORT: A 63-year-old woman, with no medical history, presented with a one-month history of erythematous nasal swelling. The lesion appeared after an accidental trauma. Erythematous infiltrative plaque was noted on the center of the face. There were also crust formations on the traumatic region. Despite local treatment and oral antibiotherapy, there was no improvement. The diagnosis of cutaneous leishmaniasis was confirmed by positive skin smears. Histopathological examinations of a skin biopsy showed no malignancy. The patient was treated intramuscularly with 10mg/kg per day systemic meglumine antimoniate with partial regression of symptoms. CONCLUSION: The erysipeloid type is a rare and unusual presentation of cutaneous leishmaniasis that often causes late diagnosis. Diagnosis is confirmed by the demonstration of the parasite by skin smear, histopathological examination and polymerase chain reaction. There are various therapeutic options. The evolution is generally favourable. PMID- 21251896 TI - The effect of nebivolol versus metoprolol succinate extended release on asymmetric dimethylarginine in hypertension. AB - This study sought to determine if metoprolol succinate ER (MET), and nebivolol (NEB), a beta1-AR with increased bioavailability of nitric oxide (NO), would have differing effects on plasma asymmetric dimethylarginine concentration in hypertensives. It was hypothesized that NEB, a beta1-AR antagonist and beta3-AR agonist with NO-releasing properties, and MET, only a beta1-AR antagonist, would have different effects on plasma asymmetric dimethylarginine (ADMA) concentration. Forty-one hypertensive subjects randomly received either 50 mg of MET (n = 19) or 5 mg of NEB (n = 22) for 4 weeks followed by 100 mg MET and 10 mg NEB for 4 weeks. ADMA and insulin-like growth factor-1 (IGF-1) were measured by enzyme-linked immunosorbent assay kit; endothelial progenitor cells were estimated using fluorescein-labeled monoclonal antibody to KDR and CD133 receptors; arterial augmentation index was measured by radial tonometry. Baseline systolic/diastolic blood pressure was 155.1 +/- 18.7/85.3 +/- 12.5 mm Hg for MET subjects and 157.6 +/- 20.7/87.1 +/- 14.0 mm Hg for NEB subjects. Baseline ADMA was 0.32 +/- 0.123 MUmol/L in the MET group and 0.4035 +/- 0.1378 in the NEB group. ADMA increased 44.78% and 72% in the MET group at weeks 4 and 8 (P < .05 for both), respectively, without increase in the NEB group. At week 8, augmentation index was increased in the MET group (P < .05). IGF-1 and endothelial progenitor cells were unchanged by treatment. Plasma ADMA and augmentation index are increased in a dose-dependent fashion by MET but not with NEB. PMID- 21251897 TI - Both hypertensive men and women are inadequately treated in Finnish general practice. AB - A general comprehension is that men are treated poorer than women. This study was planned to assess the Finnish hypertensive care with interests in possible hypertensive and cardiovascular control differences between men and women. A cross-sectional study was carried out by nationwide questionnaire survey of 714 consecutive drug-treated hypertensive patients having visited general practice during autumn 2006. Mean (SD) blood pressure (BP) of the women was 148.3 (21.1)/86.8 (11.7) mm Hg and of men 146.5 (19.5)/89.0 (11.8). Women had significantly lower diastolic BP (P = .016). The mean LDL cholesterol of women was 2.94 (0.91) mmol/L and of men 2.95 (0.94) mmol/L (P = .94). The blood pressure target <140/85 mm Hg was reached by 25% of the women and 23% of the men (P = .70). Of the women 30.7% and of the men 31.1% reached low-density lipoprotein (LDL)-cholesterol <2.5 mmol/L. Women used more diuretics than men (P = .06). No significant difference was seen between women and men in the number of patients reaching the target pressure <140/85 mm Hg, although diastolic blood pressure of the women was significantly lower. Hypertensive women and men were equally undertreated, and regardless of the sex, antihypertensive and hyperlipidemic control of hypertensive patients should be intensified. PMID- 21251900 TI - Elucidation of the full genetic information of Japanese rubella vaccines and the genetic changes associated with in vitro and in vivo vaccine virus phenotypes. AB - Rubella is a mild disease characterized by low-grade fever, and a morbilliform rash, but causes congenital defects in neonates born from mothers who suffered from rubella during the pregnancy. After many passages of wild-type rubella virus strains in various types of cultured cells, five live attenuated rubella vaccines were developed in Japan. An inability to elicit anti-rubella virus antibodies in experimentally infected animals was used as an in vivo marker phenotype of Japanese rubella vaccines. All Japanese rubella vaccine viruses exhibit a temperature-sensitive (ts) phenotype, and replicate very poorly at a high temperature. We determined the entire genome sequences of three Japanese rubella vaccines (Matsuba, TCRB19, and Matsuura), thereby completing the sequencing of all five Japanese rubella vaccines. In addition, the entire genome sequences of three vaccine progenitors were determined. Comparative nucleotide sequence analyses revealed mutations that were introduced into the genomes of the TO-336 and Matsuura vaccines during their production by laboratory passaging. Analyses involving cellular expression of viral P150 nonstructural protein-derived peptides revealed that the N1159S mutation conferred the ts phenotype on the TO 336 vaccine, and that reduced thermal stability of the P150 protease domain was a cause of the ts phenotype of some rubella vaccine viruses. The ts phenotype of vaccine viruses was not necessarily correlated with their inability to elicit humoral immune responses in animals. Therefore, the molecular mechanisms underlying the inability of these vaccines to elicit humoral responses in animals are more complicated than the previously considered mechanism involving the ts phenotype as the major cause. PMID- 21251901 TI - A new intranasal influenza vaccine based on a novel polycationic lipid-ceramide carbamoyl-spermine (CCS). II. Studies in mice and ferrets and mechanism of adjuvanticity. AB - We recently showed that lipid assemblies comprised of a novel polycationic sphingolipid (ceramide carbamoyl-spermine, CCS) are an effective adjuvant/carrier when complexed with cholesterol (CCS/C) for influenza and other vaccines administered parenterally and intranasally (i.n.) in mice. Here we expand these studies to ferrets, an established model of influenza infection. We also address the question of why the CCS/C-based liposomal vaccine (also known as VaxiSomeTM) in mice is superior to vaccines based on liposomes of other lipid compositions (neutral, anionic or cationic). Ferrets immunized i.n. with CCS/C-influenza vaccine produced significantly higher hemagglutination inhibition (HI) antibody titers compared to ferrets immunized intramuscularly with the unadjuvanted influenza vaccine, indicating that the CCS/C-based vaccine is very immunogenic. Furthermore, the i.n. adjuvanted vaccine was shown to significantly reduce the severity of influenza virus infection in ferrets following homologous viral challenge as determined by weight loss, temperature rise and viral titer. No adverse reactions were observed. Pharmacokinetic and biodistribution studies following i.n. administration in mice of CCS/C-based vaccine showed that both the lipids and antigens are retained in the nose and lung for at least 24h, and it appears that this retention correlates with the superior immunogenicity elicited by the adjuvanted vaccine formulation. The CCS lipid also increases production of cytokines (mainly IFN gamma, IL-2 and IL-12) and co-stimulatory molecules' expression, which might further explain the robust adjuvantation of this liposome based vaccine. PMID- 21251902 TI - Recombinant heat shock protein 65 carrying PADRE and HBV epitopes activates dendritic cells and elicits HBV-specific CTL responses. AB - BCG Hsp65 and PADRE have been shown to be potent to enhance antigen specific immunity. In order to explore the possibility to utilize them for the development of HBV therapeutic vaccine, a chimeric protein, Hsp65-HBV, was created by fusing PADRE and epitopes from HBV to the carboxyl-terminus of BCG Hsp65 and expressed in E. coli. We evaluated its effects on human dendritic cell maturation and specific CTL induction in vitro. Results showed that Hsp65-HBV could activate human dendritic cells by up-regulating the expressions of HLA-A2, HLA-DR and CD86, companioning with high level of IL-12 secretion. Furthermore, Hsp65-HBV matured DCs could significantly stimulate human autologous CD8(+) T cell proliferation and induce HBV-specific CTLs. Hsp65-HBV was also shown to generate HBsAg-specific CTLs in vivo in mice. These results indicated that Hsp65-HBV might be a candidate for the treatment of chronic HBV infection. PMID- 21251903 TI - Preclinical evaluation of the saponin derivative GPI-0100 as an immunostimulating and dose-sparing adjuvant for pandemic influenza vaccines. AB - With the current global influenza vaccine production capacity the large demand for vaccines in case of a pandemic can only be fulfilled when antigen dose sparing strategies are employed. Here we used a murine challenge model to evaluate the potential of GPI-0100, a semi-synthetic saponin derivative, to serve as a dose-sparing adjuvant for influenza subunit vaccine. Balb/c mice were immunized with different doses of A/PR8 (H1N1) subunit antigen alone or in combination with varying doses of GPI-0100. The addition of GPI-0100 significantly stimulated antibody and cellular immune responses, especially of the Th1 phenotype. Furthermore, virus titers detected in the lungs of mice challenged one week after the second immunization were significantly reduced among the animals that received GPI-0100-adjuvanted vaccines. Remarkably, adjuvantation of subunit vaccine with GPI-0100 allowed a 25-fold reduction in hemagglutinin dose without compromising the protective potential of the vaccine. PMID- 21251904 TI - Prospective pertussis surveillance in Switzerland, 1991-2006. AB - Pertussis has been monitored in Switzerland since 1991 by the nationwide Swiss Sentinel Surveillance Network (SSSN), consisting of approximately 200 general practitioners, internists and pediatricians representing about 3% of the total primary care physicians of these specialities. SSSN members report patients with cough >= 14 days plus either an epidemiological link or characteristic symptoms (paroxysms, whoop, post-tussive vomiting) on a weekly basis to the Federal Office of Public Health. Confirmatory PCR from nasopharyngeal specimens is offered for free. A total of 4992 cases have been reported until 2006. Yearly incidence has dropped from 70 cases per 100,000 inhabitants in 1992 to 40 in 2006, with a single epidemic in 1994-1995 with 280-370 cases/100,000. On average 80% of reported cases were tested by PCR, 24% of these were confirmed as Bordetella pertussis infections. For 2.6% of patients complications were reported, most commonly pneumonia, asthma bronchiale, otitis media, bronchitis and rib fractures. On average, 1.5% of patients were hospitalized. Disease in vaccinated patients was mitigated with less frequent complications (unvaccinated: 5.1%; 3 doses: 3.0%; >= 4 doses: 1.7%), hospitalizations (unvaccinated: 3.6%; >= 1 dose: 1.1%) and various clinical symptoms compared to unvaccinated patients. Comparing the periods 1991-1996, 1997-2001 and 2002-2006, a shift of pertussis from age group 1-9 years to 10-19 and >= 40 years was observed among patients cared for by general practitioners and internists. The benefits of further booster doses in adolescents and/or adults need to be considered. PMID- 21251906 TI - Effects of extract of soapnut Sapindus emarginatus on esterases and phosphatases of the vector mosquito, Aedes aegypti (Diptera: Culicidae). AB - Our earlier investigations with kernels from the soapnut Sapindus emarginatus revealed it as a new source of botanical biocide with potent antimosquito activity, as evident from the proven unique ability of the aqueous kernel extract to kill all the developmental stages of three important vector mosquito species, Aedes aegypti, Anopheles stephensi and Culex quinquefasciatus. This extract was also found to be safe for two non-target aquatic insects. As a sequel to these findings, we have further examined quantitative and qualitative changes in total proteins, esterases, and phosphatases in whole body homogenates of fourth instar larvae and pupae of A. aegypti exposed to this extract at an appropriate threshold time for its lethal effect to gain insights into the impact of the botanical biocide on biochemical characteristics of the target vector mosquito at two distinct developmental stages. The profiles of proteins, esterases (acetylcholinesterse, alpha- and beta-carboxylesterases), and phosphatases (acid and alkaline) exhibited distinct patterns of variation during normal development of fourth instar larvae and pupae, indicating intrinsic difference in biochemical features between these two developmental stages of A. aegypti. Upon exposure of the larvae to the extract, significant reduction in the activities of acetylcholinesterse, beta-carboxylesterase, and acid phosphatases were recorded, whereas the total proteins, alpha-carboxylesterase and alkaline phosphatase activities were unaffected. By contrast, only alkaline phosphatase activity was significantly affected in pupae exposed to the extract. Analysis of these enzymes in native PAGE revealed that they exist in isoforms in both the larvae and pupae. The alterations in the levels of enzymatic activities observed from the quantitative assays of various enzymes were reflected by the respective zymograms with perceptible differences in the intensity and the number of bands detected especially with beta-carboxylesterase, acid and alkaline phosphatase activity between the control and exposed test organisms. Despite the fact that the soapnut kernel extract causes mortality of both the larvae and pupae of A. aegypti, the findings of this study demonstrate that the impact of this extract is most pronounced in various enzyme profiles of the larvae rather than the pupae. Such discrepancy implicates the presence of unique biochemical mechanisms in the pupae of mosquito for detoxification of botanical biocides. PMID- 21251905 TI - Consistent interactions between tumor cell IL-6 and macrophage TNF-alpha enhance the growth of human prostate cancer cells in the bone of nude mouse. AB - To test the hypothesis that tumor-associated macrophages (TAMs) enhance the growth and metastasis of human prostate cancer in the bone, we evaluated the effects of decreasing interleukin-6 (IL-6) production by tumor cells and TAMs in a mouse model of bone metastasis. Human PC-3MM2 cells that produce IL-6 were transfected with lentivirus containing IL-6 small hairpin RNA (shRNA) or nonspecific RNA and injected into the tibias of nude mice treated intraperitoneally every 5days for 5weeks with phosphate-buffered saline (PBS), liposomes containing PBS, or liposomes containing clodronate (to decrease the number of macrophages). Transfection of PC-3MM2 cells with IL-6 shRNA significantly decreased cellular expression of IL-6 and the number of TAMs and osteoclasts in bone tumors, which correlated with significant decreases in tumor size, bone lysis, and incidence of lymph node metastasis. Treatment of mice with clodronate liposomes significantly decreased the number of TAMs and osteoclasts in the bone tumors, the expression of IL-6 in the PC3-MM2 cells, and the production of tumor necrosis factor (TNF)-alpha by TAMs. These findings correlated with a significant decrease in tumor size, bone lysis, and lymph node metastasis. Knocking down IL-6 in tumor cells and decreasing TAMs was associated with the lowest incidences of bone tumors and lymph node metastasis. These results suggest that TAMs enhance the growth of prostate cancer cells in the bone. PMID- 21251907 TI - Activity of some hypocrealean fungi collected in a Cerrado ecosystem against Rhodnius spp. (Hemiptera: Reduviidae) under laboratory conditions. AB - The hypocrealean invertebrate-pathogenic fungi Lecanicillium psalliotae, Paecilomyces lilacinus and Pochonia chlamydosporia isolated from soils in Central Brazil were tested against palm-dwelling Rhodnius neglectus, R. nasutus, R. prolixus, and R. robustus; all of these insects are vectors of Chagas disease. Particularly R. neglectus and R. nasutus, which are both important secondary intruders of human habitations were susceptible to all three of the fungi tested, and fungi sporulated successfully on the cadavers. This is the first report of activity of L. psalliotae, P. lilacinus and P. chlamydosporia against Rhodnius spp., and these fungi have interest for integrated control of triatomine vectors. PMID- 21251908 TI - Importance of inverse correlation between ALDH3A1 and PPARgamma in tumor cells and tissue regeneration. AB - Aldehyde dehydrogenase (ALDH) enzymes are involved in maintaining cellular homeostasis by metabolizing both endogenous and exogenous reactive aldehydes. They modulate several cell functions including proliferation, differentiation, survival as well as cellular response to oxidative stress. We previously reported that ALDH3A1 expression is inversely correlated with the activation of PPARs (Peroxisome Proliferators-Activated Receptors), a category of orphan nuclear hormone receptors, in both rat and human cells. PPARgamma is involved in cell proliferation. In this study, we have used PPARgamma transfection and inhibition to examine the relationship between ALDH3A1 and PPARgamma and their role as regulators of cell proliferation. Induction of PPARgamma in A549 and NCTC 2544 cells by transfection caused a decrease in ALDH3A1 and inhibition of cell proliferation, a result we obtained previously using ligands that induce PPARgamma. A reduction of PPARgamma expression using siRNA increased ALDH3A1 expression and cell proliferation. In cells induced to proliferate in a model of tissue regeneration, ALDH3A1 expression increased during the period of proliferation, whereas PPARgamma expression decreased. In conclusion, through modulation of PPARgamma or ALDH3A1, it may be possible to reduce cell proliferation in tumor cells or stimulate cell proliferation in normal cells during tissue regeneration. PMID- 21251909 TI - Expression of leukemia/lymphoma related factor (LRF/Pokemon) in human benign prostate hyperplasia and prostate cancer. AB - Leukemia/lymphoma related factor (LRF), also known as Pokemon, is a protein that belongs to the POK family of transcriptional repressors. It has an oncogenic role in many different solid tumors. In this study, the expression of LRF was evaluated in benign prostate hyperplastic (BPH) and prostate cancer (PC) tissues. The functional expression of LRF was studied using multiple cellular and molecular methods including RT-PCR, western blotting, immunohistochemistry, and immunofluorescence. Paraffin-embedded human tissues of BPH and PC were used to examine LRF expression. Histological staining of the BPH and PC tissue sections revealed nuclear expression of LRF with minimal expression in the surrounding stroma. The semi-quantitative RT-PCR and western immunoblot analyses demonstrated significantly higher mRNA transcripts and protein expression in PC than BPH. High expression of LRF suggests that it may have a potential role in the pathogenesis of both BPH and prostate cancer. Further studies will help elucidate the mechanisms and signaling pathways that LRF may follow in the pathogenesis of prostate carcinoma. PMID- 21251910 TI - Both plant and animal LEA proteins act as kinetic stabilisers of polyglutamine dependent protein aggregation. AB - LEA (late embryogenesis abundant) proteins are intrinsically disordered proteins that contribute to stress tolerance in plants and invertebrates. Here we show that, when both plant and animal LEA proteins are co-expressed in mammalian cells with self-aggregating polyglutamine (polyQ) proteins, they reduce aggregation in a time-dependent fashion, showing more protection at early time points. A similar effect was also observed in vitro, where recombinant LEA proteins were able to slow the rate of polyQ aggregation, but not abolish it altogether. Thus, LEA proteins act as kinetic stabilisers of aggregating proteins, a novel function in protein homeostasis consistent with a proposed role as molecular shields. PMID- 21251911 TI - Acidic extracellular pH induces p120-catenin-mediated disruption of adherens junctions via the Src kinase-PKCdelta pathway. AB - An acidic microenvironment induces disruption of adherens junctions (AJs) of hepatoma cells. This study investigated the impact of an acidic extracellular pH (pHe) on p120-catenin (p120-ctn) serine phosphorylation. pH 6.6 treatment increased intracellular calcium levels, activated protein kinase C (PKC)alpha and PKCdelta, and decreased serine phosphorylation of p120-ctn. Further knockdown of PKCalpha and delta by small interference RNA (siRNA) prevented the pH 6.6-induced downregulation of p120-ctn at AJ and the serine dephosphorylation of p120-ctn. Moreover, PP2 pretreatment and siRNA of c-Src abrogated the pH 6.6-induced PKCdelta activation. Together, the c-Src-PKCdelta cascade and PKCalpha regulate the acidic pHe-induced AJ disruption. PMID- 21251912 TI - An interaction between human Sec63 and nucleoredoxin may provide the missing link between the SEC63 gene and polycystic liver disease. AB - The formation of multiple cysts in one or several organs is a characteristic of several human inherited diseases. Recent research suggests that problems in planar cell polarity may be the common denominator in polycystic diseases. Mutations in at least two genes are linked to autosomal dominant polycystic liver disease (PCLD), PRKCSH and SEC63. A recent study linked PRKCSH to the signaling- and cytoskeletal adaptor-component beta-catenin. In a yeast two hybrid screen we identified the cytosolic protein nucleoredoxin (NRX) as an interaction partner of human Sec63. Since NRX is involved in the Wnt signaling pathways, we characterized this interaction. Thus, Sec63 is linked to the Wnt signaling pathways and this interaction may be the reason why mutations in SEC63 can lead to PCLD. PMID- 21251913 TI - Cysteine S-glycosylation, a new post-translational modification found in glycopeptide bacteriocins. AB - O-Glycosylation is a ubiquitous eukaryotic post-translational modification, whereas early reports of S-linked glycopeptides have never been verified. Prokaryotes also glycosylate proteins, but there are no confirmed examples of sidechain glycosylation in ribosomal antimicrobial polypeptides collectively known as bacteriocins. Here we show that glycocin F, a bacteriocin secreted by Lactobacillus plantarum KW30, is modified by an N-acetylglucosamine beta-O-linked to Ser18, and an N-acetylhexosamine S-linked to C-terminal Cys43. The O-linked N acetylglucosamine is essential for bacteriostatic activity, and the C-terminus is required for full potency (IC(50) 2 nM). Genomic context analysis identified diverse putative glycopeptide bacteriocins in Firmicutes. One of these, the reputed lantibiotic sublancin, was shown to contain a hexose S-linked to Cys22. PMID- 21251914 TI - Evidence incriminating midges (Diptera: Ceratopogonidae) as potential vectors of Leishmania in Australia. AB - The first autochthonous Leishmania infection in Australia was reported by Rose et al. (2004) and the parasite was characterised as a unique species. The host was the red kangaroo (Macropus rufus) but the transmitting vector was unknown. To incriminate the biological vector, insect trapping by a variety of methods was undertaken at two field sites of known Leishmania transmission. Collected sand flies were identified to species level and were screened for Leishmania DNA using a semi-quantitative real-time PCR. Collections revealed four species of sand fly, with a predominance of the reptile biter Sergentomyia queenslandi (Hill). However, no Leishmania-positive flies were detected. Therefore, alternative vectors were investigated for infection, giving startling results. Screening revealed that an undescribed species of day-feeding midge, subgenus Forcipomyia (Lasiohelea) Kieffer, had a prevalence of up to 15% for Leishmania DNA, with high parasitemia in some individuals. Manual gut dissections confirmed the presence of promastigotes and in some midges material similar to promastigote secretory gel, including parasites with metacyclic-like morphology. Parasites were cultured from infected midges and sequence analysis of the Leishmania RNA polymerase subunit II gene confirmed infections were identical to the original isolated Leishmania sp. Phylogenetic analysis revealed the closest known species to be Leishmania enriettii, with this and the Australian species confirmed as members of Leishmania sensu stricto. Collectively the results strongly suggest that the day feeding midge (F. (Lasiohelea) sp. 1) is a potential biological vector of Leishmania in northern Australia, which is to our knowledge the first evidence of a vector other than a phlebotomine sand fly anywhere in the world. These findings have considerable implications in the understanding of the Leishmania life cycle worldwide. PMID- 21251915 TI - The effect of Parkinson's-disease-associated mutations on the deubiquitinating enzyme UCH-L1. AB - The neuronal ubiquitin C-terminal hydrolase (UCH) UCH-L1 has been linked to Parkinson's disease (PD) and other neurodegenerative diseases. Here, we present a study on the structure, stability, unfolding, and dynamics of wild-type and mutant UCH-L1. Fluorescence, far-UV CD, and NMR measurements were used to establish that the unfolding of UCH-L1 is three-state under equilibrium conditions and that an intermediate is populated. S18Y and I93M mutants, which are associated with a decreased risk or an increased risk of PD, respectively, are less stable than wild type. However, while there is minimal structural perturbation in the S18Y mutant, the I93M mutation is more disruptive. In particular, the NMR data suggest that there are local rearrangements around the site of the mutation, which we propose results in the exposure of hydrophobic surface area. This may have two consequences: an increased tendency towards, firstly, aggregation in vivo, and, secondly, aberrant interactions with tubulin and the chaperone-mediated autophagy machinery as observed by other groups, both of which may be involved in neurodegenerative processes. PMID- 21251916 TI - Chronic administration of the anabolic androgenic steroid nandrolone alters neurosteroid action at the sigma-1 receptor but not at the sigma-2 or NMDA receptors. AB - Studies have shown that anabolic androgenic steroids (AASs) can induce profound changes to mental health. Commonly reported psychiatric side effects among AAS users include aggression, anxiety, depression, drug abuse and cognitive disabilities. In experimental animals, many of these effects have been associated with alterations in a number of neurotransmitter systems. We have observed that chronic administration of the AAS nandrolone (nandrolone decanoate) can affect excitatory amino acids as well as monoaminergic and peptidergic pathways in a way that is compatible with nandrolone-induced behavioural changes. The aim of the present work was to further explore the mechanisms underlying nandrolone-induced effects, with a particular focus on components known to be involved in aggression and cognitive function. Male rats were given daily injections of nandrolone decanoate for 14 days and the effects on neurosteroid interactions with sites on the N-methyl-D-aspartyl (NMDA) and sigma receptors were examined. These receptors were chosen because of their involvement in aggressive and cognitive behaviors and the hypothesis that nandrolone might affect the brain via interaction with neurosteroids. Radiolabelled [3H]ifenprodil was used in the binding studies because of its significant affinity for the NMDA and sigma receptors. The results indicated that [3H]ifenprodil binds to both sigma-1 and sigma-2 sites and can be displaced to a certain extent from both sites by the neurosteroids pregnenolone sulphate (PS), pregnanolone sulphate (3alpha5betaS) and dehydroepiandrosterone sulphate (DHEAS). The remainder of the [3H]ifenprodil was displaced from the sigma-1 site by the sigma-1 receptor-selective ligand (+)-SKF 10,047. Chronic nandrolone treatment changed the sigma-1 receptor target for the neurosteroids but not for ifenprodil. The sigma-2 receptor site was unaltered by treatment with nandrolone decanoate. The results also indicated that the neurosteroid-induced allosteric modulation of the NMDA receptor subunit NR2B was not affected by nandrolone treatment. We conclude that chronic treatment with nandrolone changes the affinity of the neurosteroids PS, 3alpha5betaS and DHEAS at the sigma-1 site but not at the sites on the sigma-2 receptor or the NMDA receptor subunit NR2B. PMID- 21251917 TI - Serotonergic regulation of neuronal excitability in the prefrontal cortex. AB - The cerebral cortex receives a dense serotonergic innervation originating predominantly from the dorsal raphe nucleus. This innervation regulates cortical functioning by activating multiple serotonin receptors that are differentially expressed by pyramidal cells and interneurons. Electrophysiological studies in the prefrontal cortex indicate that receptors of the 5-HT(1A) and 5-HT(2A) subtypes are the main serotonin receptors regulating membrane excitability in pyramidal cells. Most pyramidal cells in layer V coexpress 5-HT(1A) and 5-HT(2A) receptors that together regulate how these neurons encode excitatory input into neuronal firing. In contrast, a subset of large pyramidal cells of deep layer V appears to express exclusively 5-HT(2A) receptors that depolarize and excite these cells. Serotonin also depolarizes and excites at least two classes of GABAergic interneurons by acting on 5-HT(3) and 5-HT(2A) receptors. The differential expression of serotonin receptors in different pyramidal cells and interneurons is consistent with a growing appreciation of the anatomical, molecular and functional heterogeneity of pyramidal cells and interneurons of the cerebral cortex. These findings begin to lay the ground for a cellular-level understanding of the serotonergic regulation of the prefrontal cortex. PMID- 21251918 TI - Serotonin-dependent depression in Parkinson's disease: a role for the subthalamic nucleus? AB - Depression is the most common neuropsychiatric co-morbidity in Parkinson's disease (PD). The underlying mechanism of depression in PD is complex and likely involves biological, psychosocial and therapeutic factors. The biological mechanism may involve changes in monoamine systems, in particular the serotonergic (5-hydroxytryptamine, 5-HT) system. It is well established that the 5-HT system is markedly affected in the Parkinsonian brain, with evidence including pathological loss of markers of 5-HT axons as well as cell bodies in the dorsal and median raphe nuclei of the midbrain. However, it remains unresolved whether alterations to the 5-HT system alone are sufficient to confer vulnerability to depression. Here we propose low 5-HT combined with altered network activity within the basal ganglia as critically involved in depression in PD. The latter hypothesis is derived from a number of recent findings that highlight the close interaction between the basal ganglia and the 5-HT system, not only in motor but also limbic functions. These findings include evidence that clinical depression is a side effect of deep brain stimulation (DBS) of the subthalamic nucleus (STN), a treatment option in advanced PD. Further, it has recently been demonstrated that STN DBS in animal models inhibits 5-HT neurotransmission, and that this change may underpin depressive-like side effects. This review provides an overview of 5-HT alterations in PD and a discussion of how these changes might combine with altered basal ganglia network activity to increase depression vulnerability. PMID- 21251919 TI - Intermittent ethanol consumption depresses endocannabinoid-signaling in the dorsolateral striatum of rat. AB - Recent research suggests that adaptations elicited by drugs of abuse share common features with traditional learning models, and that drugs of abuse cause long term changes in behavior by altering synaptic function and plasticity. In this study, endocannabinoid (eCB) signaling in the dorsolateral striatum, a brain region vital for habit formation, was evaluated in acutely isolated brain slices from ethanol (EtOH)-consuming rats and control rats. EtOH-consuming rats had free access to a 20% EtOH solution for three 24 hour sessions a week during seven weeks and consumed an average of 3.4 g/kg per session. eCB-mediated long-lasting disinhibition (DLL) of population spike (PS) amplitude induced by moderate frequency stimulation was impaired in EtOH-consuming rats, and was not restored by the muscarinic receptor antagonist scopolamine (10 MUM). The lack of DLL could be linked to a reduced GABA(A) receptor tone, since bicuculline-mediated disinhibition of striatal output was significantly reduced in slices from EtOH consuming rats. However, eCB signaling induced by high frequency stimulation (HFS) was also impaired in slices from EtOH-consuming rats and isolated control rats. Activation of presynaptic cannabinoid 1 receptors (CB1R) with WIN55,212-2 (250 nM, 1 MUM) significantly modulated PS amplitude in slices from age-matched control rats while slices from EtOH-consuming rats remained unaffected, indicating that eCB signaling is inhibited at a level that is downstream from CB1R activation. Intermittent alcohol intake for seven weeks might thus be sufficient to modulate a presynaptic mechanism that needs to be synergized with CB1R activation for induction of long-term depression (LTD). In conclusion, alcohol consumption inhibits striatal eCB signaling in a way that could be of importance for understanding the neurological underpinnings of addictive behavior. PMID- 21251920 TI - The role of propriospinal interneurons in recovery from spinal cord injury. AB - Over one hundred years ago, Sir Charles Sherrington described a population of spinal cord interneurons (INs) that connect multiple spinal cord segments and participate in complex or 'long' motor reflexes. These neurons were subsequently termed propriospinal neurons (PNs) and are known to play a crucial role in motor control and sensory processing. Recent work has shown that PNs may also be an important substrate for recovery from spinal cord injury (SCI) as they contribute to plastic reorganisation of spinal circuits. The location, inter-segmental projection pattern and sheer number of PNs mean that after SCI, a significant number of them are capable of 'bridging' an incomplete spinal cord lesion. When these properties are combined with the capacity of PNs to activate and coordinate locomotor central pattern generators (CPGs), it is clear they are ideally placed to assist locomotor recovery. Here we summarise the anatomy, organisation and function of PNs in the uninjured spinal cord, briefly outline the pathophysiology of SCI, describe how PNs contribute to recovery of motor function, and finally, we discuss the mechanisms that underlie PN plasticity. We propose there are two major challenges for PN research. The first is to learn more about ways we can promote PN plasticity and manipulate the 'hostile' micro-environment that limits regeneration in the damaged spinal cord. The second is to study the cellular/intrinsic properties of PNs to better understand their function in both the normal and injured spinal cord. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'. PMID- 21251921 TI - Left anterior temporal cortex actively engages in speech perception: A direct cortical stimulation study. AB - Recent neuroimaging studies proposed the importance of the anterior auditory pathway for speech comprehension. Its clinical significance is implicated by semantic dementia or pure word deafness. Neurodegenerative or cerebrovascular nature, however, precluded precise localization of the cortex responsible for speech perception. Electrical cortical stimulation could delineate such localization by producing transient, functional impairment. We investigated engagement of the left anterior temporal cortex in speech perception by means of direct electrical cortical stimulation. Subjects were two partial epilepsy patients, who underwent direct cortical stimulation as a part of invasive presurgical evaluations. Stimulus sites were coregistered to presurgical 3D-MRI, and then to MNI standard space for anatomical localization. Separate from the posterior temporal language area, electrical cortical stimulation revealed a well restricted language area in the anterior part of the superior temporal sulcus and gyrus (aSTS/STG) in both patients. Auditory sentence comprehension was impaired upon electrical stimulation of aSTS/STG. In one patient, additional investigation revealed that the functional impairment was restricted to auditory sentence comprehension with preserved visual sentence comprehension and perception of music and environmental sounds. Both patients reported that they could hear the voice but not understand the sentence well (e.g., heard as a series of meaningless utterance). The standard coordinates of this restricted area at left aSTS/STG well corresponded with the coordinates of speech perception reported in neuroimaging activation studies in healthy subjects. The present combined anatomo functional case study, for the first time, demonstrated that aSTS/STG in the language dominant hemisphere actively engages in speech perception. PMID- 21251922 TI - Dissecting teleost B cell differentiation using transcription factors. AB - B cell developmental pathways in teleost fishes are poorly understood. In the absence of serological reagents, an alternative approach to dissecting teleost B cell development is to use transcription factors that are differentially expressed during B cell development. This review discusses the structure and function of six transcription factors that play essential roles during teleost B cell development: Ikaros, E2A, EBF, Pax5, Blimp1, and XbpI. Research on alternative splicing of both the Ikaros and Pax5 genes in rainbow trout is presented, including their functional significance. An application is discussed that should aid in elucidating teleost B cell development and activation, by using transcription factors as developmental markers in flow cytometric analysis. Possible future studies in teleost B cell development are suggested in the context of gene regulation. Lastly, broader impacts and practical applications are discussed. PMID- 21251923 TI - Evolutionary functions of early social modulation of hypothalamic-pituitary adrenal axis development in humans. AB - The hypothalamic-pituitary-adrenal axis (HPAA) is highly responsive to social challenges. Because stress hormones can have negative developmental and health consequences, this presents an evolutionary paradox: Why would natural selection have favored mechanisms that elevate stress hormone levels in response to psychosocial stimuli? Here we review the hypothesis that large brains, an extended childhood and intensive family care in humans are adaptations resulting from selective forces exerted by the increasingly complex and dynamic social and cultural environment that co-evolved with these traits. Variations in the modulation of stress responses mediated by specific HPAA characteristics (e.g., baseline cortisol levels, and changes in cortisol levels in response to challenges) are viewed as phenotypically plastic, ontogenetic responses to specific environmental signals. From this perspective, we discuss relations between physiological stress responses and life history trajectories, particularly the development of social competencies. We present brief summaries of data on hormones, indicators of morbidity and social environments from our long-term, naturalistic studies in both Guatemala and Dominica. Results indicate that difficult family environments and traumatic social events are associated with temporal elevations of cortisol, suppressed reproductive functioning and elevated morbidity. The long-term effects of traumatic early experiences on cortisol profiles are complex and indicate domain-specific effects, with normal recovery from physical stressors, but some heightened response to negative-affect social challenges. We consider these results to be consistent with the hypothesis that developmental programming of the HPAA and other neuroendocrine systems associated with stress responses may facilitate cognitive targeting of salient social challenges in specific environments. PMID- 21251925 TI - Epigenetic mechanisms mediating vulnerability and resilience to psychiatric disorders. AB - The impact that stressful encounters have upon long-lasting behavioural phenotypes is varied. Whereas a significant proportion of the population will develop "stress-related" conditions such as post-traumatic stress disorder or depression in later life, the majority are considered "resilient" and are able to cope with stress and avoid such psychopathologies. The reason for this heterogeneity is undoubtedly multi-factorial, involving a complex interplay between genetic and environmental factors. Both genes and environment are of critical importance when it comes to developmental processes, and it appears that subtle differences in either of these may be responsible for altering developmental trajectories that confer vulnerability or resilience. At the molecular level, developmental processes are regulated by epigenetic mechanisms, with recent clinical and pre-clinical data obtained by ourselves and others suggesting that epigenetic differences in various regions of the brain are associated with a range of psychiatric disorders, including many that are stress related. Here we provide an overview of how these epigenetic differences, and hence susceptibility to psychiatric disorders, might arise through exposure to stress-related factors during critical periods of development. PMID- 21251924 TI - Pleasure seeking and birdsong. AB - Songbirds sing at high rates within multiple contexts, suggesting that they are highly motivated to communicate and that the act of singing itself may be rewarding. Little is known about the neural regulation of the motivation to communicate. Dopamine and opioid neuropeptides play a primary role in reward seeking and sensory pleasure. In songbirds, these neurochemicals are found within brain regions implicated in both motivation and reward, including the medial preoptic nucleus (mPOA) and ventral tegmental area (VTA). Several lines of research indicate that dopamine and opioids in these regions play a role in birdsong that differs depending upon whether song is used to attract females (female-directed song) or is not directed towards other individuals (undirected song). Evidence is reviewed supporting the hypotheses: (1) that distinct patterns of dopamine activity influence the motivation to produce undirected and female directed song, (2) that undirected communication is intrinsically reinforced by immediate release of opioids induced by the act of singing, and (3) that directed communication is socially reinforced by opioids released as part of social interactions. PMID- 21251927 TI - A catecholamine transporter from the human parasite Schistosoma mansoni with low affinity for psychostimulants. AB - The trematode Schistosoma mansoni is the primary cause of schistosomiasis, a devastating neglected tropical disease that affects 200 million individuals. Identifying novel therapeutic targets for the treatment of schistosomiasis is therefore of great public interest. The catecholamines norepinephrine (NE) and dopamine (DA) are essential for the survival of the parasite as they cause muscular relaxation and a lengthening in the parasite and thereby control movement. Here we characterize a novel dopamine/norepinephrine transporter (SmDAT) gene transcript, from S. mansoni. The SmDAT is expressed in the adult form and in the sporocyst form (infected snails) of the parasite, and also in the egg and miracidium stage. It is absent in the cercariae stage but curiously a transcript missing the exon encoding transmembrane domain 8 was identified in this stage. Heterologous expression of the cDNA in mammalian cells resulted in saturable, dopamine transport activity with an apparent affinity for dopamine comparable to that of the human dopamine transporter. Efflux experiments reveal notably higher substrate selectivity compared with its mammalian counterparts as amphetamine is a much less potent efflux elicitor against SmDAT compared to the human DAT. Pharmacological characterization of the SmDAT revealed that most human DAT inhibitors including psychostimulants such as cocaine were significantly less potent in inhibiting SmDAT. Like DATs from other simpler organisms the pharmacology for SmDAT was more similar to the human norepinephrine transporter. We were not able to identify other dopamine transporting carriers within the completed parasite genome and we hypothesize that the SmDAT is the only catecholamine transporter in the parasite and could be responsible for not only clearing DA but also NE. PMID- 21251926 TI - Rat pup social motivation: a critical component of early psychological development. AB - Examining the role of the offspring in early social dynamics is especially difficult. Human developmental psychology has found infant behavior to be a vital part of the early environmental setting. In the rodent model, the different ways that a rodent neonate or pup can influence social dynamics are not well known. Typically, litters of neonates or pups offer complex social interactions dominated by behavior seemingly initiated and maintained by the primary caregiver (e.g., the dam). Despite this strong role for the caregiver, the young most likely influence the litter dynamics in many powerful ways including communication signals, discrimination abilities and early approach behavior. Nelson and Panksepp (1996) developed a preference task to examine early rodent pup social motivation. We have used the same task to examine how variations in maternal care or different environmental perturbations could alter the rat pup preferences for social-related stimuli. Rat pups receiving low levels of maternal licking and grooming were impaired in maternal odor cue learning and emitted lower levels of 22kHz ultrasounds compared to pups from the high licking and grooming cohort. Prenatal stress or early exposure to a toxicant (polychlorinated biphenyl) altered early social preferences in the rat pup in different ways indicating that diverse strategies are expressed and specific to the type of perturbation exposure. A greater focus on the offspring motivation following early 'stressors' will allow for more complete understanding of the dynamics in behavior during early social development. PMID- 21251928 TI - Quantitative retrotransposon anchored PCR confirms transduction efficiency of transgenes in adult Schistosoma mansoni. AB - A quantitative retrotransposon anchored PCR (qRAP) that utilizes endogenous retrotransposons as a chromosomal anchor was developed to investigate integration of transgenes in Schistosoma mansoni. The qRAP technique, which builds on earlier techniques, (i) Alu-PCR which has been used to quantify lentiviral (HIV-1) proviral insertions in human chromosomes and (ii) a non-quantitative retrotransposon anchored PCR known to detect the presence of transgenes in the S. mansoni genome, was tested here in a model comparison of retrovirus-transduced adult schistosomes in which one group included intact worms, the other included fragments of adult worms. At the outset, after transducing intact and viable fragments of schistosomes with reporter RNAs, we observed more reporter activity in fragments of worms than in intact worms. We considered this simply reflects the increased surface area in fragments compared to intact worms exposed to the exogenous reporter genes. Subsequently, intact worms and worm fragments were transduced with pseudotyped virions. Transgene integration events in genomic DNA extracted from the virion-exposed worms and worm fragments were quantified by the qRAP, which revealed that fragmenting adult schistosomes resulted in increased density of proviral integrations. The qRAP findings confirmed the likely value of this qRAP technique for quantification of transgenes integrated in schistosome chromosomes. Last, considering the absence of schistosome cell or tissue lines, primary culture of fragmented worms offers an opportunity to optimize transgenesis, and other functional genomic approaches. PMID- 21251929 TI - Plasmodium falciparum field isolates use complement receptor 1 (CR1) as a receptor for invasion of erythrocytes. AB - A majority of Plasmodium falciparum strains invade erythrocytes through interactions with sialic acid (SA) on glycophorins. However, we recently reported that complement receptor 1 (CR1) is a SA-independent invasion receptor of many laboratory strains of P. falciparum. To determine the role of CR1 in erythrocyte invasion among P. falciparum field isolates, we tested eight isolates obtained from children in Kenya. All the parasites examined were capable of invading in a SA-independent manner, and invasion of neuraminidase-treated erythrocytes was nearly completely blocked by anti-CR1 and soluble CR1 (sCR1). In addition, anti CR1 and sCR1 partially inhibited invasion of intact erythrocytes in a majority of isolates tested. Sequencing of the hypervariable region of P. falciparum AMA-1 showed considerable diversity among all the isolates. These data demonstrate that CR1 mediates SA-independent erythrocyte invasion in P. falciparum field isolates. PMID- 21251930 TI - Yeast dihydroorotate dehydrogenase as a new selectable marker for Plasmodium falciparum transfection. AB - Genetic manipulation of Plasmodium falciparum in culture through transfection has provided numerous insights into the molecular and cell biology of this parasite. The procedure is rather cumbersome, and is limited by the number of drug resistant markers that can be used for selecting transfected parasites. Here we report a new selectable marker that could allow multiple transfections. We have taken advantage of our finding that a critical function of the mitochondrial electron transport chain (mtETC) in the erythrocytic stages of P. falciparum is the regeneration of ubiquinone as co-substrate of dihydroorotate dehydrogenase (DHODH), and that transgenic P. falciparum expressing ubiquinone-independent DHODH from yeast (yDHODH) are resistant to all mtETC inhibitors. We assessed the possibility of using yDHODH as a positive selectable marker for transfections of P. falciparum, including its use in gene disruption strategies. We constructed a transfection vector designed for gene disruption, termed pUF-1, containing the yDHODH gene as the positive selection marker in combination with a previously described fused yeast cytosine deaminase-uracil phosphoribosyl transferase gene as a negative selection marker. Transfection of the D10 strain followed by selection with atovaquone yielded positively selected parasites containing the plasmid, demonstrating that yDHODH can be used as a selective marker. Atovaquone, however, could not be used for such selection with the Dd2 strain of P. falciparum. On the other hand, we demonstrated that yDHODH transgenic parasites could be selected in both strains by Plasmodium DHODH-specific triazolopyrimidine based inhibitors. Thus, selection with DHODH inhibitors was superior in that it successfully selected transgenic Dd2 parasites, as well as yielded transgenic parasites after a shorter period of selection. As a proof of concept, we have successfully disrupted the type II vacuolar proton-pumping pyrophosphatase gene (PfVP2) in P. falciparum by double crossover recombination, showing that this gene is not essential for the survival of blood stage parasites. PMID- 21251931 TI - Ac-AP-12, a novel factor Xa anticoagulant peptide from the esophageal glands of adult Ancylostoma caninum. AB - Immunoscreening an Ancylostoma caninum cDNA library with canine hookworm-infected dog serum resulted in the isolation of a 461 bp cDNA encoding Ac-AP-12, a new 9.1 kDa anticoagulant peptide (100 amino acids) with 43-69% amino acid homology to other nematode anticoagulant peptides (NAPs) from Ancylostoma hookworms. Messenger RNA transcription and expression of Ac-AP-12 was unique to the adult stage of A. caninum. The yeast expressed recombinant Ac-AP-12 demonstrated potent anticoagulant activity on human blood plasma in a concentration dependent manner, and was shown to specifically inhibit human factor Xa activity. Immunolocalization with specific rabbit antiserum showed that Ac-AP-12 was exclusively located in the esophageal glands of adult hookworm. Ac-AP-12 is hypothesized to facilitate both parasite blood feeding and digestion. PMID- 21251932 TI - Design of anti-parasitic and anti-fungal hydroxy-naphthoquinones that are less susceptible to drug resistance. AB - Atovaquone is a hydroxy-naphthoquinone that is used to treat parasitic and fungal infections including Plasmodium falciparum (malaria), Pneumocystis jivorecii (pneumonia) and Toxoplasma gondii (toxoplasmosis). It blocks mitochondrial oxidation of ubiquinol in these organisms by binding to the ubiquinol oxidation site of the cytochrome bc(1) complex. Failure of atovaquone treatment has been linked to the appearance of mutations in the mitochondrially encoded gene for cytochrome b. In order to determine the optimal parameters required for inhibition of respiration in parasites and pathogenic fungi and overcome drug resistance, we have synthesized and tested the inhibitory activity of novel hydroxy-naphthoquinones against blood stage P. falciparum and liver stage P. berghei and against cytochrome bc(1) complexes isolated from yeast strains bearing mutations in cytochrome b associated with resistance in Plasmodium, Pneumocystis, and Toxoplasma. One of the new inhibitors is highly effective against an atovaquone resistant Plasmodium and illustrates the type of modification to the hydroxy-naphthoquinone ring of atovaquone that might mitigate drug resistance. PMID- 21251933 TI - Mechanism of growth inhibition of intraerythrocytic stages of Plasmodium falciparum by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). AB - Purine nucleotide synthesis in Plasmodium falciparum takes place solely by the purine salvage pathway in which preformed purine base(s) are salvaged from the host and acted upon by a battery of enzymes to generate AMP and GMP. Inhibitors of this pathway have a potent effect on the in vitro growth of P. falciparum and are hence, implicated as promising leads for the development of new generation anti-malarials. Here, we describe the mechanism of inhibition of the intraerythrocytic growth of P. falciparum by the purine nucleoside precursor, 5 aminoimidazole-4-carboxamide ribonucleoside (AICAR). Our results show that AICAR toxicity is mediated through the erythrocyte in which AICAR is phosphorylated to its nucleotide, ZMP. Further, purine metabolite labeling of the parasitized erythrocytes by [(3)H]-hypoxanthine, in the presence of AICAR, showed a significant decrease in radioactive counts in adenylate fractions but not in guanylate fractions. The most dramatic effect on parasite growth was observed when erythrocytes pretreated with AICAR were used in culture. Pretreatment of erythrocytes with AICAR led to significant intracellular accumulation of ZMP and these erythrocytes were incapable of supporting parasite growth. These results implicate that in addition to the purine salvage pathway in P. falciparum, AICAR alters the metabolic status of the erythrocytes, which inhibits parasite growth. As AICAR and ZMP are metabolites in the human serum and erythrocytes, our studies reported here throw light on their possible role in disease susceptibility, and also suggests the possibility of AICAR being a potential prophylactic or chemotherapeutic anti-malarial compound. PMID- 21251934 TI - Autonomic reactivity and romantic relational aggression among female emerging adults: moderating roles of social and cognitive risk. AB - This study investigates the association between autonomic arousal in response to a relational stressor and the perpetration of relational aggression against romantic partners. In addition, the moderating role of social risk (relational victimization by a romantic partner) and cognitive risk (hostile attribution biases) was explored. Skin conductance, heart rate, and respiratory sinus arrhythmia during an experience of exclusion were assessed in a sample of female emerging adults (N=131). Participants provided self-reports of romantic relational aggression, romantic relational victimization, and hostile attribution biases. Results indicated that both heightened and blunted reactivity served as risk factors for the perpetration of romantic relational aggression depending on women's social and contextual risks. Implications for understanding the development of intimate aggression are discussed. PMID- 21251935 TI - Gene delivery by pullulan derivatives in brain capillary endothelial cells for protein secretion. AB - The blood-brain barrier (BBB) formed by brain capillary endothelial cells protects the brain against potentially harmful substances present in the circulation, but also restricts exogenous substances such as pharmacologically acting drugs or proteins from entering the brain. A novel and rather unchallenged approach to allow proteins to enter the brain is gene therapy based on delivery of genetic material into brain capillary endothelial cells. In theory in vivo transfection will allow protein expression and secretion from brain capillary endothelial cells and further into the brain. This would denote a new paradigm for therapy to transport proteins across the BBB. The aim of this study was to investigate the possibility to use brain capillary endothelial cells as factories for recombinant protein production. Non-viral gene carriers were prepared from pullulan, a polysaccharide, and spermine, a naturally occurring polyamine that were additionally conjugated with plasmid DNA. We were able to transfect rat brain endothelial cells (RBE4s) and human brain microvascular endothelial cells (HBMECs). Transfection of HBMECs with pullulan-spermine conjugated with plasmid DNA bearing cDNA encoding human growth hormone 1 (hGH1), led to secretion of hGH1 protein into the growth medium. Hence, the pullulan-spermine delivery system is a very promising method for delivering DNA to brain endothelial cells with potential for using these cells as factories for secretion of proteins. PMID- 21251937 TI - Inhibition of PDGF, TGF-beta, and Abl signaling and reduction of liver fibrosis by the small molecule Bcr-Abl tyrosine kinase antagonist Nilotinib. AB - BACKGROUND & AIMS: Nilotinib is a novel tyrosine kinase inhibitor of Bcr-Abl and other kinases. In this study, we have examined its activity as an anti-fibrotic agent. METHODS: The in vitro effect of Nilotinib on rat and human HSCs was assessed using proliferation assays and Western blotting. The in vivo antifibrotic efficacy of Nilotinib was assessed in mice with liver fibrosis induced by CCl(4) and bile duct ligation (BDL). RESULTS: Nilotinib inhibited proliferation, migration, and actin filament formation, as well as the expression of alpha-SMA and collagen in activated HSCs. Nilotinib induced apoptosis of HSCs, which was correlated with reduced bcl-2 expression, increased p53 expression, cleavage of PARP, as well as increased expression of PPARgamma and TRAIL-R. Nilotinib also induced cell cycle arrest, accompanied by increased expression of p27 and downregulation of cyclin D1. Interestingly, Nilotinib not only inhibited activation of PDGFR, but also TGFRII through Src. Nilotinib significantly inhibited PDGF and TGFbeta-simulated phosphorylation of ERK and Akt. Furthermore, PDGF- and TGFbeta-activated phosphorylated form(s) of Abl in human HSCs were inhibited by Nilotinib. In vivo, Nilotinib reduced collagen deposition and alpha SMA expression in CCl(4) and BDL-induced fibrosis. These beneficial effects were associated with suppressed expression of procollagen-(I), TIMP-1, CD31, CD34, VEGF, and VEGFR. Nilotinib could induce HSC undergoing apoptosis in vivo, which was correlated with downregulation of bcl-2. We also observed reduced expression of phosphorylated ERK, Akt, and Abl in the Nilotinib-treated CCl(4) and BDL livers. In addition to its antifibrotic activity, the drug was hepatoprotective and reduced the elevations of ALT and AST after CCl(4) and BDL. CONCLUSIONS: These studies uncover a novel role of Bcr-Abl activity in treatment of liver fibrosis through multiple mechanisms and indicate that Nilotinib represents a potentially effective antifibrotic agent. PMID- 21251938 TI - Safety of complete and sustained prophylaxis withdrawal in patients liver transplanted for HBV-related cirrhosis at low risk of HBV recurrence. AB - BACKGROUND & AIMS: HBV reactivation after liver transplantation may be related to persistence of covalently closed circular (ccc) DNA. We investigated the safety of HBV prophylaxis withdrawal in selected HBV transplanted patients. METHODS: Thirty patients transplanted 64-195months earlier (23 males, median age 56yrs), HBsAg-positive, HBeAg, and HBV-DNA negative at transplant (43% HCV/HDV co infected), with undetectable intrahepatic total and ccc-DNA were enrolled. All patients underwent HBIg withdrawal and continued lamivudine with monthly HBsAg and HBV-DNA monitoring and sequential liver biopsies. Those with confirmed intrahepatic total and ccc-DNA undetectability 24weeks after stopping HBIg, also underwent lamivudine withdrawal and were followed-up without prophylaxis. RESULTS: Twenty-five patients did not exhibit signs of HBV recurrence after prophylaxis withdrawal (median follow-up 28.7months, range 22-42). Five patients became HBsAg-positive: one early after HBIg withdrawal, the other four after HBIG and lamivudine withdrawal. None of these patients experienced clinically relevant events. In the first patient, HBIg were reinstituted with prompt HBsAg negativization. Of the other four, one remained HBsAg-positive with detectable HBV-DNA and mild ALT elevation and was successfully treated with tenofovir. In the remaining three, HBsAg positivity was transient and followed by anti-HBs seroconversion, thus no antiviral treatment was needed. CONCLUSIONS: Patients with undetectable HBV viremia at transplant and no evidence of intrahepatic total and cccDNA may safely undergo cautious weaning of prophylaxis, showing low rate of HBV recurrence after a 2 year follow-up. Undetectability of intrahepatic ccc DNA may help to identify patients at low-risk of recurrence, yet studies with longer follow-up are needed. PMID- 21251939 TI - Is transient elastography inaccurate in chronic hepatitis B and non-alcoholic fatty liver disease? PMID- 21251940 TI - Ethical, legal, and social implications (ELSI) of microdose clinical trials. AB - A "microdose clinical trial" (microdosing) is one kind of early phase exploratory clinical trial, administering the compound at doses estimated to have no pharmacological or toxicological effects, aimed at screening candidates for further clinical development. This article's objective is to clarify the ethical, legal, and social implications (ELSI) of such an exploratory minimum-risk human trial. The definition and non-clinical study requirements for microdosing have been harmonized among the European Union (EU), United States (US), and Japan. Being conducted according to these regulations, microdosing seems to be ethically well justified in terms of respect for persons, beneficence, justice, human dignity, and animal welfare. Three big projects have been demonstrating the predictability of therapeutic dose pharmacokinetics from microdosing. The article offers suggestions as how microdosing can become a more useful and socially accepted strategy. PMID- 21251941 TI - Project TwEATs. A feasibility study testing the use of automated text messaging to monitor appetite ratings in a free-living population. AB - There are no standardized methods for monitoring appetite in free-living populations. Fifteen participants tested a computer-automated text-messaging system designed to track hunger ratings over seven days. Participants were sent text-messages (SMS) hourly and instructed to reply during waking hours with their current hunger rating. Of 168 SMS, 0.6-7.1% were undelivered, varying by mobile service provider. On average 12 SMS responses were received daily with minor variations by observation day or day of the week. Compliance was over 74%, and 93% of the ratings were received within 30-min. Automated text-messaging is a feasible method to monitor appetite ratings in this population. PMID- 21251942 TI - Evaluation of EPA's Tier 1 Endocrine Screening Battery and recommendations for improving the interpretation of screening results. AB - EPA's Endocrine Disruptor Screening Program (EDSP) was implemented in 2009-2010 with the issuance of test orders requiring manufacturers and registrants of 58 pesticide active ingredients and nine pesticide inert/high production volume chemicals to evaluate the potential of these chemicals to interact with the estrogen, androgen and thyroid hormone systems. The required endocrine screening will be conducted over the next 2-3years. Based on estimates of the impacted sectors, costs are at least $750,000-$1,000,000 per substance if all of the Tier 1 assays must be conducted. The screening will entail evaluation of responses in EPA's Tier 1 Endocrine Screening Battery (EDSP ESB), consisting of 11 distinct in vitro and in vivo assays. We reviewed the details of each test method and describe the critical factors integral to the design and conduct of the EDSP ESB assays as well as the limitations related to specificity and sensitivity. We discuss challenges to evaluating each assay, identify significant shortcomings, and make recommendations to enhance interpretation of results. Factors that affect the length of time necessary to complete the EDSP ESB for any particular substance are presented, and based on the overall analysis, we recommend a sequence for running the EDSP ESB assays. It is imperative that a structured, systematic weight of evidence framework is promptly developed, subjected to peer review and adopted. This will help to ensure an objective analysis of the results of the required EDSP screening, consistent integration of results across the EDSP ESB assays, and consistent decision making as to whether subsequent testing for adverse effects is needed. Based upon the limitations of the current EPA EDSP ESB, we concur with the Agency's Scientific Advisory Panel's recommendation that after the initial set of substances has been screened, the EDSP ESB should pause so that the results can be fully analyzed to determine the value of the existing assays. After this analysis, assays that are unnecessarily redundant or that lack endocrine specificity should be eliminated and if necessary, replaced by new or revised screens that are more mechanistically specific, rapid, reliable, and cost effective. PMID- 21251943 TI - Protective effect of N-acetyl-L-cysteine against maneb induced oxidative and apoptotic injury in Chinese hamster V79 cells. AB - The role of antioxidant N-acetyl-L-cysteine (NAC) in protection against cellular changes triggered by maneb during in vitro exposure was investigated in cultured Chinese hamster V79 cells. We observed high apoptotic activity and high oxidative stress induced by exposure to maneb evidenced by a statistically significant increase in lipid peroxidation (measured as TBARS--thiobarbituric acid reactive substances) as well as a decrease of glutathione (GSH) and glutathione disulfide (GSSG) ratio (GSH/GSSG). Maneb did not exhibit any effect on protein oxidation (measured by protein carbonyls content). NAC suppressed cellular changes induced by maneb in V79 cells. NAC pre-treatment prevented TBARS production and significantly decreased the number of apoptotic cells. However, protective effect of NAC on GSH and GSSG levels has been shown only in cells exposed to lower concentration of maneb (100 MUM). PMID- 21251944 TI - Links between DNA polymerase beta expression and sensitivity to bleomycin. AB - Bleomycin (BLM), an important anti-tumor antibiotic, enables cell death through oxidative DNA damage mediated by reactive oxygen species (ROS). However, increasing cellular resistance has become a serious limitation to its clinical application. Base excision repair (BER), the major pathway for repairing oxidative bases, is involved in resistance of DNA-damaging anticancer drugs. DNA polymerase beta (pol beta), a critical BER enzyme, has been reported to play a crucial role in combating BLM-induced oxidative DNA damage, as a result, pol beta inhibition may increase the sensitivity to BLM. To test this hypothesis, we evaluated the sensitivity to BLM using mouse embryo fibroblasts (MEFs) with distinct pol beta expression levels (wild-type, pol beta deficiency) and explored the underlying mechanisms. The results showed that cell viability of pol beta deficient MEFs was significantly lower than that of isogenic wild type when treated with the same BLM dosage. In addition, increased ROS level, DNA single strand breaks, and chromosomal breakage were observed in pol beta deficient cells, indicating impaired DNA repair and enhanced oxidative DNA damage under pol beta deficiency. In agreement with the findings, an enhanced hprt gene mutation frequency was also detected in pol beta null cells. In summary, this study demonstrated that BLM-induced DNA damage could be repaired through BER pathway and absence of pol beta allows oxidative DNA/chromosome damage and gene mutation, which contributes to BLM hypersensitivity. PMID- 21251945 TI - Effects of the marine toxin palytoxin on human skin keratinocytes: role of ionic imbalance. AB - Palytoxin (PLTX), a marine toxin identified in Palythoa zoanthid corals and Ostreopsis dinoflagellates, represents an increasing hazard for human health. Recently, dermatological problems have been associated to cutaneous exposure to PLTX during Ostreopsis blooms arising the need for experimental data characterizing PLTX effects on the skin. This study highlights in vitro the cytotoxic effects of PLTX on human keratinocytes (HaCaT cell line). A short time exposure (4h) to PLTX reduced mitochondrial activity (MTT assay), cell mass (SRB assay) and plasma membrane integrity (LDH leakage) with different potencies: EC50 values of 6.1 +/- 1.3*10-11, 4.7 +/- 0.9 * 10-10 M and 1.8 +/- 0.1 * 10-8 M, respectively. PLTX effect on mitochondrial activity was ouabain- and Na+ sensitive, but only partially sensitive to removal of Ca2+ ions. One hour exposure to the toxin also induced a Na+-dependent and Ca2+-independent superoxide anion production. These results indicate that among the chain of intracellular events following the interaction of PLTX with the Na+/K+-ATPase the first and crucial step is the increased intracellular Na+ concentration that triggers a sequence of cell dysfunction involving mitochondrial affection and oxidative stress, leading to an irreversible cell death. The PLTX concentrations inducing cytotoxicty seem to be lower than those of potential cutaneous human exposure during Ostreopsis ovata blooms, indicating the harmful potential of the toxin. PMID- 21251946 TI - alpha-Lipoic acid inhibits liver fibrosis through the attenuation of ROS triggered signaling in hepatic stellate cells activated by PDGF and TGF-beta. AB - Reactive oxygen species (ROS) have been implicated in hepatic stellate cell activation and liver fibrosis. We previously reported that alpha-lipoic acid (LA) and its reduced form dihydrolipoic acid (DHLA) inhibited toxicant-induced inflammation and ROS generation. In the present study, we further examined the effects of LA/DHLA on thioacetamide (TAA)-induced liver fibrosis in rats and the possible underlying mechanisms in hepatic stellate cells in vitro. We found that co-administration of LA to rats chronically treated with TAA inhibited the development of liver cirrhosis, as indicated by reductions in cirrhosis incidence, hepatic fibrosis, and AST/ALT activities. We also found that DHLA inhibited TGF-beta/PDGF-stimulated HSC-T6 activation and ROS generation. These effects could be mediated by the MAPK and PI3K/Akt pathways. According to our current results, LA may have a beneficial role in the treatment of chronic liver diseases caused by ongoing hepatic damage. PMID- 21251947 TI - Disrupting effects of bifenthrin on ovulatory gene expression and prostaglandin synthesis in rat ovarian granulosa cells. AB - Synthetic pyrethroids (SPs) are one of the most frequently and widely used classes of pesticides. Although exposure to SPs is associated with reproductive toxicity in mammals, limited information is available regarding the effects of SPs on female ovulatory function. Bifenthrin (BF), a broad-spectrum type I SP, has been widely used for pest control for two decades. Previous studies showed that BF had estrogen-like activity as an endocrine-disrupting chemical. In this work, we showed the in vitro inhibitory effects of BF on luteinizing hormone (LH) inducible ovulatory gene expression in rat ovarian granulosa cells, including genes P450scc, StAR, PR, AREG, EREG, TGF-beta1, C/EBP beta, RUNX1, p21, cyclin E1, CYP19a1, SULT1E1 and PTGS2. Our in vivo studies demonstrated that short-term administration of BF to gonadotropin-primed rats disrupted the expression of LH responsible ovulatory genes, suggesting that BF has similar disrupting effects on in vitro and in vivo LH signaling. Because prostaglandins and their key synthetic enzyme PTGS2 play pivotal roles in ovulatory process, we further investigated the molecular mechanism of disruption of PTGS2 by BF. Importantly, we found that BF blocked LH-inducible prostaglandin E2 (PGE2) accumulation in cultured medium of granulosa cells. Forskolin stimulated PTGS2 expression was decreased by treatment with BF, indicating that BF may inhibit LH-induced PTGS2 expression through the protein kinase A (PKA)-mediated signaling pathway. In addition, the reduction in transcriptional activity of forskolin-stimulated PTGS2 promoter by BF, indicates that BF blocks the expression of PTGS2 gene at the transcriptional level. Taken together, our present study firstly shows the systemic disrupting effects of BF on the network of ovulatory gene expression patterns as well as prostaglandin synthesis, and suggest that exposure to BF may increase the risk of ovulatory dysfunction in females. PMID- 21251948 TI - PFOS prenatal exposure induce mitochondrial injury and gene expression change in hearts of weaned SD rats. AB - Xenobiotics exposure in early life may have adverse effects on animals' development through mitochondrial injury or dysfunction. The current study demonstrated the possibility of cardiac mitochondrial injury in prenatal PFOS exposed weaned rat heart. Pregnant Sprague-Dawley (SD) rats were exposed to perfluorooctane sulfonate (PFOS) at doses of 0.1, 0.6 and 2.0 mg/kg/d and 0.05% Tween 80 as control by gavage from gestation days 2-21. The dams were allowed to give nature delivery and then heart tissues from weaned (postnatal day 21) offspring rats were analyzed for mitochondrial injury through ultrastructure observation by electron microscope, global gene expression profile by microarray, as well as related mRNA and proteins expression levels by quantitative PCR and western blot. Ultrastructural analysis revealed significant vacuolization and inner membrane injury occurred at the mitochondria of heart tissues from 2.0 mg/kg/d dosage group. Meanwhile, the global gene expression profile showed significant difference in level of some mRNA expression associated with mitochondrial function at 2.0 mg/kg/d dosage group, compared to the control. Furthermore, dose-response trends for the expression of selected genes were analyzed by quantitative PCR and western blot analysis. The selected genes were mainly focused on those encoding for proteins involved in energy production, control of ion levels, and maintenance of heart function. The down-regulation of mitochondrial ATP synthetase (ATP5E, ATP5I and ATP5O) implicated a decrease in energy supply. This was accompanied by down-regulation of gene transcripts involved in energy consumption such as ion transporting ATPase (ATP1A3 and ATP2B2) and inner membrane protein synthesis (SLC25A3, SLC25A4, SLC25A10, SLC25A29). The up-regulation of gene transcripts encoding for uncoupling proteins (UCP1 and UCP3), epidermal growth factor receptor (EGFR) and connective tissue growth factor (CTGF), was probably a protective process to maintain heart function. The results indicate PFOS prenatal exposure can induce cardiac mitochondrial injury and gene transcript change, which may be a significant mechanism of the developmental toxicity of PFOS to rat. PMID- 21251949 TI - Activity profiles of 309 ToxCastTM chemicals evaluated across 292 biochemical targets. AB - Understanding the potential health risks posed by environmental chemicals is a significant challenge elevated by the large number of diverse chemicals with generally uncharacterized exposures, mechanisms, and toxicities. The present study is a performance evaluation and critical analysis of assay results for an array of 292 high-throughput cell-free assays aimed at preliminary toxicity evaluation of 320 environmental chemicals in EPA's ToxCastTM project (Phase I). The chemicals (309 unique, 11 replicates) were mainly precursors or the active agent of commercial pesticides, for which a wealth of in vivo toxicity data is available. Biochemical HTS (high-throughput screening) profiled cell and tissue extracts using semi-automated biochemical and pharmacological methodologies to evaluate a subset of G-protein coupled receptors (GPCRs), CYP450 enzymes (CYPs), kinases, phosphatases, proteases, HDACs, nuclear receptors, ion channels, and transporters. The primary screen tested all chemicals at a relatively high concentration 25 MUM concentration (or 10 MUM for CYP assays), and a secondary screen re-tested 9132 chemical-assay pairs in 8-point concentration series from 0.023 to 50 MUM (or 0.009-20 MUM for CYPs). Mapping relationships across 93,440 chemical-assay pairs based on half-maximal activity concentration (AC50) revealed both known and novel targets in signaling and metabolic pathways. The primary dataset, summary data and details on quality control checks are available for download at http://www.epa.gov/ncct/toxcast/. PMID- 21251950 TI - Formation of protein complexes containing plant virus movement protein TGBp3 is necessary for its intracellular trafficking. AB - Cell-to-cell movement of Poa semilatent virus (genus Hordeivirus) in infected plants is mediated by three viral 'triple gene block' (TGB) proteins. One of those termed TGBp3 is an integral membrane protein essential for intracellular transport of other TGB proteins and viral genomic RNA to plasmodesmata. TGBp3 targeting to plasmodesmata-associated sites is believed to involve an unconventional mechanism which does not employ endoplasmic reticulum-derived transport vesicles. Previously TGBp3 has been shown to contain a composite transport signal consisting of the central hydrophilic protein region which includes a conserved pentapeptide YQDLN and the C-terminal transmembrane segment. This study demonstrates that these TGBp3 structural elements have distinct functions in protein transport. The YQDLN-containing region is essential for TGBp3 incorporation into high-molecular-mass protein complexes. In transient expression assay formation of such complexes is necessary for entering the TGBp3 specific pathway of intracellular transport and protein delivery to plasmodesmata associated sites. In virus-infected plants TGBp3 is also found predominantly in the form of high-molecular-mass complexes. When the complex-formation function of YQDLN-containing region is disabled by a mutation, targeting to plasmodesmata associated sites can be complemented by a heterologous peptide capable of formation multimeric complexes. The C-terminal transmembrane segment is found to be an essential signal of TGBp3 intracellular transport to peripheral sites. PMID- 21251951 TI - Mitochondrial DNA replication and OXPHOS gene transcription show varied responsiveness to Rieske protein knockdown in 143B cells. AB - Genetic, biochemical and phenotypic diversity is a hallmark of OXPHOS deficiencies. Among the responses frequently reported for these deficiencies is differential expression of several genes involved in mitochondrial biogenesis. These responses are often associated with elevated oxygen radical production. The genetic diversity of tissue and cell lines used in these investigations, however, complicates the interpretation of observations. We investigated mtDNA copy number and selected transcriptional responses after inducing stable Rieske protein knockdown in 143B cells. Despite the significant loss of complex III activity, hydrogen peroxide levels remained comparable to controls. Furthermore, no significant change in mtDNA copy number was observed. Mitochondrial L-strand- and D-loop transcript levels remained unchanged, while the H-strand transcript for COXII was reduced. With the exception of mitochondrial single-stranded binding protein (mtSSB), which was reduced, no transcriptional changes of the mtDNA replication and transcription machinery were observed. Notably however, a selection of nuclear-encoded OXPHOS gene transcripts was generally reduced (statistically insignificant), except for NDUFS3 and COX4I1 transcripts, which were significantly reduced. From these results we conclude that the induction of a low superoxide producing complex III deficiency in 143B cells has an insignificant effect on mtDNA replication and function, but that expression of OXPHOS genes is generally down regulated. This may indicate a lowering of mitochondrial biogenesis and a shift towards anaerobic energy metabolism to improve cellular survival. PMID- 21251952 TI - HT-29 colorectal cancer cells undergoing apoptosis overexpress COX-2 to delay ursolic acid-induced cell death. AB - Colorectal cancer is one of the most common cancer types and the third leading cause of cancer-related death in the western world. Generally, colorectal cancers are resistant to anticancer drugs. Several lines of evidence support a critical role for cyclooxygenase-2 (COX-2) during colorectal tumorigenesis and its role in chemoresistance. In this study, we focused our interest on the role played by COX 2 in apoptosis induced in HT-29 human colorectal cancer cells by ursolic acid (UA), a triterpenoid found in a large variety of plants. We showed that UA induced apoptosis and that COX-2 was overexpressed only in apoptotic cells. We demonstrated that this overexpression was mediated by the p38 MAP kinase pathway as inhibiting its activation using a p38-specific inhibitor, SB 203580, abrogated COX-2 expression. Inhibiting COX-2 expression either by using a p38-specific inhibitor or COX-2-specific siRNA increased apoptosis. These results demonstrated that COX-2 was involved in a resistance mechanism to UA-induced apoptosis in HT 29 cells. Cells undergoing apoptosis were able to trigger a resistance mechanism by overexpressing a protein such as COX-2 to delay their death. Furthermore, we demonstrated that this resistance mechanism was independent of PGE(2) production as the addition of the specific COX-2 activity inhibitor, NS-398, did not affect apoptosis in UA-treated cells. PMID- 21251953 TI - Modulation of neuronal stem cell differentiation by hypoxia and reactive oxygen species. AB - Low oxygen concentrations (hypoxia) occur in several physiological and pathological cellular situations such as embryogenesis and stem cell modulation (in terms of differentiation/proliferation), or ischemic stroke and cancer. On the other side of the coin, the generation of reactive oxygen species (ROS) is tightly controlled by the cell. ROS control redox sensitive signaling pathways and thus regulate cell physiology, such as programmed cell death, inflammation and/or stem cell modulation. Herein we analyze the role of hypoxia and ROS in the modulation of neuronal differentiation focusing on: (i) in vivo neurogenesis and (ii) in vitro neuronal differentiation from neural stem/precursor cells. In vivo, hypoxia promotes neurogenesis in embryos, newborns and adults, as well as in response to noxious stimuli such as ischemia. On the other hand, oxygen and ROS also play a role in in vitro neuronal differentiation. They further impact tumor growth by influencing cell proliferation and differentiation, such as in neuroblastoma development. Therefore, manipulating hypoxia and ROS production represents a useful therapeutic tool if one needs either to enhance or to modulate neurogenesis and neuronal differentiation, such as in cell replacement or in malignant cell proliferation. PMID- 21251954 TI - In vivo and in vitro evaluation of the residual allergenicity of partially hydrolysed infant formulas. AB - Hypoallergenic infant formulas are commonly used for genetically predisposed children and infants diagnosed with cow's milk allergy. This study describes both in vitro and in vivo approaches to assess residual allergenicity of partially hydrolysed infant formulas. Electrophoretic patterns indicated that beta lactoglobulin and other whey proteins were largely degraded. For safety reasons, according to the European commission-guidelines, it is required that the sensitizing capacity of hypoallergenic formulas is tested in an animal model. In contrast to whey sensitization, no elevated levels of whey-specific IgE, anaphylactic reactions or drop in body temperature were observed in sensitized mice exposed to whey hydrolysates. This indicates that the whey hydrolysates lost their putative sensitizing capacity in a mouse model using oral sensitization, which is highly relevant in relation to the human situation. In combination with the lost capacity of hydrolysed infant formulas to cross-link human IgE antibodies on RBL-huFcERI in vitro, both the sensitization and the challenge phase of the allergic response were studied. This combination of assays is proposed as a strategy for the screening of new hypoallergenic formulas aimed at preventing sensitization in atopic children and avoiding clinical symptoms in infants suffering from cow's milk allergy. PMID- 21251955 TI - Permethrin modulates cholinergic mini-synaptic currents by partially blocking the calcium channel. AB - Pyrethroid insecticide modulation of the voltage-gated sodium channel (VGSC) is proposed to underlie their effects on neuronal excitability by inhibiting channel inactivation and increasing channel open time. However, some in vitro evidences indicate that target sites other than VGSCs could contribute to pyrethroid disruption of neuronal activity. Cholinergic excitability in Drosophila, as in other insects and mammals, is important for activity in the central nervous system. The effects of permethrin, a putative calcium antagonist, on calcium current and cholinergic mini-synaptic transmission were investigated in the Drosophila brain. At concentration of 2.5MUM, permethrin significantly decreased the calcium current and cholinergic mini-synaptic current. However, the permethrin could not antagonize the calcium current completely. Removal of calcium from the external solution produced a significant decrease of cholinergic mini-synaptic transmission. The results are consistent with the hypothesis that permethrin may modulate cholinergic mini-synaptic currents by partially blocking the calcium channel. PMID- 21251956 TI - The fragility of omics risk and benefit perceptions. AB - How do individuals judge the risks and benefits of toxicogenomics, an emerging field of research which is completely unfamiliar to them? The hypothesis is that individuals' perceptions of the risks and benefits of toxicogenomics are fragile and can by influenced by different issues and context framings as a technology. The researchers expected that the effects on risk and benefit judgements would differ between lay individuals and experts in toxicogenomics. A 2*2*2 experiment that encompassed three factors was conducted. The first factor, issue framing incorporated the field of application for the technology (therapy vs. diagnosis setting). The second factor, context framing included organisations and institutions that would profit from the technology (companies vs. regulatory agencies) and the third factor encompasses the quality of individuals' level of knowledge, for example lay vs. expert knowledge. Research results suggest the differential power of framing effects. It seems that the clues provided by context frames - but not by issue frames - are able to influence the ways in which lay people and experts process information. The findings are interpreted in the line of the fuzzy trace theory that predicts reliance on fuzzy gist representations formed by stereotypes on a wide range of judgement problem including risk and benefit perceptions. PMID- 21251957 TI - Modeling of drug release from matrix systems involving moving boundaries: approximate analytical solutions. AB - The purpose of this review is to provide an overview of approximate analytical solutions to the general moving boundary diffusion problems encountered during the release of a dispersed drug from matrix systems. Starting from the theoretical basis of the Higuchi equation and its subsequent improvement and refinement, available approximate analytical solutions for the more complicated cases involving heterogeneous matrix, boundary layer effect, finite release medium, surface erosion, and finite dissolution rate are also discussed. Among various modeling approaches, the pseudo-steady state assumption employed in deriving the Higuchi equation and related approximate analytical solutions appears to yield reasonably accurate results in describing the early stage release of a dispersed drug from matrices of different geometries whenever the initial drug loading (A) is much larger than the drug solubility (C(s)) in the matrix (or A?C(s)). However, when the drug loading is not in great excess of the drug solubility (i.e. low A/C(s) values) or when the drug loading approaches the drug solubility (A->C(s)) which occurs often with drugs of high aqueous solubility, approximate analytical solutions based on the pseudo-steady state assumption tend to fail, with the Higuchi equation for planar geometry exhibiting a 11.38% error as compared with the exact solution. In contrast, approximate analytical solutions to this problem without making the pseudo-steady state assumption, based on either the double-integration refinement of the heat balance integral method or the direct simplification of available exact analytical solutions, show close agreement with the exact solutions in different geometries, particularly in the case of low A/C(s) values or drug loading approaching the drug solubility (A->C(s)). However, the double-integration heat balance integral approach is generally more useful in obtaining approximate analytical solutions especially when exact solutions are not available. PMID- 21251958 TI - Preparation of Tacrolimus loaded micelles based on poly(E-caprolactone) poly(ethylene glycol)-poly(E-caprolactone). AB - Self-assembled polymeric micelles are widely applied in drug delivery system. In this study, Tacrolimus (FK506) loaded micelles were prepared based on biodegradable poly(E-caprolactone)-poly(ethylene glycol)-poly(E-caprolactone) (PCEC) copolymers. Micelles were prepared by self-assembly of triblock copolymer PCEC in distilled water triggered by its amphiphilic characteristics. Drug loading and encapsulation efficiency were determined by adjusting the weight ratio of FK506 and PCEC. The particle size distribution and variation of obtained micelles were determined using Malvern laser particle size analyzer, while the spherical geometry was observed on transmission electron microscope (TEM), and the crystallographic assays were fulfilled by X-ray diffractometer (XRD). Besides, in vitro release profile demonstrated a significant difference between rapid release of free Tacrolimus and much slower and sustained release of FK506 loaded micelles. These results suggested that we have successfully prepared Tacrolimus loaded micelles in an improved method which is safer and more efficient. The prepared micelles might be potential carriers for Tacrolimus delivery in immunosuppressive therapy. PMID- 21251959 TI - Preparation and characterization of liposomal formulations of neurotensin degrading enzyme inhibitors. AB - Neurotensin-degrading enzyme (NTDE) inhibitors hold great potential for treating psychotic disorders. However, brain uptake of such compounds in vivo is generally low due to the presence of the blood-brain barrier. In this study, liposomal formulations of two NTDE inhibitors, named compound 1 (C1) and compound 2 (C2) were prepared. Association of these compounds with the liposomal bilayer, subsequent liposomal stability, and compound release in the presence of albumin was studied. Entrapment of the compounds in the liposomal bilayer showed the solubilizing properties of the liposomes. Size and polydispersity index of the compound-entrapped liposomes did not change over 1 month, showing colloidal stability of the liposomal drug formulations. The amount of compounds associated with the liposomes decreased within one day. After this, the association remained stable at 4 degrees C. For C1, association remained stable at 37 degrees C in HEPES buffered saline, and the compound was gradually released in the presence of bovine serum albumin. For C2, the release was rapid in both HBS and BSA at 37 degrees C. In conclusion, the formulation of NTDE inhibitors C1 and C2 in liposomes has been demonstrated and holds promise to deliver NTDE inhibitors in vivo. PMID- 21251960 TI - Selegiline-functionalized, PEGylated poly(alkyl cyanoacrylate) nanoparticles: Investigation of interaction with amyloid-beta peptide and surface reorganization. AB - Alzheimer's disease (AD) is a neurodegenerative disorder for which the research of new treatments is highly challenging. Since the fibrillogenesis of amyloid beta peptide 1-42 (Abeta(1-42)) peptide is considered as a major cause of neuronal degeneration, specific interest has been focused on aromatic molecules for targeting this peptide. In this paper, the synthesis of selegiline functionalized and fluorescent poly(alkyl cyanoacrylate) nanoparticles (NPs) and their evaluation for the targeting of the Abeta(1-42) peptide are reported. The synthetic strategy relied on the design of amphiphilic copolymers by tandem Knoevenagel-Michael addition of cyanoacetate derivatives, followed by their self assembly in aqueous solutions to give the corresponding NPs. Different cyanoacetates were used: (i) hexadecyl cyanoacetate (HDCA) to form the hydrophobic core of the NPs; (ii) rhodamine B cyanoacetate (RCA) for fluorescent purposes; (iii) methoxypoly(ethylene glycol) cyanoacetate (MePEGCA) for stealth properties and (iv) selegiline-poly(ethylene glycol) cyanoacetate (SelPEGCA) to obtain the desired functionality. Two different amphiphilic copolymers were synthesized, a selegiline-containing copolymer, P(MePEGCA-co-SelPEGCA-co-HDCA), and a rhodamine-labelled counterpart, P(MePEGCA-co-RCA-co-HDCA), further blended at variable ratios to tune the amount of selegiline moieties displayed at the surface of the NPs. Optimal formulations involving the different amphiphilic copolymers were determined by the study of the NP colloidal characteristics. Interestingly, it was shown that the zeta potential value of the selegiline functionalized nanoparticles dramatically decreased, thus emphasizing a significant modification in the surface charge of the nanoparticles. Capillary electrophoresis has then been used to test the ability of the selegiline functionalized NPs to interact with the Abeta(1-42) peptide. In comparison with non functionalized NPs, no increase of the interaction between these functionalized NPs and the monomeric form of the Abeta(1-42) peptide was observed, thus highlighting the lack of availability of the ligand at the surface of the nanoparticles. A mechanism explaining this result has been proposed and was mainly based on the burial of the hydrophobic selegiline ligand within the nanoparticles core. PMID- 21251961 TI - Opto-Thermal Transient Emission Radiometry (OTTER) to image diffusion in nails in vivo. AB - This work describes the first application of Opto-Thermal Transient Emission Radiometry (OTTER), an infrared remote sensing technique, to probe the extent to which solvents permeate the human nail in vivo. Decanol, glycerol and butyl acetate were selected as model solvents. After application of the solvents, individually, to human volunteers, OTTER was used to depth profile the solvents. The permeation rate of the solvents was ranked as glycerol>decanol>butyl acetate. It is possible that some of the butyl acetate may have evaporated during the experiment. The ability of decanol to extract lipids from biological tissue is also considered. These preliminary results demonstrate the potential of OTTER as a tool to identify optimal excipients with which to target drugs to the nail. PMID- 21251962 TI - Decoration of fibrinogen gamma-chain peptide on adenosine diphosphate encapsulated liposomes enhances binding of the liposomes to activated platelets. AB - For the purpose of efficient hemostasis, we previously developed ADP-encapsulated liposomes modified with a dodecapeptide (HHLGGAKQAGDV, H12), H12-(ADP)Lipo. This liposome actually enhanced platelet aggregation in vitro, and showed significant hemostatic effect in vivo. Since fibrinogen (Fbg) is abundant in the bloodstream, it is unclear why this liposome binds platelets so efficiently, overcoming the competition with Fbg. Therefore, we investigated the relationship between H12 density on the liposome and the binding ability to platelets, and evaluated the inhibitory effect of Fbg on the binding of H12-(ADP)Lipo to platelets. As a result, the binding ability to platelets steeply increased depending on H12 density until it reached about 3*10(15) H12 molecules/m(2). The 50% inhibition concentration of Fbg on the binding of H12-(ADP)Lipo to platelets was about 25 fold over the concentration of H12 molecules on the liposome. Moreover, almost no inhibition by Fbg was observed at the physiological concentration of it. This result suggests that the ability of H12 to bind to GPIIb/IIIa increased overwhelmingly by the anchoring to the liposome that enabled the cooperative binding of H12 peptides to the platelets. PMID- 21251963 TI - Time-oriented experimental design method to optimize hydrophilic matrix formulations with gelation kinetics and drug release profiles. AB - A new experimental design methodology was developed by integrating the response surface methodology and the time series modeling. The major purposes were to identify significant factors in determining swelling and release rate from matrix tablets and their relative factor levels for optimizing the experimental responses. Properties of tablet swelling and drug release were assessed with ten factors and two default factors, a hydrophilic model drug (terazosin) and magnesium stearate, and compared with target values. The selected input control factors were arranged in a mixture simplex lattice design with 21 experimental runs. The obtained optimal settings for gelation were PEO, LH-11, Syloid, and Pharmacoat with weight ratios of 215.33 (88.50%), 5.68 (2.33%), 19.27 (7.92%), and 3.04 (1.25%), respectively. The optimal settings for drug release were PEO and citric acid with weight ratios of 191.99 (78.91%) and 51.32 (21.09%), respectively. Based on the results of matrix swelling and drug release, the optimal solutions, target values, and validation experiment results over time were similar and showed consistent patterns with very small biases. The experimental design methodology could be a very promising experimental design method to obtain maximum information with limited time and resources. It could also be very useful in formulation studies by providing a systematic and reliable screening method to characterize significant factors in the sustained release matrix tablet. PMID- 21251964 TI - The application of monolayer studies in the understanding of liposomal formulations. AB - The study of surfactant monolayers is certainly not a new technique, but the application of monolayer studies to elucidate controlling factors in liposome design remains an underutilised resource. Using a Langmuir-Blodgett trough, pure and mixed lipid monolayers can be investigated, both for their interactions within the monolayer, and for interfacial interactions with drugs in the aqueous sub-phase. Despite these monolayers effectively being only half a bilayer, with a flat rather than curved structure, information from these studies can be effectively translated into liposomal systems. Here we outline the background, general protocols and application of Langmuir studies with a focus on their application in liposomal systems. A range of case studies are discussed which show how the system can be used to support its application in the development of liposome drug delivery. Examples include investigations into the effect of cholesterol within the liposome bilayer, understanding effective lipid packaging within the bilayer to promote water soluble and poorly soluble drug retention, the effect of alkyl chain length on lipid packaging, and drug-monolayer electrostatic interactions that promote bilayer repackaging. PMID- 21251965 TI - Development of gene therapy for inner ear disease: Using bilateral vestibular hypofunction as a vehicle for translational research. AB - Despite the significant impact of hearing and balance disorders on the general population there are currently no dedicated pharmaceuticals that target the inner ear. Advances in molecular biology and neuroscience have improved our understanding of the inner ear allowing the development of a range of molecular targets that have the potential to treat both hearing and balance disorders. One of the principal advantages of the inner ear is that it is accessible through a variety of approaches that would allow a potential to be delivered locally rather than systemically. This significantly broadens the potential medications that can be developed and opens the possibility of local gene delivery as a therapeutic intervention. Several potential clinical targets have been identified including delivery of neurotrophin expressing genes as an adjunct to cochlear implantation, delivery of protective genes to prevent trauma and the development of strategies for regenerating inner ear sensory cells. In order to translate these potential therapeutics into humans we will want to optimize the gene delivery methodology, dosing and activity of the drug for therapeutic value. To this end we have developed a series of adenovectors that efficiently transduce the inner ear. The use of these gene delivery approaches are attractive for the potential of hair cell regeneration after loss induced by trauma or ototoxins. This approach is particularly suited for the development of molecular therapies targeted at the vestibular system given that no device based therapeutic such a cochlear implant available for vestibular loss. PMID- 21251966 TI - Ethnobotanical study of medicinal plants utilised by Hani ethnicity in Naban River Watershed National Nature Reserve, Yunnan, China. AB - AIM OF THE STUDY: This study was conducted in the Naban River Watershed National Nature Reserve to identify and analyse knowledge and use of wild plants for medicinal purposes by Hani ethnicity and to search out culturally as well as economically important plant species and land use types. MATERIAL AND METHODS: Ethnobotanical data was collected using freelisting interviews with randomly selected informants and semi-structured as well as field interviews. Plant specimens were collected, identified and deposited at the Herbarium of Xishuangbanna Tropical Botanical Garden, Mengla, Yunnan Province, China. Data were analysed by use-reports, in addition important indices like relative frequency of citation (RFC) and cultural importance index (CI) were calculated. Smith's salience index was assessed using Anthropac 4.08. Consensus analysis was applied to measure informant agreement on plants used in different medicinal use categories. RESULTS: A total of 199 medicinal plants belonging to 73 families were recorded. Dominant families are Asteraceae (5.5%), Piperaceae and Verbenaceae (4.5%), Fabaceae, Liliaceae (4.0%) and Euphorbiaceae, Lamiaceae and Solanaceae (3.5%). Most culturally salient species from freelisting analysis were Dendrobium crepidatum Lindl. ex Paxt. (Smith's SI=0.41), Aristolochia sp. (0.306), Microstegium ciliatum (Trin.) A. Camus (0.129), Eupatorium coelestinum L. (0.119), Litsea martabanica (Kurz) Hook. F. (0.116) and Psidium guajava L. (0.103). The majority of the utilised species were collected from forest (51.9%), followed by fallow land (22.52%), arable fields (14.5%), and homegardens (11.08%). CONCLUSIONS: It became clear that the knowledge of medicinal plants is not homogenously distributed among Hani. Based on the percentage of collected medicinal plants from four habitat types, forest is the most important source of medicinal plants for Hani but when considering the cultural importance of species it seems that homegardens are slightly more important than other habitats. PMID- 21251967 TI - Inhibitory effects of casticin on migration of eosinophil and expression of chemokines and adhesion molecules in A549 lung epithelial cells via NF-kappaB inactivation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The fruits of Vitex rotundifolia L. have long been used for the treatment of inflammation of the respiratory tract in East Asia. AIM: To determine if casticin, one of the constituents of Vitex rotundifolia L., has anti-allergic and anti-inflammatory effects in asthma. MATERIALS AND METHODS: The in vitro anti-inflammatory activity of casticin was studied in A549 human type II-like epithelial lung cells using an eotaxin inhibition assay. Additionally, its effects on eotaxin, regulated on activation normal T cell expressed and secreted (RANTES), vascular cell adhesion molecule (VCAM)-1, and inter-cellular adhesion molecule (ICAM)-1 expression were investigated by real time-polymerase chain reaction (real time-PCR). The inhibition of nuclear factor kappaB (NF-kappaB) activity in the presence of casticin was determined by analyzing confocal microscopy images of fluorescence immunocytochemical analysis while the suppression of inhibitory kappaB (IkappaB) alpha phosphorylation was studied using Western blot analysis. Finally, the inhibitory effect of casticin on eosinophil migration toward prestimulated A549 cell media was measured using the human eosinophilic leukemia cell line. RESULTS AND DISCUSSION: Casticin significantly suppressed eotaxin production in cytokine activated A549 lung epithelial cells. Casticin also suppressed the mRNA expression levels of eotaxin, RANTES, VCAM-1, and ICAM-1, which subsequently contributed to the inhibition of eosinophil migration. Furthermore, casticin inhibited IkappaB-alpha phosphorylation and nuclear translocation of p65 in A549 cells. CONCLUSION: Casiticin inhibited the eosinophil migration and activity of chemokines and adhesion molecules involved in the inflammatory process of asthma by suppressing the NF-kappaB pathway. These results suggest that casticin has the potential for use in the treatment of allergic asthma. PMID- 21251968 TI - Macroscopic identification of Chinese medicinal materials: traditional experiences and modern understanding. AB - Authentication is fundamental for the standardization of Chinese Materia Medica. Macroscopic identification, an important method of authentication, has a long history rooted in practice and experience over generations. In ancient times, macroscopic features were used not only to identify the genuineness, but also to evaluate the quality of Chinese medicinal materials (CMMs). In many ancient documents, picturesque terms were used to describe the quality of certain specific CMMs. These traditional macroscopic descriptions used for identification are filled with characteristics, quality descriptions, and specifications of CMM that need to be confirmed by modern scientific analysis. In this paper, the essential and fundamental components of macroscopic identification are introduced. As the quality and macroscopic characteristics of CMM are traditionally thought to be closely related, modern scientific approaches to confirm the validity of these associations are discussed. This review clarifies the role of macroscopic features in the quality assessment of CMM. PMID- 21251969 TI - Evaluation of anticancer activity of ethanol extract of Sesbania grandiflora (Agati Sesban) against Ehrlich ascites carcinoma in Swiss albino mice. AB - ETHNO PHARMACOLOGICAL RELEVANCE: The plant Sesbania grandiflora (Fabaceae) is commonly known as "Sesbania" and "agathi" in ayurvedic system of medicine and reputed in the indigenous medicine in India. It is also known as "Agati Sesban" or "humming bird tree" in English. All parts of this unique plant are useful and have a wide spectrum of medicinal properties. The plant has various uses in folk and traditional medicines for headache, swellings, anemia, bronchitis, pains, liver disorders and tumors. AIM OF THE STUDY: The objective of the present study was to explore the anticancer activity of the ethanol extract of Sesbania grandiflora against Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice. MATERIALS AND METHODS: Anticancer activity of ethanol extract of Sesbania grandiflora (EESG) of both leaves and flowers were evaluated in Swiss albino mice against Ehrlich Ascites Carcinoma (EAC) cell line at the doses of 100 and 200mg/kg body weight intraperitoneally. The extracts were administered for 14 consecutive days. Twenty-four hours of last dose and 18 h of fasting, the mice were sacrificed and the anticancer effect of EESG was assessed by evaluating tumor volume, viable and nonviable tumor cell count, tumor weight, hematological parameters and biochemical parameters of EAC bearing host. RESULTS: Sesbania grandiflora extracts showed significant decrease in (p<0.01) tumor volume, viable cell count, tumor weight and elevated the life span of EAC bearing mice. Hematological profile such as RBC, hemoglobin and lymphocyte count reverted to normal level in EESG treated mice. The extracts significantly (p<0.05) decreased the levels of lipid peroxidation and significantly (p<0.05) increased the levels of GSH, SOD and CAT. CONCLUSION: The results showed that the ethanol extract of Sesbania grandiflora was effective in inhibiting the tumor growth in ascitic models and that is comparable to 5-Fluorouracil. PMID- 21251970 TI - Suppressive effects of methoxyflavonoids isolated from Kaempferia parviflora on inducible nitric oxide synthase (iNOS) expression in RAW 264.7 cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The rhizomes of Kaempferia parviflora Wall. ex Baker have been traditionally used in Thailand to treat abscesses, gout, and peptic ulcers. AIM: Previously, we reported that the chloroform fraction of a Kaempferia parviflora extract had an inhibitory effect on rat paw-edema. In the present study, we isolated the constituents of this fraction and investigated the anti-inflammatory mechanism against nitric oxide (NO) production, tumor necrosis factor-alpha (TNF-alpha) and the expression of inducible nitric oxide synthase (iNOS) as well as phosphorylated extracellular signal-regulated kinase (p-ERK), and phosphorylated c-Jun N-terminal kinase (p-JNK). In addition, effects of trimethylapigenin (4) on the enzyme activities of protein kinases possibly leading to iNOS expression were examined to clarify the targets. MATERIALS AND METHODS: The chloroform fraction was isolated using silica gel column chromatography and HPLC. Isolated compounds were tested against NO and TNF-alpha using RAW264.7 cells. Cytotoxicity and iNOS, p-ERK and p-JNK expression were also examined. RESULTS: Three active components, 5,7-dimethoxyflavone (2), trimethylapigenin (4), and tetramethylluteolin (5), markedly inhibited the production of NO in lipopolysaccharide (LPS)-activated RAW264.7 cells. Compounds 2, 4, and 5 moderately inhibited production of TNF-alpha. Compounds 2, 4, and 5 strongly inhibited expression of iNOS mRNA and iNOS protein in a dose-dependent manner, but did not inhibit p-ERK or p-JNK protein expression. The most active compound, 4, did not inhibit the enzyme activity of inhibitor of kappaB kinases or mitogen-activated protein kinases, but inhibited that of spleen tyrosine kinase (SYK). CONCLUSION: The mechanism responsible for the anti-inflammatory activity of methoxyflavonoids from the chloroform fraction of the rhizomes of Kaempferia parviflora is mainly the inhibition of iNOS expression, and the inhibition of SYK by 4 may be involved in the suppression of LPS-induced signaling in macrophages. PMID- 21251971 TI - Morus bombycis Koidzumi extract suppresses collagen-induced arthritis by inhibiting the activation of nuclear factor-kappaB and activator protein-1 in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Morus bombycis Koidzumi is widely distributed in Asia. In Korea, it has been used in traditional medicine because of its apparent anti-inflammatory, antioxidant, and hepatoprotective properties. AIM OF THE STUDY: Although the extract of Morus bombycis Koidzumi (MB) has long since been used as a traditional anti-inflammatory medicine in Korea, its effect on arthritis remains unknown. We aimed to investigate the anti-arthritis activity of MB and the mechanism underlying it. MATERIALS AND METHODS: The anti-arthritis activity of MB was assessed by using mouse models of type II collagen-induced arthritis (CIA). The clinical arthritis index and histopathological changes were evaluated in mice. Reverse transcriptase-polymerase chain reaction (RT-PCR), electrophoretic mobility shift assay (EMSA), and other biologic approaches were used for measuring the effect of MB on arthritis and understanding the underlying mechanism. RESULTS: MB significantly decreased the clinical arthritis index in CIA mice; this was confirmed by examining histological changes in joints. Infiltration of immune cells, synovial hyperplasia, cartilage destruction, and bone erosion in the hind paw were largely suppressed by MB. The mRNA levels of matrix metalloproteinase (MMP)-1/MMP-3, inflammatory cytokines (tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6), and chemokines (macrophage inflammatory protein (MIP)-1, monocyte chemoattractant protein (MCP)-1, RANTES) were significantly suppressed by MB in a dose-dependent manner. The number of osteoclasts in the hind tibia was also significantly decreased. With regard to the mechanism, MB suppressed the activation of nuclear factor (NF)-kappaB and activator protein (AP)-1 in CIA mice. CONCLUSIONS: MB produced an anti-arthritis effect in CIA mice by inhibiting the production of critical inflammatory mediators and osteoclasts through the downregulation of NF-kappaB and AP-1. PMID- 21251972 TI - Modulation of inflammatory markers by the ethanolic extract of Leucas aspera in adjuvant arthritis. AB - AIM OF THE STUDY: To investigate the anti-inflammatory and antioxidant potential of ethanolic extract of Leucas aspera (EELA) in adjuvant arthritis. MATERIALS AND METHODS: Complete Freund's adjuvant served to induce arthritis. EELA was administered in two doses along with vehicle control (0.1% carboxymethyl cellulose) and positive control (Diclofenac). Levels of tumour necrosis factor (TNF-)-alpha, C-reactive protein (CRP), Interleukin-2 (IL-2), Cathepsin D, activities of antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT) were estimated in plasma/hemolysate and tissue. HPLC analysis of EELA was also performed. RESULTS: EELA exhibited significant anti-inflammatory (p<0.001) and antioxidant activity (p<0.001). It did not show mortality up to 2000 mg/kg body weight. Histopathological studies confirmed complete cartilage regeneration and near normal joint in EELA2 treated arthritic rats. CONCLUSION: This study highlighted the antioxidant and anti inflammatory potential of Leucas aspera. Three major families of compounds present in EELA may explain these activities: catechins (epicatechin, beta epicatechin), flavonoids (procyanidin), phytosterols (beta-sitosterol) apart from glycosides, phenolic compounds and tannins. PMID- 21251973 TI - Bioreactor technology in marine microbiology: from design to future application. AB - Marine micro-organisms have been playing highly diverse roles over evolutionary time: they have defined the chemistry of the oceans and atmosphere. During the last decades, the bioreactors with novel designs have become an important tool to study marine microbiology and ecology in terms of: marine microorganism cultivation and deep-sea bioprocess characterization; unique bio-chemical product formation and intensification; marine waste treatment and clean energy generation. In this review we briefly summarize the current status of the bioreactor technology applied in marine microbiology and the critical parameters to take into account during the reactor design. Furthermore, when we look at the growing population, as well as, the pollution in the coastal areas of the world, it is urgent to find sustainable practices that beneficially stimulate both the economy and the natural environment. Here we outlook a few possibilities where innovative bioreactor technology can be applied to enhance energy generation and food production without harming the local marine ecosystem. PMID- 21251974 TI - Neonatal lipopolysaccharide exposure impairs sexual development and reproductive success in the Wistar rat. AB - We investigated, in rats, whether neonatal exposure to bacterial lipopolysaccharide (LPS) impairs sexual development, sexual decline, and reproductive behaviour in later life. Rats were administered either LPS (Salmonella enterica, serotype enteritidis, 0.05 mg/kg, ip) or saline (equivolume) on days 3 and 5 postpartum. The immediate and long-term effect of treatment on HPA and HPG hormones, testicular morphology, and mating behaviour was assessed. Neonatal LPS exposure induced a significant increase in corticosterone compared to controls, as well as reduced testosterone and LH in males and LH in females immediately following neonatal drug exposure. Neonatal LPS exposure disrupted the normal weight-to-age ratio of puberty onset in males and females, and impaired sexual performance in adulthood. Reproductive function was reflected in significantly diminished sperm presence in rats that had received neonatal LPS. LPS-treated females exhibited LH suppression during puberty, and males demonstrated testosterone suppression in late adulthood. Testosterone and LH surges during mating were significantly reduced in adult offspring treated with LPS as neonates. Furthermore, animals exposed to neonatal LPS and subsequent stress in adulthood, exhibited significantly blunted corticosterone responses. Morphometric assessment of testes taken from neonates revealed reduced gonocyte genesis immediately following LPS exposure and increased seminiferous disorganisation of the epithelium in these animals in adulthood. This research demonstrates the long-term impact of neonatal bacterial exposure on reproductive success given that early life exposure to bacteria disrupted puberty onset and sexual performance. Associated changes in neuroendocrine functioning suggest a possible mechanism through which a subfertile phenotype may arise. PMID- 21251975 TI - Development of shellac-coated sustained release pellet formulations. AB - Shellac is an important coating material for food products. Since the introduction of aqueous ammoniacal solutions it also regained importance for pharmaceutical applications. Because of the comparatively high dissolution pH of this material, further additives are required if shellac is used as enteric coating material. However, this dissolution behaviour of shellac may be of interest for sustained release or colon targeting applications. In the present study different subcoats containing calcium chloride, citric acid or Eudragit((r)) E, respectively, were applied to immediate release theophylline pellets which were subsequently coated with shellac. Drug release from the resulting pellet formulations was measured. The mechanism of interaction between the modifying subcoat ingredients and the shellac coating was investigated using FT-IR spectroscopy. All formulations with modifying subcoat prolonged drug release. Whereas the effect of calcium chloride was a result of ionic interactions with shellac, the effect of citric acid was a reduction of the degree of dissociation of shellac. The influence of Eudragit((r)) E can be explained by the solubility characteristics of this basic polymer. The application of modifying subcoats is an easy and effective means to achieve sustained release from shellac-coated dosage forms. The choice of a suitable substance and the adjustment of its concentration allow tailor made sustained release profiles. PMID- 21251976 TI - Induction of type XVI collagen expression facilitates proliferation of oral cancer cells. AB - Type XVI collagen belongs to the family of fibril-associated collagens with interrupted triple helices (FACIT). Recently, high affinity to integrin alpha1beta1 has been shown allowing cells expressing those integrins to attach and spread on recombinant type XVI collagen. Here, we show that type XVI collagen is overexpressed in dysplastic areas of mucosal epithelium from oral squamous cell carcinoma (OSCC) patients. Induction of its expression in OSCC cell lines (COLXVI cells) leads to an increased expression of Kindlin-1. Moreover, we demonstrate a significantly increased Kindlin-1/beta1-integrin interaction. Additionally, we detected a higher number of activated beta1-integrins in COLXVI cells and found a neo-expression of alpha1 integrin subunit on these cells. FACS analysis revealed a significantly higher amount of COLXVI cells in S-phase and G2/M-phase 6h after synchronisation leading to a markedly higher proliferation activity. Blocking beta1-integrins with a specific antibody resulted in reduced proliferation of COLXVI cells. In summary, we demonstrate that overexpression of type XVI collagen in aberrant oral keratinocytes leads to Kindlin-1 induction, increased Kindlin-1/beta1-integrin interaction, integrin activation and subsequently to a proliferative cellular phenotype. PMID- 21251977 TI - Hyaluronan deposition and correlation with inflammation in a murine ovalbumin model of asthma. AB - Asthma is a chronic inflammatory disease of the airways characterized by airway remodeling, which includes changes in the extracellular matrix (ECM). However the role of the ECM in mediating these changes is poorly understood. Hyaluronan (HA), a major component of the ECM, has been implicated in asthma as well as in many other biological processes. Our study investigates the processes involved in HA synthesis, deposition, localization and degradation during an acute and chronic murine model of ovalbumin (OVA)-induced allergic pulmonary inflammation. Mice were sensitized, challenged to OVA and sacrificed at various time points during an 8-week challenge protocol. Bronchoalveolar lavage (BAL) fluids, blood, and lung tissue were collected for study. RNA, HA, protein and histopathology were analyzed. Analyses of lung sections and BAL fluids revealed an early deposition and an increase in HA levels within 24 h of antigen exposure. HA levels peaked at day 8 in BAL, while inflammatory cell recovery peaked at day 6. Hyaluronan synthase (HAS)1 and HAS2 on RNA levels peaked within 2 h of antigen exposure, while hyaluronidase (HYAL)1 and HYAL2 on RNA levels decreased. Both inflammatory cell infiltrates and collagen deposition co-localized with HA deposition within the lungs. These data support a role for HA in the pathogenesis of inflammation and airway remodeling in a murine model of asthma. HA deposition appears largely due to up regulation of HAS1 and HAS2. In addition, HA appears to provide the scaffolding for inflammatory cell accumulation as well as for new collagen synthesis and deposition. PMID- 21251978 TI - Identification of C-terminally and N-terminally truncated estrogen receptor alpha variants in the mouse. AB - We re-examined mouse ERalpha mRNA variants using rapid amplification of cDNA ends (RACE) and RT-PCR. Our analysis showed the presence of several mRNA variants containing unique 5'- or 3'-nucleotide sequences. We mapped the cDNA sequences on the mouse genome, and identified four novel 3'-terminal and 5'-leader exons in the intronic region between exons 4 and 5. RT-PCR analysis revealed that the expression patterns of the C-terminally truncated ERalpha products (CTERPs) were similar to that of Wild-type ERalpha and that the N-terminally truncated ERalpha products (NTERPs) appeared to have different expression profiles. Moreover, we constructed expression vectors and analyzed the subcellular localization and the transcriptional activation abilities of the variant proteins in transfected HEK293 cells using immunocytochemistry and luciferase reporter assay. The CTERP variants localized in the nuclei and constitutively activated estrogen response element (ERE)-driven promoters, while the NTERP variant was located in the extra nuclear regions and had no ability to activate the ERE promoters in the presence or absence of 10 nM estradiol. Our results indicate that the mouse ERalpha gene is more complex than previously thought in terms of genomic organization and that alternative splicing and alternative usage of intronic promoters contribute to the remarkable diversity of ERalpha mRNAs and proteins. PMID- 21251980 TI - Altered gonadal expression of TGF-beta superfamily signaling factors in environmental contaminant-exposed juvenile alligators. AB - Environmental contaminant exposure can influence gonadal steroid signaling milieus; however, little research has investigated the vulnerability of non steroidal signaling pathways in the gonads. Here we use American alligators (Alligator mississippiensis) hatched from field-collected eggs to analyze gonadal mRNA transcript levels of the activin-inhibin-follistatin gene expression network and growth differentiation factor 9. The eggs were collected from Lake Woodruff National Wildlife Refuge, a site with minimal anthropogenic influence, and Lake Apopka, a highly contaminated lake adjacent to a former EPA Superfund site. The hatchling alligators were raised for 13 months under controlled conditions, thus limiting differences to embryonic origins. Our data reveal sexually dimorphic mRNA expression in 13-month-old alligator gonads similar to patterns established in vertebrates with genetic sex determination. In addition, we observed a relationship between lake of origin and mRNA expression of activin/inhibin subunits alpha and betaB, follistatin, and growth differentiation factor 9. Our study suggests that embryonic exposure to environmental contaminants can affect future non-steroidal signaling patterns in the gonads of a long-lived species. PMID- 21251979 TI - Minireview: PPARgamma as the target of obesogens. AB - The peroxisome proliferator-activated receptor gamma (PPARgamma) is a key regulator of adipogenesis and is medically important for its connections to obesity and the treatment of type II diabetes. Activation of this receptor by certain natural or xenobiotic compounds has been shown to stimulate adipogenesis in vitro and in vivo. Obesogens are chemicals that ultimately increase obesity through a variety of potential mechanisms, including activation of PPARgamma. The first obesogen for which a definitive mechanism of action has been elucidated is the PPARgamma and RXR activator tributyltin; however, not all chemicals that activate PPARgamma are adipogenic or correlated with obesity in humans. There are multiple mechanisms through which obesogens can target PPARgamma that may not involve direct activation of the receptor. Ligand-independent mechanisms could act through obesogen-mediated post-translational modification of PPARgamma which cause receptor de-repression or activation. PPARgamma is active in multipotent stem cells committing to the adipocyte fate during fat cell development. By modifying chromatin structure early in development, obesogens have the opportunity to influence the promoter activity of PPARgamma, or the ability of PPARgamma to bind to its target genes, ultimately biasing the progenitor pool towards the fat lineage. Obesogens that act by directly or indirectly activating PPARgamma, by increasing the levels of PPARgamma protein, or enhancing its recruitment to promoters of key genes in the adipogenic pathway may ultimately play an important role in adipogenesis and obesity. PMID- 21251981 TI - Soluble donor-like MHC class I proteins induce CD4(+)CD25(+)CD8(-)FoxP3(+) cells with potential to ameliorate graft chronic injury. AB - Conventional immunosuppressive therapies failed to prevent allograft chronic rejection. New approaches to modulate recipient immune response are needed. Donor like MHC class I soluble proteins demonstrated therapeutic potential to suppress chronic rejection. The present study was designed to clarify the ability of MHC class I soluble proteins to induce T regulatory cells with true regulatory potential in a fully allogeneic rat cardiac transplant model. Donor-like MHC class I proteins upregulate small population of splenic CD8(-) negative CD4(+)CD25(+)FoxP3(+) positive cells. CD4(+) splenocytes after MHC therapy suppress lymphocyte proliferation against donor antigens in vitro. ACI recipients of WF hearts treated with CD4(+) cells, induced with donor-like MHC class I proteins (CD4-MHC), demonstrated stable survival of the transplanted organ (MST >120 days; n=17). Histology revealed that grafts of recipients treated with CD4 MHC had 23.6% vessels affected 100 days postgrafting. On the contrary, hearts obtained from long-term surviving hosts treated with CD4(+) cells induced with high-dose CsA (CD4-CsA) had 50-70% of affected vessels. CD4-MHC class I treated transplants were mostly CD3(-) negative, had low level of mast and FoxP3(+) cell infiltration compared to CD4-CsA treated hearts. Intragraft CD4(+) cells were close to mast cells in morphology. The same graft tissues had similar number of CD4(+) positive cells and mast cells suggesting existence of CD4(+) positive mast cells. On the other hand, a negligible number of FoxP3(+) positive cells in the grafts after CD4-MHC treatment supports the idea of CD4(+) positive FoxP3(+) negative mast cells population. We demonstrate that donor-like MHC class I protein therapy induces population of CD4(+)CD25(+)CD8(-)FoxP3(+) cells with potential to ameliorate development of transplant vascular disease and evoke CD4(+) positive FoxP3 negative mast cells in the secondary hosts. PMID- 21251983 TI - The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. AB - Metastasis is a multistep process that requires acquisition of malignant cell phenotypes which allow tumor cells to escape from the primary tumor site. Each of the steps during metastatic progression involves co-evolution of the tumor and its microenvironment. Although tumor cells are the driving force of metastasis, new findings suggest that the host cells within the tumor microenvironment play a key role in influencing metastatic behavior. Many of these contributing cells are derived from the bone marrow; in particular, recruited bone marrow progenitor cells generate the "pre-metastatic niche" to which the tumor cells metastasize. Analysis of the molecular mechanisms involved in pre-metastatic niche formation has revealed that secreted soluble factors are key players in bone marrow cell mobilization during metastasis. In addition, membrane vesicles derived from both tumor and host cells have recently been recognized as new candidates with important roles in the promotion of tumor growth and metastasis. This review describes old ideas and presents new insights into the role of tumor and bone marrow-derived microvesicles and exosomes in pre-metastatic niche formation and metastasis. PMID- 21251982 TI - Endothelins and their receptors in cancer: identification of therapeutic targets. AB - Endothelins and their receptors are important in normal physiology, but have been implicated in various pathophysiological conditions. Members of the so-called "endothelin axis" are dysregulated in a wide range of human cancers, opening the door for novel anticancer therapies. Established cancer chemotherapeutic agents and drugs that target specific components of the endothelin axis have been combined with promising results, but more work is needed in this area. The endothelin axis affects numerous signaling pathways, including Ras, mitogen activated protein kinases, beta-catenin/T-cell factor/lymphoid enhancer factor, nuclear factor-kappaB (NFkappaB), SNAIL, and mammalian target of rapamycin (mTOR). There is much still to learn about optimizing drug specificity in this area, while minimizing off-target effects. Selective agonists and antagonists of endothelins, their receptors, and upstream processing enzymes, as well as knockdown strategies in vitro, are providing valuable leads for testing in the clinical setting. The endothelin axis continues to be an attractive avenue of scientific endeavor, both in the cancer arena and in other important health related disciplines. PMID- 21251984 TI - Water permeability and characterization of aquaporin-11. AB - The water permeability of aquaporin-11 (AQP11), which has a cysteine substituted for an alanine at a highly conserved asparagine-proline-alanine (NPA) motif in the water channel family, is controversial. Our previous study, however, showed that AQP11 is water permeable in proteoliposomes in which AQP11 molecules were reconstituted after purification with Fos-choline 10, which is the most suitable detergent available for stable solubilization of AQP11. In our previous study, we were unable to exclude the effect of the detergent on the water conductance. Therefore, in the present study, we measured the water permeability of AQP11 without detergent using vesicles that directly formed from Sf9 cell membranes expressing AQP11 molecules. The water permeability of AQP11 was 8-fold lower than that of AQP1 and 3-fold higher than that of mock-infected cell membrane, and was reversibly inhibited by mercury ions. Considering the slow but constant water permeable functions of AQP11, we performed homology modeling to search for a common structural feature. When comparing our model with those of other AQP structures, we found that Tyr83 facing the channel pore might be a key amino acid residue that decreases the water permeation of AQP11. Our findings indicate that AQP11 could be involved in slow but constant water movement across the membrane. PMID- 21251985 TI - Long-term open-label study of tanezumab for moderate to severe osteoarthritic knee pain. AB - OBJECTIVE: This study was designed to evaluate the long-term safety and effectiveness of repeated doses of the humanized anti-nerve growth factor antibody, tanezumab, during open-label treatment of patients with OA knee pain. DESIGN: The current study (clinicaltrials.gov identifier: NCT00399490) was a multicenter, phase II, open-label, multiple-dose extension of an earlier randomized clinical trial. All patients (N=281) received infusions of tanezumab 50MUg/kg on Days 1 and 56 with subsequent doses administered at 8-week intervals (up to a total of eight infusions). The primary endpoint of this study was safety. Effectiveness evaluations included overall knee pain, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index subscales, and subject global assessment (SGA) of response to therapy on 0-100 point visual analog scales. RESULTS: Repeated administration of tanezumab resulted in a low incidence of treatment-related adverse events (AEs; 7.5%). The rate of serious AEs was also low (2.8%) with none considered treatment-related. Few AEs of abnormal peripheral sensation were reported; hypoesthesia was reported by nine patients (3.2%), paresthesia by seven patients (2.5%), and hyperesthesia, peripheral neuropathy, and sensory disturbance were each reported by one patient (0.4% for each). Most AEs of abnormal peripheral sensation were rated as mild (95%) and the majority (65%) resolved before study completion. At Week 8, overall knee pain and SGA improved from baseline by a mean (+/- standard error) of -12.8 (+/-1.78) and 8.0 (+/-1.66), respectively. Similar improvements occurred for WOMAC subscales. CONCLUSIONS: Repeated injections of tanezumab in patients with moderate to severe knee OA provide continued pain relief and improved function with a low incidence of side effects. Additional studies to define the efficacy and duration of pain reduction and to provide a more complete assessment of long-term safety are warranted. PMID- 21251986 TI - Oral salmon calcitonin reduces cartilage and bone pathology in an osteoarthritis rat model with increased subchondral bone turnover. AB - OBJECTIVES: Traumatic osteoarthritis (OA) is possibly augmented by effects from loss of sex hormones. Salmon calcitonin is shown to reduce OA pathogenesis and bone resorption. We investigated the effects of oral salmon calcitonin treatment and ovariectomy on cartilage and bone pathology in a traumatic OA model. METHODS: Six groups with 10 7-month-old female Sprague Dawley rats each were subjected to bilateral meniscectomy (MNX), ovariectomy (OVX) or Sham surgery and treated for 8 weeks with oral salmon calcitonin (CT) or vehicle (V) in the following way: (1) Sham+V; (2) MNX+V; (3) MNX+CT; (4) OVX+V; (5) MNX/OVX+V; (6) MNX/OVX+CT. Weights were recorded weekly and CTX-II was measured in serum. At termination 56 days post-surgery, the right tibia was analyzed for changes in articular cartilage thickness, extent of cartilage damage and subchondral bone changes in predefined zones, as recommended in the novel OARSI histopathology score. RESULTS: The combined MNX/OVX model produced a significantly reduced cartilage thickness (P=0.033) in the outer zone (Z1) of the tibial plateau and increased calcified cartilage damage (P=0.0004) and serum CTX-II (P=0.003). Addition of OVX to MNX significantly increased the width of matrix damage at the surface (P=0.025) and 50% cartilage depth (P=0.004). Treatment with oral salmon calcitonin counteracted the loss of cartilage thickness (P=0.055), significantly reduced subchondral bone damage score (P=0.019) and reduced the type II collagen degradation (P=0.009). CONCLUSIONS: Addition of ovariectomy augmented site-specific traumatic OA pathology, which was reduced by oral salmon calcitonin treatment. Treatments for OA might ideally affect both bone and cartilage. PMID- 21251987 TI - The effect of glucosamine on glucose metabolism in humans: a systematic review of the literature. AB - OBJECTIVE: Glucosamine is commonly used for the treatment of osteoarthritis. It is available as an over the counter preparation and also as a prescription pharmaceutical. There is concern from animal experiments that glucosamine may alter glucose metabolism through the hexosamine biosynthetic pathway. The objective of this systematic review is to determine if exogenous glucosamine adversely affects glucose metabolism in humans. This review does not separate out the effects on glucose metabolism of the various glucosamine preparations. METHOD: An English-language literature search of MEDLINE, EMBASE and EBM Reviews (1950-February 2009) was conducted. The bibliographies of selected papers were manually searched for additional references. Two reviewers independently analyzed studies for quality and content using a standardized data extraction form. RESULTS: Eleven studies were included. Six studies were randomized controlled trials and the remaining five were prospective studies with or without controls. Four of the studies found decreased insulin sensitivity or increased fasting glucose in subjects taking glucosamine. Three of these were clinical studies using oral glucosamine. Studies that included subjects with baseline impaired glucose tolerance or insulin resistance were more likely to detect an effect on glucose metabolism than studies without such subjects. CONCLUSION: Clinical studies, including three using oral glucosamine, have provided mixed evidence about the effect of exogenous glucosamine on glucose metabolism in humans. Therefore, more studies are needed, particularly including subjects at high risk for impairments in glucose homeostasis, before a definite conclusion can be made. PMID- 21251988 TI - Proprioception in knee osteoarthritis: a narrative review. AB - OBJECTIVE: To give an overview of the literature on knee proprioception in knee osteoarthritis (OA) patients. METHOD: A literature search was performed and reviewed using the narrative approach. RESULTS: (1) Three presumed functions of knee proprioception have been described in the literature: protection against excessive movements, stabilization during static postures, and coordination of movements. (2) Proprioceptive accuracy can be measured in different ways; correlations between these methods are low. (3) Proprioceptive accuracy in knee OA patients seems to be impaired when compared to age-matched healthy controls. Unilateral knee OA patients may have impaired proprioceptive accuracy in both knees. (4) Causes of impaired proprioceptive accuracy in knee OA remain unknown. (5) There is currently no evidence for a role of impaired proprioceptive accuracy in the onset or progression of radiographic osteoarthritis (ROA). (6) Impaired proprioceptive accuracy could be a risk factor for progression (but not for onset) of both knee pain and activity limitations in knee OA patients. (7) Exercise therapy seems to be effective in improving proprioceptive accuracy in knee OA patients. CONCLUSIONS: Recent literature has shown that proprioceptive accuracy may play an important role in knee OA. However, this role needs to be further clarified. A new measurement protocol for knee proprioception needs to be developed. Systematic reviews focusing on the relationship between impaired proprioceptive accuracy, knee pain and activity limitations and on the effect of interventions (in particular exercise therapy) on proprioceptive accuracy in knee OA are required. Future studies focusing on causes of impaired proprioceptive accuracy in knee OA patients are also needed, taking into account that also the non-symptomatic knee may have proprioceptive impairments. Such future studies may also provide knowledge of mechanism underlying the impact of impaired proprioceptive accuracy on knee pain and activity limitations. PMID- 21251989 TI - Instruments to assess physical activity in patients with osteoarthritis of the hip or knee: a systematic review of measurement properties. AB - OBJECTIVE: There is no consensus on the best approach for measuring physical activity in patients with osteoarthritis (OA) of the hip or knee. The aims of this study were (1) to identify all physical activity measures that have been validated in patients with OA of the hip or knee and to systematically review their measurement properties, and (2) to give recommendations on which instrument is most suitable for what purpose. DESIGN: A search was performed in PubMed, Embase, and Sportdiscus (complete databases until November 10, 2010). Three reviewers independently evaluated the quality of the included studies, using the Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) checklist. Subsequently, the reviewers independently evaluated the quality of the included physical activity instruments, using the recently developed QAPAQ checklist for appraising the qualitative attributes and measurement properties of physical activity questionnaires. RESULTS: Nine studies were included, in which 12 measurement instruments were evaluated: five single item rating scales, six multi-item questionnaires, and one pedometer. In general, the methodological quality of the studies was poor to moderate. Only the Lower Extremity Activity Scale (LEAS) and the pedometer received positive ratings for content validity. The LEAS and Baecke questionnaire received positive ratings for reliability. The University of California at Los Angeles (UCLA), the Tegner score, and the LEAS received positive ratings for construct validity. The Daily Activity Questionnaire (DAQ) received a positive rating for criterion validity. Responsiveness was not evaluated for any of the included instruments. CONCLUSION: For monitoring physical activity levels of populations the UCLA or LEAS seem most useful. For studies measuring physical activity as a risk factor for developing OA or as a protective factor against functional decline there is not enough evidence for any instrument to conclude that it has adequate measurement properties. For follow-up studies on wear in joint replacement patients we recommend to use accelerometers. However, more validation studies of adequate quality are needed for all included instruments. PMID- 21251990 TI - Electroporation-mediated gene transfer of SOX trio to enhance chondrogenesis in adipose stem cells. AB - OBJECTIVE: The aim of the present study was to determine if the electroporation mediated gene transfer of SOX trio enhances the chondrogenic potential of adipose stem cells (ASCs). DESIGN: ASCs were transfected with SOX trio genes using an electroporation technique and cultured for 3 weeks. The pellets were analyzed for DNA and glycosaminoglycan (GAG) analysis, and the gene and protein expression of SOX-5, SOX-6, SOX-9, type 1 collagen (COL1Al), type 2 collagen (COL2Al) and type 10 collagen (COL10A1) using real-time PCR and Western blot analysis. Further in vivo studies were carried out by subcutaneous transplantation of pellets in severe combined immunodeficiency (SCID) mice for 3 weeks. RESULTS: The gene transfer efficiency was high (approximately 70%). Transfected ASCs showed high expression of corresponding genes after 21 days, and each SOX protein was detected in ASCs transfected with the corresponding gene. The chondrogenic differentiation of ASCs, as demonstrated by GAG levels and Safranin-O staining, showed significant enhancement when SOX trio were co-transfected, while subsets with single gene transfer of SOX-5, -6, or -9 did not show significant elevation. SOX trio co-transfection enhanced COL2A1 mRNA, but did not increase COL1A1 and COL10A1 mRNA. Type II collagen protein dramatically increased, and type X collagen decreased with co-transfection of the SOX trio. When pellets were implanted in the subcutaneous pouch of SCID mice for 3 weeks, ASCs co-transfected with SOX trio demonstrated abundant proteoglycan, significantly reduced mineralization. CONCLUSION: The electroporation-mediated transfection of SOX trio greatly enhances chondrogenesis from ASCs, while decreasing hypertrophy. PMID- 21251991 TI - Change in knee osteoarthritis cartilage detected by delayed gadolinium enhanced magnetic resonance imaging following treatment with collagen hydrolysate: a pilot randomized controlled trial. AB - OBJECTIVE: To determine whether either of two magnetic resonance imaging approaches - delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC), or T2 mapping - can detect short-term changes in knee hyaline cartilage among individuals taking a formulation of collagen hydrolysate. DESIGN: Single center, prospective, randomized, placebo-controlled, double-blind, pilot trial of collagen hydrolysate for mild knee osteoarthritis (OA). Participants were allowed to continue the prior analgesic use. The primary outcome was change in dGEMRIC T1 relaxation time in the cartilage regions of interest at the 24-week timepoint. Secondary endpoints included the change in dGEMRIC T1 relaxation time between baseline and 48 weeks, the change in T2 relaxation time at 0, 24 and 48 weeks, the symptom and functional measures obtained at each of the visits, and overall analgesic use. RESULTS: Among a sample of 30 randomized subjects the dGEMRIC score increased in the medial and lateral tibial regions of interest (median increase of 29 and 41 ms respectively) in participants assigned to collagen hydrolysate but decreased (median decline 37 and 36 ms respectively) in the placebo arm with the changes between the two groups at 24 weeks reaching significance. No other significant changes between the two groups were seen in the other four regions, or in any of the T2 values or in the clinical outcomes. CONCLUSIONS: These preliminary results suggest that the dGEMRIC technique may be able to detect change in proteoglycan content in knee cartilage among individuals taking collagen hydrolysate after 24 weeks. PMID- 21251992 TI - Temporal expression and tissue distribution of interleukin-1beta in two strains of guinea pigs with varying propensity for spontaneous knee osteoarthritis. AB - OBJECTIVE: To provide a comprehensive immunohistochemical (IHC) map of the temporal expression and tissue distribution of interleukin-1beta (IL-1beta) through progression of osteoarthritis (OA) in two strains of guinea pigs with varying propensity for spontaneous knee joint disease. METHODS: OA-prone Hartley and OA-resistant Strain 13 guinea pigs were collected at 60, 120, 180, 240, 360, and 480 days of age (N=4 animals per strain per date). IHC was performed on whole joint preparations; the distribution of IL-1beta expression on coronal sections was mapped, semi-quantitatively scored, and correlated to OA grade using Mankin criteria with guinea pig-specific modifications. OA and IHC indices were compared among times and between strains using the Kruskal-Wallis one-way analysis of variance by ranks followed by Dunn's post test. RESULTS: OA indices for both strains increased from 60 to 480 days of age; a statistically higher score (P <= 0.01) was found in Hartley animals at 180, 240, 360, and 480 days. At 60 days of age, IL-1beta expression was detected in cartilage, menisci, synovium, and subchondral bone in both strains. Persistent and statistically increased (P<0.05) IL-1beta expression was found in these same tissues in Hartley animals at 120 and 180 days, while Strain 13 animals demonstrated a significant reduction in positive immunostaining. Statistical differences in IHC indices between strains beyond 240 days of age were restricted to synovium (days 240 and 480) and subchondral bone (days 360 and 480). CONCLUSIONS: As expected, histologic OA proceeded in an accelerated manner in Hartley animals relative to Strain 13 animals. The OA-prone strain did not demonstrate reduced IL-1beta expression during adult maturity as occurred in the OA-resistant strain, and this persistent expression may have corresponded to early incidence of OA. Future interventional studies are warranted to explore whether dysregulation of IL-1beta expression may contribute to premature onset of spontaneous disease in the Hartley guinea pig. PMID- 21251993 TI - Inhaled corticosteroids may have a beneficial effect on bone metabolism in newly diagnosed asthmatic children. AB - BACKGROUND: The adverse effect of inhaled corticosteroids (ICS) treatment on bone metabolism in children with asthma is still controversial, and a possible beneficial effect of vitamin D added to ICS on bone turnover is uncertain. OBJECTIVE: We conducted a randomized, double-blind, parallel-group, 6-month trial to assess the effects of a medium and high dose of ICS and a high-dose ICS with vitamin D on bone metabolism in children with newly diagnosed atopic asthma. METHODS: 96 children were equally randomized to 4 groups receiving the following doses of inhaled budesonide [MUg/day]: 400 (ICS 400 group), 800 (ICS 800 group), 800 with oral vitamin D (ICS 800 with vit D group), and montelukast as a control (control group). Markers of bone production (osteocalcin, alkaline phosphatase) and bone degradation (amino-terminal cross-linked telopeptide of type I collagen- NTx, carboxy-terminal telopeptides of type I collage), and also concentration of 25-hydroxycholecalciferol (25OH D) and calcium-phosphorus balance (calcium, phosphorus, parathormon-PTH) in serum and/or urine were assessed twice: before and after 6 months of treatment. RESULTS: We obtained a significant decrease in phosphorus and PTH serum levels in ICS 400 and ICS 800 with vit D groups compared to control group, and a significant decrease of NTx urine level in ICS 800 with vit D group. CONCLUSIONS: Medium doses of inhaled corticosteroids exert an advantageous effect on bone metabolism in newly diagnosed asthmatic children. Vitamin D together with a high dose of inhaled corticosteroids has a beneficial effect on both calcium-phosphorus balance and collagen turnover. PMID- 21251994 TI - Differential response to intravenous prostacyclin analog therapy in patients with pulmonary arterial hypertension. AB - BACKGROUND: Treprostinil is an intravenous prostacyclin analog approved for the treatment of pulmonary arterial hypertension (PAH). Few studies have compared the pharmacodynamics and effectiveness of treprostinil and epoprostenol in patients with high-risk PAH. METHODS: Case series of patients with PAH admitted to a Medical Intensive Care Unit for transition from epoprostenol to intravenous treprostinil for refractory class III-IV functional symptoms or right heart failure. Mixed linear models were used for comparisons between repeated hemodynamic measurements. RESULTS: Five of fourteen patients treated with intravenous treprostinil during the study period underwent transition to epoprostenol. Two had PAH associated with systemic sclerosis, three had idiopathic PAH. Pulmonary arterial pressures (PAP) and pulmonary vascular resistance significantly increased within 1 h after discontinuation of treprostinil in all subjects. Mean PAPs immediately prior to discontinuation of treprostinil (53.4 +/- 7.5 mmHg) were significantly lower than the values 1 h after discontinuation (63.6 +/- 9.6 mmHg, p = 0.026), but were significantly higher than the values following transition to epoprostenol (45.4 +/- 5.5, p = 0.0493); 4/5 subjects had short-term clinical follow-up data available; all improved in functional class. No subject experienced adverse events during the transition. CONCLUSIONS: High-risk PAH patients with an inadequate response to treprostinil may have significant clinical and hemodynamic response to epoprostenol. Following discontinuation of treprostinil in these patients, the hemodynamic effects of discontinuation were seen in substantially shorter time than what is known to be the pharmacokinetic terminal half-life. PMID- 21251995 TI - [Allergic fungal rhinosinusitis caused by Curvularia sp.]. AB - Allergic fungal rhinosinusitis is a benign and non-invasive sinusal disease related to a hypersensitivity reaction to fungal antigens. This process can cause tissue edema with chronic inflammatory disturbances of the respiratory mucosa. We present the case of a 17 year-old immunocompetent male, with history of seasonal allergic rhinosinusitis, nasal polyps and previous surgery for mucocele of the frontal sinus. Sticky material was removed in the last surgery that revealed pigmented and septed filaments on direct examination, and yielded Curvularia on Sabouraud dextrose agar. After a course of amphotericin B, treatment was switched to itraconazole, with good tolerance and favorable clinical outcome. PMID- 21251996 TI - In vitro antifungal susceptibility pattern and ergosterol content in clinical yeast strains. AB - BACKGROUND: Absence or severe reduction in the amount of ergosterol in the fungal membrane and its replacement with other sterols have been described as potential antifungal resistance mechanisms in fungi. AIMS AND METHODS: The ergosterol content in a collection of 51 clinical yeast isolates, including susceptible and resistant strains to amphotericin B and azoles, was estimated by a simple chromatographic method (HPLC-UV). RESULTS: A high content of ergosterol was detected for several strains of Candida glabrata, Candida tropicalis or Pichia membranifaciens. In contrast, strains of Cryptococcus neoformans and Dipodascus capitatus had the lowest ergosterol concentrations. No significant correlation was observed between antifungal susceptibility patterns and ergosterol content. CONCLUSIONS: We conclude from this study that ergosterol content on yeasts may not be associated with specific resistant patterns. PMID- 21251998 TI - Increased prevalence of the Plasmodium falciparum Pfmdr1 86N genotype among field isolates from Franceville, Gabon after replacement of chloroquine by artemether lumefantrine and artesunate-mefloquine. AB - Despite global antimalarial measures, Plasmodium falciparum malaria remains a major public health problem. WHO has recommended the use of arteminisin-based combination therapy to limit the emergence of antimalarial drug resistance. However, ACT treatment failures have been linked to the selection of the wild types 86N genotype of P. falciparum multidrug resistance 1 (Pfmdr1) and the 76K genotype of P. falciparum chloroquine resistance (Pfcrt) genes. The aim of this study was to investigate the molecular impact of widespread implementation of artemether-lumefantrine and artesunate-mefloquine on local parasite population in Franceville, Gabon. We analyzed 230 pediatric field isolates (96 from 2004 and 134 from 2009). Routine hematological parameters were collected. Pfmdr1 codons 86 and 1246 and Pfcrt codon 76 were genotyped using PCR-RFLP and the prevalence of the genotypes was compared. The children's mean age did not differ between 2004 and 2009 (respectively 31.8 (6-84) months vs 38.6 (6-84) months, p=0.32), and neither did mean parasitemia [16,750 (1000-96,234) and 14,587 (1093-83,941) parasites/MUL, respectively (p=0.21)]. The mean hemoglobin level was higher in 2009 than in 2004 (11.0 +/- 2.4 vs 7.8 +/- 2.0 g/dL, respectively; p=0.04). More interesting, the prevalence of Pfmdr1 wild type 86N increased from 15.6% (n=15/96) in 2004 to 31.3% (n=42/134) in 2009 (p=0.007). A significant increase combining pure and mixed genotypes (86N+86N/Y) was also found between 2004 and 2009 (p=0.02), while the prevalence of genotypes Pfmdr1 1246D, Pfcrt wild type 76T and all mixed genotypes (Pfmdr1 86N/Y and 1246D/Y, and 76K/T) remained stable. The complexity of isolates was high (around 2.9 and 2.4) and the FC27 allele of Pfmsp2 was more prevalent. These findings show a substantial benefice of artemether-lumefantrine and artesunate-mefloquine and of new control measures. The selection, in the general population, of wild type Pfmdr1 86N, which is associated with antiplasmodial resistance against some drugs, has been induced underlining the need for molecular surveillance of the impact of ACT on antimalarial resistance. PMID- 21251999 TI - Multilocus nuclear DNA markers and genetic parameters in an Indian Anopheles minimus population. AB - Estimation of population genetic parameters is highly dependent on the choice of genetic markers. Furthermore, inferences based on single genes could lead to erroneous conclusions and population genetic outcomes, thus usage of multiple loci is suggested. Considering malaria is a highly fatal vector-borne infectious disease, inference on population genetic structure and demography could be of help in the long run for malaria vector management and control. Using the published genome sequence information of Anopheles gambiae we designed EPIC primers to amplify DNA fragments in An. minimus nuclear genome. Eight such DNA fragments could be successfully amplified and sequenced and homology to corresponding genes of An. gambiae was established. All the eight DNA fragments were found to be polymorphic for single nucleotide polymorphisms (SNPs) in a population sample of An. minimus from India. Several tests of neutrality confirmed that all the eight fragments evolve under a standard neutral model of molecular evolution. Furthermore, multilocus linkage disequilibrium studies revealed that the DNA fragments were not genetically linked to each other and thus are independently evolving. Tests of past population demographic events clearly revealed that this Indian population of An. minimus follows demographic equilibrium model, without any significant recent population bottleneck or expansion. The eight multilocus nuclear DNA fragments thus could be considered as 'putatively neutral' and be used to infer population structure and demographic history of An. minimus, a major malaria vector in the Southeast Asia and India. Moreover, the estimations of population demography using these putatively neutral markers can provide a baseline against which, test for the role of natural selection in functionally relevant genes of An. minimus would be possible. PMID- 21251997 TI - Evolutionary history of hepatitis C virus genotype 5a in France, a multicenter ANRS study. AB - The epidemic history of HCV genotype 5a is poorly documented in France, where its prevalence is very low, except in a small central area, where it accounts for 14.2% of chronic hepatitis C cases. A Bayesian coalescent phylogenetic investigation based on the E1 envelope gene and a non-structural genomic segment (NS3/4) was carried out to trace the origin of this epidemic using a large sample of genotype 5a isolates collected throughout France. The dates of documented transmissions by blood transfusion were used to calibrate five nodes in the phylogeny. The results of the E1 gene analysis showed that the best-fitting population dynamic model was the expansion growth model under a relaxed molecular clock. The rate of nucleotide substitutions and time to the most recent common ancestors (tMRCA) of genotype 5a isolates were estimated. The divergence of all the French HCV genotype 5a strains included in this study was dated to 1939 [95% HPD: 1921-1956], and the tMRCA of isolates from central France was dated to 1954 [1942-1967], which is in agreement with epidemiological data. NS3/4 analysis provided similar estimates with strongly overlapping HPD values. Phylodynamic analyses give a plausible reconstruction of the evolutionary history of HCV genotype 5a in France, suggesting the concomitant roles of transfusion, iatrogenic route and intra-familial transmission in viral diffusion. PMID- 21252000 TI - Genetic exchange and emergence of novel strains in directly transmitted trypanosomatids. AB - The breeding structure of protozoan infections, i.e. whether and how frequently parasites exchange genes ("sexual reproduction"), is a crucially important parameter for many important questions; it also matters for how new virulent strains might emerge. Whether protozoan parasites are clonal or sexual is therefore a hotly debated issue. For trypanosomatids, few experimental tests of breeding structure exist to date and are limited to the vector-borne human diseases Trypanosoma brucei, Trypanosoma cruzi, and Leishmania major. We infected the natural host (Bombus terrestris) of the monoxenous parasite Crithidia bombi (Trypanosomatida) either with a single strain of the parasite or in mixed infections and tested for genetic exchange among co-infecting strains using microsatellite markers. We show that strains regularly exchange genetic material, with occasional self-crossing during mixed infections. Most offspring clones fit the expected allelic pattern from a standard Mendelian segregation. In some cases, alleles are lost or gained, leading to an entirely new genotype different from either parent. Genetic exchange in C. bombi therefore does occur and the process also leads to allelic loss or gain that could result from slippage during recombination. The majority of novel offspring types correspond to a recombination of parental alleles. The case of C. bombi demonstrates that directly transmitted, monoxenic trypanosomatids can also exchange genes. Sex therefore seems to be found in very different lineages of the trypanosomatids. Furthermore, the data allowed estimating a frequency at which C. bombi shows genetic exchange in populations. PMID- 21252001 TI - Synthesis and analysis of degradation, mechanical and toxicity properties of poly(beta-amino ester) degradable hydrogels. AB - Biodegradable hydrogels have been studied extensively in recent years for biomedical applications, including tissue engineering and drug delivery, due to their tunable properties and similarities to natural soft tissue. In this work, two poly(beta-amino ester) biodegradable hydrogel systems were synthesised and studied in vitro. Different degradation profiles were observed, ranging from 7 h to 4 months, and the compressive modulus was shown to decrease as degradation proceeded. MTT cytotoxicity analysis was used to analyze the cellular response to the degradation products, and the hydrogel systems exhibited similar toxicity to poly(dl-lactide-co-glycolide) degradation products. Finally, cell attachment was studied by seeding pluripotent mesenchymal cells directly onto the hydrogel surfaces followed by a live/dead assay and fluorescent imaging. Cells showed significant viability at 24h (98%) and slightly lower, but still substantial viability, at 48 h (72%). These hydrogels exhibited a range of properties and favorable cellular responses, all which indicate that these materials could be viable materials for tissue regeneration and other biomedical applications. PMID- 21252002 TI - Letter to editor: "Comparisons between the responsibilities and roles of airline pilots and surgeons". PMID- 21252003 TI - Clinical profile and surgical outcome for pulmonary aspergilloma: nine year retrospective observational study in a tertiary care hospital. AB - BACKGROUND: The indications and the outcome of surgery for pulmonary aspergilloma remain highly controversial. This retrospective observational study was conducted to study the clinical profile, indications, post-operative complications and long term outcome of patients having pulmonary aspergilloma. METHODS: From January 2000 to October 2008, 52 patients underwent surgery for pulmonary aspergilloma at our tertiary care institute. RESULTS: The group consisted of 32 males and 20 females with a mean age of 39.3 +/- 11.2 years. The most common indication for surgery was hemoptysis (96.15%). The underlying lung diseases were tuberculosis (75%), bronchiectasis (5.76%), and lung abscess (5.76%). In one patient (2%), concomitant ruptured lung hydatid cyst and an aspergilloma was present. The procedures performed were lobectomy (n = 43), bilobectomy (n = 3). pneumonectomy (n = 3), segmental resection (n = 3). The post-operative mortality was 1.92% (one patient). Overall complications occurred in 12 (23.07%) patients. The complications included prolonged air leak (n = 6), bleeding (n = 3), empyema (n = 1), repeated pneumothorax (n = 1), and wound dehiscence (n = 1). The mean follow up period was 38 +/- 18.6 months. There was no recurrence of disease or hemoptysis. CONCLUSION: Pulmonary aspergilloma is common in developing countries like India in which there is high prevalence of pulmonary tuberculosis. Surgical resection of pulmonary aspergilloma is effective in preventing recurrence of symptoms including hemoptysis. We recommend early surgical resection of symptomatic aspergilloma with reasonable complications. Pre-operative preparation of the patients, meticulous surgical technique and post-operative chest physiotherapy reduces the rate of complications. Complications may still occur and are largely related to the underlying lung pathology; however, the long term outcome is good. PMID- 21252005 TI - Diploid/triploid mosaicism: a rare event or an under-diagnosed syndrome? PMID- 21252004 TI - Prenatal and postnatal growth retardation, microcephaly, developmental delay, and pigmentation abnormalities: Naegeli syndrome, dyskeratosis congenita, poikiloderma Clericuzio type, or separate entity? AB - Naegeli(-Franceschetti-Jadassohn) syndrome and Dermatopathia Pigmentosa Reticularis are allelic disorders, both characterized by a congenital generalized reticulate hyperpigmentation, palmoplantar hyperkeratosis and other ectodermal symptoms. The disorders differ in their primary pigmentation localization and hair and dental manifestations. They resemble Dyskeratosis Congenita and Poikiloderma Clericuzio type in many of the skin changes, but especially the presence of leukoplakia and bone marrow disfunctioning in the first, and of telangiectasias, generalized hyperkeratosis of palms and soles, and nail pachyonychia in the latter are distinguishing features. Here we present two unrelated patients who have prenatal and postnatal growth retardation, microcephaly, developmental delay, generalized reticulate hyperpigmentation, hypohidrosis, absent fingertip prints, and absent palmoplantar hyperkeratosis. The patients differ in nail manifestations and hair colour. No Keratin14 mutation or genomic imbalance at CGHarray could be found in either of them. Although their phenotype overlaps with Naegeli syndrome, dermatopathia pigmentosa reticularis, dyskeratosis congenita and poikiloderma Clericuzio type, the differences in ectodermal manifestations, immunological functioning, growth pattern and cognition may indicate the presence of a separate entity. PMID- 21252006 TI - Formation of acrylamide from glucans and asparagine. AB - Model foods consisting of carbohydrates, asparagine (Asn), albumin, and sodium chloride were heated at 180 degrees C for various times, and the levels of acrylamide (AA) in these foods were determined by LC/MS/MS. When glucans such as beta-cyclodextrin (beta-CD), starch and cellulose were used as carbohydrates in the above model, the levels of AA formed were approximately the same as or much higher than those observed in the glucose model. Glucans were heated in the absence of Asn for one hour, and their degradation products were analyzed for sugar components by HPAEC-PAD and for volatile compounds by GC/MS. The amounts of glucose detected in the glucan models, however, were too low to consider that AA was formed from the glucans in these model foods via the intermediate production of glucose. By contrast, several carbonyl compounds such as acetaldehyde and acetone were detected in the glucan degradation products. Furthermore, AA was formed when acetaldehyde and Asn were heated together in sealed vials at 180 degrees C. These results showed that AA was formed from glucans and Asn, not via glucose produced by glucan hydrolysis, but via volatile carbonyl compounds such as acetaldehyde produced by glucan pyrolysis. PMID- 21252007 TI - Lithium in drinking water and thyroid function. AB - BACKGROUND: High concentrations of lithium in drinking water were previously discovered in the Argentinean Andes Mountains. Lithium is used worldwide for treatment of bipolar disorder and treatment-resistant depression. One known side effect is altered thyroid function. OBJECTIVES: We assessed associations between exposure to lithium from drinking water and other environmental sources and thyroid function. METHODS: Women (n=202) were recruited in four Andean villages in northern Argentina. Lithium exposure was assessed based on concentrations in spot urine samples, measured by inductively coupled plasma mass spectrometry. Thyroid function was evaluated by plasma free thyroxine (T4) and pituitary gland thyroid-stimulating hormone (TSH), analyzed by routine immunometric methods. RESULTS: The median urinary lithium concentration was 3,910 MUg/L (5th, 95th percentiles, 270 MUg/L, 10,400 MUg/L). Median plasma concentrations (5th, 95th percentiles) of T4 and TSH were 17 pmol/L (13 pmol/L, 21 pmol/L) and 1.9 mIU/L, (0.68 mIU/L, 4.9 mIU/L), respectively. Urine lithium was inversely associated with T4 [beta for a 1,000-MUg/L increase=-0.19; 95% confidence interval (CI), 0.31 to -0.068; p=0.002] and positively associated with TSH (beta=0.096; 95% CI, 0.033 to 0.16; p=0.003). Both associations persisted after adjustment (for T4, beta=-0.17; 95% CI, -0.32 to -0.015; p=0.032; for TSH: beta=0.089; 95% CI, 0.024 to 0.15; p=0.007). Urine selenium was positively associated with T4 (adjusted T4 for a 1 MUg/L increase: beta=0.041; 95% CI, 0.012 to 0.071; p=0.006). CONCLUSIONS: Exposure to lithium via drinking water and other environmental sources may affect thyroid function, consistent with known side effects of medical treatment with lithium. This stresses the need to screen for lithium in all drinking water sources. PMID- 21252009 TI - Skeletal myoblasts for myocardial regeneration in patients with congestive heart failure: where have all the answers gone? PMID- 21252010 TI - Autologous cell therapy for enhanced endovascular repair after coronary stent implantation. PMID- 21252011 TI - Interventional cardiology: an imaging subspecialty. PMID- 21252012 TI - TEVAR: a bridge too far? PMID- 21252013 TI - Final results of a phase IIa, randomised, open-label trial to evaluate the percutaneous intramyocardial transplantation of autologous skeletal myoblasts in congestive heart failure patients: the SEISMIC trial. AB - AIMS: The SEISMIC study was an open-label, prospective, randomised study to assess the safety and feasibility of percutaneous myoblast implantation in heart failure patients with implanted cardioverter-defibrillators (ICD). METHODS AND RESULTS: Patients were randomised 2:1 to autologous skeletal myoblast therapy vs. optimal medical treatment. The primary safety end-point was defined as the incidence of procedural and device related serious adverse events, whereas the efficacy endpoints were defined as the change in global LVEF by MUGA scan, change in NYHA classification of heart failure and in the distance achieved during a six minute walk test (6MW) at 6-month follow-up. Forty subjects were randomised to the treatment arm (n=26), or to the control arm (n=14). There were 12 sustained arrhythmic events and one death after episodes of ventricular tachycardia (VT) in the treatment group and 14 events in the control group (P=ns). At 6-month follow up, 6MW distance improved by 60.3+/-54.1?meters in the treated group as compared to no improvement in the control group (0.4+/-185.7?meters; P=ns). In the control group, 28.6% experienced worsening of heart failure status (4/14), while 14.3% experienced an improvement in NYHA classification (2/14). In the myoblast treatment arm, one patient experienced a deterioration in NYHA classification (8.0%), whereas five patients improved one or two classes (20.0%; P=0.06). However, therapy did not improve global LVEF measured by MUGA at 6-month follow up. CONCLUSIONS: These data indicate that implantation of myoblasts in patients with HF is feasible, appears to be safe and may provide symptomatic relief, though no significant effect was detected on global LVEF. PMID- 21252014 TI - A randomised, double-blind, placebo-controlled, multicentre study of the safety and efficacy of BIOBYPASS (AdGVVEGF121.10NH) gene therapy in patients with refractory advanced coronary artery disease: the NOVA trial. AB - AIMS: Genes encoding vascular endothelial growth factor (VEGF) can potentially augment myocardial perfusion in patients with coronary artery disease (CAD). We conducted a randomised, double-blind, placebo-controlled gene therapy study with the adenovirus carrying VEGF121 (BIOBYPASS [AdGVVEGF121.10NH]). METHODS AND RESULTS: Seventeen patients with severe CAD were 2:1 randomised to BIOBYPASS (n=12; 61 years) or placebo (n=5; 64) as 12 intra-myocardial injections into the ischaemic area using the NOGA XP(r) system. The study was terminated prematurely due to a company product portfolio decision. Mean change in total exercise duration from baseline to 12, 26 and 52 weeks was 20.2, 21.4 and 16.4 sec in BIOBYPASS treated and 46.2, 31.4 and 12.4 sec in placebo (NS). Change from baseline to at least 1 mm ST depression during exercise at 12, 26 and 52 weeks did not differ between BIOBYPASS and placebo. Change in stress-induced ischaemia score was similar in the BIOBYPASS (3.4%) and placebo (2.0%) groups. An improvement in symptoms was seen in patients treated with BIOBYPASS, but no difference between the groups. CONCLUSIONS: Direct intramyocardial injection of BIOBYPASS (AdGVVEGF121.10NH) was safe but did not improve exercise capacity, time to ischaemic threshold or myocardial perfusion compared to sham injection in patients with refractory myocardial ischaemia. PMID- 21252015 TI - Clinical results after coronary stenting with the GenousTM Bio-engineered R stentTM: 12-month outcomes of the e-HEALING (Healthy Endothelial Accelerated Lining Inhibits Neointimal Growth) worldwide registry. AB - AIMS: e-HEALING is a worldwide, internet-based registry designed to capture post marketing clinical data on the use of the GenousTM EPC capturing R stentTM. Rapid restoration of a healthy endothelial layer after stent placement by capturing circulating endothelial progenitor cells may reduce both stent thrombosis (ST) and in-stent-restenosis. METHODS AND RESULTS: We planned a 5,000 patient registry with >=1 lesion suitable for stenting. The 12-month primary outcome was target vessel failure (TVF), defined as target vessel-related cardiac death or myocardial infarction (MI) and target vessel revascularisation. Secondary outcomes were the composite of cardiac death, MI or target lesion revascularisation (TLR), and individual outcomes including ST. A total of 4,939 patients received >=1 Genous stent between 2005 and 2007. Baseline characteristics showed a median age of 63 years, 79% males, 25% diabetics, and 37% with prior MI. A total of 49% of lesions treated were ACC/AHA type B2 or C; 1.1 stents per lesion were used. At 12 months, TVF occurred in 8.4% and the composite of cardiac death, MI or TLR in 7.9%. Twelve-month TLR and ST were 5.7% and 1.1%, respectively. CONCLUSIONS: Coronary stenting with the Genous results in good clinical outcomes, and low incidences of repeat revascularisation and ST. PMID- 21252016 TI - Percutaneous coronary interventions with an endothelial progenitor cell capture stent (EPC) for high risk patients with no option for drug eluting stents: long term clinical outcomes of a single centre registry. AB - AIMS: Drug eluting stents (DES) are currently considered the gold standard for reducing restenosis of coronary artery lesions. Owing to their effect on the healing process, DES use requires mandatory prolonged dual antiplatelet therapy (DAT). The endothelial progenitor cell (EPC) capture stent, attracting circulating EPCs, promotes vascular healing and allows a short post-procedural period of DAT. The aim of the present study was to evaluate the short and long term clinical outcomes of the use of the Genos R stentTM in a selected high risk population with "no option" for DES. METHODS AND RESULTS: From December 2005 to October 2008, 61 high risk patients with clear contraindications to a prolonged period of DAT who underwent PCI with EPC capture stent implantation in our institution were prospectively selected and analysed. Technical success rate was 100%. Procedural success rate was 95.1%. After two years, major adverse cardiovascular events (MACE) free survival was 80.6%. According to the Academic Research Consortium definitions, cardiac death occurred in 1.6% of patients, and re-infarction, target lesion revascularisation (TLR), and target vessel revascularisation (TVR) occurred in 6.6%, 9.8%, and 11.5% of patients, respectively. Definite stent thrombosis occurred in one patient (specifically at 0 days). In patients who underwent surgery, no post-procedural MACE and no stent thrombosis were recorded. CONCLUSIONS: EPC capture stent implantation in high risk patients with no option for DES seems encouraging, with satisfactory clinical outcomes both at short and at long term follow-up. PMID- 21252017 TI - Endothelial progenitor cell capturing stent and short dual antiplatelet therapy in patients on chronic anti-vitamin k regimen undergoing percutaneous coronary interventions: long-term outcomes of a single centre registry. AB - AIMS: To evaluate outcomes of the endothelial progenitor cell (EPC) capture stent in patients on chronic anti-vitamin K (AVK) regimen, requiring percutaneous coronary intervention (PCI). METHODS AND RESULTS: Between February 2007 and February 2008, 78 consecutive patients under chronic AVK treatment undergoing PCI were enrolled in the registry and received an EPC capture stent. The incidence of comorbid conditions was analysed by the Charlson index. Dual antiplatelet therapy (DAT, aspirin and clopidogrel) was prescribed for one month only together with the AVK treatment, after PCI. Major adverse clinical events (MACE) rate, included death, acute myocardial infarction (MI) or target lesion revascularisation (TLR), incidence of stent thrombosis and rate of haemorrhagic events were collected. A?Charlson index >3 was present in 89% of patients. At 14+/-8 months the cumulative rate of MACE was 22%: 10 deaths (six cardiac deaths), and six TLR. No MI or definitive/probable stent thromboses occurred during follow-up. Four major haemorrhagic episodes occurred during follow-up, all of them after the first month. CONCLUSIONS: Patients on AVK treatment represent a highly comorbid population with a high event rate after PCI. The strategy of PCI with an EPC capture stent and short duration of DAT may be used in patients who need a short term DAT. PMID- 21252018 TI - Influence of age on the clinical outcomes of coronary revascularisation for the treatment of patients with multivessel de novo coronary artery lesions: sirolimus eluting stent vs. coronary artery bypass surgery and bare metal stent, insight from the multicentre randomised Arterial Revascularisation Therapy Study Part I (ARTS-I) and Part II (ARTS-II). AB - AIMS: We sought to evaluate the prognostic impact of age on the procedural results and subsequent clinical outcomes in patients with multivessel disease (MVD) treated either by coronary artery bypass surgery (CABG) or by percutaneous coronary intervention (PCI) with or without drug eluting stents, based on data of the Arterial Revascularisation Therapies Study (ARTS) part I and part II. The potential influence of age in determining the most appropriate revascularisation strategy for patients with MVD is largely unknown. METHODS AND RESULTS: Three year clinical outcome of ARTS I patients randomised to PCI with bare metal stent (BMS) (n= 600) or CABG (n= 605), and matched patients treated by PCI with sirolimus-eluting stents (SES) in ARTS II (n= 607) were reviewed according to four age quartiles. Endpoints were measured in terms of major adverse cardiac and cerebrovascular events MACCE) during hospital stay and up to three years. The frequency of female, diabetes, hypertension, peripheral vascular disease, pulmonary disease, as well as lesion complexity increased with age. At three years, MACCE free survival was comparable between patients treated by CABG or SES PCI, regardless of age quartile. The incidence of MACCE was higher among ARTS I BMS treated patients in all but the second age quartile. This was primarily related to a higher need for repeat revascularisation among BMS treated patients. However, age, which emerged as a strong independent predictor of MACCE following CABG (p<0.005), was not predictive of adverse events following PCI. Conversely, diabetes was the strongest independent predictor of MACCE among PCI treated patients (p<0.02), but didn't affect three-year outcomes following CABG. CONCLUSIONS: Age seems to influence the CABG outcome in-hospital but not PCI. PCI SES could offer lower immediate risk in patients with MVD and comparable long term outcome as CABG especially in older patients. The worst outcome of PCI-BMS group is primarily related to the need for repeat revascularisation. Diabetes is the most important predictor of MACCE following PCI. PMID- 21252019 TI - Double stenting: a method for treating acute stent recoil and luminal filling defects. AB - AIMS: Acute stent recoil and luminal filling defects can result in a suboptimal angiographic result following stent deployment and are associated with an increased risk of adverse outcomes. We aimed to evaluate the effect of double stenting, deployment of a second stent within the first, in the treatment of these conditions and to review the literature on this procedure. METHODS AND RESULTS: Thirteen cases of double stenting performed by a single operator at the Manchester Royal Infirmary over a three year period were identified and quantitative coronary angiography was performed. The indication for double stenting was acute stent recoil in eight cases, luminal filling defects in three cases and a combination of recoil and filling defects in two cases. There was a high frequency of target vessel calcification (77%) and ostial lesions (23%). Following double stenting, mean minimum lumen diameter increased significantly from 2.5 mm to 3.5 mm (p <0.001). There were no procedural complications. At mean clinical follow-up of 19 months (range six to 37 months), there were no major adverse cardiac events. CONCLUSIONS: Double stenting can significantly improve angiographic outcome in cases of acute stent recoil and luminal filling defects, with excellent clinical results in the medium term. PMID- 21252020 TI - Abortion of myocardial infarction by primary angioplasty mainly depends on preprocedural TIMI flow. AB - AIMS: To define frequency and predictors of aborted myocardial infarctions (MI) after primary angioplasty. METHODS AND RESULTS: We analysed 196 consecutive patients with the clinical diagnosis of ST-elevation acute coronary syndrome (ST ACS) admitted for primary angioplasty to one interventional facility between October 2005 and September 2006. Aborted MI was defined as a creatine increase of less than two times the upper limit of normal, combined with typical evolutionary electrocardiographic changes. Masquerading MI was diagnosed if evolutionary changes were missing or could be attributed to other causes. Thirty-four patients (17,3%) had an aborted and nine (4,6%) a masquerading MI. The main predictor of abortion was Thrombolysis In Myocardial Infarction (TIMI) flow 2 or 3 prior to procedure. The in-hospital mortality of aborted MI was 0%, the one year mortality 2.9%. Sixteen patients without prior or inter-current myocardial infarction had a preserved ejection fraction on cardiac MR at 12 months; in six patients even without any detection of late enhancement. CONCLUSIONS: There is a substantial proportion of aborted myocardial infarction after primary angioplasty, corresponding to a small or even non detectable scar formation in terms of late enhancement on cardiac MR. Preprocedural TIMI flow 2 or 3 is the main predictor of aborted MI. PMID- 21252021 TI - Long-term safety and sustained left ventricular recovery: long-term results of percutaneous left ventricular support with Impella LP2.5 in ST-elevation myocardial infarction. AB - AIMS: Mechanical left ventricular (LV) unloading may reduce infarct size when combined with primary percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI). The Impella LP2.5 is a novel percutaneous left ventricular assist device. Although the short-term safety and feasibility of this device have been demonstrated, the long-term effects are unknown. The purpose of the current study was to evaluate the long-term effects of the Impella LP2.5 support on the aortic valve and left ventricular ejection fraction (LVEF). METHODS AND RESULTS: In 2006, 10 patients with anterior STEMI received 3-day support with the Impella LP2.5 after PCI. The control group consisted of 10 comparable patients, treated according to routine care. For the current study, echocardiography was performed and adverse events were recorded. Mean duration of follow-up was 2.9+/-0.6 years in the Impella group and 3.0+/-0.3 years in the control group. No differences in aortic valve abnormalities and LVEF were demonstrated between the groups; nevertheless, LVEF increase from baseline was significantly greater in Impella-treated patients (23.6+/-8.9% versus 6.7+/ 7.0%, P=0.008). CONCLUSIONS: Three-day support with the Impella LP2.5 is not associated with adverse effects on the aortic valve at long-term follow-up. LVEF was similar in both groups; however, recovery was significantly greater in the Impella group. PMID- 21252022 TI - SCAI consensus document on occupational radiation exposure to the pregnant cardiologist and technical personnel. AB - Concerns regarding radiation exposure and its effects during pregnancy are often quoted as an important barrier preventing many women from pursuing a career in Interventional Cardiology. Finding the true risk of radiation exposure from performing cardiac catheterisation procedures can be challenging and guidelines for pregnancy exposure have been inadequate. The Women in Innovations group of Cardiologists with endorsement of the Society for Cardiovascular Angiography and Interventions aim to provide guidance in this publication by describing the risk of radiation exposure to pregnant physicians and cardiac catheterisation personnel, to educate on appropriate radiation monitoring and to encourage mechanisms to reduce radiation exposure. Current data do not suggest a significant increased risk to the fetus of pregnant women in the cardiac catheterisation laboratory and thus do not justify precluding pregnant physicians from performing procedures in the cardiac catheterisation laboratory. However, radiation exposure among pregnant physicians should be properly monitored and adequate radiation safety measures are still warranted. PMID- 21252023 TI - In vitro validation of new Fourier-domain optical coherence tomography. AB - AIMS: To validate the accuracy and evaluate the intra- and inter-observer variability of vascular measurements using novel Fourier-domain optical coherence tomography (FD-OCT) versus intravascular ultrasound (IVUS) in a coronary phantom model. METHODS AND RESULTS: A dedicated cylindrical phantom comprised of four sections with differing dimensions was used to compare images generated by five FD-OCT and five IVUS catheters. Each FD-OCT catheter was tested using three different consoles, generating 15 imaging pullbacks. Two independent experts, blinded to the phantom data, performed measurements. There were 180 FD-OCT and 60 IVUS cross-sectional measurements of mean lumen diameter (MeanLD), minimal lumen diameter (MLD), maximum lumen diameter (MaxLD) and lumen area (LA) at three points in each section. FD-OCT measurements had excellent correlations with IVUS (concordance correlation coefficient [CCC]: >=0.9769 for MeanLD, LA or longitudinal length [LL]) and phantom dimensions (CCCs for FD-OCT: >=0.9958 for MeanLD, LA or LL). FD-OCT measurements were larger than IVUS (p<0.0001), but showed less measurement errors compared to IVUS (p<0.0001). Moreover, FD-OCT caused less discrepancy between MaxLD and MLD versus IVUS (p<0.0001). Intra- and inter-observer variability was low for both FD-OCT (CCCs for MeanLD, LA and LL >=0.9996) and IVUS (>=0.9935). Image catheter position did not influence FD-OCT measurements. CONCLUSIONS: FD-OCT was more accurate than IVUS and had similar high reproducibility to determine vascular dimensions in vitro. These results support the use of FD-OCT in the clinical setting. PMID- 21252024 TI - Percutaneous coronary interventions for acute myocardial infarction. PMID- 21252025 TI - Substitution of ethanol with specially designed microspheres in a TASH procedure. AB - AIMS: We present our first clinical experience to substitute ethanol with special designed microspheres in a TASH procedure (transcatheter ablation of septal hypertrophy). TASH is a standard approach for the treatment of patients with hypertrophic obstructive cardiomyopathy, severely symptomatic despite maximal medical therapy. However, the injection of alcohol remains a source of some possible complications. METHODS AND RESULTS: We substituted alcohol with special designed microspheres. A highly symptomatic HOCM patient underwent a procedure of percutaneous ablation of his hypertrophied septum with the use of Embozene microspheres. The procedure was successful, as the gradient was reduced from 70 before the procedure to 10 mmHg afterwards. CONCLUSIONS: TASH by means of microspheres embolisation instead of alcohol was a safe and successful in the short-term procedure. PMID- 21252026 TI - Usefulness of a novel balloon-expandable vascular sheath for facilitated large bore arterial access for transcatheter aortic valve implantation. PMID- 21252027 TI - How should I treat a spontaneously reperfused acute STEMI that involves the left main stem and proximal LAD? AB - BACKGROUND: A 41-year-old female with 90 minutes of severe chest pain and ST elevation in leads V1-V2 underwent emergency coronary angiography with a view to primary angioplasty. INVESTIGATIONS: Physical examination, electrocardiography, coronary angiography. DIAGNOSIS: ST-segment elevation anterior myocardial infarction. MANAGEMENT: Coronary angiography, antiplatelet and antithrombotic therapy, statin, angiotensin-converting enzyme inhibitor, beta blocker, IVUS and percutaneous coronary intervention (PCI) PMID- 21252028 TI - Tools & techniques: PCI for acute MI tips and tricks. PMID- 21252029 TI - Huge saphenous vein graft aneurysm after coronary artery bypass grafting. PMID- 21252030 TI - Left main stenting: don't forget the angiographic follow-up! PMID- 21252031 TI - Mesalazine-induced photosensitivity. PMID- 21252032 TI - Tubular apocrine adenoma of the nose. PMID- 21252033 TI - Generalized acquired cutis laxa treated with facial plastic surgery. PMID- 21252034 TI - Patient-reported outcomes as a source of evidence in off-label prescribing: analysis of data from PatientsLikeMe. AB - BACKGROUND: Evaluating a new use for an existing drug can be expensive and time consuming. Providers and patients must all too often rely upon their own individual-level experience to inform clinical practice, which generates only anecdotal and unstructured data. While academic-led clinical trials are occasionally conducted to test off-label uses of drugs with expired patents, this is relatively rare. In this work, we explored how a patient-centered online research platform could supplement traditional trials to create a richer understanding of medical products postmarket by efficiently aggregating structured patient-reported data. PatientsLikeMe is a tool for patients, researchers, and caregivers (currently 82,000 members across 11 condition-based communities) that helps users make treatment decisions, manage symptoms, and improve outcomes. Members enter demographic information, longitudinal treatment, symptoms, outcome data, and treatment evaluations. These are reflected back as longitudinal health profiles and aggregated reports. Over the last 3 years, patients have entered treatment histories and evaluations on thousands of medical products. These data may aid in evaluating the effectiveness and safety of some treatments more efficiently and over a longer period of time course than is feasible through traditional trials. OBJECTIVE: The objective of our study was to examine the illustrative cases of amitriptyline and modafinil - drugs commonly used off-label. METHODS: We analyzed patient-reported treatment histories and drug evaluations for each drug, examining prevalence, treatment purpose, and evaluations of effectiveness, side effects, and burden. RESULTS: There were 1948 treatment histories for modafinil and 1394 treatment reports for amitriptyline reported across five PatientsLikeMe communities (multiple sclerosis, Parkinson's disease, mood conditions, fibromyalgia/chronic fatigue syndrome, and amyotrophic lateral sclerosis). In these reports, the majority of members reported taking the drug for off-label uses. Only 34 of the 1755 (1%) reporting purpose used modafinil for an approved purpose (narcolepsy or sleep apnea). Only 104 out of 1197 members (9%) reported taking amitriptyline for its approved indication, depression. Members taking amitriptyline for off-label purposes rated the drug as more effective than those who were taking it for its approved indication. While dry mouth is a commonly reported side effect of amitriptyline for most patients, 88 of 220 (40%) of people with amyotrophic lateral sclerosis on the drug reported taking advantage of this side effect to treat their symptom of excess saliva. CONCLUSIONS: Patient-reported outcomes, like those entered within PatientsLikeMe, offer a unique real-time approach to understand utilization and performance of treatments across many conditions. These patient-reported data can provide a new source of evidence about secondary uses and potentially identify targets for treatments to be studied systematically in traditional efficacy trials. PMID- 21252035 TI - Confirmation of a two-factor model for interpretation of the comprehensive trail making test with children. AB - Exploratory factor analyses (EFAs) of the Comprehensive Trail Making Test suggested a possible two-factor solution that might better reflect the differences in Trails 1-3 and Trails 4 and 5 as opposed to a single Composite Index for the total standardization sample. The purpose of this study was to conduct a confirmatory factor analysis (CFA) of the two-factor structure with a subset of the standardization sample ages 18 or younger that had completed all five-trail tasks. The sample included 251 boys and 306 girls, ages 8-18, with a mean age of 12.76 (SD = 3.07). Data were collected across 16 states with representation from all regions of the USA. Standardized scores on each of the trails (1-5) tasks were considered. The results of CFA using M-plus indicated a good fit for the two-factor model, chi(2)(4) = 18.686, p = .0009, root mean square error of approximation = 0.081, comparative fit index = 0.986 and standardized root-mean-squared residual = 0.021. A one-factor model was not supported. As suggested by the EFA in the manual, Trails 1-3 and Trails 4 and 5, while related, appear to be different in subtle ways that may be most meaningful in conjunction with evaluation of children with neurodevelopmental differences. Implications and possible explanations for this difference are discussed. PMID- 21252036 TI - Predicting who will use intensive social care: case finding tools based on linked health and social care data. AB - BACKGROUND: the costs of delivering health and social care services are rising as the population ages and more people live with chronic diseases. OBJECTIVES: to determine whether predictive risk models can be built that use routine health and social care data to predict which older people will begin receiving intensive social care. DESIGN: analysis of pseudonymous, person-level, data extracted from the administrative data systems of local health and social care organisations. SETTING: five primary care trust areas in England and their associated councils with social services responsibilities. SUBJECTS: people aged 75 or older registered continuously with a general practitioner in five selected areas of England (n = 155,905). METHODS: multivariate statistical analysis using a split sample of data. RESULTS: it was possible to construct models that predicted which people would begin receiving intensive social care in the coming 12 months. The performance of the models was improved by selecting a dependent variable based on a lower cost threshold as one of the definitions of commencing intensive social care. CONCLUSIONS: predictive models can be constructed that use linked, routine health and social care data for case finding in social care settings. PMID- 21252037 TI - Longitudinal changes in serum lipids in older people the Turku elderly study 1991 2006. PMID- 21252038 TI - Motivating older adults to exercise: what works? PMID- 21252039 TI - Can maintaining cognitive function at 65 years old predict successful ageing 6 years later? The PROOF study. AB - BACKGROUND: preservation of cognitive abilities is required to have a good quality of life. The predictive value of cognitive functioning at 65 years old on successful ageing 6 years later is not established. METHODS: nine hundred and seventy-six questionnaires were sent by mail to a sample of healthy and voluntary French pensioners. Successful ageing was defined through health status and well being. Cognitive abilities had been assessed 6 years earlier according to an objective method (Free and Cued Selective Recall Reminding Test (FCSRT), the Benton visual retention test and the similarities subtest of the Wechsler Adult Intelligence Scale-Revised) and a subjective one (Goldberg's anxiety scale, Mac Nair's scale and a Visual Analogue Scale to evaluate memory abilities change in the last 5 years). RESULTS: six hundred and eighty-six questionnaires could be analysed. The mean age was 72.9 +/- 1.2 years old with 59% of women and 99% lived at home. Well-being was negatively correlated with the FCSRT (r = -0.08, P = 0.0318) but positively related with the Benton (r = 0.09, P = 0.0125) and the similarities tests (r = 0.09, P = 0.0118). There is a negative correlation between anxious and cognitive complaints measured at baseline, and successful ageing indicators 6 years later. CONCLUSION: preservation of cognitive abilities at the age of retirement can predict a successful ageing 6 years later. ClinicalTrials.gov Identifier: NCT00759304. PMID- 21252040 TI - Fibrous dysplasia-like appearance of the frontal process of the maxilla on CT: prevalence in North China. AB - The frontal process of the maxilla occasionally shows a localized FD-like appearance. The purpose of this study was to determine its prevalence and findings on CT. A retrospective study of 1000 consecutive paranasal sinus CT scans was preformed on outpatients without a history of trauma or previous surgery in our hospital during 6 months. CT images were interpreted independently by 2 experienced head and neck radiologists on a PACS system in a bone window setting. Of the 1000 patients (546 males; 454 females), 51 (5.1%,41 males and 10 females) had an FD-like appearance in the frontal process of the maxilla. There was a statistically significant difference between sexes (P < .001). Twenty-nine (56.9%) entities arose from the right frontal process and 22 (43.1%) from the left frontal process. These entities, with well-defined margins, were located at the base of the frontal process of the maxilla, appearing as an ovoid or triangular configuration on axial-plane CT and as a spindle or elliptic shape on the coronal plane. The mean maximal diameter was 9.8 mm (range, 3.6-16.1 mm). These entities exhibited a pagetoid appearance (type I) in 37 (72.5%), a ground glass appearance (type II) in 8 (15.7%), and a cyst-like appearance (type III) in 6 (11.8%) patients on CT. The FD-like appearance of the frontal process of the maxilla is not rare and can be readily detected by CT. PMID- 21252041 TI - Diagnostic dilemma of pseudoprogression in the treatment of newly diagnosed glioblastomas: the role of assessing relative cerebral blood flow volume and oxygen-6-methylguanine-DNA methyltransferase promoter methylation status. AB - BACKGROUND AND PURPOSE: Methylation of the MGMT gene promoter is associated with a favorable prognosis in adult patients with GBM treated with TMZ. We determined the incidence of pseudoprogression according to the MGMT methylation status and the potential value of DSC perfusion MR images for predicting pseudoprogression. MATERIALS AND METHODS: New or enlarged enhancing lesions after CCRT in adult patients with newly diagnosed GBMs were prospectively assessed by measuring their rCBV by using DSC perfusion MR images. Tumor tissue was assayed to determine MGMT promoter methylation status. All patients were regularly followed up at an interval of 2 months by MR images, including DSC perfusion MR images. RESULTS: Ninety eligible patients were enrolled in this study. After CCRT, new or enlarged enhanced lesions were found in 59 of 90 patients, which were subsequently classified as pseudoprogression (26 patients, 28.9%) and real progression (33 patients, 36.7%). Overall, there was a significant difference in the mean rCBV between pseudoprogression and real tumor progression (P = .003). The ROC curve revealed that an rCBV ratio >1.47 had an 81.5% sensitivity and a 77.8% specificity. The unmethylated MGMT promoter group had a significant difference of mean rCBV between pseudoprogression and real progression (P = .009), though the methylated MGMT promoter group had no significant difference (P = .258). CONCLUSIONS: The current study suggests that rCBV measured by DSC perfusion MR images has a differential impact on the predictability of pseudoprogression in patients with GBM. PMID- 21252042 TI - Type of edema in posterior reversible encephalopathy syndrome depends on serum albumin levels: an MR imaging study in 28 patients. AB - PRES is a clinicoradiologic entity, combining seizures, blindness, and coma with MR imaging findings of predominantly vasogenic and occasional cytotoxic edema. In this clinical report, we determined the type of edema by using DWI and FLAIR sequences on MR imaging as well as ADC maps in 28 patients with PRES. The neuradiologic findings were correlated with levels of serum albumin, which is a main contributor to colloid osmotic pressure and vascular integrity. The presence of vasogenic edema was significantly associated with decreased serum albumin levels, which may be a particular risk factor for the development of PRES. PMID- 21252043 TI - Observer agreement regarding the necessity of retreatment of previously coiled recurrent cerebral aneurysms. AB - BACKGROUND AND PURPOSE: The decision regarding whether or not to retreat a previously treated aneurysm not only directly impacts patient care but also serves as a primary outcome measure in numerous, leading randomized controlled trials of modified coils. Our aim was to determine the degree of interobserver variability regarding the need and type of treatment for recurrent aneurysms following coil embolization. MATERIALS AND METHODS: Twenty-seven previously treated recurrent aneurysms were identified. Five independent readers rated each aneurysm on a 5-point scale: 1, definitely do not retreat; 2, probably do not retreat; 3, unsure; 4, probably retreat; and 5, definitely retreat. The readers noted, in grades 2-5, the type of retreatment preferred, including simple coiling, balloon- or stent-assist coiling, or surgical clipping. Intraobserver agreement kappa was calculated. Retreatment recommendations were evaluated between observers by using a Wilcoxon signed rank comparison. Descriptive statistics were performed for categoric treatment-type comparisons. RESULTS: At least 2- or 3-point differences between 2 readers were present in 17 (63%) and 11 (41%) of 27 cases, respectively. The median kappa was 0.27 (range, 0.04-0.43), which indicates fair agreement. Differences between readers varied, with readers 4 and 5 more often recommending retreatment compared with reviewers 1-3 (P < .05). Wide variation was noted in treatment approach, with recommendations for surgical clipping ranging from 2 (7%) to 18 (67%) of 27 cases between readers 1 and 5. CONCLUSIONS: The current study demonstrates substantial variability among observers not only in whether to retreat a recurrent aneurysm but also how to treat it. These findings suggest that patient management varies widely across treating physicians and also calls into question the use of "retreatment" as an objective end point in clinical trials. PMID- 21252044 TI - NHE2X3 DKO mice exhibit gender-specific NHE8 compensation. AB - NHE8, the newest member of the sodium/hydrogen exchanger family, is expressed in the epithelial cells of the intestine and the kidney. Intestinal expression of NHE8 is significantly higher than that of NHE2 and NHE3 at a young age, suggesting that NHE8 is an important player for intestinal sodium absorption during early development. The current study was designed to explore if NHE8 plays a compensatory role for the loss of NHE2 and NHE3 function in NHE2X3 double knockout (NHE2X3 DKO) mice. We further explored the regulatory mechanism(s) responsible for the change in NHE8 expression in NHE2X3 DKO mice. We found that >95% of NHE2X3 DKO mice survived through weanling. However, only 60% of male NHE2X3 DKO mice and 88% of female NHE2X3 DKO mice survived to 6 wk of life. We also found that the expression of NHE8 in wild-type female mice was higher compared with wild-type male mice after puberty. In NHE2X3 KDO mice, NHE8 expression was increased in females but not in males. Using Caco-2 cells as a model of the small intestine, we showed that testosterone inhibited endogenous NHE8 expression by reducing NHE8 mRNA synthesis, whereas estrogen had no effect on NHE8 expression. Thus our data show for the first time that intestinal NHE8 has a compensatory role in NHE2X3 DKO mice and this regulation is gender dependent. PMID- 21252045 TI - The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. AB - The extracellular calcium-sensing receptor (CaSR) has recently been recognized as an L-amino acid sensor and has been implicated in mediating cholecystokinin (CCK) secretion in response to aromatic amino acids. We investigated whether direct detection of L-phenylalanine (L-Phe) by CaSR results in CCK secretion in the native I cell. Fluorescence-activated cell sorting of duodenal I cells from CCK enhanced green fluorescent protein (eGFP) transgenic mice demonstrated CaSR gene expression. Immunostaining of fixed and fresh duodenal tissue sections confirmed CaSR protein expression. Intracellular calcium fluxes were CaSR dependent, stereoselective for L-Phe over D-Phe, and responsive to type II calcimimetic cinacalcet in CCK-eGFP cells. Additionally, CCK secretion by an isolated I cell population was increased by 30 and 62% in response to L-Phe in the presence of physiological (1.26 mM) and superphysiological (2.5 mM) extracellular calcium concentrations, respectively. While the deletion of CaSR from CCK-eGFP cells did not affect basal CCK secretion, the effect of L-Phe or cinacalcet on intracellular calcium flux was lost. In fact, both secretagogues, as well as superphysiological Ca(2+), evoked an unexpected 20-30% decrease in CCK secretion compared with basal secretion in CaSR(-/-) CCK-eGFP cells. CCK secretion in response to KCl or tryptone was unaffected by the absence of CaSR. The present data suggest that CaSR is required for hormone secretion in the specific response to L-Phe by the native I cell, and that a receptor-mediated mechanism may inhibit hormone secretion in the absence of a fully functional CaSR. PMID- 21252046 TI - Estrogen receptor-beta signaling modulates epithelial barrier function. AB - Impaired epithelial barrier function and estrogens are recognized as factors influencing inflammatory bowel disease (IBD) pathology and disease course. Estrogen receptor-beta (ERbeta) is the most abundant estrogen receptor in the colon and a complete absence of ERbeta expression is associated with disrupted tight-junction formation and abnormal colonic architecture. The aim of this study was to determine whether ERbeta signaling has a role in the maintenance of epithelial permeability in the colon. ERbeta mRNA levels and colonic permeability were assessed in IL-10-deficient mice and HLA-B27 rats by RT-PCR and Ussing chambers. ERbeta expression and monolayer resistance were measured in HT-29 and T84 colonic epithelial monolayers by RT-PCR and electric cell-substrate impedance sensing. The effect of 17beta-estradiol and an estrogen agonist [diarylpropionitrile (DPN)] and antagonist (ICI 182780) on epithelial resistance in T84 cells was measured. Expression of ERbeta and proinflammatory cytokines was investigated in colonic biopsies from IBD patients. Levels of ERbeta mRNA were decreased, whereas colonic permeability was increased, in IL-10-deficient mice and HLA-B27 transgenic rats prior to the onset of colitis. T84 cells demonstrated higher resistance and increased levels of ERbeta mRNA compared with HT-29 cells. 17beta-estradiol and DPN induced increased epithelial resistance in T84 cells, whereas an ERbeta blocker prevented the increased resistance. Decreased ERbeta mRNA levels were observed in colonic biopsies from IBD patients. This study suggests a potential role for ERbeta signaling in the modulation of epithelial permeability and demonstrates reduced ERbeta mRNA in animal models of colitis and colon of patients with inflammatory bowel disease. PMID- 21252047 TI - Mammalian target of rapamycin mediates the angiogenic effects of leptin in human hepatic stellate cells. AB - Leptin modulates the angiogenic properties of hepatic stellate cells (HSC), but the molecular mechanisms involved are poorly understood. We investigated the pathways regulating hypoxia-inducible factor 1alpha (HIF-1alpha) and vascular endothelial growth factor (VEGF) in leptin-stimulated myofibroblastic HSC. Exposure to leptin enhanced the phosphorylation of TSC2 on T1462 residues and of p70 S6 kinase and the translational inhibitor 4E-binding protein-1, indicating the ability of leptin to activate the mammalian target of rapamycin (mTOR) pathway. Similar findings were observed when HSC were exposed to PDGF. Both leptin and PDGF increased the expression of HIF-1alpha and VEGF in HSC. In the presence of rapamycin, a specific mTOR inhibitor, leptin and PDGF were no longer able to activate mTOR, and expression of VEGF was reduced, whereas HIF-1alpha abundance was not affected. Moreover, knockdown of Raptor, a component of the mTORC1 complex, reduced the ability of leptin to increase VEGF. mTOR was also necessary for leptin- and PDGF-dependent increase in HSC migration. Leptin increased the generation of reactive oxygen species in HSC, which was reduced by NADP(H) oxidase inhibitors. Both N-acetyl cysteine and diphenylene iodonium, a NADP(H) inhibitor, inhibited the expression of HIF-1alpha and VEGF stimulated by leptin or PDGF. Finally, conditioned media from HSC treated with leptin or PDGF induced tube formation in cultured human umbilical vein endothelial cells. In conclusion, in HSC exposed to leptin or PDGF, increased expression of VEGF requires both activation of mTOR and generation of reactive oxygen species via NADPH-oxidase. Induction of HIF-1alpha requires NADP(H) oxidase but not mTOR activation. PMID- 21252048 TI - Intestinal myofibroblasts: targets for stem cell therapy. AB - The subepithelial intestinal myofibroblast is an important cell orchestrating many diverse functions in the intestine and is involved in growth and repair, tumorigenesis, inflammation, and fibrosis. The myofibroblast is but one of several alpha-smooth muscle actin-positive (alpha-SMA(+)) mesenchymal cells present within the intestinal lamina propria, including vascular pericytes, bone marrow-derived stem cells (mesenchymal stem cells or hematopoietic stem cells), muscularis mucosae, and the lymphatic pericytes (colon) and organized smooth muscle (small intestine) associated with the lymphatic lacteals. These other mesenchymal cells perform many of the functions previously attributed to subepithelial myofibroblasts. This review discusses the definition of a myofibroblast and reconsiders whether the alpha-SMA(+) subepithelial cells in the intestine are myofibroblasts or other types of mesenchymal cells, i.e., pericytes. Current information about specific, or not so specific, molecular markers of lamina propria mesenchymal cells is reviewed, as well as the origins of intestinal myofibroblasts and pericytes in the intestinal lamina propria and their replenishment after injury. Current concepts and research on stem cell therapy for intestinal inflammation are summarized. Information about the stem cell origin of intestinal stromal cells may inform future stem cell therapies to treat human inflammatory bowel disease (IBD). PMID- 21252051 TI - Ear-worn body sensor network device: an objective tool for functional postoperative home recovery monitoring. AB - Patients' functional recovery at home following surgery may be evaluated by monitoring their activities of daily living. Existing tools for assessing these activities are labor-intensive to administer and rely heavily on recall. This study describes the use of a wireless ear-worn activity recognition sensor to monitor postoperative activity levels continuously using a Bayesian activity classification framework. The device was used to monitor the postoperative recovery of five patients following abdominal surgery. Activity was classified into four groups ranging from very low (level 0) to high (level 3). Overall, patients were found to be undertaking a higher proportion of level 0 activities on postoperative day 1 which was gradually replaced by higher-level activities over the next 3 days. This study demonstrates how a pervasive healthcare technology can objectively monitor functional recovery in the unsupervised home setting. This may be a useful adjunct to existing postoperative monitoring systems. PMID- 21252050 TI - Assessing alternative measures of wealth in health research. AB - OBJECTIVES: We assessed whether it would be feasible to replace the standard measure of net worth with simpler measures of wealth in population-based studies examining associations between wealth and health. METHODS: We used data from the 2004 Survey of Consumer Finances (respondents aged 25-64 years) and the 2004 Health and Retirement Survey (respondents aged 50 years or older) to construct logistic regression models relating wealth to health status and smoking. For our wealth measure, we used the standard measure of net worth as well as 9 simpler measures of wealth, and we compared results among the 10 models. RESULTS: In both data sets and for both health indicators, models using simpler wealth measures generated conclusions about the association between wealth and health that were similar to the conclusions generated by models using net worth. The magnitude and significance of the odds ratios were similar for the covariates in multivariate models, and the model-fit statistics for models using these simpler measures were similar to those for models using net worth. CONCLUSIONS: Our findings suggest that simpler measures of wealth may be acceptable in population-based studies of health. PMID- 21252049 TI - Innate immunity in alcoholic liver disease. AB - Excessive alcohol consumption is a leading cause of chronic liver disease in the Western world. Alcohol-induced hepatotoxicity and oxidative stress are important mechanisms contributing to the pathogenesis of alcoholic liver disease. However, emerging evidence suggests that activation of innate immunity involving TLR4 and complement also plays an important role in initiating alcoholic steatohepatitis and fibrosis, but the role of adaptive immunity in the pathogenesis of alcoholic liver disease remains obscure. Activation of a TLR4-mediated MyD88-independent (TRIF/IRF-3) signaling pathway in Kupffer cells contributes to alcoholic steatohepatitis, whereas activation of TLR4 signaling in hepatic stellate cells promotes liver fibrosis. Alcohol consumption activates the complement system in the liver by yet unidentified mechanisms, leading to alcoholic steatohepatitis. In contrast to activation of TLR4 and complement, alcohol consumption can inhibit natural killer cells, another important innate immunity component, contributing to alcohol-mediated acceleration of viral infection and liver fibrosis in patients with chronic viral hepatitis. Understanding of the role of innate immunity in the pathogenesis of alcoholic liver disease may help us identify novel therapeutic targets to treat this disease. PMID- 21252052 TI - Governance for clinical decision support: case studies and recommended practices from leading institutions. AB - OBJECTIVE: Clinical decision support (CDS) is a powerful tool for improving healthcare quality and ensuring patient safety; however, effective implementation of CDS requires effective clinical and technical governance structures. The authors sought to determine the range and variety of these governance structures and identify a set of recommended practices through observational study. DESIGN: Three site visits were conducted at institutions across the USA to learn about CDS capabilities and processes from clinical, technical, and organizational perspectives. Based on the results of these visits, written questionnaires were sent to the three institutions visited and two additional sites. Together, these five organizations encompass a variety of academic and community hospitals as well as small and large ambulatory practices. These organizations use both commercially available and internally developed clinical information systems. MEASUREMENTS: Characteristics of clinical information systems and CDS systems used at each site as well as governance structures and content management approaches were identified through extensive field interviews and follow-up surveys. RESULTS: Six recommended practices were identified in the area of governance, and four were identified in the area of content management. Key similarities and differences between the organizations studied were also highlighted. CONCLUSION: Each of the five sites studied contributed to the recommended practices presented in this paper for CDS governance. Since these strategies appear to be useful at a diverse range of institutions, they should be considered by any future implementers of decision support. PMID- 21252053 TI - Evaluation of computer-generated reminders to improve CD4 laboratory monitoring in sub-Saharan Africa: a prospective comparative study. AB - OBJECTIVE: Little evidence exists on effective interventions to integrate HIV care guidelines into practices within developing countries. This study tested the hypothesis that clinical summaries with computer-generated reminders could improve clinicians' compliance with CD4 testing guidelines in the resource limited setting of sub-Saharan Africa. DESIGN: A prospective comparative study of two randomly selected outpatient adult HIV clinics in western Kenya. Printed summaries with reminders for overdue CD4 tests were made available to clinicians in the intervention clinic but not in the control clinic. MEASUREMENTS: Changes in order rates for overdue CD4 tests were compared between and within the two clinics. RESULTS: The computerized reminder system identified 717 encounters (21%) with overdue CD4 tests. Analysis by study assignment (regardless of summaries being printed or not) revealed that with computer-generated reminders, CD4 order rates were significantly higher in the intervention clinic compared to the control clinic (53% vs 38%, OR = 1.80, CI 1.34 to 2.42, p < 0.0001). When comparison was restricted to encounters where summaries with reminders were printed, order rates in intervention clinic were even higher (63%). The intervention clinic increased CD4 ordering from 42% before reminders to 63% with reminders (50% increase, OR = 2.32, CI 1.67 to 3.22, p < 0.0001), compared to control clinic with only 8% increase from prestudy baseline (CI 0.83 to 1.46, p = 0.51). Limitations Evaluation was conducted at two clinics in a single institution. CONCLUSIONS: Clinical summaries with computer-generated reminders significantly improved clinician compliance with CD4 testing guidelines in the resource-limited setting of sub-Saharan Africa. This technology can have broad applicability to improve quality of HIV care in these settings. PMID- 21252054 TI - Prenatal application of the individualized fetal growth reference. AB - The individualized reference for defining small for gestational age (SGA) at birth has gained popularity in recent years. However, its utility on fetal assessment has not been evaluated. The authors compare an individualized with an ultrasound reference in predicting poor perinatal outcomes. Data from a large clinical trial in predominantly white US women (1987-1991) with singleton pregnancies (n = 9,526) were used. The individualized reference classified fewer SGA fetuses than the ultrasound reference, but the risks of adverse outcomes were similar between fetuses classified by both references. The risk increased substantially only when the percentiles fell below the 5th percentile (likelihood ratio positive at birth = 2.68 (95% confidence interval (CI): 2.00, 3.58) and 3.13 (95% CI: 2.34, 4.18) for ultrasound and individualized references, respectively). SGA fetuses defined by either the individualized or ultrasound reference alone had risk ratios of adverse outcomes of 1.91 (95% CI: 0.77, 4.77) and 1.18 (95% CI: 0.37, 3.77), respectively, compared with normal fetuses (the difference between these 2 risk ratios, P = 0.71). The authors conclude that neither the ultrasound-based nor the individualized reference does well in predicting adverse perinatal outcomes. The 5th percentile may be a better cutpoint than the 10th percentile in defining SGA. PMID- 21252055 TI - The effect of smoking on the risk of lung cancer mortality for asbestos workers in Great Britain (1971-2005). AB - OBJECTIVES: Workers in the asbestos industry tend to have high smoking rates compared to the general population. Both asbestos exposure and cigarette smoking are recognized risk factors for lung cancer mortality, but the exact nature of the interaction between the two remains uncertain. The aim of this study was to examine the effect of smoking and smoking cessation among asbestos workers in Great Britain (GB) and investigate the interaction between asbestos exposure and smoking. METHODS: The study population consisted of 98 912 asbestos workers recruited into the GB Asbestos Survey from 1971, followed-up to December 2005. Poisson regression was used to estimate relative risks of lung cancer mortality associated with smoking habits of the asbestos workers and to assess whether these effects differed within various categories of asbestos exposure. The interaction between asbestos exposure and smoking was examined using the Synergy (S) and Multiplicativity (V) indices, which test the hypotheses of additive and multiplicative interaction, respectively. The proportion of lung cancers among smokers attributable to the interaction of asbestos and smoking was also estimated. RESULTS: During 1 780 233 person-years of follow-up, there were 1878 deaths from lung cancer (12% of all deaths). Risk of lung cancer mortality increased with packs smoked per day, smoking duration, and total smoke exposure (pack-years). Asbestos workers who stopped smoking remained at increased risk of lung cancer mortality up to 40 years after smoking cessation compared to asbestos workers who never smoked. The effects of smoking and stopping smoking did not differ by duration of asbestos exposure, main occupation, age at first asbestos exposure, year of first exposure, or latency period. The interaction between asbestos exposure and smoking for asbestos workers was greater than additive [S 1.4, 95% confidence interval (CI) 1.2-1.6], and the multiplicative hypothesis could not be rejected (V 0.9, 95% CI 0.3-2.4). For those asbestos workers who smoked, an estimated 26% (95% CI 14-38%) of lung cancer deaths were attributable to the interaction of asbestos and smoking. CONCLUSIONS: This study emphasizes the importance of smoking prevention and cessation among those who work in the asbestos industry. PMID- 21252056 TI - Biological monitoring for isocyanates. AB - Isocyanates are reactive chemicals and thousands of workers may be exposed to them during their manufacture and use in a wide range of products. They are classed as sensitizers and are a major cause of occupational asthma in the UK. Workplace exposure limits are low and control of exposure often depends on personal respiratory protection. Biological monitoring is increasingly used to assess exposure and the efficacy of control measures, including the behavioural aspects of controls. Biological monitoring methods are available for the most common isocyanates hexamethylene diisocyanate, toluene diisocyanate, isophorone diisocyanate, and methylenediphenyl diisocyanate. They are based on the analysis of hexamethylene diamine, toluene diamine, isopherone diamine, and methylenediamine released after hydrolysis of isocyanate-protein adducts in urine or blood. Volunteer and occupational studies show good correlations between inhalation exposure to isocyanate monomers and isocyanate-derived diamines in urine or blood. However, occupational exposure to isocyanates is often to a mixture of monomers and oligomers so there is some uncertainty comparing biological monitoring results with airborne exposure to 'total NCO'. Nevertheless, there is a substantial body of work demonstrating the utility of biological monitoring as a tool to assess exposure and the efficacy of controls, including how they are used in practice. Non-health-based biological monitoring guidance values are available to help target when and where further action is required. Occupational hygienists will need to use their knowledge and experience to determine the relative contributions of different routes of exposure and how controls can be improved to reduced the risk of ill health. PMID- 21252057 TI - Novel approaches and future directions in castration-resistant prostate cancer. AB - Recent advances in the treatment of castration-resistant prostate cancer (CRPC) have started to change the therapeutic landscape allowing clinicians to choose from a broad range of treatment options. Understanding the mechanisms that transform prostate cancer (PCA) into a castration-resistant state has enabled investigators to explore critical pathways involved in such process allowing for rational therapeutic design. These novel therapies complement the modest success that chemotherapy has demonstrated in recent years. In this review, we discuss the different mechanisms that render PCA castration resistant and elaborate on the nonchemotherapy approaches evolving in CRPC. These include agents targeting the epidermal growth factor receptor, endothelin receptor antagonists, angiogenesis inhibitors, immunomodulatory agents, immunotherapy, novel antiandrogens, and delivery of cytotoxic agents via therapeutic antibodies. This timely review coincides with the identification of newer therapies in this setting affirming our steady movement towards better disease control. PMID- 21252058 TI - Advanced breast cancer incidence following population-based mammographic screening. AB - BACKGROUND: Breast cancer mortality is declining in many Western countries. If mammography screening contributed to decreases in mortality, then decreases in advanced breast cancer incidence should also be noticeable. PATIENTS AND METHODS: We assessed incidence trends of advanced breast cancer in areas where mammography screening is practiced for at least 7 years with 60% minimum participation and where population-based registration of advanced breast cancer existed. Through a systematic Medline search, we identified relevant published data for Australia, Italy, Norway, Switzerland, The Netherlands, U.K. and the U.S.A. Data from cancer registries in Northern Ireland, Scotland, the U.S.A. (Surveillance, Epidemiology and End Results (SEER), and Connecticut), and Tasmania (Australia) were available for the study. Criterion for advanced cancer was the tumour size, and if not available, spread to regional/distant sites. RESULTS: Age-adjusted annual percent changes (APCs) were stable or increasing in ten areas (APCs of -0.5% to 1.7%). In four areas (Firenze, the Netherlands, SEER and Connecticut) there were transient downward trends followed by increases back to pre-screening rates. CONCLUSIONS: In areas with widespread sustained mammographic screening, trends in advanced breast cancer incidence do not support a substantial role for screening in the decrease in mortality. PMID- 21252059 TI - A large single-center experience with allogeneic stem-cell transplantation for peripheral T-cell non-Hodgkin lymphoma and advanced mycosis fungoides/Sezary syndrome. AB - BACKGROUND: The prognosis for patients with most forms of T-cell lymphoma is poor. Allogeneic hematopoietic stem-cell transplantation (HSCT) may improve the outcome. PATIENTS AND METHODS: This study examines the outcome of 52 patients who underwent ablative or nonablative allogeneic HSCT for peripheral T-cell lymphoma (PTCL) or advanced mycosis fungoides/Sezary syndrome over a 12-year period at a single institution. We divided the patients into those with predominantly nodal histologies: peripheral T-cell not otherwise specified (PTCL NOS), angioimmunoblastic (AITL), or anaplastic large cell lymphoma, T/null type (systemic) (ALCL), and predominantly extranodal histologies: natural killer (NK)/T cell, enteropathy type, hepatosplenic, subcutaneous panniculitic, mycosis fungoides, or T cell or NK cell other. RESULTS: Median follow-up of survivors is 49 months. Non-relapse mortality and relapse at 3 years was 27% and 43%, respectively. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 21%. The incidence of extensive chronic GVHD at 2 years was 27%. The 3-year progression-free survival was 30%: 45% in patients with predominantly nodal histologies (PTCL NOS, AITL, and ALCL) and 6% in patients with predominantly extranodal histologies (P = 0.016). Overall survival at 3 years was 41% for all patients. CONCLUSION: Allogeneic HSCT can produce long-term remissions in relapsed/refractory T-cell lymphoma, especially those with nodal histologies. PMID- 21252062 TI - Steroid-induced alterations of behaviour during treatment for acute lymphoblastic leukaemia: a sibling's description. PMID- 21252061 TI - Quality of life, geriatric assessment and survival in elderly patients with non small-cell lung cancer treated with carboplatin-gemcitabine or carboplatin paclitaxel: NVALT-3 a phase III study. AB - BACKGROUND: Elderly patients with advanced non-small-cell lung cancer (NSCLC) may derive similar benefit from platinum-based chemotherapy as younger patients. Quality of life (QoL) and comprehensive geriatric assessment (CGA) is often advocated to assess benefits and risks. PATIENTS AND METHODS: A total of 181 chemotherapy-naive patients [>=70 years, performance score (PS) of 0-2] with stage III-IV NSCLC received carboplatin and gemcitabine (CG) (n = 90) or carboplatin and paclitaxel (CP) (n = 91) every 3 weeks for up to four cycles. Primary end point was change in global QoL from baseline compared with week 18. Pretreatment CGA and mini geriatric assessment during and after treatment were undertaken. A principal component (PC) analysis was carried out to determine the underlying dimensions of CGA and QoL and subsequently related to survival. RESULTS: There were no changes in QoL after treatment. The number of QoL responders (CG arm, 12%; CP arm, 5%) was not significantly different. CGA items were only associated with neuropsychiatric toxicity. Quality-adjusted survival was not different between treatment arms. The PC analysis derived from nine CGA, six QoL and one PS score indicated only one dominant dimension. This dimension was strongly prognostic, and physical and role functioning, Groningen Frailty Indicator and Geriatric Depression Scale were its largest contributors. CONCLUSIONS: Paclitaxel or gemcitabine added to carboplatin did not have a differential effect on global QoL. CGA was associated with toxic effects in a very limited manner. CGA and QoL items measure one underlying dimension, which is highly prognostic. PMID- 21252060 TI - Primary plasma cell leukemia: a retrospective multicenter study of 73 patients. AB - BACKGROUND: Epidemiological and clinical information on primary plasma cell leukemia (pPCL) are rarely reported. The aims are to evaluate the clinical features, prognostic factors, and efficacy of treatments in pPCL. PATIENTS AND METHODS: A multicenter retrospective cohort study was carried out from January 2000 to December 2008 in 26 Italian hematology divisions. A total of 128 cases of plasma cell leukemia were collected, and 73 of them (57%) were classified as primary (male/female 43/30). RESULTS: Sixty-four patients had at least 1 sign of end-organ damage and 10 had extramedullary localization. One patient died early; of the remaining patients, 36 (50%) received anthracycline-based regimens as first-line therapy, 17 (24%) single alkylating agents, and 30 (42%) bortezomib or thalidomide as additional (n = 11) or unique treatments (n = 19). Twenty-three patients (31%) underwent autologous and/or allogeneic hematopoietic stem cell transplantation (HSCT). The median overall survival (OS) was 12.6 months; complete or partial response was achieved in 22 (30%) and 18 patients (25%), respectively; the median duration of response (DOR) was 16.4 months. HSCT patients had a longer OS and DOR (median 38.1 and 25.8 months, respectively) compared with nontransplanted patients (9.1 and 7.3 months, respectively, P < 0.001). OS was influenced by nonresponse to treatment, hypoalbuminemia, and HSCT. DOR was favorably influenced only by HSCT. CONCLUSIONS: pPCL is an aggressive disease with a poor prognosis and a low response rate to conventional therapy. HSCT is effective, increasing OS and DOR by 69% and 88%, respectively. The use of bortezomib and thalidomide may improve outcomes. PMID- 21252063 TI - Ossification centres, not rib fractures. PMID- 21252064 TI - Cosegregation of aortic root atherosclerosis and intermediate lipid phenotypes on chromosomes 2 and 8 in an intercross of C57BL/6 and BALBc/ByJ low-density lipoprotein receptor-/- mice. AB - OBJECTIVE: We sought to identify novel atherosclerosis-modifying loci and their potential functional links in a genome-wide approach using cosegregation analysis of atherosclerosis and related intermediate phenotypes in mice. METHODS AND RESULTS: We carried out an F2 intercross between atherosclerosis-susceptible C57BL/6 mice and atherosclerosis-resistant BALB/cByJ mice on the low-density lipoprotein receptor(-/-) background to examine the genetic basis for their differences in atherosclerosis susceptibility. Atherosclerotic lesion size and a comprehensive panel of 61 atherosclerosis-related phenotypes, including plasma levels of lipids, cytokines, and chemokines were measured in 376 F2 mice. Quantitative trait locus mapping revealed a novel significant locus (logarithm of odds, 6.18) for atherosclerosis on proximal mouse chromosome (Chr) 2 (Ath39), which was associated with major variations in lesion size (14%). Plasma very-low density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, lanosterol, and phytosterol levels cosegregated with atherosclerosis at this locus. Moreover, these lipid traits showed significant correlations with lesion size, suggesting that they share the same underlying genetic factor. We also describe a second male-specific locus on Chr 8 (Ath40) where atherosclerosis and lipids cosegregated. CONCLUSIONS: Our study revealed new loci for atherosclerosis susceptibility on mouse Chr 2 and 8, which might exert their effects on lesion size via plasma lipid levels. PMID- 21252065 TI - Platelet protein kinase C-theta deficiency with human RUNX1 mutation: PRKCQ is a transcriptional target of RUNX1. AB - OBJECTIVE: Mutations in the hematopoietic transcription factor RUNX1 cause thrombocytopenia and impaired platelet function. In a patient with a heterozygous mutation in RUNX1, we have described decreased platelet pleckstrin phosphorylation and protein kinase C- (PKC-, gene PRKCQ) associated with thrombocytopenia, impaired platelet aggregation, and dense granule secretion. Little is known regarding regulation of PKC- in megakaryocytes and platelets. We have addressed the hypothesis that PRKCQ is a direct transcriptional target of RUNX1. METHODS AND RESULTS: In a chromatin immunoprecipitation assay using megakaryocytic cells, there was RUNX1 binding in vivo to PRKCQ promoter region 1225 to -1056 bp containing a RUNX1 consensus site ACCGCA at -1088 to -1069 bp; an electrophoretic mobility shift assay showed RUNX1 binding to the specific site. In RUNX1 overexpression studies, PKC- protein expression and promoter activity were enhanced; mutation of RUNX1 site showed decreased activity even with RUNX1 overexpression. Lastly, PRKCQ promoter activity and PKC- protein were decreased by short interfering RNA knockdown of RUNX1. CONCLUSIONS: Our results provide the first evidence that PRKCQ is regulated at the transcriptional level by RUNX1 in megakaryocytic cells and a mechanism for PKC- deficiency associated with RUNX1 haplodeficiency. PMID- 21252066 TI - Tissue factor-bearing microparticles and thrombus formation. AB - Blood microparticles are vesicular structures with a diameter of 100 to 1000 nm that are present in the blood of normal subjects and in patients with various diseases. These microparticles are derived from cells that circulate in the blood and cells associated with the blood vessel wall. Microparticle membranes retain the protein receptors of their parent cells and may retain RNAs and other cytosolic content. On the basis of surface protein expression, microparticles are known to be derived from platelets, granulocytes, monocytes, endothelial cells, smooth muscle cells, and tumor cells. Only a subpopulation of these microparticles expresses tissue factor. PMID- 21252067 TI - Novel role of platelets in mediating inflammatory responses and ventricular rupture or remodeling following myocardial infarction. AB - OBJECTIVE: The goal of this study was to investigate the role of platelets in systemic and cardiac inflammatory responses and the development of postinfarct ventricular complications, as well as the efficacy of antiplatelet interventions. METHODS AND RESULTS: Using a mouse myocardial infarction (MI) model, we determined platelet accumulation and severity of inflammation within the infarcted myocardium by immunohistochemistry and biochemical assays, analyzed peripheral blood platelet-leukocyte conjugation using flow cytometry, and tested antiplatelet interventions, including thienopyridines and platelet depletion. Platelets accumulated within the infarcted region early post-MI and colocalized with inflammatory cells. MI evoked early increase in circulating platelet leukocyte conjugation mediated by P-selectin/P-selectin glycoprotein ligand-1. Antiplatelet interventions inhibited platelet-leukocyte conjugation in peripheral blood, inflammatory infiltration, content of matrix metalloproteinases or plasminogen activation, and expression of inflammatory mediators in the infarcted myocardium (all P<0.05) and lowered rupture incidence (P<0.01). Clopidogrel therapy alleviated the extent of chronic ventricular dilatation by serial echocardiography. CONCLUSIONS: Platelets play a pivotal role in promoting systemic and cardiac inflammatory responses post-MI. Platelets accumulate within the infarcted myocardium, contributing to regional inflammation, ventricular remodeling, and rupture. Antiplatelet therapy reduces the severity of inflammation and risk of post-MI complications, demonstrating a previously unrecognized protective action. PMID- 21252068 TI - Worsening of diet-induced atherosclerosis in a new model of transgenic rabbit expressing the human plasma phospholipid transfer protein. AB - OBJECTIVE: Plasma phospholipid transfer protein (PLTP) is involved in intravascular lipoprotein metabolism. PLTP is known to act through 2 main mechanisms: by remodeling high-density lipoproteins (HDL) and by increasing apolipoprotein (apo) B-containing lipoproteins. The aim of this study was to generate a new model of human PLTP transgenic (HuPLTPTg) rabbit and to determine whether PLTP expression modulates atherosclerosis in this species that, unlike humans and mice, displays naturally very low PLTP activity. METHODS AND RESULTS: In HuPLTPTg rabbits, the human PLTP cDNA was placed under the control of the human eF1-alpha gene promoter, resulting in a widespread tissue expression pattern and in increased plasma PLTP. The HuPLTPTg rabbits showed a significant increase in the cholesterol content of the plasma apoB-containing lipoprotein fractions, with a more severe trait when animals were fed a cholesterol-rich diet. In contrast, HDL cholesterol level was not modified in HuPLTPTg rabbits. Formation of aortic fatty streaks was increased in hypercholesterolemic HuPLTPTg animals as compared with nontransgenic littermates. CONCLUSIONS: Human PLTP expression in HuPLTPTg rabbit worsens atherosclerosis as a result of increased levels of atherogenic apoB-containing lipoproteins but not of alterations in their antioxidative protection or in cholesterol content of plasma HDL. PMID- 21252069 TI - Angiotensin-converting enzyme 2 deficiency in whole body or bone marrow-derived cells increases atherosclerosis in low-density lipoprotein receptor-/- mice. AB - OBJECTIVE: The renin-angiotensin system contributes to atherosclerotic lesion formation. Angiotensin-converting enzyme 2 (ACE2) catabolizes angiotensin II (Ang II) to angiotensin 1-7 (Ang-(1-7)) to limit effects of the renin-angiotensin system. The purpose of this study was to define the role of ACE2 in atherosclerosis. METHODS AND RESULTS: Male Ace2(-/y) mice in an low-density lipoprotein receptor-deficient background were fed a high-fat diet for 3 months. ACE2 deficiency increased atherosclerotic area (Ace2(+/y), 17 +/- 1; Ace2(-/y), 23 +/- 2 mm(2), P < 0.002). This increase was blunted by losartan. To determine whether leukocytic ACE2 influenced atherosclerosis, irradiated low-density lipoprotein receptor-deficient male mice were repopulated with bone marrow derived cells from Ace2(+/y) or Ace2(-/y) mice and fed a high-fat diet for 3 months. ACE2 deficiency in bone marrow-derived cells increased atherosclerotic area (Ace2(+/y), 1.6 +/- 0.3; Ace2(-/y), 2.8 +/- 0.3 mm(2); P < 0.05). Macrophages from Ace2(-/y) mice exhibited increased Ang II secretion and elevated expression of inflammatory cytokines. Conditioned media from mouse peritoneal macrophages of Ace2(-/y) mice increased monocyte adhesion to human umbilical vein endothelial cells. Incubation of human umbilical vein endothelial cells with Ang II promoted monocyte adhesion, which was blocked by Ang-(1-7). Coinfusion of Ang (1-7) with Ang II reduced atherosclerosis. CONCLUSIONS: These results demonstrate that ACE2 deficiency in bone marrow-derived cells promotes atherosclerosis through regulation of Ang II/Ang-(1-7) peptides. PMID- 21252071 TI - Cleaved high-molecular-weight kininogen accelerates the onset of endothelial progenitor cell senescence by induction of reactive oxygen species. AB - OBJECTIVE: Cleaved high-molecular-weight kininogen (HKa), an activation product of the plasma kallikrein-kinin system, inhibits endothelial cell functions. We questioned whether HKa affects the function of endothelial progenitor cells (EPCs) and accelerates their senescence. METHODS AND RESULTS: Treatment with HKa for 2 weeks markedly inhibited the formation of large colonies and proliferation of EPCs on collagen surfaces, whereas HKa did not affect collagen-mediated EPC adhesion and survival. Concomitantly, treated EPCs displayed flattened and giant cell morphological changes and formation of intracellular vacuoles. As determined by acidic beta-galactosidase staining, HKa increased senescent EPCs by 2- and >3 fold after culture for 1 and 2 weeks, respectively. In addition, HKa suppressed the telomerase activity of EPCs. HKa concentration-dependently increased the generation of intracellular reactive oxygen species (ROS) and markedly upregulated p38 kinase phosphorylation and prosenescence molecule p16(INK4a) expression. SB203580, a p38 inhibitor, attenuated the level of HKa-enhanced p16(INK4a) expression. Either quenching of ROS or inhibition of p38 kinase prevented HKa-induced EPC senescence. CONCLUSIONS: HKa accelerates the onset of EPC senescence by activating the ROS-p38 kinase-p16(INK4a) signaling cascade. This novel activity of HKa points out the likelihood of HKa serving as an endogenous inducer of EPC senescence. PMID- 21252070 TI - Detection of macrophages in aortic aneurysms by nanoparticle positron emission tomography-computed tomography. AB - OBJECTIVE: Current management of aortic aneurysms (AAs) relies primarily on size criteria to determine whether invasive repair is indicated to preempt rupture. We hypothesized that emerging molecular imaging tools could be used to more sensitively gauge local inflammation. Because macrophages are key effector cells that destabilize the extracellular matrix in the arterial wall, it seemed likely that they would represent suitable imaging targets. We here aimed to develop and validate macrophage-targeted nanoparticles labeled with fluorine-18 ((18)F) for positron emission tomography-computed tomography (PET-CT) detection of inflammation in AAs. METHODS AND RESULTS: Aneurysms were induced in apolipoprotein E-/- mice via systemic administration of angiotensin II. Mice were imaged using PET-CT and a monocyte/macrophage-targeted nanoparticle. AAs were detected by contrast-enhanced micro-CT and had a mean diameter of 1.85 +/- 0.08 mm, whereas normal aortas measured 1.07 +/- 0.03 (P < 0.05). The in vivo PET signal was significantly higher in aneurysms (standard uptake value, 2.46 +/- 0.48) compared with wild-type aorta (0.82 +/- 0.05, P < 0.05). Validation with scintillation counting, autoradiography, fluorescence, and immunoreactive histology and flow cytometry demonstrated that nanoparticles localized predominantly to monocytes and macrophages within the aneurysmatic wall. CONCLUSIONS: PET-CT imaging with (18)F-labeled nanoparticles allows quantitation of macrophage content in a mouse model of AA. PMID- 21252072 TI - Critical assessment of high-throughput standalone methods for secondary structure prediction. AB - Sequence-based prediction of protein secondary structure (SS) enjoys wide-spread and increasing use for the analysis and prediction of numerous structural and functional characteristics of proteins. The lack of a recent comprehensive and large-scale comparison of the numerous prediction methods results in an often arbitrary selection of a SS predictor. To address this void, we compare and analyze 12 popular, standalone and high-throughput predictors on a large set of 1975 proteins to provide in-depth, novel and practical insights. We show that there is no universally best predictor and thus detailed comparative studies are needed to support informed selection of SS predictors for a given application. Our study shows that the three-state accuracy (Q3) and segment overlap (SOV3) of the SS prediction currently reach 82% and 81%, respectively. We demonstrate that carefully designed consensus-based predictors improve the Q3 by additional 2% and that homology modeling-based methods are significantly better by 1.5% Q3 than ab initio approaches. Our empirical analysis reveals that solvent exposed and flexible coils are predicted with a higher quality than the buried and rigid coils, while inverse is true for the strands and helices. We also show that longer helices are easier to predict, which is in contrast to longer strands that are harder to find. The current methods confuse 1-6% of strand residues with helical residues and vice versa and they perform poorly for residues in the beta- bridge and 3(10)-helix conformations. Finally, we compare predictions of the standalone implementations of four well-performing methods with their corresponding web servers. PMID- 21252073 TI - Compression of DNA sequence reads in FASTQ format. AB - MOTIVATION: Modern sequencing instruments are able to generate at least hundreds of millions short reads of genomic data. Those huge volumes of data require effective means to store them, provide quick access to any record and enable fast decompression. RESULTS: We present a specialized compression algorithm for genomic data in FASTQ format which dominates its competitor, G-SQZ, as is shown on a number of datasets from the 1000 Genomes Project (www.1000genomes.org). AVAILABILITY: DSRC is freely available at http:/sun.aei.polsl.pl/dsrc. PMID- 21252074 TI - PhyloPro: a web-based tool for the generation and visualization of phylogenetic profiles across Eukarya. AB - SUMMARY: With increasing numbers of eukaryotic genome sequences, phylogenetic profiles of eukaryotic genes are becoming increasingly informative. Here, we introduce a new web-tool Phylopro (http://compsysbio.org/phylopro/), which uses the 120 available eukaryotic genome sequences to visualize the evolutionary trajectories of user-defined subsets of model organism genes. Applied to pathways or complexes, PhyloPro allows the user to rapidly identify core conserved elements of biological processes together with those that may represent lineage specific innovations. PhyloPro thus provides a valuable resource for the evolutionary and comparative studies of biological systems. PMID- 21252075 TI - Dalliance: interactive genome viewing on the web. AB - SUMMARY: Dalliance is a new genome viewer which offers a high level of interactivity while running within a web browser. All data is fetched using the established distributed annotation system (DAS) protocol, making it easy to customize the browser and add extra data. AVAILABILITY AND IMPLEMENTATION: Dalliance runs entirely within your web browser, and relies on existing DAS server infrastructure. Browsers for several mammalian genomes are available at http://www.biodalliance.org/, and the use of DAS means you can add your own data to these browsers. In addition, the source code (Javascript) is available under the BSD license, and is straightforward to install on your own web server and embed within other documents. PMID- 21252076 TI - Length bias correction for RNA-seq data in gene set analyses. AB - MOTIVATION: Next-generation sequencing technologies are being rapidly applied to quantifying transcripts (RNA-seq). However, due to the unique properties of the RNA-seq data, the differential expression of longer transcripts is more likely to be identified than that of shorter transcripts with the same effect size. This bias complicates the downstream gene set analysis (GSA) because the methods for GSA previously developed for microarray data are based on the assumption that genes with same effect size have equal probability (power) to be identified as significantly differentially expressed. Since transcript length is not related to gene expression, adjusting for such length dependency in GSA becomes necessary. RESULTS: In this article, we proposed two approaches for transcript-length adjustment for analyses based on Poisson models: (i) At individual gene level, we adjusted each gene's test statistic using the square root of transcript length followed by testing for gene set using the Wilcoxon rank-sum test. (ii) At gene set level, we adjusted the null distribution for the Fisher's exact test by weighting the identification probability of each gene using the square root of its transcript length. We evaluated these two approaches using simulations and a real dataset, and showed that these methods can effectively reduce the transcript length biases. The top-ranked GO terms obtained from the proposed adjustments show more overlaps with the microarray results. AVAILABILITY: R scripts are at http://www.soph.uab.edu/Statgenetics/People/XCui/r-codes/. PMID- 21252077 TI - Biological assessment of robust noise models in microarray data analysis. AB - MOTIVATION: Although several recently proposed analysis packages for microarray data can cope with heavy-tailed noise, many applications rely on Gaussian assumptions. Gaussian noise models foster computational efficiency. This comes, however, at the expense of increased sensitivity to outlying observations. Assessing potential insufficiencies of Gaussian noise in microarray data analysis is thus important and of general interest. RESULTS: We propose to this end assessing different noise models on a large number of microarray experiments. The goodness of fit of noise models is quantified by a hierarchical Bayesian analysis of variance model, which predicts normalized expression values as a mixture of a Gaussian density and t-distributions with adjustable degrees of freedom. Inference of differentially expressed genes is taken into consideration at a second mixing level. For attaining far reaching validity, our investigations cover a wide range of analysis platforms and experimental settings. As the most striking result, we find irrespective of the chosen preprocessing and normalization method in all experiments that a heavy-tailed noise model is a better fit than a simple Gaussian. Further investigations revealed that an appropriate choice of noise model has a considerable influence on biological interpretations drawn at the level of inferred genes and gene ontology terms. We conclude from our investigation that neglecting the over dispersed noise in microarray data can mislead scientific discovery and suggest that the convenience of Gaussian-based modelling should be replaced by non-parametric approaches or other methods that account for heavy-tailed noise. PMID- 21252078 TI - Exploration of empirical Bayes hierarchical modeling for the analysis of genome wide association study data. AB - In the analysis of genome-wide association (GWA) data, the aim is to detect statistical associations between single nucleotide polymorphisms (SNPs) and the disease or trait of interest. These SNPs, or the particular regions of the genome they implicate, are then considered for further study. We demonstrate through a comprehensive simulation study that the inclusion of additional, biologically relevant information through a 2-level empirical Bayes hierachical model framework offers a more robust method of detecting associated SNPs. The empirical Bayes approach is an objective means of analyzing the data without the need for the setting of subjective parameter estimates. This framework gives more stable estimates of effects through a reduction of the variability in the usual effect estimates. We also demonstrate the consequences of including additional information that is not informative and examine power and false-positive rates. We apply the methodology to a number of genome-wide association (GWA) data sets with the inclusion of additional biological information. Our results agree with previous findings and in the case of one data set (Crohn's disease) suggest an additional region of interest. PMID- 21252079 TI - Causal assessment of surrogacy in a meta-analysis of colorectal cancer trials. AB - When the true end points (T) are difficult or costly to measure, surrogate markers (S) are often collected in clinical trials to help predict the effect of the treatment (Z). There is great interest in understanding the relationship among S, T, and Z. A principal stratification (PS) framework has been proposed by Frangakis and Rubin (2002) to study their causal associations. In this paper, we extend the framework to a multiple trial setting and propose a Bayesian hierarchical PS model to assess surrogacy. We apply the method to data from a large collection of colon cancer trials in which S and T are binary. We obtain the trial-specific causal measures among S, T, and Z, as well as their overall population-level counterparts that are invariant across trials. The method allows for information sharing across trials and reduces the nonidentifiability problem. We examine the frequentist properties of our model estimates and the impact of the monotonicity assumption using simulations. We also illustrate the challenges in evaluating surrogacy in the counterfactual framework that result from nonidentifiability. PMID- 21252080 TI - Efficient measurement error correction with spatially misaligned data. AB - Association studies in environmental statistics often involve exposure and outcome data that are misaligned in space. A common strategy is to employ a spatial model such as universal kriging to predict exposures at locations with outcome data and then estimate a regression parameter of interest using the predicted exposures. This results in measurement error because the predicted exposures do not correspond exactly to the true values. We characterize the measurement error by decomposing it into Berkson-like and classical-like components. One correction approach is the parametric bootstrap, which is effective but computationally intensive since it requires solving a nonlinear optimization problem for the exposure model parameters in each bootstrap sample. We propose a less computationally intensive alternative termed the "parameter bootstrap" that only requires solving one nonlinear optimization problem, and we also compare bootstrap methods to other recently proposed methods. We illustrate our methodology in simulations and with publicly available data from the Environmental Protection Agency. PMID- 21252081 TI - Biological pathway selection through nonlinear dimension reduction. AB - In the analysis of high-throughput biological data, it is often believed that the biological units such as genes behave interactively by groups, that is, pathways in our context. It is conceivable that utilization of priorly available pathway knowledge would greatly facilitate both interpretation and estimation in statistical analysis of such high-dimensional biological data. In this article, we propose a 2-step procedure for the purpose of identifying pathways that are related to and influence the clinical phenotype. In the first step, a nonlinear dimension reduction method is proposed, which permits flexible within-pathway gene interactions as well as nonlinear pathway effects on the response. In the second step, a regularized model-based pathway ranking and selection procedure is developed that is built upon the summary features extracted from the first step. Simulations suggest that the new method performs favorably compared to the existing solutions. An analysis of a glioblastoma microarray data finds 4 pathways that have evidence of support from the biological literature. PMID- 21252082 TI - Semiparametric inference for a 2-stage outcome-auxiliary-dependent sampling design with continuous outcome. AB - Two-stage design has long been recognized to be a cost-effective way for conducting biomedical studies. In many trials, auxiliary covariate information may also be available, and it is of interest to exploit these auxiliary data to improve the efficiency of inferences. In this paper, we propose a 2-stage design with continuous outcome where the second-stage data is sampled with an "outcome auxiliary-dependent sampling" (OADS) scheme. We propose an estimator which is the maximizer for an estimated likelihood function. We show that the proposed estimator is consistent and asymptotically normally distributed. The simulation study indicates that greater study efficiency gains can be achieved under the proposed 2-stage OADS design by utilizing the auxiliary covariate information when compared with other alternative sampling schemes. We illustrate the proposed method by analyzing a data set from an environmental epidemiologic study. PMID- 21252083 TI - Clinical presentation and group classification of newly diagnosed intraocular retinoblastoma in China. AB - Aim To describe the clinical presentation and group classification of newly diagnosed retinoblastoma patients in China, and to identify future priorities for improving the medical care of this disease. Methods The retrospective review included all patients who presented with previously untreated intraocular retinoblastoma at Beijing Tongren Hospital between August 2006 and August 2009. The clinical charts were reviewed and fundus images taken for all patients were analysed. The tumours were classified according to the International Intraocular Retinoblastoma Classification. Results The study included 595 eyes (470 patients) with untreated retinoblastoma. The mean age at diagnosis was 23 months, with 84% of the patients being younger than 3 years at the time of diagnosis. Bilateral retinoblastoma was present in 150 (32%) of the patients. Bilateral retinoblastoma as compared with unilateral retinoblastoma was diagnosed at a significantly (p<0.001) younger mean age (15 months vs 27 months). Leucocoria was the most common leading sign (73% of patients). The vast majority of eyes (501/595 or 84%) presented with an advanced stage of the tumour (Group D or E of International Intraocular Retinoblastoma Classification). Conclusion In China, diagnosis of retinoblastoma occurs at a relatively advanced clinical stage of the disease. An intensified programme for earlier detection of retinoblastoma including educating parents and physicians may be warranted to improve clinical outcome with fewer enucleations. PMID- 21252084 TI - A randomised placebo-controlled trial of topical steroid in presumed viral conjunctivitis. AB - AIMS: To assess whether topical steroids improve patient comfort compared with hypromellose in acute presumed viral conjunctivitis. METHODS: Patients presenting with acute follicular conjunctivitis, presumed viral in origin, were randomised to receive either dexamethasone 0.1% or hypromellose 0.3% drops four times daily for 1 week. At review after 5-7 days patients completed questionnaires on whether they thought the treatment had helped and on their level of discomfort. A physician assessed conjunctival hyperaemia using a grading scale. RESULTS: 111 patients were randomised: 56 received dexamethasone drops and 55 received hypromellose lubricant drops. Eighty-eight returned for review. Most patients (39/45 (87%)) receiving dexamethasone and most of those receiving hypromellose 30/43 (70%) felt that the treatment helped. Analysis of all responses showed a significant difference between treatments (p=0.0248, rank sum test). No significant differences between dexamethasone and hypromellose arms were found in the patients' perceived level of discomfort or the physician grading of conjunctival hyperaemia. No patient experienced a serious complication. CONCLUSIONS: There us now evidence to support the use of a short course of topical dexamethasone for patients presenting with acute follicular conjunctivitis presumed to be viral in origin. Where topical dexamethasone is prescribed we have not found it to be harmful. TRIAL REGISTRATION: http://www.controlled-trials.com/ISRCTN50728656. PMID- 21252085 TI - Adjuvant 5-fluorouracil in the treatment of localised ocular surface squamous neoplasia. AB - AIM: To report the outcome of treatment of localised non-invasive ocular surface squamous neoplasia (OSSN) where topical 5-fluorouracil (5-FU 1%) is used as an adjuvant to surgical excision. METHODS: The study was a prospective non comparative interventional case series. 55 cases of primary localised OSSN and 10 cases of recurrent localised OSSN were treated with excision, cryotherapy and adjuvant 5-FU 1%. In all cases, irrespective of the involvement of surgical margins, a single cycle of 5-FU 1% was administered, four times a day for 2 weeks continuously. The main outcome measures were (1) recurrence and (2) complications related to adjuvant topical chemotherapy. Individuals were reviewed for a minimum of 12 months. RESULTS: There was a single case of recurrence (1.5%). 57% of patients had short-term complications secondary to 5-FU 1%, most frequently lid toxicity (49%), followed by superficial keratitis, epiphora and corneal epithelial defects. Four patients were unable to complete the course of 5-FU 1% because of local toxicity. CONCLUSIONS: The management of localised non-invasive OSSN with adjuvant 5-FU 1% was associated with a low rate of local recurrence. Although 5-FU 1% frequently results in short-term complications, most commonly lid toxicity, a full course is usually tolerated. Serious complications appear uncommon in the treatment of localised disease. PMID- 21252086 TI - BJSM reviews: A-Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance. Part 17. PMID- 21252087 TI - Interval and continuous training are similarly effective in chronic obstructive pulmonary disease. PMID- 21252088 TI - Factor VIIa bound to endothelial cell protein C receptor activates protease activated receptor-1 and mediates cell signaling and barrier protection. AB - Recent studies have shown that factor VIIa (FVIIa) binds to the endothelial cell protein C receptor (EPCR), a cellular receptor for protein C and activated protein C, but the physiologic significance of this interaction is unclear. In the present study, we show that FVIIa, upon binding to EPCR on endothelial cells, activates endogenous protease activated receptor-1 (PAR1) and induces PAR1 mediated p44/42 mitogen-activated protein kinase (MAPK) activation. Pretreatment of endothelial cells with FVIIa protected against thrombin-induced barrier disruption. This FVIIa-induced, barrier-protective effect was EPCR dependent and did not involve PAR2. Pretreatment of confluent endothelial monolayers with FVIIa before thrombin reduced the development of thrombin-induced transcellular actin stress fibers, cellular contractions, and paracellular gap formation. FVIIa induced p44/42 MAPK activation and the barrier-protective effect are mediated via Rac1 activation. Consistent with in vitro findings, in vivo studies using mice showed that administration of FVIIa before lipopolysaccharide (LPS) treatment attenuated LPS-induced vascular leakage in the lung and kidney. Overall, our present data provide evidence that FVIIa bound to EPCR on endothelial cells activates PAR1-mediated cell signaling and provides a barrier-protective effect. These findings are novel and of great clinical significance, because FVIIa is used clinically for the prevention of bleeding in hemophilia and other bleeding disorders. PMID- 21252089 TI - Coagulation-induced shedding of platelet glycoprotein VI mediated by factor Xa. AB - This study evaluated shedding of the platelet collagen receptor, glycoprotein VI (GPVI) in human plasma. Collagen or other ligands induce metalloproteinase mediated GPVI ectodomain shedding, generating approximately 55-kDa soluble GPVI (sGPVI) and approximately 10-kDa platelet-associated fragments. In the absence of GPVI ligands, coagulation of platelet-rich plasma from healthy persons induced GPVI shedding, independent of added tissue factor, but inhibitable by metalloproteinase inhibitor, GM6001. Factor Xa (FXa) common to intrinsic and tissue factor-mediated coagulation pathways was critical for sGPVI release because (1) shedding was strongly blocked by the FXa-selective inhibitor rivaroxaban but not FIIa (thrombin) inhibitors dabigatran or hirudin; (2) Russell viper venom that directly activates FX generated sGPVI, with complete inhibition by enoxaparin (inhibits FXa and FIIa) but not hirudin; (3) impaired GPVI shedding during coagulation of washed platelets resuspended in FX-depleted plasma was restored by adding purified FX; and (4) purified FXa induced GM6001-inhibitable GPVI shedding from washed platelets. In 29 patients with disseminated intravascular coagulation, mean plasma sGPVI was 53.9 ng/mL (95% confidence interval, 39.9-72.8 ng/mL) compared with 12.5 ng/mL (95% confidence interval, 9.0 17.3 ng/mL) in thrombocytopenic controls (n = 36, P < .0001), and 14.6 ng/mL (95% confidence interval, 7.9-27.1 ng/mL) in healthy subjects (n = 25, P = .002). In conclusion, coagulation-induced GPVI shedding via FXa down-regulates GPVI under procoagulant conditions. FXa inhibitors have an unexpected role in preventing GPVI down-regulation. PMID- 21252090 TI - Activation peptides prolong the murine plasma half-life of human factor VII. AB - Coagulation factors VII (FVII), IX (FIX), X (FX), and protein C share the same domain organization but display very different plasma half-lives. It is plausible that the half-life is influenced by the activation peptide, differing in length and glycosylation and missing in FVII. To test this hypothesis, the influence of activation peptides on the plasma half-life of human FVII was studied by administering human FVII variants containing activation peptide motifs to mice. Insertion of the activation peptide from FX gave 4-fold longer terminal half-life (5.5 hours vs 1.4 hours for FVII), whereas the activation peptide from FIX and protein C resulted in half-lives of 4.3 and 1.7 hours, respectively. Using FX's activation peptide we identified the N-linked glycans as structural features important for the half-life. The peptide location within the FVII molecule appeared not to be critical because similar prolongation was obtained with the activation peptide inserted immediately before the normal site of activation and at the C-terminus. However, only the latter variant was activatable, yielding full amidolytic activity and reduced proteolytic activity with preserved long half-life. Our data support that activation peptides function as plasma retention signals and constitute a new manner to extend the half-life of FVII(a). PMID- 21252091 TI - Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor-, granulocyte-macrophage colony-stimulating factor-, and interleukin-3-expressing NOD-SCID IL2Rgamma(null) humanized mice. AB - Human hematolymphoid mice have become valuable tools for the study of human hematopoiesis and uniquely human pathogens in vivo. Recent improvements in xenorecipient strains allow for long-term reconstitution with a human immune system. However, certain hematopoietic lineages, for example, the myeloid lineage, are underrepresented, possibly because of the limited cross-reactivity of murine and human cytokines. Therefore, we created a nonobese diabetic/severe combined immunodeficiency/interleukin-2 receptor-gamma-null (NOD-SCID IL2Rgamma(null)) mouse strain that expressed human stem cell factor, granulocyte macrophage colony-stimulating factor, and interleukin-3, termed NSG-SGM3. Transplantation of CD34(+) human hematopoietic stem cells into NSG-SGM3 mice led to robust human hematopoietic reconstitution in blood, spleen, bone marrow, and liver. Human myeloid cell frequencies, specifically, myeloid dendritic cells, were elevated in the bone marrow of humanized NSG-SGM3 mice compared with nontransgenic NSG recipients. Most significant, however, was the increase in the CD4(+)FoxP3(+) regulatory T-cell population in all compartments analyzed. These CD4(+)FoxP3(+) regulatory T cells were functional, as evidenced by their ability to suppress T-cell proliferation. In conclusion, humanized NSG-SGM3 mice might serve as a useful model to study human regulatory T-cell development in vivo, but this unexpected lineage skewing also highlights the importance of adequate spatiotemporal expression of human cytokines for future xenorecipient strain development. PMID- 21252092 TI - Imatinib mesylate versus allogeneic hematopoietic stem cell transplantation for patients with chronic myelogenous leukemia in the accelerated phase. AB - The relative merits of allogeneic hematopoietic stem cell transplantation (allo HSCT) and imatinib for chronic myelogenous leukemia in the accelerated phase (AP CML) have not previously been evaluated. This cohort study was designed to compare the outcomes of imatinib (n = 87) versus allo-HSCT (n = 45) for AP-CML. A multivariate analysis of the total population revealed that a CML duration >= 12 months, hemoglobin < 100 g/L, and peripheral blood blasts >= 5% were independent adverse prognostic factors for both overall survival (OS) and progression-free survival (PFS). Both treatments resulted in similar survival in low-risk (no factor) patients, with 6-year event-free survival (EFS), OS, and PFS rates of more than 80.0%. Intermediate-risk (any factor) patients showed no difference in EFS and OS, but 6-year PFS rates were 55.7% versus 92.9% (P = .047) with imatinib versus allo-HSCT, respectively. Among high-risk (at least 2 factors) patients, imatinib was by far inferior to allo-HSCT, with 5-year EFS, OS, and PFS rates of 9.3% versus 66.7% (P = .034), 17.7% versus 100% (P = .008), and 18.8% versus 100% (P = .006), respectively. We conclude that allo-HSCT confers significant survival advantages for high- and intermediate-risk patients with AP-CML compared with imatinib treatment; however, the outcomes of the 2 therapies are equally good in low-risk patients. All trials were registered with the Chinese Clinical Trial Registry (www.chictr.org) as CHiCTR-TNC-10000955. PMID- 21252094 TI - So what if blood is thicker than water? PMID- 21252095 TI - Families get mobilized to treat AML. PMID- 21252093 TI - Sezary syndrome cells overexpress syndecan-4 bearing distinct heparan sulfate moieties that suppress T-cell activation by binding DC-HIL and trapping TGF-beta on the cell surface. AB - Because syndecan-4 (SD-4) on effector and memory T cells inhibits T-cell activation by binding dendritic cell-associated heparan sulfate proteoglycan integrin ligand (DC-HIL) on antigen presenting cells and because malignant cells of the cutaneous T-cell lymphoma (CTCL) subset, Sezary syndrome (SS), exhibit memory T-cell phenotype, we posited SS cells to express SD-4. Indeed, malignant T cells from patients with SS and from CTCL cell lines constitutively expressed SD 4 at high levels, in contrast to T cells from healthy volunteers and patients with other inflammatory skin diseases and to non-CTCL cell lines that did not. SS cells also bound to DC-HIL at a level higher than normal T cells activated in vitro, resulting in their inhibited proliferation to anti-CD3 antibody. SD-4 on SS cells also trapped transforming growth factor-beta1 to their cell surface, enhancing their ability to inhibit activation of syngeneic and allogeneic normal T cells. All of these inhibitory properties were dependent on overexpression of distinct heparan sulfate (HS) moieties by SD-4 on SS cells. Finally, we showed toxin-conjugated DC-HIL to abrogate the ability of SS cells to proliferate in vitro. These findings indicate that SD-4 bearing distinct HS moieties plays a pathogenic role in SS and may be targeted for treatment. PMID- 21252096 TI - Anchoring at an island to relieve stress. PMID- 21252097 TI - Breathing easy with pathogen inactivation. PMID- 21252098 TI - Can Treg therapy prevent GVHD? PMID- 21252099 TI - Potential use of HMG-CoA reductase inhibitors (statins) as radioprotective agents. AB - HMG-CoA reductase inhibitors (statins) are widely used in the therapy of hypercholesterolemia. Apart from their lipid-lowering activity, they have pleiotropic effects that are attributed to the inhibition of regulatory proteins, including Ras-homologous (Rho) GTPases. Here, we discuss the potential usefulness of statins to prevent normal tissue damage provoked by radiotherapy. Statins reduce the mRNA expression of pro-inflammatory and pro-fibrotic cytokines stimulated by ionizing radiation in vitro and alleviate IR-induced inflammation and fibrosis in vivo. The currently available data indicate that statins accelerate the rapid repair of DNA double-strand breaks and, moreover, mitigate the DNA damage response induced by IR. Furthermore, statins increase the mRNA expression of DNA repair factors in vivo. Thus, although the molecular mechanisms involved are still ambiguous, preclinical data concordantly show a promising radioprotective capacity of statins. PMID- 21252102 TI - Finding the techniques to nudge the population to better health. PMID- 21252101 TI - Planned alcohol pricing will have "negligible impact" on health problems, say critics. PMID- 21252103 TI - Joint hypermobility syndrome. PMID- 21252105 TI - Doctors are reluctant to use telemedicine and misunderstand what patients want, says NHS Confederation report. PMID- 21252104 TI - Use of non-steroidal anti-inflammatory drugs and risk of Parkinson's disease: nested case-control study. AB - OBJECTIVE: To evaluate the relation between Parkinson's disease and prior use of non-steroidal anti-inflammatory drugs (NSAIDs) in a large cohort of men. DESIGN: Case-control analysis nested in the Physicians' Health Study. PARTICIPANTS: 22,007 male physicians aged 40-84 years without indications for or contraindications to regular NSAID use and free of Parkinson's disease at baseline. Cases and controls were matched by age alone or by age and scores for confounders (comorbidity and indicators of NSAID use). Up to five controls were matched to each of 616 cases by age and 565 cases by age and confounder scores. SETTING: United States. MAIN OUTCOME MEASURES: Odds of having been exposed to prior non-aspirin NSAID or aspirin use by participants with Parkinson's disease and by their controls in each case-control set. RESULTS: Participants who had ever used non-aspirin NSAIDs had an increased risk of Parkinson's disease (odds ratio 1.28 (95% CI 1.05 to 1.56) in the age matched group but not in the group also matched on confounder scores (odds ratio 1.17 (0.94 to 1.46)). There was an increased risk of Parkinson's disease in men who had 1-2 years of regular non aspirin NSAID use (odds ratio 1.35 (1.07 to 1.70)), a finding that remained significant after matching for confounder scores as well (odds ratio 1.35 (1.05 to 1.75)). In contrast, the significant association of use of non-aspirin NSAIDs for >= 5 years (odds ratio 1.48 (1.05 to 2.09)) in the age matched group was entirely attenuated in the group also matched on confounder scores (1.03 (0.70 to 1.53)). There was also a suggestion that men who regularly used aspirin had an increased risk of Parkinson's disease. Positive associations between non-aspirin NSAID or aspirin and risk of Parkinson's disease tended to disappear when analyses were limited to drug use >= 5 years before the disease diagnosis. CONCLUSIONS: This case-control study did not find evidence that NSAID use reduces Parkinson's disease risk. The positive associations observed between NSAID use and Parkinson's disease might have been due to confounding by indication as the use was clustered in the few years before disease diagnosis. PMID- 21252106 TI - Head of inquiry into WHO's handling of the H1N1 pandemic says he will present a "critical" report. PMID- 21252109 TI - Robotic touch shifts perception of embodiment to a prosthesis in targeted reinnervation amputees. AB - Existing prosthetic limbs do not provide amputees with cutaneous feedback. Tactile feedback is essential to intuitive control of a prosthetic limb and it is now clear that the sense of body self-identification is also linked to cutaneous touch. Here we have created an artificial sense of touch for a prosthetic limb by coupling a pressure sensor on the hand through a robotic stimulator to surgically redirected cutaneous sensory nerves (targeted reinnervation) that once served the lost limb. We hypothesize that providing physiologically relevant cutaneous touch feedback may help an amputee incorporate an artificial limb into his or her self image. To investigate this we used a robotic touch interface coupled with a prosthetic limb and tested it with two targeted reinnervation amputees in a series of experiments fashioned after the Rubber Hand Illusion. Results from both subjective (self-reported) and objective (physiological) measures of embodiment (questionnaires, psychophysical temporal order judgements and residual limb temperature measurements) indicate that returning physiologically appropriate cutaneous feedback from a prosthetic limb drives a perceptual shift towards embodiment of the device for these amputees. Measurements provide evidence that the illusion created is vivid. We suggest that this may help amputees to more effectively incorporate an artificial limb into their self image, providing the possibility that a prosthesis becomes not only a tool, but also an integrated body part. PMID- 21252110 TI - Primary retinal pathology in multiple sclerosis as detected by optical coherence tomography. AB - Optical coherence tomography studies in multiple sclerosis have primarily focused on evaluation of the retinal nerve fibre layer. The aetiology of retinal changes in multiple sclerosis is thought to be secondary to optic nerve demyelination. The objective of this study was to use optical coherence tomography to determine if a subset of patients with multiple sclerosis exhibit primary retinal neuronopathy, in the absence of retrograde degeneration of the retinal nerve fibre layer and to ascertain if such patients may have any distinguishing clinical characteristics. We identified 50 patients with multiple sclerosis with predominantly macular thinning (normal retinal nerve fibre-layer thickness with average macular thickness < 5th percentile), a previously undescribed optical coherence tomography defined phenotype in multiple sclerosis, and compared them with 48 patients with multiple sclerosis with normal optical coherence tomography findings, 48 patients with multiple sclerosis with abnormal optical coherence tomography findings (typical for multiple sclerosis) and 86 healthy controls. Utilizing a novel retinal segmentation protocol, we found that those with predominant macular thinning had significant thinning of both the inner and outer nuclear layers, when compared with other patients with multiple sclerosis (P < 0.001 for both), with relative sparing of the ganglion cell layer. Inner and outer nuclear layer thicknesses in patients with non-macular thinning predominant multiple sclerosis were not different from healthy controls. Segmentation analyses thereby demonstrated extensive deeper disruption of retinal architecture in this subtype than may be expected due to retrograde degeneration from either typical clinical or sub-clinical optic neuropathy. Functional corroboration of retinal dysfunction was provided through multi-focal electroretinography in a subset of such patients. These findings support the possibility of primary retinal pathology in a subset of patients with multiple sclerosis. Multiple sclerosis-severity scores were also significantly increased in patients with the macular thinning predominant phenotype, compared with those without this phenotype (n = 96, P=0.006). We have identified a unique subset of patients with multiple sclerosis in whom there appears to be disproportionate thinning of the inner and outer nuclear layers, which may be occurring as a primary process independent of optic nerve pathology. In vivo analyses of retinal layers in multiple sclerosis have not been previously performed, and structural demonstration of pathology in the deeper retinal layers, such as the outer nuclear layer, has not been previously described in multiple sclerosis. Patients with inner and outer nuclear layer pathology have more rapid disability progression and thus retinal neuronal pathology may be a harbinger of a more aggressive form of multiple sclerosis. PMID- 21252111 TI - Predicting functional decline in behavioural variant frontotemporal dementia. AB - Behavioural variant frontotemporal dementia is characterized by a change in comportment. It is associated with considerable functional decline over the course of the illness albeit with sometimes dramatic variability among patients. It is unknown whether any baseline features, or combination of features, could predict rate of functional decline in behavioural variant frontotemporal dementia. The aim of this study was to investigate the effects of different baseline clinical, neuropsychological, neuropsychiatric, genetic and anatomic predictors on the rate of functional decline as measured by the Clinical Dementia Rating Sum of Boxes scale. We identified 86 subjects with behavioural variant frontotemporal dementia that had multiple serial Clinical Dementia Rating Sum of Boxes assessments (mean 4, range 2-18). Atlas-based parcellation was used to generate volumes for specific regions of interest at baseline. Volumes were utilized to classify subjects into different anatomical subtypes using the advanced statistical technique of cluster analysis and were assessed as predictor variables. Composite scores were generated for the neuropsychological domains of executive, language, memory and visuospatial function. Behaviours from the brief questionnaire form of the Neuropsychiatric Inventory were assessed. Linear mixed effects regression modelling was used to determine which baseline features predict rate of future functional decline. Rates of functional decline differed across the anatomical subtypes of behavioural variant frontotemporal dementia, with faster rates observed in the frontal dominant and frontotemporal subtypes. In addition, subjects with poorer performance on neuropsychological tests of executive, language and visuospatial function, less disinhibition, agitation/aggression and night-time behaviours at presentation, and smaller medial, lateral and orbital frontal lobe volumes showed faster rates of decline. In many instances, the effect of the predictor variables observed across all subjects was also preserved within anatomical subtypes. Furthermore, some of the predictor variables improved our prediction of rate of functional decline after anatomical subtype was taken into account. In particular, age at onset was a highly significant predictor but only after adjusting for subtype. We also found that although some predictor variables, for example gender, Mini-Mental State Examination score, and apathy/indifference, did not affect the rate of functional decline; these variables were associated with the actual Clinical Dementia Rating Sum of Boxes score estimated for any given time-point. These findings suggest that in behavioural variant frontotemporal dementia, rate of functional decline is driven by the combination of anatomical pattern of atrophy, age at onset, and neuropsychiatric characteristics of the subject at baseline. PMID- 21252112 TI - Inherited demyelinating neuropathies with micromutations of peripheral myelin protein 22 gene. AB - The peripheral myelin protein 22 gene (PMP22) encodes an intrinsic membrane protein of compact myelin. Duplication or deletion of PMP22 causes the most common autosomal dominant neuropathies, Charcot-Marie-Tooth disease type 1A or hereditary neuropathy with liability to pressure palsies. Charcot-Marie-Tooth disease type 1A is a hypertrophic de-remyelinating neuropathy manifesting with peroneal muscular atrophy and uniform, marked, slowing of nerve conduction velocities. Hereditary neuropathy with liability to pressure palsies is a recurrent focal neuropathy with sausage-like myelin thickening (tomacula) and non uniform nerve conduction velocity changes. Missense or nonsense mutations also cause more severe Charcot-Marie-Tooth disease type 1A forms of infancy or hereditary neuropathy with liability to pressure palsies, but they are presumably very rare. We performed a mutational scanning of PMP22 in 229 index patients (46 familial, 183 isolated) referred for suspected inherited neuropathy. The series included 125 cases with hereditary neuropathy with liability to pressure palsies (mean age 42.5 years), 47 cases with Charcot-Marie-Tooth disease type 1A (motor nerve conduction velocities at median nerve below 38 m/s) (mean age 40.7 years) and 57 cases with Charcot-Marie-Tooth with unknown nerve conduction velocities (mean age 43 years). Preliminary molecular studies ruled out PMP22 duplication or deletion or mutations in a comprehensive panel of Charcot-Marie-Tooth genes. Mutational scanning of PMP22 was done by denaturing high performance liquid chromatography and automated nucleotide sequencing. To investigate the molecular basis of phenotype-to-genotype correlations, we performed a transcriptional analysis of PMP22 using reverse-transcriptase polymerase chain reaction and quantitative real-time polymerase chain reaction in two phenotypically divergent nerve biopsies. Ten patients harboured eight micromutations of PMP22 including four novel changes. In six familial and three sporadic cases, detected mutations caused premature or delayed stop codons and were associated with hereditary neuropathy with liability to pressure palsies; the related pathological pictures ranged from classical tomaculous neuropathy to a mild demyelinating neuropathy with atypical non-tomaculous myelin thickenings. In a single family a c.179-2A> G mutation affecting the splice acceptor site of intron 2 cosegregated with a Charcot-Marie-Tooth disease type 1A-like syndrome and a peculiar pathological picture of demyelinating neuropathy without Charcot-Marie-Tooth disease type 1A like classical onion bulbs or tomacula. Transcriptional analysis of a novel c.174_178 + 7delAAACGGTGAGGC deletion involving exon 2 and intron 2 demonstrated an unstable mutant transcript leading to a p.Asn59GlyfsX12 change; the mutation represented a null allele and caused a typical tomaculous hereditary neuropathy with liability to pressure palsies. The Charcot-Marie-Tooth disease type 1-like c.179-2A > G allele led to a stable transcript with an in-frame deletion of exon 3 (p.Glu60_Ala106del); the predicted shorter protein could exert variable molecular effects. In conclusion, micromutations of PMP22 cause a clinical and pathological continuum of demyelinating neuropathies that may include atypical phenotypes. PMID- 21252113 TI - Troxerutin protects against high cholesterol-induced cognitive deficits in mice. AB - Recent findings suggest that neurotoxicity is the mechanism underlying the induction of neuronal insulin resistance by a high cholesterol diet. Troxerutin, a naturally occurring flavonoid, has been reported to possess biological activity beneficial to human health. Our recent studies have demonstrated that troxerutin attenuates cognitive impairment and oxidative stress induced by D-galactose in mouse brain through decreasing advanced glycation end products, reactive oxygen species and protein carbonyl levels and enhancing phosphoinositide 3-kinase/Akt activation. In this study, we evaluated the effect of troxerutin on cognitive impairment induced by brain insulin resistance in mice fed a high-cholesterol diet, and explored its potential mechanism. Our results showed that oral administration of troxerutin to these mice significantly improved behavioural performance in a step-through passive avoidance task and a Morris water maze task, at least in part, by decreasing the levels of reactive oxygen species, protein carbonyl and advanced glycation end products and blocking endoplasmic reticulum stress via reduced phosphorylation of the pancreatic endoplasmic reticulum-resident kinase and eukaryotic translation initiation factor 2alpha. Furthermore, troxerutin significantly inhibited the activation of c-jun N terminal kinase 1 and IkappaB kinase beta/nuclear factor-kappaB induced by endoplasmic reticulum stress and enhanced insulin signalling pathway, which prevented obesity, restored normal levels of blood glucose, fatty acids and cholesterol and increased the phosphorylation of cyclic adenosine monophosphate response element-binding protein and the expression levels of c-fos in the hippocampus. Moreover, troxerutin significantly inhibited endoplasmic reticulum stress-induced apoptosis and decreased the activation of caspase-12 and caspase 3, and reduced the mean optical density of the terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end label-positive cells in the hippocampus. However, intra-cerebroventricular infusion of PI-103, a specific phosphoinositide 3-kinase 110alpha inhibitor, significantly inhibited the expression levels of phosphoinositide 3-kinase 110alpha and phosphoinositide 3 kinase downstream signalling in the hippocampus of mice co-treated with high cholesterol and troxerutin and vehicle control mice. These results suggest that troxerutin could be recommended as a possible candidate for the prevention and therapy of cognitive deficits in type 2 diabetes mellitus and Alzheimer's disease. PMID- 21252114 TI - Natural killer cells efficiently reject lymphoma silenced for the endoplasmic reticulum aminopeptidase associated with antigen processing. AB - The endoplasmic reticulum aminopeptidase ERAAP is involved in the final trimming of peptides for presentation by MHC class I (MHC-I) molecules. Herein, we show that ERAAP silencing results in MHC-I peptide-loading defects eliciting rejection of the murine T-cell lymphoma RMA in syngeneic mice. Although CD4 and CD8 T cells are also involved, rejection is mainly due to an immediate natural killer (NK) cell response and depends on the MHC-I-peptide repertoire because replacement of endogenous peptides with correctly trimmed, high-affinity peptides is sufficient to restore an NK-protective effect of MHC-I molecules through the Ly49C/I NK inhibitory receptors. At the crossroad between innate and adaptive immunity, ERAAP is therefore unique in its two-tiered ability to control tumor immunogenicity. Because a large fraction of human tumors express high levels of the homologous ERAP1 and/or ERAP2, the present findings highlight a convenient, novel target for cancer immunotherapy. PMID- 21252115 TI - Human CD59 inhibitor sensitizes rituximab-resistant lymphoma cells to complement mediated cytolysis. AB - Rituximab efficacy in cancer therapy depends in part on induction of complement dependent cytotoxicity (CDC). Human CD59 (hCD59) is a key complement regulatory protein that restricts the formation of the membrane attack complex, thereby inhibiting induction of CDC. hCD59 is highly expressed in B-cell non-Hodgkin's lymphoma (NHL), and upregulation of hCD59 is an important determinant of the sensitivity of NHL cells to rituximab treatment. Here, we report that the potent hCD59 inhibitor rILYd4 enhances CDC in vitro and in vivo, thereby sensitizing rituximab-resistant lymphoma cells and primary chronic lymphocytic leukemia cells (CLL) to rituximab treatment. By defining pharmcokinetic/pharmacodynamic profiles of rILYd4 in mice, we showed that by itself rILYd4 does not adversely mediate in vivo hemolysis of hCD59-expressing erythrocytes. Increasing expression levels of the complement regulators CD59 and CD55 in rituximab-resistant cells occur due to selection of preexisting clones rather than de novo induction of these proteins. Moreover, lymphoma cells overexpressing CD59 were directly responsible for the resistance to rituximab-mediated CDC therapy. Our results rationalize the use of rILYd4 as a therapeutic adjuvant for rituximab treatment of rituximab-resistant lymphoma and CLL. Furthermore, they suggest that preemptive elimination of CD59 overexpressing subpopulations along with rituximab treatment may be a useful approach to ablate or conquer rituximab resistance. PMID- 21252116 TI - IMP-1 displays cross-talk with K-Ras and modulates colon cancer cell survival through the novel proapoptotic protein CYFIP2. AB - Insulin-like growth factor 2 mRNA-binding protein-1 (IMP-1) is an oncofetal protein that binds directly to and stabilizes oncogenic c-Myc and regulates, in turn, its posttranscriptional expression and translation. In contrast to normal adult tissue, IMP-1 is reexpressed and/or overexpressed in human cancers. We show that knockdown of c-Myc in human colon cancer cell lines increases the expression of mature let-7 miRNA family members and downregulates several of its mRNA targets: IMP-1, Cdc34, and K-Ras. We further show that loss of IMP-1 inhibits Cdc34, Lin-28B, and K-Ras, suppresses SW-480 cell proliferation and anchorage independent growth, and promotes caspase- and lamin-mediated cell death. We also found that IMP-1 binds to the coding region and 3'UTR of K-Ras mRNA. RNA microarray profiling and validation by reverse transcription PCR reveals that the p53-inducible proapoptotic protein CYFIP2 is upregulated in IMP-1 knockdown SW480 cells, a novel finding. We also show that overexpression of IMP-1 increases c-Myc and K-Ras expression and LIM2405 cell proliferation. Furthermore, we show that loss of IMP-1 induces Caspase-3- and PARP-mediated apoptosis, and inhibits K-Ras expression in SW480 cells, which is rescued by CYFIP2 knockdown. Importantly, analysis of 228 patients with colon cancers reveals that IMP-1 is significantly upregulated in differentiated colon tumors (P <= 0.0001) and correlates with K Ras expression (r = 0.35, P <= 0.0001) relative to adjacent normal mucosa. These findings indicate that IMP-1, interrelated with c-Myc, acts upstream of K-Ras to promote survival through a novel mechanism that may be important in colon cancer pathogenesis. PMID- 21252117 TI - Polymorphisms in inflammatory pathway genes, host factors and lung cancer risk in Chinese female never-smokers. AB - Inflammation appears to be important in lung carcinogenesis among smokers, but its role among never-smokers is not well established. We hypothesized that inflammatory medical conditions and gene polymorphisms interact to increase lung cancer risk in never-smokers. We interviewed 433 Singaporean female never-smoker lung cancer patients and 1375 hospital controls, and evaluated six polymorphisms in the interleukin 1-beta, interleukin 6 (IL6), cyclooxygenase-2, peroxisome proliferator-activated receptor-gamma and interleukin 1-beta receptor antagonist (IL1RN) genes. Tuberculosis was associated with a non-significant elevated risk of lung cancer [odds ratio (OR) 1.58, 95% confidence interval (CI) 0.95-2.62]. There was no effect of asthma, atopy or chronic productive cough individually. However, the presence of one or more of these conditions (asthma, cough or atopy) increased risk (OR 2.24, 95%CI 1.15-4.38) in individuals possessing the T/T genotype at interleukin 1-beta -31T/C, but not in those possessing the C/T (OR 0.87, 95%CI 0.51-1.57) or C/C genotypes (OR 0.58, 95%CI 0.27-1.27), and in individuals having the *2 variable number of tandem repeat allele of IL1RN [OR 5.09 (1.39-18.67)], but not in those without (OR 0.93, 95%CI 0.63-1.35). The IL6 634 G allele increased the risk of lung cancer (OR 1.44, 95%CI 1.07-1.94). Lung cancer risk also increased with the number of polymorphism sites where at least 1 'risk' allele was present [interleukin 1-beta -31T/C (T allele), IL1RN (*2 allele) and IL6-634C/G (G allele)] among those with asthma, cough or atopy (Ptrend 0.001) but not in those without (Ptrend 0.47). Our results suggest that the effect of inflammatory medical conditions on lung cancer in never-smokers is modulated by host genetic susceptibility and will need to be confirmed in other studies conducted in similar populations. PMID- 21252118 TI - Osteopontin promotes CCL5-mesenchymal stromal cell-mediated breast cancer metastasis. AB - The interaction between cancer and its local microenvironment can determine properties of growth and metastasis. A critical component of the tumor microenvironment in this context is the cancer-associated fibroblast (CAF), which can promote tumor growth, angiogenesis and metastasis. It has been hypothesized that CAF may be derived from mesenchymal stromal cells (MSC), derived from local or distant sources. However, the signaling mechanisms by which tumors and MSCs interact to promote CAF-dependent cancer growth are largely unknown. In this study with in vitro and in vivo models using MDA-MB231 human breast cancer cells, we demonstrate that tumor-derived osteopontin (OPN) induces MSC production of CCL5; the mechanism involves OPN binding to integrin cell surface receptors and activator protein-1 c-jun homodimer transactivation. In a murine xenograft model, concomitant inoculation of MSC with MDA-MB231 cells induces: (i) significantly increased growth and metastasis of MB231 cells and (ii) increased MSC migration to metastatic sites in lung and liver; this mechanism is both OPN and CCL5 dependent. MSCs retrieved from sites of metastases exhibit OPN-dependent expression of the CAF markers, alpha-smooth muscle actin, tenascin-c, CXCL12 (or stromal cell-derived factor 1) and fibroblast-specific protein-1 and the matrix metalloproteinases (MMP)-2 and MMP-9. Based upon these results, we propose that tumor-derived OPN promotes tumor progression via the transformation of MSC into CAF. PMID- 21252119 TI - ATRA activates and PDGF-BB represses the SM22alpha promoter through KLF4 binding to, or dissociating from, its cis-DNA elements. AB - AIMS: Kruppel-like factor 4 (KLF4) is implicated in all-trans retinoic acid (ATRA)-induced and platelet-derived growth factor-BB (PDGF-BB)-repressed SM22alpha expression in vascular smooth muscle cells (VSMCs). However, its exact mechanism of action remains unclear. We determined how KLF4 plays different roles in ATRA- and PDGF-BB-dependent regulation of the SM22alpha gene. METHODS AND RESULTS: ATRA and PDGF-BB induced KLF4 expression but exhibited an opposite effect on SM22alpha expression and VSMC proliferation. Chromatin immunoprecipitation and oligonucleotide pull-down assays showed that KLF4 was directly bound to the KLF4 binding sites 1 ((-263)CACCC(-259)) and 2 (( 136)GTGGG(-132)) of the SM22alpha promoter. ATRA increased the binding of KLF4 to site 2, whereas PDGF-BB decreased the binding of KLF4 to site 1. ATRA stimulated KLF4 acetylation by inducing KLF4 phosphorylation and increasing its interaction with p300 via activating c-Jun NH(2)-terminal kinase (JNK) and p38 pathways, and acetylated KLF4 increased its binding activity to site 2. PDGF-BB stimulated KLF4 deacetylation by inducing KLF4 dephosphorylation and increasing its interaction with histone deacetylase 2 (HDAC2) via activating extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathways, and deacetylated KLF4 dissociated from site 1. CONCLUSIONS: In VSMCs, ATRA activates and PDGF-BB represses SM22alpha expression through KLF4 binding to, or dissociating from, its different cis-elements in an acetylation-dependent manner. PMID- 21252120 TI - Continuity of care is good for elderly people with diabetes: retrospective cohort study of mortality and hospitalization. AB - OBJECTIVE: To examine the relationship between continuity of family physician care and all-cause mortality and acute hospitalizations in older people with diabetes. DESIGN: Retrospective cohort study of administrative health databases. Continuity of family physician care for elderly patients newly diagnosed with diabetes was estimated by 3 continuity indexes using physician claims data. The relationship of continuity of family physician care to mortality and acute hospitalizations was investigated. SETTING: The province of Newfoundland and Labrador. PARTICIPANTS: A total of 305 family practice patients 65 years of age or older with diabetes. MAIN OUTCOME MEASURES: Death rate and hospitalization rate during a 3-year period. RESULTS: Overall, continuity of family physician care was high. In the 3 years examined, the higher-continuity group had lower rates of hospitalization (53.5% vs 68.2%) and death (8.6% vs 18.5%) than the lower-continuity group. CONCLUSION: The findings suggest an association between higher continuity of family physician care and reductions in likelihood of death and hospitalizations in older people with diabetes. PMID- 21252121 TI - Effect of advanced access scheduling on chronic health care in a Canadian practice. AB - OBJECTIVE: To determine the effect of advanced access scheduling (AAS) on the care of patients with chronic disease within a Canadian family practice. DESIGN: Chart abstraction. SETTING: A single family physician's practice in Brantford, Ont. PARTICIPANTS: Patient charts were reviewed for all patients with a history of hypertension, type 2 diabetes mellitus, or coronary artery disease during the years before and after implementation of AAS. MAIN OUTCOME MEASURES: The following information was extracted for each study patient: total number of appointments, number of appointments specific to chronic disease management, number of appointments for non-chronic disease, blood pressure (BP), and laboratory markers, including hemoglobin A(1c) (HbA(1c)) and low-density lipoprotein levels. RESULTS: For the year before and the year after implementation of AAS, the mean number of visits per patient was 4.3. The mean number of appointments for chronic disease management decreased significantly from 2.6 to 2.2 (P = .024), and the mean number of visits for non-chronic disease increased significantly from 1.7 to 2.1 (P = .001). The number of times clinical parameters of BP, HbA(1c), and low-density lipoprotein were measured decreased; however, there were no significant changes in actual BP or HbA(1c) levels. CONCLUSION: Following a 1-year period using AAS, use of the family health practice by patients with chronic disease was unchanged overall; however, AAS allowed for an increase in visits for non-chronic health conditions without significantly affecting the clinical parameters of BP or HbA(1c). PMID- 21252122 TI - Debiasing the hidden curriculum: academic equality among medical specialties. AB - OBJECTIVE: To compare the academic performance of students who entered family medicine residency programs with that of students who entered other disciplines and discern whether or not family physicians are as academically talented as their colleagues in other specialties. DESIGN: Retrospective quantitative study. SETTING: University of Calgary in Alberta. PARTICIPANTS: Three graduating classes of students (2004 to 2006) from the University of Calgary medical school. MAIN OUTCOME MEASURES: Student performance on various undergraduate certifying examinations in years 1, 2, and 3, along with third-year in-training evaluation reports and total score on the Medical Council of Canada Qualifying Examination Part I. RESULTS: Complete data were available for 99% of graduates (N = 295). In the analysis, residency program (family medicine [n = 96] versus non-family medicine [n = 199]) served as the independent variable. Using a 1-way multivariate ANOVA (analysis of variance), no significant difference among any of the mean performance scores was observed (F(5289) = 1.73, P > .05). Students who entered family medicine were also well represented within the top 10 rankings of the various performance measures. CONCLUSION: The academic performance of students who pursued careers in family medicine did not differ from that of students who chose other specialties. Unfounded negativity toward family medicine has important societal implications, especially at a time when the gap between the number of family physicians and patients seeking primary care services appears to be widening. PMID- 21252125 TI - Developmental disability application. PMID- 21252124 TI - Mitigating epidemic vitamin D deficiency: the agony of evidence. PMID- 21252126 TI - Nonseptic olecranon bursitis management. PMID- 21252127 TI - Support for home care. PMID- 21252128 TI - Effect of methotrexate treatment of ectopic pregnancy on subsequent pregnancy. AB - QUESTION: My last pregnancy was diagnosed as ectopic, and I was treated successfully with intramuscular methotrexate (MTX) 8 weeks ago. I am currently planning for another pregnancy; however, I have read that MTX causes birth defects and that it stays in my body for a very long time, ranging from 1 to 12 months after treatment. When is it safe to conceive? ANSWER: We suggest that the outcomes of pregnancies conceived shortly after MTX therapy for extrauterine pregnancy are most likely to be favourable and similar to those pregnancies conceived 6 months after MTX treatment. However, as data are not sufficient to draw a definitive conclusion or to confirm the exact safe timing after MTX treatment, at least a 3-month waiting period is recommended for women who are planning pregnancy. Nevertheless, conception within 3 months of MTX treatment of extrauterine pregnancy should not be considered a definite indication of termination, and further targeted fetal anatomy assessment is recommended. Further retrospective and prospective studies are needed to define the safety period before 3 months and to solidify this recommendation. PMID- 21252129 TI - Reducing inappropriate antibiotic use among children with influenza infection. AB - QUESTION: With the influenza season reaching a peak, I see numerous children in my clinic with fever and influenza-like illnesses. Parents are concerned and at times ask for antibiotic treatment in hopes that the treatment will shorten the duration of illness. What strategies can I use in order to minimize inappropriate prescription of antibiotics during the influenza season? ANSWER: Use of antibiotics for treatment of viral infections such as influenza contributes to the emergence of resistant bacteria strains. Misuse and overuse of antibiotics can be reduced by preventing the infection and its complications through vaccination, point-of-care rapid influenza testing, and early antiviral treatment when appropriate, as well as constantly increasing the knowledge of both physicians and families regarding the appropriate use of antibiotics. PMID- 21252130 TI - Sticks and stones and broken bones: distal radius fractures in children. PMID- 21252131 TI - Pharmacotherapy for smoking. PMID- 21252133 TI - Ophthaproblem. Can you identify this condition? Dacryocystitis. PMID- 21252132 TI - Acute cough in adults. PMID- 21252134 TI - Dermacase. Can you identify this condition? Guttate psoriasis. PMID- 21252136 TI - Why are you here to see the doctor today? PMID- 21252135 TI - Burden of acute otitis media on Canadian families. AB - OBJECTIVE: To estimate the burden of acute otitis media (AOM) on Canadian families. DESIGN: Telephone survey using random-digit dialing. SETTING: All Canadian provinces between May and June 2008. PARTICIPANTS: Caregivers of 1 or more children aged 6 months to 5 years. MAIN OUTCOME MEASURES: Caregivers' reports on the number of AOM episodes experienced by the child in the past 12 months, as well as disease characteristics, health services and medication use, time spent on medical consultations (including travel), and time taken off from work to care for the sick children. RESULTS: A total of 502 eligible caregivers were recruited, 161 (32%) of whom reported at least 1 AOM episode for their children and 42 (8%) of whom reported 3 or more episodes during the past 12 months. Most children (94%, 151 of 161) visited with health professionals during their most recent AOM episodes. The average time required for medical examination was 3.1 hours in an emergency department and 1.8 hours in an outpatient clinic. Overall, 93% of episodes resulted in antibiotics use. A substantial proportion of caregivers (38%) missed work during this time; the average time taken off work was 15.9 hours. CONCLUSION: In Canada, episodes of AOM are still associated with substantial use of health services and indirect costs to the caregivers. PMID- 21252137 TI - Clinical uncertainty: helping our learners. PMID- 21252138 TI - Epiphanies in family medicine. PMID- 21252140 TI - Viral decay rates are similar in HIV-infected patients with and without TB coinfection during treatment with an Efavirenz-based regimen. AB - Viral decay rates during efavirenz-based therapy were compared between human immunodeficiency virus (HIV)-infected patients without tuberculosis (n = 40) and those with tuberculosis coinfection who were receiving concurrent antituberculous therapy (n = 34). Phase I and II viral decay rates were similar in the 2 groups (P > .05). Overall, concurrent antituberculous therapy did not reduce the efficacy of the HIV treatment. PMID- 21252141 TI - Dyslipidemia among HIV-infected Patients with tuberculosis taking once-daily nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy in India. AB - BACKGROUND: Our aim was to study the incidence and pattern of dyslipidemia among human immunodeficiency virus (HIV)-infected patients with tuberculosis (TB) who received once-daily antiretroviral therapy (ART). METHODS: Antiretroviral-naive HIV-infected patients with TB were recruited to a trial of once-daily nonnucleoside reverse-transcriptase inhibitor (NNRTI)-based ART and treated with rifampicin-based thrice-weekly antituberculosis treatment (ATT); participants were randomized to receive didanosine (250/400 mg) and lamivudine (300 mg) with either efavirenz (600 mg) or nevirapine (400 mg) once-daily after an intensive phase of ATT. Fasting triglyceride (TG) level, total cholesterol (TC) level, low density cholesterol (LDL-c) level and high-density cholesterol (HDL-c) level were measured at baseline and at 6 and 12 months. Lipid levels at 6 and 12 months were compared with baseline values with use of repeated measures analyses. McNemar test was used to compare the proportion of patients with lipid abnormality at baseline versus at 12 months, and chi2 test was used to compare between the 2 groups. RESULTS: Of 168 patients (79% men; mean age, 36 years; mean weight, 42 kg; median CD4+ cell count, 93 cells/mm3), 104 received efavirenz-based ART, and 64 received nevirapine-based ART. After 6 months, TC levels increased by 49 mg/dL, LDL-c levels by 30 mg/dL, and HDL-c levels increased by 18 mg/dL (P < .001 for all). At baseline and at 12 months, TC was >200 mg/dL for 1% and 26% of patients, respectively; LDL-c level was >130 mg/dL for 3% and 23%, respectively; HDL-c level was <40 mg/dL for 91% and 23%, respectively; and blood glucose level was >110 mg/dL for 14% and 13%, respectively. TC level >200 mg/dL was more common among patients who received efavirenz than among those who received nevirapine (32% vs 16%; P = .04). CONCLUSIONS: HIV-infected patients with TB who initiate NNRTI-based ART undergo complex changes in lipid profile, highlighting the importance of screening and treating other cardiovascular disease risk factors in this population. PMID- 21252142 TI - Estimating the impact of human papillomavirus (HPV) vaccination on HPV prevalence and cervical cancer incidence in Mali. AB - Human papillomavirus vaccines have potential to reduce cervical cancer incidence and mortality; however, cultural and economic barriers may hinder success in developing countries. We assessed impact of a single vaccine campaign in Mali with use of mathematical modeling. Our model shows that decreases in the prevalence of Human papillomavirus infection are proportional to achieved vaccination coverage. PMID- 21252143 TI - Targeted next-generation sequencing for the molecular genetic diagnostics of cardiomyopathies. AB - BACKGROUND: Today, mutations in more than 30 different genes have been found to cause inherited cardiomyopathies, some associated with very poor prognosis. However, because of the genetic heterogeneity and limitations in throughput and scalability of current diagnostic tools up until now, it is hardly possible to genetically characterize patients with cardiomyopathy in a fast, comprehensive, and cost-efficient manner. METHODS AND RESULTS: We established an array-based subgenomic enrichment followed by next-generation sequencing to detect mutations in patients with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). With this approach, we show that the genomic region of interest can be enriched by a mean factor of 2169 compared with the coverage of the whole genome, resulting in high sequence coverage of selected disease genes and allowing us to define the genetic pathogenesis of cardiomyopathies in a single sequencing run. In 6 patients, we detected disease-causing mutations, 2 microdeletions, and 4 point mutations. Furthermore, we identified several novel nonsynonymous variants, which are predicted to be harmful, and hence, might be potential disease mutations or modifiers for DCM or HCM. CONCLUSIONS: The approach presented here allows for the first time a comprehensive genetic screening in patients with hereditary DCM or HCM in a fast and cost-efficient manner. PMID- 21252144 TI - Lipoprotein(a) genetic variants associated with coronary and peripheral vascular disease but not with stroke risk in the Heart Protection Study. AB - BACKGROUND: Genetic studies have identified 2 single-nucleotide polymorphisms (SNPs) at the LPA locus (rs3798220 and rs10455872) that are strongly and independently related to lipoprotein(a) levels and to coronary disease risk, but their relevance for other atherothrombotic disease is uncertain. METHODS AND RESULTS: These 2 LPA SNPs were examined together as an LPA genotype score for associations with vascular outcomes among participants in the Heart Protection Study. The LPA score was examined first in 12 236 participants with prevalent vascular disease (9277 coronary disease cases, and 1326 ischemic stroke and 2011 peripheral vascular disease cases with no history of coronary disease) and 3687 vascular disease-free controls and, subsequently, in 3251 participants who had incident major vascular events during follow-up (2106 coronary disease, 507 ischemic stroke, and 707 peripheral vascular disease events). For prevalent disease, the LPA score was strongly associated with coronary disease (odds ratio [OR] per variant allele, 1.19; 95% CI, 1.08 to 1.30) and peripheral vascular disease (OR, 1.18; 95% CI, 1.04 to 1.34) but not with ischemic stroke (OR, 1.03; 95% CI, 0.89 to 1.20). Similarly, for incident disease, the LPA score was strongly associated with coronary disease (hazard ratio [HR], 1.19; 95% CI, 1.09 to 1.30) and peripheral vascular disease (HR, 1.20; 95% CI, 1.02 to 1.40) but not with ischemic stroke (HR, 0.83; 95% CI, 0.67 to 1.03). CONCLUSIONS: The comparable strength of associations of the LPA score with coronary disease and peripheral vascular disease but not with stroke suggest that lipoprotein(a) may have effects on atherothrombotic vascular disease that are only relevant at specific sites. Clinical Trial Registration- URL: http://isrctn.org. Unique identifier: ISRCTN48489393. PMID- 21252146 TI - Blink and you'll see it: how to detect Ca2+ quarks. PMID- 21252145 TI - Physical activity modifies the effect of LPL, LIPC, and CETP polymorphisms on HDL C levels and the risk of myocardial infarction in women of European ancestry. AB - BACKGROUND: Recent genome-wide association studies have identified common variants associated with high-density lipoprotein cholesterol (HDL-C). Whether these associations are modified by physical activity, which increases HDL-C levels and reduces the risk of cardiovascular disease, is uncertain. METHODS AND RESULTS: In a prospective cohort study of 22 939 apparently healthy US women of European ancestry, we selected 58 single nucleotide polymorphisms (SNPs) in 9 genes that demonstrated genome-wide association (P<5*10(-8)) with HDL-C levels and sought evidence of effect modification according to levels of physical activity. Physical activity modified the effects on HDL-C of 7 SNPs at 3 loci, and the strongest evidence of effect was observed for rs10096633 at lipoprotein lipase (LPL), rs1800588 at hepatic lipase (LIPC), and rs1532624 at cholesteryl ester transfer protein (CETP) (each P-interaction<0.05). The per-minor-allele increase in HDL-C for rs1800588 at LIPC and rs1532624 at CETP was greater in active than inactive women, whereas the reverse was observed for rs10096633 at LPL. Minor-allele carrier status at the LPL SNP was associated with a reduced risk of myocardial infarction in active (hazard ratio, 0.51; 95% confidence interval 0.30-0.86) but not among inactive women (hazard ratio 1.13; 95% confidence interval 0.79 to 1.61; P-interaction=0.007). By contrast, carrier status at the CETP SNP was associated with a reduced risk of myocardial infarction regardless of activity level (hazard ratio, 0.72; 95% confidence interval, 0.57 to 0.92; P-interaction=0.71). No association between LIPC SNP carrier status and myocardial infarction risk was noted. CONCLUSIONS: The effects of common variants in the LPL, LIPC, and CETP genes on HDL-C levels are modified by physical activity. For a common variant in LPL, the impact on myocardial infarction varied by activity level, whereas the effects of a common variant in CETP on myocardial infarction risk did not. PMID- 21252147 TI - Commentaries--another addition to the portfolio of Circulation Research. PMID- 21252148 TI - Sorting out sortilin. PMID- 21252149 TI - Landmark approach to generating human stem cells. PMID- 21252150 TI - The art of microRNA research. AB - Originally identified as moderate biological modifiers, microRNAs have recently emerged as powerful regulators of diverse cellular processes with especially important roles in disease and tissue remodeling. The rapid pace of studies on microRNA regulation and function necessitates the development of suitable techniques for measuring and modulating microRNAs in different model systems. This review summarizes experimental strategies for microRNA research and highlights the strengths and weaknesses of different approaches. The development of more specific and sensitive assays will further illuminate the biology behind microRNAs and will advance opportunities to safely pursue them as therapeutic modalities. PMID- 21252152 TI - Vascular calcification in chronic renal failure: what have we learned from animal studies? AB - Accelerated atherosclerotic plaque calcification and extensive medial calcifications are common and highly detrimental complications of chronic kidney disease. Valid murine models have been developed to investigate both pathologically distinguishable complications, which allow for better insight into the cellular mechanisms underlying these vascular pathologies and evaluation of compounds that might prevent or retard the onset or progression of vascular calcification. This review describes various experimental models that have been used for the study of arterial intimal and/or medial calcification and discusses the extent to which this experimental research has contributed to our current understanding of vascular calcification, particularly in the setting of chronic renal failure. PMID- 21252153 TI - TRPC channels as effectors of cardiac hypertrophy. AB - Transient receptor potential (TRP) channels of multiple subclasses are expressed in the heart, although their functions are only now beginning to emerge, especially for the TRPC subclass that appears to regulate the cardiac hypertrophic response. Although TRP channels permeate many different cations, they are most often ascribed a specific biological function because of Ca(2+) influx, either for microdomain signaling or to reload internal Ca(2+) stores in the endoplasmic reticulum through a store-operated mechanism. However, adult cardiac myocytes arguably do not require store-operated Ca(2+) entry to regulate sarcoplasmic reticulum Ca(2+) levels and excitation-contraction coupling; hence, TRP channels expressed in the heart most likely coordinate signaling within local domains or through direct interaction with Ca(2+)-dependent regulatory proteins. Here, we review the emerging evidence that TRP channels, especially TRPCs, are critical regulators of microdomain signaling in the heart to control pathological hypertrophy in coordination with signaling through effectors such as calcineurin and NFAT (nuclear factor of activated T cells). PMID- 21252151 TI - Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. AB - Oxidation reactions are vital parts of metabolism and signal transduction. However, they also produce reactive oxygen species, which damage lipids, proteins and DNA, generating "oxidation-specific" epitopes. In this review, we discuss the hypothesis that such common oxidation-specific epitopes are a major target of innate immunity, recognized by a variety of "pattern recognition receptors" (PRRs). By analogy with microbial "pathogen-associated molecular patterns" (PAMPs), we postulate that host-derived, oxidation-specific epitopes can be considered to represent "danger (or damage)-associated molecular patterns" (DAMPs). We also argue that oxidation-specific epitopes present on apoptotic cells and their cellular debris provided the primary evolutionary pressure for the selection of such PRRs. Furthermore, because many PAMPs on microbes share molecular identity and/or mimicry with oxidation-specific epitopes, such PAMPs provide a strong secondary selecting pressure for the same set of oxidation specific PRRs as well. Because lipid peroxidation is ubiquitous and a major component of the inflammatory state associated with atherosclerosis, the understanding that oxidation-specific epitopes are DAMPs, and thus the target of multiple arcs of innate immunity, provides novel insights into the pathogenesis of atherosclerosis. As examples, we show that both cellular and soluble PRRs, such as CD36, toll-like receptor-4, natural antibodies, and C-reactive protein recognize common oxidation-specific DAMPs, such as oxidized phospholipids and oxidized cholesteryl esters, and mediate a variety of immune responses, from expression of proinflammatory genes to excessive intracellular lipoprotein accumulation to atheroprotective humoral immunity. These insights may lead to improved understanding of inflammation and atherogenesis and suggest new approaches to diagnosis and therapy. PMID- 21252154 TI - Reactive oxygen species-activated Ca/calmodulin kinase IIdelta is required for late I(Na) augmentation leading to cellular Na and Ca overload. AB - RATIONALE: In heart failure Ca/calmodulin kinase (CaMK)II expression and reactive oxygen species (ROS) are increased. Both ROS and CaMKII can increase late I(Na) leading to intracellular Na accumulation and arrhythmias. It has been shown that ROS can activate CaMKII via oxidation. OBJECTIVE: We tested whether CaMKIIdelta is required for ROS-dependent late I(Na) regulation and whether ROS-induced Ca released from the sarcoplasmic reticulum (SR) is involved. METHODS AND RESULTS: 40 MUmol/L H(2)O(2) significantly increased CaMKII oxidation and autophosphorylation in permeabilized rabbit cardiomyocytes. Without free [Ca](i) (5 mmol/L BAPTA/1 mmol/L Br(2)-BAPTA) or after SR depletion (caffeine 10 mmol/L, thapsigargin 5 MUmol/L), the H(2)O(2)-dependent CaMKII oxidation and autophosphorylation was abolished. H(2)O(2) significantly increased SR Ca spark frequency (confocal microscopy) but reduced SR Ca load. In wild-type (WT) mouse myocytes, H(2)O(2) increased late I(Na) (whole cell patch-clamp). This increase was abolished in CaMKIIdelta(-/-) myocytes. H(2)O(2)-induced [Na](i) and [Ca](i) accumulation (SBFI [sodium-binding benzofuran isophthalate] and Indo-1 epifluorescence) was significantly slowed in CaMKIIdelta(-/-) myocytes (versus WT). CaMKIIdelta(-/-) myocytes developed significantly less H(2)O(2)-induced arrhythmias and were more resistant to hypercontracture. Opposite results (increased late I(Na), [Na](i) and [Ca](i) accumulation) were obtained by overexpression of CaMKIIdelta in rabbit myocytes (adenoviral gene transfer) reversible with CaMKII inhibition (10 MUmol/L KN93 or 0.1 MUmol/L AIP [autocamtide 2-related inhibitory peptide]). CONCLUSIONS: Free [Ca](i) and a functional SR are required for ROS activation of CaMKII. ROS-activated CaMKIIdelta enhances late I(Na), which may lead to cellular Na and Ca overload. This may be of relevance in hear failure, where enhanced ROS production meets increased CaMKII expression. PMID- 21252155 TI - alphaMbeta2 integrin activation prevents alternative activation of human and murine macrophages and impedes foam cell formation. AB - RATIONALE: The alternative activation of monocytes by interleukin (IL)-13 and IL 4 is a significant component of the inflammatory response. The consequences of alternative activation in inflammatory diseases remain to be determined. OBJECTIVE: In this report, we explored how integrins, receptors important for monocyte migration to inflammatory sites, regulate IL-13-mediated monocyte activation. We focused on the analysis of 2 proteins, which are upregulated during the alternative activation and are important for the development of atherosclerosis, an oxidative enzyme 15-lipoxygenase (15-LO) and a scavenger receptor CD36. METHODS AND RESULTS: We found that adhesion of resting monocytes through beta(2) integrins and inside-out activation of beta(2) integrins by monocyte chemoattractant protein-1 did not change IL-13-stimulated 15-LO upregulation; however, preincubation of monocytes with the antibody MEM48, which generates full activation of beta(2) integrins, significantly inhibited 15-LO mRNA and protein expression. In contrast, activation of beta(1) integrins had no effect on 15-LO expression. Analysis of integrin clustering through alpha(M), alpha(L), alpha(X), and alpha(D) subunits demonstrated the pivotal role for integrin alpha(M)beta(2) in inhibiting 15-LO expression. IL-13 treatment upregulates 15-LO-dependent CD36 expression on human monocytes; our studies showed that beta(2) integrin activation and alpha(M) integrin clustering significantly inhibited IL-13-dependent CD36 mRNA and protein expression, as well as CD36-related foam cell formation. Moreover, IL-13 stimulation of alpha(M) deficient peritoneal macrophages demonstrated an upregulated level of 15-LO induction, CD36 expression, and lipid accumulation as compared with wild-type controls. CONCLUSIONS: The adhesion of monocytes/macrophages through activated integrin alpha(M)beta(2) has a regulatory and potential atheroprotective function during the alternative activation of macrophages. PMID- 21252157 TI - Notch signaling regulates smooth muscle differentiation of epicardium-derived cells. AB - RATIONALE: The embryonic epicardium plays a crucial role in the formation of the coronary vasculature and in myocardial development, yet the exact contribution of epicardium-derived cells (EPDCs) to the vascular and connective tissue of the heart, and the factors that regulate epicardial differentiation, are insufficiently understood. OBJECTIVE: To define the role of Notch signaling in murine epicardial development. METHODS AND RESULTS: Using in situ hybridization and RT-PCR analyses, we detected expression of a number of Notch receptor and ligand genes in early epicardial development, as well as during formation of coronary arteries. Mice with epicardial deletion of Rbpj, the unique intracellular mediator of Notch signaling, survived to adulthood and exhibited enlarged coronary venous and arterial beds. Using a Tbx18-based genetic lineage tracing system, we show that EPDCs give rise to fibroblasts and coronary smooth muscle cells (SMCs) but not to endothelial cells in the wild type, whereas in Rbpj-deficient embryos EPDCs form and surround the developing arteries but fail to differentiate into SMCs. Conditional activation of Notch signaling results in premature SMC differentiation of epicardial cells and prevents coronary angiogenesis. We further show that Notch signaling regulates, and cooperates with transforming growth factor beta signaling in SM differentiation of EPDCs. CONCLUSIONS: Notch signaling is a crucial regulator of SM differentiation of EPDCs, and thus, of formation of a functional coronary system. PMID- 21252156 TI - Endothelial cell-specific deficiency of Ang II type 1a receptors attenuates Ang II-induced ascending aortic aneurysms in LDL receptor-/- mice. AB - RATIONALE: Human studies and mouse models have provided evidence for angiotensin II (Ang II)-based mechanisms as an underlying cause of aneurysms localized to the ascending aorta. In agreement with this associative evidence, we have published recently that Ang II infusion induces aneurysmal pathology in the ascending aorta. OBJECTIVE: The aim of this study was to define the role of angiotensin II type 1a (AT(1a)) receptors and their cellular location in Ang II-induced ascending aortic aneurysms (AAs). METHODS AND RESULTS: Male LDL receptor(-/-) mice were fed a saturated fat-enriched diet for 1 week before osmotic mini-pump implantation and infused with either saline or Ang II (1000 ng/kg per minute) for 28 days. Intimal surface areas of ascending aortas were measured to quantify ascending AAs. Whole body AT(1a) receptor deficiency ablated Ang II-induced ascending AAs (P<0.001). To determine the role of AT(1a) receptors on leukocytes, LDL receptor(-/-)*AT(1a) receptor(+/+) or AT(1a) receptor(-/-) mice were irradiated and repopulated with bone marrow-derived cells isolated from either AT(1a) receptor(+/+) or AT(1a) receptor(-/-) mice. Deficiency of AT(1a) receptors in bone marrow-derived cells had no effect on Ang II-induced ascending AAs. To determine the role of AT(1a) receptors on vascular wall cells, we developed AT(1a) receptor floxed mice with depletion on either smooth muscle or endothelial cells using Cre driven by either SM22 or Tek, respectively. AT(1a) receptor deletion in smooth muscle cells had no effect on ascending AAs. In contrast, endothelial-specific depletion attenuated this pathology. CONCLUSIONS: Ang II infusion promotes aneurysms in the ascending aorta via stimulation of AT(1a) receptors that are expressed on endothelial cells. PMID- 21252158 TI - Nuclear factor kappaB downregulates the transient outward potassium current I(to,f) through control of KChIP2 expression. AB - RATIONALE: The fast transient outward K(+) current (I(to,f)) plays a critical role in early repolarization of the heart. I(to,f) is consistently downregulated in cardiac disease. Despite its importance, the regulation of I(to,f) in disease remains poorly understood. OBJECTIVE: Because the transcription factor nuclear factor (NF)-kappaB is activated in cardiac hypertrophy and disease, we studied the role of NF-kappaB in mediating I(to,f) reductions induced by hypertrophy. METHODS AND RESULTS: Culturing neonatal rat ventricular myocytes in the presence of phenylephrine (PE) plus propranolol (Pro), to selectively activate alpha(1) adrenergic receptors, caused reductions in I(to,f), as well as KChIP2 and Kv4.3 expression, while increasing Kv4.2 expression. Inhibition of NF-kappaB, via overexpression of a phosphorylation-deficient mutant of IkappaBalpha (IkappaBalphaSA) prevented PE/Pro-induced reductions in I(to,f) and KChIP2 mRNA, without affecting Kv4.2 or Kv4.3 expression, suggesting NF-kappaB mediates the I(to,f) reductions by repressing KChIP2. Indeed, overexpression of the NF-kappaB activator IkappaB kinase-beta also decreased KChIP2 expression and I(to,f) (despite increasing Kv4.2), whereas IkappaBalphaSA overexpression elevated KChIP2 and decreased Kv4.2 levels. In addition, the classic NF-kappaB activator tumor necrosis factor alpha also induced NF-kappaB-dependent reductions of KChIP2 and I(to,f). Finally, inhibition of calcineurin did not prevent PE/Pro-induced reductions in KChIP2. CONCLUSIONS: NF-kappaB regulates KChIP2 and Kv4.2 expression. The reductions in I(to,f) observed following alpha-adrenergic receptor stimulation or tumor necrosis factor alpha application require NF-kappaB dependent decreases in KChIP2 expression. PMID- 21252159 TI - Enhancement of T-cell-mediated antitumor response: angiostatic adjuvant to immunotherapy against cancer. AB - PURPOSE: Tumor-released proangiogenic factors suppress endothelial adhesion molecule (EAM) expression and prevent leukocyte extravasation into the tumor. This is one reason why immunotherapy has met with limited success in the clinic. We hypothesized that overcoming EAM suppression with angiogenesis inhibitors would increase leukocyte extravasation and subsequently enhance the effectiveness of cellular immunotherapy. EXPERIMENTAL DESIGN: Intravital microscopy, multiple color flow cytometry, immunohistochemistry, and various tumor mouse (normal and T cell deficient) models were used to investigate the temporal dynamics of cellular and molecular events that occur in the tumor microenvironment during tumor progression and angiostatic intervention. RESULTS: We report that while EAM levels and T-cell infiltration are highly attenuated early on in tumor growth, angiostatic therapy modulates these effects. In tumor models with normal and T cell-deficient mice, we show the active involvement of the adaptive immune system in cancer and differentiate antiangiogenic effects from antiangiogenic mediated enhancement of immunoextravasation. Our results indicate that a compromised immune response in tumors can be obviated by the use of antiangiogenic agents. Finally, with adoptive transfer studies in mice, we show that a phased combination of angiostatic therapy and T-cell transfer significantly (P < 0.0013) improves tumor growth inhibition. CONCLUSIONS: This research contributes to understand the cellular mechanism of action of angiostatic agents and the immune response within the tumor microenvironment, in particular as a consequence of the temporal dynamics of EAM levels. Moreover, our results suggest that adjuvant therapy with angiogenesis inhibitors holds promise for cellular immunotherapy in the clinic. PMID- 21252161 TI - A decision aid to enhance informed decision making about bowel cancer screening improved knowledge but reduced screening uptake. PMID- 21252160 TI - Overexpression of HMGA2 promotes metastasis and impacts survival of colorectal cancers. AB - PURPOSE: This study aims to address the hypothesis that the high-mobility group A2 (HMGA2), an oncofetal protein, relates to survivability and serves as a prognostic biomarker for colorectal cancer (CRC). EXPERIMENTAL DESIGN: This is a retroprospective multiple center study. The HMGA2 expression level was determined by performing immunohistochemistry on surgical tissue samples of 89 CRCs from a training set and 191 CRCs from a validation set. The Kaplan-Meier analysis and COX proportional hazard model were employed to analyze the survivability. RESULTS: Multivariate logistic analysis indicated that the expression of HMGA2 significantly correlates with distant metastasis in training set (odds ratio, OR = 3.53, 95% CI: 1.37-9.70) and validation set (OR = 6.38, 95% CI: 1.47-43.95). Survival analysis revealed that the overexpression of HMGA2 is significantly associated with poor survival of CRC patients (P < 0.05). The adjusted HRs for overall survival were 2.38 (95% CI: 1.30-4.34) and 2.14 (95% CI: 1.21-3.79) in training and validation sets, respectively. Further investigation revealed that HMGA2 delays the clearance of gamma-H2AX in HCT-116 and SW480 cells post gamma irradiation, which supports our finding that CRC patients with HMAG2-positive staining in primary tumors had augmented the efficacy of adjuvant radiotherapy (HR = 0.18, 95% CI: 0.04-0.63). CONCLUSION: Overexpression of HMGA2 is associated with metastasis and unequivocally occurred in parallel with reduced survival rates of patients with CRC. Therefore, HMGA2 may potentially serve as a biomarker for predicting aggressive CRC with poor survivability and as an indicator for better response of radiotherapy. PMID- 21252162 TI - Tricyclic antidepressants reduce frequency of tension-type and migraine headaches compared with placebo, and intensity of headaches compared with SSRIs, but cause greater adverse effects. PMID- 21252163 TI - Combined prophylactic beta-blocker and behavioural migraine management improves 30-day migraine outcomes compared with either strategy alone, or optimised acute treatment only. PMID- 21252164 TI - Migraine with aura--indication of an increased risk of hemorrhagic stroke in women (Women's Health Study) and increased risk of overall death in an Icelandic population (Reykjavik Study). PMID- 21252166 TI - Odds of favourable 3-month outcome following ischaemic stroke are greatest when treatment with intravenous alteplase is initiated up to 90 min following event, with no benefit seen if alteplase is given after 270 min. PMID- 21252170 TI - Minor elevations in troponin I are associated with mortality and adverse cardiac events in patients with atrial fibrillation. AB - AIMS: In patients with atrial fibrillation, minor troponin I elevation is regularly detected; however, the prognostic significance of this finding is unknown. We therefore sought to examine the prognostic value of elevated troponin I in patients with atrial fibrillation. METHODS AND RESULTS: A prospective study was conducted analysing all consecutive patients admitted with atrial fibrillation in a 2-year period. Patients with an ST-elevation myocardial infarction (MI) were excluded. Minor troponin elevation was defined as a troponin I level between 0.15 and 0.65 ng/mL, which is still below the 99th percentile of the upper reference limit. A positive troponin I was defined as >= 0.65 ng/mL. Study outcomes were all-cause mortality (death), death and myocardial infarction (death/MI), or all major adverse cardiac events (MACE: death, MI, or revascularization). A total of 407 patients were eligible for inclusion. The median duration of follow-up was 688 days. A minor elevation occurred in 81 (20%) patients and 77 (19%) had a positive troponin I. In a multivariate model, minor troponin I elevation and a positive troponin I were independently associated with death [hazard ratio (HR): 2.36, 95% confidence interval (CI): 1.17-4.73 for minor elevation and HR: 3.77, 95% CI: 1.42-10.02 for positive troponin I]. Also, there was an independent correlation between the combined endpoints of death/MI and MACE and both a minor elevation and a positive troponin I. CONCLUSION: Minor elevations in troponin I on hospital admission are associated with mortality and cardiac events in patients with atrial fibrillation and might be useful for risk stratification. PMID- 21252171 TI - A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial. AB - AIMS: Patients with diabetes mellitus (DM) have increased platelet reactivity and reduced platelet response to clopidogrel compared with patients without DM. Prasugrel, a more potent antiplatelet agent, is associated with greater reductions in ischaemic events compared with clopidogrel, particularly in patients with DM. The aim of this study was to perform serial pharmacodynamic assessments of prasugrel with high-dose clopidogrel in patients with DM. METHODS AND RESULTS: Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 was a prospective, randomized, double-blind, crossover study in patients with type 2 DM and coronary artery disease (CAD). Patients (n= 35) were randomly assigned to either prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD) or clopidogrel 600 mg LD/150 mg MD over two 1-week treatment periods separated by a 2-week washout period. Platelet function was assessed by VerifyNow(r) P2Y12 assay, light transmission aggregometry, and vasodilator-stimulated phosphoprotein phosphorylation at 0, 1, 4, and 24 h and 7 days. Greater platelet inhibition by VerifyNow(r) P2Y12 was achieved by prasugrel compared with clopidogrel at 4 h post-LD (least squares mean, 89.3 vs. 27.7%, P< 0.0001; primary endpoint). The difference in platelet inhibition between prasugrel and clopidogrel was significant from 1 h through 7 days (P < 0.0001). Similar results were obtained using all other platelet function measures. Prasugrel resulted in fewer poor responders at all time points irrespective of definition used. CONCLUSION: In patients with type 2 DM and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel. PMID- 21252172 TI - Infection after pacemaker implantation: infection rates and risk factors associated with infection in a population-based cohort study of 46299 consecutive patients. AB - AIMS: Infection is a serious complication of pacemaker (PM) systems. Although the rate of infection has been debated, the figures are largely unknown. We therefore studied the incidence of PM infection and its associated risk factors in the Danish population. METHODS AND RESULTS: Since 1982, all PM implantation and removal procedures performed in Denmark have been prospectively recorded in the Danish Pacemaker Register. All patients (n = 46299) who underwent implantation between 1982 and 2007 were included. The total length of surveillance was 236,888 PM-years. The incidence of infection was calculated according to the total number of PM-years. The incidence of surgical site infection (<= 365 days after PM implantation) was compared with later infection in first implant and replacement procedures. Multiple-record and multiple-event-per-subject proportional hazards analyses were used to identify the independent risk factors of PM infection. Surgical site infection occurred in 192 cases after first implantation (incidence rate 4.82/1000 PM-years), and in 133 cases after replacement (12.12/1000 PM years). Infections occurring more than 365 days after the first implantation occurred in 153 cases (1.02/1000 PM-years), and in 118 cases after replacement (3.26/1000 PM-years). Independent factors associated with an increased risk of PM infection were a greater number of PM operations (including replacements), male sex, younger age, implantation during the earliest part of the study period, and absence of antibiotics (P< 0.001). CONCLUSION: The overall risk of infection after PM implantation was low. A greater number of operations augmented the risk of infection. This should be taken into account when considering revisions of PM systems. PMID- 21252173 TI - Surgical outcomes and prognostic factors of transsphenoidal surgery for prolactinoma in men: a single-center experience with 87 consecutive cases. AB - Context Little systematic data on male prolactinomas treated with surgery are available. Objective To clarify the clinical features and confirm the efficacy of transsphenoidal surgery for male prolactinomas and predictive factors after initial surgery. Patients and methods This retrospective study included 87 male patients with prolactinoma treated by transsphenoidal surgery at an academic medical center. Hormonal and visual status, remission rates, and the rate of tumor relapse, as well as predictive factors, were evaluated. Results Postoperative initial remission was achieved in 52.9% of patients. The remission rate was markedly higher in microadenomas (83.3%) than in macroadenomas (44.9%). Logistic regression analysis showed that the predictive factors of the early negative outcomes were high preoperative prolactin (PRL) levels and tumor invasion. After a median follow-up of 45 months, the long-term remission rate was 42.5%, and relapse of hyperprolactinemia occurred in 19.6% of the cured patients. The 5-year recurrence-free survival was 78.2% (95% confidence interval, 62.3 88.1%). When surgery was followed by adjuvant treatment in uncured and recurrent patients, 78.8% of patients in the entire group in the absence of dopamine agonists obtained biochemical remission at the end of follow-up. Conclusion Transsphenoidal surgery is a viable treatment alternative for male prolactinomas. The remission rates of male patients with microadenomas and/or intrasellar macroprolactinomas by surgery alone remain excellent, and surgery followed by adjuvant therapy as necessary is required for optimizing management of male prolactinomas, especially for extrasellar macroprolactinomas. The early negative results are associated with preoperative PRL levels and tumor invasion. PMID- 21252174 TI - Assessment of ACTH assay variability: a multicenter study. AB - OBJECTIVE: Measurement of plasma ACTH plays a pivotal role in the diagnosis and treatment of several endocrine disorders. Little is known, however, on the variability of ACTH assay results and its impact on clinical practice. The aim of the present study was to assess the performance of routine plasma ACTH measurements. DESIGN: Twenty-five fresh-frozen plasma samples collected from patients with either high, low, or normal ACTH concentrations were measured using seven different assays by 35 different laboratories. Assay precision, method agreement, and result classification were estimated. RESULTS: Inter- and intra assay coefficient of variation varied considerably with some assays achieving <10%, others consistently achieving >20%. Overall method agreement was good (mean ratio versus target value 1.02) but subject to exceedingly large excursion (lower and upper limits of agreement at 0.13 and 1.91 respectively). Both differences between assays and between laboratories contributed to variability of method agreement. Assays correctly classified most patients with normal and high ACTH concentrations (90% (95% CI 82-97%) and 95% (95% CI 86-100%) respectively), whereas only 60% (95% CI 52-67%) of measurements from patients with low ACTH values were assigned correctly. CONCLUSIONS: Field ACTH assays have to be interpreted with caution as they are burdened by high variability and often fail to correctly identify patients with suppressed ACTH secretion. The endocrine community has to include ACTH assays among those requiring standardization. PMID- 21252175 TI - Determinants of clinically important pain severity reduction in the prehospital setting. AB - This retrospective, electronic patient care record review examined a consecutive sample of patients presenting with pain to the metropolitan region of Ambulance Victoria over a 12 month period in 2008. Seven factors were found to be associated with the likelihood of clinically important pain reduction following multivariate analyses. These included age, time criticality of the patient, pain aetiology, initial pain severity, analgesic agent or combination administered to the patient and prehospital time. PMID- 21252177 TI - Increased adiposity programmed by catch-up growth: requirement for leptin signals? PMID- 21252178 TI - Stress hypogonadism: not everything that suppresses must converge. PMID- 21252180 TI - Muscle matters--dendrites grow up. PMID- 21252179 TI - MPA: medroxy-progesterone acetate contributes to much poor advice for women. PMID- 21252189 TI - Inter-examiner variability in orthodontic treatment decisions for Danish children with 'borderline' treatment need. AB - This study explored the variation between examiners in the orthodontic treatment need assessments of fifth-grade children with a borderline orthodontic treatment need. Each of three groups of children with borderline treatment need (n = 18, 19, and 19, respectively) were examined by one of three groups of orthodontists (33 in each group), whereby each of 56 children had 33 orthodontic treatment need assessments based on a clinical examination. This treatment need determination exercise was subsequently repeated with treatment need determined based on study casts and extraoral photographs. The proportion of positive treatment decisions based on the clinical examination was 49.3, 49.6, and 52.5 per cent, respectively, and 45.7, 46.3, and 50.5 per cent, based on the model assessments. There was a considerable disagreement between examiners in the treatment need assessments, whether assessments were based on a clinical examination or on a model-based case presentation. The average percentage agreement between two orthodontists for the treatment need based on clinical examination was 69, 66, and 61, respectively, corresponding to mean kappa values of 0.38, 0.32, and 0.22. When the model-based assessments were considered, the average percentage agreement between two orthodontists was 62, 58, and 69, respectively, corresponding to mean kappa values of 0.25, 0.16, and 0.37. Linear regression analysis of the orthodontists' treatment propensity as a function of their gender, place of education, years of orthodontic treatment experience, type of workplace, and place of work showed that only the orthodontic experience was influential for the model-based treatment propensity [beta = 0.34 per cent/year (95 per cent confidence interval = 0.01-0.66)]. PMID- 21252190 TI - Cervical vertebrae anomalies in subjects with Class II malocclusion assessed by lateral cephalogram and cone beam computed tomography. AB - A high prevalence of cervical vertebrae anomalies (CVA) has been recently associated with various malocclusions. Our aim was to study the prevalence of CVA on lateral cephalograms in Class II subjects and to compare the findings with those obtained from cone beam computed tomography (CBCT). Standardized cephalograms of 238 Class II patients were analysed for CVA. Cephalogram and CBCT were available for an additional 21 subjects. Cephalometric values were correlated with vertebrae morphology; logistic regressions and intraobserver agreement were evaluated. Inspection of lateral cephalograms could exclude CVA in 90.3 per cent of the subjects, while 9.7 per cent showed potential fusions. No correlations were found between the cephalometric values and potential vertebrae anomalies. In the 21 patients with a CBCT and a lateral cephalogram, the visual assessment of the cephalogram yielded a potential fusion in nine cases. None could be confirmed by CBCT. A low number of potentially fused cervical vertebrae could be detected on lateral cephalograms. The possible fusions did not correlate to any cephalometric values nor could they be confirmed by CBCT, the gold standard for assessing CVA. Visual examination of a cephalogram may result in a false-positive finding and does not allow reliable diagnosis of CVA. PMID- 21252191 TI - An in vitro evaluation of electromagnetic interference between implantable cardiac devices and ophthalmic laser systems. AB - AIMS: Ophthalmic laser treatments are discouraged in patients with implantable pulse generators (IPGs, pacemakers) and implantable cardioverter defibrillators (ICD) due to potential effects of the electromagnetic interference (EMI) emitted by ophthalmic laser systems. We assessed the effects of EMI generated by ophthalmic laser systems and laser discharge on IPG and ICD function. METHODS AND RESULTS: Two implantable devices, one Victory dual-chamber IPG (St Jude Medical, Minneapolis, MN, USA) and one Atlas II + dual-chamber ICD (St Jude Medical), were consecutively placed in a simulated thoracic chamber and exposed to three ophthalmic laser systems: the VISX Star S4 Excimer Laser, Lumenis Selecta II 532 neodymium-doped yttrium aluminium garnet (Nd:YAG) laser, and Ellex Ultra Q 1064 nm Nd:YAG laser. For each laser system, the apparatus was placed in the relative position of a patient while common laser procedures were delivered to a plastic object. Device pacing parameters were programmed to the highest possible sensitivity settings. The pacing and defibrillation function of the implantable devices, including electrograms, were continuously monitored. The EMI emitted from ophthalmic lasers did not lead to oversensing, inappropriate therapy, or change in the programming of the implantable cardiac devices. Manufacturing electrical tests performed on both devices showed that the cardiac devices continued to meet all the specifications for proper device function. CONCLUSION: The St Jude Medical Victory IPG and Atlas II + ICD were not affected by the EMI emitted by the ophthalmic laser systems. PMID- 21252192 TI - Defibrillation threshold testing fails to show clinical benefit during long-term follow-up of patients undergoing cardiac resynchronization therapy defibrillator implantation. AB - BACKGROUND: The utility of defibrillation threshold testing in patients undergoing implantable cardioverter-defibrillator (ICD) implantation is controversial. Higher defibrillation thresholds have been noted in patients undergoing implantation of cardiac resynchronization therapy defibrillators (CRT D). Since the risks and potential benefits of testing may be higher in this population, we sought to assess the impact of defibrillation safety margin or vulnerability safety margin testing in CRT-D recipients. METHODS AND RESULTS: A total of 256 consecutive subjects who underwent CRT-D implantation between January 2003 and December 2007 were retrospectively reviewed. Subjects were divided into two groups based on whether (n= 204) or not (n= 52) safety margin testing was performed. Patient characteristics, tachyarrhythmia therapies, procedural results, and clinical outcomes were recorded. Baseline characteristics, including heart failure (HF) severity, were comparable between the groups. Four cases of HF exacerbation (2%), including one leading to one death, were recorded in the tested group immediately post-implantation. No complications were observed in the untested group. After a mean follow-up of 32 +/- 20 months, the proportion of appropriate shocks in the two groups was similar (31 vs. 25%, P = 0.49). There were three cases of failed appropriate shocks in the tested group, despite adequate safety margins at implantation, whereas no failed shocks were noted in the untested group. Survival was similar in the two groups. CONCLUSION: Defibrillation efficacy testing during implant of CRT-D was associated with increased morbidity and did not predict the success of future device therapy or improve survival during long-term follow-up. PMID- 21252193 TI - Comparison of operator radiation exposure during coronary sinus catheter placement via the femoral or jugular vein approach. AB - AIMS: To evaluate and compare operator radiation exposure during the catheter placement in the coronary sinus via the femoral vein with a steerable catheter or the jugular vein with a fixed curve catheter. METHODS AND RESULTS: A total of 156 patients undergoing electrophysiological study or radiofrequency catheter ablation were prospectively assigned in a random fashion to either the femoral vein access (FVA) with a steerable curve deca-polar catheter (n= 80) or the jugular vein access (JVA) with a fixed curve deca-polar catheter (n = 76). All the catheterization procedures were performed by the same operator who had extensive experience in both accesses. Operator radiation exposure was measured with an electronic radiation dosimeter attached to the breast pocket of the operator on the outside of the lead apron and estimates of the ambient dose equivalent were derived. The operator radiation exposure was reduced significantly by using the FVA compared with the JVA (1.8 +/- 1.3 vs. 8.6 +/- 6.5 MUSv; P < 0.001). The fluoroscopy time (62.7 +/- 45.8 vs. 61.9 +/- 46.5 s; P = NS) and dose-area product (3.2 +/- 2.3 vs. 3.1 +/- 2.1 Gy cm(2); P = NS) were not statistically different. CONCLUSION: Operator radiation exposure can be significantly reduced by using the FVA approach with a steerable curve catheter compared with the JVA approach with a fixed curve catheter, without increasing the fluoroscopy time and dose-area product. PMID- 21252194 TI - Polyunsaturated fatty acids for prevention of atrial fibrillation: a 'fishy' story. PMID- 21252195 TI - Remote monitoring of implantable-cardioverter defibrillators: results from the Reliability of IEGM Online Interpretation (RIONI) study. AB - AIMS: Intracardiac electrograms (IEGMs) recorded by implantable cardioverter defibrillators (ICDs) are essential for arrhythmia diagnosis and ICD therapy assessment. Short IEGM snapshots showing 3-10 s before arrhythmia detection were added to the Biotronik Home Monitoring system in 2005 as the first-generation IEGM Online. The RIONI study tested the primary hypothesis that experts' ratings regarding the appropriateness of ICD therapy based on IEGM Online and on standard 30 s IEGM differ in <10% of arrhythmia events. METHODS AND RESULTS: A total of 619 ICD patients were enrolled and followed for 1 year. According to a predefined procedure, 210 events recorded by the ICDs were selected for evaluation. Three expert board members rated the appropriateness of ICD therapy and classified the underlying arrhythmia using coded IEGM Online and standard IEGM to avoid bias. The average duration of IEGM Online was 4.4+/-1.5 s. According to standard IEGM, the underlying arrhythmia was ventricular in 135 episodes (64.3%), supraventricular in 53 episodes (25.2%), oversensing in 17 episodes (8.1%), and uncertain in 5 episodes (2.4%). The expert board's rating diverged between determinable IEGM Online tracings and standard IEGM in 4.6% of episodes regarding the appropriateness of ICD therapy (95% CI up to 8.0%) and in 6.6% of episodes regarding arrhythmia classification (95% CI up to 10.5%). CONCLUSION: By enabling accurate evaluation of the appropriateness of ICD therapy and the underlying arrhythmia, the first-generation IEGM Online provided a clinically effective basis for timely interventions and for optimized patient management schemes, which was comparable with current IEGM recordings. PMID- 21252196 TI - Validation of rapid automated tissue synchronization imaging for the assessment of cardiac dyssynchrony in sinus and non-sinus rhythm. AB - AIMS: Cardiac resynchronization therapy is showing benefits for an increasing number of indications but fails to predict response in up to 20-30% of subjects. Echocardiographically assessed dyssynchrony has been proposed as a potential stratifier but current methods are time-consuming and suffer poor reproducibility, thus limiting their clinical utility. This study compared the accuracy, time efficiency, and reproducibility of automated tissue synchronization imaging (Auto TSI) vs. established manual tissue velocity imaging (TVI) techniques for the assessment of intra-ventricular dyssynchrony in sinus and non-sinus rhythm. METHODS AND RESULTS: Fifty consecutive stable systolic heart failure patients on optimal guideline-based medical therapy underwent intra ventricular dyssynchrony assessment [time to peak velocity (Ts), septal to lateral delay (SLD), and dyssynchrony index (DI)] with TVI and Auto TSI techniques, enabling the assessment of agreement, time efficiency, and reproducibility. Statistical analyses included Pearson's correlation, Bland Altman's statistics, and coefficient of reproducibility. There was excellent agreement between Auto TSI and TVI for the measurement of Ts [r=0.92, P<0.001, limits of agreement (LOA): -27.3 to 56.5 ms], SLD (r=0.94, P<0.001, LOA: -41 to 49 ms), and DI (r=0.89, P<0.001, LOA: -12.2 to 12.6 ms) which persisted irrespective of cardiac rhythm [Ts: sinus (n=32) r=0.93, P<0.001; non-sinus (n=18) r=0.91, P<0.001]. Automated TSI was more time efficient (3+/-1 vs. 14+/-2 min, P<0.001) and demonstrated superior reproducibility: intra-observer (5.5 vs. 9.6%) and inter-observer variability (9.5 vs. 13.4%). CONCLUSION: Automated TSI enables rapid, reproducible intra-ventricular dyssynchrony assessment and overcomes some of the limitations of conventional techniques in sinus and non sinus rhythm. PMID- 21252197 TI - Successful ICD lead implantation via an angulated and tortuous collateral vein after subclavian vein occlusion. PMID- 21252198 TI - Prevalence and timing of pregnancy termination for brain malformations. AB - OBJECTIVE: To determine the prevalence and the timing of pregnancy termination relative to the type of central nervous system (CNS) malformations. Design Retrospective cohort study. SETTING: Multidisciplinary centre for prenatal diagnosis in the Languedoc-Roussillon region, France. POPULATION: A cohort of 481 pregnancy terminations performed between 2005 and 2009. METHODS: Detailed post termination fetal and neuropathological analyses were carried out to identify the CNS malformations. Then, the prevalence and timing of pregnancy termination were assessed relative to the identified malformations. RESULTS: About one-third of pregnancy terminations (143/481) were performed for severe CNS malformations. Up to 24 weeks of gestation (WG), pregnancy terminations (56.6%) were carried out mainly for defects occurring during the two major first steps of CNS development (neurulation and differentiation of cerebral vesicles). After 24 WG, pregnancy terminations (43.3%) were mainly performed for corpus callosum agenesis (16/17), vermian agenesis (10/12) and gyral anomalies (13/15). For hindbrain malformations and gyral anomalies, there was a significant relationship between the timing of pregnancy termination and the presence of a severe ventriculomegaly at prenatal diagnosis (p=0.002 and p=0.02, respectively). CONCLUSION: By classifying CNS malformations according to the neuropathological analysis, the authors show that the timing and prevalence of pregnancy termination are distributed in a manner that is consistent with what is currently known on the development of brain. They are also influenced by the French prenatal screening policy and the variable expressivity of the brain malformations and associated lesions. PMID- 21252199 TI - Ultrasonically detectable cerebellar haemorrhage in preterm infants. AB - OBJECTIVE: To determine the frequency and pattern of cerebellar haemorrhage (CBH) on routine cranial ultrasound (cUS) imaging in infants of <=32 weeks gestation, and to investigate how extremely preterm infants with CBH differ from those with severe intraventricular haemorrhage (IVH). METHODS: 672 infants of <=32 weeks gestation were prospectively examined for CBH on serial cUS imaging. In a separate case--control analysis, the clinical features, ultrasound findings and outcome of preterm infants with CBH were compared to those of infants with isolated severe IVH (grade III-IV). RESULTS: Nine cases of CBH were identified among 53 infants with severe IVH. The incidence of CBH in infants of <=32 weeks gestation was 1.3%. Five infants had bilateral CBH involving both hemispheres, three had unilateral left sided CBH and one had a right hemispheric lesion. Infants with CBH were male, significantly more preterm (24.4 vs 27.0 weeks) and of lower birth weight (692 g vs 979 g). Vaginal births predominated in the CBH group (89% vs 50%). The median time to identification of haemorrhage for both groups was 3 days. Mortality in the CBH group was 100% (9/9) compared to 43% (19/44) in the severe IVH group. CONCLUSIONS: Extensive CBH in preterm infants is rare and devastating. It appears to be confined to very preterm, extremely low birthweight infants and may have a male predominance. The co-existence of severe IVH and extensive CBH on routine cot-side cUS in the early neonatal period is an ominous finding. PMID- 21252200 TI - Vitamin D deficiency and guideline awareness. PMID- 21252201 TI - Large duplications at reciprocal translocation breakpoints that might be the counterpart of large deletions and could arise from stalled replication bubbles. AB - Reciprocal chromosome translocations are often not exactly reciprocal. Most familiar are deletions at the breakpoints, up to megabases in extent. We describe here the opposite phenomenon-duplication of tens or hundreds of kilobases at the breakpoint junction, so that the same sequence is present on both products of a translocation. When the products of the translocation are mapped on the genome, they overlap. We report several of these "overlapping-breakpoint" duplications in breast cancer cell lines HCC1187, HCC1806, and DU4475. These lines also had deletions and essentially balanced translocations. In HCC1187 and HCC1806, we identified five cases of duplication ranging between 46 kb and 200 kb, with the partner chromosome showing deletions between 29 bp and 31 Mb. DU4475 had a duplication of at least 200 kb. Breakpoints were mapped using array painting, i.e., hybridization of chromosomes isolated by flow cytometry to custom oligonucleotide microarrays. Duplications were verified by fluorescent in situ hybridization (FISH), PCR on isolated chromosomes, and cloning of breakpoints. We propose that these duplications are the counterpart of deletions and that they are produced at a replication bubble, comprising two replication forks with the duplicated sequence in between. Both copies of the duplicated sequence would go to one daughter cell, on different products of the translocation, while the other daughter cell would show deletion. These duplications may have been overlooked because they may be missed by FISH and array-CGH and may be interpreted as insertions by paired-end sequencing. Such duplications may therefore be quite frequent. PMID- 21252202 TI - Glycoconjugate expression on the cell wall of tps1/tps1 trehalose-deficient Candida albicans strain and implications for its interaction with macrophages. AB - The yeast Candida albicans has developed a variety of strategies to resist macrophage killing. In yeasts, accumulation of trehalose is one of the principal defense mechanisms under stress conditions. The gene-encoding trehalose-6 phosphate synthase (TPS1), which is responsible for trehalose synthesis, is induced in response to oxidative stress, as in phagolysosomes. Mutants unable to synthesize trehalose are sensitive to oxidative stress in vitro. In mice, the TPS1-deficient strain, tps1/tps1, displays a lower infection rate than its parental strain (CAI4). We have previously demonstrated the reduced binding capacity of tps1/tps1 and its lower resistance to macrophages. At the same time, its outer cell wall layer was seen to be altered. In this study, we show that depending on the culture conditions, the tps1/tps1 strain regulates the carbohydrate metabolism in a different way to CAI4, as reflected by the enhanced beta-mannosylation of cell wall components, especially at the level of the 120 kDa glycoprotein species, accessible at the cell surface of tps1/tps1 when cultured in liquid medium, but not on solid medium. This leads to changes in its surface properties, as revealed by decreased hydrophobicity, and the lower levels of ERK1/2 phosphorylation and tumor necrosis factor-alpha (TNF-alpha) production in macrophages, thus increasing the resistance to these cells. In contrast, in solid medium, in which over-glycosylation was less evident, tps1/tps1 showed similar macrophage interaction properties to CAI4, but was less resistant to killing, confirming the protective role of trehalose. Thus, the lack of trehalose is compensated by an over-glycosylation of the cell wall components in the tps1/tps1 mutant, which reduces susceptibility to killing. PMID- 21252203 TI - Insulin resistance and hepatitis C: an evolving story. AB - Insulin resistance and diabetes are inextricably linked to chronic hepatitis C. Our understanding of this relationship continues to improve. This review focuses on the molecular mechanisms relating insulin resistance to hepatitis C with a subsequent overview of the consequences of hepatitis C-associated insulin resistance and diabetes, as well as perspectives for future management. PMID- 21252204 TI - Crohn's disease: NOD2, autophagy and ER stress converge. AB - Polymorphisms in NOD2, encoding an intracellular pattern recognition receptor, contribute the largest fraction of genetic risk for Crohn's disease among the >40 risk loci identified so far. Autophagy plays a prominent role in the innate immune response towards intracellular bacteria. The discovery of the autophagy genes ATG16L1 and IRGM as risk factors for Crohn's disease turned autophagy into the spotlight in inflammatory bowel disease (IBD). Remarkably, NOD2 has recently been identified as a potent autophagy inducer. A physical interaction of NOD2 and ATG16L1 appears to be required for autophagic clearance of intracellular pathogens. Moreover, Crohn's disease-associated NOD2 and ATG16L1 variants exhibit a defect in the induction of an autophagic response and hence predict autophagy as a key converging mechanism that leads to Crohn's disease. Another pathway that is closely intertwined with autophagy and mutually cross-regulated is the unfolded protein response (UPR), which is induced by endoplasmic reticulum (ER) stress. Genes involved in the UPR (XBP1, ORMDL3) have also been genetically associated with Crohn's disease and ulcerative colitis. Moreover, the intestinal epithelium at the interface between host and microbe appears particularly affected by IBD-associated hypomorphic function of autophagy and the UPR. The functional convergence of main genetic risk factors for IBD on these innate immune pathways has hence important implications for the host's interaction with the microbiota. Moreover, the genetic convergence on these molecular mechanisms may open novel therapeutic options for IBD that deserve further exploration. PMID- 21252206 TI - Spatial and temporal correlation between neuron loss and neuroinflammation in a mouse model of neuronopathic Gaucher disease. AB - Gaucher disease (GD), the most common lysosomal storage disorder, is caused by a deficiency in the lysosomal enzyme glucocerebrosidase (GlcCerase), which results in intracellular accumulation of glucosylceramide (GlcCer). The rare neuronopathic forms of GD are characterized by profound neurological impairment and neuronal cell death, but little is known about the neuropathological changes that underlie these events. We now systematically examine the onset and progression of various neuropathological changes (including microglial activation, astrogliosis and neuron loss) in a mouse model of neuronopathic GD, and document the brain areas that are first affected, which may reflect vulnerability of these areas to GlcCerase deficiency. We also identify neuropathological changes in several brain areas and pathways, such as the substantia nigra reticulata, reticulotegmental nucleus of the pons, cochlear nucleus and the somatosensory system, which could be responsible for some of the neurological manifestations of the human disease. In addition, we establish that microglial activation and astrogliosis are spatially and temporally correlated with selective neuron loss. PMID- 21252205 TI - Risk- and non-risk-associated variants at the 10q26 AMD locus influence ARMS2 mRNA expression but exclude pathogenic effects due to protein deficiency. AB - Fifteen variants in 10q26 are in strong linkage disequilibrium and are associated with an increased risk for age-related macular degeneration (AMD), a frequent cause of blindness in developed countries. These variants tag a single-risk haplotype encompassing the genes ARMS2 (age-related maculopathy susceptibility 2) and part of HTRA1 (HtrA serine peptidase 1). To define the true AMD susceptibility gene in 10q26, several studies have focused on the influence of risk alleles on the expression of ARMS2 and/or HTRA1, but the results have been inconsistent. By heterologous expression of genomic ARMS2 variants, we now show that ARMS2 mRNA levels transcribed from the risk haplotype are significantly reduced compared with non-risk mRNA isoforms. Analyzing variant ARMS2 constructs, this effect could specifically be assigned to the known insertion/deletion polymorphism (c.(*)372_815del443ins54) in the 3'-untranslated region of ARMS2. Reporter gene assays with HTRA1 promoter sequences demonstrated the presence of a Muller glia-specific cis-regulatory region further upstream of the transcription start site. However, AMD risk alleles had little or no effect on HTRA1 promoter activity in the retina. Analysis of a large series of human post-mortem retina/retinal pigment epithelial samples heterozygous for the risk haplotype confirmed the in vitro/ex vivo results and demonstrated that the risk haplotype affects ARMS2 but not HTRA1 mRNA expression. Furthermore, we provide in vivo evidence that a common non-risk-associated non-synonymous variant (rs2736911) also leads to decreased ARMS2 transcript levels. Consequently, our data suggest that pathogenic effects due to ARMS2 protein deficiency are unlikely to account for AMD pathology. PMID- 21252207 TI - Late presentation of foreign body aspiration requiring extracorporeal membrane oxygenation support for surgical management. AB - We present the case of a near fatal aspiration of a foreign body requiring extracorporeal membrane oxygenation (ECMO) support. The use of ECMO to support treatment for a foreign body in the distal trachea is rare and there are only two cases reported in the literature. A 13-year-old male presented with a three weeks' history of a cough and swinging fevers. Subsequent investigation revealed a foreign body causing collapse of the right middle and lower lobe with abscess formation. On attempted bronchoscopic removal, copious amounts of pus were aspirated, soiling both lungs. The patient became severely hypoxic and hypotensive. He was unstable on ventilation and inotropes and ECMO was used to stabilise him and facilitate removal of the foreign body and infected lung. He made excellent recovery and suffered no neurological sequalae. This is the first reported use of ECMO support for an acute presentation of a chronic problem. If the patient is too unstable for bronchoscopy, ECMO can be used to temporarily stabilise the patient allowing safe removal of the object. If the patient is acutely unwell and septic, ECMO should be more readily considered. PMID- 21252208 TI - Mini-cardiopulmonary bypass impact on blood conservation strategy in coronary artery bypass grafting. AB - OBJECTIVE: Cardiopulmonary bypass (CPB) using a closed circuit system with minimal priming volume can be a solution to ameliorate adverse effects of CPB. We hypothesize that the use of mini-bypass in routine coronary artery bypass grafting (CABG) reduces homologous blood product use and postoperative bleeding. The study is designed to determine the differences in blood loss and transfusion requirements associated with a minimized CPB circuit vs. a standard bypass circuit. METHODS: From February 2009 to August 2009, 80 patients were prospectively randomized to undergo elective CABG. Group A included 40 patients who had the minimized bypass circuit (Medtronic Resting Heart Circuit). Group B had an equal number of patients who had the standard CPB circuit (Stockert III, SEC.BM). Laboratory parameters for hemoglobin, hematocrit and platelet count were measured at baseline after initiation of CPB and after bypass. Blood usage was controlled by study-specific protocol (transfusion for hemoglobin <8 g/dl). Records were kept for blood products. The chest and mediastinal drainage was monitored for the first 24 postoperative hours. Ventilation time, inotropic use and intensive care unit (ICU) stay was compared in both groups. RESULTS: There were no statistical differences in terms of patients' demographics. Statistically significant differences were seen in transfused red blood cells volume (1.47+/ 1.13 units in group A vs. 2.05+/-1.19 in group B, P<0.05), fresh frozen plasma (2.5+/-1.62 unit vs. 3.55+/-2.58 units, P<0.001), platelets (1.95+/-2.95 units vs. 3.23+/-2.85), and postoperative drainage in 24 hours (531.62+/-220.12 ml vs. 729+/-294.9 ml, P<0.05). The hematocrit was 33+/-5% in group A, and 27+/-1% in group B. There was statistical differences seen in the mean hemoglobin level which was 10.19+/-0.65 g/dl in group A, and 9.4+/-0.68 g/dl in group B. There was statistical difference in the duration of ventilation, length of ICU stay. The requirement of inotropic support was lower in group A. CONCLUSIONS: The adoption of mini-bypass significantly reduces morbidity including donor blood usage and postoperative bleeding in routine CABG patients. PMID- 21252209 TI - Reoperation for ascending aorta false aneurysm using deep hypothermia and circulatory arrest. AB - OBJECTIVES: Ascending aorta false aneurysms after cardiac surgery are uncommon. Resternotomy is hazardous and may result in massive and uncontrollable hemorrhage if the false aneurysm is entered. Here we report our experience with the use of deep hypothermia and circulatory arrest to avoid this risk. METHODS: From March 2000 to December 2007, seven patients (mean age 50 years) were reoperated for an ascending aorta false aneurysm. Three patients had undergone an aortic valve replacement (n=2) or an aortic valve repair (n=1). Three had undergone an ascending aorta replacement with a valved conduit (n=2) or an aortic valve repair (n=1) for type A dissection. One had undergone a coronary artery bypass grafting. Mean delay to reoperation was 133 months (range 22-324 months). Two patients had positive blood cultures (Staphylococcus species). Cardiopulmonary bypass was established by extramediastinal access. Patients were cooled to 18 degrees C. RESULTS: Resternotomy was performed uneventfully under total circulatory arrest in all patients. Four patients underwent an ascending aorta replacement with a valved conduit (n=2) or a dacron conduit (n=2) associated with a mitral valve replacement in one patient. Direct suture was performed in two patients and in one patient the aorta was repaired using a saphenous vein patch. There was one hospital death. Mean follow-up was 53 months (range 14-90 months). CONCLUSION: Resternotomy under circulatory arrest and deep hypothermia is a safe technique well-adapted to patients with an ascending aorta false aneurysm. PMID- 21252211 TI - Commentary: Co-occurrence of tuberculosis and diabetes: new paradigm of epidemiological transition. PMID- 21252210 TI - Diabetes mellitus and tuberculosis in countries with high tuberculosis burdens: individual risks and social determinants. AB - BACKGROUND: A growing body of evidence supports the role of type 2 diabetes as an individual-level risk factor for tuberculosis (TB), though evidence from developing countries with the highest TB burdens is lacking. In developing countries, TB is most common among the poor, in whom diabetes may be less common. We assessed the relationship between individual-level risk, social determinants and population health in these settings. METHODS: We performed individual-level analyses using the World Health Survey (n = 124,607; 46 countries). We estimated the relationship between TB and diabetes, adjusting for gender, age, body mass index, education, housing quality, crowding and health insurance. We also performed a longitudinal country-level analysis using data on per-capita gross domestic product and TB prevalence and incidence and diabetes prevalence for 1990 95 and 2003-04 (163 countries) to estimate the relationship between increasing diabetes prevalence and TB, identifying countries at risk for disease interactions. RESULTS: In lower income countries, individuals with diabetes are more likely than non-diabetics to have TB [univariable odds ratio (OR): 2.39; 95% confidence interval (CI): 1.84-3.10; multivariable OR: 1.81; 95% CI: 1.37-2.39]. Increases in TB prevalence and incidence over time were more likely to occur when diabetes prevalence also increased (OR: 4.7; 95% CI: 1.0-22.5; OR: 8.6; 95% CI: 1.9-40.4). Large populations, prevalent TB and projected increases in diabetes make countries like India, Peru and the Russia Federation areas of particular concern. CONCLUSIONS: Given the association between diabetes and TB and projected increases in diabetes worldwide, multi-disease health policies should be considered. PMID- 21252212 TI - Modifying effects of wealth on the response to nutrient supplementation in pregnancy on birth weight, duration of gestation and perinatal mortality in rural western China: double-blind cluster randomized controlled trial. AB - BACKGROUND: There have been few reports of differential responses to nutrition interventions in women and children from poor households. Women from poor households have greater nutritional risks and are potentially a target group for programmes. We assessed the modifying effects of household wealth on responses to micronutrient supplements in pregnancy on newborn anthropometry and perinatal mortality. METHODS: A cluster randomized double-blind controlled trial conducted in two rural counties in northwestern China. All pregnant women in villages were randomly allocated from enrolment until delivery to daily supplementation with folic acid (control), iron/folic acid or multiple micronutrients (MMNs) with a recommended allowance of 15 vitamins and minerals. Wealth was based on a score from an inventory of household assets. RESULTS: In the pregnant women from the poorest one-third of the households, MMN supplements significantly increased birth weight by 68 g [95% confidence interval (CI) 4-131 g], reduced low birth weight by 60% [relative risks (RRs) 0.40, 95% CI 0.21-0.78] and tended to reduce early neonatal mortality by 52% (RR 0.48, 95% CI 0.17-1.36) compared with folic acid. Iron/folic acid significantly increased the duration of gestation by 0.41 weeks (95% CI 0.18-0.65), reduced pre-term birth by 45% (RR 0.55, 95% CI 0.32 0.93) and significantly reduced early neonatal mortality by 90% (RR 0.10, 95% CI 0.01-0.79) compared with folic acid. Iron/folic acid and MMN supplements had no significant effects in women from wealthier households. CONCLUSIONS: In rural China, women from the poorest households had the largest perinatal outcome responses to micronutrient supplementation. In these women, standard iron/folic acid provided more protection for neonatal survival than MMN supplements. PMID- 21252213 TI - Commentary: is there a best index of weight for height? PMID- 21252214 TI - Junior doctors' extended work hours and the effects on their performance: the Irish case. AB - OBJECTIVE: To explore the relationship between junior doctors' long working hours and their performance in a variety of cognitive and clinical decision-making tests. Also, to consider the implications of performance decrements in such tests for healthcare quality. DESIGN: A within-subject design was used to eliminate variation related to individual differences. Each participant was tested twice, once post call and once rested. At each session, participants were tested on cognitive functioning and clinical decision-making. SETTING: The study was based on six acute Irish hospitals during 2008. PARTICIPANTS: Thirty junior hospital doctors, ages ranged from 23 to 30 years; of them, 17 of the participants were female and 13 were male. Measures Cognitive functioning was measured by the MindStreams Global Assessment Battery (NeuroTrax Corp., NY, USA). This is a set of computerized tests, designed for use in medical settings, that assesses performance in memory, executive function, visual spatial perception, verbal function, attention, information processing speed and motor skills. Clinical decision-making was tested using Key Features Problems. Each Key Features Problem consists of a case scenario and then three to four questions about this scenario. In an effort to make it more realistic, the speed with which participants completed the three problems was also recorded. RESULTS: Participants' global cognitive scores, attention, information processing speed and motor skills were significantly worse post call than when rested. They also took longer to complete clinical decision-making questions in the post-call condition and obtained lower scores than when rested. CONCLUSIONS: There are significant negative changes in doctors' cognitive functioning and clinical decision-making performance that appear to be attributable to long working hours. This therefore raises the important question of whether working long hours decreases healthcare quality and compromises patient safety. PMID- 21252215 TI - The occurrence of refractoriness and mast cell mediator release following mannitol-induced bronchoconstriction. AB - For several hours after exercise-induced bronchoconstriction, there is diminished responsiveness to repeated challenge. The mechanism causing this refractoriness is unclear. Inhalation of dry powder mannitol is a new bronchial provocation test that has been suggested as a surrogate for an exercise challenge. Refractoriness to repeated mannitol challenge has however not been established. Our objective was to investigate if repeated challenge with mannitol is associated with refractoriness and diminished release of mast cell mediators of bronchoconstriction. Sixteen subjects with asthma underwent repeated inhalation of mannitol 90 min apart. Lung function was assessed by forced expiratory volume in 1 s (FEV1). The urinary excretion (ng/mmol creatinine) of the mediators 9alpha,11beta-prostaglandin (PG) F2 and leukotriene (LT) E4 were measured. The group mean fall in FEV1 after the second challenge was 48.5 +/- 5.8% of the first (P < 0.001). The protection afforded by the initial challenge, however, varied considerably between subjects (range 88-0%). Furthermore, the urinary excretion of the two mediators was increased after both challenges. The average excretion of mediators after the challenges was significantly higher for the six most refractory subjects. This was observed both for LTE4 (95.6 +/- 5.2 vs. 58.0 +/- 2.4 for the 6 least refractory) (P < 0.001) and for 9alpha,11beta-PGF2 (137.6 +/- 6.7 vs. 50.1 +/- 1.1 for the 6 least refractory) (P = 0.002). As occurs with exercise-induced bronchoconstriction, repeated inhalation of mannitol induced refractoriness. We propose that refractoriness is due to tachyphylaxis at the level of the airway smooth muscle responsiveness to mediators of bronchoconstriction rather than due to fatigue of their release from mast cells. PMID- 21252216 TI - Resistance and aerobic exercise protects against acute endothelial impairment induced by a single exposure to hypertension during exertion. AB - Resistance and aerobic exercise is recommended for cardiovascular health and disease prevention. However, the accompanying increase in arterial pressure during resistance exercise may be detrimental to vascular health. This study tests the vascular benefits of aerobic compared with resistance exercise on preventing impaired vascular function induced by a single weight lifting session that is associated with acute hypertension. Healthy, lean sedentary (SED) subjects, weight lifters, runners (>15 miles/wk), and cross trainers (chronic aerobic and resistance exercisers), underwent a single progressive leg press weight lifting session with blood pressure measurements. Brachial artery flow mediated vasodilation (FMD; an index of arterial endothelial function) was determined using ultrasonography immediately before and after weight lifting. Sublingual nitroglycerin (0.4 mg) was used to determine endothelium-independent dilation after weight lifting. All subjects were normotensive with similar blood pressure responses during exercise. Baseline FMD was lower in runners (5.4 +/- 0.5%; n = 13) and cross trainers (4.44 +/- 0.3%; n = 13) vs. SED (8.5 +/- 0.8%; n = 13; P = 0.037). Brachial FMD improved in conditioned weight lifters (to 8.8 +/- 0.9%; P = 0.007) and runners (to 7.6 +/- 0.6%; P < 0.001) but not cross trainers (to 5.3 +/- 0.6%; P = NS) after acute hypertension. FMD was decreased in SED (to 5.7 +/- 0.4%; P = 0.019). Dilation to nitroglycerin was similar among groups. These data suggest that endothelial responses are maintained after exposure to a single bout of weight lifting in resistance and aerobic athletes. Resistance and aerobic exercise may confer similar protection against acute vascular insults such as exertional hypertension. PMID- 21252217 TI - Possible role of differential growth in airway wall remodeling in asthma. AB - Airway remodeling in patients with chronic asthma is characterized by a thickening of the airway walls. It has been demonstrated in previous theoretical models that this change in thickness can have an important mechanical effect on the properties of the wall, in particular on the phenomenon of mucosal folding induced by smooth muscle contraction. In this paper, we present a model for mucosal folding of the airway in the context of growth. The airway is modeled as a bilayered cylindrical tube, with both geometric and material nonlinearities accounted for via the theory of finite elasticity. Growth is incorporated into the model through the theory of morphoelasticity. We explore a range of growth possibilities, allowing for anisotropic growth as well as different growth rates in each layer. Such nonuniform growth, referred to as differential growth, can change the properties of the material beyond geometrical changes through the generation of residual stresses. We demonstrate that differential growth can have a dramatic impact on mucosal folding, in particular on the critical pressure needed to induce folding, the buckling pattern, as well as airway narrowing. We conclude that growth may be an important component in airway remodeling. PMID- 21252219 TI - Self-organized patterns of airway narrowing. AB - The behavior of respiratory diseases such as asthma and COPD may involve complicated interactions among multiple factors. Theoretical and experimental data suggest that interdependence among the airways of the bronchial tree leads to the emergence of self-organized patterns of airway narrowing, ventilation defects, and other phenomena when a tipping point is passed. Additionally, evidence from several studies shows that the behavior of an isolated airway is different from an identical airway embedded in the bronchial tree so that experimental results of isolated elements such as airways, airway smooth muscle, or inflammatory pathways may not explain the whole organ behavior. However, there may be factors in the isolated elements that can dramatically change the complex system's behavior. More effective strategies for prevention or recovery from a disease, such as asthma, will depend on our progress in identifying and understanding the essential parts of the self-organized behavior that is involved. PMID- 21252218 TI - Interactive effects of APOE haplotype, sex, and exercise on postheparin plasma lipase activities. AB - Hepatic lipase (HL) and lipoprotein lipase (LPL) activities (HLA, LPLA) modify lipoproteins and facilitate their binding to hepatic receptors. Apolipoprotein E (APOE) physically interacts with the lipases, and the three common haplotypes of the APOE gene (epsilon2, epsilon3, and epsilon4) yield protein isoforms (E2, E3, and E4, respectively) that are functionally different. Lipase activities themselves differ by sex and exercise training status. The interaction of APOE genotype, exercise training, and sex effects on lipase activities has not been studied. We measured postheparin plasma lipase activities in normolipidemic men and women with the three most common APOE genotypes, which are the haplotype combinations epsilon2/epsilon3 (n = 53 ), epsilon3/epsilon3 (n = 62), and epsilon4/epsilon3 (n = 52), enrolled in 6 mo of aerobic exercise training. These haplotype combinations comprise an estimated 11.6, 62.3, and 21.3% of the population, respectively. Baseline HLA was 35% lower in women than in men (P < 0.0001). In men but not women, HLA was higher in epsilon2/epsilon3 group compared with epsilon4/epsilon3 (P = 0.01) and epsilon3/epsilon3 (P = 0.05). Neither sex nor APOE genotype affected baseline LPLA. Training decreased HLA by 5.2% (P = 0.018) with no APOE effect. The apparent increase in LPLA following exercise was significant and APOE dependent only when corrected for baseline insulin (P < 0.05). Exercise decreased LPLA by 0.8 MUmol free fatty acid (FFA).ml-1.h-1 (-6%) in epsilon3/epsilon3 compared with the combined increases of 6.6% in epsilon2/epsilon3 and 12% in epsilon4/epsilon3 (P = 0.018 vs. epsilon3/epsilon3). However, these differences were statistically significant only after correcting for baseline insulin. We conclude that common APOE genotypes interact with 1) sex to modulate HLA regardless of training status, with epsilon2/epsilon3 men demonstrating higher HLA than epsilon3/epsilon3 or epsilon4/epsilon3 men, and 2) aerobic training to modulate LPLA, regardless of sex, with epsilon3/epsilon3 subjects showing a significant decrease compared with an increase in epsilon2/epsilon3 and epsilon3/epsilon4 after controlling for baseline insulin. PMID- 21252220 TI - Turning the PAGe on central control of the exercise pressor reflex in humans. PMID- 21252221 TI - Effects of polycythemia on systemic endothelial function in chronic hypoxic lung disease. AB - Chronic obstructive pulmonary disease (COPD) is a major risk factor for cardiovascular disease. Polycythemia, a common complication of hypoxic COPD, may affect systemic vascular function by altering blood viscosity, vessel wall shear stress (WSS), and endothelium-derived nitric oxide (NO) release. Here, we evaluated the effects of hypoxia-related polycythemia on systemic endothelial function in patients with COPD. We investigated blood viscosity, WSS, and endothelial function in 15 polycythemic and 13 normocythemic patients with COPD of equal severity, by recording brachial artery diameter variations in response to hyperemia and by using venous occlusion plethysmography (VOP) to measure forearm blood flow (FBF) responses to a brachial artery infusion of acetylcholine (ACh), bradykinin (BK), sodium nitroprusside (SNP), substance P (SP), isoptin, and N-monomethyl-L-arginine (L-NMMA). At baseline, polycythemic patients had higher blood viscosity and larger brachial artery diameter than normocythemic patients but similar calculated WSS. Flow-mediated brachial artery vasodilation was increased in the polycythemic patients, in proportion to the hemoglobin levels. ACh-induced vasodilation was markedly impaired in the polycythemic patients and negatively correlated with hemoglobin levels. FBF responses to endothelium- (BK, SP) and non-endothelium-dependent (SNP, isoptin) vasodilators were not significantly different between the two groups. L-NMMA infusion induced a similar vasoconstrictor response in both groups, in accordance with their similar baseline WSS. In conclusion, systemic arteries in polycythemic patients adjust appropriately to chronic or acute WSS elevations by appropriate basal and stimulated NO release. Overall, our results suggest that moderate polycythemia has no adverse effect on vascular function in COPD. PMID- 21252222 TI - Regulation of human mitochondrial aldehyde dehydrogenase (ALDH-2) activity by electrophiles in vitro. AB - Recently, mitochondrial aldehyde dehydrogenase (ALDH-2) was reported to reduce ischemic damage in an experimental myocardial infarction model. ALDH-2 activity is redox-sensitive. Therefore, we here compared effects of various electrophiles (organic nitrates, reactive fatty acid metabolites, or oxidants) on the activity of ALDH-2 with special emphasis on organic nitrate-induced inactivation of the enzyme, the biochemical correlate of nitrate tolerance. Recombinant human ALDH-2 was overexpressed in Escherichia coli; activity was determined with an HPLC-based assay, and reactive oxygen and nitrogen species formation was determined by chemiluminescence, fluorescence, protein tyrosine nitration, and diaminonaphthalene nitrosation. The organic nitrate glyceryl trinitrate caused a severe concentration-dependent decrease in enzyme activity, whereas incubation with pentaerythritol tetranitrate had only minor effects. 4-Hydroxynonenal, an oxidized prostaglandin J(2), and 9- or 10-nitrooleate caused a significant inhibition of ALDH-2 activity, which was improved in the presence of Mg(2+) and Ca(2+). Hydrogen peroxide and NO generation caused only minor inhibition of ALDH 2 activity, whereas peroxynitrite generation or bolus additions lead to severe impairment of the enzymatic activity, which was prevented by the thioredoxin/thioredoxin reductase (Trx/TrxR) system. In the presence of glyceryl trinitrate and to a lesser extent pentaerythritol tetranitrate, ALDH-2 may be switched to a peroxynitrite synthase. Electrophiles of different nature potently regulate the enzymatic activity of ALDH-2 and thereby may influence the resistance to ischemic damage in response to myocardial infarction. The Trx/TrxR system may play an important role in this process because it not only prevents inhibition of ALDH-2 but is also inhibited by the ALDH-2 substrate 4 hydroxynonenal. PMID- 21252223 TI - The role of the human SWI5-MEI5 complex in homologous recombination repair. AB - The Swi5-Mei5 complex and its homologues are involved in specialized recombination pathways in budding and fission yeasts. Although the fission yeast homologue Swi5-Sfr1 is critical for homologous recombination repair, the budding yeast counterpart Sae3-Mei5 is meiosis-specific, interacts with Dmc1, and promotes assembly of Dmc1 on meiotic chromosomes. Here, we identify and characterize the human SWI5-MEI5 (C9orf119-C10orf78) complex. We showed that SWI5 and MEI5 form a stable complex in vitro and in vivo. The C-terminal Swi5 domain of SWI5 and the middle coiled-coil region of MEI5 dictate this conserved interaction. In addition, SWI5-MEI5 directly interacts with RAD51 in vitro. Depletion of SWI5 or MEI5 in human cells causes defects in homologous recombination repair. Finally, SWI5- or MEI5-depleted cells display enhanced sensitivity to ionizing radiation, consistent with the role of this complex in HR repair. Our results suggest that human SWI5-MEI5 has an evolutionarily conserved function in homologous recombination repair. PMID- 21252224 TI - Transcript profiling and inference of Escherichia coli K-12 ArcA activity across the range of physiologically relevant oxygen concentrations. AB - Oxygen availability is the major determinant of the metabolic modes adopted by Escherichia coli. Although much is known about E. coli gene expression and metabolism under fully aerobic and anaerobic conditions, the intermediate oxygen tensions that are encountered in natural niches are understudied. Here, for the first time, the transcript profiles of E. coli K-12 across the physiologically significant range of oxygen availabilities are described. These suggested a progressive switch to aerobic respiratory metabolism and a remodeling of the cell envelope as oxygen availability increased. The transcriptional responses were consistent with changes in the abundance of cytochrome bd and bo' and the outer membrane protein OmpW. The observed transcript and protein profiles result from changes in the activities of regulators that respond to oxygen itself or to metabolic and environmental signals that are sensitive to oxygen availability (aerobiosis). A probabilistic model (TFInfer) was used to predict the activity of the indirect oxygen-sensing two-component system ArcBA across the aerobiosis range. The model implied that the activity of the regulator ArcA correlated with aerobiosis but not with the redox state of the ubiquinone pool, challenging the idea that ArcA activity is inhibited by oxidized ubiquinone. The amount of phosphorylated ArcA correlated with the predicted ArcA activities and with aerobiosis, suggesting that fermentation product-mediated inhibition of ArcB phosphatase activity is the dominant mechanism for regulating ArcA activity under the conditions used here. PMID- 21252225 TI - Beta-N-acetylhexosaminidases HEXO1 and HEXO3 are responsible for the formation of paucimannosidic N-glycans in Arabidopsis thaliana. AB - Most plant glycoproteins contain substantial amounts of paucimannosidic N-glycans instead of their direct biosynthetic precursors, complex N-glycans with terminal N-acetylglucosamine residues. We now demonstrate that two beta-N acetylhexosaminidases (HEXO1 and HEXO3) residing in different subcellular compartments jointly account for the formation of paucimannosidic N-glycans in Arabidopsis thaliana. Total N-glycan analysis of hexo knock-out plants revealed that HEXO1 and HEXO3 contribute equally to the production of paucimannosidic N glycans in roots, whereas N-glycan processing in leaves depends more heavily on HEXO3 than on HEXO1. Because hexo1 hexo3 double mutants do not display any obvious phenotype even upon exposure to different forms of abiotic or biotic stress, it should be feasible to improve the quality of glycoprotein therapeutics produced in plants by down-regulation of endogenous beta-N-acetylhexosaminidase activities. PMID- 21252226 TI - Induction of glutathione peroxidase 4 expression during enterocytic cell differentiation. AB - Glutathione peroxidase 4 (GPx4), an abundant selenoenzyme, is ubiquitously expressed in a tissue-, cell- and differentiation-dependent manner, and it is localized in cytoplasmic, mitochondrial, and nuclear cellular compartments. Here, we report cytoplasmic and nuclear localization of GPx4 in Caco-2 intestinal epithelial cells. Enterocytic differentiation of Caco-2 cells triggers an increase in GPx4 mRNA and protein levels, mediated by enhanced promoter activity. We identified a combined cAMP response element (CREB) and CCAAT/enhancer binding protein (C/EBP) site as critical for the differentiation-triggered GPx4 promoter activity. Induction of GPx4 correlated with C/EBPalpha transcript levels during differentiation, suggesting a role of C/EBPalpha as regulator of enterocytic GPx4 expression. Consistent with the in vitro results, GPx4 protein was detected in cytoplasmic and nuclear compartments of enterocytes in human intestinal epithelia. GPx4 is uniformly expressed in colonic crypts and is differentially expressed along the crypt-to-villus axis in the small intestine with a more pronounced expression of GPx4 in the upper villi, which contain fully differentiated enterocytes. These data suggest that intestinal GPx4 expression is modulated by the enterocytic differentiation program, and the results support a direct role of nuclear GPx4 in the (selenium-dependent) prevention of oxidative damage in the gastrointestinal tract. PMID- 21252227 TI - Structure and activity of alpha-conotoxin PeIA at nicotinic acetylcholine receptor subtypes and GABA(B) receptor-coupled N-type calcium channels. AB - alpha-Conotoxins are peptides from cone snails that target the nicotinic acetylcholine receptor (nAChR). RgIA and Vc1.1 have analgesic activity in animal pain models. Both peptides target the alpha9alpha10 nAChR and inhibit N-type calcium channels via GABA(B) receptor activation, but the mechanism of action of analgesic activity is unknown. PeIA has previously been shown to inhibit the alpha9alpha10 and alpha3beta2 nAChRs. In this study, we have determined the structure of PeIA and shown that it is also a potent inhibitor of N-type calcium channels via GABA(B) receptor activation. The characteristic alpha-conotoxin fold is present in PeIA, but it has a different distribution of surface-exposed hydrophobic and charged residues compared with Vc1.1. Thus, the surface residue distribution, rather than the overall fold, appears to be responsible for the 50 fold increase in selectivity at the alpha3beta2 nAChR by PeIA relative to Vc1.1. In contrast to their difference in potency at the nAChR, the equipotent activity of PeIA and Vc1.1 at the GABA(B) receptor suggests that the GABA(B) receptor is more tolerant to changes in surface residues than is the nAChR. The conserved Asp Pro-Arg motif of Vc1.1 and RgIA, which is crucial for potency at the alpha9alpha10 nAChR, is not required for activity at GABA(B) receptor/N-type calcium channels because PeIA has a His-Pro-Ala motif in the equivalent position. This study shows that different structure-activity relationships are associated with the targeting of the GABA(B) receptor versus nAChRs. Furthermore, there is probably a much more diverse range of conotoxins that target the GABA(B) receptor than currently realized. PMID- 21252228 TI - Mutant A53T alpha-synuclein induces neuronal death by increasing mitochondrial autophagy. AB - Parkinson disease is characterized by the accumulation of aggregated alpha synuclein as the major component of the Lewy bodies. alpha-Synuclein accumulation in turn leads to compensatory effects that may include the up-regulation of autophagy. Another common feature of Parkinson disease (PD) is mitochondrial dysfunction. Here, we provide evidence that the overactivation of autophagy may be a link that connects the intracellular accumulation of alpha-synuclein with mitochondrial dysfunction. We found that the activation of macroautophagy in primary cortical neurons that overexpress mutant A53T alpha-synuclein leads to massive mitochondrial destruction and loss, which is associated with a bioenergetic deficit and neuronal degeneration. No mitochondrial removal or net loss was observed when we suppressed the targeting of mitochondria to autophagosomes by silencing Parkin, overexpressing wild-type Mitofusin 2 and dominant negative Dynamin-related protein 1 or blocking autophagy by silencing autophagy-related genes. The inhibition of targeting mitochondria to autophagosomes or autophagy was also partially protective against mutant A53T alpha-synuclein-induced neuronal cell death. These data suggest that overactivated mitochondrial removal could be one of the contributing factors that leads to the mitochondrial loss observed in PD models. PMID- 21252229 TI - REST regulates DYRK1A transcription in a negative feedback loop. AB - DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) has been shown to be involved in learning and memory impairments in Alzheimer disease and Down syndrome. As a homolog of Drosophila minibrain gene, DYRK1A also plays important roles in neurodevelopment; however, the function and regulatory mechanism of DYRK1A in neurodevelopment remain elusive. REST (RE1 silencing transcription factor) plays vital roles in neuronal differentiation. Here, we found that REST can activate DYRK1A transcription via a neuron-restrictive silencer element at bp -833 to -815 of human DYRK1A promoter. The coordinated expression of DYRK1A and REST in mouse brain further supports the cross interaction of DYRK1A and REST during neurodevelopment. Moreover, we showed that DYRK1A dosage imbalance reduced REST protein stability and transcriptional activity through facilitating ubiquitination and subsequent degradation of REST protein. Therefore, the regulation of DYRK1A by REST in a negative feedback loop suggests that DYRK1A and REST are closely related in neurodevelopment. PMID- 21252230 TI - New regulators of a high affinity Ca2+ influx system revealed through a genome wide screen in yeast. AB - The bakers' yeast Saccharomyces cerevisiae utilizes a high affinity Ca(2+) influx system (HACS) to survive assaults by mating pheromones, tunicamycin, and azole class antifungal agents. HACS consists of two known subunits, Cch1 and Mid1, that are homologous and analogous to the catalytic alpha-subunits and regulatory alpha2delta-subunits of mammalian voltage-gated calcium channels, respectively. To search for additional subunits and regulators of HACS, a collection of gene knock-out mutants was screened for abnormal uptake of Ca(2+) after exposure to mating pheromone or to tunicamycin. The screen revealed that Ecm7 is required for HACS function in most conditions. Cycloheximide chase experiments showed that Ecm7 was stabilized by Mid1, and Mid1 was stabilized by Cch1 in non-signaling conditions, suggesting they all interact. Ecm7 is a member of the PMP 22/EMP/MP20/Claudin superfamily of transmembrane proteins that includes gamma subunits of voltage-gated calcium channels. Eleven additional members of this superfamily were identified in yeast, but none was required for HACS activity in response to the stimuli. Remarkably, many dozens of genes involved in vesicle mediated trafficking and protein secretion were required to prevent spontaneous activation of HACS. Taken together, the findings suggest that HACS and calcineurin monitor performance of the membrane trafficking system in yeasts and coordinate compensatory processes. Conservation of this quality control system in Candida glabrata suggests that many pathogenic species of fungi may utilize HACS and calcineurin to resist azoles and other compounds that target membrane biosynthesis. PMID- 21252231 TI - Expression of water-soluble, ligand-binding concatameric extracellular domains of the human neuronal nicotinic receptor alpha4 and beta2 subunits in the yeast Pichia pastoris: glycosylation is not required for ligand binding. AB - Nicotinic acetylcholine receptors (nAChRs) are ligand-gated cation channels that are responsible for cell communication via the neurotransmitter acetylcholine. The predominant nAChR subtype in the mammalian brain with a high affinity for nicotine is composed of alpha4 and beta2 subunits. This nAChR subtype is responsible for addiction to nicotine and is thought to be implicated in Alzheimer and Parkinson diseases and therefore presents an important target for drug design. In an effort to obtain water-soluble, ligand-binding domains of the human alpha4beta2 nAChR for structural studies, we expressed the extracellular domains (ECDs) of these subunits in the eukaryotic expression system Pichia pastoris. The wild-type ECDs and their mutants containing the more hydrophilic Cys-loop from the snail acetylcholine-binding protein (individually expressed or coexpressed) did not demonstrate any specific interaction with ligands. We then linked the mutated ECDs with the 24-amino acid peptide (AGS)(8) and observed that the beta2-24-alpha4 ECD concatamer, but not the alpha4-24-beta2 one, exhibited very satisfactory water solubility and ligand binding properties. The (125)I epibatidine and [(3)H]nicotine bound to beta2-24-alpha4 with dissociation constants (K(d)) of 0.38 and 19 nm, respectively, close to the published values for the intact alpha4beta2 AChR. In addition, (125)I-epibatidine binding was blocked by nicotine, cytisine, acetylcholine, and carbamylcholine with inhibition constants (K(i)) of 20.64, 3.24, 242, and 2,254 nm, respectively. Interestingly, deglycosylation of the concatamer did not affect its ligand binding properties. Furthermore, the deglycosylated beta2-24-alpha4 ECD existed mainly in monomeric form, thus forming an appropriate material for structural studies and possibly for pharmacological evaluation of novel alpha4beta2 nAChR-specific agonists. PMID- 21252232 TI - Myosin phosphatase-targeting subunit 1 controls chromatid segregation. AB - Myosin phosphatase is a heterotrimeric holoenzyme consisting of myosin phosphatase-targeting subunit 1 (MYPT1), a catalytic subunit of PP1Cbeta, and a 20-kDa subunit of an unknown function. We have previously reported that myosin phosphatase also controls mitosis, apparently by antagonizing polo-like kinase 1 (PLK1). Here we found that depletion of MYPT1 by siRNA led to precocious chromatid segregation when HeLa cells were arrested at metaphase by a proteasome inhibitor, MG132, or by Cdc20 depletion. Consistently, cyclin B1 and securin were not degraded, indicating that the chromatid segregation is independent of the anaphase-promoting complex/cyclosome. Precocious segregation induced by MYPT1 depletion requires PLK1 activity because a PLK1 inhibitor, BI-2536, blocked precocious segregation. Furthermore, the expression of an unphosphorylatable mutant of SA2 (SCC3 homologue 2), a subunit of the cohesin complex, prevented precocious chromatid segregation induced by MYPT1 depletion. It has been shown that SA2 at centromeres is protected from phosphorylation by PP2A phosphatase recruited by Shugoshin (Sgo1), whereas SA2 along chromosome arms is phosphorylated by PLK1, leading to SA2 dissociation at chromosome arms. Taken together, our results suggest that hyperactivation of PLK1 caused by MYPT1 reduction could override the counteracting PP2A phosphatase, resulting in precocious chromatid segregation. We propose that SA2 at the centromeres is protected by two phosphatases. One is PP2A directly dephosphorylating SA2, and the other is myosin phosphatase counteracting PLK1. PMID- 21252233 TI - A WNT/beta-catenin signaling activator, R-spondin, plays positive regulatory roles during skeletal myogenesis. AB - R-spondins (RSPOs) are a recently characterized family of secreted proteins that activate WNT/beta-catenin signaling. In this study, we investigated the potential roles of the RSPO proteins during myogenic differentiation. Overexpression of the Rspo1 gene or administration of recombinant RSPO2 protein enhanced mRNA and protein expression of a basic helix-loop-helix (bHLH) class myogenic determination factor, MYF5, in both C2C12 myoblasts and primary satellite cells, whereas MYOD or PAX7 expression was not affected. RSPOs also promoted myogenic differentiation and induced hypertrophic myotube formation in C2C12 cells. In addition, Rspo2 and Rspo3 gene knockdown by RNA interference significantly compromised MYF5 expression, myogenic differentiation, and myotube formation. Furthermore, Myf5 expression was reduced in the developing limbs of mouse embryos lacking the Rspo2 gene. Finally, we demonstrated that blocking of WNT/beta catenin signaling by DKK1 or a dominant-negative form of TCF4 reversed MYF5 expression, myogenic differentiation, and hypertrophic myotube formation induced by RSPO2, indicating that RSPO2 exerts its activity through the WNT/beta-catenin signaling pathway. Our results provide strong evidence that RSPOs are key positive regulators of skeletal myogenesis acting through the WNT/beta-catenin signaling pathway. PMID- 21252234 TI - A novel TIP30 protein complex regulates EGF receptor signaling and endocytic degradation. AB - Activated epidermal growth factor receptor (EGFR) continues to signal in the early endosome, but how this signaling process is regulated is less well understood. Here we describe a protein complex consisting of TIP30, endophilin B1, and acyl-CoA synthetase long chain family member 4 (ACSL4) that interacts with Rab5a and regulates EGFR endocytosis and signaling. These proteins are required for the proper endocytic trafficking of EGF-EGFR. Knockdown of TIP30, ACSL4, endophilin B1, or Rab5a in human liver cancer cells or genetic knock-out of Tip30 in mouse primary hepatocytes results in the trapping of EGF-EGFR complexes in early endosomes, leading to delayed EGFR degradation and prolonged EGFR signaling. Furthermore, we show that Rab5a colocalizes with vacuolar (H(+)) ATPases (V-ATPases) on transport vesicles. The TIP30 complex facilitates trafficking of Rab5a and V-ATPases to EEA1-positive endosomes in response to EGF. Together, these results suggest that this TIP30 complex regulates EGFR endocytosis by facilitating the transport of V-ATPases from trans-Golgi network to early endosomes. PMID- 21252235 TI - A novel member of the RNase D exoribonuclease family functions in mitochondrial guide RNA metabolism in Trypanosoma brucei. AB - RNA turnover and RNA editing are essential for regulation of mitochondrial gene expression in Trypanosoma brucei. RNA turnover is controlled in part by RNA 3' adenylation and uridylation status, with trans-acting factors also impacting RNA homeostasis. However, little is known about the mitochondrial degradation machinery or its regulation in T. brucei. We have identified a mitochondrial exoribonuclease, TbRND, whose expression is highly up-regulated in the insect proliferative stage of the parasite. TbRND shares sequence similarity with RNase D family enzymes but differs from all reported members of this family in possessing a CCHC zinc finger domain. In vitro, TbRND exhibits 3' to 5' exoribonuclease activity, with specificity toward uridine homopolymers, including the 3' oligo(U) tails of guide RNAs (gRNAs) that provide the sequence information for RNA editing. Several lines of evidence generated from RNAi-mediated knockdown and overexpression cell lines indicate that TbRND functions in gRNA metabolism in vivo. First, TbRND depletion results in gRNA tails extended by 2-3 nucleotides on average. Second, overexpression of wild type but not catalytically inactive TbRND results in a substantial decrease in the total gRNA population and a consequent inhibition of RNA editing. The observed effects on the gRNA population are specific as rRNAs, which are also 3'-uridylated, are unaffected by TbRND depletion or overexpression. Finally, we show that gRNA binding proteins co purify with TbRND. In summary, TbRND is a novel 3' to 5' exoribonuclease that appears to have evolved a function highly specific to the mitochondrion of trypanosomes. PMID- 21252236 TI - NMR structure and action on nicotinic acetylcholine receptors of water-soluble domain of human LYNX1. AB - Discovery of proteins expressed in the central nervous system sharing the three finger structure with snake alpha-neurotoxins provoked much interest to their role in brain functions. Prototoxin LYNX1, having homology both to Ly6 proteins and three-finger neurotoxins, is the first identified member of this family membrane-tethered by a GPI anchor, which considerably complicates in vitro studies. We report for the first time the NMR spatial structure for the water soluble domain of human LYNX1 lacking a GPI anchor (ws-LYNX1) and its concentration-dependent activity on nicotinic acetylcholine receptors (nAChRs). At 5-30 MUM, ws-LYNX1 competed with (125)I-alpha-bungarotoxin for binding to the acetylcholine-binding proteins (AChBPs) and to Torpedo nAChR. Exposure of Xenopus oocytes expressing alpha7 nAChRs to 1 MUM ws-LYNX1 enhanced the response to acetylcholine, but no effect was detected on alpha4beta2 and alpha3beta2 nAChRs. Increasing ws-LYNX1 concentration to 10 MUM caused a modest inhibition of these three nAChR subtypes. A common feature for ws-LYNX1 and LYNX1 is a decrease of nAChR sensitivity to high concentrations of acetylcholine. NMR and functional analysis both demonstrate that ws-LYNX1 is an appropriate model to shed light on the mechanism of LYNX1 action. Computer modeling, based on ws-LYNX1 NMR structure and AChBP x-ray structure, revealed a possible mode of ws-LYNX1 binding. PMID- 21252237 TI - Kinetic evidence that Glut4 follows different endocytic pathways than the receptors for transferrin and alpha2-macroglobulin. AB - Insulin regulates glucose uptake through effects on the trafficking of the glucose transporter Glut4. To investigate the degree of overlap between Glut4 and the general endocytic pathways, the kinetics of trafficking of Glut4 and the receptors for transferrin (Tf) and alpha(2)-macroglobulin (alpha-2-M; LRP-1) were compared using quantitative flow cytometric assays. Insulin increased the exocytic rate constant (k(ex)) for both Glut4 and Tf. However, the k(ex) of Glut4 was 5-15 times slower than Tf in both basal and insulin-stimulated cells. The endocytic rate constant (k(en)) of Glut4 was also five times slower than Tf. Insulin did not affect the k(en) of either protein. In basal cells, the k(en) for alpha-2-M/LRP-1 was similar to Glut4 but 5-fold slower than Tf. Insulin increased k(en) for alpha-2-M/LRP-1 by 30%. In contrast, the k(ex) for LRP-1 was five times faster than Glut4 in basal cells, and insulin did not increase this rate constant. Thus, although there is overlap in the protein machineries/compartments utilized, the differences in trafficking kinetics indicate that Glut4, the Tf receptor, and LRP-1 are differentially processed both within the cell and at the plasma membrane. It has been reported that insulin decreases the k(en) of Glut4 in adipocytes. However, the effect of exocytosis on the "internalization" assays was not considered. Because it is counterintuitive, the effect of exocytosis on these assays is often overlooked in endocytosis studies. Using mathematical modeling and simulation, we show that the reported decrease in Glut4 k(en) can be entirely accounted for by the well established increase in Glut4 k(ex). PMID- 21252238 TI - TDP-43 is a transcriptional repressor: the testis-specific mouse acrv1 gene is a TDP-43 target in vivo. AB - TDP-43 is an evolutionarily conserved ubiquitously expressed DNA/RNA-binding protein. Although recent studies have shown its association with a variety of neurodegenerative disorders, the function of TDP-43 remains poorly understood. Here we address TDP-43 function using spermatogenesis as a model system. We previously showed that TDP-43 binds to the testis-specific mouse acrv1 gene promoter in vitro via two GTGTGT-motifs and that mutation of these motifs led to premature transcription in spermatocytes of an otherwise round spermatid-specific promoter. The present study tested the hypothesis that TDP-43 represses acrv1 gene transcription in spermatocytes. Plasmid chromatin immunoprecipitation demonstrated that TDP-43 binds to the acrv1 promoter through GTGTGT motifs in vivo. Reporter gene assays showed that TDP-43 represses acrv1 core promoter driven transcription via the N-terminal RRM1 domain in a histone deacetylase independent manner. Consistent with repressor role, ChIP on physiologically isolated germ cells confirmed that TDP-43 occupies the endogenous acrv1 promoter in spermatocytes. Surprisingly, however, TDP-43 remains at the promoter in round spermatids, which express acrv1 mRNA. We show that RNA binding-defective TDP-43, but not splice variant isoforms, relieve repressor function. Transitioning from repressive to active histone marks has little effect on TDP-43 occupancy. Finally, we found that RNA polymerase II is recruited but paused at the acrv1 promoter in spermatocytes. Because mutation of TDP-43 sites caused premature transcription in spermatocytes in vivo, TDP-43 may be involved in pausing RNAPII at the acrv1 promoter in spermatocytes. Overall, our study shows that TDP-43 is a transcriptional repressor and that it regulates spatiotemporal expression of the acrv1 gene during spermatogenesis. PMID- 21252239 TI - Differential regulation of gene expression by protein kinase C isozymes as determined by genome-wide expression analysis. AB - Protein kinase C (PKC) isozymes are key signal transducers involved in normal physiology and disease and have been widely implicated in cancer progression. Despite our extensive knowledge of the signaling pathways regulated by PKC isozymes and their effectors, there is essentially no information on how individual members of the PKC family regulate gene transcription. Here, we report the first PKC isozyme-specific analysis of global gene expression by microarray using RNAi depletion of diacylglycerol/phorbol ester-regulated PKCs. A thorough analysis of this microarray data revealed unique patterns of gene expression controlled by PKCalpha, PKCdelta, and PKCepsilon, which are remarkably different in cells growing in serum or in response to phorbol ester stimulation. PKCdelta is the most relevant isoform in controlling the induction of genes by phorbol ester stimulation, whereas PKCepsilon predominantly regulates gene expression in serum. We also established that two PKCdelta-regulated genes, FOSL1 and BCL2A1, mediate the apoptotic effect of phorbol esters or the chemotherapeutic agent etoposide in prostate cancer cells. Our studies offer a unique opportunity for establishing novel transcriptional effectors for PKC isozymes and may have significant functional and therapeutic implications. PMID- 21252240 TI - Impaired regulation of the incretin effect in patients with type 2 diabetes. AB - OBJECTIVE: In healthy subjects, the incretin effect during an oral glucose tolerance test increases with the size of glucose load, resulting in similar glucose excursions independently of the glucose loads. Whether patients with type 2 diabetes mellitus (T2DM) are able to regulate their incretin effect is unknown. RESEARCH DESIGN AND METHODS: Incretin effect was measured over 6 d by means of three 4-h oral glucose tolerance test with increasing glucose loads (25, 75, and 125 g) and three corresponding isoglycemic iv glucose infusions in eight patients with T2DM [fasting plasma glucose, mean 7.7 (range 7.0-8.9) mM; glycosylated hemoglobin, 7.0% (6.2-8.4%)] and eight matched healthy control subjects [fasting plasma glucose, 5.3 (4.8-5.7) mM; glycosylated hemoglobin, 5.4% (5.0-5.7%)]. RESULTS: Patients with T2DM exhibited higher peak plasma glucose in response to increasing oral glucose loads, whereas no differences in peak plasma glucose values among control subjects were observed. The incretin effect was significantly (P < 0.003) lower in patients with T2DM (0 +/- 7, 11 +/- 9, and 36 +/- 5%) as compared with control subjects (36 +/- 5, 53 +/- 6, and 65 +/- 6%). Equal and progressively delayed gastric emptying due to the increasing loads was found in both groups. Incretin hormone responses were similar. CONCLUSIONS: Up regulation of the incretin effect in response to increasing oral glucose loads seems to be crucial for controlling glucose excursions in healthy subjects. Patients with T2DM are characterized by an impaired capability to regulate their incretin effect, which may contribute to the exaggerated glucose excursions after oral ingestion of glucose in these patients. PMID- 21252241 TI - Prolonged exercise-induced stimulation of skeletal muscle glucose uptake is due to sustained increases in tissue perfusion and fractional glucose extraction. AB - CONTEXT: The mechanisms behind the positive effects of physical activity on glucose metabolism in skeletal muscle and the time course of the effects need to be more elucidated. OBJECTIVE: The aim was to examine the prolonged effects of an acute bout of one-legged exercise on local skeletal muscle glucose utilization and tissue perfusion. DESIGN AND SETTING: Interstitial glucose concentration, local tissue perfusion, glucose uptake, and effects of insulin infusion were studied 12 h after an acute bout of exercise and without prior exercise. PARTICIPANTS: Ten healthy subjects, five women and five men, participated in the study. INTERVENTION: Microdialysis measurements, (133)Xe clearance, and a 2-h hyperinsulinemic euglycemic clamp were performed on two occasions. MAIN OUTCOME MEASURES: We measured interstitial glucose concentration and tissue perfusion in the quadriceps femoris muscle of both legs. RESULTS: Tissue perfusion (3.3 +/- 0.6 ml * 100 g(-1) * min(-1) vs. 1.4 +/- 0.2 ml * 100 g(-1) * min(-1); P = 0.007) and basal glucose uptake (2.3 +/- 0.5 MUmol * 100 g(-1) * min(-1) vs. 0.9 +/- 0.2 MUmol * 100 g(-1) * min(-1); P = 0.006) were increased in the leg that had exercised compared to the resting leg; the findings in the resting leg were comparable to those in the control experiment without prior exercise. The relative effect of insulin on fractional skeletal muscle glucose uptake was the same in all experimental settings, and insulin did not affect tissue perfusion. CONCLUSIONS: The prolonged stimulatory effect of physical exercise on skeletal muscle glucose uptake was mediated via vascular effects combined with an increase in basal glucose transport independent of enhancement of insulin responses. PMID- 21252242 TI - Polymorphisms in the SHBG gene influence serum SHBG levels in women with polycystic ovary syndrome. AB - CONTEXT: Single-nucleotide polymorphisms (SNPs) in the SHBG gene are associated with type 2 diabetes mellitus. SHBG has also been proposed as a candidate gene for the polycystic ovary syndrome (PCOS). OBJECTIVE: The study aims were 1) to determine whether any of four SHBG SNPs (rs1779941, rs6297, rs6259, and rs727428) are associated with PCOS and 2) to determine whether SNP genotype influences SHBG levels in PCOS women. DESIGN: Using the transmission disequilibrium test, evidence of associations between SHBG SNPs and PCOS were analyzed. Additionally, correlations between SHBG levels and SNP genotype, body mass index, non-SHBG bound testosterone, and insulin resistance estimated by the homeostasis model were determined. SETTING: The study was conducted at academic medical centers. PATIENTS OR OTHER PARTICIPANTS: A total of 430 families having a proband with PCOS were included in the family-based study. Associations between SNP genotypes, SHBG, and metabolic parameters were determined in 758 women with PCOS including probands from the family cohort. MAIN OUTCOME MEASURES: Primary outcome measures included transmission frequency of SNP alleles and correlation coefficients between SHBG and allele frequency/metabolic parameters. RESULTS: No evidence of association between SNPs of interest and PCOS was found. However, in multivariate analyses, SHBG levels varied significantly with rs1799941 and rs727428 genotype after controlling for body mass index, non-SHBG-bound testosterone, and homeostasis model for insulin resistance. CONCLUSIONS: Although SHBG SNPs associated with type 2 diabetes mellitus do not appear to be associated with PCOS status, rs1799941 and rs727428 genotypes are associated with SHBG levels independent of the effects of insulin resistance and obesity. PMID- 21252243 TI - Interrelationship between fatty liver and insulin resistance in the development of type 2 diabetes. AB - CONTEXT: Although fatty liver and insulin resistance are known to be associated, the relationship between the two in the development of type 2 diabetes mellitus (T2DM) is unclear. OBJECTIVE: We investigated the 5-yr risk of developing T2DM in individuals diagnosed with fatty liver using ultrasound and stratified by insulin sensitivity using quartiles of fasting insulin concentration. DESIGN AND METHODS: We examined the clinical and laboratory data of 11,091 Koreans who had a medical evaluation including fasting insulin concentration and abdominal ultrasound at baseline and had a follow-up after 5 yr. RESULTS: At baseline, 27% of the population had fatty liver. Almost half (47%) of the individuals with fatty liver had baseline insulin concentration in the highest quartile compared with 17% in those without fatty liver (P < 0.001). Regardless of baseline insulin concentration, individuals with fatty liver had significantly (P < 0.001) more baseline clinical and metabolic abnormalities, including higher glucose and triglyceride concentration and lower high-density lipoprotein cholesterol concentration. In addition, regardless of baseline insulin concentration, individuals with fatty liver had a significantly increased risk for incident T2DM compared with those without fatty liver [crude odds ratio, 5.05 (95% confidence interval, 2.08-12.29) in the lowest insulin quartile and 6.34 (3.58-11.21) in the highest quartile]. In individuals in the highest insulin quartile, the odds ratio for developing T2DM remained significant even after multivariate adjustment including baseline glucose concentration [2.42 (1.23-4.75)]. CONCLUSION: Although associated with insulin resistance, fatty liver diagnosed by ultrasound appears to independently increase the risk of T2DM. PMID- 21252244 TI - Aberrations in pseudoautosomal regions (PARs) found in infertile men with Y chromosome microdeletions. AB - CONTEXT: The pseudoautosomal regions (PARs) of the Y-chromosome undergo meiotic recombination with the X-chromosome. PAR mutations are associated with infertility and mental and stature disorders. OBJECTIVE: The aim of the study was to determine whether men with Y-chromosome microdeletions have structural defects in PARs. DESIGN AND PARTICIPANTS: Eighty-seven infertile men with Y-chromosome microdeletions and 35 controls were evaluated for chromosomal rearrangements using commercial or custom (X- and Y-chromosome) array comparative genomic hybridization or by quantitative PCR of selected PAR genes. Multisoftware-defined chromosomal gains or losses were validated by quantitative PCR and FISH. RESULTS: Array comparative genomic hybridization confirmed the AZF deletions identified by multiplex PCR. All men with Y-chromosome microdeletions and an abnormal karyotype displayed PAR abnormalities, as did 10% of men with Y-chromosome microdeletions and a normal karyotype. None of the control subjects or infertile men without Y chromosome microdeletions had PAR duplications or deletions. SHOX aberrations occurred in 14 men (nine gains and five losses); four were short in stature (<10th percentile), and one was tall (>95th percentile). In contrast, the height of 23 men with Y-chromosome microdeletions and normal PARs was average at 176.8 cm (50th percentile). CONCLUSIONS: Y-chromosome microdeletions can include PAR defects causing genomic disorders such as SHOX, which may be transmitted to offspring. Previously unrecognized PAR gains and losses in men with Y-chromosome microdeletions may have consequences for offspring. PMID- 21252245 TI - Effect of oral phosphate and alendronate on bone mineral density when given as adjunctive therapy to growth hormone replacement in adult growth hormone deficiency. AB - BACKGROUND: Adult GH deficiency (AGHD) is associated with osteoporosis, which occurs as the result of reduced sensitivity of the bone and kidney to the effect of PTH. AIM: The aim of the study was to examine the effect of oral phosphate and alendronate therapy on PTH sensitivity, bone turnover, and bone mineral density (BMD) in AGHD patients. METHODS: Forty-four AGHD patients were hospitalized for 24 h, and half-hourly blood and 3-hourly urine samples were collected for PTH, nephrogenous cAMP (marker of renal PTH activity), procollagen type-I amino terminal propeptide, and type-I collagen beta C-telopeptide. Patients were randomized to one of six groups: patients who were previously naive to GH were randomized to receive GH replacement (GHR) alone, GHR+alendronate, or GHR+phosphate-sandoz, whereas patients already receiving GHR were randomized to continue GHR alone, GHR+alendronate, or GHR+phosphate-sandoz. Study visits were repeated after 1, 3, 6, and 12 months in the previously GH-naive group and after 12 months in the previously GH-replaced group. BMD was measured at 0 and 12 months. RESULTS: Patients receiving GHR+phosphate had greater increases in nephrogenous cAMP and bone markers than patients receiving GHR alone (P < 0.01), and this was associated with greater increases in BMD (P < 0.01). In the GHR+alendronate groups, type-I collagen beta C-telopeptide decreased (P < 0.001), and BMD increases were greater than in those receiving GHR alone (P < 0.05). The greatest increases in BMD were seen in patients receiving GHR+phosphate. CONCLUSIONS: Phosphate and alendronate therapy given in combination with GHR confer advantage in terms of BMD increase. Phosphate appears to exert its effect by increasing PTH target-organ action, whereas alendronate acts primarily through reduction in bone resorption. PMID- 21252246 TI - The water permeability channels aquaporins 1-4 are differentially expressed in granulosa and theca cells of the preovulatory follicle during precise stages of human ovulation. AB - CONTEXT: Changes in vascular permeability and expansion of the fluid-filled antrum are major events in the LH-induced ovulatory process. OBJECTIVES: Our objective was to investigate the presence and expression levels of aquaporins (AQPs) in the granulosa and theca cell compartments of the follicle during defined phases of human ovulation. DESIGN AND SETTING: We conducted a prospective experimental study at the Department of Obstetrics and Gynaecology at a university hospital. PARTICIPANTS: Twenty-eight women underwent laparoscopic sterilization and at the same time follicle retrieval at four periovulatory phases. MAIN OUTCOME MEASURES: mRNA levels of AQP1-4 were measured in separated granulosa and theca cells from preovulatory phase, early ovulatory (EO) phase, late ovulatory phase, and postovulatory phase. Immunohistochemistry was done for AQP1-4 in intact human follicles. RESULTS: All four AQPs were expressed in both the theca and granulosa cells during ovulation. In granulosa cells, AQP1 levels increased in the late ovulatory and postovulatory phases. Expression of AQP2-3 followed a similar pattern with a marked increase in the EO phase, whereas AQP4 levels decreased from preovulatory to the EO phase. The presence of AQP1-4 in the human follicle was verified by immunohistochemistry. CONCLUSIONS: The results show for the first time the presence of AQP1-4 in human follicles during ovulation. The marked early rise in expression of AQP2 and AQP3 suggests a role during the process leading to follicular rupture, and the late rise of AQP1 suggests a role in corpus luteum formation. PMID- 21252247 TI - Genome-wide homozygosity analysis reveals HADH mutations as a common cause of diazoxide-responsive hyperinsulinemic-hypoglycemia in consanguineous pedigrees. AB - CONTEXT AND OBJECTIVE: Recessive mutations in the hydroxyacyl-CoA dehydrogenase (HADH) gene encoding the enzyme 3-hydroxyacyl-CoA dehydrogenase are a rare cause of diazoxide-responsive hyperinsulinemic hypoglycemia (HH) with just five probands reported to date. HADH deficiency in the first three identified patients was associated with detectable urinary 3-hydroxyglutarate and raised plasma 3 hydroxybutyryl-carnitine levels, but two recent cases did not have abnormal urine organic acids or acylcarnitines. RESEARCH DESIGN AND METHODS: We studied 115 patients with diazoxide-responsive HH in whom the common genetic causes of HH had been excluded. No patients were reported to have abnormal acylcarnitines or urinary organic acids. Homozygosity mapping was undertaken in probands from 13 consanguineous pedigrees to search for regions harboring mutations that are identical by descent. RESULTS: HADH sequencing was performed after genome-wide single nucleotide polymorphism analysis revealed a large shared region of homozygosity spanning the HADH locus in six unrelated probands. Homozygous mutations were identified in three of these patients and in a further two probands from consanguineous families. HADH analysis in the remainder of the cohort identified mutations in a further six probands for whom consanguinity was not reported, but who originated from countries with high rates of consanguinity. Six different HADH mutations were identified in 11/115 (10%) patients tested. CONCLUSION: HADH mutations are a relatively common cause of diazoxide-responsive HH with a frequency similar to that of GLUD1 and HNF4A mutations. We recommend that HADH sequence analysis is considered in all patients with diazoxide responsive HH when recessive inheritance is suspected. PMID- 21252248 TI - Coagulation and fibrinolytic disturbances in women with polycystic ovary syndrome. AB - CONTEXT: Studies of fibrinolysis/coagulation status in women with polycystic ovary syndrome (PCOS) are contradictory. OBJECTIVES: The aim of the study was to investigate whether women with PCOS have disturbed circulating levels of fibrinolysis/coagulation markers and, if so, whether the disturbances are related to hemodynamics, metabolic variables, sex steroids, SHBG, lipids, and inflammatory variables in women with PCOS. DESIGN/MAIN OUTCOME MEASURES: Anthropometric variables, hemodynamics, circulating hemostatic and inflammatory markers, and serum lipid profile were measured in women with untreated PCOS (n = 74) and controls (n = 31). RESULTS: After adjustments for age and body mass index (BMI), circulating plasminogen activator inhibitor 1 (PAI-1) activity and fibrinogen levels were higher in women with PCOS than controls; lipid profile, blood pressure, and levels of D-dimer, von Willebrand factor, factor VIII, tissue plasminogen activator, and inflammatory markers were comparable in the two groups. In multiple linear regression analyses including women with PCOS, low SHBG and high insulin predicted high PAI-1 activity (R(2) = 0.526; P < 0.001); elevated high-sensitivity C-reactive protein and soluble E-selectin in combination with heart rate predicted high fibrinogen (R(2) = 0.333; P < 0.001). Differences in PAI-1 activity were not significant after adjustments for age, BMI, SHBG, and insulin. CONCLUSIONS: PCOS is characterized by a prothrombotic state, as reflected by increased PAI-1 activity and fibrinogen, without signs of dyslipidemia or a proinflammatory state. Low SHBG and high insulin may partly explain the BMI-independent difference in PAI-1 activity between women with PCOS and controls. High-sensitivity C-reactive protein and E-selectin may be involved in regulating fibrinogen in PCOS. PMID- 21252249 TI - Plasma cholesteryl ester transfer, but not cholesterol esterification, is related to lipoprotein-associated phospholipase A2: possible contribution to an atherogenic lipoprotein profile. AB - CONTEXT: Plasma lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) predicts incident cardiovascular disease and is associated preferentially with negatively charged apolipoprotein B-containing lipoproteins. The plasma cholesteryl ester transfer (CET) process, which contributes to low high-density lipoprotein cholesterol and small, dense low-density lipoproteins, is affected by the composition and concentration of apolipoprotein B-containing cholesteryl ester acceptor lipoproteins. OBJECTIVE: We tested relationships of CET with Lp-PLA(2) in subjects with and without metabolic syndrome (MetS). DESIGN AND SETTING: In 68 subjects with MetS and 74 subjects without MetS, plasma Lp-PLA(2) mass, cholesterol esterification (EST), lecithin:cholesterol acyltransferase (LCAT) activity level, CET, CET protein (CETP) mass, and lipoproteins were measured. RESULTS: EST, LCAT activity, CET (P < 0.001 for all), and CETP (P = 0.030) were increased, and Lp-PLA(2) was decreased (P = 0.043) in MetS. CET was correlated positively with Lp-PLA(2) in subjects with and without MetS (P < 0.05 for both). EST and LCAT activity were unrelated to Lp-PLA(2), despite a positive correlation between EST and CET (P < 0.001). After controlling for age, sex, and diabetes status, CET was determined by Lp-PLA(2) in the whole group (beta = 0.245; P < 0.001), and in subjects with (beta = 0.304; P = 0.001) and without MetS (beta = 0.244; P = 0.006) separately, independently of triglycerides and CETP. CONCLUSIONS: Plasma CET is related to Lp-PLA(2) in subjects with and without MetS. The process of CET, but not EST, may be influenced by Lp-PLA(2). These findings provide a rationale to evaluate whether maneuvers that inhibit Lp-PLA(2) will reduce CET, and vice versa to document effects of CETP inhibition on Lp PLA(2). PMID- 21252250 TI - Integrated genomic analysis of nodular tissue in macronodular adrenocortical hyperplasia: progression of tumorigenesis in a disorder associated with multiple benign lesions. AB - CONTEXT: Massive macronodular adrenocortical disease or ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a clinically and genetically heterogeneous disorder. OBJECTIVE AND DESIGN: Whole-genome expression profiling and oligonucleotide array comparative genomic hybridization changes were analyzed in samples of different nodules from the same patients with AIMAH. Quantitative RT-PCR and staining were employed to validate the mRNA array data. RESULTS: Chromosomal gains were more frequent in larger nodules when compared with smaller nodules from the same patients. Among the 50 most overexpressed genes, 50% had a chromosomal locus that was amplified in the comparative genomic hybridization data. Although the list of most over- and underexpressed genes was similar between the nodules of different size, the gene set enrichment analysis identified different pathways associated with AIMAH that corresponded to the size; the smaller nodules were mainly enriched for metabolic pathways, whereas p53 signaling and cancer genes were enriched in larger nodules. Confirmatory studies demonstrated that BCL2, E2F1, EGF, c-KIT, MYB, PRKCA, and CTNNB1 were overexpressed in the larger nodules at messenger and/or protein levels. Chromosomal enrichment analysis showed that chromosomes 20q13 and 14q23 might be involved in progression of AIMAH from smaller to larger tumors. CONCLUSION: Integrated transcriptomic and genomic data for AIMAH provides supporting evidence to the hypothesis that larger adrenal lesions, in the context of this chronic, polyclonal hyperplasia, accumulate an increased number of genomic and, subsequently, transcript abnormalities. The latter shows that the disease appears to start with mainly tissue metabolic derangements, as suggested by the study of the smaller nodules, but larger lesions showed aberrant expression of oncogenic pathways. PMID- 21252251 TI - Decreased cerebrospinal fluid/plasma ratio of the novel satiety molecule, nesfatin-1/NUCB-2, in obese humans: evidence of nesfatin-1/NUCB-2 resistance and implications for obesity treatment. AB - CONTEXT: The novel adipokine, nesfatin-1/NUCB-2, reduces food intake, levels of which are elevated in overweight individuals. OBJECTIVES: The aim of the study was to investigate the mechanisms underlying brain nesfatin-1/NUCB-2 uptake and to determine whether reduced uptake may contribute to nesfatin-1/NUCB-2 resistance. DESIGN: Cerebrospinal fluid (CSF) and corresponding plasma nesfatin 1/NUCB-2 were measured by ELISA [18 men and 20 women; age, 19-80 yr; body mass index (BMI), 16.2-38.1 kg/m(2)] and correlated to body adiposity and metabolic parameters. RESULTS: CSF/plasma nesfatin-1/NUCB-2 ratio was significantly negatively associated with BMI, body weight, fat mass, and CSF glucose. BMI was predictive of CSF/plasma nesfatin-1/NUCB-2 ratio (beta = -0.786; P = 0.045). CSF nesfatin-1/NUCB-2 was significantly positively associated with plasma nesfatin 1/NUCB-2 (R = 0.706; P < 0.01). There was a significant linear relation between CSF and plasma nesfatin-1/NUCB-2 in lean (BMI <25 kg/m(2); R = 0.744; P = 0.002) and obese (BMI >= 30 kg/m(2); R = 0.693; P = 0.026) subjects. Subjects in the highest plasma nesfatin-1/NUCB-2 quintile had lower CSF/plasma nesfatin-1/NUCB-2 ratio [26.5% (26.0-29.5%)] compared to the lowest plasma nesfatin-1/NUCB-2 quintile [38.5% (34.0-42.0%)] (P < 0.01), corresponding BMI [32.4 (31.0-35.0) vs. 23.3 (19.7-23.5) kg/m(2); P < 0.01], and fat mass [32.8 (29.5-40.6) vs. 30.7 (8.2 20.1) kg/m(2); P < 0.01]. CONCLUSIONS: Our observations have important implications with respect to the potential weight-reducing actions of nesfatin 1/NUCB-2 treatment. Future research should seek to clarify whether nesfatin 1/NUCB-2 would be beneficial in the management of obesity. PMID- 21252252 TI - Three weeks on a high-fat diet increases intrahepatic lipid accumulation and decreases metabolic flexibility in healthy overweight men. AB - CONTEXT: In rodents, high-fat diets increase intrahepatic lipid (IHL), but human studies are scarce. OBJECTIVE: Our objective was to examine whether high-fat diets influence IHL, intramyocellular lipids (IMCL), and insulin resistance. DESIGN: Twenty overweight men were randomly allocated to low- or high-fat groups (age, 54.0 +/- 2.3 and 56.4 +/- 2.5 yr; body mass index, 29.3 +/- 0.6 and 28.3 +/ 0.5 kg/m(2), respectively). Both groups started with a 3-wk low-fat diet [15% energy (En%) as protein, 65 En% as carbohydrates, 20 En% as fat], after which half of the subjects switched to a 3-wk isocaloric high-fat diet (15 En% protein, 30 En% carbohydrates, 55 En% fat). After 3 and 6 wk, IHL and IMCL content were assessed by (1)H magnetic resonance spectroscopy and a muscle biopsy, and insulin sensitivity was studied using a hyperinsulinemic-euglycemic clamp. An additional liver scan was performed after 1 wk in the high-fat group. RESULTS: IHL decreased by 13% in the low-fat group and increased by 17% in high-fat group (P = 0.047). IMCL content was unaffected (P = 0.304). Insulin sensitivity was unaffected. At wk 3, IHL correlated negatively with insulin sensitivity (r = -0.584; P = 0.009, all subjects combined). Metabolic flexibility, defined as change in respiratory quotient upon insulin stimulation, was decreased after 3 wk of the high-fat diet (change in respiratory quotient was +0.02 +/- 0.02 vs. -0.05 +/- 0.1 in low-fat vs. high-fat group, P = 0.009). Basal plasma glucose increased after the high-fat diet (P = 0.038). Plasma parameters insulin, free fatty acids, high-sensitivity C reactive protein, and liver enzymes and body weight were unaffected by diet. CONCLUSION: A 3-wk high-fat diet leads to IHL accumulation and a decreased metabolic flexibility, but insulin sensitivity is unaffected. PMID- 21252253 TI - A dual sugar challenge test for lipogenic sensitivity to dietary fructose. AB - CONTEXT: Increased hepatic de novo lipogenesis (DNL) in response to dietary sugar is implicated in dyslipidemia, fatty liver, and insulin resistance. OBJECTIVE: The aim of the study was to develop a simple outpatient tolerance test for lipogenic sensitivity to dietary sugar. DESIGN AND SETTING: In inpatients given repeated doses of fructose, protocol 1 compared the acute increase in DNL determined from the percentage of palmitate ("new palmitate") and the percentage of isotopically labeled palmitate ("%DNL") in very low-density lipoprotein triglyceride (TG). Protocol 2 compared the increase in new palmitate in outpatients given three different sugar beverages in a randomized crossover design. PARTICIPANTS: There were 15 lean and overweight volunteers in protocol 1 and 15 overweight volunteers in protocol 2. INTERVENTIONS: In protocol 1, subjects received 1.4 g/kg fructose in divided oral doses over 6 h; in protocol 2, subjects received 0.5 g/kg fructose, 0.5 g/kg fructose plus 0.5 g/kg glucose, or 1 g/kg fructose plus 1 g/kg glucose each as a single oral bolus. MAIN OUTCOME MEASURES: We measured the increase in DNL by two methods. RESULTS: After repeated doses of fructose, new palmitate was significantly correlated with the increase in %DNL (Delta, r = 0.814; P < 0.001) and with fasting insulin levels (area under the curve, r = 0.754; P = 0.001). After a single sugar dose, new palmitate showed a dose effect and was greater after fructose plus glucose. Very low-density lipoprotein TG and total TG significantly increased in both protocols. CONCLUSIONS: A single oral bolus of fructose and glucose rapidly increases serum TG and TG palmitate in overweight subjects. A dual sugar challenge test could prove useful to identify individuals at risk for carbohydrate-induced dyslipidemia and other adverse effects of increased DNL. PMID- 21252254 TI - Preadipocyte factor-1 is associated with metabolic profile in severe obesity. AB - CONTEXT: Dysfunctional adipose tissue has been proposed as a key pathological process linking obesity and metabolic disease. Preadipocyte factor-1 (Pref-1) has been shown to inhibit differentiation in adipocyte precursor cells and could thereby play a role in determining adipocyte size, adipose tissue functioning, and metabolic profile in obese individuals. OBJECTIVE: We hypothesized that adipose tissue from metabolically healthy obese (MHO) and matched metabolically unhealthy obese individuals would demonstrate distinct differences in relation to Pref-1 expression, adipocyte size, and inflammatory markers. DESIGN, SETTING, AND PATIENTS: This was a cross-sectional study, investigating obese patients undergoing bariatric surgery at a tertiary referral centre. Patients included 12 MHO and 17 age- and body mass index-matched metabolically unhealthy obese individuals. MAIN OUTCOME MEASURES: Pref-1, monocyte chemotactic protein-1, TNF alpha, granulocyte colony-stimulating factor, IL-6, and adiponectin levels, macrophage numbers, and adipocyte size were measured in omental and subcutaneous adipose tissue. RESULTS: The MHO group had a lower level of Pref-1 (per 1000 adipocytes) in both subcutaneous [160 (136-177) versus 194 (153-355); P < 0.05] and omental adipose tissue [102 (32-175) versus 194 (100-350); P < 0.005]. This was associated with lower numbers of macrophages, lower levels of TNF-alpha, monocyte chemotactic protein-1, and granulocyte colony-stimulating factor, and higher levels of adiponectin. Omental Pref-1 showed strong correlations with adipocyte size (r = 0.67, P < 0.0005) and metabolic and adipokine parameters, including percent fatty liver (r = 0.62, P < 0.005), fasting glucose (r = 0.68, P < 0.0005), triglyceride (r = 0.60, P < 0.005), high-density lipoprotein cholesterol (r = -0.46, P < 0.05), and adiponectin (r = -0.71, P < 0.05). CONCLUSION: Adipose tissue in MHO individuals had lower levels of Pref-1, a known inhibitor of preadipocyte differentiation, and a more favorable inflammatory profile. These factors may be key to protecting this subgroup of obese individuals from the adverse metabolic profile associated with excess adiposity. PMID- 21252255 TI - Basal plate plaque: a novel organising placental thrombotic process. AB - In contrast to thrombi and haematomas at other body sites, thrombi in the placental intervillous space are not traditionally known to undergo organisation. This report presents 11 examples of a form of organising thrombotic process that develops as a plaque on the foetal aspect of the basal plate. Originally identified in the placenta of a foetus showing severe intrauterine growth restriction, further examples of this lesion, which we term a 'basal plate plaque', show a spectrum of placental involvement. Small lesions appear to occur at points of localised stasis at the basal plate (eg, at edges of anchoring villi or in small basal plate depressions). Large areas of involvement, as seen in the original case, may be pathological markers of more generalised disturbances in placental circulation or of hypercoagulability in the intervillous space. Large basal plate plaques may therefore prove to be diagnostically significant and should be reported. PMID- 21252256 TI - Workplace bullying and common mental disorders: a follow-up study. AB - BACKGROUND: Workplace bullying has been associated with mental health, but longitudinal studies confirming the association are lacking. This study examined the associations of workplace bullying with subsequent common mental disorders 5 7 years later, taking account of baseline common mental disorders and several covariates. METHODS: Baseline questionnaire survey data were collected in 2000 2002 among municipal employees, aged 40-60 years (n=8960; 80% women; response rate 67%). Follow-up data were collected in 2007 (response rate 83%). The final data amounted to 6830 respondents. Workplace bullying was measured at baseline using an instructed question about being bullied currently, previously or never. Common mental disorders were measured at baseline and at follow-up using the 12 item version of the General Health Questionnaire. Those scoring 3-12 were classified as having common mental disorders. Covariates included bullying in childhood, occupational and employment position, work stress, obesity and limiting longstanding illness. Logistic regression analysis was used. RESULTS: After adjusting for age, being currently bullied at baseline was associated with common mental disorders at follow-up among women (OR 2.34, CI 1.81 to 3.02) and men (OR 3.64, CI 2.13 to 6.24). The association for the previously bullied was weaker. Adjusting for baseline common mental disorders, the association attenuated but remained. Adjusting for further covariates did not substantially alter the studied association. CONCLUSION The study confirms that workplace bullying is likely to contribute to subsequent common mental disorders. Measures against bullying are needed at workplaces to prevent mental disorders. PMID- 21252257 TI - The walls have ears: the role of plant CrRLK1Ls in sensing and transducing extracellular signals. AB - In plants, organ formation and cell elongation require the constant adjustment of the dynamic and adaptable cell wall in response to environmental cues as well as internal regulators, such as light, mechanical stresses, pathogen attacks, phytohormones, and other signaling molecules. The molecular mechanisms that perceive these cues and translate them into cellular responses to maintain integrity and remodelling of the carbohydrate-rich cell wall for the coordination of cell growth are still poorly understood. In the last 3 years, the function of six membrane-localized receptor-like kinases (RLKs) belonging to the CrRLK1L family has been linked to the control of cell elongation in vegetative and reproductive development. Moreover, the presence of putative carbohydrate-binding domains in the extracellular domains of these CrRLK1Ls makes this receptor family an excellent candidate for coordinating cell growth, cell-cell communication, and constant cell wall remodelling during the plant life cycle. PMID- 21252258 TI - Arabidopsis thaliana calcium-dependent lipid-binding protein (AtCLB): a novel repressor of abiotic stress response. AB - Ca(2+) is an important second messenger in plant signal transduction pathways regulating stress-induced gene expression. Functional analysis of plant proteins containing Ca(2+)-binding domains (C2 domains) will help us understand the mechanisms behind the role of transcriptional regulators in the Ca(2+) signalling pathway and open new perspectives for crop genetic improvement. We identified a novel transcriptional regulator, a Ca(2+)-dependent lipid-binding protein (AtCLB) containing a C2 domain. AtCLB binds specifically to the promoter of the Arabidopsis thalianol synthase gene (AtTHAS1), whose expression is induced by gravity and light. Here we describe the role of the Atclb gene encoding the AtCLB protein. Expression of the Atclb gene was documented in all analysed tissues of Arabidopsis (leaf, root, stem, flower, and silique) by real-time PCR analysis. Immunofluorescence analysis revealed that AtCLB protein is localized in the nucleus of cells in Arabidopsis root tips. We demonstrated that the AtCLB protein was capable of binding to the membrane lipid ceramide. The role of the Atclb gene in negatively regulating responses to abiotic stress in Arabidopsis thaliana was identified. The loss of the Atclb gene function confers an enhanced drought and salt tolerance and a modified gravitropic response in T-DNA insertion knockout mutant lines. Expression of AtTHAS1 in Atclb knockout mutant lines was increased compared with wild type and a 35S-Atclb overexpression line suggesting AtCLB as a transcriptional repressor of AtTHAS1. PMID- 21252259 TI - Plasma levels of soluble CD14 independently predict mortality in HIV infection. AB - BACKGROUND: Chronic human immunodeficiency virus (HIV) infection is associated with intestinal permeability and microbial translocation that contributes to systemic immune activation, which is an independent predictor of HIV disease progression. The association of microbial translocation with clinical outcome remains unknown. METHODS: This nested case-control study included 74 subjects who died, 120 of whom developed cardiovascular disease and 81 of whom developed AIDS during the Strategies for Management of Anti-Retroviral Therapy (SMART) study with matched control subjects. Intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), soluble CD14 (sCD14), endotoxin core antibody (EndoCAb), and 16S ribosomal DNA (rDNA) were measured in baseline plasma samples. RESULTS: Subjects with the highest quartile of sCD14 levels had a 6-fold higher risk of death than did those in the lowest quartile (95% confidence interval, 2.2 16.1; P<.001), with minimal change after adjustment for inflammatory markers, CD4(+) T cell count, and HIV RNA level. No other marker was significantly associated with clinical outcomes. I-FABP, LPS, and sCD14 were increased and EndoCAb was decreased in study subjects, compared with healthy volunteers. sCD14 level correlated with levels of IL-6, C-reactive protein, serum amyloid A and D dimer. CONCLUSIONS: sCD14, a marker of monocyte response to LPS, is an independent predictor of mortality in HIV infection. Therapeutic attenuation of innate immune activation may improve survival in patients with HIV infection. PMID- 21252260 TI - Staphylococcal enterotoxin B causes proliferation of sensory C-fibers and subsequent enhancement of neurogenic inflammation in rat skin. AB - BACKGROUND: Staphylococcal enterotoxin B (SEB) may be associated with the exacerbation of atopic dermatitis. We investigated whether SEB causes proliferation of sensory C-fibers and subsequent enhancement of plasma leakage induced by sensorineural stimulation in rat skin. METHODS: SEB was applied intracutaneously to the abdomen of preweaning and adult rats. Evans blue dye leakage into the skin induced by topical 10% formalin was measured as an index of neurogenic skin vascular permeability. Local expression of substance P, tachykinin NK1 receptors, and nerve growth factor was assessed immunohistochemically. In addition, we assessed the effects of topical tacrolimus on these skin responses induced by SEB. RESULTS: Increased neurogenic skin plasma leakage was seen 7 days after SEB treatment in 2 different age groups. Innervation of substance P-immunoreactive nerves and expression of tachykinin NK1 receptors and nerve growth factor were also promoted by SEB, peaking at 7 days, 7 days, and 56 h after SEB treatment, respectively. Tacrolimus markedly inhibited these skin changes. CONCLUSIONS: SEB increased the innervation of sensory C fibers and tachykinin NK1 receptors in rat skin, probably because of upregulated production of neurotrophins, including nerve growth factor, leading to enhancement of neurogenic skin inflammation. T cell activation induced by SEB may initiate these changes. PMID- 21252261 TI - Association of anti-oxidized LDL and candidate genes with severity of coronary stenosis in the Women's Ischemia Syndrome Evaluation study. AB - Atherosclerosis is the major cause of coronary artery disease (CAD), and oxidized LDL (oxLDL) is believed to play a key role in the initiation of the atherosclerotic process. Recent studies show that inflammation and autoimmune reactions are also relevant in atherosclerosis. In this study, we examined the association of antibodies against oxLDL (anti-oxLDL) with the severity of CAD in 558 Women's Ischemia Syndrome Evaluation (WISE) study samples (465 whites; 93 blacks) determined by coronary stenosis (< 20%, 20%-49%, > 50% stenosis). We also examined the relationship of anti-oxLDL with serum lipid levels and nine candidate genes including APOE, APOH, APOA5, LPL, LRP1, HL, CETP, PON1, and OLR1. IgM anti-oxLDL levels were significantly higher in the >20% stenosis group than in the >= 20% stenosis group in whites (0.69 +/- 0.02 vs. 0.64 +/- 0.01, respectively; P = 0.02). IgM anti-oxLDL levels correlated significantly with total cholesterol (r2 = 0.01; P = 0.03) and LDL cholesterol (r2 = 0.017; P = 0.004) in whites. Multiple regression analysis revealed a suggestive association of LPL/S447X single-nucleotide polymorphism (SNP) with both IgG anti-oxLDL (P = 0.02) and IgM anti-oxLDL (P = 0.07), as well as between IgM anti-oxLDL and the OLR1/3'UTR SNP (P = 0.020). Our data suggest that higher IgM anti-oxLDL levels may provide protection against coronary stenosis and that genetic variation in some candidate genes are determinants of anti-oxLDL levels. PMID- 21252262 TI - Shiga toxin glycosphingolipid receptors in microvascular and macrovascular endothelial cells: differential association with membrane lipid raft microdomains. AB - Vascular damage caused by Shiga toxin (Stx)-producing Escherichia coli is largely mediated by Stxs, which in particular, injure microvascular endothelial cells in the kidneys and brain. The majority of Stxs preferentially bind to the glycosphingolipid (GSL) globotriaosylceramide (Gb3Cer) and, to a lesser extent, to globotetraosylceramide (Gb4Cer). As clustering of receptor GSLs in lipid rafts is a functional requirement for Stxs, we analyzed the distribution of Gb3Cer and Gb4Cer to membrane microdomains of human brain microvascular endothelial cells (HBMECs) and macrovascular EA.hy 926 endothelial cells by means of anti-Gb3Cer and anti-Gb4Cer antibodies. TLC immunostaining coupled with infrared matrix assisted laser desorption/ionization (IR-MALDI) mass spectrometry revealed structural details of various lipoforms of Stx receptors and demonstrated their major distribution in detergent-resistant membranes (DRMs) compared with nonDRM fractions of HBMECs and EA.hy 926 cells. A significant preferential partition of different receptor lipoforms carrying C24:0/C24:1 or C16:0 fatty acid and sphingosine to DRMs was not detected in either cell type. Methyl-beta cyclodextrin (MbetaCD)-mediated cholesterol depletion resulted in only partial destruction of lipid rafts, accompanied by minor loss of GSLs in HBMECs. In contrast, almost entire disintegration of lipid rafts accompanied by roughly complete loss of GSLs was detected in EA.hy 926 cells after removal of cholesterol, indicating more stable microdomains in HBMECs. Our findings provide first evidence for differently stable microdomains in human endothelial cells from different vascular beds and should serve as the basis for further exploring the functional role of lipid raft-associated Stx receptors in different cell types. PMID- 21252263 TI - Imaging the early stages of phospholipase C/sphingomyelinase activity on vesicles containing coexisting ordered-disordered and gel-fluid domains. AB - The binding and early stages of activity of a phospholipase C/sphingomyelinase from Pseudomonas aeruginosa on giant unilamellar vesicles (GUV) have been monitored using fluorescence confocal microscopy. Both the lipids and the enzyme were labeled with specific fluorescent markers. GUV consisted of a mixture of phosphatidylcholine, sphingomyelin, phosphatidylethanolamine, and cholesterol in equimolar ratios, to which 5-10 mol% of the enzyme end-product ceramide and/or diacylglycerol were occasionally added. Morphological examination of the GUV in the presence of enzyme reveals that, although the enzyme diffuses rapidly throughout the observation chamber, detectable enzyme binding appears to be a slow, random process, with new bound-enzyme-containing vesicles appearing for several minutes. Enzyme binding to the vesicles appears to be a cooperative process. After the initial cluster of bound enzyme is detected, further binding and catalytic activity follow rapidly. After the activity has started, the enzyme is not released by repeated washing, suggesting a "scooting" mechanism for the hydrolytic activity. The enzyme preferentially binds the more disordered domains, and, in most cases, the catalytic activity causes the disordering of the other domains. Simultaneously, peanut- or figure-eight-shaped vesicles containing two separate lipid domains become spherical. At a further stage of lipid hydrolysis, lipid aggregates are formed and vesicles disintegrate. PMID- 21252264 TI - Twelfth biannual report of the Cochrane Haematological Malignancies Group--focus on tyrosine kinase inhibitors. AB - This 12th biannual report of the Cochrane Haematological Malignancies Group highlights recently published randomized controlled trials in the field of hemato oncology, covering the publication period from September 1, 2009, through June 30, 2010. Implication for clinical practice and methodological aspects are the main principles used to select trials for this report. Studies on tyrosine kinase inhibitors for patients with chronic myeloid leukemia were identified through electronic search of MEDLINE with a broad search filter that covered all topics in hemato-oncology combined with a highly sensitive search filter for randomized studies as described in the Cochrane Handbook for Systematic Reviews of Interventions. PMID- 21252265 TI - Ataxic Guillain-Barre syndrome and acute sensory ataxic neuropathy form a continuous spectrum. AB - BACKGROUND: Ataxic Guillain-Barre syndrome is characterised by profound ataxia with negative Romberg sign and no ophthalmoplegia. Its nosological relationship to acute sensory ataxic neuropathy has yet to be discussed. METHODS: Medical records were reviewed of patients suffering acute ataxia and reduced muscle stretch reflexes but without external ophthalmoplegia. Clinical features and laboratory findings were analysed. Rat muscle spindles were immunostained by anti GQ1b and -GD1b antibodies. RESULTS: The Romberg sign was negative in 37 (69%) of 54 patients with acute ataxic neuropathy without ophthalmoplegia, but positive in the other 17 (31%). The negative and positive subgroups had similar features; preceding infectious symptoms (86% vs 83%), distal paraesthesias (70% vs 88%), superficial sense impairment (27% vs 24%), IgG antibodies to GQ1b (65% vs 18%) and GD1b (46% vs 47%) and cerebrospinal fluid albuminocytological dissociation (30% vs 39%). Findings did not differ between the subgroups of 466 patients with Fisher syndrome with and without sensory ataxia. Acute ataxic neuropathy patients more often had anti-GD1b (46% vs 26%) and less often anti-GQ1b (50% vs 83%) antibodies than Fisher syndrome. Anti-GQ1b and -GD1b antibodies strongly stained parvalbumin-positive nerves in rat muscle spindles, indicative that proprioceptive nerves highly express GQ1b and GD1b. CONCLUSION: Clinical and laboratory features suggest that ataxic Guillain-Barre syndrome and acute sensory ataxic neuropathy form a continuous spectrum. The two conditions could be comprehensively referred to as 'acute ataxic neuropathy (without ophthalmoplegia)' to avoid nosological confusion because Fisher syndrome is not classified by the absence or presence of sensory ataxia. That is, acute ataxic neuropathy can be positioned as an incomplete form of Fisher syndrome. PMID- 21252266 TI - Surround modulation of global form perception. AB - We demonstrate a novel surround modulation of global form perception by using Glass patterns in a center-surround configuration. Glass patterns contain randomly distributed dot pairs, or dipoles, whose orientations are determined by a geometric transform. By integrating across dipoles, an observer can perceive a global structure in the image. We measured the coherence threshold, the minimum proportion of signal dots needed for an observer to detect the global form, at 75% accuracy. The coherence thresholds of the central target Glass patterns were measured either alone or with the presence of various Glass pattern surrounds. Concentric and spiral surrounds increased the coherence threshold for the concentric target compared with that measured for the target alone, while a radial surround had no effect. The coherence threshold for the radial pattern was elevated only by the spiral surround while the spiral and translational targets were not affected by any surrounds. The effect persisted when the center and the surround were segregated by a blank gap and peaked at an optimal gap width. Our results show that global form perception can be modulated by a surround, and this modulation depends on the shapes of the central target and the surround context. PMID- 21252267 TI - Surveillance of community genital Chlamydia trachomatis testing in the East of England, 2008-2010. AB - BACKGROUND: Widespread testing for chlamydia is expected to result in a reduction in prevalence. In 2008, coverage indicators introduced by the Department of Health (DH) required collection and submission of all tests performed outside of genitourinary medicine clinics. No mechanism existed to collect community-based tests conducted outside of the National Chlamydia Screening Programme. The Health Protection Agency Regional Epidemiology Unit in the East of England (EoE) set up a new system to routinely collect and submit these tests on behalf of the regional Primary Care Organizations (PCOs). METHODS: Testing data were requested from all laboratories commissioned to undertake chlamydia testing by EoE PCOs. Data were imported into a bespoke Structured Query Language server database and automated data processing routines were run. Data fulfilling national criteria were submitted for inclusion in the DH indicators. RESULTS: High-quality data were submitted to set deadlines with minimum impact on laboratories. Completeness of data variables varied by laboratory and by variable type. After complex data processing, 96% of laboratory reported tests in the 15-24 year age range were eligible for submission. CONCLUSIONS: This centralized method of data collection provides high-quality data, allowing for further analysis, which can be used to inform improvements in health care. These methods could be transferred to any of the hundreds of organisms for which similar laboratory data exist. PMID- 21252269 TI - Antibiotic resistance mechanisms of Vibrio cholerae. AB - As the causative agent of cholera, the bacterium Vibrio cholerae represents an enormous public health burden, especially in developing countries around the world. Cholera is a self-limiting illness; however, antibiotics are commonly administered as part of the treatment regimen. Here we review the initial identification and subsequent evolution of antibiotic-resistant strains of V. cholerae. Antibiotic resistance mechanisms, including efflux pumps, spontaneous chromosomal mutation, conjugative plasmids, SXT elements and integrons, are also discussed. Numerous multidrug-resistant strains of V. cholerae have been isolated from both clinical and environmental settings, indicating that antibiotic use has to be restricted and alternative methods for treating cholera have to be implemented. PMID- 21252268 TI - Classification of subcellular location by comparative proteomic analysis of native and density-shifted lysosomes. AB - One approach to the functional characterization of the lysosome lies in the use of proteomic methods to identify proteins in subcellular fractions enriched for this organelle. However, distinguishing between true lysosomal residents and proteins from other cofractionating organelles is challenging. To this end, we implemented a quantitative mass spectrometry approach based on the selective decrease in the buoyant density of liver lysosomes that occurs when animals are treated with Triton-WR1339. Liver lysosome-enriched preparations from control and treated rats were fractionated by isopycnic sucrose density gradient centrifugation. Tryptic peptides derived from gradient fractions were reacted with isobaric tag for relative and absolute quantitation eight-plex labeling reagents and analyzed by two-dimensional liquid chromatography matrix-assisted laser desorption ionization time-of-flight MS. Reporter ion intensities were used to generate relative protein distribution profiles across both types of gradients. A distribution index was calculated for each identified protein and used to determine a probability of lysosomal residence by quadratic discriminant analysis. This analysis suggests that several proteins assigned to the lysosome in other proteomics studies are not true lysosomal residents. Conversely, results support lysosomal residency for other proteins that are either not or only tentatively assigned to this location. The density shift for two proteins, Cu/Zn superoxide dismutase and ATP-binding cassette subfamily B (MDR/TAP) member 6, was corroborated by quantitative Western blotting. Additional balance sheet analyses on differential centrifugation fractions revealed that Cu/Zn superoxide dismutase is predominantly cytosolic with a secondary lysosomal localization whereas ATP binding cassette subfamily B (MDR/TAP) member 6 is predominantly lysosomal. These results establish a quantitative mass spectrometric/subcellular fractionation approach for identification of lysosomal proteins and underscore the necessity of balance sheet analysis for localization studies. PMID- 21252270 TI - Abbreviated identification of Candida albicans by the presence of a pseudohyphal fringe ('spiking' appearance)--some caveats. PMID- 21252271 TI - A proposed nomenclature for cell wall proteins of Clostridium difficile. AB - Strains of Clostridium difficile produce a number of surface-localized proteins, including the S-layer proteins (SLPs) and other proteins that have suspected roles in pathogenesis. During the Third International C. difficile Symposium (Bled, Slovenia, September 2010) discussions were held on standardization of nomenclature. Gene designations were proposed for the large family of cell wall proteins that are paralogues of the SLP and contain putative cell wall binding motifs. This paper summarizes the agreed nomenclature, which we hope will be used by research groups currently active in the field. PMID- 21252272 TI - Actinomadura pelletieri mycetoma--an atypical case with spine and abdominal wall involvement. AB - We describe a case of mycetoma caused by Actinomadura pelletieri with simultaneous involvement of the spine, abdominal wall and retroperitoneal space in a man who had suffered from 'Madura foot' 10 years earlier. The characteristics of this case were analysed and contextualized among those of other cases of mycetoma caused by other micro-organisms found through a review of the international literature. The rarity of the disease in industrialized countries and its possible atypical presentations may hinder a prompt diagnosis. Culture techniques that allow detection of slow-growing fungi and actinomycetes should be routinely used when dealing with tissue samples from patients from tropical and subtropical regions with chronic granulomatous infections. PMID- 21252273 TI - Detection of an Ambler class D OXA-48-type beta-lactamase in a Klebsiella pneumoniae strain in The Netherlands. AB - Traditionally, bacteria in The Netherlands have low levels of resistance to antibiotics. This report describes what is believed to be the first carbapenem resistant Klebsiella pneumoniae producing an OXA-48 type beta-lactamase in The Netherlands. The isolate co-produced a CTX-M-15 type beta-lactamase and was recovered from a patient who was transferred from a hospital in India to an intensive care unit in The Netherlands. His recovery in The Netherlands was complicated by pneumonia due to the carbapenem-resistant K. pneumoniae to which he eventually succumbed. Pre-emptive screening for carbapenem-resistant Enterobacteriaceae in selected patients could be imperative to maintain the low prevalence of these highly resistant bacteria in Dutch hospitals. PMID- 21252274 TI - Plasmid-borne 16S rRNA methylase ArmA in aminoglycoside-resistant Klebsiella pneumoniae in Poland. AB - We characterized 17 clinical isolates of Klebsiella pneumoniae producing 16S rRNA methylase ArmA. The isolates originated in Poland from 2002 to May 2010 and encompassed four XbaI-PFGE clusters. All the isolates were resistant to amikacin, gentamicin and kanamycin (MIC range: 256-1024 mg l(-1)) and carried the armA gene on a large plasmid of approximately 90 or 130 kb in 15 and 2 isolates, respectively. The armA gene was found in a ~10 kb ClaI restriction fragment of the large plasmid and was flanked by the same elements as in Tn1548. All the isolates carried the bla(CTX-M) gene for a CTX-M-type extended-spectrum beta lactamase. Our results show that ArmA has disseminated horizontally among K. pneumoniae isolates in Poland on the ~90 kb plasmid of the pCTX-M3 family. PMID- 21252275 TI - N-Octanoylhomoserine lactone signalling mediated by the BpsI-BpsR quorum sensing system plays a major role in biofilm formation of Burkholderia pseudomallei. AB - The genome of Burkholderia pseudomallei encodes three acylhomoserine lactone (AHL) quorum sensing systems, each comprising an AHL synthase and a signal receptor/regulator. The BpsI-BpsR system produces N-octanoylhomoserine lactone (C8HL) and is positively auto-regulated by its AHL product. The products of the remaining two systems have not been identified. In this study, tandem MS was used to identify and quantify the AHL species produced by three clinical B. pseudomallei isolates - KHW, K96243 and H11 - three isogenic KHW mutants that each contain a null mutation in an AHL synthase gene, and recombinant Escherichia coli heterologously expressing each of the three B. pseudomallei AHL synthase genes. BpsI synthesized predominantly C8HL, which accounted for more than 95 % of the extracellular AHLs produced in stationary-phase KHW cultures. The major products of BpsI(2) and BpsI(3) were N-(3-hydroxy-octanoyl)homoserine lactone (OHC8HL) and N-(3-hydroxy-decanoyl)homoserine lactone, respectively, and their corresponding transcriptional regulators, BpsR(2) and BpsR(3), were capable of driving reporter gene expression in the presence of these cognate lactones. Formation of biofilm by B. pseudomallei KHW was severely impaired in mutants lacking either BpsI or BpsR but could be restored to near wild-type levels by exogenous C8HL. BpsI(2) was not required, and BpsI(3) was partially required for biofilm formation. Unlike the bpsI mutant, biofilm formation in the bpsI(3) mutant could not be restored to wild-type levels in the presence of OHC8HL, the product of BpsI(3). C8HL and OHC8HL had opposite effects on biofilm formation; exogenous C8HL enhanced biofilm formation in both the bpsI(3) mutant and wild type KHW while exogenous OHC8HL suppressed the formation of biofilm in the same strains. We propose that exogenous OHC8HL antagonizes biofilm formation in B. pseudomallei, possibly by competing with endogenous C8HL for binding to BpsR. PMID- 21252276 TI - Mapping of the interactions between partition proteins Delta and Omega of plasmid pSM19035 from Streptococcus pyogenes. AB - Formation of the segrosome, a nucleoprotein complex crucial for proper functioning of plasmid partition systems, involves interactions between specific partition proteins (ParA-like and ParB-like), ATP and specific DNA sequences (the centromeric sites). Although partition systems have been studied for many years, details of the segrosome formation are not yet clear. Organization of the pSM19035-encoded partition system is unique; in contrast with other known par systems, here, the delta and omega genes do not constitute an operon. Moreover, Omega [a ParB-like protein which has a Ribbon-Helix-Helix (RHH) structure] recognizes multiple centromeric sequences located in the promoters of delta, omega and copS (copy-number control gene). The ParA-like protein Delta is a Walker-type ATPase. In this work, we identify the interaction domains and requirements for dimerization and hetero-interactions of the Delta and Omega proteins of pSM19035 plasmid. The RHH structures are involved in Omega dimerization in vivo and its N-terminal unstructured part is indispensable for association with Delta, both in vivo and in vitro. Omega does not need to form dimers to interact with Delta. ATP binding is not required for Delta dimerization but is important for interaction with Omega in vivo. The in vitro interaction between Delta and Omega depends on ATP but does not require the presence of specific DNA segments (the centromere) recognized by Omega. The C-terminal part of the Delta protein (aa 198-284) is indispensable for interaction with Omega. Delta most probably interacts with Omega as a dimer since two amino acid substitutions in a conserved region between the A' and B motifs abolish both the dimerization of Delta and its interaction with Omega. PMID- 21252277 TI - Genomic characterization of asymptomatic Escherichia coli isolated from the neobladder. AB - The replacement of the bladder with a neobladder made from ileal tissue is the prescribed treatment in some cases of bladder cancer or trauma. Studies have demonstrated that individuals with an ileal neobladder have recurrent colonization by Escherichia coli and other species that are commonly associated with urinary tract infections; however, pyelonephritis and complicated symptomatic infections with ileal neobladders are relatively rare. This study examines the genomic content of two E. coli isolates from individuals with neobladders using comparative genomic hybridization (CGH) with a pan-E. coli/Shigella microarray. Comparisons of the neobladder genome hybridization patterns with reference genomes demonstrate that the neobladder isolates are more similar to the commensal, laboratory-adapted E. coli and a subset of enteroaggregative E. coli than they are to uropathogenic E. coli isolates. Genes identified by CGH as exclusively present in the neobladder isolates among the 30 examined isolates were primarily from large enteric isolate plasmids. Isolations identified a large plasmid in each isolate, and sequencing confirmed similarity to previously identified plasmids of enteric species. Screening, via PCR, of more than 100 isolates of E. coli from environmental, diarrhoeagenic and urinary tract sources did not identify neobladder-specific genes that were widely distributed in these populations. These results taken together demonstrate that the neobladder isolates, while distinct, are genomically more similar to gastrointestinal or commensal E. coli, suggesting why they can colonize the transplanted intestinal tissue but rarely progress to acute pyelonephritis or more severe disease. PMID- 21252278 TI - TolA mediates the differential detergent resistance pattern between the Salmonella enterica subsp. enterica serovars Typhi and Typhimurium. AB - The tol-pal genes are essential for maintaining the outer membrane integrity and detergent resistance in various Gram-negative bacteria, including Salmonella. The role of TolA has been well established for the bile resistance of Salmonella enterica subsp. enterica serovar Typhimurium. We compared the bile resistance pattern between the S. enterica serovars Typhi and Typhimurium and observed that Typhi is more resistant to bile-mediated damage. A closer look revealed a significant difference in the TolA sequence between the two serovars which contributes to the differential detergent resistance. The tolA knockout of both the serovars behaves completely differently in terms of membrane organization and morphology. The role of the Pal proteins and difference in LPS organization between the two serovars were verified and were found to have no direct connection with the altered bile resistance. In normal Luria broth (LB), S. Typhi DeltatolA is filamentous while S. Typhimurium DeltatolA grows as single cells, similar to the wild-type. In low osmolarity LB, however, S. Typhimurium DeltatolA started chaining and S. Typhi DeltatolA showed no growth. Further investigation revealed that the chaining phenomenon observed was the result of failure of the outer membrane to separate in the dividing cells. Taken together, the results substantiate the evolution of a shorter TolA in S. Typhi to counteract high bile concentrations, at the cost of lower osmotic tolerance. PMID- 21252279 TI - UafB is a serine-rich repeat adhesin of Staphylococcus saprophyticus that mediates binding to fibronectin, fibrinogen and human uroepithelial cells. AB - Staphylococcus saprophyticus is an important cause of urinary tract infection (UTI), particularly among young women, and is second only to uropathogenic Escherichia coli as the most frequent cause of UTI. The molecular mechanisms of urinary tract colonization by S. saprophyticus remain poorly understood. We have identified a novel 6.84 kb plasmid-located adhesin-encoding gene in S. saprophyticus strain MS1146 which we have termed uro-adherence factor B (uafB). UafB is a glycosylated serine-rich repeat protein that is expressed on the surface of S. saprophyticus MS1146. UafB also functions as a major cell surface hydrophobicity factor. To characterize the role of UafB we generated an isogenic uafB mutant in S. saprophyticus MS1146 by interruption with a group II intron. The uafB mutant had a significantly reduced ability to bind to fibronectin and fibrinogen. Furthermore, we show that a recombinant protein containing the putative binding domain of UafB binds specifically to fibronectin and fibrinogen. UafB was not involved in adhesion in a mouse model of UTI; however, we observed a striking UafB-mediated adhesion phenotype to human uroepithelial cells. We have also identified genes homologous to uafB in other staphylococci which, like uafB, appear to be located on transposable elements. Thus, our data indicate that UafB is a novel adhesin of S. saprophyticus that contributes to cell surface hydrophobicity, mediates adhesion to fibronectin and fibrinogen, and exhibits tropism for human uroepithelial cells. PMID- 21252280 TI - Transcriptional repressor CopR acts by inhibiting RNA polymerase binding. AB - CopR is a transcriptional repressor encoded by the broad-host-range streptococcal plasmid pIP501, which also replicates in Bacillus subtilis. It acts in concert with the antisense RNA, RNAIII, to control pIP501 replication. CopR represses transcription of the essential repR mRNA about 10- to 20-fold. In previous work, DNA binding and dimerization constants were determined and the motifs responsible localized. The C terminus of CopR was shown to be required for stability. Furthermore, SELEX of the copR operator revealed that in vivo evolution was for maximal binding affinity. Here, we elucidate the repression mechanism of CopR. Competition assays showed that CopR-operator complexes are 18-fold less stable than RNA polymerase (RNAP)-pII complexes. DNase I footprinting revealed that the binding sites for CopR and RNAP overlap. Gel-shift assays demonstrated that CopR and B. subtilis RNAP cannot bind simultaneously, but compete for binding at promoter pII. Due to its higher intracellular concentration CopR inhibits RNAP binding. Additionally, KMnO(4) footprinting experiments indicated that prevention of open complex formation at pII does not further contribute to the repression effect of CopR. PMID- 21252281 TI - Causes and consequences of variability in peptide mating pheromones of ascomycete fungi. AB - The reproductive genes of fungi, like those of many other organisms, are thought to diversify rapidly. This phenomenon could be associated with the formation of reproductive barriers and speciation. Ascomycetes produce two classes of mating type-specific peptide pheromones. These are required for recognition between the mating types of heterothallic species. Little is known regarding the diversity or the extent of species specificity in pheromone peptides among these fungi. We compared the putative protein-coding DNA sequences of the 2 pheromone classes from 70 species of Ascomycetes. The data set included previously described pheromones and putative pheromones identified from genomic sequences. In addition, pheromone genes from 12 Fusarium species in the Gibberella fujikuroi complex were amplified and sequenced. Pheromones were largely conserved among species in this complex and, therefore, cannot alone account for the reproductive barriers observed between these species. In contrast, pheromone peptides were highly diverse among many other Ascomycetes, with evidence for both positive diversifying selection and relaxed selective constraint. Repeats of the alpha factor-like pheromone, which occur in tandem arrays of variable copy number, were found to be conserved through purifying selection and not concerted evolution. This implies that sequence specificity may be important for pheromone reception and that interspecific differences may indeed be associated with functional divergence. Our findings also suggest that frequent duplication and loss causes the tandem repeats to experience "birth-and-death" evolution, which could in fact facilitate interspecific divergence of pheromone peptide sequences. PMID- 21252282 TI - The origin and characterization of new nuclear genes originating from a cytoplasmic organellar genome. AB - Endosymbiotic transfer of DNA and functional genes from the cytoplasmic organelles (mitochondria and chloroplasts) to the nucleus has been a major factor driving the origin of new nuclear genes, a process central to eukaryote evolution. Although organelle DNA transfers very frequently to the nucleus, most is quickly deleted, decays, or is alternatively scrapped. However, a very small proportion of it gives rise, immediately or eventually, to functional genes. To simulate the process of functional transfer, we screened for nuclear activation of a chloroplast reporter gene aadA, which had been transferred from the chloroplast to independent nuclear loci in 16 different plant lines. Cryptic nuclear activity of the chloroplast promoter was revealed, which became conspicuous when present in multiple nuclear copies. We screened ~50 million cells of each line and retrieved three plants in which aadA showed strong nuclear activation. Activation occurred by acquisition of the CaMV 35S nuclear promoter or by nuclear activation of the native chloroplast promoter. Two fortuitous sites within the 3' UTR of aadA mRNA both promoted polyadenylation without any sequence change. Complete characterization of one nuclear sequence before and after gene transfer demonstrated integration by nonhomologous end joining involving simultaneous insertion of multiple chloroplast DNA fragments. The real-time observation of three different means by which a chloroplast gene can become expressed in the nucleus suggests that the process, though rare, may be more readily achieved than previously envisaged. PMID- 21252283 TI - sFLT01: a novel fusion protein with antiangiogenic activity. AB - sFLT01 is a novel fusion protein that consists of the VEGF/PlGF (placental growth factor) binding domain of human VEGFR1/Flt-1 (hVEGFR1) fused to the Fc portion of human IgG(1) through a polyglycine linker. It binds to both human VEGF (hVEGF) and human PlGF (hPlGF) and to mouse VEGF (mVEGF) and mouse PlGF (mPlGF). In vitro, sFLT01 inhibited the proliferation of human umbilical vein endothelial cells and pericytes stimulated by either hVEGF or hPlGF. In vivo, sFLT01 had robust and significant antitumor activity in numerous preclinical subcutaneous tumor models including H460 non-small cell lung carcinoma, HT29 colon carcinoma, Karpas 299 lymphoma, MOLM-13 AML (acute myeloid leukemia), 786-O, and RENCA renal cell carcinoma (RCC). sFLT01 also increased median survival in the orthotopic RENCA RCC model. sFLT01 had strong antiangiogenic activity and altered intratumoral microvessel density, blood vessel lumen size and perimeter, and vascular and vessel areas in RCC models. sFLT01 treatment resulted in fewer endothelial cells and pericytes within the tumor microenvironment. sFLT01 in combination with cyclophosphamide resulted in greater inhibition of tumor growth than either agent used alone as a monotherapy in the A673 Ewing's sarcoma model. Gene expression profiling indicated that the molecular changes in the A673 sarcoma tumors are similar to changes observed under hypoxic conditions. sFLT01 is an innovative fusion protein that possessed robust antitumor and antiangiogenic activities in preclinical cancer models. It is a dual targeting agent that neutralizes both VEGF and PlGF and, therefore, has potential as a next generation antiangiogenic therapeutic for oncology. PMID- 21252284 TI - Synergistic effects of foretinib with HER-targeted agents in MET and HER1- or HER2-coactivated tumor cells. AB - The HER and MET receptor tyrosine kinases (RTK) are coactivated in a subset of human tumors. This study characterizes MET and HER expression and signaling in a panel of human tumor cell lines and the differential susceptibility of these cell lines to single agents or combinations of foretinib, a multikinase MET inhibitor, with HER-targeted agents, erlotinib or lapatinib. Most MET-amplified tumor lines without HER1 or HER2 amplification are sensitive to foretinib, whereas MET amplified lines with HER1 or HER2 amplification are more sensitive to the combination of foretinib with lapatinib or erlotinib. Interestingly, MET overexpressing tumor cell lines with HER1 or HER2 amplification also exhibited reduced sensitivity to lapatinib or erlotinib in the presence of hepatocyte growth factor (HGF), indicating MET activation can decrease the effectiveness of HER1/2 inhibitors in some cell lines. Consistent with this observation, the effect of HGF on lapatinib or erlotinib sensitivity in these cells was reversed by foretinib, other MET inhibitors, or siRNA to MET. Western blot analyses showed that combining foretinib with erlotinib or lapatinib effectively decreased the phosphorylation of MET, HER1, HER2, HER3, AKT, and ERK in these cells. Furthermore, HER2-positive advanced or metastatic breast cancer patients treated with lapatinib who had higher tumor MET expression showed shorter progression free survival (19.29 weeks in MET-high patients vs. 28.14 weeks in MET-low patients, P < 0.0225). These data suggest that combination therapy with foretinib and HER-targeted agents should be tested as a treatment option for HER1- or HER2 positive patients with MET-amplified or -overexpressing tumors. PMID- 21252286 TI - Global microRNA analysis of the NCI-60 cancer cell panel. AB - MicroRNAs (miRNA) are a group of short noncoding RNAs that regulate gene expression at the posttranscriptional level. They are involved in many biological processes, including development, differentiation, apoptosis, and carcinogenesis. Because miRNAs may play a role in the initiation and progression of cancer, they comprise a novel class of promising diagnostic and prognostic molecular markers and potential drug targets. By applying an LNA-enhanced microarray platform, we studied the expression profiles of 955 miRNAs in the NCI-60 cancer cell lines and identified tissue- and cell-type-specific miRNA patterns by unsupervised hierarchical clustering and statistical analysis. A comparison of our data to three previously published miRNA expression studies on the NCI-60 panel showed a remarkably high correlation between the different technical platforms. In addition, the current work contributes expression data for 369 miRNAs that have not previously been profiled. Finally, by matching drug sensitivity data for the NCI-60 cells to their miRNA expression profiles, we found numerous drug-miRNAs pairs, for which the miRNA expression and drug sensitivity profiles were highly correlated and thus represent potential candidates for further investigation of drug resistance and sensitivity mechanisms. PMID- 21252285 TI - Enhanced anticancer effect of the combination of cisplatin and TRAIL in triple negative breast tumor cells. AB - Women with triple-negative breast cancer (TNBC) have a worse prognosis compared with other breast cancer subtypes. Hormonal or Herceptin-based therapies were found to be ineffective because of the loss of target receptors, such as ER, PR, and HER-2 amplification. Conventional chemo- and/ or radiation therapy also seems to have limited efficacy in TNBC patients. We studied the effects of cisplatin plus TRAIL on 1 normal and 2 TNBC cells in vitro. The in vitro studies indicate that cisplatin plus TRAIL significantly enhanced cell death in TNBC cell lines CRL2335 and MDA-MB-468 by approximately 60%-70% compared with approximately 10% 15% in CRL8799 normal breast cell line. Treatment with cisplatin/TRAIL also inhibited the expression of EGFR, p63, survivin, Bcl-2, and Bcl-xL in TNBC cells. Specific inhibition of EGFR and/or p63 protein in TNBC cells by small interfering RNA (siRNA) does not increase TRAIL-induced apoptosis. However, inhibition of survivin by siRNA enhances TRAIL-induced apoptosis. These observations suggested the possibility that survivin played an important role in cisplatin plus TRAIL induced apoptosis in TNBC cells. In vivo experiments, treatment of mice with cisplatin plus TRAIL resulted in a significant inhibition of CRL2335 xenograft tumors compared with untreated control tumors. Taken together the data suggest that cisplatin plus TRAIL treatment have the potential of providing a new strategy for improving the therapeutic outcome in TNBC patients. PMID- 21252287 TI - Comprehensive evaluation of the contribution of X chromosome genes to platinum sensitivity. AB - Using a genome-wide gene expression data set generated from Affymetrix GeneChip Human Exon 1.0ST array, we comprehensively surveyed the role of 322 X chromosome gene expression traits on cellular sensitivity to cisplatin and carboplatin. We identified 31 and 17 X chromosome genes whose expression levels are significantly correlated (after multiple testing correction) with sensitivity to carboplatin and cisplatin, respectively, in the combined HapMap CEU (Utah residents with ancestry from northern and western Europe) and YRI (Yoruba in Ibahan, Nigeria) populations (false discovery rate, FDR < 0.05). Of those, 14 overlap for both cisplatin and carboplatin. Using an independent gene expression quantification method, the Illumina Sentrix Human-6 Expression BeadChip, measured on the same HapMap cell lines, we found that 4 and 2 of these genes are significantly associated with carboplatin and cisplatin sensitivity, respectively, in both analyses. Two genes, CTPS2 and DLG3, were identified by both genome-wide gene expression analyses as correlated with cellular sensitivity to both platinating agents. The expression of DLG3 gene was also found to correlate with cellular sensitivity to platinating agents in NCI-60 cancer cell lines. In addition, we evaluated whether the expression of X chromosome genes contributed to the observed differences in sensitivity to the platinums between CEU and YRI-derived cell lines. Of the 34 distinct genes significantly correlated with either carboplatin or cisplatin sensitivity, 14 are differentially expressed (defined as P < 0.05) between CEU and YRI. Thus, sex chromosome genes play a role in cellular sensitivity to platinating agents and differences in the expression level of these genes are an important source of variation that should be included in comprehensive pharmacogenomic studies. PMID- 21252288 TI - Studies on mechanism of action of anticancer peptides by modulation of hydrophobicity within a defined structural framework. AB - In the present study, the hydrophobicity of a 26-residue alpha-helical peptide (peptide P) was altered to study the effects of peptide hydrophobicity on the mechanism of action of cationic anticancer peptides. Hydrophobicity of the nonpolar face of the peptides was shown to correlate with peptide helicity. The self-association ability of peptides in aqueous environment, determined by the reversed-phase high performance liquid chromatography temperature profiling, showed strong influence on anticancer activity. The peptide analogues with greater hydrophobicity showed stronger anticancer activity determined by IC(50) values with a necrotic-like membrane disruption mechanism. Peptide analogues exhibited high specificity against cancer cells and much higher anticancer activity than widely-used anticancer chemical drugs. The mechanism of action of anticancer peptides was also investigated. The hydrophobicity of peptides plays a crucial role in the mechanism of action against cancer cells, which could present a way, using a de novo design approach, to create anticancer peptides as potential therapeutics in clinical practices. PMID- 21252289 TI - Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins. AB - The drug-drug interaction (DDI) potential of tyrosine kinase inhibitors (TKI) as interacting drugs via transporter inhibition has not been fully assessed. Here, we estimated the half maximal inhibitory concentration (IC(50)) values for 8 small-molecule TKIs (imatinib, dasatinib, nilotinib, gefitinib, erlotinib, sunitinib, lapatinib, and sorafenib) on [(14)C]metformin transport by human organic cation transporters (OCT), OCT1, OCT2, and OCT3, and multidrug and toxic compound extrusion (MATE) proteins, MATE1 and MATE2-K, using human embryonic kidney cells stably expressing these transporters. We then compared the estimated IC(50) values to the maximum clinical concentrations of unbound TKIs in plasma (unbound C(max,sys,p)). Results showed that imatinib, nilotinib, gefitinib, and erlotinib exerted selectively potent inhibitory effects, with unbound C(max,sys,p)/IC(50) values >=0.1, on MATE1, OCT3, MATE2-K, and OCT1, respectively. In comparison to the common form of OCT1, the OCT1 polymorphism, M420del, was more sensitive to drug inhibition by erlotinib. Major metabolites of several TKIs showed IC(50) values similar to those for unchanged TKIs. Taken together, these findings suggest the potential of clinical transporter-mediated DDIs between specific TKIs and OCTs and MATEs, which may affect the disposition, efficacy, and toxicity of metformin and other drugs that are substrates of these transporters. The study provides the basis for further clinical DDI studies with TKIs. PMID- 21252290 TI - A novel defensive mechanism against acetaminophen toxicity in the mouse lateral nasal gland: role of CYP2A5-mediated regulation of testosterone homeostasis and salivary androgen-binding protein expression. AB - To identify novel factors or mechanisms that are important for the resistance of tissues to chemical toxicity, we have determined the mechanisms underlying the previously observed increases in resistance to acetaminophen (APAP) toxicity in the lateral nasal gland (LNG) of the male Cyp2g1-null/Cyp2a5-low mouse. Initial studies established that Cyp2a5-null mice, but not a newly generated strain of Cyp2g1-null mice, were resistant to APAP toxicity in the LNG; therefore, subsequent studies were focused on the Cyp2a5-null mice. Compared with the wild type (WT) male mouse, the Cyp2a5-null male mouse had intact capability to metabolize APAP to reactive intermediates in the LNG, as well as unaltered circulating levels of APAP, APAP-GSH, APAP-glucuronide, and APAP-sulfate. However, it displayed reduced tissue levels of APAP and APAP-GSH and increased tissue levels of testosterone and salivary androgen-binding protein (ABP) in the LNG. Furthermore, we found that ABP was able to compete with GSH and cellular proteins for adduction with reactive metabolites of APAP in vitro. The amounts of APAP-ABP adducts formed in vivo were greater, whereas the amounts of APAP adducts formed with other cellular proteins were substantially lower, in the LNG of APAP treated male Cyp2a5-null mice compared with the LNG of APAP-treated male WT mice. We propose that through its critical role in testosterone metabolism, CYP2A5 regulates 1) the bioavailability of APAP and APAP-GSH (presumably through modulation of the rates of xenobiotic excretion from the LNG) and 2) the expression of ABP, which can quench reactive APAP metabolites and thereby spare critical cellular proteins from inactivation. PMID- 21252291 TI - Acute disruption of bone marrow hematopoiesis by benzo(a)pyrene is selectively reversed by aryl hydrocarbon receptor-mediated processes. AB - Bone marrow (BM) hematopoietic cells are selectively sensitive to polycyclic aromatic hydrocarbons (PAH) in vivo. 7,12-Dimethylbenz(a)anthracene (DMBA), but not benzo(a)pyrene (BP), depletes BM hematopoietic cells in C57BL/6 mice. This difference is due to a BP-selective aryl hydrocarbon receptor (AhR)-mediated recovery. Colony-forming unit assays show suppression of lymphoid progenitors by each PAH within 6 h but a subsequent recovery, exclusively after BP treatment. Suppression of myeloid progenitors (6 h) occurs only for DMBA. Each progenitor responded equally to DMBA and BP in congenic mice expressing the PAH-resistant AhR (AhR(d)). AhR, therefore, mediates this BP recovery in each progenitor type. These PAH suppressions depend on Cyp1b1-mediated metabolism. Paradoxically, few genes responded to DMBA, whereas 12 times more responded to BP. Progenitor suppression by DMBA, therefore, occurs with minimal effects on the general BM population. Standard AhR-mediated stimulations (Cyp1a1, Cyp1b1, Ahrr) were similar for each PAH and for the specific agonist 2,3,7,8-tetrachlorodibenzo-p dioxin but were absent in AhR(d) mice. A group of 12 such AhR responses was sustained from 6 to 24 h. A second, larger set of BP responses (chemokines, cytokines, cyclooxygenase 2) differed in two respects; DMBA responses were low and BP responses declined extensively from 6 to 24 h. A third cluster exhibited BP-induced increases in protective genes (Nqo1, GST-mu) that appeared only after 12 h. Conversion of BP to quinones contributes oxidative signaling not seen with DMBA. We propose that genes in this second cluster, which share oxidative signaling and AhR activation, provide the AhR-dependent protection of hematopoietic progenitors seen for BP. PMID- 21252292 TI - Novel regulation of nuclear factor-YB by miR-485-3p affects the expression of DNA topoisomerase IIalpha and drug responsiveness. AB - Nuclear factor (NF)-YB, a subunit of the transcription factor nuclear factor Y (NF-Y) complex, binds and activates CCAAT-containing promoters. Our previous work suggested that NF-YB may be a mediator of topoisomerase IIalpha (Top2alpha), working through the Top2alpha promoter. DNA topoisomerase II (Top2) is an essential nuclear enzyme and the primary target for several clinically important anticancer drugs. Our teniposide-resistant human lymphoblastic leukemia CEM cells (CEM/VM-1-5) express reduced Top2alpha protein compared with parental CEM cells. To study the regulation of Top2alpha during the development of drug resistance, we found that NF-YB protein expression is increased in CEM/VM-1-5 cells compared with parental CEM cells. This further suggests that increased NF-YB may be a negative regulator of Top2alpha in CEM/VM-1-5 cells. We asked what causes the up regulation of NF-YB in CEM/VM-1-5 cells. We found by microRNA profiling that hsa miR-485-3p is lower in CEM/VM-1-5 cells compared with CEM cells. MicroRNA target prediction programs revealed that the 3'-untranslated region (3'-UTR) of NF-YB harbors a putative hsa-miR-485-3p binding site. We thus hypothesized that hsa-miR 485-3p mediates drug responsiveness by decreasing NF-YB expression, which in turn negatively regulates Top2alpha expression. To test this, we overexpressed miR-485 3p in CEM/VM-1-5 cells and found that this led to reduced expression of NF-YB, a corresponding up-regulation of Top2alpha, and increased sensitivity to the Top2 inhibitors. Results in CEM cells were replicated in drug-sensitive and -resistant human rhabdomyosarcoma Rh30 cells, suggesting that our findings represent a general phenomenon. Ours is the first study to show that miR-485-3p mediates Top2alpha down-regulation in part by altered regulation of NF-YB. PMID- 21252293 TI - Reconstitution of human RNA interference in budding yeast. AB - Although RNA-mediated interference (RNAi) is a widely conserved process among eukaryotes, including many fungi, it is absent from the budding yeast Saccharomyces cerevisiae. Three human proteins, Ago2, Dicer and TRBP, are sufficient for reconstituting the RISC complex in vitro. To examine whether the introduction of human RNAi genes can reconstitute RNAi in S. cerevisiae, genes encoding these three human proteins were introduced into S. cerevisiae. We observed both siRNA and siRNA- and RISC-dependent silencing of the target gene GFP. Thus, human Ago2, Dicer and TRBP can functionally reconstitute human RNAi in S. cerevisiae, in vivo, enabling the study and use of the human RNAi pathway in a facile genetic model organism. PMID- 21252294 TI - Crystal structure of a DNA containing the planar, phenoxazine-derived bi functional spectroscopic probe C. AB - Previously, we developed the deoxycytosine analog C (C-spin) as a bi-functional spectroscopic probe for the study of nucleic acid structure and dynamics using electron paramagnetic resonance (EPR) and fluorescence spectroscopy. To understand the effect of C on nucleic acid structure, we undertook a detailed crystallographic analysis. A 1.7 A resolution crystal structure of C within a decamer duplex A-form DNA confirmed that C forms a non-perturbing base pair with deoxyguanosine, as designed. In the context of double-stranded DNA C adopted a planar conformation. In contrast, a crystal structure of the free spin-labeled base c displayed a ~ 20 degrees bend at the oxazine linkage. Density function theory calculations revealed that the bent and planar conformations are close in energy and exhibit the same frequency for bending. These results indicate a small degree of flexibility around the oxazine linkage, which may be a consequence of the antiaromaticity of a 16-pi electron ring system. Within DNA, the amplitude of the bending motion is restricted, presumably due to base-stacking interactions. This structural analysis shows that the C forms a planar, structurally non perturbing base pair with G indicating it can be used with high confidence in EPR or fluorescence-based structural and dynamics studies. PMID- 21252295 TI - Probing RNA dynamics via longitudinal exchange and CPMG relaxation dispersion NMR spectroscopy using a sensitive 13C-methyl label. AB - The refolding kinetics of bistable RNA sequences were studied in unperturbed equilibrium via (13)C exchange NMR spectroscopy. For this purpose a straightforward labeling technique was elaborated using a 2'-(13)C-methoxy uridine modification, which was prepared by a two-step synthesis and introduced into RNA using standard protocols. Using (13)C longitudinal exchange NMR spectroscopy the refolding kinetics of a 20 nt bistable RNA were characterized at temperatures between 298 and 310K, yielding the enthalpy and entropy differences between the conformers at equilibrium and the activation energy of the refolding process. The kinetics of a more stable 32 nt bistable RNA could be analyzed by the same approach at elevated temperatures, i.e. at 314 and 316 K. Finally, the dynamics of a multi-stable RNA able to fold into two hairpin- and a pseudo knotted conformation was studied by (13)C relaxation dispersion NMR spectroscopy. PMID- 21252296 TI - Epigenetic profile of the euchromatic region of human Y chromosome. AB - The genome of a multi-cellular organism acquires various functional capabilities in different cell types by means of distinct chromatin modifications and packaging states. Acquired during early development, the cell type-specific epigenotype is maintained by cellular memory mechanisms that involve epigenetic modifications. Here we present the epigenetic status of the euchromatic region of the human Y chromosome that has mostly been ignored in earlier whole genome epigenetic mapping studies. Using ChIP-on-chip approach, we mapped H3K9ac, H3K9me3, H3K27me3 modifications and CTCF binding sites while DNA methylation analysis of selected CpG islands was done using bisulfite sequencing. The global pattern of histone modifications observed on the Y chromosome reflects the functional state and evolutionary history of the sequences that constitute it. The combination of histone and DNA modifications, along with CTCF association in some cases, reveals the transcriptional potential of all protein coding genes including the sex-determining gene SRY and the oncogene TSPY. We also observe preferential association of histone marks with different tandem repeats, suggesting their importance in genome organization and gene regulation. Our results present the first large scale epigenetic analysis of the human Y chromosome and link a number of cis-elements to epigenetic regulatory mechanisms, enabling an understanding of such mechanisms in Y chromosome linked disorders. PMID- 21252297 TI - FUBP3 interacts with FGF9 3' microsatellite and positively regulates FGF9 translation. AB - A TG microsatellite in the 3'-untranslated region (UTR) of FGF9 mRNA has previously been shown to modulate FGF9 expression. In the present study, we investigate the possible interacting protein that binds to FGF9 3'-UTR UG-repeat and study the mechanism underlying this protein-RNA interaction. We first applied RNA pull-down assays and LC-MS analysis to identify proteins associated with this repetitive sequence. Among the identified proteins, FUBP3 specifically bound to the synthetic (UG)(15) oligoribonucleotide as shown by supershift in RNA-EMSA experiments. The endogenous FGF9 protein was upregulated in response to transient overexpression and downregulated after knockdown of FUBP3 in HEK293 cells. As the relative levels of FGF9 mRNA were similar in these two conditions, and the depletion of FUBP3 had no effect on the turn-over rate of FGF9 mRNA, these data suggested that FUBP3 regulates FGF9 expression at the post-transcriptional level. Further examination using ribosome complex pull-down assay showed overexpression of FUBP3 promotes FGF9 expression. In contrast, polyribosome-associated FGF9 mRNA decreased significantly in FUBP3-knockdown HEK293 cells. Finally, reporter assay suggested a synergistic effect of the (UG)-motif with FUBP3 to fine-tune the expression of FGF9. Altogether, results from this study showed the novel RNA binding property of FUBP3 and the interaction between FUBP3 and FGF9 3'-UTR UG repeat promoting FGF9 mRNA translation. PMID- 21252298 TI - Serotonin, a tryptophan-derived signal conserved in plants and animals, regulates root system architecture probably acting as a natural auxin inhibitor in Arabidopsis thaliana. AB - Serotonin (5-hydroxytryptamine) is a well-known neurotransmitter in mammals and is widely distributed in plants. This compound is synthesized from tryptophan and shares structural similarity with IAA. To date, little is known about the morphological, physiological and molecular responses of plants to serotonin. In this study, we characterized the effects of serotonin on growth and development in Arabidopsis thaliana seedlings. Gas chromatography-mass spectrometry (GC-MS) analysis showed that plants are able to take up serotonin from the growth medium, which coincided with greatly stimulated lateral root development at concentrations from 10 to 160 MUM. In contrast, higher doses of serotonin repressed lateral root growth, primary root growth and root hair development, but stimulated adventitious root formation. To investigate the role of serotonin in modulating auxin responses, we performed experiments using transgenic Arabidopsis lines expressing the auxin-responsive marker constructs DR5:uidA, BA3:uidA and HS::AXR3NT-GUS, as well as a variety of Arabidopsis mutants defective at the AUX1, AXR1, AXR2 and AXR4 auxin-related loci. We found that serotonin strongly inhibited both DR5:uidA and BA3:uidA gene expression in primary and adventitious roots and in lateral root primordia. This compound also abolished the effects of IAA or naphthaleneacetic acid on auxin-regulated developmental and genetic responses, indicating an anti-auxin activity in the plant. Mutant analysis further showed that lateral root induction elicited by serotonin was independent of the AUX1 and AXR4 loci but required AXR1 and AXR2. Our results show that serotonin regulates root development probably by acting as a natural auxin inhibitor. PMID- 21252299 TI - Sublethal cadmium intoxication in Arabidopsis thaliana impacts translation at multiple levels. AB - To study the impact of translational regulation during heavy metal poisoning, Arabidopsis thaliana cell cultures were submitted to sublethal cadmium stress. At the concentration used, cadmium had a minimal impact on the growth of the culture but induced an accumulation of high molecular weight polysomes without de novo production of new ribosomes together with a reduction of protein synthesis. In addition, cadmium stress induces phosphorylation of eukaryotic initiation factor 2alpha by GCN2 and, in planta, gcn2 mutants are more sensitive to cadmium stress, suggesting a role for this translational regulation mechanism in the response to cadmium stress. Microarray analysis of total and polysomal RNAs in control and cadmium-treated cells reveals a large class of genes for which a variation in total RNA abundance is not linked to a variation in polysomal loading, suggesting that transcription and translation are uncoupled and that these genes are not recruited at the initiation step of translation. PMID- 21252300 TI - Identical amino acid substitutions in the repression domain of auxin/indole-3 acetic acid proteins have contrasting effects on auxin signaling. AB - Auxin/indole-3-acetic acid (Aux/IAA) proteins function as repressors of auxin response gene expression when auxin concentrations in a cell are low. At elevated auxin concentrations, these repressors are destroyed via the ubiquitin-proteasome pathway, resulting in derepression/activation of auxin response genes. Most Aux/IAA repressors contain four conserved domains, with one of these being an active, portable repression domain (domain I) and a second being an auxin dependent instability domain (domain II). Here, we have analyzed the effects of amino acid substitutions in the repression domain of selected Aux/IAA proteins. We show that stabilized versions of Aux/IAA proteins with amino acid substitutions in domain I display contrasting phenotypes when expressed in transformed Arabidopsis (Arabidopsis thaliana) plants. An alanine-for-leucine substitution in the LxLxL (where L is leucine and x is another amino acid) repression domain of IAA3, IAA6, or IAA19 confers enhanced auxin response gene expression and "high-auxin" phenotypes when expressed from the 35S or IAA19 promoter (as tested with IAA19) in transformed Arabidopsis plants. In marked contrast, a single alanine-for-leucine substitution in domain I of IAA12 or IAA17 confers repression of auxin response genes and "low-auxin" phenotypes. These results point to intrinsic differences in the repression domain(s) of IAA proteins and suggest that some IAA proteins have stronger or more complex repression domains than others. PMID- 21252301 TI - Transposable elements and small RNAs contribute to gene expression divergence between Arabidopsis thaliana and Arabidopsis lyrata. AB - Transposable elements (TEs) are often the primary determinant of genome size differences among eukaryotes. In plants, the proliferation of TEs is countered through epigenetic silencing mechanisms that prevent mobility. Recent studies using the model plant Arabidopsis thaliana have revealed that methylated TE insertions are often associated with reduced expression of nearby genes, and these insertions may be subject to purifying selection due to this effect. Less is known about the genome-wide patterns of epigenetic silencing of TEs in other plant species. Here, we compare the 24-nt siRNA complement from A. thaliana and a closely related congener with a two- to threefold higher TE copy number, Arabidopsis lyrata. We show that TEs--particularly siRNA-targeted TEs--are associated with reduced gene expression within both species and also with gene expression differences between orthologs. In addition, A. lyrata TEs are targeted by a lower fraction of uniquely matching siRNAs, which are associated with more effective silencing of TE expression. Our results suggest that the efficacy of RNA-directed DNA methylation silencing is lower in A. lyrata, a finding that may shed light on the causes of differential TE proliferation among species. PMID- 21252302 TI - Local balancing influences global structure in social networks. PMID- 21252303 TI - Hemp, an mbt domain-containing protein, plays essential roles in hematopoietic stem cell function and skeletal formation. AB - To clarify the molecular pathways governing hematopoietic stem cell (HSC) development, we screened a fetal liver (FL) HSC cDNA library and identified a unique gene, hematopoietic expressed mammalian polycomb (hemp), encoding a protein with a zinc-finger domain and four malignant brain tumor (mbt) repeats. To investigate its biological role, we generated mice lacking Hemp (hemp(-/-)). Hemp(-/-) mice exhibited a variety of skeletal malformations and died soon after birth. In the FL, hemp was preferentially expressed in the HSC and early progenitor cell fractions, and analyses of fetal hematopoiesis revealed that the number of FL mononuclear cells, including HSCs, was reduced markedly in hemp(-/-) embryos, especially during early development. In addition, colony-forming and competitive repopulation assays demonstrated that the proliferative and reconstitution abilities of hemp(-/-) FL HSCs were significantly impaired. Microarray analysis revealed alterations in the expression levels of several genes implicated in hematopoietic development and differentiation in hemp(-/-) FL HSCs. These results demonstrate that Hemp, an mbt-containing protein, plays essential roles in HSC function and skeletal formation. It is also hypothesized that Hemp might be involved in certain congenital diseases, such as Klippel-Feil anomaly. PMID- 21252304 TI - Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma. AB - Gastrin-releasing peptide (GRP) is synthesized by pulmonary neuroendocrine cells in inflammatory lung diseases, such as bronchopulmonary dysplasia (BPD). Many BPD infants develop asthma, a serious disorder of intermittent airway obstruction. Despite extensive research, early mechanisms of asthma remain controversial. The incidence of asthma is growing, now affecting >300 million people worldwide. To test the hypothesis that GRP mediates asthma, we used two murine models: ozone exposure for air pollution-induced airway hyperreactivity (AHR), and ovalbumin (OVA)-induced allergic airway disease. BALB/c mice were given small molecule GRP blocking agent 77427, or GRP blocking antibody 2A11, before exposure to ozone or OVA challenge. In both models, GRP blockade abrogated AHR and bronchoalveolar lavage (BAL) macrophages and granulocytes, and decreased BAL cytokines implicated in asthma, including those typically derived from Th1 (e.g., IL-2, TNFalpha), Th2 (e.g., IL-5, IL-13), Th17 (IL-17), macrophages (e.g., MCP-1, IL-1), and neutrophils (KC = IL-8). Dexamethasone generally had smaller effects on all parameters. Macrophages, T cells, and neutrophils express GRP receptor (GRPR). GRP blockade diminished serine phosphorylation of GRPR with ozone or OVA. Thus, GRP mediates AHR and airway inflammation in mice, suggesting that GRP blockade is promising as a broad-spectrum therapeutic approach to treat and/or prevent asthma in humans. PMID- 21252306 TI - Vulnerability of the fetal primate brain to moderate reduction in maternal global nutrient availability. AB - Moderate maternal nutrient restriction during pregnancy occurs in both developing and developed countries. In addition to poverty, maternal dieting, teenage pregnancy, and uterine vascular problems in older mothers are causes of decreased fetal nutrition. We evaluated the impact of global 30% maternal nutrient reduction (MNR) on early fetal baboon brain maturation. MNR induced major cerebral developmental disturbances without fetal growth restriction or marked maternal weight reduction. Mechanisms evaluated included neurotrophic factor suppression, cell proliferation and cell death imbalance, impaired glial maturation and neuronal process formation, down-regulation of gene ontological pathways and related gene products, and up-regulated transcription of cerebral catabolism. Contrary to the known benefits from this degree of dietary reduction on life span, MNR in pregnancy compromises structural fetal cerebral development, potentially having an impact on brain function throughout life. PMID- 21252307 TI - Content comparison of self-report measures used in vestibular rehabilitation based on the international classification of functioning, disability and health. AB - BACKGROUND: Physical therapists should understand the content included in self report questionnaires in order to choose the appropriate questionnaire for examination and follow-up purposes. The International Classification of Functioning, Disability and Health (ICF) provides a universal and standard language for the description of health and health-related states and can be used for the content comparison of self-report questionnaires. Objective The purpose of this study was to describe and compare the contents covered by 8 self-report measures used in vestibular rehabilitation based on the linkage of their content to the ICF. DESIGN: This was a cross-sectional study. METHOD: Eight vestibular questionnaires were identified and linked to the ICF by 2 health care professionals according to established linking rules. Based on the linking, the contents of the 8 questionnaires were compared and the interobserver agreement between 2 raters was estimated using kappa coefficients. RESULTS: A total of 312 meaningful concepts from the 164 items of the 8 vestibular questionnaires were identified and linked to the ICF. The meaningful concepts identified were linked to 51 different ICF components: 19 categories of the component "body functions," 30 categories of the component "activities and participation," and 2 categories of the component "environmental factors." Forty-two concepts could not be linked to any of the ICF components. The estimated kappa coefficients for 2 raters at the component and first and second levels of the ICF ranged from 0.83 to 0.96. Limitations The method of identifying vestibular measures was not based on a systematic search; instead, the most widely used instruments in the field of vestibular rehabilitation were selected. Thus, the study results are limited to the examined vestibular instruments. CONCLUSION: Using the ICF as a theoretical framework was found to be useful for comparing the content of health status questionnaires, as well as for exploring the focus of the measures currently in use in vestibular rehabilitation. PMID- 21252309 TI - Tuberculosis manifesting as an invasive pulmonary mass and liver nodules mimicking malignancy with metastases. PMID- 21252308 TI - Influence of systematic increases in treadmill walking speed on gait kinematics after stroke. AB - BACKGROUND: Fast treadmill training improves walking speed to a greater extent than training at a self-selected speed after stroke. It is unclear whether fast treadmill walking facilitates a more normal gait pattern after stroke, as has been suggested for treadmill training at self-selected speeds. Given the massed stepping practice that occurs during treadmill training, it is important for therapists to understand how the treadmill speed selected influences the gait pattern that is practiced on the treadmill. OBJECTIVE: The purpose of this study was to characterize the effect of systematic increases in treadmill speed on common gait deviations observed after stroke. DESIGN: A repeated-measures design was used. METHODS: Twenty patients with stroke walked on a treadmill at their self-selected walking speed, their fastest speed, and 2 speeds in between. Using a motion capture system, spatiotemporal gait parameters and kinematic gait compensations were measured. RESULTS: Significant improvements in paretic- and nonparetic-limb step length and in single- and double-limb support were found. Asymmetry of these measures improved only for step length. Significant improvements in paretic hip extension, trailing limb position, and knee flexion during swing also were found as speed increased. No increases in circumduction or hip hiking were found with increasing speed. Limitations Caution should be used when generalizing these results to survivors of a stroke with a self-selected walking speed of less than 0.4 m/s. This study did not address changes with speed during overground walking. CONCLUSIONS: Faster treadmill walking facilitates a more normal walking pattern after stroke, without concomitant increases in common gait compensations, such as circumduction. The improvements in gait deviations were observed with small increases in walking speed. PMID- 21252310 TI - La Mujer Barbuda by Ribera, 1631: a gender bender. PMID- 21252311 TI - Dr Google or Dr Lazy? PMID- 21252312 TI - Emotion blocks the path to learning under stereotype threat. AB - Gender-based stereotypes undermine females' performance on challenging math tests, but how do they influence their ability to learn from the errors they make? Females under stereotype threat or non-threat were presented with accuracy feedback after each problem on a GRE-like math test, followed by an optional interactive tutorial that provided step-wise problem-solving instruction. Event related potentials tracked the initial detection of the negative feedback following errors [feedback related negativity (FRN), P3a], as well as any subsequent sustained attention/arousal to that information [late positive potential (LPP)]. Learning was defined as success in applying tutorial information to correction of initial test errors on a surprise retest 24-h later. Under non-threat conditions, emotional responses to negative feedback did not curtail exploration of the tutor, and the amount of tutor exploration predicted learning success. In the stereotype threat condition, however, greater initial salience of the failure (FRN) predicted less exploration of the tutor, and sustained attention to the negative feedback (LPP) predicted poor learning from what was explored. Thus, under stereotype threat, emotional responses to negative feedback predicted both disengagement from learning and interference with learning attempts. We discuss the importance of emotion regulation in successful rebound from failure for stigmatized groups in stereotype-salient environments. PMID- 21252313 TI - Increasing solar absorption for photocatalysis with black hydrogenated titanium dioxide nanocrystals. AB - When used as a photocatalyst, titanium dioxide (TiO(2)) absorbs only ultraviolet light, and several approaches, including the use of dopants such as nitrogen, have been taken to narrow the band gap of TiO(2). We demonstrated a conceptually different approach to enhancing solar absorption by introducing disorder in the surface layers of nanophase TiO(2) through hydrogenation. We showed that disorder engineered TiO(2) nanocrystals exhibit substantial solar-driven photocatalytic activities, including the photo-oxidation of organic molecules in water and the production of hydrogen with the use of a sacrificial reagent. PMID- 21252314 TI - A bacterial protein targets the BAHD1 chromatin complex to stimulate type III interferon response. AB - Intracellular pathogens such as Listeria monocytogenes subvert cellular functions through the interaction of bacterial effectors with host components. Here we found that a secreted listerial virulence factor, LntA, could target the chromatin repressor BAHD1 in the host cell nucleus to activate interferon (IFN) stimulated genes (ISGs). IFN-lambda expression was induced in response to infection of epithelial cells with bacteria lacking LntA; however, the BAHD1 chromatin associated complex repressed downstream ISGs. In contrast, in cells infected with lntA-expressing bacteria, LntA prevented BAHD1 recruitment to ISGs and stimulated their expression. Murine listeriosis decreased in BAHD1(+/-) mice or when lntA was constitutively expressed. Thus, the LntA-BAHD1 interplay may modulate IFN-lambda-mediated immune response to control bacterial colonization of the host. PMID- 21252316 TI - Synthesis and measurement of ultrafast waveforms from five discrete optical harmonics. AB - Achieving the control of light fields in a manner similar in sophistication to the control of electromagnetic fields in the microwave and radiofrequency regimes has been a major challenge in optical physics research. We manipulated the phase and amplitude of five discrete harmonics spanning the blue to mid-infrared frequencies to produce instantaneous optical fields in the shape of square, sawtooth, and subcycle sine and cosine pulses at a repetition rate of 125 terahertz. Furthermore, we developed an all-optical shaper-assisted linear cross correlation technique to retrieve these fields and thereby verified their shapes and confirmed the critical role of carrier-envelope phase in Fourier synthesis of optical waveforms. PMID- 21252315 TI - DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. AB - Pancreatic neuroendocrine tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1, which encodes menin, a component of a histone methyltransferase complex, and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain-associated protein) and ATRX (alpha thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors. PMID- 21252317 TI - Retrieval practice produces more learning than elaborative studying with concept mapping. AB - Educators rely heavily on learning activities that encourage elaborative studying, whereas activities that require students to practice retrieving and reconstructing knowledge are used less frequently. Here, we show that practicing retrieval produces greater gains in meaningful learning than elaborative studying with concept mapping. The advantage of retrieval practice generalized across texts identical to those commonly found in science education. The advantage of retrieval practice was observed with test questions that assessed comprehension and required students to make inferences. The advantage of retrieval practice occurred even when the criterial test involved creating concept maps. Our findings support the theory that retrieval practice enhances learning by retrieval-specific mechanisms rather than by elaborative study processes. Retrieval practice is an effective tool to promote conceptual learning about science. PMID- 21252319 TI - High-energy physics. Deep potholes block the road to discovery for U.S. science. PMID- 21252318 TI - Tuberculosis in North Korea. PMID- 21252320 TI - Food safety. Food safety law will likely strain FDA science. PMID- 21252321 TI - Statistics. ESP paper rekindles discussion about statistics. PMID- 21252322 TI - Scientific publishing. Open access gains support; fees and journal quality deter submissions. PMID- 21252323 TI - Marine biology. Killer whales earn their name. PMID- 21252324 TI - Nuclear medicine. Scrambling to close the isotope gap. PMID- 21252325 TI - Nuclear medicine. A field back in vogue. PMID- 21252326 TI - Society for Integrative and Comparative Biology. Getting to the guts of tadpole carnivory. PMID- 21252327 TI - Society for Integrative and Comparative Biology. Soccer and the art of deception. PMID- 21252328 TI - Society for Integrative and Comparative Biology. Turtles are not just drifters. PMID- 21252329 TI - Fighting liverflukes with food safety education. PMID- 21252330 TI - Make a bid for bird biodiversity. PMID- 21252331 TI - Hopes for merit-based grants in China. PMID- 21252332 TI - HIV prevention in women: next steps. PMID- 21252333 TI - Research ethics. Research practice and participant preferences: the growing gulf. PMID- 21252334 TI - Immunology. The gut's Clostridium cocktail. PMID- 21252335 TI - Materials science. Low-loss plasmonic metamaterials. PMID- 21252336 TI - Neuroscience. Toward reprogramming gonads to brains. PMID- 21252337 TI - Astronomy. Disclosing identities in diffuse interstellar bands. PMID- 21252338 TI - Microbiology. Another microbial pathway for acetate assimilation. PMID- 21252339 TI - Animal migration and infectious disease risk. AB - Animal migrations are often spectacular, and migratory species harbor zoonotic pathogens of importance to humans. Animal migrations are expected to enhance the global spread of pathogens and facilitate cross-species transmission. This does happen, but new research has also shown that migration allows hosts to escape from infected habitats, reduces disease levels when infected animals do not migrate successfully, and may lead to the evolution of less-virulent pathogens. Migratory demands can also reduce immune function, with consequences for host susceptibility and mortality. Studies of pathogen dynamics in migratory species and how these will respond to global change are urgently needed to predict future disease risks for wildlife and humans alike. PMID- 21252340 TI - Mitochondrial capture by a transmissible cancer. AB - Canine transmissible venereal tumor (CTVT) is an infectious cell line circulating in many feral dog populations. It originated once, about 10,000 years ago. Phylogenetic analyses of mitochondrial sequences from dogs, wolves, and a geographically diverse collection of CTVT samples indicate that the cancer has periodically acquired mitochondria from its host. We suggest that this may be because the cancer's own mitochondria have a tendency to degenerate, due to high mutation rates and relaxed selection, resulting in host mitochondria being more fit. PMID- 21252341 TI - Quantum criticality without tuning in the mixed valence compound beta-YbAlB4. AB - Fermi liquid theory, the standard theory of metals, has been challenged by a number of observations of anomalous metallic behavior found in the vicinity of a quantum phase transition. The breakdown of the Fermi liquid is accomplished by fine-tuning the material to a quantum critical point by using a control parameter such as the magnetic field, pressure, or chemical composition. Our high-precision magnetization measurements of the ultrapure f-electron-based superconductor beta YbAlB(4) demonstrate a scaling of its free energy that is indicative of zero field quantum criticality without tuning in a metal. The breakdown of Fermi liquid behavior takes place in a mixed-valence state, which is in sharp contrast with other known examples of quantum critical f-electron systems that are magnetic Kondo lattice systems with integral valence. PMID- 21252342 TI - A magnetically focused molecular beam of ortho-water. AB - Like dihydrogen, water exists as two spin isomers, ortho and para, with the nuclear magnetic moments of the hydrogen atoms either parallel or antiparallel. The ratio of the two spin isomers and their physical properties play an important role in a wide variety of research fields, ranging from astrophysics to nuclear magnetic resonance (NMR). Unlike ortho and para H(2), however, the two water isomers remain challenging to separate, and as a consequence, very little is currently known about their different physical properties. Here, we report the formation of a magnetically focused molecular beam of ortho-water. The beam we formed also had a particular spin projection. Thus, in the presence of holding magnetic fields, the water molecules are hyperpolarized, laying the foundation for ultrasensitive NMR experiments in the future. PMID- 21252343 TI - An egg-adult association, gender, and reproduction in pterosaurs. AB - A sexually mature individual of Darwinopterus preserved together with an egg from the Jurassic of China provides direct evidence of gender in pterosaurs and insights into the reproductive biology of these extinct fliers. This new find and several other examples of Darwinopterus demonstrate that males of this pterosaur had a relatively small pelvis and a large cranial crest, whereas females had a relatively large pelvis and no crest. The ratio of egg mass to adult mass is relatively low, as in extant reptiles, and is comparable to values for squamates. A parchment-like eggshell points to burial and significant uptake of water after oviposition. This evidence for low parental investment contradicts the widespread assumption that reproduction in pterosaurs was like that of birds and shows that it was essentially like that of reptiles. PMID- 21252344 TI - Changes in climatic water balance drive downhill shifts in plant species' optimum elevations. AB - Uphill shifts of species' distributions in response to historical warming are well documented, which leads to widespread expectations of continued uphill shifts under future warming. Conversely, downhill shifts are often considered anomalous and unrelated to climate change. By comparing the altitudinal distributions of 64 plant species between the 1930s and the present day within California, we show that climate changes have resulted in a significant downward shift in species' optimum elevations. This downhill shift is counter to what would be expected given 20th-century warming but is readily explained by species' niche tracking of regional changes in climatic water balance rather than temperature. Similar downhill shifts can be expected to occur where future climate change scenarios project increases in water availability that outpace evaporative demand. PMID- 21252345 TI - Raptor nest decorations are a reliable threat against conspecifics. AB - Individual quality is often signaled by phenotypic flags, such as bright plumage patches in birds. Extended phenotype signals can similarly show quality, but in these cases the signals are external to the individual, often taking the form of objects scavenged from the environment. Through multiple manipulative experiments, we showed that objects used for nest decoration by a territorial raptor, the black kite (Milvus migrans), act as reliable threats to conspecifics, revealing the viability, territory quality, and conflict dominance of the signaler. Our results suggest that animal-built structures may serve as signaling devices much more frequently than currently recognized. PMID- 21252347 TI - A methylaspartate cycle in haloarchaea. AB - Access to novel ecological niches often requires adaptation of metabolic pathways to cope with new environments. For conversion to cellular building blocks, many substrates enter central carbon metabolism via acetyl-coenzyme A (acetyl-CoA). Until now, only two such pathways have been identified: the glyoxylate cycle and the ethylmalonyl-CoA pathway. Prokaryotes in the haloarchaea use a third pathway by which acetyl-CoA is oxidized to glyoxylate via the key intermediate methylaspartate. Glyoxylate condensation with another acetyl-CoA molecule yields malate, the final assimilation product. This cycle combines reactions that originally belonged to different metabolic processes in different groups of prokaryotes, which suggests lateral gene transfer and evolutionary tinkering of acetate assimilation. Moreover, it requires elevated intracellular glutamate concentrations, as well as coupling carbon assimilation with nitrogen metabolism. PMID- 21252346 TI - Discovery of a viral NLR homolog that inhibits the inflammasome. AB - The NLR (nucleotide binding and oligomerization, leucine-rich repeat) family of proteins senses microbial infections and activates the inflammasome, a multiprotein complex that promotes microbial clearance. Kaposi's sarcoma associated herpesvirus (KSHV) is linked to several human malignancies. We found that KSHV Orf63 is a viral homolog of human NLRP1. Orf63 blocked NLRP1-dependent innate immune responses, including caspase-1 activation and processing of interleukins IL-1beta and IL-18. KSHV Orf63 interacted with NLRP1, NLRP3, and NOD2. Inhibition of Orf63 expression resulted in increased expression of IL-1beta during the KSHV life cycle. Furthermore, inhibition of NLRP1 was necessary for efficient reactivation and generation of progeny virus. The viral homolog subverts the function of cellular NLRs, which suggests that modulation of NLR mediated innate immunity is important for the lifelong persistence of herpesviruses. PMID- 21252348 TI - The neural basis of intuitive best next-move generation in board game experts. AB - The superior capability of cognitive experts largely depends on quick automatic processes. To reveal their neural bases, we used functional magnetic resonance imaging to study brain activity of professional and amateur players in a board game named shogi. We found two activations specific to professionals: one in the precuneus of the parietal lobe during perception of board patterns, and the other in the caudate nucleus of the basal ganglia during quick generation of the best next move. Activities at these two sites covaried in relevant tasks. These results suggest that the precuneus-caudate circuit implements the automatic, yet complicated, processes of board-pattern perception and next-move generation in board game experts. PMID- 21252349 TI - Does family therapy reduce health care costs for more than the identified patient? PMID- 21252350 TI - Variants of the human PPARG locus and the susceptibility to chronic periodontitis. AB - Apart from its regulatory function in lipid and glucose metabolism, peroxisome proliferator-activated receptor (PPAR)gamma has impact on the regulation of inflammation and bone metabolism. The aim of the study was to investigate the association of five polymorphisms (rs10865710, rs2067819, rs3892175, rs1801282, rs3856806) within the PPARG gene with chronic periodontitis. The study population comprised 402 periodontitis patients and 793 healthy individuals. Genotyping of the PPARG gene polymorphisms was performed by PCR and melting curve analysis. Comparison of frequency distribution of genotypes between individuals with periodontal disease and healthy controls for the polymorphism rs3856806 showed a P-value of 0.04 but failed to reach significance after correction for multiple testing (P < 0.01). Two single nucleotide polymorphisms (SNPs) (rs10865710 and rs3892175) were found to be in strong linkage disequilibrium to rs2067819 (D' > 0.90). A 3-site analysis (rs2067819-rs1801282-rs3856860) revealed five haplotypes with a frequency of >=1% among cases and controls. Following adjustment for age, gender and smoking, none of the haplotypes was significantly different between periodontitis and healthy controls after Bonferroni correction. This study could not show a significant association between PPARG gene variants and chronic periodontitis. PMID- 21252352 TI - Crisis management in borderline personality disorder. PMID- 21252351 TI - Assessment and comparison of culturally based explanations for mental disorder among Singaporean Chinese youth. AB - BACKGROUND: Culture is important to how populations understand the cause of mental disorder, a variable that has implications for treatment-seeking behaviour. Asian populations underutilize professional mental health treatment partly because of their endorsement of supernatural causation models to explain mental disorders, beliefs that stem from their religious backgrounds. AIMS: This study sought to understand the dimensions of explanatory models used by three groups of Singaporean Chinese youth (n = 842)--Christian, Chinese religionist, no religion--and examined their responses to an instrument that combined explanations from psychological and organic perspectives on mental disorder with approaches from Asian and Western religious traditions. RESULTS: Factor analysis revealed five factors. Two were psychological corresponding to the humanistic and cognitive-behavioural perspectives respectively. Another two, which were supernatural in nature, dealt with karmaic beliefs popular among Asian religionists and more classical religious explanations common in monotheistic religions. The remaining factor was deemed a physiological model although it incorporated an item that made it consistent with an Asian organic model. CONCLUSION: While groups differed in their endorsement of supernatural explanations, psychological perspectives had the strongest endorsement among this population. Regression analysis showed that individuals who endorsed supernatural explanations more strongly tended to have no exposure to psychology courses and heightened religiosity. PMID- 21252353 TI - Farmers' suicide in India: implications for public mental health. AB - Farmers' suicide in India is a cause of concern and government figures, though conservative, predict an impending epidemic. Various measures to curb this calamity are being made in a piecemeal manner. Considering it as an issue of social and mental health concern, this article attempts to evaluate the situation based on the tenet that health and illness are the result of a complex interplay between biological, psychological, social, environmental, economic and political factors. Thus in India the agrarian crisis, among other causes, has been largely debated as the major reason for the current state of farmers. It is important that (psychiatric) epidemiology and public mental health try to evolve mechanisms to understand and implement measures, and take this into consideration when attempting health promotion and prevention. PMID- 21252354 TI - Determinants of psychological distress among migrants from Ecuador and Romania in a Spanish city. AB - BACKGROUND: Migration may have consequences on the mental health of those who enter a new cultural environment. In Spain, migration has increased tenfold in 20 years. It is important to study how these migrants are interacting within this new context and which variables hinder their personal and social development. AIMS: To analyze acculturation differences in Spain between first-generation immigrants from two different countries; to analyze the self-reported mental health of these participants; and to evaluate which variables best predict mental health disorders. METHOD: One hundred and thirty five (135) respondents from Romania and Ecuador responded to a questionnaire analyzing mental health by means of the GHQ-12, coupled with other personal, social and psychosocial acculturation variables. RESULTS: Both cultural groups differed significantly regarding the impact of personal and social variables on their well-being. Nevertheless, mental health distress was not explained by their cultural differences but by gender, gross income and perceived discrimination. Social support offered by those still living at home acted as a buffer. CONCLUSION: It is important to analyze female migration patterns in order to reduce mental health problems, stress the importance of economic income, and examine how social support offered by those living in one's home culture is an effective buffer against mental distress. PMID- 21252355 TI - Psychosocial impact of obsessive-compulsive disorder on patients and their caregivers: a comparative study with depressive disorder. AB - BACKGROUND: Little empirical research has been done to assess the impact of obsessive-compulsive disorder (OCD) on patients and their caregivers. OBJECTIVE: To assess the psychosocial impact of OCD on patients and their caregivers and compare it with depressed controls. METHOD: Thirty two patients with OCD and their caregivers and 30 patients of depression and their caregivers were assessed on sociodemographic and clinical variables and the following scales: World Health Organization Quality of Life Questionnaire-BREF version (WHOQOL-BREF); Schedule for Assessment of Psychiatric Disability; Family Burden Interview Schedule; and Family Accommodation Scale. Yale Brown Obsessive-Compulsive Disorder Scale (YBOCS) and Hamilton Depression Rating Scale (HDRS) were applied to rate the severity of obsessive-compulsive and depressive symptoms. RESULTS: Patients with OCD had the lowest scores in the psychological health domain of the WHOQOL-BREF. They were also disabled due to their illness with maximum disability being experienced in the overall behaviour domain. Caregivers of OCD patients experienced burden in several areas and had to accommodate to the patient's behaviour. Patients with OCD had a better quality of life (QOL) and were less disabled compared with depressed patients, but their caregivers were more burdened and had to accommodate to a greater degree in comparison to caregivers of depressed patients. The OCD patients' QOL and disability scores and their caregivers' burden and accommodation scores correlated significantly with several sociodemographic, clinical and psychological variables. CONCLUSION: OCD patients, when compared with depressed subjects, have a better QOL and are less disabled, but their caregivers are more burdened and have to accommodate more. PMID- 21252356 TI - The role of environmental influences on schizophrenia admissions in Israel. AB - OBJECTIVE: The role of environmental factors in hospitalization of patients with schizophrenia is incompletely understood. This study attempts to relate the pattern of hospital admissions to environmental variables such as season and to social factors such as nationally celebrated holidays. METHODS: Charts of all adults (n = 4,331) with a discharge diagnosis of schizophrenia admitted to the Abarbanel Mental Health Centre (Bat Yam, Israel) between 1 January 2001 and 31 December 2005 were reviewed. Hospitalizations were classified by gender, first or repeat admission, month and season of admission, and whether or not the admission coincided with a major Jewish holiday period. RESULTS: There was a significant reduction (p < 0.05) in first admissions for men during April, the month corresponding to Passover, the most widely celebrated holiday in Israel. This pattern was not seen for women or for repeat admissions. There was no significant effect of the season upon admission rates, using two different methods of defining the season. CONCLUSIONS: This study demonstrated significant monthly variability in admission rates and a possible protective effect of a widely celebrated public religious holiday. A consistent effect of season upon rates of admission was not found. Future studies need to identify which specific social factors exert a protective or harmful effect and study how knowledge of these effects can be translated into clinical practice. PMID- 21252357 TI - Stressors and reactions to stressors among university students. AB - BACKGROUND: University students are prone to stressors due to the transitional nature of university life. High levels of stress are believed to affect students' health as well as their academic performance. AIMS: The aims of this study were to identify stressors and reactions to stressors among university students, and to examine the correlations between student stressors and study variables. METHODS: A correlational descriptive design was used. Student-life Stress Inventory (SSI) was used to measure the stressors and reactions to stressors. Stratified random sampling was employed to recruit participants. The final sample consisted of 877 participants (students). RESULTS: RESULT: s indicated that the highest group of stressors experienced by students were 'self-imposed' stressors followed by 'pressures'. Cognitive responses were found to be the highest responses to stressors experienced by students. Negative correlations were found with student's perception of health, and father's and mother's level of education. CONCLUSIONS: This study revealed that stressors among university students come from 'self-imposed' stressors and 'pressures'. Stress management, assertiveness skills, time management and counselling sessions will be effective in reducing stress experienced by students. PMID- 21252358 TI - Perception of mental illness: preliminary exploratory research at a cross cultural outpatient psychiatric clinic. AB - This descriptive study presented an overview of culturally sensitive mental health services and potential barriers for immigrant Canadians. A semi-structured questionnaire was developed and administered to 173 patients who attended a large cross-cultural psychiatry outpatient clinic in Vancouver, British Columbia, Canada. RESULTS: indicated that only 21% of patients were able to state their diagnosis or were able to describe the symptoms of their diagnosis that met the DSM-IV criteria given by a psychiatrist. Examination of patient ethnicity showed that more South Asian (25%) or Southeast Asian (24%) patients had more diagnoses of anxiety disorder in comparison to other ethnic groups. Refugees characterized mental illness in terms of stress or stress-related factors (30%) in comparison to non-refugees (13%). There was a greater preference in women, when compared to men, to prefer the term 'client' versus 'patient'. These results elucidate the importance of cultural and systemic barriers for immigrant Canadians. The need for appropriate service delivery is discussed. PMID- 21252359 TI - Not just an individual journey: social aspects of recovery. AB - BACKGROUND: Recent literature on recovery describes the process as deeply personal and unique to each individual. While there are aspects of recovery that are unique to each individual, this article argues that focusing solely on these overlooks the fact that recovery unfolds within a social and interpersonal context. MATERIALS: Drawing from qualitative data, this article describes aspects of recovery that involve the contributions of others, the social environment and society. DISCUSSION: These aspects of recovery include relationships, adequate material conditions and responsive services and supports. CONCLUSION: The authors consider the implications of these social factors for transforming psychiatric research and theory as well as for recovery-orientated practice. PMID- 21252361 TI - Pigment-dispersing factor affects nocturnal activity rhythms, photic entrainment, and the free-running period of the circadian clock in the cricket gryllus bimaculatus. AB - Pigment-dispersing factor (PDF) is a neuropeptide widely distributed in insect brains and plays important roles in the circadian system. In this study, we used RNA interference to study the role of the pigment-dispersing factor (pdf) gene in regulating circadian locomotor rhythms in the cricket, Gryllus bimaculatus. Injections of pdf double-stranded RNA (dspdf) effectively knocked down the pdf mRNA and PDF peptide levels. The treated crickets maintained the rhythm both under light-dark cycles (LD) and constant darkness (DD). However, they showed rhythms with reduced nocturnal activity with prominent peaks at lights-on and lights-off. Entrainability of dspdf-injected crickets was higher than control crickets as they required fewer cycles to resynchronize to the LD cycles shifted by 6 h. The free-running periods of the dspdf-injected crickets were shorter than those of control crickets in DD. These results suggest that PDF is not essential for the rhythm generation but involved in control of the nocturnality, photic entrainment, and fine tuning of the free-running period of the circadian clock. PMID- 21252362 TI - Temperature entrainment of the circadian cuticle deposition rhythm in Drosophila melanogaster. AB - The cuticle deposition rhythm, which is observed in the apodeme of the furca in the thorax, is controlled by a peripheral circadian clock in the epidermal cells and entrained to light-dark (LD) cycles via CRYPTOCHROME (CRY) in Drosophila melanogaster. In the present study, we examined the effects of temperature (TC) cycles and the combination of LD and TC cycles on entrainment of the cuticle deposition rhythm. The rhythm was entrained to TC cycles, whose period was 28 h. In T = 21 and 24 h, the rhythm was entrained to TC cycles in some individuals. CRY is not necessary for temperature entrainment of the cuticle deposition rhythm because the rhythm in cry(b) (lacking functional CRY) was entrained to TC cycles. Temperature entrainment of the rhythm was achieved even when the thoraxes or furcae were cultured in vitro, suggesting that the mechanism for temperature entrainment is independent of the central clock in the brain and the site of the thermoreception resides in the epidermal cells. When LD and TC cycles with different periods were applied, the rhythm was entrained to LD cycles with a slight influence of TC cycles. Thus, the LD cycle is a stronger zeitgeber than the TC cycle. The variance of the number of the cuticle layers decreased in the flies kept under LD and TC cycles with the same period in which the thermophase coincided with the photophase. Therefore, we conclude that LD and TC cycles synergistically entrain the rhythm. Synergistic effects of LD and TC cycles on entrainment were also observed even when the thoraxes were cultured in vitro, suggesting that the light and temperature information is integrated within the peripheral circadian system. PMID- 21252363 TI - Feeding time synchronizes clock gene rhythmic expression in brain and liver of goldfish (Carassius auratus). AB - Little is known about the feeding time dependence of clock gene expression in fish. The aim of the present study was to investigate whether a scheduled feeding time can entrain the rhythmic expression of several clock genes (period and cryptocrome) in the brain and liver of a teleost, the goldfish. Fish maintained under continuous light (LL) conditions were divided into 3 groups. Two groups were fed daily at 1000 h and 2200 h, respectively, and the third group was subjected to a random schedule regime. After 30 days, the fishes under 24-h food deprivation were sacrificed through a 24-h cycle, and clock gene expression in the optic tectum, hypothalamus, and liver was quantified by real-time PCR. The findings pointed to differences between the central and peripheral tissues studied. In the absence of a light-dark cycle (constant light), a scheduled feeding regime was necessary and sufficient to maintain both the rhythmic expression of several clock genes in the optic tectum and hypothalamus, as well as daily rhythms in locomotor activity. In contrast, neither locomotor activity nor clock gene expression in brain tissues was synchronized in randomly fed fish. However, in the liver, most of the clock genes studied presented significant daily rhythms in phase (related to the time of the last meal) in all 3 experimental groups, suggesting that the daily rhythm of clock genes in this organ only depends on the last meal time. The data suggest that, as in mammals, the smooth running of the food entrainable oscillator (FEO) in fish involves the rhythmic expression of several clock genes (Per1 and Cry3) in the central and peripheral structures. The results also indicate that the food anticipatory activity (FAA) in goldfish is not only the result of rhythmic clock gene expression in the liver because rhythmic clock gene expression was observed in randomly fed fishes, while FAA was not observed. PMID- 21252364 TI - Synchronized circadian bioluminescence in cave-dwelling Arachnocampa tasmaniensis (Glowworms). AB - Larvae of the genus Arachnocampa, known as glowworms, are bioluminescent predatory insects that use light to attract prey. One species, Arachnocampa flava, is known to possess true circadian regulation of bioluminescence: light:dark cycles entrain the rhythm of nocturnal glowing. Given the absence of natural light as a cue in caves, we addressed the question of whether cave populations of Arachnocampa tasmaniensis, a species known to inhabit caves as well as epigean environments, are rhythmic. We found that the major dark-zone cave populations of A. tasmaniensis maintain a high-amplitude 24-hour rhythm of bioluminescence, with the acrophase during external daylight hours. Populations of A. tasmaniensis in caves many kilometers apart show similar, but not exactly the same, timing of the acrophase. Systematic investigation of colonies in the dark zone of a single cave showed that some smaller colonies distant to the main ceiling colony, also in the dark zone, glow in antiphase. Periodic monitoring of a single colony over several years showed that the acrophase shifted from nocturnal to diurnal some time between October 2008 and January 2009. Prey availability was investigated as a possible zeitgeber. The acrophase of prey availability, as measured by light trapping, and the acrophase of bioluminescence do not precisely match, occurring 3 hours apart. Using in-cave artificial light exposure, we show that after LD cycles, cave larvae become entrained to bioluminesce during the foregoing photophase. In contrast, epigean larvae exposed to artificial LD cycles after a period of DD become entrained to bioluminesce during the foregoing scotophase. One explanation is that individuals within colonies in the dark zone synchronize their bioluminescence rhythms through detection and matching of each other 's bioluminescence. PMID- 21252365 TI - Seasonal and diel variation of hormone metabolites in European stonechats: on the importance of high signal-to-noise ratios in noninvasive hormone studies. AB - Most vertebrates living in seasonal environments show seasonal reproductive cycles and diel rhythms. The rhythmicity in behavior and morphology is accompanied by diel and seasonal patterns of hormone secretions. In small animals, the investigation of diel patterns of hormones has been hampered because repeated blood sampling is difficult and may influence subsequent measurements. A possibility to avoid these caveats is to investigate excreted hormone metabolites instead. Here, we describe the diel excretion patterns of testosterone and corticosterone metabolites in a small captive songbird during 4 seasons: winter, early spring (Zugunruhe), summer, and autumn molt. Our approach is quite unique, because the diel patterns of steroids have rarely--if at all--been investigated in the same individuals within several seasons. Small birds should be ideal to investigate diel patterns of hormone metabolites, because they defecate frequently enough to establish a diel profile. However, concentration measurements of hormone metabolites rely on the assumptions that hormone metabolites are placed into droppings of similar mass (the "dropping amount assumption") and are excreted in constant time intervals (the "constant interval assumption"). These assumptions were clearly violated in our study, as the dropping mass per time interval and the defecation intervals varied depending on the time of day and season. We thus used the rate of hormone metabolite excretion as an alternative measure to concentration. Both testosterone and corticosterone metabolites showed diel and seasonal rhythmicity. Furthermore, the diel pattern varied depending on season. Concentration and rate measurements gave similar results when the differences between hormone metabolite levels were large-for example, when testosterone metabolites were compared across seasons. When the differences were more subtle, though, the 2 measures did not always correspond well, indicating that the violation of the 2 basic assumptions affected the comparability of concentration measurements. We conclude that diel and seasonal comparisons of hormone metabolites potentially give biologically meaningful results, especially when rates instead of concentrations are measured. However, such studies require awareness of the limitations and pitfalls of noninvasive hormone measurements, a carefully designed experiment, and very cautious interpretation of the data. PMID- 21252366 TI - Estimation of human circadian phase via a multi-channel ambulatory monitoring system and a multiple regression model. AB - Reliable detection of circadian phase in humans using noninvasive ambulatory measurements in real-life conditions is challenging and still an unsolved problem. The masking effects of everyday behavior and environmental input such as physical activity and light on the measured variables need to be considered critically. Here, we aimed at developing techniques for estimating circadian phase with the lowest subject burden possible, that is, without the need of constant routine (CR) laboratory conditions or without measuring the standard circadian markers, (rectal) core body temperature (CBT), and melatonin levels. In this validation study, subjects (N = 16) wore multi-channel ambulatory monitoring devices and went about their daily routine for 1 week. The devices measured a large number of physiological, behavioral, and environmental variables, including CBT, skin temperatures, cardiovascular and respiratory function, movement/posture, ambient temperature, and the spectral composition and intensity of light received at eye level. Sleep diaries were logged electronically. After the ambulatory phase, subjects underwent a 32-h CR procedure in the laboratory for measuring unmasked circadian phase based on the "midpoint" of the salivary melatonin profile. To overcome the complex masking effects of confounding variables during ambulatory measurements, multiple regression techniques were applied in combination with the cross-validation approach to subject-independent prediction of circadian phase. The most accurate estimate of circadian phase was achieved using skin temperatures, irradiance for ambient light in the blue spectral band, and motion acceleration as predictors with lags of up to 24 h. Multiple regression showed statistically significant improvement of variance of prediction error over the traditional approaches to determining circadian phase based on single predictors (motion acceleration or sleep log), although CBT was intentionally not included as the predictor. Compared to CBT alone, our method resulted in a 40% smaller range of prediction errors and a nonsignificant reduction of error variance. The proposed noninvasive measurement method could find applications in sleep medicine or in other domains where knowing the exact endogenous circadian phase is important (e.g., for the timing of light therapy). PMID- 21252367 TI - Correlated fluctuations of daytime skin temperature and vigilance. AB - Skin temperature shows spontaneous ultradian fluctuations during everyday-life wakefulness. Previous work showed that mild manipulations of skin temperature affect human sleep and vigilance, presumably by influencing neuronal systems involved in both thermal sensing and arousal regulation. We therefore examined whether fluctuations in skin temperature are associated with those in vigilance level under conditions similar to everyday-life situations requiring sustained attention. Eight healthy participants (30.1 +/- 8.1 years, M +/- SD) participated in a 2-day protocol, during which vigilance and skin temperature were assessed 4 times per day in a silent, dimly lit, temperature-controlled room. Vigilance was assessed by measuring reaction speed and lapses on a novel sustained vigilance task specifically designed to increase lapse rate and range of reaction times. Skin temperature was sampled at 30-second intervals from 3 locations: distal, intermediate, and proximal temperatures were obtained from the middle finger (T(finger) ), the wrist (T(wrist)), and the infraclavicular area (T(chest)), respectively. Furthermore, 3 distal to proximal gradients were calculated. Mixed effect regression analyses were used to evaluate the association of the fluctuations in temperatures and gradients and those in response speed and lapse probability. Especially the spontaneous fluctuations in proximal temperature were negatively associated with fluctuations in response speed and positively with lapse rate. If individual T(chest) temperature ranges were classified into 10 deciles, they accounted for 23% of the variance in response speed and 11% of the variance in lapse rate. The findings indicate coupling between the spontaneous fluctuations in skin temperature and vigilance during the day and are compatible with the hypothesis of overlap in brain networks involved in the regulation of temperature and vigilance. From an applied point of view, especially proximal skin temperature assessment may be of use in vigilance monitoring. PMID- 21252368 TI - Acute light exposure suppresses circadian rhythms in clock gene expression. AB - Light can induce arrhythmia in circadian systems by several weeks of constant light or by a brief light stimulus given at the transition point of the phase response curve. In the present study, a novel light treatment consisting of phase advance and phase delay photic stimuli given on 2 successive nights was used to induce circadian arrhythmia in the Siberian hamster ( Phodopus sungorus). We therefore investigated whether loss of rhythms in behavior was due to arrhythmia within the suprachiasmatic nucleus (SCN). SCN tissue samples were obtained at 6 time points across 24 h in constant darkness from entrained and arrhythmic hamsters, and per1, per2 , bmal1, and cry1 mRNA were measured by quantitative RT PCR. The light treatment eliminated circadian expression of clock genes within the SCN, and the overall expression of these genes was reduced by 18% to 40% of entrained values. Arrhythmia in per1, per2, and bmal1 was due to reductions in the amplitudes of their oscillations. We suggest that these data are compatible with an amplitude suppression model in which light induces singularity in the molecular circadian pacemaker. PMID- 21252369 TI - Lunar rhythms in the deep sea: evidence from the reproductive periodicity of several marine invertebrates. AB - While lunar rhythms are commonly documented in plants and animals living in terrestrial and shallow-water environments, deep-sea organisms have essentially been overlooked in that respect. This report describes evidence of lunar periodicity in the reproduction of 6 deep-sea species belonging to 2 phyla. Occurrences of gamete release in free spawners and larval release in brooders exhibited significant peaks around the new and full moons, respectively. The exact nature of this lunar period (endogenous or exogenous rhythm) and its adaptive significance in the deep sea remain elusive. Current knowledge suggests that proxies of moon phases at depth may include fluxes in particulate matter deposition, cyclic currents, and moonlight for species living in the disphotic zone. PMID- 21252370 TI - Students with reading and spelling disabilities: peer groups and educational attainment in secondary education. AB - The present study investigated whether the members of adolescents' peer groups are similar in reading and spelling disabilities and whether this similarity contributes to subsequent school achievement and educational attainment. The sample consisted of 375 Finnish adolescents whose reading and spelling disabilities were assessed at age 16 with the Finnish dyslexia screening test. The students also completed a sociometric nomination measure that was used to identify their peer groups. Register information on participants' school grades also was available, and educational attainment in secondary education was recorded 5 years after completion of the 9 years of basic education. The results revealed that the members of adolescent peer groups resembled each other in reading disabilities but not in those of spelling. Reading disabilities and academic achievement shared within the peer group also contributed to educational attainment in secondary education. Finally, reading disabilities played a larger role in educational attainment among males than among females. PMID- 21252371 TI - Assessing college-level learning difficulties and "at riskness" for learning disabilities and ADHD: development and validation of the learning difficulties assessment. AB - This article describes the development and validation of the Learning Difficulties Assessment (LDA), a normed and web-based survey that assesses perceived difficulties with reading, writing, spelling, mathematics, listening, concentration, memory, organizational skills, sense of control, and anxiety in college students. The LDA is designed to (a) map individual learning strengths and weaknesses, (b) provide users with a comparative sense of their academic skills, (c) integrate research in user-interface design to assist those with reading and learning challenges, and (d) identify individuals who may be at risk for learning disabilities and attention-deficit/hyperactivity disorder (ADHD) and who should thus be further assessed. Data from a large-scale 5-year study describing the instrument's validity as a screening tool for learning disabilities and ADHD are presented. This article also describes unique characteristics of the LDA including its user-interface design, normative characteristics, and use as a no-cost screening tool for identifying college students at risk for learning disorders and ADHD. PMID- 21252372 TI - Examining agreement and longitudinal stability among traditional and RTI-based definitions of reading disability using the affected-status agreement statistic. AB - Rates of agreement among alternative definitions of reading disability and their 1- and 2-year stabilities were examined using a new measure of agreement, the affected-status agreement statistic. Participants were 288,114 first through third grade students. Reading measures were Dynamic Indicators of Basic Early Literacy Skills Oral Reading Fluency and Nonsense Word Fluency, and six levels of severity of poor reading were examined (25th, 20th, 15th, 10th, 5th, and 3rd percentile ranks). Four definitions were compared, including traditional unexpected low achievement and three response-to-intervention-based definitions: low achievement, low growth, and dual discrepancy. Rates of agreement were variable but only poor to moderate overall, with poorest agreement between unexpected low achievement and the other definitions. Longitudinal stability was poor, with poorest stability for the low growth definition. Implications for research and practice are discussed. PMID- 21252373 TI - Students with LD in higher education: use and contribution of assistive technology and website courses and their correlation to students' hope and well being. AB - This study examined the extent and patterns of usage of web courses, and their contribution to the academic and social perceptions of 964 undergraduate students with and without learning disabilities studying in higher education. Students were asked to complete four questionnaires examining the usage patterns of various adaptive technologies and their contribution to the student. The questionnaires assessed Perceptions of Learning through Online Usage; Accessibility of Campus Computing; Hope Scale and Subjective Well-being Scale. A detailed examination of the usage patterns of online courses revealed that, compared to the comparison group, students with LD log more often into the course sites, going into the forum more frequently and leaving significantly more messages on the forum than students in the comparison group. Findings indicated that students with LD are more familiar with assistive technology and use it more than the comparison group. Students with LD reported higher scores on the Hope scale, they felt an increased drive to find different pathways to attain their goals, as well as being motivated to pursue those goals, and their subjective well-being was higher that of the students in the comparison group. PMID- 21252374 TI - Fact retrieval deficits in low achieving children and children with mathematical learning disability. AB - Using 4 years of mathematics achievement scores, groups of typically achieving children (n = 101) and low achieving children with mild (LA-mild fact retrieval; n = 97) and severe (LA-severe fact retrieval; n = 18) fact retrieval deficits and mathematically learning disabled children (MLD; n = 15) were identified. Multilevel models contrasted developing retrieval competence from second to fourth grade with developing competence in executing arithmetic procedures, in fluency of processing quantities represented by Arabic numerals and sets of objects, and in representing quantity on a number line. The retrieval deficits of LA-severe fact retrieval children were at least as debilitating as those of the children with MLD and showed less across-grade improvement. The deficits were characterized by the retrieval of counting string associates while attempting to remember addition facts, suggesting poor inhibition of irrelevant information during the retrieval process. This suggests a very specific form of working memory deficit, one that is not captured by many typically used working memory tasks. Moreover, these deficits were not related to procedural competence or performance on the other mathematical tasks, nor were they related to verbal or nonverbal intelligence, reading ability, or speed of processing, nor would they be identifiable with standard untimed mathematics achievement tests. PMID- 21252375 TI - Initial mental graphemic representation acquisition and later literacy achievement in children with language impairment: a longitudinal study. AB - The purpose of this study was to examine the relation between the ability to quickly acquire initial mental graphemic representations (MGRs) in kindergarten and fourth grade literacy skills in children with typical language (TL) and children with language impairment (LI). The study is a longitudinal extension of a study conducted by Wolter and Apel in which kindergarten children with LI and TL were administered early literacy measures as well as a novel written pseudoword task of MGR learning (spelling and identification of target pseudowords). In the current study (4 years later), the authors administered reading and spelling measures to 37 of the original 45 children (18 children with LI, 19 children with TL). The children with LI performed significantly lower than their peers with TL on all fourth grade literacy measures. For both groups, kindergarten initial MGR acquisition ability significantly related to fourth grade real-word reading and spelling. For the children with LI, kindergarten initial MGR acquisition ability also related to fourth grade pseudoword decoding and reading comprehension. Collectively, the findings suggest that initial MGR learning in kindergarten is an essential skill that may uniquely relate to later literacy abilities. PMID- 21252376 TI - Qualitative methods in health services and management research: pockets of excellence and progress, but still a long way to go. AB - The 10-year systematic review of published health services and management research by Weiner et al. (2011) chronicles the contributions of qualitative methods, highlights areas of substantial progress, and identifies areas in need of more progress. This article (Devers, 2011) discusses possible reasons for lack of progress in some areas--related to the under-supply of well-trained qualitative researchers and more tangible demand for their research--and mechanisms for future improvement. To ensure a robust health services research toolbox, the field must take additional steps to provide stronger education and training in qualitative methods and more funding and publication opportunities. Given the rapidly changing health care system post the passage of national health reform and the chalresearch issues associated with it, the health services research and management field will not meet its future challenges with quantitative methods alone or with a half-empty toolbox. PMID- 21252378 TI - A concise equation that captures the essential elements of one-way sensitivity analyses in health economic models. AB - OBJECTIVE: Sensitivity analyses are often performed on only a limited number of variables without justification of the choice of variables and range of each variable. External parties such as health authorities are increasingly requiring submission of the actual model, often in order to test the robustness of the outcomes of the model by performing additional sensitivity analyses. The objective of this work was to develop an alternative method to capture the critical issues of a sensitivity analysis in a health economic model, especially regarding the selection of variables and determining the range for each variable. Apart from external parties such as health authorities, journal readers who want to perform their own sensitivity analysis but do not have access to the model may find this useful. METHODS AND RESULTS: Statistical methods based on Markov chain modeling and regression analysis, using the framework of the Taylor series expansion around a point, are used to derive an equation for 1-way sensitivity analyses. In particular, equations for costs and effects are being developed, from which the cost-effectiveness ratio is built. The article shows the feasibility of such equations for the execution of 1-way sensitivity analyses. CONCLUSION: An equation that can be derived in the manner described in this article provides a substantial amount of information. The inclusion of such an equation in a report may increase transparency of the reporting of outcomes of health economic models. PMID- 21252379 TI - Genome-wide association: from confounded to confident. AB - Genome-wide association studies (GWAS) allow for a large number of samples to be assayed simultaneously, using a genome-wide tagging single nucleotide polymorphism (SNP) approach. The initial boon of success from disease studies such as macular degeneration and inflammatory bowel disease has been mitigated by lack of genome-wide significance for psychiatric disorders and related traits, despite evaluations of large populations. In addition to SNP genotypes, which are common variants typically attributing small or modest relative risk, copy number variations can be detected based on the same data set. Several rare recurrent copy number variations have been associated with psychiatric diseases in genome wide analyses. Proper and responsible study design, followed by rigorous data quality assessment of genomic matching of cases and controls, is most likely to uncover regions of significant association that replicate in independent cohorts, thereby maximizing the chance of significant and confident association. PMID- 21252380 TI - Prospects of statins in Parkinson disease. AB - Parkinson disease (PD) is second only to Alzheimer disease as the most common neurodegenerative disorder in humans. Despite intense investigations, no effective therapy is available to halt the progression of PD. Although statins are widely used cholesterol-lowering drugs throughout the world, recent studies suggest that these drugs modulate neurodegeneration-related signaling processes and may be beneficial for PD. Simvastatin is the most potent statin in crossing the blood-brain barrier, and this particular statin drug negatively correlates with the incidence of PD and shows efficacy in animal models of PD. However, PD mainly occurs in the aging population, who are more vulnerable to cholesterol or lipid-related disorders, raising questions whether this possible beneficial effect of statins in PD patients is cholesterol dependent or cholesterol independent. This article presents data on the therapeutic efficacy of simvastatin in a chronic MPTP model of PD, reviews recent literature, and discusses the pros and cons of statin therapy in PD. PMID- 21252381 TI - Courtship, competition, and the pursuit of attractiveness: mating goals facilitate health-related risk taking and strategic risk suppression in women. AB - Two experiments explored the possibility that specific health risks observed among young women may be influenced by attractiveness-enhancement goals associated with mating. Study 1 (n=257) demonstrated that priming women with intersexual courtship and intrasexual competition increased their willingness to go tanning and take dangerous diet pills. Study 2 (n=148) conceptually replicated these results and revealed that increased willingness to take these risks is mediated by diminished feelings of vulnerability to the negative health effects associated with these behaviors when mating goals are salient. Findings provide evidence that mating goals play a role in the continued popularity of these dangerous behaviors in women. Furthermore, the current results bridge the existing gap between health belief and self-presentational models of risk behaviors to yield novel insights into the psychology of risk taking. PMID- 21252382 TI - The big, the rich, and the powerful: physical, financial, and social dimensions of dominance in mating and attraction. AB - Dominance is a key feature on which romantic partners are evaluated, yet there is no clear consensus on its definition. In Study 1 (N=305), the authors developed scales to measure three putatively distinct dimensions of dominance: social, financial, and physical. In Study 2 (N=308), the authors used their scales in a mate-selection paradigm and found that women perceived physical dominance to be related to both attractiveness and social dominance. For both sexes, attractiveness predicted desirability for a one-night stand, whereas attractiveness and agreeableness were predictors of desirability for a serious relationship. In Study 3 (N=124), the authors surveyed romantic partners in monogamous relationships and found that although aspects of a partner's dominance financial for women and social for men-played a bivariate role in relationship satisfaction, agreeableness was the strongest predictor of current and future relationship satisfaction and the only significant predictor of relationship dissolution. PMID- 21252383 TI - Helping patients help themselves: chronic disease self-management interventions. PMID- 21252384 TI - The midwest nursing research society advances science to improve health. PMID- 21252385 TI - Biologically inspired phylogenetic models strongly outperform the no common mechanism model. AB - But Tuffley and Steel (1997) introduced a model called No Common Mechanism (NCM), in which characters may-but are not required to-vary their relative rates independently, both within and between branches. Because the independent variation is taken only as a possibility, not as a requirement, NCM would apply to almost any situation, and so may be accepted as realistic. This is useful because Tuffley and Steel also showed that maximum likelihood under NCM selects the same trees as does parsimony. With the realistic NCM in the background, then, most parsimonious trees have greatest power to explain available observations. Farris (2008). PMID- 21252386 TI - Phylogenetic utility of nuclear introns in interfamilial relationships of Caniformia (order Carnivora). AB - The monophyletic group Caniformia (dog-like carnivores) in the order Carnivora comprises 9 families. Except for the general consensus for the earliest divergence of Canidae and the grouping of Procyonidae and Mustelidae, conflicting phylogenetic hypotheses exist for the other caniformian families. In the present study, a data set comprising > 22 kb of 22 nuclear intron loci from 16 caniformian species is used to investigate the phylogenetic utility of nuclear introns in resolving the interfamilial relationships of Caniformia. Our phylogenetic analyses support Ailuridae as the sister taxon to a clade containing Procyonidae and Mustelidae, with Mephitinae being the sister taxon to all of them. The unresolved placements of Ursidae and Pinnipeds here emphasize a need to add more data and include more taxa to resolve this problem. The present study not only resolves some of the ambiguous relationships in Caniformia phylogeny but also shows that the noncoding nuclear markers can offer powerful complementary data for estimating the species tree. None of the newly developed introns here have previously been used for phylogeny reconstruction, thus increasing the spectrum of molecular markers available to mammalian systematics. Interestingly, all the newly developed intron data partitions exhibit intraindividual allele heterozygotes (IIAHs). There are 115 cases of IIAHs in total. The incorporation of IIAHs into phylogenetic analysis not only provides insights into the interfamilial relationships of Caniformia but also identifies two potential hybridization events occurred within Ursidae and Otariidae, respectively. Finally, the powers and pitfalls of phylogenetics using nuclear introns as markers are discussed in the context of Caniformia phylogeny. PMID- 21252387 TI - Consequences of different null models on the tree shape bias of supertree methods. PMID- 21252389 TI - A simplified model of screening questionnaire and home monitoring for obstructive sleep apnoea in primary care. AB - BACKGROUND: To address the growing burden of disease and long waiting lists for sleep services, a simplified two-stage model was developed and validated for identifying obstructive sleep apnoea (OSA) in primary care using a screening questionnaire followed by home sleep monitoring. METHODS: 157 patients aged 25 70 years attending their primary care physician for any reason at six primary care clinics in rural and metropolitan regions of South Australia participated. The first 79 patients formed the development group and the next 78 patients the validation group. A screening questionnaire was developed from factors identified from sleep surveys, demographic and anthropometric data to be predictive of moderate to severe OSA. Receiver operating characteristic (ROC) curve analysis was used to validate the two-channel ApneaLink device against full polysomnography. The diagnostic accuracy of the overall two-stage model was then evaluated. RESULTS: Snoring, waist circumference, witnessed apnoeas and age were predictive of OSA and incorporated into a screening questionnaire (ROC area under curve (AUC) 0.84, 95% CI 0.75 to 0.94, p<0.001). ApneaLink oximetry with a 3% dip rate was highly predictive of OSA (AUC 0.96, 95% CI 0.91 to 1.0, p<0.001). The two-stage diagnostic model showed a sensitivity of 0.97 (95% CI 0.81 to 1.00) and specificity of 0.87 (95% CI 0.74 to 0.95) in the development group, and a sensitivity of 0.88 (95% CI 0.60 to 0.98) and specificity of 0.82 (95% CI 0.70 to 0.90) in the validation group. CONCLUSION: A two-stage model of screening questionnaire followed by home oximetry can accurately identify patients with OSA in primary care and has the potential to expedite care for patients with this common sleep disorder. PMID- 21252388 TI - Clinical and laboratory features distinguishing pandemic H1N1 influenza-related pneumonia from interpandemic community-acquired pneumonia in adults. AB - BACKGROUND: Early identification of patients with H1N1 influenza-related pneumonia is desirable for the early instigation of antiviral agents. A study was undertaken to investigate whether adults admitted to hospital with H1N1 influenza related pneumonia could be distinguished clinically from patients with non-H1N1 community-acquired pneumonia (CAP). METHODS: Between May 2009 and January 2010, clinical and epidemiological data of patients with confirmed H1N1 influenza infection admitted to 75 hospitals in the UK were collected by the Influenza Clinical Information Network (FLU-CIN). Adults with H1N1 influenza-related pneumonia were identified and compared with a prospective study cohort of adults with CAP hospitalised between September 2008 and June 2010, excluding those admitted during the period of the pandemic. RESULTS: Of 1046 adults with confirmed H1N1 influenza infection in the FLU-CIN cohort, 254 (25%) had H1N1 influenza-related pneumonia on admission to hospital. In-hospital mortality of these patients was 11.4% compared with 14.0% in patients with inter-pandemic CAP (n=648). A multivariate logistic regression model was generated by assigning one point for each of five clinical criteria: age <= 65 years, mental orientation, temperature >= 38 degrees C, leucocyte count <= 12 * 10(9)/l and bilateral radiographic consolidation. A score of 4 or 5 predicted H1N1 influenza-related pneumonia with a positive likelihood ratio of 9.0. A score of 0 or 1 had a positive likelihood ratio of 75.7 for excluding it. CONCLUSION: There are substantial clinical differences between H1N1 influenza-related pneumonia and inter-pandemic CAP. A model based on five simple clinical criteria enables the early identification of adults admitted with H1N1 influenza-related pneumonia. PMID- 21252390 TI - Detection of allergenic compounds using an IL-4/luciferase/CNS-1 transgenic mice model. AB - The interleukin-4 (IL-4) signaling cascade has been identified as a potentially important pathway in the development of allergies. The principal objective of this study was to produce novel transgenic (Tg) mice harboring the luciferase gene under the control of the human IL-4 promoter and the enhancer of IL-4 (CNS 1), in an effort to evaluate three types of allergens including a respiratory sensitizer, vaccine additives, and crude extracts of natural allergens in vivo. A new lineage of Tg mice was generated by the microinjection of pIL-4/Luc/CNS-1 constructs into a fertilized mice egg. The luciferase activity was successfully regulated by the IL-4 promoter in splenocytes cultured from IL-4/Luc/CNS-1 Tg mice. From the first five founder lines, one (#57) evidencing a profound response to ovalbumin was selected for use in evaluating the allergens. Additionally, the lungs, thymus, and lymph nodes of IL-4/Luc/CNS-1 Tg mice evidenced high luciferase activity in response to allergens such as phthalic anhydride (PA), trimellitic anhydride, ovalbumin, gelatin, Dermatophagoides pteronyssinus extracts, and Japanese cedar pollen, whereas key allergy-related indicators including ear thickness, Immunoglobulin E concentration, and the infiltration of inflammatory leukocytes in response to PA were unaltered in the Tg mice relative to the non-Tg mice. Furthermore, the expression levels of endogenous type 2 helper T cells cytokines and proinflammatory cytokines were similarly increased in these organs of IL-4/Luc/CNS-1 Tg mice in response to allergens. These results indicate that IL-4/Luc/CNS-1 Tg mice may be used as an animal model for the evaluation and prediction of the human body response to a variety of allergens originating from the environment and from certain industrial products. PMID- 21252391 TI - Toxicokinetics of mercury after long-term repeated exposure to thimerosal containing vaccine. AB - The preservative thimerosal contains ethyl mercury (EtHg). Concerns over possible toxicity have re-emerged recently due to its presence in (swine and other) flu vaccines. We examined the potential accumulation of mercury in adults given repeated injections of a thimerosal-preserved vaccine for many years. Fifteen female patients were recruited from an outpatient clinic running a clinical trial with repeated injections (1 ml every 3-4 weeks) of a staphylococcus toxoid vaccine containing 0.01% thimerosal to treat chronic fatigue syndrome. Fifteen untreated female patients with the same diagnoses served as controls. Blood samples were taken before injecting the vaccine, 1 day later, about 2 weeks later, and just before the next injection. In the 15 controls, samples were taken twice. Blood was analyzed for total mercury and EtHg. The toxicokinetics were assessed for each patient separately as well as with a population-based pharmacokinetic model. Total mercury in blood increased on Day 1 in all treated patients (median: 0.33, range: 0.17-1.3 MUg/l), as did EtHg (median: 0.14 MUg/l, range: 0.06-0.43 MUg/l). After a few weeks, levels were back to normal and similar to those in controls. Levels of methyl mercury (MeHg; from fish consumption) were much higher than those of EtHg. After exclusion of an outlier, the mean half-life in a population-based model was 5.6 (95% CI: 4.8-6.3) days. The results indicate that mercury from thimerosal is not accumulated in blood in adults. This is in accordance with short half-lives and rapid metabolism of EtHg to inorganic mercury. PMID- 21252392 TI - Cadmium induced p53-dependent activation of stress signaling, accumulation of ubiquitinated proteins, and apoptosis in mouse embryonic fibroblast cells. AB - The tumor suppressor oncoprotein, p53, is a critical regulator of stress-induced growth arrest and apoptosis. p53 activity is regulated through the ubiquitin proteasome system (UPS) with stress-induced disruption leading to increased accumulation of p53, resulting in growth arrest. In the present study, we investigate the role of p53 to determine sensitivity to cadmium (Cd) and whether induction of stress signaling responses and perturbation of the UPS are involved in Cd-induced cytotoxicity and apoptosis. We treated synchronously cultured p53 transgenic mouse embryonic fibroblasts, both wild-type p53+/+ and knockout p53-/- cells, with cadmium chloride (Cd, 0.5-20MUM) for 24 h. Cd-induced cytotoxicity was assessed by cellular morphology disruption and neutral red dye uptake assay. Proteins in the stress signaling pathway, including p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK); ubiquitination, such as high-molecular weight of polyubiquitinated proteins (HMW-polyUb); and apoptotic pathways, were all measured. We found that Cd induced p53-dependent cytotoxicity in the p53+/+ cells, which exhibited a twofold greater sensitivity. We observed a dose-dependent stimulation of p38 MAPK and SAPK/JNK phosphorylation that corresponded to accumulation of HMW-polyUb conjugates and lead to the induction of apoptosis, as evidenced by the elevation of cleaved caspase-3. Our study suggests that Cd-mediated cytotoxicity and induction of stress signaling responses, elevated accumulation of HMW-polyUb conjugates, and resulting apoptosis are all dependent on p53 status. PMID- 21252394 TI - Embryoprotective role of endogenous catalase in acatalasemic and human catalase expressing mouse embryos exposed in culture to developmental and phenytoin enhanced oxidative stress. AB - Reactive oxygen species (ROS) are implicated in spontaneous and xenobiotic enhanced embryopathies, and protein therapy with exogenous catalase suggests an embryoprotective role, although embryonic catalase activity is only about 5% of adult activity. Using mutant catalase-deficient (acatalasemic, aCat) mice and transgenic mice expressing human catalase (hCat, enhanced catalase activity) compared with a confirmed outbred CD-1 mouse model, we investigated the protective importance of constitutive embryonic catalase against endogenous ROS and the ROS-initiating teratogen phenytoin in embryo culture. Vehicle-exposed aCat and hCat embryos, respectively, exhibited reduced and enhanced catalase activity compared with wild-type (WT) controls, with conversely enhanced and reduced spontaneous embryopathies. Phenytoin was embryopathic in all strains without altering catalase activity but less so in the WT embryos for the aCat and hCat strains, which exhibited about half the catalase activity of CD-1 embryos. Phenytoin, respectively, enhanced and reduced embryopathies in aCat and hCat embryos. Among aCat embryos exposed to phenytoin, embryopathies increased with decreasing catalase activity and were completely blocked by addition of exogenous catalase, which increased embryonic catalase activity to WT levels. These results provide the first direct evidence that (1) the low level of constitutive embryonic catalase protects the conceptus from developmental and xenobiotic enhanced oxidative stress and (2) embryonic variations in activity of this enzyme affect development. PMID- 21252393 TI - Increased sensitivity of estrogen receptor alpha overexpressing antral follicles to methoxychlor and its metabolites. AB - Methoxychlor (MXC), an organochlorine pesticide, and its metabolites, mono hydroxy MXC (MOH) and bis-hydroxy MXC (HPTE) are known ovarian toxicants and can cause inhibition of antral follicle growth. Since these chemicals bind to estrogen receptor alpha (ESR1), we hypothesized that ovaries overexpressing ESR1 (ESR1 OE) would be more susceptible to toxicity induced by MXC and its metabolites because the chemicals can bind to more ESR1 in the antral follicles. We cultured antral follicles from controls and ESR1 OE mouse ovaries with either the vehicle dimethylsulfoxide (DMSO), MXC, MOH, or HPTE. The data show that at 96 h, the cultured antral follicles from ESR1 OE antral follicles are more susceptible to toxicity induced by MXC, MOH, and HPTE because low doses of these chemicals cause follicle growth inhibition in ESR1 OE mice but not in control mice. On comparing gene expression levels of nuclear receptors in the cultured antral follicles of ESR1 OE and control follicles, we found differential messenger RNA (mRNA) expression of Esr1, estrogen receptor beta (Esr2), androgen receptor (Ar), progesterone receptor (Pr), and aryl hydrocarbon receptor (Ahr) between the genotypes. We also analyzed mRNA levels of Cyp3a41a, the enzyme metabolizing MOH and HPTE, in the cultured follicles and found that Cyp3a41a was significantly lower in DMSO-treated ESR1 OE follicles compared with controls. In ESR1 OE livers, we found that Cyp3a41a levels were significantly lower compared with control livers. Collectively, these data suggest that MXC and its metabolites cause differential gene expression in ESR1 OE mice compared with controls. The results also suggest that the increased sensitivity of ESR1 OE mouse ovaries to toxicity induced by MXC and its metabolites is due to low clearance of the metabolites by the liver and ovary. PMID- 21252395 TI - Dramatical recovery of a mechanical ventilatory dependent extremely low birth weight premature infant after Nissen fundoplication. AB - Gastroesophageal reflux disease (GERD) is a well-recognized condition in neonatal period. It is common in preterm infants, clinical spectrum is wide and the management may be difficult. Nissen fundoplication operation is well established as effective treatment for GERD in most children intractable to medical therapy, but its role in neonates is less clear and its effect in premature infants is not well established. Here, we report a case of a premature infant, who had severe respiratory system problems that needed mechanical ventilation despite all medical therapy, and demonstrate dramatical clinical and radiological improvement as a result of Nissen fundoplication surgery. PMID- 21252396 TI - The development and use of algorithms for diagnosing and choosing treatment of ostomy complications: results of a prospective evaluation . AB - Stoma complications are classified and treated based on the etiology, pathology, location, and clinical presentation of the complication. Clinical assessments and descriptions of abdominal stomal topography differ among care providers, hampering interpretation and communication. Using existing literature and clinical experience at the State Scientific Centre of Coloproctology in Russia, algorithms were developed to facilitate a uniform approach to the diagnosis and choice of treatment of ostomy complications. The algorithms consist of a definite sequence of explicit step-by-step procedures, including visual inspection, digital exploration, and instrumental exploration, for determining whether complications should be categorized and treated as a stoma problem or peristomal skin disorder. The algorithm was subsequently used by nonexpert nurses for all consecutive patients who visited the clinic during a 2-year period. Of the 1,427 patients seen, 553 (38.8%) had 742 complications. Of those, 387 were stoma complications and 355 were classified as peristomal skin disorders (eg, contact dermatitis, hypergranulation of the skin, allergic dermatitis, folliculitis, psoriasis and herpes). Of the 553 patients with complications, the most frequent complications were found to be contact dermatitis (184 patients, 33.3%), parastomal hernia (97, 17.5%), and mucocutaneous separation (72, 13.0%); 176 patients were referred to surgery and 377 received conservative treatment. Although the algorithms remain to be validated, the authors believe that studying the manifestation and causes of complications will help in the selection of justified treatments, which will eventually reduce the number of complications and improve the quality of stoma care. PMID- 21252397 TI - Bedside management of an abdominal wound containing an enteroatmospheric fistula: a case report. AB - Enteroatmospheric fistulae (EAF) - unnatural connections between the bowel and the outside environment - are a feared complication of major abdominal operations. EAF pose a life-threatening risk to patients already weakened by surgical insult by altering fluid and electrolyte balance and fostering malnutrition. The authors describe a method of wound management for a 64-year-old morbidly obese woman with a history of coronary artery disease, diabetes mellitus, and bipolar disorder who developed a large abdominal wound containing multiple high-output EAF after an incarcerated abdominal hernia repair, wound infection, and subsequent laparotomy and lysis of adhesions followed by graft placement and negative pressure wound therapy. The volume, consistency, and location of the EAF caused commercial negative pressure devices to fail and simple gauze dressings were ineffective in maintaining a clean wound base and containing odor. Effluent collection and wound healing was achieved utilizing a modified method of EAF management that included two connecting rubberized catheter drains and continuous wound irrigation with wall suction and cotton gauze for debridement. Surgical EAF closure was successful after 6 months of care. This method provided a satisfactory balance between the diagnosis of EAF and the readiness to meet the physiologic demands of definitive surgical treatment. PMID- 21252398 TI - Stomal mucocutaneous dehiscence as a complication of a dynamic wound closure system following laparostomy: a case report. AB - Dynamic retention suture techniques that allow gradual reapproximation of abdominal midline muscles and fascia as well as sufficient freedom of movement for breathing and patient care commonly are used to prevent lateral retraction of the abdominal fascia in patients whose abdominal wound closure must be delayed. A 58-year-old otherwise healthy man was admitted with severe abdominal sepsis and following surgery, which included the creation of a stoma, a dynamic wound closure system was applied. Mucocutaneous stomal dehiscence was observed a few days after starting the treatment. The complication was believed to have occurred as a result of traction on the proximal end of the stoma (the bowel inside the abdomen) due to tension on the sutures of the small part of the bowel outside the abdomen. Definite, primary closure of the abdominal fascia was achieved after 16 days, at which point the stoma was reinserted with good results. Since using a modified procedure that involves cutting a groove in the protective drape and carefully placing two flaps around the stoma, this complication has not been observed with similar patients in the authors' facility. This complication is not unique to this wound closure system; it also has been reported with other treatment modalities such as negative pressure wound therapy. The relatively small number of patients requiring delayed closure of the abdomen, coupled with the uniqueness of each case due to a wide variety of indications and comorbidities, hampers the development of evidence-based guidelines of care for these patients. A worldwide data exchange that includes patient experiences and descriptions of successful and failed attempts to address problems and complications in these patients is necessary. In the meantime, experiences with these types of wounds need to be shared in the literature. PMID- 21252399 TI - Non-lambertian reflectance modeling and shape recovery of faces using tensor splines. AB - Modeling illumination effects and pose variations of a face is of fundamental importance in the field of facial image analysis. Most of the conventional techniques that simultaneously address both of these problems work with the Lambertian assumption and thus fall short of accurately capturing the complex intensity variation that the facial images exhibit or recovering their 3D shape in the presence of specularities and cast shadows. In this paper, we present a novel Tensor-Spline-based framework for facial image analysis. We show that, using this framework, the facial apparent BRDF field can be accurately estimated while seamlessly accounting for cast shadows and specularities. Further, using local neighborhood information, the same framework can be exploited to recover the 3D shape of the face (to handle pose variation). We quantitatively validate the accuracy of the Tensor Spline model using a more general model based on the mixture of single-lobed spherical functions. We demonstrate the effectiveness of our technique by presenting extensive experimental results for face relighting, 3D shape recovery, and face recognition using the Extended Yale B and CMU PIE benchmark data sets. PMID- 21252400 TI - Tiny videos: a large data set for nonparametric video retrieval and frame classification. AB - In this paper, we present a large database of over 50,000 user-labeled videos collected from YouTube. We develop a compact representation called "tiny videos" that achieves high video compression rates while retaining the overall visual appearance of the video as it varies over time. We show that frame sampling using affinity propagation-an exemplar-based clustering algorithm-achieves the best trade-off between compression and video recall. We use this large collection of user-labeled videos in conjunction with simple data mining techniques to perform related video retrieval, as well as classification of images and video frames. The classification results achieved by tiny videos are compared with the tiny images framework [24] for a variety of recognition tasks. The tiny images data set consists of 80 million images collected from the Internet. These are the largest labeled research data sets of videos and images available to date. We show that tiny videos are better suited for classifying scenery and sports activities, while tiny images perform better at recognizing objects. Furthermore, we demonstrate that combining the tiny images and tiny videos data sets improves classification precision in a wider range of categories. PMID- 21252401 TI - Removal of partial occlusion from single images. AB - This paper examines large partial occlusions in an image which occur near depth discontinuities when the foreground object is severely out of focus. We model these partial occlusions using matting, with the alpha value determined by the convolution of the blur kernel with a pinhole projection of the occluder. The main contribution is a method for removing the image contribution of the foreground occluder in regions of partial occlusion, which improves the visibility of the background scene. The method consists of three steps. First, the region of complete occlusion is estimated using a curve evolution method. Second, the alpha value at each pixel in the partly occluded region is estimated. Third, the intensity contribution of the foreground occluder is removed in regions of partial occlusion. Experiments demonstrate the method's ability to remove the effects of partial occlusion in single images with minimal user input. PMID- 21252402 TI - [Interrelation of hyperactivity of bladder and infravesical obstruction in patients with benign prostate hyperplasia]. AB - The analysis of the data presented in the review convincingly shows the correlation between infravesical obstruction (IVO), caused by pressing of urethra by enlarged prostate, and the development of detrusor hyperactivity. The clinical importance of correlation between IVO and hyperactivity of the detrusor is convincingly illustrated by different results of effectiveness of surgical treatment of patients with benigh prostate hyperplasia (BPH) with and without hyperactivity of bladder. In patients with BPH and hyperactivity of bladder the probability of irritative symptoms is high. This data proves the necessity of the further study of the pathogenesis of development of bladder hyperactivity in patients with BPH, and the importance of a preoperative estimation of functional frustration of the bladder. PMID- 21252403 TI - High seroprevalence of Chlamydia trachomatis in newly diagnosed human immunodeficiency virus patients in georgia. AB - Due to the shared routes of transmission, co-infection with Human Immunodeficiency Virus (HIV) and other sexually transmitted infections (STIs) is common. There is strong evidence of bidirectional interactions between HIV and ulcerative STIs. Recent studies have also shown importance of non-ulcerative inflammatory STIs in the acquisition of HIV. The incidence of HIV and Chlamydia in Georgia has risen every year. We explored the extent of the problem of co infection with C. trachomatis in HIV patients in the country. Study included 234 consecutive patients diagnosed with HIV from September 2008 through May 2009. Of them, approximately two-thirds were male 162 (69.23%), up to 44% (102) of patients had more than one lifetime sexual partner and one fifth of patients reported prior history of STIs. The seroprevalence of C. trachomatis in our study was 23.93% (95% CI: 18.61%-29.92%). In multivariate analysis the strongest predictors of C. trachomatis infection were history of STI (PR 1.94, 95% CI: 1.22 3.07) and female gender (PR 1.79, 95% CI: 1.11-2.87), while younger age and not being in marriage showed borderline significance. Findings of our study have important public health and clinical implications. Data suggest that STIs may play important role in increasing heterosexual transmission of HIV in Georgia. Efforts should be made to expand HIV screening programs. Further research is needed to better understand the role of inflammatory STIs in spreading HIV. PMID- 21252404 TI - HLA-B*5701 genetic screening prior to abacavir prescription in Georgia. AB - A hypersensitivity reaction to abacavir develops in approximately 2-8% of HIV patients receiving this drug and is strongly associated with presence of the human leukocyte antigen (HLA)-B*5701. Screening for HLA-B*5701 reduces the risk of developing an abacavir hypersensitivity reaction. The carriage rate of HLA B*5701 has not been studied in Georgia before 2009. Objective of the study was to determine HLA-B*5701 prevalence in HIV-infected patients in Georgia. One hundred and sixty HIV positive patients attending Georgian Infectious Diseases, AIDS and Clinical Immunology Research Center in 2009 were recruited for the study. None of the patients had previously been treated with abacavir. Blood samples were collected and screened for HLA-B*5701 prior to abacavir prescription. Of 160 patients recruited 9 tested HLA B*5701 positive - 5.6% (95% CI: 2.6-10.4%). Of these nine patients 7 were males (male prevalence: 6.5%, 95% CI: 2.6-12.9 %) and 2 females (female prevalence: 4.8%, 95% CI: 0.6-16.2%). The first prospective study of HLA-B*5701 prevalence in Georgia show similar results to the results of other studies. Abacavir still remains one of the key drugs of antiretroviral regimens in Georgia and other countries. Therefore, prospective HLA-B*5701 screening should be implemented in all settings where abacavir is widely used to guide selection of ART regimens and to reduce the risk of potentially life threatening hypersensitivity reaction. PMID- 21252405 TI - Neuroendocrine foundation of maternal-child attachment. AB - Attachment between mother and child is the unique and complex type of relationship that ensures safety and nurturing of a child in the beginning and effective functioning and ability to establish relationships later on. Maternal behavior is generally known to be influenced by multiple psychosocial factors. However they often fail to explain the deviations in maternal behavior that emphasizes the importance and necessity of investigating involved physiological mechanisms. Series of the studies performed in animal models demonstrated that decline in progesterone level on the background of increasing estradiol concentration prepares brain for the action of progesterone and prolactin that are responsible for the rapid onset of maternal behavior postpartum. However the results of another group of researchers failed to prove the unique importance of oxytocin. Other substances such as epinephrine, norepinephrine, serotonin were also suggested though diversity in the study results interferes with making definitive conclusions. Preliminary studies suggest that hormones are also involved in induction of maternal behavior in primate and human beings. Level of oxytocin appeared to be highest during first hours after parturition and is stimulated by a newborn suckling activities and newborn touching the breast. Lower rates of anxiety and aggression and higher rates of social behavior was demonstrated in mothers having received intrapartum oxytocin infusion. However other components of maternal behavior have not been studied in these women. Controversial results have been published concerning the importance of cortisol. A group of researchers demonstrated that mothers with higher cortisol levels were less caring and more aggressive towards their offspring though according to another group of researchers higher level of cortisol is associated with increased alertness of mother towards smell and sounds produced by a child. The literature review revealed that the number of conducted studies is large though limited to animal models, controversial and insufficient to describe the biological foundation of maternal behavior in human. Thus great deal of investigations should be done to study the biological foundation of maternal behavior induction and maintenance, mechanisms of hormonal action and correlation between the biological and non-biological, namely psycho-social factors. New discoveries in this field will greatly contribute to child global development as it provides clues to the improvement of maternal-child attachment. PMID- 21252406 TI - HIV/AIDS prevalence in the Southern Caucasus. AB - According to statistics, Armenia, Azerbaijan and Georgia, are the countries with low prevalence of HIV (<0.3%). Yet the dramatic almost nine fold increases in registered HIV cases in the region between 2000 and 2008 (from 574 to 5323) remain a cause for serious concern. This report summarizes and compares the latest data on the epidemiology of HIV/AIDS in Southern Caucasus: Armenia, Azerbaijan and Georgia. It also provides a comparison with HIV/AIDS situation in Eastern Europe. The work is mainly based on the review of UNAIDS 2010 country progress reports and end-year reports of HIV/AIDS Surveillance in Europe. Tables and graphs have been created to summarize the obtained information and to improve the analysis. Trends in HIV/AIDS spread in Southern Caucasus are similar to trends in Eastern Europe: the number of HIV and AIDS cases continues to increase. The vast majority of people living with HIV/AIDS were aged 25-49-years at the time of diagnosis. The official information confirms that the epidemic in Southern Caucasus remains located among males (with 83.8% in Azerbaijan, 75% in Georgia, and 73% in Armenia) and most-at-risk populations. In Georgia and Azerbaijan, as in Eastern Europe, the predominant mode of transmission is through injecting drug use (58.8% and 64.2%, respectively), while in Armenia over the last several years the transmission has shifted from injecting drug use to heterosexual spread (50.2%). The second reported mode of transmission in Georgia and Azerbaijan is unprotected heterosexual activity (34.9% and 23.4%, respectively). Medical transmission, mother to child transmission, and transmission among men who have sex with men are rare, typically comprising less than 3% of total registered transmission in each country of the region. As UNAIDS contends the prevalence values are underestimated, and the registered numbers of HIV/AIDS cases in the region do not reflect the actual spread of the infection. There is also a substantial discrepancy between the cumulative number of HIV/AIDS cases reported in the national case reporting systems and the HIV prevalence reported in surveys (high prevalence observed in IDUs in Armenia and Azerbaijan, and in MSM in Georgia). In the context of such underreporting, population-based and community-based HIV surveys have far better public health utility in estimating burden of HIV/AIDS than the case reporting system. PMID- 21252407 TI - [Hygienic assessment of irradiation doses of Mtskheta-Mtianeti region' population]. AB - Radionuclide content in the food and water in Mtskheta-Mtianeti region of Georgia has been studied, internal and total irradiation doses for the population have been defined and preventive measures for its reduction were detected. Internal irradiation dose for the population due to (40)K was identified as 1,58 mSv/y, total irradiation dose (external and internal irradiation) - 2,57 mSv/y, that is to some extent high than acceptable levels. To reduce the total irradiation dose of a population it is necessary to prohibit the use of high activity water for drinking; provision of the population with new sources of low activity water; minimize and control of irradiation doses from artificial sources including means of regulation of medical radiological procedures and rational use of fertilizers with (40)K content. PMID- 21252408 TI - [The role of seasonal circadian rhythms in hemodynamic regulation]. AB - The review analyzes the possible role of multioscillatory circadian system in the seasonal circadian variability of basic indices of cardiovascular system and probable mechanisms of development of changes in diurnal rhythms of the organism. It was postulated the close relationship between hemodynamic parameters and homeostatic mechanisms of circulation. The destruction of relationship may initiate the development of pathologic condition - desynchronizes. Studies suggest a potential role of relationship between circadian rhythms and secretion of vasoactive peptides, such as angiotensine, endothelins, sodium uretic peptide, endothelial relaxing factor and enkephalins, the circadian rhythmicity of receptor. It is suggested the necessity of investigation of circadian hemodynamic rhythms during desinchronoses formation in purpose of rational pharmacotherapy of different cardiovascular diseases. PMID- 21252409 TI - [Several indexes needed for evaluation of hypersensitive reactions of the medicine]. AB - Drug allergy represents the dominant problem of twenty first century. Number of heavy allergic reactions is increased that is obvious through the increasing number of hospitalizations. Mentioned problem is extended through the rapid development of pharmaceutical industry. Lots of drugs industrialized on a drug market aren't analyzed properly and give rise to undesirable allergic reactions. Diagnostics of drug allergy requests some methodical approaches: detailed collection of Allergic anamnesis and appropriate in vivo and in vitro test sampling. Questionnaire, formulated under the patronage of European Association of Allergologist and clinical Immunologists ensures standard directives for the collection of detailed allergic Anamnesis. Foreseeing the regional peculiarities, we have formulated the simplified version of the questionnaire. In case of positive answer analysis are accompanied and made by Allergologist who makes the sampling of in vivo and in vitro tests. PMID- 21252410 TI - The study of melatonin protective activity on pancreatic beta-cells under the condition of alloxan-induced diabetes during aging. AB - The aim of our research was to study the influence of melatonin on pancreatic beta-cells under the condition of alloxan-induced Diabetes Mellitus - especially in old age, when the mentioned disease frequently takes place. 56 male white rats were used in the study. Two age groups were selected: adult period of life and late senescent period of life. This number of rats was divided into three groups: I - experimental group (10 adult and 10 old animals), II - experimental group (10 adult and 10 old animals), and III - control group (8 adult and 8 old animals). On the 1st day of experiment the animals of I and II experimental groups were injected with alloxan at a single dose of 60 mg/kg (into the tail vein) for Diabetes Mellitus induction. The animals of II experimental group were also given melatonin (0,15mg/kg) daily during the 14 days. During the experiment 2 old rats from I experimental group died. In III - control group the intact animals have been used. After stopping of the experiment (15th day), under the ether narcosis the animals were sacrificed. The tissue taken from pancreas has been processed for electron microscopy. Ultrastructural study was performed using electronograms. In each experimental case 100 beta-cells have been studied.. Results of research were studied statistically using computer program SPSS v.12.The results of ultrastructural study of pancreatic beta-cells have shown that in mentioned cells of animals from I experimental group ultrastructural peculiarities are markedly changed as compared with the norm, and beta-cells' injury (in some cases - irreversible changes) are prominent. The mentioned changes are more prominent in old organisms, than in adult ones. In most of pancreatic beta-cells of animals from II experimental group ulstrastructural peculiarities are not changed as compared with the norm: ultrastructures of beta cells of animals from II experimental group in both age groups are markedly defended against the damage, which suggests that melatonin has a protective activity on pancreatic beta-cells. We recommend that melatonin be taken with anti diabetic drugs, especially in senescent period of life. PMID- 21252411 TI - [Structural reaction of cardiomyocytes in response to loading on voluntary running wheel]. AB - The aims of this study were to characterize the peculiarities of structural reorganization of right and left ventricular myocardium in response of physical load. Male laboratory white rats (2 month old) were choused in free spinning running wheel (n=5) for 1 month and 2 month (n=5), non-running animals (n=5) serve as control group. Blood acid-base balance and gases were carried out as tissue hypoxia control by Astrup micromethod. Heart weight and ventricular index were measured after rats killing by overdose of intraperitoneally injected pentobarbitone sodium. Cardiomyocytes morphological response were studied by histological and electron microscopical data, also by Selye staining results. Collecting data indicates that heart weight, cardiac muscle fibre cross-sectional area and ventricular index are significantly greater after 1 month physical load modeled by voluntary wheel running in this group. Acid-base balance parameters suggest the low tissues hypoxia and alveolar hypoventilation level that provides a physiologically suitable model to cardiac muscle hypertrophy in rats. In opposite, 2 month duration load acts on the right ventricular cardiomyocytes, including fuchsinophilic dystrophia and homogenization of myofibrils that we can refereed as "physical load induced cardiomyopathy" of right ventricle, so we conclude that this is not physiologically suitable exercise response. PMID- 21252412 TI - Treatment of experimental autoimmune encephalomyelitis by vitamin in animal model. AB - Study purposed to determine the effectiveness of vitamin treatment in experimental autoimmune encephalomyelitis (EAE) animal model of multiple sclerosis (MS) by comparing several blood serum inflammatory markers, neurological deficiency and histopathological changes in untreated and treated EAE animals. Eighteen, 9-13 week old, male Wistar rats were immunised by 100 MUl MOG injection. Clinical signs of EAE scored by a masked investigator. After EAE exposition all rats were divided equally as untreated control and experimental group treated by vitamins (E, C, D3). Blood was obtained from all rats before and after immunization and on 7th day of treatment. ELISA method was used to detect the serum cytokine contents of IL-6, IFN-gamma, IL-10. On 10th day of disease the rats were euthanized and transverse sections of spinal cord were divided in 16 areas with score of 1 for each area showing lymphocyte infiltration or demyelination. Mann-Whitney U-test was used for determining the level of significance of differences between sample means. On 7th day of treatment neurological deficiency stayed unchanged in control and was ameliorated in experimental group (p<0.05). Significant histopathological differences were found between control and experimental groups on 10th day of EAE. Serum levels of IFN gamma, IL-6 and IL-10 were elevated after exposition of EAE against healthy rats, while on 7th day of treatment the experimental group revealed the significant differences as compared to untreated control. Positive correlation was found between IL-6 and IFN-gamma serum contents and neurological deficiency on 7th day of disease (r=+0.53, p<0.02 and r=+0.49; p<0.01). PMID- 21252413 TI - Wettability of biomimetic thermally grown aluminum oxide coatings. AB - In this paper, wettability behavior of a rough but intrinsically hydrophilic oxide ceramic, formed via simple thermal oxidation of a commercial metallic alloy in laboratory air, has been analyzed. Drop shape analysis (DSA) revealed static water contact angles for the rough ceramic surfaces up to 128 degrees (greater than for TeflonTM). We propose the high apparent contact angles to be a result of surface roughening via the morphological changes of the oxide scale with oxidation conditions. The surface morphological changes occurring during the growth of the oxide film resulted in the formation of vertical platelets that ably shifted the wetting behavior from a Wenzel to an unstable Cassie-Baxter state. The platelet morphology of the ceramic resembles the structure of epicuticular waxes on certain species of superhydrophobic leaves. Moreover, surface textures for very short oxidation times were also found to increase hydrophilicity in the scale and reduce the contact angle by imparting a Wenzel state. Various characterization techniques (XRD, XPS, and SEM) were performed in order to detect the crystallographic phases in the scales, analyze carbon content and determine the morphology of the oxide layer. Morphological features of the oxide platelets were quantified and platelet width, spacing and height were found to correlate well with the apparent contact angle trend as a function of oxidation time. PMID- 21252414 TI - Bone marrow stromal cells with a combined expression of BMP-2 and VEGF-165 enhanced bone regeneration. AB - Bone graft substitutes with osteogenic factors alone often exhibit poor bone regeneration due to inadequate vascularization. Combined delivery of osteogenic and angiogenic factors from biodegradable scaffolds may enhance bone regeneration. We evaluated the effects of bone morphogenetic protein 2 (BMP2) and vascular endothelial growth factor (VEGF), combined with natural coral scaffolds, on the repair of critical-sized bone defects in rabbit orbits. In vitro expanded rabbit bone marrow stromal cells (BMSCs) were transfected with human BMP2 and VEGF165 genes. Target protein expression and osteogenic differentiation were confirmed after gene transduction. Rabbit orbital defects were treated with a coral scaffold loaded with BMP2-transduced and VEGF-transduced BMSCs, BMP2 expressing BMSCs, VEGF-expressing BMSCs, or BMSCs without gene transduction. Volume and density of regenerated bone were determined by micro-computed tomography at 4, 8, and 16 weeks after implantation. Neovascularity, new bone deposition rate, and new bone formation were measured by immunostaining, tetracycline and calcein labelling, and histomorphometric analysis at different time points. The results showed that VEGF increased blood vessel formation relative to groups without VEGF. Combined delivery of BMP2 and VEGF increased new bone deposition and formation, compared with any single factor. These findings indicate that mimicking the natural bone development process by combined BMP2 and VEGF delivery improves healing of critical-sized orbital defects in rabbits. PMID- 21252416 TI - Bio-magnetic signatures of fetal breathing movement. AB - The purpose of fetal magnetoencephalography (fMEG) is to record and analyze fetal brain activity. Unavoidably, these recordings consist of a complex mixture of bio magnetic signals from both mother and fetus. The acquired data include biological signals that are related to maternal and fetal heart function as well as fetal gross body and breathing movements. Since fetal breathing generates a significant source of bio-magnetic interference during these recordings, the goal of this study was to identify and quantify the signatures pertaining to fetal breathing movements (FBM). The fMEG signals were captured using superconducting quantum interference devices (SQUIDs) The existence of FBM was verified and recorded concurrently by an ultrasound-based video technique. This simultaneous recording is challenging since SQUIDs are extremely sensitive to magnetic signals and highly susceptible to interference from electronic equipment. For each recording, an ultrasound-FBM (UFBM) signal was extracted by tracing the displacement of the boundary defined by the fetal thorax frame by frame. The start of each FBM was identified by using the peak points of the UFBM signal. The bio-magnetic signals associated with FBM were obtained by averaging the bio-magnetic signals time locked to the FBMs. The results showed the existence of a distinctive sinusoidal signal pattern of FBM in fMEG data. PMID- 21252415 TI - Enhanced detection threshold for in vivo cortical stimulation produced by Hebbian conditioning. AB - Normal brain function requires constant adaptation, as an organism learns to associate important sensory stimuli with the appropriate motor actions. Neurological disorders may disrupt these learned associations and require the nervous system to reorganize itself. As a consequence, neural plasticity is a crucial component of normal brain function and a critical mechanism for recovery from injury. Associative, or Hebbian, pairing of pre- and post-synaptic activity has been shown to alter stimulus-evoked responses in vivo; however, to date, such protocols have not been shown to affect the animal's subsequent behavior. We paired stimulus trains separated by a brief time delay to two electrodes in rat sensorimotor cortex, which changed the statistical pattern of spikes during subsequent behavior. These changes were consistent with strengthened functional connections from the leading electrode to the lagging electrode. We then trained rats to respond to a microstimulation cue, and repeated the paradigm using the cue electrode as the leading electrode. This pairing lowered the rat's ICMS detection threshold, with the same dependence on intra-electrode time lag that we found for the functional connectivity changes. The timecourse of the behavioral effects was very similar to that of the connectivity changes. We propose that the behavioral changes were a consequence of strengthened functional connections from the cue electrode to other regions of sensorimotor cortex. Such paradigms might be used to augment recovery from a stroke, or to promote adaptation in a bidirectional brain-machine interface. PMID- 21252417 TI - Sensitivity of HRV parameters including pNNxx proven by short-term exposure to 2700 m altitude. AB - Analysis of heart rate variability (HRV) is increasingly applied in research and intervention. However, the sensitivity of the variety of HRV parameters for changes in cardiovascular reactivity remains unclear. This study investigated effect sizes of HRV parameters in an experimental field study, exposing persons to 2700 m altitude. Parameters analyzed were mean heart rate (HR), atrioventricular conduction time, SDNNi, rMSSD, pNN50, pNNxx (xx = pNN05, pNN10, pNN20, pNN25, pNN30, pNN40), LF, HF, LFnu, LF/HF ratio, and Total Power, as well as ratings of arousal and mood. Forty-five persons were taken to the Dachstein mountain by cable car. HRV parameters of 40 min epochs and ratings at 170 m and 2700 m were compared. At altitude, HR increased and HRV decreased in all parameters. Although moods were not changed, test persons experienced higher arousal at altitude. Besides for HR, analysis revealed the highest effect size for SDNNi, followed by pNN20 and pNN25 and was much lower for HF. As pNNxx parameters were highly correlated with HF, they are discussed to reflect vagal activity. Moreover, pNNxx parameters are clearly defined, whereas HF is susceptible to variations in computation; thus pNNxx parameters seem preferable due to higher effect sizes and better comparability. PMID- 21252418 TI - An automated method for cell-free layer width determination in small arterioles. AB - Histogram-based thresholding techniques utilized for cell-free layer width measurement in arteriolar flow may produce an overestimation of the layer width since they do not consider faint shaded regions near the vessel wall as part of the erythrocyte column. To address this problem, we developed a new method for detecting the boundary of the erythrocyte column based on an edge detection algorithm. This automated method (grayscale method) provides local detections of the inner vessel wall as well as the boundary between the cell-free layer and the erythrocyte column without binarization of grayscale images. The cell-free layer width measurements using the grayscale method and existing techniques (minimum method and Otsu's method) were compared with those determined manually in arteriolar flows of the rat cremaster muscle. In the absence of the shaded regions, values obtained by the grayscale method and minimum method were statistically in good agreement with the manual method but not in the case of Otsu's method. When the faint shaded regions were present, the grayscale method appeared to produce more accurate results than the minimum method and Otsu's method. PMID- 21252419 TI - A comparison of gold versus silver electrode contacts for high-resolution gastric electrical mapping using flexible printed circuit board arrays. AB - Stomach contractions are initiated and coordinated by electrical events termed slow waves, and slow wave abnormalities contribute to gastric motility disorders. Recently, flexible printed circuit board (PCB) multi-electrode arrays were introduced, facilitating high-resolution mapping of slow wave activity in humans. However PCBs with gold contacts have shown a moderately inferior signal quality to previous custom-built silver-wire platforms, potentially limiting analyses. This study determined if using silver instead of gold contacts improved flexible PCB performance. In a salt-bath test, modestly higher stimulus amplitudes were recorded from silver PCBs (mean 312, s.d. 89 uV) than those from gold (mean 281, s.d. 85 uV) (p < 0.001); however, the signal-to-noise ratio (SNR) was similar (p = 0.26). In eight in vivo experimental studies, involving gastric serosal recordings from five pigs, no silver versus gold differences were found in terms of slow wave amplitudes (mean 677 versus 682 uV; p = 0.91), SNR (mean 8.8 versus 8.8 dB; p = 0.94) or baseline drift (NRMS; mean 12.0 versus 12.1; p = 0.97). Under the prescribed conditions, flexible PCBs with silver or gold contacts provide comparable results in vivo, and contact material difference does not explain the performance difference between current-generation slow wave mapping platforms. Alternative explanations for this difference and the implications for electrode design are discussed. PMID- 21252420 TI - Electrochemical dechlorination of 2,4-dichlorophenol in aqueous solution on palladium-loaded meshed titanium electrode. AB - Electrochemical dechlorination of 2,4-dichlorophenol (2,4-DCP) in aqueous solution was investigated on palladium-loaded meshed titanium (Pd/Ti) electrode at ambient temperature. Pd/Ti electrode was prepared with an electrodepositing method. Scanning Electron Microscope (SEM) micrographs show that Pd microparticles uniformly disperse on the meshed Ti supporting electrode with spheroidal structure. Dechlorination experimental results indicate that, in aqueous solution, with the current efficiency of 24.3%, the removal efficiency of 100 mg/L 2,4-DCP on Pd/Ti electrode was 93.2% under the conditions of the dechlorination current of 5 mA and dechlorination time of 90 min. The effect of initial 2,4-DCP concentration was also investigated. PMID- 21252421 TI - Electrochemical treatment of wastewater polluted by nitrate: selective reduction to N2 on boron-doped diamond cathode. AB - Electrochemical tests of nitrate reduction on Boron-Doped Diamond cathode are investigated through a Design of Experiments (DOE) method. The results show good reduction of nitrate into almost exclusively N2. In the studied domain, the best experimental conditions are high initial nitrate content, low acidic pH values and low working current densities. The application of DOE conclusions on an agro industrial wastewater gives really satisfying results: final nitrate contents lower than 50 mg/L without nitrite or ammonium formation, and with low energy consumption (under 25 kWh/kgNO3). PMID- 21252422 TI - Development of a flocculation sub-model for a 3-D CFD model based on rectangular settling tanks. AB - To assess performance and evaluate alternatives to improve the efficiency of rectangular Gould II type final settling tanks (FSTs), New York City Department of Environmental Protection and City College of NY developed a 3D computer model depicting the actual structural configuration of the tanks and the current and proposed hydraulic and solids loading rates. Fluent 6.3.26TM was the base platform for the computational fluid dynamics (CFD) model, for which sub-models of the SS settling characteristics, turbulence, flocculation and rheology were incorporated. This was supplemented by field and bench scale experiments to quantify the coefficients integral to the sub-models. The 3D model developed can be used to consider different baffle arrangements, sludge withdrawal mechanisms and loading alternatives to the FSTs. Flocculation in the front half of the rectangular tank especially in the region before and after the inlet baffle is one of the vital parameters that influences the capture efficiency of SS. Flocculation could be further improved by capturing medium and small size particles by creating an additional zone with an in-tank baffle. This was one of the methods that was adopted in optimizing the performance of the tank where the CCNY 3D CFD model was used to locate the in-tank baffle position. This paper describes the development of the flocculation sub-model and the relationship of the flocculation coefficients in the known Parker equation to the initial mixed liquor suspended solids (MLSS) concentration X0. A new modified equation is proposed removing the dependency of the breakup coefficient to the initial value of X0 based on preliminary data using normal and low concentration mixed liquor suspended solids values in flocculation experiments performed. PMID- 21252423 TI - Aquifer recharge for securing water resources: the experience in Llobregat river. AB - The Llobregat Delta Aquifer has historically been a strategic water supply resource to the Barcelona metropolitan area. The use of river water combined with the exploitation of groundwater resources during dry periods has enabled the demographic and economic growth of the Barcelona area during the last fifty years. The aquifer overexploitation has entailed the decrease of groundwater level and the penetration inland of seawater intrusion. The main consequences have been the salinization of several wells and the deterioration of the groundwater quality. In this context, aquifer recharge has been practiced during nearly 40 years with the following objectives: (i) storing excess of water for times of less water availability, (ii) introducing an additional barrier for purification of water for a specific use and (iii) preventing the degradation of groundwater resources due to overexploitation or seawater intrusion. These methods, jointly with an efficient management of well extractions, have enabled to recover groundwater quality and therefore to guarantee the sustainable exploitation of such a vulnerable aquifer. PMID- 21252424 TI - Issues of drinking water quality of small scale water services towards climate change. AB - As climate change could impact water quantity and quality, important concerns are related to water quality degradation in small scale water services (SSWS). SSWS using surface waters resources (rivers and lakes) for drinking water production are particularly vulnerable to short term transient events due to their low adaptation capacity and their lack of support and technical knowledge compared to major centralized systems. Based on weather and water quality databases, a case study was conducted on a SSWS in Brittany (France) pumping from surface water. Results show an important vulnerability in treatment efficiency related to the lowest and highest river flows and provide first assumptions about the impacts of an increase in extreme weather events with climate change on drinking water quality. PMID- 21252425 TI - Algorithmic network monitoring for a modern water utility: a case study in Jerusalem. AB - We report on the design, deployment, and use of TaKaDu, a real-time algorithmic Water Infrastructure Monitoring solution, with a strong focus on water loss reduction and control. TaKaDu is provided as a commercial service to several customers worldwide. It has been in use at HaGihon, the Jerusalem utility, since mid 2009. Water utilities collect considerable real-time data from their networks, e.g. by means of a SCADA system and sensors measuring flow, pressure, and other data. We discuss how an algorithmic statistical solution analyses this wealth of raw data, flexibly using many types of input and picking out and reporting significant events and failures in the network. Of particular interest to most water utilities is the early detection capability for invisible leaks, also a means for preventing large visible bursts. The system also detects sensor and SCADA failures, various water quality issues, DMA boundary breaches, unrecorded or unintended network changes (like a valve or pump state change), and other events, including types unforeseen during system design. We discuss results from use at HaGihon, showing clear operational value. PMID- 21252426 TI - Suspended particles in wastewater: their optical, sedimentation and acoustical characterization and modeling. AB - Wastewater regulation and treatment is still a major concern in planetary pollution management. Some pollutants, referred to as particulate matter, consist of very small particles just suspended in the water. Various techniques are used for the suspended particles survey. Few of them are able to provide real-time data. The development of new, real time instruments needs the confrontation with real wastewater. Due its instability, the modeling of wastewater in terms of suspended solids was explored. Knowing the description of real wastewater, we tried to produce a synthetic mixture made of basic organic ingredients. A good agreement in terms of turbidity and settling velocity was observed between the artificial wastewater matrix and the real one. The investigation of the individual contribution of the different compounds to the acoustical signal showed a more complex dependence. Thus the modeling of wastewater with reference to turbidity and settling velocity is not sufficient to describe it acoustically. Further studies should lead to a good comparison of the acoustical and turbidity behavior of wastewater. PMID- 21252427 TI - Developing a public information and engagement portal of urban waterways with real-time monitoring and modeling. AB - Waterways can contribute to the beauty and livelihood of urban areas, but maintaining their hydro-ecosystem health is challenging because they are often recipients of contaminated water from stormwater runoff and other discharges. Public awareness of local waterways' health and community impacts to these waterways is usually poor due to of lack of easily available information. To improve community awareness of water quality in urban waterways in New Zealand, a web portal was developed featuring a real-time waterways monitoring system, a public forum, historical data, interactive maps, contaminant modelling scenarios, mitigation recommendations, and a prototype contamination alert system. The monitoring system featured in the web portal is unique in the use of wireless mesh network technology, direct integration with online modelling, and a clear target of public engagement. The modelling aims to show the origin of contaminants within the local catchment and to help the community prioritize mitigation efforts to improve water quality in local waterways. The contamination alert system aims to keep managers and community members better informed and to provide a more timely response opportunity to avert any unplanned or accidental contamination of the waterways. Preliminary feedback has been positive and is being supported by local and regional authorities. The system was developed in a cost-effective manner providing a community focussed solution for quantifying and mitigating key contaminants in urban catchments and is applicable and transferable to other cities with similar stormwater challenges. PMID- 21252428 TI - Virus removal retention challenge tests performed at lab scale and pilot scale during operation of membrane units. AB - The determination of the virus retention capabilities of UF units during operation is essential for the operators of drinking water treatment facilities in order to guarantee an efficient and stable removal of viruses through time. In previous studies, an effective method (MS2-phage challenge tests) was developed by the Water Research Center of Veolia Environnement for the measurement of the virus retention rates (Log Removal Rate, LRV) of commercially available hollow fiber membranes at lab scale. In the present work, the protocol for monitoring membrane performance was transferred from lab scale to pilot scale. Membrane performances were evaluated during pilot trial and compared to the results obtained at lab scale with fibers taken from the pilot plant modules. PFU culture method was compared to RT-PCR method for the calculation of LRV in both cases. Preliminary tests at lab scale showed that both methods can be used interchangeably. For tests conducted on virgin membrane, a good consistency was observed between lab and pilot scale results with the two analytical methods used. This work intends to show that a reliable determination of the membranes performances based on RT-PCR analytical method can be achieved during the operation of the UF units. PMID- 21252429 TI - Characteristics of different fractions of microbial flocs and their role in membrane fouling. AB - Characteristics of different fractions (small flocs vs. large flocs) of sludge flocs from a submerged anaerobic membrane bioreactor treating thermomechanical pulping (TMP) whitewater were determined using various analytic techniques, including extraction and chemical analysis of extracellular polymeric substances (EPS), particle size analyzer, and polymer chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE). The results showed that the fraction of smaller flocs contained a higher level of bound EPS and had a higher fractal dimension as compared to the fraction of larger flocs. PCR-DGGE analysis indicated that there were significant differences in microbial community between the fraction of smaller flocs and large flocs. The microbial community of the smaller flocs was similar to that of the sludge cake layers, indicating the pioneering role of the microbial community in smaller flocs in membrane fouling. These findings provide a new insight in the difference of membrane fouling potential between smaller flocs and larger flocs fraction. PMID- 21252430 TI - Simulation of membrane fouling considering mixed liquor viscosity and variation of shear stress on membrane surface. AB - Simulation of membrane fouling in MBR was conducted considering accumulation, detachment and consolidation of extracellular polymeric substances accumulated on membrane surface. The fluctuation of shear stress working on membrane surface and the influence of the viscosity of mixed liquor were considered for the evaluation of shear stress. A flat-sheet-type membrane module was used and the change of trans-membrane pressure was measured in a laboratory-scale MBR reactor. Shear stress working on membrane surface caused by aeration was measured by a shear force sensor changing viscosity of bulk liquid. Effective shear stress on membrane surface was defined in the model as the sum of time-averaged shear stress and three times of standard deviation. The increase in the trans-membrane pressure was accurately simulated by the developed model suggesting validity of the developed fouling model and the idea of the effective shear stress on membrane surface. PMID- 21252431 TI - UV photolysis of perfluorooctanoic acid (PFOA) in dilute aqueous solution. AB - Perfluorooctanoic acid (PFOA) is very persistent in the environment and widely detected in the water environment. Only some advanced methods with extreme reaction conditions are shown to be capable of degrading the compound efficiently, and almost all the earlier investigations used very high PFOA concentrations. The compound is detected normally at very low concentrations in the water environment, while mild reaction conditions for its degradation are preferable. This article aimed to elucidate photodegradation of PFOA in dilute aqueous solutions by combined UV wavelengths (185 nm+254 nm) and 254 nm using a newly designed UV jacket. PFOA degradation was greatly enhanced with the combined wavelengths with almost one hundred percent PFOA removals in four-hour reaction. The removals were well described by the first-order reaction kinetic. The removal efficiencies and rate values significantly decreased with smaller initial PFOA concentrations. But defluorination was greatly enhanced with smaller PFOA concentrations possibly due to accelerated decomposition of fluorinated intermediates of PFOA. Formic acid and acetic acid were two tentatively identified intermediates of PFOA photolysis while the former was a major intermediate predominantly controlling solution pH during the oxidation. The results demonstrated that PFOA photolysis by the combined wavelengths with mild reaction conditions can be greatly enhanced by proper design of UV jacket and reactor system. PMID- 21252432 TI - A practical method for the restoration of clogged rural vertical subsurface flow constructed wetlands for domestic wastewater treatment using earthworm. AB - This paper presents a simple method for the restoration of clogged vertical subsurface flow constructed wetland by earthworm. Since clogging always takes place at the top layer, epigeic earthworm is suitable for restoration of the clogged wetland. Earthworm can not only loosen the substrate, but also transform 80~90% of undissolved organic particles into dissolved matters. Accordingly, the accumulated solids in substrate with earthworm are 50% less than the one without earthworm. The wetland with earthworm removed 2~5 percentage points more nitrogen and 12 percentage points more phosphorous for its better ventilation conditions, while 2 percentage points less COD because the generation of dissolved organic matter from undissolved organic particles by earthworm. In general, the influence of earthworm on the effluent quality of the wetland could be ignored. Hydrology of six full-scale clogged wetlands was restored by Eisenia foetida. The optimal strength of earthworm addition is 0.5 kg/m2, which spend RMB six yuan/m2, less than ? 0.75/m2. No specific training is required for the staffs on this method; it takes 10 days to restore the clogged wetland. PMID- 21252433 TI - Comprehensive review and compilation of pretreatments for mesophilic and thermophilic anaerobic digestion. AB - Organic matter hydrolysis prior to anaerobic digestion has been shown to improve biogas production (30-50%) and reduce solids (20-60%) by ultrasound, chemical, conventional heating, and microwave pretreatments. Numerous studies have been performed to determine the extent of digestion improvement but few focus on financial feasibility of these processes. A comprehensive model was created using Microsoft Excel and its Visual Basic Assistant to evaluate pretreatment permutations for conventional wastewater treatment plants. The four above mentioned processes were evaluated for energetic and financial demands. Well established energy equations and wastewater characteristics, both average and high, were used. Average and high flows were 460 and 750*10(3) m3/d, respectively. Net costs per influent flow for ultrasound, chemical, conventional heating, and microwave were 0.0166, 0.0217, 0.0124, 0.0119 $/m3 and 0.0264, 0.0357, 0.0187, and 0.0162 $/m3 for average and high conditions, respectively. The average cost increase from results excluding pretreatment use for all processes was 0.003 and 0.0055 $/m3 for average and high conditions, respectively. No matter the permutation, pretreatments requiring more energy to achieve required hydrolysis levels were costlier. If energetic recoveries are substantial, dewaterability is positively affected, and solids meet environmental constraints to be handled and disposed at lower costs, pretreatments can be viable. PMID- 21252434 TI - Ozonation of endogenous residue and active biomass from a synthetic activated sludge. AB - Coupling the activated sludge and the ozonation processes is an efficient, although expensive, solution for sludge reduction. A better knowledge of the mechanisms involved in the degradation of various sludge fractions by ozone is needed to optimize the coupled process. The objectives of this study were to determine the biodegradability of ozone-solubilized endogenous residue, the action of ozone on the active biomass and the solubilization yield of these two main sludge fractions. Batch tests were conducted with slug input of ozone stock solution into fresh or aerobically digested synthetic sludge. Biodegradability of the solubilized endogenous residue was increased by ozonation by up to 0.27 g BOD5/g CODi. Ozone caused biomass lysis, as opposed to an increase in maintenance needs, as shown by a correlation between the decrease in microbial activity and viability. Lysis caused by ozonation was associated with a solubilization of 20% of the lyzed cell COD mass. Solubilization yields were of 9.6 and of 1.9 to 3.6 g COD/g O3 for fresh and aerobically digested sludge, respectively. Design of sludge ozonation processes should account for the variability between the solubilization yield and biodegradability of the various sludge fractions. PMID- 21252435 TI - Advanced treatment of membrane bioreactor (MBR) effluents for effective wastewater reclamation. AB - One of the two main objectives of this work is to oxidize MBR effluents with ozone/peroxide in high pH conditions in order to improve oxidation of pharmaceuticals, which could efficiently be rejected by the nanofiltration (NF) stage. The other main objective is to effectively oxidize of dissolved organic carbon (DOC) in MBR effluents in order to decrease fouling in the filtration stage. In this work, ozone/peroxide oxidation was applied to the MBR effluents in high pH conditions in order to improve the formation of OH radicals, and oxidized effluents were filtered by the NF membrane (NE90) in order to investigate fouling potentials and the removal of pharmaceuticals. Natural and synthetic wastewater samples were used as feed solutions for the MBR system, which was equipped with a U-shaped hollow fiber membrane module. The flux decline was decreased from 29% to 15% when 9 mg/L of ozone was used, the same decline was also observed when 6 mg/L ozone and hydrogen peroxide (1/1 ozone/peroxide mol ratio) were used. A further decrease in flux decline was observed when pH was adjusted to 9.00 (29% to 9%) prior to the ozone/peroxide oxidation. In most cases, the increase in the ozone dose, the addition of hydrogen peroxide and the adjustment of the pH level led to an increase in the removal of pharmaceuticals. Iopromide, TCEP and Naproxen were found to be more resistant to the oxidation when pH was increased. PMID- 21252436 TI - Effects of the cometabolite/growth substrate ratio on the aerobic degradation of 4-monochlorophenol. AB - Chlorinated phenolic compounds like 4-monochlorophenol (4CP) are characterized by high toxicity even at relatively low concentrations and by strong persistency in both water and soils. Since cometabolism was proved to enhance 4CP biological removal, a conventional Sequencing Batch Reactor (SBR) was used in this study for the cometabolic aerobic degradation of 4CP at different influent concentrations and volumetric organic loading rates (40-50 mg/L and 0.129-0.323 kgCOD-4CP/m3.d, respectively), with sodium acetate (NaAc) as the growth substrate. The effects of different 4CP/NaAc ratios on SBR performances were evaluated in terms of 4CP removal efficiencies and maximum specific removal rates in order to maximize reactor performances: a decrease in NaAc dosage as external growth substrate would lead to definitely lower operating costs. A positive correlation was observed between 4CP maximum specific removal rates and the applied 4CP/NaAc ratios, thus making further reduction in NaAc dosage possible. PMID- 21252437 TI - The role of colloidal and particulate organic compounds in denitrification and EBPR occurring in a full-scale activated sludge system. AB - The efficiencies of denitrification and enhanced biological phosphorus removal (EBPR) in biological nutrient removal (BNR) activated sludge systems are strongly dependent on the availability of appropriate carbon sources. Due to high costs of commercial compounds (such as methanol, ethanol, acetic acid etc.) and acclimation periods (usually) required, the effective use of internal carbon sources for denitrification is preferred. The aim of this study was to determine the immediate effects of slowly biodegradable substrates on the denitrification capability and phosphate release/uptake interactions for a full-scale biomass process from the "Wschod" wastewater treatment plant (WWTP) in Gdansk (Poland). Since it is hard to distinguish the slowly biodegradable substrate in a direct way, a novel procedure based on batch experiments was developed and implemented. The laboratory experiments were carried out in two parallel, fully automatic batch reactors with the settled wastewater without pretreatment and after coagulation-flocculation. The removal of colloidal and particulate fractions resulted in the reduced observed process rates, such as denitrification, phosphate release and phosphate uptake (under aerobic and anoxic conditions). The reduction ranged from approximately 14% for the anaerobic P release to approximately 46% for the anoxic P uptake. PMID- 21252438 TI - Evaluation of effectiveness of combined sewer overflow control measures by operational data. AB - The effect of combined sewer overflow (CSO) control measures should be validated during operation based on monitoring of CSO activity and subsequent comparison with (legal) requirements. However, most CSO monitoring programs have been started only recently and therefore no long-term data is available for reliable efficiency control. A method is proposed that focuses on rainfall data for evaluating the effectiveness of CSO control measures. It is applicable if a sufficient time-series of rainfall data and a limited set of data on CSO discharges are available. The method is demonstrated for four catchments of the Berlin combined sewer system. The analysis of the 2000-2007 data shows the effect of CSO control measures, such as activation of in-pipe storage capacities within the Berlin system. The catchment, where measures are fully implemented shows less than 40% of the CSO activity of those catchments, where measures have not yet or not yet completely been realised. PMID- 21252439 TI - Reducing CSOs and giving the river back to the public: innovative combined sewer overflow control and riverbanks restoration of the St. Charles River in Quebec City. AB - After the construction of its wastewater treatment plants, the City of Quebec began to implement overflow control in wet weather to ultimately meet the effluent discharge objectives, i.e. no more than two overflows per summer season in the St. Lawrence River and no more than four in the St-Charles River. After several years of studies to determine which management strategies would best suit the purpose, and to propose optimum solutions, a first project to implement optimal and predictive management in real time, called "Pilot", came to life in 1999. Construction in phases soon followed and the work was completed in the fall of 2009. As a result, requirements with regard to environmental rejects were met in two sectors, namely the St-Charles River and the Jacques-Cartier Beach, and aquatic recreational activities could resume. Meanwhile, the City also worked at giving back access to the water courses to the public by developing sites at the Jacques-Cartier Beach and in the Bay of Beauport, and by rehabilitating the banks of the St-Charles River. PMID- 21252440 TI - P-Recovery from sewage by seeded crystallisation in a pilot plant in batch mode technology. AB - P-Recovery from actual sewage by P-RoC-technology (Phosphorus Recovery by Crystallisation of phosphate mineral phases from waste- and processwater) was studied in a pilot scale. Therewith the practicability of the pilot plant was tested and the quality of the so generated products was investigated. PMID- 21252441 TI - Could nitrite/free nitrous acid favour GAOs over PAOs in enhanced biological phosphorus removal systems? AB - Enhanced biological phosphorus removal (EBPR) normally occurs together with nitrogen removal in wastewater treatment plants (WWTPs). In recent years, efforts have been devoted to remove nitrogen via the nitrite pathway (oxidation of ammonia to nitrite and reduction of nitrite to nitrogen gas without going through nitrate), reducing the requirement for carbon and oxygen in the plant. However nitrite and free nitrous acid (FNA), the protonated species of nitrite, have been shown to cause EBPR deterioration under certain concentrations. This study provides a direct comparison between the different levels of FNA inhibition in the aerobic processes of polyphosphate accumulating organisms (PAOs) and glycogen accumulating organisms (GAOs) by reviewing the studies published in this area. Also, new data is presented assessing the FNA effect on the anaerobic metabolism of these two groups of bacteria. Overall, FNA has shown inhibitory effects on most of the processes involved in the metabolism of PAOs and GAOs. However, the inhibition-initiation levels are different between different processes and, even more importantly between the two groups. In general, PAOs appear to be more affected than GAOs at the same level of FNA, thus giving GAOs competitive advantage over PAOs in EBPR systems when nitrite is present. PMID- 21252442 TI - Long-term operation of a reactor enriched in Accumulibacter clade I DPAOs: performance with nitrate, nitrite and oxygen. AB - The microbiology of denitrifying enhanced biological phosphorus removal systems has been a subject of much debate. The question has centred on the affinities of different types of Candidatus Accumulibacter PAOs, type I and type II, towards different electron acceptors such as oxygen, nitrate and nitrite. This study used a propionate anaerobic/anoxic/aerobic lab-scale sequencing batch reactor where a microbial culture was successfully enriched in Accumulibacter type I organisms (approx. 90%). The culture was able to take up phosphorus using nitrate, nitrite and oxygen as electron acceptors, although experiments with oxygen led to the fastest P removal rate. The phosphorus uptake to nitrogen consumed ratio (P/N ratio), when using both nitrate and nitrite, was shown to be affected by pH in the range of 7-8.2, achieving higher values for lower pH values (7.0-7.5). The effect of pH on P removal seems to follow a similar trend for both nitrate and nitrite. To our knowledge, this is the first study where the impact of pH in the phosphate removal stoichiometry using the three most significant electron acceptors is shown for such a high enrichment in Accumulibacter type I. PMID- 21252443 TI - On the effect of scaling conceptual model complexity on stochastic response for water quality modeling. AB - This paper extends previous work comparing the response of water quality models under uncertainty. A new model, the River Water Quality Model no. 1 (RWQM1), is compared to the previous work of two commonly used water quality models. Additionally, the effect of conceptual model scaling within a single modelling framework, as allowed by RWQM1, is explored under uncertainty. Model predictions are examined using against real-world data for the Potomac River with a Generalized Likelihood Uncertainty Estimation used to assess model response surfaces to uncertainty. Generally, it was found that there are tangible model characteristics that are closely tied to model complexity and thresholds for these characteristics were discussed. The novel work has yielded an illustrative example but also a conceptually scaleable water quality modelling tool, alongside defined metrics to assess when scaling is required under uncertainty. The resulting framework holds substantial, unique, promise for a new generation of modelling tools that are capable of addressing classically intractable problems. PMID- 21252444 TI - History, current issues and future of the brazilian network for attending and studying Trypanosoma cruzi/HIV coinfection. AB - INTRODUCTION: In countries with endemic Chagas disease, coinfection involving Trypanosoma cruzi and HIV is expected to become more frequent. There is a clear need to structure a comprehensive care network aimed at dealing with this situation, with mobilization going from primary care to care at the highest level of technological complexity. The objective of this study was to describe the Brazilian response to the challenges of Chagas disease: the history, current issues, and future of the Brazilian Network for attending and studying T. cruzi/HIV coinfection. METHODOLOGY: This descriptive study reviewed technical documents relating to the basis and structuring process of the Brazilian network for attending and studying T. cruzi/HIV coinfection. RESULTS: The process of setting up the network was marked by technical and political debates in technical scientific meetings going back to the 1990s. This process made it possible to expand and focus on different aspects of comprehensive care for Chagas disease in Brazil, regardless of the associated immunosuppressive conditions. These meetings produced a structure of national technical guidelines and standards, health care and research protocols and research priorities, along with mobilization and awareness-raising among HIV/AIDS reference centers regarding occurrences of coinfection. CONCLUSIONS: The creation of the Brazilian network was a milestone for the country in terms of integration of control programs, with the reference point of quality of care and comprehensiveness. The possibility of extending this network to form a Latin American network is seen as a strategy for dealing more effectively with this condition. PMID- 21252445 TI - Tularemia in bulgaria 2003-2004. AB - INTRODUCTION: Tularemia is an uncommon but potentially fatal zoonosis. A second outbreak of tularemia in Bulgaria, about 40 years after the first, occurred in 1997 in two western regions, near the Serbian border. In 2003 tularemia reemerged in the same foci. This retrospective study aimed to evaluate the clinical characteristics and the efficacy of antibiotic therapy in a tularemia resurgence in the Slivnitza region in 2003-2004. METHODOLOGY: A total of 26 cases were evaluated. Using medical records, the following data were collected for all patients: symptoms, physical signs, and microbiology results of agglutination tests, cultures and PCR assays. RESULTS: Twenty-four of 26 suspected tularemia patients were laboratory confirmed by agglutination test and/or culture. Fifteen (57.7%) patients had clinical presentation compatible with oropharyngeal, 8 (30.8%) with glandular, and 3 (11.5%) with oculoglandular tularemia. The most frequent symptoms were swollen neck (84.6%) and sore throat (76.9%). Lymphadenopathy (100%) was the most common finding. Francisella tularensis (F. tularensis) was detected by PCR, providing a definitive diagnosis in 82.3% of the cases. All the patients were treated with antibiotics considered effective against F. tularensis; however, therapeutic failure was observed in 23.1% of the cases, which was related to a delay in the initiation of antibiotics. CONCLUSION: The tularemia outbreak in west Bulgaria near the Serbian border was probably food borne, associated with a surge in the rodent population. The oropharyngeal form was the most common. Although the disease runs a benign course, late initiation of antimicrobial therapy might delay complete recovery. PMID- 21252446 TI - Direct drug susceptibility testing of Mycobacterium tuberculosis against primary anti-TB drugs in northern India. AB - INTRODUCTION: The present study aimed to evaluate a rapid and inexpensive colorimetric nitrate reductase assay (NRA) performed directly on sputum specimens for detection of drug resistance in Mycobacterium tuberculosis (MTB). METHODOLOGY: A total of 55 sputum samples were decontaminated and processed by modified Petroff's method. A part of the resulting suspension was used to perform direct NRA (DNRA) and direct proportion method (DPM) analysis. Of the 55 samples, 45 could be used to compare the two methods. Indirect drug sensitivity testing (DST) was also done for 14 MTB strains. RESULTS: Excellent agreement was found between DNRA and DPM testing with K values of 1, 0.91, 0.91, and 1 for RIF, INH, STR and EMB respectively. The sensitivities and specificities of DNRA compared to that of DPM were observed to be 100 and 100%, 100 and 93%, 95 and 96%, 100 and 100 % for RIF, INH, STR, and EMB respectively. Comparing the results of DNRA, DPM and indirect NRA with those of the gold standard indirect PM for 14 MTB strains showed that sensitivities, specificities and percent agreements were 100, 100 and 100% for all four tested drugs. Results for most of the specimens (55.6%) were available in 21 days with DNRA. CONCLUSIONS: We have saved valuable time by omitting the pre-isolation step and conclude that DNRA is a rapid, accurate and inexpensive method for direct DST of MTB and may become an appropriate alternative method for the resource limited settings. PMID- 21252447 TI - Polyclonal dissemination of tetracycline resistance among Streptococcus pyogenes paediatric isolates from Brazil. AB - INTRODUCTION: Scarce data are available on Group A Streptococcus (GAS) antibiotic resistance in South America. METHODOLOGY: The antibiotic susceptibility patterns of GAS recovered from symptomatic children living in the central part of Brazil during a prospective epidemiological study were analyzed. RESULTS: No isolates were resistant to penicillin or macrolides. Sixty-one percent of the isolates were highly resistant to tetracycline, of which 85% harboured the tetM resistance gene. Ninety-five percent of these tetracycline resistant isolates were also resistant to minocycline. Thirty different emm-types were associated with tetracycline resistance. Phylogenetic analysis indicates that tetracycline resistance arose independently in distantly related emm-types. CONCLUSIONS: A high level of GAS tetracycline resistance has been observed in the central part of Brazil due to the polyclonal dissemination of resistant emm-types. PMID- 21252448 TI - Clarithromycin-based triple therapy for Helicobacter pylori treatment in peptic ulcer patients. AB - INTRODUCTION: The scheme proton pump inhibitor/amoxicillin/clarithromycin (PPI/AC) is still the first-line treatment for Helicobacter pylori (H. pylori) infections despite evidence suggesting its failure in up to 20% to 30% of patients. METHODOLOGY: This study involved 493 patients who were prescribed omeprazole (20 mg twice a day) or another proton pump inhibitor in equivalent dosage, amoxicillin (1 g twice a day), and clarithromycin (500 mg twice a day) for seven days. Efficacy was determined by negative urease test and absence of H. pylori on gastric biopsy samples twelve weeks after the end of treatment. Safety was defined according to the adverse effects reported. Mean age of the patients was (+/- SD) 48.96 +/- 13, and demographic and clinical data were recorded for correlation with treatment outcomes. RESULTS: Out of 493 patients, 316 (64.1%) presented duodenal ulcer, 111 (22.5%) gastric ulcer, and 66 (14.4%) simultaneous gastric and duodenal ulcers. Additionally, 267 (54.2%) patients had at least one risk factor for peptic ulcer disease, smoking being the most common (99 [36.5%]). Successful eradication was achieved in 408 patients. The eradication rates per protocol, and according to the intention to treat, were 88.8% and 82.7%, respectively. Of 164 (35.5%) patients who presented adverse effects, 100 (61%) reported them as mild and only six (3.7%) patients had to discontinue treatment. Previous use of tobacco and non-steroid anti-inflammatory drugs was the only risk factor for treatment failure (P = 0.00). CONCLUSION: PPI/AC is still a valuable and remarkably tolerable option for first-line H. pylori eradication in Brazil. PMID- 21252449 TI - Epidemiology and risk factors for ESBL-producing Klebsiella pneumoniae: a case control study. AB - INTRODUCTION: Increased production of extended-spectrum beta-lactamases (ESBLs) has become an important issue for treatment of severe Klebsiella pneumoniae (K. pneumoniae) infections. This study aimed to evaluate risk factors of infection from ESBL-producing K. pneumoniae (ESBL-KP). METHODOLOGY: Risk factors were evaluated using a retrospective case control design. Fifty-two patients admitted to Firat University Hospital (FUH) with invasive infections from ESBL-KP were employed as cases. Patients admitted to FUH with non-ESBL-producing K. pneumoniae invasive infection were chosen as controls. Potential risk factors of the cases and controls were evaluated using hospital charts. Pulsed-field Gel Electrophoresis (PFGE) was used to show the relatedness of ESBL-KP strains. RESULTS: In univariate analysis, the following factors were found significant for ESBL-KP: pre-infection hospital stay, nosocomial origin, central venous catheterization, surgical intervention, antibiotic use longer than one week, and previous hospitalization. In contrast, stepwise logistic regression analysis showed that two variables, previous antibiotic use (p = 0.000) and surgical intervention (p = 0.006), remained significantly associated with risk for infection with an ESBL-KP. Molecular epidemiology identified several clusters among the ESBL-producing isolates. CONCLUSIONS: Antibiotic use and surgical intervention were significant associated factors for infections with ESBL-KP. PMID- 21252450 TI - Salmonella enterica Serovars Typhi and Paratyphi A are avirulent in newborn and infant mice even when expressing virulence plasmid genes of Salmonella Typhimurium. AB - BACKGROUND: Salmonella enterica serovars Typhi and Paratyphi A are human host restricted pathogens. Therefore, there is no small susceptible animal host that can be used to assess the virulence and safety of vaccine strains derived from these Salmonella serovars. However, infant mice have been used to evaluate virulence and colonization by another human host-restricted pathogen, Vibrio cholerae. METHODOLOGY: The possibility that infant mice host could be adapted for Salmonella led us to investigate the susceptibility of newborn and infant mice to oral infection with S. Typhi and S. Paratyphi A. Salmonella enterica serovar Typhimurium causes enteric fever in adult mice and this system has been used as a model for human typhoid. The pSTV virulence plasmid, not present in S. Typhi and S. Paratyphi A, plays an essential role in S. Typhimurium colonization and systemic infection of mice. We also conjugated pSTV into S. Typhi and S. Paratyphi A serovars and evaluated these transconjugants in newborn and infant mice. RESULTS: We determined that the spv virulence genes from the S. Typhimurium virulence plasmid are expressed in S. Typhi and S. Paratyphi A in a RpoS dependent fashion. Also, we determined that S. Typhi and S. Paratyphi A with and without pSTV transiently colonize newborn and infant mice tissues. CONCLUSION: Newborn and infant mice infected with S. Typhi and S. Paratyphi A do not succumb to the infection and that carriage of the S. Typhimurium virulence plasmid, pSTV, did not influence these results. PMID- 21252451 TI - Prevalence of human papillomavirus genotype among Moroccan women during a local screening program. AB - INTRODUCTION: Many studies have indicated a causal relationship between genital human papillomavirus (HPV) infections and cervical cancer. This study aimed to determine the prevalence and genotypes of six high-risk oncogenic human papillomaviruses in cervical lesions from Moroccan women with normal and abnormal cytology. METHODOLOGY: The study included 938 women from the Children's and Mothers' Pathology Department of Ibn Sina Hospital, Rabat. Cytopathology examination was done by routine PAP smear testing. HPV DNA testing was conducted using DNA amplification by Polymerase Chain Reaction with subsequent typing by hybridization with specific probes for HPV types 16, 18, 31, 33, 35 and 45. RESULTS: Cytopathology testing showed that only 16.3 % had an abnormal cytology, with a predominance of atypical squamous cell of undetermined significance (ASCUS) cases. The overall HPV prevalence was 15.7%. According to the cytology results, HPV infection was detected in 15.8% of normal and 14.38% of abnormal cases. Specific HPV genotyping showed a predominance of HPV 16 and 18. Double infection (HPV 16 + 18) was found in two cases whereas multiple infections (HPV 16+18+31) were detected in only one case. Evaluation of the relationship between HPV status and some environmental risk factors, including individual, socio economic, and hygiene status, showed a significant association between HPV infection and oral contraceptive use. CONCLUSION: Based on these data, a combination of cytology and HPV DNA testing allows for identification of patients with a high risk of developing high-grade cervical lesions and improves cervical cancer prevention. PMID- 21252452 TI - Evaluation of a recombinant DNA hepatitis B vaccine in a vaccinated Nigerian population. AB - INTRODUCTION: Recombinant hepatitis B vaccine was introduced in 1986 and has gradually replaced the plasma-derived hepatitis B vaccine. No published data are available on the immunogenicity of hepatitis B vaccines in Nigerians. The current study aimed to evaluate protective sero-conversion rates after vaccination with Shanvac-B rDNA hepatitis B vaccine in Nigerian subjects between January and September 2009. METHODOLOGY: After having obtained informed consent and ethical clearance, 2 mL of blood were aseptically collected from each participant aged <=50 years, one month after the first, second and third doses of the vaccine. Sera were separated into cryovials and frozen at -21oC until analysed for the detection of the protective antibody titre induction. Protective antibody titre was defined as a titre of >=10 mIU/mL. RESULTS: Of the 376 participants, 192 (51.1%) were males and 184 (48.9%) were females. A total of 144 subjects participated in the first-dose group, nine (6.3%) of whom developed protective antibody titre (8.3% of males and 4.2% of females). Of the 121 participants in the second-dose group, 108 (89.3%) developed protective antibody titre (98.3% of males and 80.3% of females), while of the 111 participants in the third-dose group, 100% protectively sero-converted. Males were more likely to develop protective antibody titre than females after the second dose (P < 0.05). CONCLUSION: This data provides additional evidence for the efficacy of Shanvac-B rDNA hepatitis B vaccine and the need to adhere to the recommended three-dose schedule to achieve full and lasting sero-protection among Nigerians. PMID- 21252453 TI - Nutritional status of HIV-positive individuals on free HAART treatment in a developing nation. AB - INTRODUCTION: HIV positive individuals are prone to malnutrition due to inadequate dietary intake. Additionally, in low-income countries, including Nigeria, stigmatization and discrimination result in a lack of support for HIV positive individuals ultimately contributing to even further reduced food availability and inadequate dietary intake. This study aimed to determine the nutrirional status of HIV-positive individuals on free, highly active antiretroviral therapy (HAART) in Abakaliki, southeast Nigeria. METHODOLOGY: Subjective global assessment (SGA) technique was used to survey the nutritional status of 120 HIV-positive individuals and a control group over a one-year period. RESULTS: All the HIV-positive individuals and their control group were physically active, with a third of them belonging to the lower socioeconomic status. There were significantly more malnourished individuals among the HIV positive group than in the control group (P < 0.05). CONCLUSION: Malnutrition is common among HIV-positive patients in southeast Nigeria. PMID- 21252454 TI - Adverse effects after HAART Initiation in resource-limited settings: a prospective study from Mysore, India. AB - INTRODUCTION: There are few studies from India documenting the adverse effects of generic HAART (Highly Active Anti-retroviral Therapy). METHODOLOGY: A prospective study was conducted at Mysore, India, to study the adverse effects after HAART initiation in a cohort of 100 antiretroviral therapy (ART)-naive patients, who were evaluated prospectively every three months by clinical and laboratory monitoring for adverse effects after HAART initiation for one year. RESULTS: The most common first-line regimens were zidovudine (AZT) plus lamivudine (3TC) plus nevirapine (NVP) (42%); followed by Stavudine (d4T) plus 3TC plus NVP (33%); AZT plus 3TC plus efavirenz (EFV) (13%); and d4T plus 3TC plus EFV (12%). The first line regimen was modified in14% of patients. The most common reasons for modifying therapy were development of an adverse effect (eight cases; 57.14%) and completion of antituberculous therapy (six cases; 42.86%). The commonest cause for modifying therapy was skin rashes due to NVP (four cases) followed by anaemia two cases) and peripheral neuropathy (two cases). Grade 1 or 2 severity adverse effects by laboratory monitoring were seen in 54 patients after ART initiation and grade 3 or 4 severity adverse effects were seen in eight patients. CONCLUSIONS: A significant proportion of patients had adverse effects of a lower grade severity after HAART. A significant proportion of those started on ART substitute therapy due to adverse effects and those on NVP-based regimens are more likely to do so when compared with those on non-NVP- based regimens. PMID- 21252455 TI - The efficacy of time-based short-course acyclovir therapy in treatment of post herpetic pain. AB - INTRODUCTION: Various treatments have been used to manage post-herpetic neuralgia (PHN). Safe and effective therapies to prevent PHN are needed. METHODOLOGY: A clinical trial involving 152 patients diagnosed with acute herpes Zoster (HZ) was conducted to determine whether short-course acyclovir therapy (800 mg five times a day for four days) can alleviate HZ-associated pain and prevent post-herpetic neuralgia (PHN). The patients were divided into two groups: Group 1 had a rash with a duration of less than 72 hours and Group 2 had a rash with a duration of more than 72 hours. To assess PHN, the patients categorized and assessed the severity of their symptoms using a four-point verbal rating scale (VRS). RESULTS: By the fourth week, 134 out of 152 patients (88.2%) had complete pain response (CPR). Of these, 68 patients (89.5%) were from Group 1 and 66 from Group 2 (86.8%). After four weeks, the mean VRS scores had changed significantly in both groups compared to the scores at the beginning of study (p = 0.001), but there was no difference between the two groups (0.88 +/- 0.66 Vs. 0.94 +/- 0.72; p = 0.66) After three months no differences were observed in the treatment results between the two groups (0.51 +/- 0.13 Vs.0.54 +/- 0.19; p = 0.77). CONCLUSION: Short-course acyclovir therapy is an effective treatment for zoster and its efficacy in patients with a rash duration of more than 72 hours is similar to that in patients with rash duration of less than 72 hours. PMID- 21252456 TI - Dihydropteroate synthase (DHPS) gene mutation study in HIV-Infected Indian patients with Pneumocystis jirovecii pneumonia. AB - INTRODUCTION: Pneumocystis jirovecii dihydropteroate synthase (DHPS) gene mutations' (55th and 57th codon) association with prior sulfa prophylaxis failure has been reported from both developed and developing countries. We conducted a prospective study to determine the prevalence of P. jirovecii DHPS mutations from 2006 to 2009 on P. jirovecii isolates obtained from HIV-infected patients with a clinical diagnosis of Pneumocystis carinii pneumonia (PCP) admitted to our tertiary care reference health center in New Delhi, India. METHODOLOGY: Detection of P. jirovecii cysts was performed by direct fluorescent antibody (DFA) staining and by Grocott's-Gomori methenamine silver staining (GMS). DNA detection was performed by polymerase chain reaction (PCR) using primers for the major surface glycoprotein (MSG) gene. P. jirovecii DHPS gene was amplified by nested PCR protocol and sequenced for detecting mutations at the 55th and 57th codons. RESULTS: Out of 147 HIV-positive patients with suspected Pneumocystis pneumonia (PCP), 16 (10.8%) PCP positive cases were detected. Of 16 cases, nine (56.2%) were positive by DFA staining, four (25%) were positive by Grocott's-Gomori methenamine silver staining, and all 16 were positive by MSG PCR. DHPS mutations at the 55th and 57th codons were observed in 6.2% of HIV patients studied, which was relatively low compared to reports from developed nations. CONCLUSIONS: Prevalence of Pneumocystis jirovecii DHPS mutations associated with cotrimoxazole treatment failure may be low in the Indian subpopulation of HIV-positive patients and warrants larger studies to elucidate the true picture of Pneumocystis jirovecii sulfa drug resistance in India. PMID- 21252457 TI - Dengue infections during pregnancy: case series from a tertiary care hospital in Sri Lanka. AB - INTRODUCTION: Dengue is the most important mosquito-borne disease in Sri Lanka, leading to more than 340 deaths during the last outbreak (~35,000 reported cases) starting in mid April 2009. The predominant dengue virus serotypes during the last few years have been DENV-2 and DENV-3. Dengue infection in pregnancy carries the risk of hemorrhage for both the mother and the newborn. Other risks include premature birth, fetal death, and vertical transmission. We report clinical and laboratory findings and outcomes in pregnant women hospitalized with dengue infection during pregnancy. METHODOLOGY: Clinical, laboratory, maternal/fetal outcomes and demographic data were collected from patients with confirmed dengue infections during pregnancy treated at De Soysa Maternity Hospital, Sri Lanka from 1 May 2009 to 31 December 2009. RESULTS: Fifteen seropositive dengue infected pregnant women were diagnosed in the period. Multiorgan failure leading to intrauterine fetal and maternal death occurred in one case of dengue hemorrhagic fever (DHF) IV. One patient with DHF III had a miscarriage at the 24th week of gestation. Perinatal outcomes of the other cases were satisfactory. One woman developed dengue myocarditis but recovered with supportive treatments. No cases of perinatal transmission to the neonate occurred. CONCLUSION: Dengue in pregnancy requires early diagnosis and treatment. A high index of clinical suspicion is essential in any pregnant woman with fever during epidemic. Further studies are mandatory as evidence-based data in the management of dengue specific for pregnancy are sparse. PMID- 21252458 TI - Dynamics of multidrug resistant tuberculosis in Veracruz, Mexico between 2002 and 2008. PMID- 21252459 TI - Plasmid-mediated quinolone resistance in expanded spectrum beta lactamase producing enterobacteriaceae in Morocco. AB - INTRODUCTION: Although independently acquired, plasmid-mediated quinolone resistance appears to be linked with extended-spectrum or AmpC-type beta lactamases. Since no data are available in African countries, the prevalence of qnr genes at the University Hospital Ibn Rochd, Casablanca, Morocco, was investigated. METHODOLOGY: Between October 2006 and March 2007, the following 39 randomly selected non-duplicate Enterobacteriaceae producing an extended-spectrum beta-lactamase (ESBL), representing 20% of ESBL strains with respect to species and ward origin, were collected: Escherichia coli (n = 16); Klebsiella spp (n = 14); Enterobacter cloacae (n = 8); Proteus mirabilis (n = 1). Antibiotic susceptibility testing was performed according to CLSI guidelines. ESBL detection was performed by the double disc diffusion test. A multiplex PCR was conducted to detect qnrA, qnrB and qnrS genes that were confirmed by sequencing of the PCR product. RESULTS: The estimated overall prevalence of qnr reached 36% (n = 14; qnrA, 10.25%; qnrB, 23.07%; qnrS, 2.56%). Genes were identified in E. coli, Klebsiella and Enterobacter with a respective prevalence of 18.7%, 50% and 62.5%. The qnr genes were detected in nine wards and qnrA1, qnrB1-B2-B4 and qnrS1 variants were identified. Three genes were identified among nalidixic acid susceptible strains (n = 6); three of those were also susceptible to ciprofloxacin. Among nalidixic acid and ciprofloxacin resistant strains, all strains had qnrB. CONCLUSIONS: This study highlights the high prevalence of qnr genes among ESBL strains in the Ibn Rochd CHU, Casablanca. Moreover, qnr were present in quinolone-susceptible strains which could lead to in vivo selection of ciprofloxacin-resistant strains. PMID- 21252460 TI - Antimicrobial resistance in Salmonella enterica serovar Enteritidis in Morocco. AB - INTRODUCTION: Salmonella enterica is recognised worldwide as one of the major agents of human gastrointestinal infections. The aim of the present work is to ascertain the antimicrobial susceptibilities of 150 Salmonella enterica serovar Enteritidis isolates from humans in Morocco during the period from 2000 to 2008. METHODOLOGY: Antimicrobial resistance determination was performed by disk diffusion method using seven antibiotics. The minimal inhibitory concentration (MIC) of ciprofloxacin was determined for nalidixic acid-resistant (NAR) isolates using E-test strips. RESULTS: Sixty-one (42%) isolates were resistant to at least one class of antimicrobial agent. The largest numbers of resistant isolates were observed for nalidixic acid with 53 isolates (36%) followed by ampicillin with 7 isolates (5%), tetracycline with 6 isolates (4%), and trimethoprim/sulfamethoxazole with 2 isolates (1%).The resistant isolates were grouped in seven different resistance patterns of which two isolates were resistant to three antibiotics. Among the 53 (36%) NAR isolates, 37 (76%) had a reduced susceptibility to ciprofloxacin. CONCLUSION: Resistance rates of Salmonella enterica serovar Enteritidis from Morocco are generally low but the resistance to nalidixic acid is worryingly common. Continual surveillance of antibiotic resistance is of primary importance. PMID- 21252461 TI - Frequency and susceptibility pattern of metallo-beta-lactamase producers in a hospital in Pakistan. AB - INTRODUCTION: The rapid spread of acquired metallo-beta-lactamases (MBLs) among major Gram-negative pathogens is an emerging threat and a matter of particular concern worldwide. METHODOLOGY: This descriptive study was conducted between January and August 2009 in the department of Microbiology, Army Medical College, National University of Sciences and Technology, Rawalpindi, to determine the frequency and susceptibility patterns of MBL-producers among carbapenem-resistant Gram-negative rods (GNRs) from clinical isolates of a tertiary care hospital. All clinical samples were processed according to standard microbiological methods. Isolated GNRs were subjected to susceptibility testing against various antibiotics by disc diffusion method according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Carbapenem-resistant isolates were subjected to the detection of MBL production by the E-test MBL strip method. RESULTS: Out of 50 carbapenem resistant isolates, 39 (78%) of were confirmed to be MBL producers by the E-strip method. Acinetobacter baumannii were the most frequent MBL producers, followed by Pseudomonas aeruginosa. A total of 19 (37%) of the MBL producers were susceptible to cefoperazone-sulbactam. CONCLUSION: The findings strongly suggest that there is a need to track the detection of MBL producers and that judicious use of carbapenems is necessary to prevent the further spread of these organisms. PMID- 21252462 TI - Assessment of effectiveness and safety of Ibicella lutea extract in the control of experimental Proteus mirabilis urinary tract infection. AB - INTRODUCTION: Proteus mirabilis is an important cause of complicated urinary tract infections (UTI). Like many other microorganisms, P. mirabilis has acquired resistance to many antibiotics. Due to the serious effects associated with uropathogenic P. mirabilis and the problems related to the use of antibiotics, alternative strategies for its control must be developed. Previously, we studied the effect of Ibicella lutea extract, a South American indigenous plant, on in vitro uropathogenicity of P. mirabilis. We observed that I. lutea extract had an effect on various attributes associated with P. mirabilis urovirulence. The objective of this study was to assess I. lutea extract against UTI by P. mirabilis. METHODOLOGY: This study was based on the effect of I. lutea extract to prevent or treat P. mirabilis experimental UTI in mice and the influence of this administration on the normal intestinal flora. Also, we studied the toxicity, mutagenicity, and antimutagenicity of the extract. RESULTS: In this study, while I. lutea administration showed an effect in the prevention and treatment of UTI in the mouse, the intestinal microflora did not change. The I. lutea extract was neither toxic nor mutagenic although the extract showed antimutagenic properties. CONCLUSION: These findings suggest that the administration of I. lutea extract could represent an interesting new strategy to control P. mirabilis UTI. PMID- 21252463 TI - Study of a novel method to assist in early reporting of sepsis from the microbiology laboratory. AB - INTRODUCTION: Microbiology laboratories must provide accurate blood culture reports with rapid turnaround time (TAT) to effectively manage patients with sepsis. In this study three methods are compared for reporting blood culture results: a manual method that included use of a serum separator tube (SST), the conventional manual, and an automated method for identification and susceptibility (ID/AST). METHODOLOGY: Broth from positive blood culture bottles was added to an SST and then centrifuged. The pellet obtained was used to directly inoculate biochemical tests for identification and agar plates for AST on the first day of positivity. Biochemicals and AST plates were read the next day and final results reported on the second day at 24 hours. For conventional disk diffusion testing, the newly positive blood culture broth was also inoculated on solid media on the first day and incubated overnight. The next day AST by was performed as well as biochemical tests from pure colonies. These colonies were also used to inoculate panels for ID/AST using the automated MicroScan 40SI System. These results were recorded on the third day and results reported at 48 hours. RESULTS: The study included 851 samples Out of 106 (12.4%) positive blood cultures, 102 were included in the study; Comparison of the 3 methods showed good correlation. Identification was correctly reported in 95 (93.1%) isolates. The overall AST error rate was 3.8%. CONCLUSIONS: The use of SST and direct from pellet inoculation reduced TAT for identification and AST results between 18 and 24 hours. PMID- 21252464 TI - Application of phage typing and pulsed-field gel electrophoresis to analyse Salmonella enterica isolates from a suspected outbreak in Lagos, Nigeria. AB - INTRODUCTION: Inadequate potable water supply and poor sanitation predispose to food- and water-borne diseases associated with Salmonella enterica serovars in developing countries. In this study the possible source of an unprecedented upsurge of Salmonella-associated community gastroenteritis was traced using both phage-typing and pulsed-field gel electrophoresis (PFGE). METHODOLOGY: Nineteen Salmonella Typhimurium (three sporadic isolates included) and 13 Salmonella Enteritidis isolates from clinical, animal, and environmental samples were subjected to antimicrobial susceptibility testing, phage-typing, and PFGE analysis using standard procedures. RESULTS: Eleven (68.8%) of the 16 outbreak related multidrug resistant S. Typhimurium belonged to DT 71 phage type with cluster PFGE type X3, representing the most prevalent strain identified among human, animal, and environmental isolates. The remaining five (31.2%) outbreak related strains reacted but did not conform with clear phage types (RDNC) with cluster PFGE types X1 and X2 (96.8% similarity). Sporadic strains were untypable and belonged to X4 PFGE type. However, the evaluated S. Enteritidis strains that were multidrug resistant without a definite phage type belonged to PFGE cluster type X1e and were identified among the water and human strains. None of the Typhimurium and Enteritdis isolates was resistant to the fluoroquinolone antibiotics that were evaluated. CONCLUSION: This study emphasizes the epidemiological usefulness of PFGE typing in the detection of emerging strains of multipledrug resistant Salmonella, particularly S. Typhimurium DT71, that pose serious health implications in our environment. The study provides epidemiological links between environmental reservoirs and human infection in this community. PMID- 21252465 TI - Hospitalizations associated with 2009 influenza A (H1N1) and seasonal influenza in Saurashtra region, India. AB - INTRODUCTION: This study investigated the clinico-epidemiological characteristics of patients who were hospitalized with 2009 pandemic H1N1 influenza virus infection and seasonal influenza in the Saurashtra region of India. METHODOLOGY: From September 2009 to February 2010, a total of 773 patients with influenza virus attending different hospitals in Rajkot city were studied. Real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) testing was used to confirm infection; the clinico-epidemiological features of the disease were closely monitored. RESULTS: Of the 733 patients, 35.4% (274/773) were cases of 2009 pandemic H1N1 influenza and 64.6% (499/773) were cases of seasonal influenza. Of the 274 patients with 2009 pandemic H1N1 influenza, the median age was 29.5 years, and 51.5% were males. Only 1.1% positive patients had recent travel history to an infected region. A median time of five days was observed from onset of illness to influenza A (H1N1) diagnosis, and a median time of six days was reported for hospital stay. All admitted influenza A (H1N1) patients received Oseltamivir drug, but only 16.1% received it within two days of onset of illness. One fourth of the admitted positive patients died. The most common symptoms were cough, fever, sore throat, and shortness of breath. The coexisting conditions were diabetes mellitus, hypertension, chronic pulmonary diseases, and pregnancy (p = 0.001). Chest radiography revealed 93% of the positive patients had pneumonia. CONCLUSION: The clinical course and outcomes of the 2009 pandemic (H1N1) influenza virus are comparable to those of the currently circulating seasonal influenza, with high mortality in influenza A (H1N1) patients. PMID- 21252466 TI - Frequency of HEV contamination in sewerage waters in Pakistan. AB - INTRODUCTION: Enteric viruses, including Hepatitis E virus (HEV), are able to persist under environmental conditions and may cause public health problems by contaminating natural and drinking water resources. Routine procedures for monitoring viruses in water samples have not been established for the water microbiology screening panel. METHODOLOGY: Eighty-six raw sewerage samples were collected from the different regions of Islamabad and Rawalpindi, the twin cities of Pakistan. Samples were concentrated for HEV, using a polyethylene glycol-based method followed by viral RNA extraction using a commercial kit-based method. Reverse transcription polymerase chain reaction (RT-PCR) with HEV specific primers was used for the detection of HEV. RESULTS: The present investigation focused on 86 raw sewerage water samples taken from different locations of drainage outlets of Islamabad and Rawalpindi. After careful experimentation, 35 samples were found to be RT-PCR positive. Nineteen (44.7%) out of 47 samples from Rawalpindi city were HEV positive while 16 (41.02%) out of 39 samples from Islamabad were HEV positive. All positive samples were found in the highly congested areas. CONCLUSIONS: The high detection rate of HEV in this study shows that HEV circulates at a relatively high frequency in the sewerage waters in Pakistan. This study is the first report on detection of HEV from sewerage waste water from Pakistan and suggests that HEV might be a potent indicator of viral pollution in environmental specimens. PMID- 21252467 TI - Leptospirosis in a case of non-Hodgkin lymphoma. AB - Leptospiral meningitis, which is an important feature of anicteric leptospirosis, is generally underdiagnosed. Serological tests are not very useful in diagnosis of leptospiral meningitis. Early detection by molecular tests such as PCR and prompt institution of therapy would be life-saving. PMID- 21252468 TI - Listeria monocytogenes brain abscess in a patient with multiple myeloma. AB - Listeria monocytogenes is an uncommon cause of illness in the general population. Meningoencephalitis is the most common central nervous system (CNS) manifestation of listeriosis. However, brain abscess represents 1-10% of all CNS listeriosis. To our knowledge, L. monocytogenes brain abscess in multiple myeloma patients has not been previously reported. Thus we report a 58-year-old male patient with multiple myeloma who developed a brain abscess due to L. monocytogenes. Due to a history of penicillin allergy, he was treated with intravenous trimethoprim/sulfamoxazole (TMP-SMX) for a total of 12 weeks, and gentamicin for the first two weeks, followed by oral therapy of TMP-SMX for a total of nine months. He is alive six and a half years after the diagnosis of myeloma with occasional brief seizures despite being on two anticonvulsants. PMID- 21252469 TI - Blood group testing in developing countries: an ignored concern. PMID- 21252471 TI - The allometry of brain miniaturization in ants. AB - Extensive studies of vertebrates have shown that brain size scales to body size following power law functions. Most animals are substantially smaller than vertebrates, and extremely small animals face significant challenges relating to nervous system design and function, yet little is known about their brain allometry. Within a well-defined monophyletic taxon, Formicidae (ants), we analyzed how brain size scales to body size. An analysis of brain allometry for individuals of a highly polymorphic leaf-cutter ant, Atta colombica, shows that allometric coefficients differ significantly for small (<1.4 mg body mass) versus large individuals (b = 0.6003 and 0.2919, respectively). Interspecifically, allometric patterns differ for small (<0.9 mg body mass) versus large species (n = 70 species). Using mean values for species, the allometric coefficient for smaller species (b = 0.7961) is significantly greater than that for larger ones (b = 0.669). The smallest ants had brains that constitute ~15% of their body mass, yet their brains were relatively smaller than predicted by an overall allometric coefficient of brain to body size. Our comparative and intraspecific studies show the extent to which nervous systems can be miniaturized in taxa exhibiting behavior that is apparently comparable to that of larger species or individuals. PMID- 21252470 TI - Diminished type III collagen promotes myofibroblast differentiation and increases scar deposition in cutaneous wound healing. AB - The repair of cutaneous wounds in the postnatal animal is associated with the development of scar tissue. Directing cell activities to efficiently heal wounds while minimizing the development of scar tissue is a major goal of wound management and the focus of intensive research efforts. Type III collagen (Col3), expressed in early granulation tissue, has been proposed to play a prominent role in cutaneous wound repair, although little is known about its role in this process. To establish the role of Col3 in cutaneous wound repair, we examined the healing of excisional wounds in a previously described murine model of Col3 deficiency. Col3 deficiency (Col3+/-) in aged mice resulted in accelerated wound closure with increased wound contraction. In addition, Col3-deficient mice had increased myofibroblast density in the wound granulation tissue as evidenced by an increased expression of the myofibroblast marker, alpha-smooth muscle actin. In vitro, dermal fibroblasts obtained from Col3-deficient embryos (Col3+/- and -/ ) were more efficient at collagen gel contraction and also displayed increased myofibroblast differentiation compared to those harvested from wild-type (Col3+/+) embryos. Finally, wounds from Col3-deficient mice also had significantly more scar tissue area on day 21 post-wounding compared to wild-type mice. The effect of Col3 expression on myofibroblast differentiation and scar formation in this model suggests a previously undefined role for this ECM protein in tissue regeneration and repair. PMID- 21252472 TI - Engineered vascular tissue fabricated from aggregated smooth muscle cells. AB - The goal of this study was to develop a system to rapidly generate engineered tissue constructs from aggregated cells and cell-derived extracellular matrix (ECM) to enable evaluation of cell-derived tissue structure and function. Rat aortic smooth muscle cells seeded into annular agarose wells (2, 4 or 6 mm inside diameter) aggregated and formed thick tissue rings within 2 weeks of static culture (0.76 mm at 8 days; 0.94 mm at 14 days). Overall, cells appeared healthy and surrounded by ECM comprised of glycosoaminoglycans and collagen, although signs of necrosis were observed near the centers of the thickest rings. Tissue ring strength and stiffness values were superior to those reported for engineered tissue constructs cultured for comparable times. The strength (100-500 kPa) and modulus (0.5-2 MPa) of tissue rings increased with ring size and decreased with culture duration. Finally, tissue rings cultured for 7 days on silicone mandrels fused to form tubular constructs. Ring margins were visible after 7 days, but tubes were cohesive and mechanically stable, and histological examination confirmed fusion between ring subunits. This unique system provides a versatile new tool for optimization and functional assessment of cell-derived tissue, and a new approach to creating tissue-engineered vascular grafts. PMID- 21252473 TI - Sox9 expression during fracture repair. AB - The molecular and cellular mechanisms involved in bone development provide an insight into the nature of bone regeneration. Sox9 is a key transcription factor for chondrogenesis and is also expressed in osteochondroprogenitors during embryonic bone development. However, it has not been determined whether Sox9 expressing cells appear during fracture repair other than in the cartilaginous callus. On the other hand, the difference between bone development and repair is that the motion of the fractured segments is associated with the subsequent fate decision of osteochondrogenic precursors between osteogenesis or chondrogenesis, but the underlying mechanism of this still has to be elucidated. We herein evaluate whether Sox9-expressing cells appear during osseous regeneration in the initial stages of fracture healing in vivo. We also investigated the association between Sox9 induction and mechanical stress and the role of Runx1 expression. As a result, Sox9- and Runx1-expressing cells were detected in the periosteal callus together with Runx2 expression. Their expression levels were significantly downregulated during its ossification, as observed in embryonic bone development. The application of cyclic tension to isolated and cultured stromal cells resulted in the upregulation and maintenance of Sox9 mRNA expression in vitro. These results showed that as in early skeletal development, Sox9- and Runx1-expressing precursor cells first appear in the periosteal callus as an early fracture repair response. Our findings also suggested that the mechanical environment modulates Sox9 expression levels in osteochondrogenic precursors and consequently influences their fate decision between osteogenic and chondrogenic lineage commitment. PMID- 21252474 TI - DLX3 homeodomain mutations cause tricho-dento-osseous syndrome with novel phenotypes. AB - Tricho-dento-osseous syndrome (TDO) is a rare type of dominantly inherited ectodermal dysplasia so far described only in a few families and associated with 3 known mutations in the DLX3 homeobox gene. Here, we describe two families of Finnish origin that segregate features of TDO in several generations. The affected family members have sparse or curly/kinky hair at birth, markedly delayed or advanced dental maturity, defective tooth enamel and dentin, taurodontic molars, multiple dental abscesses and filling of tooth pulps with amorphous denticle-like material as well as an increased density and/or thickness of craniofacial bones. The disease is especially accentuated in one of the families in which the patients develop only lanugo-type hair and the dental abnormalities are severe. After mutational analysis of DLX3, we identified 2 missense mutations affecting the conserved homeodomain. We suggest that TDO is essentially caused by loss of function and haploinsufficiency of DLX3. PMID- 21252475 TI - Early detection of preeclampsia using inhibin a and other second-trimester serum markers. AB - OBJECTIVE: The purpose of this study was to determine whether second-trimester maternal serum markers including inhibin A are useful for the detection of preeclampsia. METHODS: Between January 2005 and March 2009, we analyzed the data of 4,764 subjects who underwent second-trimester multiple-marker screening for Down syndrome. Serum samples were assayed at 15+0 to 20+6 weeks for maternal serum alpha-fetoprotein (MSAFP), human chorionic gonadotrophin (hCG), unconjugated estriol (uE(3)) and inhibin A. We reviewed all medical records retrospectively, and assessed the relationships of several markers with preeclampsia using logistic regression analysis. RESULTS: The study sample included 41 patients who developed preeclampsia and a control group consisting of the other 4,723 healthy subjects treated between January 2005 and March 2009. There were no significant differences in gestational ages at blood sampling, maternal weights, gravidity and parity between the two groups. However, the mean ages, Apgar scores, gestational age at delivery and neonatal weights were significantly different between the study group and the control group. The levels of markers in the study group were significantly increased compared to the control group, 1.76 +/- 2.68 for inhibin A, 1.18 +/- 0.69 for MSAFP, and 1.62 +/- 1.18 for hCG, but uE(3) did not differ significantly between the two groups. The AUC of inhibin A was 0.715, but the AUC of a three-marker combination model (0.800) was even better. A mid-trimester inhibin A concentration of 1.5 MoM or greater had a sensitivity of 60% and a false-positive rate of 16% for the prediction of preeclampsia. Inhibin A was the best predictor of preeclampsia. Three other markers were reliable predictive markers of preeclampsia. CONCLUSIONS: Inhibin A and other second-trimester serum markers may be useful for early detection of preeclampsia. Inhibin A was in fact the most important predictable marker among the markers we surveyed. The results of this study support those of previous studies, and provide quantified data elucidating the occurrence of preeclampsia. PMID- 21252476 TI - Is ultrasonography useful in predicting thyroid cancer in children with thyroid nodules and apparently benign cytopathologic features? AB - BACKGROUND/AIMS: To assess whether the presence of certain findings on thyroid ultrasonography (US) correctly diagnoses malignancy even when a fine-needle aspiration biopsy (FNAB) suggests a benign lesion. METHODS: We reviewed the charts of 35 children and adolescents with a thyroid nodule who had had an US and a FNAB, and for whom final pathology was available. RESULTS: The global accuracy of FNAB was 83%, with a sensitivity of 75% and a specificity of 94%. 14 FNABs suggested malignancy (40%), only 1 of which was a false positive (7%). By contrast, 5 of the 21 FNABs suggesting benign lesions were false negatives (24%). These 5 cases had US findings suggestive of malignancy. When FNAB suggested a benign lesion, US had a good sensitivity (80%) but a poor specificity and accuracy (50 and 57%, respectively); its negative predictive value was 90% and its positive predictive value 36%. CONCLUSIONS: US complements FNAB in the evaluation of thyroid nodules in children. A more aggressive approach is warranted in children with a thyroid nodule and a benign FNAB if US findings suggest malignancy. PMID- 21252477 TI - A rapid activated protein C sensitivity test as a diagnostic marker for a suspected venous thromboembolism in pregnancy and puerperium. AB - OBJECTIVE: The purpose of the study was to examine whether changes in response to activated protein C (APC) can be a diagnostic marker of venous thromboembolism (VTE) during pregnancy and puerperium. METHODS: The normalized APC sensitivity ratio (sr) was examined in arbitrarily selected healthy Japanese pregnant females and compared with those in non-pregnant females and patients with VTE at the onset before anticoagulation in pregnancy and puerperium using an endogenous thrombin potential-based assay with a computer-assisted calibrated automated thrombography. RESULTS: Sensitivity to APC in patients with VTE at onset was reduced in comparison to that in late pregnancy period and puerperium (p < 0.01, Student's t test). The odds ratio for VTE was 31.9 with statistical significance in pregnant females with suspected clinical symptoms and APC-sr (>=5), although the odds ratio for VTE was not significant with D-dimer (>=5). CONCLUSION: These data suggest that an APC sensitivity test can be a possible surrogate diagnostic marker of suspected VTE during pregnancy and puerperium. PMID- 21252478 TI - Effects of short-term streptozotocin-induced diabetes and vitamin C on platelet non-enzymatic glycation. AB - Diabetes mellitus is one of the most prevalent metabolic syndromes worldwide. Glycation, a chemical modification of proteins with reducing sugars, indicates a possible explanation for the association between hyperglycemia and the wide variety of tissue pathologies. Non-enzymatic glycation (NEG) of platelet proteins is one of the key mechanisms in the pathogenesis of diabetic complications and may be significant in diabetic atherothrombosis. The aim of this study was to investigate the effects of streptozotocin (STZ)-induced short-term experimental diabetes on the glycation of platelets and to find out if vitamin C affected this glycation. A total of 40 male Wistar albino rats, 200-250 g, were randomly divided into 4 groups (2 diabetic and 2 control groups). The diabetic groups were made diabetic by intraperitoneal injection of STZ (65 mg/kg, citrate buffer pH 4.5). By daily intraperitoneal injection, 80 mg/kg vitamin C (Roche, Turkey) was administered until the end of the experiment. Blood glucose levels of the diabetic groups were significantly higher than those at day 0 and also higher than those of the non-diabetic control groups. The changes in total protein, NEG and vitamin C levels were not statistically significant. Although the differences among the groups were not statistically significant, vitamin C administration increased NEG levels in the diabetic group. The results of this study demonstrate that 8 days of STZ-induced short-term diabetes did not cause a significant increase in NEG of platelets. However, the effect of vitamin C on platelet NEG needs to be further investigated. PMID- 21252479 TI - Locusts provide clues to insect mushroom body function. PMID- 21252480 TI - Pneumothorax and bullae in Marfan syndrome. AB - BACKGROUND: Increased risk of spontaneous pneumothorax has been described in patients with Marfan syndrome and has been attributed, in part, to the presence of apical blebs and bullae. OBJECTIVES: We assess the risk of pneumothorax and its relationship to the presence of apical blebs and bullae in patients with Marfan syndrome in the era of CT imaging. METHODS: A retrospective cohort study was performed of all patients 13 years or older with Marfan syndrome evaluated at the Mayo Clinic, Rochester, Minn., USA, from 1998 through 2008. One hundred and sixty-six patients met the current diagnostic criteria for Marfan syndrome and had chest imaging studies available for review. RESULTS: The median age was 40 years (range 14-71); 37% had a smoking history. Eight of 166 patients (4.8%) had experienced 1 or more episodes of spontaneous pneumothorax, and 2 of these 8 patients had 2 or more episodes. Apical blebs or bullae were identified on radiologic imaging in 16 patients (9.6%). Four of 16 (25%) patients with apical blebs or bullae had a history of spontaneous pneumothorax compared to 4 of 150 patients (2.7%) without blebs or bullae (p = 0.003). CONCLUSIONS: The frequency of blebs is relatively low in patients with Marfan syndrome but the risk of pneumothorax is significantly higher in those with radiologically detectable blebs or bullae. Chest CT scanning to identify blebs and bullae may allow risk stratification for pneumothorax in patients with Marfan syndrome. PMID- 21252481 TI - Clinical significance of T-cadherin tissue expression in patients with bladder transitional cell carcinoma. AB - OBJECTIVE: To investigate the clinical significance of T-cadherin (T-cad) tissue expression in patients with bladder transitional cell carcinoma (TCC). MATERIALS AND METHODS: T-cad expression in 113 bladder TCC specimens and 37 normal controls were examined by immunohistochemical staining, and the results were correlated with clinicopathologic parameters. The chi(2) test, Kaplan-Meier survival analysis, log-rank test, and Cox proportional hazard model were used for statistical analysis. RESULTS: T-cad expression in bladder TCC samples was lower than in the controls. Decreased T-cad expression was correlated with advanced stage (p = 0.0027), high grade (p = 0.0078), large tumor size (p = 0.0262), and tumor relapse (p = 0.0293), but no association was found among T-cad expression and age (p = 0.1265), gender (p = 0.4236), tumor number (p = 0.0595) or tumor shape (p = 0.1779). Moreover, decreased T-cad expression was significantly associated with poor overall survival (p = 0.0168), even though it is not an independent prognostic marker (p = 0.2005). CONCLUSIONS: Decreased T-cad expression in tumor tissues is closely associated with malignancy in bladder TCC. PMID- 21252482 TI - Prostate cancer does not influence androgen levels: a radical prostatectomy cohort study. AB - AIM: To investigate the relationship between androgens and prostate cancer in patients scheduled for radical prostatectomy. SUBJECTS AND METHODS: Patients scheduled for open radical prostatectomy were enrolled. Blood samples were collected before prostate biopsy and 12 months later to evaluate testosterone, free testosterone, sex hormone-binding globulin (SHBG), PSA, calculated free and bioavailable testosterone. RESULTS: 44 patients were consecutively enrolled. 15 patients (34%) presented a Gleason score (GS) of 6, 24 patients GS 7 (54%), 1 patient (2%) GS 8, and 4 patients GS 9 (9%). Mean prostate cancer volume was 4.3 +/- 5.7 cm(3). 24 patients presented a pT2 stage, 16 a pT3a stage, and 4 a pT3b stage. Positive surgical margins were detected in 12 patients (27.3%). No significant change of testosterone (4.21 +/- 1.49 vs. 4.00 +/- 1.48 ng/ml, p = 0.46), free testosterone (9.01 +/- 3.64 vs. 8.85 +/- 3.04 pg/ml, p = 0.83), SHBG (38 +/- 14.39 vs. 38.5 +/- 17.23 nmol/l, p = 0.71), calculated free testosterone (0.091 +/- 0.13 vs. 0.067 +/- 0.026, p = 0.563), and bioavailable testosterone (1.89 +/- 0.722 vs. 1.88 +/- 0.53, p = 0.912) was observed. CONCLUSIONS: In our single-center study, prostate cancer does not impact on serum androgen levels, however our results should be confirmed in a larger study. PMID- 21252483 TI - Clinical estimation of fetal weight: is accuracy acquired with professional experience? AB - OBJECTIVE: This study was conducted in order to determine whether experience and type of obstetrical profession improves the accuracy in the clinical estimation of fetal weight among obstetricians and midwives in the delivery room. METHODS: Four groups of professionals in the delivery room clinically estimated the fetal weight in 236 parturients in active labor. Obstetric parameters such as gravidity, parity, gestational age, body mass index, amniotomy, station and cervical dilatation were recorded. Fetal weight estimations were compared with the actual birth weight after delivery. RESULTS: The mean error rate of fetal weight estimation by attending obstetricians, residents, experienced and junior midwives was 7.9 +/- 8.8, 8.0 +/- 8.4, 7.8 +/- 6.3 and 8.5 +/- 6.8%, respectively. Error rates of the 4 groups of examiners were similar, although it was increased in all subgroups when estimating birth weights <2,500 and >4,000 g. Major discrepancies of fetal weight estimation (>10% of the actual fetal birth weight) occurred in 27.2, 28.9, 31.9 and 34.7% by attending obstetricians, residents, experienced and junior midwives, respectively. CONCLUSIONS: We found no additional value for experience and type of obstetrical training in the accuracy of clinical fetal weight estimation. PMID- 21252484 TI - Eotaxin in exhaled breath condensate of allergic asthma patients with exercise induced bronchoconstriction. AB - BACKGROUND: Eosinophils are the key inflammatory cells in asthma, and more and more evidence suggests their crucial role in exercise-induced bronchoconstriction (EIB). Eotaxin, as the most important chemotactic factor for eosinophils, plays an important role in the pathogenesis of asthma. OBJECTIVES: The aim of the study was to evaluate the changes in eotaxin levels in exhaled breath condensate (EBC) following intensive exercise in allergic asthmatics. METHODS: The study was performed in a group of 27 asthmatics (17 with EIB, 13 without EIB) and 9 healthy volunteers. Changes induced by intensive exercise in the concentrations of eotaxin in EBC during the 24 h after an exercise test were assessed. The possible correlations of these measurements with the results of other tests commonly associated with eosinophilic airway inflammation were also determined. RESULTS: In asthmatic patients with EIB, a statistically significant increase in eotaxin concentrations in EBC collected during the first 24 h after an exercise test - with maximal increase after 6 h - was revealed. A statistically significant correlation between the maximum increase in eotaxin concentrations in EBC after exercise, and an increase in either serum eosinophil cationic protein or F(ENO) 24 h after exercise in the group of asthmatics with EIB, was observed. CONCLUSIONS: Our results confirm connections between EIB and airway eosinophilic inflammation. The increase of eotaxin in asthmatic airways, by promoting the migration and activation of eosinophils, may play an important role in upregulation and sustaining of the airway inflammation observed in EIB in asthmatic patients. PMID- 21252485 TI - Multicentric reticulohistiocytosis with dermatomyositis-like features: a more common disease presentation than previously thought. AB - Multicentric reticulohistiocytosis (MRH) is a rare form of non-Langerhans histiocytosis that presents with erosive arthritis and skin nodules. Approximately 25% of patients with MRH have an associated malignancy. Dermatomyositis is an inflammatory autoimmune condition that has also been associated with malignancy. To date, 7 cases of MRH have been reported to present with cutaneous features of dermatomyositis. We describe an eighth patient with MRH who presented with dermatomyositis-like features (V-neck erythema, shawl sign, Gottron's papules and periungual erythema), who developed metastatic breast cancer 1 year after diagnosis. We hypothesized that clinical overlap between MRH and dermatomyositis was not as uncommon as review of the literature suggested. Careful review of the physical exam findings and photographs of the 234 papers reporting MRH revealed 27 cases of MRH with dermatomyositis-like features. Of these 27 cases, 7 (26%) were associated with a malignancy. Skin biopsies of the cutaneous features mimicking dermatomyositis revealed pathologic features of MRH. This is a descriptive analysis of published case reports. Based on a review of published case reports, MRH presenting with dermatomyositis-like features is likely fairly common. Histological examination of skin biopsies allows for disease differentiation. Differentiating MRH from dermatomyositis is important for management decisions and comorbidity screening. PMID- 21252487 TI - Identification of the sex chromosomes of brown trout (Salmo trutta) and their comparison with the corresponding chromosomes in Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss). AB - Males are the heterogametic sex in salmonid fishes. In brown trout (Salmo trutta) the sex-determining locus, SEX, has been mapped to the end of linkage group BT 28, which corresponds to linkage group AS-8 and chromosome SSA15 in Atlantic salmon (Salmo salar). We set out to identify the sex chromosomes in brown trout. We isolated Atlantic salmon BAC clones containing microsatellite markers that are on BT-28 and also on AS-8, and used these BACs as probes for fluorescent in situ hybridization (FISH) analysis. SEX is located on the short arm of a small subtelocentric/acrocentric chromosome in brown trout, which is consistent with linkage analysis. The acrocentric chromosome SSA15 in Atlantic salmon appears to have arisen by a centric fusion of 2 small acrocentric chromosomes in the common ancestor of Salmo sp. We speculate that the fusion process that produced Atlantic salmon chromosome SSA15 disrupted the ancestral sex-determining locus in the Atlantic salmon lineage, providing the impetus either for the relocation of SEX or selection pressure for a novel sex-determining gene to arise in this species. Thus, the sex-determining genes may differ in Atlantic salmon and brown trout. PMID- 21252488 TI - Aneuploidy in the human blastocyst. AB - Studies of human cleavage stage embryos, 3 days after fertilization of the oocyte, have revealed remarkably high levels of chromosome abnormality. In addition to meiotic errors derived from the gametes, principally the oocyte, mitotic errors occurring after fertilization are also common, leading to widespread chromosomal mosaicism. The prevalence of chromosome anomalies in embryos may explain the relatively poor fertility and fecundity in humans and the low success rates of assisted reproductive treatments (e.g., IVF). While much is known concerning the incidence of aneuploidy during the first 3 days following fertilization, it is only in the last couple of years that large numbers of embryos at the final stage of preimplantation development, the blastocyst stage, 5 days after fertilization, have been subjected to detailed analysis. Here we discuss the latest data from the comprehensive cytogenetic analysis of blastocysts. These findings indicate that the majority of selection against chromosome abnormalities does not occur until the time of implantation or shortly after, with aneuploidy typically affecting more than 50% of blastocysts. Additionally, clinical results presented suggest that screening of blastocyst stage embryos for chromosome abnormality, with preferential transfer to the uterus of those found to be euploid, may help to improve the success rates of assisted reproductive treatments. PMID- 21252486 TI - Impact of hypotension and low cerebral perfusion pressure on outcomes in children treated with hypothermia therapy following severe traumatic brain injury: a post hoc analysis of the Hypothermia Pediatric Head Injury Trial. AB - Hypotension and low cerebral perfusion pressure are known to be associated with unfavorable outcome in children and adults with traumatic brain injury. Using the database from a previously published, randomized controlled trial of 24 h of hypothermia therapy in children with severe traumatic brain injury, we compared the number of patients with hypotension or low cerebral perfusion pressure between the hypothermia therapy and normothermia groups. We also determined the association between these physiologic insults and unfavorable outcome using regression analysis. There were more patients with episodes of hypotension or low cerebral perfusion pressure in the hypothermia therapy group than in the normothermia group. These physiologic insults were associated with unfavorable outcome in both intervention groups. Hypotension and low cerebral perfusion pressure should be anticipated and prevented in future trials of hypothermia therapy in patients with traumatic brain injury. PMID- 21252489 TI - Sporadic aneuploidy in PHA-stimulated lymphocytes of trisomies 21, 18, and 13. AB - Following the observation detected in a previous study that X chromosome monosomy in Turner's syndrome genotypes was associated with a sporadic loss and/or gain of other chromosomes, we studied here whether this instability is a consistent finding in constitutional autosomal trisomies. We used PHA-stimulated lymphocytes derived from 14 patients (10 patients with trisomy 21, 2 with trisomy 18, and 2 with trisomy 13). Fourteen healthy controls were compared. Fluorescence in situ hybridization, applied at interphase cells, was used to evaluate the level of aneuploidy for 3 randomly selected chromosomes (autosomes 8, 15, and 16) in each sample. For each tested chromosome, our results showed a significantly higher level of aneuploid cells in the samples from the patients than in those from controls, with no difference between the patient groups. The mean level of aneuploid cells (percentage) for all 3 tested autosomes was almost twice as high in the patient samples as in the control samples. The aneuploidy level was mainly due to monosomy, which was significantly higher in the samples from the patients than in those from controls for each one of the tested chromosomes, with no difference between the patient groups. The mean level of monosomic cells (percentage) for all 3 tested chromosomes was almost twice as high in the patient samples as in the control samples. Our study shows that various constitutional autosomal trisomies are associated with an increased frequency of non-chromosome specific aneuploidy and is a continuation of the previous study documenting sporadic aneuploidy in Turner's sample cells. It is possible that primary aneuploid cells destabilize their own genome resulting in variable aneuploidy of other chromosomes. It is also possible that one or several common factor(s) is/are involved in both constitutional and sporadic aneuploidy. PMID- 21252490 TI - Sister chromatid cohesion control and aneuploidy. AB - Apart from a personal tragedy, could Down syndrome, cancer and infertility possibly have something in common? Are there links between a syndrome with physical and mental problems, a tumor growing out of control and the incapability to reproduce? These questions can be answered if we look at the biological functions of a protein complex, named cohesin, which is the main protagonist in the regulation of sister chromatid cohesion during chromosome segregation in cell division. The establishment, maintenance and removal of sister chromatid cohesion is one of the most fascinating and dangerous processes in the life of a cell. Errors in the control of sister chromatid cohesion frequently lead to cell death or aneuploidy. Recent results showed that cohesins also have important functions in non-dividing cells, revealing new, unexplored roles for these proteins in human syndromes, currently known as cohesinopathies. In the last 10 years, we have improved our understanding of the molecular mechanisms of the cohesin and cohesin-interacting proteins regulating the different events of sister chromatid cohesion during cell division in mitosis and meiosis. PMID- 21252491 TI - Chromosome mapping of H1 histone and 5S rRNA gene clusters in three species of Astyanax (Teleostei, Characiformes). AB - We report here on the physical mapping of the H1 histone genes (hisDNA) and the 5S ribosomal DNA (rDNA) in 3 Neotropical fish species of the genus Astyanax(A. altiparanae, A. bockmanni and A. fasciatus) and the comparative analysis of the chromosomes bearing these genes. Nucleotide analyses by sequencing of both genes were also performed. The distribution of the H1 histone genes was more conserved than that of the rRNA genes, since these were always located in the pericentromeric regions of 2 chromosome pairs. 5S rDNA was found on one of the pairs that presented an H1 histone cluster; this seems to be a conserved chromosomal feature of the genus Astyanax. In addition, individuals of A. bockmanni and A. fasciatus showed clusters of 5S rDNA on 1 pair of acrocentric chromosomes, not found in A. altiparanae. The results obtained by chromosome mapping as well as by sequencing of both genes showed that A.bockmanni is more closely related to A. fasciatus than to A. altiparanae. The results allow the characterization of cytogenetic markers for improved elucidation of the processes involved in karyotype differentiation of fish genomes. PMID- 21252492 TI - Estradiol increases the expression of TNF-alpha and TNF receptor 1 in lactotropes. AB - BACKGROUND: Estrogens are recognized modulators of pituitary cell renewal, sensitizing cells to mitogenic and apoptotic signals. Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine that plays an important role in tissue homeostasis modulating cell proliferation, differentiation and death. We previously demonstrated that TNF-alpha-induced apoptosis of anterior pituitary cells from female rats is estrogen-dependent and predominant in cells from rats at proestrus when estradiol levels are the highest. AIMS: Considering that one of the mechanisms involved in the apoptotic action of estrogens can result from increased expression of cytokines and/or their receptors, the aim of the present study was to evaluate the effect of estrogens on the expression of TNF-alpha and its receptor, TNF receptor 1 (TNFR1), in anterior pituitary cells. METHODS/RESULTS: TNFR1 expression, determined by Western blot, was higher in anterior pituitary glands from rats at proestrus than at diestrus. Incubation of anterior pituitary cells from ovariectomized rats with 17beta-estradiol enhanced TNFR1 protein expression. As determined by double immunocytochemistry, the expression of TNF-alpha and TNFR1 was detected in prolactin-, GH-, LH- and ACTH bearing cells. 17beta-estradiol increased the percentage of TNF-alpha and TNFR1 immunoreactive lactotropes but did not modify the number of GH-bearing cells expressing TNF-alpha or TNFR1. CONCLUSION: Our results demonstrate that estradiol increases the expression of TNF-alpha and TNFR1 in anterior pituitary cells, especially in lactotropes. The sensitizing action of estrogens to proapoptotic stimuli at proestrus in the anterior pituitary gland may involve changes in the expression of the TNF-alpha/TNFR1 system. PMID- 21252493 TI - QT/RR coherence is associated with testosterone levels in men with chronic spinal cord injury. AB - AIM: To evaluate the effect of hypogonadism on temporal characteristics of ventricular repolarization (VR) and QT/RR coherence in men with spinal cord injury (SCI). METHODS: Thirty-four men with SCI (>1 year postinjury) were studied. After clinical evaluation, 20 subjects were diagnosed as hypogonadal and 14 as eugonadal. QT and RT time, heart rate (HR), and Bazett QTc were determined from a digital electrocardiogram during quiet rest and a cold pressor test (CPT). QT/RR coherence was calculated across three spectral frequencies including mean (Mean Coh; 0-0.2 Hz), low (LF Coh; 0.04-0.15 Hz) and high (HF Coh; 0.15-0.40 Hz). Respiration was collected via impedance pneumography. RESULTS: No statistical differences were observed among demographics. Pairwise comparisons demonstrated a significantly reduced Mean Coh at rest in the hypogonadal group compared to the eugonadal; during the CPT, the hypogonadal group had significantly elevated Mean and HF Coh. No group main effects were observed with analysis of variance. Condition main effects were observed in QT, Mean, LF and HF Coh. Significant group-condition interactions were present in Mean and HF Coh, while trends toward significance were observed on LF Coh, HR, QT and RT. Post-hoc pairwise comparisons revealed that the change from rest to CPT in Mean, LF and HF Coh was significant in the eugonadal group, but not the hypogonadal. CONCLUSION: Hypogonadism in SCI appears to adversely affect temporal VR characteristics independently of QTc. QT/RR coherence suggests an autonomic synergism with testosterone. These findings may represent a pathologic sequelae that precedes the well-documented hypogonadic effects on QTc. PMID- 21252494 TI - Modifications of the innate immune system in atopic dermatitis. AB - Atopic dermatitis (AD) is a frequent chronic inflammatory skin disease which is often complicated by recurrent microbial superinfections. Genetically based modifications which might have an impact on the innate immune system, such as impairment of the skin barrier, modifications of pattern recognition receptors, deficiency of antimicrobial peptides, antiviral natural killer cells and plasmacytoid dendritic cells, facilitate the entry of allergens and infectious microbes into the skin, where they encounter immunocompetent cells. The micromilieu in the skin of AD patients further potentiates dysfunctions of the innate immune system, leading to a vicious circle promoting the disease. This article provides an overview of modifications of the innate immune system in AD. PMID- 21252495 TI - New mutation in erythroid-specific delta-aminolevulinate synthase as the cause of X-linked sideroblastic anemia responsive to pyridoxine. AB - BACKGROUND/AIMS: Congenital sideroblastic anemias (SA) are characterized by the presence of ringed sideroblasts in the bone marrow. The most common form is X linked SA, which results from mutations in erythroid-specific delta aminolevulinate synthase (ALAS2), the first enzyme in heme biosynthesis. In addition, autosomal recessive mutations in the erythroid-specific mitochondrial transporter SLC25A38 and glutaredoxin 5 (GLRX5) have recently been identified in SA patients with isolated erythroid phenotype. MATERIALS AND METHODS: We studied 5 young males with congenital SA from the Czech Republic. Mutation analysis was performed on the complete coding regions of 3 candidate genes (ALAS2, SLC25A38 and GLRX5), and the enzyme activity of ALAS2 was measured by a continuous spectrophotometric assay. RESULTS: We found the previously published R452H and R452C ALAS2 mutations in 3 patients. A novel K156E substitution in ALAS2 was discovered in 1 pyridoxine-responsive patient. The functional study showed that this substitution severely decreases ALAS2 enzyme activity. In 1 pyridoxine refractory patient, no mutations were detected in ALAS2, SLC25A38 or GLRX5. CONCLUSION: Our report extends the list of known ALAS2 mutations, with the addition of a novel K156E substitution that is responsive to pyridoxine treatment and contributes to the general knowledge of congenital SA cases characterized worldwide. PMID- 21252496 TI - Vitamin B(12)-responsive pancytopenia mimicking myelodysplastic syndrome. AB - This study presents 12 patients (7 women and 5 men) with vitamin B(12)-responsive pancytopenia who had discordant laboratory findings and were misdiagnosed as having myelodysplastic syndrome (MDS). The median hemoglobin level was 6.5 g/dl, and the leukocyte and platelet counts were 2.85 * 10(9)/l and 55.5 * 10(9)/l, respectively. The median serum lactate dehydrogenase level was high (3,204.5 IU/l). The serum vitamin B(12) levels were within normal limits at the initial evaluation, but a serial follow-up of the vitamin B(12) levels revealed either fluctuations or a gradual decrease. The patients were initially diagnosed with MDS and responded rapidly to a 7-day parenteral B(12) treatment with normal complete blood counts (CBCs). We propose that patients suspected to have MDS may suffer from vitamin B(12) deficiency and that this can be revealed by a normalization of CBCs following 7 days of treatment with parental vitamin B(12). PMID- 21252497 TI - E109K is a SEC23B founder mutation among Israeli Moroccan Jewish patients with congenital dyserythropoietic anemia type II. AB - OBJECTIVE: Congenital dyserythropoietic anemia (CDA) is characterized by ineffective erythropoiesis, binuclearity of erythroid precursors and secondary hemochromatosis. Recently, the gene mutated in CDA type II (CDA II), SEC23B, was identified. All Israeli patients with CDA II are of North African (mainly Moroccan) Jewish descent. We investigated the molecular basis of CDA II in those patients. METHODS: Participants included 11 patients with CDA II from 8 apparently unrelated families. Clinical data were retrieved from medical files, and blood was collected for DNA analysis. RESULTS: The majority of patients (10/11) were homozygous for a common SEC23B mutation (E109K). Haplotype analysis revealed a common genetic background in all patients. One patient was a compound heterozygote for the E109K mutation and a novel mutation, T710M. All patients were transfusion independent, with increasing iron overload with age. We estimate the E109K mutation to be 2,400 years old, in line with Jewish migration history. CONCLUSIONS: Most CDA II patients in Israel are of Moroccan Jewish origin and carry a common SEC23B mutation, E109K, the first to be described as a founder mutation causing CDA II. As previously suggested, carrying 2 missense mutations is associated with a relatively nonsevere phenotype. PMID- 21252498 TI - Mean platelet volume as a marker of thrombosis in patients with missed abortion. PMID- 21252499 TI - Vitamin D status in Jordan: dress style and gender discrepancies. AB - BACKGROUND/AIMS: Vitamin D deficiency is highly prevalent worldwide and has been linked to many diseases. The aims of the present study were to assess the vitamin D status of Jordanians at the national level and to identify groups of the population at high risk for vitamin D deficiency. METHODS: Vitamin D status was assessed in a national sample of 5,640 subjects aged >=7 years. The study involved interviews, laboratory measurements of 25(OH)D and others, and physical measurements. The present report deals, exclusively, with subjects aged >18 years. RESULTS: The prevalence of low vitamin D status [25(OH)D <30 ng/ml] was 37.3% in females compared to 5.1% in males. Dress style in females was independently related to low vitamin D status; women wearing 'Hijab' (adjusted OR = 1.7, p = 0.004) or 'Niqab' (adjusted OR = 1.5, p = 0.061) were at a higher risk for low vitamin D status than were western-dressed women. CONCLUSION: The high prevalence of low vitamin D status in females in contrast with a low prevalence in males, together with a higher prevalence in women wearing Hijab or Neqab, calls for action to increase the population's awareness and to develop strategies to reduce this risk among women, particularly those wearing dress styles that cover most or all of their skin. PMID- 21252500 TI - Progressive sensorineural hearing loss and normal vestibular function in a Dutch DFNB7/11 family with a novel mutation in TMC1. AB - In a Dutch family with autosomal recessive hearing loss, genome-wide single nucleotide polymorphism analysis mapped the genetic defect to the DFNB7/11 locus. A novel homozygous A-to-G change in the TMC1 gene was detected near the splice donor site of intron 19 (c.1763+3A->G) segregating with the hearing loss in this family. One of the 6 transmembrane domains and the actual TMC channel domain are predicted to be absent in the mutant protein. The sensorineural hearing impairment in this DFNB7/11 family has a postlingual onset. Audiometric analysis initially showed a steeply downward-sloping threshold configuration. The progressive phenotype in this family resembles the phenotype previously described for families with dominant TMC1 mutations (DFNA36) rather than that of families with recessive TMC1 mutations (DFNB7/11) which invariably cause severe-to profound prelingual hearing impairment. PMID- 21252501 TI - Safety of intratympanic injection of AM-101 in patients with acute inner ear tinnitus. AB - Effective pharmacological treatments for tinnitus have proven elusive. Emerging evidence suggests that dysregulation of cochlear N-methyl-D-aspartate (NMDA) receptors may underlie aberrant excitation of the auditory nerve, which in turn is perceived as tinnitus. The blocking of these receptors thus represents a promising therapeutic approach. In a recent phase I/II clinical trial, the safety and local tolerance of intratympanic injections of the NMDA receptor antagonist AM-101 was evaluated for the first time in humans. The results from the double blind, randomized, placebo-controlled study show that intratympanically injected AM-101 was well tolerated by study participants, and provided the first indications of therapeutic efficacy. PMID- 21252502 TI - Real-time circuit pressures correlate poorly with circuit longevity in anticoagulant-free, predilution continuous venovenous hemofiltration. AB - BACKGROUND: Continuous venovenous hemofiltration (CVVH) in renal failure is compromised by circuit clotting. We hypothesized that adverse circuit pressures are predictive of clotting in circuits that last less than 24 h during predilution, anticoagulant-free CVVH. METHODS: This was a single-center retrospective study of 63 CVVH circuits of 13 critically ill intensive care unit patients with severe renal failure. Circuits were categorized into 'clotters' (C) or 'nonclotters' (NC), if spontaneous clotting occurred at <24 or >=24 h from the start of CVVH, respectively. RESULTS: Effluent pressures and pre-filter pressures were more adverse in NC compared to C starting from 6 and 4 h before spontaneous clotting, respectively. Arterial pressures and return pressures were not significantly different in C versus NC. Blood flow rate settings, hemofiltration fluid replacement and effluent drainage rates in C versus NC were comparable. CONCLUSION: Real-time circuit pressure readings seem to offer only potentially limited prognostic value in predicting circuit clotting. PMID- 21252503 TI - Left ventricular hypertrophy in incident dialysis patients randomized to treatment with hemofiltration or hemodialysis: results from the ProFil study. AB - INTRODUCTION: Left ventricular hypertrophy (LVH) is present in a majority of hemodialysis (HD) patients and is among the strongest risk factors for cardiovascular events and mortality. Hemofiltration (HF), a purely convective dialysis treatment, has been associated with enhanced hemodynamic stability compared with HD, possibly as a result of a more physiologic removal of fluid and solutes. METHODS: In a randomized controlled study conducted at ten dialysis centers in Sweden and Denmark, incident patients (HD <3 months) without clinical signs or history of cardiovascular disease were randomized to treatment with either online, predilution HF or low-flux HD. The primary endpoint was change in left ventricular mass index (LVMI), as measured by two-dimensional M-mode and Doppler echocardiography. RESULTS: The analyses included 34 patients (18 HF, 16 HD) followed for up to 2 years. At baseline, 65% of the patients had LVH, but LVMI did not differ between the study groups. In the HF group, LVMI decreased by 22 +/- 48 g/m(2) during a mean treatment time of 19 +/- 7 months, while in the HD group the decrease was 15 +/- 57 g/m(2) during 16 +/- 7 months. As analyzed by MANOVA (mixed model), the difference in LVMI over the whole period was statistically significant (p = 0.03) with a more favorable outcome in HF. Blood pressure and other study variables did not differ between the groups, but at baseline and throughout the study, HF patients required heavier antihypertensive treatment. CONCLUSIONS: In incident dialysis patients, long-term predilution HF, a purely convective dialysis treatment, is associated with a significantly more favorable development of LVMI compared with regular low-flux HD. Considering the predictive strength of LVMI as a risk factor, the quantitative difference between the treatments is of clinical importance. PMID- 21252504 TI - Differences between cerebrovascular reactivity to L-arginine in the anterior and posterior cerebral circulation. AB - BACKGROUND: Cerebral endothelial function might be different in distinct cerebrovascular territory, thereby making these areas more susceptible to ischemia and stroke. Higher incidence and prevalence of stroke in males suggest that gender could have a strong influence on this difference. In order to evaluate cerebral endothelial function, we compared cerebrovascular reactivity (CVR) to L-arginine in the anterior and posterior cerebral circulation in healthy young males and females. METHODS: Thirty healthy subjects, 15 females (32.1 +/- 7.1 years) and 15 males (32.2 +/- 6.3 years), were included. The mean arterial velocity in the middle cerebral artery (MCA) and the posterior cerebral artery (PCA) was measured by transcranial Doppler sonography before and after intravenous infusion of L-arginine, and CVR to L-arginine was then calculated. RESULTS: CVR to L-arginine was significantly higher in PCA than in MCA in all subjects (19.2 +/- 8.2 vs. 13.6 +/- 7.1%, p <= 0.01). In addition, CVR to L arginine was significantly more pronounced in females compared to males in PCA (22.7 +/- 8.3 vs. 15.8 +/- 6.7%, p <= 0.01) and MCA (16.8 +/- 6.4 vs. 10.4 +/- 6.4%, p < 0.05). CONCLUSIONS: Lower CVR to L-arginine and therefore lower cerebral endothelial function in the anterior cerebral circulation and in males might be related to the higher incidence of ischemia and stroke in the anterior cerebral circulation, particularly in males. PMID- 21252505 TI - Recurrence risk after noncardioembolic mild ischemic stroke in a Japanese population. AB - BACKGROUND AND PURPOSE: This study aimed to identify the recurrence rate and risk factors or clinical variables predictive of vascular events after mild ischemic stroke (IS). METHODS: From December 2006 to September 2007, patients with acute IS with a modified Rankin Scale of 0~1 were consecutively enrolled in this study. Variables including sex, family history of vascular disease, age, height, weight, stroke subtype, blood pressure, lipid profile, fasting glucose, HbA1c, smoking, alcohol consumption, exercise habits, waist circumference, ankle-brachial pressure index, salt intake and physical activity were assessed. The primary outcome was stroke recurrence or other vascular events such as myocardial infarction, angina pectoris, and peripheral artery disease. Survival curves were calculated by Kaplan-Meier survival analysis, and hazard ratios for recurrence were determined by univariate and multivariate Cox proportional hazards regression models. RESULTS: A total of 102 mild IS patients (78 men and 24 women, mean age 64 years) were successfully followed for 3 years. Of those 102 patients, 25 (24.5%) had stroke recurrence, and 4 (3.9%) had a coronary event. Among the variables studied, abnormal ankle-brachial pressure index, metabolic syndrome, stroke subtypes, salt intake and poor lifestyle management were significant independent predictors of stroke recurrence or cardiovascular events. CONCLUSIONS: In mild IS patients within 3 years after onset, not only pathophysiological factors but also lifestyle factors can aid in the identification of patients at high risk for recurrence. PMID- 21252506 TI - Stroke and myocardial infarction: a comparative systematic evaluation of gender specific analysis, funding and authorship patterns in cardiovascular research. AB - BACKGROUND: Major gender differences exist in cardiovascular diseases and lead to different outcomes in women and men. However, attention and incorporation of sex /gender-specific research might vary among disciplines. We therefore conducted a systematic review comparing publication characteristics and trends between stroke and myocardial infarction (MI) with respect to sex- and gender-related aspects. METHODS: A systematic literature search was performed in PubMed to identify gender-/sex-related articles published for stroke and MI between 1977 and 2008. A specifically designed text mining program was used, and all literature was rated by two independent investigators. Publications were classified according to type of research performed, publication year, funding, geographical location, and gender of first and last authors. RESULTS: 962 articles were retrieved and limited to 405 (42%) gender-relevant publications; 131 on stroke and 274 on MI. Type of performed research differed, especially in disease management, which received little attention (17%) in stroke, while representing the major focus in MI (40%). In both areas, clinical presentation received little attention (3 and 5%). Although publications progressively increased in both fields, an 8- to 10 year time gap emerged for stroke compared to MI. Last authors in both areas were predominantly men, but female last authorship is increasing more significantly over time in the field of stroke. Research on sex and gender differences in MI and stroke is largely underfunded, particularly by the EU. CONCLUSIONS: The data demonstrate how sex-/gender-specific research differs between specialties, most likely due to the diverse interest, funding opportunities and authorship distributions identified. PMID- 21252507 TI - Overview of models for the study of renal disease. AB - This manuscript presents the usefulness of various experimental models in research with the purpose to elucidate mechanisms of disease and help create treatment modalities. The emphasis is on the use of models primarily for the study and treatment of amyloidosis. This is a rare condition that has attracted much attention recently. Amyloidosis is a disease in which the information obtained in the research laboratory has played a key role in advancing our understanding of the mechanisms associated with this group of disorders and in the development of new avenues for therapeutic intervention. Both in-vivo and in vitro models are addressed. The early animal models and the more recent transgenic models are presented along with their usefulness to study the pathogenesis and dissect gene expression profiles where appropriate. Their pros and cons of the various experimental settings are highlighted. In-vitro models are presented with examples from the literature as to how they have or are being used to study a variety of conditions, renal as well as others. They also serve the purpose of resolving questions primarily relating to patho-genesis and to test the value of novel interventions prior to using in vivo models that are generally more expensive and difficult to work with. Since all models have their limitations, perhaps the best way is to utilize both in-vitro and in-vivo platforms, selecting them depending upon the questions to be answered. Employing a large variety of experimental techniques can serve to obtain and validate the data. The advantages of this approach will become obvious in the book chapters that follow. PMID- 21252508 TI - Mesangial homeostasis and pathobiology: their role in health and disease. AB - Mesangial homeostasis is an integral component of normal glomerular function. Alterations in mesangial homeostasis occur frequently, not only in primary glomerular disorders, but also in association with primary tubular interstitial and vascular pathology, although generally the disturbances are not as marked in the latter situations. Mesangial changes could be transitory and reversible or permanent and irreversible, depending on the type and degree of damage inflicted and the reparative ability of the mesangium at a given time. Understanding mesangial pathobiology is crucial for comprehending the reactive and pathological processes that occur in glomeruli. The mesangium is usually the first to react to injurious glomerular events and is often the last to return to normal after the pathological insult has ceased and repair mechanisms have been activated. This is obvious in renal biopsy specimens where mesangial hypercellularity and/or matrix expansion are very common findings in primary glomerular disorders and, as a reactive phenomenon, in primary interstitial and vascular diseases. Repairing mesangial damage represents a fundamental process needed for restoring glomerular function. Since a component of the mesangial damage frequently includes the loss of mesangial cells, a way to revamp mesangial cellularity is essential for restoring mesangial homeostasis. This fact should be taken into account when designing therapies aimed at restoring mesangial integrity and homeostasis. PMID- 21252509 TI - Parietal epithelial cells: their role in health and disease. AB - Parietal epithelial cells of Bowman's capsules were first described by Sir William Bowman in 1842 in his paper On the Structure and Use of the Malpighian Bodies of the Kidney [London, Taylor, 1842], but since then their functions have remained poorly understood. A large body of evidence has recently suggested that parietal epithelial cells represent a reservoir of renal progenitors in adult human kidney which generate novel podocytes during childhood and adolescence, and can regenerate injured podocytes. The discovery that parietal epithelial cells represent a potential source for podocyte regeneration suggests that podocyte injury can be repaired. However, recent results also suggest that an abnormal proliferative response of renal progenitors to podocyte injury can generate hyperplastic glomerular lesions that are observed in crescentic glomerulonephritis and other types of glomerular disorders. Taken together, these results establish an entirely novel view that changes the way of thinking about renal physiology and pathophysiology, and suggest that understanding how self renewal and fate decision of parietal epithelial cells in response to podocyte injury may be perturbed or modulated will be crucial for obtaining novel tools for prevention and treatment of glomerulosclerosis. PMID- 21252510 TI - Role of proximal tubules in the pathogenesis of kidney disease. AB - The proximal tubules make up a significant portion of the kidneys; proximal tubule epithelial cells are the most populous cell type in the kidney, and carry out diverse regulatory and endocrine functions where numerous transporters are located. Under normal circumstances, more than two thirds of filtered salt and water, and all filtered bicarbonate is reabsorbed in the proximal tubule. A number of inherited and acquired acid-base and tubule disorders are linked to impaired transporters in the proximal tubule cells. Equally important is the intrinsic immune characteristics of proximal tubule cells that give them the ability to also function as immune responders to a wide range of immunologic, ischemic or toxic injury. It is therefore not surprising that proximal tubule related phenomena are closely related to the pathogenesis of a vast array of kidney diseases. Many kidney diseases, acute and chronic, first manifest with proximal tubule disorders. Recent insight into molecular characteristics of transport functions in the proximal tubules, and the recognition that proximal tubule cells possess intrinsic immune responses have contributed to an improved understanding of important areas in nephrology, such as Fanconi's syndrome, renal tubular acidosis, phosphate wasting syndromes, Dent's disease, cystinuria and other amino acid transport disorders, acute kidney injury, and the role of proximal tubules in progressive kidney disease. Megalin/ cubilin-mediated endocytosis by proximal tubule cells of increased quantities of filtered proteins (protein overloading) in glomerular diseases appears to evoke cell stress responses resulting in increased inflammatory cytokines leading to tubulointerstitial inflammation and fibrosis. Finally, the proximal tubule may be the site of both active vitamin D synthesis through the action of 1-alpha hydroxylase, and the site where erythropoietin synthesis takes place. Thus, proximal tubule injury also contributes to two distressing consequences of chronic kidney disease: mineral-bone disorder and anemia. PMID- 21252511 TI - Kidney microvasculature in health and disease. AB - The renal microvasculature is composed of the glomerular and peritubular capillary beds which supply the cellular constituents of the kidney with oxygen and nutrients as well as maintain renal function by providing an adequate glomerular filtration rate. As a result, endothelial dysfunction within the kidney can lead to devastating consequences. Recently, a plethora of information regarding the molecular players involved in kidney microvasculature development and disease has emerged. Many of these studies focus on intricate signaling pathways within the local microenvironment of endothelial cells. Here, we highlight some of these studies and relate them to the molecular pathogenesis of glomerular and peritubular endothelial cells in both native and transplant renal diseases. PMID- 21252512 TI - Renal interstitial fibrosis: a critical evaluation of the origin of myofibroblasts. AB - Interstitial fibrosis is a common feature of chronic kidney disease, regardless of the etiology of the primary renal syndrome. Moreover, interstitial fibrosis is the strongest morphologic predictor of clinical outcome and is most tightly linked to progression of disease, even though the primary disease may be of glomerular origin. Also, the presence of an interstitial component in chronic kidney disease often indicates an ominous outcome. The incidence of chronic kidney disease has reached epidemic proportions; thus, understanding the pathophysiology of interstitial renal disease is paramount for the development of new therapeutic approaches to slowing progression. Experimental models of renal fibrosis have been essential in determining the mechanisms and sequence of progression of fibrogenesis, including the roles of endothelium, infiltrating leukocytes and myofibroblasts; of profibrogenic cytokine and growth factor release; of tubular injury and atrophy; and of interstitial extracellular matrix accumulation. Over the last decade, considerable attention has been paid to the origin of the myofibroblast, the cell type most responsible for interstitial matrix accumulation. However, the origin(s) of myofibroblasts and how they gain access to the peritubular interstitium has become a matter of controversy and debate. Interstitial myofibroblasts have been proposed to originate from one or more of five sources: resident fibroblasts (pericytes), adventitial fibroblasts, circulating fibrocytes, tubular epithelial-mesenchymal transition (EMT) or endothelial/ mesenchymal transition. To date, EMT has become the pre-eminent theory of the origin of myofibroblasts; however, a role for EMT in renal fibrosis is rigorously challenged by anecdotal and recent scientific evidence. This chapter will briefly discuss the experimental models used to explore interstitial renal disease in general and will then focus on the controversy related to the origin of myofibroblasts. PMID- 21252513 TI - Immunopathogenesis of idiopathic nephrotic syndrome. AB - Idiopathic nephrotic syndrome is the most frequent glomerular disease in children. The mechanisms underlying its pathophysiology have been investigated by genetic, cellular and molecular approaches. While genetic analyses have provided new insights into disease pathogenesis through the discovery of several podocyte genes mutated in distinct forms of inherited nephrotic syndrome, the molecular bases of minimal change nephrotic syndrome and focal and segmental glomerulosclerosis with relapse remain unclear. The immune system seems to play a critical role in the active phase of this disease through disturbances involving several cell subsets, mainly T cells. The innate immune system may also contribute to the immune disorders. In this review, we discuss recent insights from the molecular and immunological findings and their significance in the context of the clinical course of the disease. PMID- 21252514 TI - Membranous nephropathy. AB - The understanding of cellular and molecular mechanisms involved in the pathogenesis of membranous nephropathy (MN) has come from studies carried out in the Heymann nephritis model of MN in the rat, which closely resembles the clinical and pathologic features of the human disease. MN involves the in situ formation of subepithelial immune deposits as a result of circulating antibodies binding to podocyte antigens. Complement activation leads to assembly of C5b-9 on podocyte plasma membranes, and results in sublethal podocyte injury and proteinuria. The podocyte responds to sublethal C5b-9 attack by activating protein kinases, phospholipases, cyclooxygenases, transcription factors, growth factors, NADPH oxidase, stress pathways, proteinases, etc. These signals impact on cell metabolic pathways, the structure/function of lipids and key proteins in the cytoskeleton and slit diaphragm, and on the turnover of extracellular matrix components. Some effects of C5b-9, including dissolution of the actin cytoskeleton, loss of nephrin expression, reduction in F-actin-bound nephrin and loss of slit diaphragm integrity, affect podocytes adversely. Other effects of complement, such as endoplasmic reticulum stress, may limit injury or promote recovery. A number of studies have confirmed the relevance of several experimental insights to the pathogenesis of human MN, including the presence of autoantibodies directed to podocyte antigens in human MN. Increased understanding of nephritogenic antigens, complement activation, and the cellular signaling pathways and targets of C5b-9 will facilitate the design of new approaches to therapy of this important glomerular disease. PMID- 21252515 TI - Prospects and perspectives on IgA nephropathy from animal models. AB - The focus of this chapter is a systematic and critical review of the insights that experimental models have contributed to our understanding of IgA nephropathy (IgAN). We consider the generation of IgA subject to glomerular deposition, the partitioning of IgA between the circulation and glomeruli, the clearance of IgA and complexes containing IgA from the circulation, the 'upstream' effectors of glomerular pathophysiology, the inflammatory mediators that connect intraglomerular stimuli to functional and morphologic effects, and the contribution of animal models to our current understanding of the role that glycosylation of IgA plays in the genesis of IgAN. In each of these subsections, the evidence in favor of each principle or hypothesis is weighed in consideration of other potentially contradictory evidence and relevant issues related to IgAN in patients. The key limitations of each model system are presented, and where possible, reconciliation of discrepant observations are proposed. Subsequently, a synopsis of spontaneous models that do not offer particular mechanistic insights, and a compilation of experimental therapeutic initiatives, are reviewed. In all respects, the discussion of observations in patients or cells in vitro is limited to points where these data impinge upon interpretation of the data derived from the animal models. PMID- 21252516 TI - Infection-related glomerulonephritis. AB - The epidemiology of infection related glomerulonephritis has been changing during recent decades. With the successful treatment of streptococcal infections, the incident of classic post-streptococcal glomerulonephritis is decreasing in most developed countries. In contrast, we see staphylococcus infection related glomerulonephritis more frequently. Animal models reproducing these glomerulonephritides are scant, particularly because it is difficult to develop clinically relevant animal models of infection related glomerulonephritis. Species specific immune responses as well as differences in susceptibility between species and even between animal strains make the interpretation of animal models difficult. Still, these models significantly contributed to our understanding of infection related glomerulonephritis. This is a short review focusing on the existing animal models of infection associated glomerulonephritis. PMID- 21252517 TI - Discovery of genes related to diabetic nephropathy in various animal models by current techniques. AB - One of the major problems facing clinical nephrology currently throughout the world is an exponential increase in patients with end-stage renal disease (ESRD), which is largely related to a high incidence of diabetic nephropathy. The latter is characterized by a multitude of metabolic and signaling events following excessive channeling of glucose, which leads to an increased synthesis of extracellular matrix (ECM) glycoproteins resulting in glomerulosclerosis, interstitial fibrosis and ultimately ESRD. With the incidence of nephropathy at pandemic levels and a high rate of ESRD, physicians around the world must treat a disproportionately large number of diabetic patients with upto-date innovative measures. In this regard, identification of genes that are crucially involved in the progression of diabetic nephropathy would enhance the discovery of new biomarkers and could also promote the development of novel therapeutic strategies. Over the last decade, we focused on the recent methodologies of high throughput and genome-wide screening for identification of relevant genes in various animal models, which included the following: (1) single nucleotide polymorphism-based genome- wide screening; (2) the transcriptome approach, such as differential display reverse transcription polymerase chain reaction (DDRT PCR), representational difference analysis of cDNA (cDNA-RDA)/suppressive subtractive hybridization, SAGE (serial analysis of gene expression) and DNA Microarray; and (3) the proteomic approach and 2- dimensional polyacrylamide gel electrophoresis (2D- PAGE) coupled with mass spectroscopic analysis. Several genes, such as Tim44 (translocase of inner mitochondrial membrane- 44), RSOR/MIOX (renal specific oxidoreductase/myo-inositol oxygenase), UbA52, Rap1b (Ras-related GTPase), gremlin, osteopontin, hydroxysteroid dehydrogenase- 3beta isotype 4 and those of the Wnt signaling pathway, were identified as differentially expressed genes in kidneys of diabetic rodents. Functional analysis of these genes and the subsequent translational research in the clinical settings would be very valuable in the prevention and treatment of diabetic nephropathy. Future trends for identification of the biomarkers and therapeutic target genes should also include genome scale DNA/histonemethylation profiling, metabolomic approaches (e.g. metabolic phenotyping by 1H spectroscopy) and lectin microarray for glycan profiling along with the development of robust data-mining strategies. PMID- 21252519 TI - Experimental models of lupus nephritis. AB - A number of murine models recapitulate many of the features of systemic lupus. Spontaneous models of lupus have provided the basis for genetic linkage studies to define loci that confer an increased risk of nephritis in susceptible mice. Functional relevance of genes within susceptibility loci have been verified through the use of transgenic mice bearing targeted deletions or overexpression of candidate genes. Critical gene targets are involved in the production of autoantigens, stimulation of B cells to produce autoantibodies, stimulation of T cells to provide B cell help and cytokine-mediated damage following tissue deposition of immune complexes. In this overview, features of the commonly employed models of human lupus nephritis are reviewed. Strategies to identify candidate genes involved in the initiation and progression of lupus nephritis in these models are discussed. Finally, key studies to validate target genes as pathophysiologically relevant mediators of lupus nephritis and studies to identify potential targets for therapeutic intervention are summarized. PMID- 21252518 TI - Glomerular basement membrane disorders in experimental models for renal diseases: impact on understanding pathogenesis and improving diagnosis. AB - Animal models have provided important insights into human renal diseases that arise from mutations in genes that encode or regulate the synthesis of glomerular basement membrane proteins. This chapter describes several well-characterized animal models of type IV collagen disorders (Alport syndrome, HANAC syndrome), a laminin disorder (Pierson syndrome), nail-patella syndrome and HERNS syndrome. These models can be exploited in studies of the pathogenesis and treatment of such disorders. PMID- 21252520 TI - Experimental models of membranoproliferative glomerulonephritis, including dense deposit disease. AB - Membranoproliferative glomerulonephritis (MPGN) is characterised by mesangial expansion and hypercellularity and capillary wall thickening with capillary wall and mesangial deposits of immunoglobulin and/or complement. Two main forms are described in humans: MPGN type I with subendothelial and mesangial electron-dense deposits on electron microscopy, and MPGN type II, or dense deposit disease, with electron dense transformation of the glomerular capillary wall. Spontaneous MPGN type I has been described in dogs and sheep in association with C3 deficiency. Induced models of MPGN type I have been described in mice with cryoglobulinaemia. Glomerulonephritis resembling MPGN type II has occurred spontaneously in pigs that have a genetic deficiency of the complement control protein factor H. The animals develop capillary wall deposits of C3 before birth. Mice have been genetically engineered with a deficiency of factor H and similarly develop glomerular capillary wall C3 with MPGN. This model has been used to study both pathogenesis and therapeutic interventions. In particular, MPGN associated with factor H deficiency is absolutely dependent on both the ability to activate C3 and on the ability of factor I to cleave C3b. There is an important role for C5 activation in the development of glomerular inflammation in this model. Factor H dysfunction is associated with an increased susceptibility to complement activating nephrotoxic insults and in these scenarios C5 activation appears to play a major role in mediating glomerular injury. PMID- 21252522 TI - Monoclonal immunoglobulin light and heavy chain deposition diseases: molecular models of common renal diseases. AB - Light, light and heavy, and heavy chain deposition diseases (LCDD, LHCDD and HCDD, respectively) belong to a family of diseases featuring deposition in the kidney of a monoclonal immunoglobulin (Ig) or its isolated subunits, which also includes light chain amyloidosis, non-amyloid fibrillary and immunotactoid glomerulonephritis, and cryoglobulinemic glomerulonephritis. In clinical and pathologic terms, LCDD, LHCDD and HCDD display essentially similar characteristics, such as involvement of multiple organs, prominent renal involvement with severe renal failure, diabetes-like nodular glomerulosclerosis, marked thickening of tubular basement membranes, and monotypic deposits of Ig light chains (mostly kappa) and/or heavy chains (mostly gamma) that feature a non organized granular, electron-dense appearance by electron microscopy. The most common cause is myeloma, although in a fair proportion of cases there is no (clinically) patent hematological disease. Recent progress has been made in understanding the molecular mechanisms of Ig-chain deposition and extracellular matrix accumulation, which opens up new therapeutic avenues in addition to eradication of the Ig-secreting plasma cell clone. Because these diseases represent a model of glomerular and interstitial fibrosis that is induced by a single molecule species, a better understanding of their pathophysiological mechanism may help unraveling the pathomechanisms of kidney fibrosis and renal disease progression. PMID- 21252521 TI - Experimental models of vasculitis and glomerulonephritis induced by antineutrophil cytoplasmic autoantibodies. AB - Antineutrophil cytoplasmic autoantibodies (ANCA) are closely associated with systemic small vessel vasculitis characterized by segmental vessel wall necrotizing inflammation and a paucity of immunoglobulin deposition. Clinically, in vitro and experimental animal model observations indicate a direct pathogenic role for ANCA. This review focuses on the results of experiments utilizing a mouse model of ANCA disease induced by transfer of mouse anti-MPO IgG or anti-MPO lymphocytes into recipient mice, which causes small vessel vasculitis and glomerulonephritis that closely mimics human disease. Evidence for the following conclusion about this model, and by implication about human ANCA disease, will be summarized as follows: (1) anti-MPO IgG is sufficient even in the absence of functional T cells to cause disease and anti-MPO T lymphocytes are not sufficient to cause acute injury; (2) neutrophils are required; (3) ANCA antigens in bone marrow-derived cells are sufficient targets; (4) increased circulating pro inflammatory cytokines and microbial products exacerbate disease, and concurrent viral infection exacerbates and modulates the phenotype of disease; (5) Fcgamma receptor engagement is required for disease induction, and Fcgamma receptor repertoire modulates the phenotype of disease, especially pulmonary disease; (6) activation of the alternative pathway of complement is required, complement is activated by factors released by neutrophils stimulated by ANCA IgG and engagement of C5a receptors is a primary event in complement-mediated amplification; and (7) genetic background has a marked influence on the severity and outcome of disease, and modified gene expression in bone marrow-derived cells is the primary basis for genetically determined differences in disease susceptibility. Investigations using this animal model of ANCA disease have provided important insights into the cellular, molecular and genetic factors involved in the pathogenesis of ANCA disease which are likely to lead to the identification of improved markers of disease activity and response to therapy, as well as more effective and less toxic therapies. PMID- 21252523 TI - Renal amyloidosis: current views on pathogenesis and impact on diagnosis. AB - The amyloidoses constitute a group of diseases in which misfolding of extracellular proteins plays a fundamental role. The aggregation of normally soluble proteins into insoluble unbranching fibrils is the basic underlying pathology in amyloidosis. The process of amyloid formation generates toxic insoluble (in saline) protein aggregates that are deposited in tissues in the form of beta- pleated sheets of fibrillary material. The amyloidoses are considered to be part of the so-called protein storage diseases (protein thesauroses). In addition, due to the unusual protein folding associated with amyloid, this group of diseases has been referred to as conformational and protein folding disorders. For many years amyloidosis was considered an extremely rare, somewhat mysterious disease. However, in recent years its pathogenesis, particularly that of renal amyloidosis, has been carefully dissected in the research laboratory using in vitro and, to a lesser extent, in vivo models. These have provided a molecular understanding of sequential events that take place in the renal mesangium leading to the formation of amyloid fibrils and eventual extrusion into the mesangial matrix, which itself becomes seriously damaged and, in due time, replaced by the fibrillary material. Amyloid, once considered to be an 'inert' substance, has been proven to be involved in crucial biological processes that result in the destruction and eventual replacement of normal renal constituents. Although there are more than two dozen recognized amyloid precursor proteins (and new ones being added to the list) that can be involved in the genesis of amyloid fibrils, the pathophysiologic mechanisms that occur in the renal mesangium are likely to be very similar, if not the same, regardless of the type of amyloidosis. Likewise, the same is true of amyloid formation in the renal vasculature. Mesangial cells are essentially smooth muscle cells and the events that take place in the mesangium and vasculature (where smooth muscle cells and/or pericytes are present) in the entire body responsible for the formation of amyloid are the same. In the renal interstitium, fibroblasts likely participate in the formation of amyloid, following a similar sequence of events as smooth muscle cells. Although much of the information gathered has been from in vitro systems, an in vivo model of renal amyloidosis has recently been designed to study renal amyloidogenesis. Crucial steps in the cascade of events that result in the formation of amyloid fibrils have been elucidated in the laboratory. The information that has been gathered regarding the pathogenesis of amyloidosis has been translated to the clinical arena where implementation of new therapeutic approaches is beginning to occur. Additional molecular-based therapies will be implemented in the near future. PMID- 21252524 TI - Toward understanding renal Fanconi syndrome: step by step advances through experimental models. AB - Renal Fanconi syndrome (FS) is a generalized dysfunction of proximal tubular epithelial cells leading to the urinary leak of essential metabolites like phosphate, uric acid, glucose, amino acids and low molecular weight proteins. From inherited forms involving mutations on apparently unrelated genes to acquired forms induced by drugs, heavy metals or monoclonal immunoglobulin (Ig) light chains (LC), heterogeneous causalities of FS have complicated the understanding of this pathology for a long time. Experimental models of FS have allowed researchers to face the challenge and have helped unravel the main mechanisms disturbing proximal tubule reabsorption. Administration of cadmium to animals first demonstrated an inhibition of Na/K/ATPase activity, highlighting how a single toxic component could induce the general sodium-linked transport defect observed in FS. Today, genetically modified mice allow the development of reliable and reproducible experimental models for inherited or acquired forms of FS. One of the most exciting advances offered by these models is the unexpected major role of endocytosis in the function of the proximal tubule revealed by megalin and ClC-5 knockout mice. Using gene-targeted insertion, a transgenic mouse for LC-associated FS, the most frequent adult form of FS, has also been recently developed and represents a major step in the development of models of this pathology. Beyond deciphering molecular and cellular events at the origin of FS, these models also represent essential tools for the development of therapeutic strategies. PMID- 21252525 TI - Light chain-mediated tubulopathies. AB - Immunoglobulin light chains are low molecular weight proteins that are filtered through the glomerulus and reabsorbed into the proximal tubular epithelium by binding initially to a heteromeric receptor complex composed of megalin and cubilin. Saturation of this receptor-mediated endocytotic process results in the presence of free light chains in the distal nephron and urine. In the course of metabolism of monoclonal light chains, nephrotoxicity can occur, resulting in clinical manifestations that can include acute kidney injury and progressive chronic kidney disease. Patterns of tubulopathic renal injury include proximal tubular epithelial cell cytotoxicity, tubulointerstitial nephritis and cast nephropathy (also known as 'myeloma kidney'). Research efforts over the past two decades have refined understanding of the molecular mechanisms involved in light chain-mediated tubular injury and are the subject of this review. PMID- 21252526 TI - HIV-associated nephropathy: experimental models. AB - Since 1984 reports of renal involvement in AIDS patients have been presented in the literature. Different forms of renal disease were noted in the AIDS population including those related to systemic and local renal infections, tubulointerstitial disease, renal involvement by neoplasm and glomerular disease including collapsing glomerulopathy (CG). HIV-associated nephropathy (HIVAN) has been demonstrated to be more severe in the black population. HIVAN is the most common cause of renal failure in HIV-1-seropositive patients. The term HIVAN is reserved for the typical histopathological form of focal and segmental glomerulosclerosis (FSGS) characterized by the findings of coexistent glomerular and severe tubulointerstitial disease. In both humans and the murine model, glomerular lesions include FSGS, glomerular collapse and podocyte hyperplasia. The tubulointerstitial damage as well as the glomerular collapse can also be seen in non-HIV primary collapsing GN, raising the question of common mechanisms to HIV and other non-identified viral agents related to the development of the disease. Although controversial, increasing evidence supports a direct effect of the virus on renal cells either as a result of exposure to viral proteins or direct renal parenchyma infection. The use of a HIV-1 transgenic mouse model has demonstrated a direct etiologic link between HIV-1 expression in kidney and the development of HIVAN with unique viral-host interactions, which depend at the same time on stimulating features of the virus and the individual nature of the host response. The infection of renal cells by HIV-1 could be detected by reverse transcription-polymerase chain reaction (RT-PCR) of gag RNA at a low level. Some studies using an HIV-1 transgenic mouse model have demonstrated that expression of HIV- 1 in the kidney is required for the development of HIVAN. The final common pathway in the development of HIV-associated nephropathy is likely to involve alterations in the patterns of gene expression of renal parenchyma cells by cytokines and growth factors, leading to interstitial fibrosis and enhanced glomerular matrix synthesis. The nature of the host response to viral infection is critical to the development of nephropathy.HLA-linked responses particular to a subset of blacks may explain some of the epidemiologic features of HIVAN. There may also be biological heterogeneity in the strains of HIV-1 that could account for a particular renotropic strain. HIV strains from different parts of the world may vary by as much as 15% at the level of nucleotide sequence. The infectivity of human immunodeficiency virus (HIV-1) in human glomerular cells has been evaluated by exposing homogeneous cultures of human glomerular capillary endothelial, mesangial and epithelial cells to HIV in vitro. The mechanism of access of HIV into glomerular endothelial and mesangial cells is unknown up to now; HIV is generally infectious for cells expressing the CD4 antigen in their cell membrane. Other modes of HIV entry into cells independent of the CD4 receptor are possible through mechanisms involving Fc-receptors or coinfection with other enveloped viruses such as HTLV-l. Our understanding of the pathogenesis of HIVAN has been aided by the development of a transgenic model. The curious fact that only 3 of 8 founded transgenic lines developed nephropathy emphasizes that the expression of viral gene products per se is not sufficient to produce nephropathy. Human renal epithelium does not express CD4 receptors and in vitro attempts to infect glomerular epithelial cells using laboratory strains of HIV-1 have proven fruitless. The striking morphologic and phenotypic similarities between HIVAN and collapsing idiopathic FSGS raise the question whether the altered podocyte gene expression in collapsing idiopathic FSGS may also be due to a viral infection. This hypothesis is further supported by de novo occurrence of collapsing idiopathic FSGS in immunosuppressed renal transplantation patients and by epidemiologic data. In conclusion, there are likely to be common mechanisms in the pathogenesis for collapsing idiopathic glomerulosclerosis and HIVAN. A primary injury of the podocyte leading to dysregulation of the cellular phenotype appears to mediate the glomerular tuft collapse in both conditions. Primary collapsing glomerulopathy recurs post-transplantation, raising the possibility of circulating factors implicated in the pathogenesis of visceral epithelial cell damage in steroid-resistant minimal change disease or recurrent FSGS. Recurrence of CG can occur hours after transplantation, suggesting that the plasma of CG patients contains one or more factors capable of inducing proteinuria due to the damage of the podocyte that results in the increase in glomerular permeability. In a rat model of CG developed by our group, the injection of serum from CG patients resulted in proteinuria, glomerular tuft retraction and podocyte damage at the ultrastructural level (visceral epithelial cell foot-process effacement). No ultrastructural or light microscopy abnormalities were seen in rats injected with serum from non-collapsing FSGS or healthy subjects. Based on the experience of our group, circulating factors play a dominant role in the pathogenesis of idiopathic CG. PMID- 21252527 TI - Acute kidney injury: lessons from experimental models. AB - For decades severe tubular necrosis has been the hallmark of experimental models of acute renal failure (ARF), such as prolonged ischemia and reflow. This fits well with the still widely used traditional clinical term 'acute tubular necrosis'. Nevertheless, the rareness of tubular necrosis in human kidney biopsies in the background of hypoxic, toxic and septic AKI led to the adoption of a new term, 'acute kidney injury' (AKI), which refers to such clinical scenarios irrespective of the renal morphology. Indeed, experimental AKI models, which have more limited acute renal parenchymal compromise, underscore the focal and regional tissue injury patterns that range from adaptive stress response, through cellular dysfunction, apoptotic cell death and frank acute tubular necrosis. Such stress and injury patterns, short of necrosis, may go unnoticed morphologically and even functionally, and may even confer resistance to subsequent insults. Herein we describe the spectrum of what we call 'sublethal injury', referring to a condition, which by itself is insufficient to produce cellular death, but may or may not produce organ failure. Such sublethal injury can be detected by overt morphological changes, by the upregulation of cell survival factors, and by recently developed biomarkers and imaging techniques of organ physiology and dysfunction. The use of combined sublethal insults in animal models is an attempt to replicate the clinical situation of comorbidities, a circumstance which underlies most situations of AKI. This review will discuss the definition of such sublethal injury and the modes of its detection. PMID- 21252528 TI - Pathogenesis of tubular interstitial nephritis. AB - Injury to the interstitium of the kidney is regarded as a common pathway leading to end-stage renal insufficiency, regardless of etiology. Tubular interstitial nephritis is characterized histologically by inflammatory changes in the tubulointerstitial compartment, such as interstitial edema, leukocyte infiltration, accumulation of extracellular matrix proteins, tubular dilation and atrophy. Acute interstitial nephritis is often associated with use of drugs, such as beta-lactam antibiotics and non-steroidal anti-inflammatory drugs, and is likely mediated through allergic mechanisms. On the other hand, chronic progressive tubular interstitial nephritis has a much more diverse etiology, ranging from infection and drugs to immune-mediated, hematologic, metabolic and hereditary disorders. Experimental studies in the past decade have focused mainly on common factors and mechanisms underlying chronic tubulointerstitial injury, such as activation of peritubular fibroblasts, leukocyte infiltration, release of inflammatory cytokines and growth factors at affected regions, epithelial mesenchymal transition of tubular epithelium, and apoptosis. The execution of each is mediated by a number of local stimuli, such as filtered albumin, chronic hypoxia and oxidative stress, in addition to cytokines and growth factors. This chapter provides an overview of acute and chronic tubular interstitial nephritis, according to clinical manifestations of the disease. It also provides insight into common pathways underlying chronic tubular interstitial nephritis based on recent advances in translational and experimental research. PMID- 21252529 TI - Obstructive uropathy. AB - Chronic tubulointerstitial nephritis (TIN), characterized by tubular atrophy, interstitial fibrosis and inflammation, is a major prognostic determinant of chronic kidney disease, regardless of the original cause of the kidney disease. Understanding the pathogenesis of TIN has been hampered by the lack of an adequate experimental model. However, the demonstration that the renal lesions of obstructive uropathy induced by experimental urinary obstruction (UO) has provided an excellent model to study the pathogenesis of TIN in general and especially congenital obstructive nephropathy, the most common cause of pediatric end-stage renal disease. Since relief of experimental UO is technically possible, this model is particularly useful for studying the potential reversibility of TIN. Experimental UO is usually created by the unilateral ligation of a ureter. This induces progressive tubular epithelial cell injury, including apoptosis, proliferation, loss of differentiation and atrophy; interstitial inflammatory cell infiltrates composed predominantly of macrophages and T cells; and interstitial fibrosis characterized by an increase and activation of interstitial fibroblasts, deposition of extracellular matrix proteins and loss of peritubular capillaries. These changes collectively lead to progressive scarring and the loss of renal parenchyma and kidney function. The glomeruli and large blood vessels remain either normal or show mild changes later in the course of the disease. In addition to TIN, congenital obstructive nephropathy causes marked derangement of renal and glomerular development. Relief of UO does not seem to reverse TIN. In fact, the renal lesions of obstructive uropathy not only persist, but also progress long after UO is relieved in both adult and neonatal rats. The pathogenesis of UO-induced TIN has been well studied, at least in part because of the ready application of this model to mice, in which genetic manipulation including gene deletion or transfection of putative pathogenic molecules is technically feasible. Experimental UO immediately induces mechanical stretching of tubular epithelial cells and activates the renin-angiotensin system, leading to profound changes of the cells, including neo-expression of a large number of molecules which control cell cycle (e.g. caspases, intrinsic and extrinsic death pathway molecules, inhibitors of cyclin-dependent kinases p27 and p21, reactive oxygen species, and catalase), hypoxic response (HIF- alpha), epithelial mesenchymal transformation (e.g. hepatocyte growth factor, bone morphogenic protein 7 and nestin), and the upregulation of cytokines and growth factors (e.g. TGFbeta-1, EGF, PDGF, VEGF and TNF-alpha) as well as chemokines (MCP-1, osteopontin, IL-1, ICAM-1, VCAM-1 and selectins). Inflammatory cells are recruited immediately after UO, probably under the effect of the renin angiotensin system and later by tubular cell-derived chemokines. Several chemokines and their receptors are also expressed by the infiltrating inflammatory cells, thereby augmenting the recruitment of additional inflammatory cells through an autocrine loop. These molecules are probably also responsible for an increased number interstitial fibroblasts, which are derived not only from the proliferation of resident interstitial fibroblasts, but also from the renal homing of bone marrow-derived fibrocytes and the transformation of tubular epithelial cells, endothelial cells and pericytes into interstitial fibroblasts. Activated interstitial fibroblasts are responsible for the increased synthesis of extracellular matrix protein. This together with an impairment of various fibrolytic pathways leads to the increased deposition of extracellular matrix protein. In summary, typical features of TIN are regularly induced in the experimental model of obstructive uropathy. This versatile model has contributed much to elucidate the mechanism of TIN. The translation of this body of knowledge into TIN in general and its effective treatment of obstructive uropathy remains to be explored. PMID- 21252530 TI - Renal vasculature in essential hypertension: a review of some contrarian evidence. AB - This chapter reviews a body of evidence concerning the anatomic pathology, pathogenesis, epidemiology and possible etiologic agents of benign essential hypertension in human populations. A core finding serves as the starting point for further reasoning: intimal fibroplasia of renal interlobular arteries (arteriosclerosis) increases with age at varying rates in all populations around the world, and the rise of mean arterial pressure (MAP) with age is closely tied to this process. The weight of evidence favors the view that fibroplasia progresses for wholly unknown reasons, is not accelerated by elevations in MAP, and that it raises MAP in proportion to its severity by creating nephron heterogeneity that initiates Goldblatt mechanisms. This form of hypertension has been designated type 2 to distinguish it from a less common form, called type 1, where the fibroplasia is of mild or minimal degree. This chapter reviews evidence that indicates type 1 does not evolve into type 2 because hypertension is not accelerating the process.Experimental models of hypertension include the Goldblatt model, which resembles some aspects of type 2, and spontaneous genetic models, which mimic some aspects of type 1 hypertension. There is currently no persuasive evidence that type 2 hypertension, as it naturally develops in the human during aging of 50 years or more, can be reproduced in laboratory animals. Clues to the etiology of the arterial fibroplasia that appears to underlie most instances of essential hypertension would best be sought in the study of variations among human populations around the world, and especially of their migrants. PMID- 21252531 TI - Thrombotic microangiopathies: from animal models to human disease and cure. AB - Thrombotic microangiopathies are a group of microvascular disorders, with reduced organ perfusion and hemolytic anemia. The two most relevant conditions characterized by thrombotic microangiopathic anemia (TMA) are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). In TTP, systemic microvascular aggregation of platelets causes ischemia in the brain and other organs. In HUS, platelet-fibrin thrombi predominantly occlude the renal circulation. TTP can be inherited due to deficiencies in the activity of von Willebrand factor cleaving protease (ADAMTS13) or acquired due to the presence of autoantibodies directed against ADAMTS13. The majority of HUS cases are secondary to infections by strains of Escherichia coli that produce Shiga-like toxins (Stx HUS), while about 5- 10% of all cases are classified as atypical HUS (aHUS). Genetically derived impaired regulation of the complement system is associated with aHUS. Infusion or the exchange of fresh frozen plasma have ameliorated the prognosis of TMA; however, no specific therapies aimed at preventing or limiting the microangiopathic process have been proven to affect the course of TMA. Large mammals, small animal models, knockout and transgenic mouse models of TTP and both Stx-HUS and aHUS have been developed and have provided outstanding contributions to nearly all areas of TMA research. A better understanding of the key clinical features of the diseases and of the importance of genetic and/or environmental factors involved in the pathogenesis of the diseases have been obtained. These animal models have also allowed the set up of protocols aimed at ameliorating the clinical approach to patients and for the development of new drugs and vaccines. PMID- 21252532 TI - Glomerular repair: present status and future expectations. AB - This book covers much on mechanisms involved in glomerular damage which may lead to irreversible changes and loss of nephron function. The fact that these mechanisms have been elucidated is very important for the design of therapeutic options aiming at controlling and ameliorating tissue damage, thus delaying and, in some instances, completely stopping progression to end-stage renal disease, and facilitating repair. The ability of the body to maintain renal homeostasis indicates that a reservoir of cells should exist somewhere in the body to support normal turnover of glomerular cells but insufficient to adequately repair the damage in major glomerular damage. Although tubular cells can repopulate damaged tubules spontaneously after major injury, that is not the case with glomerular cells. Chronic progressive renal disease is characterized by glomerulosclerosis, interstitial inflammation, tubular damage and interstitial fibrosis. If the adaptive capacity of the cells present in a particular renal compartment is exceeded, the injurious agent/reaction produces irreversible damage leading to cell death which may be by apoptosis or necrosis. Lost cells need to be restored and the extracellular matrix scaffold must be remodeled to its original form. This chapter will recapitulate what is known about glomerular healing and repair. The field is evolving and changing rapidly. PMID- 21252533 TI - Apparent non-cited overlap between two published articles by the same group of authors. PMID- 21252534 TI - The QT variability index and cardiac autonomic modulation: perspectives from apparently healthy men with spinal cord injury. AB - OBJECTIVE: To describe the effect of spinal cord injury (SCI) on the QT variability index (QTVI). METHODS: Digital electrocardiograms from 113 age matched men (40 with tetraplegia, 26 with high paraplegia, 17 low paraplegia and 31 controls) were analyzed. RR interval, heart rate (HR) variability [total power (TP(RR)), low frequency (LF(RR)) and high frequency (HF(RR))], QT interval duration, Bazett HR-corrected QT (QTc), QT interval variance (QTVN) and QTVI were compared. RESULTS: Significant group main effects were present for RR, QTc, TP(RR) and LF(RR), but not QT duration, QTVN or HF(RR). Post hoc comparisons revealed the following: (1) longer RR in controls versus subjects with high paraplegia and low paraplegia, and in subjects with tetraplegia versus high paraplegia and low paraplegia; (2) QTc was longer in subjects with low paraplegia versus controls and shorter in subjects with tetraplegia versus high paraplegia, and (3) TP(RR) and LF(RR) were different in controls and subjects with high paraplegia compared to those with low paraplegia. QTVI was significantly elevated in all SCI groups compared to controls. Significant negative correlations between QTVI and HF(RR) were observed in all SCI groups, and TP(RR) and LF(RR) in subjects with tetraplegia and high paraplegia only. Age was negatively correlated in controls. CONCLUSIONS: QTVI is negatively affected in otherwise healthy SCI men compared to age-matched controls. This observation appears to reflect the attenuation of vagal modulation, sympathetic impairment above the sixth thoracic vertebra and/or a heightened degree of cardiovascular disease risk. PMID- 21252535 TI - Aortic arch calcification and vascular disease: the Guangzhou Biobank Cohort Study. AB - OBJECTIVE: To examine the association between aortic arch calcification (AAC) and vascular disease in an older Chinese sample. METHODS: For this study, 30,203 Chinese aged 50-85 years were recruited with baseline information on socioeconomic position, lifestyle and vascular risk factors. The presence and severity of AAC were diagnosed independently from chest X-ray by two radiologists. RESULTS: The age-adjusted prevalence of AAC was significantly higher in women than men [34.6% (95% CI 33.9-35.3) vs. 27.9% (95% CI 26.8-28.8), p < 0.001]. Severity of AAC was significantly associated with physician-diagnosed ischemic heart disease (adjusted OR = 1.55, 95% CI 1.35-1.79) and combined vascular disease (OR = 1.48, 95% CI 1.30-1.69) after adjusting for multiple potential confounders. Increasing severity of AAC was associated with increased risk for ischemic heart disease and vascular disease (p for trend = 0.02 to <0.001). No association between AAC and stroke was found. CONCLUSIONS: AAC was strongly and independently associated with vascular disease, suggesting that assessment of AAC from chest X-ray, which is noninvasive and relatively inexpensive, can provide useful information for risk stratification of vascular disease, and should be routinely incorporated in chest X-ray examination. PMID- 21252536 TI - Harnessing the energy of the Asia Pacific. PMID- 21252537 TI - The unparalleled challenge of aging populations. PMID- 21252538 TI - Apolipoprotein E polymorphism and dementia: a hospital-based study from southern India. AB - BACKGROUND/AIMS: To evaluate the ApoE gene polymorphism among patients with dementia from southern India. METHODS: Persons with dementia attending a geriatric clinic in a hospital setting located in southern India and matched controls were recruited. All subjects were evaluated on standard assessments and were diagnosed according to the ICD-10; genotyping was done at the apolipoprotein E (ApoE) locus. RESULTS: The study comprised 212 cases and 195 controls. The ApoE4 allele was significantly more prevalent in dementia (lambda = 0.18 vs. lambda = 0.07; p = 0.0018), especially in the Alzheimer's disease subgroup (n = 137; lambda = 0.21 vs. lambda = 0.07; p < 0.001), with a trend in vascular dementia subtype (n = 31; lambda = 0.17 vs. lambda = 0.07) in comparison with the control group. ApoE4 carrier status did not differ between the other dementia group (n = 44) and controls (p > 0.20), or between the Alzheimer's group and vascular dementia groups. Cognitive and functional deficits were not correlated to the presence ApoE4 polymorphism in the dementia group. CONCLUSION: The study confirmed the positive association of the ApoE4 polymorphism in dementia, both in the Alzheimer's and vascular etiology subgroups. Influence of this polymorphism on various clinical phenotypes, including extent of cognitive and functional deficits, needs further evaluation. PMID- 21252539 TI - IL-6-174 G/C and ApoE gene polymorphisms in Alzheimer's and vascular dementia patients attending the cognitive disorder clinic of the All India Institute of Medical Sciences, New Delhi. AB - BACKGROUND: Remarkable improvement in the life expectancy of the Indian population is expected to commensurate with the increase in number of dementia cases. Among various types of dementia, Alzheimer's disease (AD) and vascular dementia (VaD) are common and widely studied. We evaluated the role of apolipoprotein E (ApoE) and interleukin-6 (IL-6)-174 G/C gene polymorphism along with serum IL-6 levels in AD and VaD patients. METHODS: The polymorphisms in ApoE and IL-6-174 G/C genes were assessed using RFLP. Serum IL-6 level was measured by ELISA. RESULTS: The allele epsilon4 of the ApoE gene was found to be associated with AD and VaD patients (p < 0.05). No association of IL-6-174 G/C polymorphism was observed in AD patients, while the IL-6-174 C allele increased the odds of having VaD twofold. Regression analysis to assess possible interaction between ApoE and the IL-6-174 G/C genes revealed that presence of both the epsilon4 and C alleles increased the odds of having AD 13.75-fold and VaD 14.7-fold. Serum IL-6 levels did not correlate with either presence or severity of disease among AD or VaD patients. CONCLUSION: The ApoE epsilon4 allele is an important genetic marker for AD and VaD. Presence of both ApoE epsilon4 and IL-6 C genes increases the OR of having AD and VaD markedly. PMID- 21252540 TI - Family caregiving in dementia: the Asian perspective of a global problem. AB - BACKGROUND/AIMS: With an increasing life expectancy, the number of people suffering from dementia globally will rise to about 115.4 million by 2050. It is projected that in the 21st century, the majority of the world's older people will be living in Asia. This paper examines the global issues of family caregiving for older persons with dementia from an Asian perspective. METHODS: Literature review of published empirical studies from 1990 to October 2010. RESULTS: A full understanding of the specific way that culture could influence family caregivers' burdens may play an important part in the development of a holistic model for family-centered care. Well-designed psychoeducation interventions or multicomponent interventions could help in reducing caregivers' burden. With socio-economical and demographical changes, families need to be supported when taking on the caregiving role and be offered alternatives of care. CONCLUSION: There is a need for future trials with more rigorous randomization and longitudinal follow-up to assess family caregiver burdens at different illness stages. Future studies could focus on protective factors that promote caregivers' resilience. It is essential to develop psychometrically robust measures for family caregiver burden and gain. PMID- 21252541 TI - The association of metabolic syndrome with executive dysfunction independent of subclinical ischemic brain lesions in Japanese adults. AB - BACKGROUND/AIMS: The aim of this study is to examine whether metabolic syndrome is directly associated with cognitive impairment independent of subclinical ischemic brain lesions. METHODS: We examined 1,543 neurologically normal subjects (44-86 years of age). Metabolic syndrome, brain MRI, and cognitive functions including general cognition and executive function were assessed. RESULTS: After adjusting for silent brain lesions and demographic risk factors, metabolic syndrome was an independent risk factor for impairment of executive function (OR = 1.41, 95% CI = 1.17-1.25 for Kohs' Test; OR = 2.25, 95% CI = 1.64-3.07 for Frontal Assessment Battery). Among the components of metabolic syndrome, elevated fasting glucose was the only independent risk factor for impairment of executive function. CONCLUSION: Metabolic syndrome is associated with impairment of executive function independent of silent brain lesions in the Japanese population. PMID- 21252542 TI - Apolipoprotein E polymorphism and age at onset of Alzheimer's disease in a quadriethnic sample. AB - BACKGROUND: The relationship between the apolipoprotein E (ApoE) genotype and the risk for developing Alzheimer's disease (AD) or age at onset of AD is relatively well established in Caucasians, but less established in other ethnicities. We examined the association between the ApoE genotype and age at onset of AD in a quadriethnic group of community-dwelling AD patients. METHODS: AD patients were evaluated at 2 university-based outpatient memory disorder clinics. The ethnic distribution was as follows: Caucasians (n = 1,083), Hispanics (n = 55), African Americans (n = 84) and Koreans (n = 87). All were diagnosed with probable AD according to NINCDS-ADRDA diagnostic criteria. RESULTS: After adjusting for ethnicity, the epsilon4 allele was significantly associated with earlier age at onset (p < 0.0001) for the combined group. Within ethnic groups, the effect of Apo epsilon4 on age at onset was significant in Caucasians (p < 0.0001) and African Americans (p < 0.05), but nonsignificant in Koreans (p = 0.43) and in the smaller Hispanic (p = 0.07) group. CONCLUSIONS: The association between Apo epsilon4 and younger age at onset was significant in Caucasians and African Americans, where the epsilon4 allele was also most frequent. This study suggests that the impact of ApoE polymorphism on age at onset of AD may be different among distinct ethnic groups. PMID- 21252543 TI - Interethnic differences in dementia epidemiology: global and Asia-Pacific perspectives. AB - The burden of dementia will continue to rise globally, particularly in developing countries, many of which lie in the Asia-Pacific region. It was initially thought that both prevalence and incidence of dementia showed little geographic variation. More recent work has suggested differences: migrant populations attain rates between their homelands and adopted countries, and higher rates have been found in African Americans and Hispanics compared to Caucasian Whites, and also among native Australians. The only interethnic studies in the Asia-Pacific region were performed in Singapore, which showed lower standardized prevalence among ethnic Chinese compared to ethnic Malays and Indians, independent of vascular risk factors. There was conflicting information about the relative frequencies of Alzheimer's disease and vascular dementia between ethnic groups in Singapore. More research, with careful attention to potential cultural confounders, is needed to further explore and better understand interethnic differences in dementia epidemiology. PMID- 21252544 TI - Recognition, attitudes and causal beliefs regarding dementia in Italian, Greek and Chinese Australians. AB - BACKGROUND/AIM: To investigate recognition, attitudes and causal beliefs regarding dementia in Italian, Greek and Chinese Australians in comparison with 3rd generation Australians. Little is known about dementia literacy in these racial and ethnic minority groups. METHODS: A cross-sectional telephone survey was conducted of 350 Italian, 414 Greek, 437 Chinese and 500 3rd generation Australians randomly selected from the telephone directory. RESULTS: Third generation participants (85%) were more likely to recognize dementia symptoms in a vignette in comparison to Italian (61%), Greek (58%) and Chinese (72%) participants. Overall, the racial and ethnic minority groups had more negative attitudes about persons with dementia. The racial and ethnic minority groups were more likely to suggest old age and psychosocial risk factors caused dementia, whereas 3rd generation Australians were more likely to suggest brain disease. Differences between ethnic minority and 3rd generation groups remained after controlling for sociodemographic variables. There were differences between Italian, Greek and Chinese participants on markers of acculturation associated with knowledge and beliefs within each group. CONCLUSIONS: Racial and ethnic minority groups have poor dementia literacy in comparison to 3rd generation Australians. There is a need for dementia education targeted to and tailored for these groups. PMID- 21252545 TI - Why family caregivers choose to institutionalize a loved one with dementia: a Singapore perspective. AB - AIM: To examine factors associated with family caregivers' choice of care setting (own home vs. nursing home) for their relatives with dementia. METHODS: Cross sectional study involving caregivers recruited from a tertiary hospital dementia clinic and the local Alzheimer's association. Caregivers completed a questionnaire containing demographics of the person with dementia (PWD) and caregiver, their choice of care setting and the following scales: Gain in Alzheimer Care Instrument, General Health Questionnaire, Short Sense of Competence Questionnaire, Revised Memory and Behavioral Problems Checklist and Zarit Burden Interview. Multiple logistic regression was performed to identify significant variables associated with the outcome of interest. RESULTS: The final sample comprised 266 caregivers, the majority of whom were Chinese, female and children of PWD. Most (85.7%) preferred care at home, only 38 (14.3%) chose institutionalization. Four factors were associated with choice of nursing home: caregiver working (OR = 6.363, 2.120-19.086), no domestic maid (OR = 3.27, 1.458 7.331), lower caregiver gain (OR = 0.935, 0.882-0.992) and behavioral problems in PWD (OR = 1.011, 1.005-1.018). CONCLUSION: Strategies to minimize institutionalization must first address the provision of a dedicated caregiver at home. Consequently, interventions to help caregivers cope with behavioral problems in PWD and enhance caregiver gain are relevant. PMID- 21252546 TI - Association between body mass index and cognitive function among Chinese nonagenarians/centenarians. AB - AIMS: We examined the individual association between body mass index (BMI) and cognitive function among the very elderly. METHODS: The present study analyzed data from a survey that was conducted on all residents aged 90 years or more from a district which had 2,311,709 inhabitants in 2005. The subjects were divided into 4 groups according to quartiles of BMI (<16.6, 16.6-18.9, 18.9-21.1 and >21.1), and according to classification criteria of underweight, normal weight, overweight and obesity in BMI (<18.5, 18.5-23.0, 23.0-27.5 and >27.5), respectively. RESULTS: The subjects included in the statistical analysis were 211 men and 427 women. Those in the 3rd quartile of BMI (18.9-21.1) had higher cognitive function scores (p < 0.001) and were less likely to present possible dementia (p = 0.016) than the others. However, there was no difference in cognitive function scores (p = 0.350) or prevalence of possible dementia (p = 0.263) among obesity, overweight, normal weight and underweight groups. CONCLUSIONS: Concerning longevity in Chinese, there is an association between BMI and cognitive function. BMI of around 20 (18.9-21.1) is associated with the lowest risk of prevalence of possible dementia and the highest cognitive function scores. PMID- 21252547 TI - Diagnostic performance of the Chinese Frontal Assessment Battery in early cognitive impairment in an Asian population. AB - BACKGROUND: The Frontal Assessment Battery (FAB) has been shown to be useful in evaluating frontal dysfunction. There is a paucity of studies validating cutoffs in the early cognitive impairment. We aim to validate the Chinese FAB in Asian subjects with mild cognitive impairment (MCI) and early dementia. METHODS: Eighty subjects with MCI and mild dementia and 100 cognitively healthy community subjects were studied. ROC analysis was done to determine the Chinese FAB's optimal cutoff scores for age- and education-adjusted subgroups. RESULTS: Chinese FAB scores were significantly lower in early cognitive impairment compared with cognitively normal controls. The optimal cutoff score was 12/13 (sensitivity 92%, specificity 78.7%). A similar cutoff score was obtained following age-adjustment and for subjects with <6 years' education. Of note, the optimal cutoff for subjects with >=6 years' education was 13/14 (sensitivity 91.8%, specificity 70.3%), an improved diagnostic performance compared to the earlier reported 11/12 cutoff. In comparison, the Mini-Mental Status Examination (MMSE) had lower rule out accuracy (77% sensitivity, 91.2% specificity). The combination of the Chinese FAB and MMSE was superior to either test in isolation. CONCLUSION: The education adjusted Chinese FAB has good diagnostic performance, which can supplement the MMSE in early cognitive impairment evaluation with construct differences observed between the Chinese FAB and MMSE. PMID- 21252548 TI - Sociodemographic risk factors and correlates of dementia in older Malaysians. AB - OBJECTIVE: The rapid expansion of the aged population in Malaysia is expected to greatly increase the number of persons with dementia in the country. However, data on dementia prevalence at the national level is lacking, and little is known about the sociodemographic risk factors and correlates of dementia. This paper describes a nationwide study of dementia prevalence and its sociodemographic risk factors and health correlates among older Malaysians. METHODS: In the nationwide study, the Mental Health and Quality of Life of Older Malaysians, AGECAT-GMS was used to diagnose dementia in a nationally representative sample of 2,980 persons aged 60 and above. RESULTS: The prevalence rate of dementia was 14.3%. Higher dementia prevalences were found in oldest age (26.3%), women (19.7%), no formal education (24.1%), Bumiputeras (32.2%), unmarried (19.4%), unemployed (31.3%) and very poor on self-rated health (33.3%). Multivariate logistic regression analyses showed that older age, female gender, no formal education, ethnicity and very poor self-rated health were independent risk factors and correlates of dementia. CONCLUSIONS: Relatively higher prevalence rates of dementia in older Malaysians were accounted for by greater proportions without education, Malay and Bumiputera ethnicity, and other unknown factors which should be further investigated. PMID- 21252549 TI - A controlled naturalistic study on a weekly music therapy and activity program on disruptive and depressive behaviors in dementia. AB - AIM: This study explores the effects of a weekly structured music therapy and activity program (MAP) on behavioral and depressive symptoms in persons with dementia (PWD) in a naturalistic setting. METHODS: PWD attended a weekly group MAP conducted by a qualified music therapist and occupational therapist for 8 weeks. Two validated scales, the Apparent Emotion Scale (AES) and the Revised Memory and Behavioral Problems Checklist (RMBPC), were used to measure change in outcomes of mood and behavior. RESULTS: Twenty-eight subjects completed the intervention, while 15 wait-list subjects served as controls. Baseline AES and RMBPC scores were not significantly different between the intervention and control groups. After intervention, RMBPC scores improved significantly (p = 0.006) with 95% CI of the difference between the mean intervention and control group scores compared to baseline at -62.1 to -11.20. Total RMBPC scores in the intervention group improved from 75.3 to 54.5, but worsened in the control group, increasing from 62.3 to 78.6. AES scores showed a nonsignificant trend towards improvement in the intervention group. CONCLUSION: The results suggest that a weekly MAP can ameliorate behavioral and depressive symptoms in PWD. PMID- 21252550 TI - Orbitofrontal dysfunction discriminates behavioral variant frontotemporal dementia from Alzheimer's disease. AB - BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) patients show prefrontal cortex dysfunction and atrophy. METHODS: We investigated whether executive function in conjunction with prefrontal cortex atrophy discriminates bvFTD and Alzheimer's disease (AD) patients efficiently at presentation. RESULTS: AD and bvFTD patients were distinguishable by 89.5% on their performance of 3 executive tasks: the Hayling Test of Inhibitory Control, Digit Span Backward and Letter Fluency. Similarly, scan ratings showed that orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex regions distinguish both patient groups. More importantly, employing the Hayling error score in conjunction with the OFC atrophy rating showed that 92% of patients can be correctly classified into bvFTD and AD. CONCLUSION: A combination of OFC and disinhibition measures appears to be a powerful diagnostic tool in differentiating bvFTD from AD patients in this preliminary study. PMID- 21252551 TI - Functional alterations in brain activation and deactivation in mild cognitive impairment in response to a graded working memory challenge. AB - AIM: To investigate dynamic changes in functional brain activity in mild cognitive impairment (MCI) in response to a graded working memory (WM) challenge with increasing memory load. METHODS: In an event-related functional magnetic resonance imaging (fMRI) study, 35 MCI and 22 cognitively normal subjects performed a visuospatial associative WM task with 3 load levels. Potential performance differences were controlled for by individually calibrating the number of items presented at each load. RESULTS: An interaction between group and WM load was observed during stimulus encoding. At lower loads, greater activity in the right anterior cingulate and right precuneus was observed in MCI subjects. As the load increased to higher levels, reduced activation in these regions and greater deactivation in the posterior cingulate-medial precuneus were observed in MCI compared to control subjects. Stronger expression of load-related patterns of activation and deactivation in MCI subjects was associated with greater clinical severity and a more abnormal pattern of performance variability. CONCLUSION: Patterns of overactivation, underactivation and deactivation during successful encoding in MCI subjects were dependent on WM load. This type of graded cognitive challenge may operate like a 'memory stress test' in MCI and may be a useful biomarker of disease at the pre-dementia stage. PMID- 21252552 TI - Systemic inflammation is associated with MCI and its subtypes: the Sydney Memory and Aging Study. AB - BACKGROUND/AIMS: Raised low-grade systemic inflammation has been associated with dementia, and preliminary studies suggest an association with mild cognitive impairment (MCI). This study examines the relationship between systemic inflammation and MCI subtypes. METHODS: We measured the inflammatory markers C reactive protein, interleukins (IL)-1beta, -6, -8, -10 and -12, plasminogen activator inhibitor-1 (PAI-1), serum amyloid A (SAA), tumor necrosis factor-alpha (TNF-alpha) and vascular adhesion molecule-1 (VCAM-1) in the Sydney Memory and Ageing Study (MAS) cohort, a longitudinal study of 1,037 Australians aged 70-90 years. RESULTS: After adjusting for possible confounding variables, levels of TNF alpha and SAA were higher in participants with MCI compared to cognitively normal individuals, and some sex differences were apparent. Nonamnestic multiple domain MCI was associated with higher levels of IL-1beta and IL-12, TNF-alpha and SAA compared to cognitively normal, amnestic MCI (single and multiple domain) and nonamnestic single domain MCI. PAI-1 levels were higher in cognitively normal and nonamnestic multiple domain MCI than in amnestic multiple domain MCI. CONCLUSION: Our findings suggest an association between specific inflammatory markers and MCI subtypes, highlight sex differences in the association with MCI, and point to a discrete impact of systemic inflammation on cognition. PMID- 21252554 TI - Cerebral venous sinus thrombosis as a complication of a microendoscopic discectomy. PMID- 21252553 TI - Quo vadis 2010? - carpe diem: challenges and opportunities in pediatric traumatic brain injury. AB - Traumatic brain injury (TBI) in infants and children remains a public health problem of enormous magnitude. It is a complex and heterogeneous condition that presents many diagnostic, therapeutic and prognostic challenges. A number of investigative teams are studying pediatric TBI both in experimental models and in clinical studies at the bedside. This review builds on work presented in a prior supplement to Developmental Neuroscience that was published in 2006, and addresses several active areas of research on this topic, including (1) the application of novel imaging methods, (2) the use of serum and/or CSF biomarkers of injury, (3) advances in neuromonitoring, (4) the development and testing of novel therapies, (5) developments in modeling pediatric TBI, (6) the consideration of a new approach to classification of pediatric TBI, and (7) assessing the potential impact of the development of pediatric and neonatal neurocritical care services on the management and outcome of pediatric TBI. PMID- 21252555 TI - Jean-Martin Charcot at the birth of Russian neurology. AB - Russian neurology was virtually nonexistent in the middle of the 19th century which made a traineeship abroad an absolute necessity. Charcot and his school did not just offer professional training, but created the best minds, which would determine the direction of neurology and psychiatry in Russia for many decades. After returning home, young Russian doctors not only implemented everything they had learned in Western Europe, but proceeded to make their own original contributions. The most talented pupils of Charcot, including such prominent names as Kozhevnikov, Korsakov, Minor, Bekhterev and Darkshevich, became the founders of neurological schools in Russia. They laid the basis for the further development of neurology and psychiatry. Remarkably, though trained by the same teachers, each of these future 'founding fathers' of these neurological and psychiatric schools followed his own individual path which resulted in an undeniable diversity in Russian neurology and psychiatry during the period of their formation. PMID- 21252556 TI - Cerebral infarct in patients with bilateral high-grade internal carotid artery stenosis: analysis by diffusion-weighted imaging. AB - BACKGROUND: Bilateral high-grade internal carotid artery (ICA) stenosis is critical for brain perfusion, and mechanisms of cerebral infarct induced by bilateral high-grade ICA stenosis can be investigated by the infarct patterns on diffusion-weighted imaging (DWI). METHODS: From January 2006 to October 2010, we retrospectively enrolled 21 acute infarct patients with bilateral high-grade ICA stenosis. The infarct patterns were divided into territory, cortical border-zone and internal border-zone by DWI. RESULTS: The milder ICA stenosis side had a lower risk of ischemic stroke (4 of 20). None of the 8 patients with bilateral severe ICA stenosis (70-99%) suffered ischemic stroke ipsilateral to the milder ICA stenosis side. No single infarct mechanism was prominent: 10 of 21 infarcts were cortical border-zone pattern, followed by internal border-zone (7 of 21) and territory. The difference in frequency of bilateral severe ICA stenosis between the three infarct mechanisms was not significant (p = 0.856). CONCLUSIONS: Cerebral infarcts occurred less frequently in the ipsilateral to milder ICA stenosis side, especially in bilateral severe ICA stenosis. The similar frequencies and hemodynamic status between the three infarct pattern groups indicated that both artery-to-artery emboli and being hemodynamically compromised contribute synergistically to bilateral ICA stenosis. PMID- 21252558 TI - Developments in Hormone Research in Paediatrics. PMID- 21252557 TI - A reproducible porcine model of acute liver failure induced by intrajejunal acetaminophen administration. AB - BACKGROUND AND AIMS: Severe intoxication following acetaminophen overdose is the most common cause of acute liver failure (ALF) in many Western European and North American countries. A reproducible large animal model of acetaminophen intoxication has not been successfully evaluated previously. METHODS: Eight male pigs underwent acetaminophen intoxication receiving an initial enteric bolus of 250 mg/kg body weight acetaminophen followed by an acetaminophen plasma level (300-450 mg/l) adapted enteric maintenance dose of 1,000-3,000 mg/h to the onset of ALF (prothrombin time value <30%). Vital and ventilation parameters were continuously recorded until death. Saline, hydroxyethyl starch, fresh frozen plasma and erythrocyte units were used for volume substitution, and norepinephrine to prevent severe hypotension. RESULTS: All animals developed ALF after 25 +/- 3 h, which was confirmed by laboratory values, the clinical course and histological examinations. All animals died due to ALF after a further 21 +/- 5 h, precipitated by cerebral edema. CONCLUSIONS: Using an initial enteric acetaminophen bolus, followed by body weight-adapted acetaminophen plasma level intoxication, it was possible to establish a reproducible, clinically relevant porcine model which may be used for the investigation of novel therapeutic approaches in this life-threatening condition. PMID- 21252559 TI - RNA interference in mammalian cell systems. AB - In the last decade, few areas of biology have been transformed as thoroughly as RNA molecular biology. Without any doubt, one of the most significant advances has been the discovery of small (20-30 nucleotide) noncoding RNAs that regulate genes and genomes. The effects of small RNAs on gene expression and control are generally inhibitory, and the corresponding regulatory mechanisms are therefore collectively subsumed under the heading of RNA silencing and/or RNA interference. Two primary categories of these small RNAs - short interfering RNAs (siRNAs) and microRNAs (miRNAs) - act in both somatic and germline lineages of eukaryotic species to regulate endogenous genes and to defend the genome from invasive nucleic acids. Recent advances have revealed unexpected diversity in their biogenesis pathways and the regulatory mechanisms that they access. Our understanding of siRNA and miRNA-based regulation has direct implications for fundamental biology as well as disease aetiology and treatment as it is discussed in this review on 'new techniques in molecular biology'. PMID- 21252560 TI - Sex hormone priming for growth hormone stimulation testing in pre- and early adolescent children is evidence based. PMID- 21252561 TI - What's new in diabetes: incretins and C-peptide. PMID- 21252562 TI - The protective effect of the Mediterranean diet: focus on cancer and cardiovascular risk. AB - The lower occurrence of cancer and cardiovascular disease in the population around the Mediterranean basin has been linked to the dietary habits of the region. Indeed, this so-called Mediterranean diet is essentially different from the diets consumed in Western and Northern European countries and is rich in nuts, fruits, vegetables, legumes, whole-wheat bread, fish, and olive oil, with moderate amounts of red wine, which is mainly consumed during meals. Although a variety of cultural and religious traditions exist among the peoples of the Mediterranean area, olive oil, fish, and red wine hold a traditional and central position in the culinary routines of the region. The components of the diet contain an ample source of molecules with antioxidant and anti-inflammatory actions, among which omega-3 fatty acids, oleic acid, and phenolic compounds hold a prominent place. This review will summarize the results of important epidemiological studies that have investigated the protective effect of fish and olive oil on the risk of breast, prostate, and colorectal cancer and of wine on the risk of cardiovascular disease. The present review also aims to elucidate the various mechanisms by which various dietary components exhibit their beneficial action. In this respect, emphasis will be placed on the properties of omega-3 fatty acids from fish, oleic acid from olive oil, and phenolic compounds from olive oil and red wine. PMID- 21252563 TI - A comparison of the antifungal activity of herbal toothpastes against other brands of toothpastes on clinical isolates of Candida albicans and Candida dubliniensis. AB - OBJECTIVES: To evaluate the anti-Candida activity on Candida albicans and Candida dubliniensis species of 2 herbal and 7 other brands of toothpastes commonly used in Kuwait. MATERIALS AND METHODS: Antifungal activity was determined by agar diffusion test on 65 isolates of C. albicans and 21 isolates of C. dubliniensis for each toothpaste. A uniform quantity of toothpaste was filled into wells punched into Sabouraud dextrose agar medium plates inoculated with the test isolates, incubated at 37 degrees C; inhibition zone diameters were read after 24 h. RESULTS: The mean inhibition zone diameters ranged between 12 and 23 mm for C. albicans and between 12 and 27 mm for C. dubliniensis. A herbal toothpaste brand manufactured in the Middle Eastern region (United Arab Emirates) consisting of many herbal ingredients compared to other brands was found to be the most active (p < 0.001) against both Candida species tested, which also demonstrated higher inhibitory activity against C. dubliniensis isolates compared to C. albicans. CONCLUSIONS: The herbal toothpaste brand presented significant anticandidal activity over conventional toothpastes and may be useful in reducing the pathogenic potential of Candida species. PMID- 21252564 TI - Diabetic patients' knowledge of therapeutic goals in Kuwait. AB - OBJECTIVE: This study was conducted to analyze patients' knowledge about therapeutic goals for diabetic patients and factors associated with good knowledge. METHODS: A total of 266 diabetic patients were randomly selected from 6 diabetes clinics in Kuwait to be included in a cross-sectional patient survey. Data were collected via face-to-face structured interviews using a pretested questionnaire. Descriptive and logistic regression analysis was used in data analysis. RESULTS: The response rate was 93% (n = 247). The percentages [95% confidence interval (CI)] of patients who reported knowing their recent levels of low-density lipoprotein cholesterol (LDL-C), blood pressure (BP), and glycosylated hemoglobin (HbA1c) were 5% (2-8), 54% (48-60), and 8% (5-11), respectively. The percentages (95% CI) of patients who admitted knowing the target goals for LDL-C, BP, HbA1c, fasting, and postprandial blood glucose levels were 3% (1-6), 49% (43-55), 6% (3-9), 62% (56-68) and 55% (49-61), respectively. Correct target goals for LDL-C, BP, HbA1c, fasting, and postprandial blood glucose levels were reported by 2% (1-4), 43% (37-49), 5% (2-8), 60% (54-66), and 47% (41-53), respectively. Those with a high education (OR = 4.76; 95% CI 2.34 9.68) and those with a family history of diabetes (OR = 3.05; 95% CI 1.50-6.19) had good knowledge about correct targets. CONCLUSION: The current findings revealed that lack of knowledge about recent levels of BP, LDL-C and HbA1c and therapeutic goals was alarmingly high, which highlights the need for the implementation of an effective multidisciplinary team approach to encourage patient education and self-care. PMID- 21252565 TI - Implication of umbilical cord in preeclampsia. AB - OBJECTIVES: To investigate the role of biochemical changes in the umbilical cord and placenta in developing preeclampsia (PE). SUBJECTS AND METHODS: Thirty women with PE and 15 healthy pregnant women as controls were enrolled in this study. Vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor 1 (sVEGFR-1), platelet-derived endothelial cell growth factor (PD ECGF), neutrophil elastase and nitric oxide (NO) were measured. RESULTS: Both serum (maternal and fetal) and tissue (placenta and umbilical cord) levels of VEGF, sVEGFR-1, PD-ECGF and neutrophil elastase were significantly increased, whereas NO was significantly decreased (except placental tissue showed no changes) in preeclamptic patients. The cord serum level of PD-ECGF was significantly higher in severe PE compared to mild PE and normal pregnant women. The placental and cord tissue levels of PD-ECGF and neutrophil elastase were significantly higher in severe PE, while the cord tissue level of NO was significantly lower in severe PE. CONCLUSION: Our data showed that umbilical cord vessels and stroma can serve as an additional source of vasoactive and angiogenic substances that contribute to the biochemical changes occurring in PE. PMID- 21252567 TI - Blood culture contamination in a neonatal intensive care unit in Shiraz, Southwest-Central Iran. AB - OBJECTIVE: To measure bacterial contamination rates in blood culture specimens and distinguish sepsis from blood culture contamination in newborn hospitalized patients in a neonatal intensive care unit and to recognize the most commonly isolated bacteria. MATERIALS AND METHODS: Blood samples of 578 neonates were collected and cultured throughout the year of study (March 2006 to February 2007). Isolated bacteria were identified by traditional biochemical tests. Clinical criteria combined with laboratory data were used to differentiate the contaminated cultures from clinically significant cultures. RESULTS: Of the 578 neonatal blood culture samples, 78 (13.49%) were positive for bacteria, and 49 isolates (8.47%) were classified as contaminants. Pseudomonas aeruginosa and Staphylococcus aureus were the most common isolates from true bacteremia, and Staphylococcus epidermidis and diphtheroids were the most common contaminants. CONCLUSION: The blood culture contamination rate in our studied neonatal intensive care unit was high. A variety of measures are recommended for reducing the rate of blood culture contamination to avoid undesirable outcomes associated with blood culture contamination. PMID- 21252566 TI - (99m)Tc sulfur colloid and (99m)Tc mebrofenin hepatobiliary functional liver imaging in normal and diabetic rats. AB - OBJECTIVES: To use (99m)Tc sulfur colloid ((99m)Tc-SC) and (99m)Tc mebrofenin ((99m)Tc-BrIDA) to study liver function in normal and diabetic rats. MATERIALS AND METHODS: Radionuclide imaging was performed on 2 groups of rats, using (99m)Tc-SC for one group and (99m)Tc-BrIDA for the other (20 rats per group) before and after induction of diabetes mellitus (DM) using streptozotocin administration (55 mg/kg i.p.). Dynamic acquisition was obtained for 1 h after the injection of 37 MBq of radiotracer. For the (99m)Tc-SC group, organ/tissue uptake was determined by drawing regions of interest (ROI) over the heart, liver, spleen and also the whole body (WB). The ratio of the ROI of each organ to the WB ROI was calculated. For (99m)Tc-BrIDA, ratios of cumulative count rates in liver, liver parenchyma, biliary tree and abdomen ROI to a WB ROI were also calculated. Statistical analysis was performed to compare the ratios of organ/tissue uptake to WB uptake before and after DM induction using the paired t test. RESULTS: (99m)Tc-SC uptake ratios (means +/-SD) showed a lower liver-to-WB uptake ratio (0.75 +/- 0.05) in the rats after DM induction compared to baseline (0.81 +/- 0.06), while the cardiac blood pool showed higher uptake ratios in the rats after DM induction (p = 0.026). For (99m)Tc-BrIDA, there was no significant difference in radiotracer uptake ratios obtained from the rats before and after DM induction (p = 0.41). CONCLUSION: Using functional liver imaging, there was a statistically significant decrease in the liver phagocytic/reticuloendothelial system function after DM induction, as evidenced by decreased (99m)Tc-SC liver uptake and increased blood pool compared to prediabetes, while the hepatobiliary function remained unchanged after DM induction using (99m)Tc-BrIDA imaging. PMID- 21252568 TI - Skin manifestations in diabetic patients attending a diabetic clinic in the Qassim region, Saudi Arabia. AB - OBJECTIVE: To investigate the prevalence of skin manifestations in diabetic patients attending a diabetic clinic in the Qassim region, Saudi Arabia. SUBJECTS AND METHODS: A prospective observational study was performed on 320 patients (174 males and 146 females) attending the diabetic clinic. A detailed dermatological examination was carried out by a consultant dermatologist and the cutaneous findings were recorded. RESULTS: The overall prevalence of skin manifestations was 91.2%. Cutaneous lesions were seen in 12 patients (34.3%) of type 1 diabetes mellitus (DM) and 280 (98.2%) of type 2 diabetics. There was a statistically significant difference (p < 0.001) in skin manifestations between type 1 and type 2 DM patients. For those patients having diabetes of less than 5 years' duration, the incidence of skin manifestations was 80.6%; for those having had diabetes for more than 5 years, the incidence was 98%. This difference was statistically significant (p < 0.001). The skin manifestations that had a statistically significant difference (p < 0.05) in prevalence between the 2 durational groups were gangrene, diabetic dermopathy, paresthesia, diabetic feet, diabetic bullae and fungal infections. CONCLUSION: Diabetics had a greater prevalence of skin manifestations in type 2 than type 1, and as the duration of diabetes increased, the likelihood of developing skin manifestations also increased. Early referral to the dermatologist may help to detect complications of the skin in diabetes at an early stage and may prevent disability caused by these complications. PMID- 21252569 TI - Bixa orellana leaves extract inhibits bradykinin-induced inflammation through suppression of nitric oxide production. AB - OBJECTIVE: The present study was conducted to assess the anti-inflammatory effect of a crude aqueous extract of Bixa orellana leaves (AEBO) and to examine the possible involvement of nitric oxide (NO) in its anti-inflammatory mechanism. MATERIALS AND METHODS: The air-dried, powdered leaves were soaked in distilled water (1:20 w/v) at 50 degrees C for 24 h and the supernatant obtained was freeze dried (yield 8.5% w/w). The dosage was recorded as the mass of extract per kg b.w. of rats in all inflammatory assays (bradykinin-induced paw edema, peritoneal vascular permeability and NO assay). RESULTS: Pretreatment with AEBO for 4 consecutive days exhibited significant inhibitory activity against inflammatory models, the bradykinin-induced hind paw edema model and bradykinin-induced increased peritoneal vascular permeability at both doses in dose-dependent manner. In addition, AEBO was also found to significantly suppress the production of NO at doses of 50 and 150 mg/kg. CONCLUSION: This study provides scientific data to support the traditional use of B. orellana leaves in treating inflammation. Results from this study suggest that AEBO exerts anti-inflammatory effects. Part of this anti-inflammatory effect may be associated with its antibradykinin activity and may be related to a reduction of the NO production. PMID- 21252570 TI - Effect of opium dependency on burn healing in a rat model: an experimental study. AB - OBJECTIVE: This study aimed to investigate the effect of opium dependency on the healing of third-degree burns in rats. MATERIAL AND METHODS: Twenty-four rats were randomly divided to experimental and control groups. In the experimental group, opium was added to the drinking water for 21 days at increasing concentrations. The control group did not receive opium. To prove dependency on opium in the rats, naloxone was injected intraperitoneally. Full-thickness burn wounds were inflicted by applying an iron cuboid preheated to 94 degrees C to the flank of all rats for 20 s. On day 14 after burn injury, full-thickness biopsies were taken. Blind histopathologic evaluation was performed to assess length and thickness of the re-epithelialization area, number of neutrophils, fibroblasts, mononuclear cells and new vessels, and percentage of tissue in repair (neutrophilic exudate, and granulation and fibrous tissue). Findings were analyzed using SPSS software. RESULTS: The wound surface area was 95 +/- 43.35 mm(2) in the control group and 120.4 +/- 50.12 mm(2) in the experimental group (p = 0.224). The findings show that opium dependency has no significant effect on the healing of burn wounds in rats except for the number of monocytes on day 14 (p < 0.05). CONCLUSION: Morphine dependency does not seem to be as effective on third-degree burn healing. PMID- 21252571 TI - Prevalence of hypertension in a population of healthy individuals. AB - OBJECTIVES: To assess the prevalence of hypertension (HTN) in a random sample of individuals in Jeddah, Kingdom of Saudi Arabia. SUBJECTS AND METHODS: A total of 243 participants were randomly selected at a megamall in Jeddah, on May 2008. Questionnaires were distributed to all the participants by one of the researchers, who explained the purpose of the study and the content of the questionnaire. The questionnaire was designed to gather information regarding the prevalence of HTN in the general population in addition to identifying other risk factors associated with HTN. Notably, accurate blood pressure measurements were performed on all the participants. RESULTS: Of the 243 participants, 55 (22.6%) were hypertensive. Of these, 28 (50.9%) were males and 27 (49.1%) females. The probability of having HTN was significantly higher with increasing age with 7 (38.9%) of the participants >50 years of age. Similarly, HTN increased proportionately with the participant's body mass index. With regard to other risk factors, 13 (50%) of the diabetics, 10 (27.0%) of the dyslipidemic participants and 9 (18.4%) of the cigarette-smoking participants had HTN. CONCLUSIONS: The occurrence of HTN was high and was strongly associated with diabetes, the aging process and obesity. PMID- 21252572 TI - Bone mineral density in Kuwaiti patients with end-stage renal disease. AB - OBJECTIVE: This study compared an ethnically uniform group of end-stage renal disease (ESRD) Kuwaiti patients with a control group of healthy Kuwaiti subjects, in terms of their bone mineral density (BMD) and anthropometric measurements. SUBJECTS AND METHODS: Included in the study were 94 males and 129 females with a mean age of 48 +/- 10 years. Forty-five males and 53 females had ESRD. The remaining 49 males and 26 females were the control subjects. BMD was measured at total lumbar spine (L1-L4) and total left hip, using dual energy X-ray absorptiometry (HOLOGIC, QRS series, Europe, Belgium). The data were analyzed using SPSS, version 15 (SPSS Inc., Chicago, Ill., USA). The difference in BMD and the anthropometric measurements between the ESRD patients and the controls was assessed. Multivariate linear regression models were used to examine independent effects of ESRD on BMD while adjusting for relevant covariates. RESULTS: The ESRD patients had a lower BMD than the controls at the hip (0.81 +/- 0.11 vs. 0.92 +/- 0.16) and the spine (0.84 +/- 0.12 vs. 0.92 +/- 0.16), p < 0.001. They also had a lower body mass index (27.80 +/- 6.03 vs. 30.85 +/- 6.54; p < 0.001) and were taller (162.56 +/- 15.31 vs. 156.94 cm +/- 10.03; p < 0.01). The reduced BMD persisted after controlling for confounding effects of sex, age and anthropometric measurements (p < 0.001). CONCLUSION: Kuwaiti patients with ESRD had a lower BMD and, therefore, an increased risk of osteoporosis and bone fractures. PMID- 21252574 TI - Effectiveness of the passive lingual arch for E space maintenance in subjects with anterior or posterior rotation of the mandible: a retrospective study. AB - OBJECTIVE: The aim of this study was to determine whether or not lingual arches in subjects with anterior or posterior mandible rotation can produce different effects in the prevention of first permanent molar mesial migration. SUBJECTS AND METHODS: Forty-two patients with a mean age of 9 +/- 0.8 years were selected from the Department of Orthodontics, University of Catania, Italy. These subjects were treated with a passive mandibular fixed lingual arch. The sample was divided into 3 groups according to the gonial angle in order to establish the pattern of mandible growth: mandibular posterior rotation (MPR), mandibular growth in straight-downward direction (MSD) and mandibular anterior rotation (MAR). Lateral cephalograms and study models of the patients before and after treatment were examined to determine any positional changes of the mandibular first molars and incisors. RESULTS: Statistically significant differences between the MPR group and the other 2 (MSD and MAR) were found as regards mandibular first molar and incisor positional changes. No significant differences were found between the MSD and MAR groups. CONCLUSION: The results indicate that the effect of lingual arch is influenced by mandibular growth patterns. In patients with MPR, the lingual arch preserves arch length but the mesial migration of first permanent molars is not completely blocked. PMID- 21252573 TI - p53 protein accumulation and presence of visceral metastasis are independent prognostic factors for survival in patients with metastatic inflammatory breast carcinoma. AB - OBJECTIVE: The aim of this study was to determine the markers of prognosis in metastatic inflammatory breast cancer (IBC). SUBJECTS AND METHODS: The prognostic value of patients' clinical characteristics and expression of c-erbB-2, p53, Ki 67, ER and PgR were assessed in the 45 patients with IBC who had developed distant metastasis. Immunohistochemical methods were used to detect the expression of c-erbB-2, p53, Ki-67, ER and PgR in surgical resection specimens of the patients' primary tumor. RESULTS: The median overall survival (OS) measured from the diagnosis of metastatic disease was 23 months. In the univariate analysis, p53 protein accumulation and the presence of visceral metastasis were predictive of poor survival (p = 0.01 and 0.003, respectively). In the multivariate analysis, accumulation of p53 protein and the presence of visceral metastasis correlated with OS (p = 0.02 and 0.008, respectively). CONCLUSION: In metastatic IBC, accumulation of p53 protein and presence of visceral metastasis are independent prognostic factors for OS. Established prognostic factors in non IBC patients such as patient age, histologic grade, hormone receptor status and c erbB-2 status did not have independent significance in IBC in this study. PMID- 21252575 TI - TP53 codon 72 polymorphism is associated with coronary artery disease in Chilean subjects. AB - OBJECTIVE: To investigate the possible association between the codon 72 polymorphism (Pro72Arg, rs1042522) of the tumor suppressor gene (TP53) and the presence of coronary artery disease (CAD) in Chilean subjects. SUBJECTS AND METHODS: A total of 209 unrelated patients with a diagnosis of CAD confirmed by angiography (33-74 years old) and 216 healthy controls (30-68 years old) were included in this study. The Pro72Arg polymorphism of the TP53 gene was evaluated by PCR-RFLP. RESULTS: The genotype distribution for the Pro72Arg variant of the TP53 gene in CAD patients (PP: n = 13, 6.2%; PR: n = 61, 29.4%; RR: n = 135, 64.6%) and controls (PP: n = 18, 8.3%; PR: n = 94, 43.5%; RR: n = 104, 48.1%) was significantly different (p = 0.003). Similarly, the allelic frequency was also different (p = 0.003). The odds ratio for CAD related to the 72Arg allele was 2.0 (95% CI = 1.33-2.90), confirming the presence of an association. CONCLUSION: These findings suggest that the Pro72Arg polymorphism of the TP53 gene is associated with CAD in Chilean individuals. PMID- 21252576 TI - Molecular characterization and epidemiology of extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae isolates in the United Arab Emirates. AB - OBJECTIVES: The aim of this prospective study was to assess the extent of dissemination of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae at the hospital level in the United Arab Emirates (UAE). MATERIALS AND METHODS: A total of 662 Escherichia coli and Klebsiellapneumoniae samples were collected from three UAE hospitals between January and December 2008. ESBL screening and confirmatory test for ESBL phenotype were conducted using the VITEK system. Molecular typing was performed using specific primers and then sequencing. RESULTS: A total of 240 (36%) samples were identified as ESBL producers, including both E. coli (n = 150) and K. pneumoniae (n = 90). All of these isolates were resistant to cefazoline and cefotaxime, but remained susceptible to imipenem. Molecular analysis revealed that, of the 240 ESBL producers, 228 carried the ESBL bla genes. A majority of the strains 199 (87%) expressed the CTX-M-15 gene. The SHV-28 gene was detected in 29 (13%) of the strains. CONCLUSION: The present study highlighted the emergence and dissemination of CTX-M-15-producing E. coli and K. pneumoniae in the UAE. This is the first report of SHV-28-producing Enterobacteriaceae in the country. PMID- 21252577 TI - Effect of early or delayed administration of warfarin with heparin on thrombosis in pulmonary thromboembolism. AB - OBJECTIVE: The aim of this study was to investigate the effect of early or delayed warfarin administration with unfractionated heparin (UFH) on coagulation parameters in pulmonary thromboembolism (PTE). PATIENTS AND METHODS: This study was performed between November 2006 and July 2007. Thirty-three patients with PTE were sequentially slotted to early (n = 16) and delayed (n = 17) warfarin treatment groups. In the early group, both UFH infusion and warfarin were started simultaneously and in the delayed group, warfarin was added (1-3 days later) based on when partial thromboplastin time reached the therapeutic level with UFH. The proteins C and S, D-dimer, hematocrit levels, and platelet counts for all patients were studied prior to treatment and 6, 24, and 48 h after warfarin treatment. In order to determine the overall effect of early and delayed warfarin treatment on clot formation, a thromboelastogram was performed simultaneously. RESULTS: In both groups, a similar chronological decrease in protein C levels reaching maximum at 24 h with warfarin treatment was observed. However, intragroup or intergroup decreases in protein S levels were not different. On thromboelastogram, INTEM and EXTEM clotting times were significantly prolonged chronologically, but this prolongation was not different between groups. CONCLUSION: The suppressor effect of warfarin on proteins C and S in the early period of double anticoagulant treatment did not appear to aggravate the risk of thrombosis in patients with PTE in whom warfarin was started simultaneously with UFH. PMID- 21252578 TI - The relationship between urinary 8-hydroxydeoxyguanosine and metabolic risk factors in asymptomatic subjects. AB - OBJECTIVE: The aim of this study was to investigate the relationship between metabolic risk factors and oxidative stress using urinary 8-hydroxydeoxyguanosine (8-OHdG), a recently utilized biological marker, in asymptomatic subjects. METHODS: Ninety subjects (males/females = 30/60; mean age = 52 years), who were nonsmoking, nondiabetic and not on any medicine, were enrolled in the study. The body mass index, blood pressure, total cholesterol, triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and glucose as well as urinary 8-OHdG and creatinine were measured. RESULTS: The median level of 8-OHdG was 9.3 ng/mg creatinine (interquartile range: 5.8-23.2). TG (Pearson's correlation: r = 0.262, p = 0.013) and HDL-C (r = -0.259, p = 0.014) showed a significant correlation with 8-OHdG. A multiple linear regression analysis adjusted for all the variables revealed that only TG had an independently significant and positive correlation with 8-OHdG (beta = 0.231, p = 0.046). CONCLUSION: The data in this population suggest that, among metabolic risk factors, hypertriglyceridemia may be weakly but significantly associated with hyperoxidative stress as assessed by 8-OHdG. PMID- 21252579 TI - Encephalitis-associated pandemic A (H1N1) 2009 in a Kuwaiti girl. AB - OBJECTIVE: To report an 11-year-old girl with encephalitis-associated pandemic influenza A (H1N1) 2009 virus infection. CLINICAL PRESENTATION AND INTERVENTION: An 11-year-old girl presented with a 6-day history of influenza-like illness followed by an altered mental status for 1 day. She tested positive for pandemic influenza A (H1N1) 2009 virus by PCR of her nasal swab. Her CSF analysis was completely normal, including PCR for pandemic influenza A virus. Her brain MRI and EEG showed evidence suggestive of encephalitis. She was treated with oral Oseltamivir with good recovery. CONCLUSION: This case report shows that neurological complications can occur after respiratory tract infection with pandemic influenza A (H1N1) 2009 virus. PMID- 21252581 TI - Is CEA better than CYFRA 21-1 in the monitoring of squamous cell lung cancer progression? PMID- 21252580 TI - Low-molecular-weight heparin successfully used to treat a nephrotic patient complicated by superior mesenteric vein thrombosis and portal vein thrombosis. AB - OBJECTIVES: To report the success of treatment with low- molecular-weight heparins (LMWHs) in a case of nephrotic syndrome complicated by mesenteric vein thrombosis (MVT) and portal vein thrombosis (PVT). CLINICAL PRESENTATION AND INTERVENTION: A 53-year-old man with nephrotic syndrome developed persistent mild abdominal pain for 3 days. Hepatic-portal venous system thrombosis of nephrotic syndrome was suspected due to new-onset superficial vein engorgement of the abdomen without liver cirrhosis. Abdominal computed tomography revealed MVT concomitant with PVT. He was successfully treated with LMWH without thrombolytic therapy. After discharge on day 9, he received continuous anticoagulation by LWMH on an outpatient basis at the nephrology clinic. Venous thromboembolic events or proteinuria did not recur within the 6-month follow-up. CONCLUSION: This report showed a case of MVT concomitant with PVT, a critical complication of nephrotic syndrome that was diagnosed in time and successfully treated with LMWH. A high index of clinical suspicion and timely management are crucial to tackle thrombotic complications in nephrotic syndrome. PMID- 21252582 TI - Endothelial progenitor cells in long-standing asymptomatic type 1 diabetic patients with or without diabetic nephropathy. AB - A decrease in the number and dysfunction of endothelial progenitor cells (EPC) may increase the risk for progression of cardiovascular disease (CVD) in type 1 diabetic patients with diabetic nephropathy (DN). Our aim was to evaluate EPC numbers in asymptomatic CVD type 1 diabetic patients with or without DN and to study the effect of CVD and medication on EPC numbers. METHODS: We examined EPC numbers in 37 type 1 diabetic patients with DN and 35 type 1 diabetic patients with long-standing normoalbuminuria. Patients were without symptoms of CVD and the prevalence of CVD was previously shown to be very low. EPC number was assessed in in vitro cultures by fluorescent staining of attached cells. RESULTS: There was no difference in EPC numbers between patients with DN (mean +/- SD 120 +/- 49 cells/field) and normoalbuminuria (108 +/- 41 cells/field; p = 0.25). Furthermore, EPC number was not associated with CVD (p > 0.05). Conventional risk factors were significantly higher in patients with DN and they received more CVD preventive treatment. All patients receiving simvastatin or calcium-channel blockers had higher numbers of EPC compared to patients not treated with these drugs. CONCLUSIONS: Asymptomatic patients with DN had EPC numbers similar to normoalbuminuric patients, which was related to aggressive CVD intervention therapy. This may have contributed to the low prevalence of CVD. PMID- 21252584 TI - Epidemiology and socioeconomic factors in Egypt. PMID- 21252583 TI - Methods and design of the baseline survey of the neurological disorders in Salamanca (NEDISA) cohort: a population-based study in Central-Western Spain. AB - BACKGROUND: To describe the design of the baseline assessment of an epidemiological study of elderly persons living in Salamanca, central-western Spain: the Neurological Diseases in Salamanca (NEDISA) study. We assessed the epidemiology of stroke, cognitive disorders, essential tremor (ET), Parkinson's disease (PD) and restless legs syndrome. METHODS: In phase 1 (February 1 to May 31, 2007), 4 neurologists and 2 trained general physicians examined and performed phlebotomy on all participants. In phase 2 (June 1, 2007, to June 1, 2008), the participants were reexamined and had a complete neuropsychological assessment. Neuroimaging was performed in participants with cognitive disorders, ET and PD. RESULTS: The registered study population consisted of 1,077 individuals, but 45 people were ineligible (address change, refusals or death), leaving a final sample of 1,032 (95.8%). The main demographic data on the 1,032 participants (408 men, 624 women) are provided. CONCLUSIONS: Most of the registered study population was enrolled, and this may have been due to the close relationship between NEDISA researchers and the general physicians in the area of study. The NEDISA study will likely improve our knowledge of prevalence rates of the neurological diseases chosen for study as well as the set of risk factors that predispose individuals in Spain to these disorders. PMID- 21252585 TI - More epidemiological studies of neurological disorders are needed in the Arab countries. PMID- 21252586 TI - Prevalence of essential tremor in Araihazar, Bangladesh: a population-based study. AB - BACKGROUND: Essential tremor (ET) is one of the most common neurological diseases. Few prevalence studies have been conducted in South Asia, and none in Bangladesh, one of the most populated countries in the world. We estimated the prevalence of ET in a population-based study in Araihazar, Bangladesh. METHODS: As part of an in-person evaluation in a health outcomes study, each study participant produced 2 handwriting samples, from which ET diagnoses were assigned by 2 independent movement disorder neurologists. RESULTS: The crude prevalence of ET (age >=18 years) was 19/1,229 [1.5%, 95% confidence interval (CI) = 1.0-2.4], and was similar in men and women. The crude prevalence was 2.5% in participants aged >=40 years and was one half that (1.3%) among younger participants (<40 years), although the difference did not reach statistical significance (p = 0.18). The age-adjusted prevalence (United States 2000 census) was 2.0% (95% CI = 1.2-2.8). CONCLUSION: The crude prevalence of ET in Araihazar, Bangladesh, was 1.5%. There is 1 other population-based study in a developing country (Turkey) which, like ours, did not restrict enrollment to middle-aged or elderly individuals and did not rely on screening questionnaires; the crude prevalence in the 2 studies is very similar. PMID- 21252587 TI - Essential tremor: one of the most common neurodegenerative diseases? PMID- 21252588 TI - Frequency of intraductal papillary mucinous neoplasm in patients with and without pancreas cancer. AB - PURPOSE: To determine the frequency of intraductal papillary mucinous neoplasm (IPMN) in patients with and without invasive ductal adenocarcinoma (IDAC). METHODS: 82 patients underwent pancreatectomy for pancreas adenocarcinoma. 68/82 subjects underwent at least one preoperative imaging study including CT (n = 43), MRI (n = 25), or both (n = 12). Imaging studies were retrospectively evaluated to determine if IPMN was present in the gland at a location distant from IDAC. In 183 different adult patients undergoing MRI for renal mass, images were evaluated to determine the frequency of IPMN. Fisher's exact test was used to test whether the prevalence of IPMN was greater among patients with pancreas cancer than those without. RESULTS: Five of 68 (7.3%) patients who underwent pancreatic resection for IDAC had IPMN at a site distant from the cancer. Two of 182 (1.1%) patients undergoing MRI for renal cancer had imaging evidence of IPMN. There was a significant difference (p = 0.017) in the prevalence of IPMN between patients with and without IDAC. The odds ratio for IPMN as a predictor of pancreas cancer was estimated as 7.18. CONCLUSION: IPMN occurs with increased frequency in patients with pancreas cancer as opposed to those without pancreas cancer. and IAP. PMID- 21252589 TI - Analysis of the time course of the effect of subthalamic nucleus stimulation upon hand function in Parkinson's patients. AB - BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) as treatment for Parkinson's disease has been in use for more than a decade, yet the immediate effect of stimulation upon movement parameters is not well characterized. OBJECTIVE: The goal of the current study is the identification of the best time point to test hand function after programming DBS devices. METHODS: Reaction time, movement time and velocity were measured at multiple time points with a movement-sensitive glove after the deep brain stimulator had been turned on or off, during 'off medication' conditions. RESULTS: Velocity, movement time and reaction time worsened significantly in the first 20 min after the deep brain stimulator had been turned off. A 'plateau effect' after 20 min was not observed. Initiation of stimulation led to immediate significant increases in movement time and velocity and to a lesser degree a decrease in reaction time. Patients performed more inconsistently over time after onset of stimulation compared to stimulation withdrawal. Intraoperative testing showed an immediate improvement in velocity after placement of the STN deep brain stimulator. CONCLUSION: Movement time and velocity already reach their peak changes within 20 min after the deep brain stimulator has been reprogrammed, and therefore, this time point may be used to test the maximal clinical effect of stimulation. PMID- 21252590 TI - Citation measures in stereotactic radiosurgery: publication across a discipline. AB - OBJECTIVE: It is possible to judge the impact of scientific research by the number of citations a publication has received. We identified the most cited works in the field of stereotactic radiosurgery to study the evolution of this field from the perspective of publication. METHODS: A Web of Science search was performed for articles that included the word 'radiosurgery' in the title. We studied the reports with >100 citations. RESULTS: A total of 5,532 published works were available for study between 1951 and 2010. Eighty-five articles had >= 100 citations, and these were published in 19 separate journals. The majority were published in the International Journal of Radiation Oncology, Biology and Physics, the Journal of Neurosurgery and Neurosurgery. The most common topics included brain metastasis management (n = 20), arteriovenous malformations (n = 17), vestibular schwannomas (n = 9), technologies (n = 9), meningiomas (n = 8) and dose response/radiobiology (n = 6). Fifty-seven percent of the articles were published in the last 10 years. CONCLUSIONS: The first radiosurgery report by Leksell (1951) initiated the field. The 1980s were a period of new technology development followed in the 1990s by introductory articles on specific indications that consisted mainly of retrospective case series. More sophisticated higher level evidence reports were published in the last decade. The most significant works in radiosurgery include initial technology descriptions, multicenter studies with large numbers of patients, randomized clinical trials and reports that provide dose prescription guidelines. PMID- 21252591 TI - New insights for adult cardiopulmonary resuscitation. Up-coming resuscitation guidelines 2010. AB - Despite advances in cardiac arrest care, the overall survival to hospital discharge remains poor. The objective of this paper was to review the innovations in cardiopulmonary resuscitation that could influence survival or change our understanding about cardiopulmonary resuscitation. We have performed a search in the MEDLINE and the Cochrane databases for randomized controlled trials, meta analyses, expert reviews from December 2005 to March 2010 using the terms cardiac arrest, basic life support, and advanced life support. The lack of randomized trials during the last 5 years remains the main problem for crucial decisions in cardiopulmonary resuscitation. Current trends in cardiopulmonary resuscitation are toward minimizing the interruptions of chest compressions and improving the quality of cardiopulmonary resuscitation. In addition, attention should be paid to all the parts of chain of survival, which remains essential in improving survival rates. PMID- 21252592 TI - Voluntary performance. AB - Will, purpose, and volition have long been viewed as either causes of behavior or of no direct consequence to behavior. In this essay, volition affects a flexible direct coupling of participant to task, modulating the degrees of freedom for kinematics in action, a point of view first introduced in theories of motor coordination. The consequence is an explanation consistent with present knowledge about involuntary and voluntary sources of control in human performance, and also the changes of the body expressed in aging and dynamical disease. Specifically, this view explains how tradeoffs between sources of overly regular versus overly random dynamics change the structure of variability in repeated measurements of voluntary performance. PMID- 21252593 TI - Ethical dilemmas concerning decision-making within health care leadership: a systematic literature review. AB - The objective was to describe the research methods and research focuses on ethical dilemmas concerning decision-making within health care leadership. MATERIAL AND METHODS: The search was conducted on Medline and PubMed databases (1998-2008). The systematic review included 21 selected articles. RESULTS: The ethical dilemmas concerning decision-making within health care leadership are related to three levels: institutional (particular organization), political and local interface (local governmental structure), and national (professional expertise and system). The terms that are used as adequate to the term of "ethical dilemma" are the following: "continuous balancing," "result of resource allocation," "gap between professional obligations and possibilities," "ethically controversial situation," "concern about interactions," "ethical difficulty," "outcome of medical choices," "concern about society access to health care resources," "ethically difficult/challenging situation," "(the consequence of) ethical concern/ethical issue." In qualitative studies, a semi-structured interview and qualitative content analysis are the most commonly applied methods; in quantitative studies, questionnaire surveys are employed. In the research literature, there is a lack of specification according to professional qualification of health care professionals concerning ethical dilemmas by decision-making within health care management/administration. CONCLUSIONS: The research on ethical dilemmas in health care leadership, management, and administration should integrate data about levels at which ethical dilemmas occur and investigate ethical dilemmas as complex phenomena because those are attached to decision-making and specific nuances of health care management/administration. In this article, the presented scientific problem requires extensive scientific discussions and research on ethical dilemmas concerning decision-making within health care leadership at various levels. PMID- 21252594 TI - The role of high-grade prostatic intraepithelial neoplasia for biochemical relapse of prostate carcinoma after radical prostatectomy. AB - The objective of the study was to evaluate the relationship between high-grade intraepithelial neoplasia diagnosed after radical retropubic prostatectomy and the clinical and pathological characteristics of prostate cancer, and to evaluate the time to biochemical relapse of the disease within the groups of high-grade prostatic intraepithelial neoplasia (HGPIN) and non-HGPIN patients. MATERIAL AND METHODS: Patients, clinically diagnosed with local prostate carcinoma at the Clinic of Urology, Kaunas University of Medicine, during 2003-2007 and treated with radical retropubic prostatectomies, were distributed into two groups according to the HGPIN detected in the postoperative material: HGPIN and non HGPIN. The two groups were compared in terms of preoperative and postoperative characteristics. The patients who were followed up for at least 12 months were included into the study. The biochemical relapse of prostate cancer was determined if there were two consecutive rises of prostate-specific antigen (PSA) level above 0.2 ng/mL or according to the attending physician's opinion, there was a need for adjuvant treatment even with onetime rise of PSA level above 0.2 ng/mL. RESULTS: There was no significant difference between the HGPIN and non HGPIN groups in terms of time to biochemical relapse and frequency of biochemical relapses, time before surgery, the timing of the HGPIN diagnosis, age, or PSA level. After radical prostatectomy, patients in the HGPIN group were found to have significantly more often poorer cancer cell differentiation according to the Gleason score (>=7 vs. <7; P=0.001) and higher TNM stage (T3a,b vs. T2a,b,c; P=0.001). Fewer positive resection margins were diagnosed in the HGPIN group (P=0.05). The groups did not differ in terms of the degree of differentiation according to the Gleason score or perineural invasion (P=0.811 and P=0.282, respectively). CONCLUSIONS: HGPIN was more often associated with the characteristics of the poor prognosis for relapse of prostate cancer: poorer tumor cell differentiation according to the Gleason score and more cases of higher TNM stage. HGPIN did not have any influence on biochemical relapse of the disease during the short-term follow-up. PMID- 21252595 TI - The need and reasons for referrals to specialists among Lithuanian general dentists. AB - OBJECTIVE: To analyze the need for referral to a specialist and to identify the reasons of referrals among Lithuanian general dental practitioners. MATERIAL AND METHODS: Questionnaires were sent to all 2879 Lithuanian dental practitioners registered on the Lithuanian Dental Chamber license registry. The questionnaire was made with multiple-choice answers. Respondents were asked to choose only one category of answer that best fitted their clinical attitude. Questions included in the questionnaire concerned general and specific information regarding the need and main reasons for endodontic referral. RESULTS: Of the 2879 questionnaires mailed, 1532 questionnaires containing useful information were returned. The response rate was 53.2%. Of the 1532 respondents, 1431 were general dental practitioners. Majority (72.1%) of the respondents performed complicated root canal treatment by themselves. Almost half (49.6%) of them would like to refer patients to an endodontist. Two of the reasons, which restricted their decision, were the shortage of endodontists and high cost of the procedures in the specialized clinics. Approximately 19% of the respondents referred patients to an endodontist. The main reasons for referral were fractured instruments (86.6%), dental trauma (83.6%), difficulties in diagnostics (79%) followed by persistent symptoms (78.1%). CONCLUSION: The findings of the present study suggest that the need for referral of patients to an endodontist among Lithuanian dental practitioners exists. The main reasons for referrals were complications of endodontic treatment, traumatic injuries, difficulties in diagnostic procedures, and persistent symptoms. PMID- 21252596 TI - [Prevalence of human papillomavirus types in cervical intraepithelial lesions]. AB - BACKGROUND: Since the implementation of the cervical cancer screening program in Lithuania in 2004, cervical cancer incidence rates have stabilized during a 4 year period: in 2006 and 2007, 508 and 485 new cases, respectively, were diagnosed. Human papillomavirus (HPV) infection is one of the main risk factors for cervical cancer and development of intraepithelial lesions. However, not only HPV, but also HPV type, is a very important factor for malignant transformation. Cervical intraepithelial lesions with HPV 16 and 18 more frequently progress to cancer. To date, in Lithuania, studies only on HPV prevalence and risk factors have been carried out, and less attention has been paid to the identification of HPV types. The aim of this study was to identify the most common HPV types in women with various cytological lesions. MATERIAL AND METHODS: A total of 246 women with various cytological lesions (atypical squamous cells of undetermined significance [ASCUS], low-grade squamous intraepithelial lesion [LSIL], and high grade squamous intraepithelial lesion [HSIL]) were included into the study. All the women were screened for HPV infections followed by HPV typing for types 6, 11, 16, 18, 31, 33, 45, and 59. Polymerase chain reaction was used. RESULTS: Less than half (45.5%) of women with cytological lesions were infected with HPV. The highest prevalence of HPV was detected in women with HSILs (62.1%) and CIN2 (86.7%). HPV typing revealed that the most frequent type was HPV 16 (64.3%); HPV 18 and HPV 33 accounted for 5.4% and 4.5% of cases, respectively. Based on cytologic diagnosis, HPV 16 was more frequently found in women with HSILs than women with ASCUS (77.8% vs. 50.0%). CONCLUSIONS: The prevalence of HPV infection in women with cytological lesions was 45.5%. The highest prevalence of HPV was detected in women with HSILs (cytologic investigation) and CIN2 (histologic investigation). HPV 16 is the most common type in women with various cervical intraepithelial lesions. PMID- 21252597 TI - Vehicle-associated closed trauma-induced stroke in a 27-day-old girl. AB - Birth trauma, but not postnatal trauma, has been recognized as a cause of cerebral infarction in newborns. We report a case of cerebral infarction in a 27 day-old girl after a car accident. During the car accident, the child was properly restrained to the child's safety seat. The patient was admitted to the hospital for observation because of pronounced irritability. There were no focal neurological symptoms on admission. Twenty-eight hours after the accident, the child developed focal tonic-clonic seizures and mild right-sided hemiparesis. The seizures were successfully treated with phenobarbital at a dose of 30 mg per day. Computed tomography and magnetic resonance imagining performed on the second and third days after the accident, respectively, showed subdural hemorrhage in the occipital regions and cerebral ischemia in the left parieto-occipital region. Control imaging 10 days later showed signs of reperfusion. Persistent child irritability after head trauma is one of the indicating factors for performing an emergency computed tomography scan of the head. PMID- 21252598 TI - Sickness, colleagues' harassment in teachers' work and emotional exhaustion. AB - The aim of this study was to assess the relationship among colleagues' harassment, emotional exhaustion, and sickness absence with a sample of teachers. MATERIAL AND METHODS: The sample consisted of 351 teachers from 8 secondary schools in Kaunas. Instruments used in the study included the Work Harassment Scale (WHS) developed by Bjorkqvist and Osterman (1992), the Emotional Exhaustion Scale (the MBI-ES) by Maslach et al. (1996), and a questionnaire of demographic information. RESULTS: Data analysis indicated that a higher level of work harassment was related to higher emotional exhaustion. Regression analysis findings indicated that a higher level of emotional exhaustion was related to higher levels of disruption, humiliation, alienation, and indignity. Teachers who observed harassment reported higher levels of emotional exhaustion. Respondents who missed work due to illness reported higher levels of disruption on the WHS. CONCLUSIONS: The study indicated that work harassment could be an important aspect in teacher's health. The seriousness of the work harassment phenomenon may be supported by the results showing that teachers who witnessed others being harassed experienced a higher level of emotional exhaustion. The phenomenon appears to be an area that requires additional research. PMID- 21252599 TI - Parental cigarette smoking and the risk of congenital heart septal defects. AB - The objective of this study was to determine the association between parental cigarette smoking and the risk of congenital heart septal defects in Kaunas infant population in 1995-2005. MATERIAL AND METHODS: An epidemiological case control study was conducted. The study comprised 261 newborns with congenital heart septal defects (cases) and 1122 randomly selected newborns without any defects (controls), born in Kaunas city during 1995-2005. Information on potential risk factors of newborns' health was collected through an interview with parents using standardized questionnaires. Multivariate logistic regression analysis was used to assess the association between parental smoking and septal defects while controlling for possible confounders. RESULTS: According to the validated registry, 371 newborns with congenital heart malformations were born in Kaunas city during 1995-2005; 70.3% of cases had ventricular and/or atrial septal defects. After adjustment for possible confounding factors - maternal education, social status, marital status - a statistically significant relationship was observed between parental smoking and congenital heart septal defects. Parental, maternal, and paternal smoking was significantly associated with a 2.27-fold (adjusted OR=2.27; 95% CI, 1.49-3.46), 2.2-fold (adjusted OR=2.20; 95% CI, 1.01 4.79), and 1.45-fold (adjusted OR=1.45; 95% CI, 1.03-2.03) increased risk of defects if compared with nonsmoking parents. CONCLUSIONS: According to the results of our study, parental smoking was significantly associated with an increased risk of congenital heart septal defects in infants. PMID- 21252600 TI - The coagulation system changes in patients with chronic heart failure. AB - Though heart failure can mainly be caused by systolic or diastolic dysfunction, the impairments of the neurohormonal, immune, and hemostatic systems are observed too. Therefore, it is not easy to determine etiology of the syndrome. Parameters that can be helpful to predict chronic heart failure, to evaluate its course and the risk of complications are still being searched. The aim of this article is to review the recent studies in order to find the links between the coagulation system and the development of chronic heart failure. Stress is a key factor for the development of most diseases including chronic heart failure too. Signals of emotional and physical stress via particular structures trigger an increase in concentrations of the following hormones: noradrenaline, renin, angiotensin II, aldosterone, vasopressin. It is proved that it causes the disorders of the coagulation system: an increase in the following factors of plasma coagulation (fibrinogen, VII, VIII, fibrinopeptide A, thrombin-antithrombin complex), fibrinolysis (D-dimer), endothelium (interleukin 1, endothelin 1, vascular cell adhesion molecules, endothelial growth factor), platelet activity (von Willebrand factor, intercellular adhesion molecules, platelet factor 4, P-selectin, thromboxane A(2), thromboglobulin, CD63P) and cytokines (tumor necrosis factor, interleukin 6) and decrease in E-selectin. The role of particular coagulation factors for the development of chronic heart failure has not been understood yet. Thus, it is necessary to carry out further studies. PMID- 21252601 TI - Management of ununited intracapsular femoral neck fractures by using quadratus femoris muscle pedicle bone grafting in young patients. AB - OBJECTIVES: Intracapsular femoral neck fracture with delayed presentation in young patients can pose surgical challenge. Such scenarios are rare in developed countries, but common in developing countries. METHODS: We retrospectively reviewed the records and radiographs of 42 patients (28 males and 14 females) with ununited intracapsular femoral neck fracture who presented late to our unit. These subjects were managed by open reduction and internal fixation that was supplemented with cortico-cancellous bone graft from posterior iliac crest as well as quadratus femoris muscle pedicle bone graft. RESULTS: The mean delay in presentation was 9 months (range 3-18 months) after the fracture. The mean age of the patients at index procedure was 34 years (range 24-51 years). Radiological union occurred on average at 6 months (range 3-13 months). Thirty-six hip fractures (86%) proceeded to union. Six patients (14%) had non-union and needed revision surgery. Complications included varus union in 9 patients and leg length discrepancy with a mean of 1.5 cm (range 1 to 2.5 cm) in 10 patients. CONCLUSION: For the ununited intracapsular femoral neck fracture, favorable results can be achieved by anatomical reduction of the fracture, cortico-cancellous bone grafting to reconstruct the femoral neck, internal fixation with cancellous screws, and augmentation with quadratus femoris muscle pedicle bone graft. PMID- 21252602 TI - Calcium phosphate cement augmentation in the treatment of depressed tibial plateau fractures with open reduction and internal fixation. AB - OBJECTIVES: We aimed to evaluate the clinical and radiological outcomes of open reduction and internal fixation augmented with calcium phosphate cement (CPC) in the treatment of depressed tibial plateau fractures. METHODS: Twenty-eight knees of 28 patients [19 males and 9 females; mean age, 41.2 years (range 22-72 years)] who had open reduction and internal fixation combined with CPC augmentation were included in this study. Seventeen fractures were Schatzker type II, 5 were type III, 3 were type IV, 2 were type V, and 1 was type VI. CPC was used to fill the subchondral bone defects in all knees. Fixation of the fragments was done with screws in 3 knees (10%). Standard proximal tibial plates or buttress plates were used in 25 knees (90%) with an additional split fragment extending distally to achieve internal fixation. Full weight-bearing was allowed in 6.4 weeks (range 6 12 weeks) after surgery. Resorption of CPC granules was defined as the decrease in the size and density of grafting material on radiographs. Rasmussen's radiological and clinical scores were determined postoperatively. Functionality was assessed with Lysholm knee scoring system. Activity was graded with Tegner's activity scale. RESULTS: Union was achieved in all patients with a mean follow-up of 22.2 months (range 6-36 months). There were no intraoperative complications. At the latest follow-up radiographs, resorption of the graft was observed in 25 knees (89%). Rasmussen's radiologic score was excellent in 17 patients (61%), good in 9 patients (32%), and fair in 2 patients (7%). Rasmussen's clinical score was excellent in 9 patients (32%), good in 18 patients (64%), and fair in 1 patient (4%). According to the Lysholm knee score, functional results were excellent in 16 patients (57%), good in 8 patients (29%), and fair in 4 patients (14%). Twenty-two patients (78%) achieved the preoperative activity level after surgery, and there was no significant difference between the mean preoperative and postoperative Tegner scores (4.11+/-0.68 and 4.04+/-0.64, respectively, p=0.161). CONCLUSION: CPC is a safe biomaterial with many advantages in augmenting the open reduction and internal fixation of depressed tibial plateau fractures, including elimination of morbidity associated with bone graft harvesting, the unlimited supply of bone substitute, the optimum filling of irregular bone defects, and shortening of the postoperative full weight-bearing time. PMID- 21252603 TI - Hospital-based versus home-based proprioceptive and strengthening exercise programs in knee osteoarthritis. AB - OBJECTIVES: This study aimed to establish the effects of hospital- and home-based proprioceptive and strengthening exercise programs on proprioception, pain, and functional status in patients with knee osteoarthritis (OA). METHODS: Sixty patients with bilateral knee OA were randomly allocated into either a home-based or hospital-based exercise program. Hospital-based exercise group (n=30, mean age 50.23+/-9.07 years) received functional training program with proprioceptive ability, ice, and home exercises. Home-based exercise group (n=30, mean age 54.4+/-7.9 years) had a program of ice and home exercises. Treatment programs was conducted 5 days per week for 6 weeks (30 sessions). Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Monitorized Functional Squat System Proprioceptive Test (MFSS), timed performance test (TUG), and visual analogue scale (VAS) for the intensity of pain were used to quantify the variables. RESULTS: Both groups demonstrated significant improvement when pre- and post treatment results were compared for pain intensity, WOMAC, and TUG test scores (p<0.05). No statistically significant improvement was found in proprioception of the home-based group (p>0.05). Hospital-based group demonstrated significantly greater improvement in MFSS, TUG test, and VAS in activity when compared with the home-based group (p<0.05). CONCLUSION: Both hospital- and home-based exercise programs decreased joint symptoms and improved function in patients with knee OA. PMID- 21252604 TI - Immobilization of the shoulder in external rotation for prevention of recurrence in acute anterior dislocation. AB - OBJECTIVES: We aimed to compare the functional and stability outcomes of the patients with acute anterior shoulder dislocation, who were stabilized at external versus internal rotation. METHODS: A total of 33 patients (31 males and 2 females) with the diagnosis of acute primary traumatic anterior shoulder dislocation were immobilized at internal (n=17) or external rotation (n=16). The mean follow-up period was 20.85 months (range 6-41 months). Patients received rehabilitation program immediately after splinting. We assessed functionality by Constant-Murlay score and stability by Rowe scoring system in 6th month. Control examinations were performed in 12th and 24th months. RESULTS: There were no statistically significant differences between internal rotation and external rotation groups in terms of Constant-Murlay and Rowe scores. Recurrent dislocation rate was 6.3% (1/16) in external rotation group and 29.4% (5/17) in internal rotation group (p>0.05). In the subgroup of patients aged between 21-30 years, while no recurrent dislocation was seen in external rotation group, 5 patients developed recurrent dislocation in internal rotation group(p=0.035). CONCLUSION: Immobilization of the shoulder in external rotation is an effective technique for prevention of recurrent dislocations in acute anterior shoulder dislocation and should be preferred to traditional splinting in internal rotation in clinical practice. PMID- 21252605 TI - Comparison of the outcomes of two different exercise programs on frozen shoulder. AB - OBJECTIVES: The aim of the study was to compare the effects of two different exercise programs on pain, range of motion (ROM), and functional results in frozen shoulder. METHODS: Twenty-two female and 7 male patients [mean age 52.1 years (range 38-65 years)] were randomly allocated into two groups: 14 in the first group and 15 in the second group. The patients were treated for 6 weeks (30 sessions) at hospital under the supervision of physical therapist. Both groups were treated with transcutaneous electrical nerve stimulation, cold pack, and nonsteroidal antiinflammatory drugs; and were given glenohumeral ROM exercises. The scapulothoracic exercises were performed only by the second group. Functional results were assessed using the modified Constant score, pain was assessed using visual analog scale (VAS), and ROM was measured with a goniometer. Assessments were performed before treatment and repeated at 6 and 12 weeks of treatment. RESULTS: In both groups, the Constant score and ROM were increased, and VAS was decreased at the end of 6 and 12 weeks. The modified Constant score was not significantly different between the groups before and after treatment. VAS score was better in the second group at 6 weeks (p<0.01). Improvement in ROM was significantly better in the second group at 12 weeks (p=0.005). CONCLUSION: In addition to glenohumeral ROM exercises, scapulothoracic exercises contribute to decreasing pain and increasing ROM in patients with frozen shoulder. PMID- 21252606 TI - The relation between sagittal morphology of the lumbosacral spine and the degree of lumbar intervertebral disc degeneration. AB - OBJECTIVES: We investigated the relationship between the lumbosacral morphology and degree of intervertebral disc degeneration in a large sample of young patients. In addition, the relation between various morphological parameters (sacral table angle and sacral kyphosis) and lumbar disc herniation or degeneration was also evaluated. METHODS: The magnetic resonance imaging (MRI) of low back pain patients referred to our department in 2008-2009 were retrospectively evaluated. Patients with prior lumbar spinal surgery, serious congenital anomalies on MRI, incomplete or complete lumbosacral trancision, severe scoliosis, spondylolysis, or spondylolisthesis were excluded from the study. A sample of 131 females between 20-30 years of age was studied. Patients were evaluated for the presence of intervertebral disc herniation or degeneration, and the degree of degeneration was assessed. Angles of lumbar lordosis, sacral table, and sacral kyphosis were also measured for each patient. RESULTS: The degree of intervertebral disc degeneration increased in parallel to the decrease in the sacral kyphosis and lumbar lordosis angles, and to the increase in sacral table angle. A statistically significant difference with regard to the angles of lumbar lordosis, sacral kyphosis, and sacral table was determined between individuals with (23.37+/-7.09 degrees , 163.09+/-9.48 degrees , 104.34+/-5.47 degrees , respectively) and without intervertebral disc degeneration (26.94+/-7.39 degrees , 168.94+/-10.52 degrees , 100.83+/-4.32 degrees ; p=0.006, p=0.001, p=0.0001, respectively). In addition, a statistically significant difference with regard to the angles of lumbar lordosis, sacral kyphosis, and sacral table was determined between individuals with (22.82+/-6.94 degrees , 162.23+/-9.53 degrees , 104.94+/-5.19 degrees , respectively) and without intervertebral disc herniation (27.25+/-7.26 degrees , 169.39+/-9.96 degrees , 100.48+/-4.33 degrees ; p=0.001, p=0.0001, p=0.0001, respectively). CONCLUSION: The degree and risk of intervertebral disc degeneration and herniation increases in parallel to the decrease in sacral kyphosis and lumbar lordosis, and to the increase in sacral surface angle. PMID- 21252607 TI - Is there any correlation between the preoperative parameters and correction loss in patients operated for hyperkyphosis? AB - OBJECTIVES: Preoperative, postoperative, and latest follow-up data of sagittal balance and spinopelvic parameters of our patients treated surgically for hyperkyphosis were evaluated retrospectively, to determine whether there is any correlation between the preoperative pelvic incidence and postoperative correction loss. METHODS: Totally 33 patients (18 females) who were operated for hyperkyphosis and, were reached at the latest follow-up were included in the study. Age at operation, gender, date of operation, etiology and level of the deformities, instrumentation, and graft types were noted in detail. The kyphosis angles were measured by the Cobb method. The preoperative and postoperative spinopelvic parameters (pelvic incidence, sacral slope, and pelvic tilt) were recorded. RESULTS: The average follow-up was 4 years (range 3-8 years). The mean age at operation was 21 years (range 14-40 years). Scheuermann kyphosis was diagnosed as the etiological factor in 18 patients (53%). The mean preoperative kyphosis angle was 76 degrees (range 55-98 degrees ), which decreased postoperatively to 38 degrees (range 20-55 degrees ) (p<0.05). The mean kyphosis angle two years postoperatively was 41 degrees (p>0.05). Preoperative and latest follow-up spinopelvic parameters were also not significantly different. Furthermore, no correlation could be found between the age at operation, instrumentation level, spinopelvic parameters, and correction loss. CONCLUSION: There is no correlation between the preoperative pelvic incidence and postoperative correction loss in patients treated surgically for hyperkyphosis. Further studies with larger sample size and longer follow-up should be conducted. PMID- 21252608 TI - Allogeneic blood transfusion decreases with postoperative autotransfusion in hip and knee arthroplasty. AB - OBJECTIVES: We aimed to evaluate the effectiveness of postoperative autotransfusion method on prevention of the need of allogeneic blood transfusion in hip and knee arthroplasty. METHODS: Seventy-four patients who underwent 77 hip and knee arthroplasty operations were randomized into control and study groups, and evaluated prospectively. In the knee group (39 patients; 30 females, 9 males; mean age 66.6 years), cemented, cruciate retaining, and bicompartmental arthroplasty was performed under tourniquet control; whereas in the hip group (35 patients; 24 females, 11 males; mean age 59.3 years) cementless arthroplasty with posterolateral approach was performed. None of the patients received preoperative and intraoperative allogeneic blood transfusion. The collected blood in the surgical area was transfused with autotransfusion system to the patients in the study groups at the end of the fourth hour postoperatively. The mean amounts of autotransfused blood in hip and knee groups were 413 mL and 480 mL, respectively. Allogeneic blood transfusion was applied to the patients with hemoglobin level below 8 g/dL, hematocrit level below 25%, and clinical symptoms of anemia. RESULTS: Preoperative and postoperative hemoglobin-hematocrit levels did not differ significantly between study and control groups. Allogeneic blood transfusion was applied to one patient (5%) in study and 8 patients (38%) in control groups during knee arthroplasty (p=0.01); whereas 9 patients (53%) in study and 15 patients (79%) in control groups received allogeneic blood transfusion during hip arthroplasty (p=0.044). The amount of allogeneic blood transfusion in study groups was significantly lower than that in control groups (p=0.008 for knee arthroplasty, p=0.048 for hip arthroplasty). CONCLUSION: The need and amount of allogeneic transfusion were reduced with postoperative autotransfusion in both knee and hip arthroplasty groups with greater extent in knee arthroplasty. PMID- 21252609 TI - The effect of head trauma on fracture healing: biomechanical testing and finite element analysis. AB - OBJECTIVES: We aimed to evaluate the effect of head trauma on fracture healing with biomechanical testing, to compare the results obtained from a femur model created by finite element analysis with experimental data, and to develop a finite element model that can be employed in femoral fractures. METHODS: Twenty two Wistar albino rats were randomized into two groups. The control group was subjected to femoral fracture followed by intramedullary fixation, whereas the head trauma group was subjected to femoral fracture followed by intramedullary fixation along with closed blunt head trauma. Bone sections obtained with computed tomography from rat femurs were transferred into a computer and a 3D mathematical model of femur was created. At the end of week 4, femurs were examined by biomechanical testing and finite element analysis. RESULTS: The mean maximum fracture load was significantly higher in the head trauma group than in control group (p<0.05). Maximum strain values were also significantly high in the head trauma group (p<0.05). There was no significant difference between the groups with regard to maximum deformation (p>0.05). The head trauma group had significantly higher mean bending rigidity than the control group (p<0.05). The head trauma group showed no significant difference from the control group in terms of strain energy and elasticity module (p>0.05). There was no significant difference between experimental biomechanical test and finite element analysis (p>0.05). CONCLUSION: Noninvasive methods such as finite element analysis are useful in examination of the mechanical structure of bones. Experimental biomechanical test and finite element analysis methods suggest that head trauma contributes to fracture healing. PMID- 21252610 TI - The comparison of the negative effect of autoclaving and pasteurization on bone healing. AB - OBJECTIVES: The aim of this study was to compare the effects of autoclaving and pasteurization on bone healing. METHODS: Twenty-five full-grown male rabbits were included in the study; all 25 had bone blocks resected and reimplanted. In group 1, bone blocks were autoclaved; in group 2, bone blocks were pasteurized; and in group 3 (controls), resected bone blocks were reimplanted without sterilization. RESULTS: Heiple scores of the proximal parts of the fusion surfaces in group 1, group 2, and group 3 were 12.8+/-0.4, 6.8+/-1.2, and 10.2+/-1.9, respectively. Heiple scores of the distal parts of the fusion surfaces in group 1, group 2, and group 3 were 10.8+/-0.8, 6.0+/-1.1, and 9.8+/-1.5, respectively. Differences in radiologic scores were not statistically significant between the groups for proximal or distal fusion surfaces at 3 and 6 weeks. CONCLUSION: In conclusion, pasteurization has a less negative effect on bone healing than autoclaving, and can be considered for bone sterilization in certain circumstances. PMID- 21252611 TI - Neuropathic arthropathy of the shoulder associated with syringomyelia: a report of six cases. AB - Here, we report a series of 5 patients (6 shoulders) diagnosed with neuropathic arthropathy of the shoulder joint in our clinic between 2005 and 2008. Initial diagnosis, previous treatment, and radiological and clinical follow-up findings were reviewed. The mean age at diagnosis was 44.2 years. Four patients had unilateral and 1 patient had bilateral involvement. The presenting symptoms were pain, swelling, and loss in range of motion. Active forward flexion and abduction ranged from 0 degrees to 90 degrees . Hypoesthesia and loss of temperature sense was evident in 3 patients. Radiographs showed massive osteolysis of humeral head and glenoid process, and magnetic resonance imaging showed periarticular fluid collection, and degeneration at the rotator cuff and shoulder joint, resembling chronic septic arthritis or sarcoma. Biopsy was performed in 4 patients before definitive diagnosis, and synovial hypertrophy and necrotic bone was found. Two patients had a history of operated cervical syringomyelia, and the remaining 3 patients were later diagnosed to have syringomyelia and referred to neurosurgery clinic, where 2 of those were operated. Four patients were followed-up with symptomatic therapy, and 1 patient underwent an unsuccessful shoulder arthroplasty in another clinic. As a conclusion, neuropathic arthropathy of the shoulder is rare, and correct diagnosis is possible by careful physical and neurological examination and pathologic evaluation when needed. PMID- 21252612 TI - Synovial chondromatosis of the metacarpophalangeal joint of the ring finger. AB - Synovial chondromatosis is an uncommon condition, characterized by multinodular cartilagineous proliferation of the joint synovium. There are only a few case reports of synovial chondromatosis involving the hand in the literature. A case of synovial chondromatosis of the ring finger is reported in this paper. PMID- 21252613 TI - Migrating bone marrow edema syndrome: a cause of recurring knee pain. AB - Bone marrow edema syndrome is a condition of unknown etiology, presenting with painful limping. It is characterized by normal radiographs, but magnetic resonance imaging findings change with bone marrow edema. When there is osteopenia in the radiographs, the condition is called transient osteoporosis. The term migratory bone marrow edema syndrome is used when there is involvement of another joint, or another compartment in the same joint, which typically occurs within 6 months of onset of primary symptoms. Here, a case of migratory bone marrow edema syndrome in a 47-year-old male patient, which was conservatively managed, is reported. PMID- 21252615 TI - Antimicrobial peptides in healthy skin and atopic dermatitis. AB - Antimicrobial Peptides and Proteins (AMPs) represent effector molecules of the innate defense system in all organisms. AMPs are either constitutively or inducibly produced mainly by various epithelial cells, including keratinocytes. This report reviews our current knowledge about the major yet known keratinocyte derived AMPs, its role in healthy skin and atopic dermatitis. PMID- 21252614 TI - Up-regulation of BLT2 is critical for the survival of bladder cancer cells. AB - The incidence rates of urinary bladder cancer continue to rise yearly, and thus new therapeutic approaches and early diagnostic markers for bladder cancer are urgently needed. Thus, identifying the key mediators and molecular mechanisms responsible for the survival of bladder cancer has valuable implications for the development of therapy. In this study, the role of BLT2, a receptor for leukotriene B((4)) (LTB((4))) and 12(S)-hydroxyeicosatetraenoic acid (HETE), in the survival of bladder cancer 253J-BV cells was investigated. We found that the expression of BLT2 is highly elevated in bladder cancer cells. Also, we observed that blockade of BLT2 with an antagonist or BLT2 siRNA resulted in cell cycle arrest and apoptotic cell death, suggesting a role of BLT2 in the survival of human bladder cancer 253J-BV cells. Further experiments aimed at elucidating the mechanism by which BLT2 mediates survival revealed that enhanced level of reactive oxygen species (ROS) are generated via a BLT2-dependent up-regulation of NADPH oxidase members NOX1 and NOX4. Additionally, we observed that inhibition of ROS generation by either NOX1/4 siRNAs or treatment with an ROS-scavenging agent results in apoptotic cell death in 253J-BV bladder cancer cells. These results demonstrated that a 'BLT2-NOX1/4-ROS' cascade plays a role in the survival of this aggressive bladder cancer cells, thus pointing to BLT2 as a potential target for anti-bladder cancer therapy. PMID- 21252616 TI - Skin barrier-related molecules and pathophysiology of asthma. AB - The concept of "atopic march" has been well appreciated both by physicians and by dermatologists; eczema (atopic dermatitis) often precedes the development of airway diseases such as asthma and allergic rhinitis in atopic subjects. However, the underlying mechanisms for atopic march are less elucidated. It has been conceived that genetic susceptibility to atopy determines the phenotype of allergic diseases progressive from the skin to the airways, but recent discovery of filaggrin gene mutations that disturb the barrier function of the skin in patients with asthma and eczema now suggests the crucial role of epicutaneous sensitization as a precursory event for the development of asthma. In the present review, we describe updated genetic and immunological evidences that suggest the relationship between skin barrier-related molecules and the pathology of asthma. PMID- 21252617 TI - Upregulation of IL17RB during natural allergen exposure in patients with seasonal allergic rhinitis. AB - BACKGROUND: Seasonal allergic rhinitis (SAR) to Japanese cedar (Cryptomeria japonica; JC) is an IgE-mediated type I allergy affecting the nasal mucosa. However, the molecular mechanisms that underlie SAR are only partially understood. The aim of the study was to identify novel genes related to SAR during natural exposure to pollens, by using microarray analysis. METHODS: Subjects were 32 SAR patients and 25 controls. Total RNA was extracted from CD4(+) T cells isolated from peripheral blood mononuclear cells and subjected to microarray analysis with Illumina Human Ref8 BeadChip arrays. The Mann-Whitney test was performed to identify genes whose expression was altered during allergen exposure. Quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) was performed on samples collected from SAR patients and controls to verify the microarray results. RESULTS: Microarray analysis showed that the expression of 3 genes was significantly altered during allergen exposure. Among these 3 genes, the expression of interleukin 17 receptor beta (IL17RB) was confirmed to be upregulated in SAR patients compared to that of the IL17RB gene in healthy, non-allergic controls. The average fold change of IL17RB expression in the real-time RT-PCR experiment was 3.9 (P = 0.003). CONCLUSIONS: The present study identified upregulation of IL17RB during natural allergen exposure in patients with SAR, which may further elucidate the molecular mechanisms underlying SAR. PMID- 21252618 TI - Platelet derived endothelial cell growth factor/thymidine phosphorylase enhanced human IgE production. AB - BACKGROUND: Angiogenesis is one pathogenesis of allergic airway disease. METHODS: A potent angiogenic factor is platelet-derived endothelial cell growth factor (PD ECGF), also known as thymidine phosphorylase (TP) in the field of cancer associated research. Vascular endothelial growth factor (VEGF) is another representative angiogenic factor. Both factors were added to the culture system of human peripheral blood mononuclear cells (PBMC) with IL-4 and anti-CD40 monoclonal antibody (mAb). Total IgE levels in the supernatants and signal transduction of stimulated PBMC were evaluated. RESULTS: Addition of PD-ECGF enhances in vitro IgE production by PBMC in the presence of IL-4 and anti-CD40 mAb, but VEGF does not enhance IgE production. Although PD-ECGF catalyzes the reversible phosphorolysis of thymidine to 2-deoxy-D-ribose-1-phosphate (2DDR), treatment of 2DDR has no effect on IgE production by human PBMC. Both IL-4 and anti-CD40 mAb induce PD-ECGF by human PBMC. Thymidine phosphorylase inhibitor (TPI), 5-chloro-6-[1- (2-iminopyrrolidinyl) methyl] uracil hydrochloride reduce IgE production via blocking of STAT6- phosphorylation. CONCLUSIONS: Taken together, these results suggest TP involvement in the enhancement of IgE production and suggest that TPI is a novel strategy against IgE-related allergic disease. PMID- 21252619 TI - Sensitization profiles of a case of pollen-food allergy syndrome. AB - A 13-year-old girl who had had pollinosis since the age of eight began to experience itching of the ears and vomiting after eating fresh fruits such as peach, apple and watermelon. This occurred at 10 years of age. The girl displayed positive reactions to six kinds of pollens, eleven kinds of fruits, numerous vegetables and to recombinant: rBet v2 present in specific IgE antibodies. She also reacted positively to several pollens, fruits and rBet v2 in the skin prick test. In the component-resolved diagnosis (CRD) using microarray technology, she also tested positive for profilin, a pan-allergen among plants. It is reported that profilin cross-reacts between pollen, fruits, vegetables and latex. From these results, we concluded that the allergic reactions to multiple kinds of foodstuff and pollens observed in this subject were due to cross-reactivity induced by profilin. Our results demonstrate that CRD by microarray is a reliable test in the diagnosis of PFAS. PMID- 21252620 TI - Food protein-induced gastrointestinal syndromes in identical and fraternal twins. AB - BACKGROUND: It has been suggested that gene-environmental interactions play crucial roles in the development of allergy, especially in early life. Analysis of twin cases may provide novel insights into the pathogenesis and pathophysiology of allergy. Though several studies have indicated the importance of a genetic contribution to the expression of allergic diseases based on twin analyses, very few data are available regarding twins with Food Protein-Induced Gastrointestinal Syndrome (FPIGS). Two pairs of identical and fraternal twins with FPIGS are presented. CASE SUMMARY: The twins were born with no abnormalities and fed breast milk and supplemental formula. The identical twins developed vomiting and bloody stool simultaneously. The fraternal twins developed prolonged vomiting and loose stools at different times. Since their symptoms disappeared with when formula feeding was stopped, the symptoms were thought to indicate the presence of an allergy to cow's milk. The clinical symptoms and laboratory findings of the four patients were highly suggestive of FPIGS. The identical and fraternal twins showed very similar symptoms, including their onset and clinical courses. However, a substantial clinical disparity existed in the clinical features of the two pairs of twins. DISCUSSION: Comparisons of the twins' similarities and disparities suggest a profound genetic effect on the patients' clinical features, along with individual environmental factors. The prevalence of FPIGS is increasing, and it is now a major topic of public concern in Japan. Further accumulation of data on twins with FPIGS is needed to clarify the genetic contributions to this disease. PMID- 21252621 TI - Targeting autophagy in ALS: a complex mission. AB - Several neurodegenerative diseases share a common neuropathology, primarily featuring the presence of abnormal protein inclusions in the brain containing specific misfolded proteins. Strategies to decrease the load of protein aggregates and oligomers are considered relevant targets for therapeutic intervention. Many studies indicate that macroautophagy is a selective and efficient mechanism for the degradation of misfolded mutant proteins related to neurodegeneration, without affecting the levels of the corresponding wild-type form. In fact, activation of autophagy by rapamycin treatment decreases the accumulation of protein aggregates and alleviates disease features in animal models of Huntington disease and other disorders affecting the nervous system. Recent evidence, however, indicates that the expression of several disease related genes may actually impair autophagy activity at different levels, including omegasome formation, substrate recognition, lysosomal acidity and autophagosome membrane nucleation. A recent report from Zhang and co-workers indicates that treatment of an amyotrophic lateral sclerosis (ALS) mouse model with rapamycin actually exacerbates neuronal loss and disease progression, associated with enhanced apoptosis. This study reflects the need for a better understanding of the contribution of autophagy to ALS and other neurodegenerative diseases since this pathway may not only operate as a cleaning-up mechanism. Then, autophagy impairment may be part of the pathological mechanisms underlying the disease, whereas augmenting autophagy levels above a certain threshold could lead to detrimental effects in neuronal function and survival. Combinatorial strategies to repair the autophagy deficit and also enhance the activation of the pathway may result in a beneficial impact to decrease the content of protein aggregates and damaged organelles, improving neuronal function and survival. PMID- 21252622 TI - Autophagy inhibition engages Nrf2-p62 Ub-associated signaling. PMID- 21252623 TI - Mitochondria removal by autophagy. AB - Mitochondrial dysfunction has severe cellular consequences and is linked with neurodegenerative diseases and aging. Maintaining a healthy population of mitochondria is thus essential for proper cellular homeostasis. Several strategies have evolved to prevent and limit mitochondria damage, and macroautophagy plays a role in degrading superfluous or severely damaged mitochondria. Selective removal of mitochondria by autophagy (termed mitophagy) has been extensively studied recently in both yeast and mammalian cells. In this review, we summarize our current knowledge of mitophagy. We also compare the molecular process of mitophagy with other types of specific autophagic pathways and discuss its biological importance. PMID- 21252624 TI - CK1epsilon targets Cdc25A for ubiquitin-mediated proteolysis under normal conditions and in response to checkpoint activation. AB - Cdc25A phosphatase, which is essential in cell cycle progression, is degraded by the proteasome throughout interphase and in response to genotoxic stress. Phosphorylation of Cdc25A on Ser82 in the DSG motif is important in the recognition by beta-TrCP, resulting in targeting of Cdc25A for ubiquitination. Chk1 is known to phosphorylate Cdc25A on Ser76, and NEK11 or CK1alpha relays phosphorylation of Cdc25A to Ser82 in a hierarchical manner. In this study, we found that CK1epsilon has unique enzymatic activity on the serine residue in the DSG motif using a beta-catenin N-terminal region as a substrate. We then examined whether CK1epsilon has activity on the DSG motif of Cdc25A. We found CK1epsilon directly phosphorylated Ser82 without any prior phosphorylation of Cdc25A, and depletion of CK1epsilon stabilized the cellular Cdc25A in 293 cells. Moreover, we found that CK1epsilon also has activity as a relaying kinase like NEK11 or CK1alpha when the cell is exposed to DNA damage. Taken together, our results indicate that CK1epsilon regulates the cellular levels of Cdc25A in parallel with Chk1-dependent Cdc25A degradation, contributing to the precise control of cell division. PMID- 21252626 TI - A model for discrete spindle elongation. AB - It is not understood how spindles elongate by discrete lengths of approximately 0.7 um or multiples of 0.7 um during anaphase B of the cell cycle. Here, we report that GTP-tubulin segments (newly synthesized segments) on microtubules have discrete lengths of approximately 0.35 um or multiples of 0.35 um. Because two sets of microtubules, namely anti-parallel interpolar microtubules, contribute to spindle elongation, the total lengths of the GTP-tubulin segments on their plus ends should be 0.7 um or multiples of 0.7 um. Microtubule synthesis in such discrete lengths is thus hypothesized to underlie the discrete lengths in spindle elongation. PMID- 21252625 TI - Threonine 48 in the BIR domain of survivin is critical to its mitotic and anti apoptotic activities and can be phosphorylated by CK2 in vitro. AB - In this study we report that the protein kinase CK2 phosphorylates survivin specifically on threonine 48 (T48) within its BIR domain, and that T48 is critical to both the mitotic and anti-apoptotic roles of survivin. Interestingly, during mitosis T48 mutants localise normally, but are unable to support cell growth when endogenous survivin is removed by siRNA. In addition, while overexpression of survivin normally confers inhibition of TRAIL-mediated apoptosis, this protection is abolished by mutation of T48. Furthermore in interphase cells depletion of endogenous survivin causes redistribution of T48 mutants from the cytoplasm to the nucleus and treatment of cells expressing survivin-GFP with the CK2 inhibitor TBB phenocopies this nuclear redistribution. Finally, we show T48 mutants have increased affinity for borealin, and that this association and cell proliferation can be restored by introduction of a second mutation at T97. To our knowledge these data are the first to identify T48 as a key regulatory site on survivin, and CK2 as a mediator of its mitotic and anti apoptotic functions. PMID- 21252627 TI - Tools for studying the role of N-cadherin mediated extracellular interaction in neuronal development and function. AB - N-cadherin is a homophilic cell adhesion molecule that plays important roles in many aspects of neuronal development. In order to better understand the function of N-cadherin mediated cell-cell contact in activity-dependent dendrite development, we generated a number of new tools. EC1, consisting of the first extracellular domain of N-cadherin, can specifically inhibit N-cadherin, but not E-cadherin, mediated cell-cell contact, both when over-expressed in neurons and added as a purified protein. Ncad-HA is an extracellularly epitope-tagged version of N-cadherin that, when over-expressed under the activity-independent pCS2min promoter, can be used to assay surface N-cadherin level following various manipulations. These tools are likely to be very useful for studying the function of N-cadherin in multiple aspects of neural circuit development. PMID- 21252628 TI - A new in vitro system for activating the cell cycle checkpoint. AB - In response to DNA damage, cells launch elegant networks of genome surveillance mechanisms, called cell cycle checkpoints, to detect and repair damaged DNA to maintain the genome stability. Key components of cell cycle checkpoints are two PI3K-related protein kinases (PIKK), ATR and ATM, which participate in both sensing the DNA damage and transducing the damage signal through phosphorylating two target protein kinases, Chk1 and Chk2, respectively. However, how exactly cell cycle checkpoints are activated, maintained, and terminated are not completely understood. Given the complexity of the cell cycle checkpoint signaling and the cellular environment, systems that can faithfully mimic the cell cycle checkpoint activation in vitro, such as the Xenopus egg extracts, are of extreme value in dissecting the precise molecular mechanisms underlying DNA damage response. Here we describe that the well-established in vitro transcription and translation (IVTNT) system has the capability to induce protein phosphorylation of substrates for ATR or ATM, including Chk1, Rad17, and ATM itself. These phosphorylation events highly mimic those occurring in cells when treated with DNA damaging agents. Our results demonstrate that the IVTNT system could be developed into a novel in vitro system to facilitating the dissecting of mechanisms leading to cell cycle checkpoint activation in vivo. PMID- 21252629 TI - Spindly switch controls anaphase: spindly and RZZ functions in chromosome attachment and mitotic checkpoint control. AB - Spindly is a coiled-coil domain containing protein, also known as CCDC99, that is an important regulator of the mitotic checkpoint. It belongs to a functionally conserved family of proteins that controls the localization and function of cytoplasmic dynein at kinetochores. At kinetochores Spindly interacts with the RZZ (Rod/ZW10/Zwilch) complex and is required for the recruitment of cytoplasmic dynein to kinetochores. Loss of Spindly results in loss of kinetochore dynein functions, which impairs poleward chromosome movements and mitotic checkpoint inactivation. In addition, Spindly regulates the establishment of stable microtubule attachments via regulation of the RZZ complex. Thus, Spindly couples dynein-mediated poleward chromosome movements to the establishment of stable microtubule attachments and subsequent mitotic checkpoint inactivation and provides an important switch for the control of mitosis. PMID- 21252630 TI - Incidence of and risk factors for community acquired pneumonia in US HIV-infected children, 2000-2005. AB - The incidence of and risk factors for community-acquired pneumonia (CAP) are described from 2000 to 2005 in a multicenter US cohort of HIV-infected children. In 736 patients, 87 episodes of CAP (33.2 events/1000 person-years) had a mean CD4% of 23% (controls: 30%) and mean CD4 cell count of 668 cells/MUl (controls: 870 cells/MUl). CAP incidence decreased 44% from 2000-2001 to 2002-2005. On multivariate analysis, viral load at least 100 000 copies/ml (odds ratio 3.98; confidence interval 1.05-15.13) was associated with CAP. Herd immunity through pneumococcal immunization may have diluted the effect of individual immunization in this cohort. PMID- 21252631 TI - Vaccinogenicity. PMID- 21252632 TI - Mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. AB - OBJECTIVE: There is limited evidence on whether growing mobile phone availability in sub-Saharan Africa can be used to promote high adherence to antiretroviral therapy (ART). This study tested the efficacy of short message service (SMS) reminders on adherence to ART among patients attending a rural clinic in Kenya. DESIGN: A randomized controlled trial of four SMS reminder interventions with 48 weeks of follow-up. METHODS: Four hundred and thirty-one adult patients who had initiated ART within 3 months were enrolled and randomly assigned to a control group or one of the four intervention groups. Participants in the intervention groups received SMS reminders that were either short or long and sent at a daily or weekly frequency. Adherence was measured using the medication event monitoring system. The primary outcome was whether adherence exceeded 90% during each 12 week period of analysis and the 48-week study period. The secondary outcome was whether there were treatment interruptions lasting at least 48 h. RESULTS: In intention-to-treat analysis, 53% of participants receiving weekly SMS reminders achieved adherence of at least 90% during the 48 weeks of the study, compared with 40% of participants in the control group (P = 0.03). Participants in groups receiving weekly reminders were also significantly less likely to experience treatment interruptions exceeding 48 h during the 48-week follow-up period than participants in the control group (81 vs. 90%, P = 0.03). CONCLUSION: These results suggest that SMS reminders may be an important tool to achieve optimal treatment response in resource-limited settings. PMID- 21252633 TI - Triad of visual, auditory and corticospinal tract lesions: a new syndrome in a patient with HIV infection. AB - OBJECTIVE: A case of a rapidly progressive degeneration of the visual, auditory and corticospinal tract in a patient with a HIV infection is presented. METHODS AND RESULTS: The HIV-infected patient suffered from severe and rapidly progressive sensorineural hearing loss, blindness, dysarthria, dysphagia and tetraparesis. MRI showed degeneration of the visual, auditory and corticospinal tract. Diffusion tensor imaging showed reduced fractional anisotropy of the corticospinal tract. HAART and other salvage therapies did not save the patient from death 5 months after the onset of the symptoms. CONCLUSION: The triad of auditory, visual and corticospinal lesions has been described in rare syndromes and hereditary diseases. This is the first case of this syndrome associated with a HIV infection. PMID- 21252634 TI - Antiretroviral therapy and sexual behavior in Uganda: a cohort study. AB - OBJECTIVE: To assess evidence for sexual behavior change in response to antiretroviral therapy (ART) among members of a Ugandan clinical cohort. Secondarily, to examine factors associated with both sexual behavior and ART independently, that may help to assess the impact that ART is likely to have on the HIV epidemic. DESIGN: Retrospective analysis of data from an open cohort. METHODS: ART roll-out began in the cohort in 2004. Using 3-monthly data from 2002 to 2009, we conducted regression and descriptive analyses to examine associations between timing of ART initiation and sexual behavior among HIV-infected, and timing of ART availability and sexual behavior among HIV-uninfected. We also examined partner turnover rates, and the proportion of HIV-infected on ART - two important factors for modeling the potential impact of ART on the HIV epidemic. RESULTS: Risky sexual behavior among HIV-infected people rose on several indicators after ART initiation, but not to levels higher than two or more years before initiation. Some evidence suggests that the availability of ART may impact risky behavior among HIV-uninfected people, although this was inconsistent across different reported behavior variables. CONCLUSION: The HIV-uninfected is larger than the HIV-infected population. If risky behavior among this population increases due to the feeling of safety that ART provides, this will affect the impact of ART on the HIV epidemic. Policy makers are urged to intensify messages associating sexual behavior and HIV and to target both HIV-infected and uninfected people. PMID- 21252635 TI - Melanocytic matricoma with melanocytic atypia: report of a unique case and review of the literature. AB - Melanocytic matricoma is a rare cutaneous neoplasm of presumed anagen hair follicle origin with approximately 10 reported cases in the literature. Melanocytic matricomas are clinically and histopathologically distinct cutaneous nodular proliferations of matrical and supramatrical cells admixed with dendritic melanocytes, which typically occur in the sun-exposed areas of elderly patients. We report a new case with additional histopathologic features not previously described. An 82-year-old white man presented with an exophytic papule of the ear clinically suspicious for basal cell carcinoma. Histopathologic examination demonstrated a polypoid neoplasm consisting of an admixture of matrical and shadow cells with numerous interspersed dendritic and epithelioid melanocytes arranged singly and in large expansile nests. An unusual feature in this case included prominent melanocytic proliferation with associated nuclear atypia and increased mitotic activity. Although atypical and malignant melanocytic colonization has been reported in basal cell carcinomas and squamoproliferative lesions, to our knowledge, it has not been previously described in melanocytic matricomas. The biologic significance of atypical melanocytic proliferations within melanocytic matricomas is uncertain and requires further study of additional cases and long-term follow-up. PMID- 21252636 TI - Eccrine syringofibroadenoma and clear cell acanthoma: an association by chance? AB - A 58-year-old white woman with stasis dermatitis developed a solitary, slowly growing keratotic nodule of the dorsum of the foot. The excision biopsy specimen of this lesion showed a biphasic pattern of eccrine syringofibroadenoma and clear cell acanthoma. Such a previously unreported association is neither necessarily by chance nor necessarily a collision. Because a reactive histogenesis has been postulated for both eccrine syringofibroadenoma and clear cell acanthoma, this case could represent a morphologically biphasic pattern of epidermal and ductal hyperplasia as a consequence of the stasis-induced chronic inflammation coupled with the footwear-induced chronic trauma. PMID- 21252637 TI - Cutaneous peripheral T-cell lymphoma of cytotoxic phenotype mimicking extranodal NK/T-cell lymphoma. AB - Cutaneous peripheral T-cell lymphoma unspecified is a rare neoplasm that is infrequently associated with Epstein-Barr virus (EBV) infection. In contrast, extranodal natural killer (NK)/T-cell lymphoma, although also rare, is known to be strongly associated with EBV and occurs most commonly in the nasal region. We report the case of a 55-year-old male who presented with fever and an indurated cutaneous plaque with ulceration. This cutaneous neoplasm showed diffuse dermal lymphomatous infiltration and tumor necrosis, with neoplastic cells expressing CD2, cytoplasmic CD3 (CD3epsilon), CD8, CD16, CD30, T-cell intracellular antigen 1, and granzyme B but not CD56, BF1, or T-cell receptor (TCR) delta1. Furthermore, the tumor cells were noted to be diffusely positive for EBV by in situ hybridization. A monoclonal TCR gene rearrangement was demonstrated. The disease showed an aggressive clinical course, and the patient died within 3 weeks of diagnosis without complete staging or chemotherapy. According to the 2005 World Health Organization/European Organization for Research and Treatment of Cancer scheme for cutaneous lymphoma and the 2008 WHO classification for lymphoid neoplasms, our case would have been classified as a nasal type extranodal NK/T cell lymphoma with T-cell lineage. However, the expressions of CD8 and CD16, in addition to a monoclonal TCR gene rearrangement, are unusual findings in NK/T cell lymphoma, and we believe such a phenotype/genotype should be more appropriately classified as an EBV-positive peripheral T-cell lymphoma, unspecified with a cytotoxic phenotype. Detailed clinicopathologic and molecular studies of similar cases may shed light on the prognostic impact of NK vs. T-cell lineage on extranodal NK/T-cell lymphomas. PMID- 21252638 TI - Atypical variant of galli-galli disease (grover-like eruption with lentiginous freckling) in a liver transplant patient. AB - Galli-Galli disease is considered as a rare variant of Dowling-Degos disease, sharing the same clinical features of reticulate hyperpigmentation of the flexures. Histopathologically, there is acantholysis and suparabasal lacunae. Grover disease (transient acantholytic dermatosis) is a transient dermatosis which clinically presents as an eruption of erythematous excoriated papules located on the trunk and histologically with dyskeratosis and acantholysis. Grover disease has occasionally been reported in patients with chronic renal failure, human immunodeficiency virus infection, hematological malignancies, bone marrow allotransplantation, and renal transplantation. We report herein a case of atypical variant of Galli-Galli disease occurring in a liver transplant patient in whom the leading sign of reticulate hyperpigmentation of the large flexures was lacking. Instead, Grover-like, erythematous, keratotic, excoriated papules and lentigo-like macules with predilection for the trunk were found. Histopathology of both, an excoriated papule and a lentigo-like macule revealed the diagnostic features of Galli-Galli disease namely, elongated, pigmented, finger-like rete ridges, intraepidermal lacunae and acantholysis. However, serial sections of the lentigo-like macule were needed to reveal some suprabasal and subcorneal lacunae with minimal acantholysis. Thus, a good clinicopathological correlation is essential to make the right diagnosis of Galli-Galli disease. Although Grover disease has been described in the setting of solid organ transplantation and immunosuppression, this is the first report of an atypical variant of Galli-Galli disease occurring in a liver transplant patient. PMID- 21252639 TI - Microcystic adnexal carcinoma with multiple areas of follicular differentiation toward germinative cells and specific follicular stroma (trichoblastomatous areas). AB - We present a case of microcystic adnexal carcinoma (MAC) occurring on the upper lip of a 63-year-old man, which, in addition to the predominant areas of a conventional MAC, manifested multiple foci of follicular differentiation resulting in trichoblastomatous appearances. Some areas were highly reminiscent of desmoplastic trichoepithelioma (columnar trichoblastoma). We also reviewed 24 cases of MAC in our files, but in none of the cases were similar features observed, indicating that such histopathological findings are rare in MAC. PMID- 21252640 TI - Intermittent aortic insufficiency as an aid to diagnosing obstruction in a HeartMate II continuous-flow left ventricular assist device. AB - This report details two cases of left ventricular assist device (LVAD)-related fungal infection. In both cases, the infection occurred within the device and formed an obstruction resulting in intermittent variation in the output of the LVAD. This was manifested by a change in the pattern of aortic insufficiency (AI) from continuous to intermittent on transesophageal echocardiography. Recognition of this finding may allow for noninvasive diagnosis of LVAD flow obstruction. PMID- 21252641 TI - Weight changes in oncology patients during the first year after diagnosis: a qualitative investigation of the patients' experiences. AB - BACKGROUND: Weight changes are one of the most common symptoms experienced by patients with cancer. However, limited empirical data are available on how cancer patients react to changes in their weight following their diagnosis and treatment. OBJECTIVE: The present study aims to acquire a deeper understanding of cancer patients' experiences with the physical manifestations of weight loss or gain, the consequence of these changes on their psychosocial life, and their self management strategies. METHODS: Semistructured interviews with 54 cancer patients were conducted longitudinally 2 to 3 weeks after their diagnosis. Follow-up interviews were carried out at 3, 6, and 12 months after diagnosis. RESULTS: From the 54 patients recruited, 34 patients disclosed weight gain, whereas 37 experienced weight loss, suggesting that 17 patients experienced weight fluctuation. Analysis generated 4 themes that reflected the complex dynamics of weight change. Themes were "experiences with the physical manifestations of weight loss or gain," "psychological effects," "self-management," and "social consequences." CONCLUSION: This study confirms that weight changes have far more complicated implications for patients with cancer, extending beyond physical problems into psychosocial issues. Changes are a constant reminder of the diagnosis and treatment and are persistent across all stages. IMPLICATIONS FOR PRACTICE: These findings highlight the importance of nutritional psychosocial rehabilitation programs during the cancer trajectory. PMID- 21252642 TI - Does increased patient awareness improve accrual into cancer-related clinical trials? AB - BACKGROUND: Oncology literature cites that only 2% to 4% of patients participate in research. Up to 85% of patients are unaware that clinical trials research is being conducted at their treatment facility or that they might be eligible to participate. OBJECTIVES: It was hypothesized that patients' satisfaction with information regarding clinical trials would improve after targeted educational interventions, and accruals to clinical trials would increase in the year following those interventions. METHODS: All new patients referred to the cancer center over a 4-month period were mailed a baseline survey to assess their knowledge of clinical research. Subsequently, educational interventions were provided, including an orientation session highlighting clinical trials, a pamphlet, and a reference to a clinical trials Web site. A postintervention survey was sent to the responders of the initial survey 3 months after the initial mailing. RESULTS: Patient satisfaction with information significantly increased after the interventions. There was no increase in subsequent enrollment in clinical trials. Patients who indicated an inclination to participate in clinical trials tended to have greater satisfaction with the information they received. CONCLUSIONS: A set of educational interventions designed for cancer patients significantly improved their satisfaction with information on clinical research, but did not improve clinical trial enrollment of these participants as of 1 year after the study. IMPLICATIONS FOR PRACTICE: The development of educational interventions may be justified, but such interventions may require prolonged implementation to establish benefit. Information relating to research may be most effectively delivered by patients' primary cancer care providers. PMID- 21252644 TI - An avalanche of ignoring--a qualitative study of health care avoidance in women with malignant breast cancer wounds. AB - BACKGROUND: A contributing factor to development of malignant wounds is patient related delay caused by health care avoidance. OBJECTIVE: The purpose of this study was to describe the experience of health care avoidance in women with advanced breast cancer who have developed malignant wounds. METHODS: A qualitative study was conducted based on semistructured interviews. Seventeen women with advanced breast cancer (median age, 69 years; range, 47-90 years) who had avoided medical treatment despite development of malignant wounds participated. Systematic text-condensation analysis was used. RESULTS: The women deliberately avoided health care for a median of 24 months (minimum, 3 months; maximum, 84 months). Despite being aware of the development of a malignant wound from a breast lump, the women avoided health care because of negative health care experiences and extremely burdening life situations. The women did not seek health care until their situations became unmanageable. The essence--"an avalanche of ignoring"--is pointing to the escalating, powerful development of destructive feelings behind health care avoidance. CONCLUSIONS: Health care avoidance may be a way of coping both for women who are primary and/or bereaved caregivers. Oncologists and nurses may contribute to the prevention hereof by means of information about the early signs of cancer, benefits of early diagnosis and treatment, and by paying special attention to these women, who may be at high risk for avoidant behaviors. IMPLICATIONS FOR PRACTICE: In a preventive perspective, it seems advantageous to bring into focus the health of primary and bereaved caregivers, thereby potentially reducing patient delay and ultimately improving survival. PMID- 21252643 TI - Differences in self-reported attentional fatigue between patients with breast and prostate cancer at the initiation of radiation therapy. AB - BACKGROUND: Attentional fatigue is experienced as a decreased ability to concentrate, engage in purposeful activity, and maintain social relationships when there are competing demands on attention. Breast and prostate cancer are the 2 most common cancers in women and men, respectively. Most previous studies on self-reported attentional fatigue evaluated patients with breast cancer. OBJECTIVES: The objectives of the study were to determine if self-reported attentional fatigue differed in patients with breast cancer and prostate cancer before radiation therapy (RT) and to determine the relationships between attentional fatigue and other symptoms in these 2 groups. METHODS: Patients (n = 155) completed questionnaires before RT. Descriptive statistics, Pearson correlations, and analysis of covariance were used for data analyses. RESULTS: After controlling for age, patients with breast cancer reported significantly higher levels of attentional fatigue. In both groups, more attentional fatigue correlated significantly with more anxiety, depression, sleep disturbance, and physical fatigue. These correlations were stronger for patients with breast cancer. CONCLUSIONS: The present study is the first to identify differences in self-reported attentional fatigue between these 2 groups before RT. Additional research is warranted to determine factors that contribute to these differences, as well as mechanisms that underlie the development of attentional fatigue. IMPLICATIONS FOR PRACTICE: Clinicians should consider the capacity of their patients to direct attention when learning about RT and other treatments. It is important to simplify confusing healthcare terminology and reinforce teaching that is most important both verbally and in writing. Appropriate interventions for anxiety and depression may decrease attentional fatigue in these patients. PMID- 21252645 TI - Physiological and psychological evaluation of the wrapped warm footbath as a complementary nursing therapy to induce relaxation in hospitalized patients with incurable cancer: a pilot study. AB - BACKGROUND: The wrapped warm footbath (WW-footbath) was originally designed as a means to promote relaxation, positive emotion, comfort, pleasure, and enjoyment in hospitalized patients with incurable stomach cancer during palliative care. OBJECTIVES: This study examined the physiological and psychological effects of the WW-footbath as complementary nursing intervention to induce relaxation in hospitalized patients with incurable cancer. METHODS: Eighteen subjects were divided into a footbath group (n=9) and a control group (n=9). Heart rate variability analysis (per second) with wavelet transformation was used for evaluation of autonomic, sympathetic, and parasympathetic activities. Salivary secretory immunoglobulin A and salivary cortisol levels were used as neuroimmunological parameters. Pain and psychological conditions were measured using a visual analog scale and Face Scale (FS). RESULTS: The high-frequency component of heart rate variability was not significantly increased in either group. However, the low-frequency component versus high-frequency ratio was significantly decreased in the footbath group at periods after footbath (P=.017, P=.000, P=.000, P=.003). In the footbath group, the salivary secretory immunoglobulin A level was significantly increased (P=.019), and the cortisol level tended to be reduced. Changes in visual analog scale and FS scores showed that the footbath group experienced significant pain relief and relaxation (pain, P=.047; relaxation, P=.042; comfortability, P=.008; FS, P=.013). CONCLUSIONS: The WW-footbath significantly decreased sympathetic activity in hospitalized patients with incurable cancer and may have secondary benefit for pain relief. IMPLICATIONS FOR PRACTICE: The WW-footbath can promote relaxation in hospitalized patients with incurable cancer. Moreover, the WW-footbath appears to afford pain relief associated with enhanced overall comfort. PMID- 21252647 TI - Publication fraud: implications to the individual and to the specialty. AB - PURPOSE OF REVIEW: To provide a brief review and update on the subject of scientific misconduct relevant to the specialty of anesthesia. The overall goal is to raise awareness amongst readers of the scientific literature that although publication fraud is relatively infrequent, the reasons for fraud are complex and the consequences to the individual and for the specialty are substantial. RECENT FINDINGS: Scientific misconduct and publication fraud can easily go undetected. However, plagiarism is being detected with increasing frequency as a result of newer detection software. There are recent examples of scientific misconduct involving extensive data fabrication in the anesthesiology literature that have far-reaching, and as-yet-to-be determined implications for the scientific record. The reasons for publication fraud and methods to detect scientific misconduct are reviewed. The implications for related studies in the field, systematic reviews and practice guidelines are considered. SUMMARY: When suspected, alleged misconduct must be thoroughly investigated. When proven, scientific misconduct must be addressed by the relevant institutions and the scientific record must be corrected. Many stakeholders are involved in this complex and most unfortunate process. PMID- 21252646 TI - Sleep-wake circadian activity rhythm parameters and fatigue in oncology patients before the initiation of radiation therapy. AB - BACKGROUND: Little is known about the relationships between sleep parameters and fatigue in patients at the initiation of radiation therapy (RT). OBJECTIVES: The objectives of this study were to describe values for nocturnal sleep/rest, daytime wake/activity, and circadian activity rhythm parameters measured using actigraphy and to evaluate the relationships between these objective parameters and subjective ratings of sleep disturbance and fatigue severity, in a sample of patients at the initiation of RT. METHODS: Patients (n = 185) with breast, prostate, lung, or brain cancer completed self-report measures for sleep disturbance (ie, Pittsburgh Sleep Quality Index, General Sleep Disturbance Scale) and fatigue (Lee Fatigue Scale) and wore wrist actigraphs for a total of 48 hours prior to beginning RT. Actigraphy data were analyzed using the Cole-Kripke algorithm. Spearman rank correlations were calculated between variables. RESULTS: Approximately 30% to 50% of patients experienced sleep disturbance, depending on whether clinically significant cutoffs for the subjective or objective measures were used to calculate occurrence rates. In addition, these patients reported moderate levels of fatigue. Only a limited number of significant correlations were found between the subjective and objective measures of sleep disturbance. Significant positive correlations were found between the subjective, but not the objective measures of sleep disturbance and fatigue. CONCLUSIONS: A significant percentage of oncology patients experience significant disturbances in sleep-wake circadian activity rhythms at the initiation of RT. The disturbances occur in both sleep initiation and sleep maintenance. IMPLICATIONS FOR PRACTICE: Patients need to be assessed at the initiation of RT for sleep disturbance, so appropriate treatment is initiated. PMID- 21252648 TI - Inhalational or total intravenous anaesthesia: is total intravenous anaesthesia useful and are there economic benefits? AB - PURPOSE OF REVIEW: The comparison of inhalational and intravenous anaesthesia has been the subject of many controlled trials and meta-analyses. These reported diverse endpoints typically including measures of the speed and quality of induction of anaesthesia, haemodynamic changes, operating conditions, various measures of awakening, postoperative nausea and vomiting and discharge from the recovery area and from hospital as well as recovery of psychomotor function. In a more patient-focused Health Service, measures with greater credibility are overall patient satisfaction, time to return to work and long-term morbidity and mortality. In practice, studies using easier to measure proxy endpoints dominate even though the limitations of such research are well known. RECENT FINDINGS: Recent study endpoints are more ambitious and include impact on survival from cancer and the possibility of differential neurotoxic impact on the developing brain and implications for neuro-behavioural performance. SUMMARY: Economic analysis of anaesthesia is complex and most published studies are naive, focusing on drug acquisition costs and facility timings, real health economics are much more difficult. Preferred outcome measures would be whole institution costs or the ability to reliably add an extra case to an operating list, close an operating room and reduce the number of operating sessions offered or permanently decrease staffing. Alongside this, however, potential long-term patient outcomes should be considered. PMID- 21252649 TI - Cost-effectiveness of bispectral index monitoring. AB - PURPOSE OF REVIEW: In the current era of limited resources, organizations are evaluating the cost-effectiveness of their care. To analyze the cost effectiveness of a physiologic monitor, one must first determine what negative outcome will be reduced or what positive outcome will be promoted. For example, if one was studying the cost-effectiveness of the pulse oximeter, it would be important to state whether the endpoint is prevention of hypoxic events or prevention of myocardial infarction. One would then need outcome data demonstrating the incidence of the chosen endpoint with and without the monitor. With these data, one can begin to construct a model for cost-effectiveness. Like many medical technologies, the bispectral index (BIS) monitor has recently been the subject of several articles which study its cost-effectiveness. This review examines the rationale of cost-effectiveness analyses and their application specifically to the BIS monitor. RECENT FINDINGS: The BIS monitor has been shown in multiple prospective randomized studies to positively affect several important aspects of an anesthetic. Use of the BIS monitor results in less use of hypnotic anesthetic drugs, decreased time to extubation, decreased incidence of nausea and vomiting, and decreased intraoperative awareness. These benefits are achieved for an additional cost of around five dollars per anesthetic. In addition, there is an emerging body of literature demonstrating an association between low intraoperative BIS readings and decreasing intermediate-term survival in both noncardiac and cardiac surgical patients. SUMMARY: Given the trivial cost of the BIS and the proven benefits demonstrated in prospective randomized studies, we consider its use justified in every general anesthetic. PMID- 21252650 TI - Perioperative deep vein thrombosis prevention: what works, what does not work and does it improve outcome? AB - PURPOSE OF REVIEW: To critically evaluate the benefit/risk ratio of some strategies for venous thromboembolism prophylaxis (VTE) RECENT FINDINGS: A growing body of evidence shows that graduated elastic stockings are not effective in medical patients. Special surgical settings as bariatric surgery deserve attention with a high VTE risk and no evidence-based data with regard to prophylaxis. Extended prophylaxis is being evaluated in these patients, whereas its efficacy has been demonstrated in abdominal and pelvic surgery for cancer. New oral anticoagulants are about to change the clinical landscape but yet some issues are not solved: no antidote, no monitoring, no standardization for the perioperative bridging in patients with therapeutic doses. In addition, they have not been tested in fragile patients in whom an increased bleeding risk could be feared. Finally, a large bunch of guidelines are now available to help the physician in the decision-making process. SUMMARY: Studies evaluating the benefit/risk ratio of graduated elastic stockings should now take place in surgery. Increasing and splitting the anticoagulant dose (mainly low molecular weight heparins) by two injections a day could be recommended in bariatric surgery and morbidly obese patients. New anticoagulant agents should also be tested in special populations, following the European Medicines Agency guidance. The methodology of clinical trials in VTE prophylaxis has to be moved forward, pending the choice of debatable surrogate end-points as asymptomatic venous thrombosis and disputed issues on the assessment of major bleeding. PMID- 21252651 TI - Palliative care in heart failure: addressing the largest care gap. AB - PURPOSE OF REVIEW: Heart failure is a chronic, fatally progressive and incurable condition characterized by periods of apparent stability interspersed with acute exacerbations. Treatment models have historically emphasized management of acute exacerbations of cardiovascular disease, during which end-of-life issues figure frequently and prominently, though in a setting that is inappropriate to address the comprehensive needs of patients and their families. Consequently, in comparison to patients with malignancy, heart failure patients at the end of life are less likely to access palliative resources, and more likely to access in patient care and cardiovascular procedures. RECENT FINDINGS: Recent reports and position statements have emphasized the following critical needs for provision of optimal heart failure care: a) Cardiovascular specialists require training to obtain basic skills for provision of palliative care to management of end-of-life issues; b) Discussion of end-of-life issues should be introduced as early as feasible in patients with heart failure and should be updated with changes in clinical status; c) Provision of palliative care should be integrated into a team approach; d) Patients with heart failure frequently suffer symptoms which are not typically considered 'cardiovascular', such as pain, social/functional and psychological. Patients should be assessed for these symptoms, which should be treated. SUMMARY: This report summarizes many of these suggestions and outlines future directions for the expansion and improvement of this critical need for heart failure patients. PMID- 21252652 TI - Impact of n-3 fatty acids on endothelial function: results from human interventions studies. AB - PURPOSE OF REVIEW: Dysfunction of the endothelium plays an integral role in atherogenesis. This review summarizes recent findings on the effects of marine [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)] and plant [alpha linolenic acids (ALA)] n-3 polyunsaturated fatty acids (PUFAs) on endothelial function in healthy individuals and in patients with cardiovascular disease (CVD) risk factors or manifest CVD. RECENT FINDINGS: We identified 33 intervention trials investigating the effects of n-3 PUFA on fasting and/or postprandial endothelial function. In healthy individuals regular supplementation of EPA/DHA or ALA shows inconsistent results on endothelial function, whereas markers of endothelial function seem to be improved in overweight dyslipidaemic patients and type 2 diabetics. Conflicting results are observed in CVD patients. Reasons for discrepancies between the study results include the health status and age of participants, duration of supplementation, dose and fatty acid composition of the administered n-3 PUFAs as well as methods used to assess endothelial function. SUMMARY: In individuals with CVD risk factors including overweight, dyslipidemia and type 2 diabetes n-3 PUFAs may improve endothelial function. However, the evidence for a clinical efficacy is not strong enough to make final recommendations with respect to a specific dose and the duration of supplementation. PMID- 21252653 TI - Role of lipids in the control of food intake. AB - PURPOSE OF REVIEW: The classical hypothesis that a decrease in glucose utilization, registered by specific sensors in the brain, leads to hunger was challenged as lipids and amino acids also provide energy for cell metabolism. This review presents recent progress in the knowledge on lipid signals associated with feeding initiation or inhibition. RECENT FINDINGS: Although the brain does not utilize fatty acids as primary energy sources, recent evidence indicates that intermediates of fatty acids metabolism in the hypothalamus serve as sensors of energy status. Pharmacological or genetic inhibition of brain fatty-acid synthase and carnitine palmitoyltransferase-1c results in profound decreases in feeding and body weight in rodents. These effects depend on changes in the intracytoplasmic pool of long-chain fatty-acyl-CoA and malonyl-CoA, an intermediate of the de-novo fatty acid synthesis in neurons that integrate hormonal and nutrient-derived signals to control feeding behaviour. The central regulatory enzyme is AMP-activated protein kinase, which reversibly phosphorylates acetyl-CoA carboxylase and malonyl-CoA decarboxylase, two enzymes that increase the level of malonyl-CoA in the cells when phosphorylated in response to a low intracellular ratio of AMP/ATP due to decrease in glucose oxidation. SUMMARY: Such a mechanism is compatible with a central energostatic control of feeding based on glucose utilization by neurons and opens new therapeutic perspectives to develop pharmacological compounds that act at the level of pivotal enzymes such as AMP-activated protein kinase, acetyl-CoA carboxylase, malonyl-CoA decarboxylase, and module malonyl-CoA level in cells, to favour central inhibition of feeding. PMID- 21252654 TI - Feeding the patients with upper gastrointestinal bleeding. AB - PURPOSE OF REVIEW: It is usually believed that in case of upper gastrointestinal bleeding patients must be systematically fasted. This review will focus on oral and/or enteral feeding in patients with or at risk of upper gastrointestinal bleeding. RECENT FINDINGS: In case of upper gastrointestinal bleeding, an endoscopy is always required in order to determine the pathophysiology of the bleeding, and in some case to perform an endoscopic treatment. In patients hospitalized in ICU, enteral nutrition is the best stress ulcer prophylaxis. In patients with enteral nutrition the concomitant use of histamine-2 receptor blockers or proton-pump inhibitors may be harmful. In case of bleeding due to gastric erosions, enteral nutrition can be resumed as soon as the patient tolerates. In patients with liver cirrhosis nonbleeding oesophageal varices are not a contraindication for enteral nutrition nor nasogastric tube. In patients hospitalized for acute upper gastrointestinal bleeding due to an ulcer with high risk of rebleeding (Forrest I-IIb) or with variceal bleeding it is recommended to wait at least 48 h after endoscopic therapy before initiating oral or enteral feeding. In case of ulcer with low risk of rebleeding (Forrest IIc and III) or in patients with gastritis, Mallory-Weiss, oesophagitis, or angiodysplasia, there is no need to delay refeeding, and they can be fed as soon as tolerated. SUMMARY: Understanding the cause of the diagnosis is always necessary to adapt nutrition in patients with upper gastrointestinal bleeding. PMID- 21252655 TI - Navigating the road toward optimal initial therapy for chronic myeloid leukemia. AB - PURPOSE OF REVIEW: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) and are now widely accepted as the initial therapy of choice in this disease, supplanting interferon and allogeneic stem cell transplantation. There are currently three drugs approved by the US Food and Drug Administration (FDA) for front-line treatment of CML: imatinib, nilotinib, and dasatinib. A fourth drug, bosutinib, may also win FDA approval in 2011. The goal of this review is to summarize the most recent information on initial treatment of CML and to aid clinicians in managing newly diagnosed CML patients. RECENT FINDINGS: Phase III studies comparing imatinib with nilotinib or dasatinib in newly diagnosed CML were published in June 2010, leading to accelerated FDA approval for both of these 'second-generation' TKIs for initial therapy of CML. There are significant differences between the agents in terms of frequency and rate of responses, progression-free survival, and side-effects. However, the follow-up period on these trials is short, and there are as yet no significant differences in overall survival. Guidelines for monitoring CML patients on TKI therapy have been recently revised. SUMMARY: Management of newly diagnosed CML patients in the coming decade will begin to resemble antibiotic treatment of infection, with therapy individualized based on patient risk factors, co-morbidities, and tolerability. In addition, the cost of therapy will emerge as an important consideration as generic imatinib becomes available in 2015. In this context, clinical trials to guide decision-making in newly diagnosed CML patients are needed. PMID- 21252656 TI - Treatment-related myelodysplastic syndrome: molecular characteristics and therapy. AB - PURPOSE OF REVIEW: Treatment-related myelodysplastic syndrome (t-MDS) is a serious complication of cancer treatment. Here we review recent advances in knowledge of the risk factors, pathogenesis, and treatment of t-MDS. RECENT FINDINGS: Recent studies have provided important new information regarding genetic risk factors that may predispose individual patients to develop t-MDS after exposure to cytotoxic therapeutic agents and that may be used to predict individuals at enhanced risk for this complication. The role of specific candidate genes associated with commonly involved genetic lesions in the pathogenesis of t-MDS has also been investigated. Finally, factors determining outcomes of transplantation treatment for this disorder have been elucidated. Hematopoietic cell transplantation provides potentially curative therapy for t MDS, but additional improvements are necessary to improve outcomes. SUMMARY: Improved understanding of genetic risk factors is expected to facilitate early identification of patients at risk for t-MDS, guiding therapeutic decision making, and allowing early application of preventive or therapeutic strategies. PMID- 21252657 TI - Modifying endotracheal tubes to prevent ventilator-associated pneumonia. AB - PURPOSE OF REVIEW: The endotracheal tube (ETT) is the main avenue leading to airway contamination and subsequent ventilator-associated pneumonia (VAP) during mechanical ventilation. A number of modifications to the ETT are available, aimed at reducing the incidence of VAP. We review here available systems and devices, and clinical data regarding their efficacy. RECENT FINDINGS: Three main modifications of ETTs have been developed: coating with antimicrobials, adding a suction channel for the removal of oro-pharyngeal secretions, and modifying the design of the cuff. Each of these interventions has been shown to limit bacterial colonization of the distal airways and to decrease the incidence of VAP. Data on their ultimate effect on related clinical outcomes are still lacking. SUMMARY: Modifications of ETTs aimed at decreasing the onset of VAP show promising results. However, the lack of a significant effect on outcomes prompts us to use caution before recommending their widespread use. PMID- 21252658 TI - Controlling epidemic viral infection. AB - PURPOSE OF THE REVIEW: Due to their different virulence and infectivity, both severe acute respiratory syndrome (SARS) and H1N1 09 revealed different strengths and weaknesses in our ability to contain new viral threats over the past decade. This review focuses on recent literature around attempts to contain the impact of these two viral epidemics that have refined our approach for the future. RECENT FINDINGS: Attempts to contain emerging epidemics at the site of origin have so far failed, in part due to resourcing of surveillance. H1N1 09 revealed major problems with rigid pandemic planning and the need for much greater flexibility. Popular attempts to prevent international spread of pandemics have minimal efficacy. Availability of rapid diagnostic tests is critical to optimally managing epidemics and was a major problem with H1N1 09. Healthcare institutions have emerged as a major source of infection. SUMMARY: The experience with H1N1 09 and SARS has been very useful in informing us of the strengths and weaknesses of our current approach to emerging epidemics. Key messages are a need for improved surveillance, more flexible planning, improved diagnostic testing and retaining a focus on basic hygiene measures. PMID- 21252659 TI - How important is age in defining the prognosis of patients with community acquired pneumonia? AB - PURPOSE OF REVIEW: Given that the population is increasing in age, a better understanding of the relationship between chronological age and health-related outcomes (especially mortality) is needed, for both chronic diseases (e.g. diabetes) and acute illnesses (e.g. pneumonia). Our purpose was to review the impact of age on the prognosis of patients with community-acquired pneumonia (CAP). RECENT FINDINGS: Many studies in patients with CAP have suggested that chronological age is not necessarily independently associated with mortality. Poorer outcomes in the elderly with CAP have been related to severity of disease, comorbid disease burden, functional status, and frailty, but not to age alone. However, many of these studies suffer from 'over-adjustment' due to the use of unmodified severity scores such as the Pneumonia Severity Index or Acute Physiology and Chronic Health Evaluation II (that already include age) in multivariable analyses. Studies accounting for this over-adjustment suggest that age is, in fact, independently associated with mortality in hospitalized patients with CAP. Other outcomes including hospitalization and readmission rates, hospital length of stay, and cost of care are similarly associated with increasing age. Residual confounding is still a problem in many of the observational studies reviewed. SUMMARY: Contrary to conventional wisdom, chronological age is independently associated with adverse outcomes in patients with CAP. Until better methods (or more clinically-rich datasets) for observational studies are developed that can avoid over-adjustment and better deal with residual confounding, physicians should take into account both a patient's overall health status and his or her chronological age. PMID- 21252660 TI - The role of viruses in nosocomial pneumonia. AB - PURPOSE OF REVIEW: The frequency and impact of viruses among intensive care unit (ICU) nonimmunocompromised patients remains controversial. This review analyzes their place as causal pathogens in ventilator-associated pneumonia, as well as their effects on ICU patients' outcomes. RECENT FINDINGS: Herpesviruses, namely herpes simplex virus (HSV) and cytomegalovirus (CMV), are the most frequent viruses detected among nonimmunosuppressed ICU patients, as confirmed by recent prospective studies. Patients infected with these viruses show increased morbidity and, especially for CMV, mortality. An increase of bacterial or fungal superinfections was observed in ICU patients with CMV reactivation. A therapeutic trial of acyclovir (HSV antiviral) in ICU patients was negative. Concerning CMV, pathogenicity was suggested by histologic assessment in ICU patients, and recent murine models with a positive effect of prophylaxis with ganciclovir that prevented postseptic CMV reactivation and secondary lung damage. SUMMARY: Using efficient and rapid virologic diagnostic tests (antigenemia or PCR), the identification of viruses in ICU patients is frequent. Their role in the occurrence of ventilator-acquired pneumonia and their impact on patient outcome depend on the virus. There is sufficient evidence suggesting CMV pathogenicity to conduct an interventional randomized trial using anti-CMV drugs. PMID- 21252661 TI - Nursing home acquired pneumonia: approach to management. AB - PURPOSE OF REVIEW: Pneumonia is among the leading causes of mortality in nursing home residents and a primary reason for transfer to acute care facilities. Compared with community-dwelling individuals, residents of long-term care facilities have extensive underlying medical illnesses and more functional disabilities and are at increased risk of acquiring drug-resistant pathogens. This review focuses on recent recommendations for diagnostic work up, validity of prognostic models, and current approach to treatment of nursing home acquired pneumonia (NHAP). RECENT FINDINGS: The inconsistency in defining NHAP is considered a potential hindrance for a uniform approach to the management of pneumonia. Diagnostic evaluation varies between facilities and depends on severity of illness and access to laboratory facilities. The role of prognostic models in stratifying severity of disease remains largely unknown due to paucity of studies and lack of a specific scoring system for hospitalized patients with NHAP. A controversy still exists concerning the best therapeutic option for NHAP, but it is reasonable to believe that each setting is adapting the existing evidence according to the best local practice. SUMMARY: A unified approach to defining, assessing, and stratifying pneumonia is essential to decrease morbidity and mortality in nursing home residents. High-quality randomized, controlled trials examining empiric antibiotic therapy are needed. PMID- 21252662 TI - Genetic contribution to common epilepsies. AB - PURPOSE OF REVIEW: We review key findings over the past year in the genetics of the common epilepsies and consider their impact on the field. RECENT FINDINGS: There have been important discoveries across two major aspects of genetics of the common epilepsies. Firstly, the first genome-wide association study in epilepsy has been published, for the focal epilepsies. With reasonable power to detect even modest effect sizes, the absence of genome-wide significant association demands refinement of further single-nucleotide polymorphism (SNP)-based genome wide approaches, with a focus on more homogeneous phenotypes. Secondly, several putatively causal variants of a different type, copy number variants (CNVs), have been discovered. Several recurrent epilepsy-associated CNVs have been identified, including microdeletions at 15q13.3 and 16p13.11. CNVs constitute the commonest known genetic cause of the epilepsies. How CNVs cause disease, and why the same CNV can cause different diseases is unexplained. Nevertheless, CNVs will accelerate discovery of 'epilepsy genes', focussing attention on specific genomic regions. With the published genome-wide SNP study, CNVs are redirecting research efforts to a search for rare variants underlying common epilepsies. CNVs have also highlighted the challenges ahead in genotype-phenotype correlation. SUMMARY: Major discoveries are reshaping the genetics of the common epilepsies and prefiguring whole exome/whole genome resequencing efforts. PMID- 21252663 TI - Nocturnal hemodialysis: effects on solute clearance, quality of life, and patient survival. AB - PURPOSE OF REVIEW: Conventional hemodialysis is often an incomplete treatment for uremia. People receiving hemodialysis often report a poor quality of life and suffer from an accelerated mortality rate. Nocturnal hemodialysis provides long treatments at night in the home or dialysis center. This review will examine how long nocturnal treatments have impact on the clearance of small and larger retention products, and how these treatments influence quality of life and survival. RECENT FINDINGS: Nocturnal hemodialysis is more effective at clearing most small and middle molecule retention products, and has been associated with improvements in quality of life, especially in those domains related to the effects of kidney disease. Survival on nocturnal hemodialysis is higher than expected, and studies suggest that patients receiving nocturnal hemodialysis have a mortality rate that is about one third of what is seen in similar patients receiving conventional hemodialysis. SUMMARY: Although impressive, it is difficult to be sure how much of the results of these studies is due to the duration and timing of dialysis and how much relates to patient level factors and residual confounding, and further research in this area is required. PMID- 21252664 TI - Hyponatremia: diagnosis, complications, and management including V2 receptor antagonists. AB - PURPOSE OF REVIEW: Recent studies have consistently demonstrated the common prevalence of hyponatremia in the hospital and intensive care settings, and how it correlates with untoward outcomes. This review discusses the classification, diagnosis, and pathophysiology of hyponatremia and how these agents may influence its management, and also examines the available treatment options and their weaknesses and strengths. RECENT FINDINGS: This review is timely and relevant, as mild degrees of serum sodium lowering may be associated with adverse neurologic and musculoskeletal effects. These findings have the potential to transform our approach to managing hyponatremia. A major advance in our ability to treat hyponatremia was the introduction and approval of aquaretics (vaptans). Emerging data on vaptans and their potential role to treat hyponatremia in the settings of the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis are presented. SUMMARY: Vaptans will likely play an important role in treating hyponatremia, given their clinical effectiveness and tolerability. Cost remains a hindrance for vaptans, and more studies are needed to further define their best utilization in hyponatremic patients. PMID- 21252665 TI - The antenatal diagnosis of placental attachment disorders. AB - PURPOSE OF REVIEW: The incidence of placenta accreta is increasing as the number of cesarean sections increases. Separation of the placenta from the uterus in this situation may result in torrential bleeding. Antenatal diagnosis allows modification of the approach to delivery to conserve blood loss and avoid major medical problems. RECENT FINDINGS: Most of the imaging literature confines itself to patients who are at risk due to previous surgery and a placenta previa. In these patients, the most reliable sign of placenta accreta is the presence of irregular vascular spaces with arterial flow. In almost all patients, the signs needed for the diagnosis are present at the time of the screening examination at 18 weeks. Ultrasound is quite accurate in predicting severe placenta accreta in at-risk patients. Less severe cases, in which the placenta is solely difficult to separate, may not have any ultrasound findings. Nothing is known about the ultrasound appearance of placenta accreta in patients who have not had previous uterine surgery. SUMMARY: Antenatal identification of placenta accreta is possible with high sensitivity in patients with placenta previa and a previous cesarean section. PMID- 21252666 TI - Central compartment dissection for well differentiated thyroid cancer ... and the band plays on. AB - PURPOSE OF REVIEW: The role of central compartment dissection in the surgical management of well differentiated thyroid cancer is controversial. Lack of high quality prospective studies results in management decisions being based on expert opinions and weaker levels of evidence. The American Thyroid Association has recently revised its management guidelines with particular emphasis on this topic, and a separate working group has set out to define the surgical anatomy that encompasses this procedure. RECENT FINDINGS: Central compartment dissection comprises the removal of nodal tissue from the prelaryngeal, pretracheal and paratracheal compartments, with no role for berry-picking procedures. There is universal agreement that therapeutic nodal dissection should be performed in patients with metastatic disease detected either through preoperative imaging or during intraoperative evaluation of the central compartment, with either visual inspection or frozen-section pathology. In contrast, there may be limited benefit from routine prophylactic central compartment dissection, for either disease recurrence or survival outcomes. As such, it should be performed only in patients deemed high risk: larger tumors, extra-thyroidal extension or aggressive histologic subtypes. SUMMARY: Future studies should focus on identifying the subpopulation of patients who would most benefit from these procedures and spare low-risk patients from the unwanted complications. PMID- 21252667 TI - Anaplastic thyroid carcinoma: palliation or treatment? AB - PURPOSE OF REVIEW: To review the recent published literature on the topic of anaplastic thyroid carcinoma and discern if significant advances have occurred that alter the historically poor prognosis associated with this diagnosis. RECENT FINDINGS: Surgical resection for patients with stage IVA disease (intra-thyroidal without extracapsular extension) with postoperative chemoradiation remains the standard recommendation. Care for patients with stage IVB disease, extrathyroidal spread without distant metastases, remains varied and controversial. Research into different molecular therapies (deacetylase inhibitors, tubulin binding compounds, etc.) and the pathogenesis of anaplastic carcinoma continues to evolve. Care for patients with metastatic disease, stage IVC, is focused on quality of life. SUMMARY: Although occasional reports exist of long-term survivors with anaplastic thyroid carcinoma, the prognosis remains poor. Accurate staging is critical to offering the most appropriate treatment. Multimodality treatment is required if prolonged locoregional control or survival is desired. PMID- 21252668 TI - Liquid-based cytology in oral cavity squamous cell cancer. AB - PURPOSE OF REVIEW: Oral exfoliative cytology is a practical tool for early diagnosis of squamous cell carcinoma (OSCC) and potentially malignant lesion (OPML), but is not yet extensively used. A literature review evaluated conventional and liquid-based oral diagnostic cytology efficacy and efficiency. 'Special' techniques like liquid-based cytology, computer-assisted cytology, Oral CDx, DNA ploidy, immunocytochemistry, molecular analyses and microhistology were reviewed. RECENT FINDINGS: Cytology was useful when diagnosing OSCC and OPML. Oral CDx may assess dysplastic changes in clinically suspicious (class I) lesions, with doubtful efficacy in apparently innocuous (class II) lesions. Flow and/or image cytometry and immunocytochemistry can identify markers for the prediction of evolution of the OPML to OSCC. Molecular biology can detect the minimal residual clonal population of cancer cells in field cancerization and oral mucosa surgical margins. Microhistology is a reliable first level test in class II lesions for selected cases requiring surgical biopsy. SUMMARY: Conventional cytology helps in OSCC and OPML screening; liquid-based cytology gives better results, enhancing both sensitivity and specificity, and provides material for further investigation. Sampling with the 'curette technique' permits collection of 'accidental' tissue fragments used as microbiopsies and proved a useful first-level test for the management of class II OPML. PMID- 21252669 TI - Reduced intensity versus myeloablative allogeneic stem cell transplantation for the treatment of acute myeloid leukemia, myelodysplastic syndrome and acute lymphoid leukemia. AB - PURPOSE OF REVIEW: Use of a reduced intensity conditioning (RIC) regimen has now become standard practice among older or more infirmed stem cell transplantation candidates. Encouraging outcome in this population has led to the question of whether RIC should replace standard myeloablative conditioning (MAC) regimens. This review will summarize the available outcomes data comparing RIC and MAC approaches to stem cell transplantation in adult patients with acute myeloid leukemia, myelodysplastic syndrome (MDS) and acute lymphoid leukemia. RECENT FINDINGS: There are currently no completed prospective randomized controlled studies comparing outcomes of RIC to MAC. The best insight into differences in outcome comes from large registry-based retrospective studies. These studies demonstrate that the use of RIC is associated with a reduction in transplant related mortality but an increased risk of disease relapse. As a result, for patients undergoing stem cell transplantation in remission, disease free and overall survival are similar. SUMMARY: The current retrospective data provide justification for the use of RIC regimens in all adult stem cell transplant candidates with acute leukemia in remission and MDS. More definitive conclusions regarding differences between the MAC and RIC approach to stem cell transplantation await results of ongoing prospective randomized trials. PMID- 21252670 TI - Neuroprotection in glaucoma: recent and future directions. AB - PURPOSE OF REVIEW: The concept of neuroprotective therapy for glaucoma is that damage to retinal ganglion cells (RGCs) may be prevented by intervening in neuronal death pathways. This review focuses on strategies for neuroprotection and summarizes preclinical studies that have investigated potential agents over the last 2 years. RECENT FINDINGS: Part of the challenge of studies in neuroprotection has been the utilization of an animal model that resembles human glaucoma. Several models have been utilized including acute and chronic intraocular pressure elevation, the DBA/2J mouse, optic nerve axotomy and crush. NMDA inhibitors continued to be explored however with limited success in human trials. Memantine failed to demonstrate neuroprotection in phase III clinical trials. Although its mechanism of neuroprotection has not been fully elaborated, topical brimonidine has shown some neuroprotective benefits. Exogeneous neurotrophins delay, but do not prevent, RGC death. Bioenergetic neuroprotection that is enhancing the energy supply to RGC has been explored with benefits in animal models. Other strategies include TNF-alpha, modulation of the immune system and inflammation, and blocking apoptotic signals and stem cells. SUMMARY: Animal models of glaucoma and neuroprotective strategies continue to be refined. Establishing consensus guidelines for the execution and design of translational research in neuroprotection may optimize the facilitation of neuroprotection research. PMID- 21252671 TI - Angle closure glaucoma: a mechanistic review. AB - PURPOSE OF REVIEW: With recent advances in imaging techniques such as anterior segment optical coherence tomography and ultrasound biomicroscopy, there is a better understanding of nonpupil block mechanisms and novel risk factors contributing to the pathogenesis of angle closure glaucoma. RECENT FINDINGS: Recent studies suggest that multiple anatomical and physiological factors interplay in the pathogenesis of angle closure glaucoma. The association of greater iris convexity, area and thickness with narrow angles could result in a more anterior bowing and crowding of the peripheral iris. Other novel anatomic parameters such as greater lens vault, smaller anterior chamber width, area and volume, independently increase the risk of having angle closure. Dynamic increase or lesser reduction in iris volume during dilation supports the theory of physiological predisposition to the disease process. Choroidal expansion has been demonstrated in untreated and treated, acute and chronic primary angle closure eyes. It remains unknown whether this finding is a cause or effect in this condition. SUMMARY: With a wider availability of imaging tools and a better understanding of risk factors and mechanisms, clinicians maybe able to more accurately identify those at greater risk of developing angle closure disease and tailor their treatment according to the predominant factor(s) involved. PMID- 21252672 TI - Classification of primary angle closure disease. AB - PURPOSE OF REVIEW: Primary angle closure disease, PACD, has had a plethora of classifications and terminologies. The International Society of Geographical and Epidemiological Ophthalmology (ISGEO) classification was a simple classification, extremely useful in surveys, but could not be clinically applied because of the varied presentation of PACD. RECENT FINDINGS: Reviewing the literature, it was seen that the landmarks in progression of PACD were an anatomical predisposition; iridocorneal apposition/adhesions; chronic rise in intraocular pressure (IOP), despite an iridotomy; and glaucomatous optic neuropathy. Therefore, a staging system for PACD is proposed. PACD suspect--occludable angle; PACD I--occludable angle with evidence of closure, but a normal IOP after iridotomy; PACD II- peripheral anterior synechiae in an occludable angle with a chronically raised IOP after iridotomy, with or without a suspicious optic nerve head; and PACD III- peripheral anterior synechiae in an occludable angle, with a raised IOP after iridotomy, and glaucomatous optic neuropathy. SUMMARY: This proposed classification has amalgamated all the clinically described subtypes of PACD- subacute, acute, chronic, symptomatic, and asymptomatic--into a staging, based on extent of damage to the outflow channels and optic nerve head, providing a basis for standardized therapy and possibly a quantifiable long-term prognosis. PMID- 21252673 TI - Gene therapy for glaucoma. AB - PURPOSE OF REVIEW: Glaucoma is a chronic progressive disease for which ideal treatment would provide a localized long-lasting therapy with minimal side effects. A gene therapy approach in which a mutated gene is replaced or inactivated, or in which a new gene is introduced, could provide a novel and more effective way of targeting the disease. The aim of this review is to provide an update on recent advances in the field of gene therapy for the treatment of glaucoma. RECENT FINDINGS: Both viral and nonviral vector gene delivery systems have been used to target specific tissues involved in the pathogenesis of glaucoma. These tissues include the trabecular meshwork, ciliary body, ciliary epithelium, Muller cells, and retinal ganglion cells. Recent studies in large animal models have demonstrated effective long-term gene expression in the trabecular meshwork following intracameral delivery of adeno-associated viral vectors and lentiviral vectors with limited effect on surrounding ocular tissues. Other promising studies have focused on vector-mediated expression of neurotrophic factors and have demonstrated a neuroprotective effect following intravitreal delivery of vectors in glaucomatous animal models. SUMMARY: Given the recent laboratory studies utilizing gene therapy techniques to lower intraocular pressure and to provide neuroprotection, and the continued development of tissue-specific vectors, it seems that we are well poised for a new generation of treatments for glaucoma. PMID- 21252675 TI - Probiotics and prevention of neonatal necrotizing enterocolitis. AB - PURPOSE OF REVIEW: This review will summarize the clinical trials evaluating the role of prophylactic probiotic supplementation in preterm infants in order to reduce the incidence of necrotizing enterocolitis (NEC). RECENT FINDINGS: Evidence suggests that probiotic supplementation in preterm infants reduces the incidence of NEC. In fact, recent meta-analyses have called for the use of probiotics as preventive therapy in subsets of this population. However, although multiple studies have evaluated the use of probiotics for this indication in preterm infants, these trials have used different formulations of bacteria, at differing doses and using varied protocols for administration; thus many unanswered questions remain. In addition, theoretical safety issues and concerns regarding quality of product still need to be addressed. SUMMARY: As NEC remains a serious problem for preterm neonates, proven therapies for prevention and treatment of this dreaded disease are needed. While the evidence does support a future role for probiotics in the prevention of NEC, it is of utmost importance to first ensure that a safe and high-quality product meeting rigorous standards will be provided to these at-risk infants. PMID- 21252676 TI - Coarctation of aorta and vein of Galen aneurysmal malformation in a neonate. AB - PURPOSE OF REVIEW: A case report of a newborn with coarctation of aorta and severe vein of Galen malformation. RECENT FINDINGS: This case report reviews literature on congenital heart disease and intracranial arteriovenous malformations. Emphasis is laid on diagnostic challenges and management options. SUMMARY: Congenital heart diseases with arteriovenous malformations carry a high risk of mortality. Thorough physical examination and high index of suspicion can lead to early diagnosis, and interdisciplinary coordination leads to better outcomes. PMID- 21252674 TI - Biomarkers for the early detection of acute kidney injury. AB - PURPOSE OF REVIEW: Acute kidney injury (AKI) is a common and serious condition, the diagnosis of which depends on serum creatinine, which is a delayed and unreliable indicator of AKI. Fortunately, understanding the early stress response of the kidney to acute injuries has revealed a number of potential biomarkers. The current status of the most promising of these novel AKI biomarkers, including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM 1), liver-type fatty acid binding protein (L-FABP), and interleukin (IL)-18, is reviewed. RECENT FINDINGS: In particular, NGAL is emerging as an excellent biomarker in the urine and plasma, for the early prediction of AKI, for monitoring clinical trials in AKI, and for the prognosis of AKI in several common clinical scenarios. However, biomarker combinations may be required to improve our ability to predict AKI and its outcomes in a context-specific manner. SUMMARY: It is vital that additional large future studies demonstrate the association between biomarkers and hard clinical outcomes independent of serum creatinine concentrations and that randomization to a treatment for AKI based on high biomarker levels results in an improvement in clinical outcomes. PMID- 21252677 TI - Recent advances in invasive pulmonary aspergillosis. AB - PURPOSE OF REVIEW: This review highlights the most important and salient recent developments with regards to invasive pulmonary aspergillosis (IPA), currently the most common opportunistic fungal pneumonia in patients with hematological malignancies. RECENT FINDINGS: Besides patients in hematology units, other immunosuppressed and critically ill patients are also at risk of IPA. Identification of patients who possess specific polymorphisms of Toll-like receptor 4 and dectin-1, both of which are involved in the immune sensing of Aspergillus spp., may facilitate risk-stratification. The use of the galactomannan assay in bronchoalveolar fluid to improve diagnosis of IPA is undergoing validation. Trending galactomannan and other biomarker results may prognosticate clinical outcomes. During intensive chemotherapy for leukemia, posaconazole and aerosolized liposomal amphotericin B (L-AMB) have demonstrated efficacy as prophylaxis against invasive fungal infection. However, fluconazole remains an effective prophylactic agent in the setting of hematopoietic stem cell transplantation despite availability of newer antifungal agents. Although voriconazole is still the drug of choice for IPA, both caspofungin and L-AMB are viable alternatives. SUMMARY: Despite increasing knowledge of IPA and availability of newer antifungal agents, clinical management remains a challenge in the setting of a compromised host defense system that is unable to mount an appropriate immune response against the pathogen. PMID- 21252678 TI - Healthcare-associated pneumonia: the state of evidence to date. AB - PURPOSE OF REVIEW: As evidence about the importance of correct choice of empiric therapy in the setting of pneumonia accumulates, balancing antibiotic spectrum against the risk of selecting for resistant organisms gains importance. Healthcare-associated pneumonia (HCAP) defines a set of risk factors to underscore the probability of a resistant etiologic pathogen, requiring broader spectrum treatment than is generally needed in community-acquired pneumonia (CAP). Controversies persist as to whether HCAP is a useful designation for diagnosis, treatment and outcome prediction. RECENT FINDINGS: HCAP represents a discrete syndrome, where offending organisms and outcomes differ from those for CAP. However, HCAP designation is neither a sensitive nor a specific system to predict the presence of a resistant organism. Several other instruments have been developed that require prospective validation. Recent findings that CAP guideline concordant antibiotic treatment among HCAP patients does not alter outcomes is confounded by the emerging understanding that culture-negative HCAP may be successfully treated with therapy targeted at CAP pathogens. SUMMARY: Because HCAP is an important emerging syndrome, a systematic approach to its study is critical. As evidence in this area evolves, it remains important for investigators and clinicians to identify knowledge gaps and to set the research agenda to resolve multiple unanswered questions. PMID- 21252679 TI - Chronic obstructive pulmonary disease (COPD). PMID- 21252680 TI - Osteoporosis prevention. AB - PURPOSE OF REVIEW: Patients with osteoporosis suffer from the morbidity and mortality associated with resultant fractures. The number of persons at risk for fractures is increasing as the US population ages. This review addresses preventive strategies that can be used to decrease the risk of minimal trauma fractures. RECENT FINDINGS: Dietary and lifestyle modifications and screening to identify individuals most likely to benefit from pharmacologic interventions, important components of osteoporosis prevention, will be discussed. Currently available osteoporosis therapies and fall prevention, which should be utilized in those at increased risk of fracture, will be reviewed. SUMMARY: The ultimate goal of implementing a multipronged osteoporosis preventive program is to improve function and quality of life in later life. PMID- 21252681 TI - Exercise: necessary but not sufficient for improving function and preventing disability? AB - PURPOSE OF REVIEW: Several recent clinical trials and systematic reviews have examined functional outcomes of exercise programs in two populations: older adults and adults with knee arthritis. We synthesize recent clinical trials and systematic reviews to examine whether the links between exercise and functional outcomes are better understood than they were a decade ago. RECENT FINDINGS: Systematic reviews and current clinical trials reveal a modest beneficial effect of progressive resistance training (strengthening programs) and aerobic programs on strength, pain, and function in both populations. Few randomized controlled trials have investigated disability-level outcomes, and of those that do examine disability outcomes, the majority of studies have not shown a beneficial effect. SUMMARY: Current and recent evidence shows little to no impact of exercise on the prevention of disability. Exercise programs may need to be changed if the desire is to prevent or minimize disability. Alternatively, different strategies need to be developed to address disability more directly. PMID- 21252682 TI - Joint protection and physical rehabilitation of the adult with hypermobility syndrome. AB - PURPOSE OF REVIEW: Hypermobility and hypermobility syndrome are common conditions with universal interest. However, despite significant advances in our knowledge of the presentation and implications of lax tissues there is still much to learn about the best way to manage the symptoms. This review discusses our current knowledge on the management of joint problems associated with hypermobility syndrome. RECENT FINDINGS: Relieving joint pain and preventing its recurrence are primary aims of treatment and exercise to improve joint stability and control is a major component of physical rehabilitation. Research has identified that posture, proprioception, strength and motor control are important components in achieving this aim along with education, physical activity and fitness. SUMMARY: It is not yet known what form the optimal physical rehabilitation programme should take, but the components discussed here are based on sound scientific principles which it is hoped will further knowledge, stimulate interest and promote further research. PMID- 21252683 TI - New developments in percutaneous techniques for simple and complex branched renal stones. AB - PURPOSE OF REVIEW: Percutaneous nephrolithotomy (PNL), although practiced for almost 30 years, is still the most appropriate treatment modality for several forms of renal stones. We analysed a number of very recent advances in PNL technique, contributing to the continuous improvement of its efficacy and safety. RECENT FINDINGS: A thorough review of the recent literature identifies five major progressing areas, inspiring fruitful innovations in PNL technique: imaging (computed tomography being the standard tool) before, during and after the procedure; patient positioning (the traditional prone position being now challenged with the emerging supine positions); endoscopic combined intrarenal surgery (ECIRS), a versatile antero-retrograde approach to the upper urinary tract and a new comprehensive attitude of the urologist toward the various PNL steps; intracorporeal lithotripsy (improved by new devices combining ultrasonic and pneumatic lithotripsy, or ultrasonic and high-power holmium: YAG laser lithotripsy); and post-PNL tube management (namely nephrostomy-free and totally tubeless procedures). SUMMARY: Urologists dedicate significant efforts to the improvement of the PNL procedure, with the aim of further increasing its stone free outcomes and reducing patient morbidity. Large-scale multicentre prospective trials are needed to define benefits and identify possible drawbacks of the described innovations in percutaneous stone management. PMID- 21252684 TI - Effects of ionic and surfactant agents on the antimicrobial activity of polyhexamethylene biguanide. AB - OBJECTIVES: Polyhexamethylene biguanide (PHMB) exhibits broad-spectrum antimicrobial activity and is included in multipurpose solutions for contact lenses as a disinfectant. Both cationic and hydrophobic features of PHMB are believed to support its association with microbial cell membranes through electrostatic and hydrophobic interactions. We now evaluated the effects of ionic and surfactant agents on the antimicrobial activity of PHMB. METHODS: The antimicrobial activity of PHMB (1 ppm) against various bacteria and fungi was measured with the stand-alone procedure (ISO 14729, 2001). The effect of NaCl as an ionic isotonic agent on such an activity was determined in comparison with that of propylene glycol as a nonionic isotonic agent. The effect of the nonionic surfactant Poloxamer 407 (Px407) was similarly examined in the absence or presence of NaCl. RESULTS: The antimicrobial activity of PHMB increased with time, being especially pronounced after 60 min. This activity was inhibited by NaCl in a concentration-dependent manner but was not affected by propylene glycol. Poloxamer 407 (4%) alone slightly increased the activity of PHMB toward Staphylococcus aureus and fungi. Although Px407 prevented the inhibitory effect of NaCl on PHMB activity against bacteria, it enhanced that observed with Candida albicans. CONCLUSIONS: The antimicrobial activity of PHMB was inhibited by adjustment of osmolality with the ionic agent NaCl but not by that with the nonionic agent propylene glycol. The surfactant Px407 exhibited complex effects on PHMB activity in the presence of NaCl. These findings indicate that the electrostatic interaction with the cell membrane is a dominant factor in the antimicrobial activity of PHMB. PMID- 21252685 TI - Effects of tonicity-adjusting and surfactant agents on the antimicrobial activity of alexidine. AB - OBJECTIVES: Alexidine is a bis-biguanide disinfectant with two cationic active sites and hydrophobic ethylhexyl end groups, both of which are believed to support its association with microbial cell membranes through electrostatic and hydrophobic interactions. We evaluated the effects of tonicity-adjusting and surfactant agents on the antimicrobial activity of alexidine to assess its suitability as a disinfectant in multipurpose solutions for contact lenses. METHODS: The antimicrobial activity of alexidine (4.5 ppm) against various bacteria and fungi was measured with the stand-alone procedure (ISO 14729, 2001). The effect of NaCl as an ionic tonicity-adjusting agent on such activity was determined in comparison with that of propylene glycol as a nonionic tonicity adjusting agent. The effect of the nonionic surfactant Poloxamer 407 (Px407) was similarly examined in the absence or presence of NaCl. RESULTS: Alexidine showed robust antimicrobial activity, with no organisms surviving after 1 hr. Antifungal activity was inhibited by NaCl in a concentration-dependent manner, whereas neither antibacterial nor antifungal activity was affected by propylene glycol. The activity of alexidine was not affected by Px407 (4%) alone but was attenuated by the combination of NaCl and Px407 with all microorganisms tested. CONCLUSIONS: The antifungal activity of alexidine was inhibited by adjustment of osmolality with the ionic agent NaCl but not by that with the nonionic agent propylene glycol. The surfactant Px407 reduced antimicrobial activity only in the presence of NaCl. These findings indicate that electrostatic and hydrophobic interactions with the microbial cell membrane are a key factor in the antimicrobial activity of alexidine. PMID- 21252686 TI - Descemet membrane detachment during foldable intraocular lens implantation. AB - PURPOSE: Descemet membrane detachment (DMD) during phacoemulsification is a well known complication. Although most of the DMDs resolve on their own, some may require surgical intervention in the form of intracameral injection of air or isoexpansive gas. We report the occurrence and subsequent management of a patient with DMD caused by the leading haptic of a foldable intraocular lens (IOL) during its insertion. METHODS: A 50-year-old woman underwent coaxial phacoemulsification for age-related cataract in her right eye. Descemet membrane detachment was noted during the insertion of the foldable posterior chamber IOL through a temporal 2.2 mm incision. Corneal edema did not resolve by the third postoperative day. Scheimpflug photography demonstrated a complete separation between the posterior stroma and DM along the entirety of the cornea. Surgical intervention was performed on the fourth postoperative day, which involved creation of stab incisions into the pre-Descemet space along with intracameral air injection. RESULTS: Successful apposition of the DM followed by clearing of corneal edema was observed within 1 week. CONCLUSIONS: Our case report highlights the potential complication of DM detachment during insertion of foldable IOL. We performed stab incisions in the pre-DM space to achieve quick and successful repositioning of the detached DM with favorable results. PMID- 21252687 TI - Pythium insidiosum keratitis in Israel. AB - PURPOSE: To report with morphologic and phylogenetic speciation the first case from Israel of Pythium insidiosum keratitis associated with contact-lens wear. METHODS: Case report and literature review. RESULTS: A 21-year-old man with a history of contact-lens use and water exposure was hospitalized in Israel for a corneal ulcer. The ulcer progressed despite intensive antibiotics. He flew home to the United States for further care. Examination revealed a corneal ulcer with hypopyon. The infection progressed despite intensive medical therapy, and a therapeutic penetrating keratoplasty was performed. Histology and cornea cultures from the host cornea revealed sparsely septate, branching hyphae, consistent with P. insidiosum. DNA sequencing of the Pythium isolate supported the clinical history that the infection was acquired outside of the United States. Despite intensive medical therapy and a second corneal transplant, the ulcer progressed, ultimately requiring enucleation. CONCLUSION: This is the first reported case of culture-proven, contact lens-related Pythium keratitis originating from Israel. Pythium is a fungus-like, aquatic oomycete found in tropical climates. Human pythiosis is uncommon but associated with high morbidity. Case reports describe surgical cure of Pythium keratitis, but this case recurred despite two penetrating keratoplasties and maximal antifungal therapy. In cases of presumed fungal keratitis that do not respond to antifungals, the fungus should be sent for speciation because early surgical intervention is the only means to save the eye in ocular pythiosis. PMID- 21252688 TI - Local and systemic treatments for acute edema after burn injury: a systematic review of the literature. AB - Burn injury is a complex trauma that results in local and generalized edema. Edema fluid limits the exchange of vital nutrients in healing the burn wound and will compromise vulnerable tissues. Although the importance of edema control in tissue salvage is recognized, treatments targeted at edema control have not been critically reviewed. Thus, the objective was to assess the evidence for the effectiveness of local and systemic treatments for edema management immediately after burn injury. Searches for randomized controlled trials were conducted of online databases, research and thesis registers, and grey literature repositories. Handsearches included journals, bibliographies, and proceedings. Authors were contacted to clarify and submit extra study details. Eight studies were included. Management of acute major burn resuscitation including colloid increases lung edema (mean difference [MD], 0.04 ml/ml alv vol; 95% confidence interval [CI], 0.03-0.04; P < .00001) and mortality (risk ratio, 3.67; 95% CI, 1.16-11.58; P = .03). Continuous administration of vitamin C in acute burn resuscitation reduces local wound edema (MD, -3.50 ml/g; 95% CI, -4.63 to -2.37; P < .00001) and systemic fluid retention (MD, -8.60 kg; 95% CI, -13.47 to -3.73; P = .0005). Local acute hand burn edema is reduced (MD, -29.00 ml; 95% CI, -53.14 to -4.86; P = .02), and active hand motion increased (MD, 10.00 degrees ; 95% CI, 4.58-15.42; P = .0003), using electrical stimulation with usual physiotherapy. Each review outcome was based on a small single-facility study. Thus, future research in intervention for acute burn edema must focus on multicentre trials and validation of outcome measures in the burn population. PMID- 21252689 TI - Surgical burn wound infections and their clinical implications. AB - Typically, burn wound infections are classified by the organisms present in the wound within the first several days after injury or later by routine surveillance cultures. With universal acceptance of early excision and grafting, classification of burn wound colonization in unexcised burn wounds is less relevant, shifting clinical significance to open burn-related surgical wound infections (SWIs). To better characterize SWIs and their clinical relevance, the authors identified the pathogens responsible for SWIs, their impact on rates of regrafting, and the relationship between SWI and nosocomial infection (NI) pathogens. Epidemiologic and clinical data for 71 adult patients with >= 20% TBSA burn were collected. After excision and grafting, if a grafted site had clinical characteristics of infection, a wound culture swab was obtained and the organism identified. Surveillance cultures were not obtained. SWI pathogen, anatomic location, postburn day of occurrence, and need for regrafting were compiled. A positive culture obtained from an isolated anatomic location at any time point after excision and grafting of that location was considered a distinct infection. Pathogens responsible for NIs (urinary tract infections, pneumonia, bloodstream and catheter-related bloodstream infections, pseudomembranous colitis, and donor site infections) and their postburn day were identified. The profiles of SWI pathogens and NI pathogens were then compared. Of the 71 patients included, 2 withdrew, 6 had no excision or grafting performed, and 1 had incomplete data. Of the remaining 62 patients, 24 (39%) developed an SWI. In these 24 patients, 70 distinct infections were identified, of which 46% required regrafting. Candida species (24%), Pseudomonas aeruginosa (22%), Serratia marcescens (11%), and Staphylococcus aureus (11%) comprised the majority of pathogens. Development of an SWI with the need for regrafting increased overall length of stay, area of autograft, number of operative events, and was closely associated with the number of NIs. The %TBSA burn and depth of the burn were the main risk factors for SWI with need for regrafting. The SWI pathogen was identified as an NI pathogen 56% of the time, with no temporal correlation between shared SWI and NI pathogens. SWIs are commonly found in severely burned patients and are associated with regrafting. As a result, patients with SWIs are subjected to increased operative events, autograft placement, and increased length of hospitalization. In addition, the presence of an SWI may be a risk factor for development of NIs. PMID- 21252690 TI - Escharectomy and allografting during shock stage reduces insulin resistance induced by major burn. AB - Hyperglycemia and insulin resistance have long been recognized in severe burn patients. Early excision and grafting reduces cytokines and insulin resistance in burned rats. The authors hypothesized that early wound excision and grafting in patients would also reduce insulin resistance induced by major burn. Thirty-five adult surviving major burn patients (>40%TBSA burn) were recruited. The removal of dead devitalized tissue and allografting in escharectomy group was performed within 72 hours and in control group about 7 days after burn injury. The concentrations of plasma insulin, glucose, and cytokines were measured at 2 and 5 days postburn. Euglycemic-hyperinsulinemic glucose clamps were performed at 5 days after burn. The levels of phosphotyrosine, phosphoserine312 of insulin receptor substrate (IRS)-1, and phospho-jun N-terminal kinase (JNK) in muscle were analyzed with immunoprecipitation and Western blotting at 5 days postburn. Escharectomy and allografting during shock stage significantly reduced the levels of interleukin-6 and tumor necrosis factor-alpha, decreased the levels of phosphoserine312 and phospho-JNK, increased the level of phosphotyrosine of IRS 1, and further reduced insulin resistance at 5 days after thermal injury compared with delayed excision group. Escharectomy and allografting during shock stage seemed to have an immunomodulatory effect on the inflammatory mediators and further to reduce insulin resistance induced by major burns in patients by decreasing the phosphorylation of IRS-1 serine312 and JNK1/2. PMID- 21252691 TI - A comparison of nurses' and parents' or caregivers' perceptions during pediatric burn dressing changes: an exploratory study. AB - Providing emotional support both to children or young persons and to their parents or caregivers during pediatric burn dressing changes is a crucial aspect of nursing care in a burn unit; however, little research has examined perceptions of the effectiveness of typical interventions. Therefore, the aim of this research was to compare nurses' and parents' or caregivers' perceptions of support interventions provided before, during, and after pediatric burn dressing changes. This research was exploratory in nature and included the development of two differing questionnaires that focused on the perceptions of both parents or caregivers and nursing staff involved in dressing changes. Nurses and parents or caregivers involved in a total of 30 dressing changes completed surveys. Results were then analyzed using Microsoft Excel computer program, and a simple thematic analysis was performed on the responses to the open-ended survey questions. The survey results indicated that participants were generally favorable in their perceptions of the interventions used to support children during dressing changes; however, some gaps in the provision of care were identified. These included the need for clearer communication between the nurse and the parent or caregiver, poor pain assessment skills, and the need for debriefing for those involved in burn dressing procedures. Also highlighted were the difficulties nursing staff had in recognizing distress in parents or caregivers and when this occurred during the process. This research provided insights into coping strategies used by families and nurses and the value of support currently provided by the pediatric burn team. The results indicate that there is a need for improved communication with parents. The presence of a hospital play specialist, in addition to the parent or caregiver, was valuable. Also important was focusing on "comfort" positioning and use of distraction/alternative focus during dressing changes. The information gathered has provided additional strategies that can improve the care offered to children, young people, and families with burn injuries. Such strategies should be implemented in collaboration with the burn multidisciplinary team. PMID- 21252692 TI - Acute coronary syndromes in the elderly. AB - The elderly are a rapidly growing segment of the population with a high likelihood of acute coronary disease and worse outcomes after acute coronary syndromes than younger groups. Although underrepresented in clinical trial populations, they benefit to an equal or greater extent from treatment with proven medications and interventions, and survivors to hospital discharge have excellent longer term functional outcomes. With consideration of individual preferences for treatment and inherent risks for side-effects in this population, age alone should not determine management of elderly acute coronary syndrome patients. PMID- 21252693 TI - Chronic stable angina: pathophysiology and innovations in treatment. AB - The incidence of chronic stable angina has risen significantly over the past few decades and may affect as many as 15,000-40,000 individuals per million in the US and Europe. Whereas there are fundamental pathophysiologic differences between chronic stable angina and acute coronary syndrome, the importance of optimal medical therapy in all stages of coronary artery disease cannot be overemphasized. As the initial manifestation of coronary artery disease in nearly half of all patients, diagnosis of stable angina represents a valuable opportunity to initiate evidence-based therapies to decrease mortality among patients with coronary artery disease, in addition to symptomatic treatment. However, despite aggressive medical therapy and if appropriate, revascularization, many patients still have refractory angina. In this article, the pathophysiology, currently recommended clinical management and emerging therapies to treat symptoms of chronic stable angina are reviewed. PMID- 21252695 TI - Atrial fibrillation as the initial clinical manifestation of cardiac sarcoidosis: a case report and review of the literature. AB - Cardiac sarcoidosis is an unusually rare form of sarcoidosis that often remains silent clinically; although if not screened for and diagnosed early can lead to disastrous consequences, which include sudden death. In addition to sudden death, cardiac sarcoidosis can present with myriad manifestations, including congestive heart failure and conduction blocks, as well as atrial or ventricular arrhythmias. We hereby present a case report of 45-year-old African-American male who repeatedly presented in the emergency room with episodes of paroxysomal supraventricular tachycardia (PSVT) as well as atrial fibrillation of unknown origin. Detailed workup led to a successful diagnosis of cardiac sarcoidosis, which is being treated with 1 mg/kg of steroids daily. Our focus on this report is that with recent advances in imaging technology, cardiac sarcoidosis can be detected more easily than before. Therefore, a high degree of clinical suspicion and systematic evaluation to uncover the cardiac involvement is warranted to improve outcomes of patients with sarcoidosis and cardiac involvement. PMID- 21252694 TI - Influence of aetiology on long-term effects of resynchronization on cardiac structure and function in patients treated with beta-blockers. AB - OBJECTIVES: Cardiac resynchronization therapy (CRT) elicits more beneficial effects on left-ventricular (LV) structure and function, and long-term clinical outcomes in nonischemic heart failure patients. Rates of beta-blocker use in recent heart failure trials are higher than in CRT trials and this may influence the response to CRT. This study examined the long-term effects of CRT on LV structure and function in New York Heart Association class III-IV beta-blocker treated patients. METHODS: One hundred and four (41 ischemic and 63 nonischemic) CRT patients, who were receiving beta-blockers before and throughout 12 months following device implantation, were retrospectively selected. Variations in echocardiographic parameters recorded before, and 6 and 12 months after CRT were analyzed. RESULTS: Selected patients were all stable on beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (97%) and diuretics (97%) before implantation. CRT was associated with significant improvements in LV morphological and systo-diastolic functional parameters at 6 months, with further improvements between 6 and 12 months seen in nonischemic patients only. Accordingly, rates of echocardiographic response to CRT were similar at 6 months but significantly higher in nonischemic patients after 1 year. The degree of reduction in LV diameters and volumes, and of increase in ejection fraction, was significantly larger in nonischemic patients at both 6 and 12 months. In addition, a significant reduction in LV mass and severity of mitral regurgitation was more evident in nonischemic patients both 6 and 12 months following CRT. CONCLUSIONS: Ischemic aetiology of heart failure is associated with less favorable long-term effects of CRT on LV structure and function despite the systematic use of beta-blockers. PMID- 21252696 TI - An unusual case of ECG ST-segment elevation. PMID- 21252697 TI - One-year clinical outcome in patients with acute coronary syndrome treated with concomitant use of clopidogrel and proton pump inhibitors: results from a regional cohort study. AB - OBJECTIVES: We sought to compare the 1-year risk of re-hospitalization for acute coronary syndrome (ACS) between patients taking clopidogrel with proton pump inhibitors (PPIs) vs. clopidogrel without PPIs. MATERIALS AND METHODS: We conducted a retrospective cohort study among 3896 patients with ACS, at low risk for gastrointestinal bleeding, discharged from all hospitals of the Emilia Romagna region of Italy during the period January-August 2008. Patients' consumption of clopidogrel and PPIs at hospital discharge and follow-up was based on pharmacy refill data. Of these 3896 patients, 90% (n = 3519) were prescribed PPIs at hospital discharge and/or at some time during follow-up. RESULTS: At 1 year follow-up, hospitalization for ACS occurred in 15% of patients taking clopidogrel with PPIs vs. 3.4% of those taking clopidogrel without PPIs (P < 0.001). No difference in terms of all-cause mortality could be detected between the two groups. At multivariate regression analysis with PPI use as a time varying covariate, periods of use of clopidogrel with PPIs were associated, at 1 year follow-up, with a significantly higher risk of hospitalization for ACS (hazard ratio 1.29, P = 0.025). Notably, this event occurred mostly in patients who underwent revascularization during the index hospitalization (n = 3045, hazard ratio 1.52, P = 0.004). No significant effect of PPI prescription could be observed in terms of 1-year all-cause mortality and revascularization. CONCLUSION: This study suggests the hypothesis that a concomitant use of clopidogrel and PPIs in patients with ACS, at low risk for gastrointestinal bleeding, having mostly undergone coronary revascularization, is associated with an approximately 30% higher risk of nonfatal hospitalization for ACS. PMID- 21252698 TI - Prorenin induces vascular smooth muscle cell proliferation and hypertrophy via epidermal growth factor receptor-mediated extracellular signal-regulated kinase and Akt activation pathway. AB - BACKGROUND: It is widely acknowledged that the (pro)renin receptor mediates angiotensin (Ang) II-dependent and Ang II-independent effects of prorenin. METHOD: We examined the effect of prorenin on vascular smooth muscle cell (VSMC) signal transduction, proliferation, and hypertrophy. RESULTS: Recombinant rat prorenin dose-dependently increased extracellular signal-regulated kinase (ERK) 1/2 and Akt phosphorylation in rat VSMCs. Prorenin also significantly increased cell number, and [H]-thymidine and [H]-leucine incorporation, which were attenuated by pretreatment with inhibitors for ERK kinase and phosphatidylinositol 3 kinase. Prorenin was also found to stimulate epidermal growth factor (EGF) receptor and Src phosphorylation. Pretreatment of VSMCs with an EGF receptor tyrosine kinase inhibitor and a Src inhibitor significantly attenuated the prorenin-induced increase in ERK 1/2 and Akt phosphorylation, as well as DNA and protein synthesis. Prorenin-induced phosphorylation of the EGF receptor, ERK 1/2, and Akt, as well as DNA and protein synthesis were all blocked by (pro)renin receptor siRNA, but not by an Ang II type 1 receptor blocker, candesartan, nor an Ang-converting enzyme inhibitor, captopril. CONCLUSION: These results reveal that prorenin directly stimulates VSMC proliferative and hypertrophic changes, dependent on the (pro)renin receptor, independent of Ang II. Furthermore, EGF receptor-mediated ERK 1/2 and Akt activation contributes to prorenin-dependent proliferative and hypertrophic effects in VSMCs. PMID- 21252699 TI - Arterial stiffness predicts cardiovascular outcome in a low-to-moderate cardiovascular risk population: the EDIVA (Estudo de DIstensibilidade VAscular) project. AB - BACKGROUND: Pulse wave velocity (PWV) is a recognized marker of arterial stiffness, although little knowledge exists of their relationship to long-term cardiovascular risk in general populations. METHODS AND RESULTS: A prospective, multicenter, observational study included 2200 Portuguese nationals (1290 men), aged between 18 and 91 years (mean 46.33+/-13.76 years). They underwent clinical assessment and annual PWV measurement using a Complior device, and major adverse cardiovascular events (MACEs)--death, stroke, myocardial infarction, unstable angina, peripheral arterial disease, revascularization, or renal failure--were recorded. During a mean follow-up of 21.42+/-10.76 months, there were 47 nonfatal MACEs (2.1% of the sample). PWV was significantly higher in individuals with events than in those without events (11.76+/-2.13 vs. 10.01+/-2.01 m/s, respectively, P<0.001). The study population was divided into two groups by PWV, classified as normal (PWV<95th percentile) or high (PWV>95th percentile), according to predefined criteria for normality. Cumulative event-free survival at 2 years was 99.3% in the normal PWV group and 95% in the high PWV group. The hazard ratio for MACE in the high PWV group was 9.901 [95% confidence interval (CI) 5.00-19.59, P<0.001], and 4.832 (95% CI 2.35-9.94, P<0.001) when adjusted for other risk factors. For absolute PWV, the adjusted hazard ratio (per 1 m/s change) was 1.316 (95% CI 1.13-1.53, P<0.001). CONCLUSION: The results of the initial analysis of this study highlight the clinical relevance of PWV as a cardiovascular risk marker and demonstrate that PWV measurement can make an important contribution to assessment of cardiovascular prognosis. PMID- 21252700 TI - Radial late-SBP as a surrogate for central SBP. AB - BACKGROUND: Recent studies indicated that central SBP could be estimated by radial late-SBP (rSBP2) with a small disparity. However, most of these studies were conducted by SphygmoCor with a transfer function. The agreement between rSBP2 and central SBP was also tested in several invasive studies, but with inconsistent results. The objective of the present study was, therefore, to investigate whether rSBP2, from commercially available noninvasive devices, could practically indicate central SBP in current clinical care. METHODS: We assessed carotid SPB (cSBP) and aortic SBP (aSBP) and rSBP2 by two broadly used tonometry based devices, SphygmoCor and PulsePen, in 106 patients (57.5+/-14.1 years) from our cardiovascular department. RESULTS: In SphygmoCor and PulsePen, rSBP2 correlated well with aSBP and cSBP (R>0.80, P<0.001), but significantly underestimated them with a discrepancy ranging from 1.2+/-5.1 to 13.9+/-10.9 mmHg. The slopes of regression line in the correlation plots between the PulsePen rSBP2 and cSBPs from SphygmoCor and PulsePen were 0.91 and 0.99, respectively, and did not significantly differ from 1. CONCLUSION: PulsePen rSBP2 underestimated cSBP with a systematical but clinically substantial discrepancy, whereas SphygmoCor rSBP2 underestimated aSBP and cSBP with a nonsystematical but much smaller disparity. From a practical point of view, neither of these noninvasive devices can be applied for the precise estimation of central SBP with rSBP2 in clinical practice. PMID- 21252701 TI - Blood pressure control by the nifedipine GITS-telmisartan combination in patients at high cardiovascular risk: the TALENT study. AB - BACKGROUND: Guidelines on hypertension regard combinations between two antihypertensive drugs to be the most important treatment strategy. Because of the complementary mechanism of action and the evidence of cardiovascular protective effects they include the combination of a calcium antagonist and an angiotensin receptor antagonist among the priorital ones to employ. AIMS: To determine in hypertensive patients at high cardiovascular risk whether combining Nifedipine GITS at low dose and telmisartan reduced ambulatory and clinic blood pressure (BP) more than the combination components, controlled BP early after treatment initiation and allowed to also obtain a better long-term BP control compared to initiating treatment with the combination components and moving to the combination later. METHODS: Four hundred and five patients with a clinic SBP >= 135 mmHg and with diabetes, a metabolic syndrome or organ damage were randomized to once-a-day telmisartan 80 mg, nifedipine GITS 20 mg or the combination of the two drugs in a 1: 1: 2 ratio for 8 weeks in the context of a multicenter double-blind study design. Patients on monotherapy were then moved to combination treatment and all three groups were followed for an additional 16 week period. Both 24-h and clinic BP were measured before treatment and at various times during treatment. RESULTS: In the per-protocol patients (n = 327), baseline demographic and clinical characteristics were similar between the three groups. Baseline 24-h SBP values were 136.2 +/- 11.6 mmHg (mean +/- SD), 137.2 +/ 12.5 mmHg and 136.8 +/- 11.7 mmHg in the telmisartan monotherapy, nifedipine GITS monotherapy and combination therapy, respectively. The corresponding clinic values were 151.7 +/- 11.8, 151.3 +/- 11.9 and 151.1 +/- 11.8 mmHg, respectively. All treatments lowered 24-h SBP significantly (P < 0.0001) but combination treatment (8 weeks) reduced it significantly more than monotherapies (10.8 +/- 0.8 vs. 6.6 +/- 1.1 mmHg and 8.0 +/- 1.2 mmHg; P = 0.001 and 0.037). Similar data were obtained for clinic SBP for which the combination showed a significantly greater BP reduction (12.6 +/- 0.6 vs. 8.6 +/- 0.7 mmHg and 9.3 +/- 0.8 mmHg; P = 0.003 and 0.024) also after 2 weeks of treatment. Moving from monotherapy to combination therapy increased the antihypertensive effect and made both ambulatory and clinic SBP superimposable in the three groups after 16 and 24 weeks of treatment. Similar findings were obtained for DBP. CONCLUSION: Combination treatment with nifedipine GITS low dose and telmisartan provides a greater and earlier clinic and ambulatory BP reduction than the combination components in monotherapy. Initiating treatment with the combination did not result in any better longer term BP control compared to starting treatment with monotherapy and moving to the combination later. PMID- 21252702 TI - Potentiated sympathetic and hemodynamic responses to alcohol in hypertensive vs. normotensive individuals. AB - OBJECTIVE: Alcohol is associated with acute increases in muscle sympathetic nerve activity (MSNA) in normal individuals. The effects of alcohol on MSNA in patients with hypertension are unknown. Using a randomized, placebo-controlled study design, we tested the hypothesis that there is a differential effect of acute alcohol consumption on cardiovascular function in hypertensive patients compared with normotensive controls. METHODS: We examined the effects of oral alcohol intake (1.0 g/kg body weight) and placebo on blood pressure, heart rate, and MSNA in 13 newly diagnosed hypertensive patients and 11 normotensive controls. The two sessions were performed in random order, each study on a separate day. RESULTS: Baseline MSNA was significantly elevated in the hypertensive patients as compared to the controls (38 +/- 2 vs. 28 +/- 2 bursts/min; P < 0.01). Placebo had no significant effect on MSNA, blood pressure, or heart rate in either group. In normotensive individuals, alcohol had no significant effect on blood pressure (SBP increased by 1 +/- 4 mmHg). By contrast, SBP increased after alcohol in hypertensive patients by 24 +/- 6 mmHg (P < 0.001 vs. controls). MSNA increased after alcohol in controls by 83 +/- 34% (P < 0.01 vs. baseline). MSNA did not change significantly after alcohol in hypertensive patients (16 +/- 7%, not significant), despite a profound blood pressure increase, which would be expected to inhibit sympathetic activity. CONCLUSION: Pressor responses to acute alcohol consumption are potentiated in hypertensive patients compared with normotensive controls. Vasoconstrictor sympathetic tone is not suppressed in hypertensive patients after alcohol, despite the enhanced pressor response. Sympathetic neural mechanisms might contribute to both alcohol-related blood pressure increases and cardiovascular events in hypertensive patients. PMID- 21252703 TI - Central versus ambulatory blood pressure in the prediction of all-cause and cardiovascular mortalities. AB - OBJECTIVES: Central systolic (SBP-C) and/or pulse pressure (PP-C) better predicts cardiovascular events than does peripheral blood pressure. The present study compared the prognostic significance of office central blood pressure with multiple measurements of out-of-office ambulatory peripheral blood pressure, with reference to office peripheral systolic (SBP-B) or pulse pressure (PP-B). METHODS: In a community-based population of 1014 healthy participants, SBP-C and PP-C were estimated using carotid tonometry, and 24-h systolic (SBP-24 h) and pulse pressure (PP-24 h) were obtained from 24-h ambulatory blood pressure monitoring. Associations of SBP-B, PP-B, SBP-C, PP-C, SBP-24 h, and PP-24 h with all-cause and cardiovascular mortalities over a median follow-up of 15 years were examined by Cox regression analysis. RESULTS: In multivariate analyses accounting for age, sex, BMI, smoking, fasting plasma glucose, and total cholesterol/high density lipoprotein cholesterol ratio, only PP-C (hazard ratio 1.16, 95% confidence interval 1.01-1.32, per one standard deviation increment) was significantly predictive of all-cause mortality, whereas all but PP-B were significantly predictive of cardiovascular mortality. When SBP-B was simultaneously included in the models, SBP-24 h (2.01, 1.42-2.85) and SBP-C (1.71, 1.21-2.40) remained significantly predictive of cardiovascular mortality. When SBP-C was simultaneously included in the models, SBP-24 h (1.71, 1.16-2.52) remained significantly predictive of cardiovascular mortality. CONCLUSION: Office central blood pressure is more valuable than office peripheral blood pressure in the prediction of all-cause and cardiovascular mortalities. Out-of-office ambulatory peripheral blood pressure (SBP-24 h) may be superior to central blood pressure in the prediction of cardiovascular mortality, but PP-C may better predict all-cause mortality than SBP-24 h or PP-24 h. PMID- 21252704 TI - Deeper total intravenous anesthesia reduced the incidence of early postoperative cognitive dysfunction after microvascular decompression for facial spasm. AB - OBJECTIVE: To investigate whether the depth of total intravenous anesthesia affects postoperative cognitive dysfunction. METHODS: Ninety-six patients with facial spasm who were scheduled to receive microvascular decompression were randomly divided into 2 groups: deeper anesthesia (n = 50) and lighter anesthesia (n = 46). Exclusion criteria included: a history of neurologic or mental disease, serum creatinine in excess of 177 MUmol/L, active liver disease, cardiac dysfunction, pulmonary dysfunction, endocrine disease, metabolic disease, a history of surgery, fewer than 6 years of school, inability to complete neuropsychologic testing, vision dysfunction, and auditory dysfunction. Propofol and sufentanil were used for anesthesia induction and propofol and remifentanil were used for the maintenance of anesthesia. A battery of 9 neuropsychologic was administered preoperatively and 5 days after surgery. A postoperative deficit was defined as a postop decrement to preop score greater than 1 standard deviation on any test. Patients who experienced 2 or more deficits were deemed to have early postoperative cognitive dysfunction. RESULTS: Eighty patients completed both preoperative and postoperative neuropsychologic testing, of which 40 each were in the deeper and lighter anesthesia group. Postoperative early cognitive dysfunction occurred in 4 patients (10%) in the deeper anesthesia group and in 11 patients (27.5%) in the lighter anesthesia group. The incidence of the postoperative cognitive dysfunction was significantly reduced in the deeper anesthesia group compared with the lighter anesthesia group (P < 0.05, chi). CONCLUSION: Deeper total intravenous anesthesia can decrease the incidence of cognitive dysfunction in the early postoperative period. PMID- 21252705 TI - Successful extubation in the operating room after infratentorial craniotomy: the Cleveland Clinic experience. AB - BACKGROUND: There is lack of information in the literature about the rate of successful extubation after infratentorial craniotomy and the risk factors associated with failed extubation. This retrospective analysis assessed the rate of successful extubation after infratentorial craniotomy in a tertiary hospital. METHODS: Only infratentorial craniotomies for tumors, vascular malformations in the brainstem or cerebellum, and fourth ventricle cysts performed in prone position were included. Failed extubation was defined as the need for airway reintubation in the operating room (OR), postanesthesia care unit, or intensive care unit after surgery. Only those patients, in whom the primary reason for reintubation was respiratory failure, deteriorating level of consciousness, or inability to protect the airway were included in the statistical analysis. Prolonged intubation was defined as airway intubation longer than 48 hours from the initial intubation. RESULTS: This is a retrospective study that included perioperative information from 145 adult patients. One hundred and twenty patients (82%) were primarily extubated in the OR and the rest remained intubated (18%). From the latter group, 9 (36%) and 16 (64%) were extubated in the postanesthesia care unit or intensive care unit, respectively. The rate of failed extubation within 24 hours after primary extubation in the OR was 0.83%. Patients not extubated in the OR had a statistically significant higher American Society of Anesthesiologists score, a longer length of surgery, a larger blood loss, and a longer stay in the hospital compared with those who were extubated in the OR. CONCLUSIONS: We conclude that primary extubation in the OR after infratentorial craniotomy is feasible. However, cautions should be taken in patients with poor physical status undergoing vascular surgery and long procedures with potential significant fluid shifts. PMID- 21252706 TI - Serial measurement of static and dynamic cerebrovascular autoregulation after brain injury. AB - BACKGROUND: In patients with neuronal injury, the knowledge of the status of cerebrovascular autoregulation can help to optimize the management of the cerebral perfusion pressure. This study characterizes dynamic and static cerebrovascular autoregulation during the first 7 days after severe traumatic brain injury or intracranial hemorrhage. METHODS: After approval from the IRB, 16 patients were studied. Cerebral blood flow velocity (CBFV) was measured daily for the assessment of dynamic (10 patients) and static (16 patients) cerebrovascular autoregulation in both the middle cerebral arteries using the transcranial Doppler sonography. Dynamic cerebrovascular autoregulation (dAR) was measured using the cuff-deflation method and was expressed by the index of the dAR. The index of the static cerebrovascular autoregulation (sAR) was calculated from changes in the CBFV in relation to drug-induced alterations of the arterial blood pressure. For statistical analyses, t test and mixed effect model were used. RESULTS: Both dAR and sAR after brain injury were impaired in most of the patients. The chronologic sequence of the dAR at the ipsilateral injured hemisphere showed a significant decrease until day 4 followed by an incomplete recovery (P < 0.002). Changes in sAR were similar, however, they did not gain statistical significance. CBFV was lower at day 1-2 after injury in comparison with day 4 to 7 (P < 0.02). CONCLUSION: Daily measured dAR and sAR were impaired after brain injury with a nadir on day 4 and consecutive incomplete recovery over time. PMID- 21252707 TI - Disagreement in bilateral state entropy values in carotid artery disease. PMID- 21252708 TI - Difficult oral intubation in acromegalic patients--a way out. PMID- 21252709 TI - Vertebral artery pseudoaneurysm a complication after attempted internal jugular vein catheterization in a neurosurgical patient. PMID- 21252710 TI - NIBP monitoring as a cause for intraoperative hypotension and postoperative monoparesis in a patient undergoing lumbar laminectomy. PMID- 21252711 TI - Acute renal failure and sepsis after postembolization retroperitoneal hematoma: a case report. PMID- 21252712 TI - False negatives, muscle relaxants, and motor-evoked potentials. PMID- 21252713 TI - Nodal staging in lung cancer: lymph node location or number? PMID- 21252714 TI - You just can't call it lung cancer anymore. PMID- 21252715 TI - The new taxonomy of lung adenocarcinoma stemming from a multidisciplinary integrated approach: novel pathology concepts and perspectives. PMID- 21252717 TI - Circulating DNA is a useful prognostic factor in patients with advanced non-small cell lung cancer. AB - BACKGROUND: Circulating DNA is observed at higher concentrations in patients with lung cancer than in controls. Qualitative and quantitative analysis of circulating DNA is a promising noninvasive tool. Our aim was to prospectively study the association between the catalytic subunit of telomerase (human telomerase reverse transcriptase [hTERT]) in plasma and clinical variables and survival in a large-scale non-small cell lung cancer (NSCLC) study. METHODS: Four hundred forty-six patients with stages IIIB and IV NSCLC with a median follow-up of 9.7 months (range, 0.5-45) were analyzed. Blood samples were collected before therapy start (cisplatin/docetaxel). Quantification of baseline circulating DNA was determined as the amount of free hTERT in plasma, by using real-time quantitative polymerase chain reaction. RESULTS: Patients with hTERT <= 49.8 ng/ml (median value) had a median time to progression (TTP) of 6.3 months compared with 4.9 for hTERT more than 49.8 ng/ml (p = 0.001). Overall survival (OS) was significantly higher (10.9 versus 9.3 months) at lower hTERT levels (p = 0.012). When calculations were done using hTERT as continuous variable, we did not observe independent significant differences. Thus, there is an apparent discrepancy in p values when hTERT is considered as a continuous versus dichotomized variable. There was a tendency to differentiate median hTERT levels with respect to response rates (complete response + partial response: 33.1 versus stable disease + progressive disease: 50.7 ng/ml, p = 0.12), but other clinical variables such as age, gender, performance status, stage, histology, and number of metastatic locations were not associated with hTERT. In multivariate analysis, hTERT was an independent prognostic variable for both TTP (hazard ratio: 1.44, p < 0.001) and OS (hazard ratio: 1.33, p = 0.007). CONCLUSIONS: In advanced NSCLC, high pretreatment circulating hTERT level is an independent poor prognostic marker for TTP and OS. Circulating DNA is a noninvasive marker, which may help to improve the prognostic profile of these patients. PMID- 21252718 TI - Phase II multicenter trial of voreloxin as second-line therapy in chemotherapy sensitive or refractory small cell lung cancer. AB - INTRODUCTION: Voreloxin is an anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, causing double-strand breaks in DNA, irreversible G2 arrest, and rapid onset of apoptosis. Based on preclinical activity of voreloxin in chemoresistant tumors, early phase I clinical activity, and a mechanism of action similar to other topoisomerase II inhibitors such as the anthracyclines and etoposide, this phase II trial was undertaken as second line treatment of small cell lung cancer (SCLC). METHODS: Patients with extensive stage SCLC previously treated with one prior chemotherapy regimen were eligible. Patients with chemotherapy-sensitive or chemotherapy-refractory disease were considered as separate cohorts. Voreloxin (48 mg/m) was administered on the first day of each 21-day cycle for up to six cycles. The primary end point was objective response rate. RESULTS: Fifty-five patients were enrolled including 28 with refractory SCLC and 27 with sensitive SCLC; 47 were evaluable for response. Three patients with sensitive SCLC had an objective response, including one complete response and two partial responses (11% response rate based on intent to treat). No patients in the refractory cohort had a response. The primary grade 3 toxicity was neutropenia. CONCLUSION: Voreloxin has minimal activity in relapsed SCLC when administered at 48 mg/m in a 3-week schedule. PMID- 21252719 TI - The epidermal growth factor receptor-L861Q mutation increases kinase activity without leading to enhanced sensitivity toward epidermal growth factor receptor kinase inhibitors. AB - INTRODUCTION: Mutations in the epidermal growth factor receptor (EGFR) kinase domain such as EGFR-L858R and EGFR-G719S have been reported to activate the kinase and also sensitize a subset of patients with non-small cell lung cancer to EGFR kinase inhibitor treatment. Nevertheless, for other common point mutations such as EGFR-L861Q, it is unclear whether and to what extent they sensitize toward gefitinib and erlotinib. Thus far, there is no reliable cellular assay to compare in a ligand-independent manner intrinsic kinase activity and drug sensitivity of the unmutated (wild type) and mutated EGFR kinase domain. METHODS: To overcome this obstacle, we introduced L858R, G719S, and L861Q into the backbone of EGFRvIII. EGFRvIII has a wild type-kinase domain but is activated in a ligand-independent manner through a deletion in the extracellular domain. RESULTS: Using this tool, we show that the L861Q mutation displays enhanced kinase activity and transforming potential compared with L858R, G719S, and also to the wild type-EGFR kinase domain. Interestingly, L861Q does not increase drug sensitivity toward clinically used EGFR kinase inhibitors in contrast to the L858R and G719S mutation. In addition, we demonstrate that EGFR-L861Q could be effectively inhibited with the irreversible second-generation EGFR inhibitor WZ 4002. CONCLUSIONS: Thus, in the common EGFR-L861Q mutation, activation of the kinase domain is uncoupled from a sensitizing effect toward clinically approved kinase inhibitors. Therefore, patients with EGFR-L861Q may not have the same clinical benefit from gefitinib/erlotinib treatment as patients with EGFR-L858R and EGFR-G719S mutations. Treatment with irreversible second-generation kinase inhibitors such as WZ-4002 may be an attractive option in the future for patients with EGFR-L861Q. PMID- 21252720 TI - Giant desmoid tumor of the chest wall. PMID- 21252721 TI - Inherited germline T790M mutation and somatic epidermal growth factor receptor mutations in non-small cell lung cancer patients. PMID- 21252722 TI - Dramatic response to pemetrexed in a patient with pneumonic-type mucinous bronchioloalveolar carcinoma. PMID- 21252723 TI - Does the addition of vascular endothelial growth factor inhibitors to epidermal growth factor receptor-tyrosine kinase inhibitor overcome T790M acquired resistance? PMID- 21252724 TI - Histologic type definition in clinical trials on advanced non-small cell lung cancer. PMID- 21252725 TI - Complement and correction for meta-analysis of patients with extensive-stage small cell lung cancer managed with irinotecan/cisplatin versus etoposide/cisplatin as first-line chemotherapy. PMID- 21252716 TI - International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. AB - INTRODUCTION: Adenocarcinoma is the most common histologic type of lung cancer. To address advances in oncology, molecular biology, pathology, radiology, and surgery of lung adenocarcinoma, an international multidisciplinary classification was sponsored by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification is needed to provide uniform terminology and diagnostic criteria, especially for bronchioloalveolar carcinoma (BAC), the overall approach to small nonresection cancer specimens, and for multidisciplinary strategic management of tissue for molecular and immunohistochemical studies. METHODS: An international core panel of experts representing all three societies was formed with oncologists/pulmonologists, pathologists, radiologists, molecular biologists, and thoracic surgeons. A systematic review was performed under the guidance of the American Thoracic Society Documents Development and Implementation Committee. The search strategy identified 11,368 citations of which 312 articles met specified eligibility criteria and were retrieved for full text review. A series of meetings were held to discuss the development of the new classification, to develop the recommendations, and to write the current document. Recommendations for key questions were graded by strength and quality of the evidence according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. RESULTS: The classification addresses both resection specimens, and small biopsies and cytology. The terms BAC and mixed subtype adenocarcinoma are no longer used. For resection specimens, new concepts are introduced such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) for small solitary adenocarcinomas with either pure lepidic growth (AIS) or predominant lepidic growth with <= 5 mm invasion (MIA) to define patients who, if they undergo complete resection, will have 100% or near 100% disease-specific survival, respectively. AIS and MIA are usually nonmucinous but rarely may be mucinous. Invasive adenocarcinomas are classified by predominant pattern after using comprehensive histologic subtyping with lepidic (formerly most mixed subtype tumors with nonmucinous BAC), acinar, papillary, and solid patterns; micropapillary is added as a new histologic subtype. Variants include invasive mucinous adenocarcinoma (formerly mucinous BAC), colloid, fetal, and enteric adenocarcinoma. This classification provides guidance for small biopsies and cytology specimens, as approximately 70% of lung cancers are diagnosed in such samples. Non-small cell lung carcinomas (NSCLCs), in patients with advanced-stage disease, are to be classified into more specific types such as adenocarcinoma or squamous cell carcinoma, whenever possible for several reasons: (1) adenocarcinoma or NSCLC not otherwise specified should be tested for epidermal growth factor receptor (EGFR) mutations as the presence of these mutations is predictive of responsiveness to EGFR tyrosine kinase inhibitors, (2) adenocarcinoma histology is a strong predictor for improved outcome with pemetrexed therapy compared with squamous cell carcinoma, and (3) potential life threatening hemorrhage may occur in patients with squamous cell carcinoma who receive bevacizumab. If the tumor cannot be classified based on light microscopy alone, special studies such as immunohistochemistry and/or mucin stains should be applied to classify the tumor further. Use of the term NSCLC not otherwise specified should be minimized. CONCLUSIONS: This new classification strategy is based on a multidisciplinary approach to diagnosis of lung adenocarcinoma that incorporates clinical, molecular, radiologic, and surgical issues, but it is primarily based on histology. This classification is intended to support clinical practice, and research investigation and clinical trials. As EGFR mutation is a validated predictive marker for response and progression-free survival with EGFR tyrosine kinase inhibitors in advanced lung adenocarcinoma, we recommend that patients with advanced adenocarcinomas be tested for EGFR mutation. This has implications for strategic management of tissue, particularly for small biopsies and cytology samples, to maximize high-quality tissue available for molecular studies. Potential impact for tumor, node, and metastasis staging include adjustment of the size T factor according to only the invasive component (1) pathologically in invasive tumors with lepidic areas or (2) radiologically by measuring the solid component of part-solid nodules. PMID- 21252727 TI - Contribution of adiponectin to the cardiometabolic risk of postmenopausal women with loss-of-function lipoprotein lipase gene mutations. AB - OBJECTIVE: Cardiovascular risk significantly increases after menopause. Lipoprotein lipase (LPL) is a key enzyme in the metabolism of triglyceride (TG) rich lipoproteins, which contributes to cardiometabolic homeostasis. Adiponectin is an adipocytokine, which also influences the cardiometabolic status. The objective of this study was to evaluate the contribution of plasma adiponectin to the cardiometabolic status of women with loss-of-function LPL gene variants (LPLD). METHODS: A total of 568 white women (127 women with partial LPL deficiency and 441 controls) were included. The association of plasma adiponectin with LPLD was assessed using multiple regression models. Cardiometabolic covariates included anthropometrics, lipids (TG, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B), fasting glucose, and smoking status. RESULTS: Plasma adiponectin concentration was significantly lower in women with LPLD (8.69 +/- 5.13 vs 6.50 +/- 4.66 MUg/mL; P < 0.001). Women with LPLD also presented a significantly higher risk of coronary artery disease (P = 0.013). After menopause, adiponectin explained a significant (P < 0.01) proportion of the variance in cardiometabolic covariates in both groups. This effect was more pronounced in women with LPLD: 13% versus 8% for high-density lipoprotein cholesterol, 8% versus 4% for waist circumference, 9% versus 5% for fasting TG, and 6% versus 2% for fasting glucose. When controlling for cardiometabolic covariates, low adiponectin values independently contributed to the clinical expression of LPLD in postmenopausal women (odds ratio, 5.55; 95% CI, 0.04-0.81; P = 0.025). CONCLUSIONS: In conclusion, these results suggest that a low plasma adiponectin level significantly contributes to the cardiometabolic risk profile of postmenopausal women with LPLD, independently of anthropometrics, lipids, and other covariates. PMID- 21252728 TI - Natural S-equol decreases bone resorption in postmenopausal, non-equol-producing Japanese women: a pilot randomized, placebo-controlled trial. AB - OBJECTIVE: Equol is a metabolite of the isoflavone daidzein and may play a critical role in preventing bone loss by soy isoflavones in postmenopausal women. However, results from clinical trials have not been published. The aim of this study was to investigate the effects of equol on bone metabolism and serum sex and thyroid hormone levels in postmenopausal Japanese women. METHODS: We performed a 1-year double-blind, randomized, placebo-controlled trial with natural S-equol supplements for 93 non-equol-producing menopausal Japanese women. Participants were randomly assigned to four groups receiving the following: placebo, 2 mg of equol supplement per day, 6 mg of equol supplement per day, and 10 mg of equol supplement per day. RESULTS: Equol intervention increased equol concentrations in serum and urine in a dose-dependent manner. Urinary deoxypyridinoline was significantly decreased, with a -23.94% change in the group that received 10 mg of equol supplement per day as compared with a -2.87% change in the group that received placebo after 12 months of intervention (P = 0.020). Thus, 10 mg/day of equol supplement markedly inhibited bone resorption. Treatment with 10 mg/day of equol prevented a decrease in bone mineral density in the entire body in postmenopausal women after 12 months. Sex and thyroid hormone concentrations in serum did not differ among the four groups after intervention. CONCLUSIONS: These findings suggest that 10 mg/day of natural S-equol supplementation contributes to bone health in non-equol-producing postmenopausal women without adverse effects. PMID- 21252730 TI - Increasing the placental transfusion for preterm infants. PMID- 21252731 TI - Milking compared with delayed cord clamping to increase placental transfusion in preterm neonates: a randomized controlled trial. AB - OBJECTIVE: To compare two strategies to enhance placento-fetal blood transfusion in preterm neonates before 33 weeks of gestation. METHODS: We recruited women at risk for singleton preterm deliveries. All delivered before 33 completed weeks of gestation. In this single-center trial, women were randomized to either standard treatment (clamping the cord for 30 seconds after delivery) or repeated (four times) milking of the cord toward the neonate. Exclusion criteria included inadequate time to obtain consent before delivery, known congenital abnormalities of the fetus, Rhesus sensitization, or fetal hydrops. RESULTS: Of 58 neonates included the trial, 31 were randomized to cord clamping and 27 were randomized to repeated milking of the cord. Mean birth weight was 1,263+/-428 g in the clamping group and 1,235+/-468 g in the milking group, with mean gestational age of 29.2+/ 2.3 weeks and 29.5+/-2.7 weeks, respectively. Mean hemoglobin values for each group at 1 hour after birth were 17.3 g/L for clamping and 17.5 g/L for milking (P=.71). There was no significant difference in number of neonates undergoing transfusion (clamping group, 15; milking group, 17; P=.40) or the median number of transfusions within the first 42 days of life (median [range]: clamping group 0 [0-7]; milking group 0 [0-20]; P=.76). CONCLUSION: Milking the cord four times achieved a similar amount of placento-fetal blood transfusion compared with delaying clamping the cord for 30 seconds. CLINICAL TRIAL REGISTRATION: National Research Register UK, www.nihr.ac.uk/Pages/default.aspx, N0051177741. LEVEL OF EVIDENCE: I. PMID- 21252729 TI - The evolutionary origin and significance of menopause. AB - Contemporary women have long life expectancy (81 y, United States), especially relative to the age at menopause (51 y, United States). Menopause is a consequence of reproductive aging and follicular depletion (ovarian failure), yielding very low circulating estrogen serum concentrations and biologically disadvantageous metabolic alterations. Stated in terms of antagonistic pleiotropy, the ongoing hypoestrogenic endocrine environment, beneficial during lactation, results in acceleration of several age-related illnesses after menopause (ie, late postmenopausal osteoporosis, cardiovascular disease, and cognitive decline). Specifically, the similar hypoestrogenic hormonal milieu present during postpartum lactation provides biologic advantages (fitness) to both mother and newborn. These precepts of evolutionary medicine encourage a reassessment of hormone therapy, and on the basis of data presented the authors propose additional opportunities for disease prevention and morbidity reduction in postmenopausal women. PMID- 21252732 TI - Alcohol consumption during pregnancy: prevalence and provider assessment. AB - OBJECTIVE: To estimate the prevalence of prenatal alcohol consumption and the extent of provider screening and discussion about alcohol use during pregnancy. METHODS: Data were obtained from a stratified random sample of 12,611 mothers from Maryland who delivered live infants during the years 2001-2008 and completed the Maryland Pregnancy Risk Assessment Monitoring System survey. Analyses were conducted using Proc Surveyfreq in SAS 9.2. RESULTS: Nearly 8% (95% confidence interval 7.1-8.4) of mothers from Maryland reported alcohol consumption during the last 3 months of pregnancy. The highest prevalence of late-pregnancy alcohol consumption was reported by mothers who were non-Hispanic white, (10.9%, confidence interval 9.8-11.9), aged 35 years or older (13.4%, confidence interval 12.4-14.4), and college graduates (11.4%, confidence interval 10.2-12.6) (P<.001). Nineteen percent (confidence interval 17.6-21.0) of mothers reported that their prenatal care provider did not ask whether they were drinking alcoholic beverages, and 30% (confidence interval 28.3-30.8) reported that a healthcare provider did not counsel them about the consequences of alcohol use on the child. Reported screening and counseling were least prevalent among mothers who were non-Hispanic white, aged 35 years or older, and college graduates (P<.01). CONCLUSION: Despite the substantial number of women who continue to drink alcohol during pregnancy, healthcare providers do not routinely assess alcohol consumption or counsel all women about its harmful effects. Counseling was least prevalent among the same groups of women with the highest rates for drinking. Provider alcohol assessment, as recommended by the U.S. Surgeon General to prevent alcohol misuse, needs further promotion as a routine part of prenatal care. LEVEL OF EVIDENCE: III. PMID- 21252733 TI - Prior preterm or small-for-gestational-age birth related to maternal metabolic syndrome. AB - OBJECTIVE: To estimate whether women who deliver small babies due to preterm birth or growth restriction have excess risk for cardiovascular disease and diabetes later in life. METHODS: Eight years after pregnancy, we estimated the prevalence of metabolic syndrome and its components in a cohort study of women with prior preterm (preterm birth before 37 weeks, n=181) or small for gestational age ([SGA], less than the tenth percentile, n=192) births, compared with women with term births (37 or more weeks, n=306). Women delivered at Magee Womens Hospital in Pittsburgh, Pennsylvania, and those with preeclampsia or prepregnancy diabetes or hypertension were excluded. Women underwent a structured interview and fasting blood sampling. RESULTS: Women were, on average, 8 years postpartum and 39 years old at evaluation. Women with a prior preterm birth had higher blood pressure, triglycerides, and LDL-cholesterol compared with those in a term control group. Women with prior SGA births were leaner and more likely to smoke compared with those with term births. Women with prior preterm birth had elevated risk of metabolic syndrome, adjusted for demographic, smoking and body size factors (23% preterm compared with 17% control group; odds ratio [OR] 1.76 [1.06, 2.80]). In women with a prior preterm birth, low HDL (11% preterm compared with 5% control group; OR 2.6 [1.2, 5.2]), hypertriglyceridemia (22% compared with 14%; OR 1.9 [1.2, 2.9]), and elevated glucose (24% compared with 19%; OR 1.5 [1.0, 2.3]) accounted for this excess metabolic syndrome. In women with SGA, the only element of metabolic syndrome that was aberrant was glucose metabolism. CONCLUSION: Eight years after pregnancy, women with prior preterm or SGA births had evidence of metabolic syndrome compared with women with term births. Screening and intervention in these women after pregnancy may delay or prevent disease. LEVEL OF EVIDENCE: : II. PMID- 21252734 TI - The association of breast arterial calcification and coronary heart disease. AB - OBJECTIVE: To estimate whether mammography can be an early, valid tool for predicting the development of coronary heart disease (CHD) in women. METHODS: Women presenting for routine mammograms between June and August 2004 were recruited for the study. Baseline data collected included risk factors and family history of heart disease, as well as any cardiac events experienced by the patient. Similar follow-up data were collected during subsequent years, and these patient-completed surveys were correlated with the baseline mammograms screened for breast arterial calcifications. RESULTS: Throughout the 5-year follow-up, CHD was present in 20.8% of women who screened positive for breast arterial calcification and in 5.4% of who screened negative for breast arterial calcification (P<.001). Among women who did not have CHD at baseline, breast arterial calcification-positive women were more likely to develop CHD or a stroke than those who were breast arterial calcification-negative (6.3% compared with 2.3%, P=.003; and 58.3% compared with 13.3%, P<.001), respectively. These results remained significant even when controlling for age. CONCLUSION: The presence of breast arterial calcifications on mammograms indicates a significantly increased risk of developing CHD or a stroke. These results suggest that breast arterial calcifications should be routinely reported on mammograms and viewed as a marker for the development of CHD. LEVEL OF EVIDENCE: II. PMID- 21252735 TI - Trocar-guided mesh compared with conventional vaginal repair in recurrent prolapse: a randomized controlled trial. AB - OBJECTIVE: To compare efficacy and safety of trocar-guided tension-free vaginal mesh insertion with conventional vaginal prolapse repair in patients with recurrent pelvic organ prolapse. METHODS: Patients with recurrent pelvic organ prolapse stage II or higher were randomly assigned to either conventional vaginal prolapse surgery or polypropylene mesh insertion. Primary outcome was anatomic failure (pelvic organ prolapse stage II or higher) in the treated vaginal compartments. Secondary outcomes were subjective improvement, effects on bother, quality of life, and adverse events. Questionnaires such as the Incontinence Impact Questionnaire and Urogenital Distress Inventory were administered at baseline, 6 months, and 12 months. Anatomic outcomes were assessed by an unblinded surgeon. Power calculation with alpha=0.05 and beta=0.80 indicated that 194 patients were needed. RESULTS: Ninety-seven women underwent conventional repair and 93 mesh repair. The follow-up rate after 12 months was 186 of 190 patients (98%). Twelve months postsurgery, anatomic failure in the treated compartment was observed in 38 of 84 patients (45.2%) in the conventional group and in eight of 83 patients (9.6%) in the mesh group (P<.001; odds ratio, 7.7; 95% confidence interval, 3.3-18). Patients in either group reported less bulge and overactive bladder symptoms. Subjective improvement was reported by 64 of 80 patients (80%) in the conventional group compared with 63 of 78 patients (81%) in the mesh group. Mesh exposure was detected in 14 of 83 patients (16.9%). CONCLUSION: At 12 months, the number of anatomic failures observed after tension free vaginal mesh insertion was less than after conventional vaginal prolapse repair. Symptom decrease and improvement of quality of life were equal in both groups. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00372190. LEVEL OF EVIDENCE: I. PMID- 21252736 TI - Nongenetic factors associated with stress urinary incontinence. AB - OBJECTIVE: To explore the role of hereditary and environmental factors on the development of stress urinary incontinence in a large cohort of identical and nonidentical twins. METHODS: This is a large, population-based, classic twin study of twin sisters recruited to complete a health survey at the world's largest annual twins festival during 2003-2008. Concordance rates were calculated and structural equation models were used to estimate the contribution of genetic effects compared with environmental factors toward the development of stress urinary incontinence. RESULTS: Eight hundred eighty-two twin sister pairs (n=1,764), including 765 identical and 117 nonidentical twin sister pairs, completed the questionnaires. Sequential structural equation modeling revealed that common environmental factors contributed 77.6% (95% confidence interval [CI], 41.4-83.8; P<.001) of the variance and unique environmental factors contributed 20.9% (95% CI, 15.8-26.7; P<.001) of the variance. The effect of genetics was not statistically significant at 1.49% (95% CI, 0.0-38.8; P=.46). CONCLUSION: Female stress urinary incontinence is more a consequence of environmental risk factors than heredity. This epidemiologic insight should be considered in preventive health efforts. LEVEL OF EVIDENCE: II. PMID- 21252737 TI - Robotic-assisted, laparoscopic, and abdominal myomectomy: a comparison of surgical outcomes. AB - OBJECTIVE: To compare the surgical outcomes of robot-assisted laparoscopic myomectomy (robot-assisted), standard laparoscopic myomectomy (laparoscopic), and open myomectomy (abdominal). METHODS: Myomectomy patients were identified from the case records of the Cleveland Clinic and stratified into three groups. Operative and immediate postoperative outcomes were compared. Data analysis was performed using analysis of variance, Kruskal-Wallis analysis of ranks, chi2, and Fisher exact tests where appropriate. RESULTS: From a total of 575 myomectomies, 393 (68.3%) were abdominal, 93 (16.2%) were laparoscopic, and 89 (15.5%) were robot-assisted. The three groups were comparable regarding the size, number, and location. Significantly heavier myomas were removed in the robot-assisted group (223 [85.25, 391.50] g) compared with the laparoscopic group (96.65 [49.50, 227.25] g, P<.001) and were lower than in the abdominal group (263 [ 90.50, 449.00] g, P=.002). Higher blood loss was reported in the abdominal group compared with the other two groups, with a median (interquartile range) of blood loss in milliliters of 100 (50, 212.50), 200 (100, 437.50) and 150 (100, 200) in the laparoscopic, abdominal, and robot-assisted groups, respectively. The actual surgical time in minutes was 126 (95, 177) in the abdominal group, 155 (98, 200) in the laparoscopic group, and 181 (151, 265) in robot-assisted group (P<.001). Patients in the abdominal group had a higher median length of hospital stay of 3 (2, 3) days, compared with 1 (0, 1) day in the laparoscopic group and 1 (1, 1) days in the robot-assisted group (P<.001). CONCLUSION: Robotic-assisted myomectomy is associated with decreased blood loss and length of hospital stay compared with traditional laparoscopy and to open myomectomy. Robotic technology could improve the utilization of the laparoscopic approach for the surgical management of symptomatic myomas. LEVEL OF EVIDENCE: II. PMID- 21252739 TI - The singleton, cephalic, nulliparous woman after 36 weeks of gestation: contribution to overall cesarean delivery rates. AB - OBJECTIVE: To examine the contribution of singleton, cephalic, term (37 weeks or later) nulliparous cesarean rates to overall cesarean incidence in a single institution during a 35-year period. METHODS: Cesarean rates were examined for 1974, 1984, 1994, 1999, 2005, and 2008, applying a 10-group classification system. Groups 1 (spontaneously laboring, term nulliparous women) and 2 (prelabor cesarean and induced term nulliparous women) were combined as a composite variable-the term, singleton, cephalic nulliparous woman. RESULTS: Overall and term, singleton, cephalic nulliparous cesarean rates correlated throughout the 35 year period (r=0.93, P<.001). Between 1974 and 2008, overall cesarean rates increased from 5% to 19.1% and from 4.4% to 15.8% among term, singleton, cephalic nulliparous women. Term, singleton, cephalic nulliparous inductions increased from 19.7% to 32.7% (P<.001) and the intrapartum cesarean rate in term, singleton, cephalic nulliparous inductions rose from 4.1% to 27.3%. The cesarean rate in group 1 increased from 2.3% to 7.2%. CONCLUSION: The increase in term, singleton, cephalic nulliparous cesarean rates correlated with the increase in overall cesarean rates throughout 35 years in an institution with standard management of labor. This relationship was due to an increase in both the incidence and rate of cesarean delivery within term, singleton, cephalic nulliparous inductions. Examination of the different term, singleton, cephalic nullipara components (spontaneous labor, induction, or prelabor cesarean) can help to identify major variations in practice between institutions. LEVEL OF EVIDENCE: III. PMID- 21252738 TI - Failed labor induction: toward an objective diagnosis. AB - OBJECTIVE: To evaluate maternal and perinatal outcomes in women undergoing labor induction with an unfavorable cervix according to duration of oxytocin administration in the latent phase of labor after ruptured membranes. METHODS: This was a secondary analysis of a randomized multicenter trial in which all cervical examinations from admission were recorded. INCLUSION CRITERIA: nulliparas at or beyond 36 weeks of gestation undergoing induction with a cervix of 2 cm or less dilated and less than completely effaced. The latent phase of labor was defined as ending at a cervical dilation of 4 cm and effacement of at least 90%, or at a cervical dilation of 5 cm regardless of effacement. RESULTS: A total of 1,347 women were analyzed. The overall vaginal delivery rate was 63.2%. Most women had exited the latent phase after 6 hours of oxytocin and membrane rupture (n=939; 69.7%); only 5% remained in the latent phase after 12 hours. The longer the latent phase, the lower the vaginal delivery rate. Even so, 39.4% of the 71 women who remained in the latent phase after 12 hours of oxytocin and membrane rupture were delivered vaginally. Chorioamnionitis, endometritis, or both, and uterine atony were the only maternal adverse outcomes related to latent phase duration: adjusted odds ratios (95% confidence intervals) of 1.12 (1.07, 1.17) and 1.13 (1.06, 1.19), respectively, for each additional hour. Neonatal outcomes were not related to latent-phase duration. CONCLUSION: Almost 40% of the women who remained in the latent phase after 12 hours of oxytocin and membrane rupture were delivered vaginally. Therefore, it is reasonable to avoid deeming labor induction a failure in the latent phase until oxytocin has been administered for at least 12 hours after membrane rupture. LEVEL OF EVIDENCE: III. PMID- 21252741 TI - Thyroperoxidase and thyroglobulin antibodies in early pregnancy and placental abruption. AB - OBJECTIVE: To estimate the relationship between thyroid antibodies and placental abruption. METHODS: This cohort study assesses thyroperoxidase and thyroglobulin antibodies in relation to placental abruption among 10,062 women with singleton viable pregnancies (from the First and Second Trimester Risk of Aneuploidy [FaSTER] trial). A thyroperoxidase antibody cutoff of 50 international units/mL is used for comparison with published data from another cohort. RESULTS: Women with elevated thyroperoxidase antibody levels in the first and second trimesters have a higher rate of placental abruption than antibody-negative women. This relationship is less strong in the first trimester (1.51% compared with 0.83%; odds ratio [OR], 1.83; 95% confidence interval [CI], 0.99-3.37) than in the second trimester (1.78% compared with 0.82%; OR, 2.20; 95% CI, 1.21-3.99). A similar, but weaker, relationship is present for thyroglobulin antibodies. Sixty four of 782 thyroperoxidase antibody-positive pregnancies without abruption become negative by the second trimester; one pregnancy with abruption becomes antibody-positive. Odds ratios for pregnancies with both thyroperoxidase and thyroglobulin antibody elevations are also higher (first trimester: OR, 2.10; 95% CI, 0.91-4.86; second trimester: OR, 2.73; 95% CI, 1.17-6.33). CONCLUSION: The present data confirm an association between thyroid antibody elevations and placental abruption described in a recent report. These findings, however, do not provide support for recommending routine testing for thyroid antibodies during pregnancy. LEVEL OF EVIDENCE: II. PMID- 21252740 TI - Timing of elective repeat cesarean delivery at term and maternal perioperative outcomes. AB - OBJECTIVE: Elective repeat cesarean delivery at 37 or 38 weeks compared with 39 completed weeks of gestation is associated with adverse neonatal outcomes. We assessed whether delivery before 39 weeks is justifiable on the basis of decreased adverse maternal outcomes. METHODS: We conducted a cohort study of women with live singleton pregnancies delivered by prelabor elective repeat cesarean delivery from 1999 through 2002 at 19 U.S. academic centers. Gestational age was examined by completed weeks (eg, 37 completed weeks=37 0/7-37 6/7 weeks). Maternal outcomes included a primary composite of death, hysterectomy, uterine rupture or dehiscence, blood transfusion, uterine atony, thromboembolic complications, anesthetic complications, surgical injury or need for arterial ligation, intensive care unit admission, wound complications, or endometritis. RESULTS: Of 13,258 elective repeat cesareans performed at 37 weeks of gestation or later, 11,255 (84.9%) were between 37 0/7 and 39 6/7 weeks (6.3% at 37, 29.5% at 38, and 49.1% at 39 completed weeks), and 15.1% were at 40 0/7 weeks or more. The primary outcome occurred in 7.43% at 37 weeks, 7.47% at 38 weeks and 6.56% at 39 weeks (P for trend test=.09). Delivery before 39 weeks was not associated with a decrease in the primary outcome when compared with delivery at 39 weeks (adjusted odds ratio 1.16; 95% confidence interval 1.00-1.34). Early delivery was associated with increased maternal hospitalization of 5 days or more [1.96 (1.54, 2.49)] but not with a composite of death or hysterectomy or with individual maternal morbidities. CONCLUSION: Elective repeat cesarean delivery at 37 or 38 weeks is not associated with decreased maternal morbidity. LEVEL OF EVIDENCE: II. PMID- 21252742 TI - Maternal thyroid function at 11-13 weeks of gestation and spontaneous preterm delivery. AB - OBJECTIVE: To estimate the possible association between spontaneous early preterm delivery and maternal thyroid dysfunction in early pregnancy. METHODS: Maternal serum concentrations of thyroid-stimulating hormone (TSH), free thyroxine, antithyroperoxidase, and antithyroglobulin antibodies at 11-13 weeks of gestation were compared in 102 singleton pregnancies, resulting in spontaneous delivery before 34 weeks and 4,318 normal pregnancies delivering after this gestation. RESULTS: In the preterm delivery group, compared with the normal outcome group, there was no significant difference in antithyroid antibody positivity (16.7% compared with 16.8%). In the antithyroid antibody-negative pregnancies in the preterm delivery group, compared with the normal outcome group, the median free thyroxine multiple of the median was reduced (0.94 compared with 0.99 multiple of the median, P<.001), but the median TSH multiple of the median was not significantly different (0.99 compared with 1.01 multiple of the median, P=.331). CONCLUSION: In pregnancies resulting in spontaneous early preterm delivery, there is no evidence of increased prevalence of antithyroid antibody positivity or maternal thyroid dysfunction at 11-13 weeks. LEVEL OF EVIDENCE: II. PMID- 21252743 TI - Clinical factors affecting the accuracy of ultrasonography in symptomatic first trimester pregnancy. AB - OBJECTIVE: To evaluate factors associated with accuracy of initial ultrasonography in patients with symptomatic first-trimester pregnancy. METHODS: Ultrasound diagnosis in the emergency department was compared with an ultimate clinical diagnosis in women in need of a gynecologic consult. The sensitivity, specificity, positive predictive values, and accuracy of the initial ultrasound impression were calculated and stratified by criteria of diagnosis, serum human chorionic gonadotropin (hCG) levels, pain, and bleeding. RESULTS: Eighteen hundred eighty women were evaluated. Overall accuracy of initial ultrasound diagnosis was 78%. A probable ultrasound diagnosis of ectopic pregnancy (adnexal mass without the presence of a yolk sac or embryo) resulted in a higher sensitivity (42.1% compared with 13.2%: P<.001) but a lower positive predictive value (82.7% compared with 98%: P<.01) compared with a definite diagnosis. A probable ultrasound diagnosis of intrauterine pregnancy (double decidual sign without yolk sac or embryo) resulted in a higher sensitivity (36.0% compared with 4.0%; P<.001) and lower positive predictive value (58.8% compared with 87.0%; P>.001) compared with a definite diagnosis. The sensitivity (34.3% compared with 75.9%; P<.01) and positive predictive value (80.4% compared with 91.5%; P=.02) were lower for diagnosis of ectopic pregnancy when serum hCG level was less than 2,000 milli-international units/mL. Ultrasonography was less accurate when bleeding was the chief complaint (72.7% compared with 84.8% P<.006) but not substantially altered by pain as a chief complaint (78.0 compared with 77.8% P>.99). CONCLUSION: A substantial number of misdiagnoses can occur when initial ultrasound diagnosis of intrauterine pregnancy or ectopic pregnancy is made without evidence of a yolk sac or embryo, when hCG values are low, or when a patient has significant bleeding. LEVEL OF EVIDENCE: II. PMID- 21252744 TI - Uterine evacuation for second-trimester fetal death and maternal morbidity. AB - OBJECTIVE: To estimate maternal morbidity associated with uterine evacuation for second-trimester fetal demise compared with that associated with induced second trimester abortion. METHODS: This retrospective cohort study compared the maternal outcomes of two cohorts: 1) women diagnosed with fetal demise between 14 and 24 weeks who subsequently underwent dilation and evacuation or induction of labor; and 2) women undergoing induced abortion between 14 and 24 weeks by either dilation and evacuation or induction of labor. The primary outcome was major maternal morbidity. Assuming morbidity rates of 11% for fetal demise and 1% for induced second-trimester abortion, 94 patients were needed per group to detect significant difference in maternal morbidity (80% power, 5% alpha). RESULTS: We identified 121 women with fetal demise and 121 women who underwent induced abortion for inclusion. There were no maternal deaths. In crude and adjusted analyses, treatment for fetal demise was not associated with increased maternal morbidity (25 of 121) compared with induced abortion (27 of 121) (adjusted odds ratio [OR], 1.15; 95% confidence interval [CI], 0.57-2.32). There were more blood transfusions in the fetal demise group (N=7) compared with the induced-abortion group (N=1) (P=.07). Induction of labor was more morbid than dilation and evacuation after adjusting for confounders (OR 5.36; 95% CI 2.46-11.69), primarily as a result of increased odds of infection requiring intravenous antibiotics. Gestational age of 20 weeks or greater was significantly associated with maternal morbidity (OR 2.59; 95% CI 1.39-4.84). CONCLUSION: In the second trimester, uterine evacuation for fetal demise was not significantly associated with maternal morbidity compared with induced abortion. Induction of labor was more morbid than dilation and evacuation as a result of an increased risk of presumed infection. LEVEL OF EVIDENCE: II. PMID- 21252745 TI - Misoprostol with or without letrozole pretreatment for termination of pregnancy: a randomized controlled trial. AB - OBJECTIVE: To compare the success rate and side effects of letrozole and misoprostol versus misoprostol alone for medical termination of early pregnancy. METHODS: Patients requesting termination of pregnancy up to 63 days of gestation were randomized into two groups. The letrozole group received letrozole 10 mg daily for 3 days followed by 800 micrograms of vaginal misoprostol, while the placebo group received placebo for 3 days followed by the same dosage of misoprostol. The complete abortion rate and the side effects profiles of the two groups were compared. The primary outcome measure was the complete abortion rate. RESULTS: A total of 168 women were recruited. The complete abortion rate of the letrozole group was significantly higher than that of the placebo group (86.9% compared with 72.6%, relative risk [RR] 1.20, 95% confidence interval [CI] 1.03 1.40). The complete abortion rate in gestations up to 49 days was significantly higher in the letrozole group than in the placebo group (93.3% compared with 78.7%, RR 1.19, 95% CI 1.002-1.40), while the corresponding rates for gestation between 50 and 63 days were not significantly different between the two groups. There were significantly fewer women complaining of vomiting in the letrozole group than those in the placebo group (8.3% compared with 19.0%, P=.043, RR 2.29, 95% CI 1.005-5.27). CONCLUSION: The use of letrozole and misoprostol is associated with a higher complete abortion rate. CLINICAL TRIAL REGISTRATION: HKClinicalTrials.com, http://www.hkclinicaltrials.com, HKCTR-349. LEVEL OF EVIDENCE: I. PMID- 21252746 TI - Resident experience on reproductive endocrinology and infertility rotations and perceived knowledge. AB - OBJECTIVE: To estimate the extent to which duration and quality of reproductive endocrinology rotations are associated with residents' knowledge of reproductive endocrinology and infertility. METHODS: An anonymous, multiple-choice survey was provided to 4,744 examinees during the 2008 Council on Resident Education in Obstetrics and Gynecology In-Training Examination. The survey queried residents' experiences on their reproductive endocrinology and infertility rotation, satisfaction with the quality and duration of the rotation, and knowledge of reproductive endocrinology and infertility. Binomial regression was used to estimate the relationship between components of the reproductive endocrinology and infertility rotation and self-reported knowledge of reproductive endocrinology and infertility. RESULTS: Forty percent of residents described their knowledge of reproductive endocrinology and infertility as poor. Fewer weeks dedicated to reproductive endocrinology and infertility increased the risk of poor knowledge (P<.001). Required vacation during the rotation and non reproductive endocrinology and infertility coverage more than two times a week was associated with a 40% increase in risk of perceived poor knowledge (relative risk [RR] 1.38, 95% confidence interval [CI]): 1.20-1.60; and RR 1.40, 95% CI: 1.16-1.70, respectively), while 3 hours of didactics per week were associated with a 61% reduction in risk (RR 0.39, 95% CI: 0.31-0.50). CONCLUSION: A number of residents perceive their knowledge of reproductive endocrinology and infertility to be poor. Conflicting commitments during the reproductive endocrinology rotation results in both lower satisfaction and less knowledge. There is the potential to improve resident knowledge of reproductive endocrinology and infertility, and perhaps other aspects of obstetrics and gynecology training, with focused rotations, including didactics. LEVEL OF EVIDENCE: II. PMID- 21252747 TI - Clinical significance of borderline amniotic fluid index and oligohydramnios in preterm pregnancy. AB - OBJECTIVE: To estimate pregnancy and neonatal outcomes in women with decreased amniotic fluid index (AFI) between 24 and 34 weeks of gestation, compared with outcomes in those with normal AFI. METHODS: This is a review of singleton pregnancies that received ultrasound examinations at 24-34 weeks from 1997 to 2008. If more than one ultrasound examination was performed, the lowest AFI was used for analysis. An AFI 5 cm or less was considered oligohydramnios, 5-8 cm was considered borderline, and more than 8 cm to 24 cm was considered normal. Women with hydramnios or ruptured membranes at time of ultrasound examination were excluded. RESULTS: A total of 28,555 pregnancies met inclusion criteria. Ultrasound examination had been performed to estimate gestational age or evaluate fetal growth in 78%. Major malformations were more common in pregnancies with oligohydramnios and borderline AFI than in those with normal fluid-25%, 10%, and 2%, respectively, P<.001. Among nonanomalous fetuses, complications that occurred more often in pregnancies with oligohydramnios and borderline AFI than in those with normal fluid included preterm birth (62%, 37%, 8%), either indicated (20%, 13%, 2%) or resulting from spontaneous preterm labor (42%, 24%, 6%); cesarean delivery for nonreassuring fetal status (9%, 9%, 4%), and birth weight below the third percentile (37%, 21%, 4%), all P<.001. CONCLUSION: Pregnancies with decreased AFI between 24 and 34 weeks, including borderline AFI as well as oligohydramnios, were significantly more likely to be associated with major fetal malformations, and in the absence of malformations, to be complicated by fetal growth restriction and preterm birth. LEVEL OF EVIDENCE: II. PMID- 21252748 TI - Vaginal birth after cesarean for cephalopelvic disproportion: effect of birth weight difference on success. AB - OBJECTIVE: To estimate the effect of birth weight difference between the current and index pregnancy on vaginal birth after cesarean (VBAC) failure in patients whose prior cesarean was for cephalopelvic disproportion (CPD). METHODS: This was a retrospective cohort study of women with one cesarean for CPD, comparing the rate of VBAC failure in women whose infant was smaller, the same, or larger in the VBAC attempt compared with cesarean. The primary outcome was VBAC attempt failure, defined as a patient who attempted VBAC but subsequently required a cesarean delivery for any indication. Univariable, stratified, and multivariable analyses were used. RESULTS: Of 13,706 patients attempting VBAC, 1,511 had one prior cesarean delivery for CPD. Compared with patients with the same birth weight, a lower birth weight was associated with fewer failed VBAC attempts (29.6% compared with 37.8%, adjusted odds ratio [OR] 0.7, 95% confidence interval [CI] 0.5-1.0) and a higher birth weight was associated with more failed VBAC attempts (54.5% compared with 37.8%, adjusted OR 2.0, 95% CI 1.5-2.8). CONCLUSION: Birth weight difference has a moderate effect on the rate of VBAC success in patients whose prior cesarean delivery was for CPD. LEVEL OF EVIDENCE: II. PMID- 21252749 TI - Hypoglycemia in glyburide-treated gestational diabetes: is it dose-dependent? AB - OBJECTIVE: To estimate whether there is a relationship between glyburide dose and the rate of hypoglycemic episodes in women with gestational diabetes mellitus (GDM). METHODS: We studied 674 women with GDM who were treated with glyburide and diagnosed from 2000 to 2009. Glucose data were downloaded from memory-based meters at each visit and analyzed to estimate the incidence of recorded episodes of hypoglycemia and the association with concurrent dose of glyburide therapy (2.5, 5, 10, 15, or 20 mg). Hypoglycemia was defined as a blood glucose of less than 50 mg/dL, further classified as "severe hypoglycemia" if the event required the assistance of another person for resuscitation, "symptomatic hypoglycemia" if it was associated with typical neurogenic symptoms, or "asymptomatic hypoglycemia" if the biochemical reading was less than 50 mg/dL with no symptoms or accompanied by mild symptoms that did not impair the patient's ability to function. RESULTS: Patients recorded a mean of 272 glucose values. Sixty-seven percent of the patients experienced no blood glucose values in the hypoglycemic range. 33% had 1-7% of their total blood glucose values within the hypoglycemic range. All recordings of hypoglycemic episodes were asymptomatic; no patient reported a severe or symptomatic hypoglycemic episode. A significant association was found between the incidence of asymptomatic hypoglycemia and mean blood glucose (P<.001). No association was found between glyburide dose and incidence of asymptomatic hypoglycemia. No association between glyburide dose or mean blood glucose value and the incidence of neonatal hypoglycemia was found. CONCLUSION: Incremental increases in glyburide dose are not associated with an increase in the incidence of hypoglycemic episodes. LEVEL OF EVIDENCE: II. PMID- 21252750 TI - Prevention of learning deficit in a Down syndrome model. AB - OBJECTIVE: To evaluate whether peptides given to adult mice with Down syndrome prevent learning deficits, and to delineate the mechanisms behind the protective effect. METHODS: Ts65Dn mice were treated for 9 days with peptides D-NAPVSIPQ (NAP)+D-SALLRSIPA (SAL) or placebo, and wild-type animals were treated with placebo. Beginning on treatment day 4, the mice were tested for learning using the Morris watermaze. Probe tests for long-term memory were performed on treatment day 9 and 10 days after treatment stopped. Open-field testing was performed before and after the treatment. Calibrator-normalized relative real time polymerase chain reaction (PCR) with glyceraldehyde-3-phosphate dehydrogenase (GAPD) standardization was performed on the whole brain and hippocampus for activity-dependent neuroprotective protein, vasoactive intestinal peptide (VIP), glial fibrillary acidic protein (GFAP), NR2B, NR2A, and gamma aminobutyric acid type A (GABAA)-alpha5. Statistics included analysis of variance and the Fisher protected least significant difference, with P<.05 significant. RESULTS: The Ts65Dn plus placebo animals did not learn over the 5-day period compared with the controls (P<.001). The Ts65Dn +(D-NAP+D-SAL) learned significantly better than the Ts65Dn plus placebo (P<.05), and they retained learning similar to controls on treatment day 9, but not after 10 days of no treatment. Treatment with D-NAP+D-SAL prevented the Ts65Dn hyperactivity. Adult administration of D-NAP+D-SAL prevented changes in activity-dependent neuroprotective protein, intestinal peptide, and NR2B with levels similar to controls (all P<.05). CONCLUSION: Adult treatment with D-NAP+D-SAL prevented learning deficit in Ts65Dn, a model of Down syndrome. Possible mechanisms of action include reversal of vasoactive intestinal peptide and activity-dependent neuroprotective protein dysregulation, as well as increasing expression of NR2B, thus facilitating learning. PMID- 21252751 TI - One-year contraceptive continuation and pregnancy in adolescent girls and women initiating hormonal contraceptives. AB - OBJECTIVE: To assess contraceptive discontinuation, switching, factors associated with method discontinuation, and pregnancy among women initiating hormonal contraceptives. METHODS: This was a 12-month longitudinal cohort study of adolescent girls and women (n=1,387) aged 15 to 24 years attending public family planning clinics who did not desire pregnancy for at least 1 year and selected to initiate the patch, ring, depot medroxyprogesterone acetate, or pills. Participants completed follow-up assessments at 3, 6, and 12 months after baseline. Life table analysis was used to estimate survival rates for contraceptive continuation. Cox proportional hazards models were used to estimate factors associated with method discontinuation. RESULTS: The continuation rate (per 100 person-years) at 12 months was low for all methods; however, it was lowest for patch and depot medroxyprogesterone acetate initiators, 10.9 and 12.1 per 100 person years, respectively (P<=.003); continuation among ring initiators was comparable to pill initiators, 29.4 and 32.7 per 100 person-years, respectively (P=.06). Discontinuation was independently associated with method initiated and younger age. The only factors associated with lower risk of discontinuation were greater intent to use the method and being in school or working. The pregnancy rate (per 100 person-years) was highest for patch and ring initiators (30.1 and 30.5) and comparable for pill and depot medroxyprogesterone acetate initiators (16.5 and 16.1; P<.001). CONCLUSION: The patch and the ring may not be better options than the pill or depot medroxyprogesterone acetate for women at high risk for unintended pregnancy. This study highlights the need for counseling interventions to improve contraceptive continuation, education about longer-acting methods, and developing new contraceptives that women may be more likely to continue. LEVEL OF EVIDENCE: II. PMID- 21252752 TI - Use and misuse of the term "elective" in obstetrics. AB - The term "elective" is commonly used in obstetrics. We performed an electronic search of MEDLINE database using the terms "elective" and "obstetrics," which provided 2,208 publications. We found "elective" was more often used in relation to surgical interventions (eg, cesarean delivery, cerclage) and medical procedures (labor induction) rather than diagnostic procedures. Our review indicates the term lacks the necessary scientific specificity when used to modify procedures such as cerclage, cesarean delivery, timing of delivery, episiotomy, hysterectomy, labor induction, preterm delivery, termination of pregnancy, and ultrasonography. The lack of specificity of the term suggests the most reasonable and prudent course of action is to not use it, but rather to document the specific indication (whether medical or non-medical) for the intervention or procedure (eg, "cesarean delivery on maternal request," "history-indicated cerclage," "induction for preeclampsia"). We propose that the term "elective" should be eliminated from the vocabulary of obstetric practice. PMID- 21252753 TI - A resident conference for systems-based practice and practice-based learning. AB - Improving patient safety and quality of care is part of systems-based practice and practice-based learning for residents. We expanded our obstetrics and gynecology department's regularly scheduled morbidity and mortality conferences to teach quality assurance concepts based on patient care on obstetrics and gynecology fourth-year resident rotations. Obstetrics and gynecology fourth-year residents on one of the two rotations each presented and analyzed a systems-based problem they encountered during patient care. They used an online learning module and proposed solutions, many of which were effectively implemented. Over 5 years, case presentations from 33 conferences were available with problems identified in emergency preparedness, coordination of care, scheduling and supervision, communication, medical practice, documentation, and lack of equipment or facilities. Twenty-two of the suggested solutions were partially or totally implemented. Barriers to implementation were identified. In conclusion, a conference presentation by fourth-year residents can identify patient safety problems, aid in their resolution, and suggest changes to patient care while teaching the principles of systems-based practice and practice-based learning. PMID- 21252754 TI - Moving beyond the impasse: discussing death and dying with African American patients. AB - This article offers a historical and cultural lens through which physicians can gain a better understanding of patient-provider conflict in end-of-life discussions with African American patients and their families. Just as a practitioner would not prescribe a medication to treat a symptom without first determining its underlying cause, it is unwise, and usually ineffective, to try to discuss end-of life care with patients without first understanding the context that shapes their perspectives on death and dying. The first section of this article provides a historical and sociological context to understand the source of the patient-provider conflicting perspectives. I argue that historical factors, such as dying prematurely and experiencing unequal treatment in the health care system, along with cultural factors shaped by faith traditions, contribute to preferences for more aggressive treatment and resuscitative care at the end of life. The second section offers providers a framework-guided by Four Fs: encourage Faith, address Fear, consider Finances, and avoid Futility-to help address these conflicts and effectively navigate end-of-life discussions with African American patients and families. PMID- 21252755 TI - Auditing audaciously augmented authorship. PMID- 21252756 TI - Difficult intrauterine contraception insertion in a nulligravid patient. PMID- 21252758 TI - Physician accountability and taking responsibility for ourselves: washing the dirty white coat, one at a time. PMID- 21252757 TI - Uterine leiomyomas: individualizing the approach to a heterogeneous condition. PMID- 21252760 TI - Prophylactic and risk-reducing bilateral salpingo-oophorectomy: recommendations based on risk of ovarian cancer. PMID- 21252761 TI - Magic and mayhem. PMID- 21252763 TI - Cardiotocography plus ST analysis of fetal electrocardiogram compared with cardiotocography only for intrapartum monitoring: a randomized controlled trial. PMID- 21252765 TI - Generational issues in the ob-gyn workplace: "Marcus Welby, MD," versus "Scrubs". PMID- 21252767 TI - Overlapping compared with end-to-end repair of third- and fourth-degree obstetric anal sphincter tears: a randomized controlled trial. PMID- 21252769 TI - Overlapping compared with end-to-end repair of third- and fourth-degree obstetric anal sphincter tears: a randomized controlled trial. PMID- 21252773 TI - Retraction. ACOG Committee Opinion No. 284: Nonobstetric surgery during pregnancy. PMID- 21252770 TI - Epidemiologic research using administrative databases: garbage in, garbage out. PMID- 21252774 TI - ACOG Committee Opinion No. 474: nonobstetric surgery during pregnancy. AB - The American College of Obstetricians and Gynecologists' Committee on Obstetric Practice acknowledges that the issue of nonobstetric surgery during pregnancy is an important concern for physicians who care for women. It is important for a physician to obtain an obstetric consultation before performing nonobstetric surgery and some invasive procedures (eg, cardiac catheterization or colonoscopy) because obstetricians are uniquely qualified to discuss aspects of maternal physiology and anatomy that may affect intraoperative maternal-fetal well-being. Ultimately, each case warrants a team approach (anesthesia and obstetric care providers, surgeons, pediatricians, and nurses) for optimal safety of the woman and the fetus. PMID- 21252775 TI - ACOG Committee Opinion No. 475: antenatal corticosteroid therapy for fetal maturation. AB - A single course of corticosteroids is recommended for pregnant women between 24 weeks and 34 weeks of gestation who are at risk of preterm delivery within 7 days. A single course of antenatal corticosteroids should be administered to women with premature rupture of membranes before 32 weeks of gestation to reduce the risks of respiratory distress syndrome, perinatal mortality, and other morbidities. The efficacy of corticosteroid use at 32-33 completed weeks of gestation for preterm premature rupture of membranes is unclear, but treatment may be beneficial, particularly if pulmonary immaturity is documented. Sparse data exist on the efficacy of corticosteroid use before fetal age of viability, and such use is not recommended. A single rescue course of antenatal corticosteroids may be considered if the antecedent treatment was given more than 2 weeks prior, the gestational age is less than 32 6/7 weeks, and the women are judged by the clinician to be likely to give birth within the next week. However, regularly scheduled repeat courses or multiple courses (more than two) are not recommended. Further research regarding the risks and benefits, optimal dose, and timing of a single rescue course of steroid treatment is needed. PMID- 21252776 TI - ACOG Committee Opinion No. 476: planned home birth. AB - Although the Committee on Obstetric Practice believes that hospitals and birthing centers are the safest setting for birth, it respects the right of a woman to make a medically informed decision about delivery. Women inquiring about planned home birth should be informed of its risks and benefits based on recent evidence. Specifically, they should be informed that although the absolute risk may be low, planned home birth is associated with a twofold to threefold increased risk of neonatal death when compared with planned hospital birth. Importantly, women should be informed that the appropriate selection of candidates for home birth; the availability of a certified nurse-midwife, certified midwife, or physician practicing within an integrated and regulated health system; ready access to consultation; and assurance of safe and timely transport to nearby hospitals are critical to reducing perinatal mortality rates and achieving favorable home birth outcomes. PMID- 21252777 TI - Steroids - plenty of benefits, but not without risk. PMID- 21252778 TI - Anticipating pitfalls in surgery: preparing the mind to see. PMID- 21252779 TI - Betamethasone-induced hypokalemic periodic paralysis in pregnancy. AB - BACKGROUND: Acute hypokalemic periodic paralysis may be induced by betamethasone injections during pregnancy. CASE: A healthy 23-year-old gravid woman at 32 weeks of gestation with preterm premature rupture of membranes received two doses of 12 mg intramuscular betamethasone 24 hours apart to accelerate fetal lung maturation. She developed significant proximal muscle weakness within 16 hours after the initial dose. Her serum potassium was 1.6 mEq/L. Oral and parenteral potassium replacement restored her neuromuscular function over several days. She delivered by repeat cesarean at 34 weeks of gestation without complications for her or the neonate. CONCLUSION: Hypokalemic periodic paralysis, a rare cause of weakness, may be induced by betamethasone injections during pregnancy and is reversible with low-risk interventions. PMID- 21252780 TI - Variant iliocaval confluence discovered during sacrocolpopexy. AB - BACKGROUND: Laceration of the iliac veins and their branches is a feared complication in abdominal sacral colpopexy. Hemorrhages can be extensive and difficult to control. CASE: We report a case of a patient who, while undergoing abdominal sacral colpopexy, was found to have confluence of the iliac veins at the level of the second sacral vertebra instead of the expected fourth lumbar to first sacral vertebral bodies. The intraoperative course had to be revised because of the increased risk of bleeding. The patient tolerated the procedure well and without any complications. CONCLUSION: With pelvic reconstructive surgery becoming more commonplace, knowledge of possible anomalous vessels is important because modification of planned surgical approach may be necessary to avoid short-term and long-term complications. PMID- 21252781 TI - Extrasphincteric perianal fistulae after sacrospinous fixation for apical prolapse. AB - BACKGROUND: Delayed extrasphincteric perianal fistulae may be encountered after sacrospinous vaginal vault suspension or hysteropexy with permanent sutures. CASES: We report two cases of extrasphincteric perianal fistulae: one after a sacrospinous vaginal vault suspension and one after a sacropsinous hysteropexy. Reproduction of the vaginal dissection performed to place the sacrospinous fixation sutures failed to expose the sutures, and the fistulae persisted. Perianal fistulotomy and fistulectomy, however, resulted in identification and excision of the sutures. CONCLUSION: Perianal fistulotomy or fistulectomy offers the most successful approach to identifying the inciting sutures. PMID- 21252782 TI - Management of angiomyolipoma vena cava thrombus during pregnancy. AB - BACKGROUND: Angiomyolipoma can worsen during pregnancy. Inferior vena cava thrombus of renal angiomyolipoma during pregnancy is rare, and threatens to cause massive emboli. We report a case of vena cava tumor thrombectomy during the second trimester of pregnancy with delayed renal tumorectomy. CASE: A 34-year-old woman with bilateral known angiomyolipomas presented asymptomatic at 30 weeks of gestation with an inferior vena cava thrombus at renal follow-up ultrasonography. Retro-hepatic thrombus had fatty signal on magnetic resonance imaging (MRI). The woman had renal vein and vena cava tumor initial thrombectomy, and had normal cesarean delivery at 39 weeks of gestation. The tumor was treated by postpartum right partial nephrectomy. CONCLUSION: Successful angiomyolipoma isolated thrombectomy during pregnancy with delayed partial nephrectomy is possible. Angiomyolipoma needs follow-up during pregnancy with repeated renal ultrasonography. PMID- 21252783 TI - Primary B-cell lymphoma of the cervix presenting with bilateral hydronephrosis. AB - BACKGROUND: Primary B-cell lymphomas of the cervix are rare entities and can present with hydronephrosis. CASE: An 82-year-old woman with a history of chronic kidney disease presented with fever, altered mental status, and abdominal pain with bilateral hydronephrosis. Despite stent placement and antibiotic therapy, the patient's condition worsened. Pelvic examination and biopsies were then performed, and a B-cell lymphoma of the cervix causing hydronephrosis was diagnosed. The patient's family declined further treatment, and the patient died 2 weeks later. CONCLUSION: Gynecologic examination and suspicion for pelvic malignancies are essential in the evaluation of patients presenting with hydronephrosis. Although squamous cell carcinoma is the most common type of malignancy associated with this presentation, malignancies of other cell lines, including lymphoma, should be considered. PMID- 21252784 TI - Progression of pelvic implants to complex atypical endometrial hyperplasia after uterine morcellation. AB - BACKGROUND: Supracervical hysterectomy, a surgical technique that involves removal of the uterus while preserving the cervix, places women at an increased risk for future morbidity. CASE: The patient presented 7 years after laparoscopic supracervical hysterectomy for benign disease, with pelvic pain, urinary frequency, abdominal bloating, and tenderness. Surgical exploration revealed myometrial implants, along with a larger mass on the mesentery of the sigmoid composed of endometrium with complex atypical hyperplasia in a patient without a prior history of complex atypical hyperplasia. The patient was symptom-free 6 months postoperatively. CONCLUSION: Histology found during reoperation after laparoscopic supracervical hysterectomy includes endometriosis, residual endometrium, and leiomyomas. In this case, a woman with no prior history of endometrial atypia later developed complex adenomatous endometrial hyperplasia in a peritoneal implant. This finding adds to the list of possible complications after laparoscopic-assisted supracervical hysterectomy and uterine morcellation. PMID- 21252785 TI - Reaction to a surgical implant foreign body masquerading as recurrent uterine sarcoma. AB - BACKGROUND: Multiple products to prevent adhesions or lessen the risk of soft tissue attachments are commercially available. The long-term nature of these products is unknown, and they may cause foreign body reactions masquerading as recurrent disease in patients with cancer. CASE: A perimenopausal female underwent a hysterectomy and placement of a surgical implant, polylactic acid. Final pathology revealed stage IA low-grade endometrial stromal sarcoma. Areas suspicious for recurrence were noted on radiographic imaging 1 year later, resulting in exploratory surgery. The suspicious areas were found to be foreign body reactions. Mass spectrometry identified the main component of the reactions as polylactic acid. CONCLUSION: Adhesion barriers and other surgical implants may not always be completely metabolized and should be used with caution in patients with cancer. PMID- 21252786 TI - Resolution of uterine arteriovenous malformation and successful pregnancy after treatment with a gonadotropin-releasing hormone agonist. AB - BACKGROUND: Uterine arteriovenous malformations are a rare and potentially life threatening condition. Medical therapy has not been popular because of the propensity for excessive bleeding in the patient. As a result, the effect of gonadotropin-releasing hormone (Gn-RH) agonists on uterine arteriovenous malformations has not been established. CASE: A 30-year-old patient presented with persistent vaginal bleeding. Based on the color Doppler ultrasound and magnetic resonance imaging findings, a uterine arteriovenous malformation was diagnosed. Because initial treatment with methylergonovine maleate was unsuccessful, the patient was treated with Gn-RH agonists. The lesion completely disappeared after 6 months of Gn-RH agonist treatment. Five months after the completion of Gn-RH agonist therapy, the patient conceived spontaneously and successfully completed a normal pregnancy. The patient has remained free from recurrence of the lesion. CONCLUSION: Gonadotropin-releasing hormone agonist therapy has the potential to be a conservative treatment modality for uterine arteriovenous malformations in hemodynamically stable patients. PMID- 21252787 TI - Primary dermatologic findings with early-onset intrahepatic cholestasis of pregnancy. AB - BACKGROUND: Primary dermatologic findings are not thought to be associated with intrahepatic cholestasis of pregnancy. We report on a patient with twins who presented with a pruritic rash and cholestasis. CASE: A woman with a twin gestation and two previous term stillbirths developed a pruritic rash at 16 weeks. Scleral icterus and jaundice were observed at 27 weeks. Elevated bile acid levels confirmed a diagnosis of intrahepatic cholestasis of pregnancy, and ursodeoxycholic acid therapy was initiated. Fetal heart rate decelerations were noted at 32 4/7 weeks, prompting delivery of two live male newborns. Declining laboratory values and resolution of rash occurred within a few days of delivery. CONCLUSION: This case illustrates an unusual presentation of recurrent cholestasis of pregnancy in a twin gestation with primary dermatologic findings. PMID- 21252788 TI - Metastatic uterine leiomyosarcoma and eosinophilia. AB - BACKGROUND: Uterine sarcomas account for approximately 3% to 7% of all uterine malignancies. Distinguishing benign and malignant myomas based on physical examination and imaging alone is challenging. CASE: A postmenopausal woman with a history of leiomyomas presented to the Emergency Department with chest pain and a right upper lobe lung mass. Blood tests demonstrated profound eosinophilia (58,000/mm). Positron emission tomography-computed tomography scan to exclude distant disease as work-up for presumed lung cancer revealed increased tracer uptake in the lung mass and a pelvic mass. The patient died from complications of hypereosinophilia, and a postmortem diagnosis of metastatic uterine leiomyosarcoma was made. CONCLUSION: Significant blood eosinophilia is uncommon in leiomyomas and should raise suspicion of malignant etiology for a pelvic mass. PMID- 21252789 TI - Nickel hypersensitivity associated with an intratubal microinsert system. AB - BACKGROUND: Although known nickel hypersensitivity is a contraindication to intratubal microinsert placement in the United States, this case demonstrates that nickel hypersensitivity to intratubal microinserts can occur. CASE: A young woman developed an allergic reaction after placement of intratubal microinserts. Nickel hypersensitivity was confirmed with skin patch testing. The microinserts were removed hysteroscopically, and the patient improved. CONCLUSION: If a patient experiences symptoms of an allergic reaction after hysteroscopic sterilization, referral to an allergy specialist is recommended. If nickel hypersensitivity is confirmed, the microinserts should be removed; this may be performed under hysteroscopic guidance. PMID- 21252790 TI - Bombay blood type and use of red cell apheresis during pregnancy. AB - BACKGROUND: Bombay blood type is among the rarest in the world and is associated with anti-H antibodies. These antibodies cause severe hemolysis when exposed to any blood product except Bombay and have been reported to cause hemolytic disease of the newborn. CASE: A primigravid woman with Bombay blood type received erythropoietin and underwent autologous blood donation using red cell apheresis. Maternal anti-H immunoglobulin G antibodies were identified and serial evaluation of the middle cerebral artery peak systolic velocity was used to monitor for fetal anemia. Hemolytic disease of the newborn did not develop. CONCLUSION: Red cell apheresis is a valuable procedure that results in two units of red blood cells per donation and was well tolerated during pregnancy. PMID- 21252791 TI - Postpartum endometritis caused by herpes and cytomegaloviruses. AB - BACKGROUND: Postpartum endometritis is usually a polymicrobial infection caused by organisms that are part of the normal vaginal flora. A pathologically confirmed case of postpartum endometritis secondary to herpes and cytomegalovirus in a human immunodeficiency virus (HIV)-positive patient is reported. CASE: A 29 year-old, HIV-positive woman presented 6 days postpartum with abdominal pain and foul-smelling vaginal discharge. Pelvic ultrasonography revealed retained products of conception. Dilation and evacuation was performed, and antibiotics were started. Despite adequate antibiotics and laparoscopic drainage of a pelvic collection, fevers and pain continued. A total abdominal hysterectomy, salpingectomy, and appendectomy were performed. Pathology reported herpes and cytomegalovirus infection of the uterus. CONCLUSION: Herpes simplex virus (HSV) and cytomegalovirus need to be considered as a potential cause of postpartum endometritis. When antibiotic therapy fails, an antiviral regimen should be considered. PMID- 21252792 TI - Transmural vaginal-to-bladder injury from an obstructed labor pattern. AB - BACKGROUND: A vesicovaginal fistula, among other devastating sequelae, is a complication that can arise from obstetric trauma such as prolonged obstructed labor patterns. These are rarely seen as obstetric-related complications in well developed countries. They are thought to arise from direct ischemic injury that can occur between the fetal head and the adjacent tissues. CASE: A patient presented to the emergency room in obstructed labor. Examination revealed a crowning fetal head, no fetal heart tones, and purulent vaginal discharge. Postpartum, the patient experienced irritative voiding symptoms, vaginal stenosis, and cystoscopic evidence of injury to the bladder base. CONCLUSION: These findings may provide evidence of the transmural vaginal-to-bladder damage that can occur from obstructed labor. PMID- 21252793 TI - 2009 pandemic influenza A (H1N1) and vaccine failure in pregnancy. AB - BACKGROUND: Emerging data suggest that pregnancy conveys high risk for severe complications from the 2009 pandemic influenza A virus (2009 H1N1) infection. CASE: We describe an infected pregnant woman with critical illness owing to acute respiratory distress syndrome despite previous vaccination. Early serologic testing indicated absent immunity, followed 11 days later by a robust immune response. The patient required mechanical ventilation for 11 days, but ultimately improved, and was discharged home on hospital day 14. CONCLUSION: With the expectation that 2009 H1N1 will continue to cause disease in the immediate future, the virus has been included as a component of the 2010-2011 seasonal influenza vaccine. Vaccination of pregnant women is strongly encouraged. However, regardless of vaccination history, clinicians should remain vigilant for 2009 H1N1 infection when the virus is in circulation, and should not delay antiviral treatment of pregnant women with suspected influenza. PMID- 21252794 TI - Severe hypercalcemia associated with uterine leiomyoma in pregnancy. AB - BACKGROUND: Uterine leiomyomas are the most common pelvic tumor, and a frequent indication of the need for gynecologic surgery. Although usually asymptomatic, life-threatening cases can occur. We present a case of critical hypercalcemia associated with a leiomyoma during pregnancy with the intention of highlighting the endocrinology of leiomyomas, features shared with malignant neoplasms, and the potential for effects on obstetric outcomes. CASE: A 32-year-old gravid woman with a large leiomyoma presented at 33 5/7 weeks of gestation with critical hypercalcemia requiring intensive care. Postpartum myomectomy cured her hypercalcemia, which was driven by parathyroid hormone-related protein (PTHrP) produced by the tumor. CONCLUSION: Obstetricians should be aware of the existence of humoral hypercalcemia related to leiomyomas and the potential effects on pregnancy. PMID- 21252795 TI - Torsion of a tumor within an accessory ovary. AB - BACKGROUND: An accessory ovary is a rare congenital anomaly of the female reproductive tract. This report illustrates a case of a cyst arising from an accessory ovary complicated by torsion. CASE: A 39-year-old nulliparous woman presented with lower abdominal pain and was found on physical examination to have an 8-cm mass anterior to the uterus. Ultrasonography of the pelvis showed a 9.3*6.7 cm cystic lesion with a solid component anterior to the uterus suggestive of a left ovarian cyst. Laparoscopy was performed for presumed ovarian torsion. Torsion of a tumor arising from an accessory ovary was found intraoperatively. CONCLUSION: Patients suspected to have ovarian torsion should have emergency surgery for diagnosis and attempted ovarian preservation. Physicians should consider complications of paraovarian anomalies in the differential diagnosis. PMID- 21252796 TI - Incidental diagnosis of appendiceal mucocele with vaginal ultrasonography and computed tomography. AB - BACKGROUND: Appendiceal mucocele is an uncommon entity that may be encountered at the time of abdominal surgery performed for an unrelated indication. The diagnosis may be suggested by imaging with ultrasonography or computed tomography of the abdomen and pelvis. Whereas early resection is curative, failure to recognize the disorder may lead to rupture and the devastating consequences of pseudomyxoma peritonei. CASE: Following an annual gynecologic checkup in a healthy 63-year-old woman, vaginal ultrasonography along with a subsequent computed tomographic study raised the possibility that an incidental appendiceal mucocele was present. At laparoscopy, this diagnosis was confirmed and the lesion was resected using minimally invasive techniques. CONCLUSION: Early diagnosis and treatment of appendiceal mucocele facilitates the successful management of this rare disorder. PMID- 21252797 TI - Embryonal rhabdomyosarcoma of the cervix and appendiceal carcinoid tumor. AB - BACKGROUND: Rhabdomyosarcomas, particularly those of gynecologic origin, are very rare in adults. As a result, there is little literature on the optimal staging procedure and treatment modalities for this population. CASE: A 43-year-old woman presented with a long-standing history of menorrhagia and was subsequently diagnosed with embryonal rhabdomyosarcoma of the cervix. She underwent a total abdominal hysterectomy, bilateral salpingo-oophorectomy, lymph node dissection, omentectomy, and appendectomy, which also revealed a synchronous tubular carcinoid tumor of appendiceal origin. Plans for treatment involve adjuvant chemotherapy with vincristine, dactinomycin, and cyclophosphamide. CONCLUSION: This case adds to the small body of literature surrounding cervical embryonal rhabdomyosarcoma in women over the age of 40 years and proposes that appendectomy be considered during surgical management. PMID- 21252798 TI - Premature termination of nursing secondary to Serratia marcescens breast pump contamination. AB - BACKGROUND: Serratia marcescens, a known pathogen associated with postpartum mastitis, may be identified by its characteristic pigmentation. CASE: A 36-year old P0102 woman presented postpartum and said that her breast pump tubing had turned bright pink. S marcescens was isolated, indicating colonization. She was started on antibiotics. After viewing an Internet report in which a patient nearly died from a Serratia infection, she immediately stopped breastfeeding. CONCLUSION: Serratia colonization may be noted before the development of overt infection. Because this pathogen can be associated with mastitis, physicians should be ready to treat and should encourage patients to continue nursing after clearance of the organism. Exposure to sensational Internet reports may make treatment recommendations difficult. PMID- 21252799 TI - Nausea and vomiting after placement of tension-free vaginal tape sling. AB - BACKGROUND: Minimally invasive surgical procedures such as tension-free vaginal tape sling should not imply that a minimal preoperative evaluation is all that is required. CASE: A 52-year-old multiparous perimenopausal woman presented with postoperative nausea, vomiting, and vague abdominal-pelvic discomfort after placement of tension-free vaginal tape. The final diagnosis was invasive molar pregnancy. CONCLUSION: This case raises the awareness of the rare diagnosis of gestational trophoblastic disease in perimenopausal women and emphasizes the importance of a complete preoperative evaluation in those scheduled to undergo minimally invasive procedures. PMID- 21252800 TI - Atrial fibrillation in pregnancy. AB - BACKGROUND: Physiologic changes of pregnancy can predispose women to cardiac arrhythmias. Atrial fibrillation is rare in pregnancy and usually occurs in women with underlying cardiac anomalies. CASE: A young woman at 22 weeks of gestation presented with new-onset atrial fibrillation with rapid ventricular response. Thorough evaluation revealed atrial fibrillation with no underlying cause and ultimately required treatment with electrical cardioversion. CONCLUSION: Lone atrial fibrillation in pregnancy requires exclusion of all possible etiologies before diagnosis. Cardioversion is the treatment of choice. Women with persistent atrial fibrillation require anticoagulation and rate control, as well as fetal growth surveillance and antenatal testing. PMID- 21252801 TI - Molecular distinction of consecutive molar pregnancies. AB - BACKGROUND: It may be difficult to differentiate the consecutive occurrence of two independent molar pregnancies from gestational trophoblastic neoplasia after the initial molar pregnancy, especially when the interval between them is short. CASE: A 25-year-woman who had had a complete hydatidiform mole 6 months earlier presented with a 6-week history of secondary amenorrhea. Serum human chorionic gonadotropin had increased to 19,857 micro-international units/mL, with no gestational sac demonstrated. Dilation and curettage was performed. Pathologic examination identified a tiny amount of hydropic villi compatible with complete hydatidiform mole. Analysis of short tandem repeat polymorphisms revealed that the molar tissues of the first and second complete hydatidiform moles were of different genetic origin. The patient went into remission spontaneously without chemotherapy. CONCLUSION: Genetic profiling was useful to discriminate a recurrent mole from suspected gestational trophoblastic neoplasia. PMID- 21252802 TI - Progesterone autoimmune dermatitis with positive autologous serum skin test result. AB - BACKGROUND: Progesterone autoimmune dermatitis is a rare disease attributable to hypersensitivity to endogenous progesterone and characterized by cyclic dermatologic manifestations at the end of the luteal phase that disappear some days after menses. CASE: A 35-year-old woman experienced cyclic premenstrual urticaria and angioedema occurring from 4 days before to 5 days after menses. The diagnosis of progesterone autoimmune dermatitis was made by a progesterone positive skin test. Autologous serum skin test, using sera from estrogenic and luteal phases, also elicited a positive response. The patient became pregnant with near-clearance of the urticaria. CONCLUSION: Skin tests with progesterone and autologous serum, which are easy to perform, convenient, and inexpensive, are highly useful for establishing the diagnosis of progesterone autoimmune dermatitis and ruling out other skin disorders. PMID- 21252803 TI - Parathyroid adenoma with hypertensive crisis and intracerebral hemorrhage mimicking hemolysis, elevated liver enzymes, low platelets syndrome. AB - BACKGROUND: Hyperparathyroidism is seldom encountered during pregnancy. Moreover, when the disease does occur, it is typically masked until late pregnancy or after delivery. CASE: A previously healthy multiparous woman presented with sudden onset severe preeclampsia with hemolysis, elevated liver enzymes, low platelets syndrome at 37 weeks of gestation. Acute intracerebral hemorrhage and disseminated intravascular coagulapathy developed 24 hours after cesarean delivery and persisted after craniotomy. Hypercalcemia and hyperparathyroidism were noted, and imaging studies revealed parathyroid tumor. The patient recovered from severe preeclampsia after resection of a hemorrhagic parathyroid adenoma and was fully rehabilitated after 3 months. CONCLUSION: This patient exhibited a concealed hyperparathyroidism with acute hypertensive crisis, probably attributable to hemorrhagic parathyroid adenoma. The presentation mimics acute late-onset preeclampsia and requires vigilant diagnosis followed by surgery. PMID- 21252804 TI - Extensive thrombosis and first-trimester pregnancy loss caused by sticky platelet syndrome. AB - BACKGROUND: Sticky platelet syndrome is an autosomal-dominant thrombophilia characterized by platelet hyperaggregability in the presence of adenosine diphosphate or epinephrine. The result clinically can be widespread thromboses, often arterial, in patients without apparent risk factors for thrombotic disease. Limited data exist regarding its role in adverse pregnancy outcomes. CASE: A gravid woman with two previous first-trimester miscarriages presented at 11 weeks of gestation with a deep venous thrombosis. Despite anticoagulation, she developed extensive and progressive arterial and venous thromboses and suffered a fetal demise. A thrombophilia panel was unremarkable, but platelet aggregometry demonstrated hyperactive platelets in the presence of adenosine diphosphate and epinephrine consistent with sticky platelet syndrome. CONCLUSION: Sticky platelet syndrome causes arterial thromboses and may be an underappreciated etiology for adverse pregnancy outcomes. PMID- 21252805 TI - False-positive amphetamine toxicology screen results in three pregnant women using labetalol. AB - BACKGROUND: Labetalol is commonly used for control of hypertension in pregnancy. A component of the workup for new-onset hypertension in pregnancy often includes a urine drug screen. A labetalol metabolite is structurally similar to amphetamine and methamphetamine, thus causing potential cross-reactivity in drug immunoassays. CASES: We present one case of cocaine-induced hypertensive crisis superimposed on chronic hypertension and two cases of severe preeclampsia for which patients required escalating doses of labetalol for hypertension, with subsequent false-positive amphetamine urine drug screen results. CONCLUSION: In pregnant women requiring labetalol for treatment of hypertensive disease, a urine drug screen may be falsely positive for amphetamines and methamphetamines. Providers should be cognizant of this possibility when interpreting the results of urine drug screens. PMID- 21252806 TI - Shrinking lung syndrome in pregnancy complicated by antiphospholipid antibody syndrome. AB - BACKGROUND: Shrinking lung syndrome is characterized by pulmonary compromise secondary to unilateral or bilateral paralysis of the diaphragm. CASE: Shrinking lung syndrome was diagnosed in a patient with antiphospholipid syndrome after a cesarean delivery at 28 4/7 weeks of gestation. Signs and symptoms included unexplained right-side chest pain, dyspnea, tachypnea, and absent breath sounds at the right base of the lungs. After initiation of corticosteroids, her symptoms resolved. CONCLUSION: Although seen in association with systemic lupus erythematosus, shrinking lung syndrome has not been described with antiphospholipid syndrome or during pregnancy. Diagnosis and awareness are important because treatment with moderate- to high-dose corticosteroids appears to improve the clinical outcome. PMID- 21252807 TI - Surgical removal of a gigantic abdominal mass: a multidisciplinary approach. AB - BACKGROUND: Ovarian cystadenomas are common benign ovarian neoplasms that rarely present as gigantic abdominal masses. A variety of intraoperative and postoperative challenges may be encountered in the removal of these masses. CASE: We review the case of a 45-year-old woman who presented with massive abdominal swelling that was later identified as two distinct bilateral serous cystadenomas with a combined weight of approximately 107 kg. A multidisciplinary team including gynecology, plastic surgery, anesthesiology, and the operating room staff convened before surgery to discuss surgical technique, physiologic considerations, and logistical issues. CONCLUSION: A multidisciplinary approach had an integral role in intraoperative safety and successful recovery of our patient from this surgery. PMID- 21252808 TI - Pregnancy in inherited hypokalemic salt-losing renal tubular disorder. AB - BACKGROUND: The management of inherited hypokalemia has improved and the issue of pregnancy has become important. CASES: Between 1992 and 2010, five Italian women with the clinical diagnosis of Gitelman syndrome gave birth to a total of six newborns. Pregnancy was uneventful in four women but was complicated by tiredness and tetanic seizures in the fifth woman. Drug management included potassium chloride in four cases and magnesium and amiloride in one case each. The six neonates were born at term (n=4) or near term (n=2), with a body weight that was appropriate for gestational age. The children, aged between 6 weeks and 18 years, were healthy and neurodevelopmentally and somatically normal at the last follow up. CONCLUSION: Women with hypokalemia can become pregnant and the disorder may be managed without negative effect on the fetus. PMID- 21252809 TI - Hyperlipidemia-associated pancreatitis in pregnancy managed with fenofibrate. AB - BACKGROUND: Pancreatitis is a concerning clinical event during pregnancy, with high morbidity and mortality rates for mother and fetus. Hypertriglyceridemia is considered a rare cause of pancreatitis in pregnancy, with the majority of reported cases being associated with the lipid metabolism disorders. CASE: We report on a case of hypertriglyceridemia-induced pancreatitis in a woman presenting at 32 weeks of gestational age. Her dyslipidemia was not controlled with diet alone, necessitating medical intervention. Fenofibrate was used successfully. Recurrence of pancreatitis during the pregnancy was avoided, and a healthy neonate was delivered at 35 weeks of gestation. CONCLUSION: Fenofibrate was used safely and successfully during pregnancy in this case of hypertriglyceridemia-associated pancreatitis refractory to conservative measures. PMID- 21252810 TI - Factors associated with prolonged emergency department length of stay for admitted children. AB - OBJECTIVE: To estimate the prevalence of and to identify factors associated with prolonged emergency department length-of-stay (ED-LOS) for admitted children. METHODS: Data were from the 2001-2006 National Hospital Ambulatory Medical Care Survey. The primary outcome was prolonged ED-LOS (defined as total ED time >8 hours) among admitted children. Predictor variables included patient-level (eg, demographics including race/ethnicity, triage score, diagnosis, and admission to inpatient bed vs intensive care unit), physician-level (intern/resident vs attending physician), and system-level (eg, region, metropolitan area, ED and hospital type, time and season, and diagnostic and therapeutic procedures) factors. Multivariable logistic regression was performed to identify independent predictors of prolonged ED-LOS. RESULTS: Median ED-LOS for admitted children was 3.7 hours. Thirteen percent of pediatric patients admitted from the ED experienced prolonged ED-LOS. Factors associated with prolonged ED-LOS for admitted children were Hispanic ethnicity (odds ratio [OR], 1.76; 95% confidence interval [95% CI], 1.10-2.81), ED arrival between midnight and 8 a.m. (OR, 2.80; 95% CI, 1.87-4.20), winter season (January-March: OR, 1.81; 95% CI, 1.20-2.74), computed tomography scan or magnetic resonance imaging (OR, 1.65; 95% CI, 1.05 2.58), and intravenous fluids or medications (OR, 1.81; 95% CI, 1.10-2.97). Children requiring ICU admissions (OR, 0.29; 95% CI, 0.11-0.77) or receiving pulse oximetry in the ED (OR, 0.52; 95% CI, 0.34-0.81) had a lower risk of experiencing prolonged ED-LOS. CONCLUSIONS: We found that prolonged ED-LOS occurs frequently for admitted pediatric patients and is associated with Hispanic ethnicity, presentation during winter season, and early morning arrival. Potential strategies to reduce ED-LOS include improved availability of interpreter services and enhanced staffing and additional inpatient bed availability during winter season and overnight hours. PMID- 21252811 TI - Pediatric injuries associated with fireplaces, United States, 2002-2007. AB - OBJECTIVE: To examine injuries among pediatric patients treated in an emergency department (ED) related to contact with a fireplace. METHODS: Data were obtained from the National Electronic Injury Surveillance System for the years 2002 through 2007. National estimates of ED visits for injuries associated with fireplaces were analyzed. Average annual rates were calculated, and logistic regression analyses were used to determine risk estimates for patient demographic characteristics related to ED visits for injuries associated with fireplaces. RESULTS: From 2002 through 2007, there were an estimated 8000 ED visits annually for injuries related to fireplaces in the United States, with an average annual rate of 18.8 ED visits per 100,000 children aged birth through 10 years. The most common injuries involved lacerations (66%), burns (10%), and contusions (10%). Most injuries occurred to the face (46%) or head (31%). Most patients (98%) were treated and released the same day. Results of logistic regression analyses revealed that children aged birth to 3 years (odds ratio, 12.2; 95% confidence interval, 9.1-16.5) and children aged 4 to 6 years (odds ratio, 4.8; 95% confidence interval, 3.5-6.5) were more likely present in an ED for a fireplace related injury when compared with older children aged 7 to 10 years. CONCLUSIONS: Further research is warranted in the areas of etiology, injury prevention interventions, health communications, and surveillance to facilitate more effective injury prevention efforts. PMID- 21252812 TI - Low-risk criteria for pelvic radiography in pediatric blunt trauma patients. AB - CONTEXT: The American College of Surgeons recommends that any patient with blunt trauma undergoes radiographic evaluation, including a radiograph of the pelvis. Studies have questioned the use of such routine pelvic radiographs (PXR) in pediatrics. Selective elimination of PXR would save time, money and unshielded radiation exposure to the gonads. OBJECTIVE: To determine if a defined set of historical and clinical factors could predict low risk for pelvic fracture and incorporate these factors into a clinical decision guideline. DESIGN, SETTING, AND PATIENTS: A retrospective chart review of all blunt trauma patients 25 years or younger in whom a PXR was obtained from January 2002 to June 2006 presenting to an urban level 1 trauma center. A total of 579 patients underwent 580 trauma evaluations. MAIN OUTCOME MEASURES: Variables including sex, mechanism of injury, Glascow Coma Score, Pediatric Trauma Score, fall height, lower extremity injury, blood on rectal examination, blood at meatus, and clinical need for computed tomography (CT) were compared with outcomes of pelvic fracture and pelvic fracture requiring surgical intervention. RESULTS: There were 22 pelvic fractures identified, resulting in a fracture rate of 4%. The negative predictive value for pelvic fracture was 98.3% (95% confidence interval [95% CI], 96.9%-99.2%) if no lower extremity injury was present, 99% (95% CI, 98.2%-99.6%) if physical examination of the pelvis was normal, and 99.5% (95% CI, 98.6%-99.9%) if there was no need for abdominopelvic CT. The negative predictive value was 100% (95% CI, 98.8%-100%) if any one of these 3 factors is present. CONCLUSIONS: Using the clinical findings of (1) lack of lower extremity injury, (2) lack of an abnormal physical examination of the pelvis, and (3) no need for abdominopelvic CT, pelvic fracture can be reliably excluded. Pelvic radiography can be eliminated in the evaluation of these patients, potentially decreasing time expenditure, radiation exposure, and cost. PMID- 21252813 TI - Epidemiology of acute soccer injuries in canadian children and youth. AB - OBJECTIVES: To describe acute injury characteristics in children and youth soccer players and to identify the characteristics of patients who required hospital admission. METHODS: The analysis of the study was based on the Canadian Hospitals Injury Reporting and Prevention Program. A total of 32,149 patients (aged 5-19 years) with soccer-related injuries presenting to 16 participating hospital emergency departments from 1994 to 2004 were included in the analysis. RESULTS: Males had the highest proportion of injuries (62%). The leading injuries were sprains/strains (38%), followed by fractures/dislocations (31%) and superficial injuries (23%). A total of 896 cases (3%) required hospital admission. Based on logistic regression analysis, being a male, playing unorganized soccer, having multiple body injuries, playing soccer outside school premises, and playing during the summer/fall increased the likelihood of hospital admission. Moreover, having a head/face/neck injury (Odds ratio [OR], 1.3; 95% confidence interval [95% CI], 1.1-1.7) and trunk injury (OR, 1.7; 95% CI, 1.2-2.4) as compared with an upper extremity injury and having injuries from contact with structures/surfaces (OR, 3.1; 95% CI, 2.2-4.3) and with other players (OR, 2.5; 95% CI, 1.8-3.5) as compared with ball contact had the highest odds of hospital admission. CONCLUSIONS: Soccer accounted for a significant proportion of injuries presented to Canadian Hospitals Injury Reporting and Prevention Program emergency departments during 1994-2004. Further studies investigating potential interventional programs and techniques among this population are highly warranted. PMID- 21252814 TI - Family presence during invasive procedures at the emergency department: what is the opinion of Spanish medical staff? AB - OBJECTIVES: Family presence (FP) during invasive procedures (IPs) in children remains controversial among pediatric emergency department (PED) staff. The authors aimed to determine health care providers' attitudes toward FP during IPs in Spain, to learn whether parents are given the option of being present during different IPs, and to study which factors influence the providers' opinions. METHODS: Observational study. Physicians and nurses were asked to answer a questionnaire, which was sent to 43 PEDs and was available at the Spanish Pediatric Emergency Society Web site. RESULTS: We obtained 222 questionnaires from 36 Spanish hospitals. A total of 65.8% of the surveys were answered by physicians (66.4% pediatricians) and 34.2% by nurses. The median age of the respondents was 32 years, and 69.2% were women. Parents were given the option of being present during blood sampling (36.4%), intravenous line placement (32.7%), urethral catheterization (32.1%), lumbar puncture (13.5%), and resuscitation (1%). More than 60% of providers approved of FP during blood sampling, sutures, intravenous line placement, and urethral catheterization; however, only 10.8% of providers encourages FP during resuscitation. Against FP, health care staff argue procedural invasiveness (75.6%), parents' anxiety (87.6%), and worsened performance of the procedure (66%). Commonly expressed advantages were reducing patient distress (72.9%) and parent anxiety (62.3%). Physicians, especially the older ones, are more likely to encourage FP than nurses for some IPs. CONCLUSIONS: The PED staff tend to prefer parents not to be present during IPs as the level of invasiveness increases. Family presence is not common in Spanish PEDs. Older physicians are more likely to support FP than nurses. PMID- 21252815 TI - Analysis of child passenger safety restraint use at a pediatric emergency department. AB - PURPOSE: The objectives of the study were to determine the number of children properly restrained during transit to a pediatric emergency department for care and to ascertain parental knowledge of Alabama laws and American Academy of Pediatrics (AAP) guidelines and where they obtain this information. METHODS: An emergency department (patient care rooms) waiting area, convenience sample of Alabama parents who have children younger than or 13 years of age were surveyed over a 5-week period. Appropriate use of child passenger safety (CPS) restraints was determined using Alabama law and AAP recommendations. Use of Car Seat Checks provided by Children's Hospital and Safe Kids, knowledge of Alabama laws and CPS guidelines, and the source of information used by parents were ascertained. RESULTS: Among 525 patients identified, 520 (99.0%) participated. Appropriate use per Alabama law and AAP guidelines was 72.3% and 60.6%, respectively; 5.0% were unrestrained. Booster seats were the most commonly misused restraint. Car seats were reportedly used correctly by 81.9%. Parents who had used the Car Seat Checks program had correct booster seat and car seat use rates of 95.8% and 61.5%, respectively. Unfortunately, only 31.2% of patients had knowledge of the Car Seat Checks program, and only 40.6% knew the current law. Most often, parents stated that the hospital where their child was born was the primary (and sometimes only) source of CPS information. CONCLUSIONS: This study illustrates the need for improving parental knowledge of appropriate child passenger restraint use (especially booster seats) and Car Seat Checks programs. Car seat program assistance is associated with high levels of appropriate use. PMID- 21252816 TI - Pediatric all-terrain vehicle injuries: does legislation make a dent? AB - OBJECTIVES: We sought to determine whether North Carolina legislation pertaining to all-terrain vehicles (ATVs) has affected the frequency, distribution, or severity of injury in children. METHODS: This retrospective study reviewed the Wake Forest University Baptist Medical Center Trauma Registry from 2003 to 2008 along with North Carolina Medical Examiner's child fatality data for all children injured on an ATV. Patients were excluded if the accident did not occur in North Carolina, incomplete data, or if the vehicle was not an ATV. We evaluated the use of helmets, the extent of injury, and the mechanism of injury, comparing the patterns before the laws went into effect (2003-2005) with those after the law was enacted (2006-2008). RESULTS: Eighty-eight patients were included for analysis, predominantly white boys with a mean age of 12.1 +/- 4.1 years. Children not wearing helmets were 5-fold more likely to have a significant head/neck injury (odds ratio [OR], 5.1; confidence interval [CI], 1.61-15.88; P = 0.01) and 3.7-fold more likely to have a significant chest injury (OR, 3.73; CI, 1.01-13.86; P = 0.05). Passengers were 5-fold more likely to die or require inpatient rehabilitation (OR, 5.0; CI, 1.2-20.8; P = 0.03) and 13.7 times as likely to have a significant injury to their head/neck (OR, 13.7; CI, 3.07-60.93; P = 0.01). CONCLUSIONS: There were no significant changes seen in the children injured without and then with legislation, which may be significant if ATV use indeed is increasing. A child's vehicular position was the most significant predictor of morbidity and mortality. Helmet use was not increased once mandated by law. Further efforts to implement such legislation and educate the public are necessary to make a significant change in injuries. PMID- 21252817 TI - Improving parent-provider communication in the pediatric emergency department: results from the clear and concise communication campaign. AB - OBJECTIVE: We implemented and evaluated a quality improvement initiative targeting parents' communication with clinicians in a pediatric emergency department (ED). METHODS: A quality improvement initiative ("Clear and Concise Communication" or "3C") targeting parent-provider communication was implemented in an urban tertiary care pediatric ED. A 1-page form that solicited parent worries, questions, and expectations for care was developed. Parent-provider communication was measured using an 8-item subset of questions from an ongoing satisfaction survey adopted for pediatric emergency care. The primary outcome was the communication score for a given ED visit scaled from 0 to 100 and was calculated as the simple average of answers where the best possible response was given a value of 1 and all others were scored as 0. A multivariate model adjusting for time-related factors, ED volume, and system-level events was developed to examine the influence of the communication initiative. RESULTS: A total of 29,005 patients received care during implementation of 3C; a total of 100,810 patients received care during the 2-year period of interest. Data from 1233 satisfaction surveys were used to create the communication scores. Communication scores ranged from 0 to 100, with a mean of 88 and SD of 17.7. In a linear model adjusting for day, weekend, volume, system-level introduction of electronic charting for nurses, and electronic-order entry for physicians, the 3C initiative demonstrated a positive and statistically significant effect increasing the communication score by 2.8 points/100 d (95% confidence interval, 0.1-5.5). CONCLUSIONS: The 3C initiative succeeded in improving parents' communication experience with emergency providers during the intervention period. PMID- 21252818 TI - Visual acuity loss in recessive retinitis pigmentosa and its correlation with macular lesions. AB - PURPOSE: To determine the visual acuity loss in patients with autosomal recessive retinitis pigmentosa and its relation to the presence of macular lesions. METHODS: A total of 145 patients were included in the visual acuity analysis, and 139 patients were included in the analysis of their macular status. Patients with a history of parental consanguinity or an affected sister and parents unaffected with retinitis pigmentosa were considered as having an autosomal recessive mode of inheritance. RESULTS: Regardless of age, 68 patients (47%) had visual acuity of 20/40 or better, 109 (75%) had better than 20/200 in at least 1 eye, and 36 (25%) had an acuity of 20/200 or worse in both eyes. An evaluation of the macular status demonstrated that 55 patients (39.6%) had no macular lesion and 77 (55.4%) had an atrophic lesion (either bull's-eye or geographic). Seventy-five percent of patients with no macular lesion had a visual acuity of 20/40 or better and 34 patients (44%) with an atrophic lesion had a visual acuity better than 20/70. CONCLUSION: These data can be useful to counsel patients on the potential visual acuity impairment likely to be observed at different ages and identify the association of visual acuity loss with macular changes. PMID- 21252819 TI - Simple foot tapping test as a quantitative objective assessment of cervical myelopathy. AB - STUDY DESIGN: A clinical and cohort study. OBJECTIVE: The first purpose of this study was to investigate the standard value of a simple foot tapping test (FTT) in a large healthy population. The second purpose was to elucidate the validity of FTT as a quantitative assessment of lower extremity motor function for cervical compressive myelopathy. SUMMARY OF BACKGROUND DATA: Several clinical performance tests have been reported as objective assessments for the severity of cervical myelopathy. The FTT is the simplest and easiest method for a quantitative analysis of lower limb motor dysfunction in the upper motor neuron diseases. However, there were few studies about the FTT in cervical myelopathy. METHODS: We recruited 252 patients who were diagnosed with cervical myelopathy and 792 healthy volunteers who participated in a health promotion project. Among the patients, 126 who underwent surgery were evaluated both before and 1 year after surgery. We performed the FTT and grip and release test and evaluated the modified Japanese Orthopaedic Association (JOA) score for cervical myelopathy. RESULTS: The mean value of FTT was 23.8 +/- 7.2 in myelopathic patients, which was significantly lower than 31.7 +/- 6.4 in healthy controls and decreased with age. The value of FTT significantly correlated with the lower extremity motor function of modified JOA score and the value of grip and release test. Among the patients who underwent surgery, the average value of FTT was 22.4 +/- 7.0 preoperatively and improved to 28.4 +/- 8.1 at 1 year postoperatively. Postoperative gain of FTT significantly correlated with the gain of JOA score. CONCLUSION: The FTT results correlated with those of other tests for cervical myelopathy, and the FTT scores were improved by surgery. The FTT is an easy and useful quantitative assessment method for lower extremity motor function in patients with cervical myelopathy, especially those who cannot walk. PMID- 21252820 TI - Evidence of an inherited predisposition for cervical spondylotic myelopathy. AB - STUDY DESIGN: A retrospective, population-based study cross-referencing a genealogic database of over 2 million Utah residents with 10 years of clinical diagnosis data from a large tertiary hospital. OBJECTIVE: The objective of this study is to determine the presence or absence of an inherited predisposition to the development of cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: A genetic predisposition for the development of cervical spondylosis has been discussed in the literature with low-quality evidence. Families with a high incidence of disease or early-onset disease in monozygotic twins have both been reported. However, these suggestions of an inherited predisposition for disease have never been rigorously studied. The purpose of this study is to determine a genetic predisposition among patients diagnosed with CSM. METHODS: The Utah Population Database combines health and genealogic data on over 2 million Utah residents. International Classification of Diseases, Ninth Revision (ICD-9) codes were used to identify 486 patients in the database with a diagnosis of CSM (ICD-9 code 721.1). The hypothesis of excessive familial clustering was tested using the Genealogical Index of Familiality (GIF), and relative risks (RRs) in relatives were estimated by comparing rates of disease in relatives with rates estimated in the relatives of five matched controls for each case. This methodology has been previously reported and validated for other disease conditions but not for CSM. RESULTS: The GIF analysis for patients with CSM showed significant excess relatedness for disease (P < 0.001). RRs were significantly elevated in both first- (RR = 5.21, CI = 2.1-13.2, P < 0.001) and third-degree relatives (RR = 1.95, CI = 1.04-3.7, P < 0.05). CONCLUSION: Excess relatedness of cases and significantly elevated RRs to both close and distant relatives supports an inherited predisposition to CSM. PMID- 21252823 TI - Is a right pedicle screw always away from the aorta in scoliosis? AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: We evaluated the aorta safety in placement of a right pedicle screw in scoliotic patients. SUMMARY OF BACKGROUND DATA: Past reports emphasized the aorta risk in placing pedicle screws on the concave left side in right thoracic scoliosis. However, risk on the right side has drawn limited interest. METHODS: Thirty-four scoliotic patients with an average age of 18.0 years were evaluated. The Cobb angle averaged 59.0 degrees +/- 14.0 degrees . From computed tomographic data, we evaluated the aorta location relative to the spine at each level from T4 to L4 and simulated placement of a right pedicle screw with a direction different from the ideal trajectory. Sensitivity analysis was performed independently by variable direction errors and screw length: the maximum error of trajectory was set to 5 degrees in the medial direction and to 5 degrees , 10 degrees , or 20 degrees in the lateral direction, and a screw length was set at 40, 45 or 50 mm. We defined "aorta-at-risk" when a patient has some level where a simulated pedicle screw involves the aorta, and compared the curve characteristics (the apical vertebral translation, the Cobb angle and the Nash-Moe grade) between the aorta at-risk cases and the aorta-no-risk cases. RESULTS: In left thoracic or lumbar curves, the aorta often resided in front of right pedicles at the periapical level. In a scenario of a simulated pedicle screw with a maximum error of 20 degrees in the lateral direction and a screw length of 50 mm, the aorta was at risk in 7 (33%) of 21 left lumbar curves. Curve characteristics of the aorta-at risk cases at L1 were a larger apical vertebral translation (P = 0.003), a larger Cobb angle (P = 0.006), and a larger Nash-Moe grade (P = 0.017) compared with those of the aorta-no-risk cases. CONCLUSION: Surgeons need to pay attention to the position of the aorta in placing a pedicle screw on the right at the periapical level of a left curve either in thoracic or lumbar spine. PMID- 21252824 TI - Clinical results of lumbar total disc arthroplasty in accordance with Modic signs, with a 2-year-minimum follow-up. AB - STUDY DESIGN: Prospective study. OBJECTIVE: The aim of this prospective study is to analyze the influence of Modic type on the clinical results of lumbar total disc arthroplasty. SUMMARY OF BACKGROUND DATA: Some patients with lumbar disc degeneration have endplate signal changes on magnetic resonance images, which have been classified by Modic. Modic-1 endplates changes are associated with an inflammatory phase of the disease whereas Modic-2 endplates changes correspond to a quiescent phase with a fatty replacement. The effect of Modic endplate changes on the clinical results of lumbar fusion has been studied by multiple authors, but the influence of Modic type on clinical outcomes of lumbar disc replacement is not known. METHODS: A total of 221 patients with a mean age of 42 years were included in this study. Of which, 107 patients were classified Modic 0, 65 Modic 1, and 49 Modic 2. Clinical evaluation (Oswestry Disability Index [ODI], lumbar and radicular pain using the Visual Analog Score [VAS]) was performed preoperatively and at 3, 6, 12, and 24 months minimum postoperatively. RESULTS: Mean follow-up was 30 months (24-72 months). Significant clinical improvement (P < 0.05) was observed in pain and ODI between the preoperative evaluation and final follow-up. Multivariate analysis between the 3 groups demonstrated a significant difference in Oswestry Disability Index (size of the effect was measured at -0.3 [-0.55-0.04]) and on the radicular pain (size of the effect was measured at -0.4 [-0.7-0.1]), with lower scores in the group classified Modic 1. CONCLUSION: Superior results were achieved in the group of patients with Modic-1 endplate changes on magnetic resonance images. These data may be helpful in patient selection and in preoperative patient counseling. PMID- 21252825 TI - Remodeling capacity of malunited odontoid process fractures in kyphotic angulation in infancy: an observation up to maturity in three patients. AB - STUDY DESIGN: A retrospective case study. OBJECTIVE: To confirm the remodeling potential of the kyphotic malunited odontoid fracture in the pediatric spine. SUMMARY OF BACKGROUND DATA: Nonsurgical reduction and immobilization is the gold standard for the odontoid fracture in infancy. However, the reduction occasionally results in incomplete repositioning of the odontoid process. The cervical spine is subsequently immobilized until fusion in most cases in the hope of achieving remodeling with the growth of the remaining displacement and kyphotic angulation, although there are no precise data on the acceptable limit of the deformity. METHODS: Three patients (age at injury = 1 year 2 months to 3 years) with odontoid process fracture in infancy were treated conservatively and the fractures were observed on plain lateral radiographs until at least the age of 20 years. For evaluation of the angulated odontoid process, we used our original measurement method of the odontoid process tilting angle (OPTA). In addition, the OPTAs were also measured in 127 Japanese adult patients (57 male patients and 70 female patients; average age = 43 years) without a history of odontoid fracture, as normal controls. RESULTS: The OPTA in the normal controls was -21.4 degrees +/- 23.3 degrees . The OPTAs ranged from 41 degrees to 62 degrees at the initial evaluation, from 12 degrees to 30 degrees at the time of bony union, and from -4 degrees to -14 degrees at the final follow-up at more than 20 years of age, which were all within one standard deviation of the mean in the normal adult controls. CONCLUSION: Angulated odontoid fractures with the OPTA around 30 degrees at the time of bony union in infants younger than 3 years of age could have the capacity for remodeling to the normal morphology. No surgical reduction might be needed to recommend complete apposition of the odontoid process in the absence of severe or deteriorating neural impairment. PMID- 21252826 TI - Acutely progressing paraplegia caused by traumatic disc herniation through posterior Schmorl's node opening into the spinal canal in lumbar Scheuermann's disease. AB - STUDY DESIGN: A case report. OBJECTIVE: To report an unusual neurologic complication caused by traumatic disc herniation through atypical posterior Schmorl's node (SN) opening into the spinal canal in lumbar Scheuermann's disease. SUMMARY OF BACKGROUND DATA: Neurologic complications in Scheuermann's disease are rare and disc hernia has been reported as one of the causes of neural compression. However, there has been no report on acutely progressing paraplegia caused by traumatic disc herniation through an atypical posterior SN opening into the spinal canal in lumbar Scheuermann's disease. METHODS: A clinical and radiologic review of such a case of traumatic disc herniation through an atypical posterior SN that resulted in acutely progressing paraplegia in Scheuermann's disease was performed. RESULTS: The patient presented with severe back pain after a fall, without any neurologic abnormalities. Computed tomographic scan revealed lumbar Scheuermann's disease, acute compression fracture of T12, and a large posterior SN with "trough-like" indentation of the lower endplate of T12 opening into the spinal canal. Abruptly progressing paraplegia occurred in less than 24 hours after the first visit and the magnetic resonance imaging revealed severe spinal cord compression by large disc extrusion with superior migration at T12-L1 through the atypical posterior SN at the lower endplate of T12. The patient underwent posterior decompression and discectomy at T12-L1 through transfacet pedicle-sparing approach. Postoperatively, the patient showed immediate improvement in the sensory deficit on L1 dermatome and the perianal area and motor function of the hip flexors to grade 2 without further neurologic improvement, at 2-year follow-up. CONCLUSION: The case report highlights the clinical significance of the atypical posterior SN that could be a channel for large disc extrusion after a traumatic event in Scheuermann's disease and the clinical importance of surgeon's close attention to the possibility of abruptly progressing neurologic compromise in this situation. PMID- 21252827 TI - Early failure of metal-on-metal artificial disc prostheses associated with lymphocytic reaction: diagnosis and treatment experience in four cases. AB - STUDY DESIGN: Report of four collected cases. OBJECTIVE: The purpose of this report is to describe the presentation, diagnostic workup, treatment, and pathologic findings in four cases of lymphocytic reaction in patients receiving a metal-on-metal total disc replacement (TDR). SUMMARY OF BACKGROUND DATA: Metal-on metal designs in hip arthroplasty have gained popularity because of decreased volumetric wear rates and theoretically increased implant longevity. Systemic metal ions produced have not been associated with adverse clinical sequelae, although there have been reports of local soft-tissue reactions leading to early prosthetic failure. Histologic evaluation in these cases suggested a cell mediated delayed-type hypersensitivity reaction. Metal-on-metal bearings have also emerged in lumbar and cervical TDR. METHODS: This report is on four patients, from three centers, who underwent TDR, using a metal-on-metal implant, and later presented with symptoms that were determined to be due to lymphocytic reaction. Details of their symptoms, diagnostic work-up, treatment, and outcomes were compiled. RESULTS: All four patients initially had a good surgical outcome, followed by the onset and worsening of axial pain, and/or radicular symptoms months later. All patients had imaging findings of a mass lesion with neurologic impingement. All three of the lumbar patients underwent a decompressive posterior procedure before the eventual device removal and fusion. Intraoperatively, in all the lumbar cases, a thick, yellowish, avascular soft-tissue mass was found to be responsible for an epidural-mass effect on the thecal sac. In the cervical case, there was a gray-tinged soft-tissue response around the implant, suggestive of metallosis. Independent laboratory analysis confirmed a lymphocytic reaction to the implant. Three of the patients had a good outcome after the explant and revision surgery. The remaining patient continued to have residual symptoms related to the neural compression caused by the mass. CONCLUSIONS: In this group of patients from three centers, a metal-on-metal TDR resulted in a lymphocytic reaction causing subsequent failure of the surgery. This phenomenon has previously been recognized with metal bearings in hip arthroplasty. Surgeons using metal-on-metal TDRs should be aware of this possible occurrence. PMID- 21252828 TI - Health-related quality of life after living donor nephrectomy: a randomized controlled trial of laparoscopic versus open nephrectomy. AB - BACKGROUND: The aim of this study was to compare patient-reported health status and quality of life after randomization to laparoscopic donor nephrectomy (LDN) or short-incision open donor nephrectomy (ODN). METHODS: Live kidney donors were randomized in a 2:1 ratio to LDN (n=56) or ODN (n=28). Health-related quality of life was assessed using the Short Form 36 questionnaire preoperatively and at 6 weeks postdonation. RESULTS: Postoperative morphine requirement was lower in the LDN group (median [range], 59 [6-136]) versus ODN group (90 [35-312] mg; P=0.001). Norm adjusted physical components scores decreased significantly at 6 weeks in both the LDN and ODN groups. The bodily pain domain score of physical components score at 6 weeks returned to baseline in the laparoscopic group (86.4+/-19.8 vs. 81.8+/-15.9; P=0.2277) but not in the open group (87.3+/-18.3 vs. 69.0+/-25.0; P=0.05). The mental component score decreased in the ODN group (53.5+/-7.6 vs. 45.3+/-10.1; P=0.0084) but returned to baseline 6 weeks after LDN (53.8+/-6.5 vs. 51.9+/-7.2; P=0.2931). CONCLUSIONS: Donors undergoing laparoscopic nephrectomy reported less bodily pain in the first 6 weeks postdonation, and this was associated with an improved mental health component of quality of life compared with ODN (51.9+/-7.2 vs. 45.3+/-10.1; P=0.0009). PMID- 21252829 TI - The effects of abdominal opening on respiratory mechanics during general anaesthesia for open bariatric surgery in morbidly obese patients. AB - BACKGROUND: Morbid obesity BMI 40 kg mL-2 is associated with several changes in anatomy and physiology of the respiratory system. Respiratory work is increased whereas compliance of the chest wall and lungs is decreased. Increased intra abdominal pressure compresses the diaphragm and reduces its movability. Abdominal opening should influence respiratory mechanics. METHODS: Forty-seven morbidly obese patients (BMI 49.54 +/- 7.21 kg m-2) scheduled for elective bariatric surgery (open Roux-en-Y-Gastric Bypass - RYGB) were included in the study and divided into 3 groups: 40< BMI <50, 50< BMI <60 and BMI >60. Measurements were performed during general anaesthesia at two time points: before (T1) and after abdominal opening (T2). All patients were ventilated using the volume control mode. RESULTS: Preoperative spirometry revealed significantly decreased FEV 1% in the BMI >60 group. The conditions of mechanical ventilation during general anaesthesia deteriorated with an increasing BMI. After abdominal opening,the mechanical ventilation conditions improved: increased lung compliance and decreased airway pressures. The difference was statistically significant in the entire population studied. After dividing the population into groups, however, the difference was no longer significant in patients with BMI >60. The most significant difference in peak and plateau pressures after abdominal opening was observed in patients with BMI <50. CONCLUSION: Abdominal opening improves the conditions of mechanical ventilation in morbidly obese patients; when BMI is over 60 kg m-2, this improvement may not be relevant. PMID- 21252830 TI - Adverse effects of local anaesthetics - allergy, toxic reactions or hypersensitivity. AB - BACKGROUND: There are several kinds of adverse reactions to the administration of local anaesthetics (LAs): hypersensitivity, which causes reproducible symptoms or signs, initiated by exposure to a defined stimulus at a dose tolerated by normal subjects; toxic reactions - caused by overdose or inappropriate administration; and allergy - when an immunologic mechanism can be shown to be important.The most serious adverse reaction is anaphylaxis, which can be of allergic or non-allergic (anaphylactoid) origin. We analysed clinical adverse reactions to local anaesthetic agents that occurred in the Silesian region. METHODS: Thirty-two patients, aged 22-56 years, in whom significant reactions had occurred after administration of an LA, were investigated in our institution. The investigation was based on skin prick, intradermal injections and patch testing. In every patient, the concentration of latex IgE antibodies was measured. RESULTS: True allergic reactions were confirmed in three patients. The allergens were: lidocaine in all three cases, additionally: nickel - in one person and preservative (paraben) - in one patient. No latex allergy was diagnosed. DISCUSSION: The results showed that real allergic reactions to LA agents are rare and that most of the reported reactions were caused by hypersensitivity. Nevertheless, in each case of adverse reaction, careful review of the history, and testing of immediate and late allergic reactions not only to LA but also to latex and preservatives, should be mandatory. PMID- 21252831 TI - Severe fungal infections in intensive therapy. AB - BACKGROUND: Identification of pathogens in severe fungal infections, by positive cultures, is usually difficult, delays appropriate therapy, and impairs treatment. Despite progress in biologic sciences, the diagnosis of candidiasis still poses a challenge. Early symptoms are not specific, and cultures are usually negative. Molecular methods are rarely used in clinical practice. Common empiric therapy of suspected fungal infection is based on examination, history, and analysis of risk factors. The aim of the study was to analyse fungal infections in ITU and to find factors which may help in their recognition. METHODS: In this retrospective study, the medical histories of ITU patients were analysed. Patients were divided into two groups: I - suspected and II - confirmed, fungal infections. The factors considered were: age, gender, suspected source of fungal infection, co-existing bacterial infection, Candida Score, laboratory tests taken on the day of fungal infection diagnosis (leukocyte count, platelets, and CRP), duration of hospitalisation, declarations of infection from departments, and results of treatment. RESULTS: Statistically significant differences between the groups were found in Candida Scores, duration of hospitalisation and departments of infection. The Candida Scores were higher among those patients in whom infections were already suspected. In this group, the duration of hospitalization was shorter, and infections frequently developed during hospitalisation in the ITU. CONCLUSION: The analysis of infections and Candida Scores helped to initiate prompt antifungal therapy and to reduce the duration of hospitalisation. Infection markers that were routinely used in the ITU were not specific, did not allow identification of patients with fungal infection. PMID- 21252832 TI - Translumbar inferior vena cava cannulation. AB - BACKGROUND: The aim of the study was to review our three year experience with translumbar insertion of dialysis catheters. METHODS: In five adult patients (4 males and one female, mean age 45 yr), requiring dialysis due to end-stage chronic renal failure, the inferior vena cava was cannulated because of the impossibility of using any other approach. All procedures were performed under fluoroscopy. After visualisation of the inferior vena cava by injection of contrast medium into a peripheral vein, the vena cava was punctured with a 20 cm long needle, at the L3 level. The position of the needle was confirmed by injection of contrast medium, and the vein was then cannulated with a peel-away cannula, using a standard Seldinger technique. Subsequently, a pre-tunneled silastic catheter was introduced and secured. RESULTS: The catheters were used for from 3 to 10 months. No case of permanent catheter dysfunction was noted. Three episodes of temporary thrombosis, in two patients, were successfully treated with heparin and urokinase. Three catheters became contaminated, but they were treated without the necessity for catheter removal. CONCLUSION: The described method is a safe and effective way of securing haemodialysis access in patients where a standard approach is not possible. PMID- 21252833 TI - A survey of anaesthesiology residents' knowledge of resuscitation guidelines. AB - BACKGROUND: Several surveys have been published, documenting the lack of knowledge of cardiopulmonary resuscitation (CPR) among anaesthesiology residents. As a result, we decided to assess the competency of local trainees in basic and advanced CPR. METHODS: The survey was conducted among 26 residents in anaesthesiology who were asked twice (at the beginning, and at the end of refresher courses) to complete an open test on adult and paediatric CPR guidelines. RESULTS: The results in the first, introductory surveys were poor. Most of the wrong answers concerned the age borderline between an adult and a child; the correct CPR sequences and their modification in children; and paediatric medication. The respondents were not able to define all reversible causes of cardiac arrest. The second survey were somewhat better, but the respondents could still not name the correct lidocaine dosage in all age groups. CONCLUSIONS: Residents in anaesthesiology show the tendency their knowledge of resuscitation guidelines to decay. Refresher life support courses should be mandatory for this group of physicians. PMID- 21252834 TI - Does the Pain-free hospital certification improve the management of pain following hernioplasty? AB - BACKGROUND: Postoperative pain still poses a serious problem for 80% of patients undergoing surgery. We assessed the effects of the implementation of standards of postoperative analgesia, according to the guidelines of the "Pain-free hospital" project, and PROSPECT group recommendations, in the daily practice of a general surgical hospital ward. METHODS: One hundred adult patients, scheduled for elective inguinal or umbilical hernia surgery, were included in the study and allocated to two groups, to receive analgesics on demand (control), or postoperative analgesia according to the introduced programs. The number of additional interventions and patients' satisfaction were chosen as primary end points to assess the clinical value of the introduced standards. Additionally, the type and dose of analgesics, and duration of hospital stay were noted. RESULTS: One additional intervention (2%) was required in the treated group, and 9 (18%) - in the control group (p=0.023). In the treated group, the patient satisfaction (0 to 10) score was rated 9 by 39 patients (78%) and 10 by 11 patients (22%). The duration of hospitalisation was similar in both groups. CONCLUSION: We confirmed the success of introducing the standards of pain treatment into the daily practice of a surgical ward. PMID- 21252835 TI - Fibreoptic intubation in awake patients. AB - BACKGROUND: Awake fibreoptic intubation has been recommended for adult patients with a difficult airway in whom anaesthesia and/or relaxation could lead to the "can not ventilate, can not intubate" situation. The paper describes three cases of elective awake intubations, as examples of our strategy in cases with a predicted difficult airway. CASE REPORTS: Three male patients with Mallampati scores 2, 3 and 3, scheduled for elective surgery, were premedicated with 7.5 mg oral midazolam and 0.5 mg iv atropine. With the patient on the operating table in the anti-Trendelenburg position, the upper airways were anaesthetized with 4 mL of topical 2% lidocaine, administered from a nebulizer via face mask. Additionally, the base of the tongue, nasal cavity and lower throat were sprayed with 10% lidocaine solution. Immediately before insertion of the bronchoscope, the patients received intravenously, 2 mg of midazolam and 0.05-0.1 ug kg-1 of fentanyl. A 5.2 mm/65 cm fibreoptic bronchoscope was inserted into the trachea and a reinforced endotracheal tube was slid down over it. Oxygen and additional doses of lidocaine were administered through the working channel of the scope. CONCLUSION: The described method is safe and effective, and can be recommended for cases where there is serious doubt about the possibility of maintaining an open airway during induction of anaesthesia, or in cases where intubation has failed during previous anaesthesia. Awake intubation is rarely associated with serious episodes of desaturation and it is usually well tolerated by motivated patients. PMID- 21252836 TI - Postoperative analgesia in a morbidly obese patient with chronic renal failure. AB - BACKGROUND: The number of surgical interventions performed in obese patients has recently been increasing. Anaesthesia in a morbidly obese patient may be difficult, due to many pathophysiologic changes and co-morbidities, together with altered pharmacokinetics and pharmacodynamics of anaesthestic agents. We present a case of multimodal preventive analgesia in a bariatric patient with chronic renal failure. CASE REPORT: A 36-year-old, morbidly obese man (BMI 47.8 kg m-2) was scheduled for a laparoscopic adjustable gastric banding (LAGB). The anaesthetic risk was increased because of hypertension, chronic renal failure, steatohepatitis and obstructive sleep apnoea syndrome. 30 minutes before anaesthesia, the patient received 2 g iv paracetamol. After induction, he was given 8 mg dexamethasone and 100 mg tramadol. All port-sites were infiltrated with 0.5% bupivacaine and adrenaline, both before skin incision, and before wound closure. Since NSAIDs and opioids were contraindicated because of the patient's co-morbidities, postoperative analgesia consisted of tramadol and paracetamol, given alternately, every 3 hours. The patient was discharged home 28 hours after surgery. DISCUSSION AND CONCLUSION: According to the Polish Postoperative Pain Management Recommendations 2008, the pain after LAGB is multifactorial and rated as category 2. The pre-emptive analgesia and postoperative regimen presented in this case can be recommended in similar cases. PMID- 21252837 TI - High frequency oscillation, extracorporeal membrane oxygenation and pumpless arteriovenous lung assist in the management of severe ARDS. AB - BACKGROUND: The protective lung strategy for severe ARDS, has markedly decreased the associated morbidity and mortality. Sometimes, even the best instrumentation and therapeutic strategy may be insufficient, and extracorporeal gas exchange support is necessary. We describe a desperate case of ARDS, in which various modes of ventilation, combined with vigorous extracorporeal support, resulted in a successful outcome. CASE REPORT: A 35-year-old man, a heavy smoker, was admitted to the hospital because of lobar pneumonia. Despite wide spectrum antimicrobial therapy, he developed ARDS and was placed on a ventilator. Standard ventilation was ineffective and veno-venous ECMO was instituted. The extravascular lung water index (EVLWI) was extremely high (over 30 mL kg-1) and signs of a hyperdynamic circulation (CI 6.1 L m-2 min-1) were observed. Modification of the inotropic support and continuous infusion of furosemide resulted in normalisation of the hydration status, and over a week of ECMO therapy, the patient's general condition improved to the stage that he was scheduled to be weaned from extracorporeal treatment. On the 7th day however, he suddenly deteriorated. A lung CT-scan revealed bilateral pneumothoraces and diffuse pulmonary embolism. Three thoracic drains were inserted, but unfortunately, the drainage was complicated by massive bleeding and a subsequent thoracotomy. Two days later, a gastrointestinal haemorrhage occurred. Heparin dosage was reduced, and ECMO was discontinued and replaced with HFOV. This resulted in adequate oxygenation, however because of ineffective CO2 elimination, pumpless arteriovenous extracorporeal lung assist (PECLA) was instituted, allowing conventional ventilation to be resumed after 8 days. The further clinical course was complicated by persistent bilateral pneumothoraces, pleural effusion and Pseudomonas nosocomial infection. The man eventually recovered after 54 days in the ICU, and was transferred to a rehabilitation department. DISCUSSION AND CONCLUSION: ECMO has been recommended for severe ARDS since it avoids overdistension of the lungs and the use of high oxygen concentrations. Early institution of ECMO decreases mortality and morbidity in rapidly progressing ARDS. In the described case, ECMO was probably started too late, after volutrauma has already occurred. A combination of HFOV and PECLA may be recommended in selected cases, in which CO2 retention poses a serious problem. PMID- 21252839 TI - Haemodialysis catheters. AB - Haemodialysis central venous catheters are commonly being introduced in patients requiring emergency or chronic renal replacement therapy. There are two main categories of haemodialysis catheters: 1. Non-tunnelled, uncuffed, designed for short-term venous access of up to three weeks. They are, made of stiff materials such as polyurethane or polyvinyl. 2. Tunnelled, cuffed catheters. They are usually made of silicone, silastic elastomeric, or carbothane, are much softer and can be used for both temporary and permanent access. The latter catheters are usually inserted via peel-away sheaths, introduced using the Seldinger technique. Unlike surgically implanted devices, they can be used immediately after correct placement under fluoroscopy. The paper reviews catheters currently available, including discussion of materials, design, vascular access sites, and possible complications. PMID- 21252838 TI - Clinical importance of anaesthetic preconditioning. AB - Myocardial infarction represents one of the most serious perioperative complications. Reducing the risk of perioperative myocardial infarction is one of the most important priorities of anesthetic treatment. Discovery of cardioprotective effects of volatile anesthetics exerted strong impact on everyday anesthetic practice, particularly in cardiac-surgical setting. Anesthetic preconditioning is a complex process which is divided into two separate phenomena initiated by the same event. The first, referred to as early preconditioning, involves activation of protective enzymes within cardiomyocytes and the second, referred to as late preconditioning, is dependent on de novo synthesis of these protective proteins. Although pre-, as well as post conditioning's effects on cardiomyocytes are crucial for cardioprotective effects of volatile anesthetics, their influence on coronary endothelium may be even more important for the improvement of the long-term prognosis, demonstrated in coronary surgery patients. Improved outcome after anesthesia with volatile anesthetics in non-cardiac surgical patients at risk of perioperative myocardial infarction has not been univocally demonstrated yet. Some data indicate that volatile anesthetics, especially sevoflurane, reduces inflammatory response to ischaemia-reperfusion and other pro-inflammatory stimuli. The issue of inflammatory modulation exerted by volatile anesthetics and its influence on patients' clinical condition remains to be addressed in future studies. PMID- 21252840 TI - Awake fibreoptic intubation. AB - Awake fiberoptic intubation has been recommended for adult patients with a difficult airway in whom anaesthesia and/or relaxation could lead to the "cannnot ventilate, cannot intubate" situation. We describe the strategy and protocols of such management in cases with a predicted difficult airway. The described method is safe and effective, and can be recommended for cases where there is serious doubt about the possibility of maintaining an open airway during induction of anaesthesia, or in cases where intubation has failed during previous anaesthesia. Awake intubation is rarely associated with serious episodes of desaturation and it is usually well tolerated by motivated patients. PMID- 21252841 TI - Ceftaroline fosamil (Teflaro) - a new IV cephalosporin. PMID- 21252842 TI - Botulinum toxin for chronic migraine. PMID- 21252843 TI - Denosumab for bone metastases. PMID- 21252844 TI - Genetic screening for nevoid basal cell carcinoma syndrome in patients with a solitary keratocystic odontogenic tumour is not useful. AB - AIM: The aim of this study was to investigate the need for routine genetic counselling for identification of features of nevoid basal cell carcinoma syndrome (NBCCS) in patients presenting with a solitairy keratocystic odontogenic tumour (KCOT) of the jaws. METHODS: Sixty-nine patients treated for a solitary KCOT have been followed for the possible development of second KCOTs or other signs indicative of NBCCS. In addition, 11 randomly selected patients of this group were referred for genetic counselling, including identification of germ line mutations in the Patched gene (PTCH gene). RESULTS: In none of the 69 patients clinical and radiographic manifestations of second KCOTs and/or other features associated with NBCCS were found during a follow-up period of 49.8 months. In the 11 patients referred for genetic counselling, there were no features indicative of the presence of NBCCS. No mutations in the PTCH gene could be identified. CONCLUSION: This study does not support the need for routine genetic counselling in patients presenting with a solitairy keratocystic odontogenic tumour of the jaws. PMID- 21252845 TI - Overdentures on implants placed in bone augmented with fresh frozen bone. AB - AIM: In the last decade several studies have been performed to evaluate the clinical outcome of one or two stage loaded implants supporting overdentures. Since fresh frozen bone (FFB) has an ever-increasing number of clinical applications and few reports are available on implants inserted into FFB, we performed a retrospective study on fixtures inserted in FFB and bearing overdentures. METHODS: In the period between December 2003 and December 2006, 17 patients (14 females and 3 males with a median age of about 56 years) were grafted and 60 implants inserted thereafter. A total of 17 overdentures were delivered: 8 in the mandible and 9 in the maxilla. Multiple implant systems were used: 22 Double etched, 7 SLA, 9 Anodic oxidized, and 22 CaPo4 ceramic-blasted. Implant diameter ranged from 3.25 to 4.3 mm and length from 11.5 to 16.0 mm. Implants were inserted to replace 23 incisors, 9 cuspids, 20 premolars and 8 molars. RESULTS: No implants were lost (i.e., survival rate=100%) and no differences were detected among the studied variables. Kaplan Meier algorithm and Cox regression did not reveal any statistical differences among the studied variables also as regards the success rate. CONCLUSION: Implants inserted FFB and bearing overdentures have a high survival rate and success rates, which are comparable to those of implants inserted in non-grafted bone. FFB bone is a reliable material for alveolar ridge augmentation. No difference was detected among removable prostheses supported by two or more implants. PMID- 21252846 TI - Evaluation of the dentin-pulp complex after cavity preparation with ultrasonic diamond tip. AB - AIM: The aim of this paper was to compare the dentin-pulp complex response to cavity preparation in human teeth using ultrasonic chemical vapor deposition (CVD) diamond tip and high-speed diamond bur. METHODS: Class V buccal cavities were randomly prepared in 40 premolars from 14 patients aged 11 to 15 years. The cutting time was recorded and the cavities had the axial walls protected with gutta-percha and were filled with glass ionomer cement. The teeth were extracted at intervals of 0, 5, 10 and 20 days, and were decalcified, sectioned and stained by Hematoxylin & Eosin, Masson's Trichrome and Brown & Brenn techniques. The inflammatory response and cell disorganization were blindly evaluated by two examiners. The remaining dentin thickness (RDT) was measured by a linear scale using computer software. Statistical analysis by one-way ANOVA showed no statistically significant difference (P<=0.05) among the cavities prepared with either type of instrument, with mean RDT of 1132.50 mm. Cutting time and the pulp dentin complex responses were analyzed statistically by Kruskal-Wallis and Dunn tests (P<=0.05). RESULTS: The ultrasonic CVD diamond tip took 5 times longer to prepare the cavities and there were no typical inflammatory pulp responses in cavities prepared with either type of cutting instrument, only mild to moderate cell disorganization was present. CONCLUSION: Even taking longer to cut the dental substrate, the ultrasonic CVD diamond tip produced similar pulp response compared to the conventional high-speed diamond bur. PMID- 21252848 TI - Warm gutta-percha obturation technique: a critical review. AB - Cleaning and shaping the root canals play an important role to remove the organic debris within the endodontic system. The result, however, must be maintained over time through an effective root canal fillings preventing the entry of micro organisms and tissutal fluid in the root canal system. Recently new materials have been introduced on the market, hence alternatives techniques for the root canals obturation have been developed and proposed. Even if cold lateral condensation is still considered the technique to refer to, there are numerous alternatives that use heat to achieve optimal adaptation of gutta-percha to the root canal space. The purpose of this work is to emphasize the positive aspect and points of weaknesses of different methods used for filling the root canals in order to allow the clinician to carry out choices as possible based on scientific evidence. Although many clinical trials still have not identified the superiority of one obturation technique over the others, the importance of this stage is objectively primary, so much that in the clinical practice we can notice an increasing success of endodontic treatment. PMID- 21252847 TI - Evaluation of MMP-1, MMP-10, TIMP-1, a-SMA and TGF-b1 in angiofibromas of tuberous sclerosis. AB - AIM: Tuberous sclerosis is a neurocutaneous syndrome characterized by affect multiple organs such as brain, kidneys, heart, eyes, lungs and skin. The aim of this study was to analyze the pattern of immunolocalization of markers MMP-1, MMP 10, TIMP-1, alpha-SMA and TGF-beta1 in oral and facial angiofibromas in individuals affected by tuberous sclerosis. METHODS: Microscopical analyses on hematoxilin-eosin and immunohistochemistry reactions were performed to analyze the previously cited biological markers pattern in orofacial angiofibromas. RESULTS: Reactivity was observed for MMP-1, MMP-10 and TGF-beta1, in addition to negative for TIMP-1 and alpha-SMA, except perivascular and epithelial staining for this. Concerning the intensity, a strong marking for MMP-1 in the basal layer of the epithelium, and a slight positivity in the suprabasal layers predominated. MMP-10 was slightly expressed in all epithelial layers. The connective tissue showed slight to moderate reactivity for MMP-1 and MMP-10. TIMP-1 demonstrated slight to moderate marking in the various layers of a single lesion and to TGF beta1 expression showed varied in intensity staining both between lesions and between tissue layers. CONCLUSION: MMP-1, MMP-10 and TGF-beta1 exhibited reactivity in oral and cutaneous angiofibromas with heterogeneous distribution patterns among both tissue elements analyzed in the intensity of marking the same among the specimens. TIMP-1 showed reactivity predominantly negative in the specimens analyzed and alpha-SMA presented restricted to epithelial and perivascular regions of these lesions. PMID- 21252849 TI - Frenulectomy: proposal of a new surgical approach and case report. AB - The frenula of the oral cavity represent the insertion of perioral muscles in jaws, consisting of a fold of the triangular fibro-connective tissue covered with mucous membrane and usually inserted at the mucogingival line. The purpose of this work, after a review of literature, was to provide the clinical signs above the median frenum removal order for the orthodontic closure of a interincisor diastema and to present a new surgical technique. PMID- 21252850 TI - Occlusion and temporomandibular disorders: a malpractice case with medical legal considerations. AB - Occlusion and temporomandibular The issue of temporomandibular disorders (TMD) diagnosis and treatment has become a matter of increasing interest in the medical legal field in recent years. The old-fashioned theories based on the occlusal paradigm was proven to be erroneous, and clinicians who still provide irreversible treatments to TMD patients have to be conscious of the potential legal consequences of their behavior. The present paper described an illustrative case report of a patient to whom extensive and irreversible occlusal therapies were performed with the unique aim to provide relief from TMD symptoms. The treatment was unsuccessful and the dental practitioner was called into cause for a professional liability claim. The clinician was judged guilty of malpractice on the basis of the lack of scientific evidence of the irreversible occlusal approaches to TMD, which were erroneously used and did not give the patient any benefit, thus forcing him to a non necessary financial and biological cost. The failure to satisfy the contract with the patient, which is usually not covered by any insurance company, forced the practitioner to give the money back to the patient. The ethical and legal implications of such case were discussed, with particular focus on the concept that medical legal advices need to satisfy the highest standards of evidence and have to be strictly based on scientific knowledge. PMID- 21252851 TI - Bisphosponates and dental implants: a case report and a brief review of literature. AB - This paper reports a brief review of literature about dental implant in patients taking bisphosphonates (BPs) and a case of a patient taking zoledronate, submitted to postextractive implant surgery. A 54-years-old woman was referred to our observation, at the First Section of Dentistry of Department of Medical Surgical Specialties, University of Catania. The patient, affected by multiple myeloma, reported being subjected to implant surgery, during the administration of zoledronate. Clinical and radiographic evaluations showed an area of BPs related osteonecrosis in the only postextraction site where no implant was positioned. From this brief review of literature, we can conclude that the risk of bisphosphonates-related osteonecrosis and of implant failure in patients taking oral bisphosphonates may be low. This is a unique case of implant surgery in patient taking intravenous bisphosphonates. For that, we cannot conclude that implant surgery is safe in patients taking intravenous bisphosphonates or that the immediate implant placement following extraction may prevent the osteonecrosis. According to guidelines of AAOMS, to date any kind of surgical procedure involving alveolar bone in patients treated with itravenous BPs is contraindicated. More studies would be needed to optimize the clinical guidelines for the treatment of patients taking BPs. PMID- 21252852 TI - An unusual case of adenoid cystic carcinoma with hard palate perforation. AB - Adenoid cystic carcinoma is a malignant tumor which occurs frequently in hard palate associated with minor salivary glands. The lesion generally presents as a painful slow growing mass and it is characterized by recurrences and distant metastasis resulting in a poor prognosis for the patient. This paper reports an atypical adenoid cystic carcinoma with palatal perforation which occurred in a young woman. Initial diagnostic hypothesis were necrotizing sialometaplasia and lues. Although adenoid cystic carcinoma is common in hard palate, cases with palatal perforation are uncommon and may lead to delay in diagnosis and therapy. PMID- 21252853 TI - Primary diffuse large B-cell lymphoma of the mandible. A case report. AB - Diffuse large B-cell lymphoma is the most common type of non-Hodgkin lymphoma and is characterized by the appearance of rapidly developing tumor lesions in the lymph nodes, spleen, liver, bone marrow or other organs. Primary extranodal presentations of this entity in bone are rare (5% of all extranodal lymphomas) and their initial manifestation is usually in the form of a single bone lesion. This paper addresses a case of a 62-year-old male diagnosed with diffuse large B cell lymphoma in the mandible. The patient had left mandibular swelling with intermittent paresthesia of the left lower lip and chin, without apparent neck adenopathies. No other locations were identified in the several exams performed, and the final diagnosis was an asymptomatic diffuse extranodal large B-cell lymphoma (IE-A) in the body of the left mandible. Four cycles of chemotherapy were given according to the R-CHOP protocol (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus external radiotherapy targeted to the involved site, resulting in complete remission of the tumor. Such lesions are fairly uncommon in daily clinical practice. However, considering their severity and the importance of an early diagnosis, such conditions should be included in the differential diagnosis of bone lesions in the orofacial region. PMID- 21252854 TI - Colony forming cell (CFC) assay for human hematopoietic cells. AB - Human hematopoietic stem/progenitor cells are usually obtained from bone marrow, cord blood, or peripheral blood and are used to study hematopoiesis and leukemogenesis. They have the capacity to differentiate into lymphoid and myeloid lineages. The colony forming cell (CFC) assay is used to study the proliferation and differentiation pattern of hematopoietic progenitors by their ability to form colonies in a semisolid medium. The number and the morphology of the colonies formed by a fixed number of input cells provide preliminary information about the ability of progenitors to differentiate and proliferate. Cells can be harvested from individual colonies or from the whole plate to further assess their numbers and differentiation states using flow cytometry and morphologic evaluation of Giemsa-stained slides. This assay is useful for assessing myeloid but not lymphoid differentiation. The term myeloid in this context is used in its wider sense to encompass granulocytic, monocytic, erythroid, and megakaryocytic lineages. We have used this assay to assess the effects of oncogenes on the differentiation of primary human CD34+ cells derived from peripheral blood. For this purpose cells are transduced with either control retroviral construct or a construct expressing the oncogene of interest, in this case NUP98-HOXA9. We employ a commonly used retroviral vector, MSCV-IRES-GFP, that expresses a bicistronic mRNA that produces the gene of interest and a GFP marker. Cells are pre-activated by growing in the presence of cytokines for two days prior to retroviral transduction. After another two days, GFP+ cells are isolated by fluorescence-activated cell sorting (FACS) and mixed with a methylcellulose containing semisolid medium supplemented with cytokines and incubated till colonies appear on the surface, typically 14 days. The number and morphology of the colonies are documented. Cells are then removed from the plates, washed, counted, and subjected to flow cytometry and morphologic examination. Flow cytometry with antibodies specific to the cell surface markers expressed during hematopoiesis provides information about lineage and maturation stage. Morphological studies of individual cells under a microscope after Wright- Giemsa staining provide further information with regard to lineage and maturation. Comparison of cells transduced with control empty vector to those transduced with an oncogene reveals the effects of the oncogene on hematopoietic differentiation. PMID- 21252855 TI - A single immunoglobulin-domain protein required for clustering acetylcholine receptors in C. elegans. AB - At Caenorhabditis elegans neuromuscular junctions (NMJs), synaptic clustering of the levamisole-sensitive acetylcholine receptors (L-AChRs) relies on an extracellular scaffold assembled in the synaptic cleft. It involves the secreted protein LEV-9 and the ectodomain of the transmembrane protein LEV-10, which are both expressed by muscle cells. L-AChRs, LEV-9 and LEV-10 are part of a physical complex, which localizes at NMJs, yet none of its components localizes independently at synapses. In a screen for mutants partially resistant to the cholinergic agonist levamisole, we identified oig-4, which encodes a small protein containing a single immunoglobulin domain. The OIG-4 protein is secreted by muscle cells and physically interacts with the L-AChR/LEV-9/LEV-10 complex. Removal of OIG-4 destabilizes the complex and causes a loss of L-AChR clusters at the synapse. Interestingly, OIG-4 partially localizes at NMJs independently of LEV-9 and LEV-10, thus providing a potential link between the L-AChR-associated scaffold and local synaptic cues. These results add a novel paradigm for the immunoglobulin super-family as OIG-4 is a secreted protein required for clustering ionotropic receptors independently of synapse formation. PMID- 21252856 TI - PICK1 inhibition of the Arp2/3 complex controls dendritic spine size and synaptic plasticity. AB - Activity-dependent remodelling of dendritic spines is essential for neural circuit development and synaptic plasticity, but the precise molecular mechanisms that regulate this process are unclear. Activators of Arp2/3-mediated actin polymerisation are required for spine enlargement; however, during long-term depression (LTD), spines shrink via actin depolymerisation and Arp2/3 inhibitors in this process have not yet been identified. Here, we show that PICK1 regulates spine size in hippocampal neurons via inhibition of the Arp2/3 complex. PICK1 knockdown increases spine size, whereas PICK1 overexpression reduces spine size. NMDA receptor activation results in spine shrinkage, which is blocked by PICK1 knockdown or overexpression of a PICK1 mutant that cannot bind Arp2/3. Furthermore, we show that PICK1-Arp2/3 interactions are required for functional hippocampal LTD. This work demonstrates that PICK1 is a novel regulator of spine dynamics. Via Arp2/3 inhibition, PICK1 has complementary yet distinct roles during LTD to regulate AMPA receptor trafficking and spine size, and therefore functions as a crucial factor in both structural and functional plasticity. PMID- 21252858 TI - Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. AB - A new lung adenocarcinoma classification is being proposed by the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society (IASLC/ATS/ERS). This proposal has not yet been tested in clinical datasets to determine whether it defines prognostically significant subgroups of lung adenocarcinoma. In all, 514 patients who had pathological stage I adenocarcinoma of the lung classified according to the Union for International Cancer Control/American Joint Committee on Cancer 7th Edition, and who had undergone a lobectomy with mediastinal lymph node dissection were retrospectively reviewed. Comprehensive histological subtyping was used to estimate the percentage of each histological subtype and to identify the predominant subtype. Tumors were classified according to the proposed new IASLC/ATS/ERS adenocarcinoma classification. Statistical analyses were made including Kaplan-Meier and Cox regression analyses. There were 323 females (63%) and 191 males (37%) with a median age of 69 years (33-89 years) and 298 stage IA and 216 stage IB patients. Three overall prognostic groups were identified: low grade: adenocarcinoma in situ (n=1) and minimally invasive adenocarcinoma (n=8) had 100% 5-year disease free survival; intermediate grade: non-mucinous lepidic predominant (n=29), papillary predominant (n=143) and acinar predominant (n=232) with 90, 83 and 84% 5-year disease-free survival, respectively; and high grade: invasive mucinous adenocarcinoma (n=13), colloid predominant (n=9), solid predominant (n=67) and micropapillary predominant (n=12), with 75, 7170 and 67%, 5-year disease-free survival, respectively (P<0.001). Among the clinicopathological factors, stage 1B versus 1A (P<0.001), male sex (P<0.008), high histological grade (P<0.001), vascular invasion (P=0.002) and necrosis (P<0.001) were poorer prognostic factors on univariate analysis. Both gross tumor size (P=0.04) and invasive tumor size adjusted by the percentage of lepidic growth (P<0.001) were significantly associated with disease-free survival with a slightly stronger association for the latter. Multivariate analysis showed the prognostic groups of the IASLC/ATS/ERS histological classification (P=0.038), male gender (P=0.007), tumor invasive size (P=0.026) and necrosis (P=0.002) were significant poor prognostic factors. In summary, the proposed IASLC/ATS/ERS classification of lung adenocarcinoma identifies histological categories with prognostic differences that may be helpful in identifying candidates for adjunctive therapy. The slightly stronger association with survival for invasive size versus gross size raises the need for further studies to determine whether this adjustment in measuring tumor size could impact TNM staging for small adenocarcinomas. PMID- 21252859 TI - Molecular mechanisms of epidermal growth factor receptor overexpression in patients with cervical cancer. AB - The epidermal growth factor receptor is overexpressed in 70-90% of cervical cancers. Previously, we have shown that epidermal growth factor receptor overexpression independently predicts poor prognosis in cervical cancer patients, which makes it a potential therapeutic target. The aim of this study was to systematically analyze the molecular mechanism leading to epidermal growth factor receptor overexpression in cervical cancer. All experiments were performed on archival paraffin-embedded material. In 166 cervical cancer patients, cytoplasmic, membrane and phosphorylated epidermal growth factor receptor protein expression were studied in association with patient survival. Membrane epidermal growth factor receptor overexpression was associated with poor disease-specific survival (P=0.027). This association was particularly present in human papillomavirus 16-positive patients (P=0.029). We analyzed whether epidermal growth factor receptor overexpression was caused by gene amplification using fluorescence in situ hybridization. Epidermal growth factor receptor gene copy number was linked to chromosome 7 ploidy, as no gene amplification could be detected when corrected for chromosome 7 centromeric signals. Chromosome 7 aneuploidy was associated with membrane epidermal growth factor receptor overexpression (P=0.013). Additional mutation analysis was performed by sequencing pure, flow-sorted tumor cells, but no mutations were detected. Furthermore, human papillomavirus 16 E5 and E6 oncogene mRNA expression was measured, using quantitative real-time polymerase chain reaction, to determine the association between the human papillomavirus and epidermal growth factor receptor overexpression. High human papillomavirus 16 E5 and E6 mRNA expression were associated with decreased survival (P=0.045 and 0.047, respectively). High human papillomavirus 16 E6 mRNA expression was associated with membrane epidermal growth factor receptor overexpression (P=0.013). This is the first study performed on cancer patient material showing that chromosome 7 aneuploidy and high human papillomavirus 16 E6 mRNA expression lead to membrane epidermal growth factor receptor overexpression in cervical cancer. PMID- 21252857 TI - The role of Mediator in small and long noncoding RNA production in Arabidopsis thaliana. AB - Mediator is a conserved multi-subunit complex known to promote the transcription of protein-coding genes by RNA polymerase II (Pol II) in eukaryotes. It has been increasingly realized that Pol II transcribes a large number of intergenic loci to generate noncoding RNAs, but the role of Mediator in Pol II-mediated noncoding RNA production has been largely unexplored. The role of Mediator in noncoding RNA production in plants is particularly intriguing given that plants have evolved from Pol II two additional polymerases, Pol IV and Pol V, to specialize in noncoding RNA production and transcriptional gene silencing at heterochromatic loci. Here, we show that Mediator is required for microRNA (miRNA) biogenesis by recruiting Pol II to promoters of miRNA genes. We also show that several well characterized heterochromatic loci are de-repressed in Mediator mutants and that Mediator promotes Pol II-mediated production of long noncoding scaffold RNAs, which serve to recruit Pol V to these loci. This study expands the function of Mediator to include Pol II-mediated intergenic transcription and implicates a role of Mediator in genome stability. PMID- 21252860 TI - Association of arterial stiffness indexes, determined from digital volume pulse measurement and cardiovascular risk factors in chronic kidney disease. AB - BACKGROUND: Progression of atherosclerosis with increased arterial stiffness is associated with increased cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Compliance index (CI) derived from digital volume pulse (DVP), measuring the relationship between volume and pressure changes in fingertip, can evaluate the local arterial stiffness. The purpose of this study was to measure the stiffness of different arteries and determine the relationships of CI-DVP with clinical characteristics and renal function in CKD patients. METHODS: This cross-sectional pilot study included 186 CKD and 46 healthy subjects. Evaluation of different arterial stiffness was performed by DVP using dual-channel photoplethysmography and measured as CI (CI-DVP) and pulse wave velocity (PWV)-DVP. RESULTS: CKD patients had lower CI-DVP and higher PWV DVP than that in the healthy group. There was a trend of stepwise decrease in CI DVP and increase in PWV-DVP related to the advance of CKD from early to late stage. Decrease of CI-DVP was associated with the increase in number of cardiovascular risk factors. Multivariate linear regression analysis revealed that CI-DVP (B = 4.59, P < 0.01) was independently associated with estimated glomerular filtration rate (eGFR). Male gender, eGFR, and systolic blood pressure (BP) were independent determinants for CI-DVP (B = -0.25, P = 0.01; B = 0.007, P = 0.03; and B = -0.03, P < 0.0001; whole model R(2) = 0.28, P < 0.0001). CONCLUSIONS: Our data demonstrate a significant association between CI-DVP, a new surrogate marker of arterial stiffness different from PWV, and renal function and cardiovascular risk factors in CKD patients. PMID- 21252861 TI - First trimester uric acid and adverse pregnancy outcomes. AB - BACKGROUND: The association of elevated serum uric acid with the development of hypertension is established outside of pregnancy. We investigated whether first trimester uric acid was associated with the development of the following: gestational hypertension or pre eclampsia, these outcomes stratified by presence of hyperuricemia at delivery since this denotes more severe disease, preterm birth, or small for gestational age (SGA). METHODS: Uric acid was measured in 1,541 banked maternal plasma samples from a prior prospective cohort study that were collected at a mean gestational age of 9.0 (+/- 2.5) weeks. Polytomous regressions were performed and adjusted for parity and prepregnancy body mass index (BMI). RESULTS: First trimester uric acid in the highest quartile (>3.56 mg/dl) compared to lowest three quartiles was associated with an increased risk of developing pre-eclampsia (adjusted odds ratio (OR) = 1.82; 95% confidence interval (CI), 1.03-3.21) but not gestational hypertension. In women with hypertensive disease complicated by hyperuricemia at delivery, high first trimester uric acid was associated with a 3.22-fold increased risk of hyperuricemic gestational hypertension (HU) and a 3.65-fold increased risk of hyperuricemic pre-eclampsia (HPU). High first trimester uric acid was not associated with gestational hypertension or pre-eclampsia without hyperuricemia (H or HP) at delivery, preterm birth, or SGA. In women who developed hypertensive disease, elevated uric acid at delivery was only partly explained by elevated uric acid in the first trimester (r(2) = 0.23). CONCLUSIONS: First trimester elevated uric acid was associated with later pre-eclampsia and more strongly with pre-eclampsia and gestational hypertension with hyperuricemia. PMID- 21252862 TI - NOS3 variants, physical activity, and blood pressure in the European Youth Heart Study. AB - BACKGROUND: In this study, we examined the influence of genetic variation in NOS3 on resting blood pressure (BP) in children and adolescents from the European Youth Heart Study (EYHS). Because the NOS3 gene expression is altered by physical activity (PA), we also tested for interaction between habitual PA and NOS3 variants on BP. METHODS: A cross-sectional, random sample of 8-10-year old children (n = 1,214) and 14-16-year old adolescents (n = 1,141) from Denmark and Estonia were genotyped for four NOS3 tagging polymorphisms (rs1800783, rs1799983 (Glu298Asp), rs3918227, rs743507). PA was measured objectively using a hip mounted accelerometer and through self-reported bicycling and TV-viewing. Permutation testing was used to correct for multiple testing, yielding an alpha level of 0.006. RESULTS: Glu298Asp showed age-group-dependent associations with BP. In adolescents, Asp298 allele homozygotes had 0.19 s.d. (95% confidence interval (CI): 0.06; 0.13, P = 0.004) higher diastolic BP (DBP) and 0.25 s.d. (95% CI: 0.05; 0.46, P = 0.015) higher systolic BP (SBP), compared to Glu298 allele carriers. None of the three other single-nucleotide polymorphisms (SNPs) were associated with BP in adolescents. In children, none of the SNPs were associated with BP. No evidence of interaction between Glu298Asp and objectively measured PA was observed. Both self-reported bicycling and TV-viewing nominally modified the association between Glu298Asp and BP in adolescents (P < 0.05), the genetic effect being most apparent in inactive individuals. However, none of the interactions persisted after correcting for multiple testing. CONCLUSIONS: The NOS3 Glu298Asp variant may associate with resting BP in adolescence but not in childhood, an effect that could be modified by PA. PMID- 21252863 TI - Histidine-rich glycoprotein as an early biomarker of preeclampsia. AB - BACKGROUND: Prediction of preeclampsia is of great interest and the coagulation system as well as the angiogenic pathway is known to be dysfunctional in preeclampsia. Histidine-rich glycoprotein (HRG) is a protein interacting with both these biological systems and the purpose of this prospective, longitudinal cohort study was to analyze whether there is a difference in circulating levels of HRG during pregnancy in women developing preeclampsia compared to normal healthy pregnancies. We furthermore wanted to evaluate whether HRG has the potential of being an early biomarker of preeclampsia. METHODS: A cohort of healthy pregnant women (n = 469) was enrolled at gestational weeks 8-12. Plasma samples were collected at gestational weeks 10, 25, 28, 33, and 37 and analyzed with an enzyme-linked immunosorbent assay. RESULTS: The levels of HRG decreased during pregnancy in all women, but the levels were significantly lower at gestational weeks 10, 25, and 28 in women who later developed preeclampsia than in normal pregnant women (P < 0.05, P < 0.05, and P < 0.05). CONCLUSION: Our data indicates that HRG levels in plasma might be a possible biomarker already in gestational week 10 for prediction of later onset of preeclampsia in a low risk population. PMID- 21252864 TI - Do parents of children with caries choose to opt out of positive consent dental surveys in Wales? AB - BACKGROUND: Recently, positive consent has been required for dental surveys in some parts of the UK. Concerns have been raised that when positive consent is used participation is reduced in deprived areas and reported caries levels are biased as a consequence. This paper analyses caries data collected under positive and negative consent arrangements to explore this issue further. METHOD: Retrospective analysis of response rates by deprivation fifth and by caries experience of participating children in NHS coordinated dental surveys in Wales undertaken from 2001/2 until 2005/6 using negative consent and in 2007/8 using positive consent. RESULTS: Across Wales, the change from negative to positive consent was associated with greatly decreased participation. In comparison with previous surveys there was a large increase in children sampled but not examined. The decrease in the proportion of children sampled, who were examined and found to have no decay was similar across all deprivation fifths, with no obvious deprivation-related trend. There was a much larger reduction in the number of children with decay who participated across all quintiles of deprivation. CONCLUSION: Caries status could be a more important factor than deprivation regarding opting out of the survey. It appears that children with caries are more likely to be opted out of the survey than similarly deprived peers without caries. Parents appear to be more likely to opt children with caries out of dental surveys when positive consent is used. These findings have significant implications for targets aimed at improving oral health which were set before the change in consent procedures, but reported upon after. PMID- 21252865 TI - The validity and value of revalidation. PMID- 21252866 TI - Paediatric maxillofacial injuries. PMID- 21252867 TI - Nonsultations. PMID- 21252868 TI - Duty of care. PMID- 21252869 TI - Four handed wisdom. PMID- 21252870 TI - Undermining consent. PMID- 21252871 TI - Appropriate dispensing. PMID- 21252872 TI - Dental doctor. PMID- 21252873 TI - Keep publishing! PMID- 21252882 TI - Improving oral health among schoolchildren - which approach is best? AB - This opinion piece considers the focus of the coalition government on improving the dental health of schoolchildren. It shows how oral health improvement teams have moved on from approaches which involve the education of children alone. More modern interventions are selected from a palette of evidence-informed options to suit the needs of the local population. Such options should ensure a multilevel approach. A plea is made for any new guidance to be informed by dental public health specialists who have practical experience to ensure that outdated methods are not re-introduced. PMID- 21252883 TI - The prosthetic management of gingival aesthetics. AB - Periodontal disease, trauma, and congenital defects can result in both soft tissue and hard tissue defects that can present with aesthetic problems. The management of these problems may be limited to prevention or surgical management which can result in significant morbidity especially if a second surgical site for grafting is utilised. This article describes the various prosthodontic techniques to improve gingival aesthetics using contemporary materials such as gingivally coloured composite and gingivally coloured porcelain in addition to more traditional materials such as standard prosthetic acrylic. PMID- 21252888 TI - Summary of: do parents of children with caries choose to opt out of positive consent dental surveys in Wales? PMID- 21252889 TI - NHS dental professionals' evaluation of a child protection learning resource. AB - The aim of this survey was to evaluate the impact of an educational child protection resource which had been developed and made available, free of charge, to all NHS dental practices and salaried primary dental care services in England and concurrently published online. A postal questionnaire was sent to a random sample of 1000 NHS dental practices to assess whether the learning objectives of the educational resource had been met. A total of 467 questionnaires were completed (46.7% response rate). Almost two thirds of participants (63.4%) remembered receiving the Child Protection and Dental Team (CPDT) handbook or seeing the website and almost all of them had used (looked at or read) it and felt able to access it if needed. Of the 265 users, 76.2% felt it had improved their knowledge of child protection, 60.5% had adopted a child protection policy, 53.7% had identified a child protection lead and 25.8% had arranged further training as a result of using the educational resource. The findings from the evaluation indicated that the learning objectives of the CPDT educational resource had been met and highlighted ways in which the resource could be further improved to effectively meet the needs of dental professionals. PMID- 21252890 TI - Sir John Lavery's The Dentist (Conrad Ackner and his Patient). AB - The rise of the dental profession coinciding with the invention and rapid spread of photography means that there are very few paintings of dentists in action. The present article describes Sir John Lavery's unusual depiction of The Dentist (Conrad Ackner and his Patient) in which the conventions of contemporary society portraiture are set aside. The resulting canvas has much to tell us about the up to-date equipment used in a surgery of the late twenties by a successful practitioner who pioneered the use of X-rays. PMID- 21252908 TI - F-box protein 10, an NF-kappaB-dependent anti-apoptotic protein, regulates TRAIL induced apoptosis through modulating c-Fos/c-FLIP pathway. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces selective apoptotic death of human cancer cells while sparing normal human cells. Although TRAIL holds great promise as a potential anticancer agent, some tumors develop resistance to TRAIL. Previously, we have shown that the activator protein 1 (AP 1) family member, c-Fos, is an important modulator of apoptosis. Although F- box protein 10 (FBXL10) has been implicated to regulate an AP-1 family protein, c Jun, its role in mediating apoptotic pathways has not been previously investigated. Here, we report that FBXL10 is a transcriptional repressor of c-Fos and a target gene of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB)-p65 in human cancers. We demonstrate that FBXL10 is an important anti-apoptotic molecule, which directly binds and represses c-Fos promoter in order for cancer cells to resist TRAIL-induced apoptosis. FBXL10 indirectly regulates c-FLIP(L) levels via c-Fos-dependent pathways. Silencing of FBXL10 sensitizes resistant cells to TRAIL, while, overexpression of FBXL10 represses TRAIL-induced apoptosis. Moreover, our results indicate that expression of FBXL10 functions via an NF-kappaB-dependent pathway, and TRAIL or proteasome inhibitors downregulate FBXL10 via inhibiting NF-kappaB signaling. Taken together, we find a novel functional role for FBXL10 as an anti-apoptotic molecule, and describe a new apoptotic-related pathway that involves NF kappaB/FBXL10/c-Fos/c-FLIP. Therefore, silencing FBXL10 can help overcome resistant cancer cells for pro-apoptotic therapies. PMID- 21252909 TI - Diacylglycerol kinase alpha regulates the formation and polarisation of mature multivesicular bodies involved in the secretion of Fas ligand-containing exosomes in T lymphocytes. AB - Multivesicular bodies (MVBs) are endocytic compartments that contain intraluminal vesicles formed by inward budding from the limiting membrane of endosomes. In T lymphocytes, these vesicles contain pro-apoptotic Fas ligand (FasL), which may be secreted as 'lethal exosomes' upon fusion of MVBs with the plasma membrane. Diacylglycerol kinase alpha (DGKalpha) regulate the secretion of exosomes, but it is unclear how this control is mediated. T-lymphocyte activation increases the number of MVBs that contain FasL. DGKalpha is recruited to MVBs and to exosomes in which it has a double function. DGKalpha kinase activity exerts a negative role in the formation of mature MVBs, as we demonstrate by the use of an inhibitor. Downmodulation of DGKalpha protein resulted in inhibition of both the polarisation of MVBs towards immune synapse and exosome secretion. The subcellular location of DGKalpha together with its complex role in the formation and polarised traffic of MVBs support the notion that DGKalpha is a key regulator of the polarised secretion of exosomes. PMID- 21252910 TI - Repression of Puma by scratch2 is required for neuronal survival during embryonic development. AB - Although Snail factors promote cell survival in development and cancer, the tumor suppressor p53 promotes apoptosis in response to stress. p53 and Snail2 act antagonistically to regulate p53 upregulated modulator of apoptosis (Puma) and cell death in hematopoietic progenitors following DNA damage. Here, we show that this relationship is conserved in the developing nervous system in which Snail genes are excluded from vertebrate neurons and they are substituted by Scratch, a related but independent neural-specific factor. The transcription of scratch2 is induced directly by p53 after DNA damage to repress puma, thereby antagonizing p53-mediated apoptosis. In addition, we show that scratch2 is required for newly differentiated neurons to survive by maintaining Puma levels low during normal embryonic development in the absence of damage. scratch2 knockdown in zebrafish embryos leads to neuronal death through the activation of the intrinsic and extrinsic apoptotic pathways. To compensate for neuronal loss, the proliferation of neuronal precursors increases in scratch2-deficient embryos, reminiscent of the activation of progenitor/stem cell proliferation after damage-induced apoptosis. Our data indicate that the regulatory loop linking p53/Puma with Scratch is active in the vertebrate nervous system, not only controlling cell death in response to damage but also during normal embryonic development. PMID- 21252911 TI - Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells: implications for Alzheimer's disease. AB - Protein folding stress in the endoplasmic reticulum (ER) may lead to activation of the unfolded protein response (UPR), aimed to restore cellular homeostasis via transcriptional and post-transcriptional mechanisms. ER stress is also reported to activate the ER overload response (EOR), which activates transcription via NF kappaB. We previously demonstrated that UPR activation is an early event in pre tangle neurons in Alzheimer's disease (AD) brain. Misfolded and unfolded proteins are degraded via the ubiquitin proteasome system (UPS) or autophagy. UPR activation is found in AD neurons displaying both early UPS pathology and autophagic pathology. Here we investigate whether activation of the UPR and/or EOR is employed to enhance the proteolytic capacity of neuronal cells. Expression of the immunoproteasome subunits beta2i and beta5i is increased in AD brain. However, expression of the proteasome subunits is not increased by the UPR or EOR. UPR activation does not relocalize the proteasome or increase overall proteasome activity. Therefore proteasomal degradation is not increased by ER stress. In contrast, UPR activation enhances autophagy and LC3 levels are increased in neurons displaying UPR activation in AD brain. Our data suggest that autophagy is the major degradational pathway following UPR activation in neuronal cells and indicate a connection between UPR activation and autophagic pathology in AD brain. PMID- 21252913 TI - Lost in translation: bridging the gap between cancer research and effective therapies. PMID- 21252912 TI - CASZ1, a candidate tumor-suppressor gene, suppresses neuroblastoma tumor growth through reprogramming gene expression. AB - Neuroblastoma (NB) is a common childhood malignant tumor of the neural crest derived sympathetic nervous system. In NB the frequent loss of heterozygosity (LOH) on chromosome 1p raises the possibility that this region contains tumor suppressor genes whose inactivation contributes to tumorigenesis. The human homolog of the Drosophila neural fate determination gene CASZ1, a zinc-finger transcription factor, maps to chromosome 1p36.22, a region implicated in NB tumorigenesis. Quantitative real-time PCR analysis showed that low-CASZ1 expression is significantly correlated with increased age (>=18 months), Children's Oncology Group high-risk classification, 1p LOH and MYCN amplification (all P<0.0002) and decreased survival probability (P=0.0009). CASZ1 was more highly expressed in NB with a differentiated histopathology (P<0.0001). Retinoids and epigenetic modification agents associated with regulation of differentiation induced CASZ1 expression. Expression profiling analysis revealed that CASZ1 regulates the expression of genes involved in regulation of cell growth and developmental processes. Specific restoration of CASZ1 in NB cells induced cell differentiation, enhanced cell adhesion, inhibited migration and suppressed tumorigenicity. These data are consistent with CASZ1 being a critical modulator of neural cell development, and that somatically acquired disruption of normal CASZ1 expression contributes to the malignant phenotype of human NB. PMID- 21252928 TI - Comparative effectiveness: the fourth hurdle in drug development and a role for clinical pharmacology. PMID- 21252914 TI - Autocrine motility factor/phosphoglucose isomerase regulates ER stress and cell death through control of ER calcium release. AB - Autocrine motility factor/ phosphoglucose isomerase (AMF/PGI) promotes cell survival by the pAkt survival pathway. Its receptor, gp78/AMFR, is an E3 ubiquitin ligase implicated in endoplasmic reticulum (ER)-associated protein degradation. We demonstrate here that AMF/PGI also protects against thapsigargin (TG)- and tunicamycin (TUN)-induced ER stress and apoptosis. AMF/PGI protection against the ER stress response is receptor mediated as it is not observed in gp78/AMFR-knockdown HEK293 cells. However, AMF/PGI protection against the ER stress response by TG and TUN was mediated only partially through PI3K/Akt activation. AMF/PGI reduction of the elevation of cytosolic calcium in response to either TG or inositol 1,4,5-trisphosphate receptor activation with ATP was gp78/AMFR-dependent, independent of mitochondrial depolarization and not associated with changes in ER calcium content. These results implicate regulation of ER calcium release in AMF/PGI protection against ER stress and apoptosis. Indeed, sequestration of cytosolic calcium with BAPTA-AM limited the ER stress response. Importantly, elevation of cytosolic calcium upon treatment with the calcium ionophore ionomycin, while not inducing an ER stress response, did prevent AMF/PGI protection against ER stress. By regulating ER calcium release, AMF/PGI interaction with gp78/AMFR therefore protects against ER stress identifying novel roles for these cancer-associated proteins in promoting tumor cell survival. PMID- 21252931 TI - Merrill Jon Egorin, MD, 1948-2010. AB - Merrill Egorin was born in Baltimore, Maryland, where he completed his undergraduate and graduate education. He was a pioneer in understanding the relationship of pharmacokinetic variability to the pharmacodynamics of anticancer agents. He is remembered as a compassionate physician, an outstanding scientist, an entertaining lecturer, a superb mentor, and a friend to many. PMID- 21252932 TI - Clinical pharmacology for development of topical dermatological products: present and future opportunities for safety and efficacy. AB - The development of topical products for dermatological diseases represents an untapped opportunity for the clinical pharmacologist. Assessment of bioavailability of topical drugs and its utility in weighing benefit vs. risk has been unique and challenging, compared with assessments for conventional systemic drugs. However, with continued advances in analytical methods and growing interests in discovering biomarkers, the future opportunities for clinical pharmacology to advance topical drug development processes are enormous and will be limited only by our drive and determination to push science forward. PMID- 21252933 TI - Has the FDA Amendments Act of 2007 impaired drug development? AB - Perched at the midpoint of "v.4" of the Prescription Drug User Fee Act (PDUFA-4), better known as the US Food and Drug Administration Amendments Act (FDAAA), it seems presumptuous to draw critical conclusions based on an "interim analysis" of this work in progress. Because drug development is a complex process measured in decades, one must rely on "surrogate markers" to impute FDAAA outcomes. Even so, there are many indications that the FDAAA has doused the fires of innovation, in scope, spirit, and interim results. PMID- 21252934 TI - The emergency use authorization of peramivir IV: a view from the manufacturer. AB - The 2009 H1N1 influenza pandemic prompted the US Food and Drug Administration (FDA) to issue an emergency use authorization (EUA) for the intravenous antiviral peramivir, an unapproved neuraminidase inhibitor (NAI) currently under development. Peramivir use was limited to patients for whom other NAI therapy had failed or in whom oral or inhalational drug absorption was believed to be unreliable. This introduced a patient selection bias that precluded safety and efficacy assessment. Despite the challenges and risks, there was a compelling public health need for an intravenous agent during the 2009 H1N1 pandemic. PMID- 21252935 TI - A venture capital view of challenges, opportunities, and innovation in biomedical research. AB - Small biotech companies have been an important source of innovation, pipelines, and new products for the pharmaceutical industry, and are primarily financed by venture capital (VC). The significant changes happening within the VC industry have broad implications for these small companies. This includes a shift to financing later-stage programs with increasing interest in orphan or specialty indications. Nontraditional sources of capital and innovative risk-sharing structures can enable early-stage companies. PMID- 21252936 TI - The African medicines regulatory harmonization initiative: rationale and benefits. AB - Medicines regulation remains an important but neglected component of promotion and protection of public health because it helps to ensure that patients have access to quality, safe, and efficacious medicines. Investing in the African Medicines Regulatory Harmonization (AMRH) initiative provides an opportunity for strengthening regulatory capacity, cost-effective use of the limited financial and human resources, attainment of the three health-related Millennium Development Goals (MDGs), and promotion of trade and socioeconomic development for African countries and regions. PMID- 21252937 TI - Refining the benefit-risk framework for the assessment of medicines: valuing and weighting benefit and risk parameters. AB - A common framework is necessary for the transparent articulation of the benefits and risks of a therapeutic product across disparate stakeholders. The assignment of value and weighting to each component parameter presents challenges deriving from different stakeholder objectives, methods, and perspectives. Building on prior experiences with a validated framework approach, this forum focused on identifying challenges and approaches to the assignment of values and weightings using a case study applied to a hypothetical medicinal product. PMID- 21252940 TI - BamE structure: the assembly of beta-barrel proteins in the outer membranes of bacteria and mitochondria. PMID- 21252941 TI - BAG3 mediates chaperone-based aggresome-targeting and selective autophagy of misfolded proteins. AB - Increasing evidence indicates the existence of selective autophagy pathways, but the manner in which substrates are recognized and targeted to the autophagy system is poorly understood. One strategy is transport of a particular substrate to the aggresome, a perinuclear compartment with high autophagic activity. In this paper, we identify a new cellular pathway that uses the specificity of heat shock protein 70 (Hsp70) to misfolded proteins as the basis for aggresome targeting and autophagic degradation. This pathway is regulated by the stress induced co-chaperone Bcl-2-associated athanogene 3 (BAG3), which interacts with the microtubule-motor dynein and selectively directs Hsp70 substrates to the motor and thereby to the aggresome. Notably, aggresome-targeting by BAG3 is distinct from previously described mechanisms, as it does not depend on substrate ubiquitination. PMID- 21252942 TI - Molecular breeding of healthy vegetables. PMID- 21252943 TI - Purification and identification of endogenous polySUMO conjugates. AB - The small ubiquitin-like modifier (SUMO) can undergo self-modification to form polymeric chains that have been implicated in cellular processes such as meiosis, genome maintenance and stress response. Investigations into the biological role of polymeric chains have been hampered by the absence of a protocol for the purification of proteins linked to SUMO chains. In this paper, we describe a rapid affinity purification procedure for the isolation of endogenous polySUMO modified species that generates highly purified material suitable for individual protein studies and proteomic analysis. We use this approach to identify more than 300 putative polySUMO conjugates from cultured eukaryotic cells. PMID- 21252945 TI - Development of polypoidal lesions in age-related macular degeneration. AB - PURPOSE: To investigate the development of polypoidal lesions using indocyanine green angiography (IA) in eyes with typical age-related macular degeneration (AMD). METHODS: We retrospectively reviewed the medical records of 47 consecutive patients (47 eyes) with typical AMD who had been followed up with IA for at least 2 years. RESULTS: At the initial visit, although all eyes showed classic and/or occult choroidal neovascularization (CNV) associated with AMD, no eyes showed polypoidal lesions by IA. However, during follow-up, 13 (27.7%) of the 47 eyes did show polypoidal lesions. All polypoidal lesions developed at the edge of persistent CNV or, more often, at the terminus of recently progressed CNV. Of 12 eyes with a final lesion area >8 disc area, 7 (58.3%) showed newly developed polypoidal lesions. In the eyes with these newly developed polypoidal lesions, the mean area of the vascular lesion had extended significantly from 10.50 +/- 7.88 mm2 to 20.87 +/- 10.21 mm2 during follow-up (P=0.0018). CONCLUSION: The current observation suggests that IA of active AMD sometimes reveals polypoidal lesions if there is progression of the CNV in the subretinal pigment epithelium space. PMID- 21252944 TI - Tracking adult stem cells. AB - The maintenance of stem-cell-driven tissue homeostasis requires a balance between the generation and loss of cell mass. Adult stem cells have a close relationship with the surrounding tissue--known as their niche--and thus, stem-cell studies should preferably be performed in a physiological context, rather than outside their natural environment. The mouse is an attractive model in which to study adult mammalian stem cells, as numerous experimental systems and genetic tools are available. In this review, we describe strategies commonly used to identify and functionally characterize adult stem cells in mice and discuss their potential, limitations and interpretations, as well as how they have informed our understanding of adult stem-cell biology. An accurate interpretation of physiologically relevant stem-cell assays is crucial to identify adult stem cells and elucidate how they self-renew and give rise to differentiated progeny. PMID- 21252946 TI - Modified visual field test for ptosis surgery (Leicester Peripheral Field Test). AB - INTRODUCTION: There is lack of consensus among Primary Health Care Trusts (PCTs) and health insurers on how to reimburse ptosis surgery and upper lid blepharoplasty, as these procedures can be regarded as cosmetic. Standardised photographs are expensive and difficult to achieve, whilst the routine 24-2 visual field lacks the range to detect visually significant superior field defects.AimTo introduce a modified visual field designed to assess the functional disability associated with ptosis and dermatochalasis and to demonstrate the effectiveness of surgery in improving the visual field. METHODS: Patients who had surgery for ptosis or dermatochalasis between January 2006 and December 2009 were prospectively invited to perform a modified visual field test pre- and post operatively. RESULTS: In total, 97 patients amounting to 194 eyes were included in the study. Ninety five eyes had aponeurotic repair with or without blepharoplasty and 77 eyes had blepharoplasty alone. This modified test has a sensitivity of 98.8% of detecting ptosis. For patients who underwent ptosis surgery with or without blepharoplasty, 84.2% recorded an improvement in points seen with the test and 81% recorded an improvement in visual field height. For those who had blepharoplasty alone, 90.9% recorded an improvement in points seen in the modified visual field test and 80.6% had improvement in visual field height. CONCLUSION: Our modified visual field assessment is a quick and easy way to assess patient disability associated with ptosis and dermatochalasis. Surgery improves the demonstrated defect, confirming that ptosis and dermatochalasis can be considered a functional rather than cosmetic issue. PMID- 21252947 TI - Comment on 'Pink hypopyon caused by Klebsiella pneumonia'. PMID- 21252948 TI - The Duke Elder lecture: the challenge of equitable eye care in Pakistan. AB - PURPOSE: Pakistan, like many other developing countries, is caught in the vicious cycle of poverty, illiteracy, violence, and disease. Right from its inception, it has been facing serious challenges of fast growing population, longevity, unemployment, wars, floods, double burden of diseases including blindness, as well as earthquakes, insurgencies, and political instability. Despite such challenges, the country has managed to reduce the burden of blindness from 1.78% in 1987-88 to 0.9% in 2003.This paper will highlight the methods used to achieve such a difficult goal. METHODS: The country used the report of the World Health Organization (WHO) temporary consultant as the initial tool for advocacy to obtain political and professional commitment. Results from the first National Blindness Survey 1987-1990 were used as baseline for development of the programme. Under the Ministry of Health, national and provincial committees with respective coordinators were constituted. To ensure access and equity, the national programme was developed on the basis of district comprehensive eye care services. The concept was carefully tested in a laboratory and then piloted in a real district before it was rolled over to the country. Strong national institutes for human resource development, research and development, and service delivery were established. A strong network of high-quality national institutes was set up and run by powerful national non-governmental organizations. The second National Blindness Survey evaluated the achievements of the programme in 2001-2003. CONCLUSION: National prevalence of blindness was reduced by 100% by improving the uptake of services at the district level, especially by females. PMID- 21252949 TI - The relationship between clinical signs and dry eye symptoms. AB - PURPOSE: To evaluate (i) the relationship between traditional and new clinical tests (lid-wiper epitheliopathy (LWE), lid-parallel conjunctival folds (LIPCOF)) and dry eye symptoms in non-contact lens wearers, and (ii) that a combination of these tests can improve predictive ability for the development of dry eye symptoms. METHODS: Tear meniscus height (TMH), non-invasive break-up time (NIBUT), ocular hyperaemia, LIPCOF, phenol red thread test (PRTT), corneal and conjunctival staining, and LWE grades were observed in a cohort of 47 healthy, non-lens wearers (male=17, female=30, median age=35 years, range=19-70). Symptoms were assessed using the Ocular Surface Disease Index (OSDI). RESULTS: LWE was significantly correlated to both temporal and nasal LIPCOF (0.537 0.248, P < 0.001). Significant correlations were found between NIBUT and TMH (r=0.461, P=0.001) and PRTT (r = 0.640, P < 0.001). OSDI scores were significant correlated to NIBUT, TMH, PRTT, LIPCOF, and LWE (r>?0.31?; P<0.05). Significant discriminators of OSDI+/- were NIBUT (area under the receiver operative characteristic curve (AUC)=0.895), TMH (0.715), PRTT (0.781), LIPCOF (temporal/nasal/Sum 0.748/0.828/0.816), and LWE (0.749). Best predictive ability was achieved by combining NIBUT with nasal LIPCOF (AUC=0.944). CONCLUSIONS: The individual tests NIBUT, TMH, PRTT, LIPCOF, and LWE were significantly, but moderately, related to OSDI scores. The strongest relationship appeared by combining NIBUT with nasal LIPCOF. PMID- 21252950 TI - Evolution and management of macular hole secondary to type 2 idiopathic macular telangiectasia. PMID- 21252951 TI - OCT III imaging of whiplash maculopathy. PMID- 21252952 TI - In vitro antibiotic susceptibility patterns of bacterial keratitis isolates in Oxford, UK: a 10-year review. AB - PURPOSE: To analyse the spectrum of bacterial keratitis isolates and their in vitro antibiotic susceptibilities over a 10-year period in Oxford, UK; and to compare the in vitro efficacy of ciprofloxacin with that of the combination of gentamicin and cefuroxime over the same period. METHODS: All culture-positive corneal scrapes received from the Oxford Eye Hospital between July 1999 and June 2009 were identified retrospectively using a local microbiology database. For analysis of trends over time, the data was split into two equal 5-year periods. Statistical analysis was done using the chi2 and Fisher exact tests. RESULTS: Over the 10-year study period, 467 corneal scrapes were performed of which 252 (54.0%) had positive bacterial cultures, growing a total of 267 organisms. The most commonly isolated bacteria were Staphylococci(40.1%) followed by Pseudomonasspecies (28.5%), other Gram-negative species (17.2%), Streptococci(7.1%), and Corynebacteria(6.0%). Between the first and second time periods there was an increase in the number of coagulase-negative Staphylococciand an increased resistance of the non-Pseudomonas Gram-negative group to chloramphenicol. Of the 189 isolates tested for sensitivity to both empirical antibiotic regimens, 176 (93.2%) were susceptible to ciprofloxacin whereas 188 (99.5%) were susceptible to either gentamicin or cefuroxime (P=0.0015). CONCLUSIONS: The spectrum of bacterial keratitis isolates and their in vitro antibiotic sensitivity patterns have generally remained stable over time. The combination of gentamicin and cefuroxime provides a broader spectrum of antimicrobial cover than ciprofloxacin monotherapy in Oxford, although both regimens continue to be appropriate choices for the initial management of this condition. PMID- 21252953 TI - A new ocular trauma score in pediatric penetrating eye injuries. AB - PURPOSE: To assess the prognostic value of a new ocular trauma score (OTS) in pediatric penetrating injuries. METHODS: Children <= 15 years of age that presented to the emergency room with penetrating eye injuries between April 2007 and August 2008 were evaluated prospectively. All patients were reviewed on the basis of age, gender, time of injury and how it happened, time of admission, time of surgery, type of penetrating injury, initial and final visual acuity (VA), and concomitant eye pathology. Injuries were classified based on a new OTS, and we assessed the relationship with final VA and the new OTS. RESULTS: In total, 30 eyes in 29 patients (41.38% female, 58.62% male) with a mean age of 6.83 +/- 4.00 years (range: 1-15 years) were included in the study. Initial VA, which was evaluated in 22 patients, was as follows: no light perception (NLP) in 2 (9.09%) patients, light perception (LP) to hand motion (HM) in 8 (36.36%) patients, counting fingers in 6 (27.27%) patients, 0.1-0.5 in 4 (18.18%) patients, and >= 0.6 in 2 (9.09%) patients. Final VA, which was evaluated in 27 patients, was as follows: NLP in 3 (11.11%) patients, LP to HM in 3 (11.11%) patients, counting fingers in 2 (7.41%) patients, 0.1-0.5 in 11 (40.74%) patients, and >= 0.6 in 8 (29.63%) patients. The relationship between initial VA and final VA was statistically significant (P < 0.001). CONCLUSIONS: The new OTS calculated at initial examination may be of prognostic value in children with penetrating eye injuries. PMID- 21252955 TI - Acute endophthalmitis after cataract surgery at a referral centre in Northern Taiwan: review of the causative organisms, antibiotic susceptibility, and clinical features. PMID- 21252956 TI - Prognostic factors for visual outcomes 2-years after intravitreal bevacizumab for myopic choroidal neovascularization. AB - PURPOSE: To determine the pre-treatment ocular factors significantly associated with the visual outcome 24 months after intravitreal bevacizumab (IVB) for myopic choroidal neovascularization (mCNV). METHODS: A total of 23 eyes of 23 patients with mCNV were treated with IVB followed by as needed therapy. The efficacy of IVB was evaluated by the best-corrected visual acuity (BCVA) at 24 months after the initial treatment. Forward stepwise multiple linear regression analyses were performed to evaluate the influence of pre-treatment factors on the BCVA and the improvement of the BCVA at 24 months. RESULTS: The mean pre-IVB BCVA was 0.74 +/- 0.30 logarithm of the minimum angle of resolution (logMAR) units, and it improved to 0.43 +/- 0.31 logMAR units after 1 month (P < 0.001, paired t-test). The improvement was maintained at 24 months (0.46 +/- 0.40, P < 0.005). The mean number of IVB performed during the 24 months was 1.35 +/- 0.71. Forward stepwise regression analysis showed that the pre-IVB CNV size (standardized beta = 0.52, P < 0.01) and BCVA (standardized beta = -0.44, P < 0.05) significantly affected the visual acuity change after 24 months. The CNV size was the only factor that significantly affected the BCVA after 24 months (standardized beta=0.56, P < 0.01). CONCLUSIONS: IVB with as needed therapy for mCNV led to a rapid and sustained visual improvement. Smaller CNV size was a significant prognostic factor that predicts better visual acuity. Patients with lower pre-treatment BCVA had better visual recovery than those with better pre-treatment BCVA, however, this may be due to a ceiling/floor effect. PMID- 21252957 TI - Treatment of postoperative uveal effusion in a nanophthalmic patient with posterior sub-Tenon's triamcinolone (PSTT). PMID- 21252959 TI - Blood pressures in newborns with twin-twin transfusion syndrome. AB - OBJECTIVE: In addition to unbalanced flow through placental anastomoses, evidence suggests that transfer of circulating vasoactive elements from the donor to the recipient contribute to the pathological process of twin-twin transfusion syndrome (TTTS). The objective of this study was to test the hypothesis that TTTS recipients have higher blood pressure (BP) at birth than donors. STUDY DESIGN: Chart review of all TTTS infants born from 1996 to 2007 with both twins alive ?24 h (51 pairs; average gestational age 30+/-3 weeks). RESULTS: Both systolic and diastolic neonatal BPs were significantly higher in recipients. When expressed relative to predicted BP for birth weight (BW), BP were lower than expected in donors and higher in recipients. CONCLUSIONS: Data indicate that TTTS recipients have BP significantly higher than donors and than BP expected for BW. The long term impact of these early hemodynamic perturbations remains to be determined. PMID- 21252960 TI - Regional tissue oxygenation in preterm born infants in association with echocardiographically significant patent ductus arteriosus. AB - OBJECTIVE: To analyze the levels of regional tissue oxygenation in preterm infants in association with echocardiographically significant patent ductus arteriosus (PDA). STUDY DESIGN: Preterm infants with gestational age less than 32 week were enrolled before the first dose of the pharmacological treatment for the PDA. Non-invasive near-infrared spectroscopy (NIRS) technology was utilized to measure cerebral (rSO(2)-C), renal (rSO(2)-R) and mesenteric (rSO(2-M)) tissue oxygenation for approximately 60 min. Regional fractional oxygen extraction (FOE) was calculated using simultaneously measured arterial saturation (SaO(2)). We analyzed regional tissue oxygenation and oxygen extraction, hemodynamic parameters, and demographic and clinical information in association with the size of the PDA (moderate vs large). RESULT: Among the 38 enrolled infants, the majority were diagnosed with a large (63.2%, n=24) and the rest with a moderate sized PDA. Infants with large and moderate PDA were comparable in terms of gestational age, study age and weight, mode of delivery and hemodynamic parameters. A significantly higher proportion of infants with a moderate PDA were mechanically ventilated as compared with those with a large PDA. We found no significant differences in the rSO(2)-C and rSO(2)-R, irrespective of the type of respiratory support. However, in infants with a large PDA on continuous nasal positive airway pressure (NCPAP), the rSO(2)-M was lower and mesenteric FOE was higher than that in mechanically ventilated neonates with a large PDA, and in those with moderate PDA irrespective of the type of respiratory support. CONCLUSION: The PDA size did not affect cerebral and renal tissue oxygenation, but the mesenteric tissue oxygenation was decreased in infants with a large PDA on NCPAP. PMID- 21252961 TI - The impact of feeding interval on feeding outcomes in very low birth-weight infants. AB - OBJECTIVE: Test the hypothesis that very low birth-weight (VLBW) infants fed every 2 h (q2) are able to reach full enteral feedings more quickly than infants fed every 3 h (q3). STUDY DESIGN: We performed a retrospective cohort study comparing q2 infants (n=103) with q3 infants (n=251). The primary outcome was days from start of a feeding advance to full feedings (120 ml per kg per day). Multivariable regression models were used to control for maternal and perinatal factors that preceded the initiation of the feeding advance. RESULT: Infants fed q2 reached full feedings 2.7 days sooner than q3 infants (95% confidence interval (CI) 1.5, 3.9). After adjustment for confounders, q2 infants reached full feedings 3.7 (95% CI 1.6, 5.9) days more quickly. Infants fed q3 were more likely to receive >28 days of parenteral nutrition (odds ratio (OR) 4.7; 95% CI 1.5, 14.4), and were more likely to have feeds held for >= 7 days (OR 4.7, 95% CI 1.9, 11.7). CONCLUSION: VLBW infants demonstrate improved feeding tolerance when fed more frequently. PMID- 21252962 TI - Propofol versus midazolam for intubating preterm neonates: a randomized controlled trial. AB - OBJECTIVE: The ideal combination of premedication for neonatal tracheal intubation has not been established. The aim of this preliminary study was to compare the intubation conditions between propofol and midazolam as premedication for tracheal intubation in neonates. STUDY DESIGN: A double-blinded, randomized, controlled trial was performed, and 20 preterm neonates (28 to 34 week) underwent tracheal intubation following the use of remifentanil associated to either propofol (n = 10) or midazolam (n = 10). Intubation conditions were scored according to a four-point scale. RESULT: According to the main outcome measured (identification of a 50% difference in the intubation conditions), there were no differences regarding the number of attempts and the overall intubation conditions among the groups (P = 1.00). CONCLUSION: Both combinations of premedications have no differences regarding the quality of intubation, which could be of clinical interest. Besides midazolam, propofol could be a valid alternative as hypnotic for premedication for endotracheal intubation in neonates. PMID- 21252963 TI - 'Haptoglobin concentrations in preterm and term newborns'. AB - OBJECTIVE: To measure systemic haptoglobin (HPT) concentrations from birth in preterm (PT) and T newborns. To compare HPT in newborns without hemolysis or infection with values in bacteremic newborns. STUDY DESIGN: HPT was measured using enzyme-linked immunosorbent assay in 30 PT and 28 T newborns without hemolysis or infection at birth (cord blood), on days of life 2 to 4, and at 1 to 2 weeks of life. Concentrations were measured in eight additional newborns with bacteremia. Wilcoxon-Mann-Whitney test was used for comparisons. RESULT: HPT concentrations were consistently measurable from birth in PT and T neonates. Values were significantly greater in 2- to 4-day-old PT and T newborns than in newborns at birth (P<0.01). Bacteremic newborns had higher HPT concentrations than newborns without infection (P=0.033). CONCLUSION: HPT is detectable from birth in PT and T newborns. HPT concentrations increase in bacteremic newborns. HPT levels may have clinical utility in the evaluation of neonatal sepsis. PMID- 21252964 TI - Red blood cell transfusion, feeding and necrotizing enterocolitis in preterm infants. AB - OBJECTIVE: Preliminary studies suggested an association between red blood cell (RBC) transfusion and necrotizing enterocolitis (NEC) in premature neonates. An advantageous effect of withholding feeds during transfusion has never been studied. We aimed, first, to determine whether preterm infants who developed NEC were more likely to be transfused in the 48 to 72 h before the diagnosis of NEC; second, to test if a strict policy of withholding feeds during transfusion would decrease the incidence of transfusion-associated NEC. STUDY DESIGN: The study was conducted in two phases. Phase 1: a retrospective case-control study of premature low-birth weight (<32 weeks and <2500 g) infants who developed NEC over a 6-year period. Phase 2: a comparison study of the incidence of NEC during the 18-months preceding, and the 18 months following the change of practice to withholding feeds during RBC transfusion. RESULT: In the case-control study (25 infants with NEC and 25 controls), more infants in the NEC group received transfusions in the 48 and 72 h preceding diagnosis (56 vs 20% within 48 h, P=0.019; and 64 vs 24% within 72 h, P=0.01). The total number of transfusions and age of RBCs were not different between the two groups. Implementing the policy of withholding feeds during transfusion was associated with a decrease in the incidence of NEC from 5.3 to 1.3% (P=0.047). CONCLUSION: Infants who developed NEC frequently received RBC transfusions in the 48 and 72 h preceding presentation of NEC. A strict policy of withholding feeds during transfusion may have a protective effect from NEC. PMID- 21252966 TI - Vitamin D supplementation during pregnancy: safety considerations in the design and interpretation of clinical trials. AB - Maternal-child health benefits of optimizing vitamin D status during pregnancy may include a reduced risk of pre-eclampsia, improved fetal growth and beneficial effects on infant immune function. These hypotheses require evaluation by randomized controlled antenatal vitamin D supplementation trials using doses that are high enough to elevate serum 25-hydroxyvitamin D concentrations into the range believed to be associated with improved health outcomes. Such doses may be considerably higher than the current recommended dietary allowance (600 IU day( 1)) or standard prenatal supplement dose (400 IU day(-1)), and may even be higher than the tolerable upper intake level (4000 IU day(-1)) advised by the Institute of Medicine (2010). A critical review of the published literature yielded limited data regarding the safety of antenatal vitamin D regimens. There have been no published reports of the teratogenic effects of vitamin D on humans. Some animal studies have suggested the potential for dose-dependent fetal toxicities (for example, growth impairment, skeletal malformations and cardiovascular anomalies), but the relevance of these observations to humans is unknown. Antenatal vitamin D supplementation trials should incorporate a range of methods for objectively establishing maternal and fetal safety, and aim to identify the lowest doses of vitamin D required to achieve target outcomes. PMID- 21252965 TI - Gastrointestinal complications associated with ibuprofen therapy for patent ductus arteriosus. AB - OBJECTIVE: To review intestinal complications associated with ibuprofen treatment of patent ductus arteriosus (PDA). STUDY DESIGN: Data from preterm infants treated with ibuprofen were retrospectively reviewed. chi(2) test and Fischer's exact test were used for univariate analyses. Multivariate analyses with logistic regression modeling were used to identify risk factors. RESULT: One hundred and two infants were treated with ibuprofen for PDA. Nine (9/102, 8.8%) infants developed spontaneous intestinal perforation (SIP), whereas 93/102 (91.2%) did not. The mean (+/- s.d.) gestational age (GA) at birth in infants with and without SIP was 25.2 (+/- 1.3) vs 27.6 (+/- 2.4) weeks (P=0.02) and the median (interquartile) length of stay (LOS) was 109.5 (91.0 to 116.5) vs 75.0 (53.0 to 94.5) days (P=0.002), respectively. The mean (+/- s.d.) age at starting ibuprofen was 3.3 (+/- 1.3) vs 5.8 (+/- 3.5) days in infants with and without SIP, respectively (P=0.03). In logistic regression analyses, increasing GA and later initiation of ibuprofen treatment were protective against risk of SIP; odds ratio, 95% confidence interval (OR, 95% CI)=0.26 (0.09 to 0.75), P=0.01 and 0.63 (0.41 to 0.95), P=0.03, respectively. CONCLUSION: Infants at lower GA are at risk of SIP when treated early with ibuprofen for symptomatic PDA. PMID- 21252972 TI - Citation for a discussion of noncompliance. Don't hide it. PMID- 21252973 TI - Citation for a discussion of noncompliance. PMID- 21252974 TI - Citation for a discussion of noncompliance. A word from OLAW and USDA. PMID- 21252975 TI - Citation for a discussion of noncompliance. Retraining required. PMID- 21252976 TI - Citation for a discussion of noncompliance. Reasonable and right. PMID- 21252977 TI - Lameness in a rabbit. PMID- 21252979 TI - Urethral catheterization in the female guinea pig (Cavia porcellus). AB - Urethral catheterization of the female guinea pig has potential diagnostic, therapeutic and research applications. Urethral catheter placement in the female guinea pig is relatively easy to carry out and has fewer potential complications than does catheter placement in male guinea pigs. PMID- 21252980 TI - Anesthetic effects of clove oil and lidocaine-HCl on marine medaka (Oryzias dancena). AB - Fish may be anesthetized for various experimental and practical purposes, primarily to immobilize them in order to facilitate handling. Marine medaka (Oryzias dancena) is a teleost fish used in marine ecotoxicology studies. Despite the importance of anesthesia in handling experimental fish, the effects of anesthesia in marine medaka have not yet been investigated. In this study, the authors evaluated the anesthetic effects (time required for anesthesia to take effect and recovery time) of two anesthetic agents, clove oil and lidocaine-HCl, on marine medaka. They anesthetized fish at different water temperatures (23 degrees C, 26 degrees C and 29 degrees C) and using different concentrations of clove oil (50 ppm, 75 ppm, 100 ppm, 125 ppm, 150 ppm and 175 ppm) or lidocaine HCl (300 ppm, 400 ppm, 500 ppm, 600 ppm, 700 ppm and 800 ppm). The time required for anesthesia to take effect decreased significantly as both anesthetic concentration and water temperature increased for both clove oil and lidocaine HCl. To anesthetize marine medaka within approximately 1 min, the optimal concentrations for clove oil were 125 ppm at 23 degrees C, 100 ppm at 26 degrees C and 75 ppm at 29 degrees C and for lidocaine-HCl were 800 ppm at 23 degrees C and 700 ppm at both 26 degrees C and 29 degrees C. The authors also compared anesthetic effects in marine medaka of different sizes. Both anesthetic exposure time and recovery time were significantly shorter for smaller fish than for larger fish. These results provide a useful foundation for the laboratory handling of marine medaka. PMID- 21252981 TI - A method for removing the brain and spinal cord as one unit from adult mice and rats. AB - To collect complete rodent spinal cord samples for histological analysis, researchers typically use a method that involves fixation of the carcass, followed by decapitation and removal of the vertebrae and the spinal cord. Researchers then decalcify, process and embed the spinal column in paraffin. When this method is used, the spinal cord retains its natural curvature, which may be undesirable to some investigators. The authors describe a methodology by which the entire spinal cord, with the brain attached, can be removed from a mouse or rat, set against a rigid support material and fixed perfectly straight. This allows for more precise sectioning and simplified histological analysis. Researchers can even create block preparations, each of which contains multiple spinal cord sections, so that they can compare anatomically matched sections. This procedure can also be used to obtain fresh spinal cord samples that are free of bone and can be frozen in optimal cutting temperature medium. PMID- 21252982 TI - A dedication to mentoring. PMID- 21252983 TI - Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10. AB - The European LeukemiaNet (ELN), workpackage 10 (WP10) was designed to deal with diagnosis matters using morphology and immunophenotyping. This group aimed at establishing a consensus on the required reagents for proper immunophenotyping of acute leukemia and lymphoproliferative disorders. Animated discussions within WP10, together with the application of the Delphi method of proposals circulation, quickly led to post-consensual immunophenotyping panels for disorders on the ELN website. In this report, we established a comprehensive description of these panels, both mandatory and complementary, for both types of clinical conditions. The reason for using each marker, sustained by relevant literature information, is provided in detail. With the constant development of immunophenotyping techniques in flow cytometry and related software, this work aims at providing useful guidelines to perform the most pertinent exploration at diagnosis and for follow-up, with the best cost benefit in diseases, the treatment of which has a strong impact on health systems. PMID- 21252984 TI - Targeted next-generation sequencing detects point mutations, insertions, deletions and balanced chromosomal rearrangements as well as identifies novel leukemia-specific fusion genes in a single procedure. AB - DNA sequence enrichment from complex genomic samples using microarrays enables targeted next-generation sequencing (NGS). In this study, we combined 454 shotgun pyrosequencing with long oligonucleotide sequence capture arrays. We demonstrate the detection of mutations including point mutations, deletions and insertions in a cohort of 22 patients presenting with acute leukemias and myeloid neoplasms. Importantly, this one-step methodological procedure also allowed the detection of balanced chromosomal aberrations, including translocations and inversions. Moreover, the genomic representation of only one of the partner genes of a chimeric fusion on the capture platform also permitted identification of the novel fusion partner genes. Using acute myeloid leukemias harboring RUNX1 abnormalities as a model system, three novel chromosomal fusion sequences and KCNMA1 as a novel RUNX1 fusion partner gene were detected. This assay has the strong potential to become an important method for the comprehensive genetic characterization of particular leukemias and other malignancies harboring complex genomes. PMID- 21252985 TI - In vivo expression of an aberrant MYB-GATA1 fusion induces leukemia in the presence of GATA1 reduced levels. PMID- 21252986 TI - Improved outcome following allogeneic stem cell transplantation in chronic myeloid leukemia is associated with higher expression of BMI-1 and immune responses to BMI-1 protein. AB - BMI-1 and EZH2 are polycomb group (PcG) proteins that maintain self-renewal of stem cells, and are overexpressed in leukemia. To investigate the potential of PcG proteins as leukemia-associated antigens, and as targets for graft-versus leukemia (GVL) effects, we studied cells obtained from 86 patients with chronic myeloid leukemia (CML) and 25 human leukocyte antigen (HLA)-A*0201(+) sibling donors collected before allogeneic stem cell transplantation (SCT). Although BMI 1 overexpression in CD34(+) cells of CML patients treated with pharmacotherapy is associated with poor prognosis, we found, conversely, that in CML patients treated with SCT, a higher expression of BMI-1, and correspondingly a lower expression of its target for repression, CDKN2A, is associated with improved leukemia-free survival. Cytotoxic T-lymphocyte (CTL) responses to the BMI-1 peptide were detected in 5 of 25 (20%) donors, and in 8 of 19 (42%) HLA-A*0201(+) CML patients. BMI-1 generated more total and high-avidity immune responses, and was more immunogenic than EZH2. PcG-specific CTLs had a memory phenotype, were readily expanded in short-term cultures and were detected after SCT in recipients of PcG-specific CTL-positive donors. A higher BMI-1 expression in CML CD34(+) progenitors was associated with native BMI-1 immune responses. These immune responses to PcG proteins may target leukemia stem cells and have relevance for disease control by GVL. PMID- 21252987 TI - Phase I trial and pharmacokinetic study of high-dose clofarabine and busulfan and allogeneic stem cell transplantation in adults with high-risk and refractory acute leukemia. AB - We conducted a phase I trial to determine the maximum tolerated dose (MTD) of clofarabine with high-dose busulfan followed by allogeneic stem cell transplantation (SCT) in patients with high-risk and refractory acute leukemia. Patients received intravenous busulfan 0.8 mg/kg every 6 h on days -6 to -3 and clofarabine 30-60 mg/m(2) per day on days -6 to -2. Graft-versus-host disease prophylaxis included sirolimus plus tacrolimus (days -2 to +180). A total of 15 patients, median age 48 (30-58) years, with acute leukemia that was relapsed and refractory (n=8), primary refractory (n=6), or in CR2 (n=1), were treated at four clofarabine dose levels: 30 (n=3), 40 (n=3), 50 (n=3) and 60 mg/m(2) per day (n=6) with busulfan. All engrafted, and the MTD was not reached. Grades 3-4 non hematological toxicities included vomiting (n=3), mucositis (n=9), hand-foot syndrome (n=1), acute renal failure (n=1) and reversible elevation of aspartate aminotransferase/alanine aminotransferase (n=10). The 1-year event-free survival was 53% (95% confidence interval: 33-86%), and the 1-year overall survival was 60% (95% confidence interval: 40-91%). Given the good tolerability and promising results, we recommend clofarabine 60 mg/m(2) per day * 5 days as a phase II dose in combination with busulfan (12.8 mg per kg total dose) for further study as a myeloablative regimen for allogeneic SCT for high-risk acute leukemia. PMID- 21252988 TI - Competition between clonal plasma cells and normal cells for potentially overlapping bone marrow niches is associated with a progressively altered cellular distribution in MGUS vs myeloma. AB - Disappearance of normal bone marrow (BM) plasma cells (PC) predicts malignant transformation of monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM) into symptomatic multiple myeloma (MM). The homing, behavior and survival of normal PC, but also CD34(+) hematopoietic stem cells (HSC), B-cell precursors, and clonal PC largely depends on their interaction with stromal cell-derived factor-1 (SDF-1) expressing, potentially overlapping BM stromal cell niches. Here, we investigate the distribution, phenotypic characteristics and competitive migration capacity of these cell populations in patients with MGUS, SMM and MM vs healthy adults (HA) aged >60 years. Our results show that BM and peripheral blood (PB) clonal PC progressively increase from MGUS to MM, the latter showing a slightly more immature immunophenotype. Of note, such increased number of clonal PC is associated with progressive depletion of normal PC, B-cell precursors and CD34(+) HSC in the BM, also with a parallel increase in PB. In an ex vivo model, normal PC, B-cell precursors and CD34(+) HSC from MGUS and SMM, but not MM patients, were able to abrogate the migration of clonal PC into serial concentrations of SDF-1. Overall, our results show that progressive competition and replacement of normal BM cells by clonal PC is associated with more advanced disease in patients with MGUS, SMM and MM. PMID- 21252990 TI - Membrane trafficking: a GSK3 lockdown. PMID- 21252991 TI - 'Tit-for-tat' in cell biology. PMID- 21252989 TI - Adipokines in inflammation and metabolic disease. AB - The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose derived secreted factors or adipokines, that have pro-inflammatory or anti inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function. PMID- 21252992 TI - Cell migration: Keeping together. PMID- 21252994 TI - Cell signalling: Targeting kinases. PMID- 21252995 TI - Development: a new move for PRMT5. PMID- 21252996 TI - Autophagy: Myosin II moves in on autophagosomes. PMID- 21252997 TI - Dedifferentiation, transdifferentiation and reprogramming: three routes to regeneration. AB - The ultimate goal of regenerative medicine is to replace lost or damaged cells. This can potentially be accomplished using the processes of dedifferentiation, transdifferentiation or reprogramming. Recent advances have shown that the addition of a group of genes can not only restore pluripotency in a fully differentiated cell state (reprogramming) but can also induce the cell to proliferate (dedifferentiation) or even switch to another cell type (transdifferentiation). Current research aims to understand how these processes work and to eventually harness them for use in regenerative medicine. PMID- 21252998 TI - The MRE11 complex: starting from the ends. AB - The maintenance of genome stability depends on the DNA damage response (DDR), which is a functional network comprising signal transduction, cell cycle regulation and DNA repair. The metabolism of DNA double-strand breaks governed by the DDR is important for preventing genomic alterations and sporadic cancers, and hereditary defects in this response cause debilitating human pathologies, including developmental defects and cancer. The MRE11 complex, composed of the meiotic recombination 11 (MRE11), RAD50 and Nijmegen breakage syndrome 1 (NBS1; also known as nibrin) proteins is central to the DDR, and recent insights into its structure and function have been gained from in vitro structural analysis and studies of animal models in which the DDR response is deficient. PMID- 21252999 TI - Feedback regulation of EGFR signalling: decision making by early and delayed loops. AB - Human-made information relay systems invariably incorporate central regulatory components, which are mirrored in biological systems by dense feedback and feedforward loops. This type of system control is exemplified by positive and negative feedback loops (for example, receptor endocytosis and dephosphorylation) that enable growth factors and receptor Tyr kinases of the epidermal growth factor receptor (EGFR)/ERBB family to regulate cellular function. Recent studies show that the collection of feedback regulatory loops can perform computational tasks - such as decoding ligand specificity, transforming graded input signals into a digital output and regulating response kinetics. Aberrant signal processing and feedback regulation can lead to defects associated with pathologies such as cancer. PMID- 21253000 TI - The elusive nature and function of mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are a diverse subset of multipotent precursors present in the stromal fraction of many adult tissues and have drawn intense interest from translational and basic investigators. MSCs have been operationally defined by their ability to differentiate into osteoblasts, adipocytes and chondrocytes after in vitro expansion. Nevertheless, their identity in vivo, heterogeneity, anatomical localization and functional roles in adult tissue homeostasis have remained enigmatic and are only just starting to be uncovered. PMID- 21253001 TI - Comparing behavioral weight loss modalities: incremental cost-effectiveness of an internet-based versus an in-person condition. AB - The objective of this study was to assess the costs associated with a group behavioral weight loss intervention and compare cost-effectiveness based on treatment delivery modality (in-person vs. Internet). A randomized controlled trial examined efficacy of a group behavioral obesity intervention across in person and Internet treatment modalities. Participants (N = 323, 93% women, mean BMI = 35.8) from two centers were randomized to treatment modality, and contact time was matched between conditions. Primary outcome was weight loss. Cost effectiveness measures calculated life years gained (LYG) from changes in weight at 6 months, based on excess years of life lost (YLL) algorithm and the cost of the two modalities. In-person participants had significantly greater weight losses (-8.0 +/- 6.1 kg) than Internet participants (-5.5 +/- 5.6 kg), whereas differences in LYG were insignificant. Estimated LYG was 0.58 (95% confidence interval: 0.45, 0.71) and 0.47 (95% confidence interval: 0.34, 0.60) for the in person and Internet condition, respectively. Total cost of conducting the in person condition was $706 per person and the Internet condition was $372 per person with the difference mainly due to increased travel cost of $158 per person. The incremental cost-effectiveness ratio was $2,160 per (discounted) LYG for the Internet modality relative to no intervention/no weight loss and $7,177 per (discounted) LYG for the in-person modality relative to the Internet modality. Participant time costs are recognized as an important cost of medical and behavioral interventions. When participant time costs are included in an economic evaluation of a behavioral weight loss intervention, Internet-based weight loss delivery may be a more cost-effective approach to obesity treatment. PMID- 21253002 TI - Population-based trends of pregnancy outcome in obese mothers: what has changed over 15 years. AB - Maternal obesity is a growing concern worldwide. We aimed to determine trends of obesity in women of reproductive age over a 15-year period, the relationship between prepregnancy weight status and pregnancy-related outcomes, and possible changes over a 15-year period. Data was derived from two identical, cross sectional National Perinatal Surveys (NPSs). Analysis was restricted to the mothers of healthy, full-term, singleton infants. Overall, the study population consisted of 18,752 mother-infant pairs (7,208 from the 1st NPS and 11,544 from the 2nd NPS). The prevalence of overweight and obese women prior to pregnancy increased significantly between the two surveys, from 12 to 15.3% and 2.1 to 4.7%, respectively. In both study periods, prepregnancy weight status was positively associated with pre-eclampsia (P < 0.001) and method of delivery (P < 0.001). After adjusting for potential confounders, overweight and obese women had higher odds for caesarian section (adjusted (odd ratio) OR = 1.87) and pre eclampsia (adjusted OR = 2.59) than normal-weight women. These associations did not change between the study periods. In conclusion, prepregnancy maternal obesity is steadily increasing over time. The magnitude of the problem underlies the need for public health programs to focus on obesity prevention, particularly among women of reproductive age, and re-evaluate the guidelines for various perinatal practices. PMID- 21253003 TI - Abdominal fat mass is associated with adaptive immune activation: the CODAM Study. AB - Abdominal fat-related activation of the innate immune system and insulin resistance (IR) are implicated in the pathogenesis of cardiovascular diseases. Recent data support an important role of the adaptive immune system as well. In this study, we investigate the association between waist circumference and markers of systemic adaptive immune activation, and the potential mediating role of innate immune activation and/or IR herein. The study population consisted of 477 (304 men) individuals (mean age: 59.4 +/- 7.0 years) in whom waist circumference, HOMA2-IR (IR derived from homeostasis model assessment), and markers of innate (C-reactive protein (CRP), interleukin (IL)-6, serum amyloid A (SAA)) and adaptive (neopterin, soluble CD25 (sCD25)) immune activation were measured. These markers were compiled into an adaptive and innate immune activation score by averaging the respective z-scores. After adjustments for age, sex, glucose metabolism, smoking status, prior cardiovascular disease, and other risk factors, waist circumference was associated with the adaptive (standardized regression coefficient beta = 0.12 (95% confidence intervals: 0.04-0.20)) and the innate immune activation scores (beta = 0.24 (0.17-0.31)), and with HOMA2-IR (beta = 0.49 (0.42-0.56)). The innate immune activation score and HOMA2-IR were also positively associated with the adaptive immune activation score (beta = 0.31 (0.21-0.40) and beta = 0.11 (0.02-0.21), respectively). The association between waist circumference and the adaptive immune activation score was completely abolished when further adjusted for innate immune activation and HOMA2-IR (to beta = -0.01 (-0.10-0.08)), and the specific mediation "effects" attributable to each of these variables were 58% and 42%, respectively. We conclude that abdominal obesity is associated with systemic adaptive immune activation and that innate immune activation and IR constitute independent and equally important pathways explaining this association. PMID- 21253004 TI - Explained and unexplained regional variation in Canadian obesity prevalence. AB - The objective of our study was to examine sociodemographic and behavioral variables underlying the geographic variation of obesity in Canada. We aimed to quantify the share of regional variation in average BMI attributable to commonly cited determinants of obesity and the remaining share, which is attributable to the idiosyncrasies of the regional environment ("regional effects"). Using data from the Canadian Community Health Survey (CCHS) (2004), ordinary least squares (OLS) regression, and Blinder-Oaxaca decomposition to decompose the difference in mean BMI between regions, we quantify two parts of the difference: a share explained by different levels of the covariates and a share explained by those covariates having different effects on BMI in the different regions, using the Atlantic provinces as the reference group. We observed that some differences (e.g., average BMI for males in Quebec compared to the Atlantic provinces) are mostly explained by the different levels of socio-demographic and behavioral covariates, while others (e.g., average BMI for females in Quebec compared to the Atlantic provinces) are mostly explained by the different effects of the covariates on BMI. In the latter scenario, even if covariates were made to be identical in the different regions, the difference in average BMI would persist. Thus, targeting covariates in different regions through plans like physical activity or nutrition policy, income equalization, or education subsidies will have ambiguous effects for addressing disparate obesity levels, being plausible policy options in some regions but less so in others. Future research and policy would benefit from identifying these region-specific attributes that have local implications for BMI. PMID- 21253005 TI - Binge eating disorder and the outcome of bariatric surgery at one year: a prospective, observational study. AB - Previous studies have suggested that binge eating disorder (BED) impairs weight loss following bariatric surgery, leading some investigators to recommend that patients receive behavioral treatment for this condition before surgery. However, many of these investigations had significant methodological limitations. The present observational study used a modified intention-to-treat (ITT) population to compare 1-year changes in weight in 59 surgically treated participants, determined preoperatively to be free of a current eating disorder, with changes in 36 individuals judged to have BED. Changes in weight and binge eating in the latter group were compared with those in 49 obese individuals with BED who sought lifestyle modification for weight loss. BED was assessed using criteria proposed for the Diagnostic and Statistical Manual (DSM) 5. At 1 year, surgically treated participants without BED lost 24.2% of initial weight, compared with 22.1% for those with BED (P > 0.309). Both groups achieved clinically significant improvements in several cardiovascular disease (CVD) risk factors. Participants with BED who received lifestyle modification lost 10.3% at 1 year, significantly (P < 0.001) less than surgically treated BED participants. The mean number of binge eating days (in the prior 28 days) fell sharply in both BED groups at 1 year. These two groups did not differ significantly in BED remission rates or in improvements in CVD risk factors. The present results, obtained in carefully studied participants, indicate that the preoperative presence of BED does not attenuate weight loss or improvements in CVD risk factors at 1 year in surgically treated patients. Longer follow-up of participants is required. PMID- 21253006 TI - Natural variation of the amino-terminal glutamine-rich domain in Drosophila argonaute2 is not associated with developmental defects. AB - The Drosophila argonaute2 (ago2) gene plays a major role in siRNA mediated RNA silencing pathways. Unlike mammalian Argonaute proteins, the Drosophila protein has an unusual amino-terminal domain made up largely of multiple copies of glutamine-rich repeats (GRRs). We report here that the ago2 locus produces an alternative transcript that encodes a putative short isoform without this amino terminal domain. Several ago2 mutations previously reported to be null alleles only abolish expression of the long, GRR-containing isoform. Analysis of drop out (dop) mutations had previously suggested that variations in GRR copy number result in defects in RNAi and embryonic development. However, we find that dop mutations genetically complement transcript-null alleles of ago2 and that ago2 alleles with variant GRR copy numbers support normal development. In addition, we show that the assembly of the central RNAi machinery, the RISC (RNA induced silencing complex), is unimpaired in embryos when GRR copy number is altered. In fact, we find that GRR copy number is highly variable in natural D. melanogaster populations as well as in laboratory strains. Finally, while many other insects share an extensive, glutamine-rich Ago2 amino-terminal domain, its primary sequence varies drastically between species. Our data indicate that GRR variation does not modulate an essential function of Ago2 and that the amino-terminal domain of Ago2 is subject to rapid evolution. PMID- 21253007 TI - Regional management units for marine turtles: a novel framework for prioritizing conservation and research across multiple scales. AB - BACKGROUND: Resolving threats to widely distributed marine megafauna requires definition of the geographic distributions of both the threats as well as the population unit(s) of interest. In turn, because individual threats can operate on varying spatial scales, their impacts can affect different segments of a population of the same species. Therefore, integration of multiple tools and techniques--including site-based monitoring, genetic analyses, mark-recapture studies and telemetry--can facilitate robust definitions of population segments at multiple biological and spatial scales to address different management and research challenges. METHODOLOGY/PRINCIPAL FINDINGS: To address these issues for marine turtles, we collated all available studies on marine turtle biogeography, including nesting sites, population abundances and trends, population genetics, and satellite telemetry. We georeferenced this information to generate separate layers for nesting sites, genetic stocks, and core distributions of population segments of all marine turtle species. We then spatially integrated this information from fine- to coarse-spatial scales to develop nested envelope models, or Regional Management Units (RMUs), for marine turtles globally. CONCLUSIONS/SIGNIFICANCE: The RMU framework is a solution to the challenge of how to organize marine turtles into units of protection above the level of nesting populations, but below the level of species, within regional entities that might be on independent evolutionary trajectories. Among many potential applications, RMUs provide a framework for identifying data gaps, assessing high diversity areas for multiple species and genetic stocks, and evaluating conservation status of marine turtles. Furthermore, RMUs allow for identification of geographic barriers to gene flow, and can provide valuable guidance to marine spatial planning initiatives that integrate spatial distributions of protected species and human activities. In addition, the RMU framework--including maps and supporting metadata--will be an iterative, user-driven tool made publicly available in an online application for comments, improvements, download and analysis. PMID- 21253008 TI - Reduced fertility in patients' families is consistent with the sexual selection model of schizophrenia and schizotypy. AB - BACKGROUND: Schizophrenia is a mental disorder marked by an evolutionarily puzzling combination of high heritability, reduced reproductive success, and a remarkably stable prevalence. Recently, it has been proposed that sexual selection may be crucially involved in the evolution of schizophrenia. In the sexual selection model (SSM) of schizophrenia and schizotypy, schizophrenia represents the negative extreme of a sexually selected indicator of genetic fitness and condition. Schizotypal personality traits are hypothesized to increase the sensitivity of the fitness indicator, thus conferring mating advantages on high-fitness individuals but increasing the risk of schizophrenia in low-fitness individuals; the advantages of successful schzotypy would be mediated by enhanced courtship-related traits such as verbal creativity. Thus, schizotypy-increasing alleles would be maintained by sexual selection, and could be selectively neutral or even beneficial, at least in some populations. However, most empirical studies find that the reduction in fertility experienced by schizophrenic patients is not compensated for by increased fertility in their unaffected relatives. This finding has been interpreted as indicating strong negative selection on schizotypy-increasing alleles, and providing evidence against sexual selection on schizotypy. METHODOLOGY: A simple mathematical model is presented, showing that reduced fertility in the families of schizophrenic patients can coexist with selective neutrality of schizotypy-increasing alleles, or even with positive selection on schizotypy in the general population. If the SSM is correct, studies of patients' families can be expected to underestimate the true fertility associated with schizotypy. SIGNIFICANCE: This paper formally demonstrates that reduced fertility in the families of schizophrenic patients does not constitute evidence against sexual selection on schizotypy-increasing alleles. Futhermore, it suggests that the fertility estimates derived from extant studies may be biased to an unknown extent. These results have important implications for the evolutionary genetics of psychosis. PMID- 21253009 TI - Integrated profiling of microRNAs and mRNAs: microRNAs located on Xq27.3 associate with clear cell renal cell carcinoma. AB - BACKGROUND: With the advent of second-generation sequencing, the expression of gene transcripts can be digitally measured with high accuracy. The purpose of this study was to systematically profile the expression of both mRNA and miRNA genes in clear cell renal cell carcinoma (ccRCC) using massively parallel sequencing technology. METHODOLOGY: The expression of mRNAs and miRNAs were analyzed in tumor tissues and matched normal adjacent tissues obtained from 10 ccRCC patients without distant metastases. In a prevalence screen, some of the most interesting results were validated in a large cohort of ccRCC patients. PRINCIPAL FINDINGS: A total of 404 miRNAs and 9,799 mRNAs were detected to be differentially expressed in the 10 ccRCC patients. We also identified 56 novel miRNA candidates in at least two samples. In addition to confirming that canonical cancer genes and miRNAs (including VEGFA, DUSP9 and ERBB4; miR-210, miR 184 and miR-206) play pivotal roles in ccRCC development, promising novel candidates (such as PNCK and miR-122) without previous annotation in ccRCC carcinogenesis were also discovered in this study. Pathways controlling cell fates (e.g., cell cycle and apoptosis pathways) and cell communication (e.g., focal adhesion and ECM-receptor interaction) were found to be significantly more likely to be disrupted in ccRCC. Additionally, the results of the prevalence screen revealed that the expression of a miRNA gene cluster located on Xq27.3 was consistently downregulated in at least 76.7% of ~50 ccRCC patients. CONCLUSIONS: Our study provided a two-dimensional map of the mRNA and miRNA expression profiles of ccRCC using deep sequencing technology. Our results indicate that the phenotypic status of ccRCC is characterized by a loss of normal renal function, downregulation of metabolic genes, and upregulation of many signal transduction genes in key pathways. Furthermore, it can be concluded that downregulation of miRNA genes clustered on Xq27.3 is associated with ccRCC. PMID- 21253011 TI - Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. AB - BACKGROUND: Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible. METHODS AND FINDINGS: We prospectively followed 101 ART-naive Ugandans with AIDS and recent CM for one year after initiating ART, and used Luminex multiplex assays to compare serum cytokine levels in participants who did or did not develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, including 30% with central nervous system (CNS) manifestations. The median time to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 1.1-5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher pre ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses (area under the curve [AUC] = 0.82). An algorithm based on seven pre-ART serum biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were associated with increasing hazard of IRIS by time-to-event analysis (each p<=0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses were present, including CRP and IL-6. Mortality was predicted by pre-ART increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% CI 2.7-25.6, p<0.001). CONCLUSIONS: Pre-ART increases in Th(17) and Th(2) responses (e.g., IL 17, IL-4) and lack of proinflammatory cytokine responses (e.g., TNF-alpha, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. Although requiring validation, these biomarkers might be an objective tool to stratify the risk of CM-IRIS and death, and could be used clinically to guide when to start ART or use prophylactic interventions. PMID- 21253013 TI - The cost of the sword: escape performance in male swordtails. AB - The handicap theory of sexual selection posits that male display traits that are favored in mate choice come at a significant cost to performance. We tested one facet of this hypothesis in the green swordtail (Xiphophorus helleri). In this species, the lower ray of male caudal fin is extended into a 'sword', which serves to attract potential mates. However, bearing a long sword may increase drag and thus compromise a male's ability to swim effectively. We tested escape performance in this species by eliciting C-start escape responses, an instinctive escape behavior, in males with various sword lengths. We then removed males' swords and retested escape performance. We found no relationship between escape performance and sword length and no effect of sword removal on escape performance. While having a large sword may attract a predator's attention, our results suggest that sword size does not compromise a male's escape performance. PMID- 21253012 TI - Dual origins of dairy cattle farming--evidence from a comprehensive survey of European Y-chromosomal variation. AB - BACKGROUND: Diversity patterns of livestock species are informative to the history of agriculture and indicate uniqueness of breeds as relevant for conservation. So far, most studies on cattle have focused on mitochondrial and autosomal DNA variation. Previous studies of Y-chromosomal variation, with limited breed panels, identified two Bos taurus (taurine) haplogroups (Y1 and Y2; both composed of several haplotypes) and one Bos indicus (indicine/zebu) haplogroup (Y3), as well as a strong phylogeographic structuring of paternal lineages. METHODOLOGY AND PRINCIPAL FINDINGS: Haplogroup data were collected for 2087 animals from 138 breeds. For 111 breeds, these were resolved further by genotyping microsatellites INRA189 (10 alleles) and BM861 (2 alleles). European cattle carry exclusively taurine haplotypes, with the zebu Y-chromosomes having appreciable frequencies in Southwest Asian populations. Y1 is predominant in northern and north-western Europe, but is also observed in several Iberian breeds, as well as in Southwest Asia. A single Y1 haplotype is predominant in north-central Europe and a single Y2 haplotype in central Europe. In contrast, we found both Y1 and Y2 haplotypes in Britain, the Nordic region and Russia, with the highest Y-chromosomal diversity seen in the Iberian Peninsula. CONCLUSIONS: We propose that the homogeneous Y1 and Y2 regions reflect founder effects associated with the development and expansion of two groups of dairy cattle, the pied or red breeds from the North Sea and Baltic coasts and the spotted, yellow or brown breeds from Switzerland, respectively. The present Y1-Y2 contrast in central Europe coincides with historic, linguistic, religious and cultural boundaries. PMID- 21253015 TI - Synchronous bursts on scale-free neuronal networks with attractive and repulsive coupling. AB - This paper investigates the dependence of synchronization transitions of bursting oscillations on the information transmission delay over scale-free neuronal networks with attractive and repulsive coupling. It is shown that for both types of coupling, the delay always plays a subtle role in either promoting or impairing synchronization. In particular, depending on the inherent oscillation period of individual neurons, regions of irregular and regular propagating excitatory fronts appear intermittently as the delay increases. These delay induced synchronization transitions are manifested as well-expressed minima in the measure for spatiotemporal synchrony. For attractive coupling, the minima appear at every integer multiple of the average oscillation period, while for the repulsive coupling, they appear at every odd multiple of the half of the average oscillation period. The obtained results are robust to the variations of the dynamics of individual neurons, the system size, and the neuronal firing type. Hence, they can be used to characterize attractively or repulsively coupled scale free neuronal networks with delays. PMID- 21253014 TI - A novel strategy for inducing enhanced mucosal HIV-1 antibody responses in an anti-inflammatory environment. AB - Prophylactic vaccination against HIV-1 sexual transmission will probably require antibody elicitation at genital mucosal surfaces. However, HIV-1 envelope glycoprotein (Env)-based antigens are weakly immunogenic, particularly when applied mucosally. The polyanion PRO 2000 is safe for human vaginal application, and thus may represent a potential formulating agent for vaginal delivery of experimental vaccine immunogens. Based upon its biochemical properties, we hypothesized that PRO 2000 might enhance mucosal immunogenicity of HIV-1 envelope glycoprotein (Env)-based antigens, promoting local and systemic immune responses. Vaginal immunization with Env-PRO 2000 resulted in significantly increased titres of Env-specific mucosal IgA and IgG in mice and rabbits, respectively, compared to Env alone, revealing modest but significant mucosal adjuvant activity for PRO 2000. In vitro, PRO 2000 associated with Env, protecting the glycoprotein from proteolytic degradation in human vaginal lavage. Unexpectedly, PRO 2000 antagonized TLR4 activation, suppressing local production of inflammatory cytokines. Since inflammation-mediated recruitment of viral target cells is a major risk factor in HIV-1 transmission, the immune modulatory and anti inflammatory activities of PRO 2000 combined with its intravaginal safety profile suggests promise as an HIV-1 mucosal vaccine formulating agent. PMID- 21253016 TI - Exploitation of herpesvirus immune evasion strategies to modify the immunogenicity of human mesenchymal stem cell transplants. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent cells residing in the connective tissue of many organs and holding great potential for tissue repair. In culture, human MSCs (hMSCs) are capable of extensive proliferation without showing chromosomal aberrations. Large numbers of hMSCs can thus be acquired from small samples of easily obtainable tissues like fat and bone marrow. MSCs can contribute to regeneration indirectly by secretion of cytokines or directly by differentiation into specialized cell types. The latter mechanism requires their long-term acceptance by the recipient. Although MSCs do not elicit immune responses in vitro, animal studies have revealed that allogeneic and xenogeneic MSCs are rejected. METHODOLOGY/PRINCIPAL FINDINGS: We aim to overcome MSC immune rejection through permanent down-regulation of major histocompatibility complex (MHC) class I proteins on the surface of these MHC class II-negative cells through the use of viral immune evasion proteins. Transduction of hMSCs with a retroviral vector encoding the human cytomegalovirus US11 protein resulted in strong inhibition of MHC class I surface expression. When transplanted into immunocompetent mice, persistence of the US11-expressing and HLA-ABC-negative hMSCs at levels resembling those found in immunodeficient (i.e., NOD/SCID) mice could be attained provided that recipients' natural killer (NK) cells were depleted prior to cell transplantation. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate the potential utility of herpesviral immunoevasins to prevent rejection of xenogeneic MSCs. The observation that down-regulation of MHC class I surface expression renders hMSCs vulnerable to NK cell recognition and cytolysis implies that multiple viral immune evasion proteins are likely required to make hMSCs non-immunogenic and thereby universally transplantable. PMID- 21253017 TI - A novel peptide derived from human apolipoprotein E is an inhibitor of tumor growth and ocular angiogenesis. AB - Angiogenesis is a hallmark of tumor development and metastasis and now a validated target for cancer treatment. We previously reported that a novel dimer peptide (apoEdp) derived from the receptor binding region of human apolipoprotein E (apoE) inhibits virus-induced angiogenesis. However, its role in tumor anti angiogenesis is unknown. This study demonstrates that apoEdp has anti-angiogenic property in vivo through reduction of tumor growth in a mouse model and ocular angiogenesis in a rabbit eye model. Our in vitro studies show that apoEdp inhibits human umbilical vein endothelial cell proliferation, migration, invasion and capillary tube formation. We document that apoEdp inhibits vascular endothelial growth factor-induced Flk-1 activation as well as downstream signaling pathways that involve c-Src, Akt, eNOS, FAK, and ERK1/2. These in vitro data suggest potential sites of the apoE dipeptide inhibition that could occur in vivo.This is the first evidence that a synthetic dimer peptide mimicking human apoE has anti-angiogenesis functions and could be an anti-tumor drug candidate. PMID- 21253018 TI - MicroRNA expression profiling of the porcine developing brain. AB - BACKGROUND: MicroRNAs are small, non-coding RNA molecules that regulate gene expression at the post-transcriptional level and play an important role in the control of developmental and physiological processes. In particular, the developing brain contains an impressive diversity of microRNAs. Most microRNA expression profiling studies have been performed in human or rodents and relatively limited knowledge exists in other mammalian species. The domestic pig is considered to be an excellent, alternate, large mammal model for human-related neurological studies, due to its similarity in both brain development and the growth curve when compared to humans. Considering these similarities, studies examining microRNA expression during porcine brain development could potentially be used to predict the expression profile and role of microRNAs in the human brain. METHODOLOGY/PRINCIPAL FINDINGS: MicroRNA expression profiling by use of microRNA microarrays and qPCR was performed on the porcine developing brain. Our results show that microRNA expression is regulated in a developmentally stage specific, as well as a tissue-specific manner. Numerous developmental stage or tissue-specific microRNAs including, miR-17, miR-18a, miR-29c, miR-106a, miR-135a and b, miR-221 and miR-222 were found by microarray analysis. Expression profiles of selected candidates were confirmed by qPCR. CONCLUSIONS/SIGNIFICANCE: The differential expression of specific microRNAs in fetal versus postnatal samples suggests that they likely play an important role in the regulation of developmental and physiological processes during brain development. The data presented here supports the notion that microRNAs act as post-transcriptional switches which may regulate gene expression when required. PMID- 21253019 TI - Ralstonia solanacearum extracellular polysaccharide is a specific elicitor of defense responses in wilt-resistant tomato plants. AB - Ralstonia solanacearum, which causes bacterial wilt of diverse plants, produces copious extracellular polysaccharide (EPS), a major virulence factor. The function of EPS in wilt disease is uncertain. Leading hypotheses are that EPS physically obstructs plant water transport, or that EPS cloaks the bacterium from host plant recognition and subsequent defense. Tomato plants infected with R. solanacearum race 3 biovar 2 strain UW551 and tropical strain GMI1000 upregulated genes in both the ethylene (ET) and salicylic acid (SA) defense signal transduction pathways. The horizontally wilt-resistant tomato line Hawaii7996 activated expression of these defense genes faster and to a greater degree in response to R. solanacearum infection than did susceptible cultivar Bonny Best. However, EPS played different roles in resistant and susceptible host responses to R. solanacearum. In susceptible plants the wild-type and eps(-) mutant strains induced generally similar defense responses. But in resistant Hawaii7996 tomato plants, the wild-type pathogens induced significantly greater defense responses than the eps(-) mutants, suggesting that the resistant host recognizes R. solanacearum EPS. Consistent with this idea, purified EPS triggered significant SA pathway defense gene expression in resistant, but not in susceptible, tomato plants. In addition, the eps(-) mutant triggered noticeably less production of defense-associated reactive oxygen species in resistant tomato stems and leaves, despite attaining similar cell densities in planta. Collectively, these data suggest that bacterial wilt-resistant plants can specifically recognize EPS from R. solanacearum. PMID- 21253020 TI - Reciprocal effects of social support in major depression epidemiology. AB - BACKGROUND: The clinical course and epidemiology of major depressive episodes (MDEs) may be influenced by reciprocal interactions between an individual and the social environment. Epidemiological data concerning these interactions may assist with anticipating the clinical needs of depressed patients. METHODS: The data source for this study was a Canadian longitudinal study, the National Population Health Survey (NPHS), which provided 8 years of follow-up data. The NPHS interview included a brief diagnostic indicator for MDE, the Composite International Diagnostic Interview Short Form for Major Depression (CIDI-SFMD). The NPHS interview also incorporated the Medical Outcomes Study Social Support Scale (MOSSS) and a set of relevant demographic and health-related measures. The MOSSS assesses total social support and four specific dimensions of social support. Hazard ratios (HR) were used to quantify associations in the longitudinal data. RESULTS: LOWER QUARTILE TOTAL SOCIAL SUPPORT RATINGS PREDICTED MDE INCIDENCE: the HR adjusted for age and sex was 1.9 (95% CI 1.6 - 2.2). Lower quartile ratings in specific social support dimensions yielded similar HRs. MDE was associated with emergence of lower-quartile affection social support (age and sex adjusted HR 1.3, 95% CI 1.1 - 1.7), but other aspects of social support were not consistently associated with MDE. CONCLUSIONS: Low social support appears to be a robust risk factor for MDE and can be used to identify persons at higher risk of MDE. Evidence that MDE has a negative effect on social support was weaker and was restricted to affection social support. PMID- 21253022 TI - Native health in british columbia: a twenty-year perspective. PMID- 21253023 TI - Tradition: a past and future treasure. PMID- 21253025 TI - Questioning oral treatment of alcohol-withdrawal syndrome. PMID- 21253024 TI - Looking at HIV Antibody Tests: A Comment. PMID- 21253026 TI - Diabetes Mellitus Among Canadian Indian Women Delivering Heavy-for-Date Newborns. AB - Canadian Indian women who delivered heavy-for-date newborns were studied to see whether they were more likely to be diabetic than were similar women who delivered normal birth-weight newborns. These women delivered newborns at the Sioux Lookout Zone Hospital between January 1, 1969 and December 31, 1972. The delivery of a heavy-for-date newborn was used as an indicator for gestational diabetes. Obstetric difficulties in pairs of women, and congenital anomalies and physiologic jaundice in pairs of newborns were also compared. The study results are discussed within the context of formulating a policy to screen this population of Indians for gestational diabetes. PMID- 21253021 TI - Glycine transport inhibitors for the treatment of schizophrenia. AB - Multiple lines of evidence indicate that hypofunction of glutamatergic neurotransmission via N-methyl-D-aspartate (NMDA) receptors might be implicated in the pathophysiology of schizophrenia, suggesting that increasing NMDA receptor function via pharmacological manipulation could provide a new strategy for the management of schizophrenia. Currently, the glycine modulatory sites on NMDA receptors present the most attractive therapeutic targets for the treatment of schizophrenia. One means of enhancing NMDA receptor neurotransmission is to increase the availability of the obligatory co-agonist glycine at modulatory sites on the NMDA receptors through the inhibition of glycine transporter-1 (GlyT 1) on glial cells. Clinical studies have demonstrated that the GlyT-1 inhibitor sarcosine (N-methyl glycine) shows antipsychotic activity in patients with schizophrenia. Accordingly, a number of pharmaceutical companies have developed novel and selective GlyT-1 inhibitors for the treatment of schizophrenia. This paper provides an overview of the various GlyT-1 inhibitors and their therapeutic potential. PMID- 21253027 TI - Serum lipid distributions in canadian indians of northwestern ontario. AB - Native Indians in the Sioux Lookout Zone of Northwestern Ontario experience lower mortality from cardiovascular diseases than does the general Canadian population, despite a higher prevalence of such risk factors as smoking, obesity, and hypertension. To investigate whether this pattern may be related to the population distribution of serum lipids, the authors conducted a cross-sectional survey. One hundred and ninety-three registered Indians, 18 years of age or older, living in four isolated villages in the Zone were interviewed and examined. Age, sex, height, and weight were determined. A blood specimen was analysed for fasting serum triglyceride, cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. In relation to reference populations, the distribution of serum triglyceride, cholesterol, and LDL cholesterol values is similar to that reported in other Native and non-Native populations, while that of HDL cholesterol is higher. Elevated levels of HDL cholesterol in this population may play a role in protecting it from a higher incidence of coronary heart disease. PMID- 21253028 TI - Stress and illness in an Indian community. AB - This paper is the result of several years of analysis and discussion. It summarizes the careful record kept by the author of the serious illnesses of his patients among a community of approximately 10 000 Apache Indians living on a remote reservation. By comparing the data he recorded with the data recorded by British physicians with somewhat similar practice registers (the most closely comparable data available), the author reaches certain views of the relationship between certain life experiences (stress) and the health status (illness) of individuals. PMID- 21253029 TI - Residency training north of the treeline. AB - Several opportunities exist for medical residents to spend some of their elective time in remote Northern settings. This short article focuses on some of the unique features of such an experience: lack of technological support, temporarily becoming a member of a cultural minority, cross-cultural communication problems, adverse climatic conditions. Some of the rewards are also described. Although such an experience is not for the faint hearted, it can broaden and strengthen the knowledge base required by the primary-care physician in any setting. PMID- 21253030 TI - The health of Indian and inuit children in Canada in the 1980s and 1990s. AB - The last 20 years have seen important improvements in the health status of Native Canadian children. Discrepancies in health status remain between Native and other Canadians. Further improvement is less likely to result from adding more medical services than from broader social change. The economic and cultural base of Native communities needs strengthening. Indian and Inuit people need the opportunities and resources to assume responsibility for their own health and social services in the context of a broader transfer of control. Such a transfer will mark the end of a struggle for Native peoples and the beginning of a new challenge for Native people and for those who work on their behalf. PMID- 21253031 TI - Traditional west coast native medicine. AB - An important part of the complex culture of the Native people of Canada's Pacific coast is the traditional system of medicine each culture has developed. Population loss from epidemics and the influence of dominant European cultures has resulted in loss of many aspects of traditional medicine. Although some Native practices are potentially hazardous, continuation of traditional approaches to illness remains an important part of health care for many Native people. The use of "devil's club" plant by the Haida people illustrates that Native medicine has both spiritual and physical properties. Modern family practice shares many important foundations with traditional healing systems. PMID- 21253032 TI - Family medicine/northern medical services involvement in northern Saskatchewan. AB - To address the problems of recruitment and retention of family physicians in various remote locations in northern Saskatchewan, the University of Saskatchewan became involved through Northern Medical Services, a division of the Department of Family Medicine. The University's involvement consists of the provision of resident family-physician services, visiting consultant services, family-practise resident training, research, and a consulting role of the Medical Health Officer. This paper reviews the context in which this program was created, its role in health care in the area, and its involvement with the communities in health promotion and research. PMID- 21253033 TI - Diabetic education program in the mohawk community of kahnawake, quebec. AB - The Mohawk community of Kahnawake, Quebec, has a high prevalence rate of non insulin-dependent diabetes mellitus. This article outlines the development and implementation of an extensive diabetic education program that is offered to all diabetics. It describes the benefits gained by the diabetic patients. PMID- 21253034 TI - Family practice perspectives on psychiatric care in the northwest. AB - The major effort in psychiatric care in the North is directed toward dealing with depression. The family physician has a key role to play in the therapy of depression, both as a counsellor and as a therapist, and perhaps more important, as a team member, fostering the development of community resources to deal with family breakdown, sexual abuse, and loss of personal spiritual values. PMID- 21253036 TI - Dr. John richardson: arctic doctor. AB - Dr. John Richardson was foremost among a special breed of men, the surgeon naturalists, one of whom accompanied every exploration party sent out by Great Britain. In addition to performing medical duties, the surgeon-naturalist was expected to identify and collect specimens of plants, animals, and rocks. Dr. Richardson was a member of two of the arctic expeditions led by Sir John Franklin, and participated in the search for the long-overdue third Franklin expedition. PMID- 21253035 TI - The health of the james bay cree. AB - The health of the James Bay Cree of Quebec reflects their history and environment. Their ancestors were living in Northern Quebec for centuries before the Europeans arrived bringing new infectious diseases and developing a health care structure that has relegated traditional Cree medicine to the background. The James Bay and Northern Quebec Agreement of 1975 led to the creation of the Cree Board of Health and Social Services under the Quebec Ministry of Health. Various changes have resulted in the eight Cree villages over the past 15 years, both in the socio-economic situation and in the health status of the Cree. Improvements in health will come about through increased participation of Native people in the delivery and control of health services, more accessible health services, and the creation of healthy and health-promoting environments. PMID- 21253037 TI - Health promotion, community development, and participation: an approach to native health education. AB - Health-care parameters for Natives living in isolated northern areas of Canada show rates of life expectancy, morbidity, and infant mortality far worse than the Canadian average. Improving access to medical facilities has not affected these statistics. Socioeconomic factors such as inadequate housing and lack of sewage systems are likely contributors to poor health, as is an attitude of hopelessness and impotence on the part of Native people. Health-care providers have recognized the need for health promotion as well as treatment, but have often instituted programs that blame the victim. An approach to health education that embodies community development, participation, and the fostering of a positive self-image is discussed. The implication of this approach is that when Native Canadian groups can identify their own health problems, have access to the information needed for their solution, and develop the confidence and assertiveness to act, change may occur at a community, as well as an individual, level. PMID- 21253039 TI - NAPCRG! My, How You've Grown! PMID- 21253038 TI - Diagnostic testing: the problem of prevalence. PMID- 21253040 TI - Cimetidine-ranitidine-doxepin interaction. PMID- 21253041 TI - Your research participation is invited. PMID- 21253042 TI - Caring: preaching and practice. PMID- 21253043 TI - A Comment on "Progress Notes:-Part I If It Ain't Broke, Why Fix It?". PMID- 21253044 TI - Blood pressure measurement by family physicians. AB - Hospital-based audits of family physicians are of uncertain utility, since most family physicians conduct community-based practices. We evaluated the feasibility of using a skill-based audit procedure. Blood-pressure measurement is a common and important skill which is often performed poorly by physicians because of a combination of poorly maintained equipment and poor technique. Physicians attending a family-medicine rounds were invited to participate in an evaluation of their skills in taking blood pressure. The usual sphygmomanometer used by the physician was calibrated, and he/she then measured the blood pressure of 10 volunteers, using his/her usual technique. We found that most of the physicians obtained reasonable blood-pressure readings, although there was a significant tendency to produce diastolic readings which were lower than the gold standard (1.6 mmHg.). Eight of the 19 physicians examined demonstrated significant end digit bias. Two of 16 sphygmomanometers were very badly out of calibration. These results indicate that family physicians can produce accurate blood-pressure readings, but that their technique and equipment would benefit from adjustment. PMID- 21253045 TI - Brain tumours presenting with tias and strokes. AB - A review of 905 consecutive cases of pathologically confirmed brain tumour yielded 25 cases in which the initial presentation strongly suggested the diagnosis of occlusive cerebrovascular disease. Most of these 25 patients were admitted through the emergency department of our hospital and referred to the general medical service for investigation. Nineteen cases of transient ischemic attack and six cases of completed stroke were found in 12 cases of glioblastoma, seven of meningioma, two of metastatic renal cell carcinoma, and one case each of malignant astrocytoma, low-grade astrocytoma, oligodendroglioma, and metastatic squamous cell carcinoma. We document the clinical overlap between neoplastic and vascular syndromes, and stress the need for "tumour awareness" in the work-up of patients presenting to non-neurological practitioners with the clinical picture of occlusive cerebrovascular disease. PMID- 21253046 TI - A Decline in Generalism for Family Medicine? First-Practice Profile Ideals cf. Realities. AB - The authors compare the ideal composition of medical practice, as seen by graduating family medicine residents, with the characteristics of practice these residents were about to enter. This exploration of practice ideals finds somewhat anemic interest in several of the more technical aspects of practice. A substantially higher percentage of graduates was expecting to do obstetrics on graduation then would do so by choice, suggesting the possibility of a further decline in obstetrical activity should opportunity occur. A similar pattern emerges for family counselling, nursing-home activity and house calls, producing a composite picture of potential evolution toward more exclusive office practice. Substantial variations are shown to exist, however, among the five programs studied, both in relation to the ideals expressed by the graduates and also in relation to their first-practice profiles. Possible implications for residency programs and the profession are discussed. PMID- 21253047 TI - Diagnostic testing in family practice. AB - Laboratory and radiological investigations are central to the diagnosis and management of our patients' health problems. Physicians often order a diagnostic test routinely without giving much thought to the benefits, risks, and costs of the test. The increase in the number and use of diagnostic tests has contributed to the rising cost of health care over the last two decades. By consciously following a process when ordering tests, physicians may improve the effectiveness and efficiency of the tests they request. This paper provides a background and approach to the rational use of diagnostic tests. PMID- 21253048 TI - Take aim and fire again: laboratory investigation and the family physician. AB - This article discusses the attitude of the family physician to laboratory investigation and specifically reviews changes that have taken place in the last 12 years. It focuses on the problems of allocation of limited resources, the planning of laboratory services, out-of-laboratory testing, and responsibility for quality assurance. As well as bearing individual responsibility for the optimal use of a limited resource, the family physician has a co-operative part to exercise in support of the pathologist's role in organizing and planning the service on which their patients depend. PMID- 21253049 TI - Electromyography and nerve conduction studies. AB - Electromyography and nerve-conduction studies are very useful tools in the evaluation of disease of peripheral nerve and muscle. They should be thought of as extensions of the physical examination. The tests should be used to answer specific questions and to help arbitrate diagnostic dilemmas. The tests, however, have very definite limitations. There are significant false-negative rates, and unexpected positive results can be misleading. The tests rely heavily on careful clinical-electrophysiological correlation. PMID- 21253050 TI - L'ABC de la supervision clinique par discussion de cas. AB - Beginning with a review of the literature and a survey of instructors in family medicine, the authors show that supervision through case discussions is one of the least studied teaching tools in medicine, even though it is one of the most frequently used. On the basis of individual and collective consideration, they suggest the basic elements that seem to be requisite to this type of teaching activity: clarification of the aims of the supervisor and the resident by means of a verbal contract; a method of practice based on a clinical approach; provision of several examples of problems and various strategies for raising or solving problems. PMID- 21253051 TI - Laboratory Diagnosis of UTI in Family Practice. AB - The family physician is in the best position to practise preventive medicine and keep patients healthy by routine urinalysis during each visit. Routine screening of the fresh, meticulously collected mid-stream urine may be done by biochemical screening dipstix, followed up by microscopic examination, where positive for leukocytes, blood, or bacteria. Infections should be cultured in children and recurrent infections in the adult patient. The fresh, properly collected, mid stream, uncentrifuged urine that has motile bacteria per high-power field is equivalent to a colony count of 100 000 per mL and significant of the urinary tract infection. There is still considerable debate in the literature about the traditional criterion of 100 000 bacteria per mL for urinary tract infection, especially for adults who present with urological symptoms. More long-term research is needed in this area of family practice. PMID- 21253052 TI - Laboratory tests in the rheumatic disease. AB - Because the pathophysiologic relationship between laboratory and clinical abnormalities in many of the rheumatologic diseases is still not clearly understood, the use of the investigations dealt with in this article is based only upon statistics. The interpretation of these tests is therefore highly dependent on the result of the initial clinical assessment. Having accepted this limitation, however, the rheumatologist has available a number of powerful tools which may be used to diagnose, classify, or prognosticate. PMID- 21253053 TI - The laboratory approach to thyroid disease. AB - The author reviews thyroid-function tests from the viewpoint of clinical use of the more modern tests of basic thyroid function. Particular attention is paid to the changing use of the TSH assay, with the advent of the "sensitive" TSH tests. Following an overview of relevant physiology, the tests and their current indications are assessed. Finally, the newer strategies of measuring thyroid function are discussed by means of an example recommended by many authors, and a recommendation is made for adoption of such a strategy in the reader's laboratory. PMID- 21253054 TI - The laboratory evaluation of sleep and its disorders. AB - The physician's ability to evaluate a patient's sleep performance objectively and to study a variety of physiological functions and diseases while that patient is asleep has focused attention on sleep studies (polysomnography) as a clinically useful investigative tool. The author of this article briefly reviews the normal evolution of sleep and the classification of sleep disorders, and outlines procedures commonly used by staff of sleep-disorder clinics to assess patients. PMID- 21253055 TI - Office microscopy in the diagnosis of infectious diseases. AB - Microscopy of clinical specimens is a rapid and inexpensive method for the presumptive diagnosis of certain infectious diseases. Early diagnosis permits the physician to initiate appropriate therapy without waiting for culture results. Examination of the Gramstained smear gives information on the inflammatory response, as well as the bacteria involved. Accurate interpretation of the smear, however, requires some training and experience. This article describes the microscopic methods commonly used in the laboratory and their application to office practice. PMID- 21253056 TI - Metabolic diseases in children. AB - A family physician is likely to be the person presented with the responsibility of diagnosing a child with a metabolic disease. Such diseases can have very varied clinical presentations. This article presents a framework of laboratory tests which should be used to diagnose children presenting with acute metabolic diseases. Some specific diseases likely to be encountered are discussed and put into the overall perspective of a family practice. PMID- 21253057 TI - The monitoring of oral anticoagulants. AB - The author briefly reviews the use of anticoagulants, describing the specific tests their use requires. These tests are usually performed in a specialized laboratory. The clinical implication of the laboratory's use of different prothrombin time systems is explained. Implications of the use of oral anticoagulants in family practice are discussed. PMID- 21253058 TI - Testing for Chlamydia trachomatis. AB - Chlamydia trachomatis is a highly prevalent and damaging sexually transmitted disease. Since it may occur in an asymptomatic state, it is important for family physicians to know when screening or testing for this infection is indicated. The value of screening may be increased by correct collection, storage and transport of specimens. The techniques currently used in the laboratory to test specimens for chlamydia include cell culture, ELISA and immunofluorescent antibody (IFA) assay. Cell culture remains the 'gold standard'. The IFA and ELISA are simpler and quicker to perform than is culture and have sufficiently comparable measurements of accuracy. PMID- 21253059 TI - Rapid detection of streptococcal pharyngitis. AB - The authors discuss the controversy relating to treatment of streptococcal pharyngitis. They describe the kits now available for screening for this disorder, and their advantages, disadvantages in terms of patient welfare, cost effectiveness, and demands on staff. Sensible management and advice on the use of these kits is offered to the office practitioner. PMID- 21253060 TI - Delirium associated with possible domperidone-probantheline interaction. AB - The authors report an adverse inter-drug reaction involving domperidone and probantheline. (Can Fam Physician 1988; 34:415.). PMID- 21253061 TI - Psychiatric aspects of physical complaints. AB - The physician may find it difficult to diagnose patients who present with a psychiatric illness that has physical symptoms, or those who have a physical illness that is accompanied by changes in behaviour or mood. In this paper the author sets out guidelines for investigating and diagnosing both types of patients. PMID- 21253062 TI - A filing system for medical literature. AB - The author reviews the types of systems available for personal literature files and makes specific recommendations for filing systems for family physicians. A personal filing system can be an integral part of family practice, and need not require time out of proportion to the worth of the system. Because it is a personal system, different types will suit different users; some systems, however, are more reliable than others for use in family practice. (Can Fam Physician 1988; 34:425-433.). PMID- 21253063 TI - Computer literature searching for busy clinicians. AB - The medical literature is too vast for any of us to keep up with. However, new information technology allows us to search the literature from our offices, clinics, and homes, to solve specific patient problems as they arise. The skills required can be self-taught from instruction manuals or acquired through training programs that typically last just a few hours. The equipment needed can be a simple add-on to the office computer or a standard IBM-PC or compatible, plus an inexpensive modem. Several online vendors provide access to medical information at a reasonable price, including MEDLINE, Colleague, Dialog, EMBASE and PaperChase. The author describes the prospects and procedures for personal access to electronic literature services and provides some start-up information for readers who want to enter the "Information Age" themselves. PMID- 21253064 TI - Non-diseases I have had. PMID- 21253065 TI - Housecalls and teaching: who pays? PMID- 21253066 TI - Co-operation in Emergency Care. PMID- 21253067 TI - Antacid use in a family-practice population. AB - According to market surveys, antacid use is common in the general population. This study of antacid use in a university-based family-practice clinic supports this conclusion. In a sample of 731 adult patients, 51.3% reported taking antacids at least once in the previous six months and 10.9% took antacids daily. Highest antacid users were people 31-40 years of age. Heartburn was the most common symptom in patients taking antacids, but antacid use increased as the patients reported more symptoms. Antacid use by patients is often unknown to the physician. This has some clinical importance because antacids are known to interfere with the absorption of some commonly used drugs. Physicians should routinely ask their patients about antacid use, as well as about their use of other over-the-counter products. PMID- 21253068 TI - Chlamydia trachomitis antigen in the cervix: prevalence in a student population. AB - The prevalence of chlamydia trachomatis was investigated over a two-year period in a population of women university students attending a student health clinic for routine pelvic examination or for a gynecologic complaint. Direct immunofluorescence slide test was used to determine the presence of C. trachomatis. The overall prevalence rates for the two-years periods studied were 8.2% and 7.1%. When women who had symptoms of a urogenital infection were compared to women who were asymptomatic, it was found that symptomatic women were more likely to have C. trachomatis in the cervix. To determine whether women with positive cases showed differences in appearance of the cervix, method of contraception, or other organisms colonizing the vagina, the cases were matched with two controls, and a retrospective chart review was performed. The cases were more likely to have cervicitis and to be culture positive with gardnerella vaginalis, and they were less likely to have used condoms for contraception. In the two periods studied, the carriage rates for asymptomatic cases were 6% and 5%. Fifty-eight per cent of all positive cases were asymptomatic. If this organism is to be eradicated from college-women populations, all women attending for a urogenital infection should be screened, and women attending for routine annual examinations should be screened if there is a clinical indication. PMID- 21253069 TI - Generalists trained in family medicine. AB - Since their creation in the early 1970s, the residency programs in family medicine have attracted an increasing number of medical graduates. In Quebec, over 1000 general practitioners have received their primary-care training in these programs. In order to assess the potential impact of these new training programs, we surveyed the medical practice characteristics of a representative sample of general practitioners, 294 trained in family medicine and 442 trained in the traditional programs. Results showed that trainees in family medicine were more likely to join group practice, to work in rural areas, to deliver hospital care, to work on a salary basis in local community health centres, and to be involved in teaching and research. There were, however, no differences between the two groups of general practitioners in their interventions with patients, particularly with regard to health promotion, patient education, and humanization of care. Implications of these results are discussed. PMID- 21253070 TI - The person: a missing dimension in medical care and medical education. AB - MEDICAL EDUCATION NEEDS TO MOVE BEYOND THE BIOMEDICAL MODEL TO REDRESS THE BALANCE BETWEEN THE TWO GREAT HISTORICAL TRADITIONS IN MEDICINE: the reductionistic and the whole person approaches. Students need to understand the distinctions between disease as an abstract concept and illness as an experience lived by their patients. They need to approach the study of both the sciences and the humanities with a rigorous, thoughtful, and balanced approach, and learn to integrate these understandings and to apply them to the care of sick persons. Medical education should be more than vocational training: it must be a liberal education. The missing dimension in medical education is the person, both the person of the patient and the person of the student. The experiences of both are the very foundations of learning, growth, and healing. PMID- 21253072 TI - Male infertility: diagnosis and treatment. AB - The evaluation of the subfertile male starts with the basic history and physical examination, which often provide indication of probable cause. Aside from analysis of properly collected semen, most cases require very few tests. Etiology can be classified as pretesticular, testicular, and post-testicular. Treatment can be more specific if a definite cause is found. Unfortunately, about 25% of patients are idiopathic, and non-specific treatments generally yield unacceptably low conception rates. Improvement will occur as more becomes known, through animal research and clinical application, about the physiology of spermatogenesis and the pathological processes that can affect it. PMID- 21253071 TI - When does a man need a check-up? AB - HEALTH MAINTENANCE IN MEN: what makes sense? The author reviews guidelines of the Canadian and U.S. Preventive Task Forces on the Periodic Health Examination and recent papers on prevention issues. A healthy man between 20 and 65 years of age might visit a physician every five years. Health-maintenance visits should include evaluation of STD and HIV risk factors, blood pressure reading and, after 35, cholesterol measurement. After 65, a visit every other year should suffice, but individuals must be informed of the importance of yearly influenza vaccination. Appropriate lifestyle counselling should be part of any medical encounter. PMID- 21253073 TI - "Organic" erection dysfunction: diagnosis and treatment. AB - The author of this article discusses the basic diagnostic work-up for a physically based erection dysfunction and reviews the five current treatment options (medicinal, physical, surgical, counselling, and intracavernosal injection). PMID- 21253074 TI - Vasectomies: Motivations and Attitude of Physicians-as-Patients. AB - Vasectomies have not been as widely favoured as have techniques of sterilization in Canada for some years, in spite of having a better morbidity and mortality record than tubal sterilizations. Physicians or others who themselves have had the procedure seem to be in an especially favourable position to describe accurately the advantages and risks of this surgery, as well as its alternatives. Questionnaires inquiring about reasons for choosing vasectomy were sent to 42 medical doctors who had undergone the procedure. Counsellors can usefully proffer to inquiring patients the same advantages that reportedly motivated the medical doctors: convenience, economy, and safety. PMID- 21253075 TI - Fathering. AB - Fathering is an art, a skill, and an integral part of life to which investigators of the human condition have long paid scant attention. In an era when family dynamics and structure are again undergoing change, it is timely to look at some of our concepts of fathering. PMID- 21253076 TI - Part-time Work and Shared Parenting: An Option for Health Professionals. AB - The author and his wife, both psychologists, have worked half time for the past six years, while each has spent half time at home with their two young daughters. Factors influencing the choice of part-time work are reviewed. It is concluded that this arrangement for shared parenting, while still rare, is one of many increasingly viable options for child care, and that it has many benefits for parents, children, and employers. People who enjoy some professional autonomy in their work, such as physicians, may be particularly suited to such arrangements. PMID- 21253077 TI - Health Concerns (excluding AIDS) for Male Homosexual Patients. AB - Since 1981, the Acquired Immune Deficiency Syndrome (AIDS) has emerged as the major infectious epidemic of our time and has focused much attention on the male homosexual community. While AIDS is the most serious of gay-related health concerns, it is only one of several infectious diseases that have particular relevance for this group of patients. In addition, the mere acknowledgement of homosexuality by a male patient evokes unique psychosocial concerns that are important considerations for the primary health-care provider. The author of this article describes an approach to gay male patients for those who provide health care to such men and provides a review of specific infectious diseases (excluding AIDS) for which they are at risk. PMID- 21253079 TI - Management of obesity: an office strategy. AB - The author suggests a practical approach to managing a weight-loss program for the obese patient and strategies to help patients adhere to the regime and to maintain the weight reduction achieved. Matters to be covered in office visits are outlined, and the importance of the patient keeping a food diary is stressed. The contribution of activity to weight loss is reviewed, and particular problems relating to weight reduction and its maintenance are discussed. PMID- 21253078 TI - Oral manifestations of human immunodeficiency virus infection. AB - The AIDS epidemic continues. All health-care workers, including physicians and dental personnel, may be instrumental in recognizing risk factors associated with Acquired Immunodeficiency Syndrome (AIDS) and Human Immunodeficiency Virus (HIV) infection. Oral signs and symptoms of HIV infection may be the first presentation of the disease or may develop during the course of the disease and require management. Knowledge of the signs, symptoms and associated infections and tumours is needed to assist in recognition, diagnosis, and treatment. PMID- 21253080 TI - The family physician and the "know your blood pressure by heart" education program. AB - Patient education is an important aspect of medical practice, especially in the realm of chronic diseases such as hypertension (HT). Family physicians are in an ideal position to engage in educational activities that promote the control of HT and reduce cardiovascular risk. The Canadian Heart Foundation has developed a series of educational activities for the purpose of creating awareness about the importance of blood pressure in cardiovascular health. This program-"Know Your Blood Pressure By Heart" (KYBPBH) -is based on the concepts of wellness and self care, and is designed to increase the number of Canadians who know their blood pressure measurement. KYBPBH educational objectives, which are targeted to the middle-aged male, require active support by health professionals. This article describes the material resources available for KYBPBH and encourages family physician involvement. PMID- 21253081 TI - The "new genetics". PMID- 21253083 TI - Critical thinking and navel gazing. PMID- 21253082 TI - The unkindest cut of all? PMID- 21253084 TI - Emergency Medicine: A Field for Co-operation. PMID- 21253085 TI - Interpreting tests for syphilis: an objection. PMID- 21253086 TI - Management of cardiac arrhythmias. PMID- 21253087 TI - Is post-marketing drug surveillance possible in the family practice setting? A collaborative study. AB - Post-marketing surveillance is a mechanism to identify and quantify harmful, as well as beneficial, effects of drugs used under conditions different from those in which they were tested. The College of Family Physicians of Canada collaborated with the authors in a pilot, office-based, post-marketing, surveillance study. Target medications were selected from all prescriptions, written or authorized by participating physicians. The participants collected the prescriptions by using duplicate prescription pads. Follow-up data was collected from the patients by means of a self-administered questionnaire and from the physicians by means of a medical-chart review. This method of research allows the identification of a cohort of drug users in a systematic, non-biased fashion. PMID- 21253088 TI - Intrapartum obstetrical consultation in a rural hospital. AB - This study reviews the reasons why family physicians consult an obstetrician during their patient's labour and delivery in a small rural hospital. PMID- 21253089 TI - Female family-practice graduates at the university of manitoba: career patterns and perceptions. AB - All female graduates of the Family Practice Residency Program at the University of Manitoba over a 10-year period (1974-1983) were surveyed with respect to demographic data; training; present practice profiles; personal life and attitudes; professional attitudes; and career satisfaction. Respondents perceived two significant problem areas: combining family and career, and discrimination against women. The author of this paper makes some suggestions for alleviating these problems. More knowledge about female physicians' attitudes, their practice profiles, and the difficulties they encounter will facilitate improvements in manpower planning and medical education. PMID- 21253090 TI - Updating genograms in the practice of preventive medicine. AB - Family physicians uncover clues to genetic risk while they routinely sketch and add to patients' genograms. A symbolic international language identifies health conditions and shows inter- and intra-generational relationships of mating and descent. Time allotted to reviewing the genogram and follow-up carried out by the family physician and/or through referral to a genetics clinic lie well within the mandate to practise preventive medicine. Such vigilance is fundamental to the unwritten agreement between the family and the family physician to delay, moderate, or avoid health crises. PMID- 21253091 TI - Mendelian genetics. AB - The author reviews the inheritance patterns of diseases or conditions caused by genes at a single locus. The recurrence risk in several common family situations is illustrated for autosomal recessive, autosomal dominant, and X-linked inheritance. Patients frequently have difficulty understanding these concepts, and a few examples are provided of problems encountered in genetic counselling. PMID- 21253092 TI - Multifactorial inheritance in man. AB - The interaction of genetic and non-genetic factors, termed 'multifactorial inheritance', contributes to a large proportion of medical disorders. Spina bifida and type-II diabetes mellitus are two common conditions considered to be multifactorial. Using clinical examples, the author of this paper explores the basis of this mode of inheritance and its relevance to patient care. PMID- 21253093 TI - Basic cytogenetics for office practice. AB - There is a wide range of clinical problems, from the relatively common to the extremely rare, that result from alterations in the chromosome complement. These numerical and structural abnormalities of the chromosomes can be detected readily by cell culture and analysis in the cytogenetics laboratory, and the chromosome complement is defined by means of a simple nomenclature. The family physician can expect to see patients with potential chromosome abnormalities from infancy to adulthood and may request that the appropriate cytogenetic investigation be undertaken. The diagnosis of chromosome disorders allows more accurate patient counselling and improved patient care. PMID- 21253094 TI - Introduction to DNA-Based Genetic Diagnostics. AB - Molecular biology and recombinant DNA technology are beginning to have an effect on the medical health care field, particularly in the area of clinical genetics. Dramatic improvements in the prerequisite technology are in the process of being transferred from the research lab to routine clinical laboratories. The general practitioner, along with his genetic diagnostic colleagues, can soon expect to have access to accurate and reliable diagnostic assays for a wide variety of genetic disorders. This article introduces the basic technologies involved in genetic diagnostics and provides an indication both of their limitations and their future potential. PMID- 21253095 TI - Preconception clinical genetics. AB - In Canada today, the average family size is declining and the expectation of most couples regarding health for their children is rising. These trends are placing more "value" on each pregnancy. Couples who are concerned about future pregnancies are now more often seeking advice relating to their family history and the risks of having children born with significant disorders before they undertake a conception. The family physician can play a key role in providing preconception counselling. PMID- 21253096 TI - Non-invasive prenatal testing. AB - Non-invasive modalities to assess the ongoing pregnancy may assist the clinician to identify risk factors requiring additions or alteration to routine prenatal care. These modalities include pedigree analysis, maternal serum alphafetoprotein screening, fetal ultrasonography, and Doppler ultrasound. These methods should be used when there are appropriate clinical indications and awareness of their limitations. PMID- 21253097 TI - Invasive prenatal testing. AB - Invasive prenatal diagnosis is a major diagnostic tool which is used in modern obstetrical care. A synopsis of these techniques is provided to assist the family practitioner in providing this information to his patients. PMID- 21253098 TI - Genetic disorders in the newborn infant. AB - Genetic disorders in the neonate should be suspected in a number of different clinical situations, ranging from that of an infant with dysmorphic features and multiple congenital malformations to that of a previously well newborn who becomes acutely ill. An approach for the primary-care physician to the initial investigation and management of these situations is outlined. In addition neonatal screening tests for metabolic disorders and congenital hypothyroidism are briefly discussed. PMID- 21253099 TI - Genetics in pediatrics. AB - The prevalence of genetic disease in the pediatric population is considerable and probably accounts for at least 50% of childhood deaths and 25% of hospital pediatric admissions. A simple three-generation family history is often very useful, as is background information on ethnicity and consanguinity. A preponderance of affected males in a family should immediately suggest an X linked recessive disorder which may have widespread implications for female relatives in the family. Chromosomal errors will usually be associated with developmental handicaps and one or more major or minor dysmorphic signs. Disorders involving secondary sexual characteristics are largely genetic in origin. Many disorders which were previously thought to be one entity are now known to be many different entities (genetic heterogeneity). PMID- 21253100 TI - Predictive medicine: recombinant DNA technology and adult-onset genetic disorders. AB - Genetic factors are of great importance in common adult-onset disorders such as atherosclerosis, cancer, and neuro-degenerative diseases. Advances in DNA technology now allow identification of persons at high-risk of developing some of these diseases. This advance is leading to predictive medicine. In some genetic disorders, such as those leading to atherosclerosis and cancer, identification of high-risk individuals allows intervention which alters the natural history of the disorder. In other diseases, for which there is no treatment, such as Huntington's disease, the application of this technology provides information that relieves uncertainty and may affect quality of life, but does not alter the course of the illness. General implementation of predictive testing programs awaits the results of pilot projects, which will demonstrate the needs, appropriate levels of support, and guidelines for delivery of such testing. PMID- 21253101 TI - Problems in genetics: getting help. AB - The authors discuss the role of the family physician in identifying families who would benefit from genetic counselling. They outline reasons for referral, as well as the referral process itself, and review the genetic counselling process, with particular emphasis on the initial assessment. The importance of understanding the family's expectations, obtaining a family history, and confirming diagnosis is stressed. A list of genetic centres across Canada is appended. PMID- 21253102 TI - Support services in genetics. AB - For the patient with a genetic disease, the family physician can play a key role in maximizing patient care. This starts with discussion between the physician and the patient to identify the patient's needs. Through referrals to community and medical support services, the family physician can provide his patient with extensive information to meet those needs. By providing information to prepare patients for referrals, following up on those referrals with the patient and the referred service, the family physician can provide high-quality comprehensive care for the patient. PMID- 21253103 TI - Pregnancy and Beyond Part II: Temperature Extremes and High Altitude. AB - Over the last 35 years, transport technology has created new environmental frontiers in which family physicians are, and will continue to be, involved both in research and in administering patient care. Some frontiers address basic physiological problems that cross over into others. In a series of four articles, the author describes six of these frontiers with specific emphasis on pregnancy, from hyperbarism (undersea physiology) to microgravity (space physiology), and the problems, and linkages where evident. This second article explores the effects of temperature extremes and high altitude on the well-being of pregnant women. PMID- 21253105 TI - Hematology: 1978-1988 a decade of major advances. PMID- 21253106 TI - When does a man need a check-up? PMID- 21253104 TI - [Not Available]. AB - A great deal has been said about physicians' stress but little about their reactions to the sense of failure which faces them in their practice. This article deals with that sense of failure as it pertains to self-image and some associated factors that might complicate the adjustment of some doctors to these difficult realities. The author discusses strategies of flight and other unconscious mechanisms used to cope with these problems. PMID- 21253107 TI - Housecalls: who gains? PMID- 21253108 TI - Cheers for shared parenting! PMID- 21253109 TI - Toothpaste substitute for the elderly. PMID- 21253110 TI - An antihistamine decongestant in the prevention of acute otitis media in children with colds. AB - Most clinical drug trials relating to acute otitis media have evaluated medications in terms of treatment. In this randomized double-blind, cross-over study, the effectiveness of an antihistamine decongestant in the prevention of AOM was investigated, rather than the treatment. The medication/placebo was started at the onset of a cold and continued throughout its duration. No treatment effect was evident in the results obtained with 308 children who completed the eight-month study. However, the results indicated a strong relationship between colds and AOM, and a trend toward higher occurrence of AOM in children under four years of age. PMID- 21253111 TI - The family physician - anesthetist: a review of two training programs. AB - A considerable proportion of anesthetic services in Canada is provided by family physician anesthetists, particularly in community hospitals and rural areas not served or not fully served by specialist anesthetists. In the 1970s, the Departments of Anesthesia of the Universities of Toronto and Western Ontario established short training programs to meet the needs of these physicians and communities. In 1983, both universities surveyed the physicians who had completed the programs to assess the characteristics of the practices of these physicians and to further discussion about the appropriate training for such settings. This paper describes the two programs for training of family-physician anesthetists and reports on the survey of trainees who have completed the programs. PMID- 21253112 TI - The health care needs of southeast asian refugees. AB - Although the health of Southeast Asian refugees has been examined in the United States, the health of this population has not been studied in Canada, nor has there been an assessment of the effectiveness of the Canadian health care system in meeting the needs of this group. The authors of this article review the major health problems of Southeast Asian refugees as reported primarily by U.S. researchers, discuss the "theories of illness causation" of the refugees and the problems encountered in providing care to this group. They conclude that there is a need to examine the health of newly arrived refugees in Canada, assess their needs, and determine the adequacy of the existing health-care system to meet these needs. PMID- 21253113 TI - The Health of Canada's Native People: An Overview. AB - The health of Canada's Native people has improved considerably over the last 50 years. Nonetheless, standard rates of health measurement, including mortality and morbidity, remain remarkably elevated. There now exists a coincident burden of infectious and degenerative or chronic illness. Most significant, there is considerable mortality related to injuries, violence, and suicide, and these occurrences are related, to a large extent, to the abuse of alcohol. Many of the ensuing deaths are therefore preventable. The concepts of health promotion and of transfer of control overlap considerably. Both evidently increase the potential of improved health through individual and community empowerment. PMID- 21253114 TI - Using our north for military flight training. AB - The Native people of Northern Quebec/Labrador Peninsula face a growing conflict over the use of their traditional homeland for military flight training. The low level flight training that supports a recent revision of NATO contingency plans for war in Europe causes social disruption and physical destruction. Current and proposed training at Goose Bay, Labrador, raises serious environmental and human rights questions. A host of medical and psychological problems can be expected to follow in populations subject to the disruption and damage caused by low-level flight programs in their area. It is not possible for individuals to develop "coping strategies" adequate to meet the stress caused by stressors of this type. PMID- 21253115 TI - Multiple primary endocrine failure: a case report. AB - A case of type III autoimmune polyendocrine deficiency syndrome is discussed. This case initially presented as macrocytic anemia and was later followed by other endocrine abnormalities. Suggestions for initial investigation and follow up are discussed. PMID- 21253117 TI - Portrait of a patient. PMID- 21253116 TI - Multiculturalism, Medicine and Health Part II: Multicultural Health Care. AB - In this second article of a series, the author develops the concept of health related beliefs as belonging to one of three classifications: beliefs in "nature" or natural causation of health and illness; beliefs relating to the "self" as affecting health; and beliefs in the effects of supernatural forces on the health of individuals. He goes on to discuss beliefs in the first category and to show how physicians, by recognizing and respecting their patients' views on these matters, can improve the doctor-patient relationship and increase patient compliance. PMID- 21253118 TI - Acute leukemia: diagnosis, management, and potential for cure. AB - Acute leukemia is an uncommon malignant disorder resulting from the clonal proliferation of hematopoietic precursors of the myeloid or lymphoid lineages. Of the two major subgroups, acute lymphoblastic leukemia is more common in children, while acute myelogenous leukemia predominates in adults. With modern chemotherapy 60%-70% of all children with acute lymphoblastic leukemia can be long-term survivors and are potentially cured. Although the prognosis in acute myelogenous leukemia is less favourable, recent therapy, including bone-marrow transplantation, offers possible cure in selected patient groups. PMID- 21253119 TI - The Family Physician's Role in Managing Chronic Leukemia. AB - This article provides a brief update on the clinical approach to chronic myelogenous leukemia and chronic lymphocytic leukemia, based on advances in pathbiology and the effect of new concepts on treatment policies. These disorders were selected because family physicians take most responsibility for the day-to day management of these most common forms of chronic leukemias. PMID- 21253120 TI - Malignant lymphomas: their diagnosis, treatment and prognosis. AB - The author of this paper reviews the diagnosis and management of malignant lymphomas, as well as the prognosis for various groups of patients. PMID- 21253121 TI - Allogeneic and autologous bone-marrow transplantation. AB - The author of this paper presents an overview of the current status of bone marrow transplantation, including indications, pre-transplant considerations, the transplant procedure, acute and delayed transplant-related problems, results currently attainable, and a short discussion of possible future developments. PMID- 21253122 TI - Transfusion support of the transplant patient. AB - Organ transplant has become a much more common procedure in recent years. Data suggest that blood transfusions prior to transplant can affect allograph survival. The author discusses blood transfusion in kidney and liver transplantation. PMID- 21253123 TI - HTLV-1: A Significant Retrovirus. AB - HTLV-1, or human T-lymphotropic virus type 1, is a retrovirus causing disease in humans. Responsible for adult T-cell leukemia/lymphoma, it is the first documented viral-induced neoplasia in humans. This same virus has recently been implicated in a progressive neurological disorder, and because it is transmissible by blood transfusion, it represents a major problem in blood banking. The relationship of this virus to other newly discovered retroviruses is discussed. PMID- 21253125 TI - Hematological problems of pregnancy. AB - Hematologic complications are relatively common in pregnancy. Furthermore, many chronic hematologic disorders require special surveillance and intervention in pregnancy. In this brief review, the author discusses common nutritional anemias in pregnancy. She reviews the disorders of hemoglobin synthesis and the need for early genetic counselling and prenatal diagnosis, as well as the special requirements and problems affected patients encounter in pregnancy. An overview of the frequent causes of thrombocytopenia in pregnancy is given and an approach suggested to the management of both the mother and the fetus. An approach is also presented to the management of women at risk for thrombosis in pregnancy, a particularly vexing and controversial problem. The risks of the various forms of anticoagulation are reviewed. Finally, a brief review of obstetrical hemorrhage is presented along with some guidelines useful in its management. PMID- 21253124 TI - Intravenous IgG: A New Therapeutic Tool. AB - Since the 1950s, intramuscular gammaglobulin preparations have been used for antibody replacement in patients with immune deficiency syndromes. The authors of this article discuss newer intravenous formulations which have expanded the role of IgG preparations from simple antibody replacement to therapeutic use in high doses as an immune suppressant and an autoimmune modulator. PMID- 21253126 TI - The bleeding disorders: current concepts and management. AB - Bleeding disorders are relatively uncommon, and most bleeding episodes occur as a result of local factors. Therefore a positive history of bleeding usually does not accurately predict the presence of a bleeding disorder. In a few cases the existence of certain patterns of bleeding, such as hemarthroses and petechiae, does allow an accurate prediction. On the other hand, the absence of bleeding following significant challenge is very helpful indeed in excluding a bleeding disorder. However, a negative history of bleeding in the absence of hemostatic challenge does not exclude a bleeding disorder. Accurate clinical analysis of suspected bleeding disorder requires acquaintance with the common causes of bleeding; these are described along with a clinical approach to diagnosis. The laboratory investigation starts with the performance of the "hemostasis screen". A normal hemostasis screen excludes by far the majority of acquired defects, and further investigation, other than a repeat of the bleeding time, is rarely needed. When hereditary disorders are suspected, specific assay of individual factors, usually factors VIII (hemophilia A), IX (hemophilia B) and Von Willebrand factor, is advised. Recent advances in the understanding and the management of some disorders are described. PMID- 21253127 TI - Platelet disorders: diagnosis and management. AB - Platelet disorders are associated with a significant risk of clinical bleeding. These disorders require an evaluation that includes a platelet count, determination of bleeding time, bone-marrow evaluation, and laboratory platelet tests to establish the underlying pathophysiologic process. The physician who understands these processes can correctly interpret laboratory results and choose the most appropriate treatment option. PMID- 21253128 TI - Hematological support of a cancer patient. AB - Transfusion medicine has come to function as a pivotal support in the treatment of cancer patients in the late 1980s. The authors of this article discuss the indications for, and uses of, various blood components, including packed red blood cells, leukocyte-poor and/or washed blood cells, random donor and single donor platelets, granulocyte concentrates, fresh frozen plasma, and cryoprecipitate. They also discuss common and not-so-common risks, reactions, and diseases associated with the transfusion of the aforementioned blood components. PMID- 21253129 TI - Short-term medical consequences of the chernobyl nuclear accident: lessons for the future. AB - The author of this article discusses the world's most serious nuclear accident to date: the Chernobyl nuclear accident of April 1986. His major focus is on the short-term medical consequences of the accident, including reduction of exposure to persons at risk, evaluation of persons potentially affected, dosimetry, and specific medical interventions. PMID- 21253130 TI - Fetal movement counting. PMID- 21253132 TI - Information please! PMID- 21253131 TI - Re: the jerusalem international doctors orchestra. PMID- 21253133 TI - Making bad matters worse. PMID- 21253135 TI - Appropriate use of emergency departments. PMID- 21253134 TI - Low back pain: a comment. PMID- 21253136 TI - Comment on progress notes, october '87. PMID- 21253137 TI - Plaudits for dr. Seiden. PMID- 21253138 TI - A cautionary note. PMID- 21253139 TI - Remote skin atrophy caused by topical steroids. PMID- 21253140 TI - Re: anti-microbials during pregnancy. PMID- 21253141 TI - Emergency care: the debate continues. PMID- 21253142 TI - Daily maternal counting of fetal movement as an antenatal screening test. Part I. A review. AB - The author reviews use of maternal counting of fetal movements as an antenatal screening test. This test appears to be a sensitive indicator of fetal well-being and a useful method for preventing inexplicable stillbirths. Evidence suggests that it should be considered a routine antenatal screening test for all pregnant women, and not just for those at high risk for perinatal morbidity and mortality. Screening should begin at 28 weeks gestation. PMID- 21253143 TI - Maternal Counting of Fetal Movements. Part II: Case Presentations. AB - The use of daily maternal counting of fetal movements as an antenatal screening test is illustrated in three case studies. The cases described carry both high and low risks, and illustrate the technique of counting fetal movements. The author suggests that performing this antenatal screening test on all patients may reduce perinatal mortality. PMID- 21253144 TI - Psyllium allergy in hospital personnel: a report on twelve patients. AB - We have followed 12 patients with acute symptoms on exposure to psyllium over a three-year period. All were hospital personnel with evidence of atopy. Exposure was by inhalation on dispensing psyllium powder. Symptoms which occurred within minutes of exposure included rhinitis (12/12), conjunctivitis (10/12), shortness of breath and wheezing (9/12). All patients had psyllium-specific IgE antibodies demonstrated by either positive prick-skin tests (1:100) or serum antibodies (rast). Controls had no reactivity to psyllium. Sensitivity persisted over the entire three-year period. We conclude that sensitivity to psyllium is an IgE mediated occupational allergy in hospital personnel; that it produces significant symptoms and it is often unrecognized; and that persistance of sensitivity necessitates strict avoidance of psyllium by all routes of exposure. PMID- 21253145 TI - Work-related stress: a survey of family-practice residents in ontario. AB - A field survey of 273 residents in both years of the five family-practice residency programs in Ontario was undertaken to identify perceived sources of stress and to examine the relationship of stressors to work and career satisfaction, personal distress, and marital life. Differences were examined as between first-and second-year residents, and female and male residents, regardless of their year of training. Results of the survey indicate that first year residents work more hours per week than do second-year residents, are more stressed by time-management problems and lack of self-confidence, and are more depressed. Women residents also work more hours weekly than do male residents, experience more stress related to time management and lack of self-confidence at work, and are more depressed, but drink less alcohol daily than do male residents. These results support previous work in this area. Future directions and recommendations for residency training programs are suggested. PMID- 21253146 TI - The motor vehicle accident in family practice. AB - As family physicians, we are often asked to prepare medico-legal reports on behalf of our patients who have sustained personal injuries. Cervical myofascial injuries sustained in motor vehicle accidents are by far the most common of all injuries seen in this setting. An awareness of the problem of cervical whiplash is essential. This article reviews the current literature on cervical whiplash injuries and provides a guide for the preparation of a medico-legal report as it applies to the MVA patient in family practice. PMID- 21253147 TI - Approach to dyspepsia. AB - Dyspepsia is a common presenting problem of patients in family medicine. Dyspepsia can be caused by a number of underlying conditions, from peptic ulcer disease to functional disorders. Primary-care physicians need to develop an approach to the investigation and treatment of dyspepsia which maximizes symptom relief while minimizing patient discomfort and health costs. This article assesses the current literature on dyspepsia and outlines the evidence for various management strategies. PMID- 21253148 TI - Gastrointestinal parasitic infections. AB - This article surveys the most important gastrointestinal parasites that affect humans. The modes of acquisition, pathology, epidemiology, diagnosis, and treatment are all briefly examined. Gastrointestinal parasites have become increasingly important in the differential diagnosis of gastrointestinal disease, as a result of a number of circumstances. These circumstances include: increasing travel to developing countries; increased numbers, for one reason or another, of immunocompromised individuals; increased consumption of raw or partially cooked ethnic delicacies; more crowding in day-care centres; increased immigration from developing countries; and an endemic pocket of individuals with certain unhygienic or unsanitary practices. PMID- 21253149 TI - Recurrent abdominal pain in children. AB - The authors review some physiological and psychogenic causes of recurrent abdominal pain in children and suggest a practical approach to diagnosis and management of this common complaint. PMID- 21253150 TI - The Irritable Colon: The Family Physician's Most Common Gastroenterological Dilemma. AB - The irritable colon syndrome presents the family physician with a diagnostic dilemma that tests both diagnostic and physician-patient relationship skills. Although the syndrome is common, it has no pathology, and the pathophysiology does not explain fully its signs and symptoms, which are not distinct, but are similar to those of a number of serious organic conditions. Careful history taking, simple investigations, and the addition of 20g of wheat germ fibre to the patient's daily diet will usually control the symptoms. Regulation or reduction of aggravating factors such as anxiety, depression, dietary intolerance or food allergies, antibiotic use, GI infections, and laxative abuse will also control the symptoms. The family physician who is able to tailor the diagnosis and management of the problem to the individual patient demonstrates the benefits of having an on-going relationship with the patient. PMID- 21253151 TI - Liver disease in general practice. AB - A wide spectrum of liver disease is seen in general practice. For the most part, asymptomatic increases in transaminase may be followed for several months, but the treatable conditions described should be ruled out early on. It is essential do diagnose as promptly as possible Wilson's disease, hemochromatosis, autoimmune heaptitis, and hepatitis B. Drugs are a frequent cause of wild transaminitis. Heavy alcohol consumption as a cause of liver disease must always be suspected, but may be difficult to prove. PMID- 21253152 TI - Screening for colorectal cancer: sample techniques. AB - Colorectal cancer is a major health problem. Despite therapeutic advances, the overall five-year survival rate remains at 45%. At the present time the greatest potential for improved survival lies with early detection. The authors of this article have assessed a number of colorectal surveillance programs in an attempt to identify those individuals with potentially pre-malignant disease or early localized cancer. Differences in individual risks and the availability of numerous "screening tests" make it important to provide each patient with the most appropriate investigation. Preliminary evidence suggests that fecal occult blood tests, sigmoidoscopy, and colonoscopy with polypectomy can be effective in reducing the incidence of colon cancer. PMID- 21253153 TI - Practical management of hemorrhoids: pitfalls and plain sailing. AB - This article is not meant to be a comprehensive review of the surgical literature on treatment of hemorrhoids but rather a practical common-sense guide to the management of the patient who presents to a primary-care physician's office complaining of this disorder. The author discusses the probable differential diagnosis of the common symptoms of hemorrhoids, and suggests a rational approach to the management of internal and external forms of this disorder. The author's opinions are based on 16 years of clinical experience in accepting referrals of thousands of patients with hemorrhoid-related complaints. PMID- 21253154 TI - The esophagus as a source of non-cardiac chest pain. AB - Many patients present with chest pain and are subsequently found to have normal coronary angiography; investigation of these patients frequently stops once coronary artery disease has been ruled out. It is now clear that considerable morbidity may be associated with failure to make a definite diagnosis in these patients, and that efforts to identify a cause for the pain should continue within appropriate limits. This paper presents the evidence in support of an esophageal cause of non-cardiac angina. The authors emphasize the difficulty in distinguishing between cardiac and esophageal angina on the basis of clinical history and suggest an approach to investigation. PMID- 21253155 TI - An approach to diarrhea with emphasis on the irritable bowel syndrome. AB - Diarrhea is a symptom of a large number of serious organic illnesses, but it is also a cardinal symptom of the irritable bowel syndrome (IBS). A complete history and physical examination will narrow the etiologic possibilities greatly, as will a few routine screening tests. If the symptom seems to be caused by IBS, a combination of dietary manipulation and advice about psychologic factors should be tried, prior to the use of medications. Particularly refractory cases or those in which there is doubt concerning the diagnosis should be referred to a specialist for further assessment and management. PMID- 21253156 TI - Pregnancy and beyond: environmental frontiers. AB - Over the last 35 years transport technology has created new environmental frontiers, both in research and in the administration of patient care, in which family physicians are, and will continue to be, involved. Some of these frontiers address basic physiological problems that become interconnected with others. The author describes six of these frontiers, with specific relation to pregnancy, from hyperbarism (undersea physiology) to microgravity (space physiology). He outlines the problems and linkages, where evident, in a series of four articles, of which this first one deals with pregnancy and rapid decelerations with resultant trauma, and pregnancy and hyperbarism. PMID- 21253157 TI - Emergency cardiac care: an update. AB - The authors review the new guidelines for basic life support and advanced cardiac life support and the recommended changes to the standards. The changes recommended for basic life support will simplify the psychomotor skills required. The recommended changes to the guidelines for advanced cardiac life support, which include discontinuing the use of isoproterenol and limiting the use of sodium bicarbonate in cardiac arrest, are likely to improve survival rates. Controversies in the management of cardiac arrest are also discussed. PMID- 21253158 TI - Black plus blue equals pink: a case report of near fatal methemoglobinemia. AB - Methemoglobinemia, which is rarely seen in the emergency department, is an unusual cause of cyanosis. It often presents a peculiar and confusing picture to the clinician, and sometimes requires prompt recognition and treatment to prevent death. The following case report illustrates this point. PMID- 21253159 TI - Health care in the highlands of papua new Guinea. PMID- 21253161 TI - Medical Care of Canada's Children to the Year 2000. PMID- 21253160 TI - Alcoholism in the elderly. AB - This article concentrates on the identification confrontation, and treatment of the elderly with late-onset alcohol-abuse problems. The author reviews signs and symptoms that are common both to the aging process and to late-onset problem drinking. He also provides a list of laboratory "markers" that may be helpful for the diagnosis and follow-up of this not infrequent problem. PMID- 21253162 TI - Introducing a new drug: an objection. PMID- 21253163 TI - Should we stop doing obstetrics? PMID- 21253164 TI - Rural family practice part I: a county profile. AB - Rural family practice is a varied and challenging career combining both office and hospital-based medicine. Most rural family physicians do emergency medicine rotations and obstetric deliveries, while many do GP anesthesia. These tasks, as well as age distribution, educational backgrounds, trips to the hospital, and time spent at other select activities, are illustrated and discussed in this demographic study of full-time rural family physicians. PMID- 21253165 TI - Rural Family Practice. Part II: Preferences in Continuing Medical Education. AB - Continuing medical education is one of the many challenges facing rural family physicians. In addition to the education needed for office practice, rural family physicians must develop and maintain a special knowledge base and technical skills applicable to their major hospital roles. This study of full-time rural family physicians' CME patterns and preferences illustrates how useful and enjoyable they find various CME options. PMID- 21253166 TI - Attitudes of patients with chronic respiratory disease to smoking cessation. AB - A group of out-patients of a physician's office, all with chronic obstructive disease, were surveyed in a structured manner to assess attitudes and perception of social and environmental influences on smoking cessation. Half the patients were current smokers, and half were ex-smokers. The decision to attempt to quit smoking was based primarily on general health consequences in both successful quitters and ongoing smokers. The physician who made firm, persistent efforts to assist the smoking patient was viewed as the most important and credible source of information and effective advice concerning smoking cessation. Firm continuing pressure, first from the doctor and secondly from the family and friends, was recognized as the most powerful stimulus. The media and public announcements played very small roles as sources of information and advice. The cost of cigarettes was seldom listed as an important consideration. Smokers were rarely successful in their first attempt to quit, but persistence resulted in success. Reasons for final success could not be identified. PMID- 21253167 TI - Psychological factors and health-related behaviour change: preliminary findings. AB - A good deal of controversy surrounds the issue of optimal treatment approaches for persons with an addictive disorder. The field is rampant with questions pertaining to goals of abstinence as distinct from moderation, in-patient rather than out-patient care, and short-term rather than long-term treatment. In recent years it has become increasingly evident to clinicians and researchers that there simply is no single, best, treatment approach for all patients suffering the effects of substance abuse. These effects constitute a multi-faceted disorder that involves biological and medical aspects, social and psychological dimensions, psychiatric and policy perspectives. A "systems" approach to the treatment of alcoholism is emerging with the identification of various alcoholic syndromes, each demanding a different management strategy. Such an approach requires new methods of patient assessment, and this paper identifies psychological factors that may influence not only the diagnosis and treatment of alcoholic syndromes, but also other health-related behaviour disorders. (The opinions expressed in this article are those of the authors and do not necessarily reflect the views or policies of the Addiction Research Foundation.). PMID- 21253168 TI - Postgrad education for rural family practice. AB - In this article, the author sketches the rural family-practice setting and outlines the postgraduate educational needs of rural family physicians. He then identifies some of the problems and deficiencies that currently exist and puts forward some recommendations. PMID- 21253169 TI - The day-care physical examination. AB - Many Canadian children attend day care. Family physicians are being asked, more and more frequently, to provide assessment of a child's health status prior to day-care admission. The authors of this paper provide evidence for the most useful screening tests in the pre-school age group, outline some means of identification of children at high risk for infectious disease, and suggest rational patterns of use of laboratory investigations. They also propose a guide to the day-care physical examination. PMID- 21253170 TI - Diarrhea in children: two cases. AB - Diarrhea is a common pediatric problem. Careful attention to hygiene in diapered children in group settings can help prevent the problem. The proper presentation of stool specimens to the lab will facilitate the diagnosis. Correct electrolyte, glucose, and water solutions, followed by appropriate introduction of solid foods, will speed recovery. PMID- 21253171 TI - Adolescent contraception: an overview. AB - Adolescents are sexual beings who are undergoing important biological and social changes. Physicians must recognize the need for contraception in their teenage patients and realize when teenagers are asking for contraception. In order to deal effectively with the question of birth control, the physician must be comfortable with the issues of adolescent development and sexuality, as well as with his of her own sexuality. The birth-control pill remains the contraceptive prescription of choice, but other methods of birth control are discussed as well. Physicians must also be prepared to validate a teenager's decision not to engage in intercourse. PMID- 21253172 TI - Common problems in pediatric ophthalmology. AB - Because in children the neurological connections of sight are still plastic, any condition that is able to cause a reduction of visual acuity will also cause cortical suppression of the input from that eye. Early management of amblyopia is essential to its effective treatment. Prompt recognition of strabismus, nystagmus, dyslexia, retinoblastoma and albinism will also lead to an improved visual prognosis for the affected child. In the child with retinoblastoma, it will also vastly improve the prognosis for life. PMID- 21253173 TI - Cross-cultural integration of children into the health-care system. AB - Cultural differences are directly pertinent to the practice of medicine, as they affect the health-care behaviour of families, influence parent-child relationships, and support particular developmental and personality patterns. To deliver optimal medical care tailored to the needs of the individual patient, physicians must be familiar with various cultures and understand and accept the customs, beliefs, and values of the persons who belong to them. Equipped with such understanding, the physician can involve a family co-operatively in its own health care and can help its members to participate to their greater advantage in the health-care system. PMID- 21253174 TI - Preventive health examinations part I. AB - The family physician may conduct preventive screening of children yet unborn, beginning with assessing the rubella-immunity status of 12-year-old females and continuing through the preconception period, the prenatal period, and the process of birth. Knowledge of both parents and their family history allows family physicians to deal effectively with the very sensitive issues of risks of congenital disorders and the effects of teratogenic drugs during pregnancy. Prenatal monitoring for various disorders and risks and assessing the growth curve of pregnancy will help to improve fetal outcomes. Proper use of suctioning, oxygen, and application of the Apgar score to monitor and detect evidence of asphyxia at birth can result in healthier babies. PMID- 21253175 TI - Preventive Health Examinations Part II. AB - Screening of the newborn begins in the case room with a search for gross congenital anomalies. Early detection of such anomalies may help to prevent serious consequences. Problems include spina bifida, cleft palate, orthopedic abnormalities, congenital heart disease, imperforate anus, and esophageal atresia. In the hospital nursery, tests for phenylketonuria, hypothyroidism, hearing impairment, strabismus, and congenital hip dislocation are performed. Studies indicate that five to six well-baby visits in the first two years of life provide adequate screening of healthy infants from intact homes. During well-baby visits the physician should monitor rate of growth and risk of child abuse, and take steps to prevent childhood injuries. Appropriate screening for these conditions in every Canadian child will improve the health of the population. PMID- 21253176 TI - Vision screening programs in children. AB - Amblyopia, strabismus, and severe refractive errors are important causes of visual impairment in children. The author of this article reviews important considerations for pediatric vision screening and suggests a simple, reliable, and inexpensive approach for the primary-care physician in screening children for potentially serious visual disorders. He emphasizes the cardinal role of the primary-care physician in detecting these disorders early, when optimal treatment can be provided. Assessment of the visual acuity in each eye is the basic principle of this approach. Indications for referral in each age group, from newborns to preschoolers, are outlined. The success of such a program will depend on effective co-ordination of all factors involved: public and physician education, screening, re-screening, subsequent evaluation of diagnosis, and the adoption of an optimal treatment plan. PMID- 21253177 TI - Liberty bottle or liability bottle? AB - The number of mothers initiating breastfeeding has increased dramatically over the last decade but the percentage of mothers who terminate breastfeeding prematurely has remained constant. When mothers experience difficulty with breastfeeding, many physicians fail to diagnose and manage the problem effectively. Some physicians assume that mothers dislike breastfeeding and, in a misguided attempt to help, recommend the introduction of a bottle to solve the problem. They do not explain to the mother how the delicate symbiotic relationship of the nursing dyad may be upset by bottle feeding, and how a downward cascade to premature weaning may begin. Bottle feeding is a specific therapy for breastfeeding difficulties. If, after careful consideration, it is the therapy of choice, then the physician must give full and accurate information to the mother about the possible health hazards and consequences of introducing bottle feeds. Then the mother can make an informed decision about when to introduce a bottle, what to put in it, which nipple to use, and what the outcome might be. The physician should support the mother in whatever informed decision she makes. The author of this article reviews the issues of introducing bottle feeding and informed consent. PMID- 21253178 TI - Food allergy in children. AB - The purpose of this review is to establish a rational approach to the assessment of children with food allergy related to an immunologic state in which alteration of response to antigenic material has developed after repeated exposure. The author offers a practical approach to the problem of food allergy in children, dispels some of the myths surrounding the disorder, and discusses some of the popular but unproven and controversial practices relating to its management. PMID- 21253179 TI - Non-wheezing asthma in children. AB - The spectrum of childhood asthma is changing. The concept of non-wheezing asthma has been gaining more recognition in the recent past. The author of this article discusses the varied and often subtle presentations of non-wheezing asthma, as well as its treatment. PMID- 21253180 TI - Fever in Children: Should it be Treated? AB - Fever, which is the regulation of body temperature at an elevated level, must be differentiated from hyperthermia. The pathogenesis of fever involves exogenous pyrogens acting on macrophages/monocytes to produce the endogenous pyrogen, interleukin-1, which acts on the thermoregulatory centre and also has important effects on the body's immune responses to infection. Fever by itself is rarely harmful, and there is no evidence that febrile seizures produce long-term sequelae. On the other hand, fever may be part of the body's innate protection against infection. The main reason for treating a fever in a child is to relieve discomfort. Acetaminophen should be the drug of first choice in treatment, and sponging, if used at all, should be employed only after acetaminophen has been given first. Education of parents about fever management can be helpful. PMID- 21253181 TI - Pertussis vaccine: myths and realities. AB - Pertussis vaccine is feared by many parents, even though the alleged dangers are greatly exaggerated. No cause-and-effect relationship between pertussis vaccine and neurologic damage has ever been scientifically demonstrated. Recent epidemiologic studies indicate that serious neurologic illness occurring in temporal association with pertussis vaccine is extremely rare, and that permanent brain damage rarely, if ever, occurs. Immunization authorities in Canada, the United States, and the United Kingdom recommend that all children should be routinely immunized with the current pertussis vaccine, according to recommended schedules. PMID- 21253182 TI - Management of headaches in children. AB - Headache is a common complaint in children. Although in most cases it does not require medical attention, a thorough evaluation is mandatory for the child with severe, recurring, or unconventional headaches. Recurrent episodes of headache over a prolonged period with normal behaviour, intellectual function, and a negative physical examination suggest migraine or psychogenic headaches. Headache in a child may be indicative of a systemic illness or an intracranial process causing increased intracranial pressure. This review discusses the three most common types of headache in children, highlighting the characteristic symptoms, investigation, and management of migraine, organic, and psychogenic headaches. PMID- 21253183 TI - Long-term outcome of pre-term infants. AB - Recent advances in neonatal intensive care have resulted in significant improvements in the neonatal mortality rate in very low-birth-weight infants. Although there has been some decline in the prevalence of impairments, there are concerns that the improved survival rate may result in handicapped infants who would not have survived in an earlier era. This paper addresses the current survival and morbidity for very low-birth-weight infants and discusses the role of the family physician in meeting the new challenges in continuing care presented by these infants. PMID- 21253184 TI - Day-care centres: risks and prevention of infection. AB - Children attending day-care centres are at increased risk of acquiring various infectious diseases, some with short- and long-term costs to individuals and society. Parents may approach their family physician for advice about placement of their child in day care. It is useful to have an understanding of the attributes of good day-care facilities and of the infections commonly acquired in this setting. In co-operation with day-care personnel and public health authorities, family physicians can help to implement strategies effective in reducing the incidence of infectious diseases in day-care centres. PMID- 21253185 TI - Controversies on feeding babies: a critical review. AB - THERE ARE SIX CHIEF CONTROVERSIES RELATING TO INFANT NUTRITION: breast- vs. bottle feeding; the age to start solids; the need for supplemental iron, fluorides, or vitamins; sterilization of formulas; food allergies; and the relationship of infant feeding to subsequent coronary heart disease. This article discusses these controversies and reviews the evidence on both sides of each question. PMID- 21253186 TI - Midwifery and family practice. AB - With the release of the report of the Task Force on the Implementation of Midwifery in Ontario, in October 1987, it is clear that midwives will be legally practising in this province in the near future and probably, with time, in the rest of Canada also. Does this prospect pose a threat to family practitioners who wish to continue doing obstetrics? The author of this paper discusses the recommendations of the Task Force and argues that the introduction of midwifery should not be seen as representing competition for family physicians but as a positive step which may provide collaboration for low-risk maternity care. A number of models of co-operation are presented. PMID- 21253188 TI - Open wide! A meeting of minds. PMID- 21253187 TI - Pregnancy and Beyond Part III: Cosmic Radiation. AB - Over the last 35 years transport technology has created new environmental frontiers in which family physicians are, and will continue to be, involved both in research and in administering patient care. Some frontiers address basic physiological problems that cross over into others. In a series of four articles, the author describes six of these frontiers, with specific emphasis on pregnancy, from hyperbarism (undersea physiology) to microgravity (space physiology), and discusses the problems and linkages where evident. This third article deals with the known effects of cosmic radiation on the well-being of pregnant women in high altitude flight, and in space. PMID- 21253189 TI - Geriatric screening. PMID- 21253190 TI - The dragon research. PMID- 21253191 TI - Health, functional, and social status of an elderly primary-care population. AB - Non-institutionalized family-practice patients aged 75 years or older were screened at home by nurse practitioners using a comprehensive health-assessment instrument. A majority of subjects showed no serious impairment of physical, psychological, or social functioning. An elite minority experienced excellent health. PMID- 21253192 TI - Fluoride and dental health. AB - Studies conducted under the widest variety of controlled conditions attest to the safety, efficacy, and cost benefits of fluoridation. A program that combines the use of systemic and topical fluoride results in maximum benefits. The author of this article reviews the metabolism of fluoride and its mechanism of action, and discusses practical modes of employing fluoride in caries prevention with special emphasis on the use of fluoride supplements for infants and young children in areas of non-fluoridated water. The author also discusses the factors responsible for the dramatic decline in caries prevalence in the industrialized nations. PMID- 21253193 TI - Dental caries. AB - Dental caries is one of the most prevalent diseases afflicting mankind. It reached a peak in the 1950s but has been declining drastically in recent years in children and young adults. This article describes the three contributing factors in dental caries: microbial plaque, tooth susceptibility, and diet, and discusses practical preventive measures which help to reduce caries incidence. Some of these, such as vaccines and antimicrobial varnishes, are still in the research stages, while others, such as sucrose substitutes, low-calorie sweeteners, and limitation of frequency of sugar snacks are well established and can be promoted by family physicians. PMID- 21253194 TI - Oral and facial pain. AB - Diagnosis of oral and facial pain is often difficult because several anatomical structures within this small area are capable of producing similar symptoms, and pain referred from cranial or distant sites and emotional or psychiatric disturbances complicate matters further. This article summarizes some of the more common causes of orofacial pain, with the exception of disorders of the temporomandibular joint and associated musculature, which are covered in a separate article. PMID- 21253195 TI - Root-canal therapy: a means of treating oral pain and infection. AB - What is root-canal treatment? This article shows how endodontic treatment (root canal therapy) can preserve teeth that would otherwise be extracted, and how tooth-pulp pathology can be diagnosed. Some clinical examples illustrate how non dental infections can masquerade as dental problems, and vice versa. PMID- 21253196 TI - The temporomandibular joint pain dysfunction syndrome. AB - When a patient complains of headache, neckache, or earache and these are associated with noisy temporomandibular joint function, restricted opening or increased pain when chewing, a temporomandibular joint or masticatory muscle disorder should be considered in the differential diagnosis, because signs and symptoms of these disorders are common in all age groups. This article indicates the more common etiological contributions, that is, microtrauma, repeated microtrauma, muscle hyperactivity, and arthritis, which may contribute singly or in combination to produce the so-called temporomandibular joint pain dysfunction syndrome, and how treatment can often be improved by a team approach. PMID- 21253197 TI - Oral tumours. AB - The authors of this article review briefly the anatomy of the oral soft tissues and describe the more common benign and malignant tumours of the mouth, giving emphasis to their clinical features. PMID- 21253198 TI - Periodontal disease part I: types, etiology, and epidemiology. AB - This article comprises four short parts, each one written by a different author. In Part I the author discusses the types, etiology, and epidemiology of periodontal disease. Gingivitis is very common, affecting almost 100% of 14 year olds, while at the other end of the age scale, 50% of 70-year-old North Americans have periodontitis. PMID- 21253199 TI - Periodontal Disease Part II: Overview of Treatment Modalities. AB - In Part II of this article, the author looks at treatment modalities, emphasizing that the key to periodontal health is the removal of plaque and calculus from subgingival sites by means of a combination of effective home care, regular professional cleaning, and surgical treatment where necessary. PMID- 21253200 TI - Periodontal Disease Part III: Chemotherapeutics. AB - In Part III of this article, the author deals with chemotherapeutics, systemic and topical antibiotics, and mouth rinses as an adjunct to mechanical therapy. PMID- 21253201 TI - Periodontal Disease Part IV: Periodontal Infections. AB - In Part IV of this article, the author describes two periodontal infections, acute necrotizing ulcerative gingivitis (trench mouth) and periodontal abscess, both acute painful conditions for which patients may seek advice from their family physician rather than their dentist. PMID- 21253202 TI - Therapeutics and sedation in dentistry. AB - Sedation can help to overcome the fear that prevents many Canadians from accepting dental treatment. This article discusses the indications and contraindications for oral, intramuscular, and inhalation sedation as used by the general dental practitioner for both adult and child patients, with a note on the growing number of specialist dental anesthetists who provide intravenous out patient sedation. Local anesthesia is discussed with reference to allergic reactions, malignant hyperthermia, and the use of epinephrine as a vasoconstrictor in patients with cardiovascular diseases. PMID- 21253203 TI - Bacterial endocarditis: a short overview. AB - Bacterial (infective) endocarditis is a potentially fatal illness which may follow transient bacteremia induced by certain dental procedures. It is the purpose of this article to discuss the rationale behind the American Heart Association's current guidelines on antibiotic prophylaxis for this disease, to consider the dentist's role in implementing these recommendations, and to identify how the physician and dentist can act in the patient's best interests to prevent this illness. PMID- 21253204 TI - Infant oral health care. AB - The family physician/pediatrician who sees a child from birth as part of the well baby visit program is in the best position to identify early dental problems and to educate the family about early oral preventive health care. Since children under three years of age are not seen routinely by dentists, they are at risk of developing dental disease. This paper briefly covers the areas of infant oral pathology, early preventive care, teething, suckling habits, and dental trauma in the toddler. The physician will then be in a better position to recommend to parents when they should seek dental advice and treatment for their young children. PMID- 21253205 TI - Dentistry and the geriatric patient. AB - The number of geriatric citizens is increasing. Those who are edentulous and have been wearing complete dentures face increasing difficulty coping with these prostheses. Those who have natural teeth as they enter old age should be encouraged and assisted in every possible way to keep these teeth, since the likelihood of adjusting to dentures at this age is slim. PMID- 21253206 TI - The replacement of missing teeth. AB - Dentists have used a great deal of ingenuity in replacing lost teeth. Until recently, however, it was not possible to duplicate the natural situation and attach tooth-root analogues to the host bone. Osseointegration allows such an attachment, in which threaded unalloyed titanium implants are placed in the bone by means of a meticulous surgical procedure. The documented successful use of this process has already altered profoundly the predicament of the edentulous patient. The application of osseointegration as a treatment modality for partial edentulism offers exciting challenges for the dentist. This article reviews preliminary experiences in this area from the University of Toronto's Clinical Osseointegration Unit. PMID- 21253207 TI - Diseases of the oral mucosa. AB - This article provides a clinical approach to the more common oral mucosal lesions. Histologic diagnoses are not included, apart from their use in diagnosis and management. In a small number of oral mucosal lesions, clinical appearance is sufficiently distinctive to permit accurate diagnosis, but a biopsy is usually necessary. Clinical appearance is important in directing further investigations such as culture and serologic testing. PMID- 21253208 TI - Hospital dental departments and the provision of dental services. AB - Some hospitals have dental departments where in-patients are treated, and where a service is provided for dental patients whose medical conditions make private practice dental treatment risky. The author of this article provides a partial list of the more common or severe medical conditions for which hospital dental treatment is advisable. Ways in which collaboration between the family physician and the dentist can benefit these patients are discussed. PMID- 21253209 TI - Pregnancy and Beyond Part IV: Microgravity. AB - Transport technology in the last 35 years has created new environmental frontiers in which family physicians are, and will continue to be, involved both in research and in administering patient care. Some frontiers address basic physiological problems that cross over into others. In a series of four articles, the author describes six of these frontiers with specific emphasis on pregnancy, from hyperbarism (undersea physiology) to microgravity (space physiology), the problems, and linkages where evident. This fourth article covers the known and postulated effects of microgravity on pregnancy well-being. PMID- 21253210 TI - The Emperor's Clothes. PMID- 21253211 TI - Anxiety and childbirth. PMID- 21253212 TI - The 1987 readership survey. PMID- 21253213 TI - Breastfeeding: whose choice? PMID- 21253214 TI - A Reader's Suggestions. PMID- 21253215 TI - AIDS-Related CME Workshop. PMID- 21253216 TI - Medifacts: an invitation. PMID- 21253217 TI - Prevalence, quand tu nous tiens.. PMID- 21253218 TI - What to do about grandma. PMID- 21253219 TI - A review of a rural Saskatchewan obstetric service. AB - In a six-year retrospective audit of 405 obstetric cases managed in a small rural Saskatchewan hospital, it was demonstrated that proper patient selection leads to excellent outcomes. The standards of practice were shown to be concordant with similar practices in the United Kingdom and the United States. PMID- 21253220 TI - Midwifery in a family practice. AB - This study examined the effect on the type of maternity care given low-risk mothers in a family practice where approximately one-half of the patients were coached in labour by midwives. It was found that the same caregiver tended to make fewer obstetrical interventions with the midwife-coached patients. While the study was not methodologically rigorous, it nevertheless illustrated trends that the authors believed to be valid when midwives were involved. Future studies might document the trends more clearly and suggest areas for co-operation between family doctors and midwives. PMID- 21253221 TI - Frequency/Dysuria syndrome in young women. AB - The frequency/dysuria syndrome in women is a common problem seen in primary medical care. Only half the affected women who consult a physician have a positive urine culture at the standard of 100 000 organisms per millilitre of urine. The other half may have false-negative urine cultures, "low-count bacterial infection", or urethritis. There are no clinical differences between culture-positive and culture-negative groups that would assist identification of women for whom immediate antibiotic treatment is appropriate. A primary-care study of 103 episodes of frequency/dysuria in 101 young women attending a Student Health Service explored the temporal relationship between sexual activity and the development of urinary symptoms. The length of the last coitus-symptom onset interval proved to have no useful value in predicting the outcome of urine culture in this population. A short last coitus-symptom onset interval combined with a short duration of symptoms may reduce the accuracy of low-power microscopic bacteruria as a test for bacterial urinary infection. PMID- 21253223 TI - Man adapting: the case of the family physician in general medical practice. PMID- 21253222 TI - Providing obstetric care to a remote native population. AB - A family-practice residency program has been involved in providing direct patient care to a number of Native communities in a remote area of Manitoba. The residents and preceptors have provided care on site in the communities, as well as being the primary referral services in the tertiary-care setting. During the 12 years of the program's evolution much experience was gained in dealing with a generally high-risk obstetric population whose care was complicated by such factors as language barriers, distance, and economic and social circumstances. The author of this article reviews the nature of the program and the issues, medical and other, that it deals with, making some reference to experience of similar populations elsewhere. PMID- 21253224 TI - Who Should be Doing Obstetrics in the 1990s? AB - The role of the family doctor in obstetrical care is under attack. The author of this article discusses the reasons. Most of these reasons are related to medical politics rather than to scientific evidence. This paper is a call for family physicians to recommit themselves to the delivery of obstetric care in the 1990s. PMID- 21253225 TI - Topics for family medicine research in obstetrics. AB - Primarily because of improvements in care of the low-birthweight neonate, Canada's neonatal mortality rates have declined significantly over the last 20 years. To make further improvement, research is now focused on the prevention of prematurity. However, benefits from the implementation of such research and the maintenance of the current neonatal mortality rate depend on the availability of obstetric care providers in rural areas. The recent trend among family physicians to drop the practice of obstetrics significantly jeopardizes access to obstetric care for inhabitants of rural areas, and a significant body of literature suggests that such declines in access will be accompanied by an increase in the neonatal death rate. A logical research agenda for rural family physicians would include the forecasting of the effect of the decrease in obstetric care manpower, follwed by the study of factors behind this trend, and the evaluation programs designed to prevent family physicians abandoning obstetric practice. PMID- 21253226 TI - Screening in pregnancy. AB - Over the past 20 years, traditional elements of antenatal care have been supplemented by complex biochemical and biophysical investigations. With his/her knowledge of the patient and awareness of the principles of screening, the family physician is ideally placed to assess potential problems in pregnancy. This article reviews the rationale for screening for certain disorders in pregnancy. Genetic disorders, infectious diseases, and other specific conditions are considered. Some of the more recent controversies in prenatal screening are highlighted. PMID- 21253228 TI - Common physical discomforts of pregnancy. AB - Although pregnancy is a time of health, the physiologic changes of pregnancy often bring discomfort. The family physician is ideally placed to normalize the pregnant woman's experience and to suggest remedies. This article examines several of the commonly experienced discomforts of pregnancy, places them in the context of maternal physiology, and offers specific suggestions for alleviating symptoms. By providing information, discussion, and reassurance, the family doctor can decrease the pregnant woman's anxiety and help her enjoy her pregnancy. PMID- 21253229 TI - Obstetric ultrasound. AB - This article addresses the current indications for an obstetric ultrasound and describes the findings that it is reasonable to expect when reading an ultrasound report. The authors discuss several common obstetrical problems focussing the attention on the usefulness of the imaging information. Finally, they provide a glimpse into the future direction of obstetric ultrasound by discussing vaginal scanning, Doppler assessment of fetal blood flow, and routine ultrasound in pregnancy. PMID- 21253227 TI - Gestational diabetes: a review. AB - Gestational diabetes mellitus is a relatively common complication of pregnancy. The incidence varies from 1.6% to 13%, depending on the criteria used for evaluating glucose tolerance in studies where universal screening was employed. The glucose-challenge screening test produces many false-positive results; the patients thus identified are then subjected to further unpleasant oral glucose tolerance tests to make the diagnosis. The diagnosis labels many pregnant patients as "high risk" and exposes them to a cascade of interventions. The author examines the basis in the literature for universal screening practices. The recommendations of the Second International Workshop-Conference on Gestational Diabetes Mellitus are presented. The author discusses risks and benefits of alternative screening approaches, diagnosis, control, and reviews the current literature. PMID- 21253230 TI - Controversies in obstetrics: dermatologic problems. AB - Skin disease in pregnancy generally produces increased concern among attending physicians. Not only is the diagnosis often a problem but the safety of the therapy may also be a concern. The author of this article presents three common skin problems and their treatments to illustrate the general principles used in diagnosis and treatment of skin disease during pregnancy. PMID- 21253231 TI - Birth observed: a photographic essay. AB - The author presents 17 photographs taken during labour and delivery in a large urban teaching hospital. The text describes a family doctor's experience of normal birth. Shown are birth with the parturient in a squatting position, on hands and knees, and in the lithotomy position, using the squatting bar for high foot support. PMID- 21253232 TI - Alternative birth positions. AB - The dorsal supine position for birth appears to be an aberration practised only in North America during the last 150 years and contrasting to historical precedent and current practices in most other cultures. Alternative birth positions featuring reclining, sitting, squatting or side-lying have recently been shown to have definite physiological and psychological advantages over the conventional posture. The author of this article examines the evidence supporting these advantages and illustrates how these birthing positions may be incorporated into hospital birthing procedures. PMID- 21253233 TI - Fetal assessment in the third trimester. AB - Fetal health in the third trimester is assessed by means of clinical, ultrasound, biochemical, and biophysical techniques. Clinical examination and prenatal risk scoring should be performed at every prenatal visit. Fetal movement counting may be recommended to all pregnant women in the last trimester. A strategy is presented for use of the non-stress test and biophysical profile score for women at increased risk. Family physicians with a low-risk obstetrics practice must judge who should be referred for testing. PMID- 21253234 TI - Obstetric analgesia. AB - This article deals with current knowledge about labour pain; the effects of labour pain on the parturient, the fetus, and uterine activity; the benefits and risks of the various labour-pain options; and the parturient's right to exercise informed choice of analgesia options. PMID- 21253235 TI - Episiotomy and the second stage of labour. AB - The use of episiotomy emerged with the advent of "modern obstetrics". Few of the benefits attributed to it have been sustained by scientific study. The author of this article explores the interrelationship between episiotomy and other interventions in the second stage of labour and makes a plea for a reassessment of our management of this stage of labour. In particular, he questions the place of episiotomy in the prevention of pelvic floor relaxation. PMID- 21253236 TI - The management of post-term pregnancy. AB - Although post-term pregnancy is associated with an increased incidence of fetal distress, oligohydramnios, fetal macrosomia, fetal dysmaturity, and perinatal mortality, as many as 80% of post-term fetuses appear completely normal. The authors of this article discuss the three sub-groups of post-term pregnancies, and deal with the diagnosis and antepartum and intrapartum management of the condition. Recommendations and a protocol for management are provided. PMID- 21253237 TI - Premature rupture of membranes. AB - The management of premature rupture of the amniotic membranes before 37 weeks gestation remains controversial. The authors of this article outline the risks involved for the fetus, define the various terms related, and discuss the antepartum and intrapartum management of such an event and offer a protocol that they have developed. PMID- 21253238 TI - Assessing postpartum family functioning. AB - The birth of a child requires adaptation and reorganization within the family system in order to accommodate the new family member and to allow the family to continue in its psychosocial development. Knowledge of the normative and transitional changes required at this stage of family life will enhance family practitioners' understanding of some of the common concerns and complaints related to them by various family members during the postpartum period. The Family FIRO model represents a helpful conceptual framework to increase the family physician's understanding of the issues of inclusion, control, and intimacy that are highlighted during the transition to parenthood. The authors briefly present this model and discuss its application to postpartum adjustment and its implications for health-care professionals. PMID- 21253239 TI - Miscarriage. AB - Newer techniques for diagnosing early pregnancy have shown that post-implantation embryo loss may be four times the accepted rate of 15%-20%. This article describes various causes of spontaneous abortion and its clinical evaluation and treatment, and proffers suggestions for answering the questions of women who have experienced this loss. PMID- 21253241 TI - Bottle vs. Breastfeeding: A Protest. PMID- 21253240 TI - Compulsive antibiotic training. PMID- 21253242 TI - Re breastfeeding: a response. PMID- 21253243 TI - Factors influencing antibiotic use in acute respiratory tract infections in family practice. AB - The authors of this paper assessed the effect of psychosocial and biomedical factors on the prescription rate for upper respiratory infections. Their study, using written clinical vignettes mailed to a random sample of Ontario family practitioners, achieved a 69% response rate. Family practitioners most often used physical signs and symptoms in forming their decision to prescribe antibiotics. Psychosocial data, when present in the vignettes, significantly modified the prescription rate, often overriding the biomedical factors alone. The study is another step in exploring a complex decision-making process. PMID- 21253244 TI - Bacteriology of the Upper Respiratory Tract: What is Important? AB - Oropharyngeal and nasopharyngeal swabs are commonly collected from patients with a variety of respiratory infections. Unfortunately, the significance of potential pathogens in such specimens is clouded by the prevalence of these organisms in asymptomatic patients and in patients with non-bacterial upper respiratory tract illnesses. Specimens from the oro-and nasopharynx seldom predict the flora in other parts of the respiratory tract, and empiric antibiotic therapy for infections such as acute otitis media, sinusitis, and pneumonia is usually inevitable. The author of this article reviews the bacteriology of the upper respiratory tract and makes recommendations for diagnosis and treatment. PMID- 21253245 TI - Faculty development in Canada: a national survey of family medicine departments. AB - The authors surveyed 16 Canadian Family Medicine Departments to ascertain the availability and content of faculty development activities. The majority of Departments sponsored some faculty development; they were limited, however, by financial constraints, a lack of available manpower, and time restrictions. Few departments had a specified plan for faculty development. No comprehensive orientation activities were available for new faculty, and little attention was paid to established part-time faculty. Although teaching workshops were the most popular faculty-development activity, most programs were planned on an ad hoc basis. A number of effective local programs were not shared nationally. The authors discuss the implications of these results and the need for greater national and regional co-ordination. PMID- 21253246 TI - The history of successful community-operated health services in kahnawake, quebec. AB - Kateri Memorial Hospital Centre (KMHC) provides well-integrated and high-quality acute care and preventive health services for the Mohawk Community of Kahnawake, Quebec, with its population of 5409 persons (1985). Since 1955, the hospital centre has been administered and largely staffed by the community. This article describes the history of the development of health services, discusses why this venture has been so successful, and acknowledges some of the problems. It is hoped that our experiences will benefit, first, other Native communities that are interested in gaining control of their own health services and, secondly, non Indian staff who provide professional care. PMID- 21253247 TI - Multiculturalism, medicine and health part I: multicultural health care. AB - CULTURALLY SENSITIVE HEALTH CARE IS NOT A MATTER OF SIMPLE FORMULAS OR PRESCRIPTIONS THAT PROVIDE A SINGLE DEFINITIVE ANSWER: rather, it requires understanding of the principles on which health care is based and the manner in which culture may influence those principles. This series of six articles will examine influences that ethnic and cultural background may have on health and health care. Part I outlines the development, importance and relevance of multicultural health care. The author stresses the importance of understanding community needs, cultures and beliefs; the active interest and participation of the patient in his or her own health care; the importance of a good physician patient relationship; and the benefit of an open-minded approach by physicians and other health-care workers to the delivery of health-care services. PMID- 21253248 TI - Respiratory emergencies in infants and young children. AB - Emergencies involving the respiratory tract are not uncommonly encountered in infants and young children. The spectrum of disorders causing respiratory distress varies from self-limited disorders such as bronchiolitis to potentially life-threatening conditions such as acute epiglottitis. This article outlines the clinical manifestations of some of the common respiratory emergencies presenting in infants (beyond the neonatal period) and young children, as well as strategies for management. PMID- 21253249 TI - Dental emergencies. AB - Patients with dental emergencies sometimes present to their physician. This article outlines the role of the physician in the management of dental patients who have suffered traumatic injuries, postoperative hemorrhage, pain, and infection. It deals with those difficulties for which the physician may easily prescribe treatment and outlines the treatment that would be undertaken by a dentist who receives such a patient on referral. PMID- 21253250 TI - Treatment of acute puerperal mastitis and breast abscess. AB - Mastitis is a benign infection of the breast if it is treated early. If two days elapse before treatment is started, it can lead to serious complications such as chronic or recurrent mastitis or breast abscess. Treatment consists in frequent nursing and massaging or stripping the breast to keep it empty of milk or pus, and appropriate antibiotics. Incision and drainage of a breast abscess can be done in the office under local anesthesia, and the drainage continued at home by the mother. PMID- 21253251 TI - Newer interventions in myocardial infarction: do they make a difference? AB - Preventive aspects of coronary artery disease have made substantial advances in recent years, decreasing the incidence of coronary artery disease in Western countries. In addition to that there has been an initial drop from an in-hospital mortality of 35% to approximately 12% in the early 1960s with the establishment of coronary care units and cardiopulmonary resuscitation with defibrillation. Further to that, in recent years, it has been conclusively shown that there would be a further 20% decrease in mortality and improvement in morbidity in acute myocardial infarcts in patients treated with thrombolytic agents who present themselves within four hours of the onset of their symptoms and who are under 65 years of age. This would decrease the in-hospital mortality to approximately nine percent. PMID- 21253252 TI - Training family physicians in emergency medicine. AB - There is no Canadian literature on training family physicians in emergency medicine. The author reviews the content of the current programs at the undergraduate and postgraduate levels. He questions whether the curriculum of family-medicine programs adequately fulfills the trainee's or the community's needs. Increased competence, as well as greatly increased confidence, should result from a four-month emergency medicine rotation. The teaching should be done by full-time specialists in emergency medicine. PMID- 21253253 TI - The value of a multi-disciplinary team in critical care. AB - Intensive care medicine is a broadly based discipline. Critically ill patients follow an all too similar "common final pathway" whatever illness initially precipitates their condition. No one individual can be "all things to all patients", and the intensivist finds her/himself practising with a "foot in the door" of many sub-specialties and thus needing to integrate his/her input. Our health care system cannot sustain the demands of many parallel intensive care units, each based on an organ system or traditional specialty and each providing competitive services within the same hospital. The pressures for improved patient care, more effective intra-physician co-operation and more efficient use of resources make it imperative that we provide a multi-disciplinary team in our intensive care units. The need for increasing numbers of undifferentiated physicians to provide bedside in-hospital care may revitalize the role of the family physician in acute-care hospital units. PMID- 21253254 TI - Management principles for the overdosed patient. AB - Priorities in the treatment of the poisoned patient are maintenance of airway, breathing, and circulation. While the patient is being stabilized, a history of drug ingestion should be obtained. Because the history is so often unreliable, physical examination directed to a search for toxic syndromes assumes more importance. Discriminate use of the laboratory may be helpful in confirming a clinical diagnosis. Priorities after initial stablization and during physical examination and laboratory confirmation are preventing toxicity by removing the toxin from the gastrointestinal tract, decreasing its absorption, and increasing its elimination. For a limited number of substances, antidotes may be beneficial. Because of the wide variety of clinical situations and toxins involved, the resources and expertise available through your regional Poison Centre should be used. PMID- 21253255 TI - Emergency Family Care Following a Child's Sudden Death. AB - Sudden unexpected death is a traumatic event for all concerned, but it is of benefit to a family to have a family physician who knows the family, is available, and can put to use previously established rapport. Commonly, however, the family of the child and the physician at the hospital meet as strangers. Professionals in the Emergency Room or Intensive Care setting can be particularly effective in promoting positive bereavement outcomes, as effective early interventions make healthy and appropriate grief responses more likely for all family members.(1-3) Consequently, guidelines for appropriate intervention should be available, whether to the family's long-standing physician or to an unfamiliar physician meeting the family for the first time in an emergency situation. PMID- 21253256 TI - Acute ankle injuries: clinical/radiologic assessment in diagnosis. AB - Acute ankle injuries represent a large burden of illness in the primary care/emergency setting. Concern has been expressed in the medical literature about the unnecessary use of X-rays in the assessment of these patients. A literature review was conducted to address the question: "Can clinical examination alone accurately diagnose fractures and sprains in patients with acute ankle injuries?" Published reports offer inconsistent conclusions on the value of clinical criteria in the diagnosis of fractures or sprains. These inconsistent conclusions appear to result from numerous biases, different patient populations studied, varied interpretations of normal and abnormal results, and different groups of examiners. The only criteria associated with the diagnosis of fracture in more than one study are age greater than 40 years, inability to bear weight on examination, "point" or "bone" tenderness, and swelling. Until consistent results are available, no change in the rate of X-ray referral should be expected. PMID- 21253257 TI - Evaluation of the injured eye. AB - Ocular injury is responsible for 50% of eye emergencies and is a common cause or possible source of visual loss. It is a common and at times worrisome problem in an office practice because it may present as an insignificant injury when, in fact, a proper evaluation may reveal a more serious condition. For example, a "black eye" may need more than cold compresses. A very careful eye examination may reveal a small hyphema, a distorted iris, a small corneal laceration, an occult perforation, or intraocular bleeding secondary to a retinal tear. These findings would necessitate prompt referral to an ophthalmologist for further evaluation. It is, therefore, imperative that as thorough an evaluation as possible be done by proper history taking and meticulous comprehensive examination. More mistakes are made by not inquiring and looking than by not knowing. PMID- 21253258 TI - The appropriate use of oxygen. AB - The scientific evidence for the efficacy of oxygen therapy in acute hypoxemia is limited. In chronic hypoxemia continuous oxygen therapy appears to decrease mortality. Current indications for oxygen treatment are PaO(2) less than 60 in acute hypoxemia and less than 55 in chronic hypoxemia. Physical and physiological hazards of oxygen are reviewed. Three syndromes of pulmonary oxygen toxicity are described: tracheobronchitis, adult respiratory distress syndrome, and bronchopulmonary dysplasia. PMID- 21253259 TI - The Making of Ontario's Emergency Health Services System. AB - In 1981, the Ontario Ministry of Health began a lengthy and systematic process to build a modern and integrated Emergency Health Services System. This article outlines the Ministry's vision for emergency health services, the strategy used to realize this vision, and the accomplishments which have been achieved so far. Some of the concepts used successfully in this building process are also discussed, including the marketing of the systems approach, an emphasis on co ordination and integration of efforts towards a well-defined common goal, and the involvement of an extensive network of health-care planners and providers in achieving consensus and co-operation. Finally, the article raises a number of major issues which must be addressed. PMID- 21253260 TI - Swimming emergencies. AB - Persons who have undergone swimming emergencies are seen in emergency departments everywhere. They are frequently young healthy citizens. In some instances they will receive better care in large specialized referral hospitals. Other problems can be managed well at local facilities. This article attempts to equip all family physicians with some knowledge and management guidelines for dealing with swimming emergencies, submersion injuries including near-drowning, accidental hypothermia, and triathalon hypothermia. The unique problems of hot tub near drowning, infant water intoxication, and spinal injuries caused by diving are presented. PMID- 21253261 TI - Neuroleptic malignant syndrome. AB - The neuroleptic malignant syndrome (NMS) is a potentially fatal syndrome characterized by diffuse muscular rigidity, pyrexia, sweating, cardiovascular instability, and elevated serum creatinine phosphokinase. NMS occurs in 2% of all patients exposed to neuroleptics (antipsychotic drugs). A case of successfully treated NMS is presented, and the typical symptomatic presentation, etiology, pathogenesis, and treatment options of this syndrome are described. PMID- 21253262 TI - Doctors, patients and relationships. PMID- 21253263 TI - Training for rural practice: a comment. PMID- 21253264 TI - Training for rural practice: "real life" exposure. PMID- 21253265 TI - Myofascial injuries and compensation. PMID- 21253266 TI - A Family Physician's Role: Supporting Victims of MVAS. PMID- 21253267 TI - Transferring records when patients change family doctors. AB - While previous records of a new patient can be of great benefit, the process of record transfer often leads to frustration for both the receiving and sending physician. This report describes a survey of the current record-transfer practices of 475 randomly selected Ontario family physicians who responded to a questionnaire. This represented an overall response rate of 84%. Only 36.5% of respondents always or frequently found the transferred information useful. Only 51.5% of physicians regularly obtain past records for their patients. Respondents showed a preference for consultation letters and hospital-discharge summaries. Most of the respondents sent copies of consultation letters written by other physicians, even though the CMA policy on record transfer recommends against this practice. Data on office visits was seldom perceived as useful information. A written summary of the patient's history with photocopies of select information was the most popular format for transfer of patient information. Unfortunately, it is also the most time-consuming and expensive method. Approximately 62.1% of respondents thought that a fee should be charged for transfer of patient information; 42.1% thought the patient's medical care plan should pay; while 41.5% thought that the patient should be responsible. Guidelines for information transfer are suggested. PMID- 21253268 TI - The professional attitudes and clinical practices of men and women generalists. AB - Data from a 1983-84 Quebec generalists' survey were used to compare the professional attitudes and clinical practices of women physicians with those of their male colleagues. The survey was conducted on a random sample of 736 Quebec generalists and achieved a 83.7% response rate. Analyses were performed separately for fee-for-service physicians and for salaried physicians working in local community health centers (CLSCS). Results showed more gender differences among fee-for-service physicians than among salaried physicians. Women in private practice were more likely than their male colleagues to value the multidisciplinary, social, and humanistic aspects of patient care. For their part, women salaried physicians reported being significantly more involved in the social and preventive dimensions of health care than their male colleagues. Important attitudinal differences were observed between fee-for-service and salaried generalists, regardless of gender. This study suggests that neither the medical training nor the organizational constraints of the work setting succeed in levelling off all gender differences. The findings also suggest that women physicians can help promote aspects of health care to which much importance has been attributed in recent years. PMID- 21253269 TI - The "i-never-took-pills-before" syndrome and the treatment of hypertension. AB - A new condition called the "I-never-took-pills-before" syndrome has been developed to describe hypertensive patients who react adversely to a variety of medications with different side-effect profiles. The typical individual who manifests this syndrome readily admits to a dislike of taking medication in general, has rarely taken drugs before a diagnosis of hypertension was made, and tends to develop the same constellation of side-effects in response to completely different classes of drugs. Various features of this syndrome are outlined and suggestions offered to help physicians identify and treat patients with this condition. PMID- 21253270 TI - Multiculturalism, Medicine, and Health Part IV: Individual Considerations. AB - In this fourth article of his series, the author examines some specific ethnoculturally related factors in the context of the doctor-patient interaction. Physicians should be aware of these factors in order to provide appropriate and effective care to individuals of various cultural backgrounds. PMID- 21253271 TI - Perspectives on sexual assault. PMID- 21253272 TI - Benign carotenemia in children. AB - The author discusses five infants, aged eight to 11 months, with carotenemia secondary to excessive consumption of carotene-containing foods. These infants had white sclerae in spite of yellow discoloration of the skin. Simple elimination of these foods led to clearing of the yellow skin color and normalization of serum carotene levels. All infants had normal vitamin A levels, white cell count, serum glucose, lipids, liver- and thyroid-function tests. The benign nature of this condition is emphasized. PMID- 21253273 TI - The trying patient. AB - The author comments on the inevitability of encountering difficult patients in family practice and presents a case history of a patient who has been helped to develop a more appropriate relationship with her physician (the author) and his office staff. PMID- 21253274 TI - Great expectations: the doctor-patient relationship in obstetrics. AB - A close doctor-patient relationship is one of the many strengths of family practice obstetrics. This paper discusses how the relationship between the family physician and childbearing couples may be improved. Medico-legal concerns with respect to obstetrics are highly topical. Good communication is an essential step in avoiding legal entanglements. The challenges provided by complex birth plans, poor outcomes, and dissatisfied patients are reviewed, and recommendations are made. PMID- 21253275 TI - Doctor-patient communication on the telephone. AB - Since its invention, the telephone has been an important tool in medical practice, particularly for primary care physicians. Approximately half the calls made to a physician's office during regular consulting hours are for clinical problems and most are handled effectively over the phone without an immediate office visit. Telephone encounters are generally very brief, and managing such calls requires a pragmatic approach that is often quite different from the approach taken in the office visit. The telephone encounter should be recognized and recorded as a specific medical interaction in the medical chart for both clinical and legal reasons. Effective telephone encounters depend on good communication skills; decision making regarding disposition is a major goal. The physician's perception of a medical problem may be different from the patient's; patients are frequently seeking advice and reassurance rather than diagnosis and treatment, and may call because of anxiety and psychological stress. For physicians and their families who are not prepared for after-hours telephone encounters, calls that interrupt more "legitimate" activities may result in anger or frustration for the physician and dissatisfaction for the patient. PMID- 21253276 TI - The Patient's Perception of Care: A Factor in Medical Litigation. AB - What motivates a patient to sue a physician? Review of Association case files and results of research done by medical insurers in the United States indicate that strong subjective factors play a part. Patients sense an impersonality from technological medicine and look to the physician for concern and compassion. When there is a perceived lack of concern on the part of the medical treatment team, particularly in the face of an unfortunate outcome, the seed is sown for a lawsuit. The author of this article describes cases which show the effect of the patient's perception of care on the decision to commence litigation or lodge complaints. He suggests how similar situations might be dealt with, short of litigation, through more effective patient-physician communication. PMID- 21253277 TI - The teacher-student-patient relationship in family practice: common dilemmas. AB - When students are included in administering patient care, the doctor-patient relationship changes. Because of frequent turnover of students, continuity of care poses a major dilemma. One key to success is to help students deal with issues of change and loss, both in their own experience and in that of their patients. It is also important for supervisors to maintain direct patient contact, especially with new or complex patients or at a patient's request or at the request of a resident or a nurse, or when the teacher cannot get a good "feel" for the patient's problem at second hand. Supervisors should also recognize the effects of different approaches to supervision on relationships with patients and with students. PMID- 21253278 TI - Patient-centred interviewing part I: understanding patients' experiences. AB - Effective patient care requires attending as much to patients' personal experiences of illnesses as to their diseases. Diseases are ferreted out by using the conventional medical model, but understanding illnesses requires a different approach. A patient-centred method focuses on four principal dimensions of patients' experiences: their ideas about what is wrong with them; their feelings about their illnesses, especially their fears; the impact of their problems on functioning; and their expectations about what should be done. The key to this approach is attention to patients' cues related to these dimensions; the goal is to follow patients' leads, to understand patients' experiences from their own point of view. This method improves patient satisfaction, complicance and outcome, and is applicable to the everyday work of family physicians with "ordinary" patients. PMID- 21253279 TI - Patient-Centred Interviewing Part II: Finding Common Ground. AB - DEVELOPING AN EFFECTIVE MANAGEMENT PLAN REQUIRES PHYSICIANS AND PATIENTS TO REACH AGREEMENT IN THREE KEY AREAS: the nature of the problems, the goals and priorities of treatment, and the roles of the doctor and patient. Often doctors and patients have widely divergent views in each of these areas. The process of finding a satisfactory resolution is not so much one of bargaining or negotiating but rather of moving towards a meeting of minds or finding common ground. This framework reminds physicians to incorporate patients' ideas, feelings, and expectations into treatment planning. PMID- 21253280 TI - Patient-Centred Interviewing Part III: Five Provocative Questions. AB - The literature review of select studies on doctor-patient communication seeks to answer some of the frequently expressed questions and doubts about patient centred interviewing. Studies from Canada, the United States, Britain and Holland, mostly in family practice, provide us with a rich source of data to ponder. The five questions we ask are: Do patient-centred consultations make a difference to patient outcomes? Are patient-centred doctors medically competent? Are patient-centred visits long? Are physicians consistent in their interview styles from patient to patient? How do students learn the patient-centred approach? PMID- 21253281 TI - Laser surgery of early glottic cancer in elderly. AB - Aim of this retrospective study is to evaluate the impact of transoral laser surgery of early glottic cancer in elderly patients in terms of feasibility, disease-free survival, overall survival and organ preservation, in a single Institute (European Institute of Oncology). A total of 122 patients (male/female ratio 113/9), over 70s with untreated early stage glottic cancer, were consecutively evaluated and treated at the European Institute of Oncology from 2000 to 2008. None had contraindications to general anaesthesia and all patients signed informed consent to this surgical treatment. The severity of pre-operative comorbidities and the intra-operative risk were evaluated according to the American Society of Anaesthesiologists Grading classification. All patients underwent laser cordectomies according to the European Laryngological Society classification. Histopathological examination demonstrated no evidence of tumour (pT0) in 19 patients (calculated only in patients with a previous vocal cord biopsy positive for squamous cell carcinoma), pTis in 18, pT1a in 53, pT1b in 16, pT2 in 14 and pT3 in 2, respectively. A 10-year overall survival, a tumour specific survival and a laryngeal tumour-specific survival were, respectively, 64.9%, 84.8% and 94.3%. In conclusion, transoral laser surgery is feasible in elderly patients with early stage glottic cancer, providing good results in terms of disease-free survival, organ preservation and quality of life. Our group of elderly patients had no intra-operative or post-surgical complications and resumed normal activities the day after discharge from hospital. Considering these factors, we can assess, that transoral laser surgery, therefore, represents a modern treatment that should be offered as an alternative to conventional radiotherapy in elderly patients with early glottic cancer referred to medical centres with expertise for this surgical procedure. PMID- 21253282 TI - Effect of bone-conducted vibration of the midline forehead (Fz) in unilateral vestibular loss (uVL). Evidence for a new indicator of unilateral otolithic function. AB - Recently, a new indicator of vestibular otolithic function has been reported: it is a series of negative-positive myogenic potentials recorded by surface electrodes on the skin beneath the eyes in response to bone-conducted vibration (BCV) delivered to the forehead at the hairline in the midline (Fz). The potential is called the ocular vestibular-evoked myogenic potential (oVEMP) and the first component of this (n10) is a small (approximately 8 microV), short latency (~ 10 ms), negative potential. In healthy subjects, who are looking up, the n10 responses to Fz bone-conducted vibration are symmetrical beneath the two eyes. In the present investigation, in 17 patients with unilateral surgical vestibular loss, marked asymmetries were observed between the n10 beneath the two eyes: n10 is small or absent beneath the eye on the side opposite the operated ear, confirming previous evidence that n10 is a crossed vestibulo-ocular response unlike p13 of bone-conducted vibration cervical VEMPs (cVEMPs) is a ipsilateral vestibular response and also it is absent in this type of subjects. These results, together with evidence from patients with superior vestibular neuritis allow us to conclude: the asymmetry of the n10 response to Fz bone-conducted vibration is an indicator of utricular macula/superior vestibular nerve dysfunction on the operated side in patients with unilateral vestibular loss. PMID- 21253283 TI - Postural control and risk of falling in bipodalic and monopodalic stabilometric tests of healthy subjects before, after visuo-proprioceptive vestibulo-postural rehabilitation and at 3 months thereafter: role of the proprioceptive system. AB - Nine healthy volunteers (6 males, 3 females), mean age 34.5 years (SD = 11.52), underwent a vestibulo-postural rehabilitation cycle with a visuo-proprioceptive type stimulus. All subjects in the study group were evaluated by means of stabilometric bipodalic and monopodalic tests both before and immediately after treatment, and again 3 month thereafter. The Delos Postural Proprioceptive System(r), DPPS (Delos, srl, Turin, Italy), was used in performing these stabilometric tests and in the rehabilitation exercises. The first aim of the study was to evaluate to what extent the functional level of the proprioceptive system was reliable, in healthy subjects, in the control of postural stability; the second was to demonstrate the possibility to increase this level by means of a novel visuo-proprioceptive feedback training; the last was to establish whether or not the increase achieved was permanent. The bipodalic test did not reveal any deficit in posture either before or after rehabilitation. The monopodalic test prior to treatment, with eyes closed, revealed, in 2/3 of the study group, evidence of the risk of falling, expressed as the precautional strategy (8.57 +/- 6.18% SD). An increase in the proprioceptive activity, obtained in the subjects examined immediately after the visuo-proprioceptive vestibulo-postural rehabilitation, led, in the monopodalic test, with eyes closed, to a significant reduction in the risk of falling (with the precautional strategy equal to 1.09 +/ 2.63% SD, p = 0.004). The monopodalic test, with eyes closed, 3 months after rehabilitation, demonstrated results not unlike those pre-treament with values, therefore, not more significant than those emerging from the pre-treatment test. Thus, from the above-mentioned data, it can be observed that, also in healthy subjects, there may be different levels of postural proprioceptive control related to a high risk of falling. These levels can be maintained constant for a certain period of time, until a significant reduction in the risk of falling is achieved, only if continuously stimulated by appropriate sensorial information. PMID- 21253284 TI - Validity of Italian adaptation of the Dizziness Handicap Inventory (DHI) and evaluation of the quality of life in patients with acute dizziness. AB - The impact of dizziness on Quality of Life (QoL) can be assessed by the Dizziness Handicap Inventory (DHI), which is used as a discriminative and evaluative tool. Although the DHI is available in several languages, an equivalent version for the Italian population is not yet available. Aim of this study was to translate the DHI into the Italian language (DHI-I), assess its correlation to the Italian version of the Short Form-36 Health Survey and to investigate its reliability in evaluating the QoL of patients with acute dizziness. The study population consisted of 50 patients (76% females and 24% males), mean age 51.6 years, range 25-85 years (SD = 14.5). A cross-sectional design was used to examine the internal consistency (Cronbach's alpha) and concurrent validity (Pearson's product moment correlation r). The application followed the stages of translation from English to Italian and linguistic adaptation, grammatical and idiomatic equivalence review. To confirm the external validity of DHI-I, the Pearson correlation test between the total score and single subscales of DHI-I and the 8 scales of the Short Form Health Survey (SF-36) was performed. The Cronbach alpha coefficients for internal consistency were 0.92 for the DHI-I and 0.82, 0.84 and 0.75 for the sub-scale functional, emotional and physical, respectively. The frequency distribution of no one item showed a percentage higher than 75% in a single possible answer (0, 2, 4), excluding a ceiling or floor effect. Correlations with the total score of DHI-I were consistent and the correlation between total score of DHI-I and total score on SF-36 was -0.593. Of the single subscales, the emotional scale showed a closer correlation with almost all scales of the SF-36. The correlation between the total score of SF-36 and the single sub scale of DHI-I (functional, emotional, physical) were respectively -0.599, 0.563, -0.398. The DHI was culturally and linguistically adapted for its application in the Italian population. The DHI-I demonstrated a good reliability and is recommended as a measure of disability in patients with dizziness and unsteadiness. According to the DHI-I, patients with acute dizziness and with a clinical diagnosis of vestibular syndrome presented a decreased QoL; the physical aspects were the most compromised. PMID- 21253285 TI - Epidemiology of Bell's palsy in an Italian Health District: incidence and case control study. AB - The incidence of Bell's palsy has been estimated in a health district of a major Italian city, taking also into consideration the potential risk factors that might influence the occurrence of Bell's palsy. A matched case-control was therefore designed, by collecting data from the Emergency Departments of four Hospitals belonging to the same Health District in Rome (Italy), coordinated by a tertiary referral centre University Hospital. All patients affected by Bell's palsy within the health district and four controls for each case were included. Controls were selected from other ENT patients, and were matched for hospital admission, week of disease onset, and climate conditions. Information regarding possible risk factors was collected using standardized telephone interviews. The resulting dataset was analyzed using multiple conditional logistic regression. The study group comprised 381 patients with acute, unilateral, peripheral facial palsy, clinically diagnosed as Bell's palsy observed between 1st January 2006 and 31st December 2008. The cumulative incidence of Bell's palsy was found to be 53.3/100.000/year. Among the risk factors, age was found to influence onset of Bell's palsy, with an odds ratio of 2% for each one-year increase in age, with a linear trend (95% CI = 1-3%; p = 0.005). Bell's palsy was found to occur with an annual incidence close to previous reports. Among the possible known risk factors (diabetes, pregnancy, etc.), only aging was found to play a significant role. PMID- 21253286 TI - Radionecrosis of the larynx: case report and review of the literature. AB - Aim of the present report is to describe a case of radionecrosis related to radiotherapy of the larynx and to review the literature. A review was made of the hospital chart, surgery report, imaging studies and pathological findings of a 51 year-old male patient came to our attention. Results indicated that radionecrosis often requires total laryngectomy. It is very rare, but morbidity and mortality rates are high. The interval between conclusion of radiation therapy and development of radionecrosis ranges from 3 to 12 months. In this report, a case of radionecrosis is presented which has been managed using the organ sparing strategy. In conclusion, the larynx may be spared when radionecrosis occurs but more investigations are required in order to define the most appropriate treatment. PMID- 21253287 TI - A primary squamous cell carcinoma of the trachea: case report and review of the literature. AB - Primary windpipe tumour is extremely rare. Squamous cell carcinoma is the most common malignant form, especially in smokers. The radiological appearance of these neoplasms can be classified as intra-luminal, wall-thickening, exophytic form; the majority of the lesions are obstructive in nature and then tend to extra-luminal invasion. This tumour is usually diagnosed late on account of delayed specific symptoms: haemoptysis, dyspnoea, coughing, hoarseness, stridor. Surgery, followed by adjuvant radiotherapy, is the treatment of choice; primary radiotherapy, in inoperable cases, can represent a curative management option. A case of primary tracheal cancer is described and a review of the literature is presented. PMID- 21253288 TI - Microcystic adnexal carcinoma of the centrofacial region: a case report. AB - Microcystic adnexal carcinoma is a rare, locally aggressive neoplasm with both eccrine and follicular differentiation and a high probability of perineural invasion of the centrofacial region. Given the histopathological features of this tumour, early diagnosis is essential for adequate management. This report refers to a case of microcystic adnexal carcinoma of the nasogenial region, with infiltration of the deep planes extending to the anterior wall of the maxillary sinus. Surgical treatment involved wide demolition of the centrofacial region followed by reconstruction using four locoregional flaps: an Indian flap and a Mustarde flap were used for cutaneous reconstruction; a septal flap to support the maxillogenial region; a mucosal flap to separate the nasal cavities. PMID- 21253290 TI - Lateral semicircular canal benign paroxysmal positional vertigo diagnostic signs. PMID- 21253289 TI - Case reports on two patients with episodic vertigo, fluctuating hearing loss and migraine responding to prophylactic drugs for migraine. Meniere's disease or migraine-associated vertigo? AB - Recent reports have focused on a possible association between migraine and Meniere's disease; patients suffering from Meniere's disease present a higher rate of migraine. In some cases, the clinical features of migraine-associated vertigo may mimic the presentation of Meniere's disease. The present report focuses on two cases of females with recurrent episodes of rotational vertigo, fluctuating hearing loss and tinnitus lasting from a few minutes to several hours; both cases also presented migrainous attacks. As a result of repeated cochleovestibular attacks, both patients presented a permanent low frequency sensorineural hearing loss. Preventive therapies for Meniere's disease did not reduce vertigo attacks, while topiramate and acetylsalicylic acid treatment resulted in a significant reduction of both migraine and vertigo. Both the diagnosis of Meniere's disease and of migraine-associated vertigo rely on clinical history and both disorders lack a specific diagnostic test. In the early stages, differential diagnosis between Meniere's disease and migraine-associated vertigo is often very difficult; previous investigations focused on the possibility that subjects with migraine may experience all symptoms of Meniere's disease, including sensorineural fluctuating hearing loss. In conclusion, a trial with prophylactic drug treatment for migraine might be suggested in patients with clear symptoms of migraine and recurrent cochleovestibular disorders. PMID- 21253291 TI - Converting apogeotropic into geotropic lateral canalolithiasis by headpitching manoeuvre in the sitting position. PMID- 21253293 TI - Pancreas transplantation. AB - Diabetes mellitus is generally treated with oral diabetic drugs and/or insulin. However, the morbidity and mortality associated with this condition increases over time, even in patients receiving intensive insulin treatment, and this is largely attributable to diabetic complications or the insulin therapy itself. Pancreas transplantation in humans was first conducted in 1966, since when there has been much debate regarding the legitimacy of this procedure. Technical refinements and the development of better immunosuppressants and better postoperative care have brought about marked improvements in patient and graft survival and a reduction in postoperative morbidity. Consequently, pancreas transplantation has become the curative treatment modality for diabetes, particularly for type I diabetes. An overview of pancreas transplantation is provided herein, covering the history of pancreas transplantation, indications for transplantation, cadaveric and living donors, surgical techniques, immunosuppressants, and outcome following pancreas transplantation. The impact of successful pancreas transplantation on the complications of diabetes will also be reviewed briefly. PMID- 21253295 TI - Low Levels of Pepsinogen I and Pepsinogen I/II Ratio are Valuable Serologic Markers for Predicting Extensive Gastric Corpus Atrophy in Patients Undergoing Endoscopic Mucosectomy. AB - BACKGROUND/AIMS: The levels of pepsinogen (PG) I and the PGI/II ratio are useful serologic markers for chronic atrophic gastritis. This study evaluated the performance and clinical implications of these markers in patients undergoing endoscopic mucosectomy. METHODS: We enrolled 142 consecutive patients with early gastric tumors and Helicobacter pylori infection who were eligible for mucosectomy. Chronic gastritis and atrophy were assessed using four defined biopsy procedures. Serum PGs were measured by an enzyme immunoassay. Optimal diagnostic cut-offs and performance were determined using receiver operating characteristic curves. RESULTS: The PGI level and the PGI/II ratio decreased with corpus-dominant gastritis and as atrophy advanced toward the corpus greater curvature (GC). For the presence of corpus GC atrophy, the areas under the PGI and PGI/II-ratio curves were 0.82 and 0.77, respectively. The optimal cut-off levels were 59.3ug/L for PGI (sensitivity, 83.3%; specificity, 78.4%) and 3.6ug/L for PGI/II ratio (sensitivity, 70.0%; specificity, 78.4%). Using these serologic cut-off levels, we found that the frequency of corpus tumor location differed significantly (32.9% vs 11.1% for PGI <59.3 and >=59.3ug/L, respectively; and 31.1% vs 14.8% for PGI/II ratio <3.5 and >=3.5, respectively; p<0.05). CONCLUSIONS: A low PGI level and PGI/II ratio are valuable serologic markers for predicting corpus GC atrophy, and have clinical implications with respect to the corpus location of tumors in mucosectomy patients. PMID- 21253294 TI - Helicobacter pylori Seropositivity Is Associated with Gastric Cancer Regardless of Tumor Subtype in Korea. AB - BACKGROUND/AIMS: To evaluate the association between Helicobacter pylori (H. pylori) infection and gastric cancer (GC) according to tumor subtype in Korea. METHODS: H. pylori status was determined serologically using the enzyme-linked immunosorbent assay. In total, 2,819 patients with GC and 562 healthy controls were studied. A logistic regression method was used after adjusting for possible confounders. RESULTS: The prevalence of H. pylori infection was significantly higher in the GC patients (84.7%) than in the controls (66.7%) (odds ratio [OR], 3.13; 95% confidence interval [CI], 2.46-3.97). The adjusted OR was significantly higher in H. pylori-infected patients aged <60 years (OR, 4.69; 95% CI, 3.44 6.38) than in those aged >=60 years (OR, 1.48; 95% CI, 0.88-2.46; p<0.001). Subgroup analyses revealed no differences in seroprevalence between early gastric cancer (84.8%; OR, 3.01; 95% CI, 2.27-4.01) and advanced gastric cancer (84.6%; OR, 2.94; 95% CI, 2.24-3.85), cardia cancer (83.8%; OR, 2.98; 95% CI, 2.16-4.02) and noncardia cancer (84.8%; OR, 3.17; 95% CI, 2.48-4.04), and differentiated carcinoma (82.7%; OR, 2.99; 95% CI, 2.21-4.04) and undifferentiated carcinoma (86.8%; OR, 3.05; 95% CI, 2.32-4.00). CONCLUSIONS: The seroprevalence of H. pylori was higher in GC patients than in healthy controls, especially in younger patients. H. pylori infection is associated with GC, regardless of the tumor location, stage, or differentiation. PMID- 21253292 TI - The molecular targets for the diagnosis and treatment of pancreatic cancer. AB - Pancreatic cancer is considered an aggressive malignancy that responds poorly to current treatments and therefore has a dismal survival rate. This disease is usually not diagnosed until a late stage, at which point palliative chemotherapy with the purine analogue gemcitabine and/or a fluoropyrimidine or a platinum agent is the standard approach. There are some new data on the molecular and genetic changes that take place in pancreatic cancer, which may facilitate the accuracy of diagnosis and efficacy of treatments. However, translational efforts in clinical practice have increased clinicians' options with a targeted agent, erlotinib, in combination with the standard gemcitabine chemotherapy. Many other novel drugs currently being tested in the field of pharmaco-oncology target various altered biological pathways and molecules. Nevertheless, the lack of clinically significant improvements in treatments is rendering efforts to develop methods of early diagnosis both more urgent and promising. The aim of this review was to summarize the molecular basis of pancreatic carcinogenesis and the latest developments in diagnosis by molecular means, focusing on the results of clinical research into targeted and personalized treatments. PMID- 21253296 TI - A Matched Case-Control Study Using the Propensity Score on Differences in the Characteristics of Colorectal Polyps between Younger and Older Koreans: Proximal Shift in the Distribution of Colorectal Polyps among Older Koreans. AB - BACKGROUND/AIMS: Several studies have found that the frequency of colorectal polyps increases significantly from the age of 50 years. The goal of this study was to determine the differences in the clinical characteristics of colorectal polyps between patients aged 50 years and older, and younger patients. METHODS: The colonoscopy database of 3,304 patients at the Yeungnam University Medical Center between January 2009 and December 2009 was reviewed retrospectively. In total, 679 patients were divided into the younger group (n=170) and the older group (aged >=50 years) (n=509). A matched case-control study was performed using propensity scores and 117 patients selected from each group. RESULTS: Compared to the younger group, the older group had a significantly higher proportion of female patients, and patients with hypertension, a smoking history, and a history of taking medications. After performing the matched case-control study, 234 patients and 679 colon polyps were included in the analysis. Compared to the younger patients, the older patients had a significantly higher proportion of multiple lesions (57.3% vs 25.6%, p<0.001), left- and right-side distribution (35.9% vs 12.0%, p<0.001), and larger polyps (mean 9.1 mm vs 6.3 mm, p<0.001). A left-sided distribution was less common in the older group than in the younger group (35.0% vs 51.3%, p=0.025). CONCLUSIONS: The methods used to screen for colorectal cancer in older patients should include colonoscopy due to the shift to the right side as a common location for colorectal polyps in that age group. PMID- 21253297 TI - Near-infrared fluorescence imaging using a protease-specific probe for the detection of colon tumors. AB - BACKGROUND/AIMS: Early tumor detection is crucial for the prevention of colon cancer. Near-infrared fluorescence (NIRF) imaging using a target-activatable probe may permit earlier disease detection. Matrix metalloproteinases (MMPs) participate in tumorigenesis and tumor growth. The aim of this study was to determine whether NIRF imaging using an MMP-activatable probe can detect colon tumors at early stages. METHODS: WE UTILIZED TWO MURINE COLON CANCER MODELS: a sporadic colon cancer model induced by azoxymethane (AOM), and a colitis associated cancer model induced by a combination of AOM and dextran sodium sulfate (DSS). Colonic lesions were analyzed by histologic examination, Western blotting, immunohistochemical staining, and NIRF imaging using an MMP-activatable probe. RESULTS: Multiple variable-sized tumors developed in both models and progressed from adenomas to adenocarcinomas over time. At the early stage of the AOM/DSS model, diffuse inflammation was observed within the tumors. MMP expression increased progressively through normal, inflammation, adenoma, and adenocarcionoma stages. NIRF signal intensities were strongly correlated with each tumor stage from adenoma to adenocarcinoma. NIRF imaging also distinguished tumors from inflamed mucosa. CONCLUSIONS: NIRF imaging using a protease activatable probe may be a useful tool for early tumor detection. This approach could translate to improve the endoscopic detection of colon tumors, especially in patients with inflammatory bowel disease. PMID- 21253298 TI - A significant number of sessile serrated adenomas might not be accurately diagnosed in daily practice. AB - BACKGROUND/AIMS: The diagnosis of hyperplastic polyps (HPs) may involve a conglomeration of subgroups of serrated polyps. The diagnosis of HPs may therefore be revisited if this is sessile serrated adenoma (SSA). The aim of this study was to determine clinically and endoscopically relevant information associated with reclassification to SSA. METHODS: After reviewing the data from 1,372 patients who underwent colonoscopic polypectomy, 49 HPs larger than 10 mm were analyzed in this study. Two gastrointestinal pathologists reclassified each of the original 49 HPs as conventional HPs, SSAs, and others. RESULTS: Among the 49 initially diagnosed HPs, 18.4% were reclassified into SSAs or mixed polyps. Overall architectural features were useful for the diagnosis of SSA, but cytological features were less useful. The patient and polyp characteristics did not differ between HPs with and without reclassification of the initial pathological diagnosis. CONCLUSIONS: A significant number of SSAs might not be accurately diagnosed in daily clinical practice without any predilection for size, shape, and location. Therefore, when large HPs are diagnosed in clinical practice, it is necessary for physicians to have greater awareness of the diagnosis of SSA and to individualize subsequent surveillance. PMID- 21253299 TI - Three-weekly s-1 monotherapy as first-line treatment in elderly patients with recurrent or metastatic gastric cancer. AB - BACKGROUND/AIMS: Elderly patients with advanced gastric cancer (AGC) have generally been excluded from clinical trials, and there are few data available on the treatment of these patients. The efficacy of palliative S-1 monotherapy as a first-line treatment regimen for elderly patients has not been well elucidated. METHODS: For this study, 25 AGC patients were enrolled between January 1, 2007 and March 31, 2009; 4 cases were recurrent AGC and 21 cases were metastatic AGC at the time of diagnosis. These patients received S-1 therapy at a dose of 40 mg/m(2) twice daily for 14 days every 3 weeks. All of the patients were older than 70 years. RESULTS: The median follow-up duration, the median progression free survival, and the overall survival time were 8.7 months (range, 4.9 to 12.5 months), 4.9 months (range, 3.5 to 6.3 months), and 10.8 months (range, 6.6 to 15.0 months), respectively. Grade 3/4 nonhematologic toxicities were rare. Grade 3/4 neutropenia was noted in two patients. The partial response rate was 21.7% and stable disease was observed in 34.8% of the patients. Two patients (8%) died due to chemotherapy-associated toxicity during treatment (septic shock/intracranial hemorrhage). CONCLUSIONS: Oral S-1 chemotherapy seems to be effective as a first-line treatment regimen for elderly patients with metastatic or recurrent AGC. However, elderly patients receiving S-1 treatment should undergo continuous toxicity monitoring, since they are highly susceptible to adverse effects. PMID- 21253300 TI - Benign bronchoesophageal fistula in adults: endoscopic closure as primary treatment. AB - BACKGROUND/AIMS: Benign bronchoesophageal fistula (BEF) is a rare condition that is usually treated surgically; however, less invasive endoscopy procedures have been attempted to overcome the disadvantages of surgery. The aim of this study was thus to determine the results of endoscopic management as a primary treatment in patients with BEF. METHODS: We retrospectively analyzed data from 368 patients with BEF who were treated at a tertiary care, academic medical center between January 2000 and August 2009. RESULTS: Benign causes were found for only 18 of the 368 patients. Of these, seven were treated endoscopically and the others by surgery or other methods. The first endoscopy procedures failed in all seven patients, with second trials of endoscopy performed in four patients at a median of 8 days (range, 3 to 11 days) after the first procedure. The second endoscopic procedure was successful in two out of four patients; one patient showed no recurrence of the fistula, whereas the second patient experienced a recurrence after 24 months. All patients underwent successful surgical procedures after the failure of endoscopic treatment, with no further recurrences. CONCLUSIONS: Although we observed a low rate of success for primary endoscopic treatment of benign BEF, the invasive nature of surgery suggests the need for a prospective study with a large number of patients to evaluate the efficacy of less invasive procedures such as endoscopic treatment. PMID- 21253301 TI - A Planned Prospective, Randomized, Placebo-Controlled Multicenter Trial Assessing the Effect of Helicobacter pylori Eradication on the Healing of Iatrogenic Ulcer after Endoscopic Resection of Gastric Neoplasm. AB - BACKGROUND/AIMS: Helicobacter pylori eradication may facilitate the healing of iatrogenic ulcer after endoscopic resection of gastric neoplasm. This study involved designing a randomized, double-blinded, placebo-controlled, multicenter trial, performed by the Korean College of Helicobacter and Upper Gastrointestinal Research and the Medical Research Collaboration Center, Seoul National University Hospital. METHODS: We intend to enroll up to 232 patients H.-pylori-positive patients who have gastric adenoma or early gastric cancer after endoscopic resection. The enrolled patients are being randomly allocated to the H.-pylori eradication-plus-proton-pump-inhibitor group or the placebo-plus-proton-pump inhibitor group based on their histology results and the size of the resected specimen. After random allocation, the iatrogenic ulcer size and stage are evaluated at 4- and 8-week follow-ups (with a window of +/-7 days). The primary end point is the healing rate of the ulcer by stage, and the secondary end point is the rate of ulcer size reduction, relief rate from ulcer-related symptoms, and adverse-event rates. RESULTS: More than 90% of the target subjects have already been enrolled into the study and are receiving ongoing periodic monitoring by the Medical Research Collaboration Center. CONCLUSIONS: Completion of the study should reveal whether H. pylori eradication can facilitate the healing of ulcer after endoscopic resection in Korea. PMID- 21253302 TI - Distinguishing xanthogranulomatous cholecystitis from the wall-thickening type of early-stage gallbladder cancer. AB - BACKGROUND/AIMS: Xanthogranulomatous cholecystitis (XGC) mimics early-stage gallbladder (GB) cancer with wall thickening on computed tomography (CT), both clinically and radiologically. Preoperative differentiation of XGC from early stage GB cancer is important for selecting the most appropriate surgical management. Therefore, we evaluated the clinical features and multidetector CT (MDCT) findings of XGC to determine whether it can be distinguished from early stage GB cancer. METHODS: We retrospectively evaluated 25 patients with XGC and 56 patients with the wall-thickening type of T1- and T2-stage GB cancer, where all of the diagnoses were pathologically confirmed by surgical treatment. All of the patients underwent preoperative MDCT. The clinical symptoms, laboratory findings, and CT findings were compared. RESULTS: Abdominal pain, fever, and jaundice were noted more frequently in the patients with XGC. Serum aspartate aminotransferase and alanine aminotransferase levels were more elevated in patients with XGC, whereas carbohydrate antigen (CA 19-9) was higher in the patients with GB cancer. When the T-category cancer staging of XGC and early stage GB cancer were compared, diffuse GB wall thickening, intramural hypoattenuated nodule, gallstone, and pericholecystic infiltration were consistent significant findings associated with XGC, regardless of the cancer staging. CONCLUSIONS: MDCT findings such as diffuse GB wall thickening, intramural hypoattenuated nodule, gallstone, and pericholecystic infiltration together with the clinical symptoms, can provide clues for physicians to differentiate XGC from early-stage GB cancer with wall thickening on CT. PMID- 21253303 TI - Single-Step EUS-Guided Transmural Drainage of Pancreatic Pseudocysts: Analysis of Technical Feasibility, Efficacy, and Safety. AB - BACKGROUND/AIMS: With the progress of product development, single-step endoscopic ultrasound (EUS)-guided transmural drainage can overcome some disadvantages of the blind or two-step procedures used in the treatment of pancreatic pseudocysts. We therefore evaluated the technical feasibility, efficacy, and safety of single step EUS-guided transmural drainage of pancreatic pseudocysts. METHODS: Endoscopic drainage of pancreatic pseudocysts was performed in 47 patients (median age, 46 years; range, 38 years to 59 years; 40 men) by using interventional echoendoscopes with a single-step device suitable for ballooning, bougination, and plastic-stent insertion. RESULTS: Endoscopic stent placement was successful in 42 patients (89%; transgastric approach, 34/38; transduodenal approach, 8/9) and failed in 5 patients because of acute angulation (n=4) or small cyst (n=1). The volume of the pseudocyst was reduced by more than 90% or it disappeared completely in all of 41 patients (100%), based on a mean follow-up period of 17 months (range, 11 months to 20 months). The overall recurrence rate was 12% (5/41) after improvement by the procedure. Minor complications (one case of bleeding, three cases of pneumoperitoneum, and one case of peritonitis) occurred after the procedure in five patients (11%), but there were no major complications. CONCLUSIONS: Single-step EUS-guided transmural drainage can be used to treat pancreatic pseudocysts with acceptable feasibility, efficacy, and safety. PMID- 21253304 TI - A low viral load predicts a higher initial virologic response to adefovir in patients with Lamivudine-resistant chronic hepatitis B. AB - BACKGROUND/AIMS: Adefovir (ADV) is the preferred drug for treating lamivudine (LAM)-resistant hepatitis B. However, not all patients who face virologic breakthrough during LAM treatment respond to ADV. The aim of this study was to determine the factors associated with efficacy of ADV in LAM-resistant hepatitis B patients. METHODS: The medical records of 231 patients who received ADV due to LAM-resistance were reviewed. Efficacy was assessed by the initial virologic response (IVR), defined as hepatitis B virus (HBV) DNA not being undetectable by real-time PCR at 6 months of ADV treatment. RESULTS: Seventy patients (30%) achieved IVR. While 'add-on' modality, hepatitis B e antigen (HBeAg) negativity, and low baseline HBV DNA levels were associated with IVR in univariate analysis, multivariate analysis revealed HBeAg status and the DNA level to be the significant factors. The probability of IVR achievement increased sharply per each log(10) copies/mL decrement in the baseline viral load, which was 133 times in patients who had HBV DNA <10(5) copies/mL compared with those who had >=10(8) copies/mL. CONCLUSIONS: Factors associated with the IVR were HBeAg negativity and a low baseline viral load. Therefore, when virologic breakthrough with genotypic resistance emerges during LAM therapy, ADV treatment should be considered immediately before further increases in viral load. Additional long-term follow up data are warranted. PMID- 21253305 TI - Utility of Serum YKL-40 as a Tumor-Specific Marker of Hepatobiliary Malignancies. AB - BACKGROUND/AIMS: Serum YKL-40 has been linked to several human cancers. We investigated the potential role of serum YKL-40 as a marker of hepatobiliary malignancies. METHODS: Archived serum samples of patients undergoing liver transplantation evaluation at the Mayo Clinic Rochester were used to measure YKL 40 levels. Patients were divided into three groups: hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and end-stage liver disease (ESLD) without malignancies. The Model for ESLD (MELD) score was used to quantify the severity of liver disease. RESULTS: The median serum YKL-40 level was highest in the ESLD group at 296 ng/mL, compared to 259 ng/mL in the HCC group and 80 ng/mL in the CCA group (p<0.01). There was a significant correlation between the MELD score and serum YKL-40 level (r=0.50, p<0.01). In a multivariate analysis, there was no significant difference in serum YKL-40 level between ESLD and HCC. CCA was associated with lower YKL-40 levels, a finding that was attributable to a lower prevalence of cirrhosis. CONCLUSIONS: The serum YKL-40 level has little utility as a cross-sectional screening tool for hepatobiliary malignancies, namely HCC and CCA. The role of YKL-40 as a surveillance marker in the follow-up of individual patients remains to be determined. PMID- 21253306 TI - Sorafenib-induced interstitial pneumonitis in a patient with hepatocellular carcinoma: a case report. AB - Sorafenib is an oral multikinase inhibitor that has shown a survival benefit in patients with advanced hepatocellular carcinoma, and is considered to be generally safe. We treated a patient with interstitial lung disease that was associated with sorafenib therapy for the treatment of advanced hepatocellular carcinoma. A 74-year-old man with hepatitis-C-virus-related hepatocellular carcinoma was treated with sorafenib. After 8 days of sorafenib administration, he received radiation therapy for an intrahepatic tumor located in segment eight. On the 24th day of sorafenib treatment, the patient developed acute interstitial pneumonitis that rapidly improved after the discontinuation of sorafenib and treatment with high-dose steroids. This case alerts physicians to the possibility of sorafenib-induced interstitial lung disease. PMID- 21253307 TI - Complete endoscopic resection of very early stage gastric plasmacytoma. AB - Gastric plasmacytomas are very rare, and most are not detected until the disease has progressed to an advanced stage. However, there have been recent reports of cases of early-stage gastric plasmacytoma, in which neoplastic cells are confined to the mucosa or submucosa. Here we report a case of a very early stage gastric plasmacytoma that was confined to the lamina propria of the gastric mucosa. The lesion was successfully and completely removed by endoscopic submucosal dissection, and the surveillance endoscopy showed no recurrence during the follow up of 40 months. This report appears to be the first documented case of complete endoscopic removal of a primary gastric plasmacytoma. PMID- 21253308 TI - Liver cirrhosis induced by porphyria cutanea tarda: a case report and review. AB - Porphyria cutanea tarda (PCT) is a metabolic disorder that results in a decrease in uroporphyrinogen decarboxylase activity. It is characterized by photosensitivity, bullae formation, and skin pigmentation. There are four types of PCT: acquired, familial, toxic, and hepatoerythropoietic. Uroporphyrin levels are elevated in the urine of PCT patients. PCT can be differentiated from other porphyrias by its clinical characteristics and the porphyrin levels in the serum, erythrocytes, urine, and feces. This metabolic disorder can lead to liver dysfunction as well as histological changes such as fatty infiltration or hepatic fibrosis. PCT rarely manifests as liver cirrhosis. We report herein a case of PCT induced liver cirrhosis that progressed to hepatic failure. PMID- 21253309 TI - Gallbladder dysfunction diagnosed by cholescintigraphy with a Fatty meal. PMID- 21253310 TI - Lung interstitial cells during alveolarization. AB - Recent progress in neonatal medicine has enabled survival of many extremely low birth-weight infants. Prenatal steroids, surfactants, and non-invasive ventilation have helped reduce the incidence of the classical form of bronchopulmonary dysplasia characterized by marked fibrosis and emphysema. However, a new form of bronchopulmonary dysplasia marked by arrest of alveolarization remains a complication in the postnatal course of extremely low birth-weight infants. To better understand this challenging complication, detailed alveolarization mechanisms should be delineated. Proper alveolarization involves the temporal and spatial coordination of a number of cells, mediators, and genes. Cross-talk between the mesenchyme and the epithelium through soluble and diffusible factors are key processes of alveolarization. Lung interstitial cells derived from the mesenchyme play a crucial role in alveolarization. Peak alveolar formation coincides with intense lung interstitial cell proliferation. Myofibroblasts are essential for secondary septation, a critical process of alveolarization, and localize to the front lines of alveologenesis. The differentiation and migration of myofibroblasts are strictly controlled by various mediators and genes. Disruption of this finely controlled mechanism leads to abnormal alveolarization. Since arrest in alveolarization is a hallmark of a new form of bronchopulmonary dysplasia, knowledge regarding the role of lung interstitial cells during alveolarization and their control mechanism will enable us to find more specific therapeutic strategies for bronchopulmonary dysplasia. In this review, the role of lung interstitial cells during alveolarization and control mechanisms of their differentiation and migration will be discussed. PMID- 21253311 TI - Neonatal innate immunity and Toll-like receptor. AB - The innate immune response is the first line of defense against microbial infections. Innate immunity is made up of the surface barrier, cellular immunity and humoral immunity. In newborn, immunologic function and demands are different to adults. Neonatal innate immunity specifically suppresses Th1-type immune responses, and not Th2-type immune responses, which are enhanced. And the impaired response of macrophages is associated with the defective innate immunity in newborn period. Toll-like receptors (TLRs) play a key roles in the detection of invading pathogens and in the induction of innate immune responses. In newborn, the expression of TLRs is age dependent, so preterm has low expression of TLRs. Also, there are defects in signaling pathways downstream of TLRs. As a consequence, the defects of TLRs activity cause the susceptibility to infection in the neonatal period. PMID- 21253312 TI - Ureaplasma infections in pre-term infants: Recent information regarding the role of Ureaplasma species as neonatal pathogens. AB - Although numerous clinical observational studies have been conducted over a period of over 30 years, the clinical significance of Ureaplasma infection is still under debate. The Ureaplasma speices. is a commensal in the female genital tract and considered to have of low virulence; however, Ureaplasma colonization has been associated with infertility, stillbirth, preterm delivery, histologic chorioamnionitis, and neonatal morbidities, including congenital pneumonia, meningitis, bronchopulmonary dysplasia, and perinatal death. Recently, Ureaplasma was subdivided into 2 separate species and 14 serovars. Ureaplasma parvum is known as biovar 1 and contains serovars 1, 3, 6, and 14, and Ureaplasma urealyticum (biovar 2) contains the remaining serovars (2, 4, 5, and 7-13). The existence of differences in pathogenicities of these 14 serovars and 2 biovars is controversial. Although macrolides are the only antimicrobial agents currently available for use in neonatal ureaplasmal infections, in the current clinical field, it is difficult to make decisions regarding which antibiotics should be used. Future investigations involving large, multicenter, randomized, controlled studies are needed before proper recommendations can be made for clinical practice. PMID- 21253313 TI - Risk factors of ocular involvement in children with mitochondrial respiratory chain complex defect. AB - PURPOSE: Mitochondrial dysfunction can present with various symptoms depending on the organ it has affected. This research tried to analyze the ophthalmologic symptoms and ophthalmologic examination (OE) results in patients with mitochondrial disease (MD). METHODS: Seventy-four patients diagnosed with mitochondrial respiratory chain complex defect with biochemical enzyme assay were included in the study. They were divided into 2 groups based on the OE results by funduscopy and were analyzed on the basis of their clinical features, biochemical test results, morphological analysis, and neuroimaging findings. RESULTS: Thirty seven (50%) of the 74 MD patients developed ophthalmologic symptoms. Abnormal findings were observed in 36 (48.6%) patients during an OE, and 16 (21.6%) of them had no ocular symptoms. Significantly higher rates of prematurity, clinical history of epilepsy or frequent apnea events, abnormal light microscopic findings in muscle pathology, diffuse cerebral atrophy in magnetic resonance imaging, and brainstem hyperintensity and lactate peaks in magnetic resonance spectroscopy were noted in the group with abnormal OE results. CONCLUSION: Although the ophthalmologic symptoms are not very remarkable in MD patients, an OE is required. When the risk factors mentioned above are observed, a more active approach should be taken in the OE because a higher frequency of ocular involvement can be expected. PMID- 21253314 TI - Therapeutic monitoring of vancomycin according to initial dosing regimen in pediatric patients. AB - PURPOSE: This study aimed to determine the optimal initial vancomycin dose to achieve appropriate trough levels in pediatric patients. METHODS: We analyzed clinical data for 309 children treated with intravenous vancomycin between 2004 and 2009 at 2 different hospitals in South Korea. The patients were 1-16 years old and exhibited normal renal function. Patient data, including reason for treatment and initial dosing regimen, were reviewed. Two subgroups were identified and compared according to initial vancomycin dose: 40 (35-45) mg/kg/day and 60 (55-65) mg/kg/day. Trough levels were obtained at steady state after at least 4 doses of vancomycin. RESULTS: Patients who received vancomycin had post-operation or wound-related infections (37.2%), localized infection (12.9%), catheter-related infections (9.4%), meningitis (8.7%), or endocarditis (6.8%). Pathogens were confirmed in 79 cases: 28 cases of methicillin-resistant Staphylococcus epidermidis (35.4%) and 25 of methicillin-resistant Staphylococcus aureus (31.6%). Out of the 309 patients, 201 (65%) received vancomycin at 40 mg/kg/day and 108 (35%) at 60 mg/kg/day. Average trough concentrations were significantly different between the groups (P<0.001). Trough levels over 10 mg/L were less likely to be achieved in the 40 mg/kg/day group (14%) than in the 60 mg/kg/day group (49%) (P<0.001). There were no differences in renal function deterioration between the groups. CONCLUSION: A common vancomycin dosing regimen, 40 mg/kg/day, was not high enough to achieve trough levels of over 10 mg/L in pediatric patients. Careful drug monitoring must be performed, and increasing initial dose of vancomycin should be considered in pediatric patients. PMID- 21253315 TI - What is the 'objective' differential factor of diarrhea in infancy?: Normal state versus diarrheal illness in infants with chronic frequent and loose stool. AB - PURPOSE: This study aimed to identify 'objective' differential factors for normal frequent loose stool (NFLS) and diarrheal illness with dehydration and nutritional deficiency (DIDN) among infants with chronic frequent loose stool (CFLS). METHODS: Data were analyzed from infants under 2 years of age with CFLS who had been transferred from general pediatricians. These 46 patients were divided into 2 groups (NFLS versus DIDN). Nocturnal stool was defined as evacuation between 10 pm and 6 am. Maximal stool amount/day (measured using the mother's hand) was specified as the highest score during the period of CFLS obtained by adding up each evacuation's score (range, 0-2 points). RESULTS: There were 36 cases of NFLS and 10 of DIDN. A failure to gain weight (P=0.0001), fever (P=0.0079), colic/abdominal pain (P=0.0014), gross blood in stool (except allergic proctocolitis) (P=0.0113), nocturnal stool (P=0.0001), and the score of stool amount (P=0.0001) were found to significantly differentiate the groups. A failure to gain weight was observed in 39% of even NFLS. The frequency, mucus content, and microbiological findings of stools, as well as diaper dermatitis were not found to significantly differentiate the groups. CONCLUSION: NFLS was more common than DIDN in infants with CFLS. The most 'objective' differential factors were nocturnal stool and the score of stool amount (>=7 points/day). PMID- 21253316 TI - Clinical outcome of transcatheter closure of patent ductus arteriosus in small children weighing 10 kg or less. AB - PURPOSE: Transcatheter closure has become an effective therapy in most patients with patent ductus arteriosus (PDA). However, there are difficulties in transcatheter closure of PDA in small children. We reviewed clinical outcomes of transcatheter closure of PDA in children weighing less than 10 kg in a single center. METHODS: Between January 2003 and December 2009, 314 patients with PDA underwent transcatheter closure in our institute. Among them, 115 weighed less than 10 kg. All of these patients underwent transcatheter closure of PDA using either COOK Detachable Coil(r), PFM Nit-Occlud(r), or Amplatzer duct occluder(r). A retrospective review of the treatment results and complications was performed. RESULTS: The mean age of patients was 9.1+/-5.9 months (median, 8 months), and mean weight was 7.6+/-1.8 kg (median, 7.8 kg). The mean diameter of PDA was 3.2+/ 1.4 mm (median, 3 mm). Complete occlusion occurred in 113 patients (98%). One patient was sent to surgery because of a failed attempt at device closure, and another patient had a small residual shunt after device placement. The average mean length of hospital stay was 3.0+/-3.3 days, and mean follow-up duration was 21.0+/-19.6 months. There were no major complications in any of the patients. CONCLUSION: Transcatheter closure of PDA is considered safe and efficacious in infants weighing less than 10 kg. With sufficient experience and further effort, transcatheter closure of PDA can be accepted as the gold standard of treatment for this group of patients. PMID- 21253317 TI - A family with Townes-Brocks syndrome with congenital hypothyroidism and a novel mutation of the SALL1 gene. AB - Townes-Brocks syndrome (TBS) is a rare autosomal dominant congenital disorder caused by mutations in the SALL1 gene. Its signs and symptoms overlap with other genetic syndromes, including VACTERL association, Pendred syndrome, Baller-Gerold syndrome, and cat eye syndrome. Structural vertebral abnormalities, hypoplasia of the thumb, and radial bone abnormalities, which are not usually associated with TBS, help in the differential diagnosis of these syndromes. We report the case of a family whose members were diagnosed with TBS with congenital hypothyroidism and had a novel SALL1 gene mutation. PMID- 21253318 TI - A case of thanatophoric dysplasia type I with an R248C mutation in the FGFR3 gene. AB - Thanatophoric dysplasia (TD) is a short-limb neonatal dwarfism syndrome that is usually lethal in the perinatal period. It is characterized by shortening of the limbs, severely small thorax, large head with a prominent forehead, macrocephaly, curved femur, and flattened vertebral bodies. These malformations result from the mutation in fibroblast growth factor receptor 3 (FGFR-3) gene which is located on the short arm of chromosome 4. A definite diagnosis should be established by molecular genetic analysis to find out the abnormal mutations in the FGFR3 gene. We confirmed by detection of a R248C mutation in the FGFR3 gene in DNA analysis. PMID- 21253319 TI - Oxaliplatin-induced chronic peripheral neurotoxicity: a prospective analysis in patients with colorectal cancer. AB - PURPOSE: Oxaliplatin-induced chronic peripheral neurotoxicity (OXCPN) manifests as a loss of sensation and dysesthesia in the distal extremities, which may impair daily activities and increase in incidence with the amount of oxaliplatin delivered. The variation in the reported incidence and severity of OXCPN may be a consequence of differences in the baseline characteristics of patients. MATERIALS AND METHODS: This was a prospective study (ClinicalTrials.gov, NCT00977717) in which OXCPN was recorded for all consecutive colon cancer patients treated at Samsung Medical Center (Seoul, Korea) with oxaliplatin-based combination chemotherapy. The primary endpoint was the incidence of severe OXCPN (grade 2 lasting for >7 days, or grade 3). The association of severe OXCPN and pretreatment parameters was evaluated using a multivariate regression model. RESULTS: Between Jan 2008 and Feb 2010, 100 patients treated with adjuvant folinic acid/fluorouracil plus oxaliplatin (FOLFOX) and 266 patients treated with capecitabine plus oxaliplatin (XELOX) or FOLFOX for advanced disease were registered into our study. The median cumulative dose of oxaliplatin was 796 mg/m(2) (range, 85 to 1,583 mg/m(2)). Severe OXCPN was observed in 126 (34%) patients. Overall, 43 patients discontinued chemotherapy due to toxicity: 23 without severe OXCPN and 20 with severe OXCPN. In univariate analysis, severe OXCPN was frequently observed in patients with age >=55 years (p<0.01), stage II or III (p<0.01), adjuvant setting (p=0.01), FOLFOX (p<0.01), performance status of 0 (p=0.02), and those with no prior chemotherapy (p<0.01). In a multivariate regression model, the number of chemotherapy cycles and the cumulative oxaliplatin dose were not associated with the development of severe OXCPN. CONCLUSION: We failed to find a significant association between patient characteristics at baseline and the development of severe OXCPN after oxaliplatin based combination chemotherapy. Pharmacogenomic profiling using genome-wide association study in these patients is underway. PMID- 21253320 TI - Results of colorectal cancer screening of the national cancer screening program in Korea, 2008. AB - PURPOSE: This study aims to investigate the current situation of national colorectal cancer screening by analyzing participation rates, positive rates of screening methods and screening rate of secondary screening tests in colorectal screening of the national cancer screening program in 2008. MATERIALS AND METHODS: With database about target population and screened individuals of the national cancer screening program, the results of target population and participants of colorectal cancer screening in 2008 were analyzed. Among adults aged over 50 years of medical aid and beneficiaries of national health insurance paying lower 50% premiums in the total subscribers, 4,640,365 were target population of colorectal cancer screening and the data of 984,915 undergoing fecal occult blood test (FOBT) as a primary screening were analyzed. RESULTS: The colorectal cancer screening rate was 21.2% and the rates of national health insurance subscribers, females and the elderly aged 60-64 years were higher than those of others. The recipients with a positive result in FOBT recorded approximately 7.5%. Medical aid beneficiaries (7.9%), males (8.8%) and seniors aged over 75 years (9.1%) showed higher positive rates than the average one. Out of the FOBT positive recipients, 43.0% took a secondary screening and the rate undergoing colonoscopy (31.4%) was higher than that of doing double-contrast barium enema test (11.6%). CONCLUSION: Colorectal cancer screening rate of medical aid beneficiaries and people paying lower 50% premiums among national health insurance subscribers, was different according to demographic characters (gender, age and types of health insurance). This finding meant that screening for the vulnerable needed to be encouraged by considering socio-demographic characters. Additionally, more efforts were necessary to increase the secondary screening rate of people with a positive result in primary one. PMID- 21253321 TI - Trends of mammography use in a national breast cancer screening program, 2004 2008. AB - PURPOSE: Korea started breast cancer screening as part of the National Cancer Screening Program (NCSP) in 1999. In order to identify under-served groups, we investigated mammography uptake in the National Breast Cancer Screening Program. MATERIALS AND METHODS: The study population was participants in the National Breast Cancer Screening Program from 2004 to 2008. We analyzed participation rates by insurance type, age group, and area of residence. RESULTS: Total participation rates for breast cancer screening increased from 18.2% in 2004 to 35.0% in 2008. The participation rate in the group aged 60 to 69 years showed the greatest increase, 21.3%, among the four age groups. Although the screening rate increased continuously, the participation rate of the Medical Aid Program (MAP) group was low compared to the National Health Insurance (NHI) group. Moreover, the increasing trend of mammography uptake in the MAP group was much lower than that of the NHI group. CONCLUSION: The participation rate for breast cancer screening in the NCSP in Korea has increased. However, the participation rate in mammography among MAP recipients is still lower than that of NHI beneficiaries. To increase mammography uptake, it is important to make it available to everyone by ensuring inclusion of all population subgroups. PMID- 21253322 TI - Cisplatin-Based Combination Chemotherapy for Advanced Hepatocellular Carcinoma: A Single Center Experience before the Sorafenib Era. AB - PURPOSE: Systemic chemotherapy is the only option for patients with unresectable/metastatic hepatocellular carcinoma (HCC) who are not candidates for local/regional treatment. However, the response to such treatment and survival are poor, especially in hepatitis B virus (HBV) endemic areas. The aim of this study was to determine the efficacy of cisplatin-based combination chemotherapy and identify a subgroup of advanced HCC patients with favorable responses. MATERIALS AND METHODS: The medical records of all consecutive patients with unresectable/metastatic HCC who received cisplatin-based combination chemotherapy between January 2003 and October 2009 were reviewed. Time to progression (TTP) and overall survival (OS) were determined using Kaplan-Meier analysis. Univariate and multivariate analyses were performed to identify prognostic factors for TTP and OS. RESULTS: Data for 46 patients were analyzed. First-line chemotherapies consisted of cisplatin-based combination treatment with doxorubicin, fluoropyrimidines and gemcitabine. The response rate for all patients was 4.3%. The median TTP and OS were 1.8 (95%confidence interval [CI], 1.1 to 2.5) and 7.2 (95% CI, 3.0 to 11.5) months, respectively. Eastern Cooperative Oncology Group (ECOG) performance status (PS), Child classification, Cancer of the Liver Italian Program (CLIP) score and portal vein thrombosis (PVT) were identified by univariate analyses as prognostic factors for TTP and OS. ECOG PS (hazard ratio [HR], 4.51; 95% CI, 1.61 to 12.6; p=0.004) and PVT (HR, 2.12; 95% CI, 1.10 to 4.11; p=0.026) were independent prognostic factors for TTP. CONCLUSION: Cisplatin based combination chemotherapy in patients with advanced HCC has a low response rate and short TTP regardless of the chemotherapy regimen used. Patients with a good ECOG PS and without PVT can be considered candidates for cisplatin-based combination chemotherapy. PMID- 21253323 TI - Clinical characteristics of malignant pericardial effusion associated with recurrence and survival. AB - PURPOSE: We evaluated clinical outcomes after drainage for malignant pericardial effusion with imminent or overt tamponade. MATERIALS AND METHODS: Between August 2001 and June 2007, 100 patients underwent pericardiocentesis for malignant pericardial effusion. Adequate follow-up information on the recurrence of pericardial effusion and survival status was available for 98 patients. RESULTS: Recurrence of effusion occurred in 30 patients (31%), all of whom were diagnosed with adenocarcinoma. Multivariate analysis indicated that adenocarcinoma of the lung (hazard ratio [HR], 6.6; 95% confidence interval [CI], 1.9 to 22.3; p=0.003) and progressive disease despite chemotherapy (HR, 4.3; 95% CI, 1.6 to 12.0; p=0.005) were independent predictors of recurrence. Survival rates three months after pericardiocentesis differed significantly with the type of primary cancer; the rates were 73%, 18%, 90% and 30% in patients with adenocarcinoma of the lung, squamous cell carcinoma of the lung, breast cancer and other cancers, respectively. CONCLUSION: Recurrence and survival of patients with malignant pericardial effusion are dependent on the type of primary cancer and response to chemotherapy. Patients with adenocarcinoma of the lung may be good candidates for surgical drainage to avoid repeated pericardiocentesis, but pericardiocentesis is considered effective as palliative management in patients with other cancers. PMID- 21253324 TI - Clinicopathologic features of metachronous or synchronous gastric cancer patients with three or more primary sites. AB - PURPOSE: We investigated the clinicopathologic information of patients with gastric cancer with multiple primary cancers (GC-MPC) of three or more sites. MATERIALS AND METHODS: Between 1995 and 2009, 105,908 patients were diagnosed with malignancy at Severance Hospital, Yonsei University Health System. Of these, 113 (0.1%) patients with MPC of three or more sites were registered, and 41 (36.3%) of these were GC-MPC. We retrospectively reviewed the clinical data and overall survival using the medical records of these 41 GC-MPC patients. We defined synchronous cancers as those occurring within 6 months of the first primary cancer, while metachronous cancers were defined as those occurring more than 6 months later. RESULTS: Patients with metachronous GC-MPC were more likely to be female (p=0.003) and young than patients with synchronous GC-MPC (p=0.013). The most common cancer sites for metachronous GC-MPC patients were the colorectum, thyroid, lung, kidney and breast, while those for synchronous GC-MPC were the head and neck, esophagus, lung, and kidney. Metachronous GC-MPC demonstrated significantly better overall survival than synchronous GC-MPC, with median overall survival durations of 4.7 and 14.8 years, respectively, and 10 year overall survival rates of 48.2% and 80.7%, respectively (p<0.001). CONCLUSION: Multiplicity of primary malignancies itself does not seem to indicate a poor prognosis. The early detection of additional primary malignancies will enable proper management with curative intent. PMID- 21253325 TI - The CXCR4 Antagonist AMD3100 Has Dual Effects on Survival and Proliferation of Myeloma Cells In Vitro. AB - PURPOSE: AMD3100, an antagonist of the CXCR4 chemokine receptor is soon to be used clinically for the peripheral mobilization of hematopoietic stem cells (HSCs) in patients with multiple myeloma. AMD3100 has been shown to activate a G protein coupled with CXCR4 and thus acts as a partial CXCR4 agonist in vitro. Thus, we explored whether AMD3100 affected the survival and proliferation of myeloma cells in vitro. MATERIALS AND METHODS: The effects of AMD3100 on survival and proliferation of two myeloma cell lines (RPMI8226 and U266) as well as CD138+ cells obtained from several patients with multiple myeloma were analyzed by flow cytometry using annexin V and a colorimetric cell proliferation assay (CCK-8 assay). RESULTS: AMD3100, but not T140, another CXCR4 antagonist, stimulated the proliferation of myeloma cell lines and CD138+ primary human myeloma cells (-2 fold increase) in a dose-dependent manner in serum-free culture for up to 5 days, which was inhibited by pretreating the cells with pertussis toxin. AMD3100 enhanced the proliferation of U266 cells induced by interleukin-6 and partially reversed AG490-mediated growth inhibition and apoptosis induced by serum deprivation in RPMI8226 cells. AMD3100 induced the phosphorylation of Akt and MAPK p44/p42 in U266 cells and MAPK p44/p42 in RPMI8226 cells. In contrast, AMD3100 markedly increased the cell apoptosis and reduced the number of RPMI8226 cells after 5 to 7 days of culture under serum-free conditions. CONCLUSION: AMD3100 exerts dual effects, initially enhancing and subsequently inhibiting the survival and proliferation of myeloma cells, signaling via CXCR4 in vitro. PMID- 21253326 TI - A case of combined hepatocellular-cholangiocarcinoma with favorable response to systemic chemotherapy. AB - Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare form of primary liver cancer composed of cells with histopathologic features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Because of its low incidence, the information on clinical outcomes of cHCC-CC is very limited and there are no published reports describing non-surgical treatment options for cHCC CC. We report a case of cHCC-CC exhibiting a favorable response to systemic chemotherapy with doxorubicin and cisplatin. A 62-year-old man who recurred after a right lobectomy for cHCC-CC received sorafenib for palliative systemic therapy, but follow up imaging studies showed disease progression. He received 2nd line chemotherapy with doxorubicin at 60 mg/m(2) together with cisplatin at 70 mg/m(2). After 2 cycles of chemotherapy, a computed tomography scan of the chest showed markedly decreased size and number of the multiple lung metastases. After completing 8 cycles of 2nd line therapy, we changed the regimen to a fluorouracil (5-FU) mono therapy because of the toxicities associated with doxorubicin and cisplatin. To date, the patient has completed his 15th cycle of 5-FU mono therapy with the disease status remaining stable during 18 months of follow-up. PMID- 21253327 TI - A case of blastic plasmacytoid dendritic cell neoplasm initially mimicking cutaneous lupus erythematosus. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare disease. The prognosis is poor in most cases with rapid progression despite administering chemotherapy. A 67-year-old man complained of skin rashes on his back and this spread to the trunk, face, arms and thighs, and he was initially diagnosed with cutaneous lupus erythematosus according to the skin biopsy. The skin rashes then became aggravated on a trial of low dose methylprednisolone for 3 months. Repeated skin biopsy revealed a diffuse infiltration of lymphoid cells with medium sized nuclei, positive for CD4 and CD56, negative for Epstein-Barr virus (EBV), indicating a diagnosis of BPDCN. Further workups confirmed stage IVA BPDCN involving the skin, multiple lymph nodes, the peripheral blood and the bone marrow. He was treated with six cycles of combination chemotherapy consisting of ifosphamide, methotrexate, etoposide, prednisolone and L-asparaginase, and he achieved a partial response. Herein we report on a rare case of BPDCN that was initially misinterpreted as cutaneous lupus erythematosus. PMID- 21253328 TI - Reversible proximal renal tubular dysfunction after one-time Ifosfamide exposure. AB - The alkylating agent ifosfamide is an anti-neoplastic used to treat various pediatric and adult malignancies. Its potential urologic toxicities include glomerulopathy, tubulopathy and hemorrhagic cystitis. This report describes a case of proximal renal tubular dysfunction and hemorrhagic cystitis in a 67-year old male given ifosfamide for epitheloid sarcoma. He was also receiving an oral hypoglycemic agent for type 2 diabetes mellitus and had a baseline glomerular filtration rate of 51.5 mL/min/1.73 m(2). Despite mesna prophylaxis, the patient experienced dysuria and gross hematuria after a single course of ifosfamide plus adriamycin. The abrupt renal impairment and serum/urine electrolyte imbalances that ensued were consistent with Fanconi's syndrome. However, normal renal function and electrolyte status were restored within 14 days, simply through supportive measures. A score of 8 by Naranjo adverse drug reaction probability scale indicated these complications were most likely treatment-related, although they developed without known predisposing factors. The currently undefined role of diabetic nephropathy in adult ifosfamide nephrotoxicity merits future investigation. PMID- 21253329 TI - Ischemic tolerance induced by cerebral preconditioning: new urologic research area. PMID- 21253330 TI - Mechanisms and prospects of ischemic tolerance induced by cerebral preconditioning. AB - In the brain, brief episodes of ischemia induce tolerance against a subsequent severe episode of ischemia. This phenomenon of endogenous neuroprotection is known as preconditioning-induced ischemic tolerance. The purpose of this review is to summarize the current state of knowledge about mechanisms and potential applications of cerebral preconditioning and ischemic tolerance. Articles related to the terms ischemic preconditioning and ischemic tolerance were systematically searched via MEDLINE/PubMed, and articles published in English related to the nervous system were selected and analyzed. The past two decades have provided interesting insights into the molecular mechanisms of this neuroprotective phenomenon. Although both rapid and delayed types of tolerance have been documented in experimental settings, the delayed type has been found to be more prominent in the case of neuronal ischemic tolerance. Many intracellular signaling pathways have been implicated regarding ischemic preconditioning. Most of these are associated with membrane receptors, kinase cascades, and transcription factors. Moreover, ischemic tolerance can be induced by exposing animals or cells to diverse types of endogenous and exogenous stimuli that are not necessarily hypoxic or ischemic in nature. These cross-tolerances raise the hope that, in the future, it will be possible to pharmacologically activate or mimic ischemic tolerance in the human brain. Another promising approach is remote preconditioning in which preconditioning of one organ or system leads to the protection of a different (remote) organ that is difficult to target, such as the brain. The preconditioning strategy and related interventions can confer neuroprotection in experimental ischemia, and, thus, have promise for practical applications in cases of vascular neurosurgery and endo-vascular therapy. PMID- 21253331 TI - Vardenafil Enhances Oxytocin Expression in the Paraventricular Nucleus without Sexual Stimulation. AB - PURPOSE: Oxytocin is associated with the ability to form normal social attachments. c-Fos is an immediate early gene whose expression is used as a marker for stimulus-induced changes in neurons. The effect of phosphodiesterase-5 (PDE-5) inhibitors on oxytocin activation in the brain without sexual stimuli has not yet been reported. In the present study, we investigated the effects of vardenafil on oxytocin and c-Fos expression in the paraventricular nucleus (PVN) of conscious rats. METHODS: Male Sprague-Dawley rats weighing 300+/-10 g were divided into 6 groups (n=5 in each group): the control group, the 1-day-0.5 mg/kg, the 1-day-1 mg/kg, the 1-day-2 mg/kg, the 3-day-1 mg/kg, and the 7-day-1 mg/kg vardenafil administration group. The experiment was conducted without sexual stimulation. Vardenafil was orally administered. The animals in the control group received an equivalent amount of distilled water orally. The expression of oxytocin and c-Fos in the PVN was detected by immunohistochemistry. RESULTS: Oxytocin expression in the PVN was increased by 1 day administration of 2 mg/kg vardenafil, and this effect of vardenafil appeared in a duration dependent manner. c-Fos in the oxytocin neurons of the PVN was increased by 1 day administration of 2 mg/kg vardenafil, and this effect of vardenafil also appeared in a duration-dependent manner. These results showed that vardenafil augments the expression of oxytocin with activation of oxytocin neurons in the PVN. CONCLUSIONS: In this study, we showed that the PDE-5 inhibitor, vardenafil directly enhances oxytocin expression and also activates oxytocin neurons in the PVN, which indicates that vardenafil may exert positive effects on affiliation behavior and social interaction. PMID- 21253332 TI - Correlation between the Severity of Female Urinary Incontinence and Concomitant Morbidities: A Multi-Center Cross-Sectional Clinical Study. AB - PURPOSE: The aim of this study was to identify the relationship between urinary incontinence (UI) and low back pain (LBP) discomfort and disability, static balance, and demographic factors. METHODS: A total of 348 women aged 20-80 years were included in this cross-sectional study. The general characteristics of the subjects and the main outcome (UI condition, LBP discomfort, LBP disability, and static balance ability) were assessed by using clinical questionnaires and assessment tools. RESULTS: Of all the subjects, 22.8% had experienced UI. Women with UI showed a significantly higher relationship of LBP and disability, and static balance ability (P<0.01). We found a significant correlation between UI, age, LBP and disability, and static balance ability (P<0.01). CONCLUSIONS: These findings suggest that UI correlates negatively with LBP discomfort, LBP disability, and static balance ability. Further studies should focus on the identification of the precise mechanisms underlying UI and its related physical symptoms and on the development of therapeutic strategies to manage this condition. PMID- 21253333 TI - Short term effect and safety of antidiuretic hormone in the patients with nocturia. AB - PURPOSE: To investigate the short-term safety of antidiuretic hormone in elderly patients with nocturnal polyuria, focus on hyponatremia and others electrolytes disturbances and to assess short-term effects on nocturnal urine output and number of nocturnal voids. METHODS: Between June 2005 and August 2006, a total of 34 patients with nocturnal polyuria were orally administered 0.2 mg desmopressin tablet at bedtime for two weeks. Serum sodium, others electrolytes, urine sodium and urine osmolarity were assessed in the third days, one week and two weeks after treatment with desmopressin and compared adult group (<65 years of age) with elderly group (>=65 years of age). We assessed the effect of desmopressin using a frequency-volume charts and analysed. RESULTS: In total 34 patients (20 adult, 14 elderly) were analyzed. Desmopressin treatment did not significantly change serum and urine electrolytes include soduim concentration in elderly patients comparied with adult patients. Serum sodium concentration below normal range was recorded in 2 patients in elderly group, but no serious adverse events occurred and recovered without sequelae. The mean number of nocturnal voids decresed (54% reduction) and nocturnal urine output decreased (57% reduction) after using desmopressin. CONCLUSIONS: Desmopressin was well tolerated and effective in elderly patients with nocturnal polyuria without clinically significant hyponatremia. PMID- 21253334 TI - Alteration of autonomic function in female urinary incontinence. AB - PURPOSE: Stress urinary incontinence (SUI) and urge urinary incontinence (UUI) have different mechanisms of action. We believe that alteration of autonomic nervous system (ANS) activity may contribute to UUI because the lower urinary tract is regulated through the sympathetic and parasympathetic nervous systems. Heart rate variability (HRV) allows measurement of autonomic nervous function, therefore we measured and compared HRV parameters in women with urinary incontinence. METHODS: From March 2008 to March 2010, we evaluated all patients who visited 2 university hospitals for treatment of urinary incontinence. Theywere performed 3-day voiding diary, urodynamic study, physical examination and routine laboratory examination. We excluded subjects who had diabetes, cardiovascular problems, or other condition that affect ANS. Patients with mixed urinary incontinence (MUI) were also excluded. Finally 47 women with SUI (group 1) and 29 women with UUI (group 2) were enrolled according to their symptoms and voiding diary. We compared their HRV parameters. And excluding 11 patients who had detrusor underactivity, we divided them again into group A, 53 women without detrusor overactivity (DO) and group B, 12 women with DO. We compared HRV parameters between DO and non-DO group. RESULTS: Older women had a higher incidence of UUI and DO. In HRV parameters, only the ratio of low frequency (LF) and high frequency (HF) was significantly higher in group 2 than group 1 (3.5+/ 3.6 vs. 1.6+/-1.1, P<0.05). Also group A had higher mean LF/HF ratio than group B (4.3+/-3.8 vs. 1.9+/-1.9, P<0.05). CONCLUSIONS: Increased LF/HF values indicate relative sympathetic hyperactivity over parasympathetic activity. Changes in ANS activity could indicate the presence of UUI and potentially DO. PMID- 21253335 TI - Clinical Implications of Residual Urine in Korean Benign Prostatic Hyperplasia (BPH) Patients: A Prognostic Factor for BPH-Related Clinical Events. AB - PURPOSE: Although post-void residual urine (PVR) is frequently utilized clinically in patients with benign prostatic hyperplasia (BPH), mainly because of its procedural simplicity, its role as a clinical prognostic factor, predictive of treatment goals, is still under much dispute. We investigated the predictive value of PVR for BPH-related clinical events including surgery, acute urinary retention (AUR), and admission following urinary tract infection (UTI). METHODS: From January to June of 2006, patients over 50 years of age who were diagnosed with BPH for the first time at the outpatient clinic and were then treated for at least 3 years with medications were enrolled in this study. The variables of patients who underwent surgical intervention for BPH, had occurrences of AUR, or required admission due to UTI (Group 1, n=43) were compared with those of patients who were maintained with medications only (Group 2, n=266). RESULTS: Group 1 had a significantly higher PVR, more severe symptoms, and a larger prostate at the time of the initial diagnosis in both the univariate and the multivariate analysis. In the 39 patients who underwent BPH-related surgery, although there was a significant change in Qmax at the time of surgery (mean, 13.1 months), PVR and the symptom score remained unchanged compared with the initial evaluation. In the receiver-operating characteristic curve analysis, the area under the curve of Group 1 was in the order of prostate volume (0.834), PVR (0.712), and symptom score (0.621). When redivided by arbitrarily selected PVR cutoffs of 50 mL, 100 mL, and 150 mL, the relative risk of clinical BPH progression was measured as 3.93, 2.61, and 2.11. CONCLUSIONS: These data indicate that, in the symptomatic Korean population, increased PVR at baseline is a significant indicator of BPH-related clinical events along with increased symptom score or prostate volume. PMID- 21253337 TI - Predictive risk factors for impaired quality of life in middle-aged women with urinary incontinence. AB - PURPOSE: Urinary incontinence (UI) has substantial and important impacts on quality of life (QoL). The purpose of this study was to identify the associated risk factors of QoL in middle-aged women with UI. METHODS: The participants were 127 women aged 40-64 years who experienced UI. Data were collected from October to November, 2008 using a self-reported questionnaires. The data were analyzed through t-test, one-way ANOVA, Scheffe test, and multiple linear regression with SPSS ver. 16.0 program. RESULTS: The distribution of UI severity was mild 18.1%, moderate 40.2% and severe 41.7%. In univariate analysis, differences in the score for QoL according to participants' characteristics were statistically significant on the type of delivery, number of births and severity of UI. In multiple linear regression analysis after adjustment of other variables, the most powerful predictor of QoL is severity of UI. Number of births was also significant predictor. These two variables explained 25% of variance in QoL of women with UI. CONCLUSIONS: UI is highly prevalent and causes suffering and impaired QoL among middle-aged women, but it stands beyond our attention. The results of this study suggest that women with moderate to severe UI should be screened for QoL by health care providers regularly. Further research is needed to determine comprehensive factors including psychosocial factors predicting the QoL for incontinent women. PMID- 21253336 TI - Age related change of nocturia in women. AB - PURPOSE: The precise etiology and classification of nocturia in women is not enough. We evaluated age related changes and classified the type of nocturia by age in women. METHODS: We included 118 women 20 years or older with nocturia at least one time during night time. Subjects were divided into three groups by the age: group 1, under 40 years; group 2, 40 through 59 years; group 3, 60 years and above. The causes of nocturia and its pattern changed by age in women were evaluated using 3 days frequency volume chart. Nocturia was devided into three types: nocturnal polyuria, decreased nocturnal bladder capacity and mixed type. RESULTS: The mean age was 57.2+/-11.8 and the mean nocturnal frequency was 2.7+/ 1.8. In all age group, noctural polyuria was the major cause for noturia (40.8%), followed by low nocturnal bladder capacity (23.7%). As a major cause of nocturia, there was a significant increase of the incidence of nocturnal polyuria in aged people: group 1, 32.4%; group 2, 41.0%; group 3: 47.6% (P<0.04). CONCLUSIONS: Nocturnal polyuria and decreased nocturnal bladder capacity are the major causes of nocturia in women. Nocturnal polyuria was the major cause of nocturia with age over 60 years old. In aged women, nocturnal polyuria should be considered as a main cuase of nocturia and treated based on these result. PMID- 21253338 TI - Bladder pain syndrome treated with triple therapy with gabapentin, amitriptyline, and a nonsteroidal anti-inflammatory drug. AB - PURPOSE: Bladder pain syndrome is a chronic disease that manifests as bladder pain, frequency, nocturia, and urgency. Gabapentin, amitriptyline, and nonsteroidal anti-inflammatory drugs are efficacious treatments for bladder pain syndrome. Here, we assessed the effect of triple therapy with these drugs in women with bladder pain syndrome. METHODS: Between May 2007 and May 2010, we conducted a prospective nonrandomized study on 74 patients with bladder pain syndrome. Of these patients, 38 (11 men and 27 women; mean age, 55.9 years; range, 25 to 77 years; mean follow-up, 12.6 months) were administered the interstitial cystitis (IC) symptom scales (O'Leary-Sant Symptom Index) and visual analog scale (VAS) 1, 3, and 6 months after treatment to assess the efficacy of triple therapy. RESULTS: The pretreatment O'Leary-Sant IC symptom score was 11.7, and the post-treatment scores were 4.4, 3.8, and 4.0 at 1, 3, and 6 months, respectively; the pretreatment problem index score was 10.5, and the post treatment scores were 3.7, 2.7, and 2.9 at 1, 3, and 6 months, respectively. The pretreatment VAS score was 6.7, and the post-treatment scores were 1.8, 1.5, and 1.7 at 1, 3, and 6 months, respectively. The O'Leary-Sant IC symptom index and problem index and VAS scores improved considerably 1 month after treatment (P<0.05). However, the results at 1, 3, and 6 months after treatment were not significantly different (P>0.05). CONCLUSIONS: Triple therapy was sufficiently effective in patients with bladder pain syndrome and caused no significant adverse effects. However, large-scale studies should be performed to verify our findings. PMID- 21253339 TI - Analysis of initial baseline clinical parameters and treatment strategy associated with medication failure in the treatment of benign prostatic hyperplasia in Korea. AB - PURPOSE: To analyze the baseline clinical factors and medication treatment strategy used in cases with medication treatment failure of benign prostatic hyperplasia (BPH). METHODS: From January 2006 to December 2009, 677 BPH patients with at least 3 months of treatment with medication were enrolled. We analyzed clinical factors by medication failure (n=161) versus maintenance (n=516), by prostate size (less than 30 g, n=231; 30 to 50 g, n=244; greater than 50 g, n=202), and by prostate-specific antigen (PSA) levels (less than 1.4 ng/mL, n=324; more than 1.4 ng/mL, n=353). RESULTS: Age, combination medication rate, PSA, and prostate volume were statistically different between the medication treatment failure and maintenance groups. By prostate size, the PSA and medication failure rates were relatively higher and the medication period was shorter in patients with a prostate size of more than 30 g. The combination medication rate was higher in patients with a prostate size of more than 50 g. The medication failure rate and prostate volume were higher in patients with a PSA level of more than 1.4 ng/mL. However, the combination treatment rate was not significantly different in patients with a PSA level lower than 1.4 ng/mL. Suggestive cutoffs for combination medication are a prostate volume of 34 g and PSA level of 1.9 ng/mL. CONCLUSIONS: The clinical factors associated with medication failure were age, treatment type, and prostate volume. Combination therapy should be considered more in Korea in patients with a PSA level higher than 1.4 ng/mL and a prostate volume of between 30 and 50 g to prevent medication failure. PMID- 21253340 TI - The influence of preoperative bladder outlet obstruction on continence and satisfaction in patients with stress urinary incontinence after midurethral sling. AB - PURPOSE: We studied the influence of preoperative bladder outlet obstruction (BOO) on postoperative continence rates and patient satisfaction after the midurethral sling procedure. METHODS: A total of 159 women who underwent the midurethral sling procedure were evaluated. Using the Blaivas-Groutz nomogram, we assigned the patients were assigned to Group I (n=37, no obstruction), Group II (n=89, mild obstruction), or Group III (n=33, moderate to severe obstruction). Continence rates, patient satisfaction, urinary sensation scale and uroflowmetry were evaluated postoperatively. RESULTS: There were no significant differences in continence rates, satisfaction, or postoperative maximal flow rate between the 3 groups. Postoperative urgency was improved after surgery in Groups I and II (P<0.05) but not in Group III. CONCLUSIONS: BOO does not seem to be a risk factor for failure after the midurethral sling procedure. However, BOO may be considered as a potential factor for persistent storage symptoms after the midurethral sling. PMID- 21253341 TI - Laparoscopic removal of a broken sewing needle in a patient with irritative bladder symptoms. AB - A foreign body near the bladder is rare. Although foreign bodies in the bladder can be easily found and removed by endoscopic transurethral removal, extravesical foreign bodies may require the use of an open or laparoscopic procedure. Here, we report a case of a patient complaining of frequency and urgency in whom an extravesical sewing needle was successfully removed by a laparoscopic approach. A 4.5 cm rusty sewing needle was found between the bladder and the left external iliac vessels and was removed through a 5 mm trocar port by use of endo forceps with no complications. PMID- 21253342 TI - Arterial Injury Associated with Tension-Free Vaginal Tapes-SECUR Procedure Successfully Treated by Radiological Embolization. AB - Various postoperative complications have been reported after the use of tension free vaginal tapes (TVT). The transobturator approach was introduced to minimize the potential complications. The next generation of recently introduced TVT-SECUR is intended to minimize the incidence of complications. Herein we report a case of internal pudendal artery injury sustained during this procedure that was successfully treated by radiological embolization. Angiography with vessel embolization, when available, should be considered when the arterial injury is suspected. PMID- 21253343 TI - A case control study of cardiovascular health in chemical war disabled Iranian victims. AB - BACKGROUND: Sulfur mustard (SM) is an alkylating chemical warfare agent that was widely used during Iran-Iraq war between 1983 and 1988. SM exposure leads to various late complications. The aim of this study was to determine the late cardiovascular effects of SM in war-disabled Iranian victims. MATERIALS AND METHODS: This was a retrospective cohort case control study on 50 patients with symptoms of SM exposure and 50 cases who had been in Iran-Iraq war, without chemical injury. We performed exercise stress test and echocardiography for all of patients. RESULTS: The study group comprised 100 males of mean age 45.6 +/- 6.2 years. In chemical war injury group, two patients (4%) had positive exercise stress test. On coronary angiography, they were found to have coronary artery disease. One patient had severe mitral regurgitation and normal coronary angiography; he was referred for mitral valve replacement. Left ventricular (LV) diastolic abnormality was detected in 23% of these subjects. In another group, 5% had LV diastolic abnormality (P = 0.02) and all of them had normal stress test. CONCLUSIONS: Cardiovascular abnormalities are another late complication in chemical war disabled Iranian victims. Diastolic dysfunction was the most common abnormality in both groups of patients. PMID- 21253344 TI - Correlates of severe disease in patients admitted with 2009 pandemic influenza A (H1N1) infection in Saurashtra region, India. AB - BACKGROUND: India reported its first case of 2009 pandemic influenza A (H1N1) virus infection in May 2009 and in Saurashtra region in August 2009. We describe the epidemiology and factors associated with severe and non-severe cases of 2009 influenza A (H1N1) infection reported in Saurashtra region. MATERIALS AND METHODS: From September 2009 to February 2010, we observed 274 patients who were infected with 2009 influenza A (H1N1) virus and admitted in different hospitals in Rajkot city. Real-time reverse transcriptase-polymerase chain reaction (RT PCR) testing was used to confirm infection. Factors associated with severe disease were determined by comparing with non-severe cases. RESULTS: Out of 274 patients, 87 had severe disease (requiring intensive care or died) and 187 had non-severe diseases (admitted in wards and survived). The median age of severe disease patients was 30 years; the median time was 5 days from the onset of illness to diagnosis, and 4 days median time was reported for hospital stay. More than half of the patients (56.3%) were females, and 58.6% patients were residing in urban area (OR = 1.65, CI = 0.97-2.8), among severe disease patients. Significant association (P < 0.01) was reported among severe disease patients for delayed referral from general practitioner/physician after initial treatment. All patients received antiviral drug, but only 19.5% received the same within 2 days of illness. Presence of coexisting condition [odds ratio (OR) = 0.53, confidence interval (CI) = 0.31-0.90], mainly pregnancy (OR = 0.22, CI = 0.06-0.76), was strongly associated with severe disease. CONCLUSION: Delayed referral from general practitioner/physician, duration of antiviral treatment, and presence of coexisting condition (especially pregnancy) were responsible for intensive care or mortality in patients of severe influenza A (H1N1) illness. PMID- 21253345 TI - Acute kidney injury after trauma: Prevalence, clinical characteristics and RIFLE classification. AB - BACKGROUND: Acute kidney injury (AKI) is an uncommon but serious complication after trauma. The objective of this study was to evaluate the prevalence, clinical characteristics and outcome of AKI after trauma. PATIENTS AND METHODS: This was a retrospective study performed from January 2006 to January 2008 in an emergency specialized hospital in Fortaleza city, northeast of Brazil. All patients with AKI admitted in the study period were included. Prevalence of AKI, clinical characteristics and outcome were investigated. RESULTS: Of the 129 patients admitted to the intensive care unit (ICU), 52 had AKI. The mean age was 30.1 +/- 19.2 years, and 79.8% were males. The main causes of AKI were sepsis in 27 cases (52%) and hypotension in 18 (34%). Oliguria was observed in 33 cases (63%). Dialysis was required for 19 patients (36.5%). Independent risk factors associated with AKI were abdominal trauma [odds ratio (OR) = 3.66, P = 0.027] and use of furosemide (OR = 4.10, P = 0.026). Patients were classified according to RIFLE criteria as Risk in 12 cases (23%), Injury in 13 (25%), Failure in 24 (46%), Loss in 1 (2%) and End-stage in 2 (4%). Overall in-hospital mortality was 95.3%. The main cause of death was sepsis (24%). Mortality was 100% among patients with AKI. CONCLUSIONS: AKI is a fatal complication after trauma, which presented with a high mortality in the studied population. A better comprehension of factors associated with death in trauma-associated AKI is important, and more effective measures of prevention and treatment of AKI in this population are urgently needed. PMID- 21253346 TI - Cerebrovascular complications in pediatric intensive care unit. AB - Cerebrovascular complications are being frequently recognized in the pediatric intensive care unit in the recent few years. The epidemiology and risk factors for pediatric stroke are different from that of the adults. The incidence of ischemic stroke is almost slightly more than that of hemorrhagic stroke. The list of diagnostic causes is increasing with the availability of newer imaging modalities and laboratory tests. The diagnostic work up depends on the age of the child and the rapidity of presentation. Magnetic resonance imaging, computerized tomography and arteriography and venography are the mainstay of diagnosis and to differentiate between ischemic and hemorrhagic events. Very sophisticated molecular diagnostic tests are required in a very few patients. There are very few pediatric studies on the management of stroke. General supportive management is as important as the specific treatment. Most of the treatment guidelines and suggestions are extrapolated from the adult studies. Few guidelines are available for the use of anticoagulants and thrombolytic agents in pediatric patients. So, our objective was to review the available literature on the childhood stroke and to provide an insight into the subject for the pediatricians and critical care providers. PMID- 21253347 TI - Enteral feed obstructing its own way. AB - Esophageal obstruction due to solidified enteral feeds is a rare but distressful complication in intensive care unit (ICU) patients. It has been suggested that gastroesophageal reflux, very low gastric pH, decreased pepsin and pancreatic enzyme secretions may be responsible for the solidification of casein containing enteral formulas. Recognition and avoidance of these factors will prevent such complication. PMID- 21253348 TI - Light at a tunnel's end: The lightwand as a rapid tracheal location aid when encountering false passage during tracheostomy. AB - False passage and loss of airway during tracheostomy are not uncommon, especially in patients with short and thick necks. Distorted neck anatomy following either repeated insertion attempts or due to underlying malignancy may make it very difficult to locate the trachea even while attempting open/surgical tracheostomy, despite good exposure of the neck in such situations. The lightwand is not an ideal device for tracheal intubation in such patients. However, it can be useful in these patients while performing open tracheostomy. Passing the lightwand through the orotracheal tube can aid in rapid identification of the trachea in such situations and may help reduce the occurrence of complications subsequent to repeated false passage. We report a series of four such cases where use of lightwand aided in rapidly locating the trachea during tracheostomy complicated by distorted anatomy. PMID- 21253349 TI - Use of recombinant human activated protein C in nonmenstrual staphylococcal toxic shock syndrome. AB - Toxic shock syndrome (TSS) is a serious, potentially life-threatening condition resulting from an overwhelming immunological response to an exotoxin released by Staphylococcus aureus and group A streptococci. High index of suspicion, early diagnosis and aggressive therapeutic measures must be instituted in view of high mortality of the TSS. In recent years, new agents have been tested to reduce morbidity and mortality in patients with severe sepsis, in addition to standard supportive measures. Among them, recombinant human activated protein C (rhAPC) has been reported to significantly reduce mortality and morbidity in patients with severe sepsis and two or more acute organ failures. We describe our experience with this drug in the early reversal of septic shock from TSS. PMID- 21253350 TI - Functional residual capacity tool: A practical method to assess lung volume changes during pulmonary complications in mechanically ventilated patients. AB - In this report, we describe a patient in whom we used a functional residual capacity (FRC) tool available on a critical care ventilator to identify the loss of lung volume associated with pulmonary complications and increase in FRC with the application of a recruitment maneuver. The case report underlines the utility of the FRC tool in rapid visualization of the lung volume changes and the effects of application of corrective strategies in patients receiving mechanical ventilation. PMID- 21253351 TI - Morganella morganii could be an important Intensive Care Unit pathogen. PMID- 21253352 TI - Pandemic (H1N1) 2009 influenza: Experience from a critical care unit in India. AB - This case series details our experience with seven patients with pandemic (H1N1) 2009 influenza from an intensive care unit in India.All the patients had respiratory failure requiring ventilation except one;two patients developed pneumothorax. Of the seven patients, two died (28.5%) and five recovered. Four patients had co-morbid conditions and one was morbidly obese; all the five patients were discharged alive. PMID- 21253353 TI - Unexpected cause of esophageal obstruction due to accidental use of traditional medicine in a critically ill patient fed through naso-gastric tube. PMID- 21253354 TI - Management with colistin. PMID- 21253355 TI - Authors' reply. PMID- 21253356 TI - Patient communication in Intensive Care Unit-Application in pediatric population. PMID- 21253357 TI - FieldTrip: Open source software for advanced analysis of MEG, EEG, and invasive electrophysiological data. AB - This paper describes FieldTrip, an open source software package that we developed for the analysis of MEG, EEG, and other electrophysiological data. The software is implemented as a MATLAB toolbox and includes a complete set of consistent and user-friendly high-level functions that allow experimental neuroscientists to analyze experimental data. It includes algorithms for simple and advanced analysis, such as time-frequency analysis using multitapers, source reconstruction using dipoles, distributed sources and beamformers, connectivity analysis, and nonparametric statistical permutation tests at the channel and source level. The implementation as toolbox allows the user to perform elaborate and structured analyses of large data sets using the MATLAB command line and batch scripting. Furthermore, users and developers can easily extend the functionality and implement new algorithms. The modular design facilitates the reuse in other software packages. PMID- 21253358 TI - Spatiotemporal analysis of multichannel EEG: CARTOOL. AB - This paper describes methods to analyze the brain's electric fields recorded with multichannel Electroencephalogram (EEG) and demonstrates their implementation in the software CARTOOL. It focuses on the analysis of the spatial properties of these fields and on quantitative assessment of changes of field topographies across time, experimental conditions, or populations. Topographic analyses are advantageous because they are reference independents and thus render statistically unambiguous results. Neurophysiologically, differences in topography directly indicate changes in the configuration of the active neuronal sources in the brain. We describe global measures of field strength and field similarities, temporal segmentation based on topographic variations, topographic analysis in the frequency domain, topographic statistical analysis, and source imaging based on distributed inverse solutions. All analysis methods are implemented in a freely available academic software package called CARTOOL. Besides providing these analysis tools, CARTOOL is particularly designed to visualize the data and the analysis results using 3-dimensional display routines that allow rapid manipulation and animation of 3D images. CARTOOL therefore is a helpful tool for researchers as well as for clinicians to interpret multichannel EEG and evoked potentials in a global, comprehensive, and unambiguous way. PMID- 21253359 TI - Subthreshold alpha2-adrenergic activation counteracts glucagon-like peptide-1 potentiation of glucose-stimulated insulin secretion. AB - The pancreatic beta cell harbors alpha2-adrenergic and glucagon-like peptide-1 (GLP-1) receptors on its plasma membrane to sense the corresponding ligands adrenaline/noradrenaline and GLP-1 to govern glucose-stimulated insulin secretion. However, it is not known whether these two signaling systems interact to gain the adequate and timely control of insulin release in response to glucose. The present work shows that the alpha2-adrenergic agonist clonidine concentration-dependently depresses glucose-stimulated insulin secretion from INS 1 cells. On the contrary, GLP-1 concentration-dependently potentiates insulin secretory response to glucose. Importantly, the present work reveals that subthreshold alpha2-adrenergic activation with clonidine counteracts GLP-1 potentiation of glucose-induced insulin secretion. This counteractory process relies on pertussis toxin- (PTX-) sensitive Gi proteins since it no longer occurs following PTX-mediated inactivation of Gi proteins. The counteraction of GLP-1 potentiation of glucose-stimulated insulin secretion by subthreshold alpha2 adrenergic activation is likely to serve as a molecular mechanism for the delicate regulation of insulin release. PMID- 21253360 TI - Effects of statins on the epicardial fat thickness in patients with coronary artery stenosis underwent percutaneous coronary intervention: comparison of atorvastatin with simvastatin/ezetimibe. AB - BACKGROUND: Epicardial fat is a visceral thoracic fat and known to be related with presence of dyslipidemia and coronary arterial stenosis. We evaluated the effects and differences of statins on epicardial fat thickness (EFT) in patients underwent successful percutaneous coronary intervention (PCI). METHODS: In this retrospective cohort study, we enrolled consecutive patients underwent successful PCI and scheduled six to eight-months follow-up coronary angiography from March 2007 to June 2009. EFT was measured by echocardiography twice at the time of PCI and the follow-up coronary angiography. We included 145 patients (58 females; mean, 63.5 +/- 9.5 years). RESULTS: Of the 145 patients, 82 received 20 mg of atorvastatin (atorvastatin group) and 63 medicated with 10 mg of simvastatin with 10 mg of ezetimibe (simvastatin/ezetimibe group). With statin treatments, total cholesterol concentration (189.1 +/- 36.1 to 143.3 +/- 36.5 mg/dL, p < 0.001), triglycerides (143.5 +/- 65.5 to 124.9 +/- 63.1 mg/dL, p = 0.005), low density lipoprotein-cholesterol (117.4 +/- 32.5 to 76.8 +/- 30.9 mg/dL, p < 0.001) and EFT (4.08 +/- 1.37 to 3.76 +/- 1.29 mm, p < 0.001) were significantly decreased. Atorvastatin and simvastatin/ezetimibe showed similar improvements in the cholesterol profiles. However, atorvastatin decreased EFT more significantly than simvastatin/ezetimibe (EFT change 0.47 +/- 0.65 in the atorvastatin vs. 0.12 +/- 0.52 mm in the simvastatin/ezetimibe group; p = 0.001). CONCLUSION: In this study, the atorvastatin group showed significant reduction in EFT than in the simvastatin/ezetimibe group. This might be originated from the statin difference. More large, randomized study will be needed to evaluate this statin difference. PMID- 21253361 TI - Progression rate of aortic valve stenosis in korean patients. AB - BACKGROUND: Although there were studies about ethnic differences in aortic valve thickness and calcification that they may play a role in aortic valvular stenosis (AVS) progression, few studies about the progression rate of AVS in Asian population have been reported. The purpose of this study was to evaluate the progression rate of AVS in Korean patients. METHODS: We retrospectively analyzed 325 patients (181 men, age: 67 +/- 13 years) with AVS who had 2 or more echocardiograms at least 6 months apart from 2003 to 2008. The patients with other significant valvular diseases or history of cardiac surgery were excluded. The progression rate of AVS was expressed in terms of increase in maximum aortic jet velocity per year (meter/second/year). RESULTS: Baseline AVS was mild in 207 (64%), moderate in 81 (25%), and severe in 37 (11%). There were no significant differences among the three groups in terms of age, gender, hypertension, smoking, and hypercholesterolemia. The mean progression rate was 0.12 +/- 0.23 m/s/yr and more rapid in severe AVS (0.28 +/- 0.36 m/s/yr) when compared to moderate (0.14 +/- 0.26 m/s/yr) and mild AVS (0.09 +/- 0.18 m/s/yr) (p < 0.001). The progression rate in bicuspid AVS was significantly higher than other AVS (0.23 +/- 0.35 vs. 0.11 +/- 0.20 m/s/yr, p = 0.002). By multivariate analysis, initial maximum aortic jet velocity (Beta = 0.175, p = 0.003), bicuspid aortic valve (Beta = 0.127, p = 0.029), and E velocity (Beta = -0.134, p = 0.018) were significantly associated with AVS progression. CONCLUSION: The progression rate of AVS in Korean patients is slower than that reported in Western population. Therefore, ethnic difference should be considered for the follow-up of the patients with AVS. PMID- 21253362 TI - Urine Albumin Creatinine Ratio is Associated with Carotid Atherosclerosis in a Community Based Cohort: Atherosclerosis Risk of Rural Area in Korean General Population Study. AB - BACKGROUND: Albuminuria is a surrogate marker of endothelial dysfunction and a predictor of cardiovascular events. Data are limited with regard to the relationship between albuminuria and subclinical atherosclerosis in a community based cohort. We determined the association between albuminuria measured by the urine albumin creatinine ratio (UACR) and carotid intima media thickness (CIMT) in a Korean rural population. METHODS: We enrolled 1,369 healthy subjects older than 40 years (857 males and 518 females) with normal renal function and measured the CIMT. We excluded subjects with overt proteinuria (> 300 mg/day) or with treatment of diabetes mellitus, hypertension, dyslipidemia, and any cardiovascular disease. The subjects were stratified into the quartile value of the UACR (lowest quartile: UACR < 4.8 and highest quartile: UACR > 17.7). And we evaluate the relationship between UACR and CIMT by linear regression and logistic regression analysis. RESULTS: Increasing quartile of the UACR had a stepwise increase in body mass index, blood pressure, cholesterol profile [low density lipoprotein (LDL)-cholesterol and triglyceride], glucose, homeostratic model assessment of insulin resistance (HOMA-IR), and C-reactive protein (all p values < 0.001). Maximal CIMT from the 1(st) to the 4(th) quartile values of the UACR were 0.74 +/- 0.17, 0.77 +/- 0.18, 0.78 +/- 0.18, and 0.82 +/- 0.21 mm, respectively (p < 0.001). In a multivariate regression model adjusted for age, sex, systolic blood pressure, triglyceride, LDL-cholesterol, fasting blood sugar, waist circumference, adiponectin, HOMA-IR, high sensitive C-reactive protein, smoking, UACR showed a significant association with maximal CIMT (B = 0.014, R(2) = 0.145, p = 0.002). CONCLUSION: Albuminuria measured by the UACR was significantly associated with both CIMT and traditional risk factors of atherosclerosis except for smoking in healthy Koreans. PMID- 21253363 TI - B-type natriuretic Peptide in isolated severe tricuspid regurgitation: determinants and impact on outcome. AB - BACKGROUND: The plasma B-type natriuretic peptide (BNP) level is a useful prognostic marker in heart failure and valvular heart disease. In patients with isolated severe tricuspid regurgitation (TR), little is known about the determinants of plasma BNP levels and the correlation with future outcome. The purpose of this study was to identify the determinants of plasma BNP levels in patients with isolated severe TR and the value of the BNP level in predicting postoperative outcomes after corrective surgery. METHODS: We prospectively enrolled 39 patients with isolated, severe TR undergoing corrective surgery. A plasma BNP assay and cardiac magnetic resonance (CMR) imaging were performed before surgery. The combined end-point was the occurrence of cardiac death or readmission due to heart failure. RESULTS: Linear regression analysis showed that the left ventricular ejection fraction and right ventricular end systolic volume were the most important determinants of the BNP levels (p = 0.002, R(2) = 0.315). Based on the receiver operating characteristics (ROC) curve, we were able to derive an optimal cutoff value (200 pg/mL) to predict postoperative cardiac death with a sensitivity of 80% and a specificity of 85%. The one-year survival rate was 96% in patients with a BNP < 200 pg/mL and 53% in patients with a BNP >= 200 pg/dL (p = 0.001). CONCLUSION: An elevation in the BNP level is determined by the functional status of the right and left ventricles in patients with isolated, severe TR. An elevated BNP predicts adverse events after corrective surgery. Therefore, the BNP level should be included in the clinical evaluation and risk stratification of patients with isolated TR. PMID- 21253364 TI - Relationship between Urinary Albumin Excretion and Carotid Atherosclerosis in General Korean Population. PMID- 21253365 TI - Spontaneous systemic tumor embolism caused by tumor invasion of pulmonary vein in a patient with advanced lung cancer. AB - We describe a 72-year-old man who presented with left hemiparesis due to acute cerebral infarction in the right fronto-temporal lobe. Three months prior to admission, he was hospitalized for right hemiparesis due to the acute cerebral infarction in the left anterior cerebral artery territory. To investigate the cause of his recurrent embolic event, a chest computed tomography scan and echocardiography were performed, which revealed advanced lung cancer invading contiguously through the pulmonary veins to the right main pulmonary artery and left atrium. Tumor embolism is a rare cause of stroke, occurring with primary or metastatic neoplasms of the lung. Echocardiography is a useful tool in patients with cerebral embolic episodes. PMID- 21253366 TI - Massive left atrial calcification associated with mitral valve replacement. AB - Calcification of the left atrium can be observed in patients with a long-lasting rheumatic heart disease. However, massive calcification of the atrial wall, so called porcelain or coconut atrium is very rare and has been generally reported only as incidental radiographic findings. We report a case of massive and firm calcifications at the left atrium in patient who underwent mitral valve replacement. PMID- 21253367 TI - Left atrial mass with stalk: thrombus or myxoma? AB - A 63-year-old female was presented to emergency room with an abdominal pain. The patient had moderate mitral valve stenosis and atrial fibrillation. Abdominal computed tomography revealed right renal infarction. Transthoracic echocardiography showed a large mobile mass in the left atrium. Transesophageal two-and three-dimensional echocardiography showed a large mobile ovoid mass with a narrow stalk attached to the left atrial septum. It was thought to be a myxoma rather than thrombus. Anticoagulation with heparin was continued. When the operation was performed, there was no mass in the left atrium. It must be a thrombus and melt away. PMID- 21253368 TI - A case of left ventricular pseudoaneurysm in the left atrioventricular groove after mitral valve replacement. AB - Left ventricle-coronary sinus fistula and left ventricular pseudoaneurysm are unusual and frightening complications after mitral valve replacement. A 27-year old female patient underwent mitral valve replacement 5 years previously and trans-thoracic echocardiography showed an outpouching lesion at the atrioventricular groove. It was difficult to differentiate whether the lesion was a left ventricle-coronary sinus fistula or a left ventricular pseudoaneurysm by two-dimensional echocardiography. Cardiac computed tomography confirmed a left ventricular pseudoaneurysm compressing the coronary sinus. PMID- 21253369 TI - Progression of left ventricular pseudoaneurysm after an acute myocardial infarction. AB - Left ventricular (LV) pseudoaneurysms rarely occur, but are detected more often with the development of new diagnostic tools. Since LV pseudoaneurysms are life threatening, early surgical intervention is recommended. This report describes an 87-year-old woman with heart failure and a large LV pseudoaneurysm which progressed from a small LV pseudoaneurysm after an acute myocardial infarction over a 1-year period. PMID- 21253370 TI - A case of idiopathic aortitis mimicking severe aortic stenosis. AB - Aortitis is the all-encompassing pathological term ascribed to inflammation of the aorta. Regardless of the etiology, it frequently results in aortic root dilatation and aortic insufficiency rather than aortic stenosis. The rare case of aortitis such as isolated idiopathic aortitis may occur without evidence of systenic inflammatory disease or infection, and usually has subclinical nature. Even though the goals of therapy include immediate treatment of aortic inflammation or infection, the optimal management of isolated idiopathic aortitis is uncertain. We report a rare case of isolated idiopathic aortitis mimicking acute severe aortic stenosis, which was improved after steroid therapy. PMID- 21253371 TI - Small interfering RNA (siRNA): a hope for the loss-of-function studies in anesthesiology? PMID- 21253372 TI - Interactions of propofol and remifentanil on bispectral index under 66% N(2)O: analysis by dose-effect curve, isobologram, and combination index. AB - BACKGROUND: Propofol and remifentanil are usually co-administered and have shown synergistic effect for anesthesia. However, the synergistic effect of the two drugs on hypnosis measured by bispectral index (BIS) was controversial in previous studies. The aim of this study was to identify the interaction of propofol and remifentanil on BIS and the optimal dose combinations for hypnosis under 66% N(2)O during surgery. METHODS: Patients (age 55-75 and American Society of Anesthesiologists [ASA] 1-2) undergoing gastrectomy were enrolled in this study. Propofol and remifentanil were co-administered incrementally at 1 : 1 potent ratio (the P1R1 group), at 1 : 2 potent ratio (the P1R2 group), or at 2 : 1 potent ratio (the P2R1 group) using effect site target-controlled infusion and BIS was measured. 66% N(2)O was concomitantly administered to all groups. The dose-effect curves, the 90% effective dose (EC(90)) for adequate hypnosis (BIS 40), isobolograms and combination index were obtained by Calcusyn program (Biosoft) to reveal the interaction of propofol and remifentanil. RESULTS: The P2R1 group showed synergistic action on BIS. However, the other groups needed larger amount of each drug than the doses of additive action. The EC(90) of the P2R1 group was propofol, 3.34 ug/ml and remifentanil, 2.41 ng/ml under 66% of N(2)O. CONCLUSIONS: Propofol dominant co-administration is needed for dose reduction in BIS guided hypnosis. PMID- 21253373 TI - Comparison of surgical condition in endoscopic sinus surgery using remifentanil combined with propofol, sevoflurane, or desflurane. AB - BACKGROUND: Various maneuvers are commonly used to achieve the ideal operative field necessary for successful endoscopic sinus surgery (ESS). There are a few contradictory reports on this subject and the consensus is that propofol anesthesia results in a better or similar surgical field and less or similar amount of bleeding than volatile anesthesia. The aim of this study was to compare the surgical field in patients in whom intravenous anesthesia is used as opposed to balanced general anesthesia. METHODS: SIXTY PATIENTS UNDERGOING ESS WERE RANDOMLY ASSIGNED INTO THREE GROUPS, EACH OF WHICH USED A DIFFERENT TYPE OF ANESTHESIA: propofol/remifentanil (PRO/REM) group, sevoflurane/remifentanil (SEV/REM) group, and desflurane/remifentanil (DES/REM) group. We aimed to maintain the intraoperative mean blood pressure (MBP) at 65 mmHg and the heartrate (HR) at about 75 beats per minute. The quality of visibility of the surgical field was graded, using a validated scoring system, 60 minutes after the start of the operation. RESULTS: All groups had a similar MBP and mean HR at 60 minutes after the operation started. There was no significant differences among the three groups for surgical grade score (P = 0.83). CONCLUSIONS: In this comparative study of three anesthetic combinations (PRO/REM, SEV/REM, and DES/REM) in patients undergoing ESS with controlled BP and HR, we did not observe any significant differences in the surgical grade scores. PMID- 21253374 TI - Laparoscopic cholecystectomy under epidural anesthesia: a clinical feasibility study. AB - BACKGROUND: Laparoscopic cholecystectomy (LC) has traditionally been performed under general anesthesia, however, owing in part to the advancement of surgical and anesthetic techniques, many laparoscopic cholecystectomies have been successfully performed under the spinal anesthetic technique. We hoped to determine the feasibility of segmental epidural anesthesia for LC. METHODS: Twelve American Society of Anesthesiologists class I or II patients received an epidural block for LC. The level of epidural block and the satisfaction score of patients and the surgeon were checked to evaluate the efficacy of epidural block for LC. RESULTS: LC was performed successfully under epidural block, with the exception of 1 patient who required a conversion to general anesthesia owing to severe referred pain. There were no special postoperative complications, with the exception of one case of urinary retention. CONCLUSIONS: Epidural anesthesia might be applicable for LC. However, the incidence of intraoperative referred shoulder pain is high, and so careful patient recruitment and management of shoulder pain should be considered. PMID- 21253375 TI - Intrathecal meperidine reduces intraoperative shivering during transurethral prostatectomy in elderly patients. AB - BACKGROUND: Shivering is a frequent event during the perioperative period. We performed a prospective, randomized, double-blind study to determine whether intrathecal meperidine (0.2 mg/kg) decreases the incidence and intensity of shivering after spinal anesthesia for transurethral operations. METHODS: Fifty patients scheduled for elective transurethral resection operations under spinal anesthesia were randomly allocated to two groups. Spinal anesthesia consisted of 0.5% hyperbaric bupivacaine 8 mg and, mperidine (0.2 mg/kg) (meperidine group) or, normal saline (saline group). Data collection, including sensory block level (by pinprick), blood pressure, heart rate, sublingual temperature, incidence and intensity of shivering, pruritus, nausea, and vomiting was performed at 10 minute intervals. RESULTS: The incidence and intensity of shivering was significantly less in the meperidine group than saline group (P = 0.012 and P = 0.008, for incidence and intensity, respectively). However, pruritus was more common in the meperidine group compared with the saline group (16% vs. 0%, P < 0.05). CONCLUSIONS: The addition of meperidine 0.2 mg/kg to intrathecal bupivacaine lowers the incidence and severity of shivering during transurethral prostatectomy in elderly patients. PMID- 21253376 TI - Ultrasonic doppler flowmeter-guided occipital nerve block. AB - BACKGROUND: Greater occipital nerve block is used in the treatment of headaches and neuralgia in the occipital area. We evaluated the efficacy of ultrasonic doppler flowmeter-guided occipital nerve block in patients experiencing headache in the occipital region in a randomized, prospective, placebo-controlled study. METHODS: Twenty-six patients, aged 18 to 70, with headache in the occipital region, were included in the study. Patients received a greater occipital nerve block performed either under ultrasonic doppler flowmeter guidance using 1% lidocaine or the traditional method. Sensory examination findings in the occipital region were evaluated. RESULTS: The complete block rate of greater occipital nerve blockade in the doppler group was significantly higher than in the control group respectively (76.9% vs. 30.8%, P < 0.05). Only one patient in the control group had a complication (minimal bleeding). CONCLUSIONS: Ultrasonic doppler flowmeter-guided occipital nerve block may be a useful method for patients suffering headache in the occipital region. PMID- 21253377 TI - Position of dorsal root ganglia in the lumbosacral region in patients with radiculopathy. AB - BACKGROUND: When applying pulsed radiofrequency on dorsal root ganglia for treating chronic lower back pain, maximum efficiency can be expected when a needle is placed 1-2 cm peripheral to the dorsal root ganglion. The object of this study is to analyze images taken after adding contrast to transforaminal epidural injection, categorize root ganglia according to anatomical position, and provide a reference for efficient needle positioning in applying pulsed radiofrequency on dorsal root ganglia. METHODS: From January 2008 to January 2009, 457 patients who visited our hospital for root pain or radiculopathy were treated with transforaminal epidural injection on the nerve roots based on the dermatome of the painful area. Anteroposterior views were taken after injection of contrast. A virtual line was made by connecting the internal and external parts of the spinal pedicle from the contrast images. Then the dorsal root ganglia were categorized as intraspinal (IS), intraforaminal (IF), or extraforaminal (EF). RESULTS: In the fourth lumbar spine, dorsal root ganglia positions were 48% IF, 41% IS, and 6% EF. In the fifth lumbar spine, dorsal root ganglia positions were 75% IF, 10% IS, and 6% EF. In the first sacral spine, dorsal root ganglia locations were 8% IF and 83% IS. CONCLUSIONS: Positional categorization of dorsal root ganglia according to contrast images was proven to be good anatomical references for effective radiofrequency or blocking of dorsal root ganglia. PMID- 21253378 TI - The optimal concentration of siRNA for gene silencing in primary cultured astrocytes and microglial cells of rats. AB - BACKGROUND: Small interfering RNAs (siRNAs) have been used to knockdown specific gene expression in various cells. Astrocytes and microglial cells play a key role in fundamental central nervous system functions and in chronic neuroinflammation. The aims of this study were to determine the optimal concentration of siRNA demonstrating efficient transfection and inhibition of gene expression via RNA interference (RNAi) and lower cytotoxicity, in primary cultured astrocytes and microglial cells of rats. METHODS: Astrocytes and microglial cells were isolated from the cerebral cortices of 2-day-old rats. Both the cells were transfected using transfection reagent (LipofectamineTM 2000), and fluorescein-labeled double stranded RNA (dsRNA) or siRNA targeting green fluorescent protein. Transfection efficiency and cytotoxicity of dsRNA, and the degrees of RNAi induced by siRNA in these cells, were evaluated at various concentrations of RNA. RESULTS: Transfection efficiencies of dsRNA in both astrocytes and microglial cells were significantly higher (P < 0.05) at the concentrations of 20, 40, and 80 nM than at the concentrations of 0, 5, and 10 nM. There were no significant cytotoxicities within the applied concentrations of dsRNA (0-80 nM). The degrees of RNAi induced by siRNA were significantly higher (P < 0.05) at the concentrations of 5, 10, 20, 40, 80 nM, and 20, 40, 80 nM in astrocytes and microglial cells, respectively, compared with the control (0 nM). CONCLUSIONS: The siRNA concentration of 20 nM may be appropriate to induce RNAi in both astrocytes and microglial cells, while demonstrating low cytotoxicity, high transfection efficiency, and effective RNAi. PMID- 21253379 TI - Rocuronium bromide induced anaphylaxis in a child -A case report-. AB - Anaphylaxis or anaphylactoid reaction in pediatric patient during anesthesia is rare. We report a rocuronium induced anaphylactic reaction in a 33-month-old female. The patient was scheduled to undergo escharectomy due to injuries suffered from a major burn. Shortly after administration of rocuronium, the patient developed severe hypotension, tachycardia, and hypoxia. A similar reaction occurred after administration of rocuronium on subsequent anesthesia. She underwent uneventful anesthesia with volatile induction and maintenance of anesthesia with sevoflurane on her next 7 operations without using of muscle relaxant. PMID- 21253380 TI - Rupture of endotracheal tube cuff during robot-assisted endoscopic thyroidectomy A case report-. AB - We encountered a case of a rupture of an endotracheal tube cuff during robot assisted thyroid surgery in a 35-year-old male patient. Two hours after commencing surgery, the bellows of the ventilator were not filled and a rupture of the endotracheal tube cuff was suspected. Once the robot-manipulator is engaged, the position of the operating table cannot be altered without removing it from the patient. Reintubation with direct laryngoscopy was performed with difficulty in the narrow space between the patient's head and robot-manipulator without moving the robot away from the patient. The rupture of the endotracheal tube cuff was confirmed by observing air bubbles exiting from the balloon in water. The patient was discharged 3 days after surgery without complications. In robot-assisted thyroid surgery, a preoperative arrangement of the robot away from the patient's head to obtain easy access to the patient is essential for safe anesthetic care. PMID- 21253381 TI - Tension pneumothorax in a newborn after Cesarean-section delivery -A case report . AB - Tension pneumothorax in newborns is a rare but life-threatening complication. We encountered a case of a full-term neonate with a breech presentation. An elective cesarean section was scheduled. Immediately after delivery, the newborn was found to be breathless with a heart rate <60/min. During intubation and cardiac massage, the patient's femoral artery and vein were accessed. The infantogram revealed a right side tension pneumothorax. A 22 gauge needle thoracentesis relieved the right side chest pressure and a closed thoracostomy was performed. The severe acidosis was corrected with sodium bicarbonate. The patient was managed in the neonatal intensive care unit, but died from uncorrectable acidosis. We report this case with a review of the relevant literature. PMID- 21253382 TI - The use of chest band to prevent CO(2) subcutaneous emphysema expansion -Two case reports-. AB - CO(2) subcutaneous emphysema is one of the complications of laparoscopic surgery using CO(2) gas. During laparoscopic surgery, CO(2) gas can spread to the entire body surface through the subcutaneous tissue layer. Extensive CO(2) subcutaneous emphysema results in hypercarbia and acute respiratory acidosis. Hypercarbia and acidosis can lead to decreased cardiac contractility and arrhythmia. A cloth band, 5 cm in width and 120 cm in length, was made with Velcro tape at both tips, and placed on the patient's xyphoid process level and inframammary fold to prevent CO(2) subcutaneous emphysema. This report describes two successful cases using a chest band to prevent the expansion of CO(2) subcutaneous emphysema. PMID- 21253383 TI - Pneumothorax in a post-anesthetic care unit after right thyroidectomy with left neck dissection -A case report-. AB - A 46-year-old woman underwent a right thyroidectomy with left neck dissection under general anesthesia. The operation was performed successfully for over the course of 3 hours 30 minutes. After extubation, the patient was transferred to post-anesthetic care unit (PACU). After 10 minutes, dyspnea, chest discomfort, desaturation was suddenly occurred. Intubation was performed in PACU. The emergency chest X-ray revealed a right pneumothorax, and the patient was treated by chest tube insertion. The patient was improved and was discharged uneventfully from hospital 8 days later. PMID- 21253384 TI - tRNA/mRNA Mimicry by tmRNA and SmpB in Trans-Translation. AB - Since accurate translation from mRNA to protein is critical to survival, cells have developed translational quality control systems. Bacterial ribosomes stalled on truncated mRNA are rescued by a system involving tmRNA and SmpB referred to as trans-translation. Here, we review current understanding of the mechanism of trans-translation. Based on results obtained by using directed hydroxyl radical probing, we propose a new type of molecular mimicry during trans-translation. Besides such chemical approaches, biochemical and cryo-EM studies have revealed the structural and functional aspects of multiple stages of trans-translation. These intensive works provide a basis for studying the dynamics of tmRNA/SmpB in the ribosome. PMID- 21253385 TI - Gastric electrical stimulation for gastroparesis: a goal greatly pursued, but not yet attained. AB - The lack of an effective medical treatment for gastroparesis has pushed the research of new techniques of gastric electrical stimulation (GES) for nearly half a century of experimentation with a large variety of electrical stimuli delivered to the gastric wall of animals and patients with gastroparesis. Three principal methods are currently available: gastric low-frequency/high-energy GES with long pulse stimulation, high-frequency/low-energy GES with short pulse stimulation and neural sequential GES. The first method aims to reset a regular slow wave rhythm, but has variable effects on contractions and requires devices with large and heavy batteries unsuitable for implantation. High-frequency/low energy GES, although inadequate to restore a normal gastric electro-mechanical activity, improves dyspeptic symptoms, such as nausea and vomiting, giving patients a better quality of life together with a more satisfactory nutritional status and is suitable for implantation. Unfortunately, the numerous clinical studies using this type of GES, with the exception of two, were not controlled and there is a need for definitive verification of the effectiveness of this technique to justify the cost and the risks of this procedure. The last method, which is neural sequential GES, consists of a microprocessor-controlled sequential activation of a series of annular electrodes along the distal two thirds of the stomach and is able to induce propagated contractions causing forceful emptying of the gastric content. The latter method is the most promising, but has been used only in animals and needs to be tested in patients with gastroparesis before it is regarded as a solution for this disease. PMID- 21253386 TI - Quantification of HBsAg: basic virology for clinical practice. AB - Hepatitis B surface antigen (HBsAg) is produced and secreted through a complex mechanism that is still not fully understood. In clinical fields, HBsAg has long served as a qualitative diagnostic marker for hepatitis B virus infection. Notably, advances have been made in the development of quantitative HBsAg assays, which have allowed viral replication monitoring, and there is an opportunity to make maximal use of quantitative HBsAg to elucidate its role in clinical fields. Yet, it needs to be underscored that a further understanding of HBsAg, not only from clinical point of view but also from a virologic point of view, would enable us to deepen our insights, so that we could more widely expand and apply its utility. It is also important to be familiar with HBsAg variants and their clinical consequences in terms of immune escape mutants, issues resulting from overlap with corresponding mutation in the P gene, and detection problems for the HBsAg variants. In this article, we review current concepts and issues on the quantification of HBsAg titers with respect to their biologic nature, method principles, and clinically relevant topics. PMID- 21253387 TI - Genomic and genetic alterations influence the progression of gastric cancer. AB - Gastric cancer is one of the leading causes of cancer-related deaths worldwide, although the incidence has gradually decreased in many Western countries. Two main gastric cancer histotypes, intestinal and diffuse, are recognised. Although most of the described genetic alterations have been observed in both types, different genetic pathways have been hypothesized. Genetic and epigenetic events, including 1q loss of heterozygosity (LOH), microsatellite instability and hypermethylation, have mostly been reported in intestinal-type gastric carcinoma and its precursor lesions, whereas 17p LOH, mutation or loss of E-cadherin are more often implicated in the development of diffuse-type gastric cancer. In this review, we summarize the sometimes contradictory findings regarding those markers which influence the progression of gastric adenocarcinoma. PMID- 21253388 TI - Hepatocellular carcinoma xenograft supports HCV replication: a mouse model for evaluating antivirals. AB - AIM: To develop a hepatocellular carcinoma (HCC) xenograft model for studying hepatitis C virus (HCV) replication in a mice, and antiviral treatment. METHODS: We developed a stable S3-green fluorescence protein (GFP) cell line that replicated the GFP-tagged HCV sub-genomic RNA derived from a highly efficient JFH1 virus. S3-GFP replicon cell line was injected subcutaneously into gamma irradiated SCID mice. We showed that the S3-GFP replicon cell line formed human HCC xenografts in SCID mice. Cells were isolated from subcutaneous tumors and then serially passaged multiple times in SCID mice by culturing in growth medium supplemented with G-418. The mouse-adapted S3-GFP replicon cells were implanted subcutaneously and also into the liver of SCID mice via intrasplenic infusion to study the replication of HCV in the HCC xenografts. The tumor model was validated for antiviral testing after intraperitoneal injection of interferon-alpha (IFN alpha). RESULTS: A highly tumorigenic S3-GFP replicon cell line was developed that formed subcutaneous tumors within 2 wk and diffuse liver metastasis within 4 wk in SCID mice. Replication of HCV in the subcutaneous and liver tumors was confirmed by cell colony assay, detection of the viral RNA by ribonuclease protection assay and real-time quantitative reverse transcription polymerase chain reaction. High-level replication of HCV sub-genomic RNA in the tumor could be visualized by GFP expression using fluorescence microscopy. IFN-alpha cleared HCV RNA replication in the subcutaneous tumors within 2 wk and 4 wk in the liver tumor model. CONCLUSION: A non-infectious mouse model allows us to study replication of HCV in subcutaneous and metastatic liver tumors. Clearance of HCV by IFN-alpha supports use of this model to test other anti-HCV drugs. PMID- 21253389 TI - Octreotide induces caspase activation and apoptosis in human hepatoma HepG2 cells. AB - AIM: To investigate the role of octreotide on cellular proliferation and apoptosis of human hepatoma (HepG2) cells. METHODS: We studied cellular proliferation, apoptosis and the possible internal caspase-mediated apoptosis pathway involved, after treatment of HepG2 carcinoma cells with octreotide in comparison with the apoptosis caused by tumor necrosis factor-alpha (TNF-alpha). Activities of caspase-3, caspase-9, caspase-8 and caspase-2 were studied, while apoptosis was investigated through detection of DNA fragmentation and through identification of apoptotic cells with the annexin-V/propidium iodide flow cytometric method. RESULTS: After an initial increase in HepG2 cellular proliferation, a significant inhibition was observed with 10-8 mol/L octreotide, while TNF-alpha dose-dependently decreased proliferation. Early and late apoptosis was significantly increased with both substances. Octreotide significantly increased caspase-3, caspase-8 and caspase-2 activity. TNF-alpha significantly increased only caspase-2. Cellular proliferation was decreased after treatment with octreotide or TNF-alpha alone but, in contrast to TNF-alpha, octreotide decreased proliferation only at concentrations of 10-8 mol/L, while lower concentrations increased proliferation. CONCLUSION: Our findings are suggestive of caspase-mediated signaling pathways of octreotide antitumor activity in HepG2 cells, and indicate that measurements of serum octreotide levels may be important, at least in clinical trials, to verify optimal therapeutic drug concentrations. PMID- 21253390 TI - Effect of heme oxygenase-1 on renal function in rats with liver cirrhosis. AB - AIM: To investigate the role of heme oxygenase-1 (HO-1) in pathogenesis of experimental hepatorenal syndrome (HRS). METHODS: Rats were divided into liver cirrhotic group, zinc protoporphyrin IX (ZnPP) treatment group, cobalt protoporphyrin (CoPP) treatment group and sham group. Biliary cirrhosis was established by bile duct ligation in the first three groups. Rats in the ZnPP and CoPP treatment groups received intraperitoneal injection of ZnPP and CoPP, respectively, 24 h before sample collection. Expression of HO-1 mRNA in kidney was detected by reverse-transcription polymerase chain reaction, while protein expression was determined by immunohistochemical analysis. Hematoxylin and eosin staining was performed to observe liver cirrhosis and renal structure. Renal artery blood flow, mean arterial pressure and portal vein pressure, 24 h total urinary volume, serum and urine sodium concentrations, and creatinine clearance rate (Ccr) were also measured. RESULTS: The HO-1 mRNA and protein expression levels in kidney, 24 h total urinary volume, renal artery blood flow, serum and urine sodium concentration and Ccr were lower in cirrhotic group than in sham group (P < 0.05). However, they were significantly lower in ZnPP treatment group than in cirrhotic group and significantly higher in CoPP treatment group than in cirrhotic group (P < 0.05). CONCLUSION: Low HO-1 expression level in kidney is an important factor for experimental HRS. PMID- 21253391 TI - Low red blood cell levels of deglycating enzymes in colorectal cancer patients. AB - AIM: To investigate Glyoxalase I and fructosamine-3-kinase (FN3K) activity in red blood cells from patients with colorectal adenomas and cancer. METHODS: Thirty three consecutive subjects with one or more histologically confirmed colorectal adenomatous polyps, 16 colorectal cancer patients and a group of 11 control subjects with normal colonoscopy were included in the study. Glyoxalase I and FN3K activities were measured in red blood cells using a spectrophotometric and radiometric assay, respectively. RESULTS: A significant reduction in both Glyoxalase I and FN3K activity was detected in patients with tumors compared to patients with adenomas and the controls. Erythrocyte Glyoxalase I activity in colorectal cancer was approximately 6 times lower than that detected in patients with adenoma (0.022 +/- 0.01 mmol/min per milliliter vs 0.128 +/- 0.19 mmol/min per milliliter of red blood cells, P = 0.003, Tukey's test). FN3K activity in red blood cells from patients with colon cancer was approximately 2 times lower than that detected in adenoma patients (19.55 +/- 6.4 pmol/min per milliliter vs 38.6 +/- 31.7 pmol/min per milliliter of red blood cells, P = 0.04, Tukey's test). CONCLUSION: These findings suggest that deglycating enzymes may be involved in the malignant transformation of colon mucosa. PMID- 21253392 TI - Bones and Crohn's: no benefit of adding sodium fluoride or ibandronate to calcium and vitamin D. AB - AIM: To compare the effect of calcium and cholecalciferol alone and along with additional sodium fluoride or ibandronate on bone mineral density (BMD) and fractures in patients with Crohn's disease (CD). METHODS: Patients (n =148) with reduced BMD (T-score < -1) were randomized to receive cholecalciferol (1000 IU) and calcium citrate (800 mg) daily alone(group A, n = 32) or along with additional sodium fluoride (25 mg bid) (group B, n = 62) or additional ibandronate (1 mg iv/3-monthly) (group C, n = 54). Dual energy X-ray absorptiometry of the lumbar spine (L1-L4) and proximal right femur and X-rays of the spine were performed at baseline and after 1.0, 2.25 and 3.5 years. Fracture assessment included visual reading of X-rays and quantitative morphometry of vertebral bodies (T4-L4). RESULTS: One hundred and twenty three (83.1%) patients completed the first year for intention-to-treat (ITT) analysis. Ninety two (62.2%) patients completed the second year and 71 (47.8%) the third year available for per-protocol (PP) analysis. With a significant increase in T-score of the lumbar spine by +0.28 +/- 0.35 [95% confidence interval (CI): 0.162-0.460, P < 0.01], +0.33 +/- 0.49 (95% CI: 0.109-0.558, P < 0.01), +0.43 +/- 0.47 (95% CI: 0.147-0.708, P < 0.01) in group A, +0.22 +/- 0.33 (95% CI: 0.125-0.321, P < 0.01); +0.47 +/- 0.60 (95% CI: 0.262-0.676, P < 0.01), +0.51 +/- 0.44 (95% CI: 0.338-0.682, P < 0.01) in group B and +0.22 +/- 0.38 (95% CI: 0.111-0.329, P < 0.01), +0.36 +/- 0.53 (95% CI: 0.147-0.578, P < 0.01), +0.41 +/- 0.48 (95% CI: 0.238-0.576, P < 0.01) in group C, respectively, during the 1.0, 2.25 and 3.5 year periods (PP analysis), no treatment regimen was superior in any in- or between-group analyses. In the ITT analysis, similar results in all in- and between-group analyses with a significant in-group but non-significant between group increase in T-score of the lumbar spine by 0.38 +/- 0.46 (group A, P < 0.01), 0.37 +/- 0.50 (group B, P < 0.01) and 0.35 +/- 0.49 (group C, P < 0.01) was observed. Follow-up in ITT analysis was still 2.65 years. One vertebral fracture in the sodium fluoride group was detected. Study medication was safe and well tolerated. CONCLUSION: Additional sodium fluoride or ibandronate had no benefit over calcium and cholecalciferol alone in managing reduced BMD in CD. PMID- 21253393 TI - T-regulatory lymphocytes in peripheral blood of gastric and colorectal cancer patients. AB - AIM: To assess the absolute number of T-regulatory cells (Tregs; CD4+CD25+Foxp3+) in the peripheral blood of gastric and colorectal cancer patients. METHODS: We enrolled 70 cancer patients (33 gastric cancer, 37 colorectal cancer) and 17 healthy volunteers. The CD3+CD4+ lymphocytes and CD4+CD25+Foxp3+ Tregs in the peripheral blood were analyzed with flow cytometry. The absolute numbers of Tregs were calculated based on the CD4+CD25+Foxp3+ cells percentage of CD3+CD4+ cells and the absolute numbers of CD3+CD4+ cells per microliter. RESULTS: The mean number of CD4+CD25+Foxp3+ cells per microliter in colorectal cancer patients was 15.7 (SD: 21.8), for gastric cancer patients 12.2 (SD: 14.3), and for controls 17.5 (SD: 11.4). The absolute number of Tregs was significantly lower in gastric cancer patients than in controls (P = 0.026). There was no statistically significant difference for gastric vs colorectal cancer or colorectal cancer vs controls. The absolute number of Tregs was also significantly depressed in N+ vs N- cancer patients [22.0 (27.7) vs 10.1 (9.0), P = 0.013], and in the subgroup of gastric cancer patients [30.3 (27.6) vs 9.6 (8.0), P = 0.003]. No statistical difference was observed in the proportion of Tregs in the CD4+ population between the groups. CONCLUSION: The absolute number of Tregs in peripheral blood of gastric cancer but not colorectal cancer patients was significantly decreased in comparison with that in healthy controls. PMID- 21253394 TI - Detection of Helicobacter pylori: A faster urease test can save resources. AB - AIM: To investigate whether differences in the rapidity of a positive result for Helicobacter pylori can save resources, by comparing two commercially available urease kits. METHODS: One hundred and eighty-five adults (130 outpatients, 55 inpatients) undergoing gastroscopy were entered prospectively. Patients were divided into two groups: Group 1 (if they were not on PPIs, antibiotics, H2A, bismuth or sucralfate for up to 14 d prior to the endoscopy) and Group 2 (if they were on, or had been on, any of the above medication in the previous 14 d). At endoscopy two sets of biopsies, taken in random order, were placed in the wells of the Campylobacter-like organism (CLO) test (Kimberly-Clark, Utah, USA) and the Quick test (Biohit Plc, Helsinki, Finland). Five additional gastric biopsies were taken for histology/Giemsa and immunohistochemical study. The two urease test slides were read at 2 min, 30 min, 2 h and 24 h. Sensitivity and specificity at 24 h were determined. RESULTS: At 24 h, for all patients, there was no difference in sensitivity (100% vs 97.5%), specificity (99.3%), positive (97.5%) and negative predictive values (100% vs 99.3%) between the CLO and Quick tests, respectively. There was a positive result at 30 min in 17/41 (41.5%) CLO tests, and in 28/40 (70%) Quick tests, P = 0.05. Quick test enabled the prescription of eradication therapy before discharge in all 28/40 patients. Only 12 (30%) follow up appointments were needed. If the CLO test had been used alone, only 17 (41.5%) prescriptions would have been possible prior to discharge and 24 (58%) follow-up appointments would be needed (P = 0.001). Of 2000 gastroscopies performed annually at our unit, a saving of 123 follow-up appointments (total: 8856 Euros or 11 808 USD) would be achieved if we switched to the Quick test. CONCLUSION: Direct comparison of locally available urease test kits is worthwhile, since the appropriate choice results in a significant saving of resources. Local costs and follow-up protocols will determine the magnitude of these savings. PMID- 21253396 TI - Intrahepatic biliary cystic neoplasms: Surgical results of 9 patients and literature review. AB - AIM: To investigate the eligible management of the cystic neoplasms of the liver. METHODS: The charts of 9 patients who underwent surgery for intrahepatic biliary cystic liver neoplasms between 2003 and 2008 were reviewed retrospectively. Informed consent was obtained from the patients and approval was obtained from the designated review board of the institution. RESULTS: All patients were female with a median (range) age of 49 (27-60 years). The most frequent symptom was abdominal pain in 6 of the patients. Four patients had undergone previous laparotomy (with other diagnoses) which resulted in incomplete surgery or recurrences. Liver resection (n = 6) or enucleation (n = 3) was performed. The final diagnosis was intrahepatic biliary cystadenoma in 8 patients and cystadenocarcinoma in 1 patient. All symptoms resolved after surgery. There has been no recurrence during a median (range) 31 (7-72) mo of follow up. CONCLUSION: In spite of the improvement in imaging modalities and increasing recognition of biliary cystadenoma and cystadenocarcinoma, accurate preoperative diagnosis may be difficult. Complete surgical removal (liver resection or enucleation) of these lesions yields satisfying long-term results. PMID- 21253395 TI - Dietary zinc and metallothionein on small intestinal disaccharidases activity in mice. AB - AIM: To examine the effect of increasing dietary zinc (Zn) intake and the lack of metallothionein (MT) expression on activity of small intestinal disaccharidases. METHODS: MT-I and II knockout (MT-/-) and wild-type (MT+/+) female mice at 3.5 wk of age were randomly fed with a diet containing 2 (2 Zn), 15 (15 Zn) or 50 (50 Zn) mg Zn/kg (n = 8/group/genotype) for 5 wk. Small intestinal segments (duodenum, jejunum and ileum) were collected and either fixed in 10% formalin for histological analysis or snap frozen in liquid nitrogen for sucrase, lactase and maltase activity analyses. RESULTS: Plasma Zn was significantly (P < 0.05) lower (33%) in MT-/- compared with MT+/+ mice fed the 2 Zn diet. Villus height and crypt depth were increased by approximately 15% in MT+/+ mice compared with MT-/- mice. Duodenal disaccharidase activities were significantly higher in MT+/+ compared with MT-/- mice particularly in those fed the 2 Zn diet. For the 50 Zn diet, jejunal sucrase and lactase activities were significantly higher in MT-/- (13 313 +/- 2314; 4107 +/- 364 MUmol glucose/well/min/g tissue, respectively) compared with MT+/+ mice (7054 +/- 608; 1818 +/- 174). Similarly, ileal lactase activities were higher in MT-/- (1480 +/- 192) compared with MT+/+ (629 +/- 353) mice particularly those fed the 2 Zn diet. CONCLUSION: Increasing dietary Zn has little effect on disaccharidases activity in MT wild-type mice. The presence of MT may enhance morphological and functional development of the gut. PMID- 21253397 TI - Analysis of the delayed approach to the management of infected pancreatic necrosis. AB - AIM: To analyze outcomes of delayed single-stage necrosectomy after early conservative management of patients with infected pancreatic necrosis (IPN) associated with severe acute pancreatitis (SAP). METHODS: Between January 1998 and December 2009, data from patients with SAP who developed IPN and were managed by pancreatic necrosectomy were analyzed. RESULTS: Fifty-nine of 61 pancreatic necrosectomies were performed by open surgery and 2 laparoscopically. In 55 patients, single-stage necrosectomy could be performed (90.2%). Patients underwent surgery at a median of 29 d (range 13-46 d) after diagnosis of acute pancreatitis. Sepsis and multiple organ failure accounted for the 9.8% mortality rate. Pancreatic fistulae (50.8%) predominantly accounted for the morbidity. The median hospital stay was 23 d, and the median interval for return to regular activities was 110 d. CONCLUSION: This series supports the concept of delayed single-stage open pancreatic necrosectomy for IPN. Advances in critical care, antibiotics and interventional radiology have played complementary role in improving the outcomes. PMID- 21253398 TI - Liver function alterations after laparoscopy-assisted gastrectomy for gastric cancer and its clinical significance. AB - AIM: To evaluate the factors associated with liver function alterations after laparoscopy-assisted gastrectomy (LAG) for gastric cancer. METHODS: We collected the data of gastrectomy patients with gastric cancer and divided them into 2 groups: open gastrectomy (OG) and LAG. We also collected the data of patients with colon cancer to evaluate the effect of liver manipulations during surgery on liver function alterations. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, and alkaline phosphatase were measured on the preoperative day and postoperative day 1 (POD1), POD3, POD5, and POD7. RESULTS: No changes in liver function were observed after the operation in patients with colon cancer (n = 121). However, in gastric cancer patients (n = 215), AST and ALT levels increased until POD5 compared to those in colon cancer patients and these findings were observed both in the LAG and OG without a significant difference except at POD1. The mean hepatic enzyme levels at POD1 in the LAG group were significantly higher than those in the OG group (P = 0.047 for AST and P = 0.039 for ALT). The factors associated with elevated ALT on POD1 in patients with gastric cancer were body mass index (P < 0.001), operation time (P < 0.001), intraoperative hepatic injury (P = 0.048), and ligation of an aberrant left hepatic artery (P = 0.052) but not type of operation (OG vs LAG, P = 0.094). CONCLUSION: We conclude that the liver function alteration after LAG may have been caused by direct liver manipulation or aberrant hepatic artery ligation rather than the CO2 pneumoperitoneum. PMID- 21253399 TI - Necrotic stercoral colitis: importance of computed tomography findings. AB - AIM: To study the computed tomography (CT) signs in facilitating early diagnosis of necrotic stercoral colitis (NSC). METHODS: Ten patients with surgically and pathologically confirmed NSC were recruited from the Clinico-Pathologic Radiologic conference at Chang Gung Memorial Hospital, Taoyuan, Taiwan. Their CT images and medical records were reviewed retrospectively to correlate CT findings with clinical presentation. RESULTS: All these ten elderly patients with a mean age of 77.1 years presented with acute abdomen at our Emergency Room. Nine of them were with systemic medical disease and 8 with chronic constipation. Seven were with leukocytosis, two with low-grade fever, two with peritoneal sign, and three with hypotensive shock. Only one patient was with radiographic detected abnormal gas. Except the crux of fecal impaction, the frequency of the CT signs of NSC were, proximal colon dilatation (20%), colon wall thickening (60%), dense mucosa (62.5%), mucosal sloughing (10%), perfusion defect (70%), pericolonic stranding (80%), abnormal gas (50%) with pneumo-mesocolon (40%) in them, pericolonic abscess (20%). The most sensitive signs in decreasing order were pericolonic stranding, perfusion defect, dense mucosal, detecting about 80%, 70%, and 62.5% of the cases, respectively. CONCLUSION: Awareness of NSC and familiarity with the CT diagnostic signs enable the differential diagnosis between NSC and benign stool impaction. PMID- 21253400 TI - Management of patients with sphincter of Oddi dysfunction based on a new classification. AB - AIM: To propose a new classification system for sphincter of Oddi dysfunction (SOD) based on clinical data of patients. METHODS: The clinical data of 305 SOD patients documented over the past decade at our center were analyzed retrospectively, and typical cases were reported. RESULTS: The new classification with two more types (double-duct, biliary-pancreatic reflux) were set up on the basis of the Milwaukee criteria. There were 229 cases of biliary-type SOD, including 192 (83.8%) cases cured endoscopically, and 29 (12.7%) cured by open abdominal surgery, and the remaining 8 (3.5%) cases observed with unstable outcomes. Eight (50%) patients with pancreatic-type SOD were cured by endoscopic treatment, and the remaining 8 patients were cured after open abdominal surgery. There were 19 cases of double-duct-type SOD, which consisted of 7 (36.8%) patients who were cured endoscopically and 12 (63.2%) who were cured surgically. A total of 41 cases were diagnosed as biliary-pancreatic-reflux-type SOD. Twenty (48.8%) of them were treated endoscopically, 16 (39.0%) were treated by open abdominal surgery, and 5 (12.2%) were under observation. CONCLUSION: The newly proposed SOD classification system introduced in this study better explains the clinical symptoms of SOD from the anatomical perspective and can guide clinical treatment of this disease. PMID- 21253401 TI - Effect of preoperative biliary drainage on malignant obstructive jaundice: a meta analysis. AB - AIM: To evaluate the effect of preoperative biliary drainage (PBD) on obstructive jaundice resulting from malignant tumors. METHODS: According to the requirements of Cochrane systematic review, studies in the English language were retrieved from MEDLINE and Embase databases from 1995 to 2009 with the key word "preoperative biliary drainage". Two reviewers independently screened the eligible studies, evaluated their academic level and extracted the data from the eligible studies confirmed by cross-checking. Data about patients with and without PBD after resection of malignant tumors were processed for meta-analysis using the Stata 9.2 software, including postoperative mortality, incidence of postoperative pancreatic and bile leakage, abdominal abscess, delayed gastric emptying and incision infection. RESULTS: Fourteen retrospective cohort studies involving 1826 patients with malignant obstructive jaundice accorded with our inclusion criteria, and were included in meta-analysis. Their baseline characteristics were comparable in all the studies. No significant difference was found in combined risk ratio (RR) of postoperative mortality and incidence of pancreatic and bile leakage, abdominal abscess, delayed gastric emptying between patients with and without PBD. However, the combined RR for the incidence of postoperative incision infection was improved better in patients with PBD than in those without PBD (P < 0.05). CONCLUSION: PBD cannot significantly reduce the postoperative mortality and complications of malignant obstructive jaundice, and therefore should not be used as a preoperative routine procedure for malignant obstructive jaundice. PMID- 21253402 TI - Adjuvant radiotherapy for gallbladder cancer: a dosimetric comparison of conformal radiotherapy and intensity-modulated radiotherapy. AB - AIM: To assess the efficacy and toxicity of conformal radiotherapy (CRT) and compare with intensity-modulated radiotherapy (IMRT) in the treatment of gallbladder cancer. METHODS: Between November 2003 and January 2010, 20 patients with gallbladder cancer were treated with CRT with or without chemotherapy after surgical resection. Preliminary survival data were collected and examined using both Kaplan-Meier and actuarial analysis. Demographic and treatment parameters were collected. All patients were planned to receive 46-56 Gy in 1.8 or 2.0 Gy per fraction. CRT planning was compared with IMRT. RESULTS: The most common reported acute toxicities requiring medication (Radiation Therapy Oncology Group, Radiation Therapy Oncology Group Grade 2) were nausea (10/20 patients) and diarrhea (3/20). There were no treatment-related deaths. Compared with CRT planning, IMRT significantly reduced the volume of right kidney receiving > 20 Gy and the volume of liver receiving > 30 Gy. IMRT has a negligible impact on the volume of left kidney receiving > 20 Gy. The 95% of prescribed dose for a planning tumor volume using either 3D CRT or IMRT planning were 84.0% +/- 6.7%, 82.9% +/- 6.1%, respectively (P > 0.05). CONCLUSION: IMRT achieves similar excellent target coverage as compared with CRT planning, while reducing the mean liver dose and volume above threshold dose. IMRT offers better sparing of the right kidney compared with CRT planning, with a significantly lower mean dose and volume above threshold dose. PMID- 21253403 TI - Hepatic veins as a site of clot formation following liver resection. AB - Pulmonary embolism occurs more frequently after hepatectomy than previously thought but is infrequently associated with peripheral deep vein thrombosis. In this paper, we report 2 cases of postoperative hepatic vein thrombosis after liver resection. Both patients had undergone major hepatectomy of a non-cirrhotic liver largely exposing the middle hepatic vein. Clots were incidentally found in the middle hepatic vein 4 and 17 d after surgery despite routine systemic thrombo prophylaxis with low molecular weight heparin. Coagulation of the transition plan in a context of mutation of the prothrombin gene and inflammation induced biloma were the likely predisposing conditions. Clots disappeared following curative anticoagulation. We conclude that thrombosis of hepatic veins may occur after liver resection and is a potential source of pulmonary embolism. PMID- 21253404 TI - Comments on the article about correlation between computerized tomography and surgery in acute pancreatitis. AB - We read with great interest the article by Vege et al published in issue 34 of World J Gastroenterol 2010. The article evaluates the ability of contrast enhanced computerized tomography (CECT) to characterize the nature of peripancreatic collections found at surgery. The results of their study indicate that most of the peripancreatic collections seen on CECT in patients with severe acute pancreatitis who require operative intervention contain necrotic tissue and CECT has a limited role in differentiating various types of collections. However, there are some points that need to be addressed, including data about the stage of acute pancreatitis in which CECT was done and the time span between CECT examination and surgery. PMID- 21253405 TI - The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. AB - Neurotrophic factors are critical regulators of the formation and plasticity of neuronal networks. Brain-derived neurotrophic factor (BDNF) is abundant in the brain and periphery, and is found in both human serum and plasma. Animal studies have demonstrated that stress reduces BDNF expression or activity in the hippocampus and that this reduction can be prevented by treatment with antidepressant drugs. A similar change in BDNF activity occurs in the brain of patients with major depression disorder (MDD). Recently, clinical studies have indicated that serum or plasma BDNF levels are decreased in untreated MDD patients. Antidepressant treatment for at least four weeks can restore the decreased BDNF function up to the normal value. Therefore, MDD is associated with impaired neuronal plasticity. Suicidal behavior can be a consequence of severe impaired neuronal plasticity in the brain. Antidepressant treatment promotes increased BDNF activity as well as several forms of neuronal plasticity, including neurogenesis, synaptogenesis and neuronal maturation. BDNF could also play an important role in the modulation of neuronal networks. Such a neuronal plastic change can positively influence mood or recover depressed mood. These alterations of BDNF levels or neuronal plasticity in MDD patients before and after antidepressant treatment can be measured through the examination of serum or plasma BDNF concentrations. BDNF levels can therefore be useful markers for clinical response or improvement of depressive symptoms, but they are not diagnostic markers of major depression. PMID- 21253406 TI - Effects of BDNF polymorphisms on antidepressant action. AB - Evidence suggests that the down-regulation of the signaling pathway involving brain-derived neurotrophic factor (BDNF), a molecular element known to regulate neuronal plasticity and survival, plays an important role in the pathogenesis of major depression. The restoration of BDNF activity induced by antidepressant treatment has been implicated in the antidepressant therapeutic mechanism. Because there is variability among patients with major depressive disorder in terms of response to antidepressant treatment and since genetic factors may contribute to this inter-individual variability in antidepressant response, pharmacogenetic studies have tested the associations between genetic polymorphisms in candidate genes related to antidepressant therapeutic action. In human BDNF gene, there is a common functional polymorphism (Val66Met) in the pro region of BDNF, which affects the intracellular trafficking of proBDNF. Because of the potentially important role of BDNF in the antidepressant mechanism, many pharmacogenetic studies have tested the association between this polymorphism and the antidepressant therapeutic response, but they have produced inconsistent results. A recent meta-analysis of eight studies, which included data from 1,115 subjects, suggested that the Val/Met carriers have increased antidepressant response in comparison to Val/Val homozygotes, particularly in the Asian population. The positive molecular heterosis effect (subjects heterozygous for a specific genetic polymorphism show a significantly greater effect) is compatible with animal studies showing that, although BDNF exerts an antidepressant effect, too much BDNF may have a detrimental effect on mood. Several recommendations are proposed for future antidepressant pharmacogenetic studies of BDNF, including the consideration of multiple polymorphisms and a haplotype approach, gene-gene interaction, a single antidepressant regimen, controlling for age and gender interactions, and pharmacogenetic effects on specific depressive symptom clusters. PMID- 21253407 TI - The role of BDNF as a mediator of neuroplasticity in bipolar disorder. AB - The cognitive impairment and neuroanatomical changes that takes place among patients with bipolar disorder (BD) patients has been well described. Recent data suggest that changes in neuroplasticity, cell resilience and connectivity are the main neuropathological findings in BD. Data from differential lines of research converges to the brain-derived neurotrophic factor (BDNF) as an important contributor to the neuroplasticity changes described among BD patients. BDNF serum levels have been shown to be decreased in depressive and manic episodes, returning to normal levels in euthymia. BDNF has also been shown to decrease as the disorder progresses. Moreover, factors that negatively influence the course of BD, such as life stress and trauma have been shown to be associated with a decrease in BDNF serum levels. These findings suggest that BDNF plays a central role in the progression of BD. The present review discusses the role of BDNF as a mediator of the neuroplastic changes that occur in portion with mood episodes and the potential use of serum BDNF as a biomarker in BD. PMID- 21253408 TI - Epigenetic regulation of BDNF gene in response to stress. AB - Neuronal plasticity induced by changes in synaptic morphology and function is well known to play a pivotal role in leaning and memory as well as adaptation to stress. It is suggested that these plastic changes are due to orchestration of alterations in gene expression in the brain. Recent advances in molecular biology have provided evidence that epigenetic mechanisms, such as DNA methylation and histone modification, are crucial to gene transcription in the mammalian brain. Our research group has recently investigated the involvement of histone actylation at the promoter of the brain-derived neurotrophic factor (BDNF) gene in stress-induced reduction in BDNF, as well as in fear conditioning-induced enhancement of BDNF, in the rat hippocampus. The results of the stress study demonstrated that single-immobilization stress significantly reduced the levels of total, exon I, and exon IV BDNF mRNA, and also significantly reduced acetylation levels of histone H3, but not H4, at the promoter of exons I, IV, and VI. The results of the fear conditioning study showed that footshock stress significantly increased the levels of total, exon I, and exon IV BDNF mRNA, with significantly increased acetylation levels of both histone H3 and H4, at the promoter of exons I and IV, followed by enhanced freezing to fear-context exposure. These findings suggest that changes in BDNF transcription in the rat hippocampus in response to stressful stimuli are, at least in part, regulated by histone acetylation status. PMID- 21253409 TI - The reliability and validity of the korean version of the structured interview for prodromal syndrome. AB - OBJECTIVE: The Structured Interview for Prodromal Syndrome (SIPS) from Yale University is intended to diagnose prodromal syndrome of psychosis and to measure the severity of prodromal symptoms. Here, a Korean version of SIPS is presented, and its reliability, validity, and factor structures are examined using a representative Korean sample. METHODS: The Korean version of SIPS was administered to 40 participants over a period of 1 year. The inter-rater reliability and internal consistency of the SIPS were then evaluated. In addition, its factor structure was investigated using principal-axis factor analysis. Concurrent validity was explored using Pearson correlation coefficients with the Positive and Negative Syndrome Scale (PANSS). RESULTS: Of the 40 subjects, 12.5% developed psychotic disorders during the 1-year follow-up period. Inter-rater reliability was good (intra-class correlations=0.96), and internal consistency was acceptable (Cronbach's alpha=0.83). A three-factor resolution displayed the best simple structure and accounted for 52.6% of all item variance. Factors 1 and 2 showed strong correlations with negative symptoms and cognitive dysfunction, respectively, on the PANSS. Factor 3 was not correlated with any factor on the PANSS. CONCLUSION: The Korean version of SIPS is a reliable instrument for the assessment of prodromal symptoms in subjects and may be used to evaluate prodromal psychosis. PMID- 21253410 TI - Thyroid stimulating hormone, cognitive impairment and depression in an older korean population. AB - OBJECTIVE: Associations of thyroid dysfunction with cognitive impairment and depression in late-life have been described but remain controversial. This study aimed to investigate the associations of serum thyroid stimulating hormone (TSH) levels with cognitive impairment and depression after controlling for potential confounding factors. METHODS: The sample consisted of 495 community residents aged 65 or over in whom serum TSH had been assayed. Cognitive impairment was defined using the Community Screening Interview for Dementia, and depression was diagnosed using the Geriatric Mental State schedule. Age, gender, education, smoking history, physical activity, blood pressure, diabetes, and serum total cholesterol and albumin were included as covariates. RESULTS: There was a significant association between lower (hyperthyroid) serum TSH levels (<0.5 mIU/L) and cognitive impairment after adjustment [odds ratio 7.12 (95% confidence interval 1.35-37.5)]. However, no association was found between TSH levels and depression. CONCLUSION: Based on TSH levels, hyperthyroidism but not hypothyroidism was associated with cognitive impairment in this sample, and we found no evidence for an association of either with depression. PMID- 21253411 TI - The genetic factors affecting drinking behaviors of korean young adults with variant aldehyde dehydrogenase 2 genotype. AB - OBJECTIVE: We determined whether aldehyde dehydrogenase 2 (ALDH2) activity alters the way in which drinking behaviors are affected by gene polymorphisms of other alcohol-metabolizing enzymes and serotonin-related proteins. METHODS: Through a follow-up survey with a cohort comprising 551 university freshmen over a period of 6 years, we examined the genetic factors affecting drinking behaviors. In 2000, drinking behaviors were assessed and tryptophan hydroxylase (TPH) and ALDH2 gene polymorphisms were determined. Drinking behaviors were repeated in 2006 (n=150), and the gene polymorphisms of ADH1B, ADH1C, CYP2E1, 5-HTR2A 1438A/G, and 5-HTR2A IVS2 were also determined. RESULTS: In 2000, the variant and wild-type ALDH2 groups exhibited little difference in terms of drinking frequency and problem drinking. Furthermore, some genotypes influenced only the variant group: ADH1B*2/*2 was associated with a lower drinking frequency, and CYP2E1 c2 allele was associated with an increased risk of problem drinking. In 2006, drinking frequency and risk of problem drinking were significantly lower in the variant group than in the wild-type group. However, the TPH AA genotype disturbed that difference, meaning that the subjects in the variant group had developed a similar level of risk of problem drinking to that in the wild-type group. CONCLUSION: Korean university freshmen who were identified as a variant group drank as frequently as those in the wild-type group. For the subsequent 6 years they drank less frequently, thus decreasing the risk of problem drinking. However, that frequency drop was interrupted in those with gene polymorphisms such as ADH1B*1, CYP2E1 c2, and TPH A. PMID- 21253412 TI - Bone density in chronic schizophrenia with long-term antipsychotic treatment: preliminary study. AB - OBJECTIVE: Decreased bone mineral density has been found in the chronic schizophrenic patients who have been given a long-term administration of antipsychotics. Hyperprolactinemia from the antipsychotics and the negative symptom of schizophrenia were considered as the causes for this finding. In this study, the effect of hyperprolactinemia and the negative symptom of schizophrenia on bone mineral density was investigated on male schizophrenic patients. METHODS: The cross-sectional study was carried out with the subjects of 45 male schizophrenic patients who have undertaken the monotherapy with risperidone, olanzapine and clozapine for at least one year. The demographic factors, clinical symtoms, bone mineral density and hematological test were examined for all the subjects. RESULTS: No significant relationship was found between hyperprolactinemia and the decreased bone mineral density in the subjects. The negative schizophrenia symptom of the subjects showed a significant effect on the decreased bone mineral density. CONCLUSION: The decreased bone mineral density finding in the male schizophrenic patients may be caused by the negative schizophrenia symptom rather than the hyperprolactinemia due to the antipsychotics. Additional studies are further required regarding other factors that may affect the decreased bone mineral density such as activity, calcium intake and exposure to sunlight. PMID- 21253413 TI - Gender-specific association of the brain-derived neurotrophic factor gene with attention-deficit/hyperactivity disorder. AB - OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder with a strong genetic component. Brain-derived neurotrophic factor (BDNF), which participates in the differentiation and survival of dopaminergic and noradrenergic neurons, could play a role in ADHD development. We aimed to explore the relationships between ADHD and BDNF gene polymorphism. METHODS: We conducted a case-control analysis of 202 ADHD subjects and 159 controls, performed a transmission disequilibrium test on 151 trios, and compared the results of a continuous performance test (CPT) according to the genotype of the three single nucleotide polymorphisms (rs11030101, rs6265, rs16917204) in the BDNF gene. RESULTS: In the case-control analysis, the AA genotype of the BDNF rs11030101 polymorphism was significantly associated with ADHD only in girls (p=0.024, odds ratio=3.00). The T-G-G haplotype was significantly less frequent (p=0.005) and A-G-G was more frequent (p=0.048) in girls with ADHD than in control girls (global p=0.027). A multivariate analysis of variance for commission errors on the CPT showed a significant main effect for the rs11030101 genotype (p=0.026) and an interaction effect of the rs11030101 genotype and gender (p=0.032) in ADHD probands. CONCLUSION: These results provide preliminary evidence for a gender-specific association between BDNF and ADHD in the Korean population. PMID- 21253414 TI - Deficits in facial emotion recognition in schizophrenia: a replication study with korean subjects. AB - OBJECTIVE: We investigated the deficit in the recognition of facial emotions in a sample of medicated, stable Korean patients with schizophrenia using Korean facial emotion pictures and examined whether the possible impairments would corroborate previous findings. METHODS: Fifty-five patients with schizophrenia and 62 healthy control subjects completed the Facial Affect Identification Test with a new set of 44 colored photographs of Korean faces including the six universal emotions as well as neutral faces. RESULTS: Korean patients with schizophrenia showed impairments in the recognition of sad, fearful, and angry faces [F(1,114)=6.26, p=0.014; F(1,114)=6.18, p=0.014; F(1,114)=9.28, p=0.003, respectively], but their accuracy was no different from that of controls in the recognition of happy emotions. Higher total and three subscale scores of the Positive and Negative Syndrome Scale (PANSS) correlated with worse performance on both angry and neutral faces. Correct responses on happy stimuli were negatively correlated with negative symptom scores of the PANSS. Patients with schizophrenia also exhibited different patterns of misidentification relative to normal controls. CONCLUSION: These findings were consistent with previous studies carried out with different ethnic groups, suggesting cross-cultural similarities in facial recognition impairment in schizophrenia. PMID- 21253415 TI - Impaired Set-Shifting Ability in Patients with Eating Disorders, Which Is Not Moderated by Their Catechol-O-Methyltransferase Val158Met Genotype. AB - The aim of this study was to examine the set-shifting ability in women with both anorexia nervosa (AN) and bulimia nervosa (BN) and to investigate whether it is contributed by the catechol-O-methyltransferase (COMT) Val158Met genotype. A total of 102 Korean participants-40 women with lifetime AN, 28 women with lifetime BN, and 34 healthy women of comparable age and intelligence quotient- were examined. A neuropsychological battery of tests was applied and blood samples were obtained for COMT Val158Met genotyping. Set-shifting impairments Trail Making Test (TMT, Part B) were found in patients with AN and BN, respectively. Furthermore, the eating disorders were also linked to deficits in attentional mechanisms (TMT, Part A) and motor skills (Finger Tapping Test). Finally, set-shifting and its link to eating disorders were not moderated by COMT Val158Met genotype. PMID- 21253416 TI - Oseltamivir (tamiflu) induced depressive episode in a female adolescent. AB - Oseltamivir was developed for prophylactic and therapeutic use against influenza, specifically targeting the viral enzyme's highly-conserved active site. In recent years, there have been case reports of neuropsychiatric events during or after oseltamivir treatment, in Japan and other countries. However, a search of the literature revealed no such cases in South Korea. We present the case of a 15 year-old female adolescent diagnosed with depressive episode after taking oseltamivir. Oseltamivir is generally well tolerated. Its most frequent adverse effects include nausea and vomiting, diarrhea, and abdominal pain. In influenza patients taking oseltamivir, neuropsychiatric adverse events include delirium, behavioral disturbance, suicide, delusion, panic attack, convulsion, depressed mood, loss of consciousness, etc. Reportedly, such neuropsychiatric adverse events were more common in children than in adults and generally occurred within 48 hours of administration. Here, we report a retrospective review case of an oseltamivir-related neuropsychiatric event in a female adolescent in South Korea. PMID- 21253417 TI - Manic episode associated with mega cisterna magna. AB - Mega cisterna magna is a part of "Dandy-Walker Complex" and it is characterized by the enlargement of the cisterna magna, morphologically intact vermis and cerebellar hemispheres. We report a case of manic attack in a 23-year-old man with mega cisterna magna. The patient was treated with quetiapine 1,000 mg/day and sodium valproate 1,500 mg/day and the symptoms were ameliorated within 2.5 months. In this case, mega cisterna magna and manic symptoms may be found together coincidentally or any cerebellar dysfunction due to mega cisterna magna may cause or contribute to the appearance of affective symptoms. To our knowledge, this is the first case reporting manic attack with psychotic symptoms associated with mega cisterna magna. This report suggests that any lesion in the cerebellum might contribute to the occurrences of some affective and psychotic symptoms seen in bipolar disorder. PMID- 21253418 TI - Assessment of thrombin-activatable fibrinolysis inhibitor (TAFI) activation in acquired hemostatic dysfunction: a diagnostic challenge. PMID- 21253419 TI - What do patients want from the National Health Insurance? PMID- 21253421 TI - Auer rod-like crystal inclusions in plasma cells of multiple myeloma. PMID- 21253420 TI - Mesenchymal stromal cells: new insight on their identity and potential role in cell therapy. PMID- 21253422 TI - Plasmablastic plasma cell myeloma mimicking plasmablastic lymphoma. PMID- 21253423 TI - The immunobiology of cord blood transplantation. AB - Despite significant recent advances in the applicability and outcome following unrelated cord blood transplantation (UCBT), infections remain a major cause of mortality associated with poor immune recovery in the first 6 months after UCBT. Enhanced immune reconstitution not only could improve survival by reduced transplant related mortality, but may also favorably impact on relapse incidence by improved graft-versus-leukemia effects. This review will summarize our current understanding of the biology of immune recovery post-UCBT with an emphasis on adaptive T cell dependent immunity. New efforts to boost immunity will be also highlighted including our own laboratory, where ex vivo T cell expansion is pursued towards adoptive immunotherapy. PMID- 21253424 TI - Outcome of childhood acute promyelocytic leukemia treated using a modified AIDA protocol. AB - BACKGROUND: Combination treatment with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy has led to major advances in the treatment of acute promyelocytic leukemia (APL). METHODS: In this study, we reviewed the outcome of pediatric APL patients treated using a modified AIDA protocol at our institution. RESULTS: Between May 1999 and December 2007, 23 patients were diagnosed with APL at the Department of Pediatrics, Saint Mary's Hospital, The Catholic University of Korea. Eleven patients were male (48%) (median age at diagnosis, 11 (range, 2-14) years). The treatment protocol consisted of remission induction (achieved by coadministration of ATRA and idarubicin), 3 courses of consolidation treatment, and 2 years of maintenance treatment during which ATRA was also administered. Three patients died early during remission induction due to CNS hemorrhage. The remaining 20 patients achieved complete remission (CR), with an overall CR rate of 87%. Two patients relapsed and died, and another patient died of pneumonia unrelated to APL. Four patients (17%) were diagnosed with ATRA syndrome, and all patients showed resolution of symptoms. The event free survival (EFS) and overall survival (OS) of the cohort were 78.3+/-8.6% and 76.3+/-9.5%, respectively. Initial WBC count at diagnosis was the only significant prognostic factor for the rate of CR (P=0.039) and OS (P=0.039). CONCLUSION: A modified AIDA protocol for the treatment of childhood APL leads to improved EFS and OS, with limited ATRA syndrome-associated toxicity. Active monitoring and treatment of patients with high initial WBC counts may help in reducing mortality. PMID- 21253425 TI - Incidence and clinical characteristics of clonal cytogenetic abnormalities of acquired aplastic anemia in adults. AB - BACKGROUND: Cytogenetic abnormalities (CAs) have been reported frequently in patients with otherwise typical aplastic anemia (AA), but their implications in the prognosis and in the evolution to hematologic malignancies are controversial. METHODS: We retrospectively analyzed 127 adult AA patients who had successful cytogenetic analysis at initial diagnosis. RESULTS: The patients were classified into 3 groups according to the initial and follow-up results of cytogenetic profiles. Group 1 included patients who had persistent AA with normal cytogenetic profiles (N=117); Group 2, those who had a normal cytogenetic profile at initial diagnosis but later acquired CA (N=4, 3.1%); and Group 3, those who had CA at the initial diagnosis, regardless of follow-up cytogenetic status (N=6,4.7%). In Group 2, 2 patients later developed CA without progression to acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS); the other 2 patients later progressed to AML. None of the patients in Group 3 progressed to AML or MDS. There was no significant difference in overall survival between Groups 1 and 3. CONCLUSION: AA patients with CA at initial diagnosis or follow-up may not be at greater risk for evolution to AML or MDS, or show shorter survival periods. Prospective studies and a larger patient samples are needed to establish the clinical relevance of CA. PMID- 21253426 TI - Role of p16 in the pathogenesis of Langerhans cell histiocytosis. AB - BACKGROUND: It has been hypothesized that genetic alteration at the cellular level may have a significant effect on cellular mechanisms controlling the proliferation and apoptosis of Langerhans cells (LCs). METHODS: We examined whether p16 protein expression can be used to predict the outcome of Langerhans cell histiocytosis (LCH). Archival paraffin blocks from children diagnosed with LCH and followed at the Asan Medical Center and Chungnam National University Hospital between March 1998 and February 2008 were studied. RESULTS: Slides were stained with p16 antibody and evaluated semi-quantitatively using the following scale: negative, no staining; +/-, weakly positive; 1+, staining similar to lymphocytes surrounding the LCs; 2+, stronger staining than lymphocytes; 3+, much stronger staining than lymphocytes. Negative and +/- groups were assigned to a lower expression group (LEG) and the 1+, 2+, and 3+ groups were assigned to a higher expression group (HEG). The median age of the 51 patients (24 girls, 27 boys) was 49 (range, 0.6-178) months, and LCH was diagnosed based on CD1a positivity. p16 protein was expressed to varying degrees in all but one specimen. There was a greater tendency toward multisystem disease, risk organ involvement, and relapse in the HEG than in the LEG. CONCLUSION: The p16 protein may have a significant effect on cellular mechanisms controlling the proliferation and apoptosis of LCs, and thus may influence the clinical outcome and prognosis of LCH. PMID- 21253427 TI - Additional rituximab-CHOP (R-CHOP) versus involved-field radiotherapy after a brief course of R-CHOP in limited, non-bulky diffuse large B-cell lymphoma: a retrospective analysis. AB - BACKGROUND: Standard treatment for stage I or non-bulky stage II diffuse large B cell lymphoma (DLBCL) has been either a brief course of chemotherapy plus involved-field radiotherapy (IFRT) or prolonged cycles of chemotherapy. The introduction of rituximab has necessitated re-evaluation of the treatment for limited disease (LD) DLBCL. METHODS: Thirty-nine LD DLBCL patients (median age, 52 years; range, 24-85) treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) were retrospectively analyzed. Treatment outcomes were evaluated, and toxicity, event-free survival (EFS), and overall survival (OS) were compared according to the treatment and risk factors. RESULTS: The median follow-up duration was 34.6 months (range, 9.1-65.4). The 3-year EFS and OS were 76.0% and 86.0%, respectively. Among the 36 patients who underwent either 3-4 cycles of R-CHOP followed by IFRT (N=22) or 6-8 cycles of R-CHOP (N=14), there was no difference in the 3-year EFS (79.4% vs. 71.6%, P=0.638) and 3-year OS (85.7% vs. 92.9%, P=0.732). Severe neutropenia and neutropenic fever were more frequent in patients treated with R-CHOP alone, with 1 treatment related mortality. Among the IFRT patients, 1 required hospital admission for IFRT-related complications. No events or deaths were reported among patients without adverse risk factors. CONCLUSION: The difference in outcomes between the 2 treatment options was not significant. Analysis of treatment outcomes suggested that baseline characteristics and expected toxicities should be considered in LD DLBCL treatment. Further studies are needed to define the optimal treatment in the rituximab era. PMID- 21253428 TI - Diagnosis of non-overt disseminated intravascular coagulation made according to the International Society on Thrombosis and Hemostasis criteria with some modifications. AB - BACKGROUND: An early diagnosis of disseminated intravascular coagulation (DIC) before its progression to an overt stage is necessary for early treatment and positive outcomes. In 2001, the Scientific and Standardization Committee (SCC) of the International Society on Thrombosis and Hemostasis (ISTH) proposed new criteria for the preclinical diagnosis of overt and non-overt DICs. We investigated the clinical usefulness of the modified ISTH criteria for non-overt DIC diagnosis. METHODS: We enrolled 296 DIC patients (170 males and 126 females) admitted and evaluated at the Gangnam Severance Hospital, Seoul, Korea, between March 2006 and April 2007. Hemostatic tests, including platelet counts, prothrombin time (PT), D-dimer levels with antithrombin, and protein-C levels, were evaluated by excluding negative scores with clinical signs, in which more than 5 points of interest denoted non-overt DIC. Mortality rates were also evaluated. RESULTS: There were 289 patients with increased D-dimer levels and significant parametric changes suggesting DIC progression. Protein C and antithrombin levels were lower (99.2% each) and appeared earlier in patients with non-overt DIC than in patients with overt DIC. In all, 125 (43.3%) patients had non-overt DIC and, of which 27 died (mortality rate, 21.6%). The sensitivity and specificity for mortality were 73.0% and 55.9%, respectively, which were same as those for the original ISTH criteria. CONCLUSION: The modified ISTH criteria can be used for the early detection of non-overt DIC, and may be useful for the improvement of outcomes of non-overt DIC patients. PMID- 21253429 TI - Elevated levels of activated and inactivated thrombin-activatable fibrinolysis inhibitor in patients with sepsis. AB - BACKGROUND: In sepsis, large scale inflammatory responses can cause extensive collateral damage to the vasculature, because both coagulation and fibrinolysis are activated unevenly. Thrombin-activatable fibrinolysis inhibitor (TAFI) plays a role in modulating fibrinolysis. Since TAFI can be activated by both thrombin and plasmin, it is thought to be affected in sepsis. Hence, activated and inactivated TAFI (TAFIa/ai) may be used to monitor changes in sepsis. METHODS: TAFIa/ai-specific in-house ELISA can detect only the TAFIa/ai form, because the ELISA capture agent is potato tuber carboxypeptidase inhibitor (PTCI), which has selective affinity towards only the TAFIa and TAFIai isoforms. TAFIa/ai levels in plasma from 25 patients with sepsis and 19 healthy volunteers were quantitated with the in-house ELISA. RESULTS: We observed increased TAFIa/ai levels in samples from patients with sepsis (48.7+/-9.3 ng/mL) than in samples from healthy individuals (10.5+/-5.9 ng/mL). In contrast, no difference in total TAFI concentration was obtained between sepsis patients and healthy controls. The results suggest that TAFI zymogen was activated and that TAFIa/ai accumulated in sepsis. CONCLUSION: The detection of TAFIa/ai in plasma could provide a useful and simple diagnostic tool for sepsis. Uneven activation of both coagulation and fibrinolysis in sepsis could be caused by the activation of TAFI zymogen and elevation of TAFIa/ai. TAFIa/ai could be a novel marker to monitor sepsis and other blood-related disturbances. PMID- 21253430 TI - The use of the complement inhibitor eculizumab (Soliris(r)) for treating Korean patients with paroxysmal nocturnal hemoglobinuria. AB - BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder characterized by chronic complement-mediated hemolysis. Eculizumab, a humanized monoclonal antibody against the terminal complement protein C5, potently reduces chronic intravascular hemolysis. We tested the clinical efficacy and safety of a 24-week treatment with eculizumab in 6 Korean patients with PNH. METHODS: We enrolled 6 patients with PNH who had clinically significant hemolysis. Eculizumab was administered intravenously at 600 mg/week for the first 4 weeks followed by 900 mg at week 5 and 2nd weekly thereafter. RESULTS: Three men and 3 women with a median age of 39.5 years (24-61 years) were enrolled. The median duration of PNH was 11 years (6-25 years). Hemolysis occurred in all patients [median lactate dehydrogenase (LDH) level, 7.95 times the upper limit of the reference range of LDH]. All patients treated with eculizumab had a rapid and sustained reduction in the degree of hemolysis. RBC transfusion requirements for 3 months were decreased from 0-12 units (median requirement, 1.5 units) to 0-6 units (median requirement, 0 units). Improvement in fatigue was noted in 4 patients. Further, 5 patients who had been receiving corticosteroids either reduced the dose or discontinued therapy. No significant adverse events related to eculizumab therapy were observed. CONCLUSION: These results show that eculizumab reduces the degree of intravascular hemolysis, reduces or eliminates the requirement of RBC transfusion, and improves anemia and fatigue in patients with PNH. Eculizumab is an effective and safe option for treating Korean patients with PNH. PMID- 21253431 TI - Primary renal aspergillosis and renal stones in both kidneys associated with hematopoietic stem cell transplant. AB - Invasive aspergillosis (IA) is a leading cause of infectious mortality in patients who have undergone a hematopoietic stem cell transplant (HSCT); the mortality due to IA ranges from 70% to 93% in HSCT patients. Early diagnosis and treatment are the cornerstones for the good prognosis of IA. Primary renal aspergillosis is an extremely rare presentation in patients who have undergone HSCT, and the risk factor for this uncommon presentation is not well known. We report a patient who developed primary renal aspergillosis and renal stones in both the kidneys after HSCT. Invasive renal aspergillosis was diagnosed after a nephrectomy, which was performed to treat massive renal hematoma. PMID- 21253432 TI - Wernicke's encephalopathy following allogeneic hematopoietic stem cell transplantation. AB - Wernicke's encephalopathy is caused by thiamine deficiency, and is characterized by acute mental confusion, ataxia, and ophthalmoplegia. It is also a rare neurologic complication of hematopoietic stem cell transplantation (HSCT). However, because of its rare incidence, Wernicke's encephalopathy can easily be overlooked in HSCT patients, and a few misleading steps in the early stage of the disease may result in permanent neurologic disability or even mortality. We recently encountered a case of Wernicke's encephalopathy in a patient who underwent allogeneic HSCT. Based on our own experience and previously published documents, we suggest early radiologic surveillance and treatment for patients with findings compatible with Wernicke's encephalopathy following HSCT. PMID- 21253433 TI - Long-term disease-free survival of patients with primary cardiac lymphoma treated with systemic chemotherapy and radiotherapy. AB - Primary cardiac lymphoma (PCL) is a rare disease entity with only a few reported cases in Korea. In this paper, we report a case of PCL in a 59-year-old man presenting with chest pain. Diffuse large B-cell lymphoma was diagnosed through a cardiac catheterization-assisted percutaneous endomyocardial biopsy, and there was no evidence of extracardiac involvement of the lymphoma.The patient had a complete clinical response after systemic chemotherapy with a rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen and additional post-chemotherapeutic radiation therapy. The patient experienced a long-term disease-free survival of over 4 years. However, he received coronary artery bypass graft surgery due to an acute myocardial infarction that occurred 3 years after the completion of the radiation therapy. Although the addition of radiation therapy to the treatment is thought to decrease the risk of relapse in patients with PCL, a careful and thorough consideration of the potential complications of radiation therapy, particularly with respect to cardiac complications, should be considered. PMID- 21253434 TI - Concerns in assessing risk factors for herpes zoster infection in multiple myeloma patients. PMID- 21253436 TI - Molecular Roles of Cdk5 in Pain Signaling. AB - Injury and inflammation trigger activation of several critical cellular pathways in nociceptive signaling in the peripheral nervous system, but their precise molecular mechanisms have not been clearly defined. Cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase, is mainly expressed in the post-mitotic neurons, and has many important roles in the development, functions and pathophysiology of diseases of the nervous system. Although many functional roles of Cdk5 have been identified in neurons, its precise role in pain signaling has not been well determined. Experimental inflammation in the hind paws of mice resulted in increased mRNA and protein levels of Cdk5 and its activator p35, as well as the Cdk5 activity in nociceptive neurons (Pareek et al., 2006). Furthermore, we also identified that Cdk5 phosphorylates transient receptor potential vanilloid 1 (TRPV1), a key receptor that modulates agonist-induced calcium influx in the neurons (Pareek et al., 2007). We subsequently demonstrated that inflammation triggers increase in Cdk5 activity through activation of early growth response 1 (Egr-1) and p35 expression by tumor necrosis factor alpha (TNF alpha) (Utreras et al., 2009). These findings suggest that Cdk5 plays an important role in pain signaling and therefore Cdk5 and its activators are potentially important drug targets for development of novel analgesics to treat neuropathic pain. PMID- 21253437 TI - Eye-Tracking Data: New Insights on Response Order Effects and Other Cognitive Shortcuts in Survey Responding. AB - Survey researchers since Cannell have worried that respondents may take various shortcuts to reduce the effort needed to complete a survey. The evidence for such shortcuts is often indirect. For instance, preferences for earlier versus later response options have been interpreted as evidence that respondents do not read beyond the first few options. This is really only a hypothesis, however, that is not supported by direct evidence regarding the allocation of respondent attention. In the current study, we used a new method to more directly observe what respondents do and do not look at by recording their eye movements while they answered questions in a Web survey. The eye-tracking data indicate that respondents do in fact spend more time looking at the first few options in a list of response options than those at the end of the list; this helps explain their tendency to select the options presented first regardless of their content. In addition, the eye-tracking data reveal that respondents are reluctant to invest effort in reading definitions of survey concepts that are only a mouse click away or paying attention to initially hidden response options. It is clear from the eye-tracking data that some respondents are more prone to these and other cognitive shortcuts than others, providing relatively direct evidence for what had been suspected based on more conventional measures. PMID- 21253438 TI - Molecular MRI of Thrombosis. AB - This review focuses on recent approaches in using targeted MRI probes for noninvasive molecular imaging of thrombosis. Probe design strategies are discussed: choice of molecular target; nanoparticle versus small-molecule probe; and gadolinium versus iron oxide imaging reporter. Examples of these different design strategies are chosen from the recent literature. Novel contrast agents used to image direct and indirect binding to fibrin have been described as well as direct binding to activated platelets. Emphasis is placed on probes where utility has been demonstrated in animal models or in human clinical trials. PMID- 21253435 TI - Rodent preclinical models for developing novel antiarthritic molecules: comparative biology and preferred methods for evaluating efficacy. AB - Rodent models of immune-mediated arthritis (RMIA) are the conventional approach to evaluating mechanisms of inflammatory joint disease and the comparative efficacy of antiarthritic agents. Rat adjuvant-induced (AIA), collagen-induced (CIA), and streptococcal cell wall-induced (SCW) arthritides are preferred models of the joint pathology that occurs in human rheumatoid arthritis (RA). Lesions of AIA are most severe and consistent; structural and immunological changes of CIA best resemble RA. Lesion extent and severity in RMIA depends on experimental methodology (inciting agent, adjuvant, etc.) and individual physiologic parameters (age, genetics, hormonal status, etc.). The effectiveness of antiarthritic molecules varies with the agent, therapeutic regimen, and choice of RMIA. All RMIA are driven by overactivity of proinflammatory pathways, but the dominant molecules differ among the models. Hence, as with the human clinical experience, the efficacy of various antiarthritic molecules differs among RMIA, especially when the agent is a specific cytokine inhibitor. PMID- 21253439 TI - Multiple Dimensions of Private Information: Evidence from the Long-Term Care Insurance Market. AB - We demonstrate the existence of multiple dimensions of private information in the long-term care insurance market. Two types of people purchase insurance: individuals with private information that they are high risk and individuals with private information that they have strong taste for insurance. Ex post, the former are higher risk than insurance companies expect, while the latter are lower risk. In aggregate, those with more insurance are not higher risk. Our results demonstrate that insurance markets may suffer from asymmetric information even absent a positive correlation between insurance coverage and risk occurrence. The results also suggest a general test for asymmetric information. PMID- 21253440 TI - Voice acoustic measures of depression severity and treatment response collected via interactive voice response (IVR) technology. AB - Efforts to develop more effective depression treatments are limited by assessment methods that rely on patient-reported or clinician judgments of symptom severity. Depression also affects speech. Research suggests several objective voice acoustic measures affected by depression can be obtained reliably over the telephone. Thirty-five physician-referred patients beginning treatment for depression were assessed weekly, using standard depression severity measures, during a six-week observational study. Speech samples were also obtained over the telephone each week using an IVR system to automate data collection. Several voice acoustic measures correlated significantly with depression severity. Patients responding to treatment had significantly greater pitch variability, paused less while speaking, and spoke faster than at baseline. Patients not responding to treatment did not show similar changes. Telephone standardization for obtaining voice data was identified as a critical factor influencing the reliability and quality of speech data. This study replicates and extends previous research with a larger sample of patients assessing clinical change associated with treatment. The feasibility of obtaining voice acoustic measures reflecting depression severity and response to treatment using computer-automated telephone data collection techniques is also established. Insight and guidance for future research needs are also identified. PMID- 21253441 TI - Anti-inflammatory and Anti-arthritic Effects of a Novel Leflunomide Analogue, UTL 5b (GBL-5b). AB - Rheumatoid arthritis (RA) is a common disease characterized by chronic inflammation and irreversible destruction of articular cartilage and bone. In this report, we examined the anti-inflammatory and anti-arthritic effects of a novel leflunomide analogue, UTL-5b (also known as GBL-5b), for potential RA treatment. Using a carrageenan-induced edema study in rats, UTL-5b exhibited a better anti-inflammatory effect as compared with leflunomide and its metabolite. The chronic efficacy of UTL-5b was examined using type II collagen-induced arthritis (CIA) mouse model. UTL-5b exerted an anti-arthritic effect in a dose dependant manner with mice given 30 mg/kg exhibiting amelioration of disease early in the trial, but losing statistical significance over time. In contrast, mice treated with 60 mg/kg showed reduced clinical disease parameters early in the trial and these effects were sustained over the ten week trial period. Mechanistic studies indicate that UTL-5b is an inhibitor of TNF-alpha production in vivo. Oral administration of UTL-5b prior to i.p. injection with lethal dose of lipopolysaccharide (LPS)/D-galactosamine markedly reduced the levels of serum TNF-alpha and increased survival rates of animals from septic shock-induced death. Acute toxicity study using mice receiving increasing doses of UTL-5b showed that no animals were killed by UTL-5b at 2,000 mg/kg (LD(50) >2,000 mg/kg). Our studies show that UTL-5b represents a novel anti-inflammatory and anti-arthritic agent with potential therapeutic application for RA treatment. PMID- 21253443 TI - Borderline Personality Disorder, Bulimia Nervosa, Antisocial Personality Disorder, ADHD, Substance Use: Common Threads, Common Treatment Needs, and the Nature of Impulsivity. PMID- 21253444 TI - Modeling G Protein-Coupled Receptors: a Concrete Possibility. AB - G protein-coupled receptors (GPCRs) are a large superfamily of membrane bound signaling proteins that are involved in the regulation of a wide range of physiological functions and constitute the most common target for therapeutic intervention. Due to the paucity of crystal structures, homology modeling has become a widespread technique for the construction of GPCR models, which have been applied to the study of their structure-function relationships and to the identification of lead ligands through virtual screening. Rhodopsin has been for years the only available template. However, recent breakthroughs in GPCR crystallography have led to the solution of the structures of a few additional receptors. In light of these newly elucidated crystal structures, we have been able to produce a substantial amount of data to demonstrate that accurate models of GPCRs in complex with their ligands can be constructed through homology modeling followed by fully flexible molecular docking. These results have been confirmed by our success in the first blind assessment of GPCR modeling and docking, organized in coordination with the solution of the X-ray structure of the adenosine A(2A) receptor. Taken together, these data indicate that: a) the transmembrane helical bundle can be modeled with considerable accuracy; b) predicting the binding mode of a ligand, although doable, is challenging; c) modeling of the extracellular and intracellular loops is still problematic. PMID- 21253445 TI - The Legacy of Dr. Ralph Seal Paffenbarger, Jr. - Past, Present, and Future Contributions to Physical Activity Research. PMID- 21253447 TI - Ruthenium- and Osmium-Arene Complexes of 2-Substituted Indolo[3,2-c]quinolines: Synthesis, Structure, Spectroscopic Properties, and Antiproliferative Activity. AB - The synthesis of new modified indolo[3,2-c]quinoline ligands L(1)-L(8) with metal binding sites is reported. By coordination to ruthenium- and osmium-arene moieties 16 complexes of the type [(eta(6)-p-cymene)M(L)Cl]Cl (1a,b-8a,b), where M is Ru(II) or Os(II) and L is L(1)-L(8), have been prepared. All compounds were comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, IR, UV-vis, and NMR spectroscopy, thermogravimetric analysis, and single-crystal X-ray diffraction (2a, 4a, 4b, 5a, 7a, and 7b). The complexes were tested for antiproliferative activity in vitro in three human cancer cell lines, namely, CH1 (ovarian carcinoma), SW480 (colon adenocarcinoma), and A549 (non small-cell lung cancer), yielding IC(50) values in the submicromolar or low micromolar range. PMID- 21253448 TI - Pegylated interferon and ribavirin treatment for hepatitis C virus infection. PMID- 21253446 TI - Kindling and Oxidative Stress as Contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. AB - Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) is one of the more complex illnesses involving multiple systems within the body. Onset of ME/CFS frequently occurs quickly, and many patients report a prior exposure to a viral infection. This debilitating illness can affect the immune, neuroendocrine, autonomic, and neurologic systems. Abnormal biological findings among some patients have included aberrant ion transport and ion channel activity, cortisol deficiency, sympathetic nervous system hyperactivity, EEG spike waves, left ventricular dysfunction in the heart, low natural killer cell cytotoxicity, and a shift from Th1 to Th2 cytokines. We propose that the kindling and oxidative stress theories provide a heuristic template for better understanding the at times conflicting findings regarding the etiology and pathophysiology of this illness. PMID- 21253449 TI - Outcome of Very Late Relapse in Patients with Hodgkin's Lymphomas. AB - Recurrences of Hodgkin's Lymphoma (HL) 5 years after the initial therapy are rare. The aim of this study is to report a single centre experience of the clinical characteristics, outcome, and toxicity of pts who experienced very late relapses, defined as relapses that occurred 5 or more years after the achievement of first complete remission. Of 532 consecutive pts with classical HL treated at our Institute from 1985 to 1999, 452 pts (85%) achieved a complete remission. Relapse occurred in 151 pts: 135 (29.8%) within 5 years and 16 over 5 years (3.5%, very late relapses). Very late relapses occurred after a median disease free interval of 7 years (range: 5-18). Salvage treatment induced complete remission in 14 pts (87.5%). At a median of 4 years after therapy for very late relapse, 10 pts (63%) are still alive and free of disease and 6 (37%) died (1 from progressive HL, 1 from cardiac disease, 1 from thromboembolic disease, 1 from HCV reactivation, and 2 from bacterial infection). The probability of failure-free survival at 5 years was 75%. The majority of deaths are due to treatment-related complications. Therapy regimens for very late relapse HL are warranted to minimize complications. PMID- 21253450 TI - Human T cell and antibody-mediated responses to the Mycobacterium tuberculosis recombinant 85A, 85B, and ESAT-6 antigens. AB - Tuberculosis remains a major health problem throughout the world causing large number of deaths. Effective disease control and eradication programs require the identification of major antigens recognized by the protective responses against M. tuberculosis. In this study, we have investigated humoral and cellular immune responses to M. tuberculosis-specific Ag85A, Ag85B, and ESAT-6 antigens in Brazilian patients with pulmonary (P, n = 13) or extrapulmonary (EP, n = 12) tuberculosis, patients undergoing chemotherapy (PT, n = 23), and noninfected healthy individuals (NI, n = 7). Compared to NI, we observed increased levels of IgG1 responses to Ag85B and ESAT-6 in P and PT groups. Regarding cellular immunity, Ag85A and ESAT-6 were able to discriminate P, PT, and EP patients from healthy individuals by IFN-gamma production and P and PT groups from EP individuals by production of TNF-alpha. In summary, these findings demonstrate the ability of Ag85A, Ag85B, and ESAT-6 to differentiate TB patients from controls by IgG1, IFN-gamma and TNF-alpha production. PMID- 21253451 TI - Safety and efficacy of fluticasone propionate/salmeterol hydrofluoroalkane 134a metered-dose-inhaler compared with fluticasone propionate/salmeterol diskus in patients with chronic obstructive pulmonary disease. AB - PURPOSE: To provide information on the efficacy and safety of Fluticasone Propionate/Salmeterol Hydrofluoroalkane 134a Metered-Dose-Inhaler 230/42mcg (FSC MDI) and its comparable dose of Fluticasone Propionate/Salmeterol DISKUS 250/50mcg (FSC DISKUS) in patients with COPD. METHODS: This multicenter, randomized, double-blind, 12 week study was designed to evaluate FSC MDI treatment responses as compared with FSC DISKUS. The primary comparison of interest was non-inferiority between the FSC MDI treatment group and the FSC DISKUS treatment group assessed in terms of 2-hour post-dose FEV(1) change from baseline at endpoint. The non-inferiority criterion bound was 75mL (lower confidence limit of -75mL). INCLUSION CRITERIA: Male or female aged >= 40, post bronchodilator FEV(1) <= 70% predicted normal, FEV(1)/FVC <= 70% and >= 10 pack years smoking history. Adverse events were recorded by patients throughout the study on daily diary cards. Adverse events were collected in eCRFs at all clinic visits and during a final follow-up phone call. RESULTS: Patients (N=247) were randomized to FSC MDI (FEV(1)% 49.3 +/- 12.3, FEV(1)/FVC 50.5 +/- 10.0) and FSC DISKUS (FEV(1)% 48.4 +/- 11.0, FEV(1)/FVC 50.3 +/- 10.3). From an ANCOVA model the least squares (LS) mean difference (FSC MDI- FSC DISKUS) for the 2-hour post dose FEV(1) at endpoint was -2.0mL (95% CI -64mL, 59mL). Pre-dose FEV(1), FVC, PEF, and albuterol use were also similar between the two formulations. The most common adverse events (AE) during treatment were headache (8% and 6% of patients), nasopharyngitis (4% and 6%), cough (3% and 4%), and sinusitis (2% and 5%) for FSC MDI and FSC DISKUS, respectively. Pneumonia was recorded as an AE for 2 (2%) patients in the FSC DISKUS arm. CONCLUSION: This is the first study to demonstrate that FSC MDI has a similar efficacy and safety profile to FSC DISKUS in COPD patients. PMID- 21253452 TI - The efficacy of spirometry as a screening tool in detection of air flow obstruction. AB - BACKGROUND/OBJECTIVES: In developing countries, spirometry has not been considered a part of routine medical check-up. The purpose of the study was to establish the usefulness of spirometry as a primary screening tool in detecting air flow obstruction (AFO) during routine medical check-up (RMC). METHODS: This was a hospital based, retrospective, non-randomized case series study of 3696 participants, who presented to hospital for routine medical check-up. All subjects were assisted at the Pulmonary Medicine Department, from January 2003 till December 2008 who, having met other inclusion criteria, underwent spirometry. Data were analyzed using proportion, group means, standard deviations and Pearson Chi Square test. RESULTS: The overall yield from spirometry in detecting AFO was 211 patients (5.7%); 174 males (6.1%) and 37 females (4.4%) (P=0.158, Pearson Chi Square test). Greater age at presentation and BMI correlated significantly with AFO in the target group (P=<0.001; P=<0.005) respectively. Dyspnoea was the most frequent symptomatology observed in those diagnosed with AFO. CONCLUSION: These results suggest that spirometry during RMC for all persons can detect a significant number of patients with AFO particularly among the middle and older age groups with a low BMI. PMID- 21253453 TI - Efficacy and Safety of Once Daily Fluticasone Furoate Nasal Spray for Treatment of Irritant (Non-allergic) Rhinitis. AB - INTRODUCTION: The safety and efficacy of fluticasone furoate nasal spray (FFNS) for the symptoms of seasonal and perennial allergic rhinitis have been previously demonstrated in several clinical studies. The objective of this pilot study was to compare the efficacy and safety of FFNS 110 mcg once daily with placebo in patients with irritant (non-allergic) rhinitis triggered predominantly by air pollution. METHODS: This was a randomized, double-blind, placebo-controlled, 4 week study of subjects in Thailand with irritant rhinitis who received either FFNS 110 mcg (N=53) or placebo (N=49) once-daily. Subjects with a >=2 year history of air pollution as their predominant rhinitis trigger, negative skin test to local seasonal/perennial allergens, positive histamine skin test, and normal sinus radiograph were enrolled if they met minimum reflective total nasal symptom score (rTNSS) >=4.5 (maximum=9) and a nasal congestion score of >=2 (maximum =3). All were assessed for nasal eosinophilia at study entry and completion. Air quality was monitored throughout the study. The primary efficacy endpoint was the mean change from baseline over the treatment period in daily rTNSS, the average of the morning and evening rTNSS. The key secondary measure was the mean change from baseline over the entire treatment period in morning pre dose instantaneous total nasal symptom score (iTNSS). RESULTS: The Air Quality Index (AQI) during the study generally did not reach unhealthy levels. Baseline daily rTNSS scores were similar between treatment groups (FFNS=6.7; placebo=6.4). The least square mean change from baseline in rTNSS was -2.17 and -2.10 for FFNS and placebo, respectively, with a difference of -0.065 (p=0.845). Gradual improvements were seen in both treatment groups for iTNSS; however, the treatment difference (-0.075) was not statistically significant (p=0.827). Additionally, there were no statistically significant differences between treatment groups for AM and PM rTNSS, individual nasal symptoms, daily reflective, AM and PM reflective and AM pre-dose instantaneous total ocular symptom scores (TOSS) or individual ocular symptom scores. Nasal cytology at baseline found more than two thirds of subjects had <20% eosinophils. Adverse events were few and similar between groups and noted as mild in intensity. CONCLUSION: Subjects receiving FFNS had similar improvement to placebo in their rhinitis symptoms. The lack of a treatment effect may be in part due to the overall good air quality present throughout the study or an insufficient dose or duration of FFNS. The safety findings showed FFNS 110 mcg once daily to be well tolerated. PMID- 21253454 TI - Prevalence of Group A b-Hemolytic Streptococcus Among Children with Tonsillopharyngitis in Kyrgyzstan: The Difficulty of Diagnostics and Therapy. AB - OBJECTIVE: Rheumatic fever (RF) is well known disease as a result of frequent complication of the group A b-hemolytic streptococcal (GABHS) tonsillopharyngitis, have noticeably grown for the last 15 years among young generation in the Kyrgyz Republic. It is important to hold a study about the prevalence of RF and GABHS and their susceptibility to antibiotics in the Kyrgyz Republic. MATERIALS AND METHODS: We have studied 200 children with chronic tonsillopharyngitis at the National Center of Pediatrics and Child Surgery in Bishkek (the Kyrgyz Republic) from August till September 2008. 188 (48 out of them are with RF) out of total 200 children are Kyrgyz and 12 are Russian (2 out of them are with RF). 111 out of total are female (34 out of them are with RF) and 89 are male (17 out of them are with RF). The average age of the subjects is 10.9+/-6.0 (from 3 to 17 years old). The presence of GABHS was assessed using two ways: by the rapid antigen detection test (RADT) for outcrop of streptococcus antigen in smear from mucosal surface of tonsils, and by bacterial culture analysis (BA). RADT was used to determine its specificity and sensitivity in order to recommend practitioners its further wide use. Furthermore, the discovered culture of GABHS have been investigated on susceptibility to antibiotics by disc-diffusion method. RESEARCH RESULTS: GABHS antigen was positive in 72 (36.0 %) subjects from RADT and in 80 (40.0%) subjects from BA out of 200 total subjects. In the patients with RF (n=51), GABHS was positive in 18 (35.2%) subjects by RADT and in 24 (47.0%) subjects by BA. In the subjects without RF (n=149), GABHS was positive in 54 (36.2%) subjects by RADT and in 56 (37.5%) by BA. Among 80 GABHS positive results sensitive to antibiotics were: to penicillin only 10 (12.5%), to ampicillin-29 (36.2%), to amoxicillin-36 (45.0%), to ceftriaxon - 31 (38.7%), to roxithromycin - 21 (26.2%), to erythromycin- 19 (23.7%). It is noted that 21 (26.2%) GABHS positive results were absolutely resistant for all these tested antibiotics. RADT showed that its specificity is 85% as well as its sensitivity is equal to 67.5%. CONCLUSION: In this study the sensitivity of RADT was low; therefore, the negative results of RADT don't exclude presence of GABHS. High prevalence of GABHS antigen demonstrates not only in patients with RF, but also among healthy children (without RF) of the Kyrgyz Republic. The high prevalence of GABHS at children with RF (47.0%), probably, presents a low sensitivity to antibiotics and irregular secondary prophylaxis. Significant presence of GABHS among healthy children (37.5%) requires improvement of primary prevention to prevent further spread of RF and Rheumatic Heart Disease (RHD) in the country. PMID- 21253455 TI - Use of yeast chemigenomics and COXEN informatics in preclinical evaluation of anticancer agents. AB - Bladder cancer metastasis is virtually incurable with current platinum-based chemotherapy. We used the novel COXEN informatic approach for in silico drug discovery and identified NSC-637993 and NSC-645809 (C1311), both imidazoacridinones, as agents with high-predicted activity in human bladder cancer. Because even highly effective monotherapy is unlikely to cure most patients with metastasis and NSC-645809 is undergoing clinical trials in other tumor types, we sought to develop the basis for use of C1311 in rational combination with other agents in bladder cancer. Here, we demonstrate in 40 human bladder cancer cells that the in vitro cytotoxicity profile for C1311 correlates with that of NSC-637993 and compares favorably to that of standard of care chemotherapeutics. Using genome-wide patterns of synthetic lethality of C1311 with open reading frame knockouts in budding yeast, we determined that combining C1311 with a taxane could provide mechanistically rational combinations. To determine the preclinical relevance of these yeast findings, we evaluated C1311 singly and in doublet combination with paclitaxel in human bladder cancer in the in vivo hollow fiber assay and observed efficacy. By applying COXEN to gene expression data from 40 bladder cancer cell lines and 30 human tumors with associated clinical response data to platinum-based chemotherapy, we provide evidence that signatures of C1311 sensitivity exist within nonresponders to this regimen. Coupling COXEN and yeast chemigenomics provides rational combinations with C1311 and tumor genomic signatures that can be used to select bladder cancer patients for clinical trials with this agent. PMID- 21253456 TI - Marriage decision making, spousal communication, and reproductive health among married youth in Pakistan. AB - BACKGROUND: Married young women's reproductive needs are a challenge in traditional Pakistani society. The decisions regarding family planning and pregnancy are controlled by the family, often involving complex negotiations. The current study was undertaken to explore how young married women's involvement in the arrangements surrounding their marriage is associated with their ability to negotiate sexual and reproductive health decisions in marriage. OBJECTIVE: The study explores the associations between young women's involvement in their marriage arrangements and their ability to negotiate for contraceptive use and fertility decisions. METHODOLOGY: A subset of 1,803 married young women aged 15 24 years was drawn from a nationally representative adolescent and youth survey conducted in Pakistan in 2001-2002 by the Population Council. Regression models were fitted to outcomes: reported agreement with spouse on the number of children to have, current use of contraceptives, intention to use contraceptives in the future, and the time elapsed between marriage and first contraceptive use. Key covariates of interest were variables that measure the involvement of young women in their marriage: (a) having a say in selection of spouse, (b) having met him prior to marriage, and (c) whether he was related to respondent's family. Other factors explored were respondents' mobility outside of household, social role, and decision making in their homes. RESULTS: Having a say in the selection of a spouse was significantly associated with agreement with spouse over number of children to have, intention to use contraceptives, and the time between marriage and first contraceptive use. These relationships existed after controlling for education, socioeconomic status, mobility outside of house, and decision making in the home. DISCUSSION: Women who had decision-making freedom in their parental home carried this ability with them into marriage in their new home and were better able to negotiate about their fertility. PMID- 21253457 TI - Genome-scale identification of resistance functions in Pseudomonas aeruginosa using Tn-seq. AB - We describe a deep-sequencing procedure for tracking large numbers of transposon mutants of Pseudomonas aeruginosa. The procedure employs a new Tn-seq methodology based on the generation and amplification of single-strand circles carrying transposon junction sequences (the Tn-seq circle method), a method which can be used with virtually any transposon. The procedure reliably identified more than 100,000 transposon insertions in a single experiment, providing near-saturation coverage of the genome. To test the effectiveness of the procedure for mutant identification, we screened for mutations reducing intrinsic resistance to the aminoglycoside antibiotic tobramycin. Intrinsic tobramycin resistance had been previously analyzed at genome scale using mutant-by-mutant screening and thus provided a benchmark for evaluating the new method. The new Tn-seq procedure identified 117 tobramycin resistance genes, the majority of which were then verified with individual mutants. The group of genes with the strongest mutant phenotypes included nearly all (13 of 14) of those with strong mutant phenotypes identified in the previous screening, as well as a nearly equal number of new genes. The results thus show the effectiveness of the Tn-seq method in defining the genetic basis of a complex resistance trait of P. aeruginosa and indicate that it can be used to analyze a variety of growth-related processes. PMID- 21253458 TI - Efficacy and Safety of Abacavir/Lamivudine/Zidovudine Plus Tenofovir in HBV/HIV-1 Coinfected Adults: 48-Week Data. AB - In HBV/HIV-coinfected patients, the risk of end-stage liver disease and death is increased. This open-label, prospective, pilot study evaluated abacavir/lamivudine/zidovudine twice daily plus tenofovir once daily in HBV/HIV coinfected antiretroviral-naive subjects. Nine adults (8 males) enrolled, with baseline mean HIV-1 RNA = 4.5 log(10) copies/mL, HBV DNA = 9.0 log(10) copies/mL, and median CD4 count =158 cells/mm(3). No subject had baseline ALT >5x ULN.SIX SUBJECTS COMPLETED THE STUDY: 1 withdrew due to non-treatment-related toxoplasmosis and 2 were lost-to-follow-up. At week 48, 100% (6/6) of remaining subjects had >=2 log(10) decrease in HBV DNA, and 100% (6/6) and 83% (5/6) had HIV-1 RNA <400 and <50 copies/mL, respectively. Median change from baseline in CD4 count was 157 cells/mm(3). One subject experienced treatment-related grade 3 leukopenia. These results demonstrate that abacavir/lamivudine/zidovudine and tenofovir were well tolerated with sustained HIV-1 and HBV antiviral activity through 48 weeks in HBV/HIV-coinfected, antiretroviral-naive subjects. PMID- 21253459 TI - The use of antidepressant drugs and the lifetime prevalence of major depressive disorders in Italy. AB - BACKGROUND: The increased use of antidepressant drugs (ADs) improved the response to the needs of care although some community surveys have shown that subjects without lifetime psychiatric diagnosis (anxiety/depression) used ADs. OBJECTIVES: To evaluate the appropriateness and amount of prescription of psychotropic drugs in people with lifetime diagnosis of Major Depressive Disorder (MDD) by means of community survey with a semi-structured interview as a diagnostic instrument, administered by clinicians. METHODS: STUDY DESIGN: community survey. STUDY POPULATION: samples randomly drawn, after stratification from the adult population of municipal records. SAMPLE SIZE: 4.999 people were drawn in 7 centres of 6 Italian regions. TOOLS: questionnaire on psychotropic drug consumption, prescription, health services utilization; Structured Clinical Interview for DSM-IV modified (ANTAS); Training: interviewers were trained psychologists or medical doctors. RESULTS: 3.398 subjects were interviewed (68% of the recruited sample). The lifetime prevalence of DSM-IV MDD was 4.3% in males and 11.5% in females; antidepressant drugs were taken by 4.7% of subjects, 2.9% male and 5.9% female. 38% of males and 57% of females with lifetime diagnosis of MDD were taking ADs. CONCLUSIONS: Compared with studies using lay interviewers and structured tools the prevalence of the MDD was quite lower; ADs use was higher and tallied well with the data regarding antidepressant sales in Italy; the correspondence between lifetime diagnosis of MDD and ADs use was closer. PMID- 21253460 TI - Strong Strand Composition Bias in the Genome of Ehrlichia canis Revealed by Multiple Methods. AB - Genes located on the two replicating strands are found to have two separate base/codon usages in Ehrlichia canis genome. Although strand-specific codon usage is not the first observation, for the first time we have applied multiple methods to the analysis of strand composition bias. By combining multiple methods, comprehensive and interesting results are obtained. Among three types of correspondence analysis (COA), absolute codon usages between genes on the two replicating strands are more distinct than relative synonymous codon usage (RSCU) and base usages are more sensitive than both types of codon usages. PR2-plots show that replication-induced bias is much higher than transcription/translation associated bias in the genome. By using the Z curve method, two common genomic characters, i.e., stronger strand composition bias and lower rearrangement frequency are found to exist in 11 obligate intracellular bacteria with separate base/codon usages. We hope more and more researchers will use the multiple methods to analyze strand composition bias in sequenced microbes, particularly obligate intracellular bacteria. PMID- 21253461 TI - PTSD-8: A Short PTSD Inventory. AB - Traumatic events pose great challenges on mental health services in scarcity of specialist trauma clinicians and services. Simple short screening instruments for detecting adverse psychological responses are needed. Several brief screening instruments have been developed. However, some are limited, especially in relation to reflecting the posttraumatic stress disorder (PTSD) diagnosis. Recently, several studies have challenged pre-existing ideas about PTSD's latent structure. Factor analytic research currently supports two four factor models. One particular model contains a dysphoria factor which has been associated with depression and anxiety. The symptoms in this factor have been hailed as less specific to PTSD. The scope of this article is therefore to present a short screening instrument, based on this research; Posttraumatic Stress Disorder (PTSD) - 8 items. The PTSD-8 is shown to have good psychometric properties in three independent samples of whiplash patients (n=1710), rape victims (n=305), and disaster victims (n=516). Good test-rest reliability is also shown in a pilot study of young adults from families with alcohol problems (n=56). PMID- 21253462 TI - Effect of co-inoculation with mycorrhiza and rhizobia on the nodule trehalose content of different bean genotypes. AB - Studies on Rhizobium-legume symbiosis show that trehalose content in nodules under drought stress correlates positively with an increase in plant tolerance to this stress. Fewer reports describe trehalose accumulation in mycorrhiza where, in contrast with rhizobia, there is no flux of carbohydrates from the microsymbiont to the plant. However, the trehalose dynamics in the Mycorrhiza Rhizobium-Legume tripartite symbiosis is unknown. The present study explores the role of this tripartite symbiosis in the trehalose content of nodules grown under contrasting moisture conditions. Three wild genotypes (P. filiformis, P. acutifolis and P. vulgaris) and two commercial genotypes of Phaseolus vulgaris (Pinto villa and Flor de Mayo) were used. Co-inoculation treatments were conducted with Glomus intraradices and a mixture of seven native rhizobial strains, and trehalose content was determined by GC/MS. The results showed a negative effect of mycorrhizal inoculation on nodule development, as mycorrhized plants showed fewer nodules and lower nodule dry weight compared to plants inoculated only with Rhizobium. Mycorrhizal colonization was also higher in plants inoculated only with Glomus as compared to plants co-inoculated with both microsymbionts. In regard to trehalose, co-inoculation negatively affects its accumulation in the nodules of each genotype tested. However, the correlation analysis showed a significantly positive correlation between mycorrhizal colonization and nodule trehalose content. PMID- 21253463 TI - Validation of Microcapillary Flow Cytometry for Community-Based CD4+ T Lymphocyte Enumeration in Remote Burkina Faso. AB - BACKGROUND: CD4+ T lymphocyte enumeration plays a critical role in the initiation and monitoring of HIV-infected patients on antiretroviral therapy. There is an urgent need for low-cost CD4+ enumeration technologies, particularly for use in dry, dusty climates characteristic of many small cities in Sub-Saharan Africa. DESIGN: Cross-sectional study. METHODS: Blood samples from 98 HIV-infected patients followed in a community HIV clinic in Ouahigouya, Burkina Faso were obtained for routine CD4+ T lymphocyte count monitoring. The blood samples were divided into two aliquots, on which parallel CD4+ measurements were performed using microcapillary (Guava EasyCD4) and dedicated (Becton Dickinson FACSCount) CD4+ enumeration systems. Spearman rank correlation coefficient was calculated, and the sensitivity, specificity and positive predictive value (PPV) for EasyCD4 <200 cells/uL were determined compared to the reference standard FACSCount CD4 <200 cells/uL. RESULTS: Mean CD4 counts for the EasyCD4 and FACSCount were 313.75 cells/uL and 303.47 cells/uL, respectively. The Spearman rank correlation coefficient was 0.92 (p<0.001). Median values using EasyCD4 were higher than those with the FACSCount (p=0.004). For a CD4<350 cells/uL, sensitivity of the EasyCD4 was 93.9% (95%CI 85.2-98.3%), specificity was 90.6% (95% CI 75.0-98.0%), and PPV was 95.4% (95%CI 87.1-99.0%). CONCLUSION: Use of the EasyCD4 system was feasible and highly accurate in the harsh conditions of this remote city in Sub Saharan Africa, demonstrating acceptable sensitivity and specificity compared to a standard operating system. Microcapillary flow cytometry offers a cost effective alternative for community-based, point-of-care CD4+ testing and could play a substantial role in scaling up HIV care in remote, resource-limited settings. PMID- 21253464 TI - The Saccharomyces cerevisiae Genes, AIM45, YGR207c/CIR1 and YOR356w/CIR2, Are Involved in Cellular Redox State Under Stress Conditions. AB - Mammalian electron transfer flavoproteins comprise a mitochondrial matrix heterodimer, and an electron transfer flavoprotein dehydrogenase localized in the mitochondrial inner membrane. Electrons from primary acyl-CoA dehydrogenases, of mitochondrial metabolism of fatty acids and amino acids, are transferred to the matricial heterodimer and, subsequently, to the electron transfer flavoprotein dehydrogenase, which transfers electrons to ubiquinone of the mitochondrial electron transport chain. Several evidences suggest that these proteins may convey electrons directly to molecular oxygen, yielding reactive oxygen species. In this work, we investigated phenotypes of the yeast mutants affected in the orthologous genes of the matrix heterodimer (AIM45 and YGR207c/CIR1) and of the electron transfer flavoprotein dehydrogenase (YOR356w/CIR2). The mutant strains aim45 and yor356w/cir2 displayed better growth on several non-fermentable carbon sources, which depended on the component of the electron transport chain that accepts the electrons resulting from its mitochondrial oxidation. Furthermore, upon heat shock, the mutant strains presented decreased intracellular oxidation, suggesting that these flavoproteins are a source of reactive oxygen species. Other phenotypes identified suggest that AIM45, YGR207c/CIR1 and YOR356w/CIR2 can protect cells from oxidative and heat stress, which encompass increased heat stress sensitivity, superoxide sensitivity, both only on non-fermentable carbon sources. PMID- 21253465 TI - Impact of autologous and allogeneic stem cell transplantation in peripheral T cell lymphomas. AB - Peripheral T/NK-cell lymphomas (PTCLs) are rare malignancies characterized by poor prognosis. So far, no standard therapy has been established, due to the lack of randomised studies. High-dose therapy and autologous stem cell transplantation (HDT-autoSCT) have shown good feasibility with low toxicity in retrospective studies. In relapsing and refractory PTCL several comparison analyses suggest similar efficacy for PTCL when compared with aggressive B-cell lymphoma. In the upfront setting, prospective data show promising results with a long-lasting overall survival in a relevant subset of patients. Achieving a complete remission at transplantation seems to be the most important prognostic factor. Allogeneic stem cell transplantation (alloSCT) has been investigated only as salvage treatment. Especially when using reduced intensity conditioning regimen, eligible patients seem to benefit from this approach. To define the role for upfront stem cell transplantation a randomised trial by the German High-Grade Non-Hodgkin Lymphoma Study Group comparing HDT-autoSCT and alloSCT will be initiated this year. PMID- 21253466 TI - Effect of Aqueous Extract of Massularia acuminata Stem on Sexual Behaviour of Male Wistar Rats. AB - Ancient literature alluded to the use of a number of plants/preparations as sex enhancer. One of such botanicals is Massularia acuminata in which the stem has been acclaimed to be used as an aphrodisiac. Documented experiments or clinical data are, however, lacking. Therefore, this study was undertaken to evaluate the acclaimed aphrodisiac activity of M. acuminata stem. Sixty male rats were completely randomized into 4 groups (A-D) of 15 each. Rats in group A (control) were administered with 1 mL of distilled water (the vehicle) while those in groups B, C, and D were given same volume containing 250, 500, and 1000 mg/kg body weight of the extract, respectively. Sexual behaviour parameters were monitored in the male rats for day 1 (after a single dose), day 3 (after three doses, once daily), and day 5 (after five doses, once daily) by pairing with a receptive female (1 : 1). The male serum testosterone concentration was also determined. Cage side observation on the animals revealed proceptive behaviour (ear wiggling, darting, hopping, and lordosis) by the receptive female rats and precopulatory behaviour (chasing, anogenital sniffing and mounting) by the extract-treated male rats. The extract at 500, and 1000 mg/kg body weight significantly (P < .05) increased the frequencies of mount and intromission. In addition, the ejaculation latency was significantly prolonged (P < .05). The latencies of mount and intromission were reduced significantly whereas ejaculation frequency increased. The extract also reduced the postejaculatory interval of the animals. Computed percentages of index of libido, mounted, intromitted, ejaculated and copulatory efficiency were higher in the extract treated animals compared to the distilled water-administered control whereas the intercopulatory interval decreased significantly. The extract also significantly (P < .05) increased the serum testosterone content of the animals except in those administered with 250 mg/kg body weight on days 1 and 3. Data from this study identified that the aqueous extract of Massularia acuminata stem enhanced sexual behaviour in male rats. The improved sexual appetitive behaviour in male rats at the doses of 500 and 1000 mg/kg body weight of Massularia acuminata stem may be attributed, at least in part, to the alkaloids, saponins, and/or flavonoids since these phytochemicals has engorgement, androgen enhancing, and antioxidant properties. PMID- 21253467 TI - A unique case of hepatocellular carcinoma treated with radiofrequency ablation with more than 12 years overall survival: a case report. AB - The case of a 72-year-old male patient with HCC is presented in whom percutaneous RFA was used as the sole first-line anticancer treatment, since he denied having partial hepatectomy. The patient underwent RFA two more times, at 1.5 years for treating a local tumor progression at the initial ablation site and at 11 years after the first session for treating a new remote intrahepatic recurrence. He revealed a long-term survival of more than 12 years so far and still remains in excellent clinical status. PMID- 21253468 TI - Crystalline ultrastructures, inflammatory elements, and neoangiogenesis are present in inconspicuous aortic valve tissue. AB - Morbidity from calcific aortic valve disease (CAVD) is increasing. Recent studies suggest early reversible changes involving inflammation and neoangiogenesis. We hypothesized that microcalcifications, chemokines, and growth factors are present in unaffected regions of calcific aortic valves. We studied aortic valves from 4 patients with CAVD and from 1 control, using immunohistochemistry, scanning electron microscopy, and infrared spectrography. We revealed clusters of capillary neovessels in calcified (ECC), to a lesser extent in noncalcified (ECN) areas. Endothelial cells proved constant expression of SDF-1 in ECC, ECN, and endothelial cells from valvular surface (ECS). Its receptor CXCR4 was expressed in ECC. IL-6 expression correlated with CXCR4 staining and presence of lymphocytes. VEGF was expressed by ECS, its receptor by ECC and ECN. Crystalline ultrastructures were found on the surface of histologically noncalcified areas (HNCAs), spectrography revealed calcium hydroxylapatite. Our results demonstrate that crystalline ultrastructures are present in HNCAs, undergoing neoangiogenesis in an inflammatory context. These alterations could be an early witness of disease and an opening to therapy. PMID- 21253469 TI - Choline modulation of the abeta p1-40 channel reconstituted into a model lipid membrane. AB - Nicotinic acetylcholine receptors (AChRs), implicated in memory and learning, in subjects affected by Alzheimer's disease result altered. Stimulation of alpha7 nAChRs inhibits amyloid plaques and increases ACh release. beta-amyloid peptide (AbetaP) forms ion channels in the cell and model phospholipid membranes that are retained responsible in Alzheimer disease. We tested if choline, precursor of ACh, could affect the AbetaP1-40 channels in oxidized cholesterol (OxCh) and in palmitoyl-oleoyl-phosphatidylcholine (POPC):Ch lipid bilayers. Choline concentrations of 5 * 10(-11) M-1.5 * 10(-8) M added to the cis- or trans-side of membrane quickly increased AbetaP1-40 ion channel frequency (events/min) and ion conductance in OxCh membranes, but not in POPC:Ch membranes. Circular Dichroism (CD) spectroscopy shows that after 24 and 48 hours of incubation with AbetaP1-40, choline stabilizes the random coil conformation of the peptide, making it less prone to fibrillate. These actions seem to be specific in that ACh is ineffective either in solution or on AbetaP1-40 channel incorporated into PLMs. PMID- 21253470 TI - gammadelta T cells cross-link innate and adaptive immunity in Mycobacterium tuberculosis infection. AB - Protective immunity against mycobacterial infections such as Mycobacterium tuberculosis is mediated by interactions between specific T cells and activated antigen presenting cells. To date, many aspects of mycobacterial immunity have shown that innate cells could be the key elements that substantially may influence the subsequent adaptive host response. During the early phases of infection, innate lymphocyte subsets play a pivotal role in this context. Here we summarize the findings of recent investigations on gammadelta T lymphocytes and their role in tuberculosis immunity. PMID- 21253471 TI - Long-term follow-up of HLA-A2+ patients with high-risk, hormone-sensitive prostate cancer vaccinated with the prostate specific antigen peptide homologue (PSA146-154). AB - Twenty-eight HLA-A2+ patients with high-risk, locally advanced or metastatic, hormone-sensitive prostate cancer were immunized with a peptide homologue of prostate-specific antigen, PSA146-154, between July 2002 and September 2004 and monitored for clinical and immune responses. Fifty percent of the patients developed strong PSA146-154-peptide-specific delayed-type hypersensitivity skin responses, tetramer and/or IFN-gamma responses within one year. Thirteen patients had stable or declining serum levels of PSA one year post-vaccination. A decreased risk of biochemical progression was observed in patients who developed augmented tetramer responses at six months compared to pre-vaccination levels (P = .02). Thirteen patients have died while 15 patients remain alive with a mean overall survival of 60 months (95% CI, 51 to 68 months) per Kaplan-Meier analysis. A trend towards greater overall survival was detected in men with high risk, hormone-sensitive CaP who developed specific T-cell immunity following vaccination with PSA146-154 peptide. PMID- 21253472 TI - Circulating tumor cells in breast cancer patients: an evolving role in patient prognosis and disease progression. AB - In this paper, we examine the role of circulating tumor cells (CTCs) in breast cancer. CTCs are tumor cells present in the peripheral blood. They are found in many different carcinomas but are not present in patients with benign disease. Recent advances in theories regarding metastasis support the role of early release of tumor cells in the neoplastic process. Furthermore, it has been found that phenotypic variation exists between the primary tumor and CTCs. Of particular interest is the incongruency found between primary tumor and CTC HER2 status in both metastatic and early breast cancer. Overall, CTCs have been shown to be a poor prognostic marker in metastatic breast cancer. CTCs in early breast cancer are not as well studied, however, several studies suggest that the presence of CTCs in early breast cancer may also suggest a poorer prognosis. Studies are currently underway looking at the use of CTC level monitoring in order to guide changes in therapy. PMID- 21253473 TI - Occupational health and safety issues in Ontario sawmills and veneer/plywood plants: a pilot study. AB - A pilot study was conducted within the Ontario sawmill and veneer/plywood manufacturing industry. Information was collected by postal questionnaire and observational walk-through surveys. Industrial hygiene walk-through surveys were conducted at 22 work sites, and measurements for wood dust, noise, and bioaerosol were taken. The aim of the study was to obtain data on the current status regarding health and safety characteristics and an estimate of wood dust, noise, and bioaerosol exposures. The occupational exposure to wood dust and noise are similar to what has been reported in this industry in Canada and elsewhere. Airborne wood dust concentration ranged between 0.001 mg/m3 and 4.87 mg/m3 as total dust and noise exposure ranged between 55 and 117 dB(A). The study indicates the need for a more comprehensive industry-wide study of wood dust, noise, and bioaersols. PMID- 21253474 TI - UK Guidelines for the Management of Bone Sarcomas. AB - These guidelines have been developed in order to provide an overview and a set of broad-based key recommendations for the management of patients with bone sarcomas in the UK. They have taken into consideration the most up-to-date scientific literature along with the recent recommendations by the European Society of Medical Oncology. The principles of the NICE guidance on both "improving outcomes for patients with sarcomas" and "improving outcomes with children and young people with cancer" have been incorporated. As care evolves, it is acknowledged that these guidelines will need updating. The key recommendations are that bone pain or a palpable mass should always lead to further investigation and patients with clinicoradiological findings suggestive of a primary bone tumour should be sent to a reference centre. Patients should then have their care managed at such a specialist centre by a fully accredited multidisciplinary team. PMID- 21253476 TI - Cavitating mesenteric lymph node syndrome in association with coeliac disease and enteropathy associated T-cell lymphoma: a case report and review of the literature. AB - Cavitating mesenteric lymph node syndrome (CMLNS) is a rare and poorly understood complication of coeliac disease (CD), with only 37 cases reported in the literature. CD is an immune-mediated enteropathy, with alterations seen in the small bowel architecture on exposure to ingested gluten. Those who fail to respond to a strict gluten-free diet are termed to have refractory coeliac disease (RCD). This is associated with serious complications such as enteropathy associated T-cell lymphoma (EATL). We present the case of a 71-year-old female investigated for weight loss and a palpable intraabdominal mass. Abdominal computed tomographic (CT) scan showed multiple necrotic mesenteric lymph nodes. At operation, multiple cavitating mesenteric lymph nodes, containing milky fluid, were found. An incidental EATL was found at the terminal ileum, which was resected. The patient subsequently tested positive for CD. This is the second case report to document an association between CMLNS and EATL. This paper highlights the varied presentation of CD. In this case, the diagnosis of CD was made retrospectively after the complications were dealt with. This paper is followed by a review of relevant literature. PMID- 21253475 TI - Receptor tyrosine kinases as therapeutic targets in rhabdomyosarcoma. AB - Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas of childhood and adolescence. To date, there are no effective treatments that target the genetic abnormalities in RMS, and current treatment options for high-risk groups are not adequate. Over the past two decades, research into the molecular mechanisms of RMS has identified key genes and signaling pathways involved in disease pathogenesis. In these studies, members of the receptor tyrosine kinase (RTK) family of cell surface receptors have been characterized as druggable targets for RMS. Through small molecule inhibitors, ligand-neutralizing agents, and monoclonal receptor-blocking antibodies, RTK activity can be manipulated to block oncogenic properties associated with RMS. Herein, we review the members of the RTK family that are implicated in RMS tumorigenesis and discuss both the problems and promise of targeting RTKs in RMS. PMID- 21253477 TI - Immunohistochemical Expression of p53 in Pleomorphic Adenoma and Carcinoma Ex Pleomorphic Adenoma. AB - Context. Immunohistochemical stains for p53 are used as a diagnostic marker associated with malignancy in several histologic types of salivary gland tumors. This marker may be useful in differentiating pleomorphic adenoma (PA) from carcinoma ex pleomorphic adenoma (CPA), as these tumors are often difficult to distinguish on the basis of morphology alone. Objective. to evaluate whatever inactivation of tumor suppressor gene (p53) increases with the tumor progression from normal salivary tissue to PA and eventually CPA. Design. Paraffin blocks of 29 cases of PA, which were surrounded by normal parotid gland, and 27 cases of carcinoma ex pleomorphic adenoma were retrieved and validated. In all cases of carcinoma ex pleomorphic adenoma, a PA "ghost" was identified, and the malignant element was either undifferentiated carcinoma or adenocarcinoma. Results. The results showed negative nuclear expression of P53 in normal parotid gland. Nuclear P53 was expressed strongly in 6/29 (20.7%) pleomorphic salivary adenoma and 10/27 (37%) carcinoma ex pleomorphic adenoma. Conclusion. Our data suggest that inactivation of p53 may play an important role in the evolution of pleomorphic salivary adenoma and carcinoma ex pleomorphic adenoma. PMID- 21253478 TI - Glycemic index and pregnancy: a systematic literature review. AB - Background/Aim. Dietary glycemic index (GI) has received considerable research interest over the past 25 years although its application to pregnancy outcomes is more recent. This paper critically evaluates the current evidence regarding the effect of dietary GI on maternal and fetal nutrition. Methods. A systematic literature search using MEDLINE, EMBASE, CINAHL, Cochrane Library, SCOPUS, and ISI Web of Science, from 1980 through September 2010, was conducted. Results. Eight studies were included in the systematic review. Two interventional studies suggest that a low-GI diet can reduce the risk of large-for-gestational-age (LGA) infants in healthy pregnancies, but one epidemiological study reported an increase in small-for-gestational-age (SGA) infants. Evidence in pregnancies complicated by gestational diabetes mellitus (GDM), though limited (n = 3), consistently supports the advantages of a low-GI diet. Conclusion. There is insufficient evidence to recommend a low-GI diet during normal pregnancy. In pregnancy complicated by GDM, a low-GI diet may reduce the need for insulin without adverse effects on pregnancy outcomes. Until larger-scale intervention trials are completed, a low-GI diet should not replace the current recommended pregnancy diets from government and health agencies. Further research regarding the optimal time to start a low-GI diet for maximum protection against adverse pregnancy outcomes is warranted. PMID- 21253479 TI - Bone marrow-derived mesenchymal stem cells: current and future applications in the urinary bladder. AB - Mesenchymal stem cells can be isolated from almost any adult tissue. In this paper we focus on bone marrow-derived mesenchymal stem cells which have captured the interest of researchers since their introduction because of the promising potential of tissue regeneration and repair. They are known for their ability to self-renew and differentiate into diverse lineages while maintaining low immunogenicity. The exact mechanisms behind how these cells work still remain unclear, and there is a continuing shift in the paradigms that support them. There has been extensive research in multiple organ systems; however, the genitorurinary system has been vastly underrepresented. This article discusses the background behind bone marrow-derived mesenchymal stem cells and they are currently being applied to the urinary bladder in the realm of tissue engineering. We also postulate on their future applications based on the current literature in other organ systems. PMID- 21253480 TI - Progression of Left Ventricular Dysfunction and Remodelling under Optimal Medical Therapy in CHF Patients: Role of Individual Genetic Background. AB - Background. Neurohormonal systems play an important role in chronic heart failure (CHF). Due to interindividual heterogeneity in the benefits of therapy, it may be hypothesized that polymorphisms of neurohormonal systems may affect left ventricular (LV) remodelling and systolic function. We aimed to assess whether genetic background of maximally treated CHF patients predicts variations in LV systolic function and volumes. Methods and Results. We prospectively studied 131 CHF outpatients on optimal treatment for at least six months. Echocardiographic evaluations were performed at baseline and after 12 months. Genotype analysis for ACE I/D, beta1adrenergic receptor (AR) Arg389Gly, beta2AR Arg16Gly, and beta2AR Gln27Glu polymorphisms was performed. No differences in baseline characteristics were detected among subgroups. ACE II was a significant predictor of improvement of LV end-diastolic and end-systolic volume (P = .003 and P = .002, respectively) but not of LV ejection fraction (LVEF); beta1AR389 GlyGly was related to improvement of LVEF (P = .02) and LV end-systolic volume (P = .01). The predictive value of polymorphisms remained after adjustment for other clinically significant predictors (P < .05 for all). Conclusions. ACE I/D and beta1AR Arg389Gly polymorphisms are independent predictors of reverse remodeling and systolic function recovery in CHF patients under optimal treatment. PMID- 21253482 TI - Canine and human dirofilariosis in the rostov region (southern Russia). AB - Epidemiological data on canine and human dirofilariosis in the Rostov Region (Southern Russia) are presented. Prevalence of Dirofilaria spp. infections in 795 autochthonous dogs, assessed by the Knott test, was 20.25%. The highest prevalence was found in Novocherkassk (38.3%) and Rostov-on-Don (18.5%), while prevalences were lower in other points of the region. Prevalence of D. repens was 44.7%, prevalence of D. immitis was 30.3%, and coinfections were observed in 25.0% of the dog population. A case finding study carried out during 9 years (2000-2009) revealed 131 cases of human dirofilariosis in the Rostov Region, 129 of subcutaneous dirofilariosis and 2 of pulmonary dirofilariosis. Seroprevalence among 317 healthy blood donors from the Rostov Region was 10.4%, while seroprevalence in policemen living in Rostov city and working in training dogs was 19%. These data show high infection rates of Dirofilaria spp. in both human and dog populations of Rostov, probably because of the existence of favorable conditions for the transmission in this region. PMID- 21253481 TI - Resistance exercise training-induced muscle hypertrophy was associated with reduction of inflammatory markers in elderly women. AB - Aging is associated with low-grade inflammation. The benefits of regular exercise for the elderly are well established, whereas less is known about the impact of low-intensity resistance exercise on low-grade inflammation in the elderly. Twenty-one elderly women (mean age +/- SD, 85.0 +/- 4.5 years) participated in 12 weeks of resistance exercise training. Muscle thickness and circulating levels of C-reactive protein (CRP), serum amyloid A (SAA), heat shock protein (HSP)70, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, monocyte chemotactic protein (MCP-1), insulin, insulin-like growth factor (IGF)-I, and vascular endothelial growth factor (VEGF) were measured before and after the exercise training. Training reduced the circulating levels of CRP, SAA (P < .05), HSP70, IGF-I, and insulin (P < .01). The training-induced reductions in CRP and TNF alpha were significantly (P < .01, P < .05) associated with increased muscle thickness (r = -0.61, r = -0.54), respectively. None of the results were significant after applying a Bonferroni correction. Resistance training may assist in maintaining or improving muscle volume and reducing low-grade inflammation. PMID- 21253483 TI - The melanocortin 3 receptor: a novel mediator of exercise-induced inflammation reduction in postmenopausal women? AB - The purpose of this study was to determine whether resistance exercise training induced reductions in inflammation are mediated via melanocortin 3 receptor expression in obese (BMI 32.7 +/- 3.7) women (65.6 +/- 2.8 yrs) randomized to either a control (N = 11) or resistance training group (N = 12). The resistance trained group performed resistance training 3 days/week for 12 weeks. Resting blood samples were collected before and after the training intervention in both resistance trained and control groups. Resistance training upregulated melanocortin 3 receptor mRNA by 16-fold (P = .035) and decreased monocyte count, without changing leukocyte number, body composition, or body weight. Resistance trained individuals exhibited increased sensitivity to inflammatory stimuli, whereas control individuals exhibited no change. While there was no change in whole blood tumor necrosis factor alpha mRNA between the groups, whole blood interleukin 10 mRNA was higher in the resistance trained group following the intervention period. In summary, it appears that resistance training may modulate melanocortin 3 receptor expression, providing a possible mechanism for the anti inflammatory effects of exercise training. PMID- 21253485 TI - Alzheimer's disease and glaucoma: imaging the biomarkers of neurodegenerative disease. AB - Imaging through the visual system in Alzheimer's disease, with the technology currently in widespread use for the diagnosis and management of eye disease such as glaucoma and macular degeneration, is proving to be promising. In vivo cross section imaging during an annual comprehensive eye exam has been available for a decade for glaucoma and macular degeneration, and this same imaging, using Optical Coherence Tomography, has been demonstrated to show deficits specific to AD and mild cognitive impairment. These deficits are in the form of nerve fiber layer tissue drop out in the retina and optic nerve. The retrograde loss of nerve fiber layer tissue in the retina and optic nerve may be an early biomarker of AD, and these deficits in the nerve fiber layer of the retina and optic nerve may be the earliest sign of AD, even prior to damage to the hippocampal region that impacts memory. PMID- 21253486 TI - VURD Syndrome in a Female. AB - VURD syndrome has been repeatedly described as unilateral reflux into a nonfunctioning renal moiety. This syndrome is considered a pop-off mechanism dissipating pressure in lower urinary tract obstruction: it may be found in association with other protective mechanisms occurring in utero, such as ascites and/or urinomas, and has been exclusively described in male patients. A premature female baby with signs and symptoms of outflow obstruction underwent diagnostic workup revealing congenital urethral hypoplasia with unilateral reflux into a dysplastic kidney. Obstetrical history was positive for early onset, serologically negative ascites without cardiomegaly, which required serial aspirations. Reconstructive surgery was carried out with good results: ascites and VURD syndrome were both deemed to be perinatal protective mechanism against excess pressure in the urinary tract. Although rare, lower urinary tract obstruction in the female can lead to the same protective mechanisms seen in male fetuses/newborns. VURD syndrome and ascites should be interpreted as such and require perinatal specialist counselling. PMID- 21253484 TI - Modulation of cell death by M. tuberculosis as a strategy for pathogen survival. AB - It has been clearly demonstrated that in vitro, virulent M. tuberculosis can favor necrosis over apoptosis in infected macrophages, and this has been suggested as a mechanism for evading the host immune response. We recently reported that an effect consistent with this hypothesis could be observed in cells from the blood of TB patients, and in this paper, we review what is known about evasion strategies employed by M. tuberculosis and in particular consider the possible interaction of the apoptosis-inhibiting effects of M. tuberculosis infection with another factor (IL-4) whose expression is thought to play a role in the failure to control M. tuberculosis infection. It has been noted that IL-4 may exacerbate TNF-alpha-induced pathology, though the mechanism remains unexplained. Since pathology in TB typically involves inflammatory aggregates around infected cells, where TNF-alpha plays an important role, we predicted that IL-4 would inhibit the ability of cells to remove M. tuberculosis by apoptosis of infected cells, through the extrinsic pathway, which is activated by TNF-alpha. Infection of human monocytic cells with mycobacteria in vitro, in the presence of IL-4, appears to promote necrosis over apoptosis in infected cells-a finding consistent with its suggested role as a factor in pathology during M. tuberculosis infection. PMID- 21253488 TI - Endoscopic right lobectomy axillary-breast approach: a report of two cases. AB - Background. We reported our two initial experiences in the treatment of thyroid disease with endoscopic thyroidectomy. Minimally invasive video-assisted technique (MIVAT) was initially introduced by Miccoli. The modification was made by using axillary and breast technique. Method. Two young women patients, with 4 and 5 cm right lobe thyroid disease suspected to be benign. From physical examination, sonography, and FNAB findings, the two cases were categorized as benign. We performed endoscopic right lobectomy through incision of 5-10 mm on axillary line and breast using CO2 insufflation. Result. Duration of first operation was 300 minutes and the second one was 120 minutes, with minimal blood loss and no major complication. Patients were discharged 24 hours after operation. Cosmetic result was excellent. Postoperative complications were shoulder discomfort and neck swelling. Conclusion. We reported two cases of endoscopic right lobectomy as a safe, reproducible technique with an indication in a minority of patients candidates for thyroidectomy and is characterized by less postoperative discomfort. PMID- 21253487 TI - Molecular characterization of putative chordoma cell lines. AB - Immortal tumor cell lines are an important model system for cancer research, however, misidentification and cross-contamination of cell lines are a common problem. Seven chordoma cell lines are reported in the literature, but none has been characterized in detail. We analyzed gene expression patterns and genomic copy number variations in five putative chordoma cell lines (U-CH1, CCL3, CCL4, GB60, and CM319). We also created a new chordoma cell line, U-CH2, and provided genotypes for cell lines for identity confirmation. Our analyses revealed that CCL3, CCL4, and GB60 are not chordoma cell lines, and that CM319 is a cancer cell line possibly derived from chordoma, but lacking expression of key chordoma biomarkers. U-CH1 and U-CH2 both have gene expression profiles, copy number aberrations, and morphology consistent with chordoma tumors. These cell lines also harbor genetic changes, such as loss of p16, MTAP, or PTEN, that make them potentially useful models for studying mechanisms of chordoma pathogenesis and for evaluating targeted therapies. PMID- 21253489 TI - Oxidative damage in lymphocytes of copper smelter workers correlated to higher levels of excreted arsenic. AB - Arsenic has been associated with multiple harmful effects at the cellular level. Indirectly these defects could be related to impairment of the integrity of the immune system, in particular in lymphoid population. To characterize the effect of Arsenic on redox status on this population, copper smelter workers and arsenic unexposed donors were recruited for this study. We analyzed urine samples and lymphocyte enriched fractions from donors to determinate arsenic levels and lymphocyte proliferation. Moreover, we studied the presence of oxidative markers MDA, vitamin E and SOD activity in donor plasma. Here we demonstrated that in human beings exposed to high arsenic concentrations, lymphocyte MDA and arsenic urinary levels showed a positive correlation with SOD activity, and a negative correlation with vitamin E serum levels. Strikingly, lymphocytes from the arsenic exposed population respond to a polyclonal stimulator, phytohemaglutinin, with higher rates of thymidine incorporation than lymphocytes of a control population. As well, similar in vitro responses to arsenic were observed using a T cell line. Our results suggest that chronic human exposure to arsenic induces oxidative damage in lymphocytes and could be considered more relevant than evaluation of T cell surveillance. PMID- 21253490 TI - Physician assistant distribution in Texas-Mexico border counties: public health implications. AB - PURPOSE: Texas Medical Board physician assistant (PA) data were assessed to assist workforce education and planning strategies for PA programs in regions with high percentages of Hispanic populations. METHODS: Data were assessed for gender, ethnicity, program attended and current employment addresses within the 14 Texas-Mexico border counties. RESULTS: Of the 329 border county PAs, 227 self reported as Hispanic (69%), and 53% were female. Remarkably, 72% of all Hispanic PAs attended two of the six public Texas PA Programs. CONCLUSIONS: The Sullivan Commission report of 2004 concluded that the primary cause of poor public health care for minorities resulted from unequal representation of minorities in the health care professions. Two public Texas PA programs have made substantial contributions to public health care access in poverty-stricken border areas by educating and placing Hispanic PAs within medically underserved communities. PMID- 21253491 TI - Subjective and objective appraisal of activity in adults with obstructive sleep apnea. AB - Objective. This study examined the association between obstructive sleep apnea (OSA), daytime sleepiness, functional activity, and objective physical activity. Setting. Subjects (N = 37) being evaluated for OSA were recruited from a sleep clinic. Participants. The sample was balanced by gender (53% male), middle-aged, primarily White, and overweight or obese with a mean BMI of 33.98 (SD = 7.35; median BMI = 32.30). Over 40% reported subjective sleepiness (Epworth Sleepiness Scale (ESS) >=10) and had OSA (78% with apnea + hypopnea index (AHI) >=5/hr). Measurements. Evaluation included questionnaires to evaluate subjective sleepiness (Epworth Sleepiness Scale (ESS)) and functional outcomes (Functional Outcomes of Sleep Questionnaire (FOSQ)), an activity monitor, and an overnight sleep study to determine OSA severity. Results. Increased subjective sleepiness was significantly associated with lower scores on the FOSQ but not with average number of steps walked per day. A multiple regression analysis showed that higher AHI values were significantly associated with lower average number of steps walked per day after controlling patient's age, sex, and ESS. Conclusion. Subjective sleepiness was associated with perceived difficulty in activity but not with objectively measured activity. However, OSA severity was associated with decreased objective physical activity in aging adults. PMID- 21253492 TI - WY-14643, a Potent Peroxisome Proliferator Activator Receptor-alpha PPAR-alpha Agonist Ameliorates the Inflammatory Process Associated to Experimental Periodontitis. AB - We have investigated the effects of WY14643, a potent peroxisome proliferator activator receptor-alpha (PPAR-alpha) agonist, in a rat model of ligature-induced periodontitis. Male Sprague-Dawley rats were lightly anaesthetized with pentobarbitone (35 mg/kg). Sterile, 2-0 black braided silk thread was placed around the cervix of the lower left first molar and knotted medially. Animals received WY14643 (1 mg/kg i.p, daily for eight days). Eighths days after placement of the ligature, we evaluated several markers of inflammation such us (1) myeloperoxidase activity, (2) a cytokines and adhesion molecules expression, (3) NF-kappaB expression, (4) iNOS expression, (5) the nitration of tyrosine residues, (6) activation of the nuclear enzyme poly(ADP-ribose) polymerase, (7) apoptosis, and (8) the degree of gingivomucosal tissues injury. Administration of WY14643 significantly decreased all of the parameters of inflammation as described above. These results demonstrate that WY14643 exerts an anti inflammatory role during experimental periodontitis and is able to ameliorate the tissue damage. PMID- 21253493 TI - The representative porcine model for human cardiovascular disease. AB - To improve human health, scientific discoveries must be translated into practical applications. Inherent in the development of these technologies is the role of preclinical testing using animal models. Although significant insight into the molecular and cellular basis has come from small animal models, significant differences exist with regard to cardiovascular characteristics between these models and humans. Therefore, large animal models are essential to develop the discoveries from murine models into clinical therapies and interventions. This paper will provide an overview of the more frequently used large animal models, especially porcine models for preclinical studies. PMID- 21253494 TI - Rabbit model of retinoblastoma. AB - We created a rabbit model of retinoblastoma and confirmed the tumor clinically and histopathologically. Seventeen New Zealand rabbits were immunosuppressed with cyclosporin A at doses of 10-15 mg/kg. At day 3, the animals received a 30 MUl subretinal injection of 1 x 106 cultured WERI retinoblastoma cells. Digital fundus images were captured before euthanasia, and the eyes were submitted for histopathology. Retinoblastoma cells grew in all the inoculated eyes and established a tumor under the retina and/or in the vitreous. New blood vessels in the tumor were observed starting at week 5. Cuffs of viable tumor cells surrounded the blood vessels with regions of necrosis present at 70-80 MUm from nutrient vessels. Occasional tumor seeds in the vitreous histologically exhibited central necrosis. This rabbit model demonstrated similar fundus appearance and pathologic features to human retinoblastoma and may be used as a model to test various routes of drug delivery for retinoblastoma. PMID- 21253495 TI - Pathobiology of hodgkin lymphoma. AB - Despite its well-known histological and clinical features, Hodgkin's lymphoma (HL) has recently been the object of intense research activity, leading to a better understanding of its phenotype, molecular characteristics, histogenesis, and possible mechanisms of lymphomagenesis. There is complete consensus on the B cell derivation of the tumor in most cases, and on the relevance of Epstein-Barr virus infection and defective cytokinesis in at least a proportion of patients. The REAL/WHO classification recognizes a basic distinction between lymphocyte predominance HL (LP-HL) and classic HL (cHL), reflecting the differences in clinical presentation and behavior, morphology, phenotype, and molecular features. cHL has been classified into four subtypes: lymphocyte rich, nodular sclerosing, with mixed cellularity, and lymphocyte depleted. The borders between cHL and anaplastic large-cell lymphoma have become sharper, whereas those between LP-HL and T-cell-rich B-cell lymphoma remain ill defined. Treatments adjusted to the pathobiological characteristics of the tumor in at-risk patients have been proposed and are on the way to being applied. PMID- 21253496 TI - Leber's Hereditary Optic Neuropathy-Gene Therapy: From Benchtop to Bedside. AB - Leber's hereditary optic neuropathy (LHON) is a maternally transmitted disorder caused by point mutations in mitochondrial DNA (mtDNA). Most cases are due to mutations in genes encoding subunits of the NADH-ubiquinone oxidoreductase that is Complex I of the electron transport chain (ETC). These mutations are located at nucleotide positions 3460, 11778, or 14484 in the mitochondrial genome. The disease is characterized by apoplectic, bilateral, and severe visual loss. While the mutated mtDNA impairs generation of ATP by all mitochondria, there is only a selective loss of retinal ganglion cells and degeneration of optic nerve axons. Thus, blindness is typically permanent. Half of the men and 10% of females who harbor the pathogenic mtDNA mutation actually develop the phenotype. This incomplete penetrance and gender bias is not fully understood. Additional mitochondrial and/or nuclear genetic factors may modulate the phenotypic expression of LHON. In a population-based study, the mtDNA background of haplogroup J was associated with an inverse relationship of low-ATP generation and increased production of reactive oxygen species (ROS). Effective therapy for LHON has been elusive. In this paper, we describe the findings of pertinent published studies and discuss the controversies of potential strategies to ameliorate the disease. PMID- 21253497 TI - Antibiotic Treatment of Dogs and Cats during Pregnancy. AB - The use of pharmacological agents in pregnant females poses a major clinical challenge due to the marked physiological changes that may modify the pharmacokinetics of drugs and to the potential effects on the fetus. The purpose of this paper is to review briefly our knowledge on the use of antibacterial drugs during pregnancy and to provide information for the judicious selection of an antimicrobial treatment for use in pregnant bitches and queens. The risk to the fetus is a result of the ability of a drug to reach the fetal circulation and to produce toxic effects. The placenta functions as a barrier that protects the fetus due to the presence of transporters and metabolising enzymes; however, during pregnancy, the presence and activity of both enzymes and transporters may change. Antimicrobial agents that have been shown to be safe for use during pregnancy include betalactams, macrolides, and lincosamides. Pharmacotherapy during pregnancy in all species may affect adversely the developing fetus; therefore, it should be avoided when possible. PMID- 21253498 TI - Gene by sex interaction for measures of obesity in the framingham heart study. AB - Obesity is an increasingly prevalent and severe health concern with a substantial heritable component and marked sex differences. We sought to determine if the effect of genetic variants also differed by sex by performing a genome-wide association study modeling the effect of genotype-by-sex interaction on obesity phenotypes. Genotype data from individuals in the Framingham Heart Study Offspring cohort were analyzed across five exams. Although no variants showed genome-wide significant gene-by-sex interaction in any individual exam, four polymorphisms displayed a consistent BMI association (P-values .00186 to .00010) across all five exams. These variants were clustered downstream of LYPLAL1, which encodes a lipase/esterase expressed in adipose tissue, a locus previously identified as having sex-specific effects on central obesity. Primary effects in males were in the opposite direction from females and were replicated in Framingham Generation 3. Our data support a sex-influenced association between genetic variation at the LYPLAL1 locus and obesity-related traits. PMID- 21253499 TI - Efficacy of dietary behavior modification for preserving cardiovascular health and longevity. AB - Cardiovascular disease (CVD) and its predisposing risk factors are major lifestyle and behavioral determinants of longevity. Dietary lifestyle choices such as a heart healthy diet, regular exercise, a lean weight, moderate alcohol consumption, and smoking cessation have been shown to substantially reduce CVD and increase longevity. Recent research has shown that men and women who adhere to this lifestyle can substantially reduce their risk of coronary heart disease (CHD). The preventive benefits of maintaining a healthy lifestyle exceed those reported for using medication and procedures. Among the modifiable preventive measures, diet is of paramount importance, and recent data suggest some misconceptions and uncertainties that require reconsideration. These include commonly accepted recommendations about polyunsaturated fat intake, processed meat consumption, fish choices and preparation, transfatty acids, low carbohydrate diets, egg consumption, coffee, added sugar, soft drink beverages, glycemic load, chocolate, orange juice, nut consumption, vitamin D supplements, food portion size, and alcohol. PMID- 21253501 TI - The Fetus as a Cardiac Patient: Assessment and Therapy of Cardiovascular Pathology before Birth. PMID- 21253500 TI - The traditional Japanese formula keishibukuryogan inhibits the production of inflammatory cytokines by dermal endothelial cells. AB - Keishibukuryogan (KBG) is one of the traditional herbal formulations widely administered to patients with blood stagnation for improving blood circulation; currently, it is the most frequently prescribed medicine in Japan. KBG has been reported to improve conjunctional microcirculation. The aim of this study was to evaluate the role of KBG and paeoniflorin, a bioactive compound of KBG, in inhibiting the production of inflammatory cytokines using human dermal microvessel endothelial cells (HDMECs). The authors observed that lipopolysaccharide (LPS; 1 MUg/mL) stimulated the secretion of proinflammatory cytokines in HDMECs. KBG treatment (10 mg/mL) significantly suppressed the mRNA levels of migration inhibitory factor (MIF), interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-alpha in LPS-stimulated cultured HDMECs. Similarly, paeoniflorin significantly suppressed the mRNA levels of these cytokines in LPS stimulated cultured HDMECs. ELISA showed that KBG and paeoniflorin suppressed the production of MIF, IL-6, IL-8, and TNF-alpha in LPS-stimulated HDMECs. Moreover, KBG and paeoniflorin decreased the expression of cyclooxygenase-2 and inducible nitric oxide synthase (iNOS) in these cells. These results suggest that KBG may be useful for improving microvascular inflammation in patients with skin diseases. PMID- 21253502 TI - Short-Term Prognostic Index for Breast Cancer: NPI or Lpi. AB - Axillary lymph node involvement is an important prognostic factor for breast cancer survival but is confounded by the number of nodes examined. We compare the performance of the log odds prognostic index (Lpi), using a ratio of the positive versus negative lymph nodes, with the Nottingham Prognostic Index (NPI) for short term breast cancer specific disease free survival. A total of 1818 operable breast cancer patients treated in the University Hospital of Leuven between 2000 and 2005 were included. The performance of the NPI and Lpi were compared on two levels: calibration and discrimination. The latter was evaluated using the concordance index (cindex), the number of patients in the extreme groups, and difference in event rates between these. The NPI had a significant higher cindex, but a significant lower percentage of patients in the extreme risk groups. After updating both indices, no significant differences between NPI and Lpi were noted. PMID- 21253503 TI - A rabbit model of thrombosis on atherosclerotic lesions. AB - Thrombus formation on a disrupted atherosclerotic plaque is a key event that leads to atherothrombosis. Because thrombus is induced by chemical or physical injury of normal arteries in most animal models of thrombosis, the mechanisms of thrombogenesis and thrombus growth in atherosclerotic vessels should be investigated in diseased arteries of appropriate models. Pathological findings of human atherothrombosis suggest that tissue factor, an initiator of the coagulation cascade, significantly affects enhanced platelet aggregation and fibrin formation after plaque disruption. We established a rabbit model of atherothrombosis based on human pathology in which differences in thrombus formation between normal and atherosclerotic arteries, factors contributing to thrombus growth, and mechanisms of plaque erosion can be investigated. Emerging transgenic and stem cell technologies should also provide an invaluable rabbit experimental model in the near future. PMID- 21253504 TI - Epigenetic regulation of apoptosis and cell cycle in osteosarcoma. AB - The role of genetic mutations in the development of osteosarcoma, such as alterations in p53 and Rb, is well understood. However, the significance of epigenetic mechanisms in the progression of osteosarcoma remains unclear and is increasingly being investigated. Recent evidence suggests that epigenetic alterations such as methylation and histone modifications of genes involved in cell cycle regulation and apoptosis may contribute to the pathogenesis of this tumor. Importantly, understanding the molecular mechanisms of regulation of these pathways may give insight into novel therapeutic strategies for patients with osteosarcoma. This paper serves to summarize the described epigenetic mechanisms in the tumorigenesis of osteosarcoma, specifically those pertaining to apoptosis and cell cycle regulation. PMID- 21253505 TI - Effects of calcium ion, calpains, and calcium channel blockers on retinitis pigmentosa. AB - Recent advances in molecular genetic studies have revealed many of the causative genes of retinitis pigmentosa (RP). These achievements have provided clues to the mechanisms of photoreceptor degeneration in RP. Apoptosis is known to be a final common pathway in RP and, therefore, a possible therapeutic target for photoreceptor rescue. However, apoptosis is not a single molecular cascade, but consists of many different reactions such as caspase-dependent and caspase independent pathways commonly leading to DNA fractionation and cell death. The intracellular concentration of calcium ions is also known to increase in apoptosis. These findings suggest that calpains, one of the calcium-dependent proteinases, play some roles in the process of photoreceptor apoptosis and that calcium channel antagonists may potentially inhibit photoreceptor apoptosis. Herein, the effects of calpains and calcium channel antagonists on photoreceptor degeneration are reviewed. PMID- 21253506 TI - Maternal serum levels of TNF-alpha and IL-6 long after delivery in preeclamptic and normotensive pregnant women. AB - AIM: To evaluate maternal TNF-alpha and IL-6 plasma levels in normotensive pregnant women, women with preeclampsia, and to examine the temporal changes in their levels from the antepartum to the postpartum period correlated with the regression of preeclampsia. METHOD: A prospective study was performed in the 2nd Department of Obstetrics and Gynecology, University of Athens. Blood samples were obtained: (1) antepartum at the time of clinical diagnosis of the syndrome, 2. 12 14 weeks postpartum. RESULTS: No statistically significant differences were found in IL-6 levels, whereas a difference was found in TNF-alpha levels between preeclamptic and controls in antepartum period (0.80 pg/ml versus 0.60 pg/ml, P : .04). Long after delivery, TNF-alpha levels were significantly higher in preeclamptic compared to normotensive controls (0.86 pg/ml versus 0.60 pg/ml, P : .004). No difference was observed in TNF-alpha before and after delivery in both groups. No difference was noticed in IL-6 levels in women of normotensive group long after delivery compared to that before delivery. Long after delivery IL-6 levels were statistically significant higher in preeclamptic women compared to normal controls (3.53 +/- 0.52 pg/ml versus 1.69 +/- 0.48 pg/ml, P : .02). CONCLUSION: Preeclamptic women remain under a status of increased inflammatory stress up to 12-14 weeks postpartum despite the fact that all the other signs of preeclampsia are resolved. PMID- 21253507 TI - Blood-brain barrier integrity and breast cancer metastasis to the brain. AB - Brain metastasis, an important cause of cancer morbidity and mortality, occurs in at least 30% of patients with breast cancer. A key event of brain metastasis is the migration of cancer cells through the blood-brain barrier (BBB). Although preventing brain metastasis is immensely important for survival, very little is known about the early stage of transmigration and the molecular mechanisms of breast tumor cells penetrating the BBB. The brain endothelium plays an important role in brain metastasis, although the mechanisms are not clear. Brain Microvascular Endothelial Cells (BMECs) are the major cellular constituent of the BBB. BMECs are joined together by intercellular tight junctions (TJs) that are responsible for acquisition of highly selective permeability. Failure of the BBB is a critical event in the development and progression of several diseases that affect the CNS, including brain tumor metastasis development. Here, we have delineated the mechanisms of BBB impairment and breast cancer metastasis to the brain. Understanding the molecular mediators that cause changes in the BBB should lead to better strategies for effective treatment modalities targeted to inhibition of brain tumors. PMID- 21253508 TI - Treatment of Obesity-Related Complications with Novel Classes of Naturally Occurring PPAR Agonists. AB - The prevalence of obesity and its associated comorbidities has grown to epidemic proportions in the US and worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely. Activation of peroxisome proliferator-activated receptors (PPARs) alpha, gamma, and delta through several classes of pharmaceuticals can prevent or treat a variety of metabolic and inflammatory diseases, including type II diabetes (T2D). Thus, PPARs represent important molecular targets for developing novel and better treatments for a wide range of debilitating and widespread obesity-related diseases and disorders. However, available PPAR gamma agonistic drugs such as Avandia have significant adverse side effects, including weight gain, fluid retention, hepatotoxicity, and congestive heart failure. An alternative to synthetic agonists of PPAR gamma is the discovery and development of naturally occurring and safer nutraceuticals that may be dual or pan PPAR agonists. The purpose of this paper is to summarize the health effects of three plant-derived PPAR agonists: abscisic acid (ABA), punicic acid (PUA), and catalpic acid (CAA) in the prevention and treatment of chronic inflammatory and metabolic diseases and disorders. PMID- 21253510 TI - Involvement of the soluble urokinase receptor in chondrosarcoma cell mobilization. AB - High levels of urokinase receptor (uPAR) in tissue and serum of patients with chondrosarcoma correlate with poor prognosis. First, we analyzed the uPAR levels in tissues and plasma of five patients affected by chondrosarcoma. Interestingly, very high levels of uPAR and its soluble forms (SuPAR) were found on tumor cell surfaces and plasma, respectively, of two patients with lung metastases. Therefore, to investigate the role of SuPAR in chondrosaromas, we generated a primary cell culture from a chondrosarcoma tissue overexpressing uPAR on cell surfaces. We found that chondrosarcoma-like primary culture cells release a large amount of SuPAR in the medium. In vitro, SuPAR elicits chondrosarcoma cell migration likely through its uPAR(88-92) sequence, since the DII(88-183) or DIIDIIR(88-284) uPAR domains retain motogen effect whereas DI(1-87) or DIII(184 284) domains, both lacking the uPAR(88-92) sequence, are ineffective. Chondrosarcoma cells cross matrigel in response to SuPAR, and their invasion capability is abrogated by RERF peptide which inhibits uPAR(88-92) signalling. These findings assign a role to uPAR in mobilizing chondrosarcoma cells and suggest that RERF peptide may be regarded as a prototype to generate new therapeutics for the chondrosarcoma treatment. PMID- 21253509 TI - Reverse genetics modification of cytomegalovirus antigenicity and immunogenicity by CD8 T-cell epitope deletion and insertion. AB - The advent of cloning herpesviral genomes as bacterial artificial chromosomes (BACs) has made herpesviruses accessible to bacterial genetics and has thus revolutionised their mutagenesis. This opened all possibilities of reverse genetics to ask scientific questions by introducing precisely accurate mutations into the viral genome for testing their influence on the phenotype under study or to create phenotypes of interest. Here, we report on our experience with using BAC technology for a designed modulation of viral antigenicity and immunogenicity with focus on the CD8 T-cell response. One approach is replacing an intrinsic antigenic peptide in a viral carrier protein with a foreign antigenic sequence, a strategy that we have termed "orthotopic peptide swap". Another approach is the functional deletion of an antigenic peptide by point mutation of its C-terminal MHC class-I anchor residue. We discuss the concepts and summarize recently published major scientific results obtained with immunological mutants of murine cytomegalovirus. PMID- 21253511 TI - Conditional gene targeting: dissecting the cellular mechanisms of retinal degenerations. AB - Retinal neuron degeneration and survival are often regulated by the same trophic factors that are required for embryonic development and are usually expressed in multiple cell-types. Therefore, the conditional gene targeting approach is necessary to investigate the cell-specific function of widely expressed and developmentally regulated genes in retinal degeneration. The discussion in this review will be focused on the use of Cre/lox-based conditional gene targeting approach in mechanistic studies for retinal degeneration. In addition to the basic experimental designs, this article addresses various factors influencing the outcomes of conditional gene targeting studies, limitations of current technologies, availability of Cre-drive lines for various retinal cells, and issues related to the generation of Cre-expressing mice. Finally, this review will update the current status on the use of Cre/lox-based gene targeting approach in mechanistic studies for retinal degeneration, which includes rod photoreceptor survival under photo-oxidative stress and protein trafficking in photoreceptors. PMID- 21253513 TI - Perspectives of CB1 Antagonist in Treatment of Obesity: Experience of RIO-Asia. AB - Rimonabant, a selective cannabinoid-1 (CB1) receptor antagonist, has been shown to reduce weight and enhance improvements in cardiometabolic risk parameters in Western populations. This study assessed these effects of rimonabant in Asian population. A total of 643 patients (BMI 25 kg/m(2) or greater without diabetes) from China, Republic of Korea, and Taiwan were prescribed a hypocaloric diet (600 kcal/day deficit) and randomized to rimonabant 20 mg (n = 318) or placebo (n = 325) for 9months. The primary efficacy variable was weight change from baseline after 9 months of treatment. Results showed that rimonabant group lost more weight than placebo, (LSM +/- SEM of -4.7 +/- 0.3 kg vs. -1.7 +/- 0.3 kg, P < .0001). The 5% and 10% responders were 2 or 3 folds more in the rimonabant group (53.0% vs. 20.0% and 21.5% vs. 5.7%, resp.) (P < .0001). Rimonabant also significantly increased HDL-cholesterol, decreased triglycerides and waist circumference,by 7.1%, 10.6%, and 2.8 cm, respectively (P < .0001). This study confirmed the comparable efficacy and safety profile of rimonabant in Asian population to Caucasians. Owing to the recent suspension of all the CB1 antagonists off the pharmaceutical market for weight reduction in Europe and USA, a perspective in drug discovery for intervening peripheral CB1 receptor in the management of obesity is discussed. PMID- 21253512 TI - Impact of orlistat-induced weight loss on diastolic function and heart rate variability in severely obese subjects with diabetes. AB - Objective. Determine the impact of Orlistat-induced weight loss on metabolic profile and cardiovascular function in severely obese patients with type 2 diabetes. Methods. Twenty-nine patients were randomized either to a nonplacebo control group or to a treatment group with Orlistat thrice a day. Metabolic profile, anthropometric parameters, heart rate variability indices, and echocardiographic variables were measured before and after a 12-week treatment period. Results. Treatment with Orlistat induced a modest but significant weight loss compared to controls (3.7 +/- 3.0 versus 0.5 +/- 2.2 kg, resp.; P = .003). There was significant decrease in fasting glycemia (7.9 +/- 3.0 versus 6.7 +/- 2.2 mmol/L; P = .03) and significant improvements in left ventricular diastolic function (P = .03) and in the sympathovagal balance (LF/HF ratio) (P = .04) in the Orlistat group. Conclusion. These results suggest that a modest weight loss improves fasting glycemia, left ventricular diastolic function, and sympathovagal balance in severely obese patients with type 2 diabetes. PMID- 21253514 TI - Gender differences of plaque characteristics in elderly patients with stable angina pectoris: an intravascular ultrasonic radiofrequency data analysis. AB - The purpose of this study was to evaluate the relation between gender and plaque characteristics assessed by virtual histology-intravascular ultrasound (VH-IVUS) in patients with stable angina pectoris. Preinterventional VH-IVUS image was available for analysis in 88 men and 60 women patients. Women had significantly smaller vessel volume (12.7 +/- 3.9 versus 14.5 +/- 4.2 mm(3)/mm, P = .01) and smaller plaque volume (8.4 +/- 3.5 versus 9.7 +/- 3.5 mm(3)/mm, P = .04). However, these differences were no longer significant when corrected for body surface area (BSA). In VH-IVUS analysis, women had significantly higher dense calcium when corrected for BSA in the culprit lesion (volume: 0.32 +/- 0.26 versus 0.44 +/- 0.40 mm(3)/mm/BSA, P = .03; proportion: 8.2 +/- 6.1 versus 11.2 +/- 7.6%, P = .009). VH-IVUS analysis of plaque components in elderly patients with stable angina showed that women had higher calcium contents compared with men. PMID- 21253515 TI - Aerobic exercise and whole-body vibration in offsetting bone loss in older adults. AB - Osteoporosis and its associated fractures are common complications of aging and most strategies to prevent and/or treat bone loss focused on antiresorptive medications. However, aerobic exercise (AEX) and/or whole-body vibration (WBV) might have beneficial effect on bone mass and provide an alternative approach to increase or maintain bone mineral density (BMD) and reduce the risk of fractures. The purpose of this paper was to investigate the potential benefits of AEX and WBV on BMD in older population and discuss the possible mechanisms of action. Several online databases were utilized and based on the available literature the consensus is that both AEX and WBV may increase spine and femoral BMD in older adults. Therefore, AEX and WBV could serve as nonpharmacological and complementary approaches to increasing/maintaining BMD. However, it is uncertain if noted effects could be permanent and further studies are needed to investigate sustainability of either type of the exercise. PMID- 21253516 TI - Case report: late complication of a dry socket treatment. AB - Dry socket is often treated in dentistry with intra-alveolar dressings; the use of them remains controversial and has been related to some side effects such as neuritis, foreign body reactions, and myospherulosis. We present a case of an intra-alveolar dressing (zinc-oxide eugenol paste) that mimicked a trigeminal neuralgia for 3 years and caused a right maxillary chronic osteomyelitis and foreign body reaction in a zone corresponding to the alveolus of the maxillary first molar. This long-term complication was successfully managed by complete removal of the foreign body and curettage of the affected area. PMID- 21253518 TI - The natural history of globus pharyngeus. AB - Globus pharyngeus is a common disorder and accounts for 5% of all ENT referrals. Objectives. To evaluate the role of barium swallow and endoscopy in these patients, to ascertain the incidence, if any, of aerodigestive tract malignancy in this group and to assess the natural evolution of globus pharyngeus. Materials and Methods. Seventy-nine patients underwent barium swallow and rigid oesophagoscopy for globus pharyngeus between January 2005 and October 2008. Fifty five patients were contacted by phone on average 5 years and 3 months after intervention and asked if their symptoms still persisted. Twenty-four patients were uncontactable or lost to followup, three patients were deceased, two of cardiac related disease and one of renal failure. Results. The majority of patients, 36 of 55 (65%), had a normal barium swallow. Forty-five of 55 (82%) of patients had normal rigid endoscopies. Thirty-one of 55 (56%) patients were at an average followup time of 5 years and 3 months. No patient developed a malignant lesion. Conclusion. Globus pharyngeus is a relatively common but benign condition of indeterminate origin. Our study demonstrates that many of these patients spontaneously improve with time. PMID- 21253517 TI - Cardiovascular Complications in CKD Patients: Role of Oxidative Stress. AB - Starting with the early stages, patients with chronic kidney disease (CKD) experience higher burden of cardiovascular disease (CVD). Moreover, CVD complications are the major cause of mortality in CKD patients as compared with complications from chronic kidney failure. While traditional CVD risk factors, including diabetes, hypertension, hyperlipidemia, obesity, physical inactivity, may be more prevalent among CKD patients, these factors seem to underestimate the accelerated cardiovascular disease in the CKD population. Search for additional biomarkers that could explain the enhanced CVD risk in CKD patients has gained increasing importance. Although it is unlikely that any single nontraditional risk factor would fully account for the increased CVD risk in individuals with CKD, oxidative stress appears to play a central role in the development and progression of CVD and its complications. We will review the data that support the contribution of oxidative stress in the pathogenesis of CVD in patients with chronic kidney failure. PMID- 21253519 TI - Obesity hypertension: the regulatory role of leptin. AB - Leptin is a 16-kDa-peptide hormone that is primarily synthesized and secreted by adipose tissue. One of the major actions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake and elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect mechanisms, may play an important role in cardiovascular and renal regulation. While the relevance of endogenous leptin needs further clarification, it appears to function as a pressure and volume-regulating factor under conditions of health. However, in abnormal situations characterized by chronic hyperleptinemia such as obesity, it may function pathophysiologically for the development of hypertension and possibly also for direct renal, vascular, and cardiac damage. PMID- 21253520 TI - Role of the rostral ventrolateral medulla in the arterial hypertension in chronic renal failure. AB - Sympathetic activation in chronic renal failure (CRF) is a major mechanism leading to the progression of renal disease and hypertension. In the present study, we tested the hypothesis that in CRF increased reactive oxygen species (ROS) production in the RVLM mediated by enhanced circulating Angiotensin II (Ang II) is an important mechanism leading to hypertension in CRF. In CRF rats we found an increase in the abundance of p47(phox) and gp91(phox) mRNA within the RVLM associated with a reduction of Ang II type 1 receptors (AT(1)) mRNA in the brainstem compared to controls (C). Tempol but not candesartan into the RVLM decreased MAP in CRF but not in C rats. GABA into the RVLM decreased MAP in CRF (63 +/- 8 mmHg) more intensely than in C (33 +/- 3 mmHg). The results suggest that increased oxidative stress within the RVLM has an important participation to maintain hypertension in CRF rats apparently independently of AT(1) Ang II receptors. PMID- 21253521 TI - Immunotherapy for renal cell carcinoma. AB - Immunotherapy plays a significant role in the management of renal cell carcinoma (RCC) patients with metastatic disease because RCC is highly resistant to both chemotherapy and radiation therapy. Many reports illustrate various approaches to the treatment of RCC, such as cytokine-, antigen- or dendritic cell- (DC-) based immunotherapy, and the safety and effectiveness of immunotherapy have been highlighted by multiple clinical trials. Although antitumor immune responses and clinically significant outcomes have been achieved in these trials, the response rate is still low, and very few patients show long-term clinical improvement. Recently, the importance of immune regulation by antigen-presenting cells (APC) and regulatory T cells (Treg cells) has also been discussed. The authors outline the principles of cell-mediated tumor immunotherapy and discuss clinical trials of immunotherapy for RCC. PMID- 21253522 TI - Assessing the Health Needs of Chinese Older Adults: Findings from a Community Based Participatory Research Study in Chicago's Chinatown. AB - The objective of this study is to examine the cultural views of healthy aging, knowledge and barriers to services, and perception of health sciences research among community-dwelling Chinese older adults in Chicago's Chinatown. This qualitative study is guided by the Precede-Proceed conceptual model with community-based participatory research design. Data analysis is based on eight focus group interviews with Chinese older (age 60+) adults (n = 78). We used a grounded theory framework to systematically guide the thematic structure of our data. Findings show participants described cultural conception of health in terms of physical function, psychological well-being, social support, and cognitive function. The availability, affordability, and cultural barriers towards health care services were major negative enabling factors that inhibit participants from fulfilling health needs. Perception and knowledge of health sciences research were also discussed. This study has implications for the delivery of culturally appropriate health care services to the Chinese aging population. PMID- 21253524 TI - Effects of IFN-B on TRAIL and Decoy Receptor Expression in Different Immune Cell Populations from MS Patients with Distinct Disease Subtypes. AB - Using quantitative RT-PCR, we compared mRNA levels for TRAIL [tumor necrosis factor (TNF)-related apoptosis-inducing ligand] and its receptors in various immune cell subsets derived from the peripheral blood of untreated normal subjects (NS) and patients with distinct subtypes of multiple sclerosis (MS): active relapsing-remitting MS (RRA), quiescent relapsing-remitting MS (RRQ), secondary-progressive MS (SPMS) or primary-progressive MS (PPMS). Consistent with a role for TRAIL in the mechanism of action of interferon-beta (IFN-beta), TRAIL mRNA levels were increased in monocytes from patients clinically responsive to IFN-beta (RRQ) but not those unresponsive to this therapeutic (RRA). TRAIL-R3 (decoy receptor) expression was elevated in T cells from untreated RRMS patients while IFN-beta therapy reversed this increase suggesting that IFN-beta may promote the apoptotic elimination of autoreactive T cells by increasing the amount of TRAIL available to activate TRAIL death receptors. Serum concentrations of soluble TRAIL were increased to a similar extent by IFN-beta therapy in RRQ, RRA and SPMS patients that had not generated neutralizing antibodies against this cytokine. Although our findings suggest altered TRAIL signaling may play a role in MS pathogenesis and IFN-beta therapy, they do not support use of TRAIL as a surrogate marker for clinical responsiveness to this therapeutic. PMID- 21253523 TI - Brain imaging of nicotinic receptors in Alzheimer's disease. AB - Neuronal nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated ion channels which are widely distributed in the human brain. Several lines of evidence suggest that two major subtypes (alpha4beta2 and alpha7) of nAChRs play an important role in the pathophysiology of Alzheimer's disease (AD). Postmortem studies demonstrated alterations in the density of these subtypes of nAChRs in the brain of patients with AD. Currently, nAChRs are one of the most attractive therapeutic targets for AD. Therefore, several researchers have made an effort to develop novel radioligands that can be used to study quantitatively the distribution of these two subtypes in the human brain with positron emission tomography (PET) and single-photon emission computed tomography (SPECT). In this paper, we discuss the current topics on in vivo imaging of two subtypes of nAChRs in the brain of patients with AD. PMID- 21253525 TI - Bovine model of doxorubicin-induced cardiomyopathy. AB - Left ventricular assist devices (LVADs) constitute a recent advance in heart failure (HF) therapeutics. As the rigorous experimental assessment of LVADs in HF requires large animal models, our objective was to develop a bovine model of cardiomyopathy. Male calves (n = 8) were used. Four animals received 1.2 mg/kg intravenous doxorubicin weekly for seven weeks and four separate animals were studied as controls. Doxorubicin-treated animals were followed with weekly echocardiography. Target LV dysfunction was defined as an ejection fraction <= 35%. Sixty days after initiating doxorubicin, a terminal study was performed to determine hemodynamic, histological, biochemical, and molecular parameters. All four doxorubicin-treated animals exhibited significant (P < 0.05) contractile dysfunction, with target LV dysfunction achieved in three animals. Doxorubicin treated hearts exhibited significantly reduced coronary blood flow and interstitial fibrosis and significantly increased apoptosis and myocyte size. Gene expression of atrial natriuretic factor increased more than 3-fold. Plasma norepinephrine and epinephrine levels were significantly increased early and late during the development of cardiomyopathy, respectively. We conclude that sequential administration of intravenous doxorubicin in calves induces a cardiomyopathy with many phenotypic hallmarks of the failing human heart. This clinically-relevant model may be useful for testing pathophysiologic responses to LVADs in the context of HF. PMID- 21253526 TI - Major limb replantation. PMID- 21253527 TI - Skin lesions in the upper lip/nasal region. PMID- 21253528 TI - Cooperation of cancer stem cell properties and epithelial-mesenchymal transition in the establishment of breast cancer metastasis. AB - Epithelial-mesenchymal transition (EMT) is a multistep process in which cells acquire molecular alterations such as loss of cell-cell junctions and restructuring of the cytoskeleton. There is an increasing understanding that this process may promote breast cancer progression through promotion of invasive and metastatic tumor growth. Recent observations imply that there may be a cross-talk between EMT and cancer stem cell properties, leading to enhanced tumorigenicity and the capacity to generate heterogeneous tumor cell populations. Here, we review the experimental and clinical evidence for the involvement of EMT in cancer stem cell theory, focusing on the common characteristics of this phenomenon. PMID- 21253529 TI - The cardiorenal syndrome: a review. AB - Cardiorenal syndrome (CRS) is the umbrella term used to describe clinical conditions in which cardiac and renal dysfunctions coexist. Much has been written on this subject, but underlying pathophysiological mechanisms continue to be unravelled and implications for management continue to be debated. A classification system-incorporating five subtypes-has recently been proposed though it has yet to permeate into day-to-day clinical practice. CRS has garnered much attention from both the cardiological and nephrological communities since the condition is associated with significant morbidity and mortality. Renal dysfunction is highly prevalent amongst patients with heart failure and has been shown to be as powerful and independent a marker of adverse prognosis as ejection fraction. Similarly, patients with renal failure are considerably more likely to suffer cardiovascular disease than matched subjects from the general population. This paper begins by reviewing the epidemiology and classification of CRS before going on to consider the different pathological mechanisms underlying cardiorenal dysfunction. We then focus on management strategies and conclude by discussing future directions in the diagnosis and management of patients suffering with CRS. PMID- 21253530 TI - HDAC activity is required for efficient core promoter function at the mouse mammary tumor virus promoter. AB - Histone deacetylases (HDACs) have been shown to be required for basal or inducible transcription at a variety of genes by poorly understood mechanisms. We demonstrated previously that HDAC inhibition rapidly repressed transcription from the mouse mammary tumor virus (MMTV) promoter by a mechanism that does not require the binding of upstream transcription factors. In the current study, we find that HDACs work through the core promoter sequences of MMTV as well as those of several cellular genes to facilitate transcriptional initiation through deacetylation of nonhistone proteins. PMID- 21253531 TI - A factor analytic approach to symptom patterns in dementia. AB - Previous publications have shown a high diagnostic sensitivity and specificity of three short clinical rating scales for Alzheimer's disease (AD), frontotemporal dementia (FTD), and vascular dementia (VaD) validated against neuropathological (NP) diagnoses. In this study, the aim was to perform an exploratory factor analysis of the items in these clinical rating scales. The study included 190 patients with postmortem diagnoses of AD (n = 74), VaD (n = 33), mixed AD/VaD (n = 31), or FTD (n = 52). The factor analysis produced three strong factors. Factor 1 contained items describing cerebrovascular disease, similar to the Hachinski Ischemic Score. Factor 2 enclosed major clinical characteristics of FTD, and factor 3 showed a striking similarity to the AD scale. A fourth symptom cluster was described by perception and expression of emotions. The factor analyses strongly support the construct validity of the diagnostic rating scales. PMID- 21253533 TI - Novel Organotin(IV)-Schiff Base Complexes: Synthesis, Characterization, Antimicrobial Activity, and DNA Interaction Studies. AB - Four organotin(IV) complexes with 2-(2-hydroxybenzylideneamino)isoindoline-1,3 dione (L(1)), and 4-(4-hydroxy-3-methoxybenzylideneamino-N-(pyrimidin-2 yl)benzenesulfonamide (L(2)) were synthesized and well characterized by analytical and spectral studies. The synthesized compounds were tested for antimicrobial activity by disc diffusion method. The DNA binding of the complexes 1 and 3 with CT-DNA has been performed with absorption spectroscopy, which showed that both the complexes are avid binders of CT-DNA. Also the nuclease activity of complexes 1 and 3 with plasmid DNA (pUC19) was studied using agarose gel electrophoresis. The complex 1 can act as effective DNA cleaving agent when compared to complex 3 resulting in the nicked form of DNA under physiological conditions. The gel was run both in the absence and presence of the oxidizing agent. PMID- 21253532 TI - Prognostication and Risk-Adapted Therapy of Hodgkin's Lymphoma Using Positron Emission Tomography. AB - The use of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) for response assessment in lymphoma is now widespread. Prognostic information obtained from PET performed after two to three cycles of chemotherapy may guide more individualized, risk-adapted therapeutic strategies. Progress in the risk stratification of Hodgkin's lymphoma through midtreatment PET is reviewed, with a focus on management implications in newly diagnosed and relapsed disease. How to tailor treatment on the basis of the interim PET result is not yet defined but is the subject of ongoing trials. PMID- 21253534 TI - IL23R and IL12B SNPs and Haplotypes Strongly Associate with Crohn's Disease Risk in a New Zealand Population. AB - DNA samples from 339 Crohn's disease (CD) and 407 randomly selected controls from the Auckland (New Zealand) IBD project, were genotyped for five common single nucleotide polymorphisms in IL-23R (rs11805303, rs7517847, rs1343151, rs11209026, and rs10889677) and two in IL-12B (rs1363670 and rs6887695). While the IL-12B variants did not show an overall association and other IL23R variants led to minor changes in the risk of CD, rs1343151 and/or rs7517847 variants in the IL 23R gene strongly reduced the risk of developing CD at both allelic and genotype levels. A significantly decreased risk of first diagnosis of childhood CD was observed in individuals carrying the A allele of rs1343151, or between 17-40 y in individuals carrying the G allele in rs7517847 of IL-23R. A significantly decreased risk of ileocolonic or structuring disease was observed in individuals carrying the A allele in either rs11209026 or rs1343151, or the G allele in rs7517847 of IL-23R, and when such individuals did develop the disease, they were unlikely to require a bowel resection. Certain haplotypes very strongly modified risk. There was evidence for interactions of IL-23R variants with the NOD2 wild type (d/d) genotype. Down-regulating the function of the IL-23R gene may decrease CD risk in the normal population. PMID- 21253535 TI - Development of bioartificial myocardium using stem cells and nanobiotechnology templates. AB - Cell-based regenerative therapy is undergoing experimental and clinical trials in cardiology, in order to limit the consequences of decreased contractile function and compliance of damaged ventricles following myocardial infarction. Over 1000 patients have been treated worldwide with cell-based procedures for myocardial regeneration. Cellular cardiomyoplasty seems to reduce the size and fibrosis of infarct scars, limit adverse postischemic remodelling, and improve diastolic function. The development of a bioartificial myocardium is a new challenge; in this approach, tissue-engineered procedures are associated with cell therapy. Organ decellularization for bioscaffolds fabrication is a new investigated concept. Nanomaterials are emerging as the main candidates to ensure the achievement of a proper instructive cellular niche with good drug release/administration properties. Investigating the electrophysiological properties of bioartificial myocardium is the challenging objective of future research, associating a multielectrode network to provide electrical stimulation could improve the coupling of grafted cells and scaffolds with host cardiomyocytes. In summary, until now stem cell transplantation has not achieved clear hemodynamic benefits for myocardial diseases. Supported by relevant scientific background, the development of myocardial tissue engineering may constitute a new avenue and hope for the treatment of myocardial diseases. PMID- 21253537 TI - Semiquantitative assessment of bowel habits and its relation with calcium metabolism after gastric bypass surgery: a retrospective study. AB - Background. Calcium malabsorption after bariatric surgery may be harmful to skeletal health and demands for optimal skeletal management. Methods. 103 Patients were evaluated retrospectively at 12 months after surgery. The evaluation included a questionnaire about stool frequency and consistency and laboratory assessments. Results. 103 Patients, 27 males and 76 females, were included in the study. 83 Patients had an alimentary limb of 100 cm and 20 patients one of 150 cm. At 12 months after surgery, 77.7% reported changes of bowel habits, albumin adjusted calcium levels were normal in all but 2 patients, and PTH levels were increased in 35%. Correlations between semiquantified bowel scores (fecal scores) and data from the laboratory demonstrated increasing PTH values along with more frequent and softer/watery stools (RR 30.5, CI 6.2-149.2, P < .001). There was a trend for higher PTH levels in patients with an alimentary limb of 150 cm. Normal PTH levels were more frequently found in case of calcium and vitamin D3 use (RR 14.3, CI 3.6-56.5, P < .001). Conclusion. This study demonstrates interrelationships between semi-quantified fecal scores, PTH levels, and the compliance of taking calcium/vitamin D3 suppletion. However, prospective randomized studies are necessary to show causal relationships. PMID- 21253536 TI - Xenobiotic exposure and autoimmune hepatitis. AB - Although genetics contributes to the development of autoimmune diseases, it is clear that "environmental" factors are also required. These factors are thought to encompass exposure to certain drugs and environmental pollutants. This paper examines the mechanisms that normally maintain immune unresponsiveness in the liver and discusses how exposure to certain xenobiotics such as trichloroethylene may disrupt those mechanisms and promote autoimmune hepatitis. PMID- 21253538 TI - Recent advancements in toxin and antitoxin systems involved in bacterial programmed cell death. AB - Programmed cell death (PCD) systems have been extensively studied for their significant role in a variety of biological processes in eukaryotic organisms. Recently, more and more researches have revealed the existence of similar systems employed by bacteria in response to various environmental stresses. This paper summarized the recent researching advancements in toxin/antitoxin systems located on plasmids or chromosomes and their regulatory roles in bacterial PCD. The most studied yet disputed mazEF system was discussed in depth, and possible roles and status of such a special bacterial death and TA systems were also reviewed from the ecological and evolutionary perspectives. PMID- 21253539 TI - Application of a chairside anaerobic culture test for endodontic treatment. AB - Periapical lesions are caused by bacterial infections. The fundamental objective of endodontic treatment is to eliminate bacteria present in the root canal system because they play an important role in the development and maintenance of periapical lesions. Therefore, confirming the absence of bacteria before filling root canals is important. Anaerobic culture tests have been used in many endodontic cases, and they have brought about good treatment outcomes. These tests, however, require specific apparatuses and bacteriological techniques. Here, we report a chairside anaerobic culture test that does not require any specialized apparatuses or techniques. We also report two endodontic cases in which this simple test was used. Both patients were diagnosed with chronic purulent periapical lesions. After confirming the absence of bacteria in the root canals, they were filled with gutta-percha points. At followup, the radiolucencies showed recovery, although longterm observation is under way. From these results, the authors conclude that this simple chairside anaerobic culture test is effective for evaluating periapical lesion treatment procedures. PMID- 21253541 TI - Breast cancer in developing countries: opportunities for improved survival. AB - Breast cancer survival in the USA has continually improved over the last six decades and has largely been accredited to the use of mammography, advanced surgical procedures, and adjuvant therapies. Data indicate, however, that there were substantial improvements in survival in the USA even prior to these technological and diagnostic advances, suggesting important opportunities for early detection and treatment in low- and middle-income countries where these options are often unavailable and/or unaffordable. Thus, while continuing to strive for increased access to more advanced technology, improving survival in these settings should be more immediately achievable through increased awareness of breast cancer and of the potential for successful treatment, a high-quality primary care system without economic or cultural barriers to access, and a well functioning referral system for basic surgical and hormonal treatment. PMID- 21253540 TI - Methanogens: methane producers of the rumen and mitigation strategies. AB - Methanogens are the only known microorganisms capable of methane production, making them of interest when investigating methane abatement strategies. A number of experiments have been conducted to study the methanogen population in the rumen of cattle and sheep, as well as the relationship that methanogens have with other microorganisms. The rumen methanogen species differ depending on diet and geographical location of the host, as does methanogenesis, which can be reduced by modifying dietary composition, or by supplementation of monensin, lipids, organic acids, or plant compounds within the diet. Other methane abatement strategies that have been investigated are defaunation and vaccines. These mitigation methods target the methanogen population of the rumen directly or indirectly, resulting in varying degrees of efficacy. This paper describes the methanogens identified in the rumens of cattle and sheep, as well as a number of methane mitigation strategies that have been effective in vivo. PMID- 21253542 TI - Torsade de Pointes due to Methadone Use in a Patient with HIV and Hepatitis C Coinfection. AB - We present a case of Torsade de Pointes secondary to multiple factors including patient susceptibility and iatrogenic influences. Contributing causes are presented, and the approach to treatment is discussed. PMID- 21253543 TI - Nanotechnology and dental implants. AB - The long-term clinical success of dental implants is related to their early osseointegration. This paper reviews the different steps of the interactions between biological fluids, cells, tissues, and surfaces of implants. Immediately following implantation, implants are in contact with proteins and platelets from blood. The differentiation of mesenchymal stem cells will then condition the peri implant tissue healing. Direct bone-to-implant contact is desired for a biomechanical anchoring of implants to bone rather than fibrous tissue encapsulation. Surfaces properties such as chemistry and roughness play a determinant role in these biological interactions. Physicochemical features in the nanometer range may ultimately control the adsorption of proteins as well as the adhesion and differentiation of cells. Nanotechnologies are increasingly used for surface modifications of dental implants. Another approach to enhance osseointegration is the application of thin calcium phosphate (CaP) coatings. Bioactive CaP nanocrystals deposited on titanium implants are resorbable and stimulate bone apposition and healing. Future nanometer-controlled surfaces may ultimately direct the nature of peri-implant tissues and improve their clinical success rate. PMID- 21253545 TI - Exercise in Children during Health and Sickness. PMID- 21253544 TI - Cellular and Molecular Characteristics of Scarless versus Fibrotic Wound Healing. AB - The purpose of this paper is to compare and contrast the discrete biology differentiating fetal wound repair from its adult counterpart. Integumentary wound healing in mammalian fetuses is essentially different from wound healing in adult skin. Adult (postnatal) skin wound healing is a complex and well orchestrated process spurred by attendant inflammation that leads to wound closure with scar formation. In contrast, fetal wound repair occurs with minimal inflammation, faster re-epithelialization, and without the accumulation of scar. Although research into scarless healing began decades ago, the critical molecular mechanisms driving the process of regenerative fetal healing remain uncertain. Understanding the molecular and cellular events during regenerative healing may provide clues that one day enable us to modulate adult wound healing and consequently reduce scarring. PMID- 21253546 TI - Human Herpesvirus-8 Infection Associated with Kaposi Sarcoma, Multicentric Castleman's Disease, and Plasmablastic Microlymphoma in a Man with AIDS: A Case Report with Review of Pathophysiologic Processes. AB - Kaposi sarcoma (KS), multicentric Castleman's disease (MCD), and plasmablastic microlymphoma, are all linked to human herpesvirus-8 (HHV-8) infection and HIV induced immunodeficiency. Herein, we describe the case of a Kenyan man diagnosed with HIV in 2000. He deferred highly active antiretroviral therapy (HAART) and remained in good health until his CD4+ count declined in 2006. He was hospitalized with bacterial pneumonia in 2008, after which he agreed to take HAART but did so sporadically. In 2010, he was hospitalized with fever, lymphadenopathy, pancytopenia, and an elevated HHV-8 viral load. A lymph node biopsy showed findings consistent with KS, MCD, and plasmablastic microlymphoma. Eight months after starting liposomal doxorubicin, Rituximab, and a new HAART regimen, he has improved clinically, and his HIV and HHV-8 viral loads are suppressed. These three conditions, found in the same lymph node, underscore the inflammatory and malignant potential of HHV-8, particularly in the milieu of HIV induced immunodeficiency. PMID- 21253547 TI - Gonadal Dysgenesis 46, XX Associated with Mayer-Rokitansky-Kuster-Hauser Syndrome: One Case Report. AB - Introduction. The association of gonadal dysgenesis and Mayer-Rokitansky-Kuster Hauser syndrome is very rare and appears to be coincidental, independent of chromosomal anomalies. Case Report. We report the case of a 19-year-old woman who presented primary amenorrhea and impuberism. The endocrine study revealed hypergonadotrophic hypogonadism. The karyotype was normal, 46XX. No chromosome Y was detected at the FISH analysis. Internal genitalia could not be identified on the pelvic ultrasound and pelvic MRI. Laparoscopy was undertaken and revealed concomitant ovarian dysgenesis and Mayer-Rokitansky-Kuster-Hauser syndrome. There were no other morphological malformations. Conclusion. The pathogenesis of the association of gonadal dysgenesis and Mayer Rokitansky kuster hauser syndrome is still mysterious. The treatment is based essentially on hormone substitution therapy. The fertility prognosis is unfortunately compromised. PMID- 21253548 TI - Survivin selectively modulates genes deregulated in human leukemia stem cells. AB - ITD-Flt3 mutations are detected in leukemia stem cells (LSCs) in acute myeloid leukemia (AML) patients. While antagonizing Survivin normalizes ITD-Flt3-induced acute leukemia, it also impairs hematopoietic stem cell (HSC) function, indicating that identification of differences in signaling pathways downstream of Survivin between LSC and HSC are crucial to develop selective Survivin-based therapeutic strategies for AML. Using a Survivin-deletion model, we identified 1,096 genes regulated by Survivin in ITD-Flt3-transformed c-kit(+), Sca-1(+), and lineage(neg) (KSL) cells, of which 137 are deregulated in human LSC. Of the 137, 124 genes were regulated by Survivin exclusively in ITD-Flt3(+) KSL cells but not in normal CD34(neg) KSL cells. Survivin-regulated genes in LSC connect through a network associated with the epidermal growth factor receptor signaling pathway and falls into various functional categories independent of effects on apoptosis. Pathways downstream of Survivin in LSC that are distinct from HSC can be potentially targeted for selective anti-LSC therapy. PMID- 21253549 TI - In Vitro Activity of Geldanamycin Derivatives against Schistosoma japonicum and Brugia malayi. AB - Geldanamycin (GA) is a benzoquinone-containing ansamycin that inhibits heat shock protein 90. GA derivatives are being evaluated as anti-neoplastic agents, but their utility against parasites whose heat shock proteins (Hsps) have homology with human Hsp90 is unknown. The activities of four synthetic GA derivatives were tested in vitro using adult Brugia malayi and Schistosoma japonicum. Two of the derivatives, 17-N-allyl-17-demethoxygeldanamycin (17-AAG) and 17-N-(2 dimethylaminoethylamino)-17-demethoxygeldanamycin (DMAG), are currently in human clinical trials as anticancer drugs. Using concentrations considered safe peak plasma concentrations for these two derivatives, all four derivatives were active against both parasites. The less toxic derivative 17-AAG was as effective as GA in killing S. japonicum, and both DMAG and 5'-bromogeldanoxazinone were more active than 17-AAG against B. malayi. This work supports continued evaluation of ansamycin derivatives as broad spectrum antiparasitic agents. PMID- 21253550 TI - Effect of Metal Chelators on gamma-Secretase Indicates That Calcium and Magnesium Ions Facilitate Cleavage of Alzheimer Amyloid Precursor Substrate. AB - Gamma-secretase is involved in the production of Abeta amyloid peptides. It cleaves the transmembrane domain of the amyloid precursor protein (APP) at alternative sites to produce Abeta and the APP intracellular domain (AICD). Metal ions play an important role in Abeta aggregation and metabolism, thus metal chelators and ligands represent potential therapeutic agents for AD treatment. A direct effect of metal chelators on gamma-secretase has not yet been investigated. The authors used an in vitro gamma-secretase assay consisting of cleavage of APP C100-3XFLAG by endogenous gamma-secretase from rodent brains and human neuroblastoma SH-SY5Y, and detected AICD production by western blotting. Adding metalloprotease inhibitors to the reaction showed that clioquinol, phosphoramidon, and zinc metalloprotease inhibitors had no significant effect on gamma-secretase activity. In contrast, phenanthroline, EDTA, and EGTA markedly decreased gamma-secretase activity that could be restored by adding back calcium and magnesium ions. Mg(2+) stabilized a 1,000 kDa presenilin 1 complex through blue native gel electrophoresis and size-exclusion chromatography. Data suggest that Ca(2+) and Mg(2+) stabilize gamma-secretase and enhance its activity. PMID- 21253551 TI - Basal cell carcinoma: from the molecular understanding of the pathogenesis to targeted therapy of progressive disease. AB - Due to intensified research over the past decade, the Hedgehog (HH) pathway has been identified as a pivotal defect implicated in roughly 25% of all cancers. As one of the most frequent cancer worldwide, the development of Basal cell carcinoma (BCC) due to activation of the HH pathway has been convincingly demonstrated. Thus the discovery of this central tumor-promoting signalling pathway has not only revolutionized the understanding of BCC carcinogenesis but has also enabled the development of a completely novel therapeutic approach. Targeting just a few of several potential mutations, HH inhibitors such as GDC 0449 achieved already the first promising results in metastatic or locally advanced BCC. This paper summarizes the current understanding of BCC carcinogenesis and describes the current "mechanism-based" therapeutic strategies. PMID- 21253552 TI - Occurrence of type 1 diabetes in graves' disease patients who are positive for antiglutamic Acid decarboxylase antibodies: an 8-year followup study. AB - Glutamic acid decarboxylase antibodies (GADAs) are one of the markers of islet cell autoimmunity and are sometimes present before the onset of type 1 diabetes (T1D). GADA can be present in Graves' patients without diabetes; however, the outcome of GADA-positive Graves' patients is not fully understood, and the predictive value of GADA for the development of T1D in Graves' patients remains to be clarified. We investigated the prevalence of GADA in 158 patients with Graves' disease and detected GADA in 10 patients. They were followed up to discover whether or not T1D developed. In the course of eight years, 2 patients with high titers of GADA developed T1D, both had long-standing antithyroid drug resistant Graves' disease. Thus, Graves' disease with high GADA titer seems to be at high risk for T1D. PMID- 21253553 TI - The discussion goes on: What is the role of Euryarchaeota in humans? AB - The human body (primarily the intestinal tract, the oral cavity, and the skin) harbours approximately 1,000 different bacterial species. However, the number of archaeal species known to colonize man seems to be confined to a handful of organisms within the class Euryarchaeota (including Methanobrevibacter smithii, M. oralis, and Methanosphaera stadtmanae). In contrast to this conspicuously low diversity of Archaea in humans their unique physiology in conjunction with the growing number of reports regarding their occurrence at sites of infection has made this issue an emerging field of study. While previous review articles in recent years have addressed the putative role of particularly methanogenic archaea for human health and disease, this paper compiles novel experimental data that have been reported since then. The aim of this paper is to inspire the scientific community of "Archaea experts" for those unique archaeal organisms that have successfully participated in the human-microbe coevolution. PMID- 21253555 TI - Measuring the evolutionary rewiring of biological networks. AB - We have accumulated a large amount of biological network data and expect even more to come. Soon, we anticipate being able to compare many different biological networks as we commonly do for molecular sequences. It has long been believed that many of these networks change, or "rewire", at different rates. It is therefore important to develop a framework to quantify the differences between networks in a unified fashion. We developed such a formalism based on analogy to simple models of sequence evolution, and used it to conduct a systematic study of network rewiring on all the currently available biological networks. We found that, similar to sequences, biological networks show a decreased rate of change at large time divergences, because of saturation in potential substitutions. However, different types of biological networks consistently rewire at different rates. Using comparative genomics and proteomics data, we found a consistent ordering of the rewiring rates: transcription regulatory, phosphorylation regulatory, genetic interaction, miRNA regulatory, protein interaction, and metabolic pathway network, from fast to slow. This ordering was found in all comparisons we did of matched networks between organisms. To gain further intuition on network rewiring, we compared our observed rewirings with those obtained from simulation. We also investigated how readily our formalism could be mapped to other network contexts; in particular, we showed how it could be applied to analyze changes in a range of "commonplace" networks such as family trees, co-authorships and linux-kernel function dependencies. PMID- 21253556 TI - Relationships between gene expression and brain wiring in the adult rodent brain. AB - We studied the global relationship between gene expression and neuroanatomical connectivity in the adult rodent brain. We utilized a large data set of the rat brain "connectome" from the Brain Architecture Management System (942 brain regions and over 5000 connections) and used statistical approaches to relate the data to the gene expression signatures of 17,530 genes in 142 anatomical regions from the Allen Brain Atlas. Our analysis shows that adult gene expression signatures have a statistically significant relationship to connectivity. In particular, brain regions that have similar expression profiles tend to have similar connectivity profiles, and this effect is not entirely attributable to spatial correlations. In addition, brain regions which are connected have more similar expression patterns. Using a simple optimization approach, we identified a set of genes most correlated with neuroanatomical connectivity, and find that this set is enriched for genes involved in neuronal development and axon guidance. A number of the genes have been implicated in neurodevelopmental disorders such as autistic spectrum disorder. Our results have the potential to shed light on the role of gene expression patterns in influencing neuronal activity and connectivity, with potential applications to our understanding of brain disorders. Supplementary data are available at http://www.chibi.ubc.ca/ABAMS. PMID- 21253554 TI - Liposarcoma: molecular genetics and therapeutics. AB - Sarcomas are a group of heterogeneous tumours with varying genetic basis. Cytogenetic abnormalities range from distinct genomic rearrangements such as pathognomonic translocation events and common chromosomal amplification or loss, to more complex rearrangements involving multiple chromosomes. The different subtypes of liposarcoma are spread across this spectrum and constitute an interesting tumour type for molecular review. This paper will outline molecular pathogenesis of the three main subtypes of liposarcoma: well differentiated/dedifferentiated, myxoid/round cell, and pleomorphic liposarcoma. Both the molecular basis and future avenues for therapeutic intervention will be discussed. PMID- 21253557 TI - Predicting novel binding modes of agonists to beta adrenergic receptors using all atom molecular dynamics simulations. AB - Understanding the binding mode of agonists to adrenergic receptors is crucial to enabling improved rational design of new therapeutic agents. However, so far the high conformational flexibility of G protein-coupled receptors has been an obstacle to obtaining structural information on agonist binding at atomic resolution. In this study, we report microsecond classical molecular dynamics simulations of beta(1) and beta(2) adrenergic receptors bound to the full agonist isoprenaline and in their unliganded form. These simulations show a novel agonist binding mode that differs from the one found for antagonists in the crystal structures and from the docking poses reported by in silico docking studies performed on rigid receptors. Internal water molecules contribute to the stabilization of novel interactions between ligand and receptor, both at the interface of helices V and VI with the catechol group of isoprenaline as well as at the interface of helices III and VII with the ethanolamine moiety of the ligand. Despite the fact that the characteristic N-C-C-OH motif is identical in the co-crystallized ligands and in the full agonist isoprenaline, the interaction network between this group and the anchor site formed by Asp(3.32) and Asn(7.39) is substantially different between agonists and inverse agonists/antagonists due to two water molecules that enter the cavity and contribute to the stabilization of a novel network of interactions. These new binding poses, together with observed conformational changes in the extracellular loops, suggest possible determinants of receptor specificity. PMID- 21253558 TI - Thermodynamic stability of histone H3 is a necessary but not sufficient driving force for its evolutionary conservation. AB - Determining the forces that conserve amino acid positions in proteins across species is a fundamental pursuit of molecular evolution. Evolutionary conservation is driven by either a protein's function or its thermodynamic stability. Highly conserved histone proteins offer a platform to evaluate these driving forces. While the conservation of histone H3 and H4 "tail" domains and surface residues are driven by functional importance, the driving force behind the conservation of buried histone residues has not been examined. Using a computational approach, we determined the thermodynamically preferred amino acids at each buried position in H3 and H4. In agreement with what is normally observed in proteins, we find a significant correlation between thermodynamic stability and evolutionary conservation in the buried residues in H4. In striking contrast, we find that thermodynamic stability of buried H3 residues does not correlate with evolutionary conservation. Given that these H3 residues are not post translationally modified and only regulate H3-H3 and H3-H4 stabilizing interactions, our data imply an unknown function responsible for driving conservation of these buried H3 residues. PMID- 21253560 TI - Ten simple rules for getting ahead as a computational biologist in Academia. PMID- 21253559 TI - A novel approach to pharmacodynamic assessment of antimicrobial agents: new insights to dosing regimen design. AB - Pharmacodynamic modeling has been increasingly used as a decision support tool to guide dosing regimen selection, both in the drug development and clinical settings. Killing by antimicrobial agents has been traditionally classified categorically as concentration-dependent (which would favor less fractionating regimens) or time-dependent (for which more frequent dosing is preferred). While intuitive and useful to explain empiric data, a more informative approach is necessary to provide a robust assessment of pharmacodynamic profiles in situations other than the extremes of the spectrum (e.g., agents which exhibit partial concentration-dependent killing). A quantitative approach to describe the interaction of an antimicrobial agent and a pathogen is proposed to fill this unmet need. A hypothetic antimicrobial agent with linear pharmacokinetics is used for illustrative purposes. A non-linear functional form (sigmoid Emax) of killing consisted of 3 parameters is used. Using different parameter values in conjunction with the relative growth rate of the pathogen and antimicrobial agent concentration ranges, various conventional pharmacodynamic surrogate indices (e.g., AUC/MIC, Cmax/MIC, %T>MIC) could be satisfactorily linked to outcomes. In addition, the dosing intensity represented by the average kill rate of a dosing regimen can be derived, which could be used for quantitative comparison. The relevance of our approach is further supported by experimental data from our previous investigations using a variety of gram-negative bacteria and antimicrobial agents (moxifloxacin, levofloxacin, gentamicin, amikacin and meropenem). The pharmacodynamic profiles of a wide range of antimicrobial agents can be assessed by a more flexible computational tool to support dosing selection. PMID- 21253561 TI - Neural development features: spatio-temporal development of the Caenorhabditis elegans neuronal network. AB - The nematode Caenorhabditis elegans, with information on neural connectivity, three-dimensional position and cell linage, provides a unique system for understanding the development of neural networks. Although C. elegans has been widely studied in the past, we present the first statistical study from a developmental perspective, with findings that raise interesting suggestions on the establishment of long-distance connections and network hubs. Here, we analyze the neuro-development for temporal and spatial features, using birth times of neurons and their three-dimensional positions. Comparisons of growth in C. elegans with random spatial network growth highlight two findings relevant to neural network development. First, most neurons which are linked by long-distance connections are born around the same time and early on, suggesting the possibility of early contact or interaction between connected neurons during development. Second, early-born neurons are more highly connected (tendency to form hubs) than later-born neurons. This indicates that the longer time frame available to them might underlie high connectivity. Both outcomes are not observed for random connection formation. The study finds that around one-third of electrically coupled long-range connections are late forming, raising the question of what mechanisms are involved in ensuring their accuracy, particularly in light of the extremely invariant connectivity observed in C. elegans. In conclusion, the sequence of neural network development highlights the possibility of early contact or interaction in securing long-distance and high-degree connectivity. PMID- 21253562 TI - A comprehensive model of the spatio-temporal stem cell and tissue organisation in the intestinal crypt. AB - We introduce a novel dynamic model of stem cell and tissue organisation in murine intestinal crypts. Integrating the molecular, cellular and tissue level of description, this model links a broad spectrum of experimental observations encompassing spatially confined cell proliferation, directed cell migration, multiple cell lineage decisions and clonal competition.Using computational simulations we demonstrate that the model is capable of quantitatively describing and predicting the dynamic behaviour of the intestinal tissue during steady state as well as after cell damage and following selective gain or loss of gene function manipulations affecting Wnt- and Notch-signalling. Our simulation results suggest that reversibility and flexibility of cellular decisions are key elements of robust tissue organisation of the intestine. We predict that the tissue should be able to fully recover after complete elimination of cellular subpopulations including subpopulations deemed to be functional stem cells. This challenges current views of tissue stem cell organisation. PMID- 21253563 TI - Decrypting the sequence of structural events during the gating transition of pentameric ligand-gated ion channels based on an interpolated elastic network model. AB - Despite many experimental and computational studies of the gating transition of pentameric ligand-gated ion channels (pLGICs), the structural basis of how ligand binding couples to channel gating remains unknown. By using a newly developed interpolated elastic network model (iENM), we have attempted to compute a likely transition pathway from the closed- to the open-channel conformation of pLGICs as captured by the crystal structures of two prokaryotic pLGICs. The iENM pathway predicts a sequence of structural events that begins at the ligand-binding loops and is followed by the displacements of two key loops (loop 2 and loop 7) at the interface between the extracellular and transmembrane domain, the tilting/bending of the pore-lining M2 helix, and subsequent movements of M4, M3 and M1 helices in the transmembrane domain. The predicted order of structural events is in broad agreement with the Phi-value analysis of alpha subunit of nicotinic acetylcholine receptor mutants, which supports a conserved core mechanism for ligand-gated channel opening in pLGICs. Further perturbation analysis has supported the critical role of certain intra-subunit and inter-subunit interactions in dictating the above sequence of events. PMID- 21253564 TI - Quaking regulates Hnrnpa1 expression through its 3' UTR in oligodendrocyte precursor cells. AB - In mice, Quaking (Qk) is required for myelin formation; in humans, it has been associated with psychiatric disease. QK regulates the stability, subcellular localization, and alternative splicing of several myelin-related transcripts, yet little is known about how QK governs these activities. Here, we show that QK enhances Hnrnpa1 mRNA stability by binding a conserved 3' UTR sequence with high affinity and specificity. A single nucleotide mutation in the binding site eliminates QK-dependent regulation, as does reduction of QK by RNAi. Analysis of exon expression across the transcriptome reveals that QK and hnRNP A1 regulate an overlapping subset of transcripts. Thus, a simple interpretation is that QK regulates a large set of oligodendrocyte precursor genes indirectly by increasing the intracellular concentration of hnRNP A1. Together, the data show that hnRNP A1 is an important QK target that contributes to its control of myelin gene expression. PMID- 21253565 TI - A mutation in the gene encoding mitochondrial Mg2+ channel MRS2 results in demyelination in the rat. AB - The rat demyelination (dmy) mutation serves as a unique model system to investigate the maintenance of myelin, because it provokes severe myelin breakdown in the central nervous system (CNS) after normal postnatal completion of myelination. Here, we report the molecular characterization of this mutation and discuss the possible pathomechanisms underlying demyelination. By positional cloning, we found that a G-to-A transition, 177 bp downstream of exon 3 of the Mrs2 (MRS2 magnesium homeostasis factor (Saccharomyces cerevisiae)) gene, generated a novel splice acceptor site which resulted in functional inactivation of the mutant allele. Transgenic rescue with wild-type Mrs2-cDNA validated our findings. Mrs2 encodes an essential component of the major Mg2+ influx system in mitochondria of yeast as well as human cells. We showed that the dmy/dmy rats have major mitochondrial deficits with a markedly elevated lactic acid concentration in the cerebrospinal fluid, a 60% reduction in ATP, and increased numbers of mitochondria in the swollen cytoplasm of oligodendrocytes. MRS2-GFP recombinant BAC transgenic rats showed that MRS2 was dominantly expressed in neurons rather than oligodendrocytes and was ultrastructurally observed in the inner membrane of mitochondria. Our observations led to the conclusion that dmy/dmy rats suffer from a mitochondrial disease and that the maintenance of myelin has a different mechanism from its initial production. They also established that Mg2+ homeostasis in CNS mitochondria is essential for the maintenance of myelin. PMID- 21253566 TI - Signaling role of fructose mediated by FINS1/FBP in Arabidopsis thaliana. AB - Sugars are evolutionarily conserved signaling molecules that regulate the growth and development of both unicellular and multicellular organisms. As sugar producing photosynthetic organisms, plants utilize glucose as one of their major signaling molecules. However, the details of other sugar signaling molecules and their regulatory factors have remained elusive, due to the complexity of the metabolite and hormone interactions that control physiological and developmental programs in plants. We combined information from a gain-of-function cell-based screen and a loss-of-function reverse-genetic analysis to demonstrate that fructose acts as a signaling molecule in Arabidopsis thaliana. Fructose signaling induced seedling developmental arrest and interacted with plant stress hormone signaling in a manner similar to that of glucose. For fructose signaling responses, the plant glucose sensor HEXOKINASE1 (HXK1) was dispensable, while FRUCTOSE INSENSITIVE1 (FINS1), a putative FRUCTOSE-1,6-BISPHOSPHATASE, played a crucial role. Interestingly, FINS1 function in fructose signaling appeared to be independent of its catalytic activity in sugar metabolism. Genetic analysis further indicated that FINS1-dependent fructose signaling may act downstream of the abscisic acid pathway, in spite of the fact that HXK1-dependent glucose signaling works upstream of hormone synthesis. Our findings revealed that multiple layers of controls by fructose, glucose, and abscisic acid finely tune the plant autotrophic transition and modulate early seedling establishment after seed germination. PMID- 21253568 TI - A novel RNA-recognition-motif protein is required for premeiotic G1/S-phase transition in rice (Oryza sativa L.). AB - The molecular mechanism for meiotic entry remains largely elusive in flowering plants. Only Arabidopsis SWI1/DYAD and maize AM1, both of which are the coiled coil protein, are known to be required for the initiation of plant meiosis. The mechanism underlying the synchrony of male meiosis, characteristic to flowering plants, has also been unclear in the plant kingdom. In other eukaryotes, RNA recognition-motif (RRM) proteins are known to play essential roles in germ-cell development and meiosis progression. Rice MEL2 protein discovered in this study shows partial similarity with human proline-rich RRM protein, deleted in Azoospermia-Associated Protein1 (DAZAP1), though MEL2 also possesses ankyrin repeats and a RING finger motif. Expression analyses of several cell-cycle markers revealed that, in mel2 mutant anthers, most germ cells failed to enter premeiotic S-phase and meiosis, and a part escaped from the defect and underwent meiosis with a significant delay or continued mitotic cycles. Immunofluorescent detection revealed that T7 peptide-tagged MEL2 localized at cytoplasmic perinuclear region of germ cells during premeiotic interphase in transgenic rice plants. This study is the first report of the plant RRM protein, which is required for regulating the premeiotic G1/S-phase transition of male and female germ cells and also establishing synchrony of male meiosis. This study will contribute to elucidation of similarities and diversities in reproduction system between plants and other species. PMID- 21253567 TI - Genome sequencing and comparative transcriptomics of the model entomopathogenic fungi Metarhizium anisopliae and M. acridum. AB - Metarhizium spp. are being used as environmentally friendly alternatives to chemical insecticides, as model systems for studying insect-fungus interactions, and as a resource of genes for biotechnology. We present a comparative analysis of the genome sequences of the broad-spectrum insect pathogen Metarhizium anisopliae and the acridid-specific M. acridum. Whole-genome analyses indicate that the genome structures of these two species are highly syntenic and suggest that the genus Metarhizium evolved from plant endophytes or pathogens. Both M. anisopliae and M. acridum have a strikingly larger proportion of genes encoding secreted proteins than other fungi, while ~30% of these have no functionally characterized homologs, suggesting hitherto unsuspected interactions between fungal pathogens and insects. The analysis of transposase genes provided evidence of repeat-induced point mutations occurring in M. acridum but not in M. anisopliae. With the help of pathogen-host interaction gene database, ~16% of Metarhizium genes were identified that are similar to experimentally verified genes involved in pathogenicity in other fungi, particularly plant pathogens. However, relative to M. acridum, M. anisopliae has evolved with many expanded gene families of proteases, chitinases, cytochrome P450s, polyketide synthases, and nonribosomal peptide synthetases for cuticle-degradation, detoxification, and toxin biosynthesis that may facilitate its ability to adapt to heterogeneous environments. Transcriptional analysis of both fungi during early infection processes provided further insights into the genes and pathways involved in infectivity and specificity. Of particular note, M. acridum transcribed distinct G-protein coupled receptors on cuticles from locusts (the natural hosts) and cockroaches, whereas M. anisopliae transcribed the same receptor on both hosts. This study will facilitate the identification of virulence genes and the development of improved biocontrol strains with customized properties. PMID- 21253569 TI - Genome-wide association study SNPs in the human genome diversity project populations: does selection affect unlinked SNPs with shared trait associations? AB - Genome-wide association studies (GWAS) have identified more than 2,000 trait-SNP associations, and the number continues to increase. GWAS have focused on traits with potential consequences for human fitness, including many immunological, metabolic, cardiovascular, and behavioral phenotypes. Given the polygenic nature of complex traits, selection may exert its influence on them by altering allele frequencies at many associated loci, a possibility which has yet to be explored empirically. Here we use 38 different measures of allele frequency variation and 8 iHS scores to characterize over 1,300 GWAS SNPs in 53 globally distributed human populations. We apply these same techniques to evaluate SNPs grouped by trait association. We find that groups of SNPs associated with pigmentation, blood pressure, infectious disease, and autoimmune disease traits exhibit unusual allele frequency patterns and elevated iHS scores in certain geographical locations. We also find that GWAS SNPs have generally elevated scores for measures of allele frequency variation and for iHS in Eurasia and East Asia. Overall, we believe that our results provide evidence for selection on several complex traits that has caused changes in allele frequencies and/or elevated iHS scores at a number of associated loci. Since GWAS SNPs collectively exhibit elevated allele frequency measures and iHS scores, selection on complex traits may be quite widespread. Our findings are most consistent with this selection being either positive or negative, although the relative contributions of the two are difficult to discern. Our results also suggest that trait-SNP associations identified in Eurasian samples may not be present in Africa, Oceania, and the Americas, possibly due to differences in linkage disequilibrium patterns. This observation suggests that non-Eurasian and non-East Asian sample populations should be included in future GWAS. PMID- 21253570 TI - The Caenorhabditis elegans mucin-like protein OSM-8 negatively regulates osmosensitive physiology via the transmembrane protein PTR-23. AB - The molecular mechanisms of animal cell osmoregulation are poorly understood. Genetic studies of osmoregulation in yeast have identified mucin-like proteins as critical regulators of osmosensitive signaling and gene expression. Whether mucins play similar roles in higher organisms is not known. Here, we show that mutations in the Caenorhabditis elegans mucin-like gene osm-8 specifically disrupt osmoregulatory physiological processes. In osm-8 mutants, normal physiological responses to hypertonic stress, such as the accumulation of organic osmolytes and activation of osmoresponsive gene expression, are constitutively activated. As a result, osm-8 mutants exhibit resistance to normally lethal levels of hypertonic stress and have an osmotic stress resistance (Osr) phenotype. To identify genes required for Osm-8 phenotypes, we performed a genome wide RNAi osm-8 suppressor screen. After screening ~18,000 gene knockdowns, we identified 27 suppressors that specifically affect the constitutive osmosensitive gene expression and Osr phenotypes of osm-8 mutants. We found that one suppressor, the transmembrane protein PTR-23, is co-expressed with osm-8 in the hypodermis and strongly suppresses several Osm-8 phenotypes, including the transcriptional activation of many osmosensitive mRNAs, constitutive glycerol accumulation, and osmotic stress resistance. Our studies are the first to show that an extracellular mucin-like protein plays an important role in animal osmoregulation in a manner that requires the activity of a novel transmembrane protein. Given that mucins and transmembrane proteins play similar roles in yeast osmoregulation, our findings suggest a possible evolutionarily conserved role for the mucin-plasma membrane interface in eukaryotic osmoregulation. PMID- 21253571 TI - H3K9me-independent gene silencing in fission yeast heterochromatin by Clr5 and histone deacetylases. AB - Nucleosomes in heterochromatic regions bear histone modifications that distinguish them from euchromatic nucleosomes. Among those, histone H3 lysine 9 methylation (H3K9me) and hypoacetylation have been evolutionarily conserved and are found in both multicellular eukaryotes and single-cell model organisms such as fission yeast. In spite of numerous studies, the relative contributions of the various heterochromatic histone marks to the properties of heterochromatin remain largely undefined. Here, we report that silencing of the fission yeast mating type cassettes, which are located in a well-characterized heterochromatic region, is hardly affected in cells lacking the H3K9 methyltransferase Clr4. We document the existence of a pathway parallel to H3K9me ensuring gene repression in the absence of Clr4 and identify a silencing factor central to this pathway, Clr5. We find that Clr5 controls gene expression at multiple chromosomal locations in addition to affecting the mating-type region. The histone deacetylase Clr6 acts in the same pathway as Clr5, at least for its effects in the mating-type region, and on a subset of other targets, notably a region recently found to be prone to neo-centromere formation. The genomic targets of Clr5 also include Ste11, a master regulator of sexual differentiation. Hence Clr5, like the multi-functional Atf1 transcription factor which also modulates chromatin structure in the mating type region, controls sexual differentiation and genome integrity at several levels. Globally, our results point to histone deacetylases as prominent repressors of gene expression in fission yeast heterochromatin. These deacetylases can act in concert with, or independently of, the widely studied H3K9me mark to influence gene silencing at heterochromatic loci. PMID- 21253572 TI - Biofilm development on Caenorhabditis elegans by Yersinia is facilitated by quorum sensing-dependent repression of type III secretion. AB - Yersinia pseudotuberculosis forms biofilms on Caenorhabditis elegans which block nematode feeding. This genetically amenable host-pathogen model has important implications for biofilm development on living, motile surfaces. Here we show that Y. pseudotuberculosis biofilm development on C. elegans is governed by N acylhomoserine lactone (AHL)-mediated quorum sensing (QS) since (i) AHLs are produced in nematode associated biofilms and (ii) Y. pseudotuberculosis strains expressing an AHL-degrading enzyme or in which the AHL synthase (ypsI and ytbI) or response regulator (ypsR and ytbR) genes have been mutated, are attenuated. Although biofilm formation is also attenuated in Y. pseudotuberculosis strains carrying mutations in the QS-controlled motility regulator genes, flhDC and fliA, and the flagellin export gene, flhA, flagella are not required since fliC mutants form normal biofilms. However, in contrast to the parent and fliC mutant, Yop virulon proteins are up-regulated in flhDC, fliA and flhA mutants in a temperature and calcium independent manner. Similar observations were found for the Y. pseudotuberculosis QS mutants, indicating that the Yop virulon is repressed by QS via the master motility regulator, flhDC. By curing the pYV virulence plasmid from the ypsI/ytbI mutant, by growing YpIII under conditions permissive for type III needle formation but not Yop secretion and by mutating the type III secretion apparatus gene, yscJ, we show that biofilm formation can be restored in flhDC and ypsI/ytbI mutants. These data demonstrate that type III secretion blocks biofilm formation and is reciprocally regulated with motility via QS. PMID- 21253573 TI - Structural basis for the recognition of cellular mRNA export factor REF by herpes viral proteins HSV-1 ICP27 and HVS ORF57. AB - The herpesvirus proteins HSV-1 ICP27 and HVS ORF57 promote viral mRNA export by utilizing the cellular mRNA export machinery. This function is triggered by binding to proteins of the transcription-export (TREX) complex, in particular to REF/Aly which directs viral mRNA to the TAP/NFX1 pathway and, subsequently, to the nuclear pore for export to the cytoplasm. Here we have determined the structure of the REF-ICP27 interaction interface at atomic-resolution and provided a detailed comparison of the binding interfaces between ICP27, ORF57 and REF using solution-state NMR. Despite the absence of any obvious sequence similarity, both viral proteins bind on the same site of the folded RRM domain of REF, via short but specific recognition sites. The regions of ICP27 and ORF57 involved in binding by REF have been mapped as residues 104-112 and 103-120, respectively. We have identified the pattern of residues critical for REF/Aly recognition, common to both ICP27 and ORF57. The importance of the key amino acid residues within these binding sites was confirmed by site-directed mutagenesis. The functional significance of the ORF57-REF/Aly interaction was also probed using an ex vivo cytoplasmic viral mRNA accumulation assay and this revealed that mutants that reduce the protein-protein interaction dramatically decrease the ability of ORF57 to mediate the nuclear export of intronless viral mRNA. Together these data precisely map amino acid residues responsible for the direct interactions between viral adaptors and cellular REF/Aly and provide the first molecular details of how herpes viruses access the cellular mRNA export pathway. PMID- 21253574 TI - Critical role of IRF-5 in the development of T helper 1 responses to Leishmania donovani infection. AB - The transcription factor Interferon Regulatory Factor 5 (IRF-5) has been shown to be involved in the induction of proinflammatory cytokines in response to viral infections and TLR activation and to play an essential role in the innate inflammatory response. In this study, we used the experimental model of visceral leishmaniasis to investigate the role of IRF-5 in the generation of Th1 responses and in the formation of Th1-type liver granulomas in Leishmania donovani infected mice. We show that TLR7-mediated activation of IRF-5 is essential for the development of Th1 responses to L. donovani in the spleen during chronic infection. We also demonstrate that IRF-5 deficiency leads to the incapacity to control L. donovani infection in the liver and to the formation of smaller granulomas. Granulomas in Irf5-/- mice are characterized by an increased IL-4 and IL-10 response and concomitant low iNOS expression. Collectively, these results identify IRF-5 as a critical molecular switch for the development of Th1 immune responses following L. donovani infections and reveal an indirect role of IRF-5 in the regulation of iNOS expression. PMID- 21253575 TI - Distinct patterns of IFITM-mediated restriction of filoviruses, SARS coronavirus, and influenza A virus. AB - Interferon-inducible transmembrane proteins 1, 2, and 3 (IFITM1, 2, and 3) are recently identified viral restriction factors that inhibit infection mediated by the influenza A virus (IAV) hemagglutinin (HA) protein. Here we show that IFITM proteins restricted infection mediated by the entry glycoproteins (GP(1,2)) of Marburg and Ebola filoviruses (MARV, EBOV). Consistent with these observations, interferon-beta specifically restricted filovirus and IAV entry processes. IFITM proteins also inhibited replication of infectious MARV and EBOV. We observed distinct patterns of IFITM-mediated restriction: compared with IAV, the entry processes of MARV and EBOV were less restricted by IFITM3, but more restricted by IFITM1. Moreover, murine Ifitm5 and 6 did not restrict IAV, but efficiently inhibited filovirus entry. We further demonstrate that replication of infectious SARS coronavirus (SARS-CoV) and entry mediated by the SARS-CoV spike (S) protein are restricted by IFITM proteins. The profile of IFITM-mediated restriction of SARS-CoV was more similar to that of filoviruses than to IAV. Trypsin treatment of receptor-associated SARS-CoV pseudovirions, which bypasses their dependence on lysosomal cathepsin L, also bypassed IFITM-mediated restriction. However, IFITM proteins did not reduce cellular cathepsin activity or limit access of virions to acidic intracellular compartments. Our data indicate that IFITM-mediated restriction is localized to a late stage in the endocytic pathway. They further show that IFITM proteins differentially restrict the entry of a broad range of enveloped viruses, and modulate cellular tropism independently of viral receptor expression. PMID- 21253576 TI - Molecular basis of increased serum resistance among pulmonary isolates of non typeable Haemophilus influenzae. AB - Non-typeable Haemophilus influenzae (NTHi), a common commensal of the human pharynx, is also an opportunistic pathogen if it becomes established in the lower respiratory tract (LRT). In comparison to colonizing isolates from the upper airway, LRT isolates, especially those associated with exacerbations of chronic obstructive pulmonary disease, have increased resistance to the complement- and antibody-dependent, bactericidal effect of serum. To define the molecular basis of this resistance, mutants constructed in a serum resistant strain using the mariner transposon were screened for loss of survival in normal human serum. The loci required for serum resistance contribute to the structure of the exposed surface of the bacterial outer membrane. These included loci involved in biosynthesis of the oligosaccharide component of lipooligosaccharide (LOS), and vacJ, which functions with an ABC transporter encoded by yrb genes in retrograde trafficking of phospholipids from the outer to inner leaflet of the cell envelope. Mutations in vacJ and yrb genes reduced the stability of the outer membrane and were associated with increased cell surface hyrophobicity and phospholipid content. Loss of serum resistance in vacJ and yrb mutants correlated with increased binding of natural immunoglobulin M in serum as well as anti oligosaccharide mAbs. Expression of vacJ and the yrb genes was positively correlated with serum resistance among clinical isolates. Our findings suggest that NTHi adapts to inflammation encountered during infection of the LRT by modulation of its outer leaflet through increased expression of vacJ and yrb genes to minimize recognition by bactericidal anti-oligosaccharide antibodies. PMID- 21253577 TI - A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages. AB - Parasitic worms alter their host's immune system to diminish the inflammatory responses directed against them, using very efficient immunomodulating molecules. We have previously shown that the helminth immunomodulator cystatin (AvCystatin) profoundly reduces the progression of inflammatory diseases via modulation of macrophages. Here we elucidate the signaling events in macrophages triggered by AvCystatin. Labeled AvCystatin was predominantly taken up by macrophages and subsequently induced the phosphorylation of the mitogen-activated protein kinases (MAPK) ERK1/2 and p38. IL-10 expression induced by AvCystatin in macrophages was tyrosine kinase sensitive and dependent on activation of both MAP kinases, in clear contrast to expression of IL-12/23p40. In addition, phosphorylation of the transcription factors CREB and STAT3 was induced by AvCystatin and regulated by phospho-ERK. Chemical inhibition of phosphoinositide 3-kinase (PI3K) reduced AvCystatin-induced cytokine release; however, AKT, the downstream target of PI3K, was not activated following AvCystatin exposure. To characterize signaling elements involved in alteration of the macrophage phenotype we applied mathematical modeling. Experimental testing of the in silico generated hypotheses identified dual specificity phosphatase (DUSP) 1 and 2, as regulators in AvCystatin triggered macrophages in vitro and in vivo. In particular, DUSP1 was subsequently found to be responsible for regulation of ERK- and p38 phosphorylation and controlled the IL-10 expression in macrophages by AvCystatin. Thus, we show that AvCystatin exploits activation and deactivation pathways of MAP kinases to induce regulatory macrophages. This study provides insights into molecular mechanisms of macrophage manipulation by parasites and highlights the utility of mathematical modeling for the elucidation of regulatory circuits of immune cells. PMID- 21253578 TI - Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. AB - Cholangiocarcinoma, also known as bile duct cancer, is the second most common primary hepatic carcinoma with a median survival of less than 2 years. The molecular mechanisms underlying the development of this disease are not clear. To survey activated tyrosine kinases signaling in cholangiocarcinoma, we employed immunoaffinity profiling coupled to mass spectrometry and identified DDR1, EPHA2, EGFR, and ROS tyrosine kinases, along with over 1,000 tyrosine phosphorylation sites from about 750 different proteins in primary cholangiocarcinoma patients. Furthermore, we confirmed the presence of ROS kinase fusions in 8.7% (2 out of 23) of cholangiocarcinoma patients. Expression of the ROS fusions in 3T3 cells confers transforming ability both in vitro and in vivo, and is responsive to its kinase inhibitor. Our data demonstrate that ROS kinase is a promising candidate for a therapeutic target and for a diagnostic molecular marker in cholangiocarcinoma. The identification of ROS tyrosine kinase fusions in cholangiocarcinoma, along with the presence of other ROS kinase fusions in lung cancer and glioblastoma, suggests that a more broadly based screen for activated ROS kinase in cancer is warranted. PMID- 21253579 TI - Dissecting the within-Africa ancestry of populations of African descent in the Americas. AB - BACKGROUND: The ancestry of African-descended Americans is known to be drawn from three distinct populations: African, European, and Native American. While many studies consider this continental admixture, few account for the genetically distinct sources of ancestry within Africa--the continent with the highest genetic variation. Here, we dissect the within-Africa genetic ancestry of various populations of the Americas self-identified as having primarily African ancestry using uniparentally inherited mitochondrial DNA. METHODS AND PRINCIPAL FINDINGS: We first confirmed that our results obtained using uniparentally-derived group admixture estimates are correlated with the average autosomal-derived individual admixture estimates (hence are relevant to genomic ancestry) by assessing continental admixture using both types of markers (mtDNA and Y-chromosome vs. ancestry informative markers). We then focused on the within-Africa maternal ancestry, mining our comprehensive database of published mtDNA variation (~5800 individuals from 143 African populations) that helped us thoroughly dissect the African mtDNA pool. Using this well-defined African mtDNA variation, we quantified the relative contributions of maternal genetic ancestry from multiple W/WC/SW/SE (West to South East) African populations to the different pools of today's African-descended Americans of North and South America and the Caribbean. CONCLUSIONS: Our analysis revealed that both continental admixture and within Africa admixture may be critical to achieving an adequate understanding of the ancestry of African-descended Americans. While continental ancestry reflects gender-specific admixture processes influenced by different socio-historical practices in the Americas, the within-Africa maternal ancestry reflects the diverse colonial histories of the slave trade. We have confirmed that there is a genetic thread connecting Africa and the Americas, where each colonial system supplied their colonies in the Americas with slaves from African colonies they controlled or that were available for them at the time. This historical connection is reflected in different relative contributions from populations of W/WC/SW/SE Africa to geographically distinct Africa-derived populations of the Americas, adding to the complexity of genomic ancestry in groups ostensibly united by the same demographic label. PMID- 21253580 TI - Novel concept of motor functional analysis for spinal cord injury in adult mice. AB - In basic research on spinal cord injury (SCI), behavioral evaluation of the SCI animal model is critical. However, it is difficult to accurately evaluate function in the mouse SCI model due to the small size of mice. Although the open field scoring scale is an outstanding appraisal method, supplementary objective tests are required. Using a compact SCANET system, in which a mouse carries out free movement for 5 min, we developed a novel method to detect locomotor ability. A SCANET system samples the horizontal coordinates of a mouse every 0.1 s, and both the speed and acceleration of its motion are calculated at each moment. It was found that the maximum speed and acceleration of motion over 5 min varied by injury severity. Moreover, these values were significantly correlated with open field scores. The maximum speed and acceleration of SCI model mice using a SCANET system are objective, easy to obtain, and reproducible for evaluating locomotive function. PMID- 21253581 TI - Morphological and molecular alterations in 1,2 dimethylhydrazine and azoxymethane induced colon carcinogenesis in rats. AB - The dimethyhydrazine (DMH) or azoxymethane (AOM) model is a well-established, well-appreciated, and widely used model of experimental colon carcinogenesis. It has many morphological as well as molecular similarities to human sporadic colorectal cancer (CC), which are summarized and discussed in this paper. In addition, the paper combines present knowledge of morphological and molecular features in the multistep development of CC recognized in the DMH/AOM rat model. This understanding is necessary in order to accurately identify and interpret alterations that occur in the colonic mucosa when evaluating natural or pharmacological compounds in DMH/AOM rat colon carcinogenesis. The DMH/AOM model provides a wide range of options for investigating various initiating and environmental factors, the role of specific dietary and genetic factors, and therapeutic options in CC. The limitations of this model and suggested areas in which more research is required are also discussed. PMID- 21253582 TI - Rodent models for metabolic syndrome research. AB - Rodents are widely used to mimic human diseases to improve understanding of the causes and progression of disease symptoms and to test potential therapeutic interventions. Chronic diseases such as obesity, diabetes and hypertension, together known as the metabolic syndrome, are causing increasing morbidity and mortality. To control these diseases, research in rodent models that closely mimic the changes in humans is essential. This review will examine the adequacy of the many rodent models of metabolic syndrome to mimic the causes and progression of the disease in humans. The primary criterion will be whether a rodent model initiates all of the signs, especially obesity, diabetes, hypertension and dysfunction of the heart, blood vessels, liver and kidney, primarily by diet since these are the diet-induced signs in humans with metabolic syndrome. We conclude that the model that comes closest to fulfilling this criterion is the high carbohydrate, high fat-fed male rodent. PMID- 21253583 TI - The development and the use of experimental animal models to study the underlying mechanisms of CA formation. AB - Cerebral aneurysms (CAs) have a high prevalence and can cause a lethal subarachnoid hemorrhage. Currently, CAs can only be treated with invasive surgical procedures. To unravel the underlying mechanisms of CA formation and to develop new therapeutic drugs for CAs, animal models of CA have been established, modified, and analyzed. Experimental findings from these models have clarified some of the potential mechanisms of CA formation, especially the relationship between hemodynamic stress and chronic inflammation. Increased hemodynamic stress acting at the site of bifurcation of cerebral arteries triggers an inflammatory response mediated by various proinflammatory molecules in arterial walls, inducing pathological changes in the models similar to those observed in the walls of human CAs. Findings from animal studies have provided new insights into CA formation and may contribute to the development of new therapeutic drugs for CAs. PMID- 21253584 TI - Current concepts: mouse models of Sjogren's syndrome. AB - Sjogren's syndrome (SjS) is a complex chronic autoimmune disease of unknown etiology which primarily targets the exocrine glands, resulting in eventual loss of secretory function. The disease can present as either primary SjS or secondary SjS, the latter of which occurs concomitantly with another autoimmune disease such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or primary biliary cirrhosis. Current advancements in therapeutic prevention and treatment for SjS are impeded by lack of understanding in the pathophysiological and clinical progression of the disease. Development of appropriate mouse models for both primary and secondary SjS is needed in order to advance knowledge of this disease. This paper details important features, advantages, and pitfalls of current animal models of SjS, including spontaneous, transgenic, knockout, immunization, and transplantation chimera mouse models, and emphasizes the need for a better model in representing the human SjS phenotype. PMID- 21253585 TI - Culture conversion among HIV co-infected multidrug-resistant tuberculosis patients in Tugela Ferry, South Africa. AB - BACKGROUND: Little is known about the time to sputum culture conversion in MDR-TB patients co-infected with HIV, although such patients have, historically, had poor outcomes. We describe culture conversion rates among MDR-TB patients with and without HIV-co-infection in a TB-endemic, high-HIV prevalent, resource limited setting. METHODS: Patients with culture-proven MDR-TB were treated with a standardized second-line regimen. Sputum cultures were taken monthly and conversion was defined as two negative cultures taken at least one month apart. Time-to-conversion was measured from the day of initiation of MDR-TB therapy. Subjects with HIV received antiretroviral therapy (ART) regardless of CD4 count. RESULTS: Among 45 MDR-TB patients, 36 (80%) were HIV-co-infected. Overall, 40 (89%) of the 45 patients culture-converted within the first six months and there was no difference in the proportion who converted based on HIV status. Median time-to-conversion was 62 days (IQR 48-111). Among the five patients who did not culture convert, three died, one was transferred to another facility, and one refused further treatment before completing 6 months of therapy. Thus, no patients remained persistently culture-positive at 6 months of therapy. CONCLUSIONS: With concurrent second-line TB and ART medications, MDR-TB/HIV co infected patients can achieve culture conversion rates and times similar to those reported from HIV-negative patients worldwide. Future studies are needed to examine whether similar cure rates are achieved at the end of MDR-TB treatment and to determine the optimal use and timing of ART in the setting of MDR-TB treatment. PMID- 21253586 TI - A novel role for Niemann-Pick disease type 2C protein in papillae formation. AB - BACKGROUND: Despite the presence of papillary structures and papillary tumors in humans, the mechanism of papillae formation is unknown. We describe herein a novel role for Niemann-Pick disease type 2C (NPC2) protein, a cholesterol binding protein in the lysosome, in papillae formation. METHODOLOGY/PRINCIPAL FINDING: We examined NPC2 protein expression in surgical samples of papillary tissues by immunohistochemical stain, and all papillary tissues expressed NPC2 protein in the epithelium. To examine our hypothesis of NPC2 protein-mediated papillae formation, we carried out xenograft experiments using wild H460 cells (large cell lung carcinoma cell line) that constitutively expressed abundant NPC2 protein and NPC2 protein-depleted H460 cells by NPC2 shRNA. The xenografts of wild H460 cells and empty shRNA vector cells showed distinct papillae formation, whereas NPC2 protein-depleted H460 cells displayed markedly reduced or no papillae. Since all papillary tissues have open spaces we examined whether NPC2 protein might also contribute to the creation of open spaces. The TUNEL assay in the xenografts of wild and empty shRNA vector H460 cells showed massive cell death, and NPC2 protein-depleted cells displayed minimal cell death. Measurement of caspase 3/7 activities in cultured H460 cells supported NPC2 protein-mediated apoptotic cell death. The presence of excess NPC2 protein, however, did not always produce papillae as seen in the xenografts of CHO cells that were stably transfected with NPC2. CONCLUSIONS/SIGNIFICANCE: The NPC2 protein of certain cells forms papillae coupled with apoptosis that creates open space. This protein may have future applications to modulate papillae formation and papillary growth in tumor tissues. PMID- 21253587 TI - Tobacco smoke mediated induction of sinonasal microbial biofilms. AB - Cigarette smokers and those exposed to second hand smoke are more susceptible to life threatening infection than non-smokers. While much is known about the devastating effect tobacco exposure has on the human body, less is known about the effect of tobacco smoke on the commensal and commonly found pathogenic bacteria of the human respiratory tract, or human respiratory tract microbiome. Chronic rhinosinusitis (CRS) is a common medical complaint, affecting 16% of the US population with an estimated aggregated cost of $6 billion annually. Epidemiologic studies demonstrate a correlation between tobacco smoke exposure and rhinosinusitis. Although a common cause of CRS has not been defined, bacterial presence within the nasal and paranasal sinuses is assumed to be contributory. Here we demonstrate that repetitive tobacco smoke exposure induces biofilm formation in a diverse set of bacteria isolated from the sinonasal cavities of patients with CRS. Additionally, bacteria isolated from patients with tobacco smoke exposure demonstrate robust in vitro biofilm formation when challenged with tobacco smoke compared to those isolated from smoke naive patients. Lastly, bacteria from smoke exposed patients can revert to a non biofilm phenotype when grown in the absence of tobacco smoke. These observations support the hypothesis that tobacco exposure induces sinonasal biofilm formation, thereby contributing to the conversion of a transient and medically treatable infection to a persistent and therapeutically recalcitrant condition. PMID- 21253588 TI - The C-terminus of H-Ras as a target for the covalent binding of reactive compounds modulating Ras-dependent pathways. AB - Ras proteins are crucial players in differentiation and oncogenesis and constitute important drug targets. The localization and activity of Ras proteins are highly dependent on posttranslational modifications at their C-termini. In addition to an isoprenylated cysteine, H-Ras, but not other Ras proteins, possesses two cysteine residues (C181 and C184) in the C-terminal hypervariable domain that act as palmitoylation sites in cells. Cyclopentenone prostaglandins (cyPG) are reactive lipidic mediators that covalently bind to H-Ras and activate H-Ras dependent pathways. Dienone cyPG, such as 15-deoxy-Delta(12,14)-PGJ(2) (15d PGJ(2)) and Delta(12)-PGJ(2) selectively bind to the H-Ras hypervariable domain. Here we show that these cyPG bind simultaneously C181 and C184 of H-Ras, thus potentially altering the conformational tendencies of the hypervariable domain. Based on these results, we have explored the capacity of several bifunctional cysteine reactive small molecules to bind to the hypervariable domain of H-Ras proteins. Interestingly, phenylarsine oxide (PAO), a widely used tyrosine phosphatase inhibitor, and dibromobimane, a cross-linking agent used for cysteine mapping, effectively bind H-Ras hypervariable domain. The interaction of PAO with H-Ras takes place in vitro and in cells and blocks modification of H-Ras by 15d PGJ(2). Moreover, PAO treatment selectively alters H-Ras membrane partition and the pattern of H-Ras activation in cells, from the plasma membrane to endomembranes. These results identify H-Ras as a novel target for PAO. More importantly, these observations reveal that small molecules or reactive intermediates interacting with spatially vicinal cysteines induce intramolecular cross-linking of H-Ras C-terminus potentially contributing to the modulation of Ras-dependent pathways. PMID- 21253589 TI - PPAR-gamma ligands repress TGFbeta-induced myofibroblast differentiation by targeting the PI3K/Akt pathway: implications for therapy of fibrosis. AB - Transforming growth factor beta (TGFbeta) induced differentiation of human lung fibroblasts to myofibroblasts is a key event in the pathogenesis of pulmonary fibrosis. Although the typical TGFbeta signaling pathway involves the Smad family of transcription factors, we have previously reported that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands inhibit TGFbeta mediated differentiation of human lung fibroblasts to myofibroblasts via a Smad independent pathway. TGFbeta also activates the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway leading to phosphorylation of Akt(S473). Here, we report that PPAR-gamma ligands, 2-cyano-3,12-dioxooleana-1,9 dien-28-oic acid (CDDO) and 15-deoxy-(12,14)-15d-prostaglandin J(2) (15d-PGJ(2)), inhibit human myofibroblast differentiation of normal and idiopathic pulmonary fibrotic (IPF) fibroblasts, by blocking Akt phosphorylation at Ser473 by a PPAR gamma-independent mechanism. The PI3K inhibitor LY294002 and a dominant-negative inactive kinase-domain mutant of Akt both inhibited TGFbeta-stimulated myofibroblast differentiation, as determined by Western blotting for alpha-smooth muscle actin and calponin. Prostaglandin A(1) (PGA(1)), a structural analogue of 15d-PGJ(2) with an electrophilic center, also reduced TGFbeta-driven phosphorylation of Akt, while CAY10410, another analogue that lacks an electrophilic center, did not; implying that the activity of 15d-PGJ(2) and CDDO is dependent on their electrophilic properties. PPAR-gamma ligands inhibited TGFbeta-induced Akt phosphorylation via both post-translational and post transcriptional mechanisms. This inhibition is independent of MAPK-p38 and PTEN but is dependent on TGFbeta-induced phosphorylation of FAK, a kinase that acts upstream of Akt. Thus, PPAR-gamma ligands inhibit TGFbeta signaling by affecting two pro-survival pathways that culminate in myofibroblast differentiation. Further studies of PPAR-gamma ligands and small electrophilic molecules may lead to a new generation of anti-fibrotic therapeutics. PMID- 21253590 TI - Tissue-specific analysis of glycogen synthase kinase-3alpha (GSK-3alpha) in glucose metabolism: effect of strain variation. AB - BACKGROUND: Over-activity and elevated expression of glycogen synthase kinase-3 (GSK-3) has been implicated in the etiology of insulin resistance and Type 2 diabetes. Administration of specific GSK-3 inhibitors to diabetic or obese rodent models improves glycaemic control and insulin sensitivity. However, due to the indiscriminatory nature of these inhibitors, the relative contribution of the two isoforms of GSK-3 (GSK-3alpha and GSK-3beta) is not known. Recently, we demonstrated that an out-bred strain of mice (ICR) lacking expression of GSK 3alpha in all tissues displayed improved insulin sensitivity and enhanced hepatic glucose metabolism. We also found that muscle (but not liver) inactivation of GSK 3beta conferred insulin and glucose sensitization in an in-bred strain of mice (C57BL/6). METHODOLOGY/PRINCIPAL FINDINGS: Here, we have employed tissue-specific deletion of GSK-3alpha, to examine the relative contribution of two insulin sensitive tissues, muscle and liver, towards the insulin sensitization phenotype originally observed in the global GSK-3alpha KO animals. We found that mice in which GSK-3alpha has been inactivated in either skeletal-muscle or liver displayed no differences in glucose tolerance or insulin sensitivity compared to wild type littermates. Given the strain differences in our original analyses, we examined the insulin and glucose sensitivity of global GSK-3alpha KO animals bred onto a C57BL/6 background. These animals also revealed no significant differences in glucose metabolism/insulin sensitivity compared to their wild type littermates. Furthermore, deletion of hepatic GSK-3alpha on the out-bred, ICR background failed to reproduce the insulin sensitivity manifested by the global deletion of this isoform. CONCLUSIONS/SIGNIFICANCE: From these data we conclude that the improved insulin sensitivity and hepatic glucose homeostasis phenotype observed upon global inactivation of GSK-3alpha is strain-specific. We surmise that the insulin-sensitization observed in the out-bred strain of mice lacking GSK-3alpha is mediated by indirect means that do not require intrinsic function of GSK-3alpha in skeletal muscle and liver tissues. PMID- 21253591 TI - Effective caspase inhibition blocks neutrophil apoptosis and reveals Mcl-1 as both a regulator and a target of neutrophil caspase activation. AB - Human tissue inflammation is terminated, at least in part, by the death of inflammatory neutrophils by apoptosis. The regulation of this process is therefore key to understanding and manipulating inflammation resolution. Previous data have suggested that the short-lived pro-survival Bcl-2 family protein, Mcl 1, is instrumental in determining neutrophil lifespan. However, Mcl-1 can be cleaved following caspase activity, and the possibility therefore remains that the observed fall in Mcl-1 levels is due to caspase activity downstream of caspase activation, rather than being a key event initiating apoptosis in human neutrophils.We demonstrate that apoptosis in highly purified neutrophils can be almost completely abrogated by caspase inhibition with the highly effective di peptide caspase inhibitor, Q-VD.OPh, confirming the caspase dependence of neutrophil apoptosis. Effective caspase inhibition does not prevent the observed fall in Mcl-1 levels early in ultrapure neutrophil culture, suggesting that this fall in Mcl-1 levels is not a consequence of neutrophil apoptosis. However, at later timepoints, declines in Mcl-1 can be reversed with effective caspase inhibition, suggesting that Mcl-1 is both an upstream regulator and a downstream target of caspase activity in human neutrophils. PMID- 21253592 TI - Involvement of 5-lipoxygenase in the corticosteroid-dependent amyloid beta formation: in vitro and in vivo evidence. AB - BACKGROUND: Numerous studies show that high circulating level of glucocorticosteroids is a biochemical characteristic of Alzheimer's disease (AD). These stress hormones can increase the amount of AD-like pathology in animal models of the disease. Since they also up-regulate the 5-Lipoxygenase (5-LO), an enzyme which modulates amyloid beta (Abeta) formation, in the present paper we tested the hypothesis that this enzymatic pathway is involved in the glucocorticoid-induced pro-amyloidotic effect. METHODOLOGY/PRINCIPAL FINDINGS: Incubation of neuronal cells with dexamethasone resulted in a significant increase in 5-LO activity and Abeta formation. By contrast, pharmacological inhibition of 5-LO prevented the dexamethasone-dependent increase in Abeta levels. Mouse embryonic fibroblasts responded with a significant increase in Abeta formation after dexamethasone challenge. However, this effect was abolished when dexamethasone was incubated with fibroblasts genetically deficient for 5-LO. No difference in the glucocorticoid receptor levels was observed between the two groups. Finally, treatment of wild type mice with dexamethasone resulted in a significant increase in endogenous brain Abeta levels, which was prevented in mice genetically lacking 5-LO. CONCLUSIONS: These findings suggest that 5-LO plays a functional role in the glucocorticoid-induced brain AD-like amyloid pathology. PMID- 21253593 TI - Retinoic acid and rapamycin differentially affect and synergistically promote the ex vivo expansion of natural human T regulatory cells. AB - Natural T regulatory cells (Tregs) are challenging to expand ex vivo, and this has severely hindered in vivo evaluation of their therapeutic potential. All trans retinoic acid (ATRA) plays an important role in mediating immune homeostasis in vivo, and we investigated whether ATRA could be used to promote the ex vivo expansion of Tregs purified from adult human peripheral blood. We found that ATRA helped maintain FOXP3 expression during the expansion process, but this effect was transient and serum-dependent. Furthermore, natural Tregs treated with rapamycin, but not with ATRA, suppressed cytokine production in co cultured effector T cells. This suppressive activity correlated with the ability of expanded Tregs to induce FOXP3 expression in non-Treg cell populations. Examination of CD45RA+ and CD45RA- Treg subsets revealed that ATRA failed to maintain suppressive activity in either population, but interestingly, Tregs expanded in the presence of both rapamycin and ATRA displayed more suppressive activity and had a more favorable epigenetic status of the FOXP3 gene than Tregs expanded in the presence of rapamycin only. We conclude that while the use of ATRA as a single agent to expand Tregs for human therapy is not warranted, its use in combination with rapamycin may have benefit. PMID- 21253595 TI - Do meio- and macrobenthic nematodes differ in community composition and body weight trends with depth? AB - Nematodes occur regularly in macrobenthic samples but are rarely identified from them and are thus considered exclusively a part of the meiobenthos. Our study compares the generic composition of nematode communities and their individual body weight trends with water depth in macrobenthic (>250/300 um) samples from the deep Arctic (Canada Basin), Gulf of Mexico (GOM) and the Bermuda slope with meiobenthic samples (<45 um) from GOM. The dry weight per individual (ug) of all macrobenthic nematodes combined showed an increasing trend with increasing water depth, while the dry weight per individual of the meiobenthic GOM nematodes showed a trend to decrease with increasing depth. Multivariate analyses showed that the macrobenthic nematode community in the GOM was more similar to the macrobenthic nematodes of the Canada Basin than to the GOM meiobenthic nematodes. In particular, the genera Enoploides, Crenopharynx, Micoletzkyia, Phanodermella were dominant in the macrobenthos and accounted for most of the difference. Relative abundance of non-selective deposit feeders (1B) significantly decreased with depth in macrobenthos but remained dominant in the meiobenthic community. The occurrence of a distinct assemblage of bigger nematodes of high dry weight per individual in the macrobenthos suggests the need to include nematodes in macrobenthic studies. PMID- 21253594 TI - Increased memory conversion of naive CD8 T cells activated during late phases of acute virus infection due to decreased cumulative antigen exposure. AB - BACKGROUND: Memory CD8 T cells form an essential part of protective immunity against viral infections. Antigenic load, costimulation, CD4-help, cytokines and chemokines fluctuate during the course of an antiviral immune response thus affecting CD8 T cell activation and memory conversion. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, naive TCR transgenic LCMV-specific P14 CD8 T cells engaged at a late stage during the acute antiviral LCMV response showed reduced expansion kinetics but greater memory conversion in the spleen. Such late activated cells displayed a memory precursor effector phenotype already at the peak of the systemic antiviral response, suggesting that the environment determined their fate during antigen encounter. In the spleen, the majority of late transferred cells exhibited a central memory phenotype compared to the effector memory displayed by the early transferred cells. Increasing the inflammatory response by exogenous administration of IFNgamma, PolyI:C or CpG did not affect memory conversion in the late transferred group, suggesting that the diverging antigen load early versus later during acute infection had determined their fate. In agreement, reduction in the LCMV antigenic load after ribavirin treatment enhanced the contribution of early transferred cells to the long lasting memory pool. CONCLUSIONS/SIGNIFICANCE: Our results show that naive CD8 cells, exposed to reduced duration or concentration of antigen during viral infection convert into memory more efficiently, an observation that could have significant implications for vaccine design. PMID- 21253596 TI - Analysis and prediction of translation rate based on sequence and functional features of the mRNA. AB - Protein concentrations depend not only on the mRNA level, but also on the translation rate and the degradation rate. Prediction of mRNA's translation rate would provide valuable information for in-depth understanding of the translation mechanism and dynamic proteome. In this study, we developed a new computational model to predict the translation rate, featured by (1) integrating various sequence-derived and functional features, (2) applying the maximum relevance & minimum redundancy method and incremental feature selection to select features to optimize the prediction model, and (3) being able to predict the translation rate of RNA into high or low translation rate category. The prediction accuracies under rich and starvation condition were 68.8% and 70.0%, respectively, evaluated by jackknife cross-validation. It was found that the following features were correlated with translation rate: codon usage frequency, some gene ontology enrichment scores, number of RNA binding proteins known to bind its mRNA product, coding sequence length, protein abundance and 5'UTR free energy. These findings might provide useful information for understanding the mechanisms of translation and dynamic proteome. Our translation rate prediction model might become a high throughput tool for annotating the translation rate of mRNAs in large-scale. PMID- 21253597 TI - Global transcriptional analysis of spontaneous sakacin P-resistant mutant strains of Listeria monocytogenes during growth on different sugars. AB - Subclass IIa bacteriocins have strong antilisterial activity and can control the growth of Listeria monocytogenes in food. However, L. monocytogenes may develop resistance towards such bacteriocins. In this follow-up study, the transcriptomes of a high level (L502-1) and a low level (L502-6) spontaneous sakacin P-resistant mutant strain of L. monocytogenes were compared to the wild-type (L502). The growth of the resistant strains was reduced on mannose but not affected on cellobiose and the transcriptomics was performed during growth on these sugars. The mannose phosphotransferase system (PTS) encoded by the mptACD operon (mpt) is known for transporting mannose and also act as a receptor to class IIa bacteriocins. The mpt was repressed in L502-1 and this is in accordance with abolition of the bacteriocin receptor with resistance to class IIa bacteriocins. In contrast, the mpt was induced in L502-6. Despite the induction of the mpt, L502-6 showed 1,000 times more resistance phenotype and reduced growth on mannose suggesting the mannose-PTS may not be functional in L502-6. The microarray data suggests the presence of other transcriptional responses that may be linked to the sakacin P resistance phenotype particularly in L502-6. Most of commonly regulated genes encode proteins involved in transport and energy metabolism. The resistant strains displayed shift in general carbon catabolite control possibly mediated by the mpt. Our data suggest that the resistant strains may have a reduced virulence potential. Growth sugar- and mutant-specific responses were also revealed. The two resistant strains also displayed difference in stability of the sakacin P resistance phenotype, growth in the presence of both the lytic bacteriophage P100 and activated charcoal. Taken together, the present study showed that a single time exposure to the class IIa bacteriocin sakacin P may elicit contrasting phenotypic and transcriptome responses in L. monocytogenes possibly through regulation of the mpt. PMID- 21253598 TI - Reprogramming of sheep fibroblasts into pluripotency under a drug-inducible expression of mouse-derived defined factors. AB - Animal embryonic stem cells (ESCs) provide powerful tool for studies of early embryonic development, gene targeting, cloning, and regenerative medicine. However, the majority of attempts to establish ESC lines from large animals, especially ungulate mammals have failed. Recently, another type of pluripotent stem cells, known as induced pluripotent stem cells (iPSCs), have been successfully generated from mouse, human, monkey, rat and pig. In this study we show sheep fibroblasts can be reprogrammed to pluripotency by defined factors using a drug-inducible system. Sheep iPSCs derived in this fashion have a normal karyotype, exhibit morphological features similar to those of human ESCs and express AP, Oct4, Sox2, Nanog and the cell surface marker SSEA-4. Pluripotency of these cells was further confirmed by embryoid body (EB) and teratoma formation assays which generated derivatives of all three germ layers. Our results also show that the substitution of knockout serum replacement (KSR) with fetal bovine serum in culture improves the reprogramming efficiency of sheep iPSCs. Generation of sheep iPSCs places sheep on the front lines of large animal preclinical trials and experiments involving modification of animal genomes. PMID- 21253599 TI - PoPoolation: a toolbox for population genetic analysis of next generation sequencing data from pooled individuals. AB - Recent statistical analyses suggest that sequencing of pooled samples provides a cost effective approach to determine genome-wide population genetic parameters. Here we introduce PoPoolation, a toolbox specifically designed for the population genetic analysis of sequence data from pooled individuals. PoPoolation calculates estimates of theta(Watterson), theta(pi), and Tajima's D that account for the bias introduced by pooling and sequencing errors, as well as divergence between species. Results of genome-wide analyses can be graphically displayed in a sliding window plot. PoPoolation is written in Perl and R and it builds on commonly used data formats. Its source code can be downloaded from http://code.google.com/p/popoolation/. Furthermore, we evaluate the influence of mapping algorithms, sequencing errors, and read coverage on the accuracy of population genetic parameter estimates from pooled data. PMID- 21253600 TI - Assembly of linear nano-chains from iron oxide nanospheres with asymmetric surface chemistry. AB - Besides the multifunctionality, another equally important aspect of nanoparticles is their engineerability to control the geometrical and chemical properties during fabrication. In this work, we exploited this aspect to define asymmetric surface chemistry of an iron oxide nanosphere by controlling the topology of ligand expression on its surface resulting in a particle with two faces, one displaying only amines and the other only thiols. Specifically, amine functionalized iron oxide nanospheres were attached on a solid support via a crosslinker containing a disulfide bridge. Liberation of the nanosphere using thiolytic cleavage created thiols on the portion of the particle's surface that interacted with the solid support. Employing a solid-phase strategy and a step-by step addition of particles, the two unique faces on the same nanosphere served as fittings to assemble them into linear nano-chains. Assembly of chains with various lengths and aspect ratios was controlled by the size and number of the added nanospheres. The characteristics of those chains showed a high degree of uniformity indicating the exceptional control of the synthetic process. Notably, one of the unique properties of the iron oxide nano-chains was an increased magnetic relaxivity, indicating their potential use as contrast agents for magnetic resonance imaging. PMID- 21253601 TI - Genetic interaction of centrosomin and bazooka in apical domain regulation in Drosophila photoreceptor. AB - BACKGROUND: Cell polarity genes including Crumbs (Crb) and Par complexes are essential for controlling photoreceptor morphogenesis. Among the Crb and Par complexes, Bazooka (Baz, Par-3 homolog) acts as a nodal component for other cell polarity proteins. Therefore, finding other genes interacting with Baz will help us to understand the cell polarity genes' role in photoreceptor morphogenesis. METHODOLOGY/PRINCIPAL FINDINGS: Here, we have found a genetic interaction between baz and centrosomin (cnn). Cnn is a core protein for centrosome which is a major microtubule-organizing center. We analyzed the effect of the cnn mutation on developing eyes to determine its role in photoreceptor morphogenesis. We found that Cnn is dispensable for retinal differentiation in eye imaginal discs during the larval stage. However, photoreceptors deficient in Cnn display dramatic morphogenesis defects including the mislocalization of Crumbs (Crb) and Bazooka (Baz) during mid-stage pupal eye development, suggesting that Cnn is specifically required for photoreceptor morphogenesis during pupal eye development. This role of Cnn in apical domain modulation was further supported by Cnn's gain-of function phenotype. Cnn overexpression in photoreceptors caused the expansion of the apical Crb membrane domain, Baz and adherens junctions (AJs). CONCLUSIONS/SIGNIFICANCE: These results strongly suggest that the interaction of Baz and Cnn is essential for apical domain and AJ modulation during photoreceptor morphogenesis, but not for the initial photoreceptor differentiation in the Drosophila photoreceptor. PMID- 21253603 TI - TCM Database@Taiwan: the world's largest traditional Chinese medicine database for drug screening in silico. AB - Rapid advancing computational technologies have greatly speeded up the development of computer-aided drug design (CADD). Recently, pharmaceutical companies have increasingly shifted their attentions toward traditional Chinese medicine (TCM) for novel lead compounds. Despite the growing number of studies on TCM, there is no free 3D small molecular structure database of TCM available for virtual screening or molecular simulation. To address this shortcoming, we have constructed TCM Database@Taiwan (http://tcm.cmu.edu.tw/) based on information collected from Chinese medical texts and scientific publications. TCM Database@Taiwan is currently the world's largest non-commercial TCM database. This web-based database contains more than 20,000 pure compounds isolated from 453 TCM ingredients. Both cdx (2D) and Tripos mol2 (3D) formats of each pure compound in the database are available for download and virtual screening. The TCM database includes both simple and advanced web-based query options that can specify search clauses, such as molecular properties, substructures, TCM ingredients, and TCM classification, based on intended drug actions. The TCM database can be easily accessed by all researchers conducting CADD. Over the last eight years, numerous volunteers have devoted their time to analyze TCM ingredients from Chinese medical texts as well as to construct structure files for each isolated compound. We believe that TCM Database@Taiwan will be a milestone on the path towards modernizing traditional Chinese medicine. PMID- 21253602 TI - Detection of resistance mutations to antivirals oseltamivir and zanamivir in avian influenza A viruses isolated from wild birds. AB - The neuraminidase (NA) inhibitors oseltamivir and zanamivir are the first-line of defense against potentially fatal variants of influenza A pandemic strains. However, if resistant virus strains start to arise easily or at a high frequency, a new anti-influenza strategy will be necessary. This study aimed to investigate if and to what extent NA inhibitor-resistant mutants exist in the wild population of influenza A viruses that inhabit wild birds. NA sequences of all NA subtypes available from 5490 avian, 379 swine and 122 environmental isolates were extracted from NCBI databases. In addition, a dataset containing 230 virus isolates from mallard collected at Ottenby Bird Observatory (Oland, Sweden) was analyzed. Isolated NA RNA fragments from Ottenby were transformed to cDNA by RT PCR, which was followed by sequencing. The analysis of genotypic profiles for NAs from both data sets in regard to antiviral resistance mutations was performed using bioinformatics tools. All 6221 sequences were scanned for oseltamivir- (I117V, E119V, D198N, I222V, H274Y, R292K, N294S and I314V) and zanamivir-related mutations (V116A, R118K, E119G/A/D, Q136K, D151E, R152K, R224K, E276D, R292K and R371K). Of the sequences from the avian NCBI dataset, 132 (2.4%) carried at least one, or in two cases even two and three, NA inhibitor resistance mutations. Swine and environmental isolates from the same data set had 18 (4.75%) and one (0.82%) mutant, respectively, with at least one mutation. The Ottenby sequences carried at least one mutation in 15 cases (6.52%). Therefore, resistant strains were more frequently found in Ottenby samples than in NCBI data sets. However, it is still uncertain if these mutations are the result of natural variations in the viruses or if they are induced by the selective pressure of xenobiotics (e.g., oseltamivir, zanamivir). PMID- 21253604 TI - The transcription factor YY1 is a substrate for Polo-like kinase 1 at the G2/M transition of the cell cycle. AB - Yin-Yang 1 (YY1) is an essential multifunctional zinc-finger protein. It has been shown over the past two decades to be a critical regulator of a vast array of biological processes, including development, cell proliferation and differentiation, DNA repair, and apoptosis. YY1 exerts its functions primarily as a transcription factor that can activate or repress gene expression, dependent on its spatial and temporal context. YY1 regulates a large number of genes involved in cell cycle transitions, many of which are oncogenes and tumor-suppressor genes. YY1 itself has been classified as an oncogene and was found to be upregulated in many cancer types. Unfortunately, our knowledge of what regulates YY1 is very minimal. Although YY1 has been shown to be a phosphoprotein, no kinase has ever been identified for the phosphorylation of YY1. Polo-like kinase 1 (Plk1) has emerged in the past few years as a major cell cycle regulator, particularly for cell division. Plk1 has been shown to play important roles in the G/M transition into mitosis and for the proper execution of cytokinesis, processes that YY1 has been shown to regulate also. Here, we present evidence that Plk1 directly phosphorylates YY1 in vitro and in vivo at threonine 39 in the activation domain. We show that this phosphorylation is cell cycle regulated and peaks at G2/M. This is the first report identifying a kinase for which YY1 is a substrate. PMID- 21253605 TI - A new topology of the human Y chromosome haplogroup E1b1 (E-P2) revealed through the use of newly characterized binary polymorphisms. AB - Haplogroup E1b1, defined by the marker P2, is the most represented human Y chromosome haplogroup in Africa. A phylogenetic tree showing the internal structure of this haplogroup was published in 2008. A high degree of internal diversity characterizes this haplogroup, as well as the presence of a set of chromosomes undefined on the basis of a derived character. Here we make an effort to update the phylogeny of this highly diverse haplogroup by including seven mutations which have been newly discovered by direct resequencing. We also try to incorporate five previously-described markers which were not, however, reported in the 2008 tree. Additionally, during the process of mapping, we found that two previously reported SNPs required a new position on the tree. There are three key changes compared to the 2008 phylogeny. Firstly, haplogroup E-M2 (former E1b1a) and haplogroup E-M329 (former E1b1c) are now united by the mutations V38 and V100, reducing the number of E1b1 basal branches to two. The new topology of the tree has important implications concerning the origin of haplogroup E1b1. Secondly, within E1b1b1 (E-M35), two haplogroups (E-V68 and E-V257) show similar phylogenetic and geographic structure, pointing to a genetic bridge between southern European and northern African Y chromosomes. Thirdly, most of the E1b1b1* (E-M35*) paragroup chromosomes are now marked by defining mutations, thus increasing the discriminative power of the haplogroup for use in human evolution and forensics. PMID- 21253606 TI - A SNP and SSR based genetic map of asparagus bean (Vigna. unguiculata ssp. sesquipedialis) and comparison with the broader species. AB - Asparagus bean (Vigna. unguiculata ssp. sesquipedialis) is a distinctive subspecies of cowpea [Vigna. unguiculata (L.) Walp.] that apparently originated in East Asia and is characterized by extremely long and thin pods and an aggressive climbing growth habit. The crop is widely cultivated throughout Asia for the production of immature pods known as 'long beans' or 'asparagus beans'. While the genome of cowpea ssp. unguiculata has been characterized recently by high-density genetic mapping and partial sequencing, little is known about the genome of asparagus bean. We report here the first genetic map of asparagus bean based on SNP and SSR markers. The current map consists of 375 loci mapped onto 11 linkage groups (LGs), with 191 loci detected by SNP markers and 184 loci by SSR markers. The overall map length is 745 cM, with an average marker distance of 1.98 cM. There are four high marker-density blocks distributed on three LGs and three regions of segregation distortion (SDRs) identified on two other LGs, two of which co-locate in chromosomal regions syntenic to SDRs in soybean. Synteny between asparagus bean and the model legume Lotus. japonica was also established. This work provides the basis for mapping and functional analysis of genes/QTLs of particular interest in asparagus bean, as well as for comparative genomics study of cowpea at the subspecies level. PMID- 21253607 TI - Antarctic krill 454 pyrosequencing reveals chaperone and stress transcriptome. AB - BACKGROUND: The Antarctic krill Euphausia superba is a keystone species in the Antarctic food chain. Not only is it a significant grazer of phytoplankton, but it is also a major food item for charismatic megafauna such as whales and seals and an important Southern Ocean fisheries crop. Ecological data suggest that this species is being affected by climate change and this will have considerable consequences for the balance of the Southern Ocean ecosystem. Hence, understanding how this organism functions is a priority area and will provide fundamental data for life history studies, energy budget calculations and food web models. METHODOLOGY/PRINCIPAL FINDINGS: The assembly of the 454 transcriptome of E. superba resulted in 22,177 contigs with an average size of 492bp (ranging between 137 and 8515bp). In depth analysis of the data revealed an extensive catalogue of the cellular chaperone systems and the major antioxidant proteins. Full length sequences were characterised for the chaperones HSP70, HSP90 and the super-oxide dismutase antioxidants, with the discovery of potentially novel duplications of these genes. The sequence data contained 41,470 microsatellites and 17,776 Single Nucleotide Polymorphisms (SNPs/INDELS), providing a resource for population and also gene function studies. CONCLUSIONS: This paper details the first 454 generated data for a pelagic Antarctic species or any pelagic crustacean globally. The classical "stress proteins", such as HSP70, HSP90, ferritin and GST were all highly expressed. These genes were shown to be over expressed in the transcriptomes of Antarctic notothenioid fish and hypothesized as adaptations to living in the cold, with the associated problems of decreased protein folding efficiency and increased vulnerability to damage by reactive oxygen species. Hence, these data will provide a major resource for future physiological work on krill, but in particular a suite of "stress" genes for studies understanding marine ectotherms' capacities to cope with environmental change. PMID- 21253608 TI - Homo- and heterosubtypic low pathogenic avian influenza exposure on H5N1 highly pathogenic avian influenza virus infection in wood ducks (Aix sponsa). AB - Wild birds in the Orders Anseriformes and Charadriiformes are the natural reservoirs for avian influenza (AI) viruses. Although they are often infected with multiple AI viruses, the significance and extent of acquired immunity in these populations is not understood. Pre-existing immunity to AI virus has been shown to modulate the outcome of a highly pathogenic avian influenza (HPAI) virus infection in multiple domestic avian species, but few studies have addressed this effect in wild birds. In this study, the effect of pre-exposure to homosubtypic (homologous hemagglutinin) and heterosubtypic (heterologous hemagglutinin) low pathogenic avian influenza (LPAI) viruses on the outcome of a H5N1 HPAI virus infection in wood ducks (Aix sponsa) was evaluated. Pre-exposure of wood ducks to different LPAI viruses did not prevent infection with H5N1 HPAI virus, but did increase survival associated with H5N1 HPAI virus infection. The magnitude of this effect on the outcome of the H5N1 HPAI virus infection varied between different LPAI viruses, and was associated both with efficiency of LPAI viral replication in wood ducks and the development of a detectable humoral immune response. These observations suggest that in naturally occurring outbreaks of H5N1 HPAI, birds with pre-existing immunity to homologous hemagglutinin or neuraminidase subtypes of AI virus may either survive H5N1 HPAI virus infection or live longer than naive birds and, consequently, could pose a greater risk for contributing to viral transmission and dissemination. The mechanisms responsible for this protection and/or the duration of this immunity remain unknown. The results of this study are important for surveillance efforts and help clarify epidemiological data from outbreaks of H5N1 HPAI virus in wild bird populations. PMID- 21253609 TI - Deciphering human heat shock transcription factor 1 regulation via post translational modification in yeast. AB - Heat shock transcription factor 1 (HSF1) plays an important role in the cellular response to proteotoxic stresses. Under normal growth conditions HSF1 is repressed as an inactive monomer in part through post-translation modifications that include protein acetylation, sumoylation and phosphorylation. Upon exposure to stress HSF1 homotrimerizes, accumulates in nucleus, binds DNA, becomes hyper phosphorylated and activates the expression of stress response genes. While HSF1 and the mechanisms that regulate its activity have been studied for over two decades, our understanding of HSF1 regulation remains incomplete. As previous studies have shown that HSF1 and the heat shock response promoter element (HSE) are generally structurally conserved from yeast to metazoans, we have made use of the genetically tractable budding yeast as a facile assay system to further understand the mechanisms that regulate human HSF1 through phosphorylation of serine 303. We show that when human HSF1 is expressed in yeast its phosphorylation at S303 is promoted by the MAP-kinase Slt2 independent of a priming event at S307 previously believed to be a prerequisite. Furthermore, we show that phosphorylation at S303 in yeast and mammalian cells occurs independent of GSK3, the kinase primarily thought to be responsible for S303 phosphorylation. Lastly, while previous studies have suggested that S303 phosphorylation represses HSF1-dependent transactivation, we now show that S303 phosphorylation also represses HSF1 multimerization in both yeast and mammalian cells. Taken together, these studies suggest that yeast cells will be a powerful experimental tool for deciphering aspects of human HSF1 regulation by post-translational modifications. PMID- 21253610 TI - Differential conservation and divergence of fertility genes boule and dazl in the rainbow trout. AB - BACKGROUND: The genes boule and dazl are members of the DAZ (Deleted in Azoospermia) family encoding RNA binding proteins essential for germ cell development. Although dazl exhibits bisexual expression in mitotic and meiotic germ cells in diverse animals, boule shows unisexual meiotic expression in invertebrates and mammals but a bisexual mitotic and meiotic expression in medaka. How boule and dazl have evolved different expression patterns in diverse organisms has remained unknown. METHODOLOGY AND PRINCIPAL FINDINGS: Here we chose the fish rainbow trout (Oncorhynchus mykiss) as a second lower vertebrate model to investigate the expression of boule and dazl. By molecular cloning and sequence comparison, we identified cDNAs encoding the trout Boule and Dazl proteins, which have a conserved RNA-recognition motif and a maximal similarity to their homologs. By RT-PCR analysis, adult RNA expression of trout boule and dazl is restricted to the gonads of both sexes. By chromogenic and two-color fluorescence in situ hybridization, we revealed bisexual and germline-specific expression of boule and dazl. We found that dazl displays conserved expression throughout gametogenesis and concentrates in the Balbinani's body of early oocytes and the chromatoid body of sperm. Surprisingly, boule exhibits mitotic and meiotic expression in the male but meiosis-specific expression in the female. CONCLUSIONS: Our data underscores differential conservation and divergence of DAZ family genes during vertebrate evolution. We propose a model in which the diversity of boule expression in sex and stage specificity might have resulted from selective loss or gain of its expression in one sex and mitotic germ cells. PMID- 21253611 TI - Lensfree fluorescent on-chip imaging of transgenic Caenorhabditis elegans over an ultra-wide field-of-view. AB - We demonstrate lensfree on-chip fluorescent imaging of transgenic Caenorhabditis elegans (C. elegans) over an ultra-wide field-of-view (FOV) of e.g., >2-8 cm(2) with a spatial resolution of ~10 um. This is the first time that a lensfree on chip platform has successfully imaged fluorescent C. elegans samples. In our wide field lensfree imaging platform, the transgenic samples are excited using a prism interface from the side, where the pump light is rejected through total internal reflection occurring at the bottom facet of the substrate. The emitted fluorescent signal from C. elegans samples is then recorded on a large area opto electronic sensor-array over an FOV of e.g., >2-8 cm(2), without the use of any lenses, thin-film interference filters or mechanical scanners. Because fluorescent emission rapidly diverges, such lensfree fluorescent images recorded on a chip look blurred due to broad point-spread-function of our platform. To combat this resolution challenge, we use a compressive sampling algorithm to uniquely decode the recorded lensfree fluorescent patterns into higher resolution images, demonstrating ~10 um resolution. We tested the efficacy of this compressive decoding approach with different types of opto-electronic sensors to achieve a similar resolution level, independent of the imaging chip. We further demonstrate that this wide FOV lensfree fluorescent imaging platform can also perform sequential bright-field imaging of the same samples using partially coherent lensfree digital in-line holography that is coupled from the top facet of the same prism used in fluorescent excitation. This unique combination permits ultra-wide field dual-mode imaging of C. elegans on a chip which could especially provide a useful tool for high-throughput screening applications in biomedical research. PMID- 21253612 TI - Elimination of hepatitis C virus from hepatocytes by a selective activation of therapeutic molecules. AB - To eliminate hepatitis C virus (HCV) from infected hepatocytes, we generated two therapeutic molecules specifically activated in cells infected with HCV. A dominant active mutant of interferon (IFN) regulatory factor 7 (IRF7) and a negative regulator of HCV replication, VAP-C (Vesicle-associated membrane protein associated protein subtype C), were fused with the C-terminal region of IPS-1 (IFNbeta promoter stimulator-1), which includes an HCV protease cleavage site that was modified to be localized on the ER membrane, and designated cIRF7 and cVAP-C, respectively. In cells expressing the HCV protease, cIRF7 was cleaved and the processed fragment was migrated into the nucleus, where it activated various IFN promoters, including promoters of IFNalpha6, IFNbeta, and IFN stimulated response element. Activation of the IFN promoters and suppression of viral RNA replication were observed in the HCV replicon cells and in cells infected with the JFH1 strain of HCV (HCVcc) by expression of cIRF7. Suppression of viral RNA replication was observed even in the IFN-resistant replicon cells by the expression of cIRF7. Expression of the cVAP-C also resulted in suppression of HCV replication in both the replicon and HCVcc infected cells. These results suggest that delivery of the therapeutic molecules into the liver of hepatitis C patients, followed by selective activation of the molecules in HCV-infected hepatocytes, is a feasible method for eliminating HCV. PMID- 21253615 TI - [Message of the new president of the Italian Society of Rheumatology]. PMID- 21253614 TI - Ncf1 (p47phox) is essential for direct regulatory T cell mediated suppression of CD4+ effector T cells. AB - BACKGROUND: Multiple mechanisms have been advanced to account for CD4+FOXP3+ regulatory T cell (Treg)-mediated suppression of CD4+ effector T cells (Teffs) but none appear to completely explain suppression. Previous data indicates that Tregs may affect the microenvironment redox state. Given the inherent redox sensitivity of T cells, we tested the hypothesis that oxidants may mediate the direct suppression of Teffs by Tregs. METHODOLOGY/PRINCIPAL FINDINGS: Tregs and Teffs were isolated from the spleens of wild type (WT) C57BL/6 mice or Ncf1(p47phox)-deficient C57BL/6 mice which lack NADPH oxidase function. Teffs were labeled with CFSE and co-cultured with unlabeled Tregs at varying Treg:Teff ratios in the presence of anti-CD3/CD28 coated beads for 3 days in suppression assays. Treg-mediated suppression was quantified by flow cytometric analysis of CFSE dilution in Teffs. The presence of the antioxidants n-acetylcysteine (NAC) or 2-mercaptoethanol or inhibitors of NADPH oxidase (diphenyleneiodonium and VAS 2870) resulted in reduced WT Treg-mediated suppression. The observed suppression was in part dependent upon TGFbeta as it was partially blocked with neutralizing antibodies. The suppression of Teff proliferation induced by exogenous TGFbeta treatment could be overcome with NAC. Ncf1-deficient Teff were slightly but significantly less sensitive than WT Teff to suppression by exogenous TGFbeta. Ncf1-deficient Tregs suppressed Ncf1-deficient Teff very poorly compared to wild type controls. There was partial but incomplete reconstitution of suppression in assays with WT Tregs and Ncf1-deficient Teff. CONCLUSIONS/SIGNIFICANCE: We present evidence that NADPH oxidase derived ROS plays a role in the direct Treg mediated suppression of CD4+ effector T cells in a process that is blocked by thiol-containing antioxidants, NADPH oxidase inhibitors or a lack of Ncf1 expression in Tregs and Teffs. Oxidants may represent a potential new target for therapeutic modulation of Treg function. PMID- 21253616 TI - [The role of nailfold videocapillaroscopy in Raynaud's phenomenon monitoring and early diagnosis of systemic sclerosis]. AB - Several connective tissue diseases, in particular systemic sclerosis (SSc), have Raynaud's phenomenon (RP) as their first clinical manifestation. Primary RP represents a benign condition often observed in otherwise healthy subjects, especially women: it is due to an exaggerated response to the physiological cold induced vasospasm, whereas the secondary form of RP is typically associated with connective tissue diseases, especially SSc. Nailfold videocapillaroscopy (NVC), particulary after the recent technological advances, is a safe and reliable method to observe the microvascular structure and its early changes, especially during the transition from primary to secondary RP. In case of SSc, by considering validated patterns and scoring systems, NVC is the main tool that rheumatologists can rely on, besides the presence of specific auto-antibodies, to perform a very early diagnosis of the disease. This implies the possibility of early treatment of SSc, with an eye of predicting and preventing its major clinical complications. PMID- 21253613 TI - Proliferating cell nuclear antigen (PCNA) regulates primordial follicle assembly by promoting apoptosis of oocytes in fetal and neonatal mouse ovaries. AB - Primordial follicles, providing all the oocytes available to a female throughout her reproductive life, assemble in perinatal ovaries with individual oocytes surrounded by granulosa cells. In mammals including the mouse, most oocytes die by apoptosis during primordial follicle assembly, but factors that regulate oocyte death remain largely unknown. Proliferating cell nuclear antigen (PCNA), a key regulator in many essential cellular processes, was shown to be differentially expressed during these processes in mouse ovaries using 2D-PAGE and MALDI-TOF/TOF methodology. A V-shaped expression pattern of PCNA in both oocytes and somatic cells was observed during the development of fetal and neonatal mouse ovaries, decreasing from 13.5 to 18.5 dpc and increasing from 18.5 dpc to 5 dpp. This was closely correlated with the meiotic prophase I progression from pre-leptotene to pachytene and from pachytene to diplotene when primordial follicles started to assemble. Inhibition of the increase of PCNA expression by RNA interference in cultured 18.5 dpc mouse ovaries strikingly reduced the apoptosis of oocytes, accompanied by down-regulation of known pro-apoptotic genes, e.g. Bax, caspase-3, and TNFalpha and TNFR2, and up-regulation of Bcl-2, a known anti-apoptotic gene. Moreover, reduced expression of PCNA was observed to significantly increase primordial follicle assembly, but these primordial follicles contained fewer granulosa cells. Similar results were obtained after down-regulation by RNA interference of Ing1b, a PCNA-binding protein in the UV induced apoptosis regulation. Thus, our results demonstrate that PCNA regulates primordial follicle assembly by promoting apoptosis of oocytes in fetal and neonatal mouse ovaries. PMID- 21253617 TI - [How much does an antiinflammatory treatment cost?]. AB - NSAIDs are among the most popular drugs in the world for their efficacy in controlling pain and acute and chronic inflammation. The efficacy of these therapies is hampered by their safety profile, in particular regarding the gastroenteric tract. The NSAIDs' side effects may heavily influence the health of the single patient and the economy of the health systems. The pharmacoeconomic evaluation of antinflammatory treatment usually considers, in addition to the drug purchase prize, also the shadow costs. This cost is mainly due to the management and prevention of gastropathy. Coxibs, even if more expensive, may become cost-effective for their better gastronteric safety. As a matter of fact, coxib treatment can be considered equivalent to a treatment with NSAID plus PPI. However, the first requirement of these drugs, that should control pain, must be the efficacy and not only safety. In this case the NNT (Number Needed to Treat) is a good marker of efficacy. To calculate the real cost we must pay to reach the target (pain resolution in one patient), we can multiply NNT for the prize of a specific drug. The total cost will depend on drug prize (the cheaper, the better) and on the efficacy expressed by NNT (the lower, the better). In a recent meta analysis, the NNT of several antinflammatory drugs has been calculated. When the treatment cost was adjusted for its efficacy (NNT), the difference in favour of NSAIDs became so little to disappear because of the higher safety of coxibs (especially of etoricoxiband the possibility to reach antinflammatory and analgesic doses that are difficult to obtain with NSAIDs. Moreover, if also the cost of gastroprotection is considered, the economic impact of NSAIDs can be much higher. In conclusion the pharmacoeconomic analysis of an antinflammatory therapy cannot be based only on safety issues but also on efficacy evaluation that is the main effect we ask to these drugs. PMID- 21253618 TI - Study on the possible role of the -174G>C IL-6 promoter polymorphism in predicting response to rituximab in rheumatoid arthritis. AB - OBJECTIVE: Identification of genetic biomarkers of response to biologics in rheumatoid arthritis (RA) is a relevant issue. The -174G>C interleukin-6 (IL-6) promoter polymorphism was investigated in RA patients treated with rituximab (RTX), being IL-6 a key cytokine for B cell survival and proliferation, thus possibly implicated in rituximab efficacy. METHODS: The study was conducted in a real-life retrospective cohort of 142 unselected RA patients (120F/22M) treated with RTX and referred to 7 rheumatologic centres in the north of Italy. One hundred and thirteen (79.6%) patients were rheumatoid factor (RF)-positive and 112 (78.9%) were anti-CCP antibodies positive. The response to therapy was evaluated at the end of the sixth month after the first RTX infusion, by using both the EULAR criteria (DAS28) and the ACR criteria. The IL-6 -174G>C promoter polymorphism was analyzed by RFLP following previously reported methods. RESULTS: Lack of response to RTX at month +6 by EULAR criteria was more prevalent in RA patients with the IL-6 -174 CC genotypes (9/21, 42.8%), than in the GC/GG patients (23/121, 19.0%) (OR 3.196, 95% CI=1.204-8.485; p=0.0234). Similar results were found when evaluating the response by ACR criteria. No differences were found in RA duration, baseline DAS28, baseline HAQ, RF status, anti-CCP status according to the different IL-6 -174 genotypes. CONCLUSION: IL-6 promoter genotyping may be useful to better plan treatment with RTX in RA. Larger replication studies are in course to confirm these preliminary results. PMID- 21253619 TI - [BAFF/APRIL pathway in Sjogren syndrome and systemic lupus erythematosus: relationship with chronic inflammation and disease activity]. AB - OBJECTIVES: BAFF and APRIL belong to the tumor necrosis factor (TNF) superfamily and are crucial for the survival, maturation, and differentiation of B cells. Aim of the study is to evaluate BAFF and APRIL in patients affected by Sjogren syndrome (SS) and systemic lupus erythematosus (SLE). METHODS: Sixty patients, (40 SLE, 20 SS) and 20 healthy subjects were enrolled in this study. All subjects were evaluated for laboratory data (ESR, CRP, immunoglobulin G, A and M, complement fragments C3 and C4, LDH, beta2microglobulin, serum levels of rheumatoid factor), autoantibodies (ANA; ENA-SSA, -SSB, -Sm) and lymphocytes subpopulations. For patients, disease activity and damage indexes were assessed with the use of SLEDAI and SLICC and SSDAI and SSDDI for SLE and SS, respectively. BAFF and APRIL were determined by commercial sandwich ELISA kit (R&D Systems, Bender MedSystem). Statistical analysis has been performed with software Prism (Graphpad Instat, version 5.00). RESULTS: APRIL levels were higher among SLE and SS patients compared to controls (p<0.0001, and p0.0001, respectively). BAFF levels in SLE were significantly higher than in SS (p<0.0001). We found higher BAFF levels in SLE and SS compared to controls (p<0.0001). Among SLE patients APRIL correlated with SLEDAI (r 0.3, p 0.04), SLICC (r 0.5,p 0.001), ESR (r 0.3, p 0.005) and CRP (r 0.4, p 0.02). Among SS patients APRIL correlated with SSDAI (r 0.4, p 0.02), SSDDI (r 0.4, p0.01), IgG (r 0.5, p0.01), ESR (r 0.6, p 0.01), CRP (r 0.6, p 0.02) and CD19 B lymphocytes absolute count (r 0.4, p 0.04); BAFF correlated with SSDDI (r 0.7, p 0.004) and CD19 B lymphocytes absolute count (r 0.5, p 0.04). CONCLUSIONS: In this study we showed a correlation between disease activity, damage indexes and BAFF/APRIL levels in SLE and SS patients suggesting a role in the strong activation of the immune system in patients with active disease. PMID- 21253620 TI - [HDL inhibit cytokine production in a mouse model of urate crystal-induced inflammation]. AB - OBJECTIVES: To evaluate whether high density lipoproteins (HDL) affect monosodium urate (MSU) crystal-induced inflammation in the murine air pouch model. METHODS: MSU crystals were prepared by Denko's method and sterilized by heating at 180 degrees C for 2 h before each experiment. Human HDL were isolated from peripheral blood of healthy volunteers. MSU crystals (2 mg in 1 ml of PBS) were injected into subcutaneous air pouches in mice in the presence or absence of HDL (0.1 mg). Negative control pouches received 1 ml of PBS. To recover pouch fluid, the pouches were washed with 2 ml of PBS after the animals were sacrificed. The leukocyte count in the lavage fluids was obtained using a hemocytometer and differential leukocyte count was determined by May-Grunwald-Giemsa staining. IL 6, KC, CCL2 and TNF-alpha levels were measured in exudates by ELISA. RESULTS: MSU crystals increased the number of leukocytes and the neutrophil migration, as well as the concentrations of IL-6, KC and CCL2 in pouch fluids, while the TNF-alpha levels were not detectable. The treatment with HDL led to a reduction in all inflammatory parameters: the leukocyte count decreased by 73%; the neutrophil density decreased by 35%; the IL-6, KC and CCL2 concentration decreased by 4-, 6- and 5-fold respectively. CONCLUSIONS: This study shows that HDL may limit the inflammatory process by inhibiting leukocyte recruitment and cytokine release. HDL are likely to represent a mechanism of control of crystal-induced inflammation. PMID- 21253621 TI - [Risk factors for hip fracture in elderly persons]. AB - OBJECTIVE: The aim of this observational study, promoted by the Health Authorities of the Regione Veneto (Italy), is to assess the prevalence of the most relevant environmental and individual risk factors in subjects with a recent hip fracture. METHODS: Patients aged more than 60 years of both genders with a recent hip fracture not associated with malignancies, were administered questionnaires on dietary habits, sun exposure, and disability score. A complete family, pharmacological and pathology history was collected together with information on previous falls, details of the fracture index, and anthropometric data. In all subjects, blood was taken for the measurement of serum 25 hydroxy vitamin D (25OHD). RESULTS: The study included 704 patients (573 women and 131 men). Mean age was 81 +/- 8 years (range 60-102). Severe pre-fracture disability was a common feature (58%) associated with multiple co-morbidities (84%), more frequently cardiovascular and neurological diseases, and specific medications. In a large proportion (86%) of the patients, environmental or individual risk factors for falling were found. Vitamin D insufficiency (serum 25OHD levels < 75 nmol/l) was quite common (70%), particularly in the regional Health Districts were strategies for preventing vitamin D deficiency were not implemented (91%). Only a small proportion (17%) of the study population had been evaluated and treated for osteoporosis. CONCLUSIONS: In senile patients with a recent hip fracture, pre-existing disability, multiple co-morbidities, high risk of falling and inadequate intake of calcium and vitamin D is relatively common. Community and case-finding interventions aimed at selecting subjects at high risk of osteoporosis, preventing vitamin D and dietary calcium deficiency, and increasing awareness on the environmental risks of falling are highly warranted. PMID- 21253622 TI - [Acute toxoplasmosis infection in a patient with ankylosing spondylitis treated with adalimumab: a case report]. AB - We present a case of acute toxoplasmosis infection in a 36-year-old man with long standing ankylosing spondylitis, treated with adalimumab. We review the association between antitumor necrosis factor therapy and toxoplasmosis. Our case illustrates that opportunistic infections may occur in patients treated with adalimumab, and emphasizes the importance of clinical suspicion and serological tests. PMID- 21253623 TI - [Multimodality imaging of chronic tophaceous gout]. AB - The diagnosis of gout is usually based on clinical presentation and laboratory findings. Imaging plays a role in the assessment and grading of articular damage related to chronic, long-standing disease, which is characterized by granulomatous synovitis, tophi, and erosions. Multimodality imaging of chronic tophaceous gout may be useful in clinical practice for a variety of purposes, including assessment of disease-related anatomical changes and monitoring of articular and soft-tissue lesions over time, especially in response to urate lowering therapy. Radiography remains the primary imaging technique. Ultrasonography may detect monosodium urate crystals on cartilage, is helpful to assess small joint effusion, to guide to joint aspiration, and to evaluate the volume of tophi. Computed tomography is considered to be more sensitive than plain radiography in the detection and evaluation of cortical bone erosions associated with tophi. MRI represents the only imaging modality which provides visualization of bone marrow oedema associated with erosions and may be useful to characterize and distinguish tophi from other soft tissue nodules. PMID- 21253624 TI - [A short history of anti-rheumatic therapy. IV. Corticosteroids]. AB - In 1948 a corticosteroid compound was administered for the first time to a patient affected by rheumatoid arthritis by Philip Showalter Hench, a rheumatologist at the Mayo Clinic in Rochester, Minnesota (USA). He was investigating since 1929 the role of adrenal gland-derived substances in rheumatoid arthritis. For the discovery of cortisone and its applications in anti rheumatic therapy, Hench, along with Edward Calvin Kendall and Tadeusz Reichstein, won the 1950 Nobel Prize for Medicine. In this review we summarize the main stages that led to the identification of the so-called compound E, which was used by Hench. We also consider the subsequent development of steroid therapy in rheumatic diseases, through the introduction of new molecules with less mineralocorticoid effects, such as prednisone, and more recently, deflazacort. PMID- 21253625 TI - Responses to unsaturation in iridium mono(N-heterocyclic carbene) complexes: synthesis and oligomerization of [LIr(H)2Cl] and [LIr(H)2]+. AB - Highly unsaturated mono(N-heterocyclic carbene) Ir(iii) systems have been targeted via ligand abstraction protocols. Hydrogenation of Ir(IPr)(cod)Cl (1a) leads to the formation of the highly reactive (fluxional) trimer [Ir(IPr)(H)(2)Cl](3), while the related IMes system undergoes further C-H bond activation. Chloride abstraction from 1a prior to hydrogenation allows access to sources of the 12-electron [Ir(IPr)(H)(2)](+) fragment, which, in the absence of a suitable donor, dimerizes to give [{Ir(IPr)(H)(MU-H)}(2)](2+). PMID- 21253626 TI - Self-crosslinking for dimensionally stable and solvent-resistant quaternary phosphonium based hydroxide exchange membranes. AB - A simple self-crosslinking strategy, without the needs of a separate crosslinker or a catalyst, is reported here. The crosslinking drastically lowers the water swelling ratio (e.g., 5-10 folds reduction) and provides excellent solvent resistance. The self-crosslinked membrane (DCL: 5.3%) shows the highest IEC normalized hydroxide conductivity among all crosslinked HEMs reported. PMID- 21253627 TI - Direct covalent post-synthetic chemical modification of Cr-MIL-101 using nitrating acid. AB - For the first time, functionality has been covalently introduced into the Cr-MIL 101 network by post-synthetic modification of the terephthalate linker molecule through nitration. The nitro group was reduced and the amino group was reacted with ethyl isocyanate to yield the corresponding urea derivative. PMID- 21253628 TI - A pH-driven DNA nanoswitch for responsive controlled release. AB - An intelligent pH-responsive carrier and release system based on DNA nanoswitch controlled organization of gold nanoparticles (AuNPs) attached to mesoporous silica (MS) has been designed and demonstrated. PMID- 21253629 TI - Pyridine as trigger for chloride isomerisation in chelated ruthenium benzylidene complexes: implications for olefin metathesis. AB - The cationic pyridine adduct of a ruthenium complex bearing a chelating benzylidene and an N-heterocyclic carbene was identified as an intermediate during the activation of cis dichloro species and a novel triggering concept for olefin metathesis catalysts based on cationic species was disclosed. PMID- 21253630 TI - Ordered mesoporous materials as adsorbents. AB - Environmental pollution, energy consumption and biotechnology have induced more and more public concerns. Problems imposed by these issues will circulate in the 21st century. Adsorption-based processes may lead to one of the most efficient routes for removal of toxic substances, energy storage and bio-applications. The fundamental and great challenge is developing highly efficient adsorbents. In this regard, ordered mesoporous materials (OMMs) may be the answer in the future. They possess intrinsic high specific surface areas, regular and tunable pore sizes, large pore volumes, as well as stable and interconnected frameworks with active pore surfaces for modification or functionalization. Such features meet the requirements as excellent adsorbents, not only providing huge interface and large space capable of accommodating capacious guest species, but also enabling the possibility of specific binding, enrichment and separation. As a result, these materials have been extensively studied as advanced adsorbents and hundreds of papers have been published since the millennium. In this Highlight, we will mainly summarize and outlook the development in pollution control, gas storage and bioadsorption by using OMMs as adsorbents. PMID- 21253631 TI - Facile synthesis of ultrasmall GdF3 nanowires via an oriented attachment growth and their luminescence properties. AB - Ultrasmall nanowires of rare-earth fluoride were prepared via an oriented attachment growth for the first time, and the formation process and the role of the capping ligand were discussed. Furthermore, as a luminescence host, they showed higher emitting intensity with Eu(3+) doping. PMID- 21253632 TI - A well-defined silica-supported aluminium alkyl through an unprecedented, consecutive two-step protonolysis-alkyl transfer mechanism. AB - Impregnation of [(AliBu(3))(Et(2)O)] on partially dehydroxylated SBA-15 affords a mesoporous material bearing the well-defined single site surface aluminium species [(=SiO)(2)Al(iBu)(Et(2)O)]. PMID- 21253633 TI - Stabilization of vesicular and supported membranes by glycolipid oxime polymers. AB - We report herein new synthetic glycolipid dimers and polymers that provide unprecedented stability to both supported (SLBs) and vesicular lipid bilayers against dehydration and serum exposure. These novel physical properties will enable pharmaceutical delivery and development of SLB bioanalytical devices. PMID- 21253634 TI - An electrochemical approach for detection of DNA methylation and assay of the methyltransferase activity. AB - This work develops an electrochemical approach for rapid detection of the genomic DNA methylation level, assay of methyltransferase activity, and evaluation and screening of the inhibitors of methyltransferase. This method may be a help for the discovery of anticancer drugs. PMID- 21253635 TI - Restricted rotation due to the lack of free space within a capsule translates into product selectivity: photochemistry of cyclohexyl phenyl ketones within a water-soluble organic capsule. AB - The rotational mobility of organic guest molecules when included within a confined capsule is restricted and this feature could be translated into product selectivity as established with the photochemical behavior of cyclohexyl phenyl ketones. PMID- 21253636 TI - DFT study of propane dehydrogenation on Pt catalyst: effects of step sites. AB - Self-consistent periodic slab calculations based on gradient-corrected density functional theory (DFT-GGA) have been conducted to examine the reaction network of propane dehydrogenation over close-packed Pt(111) and stepped Pt(211) surfaces. Selective C-H or C-C bond cleaving is investigated to gain a better understanding of the catalyst site requirements for propane dehydrogenation. The energy barriers for the dehydrogenation of propane to form propylene are calculated to be in the region of 0.65-0.75 eV and 0.25-0.35 eV on flat and stepped surfaces, respectively. Likewise, the activation of the side reactions such as the deep dehydrogenation and cracking of C(3) derivatives depends strongly on the step density, arising from the much lower energy barriers on Pt(211). Taking the activation energy difference between propylene dehydrogenation and propylene desorption as the descriptor, we find that while step sites play a crucial role in the activation of propane dehydrogenation, the selectivity towards propylene is substantially lowered in the presence of the coordinatively unsaturated surface Pt atoms. As the sole C(3) derivative which prefers the cleavage of the C-C bond to the C-H bond breaking, propyne is suggested to be the starting point for the C-C bond breaking which eventually gives rise to the formation of ethane, methane and coke. These findings provide a rational interpretation of the recent experimental observations that smaller Pt particles containing more step sites are much more active but less selective than larger particles in propane dehydrogenation. PMID- 21253637 TI - Characterization of active sites, determination of mechanisms of H(2)S, COS and CS(2) sorption and regeneration of ZnO low-temperature sorbents: past, current and perspectives. AB - The intellectually and technically challenging pursuit of the emerging global environmentally "green" and energy-efficient infrastructure of the 21st century requires the development of a worldwide network of low- to medium-power fuel cell (FC) based portable electric power-generating devices and high-power biomass/clean coal "electric+chemical plants" with zero carbon footprint utilizing integrated coal gasification combined cycle with geologic carbon sequestration (IGCC-GCS) under energy-efficient low-temperature conditions. These emerging technologies require the deep and ultradeep desulfurization of gaseous feeds, since sulfur compounds, especially hydrogen sulfide H(2)S are highly corrosive and poisonous to both technological processes and the environment. Therefore, it is of crucial importance for both academic and industrial research communities to have a solid understanding of the atomic-level structures of active sites and molecular-level mechanisms of surface chemical reactions of the novel deep and ultradeep desulfurization materials, especially desulfurization sorbents. This review critically analyzes the recent literature (last ~20 years) on the experimental determination of molecular and atomic-level nature of adsorption sites, effects of desulfurization promoters, mechanisms of chemical reactions of H(2)S, COS and CS(2) and physical processes during and upon regeneration of "spent" low-temperature H(2)S sorbents based on ZnO that were developed for desulfurization of fuel reformates, syngas and similar streams. Recent trends in research on the ultradeep H(2)S sorbents are discussed with an impetus on real-time in situ and Operando techniques of instrumental chemical analysis, and the challenges of direct determination of the structure of active sites and of the experimental mechanistic studies in general are described. PMID- 21253638 TI - A superfluorescent fluorenyl probe with efficient two-photon absorption. AB - The linear photophysical, excited state absorption (ESA), superfluorescence, and two-photon absorption (2PA) properties of 4,4'-(1E,1'E)-2,2' (7,7'(1E,1'E)2,2'(4,4'-sulfonylbis(4,1-phenylene))bis(ethane-2,1-diyl)bis(9,9 didecy-9H-fluorene7,2-diyl))bis(ethane-2,1-diyl)bis(N,N-diphenylaniline) (1) were investigated in organic and aqueous media with respect to its potential application in biological imaging. The analysis of linear photophysical properties revealed a rather complex nature of the main one-photon absorption band, strong solvatochromic effects in the steady-state fluorescence spectra, single-exponential fluorescence decay, and high fluorescence quantum yields in organic solvents (~1.0). The ESA spectra of 1 suggested potential for light amplification in nonpolar media while efficient superfluorescence in cyclohexane was demonstrated. The degenerate 2PA spectra of 1 were obtained over a broad spectral range (640-900 nm), using a standard two-photon induced fluorescence method under 1 kHz femtosecond excitation. Two well defined 2PA bands with maximum 2PA cross sections up to 1700 GM in the higher energy, short wavelength band and ~1200 GM in the lower energy, long wavelength band of 1 were shown. The potential use of 1 in bioimaging was demonstrated via one- and two-photon in vitro fluorescence imaging of HCT 116 cells. PMID- 21253639 TI - Stability conditions for density functional reactivity theory: an interpretation of the total local hardness. AB - The second-order Taylor series expansions commonly used in the density functional chemical reactivity theory are used to define local stability conditions for electronic states. Systems which satisfy these conditions are stable to infinitesimal perturbations due to approaching chemical reagents. The basic formalism considered here supersedes previous variational approaches to chemical reactivity theory like the electrophilicity, potentialphilicity, and chargephilicity. The total local hardness emerges naturally in this analysis, and can be clearly interpreted. When the total local hardness is small, the system is relatively insensitive to perturbations. Furthermore, minus the total local hardness is an energetically favorable perturbation of the external potential. PMID- 21253640 TI - Role of axially coordinated surface sites for electrochemically controlled carbon monoxide adsorption on single crystal copper electrodes. AB - The adsorption of CO on low index copper single crystals in electrochemical environments has been investigated. The results, analysed through a combination of in situ infrared spectroscopy, DFT and cyclic voltammetry, reveal a unique adsorption behaviour when compared to previous studies on copper and the more widely studied noble metal surfaces. By employing small, weakly specifically adsorbed electrolytes, it is shown that carbon monoxide is adsorbed over a much wider electrode potential range than previously reported. The electrochemical Stark shift (deltanu/deltaE) observed is similar for the three Cu(hkl) surfaces examined despite different surface coverages. Most notably, however, is an electrochemical feature observed at ca. -1.0 V (vs. Ag/AgCl) on the (110) surface. It is proposed that this voltammetric feature arises from the reduction/oxidation of Cu(delta+) surface sites involved in the binding of carbon monoxide with the participation of the electrolyte anion. This provides additional specific sites for CO adsorption. DFT calculations support the proposed presence of low-coordination copper sites stabilised by electrolyte anions. An experimental electron transfer rate constant of 4.2 s(-1) to the Cu(delta+) surface sites formed was found. These new observations concerning the surface electrochemistry of CO on Cu indicate that the electrocatalytic behaviour of Cu electrodes in processes such as CO(2) reduction need to be re-evaluated to take account of the rich adsorption behaviour of CO, including the co-adsorption of the electrolyte anion to these sites. PMID- 21253641 TI - Novel view on the mechanism of water-assisted proton transfer in the DNA bases: bulk water hydration. AB - In the present work, the conventional static ab initio picture of a water assisted mechanism of the tautomerization of Nucleic Acid Bases (NABs) in an aqueous environment is enhanced by the classical and Car-Parrinello molecular dynamics simulations. The inclusion of the dynamical contribution is vital because the formation and longevity of the NAB-water bridge complexes represent decisive factors for further tautomerization. The results of both molecular dynamic techniques indicate that the longest time when such complexes exist is significantly shorter than the time required for proton transfer suggested by the static ab initio level of theory. New rate constants of tautomerization corrected for the dynamic effect of environment are proposed based on the first principles molecular dynamics data. Those values are used for the evaluation of a water assisted mechanism that is feasible in such biological systems as E. coli cell. PMID- 21253642 TI - Electrolytes for solid-state lithium rechargeable batteries: recent advances and perspectives. AB - This critical review presents an overview of the various classes of Li(+) conductors for use as electrolytes in lithium polymer batteries and all-solid state microbatteries. Initially, we recall the main models for ion transport and the structure-transport relationships at the basis of the observed conductivity behaviours. Emphasis is then placed on the physico-chemical and functional parameters relevant for optimal electrolytes preparation, as well as on the techniques of choice for their evaluation. Finally, the state of the art of polymer and ceramic electrolytes is reported, and the most interesting strategies for the future developments are described (121 references). PMID- 21253644 TI - TTF salts of optically pure cobalt pyridine amidates; detection of soluble assemblies with stoichiometry corresponding to the solid state. AB - Optically pure anionic complexes of pyridinecarboxamide ligands, N(2),N(6) bis((R)-alpha-methylbenzyl)pyridine-2, 6-dicarboxamide H(2)(R,R-L(1)) and N(2),N(6)-bis((S)-1-methoxypropan-2-yl)pyridine-2, 6-dicarboxamide H(2)(S,S-L(2)) have been synthesised and fully characterised. The complexes: (18-crown 6)K[Co(III)(R,R-L(1))(2)], (18-crown-6)K[Fe(III)(R,R-L(1))(2)] and K[Co(III)(S,S L(2))(2)].3H(2)O show interesting extended structures from 0D discrete units through 1D zigzag chains to 2D honeycomb layers. The complex anions were used in the synthesis of radical cation salts with tetrathiafulvalene (TTF). The salts (TTF)[Co(III)(R,R-L(1))(2)] and (TTF)[Co(III)(S,S-L(2))(2)].EtOAc were characterised by single crystal X-ray diffraction and conductivity measurements. Both compounds comprise mono-oxidised TTF molecules and exhibit similar layered structures with no direct TTF stacking but in which phenyl substituents from the complex anion or co-crystallised ethyl acetate alternate with TTF(+) units. Solution spectroscopic and cyclic voltammetric evidence points to the formation of soluble assemblies between TTF(+) and the counterion which correspond to the stoichiometry observed by crystallography and other methods in the solid state. PMID- 21253643 TI - Phosphorescent heavy-metal complexes for bioimaging. AB - The application of phosphorescent heavy-metal complexes with d(6), d(8) and d(10) electron configurations for bioimaging is a new and promising research field and has been attracting increasing interest. In this critical review, we systematically evaluate the advantages of phosphorescent heavy-metal complexes as bioimaging probes, including their photophysical properties, cytotoxicity and cellular uptake mechanisms. The progress of research into the use of phosphorescent heavy-metal complexes for staining different compartments of cells, monitoring intracellular functional species, providing targeted bioimaging, two-photon bioimaging, small-animal bioimaging, multimodal bioimaging and time-resolved bioimaging is summarized. In addition, several possible future directions in this field are also discussed (133 references). PMID- 21253645 TI - Structure, adsorption and magnetic properties of chiral metal-organic frameworks bearing linear trinuclear secondary building blocks. AB - The reactions of new chiral organic ligands trimesoyltri(L-alanine) (L-TMTAH(3)) or trimesoyltri(D-alanine) (D-TMTAH(3)) with transition metal salts in the presence of an ancillary ligand of 4,4'-bipyridine gave two pairs of three dimensional frameworks [Co(3)(L-TMTA)(2)(4,4'-bpy)(4)].28H(2)O (1), [Co(3)(D TMTA)(2)(4,4'-bpy)(4)].28H(2)O (2) [Ni(3)(L-TMTA)(2)(4,4' bpy)(4)].2C(2)H(5)OH.14H(2)O (3) and [Ni(3)(D-TMTA)(2)(4,4' bpy)(4)].2C(2)H(5)OH.14H(2)O (4). These compounds were characterized by elemental analysis, IR, and X-ray powder diffraction analysis and the structures of 1-3 were determined from X-ray single crystal diffraction analysis. Complexes 1-4 feature linear trinuclear secondary building blocks [M(3)(COO)(4)](2+) formed via the connection of three metal ions by four carboxylato groups from four TMTA(3-) ligands. Every adjacent two linear trinuclear secondary building blocks are linked by one and three 4,4'-bipyridine molecules along the a and c axis, respectively, to form two-dimensional sheets, which are further connected by TMTA(3-) ligands to construct a porous three dimensional framework with one dimensional channels. Compound 3 was taken as an example to investigate the adsorption properties of compounds 1-4. It revealed a saturated hydrogen uptake of 216.6 cm(3) g(-1) (2.0 wt%) at 11.1 atm measured at 77 K, a maximum CO(2) uptake of 119.4 cm(3) g(-1) (23.5 wt%) at 19.5 atm measured at 298 K and a saturated CH(4) uptake of 77.8 cm(3) g(-1) (5.6 wt%) at 27.1 atm measured at 298 K. The magnetic studies of complexes 1 and 3 indicate the presence of antiferromagnetic interactions between the metal ions in the two compounds. PMID- 21253646 TI - Geographic differences in organic contaminants and stable isotopes (delta13C, delta15N) in thick-billed murre (Uria lomvia) eggs from Alaska. AB - The contents from thick-billed murre (Uria lomvia) eggs collected at four Alaskan colonies in 2002 were analyzed for organic contaminants and carbon delta13C) and nitrogen (delta15N) stable isotopes. Contaminant concentrations in the eggs varied from below detection limits to 230 ng g-1 wet mass for 4,4'-DDE in one egg from St Lazaria Island in the Gulf of Alaska. Eggs from this colony generally contained higher levels of contaminants and exhibited significantly different patterns compared to eggs from the Bering and Chukchi seas. Stable isotope values also varied geographically; however, these differences appeared to be related to differences in C and N baselines in the food webs instead of differences in prey. Contaminant and stable isotope correlations were inconclusive, suggesting that better information on regional food web differences and differential offloading of contaminants and stable isotopes to the eggs must be obtained before these kinds of data can be fully incorporated into seabird egg contaminant monitoring programs. PMID- 21253647 TI - Magnetic core shell nanoparticles trapping in a microdevice generating high magnetic gradient. AB - Magnetic core shell nanoparticles (MCSNPs) 30 nm diameter with a magnetic weight of 10% are usually much too small to be trapped in microfluidic systems using classical external magnets. Here, a simple microchip for efficient MCSNPs trapping and release is presented. It comprises a bed of micrometric iron beads (6-8 MUm diameter) packed in a microchannel against a physical restriction and presenting a low dead volume of 0.8 nL. These beads of high magnetic permeability are used to focus magnetic field lines from an external permanent magnet and generate local high magnetic gradients. The nanoparticles magnetic trap has been characterised both by numerical simulations and fluorescent MCSNPs imaging. Numerical simulations have been performed to map both the magnetic flux density and the magnetic force, and showed that MCSNPs are preferentially trapped at the iron bead magnetic poles where the magnetic force is increased by 3 orders of magnitude. The trapping efficiency was experimentally determined using fluorescent MCSNPs for different flow rates, different iron beads and permanent magnet positions. At a flow rate of 100 MUL h(-1), the nanoparticles trapping/release can be achieved within 20 s with a preconcentration factor of 4000. PMID- 21253648 TI - The Haptoglobin beta chain as a supportive biomarker for human lung cancers. AB - Haptoglobin (Hp) is produced as an acute phase reactant during inflammation, infection, malignant diseases, and several cancers. In proteomics analysis using human blood samples, the Hp peptide levels were about 3-fold higher in lung cancer patients versus normal individuals. This study is aimed at analyzing the elevation of which chain of Hp is closely related to lung cancers and can be a serum biomarker for lung cancers. In Western blot (WB) analysis, we found that the Hp beta chain can be a better diagnostic biomarker for lung cancers. In the result of the Hp beta chain ELISA developed by us, the concentrations of the Hp beta chain in the sera increased about 4-fold in 190 lung adenocarcinoma patients versus 190 healthy controls (8.0 +/- 3.8 MUg ml(-1)vs. 1.9 +/- 1.2 MUg ml(-1)). ELISA data showed that the serum levels of the Hp beta chain in breast cancer (1.5 +/- 0.5 MUg ml(-1)) and hepatocellular carcinoma (HCC) (1.4 +/- 1.0 MUg ml( 1)) patients remained similar to those of healthy controls. Compared to lung adenocarcinoma, the Hp beta chain levels in the plasma of patients with other respiratory diseases such as tuberculosis (TBC), idiopathic pulmonary fibrosis (IPF) and bronchial asthma (BA) were closer to those of healthy controls. Our data suggest that an increase of the Hp beta chain can be a potential serum biomarker for lung cancers. PMID- 21253649 TI - Zinc finger proteins as templates for metal ion exchange and ligand reactivity. Chemical and biological consequences. AB - Zinc finger reactions with inorganic ions and coordination compounds are as diverse as the zinc fingers themselves. Use of metal ions such as Co(2+) and Cd(2+) has given structural, thermodynamic and kinetic information on zinc fingers and zinc-finger-DNA/RNA interactions. It is a general truism that alteration of the coordination sphere in the finger environment will disrupt the recognition with DNA/RNA and this has implications for mechanism of toxicity and carcinogenesis of metal ions. Structural zinc fingers are susceptible to electrophilic attack and the recognition that the coordination sphere of inorganic compounds may be modulated for control of electrophilic attack on zinc fingers raises the possibility of systematic studies of zinc fingers as drug targets using inorganic chemistry. Some inorganic compounds such as those of As(III) and Au(I) may exert their biological effects through inactivation of zinc fingers and novel approaches to specifically attack the zinc-bound ligands using Co(III)-Schiff bases and Platinum(II)-Nucleobase compounds have been proposed. The genomic importance of zinc fingers suggests that the "coordination chemistry" of zinc fingers themselves is ripe for exploration to design new targets for medicinal inorganic chemistry. PMID- 21253650 TI - The role of nanomaterials in redox-based supercapacitors for next generation energy storage devices. AB - The development of more efficient electrical storage is a pressing requirement to meet future societal and environmental needs. This demand for more sustainable, efficient energy storage has provoked a renewed scientific and commercial interest in advanced capacitor designs in which the suite of experimental techniques and ideas that comprise nanotechnology are playing a critical role. Capacitors can be charged and discharged quickly and are one of the primary building blocks of many types of electrical circuit, from microprocessors to large-sale power supplies, but usually have relatively low energy storage capability when compared with batteries. The application of nanostructured materials with bespoke morphologies and properties to electrochemical supercapacitors is being intensively studied in order to provide enhanced energy density without comprising their inherent high power density and excellent cyclability. In particular, electrode materials that exploit physical adsorption or redox reactions of electrolyte ions are foreseen to bridge the performance disparity between batteries with high energy density and capacitors with high power density. In this review, we present some of the novel nanomaterial systems applied for electrochemical supercapacitors and show how material morphology, chemistry and physical properties are being tailored to provide enhanced electrochemical supercapacitor performance. PMID- 21253651 TI - Growth stimulation of gram (Cicer arietinum) plant by water soluble carbon nanotubes. AB - Water soluble carbon nanotubes (wsCNTs) show enhancement of the growth rate of common gram (Cicer arietinum) plants. Treating plants with up to 6.0 MUg mL(-1) of wsCNT shows an increased growth rate in every part of the plant including the roots, shoots and also in branching. The noticeable difference between the wsCNT treated and controlled gram is the water uptake; in the former it is dramatically enhanced, suggesting better water absorption and retention related to enhanced growth. This work shows that unlike CNTs, wsCNTs are non-toxic to plant cells that conserve water transport in plants. PMID- 21253652 TI - Chemo-, regio-, and diastereoselectivity preferences in the reaction of a sulfur ylide with a dienal and an enone. AB - Mechanistic insights into an interesting class of reaction between sulfur ylides with (i) a dienal, and (ii) an enone, obtained by using density functional theory, is reported. The kinetic and thermodynamic factors responsible for chemo , regio-, and diastereoselectivities are established by identifying all key transition states and intermediates along the reaction pathway for 1,2-, 1,4-, and 1,6- modes of attack of dimethylsulfonium benzylide to 5-phenylpenta-2,4 dienal. The reaction profiles for 1,2- and 1,4- modes of addition are also evaluated for the reaction between dimethylsulfonium benzylide and pent-3-en-2 one. Our results show that the final outcome of the reaction with both these substrates would be decided by the interplay between kinetic and thermodynamic factors. It is found that the addition of a semi-stabilized ylide to conjugated carbonyl compounds prefers to proceed through a 1,4- (conjugate) pathway under thermodynamic conditions, which is in accordance with the available experimental reports. However, the formation of epoxides via a 1,2- (direct) addition pathway is computed to be equally competitive, which could be the favored pathway under kinetic conditions. Even though the lower barrier for the initial addition step is kinetically advantageous for the direct (or 1,2-) addition pathway, the higher energy of the betaine intermediates--as well as the reversibility of the accompanying elementary step--may disfavor product formation in this route. Thus, high diastereoselectivity in favor of 2,3-trans cyclopropanecarbaldehyde is predicted in the case of the dienal, using the most favored conjugate addition (1,4-addition) pathway. Along similar lines, ylide addition to the enone is identified to exhibit a preference toward conjugate addition over direct (1,2-) addition. The importance of transition state analysis in delineating the controlling factors towards product distribution and diastereoselectivity is established. PMID- 21253653 TI - Observation of the reversibility of a covalent pyrrolobenzodiazepine (PBD) DNA adduct by HPLC/MS and CD spectroscopy. AB - Pyrrolobenzodiazepines (PBDs) are sequence-selective DNA minor-groove binding agents that covalently bond to guanine with a reported preference for Pu-G-Pu sequences (Pu = Purine). Using HPLC/MS and Circular Dichroism (CD) methodologies, we have established for the first time that the aminal bond formed between PBD molecules and DNA is reversible. Furthermore, we have shown that while the rate of aminal bond cleavage does not depend on the sequence preference of a PBD molecule for a particular binding site, the rate of re-formation of the PBD-DNA adduct does. We have also shown that the PBD anthramycin (2) appears to be an exception to this rule in that, during cleavage from the DNA, its C-ring aromatizes and it cannot then re-attach due to a loss of electrophilicity at the C11-position. Although the C-ring aromatization of anthramycin has been previously reported to occur in the absence of DNA and after treatment with trifluoroacetic acid (TFA), in this case no pH lowering was required, with the DNA itself appearing to catalyse the process. PMID- 21253655 TI - Lewis acid-catalysed one pot synthesis of substituted xanthenes. AB - A direct synthesis of substituted xanthenes from salicylaldehydes and cyclohexenones or tetralones has been developed. The reaction is catalysed by Lewis acids like scandium triflate and furnishes substituted xanthenes in good to excellent yields using either microwave or thermal heating. Microwave heating results in significantly shortened reaction times of 30 min and generally higher yields. PMID- 21253654 TI - Probing the acceptor substrate binding site of Trypanosoma cruzi trans-sialidase with systematically modified substrates and glycoside libraries. AB - Systematically modified octyl galactosides and octyl N-acetyllactosamines were assessed as inhibitors of, and substrates for, T. cruzi trans-sialidase (TcTS) in the context of exploring its acceptor substrate binding site. These studies show that TcTS, which catalyses the alpha-(2->3)-sialylation of non-reducing terminal beta-galactose residues, is largely intolerant of substitution of the galactose 2 and 4 positions whereas substitution of the galactose 6 position is well tolerated. Further studies show that even the addition of a bulky sugar residue (glucose, galactose) does not impact negatively on TcTS binding and turnover, which highlights the potential of 'internal' 6-substituted galactose residues to serve as TcTS acceptor substrates. Results from screening a 93-membered thiogalactoside library highlight a number of structural features (notably imidazoles and indoles) that are worthy of further investigation in the context of TcTS inhibitor development. PMID- 21253656 TI - New synthetic route to N-tocopherol derivatives: synthesis of pyrrolopyridinol analogue of alpha-tocopherol from pyridoxine. AB - A new synthetic route to pyrrolopyridinol antioxidants from easily accessible pyridoxine was developed which includes phase-transfer catalytic alkylation and intramolecular Cu(I)-catalyzed amination as key steps. PMID- 21253657 TI - Initial excited-state relaxation of the bilin chromophores of phytochromes: a computational study. AB - The geometric relaxation following light absorption of the biliverdin, phycocyanobilin and phytochromobilin tetrapyrrole chromophores of bacterial, cyanobacterial and plant phytochromes has been investigated using density functional theory methods. Considering stereoisomers relevant for both red absorbing Pr and far-red-absorbing Pfr forms of the photoreceptor, it is found that the initial excited-state evolution is dominated by torsional motion at the C10-C11 bond. This holds true for all three chromophores and irrespective of which configuration the chromophores adopt. This finding suggests that the photochromic cycling of phytochromes between their Pr and Pfr forms, which is known to be governed by Z/E photoisomerizations at the C15-C16 bond, relies on interactions between the chromophore and the protein to prevent photoisomerizations at C10-C11. Further, it is found that the uneven distribution of positive charge between the pyrrole rings is a major factor for the photochemical reactivity of the C10-C11 bond. PMID- 21253658 TI - Photophysical properties of ternary rare earth (Sm3+, Eu3+) centered hybrids with N-heterocyclic modified Si-O bridge and terminal ligands. AB - 5-Amino-1,10-phenanthroline (Phen-NH(2)) is grafted to 3-(triethoxysilyl)-propyl isocyanate (TESPIC) to achieve the organic precursor Phen-Si, which is coordinated to rare earth ions (Sm(3+) or Eu(3+)) and formed Si-O networks with tetraethoxysilane (TEOS) (Phen-Si-RE) after hydrolysis and polycondensation processes to obtain the hybrids Phen-Si-Ln. To investigate the influence of the second ligands to the photophysical properties of the hybrid material Phen-Si-RE, the organic ligand nicotinic acid (NA) and the polymers polyvinylpyrrolidone (PVP) (or PMMA) are further introduced into the above system to assemble the ternary hybrid materials Phen-Si-RE-NA and Phen-Si-RE-PVP (or Phen-Si-RE-PMMA), respectively. These hybrids are amorphous and especially the photophysical properties of them indicate that the introduction of the second ligands is favorable for the luminescence lifetime and quantum efficiency. PMID- 21253659 TI - Photodynamic therapy enhancement of anti-tumor immunity. AB - Photodynamic therapy (PDT) is an FDA-approved modality for the treatment of early stage disease and palliation of late-stage disease. Pre-clinical studies using mouse models and clinical studies in patients have demonstrated that PDT is capable of influencing the immune system. The effect of PDT on the generation of anti-tumor immunity is regimen-dependent and is tightly linked to the degree and nature of inflammation induced by PDT. However, the precise mechanism underlying PDT-regulated adaptive anti-tumor immunity remains unclear. This review will focus on the current knowledge of immune regulation by PDT. PMID- 21253660 TI - Ozone depletion and climate change: impacts on UV radiation. AB - The Montreal Protocol is working, but it will take several decades for ozone to return to 1980 levels. The atmospheric concentrations of ozone depleting substances are decreasing, and ozone column amounts are no longer decreasing. Mid latitude ozone is expected to return to 1980 levels before mid-century, slightly earlier than predicted previously. However, the recovery rate will be slower at high latitudes. Springtime ozone depletion is expected to continue to occur at polar latitudes, especially in Antarctica, in the next few decades. Because of the success of the Protocol, increases in UV-B radiation have been small outside regions affected by the Antarctic ozone hole, and have been difficult to detect. There is a large variability in UV-B radiation due to factors other than ozone, such as clouds and aerosols. There are few long-term measurements available to confirm the increases that would have occurred as a result of ozone depletion. At mid-latitudes UV-B irradiances are currently only slightly greater than in 1980 (increases less than ~5%), but increases have been substantial at high and polar latitudes where ozone depletion has been larger. Without the Montreal Protocol, peak values of sunburning UV radiation could have been tripled by 2065 at mid northern latitudes. This would have had serious consequences for the environment and for human health. There are strong interactions between ozone depletion and changes in climate induced by increasing greenhouse gases (GHGs). Ozone depletion affects climate, and climate change affects ozone. The successful implementation of the Montreal Protocol has had a marked effect on climate change. The calculated reduction in radiative forcing due to the phase-out of chlorofluorocarbons (CFCs) far exceeds that from the measures taken under the Kyoto protocol for the reduction of GHGs. Thus the phase-out of CFCs is currently tending to counteract the increases in surface temperature due to increased GHGs. The amount of stratospheric ozone can also be affected by the increases in the concentration of GHGs, which lead to decreased temperatures in the stratosphere and accelerated circulation patterns. These changes tend to decrease total ozone in the tropics and increase total ozone at mid and high latitudes. Changes in circulation induced by changes in ozone can also affect patterns of surface wind and rainfall. The projected changes in ozone and clouds may lead to large decreases in UV at high latitudes, where UV is already low; and to small increases at low latitudes, where it is already high. This could have important implications for health and ecosystems. Compared to 1980, UV-B irradiance towards the end of the 21st century is projected to be lower at mid to high latitudes by between 5 and 20% respectively, and higher by 2-3% in the low latitudes. However, these projections must be treated with caution because they also depend strongly on changes in cloud cover, air pollutants, and aerosols, all of which are influenced by climate change, and their future is uncertain. Strong interactions between ozone depletion and climate change and uncertainties in the measurements and models limit our confidence in predicting the future UV radiation. It is therefore important to improve our understanding of the processes involved, and to continue monitoring ozone and surface UV spectral irradiances both from the surface and from satellites so we can respond to unexpected changes in the future. PMID- 21253661 TI - Effects of solar ultraviolet radiation on terrestrial ecosystems. Patterns, mechanisms, and interactions with climate change. AB - Ultraviolet radiation (UV) is a minor fraction of the solar spectrum reaching the ground surface. In this assessment we summarize the results of previous work on the effects of the UV-B component (280-315 nm) on terrestrial ecosystems, and draw attention to important knowledge gaps in our understanding of the interactive effects of UV radiation and climate change. We highlight the following points: (i) The effects of UV-B on the growth of terrestrial plants are relatively small and, because the Montreal Protocol has been successful in limiting ozone depletion, the reduction in plant growth caused by increased UV-B radiation in areas affected by ozone decline since 1980 is unlikely to have exceeded 6%. (ii) Solar UV-B radiation has large direct and indirect (plant mediated) effects on canopy arthropods and microorganisms. Therefore, trophic interactions (herbivory, decomposition) in terrestrial ecosystems appear to be sensitive to variations in UV-B irradiance. (iii) Future variations in UV radiation resulting from changes in climate and land-use may have more important consequences on terrestrial ecosystems than the changes in UV caused by ozone depletion. This is because the resulting changes in UV radiation may affect a greater range of ecosystems, and will not be restricted solely to the UV-B component. (iv) Several ecosystem processes that are not particularly sensitive to UV-B radiation can be strongly affected by UV-A (315-400 nm) radiation. One example is the physical degradation of plant litter. Increased photodegradation (in response to reduced cloudiness or canopy cover) will lead to increased carbon release to the atmosphere via direct and indirect mechanisms. PMID- 21253662 TI - Effects of UV radiation on aquatic ecosystems and interactions with climate change. AB - The health of freshwater and marine ecosystems is critical to life on Earth. The impact of solar UV-B radiation is one potential stress factor that can have a negative impact on the health of certain species within these ecosystems. Although there is a paucity of data and information regarding the effect of UV-B radiation on total ecosystem structure and function, several recent studies have addressed the effects on various species within each trophic level. Climate change, acid deposition, and changes in other anthropogenic stressors such as pollutants alter UV exposure levels in inland and coastal marine waters. These factors potentially have important consequences for a variety of aquatic organisms including waterborne human pathogens. Recent results have demonstrated the negative impacts of exposure to UV-B radiation on primary producers, including effects on cyanobacteria, phytoplankton, macroalgae and aquatic plants. UV-B radiation is an environmental stressor for many aquatic consumers, including zooplankton, crustaceans, amphibians, fish, and corals. Many aquatic producers and consumers rely on avoidance strategies, repair mechanisms and the synthesis of UV-absorbing substances for protection. However, there has been relatively little information generated regarding the impact of solar UV-B radiation on species composition within natural ecosystems or on the interaction of organisms between trophic levels within those ecosystems. There remains the question as to whether a decrease in population size of the more sensitive primary producers would be compensated for by an increase in the population size of more tolerant species, and therefore whether there would be a net negative impact on the absorption of atmospheric carbon dioxide by these ecosystems. Another question is whether there would be a significant impact on the quantity and quality of nutrients cycling through the food web, including the generation of food proteins for humans. Interactive effects of UV radiation with changes in other stressors, including climate change and pollutants, are likely to be particularly important. PMID- 21253663 TI - Effects of solar UV radiation and climate change on biogeochemical cycling: interactions and feedbacks. AB - Solar UV radiation, climate and other drivers of global change are undergoing significant changes and models forecast that these changes will continue for the remainder of this century. Here we assess the effects of solar UV radiation on biogeochemical cycles and the interactions of these effects with climate change, including feedbacks on climate. Such interactions occur in both terrestrial and aquatic ecosystems. While there is significant uncertainty in the quantification of these effects, they could accelerate the rate of atmospheric CO(2) increase and subsequent climate change beyond current predictions. The effects of predicted changes in climate and solar UV radiation on carbon cycling in terrestrial and aquatic ecosystems are expected to vary significantly between regions. The balance of positive and negative effects on terrestrial carbon cycling remains uncertain, but the interactions between UV radiation and climate change are likely to contribute to decreasing sink strength in many oceanic regions. Interactions between climate and solar UV radiation will affect cycling of elements other than carbon, and so will influence the concentration of greenhouse and ozone-depleting gases. For example, increases in oxygen-deficient regions of the ocean caused by climate change are projected to enhance the emissions of nitrous oxide, an important greenhouse and ozone-depleting gas. Future changes in UV-induced transformations of aquatic and terrestrial contaminants could have both beneficial and adverse effects. Taken in total, it is clear that the future changes in UV radiation coupled with human-caused global change will have large impacts on biogeochemical cycles at local, regional and global scales. PMID- 21253664 TI - Effects of solar UV and climate change on materials. AB - Increased solar ultraviolet radiation (UV) reaches the surface of the Earth as a consequence of a depleted stratospheric ozone layer and changes in factors such as cloud cover, land-use patterns and aerosols. Climate change is expected to result in a 1.1-6.4 degrees C increase in average temperature by the end of this century, depending on location. Increased levels of UV radiation, especially at high ambient temperatures, are well-known to accelerate the degradation of plastics, rubber and wood materials, thereby reducing their useful lifetimes in outdoor applications. Plastics used routinely outdoors are generally light stabilized using chemical additives to ensure their useful lifetimes. Wood products are coated for resistance to UV radiation, since photodamage results in enhanced water-susceptibility and their consequent biodegradation under outdoor exposure. The increased damage to materials due to an increased UV-B (280-315 nm) component in solar radiation reaching the Earth likely can be countered using light-stabilization technologies, surface coatings or, in most instances, by substituting the materials in question with greater UV radiation-resistant materials. However, even if these options could be used with all common materials affected, they will invariably result in higher costs. Reliable estimates of the incremental costs involved depend on the anticipated damage and the effectiveness of mitigation strategies employed. We summarize and assess recent findings on light-induced damage to plastic materials, including wood-plastics composites and nanocomposites. The combined effect of increased UV-B radiation and ambient temperature is of special interest, since these two factors represent particularly harsh environmental conditions for most materials. Advances in approaches to light stabilization of materials are also assessed. PMID- 21253665 TI - Changes in air quality and tropospheric composition due to depletion of stratospheric ozone and interactions with climate. AB - Air pollution will be directly influenced by future changes in emissions of pollutants, climate, and stratospheric ozone, and will have significant consequences for human health and the environment. UV radiation is one of the controlling factors for the formation of photochemical smog, which includes tropospheric ozone (O(3)) and aerosols; it also initiates the production of hydroxyl radicals (OH), which control the amount of many climate- and ozone relevant gases (e.g., methane and HCFCs) in the atmosphere. Numerical models predict that future changes in UV radiation and climate will modify the trends and geographic distribution of OH, thus affecting the formation of photochemical smog in many urban and regional areas. Concentrations of OH are predicted to decrease globally by an average of 20% by 2100, with local concentrations varying by as much as a factor of two above and below current values. However, significant differences between modelled and measured values in a limited number of case studies show that chemistry of hydroxyl radicals in the atmosphere is not fully understood. Photochemically produced tropospheric ozone is projected to increase. If emissions of anthropogenic air pollutants from combustion of fossil fuels, burning of biomass, and agricultural activities continue to increase, concentrations of tropospheric O(3) will tend to increase over the next 20-40 years in certain regions of low and middle latitudes because of interactions of emissions, chemical processes, and climate change. Climate-driven increases in temperature and humidity will also increase production of tropospheric O(3) in polluted regions, but reduce it in more pristine regions. Higher temperatures tend to increase emissions of nitrogen oxides (NO(x)) from some soils and release of biogenic volatile organic compounds (VOCs) from vegetation, leading to greater background concentrations of ozone in the troposphere. The net effects of future changes in UV radiation, meteorological conditions, and anthropogenic emissions may be large, thus posing challenges for prediction and management of air quality. Aerosols composed of organic substances have a major role in both climate and air quality, and contribute a large uncertainty to the energy budget of the atmosphere. These aerosols are mostly formed via the UV-initiated oxidation of VOCs from anthropogenic and biogenic sources, although the details of the chemistry are still poorly understood and current models under-predict their abundance. A better understanding of their formation, chemical composition, and optical properties is required to assess their significance for air quality and to better quantify their direct and indirect radiative forcing of climate. Emissions of compounds containing fluorine will continue to have effects on the chemistry of the atmosphere and on climate change. The HCFCs and HFCs used as substitutes for ozone-depleting CFCs can break down into trifluoroacetic acid (TFA), which will accumulate in oceans, salt lakes, and playas. Based on historical use and projections of future uses, including new products entering the market, such as the fluoro-olefins, increased loadings of TFA in these environmental sinks will be small. Even when added to existing amounts from natural sources, risks to humans or the environment from the historical use of CFCs or continued use of their replacements is judged to be negligible. PMID- 21253667 TI - Environmental effects of ozone depletion and its interactions with climate change: 2010 assessment. Introduction. PMID- 21253669 TI - Environmental effects of ozone depletion and its interactions with climate change: 2010 assessment. Executive summary. PMID- 21253670 TI - The human health effects of ozone depletion and interactions with climate change. AB - Depletion of the stratospheric ozone layer has led to increased solar UV-B radiation (280-315 nm) at the surface of the Earth. This change is likely to have had an impact on human exposure to UV-B radiation with consequential detrimental and beneficial effects on health, although behavioural changes in society over the past 60 years or so with regard to sun exposure are of considerable importance. The present report concentrates on information published since our previous report in 2007. The adverse effects of UV radiation are primarily on the eye and the skin. While solar UV radiation is a recognised risk factor for some types of cataract and for pterygium, the evidence is less strong, although increasing, for ocular melanoma, and is equivocal at present for age-related macular degeneration. For the skin, the most common harmful outcome is skin cancer, including melanoma and the non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma. The incidence of all three of these tumours has risen significantly over the past five decades, particularly in people with fair skin, and is projected to continue to increase, thus posing a significant world-wide health burden. Overexposure to the sun is the major identified environmental risk factor in skin cancer, in association with various genetic risk factors and immune effects. Suppression of some aspects of immunity follows exposure to UV radiation and the consequences of this modulation for the immune control of infectious diseases, for vaccination and for tumours, are additional concerns. In a common sun allergy (polymorphic light eruption), there is an imbalance in the immune response to UV radiation, resulting in a sun-evoked rash. The major health benefit of exposure to solar UV-B radiation is the production of vitamin D. Vitamin D plays a crucial role in bone metabolism and is also implicated in protection against a wide range of diseases. Although there is some evidence supporting protective effects for a range of internal cancers, this is not yet conclusive, but strongest for colorectal cancer, at present. A role for vitamin D in protection against several autoimmune diseases has been studied, with the most convincing results to date for multiple sclerosis. Vitamin D is starting to be assessed for its protective properties against several infectious and coronary diseases. Current methods for protecting the eye and the skin from the adverse effects of solar UV radiation are evaluated, including seeking shade, wearing protective clothing and sunglasses, and using sunscreens. Newer possibilities are considered such as creams that repair UV-induced DNA damage, and substances applied topically to the skin or eaten in the diet that protect against some of the detrimental effects of sun exposure. It is difficult to provide easily understandable public health messages regarding "safe" sun exposure, so that the positive effects of vitamin D production are balanced against the negative effects of excessive exposure. The international response to ozone depletion has included the development and deployment of replacement technologies and chemicals. To date, limited evidence suggests that substitutes for the ozone-depleting substances do not have significant effects on human health. In addition to stratospheric ozone depletion, climate change is predicted to affect human health, and potential interactions between these two parameters are considered. These include altering the risk of developing skin tumours, infectious diseases and various skin diseases, in addition to altering the efficiency by which pathogenic microorganisms are inactivated in the environment. PMID- 21253671 TI - Questions and answers about the environmental effects of ozone depletion and its interactions with climate change: 2010 assessment. PMID- 21253672 TI - Controlled nanostructures for applications in catalysis. PMID- 21253673 TI - Antiproliferative effect of natural tetrasulfides in human breast cancer cells is mediated through the inhibition of the cell division cycle 25 phosphatases. AB - For many years, in vitro and in vivo studies have reported that organosulfur compounds (OSCs), naturally found in Allium vegetables, are able to suppress the proliferation of various tumor cells. In spite of recent advances, the specific molecular mechanisms involved in OSC activity are still unclear. Considering the antiproliferative effects observed in cancer cells, we postulated that OSCs might target the cell division cycle (Cdc) 25 phosphatases which are crucial enzymes of the cell cycle. Our findings suggest phosphatases Cdc25 as possible targets of naturally occuring polysulfides contributing to their anticancer properties. We report on the inhibitory activity of tetrasulfides occurring naturally in garlic and onion towards the human Cdc25 phosphatases. Diallyl- and dipropyltetrasulfides have emerged as interesting irreversible inhibitors of the Cdc25 isoforms A and C in vitro. Furthermore, growth of both sensitive (MCF-7) and resistant (Vcr-R) human breast carcinoma cells was significantly decreased by these tetrasulfides. The observed antiproliferative effect appeared to be associated with a G2-M cell cycle arrest. PMID- 21253674 TI - The anti-leukemic effect and molecular mechanisms of novel hydroxamate and benzamide histone deacetylase inhibitors with 5-aza-cytidine. AB - Histone deacetylase inhibitors (HDACi) demonstrate considerable in vitro and in vivo activity and clinical efficacy in the treatment of hematological malignancies. Pre-clinical and early phase clinical trials identify therapeutic activity using a combination of HDACi and demethylating agents which may be more efficacious than single agent treatment. Our studies aimed to determine the effects and molecular mechanisms of action of novel hydroxamate (MCT-3) and benzamide [MGCD0103 (MG)] HDACi's in the HL-60 cell line alone and in combination with the demethylating agent 5-aza-cytidine (AZA). MG, MCT-3 and AZA treatment significantly inhibited HL-60 cell growth in vitro with MG being the most potent agent. MG in combination with AZA demonstrated no significant increase in inhibition of cell growth over MG treatment alone whilst MCT-3 in combination with AZA demonstrated increased inhibition of cell growth over either agent alone although no more significant than MG alone. MG alone or MCT-3 in combination with AZA significantly increased p15 and caspase-3 expression. MG and MCT-3 significantly attenuated AZA-induced MMP-9 mRNA expression and proteolytic activity. Interestingly, MCT-3, MG and AZA alone and in combination increased expression of the novel tumour suppressor gene Nur77, important in leukemogenesis, with MG a more potent inducer as a single agent. These observations suggest the enhanced anti-leukemia activity of the combination of AZA and HDACi may only reside with certain HDACi classes and may be in-part explained by regulation of genes associated with cell cycle arrest, apoptosis and tumour suppression. PMID- 21253675 TI - Imaging agents for in vivo molecular profiling of disseminated prostate cancer- targeting EGFR receptors in prostate cancer: comparison of cellular processing of [111In]-labeled affibody molecule Z(EGFR:2377) and cetuximab. AB - Expression of receptor tyrosine-kinase (RTK) EGFR is low in normal prostate, but increases in prostate cancer. This receptor is significantly up-regulated as tumors progress into higher grade, androgen-insensitive and metastatic lesions. The up-regulated receptors could serve as targets for novel selective anti-cancer drugs, e.g. antibodies and tyrosine kinase inhibitors. Radionuclide imaging of RTK can facilitate patient stratification and monitoring of anti-RTK therapy of prostate cancer. The goal of the study was to evaluate binding and cellar processing of radiolabeled EGFR-targeting conjugates by prostate cancer cell lines. Receptor expression of EGFR was studied in three prostate cancer cell lines: DU145 (brain metastasis of PC, hormone insensitive), PC3 (bone metastasis of PC) and LNCaP (lymph node metastasis of PC, androgen and estrogen receptor positive). Uptake and internalization of anti-EGFR mAbs (cetuximab) and affibody molecule (Z2377) labeled with indium-111 was investigated. EGFR expression on prostate cancer cell lines was clearly demonstrated. Both labelled conjugates 111In-Z2377 and 111In-cetuximab bound to prostate cancer cells in the receptor mediated model. Expression levels were modest but correlate with degree of hormone independence. Internalization of Affibody molecules was relatively slow in all cell lines. Internalization of mAbs was more rapid. The level of EGFR expression in these cell lines is sufficient for in vivo molecular imaging. Slow internalization indicates possibility of the use of non-residualizing labels for affibody molecules. PMID- 21253676 TI - Overexpression of SUMO perturbs the growth and development of Caenorhabditis elegans. AB - Small ubiquitin-related modifiers (SUMOs) are important regulator proteins. Caenorhabditis elegans contains a single SUMO ortholog, SMO-1, necessary for the reproduction of C. elegans. In this study, we constructed transgenic C. elegans strains expressing human SUMO-1 under the control of pan-neuronal (aex-3) or pan muscular (myo-4) promoter and SUMO-2 under the control of myo-4 promoter. Interestingly, muscular overexpression of SUMO-1 or -2 resulted in morphological changes of the posterior part of the nematode. Movement, reproduction and aging of C. elegans were perturbed by the overexpression of SUMO-1 or -2. Genome-wide expression analyses revealed that several genes encoding components of SUMOylation pathway and ubiquitin-proteasome system were upregulated in SUMO overexpressing nematodes. Since muscular overexpression of SMO-1 also brought up reproductive and mobility perturbations, our results imply that the phenotypes were largely due to an excess of SUMO, suggesting that a tight control of SUMO levels is important for the normal development of multicellular organisms. PMID- 21253677 TI - [A rare tumor-like lesion of the pancreatic head with bile duct obstruction]. AB - Tumors of the pancreatic head commonly consist of carcinomas whereas other entities are rare exceptions. Extrapulmonary sarcoidosis is well-known but is extremely rare when detected as a mass in the pancreatic head. In general the diagnosis of sarcoidosis requires histologic examination with verification of non caseous, epithelioid cell-like granulomas. Systemic therapy consists of steroids when the patient exhibits symptoms or in the case of progression of the disease. However, in some cases extended abdominal resections are also required to confirm the diagnosis and/or to treat symptoms. PMID- 21253678 TI - [Primary tracheal tumors of the neck and mediastinum : resection and reconstruction procedures]. AB - Primary tumors of the trachea account for less than 0.1% of all tumors. They are malignant in more than 90% of cases with squamous cell carcinoma and adenoidcystic carcinoma accounting for 2/3 of all tracheal tumors. Since they are often misdiagnosed as asthma or chronic lung disease, diagnosis can be delayed for years. Once the diagnosis has been established, surgical resection being the only curative treatment should be considered first. Modern techniques for tracheal surgery such as laryngotracheal, tracheal or carinal resection and different tracheal mobilisation maneuvers such as laryngeal and hilar release allow for resection of more than 50% of the trachea and anastomosis without excessive tension. Results in patients with complete tumor resection are good with 5-year and 10-year survival between 39% and 79% and between 18% and 51%, respectively. However, careful patient evaluation, preservation of tracheal blood supply and accepting the limits of resectability are mandatory to avoid major complications that accompany tracheal resections in more than 20% of cases depending on the type of resection. PMID- 21253679 TI - [Helping patients quit smoking : A role for the dermatologist?]. PMID- 21253680 TI - [Chronic myeloid leukemia. Diagnostics, therapy and future strategy]. AB - Survival of patients with chronic myeloid leukemia (CML) has dramatically improved with the introduction of the BCR-ABL-specific tyrosine kinase inhibitor imatinib. As a rule patients on therapy with imatinib achieve permanent complete cytogenetic and molecular remission. Patients who are primarily refractive to imatinib or lose remission achieved using imatinib are in the minority. This group has a poor prognosis. This article gives a transparent review of the diagnostics necessary when CML is primarily diagnosed and for assessment of the response during the course of the therapy. The guidelines developed for this procedure by the European leukemia network on the type and frequency of surveillance controls as well as the diagnostic criteria for imatinib resistance or suboptimal response will be presented. The indications for allogenic stem cell transplantation and the administration of second generation BCR-ABL inhibitors will be discussed as therapeutic alternatives in cases of imatinib failure in a stage-specific manner. Finally a view on therapy targets and forms of future first-line therapy of CML will be given. PMID- 21253681 TI - [71-year old patient with sepsis, pericardial effusion and pulmonary infiltrates]. AB - A 71-year old man with sepsis, hemorrhagic pericardial effusion and pulmonary embolism was admitted on the intensive care unit. In blood cultures and in pericardial effusion, Staphylococcus aureus was isolated. Transeosophageal echocardiography showed a massive pulmonary valve endocarditis. Right-sided endocarditis is a rare variant of endocarditis and may occur in consequence of contaminated drug solutions or infected intravenous catheter. The prognosis is relatively good, worse prognosis show fungal infections and vegetation with a length >20 mm. PMID- 21253682 TI - [Diagnostic evaluation of lung cancer]. AB - Lung cancer is the fourth rate cause of death in Germany. Symptoms are mainly unspecific and develop lately. Clinical history and examination come in first place of the diagnostic procedure. X-ray of the thorax is the basis of imaging and is completed by a CT scan of the chest. Afterwards, a biopsy for histological or cytological evaluation should be performed by the least invasive method, mostly bronchoscopy. Supplemented by modern techniques as narrow-band-imaging, endobronchial ultrasound and electromagnetic navigation, bronchoscopy takes a high value in the diagnostic procedure. Further staging is performed depending upon individual therapeutic options. Positron-emission-tomography has good evidence in lung cancer. On the one hand it serves for further evaluation of mediastinal lymphadenopathy and on the other it can complete extrathoracical staging. This should comprise the most prevalent localizations of metastasis, the adrenal glands, liver, and bones, while especially the brain should be imaged with usage of magnet resonance imaging. PMID- 21253683 TI - Evidence for high taxonomic and morphologic tyrannosauroid diversity in the Late Cretaceous (late Campanian) of the American Southwest and a new short-skulled tyrannosaurid from the Kaiparowits Formation of Utah. AB - The fossil record of late Campanian tyrannosauroids of western North America has a geographic gap between the Northern Rocky Mountain Region (Montana, Alberta) and the Southwest (New Mexico, Utah). Until recently, diagnostic tyrannosauroids from the Southwest were unknown until the discovery of Bistahieversor sealeyi from the late Campanian of New Mexico. Here we describe an incomplete skull and postcranial skeleton of an unusual tyrannosaurid from the Kaiparowits Formation (Late Cretaceous) of Utah that represents a new genus and species, Teratophoneus curriei. Teratophoneus differs from other tyrannosauroids in having a short skull, as indicated by a short and steep maxilla, abrupt angle in the postorbital process of the jugal, laterally oriented paroccipital processes, short basicranium, and reduced number of teeth. Teratophoneus is the sister taxon of the Daspletosaurus + Tyrannosaurus clade and it is the most basal North American tyrannosaurine. The presence of Teratophoneus suggests that dinosaur faunas were regionally endemic in the west during the upper Campanian. The divergence in skull form seen in tyrannosaurines indicates that the skull in this clade had a wide range of adaptive morphotypes. PMID- 21253684 TI - Reclaiming the crown: queen to worker conflict over reproduction in Aphaenogaster cockerelli. AB - In many social taxa, reproductively dominant individuals sometimes use aggression to secure and maintain reproductive status. In the social insects, queen aggression towards subordinate individuals or workers has been documented and is predicted to occur only in species with a small colony size and a low level of queen-worker dimorphism. We report queen aggression towards reproductive workers in the ant species Aphaenogaster cockerelli, a species with a relatively large colony size and a high level of reproductive dimorphism. Through analysis of cuticular hydrocarbon profiles, we show that queens are aggressive only to reproductively active workers. Non-reproductive workers treated with a hydrocarbon typical for reproductives are attacked by workers but not by queens, which suggests different ways of recognition. We provide possible explanations of why queen aggression is observed in this species. PMID- 21253685 TI - [Detection of atrial fibrillation after stroke]. AB - Approximately every fourth stroke results from cardiac embolism. Atrial fibrillation has been recognized as a common cause for thromboembolic stroke. Detection of unknown atrial fibrillation is an important clinical challenge, as anticoagulation may effectively reduce the risk of recurrent ischemic stroke. In all patients with a cryptogenic stroke 24-h Holter monitoring should be performed in addition to a standard ECG to detect paroxysmal atrial fibrillation. In addition, it is useful to pay attention to atrial fibrillation during continuous bedside ECG monitoring on the stroke unit and in pacemaker interrogation. The indication for longer ECG monitoring by implantable loop recorders may be considered individually based on the expected probability of atrial fibrillation. The potential benefit of these devices is currently being evaluated in clinical trials. PMID- 21253686 TI - [Lung cancer staging]. AB - Lung cancer is the third most frequent new cancer diagnosis in Germany. An elaborate clinical diagnosis is essential for successful therapy planning. The necessary examinations are defined in the current S3 guideline on lung cancer diagnosis and therapy. A compilation of diagnostic reports has led to the current 7th edition of the TNM system. According to this update staging is carried out in terms of tumor extent, lymph node status and distant metastases. The resultant tumor stage forms the basis for individual therapy planning. Current guidelines as well as the current TNM system are presented. The usefulness of modern cross sectional imaging and the possible modalities in this system is reported. PMID- 21253687 TI - [Diagnostic imaging of subarachnoid hemorrhage]. AB - Subarachnoid hemorrhage is characterized by the extravasation of blood into the spaces covering the central nervous system which are filled with cerebrospinal fluid. The leading cause of non-traumatic subarachnoid hemorrhage is rupture of an intracranial aneurysm. Computed tomography (CT) scanning of the head should be the first examination performed in any patient with suspected subarachnoid hemorrhage. The characteristic appearance of extravasated blood is hyperdense. Head CT scanning can also demonstrate intraparenchymal hematomas, hydrocephalus and cerebral edema and can help predict the site of aneurysm rupture. PMID- 21253688 TI - [New forms of scientific communication of medical societies: thoughts on scientific collections and museums for urology]. AB - Collections from medical societies which are not connected with a university or another public institution cannot be legitimized on the basis of the argument of conserving historical heritage. Even the museum itself with its many tasks and classical site of scientific communication comes into public view and becomes a topic of scientific interest. PMID- 21253689 TI - [Urine markers with special regard to fluorescent in situ hybridization (FISH)]. AB - Patient care with noninvasive or minimally invasive methods is appealing for the patient. It has to be assessed in terms of validity to guarantee improvement of patient care. Urine cytology for the detection of tumour cells can be considered a valid method since its specificity and sensitivity is high when high-grade tumour cells are sought. High-grade tumour cells are considered the clinically most relevant finding in urine specimens. Fluorescent in situ hybridization of interphase nuclei on centromeric and gene loci has been optimized for urothelial carcinoma and increases the sensitivity of tumour findings. It also gives a valid chance to adapt the number of cystoscopies in the follow-up of bladder cancer patients more individually. PMID- 21253691 TI - [Representation of cystectomy and urinary diversion in the G-DRG system 2010: an example for the complexity of the reimbursement system]. AB - Cystectomy and urinary diversion is an excellent example for the growing complexity of the G-DRG (German diagnosis-related groups) system. Based on different diagnoses (malignant tumor of the urinary tract, benign disease of the urinary tract, malignant tumor of the female genital tract, or malignant tumor of the male genital tract), identical cases may lead to very different codes, resulting in even more differences in reimbursement. PMID- 21253690 TI - [Treatment of azoospermia: surgical sperm retrieval (MESA, TESE, micro-TESE)]. AB - The introduction of intracytoplasmic sperm injection (ICSI) into the spectrum of assisted reproductive technologies has offered men who suffer from severe disorders of spermatogenesis and azoospermia the possibility of fathering a child. Different surgical techniques can be used to extract spermatozoa from these men from either the epididymis and/or the testis. Surgical sperm retrieval offers a treatment for patients with testicular and/or obstructive azoospermia in cases where microsurgical refertilization is not an option or has already failed. Among surgical techniques that have been explored over the years, microsurgical epididymal sperm aspiration (MESA) and testicular sperm extraction (TESE) have become the most popular. Percutaneous techniques (such as TEFNA) are available but have disadvantages versus open surgical procedures. Together with cryopreservation of extracted spermatozoa, these techniques facilitate retrieval of spermatozoa for several ICSI attempts by a single surgical intervention. PMID- 21253692 TI - [AUO (Working Group on Urological Oncology) study of metastasized renal cell carcinoma: prospective randomized multicenter phase II study on resection of pulmonary metastases in clear cell renal cell carcinoma with or without adjuvant sunitinib therapy over 1 year (SMAT - AN 20/04 AUO)]. PMID- 21253697 TI - Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. AB - AIMS/HYPOTHESIS: Glucagon-like peptide-1 (GLP-1) has various extra-pancreatic actions, in addition to its enhancement of insulin secretion from pancreatic beta cells. The GLP-1 receptor is produced in kidney tissue. However, the direct effect of GLP-1 on diabetic nephropathy remains unclear. Here we demonstrate that a GLP-1 receptor agonist, exendin-4, exerts renoprotective effects through its anti-inflammatory action via the GLP-1 receptor without lowering blood glucose. METHODS: We administered exendin-4 at 10 MUg/kg body weight daily for 8 weeks to a streptozotocin-induced rat model of type 1 diabetes and evaluated their urinary albumin excretion, metabolic data, histology and morphometry. We also examined the direct effects of exendin-4 on glomerular endothelial cells and macrophages in vitro. RESULTS: Exendin-4 ameliorated albuminuria, glomerular hyperfiltration, glomerular hypertrophy and mesangial matrix expansion in the diabetic rats without changing blood pressure or body weight. Exendin-4 also prevented macrophage infiltration, and decreased protein levels of intercellular adhesion molecule-1 (ICAM-1) and type IV collagen, as well as decreasing oxidative stress and nuclear factor-kappaB activation in kidney tissue. In addition, we found that the GLP-1 receptor was produced on monocytes/macrophages and glomerular endothelial cells. We demonstrated that in vitro exendin-4 acted directly on the GLP-1 receptor, and attenuated release of pro-inflammatory cytokines from macrophages and ICAM-1 production on glomerular endothelial cells. CONCLUSIONS/INTERPRETATION: These results indicate that GLP-1 receptor agonists may prevent disease progression in the early stage of diabetic nephropathy through direct effects on the GLP-1 receptor in kidney tissue. PMID- 21253698 TI - Polycyclic aromatic hydrocarbons in water from the Menderes River, Turkey. AB - This study was undertaken to determine the possibility of potential impact of PAHs on the aquatic biota. First, we had developed a new method for measuring 13 different priority pollutant PAHs in waste water samples. Then, eight different water samples collected from different sites along the Menderes River were analysed by this method involving SPE extraction and reverse-phase HPLC. The method presented here is suitable for rapid and accurate determination of PAH in surface waters and the PAH recoveries are practically quantitative. The levels of PAH in the analyzed samples range from 1.8 MUg/L to 24.9 MUg/L and industrialized areas were found to be highly polluted. PMID- 21253699 TI - Bioaccumulation of aluminum by Lemna gibba L. from secondary treated municipal wastewater effluents. AB - In this study, Lemna gibba as a sample aquatic plant was used to remove Al from a municipal secondary waste water effluence. Lemna gibba was acclimatized to the effluent in situ. The concentration of Al in the plant samples was examined for 7 days. Lemna gibba accumulated 500 MUg Al g-1 on the first day and reached saturation level with an increase of 100 MUg g-1 on the second day. The results indicated that Lemna gibba can be used as an effective aquatic plant at low costs for the treatment of municipal secondary waste water effluent. It was also noted that the plant should be harvested every 2 days for obtaining maximum efficiency. PMID- 21253700 TI - Persistence and dissipation of fluopicolide in/on grape berries and soil under semi arid tropical climatic conditions of India. AB - Fluopicolide, a relatively new fungicide is used for control of downy mildew of grape. Persistence study of fluopicolide was carried out on grape berries following treatment of the combination product, fluopicolide 4.44% + fosetyl aluminium 66.7% (Profiler 71.14 WG) at the recommended and double the recommended dose of 2.5 and 5.0 kg ha-1. Four treatment sprays were given at 15 day intervals, starting from 1 month after pruning of the vines. Residues of fluopicolide in grape berries were estimated on 0 (1 h), 1, 3, 5, 7, 10, 15, 20, 25, 30 day and at harvest (64 days after the last spray application). The initial residue deposits of fluopicolide on grape berries were 0.58 and 1.32 mg kg-1 from treatment at the recommended and double dose, respectively. Dissipation of fluopicolide residues was a slow process. After 30 days of treatment, 0.068 and 0.204 mg kg-1 of residues still remained in the berries from treatment at the recommended and double dose, respectively. Fluopicolide residues in grape berries dissipated with the half-life of 10.2 and 12.3 days. Residues in grape berries and soil at harvest were below the quantifiable limit of 0.01 mg kg-1 from both the treatments. PMID- 21253701 TI - Gas chromatographic method for residue analysis of metsulfuron methyl from soil. AB - Gas chromatographic method has been developed for the determination of metsulfuron methyl residues from soil. Due to the thermal unstability of this herbicide and its mono methyl derivative, it was derivatized to a dimethyl derivative using diazomethane. Structure of the derivatized product was confirmed by GC-MS. Time for methylation reaction was standardized and 24 h was found to be the optimum time in ethylacetate solvent. Using this method, recovery of metsulfuron methyl from soil was above 70%. Limit of detection (LOD) and limit of quantification (LOQ) of the method were 0.1 MUg mL-1 and 0.2 MUg g-1 respectively. PMID- 21253702 TI - Dietary intake of total and inorganic arsenic by adults in arsenic-contaminated Dan Chang district, Thailand, using duplicate food approach. AB - Dan Chang district, approximately 100 km west of Bangkok, was a site of tin mines operated almost 40 years ago. Mining operations caused arsenic contamination in soil, surface water, and groundwater within the district. The specific aim of this study was to estimate the dietary intakes of total and inorganic arsenic in 60 adults (30 males and 30 females) residing in Dan Chang district, using a duplicate food approach. The daily intake rates of inorganic arsenic ranged from 0.496 to 1.817 MUg/kg BW for males and 0.342 to 1.778 MUg/kg BW for females. PMID- 21253703 TI - Relationship between the MIC of vancomycin and clinical outcome in patients with MRSA nosocomial pneumonia. AB - PURPOSE: The objective of this study is to assess the distribution of vancomycin minimum inhibitory concentrations (MICs) in methicillin-resistant Staphylococcus aureus (MRSA) isolates and evaluate the efficacy of vancomycin relative to vancomycin MICs in adult patients with MRSA nosocomial pneumonia. METHODS: This retrospective cohort study involved adults with MRSA nosocomial pneumonia treated with vancomycin. Vancomycin MICs were determined using Etest. Patients with MRSA and vancomycin MICs >= 1.5 MUg/mL and those with MRSA and MICs <= 1 MUg/mL were placed in the high- and low-MIC group, respectively. The primary outcomes assessed were clinical response and relapse of MRSA pneumonia within 28 days after vancomycin discontinuation. Secondary outcomes included 28-day mortality, in-hospital mortality and length of hospital stay. RESULTS: Seventy patients met the inclusion criteria. Mean age and mean Acute Physiological and Chronic Health Evaluation (APACHE) II score upon intensive care unit (ICU) admission of these patients were 67.0 years and 25.9, respectively. Thirty-four (48.6%) isolates had high vancomycin MICs, and 36 (51.4%) had low MICs. There were no significant differences in baseline characteristics between the two groups. Early clinical response rates in the low- and high-MIC groups were 63.9% and 35.3%, respectively (p = 0.031). The high-MIC group had an 8% lower final clinical response rate, but this difference was not significant (p = 0.609). The relapse rate within 28 days was significantly higher in the high-MIC group than in the low-MIC group (29.6% versus 6.9%, p = 0.038). On multivariate analysis, infection by high-MIC strains was an independent predictor of early clinical response failure. CONCLUSIONS: About half of the MRSA isolates had high vancomycin MIC. Patients infected with these strains showed slower clinical response and higher relapse rate than patients infected with low vancomycin MIC isolates. PMID- 21253704 TI - Multi-site and multi-depth near-infrared spectroscopy in a model of simulated (central) hypovolemia: lower body negative pressure. AB - PURPOSE: To test the hypothesis that the sensitivity of near-infrared spectroscopy (NIRS) in reflecting the degree of (compensated) hypovolemia would be affected by the application site and probing depth. We simultaneously applied multi-site (thenar and forearm) and multi-depth (15-2.5 and 25-2.5 mm probe distance) NIRS in a model of simulated hypovolemia: lower body negative pressure (LBNP). METHODS: The study group comprised 24 healthy male volunteers who were subjected to an LBNP protocol in which a baseline period of 30 min was followed by a step-wise manipulation of negative pressure in the following steps: 0, -20, 40, -60, -80 and -100 mmHg. Stroke volume and heart rate were measured using volume-clamp finger plethysmography. Two multi-depth NIRS devices were used to measure tissue oxygen saturation (StO2) and tissue hemoglobin index (THI) continuously in the thenar and the forearm. To monitor the shift of blood volume towards the lower extremities, calf THI was measured by single-depth NIRS. RESULTS: The main findings were that the application of LBNP resulted in a significant reduction in stroke volume which was accompanied by a reduction in forearm StO2 and THI. CONCLUSIONS: NIRS can be used to detect changes in StO2 and THI consequent upon central hypovolemia. Forearm NIRS measurements reflect hypovolemia more sensitively than thenar NIRS measurements. The sensitivity of these NIRS measurements does not depend on NIRS probing depth. The LBNP-induced shift in blood volume is reflected by a decreased THI in the forearm and an increased THI in the calf. PMID- 21253705 TI - Anatomic attachment of the ACL. Comparison between radiological and CT analysis. AB - PURPOSE: The following hypothesis was tested: the location of the tibial and femoral anterior cruciate ligament (ACL) attachments will differ according to the measurement technique (plain radiographs or CT-scan) in relation to the anatomic frame of reference. METHODS: 10 gross specimens were studied. The location of metallic reference pins implanted around the tibial and femoral ACL attachments was recorded with reference to the bone contours with a caliper on the anatomic preparation, with standard plain AP and lateral radiographs and with a CT-scan. Results were compared with appropriate statistical tests at a 0.05 level of significance. RESULTS: The mean ratio between the antero-posterior tibia measurement and the center of the ACL tibial attachment varied from 50 to 52%. The mean ratio between the medio-lateral tibia measurement and the center of the ACL tibial attachment varied from 49 to 51%. The mean ratio between the antero posterior femur measurement and the center of the ACL femoral attachment varied from 74 to 80%. The results were significantly different between the three techniques (respectively P = 0.003, P = 0.02 and P = 0.045). DISCUSSION: The paired differences were small (3% at the tibia, 6% at the femur). There was a strong correlation and a good agreement between the three techniques. It is likely that the small differences on the tibia have few, if any, clinical relevance. CONCLUSION: Both radiographic and CT-scan measurement techniques used during the present study have the potential to be used as quality control after ACL replacement. LEVEL OF EVIDENCE: Diagnostic study-investigating a diagnostic test. Development of diagnostic criteria in a consecutive series of patients and a universally applied "gold" standard, Level II. PMID- 21253708 TI - Stem cells in toxicity testing. PMID- 21253706 TI - The use of a non-benzodiazepine hypnotic sleep-aid (Zolpidem) in patients undergoing ACL reconstruction: a randomized controlled clinical trial. AB - PURPOSE: Previous studies have addressed post-operative pain management after ACL reconstruction by examining the use of intra-articular analgesia and/or modification of anesthesia techniques. To our knowledge, however, no previous studies have evaluated the effect of zolpidem on post-operative narcotic requirements, pain, and fatigue in patients undergoing outpatient arthroscopic ACL reconstruction. The purpose of this prospective, blinded, randomized, controlled clinical study was to evaluate the effect of zolpidem on post operative narcotic requirements, pain, and fatigue in patients undergoing outpatient arthroscopic ACL reconstruction. METHODS: Twenty-nine patients undergoing arthroscopic ACL reconstruction were randomized to a treatment group or placebo group. Both groups received post-operative hydrocodone/acetaminophen bitartrate (Vicodin ES). Patients in the treatment group received a single dose of zolpidem for the first seven post-operative nights. Patients in the placebo group received a gelatin capsule similar in appearance to zolpidem. The amount of Vicodin used in each group, the amount of post-operative pain, and the amount of post-operative fatigue were analyzed. RESULTS: Following ACL reconstruction, a 28% reduction was seen in the total amount of narcotic consumed with zolpidem (P = 0.047) when compared to placebo. There were no significant differences in post operative pain or fatigue levels between zolpidem and placebo. CONCLUSION: Adding zolpidem to the post-operative medication regimen after arthroscopic ACL reconstruction helps to lower the amount of narcotic pain medication required for adequate analgesia. LEVEL OF EVIDENCE: Randomized controlled clinical trial, Level I. PMID- 21253707 TI - A new diagnostic approach using regional analysis of anterior knee laxity in patients with anterior cruciate ligament deficiency. AB - PURPOSE: The first purpose of this study was to analyze the characteristics of the anterior knee laxity in the three regions of different stiffness in the force displacement curve, which was obtained from a frequently used arthrometer for quantifying knee joint stability in the patients with anterior cruciate ligament (ACL) rupture and the healthy controls. The second purpose was to compare the characteristics from the regional analysis of the anterior knee laxity between the two subject groups in order to explore proper diagnosis criteria. METHODS: Seventy-one patients with unilateral ACL tear and eighty healthy controls were enrolled and their anterior knee laxities were tested using the KT-2000 arthrometer. The displacements and stiffness of the three regions were extracted separately and compared between groups to further develop the diagnostic criteria. RESULTS: The results indicated that the laxity behavior was mostly affected in Region 2 and Region 3 after ACL tear. Two good indicators for ACL tear were found in the receiver operating characteristic (ROC) curve analysis: Region 2 with the displacement larger than 3.7 mm and Region 3 with the stiffness smaller than 22 N/mm. These two criteria provided a better diagnostic accuracy with increased sensitivity. CONCLUSIONS: The regional analysis method developed in this study could provide more information for understanding the characteristics of the anterior knee laxity and help increase the diagnostic accuracy for ACL rupture. LEVEL OF EVIDENCE: II. PMID- 21253711 TI - Fast liquid chromatography combined with mass spectrometry for the analysis of metabolites and proteins in human body fluids. AB - In the last decade various analytical strategies have been established to enhance separation speed and efficiency in high performance liquid chromatography applications. Chromatographic supports based on monolithic material, small porous particles, and porous layer beads have been developed and commercialized to improve throughput and separation efficiency. This paper provides an overview of current developments in fast chromatography combined with mass spectrometry for the analysis of metabolites and proteins in clinical applications. Advances and limitations of fast chromatography for the combination with mass spectrometry are discussed. Practical aspects of, recent developments in, and the present status of high-throughput analysis of human body fluids for therapeutic drug monitoring, toxicology, clinical metabolomics, and proteomics are presented. PMID- 21253712 TI - Use of bisphosphonates and risk of breast cancer. AB - A decreased risk of breast cancer has been reported among patients given bisphosphonates. The present aims were to study potential associations between different antiosteoporosis drugs, including bisphosphonates, and the risk of breast cancer before and after start of treatment and to appraise possible dose effect relationships. From national Danish registers, all female users of bisphosphonates aged >=40 years and other drugs against osteoporosis between 1996 and 2006 were identified (n = 87,104). This cohort was compared with a control group, where each patient was matched on age with three nonexposed women from the general population (n = 261,322). Before start of most drugs against osteoporosis an increased risk of breast cancer was seen compared to controls (e.g., adjusted OR = 1.09, 95% CI 1.04-1.16 for alendronate). This excess risk was higher in younger women (e.g., OR = 4.48, 95% CI 2.98-6.75 for alendronate in women <=50 years) and disappeared in women older than 70 years (e.g., OR = 0.95, 95% CI 0.88 1.01 for alendronate). In contrast, a decreased risk of breast cancer was seen after start of alendronate (HR = 0.53, 95% CI 0.38-0.73), etidronate (HR = 0.80, 95% CI 0.73-0.89), and raloxifene (HR = 0.53, 95% CI 0.38-0.73). No dose-response relationship was present for alendronate and etidronate, whereas a decreasing risk was seen with increasing daily dose of raloxifene. Bisphosphonate treatment in women was associated with a reduced risk of breast cancer. However, no causal relationship seemed to be present. PMID- 21253713 TI - Predictors of bone responsiveness to growth hormone (GH) replacement in adult GH deficient patients. AB - Growth hormone (GH) replacement in adulthood results in variable bone responses as a function of the gonadic hormonal milieu. We performed a retrospective analysis of a large cohort of adult males and females with confirmed GH deficiency (GHD) prior to treatment and during 3 years of replacement therapy. Potential confounders and effect modifiers were taken into account. Sixty-four adult patients with GHD (20 females and 44 males; mean age 34 years, range 18-64) were included in the analysis. GH replacement induced a different effect on bone in males compared to females. Bone mineral content increased in males and decreased in females at the lumbar spine, total femur, and femoral neck; bone mineral density showed a similar trend at the lumbar spine and femoral neck. There was no significant gender difference in bone area at any measured bone site. In both sexes we observed a similar trend for serum markers of bone remodeling. Sex predicted bone outcome on multivariate analysis, as did age, onset of GHD (childhood/adulthood), pretreatment bone mass, baseline body mass index (BMI), and BMI change during GH replacement. Serum IGF-I levels during treatment did not show any relationship with bone outcome at any measured site. This study confirms that bone responsiveness to GH replacement in adult GHD varies as a function of sex even after controlling for potential confounders and highlights the importance of other cofactors that may affect the interaction between GH replacement therapy and bone remodeling. PMID- 21253714 TI - Parathyroid hormone treatment increases fixation of orthopedic implants with gap healing: a biomechanical and histomorphometric canine study of porous coated titanium alloy implants in cancellous bone. AB - Parathyroid hormone (PTH) administered intermittently is a bone-building peptide. In joint replacements, implants are unavoidably surrounded by gaps despite meticulous surgical technique and osseointegration is challenging. We examined the effect of human PTH(1-34) on implant fixation in an experimental gap model. We inserted cylindrical (10 * 6 mm) porous coated titanium alloy implants in a concentric 1-mm gap in normal cancellous bone of proximal tibia in 20 canines. Animals were randomized to treatment with PTH(1-34) 5 MUg/kg daily. After 4 weeks, fixation was evaluated by histomorphometry and push-out test. Bone volume was increased significantly in the gap. In the outer gap (500 MUm), the bone volume fraction median (interquartile range) was 27% (20-37%) for PTH and 10% (6 14%) for control. In the inner gap, the bone volume fraction was 33% (26-36%) for PTH and 13% (11-18%) for control. At the implant interface, the bone fraction improved with 16% (11-20%) for PTH and 10% (7-12%) (P = 0.07) for control. Mechanical implant fixation was improved for implants exposed to PTH. For PTH, median (interquartile range) shear stiffness was significantly higher (PTH 17.4 [12.7-39.7] MPa/mm and control 8.8 [3.3-12.4] MPa/mm) (P < 0.05). Energy absorption was significantly enhanced for PTH (PTH 781 [595-1,198.5] J/m(2) and control 470 [189-596] J/m(2)). Increased shear strength was observed but was not significant (PTH 3.0 [2.6-4.9] and control 2.0 [0.9-3.0] MPa) (P = 0.08). Results show that PTH has a positive effect on implant fixation in regions where gaps exist in the surrounding bone. With further studies, PTH may potentially be used clinically to enhance tissue integration in these challenging environments. PMID- 21253715 TI - Calcium plus vitamin D supplementation has limited effects on femoral geometric strength in older postmenopausal women: the Women's Health Initiative. AB - Calcium plus vitamin D (CaD) supplementation has a modest but significant effect on slowing loss of femoral bone mass and reducing risk of hip fractures in adherent postmenopausal women. The goal of this study was to determine if CaD supplementation influences hip structural parameters that are associated with fracture risk. We studied 1,970 postmenopausal women enrolled in the Women's Health Initiative randomized controlled trial of CaD at one of three bone mineral density (BMD) clinical centers. Hip structural analysis software measured BMD and strength parameters on DXA scans at three regions: femoral narrow neck, intertrochanter, and shaft. Random effects models were used to test the average differences in hip BMD and geometry between intervention and placebo. There was greater preservation of hip BMD at the narrow neck with CaD relative to placebo across 6 years of intervention. CaD also altered the underlying cross-sectional geometry at the narrow neck in the direction of greater strength, with small increases in cross-sectional area and section modulus and a decrease in buckling ratio with CaD relative to placebo. While trends at both the intertrochanter and shaft regions were similar to those noted at the narrow neck, no significant intervention effects were evident. There was no significant interaction of CaD and age or baseline calcium levels for hip structural properties. CaD supplementation is associated with modest beneficial effects on hip structural features at the narrow neck, which may explain some of the benefit of CaD in reducing hip fracture risk. PMID- 21253716 TI - Pharmacodynamic and pharmacokinetic drug interactions reported to VigiBase, the WHO global individual case safety report database. AB - OBJECTIVE: Drug interactions resulting in adverse drug reactions (ADRs) represent a major health problem both for individuals and the community. Despite this, limited information is reported in the literature on the drug interaction categories responsible for causing ADRs. In the study reported here, we investigated the drug combinations most frequently co-reported as interacting in the WHO Global Individual Case Safety Report (ICSR) database, VigiBase, and categorised these according to the drug interaction mechanism. METHODS: Reports in which drug combinations were co-reported as interacting in at least 20 reports in VigiBase during the past 20 years were included in the study. Each drug combination was reviewed in the literature to identify the mechanism of interaction and subsequently classified as pharmacodynamic and/or pharmacokinetic reaction. Report characteristics were also analysed. RESULTS: A total of 3766 case reports of drug interactions from 47 countries were identified. Of the 123 different drug combinations reported, 113 were described in the literature to interact. The mechanism of the drug interaction was categorised as pharmacodynamic (46 combinations; 41%), pharmacokinetic (28; 25%), a combination of both types (18; 16%) and unidentified (21; 19%). Pharmacodynamic drug interactions primarily concerned pharmacological additive effects, whereas enzyme inhibition was the most frequent pharmacokinetic interaction. The combinations reviewed primarily implicated drugs such as warfarin, heparin, carbamazepine and digoxin. CONCLUSIONS: Drug interactions reported in globally collected ADR reports cover both pharmacodynamic, specifically additive pharmacological effects, and pharmacokinetic mechanisms primarily accredited to the inhibition of hepatic cytochrome P450 enzymes. These ADR reports often concern serious threats to patients' safety and are particularly related to the use of high risk drugs such as warfarin and heparin. PMID- 21253717 TI - Monomer abundance distribution patterns as a universal biosignature: examples from terrestrial and digital life. AB - Organisms leave a distinctive chemical signature in their environment because they synthesize those molecules that maximize their fitness. As a result, the relative concentrations of related chemical monomers in life-bearing environmental samples reflect, in part, those compounds' adaptive utility. In contrast, rates of molecular synthesis in a lifeless environment are dictated by reaction kinetics and thermodynamics, so concentrations of related monomers in abiotic samples tend to exhibit specific patterns dominated by small, easily formed, low-formation-energy molecules. We contend that this distinction can serve as a universal biosignature: the measurement of chemical concentration ratios that belie formation kinetics or equilibrium thermodynamics indicates the likely presence of life. We explore the features of this biosignature as observed in amino acids and carboxylic acids, using published data from numerous studies of terrestrial sediments, abiotic (spark, UV, and high-energy proton) synthesis experiments, and meteorite bodies. We then compare these data to the results of experimental studies of an evolving digital life system. We observe the robust and repeatable evolution of an analogous biosignature in a digital lifeform, suggesting that evolutionary selection necessarily constrains organism composition and that the monomer abundance biosignature phenomenon is universal to evolved biosystems. PMID- 21253718 TI - Image Gently pediatric digital radiography summit: executive summary. PMID- 21253719 TI - Crystal structure of Clostridium thermocellum ribose-5-phosphate isomerase B reveals properties critical for fast enzyme kinetics. AB - Ribose-5-phosphate isomerase (Rpi) catalyzes the conversion of D-ribose 5 phosphate (R5P) to D-ribulose 5-phosphate, which is an important step in the non oxidative pathway of the pentose phosphate pathway and the Calvin cycle of photosynthesis. Recently, Rpis have been used to produce valuable rare sugars for industrial purposes. Of the Rpis, D-ribose-5-phosphate isomerase B from Clostridium thermocellum (CtRpi) has the fastest reactions kinetics. While Thermotoga maritime Rpi (TmRpi) has the same substrate specificity as CtRpi, the overall activity of CtRpi is approximately 200-fold higher than that of TmRpi. To understand the structural basis of these kinetic differences, we determined the crystal structures, at 2.1-A resolution or higher, of CtRpi alone and bound to its substrates, R5P, D-ribose, and D-allose. Structural comparisons of CtRpi and TmRpi showed overall conservation of their structures with two notable differences. First, the volume of the CtRpi substrate binding pocket (SBP) was 20% less than that of the TmRpi SBP. Second, the residues next to the sugar-ring opening catalytic residue (His98) were different. We switched the key residues, involved in SBP shaping or catalysis, between CtRpi and TmRpi by site-directed mutagenesis, and studied the enzyme kinetics of the mutants. We found that tight interactions between the two monomers, narrow SBP width, and the residues near the catalytic residue are all critical for the fast enzyme kinetics of CtRpi. PMID- 21253720 TI - Maximal release of highly bifidogenic soluble dietary fibers from industrial potato pulp by minimal enzymatic treatment. AB - Potato pulp is a poorly utilized, high-volume co-processing product resulting from industrial potato starch manufacturing. Potato pulp mainly consists of the tuber plant cell wall material and is particularly rich in pectin, notably galactan branched rhamnogalacturonan I type pectin which has previously been shown to exhibit promising properties as dietary fiber. The objective of this study was to solubilize dietary fibers from potato pulp by a one-step minimal treatment procedure and evaluate the prebiotic potential of the fibers. Statistically designed experiments were conducted to investigate the influence of enzyme type, dosage, substrate level, incubation time, and temperature on the enzyme catalyzed solubilization to define the optimal minimal enzyme treatment for maximal fiber solubilization. The result was a method that within 1 min released 75% [weight/weight (w/w)] dry matter from 1% (w/w) potato pulp treated with 1.0% (w/w) [enzyme/substrate (E/S)] pectin lyase from Aspergillus nidulans and 1.0% (w/w) E/S polygalacturonase from Aspergillus aculeatus at pH 6.0 and 60 degrees C. Molecular size fractionation of the solubilized fibers revealed two major fractions: one fraction rich in galacturonic acid of 10-100 kDa indicating mainly homogalacturonan, and a fraction >100 kDa rich in galactose, presumably mainly made up of beta-1,4-galactan chains of rhamnogalacturonan I. When fermented in vitro by microbial communities derived from fecal samples from three healthy human volunteers, both of the solubilized fiber fractions were more bifidogenic than fructo-oligosaccharides (FOS). Notably the fibers having molecular masses of >100 kDa selectively increased the densities of Bifidobacterium spp. and Lactobacillus spp. 2-3 times more than FOS. PMID- 21253721 TI - Quantitative analyses of ammonia-oxidizing Archaea and bacteria in the sediments of four nitrogen-rich wetlands in China. AB - With the rapid development of ammonia-synthesizing industry, the ammonia-nitrogen pollution in wetlands acting as the sink of point and diffuse pollution has been increased dramatically. Most of ammonia-nitrogen is oxidized at least once by ammonia-oxidizing prokaryotes to complete the nitrogen cycle. Current research findings have expanded the known ammonia-oxidizing prokaryotes from the domain Bacteria to Archaea. However, in the complex wetlands environment, it remains unclear whether ammonia oxidation is exclusively or predominantly linked to Archaea or Bacteria as implied by specific high abundance. In this research, the abundance and composition of Archaea and Bacteria in sediments of four kinds of wetlands with different nitrogen concentration were investigated by using quantitative real-time polymerase chain reaction, cloning, and sequencing approaches based on amoA genes. The results indicated that AOA distributed widely in wetland sediments, and the phylogenetic tree revealed that archaeal amoA functional gene sequences from wetlands sediments cluster as two major evolutionary branches: soil/sediment and sediment/water. The bacteria functionally dominated microbial ammonia oxidation in different wetlands sediments on the basis of molecule analysis, potential nitrification rate, and soil chemistry. Moreover, the factors influencing AOA and AOB abundances with environmental indicator were also analyzed, and the results addressed the copy numbers of archaeal and bacterial amoA functional gene having the higher correlation with pH and ammonia concentration. The pH had relatively great negative impact on the abundance of AOA and AOB, while ammonia concentration showed positive impact on AOB abundance only. These findings could be fundamental to improve understanding of the importance of AOB and AOA in nitrogen and other nutrients cycle in wetland ecosystems. PMID- 21253722 TI - Short-term evaluation of liver tumors after transarterial chemoembolization: limitations and feasibility of contrast-enhanced ultrasonography. AB - PURPOSE: To evaluate the limitations and the feasibility of contrast-enhanced ultrasonography (CEUS) for the assessment of tumor response shortly after transarterial chemoembolization (TACE). MATERIALS AND METHODS: Fifty seven patients (41 patients with hepatomas, 16 patients with metastases) were studied with CEUS before, 1 day after, and 30 days after TACE. A CEUS-efficiency score (CEUS-ES) was calculated, which evaluated: (a) the completeness of visualization of the target tumor(s) (2: good, 1: adequate, 0: poor) and (b) the quality of delineation of post-TACE necroses (2: good, 1: adequate, 0: poor). A CEUS study was considered as "diagnostic," if each of the aforementioned parameters was associated with grade 1 or 2. RESULTS: CEUS studies were "diagnostic" in 36/57 patients (63.1%). Patients with hepatomas were more likely to undergo "diagnostic" CEUS than patients with metastases (70.7% vs. 43.7%, P = 0.0728). Lesions' multiplicity, deep location, hypoenhancement on pretreatment CEUS, and diffuse growth had a statistically significant (P < 0.05) negative impact on CEUS ES. Hyperechogenicity on pre-treatment, unenhanced US had a non-statistically significant (P = 0.176) negative impact. Differences between "diagnostic" CEUS studies and CT/MR regarding detection of residual tumor were insignificant (P = 0.8178). CONCLUSION: The percentage of lesions which are unsuitable for post-TACE evaluation with CEUS is not negligible. For the rest, the respective role of CEUS is promising. PMID- 21253723 TI - Hepatocellular nodules in liver cirrhosis: contrast-enhanced ultrasound. AB - Contrast-enhanced ultrasound (CEUS) using microbubble contrast agents has expanded the role of US in the diagnosis of liver nodules in high risk patients for hepatocellular carcinoma (HCC). HCC is typically characterized by arterial hypervascularity and later washout (negative enhancement). Washout in the portal phase is often not obvious until late (>90 s). Benign nodules such as regenerative nodules or dysplastic nodules are usually isoechoic or slightly hypoechoic in the arterial and portal venous phases. However, there are occasional cases with overlap of imaging features between benign and malignant nodules, including hypovascular HCC and hypervascular HCC without washout. CEUS is helpful to characterize potential mimickers of HCC on imaging such as nontumorous arterioportal shunt or hemangioma. CEUS is also useful for a guidance of percutaneous local therapy of HCC and post-procedure monitoring of therapeutic response. CEUS can be effectively used in the diagnostic algorithm of small (1-2 cm) newly detected nodules during HCC surveillance. PMID- 21253724 TI - The absence of B lymphocytes reduces the number and function of T-regulatory cells and enhances the anti-tumor response in a murine tumor model. AB - Increasing evidence suggests that B lymphocytes play a central role in inhibiting the immune response against certain tumors, but the underlying mechanisms by which B cells facilitate tumor growth are still poorly understood. In this study, we investigated how the presence or absence of B cells affects expansion and function of T-regulatory cells ('T-regs') in a murine breast tumor model (EMT-6). We compared tumor growth, and the number and function of T-reg cells in wild-type immune-competent mice (ICM) and B-cell-deficient mice (BCDM). Mice were either tumor-naive or implanted with EMT-6 mammary adenocarcinoma cells. Tumor growth was markedly inhibited in BCDM, compared to wild-type mice (ICM). Increased T-reg expansion as defined by CD4+/CD25+/FOXP3+ cells was evident following EMT-6 inoculation in ICM in comparison with non-tumor-bearing mice or compared to BCDM in which tumor had been implanted. The percentage and absolute number of T-regs in the spleen, tumor draining lymph nodes, and tumor bed were significantly reduced in BCDM compared to ICM. T-reg function, measured by suppression and proliferation assays, was also reduced in tumor inoculated BCDM compared to ICM. Our studies indicate that absence of B cells may play a role in augmenting the T cell anti-tumor response, in part due to effects on T-regulatory cell expansion and function. PMID- 21253725 TI - Intra-articular injection of tranexamic acid reduces not only blood loss but also knee joint swelling after total knee arthroplasty. AB - PURPOSE: This is a randomised controlled trial to examine whether intra-articular injection of tranexamic acid (TXA) decreases blood loss, as well as reducing leg swelling after total knee arthroplasty (TKA). METHODS: We performed 100 TKA in osteoarthritis patients. At closure, a total of 2,000 mg/20 ml TXA was injected into the knee joint through a closed suction drain (TXA group). For the control group, the same volume of physiological saline was injected. The pre-operative condition of the patients, post-operative haemoglobin (Hb) levels, discharge volumes from drain, D-dimer and needs for transfusion were compared between these two groups. Furthermore, leg diameters (thigh, suprapatellar portion and calf girth) were measured pre- and post-operatively to investigate whether TXA has an influence on leg swelling after surgery. RESULTS: The results revealed that post operative decrease in Hb level was significantly reduced in the TXA group. Furthermore, knee joint swelling after operation was significantly suppressed in the TXA group compared to the control group. CONCLUSIONS: The results revealed intra-articular administration of TXA decreased not only blood loss, but also knee joint swelling after TKA. PMID- 21253726 TI - Is robotic surgery superior to endoscopic and open surgeries in thyroid cancer? AB - BACKGROUND: Endoscopic thyroidectomies have been performed using various approaches, and indications have expanded with the development of new surgical techniques and instruments. Endoscopic thyroid surgery using bilateral axillo breast approaches have excellent cosmetic results and a symmetrical, optimal operative view. However, because of the two-dimensional view and the nonflexible instruments, these approaches are not easy to use in performing a central lymph node dissection (CND). Robotic surgery has drawn attention as a potentially safe and effective method for treating thyroid cancer. The aim of the present study was to determine whether robotic surgery is superior to endoscopic and open surgery through comparing technical aspects and surgical outcomes. METHODS: From October 2008 to December 2009, 302 patients had total thyroidectomies and CND with cancer less than 1 cm. Patients were divided into three groups according to operation methods (open group; n = 138), (endo group; n = 95), (robot group; n = 69). RESULTS: Young patients preferred the robotic and endoscopic surgery. The number of retrieved lymph nodes in the open group (4.8 +/- 2.8) was not different from the robot group (4.7 +/- 2.7) and the endo group (4.6 +/- 3.7). The operative time of the robot group was longer than the open and the endo group. The total drain amount in the robot group was more than the open and endo groups; however, there was no difference in the length of hospitalization and complication rates. There were no differences between the open (0.8 +/- 2.0) and robot groups (0.8 +/- 1.4), but the endo group (2.4 +/- 6.3) showed higher postoperative serum thyroglobulin off thyroid hormone (Off-Tg) when compared to the open and robot groups. CONCLUSIONS: Robotic surgery was equal to open surgery except with respect to operative time and was superior to endoscopic surgery in Off-Tg levels presenting completeness of the operation in thyroid cancer surgery. Because it has excellent cosmetic results and various technical advantages, it should be considered in young, low-risk patients with thyroid carcinoma less than 1 cm. PMID- 21253727 TI - Variations of lobar branches of pulmonary arteries in thoracic surgery patients. AB - PURPOSE: Anatomical investigation is important for safer surgical procedures and to focus on aims. Pulmonary artery anatomy is very important point for thoracic surgery, especially in lobectomy procedure. METHOD: Between January 2005 and December 2008 at Eskisehir Osmangazi University Faculty of Medicine, Department of Thoracic Surgery, 85 right or left, upper, middle or lower lobectomy patients were included in this study who were operated because of various lung diseases which include bronchial carcinoma, inflammatory pseudotumor, bronchiectasis, carcinoid tumor of lung. Seventy-four male and 11 female patients were included in this study. Mean age of patients was 59 years. RESULTS: Different types of variations were observed in 10 of 85 lobectomy cases; two types of variations could not be found in literature. CONCLUSION: The vascular anatomy of the lung and possible variations of the pulmonary artery should be well known by surgeon to prevent complications. The various branching pattern of the pulmonary arteries should be determined to prevent excessive and unnecessary resection with life threatening bleeding. PMID- 21253729 TI - Osteointegration of orthopaedic devices. AB - The different properties of bone must be considered in order to understand the relation between orthopaedic devices and bone. The epi-/metaphyseal areas are defined by their rigidity, their high vascularity and their quick remodelling process. In contrast, the diaphyses of bone are rather elastic and built of dense, scarcely vascularised bone presenting slow remodelling. Implants can integrate by pure mechanical contact without real affinity to bone or, alternatively, they can favour ongrowth of bone, provided that they are osteoconductive. Amongst different bone substitutes, only some of them are absorbable. Only derivates of bone may present the property of osteoinduction, which is the power to create new bone in any region of the body. Orthopaedic devices are characterised by their shape, their stiffness or elasticity and by the characteristic properties of material. They may be osteoconductive such as titanium alloys and some ceramics, allowing integration in bone. Alternatively, other materials such as steel, CoCr alloys and PMMA cements remain separated from bone by a tiny layer of collagen. The surface structure influences the quality of integration. The integration of implants depends on the mutual interaction of the material with the tissue on the implantation site. All implants undergo fatiguing which can lead to fracture of the implant. All implant-bone contacts are threatened by granulation tissue mainly formed because of wear products, infection and other reasons. PMID- 21253730 TI - Display of Bombyx mori nucleopolyhedrovirus GP64 on the Bacillus subtilis spore coat. AB - To investigate whether Bombyx mori immunized with Bacillus subtilis spore displaying GP64 escape from the B. mori nucleopolyhedrovirus (BmNPV) attack, a recombinant integrative plasmid named pJS700-GP64 was constructed, which carries a recombinant cotC-Gp64 gene under the control of the cotC promoter. In this study, pJS700-GP64 was transformed into B. subtilis 168 (trp(-)) competent cells, an amylase (amyE) inactivated mutant was selected, and was confirmed to be a double cross-over integrant, cotC-Gp64 fragment of which was integrated into B. subtilis chromosome. Gp64 was expressed on the spore surface and recognized by Gp64-specific antibody. Results of B. mori when challenged with BmNPV indicated that B. mori vaccinated with the recombinant spores possessed resistance to the invasion of BmNPV at some degree. PMID- 21253731 TI - Prevalence of depression and depressive symptoms in patients with systemic lupus erythematosus: Iranian experience. AB - Psychiatric disorders including depression represent clinical manifestation of systemic lupus erythematosus (SLE). Recognition of depression in SLE patients is of utmost importance since it is treatable and can be of fatal consequences if unrecognized. This study was conducted to determine the prevalence of depression and depressive symptoms in SLE patients in terms of age, gender, disease duration and severity, and duration of steroid treatment in SLE patients. Eighty-five SLE patients (77 women, 8 men) with verified SLE diagnosis completed Beck's depression inventory, a self-reported measure of depression. Clinical data on disease and treatment were obtained from patient files. In total, 60% of patients achieved scores indicating depression. The most common depressive symptoms in participants were fatigue and weakness (88.2%), irritability (82.3%), sadness (77.6%), and somatic preoccupation (76.4%), while the least common symptoms were weight loss (34.1%), low level of energy (28.2%), and suicide ideation (10.5%). There was a significant difference between the disease activity and the severity of depression (P = 0.0001). Our findings show higher prevalence of depression in our sample in comparison with previous studies, suggesting that the prevalence of depression varies across different populations. Severity of depression increases with more severe disease course. PMID- 21253732 TI - Prevalence and associated factors of knee osteoarthritis in a community-based population in Heilongjiang, Northeast China. AB - Few data exist concerning the prevalence of knee OA and associated factors in Northeast China. This study was undertaken to estimate the prevalence of radiographic and symptomatic knee OA among community residents and to elucidate relevant risk factors. Unmatched case-control study was adopted to study risk factors of knee OA. Radiographic OA was evaluated according to the Kellgren and Lawrence grading scheme. Statistical analyses included tests and logistic model regressions. A total of 1,196 people aged 40-84 years participated in the community-based health survey in Northeast China in 2005. Survey participants completed an interviewer-based questionnaire. The standardized prevalence of symptomatic knee OA was 16.05% and it was significantly higher in women than in men (19.87% vs. 11.91%, = 13.76, P < 0.001). There was also an increased tendency with age in both sex (men: x (2) = 29.67, P (trend) < 0.001; women: x (2) = 40.26, P (trend) < 0.001). The prevalence of symptomatic knee OA was significantly higher than that in Beijing and Shantou, while lower than that in Wuchuan county of inner Mongolia with nonsignificant difference. Logistic regressions revealed that age, sex, BMI, and work status might be risk factors for knee OA in urban residents, whereas age, BMI, and smoking habits might be risk factors in rural dwellers. Symptomatic knee OA is extremely common with preponderance for elderly women and constitutes a major public health problem. The findings will be useful to guide the distribution of future health care resources and preventive strategies. PMID- 21253733 TI - Interleukin-23 receptor genetic polymorphisms and ankylosing spondylitis susceptibility: a meta-analysis. AB - Up to now, many publications have evaluated the correlation between IL-23R polymorphisms and ankylosing spondylitis with conflicting results. We perform this meta-analysis to collect all the relevant studies up to date to further clarify the association of IL-23R polymorphisms with AS. Relevant published data were retrieved through Medline, PubMed, Embase, Web of Science, CNKI, Chinese BioMedical Literature Database on disc, and the statistical analysis was conducted using Stata 11.0. (1) A total of 11 literatures, including 13 population samples, were studied. (2) The allele A frequency of rs11209032 was higher in the AS group than in the controls (A vs. G: OR = 1.173, 95% CI = 1.107 1.243, P < 0.001). (3) The allele A of rs1004819 was higher in the AS group than in the controls in both all-pooled population (A vs. G: OR = 1.147, 95% CI = 1.022-1.287, P = 0.02) and Europe-pooled population (A vs. G: OR = 1.199, 95% CI = 1.007-1.429, P = 0.042). (4) The allele frequency T of rs1343151, G of rs10489629, and A of rs11209026 was lower in the AS group than in the controls. (5) No significant differences were found in allele frequency of rs10889677 polymorphism between cases and controls by random effects model. We concluded that the genetic susceptibility for AS is associated with the IL-23R gene polymorphisms. The protective SNPs include rs1343151, rs10489629, and rs11209026 while rs1004819 and rs11209032 may be the susceptibility SNPs. PMID- 21253734 TI - Rheumatic complications of long term treatment with hemodialysis. AB - Patients undergoing hemodialysis therapy develop serious osteoarticular diseases. The treatment is based on prevention. The aim of our study is to determine the frequency and the associated factors to the rheumatic manifestations in hemodialysis patients. A cross-sectional study was conducted, including all hemodialysed patients in our dialysis unit. Information was obtained from patients' symptoms, examination findings, and biological and radiological signs. The frequency of symptoms was 70% in our patients. It was proportional to the duration of hemodialysis and number of hemodialysis sessions per week. Early transplantation is of course a plausible solution, but other therapies such as improved dialysis must be considered. PMID- 21253737 TI - Association of the C-285T and A5954G polymorphisms in the DNA repair gene OGG1 with the susceptibility of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease and can lead to deformities and severe disabilities, due to irreversible damage of tendons, joints, and bones. Previous study indicated that DNA repair system was involved in the pathology of RA. In this study, we investigated the association of two 8 oxoguanine glycosylase 1 (OGG1) gene polymorphisms (rs159153 and rs3219008) with the susceptibility to RA in 384 Taiwanese individuals (192 patients with RA and 192 controls). Our data showed that statistically significant difference in genotype frequency distributions was found at rs3219008 SNP between patients with RA and control groups (P = 5.6E-0.5). Our data also indicated that individuals with the AG genotype at rs3219008 SNP may have a higher risk of developing RA. We did not observe any statistically significant association of OGG1 haplotype frequencies (rs159153 and rs3219008) with RA progression. The study suggested that OGG1 polymorphisms (rs159153 and rs3219008) are associated with RA progression and that these may be used as molecular markers of RA. PMID- 21253736 TI - Clinical and magnetic resonance imaging findings of the temporomandibular joint and masticatory muscles in patients with rheumatoid arthritis. AB - The aim of this study was to investigate the clinical, radiographic, and magnetic resonance imaging (MRI) findings of temporomandibular joint (TMJ) and masticatory muscles in rheumatoid arthritis (RA) patients. Twenty-eight RA patients and 29 healthy subjects were participated in the study. The patient underwent clinical and laboratory investigation. DAS28 scores were calculated. Lateral panoramic radiography was performed to evaluate condylar erosion and condylar movement. Craniofacial MRI was performed to evaluate TMJ and masseter, medial and lateral pterygoid muscles' thickness, and cross-sectional area. It was found that the mean maximal interincisal distance, range of lateral, retrusive (P < 0.05) and protrusive motion were all lesser in RA group. Lateral panoramic radiography revealed a distinct erosion in 10.7% (3/28) and restricted condylar movement in 53.6% (15/28) of RA patients. Two RA patients demonstrating marked condylar erosion in lateral panoramic radiographs were RF negative and had DAS28 scores 3.41 and 4.61. MRI findings revealed condylar erosion and effusion in one RA patient and atrophic changes of masticatory muscles in another patient. There was no statistical significance between RA and healthy groups for the thickness and cross-sectional areas of the masticatory muscles. RA group revealed a strong linear relationship for the right and left muscle thickness and cross-sectional areas in regression analysis. TMJ symptoms are frequent findings and thought to be affected from mean disease duration in RA. Laboratory findings should be considered for disease activity-related TMJ involvement. RA patients did not present muscular atrophy or hypertrophy. PMID- 21253735 TI - Pattern of joint damage in persons with knee osteoarthritis and concomitant ACL tears. AB - Anterior cruciate ligament (ACL) tears are known to be a risk factor for incident knee osteoarthritis (OA). At the present time, it is unknown whether an incidental ACL tear in those with established knee OA alters the pattern of synovial joint damage. Therefore, our aim was to assess whether ACL tears in persons with knee OA are associated with specific patterns of cartilage loss, meniscal degeneration, and bone marrow lesion (BML) location. We included 160 participants from the progression subcohort of the Osteoarthritis Initiative (OAI) Study, an ongoing 4-year, multicenter study, focusing on knee OA. Regional cartilage morphometry measures including cartilage volume (mm(3)), denuded area, normalized cartilage volume, bone surface area, as well as location of meniscal pathology and BMLs in index knees on the same side were compared between those with and without ACL tears. Of the 160 subjects (51% women, age 62.1 (+/-9.9), BMI 30.3 (+/-4.7) kg/m(2)), 14.4% had an ACL tear. After adjusting for age, BMI and gender participants with ACL tears had significantly greater cartilage volume in the posterior lateral femur (P = 0.04) and the central medial tibia (0.001) compared to those without ACL tears. Normalized cartilage volume was not different between those with and without ACL tears. In addition, individuals with ACL tears had significantly larger bone surface areas in the medial tibia (P = 0,006), the central medial tibia (P = 0.008), the posterior lateral femur (P = 0.004), and the posterior medial femur (P = 0.04). Furthermore, participants with ACL tears showed significantly more meniscal derangement in the lateral posterior horn (P = 0.019) and significantly more BMLs in the lateral femur (P = 0.0025). We found clear evidence of predominant lateral tibiofemoral involvement, with OA associated findings on MRI, including increased denuded area and bone surface area, BMLs, and meniscal derangement in knees of individuals with ACL tears compared to those without. PMID- 21253738 TI - Lack of association between promoter polymorphisms of HLA-G gene and rheumatoid arthritis in Korean population. AB - The aim of this study was to determine whether the HLA-G gene was associated with susceptibility to rheumatoid arthritis (RA). Major histocompatibility complex, class I, G (HLA-G) is involved in immunoregulatory processes and particularly in pathogenesis of inflammatory disorders. To investigate possible association between HLA-G and RA, 296 RA patients and 468 healthy controls were enrolled in this study. Two-promoter single-nucleotide polymorphisms (SNPs) (rs1736936, 1202T/C and rs2735022, -586C/T) in HLA-G gene were analyzed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). For analysis of data, Helixtree software, SNPAnalyzer, SNPStats, and Haploview version 4.2 were used. Multiple logistic regression models (codominant, dominant, and recessive) were performed for odds ratio (OR), 95% confidence interval (CI), and P value. There were no significant differences in distributions of genotypes and haplotypes between RA patients and control subjects. In clinical features of RA, we found differences between C-reactive protein levels (>=0.5 or <0.5 mg/dL) and two-promoter SNPs. Rs1736936 was significant in codominant (P = 0.028, OR = 0.66, 95% CI = 0.45-0.96) and dominant (P = 0.046, OR = 0.58, 95% CI = 0.34-0.99) models. Also, rs2735022 was significant in codominant (P = 0.038, OR = 0.67, 95% CI = 0.46-0.98) and dominant (P = 0.03, OR = 0.55, 95% CI = 0.33-0.94) models. However, these significant associations disappear after Bonferroni correction. Our results suggest that HLA-G promoter polymorphisms may be not associated with the development of RA in Korean population. PMID- 21253739 TI - The outcomes and cost-effectiveness of intraarticular injection of the rheumatoid knee. AB - Although intraarticular injections are important to the management of rheumatoid arthritis, there are few studies regarding the cost-effectiveness of alternative injection techniques. This randomized controlled study addressed the cost effectiveness of two different low-cost, anatomic landmark palpation-directed intraarticular injection techniques. Ninety-six symptomatic rheumatoid knees were randomized to two different low-cost, palpation-guided intraarticular injection techniques utilizing (1) a conventional syringe or (2) a mechanical syringe, the RPD (the reciprocating procedure device). Three milliliters of 1% lidocaine were used to anesthetize the synovial membrane, followed by arthrocentesis and hydrodissection, and injection of 80 mg of triamcinolone acetonide utilizing the one-needle two-syringe technique. Baseline pain, procedural pain, aspirated fluid volume, pain at outcome (2 weeks and 6 months), responders, reinjection rates, cost/patient/year, and cost/responder/year were determined. Pain was measured with the 10 cm Visual Analogue Pain Scale (VAS). Both techniques significantly reduced pain scores at outcome from baseline (P < 0.001). The mechanical syringe technique resulted in a greater volume of aspirated fluid (P < 0.01), a 38% reduction in procedural pain (P < 0.001), a 24% reduction in pain scores at outcome (P < 0.03), an increase in the responder rate (P < 0.025), 33% increase in the time to next injection (P < 0.001), 23% ($35 US) reduction in cost/patient/year for a patient treated in a physician office (P < 0.001), 24% reduction ($26 US) in cost/patient/year for a hospital outpatient (P < 0.001), and 51% ($151 US) reduction in cost/responder/year (P < 0.001). The outcomes and cost-effectiveness of intraarticular injection of the rheumatoid knee can be improved significantly with low-cost alternations in technique. PMID- 21253740 TI - Capillaroscopic pattern in paraneoplastic Raynaud's phenomenon. AB - The capillaroscopic pattern in paraneoplastic Raynaud's phenomenon (RP) has not been investigated systematically and is not well-defined. Here, we present three case reports of patients with paraneoplastic rheumatic conditions, manifested with severe secondary RP with emphasis upon capillaroscopic findings. The first patient is a 58-year-old male with known psoriasis and psoriatic arthritis, severe RP and scleroderma-like syndrome, resulting in a paraneoplastic syndrome in the context of a lung cancer. At capillaroscopic examination classic "scleroderma" pattern, an "early" type was found. The second patient is a 48-year old woman with an abrupt onset of paraneoplastic dermatomyositis, severe RP, and a lung cancer. The capillaroscopic examination revealed frequent dilated and giant capillaries, hemorrhages and severe microvascular disarrangement-the so called "scleroderma-like" pattern typical of the idiopathic forms of the disease. The third patient is a 56-year-old woman with paraneoplastic dermatomyositis, secondary RP, and thyroid cancer. The capillaroscopic examination showed dilated and giant capillaries, elongated capillaries, decreased mean capillary density with avascular areas, severe disarrangement, single hemorrhages, and clear evidence of neoangiogenesis. These capillaroscopic features characteristic of the "scleroderma-like" pattern are indistinguishable from those in idiopathic dermatomyositis like in the second case. Taken together, the cases illustrate the problem that capillaroscopic patterns in paraneoplastic RP in the context of scleroderma-like syndrome and dermatomyositis appear to be indistinguishable from the microvascular changes in the respective idiopathic rheumatic diseases. PMID- 21253742 TI - [Biologics. Magic bullets - magic effects - magic costs? New therapeutics and their effects]. AB - Biologics and especially therapeutic monoclonal antibodies have an ever increasing impact in the therapy of inflammatory and malignant diseases. They allow a selective blockade of cytokines, receptors and other molecules. This review summarizes the immunological background, the current state and future trends in the development of these therapeutic agents. PMID- 21253744 TI - [ The ABC's of medical statistics. Reading and understanding clinical trials]. AB - Clinical trials test hypotheses that are accepted or rejected according to a predetermined probability of error (level of significance). Significance does not however mean relevance. Good parameters of relevance are absolute risk reduction and based on this the calculation of the number of patients who need to be treated for one additional patient to benefit. The randomized controlled trial is the gold standard for comparative evaluation of effects. In the ideal scenario it is designed so that a difference established by statistical methods becomes probable. In non-inferiority studies care should be taken that no equivalence is shown but rather that the difference is not greater than a predefined margin of error for differences. Meta-analyses of studies with similar endpoints have the potential to improve the level of evidence. Since the findings of meta-analyses depend on the studies included, critical assessment of the results is essential. PMID- 21253743 TI - [Monitoring treatment with biologics in non-infectious uveitis]. AB - Biologics are increasingly being used in the treatment of non-infectious sight threatening uveitis. While the advantages of biologics, such as avoidance of glucocorticoid side-effects or rapid control of intraocular inflammation therapy refractive to corticosteroids, cannot be dismissed the treating ophthalmologist should be aware of the specific risks. Biologics increase the risk for severe and atypical infections, lymphomas and other malignancies. Treatment should only be initiated when profound knowledge about indications, management and monitoring of treatment with biologics is readily available. Weighing up the risks versus the benefits should be made on an individual basis and guide patient consultation. PMID- 21253745 TI - [New aspects in the treatment of neovascular age-related macular degeneration: the criteria of re-treatment with the anti-VEGF therapy.]. PMID- 21253746 TI - [Pharmacological treatment of nystagmus]. AB - Nystagmus can be associated with strong discomfort due to oscillopsia, blurry vision and dizziness. Since generally no curative treatment methods exist, studies focus on potential pharmaceuticals to dampen the nystagmus. An overview is given on which forms of nystagmus can be treated with what kind of pharmacological substances and their possible mechanism of nystagmus dampening. Controlled studies found gabapentin and memantine to be effective in acquired pendular nystagmus and early-onset idiopathic nystagmus, and an efficacy of 4 aminopyridine in downbeat nystagmus. PMID- 21253747 TI - [Cytoprotective and antiangiogenic effects of the multikinase inhibitor sorafenib on human retinal pigmentepithelium]. AB - BACKGROUND: Cumulative light exposure is significantly associated with progression of age-related macular degeneration (AMD). Inhibition of vascular endothelial growth factor A (VEGF) is the main target of current antiangiogenic treatment strategies for AMD. Previous reports indicated that sorafenib, an oral multikinase inhibitor, might have beneficial effects on exudative AMD. This study investigates the effects of sorafenib on light-induced overexpression of VEGF and its receptors VEGFR1 and 2 in human retinal pigment epithelial (RPE) cells. METHODS: The effects of sorafenib on VEGFR1 and 2 expression of primary human RPE cells was investigated by reverse transcription polymerase chain reaction (RT PCR), immunohistochemistry and western blotting. In addition, RPE cells were exposed to white light and incubated with sorafenib. Viability, expression of VEGF and its mRNA were determined by RT-PCR, immunohistochemistry, western blotting, and enzyme-linked immunosorbent assays. RESULTS: Sorafenib reduced VEGFR1 and 2 expression of RPE cells. Light exposure decreased cell viability and increased expression and secretion of VEGF. These light-induced effects were significantly reduced when cells were treated with sorafenib at a dose of 1 ug/ml. CONCLUSION: The results show that sorafenib has promising properties as a potential antiangiogenic treatment for AMD. PMID- 21253748 TI - Mechanisms of chloride uptake in frog olfactory receptor neurons. AB - Odorant stimulation of olfactory receptor neurons (ORNs) leads to the activation of a Ca(2+) permeable cyclic nucleotide-gated (CNG) channel followed by opening of an excitatory Ca(2+)-activated Cl(-) channel, which carries about 70% of the odorant-induced receptor current. This requires ORNs to have a [Cl(-)](i) above the electrochemical equilibrium to render this anionic current excitatory. In mammalian ORNs, the Na(+)-K(+)-2Cl(-) co-transporter 1 (NKCC1) has been characterized as the principal mechanism by which these neurons actively accumulate Cl(-). To determine if NKCC activity is needed in amphibian olfactory transduction, and to characterize its cellular location, we used the suction pipette technique to record from Rana pipiens ORNs. Application of bumetanide, an NKCC blocker, produced a 50% decrease of the odorant-induced current. Similar effects were observed when [Cl(-)](i) was decreased by bathing ORNs in low Cl(-) solution. Both manipulations reduced only the Cl(-) component of the current. Application of bumetanide only to the ORN cell body and not to the cilia decreased the current by again about 50%. The results show that NKCC is required for amphibian olfactory transduction, and suggest that the co-transporter is located basolaterally at the cell body although its presence at the cilia could not be discarded. PMID- 21253750 TI - Spinal cord tumors in children under the age of 3 years: a retrospective Canadian review. AB - BACKGROUND: Tumors of the spinal cord are exceedingly rare in infancy and only a paucity of literature exists describing the spectrum of this disease and its management. The objectives of our study were to describe the demographic characteristics of spinal cord tumors (SCT) in children less than 3 years of age at diagnosis and to review their treatment and outcome. METHODS: A national retrospective chart review was conducted on patients under the age of 3 years diagnosed with a primary tumor of the central nervous system (CNS) between 1990 and 2005 across Canada. Inclusion criteria were: age <= 3 years, histologic confirmation of the diagnosis, and residency in Canada. A centralized database was created and information regarding SCT was extracted. RESULTS: Twenty-five of five hundred seventy-nine patients (4.3%) in the data bank had a SCT. The majority of tumors were low-grade astrocytomas (14/25). Leptomeningeal dissemination based on neuroradiologic imaging and/or cerebrospinal fluid cytology was present in five (20%) patients. The majority of patients underwent an incomplete surgical resection (52%). Most patients (64%) did not receive postoperative radiotherapy or chemotherapy. Seventy-two percent (18/25) developed recurrent/progression of disease. Overall 2- and 5-year survival for low- and high-grade malignancies was 93 +/- 6.4% and 37.5 +/- 17.1% respectively. Significant predictors of survival included mean duration of symptoms prior to initial diagnosis and recurrence/progression of disease. CONCLUSIONS: Relapse/progression of disease in infant SCT is frequent. Prolonged survival of low-grade tumors is possible with further therapy; however, the prognosis of high grade malignancies remains poor. PMID- 21253749 TI - Physiology of aging among healthy, older bottlenose dolphins (Tursiops truncatus): comparisons with aging humans. AB - Changes in hematological and serum chemistry values have been identified among older compared to younger humans. We hypothesized that healthy bottlenose dolphins (Tursiops truncatus) 30 years and older may demonstrate similar clinicopathological changes with increasing age. Retrospective hematological and serum chemistry data generated from routine, fasted blood samples collected over 10 to 20 years among six healthy dolphins that lived at least 40 years were analyzed to (1) assess linear trends in blood variable values with increasing age, (2) compare mean blood values by older age categories (30-35 years, 36-40 years, and >40 years), and (3) compare the prevalence of clinically high or low blood values by older age categories. Absolute lymphocytes, serum globulins, and mean platelet volume increased linearly with increasing old age. Mean white blood cells, neutrophils, serum globulins, erythrocyte sedimentation rates, serum cholesterol, and serum triglycerides; and the prevalence of neutrophilic leukocytosis, hyperglobulinemia, and hypercholesterolemia, were more likely to be higher as geriatric dolphins got older. A linear decrease in serum albumin with increasing age was present for five of six animals. Serum creatinine decreased among dolphins older than 40 years compared to when they were 30-40 years old. Our study demonstrates that older dolphins have changes in hematological and serum chemistry values similar to those found in older humans. As such, bottlenose dolphins may serve as a useful comparative model for aging in humans. Further studies are needed to assess whether these changes are associated with negative health outcomes and whether targeted therapeutics can help improve quality of life among aging dolphins. PMID- 21253751 TI - Hirschsprung's disease: what about mortality? AB - PURPOSE: Although significantly decreased during last decades, mortality rate for Hirschsprung's disease still ranges between 1 and 10%. The authors reviewed the main features of patients with Hirschsprung's disease treated in our Institution who died in the period between 1993 and 2010 in order to detect possible risk factors or prevention strategies. METHODS: The notes of all patients with Hirschsprung's disease admitted to our Institution between January 1993 and January 2010 were reviewed. All families were interviewed and possible unknown deaths were recorded. We reported demographic data, length of aganglionosis, type and number of associated anomalies, age and type of onset, age and cause of death, chronological relationship between death and pull-through, and all other significant details. RESULTS: Eight out of a series of 313 patients with Hirschsprung's disease died during the study period (mortality rate = 2.56%). Six patients were male for a male to female ratio of 3:1. Eleven associated anomalies were detected in five patients, including four congenital anomalies of the kidney and urinary tract, four heart, two central nervous system, and one skeletal malformations. One patient had Down Syndrome and one Cat Eye Syndrome. Two patients were born preterm. All patients had neonatal onset with delayed meconium passage. Five patients had aganglionosis confined to rectosigmoid colon (classic forms), two had total colonic aganglionosis and one had total intestinal aganglionosis. Enterostomy was performed in five patients. Median age at death was 75 days (range 30 days-8 years). The cause of death was enterocolitis in four patients, heart failure in three, and intestinal failure in one. Six patients died before the pull-through. Two patients died postoperatively. All patients but two died at home. CONCLUSIONS: Onset and clinical features do correlate with severity. Newborns and infants seem to be more likely to develop serious life threatening complications, particularly in case of associated cardiovascular malformations. Although enterostomies do not have protective effects over cardiovascular issues, prophylactic stoma should be considered in high-risk patients. Radical treatment (pull-through) should be performed as soon as possible. Alternatively, protected and cautious discharge of newborns with associated heart anomalies is strongly recommended in order to prevent serious and uncontrolled complications, regardless of the presence of a protective enterostomy. Postoperatively, close follow-up appointments are recommended. Families should be acknowledged and educated for prompt recognition and treatment of severe life-threatening complications. PMID- 21253752 TI - Liver and portal histopathological correlation with age and survival in extra hepatic biliary atresia. AB - AIM: To grade histopathological parameters in biliary atresia (BA) and correlate it with advancing age and outcome. METHOD: Liver and porta hepatis biopsies of 18 BA cases were graded for cholestasis (C), hepatocellular degeneration (HD), bile duct proliferation (BDP), bile duct fibrosis (BDF), bile duct inflammation (BDI), portal edema (PE), portal inflammation (PI) and portal fibrosis (PF) with a total histopathological score (THS) of 25. Confidence intervals were calculated. Image analysis at porta hepatis for largest subhepatic bile ductule diameter (BDD) and area was correlated with liver histopathology. Patients were followed up to at least 1 year after surgery. Four cases of neonatal autopsies were taken as control. RESULTS: Mean age at Kasai was 95.5 + 32.03 (51-172) days. Mean THS was 16.83 + 2.57 (13-23) with no significant difference in relation to age <90; >90 days (p = 0.4410) or age <60; 61-90; 91-120; >121 days (p = 0.6549). There was no significant difference with relation to age in grading of parameters; C (p = 1.000) HD (p = 0.638), BDP (p = 0.530), BDF (p = 0.342), BDI (p = 0.395), PE (p = 0.476), PI (p = 0.342), PF (p = 0.530), BDD (p = 0.1097) and area (p = 0.1097). There was no significant difference between survival and age at operation (p = 0.4178) or THS (p = 0.3025). CONCLUSION: Advanced histopathological findings even at younger age suggests the need to consider BA as an emergency. PMID- 21253753 TI - [Fertility preservation for young patients with autoimmune diseases and the need for cytotoxic treatment. Clinical experiences from interdisciplinary consultation]. AB - In cases of severe exacerbation of autoimmune diseases (AID) cytotoxic therapy, in particular with cyclophosphamide (CYC) is needed. As the peak occurrence of such AIDs occurs in young women during the childbearing years, preservation of fertility and the hormonal function of the ovaries are an interdisciplinary challenge.For ovarian protection several options exist. Gonadotropin-releasing hormone analogues in parallel with CYC treatment seem to reduce the cytotoxic effect on the ovaries. Fertilized and unfertilized oocytes can be conserved by cryoconservation after ovarian stimulation. A relatively new strategy uses cryopreservation and autotransplantation of human ovarian tissue prior to cytotoxic therapy. As all these methods are accompanied with side-effects and possible delays in the necessary CYC treatment, a close collaboration of gynecologists and internists is needed. The decision for the optimal preservation therapy should always be based on the individual patient. PMID- 21253754 TI - Dissection of the voltage-activated potassium outward currents in adult mouse ventricular myocytes: I(to,f), I(to,s), I(K,slow1), I(K,slow2), and I(ss). AB - Voltage-activated outward K(+) currents (I (Kv)) are essential for cardiac repolarization and are major factors in the electrophysiological remodeling and arrhythmias seen in heart disease. Mouse models have been useful for understanding cardiac electrophysiology. However, previous methods for separating and quantifying the components of I (Kv) in mouse myocardium have yielded inconsistencies. In this study, we developed a statistically rigorous method to uniquely quantify various I (Kv) in adult mouse ventricular myocytes, and concluded that tri-exponential functions combined with depolarizing pulses of duration greater than 20 s are essential to adequately separate the different I (Kv) components. This method enabled us to reliably dissect the kinetic components of the decay phase of I (Kv) into fast (I (to)), intermediate (K(V)1.5 encoded I (K,slow1)) and slow (K(V)2-encoded I (K,slow2)) components. The most rapid kinetic phase, I (to), can be further dissected into fast (K(V)4-encoded I (to,f)) and slow (K(V)1.4-encoded I (to,s)) components by measuring recovery from inactivation, voltage-dependence of activation and sensitivity to HpTx-2 and 4 AP. The applicability of our dissection method was validated using transgenic mice over-expressing dominant-negative K(V)1.1 transgene which largely abolished the 4-AP-sensitive portion of I (to) (i.e., I (to,s)) and the I (K,slow1) component. We also applied our method to Irx5-deficient mice and verified selective elevations of I (to) in endocardial myocytes. Our method should prove useful in future electrophysiological studies using mouse. PMID- 21253755 TI - Arthroscopic versus percutaneous release of common extensor origin for treatment of chronic tennis elbow. AB - BACKGROUND: Lateral epicondylitis is a common orthopedic problem. Rest, activity modification, and conservative therapies are generally efficacious in relieving symptoms in the majority of patients; however, a small percentage of people will experience refractory pain and require surgical intervention to alleviate their discomfort. Surgical release of the common extensor origin can be done through an open, percutaneous, or arthroscopic approach. PATIENTS AND METHODS: This prospective study includes 33 patients with chronic resistant lateral epicondylitis who had received conservative treatment including modification of activity and 2 injections of 80 mg of hydrocortisone, for more than 6 months, aiming to compare two different techniques of treatment. The first group included 14 patients with a mean age of 42 years treated by arthroscopic release of common extensor origin. The second group included 19 patients with a mean age of 48 years treated by percutaneous tenotomy. The mean follow up was 12 months for the arthroscopic group and 10 months for the percutaneous tenotomy group. RESULTS: The results were evaluated according to the Disabilities of the Arm, Shoulder and Hand (DASH) score and the visual analogue scale (VAS). In the first group (treated by arthroscopy), the average DASH score improved from 72 to 48 and the average VAS improved from 9.1 to 2. In the second group (treated by percutaneous tenotomy), the average DASH score improved from 70 to 50 and the average VAS improved from 9 to 2.1. Concerning patient satisfaction after surgery, in the first group 7 patients (50%) were pleased, 6 (42.85%) were satisfied and 1 case (7.14%) was not satisfied. In the second group, 7 patients (36.84%) were pleased, 10(52.63%) were satisfied and 2 cases (10.52%) were not satisfied. CONCLUSION: Both arthroscopic and percutaneous release of the common extensor origin can be effective in treatment of lateral epicondylitis. Arthroscopic treatment of lateral epicondylitis gives more favorable results than percutaneous tenotomy. Although technically more difficult than percutaneous tenotomy, arthroscopy has the advantage of visualization of the pathology and much better improvement of elbow functions. PMID- 21253757 TI - The effect of botulinum toxin injection on the hang-back recession of rectus muscles. AB - BACKGROUND: Hang-back recession and botulinum toxin injection are performed as one treatment option for the correction of large angles of deviation. However, the effect of botulinum toxin on hang-back recession has not been thoroughly evaluated. The purpose of this study is to investigate the effect of botulinum toxin on the hang-back recession of extraocular muscles. METHODS: Under general anesthesia, 6-mm hang-back recession of the superior rectus muscle (SR) was performed in all eyes of 12 rabbits. Botulinum toxin (5 IU, 0.1 ml) was injected into the SR of one eye in each rabbit. The inferior rectus muscles (IR) of both eyes were excised to model severe paralysis. The distance between the superior limbus and the new insertion was measured immediately after the procedure and 3 months postoperatively. Changes in the location of the insertion were evaluated and compared between both eyes. RESULTS: After excision of the IR, upward deviation was observed in all eyes. The insertion site of the recessed SR immediately after the procedure and 3 months postoperatively were significantly different in all rabbit eyes with or without botulinum injection (P = 0.002, 0.002); SR advancement was observed in both cases. The amount of advancement was 1.38 +/- 0.41 mm in the SR without botulinum toxin injection and 2.29 +/- 0.45 mm in the SR with injection; this difference was statistically significant (P = 0.002). CONCLUSIONS: Botulinum toxin injection reduced the amount of hang-back recession in deviated rabbit eyes. Surgeons should be aware that botulinum toxin can diminish the effects of hang-back recession when used simultaneously. PMID- 21253756 TI - Tumor necrosis factor-alpha as a potential therapeutic target in idiopathic inflammatory myopathies. AB - The cytokine, tumor necrosis factor alpha (TNFalpha), has been implicated in many aspects of immune system development, immune response regulation, and T cell mediated tissue injury. TNFalpha plays a less well-defined role in the pathogenesis of the idiopathic inflammatory myopathy (IIM) group of disorders, and has been considered a potential therapeutic target. Observational studies of TNFalpha-blockade in (mostly refractory) IIM have yielded inconsistent beneficial results so that administration of these biological agents is presently deemed an unreliable alternative treatment strategy. Moreover, anti-TNFalpha therapy has the rare potential to trigger myositis in patients with rheumatoid arthritis, hinting at a pre-existing "overlap disorder". The full potential of TNFalpha antagonism will be realized only if randomized controlled trials ascertain appropriate treatment regimens and identify patient subgroups most likely to benefit from such therapy. PMID- 21253758 TI - Retinal functional changes measured by frequency-doubling technology in patients treated with hydroxychloroquine. AB - BACKGROUND: Antimalarial drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) are mainly used in the treatment of rheumatologic diseases, and their use may be associated with irreversible retinal toxicity. Previous studies indicate early paracentral visual field loss (Humphrey 10-2) in patients taking HCQ". These paracentral defects appear before changes in other clinical parameters as visual acuity and fundoscopy. The mechanism of CQ toxicity remains unclear. It was reported that toxic doses of CQ administered for as long as 4.5 years to Rhesus monkeys caused an initial dramatic effect on ganglion cells, followed later by photoreceptors and RPE degeneration. The purpose of this study is to explore early retinal functional changes measured by frequency-doubling technology (FDT) in patients treated with hydroxychloroquine (HCQ). METHODS: Forty-eight eyes of 48 subjects treated with hydroxychloroquine (HCQ), with no signs of retinal toxicity, and 36 eyes of 36 age and sex-matched healthy subjects were enrolled in this cross-sectional, prospective, observational, case control study. Functional testing included frequency-doubling Humphrey-matrix perimetry (FDP), white-on-white Humphrey visual field perimetry (HFA), using the 24-2 and 10-2 threshold programs, multifocal electroretinogram (mfERG, Veris 4.9) and low contrast sensitivity (CS) measurement. RESULTS: FDP mean deviation (MD) was found to be significantly reduced in HCQ-treated patients compared to controls both in the 24-2 (-1.38 +/- 2.41 dB vs 0.21 +/- 1.83 dB, p < 0.01) and in the 10-2 program (-0.97 +/- 2.88 dB vs 0.15 +/- 1.72 dB, p < 0.01). FDP pattern standard deviation (PSD) was found to be significantly worse in HCQ-treated patients compared to controls both in the 24-2 (2.70 +/- 0.65 dB vs 2.41 +/- 0.31 dB, p < 0.01 and in the 10-2 program (2.86 +/- 0.48 dB vs 2.48 +/- 0.39 dB, p < 0.01). HFA PSD and CS was also significantly reduced in HCQ patients, while response amplitude densities (RAD) were similar between patients and controls. A statistically significant difference in the ratio of the 5 degrees -10 degrees RAD and the 0 degrees -2.5 degrees RAD (0.31 +/- 0.08 vs 0.36 +/- 0.07 respectively, p < 0.05) was found between groups. CONCLUSION: Frequency doubling perimetry could be useful to detect early retinal impairment in patients treated with hydroxychloroquine. PMID- 21253759 TI - Corneal perforation due to limbal involvement in Sezary syndrome. AB - BACKGROUND: The majority of lymphomas involving the eye and ocular adnexa are B cell lymphomas. Ocular involvement by T-cell lymphoma is rare. We report a case of corneal perforation due to direct involvement of the corneal limbus by lymphoma in a patient with Sezary syndrome. METHODS: A 58-year-old male with cutaneous T-cell lymphoma presented with painful, left-sided corneal ulceration, a dense infiltrate, severe epitheliopathy, hypopyon and a diffuse confluent dermatitis involving the lids. He had a history of Sezary syndrome. Despite maximal treatment, this severe ulcerative keratitis progressed to central corneal perforation. The eye was subsequently enucleated and submitted for histopathological examination. RESULTS: Histopathological examination confirmed corneal ulceration with perforation. There was an infiltrate of large atypical cells at the limbus, with tropism for the overlying epithelium. Immunohistochemical staining of these cells was positive for CD2, CD3, CD5, CD4 and CD7. Staining for CD8, CD30 and CD56 was negative. The appearances were those of an epitheliotrophic T-cell lymphoma, and were considered to represent spread from the patient's underlying Sezary syndrome. The patient died 2 months later from bronchopneumonia. CONCLUSIONS: Ocular involvement by cutaneous T-cell lymphoma usually occurs in advanced disease, and carries a poor prognosis. This patient was immunocompromised due to advanced malignancy, and there was a high suspicion of infection as the primary cause of corneal ulceration. This case highlights that it is important to consider direct tumour infiltration as an initiating or contributing factor for corneal ulceration in such patients. PMID- 21253760 TI - MUC1 expression in thymic epithelial tumors: MUC1 may be useful marker as differential diagnosis between type B3 thymoma and thymic carcinoma. AB - MUC1 is a transmembrane mucin that has been related to tumor progression and outcome in various malignancies. However, the clinical significance in thymic epithelial tumors remains unknown. We investigated the clinical significance of MUC1 expression in thymic epithelial tumors. Fifty-five patients with thymic epithelial tumors were included in this study. Tumors sections were stained by immunohistochemistry for MUC1, vascular endothelial growth factor (VEGF), microvessel density (MVD) determined by CD34, and p53. MUC1 were expressed in 29%. The expression of MUC1 was significantly correlated with the grade of malignancy in thymic epithelial tumors. MUC1 was closely associated with VEGF, p53 and MVD, and the overexpression of MUC1 was a prognostic marker for predicting poor outcome in univariate analysis. A positive rate of MUC1 expression was 94% (16/17) in thymic carcinomas and 0% (0/5) in type B3 thymomas, demonstrating a significant difference (p < 0.0001). The expression of MUC1 was closely related to the grade of malignancy in thymic epithelial tumors. A positive expression of MUC1 was significantly associated with poor outcome in this disease. MUC1 may be useful marker for differentiating thymic carcinoma from type B3 thymoma. PMID- 21253762 TI - Glioblastoma stem cells. AB - Glioblastomas are highly malignant primary brain tumors with one of the worst survival rates among all human cancers. With a more profound understanding of the cellular and molecular mechanisms of tumor initiation and acquired resistance to conventional radio- and chemotherapy, novel therapeutic targets might be discovered to optimize therapeutic approaches. In this regard, the identification of a small cellular subpopulation, called glioblastoma stem cell or stem-like cells or glioma-initiating cells or brain tumor propagating cells, has gained attention. In this article, we briefly summarize the current state of knowledge about this tumor cell population and discuss future directions for basic and clinical research. PMID- 21253761 TI - Identification of vitronectin as a novel serum marker for early breast cancer detection using a new proteomic approach. AB - PURPOSE: Breast cancer is the most frequent malignancy in women. However, no useful serum markers with high sensitivity and specificity for the detection of early breast cancer have been identified. The search for biological markers of early breast cancer is of continual interest in experimental and clinical breast cancer research. We recently described a simple and highly reproducible three step proteome analysis for identifying potential disease-marker candidates among the low-abundance serum proteins. METHODS: Serum samples from breast ductal carcinoma in situ (DCIS) patients and normal controls were subjected to a three step serum proteome analysis. The steps were the following: first, immunodepletion of most abundant proteins; second, fractionation using reverse phase high-performance liquid chromatography; and third, separation using two dimensional electrophoresis (2-DE). Differences revealed by protein staining were further confirmed by Western blotting, immunohistochemical staining, and enzyme linked immunosorbent assays (ELISA). RESULTS: Twenty-two upregulated and 26 downregulated spots were detected on the 2-DE gels, and a total of 33 proteins were identified by liquid chromatography and tandem mass spectrometry. Western blotting confirmed that the level of vitronectin was significantly increased in DCIS patients compared with that of normal controls. Immunohistochemical staining of vitronectin in breast cancer tissue revealed high expression in small vessel walls surrounding cancer cells and the extracellular matrix of stroma. Moreover, vitronectin serum concentrations, as measured by ELISA, were significantly increased in patients with DCIS or more advanced breast cancer compared with those of normal controls. CONCLUSIONS: Vitronectin could serve as a promising serum marker for the detection of primary breast cancer. PMID- 21253763 TI - Immunohistochemical localization of opioid peptides in the brain of the leech Theromyzon tessulatum. AB - By use of antisera directed against met-enkephalin, leu-enkephalin, dynorphin or alpha-neoendorphin, immunoreactive structures were visualized in the central nervous system and proboscis of the leech Theromyzon tessulatum. Their distribution in the various compartments of the supra- and subesophageal ganglia was mapped. No correspondence could be established between the neurons containing met- or leu-enkephalin-like substances and the different types of neurosecretory cells classically described in Hirudinea. Successive localization of leu- and met enkephalin on the same section revealed that these two peptides occur in different neurons. Only one cell located in compartment 6 of the supraesophageal ganglion was both dynorphin- and leu-enkephalin-positive. The other dynorphinimmunoreactive cells were not stained with the anti-leuenkephalin serum. The alpha-neoendorphin-immunopositive cells were leu-enkephalin immunonegative and vice versa. PMID- 21253764 TI - Two types of very long visual fibers found in the optic lobe of the flesh-fly, Boettcherisca peregrina. AB - Horseradish peroxidase (HRP) uptake (through a Corneal incision) in photoreceptor cells of the compound eye of Boettcherisca peregrina, resulted in the labeling of two types of very long visual fibers. One of them (the long fiber, If) penetrates through the lamina and medulla, and directly terminates within the lobula. The other (the bypass fiber, bpf) terminates in the medulla, like the axons of R7 and R8 photoreceptor cells, but the fibers run a considerably roundabout course. The photoreceptor cells with these very long fibers are region-dependent within the retina. Both the If and bpf are found almost exclusively in the male fly. PMID- 21253765 TI - An FMRFamide antiserum differentiates between populations of antigens in the brain and retrocerebral complex of the locust, Schistocerca gregaria. AB - The distribution of FMRFamide-irmunoreactive cell bodies in the brain and retrocerebral complex of the locust, Schistocerca gregaria, is described. Most of the immunoreactive cell bodies are found in the pars intercerebralis and in the optic lobes. Many, but not all, of the cell bodies also react with an antiserum raised against bovine pancreatic polypeptide, but this antiserum also reveals another population of cells that stain selectively with this antiserum. In addition to the cell bodies, numerous immunoreactive processes are revealed by both antisera in neuropilar regions of the brain. The results of blocking experiments suggest that a differential distribution of three locust antigens can be determined from the examination of alternate serial sections stained with the two antisera used. PMID- 21253766 TI - Structure predicts synaptic function of two classes of interneurons in the thoracic ganglia of Locusta migratoria. AB - The relationship between synaptic function and structure was examined for 32 spiking interneurons (13 inhibitory and 19 excitatory) in the meso- and metathoracic ganglia of the locust, Locusta migratoria. In no instance was the structure of an excitatory interneuron similar to that of an inhibitory interneuron. However, 12 of the 13 inhibitory interneurons shared a number of structural features, namely a ventromedially located soma, axon(s) projecting into contralateral connective(s), and a laterally bowed primary neurite. Structurally the excitatory interneurons formed a more heterogeneous group. Even so, 12 of the 19 had a combination of structural features in common, namely laterally located somata and axon(s) projecting into contralateral connective(s). The clear differences in structure of the two main groups of inhibitory and excitatory interneurons suggest that other neurons with structures similar to members of these two groups can be classified as inhibitory and excitatory, respectively. Thus we propose that structure predicts synaptic function for two distinct groups of interneurons in the thoracic ganglia of locusts. PMID- 21253767 TI - Studies on microplasmodia of Physarum polycephalum : VI. Functional analysis of a cortical and fibrillar actin system by use of fluorescent-analog cytochemistry. AB - Fluorescently labeled actin (TRITC-G-actin) and heavy meromyosin (TRITC-HMM) derived from skeletal muscle and injected into microplasmodia of the acellular slime mold Physarum polycephalum were used to analyze the function of a cortical and fibrillar actin system in living specimens. The plasma membrane-attached cortical system can be labeled with TRITC-G-actin as well as with TRITC-HMM and visualized as a continuous sheath along the entire cell surface. Long-term experiments over time periods of several hours in conjunction with digital grey value evaluations revealed that changes in the intensity of the fluorescent signal, as caused by alternative contraction and relaxation cycles of the cortical system, are distinctly correlated with periodic changes in the volume and shuttle streaming activity of the microplasmodia. The fibrillar actin system extending through the cytoplasmic matrix can be labeled only with TRITC-HMM. Formation and disappearance of fibrils were found to take place during relaxation and contraction of the cortical system, respectively. Results of the present paper indicate that the cortical actin system is mainly involved in motive force generation for alterations in cell surface morphology and locomotion activity, whereas the fibrillar actin system rather appears to maintain the mechanical stability of microplasmodia. PMID- 21253768 TI - Serotonin-immunoreactive and dopamine-immunoreactive neurones in the terminal ganglion of the cricket, Acheta domestica: Light- and electron-microscopic immunocytochemistry. AB - The distribution and ultrastructure of serotonin- and dopamine-immunoreactive (5 HTi and DAi) neurones have been investigated in the terminal ganglion of the cricket, Acheta domestica, using a pre-embedding chopper technique. Special attention has been paid to the immunoreactive structures in the neuropil. 5-HTi structures are extensively distributed and densely packed throughout the 5 neuromeres of the terminal ganglion and originate from several interneurones and efferent neurones. In contrast, DAi fibres are distributed sparsely although they extend to all neuromeres of the ganglion and originate from 6 interneurons only. For both 5-HTi and DAi neurones characteristic axonal projections and branching patterns can be distinguished. The 5-HTi axons exhibit rich varicose arborizations, whereas DAi neurones possess fewer varicosities in the neuropil. Electron microscopy shows that 5-HTi varicosities contain small (~ 60 nm) and large (~ 100 nm) agranular vesicles, and large (~ 100 nm) granular vesicles, whereas in DAi varicosities small (~ 60 nm) agranular and large (~ 100 nm) granular vesicles are seen. Both 5-HTi and DAi varicosities form synaptic contacts. We conclude that both serotonin and dopamine may be used as neurotransmitters in the terminal ganglion of the cricket. PMID- 21253769 TI - The morphology of the lung of the African lungfish, Protopterus aethiopicus : A scanning electron-microscopic study. AB - The lung of the African lungfish (Protopterus aethiopicus) is paired, long and cylindrical. It is situated on the dorsal aspect of the coelomic cavity ventral to the ribs. Much of the gas exchange tissue is found in the proximal aspect of the lung with the caudal part largely taken up by a centrally situated air-duct with a few large peripherally located alveoli. Interalveolar septa, arranged at differing hierarchical levels from the air-duct, subdivide the lung into alveoli, the gas exchange compartments. The alveolar surface is covered by some cells characterized by microvilli on their free surface, while others are devoid of such structures. The general organization of the lung of Protopterus aethiopicus is similar to that of the other genera of Dipnoi, Neoceratodus and Lepidosiren, with the interalveolar septa increasing the surface area for gas exchange through pulmonary compartmentation. The abundant septal smooth muscle fibres and elastic tissue may contribute to the physiomechanical compliance of the lung. The undifferentiated alveolar pneumocytes and the double capillary system, observed in Protopterus, in general appear to characterize the very primitive lungs of the lower air-breathing vertebrates. PMID- 21253770 TI - Temporal stability of pollinator preference in an alpine plant community and its implications for the evolution of floral traits. AB - A traditional view of diverse floral traits is that they reflect differences in foraging preferences of pollinators. The role of pollinators in the evolution of floral traits has been questioned recently by broad community surveys, especially studies concerning variation in pollinator assemblages and visitation frequency, which suggest a diminished role of pollinators in floral evolution. Here, we investigate the relationships between six categories of floral traits of 29 species and 10 pollinator functional groups in an alpine meadow in the Hengduan Mountains of China, over three consecutive years. Simpson's diversity index was used to estimate the level of pollinator generalization of each plant species by considering both pollinator groups and their relative visitation frequencies. Multivariate analyses indicated that eight of the ten pollinator groups showed constant preferences for at least two floral traits, leading to a relatively stable level of ecological generalization for most floral traits (two out of three categories), despite the fact that the level of generalization of the entire community varied across years. Shape preferences of butterflies, honeybees and beeflies varied such that open flowers exhibited a lower level of ecological generalization in 2007 than closed flowers, in contrast with the other 2 years. These results suggest that temporally stabilized preferences of diverse pollinators may contribute to the evolution of specialized versus generalized floral traits; however, their role may be moderated by variation in community structure, including both the composition and abundance of plants and pollinators. PMID- 21253771 TI - A novel and sensitive resonance scattering assay for detection of urea in serum coupled urease catalytic reaction and NH4+ associated particle reaction. AB - In the pH 6.6 Na2HPO4-NaH2PO4 buffer solutions and in the presence of urease catalyst, urea can be decomposed to form NH4+. The NH4+ reacted with sodium tetraphenyl boron (NaTPB) to form the association particles that exhibited a resonance scattering (RS) peak at 474 nm. When the urea concentration increased, NH4+ increased, and RS intensity at 474 nm enhanced linearly. Under the chosen conditions, the increased RS intensity (DeltaI (474 nm)) had a linear response to the urea concentration in the range of 0.125-15 MUM, with a detection limit of 0.058 MUM urea, and a regression equation of DeltaI (474 nm) = 31.6C + 2.1, a correlation coefficient of 0.9986. This catalytic RS method was applied for the detection of urea in human serum sample, with good selectivity and sensitivity, and the results were consistent with the reference method. PMID- 21253772 TI - Is testicular germ cell cancer associated with increased muscle mass or adiposity? AB - INTRODUCTION: The correlation between an increased body mass index and testicular germ cell cancer has been a topical subject matter of literature. The thesis examines whether for patients with germ cell cancer of the testis the relation between the body cross section and the muscle mass at a particular spot at the abdomen is dislocated toward muscle hypertrophy. PATIENTS, MATERIALS, AND METHODS: CT examinations of 120 patients with testicular tumor have been compared to CTs of 60 trauma surgery patients. MEASUREMENTS: In thickness of the layer at the lowest point of the umbilicus the area of the total body cross section and the Mm. psoas majores were determined and their quotient was calculated. Furthermore, the thickness of the M. rectus abdominis and the Mm. obliquii abdominis have been determined at the broadest spot. RESULTS: The reproducibility of the measured data has been extremely high (kappa >0.9). There has been no significant difference in any of the examined parameters between the comparison group and the total patient group. DISCUSSION: According to the literature, patients with germ cell cancer of the testis on average show a higher body-mass index (BMI) compared to a comparable group of equivalent age. The height of the umbilicus is a body region, where for adipose humans the amplitude increases markedly, hence for reference measurement appropriate. On the basis of the outcome of this thesis, the most probable explanation for the BMI rise is weight gain at other body parts. PMID- 21253773 TI - Anterior or inferior? PMID- 21253775 TI - Lenz microphthalmia syndrome? PMID- 21253774 TI - Nutritional supplementation affects postoperative oxidative stress and duration of hospitalization in patients with hip fracture. AB - OBJECTIVE: The objective of this prospective randomized controlled study was to investigate the effect of nutritional supplementation on postoperative oxidative stress and duration of hospitalization in elderly patients with hip fracture. METHODS: A total of fourteen women (= SG) with hip fracture received individually adapted supplements enriched with protein and antioxidants postoperatively, nine served as unsupplemented controls (= CG). Blood samples were taken preoperatively (T1), on the day of discharge from hospital (T2) and three weeks thereafter (T3). Plasma concentrations of albumin and total protein (TP) were measured by autoanalysis, advanced oxidation protein products (AOPP) and the total antioxidant capacity (TAC) were determined photometrically. Malondialdehyde (MDA) levels were analyzed by HPLC. RESULTS: Postoperatively, there was a significant (T1 > T2, p< 0.01) decrease in plasma albumin, TP and TAC, followed by a significant (p< 0.05) increase in the period T2-T3 in the CG, but not in the SG. This resulted in significant differences in TP (T2: SG > CG, p< 0.05) and TAC (T2: SG > CG, p< 0.01) between the investigated groups. Postoperatively, the plasma levels of AOPP and MDA increased significantly (T1 < T2, p< 0.01) in both groups, and remained at the significantly (AOPP: T1 < T3, p< 0.05; MDA: T1 < T3, p< 0.01) elevated level in the CG, but not in the SG (T2 > T3, p< 0.01). Consequently, the oxidant markers MDA and AOPP were significantly positively (p< 0.01), TAC and albumin significantly negatively (p< 0.05) related to duration of hospital stay in both groups. CONCLUSIONS: Individualized nutritional supplementation may reduce postoperative oxidative stress and shorten duration of hospitalization in patients with hip fracture. PMID- 21253776 TI - Position dependent right ventricular dysfunction caused by a giant right coronary artery aneurysm. AB - We describe an instructive case of a 79-year-old patient with a giant coronary aneurysm and a second smaller aneurysm with an uncommon symptomatology. Giant coronary artery aneurysms (>2 cm diameter) are rare pathologic entities with a prevalence of 0.02%. They either can be congenital malformations or are atherosclerotic in origin. Although spontaneous rupture of giant coronary artery aneurysms has been reported, they generally remain silent or induce myocardial ischemia. Our patient, however, showed no signs of myocardial malperfusion but transient position-dependent pre-syncope. The cardiologic work-up and the intraoperative considerations regarding patient management are described. During surgery, manipulation of the giant coronary artery aneurysm caused impairment of right ventricular function and regional wall hypokinesia, as assessed by transesophageal echocardiography. Venous cannulation of the right atrium was thus abandoned and extracorporeal circulation was established via the femoral vein. Subsequent dissection and surgical repair were uneventful and further recovery of the elderly patient was uncomplicated. This case underlines that once the diagnosis is established, proper perioperative management enables successful surgical treatment even of patients of advanced age. PMID- 21253777 TI - Effective use of cinacalcet for the treatment of secondary hyperparathyroidism in Austrian dialysis patients--results of the Austrian cohort of the ECHO study. AB - BACKGROUND: Despite extensive use of standard therapy for secondary hyperparathyroidism (sHPT) in dialysis patients, still most patients do not achieve the recommended treatment targets. In a pan-European observational study (ECHO), the effectiveness of the calcimimetic cinacalcet for the treatment of sHPT was evaluated in real-world clinical practice. A sub-analysis of the entire Austrian study cohort is presented. METHODS: Adult dialysis patients who had initiated cinacalcet therapy were included. Data on biochemical parameters of bone and mineral metabolism (intact parathyroid hormone [iPTH], calcium [Ca] and phosphorus [P]) and concurrent medication were collected 6 months prior to the initiation of cinacalcet, at initiation (baseline) and after up to 12 months of active treatment. RESULTS: A total of 320 patients (mean age (+/-SD): 56 (+/-14) years) from 34 Austrian dialysis centres were enrolled. At baseline, patients presented with elevated serum iPTH (median 605 pg/ml) and hyperphosphataemia (median 2.1 mmol/l). After 12 months of cinacalcet treatment, serum iPTH (median percentage change -48%), calcium (-2%) and phosphorus (-6%) decreased. The greatest iPTH reduction (-66%) was found in patients with most severe sHPT (>800 pg/ml at baseline). The proportion of patients achieving the recommended NKF/K DOQI(TM) treatment targets increased from baseline to month 12 for iPTH (3-36%) and phosphorus (24 to 39%) and remained stable for calcium (51 to 50%), respectively. No patient had all 3 parameters simultaneously within NKF/K DOQI(TM) treatment targets at baseline, while 7% of patients achieved this treatment goal after 12 months. During the study the use of the phosphate binder sevelamer remained fairly stable, while the relative percentage use of calcium based phosphate binders increased and the usage of aluminium-containing binders decreased; vitamin D analogue use remained stable. CONCLUSION: Additional use of cinacalcet improved biochemical parameters of bone and mineral metabolism and enabled more patients to achieve and maintain the KDOQI(TM) treatment targets for serum iPTH, calcium and phosphorus. PMID- 21253778 TI - Postoperative complications and survival rates for pancreatic cancer patients. AB - BACKGROUND/AIMS: Surgical resection offers the only potential cure for pancreatic tumor. The goal of the present study is to determine complications associated with pancreatic resection and to describe their influence on the survival rate for pancreatic cancer patients. MATERIALS AND METHODS: Between 1996 and 2009, the findings of 125 pancreatic cancer patients were analyzed in a prospective trial at the First Department of Surgery, University Hospital in Kosice, Slovakia. RESULTS: The overall mortality rate and morbidity rate were 3.2% (4 patients) and 27% (34 patients), respectively. In patients with postoperative complications, the median survival time was 12 months (range, 8-14 months), in patients without complications - 18 months (range, 15-20 months). CONCLUSION: The presence of postoperative complications after pancreatic resections has negative influence on the survival rate for pancreatic cancer patients. Patients with a small pancreatic duct size (<3 mm) or a soft pancreatic remnant were at high risk of pancreatic leakage and postoperative complications. PMID- 21253779 TI - Comparison of the fecal microbiota profiles between ulcerative colitis and Crohn's disease using terminal restriction fragment length polymorphism analysis. AB - BACKGROUND: Terminal restriction fragment length polymorphism (T-RFLP) analysis is a powerful tool to assess the diversity of a microbial community. In this study, we performed T-RFLP analysis of the fecal microbiota from patients with ulcerative colitis (UC) and those with Crohn's disease (CD). METHODS: Thirty-one patients with UC, 31 patients with CD, and 30 healthy individuals were enrolled. The polymerase chain reaction (PCR) products obtained from the 16S rRNA genes of fecal samples were digested with BslI, and T-RF lengths were determined. RESULTS: The fecal microbial communities were classified into 5 clusters. Twenty-eight of the 30 healthy individuals and 17 of the 18 patients with inactive UC were classified into clusters I, II, and III, but these clusters included a small number of patients with active UC and inactive/active CD. In contrast, 8 of the 13 patients with active UC and the majority of CD patients (12 of the 16 patients with inactive CD, and 11 of the 15 patients with active CD) were included in clusters IV and V. Based on the BslI-digested T-RFLP database, the bacteria showed a significant decrease in the Clostridium family in patients with active UC and inactive/active CD. In contrast, Bacteroides were significantly increased in CD patients. No significant differences were observed between patients with active UC and those with active CD. CONCLUSION: The fecal microbial communities of IBD patients were different from those of healthy individuals. The gut microbiota of patients with inactive UC tended to be closer to that of healthy individuals, suggesting different roles for the fecal microbiota in the pathophysiology of UC and CD. PMID- 21253780 TI - Computer tomography assessment of pedicle screw placement in lumbar and sacral spine: comparison between free-hand and O-arm based navigation techniques. AB - Transpedicular screw fixation has been accepted worldwide since Harrington et al. first placed pedicle screws through the isthmus. In vivo and in vitro studies indicated that pedicle screw insertion accuracy could be significantly improved with image-assisted systems compared with conventional approaches. The O-arm is a new generation intraoperative imaging system designed without compromise to address the needs of a modern OR like no other system currently available. The aim of our study was to check the accuracy of O-arm based and S7-navigated pedicle screw implants in comparison to free-hand technique described by Roy Camille at the lumbar and sacral spine using CT scans. The material of this study was divided into two groups, free-hand group (group I) (30 patients; 152 screws) and O-arm group (37 patients; 187 screws). The patients were operated upon from January to September 2009. Screw implantation was performed during PLIF or TLIF mainly for spondylolisthesis, osteochondritis and post-laminectomy syndrome. The accuracy rate in our work was 94.1% in the free-hand group compared to 99% in the O-arm navigated group. Thus it was concluded that free-hand technique will only be safe and accurate when it is in the hands of an experienced surgeon and the accuracy of screw placement with O-arm can reach 100%. PMID- 21253781 TI - Iatrogenic diabetes mellitus during ACTH therapy in an infant with West syndrome. AB - West syndrome is a rare epileptic disease of infancy, typified by an association of characteristic spasms, hypsarrhythmia on electroencephalography and severe psychomotor retardation or deterioration. Adrenocorticotropic hormone (ACTH) is the current first-line therapy for West syndrome despite the fact that ACTH therapy is associated with various adverse effects. We describe a rare case of iatrogenic diabetes mellitus during ACTH therapy in a patient with symptomatic West syndrome. The infant had cushingoid facies, hirsutism and biochemical evidence of diabetes due to excessive glucocorticoid production with hyperplasia of both adrenal glands at ultrasound examination, without mineralocorticoid excess; in addition, he presented also short-term weight gain, marked electrolyte disturbances, hypokalemic alkalosis and infections. When ACTH is used to treat patients with West syndrome, it is necessary to follow glycemic levels until to the end of therapy. PMID- 21253782 TI - Role of dopamine D3 and serotonin 5-HT 1A receptors in L: -DOPA-induced dyskinesias and effects of sarizotan in the 6-hydroxydopamine-lesioned rat model of Parkinson's disease. AB - Sarizotan, a 5-HT(1A) agonist with additional affinity for D(3) and D(4) receptors, has been demonstrated to have anti-dyskinetic effects. The mechanism by which these effects occur is not clear. Using unilateral 6-hydroxydopamine lesioned rats that received chronic intraperitoneal (ip) administration of L: 3,4-dihydroxyphenylalanine (L: -DOPA) we investigated the involvement of D(3) and 5-HT(1A) receptors in the effects of sarizotan on contraversive circling and abnormal involuntary movements (AIMs). Before sensitization by chronic L: -DOPA treatment (12.5 with 3.25 mg/kg benserazide ip, twice daily for 21 days), no effect of the selective D(3) agonist, PD128907 (1 or 3 mg/kg ip), or the selective D(3) antagonist, GR103691 (0.5 or 1.5 mg/kg ip), was observed. Treatment with sarizotan (1 or 5 mg/kg ip) dose-dependently inhibited the L: DOPA-induced contraversive turning and AIMs. In co-treatment with the 5-HT(1A) antagonist, WAY100635 (1 mg/kg ip), sarizotan failed to affect this behaviour, confirming the prominent 5-HT(1A) receptor-mediated mechanism of action. In the presence of PD128907 (3 mg/kg ip), the effects of sarizotan on contraversive turning, locomotive dyskinesia and axial dystonia, but not on orolingual and forelimb dyskinesia, were blocked. On its own, PD128907 had no effect on the behavioural effects of L: -DOPA except that it tended to reduce orolingual and forelimb dyskinesia. GR103691 had no effect on its own or in combination with sarizotan. These data identify an involvement of D(3) receptors in the action of sarizotan on some, but not all L: -DOPA-induced motor side effects. This selective involvement is in contrast to the more general involvement of 5-HT(1A) receptors in the anti-dyskinetic effects of sarizotan. PMID- 21253783 TI - Molecular characterisation of Raspberry bushy dwarf virus isolates from Sweden and Belarus. AB - The complete coding sequences were determined for RNA-1 and RNA-2 of five raspberry isolates of Raspberry bushy dwarf virus (RBDV) from Belarus (BY1, BY3, BY8, BY22) and Sweden (SE3). The analysed sequences for both RNA-1 and RNA-2 were highly conserved among these isolates. Phylogenetic analyses including available sequences for the CP gene and the MP gene showed that all analysed RBDV isolates from raspberry were closely related. However, there was no strong correlation between the grouping of raspberry isolates in the phylogenetic analyses and their geographical location. In contrast, RBDV isolates showed a host-dependent relationship with isolates from raspberry and grapevine, forming two distinct clades. PMID- 21253785 TI - Allocating cancer-directed expenditures: tensions between prevention, early detection and treatment is unnecessary. AB - In most countries, the allocation of financial resources for cancer prevention, early detection, and treatment come from different nonrelated "silos." Primary prevention benefits have the greatest economic return since the cancer benefits are intertwined with other major health conditions. Smoking alone accounts for about one-third cancer deaths. In most affluent countries, vaccines for selected viral caused cancers are (wisely) widely available if not optimally utilized. Estimating the additional cancer burden from obesity is still evolving. Age targeted, less frequent but higher rates of participation in early detection of cervical, breast, and colorectal cancer will likely be prudent expenditures.The last 20 years in high-income countries, there has seen an explosion in demand and the costs of cancer drug or biologic therapy, a modest growth in some forms of radiation, yet minimal or declining surgical costs for primary disease control. Expenditures for cancer drugs are now the world leader of any medication category. While a few have truly led to marked benefits, all have been priced at levels that strain or break budgets. We comment on ten steps or principles that can be applied in most countries that can meaningfully reduce cancer care costs with minimal impact on survival and maintain or enhance quality of patient's life especially with advanced disease. We emphasize limiting systemic therapies for metastatic disease to fully ambulatory patients, those who previously responded to therapy, and earlier initiation of palliative care. Changing behaviors, incentives, expectations, and the framing of treatment effects are necessary to "bend" the current unrelenting cancer care cost curve. PMID- 21253786 TI - Lessons learned from prevention programs: different endpoints should be used in secondary and tertiary prevention. AB - It is mandatory to compare cost and consequences of healthcare services if public support is requested. This request will apply to all healthcare services including prevention. As the demand for health care will always exceed the available resources, methods that make it possible to select the "best" programs for implementation have to be developed. The selection of the "best" programs is not easy because there exist so far no generally accepted quality criteria that can be used to identify the "best" prevention programs.Based on a model on structural and functional properties of a disease, it is concluded that the traditional outcomes of treatment and prevention may be useful for the evaluation of tertiary prevention programs, but not of secondary prevention programs. Neither the traditional endpoints of treatment studies nor traditional surrogate parameters are useful for the evaluation of secondary prevention programs.Using the assumptions of the model and a list of available data in secondary prevention programs we recommend to assess five indicators for description of the value of a secondary prevention program: quality of life, surrogates for life expectancy, the perspective of the assessor, the conditions of assessment, and finally the payment. As each of these five items offers two possible values prevention programs may be classified into 32 different groups. PMID- 21253787 TI - Biomarkers for early detection and as surrogate endpoints in cancer prevention trials: issues and opportunities. AB - In order to improve the early detection and diagnosis of cancer, give more accurate prognoses, stratify individuals by risk, predict response to treatment, and help the transition of basic research into clinical application, biomarkers are needed that accurately represent or predict clinical outcomes. To be useful in trials for chemopreventive agent development, biomarkers must be subject to modulation, easy to obtain and quantify, and have biological meaning, ideally representing steps in well-understood carcinogenic pathways. Though difficult to validate fully, wisely chosen biomarkers in early-phase trials can inform the prioritization of large-scale, long-term trials that measure clinical outcomes. When well-designed, smaller trials using biomarkers as surrogate endpoints should promote faster decisions regarding which targeted preventive agents to pursue, promising greater progress in the personalization of medicine. Biomarkers could become useful in distinguishing indolent from aggressive forms of ductal carcinoma in situ as well as localized invasive breast and prostate cancer, lesions that are often overtreated. Chemopreventive strategies that reduce the progression of early forms of premalignancy can benefit patients not only by reducing their risk of cancer and death from cancer but also by reducing their need for invasive interventions. Genomic and proteomic methods offer the possibility of revealing new potential markers, especially for diseases whose biology is complex or not well understood. Panels of markers may be used to accommodate the molecular heterogeneity of cancers. Biomarkers in phase 2 prevention trials of combinations of chemopreventive drugs have been used to demonstrate synergistic action of multiple agents, allowing use of lower doses, with less toxicity, a critical feature of interventions intended for cancer prevention. PMID- 21253784 TI - Targeting skin dendritic cells to improve intradermal vaccination. AB - Vaccinations in medicine are typically administered into the muscle beneath the skin or into the subcutaneous fat. As a consequence, the vaccine is immunologically processed by antigen-presenting cells of the skin or the muscle. Recent evidence suggests that the clinically seldom used intradermal route is effective and possibly even superior to the conventional subcutaneous or intramuscular route. Several types of professional antigen-presenting cells inhabit the healthy skin. Epidermal Langerhans cells (CD207/langerin(+)), dermal langerin(neg), and dermal langerin(+) dendritic cells (DC) have been described, the latter subset so far only in mouse skin. In human skin langerin(neg) dermal DC can be further classified based on their reciprocal expression of CD1a and CD14. The relative contributions of these subsets to the generation of immunity or tolerance are still unclear. Yet, specializations of these different populations have become apparent. Langerhans cells in human skin appear to be specialized for induction of cytotoxic T lymphocytes; human CD14(+) dermal DC can promote antibody production by B cells. It is currently attempted to rationally devise and improve vaccines by harnessing such specific properties of skin DC. This could be achieved by specifically targeting functionally diverse skin DC subsets. We discuss here advances in our knowledge on the immunological properties of skin DC and strategies to significantly improve the outcome of vaccinations by applying this knowledge. PMID- 21253789 TI - Thinking about the role (largely ignored) of heavy metals in cancer prevention: hexavalent chromium and melanoma as a case in point. AB - Ultraviolet (UV) light exposure accounts for only 40-50% of the attributable risk for cutaneous melanoma (CM); also classical UV-induced lesions are rare in melanomas (especially among CM with NRAS or BRAF mutations). It is therefore likely that an additional environmental factor exists as familial and genetic factors play a role in less than 5%. A large amount of (largely forgotten) epidemiologic data indicates that heavy metal exposure is strongly associated with the development of CM. Also, epidemiologic studies of patients with joint replacement indicate a marked subsequent time-related increase in melanoma in patients with metal-on-metal hip arthroplasties. In these patients chromium and cobalt levels rise to 10x normal and stay elevated at levels two- to threefold normal for at least 10 years. Chromium is widely used in industry for its anticorrosive and steel-strengthening properties and is widespread in everyday materials. Our hypothesis is therefore that chromium, alone or in conjunction with UV, plays a major role in the pathogenesis of CM. We have incubated human neonatal melanocytes for more than 10 weeks in the presence of a wide range and concentrations of metals without effect except by hexavalent chromium Cr(VI)and to a lesser degree Co2(+). After prolonged culture, chromium-incubated cells produced foci and when replated secondary colonies formed. We have just begun to study this phenomenon in more detail and studies without and with different wavelengths of UV will be explored. Of interest is that aneuploidy (a universal chromosomal change in cutaneous melanoma) in lymphocytes in patients with hip-on hip metal prostheses has been demonstrated by others. PMID- 21253788 TI - Targeting polyamines and inflammation for cancer prevention. AB - Increased polyamine synthesis and inflammation have long been associated with intraepithelial neoplasia, which are risk factors for cancer development in humans. Targeting polyamine metabolism (by use of polyamine synthesis inhibitors or polyamine catabolism activators) and inflammation (by use of nonsteroidal anti inflammatory drugs) has been studied for many cancers, including colon, prostate, and skin. Genetic epidemiology results indicate that a genetic variant associated with the expression of a polyamine biosynthetic gene is associated with risk of colon and prostate cancers. A clinical trial of difluoromethylornithine (DFMO), a selective inhibitor of polyamine synthesis, showed that the 1 year treatment duration reduced prostate volume and serum prostate-specific antigen doubling time in men with a family history of prostate cancer. A second, clinical trial of DFMO in combination with sulindac, a NSAID in patients with prior colon polyps found that the 3-year treatment was associated with a 70% reduction of all, and over a 90% reduction of advanced and/or multiple metachronous colon adenomas. In this chapter, we discuss that similar combination prevention strategies of targeting polyamines and inflammation can be effective in reducing risk factors associated with the development of human cancers. PMID- 21253790 TI - Hepatitis B virus and cancer prevention. AB - Prevention of chronic hepatitis B virus (HBV) infection can successfully reduce the incidence of liver cancer. It is the first example of cancer-preventive vaccine in human, which proves that prevention of the infection of an infectious agent can prevent its related cancer.Chronic HBV infection can lead to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). HCC is one of the five major cancers in the world population. Hepatitis B virus (HBV) is the most important etiologic agent of liver cancer globally, particularly in high prevalence areas of liver cancer.The world's first universal HBV vaccination program was launched in Taiwan in July 1984. It has provided evidences that the prevalence of HBV infection has been reduced remarkably to approximately one tenth of the original prevalence. Furthermore, reduction of the HCC incidence in children aged 6-14 years have been demonstrated in the vaccinated birth cohorts. Recently, we have further provided evidence that the prevention of HCC by this HBV vaccine extends from childhood to early adulthood.The risk of developing HCC for vaccinated cohorts was associated with incomplete HBV vaccination; prenatal maternal hepatitis B surface antigen (HBsAg) seropositivity; and prenatal maternal HBeAg seropositivity. Failure to prevent HCC results mostly from unsuccessful control of HBV infection by highly infectious mothers. Future strategies to increase the global coverage rate of HBV immunization and to interrupt mother-to- infant transmission may enhance the cancer prevention effect of HBV immunization. PMID- 21253791 TI - Chemoprevention of hepatocellular carcinoma in chronic hepatitis C. AB - Hepatitis C virus (HCV) infection causes chronic hepatitis, which can progress to cirrhosis and hepatocellular carcinoma (HCC). The incidence of hepatocellular carcinoma in the United States tripled between 1975 and 2005, and is expected to increase further, and to remain elevated for more than 20 years. Curing hepatitis C infection in patients with cirrhosis through treatment with peginterferon and ribavirin reduces the risk of developing hepatocellular carcinoma. Several noncurative treatments also appear to reduce the risk of hepatocellular carcinoma in patients with chronic hepatitis C. Prospective studies report a reduced incidence of hepatocellular carcinoma among patients treated with a mixture of carotenoids with or without myo-inositol, with vitamin K2, or with polyprenoic acid (an acyclic retinoid). Uncontrolled and/or retrospective studies have reported beneficial effects of treatment with Sho-saiko-to, glycyrrhizin and ursodeoxycholic acid on hepatocellular carcinoma incidence. Meta-analyses of epidemiologic studies show a reduced risk of hepatocellular carcinoma among liver disease patients who drink two or more cups of coffee per day. Numerous agents prevent or reduce hepatocarcinogenesis in animal models. An ongoing Phase II clinical trial is evaluating S-adenosylmethionine (SAMe) as a potential chemopreventive agent in hepatitis C cirrhosis. Overall, these data suggest that chemoprevention of hepatocellular carcinoma in patients with chronic hepatitis C is an achievable objective. PMID- 21253792 TI - Nutritional aspects of primary prostate cancer prevention. AB - There are three well-known and indisputable risk factors for development of prostate cancer, namely heredity, ethnic origin, and increasing age. Geographic variations in incidence rates are considerable and, therefore, it has been suggested that environmental factors may also play a role. Data from migration studies clearly show that men with the same genetic background raised in different environments present the risk of the disease associated with their country of residency. Prostate cancer is a good candidate for studies on primary prevention due to several specific features such as high prevalence, long latency, hormonal dependency, serum markers for monitoring (prostate specific antigen), and histological precursor lesions (prostatic intraepithelial neoplasia). Nutritional factors that may influence the disease include total energy intake (as reflected by body mass index), dietary fat, cooked meat, micronutrients and vitamins (carotenoids, retinoids, vitamins C, D and E), fruit and vegetable intake, minerals (calcium, selenium), and phytoestrogens (isoflavonoids, flavonoids, lignans). Most studies reported to date are case control analysis. The selenium and vitamin E cancer prevention trial (SELECT), however, is a population-based, prospective, randomized clinical trial to examine the effect of selenium and vitamin E alone or in combination on prostate cancer risk reduction. The trial was discontinued recently as there was no evidence of a benefit from either agent. Nevertheless, lifestyle changes could be recommended to men at risk for developing clinical prostate cancer. PMID- 21253793 TI - Prostate cancer prevention with 5 alpha-reductase inhibitors. PMID- 21253794 TI - Hormone replacement therapy and breast cancer. AB - There is evidence that hormone replacement therapy (HRT) may both stimulate and inhibit breast cancers, giving rise to a spectrum of activities, which are frequently hard to understand. Here we summarise the evidence for these paradoxical effects and, given the current data, attempt to give an indication where it may or may not be appropriate to prescribe HRT.It is clear that administration of oestrogen-progestin (E-P) and oestrogen alone (E) HRT is sufficient to stimulate the growth of overt breast tumours in women since withdrawal of HRT results in reduction of proliferation of primary tumours and withdrawal responses in metastatic tumours. E-P, E including tibolone are associated with increased local and distant relapse when given after surgery for breast cancer. For women given HRT who do not have breast cancer the only large randomised trial (WHI) of E-P or E versus placebo has produced some expected and also paradoxical results. E-P increases breast cancer risk as previously shown in observational studies. Risk is increased, particularly in women known to be compliant. Conversely, E either has no effect or reduces breast cancer risk consistent with some but not all observational studies. Two observational studies report a decrease or at least no increase in risk when E-P or E are given after oophorectomy in young women with BRCA1/2 mutations. Early oophorectomy increases death rates from cardiovascular and other conditions and there is evidence that this may be reversed by the use of E post-oophorectomy. HRT may thus reduce the risk of breast cancer and other diseases (e.g., cardiovascular) in young women and increase or decrease them in older women. PMID- 21253795 TI - Physical activity and breast cancer: review of the epidemiologic evidence and biologic mechanisms. AB - Breast cancer is the most commonly diagnosed invasive malignancy and the second leading cause of cancer death in women globally. This review considers epidemiologic evidence regarding the association between physical activity and breast cancer risk. Across these studies there was a 25% average risk reduction among physically active women as compared to the least active women. The associations were strongest for recreational activity, for activity sustained over the lifetime or done after menopause, and for activity that is of moderate to vigorous intensity and performed regularly. There is also some evidence for a stronger effect of physical activity among postmenopausal women, women who are normal weight, have no family history of breast cancer, and are parous. It is likely that physical activity is associated with decreased breast cancer risk via multiple interrelated biologic pathways that may involve adiposity, sex hormones, insulin resistance, adipokines, and chronic inflammation. Future research should include prospective observational epidemiologic studies relating proposed biomarkers to breast cancer risk and also randomized controlled trials to examine how physical activity influences the proposed biomarkers. Exercise trials will provide more clarity regarding the appropriate type, dose, and timing of activity that are related to breast cancer risk reduction.Breast cancer remains a leading cause of cancer incidence and mortality in most developed countries worldwide. While significant international research has examined risk factors for breast cancer, most identified risk factors are nonmodifiable. During the past 20 years, over 90 studies have been conducted worldwide that have examined some aspects of the association between physical activity and breast cancer risk reduction. The purpose of this chapter is to review both the epidemiologic evidence and hypothesized biologic mechanisms whereby physical activity may influence breast cancer risk. PMID- 21253796 TI - Prevention of breast cancer by newer SERMs in the future. AB - The selective oestrogen receptor modulators (SERMs) tamoxifen has been shown to reduce the incidence of oestrogen receptor positive breast cancer by about 60 to 70% in healthy high risk women. The oestrogenic effects of tamoxifen caused a beneficial effect of reduced bone loss and fracture risk in postmenopausal women. However there was also significant gynaecological toxicity including an increased risk of endometrial cancer. Further clinical trials have evaluated the newer SERMs raloxifene, arzoxifene and lasofoxifene. The latter has been shown to significantly reduce the incidence of breast cancer, vertebral and non vertebral fractures, major coronary events and stroke with no significant gynaecological toxicity. PMID- 21253797 TI - Chemoprevention of hormone receptor-negative breast cancer: new approaches needed. AB - Results from clinical trials have demonstrated that it is possible to prevent estrogen-responsive breast cancers by targeting the estrogen receptor with selective estrogen receptor modulators (SERMs) (tamoxifen, raloxifene, or lasofoxifene) or with aromatase inhibitors (AIs) (anastrozole, letrozole, or exemestene). Results from breast cancer treatment trials suggest that aromatase inhibitors may be even more effective in preventing breast cancer than SERMs. However, while SERMs and aromatase inhibitors do prevent the development of many ER-positive breast cancers, these drugs do not prevent ER-negative breast cancer. These results show that new approaches are needed for the prevention of this aggressive form of breast cancer. Our laboratory and clinical efforts have been focused on identifying critical molecular pathways in breast cells that can be targeted for the prevention of ER-negative breast cancer. Our preclinical studies have demonstrated that other nuclear receptors, such as RXR receptors, vitamin D receptors, as well as others are critical for the growth of ER-negative breast cells and for the transformation of these cells into ER-negative cancers. Other studies show that growth factor pathways including those activated by EGFR, Her2, and IGFR, which are activated in many ER-negative breast cancers, can be targeted for the prevention of ER-negative breast cancer in mice. Clinical studies have also shown that PARP inhibitors are effective for the treatment of breast cancers arising in BRCA-1 or -2 mutation carriers, suggesting that targeting PARP may also be useful for the prevention of breast cancers arising in these high-risk individuals. Most recently, we have demonstrated that ER-negative breast cancers can be subdivided into four distinct groups based on the kinases that they express. These groups include ER-negative/Her-2-positive groups (the MAPK and immunomodulatory groups) and ER-negative/Her2-negative groups (the S6K and the cell cycle checkpoint groups). These groups of ER-negative breast cancers can be targeted with kinase inhibitors specific for each subgroup. These preclinical studies have supported the development of several clinical trials testing targeted agents for the prevention of breast cancer. The results of a completed Phase II cancer prevention trial using the RXR ligand bexarotene in women at high risk of breast cancer will be reviewed, and the current status of an ongoing Phase II trial using the EGFR and Her2 kinase inhibitor lapatinib for the treatment of women with DCIS breast cancer will be presented. It is anticipated that in the future these molecularly targeted drugs will be combined with hormonal agents such as SERMs or aromatase inhibitors to prevent all forms of breast cancer. PMID- 21253798 TI - A sex difference in effect of prior experience on object-mediated problem-solving in gibbons. AB - Understanding the functionally relevant properties of objects is likely facilitated by learning with a critical role for past experience. However, current evidence is conflicting regarding the effect of prior object exposure on acquisition of object manipulation skills. This may be due to the influence of life history variables on the capacity to benefit from such experience. This study assessed effect of task-relevant object exposure on object-mediated problem solving in 22 gibbons using a raking-in task. Despite not using tools habitually, 14 gibbons spontaneously used a rake to obtain a reward. Having prior experience with the rake in an unrewarded context did not improve learning efficiency in males. However, females benefitted significantly from the opportunity to interact with the rake before testing, with reduced latencies to solution compared to those with no previous exposure. These results reflect potential sex differences in approach to novelty that moderate the possible benefits of prior experience. Due to their relatively high energetic requirements, reproductively active females may be highly motivated to explore potential resources; however, increased investment in developing offspring could make them more guarded in their investigations. Previous exposure that allows females to learn of an object's neutrality can offset this cautious exploration. PMID- 21253799 TI - Identification of CTX-M15-, SHV-28-producing Klebsiella pneumoniae ST15 as an epidemic clone in the Copenhagen area using a semi-automated Rep-PCR typing assay. AB - Rapid molecular typing methods can be a valuable aid in the investigation of suspected outbreaks. We used a semi-automated repetitive sequence-based polymerase chain reaction (Rep-PCR) typing assay and pulsed field gel electrophoresis (PFGE) to investigate the relationship between local Klebsiella pneumoniae (K. pneumoniae) producing extended spectrum beta-lactamases (ESBLs) and their relation to recognized Danish outbreak strains. PFGE and Rep-PCR produced similar clustering among isolates. Individual isolates from each cluster were further characterized by PCR amplification and sequencing of bla (TEM), bla (SHV), and bla (CTX-M), and multilocus sequence typing (MLST). Thirty-five out of 52 ESBL-producing K. pneumoniae isolates were ST15 and bla (CTX-M15), bla (SHV 28), and bla (TEM-1) positive by PCR. Ten out of 52 were ST16 and tested positive for bla (CTX-M15), bla (SHV-1), and bla (TEM-1). Isolates from previously recognized hospital outbreaks were also ST15 and PCR positive for bla (CTX-M15), bla (SHV-28), and bla (TEM-1), and typed within the main cluster by both Rep-PCR and PFGE. In conclusion, K. pneumoniae ST15 containing bla (CTX-M15) and bla (SHV 28) constitutes an epidemic clone in the Copenhagen area and this clone can be rapidly recognized by semi-automated Rep-PCR. PMID- 21253800 TI - Effect of Er:YAG laser application on the shear bond strength and microleakage between resin cements and Y-TZP ceramics. AB - The objective of this study was to investigate the effect of Er:YAG laser irradiation on shear bond strength and microleakage between resin cements and yttrium-stabilized tetragonal zirconia (Y-TZP) ceramics. Eighty disc specimens of Y-TZP ceramics (6 mm * 4 mm) were prepared. The specimens were divided into two groups according to surface treatment (control and Er:YAG laser-treated). The control and lased specimens were separated into two groups for shear bond strength test (n = 20), and microleakage evaluation (n = 10). Specimens were subjected to shear bond strength test by a universal testing machine with a crosshead speed of 1 mm/min. Specimens for microleakage evaluation were then sealed with nail varnish, stained with 0.5% basic fuchsin for 24 h, sectioned, and evaluated under a stereomicroscope. The data were analyzed with one-way ANOVA and post hoc Tukey-Kramer multiple comparisons tests (alpha = 0.05) for shear bond strengths and a two related-samples tests (alpha = 0.05) for microleakage scores. Higher bond strength values were found in the laser-treated groups compared to the control groups. Microleakage scores among the groups showed that the laser-treated specimens had lower microleakage scores than those of control specimens in the adhesive-ceramic interface. Roughening surface of Y-TZP ceramic by Er:YAG laser increased the shear bond strengths of ceramic to dentin and reduced the microleakage scores. PMID- 21253801 TI - Functional disturbance of the stress-adaptation system in patients with scleroderma. AB - There have been several reports indicating the association between recent stress experiences and the onset or the exacerbation of rheumatic diseases, although few such reports exist in patients with scleroderma (SSc). The present study was performed to elucidate whether there were any functional disturbances in the neuro-endocrine-immune system as a homeostatic system upon stress in SSc patients. Various serum levels of stress-related hormones and cytokines were examined before and after a mental calculation stress test, and a basal questionnaire study of sense of coherence (SOC, which is related to the ability to cope with stress), recent stress experiences, and quality of life (QOL) was performed in 17 SSc patients and in 38 healthy volunteers. Physical QOL state was impaired in patients, but there were no differences in recent stress experiences and SOC scores between patients and controls. Basal serum cortisol levels were similar in patients and controls, but increased levels of proinflammatory cytokine and noradrenalin were seen in SSc patients. Characteristically, contrary to the control group, whose cortisol levels increased significantly following the mental calculation stress test, no significant increase was observed in the patients when post-test cortisol levels were compared to pre-test levels, suggesting a defect in the normal cortisol response upon stress in SSc patients. The present results suggest that there may be impaired function of the neuro endocrine-immune system upon stress in SSc patients. PMID- 21253802 TI - Role of imaging studies in the diagnosis and evaluation of giant cell arteritis in Japanese: report of eight cases. AB - The objective of this study is to clarify the characteristics and imaging results of Japanese patients with giant cell arteritis (GCA). Eight patients with biopsy proven GCA were enrolled. Their clinical data and imaging results were retrospectively examined from their medical records. All the patients met the criteria for the classification of GCA by the American College of Rheumatology. Although the clinical manifestations are similar to those previously reported, none of the eight patients presented ocular symptoms, and half of them presented jaw claudication. Ultrasonography (US) of temporal artery showed the halo sign in all the patients. Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed in four patients and indicated the presence of aortitis of the patients. US is a quick and noninvasive test to detect inflammation of temporal artery, and FDG-PET is very helpful for early diagnosis of aortitis in GCA. Awareness of the disease and appropriate imaging tests will result in diagnosis of GCA. PMID- 21253803 TI - Surface nucleation in the crystallisation of polyethylene droplets. AB - The division of semi-crystalline polymeric material into small domains is an effective tool for studying crystal nucleation. The scaling behavior of the nucleation rate as a function of domain size can reveal important information about the mechanism responsible for the birth of a crystal nucleus. We have investigated the process of crystal nucleation in a system of dewetted polyethylene droplets. Through the use of a correlation sample analysis, we are able to differentiate between heterogeneous and homogeneous nucleation mechanisms in a droplet sample. An analysis of the dependence of the nucleation rate on droplet size reveals that the nucleation probability scales with the surface area of the droplet. PMID- 21253804 TI - Rapid Plateau border size variations expected in three simple experiments on 2D liquid foams. AB - Up to a global scaling, the geometry of foams squeezed between two solid plates (2D GG foams) essentially depends on two independent parameters: the liquid volume fraction and the degree of squeezing (bubble thickness to diameter ratio). We describe it in two main asymptotic regimes: fully dry floor tiles, where the Plateau border radius is smaller than the distance between the solid plates, and dry pancakes, where it is larger. We predict a rapid variation of the Plateau border radius in one part of the pancake regime, namely when the Plateau border radius is larger than the inter-plate distance but smaller than the geometric mean of that distance and the bubble perimeter. This rapid variation is not related to any topological change in the foam: in all the regimes we consider, the bubbles remain in mutual lateral contact through films located at mid-height between both plates. We provide asymptotic predictions in different types of experiments on such 2D GG foams: when foam is being progressively dried or wetted, when it is being squeezed further or stretched, when it coarsens through film breakage or through inter-bubble gas diffusion. Our analysis is restricted to configurations close to equilibrium, as we do not include stresses resulting from bulk viscous flow or from non-homogeneous surfactant concentrations. We also assume that the inter-plate distance is sufficiently small for gravity to be negligible. The present work does not provide a method for measuring small Plateau border radii experimentally, but it indicates that large (and easily observable) Plateau borders should appear or disappear rather suddenly in some types of experiments with small inter-plate gaps. It also gives expected orders of magnitude that should be helpful for designing experiments on 2D GG foams. PMID- 21253805 TI - Critical microphase properties of crosslinked polymer blends with quenched random impurities. AB - We extend published works dealing with microphase separation in crosslinked polymer blends to the case where these are surrounded by random impurities. To study their influence on critical microphase properties, from a static and kinetics point of view, we first assume that the (real) disorder caused by impurities is quenched. Second, the replica theory is used to study such critical properties, upon the impurities concentration and their interaction strength. More precisely, we compute the spinodal temperature and structure factor. We find that the spinodal temperature is shifted towards its lower and higher values, for attractive and repulsive impurities, respectively. The obtained expression for the static structure factor suggests that, contrarily to repulsive impurities, the crosslinked mixture scatters better in the presence of attractive ones. Thereafter, the study is extended to kinetics of microphase separation, when the mixture is impregnated by small random impurities. Kinetics is investigated through the growth rate, and in particular, we demonstrate that the latter is increased by the presence of repulsive impurities. This is natural, since these play a stabilizer role. Finally, the discussion is extended to crosslinked polymer blends immersed in a good solvent, which induces drastic changes of the critical microphase properties. PMID- 21253806 TI - Computer simulations of the growth of synthetic peptide fibres. AB - We present a coarse-grained computer model designed to study the growth of fibres in a synthetic self-assembling peptide system. The system consists of two 28 residue alpha-helical sequences, denoted AB and CD, in which the interactions between the half peptides, A, B, C and D, may be tuned individually to promote different types of growth behaviour. In the model, AB and CD are represented by double ended rods, with interaction sites distributed along their lengths. Monte Carlo simulations are performed to follow fibre growth. It is found that lateral and longitudinal growth of the fibre are governed by different mechanisms--the former is diffusion limited with a very small activation energy for the addition of units, whereas the latter occurs via a process of secondary nucleation at the fibre ends. As a result, longitudinal growth generally proceeds more slowly than lateral growth. Furthermore, it is shown that the aspect ratio of the growing fibre may be controlled by adjusting the temperature and the relative strengths of the interactions. The predictions of the model are discussed in the context of published data from real peptide systems. PMID- 21253807 TI - Rheological behaviour of polyoxometalate-doped lyotropic lamellar phases. AB - We study the influence of nanoparticle doping on the lyotropic liquid crystalline phase of the industrial surfactant Brij(r)30 (C12E4) and water, doped with spherical polyoxometalate nanoparticles smaller than the characteristic dimensions of the host lamellar phase. We present viscometry and in situ rheology coupled with small-angle X-ray scattering data that show that, with increasing doping concentration, the nanoparticles act to decrease the shear viscosity of the lamellar phase, and that a shear-induced transition to a multilamellar vesicle "onion" phase is pushed to higher shear rates, and in some cases completely suppressed. X-ray data reveal that the nanoparticles remain encapsulated within the membranes of the vesicles, thus indicating a viable method for the fabrication of nanoparticle incorporating organic vesicles. PMID- 21253808 TI - Influence of interstitial bone microcracks on strain-induced fluid flow. AB - It is well known that microcracks act as a stimulus for bone remodelling, initiating resorption by osteoclasts and new bone formation by osteoblasts. Moreover, microcracks are likely to alter the fluid flow and convective transport through the bone tissue. This paper proposes a quantitative evaluation of the strain-induced interstitial fluid velocities developing in osteons in presence of a microcrack in the interstitial bone tissue. Based on Biot theory in the low frequency range, a poroelastic model is carried out to study the hydro-mechanical behaviour of cracked osteonal tissue. The finite element results show that the presence of a microcrack in the interstitial osteonal tissue may drastically reduce the fluid velocity inside the neighbouring osteons. This fluid inactive zone inside osteons can cover up to 10% of their surface. Consequently, the fluid environment of bone mechano-sensitive cells is locally modified. PMID- 21253809 TI - Mechanical stimuli differentially control stem cell behavior: morphology, proliferation, and differentiation. AB - Mesenchymal stem cell (MSC) therapy has demonstrated applications in vascular regenerative medicine. Although blood vessels exist in a mechanically dynamic environment, there has been no rigorous, systematic analysis of mechanical stimulation on stem cell differentiation. We hypothesize that mechanical stimuli, relevant to the vasculature, can differentiate MSCs toward smooth muscle (SMCs) and endothelial cells (ECs). This was tested using a unique experimental platform to differentially apply various mechanical stimuli in parallel. Three forces, cyclic stretch, cyclic pressure, and laminar shear stress, were applied independently to mimic several vascular physiologic conditions. Experiments were conducted using subconfluent MSCs for 5 days and demonstrated significant effects on morphology and proliferation depending upon the type, magnitude, frequency, and duration of applied stimulation. We have defined thresholds of cyclic stretch that potentiate SMC protein expression, but did not find EC protein expression under any condition tested. However, a second set of experiments performed at confluence and aimed to elicit the temporal gene expression response of a select magnitude of each stimulus revealed that EC gene expression can be increased with cyclic pressure and shear stress in a cell-contact-dependent manner. Further, these MSCs also appear to express genes from multiple lineages simultaneously which may warrant further investigation into post-transcriptional mechanisms for controlling protein expression. To our knowledge, this is the first systematic examination of the effects of mechanical stimulation on MSCs and has implications for the understanding of stem cell biology, as well as potential bioreactor designs for tissue engineering and cell therapy applications. PMID- 21253810 TI - Single oligoarray-based detection of specific M918T mutation in RET oncogene in multiple endocrine neoplasia type 2B. AB - The most important mutation associated with Multiple Endocrine Neoplasia type 2B (MEN 2B) is the change of thymine to cytosine in codon 918 of exon 16 in the RET oncogene (ATG -> ACG). The aim of this work was to develop a single oligoarray by using tandem hybridization to detect the T918C/RET mutation for MEN 2B patients. Two genetically non-related families were studied; each family had a member affected by MEN2B. Both patients presented the T918C/RET mutation in a heterozygous fashion. None of the relatives was positive for this mutation; thus, these cases arose de novo. The proper mutation was confirmed by with different tools, PCR-Fok I endonuclease, direct sequencing, and also using our oligoarray. In this case, it is suitable to use a DNA target smaller than 150 bases with single- or double-stranded DNA and short probes of 7-mer. It was also possible to detect the mutation by employing different sources of DNA, fresh or paraffin embedded tissues. Therefore, the present oligoarray can identify the most common M918T mutation of RET oncogene from a variety of DNA sources with good specificity and be a good alternative in the molecular diagnosis for MEN 2B cases. PMID- 21253812 TI - Coverage of recommended vaccinations in subjects with diabetes mellitus and ischemic heart disease: results for women and men. AB - Vaccination is an important public health strategy to prevent adverse health outcomes in the general population and in subjects with chronic diseases. It was the aim of this study to compare data on coverage of recommended vaccinations in men and women with diabetes mellitus and after myocardial infarction (MI) and to analyse trends in three different interview surveys: 1991, 1999 and 2006-07. The data show a rise in influenza vaccination coverage rate in men and women in the general population and in high-risk groups. However, coverage rates in all analysed groups were still strikingly low. Although in soft reported earlier surveys women were vaccinated more often than men, there was a reverse trend observed in the most recent survey. In the survey of 2006-07, men with diabetes or after MI had a higher chance of being vaccinated against influenza when compared to men without these diseases (age adjusted OR: 1.61; 95% CI: 1.29-1.99 and 1.61; 95% CI: 1.21-2.15, respectively). This was, however, not the case in women (OR: 1.10; 95% CI: 0.89-1.35 and 0.87; 95% CI: 0.58-1.33, respectively). Neither men nor women with diabetes mellitus or MI had a significantly higher chance of having pneumococcal vaccination when compared to subjects without these diseases. The observed sex-specific differences demand more research regarding the underlying causes. Strategies to reach higher vaccination coverage in men and women are needed. PMID- 21253811 TI - Strain improvement in actinomycetes in the postgenomic era. AB - With the recent advances in DNA sequencing technologies, it is now feasible to sequence multiple actinomycete genomes rapidly and inexpensively. An important observation that emerged from early Streptomyces genome sequencing projects was that each strain contains genes that encode 20 or more potential secondary metabolites, only a fraction of which are expressed during fermentation. More recently, this observation has been extended to many other actinomycetes with large genomes. The discovery of a wealth of orphan or cryptic secondary metabolite biosynthetic gene clusters has suggested that sequencing large numbers of actinomycete genomes may provide the starting materials for a productive new approach to discover novel secondary metabolites. The key issue for this approach to be successful is to find ways to turn on or turn up the expression of cryptic or poorly expressed pathways to provide material for structure elucidation and biological testing. In this review, I discuss several genetic approaches that are potentially applicable to many actinomycetes for this application. PMID- 21253813 TI - [Austrian patient information materials on PSA-screening do not meet international evidence-based standards]. AB - BACKGROUND: Currently, the available evidence regarding the net benefits of prostate cancer screening with PSA (prostate-specific antigen) tests is unclear. Therefore, international guidelines do not recommend PSA-screening on a regular basis for men. Because of the unclear evidence, guidelines emphasize the importance of shared decision-making. Shared decision-making, however, requires that balanced and evidence-based information is available for those who take PSA screening into consideration. The aim of this paper was to evaluate all in Austria available patient information materials on PSA-screening with regard to their evidence-based content and their potential to facilitate informed decision making. METHODS: To get information materials, we contacted a wide variety of public, industry, and academic institutions, professional organisations, patient advocacy groups, and other organisations that are concerned with prostate cancer screening in Austria. Two persons independently evaluated the quality of each information product based on adapted criteria of the UK (United Kingdom) General Medical Council. RESULTS: We evaluated a total of 17 information leaflets. Not a single brochure fulfilled all of the criteria necessary for informed decision making. More than half fulfilled less than 50% of the recommended criteria. All of the analysed leaflets provided information about the benefits of screening, while only 35% mentioned the possibility of harms caused by screening. CONCLUSIONS: To date, Austrian patient information materials on PSA-screening do not meet international standards. Therefore, they cannot serve as a balanced and objective information base for informed decision-making. PMID- 21253814 TI - [Health complaints of Austrian adolescents - results from the HBSC-survey 1994 to 2006]. AB - BACKGROUND: This article describes changes in health complaints of Austrian adolescents during a period of 12 years. METHODS: The HBSC (Health Behaviour in School-aged Children) symptom checklist assesses how often specific physical and emotional symptoms occurred in the past 6 months. We display data collected in 1994, 1998, 2002 and 2006 for the whole sample (about 4500 students at each time point) as well as separated by age, gender and family affluence. RESULTS: The symptom load in Austrian adolescents decreased in the past 12 years slowly, but continuously. Boys and younger adolescents scored more favourably at all time points. Only in 2006, not at an earlier measurement time point, an impact of family affluence on symptom load could be detected. CONCLUSIONS: With the exception of the socioeconomic impact on symptom load in the year 2006, from an Austrian perspective, these results are favourable. The HBSC-data to be collected in 2010 will show if this trend continues to increase. PMID- 21253815 TI - The role of vasopressin and terlipressin in catecholamine-resistant shock and cardio-circulatory arrest in children: review of the literature. AB - INTRODUCTION: Arginine-vasopressin (AVP) and terlipressin (TP) are used as rescue drugs for states of shock and cardio-circulatory failure. METHODS: Review to assess AVP/TP as a rescue therapy in children with catecholamine-resistant shock or cardio-circulatory arrest. RESULTS: A total of 31 reports were included (428 patients); sixteen articles were case series, 10 case reports, 3 clinical evaluation studies, one study was a non-blind RCT while one study was a multicentre double-blind RCT. The most common indication for either drug was catecholamine-refractory septic shock (12 reports). Commonly reported responses following AVP/TP administration were a rapid increase in blood pressure, an increase in urine output, and a decrease in serum lactate. In most reports, AVP and TP led to the reduction of catecholamines. The cumulative mortality rate remained high (188/428; 43.9%) despite the use of AVP/TP. CONCLUSIONS: No firm recommendations on the use of AVP/TP in children with severe forms of cardio circulatory failure can be issued. PMID- 21253816 TI - [Successful therapy of sacroiliitis in SAPHO syndrome by etanercept]. AB - Painful, aseptic osteitis remains the major problem in the treatment of patients with SAPHO syndrome. We present a child suffering of both sacroiliitis and acne conglobata in the context of SAPHO syndrome. While acne lesions responded well to systemic isotretinoin, sacroiliitis associated pain could be controlled neither by NSAR nor by intralesional or systemic steroid injection. Worse pain limited substantially patient's mobility. This changed immediately after starting etanercept. Within a few days, pain resolved and the patient regained his mobility. This favourable response lasted for 8 months when we tried to stop etanercept under protection with the DMARD sulfazalazin. Unfortunately, within a few days, pain and immobility re-occurred requiring reinstitution of etanercept. This case demonstrates that, similar to other reports, TNF blockade is able to induce prompt and long-lasting response of SAPHO syndrome associated osteoarthritis to TNF blockade. PMID- 21253818 TI - Alternative therapy for breast cancer: outcomes, obstacles and opportunities. PMID- 21253819 TI - Biomechanical forces shape the tumor microenvironment. AB - The importance of the tumor microenvironment in cancer progression is indisputable, yet a key component of the microenvironment--biomechanical forces- remains poorly understood. Tumor growth and progression is paralleled by a host of physical changes in the tumor microenvironment, such as growth-induced solid stresses, increased matrix stiffness, high fluid pressure, and increased interstitial flow. These changes to the biomechanical microenvironment promote tumorigenesis and tumor cell invasion and induce stromal cells--such as fibroblasts, immune cells, and endothelial cells--to change behavior and support cancer progression. This review highlights what we currently know about the biomechanical forces generated in the tumor microenvironment, how they arise, and how these forces can dramatically influence cell behavior, drawing not only upon studies directly related to cancer and tumor cells, but also work in other fields that have shown the effects of these types of mechanical forces vis-a-vis cell behaviors relevant to the tumor microenvironment. By understanding how all of these biomechanical forces can affect tumor cells, stromal cells, and tumor stromal crosstalk, as well as alter how tumor and stromal cells perceive other extracellular signals in the tumor microenvironment, we can develop new approaches for diagnosis, prognosis, and ultimately treatment of cancer. PMID- 21253820 TI - GSK-3beta: a signaling pathway node modulating neural stem cell and endothelial cell interactions. AB - The neurogenic areas of the brain are highly organized structures in which there is dynamic reciprocal modulation of neural stem cells (NSC) and microvascular endothelial cells (BEC) resulting in control of neural stem cell and vascular proliferation, survival and differentiation throughout the life of the individual. Select molecules such as GSK-3beta, functioning as signaling nodes, and their downstream signaling components including HIF-1alpha, HIF-2alpha and beta-catenin participate in regulating and orchestrating the diverse responses involved in this complex process. In this report we demonstrate GSK-3beta's role as a signaling node in two mouse strains (C57BL/6, which have been found to respond to and recover from a hypoxic insult from P3 to P11 poorly and CD-1, which have been found to respond to and recover from a hypoxic insult from P3 to P11 well both in vivo and in vitro) which mimic the wide range of responsiveness to hypoxic insult observed in the very low birth weight premature infant population. Differences in levels of neural stem cell and microvascular endothelial cell GSK-3beta activation, beta-catenin serine phosphorylation, HIF 1alpha and 2alpha, BDNF, SDF-1 and VEGF, beta-III-tubulin and cleaved notch-1 expression in C57BL/6 and CD-1 subventricular zone tissues, and cultured NSC and BEC were noted. Specifically, CD1 pups, SVZ tissues and isolated NSC and BEC exhibit less GSK-3beta and beta-catenin serine phoslphorylation and greater HIF 1alpha and 2alpha, BDNF, SDF-1 and VEGF, beta-III-tubulin and cleaved notch-1 expression compared to C57BL/6. Correlating with these changes were differences of several neural stem cell and microvascular endothelial cell behaviors including proliferation, apoptosis, migration and differentiation with CD1 NSC exhibiting greater proliferation and migration and decreased apoptosis and differentiation and CD1 BEC exhibiting greater angiogenesis. Further, upon treatment with nanomolar concentrations of a GSK-3beta inhibitor (SB412682), C57 NSC and BEC behaviors could be brought to CD1 levels, consistent with the concept of GSK-3beta functioning as a multifunctional signaling pathway node, modulating several behaviors in these cells. Lastly, the therapeutic potential of targeting GSK-3beta is discussed. PMID- 21253821 TI - Preventing children's aggression in immigrant Latino families: a mixed methods evaluation of the Families and Schools Together program. AB - The effectiveness of the evidence based program, Families and Schools Together (FAST), was examined in two inter-related studies with immigrant Latino (Mexican) families in the U.S. In Study 1, we reported findings from pre-test, 3-month post test, and 12-month follow-up surveys of parents and children participating in the FAST program. Families were selected from communities that were randomly assigned to either intervention or control groups. A total of 282 parents (263 mothers and 19 fathers) participated in either the intervention (140 parents) or control (142 parents) condition over the course of 3 years. Each of the parents had a participating focal child; thus, 282 children (144 females and 138 males; average age = 9.5 years) participated in the study. A primary focus of the research was to determine whether participation in FAST led to reductions in children's aggression. Using linear growth models, no differences were noted on aggression between intervention and control groups, although intervention children did show significant improvements in social problem-solving skills and perceptions of collective efficacy. In Study 2, we conducted two focus groups with ten FAST participants to explore whether other unmeasured outcomes were noted and to understand better the mechanisms and impact of FAST. All of the parents in the focus groups reported that FAST had helped them better relate to and communicate with their children, and that the greatest effect was on the behavior of their older children. Results are discussed in terms of cultural fit of the FAST program for immigrant Latino families and future directions. PMID- 21253822 TI - L-Proline nutrition and catabolism in Staphylococcus saprophyticus. AB - Staphylococcus saprophyticus strains ATCC 15305, ATCC 35552, and ATCC 49907 were found to require L-proline but not L-arginine for growth in a defined culture medium. All three strains could utilize L-ornithine as a proline source and contained L-ornithine aminotransferase and Delta(1)-pyrroline-5-carboxylate reductase activities; strains ATCC 35552 and ATCC 49907 could use L-arginine as a proline source and had L-arginase activity. The proline requirement also could be met by L-prolinamide, L-proline methyl ester, and the dipeptides L-alanyl-L proline and L-leucyl-L-proline. The bacteria exhibited L-proline degradative activity as measured by the formation of Delta(1)-pyrroline-5-carboxylate. The specific activity of proline degradation was not affected by addition of L proline or NaCl but was highest in strain ATCC 49907 after growth in Mueller Hinton broth. A membrane fraction from this strain had L-proline dehydrogenase activity as detected both by reaction of Delta(1)-pyrroline-5-carboxylate with 2 aminobenzaldehyde (0.79 nmol min(-1) mg(-1)) and by the proline-dependent reduction of p-iodonitrotetrazolium (20.1 nmol min(-1) mg(-1)). A soluble fraction from this strain had Delta(1)-pyrroline-5-carboxylate dehydrogenase activity (88.8 nmol min(-1) mg(-1)) as determined by the NAD(+)-dependent oxidation of DL-Delta(1)-pyrroline-5-carboxylate. Addition of L-proline to several culture media did not increase the growth rate or final yield of bacteria but did stimulate growth during osmotic stress. When grown with L: -ornithine as the proline source, S. saprophyticus was most susceptible to the proline analogues L-azetidine-2-carboylate, 3,4-dehydro-DL-proline, DL-thiazolidine-2 carboxylate, and L-thiazolidine-4-carboxylate. These results indicate that proline uptake and metabolism may be a potential target of antimicrobial therapy for this organism. PMID- 21253823 TI - Association of bladder cancer risk with an NAD(P)H:quinone oxidoreductase polymorphism in an ethnic Kashmiri population. AB - NQO1 gene polymorphism at nucleotide 609 (Pro187Ser) results in a lowering of NQO1 detoxifying activity and is associated with susceptibility to various cancers. The NQO1 genotypes were identified by RFLP in 104 bladder cancer cases and 120 control subjects in an ethnic Kashmiri population. The frequency of the variant NQO1 alleles (CT/TT) was 23.3% for controls and 32.2% for cases (P < 0.05). Overall, the variant alleles were associated with a higher risk of bladder cancer in cases than in the control group (OR = 1.90; 95% CI 1.17-3.04; P < 0.01). In addition, the variant allele genotypes (CT/TT) were associated with a risk of bladder cancer that was more than threefold higher in smokers (OR = 3.47; 95% CI 1.84-6.3; P < 0.001). Results of this study strongly suggest that the variant allele of NQO1 (Pro187Ser) may affect individual susceptibility to bladder cancer, particularly among smokers, in this ethnic Kashmiri population. PMID- 21253824 TI - Identification and mapping of a novel hydroxysafflor yellow A (HSYA) biosynthetic gene in Carthamus tinctorius. PMID- 21253825 TI - Polymorphism in the prolactin promoter and its association with growth traits in chickens. AB - The pituitary hormone prolactin has a wide variety of functions involving growth, behavioral, and ovarian activities in chickens. The objectives of the present study were to identify polymorphisms in the prolactin promoter and estimate their effects on growth traits in White Leghorn chickens. Among 28 haplotypes found, the h1 haplotype was predominant. Body weight at 16 and 64 weeks and age at sexual maturity were significantly associated with haplotype combinations (P < 0.05). The h1/h1 haplogroup showed the highest body weight at 16 weeks of age, and h1/h7 was the highest at 64 weeks. The lowest age at sexual maturity was found in birds with the h1/h6 haplotype combination, and mRNA expression of prolactin was lowest in h1/h4 birds and highest in h1/h5 birds. The prolactin promoter was highly polymorphic and had significant associations with growth traits in White Leghorn chickens. PMID- 21253826 TI - PTC124 improves readthrough and increases enzymatic activity of the CPT1A R160X nonsense mutation. AB - Deficiency of carnitine palmitoyltransferase 1A (CPT1A) results in impaired hepatic long-chain fatty acid oxidation and ketogenesis. We have previously described a patient with a severe CPT1A phenotype who is homozygous for the nonsense mutation 478 C > T (R160X). It has been known for some time that gentamicin can promote readthrough of nonsense codons. Recently, a new compound (PTC124) with less clinical toxicity than gentamicin has been indicated as a therapy for patients with nonsense mutations for multiple genetic diseases. The study is designed to investigate whether PTC124 can promote readthrough of the R160X CPT1A mutation and increase normal sized CPT1 protein expression and activity in the patient's skin fibroblasts. Our study demonstrated that after both PTC 124 and gentamicin treatment, there was an increase in CPT1 activity in patient fibroblasts to levels that are similar to that of the mild Inuit P479L variant. Our results provide additional evidence for proof of principle that PTC124 is a potential therapeutic agent for treating patients with any genetic condition that results from a nonsense mutation. PMID- 21253827 TI - Growth, final height and endocrine sequelae in a UK population of patients with Hurler syndrome (MPS1H). AB - OBJECTIVE: Hurler Syndrome, (MPSIH) is an inborn error of glycosaminoglycan metabolism. Haematopoietic stem cell transplantation (HSCT) has transformed the prognosis for these children. Prior to transplant patients receive chemotherapy or chemo-radiotherapy. Regular screening for the development of endocrine sequelae is therefore essential. We present for the first time data on final adult height and endocrine complications in children with MPSIH post HSCT. DESIGN: Retrospective case note study and a prospective programme of growth and endocrine assessment. PATIENTS: 22 patients were included, mean age at last assessment 12.2 (Range 6.3-21.6) years. Mean age at HSCT was 1.3 (SD 0.6) years. Conditioning included mostly busulphan and cyclophosphamide, with 5 patients receiving total body irradiation prior to second transplant. RESULTS: Height SDS decreased over time. Final height (FH) was attained in seven patients with male FH SDS -4.3 (Range -3.8, -5.1) and female FH SDS -3.4 (Range -2.9, -5.6). Eight of 13 patients tested had evidence of high growth hormone (GH) levels, while one had GH deficiency. Adrenal and thyroid function was normal in all. 11 patients were pubertal or post pubertal. Two females had pubertal failure requiring intervention. All male patients had spontaneous, complete puberty; however three patients have reduced testicular volumes. Five out of 13 patients tested had an abnormal oral glucose tolerance test. CONCLUSION: Growth is impaired, primarily related to skeletal dysplasia, but also associated with GH resistance. Pubertal development may be compromised and abnormalities of glucose metabolism are common. We recommend a structured endocrine surveillance programme for these patients. PMID- 21253828 TI - Microbial deprivation, inflammation and cancer. AB - Dysregulated immune function is involved in the pathogenesis of many common human diseases. Living in urban, microbe-poor environment may have a profound influence on the immune function and eventually also on carcinogenesis. Unfortunately, few studies have thus far addressed the role of exposure to the environmental microbiota on the risk of cancer. Which mechanisms are broken in individuals prone to develop chronic inflammation in response to exposure that does not cause harm in others? Recent work in immunology has revealed that Th17 cells, a third subset of Th cells, and inflammatory cytokines, particularly IL-23, are closely linked with tumour-associated inflammation. Albeit the precise role of Th17 cells in cancer is still unclear and a matter of debate, accumulating evidence shows that Th17 cells are enriched in a wide range of human tumours, and that these tumour-derived Th17 cells may promote angiogenesis, tumour growth and inflammation. Regulatory T cells, in turn, appear to have counter-regulatory effects on Th17 cells and can inhibit their function. Thus, the regulatory network, induced and strengthened by continuous exposure to environmental microbiota, may play an important role in tumour immunobiology in preventing the establishment of chronic inflammation in its early phases. In addition, the discovery of the Toll-like receptor (TLR) system has brought micro-organisms to new light; continuous signalling via these TLRs and other receptors that sense microbial components is necessary for epithelial cell integrity, tissue repair, and recovery from injury. In this communication, we summarise the epidemiological data of living in environments with diverse microbial exposures and the risk of cancer, and discuss the related immunological mechanisms, focusing on the links between environmental microbiota, the Th17/IL-23 axis and cancer-associated inflammation. PMID- 21253829 TI - Alterations of the retinoblastoma gene in metastatic breast cancer. AB - Germline mutations affecting the retinoblastoma gene (RB1) predispose to inherited retinoblastomas but also other malignancies, including breast cancer. While somatic RB1 mutations have been detected in different malignancies, information about the potential role of RB1 mutations in breast cancer is limited. Recently, we discovered RB1 mutations to be associated with resistance to anthracyclines/mitomycin in primary breast cancer. The present work is the first report evaluating RB1 mutation and epigenetic status in metastatic breast cancer. Among 148 breast cancer samples analyzed by MLPA, four samples harbored intragenic deletions/duplications: Thus, exons 1-2 were deleted in two tumors and exons 21-23 in one tumor, while one sample harbored duplication of exons 18-23. The entire RB1 gene was duplicated in two tumors and multiple amplifications were revealed in one sample. Reduced copy number was observed in 17 samples (11.5%). No point mutation or promoter hypermethylation was discovered (n = 38 and 114 tumors analyzed, respectively). Interestingly, among seven tumors expressing lack of response to epirubicin, two samples harbored alterations in RB1, contrasting none out of 16 tumors with stable disease or an objective response (P = 0.08). In summary, the frequency of RB1 alterations in metastatic lesions was not increased when compared to primary breast cancer, indicating that RB1 alterations do not play a major role in metastatic development. While a non-significant association suggesting RB1 alterations to be linked to therapy resistance was observed, our data do not suggest a major role for RB1 alterations explaining acquired drug resistance. PMID- 21253830 TI - Barriers to, and strategies for, starting a long acting injection clinic in a community mental health center. AB - As many as 50% of patients with schizophrenia do not take oral antipsychotic medications as prescribed, yet long acting injections are rarely utilized. Community agencies that serve this population are often over-burdened and poorly funded. There are negative attitudes on the part of both physicians and consumers about injections. Transportation and logistics are often problematic. We describe the unique opportunity provided by the need for bi-weekly or monthly injections to establish a recovery-oriented group around injection visits. Our approach discusses methods and resources to help overcome some of the common barriers by establishing advocates within the agency, establishing necessary infrastructure, providing education for consumers, providers, and staff, sharing information about successful outcomes with clinic staff and working through billing issues. We also recommend public advocacy on the part of the clinic and consumers to work with state funding sources to change regulations that may limit appropriate clinical care. PMID- 21253831 TI - In vitro genotoxicity of rocuronium bromide in human peripheral lymphocytes. AB - Rocuronium bromide (RB), an aminosteroid type neuromuscular blocking agent, acts by reducing or inhibiting the depolarising effect of acetylcholine on the terminal disc of the muscle cell. To our knowledge, there is no adequate information on the genotoxic effects of RB, up to now. In the present study, possible genotoxic effects of RB have been determined by means of sister chromatid exchange (SCE), chromosome aberration (CA) and micronucleus (MN) analyses in human peripheral blood lymphocytes. The human peripheral blood lymphocytes were exposed to three different concentrations of RB (60, 80 and 100 MUg/mL) for 24- and 48-h. In this study, RB increased the frequency of CAs, however, did not increase the frequency of SCEs. RB did not decrease the proliferation index (PI) and mitotic index (MI). Accordingly, RB increased the frequency of micronucleus (MN) but did not decrease the nuclear division index (NDI). Findings from this study suggest that rocuronium bromide is clastogenic but not cytotoxic to cultured human peripheral blood lymphocytes. PMID- 21253832 TI - Getting to the core of the women's curriculum--it's time to change the way we train our fellows. PMID- 21253833 TI - Colloid carcinoma of the pancreas. PMID- 21253835 TI - Evidence for enhanced cytoprotective function of HSP90-overexpressing small intestinal epithelial cells. AB - BACKGROUND: In the clinical field, increasing incidence of small intestinal ulcers associated with nonsteroidal anti-inflammatory drugs (NSAIDs) has become a topic with the advances of capsule endoscopy and balloon enteroscopy technology for the detection of small intestinal lesions. However, the pathogenesis of NSAID induced mucosal damage, defensive mechanism of intestinal epithelial cells, and therapy for small intestinal mucosal lesion have not been fully understood. Heat shock proteins (HSPs) are involved in cytoprotection mediated by their function as a molecular chaperone. Since the function of HSP90 in the intestinal epithelial cells has not been well investigated, we examined the cytoprotective ability of HSP90-overexpressing small intestinal epithelial cells against hydrogen peroxide-induced or indomethacin-induced cell damage. METHODS: cDNA of human HSP90 gene was transfected to rat small intestinal epithelial cells (IEC-6 cells), and HSP90-overexpressing cells (IEC-6-90 cells) were selected and cloned. Anti-necrotic abilities and anti-apoptotic abilities of IEC-6-90 cells were compared with IEC-6-mock cells (transfected with vector alone). To examine the specific contribution of HSP90 on cytoprotection of IEC-6-90 cells, cytoprotective ability of IEC-6-90 cells was analyzed with or without pretreatment with functional inhibitor of HSP90, geldanamycine analog, followed by hydrogen peroxide-challenge or indomethacin-challenge. RESULTS: Hydrogen peroxide-induced or indomethacin-induced cell necrosis and apoptosis were significantly suppressed in IEC-6-90 cells. The cytoprotective ability of IEC-6 90 cells was suppressed by HSP90 inhibitor. CONCLUSIONS: Our results suggest that HSP90 might play an important role in protecting small intestinal epithelial cells from hydrogen peroxide-induced or indomethacin-induced cell injury in vitro, and raised the possibility of protection of small intestinal epithelial cells by manipulation of HSP90 expression. PMID- 21253834 TI - Add-on adefovir is superior to a switch to entecavir as rescue therapy for Lamivudine-resistant chronic hepatitis B. AB - BACKGROUND/AIMS: Lamivudine (LAM) has been extensively used to treat hepatitis B, but high incidence of drug resistance has required rescue studies. We validated the optimum treatment strategy for LAM-resistant patients by means of a comparative study of add-on adefovir (ADV) and a switch to entecavir (ETV). METHODS: We assessed the virologic response in consecutive LAM-resistant patients who received add-on ADV or a switch to ETV. RESULTS: The mean reduction of serum hepatitis B virus (HBV) DNA levels was significantly less in the ETV group than in the add-on ADV group (-3.45 vs. -4.17; P = 0.047 at week 24 and -3.81 vs. 4.68 log(10) IU/mL; P = 0.044 at week 48). Achievement of undetectable HBV DNA was significantly lower in the ETV group than in the add-on ADV group (P = 0.043). Multivariate analysis showed that add-on ADV, baseline HBV DNA levels, and initial virologic response were significant predictors of HBV DNA negativity (adjusted OR, 2.582; P = 0.008, 0.304; P = 0.001, and 5.928; P = 0.001). Virologic breakthrough was observed for 12 patients, in the ETV group only. CONCLUSIONS: Add-on ADV was more effective and durable than ETV as rescue therapy. Therefore, add-on ADV might be the preferred strategy for LAM-resistant patients who need long-term antiviral treatment. PMID- 21253836 TI - Impact of a perfluorinated organic compound PFOS on the terrestrial pollinator Bombus terrestris (Insecta, Hymenoptera). AB - Perfluorinated organic chemicals like perfluorooctane sulfonic acid (PFOS) are persistent environmental pollutants that have been measured in a great diversity of wildlife worldwide, especially in the aquatic compartment. However, little information is available on the presence and effects of PFOS in the terrestrial compartment. Therefore, we investigated in this project the risks for effects, bioaccumulation and potential mechanisms of activity of PFOS in the bumblebee Bombus terrestris L. (Hymenoptera: Apidae) that is an important worldwide pollinator in the terrestrial compartment of wildflowers and cultivated crops. The exposure to PFOS occurred orally via the drinking of treated sugar water in a wide range from 1 MUg/l up to 10 mg/l, containing environmentally relevant as well as high concentrations, and this was done with use of microcolonies of B. terrestris in the laboratory. A chronic toxicity assay demonstrated high bumblebee worker mortality (up to 100%) with an LC(50) of 1.01 mg/l (R(2) = 0.98). In addition, PFOS posed strong detrimental reproductive effects, and these concerted with a dramatic reduction in ovarian size. HPLC-MS demonstrated a bioaccumulation factor of 27.9 for PFOS in bumblebee workers fed with sugar water containing 100 MUg/l PFOS during 5 weeks (2184 +/- 365 ng/g BW). Finally, potential mechanisms of activity were investigated to explain the significant impact of PFOS on survival and reproduction capacity of B. terrestris. Exposure of bumblebee workers to PFOS resulted in a significant decrease in mitochondrial electron transport activity (p = 0.035) and lipid amounts (p = 0.019), while the respective p-values were 0.58 and 0.12 for protein and glucose amounts. Hence, addition of PFOS to ecdysteroid responsive Drosophila melanogaster S2 cells resulted in a strong antagonistic action on the EcR-b.act.luc reporter construct, demonstrating that PFOS may exert its effects partially through an endocrine disrupting action via the insect molting hormone or ecdysteroid receptor. PMID- 21253837 TI - Biodegradation of malachite green by Pseudomonas sp. strain DY1 under aerobic condition: characteristics, degradation products, enzyme analysis and phytotoxicity. AB - Malachite green (MG), a widely-used and recalcitrant dye, has been confirmed to be carcinogenic and mutagenic against many organisms. The main objective of this study is to investigate the capability of Pseudomonas sp. strain DY1 to decolorize MG, and to explore the possible mechanism. The results showed that this strain demonstrated high decolorizing capability (90.3-97.2%) at high concentrations of MG (100-1,000 mg/l) under shaking condition within 24 h. In static conditions, lower but still effective decolorization (78.9-84.3%) was achieved. The optimal pH and temperature for the decolorization was pH 6.6 and 28 30 degrees C, respectively. Mg(2+) and Mn(2+) (1 mM) were observed to significantly enhance the decolorization. The intermediates of the MG degradation under aerobic condition identified by UV-visible, GC-MS and LC-MS analysis included malachite green carbinol, (dimethyl amino-phenyl)-phenyl-methanone, N,N dimethylaniline, (methyl amino-phenyl)-phenyl-methanone, (amino phenyl)-phenyl methanone and di-benzyl methane. The enzyme analysis indicated that Mn peroxidase, NADH-DCIP and MG reductase were involved in the biodegradation of MG. Moreover, phytotoxicity of MG and detoxification for MG by the strain were observed. Therefore, this strain could be potentially used for bioremediation of MG. PMID- 21253838 TI - Application of physiologically based modelling and transcriptomics to probe the systems toxicology of aldicarb for Caenorhabditis elegans (Maupas 1900). AB - The toxicity of aldicarb on movement, life cycle, population growth rate and resource allocation, and the gene expression changes underpinning these effects, were investigated for Caenorhabditis elegans. A clear effect of aldicarb on nematode movement was found suggesting that this pesticide acts as a neurotoxicant. Aldicarb also had an effect on life cycle traits including low concentration life-span extension; high concentration brood size reduction and a high concentration extension of time to first egg. All life-cycle and growth data were integrated into a biology-based model (DEBtox) to characterise aldicarb effects on life-history traits, resource allocation and population growth rate within a single modelling framework. The DEBtox fits described concentration dependent effects on individual traits and population growth rate and indicated that the most probable mechanism of action of the pesticide was an increase in energy demands for somatic and reproductive tissue maintenance. Transcriptomic profiling indicated that aldicarb was associated with changes in amino acid metabolism, DNA structure, fatty acid metabolism and cytochrome P450 mediated xenobiotic metabolism. The changes in the amino acid and fatty acid pathways suggest an effect of aldicarb on protein integrity; while effects on DNA suggests that aldicarb influence DNA morphology or replication. Both these effects have the potential to incur increased costs for structural maintenance of macromolecules. These effects, coupled to the effect on biotransformation enzymes also seen, represent the materialisation of the maintenance costs indicated by DEBtox modelling. PMID- 21253839 TI - Mature care and nursing in psychiatry: notions regarding reciprocity in asymmetric professional relationships. AB - The idea behind this article is to discuss the importance and to develop the concept of reciprocity in asymmetric professional relationships. As an empirical starting point for an examination of the possible forms of reciprocity between patients and nurses in psychiatry, we chose two qualitative in-depth interviews with two different patients. The manners in which these two patients relate to medical personnel--one is dependent, the other is independent--show that this presents challenges to nurses. The theoretical context is provided by the notion of mature care as it has been developed by feminist-oriented ethics of care, in contrast to the notion of altruistic care. In relation to the concept of mature care, we discuss how nursing can be perceived in demanding relationships with patients in psychiatry. Reciprocity implies that, in principle, the interests of the nurses also matter in a nurse-patient relationship. We show that reciprocity- in practice--is complicated and challenging in a number of different ways. Mature care--with its systematic inclusion of relationships and reciprocity--provides an alternative understanding of what takes place between patients and nurses compared with an altruistic notion of care. As such, mature care can be regarded as an useful paradigm for nurse-patient relationships in psychiatry. PMID- 21253840 TI - CARTO-guided vs. NavX-guided pulmonary vein antrum isolation and pulmonary vein antrum isolation performed without 3-D mapping: effect of the 3-D mapping system on procedure duration and fluoroscopy time. AB - PURPOSE: Pulmonary vein antrum isolation (PVAI) guided by intracardiac echocardiography and a roaming circular mapping catheter is an effective treatment modality for atrial fibrillation. Unfortunately, the complexity of this technique leads to long procedure times and high fluoroscopy exposure. This study examined the effect of two different mapping systems on the procedural characteristics and clinical outcomes of PVAI for atrial fibrillation. METHODS: Referred patients underwent PVAI using a magnetic-based 3-dimensional (3-D) mapping (CARTO(r) System; group 1), a current-based system (EnSite NavXTM; group 2), or fluoroscopy without 3-D mapping (group 3) between February 2004 and November 2009. RESULTS: Data were analyzed from 71 patients in group 1, 165 patients in group 2, and 197 patients in group 3. Baseline characteristics and measured long-term outcomes did not differ between the groups. Although patients in group 1 were more likely to undergo a concurrent flutter ablation (P = 0.01), they had significantly shorter procedure time, fluoroscopy time, and radiofrequency energy delivery time compared with group 2 and 3 patients. No difference was detected among the groups with respect to recurrence, mean time to recurrence, or number of PVAI procedures. CONCLUSIONS: Use of a magnetic-based 3 D mapping system, which allows precise spatial localization of the ablation catheter, was associated with significantly lower procedure time, fluoroscopy duration, and radiofrequency energy delivery time during catheter ablation for atrial fibrillation compared with a current-based system and ablation performed without 3-D mapping, although measured short- and long-term clinical outcomes were similar. PMID- 21253841 TI - Catheter ablation of persistent atrial fibrillation: anatomically based circumferential pulmonary vein ablation in combination with a potential-guided segmental approach to achieve complete pulmonary vein isolation. AB - BACKGROUND: Catheter ablation has become the first line of therapy in patients with symptomatic, recurrent, drug-refractory atrial fibrillation. However, catheter ablation of persistent atrial fibrillation is still a challenge. Various rather complex ablation strategies exist and their results are not very favorable. Therefore, the aim of our study was to evaluate a well-defined reasonable approach to catheter ablation of persistent atrial fibrillation. The strategy consisted of a circumferential pulmonary vein ablation in combination with a potential-guided segmental approach to achieve complete pulmonary vein isolation and a linear lesion at the roof of the left atrium. METHODS: A total of 43 patients (30 men, 13 women; mean age 55 years (SD +/- 9 years)) with symptomatic persistent atrial fibrillation were enrolled in this study. All patients underwent catheter ablation of persistent atrial fibrillation using the above-mentioned approach (with the CARTO or the NAVX system). Additionally, catheter ablation of the mitral isthmus and the right atrial isthmus was performed in selected cases. In all patients, cardiac MRI or multi-detector spiral computed tomography was performed prior to the ablation procedure and a surface rendered model of the left atrium was created. After discharge, patients were scheduled for repeated visits at the arrhythmia clinic at 1, 3, 6, 9, and 12 months after the ablation procedure. RESULTS: The ablation procedure could be performed as planned in all 43 patients. Nine patients had to undergo a repeat ablation procedure, so that a total of 52 procedures were evaluated. An additional linear lesion was created at the mitral isthmus in three patients (7%) during the initial procedure and in one patient (2.3%) during the second procedure. Catheter ablation of the right atrial isthmus was performed in 11 patients (25.6%) during the first procedure and in four additional patients during the redo procedure (9.3%). Twenty-four out of 43 patients (55.8%) experienced an arrhythmia recurrence within the first 3 months after ablation requiring an electrical cardioversion. At 1-year follow-up, analysis of a 7-day Holter monitoring revealed no evidence for an arrhythmia recurrence in 26 of 43 patients (60.5%). In nine of 43 patients (20.9%), only short episodes of paroxysmal atrial fibrillation were documented. In eight patients (18.6%), a recurrence of persistent atrial fibrillation (>48 h) was revealed by the long term recordings. A duration of persistent atrial fibrillation >3 months was the most powerful predictor for arrhythmia recurrences at 1-year follow-up. A subgroup analysis revealed a markedly higher rate of stable sinus rhythm at 1 year follow-up in patients with a short duration of atrial fibrillation (<= 3 months) compared to patients with a longer duration of AF (>3 months) prior to the procedure (72.0% versus 44.4%). There were no major complications. CONCLUSIONS: Catheter ablation of persistent atrial fibrillation can be performed safely and effectively using this ablation strategy (especially in patients with short-lasting persistent atrial fibrillation (<= 3 months)). PMID- 21253842 TI - Kinetic analysis of protein aggregation monitored by real-time 2D solid-state NMR spectroscopy. AB - It is shown that real-time 2D solid-state NMR can be used to obtain kinetic and structural information about the process of protein aggregation. In addition to the incorporation of kinetic information involving intermediate states, this approach can offer atom-specific resolution for all detectable species. The analysis was carried out using experimental data obtained during aggregation of the 10.4 kDa Crh protein, which has been shown to involve a partially unfolded intermediate state prior to aggregation. Based on a single real-time 2D (13)C (13)C transition spectrum, kinetic information about the refolding and aggregation step could be extracted. In addition, structural rearrangements associated with refolding are estimated and several different aggregation scenarios were compared to the experimental data. PMID- 21253843 TI - Ecto-phosphatases in protozoan parasites: possible roles in nutrition, growth and ROS sensing. AB - The cellular plasma membrane contains enzymes whose active sites face the external medium rather than the cytoplasm. The activities of these enzymes, referred to as ecto-enzymes, can be measured using living cells. Ecto phosphatases are ecto-enzymes that presumably hydrolyze extracellular phosphorylated substrates, releasing free inorganic phosphate. Although, several alternative functions have been suggested for these enzymes, such as participation in proliferation, differentiation, adhesion, virulence, and infection, little is known about the physiological roles of these enzymes in protozoa parasites. In this review, we discuss the principal features of ecto phosphatases in protozoan parasites that are causative agents of important diseases such as Chagas' disease, leishmaniasis, amoebiasis, giardiasis, trichomoniasis and, sleeping sickness. PMID- 21253844 TI - Differential expression of uncoupling mitochondrial protein and alternative oxidase in the plant response to stress. AB - Different cell types, organs and tissues shape their mitochondrial proteome according to the cellular environment that is dictated by differentiation, development and metabolic status. Under each circumstance, members of multigenic families that encode mitochondrial proteins are differentially expressed to meet the mitochondrial metabolic demand. However, the mitochondrial proteome may drastically change in response to stress conditions. Examples of the changes in mitochondrial protein expression caused by stress are represented by the energy dissipating mitochondrial uncoupling protein (UCP) and alternative oxidase (AOx). UCP and AOx belong to multigenic families in plants, and their members, which are expressed in a time/tissue specific manner, respond differentially to stress conditions. In general, UCP and AOx are not expressed at the same levels concurrently in the same tissue, and the level of each protein varies in each stress condition. In addition, under non-stress conditions, UCP is expressed at much higher levels compared with AOx. The role of their differential expression in plant growth, development and response to stress is discussed. PMID- 21253845 TI - Solvent effect on absorption and fluorescence spectra of three biologically active carboxamides (C1, C2 and C3). Estimation of ground and excited state dipole moment from solvatochromic method using solvent polarity parameters. AB - The absorption and fluorescence spectra of three Carboxamides namely (E)-2-(4 Chlorobenzylideneamino)-N-(2-chlorophenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3 carboxamide (C(1)), (E)-N-(3-Chlorophenyl)-2-(3, 4-dimethoxybenzylideneamino) 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (C(2)) and (E)-N-(3 Chlorophenyl)-2-(3,4,5-trimethoxybenzylideneamino)-4,5,6,7 tetrahydrobenzo[b]thiophene-3-carboxamide (C(3)) have been recorded at room temperature in solvents of different polarities using dielectric constant (epsilon) and refractive index (n). Experimental ground (MU(g)) and excited (MU(e)) state dipole moments are estimated by means of solvatochromic shift method and also the excited dipole moments are estimated in combination with ground state dipole moments. It was estimated that dipole moments of the excited state were higher than those of the ground state of all three molecules. Further, the changes in dipole moment (DeltaMU) were calculated both from solvatochromic shift method and on the basis of microscopic empirical solvent polarity parameter (E(N)(T)) and the values are compared. PMID- 21253846 TI - Executive function in pathological gamblers and healthy controls. AB - Executive function (EF) deficits may underlie some of the impulse control problems seen in pathological gambling. Pathological gamblers (PGs, n = 45) and controls (n = 45) were compared on several measures of EF (including measures of response inhibition, working memory, cognitive flexibility and perseveration, planning and decision-making), as well as memory and intelligence tests to examine whether PGs evidence EF dysfunction. Compared with controls, PGs exhibited specific deficits on measures of planning and decision-making. PGs also exhibited relative deficits on a measure of perseveration, but this deficit was no longer significant after controlling for group differences in intelligence. These results suggest that PGs may experience deficits on specific components of EF. PMID- 21253847 TI - Sailing against the tide? Sustaining sexual abstinence among Christian youth in a university setting in South Africa. AB - This qualitative study sought to understand the perceptions and experiences of abstinence among young Christians in a University in South Africa. Willingness to adhere to Christian teachings of sexual chastity is the primary motivation for sexual abstinence while spiritual, mental and physical health benefits of abstinence as well as enforcement of Christian teachings by members and peers are secondary motivations that help sustain sexual abstinence. Sexual pressures come from desire to satisfy sexual urge, subtle coercion, peer pressure, momentary loss of self-control. There is need for multi-pronged interventions aimed at empowering Christian youth to deal with sources of sexual pressures. PMID- 21253848 TI - 'There is a time to be born and a time to die' (Ecclesiastes 3:2a): Jewish perspectives on euthanasia. AB - Reviewing the publications of prominent American rabbis who have (extensively) published on Jewish biomedical ethics, this article highlights Orthodox, Conservative and Reform opinions on a most pressing contemporary bioethical issue: euthanasia. Reviewing their opinions against the background of the halachic character of Jewish (biomedical) ethics, this article shows how from one traditional Jewish textual source diverse, even contradictory, opinions emerge through different interpretations. In this way, in the Jewish debate on euthanasia the specific methodology of Jewish (bio)ethical reasoning comes forward as well as a diversity of opinion within Judaism and its branches. PMID- 21253852 TI - Effect of castration on carcass quality and differential gene expression of longissimus muscle between steer and bull. AB - The effect of castration on carcass quality was investigated by ten Chinese Simmental calves. Five calves were castrated randomly at 2 months old and the others were retained as normal intact bulls. All animals were slaughtered at 22 months old. The results showed that bulls carcass had higher weight (P < 0.05), dressing percentages and bigger longissimus muscle areas (P < 0.05) than steers. But steer meat had lower shear force values and was fatter (P < 0.05) than bull. Furthermore, in order to discover genes that were involved in determining steer meat quality, we compared related candidate gene expression in longissimus muscle between steer (tester) and bull (driver) using suppressive subtractive hybridization. Ten genes were identified as preferentially expressed in longissimus muscle of steer. The expression of four selected differentially expressed genes was confirmed by quantitative real-time PCR. Overall, a 1.96, 2.41, 2.89, 2.41-fold increase in expression level was observed in steer compared with bull for actin, gamma 2, smooth muscle, tropomyosin-2, insulin like growth factor 1 and hormone-sensitive lipase, respectively. These results implied that these differentially expressed genes could play an important role in the regulation of steer meat quality. PMID- 21253851 TI - Deletion mutational analysis of BMRP, a pro-apoptotic protein that binds to Bcl 2. AB - Bcl-2 is an anti-apoptotic member of the Bcl-2 family of proteins that protects cells from apoptosis induced by a large variety of stimuli. The protein BMRP (MRPL41) was identified as a Bcl-2 binding partner and shown to have pro apoptotic activity. We have performed deletion mutational analyses to identify the domain(s) of Bcl-2 and BMRP that are involved in the Bcl-2/BMRP interaction, and the region(s) of BMRP that mediate its pro-apoptotic activity. The results of these studies indicate that both the BH4 domain of Bcl-2 and its central region encompassing its BH1, BH2, and BH3 domains are required for its interaction with BMRP. The loop region and the transmembrane domain of Bcl-2 were found to be dispensable for this interaction. The Bcl-2 deletion mutants that do not interact with BMRP were previously shown to be functionally inactive. Deletion analyses of the BMRP protein delimited the region of BMRP needed for its interaction with Bcl 2 to the amino-terminal two-thirds of the protein (amino acid residues 1-92). Further deletions at either end of the BMRP(1-92) truncated protein resulted in lack of binding to Bcl-2. Functional studies performed with BMRP deletion mutants suggest that the cell death-inducing domains of the protein reside mainly within its amino-terminal two-thirds. The region of BMRP required for the interaction with Bcl-2 is very relevant for the cell death-inducing activity of the protein, suggesting that one possible mechanism by which BMRP induces cell death is by binding to and blocking the anti-apoptotic activity of Bcl-2. PMID- 21253853 TI - Environmental isolation of Cryptococcus gattii serotype B, VGI/MATalpha strains in southern Italy. AB - Until recently, Cryptococcus gattii was believed to be endemic in tropical and subtropical regions. To date, it has unexpectedly emerged as primary pathogen in temperate climate indicating that it has evolved and adapted to new environmental conditions including those existing in the Mediterranean area. Earlier attempts to isolate C. gattii from our environment were unsuccessful but this time, 18 years after the last environmental screening for C. neoformans, we isolated C. gattii from Eucalyptus camaldulensis in Reggio Calabria, Italy. The strains were serotype B, mating type alpha and were assigned to the molecular type VGI. In this study, we reported the first real environmental isolation of C. gattii in southern Italy that emphasized the observed global expansion of this yeast. PMID- 21253855 TI - Chronic stress and lithium treatments alter hippocampal glutamate uptake and release in the rat and potentiate necrotic cellular death after oxygen and glucose deprivation. AB - This study was undertaken to evaluate the effects of chronic variate stress and lithium treatment on glutamatergic activity and neuronal vulnerability of rat hippocampus. Male Wistar rats were simultaneously treated with lithium and submitted to a chronic variate stress protocol during 40 days, and afterwards the hippocampal glutamatergic uptake and release, measured in slices and synaptosomes, were evaluated. We observed an increased synaptosomal [(3)H]glutamate uptake and an increase in [(3)H]glutamate stimulated release in hippocampus of lithium-treated rats. Chronic stress increased basal [(3)H]glutamate release by synaptosomes, and decreased [(3)H]glutamate uptake in hippocampal slices. When evaluating cellular vulnerability, both stress and lithium increased cellular death after oxygen and glucose deprivation (OGD). We suggest that the manipulation of glutamatergic activity induced by stress may be in part responsible for the neuroendangerment observed after stress exposure, and that, in spite of the described neuroprotective effects of lithium, it increased the neuronal vulnerability after OGD. PMID- 21253854 TI - Regulation of cortical neuron migration by the Reelin signaling pathway. AB - Reeler is a mutant mouse with defects in layered structures of the central nervous system, such as the cerebral cortex, hippocampus, and cerebellum, and has been extensively examined for more than half a century. The full-length cDNA for the responsible gene for reeler, reelin, was serendipitously identified, revealing that Reelin encodes a large secreted protein. So far, two Reelin receptors, apolipoprotein E receptor 2 and very low-density lipoprotein receptor, and the cytoplasmic adaptor protein Disabled homolog 1 (Dab1) have been shown to be essential for Reelin signaling. Although a number of downstream cascades of Dab1 have also been reported using various experimental systems, the physiological functions of Reelin in vivo remain controversial. Here, we review recent advances in the understanding of the Reelin-Dab1 signaling pathway in the developing cerebral cortex. PMID- 21253856 TI - Lipid composition of whole brain and cerebellum in Hurler syndrome (MPS IH) mice. AB - Hurler syndrome (MPS IH) is caused by a mutation in the gene encoding alpha-L iduronidase (IDUA) and leads to the accumulation of partially degraded glycosaminoglycans (GAGs). Ganglioside content is known to increase secondary to GAG accumulation. Most studies in organisms with MPS IH have focused on changes in gangliosides GM3 and GM2, without the study of other lipids. We evaluated the total lipid distribution in the whole brain and cerebellum of MPS IH (Idua-/-) and control (Idua(+/?)) mice at 6 months and at 12 months of age. The content of total sialic acid and levels of gangliosides GM3, GM2, and GD3 were greater in the whole brains of Idua-/- mice then in Idua (+/?) mice at 12 months of age. No other significant lipid differences were found in either whole brain or in cerebellum at either age. The accumulation of ganglioside GD3 suggests that neurodegeneration occurs in the Idua-/-) mouse brain, but not to the extent seen in human MPS IH brain. PMID- 21253857 TI - Evaluation of osteoclastogenesis via NFkappaB decoy/mannosylated cationic liposome-mediated inhibition of pro-inflammatory cytokine production from primary cultured macrophages. AB - PURPOSE: To explore the effect of NFkappaB activation in macrophages on osteoclastogenesis of bone marrow cells for potential application as a new type of therapy for preventing bone loss. METHODS: Primary cultured macrophages and bone marrow cells were prepared from mice. As macrophage-targeted carriers, Mannosylated cationic liposomes (Man-liposomes) were prepared and were allowed to form complexes with NFkappaB decoy (a double-stranded oligonucleotide). Cellular uptake, inhibition of NFkappaB activation, and cytokine production were evaluated using macrophages. Osteoclastogenesis was investigated using bone marrow cells, which were cultured in the conditioned medium prepared from macrophages with or without Man-liposome/NFkappaB decoy complexes treatment. RESULTS: Cellular accumulation of NFkappaB decoy was enhanced by Man-liposome. NFkappaB activation in macrophages and TNF-alpha production were suppressed in macrophages by Man liposome/NFkappaB decoy complexes but not by the naked NFkappaB decoy, Gal liposome/NFkappaB decoy complexes, or Man-liposome/random decoy complexes. Osteoclastogenesis of bone marrow cells was induced in the conditioned medium prepared from activated macrophages but not by activated macrophages treated with Man-liposome/NFkappaB decoy complexes. CONCLUSION: Osteoclastogenesis induced by activated macrophages could be suppressed by the treatment macrophages with Man liposome/NFkappaB decoy complexes. Macrophage-targeted delivery of NFkappaB decoys using Man-liposomes may be promising in its use for the remediation of bone loss. PMID- 21253858 TI - Acclimation to low or limiting CO2 in non-synchronous Chlamydomonas causes a transient synchronization of the cell division cycle. AB - Acclimation of Chlamydomonas reinhardtii (hereafter, Chlamydomonas) to low or limiting CO(2) or inorganic carbon (C(i)) has been studied fairly extensively with regard to the mechanisms underlying the inducible C(i) acquisition systems and the signal transduction pathway involved in recognizing and responding to decreased C(i) availability. Investigation of low C(i )acclimation responses typically is performed with non-synchronous cultures grown in continuous light to avoid any effects of the cell division cycle (CDC) confounding interpretation of acclimation responses. However, little is known about whether acclimation to low C(i) might affect the distribution of cells among the various stages of the CDC. To investigate the effects of a limiting-C(i) challenge on the CDC of Chlamydomonas, flow cytometry was used to monitor the distribution of cells among the CDC stages in both synchronous and non-synchronous cultures during acclimation to low or limiting C(i). When faced with C(i) limitation, non synchronous cultures of Chlamydomonas undergo transient synchronization as those cells past the Commitment point of the CDC undergo division, while the remainder of the cells pause their growth in early G-phase, with the result that the cells all accumulate in early G-phase, appearing transiently synchronized until acclimated sufficiently to the decreased C(i) for growth to resume. This perturbation of the CDC by a limiting-C(i) challenge has important implications for the interpretation of gene expression and other responses apparently induced by low or limiting C(i). PMID- 21253859 TI - Synthesis of oligomethylene-strapped chlorophyll derivatives and optical properties of their stereoisomers in a solution. AB - Methyl pheophorbide-a/a' derivatives covalently linked with oligomethylene chains at the 3-CH(2)OCO- and 13(2)-COO- moieties in a molecule were prepared by modifying chlorophyll-a through intramolecular ring-closing metathesis of vinyl groups. At least, a C10-length between the 3(3)- and 13(4)-positions was necessary for the cyclization and connection of a C12-strap was the most suitable to achieve the highest closure yield. The oligomethylene chain in 13(2) R-epimers derived from methyl pheophorbide-a covered the alpha-face of the chlorin pi-plane and the strap in the corresponding 13(2) S-epimers protected the beta-face. Synthetic 13(2) R-epimer with a dodecamethylene chain gave a flat chlorin pi plane, while the decamethylene chain in the 13(2) R-epimer distorted the pi system due to its shorter linkage. The distortion by strapping in the 13(2) R epimer induced a slight blue-shift of Qy peak in dichloromethane. CD spectra of the 13(2) R-epimers were similarly dependent on the chain length, i.e., the distortion of pi-plane. Visible absorption and CD spectra of all the strapped 13(2) S-epimers were almost identical and only slightly different from those of the unstrapped. The strapping in the 13(2) S-epimers shifted the Qy peak bathochromically. PMID- 21253860 TI - Photosynthetic characteristics of a multicellular green alga Volvox carteri in response to external CO2 levels possibly regulated by CCM1/CIA5 ortholog. AB - When CO(2) supply is limited, aquatic photosynthetic organisms induce a CO(2) concentrating mechanism (CCM) and acclimate to the CO(2)-limiting environment. Although the CCM is well studied in unicellular green algae such as Chlamydomonas reinhardtii, physiological aspects of the CCM and its associated genes in multicellular algae are poorly understood. In this study, by measuring photosynthetic affinity for CO(2), we present physiological data in support of a CCM in a multicellular green alga, Volvox carteri. The low-CO(2)-grown Volvox cells showed much higher affinity for inorganic carbon compared with high-CO(2) grown cells. Addition of ethoxyzolamide, a membrane-permeable carbonic anhydrase inhibitor, to the culture remarkably reduced the photosynthetic affinity of low CO(2) grown Volvox cells, indicating that an intracellular carbonic anhydrase contributed to the Volvox CCM. We also isolated a gene encoding a protein orthologous to CCM1/CIA5, a master regulator of the CCM in Chlamydomonas, from Volvox carteri. Volvox CCM1 encoded a protein with 701 amino acid residues showing 51.1% sequence identity with Chlamydomonas CCM1. Comparison of Volvox and Chlamydomonas CCM1 revealed a highly conserved N-terminal region containing zinc binding amino acid residues, putative nuclear localization and export signals, and a C-terminal region containing a putative LXXLL protein-protein interaction motif. Based on these results, we discuss the physiological and genetic aspects of the CCM in Chlamydomonas and Volvox. PMID- 21253861 TI - Transcript levels of CHL P gene, antioxidants and chlorophylls contents in olive (Olea europaea L.) pericarps: a comparative study on eleven olive cultivars harvested in two ripening stages. AB - The effects of ripening stage on the antioxidant content in olive pericarps were evaluated in eleven olive genotypes grown in the same bioagronomic conditions in Southern Italy. We examined the transcript levels of geranylgeranyl reductase (CHL P) gene and the content of tocopherols, phenolic compounds and chlorophylls in the pericarps. The examined genotypes showed an increase of CHL P transcripts during pericarps ripening. Significant differences were reported in the antioxidant proportions in the same cultivars at different pericarp ripening stage. We show an inverse correlation between phenols and tocopherols content. In particular, during the ripening phase, tocopherols increased rapidly in olive pericarps while phenolic compounds and chlorophyll levels declined significantly. The significant amounts of these antioxidants confirm the nutritional and medicinal value of olive drupes and its products (table olives and olive oil). We suggest, for the first time, a link between CHL P transcript levels and tocopherols content during the ripening of olive pericarps. Besides, we revealed that this trend of CHL P transcript levels during pericarps ripening is independent from the olive genotypes. PMID- 21253864 TI - At a glance: Proteomics in China. PMID- 21253862 TI - Comparison of two H1N2 swine influenza A viruses from disease outbreaks in pigs in Sweden during 2009 and 2010. AB - The influenza A virus subtypes H1N1, H1N2 and H3N2 are prevalent in pig populations worldwide. In the present study, two relatively uncommon swine influenza virus (SIV) H1N2 subtypes, isolated in Sweden in 2009 and 2010, were compared regarding their molecular composition and biological characteristics. The differences regarding markers purportedly related to pathogenicity, host adaptation or replication efficiency. They included a truncated PB1-F2 protein in the earlier isolate but a full length version in the more recent one; differences in the number of haemagglutinin glycosylation sites, including a characteristic human one; and a nuclear export protein with altered export signal. Of particular interest, the NS1 amino acid sequence of swine H1N2-2009 and 2010 has a 'unique or very unusual' PDZ binding domain (RPKV) at the C-terminal of the protein, a motif that has been implicated as a virulence marker. Concerning biological properties, these viruses reached lower titre and showed reduced cytopathogenicity in MDCK cells compared with an avian-like H1N1 isolate A/swine/Lidkoping/1193/2002 belonging to the same lineage as the 2009 and 2010 isolates. The findings should contribute to better understanding of factors related to the survival/extinction of this uncommon reassortant variant. PMID- 21253863 TI - Laevigatbenzoate from Croton laevigatus Vahl. AB - A new trans-clerodane diterpenoid, laevigatbenzoate (1), was isolated from the leaves of Croton laevigatus Vahl. Its structure was established on the basis of spectroscopic analysis, and the absolute configuration was determined by application of the CD excitation chirality method. This compound showed weak cytotoxicity against HeLa cells, with an IC(50) value of 45.4 MUM. PMID- 21253865 TI - Proteomic survey towards the tissue-specific proteins of mouse mitochondria. AB - Mitochondrion plays the key functions in mammalian cells. It is believed that mitochondrion exerts the common biologic functions in many tissues, but also performs some specific functions correspondent with tissues where it is localized. To identify the tissue-specific mitochondrial proteins, we carried out a systematic survey towards mitochondrial proteins in the tissues of C57BL/6J mouse, such as liver, kidney and heart. The mitochondrial proteins were separated by 2DE and identified by MALDI-TOF/TOF MS. Total of 87 unique proteins were identified as the tissue-specific ones, and some representatives were further verified through ICPL quantification and Western blot. Because these issue specific proteins are coded from nuclear genes, real-time PCR was employed to examine the mRNA status of six typical genes found in the tissues.With combining of the expression data and the co-localization images obtained from confocal microscope, we came to the conclusion that the tissue-specifically mitochondrial proteins were widely distributed among the mouse tissues. Our investigation, therefore, indeed provides a solid base to further explore the biological significance of the mitochondrial proteins with tissue-orientation. PMID- 21253866 TI - Antigenically dominant proteins within the human liver mitochondrial proteome identified by monoclonal antibodies. AB - Analysis of the mitochondrial proteome would provide valuable insight into the function of this important organelle, which plays key roles in energy metabolism, apoptosis, free radical production, thermogenesis, and calcium signaling. It could also increase our understanding about the mechanisms that promote mitochondrial disease. To identify proteins that are antigenically dominant in human liver mitochondria, we generated >240 hybridoma cell lines from native mitochondrial proteins after cell fusion, screening, and cloning. Antibodies that recognized mitochondrial proteins were identified by screening human liver cDNA expression libraries. In this study, we identified 6 major antigens that were recognized by at least 2 different monoclonal antibodies (mAbs). The proteins that were antigenically dominant were: acetyl-Coenzyme A acyltransferase 2 (mitochondrial 3-oxoacyl-Coenzyme A thiolase), aldehyde dehydrogenase 1 family member A1, carbamoyl phosphate synthetase 1, dihydrolipoamide S-acetyltransferase (E2 component of pyruvate dehydrogenase complex), enoyl coenzyme A hydratase 1, and hydroxysteroid (11-beta) dehydrogenase 1. We also determined the subcellular localizations of these enzymes within the mitochondria using immunohistocytochemistry. We believe that these well-characterized antibodies will provide a valuable resource for the Human Liver Proteome Project (HLPP), and will make studies aimed at investigating liver mitochondrial function far easier to perform in future. Our results provide strong evidence that, (i) depletion of dominant proteins from liver mitochondrial samples is possible and, (ii) the approaches adopted in this study can be used to explore or validate protein protein interactions in this important organelle. PMID- 21253867 TI - Toward a high resolution 2-DE profile of the normal human liver proteome using ultra-zoom gels. AB - The human liver is the largest organ in the body and has many important physiological functions. A global analysis of human liver proteins is essential for a better understanding of the molecular basis of the normal functions of the liver and of its diseases. As part of the Human Liver Proteome Project (HLPP), the goal of the present study was to visualize and detect as many proteins as possible in normal human livers using two-dimensional gel electrophoresis (2-DE). We have constructed a reference map of the proteins of human normal liver that can be used for the comprehensive analysis of the human liver proteome and other related research. To improve the resolution and enhance the detection of low abundance proteins, we developed and optimized narrow pH range ultra-zoom 2-DE gels. High resolution patterns of human liver in pH gradients 4.5-5.5, 5-6, 5.5 6.7, 6-9 and 6-11 are presented. To improve the poor resolution in the alkaline pH range of 2-DE gels, we optimized the isoelectric focusing protocol by including sample application using cup loading at the anode and incorporating 1.2% hydroxyethyl disulfide, 15% 2-propanol and 5% glycerol in the rehydration buffer. Using the optimized protocol, we obtained reproducibly better resolution in both analytical and preparative 2-DE gels. Compared with the 2386 and 1878 protein spots resolved in the wide range 3-10 and 4-7 pH gradients respectively, we obtained 5481 protein spots from the multiple (overlapping) narrow pH range ultra-zoom gels in the range of pH 4.5-9. The visualized reference map of normal human liver proteins presented in this paper will be valuable for comparative proteomic research of the liver proteome. PMID- 21253868 TI - Comparison of alternative extraction methods for secretome profiling in human hepatocellular carcinoma cells. AB - Secreted proteins are important sources for early detection and diagnosis of disease, and as such have received considerable attention. The extraction of low concentration proteins from large volumes of culture media, which are rich in salts and other compounds that interfere with most proteomics techniques, presents a problem for secretome studies. Ultrafiltration, precipitation, and dialysis are three major extraction methods that can be used to overcome this problem. The present study for the first time, compared the merits and shortcomings of these three methods, without bias. Centrifugal ultrafiltration provided the best extraction efficiency, and precipitation provided the highest number of identifiable proteins. The three methods yielded closely related, but different, information on the secretome; thus, they should be considered complementary or, at least, supplementary methods. Three hundred and sixty unique proteins were identified, including 211 potential secreted proteins. Compared with previous studies, this study also identified 42 new secreted proteins. The present study not only offers a reference for the selection of secretome extraction methods, but also expands the secretome database for the investigation of hepatocellular carcinoma. PMID- 21253869 TI - alpha-2-HS-glycoprotein is a potential marker predicting hepatitis B e antigen seroconversion in patients with chronic hepatitis B during treatment with pegylated interferon alpha-2b. AB - The efficacy of interferon (IFN) is limited in about 1/3 of patients with chronic hepatitis B (CHB). We used two-dimensional electrophoresis (2-DE)-based proteomic strategies to identify potential serum markers predicting hepatitis B e antigen (HBeAg) seroconversion in these patients during IFN therapy. Two groups of patients were enrolled: training and validation. In the training group, 2-DE experiments and subsequent identification of altered levels of proteins showed that alpha-2-HS-glycoprotein, leucine-rich alpha-2-glycoprotein, and haptoglobin were significantly upregulated as compared with baseline levels in the HBeAg seroconversion group, whereas apolipoprotein C-III precursor, leucine-rich alpha 2-glycoprotein, and alpha-albumin were downregulated in the non-seroconversion group. For patients with HBeAg seroconversion in the training group, Western blot analyses showed that alpha-2-HS-glycoprotein levels in 75% of patients were significantly upregulated at the end of the treatment as compared with baseline levels. Subsequent experiments in the validation group showed that alpha-2-HS glycoprotein levels were significantly increased at week 4 in 83.33% of patients in the HBeAg seroconversion group. Dynamic changes in the serum level of alpha-2 HS-glycoprotein may be a potential early marker for predicting HBeAg seroconversion during IFN treatment for CHB. PMID- 21253870 TI - Whole-cell matrix-assisted laser desorption/ionization time-of-flight mass spectrometry for rapid identification of bacteria cultured in liquid media. AB - Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been used for many years to rapidly identify whole bacteria. However, no consistent methodology exists for the rapid identification of bacteria cultured in liquid media. Thus, in this study we explored the use of MALDI-TOF MS analysis for rapid identification of cells cultured in liquid media. We determined that 2,5-dihydroxybenzoic acid (50 mg mL(-1), 50% acetonitrile, 0.1% trifluoroacetic acid) was the best matrix solution for MALDI-TOF MS for this type of study. Moreover, the tested strains were successfully differentiated by principal component analysis, and the main characteristics of the mass peaks for each species were found in mixed culture samples. In addition, we found that the minimum number of cells for detection was 1.8 * 10(3). In conclusion, our findings suggest that MS-based techniques can be developed as an auxiliary method for rapidly and accurately identifying bacteria cultured in liquid media. PMID- 21253871 TI - A novel organic-inorganic hybrid monolith for trypsin immobilization. AB - In proteomics, attention has focused on various immobilized enzyme reactors (IMERs) for the realization of high throughput digestion. In this report, a novel organic-inorganic hybrid monolith based IMER was prepared in a 100 MUm i.d. capillary with 3-glycidoxypropyltrimethoxysilane (GLYMO) as the monomer and tetraethoxysilane (TEOS) as the crosslinker. Trypsin immobilization was achieved via the reaction between vicinal diol groups, which were obtained from hydrolysis of epoxy groups, and the amino groups of trypsin. Bovine serum albumin was digested thoroughly by this IMER in 47 s. After micro-reverse phase liquid chromatography-tandem mass spectrometry (MURPLC-MS/MS) analysis and database searching, beyond 35% sequence coverage was obtained, and the result was comparable to that of 12 h in solution digestion. The present IMER has potential for high throughput digestion. PMID- 21253872 TI - TSdb: a database of transporter substrates linking metabolic pathways and transporter systems on a genome scale via their shared substrates. AB - TSdb ( http://tsdb.cbi.pku.edu.cn ) is the first manually curated central repository that stores formatted information on the substrates of transporters. In total, 37608 transporters with 15075 substrates from 884 organisms were curated from UniProt functional annotation. A unique feature of TSdb is that all the substrates are mapped to identifiers from the KEGG Ligand compound database. Thus, TSdb links current metabolic pathway schema with compound transporter systems via the shared compounds in the pathways. Furthermore, all the transporter substrates in TSdb are classified according to their biochemical properties, biological roles and subcellular localizations. In addition to the functional annotation of transporters, extensive compound annotation that includes inhibitor information from the KEGG Ligand and BRENDA databases has been integrated, making TSdb a useful source for the discovery of potential inhibitory mechanisms linking transporter substrates and metabolic enzymes. User-friendly web interfaces are designed for easy access, query and download of the data. Text and BLAST searches against all transporters in the database are provided. We will regularly update the substrate data with evidence from new publications. PMID- 21253873 TI - Tetrahymena Gene Expression Database (TGED): a resource of microarray data and co expression analyses for Tetrahymena. AB - Tetrahymena thermophila is a model eukaryotic organism. Functional genomic analyses in Tetrahymena present rich opportunities to address fundamental questions of cell and molecular biology. The Tetrahymena Gene Expression Database (TGED; available at http://tged.ihb.ac.cn) is the first expression database of a ciliated protozoan. It covers three major physiological and developmental states: growth, starvation, and conjugation, and can be accessed through a user-friendly web interface. The gene expression profiles and candidate co-expressed genes for each gene can be retrieved using Gene ID or Gene description searches. Descriptions of standardized methods of sample preparation and the opportunity to add new Tetrahymena microarray data will be of great interest to the Tetrahymena research community. TGED is intended to be a resource for all members of the scientific research community who are interested in Tetrahymena and other ciliates. PMID- 21253874 TI - Host cellular signaling induced by influenza virus. AB - A wide range of host cellular signal transduction pathways can be stimulated by influenza virus infection. Some of these signal transduction pathways induce the host cell's innate immune response against influenza virus, while others are essential for efficient influenza virus replication. This review examines the cellular signaling induced by influenza virus infection in host cells, including host pattern recognition receptor (PRR)-related signaling, protein kinase C (PKC), Raf/MEK/ERK and phosphatidy-linositol-3-kinase (PI3K)/Akt signaling, and the corresponding effects on the host cell and/or virus, such as recognition of virus by the host cell, viral absorption and entry, viral ribonucleoprotein (vRNP) export, translation control of cellular and viral proteins, and virus induced cell apoptosis. Research into influenza virus-induced cell signaling promotes a clearer understanding of influenza virus-host interactions and assists in the identification of novel antiviral targets and antiviral strategies. PMID- 21253875 TI - Comparative proteome analysis of alkaliphilic Bacillus sp. N16-5 grown on different carbon sources. AB - To determine the impact of carbohydrates on the metabolic pathway in alkaliphiles, proteomes were obtained from cultures containing different carbohydrates and were resolved on two-dimensional gel electrophoresis (2-DE). The proteomes were compared to determine differentially expressed proteins. A novel alkaliphilic bacterium (alkaliphilic Bacillus sp. N16-5 isolated from Wudunur Soda Lake, China) was isolated in media with five different carbon sources (glucose, mannose, galactose, arabinose, and xylose). Comparative proteome analysis identified 61 differentially expressed proteins, which were mainly involved in carbohydrate metabolism, amino acid transport, and metabolism, as well as energy production and conversion. The comparison was based on the draft genome sequence of strain N16-5. The abundance of enzymes involved in central metabolism was significantly changed when exposed to various carbohydrates. Notably, catabolite control protein A (CcpA) was up-regulated under all carbon sources compared with glucose. In addition, pentose exhibited a stronger effect than hexose in CcpA-mediated carbon catabolite repression. These results provided a fundamental understanding of carbohydrate metabolism in alkaliphiles. PMID- 21253876 TI - The role of peri-operative chemotherapy for resectable colorectal liver metastasis: what does the evidence support? PMID- 21253877 TI - Equipoise of outcome is sufficient to justify the laparoscopic approach for colorectal cancers. PMID- 21253878 TI - The seventy percent solution. PMID- 21253879 TI - Aging reduces complexity of heart rate variability assessed by conditional entropy and symbolic analysis. AB - Increasing age is associated with a reduction in overall heart rate variability as well as changes in complexity of physiologic dynamics. The aim of this study was to verify if the alterations in autonomic modulation of heart rate caused by the aging process could be detected by Shannon entropy (SE), conditional entropy (CE) and symbolic analysis (SA). Complexity analysis was carried out in 44 healthy subjects divided into two groups: old (n = 23, 63 +/- 3 years) and young group (n = 21, 23 +/- 2). It was analyzed SE, CE [complexity index (CI) and normalized CI (NCI)] and SA (0V, 1V, 2LV and 2ULV patterns) during short heart period series (200 cardiac beats) derived from ECG recordings during 15 min of rest in a supine position. The sequences characterized by three heart periods with no significant variations (0V), and that with two significant unlike variations (2ULV) reflect changes in sympathetic and vagal modulation, respectively. The unpaired t test (or Mann-Whitney rank sum test when appropriate) was used in the statistical analysis. In the aging process, the distributions of patterns (SE) remain similar to young subjects. However, the regularity is significantly different; the patterns are more repetitive in the old group (a decrease of CI and NCI). The amounts of pattern types are different: 0V is increased and 2LV and 2ULV are reduced in the old group. These differences indicate marked change of autonomic regulation. The CE and SA are feasible techniques to detect alteration in autonomic control of heart rate in the old group. PMID- 21253880 TI - Protective effects of breastfeeding for mothers surviving childhood cancer. AB - INTRODUCTION: Female childhood cancer survivors experience adverse health events secondary to cancer treatment. In healthy women, breastfeeding provides protection against many of these complications. Breastfeeding may be beneficial for mothers surviving childhood cancer by decreasing risks of, or ameliorating adverse late effects. Healthcare providers and survivors should be aware that successful lactation may be affected by previous cancer treatment. METHODS: The literature addressing lactation outcomes in cancer patients is reviewed, and processes that may disrupt breastfeeding are discussed. A summary of common late effects experienced by women is provided, and arguments are made for the potential amelioration of these complications by breastfeeding. RESULTS: Findings demonstrate that breastfeeding is beneficial for healthy mothers in regard to specific health conditions. There are limited data addressing breastfeeding outcomes among cancer survivors. Preliminary findings suggest that lactation is adversely affected among mothers treated for childhood cancer. CONCLUSIONS: Fundamental research is needed to determine rates of breastfeeding in childhood cancer survivors, identify specific cancer therapies and their effects on lactation, examine the efficacy of breastfeeding in risk reduction and/or amelioration of late effects, and develop interventions to increase breastfeeding among survivors of childhood cancer. IMPLICATIONS FOR CANCER SURVIVORS: As female childhood cancer survivors transition into adult medical care, it is important each patient be aware of her past medical history and the impact of treatment on her ability to successfully lactate. If lactation is possible, these women can choose to breastfeed their children, thereby engaging in a health behavior that may help protect them against many late effects of cancer treatment. PMID- 21253881 TI - Towards a personalised approach to aftercare: a review of cancer follow-up in the UK. AB - INTRODUCTION: Due to growth in cancer survivorship and subsequent resource limitations, the current UK position of follow-up services is unsustainable. With people living longer after a cancer diagnosis, supported self-management for ongoing treatment-related chronic conditions is a fundamental component of aftercare services. Alternative models to traditional hospital aftercare require consideration in terms of clinical effectiveness and cost-effectiveness. METHODS: 'Evidence to Inform the Cancer Reform Strategy: The Clinical Effectiveness of Follow-Up Services after Treatment for Cancer' (Centre for Reviews and Dissemination 2007) has been updated using a number of quality-controlled databases. Correspondence with experts was also sought to identify current initiatives. RESULT: The review highlights a shift towards patient empowerment via individualised and group education programmes aimed at increasing survivor's ability to better manage their condition and the effects of treatment, allowing for self-referral or rapid access to health services when needed. The role of specialist nurses as key facilitators of supportive aftercare is emphasised, as is a move towards technology-based aftercare in the form of telephone or web based services. CONCLUSIONS: The challenge will be replacing traditional clinic follow-up with alternative methods in a cost-effective way that is either as equally effective, or more so. To establish this, more rigorous trials are needed, with larger sample sizes and longer follow-up assessments. IMPLICATIONS FOR CANCER SURVIVORS: Increasing patient confidence to initiate follow-up specific to their needs is likely to increase the workload of primary care providers, who will need training for this. PMID- 21253882 TI - Obstructive sleep apnea and the risk for cardiovascular disease. AB - Obstructive sleep apnea (OSA) is a common disorder with major neurocognitive and cardiovascular sequelae. It is estimated that more than one quarter of the population is at risk for OSA, with increased prevalence noted in populations with hypertension, coronary artery disease, stroke, and atrial fibrillation. A number of epidemiologic and mechanistic studies have recently generated interest in the role of OSA in the pathophysiology of cardiovascular disease, a link that continues to require extensive investigation. This chapter reviews these epidemiologic studies, the current understanding of the mechanisms by which OSA may contribute to the progression of cardiovascular diseases, and the effects of OSA treatment on cardiovascular disease outcomes. PMID- 21253883 TI - Copy number variants: a new molecular frontier in clinical psychiatry. AB - Molecular genetic research, building on genetic epidemiology, has provided the field of psychiatry with a host of exciting advances. It is now clear beyond any reasonable doubt that genetic inheritance influences liability to develop almost every major psychiatric disorder. Rapid progress in identifying genes contributing to psychiatric liability, recently accelerated by the advent of approaches such as genome-wide association studies and chromosomal microarray analysis, raises a critical question for psychiatric practice and training: how will molecular genetics alter the practice of psychiatry for front-line clinicians? The premise of the present review is that our growing knowledge regarding the roles of copy number variants in behavioral disorders will soon require revision of standards of evaluation and care for psychiatric patients. PMID- 21253884 TI - Long-term treatment of pediatric depression with psychotherapies. AB - Major depressive disorder in children and adolescents is associated with significant morbidity and mortality, and benefits from intervention. However, studies have focused on acute treatment. Thus, data are limited on long-term treatment (ie, both continuation and maintenance treatment). This article discusses the naturalistic course of depression following acute treatment with psychotherapy and the efficacy of long-term psychotherapy for the prevention of relapse and recurrence in depressed children and adolescents. PMID- 21253885 TI - Genome-wide association studies of alcohol dependence and substance use disorders. AB - Genome-wide association studies (GWAS) currently represent the most systematic approach to genetic research into complex disorders. They can detect associations of common variants in genomic regions in the absence of an a priori assumption. Most of the GWAS of addiction performed to date have focused on alcohol dependence or smoking behavior. Four GWAS of alcohol dependence have been published thus far, and only two single nucleotide polymorphisms have received modest support of replication in a subsequent study. Many more GWAS have been conducted for smoking behavior. One large, single GWAS and meta-analyses of the phenotype "smoking quantity" have generated convincing evidence for the contribution of variants in genes for cholinergic nicotinic receptor subunits. This article focuses on GWAS of alcohol addiction and provides an overview of GWAS of other substance abuse disorders. PMID- 21253886 TI - Neurodevelopmental risks of pediatric anesthesia: what do we know, and what should we do? PMID- 21253888 TI - Cloning of two genes (LAT1,2) encoding specific L: -arabinose transporters of the L: -arabinose fermenting yeast Ambrosiozyma monospora. AB - We identified and characterized two genes, LAT1 and LAT2, which encode specific L: -arabinose transporters. The genes were identified in the L: -arabinose fermenting yeast Ambrosiozyma monospora. The yeast Saccharomyces cerevisiae had only very low L: -arabinose transport activity; however, when LAT1 or LAT2 was expressed, L: -arabinose transport was facilitated. When the LAT1 or LAT2 were expressed in an S. cerevisiae mutant where the main hexose transporters were deleted, the L: -arabinose transporters could not restore growth on D: -glucose, D: -fructose, D: -mannose or D: -galactose. This indicates that these sugars are not transported and suggests that the transporters are specific for L: arabinose. PMID- 21253887 TI - Impact of global medicine on urologic education. AB - Collaborative and academic partnerships between institutions in North America and those in resource-limited nations are a burgeoning trend. Leveraging the academic quality and outcomes-based infrastructure of university medical centers to increase surgical capacity in regions where urologic disease burden is immense offers potentially bilateral opportunities. Host institutions benefit from exposure to contemporary surgical approaches, while the surgical volume enables larger-scale collaborative outcome studies and exposure of residents-in-training to rare pathophysiology. This article surveys this growing trend in globalizing health care specific to urology, and the development of a program focused on urologic education at a tertiary referral center in India. PMID- 21253889 TI - Purification and characterization of a novel thermostable xylose isomerase from Opuntia vulgaris mill. AB - Thermophilic xylose isomerase from the xerophytic eukaryote Opuntia vulgaris can serve as a good alternate source of enzyme for use in the production of high fructose corn syrup. The existence of two temperature stable isoforms having optimal activity at temperatures 70 degrees C (T(70)) and 90 degrees C (T(90)), respectively, is reported here. These isoforms were purified to homogeneity using column chromatography and SDS-polyacrylamide gel electrophoretic techniques. Only the T(90) isoform was subjected to full biochemical characterization thereafter. The purified T(90) isoform was capable of converting glucose to fructose with high efficiency under the assay conditions. The enzyme at pH 7.5 exhibited a preference to yield the forward isomerization reaction. The melting temperature of the native enzyme was determined to be 90 degrees C employing differential scanning colorimetery. Thermostability of the enzyme protein was established through temperature-related denaturation kinetic studies. It is suggested that the thermostability and the wide pH activity of this eukaryotic enzyme will make it an advantageous and dependable alternate source of catalytic activity for protected use in the high fructose corn syrup sweetener industry. PMID- 21253890 TI - Altered copper level and renal dysfunction in Nigerian women using skin-whitening agents. AB - The purpose of the study was to determine the concentration of trace elements in serum samples of women who are chronic users of skin-whitening agents as well as the hepatic and renal effects of these agents on these women. The study was conducted among 23 skin-whitening users while 25 women served as the controls. The serum concentrations of Zn, Mn, and Mg were not significantly changed in these women compared with controls (p > 0.05), but Cu was significantly increased in skin-whitening agent users compared with controls (p < 0.05). Serum urea and creatinine were significantly increased compared with the controls (p < 0.05). Moreover, ALT, AST, albumin, total protein, and bilirubin were not significantly changed (p > 0.05). The significant increase in the levels of renal indices shows that these agents might be nephrotoxic after prolonged usage while increase in copper level with accompanying renal dysfunction may be an indication that copper mediates in oxidative-induced renal dysfunction. However, further study is needed to identify the cause and source of high serum copper as many of the herbal extracts may be rich sources of copper. Moreover, a large population study may be necessary to examine the exact correlation between copper and renal indices. PMID- 21253891 TI - Suboptimal selenium supply--a continuing problem in Keshan disease areas in Heilongjiang province. AB - This study explores whether the declining prevalence of Keshan disease is associated with increasing selenium levels in Keshan disease areas in Heilongjiang province. Six counties endemic with Keshan disease and three non endemic counties were selected as study areas. In each county, two townships and in each township one village were chosen in which to survey ten families about head hair, grain, and soil samples and to obtain demographic information. Selenium was measured with hydride generation-atomic fluorescence spectrometry. In each county endemic with Keshan disease, one of the villages was chosen to investigate the prevalence of the disease. We collected 534 head hair samples, 446 staple food samples, and 180 soil samples. The selenium levels of head hair and corn in the endemic counties were significantly lower than those in non endemic counties. Family demographic information was homologous except for the composition of staple food. More residents in Keshan disease areas preferred flour and corn. The detection rate for latent Keshan disease had a significantly negative correlation with the corn selenium level in six counties endemic with Keshan disease. As the population in this region is still at risk for Keshan disease, selenium surveillance measures should be intensified. PMID- 21253892 TI - Insights into the structure of the LC13 TCR/HLA-B8-EBV peptide complex with molecular dynamics simulations. AB - One key step in the immune response against infected or tumor cells is the recognition of the T-cell receptor (TCR) by class I major histocompatibility complexes. The complex between the HLA-B8 molecule and the immunodominant peptide with sequence FLRGRAYGL, derived from the Epstein-Barr virus, with the LC13 TCR has been determined by X-ray diffraction. The complex has been used as a starting point in a molecular dynamics study in order to investigate the dynamics of the complex association and to explore the specific interactions of the complex formation. The analyzed structures provided evidence that the peptide adopts an open type beta-turn conformation close to C-terminal part, which dominates peptide/TCR interactions. Conformational energy landscape analysis indicated the presence of two conformational clusters in the peptide's structure, underlying the backbone flexibility of the peptide despite being surrounded by two receptors. The peptide/MHC/TCR interface was found to hold significant number of solvent molecules, more specifically the peptide has been found to have approximately seventeen hydrogen bonds with water molecules. The molecular dynamics simulation indicated the disruption of some MHC/TCR contacts, mainly with the CDR1alpha loop. However, several other interactions emerged that resulted in a stable association during the 20 ns trajectory, as revealed by the buried surface area analysis. PMID- 21253893 TI - Enhanced gene transduction into skeletal muscle of mice in vivo with pluronic block copolymers and ultrasound exposure. AB - The pluronic block copolymers are able to enhance the ultrasound-induced gene delivery in vitro. In the present study, the effects of pluronics on the efficiency of gene transfer into skeletal muscle in vivo under sonoporation were investigated. Plasmid DNA encoding green fluorescent protein (GFP) in combination with three different pluronics, F127, L61, and P85, was injected into the tibialis anterior (TA) muscle of mice with and without adjunct ultrasound (1 MHz, 3 W/cm(2) 1 min, 20% duty cycle). Mice were killed 1 week after injection. The TA muscles were removed and snap frozen immediately in isopentane cooled by liquid nitrogen and sections of 7 MUm thick were cut. Transfection efficiency was assessed by counting the number of GFP-positive fibers under fluorescence microscopy, and tissue damage by hematoxylin and eosin staining. The results suggested that all three pluronics significantly enhanced transgene expression in skeletal muscle (P < 0.01), especially the P85 showed significantly higher efficiency than the other two pluronics (P < 0.05). Ultrasound synergistically enhanced the gene delivery efficiency with P85 (P < 0.01), but was unable to do so with F127 and L61 groups. In short, P85 displays significantly synergistic effect with ultrasound for enhancing plasmid DNA transduction in skeletal muscle of mice in vivo. PMID- 21253894 TI - Genetic relationship of Curcuma species from Northeast India using PCR-based markers. AB - Molecular genetic fingerprints of nine Curcuma species from Northeast India were developed using PCR-based markers. The aim involves elucidating there intra- and inter-specific genetic diversity important for utilization, management, and conservation. Twelve random amplified polymorphic DNA (RAPD), 19 Inter simple sequence repeats (ISSRs), and four amplified fragment length polymorphism (AFLP) primers produced 266 polymorphic fragments. ISSR confirmed maximum polymorphism of 98.55% whereas RAPD and AFLP showed 93.22 and 97.27%, respectively. Marker index and polymorphic information content varied in the range of 8.64-48.1, 19.75 48.14, and 25-28 and 0.17-0.48, 0.19-0.48, and 0.25-0.29 for RAPD, ISSR, and AFLP markers, respectively. The average value of number of observed alleles, number of effective alleles, mean Nei's gene diversity, and Shannon's information index were 1.93-1.98, 1.37-1.62, 0.23-0.36, and 0.38-0.50, respectively, for three DNA markers used. Dendrograms based on three molecular data using unweighted pair group method with arithmetic mean (UPGMA) was congruent and classified the Curcuma species into two major clusters. Cophenetic correlation coefficient between dendrogram and original similarity matrix were significant for RAPD (r = 0.96), ISSR (r = 0.94), and AFLP (r = 0.97). Clustering was further supported by principle coordinate analysis. High genetic polymorphism documented is significant for conservation and further improvement of Curcuma species. PMID- 21253895 TI - Modification and evolution of Gluconobacter oxydans for enhanced growth and biotransformation capabilities at low glucose concentration. AB - Gluconobacter oxydans is widely used in several biotechnological applications, where sorbitol or mannitol is commonly used as carbon source at high concentration. In this study, a membrane-bound glucose dehydrogenase-deficient strain (GDHK) was constructed to eliminate growth problems on glucose caused by direct oxidation of glucose in the medium. To achieve improved growth properties for the GDHK strain on glucose, a laboratory adaptive evolution experiment was performed with glucose as the sole carbon source. Results indicated evident, albeit modest, improvements in cell growth after a 50-day (about 430 generations) experimental evolution on glucose. The maximum specific growth rate and biomass yield of the resulting GDHE50 strain were increased around 1.35- to 1.4-fold compared with those of the GDHK strain. Meanwhile, two types of biotransformation reactions using resting cells of G. oxydans were investigated. Significant elevations in biotransformation performance of the GHDE50 strain were observed in comparison with that of the wild-type strain. In addition, resting cells of the GDHE50 strain grown on a relatively low concentration of glucose (10 g/l) could catalyze the biotransformation of glycerol to dihydroxyacetone and ethylene glycol to glycolic acid as efficient as the wild-type G. oxydans cultured on higher concentration of sorbitol or other carbon sources. These results suggest very favorable prospects of using glucose to lower production cost in many important industrial biocatalysis and biotransformation processes. PMID- 21253896 TI - A species-specific polymerase chain reaction assay for rapid and sensitive detection of Colletotrichum capsici. AB - Colletotrichum capsici is an important fungal species that causes anthracnose in many genera of plants causing severe economic losses worldwide. A primer set was designed based on the sequences of the ribosomal internal transcribed spacer (ITS1 and ITS2) regions for use in a conventional PCR assay. The primer set (CcapF/CcapR) amplified a single product of 394 bp with DNA extracted from 20 Mexican isolates of C. capsici. The specificity of primers was confirmed by the absence of amplified product with DNA of four other Colletotrichum species and eleven different fungal genera. This primer set is capable of amplifying only C. capsici from different contaminated tissues or fungal structures, thereby facilitating rapid diagnoses as there is no need to isolate and cultivate the fungus in order to identify it. The sensitivity of detection with this PCR method was 10 pg of genomic DNA from the pathogen. This is the first report of a C. capsici-specific primer set. It allows rapid pathogen detection and provides growers with a powerful tool for a rational selection of fungicides to control anthracnose in different crops and in the post-harvest stage. PMID- 21253897 TI - Chromobacterium violaceum and its important metabolites--review. AB - C. violaceum appeared as important bacterium in different applications and mainly these aspects are related to the production of violacein. This review discusses the last reports on biosynthetic pathways, production, genetic aspects, biological activities, pathological effects, antipathogenic screening through quorum sensing, environmental effects and the products of C. violaceum with industrial interest. An important discussion is on biological applications in medicine and as industrial products such as textile and in cosmetics. PMID- 21253898 TI - Small colony variants of Staphylococcus aureus--review. AB - Bacterial variants of Staphylococcus aureus called small colony variants (SCVs) originate by mutations in metabolic genes, resulting in emergence of auxotrophic bacterial subpopulations. These variants are not particularly virulent but are able to persist viable inside host cells. SCVs show their characteristic auxotrophic growth deficiency and depressed alpha-cytotoxin activity. Environmental pressure such as antibiotics, select for isogenic SCV cells that are frequently found coexisting with their parent wild-type strains in a mixed bacterial culture. SCV strains often grow on blood agar as non-pigmented or pinpoint pigmented colonies and their key biochemical tests are often non reactive. Their altered metabolism or auxotrophism can result in long generation time and thus SCV phenotype, more often than not SCV can be overgrown by their wild-type counterparts and other competitive respiratory flora. This could affect laboratory detection. Thus, molecular methods, such as 16S rRNA partial sequencing or amplification of species-specific DNA targets (e.g. coagulase, nuclease) directly from clinical material or isolated bacterial colonies, become the method of choice. Patients at risk of infection by S. aureus SCVs include cystic fibrosis patients (CF), patients with skin and foreign-body related infections and osteomyelitis, as they suffer from chronic staphylococcal infections and are subject to long-term antibiotic therapy. Molecular evidence of SCV development has not been found except for some random mutations of the thymidylate synthase gene (thyA) described in SCV S. aureus strains of CF patients. These variants are able to bypass the antibiotic effect of folic acid antagonists such as sulfonamides and trimethoprim. Resistance to gentamicin and aminoglycosides in the hemin or menadione auxotrophic SCVs was hypothesized as being due to decreased influx of the drugs into cells as a result of decreased ATP production and decreased electrochemical gradient on cell membranes. PMID- 21253900 TI - Bioluminescence of Pseudomonas fluorescens HK44 in the course of encapsulation into silica gel. Effect of methanol. AB - The bioluminescence (BLM) and colony-forming units (CFU) of Pseudomonas fluorescens HK44 were monitored during encapsulation into pre-polymerized Si(OMe)4. The non-induced BLM of free cells was increased in the presence of 0.5 2.5 % MeOH. After mixing silica sol with the cell suspension, both BLM and CFU dropped to 1-3 and 8-18 %, respectively; both remained lowered as long as the silica biofilm contained residual MeOH. The kinetics of MeOH being released from silica biofilms (a thickness of 2-6 mm) were first-order. The decrease of bacterial activity due to encapsulation was proportional to the biofilm thickness. MeOH evolving during encapsulation is probably the principal stress factor but not the only one. PMID- 21253899 TI - Point-of-care salivary microbial tests for detection of cariogenic species- clinical relevance thereof--review. AB - Dental caries is a highly prevalent multifactorial disease that can result in serious health impairment. It was shown that oral bacteria play a significant role in caries development. Point-of-care (POC) salivary microbial tests for detection of cariogenic species have been investigated as a potential tool for caries risk assessment. This review aims to evaluate clinical relevance of these tests in the light of recent scientific evidence. Methodology involved PubMed search using key words salivary microbial tests, cariogenic bacteria and caries risk prediction. Articles obtained by the search were cross-referenced to obtain further sources. Specificity and negative-predictive value of these tests are higher than their sensitivity and positive value. Predictive power of the POC salivary microbial tests as a single predictor is generally weak, although it increases when included in multifactorial models for caries prediction. Literature findings support the use of these tests for screening of at-risk individuals in a population of young preschool children without visible caries and for motivation of subjects on individual level. POC salivary microbial tests are simple and inexpensive and, therefore, may be advantageous from public health perspective. PMID- 21253901 TI - Production and chemical characterization of an exopolysaccharide synthesized by psychrophilic yeast strain Sporobolomyces salmonicolor AL1 isolated from Livingston Island, Antarctica. AB - The exopolysaccharide (EPS) production by psychrophilic Antarctic yeast Sporobolomyces salmonicolor AL1 reached the maximum yield in medium containing sucrose (50 g/L) and diammonium sulfate (2.5 g/L) after a 5-d fermentation (5.64 g/L) at 22 degrees C, the dynamic viscosity of the culture broth reaching (after 5 d) 15.4 mPa s. EPS showed a mannan-like structure and high molar mass, and did not affect cellular viability and proliferation of murine macrophages. It exhibited also a protective effect against the toxic activity of Avarol. PMID- 21253902 TI - Expression, purification and characterization of recombinant alpha-glucosidase in Pichia pastoris. AB - An expression plasmid containing the agdA gene encoding Aspergillus oryzae ZL-1 alpha-glucosidase was constructed and expressed in Pichia pastoris X-33. The molar mass of the purified protein was estimated by SDS-PAGE. HPLC analysis showed that the purified enzyme has a transglucosylating activity with maltose as substrate. The main component of the enzyme products was panose, while amounts of isomaltose and isomaltotriose were very low or absent. pH 5.2 and temperature of 37 degrees C were optimum for enzyme activity. PMID- 21253903 TI - Pseudomonas aeruginosa PAO1 adapted to 2-phenoxyethanol shows cross-resistance to dissimilar biocides and increased susceptibility to antibiotics. AB - The growth adaptability to increasing concentration of the biocide 2 phenoxyethanol (PE) was determined in Pseudomonas aeruginosa PAO1 (P.a.) as part of efforts to understand and control the biocide tolerance and its effect on cross-resistance to other biocides and resistance to antibiotics. After repeated subculturing in media containing increasing sub-minimum-inhibitory PE concentration, P.a. exhibited an adaptive resistance indicated by two-fold increase in MIC at the 10th passage. The resistance was stable and remained after passaging the strain in further 7 successive passages in PE-free growth media. The strain showed cross-resistance towards dissimilar biocides and displayed increased susceptibility to antibiotics, which was not influenced by the presence of the efflux inhibitor 'carbonyl cyanide m-chlorophenyl hydrazone'. Outer membranes of adapted strain showed altered protein profile when examined by SDS PAGE. PMID- 21253904 TI - Effects of mancozeb and other dithiocarbamate fungicides on Saccharomyces cerevisiae: the role of mitochondrial petite mutants in dithiocarbamate tolerance. AB - Saccharomyces cerevisiae as model system was used to evaluate the occurrence of resistant mutants and adaptation mechanism to mancozeb (MZ), a widespread fungicide of the dithiocarbamate class with a broad spectrum of action and multiple cell targets. We were unable to isolate mutants resistant to inhibitory concentration of MZ but found an unusually large number of mitochondrial defective petite mutants among cells incubated in the presence of subinhibitory MZ concentration. Similar results were obtained with two other dithiocarbamate fungicides. Comparison of wild type and petite mutants showed that the latter were more resistant to toxic effects of MZ, highlighting the role of mitochondria in MZ-tolerance. The data suggest that petite cells, arising by exposure to sub inhibitory MZ concentration, are not induced by fungicides but are spontaneous mutants already present in the population before the contact with the fungicide. PMID- 21253905 TI - Randomly-amplified microsatellite polymorphism for preliminary typing of lactic acid bacteria from Bryndza Cheese. AB - A high-throughput, medium-discrimination method for preliminary typing and selecting non-identical isolates of lactic acid bacteria in cheeses was developed. RAMP, a PCR with one microsatellite-targeted and one random primer, was used for preliminary typing of 1119 isolates of lactic acid bacteria from Slovak Bryndza cheese. A total of 59 genotypes were identified based on RAMP profiles consisting of 12-23 DNA fragments of 150-3000 bp. For example, 18, 17, 13 and 7 different RAMP-types were identified in Lactobacillus brevis, L. plantarum, L. paracasei and L. fermentum, respectively. The method facilitated well reproducible, medium-discrimination typing of Lactobacillus spp. and Pediococcus spp. at a subspecies level and proved to be suitable for preliminary typing of lactic acid bacteria isolated from cheese. PMID- 21253907 TI - Rapid detection of Vibrio metschnikovii in aquatic products by real-time PCR. AB - PCR and SYBR Green I real-time PCR techniques were applied to the rapid detection of Vibrio metschnikovii by designing primers based on infC (initiation factor 3) gene sequence. The specificity, sensitivity, and practical applications of the methods have been also analyzed. The methods showed high detecting specificity with no cross amplifications of other closely related and nonrelated species; they provide a simple and rapid tool for V. metschnikovii detection with high sensitivity and specificity. PMID- 21253906 TI - PCR screening and sequence analysis of iol clusters in Lactobacillus casei strains isolated from koumiss. AB - The iol cluster (consisting of genes involved in myo-inositol utilization) was investigated in Lactobacillus casei strains isolated from koumiss. Ten strains were tested for the presence of iol cluster by PCR screening; three strains encoded this cluster. Full-sequencing procedure was conducted; the iol cluster was identical to that of L. casei BL23 (GenBank access. no. FM177140) except for an upstream transposase. The iol cluster is not a common feature for L. casei strains isolated from koumiss. PMID- 21253908 TI - Poly-extremotolerant bacterium isolated from reverse osmosis reject: an implication toward waste water management. AB - We demonstrate the tolerance of bacterial strain SM2014 to various unsustainable conditions and suggest its implication in waste water management. Its sustainability to reverse osmosis pressure (2.1 MPa) during desalination, and survival percentage of 73 % under hyperbaric conditions (pressure tension of 3.1 MPa under absolute oxygen atmosphere) confirmed its pressure tolerance. The growth of this strain at pH 9 or 10 and at 60 degrees C alone or in combination revealed its unique physiology as poly-extremotolerant strain. As an adaptive mechanism, the ratio of saturated to unsaturated fatty acids changed with growth conditions. Under poly-extreme condition long chain saturated fatty acid (C18:0, C16:0, C14:0, C12:0) predominated at the expense of unsaturated fatty acids. The nucleotide BLAST of 16S rRNA gene sequence of strain SM2014 with the NCBI gene bank sequences showed its close identity to Bacillus licheniformis with a similarity match of 94 %. The secretion of industrially valuable enzymes proteinase, lipase and amylase under such harsh conditions further signified potential of this strain as a source of extremozymes. Its unique characteristics underscore its relevance in waste water management. PMID- 21253909 TI - Microbial phytase-induced calcium-phosphate precipitation--a potential soil stabilization method. AB - Two hypotheses were tested: (1) microbial dephosphorylation of phytate in the presence of Ca2+ ions will result in the precipitation of hydroxyapatite-like crystals and (2) precipitation of calcium-phosphate crystals on and between sand like particles can cause cementation. A growing culture of the dimorphic phytase active yeast Arxula adeninivorans was introduced into a column filled with quartz particles and subsequently a liquid growth medium amended with calcium phytate was pumped through the column resulting in increased strength and stiffness of the quartz particle matrix. Environmental scanning electron microscope analysis combined with energy-dispersive X-ray measurement revealed cementation of the quartz particles by calcium-phosphate crystals. This microbial mineralization process could provide a novel approach to improving the mechanical properties like strength and stiffness of sandy soils. PMID- 21253910 TI - Enhancement of autofluorescence of the brown-rot fungus Piptoporus betulinus by metal ions. AB - The autofluorescence (primary fluorescence, AF) of agar cultures of the brown-rot fungus Piptoporus betulinus was investigated in Zeiss Jenalumar and Nikon Eclipse 8201 fluorescence microscopes at various excitations. The strongest AF of hyphae was found in minimal medium with glucose, where the hyphae exhibited green AF at violet (450 nm) excitation and red AF at green (570 nm) excitation. Addition of metals to cultivation media led to enhanced white-blue AF in the presence of Co (at 450 nm) and yellow to yellow-brown AF at 510 nm. When cultivated with Mn and Zn, enhanced AF of intracellular content was observed. Only a weak signal was found in the presence of Cu and Fe. PMID- 21253911 TI - ITS-RFLP fingerprinting and molecular marker for detection of Fusarium oxysporum f.sp. ciceris. AB - Genetic diversity of 11 representative isolates of Fusarium oxysporum f.sp. ciceris causing chickpea wilt was determined through internal transcribed spacer (ITS) region of the ribosomal DNA-restriction fragment length polymorphism (ITS RFLP). ITS1+5.8s+ITS2 regions of the isolates were amplified with a set of primers ITS1 and ITS4 and amplified products were digested with 4 restriction enzymes (AluI, MboI, RsaI, MseI). Six different kinds of ITS-RFLP patterns were obtained. The ITS region of these isolates was sequenced and deposited to NCBI GeneBank. The nucleotide sequence homology of ITS region grouped the isolates into 5 categories. Primers were designed with sequence information using Primer 3 software. F. oxysporum f.sp. ciceris specific markers (FOC F2 and FOC R2) based on ITS region were developed for the first time for detection of the pathogen. The markers produced an amplicon of 292 bp; they were validated against the isolates of the pathogen collected from different locations of India. PMID- 21253912 TI - Multiplex PCR assay for detection of Actinobacillus pleuropneumoniae, Pasteurella multocida and Haemophilus parasuis in lungs of pigs from a slaughterhouse. AB - Multiplex PCR has been developed for parallel identification of Actinobacillus pleuropneumoniae, Pasteurella multocida and Haemophilus parasuis, important pathogens of swine, responsible for considerable economic losses in swine industry. Multiplex PCR and bacteriological cultivation was used to analyze lung samples from slaughterhouse pigs. From a total of 219 lung samples, 164 (74.9 %) were positive for P. multocida, 45 (20.5 %) for A. pleuropneumoniae and 4 (1.83 %) for H. parasuis. Bacteriological examination revealed that 145 samples (66.2 %) were positive for P. multocida, 31 (14.2 %) for A. pleuropneumoniae and 2 (0.91 %) for H. parasuis. PMID- 21253913 TI - Phenotypic characterization and putative virulence factors of human, animal and environmental isolates of Plesiomonas shigelloides. AB - Plesiomonas shigelloides (a bacterium widely distributed in aquatic ecosystems causing both intestinal and extra-intestinal diseases) shows a host of putative virulence markers, such as hemolysins, cytotoxins, production of exoenzymes associated with pathogenicity, adhesive ability and vacuolation of cell lines in vitro. Technical difficulties in detecting some of these virulence factors together with scantiness of epidemiological information, due to the lack of routine analysis for P. shigelloides as etiological agent of gastroenteritis, lead to sporadic and occasional finding of these bacteria. All this casts doubt on the real virulence potential of P. shigelloides and fuels a debate about assignment of these bacteria to the list of human pathogens. Here we demonstrated the phenotypic diversity and the putative virulence markers by examining serotype biochemical and virulence properties of 60 strains of P. shigelloides isolated from human, animal and environmental samples in different countries, which showed the unpredictable occurrence of the above properties depending on various locations and diverse sources. PMID- 21253914 TI - Lymphocyte proliferative response to Helicobacter pylori antigens in H. pylori infected patients. AB - Helicobacter pylori (Hp) contributes to the development of gastric and extra gastric diseases such as autoimmune thyroiditis (AT), and causes persistent life long infection despite local and systemic immune response. We determined the specific cellular immune response to Hp antigens and PWM (control mitogen) in two groups of Hp infected patients--group A (n = 21), involving patients with autoimmune thyroiditis and group B (n = 13) of patients without AT--using modified lymphocyte transformation test before and after eradication therapy in comparison with healthy controls (group C, n = 15). Immune reactivity to the majority of Hp antigens (aHp, hHp, HpAg, CagA) was significantly lower in group B before eradication therapy in comparison with healthy Hp negative controls. A significant increase in immune reactivity was observed in group B to certain Hp antigens after successful eradication. The same levels (but insignificant) of immune reactivity were shown in group A. Our results indicate that Hp can cause the inhibition of the specific cellular immune response in Hp infected patients with or without autoimmune diseases such as AT, which can be abrogated by successful eradication of Hp. Lymphocyte transformation test appears to be a good tool for detection of immune memory cellular response in patients with Hp infection. PMID- 21253915 TI - Quantitative evaluation of transcriptional activation of NF-kappaB p65 and p50 subunits and IkappaBalpha encoding genes in colon cancer cells by Desulfovibrio desulfuricans endotoxin. AB - Quantification of p65, p50 and IkappaBalpha mRNAs was performed by real time QRT PCR in Caco-2 cells treated with 10, 50, and 100 MUg/mL of Desulfovibrio desulfuricans LPS for 1, 6, 12, and 24 h. A strong increase in expression of p65 and IlambdaBalpha genes was induced by 10 and 100 MUg/mL of LPS at 1 h; after 6 h higher transcript amounts of both genes were observed at 100 MUg/mL LPS. The p65 expression level was significantly increased by 50 and 100 MUg/mL at 12 h and lowered by all LPS doses at 24 h. No significant differences between IkappaBalpha mRNA quantity in cells exposed to LPS at 12 and 24 h were observed. No changes in expression of p50 mRNA were induced by LPS. The expression of p65 gene positively correlated with IkappaBalpha gene expression. D. desulfuricans LPS is capable of modulating transcriptional activity of p65 and IkappaBalpha genes in intestinal epithelial cells. PMID- 21253916 TI - Newly designed, simple relief phase contrast for microscopy of microorganisms. AB - A new method providing a relief phase contrast for investigation of microorganisms by optical microscopy used a neutral filter Zeiss NG 10/1 that could be controllably slid at a certain azimuthal angle below the aperture condenser diaphragm of the microscope phase contrast. Two ways of application are described depending on the type of the microscope: (1) in a special holder, and (2) fixed on a rubber ring. The device enabled us to obtain excellent results in the area of both optical microscopy and microphotography. With the microorganisms visualized, a better resolution, higher contrast and a significant 3D effect were obtained; outer morphology and organelles (chloroplasts, nuclei, granules, oil reserve vacuoles, etc.) could also be investigated. PMID- 21253917 TI - Identification of Arcanobacterium haemolyticum isolated from postcastrational complications of a horse. AB - An Arcanobacterium haemolyticum strain isolated from a postcastrational lesion of a horse was identified phenotypically and genotypically. The latter was performed by sequencing the 16S-23S rDNA intergenic spacer region (ISR), by amplification of the gene encoding A. haemolyticum phospholipase D, by amplification of A. haemolyticum specific parts of ISR-23S rDNA and by amplification of the newly described CAMP factor family protein encoding gene of A. haemolyticum. This indicates (as described previously for seven additional A. haemolyticum strains; Hassan et al. 2009) that A. haemolyticum seems to occur also in infections of horses. PMID- 21253918 TI - Identification of Plesiomonas spp.: serological and MALDI-TOF MS methods. AB - Biochemical and serological profiles of isolates of Plesiomonas shigelloides were assayed using standard procedures in isolates from various clinical samples. Seventy-four isolates, including P. shigelloides type strain, were further characterized by MALDI-TOF MS using 3-methoxy-4-hydroxycinnamic acid as matrix. Multiple ions in the 3- to 12-kDa mass range were found in the spectra of each strain, from which the "species-identifying" unique biomarker ions were identified. After creating the species-specific patterns, a spectral database was generated for reliable, rapid, reproducible and accurate identification of Plesiomonas strains. The classical strain description (biochemical and serological) was thus complemented with the metabolic (proteomic) characterization. PMID- 21253920 TI - Kinked Perifix(r) FX Springwound epidural catheters. PMID- 21253919 TI - Validation of circulating MMP-7 level as an independent prognostic marker of poor survival in urinary bladder cancer. AB - Molecular marker analyses aiming a more accurate disease characterization and risk stratification of cancer patients provided several promising marker candidates in the last few years. However, recent reviews underlined the paramount importance of validation, since many of the initially promising results could not be confirmed in independent patient cohorts. If serum or plasma is a more appropriate sample to test for prognostic markers is a matter of debate. We recently found serum MMP-7 levels to correlate with poor patients' prognosis in urinary bladder cancer. In this study, we examined associations of the MMP-7 plasma levels with clinical follow-up data in an independent cohort of bladder cancer patients to validate our former results and to assess if plasma is also suitable for MMP-7 analysis. Plasma levels of 97 patients and 22 controls were analyzed, using enzyme-linked immunosorbent assay. Associations between MMP-7 plasma concentrations and clinical data were assessed applying both univariate and multivariate analysis. Plasma MMP-7 levels were significantly higher in patients than in controls. Similarly to our former findings in sera, high MMP-7 plasma levels proved to be significant and independent predictors of both overall and disease-specific survival. In addition, we observed a metastasis-specific difference in MMP-7 levels between serum and plasma. In summary, we confirmed the prognostic relevance of circulating MMP-7 levels in an independent cohort of patients and concluded that circulating MMP-7 levels may help to identify bladder cancer patients at high-risk of disease progression who could benefit from an adjuvant chemotherapy or from an extended lymph node dissection. PMID- 21253921 TI - Prevalence of child sexual abuse in Switzerland: a systematic review. AB - BACKGROUND: Although child sexual abuse (CSA) is considered to be a significant health risk, there is no systematic overview of studies that have investigated the prevalence of CSA in Switzerland. OBJECTIVES: To conduct a systematic review of studies on the prevalence of CSA in Switzerland. METHODS: A literature search was conducted using several online bibliographic databases. In addition, experts in the field in Switzerland were contacted to find studies that had not been published in academic journals. Studies were selected on the basis of predefined criteria. Because heterogeneity of studies did not allow meta-analytic calculations, data were suitably structured and summarised according to the most common types of CSA. RESULTS: Fifteen studies met inclusion criteria. Probably due to heterogeneity regarding definition and non-validated assessment of CSA, reported prevalence estimates varied greatly across studies. Prevalence rates were consistently higher for girls (up to 40%) than for boys (up to 11%). The most prevalent CSA with contact appears to be "perpetrator fondled victim", and the most common form of non-contact CSA was "exhibitionism". DISCUSSION: Due to inconsistent findings, conclusions that can be drawn are limited. However, results indicate that CSA prevalence rates in Switzerland are high and comparable to other European countries. In future, representative studies need to be conducted using a validated instrument based on internationally recognized definitions of CSA to obtain valid assessments of the prevalence of CSA in Switzerland. PMID- 21253922 TI - Spectrum of pathogens in surgical site infections at a Swiss university hospital. AB - BACKGROUND: The type of surgical antimicrobial prophylaxis (SAP) is determined by the spectrum and antimicrobial resistance of pathogens causing surgical site infections (SSI). The aim of this study was to define the microbiological features of SSI in general surgery patients at Basel University Hospital in order to validate our current strategy of single-shot SAP with 1.5 g cefuroxime (plus 500 mg metronidazole in colorectal surgery). METHODS: A prospective observational cohort of consecutive vascular, visceral and trauma procedures was analysed to evaluate the incidence of SSI. Surgical wounds and resulting infections were assessed to centres for disease control standards. Microbiological evaluation was performed by microscopic direct preparation, cultures and testing for antibiotic resistance. RESULTS: A total of 293 instances of SSI were detected in this cohort of 6283 surgical procedures (4.7%). Microbiological species were identified in 129 of 293 SSI (44%). Staphylococcus aureus (29.5%) was the most common pathogen causing SSI in trauma and vascular surgery, whereas Escherichia coli (20.9%) was more frequently responsible for SSI in visceral surgery. Importantly, not a single case of SSI was caused by antimicrobial-resistant pathogens in this series. CONCLUSIONS: The spectrum of pathogens causing SSI identified and the very low incidence of antimicrobial resistance at Basel University Hospital validate the continuous use of single-shot single-drug SAP with cefuroxime (plus metronidazole in colorectal surgery). PMID- 21253924 TI - Turn it off! the effects of exposure to male-male erotic imagery on heterosexuals' attitudes toward gay men. AB - Despite the recent proliferation of lesbian, gay, and bisexual (LGB) thematic content in U.S. media, there have been relatively few empirical investigations examining its impact on heterosexuals' attitudes toward LGB individuals. This study examined the effect of one type of content, male-male homoerotic imagery, on male and female heterosexuals' attitudes toward, stereotypes about, and affective reactions to gay men. One hundred ninety-eight undergraduate students were assigned to either a male-male or male-female erotica condition, and their corresponding attitudes toward gay men were assessed. Results revealed that the effect of erotic imagery (male-male vs. male-female) on participants' stereotype and affect scores differed for men and women at varying levels of sexual anxiety. The implications of these findings are discussed in light of the literature on exposure to erotic imagery and attitudes toward gay men. In particular, the study highlights the need for additional research that acknowledges within-gender heterogeneity with respect to antigay attitude valence, extremity, and function. PMID- 21253926 TI - Characterization and effect of biofouling on polyamide reverse osmosis and nanofiltration membrane surfaces. AB - Biofouling is a major reason for flux decline in the performance of membrane based water and wastewater treatment plants. Initial biochemical characterization of biofilm formation potential and biofouling on two commercially available membrane surfaces from FilmTec Corporation were investigated without filtration in laboratory rotating disc reactor systems. These surfaces were polyamide aromatic thin-film reverse osmosis (RO) (BW30) and semi-aromatic nanofiltration (NF270) membranes. Membrane swatches were fixed on removable coupons and exposed to water with indigenous microorganisms supplemented with 1.5 mg l(-1) organic carbon under continuous flow. After biofilms formed, the membrane swatches were removed for analyses. Staining and epifluorescence microscopy revealed more cells on the RO than on the NF surface. Based on image analyses of 5-MUm thick cryo sections, the accumulation of hydrated biofoulants on the RO and NF surfaces exceeded 0.74 and 0.64 MUm day(-1), respectively. As determined by contact angle the biofoulants increased the hydrophobicity up to 30 degrees for RO and 4 degrees for NF surfaces. The initial difference between virgin RO and NO hydrophobicities was ~5 degrees , which increased up to 25 degrees after biofoulant formation. The initial roughness of RO and NF virgin surfaces (75.3 nm and 8.2 nm, respectively) increased to 48 nm and 39 nm after fouling. A wide range of changes of the chemical element mass percentages on membrane surfaces was observed with X-ray photoelectron spectroscopy. The initial chemical signature on the NF surface was better restored after cleaning than the RO membrane. All the data suggest that the semi-aromatic NF surface was more biofilm resistant than the aromatic RO surface. The morphology of the biofilm and the location of active and dead cell zones could be related to the membrane surface properties and general biofouling accumulation was associated with changes in the surface chemistry of the membranes, suggesting the validity of the combination of these novel approaches for initial assessment of membrane performance. PMID- 21253927 TI - Elder abuse: factors related to perceptions of severity and likelihood of reporting. AB - This study examined factors that affect assessments of abuse as depicted in scenarios in which a caregiving daughter abuses her elderly mother through over medication. College students (N = 239) read scenarios that varied in terms of the past quality of the caregiver/elder relationship and whether or not the elder adult was depicted as suffering from dementia. The role of the participants' own family caregiving experiences also was explored. Results from a factorial ANOVA showed that individuals who perceived the relationship as difficult and whose parents had served as caregivers rated the behavior in the scenario as more abusive and were more willing to notify authorities than participants in other conditions. Results are discussed with a focus on educating families and those working with elderly populations. PMID- 21253928 TI - Elder abuse and oppression: voices of marginalized elders. AB - The voices of elderly people from marginalized groups are rarely solicited, and the relationship between elder maltreatment and belonging to an oppressed group has not been adequately investigated. This article reviews the literature on oppression and elder abuse and describes findings from the secondary analysis of data from focus group discussions on elder abuse held with marginalized older adults and (quasi)professionals caring for them in two Canadian cities. Participants identified that increased vulnerability to elder abuse was related to oppression experienced as a consequence of ageism, sexism, ableism/disability, racism, heterosexism/homophobia, classism, and various intersecting types of oppression. PMID- 21253929 TI - Do incident and perpetrator characteristics of elder mistreatment differ by gender of the victim? Results from the National Elder Mistreatment Study. AB - Perpetrator and incident characteristics were studied in regard to incidents of emotional, physical, and sexual mistreatment of older adults (age 60+) in a national sample of older men and women. Random digit dialing across geographic strata was used to compile a nationally representative sample; computer assisted telephone interviewing was used to standardize collection of demographic, mistreatment, and perpetrator and incident characteristics data. The final sample size consisted of 5,777 older adults. Approximately one in ten adults reported at least one form of mistreatment, and the majority of incidents were not reported to authorities. Perpetrators of physical mistreatment against men had more "pathological" characteristics compared to perpetrators of physical mistreatment against women. Perpetrators of physical mistreatment (compared to emotional and sexual mistreatment) also evidenced increased likelihood of legal problems, psychological treatment, substance use during incident, living with the victim, and being related to the victim. Implications for future research and social policy are discussed. PMID- 21253930 TI - Neglect of older adults in Michigan nursing homes. AB - Although research on domestic elder abuse and neglect has grown over the past 20 years, there is limited research on elder neglect in nursing homes. The purpose of this study is to estimate the incidence of elder neglect in nursing homes and identify the individual and contextual risks associated with elder neglect. Data came from a 2005 random digit dial survey of individuals in Michigan who had relatives in long term care. Our analytic sample included 414 family members who had a relative aged 65 or older in nursing homes. Results showed that about 21% of nursing home residents were neglected on one or more occasion in the last 12 months. Two nursing home residents' characteristics reported by family members appear to significantly increase the odds of neglect: functional impairments in activities of daily living and previous resident-to-resident victimization. Behavior problems also are associated with higher odds of neglect (p = 0.078). Policy implications of these results are discussed. PMID- 21253931 TI - Elder abuse and neglect in African American families: informing practice based on ecological and cultural frameworks. AB - Despite the rapid growth of the elderly African American population in the U.S., elder abuse and neglect in African American families continue to be underdeveloped areas of study. This article presents an ecological and culturally informed framework for the study of elder abuse in African American populations. The model was developed based on Bronfenbrenner's Human Ecological Theory. The model identifies risk factors associated with different systems that have an influence on the lives of African American families. Cultural protective factors also are identified in the model. The model is intended to provide an understanding of elder abuse and neglect in African American families by considering the influence of contextual factors such as the legacy of slavery, social exclusion, and structural segregation and racism. Specific suggestions for practice are proposed according to cultural strengths of African American communities as well as the ecological premises of the model. PMID- 21253932 TI - Perceptions of intimate partner violence, age, and self-enhancement bias. AB - Educational programs in human service professions such as social work, criminal justice, psychology, and public administration stress the importance of recognizing domestic/intimate partner violence as well as elder abuse. Students' abilities to recognize domestic violence in older couples have not been well investigated. In this study, three vignettes were developed (Pat and Lee at age 75, Pat and Lee at age 30, Imagine yourself with Lee at age 75) in which intimate partner violence was perpetrated by the character Lee. Twenty-five items followed each vignette. When the variables of educational standing (graduate/undergraduate), ethnicity, and academic major were controlled, there were significant differences between the vignettes in 14 of 25 items (General Linear Model, F = 1.552, df = 50, p = .012). More than three out of four respondents for each vignette identified this as domestic violence and believed there was potential for serious harm. However, respondents were less likely to believe that a 75-year-old partner would know when to terminate a relationship in which there was intimate partner violence. Respondents who were asked to imagine themselves with Lee at 75 were likely to perceive Lee as more dangerous than respondents for the other vignettes. Implications are considered for educators. PMID- 21253933 TI - The relationship between measures of cognitive attention and behavioral ratings of attention in typically developing children. AB - In the present study, we explored the relation between performance on cognitive measures of attention (selection, sustained, and control) and behavioral ratings of inattention and hyperactivity in a sample of typically developing children aged 3 to 7 years. We also examined the influence of chronological age and IQ on both task performance and behavior ratings. Four well-documented attention paradigms were employed, the Visearch (single-target search) task as a measure of selective attention, the Continuous Performance Test (CPT) as a measure of sustained attention, the Day-Night task as a measure of response inhibition, and the Visearch (dual-target search) task as a measure of inhibitory control. The Conners' Rating Scales (Cognitive/Inattention and Hyperactivity subscales) were used to allow for a finer tuned comparison of cognitive performance as related to inattentive behaviors versus hyperactive behaviors. Findings indicate that accuracy and speed in the Visearch dual search task were the most sensitive measures relating respectively to inattentive and hyperactive rated behaviors. PMID- 21253934 TI - The singular vision of William Charles Wells (1757-1817). AB - William Charles Wells retained an interest in vision throughout his life. His first book was on single vision with two eyes; he integrated vision and eye movements to determine principles of visual direction. On the basis of experiments and observations he formulated three principles of visual direction, which can readily be demonstrated. In the course of these studies, he also examined visual acuity, accommodation and convergence, visual persistence, and visual vertigo. Insights into visual processing were mainly derived from observations of afterimages that were used to provide an index of how the eyes moved. His experiments enabled him to distinguish between the consequences of active and passive eye movements (later called outflow and inflow) as well as describing nystagmus following body rotation. After providing a brief account of Wells's life, his neglected research on vision is described and assessed. PMID- 21253935 TI - Anthropological neurology: symptoms and their meanings according to Joseph Prick (1909-1978). AB - This article describes the life and work of the Dutch neurologist Joseph Prick (1909-1978) and his idea of an anthropological neurology. According to Prick, neurological symptoms should not only be explained from an underlying physico chemical substrate but also be regarded as meaningful. We present an outline of the historical and philosophical context of his ideas with a focus on the theory of the human body by the French philosopher Maurice Merleau-Ponty (1908-1961) and the concept of anthropology-based medicine developed by Frederik Buytendijk (1887 1974). We give an overview of anthropological neurology as a clinical practice and finally we discuss the value of Prick's approach for clinical neurology today. PMID- 21253936 TI - Neurognostics question. PMID- 21253937 TI - The stepping test: a step back in history. AB - The stepping test is a valuable part of the neurological examination that is used to localize labyrinthine pathology. The test is known by two eponyms: the "Fukuda Test" in the United States and Asia and the "Unterberger Test" in Europe. Some controversy exists as to which name is correct. Siegfried Unterberger was an Austrian otolaryngologist who initially described the test in 1939. It was modified in 1959 by Tadashi Fukuda, a Japanese otolaryngologist, who introduced a method to better quantify the test results. Thus, the test should be called the "Unterberger Test," unless Fukuda's methods for measurement are used. PMID- 21253938 TI - An approach to nineteenth-century medical lexicon: the term "dreamy state". AB - Hughlings-Jackson coined the concept of dreamy state: According to him, one of the sensations of a "dreamy state" was an odd feeling of recognition and familiarity, often called "deja vu". A clear sense of strangeness could also be experienced in the "dreamy state" ("jamais vu"). Jackson himself did not use these French terms, but he was quite clear about the vivid feelings of strangeness and familiarity, which can occur in both normal and pathological conditions. In order to explore some of the exchanges between medical and nonmedical vocabularies, we examine the historical origins of this technical concept. By basing the study on European (medical and nonmedical) literature of the nineteenth century, we review the first descriptions of this state and compare them with the famous Hughlings-Jackson definitions. It appears that this medical concept was partly borrowed from a wide cultural background before being rationally developed and reworked in the fields of neurology and psychiatry. PMID- 21253939 TI - Postlesion recovery of motor and sensory cortex in the early twentieth century. AB - This article addresses early work on partial recovery that followed small motor cortical lesions. Leyton and Sherrington (1917) studied the motor cortex in apes, hoping to learn more about the contralateral muscle representations. Then they placed small lesions within the precentral cortex, followed by a loss of the contralateral muscle twitches. The sudden loss remained for about one week, but recovery was observed and continued for weeks, up to a standstill. Sherrington and Graham Brown (1913) observed the same results in a serial, chronic experiment on a chimpanzee. The brain was sent to Monakow's Brain-Institute in Zurich for investigating the lesions and the degeneration pattern. Constantin von Monakow (1853-1930) had been a pioneer on recovery after acute lesions, coining the term "diaschisis." During WWI, Graham Brown and Stewart (1916) studied a soldier in a British army hospital who suffered from a cerebral gunshot wound, localized in the sensorimotor cortex. Early and prolonged rehabilitation was successful. In 1950, Glees (1909-1999) and Cole (Oxford) placed a small motor-cortical lesion in macaque monkeys; for a few days, the monkeys had difficulties and were slow for the task. Daily training was resumed and recovery was accelerated by alimentary reward. Finally, Lashley (1890-1958) understood that handicapped patients "achieved their goal with variable means." This demonstrated the value of active and prolonged rehabilitation, in addition to the (passive) recovery of function. PMID- 21253940 TI - Psychic blindness or visual agnosia: early descriptions of a nervous disorder. AB - This article briefly reports on three early contributions to the understanding of visual agnosia as a syndrome sui generis. The authors of the respective papers worked in different fields such as physiology, ophthalmology, and neurology, and, although they were not in direct contact with each other, their results converged upon a consistent view of a nervous disorder that they called psychic blindness. PMID- 21253942 TI - Neurognostics answer. PMID- 21253941 TI - The disease of the moon: the linguistic and pathological evolution of the English term "lunatic". AB - The public opinion and the scientific community incorrectly believe that the English term "lunatic" was originally related only to insanity, but it also referred to epileptic people. The aim of this article is to clarify the original meaning of the English word "lunatic" by analyzing the evolution of the relationship between psychiatric and neurological diseases and by pointing out the influence of the moon in the history of medicine, in popular traditions, and in English literature. The article also contains a detailed and accurate review of the modern scientific literature on the relationship between moon and epilepsy/psychiatric disorders. PMID- 21253944 TI - Ginsenoside-Rg1 mediates microenvironment-dependent endothelial differentiation of human mesenchymal stem cells in vitro. AB - Bone marrow-derived mesenchymal stem cells (MSCs) possess a multi-lineage differentiation potential and have the ability to repair and rebuild injured vessels. The autologous differentiated MSC transplantation also makes possible the tissue-engineered grafts. Therefore, the efficient endothelial differentiation of MSCs could be beneficial in the successful injured vessel repair and engraftment. Ginsenoside-Rg1, the most prevalent active constituent of ginseng, is a potent proangiogenic factor of vascular endothelial cells and also has the ability to enhance the proliferation of bone marrow cells. The aim of this study is to investigate the role of ginsenoside-Rg1 in the microenvironment dependent endothelial differentiation of human MSCs (hMSCs) in vitro. The endothelial differentiation environment was established by co-culturing hMSCs with mature endothelial cells (human umbilical vein endothelial cells) indirectly in vitro. Reverse transcriptase-polymerase chain reaction analysis and fluorescence immunocytochemistry showed a strong expression of endothelial specific markers such as CD31, Von Willebrand factor, and VE-cadherin. Electron microscopy showed the endothelial characteristic Weibel-Palade bodies of differentiated hMSCs. The increased expression of CD31 demonstrated that Rg1 promoted the endothelial differentiation of hMSCs. The findings here show the differentiation of hMSCs into cells with phenotypic features of endothelial cells using indirect co-culture with mature endothelial cells and provide the evidence that ginsenoside-Rg1 can promote the milieu-dependent endothelial differentiation of hMSCs in vitro. PMID- 21253945 TI - DNA damage induced by shikonin in the presence of Cu(II) ions: potential mechanism of its activity to apoptotic cell death. AB - Shikonin (beta-alkannin), a naphthazarin derivative, has shown a variety of abilities such as anti-inflammatory, antitumoral, cytotoxic, and antimicrobial activities. In the presence of Cu(II), shikonin caused breakage of supercoiled plasmid pBR322 DNA. Other metal ions tested [Mg(II), Ca(II), and Ni(II)] were ineffective and only Fe(II) has the same ability in the DNA breakage reaction. The involvement of active oxygen in the reaction was established by the inhibition of DNA breakage by superoxide dismutase, catalase, thiourea, sodium azide, potassium iodide, and sodium benzoate. Cu(I) was shown to be an essential intermediate using the Cu(I)-specific sequestering reagent neocuproine. Shikonin induced HeLa cell apoptosis involved in the mechanism of increasing intracellular reactive oxygen species (ROS). It was suggested that shikonin generated ROS as a pro-oxidant in the presence of Cu(II), and ROS resulted in DNA damage and apoptotic cell death in cells. PMID- 21253946 TI - 3,4,5,6-Tetrahydroxyxanthone preserves intercellular communication by reduction of the endogenous nitric oxide synthase inhibitor level. AB - To observe the direct effects of 3,4,5,6-tetrahydroxyxanthone on connexin43 (Cx43) expression in cultured endothelial cells, cells were treated with lysophosphatidylcholine (LPC, 10 mg/l) for 24 h in the presence or absence of different concentrations of 3,4,5,6-tetrahydroxyxanthone (1, 3, or 10 MUmol l(- 1)). The reactive oxygen species (ROS) production, cell viability, asymmetric dimethylarginine (ADMA) levels, and Cx43 expression were detected. 3,4,5,6 Tetrahydroxyxanthone significantly inhibited the increase in ROS production and ADMA level, increased cell viability and up-regulated Cx43 mRNA and protein expression induced by LPC. 3,4,5,6-Tetrahydroxyxanthone has protective effect in LPC-induced atherosclerotic lesions, which is at least partly related to the reduction of ADMA level and downregulation of Cx43 expression. PMID- 21253947 TI - Silibinin activated ROS-p38-NF-kappaB positive feedback and induced autophagic death in human fibrosarcoma HT1080 cells. AB - Our previous results demonstrated that silibinin induced autophagic and apoptotic cell death dependent on reactive oxygen species (ROS especially H(2)O(2) and [image omitted] ) in HT1080 cells. In this study, we further show that p38-NF kappaB pathway is involved in silibinin-induced ROS-mediated autophagy. Cells were pretreated with serum-free media for 24 h before being treated with silibinin. Generation of ROS and autophagy was detected in 15 min and 1 h, respectively. Development of autophagy was supported by an upregulated expression of Beclin-1 and conversion of light chain (LC3-I-LC3-II). Expression of p38/p-p38 and transposition of NF-kappaB from cytoplasm to nuclei were also increased. Inhibitors of p38 and NF-kappaB and scavengers of H(2)O(2) and O(2)(*-) reduced both generation of ROS and simultaneous occurrence of silibinin-induced autophagy. Besides, expression of p38/p-p38 and transposition of NF-kappaB from cytoplasm to nuclei were decreased by these two ROS scavengers. ROS and p38-NF kappaB pathway were possibly cooperated in a positive feedback mechanism. Inhibition of p38, NF-kappaB, H(2)O(2), or O(2)(*-) rescued cells from silibinin induced death in a long-term (12 h) manner. According to the previous study that silibinin-induced autophagy was a positive regulator of apoptotic cell death, it was possible that ROS and p38-NF-kappaB mediated silibinin-induced autophagy and eventually led to cell death. PMID- 21253948 TI - Three new flavonoid glycosides from Pinus tabulaeformis Carr. AB - Three new flavonoid glycosides, named 7,8,4'-trihydroxy-3,5-dimethoxy-6 methylflavonol-8-O-beta-D-glucopyranoside (1), 5,7,4'-trihydroxy-3-methoxy-6 methylflavonol-7-O-beta-D-glucopyranoside (2), 3,5,7,4'-tetrahydroxy-6 methylflavonol-7-O-beta-D-glucopyranoside (3), together with two known flavonoid glycosides were isolated from the needles of Pinus tabulaeformis Carr. Their structures were established on the basis of various spectroscopic analyses. PMID- 21253949 TI - Protective effect of curcumin (Curcuma longa) against D-galactose-induced senescence in mice. AB - Brain senescence plays an important role in cognitive dysfunction and neurodegenerative disorders. Curcumin was reported to have beneficial effect against several neurodegenerative disorders including Alzheimer's disease. Therefore, the present study was conducted in order to explore the possible role of curcumin against D-galactose-induced cognitive dysfunction, oxidative damage, and mitochondrial dysfunction in mice. Chronic administration of D-galactose for 6 weeks significantly impaired cognitive function (both in Morris water maze and elevated plus maze), locomotor activity, oxidative defense (raised lipid peroxidation, nitrite concentration, depletion of reduced glutathione and catalase activity), and mitochondrial enzyme complex activities (I, II, and III) as compared to vehicle treated group. Curcumin (15 and 30 mg/kg) and galantamine (5 mg/kg) treatment for 6 weeks significantly improved cognitive tasks, locomotor activity, oxidative defense, and restored mitochondrial enzyme complex activity as compared to control (D-galactose). Chronic D-galactose treatment also significantly increased acetylcholine esterase activity that was attenuated by curcumin (15 and 30 mg/kg) and galantamine (5 mg/kg) treatment. In conclusion, the present study highlights the therapeutic potential of curcumin against d galactose induced senescence in mice. PMID- 21253950 TI - Phenylpropanoids from the leaves of Acanthopanax koreanum and their antioxidant activity. AB - By various chromatographic methods, one new phenylpropanoid, acanthopanic acid (1), and three known compounds, 1,2-O-dicaffeoylcyclopenta-3-ol (2), (4S)-alpha terpineol 8-O-beta-D-glucopyranoside (3), and rutin (4), were isolated from the methanol extract of the Acanthopanax koreanum leaves. Their structures were elucidated on the basis of spectroscopic analyses, and their antioxidant activities were evaluated by the intracellular reactive oxygen species (ROS) radical scavenging 2',7'-dichlorofluorescein diacetate assay. Among them, compounds 1, 2, and 4 showed significant scavenging capacity with IC(50) values of 3.8, 2.6, and 2.9 MUM, respectively, and compound 3 showed weak scavenging capacity with the inhibition rate of 37% at 40 MUM. PMID- 21253951 TI - New anthraquinone dimer from the root bark of Cassia artemisioides (Gaudich. Ex. DC) Randell. AB - The phytochemical investigation of the root bark of Cassia artemisioides (Gaudich. Ex. DC) Randell resulted in the isolation of one new anthraquinone 1,1' dihydroxy-3,3'-dimethyl-8,8'-dimethoxy-6,6'-O-bianthraquinone (1) along with four known anthraquinones 1,6-dihydroxy-8-methoxy-3-methylanthraquinone (2), 1-hydroxy 8-methoxy-3-methylanthraquinone (3), 1,8-dihydroxy-6-methoxy-3 methylanthraquinone (4), and 1,6,8-trihydroxy-3-methylanthraquinone (5). The structures of the compounds were elucidated using spectroscopic techniques including 1D and 2D NMR. The compounds were evaluated for antioxidant activity. 1,6,8-Trihydroxy-3-methyl anthraquinone (5) showed good activity among the tested compounds. PMID- 21253952 TI - A new active compound against kidney deficiency from the fruits of Rubus corchorifolius. AB - Constituents of the fruits of Rubus corchorifolius were investigated. A new compound, namely rubusin A (1), along with three known compounds, was isolated and characterized. Among them, the new compound exhibited significant activity against kidney deficiency, and quercetin and kaempferol were isolated from the fruits of R. corchorifolius for the first time. PMID- 21253953 TI - Antibacterial sesquiterpene lactone glucoside from seed pods of Bauhinia retusa. AB - From the seed pods of Bauhinia retusa, a new eudesmane sesquiterpene glucoside, 1 O-beta-D-glucopyranosyl-9beta,15-dihydroxy-5alpha,6betaH-eudesma-3-ene-6alpha,12 olide (1), has been isolated together with three known compounds, 4'-hydroxy-7 methoxy flavane (2), beta-sitosterol (3), and stigmasterol (4). The structures of isolated compounds were verified with the help of 1D, 2D NMR, and HR-ESI-MS spectroscopies. Compound 1 showed moderate antibacterial activity against Pseudomonas aeruginosa and Escherichia coli when a disc diffusion method is used. PMID- 21253954 TI - Anti-inflammatory flavonolignans from Hydnocarpus anthelminthica seeds. AB - A new flavonolignan, anthelminthicol A (1), together with four known compounds, was isolated from the EtOAc extracts of the seeds of Hydnocarpus anthelminthica. Their structures were elucidated using extensive spectroscopic techniques. Bioassay showed that compounds 3-5 could inhibit nitric oxide production in LPS stimulated RAW 264.7 macrophage cell lines, with IC(50) values of 7.81, 9.38, and 10.55 MUM, respectively. PMID- 21253955 TI - Ozocardic A: a new alkylanacardic acid from Ozoroa pulcherrima. AB - One new alkylanacardic acid, ozocardic A (1), along with the known and related metabolites 6-tridecyl anacardic acid (2) and beta-sitosterol (3) was isolated from Ozoroa pulcherrima. The structure of the new compound was elucidated by detailed spectroscopic analysis such as (1)H, (13)C NMR, COSY, HMQC, HMBC, and HREIMS. The structures of known compounds (6-tridecyl anacardic acid (2) and beta sitosterol (3)) were identified by the comparison of their spectral data with those published in the literature. PMID- 21253956 TI - A new xanthone from Halenia elliptica D. Don. AB - A new xanthone, 1,5-dihydroxy-2,3,4-trimethoxyxanthone (1), together with 15 known compounds (2-16), was isolated from an ethanolic extract of Halenia elliptica D. Don. Their structures were elucidated by spectroscopic methods. Among the known compounds, the (13)C NMR spectroscopic data of 2,3,4,5 tetramethoxyxanthone-1-O-gentiobioside (2) were reported for the first time. PMID- 21253957 TI - Selective bias in retrospective self-reports of negative mood states. AB - Retrospective self-report questionnaires of negative mood states experienced in the past (e.g., the most recent two weeks) tend to be exaggerated in a negative direction relative to the average ratings given to the moods contemporaneously. The present study used three measures that decomposed mood states into their constituent elements to examine whether certain components selectively contributed to this negative bias or all components contributed to this bias equally. Fifty-three participants responded to the questionnaires via the Internet every evening for two weeks. On the final day, participants recalled and retrospectively evaluated their mood state over the previous two weeks as a whole. The results revealed that memory bias occurred selectively for negative mood states. Anxiety, depression, and helplessness were exaggerated in the global compared with the daily ratings. None of the positive mood components showed any bias in the retrospective global ratings. A regression analysis indicated that the difference in daily and global ratings for negative mood was partly explained by peak and final scores. Higher peak scores led to greater overestimation whereas final scores had smaller effects; the higher the final score was, the less participants overestimated their negative mood in the global ratings. PMID- 21253959 TI - Memory worries and self-reported daily forgetfulness: a psychometric evaluation of the Dutch translation of the Multifactorial Memory Questionnaire. AB - The expression of memory worries and the self-reporting of daily forgetfulness easily spark discussion among sufferers and their family or friends about what is normal or abnormal forgetfulness. One way to investigate whether the reporting of forgetfulness might be excessive is to use a standardized memory questionnaire- for instance, the Multifactorial Memory Questionnaire (MMQ). The MMQ measures worries, daily forgetfulness, and memory strategy use. In this study we present a psychometric evaluation of the Dutch translation of the MMQ and provide normative data to determine the significance of individual differences in subtest scores. In addition, clinical examples are given of the use and interpretation of percentile norms and single-case statistics. PMID- 21253958 TI - Specificity of verbal learning impairment and recovery in a marijuana-dependent male: the effects of sustained marijuana abstinence. AB - INTRODUCTION: We present the case of a young adult in treatment for marijuana dependence, with recurrent depression and a history of possible traumatic brain injury, complaining of concentration, memory, and initiation problems. METHODS: The patient was assessed longitudinally during treatment with a brief neuropsychological battery, as well as measures of marijuana use and mood. RESULTS: Testing at treatment baseline revealed performance that was generally in the high average range or higher on measures of reaction time and attention, with a selective impairment in verbal learning (borderline to extremely low range). Following 8 weeks of abstinence from marijuana, his verbal learning recovered to expected levels (high average range), with signs of improved learning strategy, efficiency, rate, and capacity. However, his reaction time and attention showed minimal evidence of change. CONCLUSIONS: This finding is consistent with the literature that demonstrates that marijuana-associated neurocognitive impairments may be most pronounced in the domain of verbal learning and may remit with abstinence. The clinical implications of these case findings and recommendations for neuropsychological assessment of marijuana abusers are discussed. PMID- 21253962 TI - The TCN/AACN 2010 "salary survey": professional practices, beliefs, and incomes of U.S. neuropsychologists. AB - Doctoral-level members of the American Academy of Clinical Neuropsychology, Division 40 (Clinical Neuropsychology) of the American Psychological Association, and the National Academy of Neuropsychology, and other neuropsychologists, were invited to participate in a web-based survey in early 2010. The sample of respondents was 56% larger than a prior related income and practice survey in 2005. The substantial proportional change in gender taking place in the field has continued, with 7 of 10 post-doctoral residents being women and, for the first time ever, more than half of the total sample of respondents being women. Whereas the median age of APA members has been over 50 since the early 1990s, the current median age of clinical neuropsychologists remains at 47 and has remained essentially unchanged since 1989, indicating substantial entrance of young psychologists into the field. The Houston Conference training model has influenced the vast majority of residency training sites, and is endorsed as compatible with prior training by two-thirds of all respondents. Testing assistant usage remains commonplace, and is much more common in institutions. The "flexible battery" approach has again increased in popularity and predominates, whereas endorsement of the "fixed/standardized battery" approach has continued to decline. The vast majority of clinical neuropsychologists work full time. Average length of time reported for evaluations increased significantly from 2005, which does not appear to be explained by changes in common referral sources or common diagnostic conditions being evaluated. The most common factors affecting evaluation length were identified, with the top three being goal of evaluation, stamina/health of examinee, and age of examinee. Pediatric specialists are more likely than others to work part time, more likely to be women, more likely to work in institutions, and report lower incomes than respondents whose professional identity is purely adult or a combination of adult and pediatric. Incomes once again vary considerably by years of clinical practice, work setting, amount of forensic practice, state, and region of country. Job satisfaction has little relationship to income and is comparable across most variables (e.g., work setting, professional identity, amount of forensic activity), whereas income satisfaction has a stronger relationship to actual income, and income satisfaction and job satisfaction are moderately correlated. Job satisfaction of neuropsychologists in general is higher than reported for other US jobs. Fewer than 5% of respondents are considering changing job position. As was true in the 2005 survey, a substantial majority of respondents reported increased incomes over the last 5 years. Actual reported income values were meaningfully higher than in 2005 across general work settings and professional identities, and were also higher for entry-level positions. Numerous breakdowns related to income and professional activities are provided. PMID- 21253964 TI - Detection of insufficient effort using the advanced clinical solutions for the Wechsler Memory Scale, fourth edition. AB - This study investigated the ability of the Wechsler Memory Scale-4th Edition (WMS IV) and the Advanced Clinical Solutions (ACS) package including the new Word Choice test (WCT) to distinguish poor performance due to intentional response bias among simulators of traumatic brain injury (TBI) from poor performance due to actual TBI. Participants were 45 survivors of moderate to severe TBI and 39 healthy adult coached to simulate TBI. Logistic regression indicated that a five variable model containing all the ACS variables and a single-variable model using only the WCT were statistically reliable. Comparing predictive accuracy of each model found that adding the WCT to the ACS increased predictive accuracy. Diagnostic efficiency for the full ACS model was considered "excellent" according to interpretive guidelines. PMID- 21253963 TI - Pre- and post- GPi DBS neuropsychological profiles in a case of X-linked dystonia Parkinsonism. AB - We present the pre to post bilateral globus pallidus interna (GPi) deep brain stimulation neuropsychological profiles of a 69-year-old patient with a 12-year history of X-linked dystonia-Parkinsonism (XDP). Pre-operative cognitive function was impaired in almost all domains and this impaired performance was not dependent on his medications. Following DBS, changes in neuropsychological functioning were examined using Reliable Change Indices and standardized z-score comparisons. Results showed reductions in processing speed in the context of stable performance in language and visuospatial domains. Post-operative improvements occurred on a cognitive screening measure, verbal memory, and a test of problem-solving skills. This is the first report on an individual with XDP who was cognitively impaired, but had good outcome following GPi bilateral stimulation to treat debilitating motor symptoms. The possible mechanisms for his stable cognitive performance include the target of his DBS, reduced medication dosage, and improvement in dystonia that may in turn have reduced patient's pain. PMID- 21253966 TI - An influenza hemagglutinin A peptide assay based on the enzyme-multiplied immunoassay technique. AB - A practical approach for constructing enzyme-multiplied immunoassay technique (EMIT)-based protein/peptide assays is described. Normally used in small-molecule drug testing, EMIT is a homogeneous assay method that is attractive for its simplicity, sensitivity, and rapidity. The EMIT-based peptide/protein assay was developed by conjugating a cysteine-modified HA peptide (from influenza hemagglutinin A) to the reporter enzyme, glucose-6-phosphate dehydrogenase. The 13-min assay gave a free HA limit of detection of 10 nM and proved effective for detection of a high-molecular-weight model protein tagged with HA. Similar EMIT based assay approaches may be developed for applications in biotoxin and infectious disease detection. PMID- 21253967 TI - Brain-derived neurotrophic factor in human saliva: ELISA optimization and biological correlates. AB - In order to assess the physiological significance of human salivary brain-derived neurotrophic factor (BDNF), we have optimized a sensitive and specific enzyme linked immunosorbent assay (ELISA). We determined the range of salivary BDNF concentrations, the impact of saliva collection method, and the association of salivary BDNF with several biological characteristics. The ELISA had a detection limit of 62.5 pg/mL, and intra-assay and interassay precisions of 4.2% and 8.2%, respectively. Salivary BDNF concentrations were highly variable between individuals (median = 618 pg/mL) and were affected by collection method. Women had significantly higher levels of salivary BDNF than men. There was no relationship, however, between salivary BDNF levels and the other biological characteristics examined. PMID- 21253968 TI - A chemifluorescent immunoassay for the determination of marinobufagenin in body fluids. AB - We describe here the development of a chemifluorescent competitive enzyme-linked immunosorbent assay (ELISA) that quantifies marinobufagenin (MBG) levels in biological fluids. Based on a polyclonal antibody raised against a novel MBG bovine serum albumin conjugate, this assay achieved an MBG detection limit of less than 9 pg/mL. MBG levels in various rat urine and serum samples were effectively determined using this methodology. Interassay variability averaged 9.8%, while intra-assay variability averaged 1.9 and 2.5% in representative serum and urine samples, respectively. Recovery of exogenously added MBG averaged 106%, and parallelism data further established the accuracy of the assay. Employment of this assay to detect MBG abnormalities represents a powerful tool for the possible diagnosis, prevention and management of human hypertensive states, particularly preeclampsia. PMID- 21253969 TI - Expression of Toll-like receptor 4, CD14, and NF-kappaB in Chinese patients with ulcerative colitis. AB - This study elucidates the significance of Toll-like receptor 4 (TLR4), CD14, and nuclear factor (NF)-kappaB on the pathogenesis of ulcerative colitis (UC). Colonic biopsy specimens were collected from active UC and controls. The expression of TLR4, CD14, and NF-kappaBp 65 was analyzed by immunohistochemistry (IHC) and reverse-transcription polymerase chain reaction (RT-PCR). In UC, disease activity index (DAI) and pathological grade were classified according to the Powell-Tuck grade system and Truelove-Richards system, respectively. Fifty six UC cases and 56 controls entered the investigation. IHC and RT-PCR revealed a significant increase of TLR4, CD14, and NF-kappaBp 65 antigen expression in colonic mucosa of UC compared with colonic mucosa of controls (p < .001). In UC, TLR4, CD14, and NF-kappaBp 65 expression were positively related to DAI (r = .873, p < .001; r = .576, p < .001; r = .747, p < .001 receptively). NF-kappaBp65 significantly correlated with TLR4 and CD14 (r = .669, p < .001; r = .576, p < .001, receptively). TLR4, CD14, and NF-kappaBp65 were positively related to pathological classification in UC (p < .01). Thus, TLR4, CD14, and NF-kappaBp65 were upregulated significantly in UC, to an extent that reflects the degree of inflammation and thereby might contribute to the occurrence and development of UC. PMID- 21253970 TI - Generation of a specific polyclonal antibody with high affinity to atorvastatin and its employment in the development of ELISA for determination of atorvastatin in plasma. AB - For the first time, a polyclonal antibody with high affinity to atorvastatin (ATR) was generated. The high specificity of the antibody for ATR among its structural analogues and co-administered therapeutic agents was proved. The antibody was employed in the development of enzyme-linked immunosorbent assay for quantitation of ATR in plasma. The assay was validated over a working range of 0.2-5 ng/mL. The intra- and interassay precisions were satisfactory; the coefficients of variations were <=5%. The accuracy of the method was proved as the mean recovery was 96.4 +/- 4.3%. The assay can be used in therapeutic monitoring and pharmacokinetic studies for ATR. PMID- 21253971 TI - The presence of TRAIL-OPG complex in human osteosarcoma and human salivary gland adenocarcinoma. AB - A sensitive sandwich enzyme-linked immunosorbent assay (ELISA) for the human tumor necrosis factor-related apoptosis-induced ligand (TRAIL)-osteoprotegerin (OPG) complex was developed by utilizing a monoclonal antibody that recognizes human soluble TRAIL as an immobilized capture component and anti-human OPG immunoglobulin G (IgG) labeled with biotin. We could quantify the TRAIL-OPG complex level (detection limit: 10 pmol/L). Employing this assay system, we demonstrated that the TRAIL-OPG complex was constitutively present in the human osteosarcoma cell lines, HOS, MG-63, and human salivary gland adenocarcinoma cell line, HSG. PMID- 21253972 TI - The impact of acute moderate intensity exercise on arterial regional stiffness, lipid peroxidation, and antioxidant status in healthy males. AB - There is a paucity of research examining the influence of acute exercise on pulse wave velocity (PWV) and oxidative stress. The purpose of this study was to examine the effects of acute moderate aerobic exercise on PWV and oxidative stress in healthy males. Eight apparently healthy males (age 23.6 +/- 2.8 yrs; stature 181.4 +/- 8.1 cm; weight 83.4 +/- 16.2 kg; all data mean +/-SD) participated in a randomized crossover design consisting of (i) a one hour bout of moderate aerobic exercise and (ii) a control trial of one hour rest. Pre- and post-exercise blood samples were drawn for the determination of lipid hydroperoxides (LOOHs) and lipid-soluble antioxidants (lycopene, retinol, and beta-carotene). Exercise had no effect on stiffness and LOOHs (P > 0.05). Retinol and lycopene were increased following exercise (P < 0.05). These findings suggest that acute moderate exercise has no effect on PWV and LOOHs, but it can increase systemic antioxidants, which may be of benefit to health. PMID- 21253973 TI - No fluid overload in male ultra-runners during a 100 km ultra-run. AB - We investigated the change in body composition and hydration status in 27 male ultra-runners during a 100 km ultra-run. The athletes drank fluids ad libitum during the run; intake of calories, fluids, and electrolytes during performance were determined. Body mass decreased by 1.9 kg, haematocrit decreased, plasma [Na(+)] remained unchanged, and urinary specific gravity and plasma volume increased. Fluid intake was 0.52 (0.18) L/h and was related to running speed (r = 0.50; p = 0.0081). Delta body mass was associated with total fluid intake during the race (r = 0.49, p = 0.0095). Sodium intake amounted to 425 (478) mg/h and potassium intake to 140 (179) mg/h. Sodium and potassium intake were not related to either postrace concentration or change in plasma concentration. Sodium intake, however, was related to Delta urinary sodium concentration (r = 0.45, p = 0.0227). The increase in plasma volume was significantly and negatively related to both postrace plasma [Na(+)] (r = - 0.42, p = 0.0278) and the postrace potassium-to-sodium ratio in urine (r = - 0.44, p = 0.0218). To conclude, we found no fluid overload in these ultra-runners, the increase in plasma volume was most probably due to a stimulation of the renin-angiotensin-aldosterone system (RAAS) since sodium intake was not related to both the change in plasma [Na(+)] or postrace plasma [Na(+)]. PMID- 21253974 TI - Step time variability and pelvis acceleration patterns of younger and older adults: effects of footwear and surface conditions. AB - This study investigated the effects of various shoe features and surfaces on step time variability and pelvis accelerations (RMS) during walking in six younger and 22 older adults. Participants walked at a self-selected speed in five shoe conditions (standard, elevated heel, soft sole, hard sole, and high collar) on two surfaces: level and irregular. Results showed an age-related reduction in step time variability on the irregular surface and increased medio-lateral (ML) acceleration RMS in older people walking on the irregular versus the level surface. When wearing the elevated heel shoes, both young and old participants displayed significant reductions in pelvis ML accelerations, suggesting a compensatory strategy to counteract for lateral instability resulting from heel elevation. Overall, the findings demonstrate that older people are less able than younger ones to meet the stepping adaptability required for negotiating an irregular surface and, as a possible consequence, have more difficulty maintaining frontal plane stability on such a surface. PMID- 21253975 TI - Hamstring functions during hip-extension exercise assessed with electromyography and magnetic resonance imaging. AB - The purpose of this study was to compare the recruitment patterns in hamstring muscles during hip extension exercise by electromyography (EMG) and muscle functional magnetic resonance imaging (mfMRI). Six male volunteers performed 5 sets of 10 repetitions of the hip extension exercise. Electromyography (EMG) activity during the exercise was recorded for the biceps femoris long head (BFlh), semitendinosus (ST), and semimembranosus (SM) muscles; mfMRI T2 values and cross-sectional areas (CSAs) of the same muscles were measured at rest, immediately after, 2 and 7 days after the exercise. The study found that EMG of the BFlh and SM were significantly higher than that of the ST. Immediately after the exercise, the T2 value and CSA changes in the SM showed a significant increase. It was concluded that the BFlh and SM were selectively recruited during the hip extension exercise. PMID- 21253976 TI - Sirtuins: a family of proteins with implications for human performance and exercise physiology. AB - The sirtuin family of proteins consists of seven members in mammals (SirT1-T7). Sirtuins share NAD dependency for their enzymatic activity, but some show NAD dependent deacetylase activity, others exhibit ADP ribosyltransferase activity or both. Sirtuins have gained considerable attention due to their impact as physiological targets for treating diseases associated with aging. Sirtuins interact with metabolic pathways and may serve as entry points for drugs. This review discusses the biology of sirtuins and their potential as mediators of caloric restriction and pharmacological targets. Reduced insulin sensitivity, mitochondrial dysfunction, and others are consequences of aging or secondary to physical inactivity. Moreover, understanding human energy metabolism through sirtuins may provide a novel approach to exercise physiology. Quercetin, a natural polyphenolic flavonoid that has been widely investigated for its other health benefits, may act as an inducer of SirT1. The benefits of quercetin for exercise performance may have implications for athletes and extended to disease prevention. PMID- 21253977 TI - Common peroneal neuropathy related to cryotherapy and compression in a footballer. AB - This report describes the effect of excessive cooling with ice, and compression with a plastic wrap on the common peroneal nerve (CPN) for 90 minutes in a professional footballer, which led to a common peroneal nerve palsy and a resulting footdrop. It highlights the need to be cautious with regards to the duration and frequency of icing as well as the choice of anchoring material when applying ice to injured areas that have superficial nerves passing nearby. Full recovery of the CPN function occurred in this athlete after five weeks. The major causes of footdrop and common causes of common peroneal neuropathy are discussed. PMID- 21253978 TI - Unintended consequences. PMID- 21253980 TI - Isolation of airborne oxacillin-resistant Staphylococcus aureus from culturable air samples of urban residences. AB - Culturable single-stage impactor samples were collected onto nutrient agar in kitchen and bedroom areas of eight urban and four suburban residences in Philadelphia, Pennsylvania. Staphylococcus aureus colonies were identified by replica plating of the original impactor samples onto Chapman Stone medium followed by isolation of up to eight colonies for coagulase testing. Kirby-Bauer disk diffusion method was utilized to evaluate S. aureus resistance to both oxacillin and cefaclor. The median concentrations of total culturable bacteria observed in bedrooms and trash areas were 300 CFU/m(3) and 253 CFU/m(3), respectively. Median culturable Staphylococcus spp. concentrations in bedrooms and trash areas were 142 CFU/m(3) and 204 CFU/m(3), respectively. A total of 148 individual S. aureus colonies were isolated and tested for antibiotic resistance. Cefaclor resistance was encountered among only 6 of the 148 (4%) colonies. Nearly one-quarter of all S. aureus isolates tested displayed resistance (n = 30) or intermediate resistance (n = 5) to oxacillin. Twenty-six percent (n = 20) of trash area isolates and 21% (n = 15) of bedroom isolates displayed resistance or intermediate resistance to oxacillin. The median difference in percent resistance between trash and bedroom areas was 10% (p = 0.1). Results suggest that there may be a systematic difference in bacterial populations between downtown and suburban residences. Storage of household waste and handling of food may contribute to presence of the organism in the air of residences. PMID- 21253981 TI - Characterization and control of airborne particles emitted during production of epoxy/carbon nanotube nanocomposites. AB - This work characterized airborne particles generated from the weighing of bulk, multiwall carbon nanotubes (CNTs) and the manual sanding of epoxy test samples reinforced with CNTs. It also evaluated the effectiveness of three local exhaust ventilation (LEV) conditions (no LEV, custom fume hood, and biosafety cabinet) for control of particles generated during sanding of CNT-epoxy nanocomposites. Particle number and respirable mass concentrations were measured using an optical particle counter (OPC) and a condensation particle counter (CPC), and particle morphology was assessed by transmission electron microscopy. The ratios of the geometric mean (GM) concentrations measured during the process to that measured in the background (P/B ratios) were used as indices of the impact of the process and the LEVs on observed concentrations. Processing CNT-epoxy nanocomposites materials released respirable size airborne particles (P/B ratio: weighing = 1.79; sanding = 5.90) but generally no nanoparticles (P/B ratio ~1). The particles generated during sanding were predominantly micron sized with protruding CNTs and very different from bulk CNTs that tended to remain in large (>1 MUm) tangled clusters. Respirable mass concentrations in the operator's breathing zone were lower when sanding was performed in the biological safety cabinet (GM = 0.20 MUg/m(3) compared with those with no LEV (GM = 2.68 MUg/m(3) or those when sanding was performed inside the fume hood (GM = 21.4 MUg/m(3); p value < 0.0001). The poor performance of the custom fume hood used in this study may have been exacerbated by its lack of a front sash and rear baffles and its low face velocity (0.39 m/sec). PMID- 21253982 TI - Identification and measurement of diacetyl substitutes in dry bakery mix production. AB - In 2008, a company using multiple buttermilk flavorings in the production of dry bakery mixes replaced one liquid flavoring containing 15-20% diacetyl with a proprietary substitute meant to lower occupational risk for diacetyl-related bronchiolitis obliterans. Subsequently, the National Institute for Occupational Safety and Health (NIOSH) evaluated buttermilk flavoring-related exposures at this company's facility, with a focus on measuring ketones by several methods. Volatile organic compounds (VOCs) were evaluated in the headspaces of six bulk flavorings samples, including the substitute buttermilk flavoring. Ketones were evaluated in workplace air via area and personal samples collected during batch preparation of the substitute buttermilk flavoring and production of a bakery mix containing the same flavoring. Air samples were evaluated using five different methods: NIOSH 2549, Modified OSHA PV2118, OSHA 1013, NIOSH Draft Procedure SMP2, and evacuated canisters. Of five buttermilk flavorings from five different flavorings manufacturers, diacetyl was present in four, including the substitute flavoring; acetoin in two; 2,3-pentanedione in four; 2,3-hexanedione in one; and 2,3-heptanedione in three. Among material safety data sheets (MSDS) for four flavorings, only one listed a hazardous ingredient, which was acetoin. The predominant flavoring ingredient identified in the headspace of the substitute flavoring was 2,3-pentanedione; all other chemicals noted above were also present. Diacetyl and 2,3-pentanedione were measured in workplace air via evacuated canisters. In one area and one personal air sample, 2,3-pentanedione was measured by OSHA Method 1013 at concentrations of 78 and 91 ppb, respectively. Without their or the employer's knowledge, workers who used buttermilk flavorings were exposed to substitute ketones from many flavorings manufacturers. Because 2,3-pentanedione, 2,3-hexanedione, and 2,3-heptanedione all share the same functional alpha-diketone group as diacetyl, these compounds also may share diacetyl's mechanism of toxicity. Until more is known about 2,3 pentanedione and other alpha-diketone compounds, they should not be assumed to be safe. Companies using artificial buttermilk flavorings should use a precautionary approach that assumes these flavorings pose a health risk and limit exposures through engineering and administrative controls and use of personal protective equipment. PMID- 21253983 TI - The risks and benefits of chemical fumigation in the health care environment. AB - Fumigation of hospital rooms with high concentrations of toxic chemicals has been proposed to reduce microbial agents on hospital surfaces and to control infections. Chemical fumigation has been used effectively in other areas, such as building decontamination after bioterrorism events, in agriculture, and in residential structures. However, even in these situations, there have been incidents where fumigants have escaped, causing illness and death to exposed workers and the public. Before expanding the use of a potentially hazardous technology in areas where there are vulnerable individuals, it is important to fully weigh benefits and risks. This article reviews the effectiveness of fumigation as a method of inactivating microbes on environmental surfaces and in reducing patient infection rates against the potential risks. Peer-reviewed literature, consensus documents, and government reports were selected for review. Studies have demonstrated that fumigation can be effective in inactivating microbes on environmental surfaces. However, the current consensus of the infection control community is that the most important source of patient infection is direct contact with health care workers or when patients auto-infect themselves. Only one peer-reviewed, before-after study, at one hospital reported a significant reduction in infection rates following chemical fumigation. The limitations of this study were such that the authors acknowledged that they could not attribute the rate reduction to the fumigation intervention. A serious concern in the peer-reviewed literature is a lack of evidence of environmental monitoring of either occupational or non-occupational exposures during fumigation. Currently, there are neither consensus documents on safe fumigation exposure levels for vulnerable bedridden patients nor sampling methods with an acceptable limit of detection for this population. Until additional peer-reviewed studies are published, demonstrating significant reductions in patient infection rates following chemical fumigation and consensus guidance on the safe exposure levels and monitoring methods, chemical fumigation in health care should be conducted only in the most stringently controlled research settings. PMID- 21253984 TI - Anthrax letters in an open office environment: effects of selected CDC response guidelines on personal exposure and building contamination. AB - In 2001, letters filled with a powder containing anthrax (Bacillus anthracis) spores were delivered by mail to a number of governmental and media locations within the United States. In response, the U.S. Centers for Disease Control and Prevention (CDC) provided guidelines for office personnel who might encounter a letter containing suspicious powder. These guidelines were developed during the crisis and in the absence of experimental data from laboratory or field investigations. An obvious need thus exists for quantitative and scientific verification for validation of these guidelines. This study attempts to address this need, adapting earlier work that used a multiple small office test site to create a model system in an open office test site in a vacated office building in which Bacillus atrophaeus spores (as a simulant for B. anthracis spores) were released by opening a letter. Using SF(6) as a tracer gas, smoke tubes (containing stannic chloride) to visualize airflow, culturable aerosol sampling, and aerosol spectrometry we were able to characterize airflow and unmitigated spore aerosol dissemination within the office test site. Subsequently, two scripted test scenarios were used to reproduce selected portions of the existing CDC response guidelines and a modified version where the contaminated letter opener warned co-workers to evacuate then waited 5 min before doing so himself. By not leaving together with other co-workers, the risk of the letter opener cross-contaminating others was eliminated. The total potential spore aerosol exposure of the letter opener was not affected by remaining still and waiting 5 min to allow co-workers to escape first before leaving the office. Closing office doors and quickly deactivating the heating, ventilation, and air conditioning system significantly reduced spore aerosol concentrations outside the main open office in which they had been released. PMID- 21253985 TI - Effect of protein glycation in the presence or absence of wheat proteins on detection of soybean proteins by commercial ELISA. AB - Soybean (Glycine max) is the world's primary provider of protein and oil and is widely used in foodstuffs. However, the use of soybean in foodstuffs might pose a serious threat to allergic consumers since some proteins can cause allergic reactions. To date mostly ELISA methods are used for testing contamination of foodstuffs with soybean. In view of the complexity regarding allergen detection in foodstuffs and appropriate food product labelling, the aim of this study was to investigate the impact of the Maillard reaction on the detectability of soybean proteins using commercial ELISA kits. Accumulation of protein-bound carbonyls, modification of reactive lysine residues and severe aggregation as a result of incubation with glucose, in the presence or absence of soluble wheat proteins, were recorded. Moreover, detection of soybean proteins by means of three commercial ELISA kits was strongly altered and was highly dependent on the type of kit used. PMID- 21253986 TI - Exposure of consumers to deoxynivalenol from consumption of white bread in Hungary. AB - In view of the frequent occurrence of mycotoxins in cereals, a study was initiated to assess the exposure of the Hungarian adult population. Consumption data for 1360 individuals, based on a 3-day questionnaire, indicated that white bread accounted for the major intake of cereal-based products. Various cereal products were analysed for 16 mycotoxins by a LC/MS/MS multi-toxin method with LOD of 16 ug kg-1 and LOQ of 50 ug kg-1. Deoxynivalenol (DON) was most frequently detected, but no acetyl-deoxynivalenol was present in detectable concentrations. Consumer exposure was calculated with standard Monte Carlo probabilistic modelling and point estimates, taking into account bread consumption and DON contamination in independently taken wheat flour and wheat grain samples. Over 55% of cases the DON intake were below 15% of the provisional maximum tolerable daily intake (PMTDI) of 1 ug/(kg bw)/day. However, in 5-15% of cases, the intake from bread consumption alone exceeded the PMTDI. Wheat grain data led to the higher percentage. Intakes estimated from both data sets were at or below the acute reference dose (ARfD) of 8 ug/(kg bw)/day in 99.94-99.97% of cases. PMID- 21253987 TI - Introduction: The consequences of being born very early or very small. PMID- 21253988 TI - Neuropsychological and behavioral outcomes of extremely low birth weight at age three. AB - Preterm (PT) birth is an established risk factor for high mortality and morbidity rates. Infants and school-aged children have been well-studied, but few have described neuropsychological and behavioral outcomes at preschool age. We compared a 2004-2006 preterm/extremely low birth weight (ELBW) cohort (PT/ELBW; N = 60) born <= 33 weeks gestation and <1,000 g with term-born participants (N = 90) at age 3. PT/ELBW subgroups (<26 weeks; 26-33 weeks) performed more poorly than the term-born group on verbal, nonverbal, fine motor, visual-motor, visual attention, noun fluency, early number concepts, and functional communication measures prior to age correction; PT/ELBW children born <26 weeks additionally performed more poorly on action-verb fluency. Those born 26-33 weeks had executive and adaptive deficits on parental behavioral report. Age correction significantly improved preterm scores without masking relative verbal, nonverbal, motor, and behavioral weaknesses that may require early intervention. In conclusion, subtle delays in emergent neuropsychological and behavioral functions are measurable at age 3, and neurobiological immaturity remains a prepotent influence on outcome in the preschool years. Further study should enhance our understanding of the trajectory of brain development and the limits of neuroplasticity in these highly at-risk children. PMID- 21253989 TI - Neonatal white matter abnormalities predict global executive function impairment in children born very preterm. AB - Using prospective longitudinal data from 110 very preterm and 113 full term children, this article describes the executive functioning abilities of very preterm children at age 4, and examines relations between the extent of white matter abnormality on neonatal magnetic resonance imaging (MRI) and later executive function outcomes. Very preterm children performed less well than full term children on measures of planning ability, cognitive flexibility, selective attention, and inhibitory control. Executive impairments at age 4 were confined to preterm children with mild or moderate-severe white matter abnormalities on MRI. Findings support the importance of cerebral white matter integrity for later executive function. PMID- 21253990 TI - Assessment of developmental coordination disorder in children born with extremely low birth weights. AB - There is no tool that is considered the "gold" standard for identifying children with developmental coordination disorder (DCD) and various techniques have been reported in the research literature. The aim of this study was to examine the prevalence of DCD in a cohort of extremely low birth weight (ELBW; birth weight <= 1,000g) children at age 5 years using various methods including standardized motor assessment measures, an established clinic protocol, and a parent report. We also examined the association between selected neonatal risk factors and severity of the motor impairment. Four methods were used to assess motor functioning: (1) the Movement Assessment Battery for Children (Movement ABC); (2) a motor assessment battery, which included the Movement ABC, the Beery-Buktenica Developmental Test of Visual Motor Integration, and the Developmental Test of Visual Perception-2; (3) a Perinatal Follow-up Clinic protocol, which included the Geometric Design and the Mazes subtests of the Wechsler Preschool and Primary Scale of Intelligence-Revised, the Fine and Gross Motor subscales of the Child Development Inventory, and a pediatric neuromotor exam; and (4) a parent completed questionnaire (i.e., Developmental Coordination Disorder Questionnaire (DCDQ)). The prevalence of motor impairment in ELBW children was 64% on the Movement ABC, 67% on the motor assessment battery, 66% on the Perinatal Follow-up Clinic protocol, and 26% on the DCDQ. Sensitivity ranged from 36% to 100% and specificity from 65% to 92% using the Movement ABC as the reference standard. Neonatal risk factors associated with increased severity of motor impairment were bronchopulmonary dysplasia, postnatal steroids, and increasing gestational age. Children with birth weights <= 1,000 g are at considerable risk for motor impairment; therefore, developmental evaluations should include an assessment of motor functions. A standardized motor assessment test such as the Movement ABC appears to be the most effective and efficient means of identifying motor impairment in this high-risk population. PMID- 21253991 TI - Attention problems in a representative sample of extremely preterm/extremely low birth weight children. AB - The aim of this study was to examine attention in a large, representative, contemporary cohort of children born extremely preterm (EP) and/or extremely low birth weight (ELBW). Participants included 189 of 201 surviving children born EP (<28 weeks' gestation) or ELBW (<1,000 g) in 1997 in the state of Victoria, Australia. A comparison group of 173 of 199 children born full term and normal birth weight (FT/NBW) were randomly selected matching for birth hospital, expected due date, gender, mother's country of birth, and health insurance status. Participants were assessed at 8 years of age on subtests from the Test of Everyday Attention for Children (TEA-Ch) and the Wechsler Intelligence Scale for Children-4th Edition (WISC-IV). Measures of selective attention, sustained attention, attention encoding, and executive attention (inhibition, shifting attention, and divided attention) were administered. To assess behavioral elements of inattention, the primary caregiver completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Conners' ADHD/DSM-IV Scale (CADS P). The EP/ELBW group performed more poorly across all cognitive and behavioral measures than the FT/NBW group, with the exception of inhibition. The EP/ELBW group also had significantly elevated rates of impairment in selective, sustained, shifting and divided attention, as well as attention deficit hyperactivity disorder (ADHD) symptoms. No significant gender or gradient effects (e.g., <26 weeks' gestation vs. >= 26 weeks' gestation) were identified. Neonatal medical factors were not strong predictors of attention, although necrotizing enterocolitis (NEC) and cystic periventricular leukomalacia (PVL) were independent predictors of selective attention. In conclusion, our comprehensive assessment of attention provides strong evidence that children born EP/ELBW are at increased risk for attentional impairments, and as such, this population should be monitored closely during early and middle childhood with a focus on attention functioning. PMID- 21253992 TI - Educational outcomes in extremely preterm children: neuropsychological correlates and predictors of attainment. AB - This study assessed the impact of extremely preterm birth on academic attainment at 11 years of age, investigated neuropsychological antecedents of attainment in reading and mathematics, and examined early predictors of educational outcomes. Children born extremely preterm had significantly poorer academic attainment and a higher prevalence of learning difficulties than their term peers. General cognitive ability and specific deficits in visuospatial skills or phoneme deletion at 6 years were predictive of mathematics and reading attainment at 11 years in both extremely preterm and term children. Phonological processing, attention, and executive functions at 6 years were also associated with academic attainment in children born extremely preterm. Furthermore, social factors, neonatal factors (necrotizing enterocolitis, breech delivery, abnormal cerebral ultrasound, early breast milk provision), and developmental factors at 30 months (head circumference, cognitive development), were independent predictors of educational outcomes at 11 years. Neonatal complications combined with assessments of early cognitive function provide moderate prediction for educational outcomes in children born extremely preterm. PMID- 21253993 TI - Brain volumes in adolescents with very low birth weight: effects on brain structure and associations with neuropsychological outcomes. AB - The aims of this study were to examine abnormalities in brain structure in adolescents and young adults with very low birth weight (VLBW, <1,500 g) and associations of these abnormalities with neuropsychological outcomes. The sample of 108 participants from 14 to 19 years of age included 37 participants with <750 g birth weight, 35 with 750-1,499 g birth weight, and 36 normal birth weight (NBW) controls. One or both of the VLBW groups had smaller brain volumes, larger lateral ventricles, and a small surface area of the corpus callosum than the NBW controls. Group differences in white matter (WM) structures, subcortical gray matter (GM), and the cerebellum were found even when controlling for whole brain volume (WBV), and were most pronounced in the <750 g group. WM reductions in the two VLBW groups relative to NBW controls were associated with more pervasive cognitive deficits than were reductions in subcortical GM. Associations of cognitive outcomes with structural abnormalities remained when controlling for WBV or neonatal risks. The results are consistent with previous findings of residual brain abnormalities in adolescents and young adults with VLBW and provide new information on their cognitive correlates. PMID- 21253994 TI - Neonatal ultrasound results following very preterm birth predict adolescent behavioral and cognitive outcome. AB - This study investigated the association between different neonatal ultrasonographic classifications and adolescent cognitive, educational, and behavioral outcomes following very preterm birth. Participants included a group of 120 adolescents who were born very preterm (<33 weeks of gestation), subdivided into three groups according to their neonatal cerebral ultrasound (US) classifications: (a) normal (N = 69), (b) periventricular hemorrhage (PVH, N = 37), and (c) PVH with ventricular dilatation (PVH + DIL, N = 14), and 50 controls. The cognitive functions assessed were full-scale IQ, phonological and semantic verbal fluency, and visual-motor integration. Educational outcomes included reading and spelling; behavioral outcomes were assessed with the Rutter Parents' Scale and the Premorbid Adjustment Scale (PAS). Adolescent outcome scores were compared among the four groups. A main effect for group was observed for full-scale IQ, Rutter Parents' Scale total scores, and PAS total scores, after controlling for gestational age, socioeconomic status and gender, with the PVH + DIL group showing the most impaired scores compared to the other groups. The current results demonstrate that routine neonatal ultrasound classifications are associated with later cognitive and behavioral outcome. Neonatal ultrasounds could aid in the identification of subgroups of children who are at increased risk of neurodevelopmental problems. These at risk subgroups could then be referred to appropriate early intervention services. PMID- 21253995 TI - [The significance of a B cell-dependent immunopathology in multiple sclerosis]. AB - In spite of keen clinical and neuroscientific interest, the aetiology and immunopathology of multiple sclerosis (MS) remain to be elucidated. The present work seeks to give insight into the important, but thus far underestimated contribution of B cells to the disease. Emphasis will be placed on the role of B cells as producers of autoantibodies and as antigen presenting cells. In addition, the development of ectopic B cell follicles in the CNS and their potential correlation with the course of the disease and MS severity will be discussed. Finally, regulatory functions of a B cell-dependent immunopathology should be mentioned. A better understanding of the complex pathomechanisms of MS will allow for therapeutic options that are causative. Potential targets of a B cell-oriented therapy will be delineated in the following review. We hereby aim at triggering a critical re-evaluation of traditional paradigms assigned to MS, appreciating the importance of B cells in the disease. PMID- 21253996 TI - [Deep brain stimulation for Parkinson's disease and camptocormia? A case report]. AB - Camptocormia is recognised as a severe postural movement disorder complicating neurodegenerative diseases like Parkinson's disease (PD) and multisystem atrophy. Pathophysiologically two main hypotheses are discussed: (i) a disorder of the basal ganglia resulting in axial dystonia and rigidity on the one hand and (ii) an extensor truncal myopathy on the other hand. Therapeutic efforts often result in limited success. Therefore, reports on improvements by deep brain stimulation (DBS) are of great interest. However, the role of DBS in the treatment of camptocormia remains unclear. Here, we report a female PD patient who responded well to DBS of the subthalamic nucleus for severe dyskinesias and fluctuations. However, after 6 months she started to develop a rapidly progressing camptocormia which did not respond to DBS. The clinical and electrophysiological examination suggested a truncal erector myopathy. The inconsistent reports on the effects of DBS on camptocormia in PD patients suggest heterogeneous pathogenetic pathways. A pathophysiological subtype with predominant basal ganglia dysfunction and responsivity to DBS, however, seems to be rather rare. A myopathy, in contrast, seems to be more frequent and DBS is not effective in this condition. Therefore, camptocormia in PD patients is not an established indication for DBS. PMID- 21253997 TI - [Postural orthostatic tachycardia syndrome: current concepts in pathophysiology, diagnosis and therapeutic options]. PMID- 21254001 TI - PALM and STORM: unlocking live-cell super-resolution. AB - Live-cell fluorescence light microscopy has emerged as an important tool in the study of cellular biology. The development of fluorescent markers in parallel with super-resolution imaging systems has pushed light microscopy into the realm of molecular visualization at the nanometer scale. Resolutions previously only attained with electron microscopes are now within the grasp of light microscopes. However, until recently, live-cell imaging approaches have eluded super resolution microscopy, hampering it from reaching its full potential for revealing the dynamic interactions in biology occurring at the single molecule level. Here we examine recent advances in the super-resolution imaging of living cells by reviewing recent breakthroughs in single molecule localization microscopy methods such as PALM and STORM to achieve this important goal. PMID- 21254002 TI - High-performance prediction of functional residues in proteins with machine learning and computed input features. AB - One of the major challenges in genomics is to understand the function of gene products from their 3D structures. Computational methods are needed for the high throughput prediction of the function of proteins from their 3D structure. Methods that identify active sites are important for understanding and annotating the function of proteins. Traditional methods exploiting either sequence similarity or structural similarity can be unreliable and cannot be applied to proteins with novel folds or low homology with other proteins. Here, we present a machine-learning application that combines computed electrostatic, evolutionary, and pocket geometric information for high-performance prediction of catalytic residues. Input features consist of our structure-based theoretical microscopic anomalous titration curve shapes (THEMATICS) electrostatics data, enhanced with sequence-based phylogenetic information from INTREPID and topological pocket information from ConCavity. Our THEMATICS-based input features are augmented with an additional metric, the theoretical buffer range. With the integration of the three different types of input, each of which performs admirably on its own, significantly better performance is achieved than that of any of these methods by itself. This combined method achieves 86.7%, 92.5%, and 93.8% recall of annotated functional residues at 5, 8, and 10% false-positive rates, respectively. PMID- 21254003 TI - Assessing the clinical effectiveness of breast reconstruction through patient reported outcome measures. PMID- 21254004 TI - Systematic review of the effect of external beam radiation therapy to the breast on axillary recurrence after negative sentinel lymph node biopsy. AB - BACKGROUND: Axillary recurrence after negative sentinel lymph node biopsy (SLNB) in patients with invasive breast carcinoma remains a concern. Previous investigations to identify prognostic factors for axillary recurrence identified that a disproportionate number of patients with an axillary recurrence after negative SLNB were not treated with external beam radiation therapy (EBRT) of the breast as part of initial treatment. This finding prompted a systematic review to test the hypothesis that EBRT to the breast reduces the risk of axillary recurrence after negative SLNB. METHODS: A literature search was performed in PubMed, the Cochrane Library and the Spanish-language database LILACS to identify articles publishing data regarding follow-up of sentinel lymph node (SLN) negative patients. Reports and articles lacking information on the initial treatment were excluded. RESULTS: Forty-five articles were accepted for review. A total of 23,357 SLN-negative patients were identified with median follow-up ranging from 15 to 102 months. Some 18,878 patients were treated with EBRT to the breast as part of their initial treatment. One hundred and twenty-seven patients with an axillary recurrence were identified, of whom 73 had EBRT as part of their initial treatment. Meta-analysis showed that EBRT was associated with a lower rate of axillary recurrence (P < 0.001), but this finding was subject to heterogeneity. CONCLUSION: This review and meta-analysis showed that EBRT is associated with a significantly lower axillary recurrence rate after negative SLNB. PMID- 21254005 TI - Systematic review and meta-analysis of sentinel node biopsy in thyroid cancer (Br J Surg 2010; 98: 334-344). PMID- 21254006 TI - Systematic review and meta-analysis of the effects of statin therapy on abdominal aortic aneurysms. AB - BACKGROUND: The aim was to investigate the effects of statin therapy on abdominal aortic aneurysm (AAA) disease. METHODS: PubMed, the Cochrane Library, Embase and ClinicalTrials.gov were searched for all studies on any clinical effect of statin therapy on AAA. Outcomes were selected based on their inclusion in two or more studies: AAA expansion rate, 30-day mortality, and short- and long-term postoperative mortality. The data were subjected to meta-analysis by outcome. RESULTS: Twelve cohort studies were selected for inclusion involving 11 933 individuals. Meta-analysis of four studies examining all-cause postoperative mortality showed a significant improvement with statin therapy at 1, 2 and 5 years (odds ratio (OR) at 5 years 0.57, 95 per cent confidence interval (c.i.) 0.42 to 0.79; P < 0.001) with minimal heterogeneity between the four included studies. There was no significant difference in 30-day mortality after AAA treatment in patients on statin therapy (OR 0.22, 0.02 to 2.90; P = 0.25). Sensitivity analysis including four high-quality studies examining AAA expansion rates showed no significant difference with statin therapy: standardized mean difference -0.14 (95 per cent c.i. -0.33 to -0.05) mm/year (P = 0.16). CONCLUSION: The claim of a reduction in AAA expansion rate with statin therapy is based on low-quality evidence and was not significant on meta-analysis. However, statin therapy did appear to improve all-cause survival after AAA repair. PMID- 21254007 TI - Randomized clinical trial of splenic radiofrequency ablation versus splenectomy for severe hypersplenism. AB - BACKGROUND: Radiofrequency ablation (RFA) is a relatively new treatment for hypersplenism. The results of a randomized clinical trial comparing RFA and splenectomy with 5 years of follow-up are reported. METHODS: Fifty-seven patients with hypersplenism due to liver cirrhosis were assigned randomly (in a 1 : 2 ratio) to splenectomy (19 patients) or RFA (38). The RFA group was subdivided according to the percentage of the spleen ablated: less than 50 per cent (9 patients), 50-70 per cent (18) or over 70 per cent (11). Routine blood tests were performed before and after operation, and total spleen volume and ablated volume were measured by contrast-enhanced computed tomography. The primary endpoint of the trial was recurrence of hypersplenism, assessed as platelet and white cell counts, at 5 years after surgery. RESULTS: White cell and platelet counts increased rapidly after intervention in both groups. By 36 months after operation peripheral platelet and white cell counts had decreased significantly in the RFA group compared with the splenectomy group, and declined to baseline levels by 48 months. Hypersplenism recurred after 6 months in patients with less than 50 per cent of the spleen ablated. Blood cell count in the splenectomy group and in patients with more than 50 per cent of the spleen ablated decreased with time after operation, but to levels that remained significantly higher than those before operation (P < 0.050). Splenic volume reached its nadir 12 months after RFA and then increased with time. CONCLUSION: Splenic RFA represents an attractive alternative treatment for hypersplenism induced by liver cirrhosis, particularly when more than 50 per cent of the spleen is ablated. PMID- 21254008 TI - Randomized clinical trial of routine on-table cholangiography during laparoscopic cholecystectomy. AB - BACKGROUND: A randomized clinical trial was undertaken to assess the utility of routine on-table cholangiography (OTC) during laparoscopic cholecystectomy for gallstone disease. METHODS: Some 190 patients with a history of biliary colic or cholecystitis and a low predictive risk for choledocholithiasis were randomized to undergo elective laparoscopic cholecystectomy alone (99 patients) or elective laparoscopic cholecystectomy with OTC (91). Intraoperative findings and postoperative outcomes for the two groups were compared. The primary outcome measure was the incidence of common bile duct (CBD) stones. RESULTS: Of the patients undergoing OTC, ten had abnormal cholangiograms; three had CBD stones and seven had abnormalities without stones. OTC was associated with a significantly longer mean(s.e.m.) operating time (66(2) versus 54(3) min; P < 0.001), but there was no association between performance of OTC and postoperative morbidity. During a 1-year follow-up, no patient in the OTC group re-presented to hospital with recurrent biliary symptoms. In contrast, four of the patients allocated to surgery alone re-presented with symptoms suggestive of CBD obstruction; all settled with conservative treatment and the difference in readmission rate was not significant (P = 0.122). CONCLUSION: Routine cholangiography in patients with a low risk for CBD stones does not seem justified from the results of this trial. REGISTRATION NUMBER: NCT00806780 (http://www.clinicaltrials.gov). PMID- 21254009 TI - Randomized clinical trial of routine on-table cholangiography during laparoscopic cholecystectomy (Br J Surg 2011; 98: 362-367). PMID- 21254010 TI - Effect of polyethylene glycol-based preservation solutions on graft injury in experimental kidney transplantation. AB - BACKGROUND: New preservation solutions are emerging, of various ionic compositions and with hydroxyethyl starch replaced by polymers such as polyethylene glycols (PEGs), offering the potential for 'immunocamouflage'. This experimental study investigated which of three clinically available preservation protocols offered the best graft protection, based on epithelial-to-mesenchymal transition (EMT) and fibrosis. METHODS: Kidneys were preserved for 24 h at 4 degrees C with University of Wisconsin solution (UW)as standard, compared with solutions containing either 1 g/l PEG 35 kDa (Institute Georges Lopez solution, IGL) or 30 g/l PEG 20 kDa (solution de conservation des organes et des tissus, SCOT). Animals were followed for up to 3 months and development of EMT, tubular atrophy and fibrosis was evaluated in comparison with sham-operated animals. RESULTS: Functional recovery was better in the SCOT group compared with the other groups. Chronic fibrosis, EMT and inflammation were observed in the UW and IGL groups, but limited in the SCOT group. Levels of profibrosis markers such as transforming growth factor beta1, plasminogen activator inhibitor 1 and connective tissue growth factor were increased in IGL and UW groups compared with the SCOT group. Hypoxia-inducible factor (HIF) 1alpha and 2alpha expression was increased at 3 months in grafts preserved in UW and IGL, but detected transiently on day 14 when SCOT was used. Expression of HIF-regulated genes vascular endothelial growth factor and erythropoietin was increased in UW and IGL groups. CONCLUSION: The choice of colloid and ionic content is paramount in providing long-term protection against chronic graft injury after renal transplantation. Preservation solutions based on PEGs may optimize graft quality. PMID- 21254011 TI - Effect of polyethylene glycol-based preservation solutions on graft injury in experimental kidney transplantation (Br J Surg 2010; 98: 368-378). PMID- 21254012 TI - Detection of cervical metastatic lymph nodes in papillary thyroid carcinoma by Fourier transform infrared spectroscopy. AB - BACKGROUND: A previous study demonstrated that Fourier transform infrared (FTIR) spectroscopy can distinguish thyroid cancer from benign thyroid lesions. The aim of this study was to explore the use of FTIR for identifying metastatic lymph nodes of papillary thyroid cancer in vitro, and distinguishing between metastatic and non-metastatic tissue. METHODS: Some 184 freshly removed cervical lymph nodes were obtained from 22 patients with papillary thyroid cancer undergoing thyroid surgery with lymph node dissection. Samples were measured by FTIR spectroscopy before being processed for histopathological diagnosis. The FTIR spectrum of each sample identified 13 bands from 1000 to 4000 cm(-1) . The peak position, intensity and full width at half maximum of each absorbent band were measured, and the relative intensity ratios were calculated. The FTIR spectra of metastatic lymph nodes were compared with those of non-metastatic nodes, and a linear discriminant analysis was performed based on these data. RESULTS: Histopathological examination confirmed 61 metastatic and 123 non-metastatic lymph nodes. The FTIR parameters of metastatic and non-metastatic lymph nodes differed owing to the content or configuration alterations of nucleic acids, proteins, lipids and carbohydrates. The sensitivity for FTIR in diagnosing metastatic lymph nodes was 80.3 per cent, the specificity was 91.9 per cent and the accuracy was 88.0 per cent. CONCLUSION: FTIR spectroscopy is a novel technique for detection of metastatic lymph nodes and may prove useful in surgery for papillary thyroid cancer. PMID- 21254013 TI - Laparoscopy-assisted gastrectomy in patients with previous endoscopic resection for early gastric cancer. AB - BACKGROUND: Some patients undergoing endoscopic resection for early gastric cancer need further surgical treatment to achieve cure. However, the influence of endoscopic resection on subsequent laparoscopy-assisted gastrectomy (LAG) remains unclear. METHODS: A total of 711 patients who underwent LAG were analysed retrospectively; 111 patients had undergone endoscopic resection previously and the remaining 600 had no history of endoscopic resection. Patient characteristics, operative and postoperative outcomes were compared between the two groups. Risk factors associated with postoperative complications were analysed. RESULTS: Duration of operation and blood loss were comparable between the two groups. Patients who had undergone endoscopic resection had fewer dissected lymph nodes and a lower rate of preservation of the coeliac branch of the vagus nerve, especially those who had LAG within 2 months after endoscopic resection. Early postoperative outcomes, including complications, gastrointestinal recovery and length of postoperative hospital stay, were not significantly different between the two groups. Previous endoscopic resection was not a risk factor for postoperative complications. CONCLUSION: LAG can be performed safely even after endoscopic resection. Endoscopic resection might increase the difficulty of subsequent LAG, including lymph node dissection and preservation of the coeliac branch of the vagus nerve; however, it has little influence on early postoperative outcome. PMID- 21254014 TI - Bile duct injury and use of cholangiography during laparoscopic cholecystectomy. AB - BACKGROUND: Bile duct injury (BDI) remains the most serious complication of laparoscopic cholecystectomy (LC). A Swiss database was used to identify risk factors for BDI and to assess the effect of intraoperative cholangiography (IOC). METHODS: Data for patients from 114 Swiss institutions who underwent LC for acute or chronic cholecystitis between 1995 and 2005 were used in univariable and logistic regression analyses. RESULTS: In total 31 838 patients, mean(s.d.) age 54.4(15.9) years, were analysed. The incidence of BDI was 0.3 per cent (101 patients), which did not change over time (P = 0.560). Univariable analysis revealed that male patients had a higher risk of BDI (0.5 per cent versus 0.2 per cent in female patients; P = 0.001), as did patients whose operation lasted at least 150 min (1.1 per cent versus 0.1 per cent for operating time of less than 150 min; P < 0.001). Logistic regression confirmed male sex (odds ratio (OR) 1.89, 95 per cent confidence interval 1.27 to 2.81) and prolonged surgery (OR 12.60, 10.87 to 23.81) as independent risk factors. Comparison of groups with and without intraoperative cholangiography showed no difference in the incidence of BDI (both 0.3 per cent; P = 0.755) and BDIs missed during surgery (10 versus 8 per cent; P = 0.737). CONCLUSION: Male sex and prolonged laparoscopic surgery are independent risk factors for BDI during LC. Frequent use of IOC does not seem to reduce BDI or the number of injuries missed during surgery. PMID- 21254016 TI - Bile duct injury and use of cholangiography during laparoscopic cholecystectomy (Br J Surg 2011; 98: 391-396). PMID- 21254017 TI - Impact of bevacizumab on functional recovery and histology of the liver after resection of colorectal metastases. AB - BACKGROUND: The impact of bevacizumab on functional recovery and histology of the liver was evaluated in patients undergoing hepatic resection for colorectal liver metastases (CLM) following bevacizumab treatment. METHODS: Consecutive patients who had resection of CLM between July 2005 and July 2009 following preoperative chemotherapy were identified retrospectively from a prospectively collected database. Patients who had received bevacizumab before the last chemotherapy line were excluded. Postoperative liver function and histology were compared between patients with and without bevacizumab treatment. Recorded parameters included serum prothrombin time, total bilirubin concentration, and levels of aspartate and alanine aminotransferase and gamma-glutamyltransferase. RESULTS: Of 208 patients identified, 67 had received last-line bevacizumab, 44 were excluded and 97 had not received bevacizumab. Most patients in the bevacizumab group (66 per cent) received a single line of chemotherapy. Bevacizumab was most often combined with 5-flurouracil/leucovorin and irinotecan (68 per cent). The median number of bevacizumab cycles was 8.6 (range 1-34). Bevacizumab administration was stopped a median of 8 (range 3-19) weeks before surgery. There were no deaths. Postoperative morbidity occurred in 43 and 36 per cent of patients in the bevacizumab and no-bevacizumab groups respectively (P = 0.353). The mean(s.d.) degree of tumour necrosis was significantly higher in the bevacizumab group (55(27) versus 32(29) per cent; P = 0.001). Complete pathological response rates were comparable (3 versus 8 per cent; P = 0.307). Postoperative changes in functional parameters and objective signs of hepatic toxicity were similar in both groups. CONCLUSION: Preoperative administration of bevacizumab does not seem to affect functional recovery of the liver after resection of CLM. Tumour necrosis is increased following bevacizumab treatment. PMID- 21254018 TI - Volume analysis of outcome following restorative proctocolectomy. AB - BACKGROUND: This observational study aimed to determine national provision and outcome following pouch surgery (restorative proctocolectomy, RPC) and to examine the effect of institutional and surgeon caseload on outcome. METHODS: All patients undergoing primary RPC between April 1996 and March 2008 in England were identified from the administrative database Hospital Episode Statistics. Institutions and surgeons were categorized according to the total RPC caseload performed over the study interval. RESULTS: Some 5771 primary elective pouch procedures were undertaken at 154 National Health Service hospital trusts. Median follow-up was 65 (interquartile range (i.q.r.) 28-106) months. The 30-day in hospital mortality rate was 0.5 per cent and the 1-year overall mortality rate 1.5 per cent. Some 30.5 per cent of trusts performed fewer than two procedures per year, and 91.4 per cent of surgical teams (456 of 499) carried out 20 or fewer RPCs over 8 years. Median surgeon volume was 4 (i.q.r. 1-9) cases. Failure occurred in 6.4 per cent of cases. Low-volume surgeons operated on more patients at the extremes of age (P < 0.001) and a lower proportion with ulcerative colitis (P < 0.001). Older age, increasing co-morbidity, increasing social deprivation, and both lower provider and surgeon caseload were independent predictors of longer length of stay. Older patient age and low institutional volume status were independent predictors of failure. CONCLUSION: Many English institutions and surgeons carry out extremely low volumes of RPC surgery. Case selection differed significantly between high- and low-volume surgeons. Institutional volume and older age were positively associated with increased pouch failure. PMID- 21254020 TI - Toxicity and complications of preoperative chemoradiotherapy for locally advanced rectal cancer. AB - BACKGROUND: Capecitabine is an attractive radiosensitizer. In this study acute toxicity and surgical complications were evaluated in patients with locally advanced rectal cancer following total mesorectal excision (TME) after preoperative chemoradiotherapy (CRT) with capecitabine. METHODS: Between 2004 and 2008, consecutive patients with clinical tumour category (cT) 3-4 (with a threatened circumferential resection margin or cT3 within 5 cm of the anal verge) or clinical node category 2 rectal cancer were treated with preoperative CRT (25 * 2 Gy, capecitabine 825 mg/m(2) twice daily, days 1-33). TME followed 6 weeks later. Toxicity was scored according to the Common Terminology Criteria (version 3.0) and Radiation Therapy Oncology Group scoring systems. Treatment-related surgical complications were evaluated for up to 30 days after discharge from hospital using the modified Clavien-Dindo classification. RESULTS: Some 147 patients were analysed. The mean cumulative dose of capecitabine was 95 per cent and 98.0 per cent of patients received at least 45 Gy. One patient died from sepsis following haematological toxicity. Grade 3-5 toxicity developed in 32 patients (21.8 per cent), especially diarrhoea (10.2 per cent) and radiation dermatitis (11.6 per cent). There were no deaths within 30 days after surgery. Anastomotic leakage and perineal wound complications developed after 13 of 47 low anterior resections and 23 of 62 abdominoperineal resections. Surgical reintervention was required in 30 patients. Twenty-seven patients (19.6 per cent) of 138 patients who had a laparotomy were readmitted within 30 days after initial hospital discharge. CONCLUSION: Preoperative CRT with capecitabine is associated with acceptable acute toxicity, significant surgical morbidity but minimal postoperative mortality. PMID- 21254021 TI - Laparoscopic resection of advanced colorectal cancer. AB - BACKGROUND: Palliative resection of the primary tumour in asymptomatic patients with stage IV colorectal cancer is associated with improved survival and fewer complications. Laparoscopic surgery is widely employed in the curative treatment of colorectal cancer, but its value in advanced colorectal cancer remains unclear. METHODS: All patients who underwent laparoscopic resection of primary colorectal cancer in this unit between June 1991 and Jan 2010 were entered into a prospective computerized database. Outcomes for patients with laparoscopic resection of stage IV colorectal cancer were compared with those of patients who had laparoscopic surgery for stage I disease. RESULTS: Some 185 patients with stage IV colorectal cancer who underwent laparoscopic resection were compared with 310 patients who had stage I colorectal cancer. Some 94.1 and 98.4 per cent of operations respectively were completed laparoscopically. Hospital stay was slightly longer in the group with stage IV disease (mean 6.2 versus 5.3 days; P = 0.091). The 30-day mortality rate was 2.7 per cent in patients with stage IV disease and 0.6 per cent in those with stage I tumours (P = 0.061). There was no difference in complications. One-year survival rates were 77.8 and 99.0 per cent respectively (P < 0.001). CONCLUSION: Short-term outcomes after laparoscopic surgery for stage IV colorectal cancer in selected patients are equivalent to those for stage I cancers. PMID- 21254022 TI - Short-term outcomes after elective minimally invasive colectomy for diverticulitis. AB - BACKGROUND: The role of minimally invasive surgery in complicated diverticulitis is still being elucidated. The aim of this study was to compare short-term outcomes in patients undergoing minimally invasive surgery for complicated or uncomplicated diverticular disease. METHODS: All patients who had elective minimally invasive surgery for diverticulitis between 2003 and 2008 were identified from a prospectively maintained database. Complicated disease was defined as diverticulitis associated with abscess, fistula, stricture or bleeding. Univariable analysis was performed to compare safety and short-term outcomes in patients with complicated and uncomplicated diverticulitis. RESULTS: A total of 361 patients (136 with complicated and 225 with uncomplicated diverticulitis) were operated on with either a laparoscopic (36.0 per cent) or a hand-assisted laparoscopic (64.0 per cent) surgical technique. There were no significant differences between the groups with respect to age, sex, body mass index, laparoscopic approach, postoperative recovery protocol or previous open surgery. Conversion rates were similar for complicated and uncomplicated disease (14.0 versus 11.6 per cent respectively; P = 0.514). There was no difference between the groups with respect to return of bowel function (mean 3.1 versus 3.2 days respectively; P = 0.156), morbidity (27.9 versus 19.6 per cent; P = 0.070) or mean length of stay (5.4 versus 4.8 days; P = 0.186). There were no deaths within 30 days. CONCLUSION: Elective minimally invasive colectomy is feasible for patients with uncomplicated and complicated diverticulitis, with equivalent outcomes. PMID- 21254023 TI - Experimental study of radioimmunotherapy versus chemotherapy for colorectal cancer. AB - BACKGROUND: Radioimmunotherapy (RIT) has been shown to reduce the incidence of local recurrence of colorectal cancer in an experimental model. The aim of the present study was to investigate the survival benefit of RIT compared with chemotherapy. METHODS: An anastomosis was constructed in male Wag/Rij rats after intraluminal injection of CC531 tumour cells. The therapeutic efficacy of (177) Lu-labelled MG1 (single intravenous dose of 300 MBq/kg, n = 20) was compared with that of 5-fluorouracil-based chemotherapy (6 weekly cycles administered intraperitoneally, n = 20) and no treatment (n = 20). The primary endpoint was survival. Toxicity was monitored by bodyweight measurement. RESULTS: Both chemotherapy and RIT affected bodyweight, but the weight of animals in the RIT group remained significantly higher than in the chemotherapy group (median slope of bodyweight plot 0.48 versus 0.30 g/day; P < 0.001). Kaplan-Meier analysis showed that overall survival in the RIT and chemotherapy groups was significantly better than that in the control group (50 and 46 per cent versus 25 per cent respectively after 170 days; P = 0.024 and P = 0.029). Survival after treatment with RIT did not differ from that after chemotherapy (P = 0.911). CONCLUSION: RIT is as effective as chemotherapy in experimental colorectal cancer. PMID- 21254024 TI - Comparison of three separate antiadhesive barriers for intraperitoneal onlay mesh hernia repair in an experimental model. AB - BACKGROUND: Adhesion formation is a common adverse effect in intraperitoneal onlay mesh (IPOM) surgery. Different methods of adhesion prevention have been developed, including coated meshes and separate antiadhesive barriers (SABs). In this study one type of mesh was tested with different SABs, which were fixed to the sutured mesh using fibrin sealant. The primary aim was to compare adhesion prevention between different SABs. Secondary aims were the assessment of tissue integration and evaluation of SAB fixation with fibrin sealant. METHODS: Thirty two rats were randomized to one of three treatment groups (SurgiWrap, Prevadh and Seprafilm) or a control group (no SAB). Animals were operated on with an open IPOM technique (8 per group). One macroporous polypropylene mesh per animal (2 * 2 cm) was fixed with four non-absorbable sutures. An antiadhesive barrier of 2.5 * 2.5 cm was fixed with fibrin sealant. After 30 days, adhesion formation, tissue integration, seroma formation, inflammation and vascularization were evaluated macroscopically and by histology. RESULTS: Prevadh and Seprafilm groups showed a significant reduction in adhesion formation compared with the control group. Tissue integration of the mesh was reduced in these groups. Fibrin sealant fixed the SAB to the mesh securely in all groups. CONCLUSION: Prevadh and Seprafilm are potent materials for the reduction of adhesion formation. A potential relationship between effective adhesion prevention and impaired tissue integration of the implant was observed. Fibrin sealant proved an excellent agent for SAB fixation. PMID- 21254025 TI - Evaluation of procedure-based assessment for assessing trainees' skills in the operating theatre. AB - BACKGROUND: Procedure-based assessment (PBA) is used within most UK surgical training programmes for assessing trainees' procedural skills in the operating theatre. All postgraduate assessment methods require evidence to support their implementation. The aims were to evaluate the validity, reliability and acceptability of PBA. METHODS: Eighty-one trainees in six surgical specialties were assessed performing common procedures; 749 PBAs were provided across 348 operations by 57 clinical supervisors and four independent assessors. RESULTS: Construct validity was demonstrated by correlation of PBA scores with measures of surgical training and experience. Reliability (G exceeding 0.8) of the adjusted total item score and global summary score for a given procedure was achieved using four and three assessor judgements respectively; assessing a mix of procedures required more cases/assessors because performance is procedure specific. The acceptability of PBA for assessment and feedback within surgical training was predominantly positive among clinical supervisors and trainees. CONCLUSION: PBA demonstrated good overall validity and acceptability, and exceptionally high reliability. Trainees should be assessed adequately for each given procedure. PMID- 21254027 TI - Randomized clinical trial of short-term outcomes following purse-string versus conventional closure of ileostomy wounds (Br J Surg 2010; 97: 1511-1517). PMID- 21254028 TI - Hepatic ischaemia-reperfusion injury from bench to bedside (Br J Surg 2010; 97: 1461-1475). PMID- 21254030 TI - Surgical-site infection (Br J Surg 2010; 97: 1601-1602). PMID- 21254032 TI - Letter 1: Systematic review and meta-analysis of preoperative anti- sepsis with chlorhexidine versus povidone-iodine in clean-contaminated surgery (Br J Surg 2010; 97: 1614-1620). PMID- 21254033 TI - Letter 2: Systematic review and meta-analysis of preoperative anti- sepsis with chlorhexidine versus povidone-iodine in clean-contaminated surgery (Br J Surg 2010; 97: 1614-1620). PMID- 21254035 TI - Surgeons and selection of adjuvant therapy for node-negative colonic cancer (Br J Surg 2010; 97: 1459-1460). PMID- 21254036 TI - Letter 3: Systematic review and meta-analysis of preoperative antisepsis with chlorhexidine versus povidone-iodine in clean-contaminated surgery (Br J Surg 2010; 97: 1614-1620). PMID- 21254038 TI - Randomized clinical trial of gut-specific nutrients in critically ill surgical patients (Br J Surg 2010; 97: 1629-1636). PMID- 21254041 TI - Randomized clinical trial comparing polypropylene or polydioxanone for midline abdominal wall closure. AB - BACKGROUND: Incisional hernia is a frequent complication of abdominal surgery, often requiring surgical intervention. This prospective randomized trial compared suture materials for closure of the fascia after abdominal surgery. METHODS: In 456 patients the abdominal fascia was closed with either non-absorbable (polypropylene; Prolene((r))) or absorbable (polydioxanone; PDS((r))) suture material. Follow-up was by clinical examination and ultrasonography at 6-month intervals. Outcome measures were incisional hernia, surgical-site infection and suture sinus. RESULTS: Some 223 patients were analysed after closure with Prolene((r)) and 233 after PDS((r)) . Median follow-up was 32 and 31 months respectively. There was no significant difference in the incidence of incisional hernia between the groups: 20.2 per cent (45 of 223) for Prolene((r)) and 24.9 per cent (58 of 233) with PDS((r)) (P = 0.229). Kaplan-Meier analysis showed a cumulative rate after 4 years of 23.7 and 30.2 per cent for Prolene((r)) and PDS((r)) respectively (P = 0.222). Secondary outcome measures showed no significant differences. CONCLUSION: The incidence of incisional hernia in both groups was higher than expected from previous literature. There were no significant differences between the two suture methods. REGISTRATION NUMBER: ISRCTN65599814 (http://www.clinical-trials.com). PMID- 21254042 TI - Predictors of objectively identified recurrent reflux after primary Nissen fundoplication. AB - BACKGROUND: Laparoscopic Nissen fundoplication is the most frequently performed operation for gastro-oesophageal reflux disease (GORD). Studies on predictors of subjective outcome of fundoplication have yielded inconsistent results. This study identified predictors of objective reflux control after Nissen fundoplication. METHODS: This was a retrospective analysis of prospectively collected data from patients who underwent Nissen fundoplication for proton pump inhibitor-refractory GORD with pathological acid exposure in a single centre between 1997 and 2005. The predictive value of demographics, endoscopic hiatal hernia size, oesophagitis, lower oesophageal sphincter pressure, distal oesophageal contraction amplitude, percentage of peristaltic contractions and acid exposure was determined. Endpoints were recurrent pathological acid exposure on 24-h pH monitoring at 6 months and surgical reintervention for recurrent GORD up to 6 years. RESULTS: Of 177 patients, 22 had recurrent pathological acid exposure at 6 months for which 11 had surgery within 6 years. Only low percentage of peristaltic contractions (odds ratio (OR) 0.97, 95 per cent confidence interval 0.95 to 0.99; P = 0.004) and high supine acid exposure (OR 1.03, 1.00 to 1.07; P = 0.025) were independent predictors of recurrent pathological acid exposure. The absolute risk of recurrent exposure was 45.5 per cent in patients with both predictors. High supine acid exposure was also an independent predictor of surgical reintervention (OR 1.05, 1.01 to 1.08; P = 0.006). CONCLUSION: Nissen fundoplication should not necessarily be withheld from patients with poor oesophageal peristalsis or excessive supine acid exposure. As about half of patients with both variables experience recurrent pathological acid exposure after primary Nissen fundoplication, surgery should be restricted in this group. PMID- 21254047 TI - The signal of suicide rates seen from a distance in patients with pancreatic cancer. PMID- 21254048 TI - Reducing ovarian cancer death rates through screening. PMID- 21254049 TI - Development of an ovarian cancer screening decision model that incorporates disease heterogeneity: implications for potential mortality reduction. AB - BACKGROUND: Pathologic and genetic data suggest that epithelial ovarian cancer may consist of indolent and aggressive phenotypes. The objective of the current study was to estimate the impact of a 2-phenotype paradigm of epithelial ovarian cancer on the mortality reduction achievable using available screening technologies. METHODS: The authors modified a Markov model of ovarian cancer natural history (the 1-phenotype model) to incorporate aggressive and indolent phenotypes (the 2-phenotype model) based on histopathologic criteria. Stage distribution, incidence, and mortality were calibrated to data from the Surveillance, Epidemiology, and End Results Program of the US National Cancer Institute. For validation, a Monte Carlo microsimulation (1000,000 events) of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) multimodality prevalence screen was performed. Mortality reduction and positive predictive value (PPV) were estimated for annual screening. RESULTS: In validation against UKCTOCS data, the model-predicted percentage of screen detected cancers diagnosed at stage I and II was 41% compared with 47% (UKCTOCS data), and the model-predicted PPV of screening was 27% compared with 35% (UKCTOCS data). The model-estimated PPV of a strategy of annual population-based screening in the United States at ages 50 to 85 years was 14%. The mortality reduction using annual postmenopausal screening was 14.7% (1-phenotype model) and 10.9% (2-phenotype model). Mortality reduction was lower with the 2-phenotype model than with the 1-phenotype model regardless of screening frequency or test sensitivity; 68% of cancer deaths are accounted for by the aggressive phenotype. CONCLUSIONS: The current analysis suggested that reductions in ovarian cancer mortality using available screening technologies on an annual basis are likely to be modest. A model that incorporated 2 clinical phenotypes of ovarian carcinoma into its natural history predicted an even smaller potential reduction in mortality because of the more frequent diagnosis of indolent cancers at early stages. PMID- 21254050 TI - Family support and depressive symptoms: a 23-year follow-up. AB - We examined change in family support and depressive symptoms over the course of 23 years and included the potential moderators of gender and participation in treatment. A sample of 373 depressed individuals provided data in five waves, with baseline, 1-year, 4-year, 10-year, and 23-year follow-ups. Multilevel modeling was used to evaluate longitudinal relationships between variables. Higher family support was associated with less depression at baseline and predicted a steeper trajectory of recovery from depression over 23 years. This relationship was moderated by gender, such that women with supportive families reported the most rapid recovery from depression. Evaluating family context may be clinically relevant when beginning treatment with a depressed patient, particularly for female patients. PMID- 21254051 TI - Cognitive triad as mediator in the hopelessness model? a three-wave longitudinal study. AB - Several authors proposed that all elements of Beck's cognitive triad (1976) mediate the associations between inference style as described in the hopelessness model (Abramson, Alloy, & Metalsky, 1989) and depressive symptoms. Results of a 3 wave longitudinal study indicate only a partial mediation model with all elements of the cognitive triad being associated with all inference styles, with depressive symptoms fitting the data best. Controlling for direct and indirect effects, no individual element of the cognitive triad mediates the association between inference styles and depressive symptoms. The partial mediation model is not stable across sex or clinical vs subclinical samples. In general, the data supports the integration of all three elements of the cognitive triad into the hopelessness model. PMID- 21254052 TI - Shared and unique predictors of post-traumatic growth and distress. AB - This prospective longitudinal study compared pretraumatic, peritraumatic, and post-traumatic predictors of post-traumatic growth (PTG) and post-traumatic stress disorder (PTSD). A total of 103 Israeli former prisoners of the Yom Kippur War were followed over 30 years. Sociodemographic variables, trauma exposure, reactions in captivity, world assumptions, social support, and personality factors were assessed in 1991, and PTG and PTSD symptoms in 2003. Hierarchical regression modeling showed that although some predictors, namely, loss of control and active coping during captivity, predicted both PTG and PTSD, others predicted one outcome and not the other. Self-controllability predicted PTG while sociodemographic factors predicted PTSD when controlling for PTSD and PTG, respectively. The findings indicate that salutary and pathogenic trauma outcomes share some but not all precursors, underscoring their multifaceted relationship. PMID- 21254053 TI - The role of changes in activity as a function of perceived available and expended energy in nonpharmacological treatment outcomes for ME/CFS. AB - Nonpharmacological interventions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) often emphasize gradual increases in activity to promote improvement in physical functioning and fatigue. The energy envelope theory may provide a framework for understanding the relationship between changes in activity level and outcomes for patients with ME/CFS. This study examined the relationship between energy envelope and changes in activity after nonpharmacological interventions in a sample of 44 adults with ME/CFS. Results showed that those who were within their energy envelope before treatment showed more improvement in physical functioning and fatigue compared with those outside of their energy envelope. These findings suggest that an assessment of perceived available and expended energy could help guide the development of individualized nonpharmacological interventions for people with ME/CFS. PMID- 21254054 TI - Rehearsal and pedometer reactivity in children. AB - The main purpose of this study was to investigate whether rehearsal, defined as the tendency to recurrently ruminate over upsetting aversive experiences, had an effect on pedometry reactivity. A total of 156 Hong Kong Chinese children aged 9 12 years were recruited. Participants completed the Rehearsal Scale for Children Chinese (RSC-C; Ling, Maxwell, Masters, & McManus, 2010) and wore the pedometers for 3 consecutive weeks. The mean number of steps was significantly higher in Week 1 than in Week 3. High rehearsers showed a larger decrease in mean number of steps from Week 1 to Week 3 than low rehearsers. Future physical activity intervention studies should adjust for reactivity in their baseline measurements and should further examine the relationship between habitual PA and individual propensities for rehearsal. PMID- 21254055 TI - The moderation of Mindfulness-based stress reduction effects by trait mindfulness: results from a randomized controlled trial. AB - Mindfulness-based stress reduction (MBSR) has shown effectiveness for a variety of mental health conditions. However, it is not known for whom the intervention is most effective. In a randomized controlled trial (N = 30), we explored whether individuals with higher levels of pretreatment trait mindfulness would benefit more from MBSR intervention. Results demonstrated that relative to a control condition (n = 15), MBSR treatment (n = 15) had significant effects on several outcomes, including increased trait mindfulness, subjective well-being, and empathy measured at 2 and 12 months after treatment. However, relative to controls, MBSR participants with higher levels of pretreatment mindfulness showed a larger increase in mindfulness, subjective well-being, empathy, and hope, and larger declines in perceived stress up to 1 year after treatment. PMID- 21254056 TI - The role of weight stigmatization in cumulative risk for binge eating. AB - Previous research supports a positive association between weight stigmatization experiences and binge eating. However, the extent to which weight stigmatization accounts for binge eating in the context of other risk factors requires further investigation. Using a cumulative risk model, we examine previously studied risk factors (environmental stress, psychological functioning, negative coping, body dissatisfaction) as well as weight stigmatization as predictors of binge eating bariatric patients and undergraduate students. Results show a unique contribution of weight stigmatization. Analyses by sample indicated that this was only the case for the undergraduate student sample. Results support weight stigmatization as a meaningful predictor of binge eating and highlight the need for further work investigating how these experiences work to promote eating pathology. PMID- 21254057 TI - A hybrid model of social phobia: an analysis of social anxiety and related symptoms of anxiety. AB - The categorical underpinnings of the current diagnostic nomenclature have been the subject of repeated criticism. Recently, researchers have proposed several alternatives to the current system, including hybrid models of combined diagnostic categories and symptom dimensions. In the present study, we investigated the symptoms associated with a hybrid model of social phobia. The study included (a) the development of the initial set of symptom dimensions, generation of an item pool, and review by an expert panel, and (b) data collection and component analysis of the item pool to determine the structure of the symptoms. Six separate theoretically relevant symptom dimensions were identified. Implications of these findings on the development of a new hybrid model of social phobia were discussed. PMID- 21254058 TI - Interpersonal problems: self-therapist agreement and therapist consensus. AB - This study investigated patient-therapist agreement and therapist consensus of patients' interpersonal problems. The sample comprised 199 patients, who answered a questionnaire addressing interpersonal problems. At the same time, each patient was rated by two therapists on an observer version of the same questionnaire. The participants came from 10 different treatment units within the Norwegian Network of Personality-Focused Treatment Programs. Interpersonal problems were measured by a short version of the Inventory of Interpersonal Problems-Circumplex (IIP-C). The results of both patient-therapist agreements and therapist consensus of patients' interpersonal problems was low to moderate. The therapists perceived the patients to have somewhat higher levels of interpersonal problems than the patients reported, although the profile similarity between self-reports and observer reports was high. Some gender differences were revealed, but in terms of self-therapist agreement, no interaction with the therapists' length of clinical experience or acquaintance with the patient was found. PMID- 21254059 TI - Stability of long-term outcome in bulimia nervosa: a 3-year follow-up. AB - We report on the 3-year course and outcome of patients with bulimia nervosa (BN), initially treated in an inpatient or day clinic setting. Patients were assessed by structured interviews (Structured Clinical Interview for DSM Disorders I and II and Structured Interview for Anorexia and Bulimia Nervosa) and questionnaires (Eating Disorder Inventory-2, Symptom Checklist-90-R, and Social Adjustment Scale) at time points of admission, discharge, and 3-month, 12-month and 36-month follow-ups. Data of 83.7% of the 43 patients were available. After 3 years, about one third of patients showed complete remission, one third showed partial remission, and one third still fulfilled all the criteria of BN. Most changes occurred during hospitalization. Remission status showed substantial fluctuation over time, with little correlation between time points of assessment (discharge and 3-month, 12-month, and 36-month follow-ups). A cluster analysis revealed four patterns of longitudinal symptom change. Day clinic and inpatient treatment are overall effective. Longitudinal and repeated assessments are necessary to validly measure outcome in BN. PMID- 21254060 TI - Prediction of restraints among youth in a psychiatric hospital: application of translational action research. AB - This study extends a translational action research program by applying a theoretically based measure of risk in predicting incidents of restraint among children and adolescents in a secure psychiatric hospital. Youth inpatients (N = 149, aged 5-17 years) were assessed at intake for the presence of selected individual and contextual risk factors, and their involvement in critical incidents was tracked (i.e., number of episodes in which restraint was applied) for the remainder of their hospitalization. Models including history of aggression or history of previous placements as well as combined models including several individual and contextual factors significantly predicted the likelihood of a youth becoming involved in at least one restraint. Unique predictors of restraint involvement included history of aggression against adults and history of previous psychiatric hospitalizations. None of the variables assessed predicted the extent of a youth's restraint involvement. The implications of these findings are discussed with respect to future research and empirically informed practice with high-risk youth. PMID- 21254061 TI - Psychopharmacology training in clinical psychology: a renewed call for action. AB - Knowledge of psychopharmacology is essential for a clinical psychologist to practice his/her profession, regardless of whether one desires to become licensed to prescribe psychoactive medications. This commentary reiterates a call made almost 20 years ago for all practitioners to gain and utilize this knowledge. Without psychopharmacology knowledge, one is extremely limited in the ability to interact with medical prescribers and to optimally serve their patients as a valued member of the health care team. PMID- 21254062 TI - Mindfulness-based approaches: are they all the same? AB - Mindfulness-based approaches are increasingly employed as interventions for treating a variety of psychological, psychiatric and physical problems. Such approaches include ancient Buddhist mindfulness meditations such as Vipassana and Zen meditations, modern group-based standardized meditations, such as mindfulness based stress reduction and mindfulness-based cognitive therapy, and further psychological interventions, such as dialectical behavioral therapy and acceptance and commitment therapy. We review commonalities and differences of these interventions regarding philosophical background, main techniques, aims, outcomes, neurobiology and psychological mechanisms. In sum, the currently applied mindfulness-based interventions show large differences in the way mindfulness is conceptualized and practiced. The decision to consider such practices as unitary or as distinct phenomena will probably influence the direction of future research. PMID- 21254063 TI - On the accuracy of estimation of basic pharmacokinetic parameters by the traditional noncompartmental equations and the prediction of the steady-state volume of distribution in obese patients based upon data derived from normal subjects. AB - The steady-state and terminal volumes of distribution, as well as the mean residence time of drug in the body (V(ss), V(beta), and MRT) are the common pharmacokinetic parameters calculated using the drug plasma concentration-time profile C(p) (t) following intravenous (i.v. bolus or constant rate infusion) drug administration. These calculations are valid for the linear pharmacokinetic system with central elimination (i.e., elimination rate being proportional to drug concentration in plasma). Formally, the assumption of central elimination is not normally met because the rate of drug elimination is proportional to the unbound drug concentration at elimination site, although equilibration between systemic circulation and the site of clearance for majority of small molecule drugs is fast. Thus, the assumption of central elimination is practically quite adequate. It appears reasonable to estimate the extent of possible errors in determination of these pharmacokinetic parameters due to the absence of central elimination. The comparison of V(ss), V(beta), and MRT calculated by exact equations and the commonly used ones was made considering a simplified physiologically based pharmacokinetic model. It was found that if the drug plasma concentration profile is detected accurately, determination of drug distribution volumes and MRT using the traditional noncompartmental calculations of these parameters from C(p) (t) yields the values very close to that obtained from exact equations. Though in practice, the accurate measurement of C(p) (t), especially its terminal phase, may not always be possible. This is particularly applicable for obtaining the distribution volumes of lipophilic compounds in obese subjects, when the possibility of late terminal phase at low drug concentration is quite likely, specifically for compounds with high clearance. An accurate determination of V(ss) is much needed in clinical practice because it is critical for the proper selection of drug treatment regimen. For that reason, we developed a convenient method for calculation of V(ss) in obese (or underweight) subjects. It is based on using the V(ss) values obtained from pharmacokinetic studies in normal subjects and the physicochemical properties of drug molecule. A simple criterion that determines either the increase or decrease of V(ss) (per unit body weight) due to obesity is obtained. The accurate determination of adipose tissue plasma partition coefficient is crucial for the practical application of suggested method. PMID- 21254064 TI - In vitro assessment of the formation of ceftriaxone-calcium precipitates in human plasma. AB - Ceftriaxone is a third-generation cephalosporin antibiotic, which has a broad spectrum of bactericidal activity. Ceftriaxone is highly soluble as a sodium salt, but far less soluble as a calcium salt. Incompatibility of ceftriaxone with calcium and the possible formation of precipitates have been stated in the product label from early on. It was the objective of the present in vitro study to further assess the risk of precipitation of calcium-ceftriaxone in human plasma. Analytical methods were developed (high-performance liquid chromatography and flame atomic absorption spectroscopy) to quantitate calcium and ceftriaxone in human plasma supernatants and human plasma precipitates. Using high concentrations of ceftriaxone (10 mmol/L) and calcium (4.2 mmol/L) did not result in any precipitation after 2 h incubation in human plasma at 37 degrees C. Under conditions of forced precipitation only, formation of precipitation was observed. The identity of the precipitated material was confirmed by energy-dispersive X ray analysis and Fourier transform infrared spectroscopy. We conclude that calcium-ceftriaxone in human plasma has an apparent kinetic solubility product constant of greater than 0.42 * 10(-4) (mol/L)(2), which exceeds the normal thermodynamic solubility product in water by a factor of 26. Under these conditions, the formation of plasma precipitates is unlikely. PMID- 21254065 TI - Surface-active derivative of inulin (Inutec(r) SP1) is a superior carrier for solid dispersions with a high drug load. AB - The aim of this study was to compare the applicability of inulin, its surface active derivative (Inutec(r) SP1), and polyvinylpyrrolidone (PVP) as carriers in high drug load solid dispersions (SDs) for improving the dissolution rate of a range of lipophilic drugs (diazepam, fenofibrate, ritonavir, and efavirenz). The SDs were prepared by spray freeze-drying. Scanning electron microscopy showed that the obtained samples were highly porous spherical particles. Modulated differential scanning calorimetry showed that the drugs incorporated in these carriers were fully or partially amorphous. The solubility of the drugs in solutions of the different carriers was increased in an order: inulin 2.3 kDa < PVP K30 ? Inutec(r) SP1. The dissolution behavior of SD tablets was evaluated. Inutec(r) SP1-based SD tablets showed the best performance followed by PVP- and inulin-based SD tablets. The superior dissolution behavior of the drugs from Inutec(r) SP1-based SDs could be ascribed to its surface-active nature. In addition, Inutec(r) SP1-based SD tablets gave good physical stability at 20 degrees C/45% relative humidity (RH) and 40 degrees C/75% RH for 3 months. PMID- 21254066 TI - Characterization of nicergoline polymorphs crystallized in several organic solvents. AB - Nicergoline (NIC), a poorly water-soluble semisynthetic ergot derivative, was crystallized from several organic solvents, obtaining two different polymorphic forms, the triclinic form I and the orthorhombic form II. NIC samples were then characterized by several techniques such as (13)C cross-polarization magic angle spinning solid-state spectroscopy, room-temperature and high-temperature X-ray powder diffraction, differential scanning calorimetry, and by analysis of weight loss, solvent content, powder density, morphology, and particle size. Solubility and intrinsic dissolution rates determined for the two polymorphic forms in water and hydrochloride solutions (HCl 0.1 N) were always higher for form II than for form I, which is actually the form used for the industrial preparation of NIC medicinal products. Preformulation studies might encourage industry for the evaluation of polymorph II, as it is more suitable for pharmaceutical applications. Results in drug delivery, as well as those obtained by the above mentioned techniques, and the application of Burger-Ramberger's rules make it possible to conclude that there is a thermodynamic relation of monotropy between the two polymorphs. This last assumption may help formulators in predicting the relative stability of the two forms. PMID- 21254067 TI - Sustained-release and swelling characteristics of xanthan gum/ethylcellulose based injection moulded matrix tablets: in vitro and in vivo evaluation. AB - Sustained-release matrix tablets were developed by injection moulding using metoprolol tartrate (MPT) and ethylcellulose (EC) as sustained-release agent. Dibutyl sebacate was selected as plasticiser. The influence of matrix composition, plasticiser concentration, and drug load on drug release was evaluated. The influence of plasticiser addition was assessed on processability and drug release: Dibutyl sebacate was added to a dichloromethane/EC solution and subsequently spray-dried, or was mixed as a liquid with EC powder. Hydrated tablets were evaluated by frequency sweep and creep rheological tests to correlate the results with drug release. Xanthan gum (XG) was added to the formulation because drug release was too slow (<50%, 24 h) from EC/MPT matrices (70%/30%, w/w). Increasing XG concentrations provided faster MPT release rates characterised by zero-order release kinetics, no burst release was observed. Lower plasticiser concentrations and higher drug loads increased drug release substantially. The plasticiser addition method did not affect drug release. Matrix composition, drug load, and plasticiser level affected the rheological properties of the swollen matrix tablets. X-ray diffraction demonstrated the formation of solid dispersions. Formulations composed of XG/EC (ratio 1:1.5) and 30% (w/w) MPT had a low relative bioavailability compared with the commercial product Lopressor(r), which significantly improved at higher MPT concentration (50%, w/w). PMID- 21254068 TI - Development of a canine model to enable the preclinical assessment of pH dependent absorption of test compounds. AB - A preclinical canine model capable of predicting a compound's potential for pH dependent absorption in humans was developed. This involved the surgical insertion of a gastrostomy feeding tube into the stomach of a beagle dog. The tube was sutured in position to allow frequent withdrawal of gastric fluid for pH measurement. Therefore, it was possible to measure pH in the stomach and assess the effect of gastric pH-modifying agents on the absorption of various test compounds. Fasted gastric pH in the dog showed considerable inter- and intra animal variability. Pretreatment of pentagastrin (6 ug/kg intramuscularly) 20 min prior to test compound administration was determined to be adequate for simulating fasting stomach pH in humans. Pretreatment with famotidine [40 mg orally] 1 h prior to test compound administration was determined to be adequate for simulating human gastric pH when acid-reducing agents are coadministered. Pentagastrin and famotidine pretreatments were used to test two discovery compounds and distinct differences in their potential for pH-dependent absorption were observed. The model described herein can be used preclinically to screen out compounds, differentiate compounds, and support the assessment of various formulation- and prodrug-based strategies to mitigate the pH effect. PMID- 21254069 TI - Quantitative membrane protein expression at the blood-brain barrier of adult and younger cynomolgus monkeys. AB - Cynomolgus monkey has been used as a model for the prediction of drug disposition in human brain. The purpose of this study was to clarify protein expression levels of membrane proteins affecting drug distribution to brain, such as transporters, receptors, and junctional proteins, in cynomolgus monkey brain microvessels by using liquid chromatography tandem mass spectrometry. In adult monkeys, three ATP-binding cassette transporters (multidrug resistance 1 (MDR1), breast cancer resistance protein (BCRP), and multidrug resistance protein 4 (MRP4)), six solute carrier transporters (glucose transporter 1 (GLUT1), GLUT3/14, monocarboxylate transporter 1 (MCT1), MCT8, organic anion transporting polypeptide 1A2, and equilibrative nucleoside transporter 1), two junctional proteins (claudin-5 and vascular endothelial cadherin), and two receptors (insulin receptor and low-density lipoprotein receptor-related protein 1) were detected. Comparison of the expression levels with those in mouse, which we reported previously, revealed a pronounced species difference. BCRP expression in monkey was greater by 3.52-fold than that in mouse, whereas MDR1 and MRP4 expression levels in monkey were lower by 0.304- and 0.180-fold, respectively, than that in mouse. This study also investigated the developmental changes in expression of membrane proteins in neonate and child monkeys. Expression of MDR1 was similar in neonate and adult monkeys, whereas in rat, P-glycoprotein expression was reported to be significantly lower in brain microvessels of neonate as compared with adult rat. These results will be helpful to understand and predict brain concentrations of drugs in different species and at different ages of primates. PMID- 21254070 TI - Vacuum-packed ripened sausages: evolution of volatile compounds during storage. AB - BACKGROUND: Various studies have shown the ability of volatile compounds to influence the quality of charcuterie products because of their effect on sensorial properties. To the best of our knowledge, there are no data in the scientific literature concerning the evolution of volatile compounds of vacuum packed ripened sausages over time. The aim of this work was to evaluate the evolution of volatile compounds in vacuum-packed ripened sausages over time, considering that this kind of packaging is the most commonly used to prolong the shelf-life of these products. RESULTS: Sixty-nine volatile compounds were identified. Those derived from spices represented the prevailing compounds at the beginning of storage and significantly decreased (P<0.001) during 5 months of storage, as a result of the well-known antioxidant activity. Conversely, compounds derived from the autoxidation of lipids, which are among those chiefly responsible of sensorial properties of meat products, significantly increased (P<0.001). CONCLUSION: The research demonstrated that vacuum packaging influenced the evolution of volatile compounds during storage of ripened sausages. In particular, the increase of volatile compounds derived from autoxidation of the lipid fraction indicated that oxidative processes involved the fatty fraction of ripened sausages also in the scarcity of oxygen. PMID- 21254071 TI - Free amino acids profile and quantities of 'sirt', 'bohca' and 'sekerpare' pastirma, dry cured meat products. AB - BACKGROUND: Pastirma is a dry-cured and semi-fermented meat product, produced from whole beef or water buffalo muscles. Sixteen to twenty different types of pastirma can be produced from a carcass, and each pastirma type has a different name, shape and quality characteristics. The objective of this study was to determine the free amino acid (FAA) composition, pH and moisture values of 'sirt', 'bohca' and 'sekerpare' pastirma. RESULTS: Significant differences were determined among the pastirma types in glutamic acid (P<0.05), threonine (P<0.05), arginine (P<0.05), alanine (P<0.01), methionine (P<0.01), tryptophan (P<0.05), proline (P<0.01) and valine (P<0.01). Threonine, methionine and valine were higher in sirt pastirma than the others; glutamic acid, arginine and tryptophan were higher in sekerpare pastirma. The predominant FAA in the all pastirma samples was alanine, while the lowest was asparagine. The highest mean pH was in sirt pastirma, and the lowest mean pH in bohca pastirma. There was no significant difference in mean moisture values among pastirma types. CONCLUSION: Significant differences were determined among pastirma types in some FAA. Analysis results indicated that quality and nutritional properties for different pastirma types are different. The most advantageous pastirma types in terms of FAA were bohca and sirt, which contain the highest quantity of threonine, methionine and valine. PMID- 21254072 TI - Oxidative stability of cooked, frozen, reheated beef patties: effect of antioxidants. AB - BACKGROUND: The effect of selected antioxidants (grape seed extract (GS), oleoresin rosemary (OR), water-soluble oregano extract (WO), propyl gallate (PG), butylated hydroxyanisole (BHA)), butylated hydroxytoluene (BHT)) on sensory, color and oxidative stability of cooked, frozen, reheated ground beef patties was evaluated. Beef lean and trim were ground; antioxidants and salt were added. Patties were cooked (71 degrees C), overwrapped in commercial polyvinyl chloride film, and stored frozen (-18 degrees C), then evaluated monthly for 6 months. Flavor, odor and color were determined using a descriptive panel. Instrumental color was determined by a spectrocolorimeter. Lipid oxidation was determined using thiobarbituric acid reactive substances (TBARS). RESULTS: After 6 months of storage, PG and GS samples had lower rancid odor scores and TBARS than controls. Control samples and those containing BHT did not differ statistically in sensory grassy or rancid odor, indicating that they were the most oxidized. TBARS correlated with grassy, rancid, cardboard and beef odors during the 6-month storage period. CONCLUSIONS: Based on TBARS, the order of effectiveness of the antioxidants was PG and GS > OR > BHA > WO and BHT > control. TBARS were well correlated with sensory evaluations of odor and flavor. Antioxidants also protected a* values during storage. PMID- 21254073 TI - Effect of jam processing and storage on total phenolics, antioxidant activity, and anthocyanins of different fruits. AB - BACKGROUND: Fruits have been widely recognised as an excellent source of bioactive phenolic compounds. The purpose of this study was to evaluate the effect of jam processing of strawberry, cherry, apricot, fig and orange on the total phenolics, antioxidant activity and anthocyanins during 5 months of storage at 25 degrees C. RESULTS: Fresh strawberry had the highest contents of total phenolics (8503.1 mg GAE kg(-1) ) followed by cherry, apricot, fig and orange, respectively. Jam processing decreased the total phenolics, antioxidant activity, and anthocyanins of all fruits. Total phenolics of jam during storage decreased only in apricot, fig and orange. Fresh strawberry had the highest antioxidant activity (54.88% inhibition) followed by the other fruits. Antioxidant activity did not change in strawberry during jam storage, while there are reductions in the other fruits were observed. Fresh strawberry had the highest anthocyanins (2323.8 mg cya-3-glu kg(-1) ), followed by cherry and the other fruits, respectively. Results showed only a decrease of anthocyanins and pH in apricot and fig jams during 5 months of storage. CONCLUSION: Despite the reduction of these compounds in jam processing, it is considered a good method to maintain them during 5 months of storage. PMID- 21254076 TI - The real challenge of the translational process: management of expectations. PMID- 21254077 TI - Comparison of beneficial effects of undifferentiated cultured bone marrow stromal cells and omental adipose-derived nucleated cell fractions on sciatic nerve regeneration. AB - Adipose tissue is a good source for isolation of cells with stem-cell-like properties. The effects of undifferentiated cultured bone marrow stromal cells (BMSCs) and omental adipose-derived nucleated cells (OADNCs) on peripheral nerve regeneration were compared in a rat nerve regeneration model. A 10-mm sciatic nerve defect was bridged using a vein graft. In one group, the vein was filled with BMSCs and in the other group with OADNCs. Functional study, morphometric indices, and immunohistochemistry indicated there was no significant difference (P > 0.05) between groups in recovery of regenerated axons at 4, 8, and 12 weeks after surgery. OADNCs enhanced regeneration similar to undifferentiated BMSCs. These observations suggest OADNCs represent an effective and cost-saving cell population due to the shortened time interval from tissue collection to cell injection as well as procedural simplicity. This approach is clinically translatable toward new methods for enhanced peripheral nerve repair without the limitations of BMSC. PMID- 21254079 TI - Diagnostic utility of stimulated single-fiber electromyography of the orbicularis oculi muscle in patients with suspected ocular myasthenia. AB - Stimulated single-fiber electromyography (SSFEMG) is a valuable diagnostic tool in cases of myasthenia gravis with limited disease. From 1990 to 2008 SSFEMG in the orbicularis oculi muscle (OO) was performed in a cohort of 456 patients referred with clinical suspicion of myasthenia gravis (MG) and exclusively ocular symptoms. A diagnosis of MG was made on clinical grounds in 103 patients. In this patient cohort, the specificity of SSFEMG for myasthenia was 97%, and the sensitivity was 80%. MG patients with a normal SSFEMG had a benign clinical course. This study confirms a high specificity and sensitivity of SSFEMG when it is performed on patients suspected to have ocular MG. In such patients, a normal SSFEMG of the OO predicts a benign clinical course. PMID- 21254078 TI - Vascular endothelial growth factor helps differentiate neuropathies in rare plasma cell dyscrasias. AB - POEMS syndrome and amyloidosis are rare plasma cell diseases that share common features, including polyneuropathy. The aim of this study was to investigate serum vascular endothelial growth factor (sVEGF) in patients with amyloidosis and to evaluate changes in response to treatment. Twenty-five patients [17 primary light-chain amyloidosis (AL-A), 7 transthyretin amyloidosis (TTR-A), 1 senile wild-type TTR-A] were studied. sVEGF was analyzed by ELISA. Sera from 8 myeloma and 7 POEMS patients were also evaluated. The median sVEGF level was 420 pg/ml in AL-A and 179 pg/ml in TTR-A patients; this was significantly lower than in POEMS syndrome (median 2580 pg/ml, P = 0.0002 and 0.001, respectively). sVEGF of AL-A patients showed no changes in response to treatment. sVEGF was not increased in amyloid patients regardless of neuropathy, and did not mirror the course of the disease. sVEGF should be tested in patients with overlapping and atypical clinical features. PMID- 21254080 TI - Validity and reliability of the Purdue Pegboard Test in carpal tunnel syndrome. AB - There is a paucity of validated tests to quantify hand function impairment due to carpal tunnel syndrome (CTS). The aim of this study was to test the validity and reliability of the Purdue Pegboard Test (PPT) in CTS patients. We compared 190 CTS patients with 122 healthy, age-matched controls. CTS severity was determined based on electrophysiologic parameters and the Levine Self-Assessment Questionnaire. The time to complete the PPT and the test-retest reliability were tested. The test-retest reliability was high with an intraclass correlation coefficient of 0.91. Compared to healthy controls, the CTS patients were significantly slower. Although the functional performance generally declined with increasing severity of electrophysiologic abnormalities, the correlation between hand function decline and symptom severity in the young and middle-aged groups was low. We conclude that the PPT is a valid and reliable tool to quantify functional impairment caused by CTS. It can be a useful outcome measure in young and middle-aged patients. PMID- 21254081 TI - Detection of fibrillations using muscle ultrasound: diagnostic accuracy and identification of pitfalls. AB - We prospectively investigated the diagnostic accuracy and potential pitfalls of dynamic muscle ultrasound in the detection of fibrillations. The presence of fibrillations on both electromyography (EMG) and ultrasound was evaluated in 102 muscles of 38 patients with suspected fibrillation potentials, based on history and physical examination. Sensitivity and specificity were calculated. False positive and false-negative results are described to identify pitfalls. Ultrasound detected fibrillations with a sensitivity of 45% and a specificity of 66%. Specificity improved to 85% when measurements were evaluated online. Proximal muscles showed higher sensitivities (63%) than distal muscles (33%). Ultrasound currently has a poor sensitivity and moderate specificity for detecting fibrillations. Several pitfalls were identified that, when avoided, could help improve diagnostic accuracy. Ensuring a distal limb temperature of at least 34 degrees C and identifying external movement artifacts as well as voluntary contractions can improve efficacy and open the way for diagnostic application of this technique. PMID- 21254082 TI - Pediatric sciatic neuropathy associated with neoplasms. AB - Seven children with sciatic neuropathy associated with an underlying neoplasm are reported. Clinical presentation, electrophysiological data, imaging, pathology, and/or autopsy results are described. Pain and weakness, primarily foot drop, were the most common presenting symptoms. The mechanism of sciatic neuropathy was varied and included: nerve infiltration by the adjacent neoplasm (neuroblastoma, rhabdomyosarcoma, and leukemic or lymphomatous infiltration); an expanding, intrinsic neurogenic tumor (perineurioma); or intraoperative stretch injury (osteosarcoma resection). The prognosis for sciatic nerve recovery was good among children who survived their associated cancer. Three children died from the cancer or complications of treatment. One child with perineurioma remained clinically stable, and two children improved after treatment of their neoplasm. PMID- 21254083 TI - Repeated courses of granulocyte colony-stimulating factor in amyotrophic lateral sclerosis: clinical and biological results from a prospective multicenter study. AB - Granulocyte colony-stimulating factor (G-CSF) induces a transient mobilization of hematopoietic progenitor cells from bone marrow to peripheral blood. Our aim was to evaluate safety of repeated courses of G-CSF in patients with amyotrophic lateral sclerosis (ALS), assessing disease progression and changes in chemokine and cytokine levels in serum and cerebrospinal fluid (CSF). Twenty-four ALS patients entered an open-label, multicenter trial in which four courses of G-CSF and mannitol were administered at 3-month intervals. Levels of G-CSF were increased after treatment in the serum and CSF. Few and transitory adverse events were observed. No significant reduction of the mean monthly decrease in ALSFRS-R score and forced vital capacity was observed. A significant reduction in CSF levels of monocyte chemoattractant protein-1 (MCP-1) and interleukin-17 (IL-17) was observed. G-CSF treatment was safe and feasible in a multicenter series of ALS patients. A decrease in the CSF levels of proinflammatory cytokines MCP-1 and IL-17 was found, indicating a G-CSF-induced central anti-inflammatory response. PMID- 21254084 TI - The somatosensory blink reflex in upper and lower brainstem lesions. AB - The brainstem pathways that mediate the somatosensory blink reflex (SBR) are not completely understood. We hypothesized that the circuits of the SBR might be affected separately from those of the trigeminal blink reflex (TBR). We examined 7 patients with mesencephalic lesions and 8 patients with medullary lesions. The SBR was elicited by median nerve stimulation. The TBR was elicited by supraorbital nerve stimulation. In patients with upper brainstem lesions, the TBR was normal, whereas the SBR was generally abnormal. The SBR was either absent or small and was significantly delayed with respect to control subjects. The opposite was the rule in patients with lower brainstem lesions who had delayed or absent TBR and no abnormal findings in the SBR. The SBR is mediated through circuits in the upper brainstem. Study of the SBR can be helpful in the neurophysiological assessment of patients with mesencephalic lesions. PMID- 21254086 TI - Time-course of changes in the myonuclear domain during denervation in young-adult and old rat gastrocnemius muscle. AB - If myonuclear loss initiates muscle wasting, it should precede the loss of muscle mass. As aging affects muscle plasticity, the time-course of muscle atrophy during disuse may differ between young and old animals. To investigate this, gastrocnemius muscles of 5- and 25-month-old rats were exposed to 1, 2, or 4 weeks of denervation, whereas the contralateral gastrocnemius muscles served as controls. Muscle fibers of each type responded similarly to 4 weeks of denervation. For both ages most of the atrophy (36%; P < 0.001) occurred in the first 2 weeks. In young-adult muscles, the myonuclear number remained constant, but in old muscles it decreased to below control level after 4 weeks of denervation (P < 0.05). Despite this differential response, myonuclear domain size decreased similarly at both ages (P < 0.001). In both young-adult and old rats, denervation-induced atrophy was not preceded by a loss of myonuclei. PMID- 21254085 TI - Effects of electrical stimulation on neuromuscular junction morphology in the aging rat tongue. AB - Alterations in neuromuscular junction (NMJ) structure in cranial muscles may contribute to age-related deficits in critical sensorimotor actions such as swallowing. Neuromuscular electrical stimulation (NMES) is used in swallowing therapy, but it is unclear how NMJ structure is affected or if NMJ morphology is best measured in two or three dimensions. Two- and three-dimensional measurements of NMJ morphology in the genioglossus muscle were compared in rats that had undergone 8 weeks of hypoglossal nerve stimulation vs. untreated controls. The relationship between motor endplate volume and nerve terminal volume had a mean positive slope in 90% of the young adult controls, but it was positive in only 50% of the old controls; 89% of NMES old rats had a positive slope. NMJ measurements were more accurate when measured in three dimensions. In the NMJ, aging and NMES are associated with changes in the pre- and post-synaptic relationship. PMID- 21254087 TI - Rantes secreted from macrophages disturbs skeletal muscle regeneration after cardiotoxin injection in Cbl-b-deficient mice. AB - Deficiency of the Cbl-b ubiquitin ligase gene activates macrophages in mice. This study aimed to elucidate the pathophysiological roles of macrophages in muscle degeneration/regeneration in Cbl-b-deficient mice. We examined immune cell infiltration and cytokine expression in cardiotoxin-injected tibialis anterior muscle of Cbl-b-deficient mice. Ablation of the Cbl-b gene expression delayed regeneration of cardiotoxin-induced skeletal muscle damage compared with wild type mice. CD8-positive T cells were still present in the damaged muscle on day 14 after cardiotoxin injection in Cbl-b-deficient mice, but there was dispersal of the same cells over that time-frame in wild-type mice. Infiltrating macrophages in Cbl-b-deficient mice showed strong expression of RANTES (regulated on-activation, normal T cell expressed and secreted), a chemokine for CD8 positive T cells. In turn, a neutralizing antibody against RANTES significantly suppressed the infiltration of CD8-positive T cells into the muscle, resulting in restoration of the disturbed muscle regeneration. Cbl-b is an important regulatory factor for cytotoxic T-cell infiltration via RANTES production in macrophages. PMID- 21254088 TI - Fatigability of spinal reflex transmission in a mouse model (SOD1(G93A) ) of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons. To analyze the progressive motor deficits during the course of this disease, we investigated fatigability and ability of recovery of spinal motor neurons by testing monosynaptic reflex transmission with increasing stimulus frequencies in the lumbar spinal cord of the SOD1(G93A) mouse model for ALS in a comparison with wild-type (WT) mice. Monosynaptic reflexes in WT and SOD1(G93A) mice without behavioral deficits showed no difference with respect to their resistance to increasing stimulus frequencies. During the progression of motor deficits in SOD1(G93A) mice, the vulnerability of monosynaptic reflexes to higher frequencies increased, the required time for reflex recovery was extended, and recovery was often incomplete. Fatigability and demand for recovery of spinal motor neurons in SOD1(G93A) mice rose with increasing motor deficits. This supports the assumption that impairment of the energy supply may contribute to the pathogenesis of ALS. PMID- 21254089 TI - An early diagnostic tool for diabetic neuropathy: conduction velocity distribution. AB - Diabetes is a metabolic disorder that affects much of the human population. As a secondary complication, diabetic neuropathy causes time-dependent damage to peripheral nerves. In this study, experimental diabetes was induced by streptozotocin (STZ; 50 mg/kg intraperitoneally) in rats. Diabetic animals were grouped into those with 2 or 4 weeks of diabetes, whereas a control group received only the STZ vehicle (0.1 M citrate). Sciatic nerves were dissected, and compound action potentials (CAPs) were recorded. Results deduced by conventional calculation carried less information when compared with conduction velocity distribution (CVD) obtained by a computer-based mathematical model. Using the conventional approach, statistically significant changes were first seen in the fourth week of diabetes, whereas results deduced by CVD measurement could be seen in the second week. Consequently, the CVD calculation provides more information for the early diagnosis of neuropathies compared with classical conduction velocity measurements. PMID- 21254090 TI - Effects of resistance training on force steadiness and common drive. AB - The purpose of this study was to investigate the influence of an 8-week resistance training program on force steadiness and common drive for the vastus lateralis muscle. Eight untrained men performed a resistance training program. Before the program and at the end of each week, the subjects performed a trapezoid isometric muscle action of the leg extensors, and bipolar surface electromyographic signals were recorded from the vastus lateralis. The signals were decomposed into action potential trains that were cross-correlated to measure common drive. Force steadiness was quantified as the standard deviation of force during the constant-force portion of the trapezoid muscle action. The training program did not consistently affect force steadiness or common drive for any of the subjects. Although future studies are needed with different muscles and training programs, changes in the overall motor control scheme are not likely with resistance training. PMID- 21254091 TI - Subthreshold continuous electrical stimulation facilitates functional recovery of facial nerve after crush injury in rabbit. AB - We sought to determine whether electrical stimulation (ES) with subthreshold, continuous, low-frequency impulses is a viable clinical method for improving functional recovery after facial nerve crush injury. In 10 rabbits, bilateral crush injuries were made on the facial nerve by compression for 30 s with mosquito forceps, causing complete facial paralysis. Subthreshold continuous direct current ES with 20-Hz square-wave pulses was applied to the proximal stump on one side for 4 weeks. Vibrissae movement returned significantly earlier on the ES side, with a less variable recovery time. Electrophysiologically, the stimulated side had a significantly shorter latency, longer duration, and faster conduction velocity. Light and transmission electron microscopy revealed that the electrical stimulation also markedly decreased Wallerian degeneration. The average numbers of fluorescent, double-labeled nerve cells were significantly different between the ES and non-ES sides. This study shows that subthreshold, continuous, low-frequency ES immediately after a crush injury of the facial nerve results in earlier recovery of facial function and shorter overall recovery time. PMID- 21254092 TI - Spinal reflex excitability and homosynaptic depression after a bout of whole-body vibration. AB - Although whole-body vibration (WBV) affects neuromuscular performance, it remains unclear whether the effects are due to spinal reflex potentiation or inhibition, or differ between muscle groups. This study aimed to identify the effect of WBV on measures of spinal reflex excitability (H-reflex) and homosynaptic depression (HD) in the soleus (SOL) and medial gastrocnemius (MG) muscles. H-reflex and HD measurements were made in the SOL and MG muscle of 20 participants before and after a bout of WBV. H-reflex and HD were measured every 15 seconds for 10 minutes post-WBV and averaged at 1-minute increments. H-reflex amplitude was depressed for the first minute post-vibration, whereas the effect of HD was reduced for the first 2 minutes post-vibration. WBV significantly decreases spinal reflex excitability and HD, but it does so transiently and independent of muscle group. PMID- 21254093 TI - Impaired respiratory function in mdx and mdx/utrn(+/-) mice. AB - Muscle fibrosis is a prominent pathological feature that directly causes muscle dysfunction in Duchenne muscular dystrophy (DMD). The DMD mouse models, mdx mice and mdx mice with haploinsufficiency of the utrophin gene (mdx/utrn(+/-) ), display progressive diaphragm fibrosis. We performed unrestrained whole-body plethysmography (WBP) in mdx and mdx/utrn(+/-) mice, and compared them with wild type controls. Respiratory function gauged by respiratory frequency, tidal volume, minute volume, peak inspiratory flow, and peak expiratory flow was significantly impaired in the mdx mice. Consistent with more severe diaphragm fibrosis in the mdx/utrn(+/-) mice, respiratory impairment was worse than in mdx mice at 6 months. WBP is useful for monitoring in vivo respiratory function of mdx and mdx/utrn(+/-) mice, and it may serve as an outcome measurement for therapies that target diaphragm fibrosis. The mdx/utrn(+/-) mouse model may be better than the mdx model for testing antifibrotic therapies, especially at the severe stage. PMID- 21254094 TI - Effects of formoterol on protein metabolism in myotubes during hyperthermia. AB - Proteolysis in skeletal muscle is mainly carried out by the activity of the ubiquitin-dependent proteolytic system. For the study of protein degradation through the ubiquitin-proteasome pathway, we used a model of hyperthermia in murine myotubes. In C2C12 cells, hyperthermia (41 degrees C) induced a significant increase in both the rate of protein synthesis (18%) and degradation (51%). Interestingly, the addition of the beta(2) -adrenoceptor agonist formoterol resulted in a significant decrease in protein degradation (21%) without affecting protein synthesis. The decrease in proteolytic rate was associated with decreases in gene expression of the different components of the ubiquitin-dependent proteolytic system. The effects of the beta(2) -agonist on protein degradation were dependent exclusively on cAMP formation, because inhibition of adenylyl cyclase completely abolished the effects of formoterol on protein degradation. It can be concluded that hyperthermia is a suitable model for studying the anti-proteolytic potential of drugs used in the treatment of muscle wasting. PMID- 21254095 TI - Motor nerve conduction study in cauda equina with high-voltage electrical stimulation in multifocal motor neuropathy and amyotrophic lateral sclerosis. AB - In this study we aim to establish a motor nerve conduction study (NCS) for the cauda equina and examine its usefulness in multifocal motor neuropathy (MMN) and amyotrophic lateral sclerosis (ALS). NCS of the tibial nerve proximal to the knee was performed with an optimized high-voltage electrical stimulation (HV-ES) method in 21 normal subjects, 5 with MMN, and 11 with ALS. HV-ES, but not magnetic stimulation, could supramaximally stimulate the cauda equina. Cauda equina motor conduction time determined by HV-ES, but not that with F-waves, correlated well with cauda equina length on magnetic resonance imaging. HV-ES revealed proximal lesions in 4 MMN patients but in none of the ALS patients. Importantly, 1 patient with "MMN without conduction block (CB)" had a CB in the cauda equina. Cauda equina motor conduction is better evaluated by HV-ES than with F-wave study or magnetic stimulation. HV-ES can help to distinguish MMN and "MMN without CB" from ALS. PMID- 21254097 TI - Acute superficial sensory neuropathy with generalized anhidrosis, anosmia, and ageusia. AB - We report a 53-year-old woman with an unusual presentation characterized by acute onset of generalized sensory symptoms associated with anhidrosis, anosmia, ageusia, and elevated titers of anti-GalNAc-GD1a antibodies. After intravenous immunoglobulin therapy, a remarkable improvement in the pain and temperature sensation was noted in her face, trunk, and extremities. The impaired pain and temperature sensation remained distributed along cranial and spinal dermatomes in a non-length-dependent manner, suggesting that the ganglionopathy affected small neurons. PMID- 21254096 TI - Genotyping mdx, mdx3cv, and mdx4cv mice by primer competition polymerase chain reaction. AB - mdx, mdx3cv, and mdx4cv mice are among the most commonly used models for the study of Duchenne muscular dystrophy. Their disease is caused by point mutations in the dystrophin gene. Despite widespread use of these models, genotyping has not always been straightforward. Current methods require multiple polymerase chain reactions (PCRs), post-PCR manipulations, and/or special equipment/reagents. Herein we report a simple, robust PCR genotyping method based on primer competition. This approach could also be applied in genotyping other point-mutation models. PMID- 21254098 TI - Immune trigeminal sensory neuropathy with esophageal achalasia: improvement with long-term immunotherapy. AB - We report a patient who developed subacute facial-predominant numbness and anhidrosis, oral incoordination, and esophageal achalasia with resultant cachexia. Great auricular nerve biopsy showed extensive epineurial perivascular inflammatory infiltrates. Sensation, sweating, and swallowing improved with pulse intravenous methylprednisolone given over 5 years. We suggest that the patient's deficits, including achalasia, were due to an immune-mediated sensory and autonomic neuropathy and that, in such cases, pathologic studies of the great auricular nerve may be diagnostically informative. PMID- 21254099 TI - Anti-ryanodine receptor-positive acetylcholine receptor-negative myasthenia gravis: evidence of impaired excitation-contraction coupling. PMID- 21254100 TI - QSART for diagnosis of statin-associated polyneuropathy. PMID- 21254101 TI - Sarcoidosis presenting as acute inflammatory demyelinating polyradiculoneuropathy. PMID- 21254102 TI - Ultrasonography in patients with ulnar neuropathy at the elbow: comparison of cross-sectional area and swelling ratio with electrophysiological severity. PMID- 21254103 TI - Is electrical stimulation a consolidated treatment for denervated muscles and functional recovery after nerve injuries? PMID- 21254104 TI - Is stimulation of denervated muscle contraindicated when there is potential for reinnervation? PMID- 21254109 TI - Study on advanced nanoscale near-field photolithography. AB - At present, applying a near-field optical microscope to photolithographic line segment fabrication can only obtain nanoscale line segments of equal cutting depths, and cannot result in 3D shape fabrication. This study proposes an innovative line segment fabrication model of near-field photolithography that adjusts an optical fiber probe's field distance to control the exposure energy density, and moreover constructs an exposure energy density analysis method of the innovative photolithographic line segment fabrication. During the exposure simulation process of the innovative line segment fabrication model of near-field photolithography, the near-field distance between the optical fiber probe and the photoresist surface increases gradually, whereas the exposure energy density distribution decreases gradually. As a result, the cutting depth becomes shallower and the full-width at half maximum (FWHM) increases. The results of this study can serve as a theoretical reference for developing advanced nanoscale near-field photolithography techniques, to which an important and groundbreaking contribution is made. PMID- 21254110 TI - Morphological behavior and attachment of p19 neural cells to root-end filling materials. AB - Some techniques and instruments like stereomicroscopy and confocal microscopy used for observing neural cells are too complicated and dependent on preparation and cell fixation methods. This may question the results of these methods. Though, we have used scanning electron microscopy on replicated specimens to observe p19 neural cells and their cellular extensions. This manuscript has shown the feasibility of using replica (indirect) method instead of direct methods for observing morphological characteristics of this high sensitive cell line. As neural cells are very sensitive to fixation solutions and processes, we have used replica mode and observed neural cells with a novel indirect method. We have used replica mode in this study to indirectly and noninvasively evaluate the state of p19 neural cells and their cellular extensions. PMID- 21254111 TI - Effect of fluoride pretreatment on primary and permanent tooth surfaces by acid etching. AB - This study observed the effect of fluoride application on a 37% phosphoric acid etching for 20 s of the enamel surfaces of primary and permanent teeth based on a clinical protocol employed in dental hospitals, through atomic force microscopy and scanning electron microscopy. Enamel samples were prepared from 84 exfoliated and noncarious teeth. Primary (groups 1-4) and permanent (groups 5-8) tooth samples were assigned randomly to one of eight groups based on the timing of acid etching with 37% phosphoric acid after an acidulated phosphate fluoride (APF) treatment. Groups 1 and 5 received no fluoride application. Groups 2-4 and 6-8 were pretreated with fluoride and received acid-etching 2 weeks later (groups 2 and 6), 1 week later (groups 3 and 7), and immediately (groups 4 and 8). The acid etching process led to a significant increase in roughness (p<0.0001), and the APF treatment led to a decrease in primary and permanent tooth surface roughness (p<0.005). An acid-etching procedure 2 weeks after performing an APF pretreatment might be recommended to obtain the maximum enamel adhesion of a resin composite. PMID- 21254112 TI - A silanized mica substrate suitable for high-resolution fiber FISH analysis by scanning near-field optical/atomic force microscopy. AB - We applied a novel silanized mica substrate with an extremely flat surface constructed according to Sasou et al. (Langmuir 19, 9845-9849 (2003)) to high resolution detection of a specific gene on a DNA fiber by scanning near-field optical/atomic force microscopy (SNOM/AFM). The interaction between the substrate and fluorescence-dye conjugated peptide nucleic acid (PNA) probes, which causes fluorescence noise signal, was minimal. By using the substrate, we successfully obtained a fluorescence in situ hybridization signal from the ea47 gene on a lambdaphage DNA labeled with an Alexa 532-conjugated 15-base PNA probe. As the results, no fluorescence noises were observed, indicating that the surface adsorbed almost none of the PNA probe. The combination of the substrate and SNOM/AFM is an effective tool for visualizing DNA sequences at nanometer-scale resolution. PMID- 21254113 TI - Scanning electron microscopic changes in granulosa cells during follicular atresia in Caprine ovary. AB - During this study, topographic changes in healthy and atretic granulosa cells have been investigated during follicular atresia in goat ovary. Under scanning electron microscopy atresia was marked by asymmetrical shrinkage and vacuolization of cytoplasm. The specific topographical alterations observed in atretic cells were loss of micro extensions, disruption of cell-cell interaction, and smooth-textured membrane with a number of uneven depressions and ruffles. Some portions of the cell membrane were marked by extensive shrinkage due to condensation of cytosol. Irregular membrane at occasions was studded with blunt microextensions. The findings of present investigation will help in understanding the cellular changes in granulosa cells during follicular atresia and will find applications in screening of follicles for in vitro culture, in vitro fertilization and Embryo transfer technology. PMID- 21254116 TI - Theoretical models of separation selectivity for charged compounds in micellar electrokinetic chromatography. AB - Equations and theoretical models for MEKC separation selectivity (alpha(MEKC) ) were established to explain a change in separation and electrophoretic mobility order of fully charged analytes, in which alpha(MEKC) is related to the dimensionless values of mobility selectivity in CZE (alpha(CZE)) and retention selectivity (alpha(k)) in MEKC, and where alpha(CZE) and alpha(k) are defined as the ratio of electrophoretic mobility in CZE and the ratio of retention factor (k) in MEKC for two charged analytes, respectively. Using four alkylparabens as test analytes, excellent agreement was found between the observed alpha(MEKC) and the proposed alpha(MEKC) models of test analytes in MEKC over a wide range of SDS concentrations and values of k. For example, in comparison with CZE separation of charged analytes, MEKC separation can enhance separation selectivity up to the maximum value when the selectivity ratio (rho) is greater than 1.0 (rho=alpha(k)/alpha(CZE)), while lower separation selectivity is obtained with rho<1.0 (alpha(CZE) >alpha(k) >1). PMID- 21254117 TI - System peaks in capillary zone electrophoresis of anions with negative voltage polarity and counter-electroosmotic flow. AB - The system peaks that often appear on electropherograms in anion separation by CE with indirect spectrophotometric detection, negative voltage polarity and cathodic EOF are studied. The system peaks are shown to correspond to the zones with the changed concentration of the BGE constituents; they appear while the zone of each analyte anion passes through the outlet end of the capillary and are transported to the detector by EOF. An equation is suggested for predicting migration times of the system peaks with an error of 1%. The ratios of the system peak area to the analyte peak area are found to amount to 20%. It is shown that it is possible to avoid overlapping of the system peaks and analyte peaks by controlling the EOF velocity owing to hydrodynamic pressure. Using the mathematical simulation of CE shows that the system peaks and baseline shift can result from changing the transference numbers of the BGE ions and analyte ions at the capillary edge. The cases when the system peak may be incorrectly identified as the peak of analyte ion are considered. In order to avoid such errors, some practical recommendations are given. PMID- 21254118 TI - Determination of the epimerization rate constant of amygdalin by microemulsion electrokinetic chromatography. AB - A new method for separation and determination of amygdalin and its epimer (neoamygdalin) in the epimerization of amygdalin by MEEKC is proposed. For the chiral separation of amygdalin and neoamygdalin, a running buffer composed of 80 mM sodium cholate, 5.0% v/v butan-1-ol, 0.5% v/v heptane and 94.5% v/v 30 mM Na(2) B(4) O(7) buffer (pH 9.00) is proposed. Under optimum conditions, the basic separation of amygdalin and neoamygdalin can be achieved within 7 min. The calibration curve for amygdalin showed excellent linearity in the concentration range of 20-1000 MUg/mL with a detection limit of 5.0 MUg/mL (S/N=3). The epimerization rate constant of amygdalin in basic microemulsion was first determined by monitoring the concentration changes of amygdalin, and the epimerization rate constant of amygdalin was found to be 2*10(-3) min(-1) at 25 degrees C under the above optimum microemulsion conditions. PMID- 21254119 TI - Bundled capillary electrophoresis using microstructured fibres. AB - Joule heating, arising from the electric current passing through the capillary, causes many undesired effects in CE that ultimately result in band broadening. The use of narrow-bore capillaries helps to solve this problem as smaller cross sectional area results in decreased Joule heating and the rate of heat dissipation is increased by the larger surface-to-volume ratio. Issues arising from such small capillaries, such as poor detection sensitivity, low loading capacity and high flow-induced backpressure (complicating capillary loading) can be avoided by using a bundle of small capillaries operating simultaneously that share buffer reservoirs. Microstructured fibres, originally designed as waveguides in the telecommunication industry, are essentially a bundle of parallel ~5 MUm id channels that extend the length of a fibre having otherwise similar dimensions to conventional CE capillaries. This work presents the use of microstructured fibres for CZE, taking advantage of their relatively high surface to-volume ratio and the small individual size of each channel to effect highly efficient separations, particularly for dye-labelled peptides. PMID- 21254120 TI - Two-dimensional separation system by on-line hyphenation of capillary isoelectric focusing with pressurized capillary electrochromatography for peptide and protein mapping. AB - A novel on-line 2-D system was developed for peptide and protein mapping. The system combines capillary IEF (cIEF) with pressurized CEC (pCEC) using a micro injection valve as the interface. Sample fractions, which were focused and separated in the first-dimension cIEF based on their differences in pIs, were electrically mobilized and further successively resolved by their differences in size, hydrophobicity, and electrophoretic mobility in the second-dimension pCEC. In the presented system, the valve interface was free of the external electric field in two dimensions for the purpose of stabilization, safety, and facilitating manipulation. In the first dimension, cIEF separation was executed by a one-step method to simplify the operation procedure. Moreover, a home-made electrical decoupler was introduced to isolate the micro-injection valve from the cIEF electric field. For the second dimension, taking advantage of the combination of hydrodynamic flow with EOF, reversed-phase pCEC not only offers on column refocusing the effluent fractions, but also brings enhanced separation resolution and elution speed. Separation effectiveness of this 2-D system was demonstrated by the analysis of tryptic digest of BSA and human red blood cell lysate. A theoretical peak capacity of approximately 24,000 has been achieved for BSA digest, which proves its promising potential for the application in proteomics. PMID- 21254121 TI - Design of separation length and electric field strength for high-speed DNA electrophoresis. AB - Gel-based DNA separation on microchip will play an important role in future genomic analysis due to its potential for high-efficiency and high-speed. Optimal design of microchip and separation condition is essential to take full advantage of high-speed separation on microchip. Separation length L and electric field strength E, which are crucial for design of microchip system, are focused on in this paper. Simultaneous optimization of L and E was carried out to achieve the most rapid separation. It was shown that the condition of L and E and the shortest separation time is closely related to the shape of resolution Rs surface in a three-dimensional space with axes E, L, and Rs. This surface was investigated, taking sample injection, detector, diffusion, and Joule heating into account. Thermal gradient broadening due to Joule heating helps to produce camber or ridge shape of Rs surface, which is essential for the shortest separation length and separation time. Sample plug length and detection volume should be more carefully controlled in microchip. The property of diffusion coefficient was shown to play a key role in determining Rs surface. PMID- 21254122 TI - Microchip electrophoresis of N-glycans on serpentine separation channels with asymmetrically tapered turns. AB - We designed and fabricated microfluidic devices with serpentine separation channels and asymmetrically tapered turns, thus allowing high efficiency separations and minimizing band broadening associated with the "racetrack" effect. We evaluated the performance of these devices by measuring the variation in separation efficiency with separation length, electric field strength, taper ratio of the turns, and number of turns. N-Glycans derived from ribonuclease B and labeled with 8-aminopyrene-1,3,6-trisulfonic acid were electrophoretically separated on serpentine channels with separation lengths of 11, 18, 22, and 36 cm at electric field strengths from 750 to 1750 V/cm. Separations on the 36-cm channel produced plate numbers up to 940,000 with an analysis time under 3.1 min, whereas separations on the 22-cm channel had a shorter analysis time (less than 1.25 min), still with respectable efficiencies (up to 600,000 plates). Turn induced dispersion was minimized with taper ratios 2 and 3, whereas having two or four 180 degrees turns along with the separation length did not impact the overall efficiency. The developed device was used to analyze native and desialylated N-glycans derived from the blood serum of an ovarian cancer patient and a disease-free individual. Separation efficiencies similar to that achieved with the model glycans from ribonuclease B were attained for these biological samples. PMID- 21254123 TI - Mucin (MUC5AC) expression by lung epithelial cells cultured in a microfluidic gradient device. AB - We have developed a microfluidic gradient device for controlling mucin gene expression of NCI-H292 epithelial cells derived from lung tissues. We hypothesized that gradient profiles would control mucin gene expression of lung epithelial cells. However, it was not possible to generate various stable gradient profiles using conventional culture methods. To address this limitation, we used a microfluidic gradient device to create various gradient profiles (i.e. non-linear, linear, and flat) in a temporal and spatial manner. NCI-H292 lung epithelial cells were exposed to concentration gradients of epidermal growth factor in a microfluidic gradient device with continuous medium perfusion. We demonstrated an effect of gradient profiles on mucin expression of lung epithelial cells cultured in the microfluidic gradient device. It was revealed that NCI-H292 lung epithelial cells exposed to the flat gradient profile of the epidermal growth factor exhibited high expression of mucin as compared with cells exposed to non-linear and linear gradient profiles. Therefore, this microfluidic gradient device could be a potentially useful tool for regulating the mucin expression of lung epithelial cells exposed to chemokine gradient profiles. PMID- 21254124 TI - Continuous full filling capillary electrochromatography-electrospraying chromatographic nanoparticles. AB - The influence of instrumental parameters affecting the ionization in continuous full filling capillary electrochromatography/electrospray ionization mass spectrometry (CFF-CEC/ESI-MS) was investigated. The investigated parameters were the BGE and sheath liquid ion strength and organic modifier content, the nebulizer gas pressure, and the concentration of nanoparticles in the BGE. It was found that the nebulizer pressure had the largest influence on the separation efficiency and apparent retention. It was shown that even the lowest pressure investigated was sufficient to guide the nanoparticle flow away from the mass spectrometer inlet. A nebulizer pressure of 5 psi was found to be optimal; increasing the pressure significantly decreased the separation efficiency due to the generation of a hydrodynamic flow. Generally, the ion strength of both the BGE and the sheath liquid were found to have very moderate effects on the separation of a homologous series of dialkyl phthalates, whereas the ionization efficiency was found to be unaffected by the nanoparticles and the separation efficiency was found to increase with increasing concentrations up to 3.8 mg/mL, whereafter it was observed to drop. The optimized method was linear over a wide concentration range and presented LOD and LOQ more than threefold lower than those previously reported using CFF-CEC/ESI-MS. PMID- 21254125 TI - Sensitivity enhancement of fluorescence detection in CE by coupling and conducting excitation light with tapered optical fiber. AB - This paper reports the enhancement of sensitivity of detection for in-column fiber optic-induced fluorescence detection system in CE by tapered optical fiber (TOF). Two types of optical fiber, TOF and conventional cylindrical optical fiber (COF), were employed to construct the CE (TOF-CE and COF-CE) and were compared for sensitivity to riboflavin (RF). The fluorescence intensities from a RF sample with excitation light sources and fibers at various coupling angles were investigated. The fluorescence signal from TOF-CE was ca. ten times that of COF CE. In addition, the detection performance of four excitation light source-fiber configurations including Laser-TOF, Laser-COF, LED-TOF, and LED-COF were compared. The LODs for RF were 0.21, 0.82, 0.80, and 7.5 nM, respectively, for the four excitation light source-fiber configurations. The results demonstrate that the sensitivity obtained by LED-TOF is close to that of Laser-COF. Both Laser-TOF and LED-TOF can greatly improve the sensitivity of detection in CE. TOF has the major attribute of collecting and focusing the excitation light intensity. Thus, the sensitivity obtained by LED-TOF without focusing lens is just same as that of LED-COF with a focusing lens. This demonstrates that the CE system can be further simplified by eliminating the focusing lens for excitation light. LED-TOF-CE and LED-COF-CE system were applied to the separation and determination of RF in real sample (green tea), respectively. The tapered fiber optic-induced fluorescence detection system in CE is an ideal tool for trace analysis. PMID- 21254126 TI - CZE separation of amitrol and triazine herbicides in environmental water samples with acid-assisted on-column preconcentration. AB - A simple analytical scheme for the detection and quantification of amitrol and triazine herbicides (atrazine, ametryn and atraton) and degradation product (2 hydroxyatrazine) in environmental water samples by CZE is reported. On-column preconcentration of analytes from untreated water samples (mineral, spring, tap and river water) is accomplished by introducing an acid plug (200 mM citrate of pH 2.0) after the sample and then proceeding with the CZE separation, using 100 mM formiate buffer of pH 3.5 as running buffer and 25.0 KV as separation voltage. UV detection at 200 nm provides LODs from 50 to 300 nM in untreated samples and they were lowered tenfold by sample preconcentration by evaporation. Calculated recoveries were typically higher than 90%. Minimal detectable concentration of the electroactive amitrol could be decreased about 20-fold when electrochemical detection was employed by monitoring the amperometric signal at +800 mV using a carbon paste electrode (LOD of 9.6 nM, 0.81 MUg/L, versus 170 nM, 14.3 MUg/L, using amperometric and UV detection, respectively) in untreated water samples. PMID- 21254128 TI - A new CZE method for profiling human serum albumin and its related forms to assess the quality of biopharmaceuticals. AB - We present a new CZE method, which uses a polyethylene oxide-coated capillary to separate native HSA from more than five of its structural variants. These variants include oxidized, truncated, and cysteinylated forms of HSA which can all be found in biopharmaceutical products. Both CE and MS confirmed the high degree of heterogeneity of HSA preparations. Recovery studies demonstrated that adsorption of HSA on the capillary was significantly reduced under the conditions we developed, which led to a satisfactory repeatability (RSD for migration times and relative peak areas were less than 0.2 and 7.0%, respectively). Assignment of the main peaks was attempted using in vitro degraded/stressed HSA. We used our method to test batch-to-batch comparability and detected slight quantitative differences in the proportion of native HSA in batches produced from different fractionation methods. PMID- 21254127 TI - Determination of GABA, glutamate and carbamathione in brain microdialysis samples by capillary electrophoresis with fluorescence detection. AB - Disulfiram has been used as a deterrent in the treatment of alcohol abuse for almost 60 years. Our laboratory has shown that a disulfiram metabolite, S-(N,N diethylcarbamoyl) glutathione (carbamathione), is formed from disulfiram and appears in the brain after the administration of disulfiram. Carbamathione does not inhibit aldehyde dehydrogenase but has been shown to be a partial non competitive inhibitor of the N-methyl-D-aspartic acid glutamate (Glu) receptor. In light of disulfiram's apparent clinical effectiveness in cocaine dependence, and carbamathione's effect on the N-methyl-D-aspartic acid receptor, the effect of carbamathione on brain Glu and gamma-aminobutyric acid (GABA) needs to be further examined. A CE-LIF method based on derivatization with napthalene-2,3 dicarboxyaldehyde to simultaneously detect both neurotransmitter amino acids and carbamathione in brain microdialysis samples is described. The separation of Glu, GABA and carbamathione was carried out using a 50 mmol/L boric acid buffer (pH 9.6) on a 75 cm*50 MUm id fused-silica capillary (60 cm effective) at +27.5 kV voltage with a run time of 11 min. The detection limits for Glu, GABA and carbamathione were 6, 10 and 15 nmol/L, respectively. This method was used to monitor carbamathione and the amino acid neurotransmitters in brain microdialysis samples from the nucleus accumbens after the administration of an intravenous dose of the drug (200 mg/kg) and revealed a carbamathione-induced change in GABA and Glu levels. This method demonstrates a simple, rapid and accurate measurement of two amino acid neurotransmitters and carbamathione for in vivo monitoring in the brain using microdialysis sampling. PMID- 21254129 TI - Performance of nondenaturing micro 2-DE followed by third-dimension SDS-PAGE in the analysis of Escherichia coli soluble proteins. AB - In a previous paper, we reported on the analysis of Escherichia coli (strain K 12) soluble proteins by nondenaturing micro 2-DE/3-DE and MALDI-MS-PMF [Manabe, T., Jin, Y., Electrophoresis 2010, 31, 2740-2748]. To evaluate the performance of the 2-DE/3-DE technique, a nondenaturing 2-DE gel just after the second-dimension run was cut into 12 vertical strips, each 2 mm-wide strip was set on a micro slab gel, and third-dimension SDS-PAGE was run in parallel. Each of the twelve 3-DE gels showed about 150-200 CBB-stained spots. Two of the 3-DE gels were selected for the assignment of polypeptides using MALDI-MS-PMF and totally 161 polypeptides were assigned on the two 3-DE gels, in which 81 have been assigned on the nondenaturing micro 2-DE gel and 80 were newly assigned. Most of the newly assigned polypeptides resided in faintly stained spots on the 3-DE gels, which indicates that the polypeptides were purified in the process of the third dimension separation. The comparisons of the apparent mass values estimated from the second-dimension (nondenaturing pore-gradient PAGE) mobility with those estimated from the third-dimension (SDS-PAGE) mobility suggested the oligomer structures of the assigned polypeptides and they matched well with those described in a database (UniProtKnowledgebase). The technique of nondenaturing micro 2-DE/3-DE, combined with MALDI-MS-PMF, could become an efficient method to obtain information on the quaternary structures of hundreds of cellular soluble proteins simultaneously because of its high efficiency in protein/polypeptide separation and assignment. PMID- 21254130 TI - Identification of immunoreactive secretory proteins from the stationary phase culture of Burkholderia pseudomallei. AB - Bacterial secreted proteins are known to be involved in virulence and may mediate important host-pathogen interactions. In this study, when the stationary phase culture supernatant of Burkholderia pseudomallei was subjected to 2-DE, 113 protein spots were detected. Fifty-four of the secreted proteins, which included metabolic enzymes, transcription/translation regulators, potential virulence factors, chaperones, transport regulators, and hypothetical proteins, were identified using MS and database search. Twelve of these proteins were apparently reactive to antisera of mice that were immunised with B. pseudomallei secreted proteins. These proteins might be excellent candidates to be used as diagnostic markers or putative candidate vaccines against B. pseudomallei infections. PMID- 21254131 TI - Simultaneous isolation of DNA, RNA, and protein from Medicago truncatula L. AB - We describe a method for the simultaneous extraction of proteins and nucleic acids from Medicago truncatula tissues. Using a modified TRIzol reagent method, we developed a simple and an effective way to simultaneously extract proteins and nucleic acids from a single sample. We verified that this method does not affect the quality or quantitation of the isolated DNA and RNA. Furthermore, we used 2 DE to compare M. truncatula leaf, stem, and root samples processed using this new method with two commonly used methods: phenol extraction/methanol-ammonium acetate precipitation and trichloroacetic acid/acetone precipitation. The results showed that our method was superior to the other methods, based on 2-DE patterns. We also demonstrated that our protocol is compatible with proteomic analysis, as 10 out of 14 selected proteins isolated by the method were identified by MALDI TOF-MS/MS. The protocol described can be used with sample preparation protocols for proteomic, transcriptomic, and genomic studies. PMID- 21254132 TI - Proteomic approaches in myeloid leukemia. AB - After human genome is decoded, the characterization of the proteins is the next challenging task. The study of the complete protein complement of the genome, the 'proteome' referred to as proteomics, is an important tool for the identification of new therapeutic targets. Research efforts are underway to develop the technology necessary to compare the specific protein profiles of diseased versus healthy states. These technologies provide a wealth of information by rapidly generating large quantities of data. These data can be useful for predictive mathematical descriptions of biological systems for rapid identification of novel therapeutic targets and identification of biomarkers in metabolic disorders. In recent years, using proteomics, we and others have identified various interacting as well as target proteins, PTMs and protein markers in myeloid leukemia. This review summarizes the usage of proteomics in recent years as an important technique in defining the proteome of myeloid leukemia, which has helped in elaborate understanding of the disease and has provided new avenues for developing better therapeutics. PMID- 21254133 TI - Determination of stimulants and narcotics as well as their in vitro metabolites by online CE-ESI-MS. AB - A simple, rapid and sensitive CE-ESI-MS method for the simultaneous analysis of seven stimulants and narcotics (amphetamine, ephedrine, methadone, pethidine, tetracaine, codeine and heroin) was developed. The CE-ESI-MS experimental conditions were optimized as follows: 20 mmol/L ammonium acetate with pH 9.0 as running buffer, the separation voltage of 22 kV and the sheath liquid of isopropanol/water (1:1 v/v) containing 7.5 mmol/L acetic acid with 3.0 MUL/min flow rate. Under the optimized conditions, the stimulants and narcotics were well separated within 4.6 min using a 70-cm length fused-silica capillary (50 MUm id). The detection limits (S/N=3) of the CE-ESI-MS analysis were in the range of 0.40 1.0 ng/mL. Method repeatability of intra-day and inter-day was satisfactory. The recoveries obtained from the analysis of spiked urine samples were between 84.1 and 108%. The developed method was successfully applied for the simultaneous analysis of methadone, pethidine and codeine and their in vitro metabolites. PMID- 21254134 TI - Rapid quantitative determination of ephedra alkaloids in tablet formulations and human urine by microchip electrophoresis. AB - Microchip electrophoresis with fluorescence detection has been applied for fast separation and determination of ephedra alkaloids in pharmaceutical formulations and body fluids. A custom epifluorescence microscope setup was employed and the compounds were separated within 40 s, allowing the detection of less than 200 ng/L for both analytes. Quantitation of the two stimulants was performed via a derivatization step using FITC without any extraction or preconcentration steps. The effects of different microchip types and excitation light sources were investigated and the method was successfully applied for the analysis of these compounds in tablet formulations, yielding recovery rates from 100.2 to 101.1% and relative standard deviations from 1.5 to 3.4%. Analysis of ephedrines was also carried out with human urine samples at detection limits of 500-1000 ng/L and relative standard deviations from 2.2 to 3.3% using argon ion LIF detection. PMID- 21254135 TI - Evaluation of the addition of various surfactant-suspended carbon nanotubes in MEEKC with an in situ-synthesized surfactant system. AB - Dispersions of single-walled carbon nanotubes (SWNTs) in various surfactant solutions have been systematically evaluated as additives in MEEKC. The compounds examined were catechins, phenolic acids, and flavonoids. Compared with zwitterionic and neutral surfactants, the addition of anionic dispersion seemed to be better at separating the three types of analytes in microemulsion system. In order to achieve low operating currents, an in situ-synthesized surfactant system based on the combination of a long-chain alkyl acid with an organic base was used in MEEKC. The optimized buffer contained 0.5% (57 mM) ethyl acetate, 0.6% (30 mM) lauric acid, 4.0% (666 mM) propanol, 50 mM Tris solution, and 4.5 mg/L the dispersion of SWNTs. Under optimized conditions, the established method was applicable to quantify complex compounds in tea samples. PMID- 21254136 TI - A retrospective analysis of the management of acne post-inflammatory hyperpigmentation using topical treatment, laser treatment, or combination topical and laser treatments in oriental patients. AB - BACKGROUND: Post-inflammatory hyperpigmentation (PIH) is characterized by an acquired increase in pigmentation secondary to an inflammatory process, and is a commonly observed response to cutaneous injury in Fitzpatrick types III-VI patients. OBJECTIVES: To determine the effectiveness and safety of using topical treatment, laser treatment, or combination topical and laser treatments to treat acne PIH in Oriental patients. METHODS: This is a retrospective study of 34 randomly selected Chinese patients with acne PIH. They were divided into three groups, and treated with topical agents, 595 nm long pulsed dye laser and/or 1064 nm Q-switched Nd:YAG, or combination topical and laser treatments. An independent clinician assessed pre- and post-treatment photographs to determine efficacy and timing to visible and optimum improvement. RESULTS: There was significant global and focal improvement of acne PIH in patients in all three groups. However, no significant difference was found between the groups. An investigator global assessment showed improvement with all treatment modalities, with 70.6% moderate to marked improvement seen in the combination treatment group, compared to 55.6% in the laser only group, and 50% in the topical treatment only group. Visible and optimum improvement was seen by 3 months in majority of patients treated. One patient developed PIH as a result of laser treatment. CONCLUSION: Topical treatment, laser therapy, and combination topical and laser treatments all appear to be effective management strategies for acne PIH in Fitzpatrick types III and IV skin with little complications. Topical agents may be considered as first-line therapy for acne PIH, taking into consideration its effectiveness, ease of use and cost. Combined topical and laser therapy is also effective, and may be considered as second-line treatment. PMID- 21254137 TI - Fluorescence spectroscopy measurements in ultrasonic navigated resection of malignant brain tumors. AB - BACKGROUND AND OBJECTIVE: Glioblastoma multiforme is a highly malignant primary brain tumor. It has no border but at best a marginal zone, however, invisible to the surgeon. An optical touch pointer (OTP) enabling differentiation of healthy and tumor tissue by means of fiber-optic fluorescence spectroscopy has been developed. In combination with an ultrasonic navigation system, the OTP may be used for demarcation of resectable tumor tissue. The aim of the study was to evaluate the clinical performance of OTP during surgery of malignant brain tumors. STUDY DESIGN/MATERIALS AND METHODS: Nine patients were operated on with the standard surgical procedure, including white light microscopy and navigation. A total of 5 mg/kg bodyweight of 5-amino-levulin acid was orally administrated before surgery. The OTP was calibrated into the ultrasound-based navigation system and measurements were performed in tumor core and along the tumor border. The ratio between the protoporphyrin IX fluorescence at 635 nm and the autofluorescence was used for quantifications of data. Biopsies (n = 20), ultrasound images (n = 30), and visual inspection (n = 180) were compared to the fluorescence ratio. RESULTS/CONCLUSION: Healthy and tumor tissue could be identified and differentiated with the OTP (P < 0.001). The fluorescence ratio in average was 0 outside the tumor and low in the gliotic edema zone around the tumor. It increased in the marginal zone and was highest in the solid tumor tissue. In the necrotic tissue, in the center of the tumor, the ratio in average was 0. The OTP can be used in combination with ultrasound-based navigation and may help to determine whether to resect otherwise not identifiable tissue. PMID- 21254138 TI - 2-micrometer continuous wave laser treatment for multiple non-muscle-invasive bladder cancer with intravesical instillation of epirubicin. AB - BACKGROUND AND OBJECTIVES: We have reported the efficacy and safety of 2 micrometer continuous wave laser resection of non-muscle-invasive bladder tumor (NMIVBC) (World J Urology 2010;28:157-161). In this study, we evaluated the use of 2-micrometer continuous wave laser resection in combination with intravesical instillation of epirubicin for the treatment of multiple NMIVBC. MATERIALS AND METHODS: From September 2007 to April 2008, sixty patients with multiple NMIVBC were included in this study (44 cases of low grade papillary urothelial carcinoma, 10 cases of high grade papillary urothelial carcinoma, and six cases of papillary urothelial neoplasm with low malignant potential). Imaging examinations including pelvic computer tomography (CT) and intravenous urography showed no extravesical extension, lymphatic metastasis or any lesions of upper urinary tract. All patients received 2-micrometer continuous wave laser therapy under continuous epidural anesthesia, and intravesical chemotherapy with epirubicin 1 week later (intravesical instillation weekly for 8 weeks, followed by monthly maintenance to 12 months). RESULTS: Totally 211 tumors in 60 patients were successfully removed with 2-micrometer continuous wave laser. The mean operation time was 48 minutes per patient (ranged 20-90 minutes) and 13.6 minutes per tumor (range 5-25 minutes). No obturator nerve reflection or bladder perforation occurred during the procedure. All patients finished 12 months of intravesical chemotherapy without severe complications. The mean followed-up time was 23 months. Tumor recurrences were found in 13 patients (22%). CONCLUSIONS: The combination of 2-micrometer continuous wave laser and intravesical chemotherapy is feasible, safe, and efficacious for the treatment of multiple NMIVBC. PMID- 21254139 TI - A transmissive laser speckle imaging technique for measuring deep tissue blood flow: an example application in finger joints. AB - BACKGROUND AND OBJECTIVE: Laser speckle perfusion imaging (LSPI) is a minimally invasive optical measure of relative changes in blood flow, providing real-time, high resolution, two-dimensional maps of vascular structure. Standard LSI imaging uses a light-reflective geometry that limits the measurement to a thin surface layer of 0.2-1 mm. The objective of this study was to test a new LSI instrument geometry with the laser source opposed to the image capture plane (light transmissive). Captured light then travels the entire tissue thickness (10-15 mm), sampling much deeper regions of interest than conventional optical imaging techniques. STUDY DESIGN: Reflective-light (conventional) and transmissive-light LSI modes were used to measure finger joint blood flow during a timed tourniquet occlusion of the brachial artery in volunteer participants. RESULTS: There was greatly increased visibility of vessels underlying the skin in the light transmissive mode LSI mode. Established LSI algorithms were shown to still work in the light-transmissive mode, despite decorrelation due to finite laser coherence length and the light passing through a tissue thickness of 10-15 mm. CONCLUSION: Transmissive LSI can be used to measure blood flow deep (10-15 mm) into tissues. This could be useful for non-invasive measurements of finger joint synovial blood flow in diagnosing and treating peripheral vascular disorders, such as rheumatoid arthritis. PMID- 21254140 TI - Interstitial laser thermotherapy of a rat liver tumour: effect of hepatic inflow occlusion. AB - BACKGROUND AND OBJECTIVE: Interstitial laser thermotherapy was used to treat rat liver tumours. The aim was to investigate the influence of temperature and temporary hepatic inflow occlusion on tumour growth and blood perfusion. STUDY DESIGN/MATERIALS AND METHODS: Liver tumours were treated at 44 degrees C at the tumour border for 30 minutes, hepatic inflow occlusion only, or a combination of these methods. Interstitial laser Doppler flowmetry was used to measure hepatic perfusion at the tumour border during and after heat treatment, for a total time of 60 minutes. Tumour growth was evaluated 6 days after treatment. RESULTS: Tumours subjected to the combined treatment of hepatic inflow occlusion and interstitial laser thermotherapy displayed a blood perfusion reduction 30 minutes after treatment to 18 +/- 5% of initial perfusion, which was significantly lower than achieved with thermotherapy alone (52 +/- 10%, P = 0.02). The combined treatment and treatment with thermotherapy alone resulted in relative tumour growth of 0.3 +/- 0.1 and 1.0 +/- 0.2, respectively (P = 0.04). CONCLUSION: Inflow occlusion enhanced the effect of thermotherapy not by augmenting treatment temperatures but by increasing the thermal sensitivity of the tumour, reflected by an immediate effect on tumour blood perfusion. PMID- 21254141 TI - Variation of fluorescence in tissue with temperature. AB - BACKGROUND AND OBJECTIVE: Previous studies demonstrated a decrease in fluorescence intensity as tissue temperature increased. In vitro samples were increased from room temperature and in vivo canine liver from body temperature. This study investigated variations in fluorescence intensity with temperatures starting at 14 degrees C and compared in vivo and in vitro results for consistency. STUDY DESIGN/MATERIAL AND METHODS: A fiber optic-based noninvasive system was used to characterize the temperature effect on tissue fluorescence in hamster dorsal skin in vivo, and in sclera and cornea of enucleated pig eyes in vitro. As tissue was allowed to progress through the temperature range of 14-42 degrees C, the spectra of auto-fluorescence with respect to temperature was sampled every 1-2 minutes. A pulsed nitrogen laser was used to excite fluorescence through a fiber optic probe with a source-detector aperture separation of 370 um. RESULTS: Fluorescence intensity decreased as temperature increased from 14 to 42 degrees C in a phantom containing Rhodamine B dye. Results from both in vivo and in vitro tissue followed the same trend of decreasing intensity as tissue temperature increased from 14 degrees C. Spectral intensity lineshape changed around 450 nm due to absorption from tissue. CONCLUSION: Cooling a tissue increased fluorescence intensity of skin in vivo, in all experiments. In vitro results were consistent with in vivo measurements. PMID- 21254142 TI - Single walled carbon nanohorns as photothermal cancer agents. AB - BACKGROUND: Nanoparticles have significant potential as selective photo-absorbing agents for laser based cancer treatment. This study investigates the use of single walled carbon nanohorns (SWNHs) as thermal enhancers when excited by near infrared (NIR) light for tumor cell destruction. METHODS: Absorption spectra of SWNHs in deionized water at concentrations of 0, 0.01, 0.025, 0.05, 0.085, and 0.1 mg/ml were measured using a spectrophotometer for the wavelength range of 200 1,400 nm. Mass attenuation coefficients were calculated using spectrophotometer transmittance data. Cell culture media containing 0, 0.01, 0.085, and 0.333 mg/ml SWNHs was laser irradiated at 1,064 nm wavelength with an irradiance of 40 W/cm2 for 0-5 minutes. Temperature elevations of these solutions during laser irradiation were measured with a thermocouple 8 mm away from the incident laser beam. Cell viability of murine kidney cancer cells (RENCA) was measured 24 hours following laser treatment with the previously mentioned laser parameters alone or with SWNHs. Cell viability as a function of radial position was determined qualitatively using trypan blue staining and bright field microscopy for samples exposed to heating durations of 2 and 6 minutes alone or with 0.085 mg/ml SWNHs. A Beckman Coulter Vi-Cell instrument quantified cell viability of samples treated with varying SWNH concentration (0, 0.01, 0.085, and 0.333 mg/ml) and heating durations of 0-6 minutes. RESULTS: Spectrophotometer measurements indicated inclusion of SWNHs increased light absorption and attenuation across all wavelengths. Utilizing SWNHs with laser irradiation increased temperature elevation compared to laser heating alone. Greater absorption and higher temperature elevations were observed with increasing SWNH concentration. No inherent toxicity was observed with SWNH inclusion. A more rapid and substantial viability decline was observed over time in samples exposed to SWNHs with laser treatment compared with samples experiencing laser heating or SWNH treatment alone. Samples heated for 6 minutes with 0.085 mg/ml SWNHs demonstrated increasing viability as the radial distance from the incident laser beam increased. CONCLUSIONS: The significant increases in absorption, temperature elevation, and cell death with inclusion of SWNHs in laser therapy demonstrate the potential of their use as agents for enhancing photothermal tumor destruction. PMID- 21254143 TI - Application of a novel boronated porphyrin (H2OCP) as a dual sensitizer for both PDT and BNCT. AB - BACKGROUND AND OBJECTIVE: Boronated porphyrins have emerged as promising dual sensitizers for use in both photodynamic therapy (PDT) and boron neutron capture therapy (BNCT), by virtue of their known tumor affinity, low cytotoxicity in dark conditions, and easy synthesis with high boron content. Octa-anionic 5,10,15,20 tetra[3,5-(nido-carboranylmethyl)phenyl] porphyrin (H2OCP) is a boronated porphyrin having eight boron clusters linked to the porphyrin ring. To evaluate H2OCP's applicability to both PDT and BNCT, we performed an in vitro and ex vivo study using F98 rat glioma cells. MATERIALS AND METHODS: We examined the time dependent cellular uptake of H2OCP by measuring the boron concentration over time, and compared the cellular uptake/clearance of boron after exposure to H2OCP in conjunction with boronophenylalanine (BPA) and sodium borocaptate (BSH), both of which are currently used in clinical BNCT studies. We evaluated the cytotoxicity of H2OCP-mediated PDT using a colony-forming assay and assessed the tumorigenicity of the implantation of pre-treated cells using Kaplan-Meier survival curves. Fluorescence microscopy was also performed to evaluate the cellular uptake of H2OCP. RESULTS: H2OCP accumulated within cells to a greater extent than BPA/BSH, and H2OCP was retained inside the cells to approximately the same extent as BSH. The cell-surviving fraction following laser irradiation (8 J/cm2, 18 hours after exposure to 10 ug B/ml H2OCP) was <0.05. The median survival times of the pre-treated cell-implanted rats were longer than those of the untreated group (P < 0.05). The fluorescence of H2OCP was clearly demonstrated within the tumor cells by fluorescence microscopy. CONCLUSIONS: H2OCP has been proven to be a promising photosensitizer for PDT. H2OCP has also been proposed as a potentially effective replacement of BPA or BSH, or as a replacement of both BPA/BSH. Our study provides more evidence that H2OCP could be an effective novel dual sensitizing agent for use in both PDT and BNCT. PMID- 21254144 TI - Use of ethnic-specific medians for Hispanic patients reduces ethnic disparities in multiple marker screening. AB - OBJECTIVE: To estimate whether midtrimester maternal serum analyte concentrations differ between Caucasian and Hispanic women and whether using ethnic-specific medians affects quad screen performance. METHOD: Caucasian and Hispanic patients with singletons who underwent maternal serum screening in our laboratory were identified. Alfa-fetoprotein (AFP), estriol, human chorionic gonadotrophin (hCG), and inhibin-A medians were derived separately for Caucasians, Hispanics, and for the composite group. Using composite medians, intergroup mean multiples of the medians (MoMs) for each analyte were compared. Using ethnic-specific medians, new MoMs were calculated and utilized in a risk estimation algorithm. RESULTS: A total of 5478 Caucasian and 2246 Hispanic pregnancies were evaluated. Intergroup MoMs were significantly different for all analytes. AFP, hCG, and inhibin-A were lower in Hispanics, while estriol was higher (P < 0.0001). Using composite medians, the screen-positive rate (SPR) for trisomy 21 was 5.39% in Caucasians and 3.29% in Hispanics. Ethnic-specific medians reduced this disparity: 4.76% in Caucasians and 4.05% in Hispanics. The SPR for neural tube defects with composite medians was 1.44% for Caucasians and 0.89% for Hispanics; with ethnic-specific medians, the SPR was 1.42% for Caucasians and 1.07% for Hispanics. CONCLUSION: Serum analyte concentrations differ between Caucasian and Hispanic gravidas. Use of ethnic-specific medians reduces the disparity in SPR for trisomy 21 and neural tube defects. PMID- 21254145 TI - Placental volume and three-dimensional power Doppler analysis in prediction of pre-eclampsia and small for gestational age between Week 11 and 13 weeks and 6 days of gestation. AB - OBJECTIVE: To assess three-dimensional placental volume measurement and three dimensional power Doppler (3D-PD) indices between 10 weeks and 6 days and 13 weeks and 6 days in predicting pregnancy-induced hypertension (PIH) and small for gestational age (SGA). METHODS: Three hundred and eight women undergoing fetal nuchal translucency measurement were prospectively assessed using three dimensional ultrasound in order to measure placental volume and 3D-PD indices: vascularization index (VI), flow index (FI) and vascularization flow index (VFI), using the VOCAL software. The outcome was scored as normal, PIH, SGA or both. RESULTS: Eight women developed PIH and ten delivered SGA; and 17 developed PIH or SGA. The age, gestational age at the examination or delivery, number of the pregnancy and the nuchal translucency, were similar in all groups. The placental volume, FI and VFI were similar between the groups. The VI was significantly lower when PIH developed (7.86 +/- 3.92 vs. 12.02 +/- 7.09 in the normal group, P = 0.035). The crown-rump length (CRL) was significantly smaller in the group where either PIH or SGA developed compared to normal outcome (54.29 +/- 6.50 and 59.04 +/- 8.89, respectively, P = 0.02). CONCLUSION: Placental volume is not appropriate for early prediction of PIH or SGA, whereas the VI may be of some potential in detection of PIH. The significance of small CRL in these patients should be further tested. PMID- 21254146 TI - Pulmonary atresia/critical stenosis with intact ventricular septum: prediction of outcome in the second trimester of pregnancy. AB - OBJECTIVES: To determine which cardiac parameters provide the best prediction of postnatal outcome--biventricular (BV) versus non-BV--in fetuses with pulmonary atresia/critical stenosis with intact ventricular septum (PA/CS-IVS). METHODS: We searched our database for cases of PA/CS-IVS prenatally diagnosed in 2001-2009. Only fetuses diagnosed <=28 weeks were included. Data of 16 fetuses (nine PA, seven CS) were retrieved and analyzed. Receiver-operating characteristics curves were constructed to assess the sensitivity and specificity of cardiac features for predicting postnatal outcome. RESULTS: Twelve fetuses had a BV outcome and four had non-BV repair. Cut-off values yielding the best results for a non-BV outcome were a tricuspid valve/mitral valve ratio <=0.83, a pulmonary valve/aortic valve ratio <=0.75, tricuspid inflow duration/cardiac cycle length <=36.5%, and a right ventricle/left ventricle length ratio <=0.64. If 3/4 markers are present, this predicts a non-BV outcome with sensitivity of 100% and specificity of 92%, and both are 100% if all the four criteria are fulfilled. CONCLUSIONS: The postnatal outcome of fetuses with PA-CS/IVS can be predicted in the second trimester at the first echocardiography by a four-criterion scoring system. This is clinically relevant since it allows early selection of candidates for fetal intervention and early and precise parental counseling. PMID- 21254147 TI - Prenatal diagnosis of abnormal cardinal systemic venous return without other heart defects: a case series. AB - OBJECTIVES: To describe fetal spectrum and echocardiographic characteristics of anomalous systemic venous return (ASVR, cardinal veins) without other structural heart defects (isolated ASVR), evaluate associated extracardiac and genetic anomalies and review neonatal outcome. METHODS: From 2003 to 2009, 369 consecutive fetuses were diagnosed with cardiac malformation, including 27 cases with an isolated ASVR. The following variables were collected: type of ASVR, extracardiac anomalies, karyotype and short-term outcome. RESULTS: The most common forms of ASVR were persistent left superior vena cava (SVC) (n = 15) and interrupted inferior vena cava (IVC) (n = 6). The other ASVR types were a persistent left SVC without a right SVC (n = 4), bilateral agenesis of the SVC with cephalic venous drainage toward the IVC through the azygos system (n = 1) and total ASVR to the coronary sinus (n = 1). Genetic disorders were confirmed in five cases, all with a persistent left SVC, with extracardiac anomalies present in four of them. Ten other patients had extracardiac anomalies detected prenatally or postnatally. When available, ASVR diagnosis was confirmed postnatally in all cases. CONCLUSION: Isolated ASVRs can be accurately diagnosed prenatally and are frequently associated with extracardiac and genetic anomalies. A detailed morphological ultrasound and fetal karyotype should be suggested. Neonatal outcome was mainly related to the associated anomalies. PMID- 21254148 TI - Fields and field cancerization: the preneoplastic origins of cancer: asymptomatic hyperplastic fields are precursors of neoplasia, and their progression to tumors can be tracked by saturation density in culture. AB - Most basic research on cancer concerns genetic changes in benign and malignant tumors. Yet evidence indicates that the majority of the mutations in tumors occur in the preneoplastic field stage of their development. That early stage is represented by grossly invisible, broad regions of "field cancerization" which have not, heretofore, been operationally analyzed in cell culture. Conditions are described for quantitating preneoplasia by increased saturation density followed by progression to transformation. These parameters are driven by Darwinian selection of spontaneously occurring, cumulative mutations, in accordance with recent genomic analyses of human cancer, just as it is in the evolution of species. The cell culture model will allow correlation of the preneoplastic increases in saturation density with genetic changes, and development of methods for demarcating fields during surgery so that they can be excised along with the tumor, thereby reducing the possibility of recurrence at the site. PMID- 21254149 TI - Another place, another timer: Marine species and the rhythms of life. AB - The marine ecosystem is governed by a multitude of environmental cycles, all of which are linked to the periodical recurrence of the sun or the moon. In accordance with these cycles, marine species exhibit a variety of biological rhythms, ranging from circadian and circatidal rhythms to circalunar and seasonal rhythms. However, our current molecular understanding of biological rhythms and clocks is largely restricted to solar-controlled circadian and seasonal rhythms in land model species. Here, we discuss the first molecular data emerging for circalunar and circatidal rhythms and present selected species suitable for further molecular analyses. We argue that a re-focus on marine species will be crucial to understand the principles, interactions and evolution of rhythms that govern a broad range of eukaryotes, including ourselves. PMID- 21254150 TI - Energetic trade-offs between brain size and offspring production: Marsupials confirm a general mammalian pattern. AB - Recently, Weisbecker and Goswami presented the first comprehensive comparative analysis of brain size, metabolic rate, and development periods in marsupial mammals. In this paper, a strictly energetic perspective is applied to identify general mammalian correlates of brain size evolution. In both marsupials and placentals, the duration or intensity of maternal investment is a key correlate of relative brain size, but here I show that allomaternal energy subsidies may also play a role. In marsupials, an energetic constraint on brain size in adults is only revealed if we consider both metabolic and reproductive rates simultaneously, because a strong trade-off between encephalization and offspring production masks the positive correlation between basal metabolic rate and brain size in a bivariate comparison. In conclusion, starting from an energetic perspective is warranted to elucidate relations between ecology, social systems, life history, and brain size in all mammals. PMID- 21254151 TI - Bet hedging or not? A guide to proper classification of microbial survival strategies. AB - Bacteria have developed an impressive ability to survive and propagate in highly diverse and changing environments by evolving phenotypic heterogeneity. Phenotypic heterogeneity ensures that a subpopulation is well prepared for environmental changes. The expression bet hedging is commonly (but often incorrectly) used by molecular biologists to describe any observed phenotypic heterogeneity. In evolutionary biology, however, bet hedging denotes a risk spreading strategy displayed by isogenic populations that evolved in unpredictably changing environments. Opposed to other survival strategies, bet hedging evolves because the selection environment changes and favours different phenotypes at different times. Consequently, in bet hedging populations all phenotypes perform differently well at any time, depending on the selection pressures present. Moreover, bet hedging is the only strategy in which temporal variance of offspring numbers per individual is minimized. Our paper aims to provide a guide for the correct use of the term bet hedging in molecular biology. PMID- 21254152 TI - The enigmatic cytoophidium: compartmentation of CTP synthase via filament formation. PMID- 21254153 TI - Why is it so difficult to accept Darwin's theory of evolution? On the popular fallacy that evolution has a predetermined direction, and the development of a responsible worldview based on free will. PMID- 21254154 TI - Effect of a phytotherapeutic agent, Eviprostat(r), on prostatic and urinary cytokines/chemokines in a rat model of nonbacterial prostatitis. AB - BACKGROUND: Chronic inflammation in the prostate has recently been recognized as an important component of the symptom progression of benign prostatic hyperplasia. The objective of this study was to evaluate a range of cytokines/chemokines in prostate tissue and urine to identify markers of prostate inflammation in a prostatitis model and to investigate the effect of a phytotherapeutic agent, Eviprostat(r), on these markers. METHODS: Ten-month-old male Wistar rats were divided into four groups. Nonbacterial prostatitis (NBP) was experimentally induced in groups 2-4 by castration followed by daily subcutaneous injection of 17beta-estradiol for 30 days. Control rats were fed a standard diet, while animals in the Eviprostat groups were fed a diet containing 0.05 or 0.1% Eviprostat for 30 days. The levels of cytokines/chemokines in prostate tissue on the 31st day and in urine collected the day before castration and the day before removal of the prostate were determined. RESULTS: Experimentally induced NBP increased the prostatic levels of the cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha). The levels of the chemokines CCL2/monocyte chemoattractant protein-1 (MCP-1), CCL3/macrophage inflammatory protein-1alpha (MIP-1alpha), CXCL1/CINC-1, CXCL3/CINC-2, and CXCL5/LIX were elevated in both prostate and urine. Eviprostat significantly suppressed the increases in prostate IL-1beta, TNF-alpha and CCL3/MIP-1alpha and prostatic and urinary CCL2/MCP-1 and CXCL1/CINC-1. CONCLUSIONS: Chemokines, including CCL2/MCP-1 and CXCL1/CINC-1, were elevated in the prostate and urine of NBP rats, and Eviprostat potently suppressed the increases in CCL2/MCP-1 and CXCL1/CINC-1. These chemokines are therefore candidate diagnostic biomarkers for nonbacterial chronic prostatic inflammation. PMID- 21254155 TI - The value of observational research in liver diseases. PMID- 21254156 TI - What goes up must come down: the emerging role of microRNA in fibrosis. PMID- 21254157 TI - Role of interleukin-28B polymorphisms in the treatment of hepatitis C virus genotype 2 infection in Asian patients. AB - Genome-wide association studies have linked single nucleotide polymorphisms (SNPs) near the interleukin-28B gene to the hepatitis C virus genotype 1 (HCV-1) response to peginterferon/ribavirin treatment. We aimed to explore the impact on the treatment outcomes of Asian HCV-2 patients. We determined rs8105790, rs8099917, rs4803219, and rs10853728 to be candidate SNPs in 482 Asian HCV-2 patients treated with the standard of care. Because the first three SNPs were in very strong linkage disequilibrium with one another (r2 = 0.94-0.96), rs8099917 and rs10853728 were selected for an analysis of their influence on the achievement of rapid virological response [RVR; seronegativity for hepatitis C virus (HCV) RNA in treatment week 4] and sustained virological response (SVR; seronegativity for HCV RNA throughout 24 weeks of posttreatment follow-up). The rs10853728 genotype did not predict RVR or SVR in HCV-2 patients. However, patients with the rs8099917 TT genotype, in comparison with patients with GT/GG genotypes, had a significantly higher rate of achieving RVR (85.2% versus 72.0%, P = 0.017) but did have not a significantly higher rate of achieving SVR (89.4% versus 86.0%). Multivariate analysis revealed that a baseline HCV viral load <400,000 IU/mL was the strongest predictor of RVR [odds ratio (OR) = 4.27, 95% confidence interval (CI) = 2.31-7.87, P < 0.001], and this was followed by advanced liver fibrosis (OR = 0.28, 95% CI = 0.15-0.53, P < 0.001), the carriage of the rs8099917 TT genotype (OR = 3.10, 95% CI = 1.34-7.21, P = 0.008), and the pretreatment level of aspartate aminotransferase (OR = 0.996, 95% CI = 0.99-1.00, P = 0.04). Nevertheless, the achievement of RVR was the single predictor of SVR with an OR of 19.37 (95% CI = 8.89-42.23, P < 0.001), whereas the rs8099917 genotypes played no role in achieving SVR with or without RVR. CONCLUSION: The rs8099917 TT genotype is significantly independently predictive of RVR, which is the single best predictor of SVR, in Asian HCV-2 patients. PMID- 21254158 TI - Quantitation of pretreatment serum interferon-gamma-inducible protein-10 improves the predictive value of an IL28B gene polymorphism for hepatitis C treatment response. AB - Polymorphisms of the IL28B gene are highly associated with sustained virological response (SVR) in patients with chronic hepatitis C treated with peginterferon and ribavirin. Quantitation of interferon-gamma-inducible protein-10 (IP-10) may also differentiate antiviral response. We evaluated IP-10 levels in pretreatment serum from 115 nonresponders and 157 sustained responders in the Study of Viral Resistance to Antiviral Therapy of Chronic Hepatitis C cohort, including African American (AA) and Caucasian American (CA) patients. Mean IP-10 was lower in sustained responders compared with nonresponders (437 +/- 31 vs 704 +/- 44 pg/mL, P < 0.001), both in AA and CA patients. The positive predictive value of low IP 10 levels (<600 pg/mL) for SVR was 69%, whereas the negative predictive value of high IP-10 levels (>600 pg/mL) was 67%. We assessed the combination of pretreatment IP-10 levels with IL28B genotype as predictors of treatment response. The IL28B polymorphism rs12979860 was tested in 210 participants. The CC, CT, and TT genotypes were found in 30%, 49%, and 21% of patients, respectively, with corresponding SVR rates of 87%, 50%, and 39% (P < 0.0001). Serum IP-10 levels within the IL28B genotype groups provided additional information regarding the likelihood of SVR (P < 0.0001). CT carriers with low IP 10 had 64% SVR versus 24% with high IP-10. Similarly, a higher SVR rate was identified for TT and CC carriers with low versus high IP-10 (TT, 48% versus 20%; CC, 89% versus 79%). IL28B genotype and baseline IP-10 levels were additive but independent when predicting SVR in both AA and CA patients. CONCLUSION: When IL28B genotype is combined with pretreatment serum IP-10 measurement, the predictive value for discrimination between SVR and nonresponse is significantly improved, especially in non-CC genotypes. This relationship warrants further investigation to elucidate the mechanisms of antiviral response and prospective validation. PMID- 21254160 TI - Ribavirin potentiates interferon action by augmenting interferon-stimulated gene induction in hepatitis C virus cell culture models. AB - The combination of pegylated interferon (PEG-IFN) and ribavirin is the standard treatment for chronic hepatitis C. Our recent clinical study suggests that ribavirin augments the induction of interferon-stimulated genes (ISGs) in patients treated for hepatitis C virus (HCV) infection. In order to further characterize the mechanisms of action of ribavirin, we examined the effect of ribavirin treatment on ISG induction in cell culture. In addition, the effect of ribavirin on infectious HCV cell culture systems was studied. Similar to interferon (IFN)-alpha, ribavirin potently inhibits JFH-1 infection of Huh7.5.1 cells in a dose-dependent manner, which spans the physiological concentration of ribavirin in vivo. Microarray analysis and subsequent quantitative polymerase chain reaction assays demonstrated that ribavirin treatment resulted in the induction of a distinct set of ISGs. These ISGs, including IFN regulatory factors 7 and 9, are known to play an important role in anti-HCV responses. When ribavirin is used in conjunction with IFN-alpha, induction of specific ISGs is synergistic when compared with either drug applied separately. Direct up regulation of these antiviral genes by ribavirin is mediated by a novel mechanism different from those associated with IFN signaling and intracellular double stranded RNA sensing pathways such as RIG-I and MDA5. RNA interference studies excluded the activation of the Toll-like receptor and nuclear factor kappaB pathways in the action of ribavirin. CONCLUSION: Our study suggests that ribavirin, acting by way of a novel innate mechanism, potentiates the anti-HCV effect of IFN. Understanding the mechanism of action of ribavirin would be valuable in identifying novel antivirals. PMID- 21254161 TI - Meeting vaccination quality measures for hepatitis A and B virus in patients with chronic hepatitis C infection. AB - Coinfection with hepatitis A virus (HAV) or hepatitis B virus (HBV) in patients with chronic hepatitis C virus (HCV) is associated with increased morbidity and mortality. The Center for Medicare and Medicaid Services has identified HAV and HBV vaccination as a priority area for quality measurement in HCV. It is unclear to what extent patients with HCV meet these recommendations. We used national data from the Department of Veterans Affairs HCV Clinical Case Registry to evaluate the prevalence and predictors of meeting the quality measure (QM) of receiving vaccination or documented immunity to HAV and HBV in patients with chronic HCV. We identified 88,456 patients who had overall vaccination rates of 21.9% and 20.7% for HBV and HAV, respectively. The QM rates were 57.0% and 45.5% for HBV and HAV, respectively. Patients who were nonwhite or who had elevated alanine aminotransferase levels, cirrhosis, or human immunodeficiency virus were more likely to meet the HBV QM. Factors related to HCV care were also determinants of meeting the HBV QM. These factors included receiving a specialist consult, genotype testing, or HCV treatment. Patients who were older, had psychosis, and had a higher comorbidity score were less likely to meet the HBV QM. With a few exceptions, similar variables were related to meeting the HAV QM. The incidence of superinfection with acute HBV and HAV was low, but it was significantly lower in patients who received vaccination than in those who did not. CONCLUSION: Quality measure rates for HAV and HBV are suboptimal for patients with chronic HCV. In addition, several patient-related factors and receiving HCV-related care are associated with a higher likelihood of meeting QMs. PMID- 21254162 TI - Tenofovir disoproxil fumarate (TDF), emtricitabine/TDF, and entecavir in patients with decompensated chronic hepatitis B liver disease. AB - Data are limited on the safety and effectiveness of oral antivirals other than lamivudine and adefovir dipivoxil for treatment of chronic hepatitis B (CHB) in patients with decompensated liver disease. This Phase 2, double-blind study randomized 112 patients with CHB and decompensated liver disease to receive either tenofovir disoproxil fumarate (TDF; n = 45), emtricitabine (FTC)/TDF (fixed-dose combination; n = 45), or entecavir (ETV; n = 22). The primary endpoint was safety; more specifically, tolerability failure (adverse events resulting in permanent treatment discontinuation) and confirmed serum creatinine increase >= 0.5 mg/dL from baseline or confirmed serum phosphorus <2 mg/dL. Patients with insufficient viral suppression (e.g., confirmed HBV DNA >= 400 copies/mL at week 8 or 24) could begin open-label FTC/TDF but were considered failures in this interim week 48 analysis for efficacy endpoints. Tolerability failure was infrequent across arms: 6.7% TDF, 4.4% FTC/TDF, and 9.1% ETV (P = 0.622) as were confirmed renal parameters meeting threshold 8.9%, 6.7%, and 4.5% (P = 1.000), respectively. Six patients died (none considered related to study drug) and six received liver transplants (none had HBV recurrence). The adverse event and laboratory profiles were consistent with advanced liver disease and complications, with no unexpected safety signals. At week 48, HBV DNA was <400 copies/mL (69 IU/mL) in 70.5% (TDF), 87.8% (FTC/TDF), and 72.7% (ETV) of patients. Proportions with normal alanine aminotransferase were: 57% (TDF), 76% (FTC/TDF), and 55% (ETV). Hepatitis B e antigen (HBeAg) loss/seroconversion occurred in 21%/21% (TDF), 27%/13% (FTC/TDF), and 0%/0% (ETV). Child-Turcotte Pugh and Modification for End-stage Liver Disease scores improved in all groups. CONCLUSION: All treatments were well tolerated in patients with decompensated liver disease due to CHB with improvement in virologic, biochemical, and clinical parameters. PMID- 21254163 TI - Hypercytolytic activity of hepatic natural killer cells correlates with liver injury in chronic hepatitis B patients. AB - Natural killer (NK) cells are abundant in the liver and serve as a major innate immune component against microbial infection. Although NK cells have been implicated in inducing hepatocellular damage in patients with chronic hepatitis virus infections, the roles that hepatic NK cells play in chronic hepatitis B virus (HBV) infections remain obscure. In this study, we comprehensively characterized intrahepatic and peripheral NK cells and investigated their impact on liver pathology in a cohort of HBV-infected individuals; this cohort included 51 immune-activated (IA) patients, 27 immune-tolerant (IT) carriers, and 26 healthy subjects. We found that NK cells expressing NK receptors (activation receptors) preferentially accumulated in the livers of IA patients, in which they were activated and skewed toward cytolytic activity but without a concomitant increase in interferon-gamma production, in comparison with those of IT carriers and healthy subjects. Further analysis showed that the livers of IA patients, in comparison with those of IT and healthy subjects, expressed higher levels of interleukin-12 (IL-12), IL-15, and IL-18 in situ and lower levels of IL-10, which in vitro can induce the activation and degranulation of NK cells from healthy individuals. Finally, hepatic NK cells displayed more cytolytic activity than peripheral NK cells, and this was found to be positively correlated with the liver histological activity index and serum alanine aminotransferase levels in these IA patients. CONCLUSION: In IA patients, hepatic NK cells are activated and preferentially skew toward cytolytic activity, which depends on an imbalanced cytokine milieu and correlates with liver injury during chronic HBV infection. PMID- 21254164 TI - Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians. AB - A recent genome-wide study revealed an association between variation in the PNPLA3 gene and liver fat content. In addition, the PNPLA3 single-nucleotide polymorphism rs738409 (M148I) was reported to be associated with advanced alcoholic liver disease in alcohol-dependent individuals of Mestizo descent. We therefore evaluated the impact of rs738409 on the manifestation of alcoholic liver disease in two independent German cohorts. Genotype and allele frequencies of rs738409 (M148I) were determined in 1,043 alcoholic patients with or without alcoholic liver injury and in 376 at-risk drinkers from a population-based cohort. Relative to alcoholic patients without liver damage (n = 439), rs738409 genotype GG was strongly overrepresented in patients with alcoholic liver cirrhosis (n = 210; OR 2.79; P(genotype) = 1.2 * 10(-5) ; P(allelic) = 1.6 * 10( 6) ) and in alcoholic patients without cirrhosis but with elevated alanine aminotransferase levels (n = 219; OR 2.33; P(genotype) = 0.0085; P(allelic) = 0.0042). The latter, biochemically defined association was confirmed in an independent population-based cohort of at-risk drinkers with a median alcohol intake of 300 g/week (OR 4.75; P(genotype) = 0.040; P(allelic) = 0.022), and for aspartate aminotransferase (AST) levels. Frequencies of allele PNPLA3 rs738409(G) in individuals with steatosis and normal alanine aminotransferase (ALT) and AST levels were lower than in alcoholics without steatosis and normal ALT/AST (P(combined) = 0.03). The population attributable risk of cirrhosis in alcoholic carriers of allele PNPLA3 rs738409(G) was estimated at 26.6%. CONCLUSION: Genotype PNPLA3 rs738409(GG) is associated with alcoholic liver cirrhosis and elevated aminotransferase levels in alcoholic Caucasians. PMID- 21254165 TI - Enteric dysbiosis associated with a mouse model of alcoholic liver disease. AB - The translocation of bacteria and bacterial products into the circulation contributes to alcoholic liver disease. Intestinal bacterial overgrowth is common in patients with alcoholic liver disease. The aims of our study were to investigate bacterial translocation, changes in the enteric microbiome, and its regulation by mucosal antimicrobial proteins in alcoholic liver disease. We used a mouse model of continuous intragastric feeding of alcohol or an isocaloric diet. Bacterial translocation occurred prior to changes observed in the microbiome. Quantitative changes in the intestinal microflora of these animals were assessed first using conventional culture techniques in the small and large intestine. Although we found no difference after 1 day or 1 week, intestinal bacterial overgrowth was observed in the gastrointestinal tract of mice fed alcohol for 3 weeks compared with control mice fed an isocaloric liquid diet. Because <20% of all gastrointestinal bacteria can be cultured using conventional methodologies, we performed massively parallel pyrosequencing to further assess the qualitative changes in the intestinal microbiome following alcohol exposure. Sequencing of 16S ribosomal RNA genes revealed a relative abundance of Bacteroidetes and Verrucomicrobia bacteria in mice fed alcohol compared with a relative predominance of Firmicutes bacteria in control mice. With respect to the host's transcriptome, alcohol feeding was associated with down-regulation in gene and protein expression of bactericidal c-type lectins Reg3b and Reg3g in the small intestine. Treatment with prebiotics partially restored Reg3g protein levels, reduced bacterial overgrowth, and lessened alcoholic steatohepatitis. CONCLUSION: Alcohol feeding is associated with intestinal bacterial overgrowth and enteric dysbiosis. Intestinal antimicrobial molecules are dysregulated following chronic alcohol feeding contributing to changes in the enteric microbiome and to alcoholic steatohepatitis. PMID- 21254166 TI - Novel mechanism by which histone deacetylase inhibitors facilitate topoisomerase IIalpha degradation in hepatocellular carcinoma cells. AB - Histone deacetylase (HDAC) inhibitors exhibit a unique ability to degrade topoisomerase (topo)IIalpha in hepatocellular carcinoma (HCC) cells, which contrasts with the effect of topoII-targeted drugs on topoIIbeta degradation. This selective degradation might foster novel strategies for HCC treatment in light of the correlation of topoIIalpha overexpression with the aggressive tumor phenotype and chemoresistance. Here we report a novel pathway by which HDAC inhibitors mediate topoIIalpha proteolysis in HCC cells. Our data indicate that HDAC inhibitors transcriptionally activated casein kinase (CK)2alpha expression through increased association of acetylated histone H3 with the CK2alpha gene promoter. In turn, CK2 facilitated the binding of topoIIalpha to COP9 signalosome subunit (Csn)5 by way of topoIIalpha phosphorylation. Furthermore, we identified Fbw7, a Csn5-interacting F-box protein, as the E3 ligase that targeted topoIIalpha for degradation. Moreover, knockdown of CK2alpha, Csn5, or Fbw7 reversed HDAC inhibitor-induced topoIIalpha degradation. Mutational analysis indicates that the (1361) SPKLSNKE(1368) motif plays a crucial role in regulating topoIIalpha protein stability. This motif contains the consensus recognition sites for CK2 (SXXE), glycogen synthase kinase (GSK)3beta (SXXXS), and Fbw7 (SPXXS). This study also reports the novel finding that topoIIalpha may be a target of GSK3beta phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3beta-mediated phosphorylation at Ser1361. This double phosphorylation facilitated the recruitment of Fbw7 to the phospho-degron (1361) pSPKLpS(1365) of topoIIalpha, leading to its ubiquitin-dependent degradation. CONCLUSION: This study shows a novel pathway by which HDAC inhibitors facilitate the selective degradation of topoIIalpha, which underlies the complexity of the functional role of HDAC in regulating tumorigenesis and aggressive phenotype in HCC cells. PMID- 21254169 TI - p28GANK overexpression accelerates hepatocellular carcinoma invasiveness and metastasis via phosphoinositol 3-kinase/AKT/hypoxia-inducible factor-1alpha pathways. AB - The overall survival of patients with hepatocellular carcinoma (HCC) remains poor, and the molecular mechanisms underlying HCC progression and aggressiveness are unclear. Here, we report that increased expression of p28(GANK) (Gankyrin, PSMD10, or p28) in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and intrahepatic or distant metastasis, expressed high levels of p28(GANK) . Invasive tumors overexpressing p28(GANK) were featured by active epithelial-mesenchymal transition (EMT), and exhibited increased angiogenesis associated with vascular endothelial growth factor overexpression, whereas silencing p28(GANK) expression attenuated EMT and motility/invasion of tumor cells. The p28(GANK) activates phosphoinositide 3-kinase (PI3K)-V-akt Murine Thymoma Viral Oncogene Homolog (AKT)-hypoxia-inducible factor 1alpha (HIF-1alpha) signaling to promote TWIST1, vascular endothelial growth factor, and metalloproteinase 2 expression. Suppression of the PI3K-AKT-HIF-1alpha pathway interfered with p28(GANK) mediated EMT and invasion. Consistently, we detected a significant correlation between p28(GANK) expression and p-AKT levels in a cohort of HCC biopsies, and the combination of these two parameters is a more powerful predictor of poor prognosis. CONCLUSION: These results present novel mechanistic insight into a critical role of p28(GANK) in HCC progression and metastasis. PMID- 21254175 TI - Activation of serotonin receptor-2B rescues small-for-size liver graft failure in mice. AB - The implantation of grafts below 30% of the normal liver volume is associated with a high risk of failure known as small-for-size (SFS) syndrome. Strategies to rescue small grafts may have a dramatic impact on organ shortage. Serotonin is a potent growth factor for the liver. The goal of this study was to determine whether enhanced serotonin signaling could prevent the deleterious effects of SFS syndrome. We performed 30% normal liver volume transplantations in wild-type C57/BL6 and interleukin-6 (IL-6)(-/-) mice. Some animals received alpha-methyl-5 HT (DOI), an agonist of serotonin receptor-2 (5-HT2B). Endpoints included long term survival, serum and hepatic markers of liver injury and regeneration, assessment of hepatic microcirculation by intravital fluorescence microscopy and scanning electron microscopy, and transcript levels of a variety of serotonin receptors, tumor necrosis factor alpha, and IL-6. All recipients of small grafts (controls) died within 2-4 days of transplantation, whereas half of those receiving DOI survived permanently. Control animals disclosed major liver injury, including diffuse microvesicular steatosis in hepatocytes, impairment of microcirculation, and a failure of regeneration, whereas these parameters were dramatically improved in animals subjected to DOI. Blockage of 5-HT2B blunted the protective effects of DOI. Whereas IL-6 levels were higher in DOI-treated animals, IL-6(-/-) mice were still protected by DOI, suggesting a protective pathway independent of IL-6. CONCLUSION: Serotonin through its action on receptor 2B protects SFS liver grafts from injury and prevents microcirculation and regeneration. The mechanism of hepato-protection is independent of IL-6. PMID- 21254170 TI - Importance of hepatic fibrosis in cystic fibrosis and the predictive value of liver biopsy. AB - Cystic fibrosis liver disease (CFLD), which results from progressive hepatobiliary fibrosis, is an important cause of morbidity and mortality, but it is difficult to identify before portal hypertension (PHT) ensues. Clinical signs, serum alanine aminotransferase (ALT) levels, and ultrasound (US) are widely applied, but their value in predicting the presence of cirrhosis, the development of PHT, or adverse outcomes is undetermined. The potential gold standard, liver biopsy, is not standard practice and, notwithstanding sampling error considerations, has not been systematically evaluated. Forty patients with cystic fibrosis (median age = 10.6 years) with abnormal clinical, biochemical, and US findings were subjected to dual-pass percutaneous liver biopsy. Clinical outcomes were recorded over 12 years of follow-up (median = 9.5 years for survivors). Logistic regression and receiver operating characteristic analyses were applied to predict hepatic fibrosis (which was assessed by fibrosis staging and quantitative immunohistochemistry) and the occurrence of PHT. PHT occurred in 17 of 40 patients (42%), including 6 of 7 (17%) who died during follow-up. Clinical examination, serum ALT levels, and US findings failed to predict either the presence of liver fibrosis or the development of PHT. Fibrosis staging on liver biopsy, where the accuracy was improved by dual passes (P = 0.002, nonconcordance = 38%), predicted the development of PHT (P < 0.001), which occurred more frequently and at a younger age in those with severe fibrosis. CONCLUSION: Clinical modalities currently employed to evaluate suspected CFLD help to identify a cohort of children at risk for liver disease and adverse outcomes but do not predict an individual's risk of liver fibrosis or PHT development. Liver fibrosis on biopsy predicts the development of clinically significant liver disease. Dual passes help to address sampling concerns. Liver biopsy has a relevant role in the management of patients with suspected CFLD and deserves more widespread application. PMID- 21254176 TI - CXC chemokine receptor-1 is expressed by hepatocytes and regulates liver recovery after hepatic ischemia/reperfusion injury. AB - CXC chemokines mediate hepatic inflammation and injury following ischemia/reperfusion (I/R). More recently, signaling through CXC chemokine receptor-2 (CXCR2) was shown to delay liver recovery and repair after I/R injury. The chemokine receptor CXCR1 shares ligands with CXCR2, yet nothing is known about its potential role in liver pathology. In the present study, we examined the role of CXCR1 in the injury and recovery responses to I/R using a murine model. CXCR1 expression was undetectable in livers of sham-operated mice. However, after ischemia CXCR1 expression increased 24 hours after reperfusion and was maximal after 96 hours of reperfusion. CXCR1 expression was localized largely to hepatocytes. In order to assess the function of CXCR1, CXCR2(-/-) mice were treated with the CXCR1/CXCR2 antagonist, repertaxin. Prophylactic treatment with repertaxin had no effect on acute inflammation or liver injury. However, when repertaxin was administered 24 hours postreperfusion there was a significant increase in hepatocellular injury and a delay in recovery compared to control treated mice. CXCR1(-/-) mice also demonstrated delayed recovery and regeneration after I/R when compared to wild-type mice. In vitro, hepatocytes from CXCR2(-/-) mice that were stimulated to express CXCR1 showed increased proliferation in response to ligand. Hepatocyte proliferation was decreased in CXCR1(-/-) mice in vivo. CONCLUSION: This is the first report to show that CXCR1 expression is induced in hepatocytes after injury. Furthermore, the data suggest that CXCR1 has divergent effects from CXCR2 and appears to facilitate repair and regenerative responses after I/R injury. PMID- 21254177 TI - Lineage restriction of human hepatic stem cells to mature fates is made efficient by tissue-specific biomatrix scaffolds. AB - Current protocols for differentiation of stem cells make use of multiple treatments of soluble signals and/or matrix factors and result typically in partial differentiation to mature cells with under- or overexpression of adult tissue-specific genes. We developed a strategy for rapid and efficient differentiation of stem cells using substrata of biomatrix scaffolds, tissue specific extracts enriched in extracellular matrix, and associated growth factors and cytokines, in combination with a serum-free, hormonally defined medium (HDM) tailored for the adult cell type of interest. Biomatrix scaffolds were prepared by a novel, four-step perfusion decellularization protocol using conditions designed to keep all collagen types insoluble. The scaffolds maintained native histology, patent vasculatures, and ~1% of the tissue's proteins but >95% of its collagens, most of the tissue's collagen-associated matrix components, and physiological levels of matrix-bound growth factors and cytokines. Collagens increased from almost undetectable levels to >15% of the scaffold's proteins with the remainder including laminins, fibronectins, elastin, nidogen/entactin, proteoglycans, and matrix-bound cytokines and growth factors in patterns that correlate with histology. Human hepatic stem cells (hHpSCs), seeded onto liver biomatrix scaffolds and in an HDM tailored for adult liver cells, lost stem cell markers and differentiated to mature, functional parenchymal cells in ~1 week, remaining viable and with stable mature cell phenotypes for more than 8 weeks. CONCLUSION: Biomatrix scaffolds can be used for biological and pharmaceutical studies of lineage-restricted stem cells, for maintenance of mature cells, and, in the future, for implantable, vascularized engineered tissues or organs. PMID- 21254179 TI - Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection. AB - Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-lambda3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related). CONCLUSION: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection. PMID- 21254180 TI - Noninvasive assessment of liver fibrosis. AB - Liver biopsy has long been an important tool for assessing the degree of liver fibrosis. Information on the presence and degree of liver fibrosis is useful before making therapeutic decisions or predicting disease outcomes. The need to stage liver fibrosis, however, should decrease as treatment options become more successful (as has occurred with viral hepatitis). In recent years, noninvasive tests have demonstrated a reasonable ability to identify significant fibrosis, cirrhosis in particular, nor is it surprising that liver disease specialists and patients favor a noninvasive approach. However, only those tests with the highest diagnostic accuracy, cost-effectiveness, and availability should be implemented. Apart from their diagnostic accuracy, the potential ability of these tests to predict disease outcomes (a more relevant endpoint) should be compared with that of liver biopsy. Indeed, the use of a standardized system to evaluate the utility of biomarkers would facilitate their implementation in clinical practice. PMID- 21254181 TI - Hepatitis C pharmacogenetics: state of the art in 2010. AB - In 2009, a correlated set of polymorphisms in the region of the interleukin-28B (IL28B) gene were associated with clearance of genotype 1 hepatitis C virus (HCV) in patients treated with pegylated interferon-alfa and ribavirin. The same polymorphisms were subsequently associated with spontaneous clearance of HCV in untreated patients. The link between IL28B genotype and HCV clearance may impact decisions regarding initiation of current therapy, the design and interpretation of clinical studies, the economics of treatment, and the process of regulatory approval for new anti-HCV therapeutic agents. PMID- 21254183 TI - Controlling autophagy: a new concept for clearing liver disease. PMID- 21254184 TI - Identifying who is at risk of drug-induced liver injury: is human leukocyte antigen specificity the key? PMID- 21254182 TI - Endocannabinoids in liver disease. AB - Endocannabinoids are lipid mediators of the same cannabinoid (CB) receptors that mediate the effects of marijuana. The endocannabinoid system (ECS) consists of CB receptors, endocannabinoids, and the enzymes involved in their biosynthesis and degradation, and it is present in both brain and peripheral tissues, including the liver. The hepatic ECS is activated in various liver diseases and contributes to the underlying pathologies. In patients with cirrhosis of various etiologies, the activation of vascular and cardiac CB(1) receptors by macrophage-derived and platelet-derived endocannabinoids contributes to the vasodilated state and cardiomyopathy, which can be reversed by CB(1) blockade. In mouse models of liver fibrosis, the activation of CB(1) receptors on hepatic stellate cells is fibrogenic, and CB(1) blockade slows the progression of fibrosis. Fatty liver induced by a high-fat diet or chronic alcohol feeding depends on the activation of peripheral receptors, including hepatic CB(1) receptors, which also contribute to insulin resistance and dyslipidemias. Although the documented therapeutic potential of CB(1) blockade is limited by neuropsychiatric side effects, these may be mitigated by using novel, peripherally restricted CB(1) antagonists. PMID- 21254185 TI - The genetics of primary biliary cirrhosis: the revolution moves on. PMID- 21254186 TI - Linkage of the hepatitis C virus genotype and interleukin-28B genetic polymorphisms in Asian patients. PMID- 21254188 TI - Hyponatremia in patients treated with terlipressin: mechanisms and implications for clinical practice. PMID- 21254190 TI - Combinative strategy using tamoxifen and other chemotherapeutic drugs for cholangiocarcinoma chemotherapy. PMID- 21254191 TI - Life history traits, maternal behavior and infant development of blue-eyed black lemurs (Eulemur flavifrons). AB - An understanding of recruitment is important for estimating population growth and viability, and their implications for conservation. We present the first results regarding the life history, maternal behavior and infant development of the critically endangered blue-eyed black lemur (Eulemur flavifrons) of Madagascar. The species breeds seasonally, with births occurring at the end of the dry season, between late August and October. Over two successive birth seasons in 2006 and 2007, we observed a total of 13 lactating females and 22 infants from six groups. We inferred age at first reproduction as 3 years, and calculated the birth rate as 1.0 infant per female per year with a mean inter-birth interval of 358 +/- 24.81 days (319-410 days). Infants spent the first 3 weeks of life constantly with their mothers; locomotor independence and ingestion of solid food began at week 10, and the infants were weaned by week 25. After week 28, infants spent less than 20% of their time in contact with their mothers. Over the study period infant mortality was 22.7%, with predation and sickness observed as causes. Our results suggest that overall recruitment is relatively slow, which has implications for the species' survival, particularly given their restricted and threatened habitat. PMID- 21254192 TI - Lab-on-a-plate: extending the functionality of MALDI-MS and LDI-MS targets. AB - We review the literature that describes how (matrix-assisted) laser desorption/ionization (MA)LDI target plates can be used not only as sample supports, but beyond that: as functional parts of analytical protocols that incorporate detection by MALDI-MS or matrix-free LDI-MS. Numerous steps of analytical procedures can be performed directly on the (MA)LDI target plates prior to the ionization of analytes in the ion source of a mass spectrometer. These include homogenization, preconcentration, amplification, purification, extraction, digestion, derivatization, synthesis, separation, detection with complementary techniques, data storage, or other steps. Therefore, we consider it helpful to define the "lab-on-a-plate" as a format for carrying out extensive sample treatment as well as bioassays directly on (MA)LDI target plates. This review introduces the lab-on-plate approach and illustrates it with the aid of relevant examples from the scientific and patent literature. PMID- 21254193 TI - Exome sequencing allows for rapid gene identification in a Charcot-Marie-Tooth family. AB - OBJECTIVE: Charcot-Marie-Tooth (CMT) disease comprises a large number of genetically distinct forms of inherited peripheral neuropathies. The relative uniform phenotypes in many patients with CMT make it difficult to decide which of the over 35 known CMT genes are affected in a given patient. Genetic testing decision trees are therefore broadly based on a small number of major subtypes (eg, CMT1, CMT2) and the observed mutation frequency for CMT genes. Since conventional genetic testing is expensive many rare genes are not being tested for at all. METHODS: Whole-exome sequencing has recently been introduced as a novel and alternative approach. This method is capable of resequencing a nearly complete set of coding exons in an individual. We performed whole-exome sequencing in an undiagnosed family with CMT. RESULTS: Within over 24,000 variants detected in 2 exomes of a CMT family, we identified a nonsynonymous GJB1 (Cx32) mutation. This variant had been reported previously as pathogenic in X linked CMT families. Sanger sequencing confirmed complete cosegregation in the family. Affected individuals had a marked early involvement of the upper distal extremities and displayed a mild reduction of nerve conduction velocities. INTERPRETATION: We have shown for the first time in a genetically highly heterogeneous dominant disease that exome sequencing is a valuable method for comprehensive medical diagnosis. Further improvements of exon capture design, next-generation sequencing accuracy, and a constant price decline will soon lead to the adoption of genomic approaches in gene testing of Mendelian disease. PMID- 21254194 TI - Symmetry of Parkinson's disease and REM sleep: one piece of the puzzle. PMID- 21254195 TI - Validation of the urinary sensation scale (USS). AB - AIM: The purpose of this study was to assess the validity of the Urinary Sensation Scale (USS) in men with overactive bladder and voiding symptoms (OAB LUTS) and women with overactive bladder (OAB). METHODS: Data from two OAB clinical trials of tolterodine were used. The USS, a 5-point scale, assesses the amount of urinary urgency associated with each urination. Three methods to calculate the USS are: mean urgency (Mean USS); mode urgency (Mode USS); and sum urgency (sum USS). The validity and responsiveness of the scoring methods was assessed using Spearman's correlations, general linear models, and effect sizes. RESULTS: Data from 650 men (Study 1) and 413 women (Study 2) were analyzed. Mean age was 65.2 (men) and 47.8 (women); 70% were Caucasian in both studies. Correlations of USS scores with bladder diary variables were small to moderate and higher among Sum USS than Mean USS (r=0.02-0.64). Correlations among the USS and patient-reported outcomes (PROs) were again small to moderate and higher with Sum USS (r=0.05-0.41). Both the Mean USS and Sum USS significantly discriminated (all P<0.001) among all bladder diary variables (except nocturia and UUI in men) when grouped as improved/not improved as well as by the PROs. Effect sizes for men and women, respectively, were -0.52 and -1.09 for Mean USS and -0.72 and 1.36 for Sum USS. CONCLUSION: The USS is a valid and highly responsive measure of urinary urgency in men with OAB-LUTS and women with OAB. PMID- 21254196 TI - Urothelium-dependent and urothelium-independent detrusor contractility mediated by nitric oxide synthase and cyclooxygenase inhibition. AB - AIMS: The urothelium has been implicated in regulating detrusor smooth muscle contractility but the identity of the putative urothelium-derived inhibitory factor remains unconfirmed. There was inconclusive evidence on the role of nitric oxide synthase (NOS) and cyclooxygenase (COX) in mediating detrusor contractions. This study examined varying regulation by NOS and COX in transverse and longitudinal carbachol (CCh)-induced and unstimulated phasic contractions. METHODS: Rat detrusor strips with the urothelium-intact (+UE) and urothelium denuded (-UE) were isolated in both transverse and longitudinal directions. Isometric tension of the detrusor strips was recorded both during stimulation with CCh and at the unstimulated state. In the unstimulated state, phasic contractile activity was measured. Tension recordings were made with and without the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) and COX inhibitor indomethacin (Indo). RESULTS: Only transverse +UE strips responded convincingly to L-NAME and Indo treatment, generating larger CCh-induced contractions. In unstimulated tissues, L-NAME treatment increased phasic amplitude in -UE strips only. Indo treatment failed to elicit any change in the amplitude but suppressed frequency of the phasic activity in transverse +UE strips. There was no significant Indo-mediated change in other strips. CONCLUSIONS: The data suggested heterogeneity in the regulation of directional detrusor contractility via NOS- and COX-associated mechanisms. PMID- 21254197 TI - Sacral neurophysiologic study in patients with chronic spinal cord injury. AB - AIMS: Neurophysiologic testing of the sacral reflex has demonstrated utility in the diagnosis of sacral lower motor neuron lesions. The aim of the present study was to also apply this test to patients with upper motor neuron lesions. METHODS: A group of 16 male patients with chronic suprasacral spinal cord lesions was prospectively recruited. In addition to history and clinical neurologic examination (including anal sphincter tone, saddle sensation, and penilo cavernosus reflex testing), sacral neurophysiologic studies were performed. Neurophysiologic testing included quantitative electromyography of the external anal sphincter (motor unit potential (MUP) count during relaxation and MUP analysis), and neurophysiologic measurement of the penilo-cavernosus reflex (elicitation threshold and latency) on electrical stimulation. The findings were compared to data obtained in the control group of 26 men. RESULTS: Clinical elicitability of the penilo-cavernosus reflex was increased, and the neurophysiologically measured reflex threshold reduced in patients (<0.02). No significant differences were found in clinical assessment of anal sphincter tone, MUP count, reflex latency, and quantitative MUP analysis. The diagnostic sensitivity of individual parameters was low (<=25%). CONCLUSIONS: In patients with chronic spinal cord injury, increased elicitability of the penilo-cavernosus reflex was found. However, none of the assessed neurophysiologic parameters was found to assist in the diagnosis of the sacral upper motor neuron lesion in individual patients. The shortened sacral reflex latency found in individual patients is therefore not a consequence of a suprasegmental lesion, but rather of the low position of the conus medullaris (e.g., in tethered cord syndrome). PMID- 21254198 TI - Innervation of parasympathetic postganglionic neurons and bladder detrusor muscle directly after sacral root transection and repair using nerve transfer. AB - AIMS: This is a continuation of studies examining the effectiveness of root repairs and nerve transfers for bladder reinnervation. Our previous retrograde fluorogold tracing studies from the bladder to the spinal cord found regrowth of axons from the spinal cord through the nerve repair site to the bladder which was confirmed electrophysiologically [Ruggieri et al. J Neurotrauma 25:214-24, 2006]. The current study determines whether the pattern of axonal regrowth from the repaired nerves or roots to the bladder is different between the surgical reanastomosis methods. METHODS: The canine bladder was denervated by transection of all nerve roots from the sacral spinal cord mediating bladder contraction. Reinnervation surgeries included end-on-end repair of transected sacral ventral roots, transfer of coccygeal to sacral ventral roots(CGNT),or transfer of genitofemoral to pelvic nerves(GFNT). RESULTS: Postmortem dialkylcarbocyaninedye tracing with Neurotrace DiI from the distal pelvic nerve to the bladder wall, combined with PGP9.5 neuronal immunohistochemistry, demonstrated innervation by DiI-labeled axons of only parasympathetic postganglionic intramural ganglia in normal controls and sham operated controls, but reinnervation of both intramural ganglia and detrusor muscle directly after repair of sacral ventral roots. GF NT and CG NT also resulted in reinnervation of both intramural ganglia and detrusor muscle, although to a lesser extent than repaired roots. CONCLUSIONS: Bladder reinnervation with either the same nerve (orthotopic reinnervation) or with either a primarily somatic nerve (coccygeal) or a primarily sensory nerve (genitofemoral) results in reinnervation of both intramural ganglia as well as direct innervation of detrusor muscle. PMID- 21254199 TI - Falls risk reduction and treatment of overactive bladder symptoms with antimuscarinic agents: a scoping review. AB - AIMS: Overactive bladder (OAB) symptoms are associated with falls and fractures in older adults and treatment with antimuscarinic agents may decrease this falls risk. Bladder-specific antimuscarinic agents may also adversely affect falls risk because of drug-related cognitive impairment. Thus, a tension between effective treatment, falls risk reduction, and increased falls risk is created. We conducted a scoping review to determine whether sufficient studies exist to warrant a full systematic review of falls risk reduction through treatment of OAB and to identify gaps in current research. METHODS: Using an iterative scoping approach, a search of electronic databases was undertaken using key terms. Studies in any setting of older adults who had fallen or were at risk for falls and were provided pharmacological treatment of OAB to reduce of falls or falls risk were sought. Relevant articles were identified, reviewed, and used to map research activity regarding the pharmacological treatment of OAB in older adults and its relationship to falls and falls risk reduction. RESULTS: Only one study met our initial inclusion criteria. Six additional studies were useful in identification research gaps, particularly in terms of outcome measures. CONCLUSIONS: Insufficient evidence exists to recommend antimuscarinic treatment as a strategy for falls reduction, and the contribution of such agents to increased falls risk is unclear. Future studies of antimuscarinic agents for OAB must include measures of falls and falls risk and cognitive effects. PMID- 21254200 TI - Chemical irritation of the prostate sensitizes P(2)X(3) receptor-mediated responses in rat dorsal root ganglion neurons. AB - AIMS: P(2)X(3) (ATP-gated receptors) in nociceptive neurons of dorsal root ganglion (DRG) participate in transmission of pain signals from the periphery to the spinal cord. However, the role of P(2)X(3) receptors in chronic prostate pain and continued intractable pain remains unclear. MATERIALS AND METHODS: We examined ATP-evoked responses and P(2)X(3) expression in DRG neurons isolated from rats with prostatic inflammation induced by injection of complete Freund's adjuvant (CFA) into the prostate. Neurons were dissociated from the L(6)-S(1) DRG. The effect of ATP on the excitability of DRG neurons was determined using whole-cell patch clamp. P(2)X(3) receptor expression was determined with Western blot on the 3rd and 10th days after irritation of the prostate. RESULTS: Although application of ATP induced both fast- and slow-inactivating currents and caused depolarization in control and inflamed neurons, compared to the control group, the increase in ATP responses gave rise to large depolarization that exceeded the threshold of action potentials in inflamed DRG neurons. The affinity of P(2)X(3) receptor for ATP increased significantly and inflammation enhanced the expression of P(2)X(3) receptor in inflamed neurons. CONCLUSIONS: P(2)X(3) receptor upregulation could account for neuronal hypersensitivity and contribute to abnormal pain responses associated with chronic prostatitis. These results suggest that P(2)X(3) receptors are useful targets for the treatment of pain in chronic prostatitis. PMID- 21254201 TI - Cellular immunosenescence in adult male crickets, Gryllus assimilis. AB - Ecological immunity studies in invertebrates, particularly insects, have generated new insights into trade-offs between immune functions and other physiological parameters. These studies document physiologically directed reallocations of immune costs to other high-cost areas of physiology. Immunosenescence, recognized as the age-related deterioration of immune functions, is another mechanism of radically altering immune systems. We investigated the hypothesis that aging brings on immunosenescence in adult males of the cricket, Gryllus assimilis. Our data show that the intensity of melanotic nodule formation decreased with adult age from after 3-week post-adult emergence. Circulating hemocyte populations similarly decreased from about 5,000 hemocytes/ul hemolymph to about 1,000 hemocytes/ul hemolymph. The numbers of damaged hemocytes in circulation increased from less than 10% at 1-week post adult emergence to approximately 60% by 3-week post-adult emergence. The composition of hemocyte types changed with age, with increasing proportions of granulocytes and decreasing proportions of plasmatocytes. The declines in nodule formation were not linked to the adult age of sexual behaviors, which begin shortly after entering adulthood in this species. We infer that age-related senescence, rather than cost reallocations, may account for observed declines in various parameters of immune functions in insects, as seen in other animals. PMID- 21254202 TI - An efficient binary system for gene expression in the silkworm, Bombyx mori, using GAL4 variants. AB - A binary gene expression system using the yeast GAL4 DNA-binding protein and the upstream activating sequence (UAS) of galactose-driven yeast genes is an established and powerful tool for the analysis of gene function. However, in the domesticated silkworm, Bombyx mori, this system has been limited in its utility by the relatively low transcriptional activation activity of GAL4 and by its toxicity. In this study, we investigated the potential of several established GAL4 variants (GAL4Delta, GAL4VP16, GAL4VPmad2, GAL4VPmad3, and GAL4NFkappaB) and of two new GAL4 variants, GAL4Rel and GAL4Relish, which contain the transcription activating regions of the BmRel and BmRelish genes, respectively, to improve the utility of the GAL4/UAS system in B. mori. We generated constructs containing these GAL4 variants under the control of constitutive or inducible promoters and investigated their transcription-activating activity in cultured B. mori cells and embryos and in transgenic silkworms. GAL4VP16 and GAL4NFkappaB exhibited high transactivation activity but appeared to be toxic when used as transgenes under the control of a constitutive promoter. Similarly, GAL4VPmad2 and GAL4VPmad3 exhibited higher transactivation activity than GAL4, combined with strong toxicity. The transcription-activating activity of GAL4Delta was about twice that of GAL4. The two new GAL4 variants, GAL4Rel and GAL4Relish, were less active than GAL4. Using GAL4VP16 and GAL4NFkappaB constructs, we have developed a very efficient GAL4/UAS binary gene expression system for use in cultured B. mori cells and embryos and in transgenic silkworms. PMID- 21254203 TI - Internalization of Sambucus nigra agglutinins I and II in insect midgut CF-203 cells. AB - In this project, the uptake mechanisms and localization of two lectins from Sambucus nigra, further referred to as S. nigra agglutinin (SNA)-I and SNA-II, into insect midgut CF-203 cells were studied. SNA-I is a chimeric lectin belonging to the class of ribosome-inactivating proteins, whereas SNA-II is a hololectin devoid of enzymatic activity. Internalization of the fluorescein isothiocyanate-labeled lectin was investigated using confocal microscopy. Both lectins were internalized into the cytoplasm of CF-203 cells at similar rates. Preexposure of the insect midgut cells to specific inhibitors of clathrin- and caveolae-mediated endocytosis resulted in an inhibition of lectin uptake in CF 203 cells and caspase-induced cytotoxicity caused by SNA-I and SNA-II, confirming the involvement of both endocytosis pathways. Further studies demonstrated that the uptake mechanism(s) for both lectins required phosphoinositide 3-kinases, but did not depend on the actin cytoskeleton. Since the hololectin SNA-II apparently uses a similar endocytosis pathway as the chimerolectin SNA-I, it can be concluded that the endocytosis process mainly relies on the carbohydrate-binding activity of the lectins under investigation. (c) 2011 Wiley Periodicals, Inc. PMID- 21254204 TI - 2H transmit-receive NMR probes for magnetic field monitoring in MRI. AB - Measuring image encoding fields in real time and applying the information in postprocessing offer improved image quality for MRI, particularly for applications that are intrinsically sensitive to gradient imperfections. For this task, a stand-alone magnetometer system based on multiple (2)H transmit-receive NMR probes has been developed. The conceptual advantages of changing to (2)H NMR probes for (1)H magnetic field monitoring are elucidated here, and the practical design of the probes is described. In comparison to previous (1)H NMR probe-based designs, (2)H probes are perfectly decoupled from standard (1)H imaging. Utilization of RF shielding or other nonoptimal decoupling schemes is therefore not needed. Probes based on (2)H nuclei are also more easily miniaturized for high-resolution imaging. This is particularly important for diffusion tensor and phase-contrast imaging, which rely on strong motion-sensitizing gradients. The presented (2)H NMR probes have been shown to fulfill the requirements for accurate (1)H imaging down to image resolutions of 0.2 mm. Using susceptibility matching techniques, the probe's B(0) inhomogeneity-induced signal dephasing is reduced and monitoring periods beyond 200 msec are achieved. The benefit of real time magnetic field monitoring is highlighted for phase-contrast and non Cartesian multishot imaging. PMID- 21254205 TI - Magnetic resonance microimaging of human skin vasculature in vivo at 3 Tesla. AB - MRI can be used to investigate human skin microvasculature in vivo, provided adequate spatial resolution. Therefore, the sensitivity of the experiment has to be optimized to achieve sufficient signal-to-noise ratio (SNR) within reasonable measurement time to minimize motion artifacts, improve patient comfort and save costs. In this work, the high sensitivity of a 15 mm surface coil and the signal strength of a 3 Tesla scanner, together with a three-dimensional gradient echo sequence and post-processing have been combined to obtain high SNR. Images of human skin with isotropic spatial resolution of 100 MUm were acquired within 10 min and the cutaneous vasculature could be visualized in 3D [Correction made here after initial online publication.], based on three averaged scans. The presented method can be used for diagnosis and, due to its non-invasiveness, treatment monitoring of vascular pathologies in the skin, such as inflammation, vascular malformation, or neoangiogenesis in superficial tumors. PMID- 21254206 TI - Three-directional acceleration phase mapping of myocardial function. AB - An optimized acceleration encoded phase contrast method termed "acceleration phase mapping" for the assessment of regional myocardial function is presented. Based on an efficient gradient waveform design using two-sided encoding for in vivo three-directional acceleration mapping, echo and repetition times TE = 12-14 ms and TR = 15-17 ms for low accelerations sensitivity aenc = 5-8 m/s(2) were achieved. In addition to phantom validation, the technique was applied in a study with 10 healthy volunteers at 1.5T and 3T to evaluate its feasibility to assess regional myocardial acceleration at 1.5T and 3T. Results of the acceleration measurements were compared with the temporal derivative of myocardial velocities from three-directional velocity encoded standard phase contrast MRI in the same volunteers. The feasibility to assess myocardial acceleration along the radial, circumferential, and longitudinal direction of the left ventricle was demonstrated. Despite improved signal-to-noise-ratio at 3T (34% increase compared with 1.5T), image quality with respect to susceptibility artifacts was better 1.5T compared with 3T. Analysis of global and regional left ventricular acceleration showed characteristic patterns of systolic and diastolic acceleration and deceleration. Comparisons of directly measured and derived myocardial acceleration dynamics over the cardiac cycle revealed good correlation (r = 0.45-0.68, P < 0.01) between both methods. PMID- 21254207 TI - Combining phase images from multi-channel RF coils using 3D phase offset maps derived from a dual-echo scan. AB - A method is presented for the combination of phase images from multi-channel RF coils in the absence of a volume reference coil. It is based on the subtraction of 3D phase offset maps from the phase data from each coil. Phase offset maps are weighted combinations of phase measurements at two echo times. Multi-Channel Phase Combination using measured 3D phase offsets (MCPC-3D) offers a conceptually and computationally simple solution to the calculation of combined phase images. The dual-echo data required for the phase maps can be intrinsic to the high resolution gradient-echo scan to be reconstructed (MCPC-3D-I). Alternatively, a separate, fast, low-resolution dual-echo scan can be used (MCPC-3D-II). Both variants are shown to give near perfect phase matching, yielding images with high SNR throughout and high GM-WM contrast. MCPC-3D is compared with other reference free phase image combination methods; high-pass phase filtering, phase difference imaging, and matching using constant offsets (MCPC-C). Multi-Channel Phase Combination using measured 3D phase offsets method does not need an overlap between the signals from individual coils and can be used with parallel imaging, making it ideally suited to multi-channel coils with a large number of elements, and to high and ultra-high field systems. PMID- 21254208 TI - Improved diagnostic accuracy of breast MRI through combined apparent diffusion coefficients and dynamic contrast-enhanced kinetics. AB - This study investigated the relationship between apparent diffusion coefficient (ADC) measures and dynamic contrast-enhanced magnetic resonance imaging (MRI) kinetics in breast lesions and evaluated the relative diagnostic value of each quantitative parameter. Seventy-seven women with 100 breast lesions (27 malignant and 73 benign) underwent both dynamic contrast-enhanced MRI and diffusion weighted MRI. Dynamic contrast-enhanced MRI kinetic parameters included peak initial enhancement, predominant delayed kinetic curve type (persistent, plateau, or washout), and worst delayed kinetic curve type (washout > plateau > persistent). Associations between ADC and dynamic contrast-enhanced MRI kinetic parameters and predictions of malignancy were evaluated. Results showed that ADC was significantly associated with predominant curve type (ADC was higher for lesions exhibiting predominantly persistent enhancement compared with those exhibiting predominantly washout or plateau, P = 0.006), but was not significantly associated with peak initial enhancement or worst curve type (P > 0.05). Univariate analysis showed significant differences between benign and malignant lesions in both ADC (P < 0.001) and worst curve (P = 0.003). In multivariate analysis, worst curve type and ADC were significant independent predictors of benign versus malignant outcome and in combination produced the highest area under the receiver operating characteristic curve (0.85 and 0.78 with 5-fold cross validation). PMID- 21254209 TI - Modeling neuronal current MRI signal with human neuron. AB - Up to date, no consensus has been achieved regarding the possibility of detecting neuronal currents by MRI (ncMRI) in human brain. To evaluate the detectability of ncMRI, an effective way is to simulate ncMRI signal with the realistic neuronal geometry and electrophysiological processes. Unfortunately, previous realistic ncMRI models are based on rat and monkey neurons. The species difference in neuronal morphology and physiology would prevent these models from simulating the ncMRI signal accurately in human subjects. The aim of this study is to bridge this gap by establishing a realistic ncMRI model specifically for human cerebral cortex. In this model, the ncMRI signal was simulated using anatomically reconstructed human pyramidal neurons and their biophysical properties. The modeling results showed that the amplitude of ncMRI signal significantly depends on the density of synchronously firing neurons and imaging conditions such as position of imaging voxel, direction of main magnetic field (B(0) ) relative to the cortical surface and echo time. The results indicated that physiologically evoked ncMRI signal is too weak to be detected (magnitude/phase change <= -1.4 * 10(-6) /0.02 degrees ), but the phase signal induced by spontaneous activity may reach a detectable level (up to 0.2 degrees ) in favorable conditions. PMID- 21254210 TI - A new approach to autocalibrated dynamic parallel imaging based on the Karhunen Loeve transform: KL-TSENSE and KL-TGRAPPA. AB - TSENSE and TGRAPPA are autocalibrated parallel imaging techniques that can improve the temporal resolution and/or spatial resolution in dynamic magnetic resonance imaging applications. In its original form, TSENSE uses temporal low pass filtering of the undersampled frames to create the sensitivity map. TGRAPPA uses a sliding-window moving average when finding the autocalibrating signals. Both filtering methods are suboptimal in the least-squares sense and may give rise to mismatches between the undersampled k-space raw data and the corresponding coil sensitivities. Such mismatches may result in aliasing artifacts when imaging patients with heavy breathing, as in real-time imaging of wall motion by MRI following a treadmill exercise stress test. In this study, we demonstrate the use of an optimal linear filter, i.e., the Karhunen-Loeve transform filter, to estimate the channel sensitivity for TSENSE and acquire the autocalibration signals for TGRAPPA. Phantom experiments show that the new reconstruction method has comparable signal-to-noise ratio performance to traditional TSENSE/TGRAPPA reconstruction. In vivo real-time cardiac cine experiments performed in five healthy volunteers post-exercise during rapid respiration show that the new method significantly reduces the chest wall aliasing artifacts caused by respiratory motion (P < 0.001). PMID- 21254211 TI - 3D GRASE PROPELLER: improved image acquisition technique for arterial spin labeling perfusion imaging. AB - Arterial spin labeling is a noninvasive technique that can quantitatively measure cerebral blood flow. While traditionally arterial spin labeling employs 2D echo planar imaging or spiral acquisition trajectories, single-shot 3D gradient echo and spin echo (GRASE) is gaining popularity in arterial spin labeling due to inherent signal-to-noise ratio advantage and spatial coverage. However, a major limitation of 3D GRASE is through-plane blurring caused by T(2) decay. A novel technique combining 3D GRASE and a periodically rotated overlapping parallel lines with enhanced reconstruction trajectory (PROPELLER) is presented to minimize through-plane blurring without sacrificing perfusion sensitivity or increasing total scan time. Full brain perfusion images were acquired at a 3 * 3 * 5 mm(3) nominal voxel size with pulsed arterial spin labeling preparation sequence. Data from five healthy subjects was acquired on a GE 1.5T scanner in less than 4 minutes per subject. While showing good agreement in cerebral blood flow quantification with 3D gradient echo and spin echo, 3D GRASE PROPELLER demonstrated reduced through-plane blurring, improved anatomical details, high repeatability and robustness against motion, making it suitable for routine clinical use. PMID- 21254212 TI - Enhancement effects of hepatic dynamic MR imaging at 3.0 T and 1.5 T using gadoxetic acid in a phantom study: comparison with gadopentetate dimeglumine. AB - To identify the optimum sequence at gadoxetic acid enhanced hepatic dynamic magnetic resonance imaging in the arterial phase, we studied phantoms that contained gadoxetic acid or gadopentetate dimeglumine diluted in human blood. We obtained magnetic resonance images at 3.0 T and 1.5 T with one vendor (Siemens) using 3D-gradient echo (GRE)-, 2D-fast low angle shot (FLASH)-, and turbo spin echo sequences. Contrast ratio was highest for 3D-GRE; at both 3.0 T and 1.5 T it was superior when the contrast agent was gadoxetic acid. With both gadoxetic acid and gadopentetate dimeglumine, contrast ratio peaked at around 5- and 2 mmol/L on 3D-GRE- and 2D-FLASH images, respectively. Compared with gadopentetate dimeglumine, at 3.0 T, the peak contrast ratio of gadoxetic acid was 14.1% better on 3D-GRE images and 14.0% better on 2D-FLASH images; at 1.5 T it was 16.4% better on 3D-GRE- and 5.7% better on 2D-FLASH images. With respect to the magnetic field strength, at 3.0 T the peak contrast ratio of gadoxetic acid was 6.0% better than at 1.5 T on 3D-GRE images and 49.5% better on 2D-FLASH images; it was 8.5% better on 3D-GRE- and 44.6% better on 2D-FLASH images than when the contrast agent was gadopentetate dimeglumine. Thus, gadoxetic acid yielded better enhancement on 3D-GRE images acquired at 3.0 T than at 1.5 T and enhancement was better than that obtained with gadopentetate dimeglumine at the same concentration. PMID- 21254213 TI - In vivo detection of MRI-PARACEST agents in mouse brain tumors at 9.4 T. AB - Paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents are under development for biological target identification by magnetic resonance imaging. Image contrast associated with PARACEST agents can be generated by radiofrequency irradiation of the chemically shifted protons bound to a PARACEST contrast agent molecule or by direct irradiation of the on-resonance bulk water protons. The observed signal change in a magnetic resonance image after the administration of a PARACEST contrast agent is due to both altered relaxation time constants and the CEST effect. Despite high sensitivity in vitro, PARACEST agents have had limited success in vivo where sensitivity is reduced by the magnetization transfer effect from endogenous macromolecules. The purpose of this study was to demonstrate the in vivo detection of a PARACEST contrast agent using the on-resonance paramagnetic chemical exchange effect (OPARACHEE) in a mouse glioblastoma multiforme tumor model and to isolate the OPARACHEE effect from the changes in relaxation induced by the PARACEST agent. Three mice with tumors were imaged on a 9.4 T MRI scanner following tail vein injection of 150 MUL 50 mM Tm(3+)-DOTAM-glycine-lysine. A fast low angle shot pulse sequence with a low power radiofrequency pulse train (WALTZ-16) as the preparation pulse was used to generate OPARACHEE contrast. To study the dynamics of agent uptake, reference images (without the preparation pulse) and OPARACHEE images were acquired continuously in an alternating fashion before, during and after agent injection. Signal intensity decreased by more than 10% in tumor in the control images after agent administration. Despite these changes, a clear OPARACHEE contrast of 1-5% was also observed in brain tumors after contrast agent injection and maintained in the hour following injection. This result is the first in vivo observation of OPARACHEE contrast in brain tumors with correction of T(1) and T(2) relaxation effects. PMID- 21254214 TI - Quantitative analysis of intravenously administered contrast media reveals changes in vascular barrier functions in a murine colitis model. AB - Inflammatory bowel disease is a chronic inflammatory disorder of the gastrointestinal tract associated with alterations and dysfunction of the intestinal microvasculature. The goal of this work was to develop a preclinical protocol for quantitative functional characterization of the colonic microvasculature in a murine colitis model. Experimental colitis was induced in mice by addition of dextran sodium sulfate to the drinking water. Histopathologic analysis revealed severe multifocal colitis. Dynamics of intravenously injected macromolecular dextran-FITC and biotin-BSA-GdDTPA in the colonic microvasculature were imaged using fluorescent confocal endomicroscopy and MRI (9.4 T), respectively. Both MRI and fluorescent confocal endomicroscopy revealed a substantial increase in the permeability of the colonic microvasculature associated with colitis, resulting in extravascular accumulation of the macromolecular contrast agent in the lumen of the colon. MRI data were validated by immunohistochemical staining of the contrast agent and leakage of fluorescently labeled BSA-FAM coinjected with the MRI contrast agent. Leakage of plasma proteins and deposition of a provisional matrix can support inflammation and stimulate remodeling of the colonic vasculature. Thus, the plasma protein leakage from the colonic microvasculature at the focal inflammatory patches could be quantified by MRI, providing a biomarker for assessment of disease progression. PMID- 21254215 TI - Predicting multiallelic genes using unphased and flanking single nucleotide polymorphisms. AB - Recent advances in genotyping technologies have enabled genomewide association studies (GWAS) of many complex traits including autoimmune disease, infectious disease, cancer and heart disease. To facilitate interpretations and establish biological basis, it could be advantageous to identify alleles of functional genes, beyond just single nucleotide polymorphisms (SNPs) within or nearby genes. Leslie et al. ([2008] Am J Hum Genet 82:48-56) have proposed an Identity-by Decent method (IBD-based) for predicting human leukocyte antigen (HLA) alleles (multiallelic and highly polymorphic) with SNP data, and predictions have achieved a satisfactory accuracy on the order of 97%. Building upon their success, we introduce a complementary method for predicting highly polymorphic alleles using unphased SNP data as the training data set. Due to its generality and flexibility, the new method is readily applicable to large population studies. Applying it to HLA genes in a cohort of 630 healthy individuals as a training set, we constructed predictive models for HLA-A, B, C, DRB1 and DQB1. Then, we performed a validation study with another cohort of 630 healthy individuals, and the predictive models achieved predictive accuracies for HLA alleles defined at intermediate or high resolution ranging as high as (100%, 97%) for HLA-A, (98%, 96%) for B, (98%, 98%) for C, (97%, 96%) for DRB1 and (98%, 95%) for DQB1, respectively. These preliminary results suggest the feasibility of predicting other polymorphic genetic alleles, since HLA loci are almost certainly among most polymorphic genes. PMID- 21254216 TI - The impact of self-identified race on epidemiologic studies of gene expression. AB - Although population differences in gene expression have been established, the impact on differential gene expression studies in large populations is not well understood. We describe the effect of self-reported race on a gene expression study of lung function in asthma. We generated gene expression profiles for 254 young adults (205 non-Hispanic whites and 49 African Americans) with asthma on whom concurrent total RNA derived from peripheral blood CD4(+) lymphocytes and lung function measurements were obtained. We identified four principal components that explained 62% of the variance in gene expression. The dominant principal component, which explained 29% of the total variance in gene expression, was strongly associated with self-identified race (P<10(-16)). The impact of these racial differences was observed when we performed differential gene expression analysis of lung function. Using multivariate linear models, we tested whether gene expression was associated with a quantitative measure of lung function: pre bronchodilator forced expiratory volume in one second (FEV(1)). Though unadjusted linear models of FEV(1) identified several genes strongly correlated with lung function, these correlations were due to racial differences in the distribution of both FEV(1) and gene expression, and were no longer statistically significant following adjustment for self-identified race. These results suggest that self identified race is a critical confounding covariate in epidemiologic studies of gene expression and that, similar to genetic studies, careful consideration of self-identified race in gene expression profiling studies is needed to avoid spurious association. PMID- 21254217 TI - A comparison of approaches to account for uncertainty in analysis of imputed genotypes. AB - The availability of extensively genotyped reference samples, such as "The HapMap" and 1,000 Genomes Project reference panels, together with advances in statistical methodology, have allowed for the imputation of genotypes at single nucleotide polymorphism (SNP) markers that are untyped in a cohort or case-control study. These imputation procedures facilitate the interpretation and meta-analyses of genome-wide association studies. A natural question when implementing these procedures concerns how best to take into account uncertainty in imputed genotypes. Here we compare the performance of the following three strategies: least-squares regression on the "best-guess" imputed genotype; regression on the expected genotype score or "dosage"; and mixture regression models that more fully incorporate posterior probabilities of genotypes at untyped SNPs. Using simulation, we considered a range of sample sizes, minor allele frequencies, and imputation accuracies to compare the performance of the different methods under various genetic models. The mixture models performed the best in the setting of a large genetic effect and low imputation accuracies. However, for most realistic settings, we find that regressing the phenotype on the estimated allelic or genotypic dosage provides an attractive compromise between accuracy and computational tractability. PMID- 21254218 TI - Mining gold dust under the genome wide significance level: a two-stage approach to analysis of GWAS. AB - We propose a two-stage approach to analyze genome-wide association data in order to identify a set of promising single-nucleotide polymorphisms (SNPs). In stage one, we select a list of top signals from single SNP analyses by controlling false discovery rate. In stage two, we use the least absolute shrinkage and selection operator (LASSO) regression to reduce false positives. The proposed approach was evaluated using simulated quantitative traits based on genome-wide SNP data on 8,861 Caucasian individuals from the Atherosclerosis Risk in Communities (ARIC) Study. Our first stage, targeted at controlling false negatives, yields better power than using Bonferroni-corrected significance level. The LASSO regression reduces the number of significant SNPs in stage two: it reduces false-positive SNPs and it reduces true-positive SNPs also at simulated causal loci due to linkage disequilibrium. Interestingly, the LASSO regression preserves the power from stage one, i.e., the number of causal loci detected from the LASSO regression in stage two is almost the same as in stage one, while reducing false positives further. Real data on systolic blood pressure in the ARIC study was analyzed using our two-stage approach which identified two significant SNPs, one of which was reported to be genome-significant in a meta analysis containing a much larger sample size. On the other hand, a single SNP association scan did not yield any significant results. PMID- 21254219 TI - Inferring genetic causal effects on survival data with associated endo phenotypes. AB - Age-at-onset phenotypes are important traits in genetic association analyses. Often, intermediate phenotypes that are related to the age-at-onset phenotype are also associated with the marker loci that are associated with the age-at-onset phenotype. In order to understand the genetic etiology of the observed associations, statistical methodology is needed to distinguish between a direct genetic effect on the age-at-onset phenotype and an indirect effect induced by the genetic association with the endo-phenotype that is correlated with the age at-onset phenotype. In this communication, we introduce a new statistical approach to detect causal genetic effects on survival data in the presence of genetic associations with secondary phenotypes that might influence survival as well and thereby induce seemingly causal relationships. Derived using causal inference methodology, the proposed method is based on standard statistical methodology and can be implemented straight-forwardly, using standard software. Using simulation studies, the theoretical properties of the approach are verified and the power is assessed under realistic scenarios. The practical relevance of the approach is illustrated by an application to survival after cardiac surgery, where genetic components of myocardial infarctions are determined to not influence post-surgery hospital duration except through the MI-pathway. PMID- 21254220 TI - Propensity score-based nonparametric test revealing genetic variants underlying bipolar disorder. AB - Association analysis has led to the identification of many genetic variants for complex diseases. While assessing the association between genes and a disease, other factors can play an important role. The consequence of not considering covariates (such as population stratification and environmental factors) is well documented in genetic studies. We introduce a nonparametric test of association that adjusts for covariate effects. Specifically, the adjustment is realized through weights that are constructed from genomic propensity scores that summarize the contribution of all covariates. The benefit of our test is demonstrated through an important data set on bipolar disorder (BD) collected by the Wellcome Trust Case Control Consortium. When compared to other tests, our test identified an unreported region with three single nucleotide polymorphisms (SNPs) on chromosome 16 that show strong evidence of association (P-value <5 * 10(-7)). This region is near the RPGRIP1L gene known to be associated with BD. A haplotype block including these three SNPs was further discovered to be strongly associated with BD. It is also interesting to note that our nonparametric test did not reveal strong signals at two SNPs that were detected by a covariate adjusted parametric test. This suggests that different methods of covariate adjustment can complement each other. Thus, we recommend using both parametric and nonparametric testing. Additionally, we performed simulation studies to compare our proposed test with the unadjusted test and an adjusted parametric test. Our finding underscores the importance of accommodating and controlling for covariate effects in discovering genetic variants associated with complex disorders. PMID- 21254221 TI - SNP mistyping in genotyping arrays--an important cause of spurious association in case-control studies. AB - Using genome-wide association studies to identify genetic variants contributing to disease has been highly successful with many novel genetic predispositions identified and biological pathways revealed. Several pitfalls for spurious association or non-replication have been highlighted: from population structure, automated genotype scoring for cases and controls, to age-varying association. We describe an important yet unreported source of bias in case-control studies due to variations in chip technology between different commercial array releases. As cases are commonly genotyped with newer arrays and freely available control resources are frequently used for comparison, there exists an important potential for false associations which are robust to standard quality control and replication design. PMID- 21254222 TI - On optimal pooling designs to identify rare variants through massive resequencing. AB - The advent of next-generation sequencing technologies has facilitated the detection of rare variants. Despite the significant cost reduction, sequencing cost is still high for large-scale studies. In this article, we examine DNA pooling as a cost-effective strategy for rare variant detection. We consider the optimal number of individuals in a DNA pool to detect an allele with a specific minor allele frequency (MAF) under a given coverage depth and detection threshold. We found that the optimal number of individuals in a pool is indifferent to the MAF at the same coverage depth and detection threshold. In addition, when the individual contributions to each pool are equal, the total number of individuals across different pools required in an optimal design to detect a variant with a desired power is similar at different coverage depths. When the contributions are more variable, more individuals tend to be needed for higher coverage depths. Our study provides general guidelines on using DNA pooling for more cost-effective identifications of rare variants. PMID- 21254224 TI - BIRD-J-resolved HMBC and BIRD-high-resolution HMBC pulse sequences for measuring heteronuclear long-range coupling constants and proton-proton spin coupling constants in complicated spin systems. AB - Efficient pulse sequences for measuring long-range C-H coupling constants (J(C H)) and proton-proton spin coupling constants (J(H-H)), named BIRD-J-resolved HMBC and BIRD-high-resolution HMBC, respectively, have been developed. In spin systems possessing a secondary methyl group positioned between protonated carbons (e.g. -CH(2)-CH(CH(3))-CH(2)-), the methine proton splits in a complicated fashion, resulting in difficulty in the determination of its spin coupling constants. For easy and accurate measurements of the long-range J(C-H) and J(H-H) in such a spin system, the BIRD pulse [90 degrees x(H)-180 degrees x (H/C)- 90 degrees (-x)(H)] or [90 degrees x(H)-180 degrees x(H/C)-90 degrees (-x)(H)180 degrees x(C)] is incorporated into the J-resolved portion of the pulse sequence. As a result, the above secondary methyl group can be selectively decoupled, providing simplified cross-peak patterns, which are suitable for the accurate measurements of the long-range J(C-H) and J(H-H). PMID- 21254223 TI - Multiple testing corrections for imputed SNPs. AB - Multiple testing corrections are an active research topic in genetic association studies, especially for genome-wide association studies (GWAS), where tests of association with traits are conducted at millions of imputed SNPs with estimated allelic dosages now. Failure to address multiple comparisons appropriately can introduce excess false-positive results and make subsequent studies following up those results inefficient. Permutation tests are considered the gold standard in multiple testing adjustment; however, this procedure is computationally demanding, especially for GWAS. Notably, the permutation thresholds for the huge number of estimated allelic dosages in real data sets have not been reported. Although many researchers have recently developed algorithms to rapidly approximate the permutation thresholds with accuracy similar to the permutation test, these methods have not been verified with estimated allelic dosages. In this study, we compare recently published multiple testing correction methods using 2.5M estimated allelic dosages. We also derive permutation significance levels based on 10,000 GWAS results under the null hypothesis of no association. Our results show that the simpleM method works well with estimated allelic dosages and gives the closest approximation to the permutation threshold while requiring the least computation time. PMID- 21254225 TI - 1H, 13C, 195Pt and 15N NMR structural correlations in Pd(II) and Pt(II) chloride complexes with various alkyl and aryl derivatives of 2,2'-bipyridine and 1,10 phenanthroline. AB - (1)H, (13)C, (195)Pt and (15)N NMR studies of platinide(II) (M = Pd, Pt) chloride complexes with such alkyl and aryl derivatives of 2,2'-bipyridine and 1,10 phenanthroline as LL = 6,6'-dimethyl-bpy, 5,5'-dimethyl-bpy, 4,4'-di-tert-butyl bpy, 2,9-dimethyl-phen, 2,9-dimethyl-4,7-diphenyl-phen, 3,4,7,8-tetramethyl-phen, having the general [M(LL)Cl(2)] formula were performed and the respective chemical shifts (delta(1H), delta(13C), delta(195Pt), delta(15N)) reported. (1)H high-frequency coordination shifts (Delta(coord)(1H) = delta(complex)(1H) delta(ligand)(1H)) mostly pronounced for nitrogen-adjacent protons and methyl groups in the nearest adjacency of nitrogen, as well as (15)N low-frequency coordination shifts (Delta(coord)(15H) = delta(complex)(15H)-delta(ligand)(15H)) were discussed in relation to the molecular structures. PMID- 21254226 TI - Solid-state NMR detection of 14N-13C dipolar couplings between amino acid side groups provides constraints on amyloid fibril architecture. AB - Solid-state nuclear magnetic resonance (SSNMR) is a powerful technique for the structural analysis of amyloid fibrils. With suitable isotope labelling patterns, SSNMR can provide constraints on the secondary structure, alignment and registration of beta-strands within amyloid fibrils and identify the tertiary and quaternary contacts defining the packing of the beta-sheet layers. Detection of (14)N-(13)C dipolar couplings may provide potentially useful additional structural constraints on beta-sheet packing within amyloid fibrils but has not until now been exploited for this purpose. Here a frequency-selective, transfer of population in double resonance SSNMR experiment is used to detect a weak (14)N (13)C dipolar coupling in amyloid-like fibrils of the peptide H(2)N-SNNFGAILSS COOH, which was uniformly (13)C and (15)N labelled across the four C-terminal amino acids. The (14)N-(13)C interatomic distance between leucine and asparagine side groups is constrained between 2.4 and 3.8 A, which allows current structural models of the beta-spine arrangement within the fibrils to be refined. This procedure could be useful for the general structural analysis of other proteins in condensed phases and environments, such as biological membranes. PMID- 21254227 TI - Polymer-bound 4-methylcoumarin/1-heptanoyl-5-fluorouracil photodimers: NMR elucidation of dimer structure. AB - Heterodimers based on the polymer-bound chromophore 4-methylcoumarin and the prodrug 1-heptanoyl-5-fluorouracil, synthesized by photochemical [2 + 2] cycloaddition are promising photoresponsive drug depots. Drug release experiments are one possibility to deliver proof of a successful reversible drug immobilization, whereas NMR spectroscopy is a potent tool for further structural characterization of these polymer-bound heterodimers. In case of the random copolymer poly(methyl methacrylate-co-7-(2'-methacryloyloxyethoxy)-4 methylcoumarin) three dimers have been identified of which the syn head-to-tail was the predominant one. In contrast, only the syn head-to-head dimer was formed in reasonable yield when the 4-methylcoumarin monofunctionalized pMMA was used as the base polymer. 1D and 2D NMR spectroscopic techniques combined with some theoretical calculations helped in successfully closing one major gap concerning polymer bound 4-methylcoumarin/1-heptanoyl-5-fluorouracil heterodimers that are of potential use in photoresponsive drug delivery devices. PMID- 21254228 TI - Theoretical prediction and assignment of vicinal 1H-1H coupling constants of diastereomeric 3-alkoxy-6,7-epoxy-2-oxabicyclo[3.3.0]octanes. AB - Spin-spin coupling constants between nuclei in NMR spectroscopy reflect their spatial arrangement. A number of calculation methods, applying different levels of theory, have been developed to support the stereochemical assignment of novel compounds. Nevertheless, revisions of the assignment of structures in the literature are not rare. In the present work, the reliability of the calculation methods amenable for a theoretical prediction of spin-spin coupling constants of vicinal protons to support correct stereochemical assignment of substitution at five-membered rings of 3-alkoxy-6,7-epoxy-2-oxabicyclo[3.3.0]octanes was studied. Experimental (3)J(H,H) coupling constants were compared with the coupling constants calculated for all possible diastereomers. The fully quantum chemical approach provided theoretical (3)J(H,H) coupling constants with an absolute deviation of no more than 1.1 Hz for 91% of the experimentally studied coupled spins, whereas the methods without quantum chemical geometry optimization resulted in completely unreliable predictions. Consequently, for a reliable stereochemical assignment of small and medium size molecules, the protocol for calculating the coupling constants based on the results of the quantum chemical geometry optimization is recommended. PMID- 21254229 TI - Glaucasides A-C, three saikosaponins from Atriplex glauca L. var. ifiniensis (Caball) Maire. AB - From the roots of Atriplex glauca L. var. ifiniensis (Caball) Maire (syn. of Atriplex parvifolia Lowe var. genuina Maire), three new saikosaponins designated as glaucasides A-C (1-3) were isolated together with the known 3-O-beta-D glucopyranosyl-(1 -> 2)-beta-D-galactopyranosyl-saikogenin F (4). The structures of the new compounds were elucidated by extensive analysis of one-dimensional and two-dimensional NMR spectroscopy, FABMS, HR-ESIMS and chemical evidence as 13beta,28-epoxy-16beta,21beta-dihydroxyolean-11-en-3beta-yl O-beta-D-[2-O sulfate]-glucopyranosyl-(1 -> 2)-alpha-L-arabinopyranoside (1), 13beta,28-epoxy 16beta,21beta-dihydroxyolean-11-en-3beta-yl O-beta-D-[2-O-sulfate]-glucopyranosyl (1 -> 2)-alpha-L-arabinopyranosyl 21-O-{4-(secbutylamido)-butanoyl ester} (2) and 3-O-beta-D-glucopyranosyl-(1 -> 2)-beta-D-galactopyranosyl saikogenin G (3). The cytotoxic activities of these compounds were evaluated against the HT-29 and HCT 116 human colon cancer cell lines. PMID- 21254231 TI - Discontinuation of odanacatib and other osteoporosis treatments: here today and gone tomorrow? PMID- 21254230 TI - The amazing osteocyte. AB - The last decade has provided a virtual explosion of data on the molecular biology and function of osteocytes. Far from being the "passive placeholder in bone," this cell has been found to have numerous functions, such as acting as an orchestrator of bone remodeling through regulation of both osteoclast and osteoblast activity and also functioning as an endocrine cell. The osteocyte is a source of soluble factors not only to target cells on the bone surface but also to target distant organs, such as kidney, muscle, and other tissues. This cell plays a role in both phosphate metabolism and calcium availability and can remodel its perilacunar matrix. Osteocytes compose 90% to 95% of all bone cells in adult bone and are the longest lived bone cell, up to decades within their mineralized environment. As we age, these cells die, leaving behind empty lacunae that frequently micropetrose. In aged bone such as osteonecrotic bone, empty lacunae are associated with reduced remodeling. Inflammatory factors such as tumor necrosis factor and glucocorticoids used to treat inflammatory disease induce osteocyte cell death, but by different mechanisms with potentially different outcomes. Therefore, healthy, viable osteocytes are necessary for proper functionality of bone and other organs. PMID- 21254232 TI - Serum 25-hydroxyvitamin D level and acute-phase reaction following initial intravenous bisphosphonate. PMID- 21254233 TI - Crystal structure of the carbon monoxide complex of human cytoglobin. AB - Cytoglobin (Cgb) is a vertebrate heme-containing globin-protein expressed in a broad range of mammalian tissues. Unlike myoglobin, Cgb displays a hexa coordinated (bis-hystidyl) heme iron atom, having the heme distal His81(E7) residue as the endogenous sixth ligand. In the present study, we crystallized human Cgb in the presence of a reductant Na2S2O4 under a carbon monoxide (CO) atmosphere, and determined the crystal structure at 2.6 A resolution. The CO ligand occupies the sixth axial position of the heme ferrous iron. Eventually, the imidazole group of His81(E7) is expelled from the sixth position and swings out of the distal heme pocket. The flipping motion of the His81 imidazole group accompanies structural readjustments of some residues (Gln62, Phe63, Gln72, and Ser75) in both the CD-corner and D-helix regions of Cgb. On the other hand, no significant structural changes were observed in other Cgb regions, for example, on the proximal side. These structural alterations that occurred as a result of exogenous ligand (CO) binding are clearly different from those observed in other vertebrate hexa-coordinated globins (mouse neuroglobin, Drosophila melanogaster hemoglobin) and penta-coordinated sperm whale myoglobin. The present study provides the structural basis for further discussion of the unique ligand-binding properties of Cgb. PMID- 21254235 TI - Enrichment of nuclear red blood cells by membrane KCC transporter with urea intervention. AB - Intervention by membrane KCC transporter interfering selectively could promote about 5 times enrichment of nuclear red blood cells. PMID- 21254234 TI - Structural plasticity of staphylococcal nuclease probed by perturbation with pressure and pH. AB - The ionization of internal groups in proteins can trigger conformational change. Despite this being the structural basis of most biological energy transduction, these processes are poorly understood. Small angle X-ray scattering (SAXS) and nuclear magnetic resonance (NMR) spectroscopy experiments at ambient and high hydrostatic pressure were used to examine how the presence and ionization of Lys 66, buried in the hydrophobic core of a stabilized variant of staphylococcal nuclease, affect conformation and dynamics. NMR spectroscopy at atmospheric pressure showed previously that the neutral Lys-66 affects slow conformational fluctuations globally, whereas the effects of the charged form are localized to the region immediately surrounding position 66. Ab initio models from SAXS data suggest that when Lys-66 is charged the protein expands, which is consistent with results from NMR spectroscopy. The application of moderate pressure (<2 kbar) at pH values where Lys-66 is normally neutral at ambient pressure left most of the structure unperturbed but produced significant nonlinear changes in chemical shifts in the helix where Lys-66 is located. Above 2 kbar pressure at these pH values the protein with Lys-66 unfolded cooperatively adopting a relatively compact, albeit random structure according to Kratky analysis of the SAXS data. In contrast, at low pH and high pressure the unfolded state of the variant with Lys-66 is more expanded than that of the reference protein. The combined global and local view of the structural reorganization triggered by ionization of the internal Lys-66 reveals more detectable changes than were previously suggested by NMR spectroscopy at ambient pressure. PMID- 21254236 TI - Prolidase activity dysregulation and its correlation with oxidative-antioxidative status in chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a consequence of an underlying chronic inflammatory disorder of the airways that is usually progressive and causes dysregulation in the metabolism of collagen. Prolidase has an important role in the recycling of proline for collagen synthesis and cell growth. OBJECTIVE: We measured and compared prolidase activity in healthy individuals with COPD patients to find out that whether its activity might reflect disturbances of collagen metabolism in the patients. We also investigated oxidative-antioxidative status and its relationship with prolidase activity in this disease. METHODS: Thirty voluntary patients with COPD and 30 healthy control subjects with similar age range and sex were included into the study. Plasma prolidase activities, total antioxidant capacity (TAC) and lipid peroxidation (LPO) levels were measured in the patient and control groups. RESULTS: Plasma prolidase activity and TAC levels were significantly lower, and LPO levels were significantly higher in the patients than those in the control subjects (P<0.05, P<0.001, and P<0.001, respectively). Significant correlations were detected between plasma prolidase activity and TAC and LPO levels in the patients group (r=0.679, P<0.001; r=-426, P<0.05, respectively). CONCLUSIONS: The results suggest that oxidative-antioxidative balance and collagen turnover are altered by the development of COPD in human lungs, and prolidase activity may reflect disturbances of collagen metabolism in this pulmonary disease. Monitoring of plasma prolidase activity and oxidative-antioxidative balance may be useful in evaluating fibrotic processes and oxidative damage in the chronic inflammatory lung disease in human. PMID- 21254237 TI - The characteristics of new semi-quantitative method for diagnosing proteinuria by using random urine samples. AB - We assessed the characteristics of the new semi-quantitative test paper (Clinitek ATLAS Pro(12)) using random urine samples. Three hundred urine samples were analyzed using either the new test paper, conventional dipsticks, quantitative (P/C ratio), or immunological quantitative methods (A/C ratio). Our study showed that the new test paper is highly sensitive and specific for the detection of urinary protein. The new test paper also detected the urine protein more accurately than the conventional test and has a lower false-positive rate. In addition, the new test paper detected 14 of the 300 patients (4.7%) as dilute urine samples needing reassessment. Seventeen of the 300 samples tested were negative with conventional dipsticks but positive with the new test paper. The new semi-quantitative test paper not only has higher sensitivity than the conventional dipstick method, but also has potential to detect dilute samples. PMID- 21254238 TI - Direct diagnosis of Leishmania species on serosity materials punctured from cutaneous leishmaniasis patients using PCR-RFLP. AB - This study was aimed at identifying the Leishmania species using serosity materials punctured from skin lesions of cutaneous leishmaniasis (CL) patients by using internal transcribed spacer1 (ITS1) polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). We used the PCR-RFLP on 60 parasitological confirmed CL patients who referred to leishmaniasis laboratory from the School of Public Health, Tehran University of Medical Sciences. The PCR RFLP could correctly detect 51 Leishmania species of the 60 confirmed positive specimens, where all the other 10 parasitological (microscopy and culture) negative samples that were prepared from other bacterial- and fungal-infected lesions had negative results. The results also revealed that Leishmania major was the dominant species (53.3%). This study suggests that the PCR-RFLP assay with serosity materials punctured from CL patients using Hae III enzyme is useful for the rapid identification of Leishmania species. PMID- 21254239 TI - Prognosis of periodontitis recurrence after intensive periodontal treatment using examination of serum IgG antibody titer against periodontal bacteria. AB - Chronic periodontitis is associated with systemic diseases such as atherosclerosis. In this study, we evaluated the efficacy of serum IgG antibody titer to periodontal bacteria for prognosis of periodontitis recurrence during supportive periodontal therapy (SPT) phase. The 139 patients during SPT phase were selected and divided to two groups as follows: "Stable" and "Recurrence" group at SPT phase for case-control study: "High IgG titer" and "Normal IgG titer" group before transition to SPT phase for cohort study. We examined whether clinical findings or serum IgG antibody titers to periodontal bacteria are risk factors for the development of periodontitis recurrence. Case-control study showed that there were significant differences between the stable and recurrence groups in age and number of teeth. The serum IgG antibody titer to Eikenella corrodens FDC1073, Porphyromonas gingivalis SU63, and Campylobacter rectus ATCC33238 was significantly higher in the recurrence group. Next, we found, that the recurrence ratio in the high IgG titer group to Gram-negative obligate anaerobe, Prevotella intermedia, Treponema denticola, and C. rectus was significantly higher than that of the normal IgG titer group. Taken together, serum IgG antibody titer test is useful in the prognosis of periodontitis recurrence during the SPT phase. PMID- 21254240 TI - Isolation and characterizations of clarithromycin-resistant Mycobacterium avium clinical isolates. AB - Mycobacterium avium is an important intracellular pathogen, particularly in AIDS patients. It also shows the second frequency among nontuberculous mycobacteria infections in Korea. Point mutations of domain V region of the 23S rRNA gene has been known to confer clarithromycin resistance to M. avium. In order to isolate the clarithromycin-resistant strains from clinical isolates of M. avium and characterize them, we isolated the clarithromycin-resistant strains from clinical isolates of M. avium using reverse hybridization assay (RHA) and broth microdilution test (BMT). Three clarithromycin-resistant isolates with high level of MICs were found from 274 clinical isolates by BMT. Two of three resistant strains were also found by RHA, which revealed point mutations in the domain V region of the 23S rRNA. We report here clarithromycin-resistant clinical isolates of M. avium with the different characteristics from those of the resistant strains reported from earlier studies. PMID- 21254241 TI - Development of simultaneous detection of total prostate-specific antigen (tPSA) and free PSA with rapid bead-based immunoassay. AB - OBJECTIVE: Prostate-specific antigen (PSA) is the most important biochemical tumor marker for the early detection of prostate cancer; however, its diagnostic specificity is low. Therefore, free PSA (fPSA) test is recommended as an adjunct to increase the specificity. However, all the current technology only allows detecting one biomarker at one time. In this study, we reported a flexible bead based immunoassay to measure total PSA (tPSA) and fPSA simultaneously. MATERIALS AND METHODS: We used the Luminex xMAP bead array technology to measure tPSA and fPSA at one time, employing two mouse monoclonal anti-PSA antibodies (5G6 and 8A6) for coating and another mouse monoclonal anti-PSA antibody (5A6) for detection. Then we compared the data of Luminex assay with that of the conventional enzyme-linked immunosorbent assay (ELISA). RESULTS: The assay was fast with a wide dynamic range. The lower detection limit for tPSA and fPSA were 2.3 and 1.3 pg/ml. The inter-assay coefficients for tPSA and fPSA were between 5.64 and 7.65%, and the intra-assay coefficients for tPSA and fPSA were between 4.15 and 5.89%. A close correlation between the new assay and the conventional ELISA was observed. CONCLUSIONS: The bead-based platform is rapid, sensitive, and less expensive, which allows both single sample and high-throughput measurement of tPSA and fPSA over a wide range of concentrations. PMID- 21254242 TI - Effect of apolipoprotein E genotypes on incidence and development of coronary stenosis in Iranian patients with coronary artery disease. AB - BACKGROUND: Apolipoprotein (apo) E polymorphism plays a significant role in the development of coronary disease, but their involvement in coronary artery stenosis (CAS) is controversial. Therefore, the purpose of this study was to investigate the effects of this polymorphism on atherosclerosis, and severity and extent of CAS in unrelated Iranian population. METHODS: DNA was isolated from 390 study participants and APOE genotypes were determined utilizing the polymerase chain reaction and restriction fragment length polymorphism. RESULTS: The APOE epsilon4 and -epsilon2 allele frequencies were significantly higher in the CAS patients than in the control group (P<0.05). The association of Apo E polymorphism with the severity of stenosis was evaluated, which is according to the result that apolipoprotein E alleles were not significantly different when compared with the severity of stenosis (chi(2) =0.84, P>0.05). CONCLUSION: Our results suggest that APOE-epsilon4 is a risk factor for stenosis but does not has any effect on the severity of this disease. PMID- 21254243 TI - Phagocytosis and nitric oxide levels in rheumatic inflammatory states in elderly women. AB - BACKGROUND: Very few studies have investigated, in the elderly, the effect of rheumatic inflammatory states on phagocyte function and free radical production. The objective of this article is to evaluate phagocytosis by neutrophils and the production of nitric oxide (.NO) by monocytes in elderly women recruited among patients of the Brazilian Public Health System. METHODS: Forty patients aged more than 60 years with rheumatic inflammatory diseases were studied. Phagocytosis was measured by flow cytometry. .NO production was measured by the total nitrite assay and conventional inflammation markers were determined. Data were analyzed with the Mann-Whitney nonparametric test and P<0.05 was considered significant. RESULTS: C-reactive protein levels and white blood cell counts were significantly higher in inflammation than in the control group (P<0.05). The phagocytosis fluorescence intensity per neutrophil and the percentual of neutrophils expressing phagocytosis were significantly higher (P<0.05) in the test than in the control group. Furthermore, there was significant .NO overproduction by monocytes, (P<0.05). CONCLUSION: Phagocytosis and .NO production are affected by rheumatic states. This suggests that the increased .NO levels may play a part in the increased oxidative stress in rheumatic diseases in elderly women. PMID- 21254244 TI - Development and validation of 14 human serum protein assays on the Roche cobas(r) c 501. AB - Many laboratories rely on dedicated nephelometers and turbidimeters for the measurement of serum proteins. There are, however, a number of chemistry analyzers that offer open channel configurations for end-user applications. We developed and validated 14 human serum protein assays (alpha(1)-antitrypsin, alpha(2)-macroglobulin, albumin, apolipoproteins AI and B, complement components 3 and 4, haptoglobin, immunoglobulins A, G, and M, orosomucoid, transferrin, and transthyretin) on the Roche cobas((r)) c 501. We obtained excellent precision at low, normal, and high physiologic concentrations of each protein (within-run imprecision CVs <=2.5%, total imprecision CVs <=3.6%). Linearity for each method was within 5% of the expected value throughout the calibration range, and method comparison studies to commercial assays from Roche or Siemens were in good agreement (r>0.975). We observed no significant interference from bilirubin (up to 414 mg/l), hemoglobin (up to 8.9 g/l), triglyceride (up to 28 g/l), or rheumatoid factor (up to 3,930 IU/ml). Calibration was stable for at least 14 days. The instrument's small reaction cell allowed us to conserve nearly 60% of our specimen and reagent volume compared with our previous system. These newly developed assays provide precise and accurate results with high throughput, but without the associated cost of a dedicated instrument. PMID- 21254245 TI - Primary blood TSH/back up TSH measurements: an improved approach for neonatal thyroid screening. AB - OBJECTIVE: Neonatal hypothyroidism is one of the most common endocrine disorders related to mental impairment and growth retardation in newborns. In many countries, the neonatal thyroid screening programs are performed for rapid diagnosis and treatment of hypothyroidism. The major aim of this investigation was to improve the thyroid screening program using primary blood TSH/back up TSH measurements as some patients are missed due to technical and human errors. METHODS: A total of 9,118 neonates were evaluated on the protocol. On top of that, the quality control procedures were applied to improve the sampling technique and the laboratory results. RESULTS: Three missed neonates by current programs using the cutoff point more than 20 mU/l for blood TSH were found by our approach. CONCLUSION: Results showed that the programs based on the primary blood TSH/back up TSH measurements improve the thyroid screening results. PMID- 21254246 TI - Environmental Mutagen Society 41st Annual Meeting, Complex Systems in Biology and Risk Assessment, October 23-27, 2010, Fort Worth, Texas. PMID- 21254247 TI - The neurovascular relationships of the oculomotor nerve. AB - In this study, the arterial supply of the cisternal (initial) and the subcavernous parts of the oculomotor nerve (ON) and the relation between the nerve and adjacent vascular structures like posterior cerebral artery (PCA) and superior cerebellar artery (SCA) were investigated. A total of 140 formalin fixed hemispheres from 70 human cadaveric brains were examined. The nutrient branches reaching the cisternal and subcavernous parts of the ON were investigated, along with branches of adjacent vascular structures penetrating the nerve and passing through it. In the material examined, the ON, after arising from the midbrain, mostly continues laterally between PCA and SCA or between PCA and the rostral SCA trunk. However, in three hemispheres of our specimens, the ON run between the rostral and caudal SCA trunks. We observed that the branches of PCA-P1 segment supplied the cisternal part of the ON in all specimens. In one specimen, the cisternal part of the ON was supplied by a branch arising from the rostral SCA trunk which was also originating from PCA. Differently, in four hemispheres, branches arising from PCA or SCA perforated the cisternal part of the ON and passed through it. We also observed a tortuous caudal trunk of duplicated SCA in one of our specimens and considered it as a rare variation. The anatomy of the ON and its vascular relations is significant in terms of not only understanding the compression syndromes and its vascular dysfunctions, but the exact diagnosis and treatment as well. PMID- 21254248 TI - New anatomical profile of the nasal musculature: dilator naris vestibularis, dilator naris anterior, and alar part of the nasalis. AB - The aim of this study was to clarify the morphology and topography of the dilator naris vestibularis, dilator naris anterior, and alar part of the nasalis. Anatomical variations in the topographic relationships are also described to provide critical data for understanding nasal muscular functions. Anatomical and histological examinations were performed on 40 specimens of embalmed Korean adult cadavers. The dilator naris vestibularis muscle (named by the present authors) was located between the external and vestibular skin of the alar lobule. The muscle fibers radiated along the dome-shaped nasal vestibule. The dilator naris anterior muscle originated from the frontal surfaces of the lateral half of the lateral crus and the accessory alar cartilage adjacent to the lateral crus. The extent of the lower insertion of the dilator naris anterior muscle was at the alar groove. The alar part of the nasalis originated with the transverse part of nasalis from the maxilla. It ascended to attach to the alar crease and the adjacent deep surface of external skin of the alar lobule. These findings may provide anatomical knowledge required to understand the structure and function of these nasal muscles such as during rhinoplasty or other surgery of the face. PMID- 21254250 TI - Topochemical manipulation of perovskites: low-temperature reaction strategies for directing structure and properties. AB - Topochemical reaction strategies offer an important low-temperature (<500 degrees C) approach to the conscious manipulation of various inorganic host materials, allowing access to compounds that cannot be prepared by standard high temperature methods. As the utility of these strategies continues to expand, researchers will be able to more effectively target materials with technologically significant properties. This Progress Report presents recent advances in topochemical reaction strategies as applied to perovskite and perovskite-related compounds. Emphasis is placed on structural modifications and corresponding variations in properties. Additionally, the future prospects of this approach to the rational design of intricate target compounds are discussed. PMID- 21254251 TI - Recent trends in surface characterization and chemistry with high-resolution scanning force methods. AB - The current status and future prospects of non-contact atomic force microscopy (nc-AFM) and Kelvin probe force microscopy (KPFM) for studying insulating surfaces and thin insulating films in high resolution are discussed. The rapid development of these techniques and their use in combination with other scanning probe microscopy methods over the last few years has made them increasingly relevant for studying, controlling, and functionalizing the surfaces of many key materials. After introducing the instruments and the basic terminology associated with them, state-of-the-art experimental and theoretical studies of insulating surfaces and thin films are discussed, with specific focus on defects, atomic and molecular adsorbates, doping, and metallic nanoclusters. The latest achievements in atomic site-specific force spectroscopy and the identification of defects by crystal doping, work function, and surface charge imaging are reviewed and recent progress being made in high-resolution imaging in air and liquids is detailed. Finally, some of the key challenges for the future development of the considered fields are identified. PMID- 21254252 TI - Surface potential mapping of SAM-functionalized organic semiconductors by Kelvin probe force microscopy. PMID- 21254253 TI - Vertically aligned graphene layer arrays from chromonic liquid crystal precursors. PMID- 21254254 TI - Cooperation of biological and mechanical signals in cardiac progenitor cell differentiation. PMID- 21254255 TI - Multifunctional SWCNT-ZnO nanocomposites for enhancing performance and stability of organic solar cells. PMID- 21254256 TI - Solution-processable organic single crystals with bandlike transport in field effect transistors. PMID- 21254257 TI - Multilayer polymer stacking by in situ electrochemical polymerization for color stable white electroluminescence. PMID- 21254258 TI - Sub-15nm optical fiber nanoimprint lithography: A parallel, self-aligned and portable approach. PMID- 21254259 TI - Chemical sensing with polyaniline coated single-walled carbon nanotubes. PMID- 21254260 TI - Current-induced mass transport in filled multiwalled carbon nanotubes. PMID- 21254261 TI - Curvature-driven reversible in situ switching between pinned and roll-down superhydrophobic States for water droplet transportation. PMID- 21254262 TI - Decoupling local disorder and optical effects in infrared spectra: differentiating between calcites with different origins. PMID- 21254263 TI - Aromaticity in Group 14 homologues of the cyclopropenylium cation. AB - The nature of the bonding and the aromaticity of the heavy Group 14 homologues of cyclopropenylium cations E3H3+ and E2H2E'H+ (E, E' = C-Pb) have been investigated systematically at the BP86/TZ2P DFT level by using several methods. Aromatic stabilization energies (ASE) were evaluated from the values obtained from energy decomposition analysis (EDA) of charged acyclic reference molecules. The EDA-ASE results compare well with the extra cyclic resonance energy (ECRE) values given by the block localized wavefunction (BLW) method. Although all compounds investigated are Huckel 4n+2 pi electron species, their ASEs indicate that the inclusion of Group 14 elements heavier than carbon reduces the aromaticity; the parent C3H3+ ion and Si2H2CH+ are the most aromatic, and Pb3H3+ is the least so. The higher energies for the cyclopropenium analogues reported in 1995 employed an isodesmic scheme, and are reinterpreted by using the BLW method. The decrease in the strength of both the pi cyclic conjugation and the aromaticity in the order C ? Si>Ge>Sn>Pb agrees reasonably well with the trends given by the refined nucleus independent chemical shift NICS(0)pizz index. PMID- 21254264 TI - Pentanary cross-diffusion in water-in-oil microemulsions loaded with two components of the Belousov-Zhabotinsky reaction. AB - We measure cross-diffusion coefficients in a five-component system, an aerosol OT (AOT) water-in-oil microemulsion loaded with two constituents of the Belousov Zhabotinsky (BZ) reaction (H(2) O/AOT/BZ1/BZ2/octane). The species BZ1 is either NaBr, an inhibitor of the BZ reaction, or ferroin, a catalyst for the reaction. As species BZ2, we choose Br(2) , an intermediate in the reaction. The cross diffusion coefficients between BZ1 and BZ2 are found to be negative, which can be understood in terms of complexation between these species. Using a four-variable model for the BZ reaction, we find that the cross-diffusion coefficients measured here can lead to a noticeable shift in the onset of Turing instability in the BZ AOT system. PMID- 21254265 TI - Photoactive Ru(II) -polypyridyl complexes that display sequence selectivity and high-affinity binding to duplex DNA through groove binding. AB - The duplex-DNA binding properties of a nonintercalating polypyridyl ruthenium(II) complex that incorporates a linear extended ligand with a catechol moiety has been probed with a variety of photo- and biophysical techniques. These studies reveal that the complex groove binds to DNA sequences biphasically, and displays binding constants equivalent to those of high-affinity metallointercalators. The complex also displays preferential binding to AT-rich sequences. Changes in the structure of the coordinated catechol ligand and the incorporation of intercalating ancillary ligands into the complex were found to modulate both the optical-binding response and binding parameters of the system, which indicates that the catechol moiety plays a crucial role in the observed enhancement to binding affinities. PMID- 21254266 TI - Pd-catalyzed direct and selective C-H functionalization: C3-acetoxylation of indoles. PMID- 21254267 TI - Construction of tetranuclear macrocycles through C-H activation and structural transformation induced by [2+2] photocycloaddition reaction. AB - A series of binuclear complexes [{Cp*Ir(OOCCH(2)COO)}(2)(pyrazine)] (1b), [{Cp*Ir(OOCCH(2)COO)}(2)(bpy)] (2b; bpy=4,4'-bipyridine), [{Cp*Ir(OOCCH(2)COO)}(2)(bpe)] (3b; bpe=trans-1,2-bis(4-pyridyl)ethylene) and tetranuclear metallamacrocycles [{(Cp*Ir)(2)(OOC-C=C-COO)(pyrazine)}(2)] (1c), [{(Cp*Ir)(2)(OOC-C=C-COO)(bpy)}(2)] (2c), [{(Cp*Ir)(2)(OOC-C=C-COO)(bpe)}(2)] (3c), and [{(Cp*Ir)(2)[OOC(H(3)C(6))-N=N-(C(6)H(3))COO](pyrazine)}(2)] (1d), [{(Cp*Ir)(2)[OOC(H(3)C(6))-N=N-(C(6)H(3))COO](bpy)}(2)] (2d), [{(Cp*Ir)(2)[OOC(H(3)C(6))-N=N-(C(6)H(3))COO](bpe)}(2)] (3d) were formed by reactions of 1a-3a {[(Cp*Ir)(2)(pyrazine)Cl(2)] (1a), [(Cp*Ir)(2)(bpy)Cl(2)] (2a), and [(Cp*Ir)(2)(bpe)Cl(2)] (3a)} with malonic acid, fumaric acid, or H(2)ADB (azobenzene-4,4'-chcarboxylic acid), respectively, under mild conditions. The metallamacrocycles were directly self-assembled by activation of C-H bonds from dicarboxylic acids. Interestingly, after exposure to UV/Vis light, 3c was converted to [2+2] cycloaddition complex 4. The molecular structures of 2b, 1c, 1d, and 4 were characterized by single-crystal x-ray crystallography. Nanosized tubular channels, which may play important roles for their stability, were also observed in 1c, 1d, and 4. All complexes were well characterized by (1)H NMR and IR spectroscopy, as well as elemental analysis. PMID- 21254268 TI - Catalytic asymmetric synthesis of gamma-substituted vinyl sulfones. AB - A fast new entry for the stereoselective construction of gamma-substituted vinyl sulfones is presented. The key for success is the use of a readily available chiral secondary amine catalyst that allows the use of base-sensitive beta nitroethyl sulfones as masked beta-sulfonyl vinyl anions in conjugate additions. The method performed in a three-step one-pot operation gives access to a great variety of vinyl sulfones in good yields and with excellent enantioselectivities. The method has also been extended to other relatively base-sensitive beta electron-withdrawing-substituted nitroalkanes to afford products with manifold functionality, providing a quick entry to very attractive synthetic intermediates for organic synthesis. PMID- 21254269 TI - Synthesis and conformational analysis of alpha,beta-difluoro-gamma-amino acid derivatives. PMID- 21254270 TI - On the reaction of elemental tin with alcohols: a straightforward approach to tin(II) and tin(IV) alkoxides and related tinoxo clusters. PMID- 21254271 TI - Antinociceptive activity of aerial parts of Polygonatum verticillatum: attenuation of both peripheral and central pain mediators. AB - Polygonatum verticillatum All. is used traditionally as an analgesic and plant diuretic. The methanol extract of aerial parts of Polygonatum verticillatum (PA) was assessed in various experimental paradigms. The pain threshold in the form of abdominal constriction induced by acetic acid was significantly (p < 0.01) inhibited by PA at test doses (50, 100 and 200 mg/kg). In the formalin test, PA elicited a significant (p < 0.01) analgesic activity in both phases and strongly attenuated the formalin-induced flinching behaviour. The hot plate test was used to evaluate central involvement in the analgesic profile of PA. The PA significantly relieved thermal-induced pain. From a mechanistic point of view, the central antihyperalgesic activity was tested for antagonism with naloxone, but no antagonism was observed. The current investigations suggest that the active constituent(s) in PA has an analgesic profile with predominant peripheral activity which is augmented by an opioid independent central effect. In the diuretic assay, PA (300 and 600 mg/kg) showed mild insignificant diuretic activity. Our study rationalized the traditional use of Polygonatum verticillatum in the treatment of painful conditions. PMID- 21254272 TI - Antidiabetic effect of oleanolic acid: a promising use of a traditional pharmacological agent. AB - Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia. Although the clear mechanisms of DM and insulin resistance are still to be cleared, it has been well documented that reactive oxygen species (ROS) play a pivotal role in DM and multiple types of insulin resistance. For the past few years, natural substances have been shown to have the potential to treatment DM. Attention has been especially focused on plants rich in triterpenoids, which generally show antioxidant and antiglycation effect. In our previous studies, it was shown that oleanolic acid (OA), a natural triterpenoid and an aglycone of many saponins, is a potent antioxidant acting as not only a free radical-scavenger through direct chemical reactions but also as a biological molecule, which may enhance the antioxidant defenses. The present study aimed to investigate the potential antidiabetic effect of OA. Oleanolic acid showed a significant blood glucose-lowering and weight-losing effect in diabetic animals induced by streptozotocin (STZ). In the insulin resistant model, it was also shown that OA may promote insulin signal transduction and inhibit oxidative stress-induced hepatic insulin resistance and gluconeogenesis, in which process the phosphorylation of ERK and the protective effect on mitochondrial function may be involved. These findings may significantly better the understanding of the pharmacological actions of OA and advance therapeutic approaches to DM. PMID- 21254273 TI - Isolation of diacyl glycerol acyl transferase (DGAT) inhibitors from Pachydictyon coriaceum. AB - The pharmacological inhibition of acyl CoA:diacylglycerol acyltransferase (DGAT, EC 2.3.1.20) has emerged as a target for the treatment of obesity and type 2 diabetes. Chromatographic analysis of the brown alga, Pachydictyon coriaceum, led to the isolation of diterpene dictyol E and hydroxyisocrenulatin. Pharmacological assay of these compounds demonstrated DGAT inhibitory activity with IC50 values of 46.0 MUM and 23.3 MUM, respectively. PMID- 21254274 TI - What is the role of unripe Rubus coreanus extract on penile erection? AB - The effect of unripe Rubus coreanus extract on rabbit penile corpus cavernosum (PCC) was evaluated. Penises were obtained from healthy male New Zealand white rabbits (2.5-3.0 kg). The pre-contracted penis with phenylephrine (Phe, 10 MUM) was treated with various concentrations of an extract of unripe R. coreanus (0.5, 1, 2, 3 and 4 mg/mL). The change in penile tension was recorded, cyclic nucleotides in the perfusate and the PCC were measured by radioimmunoassay, and the expression of neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) in the perfused PCC were measured by western blotting. The interaction between unripe R. coreanus and sildenafil was also evaluated. The PCC relaxation induced by the extracts of R. coreanus was in a concentration dependent manner and enhanced sildenafil-induced PCC relaxation. The perfusion of penile cavernous tissue with the unripe R. coreanus extract increased cGMP and cAMP in the tissue and in the perfusate and the expression of eNOS and nNOS in the tissue. The unripe R. coreanus extract exerts a relaxing effect on penile cavernous tissue in part by activating the NO-cGMP system and it may improve erectile dysfunction (ED), which does not completely respond to sildenafil citrate. PMID- 21254275 TI - Electron ionization mass spectral studies of bridgehead-substituted norbornan-2 ones: camphor derivatives. AB - The electron ionization (EI) mass spectra of a series of bridgehead-substituted 3,3-dimethylnorbornan-2-ones, derived from natural (1R)-(+)-camphor, have been studied and their cleavage mechanisms rationalized on the basis of the substituent shifts as well as on the identification of relevant peaks through accurate mass measurements and collision-induced dissociation (CID) tandem mass spectrometric experiments. The fragmentation patterns are very dependent on both the structural nature and the electronic properties of the bridgehead substituent. The driving force for the main fragmentation pathways are competitive cleavages of the C(1)-C(2) and C(2)-C(3) bonds directed by the bridgehead substituent and either the gem-dimethyl or carbonyl groups. These cleavages lead to distonic ions in which the charge is preferentially located either at the C(1), C(2) or C(3) positions depending on the electronic character and structural nature of the bridgehead substituent. This charge distribution determines the subsequent rearrangements and fragmentations. PMID- 21254276 TI - Uncertainty evaluation in the analysis of biological samples by sector field inductively coupled plasma mass spectrometry. Part B: measurements of As, Co, Cr, Mn, Mo, Ni, Sn and V in human serum. AB - This protocol was developed to estimate the uncertainty of measurements in the sector field inductively coupled plasma mass spectrometry analysis of As, Co, Cr, Mn, Mo, Ni, Sn and V in human serum by utilizing in-house validation data. The approach is outlined in the Eurachem/Citac Guide and other relevant publications. The results generated were the followings: (i) coefficients of regression >0.9995 over two orders of magnitude of metal concentration; (ii) method quantification limits between 0.05 ug/L (Cr, Mn) and 0.49 ug/L (As); (iii) mean trueness checked against a certified reference material between 95.4% (As) and 107.7% (Ni); (iv) repeatability better than 10.2% over the range 0.1-2.0 ug/L; (v) reproducibility better than 12.0% over the range 0.1-2.0 ug/L; and (vi) expanded uncertainty budget comprised between 14.7% (Mn) and 27.9% (Cr) over the range 0.1-2.0 ug/L. PMID- 21254277 TI - Oxygen, pH, and oral-aboral axis specification in the sea urchin embryo. PMID- 21254278 TI - N-acetyl-L-cysteine counteracts oxidative stress and prevents H2O2 induced germ cell apoptosis through down-regulation of caspase-9 and JNK/c-Jun. AB - The mechanism of H(2)O(2) induced oxidative stress leading to male germ cell apoptosis was earlier reported from our laboratory. In the present study, we investigated the mechanisms by which N-acetyl-L-cysteine (NAC, which is highly cell specific with strong antioxidant and anti-genotoxic properties), stimulated cell survival under such conditions. Co-incubation with 5 mM NAC significantly (P<0.001) reduced the germ cell apoptosis induced by 10 uM H(2)O(2). Lipid peroxidation was brought down with significant restoration of activities of antioxidant enzymes, SOD, GST, and catalase. Expression of pro-apoptotic marker, Bax up-regulated following H(2)O(2) exposure, was reversed back to control levels. In contrast, expression of anti-apoptotic Bcl-2 and phospho-Akt revealed a completely opposite trend. While caspase-8 activity remained unaffected, NAC successfully attenuated the increased activities of caspase-3 and -9 in the H(2) O(2) treated cells. Simultaneously, the increased expression of caspase-9, phospho-JNK, and phospho-c-Jun after H(2)O(2) treatment was down-regulated by NAC. The above findings indicate that the mechanism of inhibition of H(2)O(2) induced male germ cell apoptosis by NAC is mediated through regulation of caspase 9 and JNK. PMID- 21254279 TI - Characterization of S100A11, a suppressive factor of fertilization, in the mouse female reproductive tract. AB - We recently found that Xenopus dicalcin, present in the extracellular egg-coating envelope, suppresses the efficiency of fertilization in vitro through binding to envelope-constituent glycoproteins. In the present study, we explored the mouse counterpart of Xenopus dicalcin, specifically its localization in the female reproductive tract and its action on mouse fertilization. Our homology and phylogenetic analyses using known S100 proteins showed that S100A11 is most closely related to Xenopus dicalcin. S100A11 was localized in the cytosol of luteal cells, but not in the follicle, in the mouse ovary, and also in the cytosol of the oviductal epithelial cells. In addition, our quantitative analyses revealed preferential expression of S100A11 in the ampullary region of the oviduct and at the estrus stage during the mouse estrous cycle. In the cumulus cell-oocyte complex dissected from the oviduct following ovulation, S100A11 was present in the plasma membrane of cumulus cells, but not in the zona pellucida, which is comparable with Ca(2+) -dependent binding of exogenously applied S100A11 to the plasma membrane of cumulus cells. Pretreatment of the cumulus cell-oocyte complex with recombinant S100A11 substantially reduced the efficiency of in vitro fertilization, but S100A10, the next closest S100 protein to Xenopus dicalcin, had no effect. These results suggested that S100A11 is the mouse counterpart of Xenopus dicalcin, suppresses the fertilization process through its action on cumulus cells, and thereby plays a key role in fertilization success in the mouse. PMID- 21254280 TI - Binding of nickel to testicular glutamate-ammonia ligase inhibits its enzymatic activity. AB - Exposure to nickel has been shown to cause damage to the testis in several animal models. It is not known if the testis expresses protein(s) that can bind nickel. To test this, we used a nickel-binding assay to isolate testicular nickel-binding proteins. We identified glutamate-ammonia ligase (GLUL) as a prominent nickel binding protein by mass spectrometry. Protein analysis and reverse transcriptase polymerase chain reaction showed that GLUL is expressed in the testis, predominantly in interstitial cells. We determined that GLUL has a higher affinity for nickel than for its regular co-factor manganese. We produced an enzymatically active, recombinant GLUL protein. Upon binding, nickel interferes with the manganese-catalyzed enzymatic activity of recombinant GLUL protein. We also determined that GLUL activity in testes of animals exposed to nickel sulfate is reduced. Our results identify testicular GLUL as the first testicular protein shown to be affected by nickel exposure. PMID- 21254281 TI - Recombinant human bone morphogenetic protein-2 and pancreatic cancer: a retrospective cohort study. AB - PURPOSE: To assess whether use of recombinant human bone morphogenetic protein-2 (rhBMP-2) during lumbar spinal fusion surgery affects subsequent risk of pancreatic cancer. METHODS: Using US Medicare claims data, we performed a retrospective cohort study of patients who underwent lumbar spinal fusion surgery between October 2003 and December 2005. The study population, all >66 years, was identified from procedure codes for lumbar fusion. Claims for a bone morphogenetic protein (BMP) served as a proxy for rhBMP-2 exposure (another BMP product shared the same code). Pancreatic cancer was identified from claims indicating this diagnosis and cancer-specific therapy. We used Cox proportional hazard regression to estimate hazard ratios (HRs) and 95%CIs. RESULTS: Of the 93,654 patients in the study, the mean age was 75 years, and 16.5% had claims for BMP. During a mean 1.4 years of follow-up, 91 patients were diagnosed with pancreatic cancer (eight in the BMP- and 83 in the non-BMP cohort). Consistent with previous research, pancreatic cancer was associated with older age, male gender, black race, and diabetes mellitus. Compared to those who did not receive BMP, patients exposed to BMP were not at increased risk of pancreatic cancer (adjusted HR=0.70, 95%CI: 0.34-1.45). A chart review substudy validated the exposure measure; 52/55 patients with claims for BMP received rhBMP-2. CONCLUSIONS: In this large study of elderly patients who underwent lumbar fusion surgery, exposure to BMP was not associated with an increased risk of pancreatic cancer. PMID- 21254282 TI - Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. AB - PURPOSE: Uncertain short- and long-term cancer risks with anti-TNF therapies is a concern, and led to a recent black box warning. This meta-analysis, requested by the European Medicines Agency, aimed at better assessing short-term risks by using meta-analytic techniques based on individual patient data from all corporate-sponsored randomized controlled trials (RCTs) of adalimumab, etanercept, and infliximab. METHODS: All 74 RCTs of TNF inhibitors of at least 4 weeks duration were provided to independent investigators, including case narratives for events occurring between trial start until 30 days after planned end of treatment and indicating a possible cancer. Relative risks were estimated using Bayesian piecewise exponential models. RESULTS: One hundred thirty (0.84%) of 15,418 individuals randomized to anti-TNF therapy were diagnosed with cancer, compared to 48 (0.64%) of 7486 individuals randomized to comparators. The relative risks associated with all anti-TNF were 0.99 (95%CI 0.61-1.68) for cancers excluding non-melanoma skin cancer (NMSC), and 2.02 (95%CI 1.11-3.95) for NMSC. There were indications of differences in the relative risks for the three anti-TNF drugs, but also of differences across the cancer rates in the three comparator arms for adalimumab, etanercept, and infliximab. CONCLUSIONS: Despite a reassuring overall short-term risk, we could neither refute nor verify that individual anti-TNF therapies affect the short-term clinical emergence of cancer. Despite representing the best available evidence, statistical precision, and differences in baseline cancer risk and reporting detail between trials of adilumumab, etanercept, and infliximab hampered distinction of drug-specific from trial effects, illustrating the challenges in safety-assessments using RCT meta analyses. Long-term risk assessment requires observational studies. PMID- 21254283 TI - Use of antidepressants and NSAIDs in relation to mortality in long-term breast cancer survivors. AB - PURPOSE: The aim of this study was to assess the post-diagnosis use of antidepressants and non-steroidal anti-inflammatory drugs (NSAIDs) in relation to all-cause, breast cancer, and cardiovascular disease (CVD) mortality among long term breast cancer survivors. METHODS: A cohort of 3058 breast cancer survivors, who previously participated in a series of case-control studies diagnosed between 1988 and 1999 in Wisconsin. Cancer survivors completed a self-administered mailed follow-up questionnaire in 1998-2001 that addressed use of medications post diagnosis, including antidepressants and NSAIDs. Vital status information was obtained through the National Death Index through 31 December 2006. We used multivariable Cox proportional hazards modeling to estimate hazard ratios and 95% confidence intervals (CI). RESULTS: We identified 463 deaths due to all-causes, 163 due to breast cancer, and 93 due to CVD during follow-up. Among women who had used any antidepressant after a breast cancer diagnosis, there was an increased risk of all-cause (adjusted HR=1.50, 95%CI: 1.12-2.02) and CVD mortality (HR=2.42, 95%CI: 1.21-4.83), but not breast cancer mortality (HR=0.93, 95%CI: 0.55-1.56). The use of NSAIDs after diagnosis was not associated with all-cause (HR=0.87, 95%CI: 0.69-1.18), breast cancer mortality (HR=0.69, 95%CI: 0.44-1.10), or CVD (HR=0.97, 95%CI: 0.57-1.65). CONCLUSIONS: The use of antidepressants or NSAIDS was not related to breast cancer mortality in long-term breast cancer survivors. In these women, however, antidepressants may increase the risk of all cause mortality. PMID- 21254285 TI - Valproate attenuates the risk of myocardial infarction in patients with epilepsy: a nationwide cohort study. AB - PURPOSE: Patients with epilepsy have increased risk of myocardial infarction (MI). Valproate can exert anti-atherosclerotic effects. We therefore examined the risk of MI in patients with epilepsy receiving valproate. METHODS: Two cohorts of patients with valproate-treated epilepsy and sex- and age-matched individuals (controls) from the general Danish population were identified by individual-level linkage of nationwide registries and followed for 10 years. The two cohorts comprised patients treated with valproate at baseline and valproate-naive patients initiating treatment in the study period, respectively. The hazard ratios (HR) of MI and all-cause death were estimated by two different Cox proportional-hazard models; valproate treatment was analysed as a baseline categorical covariate in the first cohort and as a time-dependent exposure covariate in the second cohort. RESULTS: The two cohorts comprised 53,086 and 102,003 individuals, respectively. In the first cohort, the risk of MI was decreased (HR 0.75, 95% confidence interval 0.59-0.97) while the risk of all cause death was increased (HR 2.11, 95% confidence interval 1.95-2.28), compared to the controls. In the second cohort, the risk of MI was decreased (HR 0.62, 95% confidence interval 0.53-0.73) while the risk of all-cause death was similar to the controls (HR 1.02, 95% confidence interval 0.97-1.07). CONCLUSIONS: In this nationwide pharmacoepidemiological study, we found a consistent association between valproate treatment and a reduced risk of MI in patients with epilepsy. PMID- 21254284 TI - Risks of congenital malformations and perinatal events among infants exposed to calcium channel and beta-blockers during pregnancy. AB - PURPOSE: Calcium channel blockers and beta-blockers (BBs) are widely used during pregnancy, but data on their safety for the developing infant are scarce. We used population-based data from 5 HMOs to study risks for perinatal complications and congenital defects among infants exposed in-utero. METHODS: We studied women older than 15 years delivering an infant between 1/1/96 and 12/31/00, who had been continuously enrolled with prescription drug coverage for >= 1 year prior to delivery. Information on prescription drug dispensings, inpatient, and outpatient diagnoses and procedures was obtained from automated databases at each HMO. RESULTS: There were 584 full-term infants exposed during pregnancy to BBs and 804 full-term infants exposed to calcium-channel blockers, and over 75,000 unexposed mother-infant pairs with >= 30 days follow-up. Infants exposed to BBs in the third trimester of pregnancy had over threefold increased risk for hypoglycemia (RR 3.1; 95% CI 2.2, 4.2) and an approximately twofold increased risk for feeding problems (RR 1.8; 95% CI 1.3, 2.5). Infants exposed to calcium-channel blockers in the third trimester had an increased risk for seizures (RR 3.6 95% CI 1.3, 10.4). Chart review confirmed the majority of the exposed seizure and hypoglycemia cases. There were no increased risks for congenital anomalies among either group of infants, except for the category of upper alimentary tract anomalies; this increased risk was based on only two exposed cases. CONCLUSIONS: Infants whose mothers receive BBs are at increased risk for neonatal hypoglycemia, while those whose mothers take calcium-channel blockers are at increased risk for neonatal seizures. PMID- 21254286 TI - Self-reported prevalence of hypersensitivity reactions against drugs among medical students: does awareness cause any difference? AB - PURPOSE: True epidemiologic data on hypersensitivity reactions to drugs are scarce. More accurate data may be obtained in more specific clinical settings. Considering their educational background, medical students may be an appropriate target audience for evaluating prevalence of drug hypersensitivity. This study is designed to determine the prevalence of self-reported drug hypersensitivity alongside related factors among young adults. METHODS: A structured questionnaire was administered to the students. RESULTS: A total of 1267 students (mean age: 21.71+1.90 years, F/M: 648/619) from all grades responded to the survey. The mean prevalence of self-reported drug hypersensitivity was 4.7% (60/1267). The most frequently involved drugs were beta-lactam antibiotics (55%) followed by non steroidal anti-inflammatory drugs (28%). The most commonly reported clinical presentations were cutaneous (43.3%), followed by systemic (36.8%), cardiovascular (8.3%) and respiratory (8.3%) symptoms. Factors related with reported reactions were higher grades (p=0.015, OR: 2.09), female gender (p=0.006, OR: 2.13), personal history of allergic diseases (p=0.001, OR: 2.64), and family history of drug hypersensitivity (p<0.001, OR: 5.78). Half of the students sought medical help during the acute stage of their reaction. Only 3.2% of the cases have been referred to an allergist for further evaluation. CONCLUSION: This study, the first of its kind in Turkey, with medical students showed that self-reported hypersensitivity reactions to drugs is highly prevalent and its prevalence seems to be affected by awareness of the individuals in addition to previously reported risk factors. The education of both patients and physicians on the management of drug hypersensitivity seems to be necessary. PMID- 21254287 TI - Enhanced physician adherence to antibiotic use guidelines through increased availability of guidelines at the time of drug ordering in hospital setting. AB - PURPOSE: Some studies have shown that making practice guidelines accessible to physicians when they are making clinical decisions could improve prescribing practices. The aim of the study was to assess the benefit of impact on physician adherence of the intervention that consisted of embedding previously paper-based antibiotic guidelines in the computerized physician drug order entry system of a teaching hospital in order to make these guidelines available to physician at the time of antibiotic ordering. Before the intervention, these guidelines were available in booklet form in all the wards of the hospital. METHODS: Adherence to guidelines was evaluated in 471 consecutive antibiotic orders for pneumonia, 104 just before and 367 just after the intervention. The evaluation criteria were: the choice of the antibiotic relative to the context of acquisition of pneumonia, the daily dose, the planned duration of treatment. Evaluation of antibiotic orders was performed at the initiation of antibiotic treatment. RESULTS: The intervention was followed by a significant decrease in the proportion of antibiotic orders containing at least one criterion of non-conformity to the guidelines, respectively, 33% after vs. 51% (p<0.001) before the intervention. Proportion of non-conform orders decreased in the post- vs. pre-intervention period for the daily dosage of antibiotics, respectively, 12.2% vs. 26.9% (p<0.001), for the planned duration of treatment, respectively, 7.3% vs. 18.3% (p<0.001), whereas for the choice of antibiotics relative to the context of acquisition of pneumonia, the improvement failed to reach statistical significance, respectively, 18.2% vs. 25% (p=0.12). CONCLUSION: In this study, the increased availability of antibiotic guidelines at the time of drug ordering, combined with a periodical reinforcement educational round, was associated with an enhanced physician adherence to these guidelines. PMID- 21254288 TI - Definition of patients treated with evidence based drugs in absence of prescribed daily doses: the example of acute myocardial infarction. AB - PURPOSE: Define patients treated with evidence-based drugs in a cohort discharged after acute myocardial infarction (AMI) in absence of prescribed daily doses (PDD). To compare different drug use measures and analyze their impact on the effect estimate of risk factors related to drug use. METHODS: AMI patients discharged in Rome during 2006-2007 were selected from the Hospital Information System. Drugs claimed during the 12 months after discharge were retrieved. Measures of drug use were defined as: 'continuity' (one prescription each follow up quarter-year) and the 'proportion of days covered' calculated by defined daily doses (DDDs) or pill counts (PCs) (>= 80% of individual follow-up). Poly-therapy was defined through the same drug use measure for all drug groups. Kappa index was calculated to analyze the concordance between measures. For each measure we estimated the effect of age, gender and Percutaneous Transluminal Coronary Angioplasty (PTCA) on poly-therapy. RESULTS: Poly-therapy rates varied between 11.5 and 37.8% in the cohort and between 17.3 and 56.9% in patients with at least one prescription for all drugs. Concordance between all measures was high for antiplatelets (k=0.74) and very low for beta-blockers (k=0.22). According to measures used, gender and older age effects slightly varied, while PTCA remained a strong determinant of drug use. CONCLUSIONS: Different measures of exposure to drug treatment may affect the estimate of the proportion of treated patients and the effect estimates of risk factors. Drug dispense registries are useful, but it is necessary to develop and validate methodologies in absence of PDD. PMID- 21254289 TI - Increasing off-label use of antipsychotic medications in the United States, 1995 2008. AB - OBJECTIVE: To evaluate patterns of antipsychotic use. DESIGN, SETTING, AND MEASUREMENTS: We used nationally representative data from the IMS Health National Disease and Therapeutic Index to describe outpatient antipsychotic use. The primary outcome was the volume of visits where antipsychotics were used for specific indications (treatment visits). We also quantified use without U.S. Food and Drug Administration approval (off-label use) and off-label use with compendium data suggesting an uncertain evidence base. RESULTS: Antipsychotic use increased from 6.2 million (M) treatment visits (95% CI, 5.4-7.0) in 1995 to 16.7 M visits (15.5-18.2) in 2006, then declined to 14.3 M visits (13.0-15.6) by 2008. A shift occurred from typical agents in 1995 (84% of all antipsychotic visits) to atypical agents by 2008 (93%). As they declined, typical medications shifted toward use in schizophrenia (30% in 1995 to 48% 2008). In contrast, use of atypical agents expanded for bipolar affective disorder (10 to 34%), remained stable for depression (12 to 14%), and declined for schizophrenia (56 to 23%). Overall, antipsychotic use for indications without FDA approval increased from 4.4 M visits in 1995 to 9.0 M in 2008. The estimated cost associated with off label use in 2008 was US$6.0 billion. CONCLUSIONS: Atypical use has grown far beyond substitution for the now infrequently used typical agents. Antipsychotics are increasingly used for conditions where FDA approval and associated clinical evidence is less certain. Despite the value of innovation, the benefits of widening atypical antipsychotic use should be weighed against their cost, regulatory status, and incomplete nature of available evidence. PMID- 21254290 TI - Do people regard cheaper medicines effective? Population survey on public opinion of generic substitution in Finland. AB - PURPOSE: Generic substitution (GS) is an important way to decrease medical costs. We aimed to study the opinions and attitudes of Finnish people about GS five years after it was introduced, the reasons for substituting and what people think about generic medicines. METHODS: We sent a postal survey to a random stratified population sample of 3000 Finnish people aged at least 18 years in 2008. The random sample was drawn from five mainland counties. The sampling was conducted by the Finnish Population Register Centre. The response rate was 62% (n=1844) after exclusion of unobtainable addressees (n=34). RESULTS: Most of the respondents (70.9%) considered GS a good law reform. However, there were many respondents who were unsure about their opinion (26.9%). The respondents also held the opinion that cheaper medicines are effective (80.9%) and that GS does not cause any risk to drug safety (84.9%). Most of the respondents (88.4%) who had substituted their medicines had not noticed any difference between the previously used and substituted medicines. Two main reasons for substituting were a desire to save money and recommendation by pharmacists. Of the respondents, 16.3% had experience with both substituting and refusing it. The percentage of the respondents who only had experience with refusing GS was 8.6%. Female gender, older age and use of prescription drugs were associated with refusing. CONCLUSIONS: Finnish people consider GS a good reform. They also have confidence in the effect of cheaper medicines. Savings are the main reason for accepting GS. PMID- 21254291 TI - Impact of implementing alerts about medication black-box warnings in electronic health records. AB - BACKGROUND: The Food and Drug Administration issues black-box warnings (BBWs) regarding medications with serious risks, yet physician adherence to the warnings is low. METHODS: We evaluated the impact of delivering BBW-based alerts about drug-drug, drug-disease, and drug-laboratory interactions for prescription medications in outpatients in an electronic health record with clinical decision support. We compared the frequency of non-adherence to all BBWs about drug-drug, drug-disease, and drug-laboratory interactions for 30 drugs/drug classes, and by individual drugs/drug groups with BBWs between the pre- and post-intervention periods. We used multivariate analysis to identify independent risk factors for non-adherence to BBWs. RESULTS: There was a slightly higher frequency of non adherence to BBWs after the intervention (4.8% vs. 5.1%, p=0.045). In multivariate analyses, after adjustment for patient and provider characteristics and site of care, medications prescribed during the pre-intervention period were less likely to violate BBWs compared to those prescribed during the post intervention period (OR 0.67, 95% CI, 0.47-0.96). However, black-box warning violations did decrease after the intervention for BBWs about drug-drug interactions (6.1% vs. 1.8%, p<0.0001) and drug-pregnancy interactions (5.1% vs. 3.6%, p=0.01). CONCLUSIONS: Ambulatory care computerized order entry with prescribing alerts about BBWs did not improve clinicians' overall adherence to BBWs, though it did improve adherence for specific clinically important subcategories. PMID- 21254292 TI - Impact of serum acetaminophen concentration on changes in serum potassium, creatinine and urea concentrations among patients with acetaminophen overdose. AB - BACKGROUND: Acetaminophen overdose may be accompanied by electrolyte disturbances. The basis for electrolyte change appears to be due to increased fractional urinary electrolyte excretion. PURPOSE: This study investigated the impact of serum acetaminophen concentration on changes in serum potassium, creatinine and urea concentrations in patients with acetaminophen overdose. METHODS: This was a retrospective cohort study which included patients admitted to the emergency department and hospital within 24 h of acetaminophen ingestion. The study was conducted over a period of 5 years from 1 January 2004 to 31 December 2008. Data are presented as mean +/- SD and as medians (interquartile range) and groups were compared using independent two-tailed Student t-test. Statistical Package for Social Sciences (SPSS) 15 was used for data analysis. RESULTS: Two hundred and eighty-three patients were studied (44 males and 239 females), mean age 23 +/- 7.5 years. Patients who had a serum acetaminophen concentration above a 'possible toxicity' treatment line were associated with an elevation in serum creatinine concentration (p=0.044) and a reduction in the serum potassium concentration (p<0.001) but were not associated with a reduction in serum urea concentration (p>0.99). During the study period, 63.3% (179 patients) had serum potassium concentrations less than the normal concentration (3.5 mmol/l) and 31.4% (89 patients) had serum urea concentrations less than the normal concentration (2.5 mmol/l). The serum creatinine concentration in all patients was within the normal range. CONCLUSIONS: Acetaminophen appears to cause a concentration-dependent reduction of potassium concentrations and an elevation of creatinine concentrations of short duration (<24 h) after overdose. PMID- 21254293 TI - Stratum-specific positive predictive values of claims for acute pancreatitis among commercial health insurance plan enrollees with diabetes mellitus. AB - PURPOSE: To estimate the positive predictive value (PPV) of claims for acute pancreatitis among initiators of antihyperglycemic drugs in commercial health insurance claims data. METHODS: As part of a systematic study of the occurrence of acute pancreatitis among antihyperglycemic drug initiators (N=260,255) within a large US health insurer's claims database, we identified potential cases of acute pancreatitis and confirmed them through medical record review. Potential cases had an International Classification of Diseases, 9th revision diagnosis code for acute pancreatitis (577.0) associated with an inpatient or emergency department claim. We sought 860 medical records to confirm potential cases and received 585 (70%), which were reviewed by a clinical adjudication committee. We estimated the PPV and 95% confidence intervals (CI) of claims for these medical records and a subset that had the diagnosis code listed in the first position of an inpatient claim. RESULTS: The PPV was 0.50 (95% CI 0.44-0.53) for an acute pancreatitis diagnosis code in any position and 0.60 (95% CI 0.55-0.65) if in the first position of an inpatient claim. The estimated PPV varied across strata defined by patient characteristics and was generally lower within strata where potential risk factors for acute pancreatitis were present. CONCLUSIONS: These data indicate that health insurance claims-based identification of acute pancreatitis might overestimate actual cases and introduce appreciable bias, usually toward the null. Further case confirmation or relative risk correction may be necessary to address potential bias. PMID- 21254294 TI - Clopidogrel and proton pump inhibitors: a clinically meaningful interaction? PMID- 21254295 TI - CCND1 amplification and protein overexpression in oral squamous cell carcinoma of young patients. AB - BACKGROUND: The purpose of this study was to evaluate the correlation of CCND1 amplification and protein overexpression with clinicopathological features and clinical outcomes in patients younger than 41 years old with oral squamous cell carcinoma (SCC). METHODS: Eighty-six young patients with oral SCC were evaluated using the tissue microarray technique, immunohistochemistry, and fluorescence in situ hybridization (FISH). These cases were compared with 116 patients with oral cancer aged over 50 years old (controls). RESULTS: Cyclin D1 overexpression was observed in 47.7% of tumors in the young group and in 32.8% of controls (p = .03). In the young group, CCND1 amplification and overexpression were higher than in the control patients and the differences were statistically significant. In the young group, protein overexpression correlated with diminished disease-free survival (DFS), whereas in the control patients, cyclin D1 overexpression correlated with diminished DFS and overall survival (OS). CONCLUSION: In both groups, amplification had no influence on prognosis. Protein overexpression was an indicator of worse DFS in both groups. PMID- 21254296 TI - Endoscopic-assisted management of chronic sialadenitis. AB - BACKGROUND: Chronic sialadenitis is a relatively common disorder that is frequently referred to head and neck surgeons for diagnosis and management. The management of the disorder is rapidly evolving with the introduction of salivary endoscopy. The purpose of the present study was a review of the indications and techniques of endoscopic-assisted management of chronic sialadenitis at a single U.S. institution. METHODS: This study is a retrospective case series of patients undergoing salivary endoscopy for chronic sialadenitis. Patient clinical information was reviewed to determine endoscopic findings, associated procedures, complications, rate of gland preservation, and early symptom control. RESULTS: A total of 51 patients underwent endoscopic-assisted salivary surgery over a 24 month period. Treatment indications included sialadenitis of unclear etiology (49%), sialadenitis with sialolithiasis (47%), and Sjogren syndrome (4%). Findings included obstructive stricture formation in 22 patients (43%). Associated procedures included sialodochoplasty (41%), steroid infusion (39%), and ductal stenting (8%). Gland preservation was achieved in 40 patients (78%). Of those who were treated with endoscopic-assisted techniques alone, 38 patients (84%) had symptomatic improvement whereas 7 patients (16%) did not improve. Minor complications were observed in 12% of the patients. CONCLUSION: Endoscopic assisted management of chronic sialadenitis is both safe and effective and allows gland preservation with symptom control in the majority of patients. PMID- 21254297 TI - Endoscope-assisted intraoral resection of external dermoid cyst. AB - BACKGROUND: Surgical removal of a dermoid cyst is usually accomplished through an external neck incision. However, this procedure inevitably results in a neck scar. METHODS: We report the case of a 17-year-old woman with a submental mass. We implemented a modified approach to dermoid cyst removal through the floor of the mouth using an endoscope system. RESULTS: The patient received a modified approach to dermoid cyst removal and remains free of disease 6 months after excision. CONCLUSION: Resection of the submental type dermoid cyst can be performed by an intraoral endoscope-assisted approach through the floor of the mouth. We describe the procedure of the endoscope-assisted intraoral resection. PMID- 21254298 TI - Marked aneuploidy and loss of multiple chromosomes are common in autosomal mutants isolated from normal mouse kidney epithelium. AB - Marked aneuploidy and loss of multiple chromosomes are hallmarks of cancer, but whether these events are only present in malignant cells is not known. In prior work, we showed that approximately half of spontaneous autosomal mutants isolated directly from normal kidney epithelium arose from loss of a marker chromosome 8 containing the wild type Aprt gene. Chromosome loss was detected by loss of heterozygosity (LOH) for all chromosome 8 polymorphic loci examined. To determine whether loss of chromosome 8 reflected a larger mitotic event, LOH was examined for polymorphic loci on 11 nonselected chromosomes in Aprt mutants that lost the selected chromosome 8 homologue. LOH events were detected for one or more nonselected chromosomes in 38% of these mutants. The additional LOH events also reflected apparent chromosome loss based on the molecular analysis. Metaphase spreads from mutants that lost chromosome 8 were markedly aneuploid, and chromosome painting revealed reduced levels for any chromosome shown to be lost with the LOH analysis. In contrast, LOH on nonselected chromosomes was infrequent in Aprt mutants exhibiting intragenic events or mitotic recombination for chromosome 8, and marked aneuploidy was absent. These observations suggest that the mechanism leading to chromosome loss in somatic mammalian cells is often not a simple nondisjunction event and instead could result from a single catastrophic event. They also suggest that cells with characteristics of malignancy are present in normal appearing tissue. PMID- 21254299 TI - Array comparative genomic hybridization reveals frequent alterations of G1/S checkpoint genes in undifferentiated pleomorphic sarcoma of bone. AB - Undifferentiated pleomorphic sarcoma of bone (UPSb) is a rare tumor often difficult to differentiate from fibrosarcoma of bone (FSb), diagnostically. We applied array comparative genomic hybridization (array CGH) to screen for genes with potential importance in the tumor and compared the results with alterations seen in FSb. Twenty-two fresh frozen tissue specimens from 20 patients (18 primary tumors and 4 local recurrences) with UPSb were studied. DNA was isolated and hybridized onto Agilent 244K CGH oligoarrays. The hybridization data were analyzed using Agilent DNA Analytics Software. The number of changes ranged from 2 to 168 (average = 66). Losses were most frequently seen at 8p, 9p, 10, 13q, and 18q, and gains at 4q, 5p, 6p, 7p, 8q, 12p, 14q, 17q, 19p, 20q, 22q, and X. Homozygous deletions of CDKN2A, RB1, TP53, and ING1 were seen in 8/20, 7/20, 3/20, and 2/20 cases, respectively. Hypermethylation of both p16(INK4a) and p14(ARF) was found in two cases with loss at CDKN2A. Inactivation either of CDKN2A, RB1, or TP53 was detected in 18/20 cases. One case showed high level gains of CDK4 and MDM2. Frequent gains were seen at MYC, PDGFRA, KIT, and KDR. Immunohistochemical positivity of KIT, PDGFRA, KDR, and PDGFRB was found in 8/14, 5/14, 4/14, and 4/14 cases, respectively. The regions most significantly discriminating between UPSb and FSb included RB1 and MYC. No homozygous deletions of RB1 were found in FSb. In conclusion, our analysis showed the disruption of G1/S checkpoint regulation to be crucial for the oncogenesis of UPSb. PMID- 21254300 TI - Cooperation between cholinergic and glutamatergic receptors are essential to induce BDNF-dependent long-lasting memory storage. AB - The induction of long-lasting memory storage depends on the behavioral state of humans and animals. This behavioral state is mediated by neuromodulatory systems, like the cholinergic-septum-hippocampal circuit. Cholinergic neurotransmission is known to affect short-term activity-dependent plasticity in various brain areas, including the hippocampus. We could show here that a chemical late-long-term potentiation (LTP) could be induced in the basal dendrites by the coapplication of the cholinergic receptor agonist, carbachol, and the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram at a concentration that by itself has no effect on basal synaptic transmission. This chemical late-LTP was similar to electrical late-LTP in that it is dependent on protein synthesis, cAMP, and NMDA-receptor activation. Occlusion experiments demonstrated that saturation of three tetanus (TET) late-LTP occluded carbachol-rolipram-LTP, indicating that they share similar properties. This cholinergic modulation of LTP in the basal dendrites was mediated by both muscarinic and nicotinic receptors. Carbachol also reinforced an early form of LTP into a long-lasting LTP. Most interestingly, these two forms of LTP could participate in the functional plasticity processes like synaptic tagging and capture (STC). In addition, we studied whether a cooperation between cholinergic and glutamatergic receptors is essential to induce functional synaptic-plasticity. Indeed, we could show that coactivation of acetylcholine/PDE4 inhibition must coincide with the release of glutamate to induce a long-lasting plasticity, showing a functional convergence of the two neuromodulatory systems. Moreover, we could also show that both chemical late-LTP and carbachol-reinforced early-LTP-induced STC processes are mediated by the neurotrophin BDNF. PMID- 21254301 TI - Place, space, and taste: combining context and spatial information in a hippocampal navigation system. AB - The hippocampus appears to play an important role in episodic-like, or "what, where, when" memory that may be used for goal finding. We have previously presented a model of the hippocampus describing how navigation to a distal goal location could be achieved through gradient ascent processes based on place field density. Here we extend that model to show that information about both where a goal is, and the attributes of that goal, can be incorporated with relatively simple modifications. In this model both the spatial and attribute information would be available to the animal at any location within the environment although differential recall requires two different firing modes. "Where" information is available when cells in the model are firing in "place field" firing mode. The recall of "what" information requires, however, near simultaneous firing of a large number of place cells. We discuss how this "what" firing mode could potentially depend upon sharp-wave ripple (SPW-R) events. This conception has implications for how we interpret SPW-R related firing. In particular, we suggest that the near simultaneous firing that occurs in large groups of cells during SPW Rs may be sufficient for "what" recall and that the forward and reverse "replay" of place cell sequences that are often observed during SPW-Rs may be an epiphenomenon of this process. PMID- 21254302 TI - Decreased interactions in protein kinase A-glucocorticoid receptor signaling in the hippocampus after selective removal of the basal forebrain cholinergic input. AB - Removal of the cholinergic innervation to the hippocampus via selective immunolesions of septohippocampal cholinergic neurons induces dysfunction of the hypothalamic-pituitary-adrenocortical (HPA) axis and decreases glucocorticoid receptor (GR) mRNA. This study examined whether removal of the cholinergic innervation decreased GR protein levels and induced changes in the interaction between GR and the cytoplasmic catalytic subunit of protein kinase A (PKAc) in the hippocampus. In lesioned animals, GR protein levels were markedly decreased in the nucleus, but not in the cytosol of hippocampal neurons, whereas mineralocorticoid receptor (MR) levels remained unchanged in both the nucleus and cytosol. PKAc levels did not differ between lesioned and control groups, but PKAc activity was reduced in lesion tissue compared with the controls. The interaction between GR and PKAc was also decreased in the hippocampus without cholinergic input. These results indicate that degeneration of septohippocampal cholinergic neurons leads to reduced PKAc activity in the hippocampus which, in turn, alters GR signaling. The altered GR signaling induced by the degeneration of basal forebrain cholinergic neurons may contribute to dysfunction of the HPA axis in aged animals and patients with Alzheimer's disease (AD) and lead to neuropsychiatric symptoms that occur throughout the course of AD. PMID- 21254303 TI - Adrenergic modulation of sharp wave-ripple activity in rat hippocampal slices. AB - Norepinephrine (NE) has been shown to facilitate learning and memory by modulating synaptic plasticity in the hippocampus in vivo. During memory consolidation, transiently stored information is transferred from the hippocampus into the cortical mantle. This process is believed to depend on the generation of sharp wave-ripple complexes (SPW-Rs), during which previously stored information might be replayed. Here, we used rat hippocampal slices to investigate neuromodulatory effects of NE on SPW-Rs, induced by a standard long-term potentiation (LTP) protocol, in the CA3 and CA1. NE (10-50 MUM) dose-dependently and reversibly suppressed the generation of SPW-Rs via activation of alpha1 adrenoreceptors, as indicated by the similar effects of phenylephrine (100 MUM). In contrast, the unspecific beta adrenoreceptor agonist isoproterenol (2 MUM) significantly increased the incidence of SPW-Rs. Furthermore, beta adrenoreceptor activation significantly facilitated induction of both LTP and SPW-Rs within the CA3 network. Suppression of SPW-Rs by NE was associated with a moderate hyperpolarization in the majority of CA3 pyramidal cells and with a reduction of presynaptic Ca(2+) uptake in the stratum radiatum. This was indicated by activity dependent changes in [Ca(2+) ](o) and Ca(2+) fluorescence signals, by changes in the paired pulse ratio of evoked EPSPs and by analysis of the coefficient of variance. In the presence of NE, repeated high frequency stimulation (high frequency stimulation (HFS)) failed to induce SPW-Rs, although SPW-Rs appeared following washout of NE. Together, our data indicate that the NE-mediated suppression of hippocampal SPW-Rs depends on alpha1 adrenoreceptor activation, while their expression and activity-dependent induction is facilitated via beta1 adrenoreceptors. PMID- 21254304 TI - Epidemiology of potentially inappropriate medication use in elderly patients in Japanese acute care hospitals. AB - PURPOSE: The elderly receive many medications which may have adverse effects. Little evidence is available about the epidemiology of potentially inappropriate medications being prescribed to the elderly in Japan as defined by the Beers criteria, or whether or not these medications result in harm when used in this population. METHODS: We conducted a prospective cohort study of patients aged >=65 years who were admitted to three acute care hospitals in Japan. Trained research nurses followed up patients from randomly selected wards and collected data about their medications and all potential adverse drug events (ADEs). Two independent reviewers evaluated all the data. The use of potentially inappropriate medications and their effects on patients were identified using the updated Beers criteria. RESULTS: A total of 2155 elderly patients were eligible; 56.1% received at least one drug listed in the Beers criteria (BL drug). The rates of BL drug prescriptions were 103.8 per 100 admissions and 53.6 [DOSAGE ERROR CORRECTED] per 1000 patient-days, and the incidence rate of ADEs related to BL drugs was 1.7 per 100 BL drug prescriptions. Among patients aged >=65 years, relatively younger patients (p = 0.0002) and those with less complications (p = 0.04) were likely to be prescribed BL drugs. CONCLUSIONS: Although BL drugs were frequently prescribed to elderly Japanese inpatients, the incidence of related ADEs appeared infrequent. These data suggest that re-evaluation of the appropriateness of the Beers criteria is needed before they are used in Japan and other nations to assess quality or for decision support. PMID- 21254305 TI - Disentangling WTP per QALY data: different analytical approaches, different answers. AB - A large random sample of the Danish general population was asked to value health improvements by way of both the time trade-off elicitation technique and willingness-to-pay (WTP) using contingent valuation methods. The data demonstrate a high degree of heterogeneity across respondents in their relative valuations on the two scales. This has implications for data analysis. We show that the estimates of WTP per QALY are highly sensitive to the analytical strategy. For both open-ended and dichotomous choice data we demonstrate that choice of aggregated approach (ratios of means) or disaggregated approach (means of ratios) affects estimates markedly as does the interpretation of the constant term (which allows for disproportionality across the two scales) in the regression analyses. We propose that future research should focus on why some respondents are unwilling to trade on the time trade-off scale, on how to interpret the constant value in the regression analyses, and on how best to capture the heterogeneity in preference structures when applying mixed multinomial logit. PMID- 21254306 TI - Addressing the religious and spiritual needs of dying patients by healthcare staff in Korea: patient perspectives in a multi-religious Asian country. AB - OBJECTIVE: We investigated how patients' spiritual and religious needs are addressed by healthcare staff in inpatient palliative care centers in Korea, a multi-religious country. METHODS: We performed a cross-sectional, multicenter survey of terminal cancer patients in inpatient palliative care centers. RESULTS: Approximately half (50.5%) of the patients reported that their spiritual and religious needs were addressed by healthcare staff. Patients whose needs were addressed reported better quality of life (QoL), as measured using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire for Palliative Care, than patients whose needs were not addressed (p<0.05), although these groups did not differ when measured using the Comprehensive QoL Scale. Patients with a religious affiliation [adjusted odds ratio (aOR), 2.38; 95% confidence interval (CI), 0.70-8.05], those who were admitted to a religious palliative care center (aOR, 2.61; 95% CI, 0.86-7.96), and those whose religious affiliation was the same as that of the palliative care center (aOR, 2.42; 95% CI, 0.96-6.07) tended to have their spiritual and religious needs addressed, although not statistically significant. CONCLUSIONS: Although patients whose spiritual and religious needs were addressed by healthcare staff showed significantly better QoL, such needs were not addressed in a significant proportion of patients, especially those who were not religious or were admitted to non-religious palliative care centers. Strategies should be developed to ensure that spiritual care is provided to all patients with terminal cancer, regardless of the religious background of the patient. PMID- 21254307 TI - Cognitive dysfunction and cancer: which consequences in terms of disease management? AB - OBJECTIVES: The aim of this review is to stress the importance of cognitive dysfunction in cancer survivors, and to discuss the way of assessing and managing these troubles in clinical practice. METHOD: Original studies and reviews reporting the effect of cancer and chemotherapy on cognition and published since January 2000 were selected from the Medline((r)) database using 'cognition' or 'cognitive function' and 'cancer' as subject headings. RESULTS: Main reports concerned women with advanced breast cancer or children with hematological or brain cancers. Overall, chemotherapy was found to be associated with subtle and transient cognitive dysfunctions, which were detectable only with neuropsychological testing and affected most particularly memory, concentration and speed of information processing. Some factors associated with the patient, like depression, may favor cognitive impairment, while the role of others, like age or educational level, remains to be defined. Screening of patients at risk remains limited due to the lack of standardized neuropsychological tests in clinical oncology practice. Few studies have addressed the benefits of interventional strategies but methylphenidate, modafinil and erythropoietin, as well as rehabilitation in children, have shown encouraging results. Formal studies assessing the value of a multidisciplinary approach to detect and manage cognitive impairment must be recommended. CONCLUSION: Cognitive dysfunction induced by cancer or the treatment represents a real challenge in clinical practice. Based on limited published data, few clinical recommendations can be made regarding prevention, evaluation and management of this trouble. Longitudinal studies must be conducted to evaluate its real impact on quality of life. PMID- 21254308 TI - Predictors of finding benefit after lung cancer diagnosis. AB - OBJECTIVE: We examined benefit finding in patients with lung cancer, including level of benefit finding and change in benefit finding over time, and tested a predictive model postulating that greater impact of and engagement with the stressor promotes benefit finding. METHODS: Patients diagnosed with a primary lung cancer within the past 6 months (M=16 weeks post-diagnosis) completed measures of benefit finding, cancer-related intrusions, perceived stressfulness, coping, and demographic and medical information at study entry (T1; n = 118) and 3 months later (T2; n = 79). RESULTS: Level of benefit finding at both assessments was to a 'mild-to-moderate degree'. Benefit finding increased over time for patients with small cell carcinoma, but not for those with nonsmall cell carcinoma. The proposed model explained 33% of the variance in T1 benefit finding, and 64% (using T1 coping measures) and 71% (using T2 coping measures) of the variance in T2 benefit finding. Greater benefit finding was associated with having small cell lung cancer, higher cancer-related intrusions, lower perceived cancer-related stress, and greater approach-oriented coping. Positive reframing coping emerged as the single unique approach-oriented coping scale predicting benefit finding at T1, and emotional approach coping was the single unique approach-oriented coping scale predicting benefit finding at T2. CONCLUSION: Findings provide general support for a theoretical model positing that stressor impact and engagement with the stressor contribute to the development of benefit finding after cancer. Future research with larger, more diverse samples is needed to confirm and extend these findings. PMID- 21254309 TI - Suicidal imagery in a previously depressed community sample. AB - This study sought to replicate previous findings of vivid suicide-related imagery in previously suicidal patients in a community sample of adults with a history of depression. Twenty-seven participants were interviewed regarding suicidal imagery. Seventeen participants reported prior suicidal ideation or behaviour in the clinical assessment, and the vast majority of these also reported experiencing suicide-related imagery when at their most depressed and despairing, in many cases in the form of flash-forwards to imagined future suicidal acts. Interestingly, five of the 10 participants who did not report suicidal ideation or behaviour in the clinical interview also described prominent imagery related to themes of death and suicide, but in several cases, these images were associated with meanings that seemed to act to reduce the likelihood of subsequent suicidal acts. Severity of prior suicidality was associated with lower levels of imagery-related distress and higher levels of imagery-related comfort. These findings support the idea that suicide-related imagery is an important component in the phenomenology of depression and despair and hint at potentially important differences in the meaning associated with such imagery between those individuals who report experiencing suicidal ideation or behaviour when depressed and those who do not. The findings are consistent with Joiner's model of acquired capability for suicide through habituation to pain and fear of suicide and suggest that it may be useful to tackle such imagery directly in the treatment of suicidal patients. PMID- 21254310 TI - Peptides from Royal Jelly: studies on the antimicrobial activity of jelleins, jelleins analogs and synergy with temporins. AB - Peptides isolated from natural fonts are the object of several studies aimed at finding new molecules possessing antibacterial activity. We focused our studies on peptides originally isolated from the Royal Jelly, the jelleins and on some analogs having a UV reporter at the N- or C-terminus. We found that jelleins are mainly active against gram-positive bacteria; interestingly, they act in synergy with peptides belonging to the family of temporins such as temporin A and temporin B against Staphylococcus aureus A170 and Listeria monocytogenes. PMID- 21254311 TI - Synthesis of peptides containing 5-hydroxytryptophan, oxindolylalanine, N formylkynurenine and kynurenine. AB - ROS, continuously produced in cells, can reversibly or irreversibly oxidize proteins, lipids, and DNA. At the protein level, cysteine, methionine, tryptophan, and tyrosine residues are particularly prone to oxidation. Here, we describe the solid phase synthesis of peptides containing four different oxidation products of tryptophan residues that can be formed by oxidation in proteins in vitro and in vivo: 5-HTP, Oia, Kyn, and NFK. First, we synthesized Oia and NFK by selective oxidation of tryptophan and then protected the alpha amino group of both amino acids, and the commercially available 5-HTP, with Fmoc succinimide. High yields of Fmoc-Kyn were obtained by acid hydrolysis of Fmoc NFK. All four Fmoc derivatives were successfully incorporated, at high yields, into three different peptide sequences from skeletal muscle actin, creatin kinase (M-type), and beta-enolase. The correct structure of all modified peptides was confirmed by tandem mass spectrometry. Interestingly, isobaric peptides containing 5-HTP and Oia were always well separated in an acetonitrile gradient with TFA as the ion-pair reagent on a C18-phase. Such synthetic peptides should prove useful in future studies to distinguish isobaric oxidation products of tryptophan. PMID- 21254312 TI - Non-thermal internal energy distribution of ions observed in an electrospray source interfaced with a sector mass spectrometer. AB - The internal energy distribution P(E(int)) of ions emitted in an electrospray (ESI) source interfaced with a sector mass spectrometer is evaluated by using the experimental survival yield (SY) method including the kinetic shift. This method is based on the relationship between the degree of fragmentation of an ion and its amount of internal energy and uses benzylpyridinium cations due to their simple fragmentation scheme. Quantum chemical calculations are performed, namely at G3(MP2)//B3LYP and QCISD/MP2 levels of theory. The results show that the internal energy distribution of the ions emitted in the ESI source interfaced with a sector analyzer is very narrow. The MassKinetics software is used to confirm these observations. The P(E(int)) is the parameter that allows to fit the experimental SY of each substituted benzylpyridinium cation with theoretical mass spectra generated by the MassKinetics software. The resulting internal energy distributions are similar to the ones obtained with the experimental SY method. This indicates that in the present experimental conditions, P(E(int)) cannot be compared with a 'thermal-like' Boltzmann distribution. In addition, it appears that with the sector analyzer, increasing the collision energy in the first pumping stage of the ESI source does not correspond to a warm-up of the produced ions. PMID- 21254313 TI - Investigation of the in vitro metabolism of the emerging drug candidate S107 for doping-preventive purposes. AB - The metabolic fate of the emerging drug candidate S107, possessing the potential for misuse as performance-enhancing agent in sports, was investigated by in vitro phase I and II experiments with human microsomal and S9 liver enzymes. The metabolites were identified by liquid chromatography-mass spectrometry with electrospray ionisation in positive mode (LC-ESI-MS/MS). Their collision-induced dissociation behaviour was studied by high-resolution/high accuracy Orbitrap MS(n) analysis, supported by stable isotope labelling, H/D-exchange experiments and density functional theory calculations. Monooxygenation accounted for the main phase I metabolic transformation due to N- and S-oxidation of the 1,4 benzothiazepine core, as substantiated by chemical synthesis, selective reduction methods and characteristic APCI in source fragmentation behaviour of the metabolites. Another dominant metabolic pathway was demethylation, yielding the N and O-demethylated metabolite, respectively. The latter was further conjugated by glucuronidation as well as sulfonation in subsequent phase II metabolic reactions, whereas the N-demethylated metabolite was not amenable to conjugation. The active drug molecule itself was converted to two glucuronic acid conjugates, which are proposed to consist of two quaternary S107-N(+)-glucuronide isomers. All glucuronides were susceptible to enzymatic hydrolysis with beta-glucuronidase (Escherichia coli). A comprehensive LC-ESI-MS(/MS)-based detection method for urine was developed and its fitness for purpose was assessed. The assay can serve as a potential screening and/or confirmation method for S107 in clinical drug testing and doping control analysis in the future. PMID- 21254314 TI - Considering adjustment disorders as stress response syndromes for DSM-5. PMID- 21254315 TI - Bright light treatment for high-anxious young adults: a randomized controlled pilot study. AB - BACKGROUND: Available treatments for anxiety have limitations and/or side effects. The aim of this study was to examine the influence of bright light exposure as a treatment in high-anxious young adults. METHODS: In an acute exposure study, participants (n = 33) were randomly assigned to 45 min of (1) bright light or (2) placebo. Participants then performed a 5-week study (n = 29). Following a 1-week baseline, participants were randomly assigned to 4 weeks of daily exposure to either (1) bright light (45 min/day) or (2) placebo treatment, initiated <=1 hr after awakening. Before and after the experiment, clinical ratings were conducted with the Hamilton Anxiety Scale (HAM-A), Hamilton Depression Scale, and Clinical Global Impressions scale. Following each week, blood pressure, anxiety (Spielberger State-Trait Anxiety Inventory Y1), depression, mood, sleep, and side effects were assessed. RESULTS: No significant treatment effect was found in the acute exposure study. Likewise, in the 5-week study, no significant treatment effect was found. However, bright light elicited marginally greater reductions in psychic symptoms of the HAM-A (P = .06) and other measures. CONCLUSIONS: This pilot study provides little compelling evidence for an anxiolytic effect of bright light in high-anxious young adults. PMID- 21254316 TI - Responsive photonic crystals. AB - This Review summarizes recent developments in the field of responsive photonic crystal structures, including principles for design and fabrication and many strategies for applications, for example as optical switches or chemical and biological sensors. A number of fabrication methods are now available to realize responsive photonic structures, the majority of which rely on self-assembly processes to achieve ordering. Compared with microfabrication techniques, self assembly approaches have lower processing costs and higher production efficiency, however, major efforts are still needed to further develop such approaches. In fact, some emerging techniques such as spin coating, magnetic assembly, and flow induced self-assembly have already shown great promise in overcoming current challenges. When designing new systems with improved performance, it is always helpful to bear in mind the lessons learnt from natural photonic structures. PMID- 21254317 TI - Shedding light on the ghrelin/GOAT metabolism saga. AB - Getting the GOAT: The identification of a ghrelin O-acyltransferase (GOAT) inhibitor displaying metabolic modulatory activities has recently been reported. This research might provide a link for answering key questions relating to ghrelin's role(s) in obesity and diabetes. PMID- 21254318 TI - Head-to-tail intermolecular hydrogen bonding of OH and NH groups with fluoride. AB - To explore the anion-recognition ability of the phenolic hydroxyl group and the amino hydrogen, we synthesized three different acridinedione (ADD) based anion receptors, 1, 2 and 3, having OH, NH, and combination of OH and NH groups, respectively. Absorption, emission and (1)H NMR spectral studies revealed that receptor 1, having only a phenolic OH group, shows selective deprotonation of the hydroxyl proton towards F(-), which results in an "ON-OFF"-type signal in the fluorescence spectral studies. Receptor 2, which only has an amino hydrogen, also shows deprotonation of the amino hydrogen with F(-), whereas receptor 3 (having both OH and NH groups) shows head-to-tail intermolecular hydrogen bonding of OH and NH groups with F(-) prior to deprotonation. The observation of hydrogen bonding of the OH and NH groups in a combined solution of 1 and 2 with F(-) in a head-to-tail hetero-intermolecular fashion, and the absence of head-to-head and tail-to-tail intermolecular hydrogen bonding in 1 and 2 with F(-), prove that the difference in the acidity of the OH and NH protons leads to the formation of an intermolecular hydrogen-bonding complex with F(-) prior to deprotonation. The presence of this hydrogen-bonding complex was confirmed by absorption spectroscopy, 3D emission contour studies, and (1)H NMR titration. PMID- 21254319 TI - Toward a complete understanding of the vinyl fluoride spectrum in the atmospheric region. AB - A deep and comprehensive investigation of the vinyl fluoride (CH(2)CHF) spectrum in the atmospheric window around 8.7 MUm is presented. At first, the ro vibrational patterns are modelled to an effective Hamiltonian, which also takes into account the coupling of the C-F stretching vibration, nu(7), with the neighbouring vibrational combination nu(9)+nu(12). The obtained Hamiltonian gives very accurate simulations and predictions of the ro-vibrational quantum energies. Then, in the main part of the work, an experimental and theoretical study of vinyl fluoride self-broadening collisions is carried out for the first time. The broadening coefficients obtained experimentally are compared with those calculated by a semiclassical theory, demonstrating a significant contribution of collisional coupling effects between lines connecting pairs of degenerate (or nearly degenerate) rotational levels. Finally, the experimentally retrieved integrated absorption coefficients are used to calculate the absorption cross section of the nu(7) normal mode, from which dipole transition moments are derived. The obtained results provide a deep insight into the spectral behaviour of vinyl fluoride, in a spectral region of primary relevance for atmospheric and environmental determinations. Indeed, the data presented constitute an accurate model for the remote sensing of vinyl fluoride--a molecule of proved industrial importance which can lead to hazardous effects in the atmosphere and affects human's health. PMID- 21254320 TI - Rutin inhibits human leukemia tumor growth in a murine xenograft model in vivo. AB - Numerous studies have shown that rutin has anticancer effects. We have previously reported that rutin induced cell cycle arrest and apoptosis in murine leukemia WEHI-3 cells in vitro and in vivo. However, there are no data showing that rutin inhibits human leukemia HL-60 cells in vivo in a murine xenograft animal model. Human leukemia HL-60 cells were implanted into mice and treated with vehicle (1% DMSO), rutin (120 mg/kg of body weight) or vinblastine (120 MUg/kg of body weight). Compounds and agents were injected once every four days intraperitoneally (i.p.) for 36 days. Treatment with 120 mg/kg of rutin or with 120 MUg/kg of vinblastine resulted in a reduction of tumor weight and volume when compared with the control groups. Tumor size in xenograft mice treated with 120 mg/kg of rutin was significantly smaller than that in the untreated-control group. These novel findings indicate that rutin inhibits tumor growth in a xenograft animal model. Rutin may be useful in treating leukemia but certainly much more research is needed. (c) 2011 Wiley Periodicals, Inc. Environ Toxicol, 2012. PMID- 21254321 TI - Low-dose methylmercury-induced oxidative stress, cytotoxicity, and tau hyperphosphorylation in human neuroblastoma (SH-SY5Y) cells. AB - Acute neurotoxic effects of high-dose methylmercury (MeHg) in humans have been well documented in the scientific literature. However, low-dose effects are less well described. This study was designed to evaluate the effects of low-dose MeHg (<100 nM) on human brain cells in a tissue culture model. Neuroblastoma (NB) cells (SH-SY5Y) were used in the cell culture model to study low-dose effects of MeHg on cell growth, cell survival, reactive oxygen species (ROS), and the phosphorylation of tau protein, as a measure of potential markers of cellular events associated with tauopathies. When cells were incubated in culture with MeHg (50 and 100 nM), there were significant decreases in cell viability as well as significant increase in ROS generation as determined by fluorescent dye analysis (H(2)DCFDA). Furthermore, a concomitant decrease in glutathione levels to 25% of control was observed at both 50 and 100 nM MeHg. In addition, the level of phosphorylated tau was significantly increased after treatment at both 50 and 100 nM MeHg, compared with controls. Pretreatment of NB cells with the antioxidant, N-acetylcysteine (1.25 mM) and the calpain inhibitor, MDL-28170 (10 MUM), significantly attenuated the effects of MeHg (50 and 100 nM) on cell viability as well as on tau phosphorylation. These results indicate that low-dose MeHg toxicity may be related to an induction of tau phosphorylation through an oxidative stress-dependent mechanism and that blockade of this pathway may attenuate the toxic effects of MeHg. PMID- 21254322 TI - Toxicity of food contaminant furan on liver and kidney of growing male rats. AB - Furan is a chemical used in some industrial products and occurs naturally in heat treated foods. We aimed to investigate the effects of orally administered furan on liver and kidney in growing Wistar male rats for 90 days. In this respect, biochemical, morphological, histopathological, and histomorphometrical examinations were performed. Three- to 4-week aged rats were divided into five groups of eight animals each; control, oil control; 2, 4, 8 mg/kg/day furan treatment groups. At the end of the experiment, antioxidant enzyme activities and serum AST, ALT, HDL, Urea, etc. levels were analyzed. Malondialdehyde (MDA) levels, superoxide dismutase (SOD), catalase (CAT), tumor necrosis factor-alpha (TNF-alpha), and interleukin-6 (IL-6) were also measured in liver homogenates. Also, liver and kidney were examined morphologically and histopathologically under light microscopy. According to the results of biochemical analysis, ALT, ALP, and LDL levels in treatment groups were significantly different compared with control groups. While LDL levels in treatment groups increased significantly, ALT and ALP levels decreased significantly. No significant changes were observed in liver MDA levels, superoxide dismutase and catalase activities in treatment groups. While IL-6 levels did not change in treatment groups, furan caused dose-dependent increases in liver TNF-alpha level of rats. In treatment groups, absolute and relative liver weights changed significantly, however, no significant changes were observed in kidney and relative kidney weights. Hyperemic blood vessels in the liver and congestion, edema, fibrosis, and tubular damage in the kidney of rats treated with furan were observed histopathologically. According to histomorphometric examinations, glomeruli diameters and glomerular volume decreased in the kidneys of rats in treatment groups. PMID- 21254323 TI - Oxidative damage and OGG1 expression induced by a combined effect of titanium dioxide nanoparticles and lead acetate in human hepatocytes. AB - Titanium dioxide (TiO(2)) is a widely used nanomaterial that can cause biological damage through oxidative stress. At low concentrations, TiO(2) can interact with lead acetate (PbAc) to produce different toxic responses, compared with TiO(2) or PbAc alone. In this study, we utilized the following as indicators of toxic responses in human embryo hepatocytes (L02): reactive oxygen species (ROS), reduced glutathione (GSH), superoxide dismutase (SOD), and the DNA adducts 8 hydroxydeoxyguanosine (8-OHdG) and 8-oxoguanine DNA glycosylase homolog 1 (OGG1). These were used to evaluate the oxidative stress of TiO(2) (at 0.001, 0.01, 0.1, 1, and 10 MUg mL(-1)) mixed with PbAc (1 MUg mL(-1)) on L02 cells without photoactivation. Compared with the negative control (10/00 dimethyl sulfoxide), TiO(2) mixed with PbAc induced increased release of ROS (at 0.001, 0.01, 0.1, 1, 10 MUg mL(-1) TiO(2)), intracellular SOD activity (at 0.1 and 0.01 MUg mL(-1) TiO(2)), GSH levels (at 0.01-1 MUg mL(-1) TiO(2)), 8-OHdG levels (at 1 and 10 MUg mL(-1) TiO(2)), OGG1 expression (at 0.001-1 MUg mL(-1) TiO(2)), and cytotoxicity (at 0.1, 1, and 10 MUg mL(-1) TiO(2)) in L02 cells. There were no significant changes in ROS, GSH, SOD, 8-OHdG, or OGG1 levels when L02 cells were treated with TiO(2) alone or PbAc alone. These findings indicate that TiO(2) and PbAc in combination induce cytotoxicity and oxidative stress in L02 cells in the absence of photoactivation. PMID- 21254324 TI - Radiation safety program for the cardiac catheterization laboratory. AB - The Society of Cardiovascular Angiography and Interventions present a practical approach to assist cardiac catheterization laboratories in establishing a radiation safety program. The importance of this program is emphasized by the appropriate concerns for the increasing use of ionizing radiation in medical imaging, and its potential adverse effects. An overview of the assessment of radiation dose is provided with a review of basic terminology for dose management. The components of a radiation safety program include essential personnel, radiation monitoring, protective shielding, imaging equipment, and training/education. A procedure based review of radiation dose management is described including pre-procedure, procedure and post-procedure best practice recommendations. Specific radiation safety considerations are discussed including women and fluoroscopic procedures as well as patients with congenital and structural heart disease. PMID- 21254325 TI - Biological effects of rice harbouring Bph14 and Bph15 on brown planthopper, Nilaparvata lugens. AB - BACKGROUND: Brown planthopper (Nilaparvata lugens Stal; BPH) resistance genes Bph14 and Bph15 have been introgressed singly or pyramided into rice variety Minghui 63 (MH63). The antibiosis and antixenosis effects of these rice lines on BPH and the expression of five P450 genes of BPH regulated by these rice lines were investigated in this study. RESULTS: The resistance level of rice lines harbouring resistance genes was improved compared with MH63. MH63::14 (carrying Bph14) had negative effects on the development of males, honeydew excretion of females, the female ratio and the copulation rate compared with MH63. MH63::14 also exhibited antixenosis action against BPH nymphs, female adults and oviposition. Besides these negative effects, MH63::15 (carrying Bph15) could also retard the development of females, lower the fecundity and shorten the lifespan of females. The antixenosis action of MH63::15 was stronger than that of MH63::14. When Bph14 and Bph15 were pyramided, antibiosis and antixenosis effects were significantly enhanced relative to single-introgression lines. Among the five P450 genes of BPH, expression of three genes was upregulated, one gene was downregulated and one gene was unchanged by resistant hosts. CONCLUSION: Both Bph14 and Bph15 could improve resistance levels of MH63. MH63::15 and MH63::14&15 had greater potential to control BPH infestations than MH63::14. PMID- 21254326 TI - Sensitivity to strobilurin fungicides of Italian Venturia inaequalis populations with different origin and scab control. AB - BACKGROUND: Venturia inaequalis (Cooke) Winter with reduced sensitivity to strobilurins has been reported in several countries, including Italy. This study aimed to characterise the sensitivity to strobilurins of three different types of V. inaequalis population: (a) wild types; (b) from commercial orchards satisfactorily managed with strobilurins; (c) from an experimental orchard with control failures by trifloxystrobin and kresoxim-methyl. In vitro sensitivity tests included antigerminative activity on population conidia and mycelial growth inhibition on monoconidial isolates. Cleaved amplified polymorphic sequence (CAPS) analysis was used for the detection of G143A substitution. RESULTS: Wild type populations showed EC(50) values lower than 0.031 mg L(-1), while those of orchards with good performance by strobilurins presented EC(50) values never higher than 0.063 mg L(-1). Samples with scab control failures showed a strongly reduced population sensitivity. Similar differences were confirmed in monoconidial isolates. The G143A substitution was always detected in low sensitivity populations, only sometimes in well-controlled populations and generally not in wild types. CONCLUSIONS: In vitro sensitivity assays were able to discriminate the three population types with different scab management, while the qualitative PCR analysis (CAPS) was only partially reliable. High sensitivity differences among V. inaequalis populations with good and poor field control by strobilurins were observed. PMID- 21254327 TI - The role of allelopathy in agricultural pest management. AB - Allelopathy is a naturally occurring ecological phenomenon of interference among organisms that may be employed for managing weeds, insect pests and diseases in field crops. In field crops, allelopathy can be used following rotation, using cover crops, mulching and plant extracts for natural pest management. Application of allelopathic plant extracts can effectively control weeds and insect pests. However, mixtures of allelopathic water extracts are more effective than the application of single-plant extract in this regard. Combined application of allelopathic extract and reduced herbicide dose (up to half the standard dose) give as much weed control as the standard herbicide dose in several field crops. Lower doses of herbicides may help to reduce the development of herbicide resistance in weed ecotypes. Allelopathy thus offers an attractive environmentally friendly alternative to pesticides in agricultural pest management. In this review, application of allelopathy for natural pest management, particularly in small-farm intensive agricultural systems, is discussed. PMID- 21254328 TI - Synthesis of new compounds related to the commercial fungicide tricyclazole. AB - BACKGROUND: Tricyclazole is a commercial fungicide used to control rice blast. As part of re-registration activities, samples of metabolites and process impurities are required. In addition, isotopically labeled tricyclazole samples are also required. RESULTS: Four new compounds related to tricyclazole are reported. An isotopically labeled sample of tricyclazole was prepared that contained two (15)N atoms and one (13)C atom. Radiolabeled tricyclazole with (14)C at the triazole C3 position was also synthesized. A new process impurity in technical tricyclazole was identified and synthesized. A new metabolite of tricyclazole was identified, independently synthesized and characterized by X-ray crystallography. CONCLUSION: A previously unreported metabolite of tricyclazole has been identified and structurally characterized. In addition, a new process impurity has been identified by independent synthesis. Identification of these new compounds has facilitated the continued registration of this important fungicide. PMID- 21254329 TI - Electrical penetration graph evidence that pymetrozine toxicity to the rice brown planthopper is by inhibition of phloem feeding. AB - BACKGROUND: Pymetrozine is a valuable novel insecticide for control of sucking insects, including the brown planthopper Nilaparvata lugens (Stal), one of the most serious pests on rice. This study was conducted to elucidate the action mechanisms of pymetrozine on the feeding behaviour of the planthopper. RESULTS: The activity test showed that pymetrozine primarily functioned as an antifeedant that caused starvation and death in N. lugens, rather than having neurotoxicity. Pymetrozine-treated insects died at a significantly slower speed than insects treated with starvation. Electrical penetration graph (EPG) data indicated that pymetrozine significantly increased the duration of non-probing periods and had a strong inhibition to phloem ingestion. The inhibition was strongly dose dependent, resulting in a complete suppression of the activity in the phloem region when the pymetrozine concentration was increased to 400 mg L(-1) . Starvation caused by inhibition of phloem ingestion might be a major toxicity mechanism of pymetrozine. EPG data also showed that pymetrozine had no significant effect on stylet movement and duration of xylem sap ingestion. CONCLUSION: The study revealed that pymetrozine disturbed the feeding behaviour of N. lugens mainly by increasing the non-probe period and inhibiting phloem ingestion. The inhibition resulted in a slow death similar to starvation. PMID- 21254332 TI - Irxl1 mutant mice show reduced tendon differentiation and no patterning defects in musculoskeletal system development. AB - Irxl1 (Iroquois-related homeobox like-1) is a newly identified three amino-acid loop extension (TALE) homeobox gene, which is expressed in various mesoderm derived tissues, particularly in the progenitors of the musculoskeletal system. To analyze the roles of Irxl1 during embryonic development, we generated mice carrying a null allele of Irxl1. Mice homozygous for the targeted allele were viable, fertile, and showed reduced tendon differentiation. Skeletal morphology and skeletal muscle weight in Irxl1-knockout mice appeared normal. Expression patterns of several marker genes for cartilage, tendon, and muscle progenitors in homozygous mutant embryos were unchanged. These results suggest that Irxl1 is required for the tendon differentiation but dispensable for the patterning of the musculoskeletal system in development. PMID- 21254333 TI - Functional interaction between Foxd3 and Pax3 in cardiac neural crest development. AB - The transcription factors Foxd3 and Pax3 are important early regulators of neural crest (NC) progenitor cell properties. Homozygous mutations of Pax3 or a homozygous NC-specific deletion of Foxd3 cause marked defects in most NC derivatives, but neither loss of both Foxd3 alleles nor loss of one Pax3 allele alone greatly affects overall development of cardiac NC derivatives. In contrast, compound mutant embryos homozygous for a NC-specific Foxd3 mutation and heterozygous for Pax3 have fully penetrant persistent truncus arteriosus, severe thymus hypoplasia, and midgestation lethality. Foxd3; Pax3 compound mutant embryos have increased cell death in the neural folds and a drastic early reduction of NC cells, with an almost complete absence of NC caudal to the first pharyngeal arch. The genetic interaction between these genes implicates gene dosage-sensitive roles for Foxd3 and Pax3 in cardiac NC progenitors. Foxd3 and Pax3 act together to affect survival and maintenance of cardiac NC progenitors, and loss of these progenitors catastrophically affects key aspects of later cardiovascular development. PMID- 21254335 TI - A Cre-reporter transgenic mouse expressing the far-red fluorescent protein Katushka. AB - Cre/loxP-dependent expression of fluorescent proteins represents a powerful biological tool for cell lineage, fate-mapping, and genetic analysis. Live tissue imaging has significantly improved with the development of far-red fluorescent proteins, with optimized spectral characteristics for in vivo applications. Here, we report the generation of the first transgenic mouse line expressing the far red fluorescent protein Katushka, driven by the hybrid CAG promoter upon Cre mediated recombination. After germ line or tissue-specific Cre-driven reporter activation, Katushka expression is strong and ubiquitous, without toxic effects, allowing fluorescence detection in fresh and fixed samples from all tissues examined. Moreover, fluorescence can be detected by in vivo noninvasive whole body imaging when Katuhska is expressed exclusively in a specific cell population deep within the animal body such as pancreatic beta cells. Thus, this reporter model enables early, widespread, and sensitive in vivo detection of Cre activity and should provide a versatile tool for a wide spectrum of fluorescence and live imaging applications. PMID- 21254336 TI - A modified cornish pasty method for ex ovo culture of the chick embryo. AB - Early stages of avian development are not well-suited for in ovo studies. A critical limitation of ex ovo culture is the short period of growth that can be attained for explanted embryos. Here we report a modified and simplified version of an existing ex ovo culture method, the cornish pasty culture. We show that this modified method, referred to as MC culture, can be used to grow chick and quail embryos from Hamburger and Hamilton (HH) Stage 3 to at least HH18 with normal developmental morphology. The MC culture is also applicable to generate parabiosed twins. Combination of the MC culture with electroporation and labeling techniques will be a valuable new tool in cell lineage tracing and molecular functional analyses of early avian embryogenesis. PMID- 21254334 TI - Forced involution of the functionally differentiated mammary gland by overexpression of the pro-apoptotic protein bax. AB - The mammary gland is a developmentally dynamic, hormone-responsive organ that undergoes proliferation and differentiation within the secretory epithelial compartment during pregnancy. The epithelia are maintained by pro-survival signals (e.g., Stat5, Akt1) during lactation, but undergo apoptosis during involution through inactivation of cell survival pathways and upregulation of pro apoptotic proteins. To assess if the survival signals in the functionally differentiated mammary epithelial cells can override a pro-apoptotic signal, we generated transgenic mice that express Bax under the whey acidic protein (WAP) promoter. WAP-Bax females exhibited a lactation defect and were unable to nourish their offspring. Mammary glands demonstrated: (1) a reduction in epithelial content, (2) hallmark signs of mitochondria-mediated cell death, (3) an increase in apoptotic cells by TUNEL assay, and (4) precocious Stat3 activation. This suggests that upregulation of a single pro-apoptotic factor of the Bcl-2 family is sufficient to initiate apoptosis of functionally differentiated mammary epithelial cells in vivo. PMID- 21254337 TI - Posttransplant metabolic syndrome: new evidence of an epidemic and recommendations for management. PMID- 21254338 TI - Predicting cardiovascular complications after liver transplantation: 007 to the rescue? PMID- 21254339 TI - Meeting report of the 16th Annual International Congress of the International Liver Transplantation Society. PMID- 21254340 TI - Metabolic syndrome in liver transplant recipients: prevalence, risk factors, and association with cardiovascular events. AB - Features of metabolic syndrome are not uncommon in patients after liver transplantation. To examine the prevalence and risk factors of posttransplantation metabolic syndrome (PTMS), the files of 252 transplant recipients (mean age, 54.5 +/- 2.8 years, 57.9% male) were reviewed for pretransplant and posttransplant clinical and laboratory parameters (mean follow up, 6.2 +/- 4.4 years). Rates of obesity (body mass index >30 kg/m(2) ), hypertriglyceridemia (>150 mg/dL), high-density lipoprotein cholesterol <40 mg/dL (men) or <50 mg/dL (women), hypertension, and diabetes were significantly higher after transplantation than before. Metabolic syndrome was diagnosed in 5.4% of patients before transplantation and 51.9% after. Besides significantly higher rates of the typical metabolic derangements (P < 0.0001), the patients with PTMS were older and heavier than those without PTMS, and they had a higher rate of pretransplant hepatitis C virus infection (P < 0.03) and more posttransplant major vascular and cardiac events (20 events in 15.2% of patients with PTMS versus 6 events in 4.9% of patients without PTMS; P < 0.007). There was no between-group difference in mortality or causes of death (mainly related to recurrent disease, graft failure, and sepsis). Significant independent predictors of PTMS on logistic regression analysis were age (odds ratio [OR] = 1.04), pretransplant nonalcoholic fatty liver disease (OR = 3.4), body mass index (OR = 1.13), diabetes (OR = 5.95), and triglycerides (OR = 1.01). The rate of metabolic syndrome in liver transplant recipients is more than twice that reported for the general population. PTMS is associated with cardiovascular morbidity but not mortality, and it may be predicted by pretransplantation conditions. Prospective studies are required to determine the significance and management of PTMS. PMID- 21254341 TI - Predictors of cardiovascular events after liver transplantation: a role for pretransplant serum troponin levels. AB - Cardiovascular complications are major causes of morbidity and mortality after liver transplantation. Identifying candidates at highest risk of postoperative complications is a cornerstone of optimizing outcomes and utility. Using traditional cardiac risk factors in addition to C-reactive protein (CRP) levels, troponin levels, and echocardiographic parameters before transplantation, we sought to define cardiac risk so that we could predict cardiovascular events after transplantation. From December 1998 to December 2001, 230 adult patients who underwent liver transplantation with a median follow-up of 8.2 years were studied. The risk factors for cardiac disease were as follows: male gender with a mean age of approximately 50 years (57%), smoking history (60%), diabetes (23%), hypertension (19%), elevated troponin (25%), elevated CRP (25%), and preexisting cardiac disease (16%). Fifty-nine cardiac events occurred over 8.2 years. Risk factors (univariate analysis) for first cardiac events included age in decades [hazard ratio (HR) = 1.31, P = 0.047], diabetes (HR = 2.20, P = 0.004), prior cardiovascular disease (HR = 4.77, P < 0.0001), a troponin I level > 0.07 ng/mL (HR = 2.00, P = 0.023), left ventricular hypertrophy (HR = 2.06, P = 0.047), stress wall abnormalities (HR = 2.25, P = 0.018), and ischemia on stress imaging (HR = 2.89, P = 0.015). Multivariate analysis confirmed age, diabetes, a troponin I level > 0.07, and prior cardiac disease as independent risk factors for posttransplant cardiac events. In conclusion, pretransplant elevated troponin levels, diabetes, and a history of cardiovascular disease, alone or in combination, are strongly associated with the occurrence of posttransplant cardiovascular events. PMID- 21254342 TI - Alemtuzumab induction in non-hepatitis C positive liver transplant recipients. AB - Limited data exist for the use of alemtuzumab (AL) induction in liver transplantation (LT) recipients. We compared the outcomes of hepatitis C virus negative LT recipients who received AL induction followed by tacrolimus and mycophenolate mofetil without steroids to cohort who received no AL induction, tacrolimus, and a steroid taper. Fifty-five AL-induced recipients were compared to 85 non-AL-induced recipients with similar characteristics. Two-year patient survival (80% versus 88.2%, P = 0.0665) and graft survival (76.4% versus 82.4%, P = 0.1792) were not significantly different between the AL and non-AL groups, respectively. Other outcomes, including acute rejection (20% versus 30.3%), renal dysfunction (creatinine levels: 1.3 +/- 0.3 versus 1.4 +/- 0.6 mg/dL), and immunosuppressant monotherapy (29.1% versus 44.3%), were not significantly different between the AL and non-AL groups, respectively (P > 0.05). The number of rejection episodes (12 versus 42, P = 0.02) and the number of patients with new-onset hypertension (3 versus 15, P = 0.03) were lower in the AL group, although the incidence of all posttransplant infections was higher with AL (63.6% versus 44.3%, P = 0.03), primarily because of an increase in viral infections. In conclusion, a steroid-free AL induction regimen was associated with less hypertension and rejection but with more infectious complications; thus, the overall benefit of AL induction in LT recipients is called into question. PMID- 21254343 TI - Hepatic encephalopathy is associated with posttransplant cognitive function and brain volume. AB - Hepatic encephalopathy (HE) is a common complication of cirrhosis that is associated with brain atrophy and may participate in impaired cognitive function after liver transplantation. This study analyzes the relationship of HE with cognitive function and brain volume after transplantation. A total of 52 consecutive patients with cirrhosis (24 alcohol abuse, 24 prior HE, 14 diabetes mellitus) completed a neuropsychological assessment before liver transplantation and again, 6 to 12 months after transplantation. In 24 patients who underwent the posttransplant assessment, magnetic resonance imaging was performed in addition, with measurement of brain volume and relative concentration of N-acetylaspartate (NAA) and creatine/phosphocreatine (Cr), a neuronal marker, by magnetic resonance spectroscopy. Neuropsychological assessment prior to transplantation identified minimal HE in 28 patients. All cognitive indexes improved after liver transplantation, but 7 patients (13%) showed persistent mild cognitive impairment. Global cognitive function after transplantation was poorer in patients with the following variables before liver transplantation: alcohol etiology, diabetes mellitus, and HE. Brain volume after transplantation was smaller in patients with prior HE. Brain volume correlated to NAA/Cr values (r = 0.498, P = 0.013) and poor motor function (r = 0.41, P = 0.049). In conclusion, the association of HE with cognitive function and brain volume suggests that having experienced HE before liver transplantation impairs the posttransplantation neurological outcome. PMID- 21254344 TI - Bile duct anastomotic stricture after adult-to-adult right lobe living donor liver transplantation. AB - Duct-to-duct anastomosis (DDA) and hepaticojejunostomy (HJ) are options for biliary reconstruction in patients undergoing adult-to-adult right lobe living donor liver transplantation (ARLDLT), after which biliary anastomotic stricture (BAS) is common as a complication. The risk factors for BAS are not clearly defined. We aimed to determine the rate of post-ARLDLT BAS in our center and its associated factors. In 265 ARLDLT recipients, 55 (20.8%) developed postoperative BAS. The diagnosis was based on clinical, biochemical, histological, and radiological results. The BAS rates were 21.4% (43/201) for recipients undergoing DDA during transplantation, 18.9% (10/53) for recipients undergoing HJ, and 18.2% (2/11) for recipients undergoing both procedures. BAS and non-BAS patients had comparable demographics. The number of graft bile duct openings (P = 0.516) and the size of the graft's smallest bile duct (5 versus 5 mm, P = 0.4) were not significantly different between BAS and non-BAS patients. Univariate analysis showed that the factors associated with postoperative BAS were the recipient warm ischemia time (55 versus 51 minutes, P = 0.026), graft cold ischemia time (120 versus 108 minutes, P = 0.046), stent use (21.8% versus 7.1%, P = 0.001), postoperative acute cellular rejection (29.1% versus 11.0%, P = 0.001), and University of Wisconsin solution use (21.8% versus 7.1%, P = 0.001). Multivariate analysis showed that the cold ischemia time (odds ratio = 1.012, 95% confidence interval = 1.002-1.023, P = 0.014) and acute rejection (odds ratio = 3.180, 95% confidence interval = 1.606-6.853, P = 0.002) were significant factors. The graft survival rates of BAS and non-BAS patients were comparable. One patient required retransplantation for secondary biliary cirrhosis. In conclusion, BAS remains common after ARLDLT regardless of DDA or HJ. The graft cold ischemia time and postoperative acute cellular rejection are significantly associated with postoperative BAS. PMID- 21254345 TI - Utility of uncalibrated femoral stroke volume variation as a predictor of fluid responsiveness during the anhepatic phase of liver transplantation. AB - We evaluated the value of the stroke volume variation (SVV) calculated with the Vigileo monitor, which recently has been increasingly advocated for fluid management, as a predictor of fluid responsiveness during the anhepatic phase of liver transplantation (LT). We also compared SVV to the central venous pressure (CVP) and pulmonary arterial occlusion pressure (PAOP) in patients. Thirty-three adult recipients scheduled for elective living donor LT were enrolled in this study. Twenty minutes after the start of the anhepatic phase, the CVP, PAOP, approximate inferior vena caval pressure, femoral SVV, and cardiac output values were measured before and 12 minutes after fluid loading. Fluid loading was performed with a 6% hydroxyethyl starch solution (10 mL/kg). The responders were defined as patients whose cardiac index increased >= 15% after fluid loading. Receiver operating characteristic (ROC) analysis showed that only femoral SVV (area under the curve = 0.894, P = 0.0001) could be used to predict fluid responsiveness during the anhepatic phase of LT. The area under the ROC curve for femoral SVV was 0.894 (P = 0.0001), and it was significantly larger than those for CVP (area under the curve = 0.576, P = 0.004) and PAOP (area under the curve = 0.670, P = 0.021). Femoral SVV >8% identified the responders with a sensitivity of 89% and a specificity of 80%. Our results suggest that femoral SVV derived with the Vigileo monitor would be useful for fluid management during the anhepatic phase in LT recipients. PMID- 21254346 TI - Olprinone attenuates excessive shear stress through up-regulation of endothelial nitric oxide synthase in a rat excessive hepatectomy model. AB - After extended hepatectomy, excessive shear stress in the remnant liver causes postoperative liver failure. Olprinone (OLP), a selective phosphodiesterase inhibitor, has been reported to improve microcirculation and attenuate inflammation. The aim of this study was to investigate the effects of OLP on shear stress in rats with an excessive hepatectomy (EHx) model. In this study, EHx comprised 90% hepatectomy with ligation of the left and right Glisson's sheaths in Lewis rats. OLP or saline was intraperitoneally administered with an osmotic pump 48 hours before EHx. To evaluate the shear stress, we measured the portal vein (PV) pressure. We also assessed sinusoidal endothelial cell injury by immunohistochemistry and electron microscopy. Furthermore, we assessed apoptosis in the liver with the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method. Treatment with OLP up-regulated hepatic endothelial nitric oxide synthase (eNOS) expression. The increase in the PV pressure due to Glisson's sheath ligation was attenuated in OLP-treated rats during a 30-minute period after ligation. Treatment with OLP preserved sinusoidal endothelial cells and reduced apoptosis in the remnant liver. The probability of survival in the OLP-treated rats was significantly better than that in the controls (33.3% versus 13.3%). Furthermore, the postoperative eNOS activity in the OLP-treated rats was higher than that in the controls. The administration of Nomega-nitro-l-arginine methyl ester to OLP-treated rats eliminated the effects of OLP on PV pressure and survival after EHx. Therefore, we concluded that OLP attenuates excessive shear stress through the up-regulation of eNOS and improves the survival rate after EHx. PMID- 21254347 TI - Effect of remote ischemic preconditioning on liver ischemia/reperfusion injury using a new mouse model. AB - Ischemic preconditioning of remote organs (RIPC) reduces liver ischemia/reperfusion (IR) injury in the rabbit and rat. Mice are the only species available with a large number of transgenic strains. This study describes development and validation of a mouse model of hindlimb RIPC that attenuates liver IR injury. Mice were allocated to 4 groups: (1) Sham surgery; (2) RIPC: 6 cycles of 4 * 4 minutes ischemia/reperfusion of hindlimb; (3) IR: 40 minutes lobar (70%) hepatic ischemia and 2 hours reperfusion; (4) RIPC+IR: RIPC followed by IR group procedures. Plasma liver aminotransferases and hepatic histopathological and transmission electron microscopy studies were performed at the end of the experiment. Hepatic microcirculatory blood flow was measured throughout the experiment. Postoperative complications and animal survival were evaluated. Hindlimb RIPC using a tourniquet resulted in limb paralysis. Hindlimb RIPC using direct clamping of the femoral vessels showed no side effects. Compared to liver IR alone, RIPC+IR reduced plasma aminotransferases (P < 0.05) and histopathological and ultrastructural features of injury. Hepatic microcirculatory blood flow was preserved in the RIPC+IR compared to IR group (P < 0.05). There was no mortality in any of the groups. By demonstrating a consistent improvement in these features of liver IR injury with antecedent hindlimb RIPC and by minimizing experimental confounding variables, we validated this mouse model. In conclusion, we describe a validated mouse model of hindlimb RIPC that reduces liver IR injury. With the availability of transgenic mice strains, this model should prove useful in unraveling the mechanisms of protection of hindlimb RIPC. PMID- 21254348 TI - Retransplantation for donor-derived neuroendocrine tumor. AB - Although tumor transmission through liver transplantation (LT) is a rare occurrence, the consequences can be devastating, even when a very aggressive management approach is adopted. We report the case of a donor-derived small cell neuroendocrine tumor (NET) in a patient who underwent LT for cholangiocarcinoma. Despite locoregional therapy, chemotherapy and ultimately retransplantation, the patient died from metastases. The high grade nature of the NET was the most important determinant of prognosis in this case. Our experience suggests that retransplantation for donor-derived NET should only be considered when tumor biology is favorable. PMID- 21254349 TI - Optimizing outflow in piggyback liver transplantation without caval occlusion: the three-vein technique. PMID- 21254350 TI - Split liver transplantation in adults: preoperative estimation of the weight of right and left hemiliver grafts. PMID- 21254351 TI - Hepatic liver ischemia/reperfusion injury: processes in inflammatory networks--a review. PMID- 21254353 TI - Human teratogens: update 2010. AB - A wide variety of human teratogens have been identified. The characteristics of human teratogens can be used in the assessment of apparent "new" teratogens, when postulated. Information is available through online databases, such as TERIS and Reprotox, telephone-based counseling resources (e.g., Organization of Teratogen Information Systems [OTIS] and European Network Teratology Information Services [ENTIS]), reference books, annual meetings of the Teratology Society, and published articles. There are significant deficiencies in the information available: (1) lack of knowledge about the molecular and cellular basis for most teratogenic effects; (2) the inability to genetically identify more susceptible women before pregnancy; (3) little information is available on dermal and airborne exposures during pregnancy; and (4) most clinicians receive little, if any, training in the identification of or counseling for exposure to potential teratogens. There are many current dilemmas in counseling about exposures in pregnancy, including: (1) Is exposure to specific drugs, such as selected serotonin re-uptake inhibitors (SSRIs) and the inhibitors of tumor necrosis factor-alpha, teratogenic in the first trimester of pregnancy? (2) Are the increased risks of birth defects associated with assisted reproductive technology due, in part, to epigenetic effects? (3) What are the "safe" levels of exposure to the plasticizers phthalates during pregnancy? (4) How do we convince busy physicians, nurses, and pharmacists not to use the drug categories A, B, C, D, and X in counseling and to use more accurate sources? There is a need for a national advisory center for pregnancy registries to provide guidance when new registries are being developed. PMID- 21254354 TI - High intake of folic acid disrupts embryonic development in mice. AB - BACKGROUND: Folic acid fortification and supplementation has increased folate intake and blood folate concentrations and successfully reduced the incidence of neural tube defects. However, the developmental consequences of high folate intake are unknown. This study investigated the impact of high folate intake, alone or with methylenetetrahydrofolate reductase (MTHFR) deficiency, on embryonic and placental development in mice. METHODS: Mthfr +/+ or +/- pregnant mice on a control diet (CD; recommended intake of folic acid for rodents) or folic acid-supplemented diet (FASD; 20-fold higher than the recommended intake) were examined for embryonic loss, delay, and defects at 10.5 and 14.5 days post coitum (dpc); 10.5-dpc placenta, and 14.5-dpc embryo hearts were studied histologically. RESULTS: Total plasma folate was 10-fold higher in FASD compared to CD mice; plasma homocysteine levels were not affected by diet. At 10.5 dpc, the FASD was associated with embryonic delay and growth retardation, and may confer susceptibility to embryonic defects. The FASD did not adversely affect 10.5-dpc placental development. At 14.5 dpc, embryos from the FASD Mthfr +/+ group were delayed and the FASD was associated with thinner ventricular walls in embryonic hearts. There was a significant interaction between maternal MTHFR deficiency and a high folate diet for several developmental outcomes. CONCLUSIONS: Our study suggests that high folate intake may have adverse effects on fetal mouse development and that maternal MTHFR deficiency may improve or rescue some of the adverse outcomes. These findings underscore the need for additional studies on the potential negative impact of high folate intake during pregnancy. PMID- 21254355 TI - Smoking, the xenobiotic pathway, and clubfoot. AB - BACKGROUND: Isolated clubfoot is a common orthopedic birth defect that affects approximately 135,000 newborns worldwide. It is characterized by ankle equinus, hindfoot varus, and forefoot adductus. Although numerous studies suggest a multifactorial etiology, the specific genetic and environmental components have yet to be delineated. Maternal smoking during pregnancy is the only common environmental factor consistently shown to increase the risk for clubfoot. Moreover, a positive family history of clubfoot, in conjunction with maternal smoking, increases the risk 20-fold. These findings suggest that genetic variation in smoking metabolism (xenobiotic) genes may increase susceptibility to clubfoot. Based on this reasoning, we interrogated eight candidate genes from the xenobiotic metabolism. METHODS: Twenty-two single-nucleotide polymorphisms and two null alleles in these genes (CYP1A1, CYP1A2, CYP1B1, CYP2A6, EPHX1, NAT2, GSTM1, and GSTT1) were genotyped in a dataset composed of non-Hispanic white and Hispanic multiplex and simplex families. RESULTS: Only rs1048943/CYP1A1 had significantly altered transmission in the aggregate and multiplex non-Hispanic white datasets (p = 0.003 and p = 0.009, respectively). Perturbation of CYP1A1 can cause an increase in harmful, adduct-forming metabolic intermediates. A significant interaction between EPHX1 and NAT2 was also found (p = 0.007). Importantly, for CYP1A2, significant maternal (p = 0.03; relative risk [RR] = 1.24; 95% confidence interval [CI], 1.04-1.44) and fetal (p = 0.01; RR = 1.33; 95% CI, 1.13-1.54) genotypic effects were identified, suggesting that both maternal and fetal genotypes can negatively impact limb development. No association was found between maternal smoking status and variation in xenobiotic metabolism genes. CONCLUSION: Together, these results suggest that xenobiotic metabolism genes are unlikely to play a major role in clubfoot; however, perturbation of this pathway may still play a contributory role. PMID- 21254356 TI - Maternal smoking, passive tobacco smoke, and neural tube defects. AB - BACKGROUND: Although cigarette smoke is a well-established toxin and harmful to the developing embryo, the evidence for an independent effect on the occurrence of neural tube defects (NTDs) is mixed. In this study, we examined the relation between NTDs and maternal exposures to cigarette smoke, including passive smoke exposure. METHODS: We used cases and controls from the large, multistate, population-based National Birth Defects Prevention Study. A total of 1041 NTD cases and 5862 live birth controls, delivered during 1997 to 2004, were available for analyses. Mothers were interviewed by telephone between 6 weeks and 24 months after delivery. Participation rates were 71% for NTD case mothers and 69% for control mothers. RESULTS: Compared with nonsmokers (and also not exposed to passive cigarette smoke), mothers exposed only to passive smoke had an increased NTD odds ratio (OR, 1.7; 95% confidence interval [CI], 1.4-2.0), adjusted for race-ethnicity, and study center. There was no increased OR for mothers who actively smoked 24 or fewer cigarettes per day. Mothers who smoked 25 or more cigarettes per day had an elevated OR (OR, 1.6; 95% CI, 0.9-3.0), but the OR adjusted for race-ethnicity, and center was compatible with the null. CONCLUSION: Results suggest that maternal exposure to passive smoke is associated with NTDs. Women who plan on becoming pregnant should minimize their exposure to passive smoke and refrain from smoking. PMID- 21254357 TI - Association of retinoic acid receptor genes with meningomyelocele. AB - BACKGROUND: Neural tube defects (NTDs) occur in as many as 0.5-2 per 1000 live births in the United States. One of the most common and severe neural tube defects is meningomyelocele (MM) resulting from failed closure of the caudal end of the neural tube. MM has been induced by retinoic acid teratogenicity in rodent models. We hypothesized that genetic variants influencing retinoic acid (RA) induction via retinoic acid receptors (RARs) may be associated with risk for MM. METHODS: We analyzed 47 single nucleotide polymorphisms (SNPs) that span across the three retinoic acid receptor genes using the SNPlex genotyping platform. Our cohort consisted of 610 MM families. RESULTS: One variant in the RARA gene (rs12051734), three variants in the RARB gene (rs6799734, rs12630816, rs17016462), and a single variant in the RARG gene (rs3741434) were found to be statistically significant at p < 0.05. CONCLUSION: RAR genes were associated with risk for MM. For all associated SNPs, the rare allele conferred a protective effect for MM susceptibility. PMID- 21254358 TI - Nonsyndromic cleft lip and palate: CRISPLD genes and the folate gene pathway connection. AB - BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect that has a multifactorial etiology. Despite having substantial genetic liability, <15% of the genetic contribution to NSCLP has been delineated. In our efforts to dissect the genetics of NSCLP, we found that variation in the CRISPLD2 (cysteine-rich secretory protein LCCL domain containing 2) gene is associated with NSCLP and that the protein is expressed in the developing murine craniofacies. In addition, we found suggestive linkage of NSCLP (LOD > 1.0) to the chromosomal region on 8q13.2-21.13 that contains the CRISPLD1 gene. The protein products of both CRISPLD1 and CRISPLD2 contain more cysteine residues than comparably sized proteins. Interestingly, the folic acid pathway produces endogenous cysteines, and variation in genes in this pathway is associated with NSCLP. Based on these observations, we hypothesized that variation in CRISPLD1 contributes to NSCLP and that both CRISPLD genes interact with each other and genes in the folic acid pathway. METHODS: Single nucleotide polymorphisms (SNPs) in CRISPLD1 were genotyped in our non-Hispanic white and Hispanic multiplex and simplex NSCLP families. RESULTS: There was little evidence for a role of variation for CRISPLD1 alone in NSCLP. However, interactions were detected between CRISPLD1/CRISPLD2 SNPs and variation in folate pathway genes. Altered transmission of one CRISPLD1 SNP was detected in the NHW simplex families. Importantly, interactions were detected between SNPs in CRISPLD1 and CRISPLD2 (15 interactions, 0.0031 <=p < 0.05). CONCLUSION: These novel findings suggest that CRISPLD1 plays a role in NSCLP through the interaction with CRISPLD2 and folate pathway genes. PMID- 21254359 TI - Folate pathway and nonsyndromic cleft lip and palate. AB - BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common complex birth defect. Periconceptional supplementation with folic acid, a key component in DNA synthesis and cell division, has reduced the birth prevalence of neural tube defects and may similarly reduce the birth prevalence of other complex birth defects including NSCLP. Past studies investigating the role of two common methylenetetrahydrofolate reductase (MTHFR) single-nucleotide polymorphisms (SNPs), C677T (rs1801133) and A1298C (rs1801131), in NSCLP have produced conflicting results. Most studies of folate pathway genes have been limited in scope, as few genes/SNPs have been interrogated. Here, we asked whether variations in a more comprehensive group of folate pathway genes were associated with NSCLP, and were there detectable interactions between these genes and environmental exposures? METHODS: Fourteen folate metabolism-related genes were interrogated using 89 SNPs in multiplex and simplex non-Hispanic white and Hispanic NSCLP families. RESULTS: Evidence for a risk association between NSCLP and SNPs in NOS3 and TYMS was detected in the non-Hispanic white group, whereas associations with MTR, BHMT2, MTHFS, and SLC19A1 were detected in the Hispanic group. Evidence for over-transmission of haplotypes and gene interactions in the methionine arm was detected. CONCLUSIONS: These results suggest that perturbations of the genes in the folate pathway may contribute to NSCLP. There was evidence for an interaction between several SNPs and maternal smoking, and for one SNP with gender of the offspring. These results provide support for other studies that suggest that high maternal homocysteine levels may contribute to NSCLP and should be further investigated. PMID- 21254360 TI - NAT1, NOS3, and TYMS genotypes and the risk of conotruncal cardiac defects. AB - BACKGROUND: Although congenital heart defects (CHDs) are a common and serious group of birth defects, relatively little is known about the causes of these conditions, and there are no established prevention strategies. There is, however, evidence suggesting that the risk of CHDs in general, and conotruncal and related defects (CTRDs) in particular, may be associated with maternal folate status and genetic variants of folate-related genes. Although several folate related genes have been studied as they relate to CHDs and CTRDs (e.g., MTHFR), others have not been adequately assessed. METHODS: Case-parent triads were examined using log-linear analyses to assess the associations between CTRDs and both the genotype inherited by the case and the maternal genotype for the following variants: NAT1 1095C>A, NOS3 894G>T, and TYMS 1494del6. Subgroup analyses were also conducted among cases with classic conotruncal defects and cases with normally related great arteries. RESULTS: The results provided little evidence that CTRD risk was associated with the genotype inherited by the case for any of the analyzed variants. However, our results suggest that CTRD risk may be associated with the maternal genotype for NOS3 894G>T (p = 0.024 in the subgroup with normally related great arteries) and TYMS 1494del6 (p = 0.048 in the subgroup with classic conotruncal defects). However, these results were not significant after correcting for multiple comparisons. CONCLUSION: This study provides further evidence that CTRD risk may be related to variation within folate-pathway genes and suggests that these associations are, at least in part, mediated through the maternal genotype. PMID- 21254361 TI - Letter to the editor: Ventricular septal defects and the National Birth Defects Prevention Study. PMID- 21254362 TI - Caffeine intake and risk of neural tube defects. PMID- 21254364 TI - Birth weight in children with birth defects. AB - BACKGROUND: Birth defects (BDs) are a serious public health problem in Mexico. The objective of this paper was to identify the frequency of newborns (NBs) that are born small for gestational age with a birth defect. MATERIALS AND METHODS: A cross-sectional study of NBs from hospitals part of the Mexican Institute of Social Security in Chihuahua, Mexico, was conducted. NBs were classified according to the presence or absence of a BD and according to their weight percentile using regional standards of birth weight. RESULTS: NBs diagnosed with (n = 263) or without BDs (n = 64,626) were included in this study. A greater proportion of NBs small for gestational age were identified in cases involving BDs (20%), compared with NBs without BDs (9%). Moreover, the average decrease in birth weights of NBs with BDs associated with their digestive system was 210 grams (95% confidence interval [CI], -436/-12), with their genital organs 440 grams (95% CI, -730/-151), involving chromosomal abnormalities 230 grams (95% CI, -435/-26), or with their musculoskeletal system 289 grams (95% CI, -43/-147) according to the gestational age, sex, and condition of the NB (p < 0.05). CONCLUSIONS: A greater proportion of NBs with BDs were associated with a low birth rate for their gestational age. In addition, some BDs were found to be associated with an impaired birth weight more often than others This suggests that clinical decisions regarding NBs with congenital defects and a lower birth weight for their gestational age should be diagnosed and treated for additional nutritional considerations as needed. Birth Defects Research (Part A), 2011. (c) 2011 Wiley-Liss, Inc. PMID- 21254365 TI - Maternal caffeine intake and risk of selected birth defects in the National Birth Defects Prevention Study. AB - BACKGROUND: Caffeine intake is common during pregnancy, yet few epidemiologic studies have examined the association between maternal caffeine consumption and birth defects. Using data from the National Birth Defects Prevention Study (NBDPS), we examined the association between maternal caffeine consumption and anotia/microtia, esophageal atresia, small intestinal atresia, craniosynostosis, diaphragmatic hernia, omphalocele, and gastroschisis. METHODS: The NBDPS is a multi-site population-based case-control study. The present analysis included 3,346 case infants and 6,642 control infants born from October 1997 through December 2005. Maternal telephone interview reports of demographic characteristics and conditions and exposures before and during pregnancy were collected. Odds ratios and 95% confidence intervals, adjusted for relevant covariates, were calculated to estimate the associations between maternal dietary caffeine intake (coffee, tea, soda, and chocolate) and maternal use of caffeine containing medications and each defect. RESULTS: We observed small, statistically significant elevations in adjusted odds ratios ranging from 1.3 to 1.8 for total maternal dietary caffeine intake or specific types of caffeinated beverages and anotia/microtia, esophageal atresia, small intestinal atresia, and craniosynostosis; however, dose-response patterns were absent. Periconceptional use of caffeine-containing medications was infrequent and estimates were imprecise. CONCLUSIONS: We did not find convincing evidence of an association between maternal caffeine intake and the birth defects included in this study. The increasing popularity of caffeine-containing energy drinks and other caffeinated products may result in higher caffeine intake among women of childbearing age. Future studies should consider more detailed evaluation of such products. PMID- 21254367 TI - Association between maternal diabetes and renal malformations in the offspring: more than environmental factors. PMID- 21254366 TI - Maternal DNA hypomethylation and congenital heart defects. AB - BACKGROUND: Congenital heart defects (CHDs) are among the most prevalent and serious of birth defects. Multiple maternal factors are thought to contribute to CHD development, including folate intake. Maternal DNA methylation, which is dependent on folate metabolism, may impact the risk of CHDs. Our study was designed to determine whether maternal long interspersed nucleotide elements-1 (LINE-1) DNA hypomethylation is associated with increased occurrence of non syndromic CHDs and whether maternal folate-dependent metabolites are correlated with DNA methylation status. METHODS: Using a case-control study design, we measured global DNA methylation status among mothers whose pregnancies were affected by non-syndromic CHDs (n = 180) and mothers of unaffected pregnancies (n = 187). Methylation of LINE-1 was used as a surrogate marker of global DNA methylation status. The association between DNA methylation and CHD risk was determined while adjusting for selected lifestyle factors. RESULTS: LINE-1 DNA methylation was significantly lower in cases compared to controls (p = 0.049). After covariate adjustments, a significant difference between cases and controls remained (p = 0.010). Among women with LINE-1 methylation in the lowest decile of DNA methylation, the estimated risk of having a CHD-affected pregnancy was almost twice that of women in all other deciles (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.03-3.58). CONCLUSIONS: Our findings indicate that maternal LINE 1 DNA hypomethylation is associated with an increased risk of CHDs. Future studies investigating the association between maternal DNA methylation patterns and CHDs should be pursued. PMID- 21254368 TI - Maternal exposure to multi-wall carbon nanotubes does not induce embryo-fetal developmental toxicity in rats. AB - BACKGROUND: Although the potential risk of carbon nanotubes (CNTs) to humans has recently increased due to expanding production and widespread use, the potential adverse effects of CNTs on embryo-fetal development have not yet been determined. METHODS: This study investigated the potential effects of multi-wall CNTs (MWCNTs) on pregnant dams and embryo-fetal development in rats. MWCNTs were administered to pregnant rats by gavage at 0, 40, 200, and 1,000 mg/kg/day. All dams were subjected to Cesarean section on day 20 of gestation, and the fetuses were examined for any morphological abnormalities. RESULTS: All animals survived to the end of the study. A decrease in thymus weight was observed in the high dose group in a dose-dependent manner. However, maternal body weight, food consumption, and oxidant-antioxidant balance in the liver were not affected by treatment with MWCNTs. No treatment-related differences in gestation index, fetal deaths, fetal and placental weights, or sex ratio were observed between the groups. Morphological examinations of the fetuses demonstrated no significant difference in incidences of abnormalities between the groups. CONCLUSIONS: The results show that repeated oral doses of MWCNTs during pregnancy induces minimal maternal toxicity and no embryo-fetal toxicity at 1,000 mg/kg/day in rats. The no observed-adverse-effect level of MWCNTs is considered to be 200 mg/kg/day for dams and 1,000 mg/kg/day for embryo-fetal development. In this study, the dosing formulation was not analyzed to determine the degree of reaggregation (or not), nor were blood levels of CNT's measured in the dosed animals to verify or characterize absorption. PMID- 21254369 TI - Early genetic control of craniofacial development is affected by the in vitro exposure of rat embryos to the fungicide triadimefon. AB - BACKGROUND: Previous published experiments reported that in vitro exposure of postimplantation rat embryos to the triazole fungicide triadimefon (FON) resulted in specific abnormalities at the branchial apparatus and that the sensitive period is restricted to the first 24 hr of culture and is associated with the abnormal expression of TGF family genes (some of a large panel of genes regulated by retinoic acid (RA) and involved in branchial arch morphogenesis). The aim of this study is the determination of the sensitive window to FON-induced abnormalities during in vitro development and the evaluation of the expression of some genes controlled by RA and involved in early branchial arch morphogenesis (Gsc, Msx1, Msx2, Dlx1, Dlx2, Shh, Patched (the main Shh receptor)). METHODS: Rat embryos were exposed in vitro to the FON under condition known to be able to induce 100% of abnormal embryos (250 uM) at different stages and examined after 48 hr of culture. The sensitive window for FON-induced abnormalities was during the hours E9 h8.00 PM-E10 h8.00 AM. To evaluate the expression of selected genes, embryos exposed during the sensitive stages were processed to perform quantitative PCR after 18 and 24 hr of culture. RESULTS: FON was able to affect the expression of some genes in a stage-specific manner: earlier embryos were characterized by the downregulation of Msx2 and Gsc, later embryos showed the downregulation of Gsc, Shh, and Patched. The obtained data suggest that FON induced abnormalities are mediated, at least in part, through the imbalance of the expression of RA-related signals. PMID- 21254370 TI - Parental views on tissue banking in pediatric oncology patients. AB - PURPOSE: Research using banked tissue is key to advancing risk-stratification and treatment of children with cancer. Knowledge of parental attitudes to ethical issues arising in tissue banking is very limited but essential in obtaining respectful consent. METHODS: One hundred parents of consecutively diagnosed children with cancer were offered a validated 34-item questionnaire. RESULTS: Respondents (n = 54) included 10 of 16 parents of deceased children. The majority (89%; n = 48) would agree to have tissue sent anywhere in the world but prefer pediatric aims (69%). Most (98%; n = 53) would permit genetic research, if it might improve the child's health, and 76% (n = 41) would permit it, even if no impact was anticipated. A minority (41%) would not allow painful, strictly research procedures, while 15% would regardless of the child's dissent. Just over half (54%; n = 29) wish to renew consent if stored tissue is used for another purpose. Most (98%) believe their child should confirm consent by the age of majority, but only 71% believe the mature child should be able to withdraw consent. A minority (n = 40; 74%) claim few or no rights to research profits; 83% believe these should be used to fund childhood cancer research. CONCLUSIONS: Parents are very supportive of tissue research, including genetic research. A majority of parents would prefer restricting research to pediatric conditions, and to be informed of results, even if of uncertain significance. These findings may assist Institutional Review Boards in assessing parentally perceived risks of research, and researchers in providing consent elements that support parents and adolescents in making fully informed choices. PMID- 21254371 TI - Disturbed dental development of permanent teeth in children with solid tumors and lymphomas. AB - BACKGROUND: Deficient dental root development has been reported after conventional pediatric anticancer therapy but less information is available on children with solid tumors and lymphomas. PROCEDURE: We examined dental development from panoramic radiographs (PRGs) of 37 childhood cancer survivors (CCS) treated under the age of 10 years with multimodal chemotherapy (CT) and/or head and neck radiotherapy (RT). A novel defect index (DeI) was used to describe the total damage to permanent dentition. The DeI was also tested in matched controls. RESULTS: All CCS had dental disturbances including abnormal root development (86.4%), microdontia (13.5%) and tooth agenesis (16.2%). Testing the controls gave the mean DeI value 1.9 +/- 2.7 (range, 0-12), while the index scores in the study group varied from 0 to 49 (mean 10.8 +/- 11.2) (P < 0.01). The statistical differences in the mean DeI values were insignificant between CT and CT and RT groups (P > 0.05). CONCLUSIONS: Children treated for solid tumors and lymphomas are at considerable risk of some disturbances in developing dental structures. RT increased the severity of disturbances induced by CT. Studies should further elucidate dose-, age and time-related effects of anticancer treatment on dental development. PMID- 21254372 TI - Impact of caring for a child with cancer on single parents compared with parents from two-parent families. AB - BACKGROUND: It is currently unknown how the intensive and often prolonged treatment of childhood cancer impacts on the lives of single parents. Our aims were to determine whether single parents differ from parents from two-parent families in terms of caregiver demand (the time and effort involved in caregiving), and health-related quality of life (HRQL). PROCEDURES: Forty single parents and 275 parents from two-parent families were recruited between November 2004 and February 2007 from five pediatric oncology centers in Canada. Parents were asked to complete a questionnaire booklet composed of items and scales to measure caregiver demand and HRQL (SF-36). The booklet also measured the following constructs: background and context factors, child factors, caregiving strain, intrapsychic factors, and coping factors. RESULTS: Single parents did not differ from parents from two-parent families in caregiving demand and physical and psychosocial HRQL. Compared with Canadian population norms for the SF-36, both groups reported clinically important differences (i.e., worse health) in psychosocial HRQL (effect size >= -2.00), while scores for physical HRQL were within one standard deviation of population norms. CONCLUSION: Our findings suggest that the impact of caregiving on single parents, in terms of caregiving demand and HRQL is similar to that of parents from two-parent families. PMID- 21254373 TI - Prognostic value of PAX-FKHR fusion status in alveolar rhabdomyosarcoma: a report from the cooperative soft tissue sarcoma study group (CWS). AB - BACKGROUND: Alveolar Rhabdomyosarcomas (RMA) are characterized by chromosomal translocations, fusing the PAX3 or PAX7 gene with FKHR in about 85%. Previous studies have suggested that the fusion type is associated with prognosis. In order to investigate the predictive value of the PAX-FKHR fusion status on disease outcome of patients with RMA treated in the CWS trials we performed a retrospective analysis. PROCEDURE: Between 1986 and 2004, out of 446 patients with RMA treated in four consecutive CWS trials, tumor samples from 126 patients were available for RT-PCR analysis. Survival depending on fusion status in context with known clinical risk-factors was analyzed. RESULTS: Out of 126 samples, 121 had adequate quality for PAX-FKHR fusion status analysis. PAX-FKHR fusions were detected in 101 samples: 60% PAX3-FKHR and 24% PAX7-FKHR fusions, 17% were fusion-negative. There was no significant difference in survival between patients with PAX3-FKHR versus PAX7-FKHR positive tumors. The fusion transcript negative cohort showed a more favorable outcome than the fusion transcript positive cohort among patients with metastatic disease. From the established clinical risk-factors none was associated with a significantly higher risk of failure or death in a multivariate analysis. CONCLUSIONS: PAX-FKHR fusion type was not a significant predictor for survival in our analysis. More extensive molecular analyses are needed to identify features with prognostic relevance and useful therapeutic impact. PMID- 21254374 TI - Weight-based strategy of dose administration in children using intravenous busulfan: clinical and pharmacokinetic results. AB - BACKGROUND: A prospective clinical trial was performed in order to validate the pharmacokinetic (PK) and clinical benefits of a new dosing schedule of intravenous busulfan (IV Bu) in children. PROCEDURE: IV Bu was administered as a 2-hr infusion every 6 hr for 4 days. Five dose levels were given according to body-weight strata. RESULTS: The 67 children aged from 4 months to 17.2 years were followed up over 50 months after autologous or allogeneic stem-cell transplantation. Reduced PK variability was seen after IV Bu administration enabling efficient targeting with 78% of patients within the 900-1,500 uM . min therapeutic window and reproducible exposures across administrations. No neurological complications occurred. The low incidence of hepatic veno-occlusive disease (VOD) recorded was not correlated with high area under the curve (AUC). Only stomatitis was correlated with high AUC in the autologous group. The 4-year overall survival was 59% in the autologous group and 82% in the allogeneic group. CONCLUSION: The new dosing schedule using IV Bu provides adequate therapeutic targeting from the first administration, with low toxicity and good disease control in high-risk children. The choice of this formulation of Bu should be considered because of its low morbidity and good outcome. PMID- 21254375 TI - Multiple target molecular monitoring of bone marrow and peripheral blood samples from patients with localized neuroblastoma and healthy donors. AB - BACKGROUND: Multiple target molecular monitoring of minimal residual disease in neuroblastoma (NB) patients may increase sensitivity and overcome tumor heterogeneity. However, multiple target analysis is costly and time consuming, thus improvement with respect to single target monitoring needs to be achieved. PROCEDURES: Italian patients with localized NB were evaluated at diagnosis for TH, GD2-s, DDC, DCX, ELAV-4, STX, and Phox2b mRNA expressions. Patients with metastatic NB were tested as positive controls, together with NB primary tumors and cell lines, while healthy donors were tested as negative controls. RESULTS: All NB-related markers but Phox2b were expressed in healthy donors, and in a high percentage of patients with localized NB without association with clinical events. The introduction of cut-off levels increased marker specificity, although the percentage of positive results was only slightly modified. While TH positivity in PB samples significantly associated with a worse prognosis, a paradox association was found for GD2-s mRNA expression. No correlation and agreement between quantitative and qualitative results obtained with the two assays were found. In the set of samples tested for all markers, no pattern of expression was found to be associated with a specific clinical situation. CONCLUSION: These findings suggest that positive molecular results may not reflect the presence of disease, and that correlation among different markers is small in condition of low tumor burden. Thus, to reduce cost and amount of precious samples, in addition to TH, whose prognostic value was confirmed, only Phox2b warrants further evaluation in multi-center, prospective studies for high risk patients. PMID- 21254376 TI - Different outcome in older children with acute lymphoblastic leukemia with different treatment protocols in the Netherlands. AB - BACKGROUND: From 1991 until 2004 children with acute lymphoblastic leukemia (ALL) in the Netherlands were treated according to protocols ALL-8 and ALL-9 which were based on different principles. An earlier study showed that the outcome of adolescents highly differed on these protocols. PROCEDURE: In this retrospective study, we analyzed whether the outcome of older children 10-15 years of age at diagnosis differed between the Berlin-Frankfurt-Munster (BFM)-based ALL-8 regimen and the ALL-9 regimen. Two hundred fifty-four older children who were treated according to protocol ALL-8 (n = 82) or ALL-9 (n = 172) were included in the analysis. RESULTS: A higher 5-year event-free survival (EFS) rate was found for patients treated according to ALL-8 compared to ALL-9 (79 +/- 5% vs. 65 +/- 4%, P = 0.02). Patient characteristics did not differ except for a slightly higher age in ALL-8. Therefore, additional analyses were done including only patients who were 12-15 years of age. In this age group there was also a difference in the 5 year EFS (82 +/- 5% vs. 61 +/- 5%, P = 0.00) as well as in the 5-year overall survival rate; 89 +/- 4% compared to 68 +/- 5%, respectively (P = 0.01). Major difference between protocols was the use of a consolidation and reinduction/intensification course and higher cumulative doses of asparaginase, methotrexate, and anthracyclines in ALL-8. CONCLUSIONS: Children 10-15 years of age have been undertreated with the ALL-9 regimen and benefit by intensive treatment components as used in ALL-8. We recommend using BFM-based protocols for these older children with ALL. PMID- 21254377 TI - Adipokines, body fatness, and insulin resistance among survivors of childhood leukemia. AB - BACKGROUND: Following our previous reports of an increased prevalence of insulin resistance and adiposity among acute lymphoblastic leukemia (ALL) survivors, particularly women treated with cranial radiotherapy (CRT), we aimed to (1) assess the relationships between adipokines (leptin and adiponectin), CRT, and measures of body fatness and (2) determine correlates of insulin resistance, by gender. METHODS: We conducted cross-sectional evaluation of 116 ALL survivors (median age: 23.0 years; range: 18-37; average time from treatment: 17.5 years), including fasting laboratory testing (adiponectin, leptin, insulin, and glucose), anthropometric measurements (weight, height, and waist circumference), DXA (total body fat and truncal-to-lower-body-fat ratio), and abdominal CT (visceral fat). We estimated insulin resistance using the homeostasis model for assessment of insulin resistance (HOMA-IR). Analytic approaches included regression models and Wilcoxon rank sum testing. RESULTS: Mean leptin per kilogram fat mass was higher for females (0.7 ng/ml/kg) than males (0.4 ng/ml/kg, P < 0.01), and among subjects who had received CRT compared to those who had not received CRT (females CRT =0.9 ng/ml/kg, no CRT = 0.7 ng/ml/kg; P = 0.1; males CRT = 0.5 ng/ml/kg, no CRT = 0.3 ng/ml/kg; P < 0.01). Elevated HOMA-IR was nearly uniformly present, even among subjects with BMI < 25 kg/m(2), and was associated with higher leptin:adiponectin ratio (LA ratio; P < 0.01). CONCLUSIONS: Among survivors of childhood leukemia, higher leptin levels were associated with measures of body fat and insulin resistance. Anthropomorphic and metabolic changes many years after ALL treatment remain a major health problem facing survivors and may be related to central leptin resistance. PMID- 21254378 TI - The utility of performing the initial lumbar puncture on day 8 in remission induction therapy for childhood acute lymphoblastic leukemia: TCCSG L99-15 study. AB - BACKGROUND: Traumatic lumbar puncture with leukemic blasts (TLP+), which has been reported to occur 5-10%, in the previous studies, adversely affects the outcome of children with acute lymphoblastic leukemia (ALL). Based on the results from our previous study, we deferred the initial lumbar puncture until day 8 in remission induction therapy in order to reduce the frequency of cases with TLP+. PROCEDURE: The study was conducted as a prospective cohort study within the Tokyo Children's Cancer Study Group (TCCSG) L99-15 study. Between April 1999 and June 2003, 754 children with newly diagnosed ALL enrolled. The patients received the initial intrathecal chemotherapy after 7 days of prednisolone treatment. The incidence of central nervous system (CNS)-positive (the presence of leukemic blasts in cerebrospinal fluid or cranial nerve palsy) including TLP+ cases and cumulative incidence of CNS relapse were examined. RESULTS: The incidence of CNS positive and TLP+ was 2.9% (n = 22) and 0.8% (n = 6), respectively. These incidences were much lower than those in the representative study groups employing the initial IT on day 1. Of 22 patients with CNS-positive, only one patient relapsed in CNS, whereas 22 of the remaining CNS-negative 723 patients suffered from CNS relapse. Overall, event-free survival at 4 year was 78.2 +/- 1.6%. Four-year cumulative incidence of any CNS relapse was 3.3 +/- 0.7%, which improved from our previous study in spite of limiting the use of cranial irradiation. CONCLUSIONS: Our strategy reduced the frequency of CNS-positive patients who required reinforcement of CNS-directed therapy without compromising overall outcome. PMID- 21254379 TI - The epidemiology of herpes zoster in 226 children with acute lymphoblastic leukemia. AB - BACKGROUND: Herpes zoster (HZ) is rare in healthy children, but may occur frequently and take a complicated course in children receiving chemotherapy. We determined the morbidity related to HZ in children with acute lymphoblastic leukaemia (ALL). PROCEDURE: Medical records of 226 children diagnosed with ALL were reviewed. Of these, 160 were seropositive at the time of diagnosis. HZ eruptions during primary chemotherapy, during therapy for relapse and following bone marrow transplantation (BMT) were registered. RESULTS: A total of 90 eruptions were recorded: 63 first-time attacks and 27 recurrent episodes among 14 children. All eruptions were treated with acyclovir (ACV) and in 60% it was given intravenously. Cutaneous dissemination occurred in 11 cases, post herpetic neuralgia in five, visceral dissemination in none. During primary chemotherapy 47 children (29%) had HZ. The eruption rate was significantly higher in children on high risk protocols compared to children on standard/intermediate risk protocols (0.36 vs. 0.07/0.09 per year) and was related to intensity of chemotherapy. During therapy for relapse 7 of 29 (24%) had a total of 13 eruptions. Following BMT 9 of 26 (35%) had a total of 10 eruptions. CONCLUSION: Almost one third of the seropositive children had HZ during primary chemotherapy. Of those treated on high risk protocols more than half had one or more eruptions during the course of treatment. The risk of complicated HZ is small, but prolonged intensive chemotherapy can lead to considerable morbidity from repeated eruptions. Attempts to improve immunity by vaccination after attaining remission seem warranted. PMID- 21254380 TI - Late effects in childhood cancer survivors: a review with a framing effect bias? AB - Most publications report the adverse (negative) health issues in childhood cancer survivors. Presenting information to the newly diagnosed patient in a positive manner is advocated, while noting that recurrence is the most likely adverse event. Re-analysis of population-based studies on life-threatening toxicities from Nordic, Dutch, United Kingdom, French, Italian, and N. American publications shows that 5-year survivors have a near normal life expectancy, 75% have no severe or life-threatening treatment related toxicity and 87% remain free of a second malignancy. Children who received radiation or anthracycline >250-300 mg/m(2) are at greatest risk for treatment related life-threatening toxicities. PMID- 21254381 TI - Surface chemical patterning for long-term single-cell culture. AB - Surface chemical patterning of polystyrene (PS) dishes for long-term single-cell culture was accomplished by oxygen plasma treatment through the windows of a polydimethylsiloxane membrane mask that produced hydrophilic areas of different shapes and sizes, followed by overnight incubation with either Pluronic F108 solution or a mixture of Pluronic F108 solution and fibronectin. Selective cell attachment on pattern areas of PS dishes was investigated in light of cell seeding experiments and X-ray photoelectron spectroscopy measurements. Activation of the hydrophilic areas of patterned PS surfaces by serum proteins in the culture medium was conducive to cell attachment on the pattern areas of dishes incubated with only Pluronic solution. Preferential adsorption of fibronectin on hydrophilic pattern areas enhanced selective cell attachment on patterned dishes incubated with a mixture of Pluronic solution and fibronectin. Cell-culture experiments demonstrated an effect of surface patterning on both cell and nucleus shape and confirmed the long-term (>2 weeks) stability of the produced single cell patterns in serum medium. PMID- 21254382 TI - Polysorbate cationic synthetic vesicle for gene delivery. AB - Synthetic nonionic surfactant vesicles (niosomes) are a colloidal system with closed bilayer structures, displaying distinct advantages in stability and cost compared with liposomes. In this article, polysorbate cationic niosomes (PCNs) were developed as gene carriers. The PCNs comprised nonionic surfactants (i.e., polysorbates) and a cationic cholesterol, and were synthesized using a film hydration method. The niosomes thus prepared possessed a regular morphology, and a particle size of 100 ~ 200 nm, and a zeta potential of +30 ~ 45 mV. The PCNs showed great physical stability over the course of 4 weeks at room temperature. The binding capacity of PCNs toward oligodeoxynucleotides (ODN) was assessed by a gel retardation approach, which demonstrated that the ionic complexes were formed when +/- charge ratio reached to 4 or greater. Gene transfer study showed that the PCNs exhibited a high efficiency in mediating cellular uptake and transferred DNA expression. Based on these findings, PCNs may offer the potential to function as an effective gene delivery system. PMID- 21254384 TI - Adhesion and growth of dental pulp stem cells on enamel-like fluorapatite surfaces. AB - To study how apatite crystal alignment of an enamel-like substrate affects DPSC cellular adhesion and growth as a precursor to produce an in vitro enamel/dentin superstructure for future studies. The cells were subcultured in 10% FBS DMEM up to seven weeks on the two surfaces. Specimens were observed under SEM, counted, and analyzed using the human pathway-focused matrix and adhesion PCR array. After three days, the cell number on ordered FA surface was significantly higher than on the disordered surface. Of the 84 focused pathway genes, a total of 20 genes were either up or down regulated in the cells on ordered FA surface compared to the disordered surface. More interestingly, of the cell-matrix adhesion molecules, integrin alpha 7 and 8 (ITGA 7 and 8), integrin beta 3 and 4 (ITGB3 and 4), and the vitronectin receptor-integrin alpha V (ITGAV) and the key adhesion protein-fibronectin1 (FN1) were up-regulated. In SEM, both surfaces showed good biocompatibility and supported long term growth of DPSC cells but with functional cell-matrix interaction on the ordered FA surfaces. SIGNIFICANCE: The enhanced cellular response of DPSC cell to the ordered FA crystal surface involves a set of delicately regulated matrix and adhesion molecules which could be manipulated by treating the cells with a dentin extract, to produce a dentin/enamel superstructure. PMID- 21254385 TI - Influence of polysaccharide composition on the biocompatibility of pullulan/dextran-based hydrogels. AB - The implantation of a biomaterial for tissue engineering requires the presence of a suitable scaffold on which the tissue repair and regeneration will take place. Polymers have been frequently used for that purpose because they show similar properties to that of the natural extracellular matrix. Scaffold properties and biocompatibility are modulated by the composition of the polymers used. In this work four polysaccharide-based hydrogels (PSH) made of dextran and pullulan were synthesized. Their in vitro properties were determined and then tested in vivo in a rat model. As pullulan concentration increased in dextran hydrogels, the glass transition temperature and the maximum modulus decreased. In vitro degradation studies for 30 days demonstrated no significant degradation of PSH except for 100% pullulan hydrogel. In vivo tissue response evaluated 30 days after PSH subcutaneous implantation in rats indicated that all PSH were surrounded by a fibrous capsule. Adding pullulan to dextran induced an increased inflammatory reaction compared to PSH-D(100% dextran) or PSH-D(75)P(25)(75% dextran). This in vitro and in vivo data can be used in the design of hydrogels appropriate for tissue engineering applications. PMID- 21254383 TI - PLGA-chitosan/PLGA-alginate nanoparticle blends as biodegradable colloidal gels for seeding human umbilical cord mesenchymal stem cells. AB - The natural polymers chitosan and alginate represent an attractive material choice for biodegradable inplants. These were used as coating materials to make positively and negatively charged PLGA nanoparticles, respectively. After blending at total solids concentration >10% wt/vol, these oppositely charged nanoparticles yielded a cohesive colloidal gel. Electrostatic forces between oppositely charged nanoparticles produced a stable 3D porous network that may be extruded or molded to the desired shape. This high concentration colloidal system demonstrated shear-thinning behavior due to the disruption of interparticle interactions. Once the external force was removed, the cohesive property of the colloidal gel was recovered. Scanning electron micrographs of dried colloidal networks revealed an organized, 3D microporous structure. Rheological studies were employed to probe the differences in plasticity and shear sensitivity of colloidal gels. Viability tests of hUCMSCs seeded on the colloidal gels also demonstrated the negligible cytotoxicity of the materials. All the results indicated the potential application of the biodegradable colloidal gels as an injectable scaffold in tissue engineering and drug release. PMID- 21254386 TI - Angiogenesis and osteogenesis enhanced by bFGF ex vivo gene therapy for bone tissue engineering in reconstruction of calvarial defects. AB - Reconstruction of bone defects by tissue engineered substitutes requires coordinated coupling between osteogenesis and angiogenesis. Basic fibroblast growth factor (bFGF or FGF-2) is a protein which acts actively in osteogenesis and angiogenesis during skeletal healing and development. It is hypothesized that BMSCs transfected with bFGF can directly stimulate regeneration of vascular tissue, and subsequently enhance osseous formation and remodeling after implantation of the tissue engineered bone. This study was designed to examine the impact of bFGF-BMSCs, seeded on nano-hydroxyapatite/polyamide66 (n-HA/PA66) composite scaffold, to enhance angiogenesis and osteogenesis in a calvarial critical-sized defect model in rats. To investigate the vascularization and bone formation of tissue engineered bone, the substrate was removed and processed for immunohistochemical, scanning electron microscopic examinations (SEM), reverse transcriptase-polymerase chain reaction (RT-PCR), dual energy X-ray absorptiometry (DEXA), microvessels counting, and new bone volume assay. The results demonstrate that bFGF mediated ex vivo gene transfer based on BMSCs can accelerate vascularization and bone regeneration on these composite scaffolds. The n-HA/PA66 scaffold combined with the bFGF-BMSCs may mimic the natural process of osteogenesis during repair of defect by tissue engineered bone. PMID- 21254388 TI - Controlling the porosity of fibrous scaffolds by modulating the fiber diameter and packing density. AB - Porosity has been shown to be a key determinant of the success of tissue engineered scaffolds. A high degree of porosity and an appropriate pore size are necessary to provide adequate space for cell spreading and migration as well as to allow for proper exchange of nutrients and waste between the scaffold and the surrounding environment. Electrospun scaffolds offer an attractive approach for mimicking the natural extracellular matrix (ECM) for tissue engineering applications. The efficacy of electrospinning is likely to depend on the interaction between cells and the geometric features and physicochemical composition of the scaffold. A major problem in electrospinning is the tendency of fibers to accumulate densely, resulting in poor porosity and small pore size. The porosity and pore sizes in the electrospun scaffolds are mainly dependent on the fiber diameter and their packing density. Here we report a method of modulating porosity in three dimensional (3D) scaffolds by simultaneously tuning the fiber diameter and the fiber packing density. Nonwoven poly(epsilon caprolactone) mats were formed by electrospinning under various conditions to generate sparse or highly dense micro- and nanofibrous scaffolds and characterized for their physicochemical and biological properties. We found that microfibers with low packing density resulted in improved cell viability, proliferation and infiltration compared to tightly packed scaffolds. PMID- 21254387 TI - Characterization of cytolytic neutrophil activation in vitro by amorphous hydrated calcium phosphate as a model of biomaterial inflammation. AB - Calcium ions are utilized in biomolecular biomaterial design for osteomimetic scaffolds and as divalent cross-linking agents, typically for gelation of alginates, stabilisation of protein structure (e.g., fibrinogen) and enzyme activation (e.g., thrombin). Biological interactions with defined calcium phosphates (e.g., hydroxyapatite) are exploited for osteogenesis, although crystalline calcium phosphates (e.g., calcium pyrophosphate) stimulate inflammation. We found that the calcium concentration used in the manufacture of prototype dermal scaffolds made from fibrin/alginate composite was related to the inflammatory infiltration during in vivo integration. In investigating a cause for this inflammatory response, we have identified and characterized a cytolytic inflammatory effect of amorphous calcium phosphate (CaP) formed in physiological solutions, relevant to biomaterial biocompatibility. Isolated human neutrophils (Nphi) were incubated in phosphate-buffered saline with CaCl(2) ranging 2.5-20 mM total calcium. Nphi activation was assessed by morphology and integrin-beta2 (CD18a) expression. Mediator release (Nphi-elastase, IL-8, and TNFalpha) was measured from both Nphi and whole blood cultures plus CaCl(2). CaP exposure increased CD18a expression over 1 h (maximal at 10 mM calcium/ phosphate) with concurrent phagocytosis, cytolysis, and Nphi-elastase release. CaCl(2) induced expression of IL-8 and TNFalpha in whole blood cultures. These results suggest that CaP formed from the resorption of calcium-containing biomaterials could induce inflammation and accelerate biomaterial degradation, driving further CaP release. This demonstrates a novel mechanism for biomaterial-induced inflammation. The in vitro system described could aid preclinical evaluation of novel biomaterial inflammatory potential. PMID- 21254389 TI - Hyaluronic acid stimulates neovascularization during the regeneration of bone marrow after ablation. AB - Restoration of vasculature is a critical component for successful integration of implants in musculoskeletal tissue. Sodium hyaluronate (NaHY) has been used as a carrier for demineralized bone matrix (DBM). DBM is osteoinductive and osteoconductive, but whether NaHY by itself has an effect is not known. NaHY has been reported to promote neovascularization, suggesting it may increase neovasculature when used with DBM as well. To test this, we used a rat tibial marrow ablation model to assess neovascularization during bone formation and regeneration of marrow with different combinations of NaHY alone and NaHY+DBM. To assess neovascularization during normal healing, animals were euthanized at 3-, 6 , 14-, 21-, and 28-days post-ablation, and the vasculature perfused using a radio opaque contrast agent. Vascular morphology was assessed using MUCT and histology. Peak vessel volume within the marrow cavity was observed on day-14 post-ablation. Test materials were injected into the ablated marrow space as follows: (A) empty defect controls; (B) high MW (700-800 kDa) NaHY + heat inactivated DBM; (C) DBM in PBS; (D) low MW NaHY (35 kDa) + DBM; (E) high MW NaHY + DBM; (F) D:E 50:50; (G) low MW NaHY; (H) high MW NaHY; and (I) G:H 50:50. Neovascularization varied with bone substitute formulation. MUCT results revealed that addition of NaHY resulted in an increase in vessel number compared to empty defects. Total blood vessel volume in all NaHY only groups were similar to DBM alone. Histomorphometry of sagittal sections showed that all three formulations of NaHY increased blood vessel number within the marrow cavity, confirming that NaHY promotes neovascularization. PMID- 21254390 TI - Characterization of bionanocomposite scaffolds comprised of amine-functionalized single-walled carbon nanotubes crosslinked to an acellular porcine tendon. AB - Carbon nanotubes (CNT) possess many unique electrical and mechanical properties that make them useful for a variety of industrial and biomedical applications. They are especially attractive materials for biomedical applications since their dimensions are similar to components of the extracellular matrix. In this study, amine-functionalized single-walled carbon nanotubes were crosslinked to an acellular porcine diaphragm tendon. The resulting bionanocomposite scaffolds were subjected to a number of materials characterization techniques including a collagenase assay, uniaxial tensile testing, modulated differential scanning calorimetry, and attenuated total reflectance Fourier transform infrared (ATR FTIR) spectroscopy to determine whether the properties of the original extracellular matrix were altered by the treatment processes. A variety of SWCNT concentrations were investigated. While none of the conditions investigated resulted in bionanocomposites with significantly improved physicochemical properties, no detrimental effects were observed due to any of the processing steps. Future studies should be performed to determine if carbon nanotubes can influence cellular adhesion and function in order to promote rapid integration and remodeling. PMID- 21254391 TI - The administration of BDNF and GDNF to the brain via PLGA microparticles patterned within a degradable PEG-based hydrogel: Protein distribution and the glial response. AB - Tailored delivery of neurotrophic factors (NFs) is a critical challenge that continues to inhibit strategies for guidance of axonal growth in vivo. Of particular importance is the ability to recreate innervation of distant brain regions by transplant tissue, for instance rebuilding the nigrostriatal track, one focus in Parkinson's disease research. Many strategies have utilized polymer drug delivery to target NF release in space and time, but combinatorial approaches are needed to deliver multiple NFs at relevant therapeutic times and locations without toxic side effects. Here we engineered a paradigm of PLGA microparticles entrapped within a degradable PEG-based hydrogel device to locally release two different types of NFs with two different release profiles. Hydrogel/microparticle devices were developed and analyzed for their ability to release GDNF in the caudal area of the brain, near the substantia nigra, or BDNF in the rostral area, near the striatum. The devices delivered their respective NFs in a region localized to within 100 MUm of the bridge, but not exclusively to the targeted rostral or caudal ends. BDNF was slowly released over a 56-day period, whereas a bolus of GDNF was released around 28 days. The timed delivery of NFs from implanted devices significantly reduced the microglial response relative to sham surgeries. Given the coordinated drug delivery ability and reduced localized inflammatory response, this multifaceted PEG hydrogel/PLGA microparticle strategy may be a useful tool for further development in combining tissue engineering and drug delivery, and recreating the nigrostriatal track. PMID- 21254392 TI - Real-time flow cytometry for the kinetic analysis of oncosis. AB - The standard method of distinguishing apoptotic and oncotic cells has been by microscopic analysis of nuclei and cell membrane morphology. Thus a rapid test for analyzing large numbers of cells in the study of cell necrobiology has not been possible until the recent advent of the Amnis Image-stream and real-time Lab on-a-Chip technologies. An interesting difference between apoptosis and oncosis is that they are ATP dependent and independent processes, respectively. Here we describe an assay measuring real-time kinetic changes in the potential differences of the inner mitochondrial membrane (mmp) and the plasma membrane (pmp) in cells immediately before and after the addition of the inducing agent. Live cells were loaded with carbocyanine dye DiIC(1) (5) and bis-oxonol (DiBAC(4) (5)) to measure mmp and pmp in conjunction with annexin V-FITC and DAPI labeling for gating out annexin V binding cells and dead cells respectively. Live cells gave specific membrane signatures in response to apoptotic or oncotic reagents in real-time. Apoptosis showed little change in mmp and pmp signals over the course of 25 min, the mitochondria only showed a slight hyperpolarization. In contrast chemical treatment with oxidative phosphorylation blocker, sodium azide (SA) caused an immediate hyperpolarization spike followed by a complete abrogation of mmp over a 25 min time course. Treatment with SA (1%) also caused plasma membrane depolarization. Likewise detergent (0.01% Triton X-100) treatments also caused abrogation of mmp and depolarization of pmp. Whereas heat shock (42 degrees C) treatment showed only a slight mitochondrial membrane potential depolarization. These flow cytometric observations were confirmed by confocal microscopy. This novel real-time kinetic assay measuring mitochondrial and plasma membrane potential changes has important implications in the field of cell necrobiology in that it allows the researcher to differentiate apoptotic and oncotic processes in an immediate manner for the first time. PMID- 21254393 TI - Impact of a probiotic Enterococcus faecalis in a gnotobiotic mouse model of experimental colitis. AB - SCOPE: IL-10-deficient (IL-10(-/-) ) mice are susceptible to the development of chronic intestinal inflammation in response to the colonization with commensal Enterococcus faecalis isolates. The aim of this study was to characterize the impact of a probiotic E. faecalis strain in germ-free, wild-type (WT), and disease-susceptible IL-10(-/-) mice. METHODS AND RESULTS: The probiotic E. faecalis and the colitogenic control strain OG1RF induced IL-6 and IFN-gamma inducible protein-10 secretion in the murine intestinal epithelial cell line Mode K. Epithelial cell activation involved nuclear factor kappa B, p38 and extracellular signal-regulated kinase 1/2-dependent pathways. Mouse embryonic fibroblasts from WT and toll-like receptor-2-deficient (TLR-2(-/-) ) mice confirmed that both E. faecalis strains trigger pro-inflammatory responses via the pattern recognition receptor TLR-2. Monoassociation of germ-free IL-10(-/-) mice with the probiotic E. faecalis strain revealed pro-inflammatory epithelial cell activation and colonic tissue pathology. The non-pathogenic nature of E. faecalis was confirmed in monoassociated WT mice. 2-DE and MALDI-TOF MS identified the ER stress chaperone Hspa5 (glucose-regulated protein 78) and 3 mercaptopyruvate sulfurtransferase as key targets in the epithelium from IL-10(-/ ) and TLR-2(-/-) mice. CONCLUSION: This study shows the potential of probiotic bacteria to initiate pro-inflammatory responses in the disease-susceptible but not the normal host. PMID- 21254395 TI - Pharmacokinetics of alpha-mangostin in rats after intravenous and oral application. AB - SCOPE: The xanthone alpha-mangostin is one of the major bioactive secondary metabolites in Garcinia mangostana. Until now, in vivo studies on the absorption, bioavailability, disposition, and metabolism of alpha-mangostin are limited. METHODS AND RESULTS: In the present study, an LC-MS/MS assay has been established for the determination of alpha-mangostin in rat plasma. The validated method was used successfully to support pharmacokinetic studies in rats after intravenous (i.v.) and oral administration. Both non-compartmental and compartmental analyses were performed, where the two-compartment body model had a good fit with the i.v. data. Following i.v. administration, the disposition of alpha-mangostin in rat plasma was biphasic, subdivided into a fast distribution and a slow elimination phase. The half-life of the distribution phase was 3 min, and that of the terminal elimination phase 3.5 h, indicating a high tissue binding. However, for oral administration, the bioavailability was so low that it was not possible to obtain a full concentration-time profile. CONCLUSION: Although pure alpha mangostin has shown a variety of pharmacological activities in in vitro assays at present it is uncertain if the same magnitude of effects will be achieved in vivo when its low bioavailability is considered. PMID- 21254394 TI - Resveratrol prevents embryonic oxidative stress and apoptosis associated with diabetic embryopathy and improves glucose and lipid profile of diabetic dam. AB - SCOPE: Diabetic embryopathy, a consequence of diabetic pregnancy, is associated with increase in embryonic oxidative stress and apoptosis, which lead to severe embryonic damage at early stage of organogenesis. METHODS AND RESULTS: This study investigated if resveratrol, found in red grapes and blue-berries, may prevent diabetes-induced oxidative stress and apoptosis in embryos and have beneficial effects in diabetic dams. A rodent model of diabetic embryopathy was used. Diabetes was associated with lowered reduced glutathione levels (26.98%), increased total thiol (100.47%) and lipid peroxidation (124.73%) in embryos, and increased blood sugar (384.03%), cholesterol (98.39%) and triglyceride (1025.35%) in diabetic dams. Increased apoptosis (272.20%) was also observed in the embryos of diabetic dams. Administration of resveratrol (100 mg/kg body weight (b.w.)) during pregnancy prevented both oxidative stress and apoptosis in embryos. Resveratrol reduced embryonic maldevelopment by improving embryo weight (41.23%), crown rump length (16.50%) and somite number (11.22%). It further improved the glucose (33.32%) and lipid (cholesterol 41.74%, triglyceride 60.64%) profile of the diabetic dams, which also represents the protective role of resveratrol in diabetes. CONCLUSION: Resveratrol was found to prevent embryonic oxidative stress and apoptosis. It also improved glucose and lipid profile of diabetic dams, indicating the beneficial effects in diabetic pregnancy. PMID- 21254396 TI - Well shaped Mn3O4 nano-octahedra with anomalous magnetic behavior and enhanced photodecomposition properties. AB - Very uniform and well shaped Mn3O4 nano-octahedra are synthesized using a simple hydrothermal method under the help of polyethylene glycol (PEG200) as a reductant and shape-directing agent. The nano-octahedra formation mechanism is monitored. The shape and crystal orientation of the nanoparticles is reconstructed by scanning electron microscopy and electron tomography, which reveals that the nano octahedra only selectively expose {101} facets at the external surfaces. The magnetic testing demonstrates that the Mn3O4 nano-octahedra exhibit anomalous magnetic properties: the Mn3O4 nano-octahedra around 150 nm show a similar Curie temperature and blocking temperature to Mn3O4 nanoparticles with 10 nm size because of the vertical axis of [001] plane and the exposed {101} facets. With these Mn3O4 nano-octahedra as a catalyst, the photodecomposition of rhodamine B is evaluated and it is found that the photodecomposition activity of Mn3O4 nano octahedra is much superior to that of commercial Mn3O4 powders. The anomalous magnetic properties and high superior photodecomposition activity of well shaped Mn3O4 nano-octahedra should be related to the special shape of the nanoparticles and the abundantly exposed {101} facets at the external surfaces. Therefore, the shape preference can largely broaden the application of the Mn3O4 nano-octahedra. PMID- 21254397 TI - A study on the essential oil of Ferulago campestris: how much does extraction method influence the oil composition? AB - The essential oil of different parts of Ferulago campestris (Bess.) collected in Sicily has been extracted by microwave-assisted hydrodistillation (MAHD) and by classic hydrodistillation (HD). A comparative qualitative-quantitative study on the composition of the oils was carried out. A total of 100 compounds were identified in the oils obtained by MAHD, whereas 88 compounds characterized the HD oils. The most prominent components were, in all different parts of F. campestris and in both extraction methods, 2,4,5-trimethylbenzaldehyde and 2,4,6 trimethylbenzaldehyde isomers; the latter was not previously found. The attempt to evaluate where the oil components are located in all parts of the plant was carried out by means of a kinetic study. Then, electron microscopy observation on the different parts before and after MAHD and HD was performed. PMID- 21254398 TI - Supramolecular-based dispersive liquid-liquid microextraction: a novel sample preparation technique utilizes coacervates and reverse micelles. AB - The present study reports a novel sample enrichment method termed supramolecular based dispersive liquid-liquid microextraction (SM-DLLME). The SM solvent selected was made up of reversed micelles of decanoic acid dispersed in tetrahydrofuran (THF)-water. THF plays double role, not only acts as a disperser solvent but also causes self-assembly of decanoic acid. The contaminant used as a model was Malachite Green (MG). It was a cationic dye and was preconcentrated without any derivatization or ion-pair formation reaction. In SM-DLLME, the most important advantages of DLLME technique and preconcentration strategy based on the coacervation and reverse micelles have come together. Moreover, in this method, disadvantages of DLLME such as extraction capability of only hydrophobic analytes and hiring toxic and hazardous organic solvents as the extraction solvent and disadvantages of coacervation-based extraction method such as tedious, labor-intensive and time-consuming stirring procedure have been avoided. Several variables affecting the microextraction efficiency were investigated and optimized. Under the optimized conditions and preconcentration of only 5.00 mL of sample, the enhancement factor was 52, limit of detection (LOD) was 4 MUg/L and relative standard deviations (RSDs) for 145 and 36 MUg/L of MG in textile industry wastewater were 1.8 and 3.2%, respectively (n = 6). PMID- 21254399 TI - Preparation and chromatographic performance of calix[4]crown-5 macrocycle-bonded silica stationary phase. AB - A new calix[4]crown-5 macrocycle-bonded silica stationary phase (CL-CIMS) was prepared and applied at the same time to develop a chromatographic procedure to separate aromatic amines, phenols and drugs in this study. The chromatographic behaviors of the prepared stationary phase for these analytes were studied and compared with those of ODS (octadecylsilane). The effect of organic modifier content and pH of the mobile phase on retention and selectivity of these compounds were investigated. Some aromatic amines, phenols or drugs on CL-CIMS were successfully separated. The results show that CL-CIMS exhibits high selectivities for the above analytes in high aqueous mobile phases and a bright prospect in routine, fast separation of aromatic amines, phenols and drug compounds. From chromatographic data, it can be concluded that hydrophobic interaction is mainly responsible for the retention behavior as well as hydrogen bonding interaction, pi-pi and dipole-dipole interaction. PMID- 21254400 TI - Extraction, thermal cleanup, and GC/MS quantification with disposable solid extractants: application to hydrophobic analytes in aqueous surfactant solutions. AB - Fragranced consumer products are generally formulated together with surfactants. In application, these products are often highly diluted with water. Analyzing trace amounts of fragrance ingredients in such mixtures is challenging and usually requires either time-consuming sample cleanup or extensive cleaning of the trapping device to avoid memory effect and cross-contamination between samples. To overcome these limitations, a new disposable extraction device has been developed to be used in combination with a thermodesorption-GC-MS unit. Made of PDMS foam cylinders, it efficiently extracts trace amounts of hydrophobic compounds from complex aqueous solutions and provides an online sample cleanup, thanks to the controlled desorption temperature, which allows retaining the low volatile constituents of the matrix within the absorptive foam. Combined with a stable isotope dilution assay, accurate quantifications of Cetalox((r)), MuscenoneTM, Helvetolide((r)), Polysantol((r)), Dartanol, and Myrrhone((r)) from aqueous solution containing surfactant and from water from the aeration tank of a sewage plant were successfully conducted. LOQ varied between 1 and 25 ppb (20% confidence interval, alpha = 0.1). PMID- 21254401 TI - Surfactant-assisted pressurized liquid extraction for determination of flavonoids from Costus speciosus by micellar electrokinetic chromatography. AB - Micellar electrokinetic chromatography (MEKC), a mode of capillary electrophoresis (CE), is considered an efficient analytical technique allowing for the reduction of organic solvent consumption during the experimental procedure. However, during sample preparation of natural products, the usage of large amount of organic solvent is generally unavoidable. In this article, therefore, a fast, simple, efficient, highly automatic and organic solvent-free sample preparation method, namely surfactant-assisted pressurized liquid extraction (PLE), was developed for the extraction of flavonoids in Costus speciosus flowers before MEKC analysis. The various experimental parameters such as the type and concentration of surfactant, and extraction time were evaluated systematically. Under the optimized conditions, the extraction efficiencies of surfactant-assisted PLE methods were comparable with Soxhlet extraction using organic solvent. The combination of surfactant-assisted PLE and MEKC was shown to be a green, rapid and effective approach for extraction and analysis of flavonoids in C. speciosus flowers. PMID- 21254402 TI - Semi-synthetic polysaccharide sulfates as anticoagulant coatings for PET, 1- cellulose sulfate. AB - In the present study, blood-compatible PET surfaces were prepared by coating with anticoagulant cellulose sulfates that were synthesized homogeneously in ionic liquids. The adsorption behavior of polysaccharides on PET films was investigated using QCM-D. It was demonstrated that pre-coating with different amino-group containing polysaccharides improves the affinity toward cellulose sulfate. Moreover, the effect of different degrees of sulfation on the adsorption process was evaluated. Based on these results, several layer-by-layer coated PET foils were prepared that showed significantly improved blood compatibility compared to the initial untreated material. PMID- 21254403 TI - Parachuting in the epigenome: the biology of gene vector insertion profiles in the context of clinical trials. AB - Retroviral pre-integration complexes(PICs) provide a most efficient mechanism to integrate foreign DNA into cellular chromatin. This has made retrovirus-based vectors a preferred tool for gene delivery in therapeutic settings where the chromosomal integration of a recombinant expression cassette that encodes a protein of interest can lead to a long-lasting correction of monogenetic diseases (so-called gene addition strategy). However, the efficiency of retroviral gene addition comes at the expense of a lack of precision in the choice of the integration site. Insertional mutagenesis with potential activation of proto oncogenes as a first hit in a multistep scenario of cancer development thus represents one of the major hurdles to a more widespread exploration of gene based treatments (Kustikova et al, 2010). To date, four clinical trials were reported to be associated with severe adverse reactions induced by insertional mutagenesis in haematopoietic stem and progenitor cells (HSC/P); two targeting the X-linked form of severe combined immunodeficiency (SCID-X1), one targeting chronic granulomatous disease, and most recently another trial exploring gene therapy for the Wiskott-Aldrich-Syndrome. In contrast, in the SCID caused by mutations in the gene encoding the metabolic enzyme adenosine deaminase (ADA), retroviral gene addition so far has been free of such complications. Furthermore, numerous trials using similar gene vectors to transfer genes into mature T cells have not been complicated by clonal outgrowth.This explains the great interest ina deeper understanding of retroviral vector-host interactions in the therapeutic setting of SCID-ADA. PMID- 21254405 TI - For the 60th birthday of Eiichi Nakamura. PMID- 21254404 TI - Annexin A1 released from apoptotic cells acts through formyl peptide receptors to dampen inflammatory monocyte activation via JAK/STAT/SOCS signalling. AB - The immunosuppressive effects of apoptotic cells involve inhibition of pro inflammatory cytokine release and establishment of an anti-inflammatory cytokine profile, thus limiting the degree of inflammation and promoting resolution. We report here that this is in part mediated by the release of the anti-inflammatory mediator annexin A1 from apoptotic cells and the functional activation of annexin A1 receptors of the formyl peptide receptor (FPR) family on target cells. Supernatants from apoptotic neutrophils or the annexin A1 peptidomimetic Ac2-26 significantly reduced IL-6 signalling and the release of TNF-alpha from endotoxin challenged monocytes. Ac2-26 activated STAT3 in a JAK-dependent manner, resulting in upregulated SOCS3 levels, and depletion of SOCS3 reversed the Ac2-26-mediated inhibition of IL-6 signalling. This identifies annexin A1 as part of the anti inflammatory pattern of apoptotic cells and links the activation of FPRs to established signalling pathways triggering anti-inflammatory responses. PMID- 21254407 TI - Early-transition-metal catalysts with phenoxy-imine-type ligands for the oligomerization of ethylene. AB - Early-transition-metal complexes incorporating phenoxy-imine-type bidentate and tridentate ligands, after activation, can achieve selective as well as nonselective ethylene oligomerization to produce 1-hexene, linear alpha-olefins, and vinyl-terminated low-molecular-weight polyethylenes, all with high efficiency. PMID- 21254408 TI - Nitrogen-rich azoles as ligand spacers in coordination polymers. AB - N-heterocycle-based ligands are versatile building-blocks for coordination oligomer and polymer assemblies of first-row transition metals. Herein, we review recent developments in the design and synthesis of some nitrogen-rich azole-based ligands, their assembly modes in coordination oligomers and polymers, and the potential applications of the resulting metallosupramolecules. PMID- 21254409 TI - A lattice-engineering route to heterostructured functional nanohybrids. AB - The fabrication of layered nanomaterials, such as inorganic-inorganic, organic inorganic, and bioinorganic nanohybrids has been demonstrated through controlled lattice engineering techniques including intercalation, exfoliation-reassembling, and pillaring reactions. Such a lattice engineering method gives rise to an almost unlimited set of new hybrid compounds with a large spectrum of desirable properties. Due to the unique two-dimensional structures and properties, various kinds of functional nanohybrid materials can be utilized as photocatalysts, electrode materials, superconducting thin films, gas separation membranes, drug delivery systems, and biomolecule reservoirs. PMID- 21254410 TI - The synthesis of highly coplanar oligothiophenes induced by bulky rind groups. PMID- 21254411 TI - Nickel-catalyzed, directing-group-assisted [2+2+2] cycloaddition of imine and alkynes. PMID- 21254412 TI - Synthesis and self-assembly of macrocyclic mesogens based on 1,10-phenanthroline. PMID- 21254413 TI - Remote chiral induction in vinyl sulfonium salt-mediated ring expansion of hemiaminals into epoxide-fused azepines. PMID- 21254414 TI - A mechanistic study on the formation of silver nanoplates in the presence of silver seeds and citric acid or citrate ions. PMID- 21254415 TI - Selectivities in chiral Lewis acid catalyzed Diels-Alder reactions of acetylenic ketones: explanation for differences of selectivities between acylic and cyclic dienes. PMID- 21254416 TI - A general strategy for the introduction of stereogenic centers bearing a methyl group: total synthesis of sex pheromones. PMID- 21254417 TI - Olefin hydrosilylation catalysts based on allyl bis(phenolato) complexes of the early lanthanides. PMID- 21254418 TI - Indium triflate-catalyzed coupling between nitroalkenes and phenol/naphthols: a simple and direct synthesis of arenofurans by a cyclization reaction. PMID- 21254419 TI - Sulfonamidoquinoline/palladium(II)-dimer complex as a catalyst precursor for palladium-catalyzed gamma-selective and stereospecific allyl-aryl coupling reaction between allylic acetates and arylboronic acids. PMID- 21254420 TI - Scanning tunneling microscopy investigation of copper phthalocyanine and truxenone derivative binary superstructures on graphite. AB - The binary self-assembly of copper phthalocyanine (CuPc) and 2,3,7,8,12,13 hexahexyloxy-truxenone (TrO23) at the solid/liquid interface of highly oriented pyrolytic graphite (HOPG) was investigated by using scanning tunneling microscopy (STM) and scanning tunneling spectroscopy (STS). Pseduohexagonal and linear patterned superstructures of CuPc are obtained by co-adsorbing with TrO23. High resolution STM images reveal the structural details of the arrangement of TrO23 and CuPc in the binary assembly structures. The molecular ratio between CuPc and TrO23 in the adlayer can be modulated by the CuPc concentration in liquid phase. The electronic properties of CuPc and TrO23 in the co-adsorbed self-assembly are investigated by STS. The results presented here are helpful to the design and fabrication of multi-component functional molecular nanostructures. PMID- 21254421 TI - Multiple analyte response and molecular logic operations by excited-state charge transfer modulation in a bipyridine integrated fluorophore. AB - The tunable excited-state properties of a new donor-pi-acceptor-pi-donor-type fluorophore 1 with a bipyridyl moiety and its ability to respond to different analytes in solution and on paper microchannels are described. Furthermore, the multiple analyte response of fluorophore 1 has been exploited to perform multiple logic operations. Molecule 1, by virtue of its excited-state charge transfer, exhibits solvatochromism and reversible modulation of its emission in response to multiple chemical inputs, thus resulting in different fluorescent signals. The intraligand charge-transfer (ILCT) emission of 1 at 574 nm has been modulated to three emission outputs by using different chemical inputs, such as Zn(2+), H(+), and ethylenediaminetetraacetic acid (EDTA). Thus, different logic operations such as AND, 2-input-INH, 3-input-INH, IMP, and a combination of these logic operations could be achieved. PMID- 21254422 TI - Perylene-based nanotweezers: enrichment of larger-diameter single-walled carbon nanotubes. AB - The solubilization of single-walled carbon nanotubes (SWCNTs) by a novel tweezer shaped molecule with perylene bisimide moieties that act as aromatic anchoring groups is presented. Encouraging results of the tweezer-dispersion concept is combined with the outstanding exfoliation and dispersion efficiencies of designed perylene bisimide derivatives, which have previously turned out as most-powerful SWCNT dispersants. Based on the preferred interaction between the nanotweezer and SWCNTs with diameters larger than 0.8 nm, the supernatant was depleted after mild centrifugation in SWCNT species of smaller diameters. Characterization was carried out by a combination of UV/Vis and nIR absorption spectroscopy as well as emission spectroscopy of the SWCNTs and perylene. This study presents the foundation for a further improvement of selective SWCNT dispersion and sorting by designed molecules. PMID- 21254423 TI - Precision synthesis of hybrid block copolymers by organotellurium-mediated successive living radical and cationic polymerizations. AB - Living cationic polymerization reactions using organotellurium compounds as initiators are reported. Polymerization of vinyl ethers in the presence of an organotellurium initiator and a Lewis acid, such as In(OTf)(3) and BF(3).OEt(2), affords well-controlled poly(vinyl ether)s with predetermined molecular weights and narrow molecular-weight distributions. Poly(meth)acrylates possessing organotellurium group at the omega-polymer end, which are prepared using organotellurium-mediated controlled/living radical polymerization (TERP), are used as macroinitiators for living cationic polymerization. The one-pot, two-step reaction of the macroinitiator with vinyl ether under radical and cationic conditions gives well-controlled AB diblock copolymers. ABA triblock copolymers with controlled structures are also synthesized from a bifunctional organotellurium initiator. PMID- 21254425 TI - Asymmetric coordination chemistry by chiral-auxiliary-mediated dynamic resolution under thermodynamic control. AB - A method is presented for the asymmetric synthesis of chiral ruthenium polypyridyl complexes that starts from racemic cis-[Ru(pp)(2)Cl(2)] (pp=2,2' bipyridine or 1,10-phenanthroline ligands). The chiral bidentate ligands (R)-2 (isopropylsulfinyl)phenol, (R)-SO, and preferably the more electron-rich derivative (R)-2-(isopropylsulfinyl)-4-methoxyphenol, (R)-SO', serve as convenient chiral auxiliaries for the conversion of racemic starting complexes (1a: pp=2,2'-bipyridine; 1b: pp=5,5'-dimethyl-2,2'-bipyridine; c: pp=1,10 phenanthroline) into single diastereomers Lambda-[Ru(pp)(2){(R)-SO}]PF(6) (Lambda (S)-2a-c) or Lambda-[Ru(pp)(2){(R)-SO'}]PF(6) (Lambda-(S)-2a') under a thermodynamically controlled dynamic transformation. The complexes Lambda-(S)-2a c and Lambda-(S)-2a' themselves are direct precursors for the generation of optically active ruthenium-polypyridyl complexes by trifluoroacetic-acid-induced replacement of the sulfinylphenolate auxiliaries with bidentate pp ligands under retention of configuration, thereby affording Lambda-[Ru(pp)(3)](PF(6))(2) (3a-c) complexes with high enantiomeric ratios of >=98:2. In particular, by employing the methoxy-modified chiral auxiliary (R)-SO', enantiomeric ratios of >99:1 were reached. In the strategy introduced here, the high steric crowding of an octahedral coordination sphere was exploited by placing a sulfur-based stereocenter in direct proximity to the ruthenium stereocenter, thereby leading to a large difference in the stabilities of the intermediate Lambda-S and Delta-S diastereomers and thus providing the opportunity to find suitable reaction conditions for conversion of the destabilized diastereomer into the thermodynamically more-stable one. This method should be of high practical value for the asymmetric synthesis of ruthenium-polypyridyl complexes because it allows one to use readily available racemic ruthenium complexes as starting materials. PMID- 21254424 TI - Total synthesis and biological evaluation of a series of macrocyclic hybrids and analogues of the antimitotic natural products dictyostatin, discodermolide, and taxol. AB - The design, synthesis, and biological evaluation of a series of hybrids and analogues of the microtubule-stabilizing anticancer agents dictyostatin, discodermolide, and taxol is described. A 22-membered macrolide scaffold was prepared by adapting earlier synthetic routes directed towards dictyostatin and discodermolide, taking advantage of the distinctive structural and stereochemical similarities between these two polyketide-derived marine natural products. Initial endeavors towards accessing novel discodermolide/dictyostatin hybrids led to the adoption of a late-stage diversification strategy and the construction of a small library of methyl-ether derivatives, along with the first triple hybrids bearing the side-chain of taxol or taxotere attached through an ester linkage. Biological assays of the anti-proliferative activity of these compounds in a series of human cancer cell lines, including the taxol-resistant NCI/ADR-Res cell line, allowed the proposal of various structure-activity relationships. This led to the identification of a potent macrocyclic discodermolide/dictyostatin hybrid 12 and its C9 methoxy derivative 38, accessible by an efficient total synthesis and with a similar biological profile to dictyostatin. PMID- 21254426 TI - The effects of the 4-(4-Methylpiperazine)phenyl group on nucleosides and oligonucleotides: cellular delivery, detection, and stability. AB - As drug candidates, one promising way to improve the cellular delivery efficacy of oligonucleotides is to introduce a cationic group. By introducing a cationic moiety into the oligonucleotide structure, they become capable of approaching the cell surface and also of crossing the cellular membrane. In an effort to develop cell-permeable oligonucleotides, we examined the piperazinephenyl-bearing 2' deoxyuridine ((PP)U), which can be not only cationic but also fluorescent as a cationic monomer for cationic oligonucleotides. Several modified DNA oligonucleotides with different numbers of (PP)U building blocks were synthesized and evaluated for the effect on thermal stability and conformation by the introduction of (PP)U. The cellular delivery of modified oligonucleotides was different depending on the number of (PP)U building blocks. Furthermore, these (PP)U-modified oligonucleotides had sufficient fluorescence that we were able to identify the delivery results without the use of conventional fluorescent tags. They were predominantly localized in the cell cytoplasm. In addition, they were stable enough after 3 hours in the presence of nuclease. These results showed that a piperazinephenyl moiety that is conjugated with nucleobase is able to deliver and detect the oligonucleotides, which suggests that this concept of 'dual-function oligonucleotides' might be utilized in diagnostics, therapeutics, and as a convenient biological tool for probing the activity of oligonucleotides inside cells. PMID- 21254428 TI - New isomers of trifluoromethylated derivatives of metal nitride cluster fullerene: Sc3N@C80(CF3)n (n=14 and 16). AB - Sc(3)N@C(80) (I(h)) was trifluoromethylated with CF(3)I at 400 degrees C affording a mixture of CF(3) derivatives. Two isomers of Sc(3)N@C(80)(CF(3))(14) and Sc(3)N@C(80)(CF(3))(16) were separated by HPLC and investigated by X-ray crystallography. Detailed comparison of the four isomers revealed a strong influence of the exohedral CF(3) addition pattern on the behavior of the Sc(3)N cluster inside the C(80) fullerene cage. PMID- 21254427 TI - The axial ligand effect on aliphatic and aromatic hydroxylation by non-heme iron(IV)-oxo biomimetic complexes. AB - Iron(IV)-oxo heme cation radicals are active species in enzymes and biomimetic model complexes. They are potent oxidants in oxygen atom transfer reactions, but the reactivity is strongly dependent on the ligand system of the iron(IV)-oxo group and in particular the nature of the ligand trans to the oxo group (the axial ligand). To find out what effect the axial ligand has on the reactivity of non-heme iron(IV)-oxo species, we have performed a series of density functional theory (DFT) calculations on aliphatic and aromatic hydroxylation reactions by using [Fe(IV)=O(TMC)(L)](n+) (TMC=1,4,8,11-tetramethyl-1,4,8,11 tetraazacyclotetradecane, and L=acetonitrile or chloride). The studies show that the regioselectivity of aliphatic over aromatic hydroxylation is preferred. The studies are in good agreement with experimental product distributions. Moreover, the system with the acetonitrile axial ligand is orders of magnitude more reactive than that with a chloride axial ligand. We have analyzed our results and we have shown that the metal-ligand interactions influence the orbital energies and as a consequence also the electron affinities and hydrogen atom abstraction abilities. Thermodynamic cycles explain the regioselectivity preferences. PMID- 21254429 TI - DFT study of chiral-phosphoric-acid-catalyzed enantioselective Friedel-Crafts reaction of indole with nitroalkene: bifunctionality and substituent effect of phosphoric acid. AB - The enantioselective Friedel-Crafts reaction of indoles with nitroalkenes proceeds catalytically by means of a chiral-phosphoric-acid catalyst to afford products with high enantioselectivities (up to 91% ee). The use of a 3,3'-SiPh(3) substituted (R)-binol-derived (binol=1,1'-binaphthyl-2,2'-diol) catalyst and a free indole that bears an N-H moiety is essential to achieving high enantioselectivity as well as high yield. To elucidate the reaction mechanism and the origin of the high enantioselectivity, DFT calculations were carried out. The reaction proceeded through a cyclic transition state formed by the two-point binding of both substrates to the conjugated O-P-O moiety of the catalyst, in which indoles and nitroalkenes could be simultaneously activated by Bronsted acidic (proton) and basic (phosphoryl oxygen) sites, respectively. The enantioselectivity was entirely controlled by the steric effect between the 3,3' substituent group on the (R)-binol-derived phosphoric acid catalyst and the indole ring. When the sterically demanding SiPh(3) group was used as the 3,3' substituent group, the energy difference between the most-stable diastereomeric transition states that afforded the S and R products was increased to lead to the high enantioselectivity in agreement with the experimental results. PMID- 21254430 TI - Total synthesis and bioactivities of two proposed structures of maresin. AB - Maresin is a potent anti-inflammatory lipid mediator derived from docosahexaenoic acid (DHA). A highly convergent total synthesis of two proposed structures of C7 epimeric maresins from the four known fragments was achieved in 17 steps. The three key coupling reactions were the BF(3)-mediated alkyne attack on the epoxide, chiral titanium complex-promoted enantioselective alkyne addition to the aldehyde, and a Julia-Kocienski olefination. The two synthesized diastereomers were found to be comparably active in blocking neutrophil infiltration in the acute peritonitis model. PMID- 21254431 TI - Synthetic studies toward galbulimima alkaloid (-)-GB 13 and (+)-GB 16 and (-) himgaline. AB - Condensation of (S)-3-aminobutan-1-ol with 1,3-cyclohexane-dione followed by an intramolecular alkylation afforded bicyclic enamine 32, which was converted into enone 35 through a diastereoselective hydrogenation. Mukaiyama-Michael addition of a bicyclic silyl enol ether to 35 and subsequent stereochemistry inversion by means of an oxidation/reduction strategy provided lactone 41. After reduction of lactone 41 with LAH, Swern oxidation was carried out to give enone 46 upon a spontaneous intramolecular aldol reaction and cleavage of the ketal protecting group. SmI(2) -mediated carbonyl-alkene reductive coupling of 46 proceeded smoothly in refluxing tetrahydrofuran to deliver pentacyclic intermediate 49, which was oxidized with 2-iodoxybenzoic acid and then treated with trifluoroacetic acid to furnish (-)-GB 13. The overall yield was 6.1% over 19 linear steps. By following the known procedure, our synthetic (-)-GB 13 was converted into himgaline. In addition, by starting from lactone 41, the first total synthesis of (+)-GB 16, a newly isolated member of the gabulimima alkaloid family, was achieved. This synthesis features an intramolecular condensation between an amine and a 1,3-diketone moiety. PMID- 21254432 TI - In situ Raman and pulse reaction study on the partial oxidation of methane to synthesis gas over a Pt/Al2O3 catalyst. AB - Catalytic partial oxidation of methane (POM) to synthesis gas (syngas) over Pt/Al(2)O(3) was investigated by in situ microprobe Raman and pulse reaction methods with attention focused on the mechanism of syngas formation in the oxidation zone (i.e., the catalyst zone in which O(2) was still available in the reaction feed). It was found that the amount of platinum oxide in the catalyst under POM conditions was below the detection level of Raman spectroscopy. Raman bands of carbon species that originated from methane dissociation were detected at the entrance of the catalyst bed under working conditions. The results of the pulse reaction study on POM as well as steam and CO(2) reforming of methane at 700 degrees C with a contact time of less than 1 ms over the catalyst suggest that pyrolysis of methane on reduced platinum sites followed by coupling of two surface hydrogen atoms to H(2) and partial oxidation of surface carbon species to CO are the major reactions responsible for syngas formation in the oxidation zone. Under the experimental conditions, steam and CO(2) reforming of methane play only a minor role in syngas formation in the same reaction zone. The contribution of the last two reactions increases with increasing contact time. PMID- 21254433 TI - Asymmetric trisubstituted aziridination of aldimines and ketimines using n-alpha diazoacyl camphorsultams. AB - The acid-catalyzed reaction of diazoacetates and aldimines (Brookhart-Templeton aziridination) is now recognized as a reliable method to provide enantiomerically enriched disubstituted aziridines, thus owing to the development of asymmetric catalysis. However, the extension of this method to prepare trisubstituted aziridines has not been explored to date, even for racemic products. In this context, and considering their synthetic importance and lack of alternative direct synthetic methods, we recently launched a program to realize this unmet challenge. Herein, we report a detailed study, which led to the establishment of a highly stereoselective synthesis for various trisubstituted aziridines, building on the use of N-alpha-diazoacyl camphorsultams as a key component. PMID- 21254434 TI - Late-stage diversification of chiral N-heterocyclic-carbene precatalysts for enantioselective homoenolate additions. AB - A library of chiral triazolium salts has been prepared by late-state diversification of a triazolium amine salt. By utilizing a primary amine as a functional handle, a single triazolium salt can be transformed into a variety of chiral N-heterocyclic carbene precatalysts. This approach makes the preparation of chiral N-heterocyclic carbenes possible by a single-step modification of a triazolium salt, rather than the usual need for multistep organic synthesis and challenging heterocycle formation for each member of a catalyst library. We have screened these catalysts for control of diastereo- and enantioselectivity in a gamma-lactam-forming reaction between alpha,beta-unsaturated aldehydes and cyclic ketimines. PMID- 21254435 TI - Rate-acceleration in gold-nanocluster-catalyzed aerobic oxidative esterification using 1,2- and 1,3-diols and their derivatives. AB - Aerobic oxidation of aldehydes to 1,2- and 1,3-diol monoesters was catalyzed by polymer-incarcerated gold nanoclusters under ambient conditions. The esterification proceeded much faster with 1,2- and 1,3-diols and their derivatives rather than with methanol. PMID- 21254436 TI - Synthesis, structural characterization, and reactivity of Group 4 metallacarboranes bearing the ligand [H2C(C5Me4)(C2B9H10)]3-. AB - A new organic-inorganic hybrid ligand H(2)C(C(5)Me(4)H)(C(2)B(10)H(11)) (2) has been prepared. A selective deboration reaction with piperidine in ethanol resulted in the isolation of [Me(3)NH][H(2)C(C(5)Me(4)H)(C(2)B(9)H(11))] (3). An amine-elimination reaction of 3 with [Zr(NMe(2))(4)] produced a neutral metal amide complex [eta(5):eta(5)-H(2)C(C(5)Me(4))(C(2)B(9)H(10))]Zr(NMe(2))(NHMe(2)) (4). The double-ring-opening reaction of 4 with tetrahydrofuran (THF) afforded [eta(5):eta(5)-H(2)C(C(5)Me(4))(C(2)B(9)H(10))]Zr (OCH(2)CH(2)CH(2)CH(2))(2)N(CH(3))(2) (5). Treatment of the trianionic salt of 3 with [MCl(4)(thf)(2)] gave complexes [{eta(5):eta(5) H(2)C(C(5)Me(4))(C(2)B(9)H(10))}M(MU-Cl)(2)][Li(thf)(2)] (M=Zr (6), Hf (7)). Reaction of 6 with LiCH(2)TMS generated the ionic species [{eta(5):eta(5) H(2)C(C(5)Me(4))(C(2)B(9)H(10))}Zr(CH(2)TMS)(2)][Li(thf)(3)] (9). Interaction of complex 6 with KCH(2)(NMe(2))-o-C(6)H(4) led to the formation of the neutral metal alkyl complex [eta(5):eta(5)-H(2)C(C(5)Me(4))(C(2)B(9)H(10))]Zr[sigma:sigma CH(2)(NMe(2))-o-C(6)H(4)] (10). All complexes have been fully characterized by various spectroscopic techniques and elemental analyses. Some were further confirmed by single-crystal X-ray analyses. PMID- 21254438 TI - Stereoselectivity in trimethylenemethane (TMM) diyl mediated cycloaddition reaction to angularly fused triquinanes. AB - A thorough study on the diastereoselectivity in the TMM diyl mediated [2+3] cycloaddition reaction of monosubstituted linear substrates to form angularly fused triquinanes was carried out. Substitution at position 3 provided complete diastereoselectivity, while positions 1 and 4 induced marginal stereoselectivity. Position 2 did not show any influence on the diastereoselectivity. Position 4 turned out to be incompatible with the cycloaddition reaction as the carbene intermediate underwent O-Si bond insertion to form a dihydrofuran ring. PMID- 21254437 TI - Facile one-step catalytic grafting of N-hydroxysuccinimidyl-ester-functionalized methallylsilane onto silica for enzyme immobilization. AB - A one-step grafting method of NHS-ester group is described for the immobilization of enzymes onto a silica surface at room temperature. Pure NHS-ester functionalized methallylsilane was prepared as a grafting reagent and showed remarkable grafting efficiency with acid catalysts at room temperature. As a result, mesoporous silica balls bearing a covalently immobilized enzyme could be obtained with a high loading rate compared to conventional multistep grafting methods. This one-step procedure offers the advantages of precise measurement of the high loading efficiency of the NHS-ester group, and the exclusive formation of only the NHS-ester group, which reduces the presence of unreacted functionalities. PMID- 21254439 TI - U-shaped conformation of alkyl chains bound to a synthetic receptor cucurbit[8]uril. AB - The behavior of a series of alkanes bound to the molecular host cucurbit[8]uril (CB[8]) has been systematically studied by 2D (1)H NMR spectroscopy and isothermal titration calorimetry (ITC). CB[8] and alkyltrimethylammonium (C(m) TA(+), (CH(3))(3)N(+)C(m)H(2m+1), m=6-16) form 1:1 host-guest complexes with a high binding constant (K~10(6) m(-1)). The shortest hexyl chain of C(6)TA(+) can be fully encapsulated in an extended conformation inside the CB[8] cavity, which is driven by both enthalpy and entropy. However, for the longer aliphatic chains, C(8)-C(16), the long alkyl tails take a U-shaped conformation inside the cavity, and their complexation is dominantly or almost exclusively enthalpy-driven, owing to the increased van der Waals contact between the folded aliphatic chain and the inner wall of the host cavity. As the chain length increases from C(8) to C(16), the ammonium head group of the guests moves away from the portal of CB[8] while the long aliphatic tails maintain the U-shaped conformation inside the cavity. The complexation of C(m)TA(+) with CB[8] follows the enthalpy-entropy compensation rule commonly observed in molecular recognition systems. For example, among the guest molecules, C(12)TA(+) shows the highest enthalpic gain (most favorable), owing to the large van der Waals contact between the guest and the host cavity, and at the same time the most unfavorable entropic contribution, owing to the severe conformational restriction of the U-shaped alkyl chain inside the host. The enthalpy-entropy compensation plot for the complexation suggests large conformational changes of the long alkyl chains and extensive dehydration associated with the inclusion complex formation. PMID- 21254440 TI - Scope and mechanism of tandem aza-Michael reaction/enantioselective protonation using a Pd-MU-hydroxo complex under mild conditions buffered with amine salts. AB - The tandem aza-Michael reaction/enantioselective protonation of alpha-substituted alpha,beta-unsaturated carbonyl compounds is described in detail. The key to success is the combined use of a Bronsted basic palladium-MU-hydroxo complex and amine salts, which allows for the controlled generation of active catalyst and nucleophilic free amines. This catalytic system was applicable to various acceptors and aromatic amines, and the desired beta-amino acid derivatives with a chiral center at the alpha position were produced in good yield with excellent enantioselectivity (up to 98% ee). For electron-deficient amines, the introduction of free amine as an additive was effective in promoting the reaction. The results of mechanistic studies, including determination of the absolute configuration of the product, are discussed. PMID- 21254441 TI - Synthesis of chiral biphenol-based diphosphonite ligands and their application in palladium-catalyzed intermolecular asymmetric allylic amination reactions. AB - A library of new 2,2'-bis(diphenylphosphinoyloxy)-1,1'-binaphthyl (binapo)-type chiral diphosphonite ligands was designed and synthesized based on chiral 3,3',5,5',6,6'-hexasubstituted biphenols. These bop ligands have exhibited excellent efficiency in a palladium-catalyzed intermolecular allylic amination reaction, which provides a key intermediate for the total synthesis of Strychnos indole alkaloids with enantiopurities of up to 96% ee. PMID- 21254442 TI - Anionic activators for differential sensing with cell-penetrating peptides. AB - The design, synthesis, and evaluation of small peptides with one to three negative charges and one to three hydrazides as key components of membrane-based synthetic sensing systems are reported. Their spontaneous reaction with hydrophobic aldehydes or ketones gives rapid access to small collections of amphiphilic anions. These anionic amphiphiles can activate polycations as anion transporters in lipid-bilayer membranes. Odorants are used as representative hydrophobic aldehydes and ketones, and cell-penetrating peptides (CPPs) as polycationic transporters in fluorogenic vesicles. Different activities obtained with different counterion activators are used to generate multidimensional patterns that can be recognized by principal component and hierarchical cluster analysis to extract unique "fingerprints" for individual analytes (including enantiomers, cis-trans isomers or perfumes as illustrative analyte mixtures). Comparison of the peptide activators reveals that carboxylates perform better than phosphonates. Gemini-like activators containing two carboxylates and two hydrophobic hydrazone tails are best, whereas excessive charges and tails give weaker activities. This result differs from cationic activators of polyanionic transporters such as DNA, which worked best with octopus amphiphiles with one cationic head and four hydrophobic tentacles. PMID- 21254443 TI - Vinylarene/CO copolymerization and vinylarene/polar vinyl monomer/CO terpolymerization using palladium/phosphine-sulfonate catalysts. AB - Palladium/phosphine-sulfonate complexes were effective for the alternating copolymerization of vinylarenes with carbon monoxide (CO). The obtained copolymers had iso-enriched microstructures with ll selectivity of up to circa 60%. The catalytic system was successfully applied to the terpolymerization of vinylarene and polar vinyl monomers with CO to produce novel terpolymers, which could not be obtained by using previously developed catalysts. NMR and DSC analyses suggested that vinylarene/CO units and polar vinyl monomer/CO units were randomly distributed in the terpolymer main chains. PMID- 21254445 TI - Electronic effects of para-substitution on the melting points of TAAILs. AB - Owing to numerous new applications, the interest in "task-specific" ionic liquids increased significantly over the last decade. But, unfortunately, the imidazolium based ionic liquids (by far the most frequently used cations) have serious limitations when it comes to modifications of their properties. The new generation of ionic liquids, called tunable aryl-alkyl ionic liquids (TAAILs), replaces one of the two alkyl chains on the imidazolium ring with an aryl ring which allows a large degree of functionalization. Inductive, mesomeric, and steric effects as well as potentially also pi-pi and pi-pi(+) interactions provide a wide range of possibilities to tune this new class of ILs. We investigated the influence of electron-withdrawing and -donating substituents at the para-position of the aryl ring (NO(2), Cl, Br, EtO(CO), H, Me, OEt, OMe) by studying the changes in the melting points of the corresponding bromide and bis(trifluoromethanesulfonyl)imide, (N(Tf)(2)(-)), salts. In addition, we calculated (B3LYP/6-311++G(d,p)) the different charge distributions of substituted 1-aryl-3-propyl-imidazolium cations to understand the experimentally observed effects. The results indicated that the presence of electron-donating and -withdrawing groups leads to strong polarization effects in the cations. PMID- 21254446 TI - Hydroquinone electrochemistry on carbon nanotubes is accelerated by nanographite impurities. PMID- 21254447 TI - An osteological and histological investigation of cranial joints in geckos. AB - Cranial kinesis is a widespread feature of gekkotan lizards. Previous studies of kinesis in lizards often described the relevant, mobile joints as synovial, thus characterized by the presence of a synovial cavity lined with articular cartilage. To date however, detailed investigations of cranial joint histology are lacking. We examined eight cranial joints (quadrate-articular, quadrate pterygoid, quadrate-otooccipital, quadrate-squamosal, epipterygoid-prootic, epipterygoid-pterygoid, basisphenoid-pterygoid, and frontal-parietal) in five gekkotan species (Oedura lesueuerii, Eublepharis macularius, Hemitheconyx caudicinctus, Tarentola annularis, and Chondrodactylous bibronii) using microcomputed tomography and serial histology. Particular focus was given to the relationship between the bony and soft-tissue components of the joint. Our results demonstrate that only three of these joints are synovial: the quadrate articular, epipterygoid-pterygoid, and basisphenoid-pterygoid joints. The frontal parietal and quadrate-pterygoid joints are syndesmosis (fibrous), the epipterygoid-prootic and quadrate-otooccipital joints are synchondroses (cartilaginous without a synovial cavity) and the quadrate-squamosal joint was not present. Based on previous descriptions, we determine that the structure of some cranial joints is variable among lizard taxa. We caution that osteology does not necessarily predict cranial joint histology. Although the functional implications of these findings remain to be explored we note that the development of synovial joints appears to be associated with a neural crest origin for the elements involved. PMID- 21254448 TI - A genotype resource for postmortem brain samples from the Autism Tissue Program. AB - The Autism Tissue Program (ATP), a science program of Autism Speaks, provides researchers with access to well-characterized postmortem brain tissues. Researchers access these tissues through a peer-reviewed, project-based approval process, and obtain related clinical information from a secure, online informatics portal. However, few of these samples have DNA banked from other sources (such as a blood sample from the same individual), hindering genotype phenotype correlation and interpretation of gene expression data derived from the banked brain tissue. Here, we describe an initiative to extract DNA from Brodmann Area 19, and genotype these samples using both the Affymetrix Genome-Wide Human SNP Array 6.0 and the Illumina Human1M-Duo DNA Analysis BeadChip genome-wide microarray technologies. We additionally verify reported gender, and infer ethnic background from the single nucleotide polymorphism data. We have also used a rigorous, multiple algorithm approach to identify genomic copy number variation (CNV) from these array data. Following an initial proof of principle study using two samples, 52 experimental samples, consisting of 27 subjects with confirmed or suspected autism and related disorders, 5 subjects with cytogenetically visible duplications of 15q, 2 with epilepsy and 18 age-matched normal controls were processed, yielding high-quality genotype data in all cases. The genotype and CNV data are provided via the ATP informatics portal as a resource for the autism research community. PMID- 21254452 TI - The detection of doping by means of chromatographic methods. 1966. PMID- 21254451 TI - Annual banned-substance review: analytical approaches in human sports drug testing. AB - The timely update of the list of prohibited substances and methods of doping (as issued by the World Anti-Doping Agency) is an essential aspect of international anti-doping efforts and represents consensual agreement by expert panels regarding substances and the methods of performance manipulation in sports. The annual banned-substance review for human doping controls critically summarizes recent innovations in analytical approaches; its purpose is to improve the quality of doping controls by reporting emerging and advancing methods that focus on detecting known and recently outlawed substances. This review surveys new and/or enhanced procedures and techniques of doping analysis together with information relevant to doping control that has been published in the literature between October 2009 and September 2010. PMID- 21254453 TI - Advances in equine sports testing. PMID- 21254449 TI - Deficits in adults with autism spectrum disorders when processing multiple objects in dynamic scenes. AB - People with autism spectrum disorders (ASD) process visual information in a manner that is distinct from typically developing individuals. They may be less sensitive to people's goals and, more generally, focus on visual details instead of the entire scene. To examine these differences, people with and without ASD were asked to detect changes in dynamic scenes with multiple elements. Participants viewed a brief video of a person or an inanimate object (the "figure") moving from one object to another; after a delay, they reported whether a second video was the same or different. Possible changes included the figure, the object the figure was moving from, or the object the figure was moving toward (the "goal"). We hypothesized that individuals with ASD would be less sensitive to changes in scenes with people, particularly elements that might be the person's goal. Alternately, people with ASD might attend to fewer elements regardless of whether the scene included a person. Our results indicate that, like controls, people with ASD noticed a change in the "goal" object at the end of a person's movement more often than the object at the start. However, the group with ASD did not undergo the developmental improvement that was evident typically when detecting changes in both the start and end objects. This atypical development led to deficits in adults with ASD that were not specific to scenes with people or to "goals." Improvements in visual processing that underlie mature representation of scenes may not occur in ASD, suggesting that late developing brain processes are affected. PMID- 21254450 TI - Absence of preference for social novelty and increased grooming in integrin beta3 knockout mice: initial studies and future directions. AB - Elevated whole blood serotonin 5-HT, or hyperserotonemia, is a common biomarker in autism spectrum disorder (ASD). The integrin beta3 receptor subunit gene (ITGB3) is a quantitative trait locus for whole blood 5-HT levels. Recent work shows that integrin beta3 interacts with the serotonin transporter (SERT) in both platelets and in the midbrain. Furthermore, multiple studies have now reported gene-gene interaction between the integrin beta3 and SERT genes in association with ASD. Given the lack of previous data on the impact of integrin beta3 on brain or behavioral phenotypes, we sought to compare mice with decreased or absent expression of the integrin beta3 receptor subunit (Itgb3 +/- and -/-) with wildtype littermate controls in behavioral tasks relevant to ASD. These mice did not show deficits in activity level in the open field or anxiety-like behavior on the elevated plus maze, two potential confounds in the evaluation of mouse social behavior. In the three-chamber social test, mice lacking integrin beta3 were shown to have normal sociability but did not show a preference for social novelty. Importantly, the absence of integrin beta3 did not impair olfaction or the ability to recall familiar social odors. Additionally, mice lacking integrin beta3 showed increased grooming behavior in novel environments. These preliminary studies reveal altered social and repetitive behavior in these mice, which suggests that the integrin beta3 subunit may be involved in brain systems relevant to ASD. Further work is needed to fully characterize these behavioral changes and the underlying brain mechanisms. PMID- 21254454 TI - Screen and confirmation of PEG-epoetin beta in equine plasma. AB - Methods have been developed to screen for and confirm darbepoetin alfa, recombinant human EPO, and methoxy polyethylene glycol-epoetin beta (PEG-epoetin beta) in horse plasma. All three methods screen samples with an enzyme-linked immunosorbent assay (ELISA) and confirm by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This report focuses on PEG-epoetin beta. The ELISA assay was able to detect PEG-epoetin beta at 0.02 ng/mL in 50 uL of horse plasma. Many samples had high background levels of immunoreactivity; however, introducing polyethylene glycol 6000 (PEG 6000) into the samples before the ELISA assay removed the high background and increased the apparent concentrations of PEG epoetin beta. In samples collected following the administration of 100 ug of PEG epoetin beta by the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes, PEG-epoetin beta was detectable up to 72, 144, and 120 h, respectively. The samples were prepared for LC-MS/MS analysis by extraction with anti-rHuEPO antibodies-coated Dynabeads followed by digestion with trypsin. The LC-MS/MS confirmation method used the multiple reaction monitoring (MRM) scan mode to monitor four precursor-product ion transitions of the EPO-derived peptide T6. All four transitions of T6 were detectable with S/N > 3. The limit of confirmation for PEG-epoetin beta was 1.0 ng/mL in 2 mL of horse plasma. The method successfully confirmed the presence of PEG-epoetin beta in a sample collected from a Mircera(r)-treated horse. Compared to PEG-epoetin beta, better sensitivity was achieved for darbepoetin alfa and recombinant human EPO. Darbepoetin alfa was detected in horse plasma four days after IM administration of 100 ug. PMID- 21254456 TI - Cytological, histological, and immunohistochemical findings of pulmonary carcinomas with basaloid features. AB - Pulmonary basaloid carcinoma (BC), a variant of large cell, nonsmall cell carcinoma (NSCC), and basaloid squamous cell carcinoma (BSQCC) can show features similar to small cell carcinoma (SCC) and large cell neuroendocrine carcinoma (LCNEC). Distinction from SCC, especially on FNA, is therapeutically relevant. We describe cytological, histological, and immunohistochemical features of BC and BSQCC. Numerous cytologic features were documented in cytologic preparations. Similar features and architecture were evaluated in the resections. Immunohistochemical results were recorded. Histologically confirmed BC (n = 3) and BSQCC (n = 3) were included. Five FNAs of SCC, (four with histologic follow up) were studied for comparison of cytological, histological, and immunohistochemical findings. In cytologic preparations of BC/BSQCC, cells were arranged mostly as tightly cohesive clusters (n = 4) or singly and in clusters (n = 2) with a predominance of clusters. Cytologic features of BC and BSQCC were similar: palisading (n = 6), crush artifact (n = 6), hyperchromasia (n = 5), focal nuclear molding (n = 6; very rare in 2/6), nucleoli, usually pinpoint (n = 3), scant cytoplasm (n = 6), necrosis (n = 5), apoptosis (n = 4), squamous differentiation (n = 1). BSQCC tended to have occasional larger cells, including keratinizing cells in one case. Histologic sections (n = 6) showed neuroendocrine features, including organoid arrangements, nests, and palisading. BC and BSQCC show overlapping features with SCC and LCNEC in cytological and histological specimens. Unlike SCCs, BC/BSQCC lack prominent nuclear molding, show tightly cohesive cell clusters, and demonstrate palisading. However, immunostains were the very helpful and probably necessary to accurately diagnosing BC/BSQCC, which show the immunostaining pattern of p63 (+), HMWCK (+), and TTF-1 (-). PMID- 21254458 TI - Melamed-Wolinska bodies in urine cytology an interesting aggregate in a degenerated urothelial cell. PMID- 21254457 TI - The value of p16 in ASCUS cases: a retrospective study using frozen cytologic material. AB - This study scans the efficacy of p16 immunostain on gynecological cytologies for the detection of high-grade lesions in ASCUS cases. This is a retrospective study that evaluates p16 immunostaining using frozen material from 109 cases diagnosed as ASCUS and followed for an average of 16 months. The diagnosis of ASCUS was made using liquid-based cytology (Thin Prep, Hologic, Marlborough, MA). High-risk HPV using Hybrid Capture II was performed. The immunohistochemical evaluation of p16 immunoreactivity was done following Wentzensen criteria. In the series p16 immunoreactivity showed a sensitivity and negative predictive value for HSIL, of 82.3 and 94.5% with specificity and positive predictive value of 100%. The sensitivity was similar to that found using the HC-II, though the specificity was much higher. The use of p16 immunostain in cytologic specimens applying the Wentzensen criteria helps to focus the attention in positive cells evaluating the cell changes, helps to detect some cells suspicious or diagnostic of HSIL, and could help to reclassify the ASCUS cases. PMID- 21254459 TI - Immunohistochemistry for the detection of renal cell carcinoma in effusion cytology. AB - Renal cell carcinoma (RCC) is known for its unpredictable behavior. RCC rarely involves serosal surfaces and, when present, can be difficult to distinguish from mesothelial cells in cytologic preparations. Immunohistochemical stains are frequently used with effusion cytology; however, RCCs express traditional glandular antigens less frequently than other adenocarcinomas. We investigated the utility of typical immunohistochemical stains for identifying effusion involvement by RCC, along with more specific RCC markers. The cytology databases from two academic institutions were searched for all effusions involved by RCC with retrievable cell-block material. A four-marker immunohistochemical panel we generally use for distinguishing adenocarcinoma from mesothelial proliferations was then applied (calretinin, WT1, MOC31, and B72.3). In addition, each case was stained for RCC antigen, CD10, and PAX2. Eleven cases of RCC involving serous effusions were identified: six conventional clear-cell RCCs, three papillary RCCs, and two RCCs, not otherwise specified. Neoplastic cells were positive for MOC-31 in 3 of 11 cases, RCC antigen in 5 of 11 cases, and CD10 in 10 of 11 cases. RCC cells were negative for B-72.3, WT1, and calretinin in all cases. Background mesothelial cells showed high-background cytoplasmic staining for PAX 2; all RCC tumor cells were negative or equivocal. A conventional panel used for the diagnosis of adenocarcinoma in fluids will fail to detect most cases of metastatic RCC, particularly clear-cell RCC. Additional antibodies, such as those to CD10 and RCC, may be helpful to identify these tumors. PAX2 shows high background in mesothelial cells, which makes interpretation of nuclear staining difficult. PMID- 21254460 TI - Characteristic cytologic findings of epithelioid hemangioendothelioma: A case report and review of literature. AB - Epithelioid hemangioendothelioma is a rare vascular neoplasm of low-grade malignancy. We observed a case of epithelioid hemangioendothelioma arising in a cervical lymph node. Fine needle aspiration cytology showed several characteristic findings of epithelioid hemangioendothelioma, that is, nuclear inclusion bodies, nuclear grooves, and amorphous material, in addition to physaliform chromatin pattern of a new clue. By reviewing the reports, the prevalence of these is clarified. Complex appearance of these findings is useful in the diagnosis. PMID- 21254461 TI - Conjunctival metastasis from Kaposi's sarcoma: a case report. AB - We present one case of Kaposi's sarcoma with conjunctive metastasis. The case describes a 71-years-old white male, who was admitted at hospital by malaise, slight pain on the left eyelid, nodular lesion of the left leg, and enlarge lymph nodes in inguinal regions. The conjunctive neoplasms are rare, and we most frequently can see the pigment ones followed by squamous epithelials and lymphomas. The primary Kaposi's sarcoma (KS) from conjunctiva is a rare tumor and it has increased by AIDS emergence and immunosuppression. The appearance of conjunctival metastasis from KS is a stand out event. PMID- 21254462 TI - Metastatic urothelial carcinoma with signet ring features: cytomorphologic findings in abdominal paracentesis. AB - Signet ring cells, characterized by large clear cytoplasmic vacuoles eccentrically displacing and indenting the nuclei, seen in cytopathology effusion specimens are most commonly due to metastatic adenocarcinoma of gastric, esophageal, and breast origin. Urothelial carcinoma can display a wide range of differentiation and is an extremely rare cause of metastatic signet ring cells. Here, we report the case of a 75-year-old male with high-grade urothelial carcinoma with signet ring features, who was status-post chemoradiation and radical cystoprostatectomy. The patient subsequently developed an abdominal mass and ascites. The paracentesis cytology revealed a hypercellular specimen with malignant cells dispersed singly as well as in small fragments displaying pleomorphism, nuclear irregularity, hyperchromasia, and binucleation. Numerous malignant cells displayed well-formed signet ring morphology, identical to adenocarcinoma. This is the first report of metastatic high-grade urothelial carcinoma manifesting as signet ring cells in peritoneal fluid. PMID- 21254463 TI - Nonhealing ulcer--a rare initial presentation of chronic myeloid leukemia diagnosed on aspiration cytology. AB - Involvement of skin in hematologic malignancies is rare phenomena as majority of the dermatologic lesions in leukemia patients are nonleukemic. In the absence of preceding history of leukemia, the diagnosis is often a surprise. Chronic nonhealing ulcer on the back of a 65-years-old male prompted a fine needle aspiration from its base. Smears showed an unexpected picture comprising of leukocytes in various stages of maturation against a hemorrhagic background. A cytologic diagnosis of leukemia cutis was given. Subsequent hematologic investigations revealed chronic myeloid leukemia in chronic phase. Cutaneous involvement is a rare initial presentation of leukemia in an otherwise asymptomatic patient and also an uncommon cause of nonhealing ulcer. Aspiration cytology scores over biopsy in not only being a rapid and easy diagnostic tool but also allows better appreciation of cellular details like cytoplasmic granules. PMID- 21254464 TI - Role of imprint cytology in the intraoperative diagnosis of pituitary adenomas. AB - The cytologic touch imprint alone can be diagnostic of pituitary adenomas and meningiomas, etc. A 45-year-old man was operated upon for intracranial meningioma. Imprint cytology revealed distinct cytologic features which helped arriving at the specific diagnosis of pituitary adenoma intraoperatively. Subsequent histopathology and immuno-histochemistry confirmed the diagnosis. Thus intraoperative touch preparations are of immense help in arriving at a diagnosis as well as in excluding other possible differential diagnoses and therefore can replace frozen section for intraoperative consultations of sellar and parasellar tumors. PMID- 21254465 TI - Gigantomastia in pregnancy with an accessory axillary mass masquerading as inflammatory carcinoma. AB - Giagantomastia is a rare disorder known to occur in pregnancy, causing enlargement of the breasts greater than that of gravid enlargement. The histological features of gigantomastia are glandular hyperplasia and an increase of stromal tissue. Illustrated by one documented case, cytomorphology of gigantomastia was misdiagnosed as a phyllodes tumor. We document the cytomorphology of an axillary mass in a gravid woman of 24 years with gigantomastia. She presented in her first trimester with bilateral mastalgia and swelling, nonresponsive to antibiotics. Imaging excluded mass breast lesions and a pituitary prolactinoma. The breasts progressively enlarged, became warm, tender, and developed skin ulcerations and a peau d'orange appearance. Subsequently she developed a mass in her left axilla. On aspiration of the mass, some of the cytomorphological features were suspicious for a metastasis, which correlated well with her clinical features. Careful evaluation suggested cytomorphology to be compatible with benign accessory breast tissue with possible hormone related changes of pregnancy. Histology of the excised axillary mass confirmed this diagnosis. Thus, awareness of this rare condition and careful evaluation is mandatory to avoid misdiagnosis in a similar clinical context. PMID- 21254466 TI - Imprint cytology of oncocytic papillary renal cell carcinoma. PMID- 21254467 TI - [New psychiatry model]. PMID- 21254468 TI - Commentary on end-of-life caregiving trajectories. PMID- 21254469 TI - Proceedings of the 3rd International Urolithiasis Research Symposium of the International Kidney Stone Institute. Indianapolis, Indiana, USA. December 3-4, 2009. PMID- 21254470 TI - Biomimetics of aquatic life: applications for engineering. Proceedings of the International Conference on Biological Applications for Engineering. Southampton, United Kingdom. March 17-19, 2008. PMID- 21254471 TI - VA study shows fewer patient deaths after OR team training. PMID- 21254472 TI - State governments' decision to stop participating in All-India medical entrance examination system: a retrogressive step. PMID- 21254473 TI - Evaluation of awareness and use of emergency access numbers in Delhi. PMID- 21254479 TI - Public health. White paper stalls on handover to councils. PMID- 21254480 TI - Economic squeeze. Moves to escape large overspends before April induce PCTs to delay, ban or change criteria for many procedures including IVF and surgery. PCTs restrict many treatments as overspend looms. PMID- 21254474 TI - India: the ESBL capital of the world? PMID- 21254482 TI - On vying for value. Give the kids a shot at the title. PMID- 21254481 TI - Sir Bruce Keogh and Ian Dalton on the new vital statistics. PMID- 21254483 TI - Quality. Two sides to the coin. PMID- 21254484 TI - GP commissioning. Coming to terms with consortia. PMID- 21254485 TI - Outsourcing. Pushing out the boundaries. PMID- 21254486 TI - Managing to face the music. PMID- 21254489 TI - DH speeds up abolition of PCTs and SHAs. PMID- 21254488 TI - The hospital landscape. Seeing the wood for the trees. PMID- 21254487 TI - Palliative care. Continuing choice to the end of life. PMID- 21254491 TI - Healey will 'get stuck into' broken promises on health. PMID- 21254493 TI - INFECTION CONTROL. Endoscopic camera identified as link in nine cases. Disinfection failure led to 'Delhi' bug breakout. PMID- 21254492 TI - WORKFORCE. NHS Professionals turns around previous years' losses and makes its biggest agreement to date with a major mental health trust. Bank staff firm reports first modest profits. PMID- 21254494 TI - John Middleton on the national public health service. PMID- 21254490 TI - Pound 800m savings identified through better COPD care. PMID- 21254495 TI - On local pay negotiations. Beware raiders of the lost cause. PMID- 21254496 TI - Spending review roundtable. Going back to the 1980s? PMID- 21254497 TI - Productivity. Part one of three. The eight ways to save cash and improve care. PMID- 21254498 TI - Legal. New roles and new rules for GPs. PMID- 21254499 TI - Augmentation strategies for depression. Options include psychotherapy, drugs, and dietary supplements. PMID- 21254500 TI - Reconsidering the placebo response. Acupuncture studies provide new insights into how treatment context affects outcomes. PMID- 21254501 TI - Attention deficit hyperactivity disorder and sleep. Insomnia and other sleep problems may worsen symptoms of ADHD; treatment options exist. PMID- 21254502 TI - Theories about what causes chemobrain. PMID- 21254503 TI - Recently I've been staying up until 3 or 4 in the morning to work on my oil paintings. I know I should feel tired, but I don't. One of my friends said that I might be hypomanic. What is that? PMID- 21254504 TI - [Comparative study of the interoceptive effects of afobazole and diazepam]. AB - Interoceptive effects of afobazole (20 mg/kg, i.p.) and diazepam (0.5 and 5.0 mg/kg, i.p.) have been investigated using operant drug discrimination (DD) and passive avoidance "step through" state dependent dissociative learning (DL) paradigms in male autobred rats. It is established that afobazole in contrast to classical anxiolytics (diazepam) does not produce the state dependence (DL and DD). In substitution tests, afobazole (20 mg/kg, i.p.) caused saline level responding in diazepam-trained rats and did not influence the general profile of interoceptive diazepam stimulus. The data suggest the absence of overlap in receptor mechanisms of the interoceptive effects of afobazole and diazepam and low probability of drug dependence development after long-term (clinical) afobazole treatment. PMID- 21254505 TI - [Comparative efficacy of selective serotonin reuptake inhibitors in young prenatally stressed female rats]. AB - Effects of the chronic administration of selective serotonin reuptake inhibitors (SSRIs) fluoxetine (daily 5.0 mg/kg, p.o.) and paroxetine (daily 5.0 mg/kg, p.o.) for 14 days of postnatal period on anxiety-like behavior have been studied during pubertal period in prenatally stressed female rats. It was found that prenatal stress reduced the anxiety level in test rats. Chronic administration of paroxetine in female rats did not change their anxiety-like behavior. Administration of fluoxetine resulted in an anxiogenic effect, but leveled an action of prenatal stress on the anxiety-like behavior in prenatally stressed female rats during pubertal period. PMID- 21254506 TI - [GABAergic mechanism of cerebrovasculareffect of mexidol]. AB - Experiments on rats showed that mexidol significantly increases local cerebral blood flow in animals under conditions of global transient brain ischemia, whereas in intact rats this drug initially causes a decrease in the blood flow, followed by its recovery. Mechanism of the cerebrovascular effect of mexidol is determined by its action on GABA receptors of cerebral vessels, which confirmed the fact that the cerebrovascular effect of mexidol is absent in the presence of bicuculline. PMID- 21254507 TI - [Relationship between the antioxidant effect of flavonoids and their effect on the vasodilating function of endothelium under endothelial dysfunction conditions]. AB - A relationship between the vasodilating activity of flavonoids under conditions of endothelial dysfunction in experimental diabetes and their antioxidant effect is established. Flavicin and quercetin show the maximum influence on the vasodilating function of endothelium and exhibit more pronounced antioxidant activity under conditions of endothelial dysfunction. PMID- 21254508 TI - [Correcting posthypoxic damage of myocardium in newborns with cerebral ischemia]. AB - A multicenter trial involving 30 newborns with post-hypoxic myocardial lesions associated with I-II degree cerebral ischemia has revealed that the inclusion of cytoflavin infusions into the complex standard treatment leads, besides the improvement of general clinical status, to significantly more rapid, as compared to the control group, positive dynamics of pump and contractile myocardial functions, elimination of hyperenzymemia, hypoxia and electrical instability of the myocardium, decrease in energetic deficit, and repolarization changes within the first 5 days of in-hospital therapy as well as during the follow-up from 1 to 6 months of life. PMID- 21254509 TI - [Influence of new neurohypophyseal hormone analogs on sodium and water reabsorption in rat kidney]. AB - New analogs of some neurohypophyseal hormones (oxypressin, hydrin, glumitocin, vasotocin) have been synthesized. Experiments with injection of these peptides to rats showed that substitution of C-terminal glycinamide on beta-ethanolamine (glycinol) or ethylamine in 1-deamino-arginine vasotocin resulted in loss of natriuretic but not antidiuretic activity. Analogs of oxypressin and hydrin exhibited neither natriuretic activity nor ability to affect water reabsorption. Glumitocin analog induced renal sodium ion excretion and did not influence potassium ion excretion. PMID- 21254510 TI - [Comparative analysis of the role of individual peculiarities of kidney structure in predisposition to the nephrotoxicity of gentamicin in intact and hydronephrotic rabbits]. AB - Comparative analysis of relationships between individual peculiarities of the structure of nephrons in intact and hydronephrotic right rabbit kidneys, on one hand, and the degree of expression of nephrotoxicity of gentamicin with respect to the only intact and as well hydronephrotic left kidney, on the other hand, was undertaken. Damage of the kidney by this antibiotic is more expressed in rabbits with smaller diameter of distal convoluted tubules of nephrons and smaller size of the cells lining their lumen. These peculiarities of the structure of nephrons lead to predisposition to the gentamicin-induced nephropathy in intact rabbits to a higher degree than in animals with hydronephrosis. The method of predicting individual predisposition to gentamicin-induced nephropathy has been patented (No. 7722 of 13.10.2005). PMID- 21254511 TI - [Effect of benzimidazole derivative with hypoglycemic activity on reproduction processes in females rats]. AB - Toxicological experiments showed that the new benzimidazole derivative with hypoglycemic action--diabenol--influences the sexual activity and processes of female fertilization. The estrous cycle, sexual activity and quality of fertilization were activated at females upon the administration of diabenol in a therapeutic dose of 5 mg/kg. It is established that the drug administration in a toxic dose of 160 mg/kg suppresses the sexual activity and, at the same time, does not affect the estrous cycle and quality of fertilization in females. PMID- 21254512 TI - [Experience of joint administration of neuromidin and ovestin for correcting cognitive disorders in females with hypoestrogenic syndrome]. AB - The aim of the present study was to assess the efficacy of combined administration of neuromidin and ovestin in low doses for pharmacocorrection of cognitive disorders in women after total ovariectomy. The obtained results are indicative of a pronounced efficacy of the proposed combined therapy for the pharmaco-correction of cognitive disorders as compared to the standard hormone replacement therapy in women with hypoestrogenic syndrome. This is confirmed by significant decrease of mental impairments on the conventional (Mattis dementia) clinical rating scale and in neuropsychological tests. PMID- 21254513 TI - [Pharmacological correction of the cytogenetic effects of cisplatin]. AB - Beginning with the first hours of experiments, cisplatin evoked an increase of chromosomal aberrations in CBA/CaLac bone marrow cells. Significant increase of structural infringements of chromosomes due to chromatid breaks was revealed in metaphase plates of murine bone marrow preparations through 24 h after cisplatin intraperitoneal introduction. In late terms of research (90th day), the high level of aberrations of chromosomes was retained. The most pronounced correction of cisplatin mutagenicity was achieved using a preliminary course of thiophan introduction. PMID- 21254514 TI - [Using cytoflavin for correcting x-ray contrasting agent-induced nephropathy]. AB - Experimental data on the influence of omnipak-350 introduction in a dose of 20 g/kg on the glutathione exchange processes and lipide peroxidation in kidneys, liver and erythrocytes of white outbred rats are presented. The possibility of using cytoflavin for correcting x-ray contrast agent-induced disorders in the natural cytoprotective system is shown. Probable mechanisms of the cytoprotective effect of the proposed pharmacological treatment are discussed. PMID- 21254515 TI - [GABA receptors: structure and functions]. AB - Data on the structure, localization, physiology, and pharmacology of GABA receptors are reviewed. These receptors belong to cis-loop receptors and consist of 16 subunits in various combinations and occur in both central nervous system and peripheral organs. There are a great number of their allosteric modulators, agonists and antagonists. Activation of GABA receptors is accompanied by changes in the permeability of plasmatic membranes for chloride ions, which is followed by depolarization (presynaptic inhibition) or hyperpolarization (postsynaptic inhibition). GABA receptors contain some topographically different binding sites, intended for the interaction both with the main mediator (GABA) and with allosteric regulators such as benzodiazepines, barbiturates, convulsants, ethanol, and neurosteroids. PMID- 21254516 TI - [Problems of diagnostics and treatment strategy in patients with Takayasu' arteries]. AB - Current concepts of etiology and pathogenesis of nonspecific aortoarteritis (Takayasu's disease) are considered. A.V. Pokrovsky and his team gained the largest experience with diagnostics and treatment of patients suffering this disease. In this paper, the authors describe results of the treatment of more than 200 patients including 118 operated for isolated reconstruction of aortic arch branches (n = 43), restoration of blood flow only in thoracoabdominal aorta and its branches (n = 63), reconstruction of both brachiocephalic arteries and thoracoabdominal aorta (n = 12). The authors present their view of diagnostics and treatment strategy in patients with lesioned brachiocephalic arteries, abdominal and thoracoabdominal aorta. The necessity of following up patients in the postoperative period is emphasized. PMID- 21254517 TI - [Multiple aortocoronary bypass without artificial circulation]. AB - Results of 145 surgeries for direct myocardial revascularization without artificial circulation are presented. FC III and IV angina of effort was diagnosed in 80.6% and 13.5% of the patients respectively, acute coronary syndrome in 6.5%, past myocardial infarction in 63.8%. Mean left ventricular ejection fraction (EF) prior to surgery was 48.7 +/- 5.1%; it was below 40% in 28.8% of the patients. Three- and two-vessel coronary disease was documented in 54.7% and 35.3% of the patients respectively; 10% of them presented with the affected anterior interventricular branch, 14% with the stenotic trunk of the left coronary artery. Mean revascularization index increased from 22 to 76. The frequency of complete autoarterial revascularization amounted to 42.7%. Sequential and composite grafts were used in 93 and 257 cases respectively. No patient experienced perioperative myocardial infarction, acute disturbance of cerebral circulation, acute renal or cardiac insufficiency. Immediate postoperative hemorrhage requiring resternotomy developed in 0.9% of the patients, 1.2% with suppurative complications needed additional surgical treatment. It is concluded that myocardial revascularization on a beating heart is an efficacious and reliable method ensuring good results in the immediate and late postoperative period. Its success first and foremost depends on the previously gained experience that permits to operate patients with severe multi vessel coronary artery disease and various concomitant disorders and thereby correct combined pathological conditions. The available data give reason to consider each patients in need of aortocoronary bypass as a candidate for myocardial revascularization on a beating heart regardless of the character and extent of coronary lesions and anatomical feature of the coronary bed. PMID- 21254518 TI - [On the classification of dissecting aortic aneurysms]. AB - Aortic dissections are most commonly categorized into types A and B depending on the involvement of ascending or descending aorta based on the Stanford system and into types I, II and III using DeBakey classification. The latest classification was proposed by the European Society of Cardiology in 2001. The authors present their own classification of distal aortic dissecting aneurysms that takes into account antegrade and retrograde dissection of the aorta, besides localization of proximal fenestration. Surgical strategies for the treatment of different variants of aortic dissecting aneurysms are considered. PMID- 21254519 TI - [Surgical treatment of bilateral occlusive-stenotic lesions of carotid arteries]. AB - The study included 136 patients with atherosclerotic lesions of carotid arteries allocated to 3 groups depending on the state of contralateral arteries. Group1: patients with stenosis and occlusion of contralateral internal carotid artery (ICA) (n = 31); group 2: patients with bilateral carotid stenosis (n = 62); group 3: patients with unilateral ICA stenosis (n = 43). 20, 54 and 34 patients of these groups respectively were operated. A total of 139 carotid endarterectomies (CA) were performed including 11 one-step CA. Overall postoperative lethality was 2.78, 5 and 3.7% in the respective groups. It is concluded that patients with multiple lesions of aortic arch are at highest risk of ischemic stroke. Step by step CA is recommended for their treatment. Intraluminal shunting is optional. PMID- 21254520 TI - [Results of reconstructive surgery for carotid artery occlusion in ischemic stroke survivors]. AB - The authors report results of reconstructive surgery in 316 patients with carotid artery (CA) occlusion operated after ischemic stroke. Its efficiency is estimated with reference to the degree of neurologic deficiency and treatment schedule. The results confirm effectiveness of reconstructive surgery on CA for the prevention of stroke relapses and promotion of surgical rehabilitation. PMID- 21254521 TI - [Diagnosis and treatment of inferior vena cava thrombosis]. AB - A total of 572 patients with acute thrombosis in deep veins of the inferior vena cava system were treated in the Department of Vascular Surgery. X-ray contrast retrograde iliocavography (XICG) revealed 96.5 % cases of iliocaval segment thrombosis. Signs of thromboembolism in pulmonary artery branches (TELA) were detected by angiopulmonography (APG) in 92.3% cases. Thrombectomy was undertaken in 62 (39.7%) of the patients, venous clipping or placation without thrombectomy were performed in 94 (60.3%) ones. All operated patients experienced regress of clinical symptoms of deep vein thrombosis in the absence of TELA and were discharged in good clinical condition. It is concluded that surgical techniques for the prevention of TELA should be chosen on an individual basis taking account of thrombus character and location detected by central duplex scanning, XICG and APG. PMID- 21254522 TI - [Medical standards of dispensary guarantee of call-up aged persons by ambulatory stomatological aid]. AB - The article presents results of epidemiological research of dental morbidity among persons of call-up age and indexes of their need in different types of dental aid. Were calculated medical standards for dispensary supply, elaborated propositions in standard of medical survey of persons of call-up age on specialization "stomatology" during registering on military registration and proximately during the call-up on military service in determination of fitness for military service. These data could be used in improvement of organizational structure of dental institutes of Health Ministry of social development of the Russian Federation. PMID- 21254523 TI - [Results of sociological interview of physicians of military-medical committees]. AB - Was effectuated an interview of 95 physicians of regional military-medical committees of Kirovskaya area. For the question, whether military-medical expertise (MME) was given in IHE, affirmative answer gave 10.9% of respondents. A rather low (16.4%) was percent of physicians, got education in MME during postgraduate courses. Analyze has shown that nowdays the education of physicians on the topic of MME is effectuated predominantly in the course of work, conversance of judicial consequences of expertise is insufficient. It is found that physicians underestimate value of MME and don't perceive it as a self direction. PMID- 21254525 TI - [Prevention of the alcoholic visceropathy]. AB - In the medical institutions of the Ministry of Defence of the Russian Federation was undertook the study with the aim of inclusion of the physicians to the understanding of the danger of alcoholic intoxication through the knowledge provisioning about the influence of the alcohol to the atherogenesis, progression of liver cirrhosis and liver cancer. 2033 patients who had had surgical revascularization were examined. It was found that each of those patients had drunk different doses of alcohol, but it didn't alert the atherogenesis. Also 1283 patients with liver cirrhosis and 126 died of it during 1996-2009 were examined. It was found that alcohol is the most dangerous cause of liver cirrhosis. Anonymous questionnaire of physicians for clearing up their attitude to the alcohol. It was found that only 43% of physicians deny healthful doses of alcohol. According to this fact it is necessary to intensify explanatory work among physicians. PMID- 21254524 TI - [Military medicine and medicine of accidents]. AB - The article presents an observe of such parts of military medicine as intensive aid and operative treatment on the place of case, contestation against infectious diseases, preservation of psychic health, medical and social rehabilitation. Were lighted successful activity of military physicians during liquidation of Chernobyl accident (1986), earthquakes in Armenia (1988), railway accident in Bashkiria (1989) and other accidents. Experience of military medicine (particularly using medical units of special purposes) was used in proving of conception of medicine of accidents, and in organization of medical supply of troops in armed conflicts of restricted scale--in effectuating of antiterrorist operations in Northern Caucasus (1994-1996, 1999-2002), in effectuating of peacemaking operation in Kosovo (1999-2003), natural disasters. PMID- 21254526 TI - [Diagnostics of latent vestibular disfunction among military servicemen with diseases of central nervous system in anamnesis]. AB - There were studied peculiarities of provocative nystagmus among 60 military servicemen with nervous system in anamnesis. Latent vestibular disfunction--a frequently detected syndrome among persons with diseases of nervous system in anamnesis. To examine a provocative nystagmus, was used a range of vestibulometric loading tests, which influences on different parts of vestibular system. Was marked a high role of several loading testes in diagnostics of latent vestibular disfunction. It has been found that in conditions of syndrome of vegetative imbalance of different genesis, the most effective are tests of De Klein with hyperventilation and hyperventilation test. In conditions of minimal neurological deficit the most effective is tests of Valsalve. In conditions of peripheral vestibular syndrome in anamnesis and vertebral-genic vestibular disfunction a very effective is sinocarotid test. PMID- 21254527 TI - [Complex rehabilitation of patients suffering of degenerative dystrophic joint disease with the application of minimally invasive keyhole surgery]. AB - During the period of 2004-2009 in the 6th Central Military Clinical Hospital 343 arthroscopy were performed. Control set consisted of 128 patients who refused operative treatment or operative treatment couldn't be preformed because of contraindications. During the arthroscopy in 74% of cases old laceration of meniscus was diagnosed, in 18% infra-articular osteochondral fragments were eliminated, in 32% of cases arthroscopic synovectomy was preformed, in 10% of cases forage and mikrofrakturing of subchondral bone were performed, chondroplasty and sanitation of joint were done for every patient. Together with it, during the arthroscopy signs of synovitis were diagnosed. The results of treatment were estimated by the scale of Lysholm (1982) and by the scale IKDS (1995) in 1, 3, 6 and 12 months. In 75% the results were good and excellent. PMID- 21254528 TI - [Pathogenetic aspects of hypertension in case of metabolic syndrome]. AB - Hypertension is the main disease in Russian Federation--its frequency is 39.2% in men and 41.1% in women. In recent years course of a disease is accompanied by the metabolic derangements which form the metabolic syndrome. In the basis of pathogenesis of hypertension are insulinresistance and compensatory hyperinsulinemia in combination with associated metabolic derangements. Inveterate insulinresistance leads to hypertension. PMID- 21254529 TI - [Informational function of heart and its apply if diagnostics of medical disease]. AB - Biophysical properties of the electric, magnetic and hydrodynamic impulses generated by the heart suggest the existence of the informational function of the heart: the ability to apply impulses across the body; probable variability of their main parameters, the presence in the heart of the amplitude and frequency phase modulation carries the information into the cardiosignls. The main tenets of the theory of information functions of the heart are implemented in the technology of informational analysis of electrocardiosignals based on encoding- transformation of the probable variability of parameters electrocardiosignals into the code text. Specific sets of combinations of symbols of norm and rules of internal diseases were indentified. On their basis diagnostic systems which let to diagnose the most common diseases of internal organs were tested. Practical recommendations for the use of diagnostic systems in medical practice are given. PMID- 21254530 TI - [Problem of pyoinflammatory diseases of soft tissues among military servicemen]. AB - For a period of 2002-2009 according to indexes of morbidity was examined dynamics of morbidity of staff of Privolzhsko-Uralskij military region among soldiers and sergeants, of unit weight of PIDST, of unit weight of incapacity days, was observed seasonality. Was found a mid-year increase of index of morbidity among call-up staff on 6.84%, and among contract military servicemen--on 4.5%. PIDST take about 18% of incapacity days in structure of all workmisses of call-up military servicemen and about 7% among contract military servicemen. Was found a seasonality of one-wave type with a top of annual morbidity in August-October and decrease in first decade of November. There is a need of examination of immune status of persons of call-up age. PMID- 21254531 TI - [The 175th anniversary of the District Military Clinical Hospital of the Leningrad Military District]. AB - For 175 years a hospital made a great contribution to the development of national health care, gaining a wealth experience in high quality health care for the soldiers. Especially the biggest merit was made by the hospital during the Great Patriotic War of 1941-1945, when 82% of the wounded soldiers ware returned for further service. The hospital was glorified by famous medical scientists of XIX XX-centuries, such as: V. Bekhterev, R. Wreden, N. Sklifosovsky, P. Kupriyanov, N. Petrov and others. Currently, the hospital takes a worthy place among the best military medical agencies of Russian Armed Forces. The hospital is equipped with modern medical equipment. There work highly qualified personnel: 17 distinguished doctors of the Russian Federation, 2 doctors and 27 candidates of medical sciences. In practice the hospital successfully uses achievements of the leading Russian military medical facilities. The staff treat with care historical traditions of the hospital. PMID- 21254532 TI - [The 1st native department of nervous and mental diseases]. AB - In 1860 year in Medical-surgical academy in St. Petersburg was found the first department of nervous and mental diseases. With this department are aligned names of the greatest native neurologists and psychiatrists (Merzheevsky I.P., Bekhterev V.M., Blumenau L.V., Astvatsarov M.I., Dojnikov B.S., Triumfov A.V., Razdolsky I.Ya., Panov A.G. and etc.) who took the glory of Russian neurology. For 150 years the department was the base of neurological specialists for all medical institutes of the state. The department keeps the single educational and scientific institute, supplying systematic and high-qualified preparedness of military neurologists. PMID- 21254533 TI - [The 75th anniversary of the Center of state sanitarium-epidemiological control of PUrMD]. AB - At the first of October 2010 Federal state institute "The 1026th center of state sanitarium-epidemiological control of the Ministry of Defense of RF", situated in Ekaterinburg celebrates it's 75th anniversary. Now days the Center is a large multiprofile institute of medical service of the military region, equipped by moern laboratory and instrumental environment for examination of electro-magnetic and electro-magnetic, microclimate, environment, indication of biological agents, effectuating of immune-enzymatic analyze and PCR-diagnostics. PMID- 21254534 TI - [Physiology of synapse: from molecular modules to retrograde modulation]. AB - Synapses are highly organized, specific structures assuring rapid and highly selective interactions between cells. Synaptic transmission involves the release of neurotransmitter from presynaptic neurons and its detection by specific ligand gated ion channels at the surface membrane of postsynaptic neurons. The protenomic analysis shows that for self-formation and functioning of synapses nearly 2000 proteins are involved in mammalian brain. The core complex in excitatory synapses includes glutamate receptors, potassium channels, CaMKII, scaffolding protein and actin. These proteins exist as part of a highly organized protein complex known as the postsynaptic density (PSD). The coordinated functioning of the different PSD components determines the strength of signalling between the pre- and postsynaptic neurons. Synaptic plasticity is regulated by changes in the amount of receptors on the postsynaptic membrane, changes in the shape and size of dendritic spines, posttranslational modification of PSD components, modulation kinetics of synthesis and degradation of proteins. Integration of these processes leads to long-lasting changes in synaptic function and neuronal networks underlying learning-related plasticity, memory and information treatment in nervous system of multicellular organisms. PMID- 21254535 TI - [Unknown mechanisms of the GPCR-signaling cascade in vertebrate photoreceptors]. AB - Among the GPCR-signaling cascades, phototransduction in vertebrate retinal photoreceptors has been characterized in unprecedented details. It is believed that basic mechanisms of phototransduction and adaptation are reliably and completely established, and phototransduction may serve as a benchmark for understanding other G-protein-coupled systems. In this review, we compare present scheme of phototransduction with other GPCR-cascades in order to reveal their similarities and specific features. We show, based mainly on our physiological and biophysical data, that the existing scheme misses a few important regulations whose molecular basis is unknown. There exists a fast and efficient mechanism that accelerates the turn-off of the activated G-protein (transducin) during light adaptation. A few slowly acting processes result in a long-lasting modification of the cascade's components and regulate the speed of rhodopsin and transducin quenching. Similarly to other GPCR-cascades, one may suggest that there are multiple signalling pathways that start from photoactivated rhodopsin and rely on different secondary messengers (e.g. cAMP vs. cGMP). We also show that rhodopsin in retinal rods may form areas of paracristalline organization, and that the oligomerization might be a mechanism for controlling the amplification of the signalling cascade. The missing mechanisms are by no means minor, and could ensure sensitivity regulation within two orders of magnitude range. PMID- 21254536 TI - [Mathematical modelling in physiology]. AB - The article illustrates the method of mathematical modelling in physiology as a unique tool to study physiological processes. A number of demonstrated examples appear as a result of long-term experience in mathematical modelling of electrical and mechanical phenomena in the heart muscle. These examples are presented here to show that the modelling provides insight into mechanisms underlying these phenomena and is capable to predict new ones that were previously unknown. While potentialities of the mathematical modelling are analyzed with regard to the myocardium, they are quite universal to deal with any physiological processes. PMID- 21254537 TI - [Physiology in XXI century: natural science and medicine]. AB - Progress of physiology is closely connected with achievements of the adjacent sciences that developed particularly intensively at the end of the XX century. The key role in strategy of physiological investigations is played by study of the nature of regulation of individual processes providing activity of the organism as a whole. By the example of study of renal function there are discussed the issue of integration of its incretory and secretory functions, elucidation of the mechanism of activity of regulatory systems with taking into account the wide diversity of types and subtypes of receptors, interaction of numerous variants of cotransporters, pumps, water and ion channels, which eventually provides the amazing efficiency of the coordinated work of several organs and systems for stabilization of physical-chemical parameters of the internal environment. Development of physiology is of importance for progress of natural science and clinical medicine, as its achievements facilitate discovery of mechanisms of physiological functions, elucidation of defect of the locus underlying dysfunction. PMID- 21254538 TI - [Stress in physiological studies]. AB - The review focuses on the concept of biological stress pioneered by Hans Selye, who demonstrated a key involvement of the pituitary-adrenocortical axis in the response to stress. It discusses the historic background of development of the stress concept and some aspects of modern physiological researches related to stress-induced activation of the hypothalamic-pituitary-adrenocortical axis. We focus mainly on the results demonstrating that stress-induced activation of the hypothalamic-pituitary-adrenocortical axis is a gastroprotective component of stress response. PMID- 21254539 TI - [Grooming and group structure in hamadryas baboons]. AB - The results of 3-year observation on coral living hamadryas baboons transported from natural habitat in Tuapse reservation have been presented. Despite of the fact that grooming between males and females accounted for 73% of total cases of grooming in adult individual pairs, only the relationships of males with high ranked females of their harems fully corresponded to a star-shaped sociogram. The high-ranked females were not different from all the other females either according to a total number of grooming cases with their female partners or according to a proportion of a performed and received grooming. Grooming between the related females was noted predominantly in the cases when they belonged to the same harem. Grooming between the related males accounted for 59% of all the cases of grooming between the male partners. PMID- 21254540 TI - [Modern conceptions of the atrial fibrillation development. The role of the myocardial sleeves in the pulmonary veins]. AB - Atrial fibrillation (AF) is the most common supraventricular cardiac arrhythmia. In this review several conceptions focused on the mechanisms of the AF initiation are discussed. At present time viewpoint that the ectopical activity in the pulmonary vien myocardial sleeves (PVs) account for AF in prevailing. PVs myocardium has been the subject of many anatomical and physiological investigations. PVs myocardium differs from left atria tissue and has many moprhological properties that make in convenient substrate for AF initiation and maintenance. PVs cardiomyocytes were shown to have great variability of electrophysiological properties (action potential duration, resting potential, upstroke velocity, etc.). Attempt to discuss afterdepolarization, triggered activity and abnormal automaticity as initiators of AF in PVs was made. It was shown that as in experimental condition, as in vivo in PVs can exist er-entry. Possibly, re-entry from PVs could be the one mechanism by which AF is initiated. In review big attention to the innervations of PVs and role of the sympathetic and the parasympathetic nerves in PVs ectopical activity is paid. Combined influence of autonomic nerves may be critical to initiating AF in PVs. Pharmacological intervention as a possible way to suppress or prevent the activity in the PVs that leads to AF is discussed. PMID- 21254541 TI - [A perspective of present approaches to EEG analyses performed with intention to find seizure predictors]. AB - In the late 90-s of the previous century the American Society of Epileptologists defined a priority for research as "possibilities to predict a seizure, early determinate and reduct". A method, which would allow the prediction of epileptical seizure's onset based on the EEG data registered with the patient with an epilepsy disease, would also allow implementing the new approach to treatment. If it became reliably possible to predict a moment of seizure, based on the EEG dynamics, one could create an automated closed loop system to prevent a seizure. In the article a number of works regarding this subject were reviewed. Also own results were discussed which were derived from analyses of brain electrical activity of rats with absence epilepsy and with the use of own developed software. Moreover specifics of absence initiation and course were discussed, as well as formation mechanism of thalamus-cortical loop, existing abilities of reduction not only absences, but also cognitive and emotional dissociations. Also described results of analyses of the EEG time series, that were derived by computation of correlation dimension with own developed software. PMID- 21254542 TI - [Modern approaches to human cognitive activity enhancement]. AB - Recent literature on human cognitive activity enhancement is reviewed and summarized. Two classes of pharmacological approaches are picked out, i.e. modern aspects of traditional substance utilization and application of specially developed drugs. Among non-pharmacological approaches a number of psychological, physiological, behavioral and biophysical methods to improve human cognition, memory and learning are analyzed. The most attention is paid to non-drug approaches that utilize bioelectric processes of the individual including characteristics of its brain electrical activity--electroencephalogram (EEG) to enhance different aspects of cognitive functioning. Some promising lines of these investigations are delineated. PMID- 21254543 TI - [Evolution of dissociative learning]. AB - This review considers data obtained during the entire research period of state dependent learning. Understanding of this phenomenon has significantly evolved during the past decades, as a result of the increasing amount of facts revealed while studying state-dependent learning. Consequently, a situation has arisen where different papers may describe same phenomena using different terms. This does not promote understanding of the described phenomena. Therefore a need for a paper emerged, that would analyze the evolution of state-dependent learning and would offer terminology corresponding to all the data collected on the subject. PMID- 21254544 TI - [Neurophysiological mechanisms of auditory adaptation. II. Poststimulus effects]. AB - The problem of interaction of spike neuronal activity evoked by successive sounds in single elements of auditory system is considered. The forward masking situation, when pairs of signals are presented independently, as well as the condition of long sequences of signals with different on-of ratios are analyzed. The strong increase of a diversity of single units ability to reproduce fast sequences really observed from the lowest to the higher nuclei of an auditory pathway. Complex units, reacting only on "new" signals, appear from midbrain region of auditory pathway. However such elements are found out usually not in a direct lemniscal auditory way, but in surrounding nuclei. While poststimulus adaptation to specified type of signals usually causes the considerable increase in threshold of detection, differential sensitivity to small changes can remain quite high. This aspect of auditory sensation remains poorly investigated both in physiological and in psychophysical experiments. PMID- 21254545 TI - [Analysis of sex chromosome homologies in representatives of the family Calliphoridae]. AB - The distribution of sequences homologous to the Calliphora erythrocephala Mg. sex chromosome was studied in Protophormia terranovae R-D and Lucilia sp. The chromatin structure was found to be similar in regions containing homologous DNA sequences. PMID- 21254546 TI - [Molecular composition of the chromosome 2 pericentric heterochromatin in malarial mosquitoes (Diptera, Culicidae)]. AB - Rich in repeated DNA sequences and poor in genes, the heterochromatin is an important functional part of the eukaryotic genome. Heterochromatin exhibits high evolutionary variability, which was revealed on the cytological and molecular levels in malarial mosquito species from the Anopheles maculipennis complex. In this connection, investigation of the heterochromatin molecular composition in species of this complex is of interest. PMID- 21254547 TI - [Inversion polymorphism in malarial mosquito Anopheles messeae natural populations from the north-eastern region of the range]. AB - A cytogenetic study of eight natural populations of Anopheles messeae from the north-eastern part of the species areal was conducted. Complete predominance of homozygotes XL11 and 3R11 in the northern populations was observed. Change in the chromosome 2 inversion frequencies from south northwards was shown. The 2R11 variant, which was not observed in the southern region, was found in the northern populations. These results indicate the maintenance of chromosome frequency of the distribution of inversions XL1 and 3R (in longitude) and 2R1 (in latitude). The inversion frequency distribution in the examined part of the areal have been preserved for a long time. PMID- 21254548 TI - [Location of genes in chromosomes: random or not?]. AB - The possibility is discussed that the order of genes in chromosomes is not random but determined by natural selection, i.e., is a selectively valuable character. Cases of long-term conservation of gene linkage or synteny in evolution are presented. Examples and possible mechanisms of nonrandom gene localization in prokaryotic and eukaryotic chromosomes are considered. PMID- 21254549 TI - [Chicken lampbrush chromosomes: transcription of tandemly repetitive DNA sequences]. AB - The transcribed part of the genome includes both protein-coding sequences and a variety of sequences with unknown functions. Amphibian and avian lampbrush chromosomes represent a convenient experimental system for studying cell functions and the regulation of transcription of protein-noncoding DNA. Taking lumpy loops formed on chicken (Gallusgallus domesticus) chromosome 2 at the lampbrush stage as an example, we applied an approach allowing RNA sources to be identified in the lateral loops of lampbrush chromosomes. This approach involves a bioinformatic analysis of data from the chicken genome sequencing project and a high-resolution mapping of transcripts on microsurgically isolated bivalents. As a result, a novel tandemly repetitive DNA sequence, LL2R (lumpy loop 2 repeat), of approximately 440 bp in size was identified in the chicken genome, its transcripts taking part in the formation of lumpy loops with a massive RNP matrix on chromosome 2 in growing oocytes. PMID- 21254550 TI - [Lampbrush chromosomes of the Japanese quail (Coturnix coturnix japonica): a new version of cytogenetic maps]. AB - Avian oocyte chromosomes are transfomed into giant transcriptionally active lampbrush chromosomes (LBCs) at meiosis 1 diplotene. These chromosomes are a convenient tool for high-resulution cytogenetic analysis. Using differential staining with fluorochromes DAPI and CMA3, we have constructed detailed cytological maps for lampbrush macrochromosomes 1-5 and ZW of the Japanese quail Coturnix coturnix japonica. We also performed a comparative analysis ofmitotic chromosomes and LBCs corresponding to them. We estimated the decondensation coefficient during LBC formation and determined the centromere indices for mitotic and diplotene chromosomes and thus found that different chromosomes and chromosomal regions demonstrate unequal degrees of decondensation. PMID- 21254551 TI - [Karyogenomics of species of the genus Linum L]. AB - Using the molecular cytogenetic and RAPD methods of analysis, we studied genomes of 22 cultivated flax varieties and 24 wild species from six sections of the genus Linum L. The chromosome numbers were exactly determined in the karyotypes of all studied species, and all individual chromosomes were identified by the C/DAPI-banding pattern and localization of 26S rDNA and 5S rDNA. B chromosomes were identified and studied for the first time in species of the section Syllinum Griseb. According to the data obtained, the species studied were divided into eight groups on the basis of similarity of their karyotypes, which corresponded in general to their clustering based on the RAPD results. The systematic positions and phylogenetic relationships of the flax species were verified. PMID- 21254552 TI - [Combined simultaneous analysis of morphology and fluorescence in situ hybridization as a novel sensitive method for detecting small populations of malignant cells in patients with a high risk of cancer, premalignant lesions, and minimal residual disease]. AB - Fluorescent in situ hybridization (FISH) is a valuable tool for detection of chromosome aberrations in clinical practice of malignancies. However, the relatively high false positive and false negative rates of this method complicate its application to analysis of small populations of pathological cells. Combined simultaneous analysis of morphology and FISH using a Duet multiparametric cell scanning system (BioView, Rehovot, Israel) has been developed and introduced into clinical practice. The novel method has been demonstrated to increase the specificity of identification of pathological cells inpatients with various hematological malignancies and, hence, estimate the efficiency of treatment. Studies on different premalignant disorders of the oral cavity mucosa have demonstrated that the combined method allows the identification of individual pathological cells and, hence, early detection of malignant and premalignant cells that may be overlooked by traditional histomorphological methods. PMID- 21254553 TI - [Identification of candidate genes of autism on the basis of molecular cytogenetic and in silico studies of the genome organization of chromosomal regions involved in unbalanced rearrangements]. AB - Autism is one of the most widely spread mental diseases among children. Different genetic anomalies make a considerable contribution to the etiology of this disease; therefore, the identification of candidate genes of autism can be regarded as a topical task of modern medical genetics. The molecular cytogenetic examination of children with autism was carried out using high-resolution comparative genome hybridization and subsequent in silico analysis of chromosomal regions involved in unbalanced rearrangements. Five of 126 (4%) children with autism had unbalanced rearrangements of chromosomes 5, 17, 21 (deletions) and chromosomes 4 and 22 (duplications). The following candidate genes were identified in children with autism by in silico analysis: SCARB2, TPPP, PDCD6, SEPT5, GP1BB, PI4KA, NPTX1, STCH, NRIP1, and CXADR. These methods also allowed us to find a possible association between gene clusterization and the formation of the described chromosomal rearrangements. Thus, this study demonstrates that the molecular cytogenetic and bioinformatic methods can be successfully used to search for candidate genes of different diseases and analyze the genome organization. PMID- 21254554 TI - [Instability of chromosomes in human nerve cells (normal and with neuromental diseases)]. AB - It is assumed that the genetic mechanism of pathogenesis of such widely spread neural and mental diseases as schizophrenia (SZ), autism, ataxia-telangiectasia (AT), and Alzheimer's disease (AD) is associated with structural and functional genomi? instaility in brain cells. Aneuploidy is one of the most important biological markers of genomic instability. The currently available methods of molecular cytogenetics (I-mFISH, QFISH, and ICS-MCB) facilitate the solution of numerous fundamental biological problems, including analysis ofgenomic variations in brain cells. Using these methods, we have studied for the first time aneuploidy in human embryo and adult brain cells (normal and with AT, AD, and SZ) as well as in blood cells of children with autism. The level of aneuploidy was increased two- to threefold in the embryo brain with a subsequent reduction of the number of abnormal cells in the adult brain. In the case of SZ, mosaic aneuploidy for chromosomes 1, 18, and X was found. The study of blood cells from children with autism showed chromosomal mosaicism for chromosomes X, 9, and 15. In the case of AT, we observed a global expression of aneuploidy in up to 20-50% of cortex and cerebellum neurons. In addition, a local instability of chromosome 14 was revealed in the degenerating cerebellum in the form of breaks in the 14q12 region. In the case of AD, a tenfold increase was observed in the level ofaneuploidy for chromosome 21 in brain sections subjected to neurodegeneration. These data indicate that mosaic genomic instability in nerve cells is one of the mechanism of neurodegenerative and mental diseases. PMID- 21254555 TI - [Chromosomal mosaicism in spontaneous abortions: analysis of 650 cases]. AB - It is known that up to 50% spontaneous abortions (SA) in the first trimester of pregnancy are associated with chromosomal abnormalities. We studied mosaic forms of chromosomal abnormalities in 650 SA specimens using interphase mFISH and DNAprobes for chromosomes 1,9, 13/21, 14/22, 15, 16, 18, X, and Y. Numerical chromosomal abnormalities were discovered in 58.2% (378 cases). They contained combined chromosomal abnormalities (aneuploidy of several chromosomes or aneuploidy in combination with polyploidy in the same specimen) in 7.7% (29 cases) or 4.5% of the entire SA sample; autosomal trisomy, in 45% (18.2% in chromosome 16, 8.9% in chromosomes 14/22, 7.9% in chromosomes 13/21, 3.1% in chromosome 18, and 1.4% in chromosome 9). Chromosome X aneuploidy was found in 27% cases, among which 9.6% represented chromosome X monosomy. Polyploidy was observed in 22.9% cases. In 5.1% cases, we observed mosaic form of autosomal monosomy Among the SA cases with chromosomal abnormalities mosaicism was observed in 50.3% (approximately 25% of the entire SA sample). The results of the present study indicate that significant amount of chromosomal abnormalities in SA cells are associated with disturbances in mitotic chromosome separation, which represents the most common cause of intrauterine fetal death. It was also shown that original collection of DNA probes and the technique of interphase MFISH could be useful for detection of chromosomal mosaicism in prenatal cell specimens. PMID- 21254556 TI - [Cytochrome P4501A1, glutathione S-transferase M1 and T1 gene polymorphisms in chronic myeloid leukemia]. AB - Polymorphic variants of cytochrome P4501A1 (CYP1A1), glutathione-S-transferase M1 (GSTM1) and T1 (GSTT1) distribution was studied in patients with chronic myeloid leukemia (CML) and healthy individuals. It was shown that homozygotes for the GSTT1 gene deletion occur significantly more frequently in the CML patient group compared to the control group (13.17% versus 24.10% in CML patients, Chi2 = 4.40, p < 0.05; OR = 2.09; 95% CI = 1.10-3.99). In contrast, no significant difference was observed between the healthy individuals and CML patients in the frequency of polymorphic variants of GSTM1 and CYP1A1 genes (p > 0.05). PMID- 21254557 TI - [How do chromosomes attach to synaptonemal complexes?]. AB - Fluorochrome-labeled oligonucleotides (n = 44) corresponding to mouse genome repetitive sequences were hybridized in situ with pachytene nuclei of mouse spermatocytes. Signals of the repetitive sequences MaLR, MER, and (GT)22 were found to be dispersed through chromatin, and signals of BI 1 repeats and minisatellites were mostly attached to synaptonemal complexes immunostained with anti-SYCP3 antibodies. These results suggest that B 1 repeats and minisatellites are candidates for sequences anchoring chromatin to synaptonemal complexes. PMID- 21254558 TI - [The epigenetic mechanism of the effect of mildly deleterious mutations on the viability of the progeny and their correction in meiosis]. AB - Data supporting the hypothesis about the epigenetic nature of deleterious mutations leading to the death of a part of the progeny are presented. It is assumed that during the life cycle "mutant" variants of formation of structural functional loop domains occur in chromosomes that normally are corrected during meiosis. An abnormal loop changes the activity of many tens of genes, both increasing (+) and decresing (-) it, which affects the viability of homozygotes and to a lesser extent the viability of heterozygotes. Hybrids with chromosomes containing independently accumulated deleterious mutations partly restore their viability due to the complementary interactions of + and - genes. PMID- 21254559 TI - [Some features of meiosis key events in rye and its synaptic mutants]. AB - The Peterhof Collection of spontaneous meiotic mutants of rye was used as a model to study the genetic control of meiosis key events in an organism with a large genome. A combination of methods, which included fluorescence in situ DNA-DNA hybridization, sequencing of recombinogenic proteins, and immunocytochemical analysis of meiosis proteins, clearly showed that mutation sy1 affects recombination events, asynapsis in mutant sy9 is connected with defects of the assembly of synaptonemal complex axial cores, and that synapsis defects in mutant sy10 are coupled with the presence of protein Zyp1 in the core region. The assembly of proteins Asyl and Zyp1 on the axes of meiotic chromosomes was shown to occur separately, which is a specific feature of rye, as compared to arabidopsis. PMID- 21254560 TI - [The role of the functional sites of the Merlin tumor suppressor in Drosophila spermatogenesis]. AB - The Merlin gene of Drosophila is homologous to the human Neurofibromatosis 2 (NF2) gene an important regulator of proliferation and endocytosis of cell receptors. It was earlier shown that the Thr5 residue of the Drosophila Merlin protein was homologous to Ser518 of the human protein (which was already known to undergo phosphorylation); hence, it was assumed that Thr559 of Drosophila also was a substrate of phosphorylation. The mutant Merlin proteins MerT559D (an analog of the phosphorylated form) and MerT559A (a nonphosphorylated form) were constructed and tested, under the conditions of ectopic expression for the ability to correct the spermatogenesis defects induced by the Mer4 mutation. The mutant form MerT559D was demonstrated to restore the abnormal nebenkern phenotype induced by this mutation, whereas the MerT559A substituted form did not restore this phenotype. Ectopic expression o the wild-type Merlin protein, MerT559A mutant form, and mycMer345-635 truncated protein in a normal genotype resulted in the abnormal nebenkern phenotype, whereas this phenotype was not observed in the case ofectopic expression of the MerT559D analog of the phosphorylated form. Ectopic expression of the mycMer3, mycMerABB, and mycMer-379 truncate variants led to disturbance of meiotic cytokinesis. PMID- 21254561 TI - [Exon-intron structure of the Xist gene in elephant, armadillo, and the ancestor of placental mammals]. AB - The Xist gene belongs to the class of long noncoding regulatory RNA genes which play a key role in the process of inactivation of one of the X chromosomes in females of placental mammals. Based on interspecific comparative sequence analysis performed using a set ofbioinformatic programs and approaches, the exon intron gene structure was first described in two species, elephant and armadillo, belonging to the most primitive placental mammal groups, Afrotheria and Xenarthra. Using multiple sequence alignment of the species representing all main groups of placental mammals (12 species), consensus sequence of the ancestral gene was reconstructed. In the gene structure four evolutionary conserved regions with the identity level of 90% and the sizes of more than 100 bp were identified. Substantial contribution of transposable elements to the gene origin, as well as mosaic evolution of certain elements of the Xist locus was demonstrated. It is likely that the ancestral gene consisted often exons and was formed before the radiation of placental mammals, in the period from 140 to 105 Myr ago. PMID- 21254562 TI - [Comparative organization and the origin of noncoding regulatory RNA genes from X chromosome inactivation center of human and mouse]. AB - After the radiation of primates and rodents, the evolution of X-chromosome inactivation centers in human and mouse (XIC/Xic) followed two different directions. Human XIC followed the pathway towards transposon accumulation (the repeat proportion in the center constitutes 72%), especially LINEs, which prevail in the center. On the contrary, mouse Xic eliminated long repeats and accumulated species-specific SIN Es (the repeat proportion in the center constitutes 35%). The mechanism underlying inactivation of one of the X chromosomes in female mammals appeared on the basis of trasnsposons. The key gene of the inactivation process, XIST/Xist, similarly to other long noncoding RNA genes, like TSIX/Tsix, JPX/Jpx, and FTX/Ftx, was formed with the involvement of different transposon sequences. Furthermore, two clusters ofmicroRNA genes from inactivation center originated from L2 [1]. In mouse, one of such clusters has been preserved in the form of microRNA pseudogenes. Thus, long ncRNA genes and microRNAs appeared during the period of transposable elements expansion in this locus, 140 to 105 Myr ago, after the radiation of marsupials and placental mammal lineages. PMID- 21254563 TI - [Investigation of the Tsix gene regulatory region in vole Microtus rossiaemeridionalis]. AB - The Tsix regulatory region was examined in vole Microtus rossiaemeridionalis. The minimal promoter region, three potential enhancer regulatory elements and one transcription suppressor element were identified. The enhancer regions contained potential binding sites of transcription activators, while in the region of putative silencer contained potential binding site of the ARP1 (NR2F2) protein. This protein can play the role of either activator or repressor depending on the promoter context. PMID- 21254564 TI - [Role of G(-43)A polymorphism in the promoter region of the Xist gene in non random X-chromosome inactivation in intraspecific hybrid voles]. AB - Interaction of transcription factor CTCF with the minimal promoter of Xist gene was investigated in intraspecific hybrids ofcommon voles. CTCF was shown to bind with the minimal promoter region in vivo. However, the experiments of the delay in gel resulted in the absence of interaction between the CTCF factor and its potential binding site. Probably, G(-43)A substitution influences binding efficacy of another transcription factor such as activator protein 2, AP2. PMID- 21254565 TI - [Comparative analysis of the DXPas34 regulatory region in rodents]. AB - Mouse X chromosome inactivation center contains the DXPas34 minisatellite locus which plays an important role in expression regulation of the Tsix and Xist genes, involved into female dosage compensation. Comparative analysis of the DXPas34 locus from mouse, rat, and four common vole species revealed similar organization of this region in the form of tandem repeat blocks. A search for functionally important elements in this locus showed that all the species examined carried the conservative motif monomers, which could be involved in regulation of X inactivation. PMID- 21254566 TI - [Intercalary heterochromatin in the genome of Drosophila]. AB - The modern concept of intercalary heterochromatin as polytene chromosome regions exhibiting a number of specific characteristics is formulated. DNA constituting these regions is replicated late in the S period; therefore, some strands of polytene chromosomes are underrepresented; i.e., they are underreplicated. Late replicating regions account for about 7% of the genome; genes are located there in clusters of as many as 40. In general, the gene density in the clusters is substantially lower than in the main part of the genome. Late-replicating regions have an inactivating capacity: genes incorporated into these regions as parts of transposons are inactivated with a higher probability. These regions contain a specific protein SUUR affecting the rate of replication completion. PMID- 21254568 TI - [Polycomb and trithorax control genome expression by determining the alternative epigenetic states of chromatin for key developmental regulators]. AB - The Polycomb (PcG) and Trithorax (TrxG) group proteins are essential for development in all multicellular organisms. Mutations of the PcG and TrxG genes act as early embryonic lethals, while their overexpression correlates with malignancies. Comparative genome analysis showed that PcG and TrxG form a binary regulatory system that functions as an epigenetic rheostat to determine the threshold levels of extracellular signals affecting the expression levels of key developmental genes. PMID- 21254567 TI - [Molecular combing in studies of the genome organization and DNA replication]. AB - Molecular combing (MC) yields preparations where individual DNA molecules are uniformly stretched and are parallel to each other. Fluorescence in situ hybridization on such preparations allows an exact mapping of DNA sequences, and pulsed inclusion of halogenated deoxyuridine analogs and their detection using fluorochrome-conjugated antibodies makes it possible to visualize replication. The MC technique was adapted for studying DNA replication in isolated Drosophila melanogaster organs, and it was checked whether a mutation of the Suppressor of UnderReplication (SuUR) gene directly affected the replication fork rate. PMID- 21254569 TI - [Functional organization of interbands in Drosophila polytene chromosomes]. AB - The functional organization of particular chromosome regions is tightly associated with their function in eukaryotic cells. Details of this association are among the most topical problems of modem genetics. The paper characterizes the results of recent research of the specifics of the genetic organization and chromatin decondensation in interbands of Drosophila polytene chromosomes. Data on functional heterogeneity of interbands are considered. Experimental findings point to a lack of correlation between the decondensed chromatin state and the observed transcription level in particular interbands. The DNA sequences responsible for the interband formation are principally identifiable via site specific homologous FRT/FLP recombination between two P transposons contained in chromosomes. The results allow a search for particular protein factors that are involved in the decondensed state of interbands and structural and functional differentiation of polytene chromosomes. PMID- 21254570 TI - [Dosage compensation in drosophila: sequence-specific initiation and sequence independent spreading of MSL complex to the active genes on the male X chromosome]. AB - For the dosage compensation to occur, genes on the single male X chromosomes in Drosophila must be selectively bound and acetylated by the ribonucleoprotein complex called MSL complex. It remained unknown how such exquisite specificity is achieved, and whether specific DNA sequences were involved. In the present work we demonstrate that it is transcription of the gene on the X chromosome that is important for MSL targeting, irrespective of gene origin and DNA sequence. PMID- 21254571 TI - [Clinico-experimental basis of application of biodegradable implants in surgical treatment of peripheral nerve lesions]. AB - Aim of this study was to provide clinico-experimental basis of application of biodegradable implants in surgical treatment of peripheral nerve lesions. Experimental investigations were performed on non-pedigree female rats with body weight of 200-250 grams. 10 animals were used, 20 sciatic nerves were operated. Morphological examinations were done on 21st and 101st days after surgery. Clinical part of the study was performed after finishing of experimental block and included 20 patients with peripheral nerve lesions. Information about patients included: sex, age, type and localization of lesion, preoperative neurological status, data of electrophysiological and ultrasonographic studies and MRI. Follow-up period varied between 3 and 12 months. The series included 13 male and 7 female patients, age was 20-63 years. Injection of "Sphero(r)Gel" in the area of nerve suture enables more effective regeneration of axons and their growth through the injury site. Application of "ElastoPOB(r)" membrane favors demarcation of peripheral nerve from surrounding scar tissues in the wound. Acquired data demonstrate decreased influence of scarring process on the nerve trunk in the postoperative period according to neurological examination, electroneuromyography, ultrasonography and MRI. PMID- 21254572 TI - [Methods of intraoperative control in resection of intraparenchymal brain tumors]. AB - Primary CNS tumors represent 1.4% of all malignant neoplasias and 2.4% of total oncological mortality. The principal goal of tumor resection is maximally possible radical removal with minimal injury of normal brain tissue. This is due to correlation between intraoperative trauma of the brain and postoperative neurological deficit and quality of life. Recently intraoperative ultrasonic and fluorescent methods of guidance have been widely introduced in neurosurgical practice. In conditions of altered anatomy ultrasonographic guidance is intended to optimize approach to intracerebral tumors considering eloquent areas and main vessels. This allows decrease of neurological deficit in the postoperative period. Fluorescent guidance provides possibility of visual differentiation of tumor and normal tissue thus defining the borderline. Combination of these two techniques may lead to more radical resection of tumors and minimize injury of normal brain. We operated 70 patients with primary and metastatic intraparenchymal brain tumors. Intraoperative ultrasonographic guidance was applied in 58 cases, fluorescent guidance--in 21, both methods--in 9. PMID- 21254573 TI - [Psychiatric disorders in temporal lobe gliomas]. AB - The rate of temporal lobe gliomas among all hemispheric glial tumors is up to 30%. Psychiatric disorders are typical for temporal lesions and could be even single manifestation of the disease. There is a rich variety of different psychopathologic and epileptic signs exactly in cases of temporal gliomas in comparison to tumors of other localizations. In our study we investigated psychiatric disorders on statistically significant group of patients (140 cases) with temporal lobe tumors with considerations of side, localization, histology of lesion and functional asymmetry of patients. We revealed psychiatric disorders in 72% of patients, mainly in glioblastoma. Seizures were more typical for WHO Grade I and II gliomas. Psychopathologic symptoms were more typical for left side lesions. Lefthanders had psychiatric disorders significantly more frequently than righthanders (p < 0.05). After surgical removal of tumor the rate of psychiatric disorders didn't differ statistically (p < 0.05) by 2 years follow-up. Complete regress of seizures was observe in 56% of cases. PMID- 21254574 TI - [Intraoperative identification of oculomotor, trochlear and abducent nerves in surgery of invasive cranioorbital tumors (new technique)]. AB - BACKGROUND: Aim of the study was to evaluate effectiveness of intraoperative identification of oculomotor nerves (OMN) in resection of skull base tumors invading superior orbital fissure and cavernous sinus. MATERIALS AND METHODS: 69 patients with cranioorbital tumors operated in Burdenko Neurosurgical Institute (Moscow, Russia) since 2000 until 2005 were included in the study. They were divided into 2 groups: 19 patients treated with intraoperative identification of OMN and 50 patients in the control group. Craniorbital meningiomas were in the majority among all cases. Intraoperative identification of OMN was performed using coaxial electrode while muscular response was registered through electrodes inserted in m. levator palpebrae superioris, m. obliquus superior and m. rectus lateralis (for III, IV and VI cranial nerves, respectively). Identification of IMN trunci was repeated throughout the whole stage of tumor resection for their preservation. RESULTS: comparison of dynamics of oculomotor dysfunction in early postoperative period in patients of both groups demonstrated that intraoperative identification of OMN allowed to decrease the frequency of oculomotor deficit. The rates in main and control groups were: for III and IV nerves--37% and 68% (p < 0.05), for VI nerve--47% and 54% (p > 0.05), respectively. CONCLUSION: application of intraoperative identification of OMN allows to decrease the risk of oculomotor deterioration due to III and IV nerve dysfunction by 1.8 times. Technically the method is quite simple and not time-consuming procedure. PMID- 21254575 TI - [Diagnosis and treatment of complicated subaxial injury]. AB - BACKGROUND: The aim of this study was to develop optimal tactics of surgical treatment of complicated injuries of the cervical spine, in accordance with SLIC (subaxial injury classification) and to improve the results of intervention in the acute period. MATERIALS AND METHODS: We analyzed 97 patients with complicated subaxial injury of the cervical spine. All patients were operated via anterior approach. Contraindications for surgery included constant instability of systemic haemodynamics and impairment of breathing on the background of extremely severe condition of patient, purulent-inflammatory processes. Results were evaluated by dividing our series into groups: centromedullary injury, compression-burst fractures of vertebral bodies, facet subluxations and facet fractures dislocations. RESULTS: Treatment by applied technique was effective in 88.7% of series, successful orthopaedic results was obtained in 99%. With incomplete consideration of possible limitations of the operations, early decompression and stabilization do not improve outcomes and quality of life of patients. PMID- 21254576 TI - [Clinical and prognostic significance of genetic markers of ApoE gene in traumatic brain injury]. AB - The review focuses on the analysis of available data about association of polymorphic genetic markers of gene encoding apolipoprotein E (APOE) with traumatic brain injury (TBI). The most investigated genetic marker of poor outcome after TBI is presence of 4 allele of APOE gene. According to most authors, carriers of this allele have worse functional outcome and lower indices of restoration of cognitive functions. Studies of association of polymorphic markers A(-491)T, T(-427)C and G(-219)T, located in promoter area of APOE gene, with course and outcome of TBI in Europeans, demonstrated that only carriers of TT genotype of polymorphic marker G(-219)T had much poorer recovery in comparison with carriers of GT and TT of this marker. However, in patients with TBI belonging to Chinese population association with higher risk of neurological deterioration was discovered for another polymorphic marker of the same area, A( 491). Increased risk was observed in carriers of AA genotype which determines raised level of APOE gene expression in combination with presence of 4 allele of the same gene. Analysis of the whole clinical and experimental investigations of association of different polymorphic markers of APOE gene with course and outcome of TBI allows to conclude that product of this gene, apolipoprotein E, in fact, plays important role in processes of recovery of brain and its functions being directly involved in neuroplasticity and neurotransmission thus facilitating functional integration of different brain areas. PMID- 21254577 TI - [The role of intraoperative photodynamic therapy in complex treatment of cerebral metastases]. AB - Cerebral metastases are the most common brain tumors in adults and are characterized by poor prognosis. Despite application of modern methods of treatment (microsurgery, radiation therapy, chemotherapy) survival rates of these patients remain low. This fact triggers development of new therapeutic options which are able to increase recurrence-free period and consequently overall survival. The article contains review of literature dealing with photodynamic therapy which is a newly introduced technique for treatment of cerebral metastases. PMID- 21254578 TI - [Current problems of pathogenesis and surgical treatment of symptomatic temporal epilepsy]. AB - The author presents a review of literature focusing of state-of-art of surgical management of epilepsy. The second part of review discusses basic principles of selection of patients with localization-caused epilepsy for surgical treatment, preoperative examination, substantiation of resection procedures, results of treatment. Special attention is given to controversial aspects of tactics of surgical management: neurophysiological and neuroimaging signs of epileptogenic zones, determination of required resection volume, value of preoperative invasive examination and intraoperative electrocorticography. Surgical complications, especially concerning medial temporal procedures, are also described. PMID- 21254579 TI - [The greatest organizer of military medicine and health service E.I.Smirnov about N.I.Pirogov]. AB - E.I.Smirnov's views of the role and place of organizational aspects of the greatest Russian surgeon N.I.Pirogov in development of modern medical supply system are covered on the basis of vast historiographical data. From the perspectives of historism and objectivism a degree of realization Pirogov's ideas during creation of the consistent military-medicine doctrine and organization of medical-evacuational measures during the Great Patriotic War 1941-1945 is analyzed. PMID- 21254580 TI - [Comparative analysis of community-acquired pneumonia severity in servicemen of organized military groups]. AB - The results of the treatment of 2000 patients with community-acquired pneumonia are showed, 693 of 2000 patients were vaccinated with pneumococcal vaccine "Pneumo-23". Vaccinated patients, in comparison with non-vaccinated, didn't suffer from complications and sustained course of a disease. The regression of disease's symptoms and radiological resolution of pneumonia were faster. The length of hospital stay was shorter (18.1 +/- 1.7 and 22.41 +/- 1.30 days agreeably). PMID- 21254581 TI - [35-year practice of treatment of acute coronary syndrome in 3rd central military clinical hospital n. a. A.A.Vishnevsky]. AB - Results of 35-years clinical investigation on acute coronary syndrome performed in the 3rd Central military clinical hospital named after A.A. Vishnevsky are presented. Research topics are the following: pathways of blood coagulation alterations,lipid metabolism, improving drug management of ischemic heart disease exacerbations, new medical technologies in diagnostics and treatment of acute coronary syndrome. Decision procedure in patient with acute coronary syndrome was developed in the Hospital. Criteria for percutaneous coronary interventions and coronary artery bypass surgery were elaborated. Original scale for death and cardiac complications risk assessment in patients with acute myocardial infarction undergoing coronary artery stenting was developed. According to the scale, differential scheme of antiplatelet therapy was introduced, and its implementation resulted in decrease of complications rate. Advantage of early invasive strategy vs. conservative approach was proven. PMID- 21254582 TI - [Usage of the neutral anolyte for trophic ulcer treatment in patients with postthrombophlebitic syndrome]. AB - The results of the treatment of 38 patients with trophic ulcers of lower limbs developed against the postthrombophlebitic syndrome at the age of 43-73 years. The course of a disease exceeded 10 years. Trophic ulcers recrudesced in all patients, timeline of its appearance was 2.4 +/- 0.5 months. Daily trophic ulcers were irrigated by the neutral anolyte, it took from 5 to 7 sessions. The detersion of trophic ulcers came on the 3rd-4th day; granulation tissue appeared on the 5th day. The absence of bacterial population was noted in 89.5% of patients after 5.0 +/- 0.5 sessions. Trophic ulcers were epithelialized in 1 month, while in the group of comparison the whole epithelialization came only in 32% of patients. PMID- 21254583 TI - [Diagnostic criteria, epidemiology and substantiation of clinicopathogenetic types of perioral dermatitis]. AB - The perioral dermatitis is a multifactorial disease of a face skin meeting in population with frequency of 5% also represents inflammatory process with the various morphological characteristic of an eruption. A total of 511 patients are surveyed by a perioral dermatitis. For the first time clinico-pathogenetic types of development and a disease current (it is hormonal--immunologic, allergic, gastroenterology, metabolic) with characteristic distinctive changes of the hormonal status, a metabolism and immunity system are allocated. The complex of laboratory criteria of diagnostics of the specified types of the perioral dermatitis, giving representation about mechanisms of formation, clinical features of the dermatosis is developed, allowing differentiate to prove the approach to treatment. PMID- 21254584 TI - [Epidemiology and development of prophylaxis of acute respiratory diseases and pneumonias in servicemen in modern conditions]. AB - Acute diseases of respiratory organs occupy leading position among all diseases in army. In 2009 a part of total morbidity of ARD, flu, pneumonia and acute bronchitis was 45.7% from all diseases. With the start of the usage of pneumococcal vaccine in the army continuous increase of morbidity of pneumonia gave way to reduction. In postvaccinal period in patients with pneumonia, frequency of pneumococcus's effuse reduced under the increase of frequency of detection of viruses, staphylococcus and streptococcus. Considering polyaetiology of pneumonia and ARD, significancy of immune inefficiency in its developments, it is necessary to use specific prophylactic drugs with antiviral products in period of reinforce. PMID- 21254585 TI - [Treatment of initial diacrisis of disorder of trophological status in servicemen]. AB - The authors consider the problem of objectivity of initial diacrisis of disorder of trophological status as in case of manning and troops of Northern Fleet and also in the interest of military physician expertise at determining of fitness for service. In terms of retrospective analysis of assessment's results of food status of recruits, submariners and divers in accordance with Government decree N 123 the authors quarreler ranges of denotation of body mass index which are adjusted in this document referring to their own researches. Their research let to get a new denotation of body mass index: "nutritional inadequacy"--< 16,59, "suralimentation"--16,60-19,17, normal balance of growth and weight--19,18-24,31. PMID- 21254586 TI - [About development of medical maintenance of military air forces in modern conditions]. AB - The authors prove the necessity of transformation of medical service of Air Force of all levels within the framework of the realization of program "Development of medical supply of Armed Forces of Russian Federation 2008-2012". Goals, functions of different elements of medical service, responsibilities of performers are developed. These goals have fundamental differences from previous one. New organizational structure of medical service of Air Forces and criteria of the estimation of its effectiveness are suggested. Offers of further optimization of organizational medical structure and improvement of medical supply of Air Forces are developed. PMID- 21254588 TI - [N.K.Karpinsky--first general-headquarter-doctor]. AB - The article is devoted to biographies of the first head of the Department of Anatomy and Physiology of Petersburg Medical-Surgical Academy Professor Nikon Karpovich Karpinsky (1745-1810). Karpinsky contributed to the development of domestic medicine, especially surgery. His first work "The course of surgical dressings" proved it (1776). Multi-faceted medical services Karpinsky successfully combined with various administrative assignments. In 1791 he was appointed as a member of the Medical Board--the highest government body, ruled the Russian medicine, and after its closure in 1804--the chief scientist of the expedition department in the state medical council and a member of the Medical Council. The apotheosis of his administrative career began in 1805 post-general headquarters, a doctor, who commanded all military medicine of the country. PMID- 21254587 TI - [Nikolay Ivanovich Pirogov: at the beginning (to the 220th anniversary of the greatest surgeon and anatomist birth)]. AB - The article is concern with years of youth of the greatest Russian surgeon and anatomist Nikolay Ivanovich Pirogov, his education in Moscow and Derpt University. Formation of N.I. Pirogov as a surgeon of a new type following by the deepest anatomical knowledge is showed. There is a supposition that with the departure from Derpt to Saint-Petersburg Pirogov's initial phase of work ended and began his new, mature period of work. PMID- 21254589 TI - [Effects of subchronic hemantane administration on dopamine and serotonin receptors in intact and MPP+-treated rat brain ex vivo]. AB - The influence of the new antiparkinsonian drug hemantane on D1 receptors in striatum, 5-HT1A receptors in hippocampus, and 5-HT2A receptors in frontal cortex of intact and MPP+-treated (3 microg/0.6 ml dist., intranigral) rats was studied. Hemantane (20 mg/kg, i.p.) was administrated subchronically for 7 days (beginning a day after MPP+ injection). A modulatory effect of hemantane on D1, 5-HT1A and 5 HT2A receptors was revealed. It was found that hemantane increased the binding site density (Bmax) of D1 and 5-HT1A receptors and decreased the binding site density of 5-HT2A receptors without changing the affinity (Kd) to the selective ligands. These results demonstrate that subchronic administration of hemantane leads to the functional rearrangement of dopamine and serotonin receptors in the brain of both intact and MPP+-treated rats. PMID- 21254590 TI - [Behavioral effects of m-CPP and ketanserine during ovarian cycle in female rats]. AB - A comparative analysis of the influence of chronic administration of the 5 HT2B/2C receptor agonist, m-CPP (0.5 mg/kg, i.p.), and the 5-HT2A/2C receptor antagonist, ketanserine (0.1 mg/kg, i.p.) for 14 days on the anxiety and depressive-like behavior in the adult female rats was performed. The depression in rats was modeled using the Porsolt test. The anxiety level was assessed in the elevated plus maze test. It was established that ketanserine induced antidepressive and anxiolytic effects in females during estrous and proestrous periods. The m-CPP administration also resulted in antidepressive effect in both estrous and proestrous periods. A clear modulation was observed in the anxiety behavior as dependent on the ovarian cycle phases in rats treated with m-CPP: the anxiolytic effect was manifested at an increased level of estrogens, while anxiogenic effect was manifested at a reduced level of estrogens. It is suggested that 5-HT subtype receptors are involved to different extent in the mechanisms of anxiety-depressive-like behavior depending on the alterations of hormonal balance during the ovarian cycle. The data obtained are indicative of a close interaction between the ovarian hormonal and serotonergic systems of the brain in the mechanisms of anxiety and depression. PMID- 21254591 TI - [Gender differences in action Fenotropil and its structural analog--compound RGPU 95 on anxiety-depressive behavior animals]. AB - Fenotropil and its structural analog--compound RGPU-95 to a greater extent reduce the severity of anxious and depressive behavior in male rats than in females. On expression of the anxiolytic compound RGPU-95 significantly exceeds Fenotropil, but inferior to Diazepam; of antidepressant activity--comparable to Melipramin and exceeds Fenotropil. PMID- 21254592 TI - [Tiotropium bromide for treating chronic obstructive pulmonary disease]. AB - Five different types of muscarine-sensitive receptors were identified until now. In routine practice, the nonselective antagonist of cholinoreceptors are replaced by ipratropium bromide that is selectively blocking M1, M2, and M3 subtypes with the same affinity to each of them. However, the blockage of M2 subtype leads to bronchoconstriction and is accompanied by inhibition of M3 receptors in bronchial smooth muscles. The new drug tiotropium bromide selectively inhibits only the M1 and M3 types of receptors and does not affect the M2 subtype. This drug is administered only once a day, which is very important in clinical practice. Thus tiotropium bromide is the drug of choice for basic therapy of COPD. PMID- 21254593 TI - [Pharmacological correction of Th1 and Th2 lymphocyte activity and cytokine profile in ethanol intoxicated rats]. AB - It was established in experiments on noninbred rats that their ethanol intoxication (13 days; total dose, 2.6 LD50) significantly reduces the concentration of blood cytokines IFNgamma, IL-2, IL-4, IL-10, increases the concentration of IL-6, suppresses the immune responses, and reduces the interrelation IFNgamma/IL-4 in comparison to the control, which testifies to the greater damage of Th1 cells in comparison to Th2 lymphocytes. The immunomodulator polyoxidonium administered for four days at a daily dose of 700 microg/kg fully restores the cellular and humoral immune responses and the synthesis of cytokines IFNgamma, IL-2, and IL-4 and partly restores the production of IL-10. PMID- 21254594 TI - [Effect of macrophage stimulators on development of selective depression of liver macrophage in vivo]. AB - A single administration of zymosan (50 mg/kg) and chito-carboxymethylated glucan (25 mg/kg) to mice was shown to improve the selective liver macrophage depression induced by gadolinium chloride (7.5 mg/kg, intravenous administration). Both beta 1,3-glucans (ChitoCMG and CMG) studied revealed the signs of liver macrophage stimulation: increased number and phagocytic activity of liver macrophages and increased serum chitotriosidase activity. The model of selective liver macrophage depression was characterized by decreased activity of serum chitotriosidase. ChitoCMG as well as zymosan increased the uptake of gadolinium by liver cells during preliminary (before gadolinium chloride) administration of beta-1,3 glucans. It was concluded that the model of selective liver macrophagedepression is useful for studying the protective effects of biological response modifiers such as polysaccharides (beta-1,3-glucans) in vivo. PMID- 21254595 TI - [Substituted 2,3,4,5-tetrahydro-1H-gamma-carbolines: new antagonists of histamine H1 receptors]. AB - The properties of 2,3,4,5-tetrahydro-1H-gamma-carbolines containing acid, ether, and amido-substituents, were assessed as potential antagonists of histamine H1 receptors (H1R), capable of blocking histamine-induced calcium fluxes in SK-N-SH cells. The structure--activity relationship for their antagonistic activity is discussed. Among the gamma-carbolines used in the study, the antihistamine activity considerably depends on the nature of substituents in positions 2, 5, and 8 of the heterocycle. The most active antagonist, ethyl 3-(2-methyl-8-fluoro 2,3,4,5-tetrahydro-1H-gamma-carboline-5-yl)propionate, with high affinity to the H1R (Ki = 6.5 nM), produces no adverse effects on motor activity of mice in doses 1-40 mg/kg, which shows the absence of a sedative effect. PMID- 21254596 TI - [Chemotherapy of chronic viral hepatitis B: randomized multicenter investigation results]. AB - During treatment of patients with chronic hepatitis B the best therapeutic effect was obtained with the inclusion in the scheme of antiviral therapy cycloferon. Complete stable remission was achieved in 54.1% of patients in combination cycloferon with lamivudin, but the appointment of alpha-interferon with cycloferon provided remission 44.1% of patients resistant to treatment with lamivudin. Therapy of chronic hepatitis B with cycloferon can reduce the frequency and severity of side effects, prevents the development of resistance to lamivudin and the emergence of mutant viruses. PMID- 21254597 TI - [Drug bioavailability improvement by means of nanopharmacology: pharmacokinetics of liposomal drugs]. AB - Modern approaches to increasing the efficiency of liposomal transport of substances are discussed. Examples of creating new nanopharmacological drugs that exceed the pharmacokinetic characteristic of their classical analogs are given. PMID- 21254599 TI - [Preclinical study of Reamberin and Remaxol safety]. AB - Preclinical safety of reamberin, a preparation of succinic acid intended for the treatment of patients with shock conditions of different etiology, and remaxol a drug intended for the treatment of patients with liver dysfunction caused by acute intoxication was performed. Both medicines belong to the 5th class of practically non-toxic drugs. Their administration to experimental animals for 30 days did not cause toxic effects on the functional and morphological state of main systems and organs. Both medicines do not affect specific (humoral and cellular) and non-specific immune response and do not cause sensibilization, mutagenic, embryotoxic and teratogenic effects, and also do no alter parameters of reproductive functions of rats. PMID- 21254598 TI - [Effect of mexidol on 6beta/free hydroxycortisol ratio. Possibility of CYP3A4 activation]. AB - The influence of mexidol (2-ethyl-6-methyl-3-oxypyridine) after a single peroral administration on the levels of 6beta-hydroxycortisol (6beta-OHC) and free cortisol (FC) in human urine has been evaluated. The 6beta-OHC/FC ratio is increased (approximately 2.96 +/- 0.76 times) against the basal 6beta-OHC/FC ratio during the first 24 hour after drug administration. Data analysis on the second and third day after mexidol administration did not show evident changes in 6beta-OHC/FC ratios. It is suggested that CYP3A4 activation after mexidol administration occurred only during active drug biotransformation and excretion and ceased after full excretion from the human body. PMID- 21254600 TI - [GABA B-type receptors: structure and functions]. AB - Available data on structure, localization, physiology and pharmacology of GABAB type receptors are reviewed. GABAB-receptors are pre- and postsynaptically located, belong to metabotropic ones and are connected to trimeric G-protein. Mammal GABAB-receptors, consisting of two subunits of B1 and B2 type, are allosterically regulated heterodimers (actively functioning GABAB-receptors). The activation of GABAB-type receptors leads to increasing K+ release from the cell and hyperpolarization of cell membrane. GABAB-receptors are also connected with potentially dependent Ca2+ channels, which are involved in the synaptic release of neurotransmitters. There is a great number of their allosteric modulators, agonists and antagonists. PMID- 21254601 TI - [Homeostasis of adult stem cells and carcinogenesis]. AB - Treatment of malignant tumors using radiotherapy, chemotherapy, immunosuppressive drugs required to recover bone marrow transplant by the donor bone marrow or purified adult stem cells. During the next 1-15 years of follow up of these patients compared with healthy individuals of the same age increases the risk of multiple malignancies. It used to be attributed to the influence of therapeutic effects. However, it is revealed that some of the cells and the stroma of the secondary tumors are composed of descendants of transplanted stem cells. This indicates the important role of stem cells in tumor growth. This is also evidenced by numerous studies showing that adult stem cells from both mice and humans multiplied in vitro, after transplantation into the body give the sarcoma, cancer foci and other types of malignant growth. In this, malignant growth is most intense in the presence of focal chronic inflammation. No less than the experimental data, including those obtained in humans suggest that the transplanted stem cells actively colonize stroma of tumor tissue, stimulating the growth of the tumor and its metastasis. The human condition of survival is the presence of rigid homeostatic control mechanisms of low numbers of stem cells in the body and the limit their division, even in areas of regeneration. After the transplantation of stem cells their number in the bloodstream and, consequently, in the pathological foci of regeneration, increases in many dozens of times--this level can not be achieved by the organism itself. This leads to a sharp increase in the rate of regeneration of tissues, which creates conditions for amplification of malignant growth. PMID- 21254602 TI - [Electroencephalographic characteristic of cognitive-specific alerting attention in verbal learning--III: Localized characteristics of EEG spatial synchronization]. AB - Electroencephalograms (EEG) were recorder in 19 standard derivations in 88 healthy subjects, while they were in the states: rest with eyes open; memorization (learning) of verbal bilingual semantic pairs (Latin and Russian languages); the retrieval of the rote information from memory (control). We compared estimates of EEG coherence in these states for the frequency bands theta (4-7 Hz), alpha-1 (7-10 Hz), alpha-2 (10-13 Hz), beta-1 (13-18 Hz), beta-2 (18-30 Hz), gamma (30-40 Hz). When compared with the rest most strongly expressed: for memorization a decrease of coherence in the pairs of derivations from frontal and central areas of the cortex in the EEG frequency bands; for retrieval an increase of coherence in interhemispheric derivation pairs of pariental-occipital region in majority of the frequency bands. For the retrieval also increases of coherence in the beta2 and gamma bands, along with coherence decreases at low frequencies take place in pairs formed by derivations from the parieto-occipital region with derivations from the frontal and the central ones. Dynamics of EEG coherence in comparisons of memorization and retrieval from the rest and each are expressed significantly more in the interhemispheric and crosshemispheric pairs of derivations than in the intrahemispheric pairs. Revealed topographic specificity of the dynamics of EEG coherence by changing the states is considered in terms of ideas about cognitive-specific forms of sustained goal-directed mental attention. PMID- 21254604 TI - [Healthy person's cerebral reactions to the rhythmic transcranial magnetic stimulation of different intensity]. AB - At 8 healthy examinees-volunteers of 22-25 years the functional effects of super threshold (above 1.2 T) and subthreshold (70-80% of a motor threshold) rTMS of premotor cortexes medial departments were compared. Functional brain activity changes were estimated (before and 1 hour after stimulation) by comparing data including neuropsychological testing, visual and spectral-coherent EEG-analysis, and also haemodynamic parameters. The number of the work's problem included selection of activating orientated stimulation's frequency, and also specification objective EEG--criteria of efficiency rTMS. It is established the effect of EEG-analysis during different frequency photostimulation for a choice of activating rTMS. The received results reveal EEG-coherence as one of the most informative characteristics of cerebral neuro-dynamics under rTMS-influence. Dependence of stimulation's functional effects (activated or brake character) from initial level of the intercentral coherent communications is noted. It is revealed that rTMS of the healthy examinees causes certain changes of functional activity of a brain, distinct from placebo-effects. rTMS-effect dependent on intensity (super--or sub-threshold), and also from features of an initial intercentral rations. More expressed functional changes are observed in the left hemisphere. It is shown big by reactance of the left hemisphere on this influence. In formation of brain responses on rTMS the active role of the vascular factor is shown. PMID- 21254603 TI - [EEG, ERP in selective attention paradigm and the level of some metabolites in brain prefrontal cortex]. AB - The preliminary analysis at the first stage of the research has revealed the statistically significant correlations between electrophysiological parameters and the level of several metabolites (determined by magnetic-resonance spectroscopy) in the left dorsolateral prefrontal cortex. The findings are assumed to be due to the individually specific peculiarities of activation of this brain region and its impact on the information processing. The neurophysiological markers of decreased brain functional state are associated with the lower N-acetyl aspartate and choline and higher level of creatin/phosphocreatin in the tested region of prefrontal cortex. PMID- 21254605 TI - [Age related size invariance in perception of illusory and fragmented contours]. AB - We investigated invariant perception to sizes of images. Observers were schoolmates of 7-17 years and adults. Two types of stimuli were used: fragmented line drawing of common objects and discs with deleted sectors, which represented illusory Kanizsa contours when discs were in particular positions. In experiments with fragmented images, we found an improvement in image recognition with observers' age, increasing up to 13-14 years. The probability of recognition of fragmented line drawings increased significantly with decreasing stimulus size for children of 7-12 years, indicating that size invariance at recognition for fragmented line drawings was absent in these children. However, size invariance was found for observers of 13-17 years and for adults in this task. At Kanizsa illusion appearance, the ratio of the separation between discs and disc diameter was smaller when we used larger disc diameters. This ratio increased with increasing age of observers. Obtained results provide evidence for the absence of size invariance when perceiving the Kanizsa illusion in our experimental conditions. PMID- 21254606 TI - [The comparison of characteristics of smooth pursuit in left-handed and right handed persons]. AB - The estimation of the smooth pursuit efficiency in healthy young adults by method based on stroboscopic stimulation is given. The influence of manual function asymmetry on smooth pursuit was tested. Subjects were classified as left-handed or right-handed under a well known handedness questionnaire of Annett supplemented by Luria's tests. It was shown that the strong right-handed persons have a high quality of smooth pursuit of stimuli moving horizontally in rightward and leftward directions with the velocities 20 degrees/s and 25 degrees/s. Left handed persons track similar stimuli, on the average, worse than the strong right handed ones. It haven't been observed the influence of manual function asymmetry on the dependence of the smooth pursuit efficiency from the moving stimuli direction (left to right or right to left). PMID- 21254607 TI - [Functional coupling of cortical areas during problem-solving task: an analysis of theta rhythm coherence]. AB - We analyzed the EEG theta rhythm coherence in adult subjects who performed visual object classification task in the condition of uncertainty. The coherence function was estimated for the EEG segment following a feedback signal. It was shown that the functional coupling of cortical areas was stronger in the process of strategy discovering as comparing to the final period when the strategy is already found. The theta-related functional links are characterized by a specific topographical pattern: they converge to the foci located in the polar frontal cortex and reflect the interaction between the latter and the anterior associative cortices of the left hemisphere and occipital areas of both hemispheres. This pattern of functional connectivity may reflect an interaction between limbic structures and the frontal cortex in the process of strategy formation. PMID- 21254608 TI - [Functional organization of the brain cortical areas at rest condition in children 5, 6 and 7 years old]. AB - Functional connectivity at rest was studied in children of 5, 6 and 7 years old. Connection strengths were estimated using coherence function taken at the frequencies of the major EEG rhythms. Factor analysis of the raw coherence data revealed 4 different cortico-cortical functional connectivity patterns. These patterns are stable across the studied age span although particular functional links may change reflecting the general trend of heterchronous maturation of the cortex. PMID- 21254609 TI - [Spectral power of theta and alpha EEG-bands in preschool children with different level of set plasticity]. AB - Spectral power of theta and alpha EEG-bands at different stages of visual set was studied in 5-7-year-old children. Children with a plastic set had greater alpha band spectral power values than children with a rigid set. At set formation stage children with a rigid set displayed an increase of theta-band EEG-power, which is a manifestation of "immature" arousal reaction. Children with a plastic set displayed at set formation stage an increase of alpha-band spectral power in bilateral occipital brain areas. Dynamics of EEG spectral power differed in children before and after 6 years of age. At set formation stage 5-6-year-olds displayed an above-mentioned "immature" arousal reaction, and 6-7-year-olds--an increase of alpha-band spectral power in occipital brain areas. At set actualization stage 6-7-year-olds displayed an increase of alpha-band spectral power in right posterior brain areas. At set extinction in this group a bilateral decrease of alpha-band spectral power in mid-frontal areas was observed. An importance for a quick set-shifting of certain brain areas' involvement in the process of visual perception is discussed. PMID- 21254610 TI - [The complex influence of environmental factors on the state of microcirculation]. AB - The state of microcirculation system and its regulation in peace and after growing physical activity is analyzed on people living in different ecological regions. There are three main types of microcirculation. The level of regulation mechanisms activity depends on the type of microcirculation, region of residence and the value of physical activity. People living in a relatively clean regions have stable mechanisms of regulation despite of the level of activity. Mesoemic type living in toxic radiation regions have reduced contribution of VLF and LF fluctuation (p < 0.05); hypoemic type living in toxic regions have VLF and LF fluctuation (p < 0.05); hyperemic type living in toxic regions have LF fluctuation (p < 0.05). We can conclude the tension of regulatory machanisms in microcirculation system increases under ecological pressure and borders on failure of adaptation process. PMID- 21254611 TI - [Novel method for activation of the locomotor circuitry in human]. AB - We examine the possibility for activation of the involuntary locomotion of the lower limbs by spinal electromagnetic stimulation (ES). The subject laid on the left side. The legs are supported in a gravity-neutral position by special mounting that to provide horizontal rotation in the hip, knee and ankle. ES (3 Hz and 1.56 Tesla) at the T11,-T12 vertebrae induced involuntary locomotor-like movements in the legs. The latency from the initiation of ES to the first EMG burst compoused 0.68 +/- 1.0 s and it shortened at increasing of the frequency ES from 3 Hz to 20 Hz. Thus, the spinal ES can unduce the activation of the locomotor movements in human. PMID- 21254612 TI - [Effects of long-term space flights on organization of horizontal gaze fixation reaction]. AB - Results of Russian-Austrian space experiment "Monimir" which was a part of international space program "Austromir" are presented in this paper. Characteristics of horizontal gaze fixation reaction (hGFR) to visual targets were analyzed. Seven crewmembers of "Mir" space station expeditions took part in the experiment. Experiments were carried out 4 times before space flight, 5 times in flight and 3-4 times after landing. There were revealed significant alterations in characteristics of gaze fixation reaction during flight and after its accomplishing, namely: an increase of the time of gaze fixation to the target, changes of eye and head movements' velocity and increase of the gain of vestibular-ocular reflex, that pointed out to the disturbances of the control mechanisms of vestibular-ocular reflex in weightlessness caused by changes of vestibular input's activity. There was discovered also the difference in the strategies of adaptation to microgravity conditions among the cosmonauts of flight and non-flight occupation: in the first group exposure to weightlessness was accompanied by gaze hypermetry and inhibition of head movements; in the second one--on the contrary--by increase of head movement velocity and decrease of saccades' velocity. PMID- 21254613 TI - [Computerized methods for therapy and rehabilitation of patients suffering dizziness and balance disorder]. AB - A new computerized method is proposed for correction and inhibition of unfavorable illusory (vertigo), vestibular-oculomotor (nystagmus), and vestibular postural (balance) responses. This method allows to teach the subject to block generalization of an afferent signal to effector mechanisms of the central nervous system by developing a fixational reflex, utilizing a delayed biofeedback. Three variant ofthis method were employed, depending on the kind of stimulation programs aimed at inducing abnormal responses of a certain sensory modality (visual, vestibular or combined). The study involved 36 subjects divided into 3 equal groups one of which had been taught by a visual or vestibular technique, and the last one by a combined. Each group included approximately equal numbers of subjects with vestibulopathies of an organic (peripheral or central) or psychogenic origin. It was demonstrated that the method proposed allows, with the help of computerized stimulation programs, to provoce abnormal illusory and vestibular-optooculomotor responses in the subject, and inhibit them with the help of development of a fixational reflex. Patients were taught using three various variants of the method. A subsequent comparative analysis of results obtained has shown dependence of their effectiveness on the level of disturbance in the vestibular system: the visual variant of correction was the most effective for subjects with peripheral vestibulopathia; for subjects with central vestibulopathia, the vestibular variant was more effective; the combined variant of correction was the most effective for subjects with psychogenic vestibulopathia. PMID- 21254614 TI - [Role of physiological factors in prognosis of the risk of oncological diseases development on the basis of xenobiotic metabolism enzyme system polymorphism]. AB - Summarised data about polymorphism of xenobiotic metabolism enzyme system (XMES) have been presented. Metabolic molecular mechanisms and the role of genetic polymorphism in metabolic transformation of different xenobiotics are reviewed. Significance of X-transport proteins and nuclear receptors in regulation of XMES activity are discussed. Possible connection of XMES polymorphism with the development of cancer was examined. Experimental modeling of different levels of epoxide syntase and epoxide hydratase activites has revealed their connection with cancer development. Physiological factors should be considered when evaluation of risk extent for cancer development is carried out. PMID- 21254615 TI - [Ultrastructure of statocytes and cells of distal elongation zone of Arabidopsis thaliana under clinorotation]. AB - Results of the electron-microscopic investigation of root apices of Arabidopsis thaliana 3-, 5- and 7-days-old seedlings grown in the stationary conditions and under clinorotation are presented. It was shown the similarity in the root apex cell ultrastructure in control and under clinorotation. At the same time there were some differences in the ultrastructure of statocytes and the distal elongation zone under clinorotation. For the first time the sensitivity of ER bodies, which are derivatives of GER and contain beta-glucosidase, to the influence of simulated microgravity was demonstrated by increased quantity and area of ER-bodies at the cell section as well as by higher variability of their form under clinorotation. A degree of these changes correlated with the duration of clinorotation. On the basis of experimental data a protective role of ER bodies in adaptation of plants to microgravity is supposed. PMID- 21254616 TI - [Analysis of common wheat varieties and near-isogenic lines by PCR with allele specific primers for Gli-1 and Glu-3 loci]. AB - The allelic characteristics of the Gli-A1, Gli-B1, Gli-D1 and Glu-A3 loci of 14 bread wheat varieties and 6 near-isogenic lines derived from Bezostaya 1 have been detected by PCR analysis. The conformity of molecular-genetic data and electrophoresis of storage proteins has been determined: the allelic variants of gliadins Gli-A1o and Gi-A1m correspond to the PCR-allele GliA1.2, the gliadin variants Gli-A1f, Gli-A1b, Gli-A1c correspond to the PCR-allele GliA 1.1, the allelic variants Gli-B1b, Gli-B1d--to the PCR-allele GliB1.1 and the variants Gli B1e, Gli-B1g, Gli-B1c-to the PCR-allele GliB1.2. A new PCR-allele at the GliB) locus in the line Gli-B1-12 (with the gliadin block Gli-B1o from Levent) was identified. PMID- 21254617 TI - [Monomorphism of isoenzyme loci in natural and cultivated amaranth (Amaranthus L.) populations]. AB - Starch gel electrophoresis was used for isozyme analysis of ADH, GDH, MDH, IDH, and ME in populations of amaranth. Experiments were performed with 93 populations and 4 cultivars. Some populations proved to be polymorphic, and this fact allowed analysis of the genetic control of the enzymes listed. The populations examined showed poor allozyme variability. Monomorphism for all loci studied was observed in 73 populations and 4 varieties. Starch gel electrophoresis was used for isozyme analysis ofADH, GDH, MDH, IDH, and ME in populations of amaranth. Experiments were performed with 93 populations and 4 cultivars. Some populations proved to be polymorphic, and this fact allowed analysis of the genetic control of the enzymes listed. The populations examined showed poor allozyme variability. Monomorphism for all loci studied was observed in 73 populations and 4 varieties. Only some populations demonstrated rare polymorphism for a single locus each: Adh, Mdh 2, Gdh, Idh 1, Idh 2, or Mod 2. The results demonstrate genetic monomorphism of amaranth for the studied loci. PMID- 21254618 TI - [Single nucleotide polymorphism of +276 g > t adiponectin (APM1) gene in donors of Kharkiv population]. AB - Polymorphism of adiponectine (APM1) gene in +276G > T position was studied. For this research we used blood samples of 103 donors (men/women: 65/38; 70 Ukrainian, 33 Russian) - habitants of Kharkiv. Frequencies of T and G alleles were pT = 0.55 and pG = 0.45 in a general group. They did not meaningfully differentiate either for men and women or for Russians and Ukrainians. Distribution of genotypes did not correspond to Hardy-Weinberg equilibrium: share of heterozygotes was 1.55 times higher than selectively-neutral value, share of TT homozygote is 0.55, and GG homozygote is 0.33 of equilibrium value. PMID- 21254619 TI - [Allelic polymorphism of FMR1 gene CGG-repeat region in patients with impairment of natural and stimulated ovulation]. AB - The frequency of heterozygote carriers of (risk zone, alleles of FMR1 gene (40-47 CGG-repeats) was significantly higher in group of patients with ovarian dysfunction than in control group I. The tendency for higher frequency of those alleles was observed in patients with "poor response" to superovulation induction in IVF cycles. The average number of oocytes and follicles, which was obtained after stimulation of superovulation, was significantly decreased in FMR1 gene "risk zone" alleles carriers compared to patients with normal alleles of FMR1 gene. The average general dosage of exogenous gonadotrophin, necessary for superovulation induction was significantly higher in heterozygote carriers of FMR1 gene "risk zone" alleles than in patients with normal genotype. Thereby, the FMR1 gene "risk zone" alleles can be one of the hereditary susceptibility factors of impairment nature and stimulated ovulation. PMID- 21254621 TI - [Fatty acid composition variability of rapeseed oil: classical selection and biotechnology]. AB - The problems and achievements in the rapeseed Brassica napus L. var. oleifera breeding directed on the change of fatty acid composition in seed oil with the use of traditional and genetic engineering approaches are analyzed. It is noticed that the combination of biotechnological workings out and methods of classical breeding is the optimum for the further improvement of rapeseed oil composition. PMID- 21254620 TI - [Bioinformatic search for plant homologs of protein kinase BUB1--the keypoint of mitotic spindle assembly]. AB - Fourteen plant homologs of animal, yeast and myxomycetes spindle assembly checkpoint protein kinases were identified bioinformatically. It was shown that the closest plant homologues of the BUB1 protein kinases are unknown proteins XP_002274770.1 (CBI21878.1) from Vitis vinifera, EEC82122.1 from Oryza sativa Indica, EEE67244.1 from O. sativa Japonica, EEF44403.1 from Ricinus communis and CAL57156.1 from Ostreococcus tauri. The reconstruction and analysis of spatial structures of the EEC82122.1, EEE67244.1 and XP_002274770.1 (CBI21878.1), catalytic domains confirmed their conformity to spindle assembly checkpoint protein kinases BUB1. PMID- 21254622 TI - [The role of magnetosomes in cellular homeostasis disorder and development of pathology]. AB - Literature data on magnitosomes, the nanocrystals formed during natural biomineralization have been summarized. Special attention is paid to magnitosome effect on physiological and biochemical processes, impairments of cell homeostasis and development of various pathologies. It is suggested that the increase in quantity and sizes of magnetosomes, spatial rearrangement, and modification of their crystalline substance exert substantial effect on development of pathological processes. PMID- 21254623 TI - [Lipid peroxidation, activity of Na+,k(+) -ATPase and exzymes of antioxidant defence in rats with nephropathy induced by cobalt chloride]. AB - Chronic parenteral administration of cobalt chloride (6 mg/kg) to male rats for 2 weeks or 1 month was accompanied by activation of lipid peroxidation (LPO), a decrease of superoxide dismutase activity and an increase of catalase activity. The membrane toxic action also resulted in a decrease of cortical and medullar Na+,K(+)-ATPase activity of kidneys, and the decrease in renal functions (glomerular filtration, renal water reabsorption, spontaneous diuresis, electrolyte excretion). PMID- 21254624 TI - [L-cysteine influx in diabetic erythrocytes]. AB - Erythrocyte oxidative stress has been implicated in the pathogenesis of diabetes mellitus, and the deficiency of antioxidant defense by the glutathione (GSH) pathway is thought to be one of the factors responsible for development of complications in diabetes. Erythrocytes require L-cysteine for thesynthesis of GSH and the rate of synthesis is determined only by L-cysteine availability. In the present study we have found that the L-cysteine influx in erythrocytes from type 2 diabetic patients was significantly lower compared to age-matched controls. The decreased influx may be one of the factors leading to low GSH concentration observed in type 2 diabetes. Since L-cysteine is the limiting amino acid in GSH synthesis, any strategy aimed to increase L-cysteine influx in erythrocytes may be beneficial for type 2 diabetic patients. PMID- 21254625 TI - [Biochemical activity hyperbranched polyol Boltorn H20 and polycarboxyBoltorn H20 in relation to aspartic proteinase of Candida albicans]. AB - Hyperbranched polyol Boltorn H20 and polycarboxyBoltorn H20 synthesized on its multifunctional nanoscaffold influence catalytic activity of aspartic proteinase Candida albicans (C. alb.). The results of study catalytic activity proteinase C. alb. in relation to hemoglobin at presence Boltorn H20 show, that the effect of activation is mainly observed. The inhibition effect much more poorly also has dot character. PolycarboxyBoltorn H20 render activating effect in area of high concentration (1 x 10(-3) - 5 x 10(-4) M), however this effect is stronger (140%). A kinetic parameters enzyme proteolysis of hemoglobin (the maximal speed (V(m)) and Mikhaelis constant (K(m))) are estimated, seeming types are certain and constants at presence Boltorn H20 and policarboxyBoltorn H20 are calculated. PMID- 21254626 TI - [Neuromediator systems in some brain regions of rats subjected to morphine intoxication]. AB - The content of neuromediators and its metabolites in the cortex of cerebral hemispheres, in thalamus and brain stem was studied under chronic morphine intoxication (7-21 days). The morphine intake during 7-14 days was accompanied by changes of catecholamine system functioning, which was the most pronounced in the thalamus and the brain stem. These changes included increased secretion of dophamine and noradrenaline, their decrease in the brain tissue, and the increased content of their metabolites. The changes of serotonin and GABA content were less pronounced and included a decrease of serotonin level and the increase of the GABA content in different periods of narcotization. PMID- 21254627 TI - [Functional state of rat brain mitochondria at hypoglycemia convulsive syndrome and different ways of its arresting]. AB - Respiratory and phosphorylation functions of rat brain mitochondria was studied under conditions insulin shock and after its treatment with glucose or glutamate (in combination with inhalation of hypercapnic gas mixture--air enriched with 7% CO2). Certain differences in the effects of the applied agents were found. Phosphorylation ability of mitochondria did not reach the normal level even one day after both ways of convulsive state treatment. Some respiratory parameters suggest that unfavorable changes in the respiratory chain functioning mainly occur at the respiratory chain complex I. PMID- 21254628 TI - [Regulation of cholesterol biosynthesis and metabolism in Hep G2 cells by delta8(14)-15-ketoergostane derivatives]. AB - The comparative study of effects of 5alpha-cholest-8(14)-en-15-on-3beta-ol (I), (22E)-5alpha-ergosta-8(14),22-dien-15-on-3beta-ol (II), (22S,23S)-22,23-oxido 5alpha-ergost-8(14)-en- 15-on-3beta-ol (III) and (22R,23R)-22,23-oxido-5alpha ergost-8(14)-en-15-on-3beta-ol (IV) on HMG-CoA reductase, CYP27A1 and CYP3A4 genes expression in Hep G2 cells was performed. In the contrast to 15 ketocholestane derivative (I), 15-ketoergostane derivatives (II - IV) decreased the HMG- CoA reductase mRNA level; (22R,23R)-22,23-oxido-5alpha-ergost-8(14)-en 15-on-3beta-ol (IV) significantly increased CYP3A4 mRNA level (320% from control). Ketosterol (II) was found to be a more potent inhibitor of cholesterol biosynthesis in Hep G2 cells at a prolong incubation, compared with ketosterol (I). The side chain conformation of compounds (I) - (IV) was evaluated by computational modeling; the correlation between biological activity of these compounds and conformational flexibility of their side chains was found. The results obtained indicated that delta8(14)-15-ketoergostane derivatives may be used as a sterol biosynthesis and metabolism regulators in liver cells. PMID- 21254629 TI - [The role of nitric oxide synthesis induction and inhibition in regulation of blood neutrophil cell death during oxidative disbalance]. AB - Modeling oxidative stress in vitro with 5mM H2O2 has demonstrated a protective role of nitric oxide on realization of constitutional blood neutrophil cell death. The NO-synthase inductor L-arginine and the inhibitor of nitric oxide synthesis, L-NAME, influenced on the amount of annexin-positive cells, the content of Bax protein, reactive oxygen species, cyclic nucleotides, and calcium homeostasis in neutrophils under conditions realizing programmed death during oxidative stress in vitro and under acute inflammation. During oxidative stress L arginine normalized the increased intracellular Ca2+ level and the cAMP/cGMP ratio due to increase of cGMP level, stabilized metabolism and prolonged neutrophil life. During acute inflammation NO induction was insufficient for limitation of Ca2+ release into cytosol and for onset of the apoptotic effect; blockade of NO synthesis deteriorated this situation by activating neutrophil apoptosis due to the sharp increase in Ca2+ content and reduction of cyclic nucleotides in cytosol. The protective effect of NO on neutrophil cell death during oxidative dysbalance is not associated with regulation of apoptotic protein Bax. PMID- 21254630 TI - [Study of activity of enzymes of antioxidant system of blood at HIV infection]. AB - HIV infection is accompanied by activation of lipid peroxidation, oxidative modification of lipoprotein complexes, and a decrease in activity of antioxidant enzymes (superoxide dismutase (SOD), catalase and glutathione peroxidase (GP)) in blood serum. A significant increase of glutathione reductase observed under these conditions is considered as a function of the antioxidant defence. These changes were already seen at early (symptomless) stages of this disease, however, at manifested forms they were more pronounced. PMID- 21254631 TI - [Detection of telomerase activity in gastric cancer]. AB - Telomerase activity (TA) was examined in gastric adenocarcinomas and gastric lymphoma using a modified TRAP assay. TA was present in 16 of 18 (89%) gastric adenocarcinomas and in gastric lymphoma, whereas no TA was detected in normal tissue. Almost all samples had "high" and "very high" TA levels. Telomerase is undoubtedly associated with the process of malignant transformation and therefore can be an important marker for diagnostics of gastric cancer. PMID- 21254632 TI - [HPLC determination of plasma/serum homocysteine and cysteine with UV detection and solid-phase extraction on a polymeric sorbent]. AB - Isocratic HPLC determination of plasma/serum homocysteine and cysteine with separation on reversed-phase column and UV detection at 330 nm is proposed. The mobile phase consist of acetonitrile - 0.05 M citrate-phosphate buffer with pH 2.4 - isopropanol (15:85:1, v/v/v). Full separation of cysteine, cysteamine (IS), glutathione and homocysteine was achieved within less than 10 minutes. Reduction of thiols from disulfides was performed by 1,4-dithioerithreitol, and derivatization by with Ellman's reagent [5'5-dithiobis-(2-nitrobenzoic acid)]. After that plasma/serum, containing derivatives of thiols, is cleared and concentrated on cartridge packed with 10 mg of hypercross-linked polystyrene (Purosep-200). Elution from cartridge is made with water-organic solvent (without evaporation and concentration, but without dilution), as well as waterless solvents (with evaporation and concentration). Simplicity, reproducibility in combination with high cleanliness of extracts and sufficient sensitivity (0.4 ng for homocysteine, 2 ng for glutathione and 0.2 ng for cysteine and cysteamine at a signal/noise ratio > 3), make this method suitable for routine clinical application. PMID- 21254633 TI - [Proteins-markers of placental insufficiency]. AB - The proteomic analysis of the amniotic fluids of women with physiological pregnancy and pregnancy, complicated with placental insufficiency has been carried out on the II and III trimesters. The following difference in protein patterns have been recognized: i) appearance of several proteins lacking in physiological pregnancy; ii) absence of several proteins detectable during physiological pregnancy--hippocalcin-like protein 1, CDC37-like protein, NKG2D ligand 2 (II trimester), CDC37-like protein, NKG2D ligand 2 (III trimester). The established differences in the amniotic fluid spectrum, obviously, have the pathogenetic meaning in the placental insufficiency development. The revealed proteins of distinction may serve as markers of this obstetrical pathology. PMID- 21254634 TI - [Bacterial spectrum of the urine in young healthy women]. AB - A wide spectrum of aerobic-anaerobic associations were found at bacteriological examination of 138 samples of the middle urine portion from 46 healthy women aged 17-25 years (22 sexually inactive and 24 active). Facultative-anaerobic (corinebacteria and coagulase-negative staphylococci) and non-clostridial anaerobic bacteria (peptococci and propionibacteria) predominated in both groups. The majority of facultative anaerobic bacteria had marked adhesive and antilysosyme activity indicating a pathogenic potential. Experimental and clinical trials are necessary to study the role of non-clostridial-anaerobic bacteria in development of acute and chronic infections of the kidney and urinary tract. PMID- 21254635 TI - [The role of hyperbaric oxygenation in combined treatment of acute pyelonephritis]. AB - Hyperbaric oxygenation (HBO) was used in combined treatment of 66 patients with acute pyelonephritis. In 29 of them with primary pyelonephritis it was a part of conservative treatment. In 37 patients with secondary pyelonephritis HBO was applied postoperatively. A HBO course comprised 8-10 sessions under pressure 2.0 2.4 atm for 60 min. It was found that frequency of surgical interventions in HBO administration reduced by 36.2%. Postoperative HBO administration decreased hospital stay by 16.9%. Mechanisms of HBO positive action operate through attenuation of systemic inflammatory reaction and polyorganic insufficiency 1.62 and 2.9-fold, respectively, decline of intoxication in growing glomerular filtration rate and improvement of renal hemodynamics. Moreover, HBO promotes recovery of the immune status. In experiment on 40 white rats with acute pyelonephritis HBO decreased inflammation in renal tissue. PMID- 21254637 TI - [Administration of alpha-blockers to prevent postoperative acute urinary retention after urogenital operations]. AB - Incidence of acute urinary retention following operations on the urinary tract was analysed for 151 patients. It is shown that patients given alpha1 adrenoblocker sonizin for 5 days before and 3 days after surgery reduced the risk of postoperative acute urinary retention by 14%. PMID- 21254636 TI - [Correction of local immunometabolic disturbances combined with chronic prostatitis in prostatic adenoma]. AB - We compared local immunometabolic effects of two dosage forms of longidase in patients with prostatic adenoma (PA) in combination with chronic prostatitis (CP) in the postoperative period. Transurethral resection (TUR) of the prostate was conducted in 81 patients aged 50-70 years suffering from PA and CP. All the patients after TUR were divided into three groups by postoperative treatment: group 1 (n = 25) received standard pharmacotherapy, group 2 (n = 28)--standard pharmacotherapy and longidase injections, group 3--standard pharmacotherapy plus longidase suppository. Immunological parameters were studied in biological material (urine) obtained before operation, after it and after treatment course. By changes in immunometabolic status (concentrations of cytokines TNFalpha, IL 1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-18, receptor antagonist IL-1 Ra, complement components C3-, C3a-, C4-, C5-, C5a, regulators of the complement system factor H, C1-inhibitor) and sIgA, content of acylhydroperoxides, malonic dialdehyde, stable metabolites of hitric oxide, catalase and superoxiddismutase activity it is shown that PA patients with CP have pretreatment disturbances of local immunity and oxidant status (high levels of proinflammatory cytokines, subnormal IL-10, activated complement system, lipid peroxidation, low sIgA, NO synthetic activity of capillary endothelial activity). TUR aggravates shifts of local immunometabolic status. Standard postoperative pharmacotherapy does not correct the disturbances adequately. The addition of longidase to standard postoperative treatment was effective in correction of immune and oxidant status. Thus, longidase injections and, especially, suppositories correct disturbances of local immunity and oxidant status in patients with PA and CP in postoperative period. PMID- 21254638 TI - [Efficacy of Vitaprost Forte in the treatment of adenoma]. AB - Pharmacotherapy with vitaprost forte was given to 40 patients with prostatic adenoma aged 55 to 77 years (mean age 67.6 +/- 0.9 years). Vitaprost forte suppositories were used once a day in the evening for 30 days. Micturition was assessed before the treatment, on the treatment day 15 and 30, 1 and 3 months after the treatment course. As the result of the treatment obstructive and irritative symptoms improved by 20%, on the average, Q(max) increased by 36.4%, residual urine decreased more than 3-fold. Therapeutic effects continued for 3 months and later. IPSS and other questionnaires indicated positive effects in quality of life. PMID- 21254639 TI - [Experience with application of ALMGP-01 device for local transrectal microwave hyperthermia of the prostate in the treatment of chronic prostatitis]. AB - The article presents the results of a clinical trial of efficacy of ALMGP-01 device in 34 patients with chronic prostatitis. The device provides local microwave hyperthermia of the prostate which appeared highly effective in combined treatment of chronic prostatitis. PMID- 21254640 TI - [Anastomotic urethroplasty in posttraumatic strictures of bulbomembraneous urethra]. AB - Efficacy of surgical treatment of patients with strictures of the bulbomembraneous portion of the urethra by R. Turner-Warwick in G. Webster modification was studied in 30 patients operated in 2008-2009. Efficacy of the operation was assessed by uroflowmetry and urethrography findings. Follow-up covered 3 to 20 months (median 10 months). Posttraumatic urethral strictures arose after car accident in 89% cases. Mean length of the destruction defect was 2.7 cm (1.5-5.5 cm). Efficacy of surgical treatment reached 96.7%. Erectile dysfunction due to the operation developed in 2 of 23 (8.6%) patients. Thus, urethroplasty by Turner-Warwick in Webster modification is effective and safe in the treatment of posttraumatic strictures of the posterior urethra and can be used widely in specialized centers for urethral surgery. PMID- 21254641 TI - [Open population comparative randomized clinical trial of lavomax efficacy and safety in combined treatment of non-gonococcal urethritis]. AB - A total of 40 patients with non-gonococcal urethritis (NGU) were divided into two groups. Twenty patients of group 1 received standard antibacterial treatment while 20 patients of group 2 received the same treatment plus an immunotropic drug based on tiloron (lavomax) in a course dose 1.25 g. Patients of group 2 had no recurrences while in group 1 recurrences were seen in 25% patients. Addition of lavomax resulted in clinical and etiological cure and activation of local (secretory IgA) and systemic (interferons alpha and gamma in blood serum) factors in anti-infection defense in NGU patients. PMID- 21254642 TI - [Lantox treatment of neurogenic dysfunction of the bladder]. AB - We studied correction of micturition disorders in 9 patients with neurogenic dysfunction of the bladder resistant to conservative treatment. Four patients had neurogenic detrusor hyperactivity and 5 patients had detrusor-sphincter dyssynergia. Injections of botulinic toxin preparation (lantox) were made in the wall of the bladder under endoscopic control in detrusor neurogenic hyperactivity. Women with detrusor-sphincter dyssynergia received transperineal injections of lantox in the region of external urethral sphincter. Men received botulinic toxin directly into the region of external urethral sphincter in urethroscopy. Positive results were achieved in all the cases confirming high efficacy of the method. PMID- 21254643 TI - [Sympathic hyperactivity and reservoir function of the bladder in men]. AB - Effects of the sympathetic nervous system (SNS) on detrusor function in the collection phase were studied in 57 men over 50 years of age. Heart rate (HR) was a clinical marker of SNS activity, effective volume of the bladder marked detrusor activity in 34 patients of group 1. The value HR/volume were registered in all voidings for 1-3 days. It was found that enhancement of SNS activity was accompanied by a decline of the reservoir function of the bladder. In HR < 80 and > 100 b/min the differences were significant and reached 56%. Group 2 patients (n = 23) with prostatic adenoma have undergone uroflowmetric monitoring before and after treatment with doxasozine (640 uroflowgrams). The reservoir function of the bladder increased from 111.0 to 151.4 ml (by 36.3%) in response to block of alphal-adrenoreceptors. Thus, SNS plays an essential role in management of detrusor function in the collection phase. Its hyperactivity leads to this phase decifiency. It may be a humoral process mediated by vasoconstriction and disorder of vesical blood flow. The proportion HR/volume shows "sympathetic background" in patients before administration of alpha1-adrenoblockers. PMID- 21254644 TI - [Herbal drug kanefron H in postoperative metaphylaxis of urolithiasis]. PMID- 21254645 TI - [Long-term use of the urethral stent in recurrent urethral stricture]. PMID- 21254646 TI - [Surgical treatment of patients with complicated urinary fistulas]. PMID- 21254647 TI - [Detection of PD4, CD44, PCNA protein and its clinical significance in human laryngeal carcinoma]. AB - OBJECTIVE: To study the expression of PD4, CD44 and PCNA proteins in laryngeal carcinoma and their relationships with the pathogenesis, development and prognosis of laryngeal carcinoma. METHOD: Immunohistochemistry was used to study 140 cases of laryngeal carcinoma tissues, 25 cases of precarcinoma tissues, 36 cases of vocal cord polyps and 13 cases of normal tissues adjacent to laryngeal carcinoma. RESULT: 1. The positive rates of PD4, CD44 and PCNA were 45.71% (64/140), 64.29% (90/140) and 77.86% (109/140) in laryngeal carcinoma, which were much higher than in non-carcinoma tissues (P < 0.01). 2. The third and fourth stages laryngeal carcinoma express stronger PD4 and CD44 than those of the first and second stages. Laryngeal carcinoma with cervical metastasis had higher expression than those without cervical metastasis. To 3 and 5 years' survival, PD4, CD44 and PCNA positive cases had lower chance than those negative cases(P < 0.01 or 0.05). 3. The over all positive rate of PD4, CD44 and PCNA was 27.86% (39/140) in laryngeal carcinoma tissues and 5.41% (4/74) in non-carcinoma tissues. CONCLUSION: The high expression of PD4, CD44 and PCNA proteins maybe closely related to the pathogenesis, development and prognosis of laryngeal carcinoma. PMID- 21254648 TI - [Clinical significance and relationship between HIF-1alpha, COX-2, VEGF and microvessel density expression in laryngeal carcinoma]. AB - OBJECTIVE: To evaluate the role of HIF-1alpha, COX-2, VEGF proteins and Microvessel density in angiogenesis and metastasis of laryngeal carcinoma. METHOD: Surgically resected specimens of 64 laryngeal carcinomas were studied by immunohistochemical staining for HIF-1alpha protein, COX-2 protein, VEGF and MVD. RESULT: Positive expressions of HIF-1alpha, COX-2 protein and VEGF were found in 65.63%, 68.75% and 71.88% of laryngeal carcinoma specimens, respectively. The mean MVD in this series was 35.79 +/- 9.49. The expression of HIF-1alpha, COX-2 and VEGF positively correlated with MVD expression. There was a positive relationship between HIF-1alpha, COX-2 and VEGF expression. The microvessel density (MVD) in HIF-1alpha, COX-2 and VEGF positive tumors was significantly higher in patients with cervical lymph node metastases than that in patients without metastases. CONCLUSION: HIF-1alpha, COX-2 and VEGF proteins may play an important role in the angiogenesis of laryngeal carcinoma. HIF-1alpha regulate the expression and function of its downstream target genes (COX-2 and VEGF), which play a critical role in the angiogenesis of laryngeal carcinoma, metastases in the process of laryngeal cancer cell spreading to cervical lymph nodes. PMID- 21254649 TI - [Expression of RECK, RAGE and MMP-9 in nasopharyngeal carcinoma and its significance]. AB - OBJECTIVE: To investigate the expression and the relativity of RECK,RAGE and MMP 9 in nasopharyngeal carcinoma (NPC) tissues. METHOD: RECK, RAGE and MMP-9 were detected with immunohistochemical methods in 64 NPC specimens(30 cases with cervical lymph nodes metastasis, while the other 34 cases are not) and 30 specimens with chronic nasopharyngitis. RESULT: RECK hardly expressed in chronic nasopharyngitis and NPC tissues, However, strong expression of RECK could be seen in the surrounding inflammatory cells and matrix of cancer nests. The positive rates of RECK in NPC with and without cervical lymph nodes metastasis were 3.3% (1/30) and 11.8% (4/34), separately, There was no statistical significance between the groups (P > 0.05). The positive rates of RAGE in chronic nasopharyngitis and NPC tissues were 100% (30/30) and 70.3% (45/64) respectively, while MMP-9 were 46.7% (14/30) and 78.1% (50/64). The positive rates of RAGE in NPC with and without cervical lymph nodes metastasis were 86.7% (26/30) and 55.9% (19/34) separately, whereas MMP-9 were 90.0% (27/30) and 67.7% (23/34) respectively. They all showed statistical significance between the groups. MMP-9 had a negative correlation with RECK (r = -0.369, P < 0.05) and a positive correlation with RAGE in NPC (r = 0.471, P < 0.05). CONCLUSION: The expression of RECK and RAGE in NPC were down-regulated, the expression of MMP-9 was up regulated. While the expression of RECK in NPC with cervical lymph nodes metastasis was down-regulated, while RAGE and MMP-9 were up-regulated. The abnormal expression of the three genes may be related to the progression of NPC. RECK and RAGE may be involved in the invasion and metastasis of NPC by regulating the expression of MMP-9. PMID- 21254650 TI - [Supracricoid partial laryngectomy versus other traditional partial laryngectomy for selected laryngeal cancers]. AB - OBJECTIVE: To compare the oncological and functional outcomes in patients undergoing supracricoid partial laryngectomy with other traditional partial laryngectomy. METHOD: One hundred and fourteen patients treated from 1992 to 2007 were selected from all laryngeal cancer patients undergo partial laryngectomy through random match method by tumour subsite, TNM stage and age. Among them, 58 were supraglottic cancers, 56 were glottic cancers. Patients were divided into supracricoid laryngectomy group and other partial laryngectomy group. Each group includes 57 cases. We compare the 3-year and 5-year actuarial survival, local control rate and decannulation rate between two groups. RESULT: The 3-year and 5 year actuarial survival estimate was 90% and 87% for supracricoid partial laryngectomy, 97% and 92% for other partial laryngectomy (P > 0.05); Local control rate estimate was 94.2% for supracricoid laryngectomy and 91% for other partial laryngectomy(P > 0.05); Decannulation rate was 98% for supracricoid laryngectomy and 89.5% for other partial laryngectomy(P>0. 05); The decannulation was ever lower in horizontal-vertical partial laryngectomy than supracricoid partial laryngectomy (75% versus 98%, P < 0.01). CONCLUSION: Comparing with other partial laryngectomy, supracricoid partial laryngectomy seems to have higher decannulation rate and is a considerable choice for selected laryngeal cancer. PMID- 21254651 TI - [Expression of tissue inhibitor of metalloproteinase-2 in nasopharyngeal carcinoma]. AB - OBJECTIVE: To study the expression of tissue inhibitor of matrix metalloproteinase 2 (TIMP2)in the nasopharyngeal carcinoma and to evaluate the relationships between the expression of TIMP2 and biological behavior of NPC. METHOD: The expression of TIMP2 was observed by immunohistochemical technique in 50 cases with nasopharyngeal carcinoma and 15 cases of Inflammation nasopharyngeal tissues. RESULT: The positive rates of TIMP2 are significantly higher in NPC than in Inflammation tissues (P < 0.05). The expression of TIMP2 increase significantly with lymph node metastasis (P < 0.01), but had no relevant to the rise clinical invasion stage (P > 0.05). CONCLUSION: The results indicate that TIMP2 may play a critical role in assisting carcinoma cell to degrade basement membrane to invade surrounding tissues and to form metastatic colonies in lymph node. Especially the unbalance in MMP2/TIMP2 has probably a prognostic value in nasopharyngeal carcinoma. PMID- 21254652 TI - [Relationship between hypermethylation of Runx3 gene and the development and metastasis of laryngeal carcinoma]. AB - OBJECTIVE: To explore the relationships between hypermethylation of human runt related transcription factor 3 (Runx3) gene promoter and laryngeal squamous cell cancer. METHOD: Promoter hypermethylation and mRNA expression were detected by methylation-specific PCR and RT-PCR. RESULT: The expression of Runx3 gene mRNA detected in laryngeal carcinoma (1.62 +/- 1.01) was lower than that in adjacent tissues samples (5.66 +/- 2.07) (t = 10.72, P < 0.01). No methylation of Runx3 promoter was found in adjacent tissues samples. But hypermethylation was found in 95.0% (38/40) of the laryngeal carcinoma specimens. The rate of methylation of Runx3 promoter in laryngeal carcinoma was higher than that in adjacent tissues (P < 0.01). The Runx3 mRNA were down-regulated in lymphnode metastasis or poorly differentiated groups, but the Runx3 promoter methylation were detected in those groups markedly. CONCLUSION: Hypermethylation of Runx3 promoter is one of the inactivation re-seasons in laryngeal squamous cell carcinoma, and the decreasing of Runx3 mRNA expression may be related to lymph node metastasis and development of laryngeal squamous cell carcinoma. PMID- 21254653 TI - [Analysis of factors affecting the pure tone threshold glycerol test]. AB - OBJECTIVE: To probe the factors that affect the pure-tone threshold glycerol test and the distribution of frequencies in positive glycerol test. METHOD: We tested the pure-tone threshold before and after glycerol intake in patients with Meniere's disease, and then analyzed the positive rates,distribution of positive frequencies and the time when the maximum threshold changes appeared. RESULT: The positive rate of pure-tone glycerol test was 72.09%, of which the threshold descending rate was 47.67%, and the threshold rebounding rate was 24.42%; the pure-tone threshold changes of descending group and rebounding group were (17.41 +/- 9.92) dB, (13.53 +/- 4.64) dB respectively, and the differences were significant. The distribution of positive frequencies were 250 Hz, 125 Hz, 500 Hz, 1 kHz, 4 kHz, 2 kHz, 8 kHz in descending order. The maximum pure-tone threshold changes mostly appeared within 2 or 3 hours after glycerol intake. CONCLUSIONS: Patient selection, test occasion and the judgement criteria may affect the positive rate of glycerol test; the positive frequencies distribute in the low-frequency region mainly; the maximum pure-tone threshold changes mostly appeared within 2 or 3 hours after glycerol intake. PMID- 21254654 TI - [The significance of middle thyroid vein in the VI region neck dissection]. AB - OBJECTIVE: To investigate the effect of VI region neck dissection in thyroid papillary carcinoma surgery and to prompt the key matters in such surgery. METHOD: Retrospectively analyzed 213 cases of thyroid papillary carcinoma treated by Renji ENT Department from 2003 to 2009. Under each case, we implemented the VI region neck dissection after marking recurrent laryngeal nerve with middle thyroid vein. RESULT: Among the 213 cases of thyroid papillary carcinoma performed with VI region neck dissection, 82 cases were positive, 3 cases incurred recurrent laryngeal nerve injury with 2 cases of permanent RLN injury and 2 case of temporary injury, 2 cases showed permanent Hypoparathyroidism, and 6 cases showed temporary Hypoparathyroidism. In 3 cases the metastasis of neck lymph arose within 3 years. CONCLUSION: Marking recurrent laryngeal nerve with middle thyroid vein not only helps to lower the possibility of injuring RLN and parathyroid glands in thyroidectomy, but also makes the VI region neck dissection an feasible treatment for thyroid papillary carcinoma. PMID- 21254655 TI - [Experimental studies on the antitumor immunity induced by total laryngeal carcinoma RNA- transfected dendritic cells]. AB - OBJECTIVE: The efficiency of antitumor immunity induced by dendritic cells (DCs) transfected with total RNA of laryngeal carcinoma cells was explored. METHOD: DCs, induced from human peripheral blood mononuclear cells, were transfected with total RNA of laryngeal carcinoma cells. The specific antitumor immunity of cytotoxic T Lymphocytes (CTLs) that were actived by RNA-transfected DCs were detected by MTT methods in vitro. In vivo, antitumor-specific CTLs were subcutaneously injected into the nude mice previously. After 7 days, the laryngeal carcinoma cells were seeded and the tumor occurrence rate was observed. Tumor-loaded nude mice were treated by specific CTLs once (the treated group) or twice (the retreated group). The growth of the implanted tumor was observed too. RESULT: DCs that transfected with tumor RNA can significantly active CTLs which induced antitumor-specific immune response against laryngeal carcinoma in vitro. In vivo, the tumor occurrence rate of the treatment group was predominantly reduced compared with that of the control (P < 0.01). The implanted tumor size of the treated and retreated groups were both significantly reduced (P < 0.05, P < 0.01) compared with the control too, especially the retreated ones (P < 0.05). CONCLUSION: The tumor RNA loaded DCs can significantly active CTLs and the antitumor specific CTLs can both induce antitumor specific immune response against laryngeal carcinoma in vitro and inhibit the growth of the implanted tumor in vivo. PMID- 21254656 TI - [Experimental study of sentinel lymph node biopsy in larynx by using radioactive Nano tracer]. AB - OBJECTIVE: Using radioactive Nano tracer at different sizes and doses in the Larynx of rabbits, to study the roles of them in the sentinel lymph node (SLN) biopsy in rabbits and to provide experimental evidences for the choices of ideal size and dose of radioactive Nano tracer of the sentinel lymph node biopsy in Laryngeal cancer patients. METHOD: thirty rabbits were randomly divided into six groups with five rabbits in each group. After 50 nm--0.01 ml, 50 nm--0.02 ml, 80 nm--0.01 ml, 80 nm--0.02 ml,100 nm--0.01 ml, 100 nm--0.02 ml of 99mTc-sulfur Colloid were separately injected into the Larynx, the number of SLNs, the initial and strongest radioactive time of SLNs, and the lasting time of radioactivity was obtained. RESULT: One to three SLNs were identified in one rabbit, so there were totally forty-five SLNs, which in the areas of II, III and IV. The group of 50 nm -0.02 ml had the largest number of SLNs and there were significant differences between the group of 50 nm-0.02 ml and 100 nm--0.01 ml. In the six groups, the group of 50 nm--0.02 ml was the earliest group of detecting the initial and strongest radioactivity of SLNs,which the time were 49.20 s and 178.60 s; the group of 100 nm--0.01 ml was the latest group of detecting the initial and strongest radioactivity of SLNs, which the time were 235.80 s and 311.20 s. Each group had radioactivity more than 30 minutes. CONCLUSION: The group of 50 nm- 0.02 ml was the best group, because it moved fast and had a higher rate of uptake in lymphangio. Moreover, the radioactivity time was more than 30 minutes. It was the ideal size and dose of SLN biopsy in larynx. PMID- 21254657 TI - [Stress and stress hormones in mammals]. AB - Stress and influence of stress hormones on organisms is interesting theme in many fields of study, e.g. human and veterinary medicine, zoology, ecology. Short time stress is not negative reaction, because it helps to alive. In stress response increase stress hormones levels (catecholamines, glucocorticoids), which cause elevated heart rate, blood pressure and acute elevation of blood glucose. These reactions cause better blood flow and acute utilization energy in vital organs, e.g. the brain, heart or muscles, and its cause better survive of organism. On the other hand, prolonged stress response is dangerous, e.g. chronically elevated blood pressure or levels blood glucose, sexual disorders, etc. If we know, which factor acts as stressor, we can eliminate or minimized its incidence. In case of transport its better to prefer the shortest way or better weather conditions. It's possible to improve welfare of animals in captivity, e.g. enrichment housing, physical conditions (temperature, humidity, light cycles, etc.), social structure in social animals. PMID- 21254658 TI - [The role of cholesterol in embryogenesis and the Smith-Lemli-Opitzov syndrom]. AB - The role of cholesterol in cell biology has been known for years. The sight of cholesteol biological function has changed after the discovery that the genetic disorder Smith-Lemli-Opitz syndrome is caused by a defect in cholesterol biosynthetic pathway. Cholesterol has an important role in regulation and modification of Hedgehog proteins, what links cholesterol to early embryonic development. Hedgehog proteins comprise a family of secreted signaling molecules that are essential for embryonic patterning and morphogenesis. The deficit of cholesterol during embryogenesis causes severe abnormalities in SLOS because of disrupt autoprocessing of hedgehog proteins. SLOS is an autosomal recessive disorder of sterol metabolism. The underlying pathogenetic basis for SLOS has been shown to be a deficiency of 7-dehydrocholesterol reductase, which catalyzes the last step in cholesterol biosynthesis. Reduced enzyme activity leads to a deficit of cholesterol and accumulation of precursor sterols. The human 7 dehydrocholesterol reductase gene (DHCR7) is localized on chromosome 11q 12-13. PMID- 21254659 TI - [Neurobiology of memory]. AB - In the introduction we summarized basic information about memory and indicated studies, which were milestones in the study of memory. Basic studies of memory are reviewed and neurobiological approach is highlighted. The aim of this investigation is to find the relationship among basic facts about memory and what are the underlying mechanisms. This study deals with the participating brain structures, what happens on the synapses and how neurons are influenced. Substantial part of the review is devoted to synaptic plasticity and long-lasting potentiation (LTP). They represent the in vitro approaches, which help to discover mechanisms that participate in memory. The decisive role of AMPA and NMDA receptors and signaling cascades for memory are presented. The role of hippocampus and parahippocampal formation for memory storage is described in more details. Processes of memory consolidation and reconsolidation are presented as well as mechanisms, which modulate memory processes. The review is closed by the index theory, which explains complicated situation in storage and retrieval of memory. PMID- 21254660 TI - [Noradrenaline and behavior]. AB - Noradrenaline exerts many effects and mediates a number of functions in living organisms. Recently, the essential role of noradrenaline in the central nervous system (CNS) has emerged. Noradrenaline affects behaviors of individuals including a modulation of vigilance, arousal, attention, motivation, reward, and also learning and memory. Almost all brain noradrenergic fibers arise in brainstem nuclei designated A1-A7 (approximately half of neurons belongs to the brainstem nucleus, locus coeruleus). The effects of noradrenaline are mediated by two distinct super-families of receptors, named alpha- and beta-adrenoceptors. They are further divided into subgroups exhibiting specific roles in modulating behavior and cognition of animals. Adrenoceptors are located on the periphery as well as in the CNS and selective alpha- and beta-agonists and antagonists are used to assess their function. The purpose of this review is to summarize the findings about anatomy and physiology of the noradrenergic system in the CNS and discuss the pharmacological effects on specific adrenoceptor types. This paper also shows the importance of noradrenaline to maintain the cognitive processes such as attention, perception, and particularly the memory consolidation and retrieval. Disruption of these processes may result in symptoms of neuropsychiatric diseases and neurodegeneration. PMID- 21254662 TI - [Endothelial (dys)function in the experimental model of primary hypertension]. AB - A number of vascular diseases, including hypertension, are characterised by endothelial dysfunction caused by alterations in the production and action of the endothelium-derived relaxing (EDRFs) and/or endothelium-derived contracting (EDCFs) factors. The spontaneously hypertensive rat (SHR) is one of the most widely studied animal models for human essential hypertension. Several similarities between human primary hypertension and hypertension in the SHR have been pointed out in both the pathophysiology and the clinical course of the hypertensive disease. In human hypertension as well as in SHR, endothelium dependent relaxation may be attenuated and this endothelial dysfunction contributes to the increased peripheral resistance. However, various results concerning endothelium-dependent relaxation, including impairment, no change and improvement have been reported in experimental hypertension. Endothelial dysfunction in hypertension has been linked to decrease in NO bioavailability, reflecting the impaired generation of NO and/or the enhanced inactivation of NO by reactive oxygen species. There is evidence that increased vascular oxidative stress is present in SHR. Thus, it has been proposed that oxidative inactivation of NO may account for the endothelial dysfunction seen in SHR. On the other hand, several studies demonstrate elevated basal NO synthesis in SHR rats which may be an adapting mechanism, preventing them from excessive blood pressure elevation. However, the role of NO in hypertension in SHR and in humans remains still controversial. We hypothesize that the vascular bed studied, the effect of age as well as methodological aspects, such as "precontraction" with different vasoconstrictors as well as antioxidants added to the solution for determination of the vasoreactivity may contribute to the discrepancies among studies. Nevertheless, the involvement of endothelial function in hypertension remains subject of debate and further research is needed to complete our knowledge on the role of NO, reactive oxygen species and other endothelial factors in the regulation of vascular and cardiac function. PMID- 21254663 TI - [Memory and its dysfunction]. AB - In the last decades interdisciplinary research of memory takes place and it connects regions as cognitive psychology and neuroscience. Learning and memory are theoretical concepts, which enable to explain the fact that personal experience influences the behavior of the particular person. Memory has neuronal representation, which enables recollection of obtained experiences and information, and subsequently enables changes in behavior. The review describes events as registration, formation of memory trace as well as memory retrieval. Memory classification is possible according to many criteria, e.g. according to the length, its conscious recollection and the character of deposited information. Main types of memories are episodic memory (for facts and events), semantic memory (for general knowledge) and procedural memory (the ability to learn behavioral and cognitive abilities and algorithms). At present it is generally accepted that memory is a complicated process, which utilizes several brain structures at the same time that are called memory systems; according to the type of memory the experiences and information are deposited in various brain regions. The present research enables many approaches for determination of the sites of memory deposition. In the present period important role in memory localization have the brain imaging techniques. Together with the study of memory under physiological conditions, in the center of interest there is the study of memory during various life periods, under pathological conditions and diseases. The review is closed by the list of most important diseases in which we observe memory dysfunctions, including the retrograde and anterograde amnesias. PMID- 21254664 TI - [Disodium cromoglycate--mast cell degranulation blocker in the process of tissue remodelation]. AB - Disodium cromoglycate (DSCG) is a compound commonly used in the treatment of allergic diseases. The effect of DSCG is due to its ability to stabilize the mast cell membrane and to prevent release of histamine and inflammatory mediators. Mast cells are also an abundant source of tissue metalloproteinases, serine proteases and growth factors, which play an important role in the processes of the tissue remodeling. In this view the DSCG is a substance which allows us to study the mechanisms of the pulmonary vascular bed remodeling in the experimental animals exposed to chronic hypoxia and in a phase of the recovery from hypoxia. PMID- 21254665 TI - [More attention should be paid to the treatment of fresh calcaneal fractures]. PMID- 21254666 TI - [Treatment of open calcaneal fractures]. AB - OBJECTIVE: Review the series cases of open calcaneal fractures, to discuss the clinical outcome and evaluate the effective factors associated with the prognosis. METHODS: Between 2004 and October 2009, 427 calcaneal fractures were treated, 22 of these fractures were open, 15 feet of 15 patients were available for the follow-up. There were 9 males and 6 females with a mean age of 34.7 years (range 18 to 66). According to the Sanders classification, there were 2 type I fractures, 3 type II, 6 type III and 4 type IV. According to the Gustilo classification, there were 1 of type 1, 4 of type II, 5 of type III A, and 5 of type III B open fracture. According to the open calcaneal injury subtypes (OCIS), there were 1 of type IA, 2 of type II A,7 of type II B, 2 of type IIIA and 3 of type III B. All patients were treated with intravenous antibiotics, immediate and repeat irrigation and debridement, temporary wound coverage, and initial stabilization of the limb. Clinical examination, radiographs and AOFAS ankle hindfoot scores were used for outcome measurement. RESULTS: The average follow-up time was 16.4 months (8 to 31 months). The mean AOFAS score was (74.6 +/- 10.4) (range 58 to 94). There were 4 feet required tissue transfer for wound coverage. An infection developed at the sites of 5 fractures,4 of witch were Gustilo type III, 2 deep infections with osteomyelitis developing at the site of 1 patient, no patient required amputation. CONCLUSION: These findings do not reflect as high a deep infection and osteomyelitis rate for open calcaneal fractures as previously reported, if early and satisfying debridement, evaluate the soft tissue injury carefully, and choose the right time and indications for internal fixation. In addition, early internal fixation should be avoided for Gustilo type III and OCIS type B calcaneal fractures. PMID- 21254667 TI - [Surgical treatment of calcaneus comminuted fractures involving calcaneal-talar joint]. PMID- 21254668 TI - [Effective comparison between improved lateral incision and the traditional L shaped extension incision in treatment of intra-articular calcaneal fractures]. AB - OBJECTIVE: To compare the clinical outcome between the two different approaches of improved lateral incision and the traditional L-shaped extension incision to treat intra-articular calcaneal fractures. METHODS: From January 2005 to January 2008, 36 cases of intra-articular calcaneal fractures were treated by improved lateral incision or the traditional L-shaped extension incision. In improved lateral incision group, there were 19 cases including 12 males and 7 females with an average age of (38.1 +/- 9.1) years; According to Sanders classification: 8 cases were type II, 9 were type III, 2 were type IV; The time from injury to the operation was (10.5 +/- 1.7) days. In the traditional L-shaped extension incision group,there were 17 cases including 11 males and 6 females with an average age of (38.4 +/- 7.3) years; according to Sanders classification of fractures: 7 cases were type II, 9 were type III, 1 was type IV; The time from injury to the operation was (10.6 +/- 1.8) days. Observing and comparing some items of the two groups including (1) operation time, blood loss, incision length, number of graft cases, (2) VAS pain scores after the first day, (3) wound healing, (4) Maryland foot scoring, (5) postoperative imaging results were comparative analyzed. RESULTS: Two groups of patients were followed up from 10 to 15 months with an average of 11 months. The operative time and number of graft cases were compared between two groups with no statistically significant differences. The blood loss were (94.0 +/- 9.5) ml in improved lateral incision group and (109.9 +/- 13.7) ml in L-shaped extension incision group, incision length were (6.8 +/- 1.1) cm in improved lateral incision group and (15.7 +/- 2.2) cm in L-shaped extension incision group with significant differences. Postoperative VAS pain score at the first day were (1.95 +/- 0.71) points in improved lateral incision group and (3.65 +/- 1.00) points in L-shaped incision group with significant difference. In improved lateral incision group there was 1 case of grade B wound healing, and in the traditional L-shaped extension incision group, there were 6 cases of grade B wound healing, these patients were healing by protensive time for change dress. CONCLUSION: These two incision of improved lateral incision and the traditional L shaped extension incision for treating the intra-articular calcaneal fractures are therapeutic equivalence. However, improved lateral incision has advantage of small incision and operative wound, and fewer wound complications. PMID- 21254669 TI - [Study on clinical anatomy of calcaneal fractures and its applications]. AB - OBJECTIVE: To observe and analyze the intraoperative state of calcaneal fractures, and summarize the law of displacement after calcaneal fractures, so as to guide fracture reduction and fixation. METHODS: From March 2002 to March 2009, among 572 patients with calcaneal fractures, 427 patients were male and 145 patients were female, ranging in age from 17 to 73 years, averaged 37 years. The patients were injured from falling or road accidents, and all the patients were closed fracture. The 189 patients with complete clinical data were treated with reduction and fixation through the lateral approach after observation of displacement type of the fractures. RESULTS: Among 189 patients,the fractures were found at the lower part of the articular surface in all patients, which was hillock point of calcaneus; the fractures were found at the Gissans Corner in 134 patients, and the type include cross-sectional fracture or oblique fracture; the fractures were found at calcaneal tubercle in 118 patients, and the fractures were divided into two parts from top to bottom; the fractures were found at the distal part of calcaneus only in 67 patients. CONCLUSION: Calcaneal fractures show clear law of dislocation. Preoperative and intra-operative detailed analysis and evaluation, as well as reduction and fixation according to certain sequences can insure to get better operative effects. PMID- 21254670 TI - [Surgical treatment of fracture and dislocation of wrist joint complicated by carpal tunnel syndrome]. PMID- 21254671 TI - [Surgical treatment of displaced intra-articular fractures of the calcaneus in elderly patients]. AB - OBJECTIVE: To study the clinical effects of surgical treatment of displaced intra articular fractures of the calcaneus in elderly patients, and to discuss the operative indications. METHODS: From January 2000 to December 2007, 24 elderly patients with 26 fractures underwent open reduction and internal fixation for a displaced intra-articular fracture of calcaneus, which included 18 feet of 18 males and 8 feet of 6 female, with an average age of 67 years (range, 60 to 75 years). According to Sanders classification based on CT scanning, 13 fractures were rated as type II, 12 as type III and 1 as type IV. Bohler angle and Gissane angle were measured preoperatively and postoperatively and foot function was assessed with Maryland foot score system. RESULTS: Twenty-four cases with 26 feet were followed up for an average of 18.4 months (range, 12 to 26 months). Mean Bohler angle was (10.4 +/- 8.2) degrees preoperatively and (27.8 +/- 7.4) degrees postoperatively and mean Gissane angle was (136.5 +/- 10.3) degrees preoperatively and (124.3 +/- 4.2) degrees postoperatively. The difference between preoperative and postoperative values was found with statistically significant (P < 0.05). The results were excellent in 5 feet, good in 16 feet, fair in 4 feet and poor in 1 foot. There were 3 cases of wound necerosis, 2 cases of wound infection, 1 case of sural nerve injury and 6 cases of posttraumatic subtalar arthritis complications. CONCLUSION: Good clinical result could be obtained with surgical treatment in elderly patients with displaced intra articular fractures of the calcaneus. Open reduction appears to be an acceptable method of treatment for displaced calcaneal fractures in elderly patients if they have good general conditions. PMID- 21254672 TI - [Clinical effect of percutaneous poking and tension band splint fixation for treatment of the calcaneal fracture]. AB - OBJECTIVE: To observe the clinical efficacy of percutaneous poking tension band splint fixation for the treatment of calcaneal fractures. METHODS: From September 2007 to February 2009,40 patients with calcaneal fractures (42 feet) were treated by percutaneous poking reduction, including 28 feet of male and 14 feet of female, with an average age of 34.2 years ranging from 18 to 55 years. The course was from 2 hours to 7 days. All fractures were fresh and closed intra-articular calcaneal fractures. Patients were divided into two groups according to fixation methods, plaster fixation in 20 feet, tension band splint in 22 feet. Three aspects including the heel of the foot and ankle width of recovery, functional recovery, complications were compared according to the United States Orthopedic Foot and Ankle Society clinical score. RESULTS: These 40 patients were followed up for 6 months to 2 years with an average of 9 months. The calcaneal width of the recovery, the functional recovery and force line of tension band splint group were all better than that of plaster fixation group (P < 0.05); There were no significant differences in pain between two groups (P > 0.05). Occurrence of complications in tension band splint group were lower than that of plaster fixation group (P < 0.05). CONCLUSION: Percutaneous poking tension band splint have advantage of stable calcaneal width and fewer complications on treatment of calcaneal fractures. PMID- 21254673 TI - [Effect of continuous femoral nerve block in analgesia and the early rehabilitation after total knee replacement]. AB - OBJECTIVE: To evaluate the benefit and safety of continuous femoral nerve block in patients undergoing total knee arthroplasty. METHODS: From December 2008 to August 2009, 80 patients with total knee arthroplasty were randomly divided into two groups, 40 patients in each group. In group A the pain-control was dominanted by continuous femoral nerve block, there were 5 males adn 35 females with an average age of (65.0 +/- 4.2) years old; In group B the pump of vein odynolysis was used, there were 5 males and 35 females with an average age of (64.7 +/- 8.5) years old. The treatment of relieve pain continued for 3 days. The pain of visual analog scale (VAS), sleep condition, early-stage rehabilitation and adverse effects were recorded. RESULTS: The VAS scores of group A was lower than that of group B at 2, 6, 24, 36, 48, 56, 72 h after operation (P < 0.05 or P < 0.01); The sleep condition and early-stage rehabilitation of group A were better than that of group B. The complications of group B occurrenced more than group A; The analgetica of group B were used more than that of group A. CONCLUSION: The continuous femoral nerve block is an effective pain relieve method and is benefical to rehabilitation from total knee arthroplasty early. PMID- 21254674 TI - [Surgical treatment of ankle fracture in the elderly]. AB - OBJECTIVE: To analysis the outcomes and the technique of surgical operation of osteoporotic ankle fracture in the elderly. METHODS: One hundred and twenty-eight patients with osteoporotic ankle fracture were treated by surgical operation from January 2003 to December 2008, included 26 males and 102 females, with an average age of 69 years old ranging from 50 to 82 years. According to Lange-Hanson classification, there were 113 cases of supinatio-extorsion, 18 of pronate extorsion, 5 of supinatio-adduction, 2 of pronate-abduction. The methods of fixation, the complications, and the AOFAS scores after operation were recorded. RESULTS: All the 128 patients were followed up from 6 months to 6 years (averaged in 36 months). Delayed wound healing occurred in 11 cases (8.6%). There was no deep infection, nonunion of the fracture, and revision. The average AOFAS scores after operation was 83.6 +/- 6.3 (the mean pain scores were 33.5 +/- 5.6, the mean function scores were 40.2 +/- 7.4, the mean alignment scores were 10). CONCLUSION: Surgical treatment should be the first choice in osteoporotic ankle fracture in most cases. Improved procedures can make the results better. PMID- 21254675 TI - [Treatment of recurent lumbar disc herniation with the modified Jaslow technique]. AB - OBJECTIVE: To investigate the results of using the modified Jaslow technique to treat the recurent lumbar disc herniation. METHODS: From January 2002 to December 2008,62 patients with recurrent lumbar disc herniation were treated with a modified Jaslow technique. There were 42 males and 20 females with an average age of 53.6 years old, ranging from 36 to 70 years. The primary surgical procedures were enlarged fenestration in 20 cases, unilateral semi-laminectomy in 20 cases, bilateral semi-laminectomy in 8 cases and total-laminectomy in 14 cases. The procedures were performed at L3.4 level in 2 cases, L4.5 in 32 cases, L5S1 in 15 cases, L3.4-L4.5 in 3 cases and L4.5-L5S1 in 10 cases respectively. The clinical symptoms included low back pain and radicular pain. Pre-and postoperative JOA score (including subjective symptoms, self-care ability and pain), ratio of disc height and the fusion condition of the involved segments were applied to assess clinical outcome. RESULTS: All patients were followed up for 1 to 5 years (averaged 3 years). The space height ratio increased from (62.5 +/- 10.4)% to (90.5 +/- 10.3)%, fusion rate was 96.8% (60/62) at the last follow-up. Mean JOA score was (10.42 +/- 2.50) preoperative, improved to (24.26 +/- 2.35) at last follow-up (P < 0.001). The clinic results was excellent in 39 cases, good in 14, fair in 9. CONCLUSION: The modified Jaslow technique was a good alternative method for the treantment of recurent lumbar disc herniation with complete decompression, solid interbody fusion and satisfactory clinical result. PMID- 21254676 TI - [Surgical treatment of tarsometatarsal joints injury]. AB - OBJECTIVE: To summmarize the clinical experience of open reduction and internal fixation for the treatment of tarsometatarsal joint injury ane evaluate the effects of operative treatment to tarsometatarsal joint injury. METHODS: From March to July in 2009,9 patients with tarsometatarsal joint injury were treated by open reduction and internal fixation included 7 males and 2 females with an average age of 33.5 years old ranging from 20 to 47 years. According to Quenu Kuss classification, there were 5 cases of type A, 3 of type B, 1 of type C. All patients were treated by cannulated screws and Kirschner wires through 1 to 2 microtubule straight incision on dorsum of foot. The foot function were assessed by American Orthopaedic Foot and Ankle Society (AOFAS) midfoot score. RESULTS: All patients were followed up for 5 to 12 months with an average of 8 months. Complications concluded 1 case with infection, 1 case with post-traumatic arthritis. The failure of Kirschner wires was not discovered in 9 cases. According to AOFAS system,the total scores increased from preoperative (15.5 +/- 4.2) to postoperative (92.0 +/- 5.2) (t = -45.95, P < 0.01). The results were excellent in 7 cases, good in 1, and poor in 1. CONCLUSION: Open reduction and internal fixation for the reatment of tarsometatarsal joint injury should have satisfying results. PMID- 21254677 TI - [Clinical observation of pentazocine for postoperative intravenous analgesia in patients with lumbar herniation]. AB - OBJECTIVE: To observe the effects and side effects of Pentazocine for postoperative intravenous analgesia in patients with lumbar herniation, and to investigate the difference of Pentazocine with different doses. METHODS: From January 2009 to December 2009, sixty patients undergone laminectomy and pedicle internal fixation, who using equal analgesic dosage of Pentazocine and Sulfentanil, were retrospectively analysed. The patients including 34 males and 26 females, aged 40 to 65 (average 59), weighted 60 to 80 kg (average 71 kg), ASA I-II, were divided into Sufentanil group and Pentazocine group I and Pentazocine group II, with 20 cases each. The regimens of the three groups included: Sufentanil of 2 g/kg; Pentazocine group I of 3 mg/kg; Pentazocine group II of 5 mg/kg. All were diluted with saline into 100 ml and were continuously infused at the rate of 2 ml/h. Visual analogue scale (VAS), Ramsay sedation scale and side effects were recorded at 4, 8, 12, 24, 36, and 48 h postoperatively. RESULTS: The three groups had no significant difference in analgesic effects, VAS of all groups were below 3. The sedation scale of Pentazocine group II at 4, 8, 12 h was higher than that at 4 h, significantly different than the other two groups. The incidence of nausea, vomiting and pruritus in Sufentanil group were higher than that in the other two groups. The incidence of respiratory depression in Sufentanil group and Pentazocine group II were higher than that in Pentazocine group II. The incidence of dizziness in Pentazocine group II were higher than that in the other two groups. CONCLUSION: Pentazocine can produce reliable postoperative analgesia for patients with lumbar herniation, as same as the effect of sulfentanil in equal dose. And Pentazocine has fewer adverse effects compared with sufentanil. 3 mg/kg of Pentazocine is an optimal dose for postoperative intravenous patient-control analgesia. PMID- 21254678 TI - [Experimental study of electrophysiologic effects of regenerative nerve fibres affected by control releasing FK506]. AB - OBJECTIVE: To discuss the electrophysiologic effects of regenerative nerve fibres affected by control releasing of FK506. METHODS: From Mar. to Sep. in 2008, the body weigh of 32 Sprague-Dawley rats which was 200 to 250 g,anesthesia was performed with an intraperitoneal injection of 30 mg/kg 1% continal. The sciatic nerve was transected in each rat by the excision of a 10 mm gap just proximal to the trifurcation of the nerve. The 10 mm gap of sciatic nerve had been bridged with the new double channel nerve conduit of fusiform shape, which were randomly divided into two groups basing on the different drug in the channel, each group contained 16 animals. In group A,100 microl of chitin for medical use was injected into the conduit,in group B the two branches of the conduit respectively contained 100 microl of the chitin and 10 microl FK506 (group B2) or physiologic saline (group B1). At 8 and 12 week after operation, the morphology in regenerative nerve and electrophysiologic effects by detect compound muscle active potential (CMAP) and cortical somatosensory evoked potential (CSEP) were evaluated. RESULTS: There were not significant differences of the regenerative nerve fibres between two channels in group A, but in group B2, the number of the regenerative fibres was much more than that in group B1. The latency of CMAP and CSEP in group B2 was shorter than that in group B1. But its amplitude was higher. There were highly significant difference between the groups (P < 0.01). CONCLUSION: The electrophysiologic effects of regenerative nerve fibres can be significantly promoted by FK506, which provide theory base for immunosuppressive treatment of peripheral nerve. PMID- 21254679 TI - [Influence of pedicle screws with different insertion depth on neighboring uninfused segments in a goat lumbar spinal fusion model]. AB - OBJECTIVE: To observe the influences of pedicle screws in various insertion depth on the adjacent segment disc degeneration following lumbar spinal fusion. To explore the relationship between the internal fixation rigidity and incidence of adjacent segment disease. METHODS: Sixteen hybrid male Bohr goats of 10 months old, weighting between 25 and 30 kg, were randomly devided into a control group (N group), and 3 experimental groups, each group had 4 goats. The L4 vertebra of each goat in the experimental groups was fractured, L3-L5 segments were internal fixed with pedicle screws followed by intervertebral joint fusion by a posterior approach. Three experimental groups were devided according to the length of pedicle screws applied, vertebras of goats in L group were internal fixed by the screws at the length of 25 mm, for M group and S group, 20 mm and 15 mm, accordingly. The goats in the control group were treated without any operation. Biomechanical changes and MRI index of upper unfused segment (L2) were measured 24 weeks after operation, and histological changes were observed as well. RESULTS: The pressure and straining of L2 vertebral body and intervertebral disc of L group increased more than N group (P < 0.05), and degenerated cell counting in nucleus pulposus increased as well (P < 0.05). However, MRI index remain unchanged (P > 0.05). CONCLUSIONS: Rigid internal fixation increases the pressure and straining of vertebral body and intervertebral disc of upper adjacent segment, accelerating the degeneration process following lumbar spinal fusion in goats. PMID- 21254680 TI - [Histologic changes of the cervical muscles and intervertebral discs caused by dynamic dysequilibrium of anteriorly cervical muscles in rabbits]. AB - OBJECTIVE: To observe the histologic changes of the cervical muscles and intervertebral discs caused by dynamic dysequilibrium of frontally cervical muscles in rabbits. METHODS: Thirty healthy rabbits with an average age of two years, half males and half females, the mean of weight in (2.75 +/- 0.25) kg, were divided randomly into model group and the sham operation group with fifteen rabbits in each group. The hibateral sternocleidomastoid muscles of rabbits in the model group were shortened by medical pipe to estabish the new animal model (the model was cervical dynamic dysequilibrium); and in the sham operative group, only exposed hibateral sternocleidomastoid muscles by operation. At the same time after two months, the histologic changes of the cervical muscles and intervertebral discs in all rabbits were observed, meanwhile, the myofibrillar amount and its cross section area were compared between two groups. RESULTS: After operation, the cervical muscles and intervertebral discs had significant change in model group, but no obvious change in sham operative group. The myofibrillar amount of frontal cervical muscles and back cervical muscles in model group was obviously lower than that of sham operative group (P < 0.05); likewise, the myofibrillar cross section area in model group was obviously lower than that of sham operative group (P < 0.05); the frontal cervical muscles was obviously change than the back cervical muscles. CONCLUSION: The cervical dynamic dysequilibrium caused by crispation of frontal cervical muscles can lead to pathologic degeneration of cervical muscles and intervertebral discs. The study may provide experimental proof for early cervical spondylopathy. PMID- 21254681 TI - [A case report of osteochondroma in the medial edge of the subscapular fossa on the left scapular]. PMID- 21254682 TI - [CT axial imaging of the iliolumbar ligament and its significance on locating lumbosacral vertebral segments]. AB - OBJECTIVE: To study the CT axial manifestations of iliolumbar ligament(ILL) and discusses its clinical effects on locating lumbosacral vertebral segments. METHODS: From May 2008 to March 2010, 706 adult patients diagnosed lumbar disc disease were performed with axial scans by single slice helical CT. Among the patients, 436 patients were male and 270 patients were female, ranging in age from 25 to 82 years, the median age was 44 years, 78 cases with lumbosacral transitional vertebrae (LSTV) were verified by X-radiography or fluoroscopy. The morphology, origin and insertion, courses of ILL and the relationship of ligament and spinal segments on axial plane images were used to study. The location method of spinal segments by ILL was compared with the other four location methods on CT. RESULTS: Of the 628 cases with normal lumbosacral segmentations sides of ligament, the main part of ILL originated from L5 transverse processes and terminated at the iliac crest, the morphological characters were divided into two types: double band (71.8%, 451/628) and single band (28.2%, 177/628). The tiny branches from posterior and outside edge of L4, lumbar disc were seen simultaneity in 3 cases. The ILL of 78 cases with LSTV all also originated from L5 transverse processes. Using ILL as a marker of the L5 vertebral level, 78 cases with LSTV were correctly numbered, the accuracy rate was higher than the other location methods, there was statistical significance between the location method by ILL and the location method by iliac crest (P < 0.05). CONCLUSION: The main part of ILL originates from L5 transverse processes, the anatomic location is relatively steady and can be clearly displayed on axial CT, which can be used as a measure in the idenlification of LSTV in clinical practice, it is worthy to be applied widely in basic-level hospitals. PMID- 21254683 TI - [Reply about review in clinical observation at back-rotation traction in treating external humeral epicondylitis]. PMID- 21254684 TI - [Preventive strategies of secondary spinal cord injury caused by subaxial cervical trauma]. AB - OBJECTIVE: To summarize and analyze preventive strategies of secondary spinal cord injury caused by subaxial cervical trauma. METHODS: From April 2004 to April 2009, 67 patients with secondary spinal cord injury caused by subaxial cervical trauma were retrospectively analyzed. There were 40 males and 20 females, with an average age of 40.5 years old ranging from 18 to 69 years. After admission the preventive strategies included using MP and GM-1, early decompression, and high pressure oxygen after operation. The neurological function was classified by Frankel, and the therapeutic effect was evaluated by total recovery rate and useful recovery rate. The total recovery rate was that the level of Frankel raise one or more grade, the useful recovery rate which included Frankel D, E was that the patient can walk by self or crutch, remaining some neurological deficits. RESULTS: All patients were followed up for 1 to 3 years (averaged 1.5 years), the total recovery rate was 53.7% (36/67), the useful recovery rate was 35.8% (24/67). Seven patients was death, the death rate was 10.4% (7/67), 1 was aggravated, the aggravating rate was 1.5% (1/67). CONCLUSION: As possible as using MP, GM-1, early decompression, and high pressure oxygen after operation can be effective strategies for preventing secondary spinal cord injury caused by subaxial cervical trauma. PMID- 21254685 TI - [Revision of bipolar femoral head with bipolar artificial femoral head in 8 cases]. PMID- 21254686 TI - [Improvement technique of double endobutton plate for the treatment of type III acromioclavicular joint dislocation]. AB - OBJECTIVE: To evaluate the clinical outcomes of improvement technique of double Endobutton plate for the treatment of Tossy III acromioclavicular joint dislocation. METHODS: From June 2008 to June 2009, 18 patients with Tossy III acromioclavicular joint dislocation were treated with improvement technique of double Endobutton plate. There were 11 males and 7 females, with an average age of 35 years old ranging from 28 to 55 years. The time from injury to operation was 2 to 5 days (means 3.5 days). All patients were followed and the clinical outcomes were recorded. RESULTS: These 18 patients were followed up from 4 to 8 months (averaged 6 months). All acromioclavicular joint dislocation were reduced. According to the scales of Karlsson, the post-operation function 1 of shoulder joint in 16 patients were A grade and 2 patients were B grade. CONCLUSION: The improvement technique of double Endobutton plate is an effective ideal treatment methods for Tossy III acromioclavicular joint dislocation due to its less invasion and convenience and good biocompatibility. PMID- 21254687 TI - [Treatment of tibial Pilon fracture with fixation according to different columns]. PMID- 21254688 TI - [Manipulative reduction and external fixation for the treatment of trans-scaphoid perilunar dislocation of carpus]. PMID- 21254689 TI - [Treatment of the lateral process fracture of the talus by hollow compression screw in 17 patients]. PMID- 21254690 TI - [Clinical experience about manipulative reduction of the radialis and ulnar fractures]. AB - OBJECTIVE: To observe the clinical efficacy about manipulative reduction of the radialis and ulnar fractures. METHODS: From June 2005 to June 2009, 85 patients with radialis and ulnar fractures, 50 males and 35 females, ranging in age from 1 to 20 years with an average of 10.8 years, were treated with manipulative reduction and external fixation by small splint. There were 53 cases of direct violence, 30 cases of transmission violence, 2 cases of reversing violence; and there were 6 cases of comminuted fracture, 8 cases of spiral fracture, 21 cases of oblique fracture, 50 cases of serrated or transverse fracture. The clinical effects were analyzed according to Anderson criterion. RESULTS: Forty-two cases obtained anatomical reduction and 35 cases obtained nearly anatomical reduction and 8 cases occurred re-displacement. Eight cases of re-displacement were re fixed after manipulative reduction, 2 cases obtained anatomical reduction and 4 cases obtained nearly anatomical reduction; 2 cases unsuccessfully were diverted to open reduction and internal fixation. All the fractures obtained clinically healing with average of 42 days (ranged from 28 to 80 days). All patients were followed up from 3 to 10 months with an average of 7.5 months. According to Anderson criterion, 77 case got excellent result, 5 good, 3 fair. CONCLUSION: Manipulation and external fixation by small splint for the treatment of radialis and ulnar fractures, have advantage of less trauma, forceful fixation, quick healing, cheap cost, which can obtain satisfactorily clinical effects. PMID- 21254691 TI - [Error diagnosis and inappropriate treatment for Essex-Lopresti injury in 2 cases]. AB - OBJECTIVE: To analyze the reason of error diagnosis and inappropriate treatment of radius head fractures complicating distal radioulnar joint dislocation (Essex Lopresti injury) and to seek for the reasonable treatment. METHODS: From 2008 to 2009, 2 male patients of radius head fractures complicating distal radioulnar joint dislocation were treated, the age was 56 and 66 years old respectively. The symptom included elbow swelling and limitation of forearm rotation. X-ray showed comminuted fractures of capitulum radius. There were 1 case of Mason type III and 1 cases of type IV. Two patients were treated by resection of capitulum radius and plaster fixation after operation. RESULTS: Both of the 2 cases had limited rotation of forearm and the distal radioulnar joint pain. The X-ray showed that the distal radioulnar joint was separated obviously and the proximal radius was translocated. CONCLUSION: The early diagnosis is very important for the Essex Lopresti injury. Rebuilding the longth of the radius and reduction fixating the distal radioulnar joint after fixated is an effective treatment while the interosseous membranes can't be repaired and rebuilded. PMID- 21254692 TI - [Forecasting and prevention of collapse in femur head necrosis]. AB - By discussing different ways on prediction, prevention and treatment of femur head necrosis (FHN), to provide a theory reference for future clinical application. By searching, reading and summarizing related-literatures through CNKI, VIP, CBM and foreign-related literature, to sum up the relevance methods and techniques of currently used. It was found that imaging study (especially X ray and MRI) was of great importance in prediction. There were several ways (both non-surgical or surgical) for prevention and treatment. FHN collapse was affected by many factors, but most of the researches were all focus on one aspect of the mechanism and based on small samples. It is necessary to have a research with a large sample and to compare the effect on different treatment. Early and effective imaging inspection is needed for high risk group of FHN; possibility of collapse should be predicted for existing FHN; core decompression or vascularized bone grafting are required for collapse of high risk group. Early prediction and treatment are essential for FHN patients. PMID- 21254693 TI - [Status and progress of non-surgical treatment of bone nonunion]. AB - The treatment of fracture has been greatly improved, but the incidence of nonunion is still high and which is a challenge that orthopedic clinicians. The treatment of nonunion has been the concern to the scholars. New technologys of surgical and non-surgical therapies continue to emerge, and achieve good clinical efficacy. In particular the development of non-surgical therapy has brought hope for non-invasive treatment of nonunion. This paper attempts to make a review of the status and progress of non-surgical treatment of bone nonunion which are more commonly used in clinical. PMID- 21254694 TI - [Perioperative nursing in treating Anderson II-type fracture of odontoid process with pedicle of vertebral arch fixation]. PMID- 21254695 TI - [Goals & objectives of the internal medicine curriculum: nephrology syllabus]. PMID- 21254696 TI - [Plasma B-type natriuretic peptide level predicts the renal outcome in patients with chronic kidney disease]. AB - PURPOSE: Elevation of the plasma level of B-type natriuretic peptide (BNP) is commonly seen in patients with chronic kidney disease (CKD), but its significance remains unclarified. We conducted a prospective study to evaluate the role of plasma BNP level as a predictive marker of renal outcome. METHODS: 237 patients with CKD stage 3, 4 not on dialysis were prospectively enrolled as a hospital cohort from August 2004 to December 2008. Combined renal endpoint was doubling of baseline serum creatinine or end-stage renal disease requiring dialysis. Endpoint free renal survival was calculated by Kaplan Meier analysis and compared by the log-rank test. We used Cox proportional hazards analysis to determine the independent predictor for renal outcome among the clinical data at the time of referral to a nephrologist. ROC analysis was used to determine the best cut-off value of plasma BNP level to predict the renal outcome. RESULTS: The mean follow up period was 2.5 +/- 1.1 years. Median age was 65 years. Of the subjects, 65.8% were men and 37.9% had diabetes mellitus. Median serum creatinine level was 2.7 mg/dL. Plasma BNP level was significantly higher among 147 patients who reached the combined renal endpoint compared with 90 patients who did not (116.0 pg/mL vs 54.5 pg/mL, p<0.001). After adjustment with other established predictive factors of renal outcome, plasma BNP level was selected to be the strongest predictive marker for renal endpoint (Hazard ratio 1.173, 95%CI 1.000-1.376). The optimal cut-off value of plasma BNP level suggested by ROC analysis was 69.5 pg/mL. Patients with a plasma BNP level above the cut-off point revealed a significantly poor renal outcome compared with those with a plasma BNP level below the cut-off point. CONCLUSIONS: The present study suggests that the plasma BNP level might be a predictive marker for renal outcome and a guide for management of cardio-renal interaction. PMID- 21254697 TI - [Status of board-certified nephrologists of the Japanese Society of Nephrology among 47 prefectures]. AB - To improve chronic kidney disease (CKD) outcomes, board-certified nephrologists of the Japanese Society of Nephrology (certified nephrologists) are anticipated to play an important role in community medicine and establish an effective cooperative relationship with primary care physicians. We analyzed the present status of certified nephrologists in each prefecture of Japan based on national data. As a result, in 2008, the maximum number of certified nephrologists per population among the 47 prefectures was 5.3 times higher than the minimum number. The rate of increase was not high in prefectures with a small number of certified nephrologists per population, which indicates that the disparities among the prefectures will persist in the future. To analyze how certified nephrologists participate in the community medicine of the 47 prefectures of Japan, we performed an ecological regression study. At first, it was shown that the number of certified nephrologists per resident population according to prefectures in 2007 had no significant correlation with the annual amount paid for angiotensin converting enzyme inhibitor (ACEI), angiotensin II receptor blocker (ARB), calcium channel-blocker (CCB), or erythropoiesis stimulating agent (ESA) per resident. Furthermore, to determine what parameters had a significant correlation with the incidence of dialysis in each prefecture, simple linear regression analysis was first performed. As a result, parameters with a significant correlation were the average age of the inhabitants, and the annual amounts paid for ARB, ARB plus ACEI, CCB, and ESA per resident. Furthermore, multiple regression analysis revealed that there were two variables included in the final model which could explain the low incidence of dialysis in each prefecture. One was the annual amount of ESA used for predialysis CKD patients, and the other was the number of certified nephrologists per population. Based on these findings, although our ecological study cannot identify causation, we predict that certified nephrologists can effectively prevent the progression of CKD, and an increase in certified nephrologists will decrease the incidence of dialysis. PMID- 21254698 TI - [Relationship between coronary and abdominal calcification score, serum osteoprotegerin (OPG), and serum tartrate-resistant acid phosphatase (TRACP) -5b in pre-dialysis CKD patients]. AB - Osteoprotegerin (OPG) inhibits interaction of the receptor-activator of nuclear factor-kappaB (RANK) ligand (RANKL) with its receptor RANK, which is expressed on osteoclasts. OPG appeared to accelerate vascular calcification in vitro by the inhibition of vascular osteoclast-like cells. On the contrary, early-onset arterial calcification was observed in OPG-deficient mice. We measured the coronary artery calcification score (CACS) and abdominal aortic calcification score (AAoCS) by multi-detector computed tomography in 30 pre-dialysis CKD patients (eGFR 20 mL/min on average). Biomarkers were measured, including serum OPG, soluble RANKL (sRANKL) and tartrate-resistant acid phosphatase (TRACP) -5b (the biomarker of osteoclasts independent of renal function). The median values of CACS and AAoCS were 54.4 and 1,088 Agatston units (AU), respectively. Serum OPG was increased and serum sRANKL was decreased. In a multivariate logistic regression analysis using CACS > or = 100 AU as the outcome variable, CACS was found to be positively correlated with serum corrected Ca x iP product and serum OPG, though it was not correlated with serum TRACP-5b. ROC curve analysis showed that the serum OPG cutoff value predicting CACS > or = 100 AU was 5.2 pmol/L (624 pg/mL). In a stepwise regression analysis, log (AAoCS + 1) was positively correlated with serum OPG alone, but it was not correlated with age, eGFR, serum albumin and bone alkaline phosphatase (BAP). No correlation was found between serum OPG and serum TRACP-5b. In conclusion, vascular calcification in pre dialysis CKD patients was correlated with an increase in OPG, but was independent of serum TRACP-5b. The decrease in serum sRANKL may have been caused by the increase in OPG production. PMID- 21254699 TI - [Long-term outcome of children treated with the ISKDC regimen for the first episode of INS]. AB - We retrospectively analyzed the long-term outcome of 82 children (SRNS group, 10; SDNS group, 35; IRNS group, 37) who were initially treated with the ISKDC regimen at the Saitama Children's Medical Center. The ISKDC regimen consisted of PSL 60 mg/m2/day for 4 weeks, followed by 40 mg/m2 on alternate days for another 4 weeks. The aims of our study were to identify factors at onset that could predict the relapse pattern after using the initial ISKDC regimen, and to assess the prognosis and renal histology after long-term CsA therapy in 31 children. All of six asymptomatic children without edema and identified by chance proteinuria on a urinary screening program had an extremely favorable clinical course. Initial remission time of 9 or more days and the time interval from the initial therapy to the first relapse were significant predictors of steroid dependency. The sensitivity and specificity of these findings were 100% and 90%, respectively, with a positive predictive value of 95% and a negative predictive value of 100%. In addition, after the introduction of CsA therapy, termination of steroid therapy was achieved in 56% of patients with SRNS, and 64% of SDNS, respectively. However, after CsA therapy was tapered or stopped, most patients (21/20: 95%) developed relapses of NS. Of these, 76% (16/21) returned to SDNS, resulting in the reintroduction of CsA. Ten of 22 patients taking CsA (mean duration 31.3 months) had chronic nephrotoxicity. In conclusion, the initial ISKDC regimen is useful for the early prediction of whether or not the patient will develop SDNS. When pediatric nephrologists introduce CsA therapy in children with SDNS, an alternative strategy after long-term use of the agent should be considered. PMID- 21254700 TI - [Autopsy case of Henoch-Schonlein purpura nephritis complicated with intestinal cytomegalovirus infection]. AB - A 55-year-old man was admitted to our hospital because of arthralgia, purpura, abdominal pain, melena and leg edema. Laboratory findings showed an increased serum creatinine level (2.4 mg/dL), hematuria and massive proteinuria (10.7 g/day). Renal biopsy revealed diffuse endocapillary proliferation and focal mesangial proliferation with IgA deposition predominantly in the glomerular capillary walls. Based on these findings, he was diagnosed as having Henoch Schonlein purpura nephritis and steroid therapy was started. Following steroid therapy, his nephrotic state remained unchanged, although his renal function improved concomitantly with the disappearance of arthralgia, purpura and abdominal symptoms. Therefore, cyclosporine was added to the steroid therapy to enhance immunosuppression. However, melena recurred and anemia progressed. Endoscopy revealed multiple ulcers in the duodenum and jejunum, and clipping was performed at some bleeding sites. However, he died of hemorrhagic shock. The autopsy revealed that hemorrhagic lesions having cytomegalovirus infection spread widely in the stomach, duodenum and jejunum. Recurrence of gastrointestinal bleeding during the treatment of Henoch-Schonlein purpura nephritis is usually due to severe vasculitis or steroid ulcer. However, in patients receiving strong immunosuppressive therapy, cytomegalovirus infection needs to be considered as cause of gastrointestinal bleeding. PMID- 21254701 TI - [Tardieu's spots and asphyxia--a literature study]. AB - Subpleural, epicardial and pericranial ecchymoses have been described in cases of suffocation since the 18th century. In the 19th century, great diagnostic importance was attributed to ecchymoses. Tardieu was the most determined defender of the specificity of ecchymoses for suffocations. He thought that he could diagnose violent suffocation by means of ecchymoses and claimed that he was able to differentiate violent suffocation from other unnatural causes of death (hanging, choking, strangulation, and drowning). Other physicians, among them numerous German medical examiners, proved Tardieu's opinions wrong by means of observations and animal studies. The most dedicated disputant against Tardieu's false doctrines was Liman. According to today's knowledge of pathophysiology, the haemorrhages concerned cannot have a specificity for suffocation or even a specific form of suffocation. Therefore, the confusing term of "suffocation haemorrages" should be avoided. PMID- 21254703 TI - [Reconstruction of sexual offences--forensic aspects of sperm traces]. AB - The investigation of sexual offences is a real challenge, as the injuries are often unspecific or faint and may sometimes be missing completely. Evidence recovery and analysis as well as the statements of the victims and suspects are therefore of vital importance. In both presented cases, the results of trace evidence analysis were basically consistent with a sexual assault, but the victims' statements regarding the course of events and the pattern of traces showed severe discrepancies. PMID- 21254702 TI - [Suicide with a manipulated hand grenade]. AB - Explosion injuries in civilians are rare. An uncommon case of suicide with a manipulated hand grenade is presented. The findings at the scene and on the body (i.a. massive soot blackening of the skin, singeing, size and number of splinters) gave reason to doubt the use of trinitrotoluene (TNT), the usual explosive charge in hand grenades. Further investigations showed that parts of several hand grenades and black powder from standard fire-crackers commercially available without legal restriction had been used as propelling charge. The victim, who was in a sitting position, held the hand grenade in the left hand and triggered it with the right. He bled to death due to a fracture of the right femur and lacerations of the liver. The chronological course and total circumstances of the case suggested suicide in a strongly intoxicated condition (BAC 2.5 per mille). In the flat, a larger number of unlicensed weapons and weapon parts were found. PMID- 21254704 TI - [Examination results and autopsy findings in assaults on elderly people]. AB - As the percentage of elderly people in the population grows, violence against persons of advanced age constitutes an increasing social problem. The findings of the clinical forensic examinations (CE group) and autopsies performed on elderly violence victims (> or = 60 years) between 1999 and 2008 at the Institute of Legal Medicine of the Hanover Medical School were retrospectively analysed. In all, the study material comprised 55 victims of the CE group (35 females and 20 males, median age 73.5 years) and 55 autopsies (33 females and 22 males, median age 72.7 years). In most of the autopsy cases, the suspect was a family member or partner. In contrast, the alleged perpetrator was a stranger in most cases of the CE group. Blunt force injuries were most often found in the CE group victims (63.6%). Altogether, 38.2% (CE group) and 20.0% (autopsy cases) of the violent assaults were associated with robbery. In the majority of the CE cases, the victims suffered potentially or acute life-threatening injuries. In summary, the analysis shows that elderly people frequently become victims of robbery and blunt force injury. In most homicides of old people, the perpetrator is familiar to the victim. In surviving elderly violence victims, the assault is more likely to be reported to the police if the suspect is a stranger. PMID- 21254705 TI - [Clinical forensic examination findings in assault cases among adolescents]. AB - Child and youth criminality has risen markedly over the past 25 years and causes increasing concern to the general public. The clinical forensic examination cases of youth violence victims examined at the Institute of Legal Medicine of the Hanover Medical School and its Oldenburg Branch between 1999 and 2008 were retrospectively analyzed. In all, 55 adolescents (37 females, 18 males; median age 15.5 years) were examined. In most cases the suspect was a close (40.0%) or passing (23.6%) acquaintance. 16 assaults were committed by two or more adolescents jointly. Most of the juveniles were victims of sexual assaults (56.4%). In 15 victims of sexual offences (51.7%) diagnostic findings were obtained on the basis of anogenital injuries and/or the presence of sperm. In summary, the analysis shows that adolescents frequently become victims of sexual assault. In addition, youth violence is often committed in a group. PMID- 21254706 TI - Evacuation, hygiene, and social policy: the "Our Towns" Report of 1943. PMID- 21254707 TI - The "school for modesty and humility": colonial American youth in London and their parents, 1755-1775. PMID- 21254708 TI - The making of the Penitentiary Act, 1775-1779. PMID- 21254709 TI - The casual poor and the city of London Poor Law Union, 1837-1869. PMID- 21254710 TI - The Labour Party and the Parliamentary campaign to abolish the military death penalty, 1919-1930. PMID- 21254711 TI - Improving outcomes in older people undergoing elective surgery. AB - Older people have much to gain from surgery, but pose a significant challenge not only in emergency surgery but also in elective surgery. Despite significant progress in the care of older surgical patients, they remain more likely to 'fail' pre-assessment and have higher rates of post-operative complications than younger people. The evidence suggests that this is a consequence of age-related increases in co-morbidities and reduction in physiological reserve. Numerous studies have demonstrated improvements in outcome when individual co-morbidities are appropriately assessed and optimised. However, current models of care do not allow for the translation of this evidence into routine clinical practice, particularly in those with complex co-morbidities and functional dependence. This article explores the reasons for poor outcome in older people and describes an alternative model of care for the older elective surgical patient. PMID- 21254712 TI - Witchcraft, sexuality, and colonization in the early modern world. PMID- 21254713 TI - Putting death in its place: a review essay. PMID- 21254714 TI - Changing social mobility in nineteenth-century France. PMID- 21254716 TI - Reproducing utopia: Jeanne-Marie Leprince de Beaumont's "The New Clarissa". PMID- 21254717 TI - Engendering French colonial history: the case of Indochina. PMID- 21254718 TI - [N. F. S. Grundtvig and social policy in the Danish Constituent Assembly in the spring of 1849.]. PMID- 21254720 TI - [Demographic perspectives]. PMID- 21254719 TI - [Death in childhood]. PMID- 21254723 TI - An unexpected abnormality on the EEG. PMID- 21254724 TI - Social isolation improves working memory at reversal but not primary radial-arm maze learning in rats. AB - Social isolation starting from the 21st day of birth affected neither a short term nor a long-term memory in male rats at primary acquisition learning in an 8 arm radial maze. A number of the short-term and long-term memory errors were substantially decreased during primary learning but the difference between groups was not significant. Isolates were faster to start a search in an individual trial and took less time to finish offa trial. During the reversal learning, when baited and non-baited arms were reversed, the isolates outperformed of socially reared rats on working but not reference memory task. In overall they made twice less working memory errors than socially reared animals. During the reversal learning the isolates were also faster than non-isolates in initiation and completion of a trial. Maternal separation of rat's pups on the postnatal days 1 21 for 4 hr per day did not affect either working or reference memory on both primary and reversal learning. The data obtained are discussed on basis of influence of stress in early postnatal life on hypothalamo-pituitary axis and its effects on behavior of adult animals. PMID- 21254725 TI - Births: final data for 2007. AB - OBJECTIVES: This report presents 2007 data on U.S. births according to a wide variety of characteristics; preliminary 2008 data are also referenced on key measures where available. Final 2007 data are presented for maternal demographic characteristics including age, live-birth order, race and Hispanic origin, marital status, and educational attainment; maternal lifestyle and health characteristics (medical risk factors, weight gain, and tobacco use); medical care utilization by pregnant women (prenatal care, obstetric procedures, characteristics of labor and/or delivery, attendant at birth, and method of delivery); and infant characteristics (period of gestation, birthweight, Apgar score, congenital anomalies, and multiple births). Birth and fertility rates by age, live-birth order, race and Hispanic origin, and marital status also are presented. Selected data by mother's state of residence are shown, as well as data on month and day of birth, sex ratio, and age of father. Trends in fertility patterns and maternal and infant characteristics are described and interpreted. METHODS: Descriptive tabulations are presented of data reported on the birth certificates of the 4.3 million births that occurred in 2007. Preliminary 2008 data are based on 99.9 percent of births occurring in 2008. Denominators for population-based rates are postcensal estimates derived from the U.S. 2000 census. RESULTS: A total of 4,316,233 births were registered in the United States in 2007, the largest number of births ever reported. The general fertility rate increased 1 percent to 69.5 per 1,000. Birth rates increased for women in nearly all age groups. The rate for teenagers rose 1 percent for the year and is up 5 percent from 2005. The total fertility rate increased 1 percent to 2,122.0 births per 1,000 women. Preliminary data for 2008, however, suggest a decline in the number and rate of births overall, and for most age groups under age 40 years. All measures of unmarried childbearing reached record levels in 2007. The cesarean delivery rate rose to another all-time high--31.8 percent. Preterm and low birthweight rates declined slightly, and twin and triplet and higher-order multiple birth rates were essentially unchanged. Preliminary findings for 2008 suggest that these trends continued for cesarean delivery, unmarried childbearing, and preterm births. PMID- 21254726 TI - Efficiency of phenotypic and DNA markers for a genetic diversity study of alfalfa. AB - Information on genetic diversity and germplasm characterization is essential for successful crop improvement. Diverse data sets (pedigree, morphological, biochemical, DNA based-markers) are employed in various aspects of plant analysis. The objective of this study was to determine the efficiency of phenotypic and RAPD markers in diversity assessment often alfalfa (Medicago spp.) accessions from Europe, North America and Australia. Field experiment was designed as a randomised complete block with three replications over two consecutive years (2004, 2005) at one location. Twelve morpho-agronomic traits were recorded on 50 plants per each accession. Genomic DNA's from 16-20 randomly selected individual plants per accession were used for RAPD analysis. Six primers selected in this study generated a total of 93 polymorphic RAPD bands. The number of polymorphic bands detected per primer ranged from 11 to 20. Genetic distances (GD) among investigated accessions and two-dimensional principal coordinate analysis (2D PCoA) based on phenotypic and molecular data were obtained. The average GD between (0.283-0.416) and within (0.247-0.332) accessions based on RAPD data was higher than GD values obtained by morpho-agronomic traits (0.171 0.354 and 0.157-0.261, respectively). 2D PCoA based on GD from RAPD data grouped most of the studied individual plants to four clusters according to their geographical or taxonomy origin. 2D PCoA based only on morpho-agronomic data did not group plants congruently to their origin, probably due to a strong environmental influence on studied traits. Our results indicated that the RAPD markers were effective in assessing genetic diversity within and between studied alfalfa accessions. In addition, the obtained results suggested that the RAPD markers might be useful for grouping of germplasm with similar genetic background and for prescreening of potential heterotic groups in our breeding programme. PMID- 21254727 TI - Assessment of genetic diversity among Syrian durum (Triticum turgidum ssp. durum) and bread wheat (Triticum aestivum L.) using SSR markers. AB - Genetic diversity among 49 wheat varieties (37 durum and 12 bread wheat) was assayed using 32 microsatellites representing 34 loci covering almost the whole wheat genome. The polymorphic information content (PIC) across the tested loci ranged from 0 to 0.88 with average values of 0.57 and 0.65 for durum and bread wheat respectively. B genome had the highest mean number of alleles (10.91) followed by A genome (8.3) whereas D genome had the lowest number (4.73). The correlation between PIC and allele number was significant in all genome groups accounting for 0.87, 074 and 0.84 for A, B and D genomes respectively, and over all genomes, the correlation was higher in tetraploid (0.8) than in hexaploid wheat varieties (0.5). The cluster analysis discriminated all varieties and clearly divided the two ploidy levels into two separate clusters that reflect the differences in genetic diversity within each cluster. This study demonstrates that microsatellites markers have unique advantages compared to other molecular and biochemical fingerprinting techniques in revealing the genetic diversity in Syrian wheat varieties that is crucial for wheat improvement. PMID- 21254728 TI - The effect of AmtR on growth and amino acids production in Corynebacterium glutamicum. AB - AmtR, the master regulator of nitrogen control in Corynebacterium glutamicum, plays important roles in nitrogen metabolism. To investigate the influence of AmtR on amino acids production in C. glutamicum ATCC 13032, the amtR deletion strain C. glutamicum Q1 was constructed and cultured in modified CGXII minimal medium for 60 h. The ammonium consumption rates as well as amino acids production of both strains cultured in modified CGXII minimal medium were determined. The amtR deletion in C. glutamicum caused an obvious growth defect in the exponential growth phase, but both strains had the same biomass in the stationary phases. Maybe the less alpha-oxoglutarate was used for the tricarboxylic acid cycle to influence the growth of strains. During 12 h, the rate of ammonium consumption and the concentration of Glu, Pro, Arg and Ser were higher but Asp, Gly, Ile, Leu, Lys were lower in the mutation strain. During 48 h, the Q1 had higher levels of Asp, Lys, Pro, Ala and Val,and lower levels of Glu, Arg, Leu and Ile, compared to the wild. The more Glu was synthesized by the activated GS/GOGAT pathway in Q1, and then the accumulation of relative amino acids (Pro, Arg and Ser) were up regulated within 12 h growth. After 48 h growth, the amtR deletion obviously influenced accumulation of Ala, Asp and Pro. The amtR deletion could influence the growth and amino acids production, which could be useful to the production of amino acids. PMID- 21254729 TI - Purification and characterization of an intracellular beta-glucosidase from the protoplast fusant of Aspergillus oryzae and Aspergillus niger. AB - Protoplasts of Aspergillus oryzae 3.481 and Aspergillus niger 3.316 were prepared using cellulose and snail enzyme with 0.6 M NaCl as osmotic stabilizer. Protoplast fusion has been performed using 35% polyethylene glycol 4.000 with 0.01 mM CaCl2. The fused protoplasts have been regenerated on regeneration medium and fusants were selected for further studies. An intracellular beta-glucosidase (EC 3.2.1.21) was purified from the protoplast fusant of Aspergillus oryzae 3.481 and Aspergillus niger 3.316 and characterized. The enzyme was purified 138.85 fold by ammonium sulphate precipitation, DE-22 ion exchange and Sephadex G-150 gel filtration chromatography with a specific activity of 297.14 U/mg of protein. The molecular mass of the purified enzyme was determined to be about 125 kDa by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The enzyme had an optimum pH of 5.4 and temperature of 65 degrees C, respectively. This enzyme showed relatively high stability against pH and temperature and was stable in the pH range of 3.0-6.6. Na+, K+, Ca2+, Mg2+ and EDTA completely inhibited the enzyme activity at a concentration of 10 mM. The enzyme activity was accelerated by Fe3+. The enzyme activity was strongly inhibited by glucose, the end product ofglucoside hydrolysis. The K(m) and V(max) values against salicin as substrate were 0.035 mM and 1.7215 micromol min(-1), respectively. PMID- 21254730 TI - Quality of life in multiple sclerosis. AB - An overall aim of treatment in multiple sclerosis is to lower the negative impact of the disease on functioning and quality of life of patients. Therefore, a measurement of functioning and quality of life should be included in the evaluation of the effectiveness of treatment. The most commonly used quality of life questionnaires, either generic or specific, were presented in this paper,. Information about clinical and functional status is useful in the interpretation of the quality of life assessment results. Because of that, instruments for the assessment of depression, cognitive functions, functional ability and fatigue in multiple sclerosis were also described. PMID- 21254731 TI - Heidelberg Retina Tomography analysis in optic disks with anatomic particularities. AB - Due to its objectivity, reproducibility and predictive value confirmed by many large-scale statistical clinical studies, Heidelberg Retina Tomography has become one of the most used computerized image analysis of the optic disc in glaucoma. It has been signaled, though, that the diagnostic value of Moorfieds Regression Analyses and Glaucoma Probability Score decreases when analyzing optic discs with extreme sizes. The number of false positive results increases in cases of megalopapillae and the number of false negative results increases in cases of small size optic discs. The present paper is a review of the aspects one should take into account when analyzing a HRT result of an optic disc with anatomic particularities. PMID- 21254732 TI - Gallstone ileus--clinical and therapeutic aspects. AB - Gallstone ileus represents a rare (0.3-0.5%), but serious complication of a common illness--the gallbladder lithiasis and the incidence of this fascinating disease has remained the same over the years. The main actual characteristics of this pathology are the age over 65, the female gender (men/women ratio 1/5:1:10- due to the high rate of vesicular lithiasis) and the under 50% diagnostic established preoperatively. The frequency of gallstone ileus recurrence is of 4,7 5%. In this article, we discuss the pathogenesis of this illness presenting all the mechanisms described in the medical literature. The Rigler triad found at the abdominal CT-scan generally established the diagnosis. Still, in 25% of the cases we have a misdiagnosis because of the underestimation of the size of the gallstone. Finally, the treatment of gallstone ileus has had major changes from the past. We described the endoscopic and laparoscopic approach, which represents the modern treatment of this disease. Despite these diagnostic and therapeutic possibilities, the mortality remains high and the common causes are associated comorbidities and late presentation to the physician. PMID- 21254733 TI - Anger and health risk behaviors. AB - The present paper makes a research about negative effects of anger and hostile conduct on peoples' health status. We have studied scientific articles published between 2000 and 2010, which did not contradict our initial assumption. The literature demonstrates that anger, wheatear suppressed or expressed, can determine various diseases, it can influence the conduct of people suffering from bulimia nervosa or it can be the cause for the growing number of car accidents. In order to avoid these risks, the intervention should not be limited to medication, but it should also involve a psychological help that should insist on ways of dealing with anger without exposing the person to any kind of risk for his health or wellbeing. PMID- 21254734 TI - TURP for BPH. How large is too large? AB - BPH remains one of the most common diseases that the urologist has to manage. The last decade brought numerous new techniques, aiming to improve the minimally invasive approach to BPH, but, for the moment, none had changed the place of TURP as the gold standard treatment for medium sized prostates. Based on a large personal experience, the authors present a study in which TURP is used for prostates over 80 ml, the cutoff point set by the guidelines of the European Association of Urology. The rationale for this study is that many situations require minimally invasive treatment, based on the express request of the patient, other conditions that makes open surgery very difficult or impossible, or the need for a quick discharge in an overcrowded service. The aim of the study was to prove that TURP is safe and effective even in larger prostates. The technique used is basically the classic one, with minor tactical alterations in some cases. Some cases required a two-stage approach, but offered good functional results after the first stage. The results proved that, with a good technique, a skilled urologist might achieve the same results by using TURP or open surgery for large sized prostates. PMID- 21254735 TI - Clinical application of optical coherence tomography for the imaging of non melanocytic cutaneous tumors: a pilot multi-modal study. AB - CONTEXT: Optical coherence tomography (OCT) is an emergent imaging technique, based on the interference of infrared radiation and living tissues, that allows the in vivo visualization of the skin structures, at high resolution and up to 1.6 mm depth. As such, there is mounting evidence that OCT may be an interesting technique for the diagnosis of skin diseases, including the noninvasive early detection of cutaneous tumors. OBJECTIVE: We aimed to investigate the utility of OCT for the diagnosis of non-melanocytic, non-pigmented cutaneous tumors. METHODS: Preliminary results are presented from an initiated study. Fifteen consecutive patients with clinical suspicion of epithelial cancers and precancers registered over one week in a university dermatologic department were included. As control were selected 7 patients with inflammatory skin diseases (psoriasis, lichen planus, cutaneous lupus erythematosus). In all study and control patients, the lesions and samples of normal, perilesional skin were documented by clinical digital photography, contact dermoscopy with digital image capture and OCT with central wavelength of 930 nm. Final diagnosis was certified by histopathological analysis. RESULTS: We could identify morphological features in OCT examination that distinguished between normal and lesional skin, and between neoplastic vs. inflammatory lesions. In the same time, combining OCT and dermatoscopical evaluation of a lesion improved the performance of diagnosis when compared to clinical diagnosis alone and with either OCT or dermoscopy imaging used alone. CONCLUSIONS: OCT appears as a promising method of in vivo diagnosis of early neoplastic cutaneous lesions with equivocal clinical and/or dermoscopic aspect. Continuation of our study as well as other larger investigation will be able to contribute with new insights in the role of OCT in the non-invasive diagnosis of skin disease. PMID- 21254736 TI - Cytotoxic antibodies--valuable prognostic factor for long term kidney allograft survival. AB - BACKGROUND: Since the first attempts of kidney transplant, the inflammation mediated by T lymphocytes was considered one of the most important processes implicated in graft rejection but, multiple acute and chronic graft rejects revealed that the inflammation process is not singular and humoral mechanisms may play a role in the development of chronic vascular rejection. MATERIAL AND METHODS: We evaluated 500 Romanian patients registered on the kidney transplant waiting list. We performed anti-HLA class I and class II antibodies screening and identification. Laboratory tests were performed at Centre for Immunogenetics and Virology, Fundeni Clinical Institute, Bucharest, Romania. The methods used are represented by ELISA (GTI Diagnosis, USA) and Luminex (Tepnel, USA) RESULTS: pretransplant evaluation of the subjects illustrates that 145 patients (29%) have been sensitized and 355 patients (71%) have not been sensitized. The most frequent types of anti-HLA antibodies were A2 (13%), B42 (10%), DR7 and DR11 (13%). Post transplant, the most cases with de novo antibodies were observed in the first 6 months post transplantation. High serum levels of Il-2 Receptor, TNF alpha and neopterin in post transplant sensitized patients were observed following de novo cytotoxic antibodies occurrence. CONCLUSION: post renal transplantation, patients present high risk in developing de novo cytotoxic antibodies, especially those who had HLA mismatch with the donor. These antibodies are predictors for acute graft rejection and for graft failure. PMID- 21254737 TI - The epidemiology of hypopharynx and cervical esophagus cancer. AB - At the beginning of the 21st century the hypopharynx and the cervical esophagus cancer represents a major issue for all countries of the world. The epidemiology of the hypopharynx and cervical esophagus cancer deals with the spread of the disease in the human population with regard to sex, age, profession, time and space, as well as risk factors that contribute to these phenomena. The main goal is to investigate the causes and the factors involved in the development of the tumors at the pharyngoesophageal junction, knowledge that contributes to the latest therapeutic assessment through interdisciplinary collaboration (E.N.T. surgeon, general surgeon, radiation oncologist, chemotherapist, and nutritionist). The epidemiology of the hypopharynx and cervical esophagus cancer includes three major areas of interest: descriptive (the study of the spread in mass population), analytical (the study of causal risk factors on the disease) and experimental (that verifies by experiments on animals the prior identified hypothesis). PMID- 21254739 TI - Arthroscopical and histological study of cartilaginous lesions treated by mosaicplasty. AB - AIM: The aim of our study was to assess macro- and microscopically the knee cartilaginous lesions outcome treated by mosaicplasty. MATERIAL AND METHOD: Our study included 32 patients who underwent mosaicplasty for nondegenerative cartilaginous lesions of the knee and a second look arthroscopy. In 21 patients, minibiopsies from the repaired lesion were performed under arthroscopic control (from the cartilaginous region of the transplanted osteocartilaginous grafts and from the spaces between grafts). All repaired lesions were carefully examined during arthroscopy and all harvested minifragments were studied by optical microscopy (staining method - hematoxylin eosin). RESULTS: Macroscopically, the articular surface of the repaired cartilaginous lesions was smooth and congruent to the adjacent surfaces. The aspect and resistance to compression of grafted area was similar to those of the normal surrounding cartilage. The transferred cartilage maintained its height, being at the level of the neighboring cartilage. One year postoperatively, the limits of the cartilaginous autografts were still visible. Two years postoperatively, these limits were no longer visible. Microscopically, the region of the former lesion was constituted mainly by viable hyaline cartilage. Fibrous cartilaginous tissue was visualized in the spaces between the grafts. CONCLUSIONS: The second look arthroscopy showed that after mosaicplasty the repaired articular surface was smooth, leveled, homogenous and congruent to adjacent cartilage. The spaces between grafts are progressively covered by fibrous cartilaginous tissue with a more textured and uneven surface. Mosaicplasty is a biological surgical technique, which restores the normal osteocartilaginous architecture of the most part of the grafted area. The transplanted osteocartilaginous cylindrical grafts maintain its viability and mechanical properties. PMID- 21254738 TI - The use of laparoscopic surgery in the treatment of rectal cancer. AB - The use of laparoscopic techniques in the treatment of rectal cancer was until recently regarded with skepticism, because it did not seem to fulfill the oncologic principles of open surgery. The first report of a rectal cancer case treated by using laparoscopy has been made approximately two decades ago. From that moment on, the laparoscopic technique, progressed thanks to the development of the optical devices that allowed the improvement of the laparoscopic image, as well as the progressive increase of experience of the surgical teams specialized in colorectal laparoscopic surgery. These advantages (the faster recovery of the bowel function, less postoperative pain, lower blood loss, decreased hospitalization period) make the laparoscopic surgery a viable option for the treatment of rectal cancer. Recently published studies prove the similar results between open surgery and laparoscopic surgery for rectal cancer, in terms of mortality and postoperative morbidity, local recurrence, long-term survival or postoperative complications (anastomotic fistulas, bladder dysfunction, and sexual dysfunction), some studies even revealing the superiority of the laparoscopic surgery in preserving the function of the pelvic nerves. PMID- 21254740 TI - Deficiencies of proteins C, S and antithrombin and activated protein C resistance -their involvement in the occurrence of Arterial thromboses. AB - Deficiencies of natural anticoagulants protein C, protein S, antithrombin and activated protein C resistance are components of inherited thrombophilia. Inherited thrombophilia was defined as a genetically determined tendency towards venous thromboembolism, which characteristically occurs in young patients (before 40 to 45 years old), without apparent causes, and tend to recur. There have been many debates about the implication of these defects in arterial thromboses (peripheral artery disease, myocardial infarction, cerebral infarction) in the recent years. The screening for thrombophilia is recommended for young patients with spontaneous thromboses, arterial infarctions, family history of thromboses, personal history of recurrent abortions, with thrombosis of venous dural sinuses or strokes or myocardial infarctions, in patients with venous thrombosis in unusual sites, because the diagnosis of such a disease leads to a treatment that is lifesaving [1,2]. PMID- 21254741 TI - Serum levels of adipokines resistin and leptin in patients with colon cancer. AB - Adipose tissue displays characteristics of an endocrine organ releasing a number of adipocyte-specific factors known as adipocytokines. It has been recently suggested that adipocytokines may play a role in pathogenesis and progression of certain cancers, in particular in colorectal cancer. The aim of this study was to investigate the association between several blood adipocytokine levels and clinicopathological characteristics of colon cancer patients undergoing surgery. The study group comprised of 29 patients who underwent surgical resection for colon cancer at Emergency University Hospital Bucharest and 27 healthy volunteers. The serum levels of adipocytokines were measured using multianalyte xMap profiling technology (Luminex). Resistin levels were significantly higher in colon cancer patients while leptin serum levels were significantly lower as compared to controls. Leptin levels decreased gradually with tumor stage and aggressiveness. Taken together, these results of this study suggest that adipokines, in particular resistin and leptin may be involved in development and progression of colon cancer. PMID- 21254742 TI - Heart failure--concepts and significance. Birth of a prognostic model. AB - Heart failure (HF) is a syndrome characterized by high prevalence in society, frequent hospitalization, reduced quality of life and high mortality (overall, 50% of patients are dead at an interval of 4 years, annual mortality varying from 5% to 75%). Outcomes in heart failure are highly variable, prognosis of individual patients differs considerably and trial data, though valuable, does not often give an adequate direction. Taking into account the high prevalence of heart failure in society and its complexity physicians need a model to predict the risk of death, to estimate the survival of heart failure patients. A key element of interest in this area is the survival function, usually noted by S and defined as S(t) = exp(-H0(t)e(a)Tx) = e(-H)0(t)e(a)Tx. PMID- 21254743 TI - Green paper on bio-preparedness--general comments. AB - The Commission's Green Paper on Bio-preparedness represents an important signal that the European Commission is actively involved in, working on issues related to bio-preparedness across all Member States and the international Community. In 2006, the Commission held two seminars on European Bio Preparedness and a workshop on Transport and Traceability of Bio materials. The results and recommendations emerging from these discussions have been inserted in this Green Paper. The document intends to stimulate a debate within and between the Member States and to launch a process of consultation on how to reduce biological risks and to enhance preparedness and response. All the national authorities responsible for risk prevention and response, human, animal and plant health, customs, civil protection, law enforcement authorities, the military, bio industry, epidemiological and health communities, academic institutions and bioresearch institutes are therefore called to be involved, to contribute and to improve the ability of the EU to prevent, respond to and recover from a biological incident or deliberate criminal activity. PMID- 21254744 TI - Case report. Gelastic seizures in a patient with right gyrus cinguli astrocytoma. AB - OBJECTIVE AND IMPORTANCE: Gelastic seizure (GS) also known as "gelastic epilepsy" is a rare type of seizure associated with several different conditions such as tumors--hypothalamic hamartromas, tuberous sclerosis, hemangiomas, post infectious foci, cortical temporal dysplasia. We report one case of this rare condition generated by a right gyrus cinguli gr. II astrocytoma. CLINICAL PRESENTATION: A 27 year-old male, right handed, was admitted for a 2 years history of very frequent gelastic seizures accompanied sometimes by simple motor partial seizures in both arms, more often being involved his left arm, without impairment of his consciousness state. His neurological examination was normal. Diagnosis was made on native CT scan: minimal hypodense frontal right paramedian lesion, cerebral MRI showed a small well delimited right, parenchymal, homogeneous lesion (16/22/15 mm), involving gyrus cinguli, without perilesional edema and mass effect, hyperintense both on T1 and T2 MR sequences, non-enhancing after Gadolinium. The cerebral lesion was also documented on EEG and video-EEG recordings. Using an interhemispheric microsurgical approach, above the corpus callosum and the right pericallosal artery, at the level of gyrus cinguli, a yellow-gray, infiltrative tumor, having a moderate vascularisation, has been identified and totally removed. The anatomopathological analysis revealed a grade II astrocytoma. The patient recovered very well, without deficits, no gelastic seizures or epileptic manifestations; three months after operation he is still free of seizures. CONCLUSION: A case of gelastic seizures accompanied by simple motor partial seizures in both arms, without the impairment of his consciousness state induced by a grade II right gyrus cinguli astrocytoma is described and documented by radiological and electrophysiological studies. Using microsurgical resection, the tumor was totally removed, the patient clinical condition improved. Without an affective connotation as in temporal or hypothalamus topography, gelastic seizures are not patognomonic for hypothalamic hamartomas and in the case of frontal localization of the lesion; they can be associated with motor involvement of the limbs as in our case. PMID- 21254745 TI - A late and difficult diagnosis of ochronosis. AB - Alkaptonuria is a rare autosomal recessive disorder of metabolism caused by deficiency of homogentisic acid oxidase and resulting in accumulation of homogentisic acid in collagenous structures. This causes the classic clinical triad: (1) homogentisic aciduria (urine blackens on standing when oxidized or alkalinized); (2) eumelanin-like pigmentation of skin, sclera, cartilages, etc and (3) degenerative ochronic arthropathies usually in the fourth decade of life. Other important but more rare consequences of alkaptonuric ochronosis are cardiovascular and urinary tract involvement. We present a case of ochronosis with multiple visceral involvement: skin (fingers, ear sclera), severe spondylarthropaty with extensive calcifications of intervertebral discs and reduced mobility, osteoarthritis of both knees, right hip ostonecrosis, cardiovascular involvement (severe stenosis and insufficiency of aortic valve that) and urinary tract involvement (nephrolitiasis) PMID- 21254746 TI - Forequarter amputation (upper limb and shoulder girdle) in a synovial sarcoma case--case report. AB - We are often confronted with severe cases - patients with very aggressive tumours that suppose a complex and in the same time radical approach--in our medical practice. The correct approach and management of such cases ensure both the surgical success and the patient survival. In this paper, we present the case of a young woman, who has been admitted in our clinic with a giant, irradiated tumour involving left axilla, shoulder and scapula. Due to the vast size of the tumour and to the fact that surgical biopsy revealed a poorly differentiated sarcoma; other clinics considered that the case above belongs to surgical therapy. After the clinical examination, blood tests and diagnostic imaging, which allowed the correct evaluation of the case--tumour sizes and neighbouring tissue reports--we decided to perform tumour radical excision, respectively forequarter amputation, when the patient presented a satisfactory metabolic status. The presented case supports the idea that radical excision which might involve even mutilating amputations for extensive cancers can give patients a chance, even in desperate cases. PMID- 21254747 TI - Occupational burnout levels in emergency medicine--a stage 2 nationwide study and analysis. AB - INTRODUCTION: The first stage of this nationwide study and analysis of the occupational burnout and psychological risk parameters showed a high consistency of emotional exhaustion, depersonalization and low personal accomplishment for doctors working in Emergency Departments and Emergency and Resuscitation Services. These workers were then set in the highest risk group for burnout syndrome and depression. This stage II of our research will focus on those two groups analyzing causal factors, coping mechanisms and possible repercussions of these findings. MATERIAL AND METHODS: DEMOGRAPHICS: We have issued a total of 272 surveys from which we have received a total of 263 complete and valid ones (n = 263, response rate = 96, 69%). INSTRUMENTS: The Maslach Burnout Inventory- Human Services Survey MBI-HSS is an instrument designed to assess the three components of the burnout syndrome: emotional exhaustion (EE), depersonalization (DP), and reduced personal accomplishment (PA). The COPE questionnaire is a 52 item addressing different ways of coping with stress. The Center for Epidemiologic Studies Depression Scale (CES-D) has been shown to be a reliable measure in assessing the number, types, and duration of depressive symptoms across racial, gender, and age categories. RESULTS AND DISCUSSION: Results were not correlated with gender, age or marital status, but an important correlation was found with professional experience in the Emergency Departments. We have shown that during the first 4 years of experience, the EE factor has been at a satisfying average of 2.4, this variable rising to an average of 2.85 after another 3 years of work. The same type of correlation was found with the CES-D results. CONCLUSIONS: Of the two surveyed groups, the EMD group showed higher values for all risk parameters and low personal accomplishment on the MBI-HSS survey. Also, emotional exhaustion and depression were found to have a powerful correlation with work experience. Coping mechanisms were found to be invariable to the general population, with a slight incline towards active coping and behavioral disengagement. PMID- 21254748 TI - Methylenetetrahydrofolate dehydrogenase (MTHFD) enzyme polymorphism as a maternal risk factor for trisomy 21: a clinical study. AB - Recent reports linking Down syndrome (DS) to maternal polymorphism at the methylenetetrahydrofolate dehydrogenase (MTHFD) locus have generated a great interest among investigators in the field. In the current study, we examine one genetic polymorphism involved in homocysteine/folate pathway as a risk factor for DS in a Romanian urban-area women cohort. Our results show that the frequencies of MTHFD1 alleles, as well as the frequencies of MTHFD11958 genotypes (GG, GA, AA, GA+AA) do not correlate with DS pregnancies, demonstrating no difference between the case and control groups, as opposed to the findings of Scala et al. (2006) on an Italian cohort. PMID- 21254750 TI - Importance of basic life support training for first and second year medical students--a personal statement. AB - INTRODUCTION: Current studies show that there is a significant lack of knowledge regarding the typical signs and risk factors associated with serious medical conditions among medical students and laypersons. Basic life support consists of a number of medical procedures provided to patients with life threatening conditions of the body that cause pain or dysfunction to the person. FURTHER DEVELOPMENTS: In spite of the fact that this programme is not included in the curricula, students might receive this information from various persons, even though these persons are not specialized in the domain of giving first aid. Learning medicine without placing patients at an increased risk of complications is of utmost importance in the medical profession. High-fidelity patient simulators can potentially achieve this, and, therefore they are increasingly used in the training of medical students. Recent studies regarding simulation training show that the simulation-based intervention offers a positively evaluated possibility to enhance students' skills in recognizing and handling emergencies improving the ability to manage medical emergencies. CONCLUSION: Understanding BLS courses and more than that, practicing these techniques is by far the most challenging task confronting first aid. Taking everything into consideration, we believe that an adequate education in first aid and basic life support should be considered an essential aspect of the medical curriculum. PMID- 21254749 TI - Low self-esteem in women with eating disorders and alcohol abuse as a psycho social factor to be included in their psychotherapeutic approach. AB - Authors have analyzed the psychosocial peculiarities of the women from Romania who are affected by eating disorders and alcohol excessive consumption, and studied the manner of the link between these diseases and the psychosexual. 120 participants at the study (Oltenia district) were divided into 2 groups: 60 healthy women, 30 with eating disorders and 30 alcohol dependent women. In all subjects were applied the following tests: Scale for compulsive appetite (SCA) and Scale of interest for own weight, both for eating disorders, CAGE questionnaire for alcohol dependence and two scales for determining: the gender role ambivalence (O'Neil and Caroll Scale) and the masculinity and feminity index (A. Chelcea). The results obtained in both lots of Romanian women with pathologic behavior (food and/or alcohol consumption) have indicated a low psychosexual identity versus control group but no correlation with masculinity/feminity index. PMID- 21254751 TI - Gold(III) N-heterocyclic carbene complexes mediated synthesis of beta-enaminones from 1,3-dicarbonyl compounds and aliphatic amines. AB - A series of gold(III) N-heterocyclic carbene complexes [1-(R(1))-3-(R(2))imidazol 2-ylidene]AuBr(3) [R(1) = i-Pr, R(2) = CH(2)Ph (1c); R(1) = mesityl, R(2) = CH(2)Ph (2c); R(1) = i-Pr, R(2) = CH(2)COt-Bu (3c), and R(1) = t-Bu, R(2) = CH(2)COt-Bu (4c)] act as effective precatalysts in the synthesis of beta enaminones from 1,3-dicarbonyl compounds and primary amines under ambient conditions. Specifically the 1c-4c complexes efficiently catalyzed the condensation of a variety of cyclic as well as acyclic 1,3-dicarbonyl compounds, namely, acetyl acetone, benzoylacetone, 2-acetylcyclopentanone, and ethyl-2 oxocyclopentanecarboxylate with primary aliphatic amines, viz., methylamine, ethylamine, n-propylamine, i-propylamine, and n-butylamine, yielding beta enamines at room temperature. Interestingly enough, the more electrophilic gold(III) 1c-4c complexes exhibited superior activity in comparison to the gold(I) counterparts 1b-4b. A comparison along a representative 4a-c series further underscored the importance of gold in the reaction as both the gold(I) 4b and gold(III) 4c complexes were more effective than the silver analogue 4a. The density functional theory (DFT) study revealed that the strong sigma-donating nature of the N-heterocyclic carbene ligand results in a strong C(carbene) Au(III) interaction in the 1c-4c complexes. PMID- 21254752 TI - Heterometallic cubanes: syntheses, structures, and magnetic properties of lanthanide(III)-nickel(II) architectures. AB - Reactions of lanthanide(III) perchlorate (Ln = Dy, Tb, and Gd), nickel(II) acetate, and ditopic ligand 2-(benzothiazol-2-ylhydrazonomethyl)-6-methoxyphenol (H(2)L) in a mixture of methanol and acetone in the presence of NaOH resulted in the successful assembly of novel Ln(2)Ni(2) heterometallic clusters representing a new heterometallic 3d-4f motif. Single-crystal X-ray diffraction reveals that all compounds are isostructural, with the central core composed of distorted [Ln(2)Ni(2)O(4)] cubanes of the general formula [Ln(2)Ni(2)(MU(3) OH)(2)(OH)(OAc)(4)(HL)(2)(MeOH)(3)](ClO(4)).3MeOH [Ln = Dy (1), Tb (2), and Gd (3)]. The magnetic properties of all compounds have been investigated. Magnetic analysis on compound 3 indicates ferromagnetic Gd...Ni exchange interactions competing with antiferromagnetic Ni...Ni interactions. Compound 1 displays slow relaxation of magnetization, which is largely attributed to the presence of the anisotropic Dy(III) ions, and thus represents a new discrete [Dy(2)Ni(2)] heterometallic cubane exhibiting probable single-molecule magnetic behavior. PMID- 21254753 TI - Protonation of base pairs in RNA: context analysis and quantum chemical investigations of their geometries and stabilities. AB - Base pairs involving protonated nucleobases play important roles in mediating global macromolecular conformational changes and in facilitation of catalysis in a variety of functional RNA molecules. Here we present our attempts at understanding the role of such base pairs by detecting possible protonated base pairs in the available RNA crystal structures using BPFind software, in their specific structural contexts, and by the characterization of their geometries, interaction energies, and stabilities using advanced quantum chemical computations. We report occurrences of 18 distinct protonated base pair combinations from a representative data set of RNA crystal structures and propose a theoretical model for one putative base pair combination. Optimization of base pair geometries was carried out at the B3LYP/cc-pVTZ level, and the BSSE corrected interaction energies were calculated at the MP2/aug-cc-pVDZ level of theory. The geometries for each of the base pairs were characterized in terms of H-bonding patterns observed, rmsd values observed on optimization, and base pair geometrical parameters. In addition, the intermolecular interaction in these complexes was also analyzed using Morokuma energy decomposition. The gas phase interaction energies of the base pairs range from -24 to -49 kcal/mol and reveal the dominance of Hartree-Fock component of interaction energy constituting 73% to 98% of the total interaction energy values. On the basis of our combined bioinformatics and quantum chemical analysis of different protonated base pairs, we suggest resolution of structural ambiguities and correlate their geometric and energetic features with their structural and functional roles. In addition, we also examine the suitability of specific base pairs as key elements in molecular switches and as nucleators for higher order structures such as base triplets and quartets. PMID- 21254754 TI - Evidence of the controlled interaction between PEDOT and PSS in the PEDOT:PSS complex via concentration changes of the complex solution. AB - Photoluminescence, electronic absorption, and pH studies of a poly(ethylene-3,4 dioxythiophene):poly(styrenesulfonic acid) (PEDOT:PSS) dispersion as a function of the PEDOT:PSS concentration are shown to provide a better understanding of the effect of PSS on the intramolecular conductivity of PEDOT chains. Particularly, concentration changes of PEDOT:PSS were found to be accompanied with different extents of dissociation of protons in the solution and different charge states of PSS chains, respectively, which affect the electrostatic interaction between PSS and PEDOT and intramolecular conductivity in the PEDOT backbone. PMID- 21254755 TI - Gram scale synthesis of the C(18)-C(34) fragment of amphidinolide C. AB - The synthesis of the C(18)-C(34) fragment of amphidinolide C has been achieved via two routes, culminating in both the shortest (11 steps) and highest yielding (26% overall yield) approaches to this segment. The highly convergent approach will facilitate the synthesis of analogues, including the C(18)-C(29) fragment of amphidinolide F. Synthetic highlights include the selective methylation of a diyne, and the highly efficient use of a second generation cobalt catalyst in the Mukaiyama oxidative cyclization to form the trans-THF ring. PMID- 21254756 TI - Copper-binding properties and structures of methanobactins from Methylosinus trichosporium OB3b. AB - Methanobactins (mbs) are a class of copper-binding peptides produced by aerobic methane oxidizing bacteria (methanotrophs) that have been linked to the substantial copper needs of these environmentally important microorganisms. The only characterized mbs are those from Methylosinus trichosporium OB3b and Methylocystis strain SB2. M. trichosporium OB3b produces a second mb (mb-Met), which is missing the C-terminal Met residue from the full-length form (FL-mb). The as-isolated copper-loaded mbs bind Cu(I). The absence of the Met has little influence on the structure of the Cu(I) site, and both molecules mediate switchover from the soluble iron methane mono-oxygenase to the particulate copper containing enzyme in M. trichosporium OB3b cells. Cu(II) is reduced in the presence of the mbs under our experimental conditions, and the disulfide plays no role in this process. The Cu(I) affinities of these molecules are extremely high with values of (6-7) * 10(20) M(-1) determined at pH >= 8.0. The affinity for Cu(I) is 1 order of magnitude lower at pH 6.0. The reduction potentials of copper loaded FL-mb and mb-Met are 640 and 590 mV respectively, highlighting the strong preference for Cu(I) and indicating different Cu(II) affinities for the two forms. Cleavage of the disulfide bridge results in a decrease in the Cu(I) affinity to ~9 * 10(18) M(-1) at pH 7.5. The two thiolates can also bind Cu(I), albeit with much lower affinity (~ 3 * 10(15) M(-1) at pH 7.5). The high affinity of mbs for Cu(I) is consistent with a physiological role in copper uptake and protection. PMID- 21254757 TI - Effect of solvent and counterions upon structure and NMR spin-spin coupling constants in heparin disaccharide. AB - Density functional theory (DFT) has been used to analyze structure and NMR spin spin coupling constants in heparin disaccharide. Both B3LYP/6-311++G** and M05 2X/6-311++G** methods have been used for optimization of disaccharide geometry. Solvent effect was treated by use of explicit water molecules. Solvent-caused variations of DFT-computed indirect one-bond proton-carbon coupling constants up to 17 Hz between isolated and solvated states, however, had a limited influence upon magnitudes of proton-proton spin-spin coupling constants. Interatomic distances and bond and torsion angles indicated that the structure of the 2-O sulfated iduronic acid residue affected the geometry of the N,6-sulfated glucosamine residue. Optimized disaccharide geometry showed that the change of counterion (Ca(2+) instead of Na(+)) influenced geometry of pyranose rings and the glycosidic linkage conformation. DFT-computed three-bond proton-proton spin spin coupling constants agreed well with published experimental data and indicated that the population of the (1)C(4) chair form of the 2-O-sulfated iduronic acid residue increased in the presence of Ca(2+) ions compared to the presence of Na(+) ions. Analysis also showed that the Fermi contact term was not always dominant and that paramagnetic and diamagnetic contributions considerably influenced magnitudes of proton-proton spin-spin coupling constants. PMID- 21254758 TI - Experimental and computational investigation of the sII binary He-THF hydrate. AB - The objective of this work is to study the binary He-THF hydrate with both experimental and theoretical approaches. Experimental data for the hydrate equilibrium at pressures up to 12.6 MPa are reported for the binary He-THF hydrate with stoichiometric THF composition (i.e., 5.56 mol % THF). These data are used to calibrate a thermodynamic model [J. Phys. Chem. C2009, 113, 422] for the prediction of hydrate equilibrium that is based on the van der Waals Platteeuw statistical thermodynamic theory. Then this model is used to extrapolate the obtained experimental data to much higher pressures, and good agreement is observed with other available experimental data at pressures up to 150 MPa. This model is also capable of estimating the cavity occupancies for He and THF. The results show that the large cavities are completely occupied by THF molecules, whereas the small ones are partially occupied by He atoms. The He occupancy of the small cavities is less than 60%, even at high pressures (100 MPa). The occupancies predicted from this model are in close agreement with similar results from molecular simulations and a previously reported thermodynamic approach. PMID- 21254759 TI - Thermosolutal self-organization of supramolecular polymers into nanocraters. AB - The ability of two complementary molecular modules bearing H-bonding uracilic and 2,6-(diacetylamino)pyridyl moieties to self-assemble and self-organize into submicrometer morphologies has been investigated by means of spectroscopic, thermogravimetric, and microscopic methods. Using uracilic (3)N-BOC-protected modules, it has been possible to thermally trigger the self-assembly/self organization process of the two molecular modules, inducing the formation of objects on a mica surface that exhibit crater-like morphology and a very homogeneous size distribution. Confirmation of the presence of the hydrogen bonding-driven self-assembly/self-organization process in solution was obtained by variable-temperature (VT) steady-state UV-vis absorption and emission measurements. The variation of the geometric and spatial features of the morphologies was monitored at different T by means of atomic force microscopy (AFM) and was interpreted by a nonequilibrium diffusion model for two chemical species in solution. The formation of nanostructures turned out to be affected by the solid substrate (molecular interactions at a solid-liquid interface), by the matter-momentum transport in solution (solute diffusivity D(0) and solvent kinematic viscosity nu), and the thermally dependent cleavage reaction of the BOC functions (T-dependent differential weight loss, theta = theta(Tau)) in a T interval extrapolated to ~60 K. A scaling function, f = f (nuD(0), nu/D(0), theta), relying on the onset condition of a concentration-driven thermosolutal instability has been established to simulate the T-dependent behavior of the structural dimension (i.e., height and radius) of the self-organized nanostructures as ?h? ~ f (T) and ?r? ~ 1/f (T). PMID- 21254760 TI - Andromeda: a peptide search engine integrated into the MaxQuant environment. AB - A key step in mass spectrometry (MS)-based proteomics is the identification of peptides in sequence databases by their fragmentation spectra. Here we describe Andromeda, a novel peptide search engine using a probabilistic scoring model. On proteome data, Andromeda performs as well as Mascot, a widely used commercial search engine, as judged by sensitivity and specificity analysis based on target decoy searches. Furthermore, it can handle data with arbitrarily high fragment mass accuracy, is able to assign and score complex patterns of post-translational modifications, such as highly phosphorylated peptides, and accommodates extremely large databases. The algorithms of Andromeda are provided. Andromeda can function independently or as an integrated search engine of the widely used MaxQuant computational proteomics platform and both are freely available at www.maxquant.org. The combination enables analysis of large data sets in a simple analysis workflow on a desktop computer. For searching individual spectra Andromeda is also accessible via a web server. We demonstrate the flexibility of the system by implementing the capability to identify cofragmented peptides, significantly improving the total number of identified peptides. PMID- 21254761 TI - Versatile scheme for the step-by-step assembly of nanoparticle multilayers. AB - A versatile scheme for the preparation of nanoparticle (NP) multilayers is presented. The method is based on the step-by-step assembly of NPs and bishydroxamate disulfide ligand molecules by means of metal-organic coordination using easily synthesized tetraoctylammonium bromide (TOAB)-stabilized gold NPs. The assembly of NP multilayers was carried out via a Zr(IV)-coordinated sandwich arrangement of the hydroxamate ligands on Au and glass surfaces. The latter were precoated with electrolessly deposited Au clusters to enable binding of the first NP layer. The new method avoids the need to perform elaborate colloid reactions to prepare the NP building blocks. Au NP monolayer and multilayer films prepared in this manner were characterized by UV-vis spectroscopy, atomic force microscopy (AFM), and cross-sectional transmission electron microscopy (TEM), showing a regular growth of NP layers. The use of coordination chemistry as the binding motif between repeat layers allows for the convenient assembly of hybrid nanostructures comprising molecular and NP components. This was demonstrated by the construction of Au NP multilayers with controlled spacing from the surface or between two NP layers. Drying the samples during or after the construction process induces NP aggregation and changes in the film morphology and optical properties. PMID- 21254762 TI - Theoretical modeling of molecular spectra parameters of disubstituted diacetylenes. AB - Symmetrically disubstituted diacetylenes, X-C=C-C=C-X, were studied computationally by using the DFT B3LYP/aug-cc-pVDZ method. For more than 35 substituents the bond lengths, charge density and Laplacian in bond critical points, C=C stretching vibrational frequencies, (13)C NMR chemical shifts and spin-spin CC coupling constants through diacetylene moiety were calculated and examined by using the substituent sEDA and pEDA descriptors. It is demonstrated that in disubstituted diacetylenes the triple bond length increases with the electron donating and decreases with the electron withdrawing properties of the substituents. The sigma-electron repulsion is likely to be responsible for this phenomenon. The electron density of the C-X bond critical point decreases linearly with an increase of the sigma-electron donating properties, whereas the Laplacian of electron density in the C=C bond critical point increases as the sEDA descriptor i.e., sigma-electron donating properties of the substituent, are increased. Thus, rho(C=C) is locally reduced with an increase of sEDA. The nu(as)(C=C) and nu(s)(C=C) mode frequencies decrease with the electron donating and increase with the electron withdrawing properties of the substituents. The calculated chemical shift of the C1-atom, to which the substituent is attached, does not correlate with the substituent descriptors, whereas the delta(C2) deshielding increases when the sigma-electron donating properties and C=C distance are increased. The calculated (1)J(CC) coupling constants decrease with an increase of the triple bond length, the sEDA parameter, and rho(C-X), whereas they decrease with Laplacian in the C=C BCP. PMID- 21254763 TI - Computational study of the free energy landscape of the miniprotein CLN025 in explicit and implicit solvent. AB - The prediction capabilities of atomistic simulations of peptides are hampered by different difficulties, including the reliability of force fields, the treatment of the solvent or the adequate sampling of the conformational space. In this work, we have studied the conformational profile of the 10 residue miniprotein CLN025 known to exhibit a beta-hairpin in its native state to understand the limitations of implicit methods to describe solvent effects and how these may be compensated by using different force fields. For this purpose, we carried out a thorough sampling of the conformational space of CLN025 in explicit solvent using the replica exchange molecular dynamics method as a sampling technique and compared the results with simulations of the system modeled using the analytical linearized Poisson-Boltzmann (ALPB) method with three different AMBER force fields: parm94, parm96, and parm99SB. The results show the peptide to exhibit a funnel-like free energy landscape with two minima in explicit solvent. In contrast, the higher minimum nearly disappears from the energy surface when the system is studied with an implicit representation of the solvent. Moreover, the different force fields used in combination with the ALPB method do not describe the system in the same manner. The results of this work suggest that the balance between intra- and intermolecular interactions is the cause of the differences between implicit and explicit solvent simulations in this system, stressing the role of the environment to define properly the conformational profile of a peptide in solution. PMID- 21254764 TI - Production of a PEGylated Fab' of the anti-LINGO-1 Li33 antibody and assessment of its biochemical and functional properties in vitro and in a rat model of remyelination. AB - The use of LINGO-1 antagonists to promote repair of damaged myelin is an emerging therapeutic opportunity for treatment of CNS diseases caused by demyelination such as multiple sclerosis. The Li33 anti-LINGO-1 antibody is a potent inducer of myelination in vitro and in vivo, but aggregation issues prevented the engineering of an optimal development candidate. PEGylated Li33 Fab' is one of several versions of the Li33 antibody that is being investigated in an attempt to identify the most favorable anti-LINGO-1 antibody design. For targeted PEGylation, a Li33 Fab' construct was engineered with a single unpaired cysteine in the heavy-chain hinge sequence. The Fab' was expressed in CHO cells, purified, and PEGylated with 20 kDa methoxy-poly(ethylene glycol) maleimide using a reaction strategy optimized to improve the yield of the PEG-Fab'. Biochemical analysis of the Li33 PEG-Fab' verified the selectivity of the PEGylation reaction. The in vitro and in vivo attributes of the PEG-Fab' were benchmarked against a Li33 full antibody. Both the Li33 PEG-Fab' and intact antibody bound LINGO-1 with nanomolar affinity, promoted myelination in an in vitro signaling assay, and promoted the repair of damaged myelin in the rat lysolecithin model. These studies extend our understanding of the biological activity of the Li33 mAb and validate the use of an anti-LINGO-1 PEG-Fab' for treatment of CNS diseases caused by demyelination. PMID- 21254765 TI - Immobilization of stable thylakoid vesicles in conductive nanofibers by electrospinning. AB - Electrospun fibers consisting of poly(3,4-ethylenedioxythiophene)/poly(styrene sulfonate) (PEDOT/PSS) and poly(ethylene oxide) (PEO) have been used to successfully encapsulate and stabilize thylakoid membrane vesicles isolated from spinach. Light-driven electronic properties were measured. Fibers with immobilized thylakoids show higher electrical conductivity compared with fibers without thylakoids under white light conditions. This is attributed to the electron-generating photosynthetic reactions from the thylakoids. Electron and optical microscopy show the presence of thylakoid vesicles within the fibers using lipid-specific stains. After electrospinning into fibers, the thylakoid vesicles still exhibit an ability to produce a light-driven electron gradient, indicating that activity is preserved during the electrospinning process. These electrospun fibers provide an excellent example of incorporating photosynthetic function into an artificial system. PMID- 21254766 TI - Functionalized, biocompatible coating for superparamagnetic nanoparticles by controlled polymerization of a thioglycosidic monomer. AB - It is demonstrated that water-soluble, glucosylated poly(pentafluorostyrene) derivatives revealed favorable coating material properties for magnetic iron oxide nanoparticles. To prepare the coating material in high reproducibility and purity as well as in sufficient amounts, a new route of synthesis is established. The preparation and characterization of the glucosylated, tetrafluorostyryl monomer, by thiol-para-fluorine "click" reaction, and its polymerization, via nitroxide-mediated radical process, is presented in detail. In addition, the coating material and the resulting particle properties are investigated by means of XPS, DLS, TGA, TEM, and cryo-TEM as well as flow cytometry. The glycopolymer acts as an appropriate stabilizing agent for the superparamagnetic nanoparticles by the formation of an approximately 10 nm thick shell, as shown by the XPS analysis. Furthermore, the application of FITC-labeled glycopolymer yielded fluorescent, superparamagnetic nanoparticles, which can be used for monitoring cell-carbohydrate interactions, because these particles show no cytotoxicity toward 3T3 fibroblasts. PMID- 21254768 TI - Molecular simulation of diffusion of hydrogen, carbon monoxide, and water in heavy n-alkanes. AB - The self-diffusion and mutual diffusion coefficients of hydrogen (H(2)), carbon monoxide (CO), and water (H(2)O) in n-alkanes were studied by molecular dynamics simulation. n-Alkane molecules were modeled based on the TraPPE united atom force field. NPT molecular dynamics (MD) simulations were performed for n-C(12) to n C(96) at different temperature and pressure values to validate the accuracy of the force field. In all cases, good agreement was obtained between literature experimental data and model predictions for the density and structure properties of the n-alkanes. Subsequently, the self-diffusion coefficient of the three light components in the various n-alkanes was calculated at different temperatures. Model predictions were in very good agreement with limited experimental data. Furthermore, the Maxwell-Stefan diffusion coefficients of H(2) and CO in two n alkanes, namely n-C(12) and n-C(28), were calculated based on long MD NVT simulations for different solute concentrations in the n-alkanes. Finally, the Fick diffusion coefficient of the components was calculated as a product of the Maxwell-Stefan diffusion coefficient and a thermodynamic factor. The latter was estimated from the statistical associating fluid theory (SAFT). The Fick diffusion coefficient was found to be higher than the Maxwell-Stefan diffusion coefficient for H(2) and CO in n-C(28). The empirical Darken equation was used to estimate the Maxwell-Stefan diffusion coefficient, and calculations were found to be in good agreement with simulation results. PMID- 21254767 TI - Kinetic network study of the diversity and temperature dependence of Trp-Cage folding pathways: combining transition path theory with stochastic simulations. AB - We present a new approach to study a multitude of folding pathways and different folding mechanisms for the 20-residue mini-protein Trp-Cage using the combined power of replica exchange molecular dynamics (REMD) simulations for conformational sampling, transition path theory (TPT) for constructing folding pathways, and stochastic simulations for sampling the pathways in a high dimensional structure space. REMD simulations of Trp-Cage with 16 replicas at temperatures between 270 and 566 K are carried out with an all-atom force field (OPLSAA) and an implicit solvent model (AGBNP). The conformations sampled from all temperatures are collected. They form a discretized state space that can be used to model the folding process. The equilibrium population for each state at a target temperature can be calculated using the weighted-histogram-analysis method (WHAM). By connecting states with similar structures and creating edges satisfying detailed balance conditions, we construct a kinetic network that preserves the equilibrium population distribution of the state space. After defining the folded and unfolded macrostates, committor probabilities (P(fold)) are calculated by solving a set of linear equations for each node in the network and pathways are extracted together with their fluxes using the TPT algorithm. By clustering the pathways into folding "tubes", a more physically meaningful picture of the diversity of folding routes emerges. Stochastic simulations are carried out on the network, and a procedure is developed to project sampled trajectories onto the folding tubes. The fluxes through the folding tubes calculated from the stochastic trajectories are in good agreement with the corresponding values obtained from the TPT analysis. The temperature dependence of the ensemble of Trp-Cage folding pathways is investigated. Above the folding temperature, a large number of diverse folding pathways with comparable fluxes flood the energy landscape. At low temperature, however, the folding transition is dominated by only a few localized pathways. PMID- 21254769 TI - Pentachlorophenol radical cations generated on Fe(III)-montmorillonite initiate octachlorodibenzo-p-dioxin formation in clays: density functional theory and fourier transform infrared studies. AB - Octachlorodibenzodioxin (OCDD) forms spontaneously from pentachlorophenol (PCP) on the surfaces of Fe(III)-saturated smectite clay. (1) Here, we used in situ Fourier transform infrared (FTIR) methods and quantum mechanical calculations to determine the mechanism by which this reaction is initiated. As the clay was dehydrated, vibrational spectra showed new peaks that grew and then reversibly disappeared as the clay rehydrated. First-principle density functional theory calculations of hydrated Fe/PCP clusters reproduced these transient FTIR peaks when inner-sphere complexation and concomitant electron transfer produced Fe(II) and PCP radical cations. Thus, our experimental (FTIR) and theoretical (quantum mechanical) results mutually support the hypothesis that OCDD formation on Fe smectite surfaces is initiated by the reversible formation of metastable PCP radical cations via single-electron transfer from PCP to Fe(III). The negatively charged clay surface apparently selects for this reaction mechanism by stabilizing PCP radical cations. PMID- 21254770 TI - Diaxial diureido decalins as compact, efficient, and tunable anion transporters. AB - Decalins bearing two axial -NHCONHAr substituents and an ester-linked alkyl side chain have been synthesized and studied as anion receptors and transporters. The design relates to steroid-based "cholapods" but is more compact and less intrinsically lipophilic. Transport rates depend on both NHAr and the alkyl side chain. High activities can be achieved; with optimal substitution, chloride nitrate exchange across vesicle membranes is measurable at transporter/lipid ratios as low as 1:250,000. PMID- 21254771 TI - Irreversible chemical reactions visualized in space and time with 4D electron microscopy. AB - We report direct visualization of irreversible chemical reactions in space and time with 4D electron microscopy. Specifically, transient structures are imaged following electron transfer in copper-tetracyanoquinodimethane [Cu(TCNQ)] crystals, and the oxidation/reduction process, which is irreversible, is elucidated using the single-shot operation mode of the microscope. We observed the fast, initial structural rearrangement due to Cu(+) reduction and the slower growth of metallic Cu(0) nanocrystals (Ostwald ripening) following initiation of the reaction with a pulse of visible light. The mechanism involves electron transfer from TCNQ anion-radical to Cu(+), morphological changes, and thermally driven growth of discrete Cu(0) nanocrystals embedded in an amorphous carbon skeleton of TCNQ. This in situ visualization of structures during reactions should be extendable to other classes of reactive systems. PMID- 21254772 TI - Transformable functional nanoscale building blocks with wafer-scale silicon nanowires. AB - Through the fusion of electrostatics and mechanical dynamics, we demonstrate a transformable silicon nanowire (SiNW) field effect transistor (FET) through a wafer-scale top-down approach. By felicitously taking advantage of the proposed electrostatic SiNW-FET with mechanically movable SiNWs, all essential logic gates, including address decoders, can be monolithically integrated into a single device. The unification of various functional devices, such as pn-diodes, FETs, logic gates, and address decoders, can therefore eliminate the complex fabrication issues associated with nanoscale integration. These results represent a step toward the creation of multifunctional and flexible nanoelectronics. PMID- 21254774 TI - Broccoli ( Brassica oleracea var. italica) sprouts and extracts rich in glucosinolates and isothiocyanates affect cholesterol metabolism and genes involved in lipid homeostasis in hamsters. AB - This study investigated the effects of broccoli sprouts (BS) on sterol and lipid homeostasis in Syrian hamsters with dietary-induced hypercholesterolemia. Treatments included freeze-dried BS containing 2 or 20 MUmol of glucoraphanine (BSX, BS10X), glucoraphanine-rich BS extract (GRE), sulforaphane-rich BS extract (SFE), and simvastatin. Each experimental diet was offered to eight animals (male and female) for 7 weeks. Hepatic cholesterol was reduced by BS10X and SFE treatments in all animals. This correlated with a down-regulation of gene expression of sterol regulatory element-binding proteins (SREBP-1 and -2) and fatty acid synthase (FAS) caused by GRE and SFE diets. BS10X caused changes in gene expression in a gender-specific manner; additionally, it increased coprostanol excretion in females. With the same concentration of glucoraphanin, consumption of broccoli sprouts (BS10X) had more marked effects on cholesterol homeostasis than GRE; this finding reinforces the importance of the matrix effects on the bioactivity of functional ingredients. PMID- 21254775 TI - 31P NMR characterization and efficiency of new types of water-insoluble phosphate fertilizers to supply plant-available phosphorus in diverse soil types. AB - Hydroponic plant experiments demonstrated the efficiency of a type of humic acid based water-insoluble phosphate fertilizers, named rhizosphere controlled fertilizers (RCF), to supply available phosphorus (P) to different plant species. This effect was well correlated to the root release of specific organic acids. In this context, the aims of this study are (i) to study the chemical nature of RCF using solid-state (31)P NMR and (ii) to evaluate the real efficiency of RCF matrix as a source of P for wheat plants cultivated in an alkaline and acid soil in comparison with traditional water-soluble (simple superphosphate, SSP) and water-insoluble (dicalcium phosphate, DCP) P fertilizers. The (31)P NMR study revealed the formation of multimetal (double and triple, MgZn and/or MgZnCa) phosphates associated with chelating groups of the humic acid through the formation of metal bridges. With regard to P fertilizer efficiency, the results obtained show that the RCF matrix produced higher plant yields than SSP in both types of soil, with DCP and the water-insoluble fraction from the RCF matrix (WI) exhibiting the best results in the alkaline soil. By contrast, in the acid soil, DCP showed very low efficiency, WI performed on a par with SSP, and RCF exhibited the highest efficiency, thus suggesting a protector effect of humic acid from soil fixation. PMID- 21254776 TI - Formation of Damascenone under both commercial and model fermentation conditions. AB - The fermentations, at a commercial winery, of six different grape musts encompassing the varieties Riesling, Chardonnay, Sauvignon blanc, Shiraz, Grenache, and Pinot noir were monitored for damascenone concentration. In every case, the concentration of damascenone increased during fermentation from low or undetectable levels to concentrations of several parts per billion. Further increases in damascenone concentration were observed during barrel aging of three of these wines. Two ketones, megastigma-4,6,7-triene-3,9-dione (4) and 3 hydroxymegastigma-4,6,7-trien-9-one (5), were synthesized and subjected to fermentation conditions using two yeasts, AWRI 796, and AWRI 1537. In the case of the former compound, 4, synthesis confirmed the original, tentative assignment of the structure and confirmed 4 as a natural product, isolated from honey. Both compounds, under the action of both yeasts, produced appreciable amounts of damascenone (1), with ketone 5 and AWRI 796 yeast yielding the highest concentration of 1. PMID- 21254778 TI - A dynamic open framework exhibiting guest- and/or temperature-induced bicycle pedal motion in single-crystal to single-crystal transformation. AB - A ligand bis(4-imidazol-1-yl-phenyl)diazene (azim) incorporating an azo moiety at the center and two imidazole groups at the terminals forms two coordination polymers {[Co(azim)(2)(DMF)(2)].(ClO(4))(2).2DMF}(n) (1) and {[Cd(azim)(2)(DMF)(2)].(ClO(4))(2).2DMF}(n) (2) (DMF = N,N'-dimethylformamide) at room temperature. Both 1 and 2 are isostructural with rhombic two-dimensional sheets stacking in ABAB... fashion resulting in large voids that contain DMF and ClO(4)- as guests. In 1, the azo groups and phenyl rings are disordered over two positions and as in usual cases, the pedal motion cannot be discerned. Upon heating, 1 turns amorphous. In the case of 2, however, heat treatment does not lead to loss of crystallinity. Thus, when a crystal of 2 (mother crystal) is heated slowly, it causes substantial movement or escape of both metal-bound and lattice DMF besides movement of ClO(4)- anions to give daughter crystals 2a, 2b, and 2c without losing crystallinity (single-crystal to single-crystal (SC-SC) transformation). Most interestingly, the X-ray structures of 2 and its daughter products reveal stepwise reversible bicycle-pedal or crankshaft motion of the azo group. When a crystal of 2c is kept in DMF for 10 h, crystal 2' is formed whose structure is similar to that of 2 with slight changes in the bond distances and angles. Also, crystals of 2 are converted to 3 and 4 upon being kept in acetone or DEF (DEF = N,N'-diethylformamide), respectively, for 10 h at ambient temperature in SC-SC transformation. In 3, each lattice DMF molecule is replaced by an acetone molecule, leaving the two coordinated DMF molecules intact. However, in 4, all lattice and coordinated DMF molecules are replaced by equal number of DEF molecules. Both in 3 and 4, the azo moieties show bicycle-pedal motion. Thus, bicycle-pedal motion that normally cannot be observed is shown here to be triggered by heat as well as guest molecules in SC-SC fashion. PMID- 21254777 TI - Impact of ultrafiltration membrane material on Peptide separation from a snow crab byproduct hydrolysate by electrodialysis with ultrafiltration membranes. AB - Electrodialysis with ultrafiltration membrane (EDUF) is a technology based on the separation of molecules according to their charge and molecular mass. Some works have already successfully demonstrated the recovery of bioactive peptide fractions. However, the impact of ultrafiltration membrane (UFM) material, used in the EDUF system, on the peptide migration has never been studied. Consequently, the objectives of this work were (1) to evaluate the effect of two different UFM materials on the selective separation of peptides from a snow crab byproduct hydrolysate by electrodialysis with ultrafiltration membranes and (2) to determine the effect of UFM material on their potential fouling by peptides. It appeared that, after 6 h of EDUF separation using polyether sulfone (PES) and cellulose acetate (CA) UFM, peptides with low molecular weights ranging from 300 to 700 Da represented the most abundant population in the KCl1 (compartment located near the anode for the recovery of anionic/acid peptide fractions) and KCl2 (compartment located near the cathode for the recovery of cationic/basic peptide fractions) permeates. Peptides with molecular weights ranging from 700 to 900 Da did not migrate during the EDUF treatment. Moreover, only CA UFM allowed the recovery of high molecular weight molecules (900-20000 Da) in both KCl compartments. Peptides desorbed from PES and CA UFM after 6 h of EDUF separation had low molecular weights and belonged mainly to the 600-700 Da molecular weight range. These peptides represented a low proportion of the peptides initially present in the snow crab byproduct hydrolysate with individual molecular weight range proportions from 1.52 +/- 0.31 to 10.2 +/- 2.32%. PMID- 21254779 TI - Truncated versus extended microfilms at a vapor-liquid contact line on a heated substrate. AB - The microstructure of a contact line formed by a liquid and its pure vapor on a perfectly wetted superheated smooth substrate, with the disjoining pressure most often in the form of a positive inverse cubic law (nonpolar case), is routinely considered to end up in a microfilm extended over adjacent "dry" parts of the solid surface. Invoking the spreading coefficient as an additional independent parameter within this framework, we argue however that a regime with a truncated microfilm is chosen instead if the spreading coefficient is decreased below a positive (still perfect wetting) critical value dependent upon the superheat, in which case the extended-microfilm thickness is surpassed by that of the "pancake" introduced by de Gennes and co-workers. Conversely, for a given positive spreading coefficient, there is a critical superheat above which the microfilm gets truncated, whereas for a negative one (partial wetting) the truncated regime should be preferred at any superheat. A parametric study of the apparent contact angle (a nonlinear eigenvalue of the steady microstructure problem) versus the spreading coefficient is carried out. When the latter is negative, Young's law is asymptotically recovered. Microfilm fronts on a bare surface are shown to be advancing or receding in accordance with the selected regime. A slightly more general class of disjoining pressures is also touched upon. The analysis is based in part upon thermodynamic considerations and in part upon a standard one-sided model of an evaporating liquid layer in the lubrication approximation. PMID- 21254780 TI - Voltage sweep ion mobility spectrometry. AB - Ion mobility spectrometry (IMS) is a rapid, gas-phase separation technique that exhibits excellent separation of ions as a standalone instrument. However, IMS cannot achieve optimal separation power with both small and large ions simultaneously. Similar to the general elution problem in chromatography, fast ions are well resolved using a low electric field (50-150 V/cm), whereas slow drifting molecules are best separated using a higher electric field (250-500 V/cm). While using a low electric field, IMS systems tend to suffer from low ion transmission and low signal-to-noise ratios. Through the use a novel voltage algorithm, some of these effects can be alleviated. The electric field was swept from low to high while monitoring a specific drift time, and the resulting data were processed to create a 'voltage-sweep' spectrum. If an optimal drift time is calculated for each voltage and scanned simultaneously, a spectrum may be obtained with optimal separation throughout the mobility range. This increased the resolving power up to the theoretical maximum for every peak in the spectrum and extended the peak capacity of the IMS system, while maintaining accurate drift time measurements. These advantages may be extended to any IMS, requiring only a change in software. PMID- 21254781 TI - Electron paramagnetic resonance (EPR) study of spin-labeled camptothecin derivatives: a different look of the ternary complex. AB - Camptothecin (CPT) derivatives are clinically effective poisons of DNA topoisomerase I (Top1) able to form a ternary complex with the Top1-DNA complex. The aim of this investigation was to examine the dynamic aspects of the ternary complex formation by means of site-directed spin labeling electron paramagnetic resonance (SDSL-EPR). Two semisynthetic CPT derivatives bearing the paramagnetic moiety were synthesized, and their biological activity was tested. A 22-mer DNA oligonucleotide sequence with high affinity cleavage site for Top1 was also synthesized. EPR experiments were carried out on modified CPT in the presence of DNA, of Top1, or of both. In the last case, a slow motion component in the EPR signal appeared, indicating the formation of the ternary complex. Deconvolution of the EPR spectrum allowed to obtain the relative drug amounts in the complex. It was also possible to demonstrate that the residence time of CPT "trapped" in the ternary complex is longer than hundreds of microseconds. PMID- 21254784 TI - Two-phase synthesis of colloidal annular-shaped Ce(x)La(1-x)CO3OH nanoarchitectures assembled from small particles and their thermal conversion to derived mixed oxides. AB - Undoped and cerium doped LaCO(3)OH annular-shaped nanoarchitectures with high specific surface area have been fabricated via the thermolysis of Ce(x)La(1 x)(oleate)(3) (x = 0-20 mol %) complexes in a toluene-water system containing tert-butylamine/oleylamine. The products exhibit 400 nm-sized monodisperse annular-shaped nanoarchitectures, which are constituted of 3-5 nm-sized primary particles. A possible mechanism of the reaction of Ce(x)La(1-x)(oleate)(3) and tert-butylamine for the formation of annular-shaped Ce(x)La(1-x)CO(3)OH nanoarchitectures is proposed. The thermal conversion of Ce(x)La(1-x)CO(3)OH to Ce(x)La(1-x)(CO(3))O(2) at 600 degrees C, to Ce(x)La(1-x)(OH)(3) at 800 degrees C, final to (Ce(x)La(1-x))(2)O(3-delta) at 900 degrees C were employed, while the original morphology was essentially unchanged. The dopant concentration was varied from 5 to 20 of cerium ions per LaCO(3)OH nanoparticle. The X-ray diffraction (XRD) results reveal that the cerium dopant could enter easily into the LaCO(3)OH structural lattice, whereas copper could unlikely enter into their lattice because of their large ionic radius difference. The cerium oxidation state was controlled by changing doping concentration. The X-ray photoelectron spectroscopy (XPS) results reveal that only one Ce(3+) oxidation state is in the as-synthesized Ce(x)La(1-x)CO(3)OH samples with cerium concentration ranging from 5 to 20 mol %, whereas both 3+ and 4+ ones coexisted in 20 mol % Ce:LaCO(3)OH structure. Remarkable luminescence emission intensity enhancement of 1.5-9.0 times were observed for Ce(x)La(1-x)CO(3)OH samples with cerium concentration ranging from 5 to 20 mol %, after doping with an undoped LaCO(3)OH. PMID- 21254782 TI - Negatively cooperative binding of high-density lipoprotein to the HDL receptor SR BI. AB - Scavenger receptor class B, type I (SR-BI), is a high-density lipoprotein (HDL) receptor, which also binds low-density lipoprotein (LDL), and mediates the cellular selective uptake of cholesteryl esters from lipoproteins. SR-BI also is a coreceptor for hepatitis C virus and a signaling receptor that regulates cell metabolism. Many investigators have reported that lipoproteins bind to SR-BI via a single class of independent (not interacting), high-affinity binding sites (one site model). We have reinvestigated the ligand concentration dependence of (125)I HDL binding to SR-BI and SR-BI-mediated specific uptake of [(3)H]CE from [(3)H]CE HDL using an expanded range of ligand concentrations (<1 MUg of protein/mL, lower than previously reported). Scatchard and nonlinear least-squares model fitting analyses of the binding and uptake data were both inconsistent with a single class of independent binding sites binding univalent lipoprotein ligands. The data are best fit by models in which SR-BI has either two independent classes of binding sites or one class of sites exhibiting negative cooperativity due to either classic allostery or ensemble effects ("lattice model"). Similar results were observed for LDL. Application of the "infinite dilution" dissociation rate method established that the binding of (125)I-HDL to SR-BI at 4 degrees C exhibits negative cooperativity. The unexpected complexity of the interactions of lipoproteins with SR-BI should be taken into account when interpreting the results of experiments that explore the mechanism(s) by which SR-BI mediates ligand binding, lipid transport, and cell signaling. PMID- 21254783 TI - Site-directed alkylation studies with LacY provide evidence for the alternating access model of transport. AB - In total, 59 single Cys-replacement mutants in helix VII and helix X of the lactose permease of Escherichia coli were subjected to site-directed fluorescence labeling in right-side-out membrane vesicles to complete the testing of Cys accessibility or reactivity. For both helices, accessibility/reactivity is relatively low at the level of the sugar-binding site where the helices are tightly packed. However, labeling of Cys substitutions in helix VII with tetramethylrhodamine-5-maleimide decreases from the middle toward the cytoplasmic end and increases toward the periplasmic end. Helix X is labeled mainly on the side facing the central hydrophilic cavity with relatively small or no changes in the presence of ligand. In contrast, sugar binding causes a significant increase in accessibility/reactivity at the periplasmic end of helix VII. When considered with similar findings from N-ethylmaleimide alkylation studies, the results confirm and extend support for the alternating access model. PMID- 21254785 TI - Proteomic discovery of genistein action in the rat mammary gland. AB - Genistein, the primary isoflavone component of soy, consumed in diet during the prepubertal period suppresses chemically induced mammary cancer in rats. The current study used two-dimensional gel electrophoresis (2-DE)/MS-based proteomic technology to identify proteins responsible for genistein breast cancer protection In Vivo. Female offspring were exposed via lactating dams treated with 250 mg genistein/kg AIN-76A diet from days 1 to 21 postpartum (prepubertal period). Mammary glands were collected at 21 and 50 day of age and subjected to 2 DE/MS and immuno-blot analyses. Twenty-three proteins were determined to be differentially regulated (p < 0.05) and identified using 2-DE, followed by MALDI TOF/TOF or LC-ESI-MS/MS. Five of these proteins were validated by immuno-blots. Annexin A2 was significantly increased at 21 days yet found to be decreased at 50 days. Fetuin B was found to be unchanged at day 21 but increased at day 50. Phosphoglycerate kinase 1 (PGK1) was unchanged at day 21 but decreased at day 50. Gelsolin was increased at day 21 but not at day 50. Protein disulfide-isomerase A3 (PDIA3) was decreased at day 21 and unchanged at day 50. Also, we found that vascular endothelial growth factor receptor 2 (VEGF-R2) and epidermal growth factor receptor (EGF-R) were decreased in mammary glands of 50-day-old rats treated prepubertally with genistein. This study demonstrates the usefulness of proteomics for the discovery of key proteins involved in signaling pathways to understand genistein mechanisms of action in breast cancer prevention. PMID- 21254786 TI - Facilitated transport of 2,2',5,5'-polychlorinated biphenyl and phenanthrene by fullerene nanoparticles through sandy soil columns. AB - The potential environmental implications of buckminsterfullerene (C60) and its derivatives have received much attention. In this study, we investigated facilitated transport of 2,2',5,5'-polychlorinated biphenyl (PCB) and phenanthrene by nC60 (a stable aqueous-phase aggregate of C60) through two sandy soil columns. We found that low-level (from 1.55 to 12.8 mg/L) nC60 could significantly enhance the mobility of PCB and phenanthrene. However, none of the three model dissolved organic matters (DOMs)-a humic acid, a fulvic acid, and a bovine serum albumin-had a noticeable effect on the transport of PCB when these DOMs were present at concentrations equivalent to approximately 10-11 mg/L organic carbon. We propose that the contaminant-mobilizing ability of nC60 is a result of irreversible adsorption of a fraction of nC60-associated PCB/phenanthrene (whereas DOM-associated PCB is readily desorbable). Additionally, slow desorption kinetics of nC60-adsorbed PCB/phenanthrene is another possible mechanism. The findings in this study indicate that nC60 in the subsurface environment can greatly enhance the mobility of nonionic, highly hydrophobic organic contaminants, which typically exhibit very low mobility. Such effects should be taken into account when assessing the potential environmental risks of engineered carbonaceous nanomaterials. PMID- 21254788 TI - Aripiprazole as adjunctive therapy for patients with major depressive disorder: overview and implications of clinical trial data. AB - Aripiprazole was initially approved to treat schizophrenia and later approved for bipolar mania, as a monotherapy and an adjunctive therapy (manic or mixed episodes), and for irritability associated with autism. Aripiprazole is a partial agonist at dopamine D(2) and D(3) and serotonin 5-HT(1A) receptors, and is an antagonist at 5-HT(2A) receptors. This profile, and convincing preliminary data from small-scale studies, provided the rationale for the large-scale exploration of aripiprazole for unipolar depression. Recently, three 6-week, large-scale, randomized, double-blind, placebo-controlled clinical trials demonstrated clinically meaningful efficacy for aripiprazole as an adjunctive therapy to antidepressants for treating major depressive disorder (MDD). In November 2007, aripiprazole was approved by the US FDA as an adjunctive therapy to antidepressants for treating MDD, with support from two of the above-mentioned trials. In the trials, aripiprazole was demonstrated to be safe and well tolerated, and showed a minimal trend for weight gain over the course of a 6-week treatment. The incidence of akathisia was higher than that reported in studies of patients with schizophrenia; however, most cases were mild to moderate and infrequently lead to discontinuation (5/1090 from all three trials). This comprehensive review provides an overview of the data from all three 6-week studies (including a pooled analysis) and from an unpublished 52-week, open-label extension study, to inform physicians and facilitate reasonable treatment decisions. In addition, specific issues associated with the use of aripiprazole as an adjunctive therapy in patients with MDD, including possible early treatment effect, appropriate timing of therapy initiation, appropriate dosing and duration of treatment, possible differential effect on depressive subgroups and long-term tolerability, are also discussed. PMID- 21254787 TI - Pharmacotherapy of epilepsy: newly approved and developmental agents. AB - This article discusses seven newly available antiepileptic drugs (AEDs) and agents in phase III development. Lacosamide, licensed as an adjunctive treatment for partial-onset seizures, primarily acts by enhancing sodium channel slow inactivation. At daily doses of 200-600 mg, the drug significantly reduced partial-onset seizures in adults with refractory epilepsy. The most common adverse effects are CNS related. Rufinamide, available as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome, has an unclear mechanism of action, although it does block voltage-dependent sodium channels. Coadministration of valproic acid significantly increases rufinamide circulating concentrations. The drug has been shown to have efficacy for partial-onset, primary generalized tonic-clonic, tonic-atonic, absence and atypical absence seizures. Adverse effects are mainly somnolence, nausea and vomiting. Eslicarbazepine acetate, a carbamazepine analogue, was recently licensed as adjunctive treatment for partial-onset seizures. Eslicarbazepine acetate acts at voltage-gated sodium channels, although the precise mechanism of action is unclear. The drug had efficacy for partial-onset seizures in three randomized, double-blind, placebo-controlled studies, using 400, 800 or 1200 mg/day. Adverse effects include dizziness and somnolence. Retigabine (ezogabine) exerts its anticonvulsant effect through the opening of neuronal voltage-gated potassium channels. Following significant seizure reduction rates at dosages of 600, 900 and 1200 mg/day, license applications have been submitted for its use as adjunctive treatment for patients with partial-onset seizures. Dose-related adverse effects include somnolence, confusion and dizziness. Brivaracetam is the n-propyl analogue of levetiracetam. Mixed results have been obtained in phase III studies in patients with partial-onset seizures, and further trials in children, patients with photosensitive epilepsy and patients with partial-onset seizures are ongoing. Dizziness, headache and somnolence are the most common adverse effects reported. Perampanel was designed as an AMPA-type glutamate receptor antagonist. Following encouraging results from phase II studies in patients with refractory partial-onset seizures, recruitment for phase III trials is almost complete. Ganaxolone is a neurosteroid with potent antiepileptic activity that modulates GABA(A) receptors in the CNS. Ganaxolone has shown promise in a variety of seizure types. Dizziness and somnolence have been reported in some patients. The availability of new AEDs has widened the choices for clinicians treating patients with epilepsy. However, given the minimal improvement in prognosis and disappointing efficacy outcomes in double-blind, placebo-controlled, dose-ranging regulatory trials, it seems unlikely that these novel agents will have a major impact on outcomes for people with epilepsy. PMID- 21254789 TI - Managing suicide risk in patients with schizophrenia. AB - The management of suicide risk in patients with schizophrenia poses many challenges for clinicians. Compared with the general population, these patients have an 8.5-fold greater risk of suicide. This article reviews the literature dealing with the treatment of at-risk patients with schizophrenia. An integrated psychosocial and pharmacological approach to managing this population of patients is recommended. Although there is at least modest evidence suggesting that antipsychotic medications protect against suicidal risk, the evidence appears to be most favourable for second-generation antipsychotics, particularly clozapine, which is the only medication approved by the US FDA for preventing suicide in patients with schizophrenia. In addition, treating depressive symptoms in patients with schizophrenia is an important component of suicide risk reduction. While selective serotonin receptor inhibitors (SSRIs) ameliorate depressive symptoms in patients with schizophrenia, they also appear to attenuate suicidal thoughts. Further research is needed to more effectively personalize the treatment of suicidal thoughts and behaviours and the prevention of suicide in patients with schizophrenia. PMID- 21254793 TI - Low efficacy of transdermal sumatriptan in migraine. PMID- 21254790 TI - Rapid improvement of chronic stroke deficits after perispinal etanercept: three consecutive cases. AB - BACKGROUND: Thrombolytic therapy reduces stroke size and disability by reperfusion and salvage of ischaemic penumbra. Emerging evidence suggests that retrieved penumbra may be the site of ongoing inflammatory pathology that includes extensive microglial activation. Microglial activation may be associated with excessive levels of tumour necrosis factor (TNF) and resultant neurotoxicity. Etanercept, a potent biologic TNF antagonist, reduces microglial activation in experimental models and has been therapeutically effective in models of brain and neuronal injury. Perispinal administration of etanercept, previously reported to be beneficial for the treatment of Alzheimer's disease, may facilitate delivery of etanercept into the brain. OBJECTIVE: The objective of this report is to document the initial clinical response to perispinal etanercept in the first chronic stroke cohort so treated. METHODS: Three consecutive patients with stable and persistent chronic neurological deficits due to strokes that had failed to resolve despite previous treatment and rehabilitation were evaluated at an outpatient clinic. They were treated off-label with perispinal etanercept as part of the clinic's practice of medicine. RESULTS: All three patients had chronic hemiparesis, in addition to other stroke deficits. Their stroke distributions were right middle cerebral artery (MCA), brainstem (medulla) and left MCA. The two patients with MCA strokes had both received acute thrombolytic therapy. Each of the three patients was treated with an initial dose of perispinal etanercept 13, 35 and 36 months following their acute stroke, respectively. Significant clinical improvement following perispinal etanercept administration was observed in all patients. Onset of clinical response was evident within 10 minutes of perispinal injection in all patients. Improvements in hemiparesis, gait, hand function, hemi-sensory deficits, spatial perception, speech, cognition and behaviour were noted among the patients treated. Each patient received a second perispinal etanercept dose at 22-26 days after the first dose that was followed by additional clinical improvement. CONCLUSIONS: Open-label administration of perispinal etanercept resulted in rapid neurological improvement in three consecutive patients with chronic neurological dysfunction due to strokes occurring 13-36 months earlier. These results suggest that stroke may result in chronic TNF-mediated pathophysiology that may be amenable to therapeutic intervention long after the acute event. Randomized clinical trials of perispinal etanercept for selected patients with chronic neurological dysfunction following stroke are indicated. PMID- 21254791 TI - Efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder: a meta-regression analysis. AB - BACKGROUND: The efficacy of methylphenidate for adults with attention-deficit hyperactivity disorder (ADHD) shows wide between-study variability, which yields heterogeneous results in meta-analysis. The reasons for this variability have not been comprehensively investigated. OBJECTIVES: To determine the influence of treatment-related covariates of methylphenidate for adults with ADHD by means of meta-analysis. Clinical and methodological moderators and clinical trial reporting quality were also collected to control for their potential confounding effect. METHODS: We searched for randomized, placebo-controlled clinical trials investigating the efficacy of methylphenidate for adults with ADHD. The study outcome was the efficacy of methylphenidate for reducing ADHD symptom severity. Treatment-related covariates included dose, type of drug-release formulation (formulations with a continuous drug release vs those with a non-continuous drug release), dose regimen (fixed vs flexible) and treatment length. Clinical (presence of co-morbid substance use disorders [SUD]) and methodological (design and rater) covariates were also collected, in addition to clinical trial reporting quality. The standardized mean difference (SMD) was calculated for each study. The analysis of the influence of methylphenidate effect modifiers was performed by means of random-effects meta-regression. RESULTS: Eighteen studies were included. Dose, type of formulation and SUD appeared to modify the efficacy of methylphenidate in the bivariate analysis. These variables were included in a multivariate meta-regression, which showed that methylphenidate, at an average dose of 57.4 mg/day, delivered by means of non-continuous-release formulations, had a moderate effect on ADHD symptoms compared with placebo (SMD 0.57-0.58). A dose-response relationship was found, indicating that efficacy could be increased by SMD 0.11-0.12 for every 10 mg increment of methylphenidate. Continuous-release formulations and co-morbid SUD appeared to reduce the efficacy of methylphenidate. Nevertheless, the effect of treatment formulation may have been confounded by co-morbid SUD, since all studies using this continuous-release formulation were conducted in dual ADHD-SUD patients. No residual heterogeneity was found. CONCLUSIONS: This study shows that methylphenidate improves ADHD symptoms in adults in a dose-dependent fashion. The efficacy of methylphenidate appears to be reduced in patients with co-morbid SUD. It is unclear whether methylphenidate efficacy is influenced by the type of formulation, because the effect of this covariate is confounded by that of co-morbid SUD. PMID- 21254794 TI - Successful relactation--a case history. AB - A healthy, term male infant was weaned at 10 days postpartum because of his mother's illness. The baby was breastfed by his mother's sister, but mostly he was fed with his aunt's expressed milk and with formula by bottle. At 9 weeks postpartum relactation began. Techniques used were a supplemental nursing support system device; frequent suckle at the breast, supplemented by formula given by bottle; breast pumping; domperidone; and support from an International Board Certified Lactation Consultant and family. Problems that appeared during relactation were that at 12 postpartum weeks the baby refused the supplemental nursing system device, and at 12 weeks and 3 days he refused the breast; after 3 weeks of relactation, the milk supply was still low, needing supplementation; and in the first week of exclusive breastfeeding, the baby stopped growing, then he gained weight slowly, and his gain fell down to the 15(th) percentile. Solutions and interventions used to solve the problems were usage of an artificial nipple during breast strike for 3 days and cessation of supplementary formula and frequent suckling at the breast. Four days after relactation started, colostrum appeared (for 2 weeks), and within 1 month from the beginning of relactation the baby was fully breastfed. He was exclusively breastfed until 7 months, and he was continually breastfed until 2 years. His growth was good and was around the 50th percentile on the weight/length curve. Thus relactation is possible at 9 weeks postpartum, if the mother's motivation to breastfeed is strong. The best technique to increase milk supply is frequent, short breastfeedings. PMID- 21254795 TI - Longer previous smoking abstinence relates to successful breastfeeding initiation among underserved smokers. AB - OBJECTIVES: The purpose of this study was to examine sociodemographic and behavioral factors related to successful breastfeeding initiation among medically underserved maternal smokers-a population with persistently low rates of initiation. SUBJECTS AND METHODS: Pretreatment data from a larger randomized behavioral counseling, secondhand smoke reduction trial was examined for this study. Maternal smokers with babies younger than 4 years old reported breastfeeding behaviors. Mothers who breastfed for >4 weeks (n = 50) were matched with mothers who never initiated breastfeeding based on infant age, gender, and maternal race. Multinomial logistic regression analysis tested the hypothesis that a greater duration of mothers' longest previous smoking abstinence would predict successful breastfeeding initiation in the context of other sociodemographic and behavioral factors known to relate to breastfeeding (e.g., education level, income, and maternal age). RESULTS: The sample consisted of current maternal smokers with a mean age of 28.8 +/- 7.1 years. Among participants, 94% were African American, 81% were single, 63% reported an annual family income less than $15,000, and 76% had completed a high school education or less. Logistic regression demonstrated that a longer duration of previous smoking abstinence and education beyond high school predicted breastfeeding initiation. CONCLUSIONS: Maternal smokers' previous success at smoking abstinence may increase the likelihood of successful breastfeeding initiation. To improve prenatal health education for maternal smokers with low education levels, researchers should explore the utility of merging smoking cessation and postpartum relapse prevention advice within the context of lactation counseling to maximize success of smokers' efforts to initiate breastfeeding. PMID- 21254796 TI - When memory is not enough: electrophysiological evidence for goal-dependent use of working memory representations in guiding visual attention. AB - Biased competition theory proposes that representations in working memory drive visual attention to select similar inputs. However, behavioral tests of this hypothesis have led to mixed results. These inconsistent findings could be due to the inability of behavioral measures to reliably detect the early, automatic effects on attentional deployment that the memory representations exert. Alternatively, executive mechanisms may govern how working memory representations influence attention based on higher-level goals. In the present study, we tested these hypotheses using the N2pc component of participants' event-related potentials to directly measure the early deployments of covert attention. Participants searched for a target in an array that sometimes contained a memory matching distractor. In Experiments 1 to 3, we manipulated the difficulty of the target discrimination and the proximity of distractors, but consistently observed that covert attention was deployed to the search targets and not the memory matching distractors. In Experiment 4, we showed that when participants' goal involved attending to memory-matching items, these items elicited a large and early N2pc. Our findings demonstrate that working memory representations alone are not sufficient to guide early deployments of visual attention to matching inputs and that goal-dependent executive control mediates the interactions between working memory representations and visual attention. PMID- 21254798 TI - Event-related repetitive TMS reveals distinct, critical roles for right OFA and bilateral posterior STS in judging the sex and trustworthiness of faces. AB - Judging the sex of faces relies on cues related to facial morphology and spatial relations between features, whereas judging the trustworthiness of faces relies on both structural and expressive cues that signal affective valence. The right occipital face area (OFA) processes structural cues and has been associated with sex judgments, whereas the posterior STS processes changeable facial cues related to muscle movements and is activated when observers judge trustworthiness. It is commonly supposed that the STS receives inputs from the OFA, yet it is unknown whether these regions have functionally dissociable, critical roles in sex and trustworthiness judgments. We addressed this issue using event-related, fMRI guided repetitive transcranial magnetic stimulation (rTMS). Twelve healthy volunteers judged the sex of individually presented faces and, in a separate session, whether those same faces were trustworthy or not. Relative to sham stimulation, RTs were significantly longer for sex judgments when rTMS was delivered over the right OFA but not the right or left STS, and for trustworthiness judgments on male but not female faces when rTMS was delivered over the right STS or left STS but not the right OFA. Nonetheless, an analysis of the RT distributions revealed a possible critical role also for the right OFA in trustworthiness judgments, limited to faces with longer RTs, perhaps reflecting the later, ancillary use of structural cues related to the sex of the face. On the whole, our findings provide evidence that evaluations of the trustworthiness and sex of faces rely on functionally dissociable cortical regions. PMID- 21254797 TI - Modulatory effects of levodopa on cognitive control in young but not in older subjects: a pharmacological fMRI study. AB - Older individuals show decline of prefrontal cortex (PFC) functions which may be related to altered dopaminergic neurotransmission. We investigated the effects of aging and dopaminergic stimulation in 15 young and 13 older healthy subjects on the neural correlates of interference control using fMRI. In a double-blind, placebo-controlled within-subject design, subjects were measured after levodopa (100 mg) or placebo administration. In each session, subjects performed a visual spatial interference task based on a Stroop/Simon-like paradigm. Across age groups, interference (incongruent relative to congruent trials) was associated with activations in the presupplementary motor area, ACC, and intraparietal cortex. Increased interference was found behaviorally in older volunteers. Differential activation in left dorsolateral PFC in young subjects and bilateral PFC activity in older subjects was observed to be associated with interference control. Performance deteriorated under levodopa only in young subjects. This was accompanied by an increase of neural activity in ACC (p < .05; small-volume correction for multiple comparisons). Worsening of performance under levodopa in young subjects and the associated effect on ACC may indicate that overstimulation of the dopaminergic system compromises interference control. This supports the inverted-U-shaped model of neurotransmitter action. PMID- 21254799 TI - Second-language instinct and instruction effects: nature and nurture in second language acquisition. AB - Adults seem to have greater difficulties than children in acquiring a second language (L2) because of the alleged "window of opportunity" around puberty. Postpuberty Japanese participants learned a new English rule with simplex sentences during one month of instruction, and then they were tested on "uninstructed complex sentences" as well as "instructed simplex sentences." The behavioral data show that they can acquire more knowledge than is instructed, suggesting the interweaving of nature (universal principles of grammar, UG) and nurture (instruction) in L2 acquisition. The comparison in the "uninstructed complex sentences" between post-instruction and pre-instruction using functional magnetic resonance imaging reveals a significant activation in Broca's area. Thus, this study provides new insight into Broca's area, where nature and nurture cooperate to produce L2 learners' rich linguistic knowledge. It also shows neural plasticity of adult L2 acquisition, arguing against a critical period hypothesis, at least in the domain of UG. PMID- 21254800 TI - Behavioral and electrophysiological evidence for early and automatic detection of phonological equivalence in variable speech inputs. AB - Speech sounds are not always perceived in accordance with their acoustic-phonetic content. For example, an early and automatic process of perceptual repair, which ensures conformity of speech inputs to the listener's native language phonology, applies to individual input segments that do not exist in the native inventory or to sound sequences that are illicit according to the native phonotactic restrictions on sound co-occurrences. The present study with Russian and Canadian English speakers shows that listeners may perceive phonetically distinct and licit sound sequences as equivalent when the native language system provides robust evidence for mapping multiple phonetic forms onto a single phonological representation. In Russian, due to an optional but productive t-deletion process that affects /stn/ clusters, the surface forms [sn] and [stn] may be phonologically equivalent and map to a single phonological form /stn/. In contrast, [sn] and [stn] clusters are usually phonologically distinct in (Canadian) English. Behavioral data from identification and discrimination tasks indicated that [sn] and [stn] clusters were more confusable for Russian than for English speakers. The EEG experiment employed an oddball paradigm with nonwords [asna] and [astna] used as the standard and deviant stimuli. A reliable mismatch negativity response was elicited approximately 100 msec postchange in the English group but not in the Russian group. These findings point to a perceptual repair mechanism that is engaged automatically at a prelexical level to ensure immediate encoding of speech inputs in phonological terms, which in turn enables efficient access to the meaning of a spoken utterance. PMID- 21254801 TI - The influence of emotion regulation on decision-making under risk. AB - Cognitive strategies typically involved in regulating negative emotions have recently been shown to also be effective with positive emotions associated with monetary rewards. However, it is less clear how these strategies influence behavior, such as preferences expressed during decision-making under risk, and the underlying neural circuitry. That is, can the effective use of emotion regulation strategies during presentation of a reward-conditioned stimulus influence decision-making under risk and neural structures involved in reward processing such as the striatum? To investigate this question, we asked participants to engage in imagery-focused regulation strategies during the presentation of a cue that preceded a financial decision-making phase. During the decision phase, participants then made a choice between a risky and a safe monetary lottery. Participants who successfully used cognitive regulation, as assessed by subjective ratings about perceived success and facility in implementation of strategies, made fewer risky choices in comparison with trials where decisions were made in the absence of cognitive regulation. Additionally, BOLD responses in the striatum were attenuated during decision-making as a function of successful emotion regulation. These findings suggest that exerting cognitive control over emotional responses can modulate neural responses associated with reward processing (e.g., striatum) and promote more goal-directed decision-making (e.g., less risky choices), illustrating the potential importance of cognitive strategies in curbing risk-seeking behaviors before they become maladaptive (e.g., substance abuse). PMID- 21254802 TI - Neural correlates of encoding within- and across-domain inter-item associations. AB - The neural correlates of the encoding of associations between pairs of words, pairs of pictures, and word-picture pairs were compared. The aims were to determine, first, whether the neural correlates of associative encoding vary according to study material and, second, whether encoding of across- versus within-material item pairs is associated with dissociable patterns of hippocampal and perirhinal activity, as predicted by the "domain dichotomy" hypothesis of medial temporal lobe function. While undergoing fMRI scanning, subjects (n = 24) were presented with the three classes of study pairs, judging which of the denoted objects fit into the other. Outside of the scanner, subjects then undertook an associative recognition task, discriminating between intact study pairs, rearranged pairs comprising items that had been presented on different study trials, and unstudied item pairs. The neural correlates of successful associative encoding--subsequent associative memory effects--were operationalized as the difference in activity between study pairs correctly judged intact versus pairs incorrectly judged rearranged on the subsequent memory test. Pair type independent subsequent memory effects were evident in the left inferior frontal gyrus (IFG) and the hippocampus. Picture-picture pairs elicited material selective effects in regions of fusiform cortex that were also activated to a greater extent on picture trials than on word trials, whereas word-word pairs elicited material-selective subsequent memory effects in left lateral temporal cortex. Contrary to the domain-dichotomy hypothesis, neither hippocampal nor perirhinal subsequent memory effects differed depending on whether they were elicited by within- versus across-material study pairs. It is proposed that the left IFG plays a domain-general role in associative encoding, that associative encoding can also be facilitated by enhanced processing in material-selective cortical regions, and that the hippocampus and perirhinal cortex contribute equally to the formation of inter-item associations, regardless of whether the items belong to the same or to different processing domains. PMID- 21254803 TI - Neuronal signal dynamics during preparation and execution for behavioral shifting in macaque posterior parietal cortex. AB - Cognitive flexibility arises from our ability to shift behaviors depending on demand changes. Behavioral shifting recruits both a preparatory process for an upcoming behavior and an execution process for the actual behavior. Although neuroimaging studies have shown that several brain regions, including posterior parietal cortex (PPC) participated in each component process, it remains unresolved how such processes are implemented at the single-cell level or even whether these processes are distinctively carried out across microstructures in such regions. By recording single-unit activity from PPC of two monkeys performing an analog of the Wisconsin Card Sorting Test, we found that, in the execution process, two types of neurons exhibited activity modulation depending on whether shift was (shift trial) or was not required (nonshift trial): one type showing larger activity and the other showing smaller activity in the shift trial than in the nonshift trial. In the preparatory process, in contrast, the population activity of both types became larger in the shift trial than in the nonshift trial. The majority of both types exhibited shift-related activity modulation in both processes, whereas the remaining was specialized in the execution process. The former and the latter neurons were spatially intermingled within PPC. Significantly, when the animals performed set shifting spontaneously in prospect of a demand change, the shift-related activity modulation still emerged in both processes. We suggest that both execution and preparation signals are represented within PPC, and that these signals reflect behavioral shifting mechanisms that can be driven by either internal or external triggers. PMID- 21254804 TI - Semantic diversity accounts for the "missing" word frequency effect in stroke aphasia: insights using a novel method to quantify contextual variability in meaning. AB - Word frequency is a powerful predictor of language processing efficiency in healthy individuals and in computational models. Puzzlingly, frequency effects are often absent in stroke aphasia, challenging the assumption that word frequency influences the behavior of any computational system. To address this conundrum, we investigated divergent effects of frequency in two comprehension impaired patient groups. Patients with semantic dementia have degraded conceptual knowledge as a consequence of anterior temporal lobe atrophy and show strong frequency effects. Patients with multimodal semantic impairments following stroke (semantic aphasia [SA]), in contrast, show little or no frequency effect. Their deficits arise from impaired control processes that bias activation toward task relevant aspects of knowledge. We hypothesized that high-frequency words exert greater demands on cognitive control because they are more semantically diverse- they tend to appear in a broader range of linguistic contexts and have more variable meanings. Using latent semantic analysis, we developed a new measure of semantic diversity that reflected the variability of a word's meaning across different context. Frequency, but not diversity, was a significant predictor of comprehension in semantic dementia, whereas diversity was the best predictor of performance in SA. Most importantly, SA patients did show typical frequency effects but only when the influence of diversity was taken into account. These results are consistent with the view that higher-frequency words place higher demands on control processes, so that when control processes are damaged the intrinsic processing advantages associated with higher-frequency words are masked. PMID- 21254805 TI - Task-invariant brain responses to the social value of faces. AB - In two fMRI experiments (n = 44) using tasks with different demands-approach avoidance versus one-back recognition decisions-we measured the responses to the social value of faces. The face stimuli were produced by a parametric model of face evaluation that reduces multiple social evaluations to two orthogonal dimensions of valence and power [Oosterhof, N. N., & Todorov, A. The functional basis of face evaluation. Proceedings of the National Academy of Sciences, U.S.A., 105, 11087-11092, 2008]. Independent of the task, the response within regions of the occipital, fusiform, and lateral prefrontal cortices was sensitive to the valence dimension, with larger responses to low-valence faces. Additionally, there were extensive quadratic responses in the fusiform gyri and dorsal amygdala, with larger responses to faces at the extremes of the face valence continuum than faces in the middle. In all these regions, participants' avoidance decisions correlated with brain responses, with faces more likely to be avoided evoking stronger responses. The findings suggest that both explicit and implicit face evaluation engage multiple brain regions involved in attention, affect, and decision making. PMID- 21254807 TI - Lift capabilities of hyaluronic acid fillers. AB - BACKGROUND: The lift capacity of a filler (ability to oppose deformation and flattening) relates to its suitability for correcting deeper wrinkles and folds, volumizing, and contouring. Lift capacity, considered as a function of both elastic modulus (G') and gel cohesivity, can be expected to differ among products owing to proprietary manufacturing processes. OBJECTIVES: To compare the lift capabilities of 24-mg/ml smooth, cohesive gel fillers (with ~6% and ~8% crosslinking) and a 20-mg/ml granular consistency gel filler (~2% crosslinking). METHODS: G' was measured using a parallel plate rheometer and the products were subjected to a small oscillatory strain. Cohesivity was measured using a linear compression test (quantitative) as well as a dye diffusion test (qualitative). RESULTS: The 24-mg/ml smooth, cohesive gel filler had a lower G' coupled with lower susceptibility to yield to a given strain versus the 20-mg/ml granular consistency gel filler. Both 24-mg/ml smooth, cohesive gel filler formulations demonstrated greater resistance to deformation in the linear compression test and lower rates of dye diffusion than the 20-mg/ml granular consistency gel filler. CONCLUSIONS: The 24-mg/ml smooth, cohesive HA gel fillers achieve a high lift capacity by combining higher cohesivity with lower relative G' versus the 20 mg/ml granular consistency gel filler. PMID- 21254806 TI - Frontoparietal activation distinguishes face and space from artifact concepts. AB - Empirical and theoretical studies suggest that human knowledge is partly based on innate concepts that are experience-independent. We can, therefore, consider concepts underlying our knowledge as being broadly divided into inherited and acquired ones. Using fMRI, we studied the brain reaction in 20 subjects to violation of face, space (inherited), and artifact (acquired) concepts by presenting them with deformed faces, impossible figures (i.e., impossible chairs), and deformed planes, respectively, as well as their normal counterparts. Violation of the inherited concepts of face and space led to significant activation in frontoparietal cortex, whereas artifacts did not, thus distinguishing neurologically between the two categories. Participants were further exposed to these deformities daily for 1 month to test the supposition that inherited concepts are not modifiable, hence that prolonged exposure would not change the brain circuits that are engaged when viewing them. Consistent with this supposition, our results showed no significant change in activation for both categories, suggesting that such concepts are stable at the neural level at least within a time frame of 1 month. Finally, we investigated the regions of the brain that are critical for object representation. Our results show distinct and overlapping areas in the ventral visual cortex for all three categories, with faces activating the ventral visual cortex inferiorly, especially centered on right fusiform gyrus, and chairs and planes activating more diffuse regions, overlapping with the superior part of face region and mainly located in middle occipital cortex and parietal areas. PMID- 21254809 TI - Presence of OXA-23-producing isolates of Acinetobacter baumannii in wastewater from hospitals in southern Brazil. AB - The aim of the study was to evaluate the dissemination of multiresistant isolates of Acinetobacter baumannii carrying resistance genes, by samples of wastewater from hospitals in Porto Alegre, Rio Grande do Sul, Brazil. We obtained 303 bacterial isolates from the wastewater of three hospitals in Porto Alegre, Rio Grande do Sul. For each isolate, we determined the profile of susceptibility to antimicrobials and the presence of the genes bla(OXA-23), bla(OXA-24), bla(OXA 51), bla(OXA-58), bla(SPM-1), bla(IMP), and bla(VIM.) The bla(OXA-51) gene was found in 56% of the isolates, indicating the presence of A. baumannii in this environment. Of these, three multiresistant isolates were positive for the bla(OXA-23) gene, in wastewater from two of the hospitals. The results obtained in this study indicate that isolates of A. baumannii which are multiresistant and carry resistance genes such as bla(OXA-51) and bla(OXA-23) are being released into the environment in the wastewater from the hospitals analyzed. Multiresistant Acinetobacter junii, the newly emerging pathogen, were also found among the multiresistant isolates. Hospital wastewater may be crucial to the development and dispersal of multiresistant bacteria, making waterbodies reservoirs of bacterial resistance. PMID- 21254810 TI - Molecular detection and characterization of methicillin-resistant Staphylococcus aureus (MRSA) isolates from dogs in Portugal. AB - Fifty-four healthy dogs were screened in Portugal for the presence of nasal methicillin-resistant Staphylococcus aureus (MRSA) carriage. Sixteen MRSA isolates (one/sample) were recovered from nasal samples of dogs, and they were typed by molecular methods (S. aureus protein A [spa]-, multilocus sequence typing-, staphylococcal cassette chromosome mec-typing). MRSA isolates were investigated for their susceptibility to antimicrobial agents by disk-diffusion test. The presence of resistance genes and of the Panton-Valentine leukocidin gene (lukF-lukS) was analyzed by PCR. Four different spa-types were identified among our MRSA isolates (t032, t432, t747, and t4726), with t032 as the most frequently detected. The sequence-type ST22 was identified in four tested MRSA isolates with different spa-types. All 16 isolates presented the staphylococcal cassette chromosome mec type IV. Most of MRSA isolates were resistant to ciprofloxacin, erythromycin, and clindamycin (94%-100%), and no resistance was identified to chloramphenicol, mupirocin, and trimethoprim-sulfametoxazole. The ermC and tetM resistance genes were detected in all MRSA isolates. The amino acid changes Ser84Leu in GyrA protein and Ser80Phe in GrlA protein were the most prevalent ones in our MRSA isolates. None of the MRSA strains carried the lukF lukS genes. The results presented in this study indicate that healthy dogs may be a reservoir of MRSA that could be transmitted to humans by direct contact. PMID- 21254811 TI - Discussing end-of-life issues in the last months of life: a nationwide study among general practitioners. AB - BACKGROUND: Communication is a necessary tool for ensuring the provision of quality patient-centered care for patients who have life-threatening illnesses, and discussing all relevant end-of-life issues should not be limited to cancer patients. OBJECTIVE: To examine the incidence and timing of general practitioners (GPs) discussing end-of-life issues with patients whose deaths were expected, and to identify the factors associated with them discussing these issues. METHODS: Between January and December 2008, GPs participating in a nationally representative sentinel surveillance network of GPs were asked to register, using standardised forms, the extent of discussing 10 end-of-life issues with patients. RESULTS: We examined 252 patients who died nonsuddenly, 38% of whom died of cancer, and 86% of whose treatment goal was palliative care. Our findings show that GPs often waited until very close to death before they discussed end-of-life issues with patients, and discussed spiritual and social issues less than physical symptoms, diagnoses, and psychological problems. In 74% of cases, the GPs were informed of their patients' preferred place of death; and 8 out of 10 patients with known preferences for place of death, died there. Being diagnosed with cancer was associated with a higher frequency of discussing all 10 end-of life issues than diagnosis with other (noncancer) conditions, but this is a state of mind we did not explore in this study. CONCLUSION: Promotion of timely discussion of all relevant end-of-life issues, in patients with cancer and noncancer diagnoses, is advisable based on systematic needs assessment. PMID- 21254812 TI - Measuring symptom distress in palliative care: psychometric properties of the Symptom Assessment Scale (SAS). AB - Given the variety of palliative care settings within which symptom distress must be assessed, development of a valid and reliable clinical tool that can be simply applied in every day practice is needed. The Symptom Assessment Scale (SAS) uses a 0-10 numerical scale with zero being no symptom and 10 being the worst possible. The key symptoms included in the scale are breathing, bowel problems, appetite problems, pain, insomnia, nausea and fatigue. The instrument is structured to allow either the patient, family member or nurse to assess the symptoms. The scale was tested on 572 cancer patients recruited from five palliative care services in Western Australia. Results indicated that the instrument was brief, clinically useful and was administered with minimal missing data. Internal consistency reliability estimates of the scale ranged from 0.64 0.92 as measured by the Cronbach's alpha co-efficient. Test-retest reliabilities of 0.84-0.92 were obtained using Pearson's correlation co-efficient. The instrument does not provide an in-depth assessment of individual symptoms, but serves as a screening tool to identify troublesome symptoms that warrant attentive and immediate investigation and comprehensive assessment. PMID- 21254813 TI - Edmonton symptom assessment scale as a prognosticative indicator in patients with advanced cancer. AB - BACKGROUND: Few studies incorporate patient self-assessment scales in prognostic models of survival prediction. The Edmonton Symptom Assessment Scale (ESAS) is commonly used as a symptom screening tool in cancer patients. OBJECTIVE: The goal of this study was to evaluate the prognostic value of the ESAS for survival prediction in the advanced cancer population. MATERIALS AND METHODS: Patients completed the ESAS and demographic information prior to palliative radiotherapy consultation and at follow-up at the Odette Cancer Centre between 1999 and 2009. Generalized estimating equation (GEE) methodology was applied to analyze ESAS trends within the last months of life. One-way analysis of variance (ANOVA) with repeated measurements was used to characterize trends between time periods. RESULTS: ESAS records (2377) from 808 patients (433 male and 375 female) were included in this cohort. Median age was 68 years (range 32-95) with median Karnofsky performance status (KPS) of 60 (range 10-100). Primary cancer sites were of the lung (36%), breast (20%), and prostate (19%). All nine ESAS symptoms significantly deteriorated in the last 4 weeks immediately before death when compared with those scores in the preceding months. At one week prior to death, the worst ESAS symptoms experienced by patients were fatigue, appetite, and well being with mean scores of 7.4, 6.9, and 6.1, respectively. CONCLUSIONS: All ESAS scores significantly worsened in the last 4 weeks prior to death compared with those in the previous months. Sudden deterioration of the global ESAS symptoms may predict impending death. Future studies on a prognostic model should incorporate both ESAS symptom severity and trends. PMID- 21254814 TI - Characterizing care of hospice patients in the hospital setting. AB - BACKGROUND: One measure of quality hospice care is minimization of hospitalization. Few studies have explored reasons for hospitalization and characteristics of care received by hospice patients in the hospital. OBJECTIVES: To characterize the experience of hospice patients in the hospital and determine factors associated with high intensiveness of care. DESIGN: Retrospective review of patient medical records in the Mayo Hospice Program in 2007. RESULTS: Of 263 hospice patients, 17% were hospitalized in 2007. Of those hospitalized, 42% percent died in the hospital. Average length of stay was 4 days. Almost half were admitted through the emergency department. Common reasons for admission included delirium, pain, and falls. Most patients (52%) received care of a moderate level of intensity, with 18% receiving the most intensive level of care. Receiving care of high intensity was associated with emergency department admission. Charges to patient accounts averaged over $9,000 per stay. Concordance of care in the hospital to preexisting patient goals was high, but could not be determined in 39% of cases due to lack of documentation of patient goals. CONCLUSIONS: Hospitalization of hospice patients is costly to the health care system. Most care was of low or moderate intensiveness. Quality improvements focusing on concise communication of patient goals and prevention of pain, delirium, and falls have the potential for the greatest impact on reducing hospitalizations and minimizing care that is discordant with patient goals. PMID- 21254815 TI - Assessing end-of-life preferences for advanced dementia in rural patients using an educational video: a randomized controlled trial. AB - OBJECTIVE: Few studies have evaluated the end-of-life preferences of elderly patients in rural communities and whether preferences are associated with level of health literacy. DESIGN: Randomized controlled trial of a goals-of-care video decision aid of advanced dementia. PARTICIPANTS: Elderly subjects (65 years or older) at a primary care clinic in rural Louisiana. METHODS: Half of subjects heard a verbal description of advanced dementia and the goals of care; the other half heard the same verbal description and then viewed the video decision aid. End points were the preferred goal of care in advanced dementia: life-prolonging care (cardiopulmonary resuscitation [CPR], etc.), limited care (hospitalization but not CPR), or comfort care (symptom relief). The principal category for analysis was the difference in proportions of subjects preferring comfort care for each characteristic including randomization group and health literacy level. RESULTS: Seventy-six subjects were randomized to the verbal (n = 43) or video (n = 33) arms of the study. Among subjects receiving the verbal description of advanced dementia and the goals of care, 31 (72%) preferred comfort; 5 (12%) chose limited; and 7 (16%) desired life-prolonging. In the video group, 30 (91%) preferred comfort; 3 (9%) chose limited; and none desired life-prolonging (chi(2) = 6.3, df = 2, p = 0.047). Factors associated with greater likelihood of opting for comfort included greater health literacy (unadjusted odds ratio [OR] 12.1; 95% confidence interval [CI], 2.4-62.6) and randomization to the video (unadjusted OR 3.9; 95% CI, 1.0-15.1). CONCLUSION: Rural subjects with higher health literacy were more likely to want comfort care compared to those with lower levels of health literacy. Furthermore, subjects who viewed a video decision aid were more likely to opt for comfort compared to those who solely listened to a verbal description. These findings suggest that video can help elicit preferences and that interventions to empower such patients need to be designed in a manner that is sensitive to health literacy. PMID- 21254816 TI - Family factors in end-of-life decision-making: family conflict and proxy relationship. AB - BACKGROUND: Few studies have examined proxy decision-making regarding end-of-life treatment decisions. Proxy accuracy is defined as whether proxy treatment choices are consistent with the expressed wishes of their index elder. The purpose of this study was to examine proxy accuracy in relation to two family factors that may influence proxy accuracy: perceived family conflict and type of elder-proxy relationship. METHODS: Telephone interviews with 202 community-dwelling elders and their proxy decision makers were conducted including the Life-Support Preferences Questionnaire (LSPQ), and a measure of family conflict, and sociodemographic characteristics, including type of relationship. RESULTS: Elder proxy accuracy was associated with the type of elder-proxy relationship. Adult children demonstrated the lowest elder-proxy accuracy and spousal proxies the highest elder-proxy accuracy. Elder-proxy accuracy was associated with family conflict. Proxies reporting higher family conflict had lower elder-proxy accuracy. No interaction between family conflict and relationship type was revealed. CONCLUSIONS: Spousal proxies were more accurate in their substituted judgment than adult children, and proxies who perceive higher degree of family conflict tended to be less accurate than those with lower family conflict. Health care providers should be aware of these family factors when discussing advance care planning. PMID- 21254817 TI - Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. AB - Current therapies for motor symptoms of Parkinson's disease (PD) are based on dopamine replacement. However, the disease progression remains unaffected, because of continuous dopaminergic neuron loss. Since oxidative stress is actively involved in neuronal death in PD, pharmacological targeting of the antioxidant machinery may have therapeutic value. Here, we analyzed the relevance of the antioxidant phase II response mediated by the transcription factor NF-E2 related factor 2 (Nrf2) on brain protection against the parkinsonian toxin methyl 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Intraperitoneal administration of the potent Nrf2 activator sulforaphane (SFN) increased Nrf2 protein levels in the basal ganglia and led to upregulation of phase II antioxidant enzymes heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase (NQO1). In wild-type mice, but not in Nrf2-knockout mice, SFN protected against MPTP-induced death of nigral dopaminergic neurons. The neuroprotective effects were accompanied by a decrease in astrogliosis, microgliosis, and release of pro-inflammatory cytokines. These results provide strong pharmacokinetic and biochemical evidence for activation of Nrf2 and phase II genes in the brain and also offer a neuroprotective strategy that may have clinical relevance for PD therapy. PMID- 21254818 TI - A model for tissue engineering applications: femoral critical size defect in immunodeficient mice. AB - Animal models for preclinical functionality assays lie midway between in vitro systems such as cell culture and actual clinical trials. We have developed a novel external fixation device for femoral critical size defect (CSD) in the femurs of immunodeficient mice as an experimental model for studying bone regeneration and bone tissue engineering. The external fixation device comprises four pointed rods and dental acrylic paste. A segmental bone defect (2 mm) was created in the midshaft of the mouse femur. The CSD in the femur of the mice were either left untreated or treated with a bone allograft, a cell-scaffold construct, or a scaffold-only construct. The repair and healing processes of the CSD were monitored by digital x-ray radiography, microcomputed tomography, and histology. Repair of the femoral CSD was achieved with the bone allografts, and partial repair of the femoral CSD was achieved with the cell scaffold and the scaffold-only constructs. No repair of the nongrafted femoral CSD was observed. Our results establish the feasibility of this new mouse femoral model for CSD repair of segmental bone using a simple stabilized external fixation device. The model should prove especially useful for in vivo preclinical proof-of-concept studies that involve cell therapy-based technologies for bone tissue engineering applications in humans. PMID- 21254819 TI - Who to turn to? 'Knowing the ropes' in an underbounded health care system. AB - This paper explores the impact of restructuring, conducted under the auspices of new public sector management, on the delivery of hospital based nursing care. Alderfer's model of 'overbounded' and 'underbounded' systems is used to analyse the way in which the organisation and delivery of nursing care has changed. Nursing was traditionally organised in an overbounded system which nevertheless focussed clearly and primarily on the provision of excellence in patient care. Recent research and examples from case law illustrate how nursing has moved into an underbounded system, where lines of authority and accountability are crossed and blurred. This can lead to practices of 'responsible subversion' which leave nurses feeling dissatisfied, guilty and marginalised. New management models are required to address the multiple and competing authority relations and imprecise, incomplete and overlapping role definitions. PMID- 21254820 TI - Mental illness in the nursing workplace: a collective autoethnography. AB - Many nurses are burned out, exhausted and have a high intent to leave their jobs. These factors, when experienced over a period of time, are consistent with the development of mental illness. This study takes a collective autoethnographical approach to mental illness in the nursing workplace by focusing on the stories of nurses who have experienced mental illness in clinical practice. It highlights three ways in which nursing and mental illness are connected; the nurse who is vulnerable to mental illness prior to entering the profession, the nurse who develops mental illness that is independent of her work but is nevertheless impacted by it, and the nurse who develops mental illness as a result of her work and/or role. This paper explores the hyphenated lives and bullying these nurses experience, and recommends strategies that the profession, employing organisations, and individuals can adopt to reduce nurses' progression from stress to distress and mental illness. PMID- 21254821 TI - Trial and retribution: a qualitative study of whistleblowing and workplace relationships in nursing. AB - This paper reports a study aiming to present and describe the effects of whistleblowing episodes on nurses' workplace relationships. Eighteen participants with direct experience of whistleblowing were recruited into the study, which was informed by a qualitative narrative inquiry design. Findings were clustered into four main themes, namely: Leaving and returning to work-The staff don't like you; Spoiled collegial relationships-Barriers between me and my colleagues; Bullying and excluding-They've just closed ranks; and, Damaged inter-professional relationships-I did lose trust in doctors after that. Findings suggest a need to facilitate a climate in which it is safe for nurses (and others) to raise concerns about patient care or organisational wrongdoing, and to eliminate the existing belief that whistleblowing is a negative act fuelled by revenge or sedition. PMID- 21254822 TI - A Nurse Practitioner initiated model of service delivery in caring for people with dementia. AB - The increasing number of people with dementia in aged care facilities is reported to have a high burden of care among staff. The Nurse Practitioner role can be beneficial in the provision of dementia care particularly when difficult and aggressive behaviour is being displayed. The model of service described in this paper is designed in such a way to make the outreach team contribute to staff sustainability. Such a service is different to other outreach services and focuses on a number of key deliverables. In practice, the service ensures that recommendations made by the team at the initial assessment are implemented. In addition, they work with the staff in managing the resident's behaviour, train and model suggestions for practice in interventions. Evaluation of the service is a work in progress and will highlight important aspects about the workforce for the improvement of quality of life for residents with dementia. PMID- 21254823 TI - Multidisciplinary teams caring for clients with chronic conditions: experiences of community nurses and allied health professionals. AB - In Western societies the community prevalence of chronic conditions is increasing rapidly. Evidence has shown the benefits of care given to these clients by multidisciplinary teams. However, the experience of diverse health professionals working in these teams is not well understood. This study presents the experiences of members in multidisciplinary teams caring for clients with chronic conditions in the community. A qualitative descriptive study was used with a purposive sample of 34 multidisciplinary team members who participated in focus groups that were audio-taped, transcribed and analysed. Team members' experiences of working in multidisciplinary teams are described within three categories: shared purpose, working in the team, and tensions within the team. The findings provide direction for addressing team effectiveness, including issues of team leadership and evaluation of team performance. PMID- 21254824 TI - Nurse care coordinators: definitions and scope of practice. AB - The Nurse Care Coordinator role has emerged in recent years as an important means of achieving significant outcomes for patient, their families, and the larger health system. These outcomes include increased patient satisfaction with service provision, an increase in patient access to services, and a decrease in the hospital length of stay and unplanned readmission. Despite the potential benefits, confusion around role definition and scope of practice are evident. This paper examines findings of a literature review of studies involving Nurse Care Coordinators and provides preliminary definitions of their role and practice. The primacy of the therapeutic relationship is upheld, together with the importance of facilitating continuity of care. It is proposed that these preliminary definitions require testing and refining to ensure the nursing profession is more effectively positioned to continue to enable positive outcomes for patients and health systems generally. PMID- 21254825 TI - Scope of practice conflict in nursing: a new war or just the same battle? AB - The changing roles within health care teams reflect the rapid pace of change in contemporary health care environments. Traditional nursing roles and responsibilities are being challenged as fiscal constraints drive health reform. How nursing teams are configured in the future and the scope of practice of the individuals within those teams will require clear and unambiguous boundaries. This study explores the relationships in and between scope of practice and communication amongst teams of nurses. Six focus groups with both Registered and Enrolled Nurses were undertaken in three Sydney metropolitan hospitals in New South Wales. Nurses report that confusion surrounding scope of practice particularly in the areas of medication administration, patient allocation and workload are resulting in situations whereby nurses are feeling bullied, stressed and harassed. With the imminent widespread introduction of a third tier of nursing into acute care hospitals in Australia the findings of this study are timely and suggest that unless nursing team members clearly understand their roles and scope of practice there is potential for intra-professional workplace conflict. Furthermore the impact of the conflict may have consequences for both the individual nurse and their patients. PMID- 21254826 TI - Workplace conversations: building and maintaining collaborative capital. AB - Heavy, pressured workloads are a feature of health workplaces internationally, presenting challenges to communication and contributing to tension and negative emotions. This paper explores supportive and unsupportive workplace conversations between nurses and midwives and their colleagues. The findings focus on qualitative interviews of ten nurses and midwives that were audio-taped and analysed for perceptions about the role of workplace conversations. Conversations between colleagues were significant for building and maintaining collaborative capital, but unsupportive conversations also threatened it. Findings suggest the need for considering the impact of co-worker conversations on workplace culture. Nurse managers and management may play a pivotal role in establishing and maintaining supportive conversations. Recognising the role and potential of workplace conversations for building capacities for support, conflict resolution, job satisfaction and the personal resilience of nurses and midwives can raise the collaborative capital of the workplace. PMID- 21254827 TI - The advent of mental health nurses in Australian general practice. AB - The remarkable progress that has been witnessed in the physical and material wellbeing for most Australians over the 20th century has not been paralleled by gains in the mental and subjective wellbeing of the population. General practice plays a strategic role in Australia's primary health care, which has been recognised as an essential health system that is able to deliver health to the population in a timely and equitable manner (World Health Organisation [WHO], 2008). General Practitioners are unable to provide adequate care to people experiencing a severe mental illness without support from specialist mental health professional such as a mental health nurse in the practice. The mental health nurse incentive program (MHNIP) offers opportunity for mental health nurses to work collaboratively with GPs in primary health care in the delivery of care to people with a severe mental illness. PMID- 21254828 TI - Increased numbers of Australian Indigenous nurses would make a significant contribution to 'closing the gap' in Indigenous health: what is getting in the way? AB - The provision of a well trained and culturally safe health workforce is critical to the alleviation of health inequities for Australian Indigenous peoples. Educating and graduating significant numbers of Indigenous registered nurses is one way the 'Close the Gap' initiative succeeds. Indigenous nurses bring a set of unique skills, knowledge and understanding to health service delivery. Their contribution has the potential to enhance future outcomes for Indigenous people by improving access to health services, ensure services are culturally appropriate and respectful, and assist non-Indigenous nurses to deliver culturally appropriate care. This paper discusses the background to the current numbers of Indigenous undergraduate nursing students enrolled in and completing tertiary nursing courses, with a focus on Queensland nursing programs. A range of identified barriers impede Indigenous nursing students' successful completion of their studies. We propose recommendations for education, research and employment to help overcome these problems, and ensure greater Indigenous participation in the nursing workforce. PMID- 21254829 TI - Close observation by 'specials' to promote the safety of the older person with behavioural disturbances in the acute care setting. AB - This paper reports a two-phased pilot study that explored the concept of 'specialling' older patients with challenging behaviours in acute ward situations. Previous research suggests that the nursing workforce is not equipped with the skills and resources required to provide quality care for these patients. The hospital in which this study was conducted, instigated a model where these patients were closely observed by 'specials'. Phase 1 of the study involved a retrospective analysis of de-identified 'Specials' Observation Charts' and 'Request for Patient Special' forms of patients aged 65 years and above, over 12 months in 2006. Phase 2 involved in-depth interviews with the nurses caring for these patients. Findings revealed inadequacy of the forms, gaps in service provision for this vulnerable group of patients and the need for education of specials and ward staff, with suggestions to improve care for this patient group. Findings suggest the necessity to design and structure the observation forms more efficiently. It is important to formulate clear assessment criteria for these patients and incorporate in-service education programmes for 'specials' and ward staff and adequately prepare and support them to meet the challenges of caring for older persons with behavioural disturbances in ward situations. PMID- 21254830 TI - The influence of demographics and work related goals on adaptive development for work related learning amongst private hospital employees. AB - Contemporary lifespan development models of adaptive development have been applied to the workforce to examine characteristics of the ageing employee. Few studies have examined adaptive development in terms of worker perceptions of workplace, or their learning and development issues. This study used the recently developed Revised Learning and Development Survey to investigate employee selection and engagement of learning and development goals, opportunities for learning and development at work, and constraints to learning and development at work. Demographic and career goal variables were tested amongst a sample of private hospital employees, almost all of whom were nurses. Workers under 45 years of age perceived greater opportunities for training and development than more mature aged workers. Age and physical demands interacted such that physical demands of work were associated with lower engagement in learning and development goals in mature aged workers. The opposite was observed amongst younger workers. Engagement in learning and development goals at work predicted goals associated with an intention to decrease work hours or change jobs to a different industry when opportunities to learn via work tasks were limited. At the same time limited opportunities for training and development and perceptions of constraints to development at work predicted the intention to change jobs. Results indicate consideration must be paid to employee perceptions in the workplace in relation to goals. They may be important factors in designing strategies to retain workers. PMID- 21254831 TI - Interactions between various microbes and ginseng botanicals. AB - Three kinds of interactions occur between ginseng botanicals and microorganisms: a) spoilage of the botanical by various fungi (e.g., Aspergillus, Penicillium, Alternaria, and Eurotium species) and bacteria; b) transformation of ginsenosides into more bioactive forms by bacteria such as Intrasporangium sp. GS603, Microbacterium sp. GS514, Caulobacter leidyia, Bifidobacterium sp. Int57, Bifidobacterium sp. SJ32, Fusobacterium sp. and Bacteroides sp., and moulds (e.g., Aspergillus niger, Fusarium sacchari, Paecilomyces bainier sp. 229, Rhizopus stolonifer, Myrothecium verrucaria and Acremonium strictum); and c) inhibition of certain bacteria (Propionibacterium acnes, Porphyromonas gingivalis, Staphylococcus aureus, Pseudomonas aeruginosa), fungi (Candida albicans, Aspergillus fumigatus, Fusarium oxysporum) and viruses by ginseng constituents. PMID- 21254832 TI - Current perspectives on Mycobacterium avium subsp. paratuberculosis, Johne's disease, and Crohn's disease: a review. AB - Mycobacterium avium subsp. paratuberculosis (MAP) causes the disease of cattle, Johne's. The economic impact of this disease includes early culling of infected cattle, reduced milk yield, and weight loss of cattle sold for slaughter. There is a possible link between MAP and Crohn's disease, a human inflammatory bowel disease. MAP is also a potential human food borne pathogen because it survives current pasteurization treatments. We review the current knowledge of MAP, Johne's disease and Crohn's disease and note directions for future work with this organism including rapid and economical detection, effective management plans and preventative measures. PMID- 21254833 TI - Biosurfactants as green stabilizers for the biological synthesis of nanoparticles. AB - Taking into consideration the needs of greener bioprocesses and novel enhancers for synthesis using microbial processes, biosurfactants, and/or biosurfactant producing microbes are emerging as an alternate source for the rapid synthesis of nanoparticles. A microemulsion technique using an oil-water-surfactant mixture was shown to be a promising approach for nanoparticle synthesis. Biosurfactants are natural surfactants derived from microbial origin composed mostly of sugar and fatty acid moieties, they have higher biodegradability, lower toxicity, and excellent biological activities. The biosurfactant mediated process and microbial synthesis of nanoparticles are now emerging as clean, nontoxic, and environmentally acceptable "green chemistry" procedures. The biosurfactant mediated synthesis is superior to the methods of bacterial- or fungal-mediated nanoparticle synthesis, since biosurfactants reduce the formation of aggregates due to the electrostatic forces of attraction and facilitate a uniform morphology of the nanoparticles. In this review, we highlight the biosurfactant mediated synthesis of nanoparticles with relevant details including a greener bioprocess, sources of biosurfactants, and biological synthesized nanoparticles based on the available literature and laboratory findings. PMID- 21254834 TI - Growth of Coxiella burnetii in the Ixodes scapularis-derived IDE8 tick cell line. AB - Q fever, a zoonotic disease, is caused by a gram-negative intracellular bacterium, Coxiella burnetii. Although normally transmitted during exposure to infectious aerosols, C. burnetii is also found in arthropod vectors. In the environment, ticks are thought to play a crucial role in bacterial maintenance and transmission by infecting various mammalian species. However, the nature of the pathogen-tick relationship is not well defined. To determine C. burnetii's interactions with a cultured tick cell line, we introduced purified C. burnetii NMII into Ixodes scapularis-derived IDE8 cells and assayed for bacterial presence, replication, gene expression, and subsequent infectivity for mammalian cells. Tick cells were harvested at 24 h, 72 h, 7 days, and 11 days postinfection (PI). C. burnetii uptake and subsequent replication was demonstrated by indirect immunofluorescence assay, electron microscopy, and real-time polymerase chain reaction (PCR). When a genome equivalent multiplicity of infection of 30 was used, 30%-40% of exposed cells were seen to have small, rounded, vacuoles at 72 h PI, whereas at 7 and 11 days PI, 60%-70% of cells contained enlarged vacuoles harboring large numbers of bacteria. Quantitative PCR analysis of total genomic DNA confirmed that C. burnetii genome numbers increased significantly from 24 h to 11 days PI. Expression of C. burnetii type four secretion system homologs at 7 days PI was demonstrated by reverse transcriptase PCR. Finally, indirect immunofluorescence assay demonstrated that C. burnetii propagated within IDE8 cells were infectious for mammalian cells. These studies demonstrate the utility of cultured tick cell lines as a model to investigate C. burnetii's molecular interactions with its arthropod vectors. PMID- 21254835 TI - Prevalence of Theileria equi and Babesia caballi infection in horses from northern Italy. AB - Babesia caballi and Theileria equi are the causative agents of equine piroplasmosis. In this epidemiological study, 294 horses reared in a rural area of northern Italy were studied. During January 2008-January 2009, blood samples were taken for serology (indirect fluorescent antibody test) and for polymerase chain reaction (PCR). Data on the geographical area, sex, and age were collected for statistical analysis of risk factors associated with infection. A seroprevalence of 8.5% was found: 8.2% of the animals were positive for anti-T. equi antibodies and 0.3% for anti-B. caballi antibodies. No dual infections were observed. Of those horses with positive serology to T. equi, 33% were also positive in PCR, whereas none of the seropositive horses for B. caballi was positive in PCR. No significant correlation between sex or age was found for infection status. PMID- 21254836 TI - Gene expression and promoter region polymorphisms of interleukin-10 in meningitis patients. AB - Meningitis is an inflammatory disease caused by bacteria, fungi, and viruses with various clinical symptoms. Interleukin-10 (IL-10) levels have been shown to be increased in blood or cerebrospinal fluid of patients with meningitis, but the association of IL-10 gene promoter polymorphisms or gene expression with meningitis has not been evaluated. IL-10 gene promoter polymorphisms A-592C, T 819C, and A-1082G in 61 patients with meningitis and 64 healthy controls were determined by real-time polymerase chain reaction analysis. mRNA from blood and cerebrospinal fluid samples was extracted, and real-time polymerase chain reaction was performed for IL-10 gene expression. No statistically significant differences were found in the allele and genotypic frequencies between patients and control subjects. Expression of IL-10 in meningitis at mRNA levels was detected in the infiltrating leukocytes. IL-10 gene expression in blood from patients was significantly higher than the control group. Our results suggest that there was no association between promoter polymorphisms of IL-10 and meningitis, but a significant increase of IL-10 gene expression was present in patients with meningitis. PMID- 21254837 TI - Endothelial progenitor cells: a novel tool for the therapy of ischemic diseases. AB - Circulating endothelial progenitor cells (EPCs) are believed to home to sites of neovascularization, contributing to vascular regeneration either directly via incorporation into newly forming vascular structures or indirectly via the secretion of pro-angiogenic growth factors, thereby enhancing the overall vascular and hemodynamic recovery of ischemic tissues. The therapeutic application of EPCs has been shown to be effective in animal models of ischemia, and we as well as other groups involved in clinical trials have demonstrated that the use of EPCs was safe and feasible for the treatment of critical limb ischemia and cardiovascular diseases. However, many issues in the field of EPC biology, especially in regard to the proper and unambiguous molecular characterization of these cells, still remain unresolved, hampering not only basic research but also the effective therapeutic use and widespread application of these cells. Further, recent evidence suggests that several diseases and pathological conditions are correlated with a reduction in the number and biological activity of EPCs, making the development of novel strategies to overcome the current limitations and shortcomings of this promising but still limited therapeutic tool by refinement and improvement of EPC purification, expansion, and administration techniques, a rather pressing issue. PMID- 21254838 TI - Assessment of redox changes to hydrogen peroxide-sensitive proteins during EGF signaling. AB - Hydrogen peroxide acts as a second messenger in growth factor signaling where it can oxidize and modify the function of redox-sensitive proteins. While selective thiol oxidation has been measured, there has been no global assessment of protein oxidation following growth factor activation. Significant changes to the abundant and widely distributed redox sensitive thiol proteins were observed in A431 epidermoid carcinoma cells exposed to hydrogen peroxide, but no changes were observed following treatment with epidermal growth factor (EGF). This included members of the peroxiredoxin family, which were also monitored in the presence of the thioredoxin reductase inhibitor auranofin to limit their capacity to recycle to the reduced form. We conclude that widespread thiol oxidation does not occur in cells during EGF signaling, and that hydrogen peroxide must act in a highly localized or selective manner. PMID- 21254839 TI - The quantitative significance of the transsulfuration enzymes for H2S production in murine tissues. AB - The enzymes of the transsulfuration pathway, cystathionine beta-synthase (CBS) and cystathionine gamma-lyase (CSE), are important for the endogenous production of hydrogen sulfide (H(2)S), a gaseous signaling molecule. The relative contributions of CBS and CSE to H(2)S generation in different tissues are not known. In this study, we report quantification of CBS and CSE in murine liver and kidney and their contribution to H(2)S generation in these tissues and in brain at saturating substrate concentrations. We show that CBS protein levels are significantly lower than those of CSE; 60-fold and 20-fold in liver and kidney, respectively. Each enzyme is more abundant in liver compared with kidney, twofold and sixfold for CBS and CSE, respectively. At high substrate concentrations (20 mM each cysteine and homocysteine), the capacity for liver H(2)S production is approximately equal for CBS and CSE, whereas in kidney and brain, CBS constitutes the major source of H(2)S, accounting for ~80% and ~95%, respectively, of the total output. At physiologically relevant concentrations of substrate, and adjusting for the differences in CBS versus CSE levels, we estimate that CBS accounts for only 3% of H(2)S production by the transsulfuration pathway enzymes in liver. PMID- 21254840 TI - Pathobiology of junctional adhesion molecules. AB - Junctional adhesion molecules are transmembrane proteins that belong to the immunoglobulin superfamily. In addition to their localization in close proximity to the tight junctions in endothelial and epithelial cells, junctional adhesion molecules are also expressed in circulating cells that do not form junctions, such as leukocytes and platelets. As a consequence, these proteins are associated not only with the permeability-regulating barrier function of the tight junctions, but also with other biologic processes, such as inflammatory reactions, responses to vascular injury, and tumor angiogenesis. Furthermore, because of their transmembrane topology, junctional adhesion molecules are poised both for receiving inputs from the cell interior (their expression, localization, and function being regulated in response to inflammatory cytokines and growth factors) and for translating extracellular adhesive events into functional responses. This review focuses on the different roles of junctional adhesion molecules in normal and pathologic conditions, with emphasis on inflammatory reactions and vascular responses to injury. PMID- 21254841 TI - Home management of oral anticoagulation via telemedicine versus conventional hospital-based treatment. AB - BACKGROUND AND OBJECTIVE: We have developed an expert computer system for the control of oral anticoagulation therapy, accessible by the patients via their own computer. To investigate if the weekly measurement and dosing of international normalized ratio (INR) at home using the online Internet-based system was superior to conventional treatment, we performed a randomized, controlled trial. PATIENTS AND METHODS: All 669 patients in our anticoagulation clinic were asked to participate in the trial, providing that they had Internet access and could use the CoaguChek XS system. A total of 140 patients were included and randomized to (A) once weekly measurement and report online, (B) twice weekly measurement and report online, and (C) continued conventional treatment with INR measurement in the lab every 4 weeks and dose adjustment by letter. RESULTS: Group A had 79.7% (95% CI 79.0-80.3) of time in therapeutic range (TTR), group B 80.2% (95% CI 79.4-80.9) of TTR, and group C 72.7% (95% CI 71.9-73.4) TTR. Groups A and B perform statistically significantly better than the conventional group C, with a difference of TTR of 7% points (p < 2.2 * 10(-16)), whereas no difference was seen between A and B. CONCLUSION: Home measurement of INR and the reporting and dosing of results online once a week increase TTR from 72% to 79% as compared to conventional computer-assisted monitoring in an anticoagulation clinic. PMID- 21254842 TI - Small-sized lesions of childhood vitiligo treated by autologous epidermal grafting. AB - BACKGROUND: Currently many children and adolescents with vitiligo fail to respond to traditional medical treatment. However, their parents want the lesion to be removed as soon as possible. Although surgical therapies are viable alternatives in refractory and stabilized vitiligo, there are rare reports on surgical therapies for childhood vitiligo. OBJECTIVE: To assess the effectiveness and feasibility of using suction blister epidermal grafting for small-sized childhood vitiligo. METHODS: Twenty children with small-sized lesions of stable vitiligo were treated using epidermal grafts and followed-up for 6-12 months. RESULTS: After 6-12 months of follow-up, treatment outcomes were excellent in 17 patients (85%), good in two patients (10%), and poor in one patient (5%), out of a total of 20 patients. The mean repigmentation rate was 88.55%. The location of the lesions was probably a factor in determining the outcomes of transplantation. No scar formation or other complications were observed in any patients. CONCLUSION: Suction blister autologous epidermal grafting is a rapid, safe, and effective treatment for stable childhood vitiligo, especially in refractory and stable children with small-sized lesions. PMID- 21254843 TI - Exploring the use of weekly pulsed steroids for the treatment of dermatologic diseases. PMID- 21254844 TI - Pharmacogenetic screening of N-acetyltransferase 2, thiopurine s methyltransferase, and 5,10-methylene-tetrahydrofolate reductase polymorphisms in Northwestern Mexicans. AB - Specific information about the population pharmacogenetics can be the starting point to study the inheritance of these traits, to design individual drug therapy, and to develop new drugs rationally. Pharmacogenetic studies have been performed in some regions of Mexico, such as Central and Northeast, but this kind of study has not been conducted in the Northwest region so far. Here, we report the distribution of NAT2, TPMT, and MTHFR gene polymorphisms in Baja California, Mexico. We found that our population sample exhibits allele and genotype frequencies that are highly similar to those observed in Caucasian populations, although it should be noted that there are slight similarities with those determined in other populations. As allelic variants of drug-metabolizing enzymes are prevalent in our population, it is important to consider pharmacogenetic testing as part of the standard diagnostic protocols before medication. PMID- 21254846 TI - Implementation of a cost-effective unlabeled probe high-resolution melt assay for genotyping of Factor V Leiden. AB - The Factor V Leiden mutation (FVL; c.1601G>A, p.Arg534Gln), the most common aberration underlying activated Protein C resistance, results in disruption of a major anticoagulation pathway and is a leading cause of inherited thrombophilia. A high-throughput assay for FVL mutation detection was developed using a single unlabeled probe on a high-resolution platform, the 96-well Roche 480 LightCycler (LC480) instrument. This method replaced the U.S. Food and Drug Administration approved Roche Factor V Leiden kit assay on the LightCycler PCR instrument, decreasing total cost by 48%. The analytical sensitivity and specificity of the LC480 high-resolution assay approached 100% for the FVL mutation. Factor V mutations in proximity to the FVL locus may influence probe binding efficiency and melt characteristics. One out of three very rare variants tested in a separate study, 1600delC, was not distinguishable from FVL using the described high-resolution assay. However, a c.1598G>A variant, which changes the amino acid sequence from arginine to lysine at position 533, was detected by this high resolution assay and confirmed by bidirectional sequencing. In the labeled probe LightCycler assay, the c.1598G>A variant was indistinguishable from the heterozygous FVL control. The c.1598G>A variant has not been described previously and its clinical significance is uncertain. In conclusion, the LC480 FVL assay is cost effective in a high-throughput setting, with capability to detect both previously described and novel FV variants. PMID- 21254845 TI - Culex flavivirus and West Nile virus mosquito coinfection and positive ecological association in Chicago, United States. AB - Culex flavivirus (CxFV) is an insect-specific flavivirus globally distributed in mosquitoes of the genus Culex. CxFV was positively associated with West Nile virus (WNV) infection in a case-control study of 268 mosquito pools from an endemic focus of WNV transmission in Chicago, United States. Specifically, WNV positive Culex mosquito pools were four times more likely also to be infected with CxFV than were spatiotemporally matched WNV-negative pools. In addition, mosquito pools from residential sites characterized by dense housing and impermeable surfaces were more likely to be infected with CxFV than were pools from nearby urban green spaces. Further, 6/15 (40%) WNV-positive individual mosquitoes were also CxFV positive, demonstrating that both viruses can coinfect mosquitoes in nature. Phylogenetic analysis of CxFV from Chicago demonstrated a pattern similar to WNV, consisting of low global viral diversity and lack of geographic clustering. These results illustrate a positive ecological association between CxFV and WNV, and that coinfection of individual mosquitoes can occur naturally in areas of high flaviviral transmission. These conclusions represent a challenge to the hypothesis of super-infection exclusion in the CxFV/WNV system, whereby an established infection with one virus may interfere with secondary viral infection with a similar virus. This study suggests that infection with insect-specific flaviviruses such as CxFV may not exclude secondary infection with genetically distinct flaviviruses such as WNV, and that both viruses can naturally coinfect mosquitoes that are epidemic bridge vectors of WNV to humans. PMID- 21254847 TI - Favorable clinical response by pre-prandial administration of low-dose ciclosporin to severe adult atopic dermatitis. AB - Although ciclosporin is useful for atopic dermatitis (AD), appropriate dosage and therapeutic drug monitoring (TDM) has been performed only by post-prandial ciclosporin administration. We administered ciclosporin pre-prandially to eight severe adult AD patients (four cases of erythrodermic AD, three cases of AD recalcitrant to standard therapy, and one AD case with numerous pruriginous lesions). Blood concentrations of ciclosporin at various dosages were measured and appropriate dosage in terms of therapeutic efficacy was analyzed by using the area under the concentration curve (AUC). AUC was estimated by the C1 (obtained serum concentration of ciclosporin at 1 hour after ciclosporin administration), C2 (concentration of ciclosporin at 2 hours) and C4 (concentration of ciclosporin at 4 hours) concentrations of ciclosporin. The trough levels of ciclosporin with 200 mg/day, 150 mg/day, and 100 mg/day administration were 96.5 ng/ml, 66.4 ng/ml, and 75.3 ng/ml, respectively. The peak serum concentration (C(max)) was obtained at 1 hour (C1) in most cases. The AUC of 0-4 hours (AUC 0-4) were 2099.5 ng . h/ml (200 mg/day), 1782.6 ng . h/ml (150 mg/day) and 1696.2 ng . h/ml (100 mg/day). VAS scores of itching and blood eosinophil counts were decreased significantly by the ciclosporin treatment. Pre-prandial administration of a relatively low dose of ciclosporin for severe atopic dermatitis resulted in a favorable subjective and objective clinical response and the measurement of blood concentration mostly correlated with the effective dosage assessment. PMID- 21254848 TI - Efficacy of clobetasol spray: factors beyond patient compliance. AB - Clobetasol 0.05% spray, a topical clobetasol propionate, is a non-greasy formulation that has shown increased clinical efficacy in a head-to-head comparison with foam formulation. Moreover, available data from randomized, controlled, double-blind trials suggests that clobetasol spray is, in fact, slightly more effective than most, if not all, other preparations of clobetasol. The fact that clobetasol spray is exceptionally easy to comply with may have played a major role in this outcome; however, other factors must be considered. These include vehicle metamorphosis post-application as well as vehicle and excipient effects on stratum corneum permeability. Basic concepts in topical drug delivery and how they apply to this spray vehicle may further explain the greater efficacy of clobetasol spray. PMID- 21254849 TI - AGER gene -374T>A (rs1800624) polymorphism is not associated with the severity of non-diabetic coronary artery disease in Han Chinese. PMID- 21254850 TI - Transplantation of autologous minigrafts for the treatment of stable vitiligo. AB - BACKGROUND: Surgical treatment of vitiligo is indicated when lesions are localized in poorly responding areas. Various surgical procedures are used to treat stable vitiligo with an inherited shortage in each one. OBJECTIVES: To evaluate the usefulness of the treatment of transplantation of autologous minigrafts for (local and generalized) stable vitiligo. METHODS: Eight patients (three males and five females) with stable vitiligo qualified for the study. They were treated with autologous minigrafts after ultrapulsed carbon dioxide laser abrasion. RESULTS: Seven patients showed excellent to good repigmentation with an average of 84.4% coverage of the treated patches. One patient had a poor response after at least 6 months of follow-up. CONCLUSIONS: Autologous minigrafts with ultrapulsed carbon dioxide laser abrasion appear to have the potential to achieve complete repigmentation in patients with stable vitiligo who fail to respond to medical treatments. PMID- 21254851 TI - Establishment of a porcine Oct-4 promoter-driven EGFP reporter system for monitoring pluripotency of porcine stem cells. AB - Porcine pluripotent cells with the capacity to generate germ line chimeras have not been developed yet. The transcription factor Oct-4 is an important marker of undifferentiating status and a central regulator of pluripotency in cells. Establishment of an Oct-4 promoter-based reporter system, such as that used in mice, will be a useful tool for monitoring the differentiating statuses of porcine cells both in vivo and in vitro. In the present study, we constructed a vector, pOGN2, in which enhanced green fluorescent protein (EGFP) was driven by the porcine Oct-4 promoter. In pigs containing this vector, EGFP was expected to be specifically expressed in pluripotent cells. We delivered the vectors into porcine fetal fibroblasts (PEFs) using liposomes. After transfected PEFs were selected with G418, we established eight cell lines containing the pOGN2 vector. When transgenic cells were used as donor nuclei to make somatic cell nuclear transfer (SCNT) embryos, SCNT embryos derived from four transgenic cell lines expressed green fluorescence. When PEFs with pOGN2 vectors were infected with retroviral vectors encoding the four transcription factors (Oct-4, Sox2, Klf4, and c-Myc), EGFP-expressing iPS cell colonies were observed at day 20. This work lays a foundation that can be used to generate a pig strain with an Oct4-EGFP reporter system, which would be greatly helpful in studying the differentiating and reprogramming mechanisms of pig embryos. PMID- 21254852 TI - Photodynamic therapy of vulvar intraepithelial neoplasia using methyl aminolevulinate. PMID- 21254853 TI - Balneotherapy for atopic dermatitis in children at Comano spa in Trentino, Italy. AB - BACKGROUND: No controlled studies have investigated whether balneotherapy is effective in atopic dermatitis (AD). OBJECTIVES: To investigate the efficacy and safety of balneotherapy performed at Comano spa (Trentino, Italy) compared to topical corticosteroids (TCS) in the treatment of AD. METHODS: This was an open, randomized, clinical trial including 104 children (aged 1-14 years) with mild to moderate AD who were assigned either to balneotherapy (n = 54) or TCS (n = 50) once daily for 2 weeks. AD severity and quality of life were measured using the SCORAD, investigator global assessment (IGA), patients' self global assessment (PSGA), children's dermatology life quality index (CDLQI) and family dermatitis impact questionnaire (FDIQ). Subjective measures were re-evaluated 4 months after the end of therapy. RESULTS: Balneotherapy and TCS resulted in a significant reduction of all parameters at week 2. TCS were more effective than balneotherapy regarding SCORAD (46% +/- 7.71 vs 26% +/- 9.4, mean +/- SD; p < 0.03). In contrast, IGA, PSGA, CDLQI and FDIQ improvement was similar. At month 4, the number and duration of relapses were less in patients treated with balneotherapy compared to those treated with TCS (p <0.0001). CONCLUSIONS: Balneotherapy at Comano spa appears to be beneficial in children with mild to moderate AD. PMID- 21254854 TI - Topical steroids versus PUVA therapy in moderate plaque psoriasis: a clinical trial along with cost analysis. AB - BACKGROUND: Psoriasis is a common chronic disease. It is estimated that between US$1.6 billion and US$3.2 billion is spent per year to treat psoriasis. OBJECTIVE: To compare psoralen plus UV-A (PUVA) therapy with topical steroids in moderate plaque psoriasis. METHODS: In this randomized, clinical trial with cost analysis, 88 patients with moderate plaque psoriasis were recruited in two equal groups to receive either PUVA therapy or topical steroids. The induction phase was applied for 4 months and the patients were followed-up for another 3 months, while the maintenance therapy continued. Outcome, direct cost (related to medications, phototherapy, laboratory tests, and medical consultation), indirect cost (related to transportation and other extra expenditures) and total cost (direct plus indirect costs) were compared between the two groups. RESULTS: The outcome was equally satisfactory in both groups. The indirect cost was significantly higher in the PUVA group, while the direct and total costs as well as the patients' satisfaction rate were comparable. Recurrence was significantly more frequent in the topical group. CONCLUSION: Although both PUVA therapy and topical steroids are equally efficient and cost-effective in moderate plaque psoriasis, the recurrence rate is higher in the latter group. PMID- 21254855 TI - "For all my family's sake, I should go and find out": an Australian report on genetic counseling and testing uptake in individuals at high risk of breast and/or ovarian cancer. AB - CONTEXT: Despite proven benefits, the uptake of genetic counseling and testing by at-risk family members of BRCA1 and BRCA2 mutation carriers remains low. AIMS: This study aimed to examine at-risk individuals' reported reasons for and against familial cancer clinic (FCC) attendance and genetic testing. METHODS: Thirty-nine telephone interviews were conducted with relatives of high-risk mutation carriers, 23% (n = 9) of whom had not previously attended an FCC. Interview responses were analyzed using the frameworks of Miles and Huberman. RESULTS: The reasons most commonly reported for FCC attendance were for clarification of risk status and to gain access to testing. While disinterest in testing was one reason for FCC nonattendance, several individuals were unaware of their risk (n = 3) or their eligibility to attend an FCC (n = 2), despite being notified of their risk status through their participation in a large-scale research project. Individuals' reasons for undergoing testing were in line with that reported elsewhere; however, concerns about discrimination and insurance were not reported in nontestees. CONCLUSIONS: Current guidelines regarding notifying individuals discovered to be at increased risk in a research, rather than clinical setting, take a largely nondirective approach. However, this study demonstrates that individuals who receive a single letter notifying them of their risk may not understand/value the information they receive. PMID- 21254856 TI - Brucellosis as a cause of fever of unknown origin in children admitted to a tertiary hospital in the Aegean region of Turkey. AB - The aim of the study was to determine the role of brucellosis in children with fever of unknown origin (FUO) in the Aegean region of Turkey. For this purpose, the records of all children referred or admitted with diagnosis of FUO to the Department of Pediatric Infectious Diseases, Ege University Medical School, between 2003 and 2008 were scanned and 92 cases were identified retrospectively. Fifty-eight of these 92 children (63%) were diagnosed with infectious diseases, brucellosis being the most frequent cause (15.2%). Although several other infectious diseases do appear as a cause of FUO, brucellosis should be particularly considered as a differential diagnosis. PMID- 21254857 TI - Pilot study on photodynamic therapy for acne using chlorophyll: evaluator blinded, split-face study. PMID- 21254859 TI - Opioids in chronic non-cancer pain. AB - INTRODUCTION: The use of chronic opioid therapy for chronic non-cancer pain is growing and is now accepted as an effective treatment modality. AREAS COVERED: Although there are guidelines and reviews for chronic opioid therapy for chronic non-cancer pain patients, physicians may still have concerns and be reluctant to prescribe strong opioids for chronic non-cancer pain. Common issues and concerns when prescribing opioid for chronic pain management are reviewed and discussed. The literature search was done using Medline with key words 'chronic non-cancer pain', 'chronic opioid therapy', 'effectiveness', 'opioid tolerance', 'opioid induced hyperalgesia', 'adverse effect', 'opioid dependency', 'addiction', 'monitoring', 'opioid contract' and various combinations with these key words. Studies from 1990 - 2010 have been included. This article helps readers to update, clarify and understand the common concerns when using opioid for chronic non-cancer pain. Clinical effectiveness and adverse effects with chronic opioid therapy, opioid tolerance and opioid-induced hyperalgesia, opioid dependency and addiction, monitoring during chronic opioid use, and opioid contact are discussed in detailed. EXPERT OPINION: Not much strongly positive data supports the long term use of opioids for pain relief, and the evidence for an improvement in functional activity is inconclusive. With careful selection of patients, meticulous prescription and monitoring protocol, chronic non-cancer pain patients who are likely to benefit from potent opioids should not be prevented from obtaining this treatment. PMID- 21254858 TI - Emerging role of redox dysregulation in alcoholic and nonalcoholic fatty liver disease. AB - Fatty liver disease (FLD), associated with chronic alcohol consumption or obesity, is a serious medical problem. Strong evidence indicates that oxidative stress and dysregulation of redox-sensitive signaling pathways are central to the pathobiology of FLD. Herein, this Forum summarizes current knowledge regarding mechanisms of FLD from both clinical and experimental studies. Special emphasis is given to the role of redox biology disturbances in the initiation and progression of FLD from both chronic alcohol consumption and obesity. Focus areas in this Forum include discussions on the (i) multi-hit hypothesis; (ii) interaction of adipokines and redox signaling pathways; (iii) role of sub cellular organelle systems (i.e., endoplasmic reticulum and mitochondria); and (iv) contribution of the innate immune system, in FLD. A state-of-the-art discussion is also included highlighting key lessons learned from experimental studies using rodent models of FLD. PMID- 21254860 TI - Olanzapine pamoate for the treatment of schizophrenia. AB - INTRODUCTION: Nonadherence is still a major problem in the long-term treatment of schizophrenia. Long-acting injectable or depot atypical antipsychotics are associated with better maintenance. Olanzapine pamoate, available since 2010, is the second depot atypical antipsychotic. AREAS COVERED: This review covers data on the efficacy and tolerability/safety of olanzapine pamoate, the long-acting formulation of the atypical antipsychotic olanzapine. Administered as a pamoate salt, it has an elimination half-life of 30 days, allowing a 2- or 4-week injection interval. Antipsychotic efficacy was documented in an 8-week trial in 404 acutely ill schizophrenia patients with maintenance therapy in a 24-week trial in 1065 chronic patients. The side-effect profile is comparable to that of oral olanzapine. The most relevant adverse event is the post-injection delirium/sedation syndrome, occurring at a rate of 0.07% of injections or 1.4% of patients. It requires administration by qualified personnel in settings where a post-injection observation period for 3 h by medical personnel is available. EXPERT OPINION: Olanzapine pamoate is an efficacious formulation, particularly for patients with a history of good response to oral olanzapine and doubtful adherence. Psychiatrists should reconsider their negative attitudes toward long acting or depot antipsychotics and should offer this administration to the majority of patients, not only to a negatively selected population. PMID- 21254861 TI - Current concepts in the treatment of epidermolysis bullosa acquisita. AB - INTRODUCTION: Long-term remission in EBA patients is difficult to achieve. Patients who are resistant or develop side effects to conventional immunosuppressive therapy (CIST) have been treated with several other agents. AREAS COVERED: This review focuses on the clinical outcome in patients treated with a single drug or combination, and determines if long-term remission can be induced. Data on 71 patients was analyzed. There are no controlled trials. The regimens used included dapsone, colchicine, mesalazine, cyclosporine, mycophenolic acid, intravenous immunoglobulin, rituximab, daclizumab, extracorporeal photochemotherapy, and plasmapheresis. An algorithm on treating a patient has been presented. EXPERT OPINION: The use of CIST, especially in wide spread and recalcitrant patients, usually does not produce a prolonged clinical remission and can have hazardous side effects. Intravenous immunoglobulin, rituximab and immunoadsorption have been successfully used in some, but the benefits from their use may require additional studies. The immediate future holds much promise for the development of a specific ELISA which may facilitate the early diagnosis of EBA. As the population ages, it is likely that the number of patients will increase and newer biological agents may emerge that may have a better clinical outcome. One of the challenges is to produce "targeted therapies". PMID- 21254862 TI - Prophylactic and therapeutic strategies in chemotherapy-induced neutropenia. AB - INTRODUCTION: Neutropenia poses a serious threat to patients on chemotherapy. It exposes them to the risk of infection--including potentially fatal infections- and also leads to delays in treatment and reductions in dose intensity, which can compromise the possibility of a favorable outcome. AREAS COVERED: The use of granulocyte colony-stimulating factors (G-CSF) and antibiotics to prevent febrile neutropenia (FN) and to ameliorate cancer chemotherapy-induced myelosuppression is discussed, based on a systematic search of Pubmed for clinical trials, reviews and meta-analysis published in the last 20 years. We consider that the treatment of FN, with the emphasis on careful attention to the patient, prompts antibiotic therapy and good hospital care. EXPERT OPINION: We would argue that antibiotic prophylaxis should be offered routinely to patients receiving cytotoxic chemotherapy for acute leukemia and for patients with solid tumors and lymphoma receiving high-dose chemotherapy. In patients undergoing cyclical standard-dose myelosuppressive chemotherapy, we believe that prophylaxis is indicated during the first cycle of chemotherapy in which there is an expectation of grade 4 neutropenia (< 500 neutrophils). However, although the use of antibiotics and haematopoietic growth factors may improve quality of life by reducing the risk and consequences of FN, further study of the magnitude of their effects is needed. PMID- 21254863 TI - Pharmacotherapy for acute pain in children: current practice and recent advances. AB - INTRODUCTION: Acute pain in children may be undertreated. Improved understanding of developmental neurobiology and paediatric pharmacokinetics should facilitate better management of pharmacotherapy. The objective of this review is to discuss current paediatric practice and recent advances with these analgesic agents by using an evidence-based approach. AREAS COVERED: Using PubMed an extensive literature review was conducted on the commonly used analgesic agents in children from 2000 to April 2010. EXPERT OPINION: A multimodal analgesic regimen provides better pain control and functional outcome in children. The choice of pharmacological treatment is determined by the severity and type of pain. However, more research and evidence is required to determine the optimal drug combinations. PMID- 21254864 TI - Beyond efficacy: pharmacokinetic differences between clopidogrel, prasugrel and ticagrelor. AB - INTRODUCTION: Clinical nonresponse to clopidogrel has been associated with variability in response. This has led to the development of other P2Y12 receptor inhibitors, such as prasugrel and ticagrelor, with different pharmacokinetic characteristics that influence their pharmacodynamics. AREAS COVERED: Clopidogrel response variability is attributable to its complex pharmacokinetics and is vulnerable to genetic polymorphisms in genes involved in absorption, metabolism and drug-drug interactions (i.e., proton pump inhibitors). Prasugrel which has a simpler metabolism, leading to greater bioavailability, seems to be less affected by genetic or drug-drug interactions and achieves a greater antiplatelet effect. Ticagrelor is the most novel compound approved with a simpler metabolism. Both prasugrel and ticagrelor reached their antiplatelet effect faster and to a much greater extent than clopidogrel. All these differences observed in kinetics explain, to some degree, the efficacy and safety profile observed in clinical trials for these molecules associated with other antiplatelet agents (aspirin, gpIIb/IIIa inhibitors) and anticoagulants. EXPERT OPINION: Clopidogrel is still the best standard of care. However, the pharmacokinetic advantages of both prasugrel and ticagrelor allow clinicians to center patient management by selecting the best drug for the appropriate subject. PMID- 21254866 TI - Treatment of central sensitization in patients with 'unexplained' chronic pain: what options do we have? AB - INTRODUCTION: Central sensitization accounts for chronic 'unexplained' pain in a wide variety of disorders, including chronic whiplash-associated disorders, temporomandibular disorders, chronic low back pain, osteoarthritis, fibromyalgia, chronic fatigue syndrome and chronic tension-type headache among others. Given the increasing evidence supporting the clinical significance of central sensitization in those with unexplained chronic pain, the awareness is growing that central sensitization should be a treatment target in these patients. AREAS COVERED: This article provides an overview of the treatment options available for desensitizing the CNS in patients with chronic pain due to central sensitization. It focuses on those strategies that specifically target pathophysiological mechanisms known to be involved in central sensitization. In addition, pharmacological options, rehabilitation and neurotechnology options are discussed. EXPERT OPINION: Acetaminophen, serotonin-reuptake inhibitor drugs, selective and balanced serototin and norepinephrine-reuptake inhibitor drugs, the serotonin precursor tryptophan, opioids, N-methyl-d-aspartate (NMDA)-receptor antagonists, calcium-channel alpha(2)delta (a2delta) ligands, transcranial magnetic stimulation, transcutaneous electric nerve stimulation (TENS), manual therapy and stress management each target central pain processing mechanisms in animals that - theoretically - desensitize the CNS in humans. To provide a comprehensive treatment for 'unexplained' chronic pain disorders characterized by central sensitization, it is advocated to combine the best evidence available with treatment modalities known to target central sensitization. PMID- 21254865 TI - Changing anticoagulant paradigms for atrial fibrillation: dabigatran, apixaban and rivaroxaban. AB - INTRODUCTION: Vitamin K antagonists (VKAs) are the main therapeutic agents used to prevent embolic events in patients with atrial fibrillation (AF). Despite their proven efficacy, VKAs are underused and have several limitations. In recent years, there has been great interest in the development of new oral anticoagulants with a more efficient pharmacological profile, first tested in venous thromboembolism prevention and later in AF. AREAS COVERED: The authors review the pharmacological differences between dabigatran, rivaroxaban and apixaban, and potential subgroups of patients in whom these new drugs would constitute a possible alternative to VKA therapy. Pharmacodynamic and pharmacokinetic data from each compound are analyzed in respect to their potential use in AF. This article provides an exhaustive review of the current status of this topic and the controversies still regarding each drug. EXPERT OPINION: Apixaban and rivaroxaban are under evaluation for thromboembolic prevention in AF; dabigatran was recently approved for this indication. Therefore, it is important to know the characteristics of these drugs as a potential alternative to VKAs. PMID- 21254867 TI - Effect of sequential application of topical adapalene and clindamycin phosphate in the treatment of Japanese patients with acne vulgaris. AB - The efficacy of combined therapy with a retinoid and antibiotic for Japanese patients with acne vulgaris remains to be established. Further, maintenance strategies limiting the use of topical retinoids must be identified. The objectives of this study are to determine the efficacy of sequential application of topical adapalene and clindamycin phosphate and to assess the impact of this regimen on patients' quality of life. Sixty-six patients were recruited. The regimen comprised two phases. For the 4-week initial treatment, 1% clindamycin phosphate gel was applied twice daily and 0.1% adapalene gel, once. In the 4-week maintenance phase, patients were randomly assigned to the OD group (adapalene applied once daily) or the TW group (adapalene applied once daily on 2 days per week). The acne severity score, lesion counts, microcomedone count, and sebum amount were measured. Quality of life (QOL) was assessed using Skindex-16. All parameters improved significantly by week 4 of initial treatment. No statistically significant differences were found in the improvement of clinical findings between the groups. All QOL scores improved significantly and did not significantly differ between the groups. Our regimen may enable clinical control of acne in Japanese patients and improve their QOL. For limiting retinoid use, weekly application of adapalene during maintenance is suitable. PMID- 21254868 TI - Psoriasis and psoriatic arthritis induced in a patient treated with infliximab for Crohn's disease. AB - The induction of psoriasis as a side effect of treatment with TNF-alpha inhibitors is one of a few rare complications of treatment, the pathogenic mechanism of which has not yet been completely clarified. The clinical presentation of these reactions may show the typical characteristics of psoriasis, palmoplantar pustulosis and psoriasiform exanthema; the individual variations of which may combine to give different presentations in individual patients. We present the case of a patient who, after administration of infliximab indicated for Crohn's disease, developed not only skin manifestations but also those of psoriatic arthritis. PMID- 21254869 TI - Gasless laparoscopy-assisted distal gastrectomy for early gastric cancer: analysis of initial results. AB - BACKGROUND: Laproscopic surgery is widely used in treating gastrointestinal disease. This study investigated the clinical result, short-term outcomes, and cost analysis of the newly developed gasless laparoscopy-assisted distal gastrectomy (GLADG) and compared it with conventional open distal gastrectomy (ODG). METHODS: Seventy-five patients underwent distal gastrectomy with radical lymph node dissection for early gastric cancer from December 2005 to January 2008. Thirty-one patients underwent GLADG and 44 underwent ODG. Postoperative pain, morphine use, disease-free and overall survival, and surgical and hospital costs were measured postoperatively and compared between the two groups. RESULTS: Patients in the two groups were comparable by age, sex, body mass index, tumor size, tumor location, cancer staging, and operative time. The GLADG group had early start of oral intake and shorter postoperative hospital stay (P < .05). There was less morphine use from postoperative day 1 to 4 in the GLADG group than in the ODG group (P < .05), and body temperature from postoperative day 1 to 2 was lower in the GLADG than in the ODG group (P < .05). Cost analysis showed that operation cost (100,242 +/- 5385 versus 36,455 +/- 1419) and equipment cost (65,909 +/- 5385 versus 2122 +/- 1419) was higher in the GLADG group, but its total hospital cost (193,552 +/- 12,715 versus 206,676 +/- 41,920) was lower than in the ODG group (P < .05). The 2-year disease-free and overall survival rates were not different between the two groups. CONCLUSIONS: GLADG is feasible for early gastric cancer. It is advantageous because of less pain, less postoperative inflammatory response, less blood loss, and shorter total hospital stay while achieving the same oncologic results as ODG. PMID- 21254870 TI - Molecular detection and genetic diversity of Leishmania donovani in naturally infected Phlebotomus chinensi from southwestern China. AB - Zoonotic visceral leishmaniasis is an important vector-borne infectious disease in western China. In this study, an epidemiological study was carried out on the vector of zoonotic visceral leishmaniasis in rural areas from Sichuan Province, southwestern China. In the 1263 phlebotomine sandflies captured, 859 (68.01%) were females and 404 (31.99%) males, belonging to Phlebotomus chinensis (83.37%), Sergentomyia koloshanensis (6.57%), Sergentomyia squamirostris (4.04%), and Sergentomyia barraudi (6.02%), respectively. The average prevalence of Leishmania parasites in P. chinensis females was 1.98%, which was detected by real-time quantitative PCR. Phylogenetic analysis based on ITS2-rDNA revealed that Leishmania parasites detected in sandflies belonged to the L. donovani group and formed a novel haplotype. This was the first report on molecular detection of L. donovani in naturally infected P. chinensi from China. PMID- 21254871 TI - Cyproterone acetate or drospirenone containing combined oral contraceptives plus spironolactone or cyproterone acetate for hirsutism: randomized comparison of three regimens. AB - OBJECTIVE: To compare the effectiveness of three different combinations of combined oral contraceptives (COCs) and anti-androgens in the treatment of hirsutism. METHODS: A total of 134 women with moderate and severe hirsutism were randomly assigned to three treatment regimens: Group I received 30 MUg of ethinyl estradiol (EE)/3 mg of drospirenone (DRSP) plus 100 mg of cyproterone acetate (CPA) (n = 45); group II received 30 MUg of EE/3 mg of DRSP plus 100 mg of spironolactone (n = 44); and group III received 35 MUg of EE/2 mg of CPA plus 100 mg of CPA (n = 45), daily for 6 months. The decrease in the modified Ferriman Gallwey hirsutism score (mFGS) was the main outcome measure. RESULTS: The mean decrease in mFGS after 3 and 6 months of the treatment course was 26% and 49% in group I (both p < 0.01), 27% and 49% in group II (both p < 0.01), and 25% and 45% in group III (both p < 0.01), respectively, when compared with baseline. Although the mFGS was significantly decreased in all groups, there was no significant difference between groups. CONCLUSION: CPA or DRSP containing COCs in combination with CPA or spironolactone have similar effects for the treatment of hirsutism. PMID- 21254872 TI - Safety and efficacy of olmesartan: an observational pooled-analysis of 156,682 hypertensive patients. AB - BACKGROUND: Angiotensin type 1 receptor blockers are recommended for first-line antihypertensive treatment. METHODS: We performed a pooled-analysis of 20 post authorization surveys of olmesartan involving 156,682 hypertensive patients. Olmesartan was used as monotherapy or in combination with other antihypertensive drugs, for example, hydrochlorothiazide. OBJECTIVES: We assessed the safety of olmesartan by monitoring adverse drug reactions (ADRs). The number of patients achieving systolic and diastolic blood pressure (BP) targets (< 140/90 mmHg in the overall population, < 130/80 mmHg in high-risk patients) or responding to treatment (BP decrease of >= 20/10 mmHg) was also determined. RESULTS: In all, 43.8% of patients received olmesartan monotherapy, 29% olmesartan with hydrochlorothiazide and 27.2% olmesartan in combination with other antihypertensives. The frequency of ADRs was 0.4% and not altered by dose, age >= 65 years or presence of co-morbidities. About 90% of patients were responders. Blood pressure targets were achieved in 52.8 and 35.7% of patients without risk factors and in the overall cohort, but only in 8.1 and 27.5% of patients with renal dysfunction or taking NSAIDs. CONCLUSION: Olmesartan was very well tolerated. Responder rates to olmesartan were high, although BP targets were only achieved in a minority of patients at high risk, with renal dysfunction or taking NSAIDs. PMID- 21254873 TI - Quantitative knowledge-based analysis in compound safety assessment. AB - INTRODUCTION: Despite rapid progress in OMICs and computational technologies in compound safety assessment, drug failure rate due to toxicity is still unacceptably high. One reason for this is an inadequate interpretation of high throughput preclinical data. Another reason is the poor mechanistic understanding of drug side effects as currently just a few compound targets are linked to specific adverse reactions. AREAS COVERED: Current performance issues with statistical analysis of OMICs data or gene/protein/compound lists are discussed, illustrating potential advantages of knowledge-based approaches in prediction of human toxicity. The authors show several examples of quantitative functional analysis, including cross-tissue toxicity predictions and integrated analysis of different types of OMICs data. They also describe novel approaches linking compound targets and associated pathways to side effects. The reader will gain an update on the recent developments in knowledge-based analysis in toxicogenomics and computational methods correlating protein targets with adverse reactions. EXPERT OPINION: Quantitative pathway analysis is a useful approach for deriving multi-variant predictive biomarkers for drug safety. However, more comprehensive studies are needed for direct comparison of performance between pathway- and gene centric methods. PMID- 21254875 TI - Psoriasis responds to intralesional injections of alefacept and may predict systemic response to intramuscular alefacept: interim results of a single-arm, open-label study. AB - BACKGROUND: Alefacept is a remittive treatment for generalized psoriasis but is rarely used due to its erratic efficacy. OBJECTIVE: To determine if psoriasis plaques will respond to intralesional alefacept and if this predicts a systemic response to intramuscular (IM) alefacept. METHODS: We describe a 25-week, single center, open-label study. Patients received weekly intralesional alefacept of increasing concentrations into target plaques for 3 weeks followed by IM injections for 12 weeks and concluded with an observation period of 9 weeks. The psoriasis area and severity index (PASI) was used to assess the efficacy of IM alefacept. RESULTS: Interim results are reported for the first seven patients enrolled. Two patients responded intralesionally to the most dilute 1:100 concentration of alefacept to sterile water and achieved a 59% and 100% improvement in PASI. Five patients did not respond intralesionally to the most dilute form of alefacept and none achieved PASI 75. Two of these five patients did not respond to any concentration and achieved a 26% and 38% improvement in PASI. Limitations to this study include a small sample size and being non-placebo controlled. CONCLUSION: Alefacept is effective intralesionally and may predict a systemic response - challenging the concept that biologics must work systemically. PMID- 21254876 TI - Distribution of CGG/GCC repeats at the FMR1 and FMR2 genes in an Indian population with mental retardation of unknown etiology. AB - AIMS: Fragile X syndrome is one of the X-linked disorders associated with moderate to severe mental retardation. Fragile X A syndrome (FRAXA) and fragile X E syndrome (FRAXE) are caused by trinucleotide repeat expansion of CGG and GCC repeats at the 5' untranslated region of the FMR1 and FMR2 genes, respectively. The present study was undertaken to identify the repeat polymorphism and to estimate the risk of transmission in Andhra Pradesh and surrounding states of South India. RESULTS: The FRAXA and FRAXE allelic polymorphisms were studied by radioactive polymerase chain reaction that revealed 25 FRAXA among 344 X chromosomes and 20 FRAXE allelic variants among 212 X-chromosomes in our population. The most frequent FRAXA allele size was of 29 CGG repeats (27.5%) followed by allele sizes of 28 (20.8%) and 31 (7.2%), and that of FRAXE was 15 GCC repeats (24.0%) followed by allele containing 18 repeats (18.4%) and 16 repeats (11.3%). CONCLUSIONS: CGG/GCC repeat polymorphism at the FMR1 and FMR2 loci observed in this study demonstrated a racial and ethnic variation among the populations. PMID- 21254877 TI - Toll-like receptor 9 agonists as cancer therapeutics. AB - INTRODUCTION: Toll-like receptor 9 (TLR9) agonists, commonly referred to as CpG oligodeoxynucleotides (ODN), have been added to the arsenal of anti-cancer drugs as monotherapy or in combination with chemotherapy, radiotherapy and other immunotherapeutic approaches as they increase antigen presentation and boost anti tumor T- and B-cell responses. Several synthetic TLR9 agonists have been developed for clinical grade use and displayed substantial efficacy in the preclinical and clinical models. AREAS COVERED: This review summarizes TLR9 signaling and the impact of TLR9 agonists on the immune response. The most recent experimental and clinical data are analyzed as well as the development of new TLR9 agonists in current clinical trials. EXPERT OPINION: Application of TLR9 agonists, in particular, combination strategies with chemo- or radiotherapy seem a promising and efficient immunotherapeutic approach in cancer patients even with refractory disease. Simultaneous application of TLR9 agonists aims at supporting the patient's immune response and overcoming specific immunosuppressant strategies developed by tumors. Combinatory approaches of the future might also seek for synergism of TLR9 agonists with other immunomodulatory strategies such as B-cell activation using the CD40-CD40L system. PMID- 21254874 TI - The effect of grapefruit juice on drug disposition. AB - INTRODUCTION: Since their initial discovery in 1989, grapefruit juice (GFJ)-drug interactions have received extensive interest from the scientific, medical, regulatory and lay communities. Although knowledge regarding the effects of GFJ on drug disposition continues to expand, the list of drugs studied in the clinical setting remains relatively limited. AREAS COVERED: This article reviews the in vitro effects of GFJ and its constituents on the activity of CYP enzymes, organic anion-transporting polypeptides (OATPs), P-glycoprotein, esterases and sulfotransferases. The translational applicability of the in vitro findings to the clinical setting is discussed for each drug metabolizing enzyme and transporter. Reported AUC ratios for available GFJ-drug interaction studies are also provided. Relevant investigations were identified by searching the PubMed electronic database from 1989 to 2010. EXPERT OPINION: GFJ increases the bioavailability of some orally administered drugs that are metabolized by CYP3A and normally undergo extensive presystemic extraction. In addition, GFJ can decrease the oral absorption of a few drugs that rely on OATPs in the gastrointestinal tract for their uptake. The number of drugs shown to interact with GFJ in vitro is far greater than the number of clinically relevant GFJ-drug interactions. For the majority of patients, complete avoidance of GFJ is unwarranted. PMID- 21254878 TI - Preliminary experience of one-trocar laparoscopic herniorrhaphy in infants and children. AB - OBJECTIVE: Laparoscopy is an alternative procedure for pediatric inguinal hernia, with a trend toward increasing use of extracorporeal knotting and decreasing use of working ports. The aim of this study was to evaluate the preliminary results of one-trocar laparoscopic herniorrhaphy in infants and children. METHODS: Between April 2007 and March 2010, 216 infants and children treated were retrospectively reviewed. Under laparoscopic guidance, the hernia defect was closed extracorporeally by a nonabsorbable suture, which was introduced into the abdomen by an 18-gauge vascular access on one side of the hernia defect and withdrawn on the opposite side by a homemade hook-pin through a stab incision. Preperitoneal hydrodissection was performed during the procedure. Being a developing technique, multiple linear regressions were used to model markers for the operating time, including descriptive data, diameter of scope, operation findings, and the procedural volume. RESULTS: A total of 308 procedures were successfully performed among 214 patients (99.1%) and the mean operating time was 42.9 +/- 24.7 minutes (range: 9-255 minutes). Additional working instruments were necessary in 7 patients (3.3%). Only 2 (0.9%) recurrences were observed during this period. Male gender (beta = 7.507, P = .001), prematurity (beta = 10.051, P = .004), presence of incarcerated hernia (beta = 12.188, P = .016), and both sides simultaneous operation (beta = 7.057, P = .001) would increase the operating time, while being independent of age, weight, presence of sliding hernia, and diameter of scope. However, the operating time may decrease with procedural volume (beta = -0.119, P < .001). CONCLUSIONS: Without assistant working instrument, laparoscopy-assisted extracorporeal ligation of the hernia defect may be safely performed in most infants and children. The use of preperitoneal hydrodissection and extraperitoneal knot-tying could tautly enclose the hernia defect without peritoneal gaps and approach an accepted recurrence rate. PMID- 21254880 TI - The potency of clobetasol propionate: serum levels of clobetasol propionate and adrenal function during therapy with 0.05% clobetasol propionate in patients with severe atopic dermatitis. AB - BACKGROUND: Percutaneous absorption of topically applied 0.05% clobetasol propionate (CLO) can be assessed indirectly by measuring cortisol levels. A direct way is to measure systemic levels of topically applied CLO. METHODS: Serum concentrations of CLO were measured by liquid chromatography-tandem mass spectrometry (LC/MS/MS), and were related to serum cortisol levels in 25 patients with an exacerbation of atopic dermatitis (AD) before and after the first day of treatment with 0.05% CLO in hospital. The body surface area (BSA) affected by AD was measured. RESULTS: Before the start of 0.05% CLO treatment, normal cortisol levels were measured (0.47 +/- 0.18 MUmol/l) and CLO concentrations could not be detected. After the first day of treatment, cortisol levels decreased to 0.04 +/- 0.05 MUmol/l. Serum concentrations of CLO could be detected in all patients (0.112-4.504 ng/ml). Levels did not differ between patients who had received two applications versus one application of 0.05% CLO. There was no correlation between the affected BSA and serum concentrations of CLO. CONCLUSION: Serum levels of CLO can be measured by LC/MS/MS. When prescribing 0.05% CLO, one must bear in mind that, even after an application of 20-30 g, CLO is systemically available and potent enough to induce adrenal gland suppression. PMID- 21254881 TI - Flare of pustular psoriasis after initiating ustekinumab therapy. AB - Anti-tumor necrosis factor-alpha therapy has been paradoxically associated with the new development or worsening of existing psoriasis. We describe the case of a patient who experienced a flare of pustular psoriasis after initiating anti interleukin-12/23 therapy, which subsequently improved following discontinuation of the drug. PMID- 21254882 TI - Personalizing dermatology: the future of genomic expression profiling to individualize dermatologic therapy. AB - At the start of the 21st century, the human genome project provided the scientific community with an enormous array of information as genetic blueprints. A landmark period, yet its potential contribution to medicine at the time was limited and unknown. However, with new technological advances, the benefits of identifying genomic profiles became apparent. This article reviews the historical accomplishments made by the human genome project, future applications of genomic expression profiles with the use of microarray gene chip technology, and the pharmacogenomic translational application of these models to dermatology. A new scientific movement in dermatology has begun with intentions of discovering individual genomic profiles responsible for dermatologic disease and drug metabolism, so that medical management can be personalized towards the genome rather than the disease. This review shows how pharmacogenomics has taken the lead in forming a basic framework of revealing specific drug metabolic pathways in the skin that can consequently be altered to maximize and minimize therapeutic efficacy and side effects, respectively. Dermatology as a model field in medicine has started to take advantage of these discoveries upon which deciphering genetic profiles can be used to enhance medical treatment. PMID- 21254883 TI - Virus role during intraepidemic increase in dengue disease severity. AB - Dengue epidemics in Cuba have repeatedly demonstrated a month-to-month increase in clinical severity during secondary infections. The dengue 2 outbreak that occurred in Santiago de Cuba in 1997 was accompanied by the most severe intraepidemic increase in disease severity reported to date. It was initially proposed that the appearance of neutralization escape mutants during the course of the epidemic might explain this phenomenon. Recent studies have revealed that during the course of this epidemic, nucleotide substitutions appeared only in nonstructural (NS) genes, most of which were silent, except for one change in the NS1 gene. To study whether or not variation in the NS1 gene might be associated with increased disease severity during the epidemic, this gene was partially sequenced from 15 isolates obtained at different times during the 1997 epidemic. Early epidemic isolates differed from those obtained later by replacement only of threonine with serine at position 164 in the NS1 protein, an amino acid rarely found in any genotype of dengue 2 virus. All viruses isolated from patients located in Health Districts, where dengue 2 transmissions occurred late in the epidemic, contained Serine at position 164, indicating that this change was fixed within a few months. Here we argue that this single mutation contributes to viral survival or replication efficiency, resulting in enhanced infection in the presence of enhancing antibodies, a phenomenon that we term increased virus "fitness" in contrast to "virulence," an intrinsic property of the virus. PMID- 21254884 TI - Apoptosis in glioma cells treated with PDT. AB - BACKGROUND: Despite significant advances in neurosurgical techniques, the median survival time of patients with glioblastoma has improved little over the past 50 years and remains less than one year. Photodynamic therapy (PDT) is presently established as a widely accepted modality for the treatment of a variety of solid tumors. OBJECTIVES: This study evaluated the effect of PDT-Photogem((r)) on five glioma cell lines (U87, U138, U251, U343, and T98G). METHODS: The experiments were carried out in 25-cm(3) flasks with different groups of cells seeded at a density of 1 * 10(5) cells per flask. After 3 h, the medium was removed, and the cells were incubated for 4 h with Photogem (5 MUg/mL). After the incubation time, the photosensitizer-containing medium was removed and the cells were irradiated with LED (630 nm, 25 mW/cm(2), 25 J/cm(2)) devices for 17 min. For the final steps of the PDT, the cells were returned to the incubator and kept at 37 degrees C with 5% CO(2) for 24 h, the cell viability assay was assessed using the trypan blue method, and the expression of Caspase 3 mRNA levels was assessed by real time quantitative PCR. RESULTS: Upon PDT-Photogem((r)) treatment, viable cells, as evaluated by the trypan blue dye-exclusion method, decreased in two cell lines (U87 and U138) but not in the other three. Apoptosis, as assessed by the expression of caspase-3 mRNA levels, was at least partly involved in the death mechanism of the cell lines. CONCLUSIONS: Collectively, our results indicated that PDT-Photogem((r)) can act in glioma cells, thus encouraging new experiments in this field. PMID- 21254885 TI - Gene polymorphisms and sport attitude in Italian athletes. AB - AIM: The aim of this study was to evaluate whether the distribution of polymorphisms in the ACE, ACTN3, NOS3, UCP2, and UCP3 genes, which has been reported to be correlated with different physiological parameters, played a role in sport performance. We focused on a cohort of 82 Italian athletes: first of all, athletes were divided according to type of sport: team (n=72) versus individual (n=10), and subsequently, according to the performance, into "power" sports (n=29; sprinters, short distance swimmers, and volleyball players) and "intermittent" sports (n=53; football, basketball, and hockey players). RESULTS: All the populations studied were in Hardy-Weinberg equilibrium for the following polymorphisms: ACE (I/D), ACTN3 (R577X), NOS3 (-786 T/C), UCP2 (A55V), and UCP3 ( 55 C/T). We observed that the frequency of NOS3-786 T and UCP2 C alleles was higher among power athletes compared with controls (p=0.011 and p=0.012, respectively); these alleles were also overrepresented in individual athletes (p=0.02 and p=0.045, respectively), although a small sample was analyzed. The frequency of NOS3 298G allele was higher among power athletes compared with controls (p=0.015); these data remained suggestive after correction for multiple testing. CONCLUSION: We found a suggestive association between NOS3 (-786 T/C; G298A) and UCP2 (A55V) polymorphisms and power athletes, whereas no significant correlation was found with UCP3 (-55C/T), ACE (I/D), and ACTN3 (R577X) polymorphisms, in contrast to previous studies. Analysis of multiple performance associated genetic polymorphisms needs further examination to explain the relationship between genetic background and potential success in sport performance. PMID- 21254886 TI - Cost per responder analysis of ustekinumab and etanercept for moderate to severe plaque psoriasis. AB - OBJECTIVE: To compare the cost per responder of ustekinumab with etanercept based on data from the active comparator ACCEPT trial. METHODS: In ACCEPT, patients received ustekinumab 45 mg (n = 209) or 90 mg (n = 347) at weeks 0 and 4 or etanercept 50 mg (n = 347) twice weekly for 12 weeks. The proportions of patients achieving >=75% improvement in the Psoriasis Area and Severity Index [PASI 75] were determined at week 12. The cost per PASI 75 responder was determined for week 16, a time coinciding with treatment coverage of both drugs and accounting for the different dosing intervals. Costs for 16 weeks of therapy were based on the Wholesale Acquisition Cost (WAC) in the United States. The analysis used weight-based efficacy results for ustekinumab (45 mg for patients <= 100 kg; 90 mg for patients > 100 kg) and overall efficacy for etanercept, consistent with the approved dosages. RESULTS: A total of 28% of patients weighed > 100 kg. The PASI 75 response rates at week 12 were 72.2% for the ustekinumab 45 mg group in patients <= 100 kg, 65.0% for the ustekinumab 90 mg group in patients > 100 kg, and 56.8% for the etanercept group. At week 16, the cost per responder was $17,842 for ustekinumab and $20,077 for etanercept. CONCLUSION: The cost per responder was lower for ustekinumab than for etanercept through 16 weeks in psoriasis patients. PMID- 21254887 TI - Medication use and associated health care outcomes and costs for patients with psoriasis in the United States. AB - BACKGROUND: The impacts of use of pharmacotherapy for psoriasis on patient outcomes and medication costs need further examination using up-to-date large nationally representative data. OBJECTIVE: To examine the impacts of patient demographics and medication use on patient's health status and associated medication costs. METHODS: A retrospective cross-sectional study was conducted using the 2007 Medical Expenditure Panel Survey (MEPS) database. Information on patient demographics, health status, medication utilization, and medication costs were obtained representing 543 231 patients with psoriasis. RESULTS: Weighted multiple linear regression analyses indicated that the use of biological/systemic agents yielded an increase in patient health status among all types of medications (beta = 7.9, p < 0.05). Use of biological/systemic agents also yielded an increase in annual medication spending (beta = 2.5, p < 0.01). Use of biological agents was elevated compared to previous studies. CONCLUSIONS: We observed an association between medication use for psoriasis treatment and its related patient health status and medication spending. The study findings could imply that encouraging the use of topical treatments may be an effective means to increase patient health status. The use of biologics needs further cost effectiveness studies given the findings that biologics contribute to substantial increases in both drug expenditures and patient health status. PMID- 21254888 TI - EcoR phylogenetic analysis and virulence genotyping of avian pathogenic Escherichia coli strains and Escherichia coli isolates from commercial chicken carcasses in southern Brazil. AB - Escherichia coli strains designated as avian pathogenic E. coli (APEC) are responsible for avian colibacillosis, an acute and largely systemic disease that promotes significant economic losses in poultry industry worldwide because of mortality increase, medication costs, and condemnation of carcasses. APEC is a subgroup of extraintestinal pathogenic E. coli pathotype, which includes uropathogenic E. coli, neonatal meningitis E. coli, and septicemic E. coli. We isolated E. coli from commercial chicken carcasses in a Brazilian community and compared by polymerase chain reaction-defined phylogenetic group (A, B1, B2, or D) with APEC strains isolated from sick chickens from different poultry farms. A substantial number of strains assigned to phylogenetic E. coli reference collection group B2, which is known to harbor potent extraintestinal human and animal E. coli pathogens, were identified as APEC (26.0%) in both commercial chicken carcasses and retail poultry meat (retail poultry E. coli [RPEC]) (21.25%). The majority of RPEC were classified as group A (35%), whereas the majority of APEC were groups B1 (30.8) and A (27.6%). APEC and RPEC presented the genes pentaplex, iutA, hly, iron, ompT, and iss, but with different virulence profiles. The similarity between APEC and RPEC indicates RPEC as potentially pathogenic strains and supports a possible zoonotic risk for humans. PMID- 21254889 TI - Does isotretinoin therapy have any effects on electrocardiography, heart rate and blood pressure? AB - BACKGROUND: Isotretinoin therapy is associated with numerous adverse effects of various systems. Although some cases have been reported, cardiac side effects are rare following isotretinoin treatment. OBJECTIVE: To investigate the effects of isotretinoin on the cardiovascular system. METHODS: Seventy patients with acne vulgaris were enrolled in the study. The patients were treated with a dose of 0.5 1.0 mg/kg per day of isotretinoin. Screening for biochemical and hematologic parameters, heart rate, blood pressure and electrocardiographic parameters were done before treatment and after 3 months of isotretinoin treatment. RESULTS: Heart rate, systolic/diastolic tension and electrocardiographic parameters (P wave duration and QTc duration) were not statistically different before compared with after treatment. CONCLUSION: As far as we know, there is no study researching the effect of isotretinoin on P- and QT-wave measurements in the literature. We found that isotretinoin did not affect P- and QT-wave measurement. Further studies with longer periods of follow-up are needed to understand the effect of isotretinoin on the cardiovascular system. PMID- 21254890 TI - Influence of low-level laser on the speed of orthodontic movement. AB - INTRODUCTION: This study evaluated the effect of low-level laser irradiation on the speed of orthodontic tooth movement of canines submitted to initial retraction. METHODS: Twenty-six canines were retracted by using NiTi spring (force of 150 g/side). Thirteen of those were irradiated with diode laser (780 nm, 20 mW, 10 sec, 5 J/cm(2)) for 3 days, and the other 13 were not irradiated and thus were considered the control group. Patients were followed up for 4 months, and nine laser applications were performed (three each month). The movement of the canines was evaluated through 3D casts, and the statistical analysis was performed with ANOVA and Tukey tests (p < 0.05). Periapical radiographs of the studied teeth were submitted to Levander, Malmgreen, and alveolar bone ridge analyses to evaluate tissue integrity and were compared with the Wilcoxon test (p < 0.05). RESULTS: A statistically significant increase in the movement speed of irradiated canines was observed in comparison with nonirradiated canines in all evaluation periods. No statistically significant difference was observed in bone and root resorption of canines, whether irradiated or not. CONCLUSION: The diode laser used within the protocol guidelines increased the speed of tooth movement. This might reduce orthodontic treatment time. PMID- 21254891 TI - Spirulina (Arthrospira) protects against cadmium-induced teratogenic damage in mice. AB - The role of Spirulina (Arthrospira) in preventing cadmium (Cd) teratogenicity in ICR mice was studied. Cd was administered intraperitoneally to female mice at 1.5 mg/kg on gestation day (GD)-7, and Spirulina was given by peroral (intragastric) administration at 62.5, 125, 250, or 500 mg/kg from GD-0 through GD-17 (the day when animals were sacrificed). Because among the mechanisms suggested to account for reproductive damage are oxidative stress and lipoperoxidation, embryonic hydroperoxides were also determined. Treatment with Spirulina at the three highest doses significantly decreased the frequency of fetuses with exencephaly, micrognathia, and skeletal abnormalities induced by Cd. Furthermore, Spirulina treatment significantly and dose-dependently decreased lipid peroxidation, which was dramatically increased by administration of the metal. The results of the present study clearly point to the therapeutic potential of Spirulina in Cd induced teratogenicity and probably through its antioxidant activity. PMID- 21254892 TI - Immunological, physiological, and behavioral effects of Salmonella enterica carriage and shedding in experimentally infected finishing pigs. AB - Finishing pigs infected with Salmonella pose significant food safety risks by carrying the pathogen into abattoirs. This study was conducted to determine the dynamics of Salmonella infection in finishing pigs, and associated immunological, physiological, and behavioral alterations, by longitudinally comparing infected to noninfected pigs during 6 weeks postinfection (p.i.). Bacteriological data revealed that all inoculated pigs started shedding Salmonella within 2 h p.i., and persistently shed the bacteria up to the end of the study. Ileal and cecal contents, as well as mesenteric lymph node samples, were all positive throughout the study, containing 3-4 log(10) cfu/g of Salmonella at 24 h p.i., and 4-5 log(10) cfu/g of Salmonella up to 4 weeks p.i. Levels of Salmonella dropped markedly (p < 0.05) in all samples at 5 weeks p.i. There was no difference between groups for blood cell counts. Tumor necrosis factor-alpha was greater (p < 0.05) in infected pigs: (1) in the mesenteric lymph nodes by 48 h p.i.; (2) at 24 h and 3 weeks p.i. in the ileum; and (3) in the cecum and spleen at 3 weeks p.i. Interleukin-12, interleukin-1 and its antagonist, and a porcine-specific antimicrobial peptide RNA expression in tissues changed over time, but were not different between groups. Infected pigs spent more time in ventral recumbency, standing, and sitting than controls (p < 0.01). Infected pigs were also more active (p < 0.01), and approached a novel object more quickly than control pigs (p < 0.05). No treatment differences were detected for rectal temperature or plasma cortisol (p > 0.10). This study shows that finishing pigs can carry high levels of Salmonella for up to 4 weeks p.i. in the gastrointestinal contents and mesenteric lymph nodes, shedding high levels of the bacteria without developing clinical symptoms, but developing an immune response throughout the intestinal tract. Moreover, subtle behavioral changes measured as postures were detected, and therefore warrant additional investigation. PMID- 21254893 TI - Intestinal nematode infections in Romania: an epidemiological study and brief review of literature. AB - OBJECTIVES: The main aim of this report was to present the epidemiological, clinical, laboratory, and therapeutic aspects of a series of patients admitted to a reference hospital from Romania and found to be infected with intestinal nematodes. Additionally, we attempted to overview, for the first time in the international literature, the most relevant data regarding diseases caused by these helminthes in Romania. PATIENTS AND METHODS: We have retrospectively investigated the medical records of patients admitted at Victor Babes Hospital of Infectious Diseases in Timisoara (Timis County) who presented infections with intestinal nematode helminthes between 1971 and 2007. RESULTS: Forty-two patients were found to be infected with intestinal nematode worms, with the predominance of Enterobius vermicularis (42.8%). The mean age of patients in this series was 23.5 +/- 16.4 years. Women were affected in 66.7% of cases and inhabitants of urban regions in 71.4% of cases. Of this series, 57.2% of patients were adults and most of them were people with limited formal education belonging to the low social class. Overall, abdominal pain was most frequently detected (59.5%) and the mean eosinophil count was 8.2% +/- 10.9% (range 1%-56%). Piperazine was administered in most of the cases (33.3%). CONCLUSIONS: Infections with intestinal nematodes are less frequently diagnosed in hospitalized patients despite that they are quite common in the Romanian population. To further limit their occurrence, public health measures and informative campaigns for the whole population should be implemented. PMID- 21254894 TI - Rheumatic heart disease and risk of incident heart failure among community dwelling older adults: a prospective cohort study. AB - BACKGROUND: Little is known about the association of rheumatic heart disease (RHD) with incident heart failure (HF) among older adults. DESIGN: Cardiovascular Health Study, a prospective cohort study. METHODS: Of the 4,751 community dwelling adults >= 65 years, free of prevalent HF at baseline, 140 had RHD, defined as self-reported physician-diagnosed RHD along with echocardiographic evidence of left-sided valvular disease. Propensity scores for RHD, estimated for each of the 4,751 participants, were used to assemble a cohort of 720, in which 124 and 596 participants with and without RHD, respectively, were balanced on 62 baseline characteristics. RESULTS: Incident HF developed in 33% and 22% of matched participants with and without RHD, respectively, during 13 years of follow-up (hazard ratio when RHD was compared to no-RHD 1.60; 95% confidence interval 1.13-2.28; P = 0.008). Pre-match unadjusted, multivariable-adjusted, and propensity-adjusted hazard ratios (95% confidence intervals) for RHD-associated incident heart failure were 2.04 (1.54-2.71; P < 0.001), 1.32 (1.02-1.70; P = 0.034), and 1.55 (1.14-2.11; P = 0.005), respectively. RHD was not associated with all-cause mortality (HR 1.09; 95% CI 0.82-1.45; P = 0.568). CONCLUSION: RHD is an independent risk factor for incident HF among community-dwelling older adults free of HF, but has no association with mortality. PMID- 21254895 TI - A novel screening method detects herpesviral DNA in the idiopathic pulmonary fibrosis lung. AB - BACKGROUND: Herpesviruses could contribute to the lung epithelial injury that initiates profibrotic responses in idiopathic pulmonary fibrosis (IPF). METHODS: We identified herpesviral DNA from IPF and control lung tissue using a multiplex PCR-and microarray-based method. Active herpesviral infection was detected by standard methods, and inflammatory cell subtypes were identified with specific antibodies. Patients that underwent lung transplantation were monitored for signs of herpesviral infection. RESULTS: A total of 11/12 IPF samples were positive for Epstein-Barr virus (EBV) and 10/12 for human herpesvirus 6B (HHV-6B) DNA. Control lung samples (n = 10) were negative for EBV DNA, whereas three samples were positive for HHV-6B. EBV-encoded RNA (EBER) was identified in nine IPF samples and localized mainly to lymphocytic aggregates. HHV-6B antigens were detected in mononuclear cells in IPF lung tissue. CD20+ B lymphocytic aggregates that were surrounded by CD3+ T cells were abundant in IPF lungs. CD23+ cells (activated B cells, EBV-transformed lymphoblasts, and dendritic cells) were observed in the aggregates. IPF patients had no signs of increased herpesviral activation after lung transplantation. CONCLUSIONS: Inflammatory cells are the main source of herpesviral DNA in the human IPF lung. Diagnostic tools should be actively used to elucidate whether herpesviral infection affects the pathogenesis, progression, and/or exacerbation of IPF. PMID- 21254896 TI - Association of liver enzymes with metabolic syndrome and carotid atherosclerosis in young adults. The Cardiovascular Risk in Young Finns Study. AB - OBJECTIVE: We examined whether metabolic syndrome (MetS) predicts increased alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) levels in young adults, whether spontaneous recovery from MetS has a favorable effect on liver enzyme activities, and whether these enzymes contribute to the atherogenicity of MetS (assessed by carotid intima-media thickness (IMT)). METHODS: The study included 1,553 subjects (base-line age 31.5 +/- 5.0 years). ALT and GGT were measured in 2007. MetS was diagnosed by the new Joint Interim Societies definition. RESULTS: ALT and GGT levels were higher in subjects with MetS compared to those without in 2007. The association was independent of alcohol intake and BMI. In multivariable models adjusted for base-line age, LDL cholesterol, CRP, alcohol intake, and adiponectin, MetS in 2001 predicted increased ALT (beta +/- SEM = 0.320 +/- 0.062, P < 0.0001 in men; 0.134 +/- 0.059, P = 0.02 in women) and GGT (beta +/- SEM = 0.222 +/- 0.067, P < 0.0001 in men; 0.236 +/- 0.060, P < 0.0001 in women) levels after 6 years. Subjects with MetS only at base-line (2001) had lower ALT levels after 6 years compared to subjects with persistent and incident MetS. No statistically significant interaction for MetS*ALT (P = 0.81) or MetS*GGT (P = 0.92) on IMT was observed. CONCLUSION: In young adults MetS may induce liver enzyme changes that indicate increased risk of non-alcoholic fatty liver disease, but we found no evidence that increased enzyme levels would amplify the atherogenicity of MetS. PMID- 21254898 TI - Between brown and white: novel aspects of adipocyte differentiation. AB - In all mammals including humans, most white and brown adipocytes are found together in visceral and subcutaneous depots (adipose organ) despite the well known difference in their function, respectively of storing energy and producing heat. A growing body of evidence suggests that the reason for such anatomical arrangement is their plasticity, which under appropriate stimulation allows direct conversion of one cell type into the other. In conditions of chronic cold exposure white-to-brown conversion meets the need for thermogenesis, whereas an obesogenic diet induces brown-to-white conversion to meet the need for storing energy. White-to-brown transdifferentiation is of medical interest, because the brown phenotype of the adipose organ is associated to obesity resistance, and drugs inducing this phenotype curb murine obesity and related disorders. Type 2 diabetes is the most common disorder associated to visceral obesity. Macrophages infiltrating the adipose organ are responsible for the low-grade chronic inflammation related to the removal of dead adipocytes, which leads to insulin resistance and T2 diabetes. Adipocyte death is closely related to their growth up to the critical death size. The critical death size of visceral adipocytes is smaller than that of subcutaneous adipocytes, likely accounting for the greater morbidity related to visceral fat. PMID- 21254897 TI - Role of complement and perspectives for intervention in ischemia-reperfusion damage. AB - Reperfusion of an organ following prolonged ischemia instigates the pro inflammatory and pro-coagulant response of ischemia / reperfusion (IR) injury. IR injury is a wide-spread pathology, observed in many clinically relevant situations, including myocardial infarction, stroke, organ transplantation, sepsis and shock, and cardiovascular surgery on cardiopulmonary bypass. Activation of the classical, alternative, and lectin complement pathways and the generation of the anaphylatoxins C3a and C5a lead to recruitment of polymorphonuclear leukocytes, generation of radical oxygen species, up-regulation of adhesion molecules on the endothelium and platelets, and induction of cytokine release. Generalized or pathway-specific complement inhibition using protein based drugs or low-molecular-weight inhibitors has been shown to significantly reduce tissue injury and improve outcome in numerous in-vitro, ex-vivo, and in vivo models. Despite the obvious benefits in experimental research, only few complement inhibitors, including C1-esterase inhibitor, anti-C5 antibody, and soluble complement receptor 1, have made it into clinical trials of IR injury. The results are mixed, and the next objectives should be to combine knowledge and experience obtained in the past from animal models and channel future work to translate this into clinical trials in surgical and interventional reperfusion therapy as well as organ transplantation. PMID- 21254899 TI - A role for glucocorticoid-signaling in depression-like behavior of gastrin releasing peptide receptor knock-out mice. AB - Abstract Background. The gastrin-releasing peptide receptor (GRPR) is highly expressed in the limbic system, where it importantly regulates emotional functions and in the suprachiasmatic nucleus, where it is central for the photic resetting of the circadian clock. Mice lacking GRPR presented with deficient light-induced phase shift in activity as well altered emotional learning and amygdala function. The effect of GRPR deletion on depression-like behavior and its molecular signature in the amygdala, however, has not yet been evaluated. Methods. GRPR knock-out mice (GRPR-KO) were tested in the forced-swim test and the sucrose preference test for depression-like behavior. Gene expression in the basolateral nucleus of the amygdala was evaluated by micorarray analysis subsequent to laser-capture microdissection-assisted extraction of mRNA. The expression of selected genes was confirmed by RT-PCR. Results. GRPR-KO mice were found to present with increased depression-like behavior. Microarray analysis revealed down-regulation of several glucocorticoid-responsive genes in the basolateral amygdala. Acute administration of dexamethasone reversed the behavioral phenotype and alterations in gene expression. Discussion. We propose that deletion of GRPR leads to the induction of depression-like behavior which is paralleled by dysregulation of amygdala gene expression, potentially resulting from deficient light-induced corticosterone release in GRPR-KO. PMID- 21254900 TI - Old and new anticoagulant drugs: a minireview. AB - Abstract The limits of traditional anticoagulants, such as heparin and warfarin, have prompted the search for new agents for prophylaxis and treatment of arterial and venous thromboembolism, including factor Xa and thrombin inhibitors. These agents can be given orally, and their most significant advantage is that no laboratory monitoring is needed. The anti-Xa inhibitor rivaroxaban and the direct thrombin inhibitor dabigatran etexilate are licensed for prophylaxis of venous thromboembolism (VTE) in high-risk orthopedic surgery. They are at least as safe and effective as heparins but much more expensive. Dabigatran, rivaroxaban, and other agents currently in the pipeline of clinical development have the potential to replace warfarin in the two most frequent indications for anticoagulation, i.e. secondary prophylaxis of VTE and atrial fibrillation. Prevention and treatment of coronary artery thrombosis in patients with ischemic heart disease is another area of investigation for the role of new anticoagulants. These drugs have the potential to meet some currently unmet needs of traditional anticoagulants, but available clinical data warrant confirmation and expansion. Lack of specific antidotes for anticoagulation reversal and the high cost are important limitations of their use. PMID- 21254901 TI - Naltrexone sustained-release (SR) + bupropion SR combination therapy for the treatment of obesity: 'a new kid on the block'? AB - The prevalence of obesity is growing rapidly worldwide, and therefore there is a need for effective treatment strategies. The rationale of combination therapy in treating chronic diseases, such as obesity, is the potential additive or synergistic effects. This review considers the results of phase III clinical trials with naltrexone sustained-release (SR) + bupropion SR combination therapy in obese patients with or without type 2 diabetes mellitus. We also discuss the potential therapeutic applications of this weight-reducing treatment option. Recent clinical trials have shown that the administration of naltrexone SR + bupropion SR resulted in effective weight loss. Furthermore, this treatment was associated with improvement in cardiometabolic variables. Depression and suicidal ideation were more frequently reported in the placebo compared with the combination groups. However, significantly more patients on naltrexone SR + bupropion SR experienced adverse events, mainly nausea, and discontinued treatment compared with placebo. Increases in blood pressure and pulse rate were observed only in the combination groups. Further investigation is needed to clarify the clinical significance of this weight-reducing therapeutic option. PMID- 21254902 TI - Percutaneous biopsy of the testicle: a mini review with a proposal flow chart for non-obstructive azoospermia. AB - A general consensus on the role of testicular biopsy in non-obstructive azoospermia (NOA) is needed. This paper reviews and updates technical aspects and clinical performance of the percutaneous testicular biopsy techniques, in particular large-needle aspiration biopsy (LNAB), and proposes a flow chart for the management of NOA. The English literature and original data were reviewed or analyzed. Large-needle biopsy (LNB) includes large-needle cutting biopsy (LNCB) and large-needle aspiration biopsy (LNAB). LNCB usually requires scrotal incision for the insertion of relatively large needles. Fine-needle aspiration biopsy (FNAB) does not require surgical equipment or expertise, employs the smallest needles (23- to 20-gauge), and permits sperm cytologic detection. LNAB also does not require surgical equipment or expertise, employs needles of size from 20- to 18-gauge, is safe, and can be used for testicular histology and sperm recovery. An operative flow chart is proposed for the management of NOA in which FNAB, LNAB and open surgical biopsy are used for the optimal management of NOA. PMID- 21254903 TI - Association between depressive symptoms and metabolic syndrome is not explained by antidepressant medication: results from the PPP-Botnia Study. AB - INTRODUCTION: To study whether the frequently reported association between depressive symptoms and the metabolic syndrome (MetS) and its individual components are secondary to the use of antidepressant medication and to established diabetes or cardiovascular diseases (CVD). PATIENTS AND METHODS: A population-based, random sample of 4,967 women and men aged 18-75 years. MetS was defined according to the new, harmonized criteria. Glucose tolerance was assessed by oral glucose tolerance test (OGTT). CVD, depressive symptoms, and use of antidepressant medication were self-reported. RESULTS: The odds for having the MetS increased over 10%for each standard deviation increase in depressive symptoms. Users of antidepressant medication had more than 50% increased odds for having the MetS. Depressive symptoms were also associated with higher glucose response during the OGTT, higher serum triglyceride and lower HDL-cholesterol concentrations, and higher waist circumference, while use of antidepressant medication was associated with higher triglycerides, waist circumference, and systolic blood pressure. The associations of depressive symptoms were not secondary to use of antidepressant medication and were not explained by established diabetes or CVD. DISCUSSION: Depressive symptoms, the MetS, and the individual components of MetS are related. These associations are not driven by use of antidepressant medication, established diabetes, or CVD. PMID- 21254904 TI - First surveys to investigate the presence of canine leishmaniasis and its phlebotomine vectors in Hungary. AB - Hungary is regarded as free of leishmaniasis because only a few imported cases have been reported. However, southern Hungary has a sub-Mediterranean climate, and so it was included in the EU FP6 EDEN project, which aimed to map the northern limits of canine leishmaniasis (CanL) in Europe. The numbers of traveling and imported dogs have increased in the last decade, raising concerns about the introduction of CanL caused by Leishmania infantum. Serum samples were collected from 725 dogs (22 localities, 6 counties) that had never traveled to endemic countries, as well as from other potential reservoir hosts (185 red foxes and 13 golden jackals). All sera were tested by the indirect fluorescent antibody test, but they were sero-negative using the OIE cut-off of 1:80 serum dilution except for those of two dogs resident since birth in southern Hungary. These had not received a blood transfusion, but the mode of transmission is unclear because no sandfly vectors were caught locally. From 2006 to 2009, phlebotomine sandflies were sampled in the summer months at 47 localities of 8 counties. They were trapped with castor-oil-impregnated sticky-paper, light, and CO(2)-baited traps. Small numbers of two vectors of Leishmania infantum were found. Phlebotomus neglectus occurred in three villages near to Croatia and one in north Hungary at latitude 47 degrees N, and Phlebotomus perfiliewi perfiliewi was trapped at two sites in a southeastern county close to the sites where it was first found in 1931-1932. Our report provides baseline data for future investigations into the northward spread of CanL into Hungary, which we conclude has yet to occur. PMID- 21254905 TI - Impact of new clinical trials on recent guidelines on hypertension management. AB - Guidelines on hypertension diagnosis and treatment have been issued in 2007. Since then, a number of major intervention clinical trials have been designed, carried out, and completed with the aim of investigating unsolved issues related to the impact of the blood pressure-lowering intervention on cardiovascular risk and events. These include, among others, the nephroprotective properties of antihypertensive drugs, the blood pressure targets to be achieved during treatment in uncomplicated and more so in complicated hypertensive patients, the advantages of one drug combination versus another, and the benefits of antihypertensive drugs in the very elderly. All these questions have received a clear-cut answer by the results of recently performed clinical trials, which have been included in the 2009 update document of the European guidelines. This paper will be focused on the 2007 guidelines document and the 2009 update paper, highlighting the new concepts and recommendations provided by the most recent intervention trials. PMID- 21254906 TI - Prognostic significance of serum cholesterol, lathosterol, and sitosterol in old age; a 17-year population study. AB - BACKGROUND. Low serum total cholesterol is frequently associated with worse survival in older people, but mechanisms of this association are poorly understood. AIMS. Characteristics of cholesterol metabolism were related to survival in a random 75 + population sample. METHODS. Serum cholesterol and lathosterol, and sitosterol were measured in random persons (n = 623) of birth cohorts (1904, 1909, and 1914) in 1990, and all persons were followed for 17 years. RESULTS. Total cholesterol declined in old age, and low cholesterol was associated with poor health and multi-morbidity. Cholesterol below 5.0 mmol/L was associated with accelerated all-cause mortality (age- and gender-adjusted hazard ratio (HR) 1.54; 95% CI 1.21-1.97; P < 0.001) and vascular mortality (HR 2.13 (1.42-3.07); P < 0.001). Lathosterol (indicating cholesterol synthesis) and sitosterol (indicating cholesterol absorption) also decreased with deteriorating health. Low lathosterol, sitosterol, and cholesterol predicted mortality additively and independently of each other. When all three sterols were high (> median) or low, the age- and gender-adjusted survival was 9.9 and 5.6 years (P < 0.001). CONCLUSION. Lower synthesis and absorption of cholesterol, and low serum cholesterol level are associated with deteriorating health and indicate impaired survival in old age. PMID- 21254907 TI - Menopausal hot flushes and vascular health. AB - Hot flushes are complained of by approximately 75% of all postmenopausal women, and hormone therapy (HT) is the most effective way to alleviate them. Hot flushes are characterized by altered vascular function and sympathetic nervous system activity. Hot flushes occurred more often in women attending large, non randomized observational studies (e.g. Nurses' Health Study), where HT use protected against cardiovascular disease (CVD). However, they were absent (or mild) in randomized HT trials where HT use was accompanied with an elevated risk for CVD. Hot flushes, if a factor for cardiovascular health, could partly explain the conflict between observational and randomized trials. Several cross-sectional studies imply that hot flushes are detrimental to the cardiovascular system. However, the data are not uniform, and hot flushes were recalled retrospectively or during HT use. In our prospective study hot flushes were accompanied with a vasodilatory effect during endothelial testing, and this was related to the severity of hot flushes. Night-time hot flushes were followed with transient rises in ambulatory blood pressure (BP). However, no effect of hot flushes on diurnal BP was detected. The use of estradiol showed no harmful effects on endothelial function in women with hot flushes, but in non-flushing women oral, but not transdermal, estradiol led to vasoconstrictive changes. Estradiol complemented with medroxyprogesterone acetate eliminated the vasoconstrictive effect of sole oral estradiol. Thus, both oral and transdermal estradiol are applicable in flushing women, whereas a transdermal route should be favored in non-flushing women if used e.g. for bone protection. PMID- 21254908 TI - A comparative study of the effects of bromelain and fresh pineapple juice on the early phase of healing in acute crush achilles tendon injury. AB - Bromelain, an enzyme extracted from the stem of the pineapple plant, has been reported to reduce pain and swelling in acute soft tissue injuries, but no study has been done to compare its effect with that of fresh pineapple juice on the healing of acute tendon injuries. This study compared the effects of commercial bromelain and fresh pineapple juice on tenocyte proliferation and the malondialdehyde (MDA) level in the early stage of healing in a crush injury to the Achilles tendon of Sprague-Dawley rats. Twenty-four male rats were divided randomly into three groups of eight rats each; all the rats had induced crush injury to the Achilles tendon: Group 1 (control), no treatment; Group 2, oral bromelain treatment at a dosage of 7 mg/kg of body weight daily; and Group 3, fresh diluted pineapple juice at a dosage of 30 mg/kg of body weight. Treatment was given over the first 14 days post-injury. On day 15 post-injury, the animals were sacrificed, and the tendons were excised and processed for histological study and MDA assay. Results show a significant difference in the tenocyte population between the bromelain group and the control (P < .05), whereas pineapple juice also increased the tenocyte population, although not significantly (P = .36). Pineapple juice, however, significantly lowered the MDA level compared with both the control and bromelain-treated groups. Based on this study, 600 GDU bromelain given at a dosage of 7 mg/kg had a better effect on tenocyte proliferation than fresh pineapple juice given once daily in acute tendon injury. PMID- 21254909 TI - Management of severe thyrotoxicosis when the gastrointestinal tract is compromised. AB - BACKGROUND: The management of patients with severe thyrotoxicosis in the absence of a functional gastrointestinal tract represents an uncommon but significant clinical challenge associated with a high mortality rate. This article offers a literature review and discussion of the available management options in this setting. SUMMARY: Treatment of severe thyrotoxicosis in patients unable to ingest medications by the oral route should focus on normalization of thyroid hormone levels utilizing conventional medical therapy for thyrotoxicosis, administered via non-oral routes. This includes thionamides, beta-blockers, iodine containing solutions, and glucocorticoids. When conventional medical therapy fails, plasmapheresis should be considered as a temporary therapeutic bridge until conventional therapies can be instituted effectively or emergent surgery performed. CONCLUSION: Although a rare scenario, the management of patients with severe thyrotoxicosis in the absence of a functional gastrointestinal tract represents a challenging clinical situation. Endocrinologists and critical care physicians should be apprised of the available treatment modalities which must be instituted swiftly in order to avoid a catastrophic outcome. PMID- 21254910 TI - Salmonella sp. in game (Sus scrofa and Oryctolagus cuniculus). AB - The role of wildlife in the epidemiology of Salmonella sp.-induced diseases is a matter of increasing concern to public health. However, to date, reports on the occurrence of Salmonella sp. in game hunted for human consumption are very limited. The current study was designed to evaluate the prevalence of Salmonella sp. in fecal samples of wild boars and wild rabbits hunted in Northern Portugal. The results show that 22% of the (17/77) wild boar and 48% (38/80) of the wild rabbit presented Salmonella sp. in their feces. Two serovars were identified from samples of wild boars: Salmonella Typhimurium (65%) and Salmonella Rissen (35%). Five serovars were identified from wild rabbit samples: Salmonella Rissen (29%), Salmonella Enteritidis (26%), Salmonella Havana (24%), Salmonella Typhimurium (16%), and Salmonella Derby (5%). These results confirm the importance of wild boar and wild rabbit as carriers of pathogenic Salmonella serovars. Hence, they could represent sources of infection not only for animals (wild and domestic) but also for humans. PMID- 21254911 TI - Comparison of alendronate and raloxifene in postmenopausal women with osteoporosis. AB - OBJECTIVES: To compare the efficacy and tolerability of raloxifene (RLX) 60 mg daily and alendronate (ALN) 70 mg once weekly, either alone or in combination, on bone mineral density (BMD), bone turnover, and lipid metabolism in postmenopausal women with osteoporosis. METHODS: Of the 135 women enrolled, 98 completed this 12 month, randomized, clinical study (35 in the RLX group, 31 in the ALN group, and 32 in the combination group). Measurements were taken of the BMD of the lumbar spine, femoral neck and total hip, urinary N-telopeptide (NTx) of type I collagen corrected for creatinine, serum bone-specific alkaline phosphatase (BSAP), and the lipid profile. All adverse effects were recorded. RESULTS: At 12 months, the BMD of the lumbar spine, femoral neck, and total hip significantly increased from baseline in all treatment groups. However, the increase in BMD in the combination group was significantly greater than those in the RLX and ALN groups (p < 0.0001). The reductions in both urinary NTx and serum BSAP in the combination and ALN groups were significantly greater than those in the RLX group (p < 0.0001). There were significant reductions in the serum total cholesterol and low density lipoprotein cholesterol and a significant increase in the serum high density lipoprotein cholesterol in the RLX and combination groups but not in the ALN group at 12 months. There were no significant differences in the incidence of adverse effects. CONCLUSIONS: Treatment of postmenopausal women with osteoporosis with RLX and ALN, alone and in combination, significantly increased the BMD of the lumbar spine, femoral neck and total hip and reduced markers of bone turnover. However, the effects of combined therapy were more pronounced than those of either monotherapy. On the other hand, RLX had some beneficial effects on lipid metabolism. Both medications, alone or in combination, had similar tolerability and safety profiles. PMID- 21254912 TI - Distribution of Aedes albopictus (Diptera: Culicidae) in northwestern China. AB - The Asian tiger mosquito, Aedes albopictus (Diptera: Culicidae), has a wide distribution in China with its northwestern limits among seven provinces. During 2006-2008, distribution information was collected in 33 urban and rural areas in those boundary provinces by collecting larvae or adult mosquito from different breeding sites. Additional information of seven sites was gathered from local health authorities. Three generally accepted climatic delineations affecting distribution of the species were studied for the northwestern distribution using a geographic information system software (ArcGIS). Climatic analysis showed that the annual mean temperature higher than 11 degrees C, the mean temperature of the coldest month, January, higher than -5 degrees C, and the annual precipitation above 500 mm covered almost all the confirmed areas and the seasonal expansion reached areas with nearly -10 degrees C of the mean January temperature. As a main vector of dengue fever virus in a large part of China, where Aedes aegypti is absent, Ae. albopictus is also responsible for the risk for future epidemic of dengue fever and other viral diseases in China. PMID- 21254913 TI - Ownership of uncertainty: healthcare professionals counseling and treating women from hereditary breast and ovarian cancer families who receive an inconclusive BRCA1/2 genetic test result. AB - AIM: The aim of this study was to understand more fully how healthcare professionals deal with the uncertainty intrinsic in counseling and treating women from hereditary breast/ovarian cancer families who receive inconclusive BRCA1/2 genetic test results (genetic tests that do not find a mutation to account for the family history). METHODS: We conducted a small, qualitative, exploratory study using open-ended semistructured interviews of 12 geneticists, genetic counselor/nurses, oncologists, gynecologists, and breast surgeons at a major UK cancer center. We asked questions about how these professionals dealt with the large amount of uncertainty raised by an inconclusive result, how they communicated the uncertainty involved, their feelings about presenting medical management options based on information fraught with uncertainty, the role of the media, differences in perspectives by specialty, and personal feelings about the uncertainty. RESULTS: Based on themes generated by the data, we proposed the concept "ownership of uncertainty" (sole, shared, diffused, normalized, transferred) to explain how the professionals in this study dealt with this high degree of uncertainty. A shared ownership of uncertainty was the dominant model during the presentation of information given by the professionals as part of their consultation with their patients. However, the final decision for management was left primarily to the woman seeking advice, even though several of the professionals reported feeling uneasy about this. CONCLUSION: The concept "ownership of uncertainty" helps advance the understanding of how the healthcare professionals deal with the uncertainty intrinsic to an inconclusive BRCA1/2 genetic test result within the current social context. PMID- 21254915 TI - The ail gene is present in some Yersinia enterocolitica biotype 1A strains. AB - One chromosomal virulence marker of Yersinia is the gene ail, which encodes Ail, an outer membrane protein that promotes attachment and invasion. A high correlation has been found between the ail gene and the virulence of Yersinia. Here, we report two Yersinia enterocolitica biotype 1A strains that are usually nonpathogenic and carry the ail gene. The ail gene sequences of biotype 1A strains displayed similarity to the bioserotype 1B/O:8 strain 8081. The finding suggests that ail-based detection methods for Y. enterocolitica alone are insufficient to detect real pathogenic strains. PMID- 21254916 TI - Retroperitoneal migration of a Double-J stent: an unusual occurrence. AB - Double-J stents that are inserted to span the ureterovesical anastomosis at ureteoneocystostomy may be associated with problems such as coiling or migration. An unusual occurrence of retroperitoneal migration of a Double-J stent after bilateral open ureteroneocystostomy is reported. The migrated stents were retrieved laparoscopically with construction of a laparoscopic ureteroneocystostomy. PMID- 21254914 TI - 3,3'-diindolylmethane modulates estrogen metabolism in patients with thyroid proliferative disease: a pilot study. AB - BACKGROUND: The incidence of thyroid cancer is four to five times higher in women than in men, suggesting a role for estrogen (E2) in the pathogenesis of thyroid proliferative disease (TPD) that comprises cancer and goiter. The objective of this study was to investigate the antiestrogenic activity of 3,3' diindolylmethane (DIM), a bioactive compound derived from cruciferous vegetables, in patients with TPD. METHODS: In this limited phase I clinical trial study, patients found to have TPD were administered 300 mg of DIM per day for 14 days. Patients subsequently underwent a total or partial thyroidectomy, and tissue, urine, and serum samples were collected. Pre- and post-DIM serum and urine samples were analyzed for DIM levels as well as estrogen metabolites. DIM levels were also determined in thyroid tissue samples. RESULTS: DIM was detectable in thyroid tissue, serum, and urine of patients after 14 days of supplementation. Urine analyses revealed that DIM modulated estrogen metabolism in patients with TPD. There was an increase in the ratio of 2-hydroxyestrones (C-2) to 16alpha hydroxyestrone (C-16), consistent with antiestrogenic activity that results in more of C-2 product compared with C-16. CONCLUSION: Our data suggest that DIM enhances estrogen metabolism in TPD patients and can potentially serve as an antiestrogenic dietary supplement to help reduce the risk of developing TPD. The fact that DIM is detected in thyroid tissue implicates that it can manifest its antiestrogenic activity in situ to modulate TPD. PMID- 21254917 TI - Functioning and disability in adults with myotonic dystrophy type 1. AB - PURPOSE: To provide a comprehensive description of functioning and disability with regard to stages of disease progression in adults with myotonic dystrophy type 1 (DM1). Further to explore associations of measures of manual dexterity and of walking capacity with measures of activities of daily living (ADL) and participation in social and lifestyle activities. METHODS: Seventy persons with DM1 underwent examinations, tests and answered questionnaires. Stages of disease progression were based on the muscular impairment rating scale. RESULTS: Overweight, cardiac dysfunctions, respiratory restrictions, fatigue and/or low physical activity levels were found in approximately 40% of those with DM1. Over 75% had muscle impairments, and activity limitations in manual dexterity and walking. Dependence in personal and instrumental ADL was found in 16% and 39%, respectively, and participation restrictions in social and lifestyle activities in 52%. The presence of concurrent body-function impairments, activity limitations and participation restrictions was high. Significant differences were found in muscle impairment, manual dexterity, mobility, ADL and social and lifestyle activities with regard to disease progression. Cut-off values in measures of manual dexterity and walking capacity associated to functioning are proposed. CONCLUSION: This information can be used for developing clinical practise and for health promotion for persons with DM1. PMID- 21254918 TI - Indolent medullary thyroid cancer with a RET proto-oncogene Cys618Phe mutation presenting as sporadic unilateral pheochromocytoma in a 55-year-old Korean woman. PMID- 21254919 TI - Specific antibody responses to West Nile virus infections in horses preimmunized with inactivated Japanese encephalitis vaccine: evaluation of blocking enzyme linked immunosorbent assay and complement-dependent cytotoxicity assay. AB - West Nile virus (WNV) and Japanese encephalitis (JE) virus are distributed separately in the world with some exceptions. There is a concern that WNV may invade into Asia where JE virus exists. On and after such invasion, any differential diagnosis could be complicated by serological crossreactivities. We previously demonstrated experimentally using horses infected with WNV that preimmunization with inactivated JE vaccine considerably affected the ability of neutralization tests and immunoglobulin M (IgM) antibody-capture enzyme-linked immunosorbent assay (ELISA) to diagnose WNV infection. Here, we investigated WNV specific antibody responses in vaccinated horses using a blocking ELISA and complement-dependent cytotoxicity (CDC) assay to evaluate these two newly developed serodiagnostic methods for WNV infection. Sera previously collected from six experimentally infected horses were used: Three were vaccinated before the infection, whereas the other three remained unvaccinated. WNV-specific antibody responses were successfully detected in the vaccinated and unvaccinated horses using both new methods, except for one vaccinated horse in which responses were not induced, probably as a result of crossprotection induced by JE vaccination. Specific antibody responses were at earliest detected from days 9 to 10 postinfection in the blocking ELISA, whereas the CDC assay provided earlier detection (at days 7-8) in all horses. The time courses of antibody levels were similar between vaccinated and unvaccinated horses in either method, indicating no notable effect of vaccination on detection of specific antibody responses, as far as antibodies were induced. These results indicated that blocking ELISA, but preferably the CDC assay, can be useful for detecting WNV infection in JE vaccinated horses. PMID- 21254920 TI - Mutation screening of the GJA7 (Cx45) gene in a large international series of probands with nonsyndromic hearing impairment. AB - Direct evidence of the critical physiological role of connexins (Cxs) has come through the associations of several human diseases with pathogenic mutations in specific Cx genes. Currently, mutations in genes coding for five Cx proteins (Cx26, Cx30, Cx31, Cx32, and Cx43) have been shown to cause sensorineural hearing loss. Cx45 is another gap junction protein, coded by the GJA7 gene. To investigate the possible contribution of GJA7 mutations to deafness, we sequenced the GJA7 gene in 341 unrelated probands with nonsyndromic hearing loss from Turkey, South Africa, United Kingdom, United States, and China. Three nucleotide variants not affecting the amino acid sequence, c.213C>T, c.906C>T, and c.912G>T, and one missense change, c.889C>A (p.D297N), were found. None of the identified changes appeared to be pathogenic. Our data suggest that GJA7 alterations have no or low genetic relevance in nonsyndromic hearing loss in these populations. PMID- 21254921 TI - Qualitative spectral OCT/SLO analysis of drusen change in dry age-related macular degeneration patients treated with Copaxone. AB - PURPOSE: High-resolution spectral domain OCT/SLO (SD-OCT) has become an increasingly useful tool for differentiating drusen morphologic parameters such as shape, internal reflectivity, homogeneity, and presence of overlying hyperreflective foci. Our purpose was to evaluate which types of drusen may respond to Copaxone (glatiramer acetate) treatment of dry age-related macular degeneration (AMD) patients by shrinking or disappearing. METHODS: A prospective and interventional clinical trial of patients with dry AMD who received subcutaneous treatment with Copaxone or sham injections was conducted. SD-OCT images were used for analysis of drusen ultrastructure. Morphologic characteristics for specific drusen within the macular region were assessed with serial studies. Pre- and posttreatment statuses of drusen were compared. Main outcome measure was a change of drusen morphologic parameters in Copaxone-treated and sham-treated dry AMD patients between baseline and 12 weeks of treatment. RESULTS: Three hundred eleven drusen from 26 eyes of 14 dry AMD patients were evaluated. One hundred seventy-two drusen from 14 eyes (7 patients) of Copaxone treated and 139 drusen from 12 eyes sham-treated (7 patients) were included. Overall, between baseline and 12-week visit, the percentage of drusen that disappeared/shrank in the Copaxone-treated group was 19.2% versus 6.5% in the sham-treated group (P = 0.13). The percentage of convex drusen that shrank or disappeared after 12 weeks of treatment was significantly higher in the Copaxone treated group (27.8%) in comparison with the sham-treated group (6.8%) (P = 0.008). The difference between the groups was found to be statistically significant for drusen with low and medium internal reflectivity (P = 0.019 and P = 0.036, respectively). CONCLUSIONS: Convex shape and low/medium internal reflectivity were found to be favorable parameters in prediction of drusen reduction in the Copaxone-treated patients. This study represents a preliminary attempt to identify SD-OCT features of drusen that may predict susceptibility to Copaxone treatment and therefore help clinicians decide which patients to treat. PMID- 21254922 TI - Robot-assisted laparoscopic pyeloplasty with and without a ureteral stent. AB - OBJECTIVE: Robot-assisted laparoscopic pyeloplasty (RALP) has been shown to be an efficacious treatment for ureteropelvic junction obstruction. Although the use of a ureteral stent is commonplace, the water-tight anastomosis possible with robotic assistance may obviate its need. We report a feasibility study of unstented RALPs and present our experience with both the stented (SRP) and unstented (URP) approach. MATERIALS AND METHODS: A retrospective review of RALPs completed at our institution from 2003 to 2008 was performed. Thirty-five patients had postoperative stents. Seventeen RALPs were completed without ureteral stents. Narcotic requirements, operative time, estimated blood loss, daily drain output, length of stay, and complications were examined. RESULTS: Fifty-two patients underwent RALP without conversion to open procedure (35 SRP, 17 URP). Operative time was significantly less in the URP group (p = 0.01). URPs required less narcotics and had shorter length of stay. Three complications were reported after SRP, whereas two patients with URP experienced transient ureteral obstruction, which resolved after 4 weeks with an indwelling ureteral stent. Postoperative renograms showed improved drainage in all but four patients (two SRPs and two URPs), each of whom had subjective improvement in symptoms postoperatively. CONCLUSIONS: Our data suggest that URP is a safe and feasible procedure for the treatment of ureteropelvic junction obstruction. There were no clinically significant differences between the stented and unstented groups. Further prospective evaluation is needed; however, URP can be performed by an experienced surgeon in a carefully selected patient. PMID- 21254923 TI - Pathobiological targets of depression. AB - INTRODUCTION: Depression is one of the most prevalent and life-threatening forms of mental illness associated with significant disability and mortality. About 21% of the world's population is affected by depression. AREAS COVERED: The various pathological factors involved in depression are: monoamine hypothesis, neurotransmitter receptor hypothesis, neurotrophic factor hypothesis, hypothalamic-pituitary-adrenal (HPA) dysregulation, oxidative stress, cytokine hypothesis and NO pathway. Recent drug therapies used to treat depression include: selective serotonin re-uptake inhibitors, norepinephrine and dopamine re uptake inhibitors and several herbal drugs. The present review focuses on recently unraveled pathogenetic hypotheses and therapeutics of mental depression. Moreover, various evaluation models for antidepressants are discussed. EXPERT OPINION: Stress can be considered as a major contributor to the development of depressive disorder due to the dysregulation of HPA axis. Cytokine effects on behavior are believed to be related in part to their effects on neurotransmitter and neuropeptide function, synaptic plasticity and neuroendocrine function. Although there are multiple pathways that are involved in the pathogenesis of depression, the current antidepressants mainly target monoaminergic pathway. However, the therapeutic potential of other pathways is still under investigation. Drugs targeting NO, cytokines and the kynurenine acid pathway might be the drugs of choice in near future. PMID- 21254924 TI - Early pregnancy reference intervals of thyroid hormone concentrations in a thyroid antibody-negative pregnant population. AB - BACKGROUND: Thyroid dysfunction and antibodies are increasingly recognized as risk factors during pregnancy. Thyroid function changes during pregnancy and there is a need for gestational age-specific reference intervals for thyroid hormones. The aim of this study was to calculate gestational age-specific thyrotropin (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) reference intervals in an iodine-sufficient thyroid antibody-negative population. METHODS: The study population consisted of a large, prospective population-based cohort, the Northern Finland Birth Cohort 1986 (singleton births, n = 9362), with extensive data throughout gestation. The subjects underwent serum sampling in early pregnancy. Samples were assayed for TSH, fT4, fT3, thyroid-peroxidase, and thyroglobulin antibodies (n = 5805). All mothers with thyroid antibodies or previous thyroid diseases were excluded when calculating gestational age-specific percentile categories for TSH, fT4, and fT3. Also, associations between body mass index (BMI) and thyroid hormones were established. RESULTS: The upper reference limit for TSH was 2.5 multiples of median (2.7-3.5 mU/L, depending on gestational week). The lower reference limit was as low as 0.07 mU/L. Reference intervals for fT4 rose during early pregnancy and decreased thereafter, ranging between 11-22 pmol/L. Reference intervals for fT3 were uniform throughout gestation, ranging between 3.4 and 7.0 pmol/L. BMI was associated positively with early pregnancy TSH and fT3 concentrations and negatively with fT4 concentrations. CONCLUSIONS: These gestational age-specific reference intervals for thyroid hormones provide a framework for clinical decision making. Overweight and obesity are increasing problems among fertile women and they are associated with possibility of thyroid dysfunction during pregnancy. PMID- 21254925 TI - The role of Raf-1 kinase in diabetic retinopathy. AB - Many metabolic pathways, including oxidative stress, PKC and the polyol pathway have been implicated in the development of diabetic retinopathy, but despite extensive research, its pathogenesis remains unclear. Recent studies have shown the role of a low-molecular-weight GTP-binding protein (H-Ras)-mediated signaling pathway in its development. The key effector protein of Ras function is a threonine/serine kinase-Raf kinase, and this kinase is involved in a variety of functions, including the cell cycle and proliferation and apoptosis. In animal models of diabetic retinopathy, Raf kinase is activated in the retina and its microvasculature. Activated Raf kinase is associated with increased apoptosis of retinal capillary cells, the process that precedes the development of retinal histopathology, and inhibition of Raf kinase ameliorates apoptosis. In clinical settings, inhibitors of Raf kinase have shown promising results in cancer treatment, and Raf kinase antisense oligonucleotides, iCo 007, is now in Phase II trial for macular edema, a chronic ocular disease associated with retinal neovascularization. Further elucidating the role of Raf kinase in diabetic retinopathy, and advances in the generation of antisense therapy for chronic diseases, should help test Raf antisense oligonucleotides for the treatment of this blinding complication that diabetic patients fear the most. PMID- 21254926 TI - Sequencing of a tick-borne encephalitis virus from Ixodes ricinus reveals a thermosensitive RNA switch significant for virus propagation in ectothermic arthropods. AB - Tick-borne encephalitis virus (TBEV) is a flavivirus with major impact on global health. The geographical TBEV distribution is expanding, thus making it pivotal to further characterize the natural virus populations. In this study, we completed the earlier partial sequencing of a TBEV pulled out of a pool of RNA extracted from 115 ticks collected on Toro in the Stockholm archipelago. The total RNA was sufficient for all sequencing of a TBEV genome (Toro-2003), without conventional enrichment procedures such as cell culturing or suckling mice amplification. To our knowledge, this is the first time that the genome of TBEV has been sequenced directly from an arthropod reservoir. The Toro-2003 sequence has been characterized and compared with other TBE viruses. In silico analyses of secondary RNA structures formed by the two untranslated regions revealed a temperature-sensitive structural shift between a closed replicative form and an open AUG accessible form, analogous to a recently described bacterial thermoswitch. Additionally, novel phylogenetic conserved structures were identified in the variable part of the 3'-untranslated region, and their sequence and structure similarity when compared with earlier identified structures suggests an enhancing function on virus replication and translation. We propose that the thermo-switch mechanism may explain the low TBEV prevalence often observed in environmentally sampled ticks. Finally, we were able to detect variations that help in the understanding of virus adaptations to varied environmental temperatures and mammalian hosts through a comparative approach that compares RNA folding dynamics between strains with different mammalian cell passage histories. PMID- 21254927 TI - Screening of three novel candidate genes in arrhythmogenic right ventricular cardiomyopathy. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) has been associated with mutations in genes encoding cellular adhesion proteins. However, only about 40% of patients have mutations in known genes. We hypothesized that mutations in the genes encoding beta-catenin (CTNNB1), alpha-T-catenin (CTNNA3), and PERP (PERP) all important structural proteins located at the intercalated disc-were involved in the pathogenesis of ARVC. We screened 65 unrelated patients (55 fulfilling 1994 Task Force criteria and ten borderline cases) for mutations in CTNNB1, CTNNA3, and PERP by direct sequencing and LightScanner melting curve analysis. Our comprehensive mutation scanning did not identify any disease-causing mutations. Thirty-five sequence variants were found, including one rare nonsynonymous variant of unknown significance (CTNNA3 A689V). Fourteen of the variants were novel. In conclusion, in our cohort of a limited size, no mutations were identified in the three studied candidate genes despite their involvement in formation and maintenance of the intercalated disk. We recommend focus on other components of cardiomyocyte adhesion in future research into the pathogenesis of ARVC. PMID- 21254928 TI - Effects of ferulic acid on hematopoietic cell recovery in whole-body gamma irradiated mice. AB - PURPOSE: The objective of this study was to investigate the mechanism for ferulic acid (FA)-induced radioprotection by evaluating the recovery of bone marrow cells and peripheral blood hematology. MATERIALS AND METHODS: Balb/c mice were irradiated at a dose of 2.5 Gy using cobalt-60 gamma resources. Following irradiation, FA was administered intragastrically for seven consecutive days. Hematopoietic progenitor colony-forming cell assays were used to assess the reconstitution of bone marrow after radiation-induced myelosuppression. Cytokine levels were investigated using enzyme-linked immunosorbent assay and Western blot analysis. RESULTS: The results demonstrated that FA treatment enhanced hematopoietic progenitor cell activity resulting in accelerated blood cell recovery. FA administration increased levels of granulocyte-colony stimulating factor (G-CSF) and erythropoietin. CONCLUSION: These results suggest radioprotective efficacy by FA may be a result of early recovery of hematopoietic cells due to enhanced production of G-CSF and erythropoietin. PMID- 21254929 TI - Manifestations of personality in Online Social Networks: self-reported Facebook related behaviors and observable profile information. AB - Despite the enormous popularity of Online Social Networking sites (OSNs; e.g., Facebook and Myspace), little research in psychology has been done on them. Two studies examining how personality is reflected in OSNs revealed several connections between the Big Five personality traits and self-reported Facebook related behaviors and observable profile information. For example, extraversion predicted not only frequency of Facebook usage (Study 1), but also engagement in the site, with extraverts (vs. introverts) showing traces of higher levels of Facebook activity (Study 2). As in offline contexts, extraverts seek out virtual social engagement, which leaves behind a behavioral residue in the form of friends lists and picture postings. Results suggest that, rather than escaping from or compensating for their offline personality, OSN users appear to extend their offline personalities into the domains of OSNs. PMID- 21254930 TI - Bovine trypanosomiasis an emerging disease in Maranhao State-Brazil. AB - In South American countries, bovine trypanosomiasis is caused mainly by Trypanosoma vivax. Among the infected animals, bovines are considered more susceptible, and this susceptibility varies among breeds. To determine the occurrence of T. vivax in Maranhao State, Brazil, a total of 559 cattle blood samples were collected for molecular and parasitological studies. On Sao Luis Island, no parasites were observed in the parasitological exam; however, with the polymerase chain reaction (PCR) method, three samples (1.06%) were positive. In four municipalities that compose the Pedreiras Basin, 3.39% of the animals were positive on the parasitological exam, and 6.21% of animals were positive by PCR. This finding demonstrates that PCR is more sensitive and confirms that the method is very useful in epidemiological surveys. A further interesting point is that molecular studies clearly define the differences in surface glycoproteins and antigenic variants. PMID- 21254931 TI - Mutation studies in the CFTR gene in Asian Indian subjects with congenital bilateral absence of vas deferens: report of two novel mutations and four novel variants. AB - BACKGROUND: Congenital bilateral absence of vas deferens (CBAVD) is a form of male infertility in which mutations occur in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The molecular basis of CBAVD is not completely understood, especially in developing countries. METHODS: We characterized the mutations/variants in the CFTR gene by single strand conformation polymorphism followed by sequencing in 35 CBAVD patients. None of the patients had systemic manifestations of cystic fibrosis. Fifty normal subjects were studied as controls. RESULTS: Mutations/variants in the CFTR gene were found in all CBAVD patients. Five mutations and 10 variants were detected in 35 patients. The most frequent severe mutation was F508del (34.2%) and the most common variant was IVS8 5T (54.2%). Two novel severe mutations (p.E217Gfs*11 and p.A1285V) and four novel variants (pT438A, c.4095+30insCT, c.-737G>A, and c.2909-92A>G) were detected. CONCLUSION: The protocol for identification of mutations in cases of CBAVD in developing countries would have to include a different set of mutations than those reported from western countries. PMID- 21254932 TI - Effectiveness of various anthelmintics in the treatment of moniliformiasis in experimentally infected Wistar rats. AB - Humans occasionally become infected with acanthocephalans, particularly Moniliformis moniliformis. Although several anthelmintics have been used, no controlled studies have been conducted to assess the efficacy of common anthelmintics in the treatment of moniliformiasis. The effectiveness of pyrantel pamoate, ivermectin, praziquantel, niclosamide, thiabendazole, and mebendazole was evaluated in the treatment of moniliformiasis in laboratory-infected female Wistar rats. Pyrantel pamoate and ivermectin were wholly unsuccessful in the treatment of moniliformiasis. A single dose of thiabendazole lead to a 40% reduction and two doses lead to a 57% reduction of worm burden after 2 weeks. The most effective drug in the treatment of moniliformiasis in rats was mebendazole, for which two doses resulted in a 69% reduction in worm burden after 2 weeks; however, 50% of the rats receiving the treatment died within 2 weeks after first administration of the drug. Two surviving rats that had been treated with mebendazole exhibited evidence of hepatic dysfunction characterized by extremely elevated levels of alkaline phosphatase in conjuction with depressed serum albumin levels. It is hypothesized that Mo. moniliformis may metabolize the drug and release a metabolite that is highly toxic to the host. On the basis of these data, thiabendazole is recommended as the drug of choice for the treatment of human acanthocephaliasis until more extensive testing can be conducted. PMID- 21254933 TI - Hand-assisted laparoscopic radical nephrectomy. AB - Laparoscopic radical nephrectomy is the standard of care for the management of most renal cancers. The hand-assisted approach has bridged the gap between open nephrectomy and a pure laparoscopic approach. Hand-assisted laparoscopic nephrectomy allows tactile feedback, thus shortening the learning curve for some surgeons and allowing more experienced laparoscopists to perform more complex and challenging procedures. PMID- 21254934 TI - Knowledge-sharing intention in a virtual community: a study of participants in the Chinese Wikipedia. AB - This study proposes a model for evaluating virtual community members' knowledge sharing intention toward Chinese Wikipedia. The results of this study reveal that knowledge-sharing intention is influenced directly by attitude, subjective norms, and perceived behavioral control, whereas anticipated reciprocal relationships and enjoying helping are positively related to attitude; sense of self-worth and peer influences are positively related to subjective norms; and self-efficacy and resource-facilitating conditions are positively related to perceived behavioral control on knowledge sharing. PMID- 21254936 TI - Metastatic papillary thyroid cancer misdiagnosed as non-small [corrected] cell lung cancer. AB - BACKGROUND: Thyroid and lung cancers, two malignancies with similar immunohistological characteristics, have vastly different biologic behaviors and treatment approaches. As thyroid cancers commonly spread to the lungs, metastatic thyroid cancer should be included in the differential diagnosis of a pulmonary lesion or lesions. SUMMARY: A 54-year-old woman with a remote history of stage IV nonsmall cell lung cancer was found to have FDG avidity in the thyroid and right cervical lymph nodes. Subsequent ultrasonographic findings and FNA cytology led to a total thyroidectomy, bilateral central lymphadenectomy, and right modified radical lymph node dissection for primary thyroid cancer. Reviews and comparisons of the pulmonary and cervical surgical specimens revealed that the patient had been misdiagnosed for the previous 6 years; she had metastatic papillary thyroid cancer to the lung. The patient's original diagnosis of stage IV lung cancer was based upon the original lung biopsy showing positive thyroid transcription factor 1 (TTF-1) immunostaining. The original diagnosis was questioned because of her long survival when she was diagnosed with locally advanced papillary thyroid cancer. Further analyses of the immunohistological characteristics of both surgical specimens--including staining for TTF-1, thyroglobulin, CD57, S-100, and CEA--documented the correct diagnosis. CONCLUSIONS: A thorough understanding of the natural history and surgical pathology, including immunohistology, of lung and thyroid cancers is necessary for a correct and timely diagnosis and appropriate treatment. Because TTF-1 expression is seen in both thyroid and lung cancers, careful consideration should be given to both malignancies when evaluating patients with thyroid and pulmonary nodules. PMID- 21254937 TI - News from Clinical Research Office of the Endourological Society (CROES). Audit Committee And Progress Report. PMID- 21254935 TI - Association between insulin-like growth factor binding protein-3 promoter polymorphism of -1590 C>A and lung cancer susceptibility in a Chinese Han population. AB - Recent studies have identified a negative correlation between serum levels of insulin-like growth factor binding protein-3 (IGFBP-3) and the risk of lung cancer. In this study, polymorphisms present at the -1590 site of the IGFBP-3 promoter were evaluated in relation to lung cancer risk in a Chinese Han population. A total of 248 nonsmall cell lung cancer (NSCLC) cases and 29 small cell lung cancer cases were compared with 252 matched, healthy controls. Polymerase chain reaction-based restriction fragment length polymorphism assays were used to detect polymorphisms present. The A/A genotype and an A allele were both associated with an increased risk of NSCLC after being adjusted for age and gender (adjusted odds ratio = 2.296, 95% confidence interval = 1.133-4.655; and adjusted odds ratio = 1.390, 95% confidence interval = 1.042-1.854, respectively). In conclusion, the A/A genotype and A allele of the IGFBP-3 promoter -1590 site may represent a genetic risk factor for NSCLC, with the A/A genotype being associated with a higher risk for squamous cell carcinoma than adenocarcinoma. PMID- 21254938 TI - Eastern equine encephalitis: an emerging arboviral disease threat, Maine, 2009. AB - BACKGROUND: Eastern equine encephalitis (EEE) is one of the most severe arboviral encephalitides in North America. Before 2009, limited nonhuman EEE virus activity had been reported in Maine, all from the southernmost area of the state. No human case has been reported in a Maine resident. METHODS: We review all EEE virus activity reported to Maine Centers for Disease Control in 2009 and describe current testing practices for possible human EEE cases. RESULTS: In 2009, fatal cases of EEE were identified in 15 horses, 1 llama, and 3 flocks of pheasants in Maine, with activity extending into the central part of the state. Although no human EEE cases were identified, diagnostic testing practices of most meningitis and encephalitis cases were inadequate to exclude EEE. CONCLUSIONS: Work to better define the expanding range of EEE virus in Maine is warranted, along with education of healthcare providers regarding appropriate testing for this serious disease. PMID- 21254939 TI - Daily patterns of communication and contact between Italian early adolescents and their friends. AB - The goal of the present study was to explore patterns of communication between adolescents and their friends across both "online" and "in-person" contexts. The participants were adolescents (n = 727) aged 11-16 years attending middle schools in urban and rural areas of Italy. Participants completed daily logs of their in person and online contacts with friends for 20 consecutive school days. Girls reported more total contacts with their friends than did boys as well as friendships that were closer and more intimate. However, boys indicated more contact than girls via electronic communication and online. Contacts with peers in general were less frequent among the older participants, perhaps because of increasing academic demands. Participants who complemented in-person contact with friends with electronic contact were less lonely than their counterparts who were less versatile in accessing different modalities of making contact with friends. PMID- 21254940 TI - Chitosan-coated liposomes for intracellular oligonucleotides delivery: characteristics and cell uptake behavior. AB - Surface modification of liposomes with polymer to optimize drug delivery was well developed recently. The objective of the present work was to evaluate the feasibility of chitosan-coated liposomes (CSLP) as vehicles for anti-sense oligodeoxynucleotides (ASON). CSLP was obtained by adding chitosan dropwise to liposomes under magnetic stirring. The effect of chitosan content on size, zeta potential, and coating efficiency was investigated, which showed that chitosan increased the size and zeta potential of CSLP, and the coating efficiency increased with chitosan content increasing. Agarose gel electrophoresis was employed to evaluate the loading efficiency of CSLP for ASON, from which one could see ASON was completely combined to CSLP when the mass ratio of total lipids:ASON was more than 50:1. MTT assay showed that CSLP took on very low cytotoxicity, which is much lower than chitosan. At last, cell uptake behavior was investigated by a flow cytometer, which showed that CSLP enhanced significantly the COS7 cells uptake of ASON. All the results indicated that the CSLP could be a promising non-viral ASON vehicle. PMID- 21254941 TI - Absorption enhancement of grape seed polyphenols by complexation with phosphatidyl choline. AB - Grape seed polyphenols (GPP) are reported to have various biological effects along with strong antioxidant potential. Pharmacokinetic studies of GPP reveal its poor absorption through the intestine. The objective of the present study was to enhance bioavailability of GPP by its complexation with phosphatidyl choline. A complex of GPP was prepared with phosphatidyl choline and characterized on the basis of solubility, melting point, DSC, and IR. Everted intestine sac technique was used to study ex vivo drug absorption of GPP-PC complex and plain GPP. Pharmacokinetic studies were performed in rats and the hepatoprotective activity of GPP-PC complex was also compared with GPP and GPP-PC physical mixture in isolated rat hepatocytes. Analytical reports along with spectroscopic data revealed the formation of the complex. The results of ex vivo study show that the GPP-PC complex has significantly increased absorption compared with GPP, when given in equimolar doses. The complex showed enhanced bioavailability, improved pharmacokinetics, and increased hepatoprotective activity as compared to GPP or GPP-PC physical mixtures. Enhanced bioavailability of GPP-PC complex may be due to the amphiphilic nature of the complex, which greatly enhance the lipid miscibility of GPP. The present study clearly indicates the superiority of complex over GPP, in terms of better absorption, enhanced bioavailability, and improved pharmacokinetics. PMID- 21254942 TI - Immunological status against Toxoplasma gondii in non-cat owners from an endemic region of Mexico. AB - A cross-sectional study was developed to determine anti-Toxoplasma gondii immunoglobulin G (IgG) and IgM antibodies from 80 persons aged 18-21 years without a history of previous contact with cats. Individuals who consented to take part in the survey were served with a questionnaire to obtain response on their eating habits. Blood samples were taken and specific IgM and IgG antibodies against T. gondii were measured by indirect enzyme-linked immunoassay. Seropositivity was found in 29 (37%) and 20 (25%) of 80 persons for IgM and IgG, respectively. Of the cases, 14 (18%) of 80 were positive to both IgM and IgG T. gondii antibodies. A significant association of IgM seropositivity was found in people consuming pork (p-value = 0.04) and wildlife meat (odds ratio = 4.5; confidence intervals = 1.47-14.25; p-value = 0.009). The presence of specific IgG and IgM antibodies in the studied population indicate previous contact and/or recent infections with T. gondii despite avoiding direct contact with cats. Ingestion of pork and meat from wild animals appears to be playing a key role in transmitting the parasite. PMID- 21254943 TI - Journalism as health education: media coverage of a nonbranded pharma web site. AB - OBJECTIVE: As healthcare consumers increasingly use the Internet as a source for health information, direct-to-consumer (DTC) prescription drug advertising online merits additional attention. The purpose of this research was to investigate media coverage of the joint marketing program linking the movie Happy Feet and the nonbranded disease education Web site FluFacts-a resource from Tamiflu flu treatment manufacturer Roche Laboratories Inc. MATERIALS AND METHODS: Twenty-nine articles (n = 29) were found covering the Happy Feet-FluFacts marketing campaign. A coding guide was developed to assess elements of the articles, including those common in the sample and information that ideally would be included in these articles. Two coders independently coded the articles, achieving intercoder agreement of kappa = 0.98 before resolving disagreements to arrive at a final dataset. RESULTS: The majority of articles reported that Roche operated FluFacts (51.7%) and mentioned the product Tamiflu (58.6%). Almost half (48.3%) reported FluFacts was an educational resource; yet, no articles mentioned other antiviral medications or nonmedical options for preventing the flu. Almost a quarter of the articles (24.1%) provided a call to action-telling readers to visit FluFacts or providing a link for them to do so. CONCLUSIONS: Findings suggest that journalists' coverage of this novel campaign-likely one of the goals of the campaign-helped spread the message of the Happy Feet-FluFacts relationship, often omitting other useful health information. Additional research is needed to better understand online DTC campaigns and how consumers react to these campaigns and resulting media coverage and to inform the policymakers' decisions regarding DTC advertising online. PMID- 21254944 TI - Anticoagulant use in cancer patients. AB - INTRODUCTION: the development of venous thromboembolism (VTE) in patients with cancer adversely affects their prognosis. Several autopsy- and population-based studies have clearly shown a negative impact of VTE on patient outcome in cancer patients. AREAS COVERED: an up-to-date review of VTE prophylaxis and treatment in cancer patients is provided with some insights on areas of uncertainty to be answered in the near future. Particular attention is paid to recent cohort studies, randomized clinical trials and consensus guidelines. EXPERT OPINION: cancer patients at a higher risk for VTE may be identified with five variables easily available before initiation of chemotherapy. Long-term treatment with low molecular-weight heparin (LMWH) demonstrated a superior efficacy over vitamin K antagonists. The intensity and duration of anticoagulant therapy should be tailored to the risk of VTE recurrences or bleeding in an individual patient. PMID- 21254945 TI - Adjuvant analgesics in acute pain. AB - INTRODUCTION: despite its central role in acute pain management, the exclusive use of opioids has been challenged recently in view of its immediate and long term side effects. Development of chronic postsurgical pain syndromes, hyperalgesia and immunomodulation are some particular concerns as they may be related to opioid exposure, intertwined with patient characteristics and other factors. Application of a multimodal approach, administration of preventive analgesia and paradigm shift in surgical techniques all mandate a revisit of evidence-based perioperative pain management. AREAS COVERED: adjuvant analgesics are drugs indicated for primary non-pain conditions, but have been found efficacious in analgesia either when used alone or in combination with other analgesics. Among a diverse group of adjuvant analgesics, systemic administration of ketamine, magnesium, gabapentinoids, steroids, alpha2 agonists and lidocaine are reviewed, with recent evidence compared with earlier systematic reviews or meta-analyses from a Medline search (1990 - Apr 2010). EXPERT OPINION: for acute pain management, adjuvant analgesics in appropriate doses and monitored care are beneficial in improving analgesic efficacy and reduce opioid-related side effects with good safety and tolerability. However, the quest for an optimal regime for administration and individualizing treatment remains. PMID- 21254946 TI - Medical approaches to preservation of fertility in female cancer patients. AB - INTRODUCTION: the loss or impairment of ovarian function is an irreversible side effect that can occur in young cancer patients undergoing anticancer treatments. Its incidence varies according to the type of chemotherapy and the patient's age. AREAS COVERED: the review includes studies or data available in literature from 1987 to 2010, examining current strategies to protect ovarian function and/or fertility in patients undergoing chemotherapy, which include oocyte, embryo or ovarian tissue cryopreservation, and temporary ovarian suppression during chemotherapy obtained by the administration of gonadotropin-releasing hormone analogues (GnRHa). The reader will gain an understanding of the incidence of premature ovarian function loss associated with chemotherapy; the advantages and disadvantages of the different strategies in protecting ovarian function; and the magnitude of the effect of GnRHa strategy in preserving ovarian function during chemotherapy. EXPERT OPINION: the administration of GnRHa before and during chemotherapy is associated with an absolute reduction in the incidence of early menopause of nearly 20%. Such a strategy may be offered to young cancer patients who are candidates for chemotherapy. The capability of such an approach in inducing long-term preservation of ovarian function including fertility is still unknown. PMID- 21254947 TI - Pharmacotherapy for squamous-cell carcinoma of the head and neck. AB - INTRODUCTION: squamous-cell carcinoma of the head and neck (HNSCC) is one of the most common malignancies, the treatment of which constitutes a therapeutic challenge. AREAS COVERED: the purpose of this review is to provide an update on the pharmacotherapy for the treatment of HNSCC focusing mainly on molecular targeted therapies. An overview of the different novel therapeutic agents that can selectively inhibit signaling pathways and receptors that are involved in the development and progression of cancer especially in HNSCC is presented. EXPERT OPINION: the treatment of HNSCC is traditionally based on surgery and radiotherapy for early-stage HNSCC; however, chemotherapy is no longer used only for palliation, and individualized patient treatment assisted by molecular targeted therapies represents a future therapeutic challenge. PMID- 21254948 TI - Pharmacotherapy for treatment-refractory schizophrenia. AB - INTRODUCTION: despite advances in pharmacotherapy of schizophrenia-spectrum disorders, a large percentage of persons with schizophrenia remain at least partially nonresponsive to treatment, leading to increased morbidity/mortality, increased healthcare cost, and poor quality of life for affected individuals. AREAS COVERED: this paper comprises a review of recent research in drug therapy for schizophrenia, particularly treatment-refractory schizophrenia, with a focus on research conducted between 2005 and June 2010. Databases that were searched include: Pubmed, CINAHL, Science Direct, Medline and Clinical Trials.gov. Primary search terms were 'treatment-refractory schizophrenia' and 'treatment-resistant schizophrenia', with cross reference to specific agents covered in this article. An objective perspective on current trends in pharmacotherapy for treatment refractory schizophrenia. We review the available evidence and discuss the strengths and weaknesses of published data in this field. EXPERT OPINION: although there have been many advances in pharmacotherapy for schizophrenia, more well-designed trials are required to establish true efficacy and safety of current prescribing trends in clinical practice. PMID- 21254949 TI - Ivabradine: recent and potential applications in clinical practice. AB - INTRODUCTION: published data indicate that heart rate is an independent strong predictor of cardiovascular and all-cause mortality in men and women of all ages, with and without cardiovascular disease, including atherosclerosis, ventricular arrhythmias, and left ventricular dysfunction. Ivabradine is a pure heart-rate lowering agent with well-documented antianginal and anti-ischemic properties comparable to well-established anti-anginal agents. AREAS COVERED: this short review explores recent results with ivabradine, a new medication that lowers heart rate by selectively inhibiting the I (f) current. This review also describes future potential applications. EXPERT OPINION: measurement of heart rate represents an important component of the assessment of patients with coronary artery disease and chronic heart failure, and should be viewed in the same light as other risk factors, because a high heart rate has direct detrimental effects not only on myocardial ischemia but also on the progression of atherosclerosis, ventricular arrhythmias and left ventricular function. Ivabradine has anti-ischemic and antianginal efficacy equivalent to that of beta blockers and calcium channel antagonists in the treatment of chronic stable angina pectoris. Recently ivabradine has been shown to improve cardiac outcomes in stable coronary artery disease and left ventricular systolic dysfunction in patients who have heart rates of >= 70 bpm and in patients with stable angina. PMID- 21254950 TI - Imiquimod 3.75% cream (Zyclara) for the treatment of actinic keratoses. AB - INTRODUCTION: actinic keratosis is a premalignant disease with a high incidence and is a strong predictor for the development of squamous cell carcinoma. Various treatment options have been established over recent years, including topical treatment with imiquimod, 5-fluorouracil, diclofenac or photodynamic therapy, cryotherapy and surgical procedures. AREAS COVERED: this review covers basic and clinical experiences with imiquimod 3.75% for topical treatment of actinic keratosis of the face and balding scalp and its comparators with special focus on imiquimod 5%. It also covers pharmacology of imiquimod 3.5% and its contribution to the current treatment options of actinic keratoses. EXPERT OPINION: imiquimod 3.75% is an interesting, safe and well-tolerated treatment option for actinic keratoses of the face or balding scalp especially in respect of compliance, as it is indicated for daily use for a shorter time period (2 times, 2-week cycles) and approved for use on larger areas compared with imiquimod 5%. Data from current trials indicate lower efficacy compared with imiquimod 5% cream when applied three times a week for 16 weeks or for two 4-week cycles with a 4-week no treatment interval, but indicate similar efficacy when compared with a twice weekly schedule for 16 weeks. An additive effect was observed when combining cryosurgery followed by imiquimod 3.75%. PMID- 21254952 TI - Aripiprazole for the treatment of bipolar disorder: a review of current evidence. AB - INTRODUCTION: several medications are available for the treatment of different phases of bipolar disorder, yet many of the drugs that are currently approved carry a substantial burden of side effects or do not lead all treated patients to remission. AREAS COVERED: this paper comprises a review and commentary regarding the use of oral and intramuscular aripiprazole in the acute and maintenance phases of bipolar disorder. Basic principles in dosing, switching, management of side effects and co-administration of aripiprazole with other medications are provided. This paper presents practical strategies to translate the data from clinical research into clinical practice. EXPERT OPINION: aripiprazole has proven to be an effective medication for the acute treatment of manic and mixed episodes, as well as for the prophylactic-maintenance phase of bipolar disorder in patients recovering from a manic/mixed episode. Choosing the appropriate dosing and tapering strategy, addressing the side effects, controlling withdrawal symptoms from previous medications and using adjunctive medications when necessary are key to successful treatment with aripiprazole. PMID- 21254951 TI - Travoprost/timolol fixed combination in the management of open-angle glaucoma: a clinical review. AB - INTRODUCTION: many patients with glaucoma require multiple medications for adequate disease control. This review summarizes the efficacy and safety of the travoprost/timolol fixed combination in lowering intraocular pressure in eyes with glaucoma. AREAS COVERED: phase III and IV evaluations of travoprost/timolol are reviewed, including trials comparing the fixed combination with constituents, with unfixed concomitant therapy and with other unfixed and fixed combinations of glaucoma medications. The safety of travoprost/timolol is also reviewed. EXPERT OPINION: the role of fixed-combination drugs, including travoprost/timolol, in the management of glaucoma is discussed. Unmet needs in glaucoma therapy, including long-acting drug delivery systems and therapies that treat glaucoma via mechanisms other than reduction of intraocular pressure, are also presented. PMID- 21254953 TI - Forecasting risk of tick-borne encephalitis (TBE): using data from wildlife and climate to predict next year's number of human victims. AB - BACKGROUND: Over the past quarter century, the incidence of tick-borne encephalitis (TBE) has increased in most European nations. However, the number of humans stricken by the disease varies from year to year. A method for predicting major increases and decreases is needed. METHODS: We assembled a 25-y database (1984-2008) of the number of human TBE victims and wildlife and climate data for the Stockholm region of Sweden, and used it to create easy-to-use mathematical models that predict increases and decreases in the number of humans stricken by TBE. RESULTS: Our best model, which uses December precipitation and mink (Neovison vison, formerly Mustela vison) bagging figures, successfully predicted every major increase or decrease in TBE during the past quarter century, with a minimum of false alarms. However, this model was not efficient in predicting small increases and decreases. CONCLUSIONS: Predictions from our models can be used to determine when preventive and adaptive programmes should be implemented. For example, in years when the frequency of TBE in humans is predicted to be high, vector control could be intensified where infested ticks have a higher probability of encountering humans, such as at playgrounds, bathing lakes, barbecue areas and camping facilities. Because our models use only wildlife and climate data, they can be used even when the human population is vaccinated. Another advantage is that because our models employ data from previously established databases, no additional funding for surveillance is required. PMID- 21254954 TI - Analysis of Shigella flexneri-mediated infections in model organism Caenorhabditis elegans. AB - BACKGROUND: Shigella flexneri is the causative agent of bacillary dysentery and generates a significant global disease burden. The aim of this study was to analyze the pathogenesis and host immune response, at both the physiological and molecular level, using the model organism Caenorhabditis elegans, in response to S. flexneri. C. elegans is a nematode that responds to infection with a simple innate immune system, key aspects of which have been shown to be conserved. METHODS: S. flexneri-mediated infection of C. elegans was performed in both solid and liquid assays. The expression and subsequent regulation of host candidate antimicrobial genes such as lysozymes, C-type lectins and pathogen virulence genes were kinetically analyzed in the S. flexneri-exposed nematode. RESULTS: In solid assays, worms fed with S. flexneri showed complete killing at 153 +/- 9 h. The kinetic studies showed that S. flexneri killed the worms upon continuous exposure at 41 +/- 1.7 h. However, short-time exposure of the host to S. flexneri indicated that 14 h of exposure resulted in a loss of progeny, and death occurred after 46 h. Semi-quantitative reverse transcriptase polymerase chain reaction (RT PCR) analysis revealed that mRNA levels of host candidate antimicrobial genes and pathogen virulence genes varied significantly at the time of early infection. CONCLUSIONS: The killing of C. elegans requires live bacteria, and a minimal exposure time is sufficient for S. flexneri to have a lethal effect. The candidate antimicrobial genes and virulence genes are kinetically regulated within C. elegans during S. flexneri-mediated infections, thereby exhibiting their role and contribution in the host innate immune system. PMID- 21254955 TI - Osteoporosis and periodontitis in older subjects participating in the Swedish National Survey on Aging and Care (SNAC-Blekinge). AB - Abstract Objective. We assessed the relationships between (I) ultrasonography calcaneus T-scores (PIXI) and mandibular cortex characteristics on oral panoramic radiographs in older subjects; and (II) osteoporosis and periodontitis. Material and methods. We examined 778 subjects (53% women) aged 59-96 years. Periodontitis was defined by alveolar bone loss assessed from panoramic radiographs. Results. PIXI calcaneus T-values <=-2.5 (osteoporosis) were found in 16.3% of women and in 8.1% of men. PIXI calcaneus T-values <-1.6 (osteoporosis, adjusted) were found in 34.2% of women and in 21.4% of men. The age of the subjects and PIXI T-values were significantly correlated in women (Pearson's r = 0.37, P < 0.001) and men (Pearson's r = 0.19, P < 0.001). Periodontitis was found in 18.7% of subjects defined by alveolar bone level >=5 mm. Subjects with osteoporosis defined by adjusted PIXI T-values had fewer remaining teeth [mean difference 4.1, 95% confidence interval (CI) -1.1 to -6.5, P < 0.001]. The crude odds ratio (OR) of an association between the panoramic assessment of mandibular cortex erosions as a sign of osteoporosis and the adjusted T-value (T-value cut-off <-1.6) was 4.8 (95% CI 3.1-7.2, P < 0.001; Pearson chi(2) = 60.1, P < 0.001). A significant OR between osteoporosis and periodontitis was only found in women for the T-value cut-off <=-2.5 (crude OR 1.8, 95% CI 1.1-3.3, P < 0.03). Conclusions. An association between osteoporosis and periodontitis was only confirmed in women. The likelihood that the mandibular cortex index agrees with adjusted PIXI T values is significant. PMID- 21254956 TI - Topography and presence of a smear layer in deciduous molars prepared with high speed cutting and ultrasonic abrasion: an in-vitro study. AB - OBJECTIVE: The aim of this in-vitro study was to compare the effect of high-speed cutting (HS) with ultrasonic abrasion (US) concerning the internal topography and the presence of a smear layer in a cavity preparation performed in healthy deciduous molars. MATERIAL AND METHODS: Seven first deciduous molars were used. Two occlusal cavity preparation were done, one in the medial fossula and another in the distal fossula, which were chosen randomly. One preparation was carried out with a diamond point adapted to the HS system (GI), while a chemical vapor deposition (CVD) point adapted to a US device (GII) was used for the other preparation. Subsequently, all samples (n = 14) were cleaved to observe the inside and then prepared for evaluation using scanning electron photomicroscopy. The internal topography of the prepared cavities was descriptively analyzed. In order to assess the presence of a smear layer, scores were tabulated using the 2000 GMC program and analyzed using the Mann-Whitney test. RESULTS: Concerning the internal topography, the presence of striae was verified in both groups. In the GI group they were finer, found in a greater number, and with narrower spaces between them. In the GII group, the striae were undulating, similar to the effect of wheels on sand, and with wider spaces between them. As regards the presence of a smear layer, there was no statistically significant difference between the groups (P > 0.05). CONCLUSIONS: In view of the methodology employed, it may be concluded that cavity preparation with a CVD point in a US abrasion system led to the formation of fewer striae and both devices promoted the marked presence of a smear layer, obstructing dentinal tubuli. PMID- 21254957 TI - How do we know it is really congenital cholesteatoma? PMID- 21254958 TI - Extracapsular dissection: minimally invasive surgery applied to patients with parotid pleomorphic adenoma. AB - CONCLUSIONS: We performed extracapsular dissection (ECD) on 31 patients with pleomorphic adenoma, including 7 deep lobe cases. ECD is minimally invasive and has limited complications compared with other conventional parotidectomy procedures. This is the first report on performance of ECD in patients with deep lobe parotid pleomorphic adenomas. Surgeons who are capsule-conscious can perform ECD with good results. OBJECTIVE: Pleomorphic adenoma, the most common benign neoplasm occurring in the parotid gland, has a constant frequency of recurrence and facial paralysis in patients after surgery. ECD is one of the surgical procedures performed on patients with these tumors, but its validity is still unclear because of its similarity to enucleation. METHODS: We performed ECD in patients with untreated parotid neoplasms that were clinically diagnosed as benign before surgery. Of these, resected samples from 31 patients were histologically diagnosed as pleomorphic adenoma. RESULTS: We achieved resection in patients with pleomorphic adenoma with no permanent facial paralysis or tumor recurrence, with a median follow-up time of 61 months (range 18-125 months). PMID- 21254959 TI - Pure tone auditory thresholds can change according to duration of interrupted tones in patients with psychogenic hearing loss. AB - CONCLUSION: Pure tone auditory thresholds can change according to duration of interrupted tones in patients with mild to severe psychogenic hearing loss (PHL). OBJECTIVES: To examine how the duration of stimulus tones affects the hearing thresholds of patients with PHL. METHODS: Twelve patients with PHL (21 ears) were enrolled in this study. We initially measured their hearing thresholds using interrupted tones with a duration of 2 s and equal length of on-time and off time, 225 +/- 35 ms, respectively. After a 10 min interval, we measured their hearing thresholds using the same interrupted tones conditions lasting 5 s. The average threshold gains (2 s thresholds minus 5 s thresholds) were compared to those of 15 control subjects with normal hearing (25 ears), 15 patients with cochlear hearing loss (23 ears), and 4 patients with retrocochlear lesions (4 ears). Patients with profound PHL (4 patients, 6 ears) were analyzed separately. RESULTS: The average threshold gain of PHL patients (excluding profound PHL patients) at all frequencies was 18.3 dB, which was significantly larger than that of other groups: 0.3 dB (profound PHL patients), 3.8 dB (controls with normal hearing), 3.0 dB (patients with cochlear hearing loss), and 3.2 dB (patients with retrocochlear lesions). PMID- 21254960 TI - Spontaneous otogenic pneumocephalus. AB - The diagnosis and management of spontaneous otogenic pneumocephalus with literature review is described. A young sportsman experienced headache and fluctuating mass in his occiput during increased physical activity. A large extradural intracranial pneumocephalus with corresponding emphysema was imaged on a CT scan. Transmastoid identification and plugging of temporal bone defect solved the problem with complete pneumocephalus and emphysema resorption. PMID- 21254961 TI - Audiovestibular findings in a branchio-oto syndrome patient with a SIX1 mutation. AB - CONCLUSION: A reported mutation in SIX1 was identified in a patient with familial hearing loss (HL), a left preauricular pit, and bilateral enlarged vestibular aqueducts (EVA). Although the characteristic symptoms of EVA including fluctuating HL and repetitive vertigo were not seen in the patient, further studies are needed to clarify the association between EVA and such symptoms. OBJECTIVES: To study the audiovestibular functions, and to identify the causative gene in a patient with branchio-oto syndrome. METHODS: We enrolled a 30-year-old female in whom HL was pointed out at the age of 6 years. She visited our department at the age of 21 years, and had not experienced any progression of her HL, tinnitus, or vertigo. Pure-tone audiograms showed bilateral moderate mixed HL with no apparent progression during a 9-year follow-up period. Audiovestibular examinations included distortion product otoacoustic emissions (DPOAEs), electrocochleography (ECochG), and electronystagmography (ENG). Direct sequencing was utilized to screen for SIX1, EYA1, SLC26A4, GJB2, and mitochondrial DNA MTRNR1 including 1555 position. RESULTS: The findings of DPOAEs, ECochG, and ENG indicated cochlear HL with no vestibular dysfunction. A previously reported mutation of a heterozygous c.386A > G (p.Y129C) in SIX1 was detected. No mutation was identified in EYA1, SLC26A4, GJB2, or MTRNR1. PMID- 21254962 TI - Neural excitation patterns induced by phased-array stimulation in the implanted human cochlea. AB - CONCLUSIONS: Phased-array stimulation is a promising technique, which uses electrical interaction to focus the stimulation in cochlear implants, at the expense of limited threshold shifts. It has potential advantages over, for example, tripolar stimulation. OBJECTIVES: Current spread imposes limitations in cochlear implants. Van Compernolle (1985) suggested using all electrode contacts simultaneously to reduce these effects. Van den Honert et al. (2007) validated this so-called phased array algorithm in patients with respect to the electrode potentials but the effect on neural excitation remained unclear. The present study used computational modeling to relate the effect of phased-array stimulation to the neural elements. METHODS: A computational model of the implanted human cochlea was used to compare the neural excitation patterns induced by conventional monopolar stimulation and by phased-array stimulation. Neural thresholds and electrical dynamic ranges were visualized with excitation profiles, showing the auditory nerve's response to a range of stimulus levels. RESULTS: Phased-array stimulation of a single region reduces the spread of excitation and increases the dynamic range. The phased array paradigm can be extended to stimulate multiple sites simultaneously, thereby eliminating the need for sequential stimulation, but with a more limited range of usable stimulus levels, especially with perimodiolar electrodes. PMID- 21254963 TI - The in situ inflammatory profile of lymphocutaneous and fixed forms of human sporotrichosis. AB - The most common clinical presentations of sporotrichosis are the lymphocutaneous (LC) and fixed cutaneous (F) forms, but little is known about the immunopathologic differences between them. The aim of this study was to evaluate through immunohistochemistry the composition of the in situ inflammatory reaction so as to correlate the results with the clinical presentation of the disease. The following two groups of patients were involved in the studies, i.e., LC (n=19) and F (n=11) patients. Those with the LC form, in contrast to F patients, were found to have a larger number of lesions (P=0.001), of longer duration (P=0.026) and require a more extended course of treatment (P=0.049). LC patients also presented a greater fungal burden (LC:0-6.5; F:0-1.5; P=0.021), a higher percentage of neutrophils (median LC:24.7%; F:6.7%, P=0.002), CD4(+) cells (median LC:40.9%; F:30.0%, P=0.0024), CD22(+) cells (median LC:15.3%; F:2.9%, P=0.048), and higher intensity of NOS2 expression (P=0.009). Thus, our data identified differences in cell profile and inflammatory activity in lesions of LC and F forms of human sporotrichosis. PMID- 21254964 TI - Aspergillus fumigatus biofilms in the clinical setting. AB - We discuss in this work the role of Aspergillus biofilms in the clinical setting by reviewing the most recent findings on this topic. Aspergillus fumigatus can produce in vitro an extracellular hydrophobic matrix with typical biofilm characteristics under all static conditions tested, i.e., agar media, polystyrene and bronchial epithelial cells. Under static conditions the mycelial growth is greater than in shaken, submerged conditions. The extracellular matrix (ECM) is composed of galactomannan, alpha-1,3-glucans, monosaccharides and polyols, melanin and proteins including major antigens and hydrophobins. Typical biofilm structures were observed in the aspergillomas from two patients and in a murine model of invasive pulmonary aspergillosis. The results indicate that alpha-1,3 glucans plays a predominant role in the agglutination of the hyphae together in aerial conditions, and that nutrient starvation was responsible for mycelial death in aspergilloma. Melanin was produced during the infection, suggesting that this pigment is necessary for lung tissue invasion. All antifungal drugs are significantly less effective when A. fumigatus is grown under biofilm vs. planktonic conditions. Chronic persistence of a unique genotype of A. fumigatus in the respiratory tract of CF-patients and the presence of an ECM in vivo may have some therapeutical application for aspergillosis. The most appropriate antifungal drug should not be selected only on the basis of its efficiency to kill in vitro grown fungal cells, but also on its ability to penetrate the ECM. PMID- 21254966 TI - Endemic fungal infections in the Asia-Pacific region. AB - Endemic mycoses are important fungal infections in their respective habitats. In the Asia-Pacific region, an accurate epidemiological picture of endemic mycoses is elusive; few epidemiological surveys have been performed, and limited laboratory facilities and experience with fungal infections have further hampered recognition of infection. However, pockets of endemicity do indeed exist, and endemic fungal infections can have a significant impact on public health. This article reviews the most common endemic mycoses in the Asia-Pacific region: histoplasmosis, penicilliosis, and sporotrichosis. Blastomycosis, which has been infrequently reported within the region, is also briefly discussed. Certain areas of the Asia-Pacific region are endemic for histoplasmosis; however, the ecologic niche for this infection remains unclear. Penicilliosis is restricted to Southeast and Eastern Asia, whereas sporotrichosis is encountered in tropical areas of the Asia-Pacific region linked to environmental reservoirs distinct from those seen in the Western world. Before the advent of acquired immune deficiency syndrome (AIDS), histoplasmosis and penicilliosis were only occasionally reported; however, the incidence of both mycoses has increased with the rise in the incidence of AIDS. Comprehensive studies are needed to fully assess the areas of endemicity and the impact of endemic mycoses in the Asia-Pacific region. PMID- 21254965 TI - The endocytic adaptor proteins of pathogenic fungi: charting new and familiar pathways. AB - Intracellular transport is an essential biological process that is highly conserved throughout the eukaryotic organisms. In fungi, adaptor proteins implicated in the endocytic cycle of endocytosis and exocytosis were found to be important for growth, differentiation, and/or virulence. For example, Saccharomyces cerevisiae Pan1 is an endocytic protein that regulates membrane trafficking, the actin cytoskeleton, and signaling. In Cryptococcus neoformans, a multi-modular endocytic protein, Cin1, was recently found to have pleiotropic functions in morphogenesis, endocytosis, exocytosis, and virulence. Interestingly, Cin1 is homologous to human intersectin ITSN1, but homologs of Cin1/ITSN1 were not found in ascomycetous S. cerevisiae and Candida albicans, or zygomycetous fungi. Moreover, an Eps15 protein homologous to S. cerevisiae Pan1/Ede1 and additional relevant protein homologs were identified in C. neoformans, suggesting the existence of either a distinct endocytic pathway mediated by Cin1 or pathways by either Cin1 or/and Pan1/Ede1 homologs. Whether and how the Cin1-mediated endocytic pathway represents a unique role in pathogenesis or reflects a redundancy of a transport apparatus remains an open and challenging question. This review discusses recent findings of endocytic adaptor proteins from pathogenic fungi and provides a perspective for novel endocytic machinery operating in C. neoformans. An understanding of intracellular trafficking mechanisms as they relate to pathogenesis will likely reveal the identity of novel antifungal targets. PMID- 21254967 TI - Proteinase, phospholipase, biofilm forming abilities and antifungal susceptibilities of Malaysian Candida isolates from blood cultures. AB - This study was conducted to determine the proteinase, phospholipase, and biofilm forming abilities of Candida isolates in blood cultures of specimens from patients at the University Malaya Medical Center, Kuala Lumpur, Malaysia. Proteinase and phospholipase activities were detected in 93.7% and 73.3%, respectively, of 15 Candida albicans isolates. Amongst the 26 non-C. albicans Candida isolates, proteinase and phospholipase activities were detected in 88.5% and 7.7% of the isolates, respectively. There was no significant difference in the expression levels of proteinase amongst the Candida isolates studied (P = 0.272), but the phospholipase activity of C. albicans was significantly higher than that of the non-C. albicans Candida isolates (P = 0.003). There was no significant difference in the biofilm forming abilities of C. albicans and non-C. albicans Candida isolates on the polystyrene microtiter wells (P = 0.379). In addition, the findings of this study demonstrate increased resistance of Candida isolates in biofilms to amphotericin and fluconazole, as compared to their planktonic counterparts. PMID- 21254969 TI - Cannabinoids: occurrence and medicinal chemistry. AB - With an inventory of several hundreds secondary metabolites identified, Cannabis sativa L. (hemp) is one of the phytochemically best characterized plant species. The biomedical relevance of hemp undoubtedly underlies the wealth of data on its constituents and their biological activities, and cannabinoids, a class of unique meroterpenoids derived from the alkylation of an olivetollike alkyl resorcinol with a monoterpene unit, are the most typical constituents of Cannabis. In addition to the well-known psychotropic properties of Delta(9)-THC, cannabinoids have been reported to show potential in various fields of medicine, with the capacity to address unmet needs like the relief of chemotherapy-derived nausea and anorexia, and symptomatic mitigation of multiple sclerosis. Many of the potential therapeutic uses of cannabinoids are related to the interaction with (at least) two cannabinoid G-protein coupled receptors (CB1 and CB2). However, a number of activities, like the antibacterial or the antitumor properties are non totally dependent or fully independent from the interaction with these proteins. These pharmacological activities are particularly interesting since, in principle, they could be easily dissociated by the unwanted psychotropic effects. This review aims at giving readers a survey of the more recent advances in both phytochemistry of C. sativa, the medicinal chemistry of cannabinoids, and their distribution in plants, highlighting the impact that research in these hot fields could have for modern medicinal chemistry and pharmacology. PMID- 21254968 TI - Glycosylation status of the C. albicans cell wall affects the efficiency of neutrophil phagocytosis and killing but not cytokine signaling. AB - The cell wall of the opportunistic human fungal pathogen, Candida albicans is a complex, layered network of rigid structural polysaccharides composed of beta glucans and chitin that is covered with a fibrillar matrix of highly glycosylated mannoproteins. Polymorphonuclear cells (PMNs, neutrophils) are the most prevalent circulating phagocytic leukocyte in peripheral blood and they are pivotal in the clearance of invading fungal cells from tissues. The importance of cell-wall mannans for the recognition and uptake of C. albicans by human PMNs was therefore investigated. N- and O-glycosylation-deficient mutants were attenuated in binding and phagocytosis by PMNs and this was associated with reduced killing of C. albicans yeast cells. No differences were found in the production of the respiratory burst enzyme myeloperoxidase (MPO) and the neutrophil chemokine IL-8 in PMNs exposed to control and glycosylation-deficient C. albicans strains. Thus, the significant decrease in killing of glycan-deficient C. albicans strains by PMNs is a consequence of a marked reduction in phagocytosis rather than changes in the release of inflammatory mediators by PMNs. PMID- 21254970 TI - In vitro models for the study of non-alcoholic fatty liver disease. AB - Non-alcoholic fatty liver disease is regarded as the hepatic manifestation of metabolic syndrome and is an important and common cause of chronic liver disease with a potential to develop end-stage liver disease. While important advances in the pathophysiology have been achieved using genetically modified and diet induced animal models, in-vitro models have been only recently proposed. These models include primary culture and immortalized cell lines. Here we critically review the characteristics of the in vitro models described, the advantages and limitations of the in vitro approach, and the results derived. PMID- 21254971 TI - Current trends in the application of nanoparticles in drug delivery. AB - The discovery of new biologically active compounds that can be exploited therapeutically to treat disease has stalled, with fewer new drugs entering the market every year. The spotlight has now turned onto nanoparticles (NPs) as a versatile and multifaceted platform for the delivery of drugs. NPs offer better pharmacokinetic properties, controlled and sustained release, and targeting of specific cells, tissues or organs. All these features can improve the efficacy of existing drugs. The use of NPs can dramatically impact the treatment of many diseases. Many potential therapeutics that exist for alleviating brain diseases such as epilepsy, Alzheimer's disease and tumours are not feasible due to a lack of means to deliver drugs across the blood brain barrier. NPs offer an alternative solution, since they can be modified to cross the blood brain barrier. Additionally, NPs can also play a part in alternative methods of non parental administration of drugs e.g. pulmonary and transdermally. Through active targeting and the enhanced permeation and retention effect, NPs reduce the systemic toxicity of chemotherapeutic drugs by ensuring delivery only to the site of the tumour, thus enhancing cancer treatment. We critically review the literature to provide a summary of current synthesis methodologies and applications of NPs in drug delivery. PMID- 21254972 TI - The medicinal potential of influenza virus surface proteins: hemagglutinin and neuraminidase. AB - Nowadays, influenza virus is still a big threat to human. Hemagglutinin (HA) and neuraminidase (NA) are the two viral surface proteins, which play important roles in the life cycle of influenza virus. Current influenza vaccines and anti influenza drugs work mainly by interfering with the functions of the two proteins. In this review, we will display some recent studies about the two proteins. As to HA, this review covers a lot including its fusion function, receptor specificity, antigenic shift hypothesis, novel antibodies and various inhibitors in order to deeply discuss this protein. As to NA, this review mainly focuses on studies about the newly identified 150-cavity of group-1 NAs and shows some untypical NA inhibitors aiming to provide a broader range of lead compounds for anti-influenza drug design. PMID- 21254973 TI - Non-genotoxic p53-activators and their significance as antitumor therapy of future. AB - The tumor suppressor protein p53 mediates critical cellular functions including regulation of cell cycle, apoptosis, DNA repair, and senescence. This protein has been found to be inactivated or functionally down-regulated in several malignancies such as Li-Fraumeni syndrom, hepatocellular carcinoma, breast cancer, cervical cancer, and acute myeloid leukemia. Thus, p53 represents an attractive target for therapeutic design and development of new anticancer agents. The most clinically used cytotoxic agents target stabilization of wt-p53 through DNA damage and are associated with several unwanted and life threatening side effects. There are a number of recently developed approaches that hold promise for non-genotoxic reactivation of p53. Earlier, we have reported various inhibitors of p53 and their importance to prevent unwanted death of normal cells in a variety of diseases [1]. To extend p53 protein as new target for anticancer agents, in this review we discussed the mechanisms of p53 inactivation. Subsequently, we described some of recently developed non-genotoxic activators of p53 and their significance in various neoplastic disorders. Additionally, we summarized advantages of nongenotoxic p53-activating agents over conventional anticancer therapy and challenges in future of p53 based therapy. PMID- 21254975 TI - Glycans in magnetic resonance imaging: determinants of relaxivity to smart agents, and potential applications in biomedicine. AB - Carbohydrate chemistry and glycobiology have become a "hot" subject. These extensive, complex structures serve essential roles in cell surface phenomena, but we are only beginning to understand what some of these functions are; any advances in the development of synthetic and/or analytical tools for glycobiology are extremely useful for our understanding of the roles of carbohydrates in biology, and as biomarkers of physiological/pathological states. This review provides an outlook of the potential of carbohydrate chemistry/biology in magnetic resonance imaging (MRI), a major important and prominent technique in diagnostic clinical medicine and biomedical research. During the last 30 years, MRI has developed from an intriguing research project to an essential diagnostic method in the clinic. Although MRI contrast in endogenous tissues provides excellent sensitivity for detecting subtle changes in anatomy and function, MRI still has poor specificity for attributing image contrast to specific biological processes. To overcome this limitation, MRI methods are being developed that induce changes in MR image contrast in response to molecular compositions and functions that serve as early biomarkers of pathologies. Carbohydrates with their intriguing chemistry, not only can provide structures for novel MRI probes for imaging specific biological processes, but can themselves provide novel targets/biomarkers. For example, the glycan structure can simply provide a molecular scaffold for modulating the physicochemical properties of the imaging contrast agent, or can be used for the design of novel MR agents with the ability to disclose relevant physiological or pathological cellular events. PMID- 21254974 TI - Evaluation of post-surgical cognitive function and protein fingerprints in the cerebro-spinal fluid utilizing surface-enhanced laser Desorption/Ionization time of-flight mass-spectrometry (SELDI-TOF MS) after coronary artery bypass grafting: review of proteomic analytic tools and introducing a new syndrome. AB - Cognitive dysfunction following surgery is a common complication, which increases the incidence of other co-morbid conditions, hospital and health-care costs. The reported rate of the occurrence of post-operative cognitive decline varies with different studies, depending on population profile, type of surgery, definition of cognitive disorder and detection methods, design of study, etc. It remains unclear whether these psychiatric signs and symptoms are direct results of the effects of surgery or general anesthesia. Nonetheless they are more frequent after cardiac surgery and are likely to be multi-factorial, but the patho mechanisms are not yet fully characterized. This communication provides a synopsis of proteomics tools and delineates novel SELDI-TOF results to evaluate biomarkers in this regard. Presented for the first time is a classification of the clinically relevant forms of post-operative cognitive decline with the advent of a novel subclass. PMID- 21254976 TI - New hope for the treatment of osteoarthritis through selective inhibition of MMP 13. AB - Osteoarthritis (OA) is the leading cause of joint pain and disability in middle aged and elderly patients, and is characterized by progressive loss of articular cartilage that eventually leads to a complex process involving degradation of various components of the cartilage matrix, chief among them are the cartilage specific type II collagen (CII) and aggrecan. While the loss of aggrecan is thought to be an early and reversible process, degradation of CII is considered to be irreversible and a key step in the loss of structural and functional integrity of cartilage. Among the various matrix metalloproteinases (MMPs), MMP 13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. It is the major collagenase in OA cartilage and has the highest activity against CII. However, the clinical utility of broad spectrum MMP inhibitors developed for treatment of OA has been restricted by dose and duration-dependent musculoskeletal side effects in humans. Consequently, selectively inhibiting the MMP-13 would seem to be an attractive therapeutic objective. This review mainly focuses on selective MMP-13 inhibitors development in terms of OA since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, non-zinc-binding groups. In addition, dual inhibitors of MMP-13 and aggrecanase are also reviewed. Special emphasis is placed on logistic concerns for lead compound search as well as the structure-activity relationship (SAR) in this field. Through these methods, new hope is emerging for the treatment of OA through selective inhibition of MMP-13. PMID- 21254977 TI - Progress in the development of bestatin analogues as aminopeptidases inhibitors. AB - Aminopeptidases play essential roles in protein maturation, activation, and stability as well as in the degradation and regulation of hormonal and nonhormonal peptides that can serve as important enzyme targets for drug design. This review will focus on an effective inhibitor of aminopeptidases, bestatin, including work to find better inhibitors in the past three decades that has sought to optimize bestatin and prospective developments in bestatin optimization in the future. PMID- 21254978 TI - Novel substituted quinazolines for potent EGFR tyrosine kinase inhibitors. AB - The type I receptor tyrosine kinases (RTKs) are involved in various aspects of cell growth, survival, and differentiation. Among the known RTKs, the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2) are two widely studied proteins that are prototypic members of the ErbB family which also includes ErbB-3 (Her-3) and ErbB-4 (Her-4). Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, and squamous carcinoma of head and neck). Disruption of signal transduction of these kinases has been shown to have an antiproliferative effect. Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/HerceptinTM and cetuximab/ErbituxTM) directed against the receptor, and synthetic tyrosine kinase inhibitors (gefitinib/IressaTM and erlotinib/TarcevaTM). Since many tumours overexpress ErbB receptors, simultaneous targeting of multiple ErbB receptors therefore becomes a promising approach to cancer treatment. Lapatinib (TykerbTM), a potent dual EGFR/ErbB-2 inhibitor, was approved for the treatment of ErbB-2-positive breast cancer. Despite years of intensive research on EGFR inhibitors, there is a surprising dearth of chemically distinct small inhibitors with a high degree of selectivity. There is also a need for new scaffolds due to the recent finding of EGFR mutations which render the kinase resistant to gefinitib and erlotinib. The structures under study will be quinazolines with different substituents. The structure-activity relationships and biological evaluation of compounds published during the last four years will be reviewed herein. PMID- 21254979 TI - Placebo or intervention? Is it all a sham? PMID- 21254980 TI - Evidence-based critical care medicine: seeing through a glass darkly. PMID- 21254981 TI - Is it possible to decrease the incidence of peri-operative stroke associated with acute peri-operative beta-blocker administration? PMID- 21254982 TI - Use of invasive placebos in research on local anaesthetic interventions. AB - Placebos play a vital role in clinical research, but their invasive use in the context of local anaesthetic blocks is controversial. We assessed whether recently published randomised controlled trials of local anaesthetic blocks risked harming control group patients in contravention of the Declaration of Helsinki. We developed the 'SHAM' (Serious Harm and Morbidity) scale to assess risk: grade 0 = no risk (no intervention); grade 1 = minimal risk (for example, skin allergy to dressing); grade 2 = minor risk (for example, subcutaneous haematoma, infection); grade 3 = moderate risk (with or without placebo injection) (for example, neuropraxia); and grade 4 = major risk (such as blindness, pneumothorax, or liver laceration). Placebo interventions of the 59 included trials were given a SHAM grade. Nine hundred and nineteen patients in 31 studies, including six studies with 183 children, received an invasive placebo assessed as SHAM grade >= 3. A high level of agreement (78%, kappa = 0.80, p < 0.001) for SHAM grades 0-4 increased to 100% following discussion between assessors. More than half of the randomised controlled study designs subjected patients in control groups to risks of serious or irreversible harm. A debate on whether it is justifiable to expose control group patients to risks of serious harm is overdue. PMID- 21254983 TI - Changing practice with changing research: results of two UK national surveys of intensive insulin therapy in intensive care patients. AB - We conducted two telephone surveys of all United Kingdom adult intensive care units in 2007/8 and 2010 to assess practice with regard to intensive insulin therapy for glycaemic control in critically ill patients, and to assess the change in practice following publications in 2008 and 2009 that challenged the evidence for this therapy. Of 243 units that had a written policy for intensive insulin therapy in 2007/8, 232 (96%) still had a policy in 2010. One hundred and six (46%) units had updated their policy in response to new evidence, whereas 126 (54%) stated that it had remained the same. Where intensive care units had changed their policy, we found a significant increase in target limits and a wider target range. Regional variations in practice were also seen. Across seven regions, the percentage of units where the glycaemic control policy had been updated since 2007/8 varied from nil to 78.9%. PMID- 21254984 TI - Near-patient platelet function testing in patients undergoing coronary artery surgery: a pilot study. AB - Platelet dysfunction after cardiopulmonary bypass contributes to microvascular bleeding and is associated with blood transfusion and resternotomy. Platelet count can be readily performed, but currently there are no standardised, reproducible, rapidly available platelet function tests. We studied platelet function as measured by multiple electrode platelet aggregometery (multiplate) and light transmission aggregometry in 44 patients undergoing routine coronary artery surgery. Platelet aggregation as measured by multiplate was reduced during and after cardiopulmonary bypass compared with baseline with evidence of partial recovery by the time of transfer to ITU. In patients transfused blood, platelet aggregation measured by multiplate was reduced during chest closure with adenosine diphosphate (18 U vs 29 U, p = 0.01) and thrombin receptor agonist peptide-6 agonist (65 U vs 88 U, p = 0.01) compared with patients not transfused. This suggests that multiplate, a new point of care analyser, can detect platelet dysfunction in this setting. PMID- 21254985 TI - An evaluation of underbody forced-air and resistive heating during hypothermic, on-pump cardiac surgery. AB - We conducted a randomised controlled trial to compare the efficacy of underbody forced-air warming (Arizant Healthcare Inc, Eden Prairie, MN, USA) with an underbody resistive heating mattress (Inditherm Patient Warming System, Rotherham, UK) and passive insulation in 129 patients having hypothermic cardiac surgery with cardiopulmonary bypass. Patients were separated from cardiopulmonary bypass at a core temperature of 35 degrees C and external warming continued until the end of surgery. Before cardiopulmonary bypass, the temperature-vs-time slopes were significantly greater in both active warming groups than in the passive insulation group (p < 0.001 for each). However, the slopes of forced-air and resistive warming did not differ (p = 0.55). After cardiopulmonary bypass, the rate of rewarming was significantly greater with forced-air than with resistive warming or passive insulation (p < 0.001 for each), while resistive warming did not differ from passive insulation (p = 0.14). However, absolute temperature differences among the groups were small. PMID- 21254986 TI - Controversies in the physiological basis of the 'anaerobic threshold' and their implications for clinical cardiopulmonary exercise testing. AB - This article reviews the notion of the 'anaerobic threshold' in the context of cardiopulmonary exercise testing. Primarily, this is a review of the proposed mechanisms underlying the ventilatory and lactate response to incremental exercise, which is important to the clinical interpretation of an exercise test. Since such tests are often conducted for risk stratification before major surgery, a failure to locate or justify the existence of an anaerobic threshold will have some implications for clinical practice. We also consider alternative endpoints within the exercise response that might be better used to indicate a patient's capacity to cope with the metabolic demands encountered both during and following major surgery. PMID- 21254987 TI - Complications and mortality in older surgical patients in Australia and New Zealand (the REASON study): a multicentre, prospective, observational study. PMID- 21254988 TI - Hypotension associated with leucocyte depletion filters following cell salvage in obstetrics. PMID- 21254989 TI - Avoiding intravascular injection during ultrasound-guided stellate ganglion block. PMID- 21254990 TI - The Clarus Video System as a useful diagnostic tool. PMID- 21254991 TI - Validity of anaesthetic data on a theatre information system. PMID- 21254992 TI - Elective use of cannula cricothyroidotomy. PMID- 21254993 TI - Fibreoptic bronchoscopy to facilitate ProSeal laryngeal mask airway insertion in a patient with ankylosing spondylitis. PMID- 21254994 TI - Availability and storage of sugammadex for emergency use. PMID- 21254995 TI - Sugammadex and rescue reversal. PMID- 21254997 TI - Can sugammadex save a patient in a simulated 'cannot intubate, cannot ventilate' scenario? PMID- 21254998 TI - A pitfall of Autopulse. PMID- 21254999 TI - Desflurane and oesophageal Doppler - a perfect fit? PMID- 21255001 TI - Heparin-induced thrombocytopenia and the utility of the 4Ts score in the Intensive Care Unit. PMID- 21255002 TI - South-east Asian ovalocytosis and the cryohydrocytosis form of hereditary stomatocytosis show virtually indistinguishable cation permeability defects. AB - The hereditary stomatocytoses are a group of dominantly inherited conditions in which the osmotic stability of the red cell is compromised by abnormally high cation permeability. This report demonstrates the very marked similarities between the cryohydrocytosis form of hereditary stomatocytosis and the common tropical condition south-east Asian ovalocytosis (SAO). We report two patients, one showing a novel cryohydrocytosis variant (Ser762Arg in SLC4A1) and a case of SAO. Both cases showed a mild haemolytic state with some stomatocytes on the blood film, abnormal intracellular sodium and potassium levels which were made markedly abnormal by storage of blood at 0 degrees C, increased cation 'leak' fluxes at 37 degrees C and increased Na(+) K(+) pump activity. In both cases, the anion exchange function of the mutant band 3 was destroyed. Extensive electrophysiological studies comparing the cation leak and conductance in Xenopus laevis oocytes expressing the two mutant genes showed identical patterns of abnormality. These data are consistent with the cryohydrocytosis form of hereditary stomatocytosis and we conclude that the cation leak in SAO is indistinguishable from that in cryohydrocytosis, and that SAO should be considered to be an example of hereditary stomatocytosis. PMID- 21255003 TI - Management of tumour lysis syndrome in children: what is the evidence for prophylactic rasburicase in non-hyperleucocytic leukaemia? PMID- 21255004 TI - Splenectomy produces a rapid but transient decrease of the frequency of circulating CD34+ haematopoietic progenitor cells in primary myelofibrosis. PMID- 21255005 TI - The Genetic Counseling Outcome Scale: a new patient-reported outcome measure for clinical genetics services. AB - The aim of this study was to develop a patient-reported outcome measure (PROM) for clinical genetics services. Previous research was used to develop a draft 84 item questionnaire, which was completed by 527 members of patient support groups. Responses were subjected to exploratory factor analysis (EFA). Parallel analysis was used to identify the number of factors to extract using oblique rotation. Twenty-four questions were selected to form the Genetic Counseling Outcome Scale (GCOS-24). Two hundred and forty-one patients completed a questionnaire pack before and after attendance at a genetics clinic that included the GCOS-24, and validated measures of health locus of control, perceived personal control, anxiety, depression, satisfaction with life and authenticity. Concurrent validity of the GCOS-24 was assessed using bivariate correlation. Sensitivity to change of the GCOS-24 was assessed using analysis of variance. EFA identified a single overarching construct consisting of seven dimensions. Internal consistency (alpha = 0.87) and test-retest reliability (r = 0.86) are good. The GCOS-24 shows convergent and divergent validities, and sensitivity to change over time with a medium-to-large effect size (Cohen's d = 0.70). The GCOS-24 has potential as a clinical genetics-specific PROM. PMID- 21255006 TI - A recurrent 1.71 Mb genomic imbalance at 2q13 increases the risk of developmental delay and dysmorphism. AB - Whole genome profiling such as array comparative genomic hybridization has identified novel genomic imbalances. Many of these genomic imbalances have since been shown to associate with developmental delay, intellectual disability and congenital malformation. Here we identified five unrelated individuals who have a recurrent 1.71 Mb deletion/duplication at 2q13 (Human Genome Build 19: 111,392,197-113,102,594). Four of these individuals have developmental issues, four have cranial dysmorphism. Literature review revealed 14 more cases that had similar genomic imbalances at 2q13. Many of them had developmental delay and dysmorphism. Taken together, 93% and 63% of individuals with this genomic imbalance displayed impaired developmental skills and/or abnormal facial features respectively. This copy number variant (CNV) has not been reported in normal control databases. We, therefore, propose that CNV in this region is a risk factor for developmental delay and dysmorphism. PMID- 21255007 TI - Clinical, biochemical and molecular characterization of cystinuria in a cohort of 12 patients. AB - Cystinuria is a rare autosomal inherited disorder characterized by impaired transport of cystine and dibasic aminoacids in the proximal renal tubule. Classically, cystinuria is classified as type I (silent heterozygotes) and non type I (heterozygotes with urinary hyperexcretion of cystine). Molecularly, cystinuria is classified as type A (mutations on SLC3A1 gene) and type B (mutations on SLC7A9 gene). The goal of this study is to provide a comprehensive clinical, biochemical and molecular characterization of a cohort of 12 Portuguese patients affected with cystinuria in order to provide insight into genotype phenotype correlations. We describe seven type I and five non-type I patients. Regarding the molecular classification, seven patients were type A and five were type B. In SLC3A1 gene, two large genomic rearrangements and 13 sequence variants, including four new variants c.611-2A>C; c.1136+44G>A; c.1597T (p.Y533N); c.*70A>G, were found. One large genomic rearrangement was found in SLC7A9 gene as well as 24 sequence variants including 3 novel variants: c.216C>T (p.C72C), c.1119G>A (p.S373S) and c.*82C>T. In our cohort the most frequent pathogenic mutations were: large rearrangements (33.3% of mutant alleles) and a missense mutation c.1400T>C (p.M467T) (11.1%). This report expands the spectrum of SLC3A1 and SLC7A9 mutations and provides guidance in the clinical implementation of molecular assays in routine genetic counseling of Portuguese patients affected with cystinuria. PMID- 21255008 TI - Expression and agonist responsiveness of CXCR3 variants in human T lymphocytes. AB - The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 are involved in variety of inflammatory disorders including multiple sclerosis, rheumatoid arthritis, psoriasis and sarcoidosis. Two alternatively spliced variants of the human CXCR3-A receptor have been described, termed CXCR3-B and CXCR3-alt. Human CXCR3-B binds CXCL9, CXCL10, CXCL11 as well as an additional ligand CXCL4. In contrast, CXCR3-alt only binds CXCL11. We report that CXCL4 induces intracellular calcium mobilization as well as Akt and p44/p42 extracellular signal-regulated kinase phosphorylation, in activated human T lymphocytes. These responses have similar concentration dependence and time courses to those induced by established CXCR3 agonists. Moreover, phosphorylation of Akt and p44/p42 is inhibited by pertussis toxin, suggesting coupling to Galpha(i) protein. Surprisingly, and in contrast with the other CXCR3 agonists, stimulation of T lymphocytes with CXCL4 failed to elicit migratory responses and did not lead to loss of surface CXCR3 expression. Taken together, our findings show that, although CXCL4 is coupled to downstream biochemical machinery, its role in T cells is probably distinct from that of CXCR3-A agonists. PMID- 21255009 TI - Type I interferon supports primary CD8+ T-cell responses to peptide-pulsed dendritic cells in the absence of CD4+ T-cell help. AB - CD8(+) T-cell responses to non-pathogen, cell-associated antigens such as minor alloantigens or peptide-pulsed dendritic cells (DC) are usually strongly dependent on help from CD4(+) T cells. However, some studies have described help independent primary CD8(+) T-cell responses to cell-associated antigens, using immunization strategies likely to trigger natural killer (NK) cell activation and inflammatory cytokine production. We asked whether NK cell activation by MHC I deficient cells, or administration of inflammatory cytokines, could support CD4(+) T-cell help-independent primary responses to peptide-pulsed DC. Injection of MHC I-deficient cells cross-primed CD8(+) T-cell responses to the protein antigen ovalbumin (OVA) and the male antigen HY, but did not stimulate CD8(+) T cell responses in CD4-depleted mice; hence NK cell stimulation by MHC I-deficient cells did not replace CD4(+) T-cell help in our experiments. Dendritic cells cultured with tumour necrosis factor-alpha (TNF-alpha) or type I interferon-alpha (IFN-alpha) also failed to prime CD8(+) T-cell responses in the absence of help. Injection of TNF-alpha increased lymph node cellularity, but did not generate help-independent CD8(+) T-cell responses. In contrast, CD4-depleted mice injected with IFN-alpha made substantial primary CD8(+) T-cell responses to peptide-pulsed DC. Mice deficient for the type I IFN receptor (IFNR1) made CD8(+) T-cell responses to IFNR1-deficient, peptide-pulsed DC; hence IFN-alpha does not appear to be a downstream mediator of CD4(+) T-cell help. We suggest that primary CD8(+) T-cell responses will become help-independent whenever endogenous IFN-alpha secretion is stimulated by tissue damage, infection, or autoimmune disease. PMID- 21255010 TI - EBI3 deficiency leads to diminished T helper type 1 and increased T helper type 2 mediated airway inflammation. AB - Despite extensive investigation of the signals required for development of T helper type 1 (Th1) and type 2 (Th2) immune responses, the mechanisms involved are still not well-defined. A critical role for Epstein-Barr virus-induced gene 3 (EBI3) in these responses has been proposed. EBI3, initially discovered as a transcriptionally activated gene in Epstein-Barr virus-infected B lymphocytes, codes for a subunit of the cytokine interleukin-27 (IL-27). While initial studies suggested that it had an important role in promoting Th1 responses, subsequent studies have revealed that EBI3 receptor signalling influences a variety of immune cell types and can inhibit both Th1 and Th2 responses. In the present study, we evaluated EBI3(-/-) mice for their ability to mount both Th1-mediated and Th2-mediated airway inflammatory responses. The EBI3(-/-) mice sensitized by exposure to inhaled ovalbumin plus a high dose of lipopolysaccharide, which normally results in Th1 responses in wild-type (WT) mice, instead developed Th2 type airway inflammation, with increased numbers of eosinophils. The EBI3(-/-) mice that were exposed to inhaled ovalbumin with a low dose of lipopolysaccharide, which induces Th2 responses in WT mice, showed a marked enhancement of these responses, with increased airway eosinophils, increased serum IgE levels and increased levels of Th2 cytokines (IL-4, IL-5 and IL-13) in culture supernatants of mediastinal lymph node cells. Increased production of Th2 cytokines was also seen when naive CD4(+) T cells from EBI3(-/-) mice were stimulated in vitro compared with cells from WT mice. These results provide the first evidence that EBI3 may play an inhibitory role in allergic asthma development. PMID- 21255011 TI - Interleukin-10-induced gene expression and suppressive function are selectively modulated by the PI3K-Akt-GSK3 pathway. AB - Interleukin-10 (IL-10) is an immunosuppressive cytokine that inhibits inflammatory gene expression. Phosphatidylinositol 3-kinase (PI3K) -mediated signalling regulates inflammatory responses and can induce IL-10 production, but a role for PI3K signalling in cellular responses to IL-10 is not known. In this study we investigated the involvement of the PI3K-Akt-GSK3 signalling pathway in IL-10-induced gene expression and IL-10-mediated suppression of Toll-like receptor-induced gene expression in primary human macrophages. A combination of loss and gain of function approaches using kinase inhibitors, expression of constitutively active Akt, and RNA interference in primary human macrophages showed that expression of a subset of IL-10-inducible genes was dependent on PI3K Akt signalling. The effects of PI3K-Akt signalling on IL-10 responses were mediated at least in part by glycogen synthase kinase 3 (GSK3). In accordance with a functional role for PI3K pathways in contributing to the suppressive actions of IL-10, PI3K signalling augmented IL-10-mediated inhibition of lipopolysaccharide-induced IL-1, IL-8 and cyclo-oxygenase-2 expression. The PI3K signalling selectively modulated IL-10 responses, as it was not required for inhibition of tumour necrosis factor expression or for induction of certain IL-10 inducible genes such as SOCS3. These findings identify a new mechanism by which PI3K-mediated signalling can suppress inflammation by regulating IL-10-mediated gene induction and anti-inflammatory function. PMID- 21255012 TI - Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells. AB - Summary Histamine is a well-recognized modulator of vascular inflammation. We have shown that histamine, acting via H1 receptors (H1R), synergizes lipopolysaccharide (LPS)-induced production of prostaglandin I(2) (PGI(2)), PGE(2) and interleukin-6 (IL-6) by endothelial cells. The synergy between histamine and LPS was partly attributed to histamine -induced expression of Toll like receptor 4 (TLR4). In this study, we examined whether LPS stimulates the H1R expression in human coronary artery endothelial cells (HCAEC) with resultant enhancement of histamine responsiveness. Incubation of HCAEC with LPS (10-1000 ng/ml) resulted in two-fold to fourfold increases in H1R mRNA expression in a time-dependent and concentration-dependent fashion. In contrast, LPS treatment did not affect H2R mRNA expression. The LPS-induced H1R mRNA expression peaked by 4 hr after LPS treatment and remained elevated above the basal level for 20-24 hr. Flow cytometric and Western blot analyses revealed increased expression of H1R protein in LPS-treated cells. The specific binding of [(3)H]pyrilamine to H1R in membrane proteins from LPS-treated HCAEC was threefold higher than the untreated cells. The LPS-induced H1R expression was mediated through TLR4 as gene silencing by TLR4-siRNA and treatment with a TLR4 antagonist inhibited the LPS effect. When HCAEC were pre-treated with LPS for 24 hr, washed and challenged with histamine, 17-, 10- and 15-fold increases in PGI(2), PGE(2) and IL-6 production, respectively, were noted. Histamine-induced enhancement of the synthesis of PGI(2), PGE(2) and IL-6 by LPS-primed HCAEC was completely blocked by an H1R antagonist. The results demonstrate that LPS, through TLR4 activation, up-regulates the expression and function of H1R and amplifies histamine-induced inflammatory responses in HCAEC. PMID- 21255014 TI - Chronic central leptin infusion modifies the response to acute central insulin injection by reducing the interaction of the insulin receptor with IRS2 and increasing its association with SOCS3. AB - Leptin and insulin have overlapping intracellular signaling mechanisms and exert anorexigenic actions in the hypothalamus. We aimed to determine how chronic exposure to increased leptin affects the hypothalamic response to a rise in insulin. We analyzed the activation and interactions of components of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in the hypothalamus of rats treated icv for 14 days with leptin followed by a central injection of insulin and killed 15 min later. Insulin increased glycemia and chronic leptin reduced this insulin induced rise in glucose. Leptin decreased the association between the insulin receptor beta chain (IRbeta) and insulin receptor substrate 2 (IRS2), augmented the association between Janus kinase 2 and IRS2, increased levels of the catalytic subunit of PI3K and pAkt-Ser473 and decreased forkhead box O number 1 levels. Insulin reduced the association between suppressor of the cytokine signaling 3 and IRbeta, increased IRbeta-IRS2 association and pAkt-Thr308 levels, with chronic leptin exposure blunting these effects. In conclusion, chronic exposure to leptin decreases the central response to insulin by increasing suppressor of the cytokine signaling 3 association to IR, which inhibits insulin signaling at the level of interaction of its receptor with IRS2 and activates PI3K by promoting Janus kinase 2-IRS2 association. Thus, these results suggest that this mechanism could be a target for the treatment of insulin resistance. PMID- 21255013 TI - Distribution patterns of fibre types in the triceps surae muscle group of chimpanzees and orangutans. AB - Different locomotor and postural demands are met partly due to the varying properties and proportions of the muscle fibre types within the skeletal muscles. Such data are therefore important in understanding the subtle relationships between morphology, function and behaviour. The triceps surae muscle group is of particular interest when studying our closest living relatives, the non-human great apes, as they lack a significant external Achilles tendon, crucial to running locomotion in humans and other cursorial species. The aim of this study, therefore, was to determine the proportions of type I (slow) and type II (fast) fibres throughout these muscles in chimpanzees and orangutans using immunohistochemistry. The orangutan had a higher proportion of type I fibres in all muscles compared with the chimpanzees, related to their slower, more controlled movements in their arboreal habitat. The higher proportion of type II fibres in the chimpanzees likely reflects a compromise between their need for controlled mobility when arboreal, and greater speed and power when terrestrial. Overall, the proportion of slow fibres was greater in the soleus muscle compared with the gastrocnemius muscles, and there was some evidence of proximal to distal and medial to lateral variations within some muscles. This study has shown that not only do orangutans and chimpanzees have very different muscle fibre populations that reflect their locomotor repertoires, but it also shows how the proportion of fibre types provides an additional mechanism by which the performance of a muscle can be modulated to suit the needs of a species. PMID- 21255015 TI - Mechanism of GABAB receptor-induced BDNF secretion and promotion of GABAA receptor membrane expression. AB - Recent studies have shown that GABA(B) receptors play more than a classical inhibitory role and can function as an important synaptic maturation signal early in life. In a previous study, we reported that GABA(B) receptor activation triggers secretion of brain-derived neurotrophic factor (BDNF) and promotes the functional maturation of GABAergic synapses in the developing rat hippocampus. To identify the signalling pathway linking GABA(B) receptor activation to BDNF secretion in these cells, we have now used the phosphorylated form of the cAMP response element-binding protein as a biological sensor for endogenous BDNF release. In the present study, we show that GABA(B) receptor-induced secretion of BDNF relies on the activation of phospholipase C, followed by the formation of diacylglycerol, activation of protein kinase C, and the opening of L-type voltage dependent Ca(2+) channels. We further show that once released by GABA(B) receptor activation, BDNF increases the membrane expression of beta(2/3) -containing GABA(A) receptors in neuronal cultures. These results reveal a novel function of GABA(B) receptors in regulating the expression of GABA(A) receptor through BDNF tropomyosin-related kinase B receptor dependent signalling pathway. PMID- 21255016 TI - The memory enhancing effect of the APP-derived tripeptide Ac-rER is mediated through CRMP2. AB - The diasteromeric (D/L) form of the acetylated tripeptide rER (NH2-D-arg-L-glu-D arg-COOH), derived from the external domain of amyloid precursor protein, protects against amyloid-beta induced memory loss for a passive avoidance task in young chicks and enhances retention for a weak version of the task when injected peripherally up to 12 h prior to training. The tripeptide readily crosses the blood-brain barrier, binds to receptor sites in the brain and is without adverse effects on general behaviour. The mechanisms of its action are unknown, as are its target molecules/pathways. Here, we report the binding partners for Ac-rER are collapsin response mediator protein 2 (CRMP2), syntaxin binding protein 1 and heat shock protein 70. Behavioural studies of the effects of Ac-rER on memory retention confirmed that the effect of Ac-rER is mediated via CRMP2, as anti CRMP2 antibodies if injected intracranially 30 min pre-training, induced amnesia for the passive avoidance task. However, Ac-rER, if injected prior to the anti CRMP2, rescues the memory deficits induced by anti-CRMP2 antibodies. As CRMP2 is placed at the junction of many different cellular processes during brain development and in adult neuronal plasticity as well as being implicated in Alzheimer's disease, this strengthens the claim that Ac-rER may be a potential therapeutic agent in Alzheimer's disease, although its precise mode of action remains to be elucidated. PMID- 21255017 TI - Cytosolic zinc release and clearance in hippocampal neurons exposed to glutamate- the role of pH and sodium. AB - Although Zn(2+) homeostasis in neurons is tightly regulated and its destabilization has been linked to a number of pathologies including Alzheimer's disease and ischemic neuronal death, the primary mechanisms affecting intracellular Zn(2+) concentration ([Zn(2+) ](i)) in neurons exposed to excitotoxic stimuli remain poorly understood. The present work addressed these mechanisms in cultured hippocampal neurons exposed to glutamate and glycine (Glu/Gly). [Zn(2+)](i) and intracellular Ca(2+) concentration were monitored simultaneously using FluoZin-3 and Fura-2FF, and intracellular pH (pH(i)) was studied in parallel experiments using 2',7'-bis-(2-carboxyethyl)-5(6) carboxyfluorescein. Glu/Gly applications under Na(+)-free conditions (Na(+) substituted with N-methyl-D-glucamine(+)) caused Ca(2+) influx, pH(i) drop, and Zn(2+) release from intracellular stores. Experimental maneuvers resulting in a pH(i) increase during Glu/Gly applications, such as stimulation of Na(+) dependent pathways of H(+) efflux, forcing H(+) efflux via gramicidin-formed channels, or increasing extracellular pH counteracted [Zn(2+)](i) elevations. In the absence of Na(+), the rate of [Zn(2+)](i) decrease could be correlated with the rate of pH(i) increase. In the presence of Na(+), the rate of [Zn(2+) ](i) decrease was about twice as fast as expected from the rate of pH(i) elevation. The data suggest that Glu/Gly-induced cytosolic acidification promotes [Zn(2+) ](i) elevations and that Na(+) counteracts the latter by promoting pH(i) dependent and pH(i)-independent mechanisms of cytosolic Zn(2+) clearance. PMID- 21255018 TI - Gene expression profile in JNK3 null mice: a novel specific activation of the PI3K/AKT pathway. AB - JNK3 is mainly expressed in the CNS and it plays a crucial role in neuronal death in several neurodegenerative diseases. By contrast, the isoforms JNK1 and JNK2 seem to be involved in brain development. The lack of Jnk3 confers neuroprotection, although mechanisms responsible are unknown. The present study analyzes the gene expression profile in hippocampus from mice lacking Jnk3 in comparison to wild-type mice. The microarray analysis showed that 22 genes are differentially expressed (z-score>2 in two independent arrays) in Jnk3 null mice. Among these, we focused on pi3kcb, as it is directly related to the prosurvival phosphoinositide-3-kinase (PI3K)/AKT pathway. Results from Jnk3 null mice showed an increase in pik3cb transcript and protein, together with an increase in PI3K activity and phosphorylation of AKT. By contrast, these changes were not observed in Jnk1 null mice, which do not present neuroresistance to certain neurodegenerative insults. Therefore, our results indicate that the activation of PI3K/AKT pathway in hippocampus because of the increase in pik3cb transcription and that this mechanism is specifically related to the lack of Jnk3. PMID- 21255019 TI - Serum vitamin D levels in office workers in a subtropical climate. AB - Vitamin D is necessary to maintain healthy bones, and may prevent other chronic diseases. There is limited information regarding the vitamin D status of people living in climates with relatively high ambient ultraviolet radiation. We therefore aimed to determine serum 25(OH)D levels in a group of office-workers in subtropical Australia. We collected blood from 129 office workers in summer (n = 129) and 175 in winter (91 in both seasons). Serum 25(OH)D was estimated using a commercial chemiluminescent immunoassay and we asked participants to complete questionnaires about sun exposure and diet for the month prior to blood collection. Summer and winter mean serum 25(OH)D was 74 (95% CI 70-77) nmol L(-1) and 54 (95% CI 51-57) nmol L(-1), respectively. In summer, 14% of participants were classed as "insufficient," compared with 51% in winter. High 25(OH)D levels in summer were associated with time spent outdoors in nonpeak UV periods, while in winter high levels were associated with intake of vitamin D from food or supplements. The high prevalence of vitamin D insufficiency observed in this population highlights the need for further examination of the relation between sunlight and vitamin D production to enable more accurate sun exposure recommendations. PMID- 21255020 TI - Indication for a radical intermediate preceding the signaling state in the LOV domain photocycle. AB - The blue light photoreceptor phototropin mediates crucial processes in plants leading to optimization of photosynthesis. Phototropin comprises two flavin mononucleotide-binding LOV (light-, oxygen-, or voltage-sensitive) domains. The LOV domains undergo a photocycle upon illumination, in which two intermediates have been detected by UV/Vis spectroscopy. The triplet excited state of flavin is formed and decays within a few microseconds into a photoadduct with an adjacent cysteine, which represents the signaling state of the LOV domain. For bond formation of the photoadduct, several reaction pathways have been proposed, but evidence for an intermediate at ambient conditions has not been found. Here, we performed nanosecond time-resolved UV/Vis spectroscopy on the phototropin-LOV1 domain from Chlamydomonas reinhardtii. We designed a flow cell which was used to efficiently replace the sample after each photoexcitation because the cycling time is in the order of hundreds of seconds. The comparison of difference spectra of the wild type with those of the C57S mutant that produces only the triplet excited state revealed the existence of an additional intermediate between the triplet and the adduct state. This intermediate exhibits spectral properties similar to a neutral flavin radical. This finding supports a reaction mechanism involving a neutral radical pair. PMID- 21255021 TI - A corrective emotional experience - or just a bit of exercise? The relevance of interpersonal learning in Exercise on prescription. AB - The objective of the present study was to examine psychological aspects of intra- and interpersonal learning for patients with Type 2 diabetes, hypertension and dyslipidemia treated with Exercise on prescription. The research design consists of a qualitative investigation of 30 patients in Denmark undergoing a community based exercise treatment at baseline, a post-intervention investigation after four months and a follow-up one year after the start of intervention. The results demonstrated that, for the majority of the participants, interaction under group conditions contributes to maintaining the commitment to exercise. For a corrective emotional experience- a correction of an emotional situation a person could not handle in the past - to occur requires two conditions: the group and the environment must be experienced as sufficiently safe, and there must be feedback to permit reality-testing. However, existential psychological aspects such as fear of dying or the universality of suffering triggered, but could not sustain, a change in health behavior. The article concludes that behavioral change is strengthened by interaction with health personnel and with the training group. These new insights likewise demand an increased focus on the human resources of general practitioners or physiotherapists who handle the training. They should learn about their supportive role for the participants, the regressive urges of the participants and the benefits of promoting group relations. PMID- 21255022 TI - How social position of origin relates to intelligence and level of education when adjusting for attained social position. AB - Intelligence and its relationship to achievement is a classical question within psychology. In accordance with earlier British studies, the present study, based on conscription data and follow-ups for Swedish men born 1949-51 (N = 36,156), found that when adjusting for attained social position, people with a high social position of origin tend to have higher intelligence and level of education than people with a lower social position of origin. These results could be seen to contradict the claim that more merit, at least when operationalized as intelligence or education, is required from people with a low social position of origin in order to attain a certain social level. PMID- 21255023 TI - Do men with excessive alcohol consumption and social stability have an addictive personality? AB - The existence of an "addictive" personality has been extensively debated. The current study investigated personality in male individuals with excessive alcohol consumption (n=100) in comparison to a population-based control group (n=131). The individuals with excessive alcohol consumption were recruited by advertisements in a regional daily newspaper and controls from a population based Swedish Twin Registry. Personality was assessed by the Karolinska Scales of Personality (KSP). Comparisons were made with normative data. Furthermore, by using a multivariate projection-based approach (Principal Component Analysis; PCA), hidden structures of traits and possible relationships among the individuals with excessive consumption and the controls was investigated. The individuals with excessive alcohol consumption as well as the controls had mean values within the normative range in all scales of the KSP. Moreover, the PCA analysis revealed no systematic between-group separation. Taken together, this result demonstrates that male individuals with excessive alcohol consumption do not have a personality different from that of a general population, which supports the notion of no "addictive personality". PMID- 21255024 TI - Physical attractiveness stereotype and memory. AB - Three experiments examined explicit and implicit memory for information that is congruent with the physical attractiveness stereotype (i.e. attractive-positive and unattractive-negative) and information that is incongruent with the physical attractiveness stereotype (i.e. attractive-negative and unattractive-positive). Measures of explicit recognition sensitivity and implicit discriminability revealed a memorial advantage for congruent compared to incongruent information, as evident from hit and false alarm rates and reaction times, respectively. Measures of explicit memory showed a recognition bias toward congruent compared to incongruent information, where participants tended to call congruent information old, independently of whether the information had been shown previously or not. This recognition bias was unrelated to reports of subjective confidence in retrieval. The present findings shed light on the cognitive mechanisms that might mediate discriminatory behavior towards physically attractive and physically unattractive individuals. PMID- 21255025 TI - Indigenous health: Can occupational therapy respond to the challenge to 'Close the gap'? PMID- 21255026 TI - Considerations for occupational therapy assessment for Indigenous children in Australia. AB - BACKGROUND: To date, the literature specifically relating to occupational therapy assessment of Australian Indigenous children is lacking. This article aims to present occupational therapists with practice guidelines for conducting assessments with primary school-aged Indigenous children in Australia. It highlights key considerations to be made prior to assessment, reviews potentially culturally relevant assessment tools and discusses key principles to guide assessment practice. METHOD: A literature review was carried out with the aim of investigating: (i) Australian Indigenous culture in relation to health and paediatric development; (ii) current practices for assessment with Australian Indigenous children; and (c) paediatric assessment tools and their potential use with Australian Indigenous children. RESULTS: Research relating to specific assessments does highlight some pertinent points about their use with children from non-Western cultures. CONCLUSIONS: Conducting culturally relevant assessment requires a combination of the right tools, an adaptive approach to both understanding and conducting assessments and, above all, an appreciation that each child is unique. PMID- 21255027 TI - Occupational therapy at the 'cultural interface': Lessons from research with Aboriginal and Torres Strait Islander Australians. AB - BACKGROUND: In 2008, the Council of Australian Governments announced its goals to improve Indigenous life expectancy, health, education and employment: 'Closing the Gap' (Commonwealth of Australia, 2008). Internationally, occupational therapists seek to promote social justice and human rights through occupation. Despite this effort, Australian occupational therapists have largely remained silent in response to the national agenda of closing the gap in Indigenous health. METHODS: This article identifies the challenges of research and practice at the 'cultural interface', the juncture where Western knowledge meets the Indigenous knowledge of our clients. The article draws on the first author's research experience with Indigenous peoples. Through a process of reflection on the challenges highlighted by research at the cultural interface, this article identifies a range of professional processes used to negotiate differing and conflicting perspectives. RESULTS: By comparing the research context with occupational therapy practice, the author identifies some of the actions and supports that can be used by occupational therapists to provide culturally appropriate and negotiated interventions with Indigenous people. CONCLUSIONS: Although a number of individual occupational therapists work with Indigenous communities and individuals to improve the services offered, it is suggested that the occupational therapy profession needs to work together towards closing the gap. The development of special interest groups, professional networks and a National Position Statement on Indigenous Health would provide the background to developing guidelines for practice with Indigenous clients. PMID- 21255028 TI - Closing the gap: Supporting occupational therapists to partner effectively with First Australians. AB - BACKGROUND/AIM: Occupational therapists need to be able to work competently with all clients, including First Australians. Currently, there are no national standards for occupational therapists working with First Australian clients. This article presents current issues in practice and education with First Australians and makes recommendations for the future. METHODS: A survey of 41 occupational therapists working with, or interested in First Australian health issues was conducted at a workshop held at the Australian National Occupational Therapy Conference in 2008. Results of the workshop group discussions were also collated. RESULTS: Several themes emerged from both survey data and discussions. A substantial proportion of participants rated their confidence and competence to work with First Australians as low to moderate. Higher levels of perceived confidence and competence were associated with current experience in the field. Discussions centred around six major themes: building relationships, service provision and design, education and training of occupational therapists, increasing First Australian representation within occupational therapy, professional issues and political issues. These themes were further collapsed into areas of action, which could be taken by individuals, managers, researchers and professional bodies to improve practice with First Australians. CONCLUSIONS: Occupational therapists will benefit from coordinated efforts, on individual and systemic levels, to work more effectively, and in partnership with, First Australians. Such developments should include guidelines for practice, education and research; professional development and networking opportunities; and improved collaboration, especially with First Australian partners, on a national level. PMID- 21255029 TI - Ageing well from an urban Indigenous Australian perspective. AB - INTRODUCTION: The poor health status of Indigenous Australians as demonstrated by high rates of morbidity and mortality compared with non-Indigenous Australians has been of concern to health providers for decades. Largely because of low life expectancy, Indigenous Australians are considered to be ageing from the age of 45 years. However, little is known about the needs and views of this unique group as they age. The aim of the study was to explore perspectives of older Indigenous Australians about their health and wellbeing. METHODS: A qualitative study was conducted using data from face-to-face interviews with six Indigenous people aged over 45 years living in southwest Sydney, Australia. Data were analysed using a phenomenological approach. RESULTS: Participants described important considerations for ageing well that related to the four main themes of: personal identity, family, community and perception of health and ageing. DISCUSSION: Engaging in meaningful occupations to support culturally valued roles were key elements in strengthening identity and facilitating personal, family and community health. Health and wellbeing were perceived as multidimensional concepts by participants, which did not always match available services primarily developed for non-Indigenous populations. Culturally sensitive health services are needed to meet the needs of older Indigenous people. Ageing well was associated with participating in family and community roles, connection with community networks and managing the effects of chronic health problems. Further research is needed to determine how health services can support, identity and promote health for older Indigenous Australians. PMID- 21255030 TI - Development of the Indigenous Child-Initiated Pretend Play Assessment: Selection of play materials and administration. AB - BACKGROUND/AIM: There is a need for culturally appropriate assessments for Australian Indigenous children. This article reports the selection of culturally appropriate and gender-neutral play materials, and changes in administration identified to develop further the Indigenous Child-Initiated Pretend Play Assessment (I-ChIPPA). METHOD: Twenty-three typically developing children aged four to six years from the Pilbara region in Western Australia participated in the study. Children were presented with four sets of play materials and frequency counts were recorded for each time the child used one of the play materials in a pretend play action. Twelve of the 23 children came to play in pairs. RESULTS: Both boys and girls used the Pilbara toy set including the dark coloured dolls and Pilbara region animals, more frequently than the standardised play materials from the Child-Initiated Pretend Play Assessment (ChIPPA). CONCLUSION: This study reports the first steps in the development of the I-ChIPPA. Future development will include the refinement of the administration and scoring with pairs of children, and then validity testing the assessment. PMID- 21255031 TI - Reflecting on our effectiveness: Occupational therapy interventions with Indigenous clients. AB - BACKGROUND: The health and social inequity experienced by the Indigenous population of Australia has resulted in the establishment of a national priority to close the gap in health outcomes. The occupational therapy profession is being urged to ensure the cultural appropriateness of practice interventions for Indigenous people. Although the importance of practice modification has been recognised by the occupational therapy profession, minimal research has been conducted in relation to older Aboriginal and Torres Strait Islander populations. METHOD: The aim of this study was to explore occupational therapists' views of their effectiveness when practising with Indigenous clients. The qualitative study utilises in-depth interviews with occupational therapists working in a regional centre of North Queensland to explore their views of effectiveness when modifying interventions for Indigenous clients. RESULTS: Inductive thematic analysis of the descriptive data generated four themes. The first theme provides insights into participants' views of effectiveness when providing interventions to Indigenous clients. The remaining themes identify specific modification as (i) awareness of culture and respect for the individual, (ii) developing different expectations and (iii) ensuring equality of outcomes. CONCLUSION: The study supports the importance of modifying practice to provide culturally safe occupational therapy to Indigenous clients. The importance of adopting a client centred approach in modifying interventions is also highlighted. Self-reflection by the therapist regarding their occupational therapy practice with Indigenous clients is strongly suggested. In response, a self-reflection tool has been developed from the findings of the study. PMID- 21255032 TI - Koori Occupational Therapy Scheme: Contributing to First Australian health through professional reflection, advocacy and action. PMID- 21255033 TI - Healthy eating in urban Aboriginal households may be promoted through cooking workshops and by recognising the importance of women's work, shared meals, time and cost management. PMID- 21255034 TI - Caring for country was associated with positive health outcomes for Indigenous people living in remote areas of Northern Australia. PMID- 21255035 TI - Persistency of response to omalizumab therapy in severe allergic (IgE-mediated) asthma. AB - BACKGROUND: The physician's global evaluation of treatment effectiveness (GETE) at 16 weeks has been shown to be the most effective assessment of response to omalizumab (XOLAIR(r)). This randomized, open-label, parallel-group study evaluated the persistency of treatment responder classification in patients receiving omalizumab added to optimized asthma therapy (OAT). METHODS: Patients (12-75 years, n = 400) with severe allergic asthma, uncontrolled despite Global Initiative for Asthma 2004 Step 4 therapy, received OAT and omalizumab (n = 272) or OAT (n = 128) for 32 weeks. Response or nonresponse was evaluated at Weeks 16 and 32. Response was defined as an investigator's (physician's) GETE rating of excellent or good; nonresponse was defined as a rating of moderate, poor or worsening. RESULTS: Three hundred and forty-nine patients had GETE ratings available at Weeks 16 and 32 (omalizumab n = 258, OAT n = 91). Omalizumab responders of about 171/187 (91.4%)and 44/71 (62.0%) omalizumab nonresponders at Week 16 persisted as responders or nonresponders at Week 32. The investigator's GETE at Week 16 predicted persistency of response or nonresponse to omalizumab at Week 32 for 83.3% (215/258) of patients. OAT patients showed a lower persistency of response (18/28 [64.3%]) and a higher persistency of nonresponse (57/63 [90.5%]) than omalizumab patients. Excellent and good GETE ratings in omalizumab treated patients were reflected by improvements in exacerbation rates (P < 0.001), severe exacerbation rates (P = 0.023), hospitalizations (P = 0.003), total emergency visits (P = 0.026) and Asthma Control Questionnaire overall score (P < 0.001). CONCLUSION: Response to omalizumab, as assessed by a physician's GETE at 16 weeks, is an effective predictor of continuing persistent response to omalizumab for the majority of patients. PMID- 21255036 TI - Ara h 2: crystal structure and IgE binding distinguish two subpopulations of peanut allergic patients by epitope diversity. AB - BACKGROUND: Peanut allergy affects 1% of the population and causes the most fatal food-related anaphylactic reactions. The protein Ara h 2 is the most potent peanut allergen recognized by 80-90% of peanut allergic patients. METHODS: The crystal structure of the major peanut allergen Ara h 2 was determined for the first time at 2.7 A resolution using a customized maltose-binding protein (MBP) fusion system. IgE antibody binding to the MBP fusion construct vs the natural allergen was compared by ELISA using sera from peanut allergic patients. RESULTS: The structure of Ara h 2 is a five-helix bundle held together by four disulfide bonds and related to the prolamin protein superfamily. The fold is most similar to other amylase and trypsin inhibitors. The MBP--Ara h 2 fusion construct was positively recognized by IgE from 76% of allergic patients (25/33). Two populations of patients could be identified. Subpopulation 1 (n = 14) showed an excellent correlation of IgE antibody binding to natural vs recombinant Ara h 2. Subpopulation 2 (n = 15) showed significantly reduced IgE binding to the MBP fusion protein. Interestingly, about 20% of the IgE binding in subpopulation 2 could be recovered by increasing the distance between MBP and Ara h 2 in a second construct. DISCUSSION: The reduced IgE binding to the MBP--Ara h 2 of subpopulation 2 indicates that the MBP molecule protects an immunodominant epitope region near the first helix of Ara h 2. Residues involved in the epitope(s) are suggested by the crystal structure. The MBP--Ara h 2 fusion constructs will be useful to further elucidate the relevance of certain epitopes to peanut allergy. PMID- 21255037 TI - Allergy gap between Finnish and Russian Karelia on increase. AB - BACKGROUND: Multinational time-trend analyses of atopic disease have shown that the East-West gradients in prevalence are shrinking. We set out to clarify whether the disparities in the occurrence of atopy and atopic diseases in Finnish and Russian Karelia during the past 10 years have diminished and how the prevalence of atopy has evolved with successive years of birth. METHODS: Two surveys with identical methodology were performed in 1997/1998 and 2007. The study population comprised randomly selected adults, aged 25-54 years, from Finnish and Russian Karelia. Serum samples were collected for total and specific IgE measurements. Clinical data were obtained by questionnaires. RESULTS: Sensitization rates to birch pollen increased from 7.8% to 14.8% (P < 0.001) and to cat from 6.1% to 10.8% (P < 0.001) in Finland. In Russia, no significant increase was found. Contrary to this, total IgE remained stable in Finland but decreased significantly (P < 0.001) in Russia. Analyses based on years of birth revealed that the prevalence of sensitization to allergens increased with successive birth years in Finland, but remained stable in Russia. Over the 10 years, self-reported physician-diagnosed asthma increased from 5.5% to 8.1% (P = 0.05) and hay fever from 8.1% to 13.2% (P < 0.001) in Finland. CONCLUSIONS: Disparities in the prevalence of atopy and atopic disease between Finnish and Russian Karelia have further grown. The 'allergy epidemic' continues in Finland and is mainly attributable to the years of birth effect shown in atopy prevalence. In Russia, no signs of the epidemic are discernible, although the decrease in total IgE may indicate a change in environmental exposure. PMID- 21255038 TI - Atopic dermo-respiratory syndrome is a correlate of eczema herpeticum. AB - BACKGROUND: Factors favoring the emergence of eczema herpeticum (EH) in patients with atopic dermatitis (AD) remain elusive. The aim of this work was to identify changes in clinical and laboratory parameters in acute EH patients, before and after 6 weeks of treatment, as well as differences between AD patients with and without a history of EH. METHODS: A total of 235 adult subjects were included and subdivided into six groups: (i) AD patients with acute EH, (ii) AD patients with history of EH, (iii) AD without EH but with recurrent herpes simplex virus (HSV) infections, (iv) AD without EH or recurrent HSV infections and healthy non-AD controls (v) with and (vi) without recurrent HSV infections. Clinical examination of AD, assessment of atopic status and severity were performed. Total IgE, allergen-specific IgE and differential blood count were analyzed. Clinical diagnosis of acute EH was confirmed by PCR. RESULTS: More male patients with AD were affected by EH than female patients. Acute episodes of EH are characterized by lower levels of lymphocytes and higher levels of monocytes. AD patients with history of EH display higher total IgE serum levels (ADEH(+) HSV(+) vs ADEH(-) HSV(+) , P < 0.001) and higher sensitization profiles and stronger severity of AD (EASI and SCORAD; ADEH(+) HSV(+) vs ADEH(-) HSV(+) , P < 0.001). Concomitant asthma and rhinitis were identified as correlates of EH. CONCLUSION: From these data, we conclude that AD patients with EH display a distinct clinical and biological phenotype. PMID- 21255039 TI - Validation of novel recipes for double-blind, placebo-controlled food challenges in children and adults. AB - BACKGROUND: In double-blind, placebo-controlled food challenges (DBPCFCs), the use of challenge materials in which blinding is validated is a prerequisite for obtaining true blinded conditions during the test procedure. Therefore, the aim of this study was to enlarge the available range of validated recipes for DBPCFCs to facilitate oral challenge tests in all age groups, including young children, while maximizing the top dose in an acceptable volume. METHODS: Recipes were developed and subsequently validated by a panel recruited by a matching sensory test. The best 30% of candidates were selected to participate in sensory testing using the paired comparison test. RESULTS: For young children, three recipes with cow's milk and one recipe with peanut could be validated which may be utilized in DBPCFCs. For children older than 4 years and adults, one recipe with egg, two with peanut, one with hazelnut, and one with cashew nut were validated for use in DBPCFCs. CONCLUSIONS: All recipes contained larger amounts of allergenic foods than previously validated. These recipes increase the range of validated recipes for use in DBPCFCs in adults and children. PMID- 21255040 TI - Quality of thermoplasticized and single point root fillings assessed by micro computed tomography. AB - AIM: To evaluate ex vivo the quality of root fillings completed by two thermoplasticized gutta-percha techniques (Thermafil and System B) and a cold gutta-percha technique (single point) by MUCT analysis. METHODOLOGY: A total of 30 freshly extracted human single-rooted permanent teeth were selected. Root canals were prepared with ProTaper Universal instruments and then randomly divided into three groups (n = 10) depending on the filling technique. In group 1, canals were filled with a single-point technique; group 2 was filled with Thermafil; in group 3 System B was used. In group 1 and group 3, the root filling was performed using ProTaper Universal gutta-percha points, in group 2 Thermafil obturators were used; AH-Plus sealer was used in all groups. Assessment of the root filling was carried out by MUCT, using a desktop X-ray micro focus CT scanner. Percentage of root canal filling materials and voids was calculated for each specimen. Data were statistically analysed using Kruskal-Wallis test (P < 0.05). RESULTS: Mean percentages of filling materials were 98.379 +/- 1.204 in the single-point group, 99.023 +/- 1.457 in Thermafil group, and 98.167 +/- 3.432 in System B group. No statistically significant difference was found amongst the groups. CONCLUSION: All techniques produced comparable results in terms of percentage of filling and void distribution. PMID- 21255041 TI - Evaluation of the dimensional changes of mineral trioxide aggregate sealer. AB - AIM: To evaluate the setting time, early age restrained dimensional stability, fluid uptake, microstructure and porosity of a root canal sealer based on mineral trioxide aggregate (MTAS). METHODOLOGY: The MTAS, mineral trioxide aggregate (MTA) and a commercially available sealer pulp canal sealer (PCS) were investigated. The setting time of the materials was determined according to ISO 6876; 2002. The dimensional change in the vertical direction was measured over a period of 7 days from setting time using a linear variable differential transducer. The test samples were restrained in lateral directions by the metal mould. The fluid uptake of the cements was evaluated in Hank's balanced salt solution (HBSS), and their porosity was investigated using light optical microscopy. RESULTS: The addition of a water-soluble polymer to MTA reduced its setting time but PCS displayed the shortest setting time (P < 0.05). The dimensional stability of the materials was not affected by the test environmental conditions (P > 0.05). PCS exhibited a much higher degree of shrinkage than MTA (P = 0.997, 0.640, 0.449, 0.191) and MTAS (P = 0.952, 0.523, 0.380, 0.149) at 3 h and 1, 3, 7 days, respectively, when allowed to set at 100% humidity. An increase in weight and expansion was recorded for MTA when immersed in HBSS. Microscope investigation of test specimens revealed the highest degree of porosity in MTA followed by MTAS and PCS. CONCLUSIONS: The novel sealer based on MTA demonstrated adequate setting time and was dimensionally stable. It has the potential to be used as root canal sealer cement in clinical practice. PMID- 21255042 TI - An in vitro evaluation of two resin-based sealers on proliferation and differentiation of human periodontal ligament cells. AB - AIM: To evaluate the effects of a polymethyl methacrylate resin-based sealer [Superbond sealer (SB)] on the proliferation and osteogenic differentiation of human periodontal ligament cells (HPDLCs) in vitro, compared with a methacrylate resin-based sealer [Epiphany SE sealer (EP)]. METHODOLOGY: Human periodontal ligament cells were obtained from of healthy third molar teeth of two participants with informed consent. To determine the effects of the eluent from set resin sealers on HPDLCs, the 7-day-washed (washed) or non-washed freshly prepared (fresh) set SB or EP discs were prepared. Cells cultured on these discs were evaluated by the WST-1 proliferation assay and scanning electron microscopy (SEM). The osteogenic differentiation of HPDLCs on washed SB discs was then evaluated by gene expression analysis of osteopontin (OPN) and osteocalcin (OCN) by using quantitative RT-PCR. RESULTS: Human periodontal ligament cells exhibited growth on washed SB discs, whereas fresh SB and EP discs and washed EP discs inhibited proliferation of HPDLCs. SEM observation revealed that HPDLCs tightly attached and spread on the surface of washed SB discs, whilst no HPDLCs were observed on the surface of fresh and washed EP discs. Furthermore, HPDLCs significantly upregulated gene expressions of OPN and OCN when cultured on washed SB discs in osteogenic differentiation medium for 2 weeks. CONCLUSIONS: Although Superbond sealer initially exerted cytotoxic effects on HPDLCs, these effects were reduced during washing for 7 days compared to EP, which continued to be cytotoxic even though the specimens were washed for the same period of time. Washed Superbond allowed HPDLCs to differentiate into osteogenic cells. PMID- 21255043 TI - Impact of adhesive surface and volume of luting resin on fracture resistance of root filled teeth. AB - AIM: To investigate the correlation between geometric parameters of severely compromised root filled (RCT) pre-molar teeth with irregular root canals and their fracture resistance. The null hypothesis tested was that the fracture resistance of root filled teeth is not influenced by: (i) the adhesive surface of the post-space preparation (A(PS) ), (ii) the coronal tooth surface (A(A) ), (iii) the amount of resin cement (V(C) ) and (iv) the Young's modulus of the specimens. METHODOLOGY: A total of 48 noncarious human pre-molar teeth with irregular root canals were decoronated, root filled and adhesively restored with post-retained direct composite crowns. After thermomechanical loading (1,200,000*, 5-50 degrees C), static load was applied until failure. The geometric parameters of the tooth were evaluated by microcomputed tomography (MUCT) using impressions taken after post-space preparation. Linear regression analyses were performed to correlate the geometric parameters of the specimens with their fracture resistance. RESULTS: The amount of resin cement (V(C) ) comprised up to 88% of the entire post-space (mean 67%) and had no impact on the maximal load (P = 0.88). The latter was significantly influenced by post-space preparation (P = 0.003). CONCLUSIONS: Amongst the geometric parameters tested, the surface area in the root canal had the greatest impact on fracture resistance of root filled pre-molars restored with posts and composite crowns, whilst the fit of the post was less important. PMID- 21255044 TI - Anti-CD25 antibodies (daclizumab) as renal sparing immunosuppression after liver transplantation. PMID- 21255046 TI - Smear layer dissolution by peracetic acid of low concentration. AB - AIM: To test the effect of a noncaustic concentration of peracetic acid (PAA) in a standardized smear layer model. METHODOLOGY: The smear layer dissolution kinetics of 0.5% PAA on human dentine were compared to those of 2.25% PAA and 17% ethylenediaminetetraacetic acid (EDTA) solutions. Coronal dentine discs were prepared from six human maxillary molars. A standardized smear layer was produced on the pulpal side of each disc. The smear layer-covered surface was divided into three similar areas and then exposed to one of the three solutions tested. Co site image sequences (around 40, 500 *) of the specific areas were obtained after four cumulative demineralisation times (15, 30, 60 and 180 s). An image processing and analysis sequence measured sets of images, providing data of area fraction (AF, dentine-free area in % of total analysis area). A general linear model for repeated measures was used to verify the influence of time and solution type over the change in AF from baseline (DeltaAF). RESULTS: Overall, EDTA and 2.25% PAA produced higher DeltaAF values than the 0.5% PAA solution (P < 0.05). No significant difference was observed in DeltaAF between 15 s and 30 s (P > 0.05). After 60 s of etching, all tested solutions produced similar DeltaAF (P > 0.05), whereas at 180 s, DeltaAF of both EDTA and 2.25% PAA continued to increase (P > 0.05). CONCLUSIONS: After 60 s of contact, the 0.5% PAA solution dissolved smear layer as well as 2.25% PAA and 17% EDTA. PMID- 21255047 TI - The impact of root dentine conditioning on sealing ability and push-out bond strength of an epoxy resin root canal sealer. AB - AIM: To investigate the impact of dentine conditioning on sealing ability and dentine bond strength of an epoxy resin sealer. METHODOLOGY: Root canals in 90 single-rooted teeth were instrumented using a rotary Ni-Ti system. Fifty canals were irrigated with water during instrumentation, 40 with 3% NaOCl. A final flush was performed in the water-irrigated specimens with water (negative control), 3% NaOCl, 17% EDTA, 7% maleic acid (MA) or 2% chlorhexidine. The hypochlorite irrigated specimens received a final flush with a decalcifying agent (EDTA or MA) and then 3% NaOCl or 3% NaOCl and then the decalcifying agent (n = 10, each). Canals were all filled with AH Plus. Fluid transport was measured on day 3 and 30. Roots were then sectioned, and push-out tests were performed in coronal, middle and apical root thirds. Results were analysed using analysis of variance (anova) with Bonferroni's adjustment. Spearman's rank correlation was computed between fluid transport and push-out bond strength. RESULTS: Leakage decreased over time (P < 0.05). Push-out bond strength was highest in coronal and lowest in apical root thirds (P < 0.05). Irrigating protocols with final application of a decalcifying agent greatly decreased the leakage and increased push-out bond strength values, in contrast to groups where NaOCl was applied last (P < 0.05), wherein the effect of the decalcifying agent was abolished. Chlorhexidine had no impact on the outcomes. Fluid transport and push-out bond strength correlated strongly (rho = -0.83). CONCLUSIONS: AH Plus appears to bond to the organic phase of dentine. This bond influences its sealing ability. PMID- 21255048 TI - Preliminary study of the inflammatory response to subcutaneous implantation of three root canal sealers. AB - AIM: To evaluate the kinetics of the inflammatory tissue response to three root canal sealers using a physicochemical method for quantification of the enhanced vascular permeability and histopathological analysis. METHODOLOGY: Twenty-eight male Wistar rats randomly assigned to four groups according to the evaluation periods (1, 3, 7 and 14 days) were used to assess the vascular permeability and histopathological reaction to RoekoSeal, AH Plus and Sealapex (new formulation) sealers, using saline and Chloropercha as negative and positive controls, respectively. Seven rats were sacrificed per period. The biocompatibility of the sealers was evaluated spectrophotometrically and histopathologically. RESULTS: At day 14, Sealapex produced significantly more inflammatory exudate than AH Plus and RoekoSeal (P < 0.05); however, there was no significant difference between AH Plus and RoekoSeal (P > 0.05). Sealapex (new formulation) was the most irritating sealer, producing severe inflammation with the presence of multinucleated giant cells. RoekoSeal was the most biocompatible sealer, producing the least amount of inflammatory exudate. CONCLUSIONS: RoekoSeal root canal sealer was biocompatible when implanted in connective tissue. PMID- 21255049 TI - Fusarium oxysporum and its bacterial consortium promote lettuce growth and expansin A5 gene expression through microbial volatile organic compound (MVOC) emission. AB - Fusarium oxysporum MSA 35 [wild-type (WT) strain] is a nonpathogenic Fusarium strain, which exhibits antagonistic activity to plant pathogenic F. oxysporum isolates. The fungus lives in association with a consortium of ectosymbiotic bacteria. The WT strain, when cured of the bacterial symbionts [the cured (CU) form], is pathogenic, causing wilt symptoms similar to those of pathogenic F. oxysporum f. sp. lactucae. Both WT and CU MSA 35 strains produce microbial volatile organic compounds (MVOCs), but with a different spectrum. In vitro dual culture assays were used to assess the effects of the MVOCs produced by WT and CU strains of F. oxysporum MSA 35 on the growth and expansin gene expression of lettuce seedlings. An increase in the root length (95.6%), shoot length (75.0%) and fresh weight (85.8%) was observed only after WT strain MVOCs exposure. Leaf chlorophyll content was significantly enhanced (68%) in WT strain MVOC-treated seedlings as compared with CU strain volatiles and nontreated controls. beta Caryophyllene was found to be one of the volatiles released by WT MSA 35 responsible for the plant growth promotion effect. Semi-quantitative and quantitative reverse transcription-PCR assays indicated a significant difference in the expansin gene expression level between leaf (6.7-fold) and roots (4.4 fold) exposed to WT strain volatiles when compared with the CU strain volatiles and those that were nonexposed. PMID- 21255050 TI - Spatial and temporal changes of cyanophage communities in paddy field soils as revealed by the capsid assembly protein gene g20. AB - Bacteriophages are ubiquitous in various environments. Our previous study revealed the diversity of the cyanophage community in paddy floodwater. In this study, the phylogeny and genetic diversity of cyanophage communities in paddy field soils were reported. The viral capsid assembly protein gene (g20) of cyanophage was amplified with the primers CPS1 and CPS8 from soil DNA extracted during two different sampling times at three sampling sites in Japan. The sequencing results indicated that about 93% of the clones were g20 genes. In total, 70 clones of g20 genes were obtained in this study, of which 69 clones were of cyanophage origin. As evaluated by g20 sequence assemblages in paddy field soils, the unifrac analyses results indicated that cyanophage communities changed among the sampling sites and times and differed from those communities detected in paddy floodwater. The phylogenetic analysis showed that the g20 sequences in paddy field soils were very diverse and distributed into Clusters alpha, beta and E, as well as four newly formed clusters. Within Clusters beta and E, four unique subclusters were formed from the g20 clones that were only observed in this study. These findings suggested that the cyanophage communities in paddy field soils are different from those found in freshwater, marine water and paddy floodwater. PMID- 21255051 TI - Prokaryotic abundance and 16S rRNA gene sequences detected in marine aerosols on the East Sea (Korea). AB - Modern studies on marine airborne prokaryotes over open seas have been rare. Here, to understand their distribution and composition, aerosol as well as surface seawater samples were collected at three sites in the East Sea. The abundance of airborne prokaryotes was 0.7-1.2 * 10(5) cells m(-3) . Partial sequences of the 16S rRNA gene from the aerosols were dominated by Gammaproteobacteria and Bacteroidetes. Interestingly, the numbers of phylotypes of airborne bacteria were comparable to those of seawater bacteria in coastal and remote offshore sites. Over half of the bacterial operational taxonomic units (OTUs) detected in these aerosols (12 out of 20) were of marine origin. Eight of the 19 bacterial OTUs found in the surface waters occurred in the aerosols. Thus, surface seawater seems to be a main source of marine airborne bacteria. However, in the intermediate offshore site, airborne bacterial OTUs (n=4) were all terrestrial, indicating that variations of dominant airborne bacterial phylotypes occurred over the sites (each ~160 km apart) sampled at 1-4-day intervals. Euryarchaeota sequences belonging to the MSP8 clade reported from geographically distant regions were detected in marine aerosols. Long-distance aerial transport of the marine prokaryotes seems to be quite possible. PMID- 21255052 TI - Ecological traits of planktonic viruses and prokaryotes along a full-salinity gradient. AB - Virus-prokaryote interactions were investigated in four natural sites in Senegal (West Africa) covering a salinity gradient ranging from brackish (100/00) to near salt saturation (3600/00). Both the viral and the prokaryote communities exhibited remarkable differences in their physiological, ecological and morphological traits along the gradient. Above 2400/00 salinity, viral and prokaryotic abundance increased considerably with the emergence of (1) highly active square haloarchaea and of (2) viral particles with pleiomorphic morphologies (predominantly spindle, spherical and linear shaped). Viral life strategies also showed some salinity-driven dependence, switching from a prevalence of lytic to lysogenic modes of infection at the highest salinities. Interestingly, the fraction of lysogenized cells was positively correlated with the proportion of square cells. Overall, the extraordinary abundance of viruses in hypersaline systems (up to 6.8 * 10(8) virus-like particles per milliliter) appears to be partly explained by their high stability and specific ability to persist and proliferate in these apparently restrictive habitats. PMID- 21255053 TI - Application of the major capsid protein as a marker of the phylogenetic diversity of Emiliania huxleyi viruses. AB - Studies of the Phycodnaviridae have traditionally relied on the DNA polymerase (pol) gene as a biomarker. However, recent investigations have suggested that the major capsid protein (MCP) gene may be a reliable phylogenetic biomarker. We used MCP gene amplicons gathered across the North Atlantic to assess the diversity of Emiliania huxleyi-infecting Phycodnaviridae. Nucleotide sequences were examined across >6000 km of open ocean, with comparisons between concentrates of the virus size fraction of seawater and of lysates generated by exposing host strains to these same virus concentrates. Analyses revealed that many sequences were only sampled once, while several were over-represented. Analyses also revealed nucleotide sequences distinct from previous coastal isolates. Examination of lysed cultures revealed a new richness in phylogeny, as MCP sequences previously unrepresented within the existing collection of E. huxleyi viruses (EhV) were associated with viruses lysing cultures. Sequences were compared with previously described EhV MCP sequences from the North Sea and a Norwegian Fjord, as well as from the Gulf of Maine. Principal component analysis indicates that location specific distinctions exist despite the presence of sequences common across these environments. Overall, this investigation provides new sequence data and an assessment on the use of the MCP gene. PMID- 21255054 TI - Methanogen community structure in the rumens of farmed sheep, cattle and red deer fed different diets. AB - Development of inhibitors and vaccines that mitigate rumen-derived methane by targeting methanogens relies on knowledge of the methanogens present. We investigated the composition of archaeal communities in the rumens of farmed sheep (Ovis aries), cattle (Bos taurus) and red deer (Cervus elaphus) using denaturing gradient gel electrophoresis (DGGE) to generate fingerprints of archaeal 16S rRNA genes. The total archaeal communities were relatively constant across species and diets, and were less variable and less diverse than bacterial communities. There were diet- and ruminant-species-based differences in archaeal community structure, but the same dominant archaea were present in all rumens. These were members of three coherent clades: species related to Methanobrevibacter ruminantium and Methanobrevibacter olleyae; species related to Methanobrevibacter gottschalkii, Methanobrevibacter thaueri and Methanobrevibacter millerae; and species of the genus Methanosphaera. Members of an archaeal group of unknown physiology, designated rumen cluster C (RCC), were also present. RCC-specific DGGE, clone library analysis and quantitative real time PCR showed that their 16S rRNA gene sequences were very diverse and made up an average of 26.5% of the total archaea. RCC sequences were not readily detected in the DGGE patterns of total archaeal 16S rRNA genes because no single sequence type was abundant enough to form dominant bands. PMID- 21255055 TI - Role of bacterial isolates in enhancing the bud induction in the industrially important red alga Gracilaria dura. AB - Plant growth depends on the integration of environmental cues, nitrogen fixation and phytohormone-signaling pathways. The growth and development of Gracilaria dura was significantly influenced by the association of bacterial isolates. The putative bud-inducing epiphytic Exiguobacterium homiense and endophytic Bacillus pumilus, Bacillus licheniformis were examined for their ability to fix nitrogen and produce indole-3-acetic acid (IAA). These bacterial isolates were identified to the species level by biochemical tests, fatty acid and partial 16S rRNA gene sequence analysis. The B. pumilus, B. licheniformis and E. homiense produced 445.5, 335 and 184.1 MUg mL(-1) IAA and 12.51, 10.14 and 6.9 mM mL(-1) ammonium, respectively, as determined using HPLC and spectroscopy. New bud regeneration observed after the addition of total protein of the bacterial isolates suggests that IAA is conjugated with protein. The epi- and endophytic bacterial isolates were able to induce five and 10 new buds per frond, respectively, in comparison to the control, where one to two buds were observed. The combination of 25 degrees C and 300/00 showed the optimum condition for bud induction in G. dura when incubated with the total protein of B. pumilus. Our finding revealed for the first time that IAA coupled with nitrogen fixation induce and regenerate new buds in G. dura. PMID- 21255056 TI - Synergistic activity of 1-(1-naphthylmethyl)-piperazine with ciprofloxacin against clinically resistant Staphylococcus aureus, as determined by different methods. AB - AIMS: To evaluate the interaction of 1-(1-naphthylmethyl)-piperazine (NMP) and ciprofloxacin (CPFX) in vitro against fluoroquinolone (FQ)-resistant clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). METHODS AND RESULTS: The in vitro interaction of NMP and CPFX in 12 FQ-resistant clinical isolates of MRSA was assessed using a checkerboard microdilution method. In the study, a synergistic antimicrobial effect between NMP and CPFX was observed in all 12 FQ-resistant strains tested, as determined by the fractional inhibitory concentration index (FICI), and in 10 strains using DeltaE models. No antagonistic activity was observed in any of the strains tested. These positive interactions were also confirmed using the time-killing test and agar diffusion assay for the selected strain, MRSA 1862; synergistic activity was observed when NMP was combined with the first-line antimicrobial agent CPFX against Staph. aureus. CONCLUSIONS: Synergistic activity between NMP and CPFX against clinical isolates of FQ-resistant Staph. aureus was observed in vitro. SIGNIFICANCE AND IMPACT OF THE STUDY: This report might provide alternative methods to reduce the resistance of Staph. aureus to CPFX. PMID- 21255057 TI - Diversity in UV sensitivity and recovery potential among bacterioneuston and bacterioplankton isolates. AB - AIMS: To assess the variability in UV-B (280-320 nm) sensitivity of selected bacterial isolates from the surface microlayer and underlying water of the Ria de Aveiro (Portugal) estuary and their ability to recover from previous UV-induced stress. METHODS AND RESULTS: Bacterial suspensions were exposed to UV-B radiation (3.3 W m-2). Effects on culturability and activity were assessed from colony counts and (3) H-leucine incorporation rates, respectively. Among the tested isolates, wide variability in UV-B-induced inhibition of culturability (37.4 99.3%) and activity (36.0-98.0%) was observed. Incubation of UV-B-irradiated suspensions under reactivating regimes (UV-A, 3.65 W m-2; photosynthetic active radiation, 40 W m-2; dark) also revealed diversity in the extent of recovery from UV-B stress. Trends of enhanced resistance of culturability (up to 15.0%) and enhanced recovery in activity (up to 52.0%) were observed in bacterioneuston isolates. CONCLUSIONS: Bacterioneuston isolates were less sensitive and recovered more rapidly from UV-B stress than bacterioplankton isolates, showing enhanced reduction in their metabolism during the irradiation period and decreased culturability during the recovery process compared to bacterioplankton. SIGNIFICANCE AND IMPACT OF THE STUDY: UV exposure can affect the diversity and activity of microbial communities by selecting UV-resistant strains and alter their metabolic activity towards protective strategies. PMID- 21255058 TI - Green kiwifruit modulates the colonic microbiota in growing pigs. AB - AIMS: To investigate whether green kiwifruit modulates the composition of colonic microbiota in growing pigs. METHODS AND RESULTS: Thirty-two pigs were fed the control diet or one of the three test diets containing either cellulose, freeze dried kiwifruit or kiwifruit fibre as the sole fibre source for 14-day study. A Ward's dendrogram of similarity cluster analysis on PCR-DGGE gels revealed that inclusion of freeze-dried kiwifruit and kiwifruit fibre into diets altered the bacterial community, indicating the presence of two distinct clusters. Quantification of different bacterial groups by qPCR demonstrated that pigs fed the freeze-dried kiwifruit or kiwifruit fibre diets had a significantly higher number (P < 0.05) of total bacteria and Bacteroides group and a lower number of Enterobacteria and Escherichia coli group, as well as a greater ratio of Lactobacillus to Enterobacteria when compared to pigs fed the control or cellulose diets. CONCLUSIONS: Green kiwifruit, mainly because of fibre, modulated the colonic microbiota, leading to an improved intestinal environment in growing pigs. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report regarding the effect of green kiwifruit on gut microbiota using the in vivo pig model. These results provide the first evidence of interaction between green kiwifruit and colonic microbiota. PMID- 21255059 TI - Randomised clinical trial: delayed-release oral mesalazine 4.8 g/day vs. 2.4 g/day in endoscopic mucosal healing--ASCEND I and II combined analysis. AB - BACKGROUND: Recent studies have focused on the importance of mucosal healing in ulcerative colitis (UC). However, it was still unclear whether higher doses of delayed-release mesalazine (mesalamine) could provide additional benefit. AIM: To examine how two doses of delayed-release mesalazine (4.8 g/day and 2.4 g/day) from ASCEND I and II compare in their relative ability to heal colonic mucosa over time. METHODS: Primary data from two prospective 6-week, double-blind, randomised studies in patients with mildly to moderately active UC were pooled and analysed retrospectively. The mucosal healing analysis focuses on moderately active UC patients (n=391), comprising a majority of patients (84%). Additional analyses examined the relationship between mucosal healing and dose, clinical response to therapy and patient quality of life (Inflammatory Bowel Disease Questionnaire, IBDQ). RESULTS: At week 3, mucosal healing (endoscopy subscore of 0 or 1) was achieved in 65% of moderately active UC patients on 4.8 g/day and 58% of patients on 2.4 g/day (P=0.219). At week 6, this increased to 80% for 4.8 g/day and 68% for 2.4 g/day (P=0.012). Healing rates with the higher dose were also greater across all extents of disease and in patients with prior steroid use. At 6 weeks, clinical response to therapy and mucosal healing were found to be well correlated (kappa=0.694). Likewise, the change in IBDQ at week 6 showed a significant relationship with mucosal healing (P<0.0001). CONCLUSION: Mucosal healing rates in UC achieved at 6 weeks were statistically significantly higher with delayed-release mesalazine at 4.8 g/day vs. 2.4 g/day. PMID- 21255060 TI - Redefining the intraepithelial lymphocytes threshold to diagnose gluten sensitivity in patients with architecturally normal duodenal histology. AB - BACKGROUND: Accuracy of intraepithelial lymphocytes counts for diagnosing mild enteropathy coeliac disease in absence of villous atrophy can be limited by inappropriate controls included in the studies. AIM: To determine the diagnostic accuracy of intraepithelial lymphocytes counts utilising controls lacking HLA coeliac disease-associated alleles. METHODS: Intraepithelial lymphocytes counting at villus tip and per 100 enterocytes was performed at haematoxylin and eosin (H&E) and CD3-stainings in: 29 cases (21 with potential coeliac disease and 8 affected by latent coeliac disease) representing the patient population and 14 noncoeliac controls lacking HLA-DQ2/DQ8 alleles. RESULTS: Threshold (mean+2 s.d.) of duodenal intraepithelial lymphocytes at villus tip and per 100 enterocytes in noncoeliac controls was respectively: 3.5 and 18 at H&E, 3.2 and 17 following CD3 staining. Considering the whole patient population, the sensitivity of tip intraepithelial lymphocytes in detecting mild enteropathy coeliac disease was 90% (95% CI=72.6-97.8) both at H&E and CD3-stainings. The sensitivity of intraepithelial lymphocytes per 100 enterocytes was 93% (95% CI=77.2-99.2) both at H&E and CD3-staining. Specificity of both intraepithelial lymphocytes counts was 100% (95% CI=76.8-100). Using a threshold of 25 intraepithelial lymphocytes per 100 enterocytes could miss 59% of cases at H&E and 48% following CD3 staining. CONCLUSIONS: Intraepithelial lymphocytes counts are diagnostic feasible tools to detect mild enteropathy coeliac disease. Threshold of duodenal intraepithelial lymphocytes may be lower than currently accepted. PMID- 21255061 TI - Pharmacological actions of oximino-propofol analogues at GABA(B) autoreceptors. AB - 1. GABA(B) autoreceptors are a subclass of GABA(B) receptors that inhibit the release of [(3) H]GABA from GABAergic nerve terminals. Baclofen is an agonist that reduces [(3)H]GABA, whilst the antagonist (+)-(S)-5,5-dimethylmorpholinyl-2 acetic acid (Sch 50911) enhances [(3)H]GABA release in electrically-stimulated rat neocortical brain slices preloaded with [(3)H]GABA. Here, the pharmacological actions of a series of compounds derived from the positive allosteric modulator, 2,6-di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930), were examined on GABA(B) autoreceptors. 2. The compound, 3-(3,5-ditbutyl-4 hydroxyphenyl)-2,2-dimethyl-1-oximinopropane (compound 2), at 10 MUmol/L had little effect on the stimulation-induced overflow of [(3)H]GABA when superfused alone, but when superfused in the presence of baclofen (2 MUmol/L) inhibited the overflow of [(3)H]GABA. These effects were reversed by Sch 50911 (10 MUmol/L). Although compounds 1-(4-chlorophenyl)-3-(4-hydroxy-3,5-diisopropylphenyl)-2 methyl-1-oximinopropane (compound 1), 1-[(3,5-ditbutyl-4-hydroxyphenyl)methyl]-1 oximinomethylcyclohexane (compound 3), 3-(3,5-ditbutyl-4-hydroxyphenyl)-1,2 diphenyl-1-oximinopropane (compound 4) and 4-(3,5-ditbutyl-4-hydroxyphenyl)-3 methyl-2-oximinobutane (compound 5) (each at 10 MUmol/L) tended to reduce the stimulation-induced overflow in the presence of baclofen, an effect reversed by Sch 50911, their status as modulators is not confirmed in the present study. 3. Another derivative, 3-(3,5-ditbutyl-4-hydroxyphenyl)-1-(4-chlorophenyl)-2-methyl 1-oximinopropane (compound 6) (10 MUmol/L), acted as an agonist as it inhibited the release of [(3)H]GABA by 32% (EC(50) of 3.3 MUmol/L), an effect reversed by Sch 50911 (10 MUmol/L). The other compounds, 1-[(3,5-ditbutyl-4 hydroxyphenyl)methyl]-1-methyl-2-oximinocyclohexane (compound 7), 4-(3,5-ditbutyl 4-hydroxyphenyl)-3,3-dimethyl-2-oximinobutane (compound 8) and 4-(4-hydroxy-3,5 diisopropylphenyl)-3,3-dimethyl-2-oximinobutane (compound 9) (each at 10 MUmol/L), were inactive. 4. These findings indicate that this series of compounds show different modes of activity at GABA(B) autoreceptors. PMID- 21255062 TI - Differential expression profiles between alpha-dystroglycan and integrin beta1 in ameloblastoma: two possible perlecan signalling pathways for cellular growth and differentiation. AB - AIMS: Intercellular deposition of perlecan, an extracellular matrix molecule, results in characteristic stellate reticulum-like structures in ameloblastomas. The aims of this study were to elucidate which types of perlecan receptors function within any particular type of tissue architecture of ameloblastoma. METHODS AND RESULTS: Protein and gene expression profiles for alpha-dystroglycan and integrin beta1 were examined comparatively with those of their ligands in ameloblastoma using surgical specimens and cells in primary culture. In the follicular-type tumour cell foci, alpha-dystroglycan was localized uniformly over the stellate reticulum-like cells, while integrin beta1 was restricted mainly to peripheral cells facing the stroma with the interface of the basement membrane, which was also rich in perlecan. In the plexiform-type, mRNA and protein signals for alpha-dystroglycan were enhanced in the periphery of tumour cell foci, especially in their invading fronts. Integrin beta1 was also immunolocalized in the basal cell zone, which was considered to be the proliferation centre of ameloblastoma cells. Furthermore, biosynthesis of alpha-dystroglycan and integrin beta1 by ameloblastoma cells was confirmed in vitro using immunofluorescence and reverse transcriptase-polymerase chain reaction. CONCLUSIONS: Ameloblastoma cells proliferate and are differentiated by capturing perlecan differentially with alpha-dystroglycan and integrin beta1, respectively. PMID- 21255063 TI - Glutathione S-transferases as molecular markers of tumour progression and prognosis in renal cell carcinoma. AB - AIMS: Renal cell carcinoma (RCC) often recurs as distant metastasis; there is thus a need for new indicators to identify high-risk patients. Glutathione S transferases (GST)-alpha and -pi are involved in the renal bioactivation of toxic metabolites. The aim was to investigate whether their expression is of diagnostic and prognostic value. METHODS AND RESULTS: Western blotting of microdissected normal kidney and immunostaining of histological RCC microarrays shows expression of GST-alpha in proximal tubular cells, while GST-pi was found in the distal nephron. Of the primary 174 RCC cases examined, GST-alpha immunoreactivity was restricted to conventional RCC (n=76, 68% positive) and was not seen in any other RCC subtypes. The cross-tabulation of the GST-alpha scores with other prognostic indices demonstrated that GST-alpha immunostaining was significantly more frequent in low-grade tumours (chi(2): P<0.004), and that conventional GST-alpha positive RCC patients had a mean disease-free survival of 6.0 years (95% confidence interval 5.33-6.63), compared with 4.7 years (3.54-5.90) in GST-alpha negative tumours (Kaplan-Meier survival analysis, P=0.011, log-rank test). CONCLUSIONS: GST-alpha is a highly specific diagnostic marker for primary conventional RCC, where it is a prognostic marker if grade is omitted from the multivariate analysis. PMID- 21255065 TI - Glypican 3 is a sensitive, but not a specific, marker for the diagnosis of yolk sac tumours. PMID- 21255066 TI - Numerous peritoneal loose bodies with ileus. PMID- 21255067 TI - Proximal-type epithelioid sarcoma of the uterine corpus. PMID- 21255068 TI - Increased expression of hepatoma-derived growth factor correlates with poor prognosis in human nasopharyngeal carcinoma. AB - AIMS: To examine the correlation between hepatoma-derived growth factor (HDGF) expression and clinicopathological data in nasopharyngeal carcinoma (NPC), including patient survival. METHODS AND RESULTS: Using real-time polymerase chain reaction (PCR) and Western blot, mRNA and protein expression of HDGF was detected in normal nasopharyngeal tissues, NPC tissues and cell lines. HDGF levels were determined further by an immunohistochemical analysis in a retrospective series consisting of 160 primary NPC tissues and 71 non-cancerous nasopharynx tissues. Overexpressed mRNA and HDGF protein was present in NPC. By immunohistochemical analysis, we found that 53.8% (86 of 160) and 19.4% (32 of 160) of NPC biopsy specimens showed higher HDGF expression of the nucleus and cytoplasm, respectively. Statistical analysis showed that the higher expression of nuclear HDGF was associated significantly with T stage (P=0.005) and clinical stage (P=0.038), but there was no association with lymph node (P=0.059) or distant metastasis (P=0.563). Patients with increased HDGF expression levels had poorer overall survival rates than those with low expression of HDGF levels (P=0.006). Multivariate analysis revealed that high expression of nuclear HDGF was an independent prognostic indicator of patient survival. CONCLUSIONS: Increased nuclear expression of HDGF is a potential unfavourable prognostic factor for patients with NPC. PMID- 21255069 TI - Cancerization of cutaneous flap reconstruction for oral squamous cell carcinoma: report of three cases studied with the mtDNA D-loop sequence analysis. AB - AIMS: Tissue defects, resulting from surgical resection of oral squamous cell carcinoma (OSCC), are reconstructed routinely with skin grafts. OSCC arising from the grafted skin has been described; however, it is still unclear whether primary and second tumours have a common clonal origin. The aim of this study was to evaluate the clonal relationship between the primary OSCC and secondary neoplastic changes appearing in the skin graft in three patients, by screening the mitochondrial DNA D-loop region (mtDNA). METHODS AND RESULTS: In all three cases, the neoplastic lesions arising in the skin graft showed a clonal relationship with the previous OSCC and, on the basis of the results obtained by mtDNA analysis, could be considered to be a recurrence of the primary OSCC rather than a second primary OSCC. CONCLUSIONS: Starting from a field of genetically altered cells in the oral mucosa, the spread of the clonal cell population to the cutaneous flap might be stimulated by cytokines produced by the grafted skin. More studies are needed to evaluate the molecular relationship between primary and second OSCC to identify patients at higher risk of developing a second tumour in the skin graft. PMID- 21255070 TI - The activity of bacteriocins from Carnobacterium maltaromaticum UAL307 against gram-negative bacteria in combination with EDTA treatment. AB - Bacteriocins from gram-positive bacteria are potent antimicrobial peptides that inhibit pathogenic and food-spoilage bacteria. They are usually ineffective against gram-negative bacteria because they cannot penetrate the outer membrane (OM). Disruption of the OM of some gram-negative bacteria was reported to sensitize them to certain bacteriocins. This study evaluates the activity of three purified bacteriocins [carnocyclin A (CclA), carnobacteriocin BM1 (CbnBM1) and piscicolin 126 (PisA)] produced by Carnobacterium maltaromaticum UAL307, which has been approved for preservation of food in United States and Canada, against three gram-negative bacteria (Escherichia coli DH5alpha, Pseudomonas aeruginosa ATCC 14207 and Salmonella Typhimurium ATCC 23564). Their efficacy is compared with bacteriocins of other classes: the lantibiotics nisin A (positive control) and gallidermin, and the cyclic peptide subtilosin A (SubA). In combination with EDTA, CclA inhibited both E. coli and Pseudomonas. PisA inhibited Pseudomonas, but CbnBM1 showed weak activity toward Pseudomonas. In comparison, nisin and gallidermin inhibited the growth of all three strains, whereas SubA was active against E. coli and Pseudomonas only at high concentrations. The results reveal that UAL307 bacteriocins can inhibit gram negative bacteria if the OM is weakened, and that the different classes of bacteriocins in this study exert unique modes of action toward such bacteria. PMID- 21255071 TI - Acidipila rosea gen. nov., sp. nov., an acidophilic chemoorganotrophic bacterium belonging to the phylum Acidobacteria. AB - Two strains of aerobic acidophilic chemoorganotrophic bacteria designed strains AP8(T) and AP9 were isolated from acid mine drainage and acidic soil, respectively. These isolates were gram-negative, nonmotile cocci and coccobacilli measuring 0.5-0.8 MUm in diameter. Cells were capsulated. Colonies on solid media were pink colored. The pH range for growth was 3.0-6.0 (optimum pH 4.5). Sugars, gluconate, and some amino acids were good carbon and energy sources for growth. The main components of cellular fatty acids were C(15:0) iso and C(16:1) omega7c. Menaquinone-8 was the major quinone. The G+C content of genomic DNA was 59.5%. Both strains had identical sequences of 16S rRNA genes that were most closely related to that of the type strain of Acidobacterium capsulatum (96% similarity). There were major differences between the isolates and A. capsulatum in cell morphology, carbon nutrition, and fatty acid profiles. Based on these phylogenetic and phenotypic data, we propose the name Acidipila rosea gen. nov., sp. nov. to accommodate the novel isolates. The type strain is AP8(T) (NBRC 107607(T), KCTC 23427(T)). PMID- 21255072 TI - Congenital complete absence of the pericardium: a multimodality imaging diagnostic approach. PMID- 21255074 TI - Joint British Diabetes Societies guideline for the management of diabetic ketoacidosis. AB - The Joint British Diabetes Societies guidelines for the management of diabetic ketoacidosis (these do not cover Hyperosmolar Hyperglycaemic Syndrome) are available in full at: (i) http://www.diabetes.org.uk/About_us/Our_Views/Care_recommendations/The-Management of-Diabetic-Ketoacidosis-in-Adults; (ii) http://www.diabetes.nhs.uk/publications_and_resources/reports_and_guidance; (iii) http://www.diabetologists-abcd.org.uk/JBDS_DKA_Management.pdf. This article summarizes the main changes from previous guidelines and discusses the rationale for the new recommendations. The key points are: Monitoring of the response to treatment (i) The method of choice for monitoring the response to treatment is bedside measurement of capillary blood ketones using a ketone meter. (ii) If blood ketone measurement is not available, venous pH and bicarbonate should be used in conjunction with bedside blood glucose monitoring to assess treatment response. (iii) Venous blood should be used rather than arterial (unless respiratory problems dictate otherwise) in blood gas analysers. (iv) Intermittent laboratory confirmation of pH, bicarbonate and electrolytes only. Insulin administration (i) Insulin should be infused intravenously at a weight-based fixed rate until the ketosis has resolved. (ii) When the blood glucose falls below 14 mmol/l, 10% glucose should be added to allow the fixed-rate insulin to be continued. (iii) If already taking, long-acting insulin analogues such as insulin glargine (Lantus((r)), Sanofi Aventis, Guildford, Surry, UK) or insulin detemir (Levemir((r)), Novo Nordisk, Crawley, West Sussex, UK.) should be continued in usual doses. Delivery of care (i) The diabetes specialist team should be involved as soon as possible. (ii) Patients should be nursed in areas where staff are experienced in the management of ketoacidosis. PMID- 21255075 TI - The role of blood pressure in glaucoma. AB - Although intraocular pressure (IOP) remains an important risk factor for glaucoma, it is clear that other factors can also influence disease development and progression. More recently, the role that blood pressure (BP) has in the genesis of glaucoma has attracted attention, as it represents a clinically modifiable risk factor and thus provides the potential for new treatment strategies beyond IOP reduction. The interplay between blood pressure and IOP determines the ocular perfusion pressure (OPP), which regulates blood flow to the optic nerve. If OPP is a more important determinant of ganglion cell injury than IOP, then hypotension should exacerbate the detrimental effects of IOP elevation, whereas hypertension should provide protection against IOP elevation. Epidemiological evidence provides some conflicting outcomes of the role of systemic hypertension in the development and progression of glaucoma. The most recent study showed that patients at both extremes of the blood pressure spectrum show an increased prevalence of glaucoma. Those with low blood pressure would have low OPP and thus reduced blood flow; however, that people with hypertension also show increased risk is more difficult to reconcile. This finding may reflect an inherent blood flow dysregulation secondary to chronic hypertension that would render retinal blood flow less able to resist changes in ocular perfusion pressure. Here we review both clinical and experimental studies that have attempted to clarify the relationships among blood pressure, OPP and blood flow autoregulation in the pathogenesis of glaucoma. PMID- 21255076 TI - Prescription compliance in ophthalmic lenses. AB - PURPOSE: Tolerances required for ophthalmic lenses are set down in national and international standards. It appears that the compliance of manufactured lenses has not been reported previously. Assembling a statistical quantity of lenses of a single prescription is usually an expensive process. It was, secondary to a lens impact study, possible to assemble a large number of plano lenses. In the assessment of the fracture velocity of lenses approximately 20 plano lenses of each material and thickness are required. Prior to using lenses for the impact study, they were checked for prescription. The results of the prescription measurements are reported here and the results of the impact study are reported in a separate paper. METHODS: Using an automated focimeter, 679 plano lenses in stock thickness, typical occupational eye protector thickness and up to 3.5 mm thick were measured. There were 21 combinations of material/thickness/coating from seven suppliers. The power was evaluated against Australian Standard 2228.1 1992, as the lenses were supplied in Australia. The permitted tolerances are +/ 0.09 D sphere and +/-0.06 D cylinder. RESULTS: When assessed for material/thickness/coating combination, failure rates varied from <0.0001 per cent to 77.5 per cent (with a further 17.3 per cent classified as borderline, because they were within the uncertainty of measurement of the required limit). Grouped by supplier, the failure rates ranged from <0.0001 per cent to 7.6 per cent (with a further 12.3 per cent borderline). To improve understanding of the result, it may be easier to quote the figures without considering uncertainties. When assessed by supplier, the failure rate varies from <0.0001 per cent to 12.6 per cent. CONCLUSIONS: Compliance of plano lenses should be among the easiest of tasks for a laboratory. While we know of no defined or required acceptance rates for prescription lenses, a failure rate for a laboratory of 12.6 per cent, which includes a failure rate of 88 per cent in 2.8 mm thick refractive index = 1.53 hard coated lenses (n = 20) cannot be considered satisfactory and is a strong indication of a failure to check lenses before they leave the laboratory. PMID- 21255077 TI - Validity of first post-operative day automated refraction following dense cataract extraction. AB - BACKGROUND: The aim of this study was to assess the refractive stability and validity of automated refraction obtained at day one after surgery for dense cataracts in a developing country setting, where patient follow-up is often erratic. METHODS: In a prospective study in rural Kenya, we compared automated refraction and visual acuity (VA) after manual small incision cataract surgery (SICS) and phacoemulsification cataract surgery (Phaco) at day one with autorefraction and subjective refraction obtained at a later visit. RESULTS: Ninety eyes of 83 patients fulfilled the ultimate inclusion criteria (21 SICS eyes and 69 Phaco eyes). The correlation between refraction at day one and at a later follow-up was moderately good for both SICS and Phaco (R1 = 0.61 and R2 = 0.58). Spherical equivalent (SE) values measured at day one were within one dioptre of those obtained later in 68 eyes (72 per cent); (SICS: 67 per cent; Phaco: 74 per cent) and within two dioptres in 83 eyes (92 per cent); (SICS: 86 per cent; Phaco: 94 per cent). At post-operative days 14, 28 and more than 42 for SICS and Phaco eyes, the mean SE was 0.58 and 0.48, 0.55 and 0.19, and 0.9 and 0.31 more hypermetropic than the mean SE of post-operative day one, respectively. First-day accuracy was higher in eyes with better pre-operative VA, softer cataracts and lower post-operative prediction error. The surgical technique (SICS versus Phaco) had no influence on first-day accuracy in our set-up. CONCLUSION: Refractive data from the early post-operative period can provide useful data for qualitative control and monitoring of post-operative refractive outcomes in a setup, where 'better' data are often not available; however, its accuracy is limited and, ultimately, there is no alternative to good follow up of operated patients. PMID- 21255078 TI - Single intravitreal ranibizumab injection in eyes with acute non-arteritic anterior ischaemic optic neuropathy. AB - BACKGROUND: The aim was to evaluate the effect of a single intravitreal ranibizumab injection in eyes with non-arteritic anterior ischaemic optic neuropathy. METHODS: Four eyes of four patients comprised the study group. In addition to a standard ocular examination, visual field testing and retinal nerve fibre layer thickness analysis were performed prior to injection and one and three months after the injection. RESULTS: Mean time between visual loss and the intravitreal injection was 7.8 days (range, 2-15 days). The mean age of patients was 58.2 years (range, 45-63 years). After a single dose of ranibizumab injection, all patients experienced a visual gain. Mean visual acuity (VA) was 1.15 +/- 0.26 logMar before the injection and improved to 0.37 +/- 0.09 logMar at the third post-injection month. The mean retinal nerve fibre layer thickness measured with spectral domain optical coherence tomography significantly decreased after the injection in all eyes. No complication related to the injections was observed during the following three months. CONCLUSION: Intravitreal ranibizumab injection may be a treatment option in eyes with non arteritic anterior ischaemic optic neuropathy and a short disease history. PMID- 21255079 TI - Comparison of corneal thickness measurement with the Pentacam, the PARK1 and an ultrasonic pachymeter. AB - PURPOSE: The aim was to determine the agreement between PARK1 pachymetric readings and measurements made with the Pentacam and ultrasonic pachymetry. METHODS: In this prospective study, we enrolled refractive surgery patients free of other ocular conditions and performed Pentacam and PARK1 acquisitions followed by ultrasonic pachymetry. We recorded pachymetric readings on the centre, apex and thinnest point with the Pentacam, corneal thickness values of the apex and minimum readings from the PARK1, and the central corneal thickness with the ultrasonic system. Data were compared using t-tests, and the Pearson correlations and 95% limits of agreement (LoA) of all pairs were determined. RESULTS: The mean age of the 47 participants was 32 +/- 10.4 years and data from their right eyes were used. Overall, ultrasonic measurements were significantly higher than all readings from the PARK1 and the Pentacam. The smallest difference was between the PARK-apex and Pentacam-apex readings (0.2 +/- 11 um); the 95% LoA of this pair gave a width of 43.7 um (-21.7 to 22.0 um). The smallest width pertained to the Pentacam-centre and ultrasound-centre paired readings; the width was 32.5 um ( 21.8 to 11.8 um), while the mean difference was -5.54 +/- 8 um. CONCLUSION: The PARK1 measurements of the apical corneal thickness can be a substitute for central corneal pachymetry with an ultrasonic device, provided that the range of agreement is taken into consideration in the interpretation of the results. Similar studies on populations with different corneal conditions such as keratoconus are needed. PMID- 21255080 TI - Comparative efficacies of contact lens disinfecting solutions against Pseudomonas aeruginosa. AB - PURPOSE: The aim of the present study was to evaluate the disinfection properties of multipurpose contact lens disinfection solutions, based on the International Organization for Standardization (ISO) 14729 guidelines. METHODS: Three lots of each of six multi-purpose solutions were tested as follows: Renu MultiPlus, Solo Care Aqua, All-Clean Soft, Contact All-in one Advanced, Hippia, Ginza multi purpose solution and 0.9% normal saline solution were inoculated with the standard strain of Pseudomonas aeruginosa (ATCC 9027). The surviving bacteria were quantified at specified times. An average logarithm reduction in bacterial numbers at the manufacturer's minimum recommended disinfection time was determined and compared with the criteria for stand-alone disinfection products for each multi-purpose disinfection solution against each bacterial strain. RESULTS: Renu MultiPlus, Solo Care, All-Clean Soft and Contact All-in one Advanced were effective in achieving a four logarithmic units reduction in the bacterial count; however, Renu MultiPlus and Solo Care Aqua resulted in the greatest reduction in bacterial numbers. The other solutions were not effective against Pseudomonas aeruginosa after specified times. CONCLUSIONS: Generally, Renu MultiPlus, Solo Care Aqua, All-Clean Soft and Contact All-in one Advanced meet the ISO 14729 guidelines for stand-alone contact lens solutions. PMID- 21255081 TI - Bilirubin concentrations in thalassemia heterozygotes in university students. AB - OBJECTIVES: To investigate the difference of bilirubin concentrations between alpha- and beta-thalassemia carriers and the role of variation status in the UDP glucuronosyltransferase (UGT) 1A1 gene on such a difference. METHODS: A total of 2713 university freshmen who attended a regular physical examination were enrolled in underwent screenings for thalassemias. Finally, 123 subjects whose mean corpuscular volume was <=80 fL and who had no iron deficiency anemia were tested by PCR and PCR-restriction fragment length polymorphism (RFLP) for alpha- and beta-thalassemias, respectively, and tested by PCR-RFLP for the five known variations of the UGT1A1 gene. RESULTS: Among the 123 subjects, 76 and 47 were diagnosed with heterozygous alpha-thalassemia and with heterozygous beta thalassemia, respectively. Between the alpha- and beta-thalassemia heterozygotes, variation status of the UGT1A1 gene was not statistically different (P = 0.898), while hemoglobin and bilirubin concentrations differed significantly (P = 0.005 and 0.001, respectively). Bilirubin concentrations were significantly higher among individuals with compound heterozygous variations/homozygous variation in the UGT1A1 gene than in those possessing the wild type and heterozygous variation (P < 0.001 for both alpha- and beta-thalassemia heterozygotes). Compound heterozygous variations/homozygous variation in the UGT1A1 gene and anemia were the main causes of hyperbilirubinemia in alpha- and beta-thalassemia heterozygotes, respectively. CONCLUSIONS: The difference in bilirubin concentrations between alpha- and beta-thalassemia heterozygotes may be attributable to more bilirubin being produced in beta-thalassemia heterozygotes than in alpha-thalassemia heterozygotes, while variation status of the UGT1A1 gene affects bilirubin concentrations in both alpha- and beta-thalassemia heterozygotes. PMID- 21255082 TI - Dispersion of repolarization and beta-thalassemia major: the prognostic role of QT and JT dispersion for identifying the high-risk patients for sudden death. AB - BACKGROUND: Patients with beta-thalassemia major (beta-TM) are at increased risk for sudden cardiac death (SCD). Heterogeneity of ventricular repolarization is considered to provide an electrophysiological substrate for malignant arrhythmias. QT dispersion (QTc-D) and JT dispersion (JTc-D) are electrocardiographic parameters indicative of heterogeneity of ventricular repolarization. The aim of our study was to evaluate the heterogeneity of ventricular repolarization in patients with beta-thalassemia and to test the hypothesis that an abnormal QTc and JTc dispersion may predict SCD in this population. MATERIALS AND METHODS: The study involved 51 patients with beta-TM (age 33.9+/-8.4; 33M) and 51 healthy subjects used as controls, matched for age, gender, and body mass index (BMI). Among the beta-TM group, 14 patients with beta TM (age 27+/-6.64; 11M) died from SCD during follow-up. For each patient, QTD and JTD intervals were calculated. RESULTS: Compared to the healthy control group, beta-TM group presented increased values of the QTc-D (65.36+/-33.95 vs. 37, 62+/ 17.65; P<0.003) and JTc-D (74.64+/-33.27 vs. 40.32+/-12.45; P<0.001). In the beta TM sudden death group, QTc-D and JTc-D were significantly greater than in survived beta-TM group (92.70+/-44.24 vs. 56.14+/-23.80, P=0.0001; 101.54+/-47.93 vs. 64.47+/-17.90, P=0.0001). A cutoff value of 70ms for QTc-D had a sensitivity and specificity of 77% in identifying patients at risk for SCD. A cutoff value of 100ms for JTc-D had a sensitivity of 65% and a specificity of 94% in identifying this category of patients. CONCLUSION: beta-TM is associated with significant changes in heterogeneity of ventricular repolarization. QTc and JTc dispersion are useful markers of risk of SCD in patients with beta-TM. PMID- 21255084 TI - Association between endotoxin and mite allergen exposure with asthma and specific sensitization at age 7 in high-risk children. AB - The role of endotoxin and house dust mite allergen (HDM) in allergen sensitization and asthma is unclear. The timeframe of exposure and asthma assessment appears critical. We aimed to determine, in children at 7 yr of age, the association between current exposure to endotoxin and HDM and risks of recurrent wheeze, paediatric allergist diagnosed asthma and allergen sensitization. Three hundred and eighty children who had an increased risk of asthma because of family background were assessed at age 7 yr by a questionnaire standardized interview, allergen skin testing and clinical examination by a paediatric allergist. Dust samples were collected from their homes and analysed for levels of endotoxin and HDM (Der p 1 and Der f 1). Levels of endotoxin in dust samples were associated with protection from paediatric allergist diagnosed asthma with inhaled steroid use (OR 0.69, 95% CI 0.53-0.91) and specific sensitization to dog allergen (OR 0.68, 95% CI 0.51-0.90) at the age of 7 yr; both endotoxin and HDM were associated with decreased risk of sensitization to dog allergen. In high-risk children at age 7, endotoxin levels were associated with decreased sensitization to dog, as well as with decreased asthma. PMID- 21255083 TI - Anthelminthic treatment during pregnancy is associated with increased risk of infantile eczema: randomised-controlled trial results. AB - BACKGROUND: Allergy is commoner in developed than in developing countries. Chronic worm infections show inverse associations with allergy, and prenatal exposures may be critical to allergy risk. OBJECTIVE: To determine whether anthelminthic treatment during pregnancy increases the risk of allergy in infancy. METHODS: A randomised, double-blind, placebo-controlled trial on treatment in pregnancy with albendazole versus placebo and praziquantel versus placebo was conducted in Uganda, with a 2 * 2 factorial design; 2507 women were enrolled; infants' allergy events were recorded prospectively. The main outcome was doctor-diagnosed infantile eczema. RESULTS: Worms were detected in 68% of women before treatment. Doctor-diagnosed infantile eczema incidence was 10.4/100 infant years. Maternal albendazole treatment was associated with a significantly increased risk of eczema [Cox HR (95% CI), p: 1.82 (1.26-2.64), 0.002]; this effect was slightly stronger among infants whose mothers had no albendazole susceptible worms than among infants whose mothers had such worms, although this difference was not statistically significant. Praziquantel showed no effect overall but was associated with increased risk among infants of mothers with Schistosoma mansoni [2.65 (1.16-6.08), interaction p = 0.02]. In a sample of infants, skin prick test reactivity and allergen-specific IgE were both associated with doctor-diagnosed eczema, indicating atopic aetiology. Albendazole was also strongly associated with reported recurrent wheeze [1.58 (1.13-2.22), 0.008]; praziquantel showed no effect. CONCLUSIONS: The detrimental effects of treatment suggest that exposure to maternal worm infections in utero may protect against eczema and wheeze in infancy. The results for albendazole are also consistent with a direct drug effect. Further studies are required to investigate mechanisms of these effects, possible benefits of worms or worm products in primary prevention of allergy, and the possibility that routine deworming during pregnancy may promote allergic disease in the offspring. PMID- 21255085 TI - Adipokines and psoriasis. AB - Adipose tissue is an active endocrine organ contributing to the regulation of multiple metabolic pathways via self-produced bioactive products called adipokines. These adipokines are key players in the pathogenesis of metabolic syndrome and cardiovascular diseases. Co-occurrence of obesity and psoriasis could lead to interactions of both diseases in which adipokines, at least in part, are involved and may contribute to associated comorbidities of psoriasis. Until today numerous adipokines have been identified of which the most important ones are discussed in the following within the context of obesity, chronic inflammation and their possible role in the pathogenesis of psoriasis. Adipokines could serve as a missing link in the causal relationship between psoriasis and comorbidities and may provide a biomarker for disease severity, risk of comorbidities and treatment success. PMID- 21255086 TI - Tight junction proteins and the epidermis. AB - Epithelia are found at the interfaces between body compartments where they act as selective permeability barriers that maintain the unique composition of the compartments on either side. Epithelial barrier function is dependent on tight junctions (TJs), which seal the intercellular or paracellular spaces but may permit selective permeability. In simple epithelia (one cell thick), the function of TJs is relatively well understood. By contrast, our understanding of TJ structure and function in stratified epithelia (e.g. the epidermis) is limited. This article briefly discusses what is known about TJs and their components in simple epithelia and speculates about their roles in the epidermis. PMID- 21255087 TI - The haptenation theory of vitiligo and melanoma rejection: a close-up. AB - The 'Haptenation theory' concerns the multicausal pathogenesis of vitiligo ending ultimately in the (partial) disappearance of melanocytes from the skin and/or hairs. The melanocyte specificity is attributed to the tyrosinase-catalysed production of haptogenic ortho-quinones that covalently bind to tyrosinase or other melanosomal proteins to generate neo-antigens. These latter, in turn, trigger an immunological cascade resulting in a melanocyte-specific delayed-type hypersensitivity reaction that eliminates melanocytes and produces the characteristic depigmentation. This causal chain of events is critically discussed with special reference to factors modifying the process and the possible influence of various biochemical changes, such as raised levels of catecholamines and epidermal hydrogen peroxide, which have been reported to be associated with the onset of vitiligo. This all adds up to the typical vitiligo reaction pattern or syndrome, which demands a treatment strategy involving most of the already known therapies. Similar pathogenetic mechanisms might be engaged in the enhancement of cellular immunity (vaccination) against melanoma. PMID- 21255088 TI - Death ligand TRAIL, secreted by CD1a+ and CD14+ cells in blister fluids, is involved in killing keratinocytes in toxic epidermal necrolysis. AB - Toxic epidermal necrolysis (TEN) is characterized by an acute detachment and destruction of keratinocytes, affecting large areas of the skin. It is often related to adverse drug reactions. Previous studies have shown that effector CD8+ T cells, which accumulate in the blister fluid, are functionally cytotoxic and act through a classical perforin/granzyme B pathway. It has recently been shown that these cytotoxic T cells also secrete granulysin peptide, which is lethal to keratinocytes. These cytotoxic T cells exert their killer activity against autologous keratinocytes in the presence of the drug. However, they are unlikely to be the only effectors of TEN. We therefore searched for soluble death factors in the blister fluids that might kill keratinocytes. We found that the amounts of interferon-gamma, TRAIL and TNF-alpha proteins were significantly greater in TEN blister fluids than in all controls (normal sera, TEN sera, burns and Eosinophilic pustular folliculitis blister fluids) and TNF-like weak inducer of apoptosis (TWEAK) amounts are also greater in all controls except burns. We showed that these proteins acted in synergy to induce the death of keratinocytes in vitro. We also found that TRAIL and TWEAK were secreted by CD1a+ and CD14+ cells present in the blister fluids. Thus, in addition to MHC class I-restricted cytotoxic T lymphocytes (CTLs), which lyse keratinocytes, ligands secreted by non lymphoid cells capable of inducing keratinocyte death in an MHC class I independent manner, also seem to be present in the blister fluids of patients with TEN. PMID- 21255089 TI - A large-scale multi-technique approach identifies forty-nine new players of keratinocyte terminal differentiation in human epidermis. AB - At the latest stage of terminal differentiation in the epidermis, granular keratinocytes (GKs) undergo cornification, a programmed cell death required for the establishment of a functional skin barrier. A complex genetic regulatory network orchestrates the underlying biochemical modifications, but very few transcription factors specific to this programme have been identified to date. Here, we describe a large-scale, multi-technique approach performed on cells purified from normal human epidermis, primarily focusing on the identification of regulators. We combined data from microarray analysis of cell fractions enriched in GKs or basal keratinocytes, from an expressed sequence tag (EST) library built from GKs and from an in silico promoter analysis of 52 differentiation-associated genes. Among 3576 genes potentially expressed in GK, 298 candidates were selected, and half were directly profiled for the first time in the different layers of the epidermis by quantitative real-time PCR. Forty-nine genes upregulated during terminal differentiation, associated with numerous function of GK including lipid synthesis and secretion, were identified. Of 94 transcription factors detected, 37 were found to be either positively or negatively regulated, suggesting their involvement as regulators of gene expression in the GKs. These results largely extend the number of genes known as involved in the latest step of the terminal differentiation of human epidermis as well as the number of transcription factors known to control the expression of these genes. PMID- 21255090 TI - Inhibiting scar formation in vitro and in vivo by adenovirus-mediated mutant Smad4: a preliminary report. AB - The best characterized signalling pathway employed by transforming growth factor beta (TGF-beta) is the Smad pathway. We focused on Smad4, because it is essential for the activation of Smad-dependent target genes. We aimed to explore the possibility of inhibiting scar formation after wounding by blocking TGF-beta signalling by means of a gene therapy approach using adenovirus-mediated expression of mutant Smad4. The coding sequence of the dominant-negative mutant Smad4DeltaM4, which has a deletion in the linker region of Delta275-322, was introduced by homologous recombination into an adenovirus vector to generate the recombinant vector Ad-DeltaM4, which encoded Smad4DeltaM4. Mouse fibroblast NIH 3T3 cells were transfected with Ad-DeltaM4 and cell proliferation, collagen protein production, and the expression of collagen type I and type III mRNA were evaluated in vitro using a cell proliferation test, western blot analysis, and RT PCR, respectively. Cell proliferation and the expression of collagen type I and type III mRNA and protein were all inhibited by the transfection of Ad-DeltaM4. In vivo, Ad-DeltaM4 was applied externally to wounds on rats, and histological examination and quantification of the scars were performed to evaluate the curative effect. The transfection of Ad-DeltaM4 successfully inhibited scar formation in rat wounds. In conclusion, Ad-DeltaM4 can block the TGF-beta signalling of mouse wound cells effectively. In addition, gene therapy with Ad DeltaM4 can effectively inhibit wound scarring in rats and may potentially be applied to clinical treatment of scars. PMID- 21255091 TI - Topical beta-carotene protects against infra-red-light-induced free radicals. AB - The influence of stress factors on human skin induces the production of free radicals. Free radicals react immediately with antioxidants contained in the skin, giving rise to their depletion and with the surrounding molecules, resulting in their damage, disorganization and even destruction. High amounts of free radicals are produced in the upper skin layers, i.e. mainly in the epidermis, subsequent to sun irradiation. Irradiation of the skin in the infra red (IR) range of the spectra, applied at physiological doses, can produce free radicals. The magnitude of destruction of antioxidants, such as carotenoids, can serve as a marker of the extent of the stress factor, characterized by the quantity of produced free radicals. In this study, measurements on the degradation of cutaneous carotenoids following IR skin irradiation of 12 healthy volunteers (skin type II), with two IR sources (standard infrared radiator = SIR and water filter infrared = wIRA) were taken using resonance Raman spectroscopy. Topical application of the antioxidant beta-carotene (2 mg/cm(2) ) provided protection for the human skin when exposed to IR radiation. The magnitude of the degradation of dermal carotenoids after IR irradiation was significantly higher for SIR than for wIRA irradiation, for both non-treated and cream-treated skin areas. The amount of destroyed carotenoids after IR irradiation was higher in the case of pretreatment with beta-carotene than for the untreated skin, indicating that the superficial part of antioxidants is most important for protecting against external stressors. The direct comparison of beta-carotene content was significantly higher for the cream-treated compared to untreated areas for all pairs: baseline, wIRA, after wIRA, baseline SIR and after SIR. Additionally, topically applied carotenoids as a single antioxidant component are less stable than the carotenoids in the skin incorporated by nutrition and accumulated in a mixture with different antioxidant substances. Resonance Raman spectroscopy can be used for the non-invasive measurements of carotenoids, which can be rated as marker substances of redox processes. PMID- 21255092 TI - Microdialysis documents changes in the micromilieu of psoriatic plaques under continuous systemic therapy. AB - Microdialysis is a novel technique suitable to analyse soluble mediators in the skin compartment. We applied this methodical approach to monitor changes in the micromilieu of psoriatic plaques under therapy. Tissue fluid was collected from lesional and non-lesional skin of three patients with severe plaque-type psoriasis prior to as well as after 12 weeks of continuous oral therapy with fumaric acid esters. Concentrations of a spectrum of cytokines and adipokines were measured using a commercial fluorescent bead immunoassay. The procedure was well tolerated even without local anaesthesia. Prior to initiation of therapy, we found elevated levels for IL-2, IL-6, IL-18, IL-23, and resistin in lesional versus non-lesional skin, whereas adiponectin levels were higher in non-lesional skin. All patients showed significant clinical improvement under treatment, paralleled by reduced concentrations of IL-6, IL-18, IL-23, and resistin, but not IL-2 and adiponectin in lesional skin. Thus, we were able to demonstrate through microdialysis a shift in the micromilieu of psoriatic plaques, characterized by reduced levels of pro-inflammatory mediators in three patients under effective systemic anti-inflammatory therapy with fumaric acid esters. Our observations need to be confirmed by larger studies. This approach is limited by practical aspects as it is very time-consuming, but suitable to directly explore pathomechanisms causing the psoriatic phenotype in general and insulin resistance in the skin compartment in particular. PMID- 21255093 TI - Double-stranded RNA induces melanocyte death via activation of Toll-like receptor 3. AB - As cutaneous pigment-producing cells, melanocytes can become targets of primary and secondary immune response as can be seen in diseases like vitiligo and Vogt Koyanagi-Harada (VKH) syndrome. Viral infections have previously been implicated as a possible precipitating factor in the destruction of melanocytes in these disorders. During viral replication, double-stranded RNA (dsRNA) is produced as an intermediate metabolite, which induces antiviral and inflammatory responses through Toll-like receptor 3 (TLR3) in cells of innate immune system. The functional responses of melanocytes to dsRNA, however, remain unclear. Herein, we demonstrated that human melanocytes expressed TLR3 at a constitutive and inducible level. Stimulation with poly(I:C), a synthetic dsRNA analogue, triggered apoptosis of melanocytes. The apoptosis-inducing effect was shown by RNA interference to be largely dependent on TLR3, but occurred independently of NF-kappaB activation since treatment with specific NF-kappaB inhibitor Bay 11 7082 failed to prevent the process. In contrast, IFN-beta neutralizing Ab blocked the apoptosis-inducing effect of dsRNA, indicating the involvement of IFN-beta autocrine signalling. Furthermore, studies on the intracellular signal transduction pathways revealed that dsRNA induces the activation of p38, ERK1/2 and JNK1/2 in melanocytes. Using specific inhibitors, we demonstrated that activation of p38 and ERK1/2 controlled both IFN-beta secretion and IFN-beta mediated cell death. Taken together, these data suggest that viral dsRNA stimulates TLR3 in human melanocytes and triggers the cellular apoptosis through autocrine of IFN-beta. PMID- 21255094 TI - Filaggrin knockdown and Toll-like receptor 3 (TLR3) stimulation enhanced the production of thymic stromal lymphopoietin (TSLP) from epidermal layers. AB - Keratinocytes constitute the first-line barrier against exogenous antigens and contain Toll-like receptors (TLRs), which function as pattern-recognition molecules to activate antimicrobial innate immune responses. In an effort to ascertain whether or not filaggrin (filament-aggregating protein) expression affected the TLR-mediated responses of keratinocytes, we transfected filaggrin siRNA into HaCaT human keratinocyte cells and determined that thymic stromal lymphopoietin (TSLP) and IL-6 secretion were increased by poly(I:C) stimulus. Additionally, TSLP expression is increased in filaggrin knockdown as well as TLR3 stimulation in reconstituted human epidermal layers. Therefore, the findings of this study show that reduced filaggrin levels may influence innate immune responses via TLR stimuli and may contribute to the pathogenesis of inflammatory skin disease via TSLP expression. PMID- 21255095 TI - Distinct profile of the mitochondrial DNA common deletion in benign skin lesions. AB - Mutations of mitochondrial (mt) DNA, particularly the 4977 bp long common deletion, are increased in aging tissues and preferentially found in chronologically and photoaged skin. Mutations of human mitochondrial DNA (mtDNA) have also been identified in malignant tumors of the skin and of other organs. However, benign skin lesions have not yet been investigated. We analyzed the frequency of the common deletion in 27 benign skin lesions [8 seborrheic keratoses (SK), 5 epidermal nevi (EN), 14 solar lentigos (SL)] by quantitative real-time PCR, because SK and especially SL have been related to (photo)aged skin. All SK and four of five EN displayed reduced common deletion levels compared with adjacent normal skin. In contrast, 50% of SL revealed a higher percentage of the common deletion than the adjacent normal skin, and some SL showed very high absolute common deletion levels up to 14% of total mtDNA. Our results show that the amount of the common deletion is significantly different in benign skin lesions and raise further questions regarding the pathogenesis of SL and its possible role as a precursor lesion of SK. PMID- 21255096 TI - New targets of pemphigus vulgaris antibodies identified by protein array technology. AB - We performed partial evaluation of pemphigus vulgaris (PV) autoantibody profile using the protein array technology. The sera from seven patients with acute PV and five healthy donors were probed for the presence of autoantibodies characteristic of the organ-non-specific autoimmune disorders rheumatoid arthritis, lupus erythematosus, scleroderma, diabetes and some other autoimmune disorders, but not to desmosomal proteins. The array targeted 785 human genes amplified using Mammalian Gene Clone Collection with gene-specific primers containing 20-bp nucleotide extension complementary to ends of linear pXT7 vector. The array identified PV antibodies significantly (P<0.05) differentially reactive with 16 antigens, most of which were cell-surface proteins, such as CD2, CD31, CD33, CD36, CD37, CD40, CD54, CD66c and CD84 molecules, nicotinamide/nicotinic acid mononucleotide adenylyltransferase, immunoglobulin heavy chain constant region gamma 2 and others. Reactivity with Fc-IgG helps explain an ability of the chimeric desmoglein constructs to absorb out all disease-causing PV antibodies. Anti-M(1) muscarinic receptor antibody was also identified, consistent with the facts that while blockade of this receptor causes keratinocyte detachment, its activation is therapeutic in PV. Further proteomics analysis of PV antibodies should help elucidate the immunopathogenic mechanisms underlying keratinocyte detachment and blistering. PMID- 21255097 TI - Propionibacterium acnes vaccination induces regulatory T cells and Th1 immune responses and improves mouse atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic disease characterized by a polarized Th2 immune response. Propionibacterium acnes (P. acnes) has been shown to elicit strong Th1 immune responses. We hypothesized that the host immune response to P. acnes will prevent the development of AD. To demonstrate this hypothesis, we investigated the effect of P. acnes vaccination on AD that occurs in keratin 14/driven caspase-1 transgenic mouse. Vaccination with low dose of P. acnes successfully prevented clinical manifestations in the skin of AD mice associated with systemic and cutaneous increased expression of Th1-type cytokines but without suppression of Th2 cytokines. Interestingly, the numbers of IFN-gamma(+) T cells, FoxP3(+) CD4(+) CD25(+) T cells (nTreg) and IL-10(+) T cells (Tr1) were significantly increased in the spleen. P. acnes vaccination has effects to alter the cytokine milieu and may be useful for the improvement of atopic symptom. PMID- 21255098 TI - 9th Annual Meeting of the German Dermato-Endocrinology Working Group (ADE) of Arbeitsgemeinschaft Dermatologische Forschung (ADF) 17.2.2010, Lubeck. PMID- 21255099 TI - Abstracts of the 38th Annual Meeting of the Arbeitsgemeinschaft Dermatologische Forschung (ADF). Tuebingen, Germany. February 17-19, 2011. PMID- 21255100 TI - Long-term outcome of ovotesticular disorder of sex development: a single center experience. AB - OBJECTIVES: To describe the clinical features of children with ovotesticular disorder of sex development (DSD) and to review cases of ovotesticular DSD in Japan. METHODS: Medical records of eight children diagnosed with ovotesticular DSD at our institute during the past 17 years were retrospectively evaluated. A review of 165 reported cases of ovotesticular DSD from Japanese institutions was carried out. RESULTS: Mean follow up was 8.2 years for six children, with two children lost to follow up. Mean age at first presentation was 2.4 months. All children were Japanese. The most common initial manifestation was ambiguous genitalia. The female:male ratio as the sex of rearing was 1:1. Gender reassignment, from male to female, was carried out in one child at 4-months-old. Genital surgery was always carried out in early childhood as per family desire. Appropriate gonadal tissue was preserved except for one child. No gonadal tumors were detected during follow up. Spontaneous pubertal development occurred in one boy. In reviewing Japanese data, the frequency of testes was higher than in other ethnicities and this was related to the higher incidence of 46,XY. CONCLUSIONS: According to our experience, most families in Japan desire early genital surgery in the case of ovotesticular DSD. Chromosomal and gonadal distributions in patients with ovotesticular DSD differ between Japanese and other ethnic groups. Treatment for these patients needs to be provided after considering the cultural and social backgrounds of DSD in Japan. PMID- 21255101 TI - Abstracts of the 7th ELITA-ELTR (European Society for Organ Transplantation European Liver and Intestine Transplant Association) Wintermeeting. Innsbruck, Austria. February 10-12, 2011. PMID- 21255102 TI - Priming and elongation: dissection of the lipoteichoic acid biosynthetic pathway in Gram-positive bacteria. AB - The biosynthesis of lipoteichoic acids is a potential target for the development of novel antimicrobials against significant Firmicute pathogens. Excellent progress has been made in recent years towards understanding the biochemistry and genetics of polyglycerophosphate lipoteichoic acid biosynthesis but it has remained unclear whether this pathway requires an initial 'priming' reaction to initiate synthesis on the glycolipid anchor. Recent work from the laboratory of Angelika Grundling, including a new study by Wormann et al. in this issue of Molecular Microbiology, provides confirmation of the priming step and further insights into the functional redundancy of lipoteichoic acid biosynthesis enzymes in Bacillus subtilis. PMID- 21255103 TI - Identifying your enemies--could envelope stress trigger microbial immunity? AB - Microbes utilize defence systems with fundamental similarities to our innate and adaptive immune responses to protect themselves from harmful invaders. One system, made up of CRISPR loci & Cas proteins, incorporates recognizable features from the genomes of viruses (bacteriophages) and plasmids into bacterial genomes, where they are later used to direct a ribonucleoprotein complex to destroy invading nucleic acids upon re-exposure. CRISPR-mediated defence against invasive nucleic acids is found in most archaea and many eubacteria. Many aspects of this newly described defence system have not been worked out, including the molecular mechanisms by which foreign nucleic acids are incorporated into microbial genomes during adaption and destroyed during interference. In this issue of Molecular Microbiology, DeLisa and colleagues provide insight into how this form of microbial immunity might be regulated in eubacteria. They demonstrate that Escherichia coli CRISPR-mediated immunity requires the presence of the BaeSR two component system under certain conditions. Since BaeSR regulate an envelope stress response, their data imply that immunity against invading, foreign nucleic acids may be somehow linked to stresses to the bacterial membrane. These observations will help pave the way to understanding how and when CRISPR-based immunity may be important in driving evolution and adaptation in eubacteria. PMID- 21255104 TI - cAMP, c-di-GMP, c-di-AMP and now cGMP: bacteria use them all! PMID- 21255105 TI - Enzymatic activities and functional interdependencies of Bacillus subtilis lipoteichoic acid synthesis enzymes. AB - Lipoteichoic acid (LTA) is an important cell wall polymer in Gram-positive bacteria. The enzyme responsible for polyglycerolphosphate LTA synthesis is LtaS, first described in Staphylococcus aureus. Four LtaS orthologues, LtaS(BS) , YfnI, YqgS and YvgJ, are present in Bacillus subtilis. Using an in vitro enzyme assay, we determined that all four proteins are Mn(2+) -dependent metal enzymes that use phosphatidylglycerol as a substrate. We show that LtaS(BS) , YfnI and YqgS can produce polymers, suggesting that these three proteins are bona-fide LTA synthases while YvgJ functions as an LTA primase, as indicated by the accumulation of a GroP-Glc(2) -DAG glycolipid. Western blot analysis of LTA produced by ltaS(BS) , yfnI, yqgS and yvgJ single, triple and the quadruple mutant, showed that LTA production was only abolished in the quadruple and the YvgJ-only expressing mutant. B. subtilis strains expressing YfnI in the absence of LtaS(BS) produced LTA of retarded mobility, presumably caused by an increase in chain length as suggested by a structural analysis of purified LTA. Taken together, the presented results indicate that the mere presence or absence of LTA cannot account for cell division and sporulation defects observed in the absence of individual enzymes and revealed an unexpected enzymatic interdependency of LtaS-type proteins in B. subtilis. PMID- 21255106 TI - Envelope stress is a trigger of CRISPR RNA-mediated DNA silencing in Escherichia coli. AB - A widespread feature in the genomes of most bacteria and archaea is an array of clustered, regularly interspaced short palindromic repeats (CRISPRs) that, together with a group of CRISPR-associated (Cas) proteins, mediate immunity against invasive nucleic acids such as plasmids and viruses. Here, the CRISPR-Cas system was activated in cells expressing a plasmid-encoded protein that was targeted to the twin-arginine translocation (Tat) pathway. Expression of this Tat substrate resulted in upregulation of the Cas enzymes and subsequent silencing of the encoding plasmid in a manner that required the BaeSR two-component regulatory system, which is known to respond to extracytoplasmic stress. Furthermore, we confirm that the CasCDE enzymes form a stable ternary complex and appear to function as the catalytic core of the Cas system to process CRISPR RNA into its mature form. Taken together, our results indicate that the CRISPR-Cas system targets DNA directly as part of a defence mechanism in bacteria that is overlapping with but not limited to phage infection. PMID- 21255108 TI - Regulation of yeast Yak1 kinase by PKA and autophosphorylation-dependent 14-3-3 binding. AB - Yak1 is a member of an evolutionarily conserved family of Ser/Thr protein kinases known as dual-specificity Tyr phosphorylation-regulated kinases (DYRKs). Yak1 was originally identified as a growth antagonist, which functions downstream of Ras/PKA signalling pathway. It has been known that Yak1 is phosphorylated by PKA in vitro and is translocated to the nucleus upon nutrient deprivation. However, the regulatory mechanisms for Yak1 activity and localization are largely unknown. In the present study, we investigated the role of PKA and Bmh1, a yeast 14-3-3 protein, in regulation of Yak1. We demonstrate that PKA-dependent phosphorylation of Yak1 on Ser295 and two minor sites inhibits nuclear localization of Yak1. We also show that intramolecular autophosphorylation on at least four Ser/Thr residues in the non-catalytic N-terminal domain is required for full kinase activity of Yak1. The most potent autophosphorylation site, Thr335, plays an essential role for Bmh1 binding in collaboration with a yet unidentified second binding site in the N-terminal domain. Bmh1 binding decreases the catalytic activity of Yak1 without affecting its subcellular localization. Since the binding of 14-3-3 proteins to Yak1 coincides with PKA activity, such regulatory mechanisms might allow cytoplasmic retention of an inactive form of Yak1 under high glucose conditions. PMID- 21255107 TI - Saturation mutagenesis of a CepR binding site as a means to identify new quorum regulated promoters in Burkholderia cenocepacia. AB - Burkholderia cenocepacia is an opportunistic pathogen of humans that encodes two genes that resemble the acylhomoserine lactone synthase gene luxI of Vibrio fischeri and three genes that resemble the acylhomoserine lactone receptor gene luxR. Of these, CepI synthesizes octanoylhomoserine lactone (OHL), while CepR is an OHL-dependent transcription factor. In the current study we developed a strategy to identify genes that are directly regulated by CepR. We systematically altered a CepR binding site (cep box) upstream of a target promoter to identify nucleotides that are essential for CepR activity in vivo and for CepR binding in vitro. We constructed 34 self-complementary oligonucleotides containing altered cep boxes, and measured binding affinity for each. These experiments allowed us to identify a consensus CepR binding site. Several hundred similar sequences were identified, some of which were adjacent to probable promoters. Several such promoters were fused to a reporter gene with and without intact cep boxes. This allowed us to identify four new regulated promoters that were induced by OHL, and that required a cep box for induction. CepR-dependent, OHL-dependent expression of all four promoters was reconstituted in Escherichia coli. Purified CepR bound to each of these sites in electrophoretic mobility shift assays. PMID- 21255109 TI - The cell cycle of Leishmania: morphogenetic events and their implications for parasite biology. AB - The cell cycle is central to understanding fundamental biology of Leishmania, a group of human-infective protozoan parasites. Leishmania have two main life cycle morphologies: the intracellular amastigote in the mammalian host and the promastigote in the fly. We have produced the first comprehensive and quantitative description of a Leishmania promastigote cell cycle taking a morphometric approach to position any cell within the cell cycle based on its length and DNA content. We describe timings of cell cycle phases and rates of morphological changes; kinetoplast and nucleus S phase, division and position, cell body growth and morphology changes, flagellum growth and basal body duplication. We have shown that Leishmania mexicana undergoes large changes in morphology through the cell cycle and that the wide range of morphologies present in cultures during exponential growth represent different cell cycle stages. We also show promastigote flagellum growth occurs over multiple cell cycles. There are clear implications for the mechanisms of flagellum length regulation, life cycle stage differentiation and trypanosomatid division in general. This data set therefore provides a platform which will be of use for post-genomic analyses of Leishmania cell biology in relation to differentiation and infection. PMID- 21255110 TI - Ureaplasma antigenic variation beyond MBA phase variation: DNA inversions generating chimeric structures and switching in expression of the MBA N-terminal paralogue UU172. AB - Phase variation of the major ureaplasma surface membrane protein, the multiple banded antigen (MBA), with its counterpart, the UU376 protein, was recently discussed as a result of DNA inversion occurring at specific inverted repeats. Two similar inverted repeats to the ones within the mba locus were found in the genome of Ureaplasma parvum serovar 3; one within the MBA N-terminal paralogue UU172 and another in the adjacent intergenic spacer region. In this report, we demonstrate on both genomic and protein level that DNA inversion at these inverted repeats leads to alternating expression between UU172 and the neighbouring conserved hypothetical ORF UU171. Sequence analysis of this phase variable 'UU172 element' from both U. parvum and U. urealyticum strains revealed that it is highly conserved among both species and that it also includes the orthologue of UU144. A third inverted repeat region in UU144 is proposed to serve as an additional potential inversion site from which chimeric genes can evolve. Our results indicate that site-specific recombination events in the genome of U. parvum serovar 3 are dynamic and frequent, leading to a broad spectrum of antigenic variation by which the organism may evade host immune responses. PMID- 21255111 TI - Chemotaxis kinase CheA is activated by three neighbouring chemoreceptor dimers as effectively as by receptor clusters. AB - Chemoreceptors are central to bacterial chemotaxis. These transmembrane homodimers form trimers of dimers. Trimers form clusters of a few to thousands of receptors. A crucial receptor function is 100-fold activation, in signalling complexes, of sensory histidine kinase CheA. Significant activation has been shown to require more than one receptor dimer but the number required for full activation was unknown. We investigated this issue using Nanodiscs, soluble, nanoscale (~10 nm diameter) plugs of lipid bilayer, to limit the number of neighbouring receptors contributing to activation. Utilizing size-exclusion chromatography, we separated primary preparations of receptor-containing Nanodiscs, otherwise heterogeneous for number and orientation of inserted receptors, into fractions enriched for specific numbers of dimers per disc. Fractionated, clarified Nanodiscs carrying approximately five dimers per disc were as effective in activating kinase as native membrane vesicles containing many neighbouring dimers. At five independently inserted dimers per disc, every disc would have at least three dimers oriented in parallel and thus able act together as they would in native membrane. We conclude full kinase activation involves interaction of CheA with groups of three receptor dimers, presumably as a trimer of dimers, and that more extensive interactions among receptors are not necessary for full kinase activation. PMID- 21255112 TI - PAS/poly-HAMP signalling in Aer-2, a soluble haem-based sensor. AB - Poly-HAMP domains are widespread in bacterial chemoreceptors, but previous studies have focused on receptors with single HAMP domains. The Pseudomonas aeruginosa chemoreceptor, Aer-2, has an unusual domain architecture consisting of a PAS-sensing domain sandwiched between three N-terminal and two C-terminal HAMP domains, followed by a conserved kinase control module. The structure of the N terminal HAMP domains was recently solved, making Aer-2 the first protein with resolved poly-HAMP structure. The role of Aer-2 in P. aeruginosa is unclear, but here we show that Aer-2 can interact with the chemotaxis system of Escherichia coli to mediate repellent responses to oxygen, carbon monoxide and nitric oxide. Using this model system to investigate signalling and poly-HAMP function, we determined that the Aer-2 PAS domain binds penta-co-ordinated b-type haem and that reversible signalling requires four of the five HAMP domains. Deleting HAMP 2 and/or 3 resulted in a kinase-off phenotype, whereas deleting HAMP 4 and/or 5 resulted in a kinase-on phenotype. Overall, these data support a model in which ligand-bound Aer-2 PAS and HAMP 2 and 3 act together to relieve inhibition of the kinase control module by HAMP 4 and 5, resulting in the kinase-on state of the Aer-2 receptor. PMID- 21255113 TI - Role of a Zn-independent DksA in Zn homeostasis and stringent response. AB - DksA is a global transcriptional regulator that directly interacts with RNA polymerase (RNAP) and, in conjunction with an alarmone ppGpp, alters transcription initiation at target promoters. DksA proteins studied to date contain a canonical Cys-4 Zn-finger motif thought to be essential for their proper folding and thus activity. In addition to the canonical DksA protein, the Pseudomonas aeruginosa genome encodes a closely related paralogue DksA2 that lacks the Zn-finger motif. Here, we report that DksA2 can functionally substitute for the canonical DksA in vivo in Escherichia coli and P. aeruginosa. We also demonstrate that DksA2 affects transcription by the E. coli RNAP in vitro similarly to DksA. The dksA2 gene is positioned downstream of a putative Zur binding site. Accordingly, we show that dksA2 expression is repressed by the presence of exogenous Zn, deletion of Zur results in constitutive expression of dksA2, and Zur binds specifically to the promoter region of dksA2. We also found that deletion of dksA2 confers a growth defect in the absence of Zn. Our data suggest that DksA2 plays a role in Zn homeostasis and serves as a back-up copy of the canonical Zn-dependent DksA in Zn-poor environments. PMID- 21255114 TI - Remodelling of the Vibrio cholerae membrane by incorporation of exogenous fatty acids from host and aquatic environments. AB - The Gram-negative bacteria Vibrio cholerae poses significant public health concerns by causing an acute intestinal infection afflicting millions of people each year. V. cholerae motility, as well as virulence factor expression and outer membrane protein production, has been shown to be affected by bile. The current study examines the effects of bile on V. cholerae phospholipids. Bile exposure caused significant alterations to the phospholipid profile of V. cholerae but not of other enteric pathogens. These changes consisted of a quantitative increase and migratory difference in cardiolipin, decreases in phosphatidylglycerol and phosphatidylethanolamine, and the dramatic appearance of an unknown phospholipid determined to be lyso-phosphatidylethanolamine. Major components of bile were not responsible for the observed changes, but long-chain polyunsaturated fatty acids, which are minor components of bile, were shown to be incorporated into phospholipids of V. cholerae. Although the bile-induced phospholipid profile was independent of the V. cholerae virulence cascade, we identified another relevant environment in which V. cholerae assimilates unique fatty acids into its membrane phospholipids - marine sediment. Our results suggest that Vibrio species possess unique machinery conferring the ability to take up a wider range of exogenous fatty acids than other enteric bacteria. PMID- 21255116 TI - A dual functional origin of transfer in the ICEclc genomic island of Pseudomonas knackmussii B13. AB - Genomic islands (GEIs) are large DNA segments, present in most bacterial genomes, that are most likely acquired via horizontal gene transfer. Here, we study the self-transfer system of the integrative and conjugative element ICEclc of Pseudomonas knackmussii B13, which stands model for a larger group of ICE/GEI with syntenic core gene organization. Functional screening revealed that unlike conjugative plasmids and other ICEs ICEclc carries two separate origins of transfer, with different sequence context but containing a similar repeat motif. Conjugation experiments with GFP-labelled ICEclc variants showed that both oriTs are used for transfer and with indistinguishable efficiencies, but that having two oriTs results in an estimated fourfold increase of ICEclc transfer rates in a population compared with having a single oriT. A gene for a relaxase essential for ICEclc transfer was also identified, but in vivo strand exchange assays suggested that the relaxase processes both oriTs in a different manner. This unique dual origin of transfer system might have provided an evolutionary advantage for distribution of ICE, a hypothesis that is supported by the fact that both oriT regions are conserved in several GEIs related to ICEclc. PMID- 21255115 TI - The Neisseria gonorrhoeae photolyase orthologue phrB is required for proper DNA supercoiling but does not function in photo-reactivation. AB - Neisseria gonorrhoeae (Gc) is an obligate human pathogen and the causative agent of the sexually transmitted infection, gonorrhoea. Despite the fact that the gonococcus is not normally exposed to UV irradiation or visible light, the bacterium expresses a phrB orthologue, which in other organisms encodes a DNA photolyase that repairs UV-induced pyrimidine dimers with energy provided by visible light. We show that a Gc phrB mutant is not more sensitive to UV irradiation, independent of visible light exposure, and that the Gc phrB cannot complement an Escherichia coli phrB mutant strain. The Gc phrB mutant had a reduced colony size that was not a result of a growth defect and the mutant cells exhibited an altered morphology. Although the phrB mutant exhibited increased sensitivity to oxidative killing; it showed increased survival on media containing nalidixic acid or rifampicin, but did not have an increased mutation rate to these antibiotics or spectinomycin and kasugamycin. The Gc phrB mutant showed increased negative DNA supercoiling, but while the protein bound double stranded DNA, it did not express topoisomerase activity. We conclude that the Gc PhrB has a previously unrecognized role in maintaining DNA supercoiling that is important for normal cell physiology. PMID- 21255117 TI - A new morphogenesis pathway in bacteria: unbalanced activity of cell wall synthesis machineries leads to coccus-to-rod transition and filamentation in ovococci. AB - Bacteria display a variety of shapes, which have biological relevance. In most eubacteria, cell shape is maintained by the tough peptidoglycan (PG) layer of the cell wall, the sacculus. The organization of PG synthesis machineries, orchestrated by different cytoskeletal elements, determines the specific shapes of sacculi. In rod-shaped bacteria, the actin-like (MreB) and the tubuline-like (FtsZ) cytoskeletons control synthesis of the sidewall (elongation) and the crosswall (septation) respectively. Much less is known concerning cell morphogenesis in cocci, which lack MreB proteins. While spherical cocci exclusively display septal growth, ovococci additionally display peripheral growth, which is responsible of the slight longitudinal expansion that generates their ovoid shape. Here, we report that the ovococcus Lactococcus lactis has the ability to become rod-shaped. L. lactis IL1403 wild-type cells form long aseptate filaments during both biofilm and planktonic growth in a synthetic medium. Nascent PG insertion and the division protein FtsK localize in multiple peripheral rings regularly spaced along the filaments. We show that filamentation results from septation inhibition, and that penicillin-binding proteins PBP2x and PBP2b play a direct role in this process. We propose a model for filament formation in L. lactis, and discuss the possible biological role of such morphological differentiation. PMID- 21255118 TI - In vivo cross-linking of EpsG to EpsL suggests a role for EpsL as an ATPase pseudopilin coupling protein in the Type II secretion system of Vibrio cholerae. AB - The type II secretion system is a multi-protein complex that spans the cell envelope of Gram-negative bacteria and promotes the secretion of proteins, including several virulence factors. This system is homologous to the type IV pilus biogenesis machinery and contains five proteins, EpsG-K, termed the pseudopilins that are structurally homologous to the type IV pilins. The major pseudopilin EpsG has been proposed to form a pilus-like structure in an energy dependent process that requires the ATPase, EpsE. A key remaining question is how the membrane-bound EpsG interacts with the cytoplasmic ATPase, and if this is a direct or indirect interaction. Previous studies have established an interaction between the bitopic inner membrane protein EpsL and EpsE; therefore, in this study we used in vivo cross-linking to test the hypothesis that EpsG interacts with EpsL. Our findings suggest that EpsL may function as a scaffold to link EpsG and EpsE and thereby transduce the energy generated by ATP hydrolysis to support secretion. The recent discovery of structural homology between EpsL and a protein in the type IV pilus system implies that this interaction may be conserved and represent an important functional interaction for both the type II secretion and type IV pilus systems. PMID- 21255119 TI - The co-dependence of BxpB/ExsFA and BclA for proper incorporation into the exosporium of Bacillus anthracis. AB - The outermost layer of the Bacillus anthracis spore consists of an exosporium comprised of two distinct layers, an outer hair-like nap layer and an internal basal layer. The hair-like nap is primarily comprised of the glycosylated collagen-like protein BclA. BclA is found in a trimeric form in close association with many other exosporium proteins in high-molecular weight complexes. We previously had characterized an N-terminal sequence of BclA that is sufficient for incorporation into the exosporium. Here we utilized site-directed mutagenesis to identify BclA residues critical to two steps in this process, positioning of the protein at the site of the developing exosporium basal layer and stable incorporation which includes a proteolytic cleavage of BclA after residue 19. The BxpB (ExsFA) protein is known to be important for proper incorporation of BclA onto the exosporium. BxpB and BclA were found to be expressed at the same time in sporulating cells of B. anthracis and immediately colocalize to high-molecular weight complexes. The BxpB protein was found to be in close proximity to the BclA NTD. BxpB and BclA are co-dependent for exosporium incorporation, with the BclA NTD being sufficient to deliver BxpB to the exosporium. PMID- 21255120 TI - Characterization of a new cytotoxin that contributes to Staphylococcus aureus pathogenesis. AB - Staphylococcus aureus is an important pathogen that continues to be a significant global health threat because of the prevalence of methicillin-resistant S. aureus strains (MRSA). The pathogenesis of this organism is partly attributed to the production of a large repertoire of cytotoxins that target and kill innate immune cells, which provide the first line of defence against S. aureus infection. Here we demonstrate that leukocidin A/B (LukAB) is required and sufficient for the ability of S. aureus, including MRSA, to kill human neutrophils, macrophages and dendritic cells. LukAB targets the plasma membrane of host cells resulting in cellular swelling and subsequent cell death. We found that S. aureus lacking lukAB are severely impaired in their ability to kill phagocytes during bacteria phagocyte interaction, which in turn renders the lukAB-negative staphylococci more susceptible to killing by neutrophils. Notably, we show that lukAB is expressed in vivo within abscesses in a murine infection model and that it contributes significantly to pathogenesis of MRSA in an animal host. Collectively, these results extend our understanding of how S. aureus avoids phagocyte-mediated clearance, and underscore LukAB as an important factor that contributes to staphylococcal pathogenesis. PMID- 21255121 TI - A new ATP-binding cassette protein is involved in intracellular haem trafficking in Leishmania. AB - The characterization of LABCG5, a new intracellular ATP-binding cassette protein in Leishmania donovani, is described. Unlike other ABCG half-transporters, LABCG5 is not involved in either drug resistance or phospholipid efflux. However, we provide evidence suggesting that this protein is involved in intracellular haem trafficking. Thus, downregulation of LABCG5 function produced upon overexpression of an inactive version of the protein caused a dramatic growth arrest unless a haemin supplement was added or the mutated gene was eliminated. Supplementation with haemoglobin, an upstream metabolite normally sufficient to meet parasite haem requirements, was unable to rescue the growth defect phenotype. Haemoglobin endocytosis was not hampered in dominant-negative parasites and neither was haem uptake, a process that we show here to be dependent on a specific transporter. In contrast, LABCG5 function was required for the correct intracellular trafficking of haemoglobin-bound porphyrins to the mitochondria, not affecting the routing of free haem. Finally, LABCG5 binds haem through hydrophobic and electrostatic interactions. Altogether, these data suggest that LABCG5 is involved in the salvage of the haem released after the breakdown of internalized haemoglobin. As Leishmania is auxotrophic for haem, the pharmacological targeting of this route could represent a novel approach to control fatal visceral leishmaniasis. PMID- 21255122 TI - Identification of a biosynthesis gene cluster for flocculosin a cellobiose lipid produced by the biocontrol agent Pseudozyma flocculosa. AB - Flocculosin is an antifungal glycolipid produced by the biocontrol fungus Pseudozyma flocculosa. It consists of cellobiose, O-glycosidically linked to 3,15,16-trihydroxypalmitic acid. The sugar moiety is acylated with 2-hydroxy octanoic acid and acetylated at two positions. Here we describe a gene cluster comprising 11 genes that are necessary for the biosynthesis of flocculosin. We compared the cluster with the biosynthesis gene cluster for the highly similar glycolipid ustilagic acid (UA) produced by the phytopathogenic fungus Ustilago maydis. In contrast to the cluster of U. maydis, the flocculosin biosynthesis cluster contains an additional gene encoding an acetyl-transferase and is lacking a gene homologous to the alpha-hydroxylase Ahd1 necessary for UA hydroxylation. The functions of three acyl/acetyl-transferase genes (Fat1, Fat2 and Fat3) including the additional acetyl-transferase were studied by complementing the corresponding U. maydis mutants. While P. flocculosa Fat1 and Fat3 are homologous to Uat1 in U. maydis, Fat2 shares 64% identity to Uat2, a protein involved in UA biosynthesis but with so far unknown function. By genetic and mass spectrometric analysis, we show that Uat2 and Fat2 are necessary for acetylation of the corresponding glycolipid. These results bring unique insights into the biocontrol properties of P. flocculosa and opportunities for enhancing its activity. PMID- 21255123 TI - What subcortical-cortical relationships tell us about processing speech in noise. AB - To advance our understanding of the biological basis of speech-in-noise perception, we investigated the effects of background noise on both subcortical- and cortical-evoked responses, and the relationships between them, in normal hearing young adults. The addition of background noise modulated subcortical and cortical response morphology. In noise, subcortical responses were later, smaller in amplitude and demonstrated decreased neural precision in encoding the speech sound. Cortical responses were also delayed by noise, yet the amplitudes of the major peaks (N1, P2) were affected differently, with N1 increasing and P2 decreasing. Relationships between neural measures and speech-in-noise ability were identified, with earlier subcortical responses, higher subcortical response fidelity and greater cortical N1 response magnitude all relating to better speech in-noise perception. Furthermore, it was only with the addition of background noise that relationships between subcortical and cortical encoding of speech and the behavioral measures of speech in noise emerged. Results illustrate that human brainstem responses and N1 cortical response amplitude reflect coordinated processes with regards to the perception of speech in noise, thereby acting as a functional index of speech-in-noise perception. PMID- 21255124 TI - The brain-derived neurotrophic factor Val66Met polymorphism is associated with reduced functional magnetic resonance imaging activity in the hippocampus and increased use of caudate nucleus-dependent strategies in a human virtual navigation task. AB - Multiple memory systems are involved in parallel processing of spatial information during navigation. A series of studies have distinguished between hippocampus-dependent 'spatial' navigation, which relies on knowledge of the relationship between landmarks in one's environment to build a cognitive map, and habit-based 'response' learning, which requires the memorization of a series of actions and is mediated by the caudate nucleus. Studies have demonstrated that people spontaneously use one of these two alternative navigational strategies with almost equal frequency to solve a given navigation task, and that strategy correlates with functional magnetic resonance imaging (fMRI) activity and grey matter density. Although there is evidence for experience modulating grey matter in the hippocampus, genetic contributions may also play an important role in the hippocampus and caudate nucleus. Recently, the Val66Met polymorphism of the brain derived neurotrophic factor (BDNF) gene has emerged as a possible inhibitor of hippocampal function. We have investigated the role of the BDNF Val66Met polymorphism on virtual navigation behaviour and brain activation during an fMRI navigation task. Our results demonstrate a genetic contribution to spontaneous strategies, where 'Met' carriers use a response strategy more frequently than individuals homozygous for the 'Val' allele. Additionally, we found increased hippocampal activation in the Val group relative to the Met group during performance of a virtual navigation task. Our results support the idea that the BDNF gene with the Val66Met polymorphism is a novel candidate gene involved in determining spontaneous strategies during navigation behaviour. PMID- 21255125 TI - MuSK levels differ between adult skeletal muscles and influence postsynaptic plasticity. AB - Muscle-specific tyrosine kinase (MuSK) is involved in the formation and maintenance of the neuromuscular junction (NMJ), and is necessary for NMJ integrity. As muscle involvement is strikingly selective in pathological conditions in which MuSK is targeted, including congenital myasthenic syndrome with MuSK mutation and MuSK antibody-seropositive myasthenia gravis, we hypothesized that the postsynaptic response to MuSK-agrin signalling differs between adult muscles. Transcript levels of postsynaptic proteins were compared between different muscles in wild-type adult mice. MuSK expression was high in the soleus and sternomastoid muscles and low in the extensor digitorum longus (EDL) and omohyoid muscles. The acetylcholine receptor (AChR) alpha subunit followed a similar expression pattern, whereas expression of Dok-7, Lrp4 and rapsyn was comparable between the muscles. We subsequently examined muscles in mice that overexpressed a miniaturized form of neural agrin or MuSK. In these transgenic mice, the soleus and sternomastoid muscles responded with formation of ectopic AChR clusters, whereas such clusters were almost absent in the EDL and omohyoid muscles. Electroporation of Dok-7 revealed its important role as an activator of MuSK in AChR cluster formation in adult muscles. Together, our findings indicate for the first time that adult skeletal muscles harbour different endogenous levels of MuSK and that these levels determine the ability to form ectopic AChR clusters upon overexpression of agrin or MuSK. We believe that these findings are important for our understanding of adult muscle plasticity and the selective muscle involvement in neuromuscular disorders in which MuSK is diminished. PMID- 21255126 TI - Surround suppression by high spatial frequency stimuli in the cat primary visual cortex. AB - Surround suppression is a phenomenon whereby stimulation of the extraclassical receptive field suppressively modulates the visual responses of neurons in the primary visual cortex (V1) (also known as area 17). It is known that surround suppression tunes to spatial frequencies (SFs) that are much lower and broader than the frequencies to which the classical receptive field tunes. In this study, we tested the effects of varying SFs on surround suppression by using a circular sinusoidal grating patch that covered both the classical receptive field and the extraclassical receptive field. Using area-summation tuning curves, we found high SF-tuned surround suppression in the cat V1. This high-SF-tuned surround suppression causes the SF tuning to shift to low SF for large stimuli. By simulating a model neuron lacking a suppressive surround mechanism, we confirmed that these preferred SF shifts do not occur in the absence of surround suppression. We surmise that the high-SF-tuned suppression, which shifts the preferred SF according to size, functionally contributes to the scale-invariant processing of visual images in V1. PMID- 21255127 TI - Activation of the mitochondrial permeability transition pore modulates Ca2+ responses to physiological stimuli in adult neurons. AB - The participation of mitochondria in cellular and neuronal Ca(2+) homeostatic networks is now well accepted. Yet, critical tests of specific mitochondrial pathways in neuronal Ca(2+) responses have been hampered because the identity of mitochondrial proteins that must be integrated within this dynamic system remain uncertain. One putative pathway for Ca(2+) efflux from mitochondria exists through the formation of the permeability transition pore (PTP) that is often associated with cellular and neuronal death. Here, we have evaluated neuronal Ca(2+) dynamics and the PTP in single adult neurons in wild-type mice and those missing cyclophilin D (CyPD), a key regulator of the PTP. Using high-resolution time-lapse imaging, we demonstrate that PTP opening only follows simultaneous activation with two physiological stimuli that generate critical threshold levels of cytosolic and mitochondrial Ca(2+) . Our results are the first to demonstrate CyPD-dependent PTP opening in normal neuronal Ca(2+) homeostatic mechanisms not leading to activation of cell death pathways. As neurons in mice lacking CyPD are protected in a number of neurodegenerative disease models, the results suggest that improved viability of CyPD-knockout animals in these pathological states may be due to the transient, rather than persistent, activation of the PTP in mutant mitochondria, thereby shielding neurons from cytoplasmic Ca(2+) overload. PMID- 21255128 TI - Alpha frequency modulation in the human basal ganglia is dependent on motor task. AB - Depth recordings from the basal ganglia of patients suffering from Parkinson's disease (PD) or dystonia have revealed local field potential (LFP) activity in specific frequency bands. Depth recordings also allow us to study LFP power spectra during different types of limb movements, thus helping to elucidate the role of the basal ganglia in specific motor tasks. Accordingly, we recorded bilateral LFP activity from the subthalamic nucleus (STN) of patients with PD (n=9) and from the globus pallidus internum (GPi) of patients with dystonia (n=8). Recordings were taken during the performance of repetitive passive, active and ballistic fast extensions and flexions of the elbow joint and during rest. The first result was that the frequency spectra varied task-specifically in a similar fashion in GPi and STN. The amplitude of the alpha frequency on the contralateral side was significantly higher in ballistic fast movements compared with rest, passive and active performance in both STN and GPi. In conclusion, ballistic fast movements cause synchronized basal ganglia activity in the alpha range. Because this was seen in both patient groups (PD and dystonia) we consider this activity as task-specific rather than disease-related. PMID- 21255129 TI - Involvement of endoplasmic reticulum stress on neuronal cell death in the lateral geniculate nucleus in the monkey glaucoma model. AB - We investigated whether endoplasmic reticulum (ER) stress was involved in the pathophysiological mechanisms underlying neuronal death of the lateral geniculate nucleus (LGN) after intraocular pressure (IOP) elevation. Five cynomolgus monkeys, four with a glaucomatous left eye after laser photocoagulation treatment and one normal monkey, were studied. At 4, 11, 15 and 24 weeks after the laser photocoagulation treatment, the numbers of LGN neurons and atrophy were immunohistochemically evaluated using anti-parvalbumin-antibody, which was used to specifically label relay neurons connecting to the visual cortex. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) positive cells, polyubiquitin, and production of ER stress-related proteins, such as the phosphorylation of eukaryotic initiation factor 2alpha (p-eIF2alpha) and C/EBP-homologous protein (CHOP), were also measured using in situ hybridization and immunostaining. Loss of neurons and/or neuronal atrophy in layers 1, 4 and 6 of the LGN on the contralateral side were observed at 4-24 weeks after the laser photocoagulation treatment. Furthermore, the retinal input from the high IOP eye projected to layers 2 (magnocellular layer), 3 and 5 (parvocellular layer) on the ipsilateral side. Neuronal damage was also confirmed in these layers. In the LGN region, TUNEL-positive cells, polyubiquitin, p-eIF2alpha and CHOP were also detected at 11-24 weeks after the laser photocoagulation treatment. These findings indicate that ER stress may play a pivotal role in neuronal death of the LGN after IOP elevation. PMID- 21255130 TI - Involvement of the dorsal subiculum and rostral basolateral amygdala in cocaine cue extinction learning in rats. AB - Memory system circuitry may regulate how cues associated with cocaine are extinguished, and understanding neurosubstrates of extinction may lead to the development of improved treatment strategies for cocaine addiction. Sites within the hippocampus and amygdala were investigated for their role in regulating cocaine cue extinction learning. Initially, rats were trained to self-administer cocaine under a second-order reinforcement schedule (cocaine and cocaine cues present) followed by a 2-week abstinence period. Using lidocaine, rats next underwent bilateral inactivation of the dorsal subiculum (dSUB) or rostral basolateral amygdala (rBLA), asymmetric inactivation of the dSUB and rBLA, unilateral inactivation of the dSUB or rBLA, or ipsilateral inactivation of the dSUB and rBLA prior to cocaine cue extinction training sessions (only cocaine cues present) on two consecutive days. Relative to vehicle, bilateral and asymmetric lidocaine treatments in the dSUB and rBLA slowed cocaine cue extinction learning. Specifically, vehicle-treated rats exhibited a significantly larger difference in responding from Day 1 to Day 2 of extinction training than lidocaine-treated rats. In comparison, unilateral or ipsilateral lidocaine treatments in the dSUB and rBLA did not slow cocaine cue extinction learning. Rats treated with lidocaine and vehicle exhibited a similar difference in responding from Day 1 to Day 2 of extinction training. These results indicate that sites within the hippocampus and amygdala need to be functionally active simultaneously in at least one brain hemisphere for acquisition of cocaine cue extinction learning. These results further suggest that a serial circuit within each hemisphere mediates acquisition of cocaine cue extinction learning. PMID- 21255132 TI - Contribution of the potassium-chloride co-transporter KCC2 to the modulation of lumbar spinal networks in mice. AB - Spontaneous activity is observed in most developing neuronal circuits, such as the retina, hippocampus, brainstem and spinal cord. In the spinal cord, spontaneous activity is important for generating embryonic movements critical for the proper development of motor axons, muscles and synaptic connections. A spontaneous bursting activity can be recorded in vitro from ventral roots during perinatal development. The depolarizing action of the inhibitory amino acids gamma-aminobutyric acid and glycine is widely proposed to contribute to spontaneous activity in several immature systems. During development, the intracellular chloride concentration decreases, leading to a shift of equilibrium potential for Cl(-) ions towards more negative values, and thereby to a change in glycine- and gamma-aminobutyric acid-evoked potentials from depolarization/excitation to hyperpolarization/inhibition. The up-regulation of the outward-directed Cl(-) pump, the neuron-specific potassium-chloride co transporter type 2 KCC2, has been shown to underlie this shift. Here, we investigated whether spontaneous and locomotor-like activities are altered in genetically modified mice that express only 8-20% of KCC2, compared with wild type animals. We show that a reduced amount of KCC2 leads to a depolarized equilibrium potential for Cl(-) ions in lumbar motoneurons, an increased spontaneous activity and a faster locomotor-like activity. However, the left right and flexor-extensor alternating pattern observed during fictive locomotion was not affected. We conclude that neuronal networks within the spinal cord are more excitable in KCC2 mutant mice, which suggests that KCC2 strongly modulates the excitability of spinal cord networks. PMID- 21255131 TI - Fast oscillatory activity induced by kainate receptor activation in the rat basolateral amygdala in vitro. AB - The basolateral amygdala (BLA) has a fundamental role in affective processing. In vivo studies have revealed rhythmic population activity of a similar type to that seen in the hippocampus and cortical areas during learning tasks. The amygdala contains densely interconnected networks of inhibitory interneurons similar to those responsible for fast network activity generation in the hippocampus and other cortical structures. Here we report that neuronal networks of the BLA in isolation generate persistent, gamma frequency (30-80 Hz) oscillations upon kainate receptor activation with kainic acid. We show that, like other cortical structures, BLA oscillations are completely dependent upon gamma-aminobutyric acid (GABA)ergic inhibition. GABA(A) receptor blockade abolished all oscillations, and the activity was also sensitive to the barbiturate, pentobarbital. Blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or N-methyl-D-aspartate (NMDA) receptors had no significant effect on gamma activity. However, the GluR5-containing kainate receptor-specific antagonist (S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxybenzyl) pyrimidine-2,4 dione (UBP302) abolished oscillations-evidence that glutamatergic receptor involvement is predominantly kainate receptor mediated. The mixed AMPA/kainate receptor antagonist 6-nitro-7-sulphamoylbenzo[f]quinoxalone-2,3-dione disodium (NBQX) abolished all oscillatory activity in 8/14 of slices tested. In the remaining slices, gamma frequency activity was abolished to reveal a low amplitude, NMDA receptor-dependent, beta frequency (10-20 Hz) oscillation. Gamma oscillations are abolished by gap junction blockade. While these data show the BLA capable of generating gamma rhythms in common with other cortical areas studied to date, the network mechanisms appear to be different, suggesting a unique network structure underlies amygdala rhythmogenesis. Understanding how BLA networks produce synchronous activity is paramount to understanding how the BLA executes influence on important cognitive processes such as emotional learning. PMID- 21255133 TI - Cardiovascular disease associated with radiotherapy: activation of nuclear factor kappa-B. AB - There have been several recent reports of an increased risk of cardiovascular disease after radiotherapy. Hence, with an increasing number of cancer survivors, the incidence of cardiovascular disease caused by radiotherapy will increase. The existence of a type of vascular disease, or vasculopathy, induced by radiotherapy has been known for decades. It is important to identify and understand the molecular causes of this vasculopathy to determine preventive strategies. Recently, a chronic inflammation with similarities to atherosclerosis has been observed, with activation of the transcription factor nuclear factor kappa-B (NF kappaB) as a possible cause. However, the trigger for NF-kappaB activation is unclear although it may be that reactive oxygen species or direct DNA damage is involved. To minimize the risk of cardiovascular disease in vulnerable patients, careful selection of patients, radiation dose and fractionation are important, together with the development of new techniques that reduce radiation dose to the blood vessels. In the light of the finding of an interaction between risk factors for cardiovascular disease and radiotherapy, it is reasonable to modify these factors including diabetes mellitus, hyperlipidaemia, hypertension and smoking. We believe that preventive strategies focusing on NF-kappaB can reduce the risk of future adverse cardiovascular events. PMID- 21255134 TI - Treatment with an oral direct thrombin inhibitor decreases platelet activity but increases markers of inflammation in patients with myocardial infarction. AB - BACKGROUND: Thrombin has a role not only in the coagulation process but also in inflammatory responses. Oral direct thrombin inhibitors (DTIs) are currently being evaluated in patients with thromboembolic diseases. OBJECTIVE: To investigate whether an oral DTI affects markers for platelet and inflammatory activity after myocardial infarction (MI). METHODS: A total of 518 patients with MI were randomly assigned to ximelagatran treatment (four different dose groups) in combination with aspirin, or aspirin alone for 6 months. The levels of soluble (s) P-selectin, soluble tissue factor, C-reactive protein (CRP), interleukin (IL) 10 and IL-18 were analysed in serial blood samples. RESULTS: sP-selectin concentration increased after 1 week and persisted at an elevated level for 6 months in all study groups (P < 0.001). In the two highest ximelagatran dose groups, there was a reduced increase in sP-selectin compared to treatment with lower doses of ximelagatran and aspirin alone (P = 0.01 and P = 0.002, respectively). IL-18 levels did not change in the aspirin alone treatment group. By contrast, there was an elevation in IL-18 level in the lower and higher ximelagatran dose groups after 6 months (P = 0.006 and P < 0.001, respectively). Ximelagatran increased IL-10 levels (P = 0.002) and reduced the decrease in CRP levels after 6 months compared to treatment with aspirin alone (P = 0.002). CONCLUSION: A persistent elevation of platelet activity is found in patients with a recent MI after the cessation of acute antithrombotic treatment, and the addition of an oral DTI at higher doses decreases the activity. By contrast, long term treatment with a DTI increases the levels of several markers of inflammation. Further studies with prolonged exposure of oral DTIs are needed for evaluation of the effect on inflammatory processes and to determine whether these agents influence clinical outcomes. PMID- 21255135 TI - Intravenous immunoglobulin attenuates airway hyperresponsiveness in a murine model of allergic asthma. AB - BACKGROUND: Intravenous immunoglobulin (IVIG) has potent anti-inflammatory and immune-modulating properties. IVIG has been utilized as a steroid-sparing agent in severe asthma, but the results of clinical trials have been conflicting. OBJECTIVE: To determine whether IVIG is able to attenuate bronchial reactivity, pulmonary inflammation and T cell function using a murine model of allergic airways disease. METHODS: BALB/c or C57BL/6 mice were sensitized to ovalbumin (OVA) or a phosphate-buffered saline control using local nasal sensitization, and then received five intranasal challenges on days 28-32 before sacrifice. Mice were treated intraperitoneally with either IVIG (1-2 g/kg) or equivalent human serum albumin 24 h before the first OVA challenge. Bronchial reactivity to methacholine was examined using the FlexiVent small animal ventilator. We evaluated pulmonary histology, mRNA from lung digests for T-helper type 2 (Th2) related genes and bronchoalveolar lavage for cell counts and cytokines. Splenocytes were utilized to study OVA-induced cell proliferation, cytokine production and dendritic cell maturation. RESULTS: IVIG markedly attenuated the perivascular and peribronchial pulmonary inflammation, and decreased bronchial hyperresponsiveness to methacholine. IVIG treatment of splenocytes from sensitized animals diminished cellular proliferation to OVA, whereas IVIG treatment in vivo markedly attenuated OVA-driven splenocyte proliferation. This is accompanied by diminished IL-13 and TNF-alpha levels in splenocyte culture, decreased expression of Jagged-1, increased Delta-4 and decreased GATA-3 mRNA levels, signs that IVIG has suppressed the expected Th2 response that accompanies repeated allergen exposure. Increased regulatory T cells were found in draining pulmonary lymph nodes in IVIG-treated mice but not in controls. CONCLUSIONS AND CLINICAL RELEVANCE: IVIG was effective in ameliorating allergic airway disease in our model. IVIG may be a promising adjunct therapy requiring further study for patients with severe asthma. PMID- 21255136 TI - Bronchial hyperresponsiveness to methacholine and adenosine 5'-monophosphate, and the presence and degree of atopy in young children with asthma. AB - BACKGROUND: Bronchial hyperresponsiveness (BHR) is a characteristic feature of asthma, and is usually measured by bronchial challenges using direct or indirect stimuli. The relationship between atopy and BHR remains to be clarified, particularly in a population selected for asthma. Furthermore, data for young children are limited, although asthma frequently occurs in early childhood. OBJECTIVE: The aim of this study was to investigate methacholine (direct stimulus) and adenosine 5'-monophosphate (AMP) (indirect stimulus) responsiveness according to the presence and degree of atopy in young children with asthma. METHODS: A retrospective analysis of data from 122 preschool children (median age [range]: 5.3 years [4.0-6.8]) presenting with the diagnosis of asthma was performed. These children were characterized by skin-prick tests (SPTs) and bronchial challenges with methacholine and AMP, using a modified auscultation method. The end-point concentration, resulting in audible wheezing and/or oxygen desaturation, was determined for each challenge. Atopy was defined by at least one positive reaction to SPTs, and its degree was assessed using serum total IgE levels, number of positive SPTs, and atopic scores (sum of graded weal size). RESULTS: Atopic patients (n=97) had a significantly lower AMP end-point concentration than non-atopic patients (n=25), whereas the methacholine end-point concentration was not different between the two groups. Among the atopic patients, there was no association between the methacholine end-point concentration and any of the atopy parameters. By contrast, a significant association was found between the AMP end-point concentration and the degree of atopy reflected in serum total IgE and atopic scores (chi2 test for trend, P=0.001, 0.003, respectively). CONCLUSION AND CLINICAL RELEVANCE: Young children with atopic asthma had a significantly greater AMP responsiveness than those with non-atopic asthma, whereas methacholine responsiveness was not significantly different between the two groups. The degree of atopy appeared to be an important factor in AMP responsiveness, but not in methacholine responsiveness, and thus might be a marker of airway inflammation in asthma. PMID- 21255137 TI - Characterization of syk expression in human lung mast cells: relationship with function. AB - BACKGROUND: Previous studies indicate that the protein tyrosine kinase, syk, is critical in transducing FcERI-mediated signals. In human basophils, 'releasability' has been linked to the extent of syk expression. Human lung mast cells, like basophils, are also found to be variably responsive to IgE-dependent activation. OBJECTIVE: The aim of the present study was to determine whether the wide variability in human lung mast cell responses, following IgE-dependent activation, has a relationship with syk expression. METHODS: Mast cells were isolated from human lung tissue and 'releasability' was determined by activating the cells with a maximal releasing concentration of anti-IgE. Syk levels in mast cells were determined by immunoblotting and flow cytometry. RESULTS: Histamine release from mast cells, challenged with a maximal releasing concentration of anti-IgE, ranged from 0% to 69% (mean+/-SEM, 24+/-2%, n=53). A proportion of these preparations (nine out of 53) released very low levels of histamine (5%) in response to anti-IgE. Flow cytometry of a subset of preparations indicated that a weak response to anti-IgE was not related to a lack of surface IgE. Immunoblotting and flow cytometry studies demonstrated that, compared with mononuclear cells, human lung mast cells express low and variable levels of syk. However, there was no correlation between syk expression and mast cell releasability. Nonetheless, a number of putative inhibitors of syk including NVP QAB205 (EC50, 0.2 MUm) effectively attenuated the IgE-dependent release of histamine from mast cells. CONCLUSION AND CLINICAL RELEVANCE: These studies indicate that although syk may play an important role in mediating degranulation, the relative level of syk expression does not govern human lung mast cell releasability. Identification of the mechanisms that govern IgE-dependent activation of human lung mast cells is likely to be of wider clinical significance, given the central role that mast cells play in the development of allergic asthma. PMID- 21255138 TI - Diagnostic value of Alt a 1, fungal enolase and manganese-dependent superoxide dismutase in the component-resolved diagnosis of allergy to Pleosporaceae. AB - BACKGROUND: Over the last decades, genomics and proteomics have contributed to the current knowledge of individualized allergenic components and their potential use in the diagnosis of IgE-mediated allergies. Recent investigations have demonstrated that Alt a 1 should be considered as a relevant allergen of the Pleosporaceae group and that enolase is the main allergen involved in the cross reactivity to fungi. However, the real utility of these allergens as tools for the diagnosis of allergy to Alternaria is still unclear. OBJECTIVE: To demonstrate the current value of the available fungal allergen panel and the need to build an accurate mould allergen array for the diagnosis of allergy to Pleosporaceae. METHODS: Specific IgEs to individual mould allergens and allergenic mould extracts were evaluated using the ImmunoCAPTM system in 30 patients allergic to Alternaria and in 100 blood donors. Cross-reactivity studies were performed by Fluoro Enzyme ImmunoAssay (FEIA) and FEIA inhibition using individual allergens and allergenic extracts. Two-dimensional electrophoresis associated with a MALDI-TOF analysis was carried out to identify new allergen molecules. RESULTS: All allergic patients had positive specific IgE responses to several moulds from different taxonomical families. Classic and molecular diagnosis demonstrated that 23% of patients had multi-sensitization. The current commercially available fungal allergen array was not sufficient to establish an accurate diagnosis. Unexpected correlations between Alternaria or Alt a 1 and Curvularia or Cladosporium stimulated the investigation of a more accurate allergen panel. A manganese-dependent superoxide dismutase (MnSOD) homologous to Asp f 6 was identified as a new IgE-binding molecule from Alternaria alternata. CONCLUSIONS AND CLINICAL RELEVANCE: Alt a 1 is the marker for allergy to Pleosporaceae, not including Curvularia. MnSOD can explain 6.6% of allergy to Alternaria without Alt a 1 sensitization and should be included together with Alt a 1 and fungal enolase in the molecular array for the diagnosis of allergy to Pleosporaceae. PMID- 21255139 TI - Maternal fatty acid status in pregnancy and childhood atopic manifestations: KOALA Birth Cohort Study. AB - BACKGROUND: Prevalence of atopic disorders has increased rapidly, but aetiological factors responsible for this increase are still largely unknown. Prenatal exposure to a pro-inflammatory fatty acid status is hypothesized although little research has been carried out. OBJECTIVE: To investigate whether prenatal fatty acid exposures are associated with atopy in childhood. METHODS: In the KOALA Birth Cohort Study, maternal blood samples (n=1275) at 34-36 weeks of pregnancy were assayed for n-6 and n-3 long-chain polyunsaturated fatty acids (LCPs). The full spectrum of offspring atopic manifestations (wheeze, asthma, allergic rhinoconjunctivitis, eczema, atopic dermatitis, allergic sensitization, and high total IgE) until the age of 6-7 years was assessed by repeated parental questionnaires and measurements of total and specific IgE. Associations of maternal fatty acid status with child atopic outcomes were analysed using multivariable logistic regression and generalized estimating equations for repeated measurements. RESULTS: High ratio of maternal n-6 vs. n-3 LCPs was associated with a lower risk of eczema in the child (P for trend 0.012). More specifically, we found a decreased risk of eczema in the first 7 months of life with increasing arachidonic acid levels (P for trend 0.013). No associations were found between maternal fatty acids and offspring airway-related atopic manifestations, sensitization, or high total IgE. CONCLUSION AND CLINICAL RELEVANCE: The development of atopic disorders in early childhood is associated with prenatal exposure to n-6 vs. n-3 fatty acids, but with inconsistencies between different manifestations. Further exploration of associations with maternal diet and genetic variants in genes regulating fatty acid metabolism are required. This study shows that the influence of prenatal exposure to fatty acids on the risk of eczema in the child is limited to the first year of life. PMID- 21255140 TI - Relationship between levels of secreted phospholipase A2 groups IIA and X in the airways and asthma severity. AB - Background Secreted phospholipase A(2) (sPLA(2) ) may be important mediators of asthma, but the specific sPLA(2) s involved in asthma are not known. Objective To evaluate sPLA(2) group IIA, V, and X proteins (sPLA(2) -IIA, sPLA(2) -V, and sPLA(2) -X) in bronchoalveolar lavage (BAL) fluid, BAL cells, and airway epithelial cells of subjects with and without asthma, and examine the relationship between the levels of specific sPLA(2) enzymes and airway inflammation, asthma severity, and lung function. Methods The expression of sPLA(2) -IIA, sPLA(2) -V, and sPLA(2) -X in BAL cells and epithelial brushings was assessed by qPCR. The levels of these sPLA(2) proteins and sPLA(2) activity with and without group II and group X-specific inhibitors were measured in BAL fluid from 18 controls and 39 asthmatics. Results The airway epithelium expressed sPLA(2) -X at higher levels than either sPLA(2) -IIA or sPLA(2) -V, whereas BAL cells expressed sPLA(2) -IIA and sPLA(2) -X at similar levels. The majority of sPLA(2) activity in BAL fluid was attributed to either sPLA(2) -IIA or sPLA(2) X. After 10-fold concentration of BAL fluid, the levels of sPLA(2) -X normalized to total protein were increased in asthma and were associated with lung function, the concentration of induced sputum neutrophils, and prostaglandin E(2) . The levels of sPLA(2) -IIA were elevated in asthma when normalized to total protein, but were not related to lung function, markers of airway inflammation or eicosanoid formation. Conclusions and Clinical Relevance These data indicate that sPLA(2) -IIA and sPLA(2) -X are the major sPLA(2) s in human airways, and suggest a link between the levels of sPLA(2) -X in the airways and several features of asthma. PMID- 21255141 TI - Association between short sleep duration and the risk of sensitization to food and aero allergens in rural Chinese adolescents. AB - BACKGROUND: Both long and short sleep duration have been associated with obesity, cardiovascular disease, and diabetes. However, there have been no previous studies investigating the potential relationship between altered sleep duration and allergen sensitization. OBJECTIVE: To explore the association between sleep duration and sensitization to food and aeroallergens. METHODS: This study includes 1534 rural Chinese adolescent twins aged 12-21 years who completed standard sleep questionnaires and skin prick tests (SPTs) to nine food and five aeroallergens. Total sleep time was defined as the interval from bedtime to wake up time minus sleep latency. Sensitization was defined as having at least one positive SPT. RESULTS: Compared with individuals with the highest (third) tertile of sleep duration, those who slept less were more likely to be sensitized to any food allergen with odds ratios (ORs) of 1.9 [95% confidence interval (CI): 1.3 2.7] and 1.4 (95% CI: 1.0-1.9) for the first and second tertiles (trend test P(trend)=3*10(-4)), respectively. The corresponding ORs for sensitization to any aeroallergen were 1.5 (95% CI: 1.1-2.0) and 1.3 (95% CI: 1.0-1.7) (P(trend)=8*10( 3)). These associations were independent of percent body fat. In addition, we observed a significant dose-response association between the number of positive SPTs and percentage of shortest sleep duration (first tertile) (P(trend)=1*10( 3)). CONCLUSIONS AND CLINICAL RELEVANCE: In this sample of relatively lean rural Chinese adolescents, we found that short sleep duration was associated with increasing risk of sensitization to food and aeroallergens, independent of percent body fat. Longitudinal studies are needed to further determine the temporal and causal relationships. If short sleep duration indeed is one of the risk factors for allergic sensitization, the global burden of allergic diseases could be dramatically reduced by providing appropriate guidance on sleep duration for youth. PMID- 21255142 TI - The CC16 A38G polymorphism is associated with the development of asthma in children with allergic rhinitis. AB - BACKGROUND: Although asthma and allergic rhinitis (AR) are considered to be one syndrome, many questions remain unanswered. Why do some AR patients develop asthma but others do not, and which factors play a role in the development of asthma that have so far not been clearly elucidated. OBJECTIVE: We hypothesize that children with AR who have the Clara cell secretory protein (CC16, secretoglobin 1A1) 38A/38A genotype (rs3741240) have an increased likelihood of developing asthma. METHODS: The study sample included 117 children, with AR, but no asthma diagnosed within the following 5 years, as the control group. Cases group (n=202) included age- and gender-matched children with AR first, and asthma developed 3-5 years later, as the study group. The CC16 genotype was determined by PCR and Sau96I restriction digestion of PCR products. The serum CC16 levels were measured by ELISA. Total serum IgE, allergen specific IgE, eosinophil count and pulmonary function were also measured. RESULTS: In children with rhinitis who develop asthma, the frequencies of the AA genotype were significantly higher than those who did not develop asthma [odds ratio (OR)=2.527; 95% confidence interval (CI)=1.571-4.065; P<0.01]. Serum CC16 levels in the children with rhinitis who develop asthma and carry the AA genotype were significantly lower than those who carry the non-AA genotype and those who did not develop asthma. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study suggest that CC16 38A/38A genotype plays a role in the development of early asthma in children with AR. Early identification of rhinitis children at risk may assist in designing preventative approach to asthma development. PMID- 21255143 TI - Effects of the cyclin-dependent kinase inhibitor R-roscovitine on eosinophil survival and clearance. AB - BACKGROUND: Eosinophils are pro-inflammatory cells implicated in the pathogenesis of asthma and atopy. Apoptosis has been proposed as a potential mechanism underlying the resolution of eosinophilic inflammation and studies have indicated the ability of interventions that induce human eosinophil apoptosis to promote the resolution of eosinophilic inflammation. Recently, the cyclin-dependent kinase (CDK) inhibitor R-roscovitine was shown to enhance neutrophil apoptosis and promote the resolution of neutrophilic inflammation. OBJECTIVE: The purpose of this study was to examine the expression of CDKs in human blood eosinophils, the effects of R-roscovitine on eosinophil survival in vitro and whether R roscovitine could influence eosinophilic lung inflammation in vivo. METHODS: Eosinophils were isolated from human peripheral blood and the effects of R roscovitine on apoptosis, degranulation and phagocytic uptake examined in vitro. The effects of R-roscovitine on eosinophilic lung inflammation in vivo were also assessed using an ovalbumin mouse model. RESULTS: Our data demonstrate that human eosinophils express five known targets for R-roscovitine: CDK1, -2, -5, -7 and 9. R-roscovitine induced eosinophil apoptosis in a time- and concentration dependent manner but also accelerated transition to secondary necrosis as assessed by microscopy, flow cytometry and caspase activation. In addition, we show that R-roscovitine can override the anti-apoptotic signals of GM-CSF and IL 5. We report that the pro-apoptotic effect of R-roscovitine is associated with suppression of Mcl-1L expression and that this compound enhanced phagocytic clearance of eosinophils by macrophages. Finally, we show that R-roscovitine induces apoptosis in murine peripheral blood and spleen-derived eosinophils; despite this, R-roscovitine did not modulate the tissue and lumen eosinophilia characteristic of the ovalbumin mouse model of airway eosinophilia. CONCLUSION AND CLINICAL RELEVANCE: These data demonstrate that R-roscovitine is capable of inducing rapid apoptosis and secondary necrosis in eosinophils but does not affect the onset or improve the resolution of eosinophilic airway inflammation in vivo. PMID- 21255145 TI - Circumcision. PMID- 21255144 TI - Skin-homing CD4+ Foxp3+ T cells exert Th2-like function after staphylococcal superantigen stimulation in atopic dermatitis patients. AB - BACKGROUND: The effect of staphylococcal superantigens (SsAgs) on cutaneous lymphocyte-associated antigen (CLA)(+) CD4(+) Foxp3(+) T cells of atopic dermatitis (AD) patients is unknown. OBJECTIVE: To compare the effects of SsAgs on the ratio, function, and apoptosis of CCR6(+) subtype and CCR6(-) subtype of CLA(+) CD4(+) Foxp3(+) T cells among AD patients, asthma/allergic rhinitis (AR) patients without AD, and healthy subjects. METHODS: Using immunofluorescence staining followed by flow cytometric analysis, we analysed peripheral blood mononuclear cells cultured with or without staphylococcal enterotoxin B (SEB) stimulation in 20 AD patients, 20 asthma/AR patients without AD, and 20 healthy subjects. RESULTS: SEB decreased CCR6(+) /CCR6(-) ratio in CLA(+) CD4(+) Foxp3(+) T cells from AD patients and increased CCR6(+) /CCR6(-) ratio in those from healthy subjects. SEB induced the production of type 2 T helper cell (Th2) cytokine interleukin (IL)-5 in CCR6(-) subtype and anti-inflammatory cytokine IL 10 in CCR6(+) subtype of CLA(+) CD4(+) Foxp3(+) T cells. CLA(+) CD4(+) Foxp3(+) T cells from AD patients produced more IL-5 and less IL-10 after SEB stimulation than those from healthy subjects. CCR6(-) subtype of CLA(+) CD4(+) Foxp3(+) T cells from AD patients and CCR6(+) subtype of those cells from healthy subjects were more resistant to SEB-induced caspase-3 activation than the other subtype and those from other subjects. CONCLUSIONS AND CLINICAL RELEVANCE: Despite a phenotype of regulatory T cells, skin-homing CD4(+) Foxp3(+) T cells of AD patients exert effector Th2-like function after SsAgs stimulation, which may aggravate allergic skin inflammation. PMID- 21255146 TI - Multiple asymptomatic facial papules. PMID- 21255149 TI - Vaccines for the poor: meningococcal A conjugate vaccine in Africa. PMID- 21255150 TI - Neonatal stability following transfer from tertiary centres. PMID- 21255151 TI - Bilateral macular atrophy and papillomacular myelinated nerve fibre. PMID- 21255152 TI - Re: what's in a name by isaacs d 2009 and children's nomenclatural adventurism and medical evaluation study by Willis F R et Al. 2009. PMID- 21255153 TI - A case of impacted watermelon seed rectal bezoar in a 12-year-old girl. PMID- 21255154 TI - Comment: out of the mouths of babes. PMID- 21255155 TI - Comment: out of the mouths of babes. PMID- 21255156 TI - A differential role for ceramide kinase in antigen/FcERI-mediated mast cell activation and function. AB - BACKGROUND: Mast cells are specialized secretory cells releasing multiple inflammatory mediators when activated. Activation requires antigen/IgE cross linking of FcERI receptors, initiating a complex intracellular signalling cascade. Ceramide kinase (CERK) is a novel lipid kinase implicated in several inflammatory cellular signalling processes. OBJECTIVE: We sought to investigate a role for CERK in FCERI/IgE-mediated mast-cell activation. METHODS: The rat and human mast cell-lines RBL-2H3 and LAD-2, respectively, were stimulated via FcERI or with the active product of CERK [ceramide-1-phosphate (C-1P)]. Multiple end points were measured by enzyme-linked immunosorbent assay; histamine (pre-formed early-phase mediator), prostaglandin D2 (PGD2 - rapidly metabolized early-phase mediator) and interleukin (IL) -13 (de novo transcribed late-phase mediator). RESULTS: We demonstrated that C-1P alone induced release of histamine and PGD2 and was additive to antigen-mediated activation. C-1P did not stimulate IL-13 by a statistically significant amount. Using a specific inhibitor of CERK, antigen mediated release of histamine and PGD2 was significantly inhibited. Finally, we identified that, for histamine, CERK was downstream of spleen tyrosine kinase, phosphoinositol-3 kinases and phospholipase C, but upstream of c-jun N-terminal kinase (JNK); while for PGD2 CERK was positioned upstream of JNK, mitogen activated protein kinase kinase and cyclooxygense. CONCLUSIONS AND CLINICAL RELEVANCE: We have identified a differential role for CERK in mast-cell activation and begun to elucidate its position in the mast cell-signalling cascade, thereby suggesting a model by which CERK may be mediating its effects. This type of study is essential for complete understanding of activation pathways that may eventually be used to identify new targets for drug discovery in inflammatory diseases. PMID- 21255157 TI - The Hapten-Atopy hypothesis II: the 'cutaneous hapten paradox'. AB - One explanation for the striking increase in atopic disease in developed countries over the last 50 years has been the 'Hygiene Hypothesis'; a reduced exposure to pathogenic microorganisms. We have postulated previously that oral and cutaneous exposure to chemicals generally and to haptens in particular, may have also contributed to the increased prevalence of atopic disease; the 'Hapten Atopy Hypothesis'. The purpose here is to extend further that hypothesis by consideration of the impact interplay between the innate and adaptive immune systems may have on the development of atopic allergy. It is clear that experimental cutaneous exposure to hapten can generate immune responses of different types with regard to T-helper (Th) cell phenotype. Allergic contact dermatitis is frequently associated with a selective Th1 (and Tc1)-driven inflammation, whereas atopic dermatitis is characterized by preferential Th2 cell responses. We postulate here that initial innate immune responses to chemical haptens result in the promotion of Th1 cell responses secondary to stimulation of Toll-like receptor. However, we argue also that under conditions where there is prolonged skin exposure to hapten there will be a shift of Th cell phenotype to selective Th2-type responses. The significance of such interactions is the possibility that repeated low-level skin exposure to certain types of hapten may result in the creation of an immunological environment in which the development of Th2 immune responses to third party antigens is favoured. The hypothesis is advanced that the nature and conditions of skin exposure to common haptens may impact on the quality of cutaneous immune responses such that in some circumstances the development atopic disease is favoured. PMID- 21255159 TI - Specific immunotherapy in asthma: efficacy and safety. AB - The use of specific immunotherapy (SIT) to treat asthma has been, and still is, a matter of debate, and there are no clear or unequivocal indications in the official documents. This is partly due to the fact that there are few studies specifically designed to assess asthma, that none of such studies had a formal sample size calculation, and that objective parameters of pulmonary function have been assessed only sporadically. Nonetheless, there are good quality studies for both subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) where asthma symptoms were evaluated, and showing positive results. Moreover, several favourable meta-analyses are available, although their validity is limited by the great heterogeneity of the trials included. The disease modifying effect of SIT, that is the capacity of preventing asthma onset should be also taken into account. Concerning the safety, fatalities seem to be an exceptional event and in Europe no fatality has been reported over the last two decades. Uncontrolled asthma is universally recognized as the most important risk factor for severe adverse events. In conclusion both SLIT and SCIT can be used in asthma associated with rhinitis (which is the most common condition), provided that asthma is adequately controlled by pharmacotherapy. In such case, a measurable clinical benefit on asthma symptoms can be expected. On the other hand, SIT cannot be presently recommended as single therapy when asthma is the unique manifestation of respiratory allergy. PMID- 21255158 TI - Bone marrow stromal cells inhibit mast cell function via a COX2-dependent mechanism. AB - BACKGROUND: Mast cells (MCs) have a central role in the induction of allergic inflammation, such as seen in asthma, and contribute to the severity of certain autoimmune diseases, such as rheumatoid arthritis. The MC thus represents an important inflammatory cell, and one which has resisted therapeutic attempts to alter its role in disease. OBJECTIVE: Because bone marrow-derived stromal cells (BMSC, also known as mesenchymal stem cells or MSCs) have been reported to alter allergic inflammation in vivo, we chose to study the interaction between mouse BMSC and mouse bone marrow-derived MCs. METHODS: MC degranulation, cytokine production and chemotaxis were evaluated in vitro following co-culture with BMSCs either in cell contact or a transwell. In addition, MC degranulation was assessed in vivo following administration of BMSCs in a model of passive cutaneous anaphylaxis and a peritoneal degranulation assay. Mechanisms of MC suppression by BMSCs were determined through use of inhibitors or antibodies to COX1, COX2, nitric oxide, indoleamine 2, 3-dioxygenase, EP1-4 receptors, TGF-beta and IL-10. Lastly, we utilized either BMSCs or MCs deficient in COX1, COX2 or EP1-4 receptors to confirm the mechanisms of inhibition of MC function by BMSCs. RESULTS: We discovered that BMSCs will effectively suppress specific MC functions in vitro as well as in vivo. When MCs are cocultured with BMSCs to allow cell-to cell contact, BMSCs suppressed MC degranulation, pro-inflammatory cytokine production, chemokinesis and chemotaxis. Similarly, MC degranulation within mouse skin or the peritoneal cavity was suppressed following in vivo administration of BMSCs. Further, we found that these inhibitory effects were dependent on up regulation of COX2 in BMSCs; and were facilitated through the activation of EP4 receptors on MCs. CONCLUSION AND CLINICAL RELEVANCE: These observations support the concept that BMSCs have the ability to suppress MC activation and therefore could be the basis for a novel cell based therapeutic approach in the treatment of MC driven inflammatory diseases. PMID- 21255160 TI - Large performance variation does not affect outcome in the Finnish cervical cancer screening programme. AB - OBJECTIVE: Cytology screening for prevention of cervical cancer can reduce incidence and mortality by more than 80% in settings with good organization and rigorous quality control. Audit studies are essential for reaching and maintaining a high quality of screening. The aim of this study was to evaluate variation in performance indicators by screening laboratory and assess the impact on the effectiveness of screening as indicated by cervical intraepithelial neoplasia grade 3 and above (CIN3+) rates after a negative screen. METHODS: Seven cytology screening laboratories operating during 1990-1999 with a total of 953 610 screening tests performed were included in the study. By linking screening and cancer register files, all cases of CIN3+ diagnosed in the screened population were identified. For 395 CIN3+ cases with a preceding negative screen and 787 controls, a re-evaluation of smears was undertaken to uncover false negative screening tests. Performance parameters and rates of CIN3+ after a negative screen were analysed for interlaboratory heterogeneity. RESULTS: The rates of follow-up recommendations and referrals varied by up to 3.6- (2.8-10.2%) and 4.0-fold (0.03-0.12%), respectively. CIN1, CIN2 and CIN3+ screen detection rates differed by up to 8.5- (0.02-0.17%), 5.4- (0.05-0.25%) and 3.3-fold (0.05 0.18%). False negative rates determined by re-evaluation showed up to 2.1-fold differences (29-62%). Rates of CIN3+ after a negative screen (0.023-0.048%) and as a proportion of total CIN3+ (15-31%) in the screened population were low and did not vary significantly. CONCLUSIONS: There were large variations in the sensitivity-specificity trade-off between laboratories, reflected in all performance indicators as well as in the test validity estimates of the re evaluation phase, but not in screening effectiveness. Even though performance variations do not always have an impact on the effectiveness of screening, they lead to variations in cost, treatment and psychological burden, and should be addressed. PMID- 21255161 TI - Light inputs shape the Arabidopsis circadian system. AB - The circadian clock is a fundamental feature of eukaryotic gene regulation that is emerging as an exemplar genetic sub-network for systems biology. The circadian system in Arabidopsis plants is complex, in part due to its phototransduction pathways, which are themselves under circadian control. We therefore analysed two simpler experimental systems. Etiolated seedlings entrained by temperature cycles showed circadian rhythms in the expression of genes that are important for the clock mechanism, but only a restricted set of downstream target genes were rhythmic in microarray assays. Clock control of phototransduction pathways remained robust across a range of light inputs, despite the arrhythmic transcription of light-signalling genes. Circadian interactions with light signalling were then analysed using a single active photoreceptor. Phytochrome A (phyA) is expected to be the only active photoreceptor that can mediate far-red (FR) light input to the circadian clock. Surprisingly, rhythmic gene expression was profoundly altered under constant FR light, in a phyA-dependent manner, resulting in high expression of evening genes and low expression of morning genes. Dark intervals were required to allow high-amplitude rhythms across the transcriptome. Clock genes involved in this response were identified by mutant analysis, showing that the EARLY FLOWERING 4 gene is a likely target and mediator of the FR effects. Both experimental systems illustrate how profoundly the light input pathways affect the plant circadian clock, and provide strong experimental manipulations to understand critical steps in the plant clock mechanism. PMID- 21255162 TI - Metabolomics data reveal a crucial role of cytosolic glutamine synthetase 1;1 in coordinating metabolic balance in rice. AB - Rice plants grown in paddy fields preferentially use ammonium as a source of inorganic nitrogen. Glutamine synthetase (GS) catalyses the conversion of ammonium to glutamine. Of the three genes encoding cytosolic GS in rice, OsGS1;1 is critical for normal growth and grain filling. However, the basis of its physiological function that may alter the rate of nitrogen assimilation and carbon metabolism within the context of metabolic networks remains unclear. To address this issue, we carried out quantitative comparative analyses between the metabolite profiles of a rice mutant lacking OsGS1;1 and its background wild type (WT). The mutant plants exhibited severe retardation of shoot growth in the presence of ammonium compared with the WT. Overaccumulation of free ammonium in the leaf sheath and roots of the mutant indicated the importance of OsGS1;1 for ammonium assimilation in both organs. The metabolite profiles of the mutant line revealed: (i) an imbalance in levels of sugars, amino acids and metabolites in the tricarboxylic acid cycle, and (ii) overaccumulation of secondary metabolites, particularly in the roots under a continuous supply of ammonium. Metabolite-to metabolite correlation analysis revealed the presence of mutant-specific networks between tryptamine and other primary metabolites in the roots. These results demonstrated a crucial function of OsGS1;1 in coordinating the global metabolic network in rice plants grown using ammonium as the nitrogen source. PMID- 21255163 TI - Nicotiana benthamiana resistance to non-adapted Melon necrotic spot virus results from an incompatible interaction between virus RNA and translation initiation factor 4E. AB - Nicotiana benthamiana has been described as non-host for Melon necrotic spot virus (MNSV). We investigated the basis of this resistance using the unique opportunity provided by strain MNSV-264, a recombinant virus that is able to overcome the resistance. Analysis of chimeric MNSV mutants showed that virulence in N. benthamiana is conferred by a 49 nucleotide section of the MNSV-264 3'-UTR, which acts in this host as a cap-independent translational enhancer (3'-CITE). Although the 3'-CITE of non-adapted MNSV-Malpha5 is active in susceptible melon, it does not promote efficient translation in N. benthamiana, thus preventing expression of proteins required for virus replication. However, MNSV-Malpha5 gains the ability to multiply in N. benthamiana cells if eIF4E from a susceptible melon variety (Cm-eIF4E-S) is supplied in trans. These data show that N. benthamiana resistance to MNSV-Malpha5 results from incompatibility between the MNSV-Malpha5 3'-CITE and N. benthamiana eIF4E in initiating efficient translation of the viral genome. Therefore, non-host resistance conferred by the inability of a host susceptibility factor to support viral multiplication may be a possible mechanism for this type of resistance to viruses. PMID- 21255164 TI - The Arabidopsis Myb genes MYR1 and MYR2 are redundant negative regulators of flowering time under decreased light intensity. AB - Changes in the duration, quality and intensity of light affect flowering time. Compared with the effects of light duration and quality, less is known about the effects of light intensity on flowering. Here we describe two paralogous single Myb domain genes, MYB-RELATED PROTEIN 1 (MYR1) and MYB-RELATED PROTEIN 2 (MYR2), and their roles as repressors of responses to decreased light intensity in Arabidopsis. Homozygous myr1 myr2 double mutants flowered early under low light intensities. Additionally, myr1 myr2 mutants exhibited increases in petiole length, leaf angle and apical dominance. Genetic analyses involving mutants in the long-day, gibberellin (GA) and phyB flowering pathways indicated that all aspects of the myr1 myr2 phenotype required GA biosynthesis. The early-flowering phenotype of myr1 myr2 also required FLOWERING LOCUS T, and myr1 myr2 mutants showed an epistatic interaction with the phyB-9 mutant. Over-expression of MYR1 or MYR2 produced GA-deficiency symptoms that were rescued by application of gibberellic acid (GA3). Loss of MYR1 and MYR2 function was associated with a twofold increase in GA20ox2 expression and a 30% increase in GA4 levels, while over-expression of MYR2 led to a threefold decrease in GA20ox2 expression and a 50% decrease in GA4 levels. Considered together, these results suggest that the ability of MYR1 and MYR2 to repress flowering and organ elongation is at least partly due to their negative effect on levels of bioactive GA. PMID- 21255165 TI - Functional characterization of the CKRC1/TAA1 gene and dissection of hormonal actions in the Arabidopsis root. AB - Cytokinin (CK) influences many aspects of plant growth and development, and its function often involves intricate interactions with other phytohormones such as auxin and ethylene. However, the molecular mechanisms underlying the role of CK and its interactions with other growth regulators are still poorly understood. Here we describe the isolation and characterization of the Arabidopsis CK-induced root curling 1 (ckrc1) mutant. CKRC1 encodes a previously identified tryptophan aminotransferase (TAA1) involved in the indole-3-pyruvic acid (IPA) pathway of indole-3-acetic acid (IAA) biosynthesis. The ckrc1 mutant exhibits a defective root gravitropic response (GR) and an increased resistance to CK in primary root growth. These defects can be rescued by exogenous auxin or IPA. Furthermore, we show that CK up-regulates CKRC1/TAA1 expression but inhibits polar auxin transport in roots in an AHK3/ARR1/12-dependent and ethylene-independent manner. Our results suggest that CK regulates root growth and development not only by down-regulating polar auxin transport, but also by stimulating local auxin biosynthesis. PMID- 21255166 TI - A fast brassinolide-regulated response pathway in the plasma membrane of Arabidopsis thaliana. AB - To understand molecular processes in living plant cells, quantitative spectro microscopic technologies are required. By combining fluorescence lifetime spectroscopy with confocal microscopy, we studied the subcellular properties and function of a GFP-tagged variant of the plasma membrane-bound brassinosteroid receptor BRI1 (BRI1-GFP) in living cells of Arabidopsis seedlings. Shortly after adding brassinolide, we observed BRI1-dependent cell-wall expansion, preceding cell elongation. In parallel, the fluorescence lifetime of BRI1-GFP decreased, indicating an alteration in the receptor's physico-chemical environment. The parameter modulating the fluorescence lifetime of BRI1-GFP was found to be BL induced hyperpolarization of the plasma membrane. Furthermore, for induction of hyperpolarization and cell-wall expansion, activation of the plasma membrane P ATPase was necessary. This activation required BRI1 kinase activity, and was mediated by BL-modulated interaction of BRI1 with the P-ATPase. Our results were used to develop a model suggesting that there is a fast BL-regulated signal response pathway within the plasma membrane that links BRI1 with P-ATPase for the regulation of cell-wall expansion. PMID- 21255167 TI - Patient safety culture: an Italian experience. AB - AIMS: To understand what level of awareness health professionals working in a hospital of Northern Italy had of the patient safety culture by using the Italian version of the Hospital Survey on Patient Safety Culture questionnaire and also validate its use in this setting. BACKGROUND: The Hospital Survey on Patient Safety Culture questionnaire was developed by the Agency for Health Research and Quality in 2008 and validated by several studies. Therefore, we decided to test the Italian version of this tool to see if it could be used effectively to measure and appraise patient safety culture also in Italy. DESIGN: Survey. METHODS: To check the validity of the questionnaire, we applied the continued comparison and the global data treatment methods. RESULTS: Of the 1008 questionnaires we administered, 724 (71%) were returned. The majority of the questions were answered (mean 98, SD 3.4%). From a Chi-square test on the consistency of the answers, we found that six of the 12 perspectives we explored had a high level of significance, whereas in the other six, the differences in the answers were just casual. CONCLUSIONS: The Italian version of the Hospital Survey on Patient Safety Culture questionnaire allowed us to assess health professionals' awareness of patient safety culture and thus validate the effectiveness of this tool. RELEVANCE TO CLINICAL PRACTICE: The findings of our survey could be useful to design an objective tool that would allow the five health professional groups involved in the study (directors/coordinators, physicians, nurses/midwives, physiotherapists and technicians) gain a better knowledge of the patient safety culture and thus improve the quality of clinical practice. PMID- 21255168 TI - Knowledge of and attitude to contraception among migrant woman workers in mainland China. AB - AIMS: The aims of this paper were to determine the level of knowledge and attitude of contraception and their relationships among Chinese migrant woman workers. BACKGROUND: Studies on psychosocial variables that lead to reproductive health behaviours among Chinese migrant woman workers in China remain limited. DESIGN: A cross-sectional, descriptive and correlational design. PARTICIPANTS: One hundred and ninety young woman workers of a factory in Guangdong, a representative city of factory base in mainland China, voluntarily participated in the study with a response rate of 63%. METHODS: Data were collected through self-administered questionnaires consisting of a socio-demographic sheet, the Contraceptive Knowledge Scale and the Contraceptive Attitude Scale. Pearson product moment correlation coefficient test was employed to examine the relationships between the contraceptive knowledge and attitude, with level of significance set at p<0.05. RESULTS: The Chinese migrant woman workers demonstrated lower contraceptive knowledge and less favourable contraceptive attitude compared with previous studies of adolescents in Taiwan and women seeking abortion in Hong Kong. Although it was a weak correlation, contraceptive knowledge was statistically associated with contraceptive attitudes among the respondents (r=0.276, p<0.001). Respondents' age, education level and working experience were significantly positively correlated with the contraceptive knowledge. CONCLUSIONS: Young Chinese migrant workers reported in the current study are found to be at higher sexual risk, when compared to the adolescents in Taiwan and Hong Kong women seeking abortion. Early educational intervention for reproductive health in particular contraception and its usage to these young women is indicated. RELEVANCE TO CLINICAL PRACTICE: Migrant woman workers in mainland demonstrated poor knowledge and unfavourable attitudes towards contraception, especially for the younger, single and less educated group. Greater effort is necessary to promote young migrant women's knowledge and attitude towards contraception and sexual health. PMID- 21255169 TI - How do insects react to novel inherited symbionts? A microarray analysis of Drosophila melanogaster response to the presence of natural and introduced Spiroplasma. AB - Maternally inherited endosymbionts are found in numerous insect species and have various effects on host ecology. New symbioses are most commonly established following lateral transfer of an existing symbiont from one host species to another. Laboratory study has demonstrated that symbionts commonly perform poorly in novel hosts, with weak vertical transmission and maladaptive pathogenicity being observed in the generations following transfer. This poor performance probably limits symbiont occurrence. We here use microarray technology to test whether poor symbiont performance observed following 1 year of vertical transmission through a new host is associated with alteration in host gene expression or whether it occurs independently of this. We utilize the Drosophila melanogaster--Spiroplasma interaction and test the response of the host in the presence of both natural Spiroplasma infections and novel Spiroplasma infections transinfected previously from other host species. None of the Spiroplasma infections investigated produced upregulation in host haemolymph/fat body-based immune responses, and we therefore rejected the hypothesis that failure to thrive was associated with immune upregulation. One infection was associated with a downregulation of genes associated with egg production compared to uninfected controls, indicative of damage to the host. The Spiroplasma infection showed that the weakest vertical transmission showed no significant disturbance to host gene expression compared to uninfected controls. We conclude that the failure of Spiroplasma in novel host species is associated either with causing harm to their new hosts or through a failure to thrive in the new host that occurs independently of host responses to infection. PMID- 21255170 TI - Intraspecific specialization of the generalist parasitoid Cotesia sesamiae revealed by polyDNAvirus polymorphism and associated with different Wolbachia infection. AB - As a result of an intense host-parasite evolutionary arms race, parasitic wasps frequently display high levels of specialization on very few host species. For instance, in braconid wasps very few generalist species have been described. However, within this family, Cotesia sesamiae is a generalist species that is widespread in sub-Saharan Africa and develops on several lepidopteran hosts. In this study, we tested the hypothesis that C. sesamiae may be a cryptic specialist when examined at the intraspecific level. We sequenced exon 2 of CrV1, a gene of the symbiotic polyDNAvirus that is integrated into the wasp genome and is associated with host immune suppression. We found that CrV1 genotype was more closely associated with the host in which the parasitoid developed than any abiotic environmental factor tested. We also tested a correlation between CrV1 genotype and an infection with Wolbachia bacteria, which are known for their ability to induce reproductive isolation. The Wolbachia bacteria infection polymorphism was also found as a major factor explaining the genetic structure of CrV1, and, in addition, the best model explaining CrV1 genetic structure involved an interaction between Wolbachia infection and host species. We suggest that Wolbachia could act as an agent capable of maintaining advantageous alleles for host specialization in different populations of C. sesamiae. This mechanism could be applicable to other insect models because of the high prevalence of Wolbachia in insects. PMID- 21255171 TI - Transcriptional plasticity of a soil arthropod across different ecological conditions. AB - Ecological functional genomics, dealing with the responses of organisms to their natural environment is confronted with a complex pattern of variation and a large number of confounding environmental factors. For gene expression studies to provide meaningful information on conditions deviating from normal, a baseline or normal operating range (NOR) response needs to be established which indicates how an organism's transcriptome reacts to naturally varying ecological factors. Here we determine the transcriptional plasticity of a soil arthropod, Folsomia candida, exposed to various natural environments, as part of a first attempt in establishing such a NOR. Animals were exposed to 26 different field soils after which gene expression levels were measured. The main factor found to regulate gene expression was soil-type (sand or clay). Cell homeostasis and DNA replication were affected in collembolans exposed to sandy soil, indicating general stress. Multivariate analysis identified soil fertility as the main factor influencing gene expression. Regarding land-use, only forest soils showed an expression pattern deviating from the others. No significant effect of land use, agricultural practice or soil type on fitness was observed, but arsenic concentration was negatively correlated with reproductive output. In conclusion, transcriptional responses remained within a limited range across the different land-uses but were significantly affected by soil-type. This may be caused by the contrasting soil physicochemical properties to which F. candida strongly responds. The broad range of conditions over which this soil-living detritivore is able to survive and reproduce, indicates a strategy of high plasticity, which comes with extensive gene expression regulation. PMID- 21255172 TI - Spatial patterns of plant diversity below-ground as revealed by DNA barcoding. AB - Our understanding of the spatial organization of root diversity in plant communities and of the mechanisms of community assembly has been limited by our ability to identify plants based on root tissue, especially in diverse communities. Here, we test the effectiveness of the plastid gene rbcL, a core plant DNA barcoding marker, for investigating spatial patterns of root diversity, and relate observed patterns to above-ground community structure. We collected 3800 root fragments from four randomly positioned, 1-m-deep soil profiles (two vertical transects per plot), located in an old-field community in southern Ontario, Canada, and extracted and sequenced DNA from 1531 subsampled fragments. We identified species by comparing sequences with a DNA barcode reference library developed previously for the local flora. Nearly 85% of sampled root fragments were successfully sequenced and identified as belonging to 29 plant species or species groups. Root abundance and species richness varied in horizontal space and were negatively correlated with soil depth. The relative abundance of taxa below-ground was correlated with their frequency above-ground (r = 0.73, P = 0.0001), but several species detected in root tissue were not observed in above ground quadrats. Multivariate analyses indicated that diversity was highly structured below-ground, and associated with depth, root morphology, soil chemistry and soil texture, whereas little structure was evident above-ground. Furthermore, analyses of species co-occurrence indicates strong species segregation overall but random co-occurrence among confamilials. Our results provide insights into the role of environmental filtering and competitive interactions in the organization of plant diversity below-ground, and also demonstrate the utility of barcoding for the identification of plant roots. PMID- 21255173 TI - Mycorrhizal specificity in the fully mycoheterotrophic Hexalectris Raf. (Orchidaceae: Epidendroideae). AB - Mycoheterotrophic species have abandoned an autotrophic lifestyle and obtain carbon exclusively from mycorrhizal fungi. Although these species have evolved independently in many plant families, such events have occurred most often in the Orchidaceae, resulting in the highest concentration of these species in the tracheophytes. Studies of mycoheterotrophic species' mycobionts have generally revealed extreme levels of mycorrhizal specialization, suggesting that this system is ideal for studying the evolution of mycorrhizal associations. However, these studies have often investigated single or few, often unrelated, species without consideration of their phylogenetic relationships. Herein, we present the first investigation of the mycorrhizal associates of all species of a well characterized orchid genus comprised exclusively of mycoheterotrophic species. With the employment of molecular phylogenetic methods, we identify the fungal associates of each of nine Hexalectris species from 134 individuals and 42 populations. We report that Hexalectris warnockii associates exclusively with members of the Thelephoraceae, H. brevicaulis and H. grandiflora associate with members of the Russulaceae and Sebacinaceae subgroup A, while each member of the H. spicata species complex associates primarily with unique sets of Sebacinaceae subgroup A clades. These results are consistent with other studies of mycorrhizal specificity within mycoheterotrophic plants in that they suggest strong selection within divergent lineages for unique associations with narrow clades of mycorrhizal fungi. Our results also suggest that mycorrhizal associations are a rapidly evolving characteristic in the H. spicata complex. PMID- 21255174 TI - How much can parentage analyses tell us about precapture dispersal? AB - Estimating rates of movement among populations is never simple, and where young animals cannot all be captured at their birth sites, traditional field methods potentially underestimate dispersal rates. Genetic assignment tests appear to hold promise for detecting 'precapture' dispersal, and recent evidence suggests that even on the scale of dispersal between populations, genetic parentage analyses can also be informative. Herein, we examine the performance of both types of analysis with data from a 17-year study of dispersal in banner-tailed kangaroo rats Dipodomys spectabilis. We compare estimates of precapture dispersal from (i) the commonly used parentage analysis program cervus (ii) a pedigree reconstruction program, MasterBayes, that combines genetic with spatial and other nongenetic information and (iii) genetic assignment procedures implemented by the program geneclass2, with (iv) rates of dispersal observed through recapture of a subset of animals initially marked shortly after weaning. geneclass2 estimates a larger proportion of precapture dispersers than MasterBayes, but both approaches as well as those based on field data alone, suggest that approximately 10% of adults in local populations are immigrants and that interpopulation dispersal is slightly female-biassed. All genetic procedures detect precapture dispersal between populations, but dispersers identified by MasterBayes are particularly compatible with what is independently known about body mass at dispersal, dispersal distance and distance between parents. Parentage analyses have considerable potential to infer the value of this otherwise elusive demographic parameter when most candidate parents can be genotyped and when nongenetic information, especially the distance separating candidate mothers and fathers, can be incorporated into the procedure. PMID- 21255175 TI - Effects of adult familiarity on social behaviours in Angelman syndrome. AB - BACKGROUND: Individuals with Angelman syndrome appear strongly motivated by social contact, but there have been few studies that have examined the relationship between sociability and familiarity. In this study we compared social behaviour in Angelman syndrome when in contact with mothers and strangers. METHODS: We systematically manipulated adult familiarity, eye contact and speech to examine the effect on social approach behaviours in children with Angelman syndrome. Eleven children (deletion 15q11-13) participated and were observed during interactions with their mother and an unfamiliar adult, while adult eye contact and talking were manipulated. Laughing and smiling, looking and social approach were observed. RESULTS: There was no effect of familiarity on laughing and smiling or eye contact. Participants showed more social approach towards their mother than the unfamiliar adult but only when their mother was looking at them. CONCLUSIONS: In Angelman syndrome, looking at adults, laughing and smiling appear to be unaffected by the familiarity of the adult. However, approach behaviours are more common with mothers than strangers. The function of the approach behaviours might be to increase investment from the primary caregiver. PMID- 21255176 TI - Colour, design and reward: phenotypic integration of fleshy fruit displays. AB - The functional or structural linkage among traits [phenotypic integration (PI)] within complex structures can constrain the evolutionary response of individual traits. To analyse whether frugivores with distinct sensory ecology have shaped the patterns of fruit diversification differently, we compared PI values of fleshy fruits that are consumed by birds and mammals. We used phylogenetic comparative analyses of PI among 13 morphological, nutritional and visual fruit traits from 111 Mediterranean plant species. Results showed that morphological traits had higher PI values than nutritional and colour traits. Visual and nutritional traits show positive phylogenetic covariance, while negative covariation occurs between fruits size and nutrients. Importantly, fruits consumed by birds were relatively more integrated than fruits consumed partly or solely by mammals. Hence, we show that major groups of mutualistic frugivores can shape the covariance among some fruit traits differently and thereby influence fruit diversification. PMID- 21255177 TI - Relationships among morphology, clinging performance and habitat use in Liolaemini lizards. AB - The central tenet of ecomorphological theory holds that different ecological requirements lead to different organismal designs (morphology). Here, we studied the relationships between performance (interlocking grasping) and forelimb morphological traits in species of lizards that exploit different structural habitats in a phylogenetic context. The performance (measured by the maximum force of clinging to substrate) was measured on different substrate types. After phylogenetically informed analyses, we found that arboreal and saxicolous species showed stronger resistance to mechanical traction in all substrates when compared to generalists and sand dweller lizards. These species showed a positive relationship between forelimb dimensions (humerus length and length of claw of toe 5) and maximum force exerted, on the contrary, hand width, claw height (CH) of digits III and IV and claw length of toe 4 showed a negative relationship. In addition, we observed a partial positive correlation between CH and maximal cling force on rough surfaces, but not on smooth surfaces. PMID- 21255178 TI - Bilateral ageusia caused by a unilateral midbrain and thalamic infarction. AB - BACKGROUND: Based upon scarce clinical data in humans and experimental findings in animal studies, it has been postulated that the ascending gustatory projection from the nucleus tractus solitarii courses ipsilaterally through the pons and midbrain to the ipsilateral ventral posteromedial nucleus. Thus, it has been assumed that ischemic lesions affecting the secondary projection gustatory fibers would cause ipsilateral taste disorders. DESCRIPTION OF CASE: We report a case of bilateral ageusia following an acute right midbrain and thalamic infarction affecting the ipsilateral central trigeminal tract and ventral posteromedial nucleus in a right-handed man. CONCLUSION: The present case indicates that, in contrast to animal data, some secondary projection gustatory fibers may cross in humans and consequently unilateral right-sided posterior circulation ischemic lesions can cause bilateral gustatory deficits. PMID- 21255179 TI - Functional MRI of sensory motor cortex: comparison between finger-to-thumb and hand squeeze tasks. AB - BACKGROUND: An important imaging technique that has advanced decision-making for noninvasive preoperative evaluation is functional magnetic resonance imaging (fMRI). Preoperative fMRI imaging based on blood oxygenation level dependent (BOLD) fMRI is routinely used to map a variety of eloquent cortex brain functions such as language, visual, and sensory-motor regions. PURPOSE: The purpose of this study was to evaluate the regional volumes of sensory and motor cortex (SMC) activation by two widely used fMRI motor tasks: a simple hand squeeze (HS) versus a more complex finger-to-thumb (FTT) opposition. METHODS: Ten right-handed (five males; five females) subjects were studied using a block design BOLD fMRI technique at 1.5T. A region of interest analysis was performed in the right and left SMC following a HS and FTT task with the dominant right hand. RESULTS: Results show the total volume of motor and sensory activation for ipsilateral and contralateral areas for the FTT task was statistically larger than the HS task (P= .02). CONCLUSION: Due to the greater degree of activation of the SMC with the FTT task, we suggest use of this task over the HS task if a patient can adequately perform the more complex FTT task. The greater SMC activation using FTT task compared to the HS task was primarily due to an increase in activation in the post-central sensory cortex. There was less lateralization, and therefore a greater degree of bilateral SMC activation, in the FTT task compared to the HS task. These results show the importance of optimization and fMRI task selection for presurgical SMC mapping. PMID- 21255180 TI - The 2007 Model of the Clinical Practice of Emergency Medicine: the 2009 update. PMID- 21255181 TI - Possible involvement of peptidylprolyl isomerase Pin1 in rheumatoid arthritis. AB - The peptidylprolyl isomerase Pin1 is over-expressed in some human diseases including malignancies and chronic inflammatory diseases, this suggests that it contributes to the constitutive activation of certain intracellular signaling pathways that promote cell proliferation and cell invasion. Here, we investigate the possible role of Pin1 in rheumatoid arthritis (RA). Pin1 expression was immunohistochemically analyzed in synovial tissue (ST) obtained from patients with RA and osteoarthritis (OA). To investigate the correlation between Pin1 and motility and proliferation of synovial cells, Pin1 localization was immunohistochemically compared with matrix metalloproteinase (MMP)-1, MMP-3, and proliferating cell nuclear antigen (PCNA). Double immunofluorescent staining for Pin1 and p65 was performed to determine whether Pin1 is involved in nuclear factor kappaB (NF-kappaB) activation in RA-ST. Results showed Pin1 expression was significantly higher in RA-ST than in OA-ST. The expression of MMP-1, MMP-3, and PCNA was also significantly elevated in RA-ST. Double immunofluorescent staining revealed colocalization of Pin1 and p65 in the nuclei of RA-ST. These results suggest that Pin1 may be involved in the pathogenesis of RA binding with p65 to activate the proteins MMP-1, MMP-3, and PCNA. Therefore, Pin1 may play a pivotal role in the pathogenesis of RA. PMID- 21255182 TI - Combined expression of miR-122a, miR-1, and miR-200b can differentiate degraded RNA samples from liver, pancreas, and stomach. AB - The effect of RNA degradation on the diagnostic utility of microRNA has not been systematically evaluated in clinical samples. We asked if the microRNA profile is preserved in degraded RNA samples derived from mouse and human tissue. We selected tissue-specific microRNA candidates from published human microarray data, and validated them using quantitative reverse transcription polymerase chain reaction (QRTPCR) analyses on flash-frozen, normal mouse liver, pancreas, and stomach tissue samples. MiR-122a, miR-1, and miR-200b were identified as tissue-specific, and the 3-microRNA-based QRTPCR could predict the tissue origin for mouse tissue samples that were left at room temperature for 2 h with an accuracy of 91.7%. When we applied this 3-microRNA predictor to clinical specimens with various degree of RNA degradation, the predictor differentiated degraded RNA samples from liver, pancreas, and stomach with an accuracy of 90% (26/29). Expression levels of miR-122a, miR-1, and miR-200b were modestly changed after the extended (2-4 h) storage at room temperature, but the magnitudes of expression changes were small compared to the expression differences between various tissues of origin. This proof-of-principle study demonstrates that RNA degradation due to extended storage at room temperature does not affect the predictive power of tissue-specific microRNA QRTPCR predictor. PMID- 21255183 TI - Centrally located adenocarcinoma with endobronchial polypoid growth: clinicopathological analysis of five cases. AB - Lung adenocarcinomas that exhibit endobronchial polypoid growth and arise from the central portion of the respiratory tree are extremely rare and their clinicopathological features are not well understood. We report the clinicopathological characteristics of five cases of centrally located adenocarcinomas. Histologically, in three cases (cases 1, 2, and 3) the tumor had a papillary, acinar, and solid structure. In the other two cases (cases 4 and 5) histological examination revealed a mucin-filled glandular and cystic structure resembling mucoepidermoid carcinoma, although the lesions lacked a squamoid cell component. Immunohistochemical staining revealed that the tumor cells in all five cases were positive for MUC1 and Cytokeratin 7. The tumor cells in cases 4 and 5 were positive for MUC5AC and MUC6, and the expression pattern in these two cases was similar to that of mucoepidermoid carcinoma of the lung. Our findings allowed us to identify two distinct subtypes of centrally located adenocarcinomas with distinct morphological and immunohistochemical characteristics; these should provide new insight into the pathogenesis of central adenocarcinoma of the lung. PMID- 21255184 TI - Early modulation of gene expression used as a biomarker for chemoprevention in a preclinical model of colon carcinogenesis. AB - By using the rat azoxymethane (AOM)-induced colon carcinogenesis model, which mirrors many clinical features of human colorectal cancer, we examined whether genetic changes occurring early in colonic mucosa are predictive of treatment efficacy. In the present study the administration of the chemopreventive agent lupulone over the course of 7 weeks postinitiation reduced the number of preneoplastic lesions in the colonic mucosa by 50%. At the molecular level we observed the downregulation of genes involved in the inflammatory response, including IL-1beta and TNF-alpha, and of matrix metalloproteinase-7 gene and protein expression. We also observed a substantial upregulation of components of the innate immune system, alpha-defensin-5 and lipocalin 2. Lupulone induced the expression of apoptosis-related genes and caused a reversal of the B-cell lymphoma/leukemia 2 (Bcl-2; antiapoptotic) to Bcl-2 associated X protein (Bax; proapoptotic) transcript and protein ratios (Bcl-2/Bax > 1 in AOM controls and Bcl-2/Bax < 1 in lupulone-treated AOM rats). Here, we identify several target genes that could be considered early biomarkers of colon carcinogenesis and indicative of drug efficacy. PMID- 21255185 TI - Microcystic/reticular schwannoma of the pancreas: a potential diagnostic pitfall. AB - Schwannomas occurring in the pancreatic head are rare benign non-recurring mesenchymal neoplasms and are reported to show classic morphologic features. Herein we report a case of a 62 year old male presenting with a 5 cm mass in the pancreatic head encasing the portal vein and the truncus coeliacus. Preoperative fine needle aspiration revealed malignant tumour cells consistent with a moderately differentiated adenocarcinoma. A Whipple surgery was performed after palliative chemotherapy. Histological evaluation revealed a multinodular unencapsulated tumour with focal infiltration into pancreas parenchyma and a striking microcystic/reticular growth pattern. Anastomosing and intersecting strands of spindle cells with eosinophilic cytoplasm set in a myxoid partly collagenous stroma were observed. The tumour cell nuclei were round oval and tapered and showed inconspicuous small nucleoli. Degenerative nuclear atypia was seen. Mitotic activity was sparse (1/50 HPF). Pleomorphism or necrosis was absent. The tumour cells showed strong nuclear and cytoplasmic positivity for S 100 protein, and focal positivity for glial fibrillary acidic protein. The diagnosis of a microcystic/reticular schwannoma was made. The awareness of and, to some extent, the knowledge about this rare tumour are needed to achieve the correct diagnosis and to avoid confusion, especially with malignant pancreatic neoplasms. PMID- 21255186 TI - Total anomalous pulmonary vein drainage: report of an autopsy case associated with atresia of the common pulmonary vein and left superior pulmonary vein. AB - We describe the clinicopathological features of a case of total anomalous pulmonary vein drainage (TAPVD) associated with atresia of the common pulmonary vein (ACPV). A male Japanese infant born at 37 weeks of gestation demonstrated apnea and severe respiratory acidosis immediately after delivery. The patient died of hypoxemic respiratory failure 6 days after birth despite the initiation of artificial ventilation and administration of a surfactant. Autopsy showed the bilateral inferior pulmonary veins joined with a blind confluence, representing ACPV, accompanied by atresia of the left superior pulmonary vein. Moreover, the anomalous and small right superior pulmonary vein drained into the superior vena cava, consistent with partial and supracardiac type TAPVD. A histological examination of the lungs exhibited diffuse dilation of the lymphatic channels in the peribronchial, interlobular, hilar and focally, subpleural areas. The channels were lined with flattened endothelium which was immunohistochemically positive for D2-40. These findings conformed to a secondary form of pulmonary lymphangiectasis due to the congenital cardiovascular anomalies, including TAPVD and ACPV. To the authors' knowledge, this is the first case of TAPVD associated with ACPV, atresia of left superior pulmonary vein and pulmonary lymphangiectasis. PMID- 21255187 TI - Malignant myoepithelioma of the breast. AB - Malignant myoepithelioma of the breast is rare. A 50-year-old Japanese woman was admitted to our hospital because of a right breast tumor (11 * 10 * 5.5 cm). Core needle biopsy revealed malignant spindle cells. A mastectomy was performed. The tumor consisted of malignant spindle, round, pleomorphic and giant cells with many mitotic figures and necrotic areas. Tumor and osteoclast-like giant cells were scattered. Much lymphovascular permeation was seen. In a few areas, particularly on the tumor periphery, there were merges between the tumor cells and myoepithelial cells of the non-tumorous ducts, as if the tumor emanated from the duct myoepithelium. The tumor was invasive into the skin and pectoral muscle. Immunohistochemically, the tumor cells were diffusely positive for vimentin, CD10, alpha-smooth muscle antigen, and Ki-67 (labeling = 95%). The significant areas of the tumor were positive for S100 protein, p63, p53, CD68, caldesmon, desmin and TGFbeta1. A few areas were positive for pancytokeratin (AE1/3), cytokeratin (CK) 5/6, and CK 34betaE12. In contrast, the tumor cells were negative for pancytokeratins (WSS, CAM5.2), CK7, CK8, CK14, CK18, CK19, CK20, EMA, CEA, bcl-2, myoglobin, CD34, CD56, CD45, HMB45, GFAP, alpha-1-antitrypsin, synaptophysin, estrogen receptor, progesterone receptor, HER2/neu, MUC1, MUC2, MUC5AC and MUC6. The author diagnosed the tumor as malignant myoepithelioma, as myoepithelial markers (C10, p63, S100 protein, alpha-smooth muscle actin, caldesmon) were positive, and also because there was a transition between the tumor cells and myoepithelium of non-tumorous ducts. The grade of the tumor was high. The patient was treated with chemoradiation and was free of disease 5 months after the operation. PMID- 21255188 TI - Duodenal gangliocytic paraganglioma with regional lymph node metastasis and a glandular component. AB - Gangliocytic paraganglioma (GP) is generally considered to be a benign periampullary lesion, although it is unclear whether it should be classified as a hamartoma or as a neoplasm. Here, we present a GP case with lymph node metastasis. A 16-year-old boy complained of exertional dyspnea. Upper endoscopy and imaging studies revealed a polypoid ampullary tumor. Pancreaticoduodenectomy with lymph node dissection was performed due to swelling of peripancreatic lymph nodes. Histologically, the tumor consisted of three cell types: epithelioid; spindle; and ganglion cells. In addition to these typical components of GP, a distinct glandular component was also present. There was substantial invasion of tumor cells into the lymphovascular vessels, associated with lymph node metastases. These lymph node metastases were histologically similar to the primary tumor. To judge from these findings GP may be a true neoplasm with metastatic capacity. Pre- and intraoperative investigations for lymph node or distant metastases are required for adequate resection of this kind of tumor. PMID- 21255190 TI - Hypoglycemic/hypoxic condition in vitro mimicking the tumor microenvironment markedly reduced the efficacy of anticancer drugs. AB - Tumor tissues are often hypoxic because of defective vasculature. We previously showed that tumor tissues are also often deprived of glucose. The efficacy of anticancer drugs is affected by the tumor microenvironment, partly because of the drug delivery and cellular drug resistance; however, the precise mechanisms remain to be clarified. In the present study, we attempted to clarify whether hypoglycemic/hypoxic condition, which mimics the tumor microenvironment, might induce drug resistance, and if it did, to elucidate the underlying mechanisms. Pancreatic cancer-derived PANC-1 cells were treated with serial dilutions of anticancer drugs and incubated in either normoglycemic (1.0 g/L glucose) or hypoglycemic (0 g/L glucose) and normoxic (21% O(2)) or hypoxic (1% O(2) ) conditions. The 50% inhibitory concentration of gemcitabine was 1000 times higher for PANC-1 cells incubated under the hypoglycemic/hypoxic condition than for those incubated under the normoglycemic/normoxic condition. Conventional anticancer drugs target rapidly growing cells, so that non-proliferating or slowly proliferating cells usually show resistance to drugs. Though the cell cycle was delayed, sufficient cellular uptake and DNA incorporation of gemcitabine occurred under the hypoglycemic/hypoxic condition to cause DNA lesions and S-phase arrest. To overcome hypoglycemic/hypoxia-induced drug resistance, we examined kinase inhibitors targeting Chk1 or cell-survival signaling pathways. Among the compounds examined, the combination of UCN-01 and LY294002 partially sensitized the cells to gemcitabine under the hypoglycemic/hypoxic condition. These findings suggested that the adoption of suitable strategies may enhance the cytotoxicities of clinically used anticancer drugs against cancer cells. PMID- 21255189 TI - Anti-tumor effect of lentivirus-mediated gene transfer of alphastatin on human glioma. AB - Alphastatin, an endogenous angiogenesis inhibitor, has recently been used as an anticancer agent in several tumor models. This study was to investigate whether local sustained long-term expression of alphastatin could serve to diminish tumor growth of a human xenograft glioma model. We found that the recombinant alphastatin lentiviruses were able to stably infect HUVECs, and infected HUVECs could sustainably secrete alphastatin, which exhibited potent inhibitory effects on HUVECs migration, differentiation but not proliferation induced by vascular endothelial growth factor (VEGF) or basic fibroblast growth factor(bFGF). And the expression of secreted protein alphastatin markedly decreased tumor vascularization and inhibited tumor growth. Additionally, alphastatin inhibited VEGF- or bFGF-induced initial stage of angiogenesis by reducing JNk and ERK phosphorylation in vitro. Taken together, these data demonstrate that secreted protein alphastatin inhibits VEGF- or bFGF-induced angiogenesis by suppressing JNK and ERK kinases activation pathways in HUVECs, and markedly inhibits tumor angiogenesis in vivo. Consequently lentivirus-mediated gene transfer might represent an effective strategy for expression of alphastatin to achieve inhibition of human malignant glioma proliferation and tumor progression. PMID- 21255191 TI - Heterotrimeric stimulatory GTP-binding proteins inhibit cisplatin-induced apoptosis by increasing X-linked inhibitor of apoptosis protein expression in cervical cancer cells. AB - Treatment with cisplatin (cis-dichlorodiammineplatinum (II)) induces DNA double stranded breaks and apoptosis in many human cancer cells. We have reported that heterotrimeric stimulatory GTP-binding proteins (Galphas) can modulate the apoptotic response of several cancer cells. This study investigated the effect of Galphas on apoptosis triggered by cisplatin and its underlying molecular mechanism in cervical cancer cells. Stable expression of constitutively active Galphas (GalphasQL) decreased the release of cytochrome c from the mitochondria to the cytosol and cleavage of caspase-3 and poly(ADP-ribose) polymerases in HeLa cells treated with 30 MUM cisplatin, indicating that Galphas inhibited cisplatin induced apoptosis. Treatment with forskolin also inhibited apoptosis of C33A and CaSKi cervical cancer cells. Expression of GalphasQL increased the expression of the X-linked inhibitor of apoptosis protein (XIAP) and partially maintained increased XIAP after cisplatin treatment. Knockdown of XIAP by siRNA augmented apoptosis. Expression of GalphasQL increased XIAP mRNA; this increase was inhibited by a protein kinase A inhibitor and cAMP response element (CRE) decoy. A cAMP response element (CRE)-like element at -1396 bp in the XIAP promoter was found to mediate the induction of XIAP by Galphas. In addition, expression of GalphasQL protected against the ubiquitin/proteasome-dependent degradation of the XIAP protein. This study shows that Galphas inhibits cisplatin-induced apoptosis by increasing transcription of XIAP and by decreasing degradation of XIAP protein in HeLa cervical cancer cells. PMID- 21255192 TI - The cell cycle regulator Cdh1 controls the pool sizes of hematopoietic stem cells and mature lineage progenitors by protecting from genotoxic stress. AB - Various key cell cycle components, especially G0/G1 regulators, have effects not only on cell proliferation but also on cell differentiation. Cdh1, one of the co activators that maintain anaphase-promoting complex/cyclosome activity, plays a crucial role in the mitotic phase, but has recently been identified as a G0/G1 regulator, suggesting that the role of Cdh1 in cell differentiation. Here, we generated Cdh1 conditional gene-trap mice to examine Cdh1 functions in adult tissues by overcoming the embryonic lethality of Cdh1 homozygous gene-trap mice. We focused on the hematopoietic system and found that Cdh1-deficient mice exhibited a general decrease in mature lineage progenitor cells and a significant increase in short-term hematopoietic stem cells. This phenomenon became conspicuous by irradiation shortly after Cdh1 downregulation, suggesting that Cdh1 regulates the pool sizes of the hematopoietic stem cells and mature lineage progenitor cells by protecting cells from genotoxic stress. We also found that the irradiation-induced G2/M checkpoint was defective in Cdh1-deficient BM cells, causing the loss of stem/progenitor cells. This is the first report revealing Cdh1 function in adult hematopoiesis and showing a role of Cdh1 in a G2/M checkpoint regulation in vivo. PMID- 21255193 TI - Understanding gut-brain interactions in gastrointestinal pain by neuroimaging: lessons from somatic pain studies. AB - BACKGROUND: Neuroimaging research on gut-brain interactions has greatly improved our understanding of the brain mechanisms involved in processing and perceiving visceral pain in health and functional gastrointestinal disorders (FGID). However, discrepancies in the results of these studies continue to exist, which is at least partially due to the fact that important factors contributing to the intrinsic heterogeneity of symptom-based FGID, including psychological processes and psychiatric comorbidity, are insufficiently integrated in visceral pain neuroimaging research. PURPOSE: This review will defend the thesis that, to increase our understanding of the heterogeneous etiopathogenesis of FGID, visceral pain neuroimaging studies need to be integrated with: (i) epidemiological and behavioral evidence on the influence of psychological processes on visceral pain in health and FGID, and (ii) methodology and evidence from affective, cognitive, and psychiatric neuroimaging studies. To illustrate this point, the somatic pain neuroimaging field will be taken as an example before giving an overview of novel and integrative visceral pain studies in health and FGID. Some limitations of current pain neuroimaging studies will be outlined, before providing a summary of suggestions for moving the visceral pain neuroimaging field forward. PMID- 21255194 TI - Factors associated with co-morbid irritable bowel syndrome and chronic fatigue like symptoms in functional dyspepsia. AB - BACKGROUND: It is unclear which factors explain the high co-morbidity between functional dyspepsia (FD) and other functional somatic syndromes. The aim of this study is to investigate the association between gastric sensorimotor function, psychosocial factors and 'somatization' on the one hand, and co-morbid irritable bowel syndrome (IBS) and chronic fatigue (CF)-like symptoms on the other, in FD. METHODS: In 259 tertiary care FD patients, we studied gastric sensorimotor function with barostat (sensitivity, accommodation). We measured psychosocial factors (abuse history, alexithymia, trait anxiety, depression, panic disorder) and 'somatization' using self-report questionnaires, and presence of IBS and CF like symptoms. Hierarchical multiple logistic regression was used to determine which of these factors were independently associated with co-morbid IBS and CF like symptoms, including testing of potential mediator effects. KEY RESULTS: Co morbid IBS or CF-like symptoms respectively were found in 142 (56.8%) and 102 (39.4%) patients; both co-morbidities were not significantly associated (P=0.27). Gastric accommodation (beta=0.003, P=0.04) and 'somatization' (beta=0.17, P= 0.0003) were independent risk factors for IBS (c=0.74, P<0.0001); the effect of adult abuse (beta=0.72, P=0.20) was mediated by 'somatization'. Depression (beta=0.16, P=0.008) and 'somatization' (beta=0.18, P=0.004) were overlapping risk factors for CF-like symptoms (c=0.83, P<0.0001); the effects of alexithymia and lifetime abuse were mediated by depression and 'somatization', respectively. CONCLUSIONS & INFERENCES: 'Somatization' is a common risk factor for co-morbid IBS and CF-like symptoms in FD and mediates the effect of abuse. Gastric sensorimotor function and depression are specific risk factors for co-morbid IBS and CF-like symptoms, respectively. PMID- 21255195 TI - Effect of mianserin on gastric sensorimotor function and gastric emptying: a randomized, placebo-controlled, double-blind, crossover study in healthy volunteers. AB - BACKGROUND: Antidepressants such as mianserin can improve symptoms in some functional dyspeptic patients but their mechanism of action remains unclear. We aimed to assess the effects of mianserin on gastric sensorimotor function in man. METHODS: In this randomized, placebo-controlled, double-blind, crossover study 12 healthy subjects (six men) underwent a gastric barostat study and a gastric emptying breath test after 7 days pretreatment with placebo or mianserin (20 mg; p.o.). Graded isobaric and isovolumetric distentions were performed to determine gastric compliance and sensitivity. Subsequently, intrabag pressure was held constant and the volume increase after administration of a liquid meal (200 mL; 300 kcal) was studied. Breath was sampled before and after ingestion of a test meal and half-emptying times for solids and liquids were determined from the breath samples. Mianserin was compared to placebo using t-tests and mixed model analysis (mean +/- SD). KEY RESULTS: Mianserin did not affect pressures or volumes needed to induce first perception or discomfort. During isovolumetric distensions compliance was decreased after mianserin treatment (1.8 +/- 0.4 vs 2.0 +/- 0.3 mmHg 100 mL(-1); P < 0.05). Premeal volumes were comparable in both treatment arms (221 +/- 99 vs 220 +/- 88 mL), but meal-induced relaxation during the first 30 min was significantly inhibited after mianserin treatment (F(6,40) = 2.58, P < 0.05). Mianserin did not affect either solid or liquid gastric emptying. CONCLUSIONS & INFERENCES: Mianserin does not alter gastric emptying rate or sensitivity to gastric distension, but inhibits gastric accommodation to a meal in its early phase. These observations provide no explanation for the effects of mianserin in functional dyspeptic patients. PMID- 21255196 TI - The management of Parkinson's disease - what is new? PMID- 21255197 TI - Drugs and drug delivery in PD: optimizing control of symptoms with pramipexole prolonged-release. AB - Intermittent or pulsatile dopamine-receptor stimulation is postulated to induce plastic changes in motor systems that are responsible for the development of motor fluctuations and dyskinesia, complicating long-term levodopa therapy of Parkinson's disease (PD). Continuous dopamine stimulation (CDS) is a concept that refers to the hypothesis that more continuous dopamine-receptor stimulation will reduce the risk of motor complications, particularly dyskinesias, and may also treat established dyskinesias. In line with this hypothesis, the intermittent administration of dopaminergic agents with short half-lives induce motor complications in animal models, whilst the continuous administration of the same compounds via mini-pumps substantially reduces such symptoms. Continuous drug delivery (CDD) strategies are therefore explored in clinical trials to prevent or manage motor complications. The early use of a dopamine agonist reduces the risk of motor fluctuations compared with levodopa. Conversely, the early combination of the catechol-O-methyltransferase inhibitor entacapone with levodopa has failed to demonstrate a comparable advantage. Outcomes of uncontrolled long-term studies of PD patients with motor complications treated for several months with subcutaneous continuous infusion of apomorphine or intraduodenal levodopa are compatible with CDS. New once-daily prolonged-release formulations of dopamine agonists have demonstrated antiparkinsonian efficacy in randomized trials conducted in early as well as advanced patients with PD. Once-daily administration is convenient and may improve compliance. Other theoretical advantages in terms of efficacy or tolerability deserve further exploration. PMID- 21255198 TI - Treatment of depressive symptoms in Parkinson's disease. AB - Significant depressive disorders are present in approximately 30-40% of patients with Parkinson's disease (PD). Depressive symptoms are correlated with poor health-related quality-of-life (HRQoL) scores, and are the major determinant of HRQoL. Studies that have evaluated pharmacotherapy for depressive symptoms in PD have shown that there is substantial variability in outcomes. Recently, two double-blind, placebo-controlled studies showed the superiority of nortriptyline and desipramine versus placebo and selective serotonin reuptake inhibitors. The antidepressant effects of dopamine agonists have been explored mainly in open and non-controlled studies. In a 14-week randomized trial comparing pramipexole with sertraline in depressed patients without motor complications, the Hamilton Depression Rating Scale score decreased in both groups; however, in the pramipexole group, the proportion of patients who recovered was significantly higher. Recently, in the first 12-week double-blind placebo-controlled clinical trial in PD patients without motor fluctuations on stable levodopa treatment, pramipexole reduced depressive symptoms as measured by Beck Depression Inventory score, with a significant difference in efficacy in favour of pramipexole. These data suggest that pramipexole might represent an alternative to antidepressant drugs to treat depressive symptoms in PD without adding the risk of antidepressant adverse events, and avoid polypharmacy. PMID- 21255199 TI - Challenges to the development of disease-modifying therapies in Parkinson's disease. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder that involves the neurones of multiple transmitter pathways. The dopaminergic neuronal degeneration determines the main early clinical characteristics of the disease. There have been many recent valuable insights into the pathogenesis of PD, driven primarily by research of the genetic causes of the disease. These now provide a clearer view of the pathways that lead to neuronal dysfunction and death. Perhaps surprisingly, the same pathways initiated by gene mutations causing familial PD are those already identified to be involved in idiopathic sporadic PD, namely mitochondrial dysfunction, oxidative stress and protein misfolding and aggregation. Novel therapies designed to slow PD progression are likely to intervene in one or more of these pathways. Some candidates have been tested based upon this hypothesis, albeit with varying results. Significant developments in this area face several challenges including effective disease-modelling systems and clinical trial designs that can enable a true positive result to be obtained in a relatively short period. PMID- 21255200 TI - Let your intuition be your guide? Individual differences in the evidence-based practice attitudes of psychotherapists. AB - RATIONALE, AIMS AND OBJECTIVES: Despite increasing dissemination efforts, many psychotherapists still do not use treatments that are supported by research. Some have claimed that psychotherapists rely more on their clinical intuition than scientific evidence when making treatment decisions, but there is a paucity of research on this topic. The aim of the study was to examine the relationship between intuition and therapists' attitudes towards evidence-based practices (EBPs). METHODS: Psychotherapists from diverse professional backgrounds completed an Internet-based survey that assessed EBP attitudes, reliance on an intuitive thinking style, attitudes about alternative therapies and endorsement of erroneous health beliefs that are not supported by scientific evidence. RESULTS: Regression analyses showed that an intuitive thinking style was associated with several dimensions of EBP attitudes, including more negative attitudes towards research, less openness to research-based treatments, and less willingness to use evidence-based treatments if required to do so, even after controlling for background factors such as education level. Furthermore, a tendency to rely on intuition was associated with more positive attitudes towards alternative therapies and the endorsement of erroneous health beliefs. CONCLUSIONS: Most dissemination efforts targeted at psychotherapists focus only on education about EBPs. However, results of this study suggest that dissemination efforts may need to more directly address the potential barriers to using EBPs (i.e. reliance on intuition) to be optimally effective in changing therapists' attitudes and behaviours. PMID- 21255201 TI - How should we train consultant appraisers? Description and evaluation of a pilot training model developed in Scotland. AB - OBJECTIVES: This paper outlines a model developed by NHS Education for Scotland to pilot consultant appraiser training. The training was aimed at both new/inexperienced appraisers and experienced appraisers. A Course for New/Inexperienced Appraisers was held over 2 days and the Experienced Course over 1 day. Both are described, as is an initial tutor induction day designed to recruit consultant tutors who could contribute to delivering the courses. A thorough qualitative evaluation of the courses was undertaken and this is reported. The paper also discusses the desirability and implications of rolling out the pilot on a wider scale. METHOD: A qualitative evaluation design using interviews to collect feedback from participants who had attended all three courses - the Induction event, the Inexperienced Appraiser Course and the Experienced Appraiser Course - was employed. Telephone interviews were transcribed and analysed using framework analysis and aided by NVivo 7. RESULTS: The response of those interviewed for this evaluation of the three courses was very positive. The content, organization, skills of the tutors and usefulness of the courses were commended. Suggested improvements were relatively minor and included: introducing more material on the requirements of revalidation, more small group discussions and making the course more secondary care-orientated. However, it was recognized that with the requirements for 'enhanced' appraisal and revalidation still uncertain, this created difficulties and the course would evolve to take account of further developments. CONCLUSIONS: The training piloted represents an effective way to train consultants in appraisal skills. Interviewees were supportive of the pilot being continued: either nationally or cascaded down locally. Exactly what model is achievable and desirable will depend on the number of appraisers to be trained and the availability of resources to support 'enhanced' appraisal in secondary care. PMID- 21255202 TI - Validation of a new outcome measure for orthopaedic trauma inpatients. AB - BACKGROUND: Functional performance is the most relevant outcome for trauma patients. Currently, no functional outcome measure for trauma inpatients exists. OBJECTIVE: To report on reliability and validity testing of a new functional outcome measure for orthopaedic trauma inpatients. METHODOLOGY: Descriptive study conducted to test selected psychometric properties of the new Functional Scale for Trauma Inpatients at Rashid Hospital in Dubai, United Arab Emirates. A total of 100 eligible male and female orthopaedic trauma inpatients aged 17 years and older were consecutively sampled. Physiotherapists administered the new scale to eligible patients. Descriptive statistics were used to describe the sample. Internal consistency was assessed by calculating Cronbach's alpha statistics. Sensitivity to change was assessed using one-way analysis of variance. RESULTS: Eighty-eight per cent of the 100 eligible subjects were male (mean age 34.75 +/- 14.46 years). Sixty-three per cent of the patients had trauma to the lower extremity. The Cronbach's alpha-values were good (range 0.76-0.97). There was a significant difference in the mean scores over three administrations of 'bed', 'out of bed' and 'activities of daily living (ADL)' activity items of Functional Scale for Trauma Inpatients (P = 0.0000). Floor effects were noted at discharge for 'bed activities' and at discharge for 'ADL activities'. The only ceiling effect was noted at admission for 'out of bed activities'. CONCLUSION: The psychometric tests indicated that the tool is reliable, has sound internal consistency and has the ability to detect changes in functional performance of trauma inpatients. The scale fills an important need for physiotherapists working in trauma inpatient wards. Psychometric properties of the new scale should be tested in other countries. PMID- 21255204 TI - TB and HIV integration: obstacles and possible solutions to implementation in South Africa. AB - OBJECTIVES: To identify key obstacles to operational integration of TB and HIV services and to suggest strategies to promote integration in the prevention, treatment and care of patients with TB and HIV. METHODS: This is a health systems research case study of operational integration of TB and HIV in South Africa. Peer-reviewed and grey literature together with the experiences of the authors were used to identify key obstacles to integration in service implementation practices and community-level care. Relevant legislation, policies and guidelines were analysed to determine whether they facilitated or undermined the integration of TB and HIV services. RESULTS: Obstacles to integration exist at contextual and epidemiological levels as well as at intervention design and implementation levels. Importantly, integration at an operational level is undermined by fundamentally different principles underpinning the design of TB and HIV programmes and national policies and legislation which mitigate against integration. CONCLUSION: South Africa has an opportunity to effect changes that will facilitate TB/HIV integration and improve care for all those infected with TB, HIV or both conditions. An analytic approach necessary to understand the obstacles to and ensure effective strategies facilitating integration is required. This needs to be followed by mobilisation of clinical and health systems expertise, health infrastructure, commitment and experience in creative and appropriate ways for the variety of health care settings. PMID- 21255205 TI - Susceptibility of Anopheles gambiae s.l. to DDT, malathion, permethrin and deltamethrin in Ethiopia. AB - OBJECTIVE: To assess the susceptibility/resistance level of Anopheles gambiae s.l. to DDT, malathion, permethrin and deltamethrin in different parts of Ethiopia. METHODS: Field collected female An.gambiae s.l. was exposed for 1 h to discriminating dosage of 4% DDT, 5% malathion, 0.75% permethrin and 0.05% deltamethrin using WHO insecticide susceptibility test kits and procedures. Knockdown and mortality rates were recorded at 10, 15, 20, 30, 40, 50 and 60 min and 24 h post-exposure respectively. RESULTS: Anopheles gambiae s.l. was sensitive to DDT only in 2 of 16 localities where susceptibility studies were carried out in northern Ethiopia; it was resistant in 11 sites and potentially resistant in three. To malathion, the test population was sensitive in four of the six study sites in southern Ethiopia and potentially resistant in the other two sites. In northern Ethiopia, the population was resistant in five localities and sensitive in three. Of the six localities in northern Ethiopia where permethrin was tested, populations were sensitive in three, resistant in one and potentially resistant in two. In southern Ethiopia, the populations were resistant in five of the six sites. Against deltamethrin, the population was sensitive in five of 13 localities, three in northern and two in southern Ethiopia. It was resistant only in two localities, one in northern and one in southern Ethiopia, and potentially resistant in five localities. In eastern Ethiopia at Sabure, the population was sensitive to all insecticides but DDT to which it was potentially resistant. CONCLUSION: The existence of high level of DDT and pyrethroid resistance with the possibility of cross-resistance to each other and other classes of agricultural pesticides could seriously jeopardise the efficacy of both ITNs and IRS in the country in the future. Insecticide resistance monitoring and surveillance systems as part of a malaria control programme are mandatory for proper management of resistance. The use of a mixture of unrelated insecticides for impregnating nets and rotational use of insecticides for IRS is suggested as a way forward. PMID- 21255206 TI - Emergence of a new focus of anthroponotic cutaneous leishmaniasis due to Leishmania tropica in rural communities of Bam district after the earthquake, Iran. AB - OBJECTIVES: To describe a new emerging focus of anthroponotic cutaneous leishmaniasis (ACL) due to Leishmania tropica in rural areas of Dehbakry county, south-eastern Iran, after the earthquake of 2003. METHODS: House-to-house survey of 3884 inhabitants for active leishmaniasis lesions or scars. The diagnosis was confirmed by smears, cultures and identification of the parasite by polymerase chain reaction (PCR). RESULTS: All age groups were affected, although patients <=10 years of age showed the highest rate of infection (P = 0.0001). The overall prevalence rate was 5.3%; 6.3% in females and 4.3% in males. Of 204 cases, 1.8% had active sores and 3.5% had scars, with a significant difference between the sexes (P = 0.005). 47% of the lesions were on the face and 77.9% had one lesion. The incidence rose gradually 2004-2005, but grew exponentially 2006-2008. Electrophoresis of PCR products indicated that L. tropica was the causative agent. CONCLUSIONS: The current emergence was unexpected in this rural locality, where no previous history of CL was recorded. According to our knowledge this is the first report of a gradually establishing new ACL focus in rural communities after the 2003 earthquake. PMID- 21255207 TI - Survival characteristics of environmental and clinically derived strains of Cronobacter sakazakii in infant milk formula (IMF) and ingredients. AB - AIMS: The study aimed to compare survival of Cronobacter sakazakii strains in plant-derived infant milk formula (IMF) ingredients and their thermotolerance in reconstituted IMF. METHODS AND RESULTS: Inulin and lecithin were inoculated with isolates of C. sakazakii including the typed clinical strains, NCTC 11467(T) and BAA 894; a mutant strain in which the wcaD gene had been disrupted; and two environmental strains isolated from IMF processing facilities. Samples were stored and examined for C. sakazakii. All strains were still detectable in both matrices after 338 days storage, except for the mutant strain that was no longer detectable at that time. Higher numbers of the environmental strains were recoverable after 338 days than the clinical strains. The thermotolerance of the five strains was investigated in reconstituted IMF at 55, 60 and 65 degrees C. The clinically derived type strain, NCTC 11467(T), and the mutant strain were shown to be significantly more thermotolerant than other strains tested. CONCLUSIONS: Environmental strains were more persistent than the clinical strains in inulin and lecithin, indicating that patho-adaptation may have contributed to a reduction in the desiccation tolerance phenotype. However, the thermotolerance results could indicate that the ability to produce extracellular polysaccharide decreases thermotolerance. SIGNIFICANCE AND IMPACT OF THE STUDY: These results indicate that desiccation resistance may play a role in survival of C. sakazakii in dry IMF ingredients and processing plants; however, this trait may be of less importance in clinical environs. PMID- 21255208 TI - Prevention of the accumulation of Alicyclobacillus in apple concentrate by restricting the continuous process running time. AB - AIMS: To study the accumulation of vegetative cells and endospores of Alicyclobacillus, as well as viable aerobic counts during the continuous production of apple juice concentrate. METHODS AND RESULTS: Apples were processed for a continuous process running time of 108 h (processing rate 1.8-2.0 t h(-1) ) without clean-in-place (CIP) procedures in-between different batches. Samples from single-strength apple juice, concentrate after evaporation (+/- 30 degrees Brix), the final product (concentrate pasteurized at 102-104 degrees C for 90 s) and condensate water (by-product of the juice concentration process) were collected every 12 h. From 12 to 84 h of processing, vegetative Alicyclobacillus counts in single-strength apple juice increased significantly (P < 0.05) from 1 to 3.15 log(10) CFU ml(-1). Accumulation patterns of vegetative cells in apple concentrate and the final product were similar from 24 to 84 h of processing, with the respective counts increasing from 0.13 to 1.63 and 0.01 to 1.69 log(10) CFU ml(-1). The highest Alicyclobacillus endospore counts in single-strength juice, concentrate and the final product was at 84 h of processing with 1.32, 1.59 and 1.64 log(10) CFU ml(-1), respectively. CONCLUSIONS: Alicyclobacillus vegetative cells and endospores accumulate in fruit concentrates during a continuous process running time of 108 h. SIGNIFICANCE AND IMPACT OF THE STUDY: In conjunction with good manufacturing practices, fruit concentrate manufactures can minimize Alicyclobacillus accumulation in fruit concentrates by limiting the continuous process running time between clean-ups to under 84 h. PMID- 21255209 TI - Superantigenic activity of toxic shock syndrome toxin-1 is resistant to heating and digestive enzymes. AB - AIMS: To elucidate the stability of superantigenic activity and pathogenesis of toxic shock syndrome toxin 1 (TSST-1) and staphylococcal enterotoxin A (SEA) against heating and digestive enzymes. METHODS AND RESULTS: Purified TSST-1 and SEA were treated with heating, pepsin and trypsin that are related to food cooking, stomach and intestine conditions. The integrity, superantigenic activity and toxicity of treated TSST-1 and SEA were analysed by Western blotting, spleen cell culture, cytokine assay and toxic shock models. Both TSST-1 and SEA showed strong resistance to heating, pepsin and trypsin digestion. Furthermore, the treated TSST-1 showed significant higher induction of interferon-gamma and toxic shock compared with that of SEA. Pepsin- or trypsin-digested TSST-1 fragments still showed significant superantigenic and lethal shock toxicities. CONCLUSIONS: The superantigenic activity of TSST-1 was stable to heating and digestive enzymes. Pepsin- and trypsin-digested TSST-1 fragments still showed superantigenic and lethal shock activities, indicating that digested TSST-1 could cross epithelial cells and induce systemic toxicity. SIGNIFICANCE AND IMPACT OF THE STUDY: This study found, for the first time, that pepsin- or trypsin-digested smaller TSST-1 retained significant superantigenic and lethal shock activities. The different resistance of TSST-1 and SEA participates in the different pathogenic activities during food poisoning and toxic shock syndrome. PMID- 21255210 TI - The prevalence of antimicrobial-resistant Escherichia coli in sympatric wild rodents varies by season and host. AB - AIMS: To investigate the prevalence and temporal patterns of antimicrobial resistance in wild rodents with no apparent exposure to antimicrobials. METHODS AND RESULTS: Two sympatric populations of bank voles and wood mice were trapped and individually monitored over a 2- year period for faecal carriage of antimicrobial-resistant Escherichia coli. High prevalences of ampicillin-, chloramphenicol-, tetracycline- and trimethoprim-resistant E. coli were observed. A markedly higher prevalence of antimicrobial-resistant E. coli was found in wood mice than in bank voles, with the prevalence in both increasing over time. Superimposed on this trend was a seasonal cycle with a peak prevalence of resistant E. coli in mice in early- to mid-summer and in voles in late summer and early autumn. CONCLUSIONS: These sympatric rodent species had no obvious contact with antimicrobials, and the difference in resistance profiles between rodent species and seasons suggests that factors present in their environment are unlikely to be drivers of such resistance. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings suggest that rodents may represent a reservoir of antimicrobial resistant bacteria, transmissible to livestock and man. Furthermore, such findings have implications for human and veterinary medicine regarding antimicrobial usage and subsequent selection of antimicrobial-resistant organisms. PMID- 21255211 TI - Rab GTPases regulating phagosome maturation are differentially recruited to mycobacterial phagosomes. AB - Mycobacterium tuberculosis (M. tb) is an intracellular pathogen that can replicate within infected macrophages. The ability of M. tb to arrest phagosome maturation is believed to facilitate its intracellular multiplication. Rab GTPases regulate membrane trafficking, but details of how Rab GTPases regulate phagosome maturation and how M. tb modulates their localization during inhibiting phagolysosome biogenesis remain elusive. We compared the localization of 42 distinct Rab GTPases to phagosomes containing either Staphylococcus aureus or M. tb. The phagosomes containing S. aureus were associated with 22 Rab GTPases, but only 5 of these showed similar localization kinetics as the phagosomes containing M. tb. The Rab GTPases responsible for phagosome maturation, phagosomal acidification and recruitment of cathepsin D were examined in macrophages expressing the dominant-negative form of each Rab GTPase. LysoTracker staining and immunofluorescence microscopy revealed that Rab7, Rab20 and Rab39 regulated phagosomal acidification and Rab7, Rab20, Rab22b, Rab32, Rab34, Rab38 and Rab43 controlled the recruitment of cathepsin D to the phagosome. These results suggest that phagosome maturation is achieved by a series of interactions between Rab GTPases and phagosomes and that differential recruitment of these Rab GTPases, except for Rab22b and Rab43, to M. tb-containing phagosomes is involved in arresting phagosome maturation and inhibiting phagolysosome biogenesis. PMID- 21255212 TI - The bacterial SRP receptor, SecA and the ribosome use overlapping binding sites on the SecY translocon. AB - Signal recognition particle (SRP)-dependent protein targeting is a universally conserved process that delivers proteins to the bacterial cytoplasmic membrane or to the endoplasmic reticulum membrane in eukaryotes. Crucial during targeting is the transfer of the ribosome-nascent chain complex (RNC) from SRP to the Sec translocon. In eukaryotes, this step is co-ordinated by the SRbeta subunit of the SRP receptor (SR), which probably senses a vacant translocon by direct interaction with the translocon. Bacteria lack the SRbeta subunit and how they co ordinate RNC transfer is unknown. By site-directed cross-linking and fluorescence resonance energy transfer (FRET) analyses, we show that FtsY, the bacterial SRalpha homologue, binds to the exposed C4/C5 loops of SecY, the central component of the bacterial Sec translocon. The same loops serve also as binding sites for SecA and the ribosome. The FtsY-SecY interaction involves at least the A domain of FtsY, which attributes an important function to this so far ill defined domain. Binding of FtsY to SecY residues, which are also used by SecA and the ribosome, probably allows FtsY to sense an available translocon and to align the incoming SRP-RNC with the protein conducting channel. Thus, the Escherichia coli FtsY encompasses the functions of both the eukaryotic SRalpha and SRbeta subunits in one single protein. PMID- 21255213 TI - Superfolder GFP is fluorescent in oxidizing environments when targeted via the Sec translocon. AB - The ability to study proteins in live cells using genetically encoded fluorescent proteins (FPs) has revolutionized cell biology (1-3). Researchers have created numerous FP biosensors and optimized FPs for specific organisms and subcellular environments in a rainbow of colors (4,5). However, expressing FPs in oxidizing environments such as the eukaryotic endoplasmic reticulum (ER) or the bacterial periplasm can impair folding, thereby preventing fluorescence (6,7). A substantial fraction of enhanced green fluorescent protein (EGFP) oligomerizes to form non-fluorescent mixed disulfides in the ER (6) and EGFP does not fluoresce in the periplasm when targeted via the SecYEG translocon (7). To overcome these obstacles, we exploited the highly efficient folding capability of superfolder GFP (sfGFP) (8). Here, we report sfGFP does not form disulfide-linked oligomers in the ER and maltose-binding protein (MBP) signal sequence (peri)-sfGFP (9) is brightly fluorescent in the periplasm of Escherichia coli. Thus, sfGFP represents an important research tool for studying resident proteins of oxidizing environments. PMID- 21255215 TI - Effects of pioglitazone versus metformin on circulating endothelial microparticles and progenitor cells in patients with newly diagnosed type 2 diabetes--a randomized controlled trial. AB - AIM: Endothelial microparticles (EMPs) and endothelial progenitor cells (EPCs) are markers of endothelial injury and repair. We compared the effects of pioglitazone versus metformin on the circulating numbers of EMPs and EPCs in patients with newly diagnosed type 2 diabetes. METHODS: This was a randomized, double-blind, comparator-controlled, 24-week single-centre trial conducted in a Teaching Hospital in Naples, Italy. One hundred and ten people with newly diagnosed type 2 diabetes who were never treated with antihyperglycaemic drugs and had haemoglobin A1c (HbA1c) levels between 7 and 10% were given pioglitazone hydrochloride (15-45 mg/day) (n = 55) or metformin (1000-2000 mg/day) (n = 55) as an active comparator. Absolute change from baseline to final visit in circulating EMPs and EPCs and their ratio were the main outcomes. RESULTS: Baseline characteristics did not differ between the study groups. The decrease in circulating EMPs CD31+ [intergroup difference, -32 counts/ul (95% CI -51 to -9)] and the increase in EPCs CD34+/KDR+ [intergroup difference, 33 cells/10(6) events (95% CI 13 to 55)] were greater with pioglitazone versus metformin. EMPs/EPCs ratio was reduced with pioglitazone and unchanged with metformin [difference, 1.5 (95% CI -2.6 to -0.5), p < 0.001]. Participants assigned to pioglitazone gained more weight and experienced greater improvements in some coronary risk measures [high-density lipoprotein (HDL)-cholesterol, triglycerides, adiponectin and C-reactive protein (CRP)] than did those assigned to metformin. CONCLUSION: Compared with metformin, pioglitazone treatment improved the imbalance between endothelial damage and repair capacity and led to more favourable changes in coronary risk factors in patients with newly diagnosed type 2 diabetes. PMID- 21255216 TI - JTT-130, a novel intestine-specific inhibitor of microsomal triglyceride transfer protein, suppresses high fat diet-induced obesity and glucose intolerance in Sprague-Dawley rats. AB - AIM: Microsomal triglyceride transfer protein (MTP) takes part in the mobilization and secretion of triglyceride-rich lipoproteins from enterocytes and hepatocytes. We investigated the effects of JTT-130, a novel intestine-specific MTP inhibitor, on high fat diet-induced obesity and glucose intolerance. METHODS: Male Sprague-Dawley rats were fed a 3.1% fat diet or a 35% fat diet with or without JTT-130 as a food admixture (0.029%). Food intake, body weight, abdominal fat, hepatic triglyceride, faecal free fatty acids and plasma levels of glucagon like peptide-1 (GLP-1) and peptide YY (PYY) were assessed. Plasma levels of glucose and insulin were measured during intraperitoneal glucose tolerance tests. In addition, indirect calorimetry was performed on rats fed with a 35% fat diet. RESULTS: JTT-130 treatment decreased body weights, abdominal fat and hepatic triglyceride with suppression of food intake and elevation of faecal free fatty acids and plasma GLP-1 and PYY levels in rats fed with the 35% fat diet, whereas no significant effects on these parameters except for increased faecal free fatty acids were observed in rats fed with the 3.1% fat diet. JTT-130 treatment decreased plasma levels of glucose and insulin during intraperitoneal glucose tolerance tests on rats fed with the 35% fat diet, but not on rats fed with the 3.1% fat diet. JTT-130-treated rats showed increased O(2) consumption and CO(2) production on a 35% fat diet. CONCLUSIONS: JTT-130 suppresses high fat diet induced obesity and glucose intolerance with suppression of food intake and fat absorption and could be useful for prevention and treatment of obesity and obesity-related insulin resistance. PMID- 21255217 TI - Laparoscopic colorectal surgery: the end of the beginning. PMID- 21255218 TI - Commentary on 'T4 colorectal cancer: is laparoscopic resection contraindicated?' by Bretagnol et al. PMID- 21255221 TI - Influenza A H1N1 in HIV-infected adults. AB - OBJECTIVES: HIV-infected adults are considered to be at higher risk for influenza A H1N1 complications but data supporting this belief are lacking. We aimed to compare epidemiological data, clinical characteristics, and outcomes of influenza A H1N1 infection between HIV-infected and -uninfected adults. METHODS: From 26 April to 6 December 2009, each adult presenting with acute respiratory illness at the emergency department of our institution was considered for an influenza A H1N1 diagnosis by specific multiplex real-time polymerase chain reaction. For every HIV-infected adult diagnosed, three consecutive adults not known to be HIV infected diagnosed in the same calendar week were randomly chosen as controls. RESULTS: Among 2106 adults tested, 623 (30%) had influenza A H1N1 infection confirmed. Fifty-six (9%) were HIV-positive and were compared with 168 HIV negative controls. Relative to HIV-negative controls, HIV-positive patients were older, more frequently male, and more frequently smokers (P<=0.02). In the HIV positive group, prior or current AIDS-defining events were reported for 30% of patients, 9% and 30% had CD4 counts of <200 and 200-500cells/MUL, respectively, and 95% had HIV-1 RNA <50copies/mL. Pneumonia (9%vs. 25%, respectively, in the HIV-positive and HIV-negative groups; P=0.01) and respiratory failure (9%vs. 21%, respectively; P=0.04) were less common in the HIV-positive group. Oseltamivir (95%vs. 71% in the HIV-positive and HIV-negative groups, respectively; P=0.003) was administered more often in HIV-positive patients. Three patients (all HIV negative) died. In the HIV-positive group, CD4 cell count and plasma HIV-1 RNA did not differ before and 4-6 weeks after influenza A H1N1 diagnosis (P>0.05). CONCLUSIONS: HIV infection did not increase the severity of influenza A H1N1 infection, and influenza A H1N1 infection did not have a major effect on HIV infection. PMID- 21255222 TI - Novel role of aquaporin-4 in CD4+ CD25+ T regulatory cell development and severity of Parkinson's disease. AB - Aquaporin-4 (AQP4) is highly expressed in mammalian brains and is involved in the pathophysiology of cerebral disorders, including stroke, tumors, infections, hydrocephalus, epilepsy, and traumatic brain injury. We found that AQP4-deficient mice were hypersensitive to stimulations such as 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) or lipopolysaccharide compared to wild-type (WT) littermates. In a mouse model of MPTP-induced Parkinson's disease (PD), AQP4 deficient animals show more robust microglial inflammatory responses and more severe loss of dopaminergic neurons (DNs) compared with WT mice. However, a few studies have investigated the association of abnormal AQP4 levels with immune dysfunction. Here, for the first time, we report AQP4 expression in mouse thymus, spleen, and lymph nodes. Furthermore, the significantly lower numbers of CD4(+) CD25(+) regulatory T cells in AQP4-deficient mice compared to WT mice, perhaps resulting from impaired thymic generation, may be responsible for the uncontrolled microglial inflammatory responses and subsequent severe loss of DNs in the substantia nigra pars compacta in the MPTP-induced PD model. These novel findings suggest that AQP4 deficiency may disrupt immunosuppressive regulators, resulting in hyperactive immune responses and potentially contributing to the increased severity of PD or other immune-associated diseases. PMID- 21255223 TI - Regulation of longevity by regulator of G-protein signaling protein, Loco. AB - Regulator of G-protein signaling (RGS) proteins contribute to G-protein signaling pathways as activators or repressors with GTPase-activating protein (GAP) activity. To characterize whether regulation of RGS proteins influences longevity in several species, we measured stress responses and lifespan of RGS overexpressing and RGS-lacking mutants. Reduced expression of Loco, a RGS protein of Drosophila melanogaster, resulted in a longer lifespan for both male and female flies, also exhibiting stronger resistance to three different stressors (starvation, oxidation, and heat) and higher manganese-containing superoxide dismutase (MnSOD) activity. In addition, this reduction in Loco expression increased fat content and diminished cAMP levels. In contrast, overexpression of both genomic and cDNA loco gene significantly shortened the lifespan with weaker stress resistance and lower fat content. Deletion analysis of the Loco demonstrated that its RGS domain is required for the regulation of longevity. Consistently, when expression of RGS14, mammalian homologue of Loco, was reduced in rat fibroblast cells, the resistance to oxidative stress increased with higher MnSOD expression. The changes of yeast Rgs2 expression, which shares a conserved RGS domain with the fly Loco protein, also altered lifespan and stress resistance in Saccharomyces cerevisiae. Here, we provide the first evidence that RGS proteins with GAP activity affect both stress resistance and longevity in several species. PMID- 21255245 TI - Clopidogrel differentially affects platelet-mediated thrombosis and inflammatory response in patients with acute coronary syndromes. PMID- 21255246 TI - Osteoprotegerin, a new actor in vasculogenesis, stimulates endothelial colony forming cells properties. AB - BACKGROUND: Osteoprotegerin (OPG), a soluble receptor of the tumour necrosis factor family, and its ligand, the receptor activator of nuclear factor-kappaB ligand (RANKL), are emerging as important regulators of vascular pathophysiology. OBJECTIVES: We evaluated their effects on vasculogenesis induced by endothelial colony-forming cells (ECFC) and on neovessel formation in vivo. METHODS: Effects of OPG and RANKL on in vitro angiogenesis were evaluated after ECFC incubation with OPG or RANKL (0-50 ng mL(-1)). Effects on microvessel formation were evaluated with an in vivo murin Matrigel plug assay. Vascularization was evaluated by measuring plug hemoglobin and vascular endothelial growth factor (VEGF)-R2 content 14 days after implantation. RESULTS: We found that ECFC expressed OPG and RANK but not RANKL mRNA. Treatment of ECFC with VEGF or stromal cell-derived factor-1 (SDF-1) upregulated OPG mRNA expression. OPG stimulated ECFC migration (P < 0.05), chemotaxis (P < 0.05) and vascular cord formation on Matrigel((r)) (P < 0.01). These effects were correlated with SDF-1 mRNA overexpression, which was 30-fold higher after 4 h of OPG stimulation (P < 0.01). OPG-mediated angiogenesis involved the MAPK signaling pathway as well as Akt or mTOR cascades. RANKL also showed pro-vasculogenic effects in vitro. OPG combined with FGF-2 promoted neovessel formation in vivo, whereas RANKL had no effect. CONCLUSIONS: OPG induces ECFC activation and is a positive regulator of microvessel formation in vivo. Our results suggest that the OPG/RANK/RANKL axis may be involved in vasculogenesis and strongly support a modulatory role in tissue revascularization. PMID- 21255248 TI - Fibroblast activation in vascular inflammation. AB - Vascular inflammation is implicated in both local and systemic inflammatory conditions. Endothelial activation and leukocyte extravasation are key events in vascular inflammation. Lately, the role of the stromal microenvironment as a source of proinflammatory stimuli has become increasingly appreciated. Stromal fibroblasts produce cytokines, growth factors and proteases that trigger and maintain acute and chronic inflammatory conditions. Fibroblasts have been associated with connective tissue pathologies such as scar formation and fibrosis, but recent research has also connected them with vascular dysfunctions. Fibroblasts are able to modulate endothelial cell functions in a paracrine manner, including proinflammatory activation and promotion of angiogenesis. They are also able to activate and attract leukocytes. Stromal fibroblasts can thus cause a proinflammatory switch in endothelial cells, and promote leukocyte infiltration into tissues. New insights in the role of adventitial fibroblasts have further strengthened the link between stromal fibroblasts and proinflammatory vascular functions. This review focuses on the role of fibroblasts in inducing and maintaining vascular inflammation, and describes recent findings and concepts in the field, along with examples of pathologic implications. PMID- 21255247 TI - The septic milieu triggers expression of spliced tissue factor mRNA in human platelets. AB - BACKGROUND: Activated platelets have previously-unrecognized mechanisms of post transcriptional gene expression that may influence hemostasis and inflammation. A novel pathway involves splicing of pre-mRNAs in resting platelets to mature, translatable mRNAs in response to cellular activation. OBJECTIVES: We asked if bacterial products and host agonists present in the septic milieu induce tissue factor pre-mRNA splicing in platelets from healthy subjects. In parallel, we asked if spliced tissue factor (TF) mRNA is present in platelets from septic patients in a proof-of-principle analysis. PATIENTS/METHODS: TF pre-mRNA and mRNA expression patterns were characterized in platelets from septic patients and in platelets isolated from healthy subjects activated with bacteria, toxins and inflammatory agonists. Procoagulant activity was also measured. RESULTS AND CONCLUSIONS: Live bacteria, staphylococcal alpha-toxin and lipopolysaccharide (LPS) induced TF pre-mRNA splicing in platelets isolated from healthy subjects. Toxin-stimulated platelets accelerated plasma clotting, a response that was blocked by a previously-characterized splicing inhibitor and by an anti-tissue factor antibody. Platelets from septic patients expressed spliced TF mRNA, whereas it was absent from unselected and age-matched control subjects. Tissue factor-dependent procoagulant activity was elevated in platelets from a subset of septic patients. Thus, bacterial and host factors induce splicing of TF pre-mRNA, expression of TF mRNA and tissue factor-dependent clotting activity in human platelets. TF mRNA is present in platelets from some septic patients, indicating that it may be a marker of altered platelet phenotype and function in sepsis and that splicing pathways are induced in this syndrome. PMID- 21255249 TI - Traffic exposure and incident venous thromboembolism in the Atherosclerosis Risk in Communities (ARIC) Study. AB - BACKGROUND: Two recent case-control studies in Italy reported that long-term exposure to particulate air pollution or living near major traffic roads was associated with an increased risk of deep vein thrombosis (DVT). No prospective evidence exists on the possible association between long-term traffic-related air pollution and incident venous thromboembolism (VTE). OBJECTIVES: To examine the association between long-term traffic exposure and incident VTE in a population based prospective cohort study. METHODS: We studied 13,143 middle-aged men and women in the Atherosclerosis Risk in Communities Study without a history of DVT or pulmonary embolism at baseline examination (1987-1989). The Geographical Information System-mapped traffic density and distance to major roads in the four study communities served as measures of traffic exposure. We examined the association between traffic exposure and incident VTE with proportional hazards regression models. RESULTS: A total of 405 subjects developed VTE in 2005. Traffic density was not significantly associated with VTE. Relative to those in the lowest quartile of traffic density, the adjusted hazard ratios across increasing quartiles were 1.18 (95% confidence interval [CI] 0.88-1.57), 0.99 (95% CI 0.74-1.34) and 1.14 (95% CI 0.86-1.51) (P-value for trend across quartiles = 0.64). For residents living within 150 m of major roads, as compared with subjects living further away, the adjusted hazard ratio was 1.16 (95% CI 0.95-1.42, P = 0.14). CONCLUSIONS: This first prospective study in the general population does not support an association between air pollution exposure or traffic proximity and risk of DVT. More data may be needed to clarify whether traffic or air pollution influences the risk of VTE. PMID- 21255250 TI - Prothrombin complex concentrate and recombinant prothrombin alone or in combination with recombinant factor X and FVIIa in dilutional coagulopathy: a porcine model. AB - BACKGROUND: This study was conducted to assess whether newly developed recombinant clotting factor concentrates enable the reversal of dilutional coagulopathy. METHODS: In 50 anesthetized pigs, ~60% of the blood volume was withdrawn and replaced with hydroxyethyl starch. Pigs were randomized to receive either 200 mg kg(-1) fibrinogen (n = 10), fibrinogen and 35 IU kg(-1) prothrombin complex concentrate (PCC) (n = 10), fibrinogen and 4 mg kg(-1) recombinant human factor II (rhFII) concentrate (n = 10), fibrinogen and a three-factor combination (3F) of 4 mg kg(-1) rhFII, 0.006 mg kg(-1) recombinant human FVIIa and 0.32 mg kg(-1) recombinant human FX (n = 10), or saline (n = 10). Thereafter, a standardized liver laceration was performed to induce uncontrolled hemorrhage. Survival time and blood loss were determined, and standard coagulation tests and thrombelastometry were performed. RESULTS: Fibrinogen combined with rhFII or PCC improved survival. Blood loss was significantly decreased in all groups as compared with the animals receiving saline. Clotting time was significantly shortened in the animals treated with fibrinogen and PCC, as well as in those treated with fibrinogen and 3F. One animal died after administration of fibrinogen and PCC. CONCLUSION: Following hemodilution, a combination of fibrinogen and PCC, rhFII or 3F enhances coagulation and final clot strength. Mortality was reduced statistically significantly only in the animals treated with fibrinogen and rhFII or PCC, whereas administration of the combination of fibrinogen and PCC caused a fatal thromboembolic complication. The combination of fibrinogen and rhFII might be effective in reversing dilutional coagulopathy and may reduce blood loss in cases of dilutional coagulopathy. PMID- 21255251 TI - Patient-derived monoclonal antibodies directed towards beta2 glycoprotein-1 display lupus anticoagulant activity. AB - BACKGROUND: Patients with antiphospholipid syndrome (APS) display a heterogeneous population of antibodies with beta(2) glycoprotein-1 (beta(2)GP1) as the major antigen. OBJECTIVES: We isolated and characterized human mAbs directed against beta(2)GP1 from the immune repertoire of APS patients. METHODS: Variable heavy chain repertoires from B cells from two APS patients with anti-beta(2)GP1 antibodies were cloned into the pHEN1-VLrep vector. Constructed full-length IgG antibodies were tested for lupus anticoagulant (LAC) activity and binding to beta(2)GP1 and its domains. RESULTS: Two clones of each patient were selected on the basis of the reactivity of single chain Fv (scFv) fragments displayed on phages towards full-length beta(2)GP1 and its isolated domain I. The affinity of selected antibodies for beta(2)GP1 was lost when transforming from phages to monovalent scFvs, and was regained when antibodies were constructed as complete IgG, indicating a role for bivalency in binding to beta(2)GP1. Both selected clones from patient 2 recognized domain I of beta(2)GP1, and for both clones selected from patient 1, binding required the presence of both domain I and domain II. All mAbs displayed LAC activity in both activated partial thromboplastin time-based and dilute Russell's viper venom test-based clotting assays and in thrombin generation. CONCLUSIONS: In this study, we show successful cloning of patient-derived mAbs that require domain I of beta(2)GP1 for binding, and that display LAC activity that is dependent on their affinity for beta(2)GP1. These antibodies can help us to gain more insights into the pathogenesis of APS, and may facilitate standardization of APS diagnosis. PMID- 21255252 TI - Predicting the warfarin maintenance dose in elderly inpatients at treatment initiation: accuracy of dosing algorithms incorporating or not VKORC1/CYP2C9 genotypes. AB - BACKGROUND: Initiating warfarin is challenging in frail elderly patients because of low-dose requirements and interindividual variability. OBJECTIVES: We investigated whether incorporating VKORC1 and CYP2C9 genotype information in different models helped to predict the warfarin maintenance dose when added to clinical data and INR values at baseline (Day 0), and during warfarin induction. PATIENTS: We prospectively enrolled 187 elderly inpatients (mean age, 85.6 years), all starting on warfarin using the same 'geriatric dosing-algorithm' based on the INR value measured on the day after three 4-mg warfarin doses (INR(3)) and on INR(6 +/- 1). RESULTS: On Day 0, the clinical model failed to accurately predict the maintenance dose (R(2) < 0.10). Adding the VKORC1 and CYP2C9 genotypes to the model increased R(2) to 0.31. On Day 3, the INR(3) value was the strongest predictor, completely embedding the VKORC1 genotype, whereas the CYP2C9 genotype remained a significant predictor (model- R(2) 0.55). On Day 6 +/- 1, none of the genotypes predicted the maintenance dose. Finally, the simple 'geriatric dosing-algorithm' was the most accurate algorithm on Day 3 (R(2) 0.77) and Day 6 (R(2) 0.81), under-estimating (>= 1 mg) and over-estimating the dose (>= 1 mg) in fewer than 10% and 2% of patients, respectively. Clinical models and the 'geriatric dosing-algorithm' were validated on an independent sample. CONCLUSIONS: Before starting warfarin therapy, the VKORC1 genotype is the best predictor of the maintenance dose. Once treatment is started using induction doses tailored for elderly patients, the contribution of VKORC1 and CYP2C9 genotypes in dose refinement is negligible compared with two INR values measured during the first week of treatment. PMID- 21255253 TI - A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). AB - BACKGROUND: Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients' well-being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well- of children with hemophilia. OBJECTIVE: This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image-proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10-year time period. METHODS: Forty-five children with severe hemophilia A, aged 1-7 years (median 4), with negative clinical-radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25 IU kg(-1) 3 * week) or episodic therapy with >=25 IU kg(-1) every 12-24 h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated. RESULTS: Twenty-one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P < 0.02). Plain-film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P < 0.05). Prophylaxis was more effective when started early (<=36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy. CONCLUSION: This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life. PMID- 21255254 TI - Rates of venous thromboembolism in multiple myeloma patients undergoing immunomodulatory therapy with thalidomide or lenalidomide: a systematic review and meta-analysis. AB - INTRODUCTION: The incidence of venous thromboembolism (VTE) in patients with multiple myeloma (MM) treated with thalidomide- and lenalidomide-based regimens is high. Recent observational studies have suggested that thromboprophylaxis might be efficacious in decreasing the risk of VTE in this population. PURPOSE: To determine the absolute rates of VTE with and without different thromboprophylactic agents in patients with newly diagnosed or previously treated MM receiving thalidomide- or lenalidomide-based regimens. RESULTS: Patients with newly diagnosed MM treated with thalidomide in combination with dexamethasone have a VTE risk of 4.1 (95% CI, 2.8-5.9) per 100 patient-cycles. Therapeutic doses of anticoagulants seem to provide the largest absolute risk reduction of VTE. The rate of VTE in patients with previously treated MM receiving thalidomide in combination with dexamethasone is 0.8 (95% CI, 0.1-2.1) per 100 patient months. A combination of lenalidomide and dexamethasone is associated with of risk of VTE of 0.8 (95% CI, 0.07-2.0) per 100 patient-cycles and 0.7 (95% CI, 0.4 0.9) per 100 patient-cycles in patients with newly diagnosed and previously treated MM, respectively. Similarly, the rates of VTE in patients also receiving thromboprophylaxis with aspirin were 0.9 (95% CI, 0.5-1.5) and 0.6 (95% CI, 0.01 2.1), respectively. CONCLUSION: Patients with newly diagnosed or previously treated MM receiving thalidomide- or lenalidomide-based regimens in combination with dexamethasone are at high risk of VTE. The benefit of various types of thromboprophylaxis is difficult to quantify in patients with MM receiving immunomodulatory therapy, especially in those receiving lenalidomide-based therapy or who have previously treated MM. Randomized controlled trials are needed to address this important clinical need. PMID- 21255255 TI - Clopidogrel 150 vs. 75 mg day(-1) in patients undergoing percutaneous coronary intervention: a meta-analysis. AB - BACKGROUND: Whether an increase in the daily oral maintenance dose of clopidogrel may improve clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) is still debated. OBJECTIVES: This meta-analysis aimed to estimate the relative effect of a 150- vs. 75-mg daily maintenance dosage of clopidogrel on clinical and laboratory end-points in patients undergoing PCI. METHODS: We searched electronic and printed sources (up to 14 December 2010) for both randomized control trials and observational studies satisfying the predefined inclusion criteria. RESULTS: We retrieved 12 reports of studies including a total of 23,814 patients. Clopidogrel, 150 mg day(-1), was associated with significant reductions in major adverse cardiac and/or cerebrovascular events (odds ratio [OR], 0.67; 95% confidence interval [CI], 0.48-0.94), myocardial infarction (OR, 0.72; 95% CI, 0.60-0.86), target vessel revascularization (OR, 0.27; 95% CI, 0.12-0.62) and stent thrombosis (OR, 0.64; 95% CI, 0.53-0.77) and decreased adenosine diphosphate-induced maximal platelet aggregation. However, as compared with 75 mg day(-1), the 150-mg daily maintenance dosage significantly increased the risk of minor bleeding (OR, 1.21; 95% CI, 1.08-1.36). CONCLUSION: As compared with the currently recommended 75-mg day(-1) maintenance dosage of clopidogrel, the 150-mg day(-1) dosage can reduce major adverse cardiac and/or cerebrovascular events but may increase the risk of minor bleeding. PMID- 21255257 TI - Letter to the editor: the importance of using a cross-cultural adaptation in nursing questionnaires and tools. PMID- 21255258 TI - Clinical indicators of ineffective breathing pattern in children with congenital heart diseases. AB - PURPOSE: The study aims to assess indicators of Nursing Outcomes Classification (NOC) related to the nursing diagnosis Ineffective Breathing Pattern (IBP) in children with congenital heart disease (CHD). METHODS: The study used a cross sectional study carried out in 63 children with CHD up to 2 years old. Seventeen operational indicators of NOC related to IBP were evaluated. FINDINGS: Seven indicators presented statistically significant differences between children with and without IBP. Impaired expiration was the indicator assessed with greatest frequency in both groups. CONCLUSIONS: The study showed differences in the clinical indicators between children with and without IBP. IMPLICATIONS FOR NURSING PRACTICE: The use of NOC indicators allowed an assessment of the differences and the level of respiratory impairment among children with and without IBP. PMID- 21255259 TI - Most frequent nursing diagnoses, nursing interventions, and nursing-sensitive patient outcomes of hospitalized older adults with heart failure: part 1. AB - PURPOSE: Rank and compare the 10 most frequently documented nursing diagnoses, interventions, and patient outcomes using NANDA International, Nursing Interventions Classification, and Nursing Outcomes Classification for care of patients with heart failure (HF). METHODS: A descriptive comparative multisite study of documented care for 302 older adults with HF. FINDINGS: There were four common nursing diagnoses, two interventions, and only three common outcomes across three sites. CONCLUSIONS: This and similar analyses of clinical nursing data can be used by nursing administrators and clinicians to monitor the quality and effectiveness of nursing care. IMPLICATIONS: Similar analyses may be used for continuing education, quality improvement, and documentation system refinement. Part 2 will discuss data retrieval and implications for building a multiorganizational data warehouse. PMID- 21255260 TI - Special report: Nursing diagnoses and interventions for a child with dilated cardiomyopathy requiring intra-aortic balloon pump support--case report. AB - OBJECTIVE: The study aims to identify the nursing diagnoses and interventions for a child requiring intra-aortic balloon pump support. METHODS: This was a case study of a 7-year-old child. The nursing diagnoses and interventions were obtained by three cardiology and pediatric specialist nurses, familiar with NANDA International and Nursing Intervention Classification taxonomies. RESULTS: Many nursing diagnoses and interventions were identified, but the main diagnosis for this patient was decreased cardiac output. CONCLUSIONS: The nursing care for a child with an intra-aortic balloon requires well-qualified professionals, prepared to handle the diagnoses and interventions identified in this study. PRACTICAL IMPLICATIONS: The use of a standard language system is essential to guide professionals in the caring process, providing essential elements to optimize interpretations. PMID- 21255261 TI - Content validation of hopelessness in Slovakia and Czech Republic. AB - PURPOSE: The purpose of this study was to validate the content of nursing diagnosis hopelessness in Slovak and Czech social and cultural contexts. METHODS: The Fehring's Diagnostic Content Validity Model was used to measure the importance of diagnostic characteristics of hopelessness. FINDINGS: Only three NANDA characteristics and five Nowotny Hope Scale characteristics have reached the value of weighted average of the scores for defining characteristics. CONCLUSION: NANDA characteristics are concerned with the affective-behavioral dimension of hopelessness. Nowotny Hope Scale characteristics that reached high importance in our study are concerned with its cognitive-temporal dimension. IMPLICATIONS FOR NURSING PRACTICE: The defining characteristics of hopelessness identified in our study could be tested in the development of instrument to measure hope in clinical practice. PMID- 21255262 TI - A case study of teen parenting. AB - PURPOSE: The purpose of this case study is to demonstrate how the use of the standard nursing languages of NANDA International (NANDA-I), the Nursing Interventions Classification (NIC), and the Nursing Outcomes Classification (NOC) help a teen mother provide safe care for her newborn. In addition, this study aims to demonstrate how important standardized nursing languages are in documenting the care provided. DATA SOURCES: The data sources for this article are clinical nursing practice, research evidence in the form of care directives from the American Academy of Pediatrics regarding newborn safety and feeding, and the books that provide directions for the use of NANDA-I, NIC, and NOC. DATA SYNTHESIS: This case demonstrates the use of the nursing process in providing care for a teen mother and a newborn. CONCLUSIONS: Many new mothers, especially teens, are poorly informed regarding normal newborn care and safety upon hospital discharge. For this reason, teen mothers should be referred for nursing assessments in the home environment after discharge. IMPLICATIONS FOR NURSING: This case demonstrates the need for education of all parents prior to hospital discharge and supports the need for home-based evaluations to ensure the safety of the infant. This case also supports the use of standardized nursing language to document the care provided. PMID- 21255263 TI - Palmitoylethanolamide counteracts reactive astrogliosis induced by beta-amyloid peptide. AB - Emerging evidence indicates that astrogliosis is involved in the pathogenesis of neurodegenerative disorders. Our previous findings suggested cannabinoids and Autacoid Local Injury Antagonism Amides (ALIAmides) attenuate glial response in models of neurodegeneration. The present study was aimed at exploring palmitoylethanolamide (PEA) ability to mitigate beta-amyloid (Abeta)-induced astrogliosis. Experiments were carried out to investigate PEA's (10(-7) M) effects upon the expression and release of pro-inflammatory molecules in rat primary astrocytes activated by soluble Abeta(1-42) (1 MUg/ml) as well as to identify mechanisms responsible for such actions. The effects of Abeta and exogenous PEA on the astrocyte levels of the endocannabinoidsand of endogenous ALIAmides were also studied. The peroxisome proliferator-activated receptor (PPAR)-alpha (MK886, 3 MUM) or PPAR-gamma (GW9662, 9 nM) antagonists were co administered with PEA. Abeta elevated endogenous PEA and d5-2 arachidonoylglycerol (2-AG) levels. Exogenous PEA blunted the Abeta-induced expression of pro-inflammatory molecules. This effect was reduced by PPAR-alpha antagonist. Moreover, this ALIAmide, like Abeta, increased 2-AG levels. These results indicate that PEA exhibits anti-inflammatory properties able to counteract Abeta-induced astrogliosis, and suggest novel treatment for neuroinflammatory/ neurodegenerative processes. PMID- 21255264 TI - Prolyl hydroxylase 2: a novel regulator of beta2 -adrenoceptor internalization. AB - Adrenergic receptor (AR)-mediated signalling is modulated by oxygen levels. Prolyl hydroxylases (PHDs) are crucial for intracellular oxygen sensing and organism survival. However, it remains to be clarified whether or how PHDs are involved in the regulation of beta(2) -adrenoceptor (beta(2) -AR) signalling. Here we show that PHD2 can modulate the rate of beta(2) -AR internalization through interactions with beta-arrestin 2. PHD2 hydroxylates beta-arrestin 2 at the proline (Pro)(176), Pro(179) and Pro(181) sites, which retards the recruitment of beta-arrestin 2 to the plasma membrane and inhibits subsequent co internalization with beta(2) -AR into the cytosol. beta(2) -AR internalization is critical to control the temporal and spatial aspects of beta(2) -AR signalling. Identifying novel regulators of beta(2) -AR internalization will enable us to develop new strategies to manipulate receptor signalling and provide potential targets for drug development in the prevention and treatment of diseases associated with beta(2) -AR signalling dysregulation. PMID- 21255265 TI - Association study of catechol-O-methyltransferase gene polymorphisms with schizophrenia and psychopathological symptoms in Han Chinese. AB - Although dysfunction of catechol-O-methyltransferase (COMT)-mediated dopamine transmission is implicated in the etiology of schizophrenia, the human COMT gene has not been associated consistently with schizophrenia. The purpose of this study was to investigate whether the COMT gene is associated with the development of schizophrenia and whether the polymorphisms of this gene influence the psychopathological symptoms in patients with schizophrenia. Fourteen polymorphisms of the COMT gene were analyzed in a case-control study of 876 Han Chinese individuals (434 patients and 442 controls). All participants were screened using a Chinese version of the modified Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-L) and all patients met the criteria for schizophrenia. Furthermore, pretreatment of psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS) in a subset of 224 hospitalized schizophrenia patients, who were drug-naIve or drug-free, to examine the association between clinical symptomatology and COMT polymorphisms. No significant differences in allele or genotype frequencies were observed between schizophrenia patients and controls, for all variants investigated. Haplotype analysis showed that three haplotype blocks of the COMT gene were not associated with the development of schizophrenia. Moreover, these COMT polymorphisms did not influence the PANSS scores of schizophrenia patients. This study suggests that the COMT gene may not contribute to the risk of schizophrenia and to the psychopathological symptoms of schizophrenia among Han Chinese. PMID- 21255266 TI - Steroid sulfatase is a potential modifier of cognition in attention deficit hyperactivity disorder. AB - Deletions encompassing the X-linked STS gene (encoding steroid sulfatase) have been observed in subjects with neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD). Recently, two single nucleotide polymorphisms (SNPs) within STS (rs12861247 and rs17268988) have been reported to be associated with ADHD risk and inattentive symptoms in ADHD, respectively. Using a UK sample of ADHD subjects (aged 5-18 years), we tested the hypothesis that rs12861247 is associated with ADHD risk using a case-control approach (comparing 327 ADHD cases with 358 male controls from the Wellcome Trust Case Control Consortium). Using a subset of males from the ADHD sample, we also examined whether variation within STS is associated with symptomatology/cognitive function in ADHD. We then tested whether SNPs associated with cognitive function in ADHD were also associated with cognitive function in healthy male subjects using a German sample (n = 143, aged 18-30 years), and whether STS was expressed in brain regions pertinent to ADHD pathology during development. We did not replicate the previously identified association with rs12861247. However, in ADHD males, variation at rs17268988 was associated with inattentive symptoms, while variation within STS was significantly associated with performance on three cognitive measures. Three SNPs associated with cognitive function in ADHD males were not associated with cognitive function in healthy males. STS was highly expressed in the developing cerebellar neuroepithelium, basal ganglia, thalamus, pituitary gland, hypothalamus and choroid plexus. These data suggest that genetic variants affecting STS expression and/or activity could influence the function of brain regions perturbed in ADHD. PMID- 21255267 TI - MTHFR polymorphisms and cognitive ageing in the ninth decade: the Lothian Birth Cohort 1921. AB - Low blood levels of B vitamins have been implicated in age-associated cognitive impairment. The present study investigated the association between genetic variation in folate metabolism and age-related cognitive decline in the ninth decade of life. Both the 677C>T (rs1801133) polymorphism and the scarcely studied 1298A>C (rs1801131) polymorphism of the MTHFR gene were assessed in relation to cognitive change over 8 years in older community-dwelling individuals. MTHFR genotype was determined in 476 participants of the Lothian Birth Cohort 1921, whose intelligence was measured in childhood in the Scottish Mental Survey of 1932. Cognitive performance on the domains of verbal memory, reasoning and verbal fluency was assessed at mean age of 79 (n = 476) and again at mean ages of 83 (n = 275) and 87 (n = 180). Using linear mixed models, the MTHFR 677C>T and 1298A>C variants were not associated with the rate of cognitive change between 79 and 87 years, neither in the total sample, nor in a subsample of individuals with erythrocyte folate levels below the median. APOE E4 allele carrier status did not interact with MTHFR genotype in affecting change in cognitive performance over 8 years. No significant combined effect of the two polymorphisms was found. In conclusion, MTHFR 677C>T and 1298A>C polymorphisms were not associated with individual change in cognitive functioning in the ninth decade of life. Although polymorphisms in the MTHFR gene may cause disturbances in folate metabolism, they do not appear to be accompanied by changes in cognitive functioning in old age. PMID- 21255268 TI - BDNF-restricted knockout mice as an animal model for aggression. AB - Mice with global deletion of one brain-derived neurotrophic factor (BDNF) allele or with forebrain-restricted deletion of both alleles show elevated aggression, but this phenotype is accompanied by other behavioral changes, including increases in anxiety and deficits in cognition. Here we performed behavioral characterization of conditional BDNF knockout mice generated using a Cre recombinase driver line, KA1-Cre, which expresses Cre in few areas of brain: highly at hippocampal area CA3 and moderately in dentate gyrus, cerebellum and facial nerve nucleus. The mutant animals exhibited elevated conspecific aggression and social dominance, but did not show changes in anxiety-like behaviors assessed using the elevated plus maze and open field test. There were no changes in depression-like behaviors tested in the forced swim test, but small increase in immobility in the tail suspension test. In cognitive tasks, mutants showed normal social recognition and normal spatial and fear memory, but exhibited a deficit in object recognition. Thus, this knockout can serve as a robust model for BDNF-dependent aggression and object recognition deficiency. PMID- 21255269 TI - Intranasal vasopressin affects pair bonding and peripheral gene expression in male Callicebus cupreus. AB - Arginine vasopressin (AVP) is a neuropeptide hormone and neurotransmitter that has peripheral functions in water regulation, and central functions in the stress response and social bonding in male rodents. In this study, we investigated the role of AVP in partner preference behavior in a monogamous primate, the coppery titi monkey (Callicebus cupreus). Seven titi males each received three intranasal treatments: saline, low AVP (40 IU) and high AVP (80 IU) in random order, 1 week apart. They experienced a series of stimulus exposures to their female partner, a female stranger and an empty cage. Males were more likely to contact the stimulus and do so faster when either female stimulus was present. When pretreated with saline, males contacted the stranger more frequently than their partner; when pretreated with the high dosage of AVP, males contacted their partner more frequently than the stranger. We used microarray to measure peripheral changes in gene expression associated with intranasal AVP and found reduced expression of several genes coding for proinflammatory cytokines. The data presented here suggest that intranasally administered AVP has both central influences on social behavior and peripheral influences on inflammation in a nonhuman primate. PMID- 21255270 TI - Twenty one important things you should know. PMID- 21255271 TI - Genetically engineered plants: greener than you think. PMID- 21255272 TI - Genomics of plant-associated microbes. PMID- 21255273 TI - Life of microbes that interact with plants. PMID- 21255274 TI - Agrobacterium tumefaciens and A. rhizogenes use different proteins to transport bacterial DNA into the plant cell nucleus. AB - Agrobacterium tumefaciens and A. rhizogenes transport single-stranded DNA (ssDNA; T-strands) and virulence proteins into plant cells through a type IV secretion system. DNA transfer initiates when VirD2 nicks border sequences in the tumour inducing plasmid, attaches to the 5' end, and pilots T-strands into plant cells. Agrobacterium tumefaciens translocates ssDNA-binding protein VirE2 into plant cells where it targets T-strands into the nucleus. Some A. rhizogenes strains lack VirE2 but transfer T-strands efficiently due to the GALLS gene, which complements an A. tumefaciens virE2 mutant. VirE2 and full-length GALLS (GALLS FL) contain nuclear localization sequences that target these proteins to the plant cell nucleus. VirE2 binds cooperatively to T-strands allowing it to move ssDNA without ATP hydrolysis. Unlike VirE2, GALLS-FL contains ATP-binding and helicase motifs similar to those in TraA, a strand transferase involved in conjugation. VirE2 may accumulate in the nucleus and pull T-strands into the nucleus using the force generated by cooperative DNA binding. GALLS-FL accumulates inside the nucleus where its predicted ATP-dependent strand transferase may pull T-strands into the nucleus. These different mechanisms for nuclear import of T-strands may affect the efficiency and quality of transgenic events in plant biotechnology applications. PMID- 21255275 TI - Developing microbe-plant interactions for applications in plant-growth promotion and disease control, production of useful compounds, remediation and carbon sequestration. AB - Interactions between plants and microbes are an integral part of our terrestrial ecosystem. Microbe-plant interactions are being applied in many areas. In this review, we present recent reports of applications in the areas of plant-growth promotion, biocontrol, bioactive compound and biomaterial production, remediation and carbon sequestration. Challenges, limitations and future outlook for each field are discussed. PMID- 21255276 TI - Nitrilase enzymes and their role in plant-microbe interactions. AB - Nitrilase enzymes (nitrilases) catalyse the hydrolysis of nitrile compounds to the corresponding carboxylic acid and ammonia, and have a wide range of industrial and biotechnological applications, including the synthesis of industrially important carboxylic acids and bioremediation of cyanide and toxic nitriles. Nitrilases are produced by a wide range of organisms, including plants, bacteria and fungi, but despite their biotechnological importance, the role of these enzymes in living organisms is relatively underexplored. Current research suggests that nitrilases play important roles in a range of biological processes. In the context of plant-microbe interactions they may have roles in hormone synthesis, nutrient assimilation and detoxification of exogenous and endogenous nitriles. Nitrilases are produced by both plant pathogenic and plant growth promoting microorganisms, and their activities may have a significant impact on the outcome of plant-microbe interactions. In this paper we review current knowledge of the role of nitriles and nitrilases in plants and plant-associated microorganisms, and discuss how greater understanding of the natural functions of nitrilases could be applied to benefit both industry and agriculture. PMID- 21255277 TI - Bacterial responses and interactions with plants during rhizoremediation. AB - With the increase in quality of life standards and the awareness of environmental issues, the remediation of polluted sites has become a priority for society. Because of the high economic cost of physico-chemical strategies for remediation, the use of biological tools for cleaning-up contaminated sites is a very attractive option. Rhizoremediation, the use of rhizospheric microorganisms in the bioremediation of contaminants, is the biotechnological approach that we explore in this minireview. We focus our attention on bacterial interactions with the plant surface, responses towards root exudates, and how plants and microbes communicate. We analyse certain strategies that may improve rhizoremediation, including the utilization of endophytes, and finally we discuss several rhizoremediation strategies that have opened ways to improve biodegradation. PMID- 21255278 TI - The outer membrane protein TolC is required for phytoalexin resistance and virulence of the fire blight pathogen Erwinia amylovora. AB - Erwinia amylovora causes fire blight on several plant species such as apple and pear, which produce diverse phytoalexins as defence mechanisms. An evolutionary successful pathogen thus must develop resistance mechanisms towards these toxic compounds. The E. amylovora outer membrane protein, TolC, might mediate phytoalexin resistance through its interaction with the multidrug efflux pump, AcrAB. To prove this, a tolC mutant and an acrB/tolC double mutant were constructed. The minimal inhibitory concentrations of diverse antimicrobials and phytoalexins were determined for these mutants and compared with that of a previously generated acrB mutant. The tolC and arcB/tolC mutants were considerably more susceptible than the wild type but showed similar levels as the acrB mutant. The results clearly indicated that neither TolC nor AcrAB significantly interacted with other transport systems during the efflux of the tested toxic compounds. Survival and virulence assays on inoculated apple plants showed that pathogenicity and the ability of E. amylovora to colonize plant tissue were equally impaired by mutations of tolC and acrB/tolC. Our results allowed the conclusion that TolC plays an important role as a virulence and fitness factor of E. amylovora by mediating resistance towards phytoalexins through its exclusive interaction with AcrAB. PMID- 21255279 TI - Endopathogenic lifestyle of Pseudomonas savastanoi pv. savastanoi in olive knots. AB - The endophytic phase of Pseudomonas savastanoi pv. savastanoi in olive stems and the structural and ultrastructural histogenesis of olive knots have been studied. Construction of a stable plasmid vector expressing the green fluorescent protein, in combination with the use of in vitro olive plants, allowed real-time monitoring of P. savastanoi pv. savastanoi infection. The infection process was also examined by bright field and epifluorescence microscopy as well as by scanning and transmission electron microscopy. Hypertrophy of the stem tissue was concomitant with the formation of bacterial aggregates, microcolonies and multilayer biofilms, over the cell surfaces and the interior of plasmolysed cells facing the air-tissue interface of internal opened fissures, and was followed by invasion of the outer layers of the hypertrophied tissue. Pathogenic invasion of the internal lumen of newly formed xylem vessels, which were connected with the stem vascular system, was also observed in late stages of infection. Ultrastructural analysis of knot sections showed the release of outer membrane vesicles from the pathogen surface, a phenomenon not described before for bacterial phytopathogens during host infection. This is the first real-time monitoring of P. savastanoi disease development and the first illustrated description of the ultrastructure of P. savastanoi-induced knots. PMID- 21255280 TI - Three independent signalling pathways repress motility in Pseudomonas fluorescens F113. AB - Motility is one of the most important traits for rhizosphere colonization by pseudomonads. Despite this importance, motility is severely repressed in the rhizosphere-colonizing strain Pseudomonas fluorescens F113. This bacterium is unable to swarm under laboratory conditions and produce relatively small swimming haloes. However, phenotypic variants with the ability to swarm and producing swimming haloes up to 300% larger than the wild-type strain, arise during rhizosphere colonization. These variants harbour mutations in the genes encoding the GacA/GacS two-component system and in other genes. In order to identify genes and pathways implicated in motility repression, we have used generalized mutagenesis with transposons. Analysis of the mutants has shown that besides the Gac system, the Wsp system and the sadB gene, which have been previously implicated in cyclic di-GMP turnover, are implicated in motility repression: mutants in the gacS, sadB or wspR genes can swarm and produce swimming haloes larger than the wild-type strain. Epistasis analysis has shown that the pathways defined by each of these genes are independent, because double and triple mutants show an additive phenotype. Furthermore, GacS, SadB and WspR act at different levels. Expression of the fleQ gene, encoding the master regulator of flagella synthesis is higher in the gacS(-) and sadB(-) backgrounds than in the wild-type strain and this differential expression is reflected by a higher secretion of the flagellin protein FliC. Conversely, no differences in fleQ expression or FliC secretion were observed between the wild-type strain and the wspR(-) mutant. PMID- 21255281 TI - Colonization process of olive tissues by Verticillium dahliae and its in planta interaction with the biocontrol root endophyte Pseudomonas fluorescens PICF7. AB - The colonization process of Olea europaea by the defoliating pathotype of Verticillium dahliae, and the in planta interaction with the endophytic, biocontrol strain Pseudomonas fluorescens PICF7 were determined. Differential fluorescent protein tagging was used for the simultaneous visualization of P. fluorescens PICF7 and V. dahliae in olive tissues. Olive plants were bacterized with PICF7 and then transferred to V. dahliae-infested soil. Monitoring olive colonization events by V. dahliae and its interaction with PICF7 was conducted using a non-gnotobiotic system, confocal laser scanner microscopy and tissue vibratoming sections. A yellow fluorescently tagged V. dahliae derivative (VDAT 36I) was obtained by Agrobacterium tumefaciens-mediated transformation. Isolate VDAT-36I quickly colonized olive root surface, successfully invaded root cortex and vascular tissues via macro- and micro-breakages, and progressed to the aerial parts of the plant through xylem vessel cells. Strain PICF7 used root hairs as preferred penetration site, and once established on/in root tissues, hindered pathogen colonization. For the first time using this approach, the entire colonization process of a woody plant by V. dahliae is reported. Early and localized root surface and root endophytic colonization by P. fluorescens PICF7 is needed to impair full progress of verticillium wilt epidemics in olive. PMID- 21255282 TI - Translocation and insecticidal activity of Bacillus thuringiensis living inside of plants. AB - The major biological pesticide for the control of insect infestations of crops, Bacillus thuringiensis was found to be present naturally within cotton plants from fields that had never been treated with commercial formulations of this bacterium. The ability of B. thuringiensis to colonize plants as an endophyte was further established by the introduction of a strain marked by production of green fluorescent protein (GFP). After inoculation of this preparation close to the roots of cotton and cabbage seedlings, GFP-marked bacteria could be re-isolated from all parts of the plant, having entered the roots and migrated through the xylem. Leaves taken from the treated plants were able to cause toxicity when fed to the Lepidoptera Spodoptera frugiperda (cotton) and Plutella xylostella (cabbage). These results open up new horizons for understanding the natural ecology and evolution of B. thuringiensis and use of B. thuringiensis in insect control. PMID- 21255283 TI - Transgenic expression of glucose dehydrogenase in Azotobacter vinelandii enhances mineral phosphate solubilization and growth of sorghum seedlings. AB - The enzyme quinoprotein glucose dehydrogenase (GDH) catalyses the oxidation of glucose to gluconic acid by direct oxidation in the periplasmic space of several Gram-negative bacteria. Acidification of the external environment with the release of gluconic acid contributes to the solubilization of the inorganic phosphate by biofertilizer strains of the phosphate-solubilizing bacteria. Glucose dehydrogenase (gcd) gene from Escherichia coli, and Azotobacter-specific glutamine synthetase (glnA) and phosphate transport system (pts) promoters were isolated using sequence-specific primers in a PCR-based approach. Escherichia coli gcd, cloned under the control of glnA and pts promoters, was mobilized into Azotobacter vinelandii AvOP and expressed. Sorghum seeds were bacterized with the transgenic azotobacters and raised in earthen pots in green house. The transgenic azotobacters, expressing E. coli gcd, showed improved biofertilizer potential in terms of mineral phosphate solubilization and plant growth-promoting activity with a small reduction in nitrogen fixation ability. PMID- 21255285 TI - New molecular tools for enhancing methane production, explaining thermodynamically limited lifestyles and other important biotechnological issues. PMID- 21255286 TI - Special issue: Microbiology of energy biotechnology. PMID- 21255287 TI - Waste lipids to energy: how to optimize methane production from long-chain fatty acids (LCFA). AB - The position of high-rate anaerobic technology (HR-AnWT) in the wastewater treatment and bioenergy market can be enhanced if the range of suitable substrates is expanded. Analyzing existing technologies, applications and problems, it is clear that, until now, wastewaters with high lipids content are not effectively treated by HR-AnWT. Nevertheless, waste lipids are ideal potential substrates for biogas production, since theoretically more methane can be produced, when compared with proteins or carbohydrates. In this minireview, the classical problems of lipids methanization in anaerobic processes are discussed and new concepts to enhance lipids degradation are presented. Reactors operation, feeding strategies and prospects of technological developments for wastewater treatment are discussed. Long-chain fatty acids (LCFA) degradation is accomplished by syntrophic communities of anaerobic bacteria and methanogenic archaea. For optimal performance these syntrophic communities need to be clustered in compact aggregates, which is often difficult to achieve with wastewaters that contain fats and lipids. Driving the methane production from lipids/LCFA at industrial scale without risk of overloading and inhibition is still a challenge that has the potential for filling a gap in the existing processes and technologies for biological methane production associated to waste and wastewater treatment. PMID- 21255288 TI - Current state and perspectives of producing biodiesel-like compounds by biotechnology. AB - The global demand for crude oil is expected to continue to rise in future while simultaneously oil production is currently reaching its peak. Subsequently, rising oil prices and their negative impacts on economy, together with an increased environmental awareness of our society, directed the focus also on the biotechnological production of fuels. Although a wide variety of such fuels has been suggested, only the production of ethanol and biodiesel has reached a certain economic feasibility and volume, yet. This review focuses on the current state and perspectives of biotechnological production of biodiesel-like compounds. At present by far most of the produced biodiesel is obtained by chemical transesterification reactions, which cannot meet the demands of a totally 'green' fuel production. Therefore, also several biotechnological biodiesel production processes are currently being developed. Biotechnological production can be achieved by purified enzymes in the soluble state, which requires cost-intensive protein preparation. Alternatively, enzymes could be immobilized on an appropriate matrix, enabling a reuse of the enzyme, although the formation of by-products may provide difficulties to maintain the enzyme activity. Processes in presence of organic solvents like t-butanol have been developed, which enhance by-product solubility and therefore prevent loss of enzyme activity. As another approach the application of whole-cell catalysis for the production of fatty acid ethyl esters, which is also referred to as 'microdiesel', by recombinant microorganisms has recently been suggested. PMID- 21255289 TI - The thermodynamic landscape of methanogenic PAH degradation. AB - Methanogenic degradation of polycyclic aromatic hydrocarbons (PAHs) has long been considered impossible, but evidence in contaminated near surface environments and biodegrading petroleum reservoirs suggests that this is not necessarily the case. To evaluate the thermodynamic constraints on methanogenic PAH degradation we have estimated the Gibbs free energy values for naphthalene, phenanthrene, anthracene, pyrene and chrysene in the aqueous phase, and used these values to evaluate several possible routes whereby PAHs may be converted to methane. Under standard conditions (25 degrees C, solutes at 1 M concentrations, and gases at 1 atm), methanogenic degradation of these PAHs yields between 209 and 331 kJ mol(-1). Per mole of methane produced this is 27-35 kJ mol(-1), indicating that PAH-based methanogenesis is exergonic. We evaluated the energetics of three potential PAH degradation routes: oxidation to H(2)/CO(2), complete conversion to acetate, or incomplete oxidation to H(2) plus acetate. Depending on the in situ conditions the energetically most favourable pathway for the PAH-degrading organisms is oxidation to H(2)/CO(2) or conversion into acetate. These are not necessarily the pathways that prevail in the environment. This may be because the kinetic theory of optimal length of metabolic pathways suggests that PAH degraders may have evolved towards incomplete oxidation to acetate plus H(2) as the optimal pathway. PMID- 21255290 TI - Substrate-dependent transcriptomic shifts in Pelotomaculum thermopropionicum grown in syntrophic co-culture with Methanothermobacter thermautotrophicus. AB - Pelotomaculum thermopropionicum is a syntrophic propionate-oxidizing bacterium that catalyses the intermediate bottleneck step of the anaerobic-biodegradation process. As it thrives on a very small energy conserved by propionate oxidation under syntrophic association with a methanogen, its catabolic pathways and regulatory mechanisms are of biological interest. In this study, we constructed high-density oligonucleotide microarrays for P. thermopropionicum, and used them to analyse global transcriptional responses of this organism to different growth substrates (propionate, ethanol, propanol and lactate) in co-culture with a hydrogenotrophic methanogenic archaeon, Methanothermobacter thermautotrophicus (by reference to fumarate monoculture). We found that a substantial number of genes were upregulated in the syntrophic co-cultures irrespective of growth substrates (including those related to amino-acid and cofactor metabolism), suggesting that these processes were influenced by the syntrophic partner. Expression of the central catabolic pathway (the propionate-oxidizing methylmalonyl-CoA pathway) was found to be substrate-dependent and was largely stimulated when P. thermopropionicum was grown on propionate and lactate. This finding was supported by results of growth tests, revealing that syntrophic propionate oxidation was largely accelerated by supplementation with lactate. These results revealed that P. thermopropionicum has complex regulatory mechanisms that alter its metabolism in response to the syntrophic partner and growth substrates. PMID- 21255292 TI - Hydrocarbon-degrading bacteria: the oil-spill clean-up crew. PMID- 21255293 TI - Fresh produce as a potential vector for bacterial human pathogens. PMID- 21255294 TI - The heat, drugs and knockout systems of microbial biotechnology. PMID- 21255295 TI - Bacteriophage biocontrol in animals and meat products. AB - Since their discovery almost a century ago, bacterial viruses (bacteriophages or 'phages') have been used to prevent and treat a multitude of bacterial infections (phage therapy: PT). In addition, they have been the basis for many advances in genetics and biochemistry. Phage therapy was performed on human subjects in the United States, Europe and Asia in the few decades following their discovery. However, Western countries largely abandoned PT in favour of antibiotics in the 1940s. The relatively recent renaissance of PT in the West can be attributed partly to the increasing prevalence of antibiotic resistance in human and animal pathogens. However, the stringent controls on human trials now required in the United States and Europe have led to a greater number of domestic animal and agricultural applications as an alternative to PT in man. This trend is set to continue, at least in the short term, with recent approval from the Food and Drug Administration allowing commercial phage treatments to be used in human food in the USA. Nevertheless, despite these significant milestones and the growing number of successful PT trials, significant obstacles remain to their widespread use in animals, food and ultimately medicine in many parts of the world. This review will provide a brief overview of the history of PT in the West and will summarize some of the key findings of phage biocontrol studies in animals and meat products. PMID- 21255296 TI - Dynamic of active microorganisms inhabiting a bioleaching industrial heap of low grade copper sulfide ore monitored by real-time PCR and oligonucleotide prokaryotic acidophile microarray. AB - The bioleaching of metal sulfide has developed into a very important industrial process and understanding the microbial dynamic is key to advancing commercial bioleaching operations. Here we report the first quantitative description of the dynamic of active communities in an industrial bioleaching heap. Acidithiobacillus ferrooxidans was the most abundant during the first part of the leaching cycle, while the abundance of Leptospirillum ferriphilum and Ferroplasma acidiphilum increased with age of the heap. Acidithiobacillus thiooxidans kept constant throughout the leaching cycle, and Firmicutes group showed a low and a patchy distribution in the heap. The Acidiphilium-like bacteria reached their highest abundance corresponding to the amount of autotrophs. The active microorganisms in the leaching system were determined using two RNA-based sensitive techniques. In most cases, the 16S rRNA copy numbers of At. ferrooxidans, L. ferriphilum, At. thiooxidans and F. acidiphilum, was concomitant with the DNA copy numbers, whereas Acidiphilium-like bacteria and some Firmicutes members did not show a clear correlation between 16S rRNA accumulation and DNA copy numbers. However, the prokaryotic acidophile microarray (PAM) analysis showed active members of Alphaproteobacteria in all samples and of Sulfobacillus genus in older ones. Also, new active groups such as Actinobacteria and Acidobacterium genus were detected by PAM. The results suggest that changes during the leaching cycle in chemical and physical conditions, such as pH and Fe(3+)/Fe(2+) ion rate, are primary factors shaping the microbial dynamic in the heap. PMID- 21255297 TI - Tyramine biosynthesis in Enterococcus durans is transcriptionally regulated by the extracellular pH and tyrosine concentration. AB - The microbial decarboxylation of some amino acids leads to the undesirable presence of biogenic amines in foods. One of the most abundant and frequent biogenic amines found in fermented foods is tyramine, which is produced by the decarboxylation of tyrosine. In the present work, transcriptional analysis of tyramine biosynthesis in Enterococcus durans IPLA655, a strain isolated from cheese, was studied. The gene coding for the tyrosine decarboxylase (tdcA) and that coding for the tyrosine-tyramine antiporter (tyrP) form an operon transcribed from the promoter P(tdcA), the expression of which is regulated by the extracellular pH and tyrosine concentration. Quantification of gene expression during the log phase of growth showed high concentrations of tyrosine and acidic pH conditions to induce tdcA-tyrP polycistronic messenger transcription. PMID- 21255298 TI - Viscoelastic properties of Staphylococcus aureus and Staphylococcus epidermidis mono-microbial biofilms. AB - The viscoelastic properties of mono-microbial biofilms produced by ocular and reference staphylococcal strains were investigated. The microorganisms were characterized for their haemolytic activity and agr typing and the biofilms, grown on stainless steel surface under static conditions, were analysed by Confocal Laser Scanning Microscopy. Static and dynamic rheometric tests were carried out to determine the steady-flow viscosity and the elastic and viscous moduli. The analysed biofilms showed the typical time-dependent behaviour of viscoelastic materials with considerable elasticity and mechanical stability except for Staphylococcus aureus ATCC 29213 biofilm which showed a very fragile structure. In particular, S. aureus 6ME biofilm was more compact than other staphylococcal biofilms studied with a yield stress ranging between 2 and 3Pa. The data obtained in this work could represent a starting point for developing new therapeutic strategies against biofilm-associated infections, such as improving the drug effect by associating an antimicrobial agent with a biofilm viscoelasticity modifier. PMID- 21255300 TI - Probiotics genomics. PMID- 21255301 TI - Metabolic engineering, new antibiotics and biofilm viscoelasticity. AB - In the following highlight we refer to a number of new advances in the field of Biotechnology that address issues relating to the synthesis of new antibiotics, new biocatalysts and matrices in biofilms. PMID- 21255302 TI - LOVely enzymes - towards engineering light-controllable biocatalysts. AB - Light control over enzyme function represents a novel and exciting field of biocatalysis research. Blue-light photoreceptors of the Light, Oxygen, Voltage (LOV) family have recently been investigated for their applicability as photoactive switches. We discuss here the primary photochemical events leading to light activation of LOV domains as well as the proposed signal propagation mechanism to the respective effector domain. Furthermore, we describe the construction of LOV fusions to different effector domains, namely a dihydrofolate reductase from Escherichia coli and a lipase from Bacillus subtilis. Both fusion partners retained functionality, and alteration of enzyme activity by light was also demonstrated. Hence, it appears that fusion of LOV photoreceptors to functional enzyme target sites via appropriate linker structures may represent a straightforward strategy to design light controllable biocatalysts. PMID- 21255304 TI - Directed evolution of the transcription factor XylS for development of improved expression systems. AB - The inducible Pm promoter together with its cognate positive transcription regulator XylS has been shown to be useful for recombinant protein production under high cell density conditions. Here we report directed evolution of XylS resulting in mutant proteins with increased ability to stimulate transcription in Escherichia coli from Pm. A first round of mutagenesis using error-prone PCR on xylS was used to construct a library consisting of about 430,000 clones, and this library could be efficiently screened with respect to stimulation of expression from Pm due to a positive correlation between the level of expression of the reporter gene, bla (encoding beta-lactamase), and the ampicillin tolerance of the corresponding host cells. Fourteen different amino acid substitutions in XylS were found to separately lead to up to nearly a threefold stimulation of expression under induced conditions, relative to wild type. These mutations were all located in the part corresponding to the N-terminal half of the protein. Varying combinations of the mutations resulted in further stimulation, and the best results (about 10-fold stimulation under induced conditions) were obtained by using a random shuffling procedure followed by a new round of screening. The uninduced levels of expression for the same mutants also increased, but only about four times. Through in silico 3D modelling of the N-terminal domain of XylS, it was observed that the evolved mutant proteins contained substitutions that were positioned in different parts of the predicted structure, including a beta-barrel putatively responsible for effector binding and a coiled coil probably important for dimerization. The total production of the host-toxic antibody fragment scFv-phOx expressed from Pm with the evolved XylS mutant protein StEP-13 was about ninefold higher than with wild-type XylS, demonstrating that directed evolution of transcription factors can be an important new tool to achieve high-level recombinant protein production. PMID- 21255303 TI - Metabolic engineering of cobalamin (vitamin B12) production in Bacillus megaterium. AB - Cobalamin (vitamin B(12)) production in Bacillus megaterium has served as a model system for the systematic evaluation of single and multiple directed molecular and genetic optimization strategies. Plasmid and genome-based overexpression of genes involved in vitamin B(12) biosynthesis, including cbiX, sirA, modified hemA, the operons hemAXCDBL and cbiXJCDETLFGAcysG(A)cbiYbtuR, and the regulatory gene fnr, significantly increased cobalamin production. To reduce flux along the heme branch of the tetrapyrrole pathway, an antisense RNA strategy involving silencing of the hemZ gene encoding coproporphyrinogen III oxidase was successfully employed. Feedback inhibition of the initial enzyme of the tetrapyrrole biosynthesis, HemA, by heme was overcome by stabilized enzyme overproduction. Similarly, the removal of the B(12) riboswitch upstream of the cbiXJCDETLFGAcysG(A)cbiYbtuR operon and the recombinant production of three different vitamin B(12) binding proteins (glutamate mutase GlmS, ribonucleotide triphosphate reductase RtpR and methionine synthase MetH) partly abolished B(12) dependent feedback inhibition. All these strategies increased cobalamin production in B. megaterium. Finally, combinations of these strategies enhanced the overall intracellular vitamin B(12) concentrations but also reduced the volumetric cellular amounts by placing the organism under metabolic stress. PMID- 21255305 TI - Inter-conversion of catalytic abilities in a bifunctional carboxyl/feruloyl esterase from earthworm gut metagenome. AB - Carboxyl esterases (CE) exhibit various reaction specificities despite of their overall structural similarity. In present study we have exploited functional metagenomics, saturation mutagenesis and experimental protein evolution to explore residues that have a significant role in substrate discrimination. We used an enzyme, designated 3A6, derived from the earthworm gut metagenome that exhibits CE and feruloyl esterase (FAE) activities with p-nitrophenyl and cinnamate esters, respectively, with a [(k(cat)/K(m))](CE)/[(k(cat)/K(m))](FAE) factor of 17. Modelling-guided saturation mutagenesis at specific hotspots (Lys(281), Asp(282), Asn(316) and Lys(317)) situated close to the catalytic core (Ser(143)/Asp(273)/His(305)) and a deletion of a 34-AA-long peptide fragment yielded mutants with the highest CE activity, while cinnamate ester bond hydrolysis was effectively abolished. Although, single to triple mutants with both improved activities (up to 180-fold in k(cat)/K(m) values) and enzymes with inverted specificity ((k(cat)/K(m))(CE)/(k(cat)/K(m))(FAE) ratio of ~0.4) were identified, no CE inactive variant was found. Screening of a large error-prone PCR-generated library yielded by far less mutants for substrate discrimination. We also found that no significant changes in CE activation energy occurs after any mutation (7.3 to -5.6 J mol(-1)), whereas a direct correlation between loss/gain of FAE function and activation energies (from 33.05 to -13.7 J mol(-1)) was found. Results suggest that the FAE activity in 3A6 may have evolved via introduction of a limited number of 'hot spot' mutations in a common CE ancestor, which may retain the original hydrolytic activity due to lower restrictive energy barriers but conveys a dynamic energetically favourable switch of a second hydrolytic reaction. PMID- 21255306 TI - Enantioselective kinetic resolution of phenylalkyl carboxylic acids using metagenome-derived esterases. AB - Enantiomerically pure beta-arylalkyl carboxylic acids are important synthetic intermediates for the preparation of a wide range of compounds with biological and pharmacological activities. A library of 83 enzymes isolated from the metagenome was searched for activity in the hydrolysis of ethyl esters of three racemic phenylalkyl carboxylic acids by a microtiter plate-based screening using a pH-indicator assay. Out of these, 20 enzymes were found to be active and were subjected to analytical scale biocatalysis in order to determine their enantioselectivity. The most enantioselective and also enantiocomplementary biocatalysts were then used for preparative scale reactions. Thus, both enantiomers of each of the three phenylalkyl carboxylic acids studied could be obtained in excellent optical purity and high yields. PMID- 21255307 TI - Nature versus nurture in two highly enantioselective esterases from Bacillus cereus and Thermoanaerobacter tengcongensis. AB - There is an increasing need for the use of biocatalysis to obtain enantiopure compounds as chiral building blocks for drug synthesis such as antibiotics. The principal findings of this study are: (i) the complete sequenced genomes of Bacillus cereus ATCC 14579 and Thermoanaerobacter tengcongensis MB4 contain a hitherto undescribed enantioselective and alkaliphilic esterase (BcEST and TtEST respectively) that is specific for the production of (R)-2-benzyloxy-propionic acid ethyl ester, a key intermediate in the synthesis of levofloxacin, a potent antibiotic; and (ii) directed evolution targeted for increased thermostability of BcEST produced two improved variants, but in either case the 3-5 degrees C increase in the apparent melting temperature (T(m)) of the mutants over the native BcEST that has a T(m) of 50 degrees C was outperformed by TtEST, a naturally occurring homologue with a T(m) of 65 degrees C. Protein modelling of BcEST mapped the S148C and K272R mutations at protein surface and the I88T and Q110L mutations at more buried locations. This work expands the repertoire of characterized members of the alpha/beta-fold hydrolase superfamily. Further, it shows that genome mining is an economical option for new biocatalyst discovery and we provide a rare example of a naturally occurring thermostable biocatalyst that outperforms experimentally evolved homologues that carry out the same hydrolysis. PMID- 21255308 TI - Simple enzymatic procedure for L-carnosine synthesis: whole-cell biocatalysis and efficient biocatalyst recycling. AB - beta-Peptides and their derivates are usually stable to proteolysis and have an increased half-life compared with alpha-peptides. Recently, beta-aminopeptidases were described as a new enzyme class that enabled the enzymatic degradation and formation of beta-peptides. As an alternative to the existing chemical synthesis routes, the aim of the present work was to develop a whole-cell biocatalyst for the synthesis and production of beta-peptides using this enzymatic activity. For the optimization of the reaction system we chose the commercially relevant beta,alpha-dipeptide L-carnosine (beta-alanine-L-histidine) as model product. We were able to show that different recombinant yeast and bacteria strains, which overexpress a beta-peptidase, could be used directly as whole-cell biocatalysts for the synthesis of L-carnosine. By optimizing relevant reaction conditions for the best-performing recombinant Escherichia coli strain, such as pH and substrate concentrations, we obtained high l-carnosine yields of up to 71%. Long-time as well as biocatalyst recycling experiments indicated a high stability of the developed biocatalyst for at least five repeated batches. Application of the recombinant E. coli in a fed-batch process enabled the accumulation of l carnosine to a concentration of 3.7 g l(-1). PMID- 21255309 TI - Hyperthermostable acetyl xylan esterase. AB - An esterase which is encoded within a Thermotoga maritima chromosomal gene cluster for xylan degradation and utilization was characterized after heterologous expression of the corresponding gene in Escherichia coli and purification of the enzyme. The enzyme, designated AxeA, shares amino acid sequence similarity and its broad substrate specificity with the acetyl xylan esterase from Bacillus pumilus, the cephalosporin C deacetylase from Bacillus subtilis, and other (putative) esterases, allowing its classification as a member of carbohydrate esterase family 7. The recombinant enzyme displayed activity with p-nitrophenyl-acetate as well as with various acetylated sugar substrates such as glucose penta-acetate, acetylated oat spelts xylan and DMSO (dimethyl sulfoxide) extracted beechwood xylan, and with cephalosporin C. Thermotoga maritima AxeA represents the most thermostable acetyl xylan esterase known to date. In a 10 min assay at its optimum pH of 6.5 the enzyme's activity peaked at 90 degrees C. The inactivation half-life of AxeA at a protein concentration of 0.3 ug ul(-1) in the absence of substrate was about 13 h at 98 degrees C and about 67 h at 90 degrees C. Differential scanning calorimetry analysis of the thermal stability of AxeA corroborated its extreme heat resistance. A multi-phasic unfolding behaviour was found, with two apparent exothermic peaks at approximately 100-104 degrees C and 107.5 degrees C. In accordance with the crystal structure, gel filtration analysis at ambient temperature revealed that the enzyme has as a homohexameric oligomerization state, but a dimeric form was also found. PMID- 21255310 TI - Pleurotus ostreatus manganese-dependent peroxidase silencing impairs decolourization of Orange II. AB - Decolourization of azo dyes by Pleurotus ostreatus, a white-rot fungus capable of lignin depolymerization and mineralization, is related to the ligninolytic activity of enzymes produced by this fungus. The capacity of P. ostreatus to decolourize the azo dye Orange II (OII) was dependent and positively co-linear to Mn(2+) concentration in the medium, and thus attributed to Mn(2+)-dependent peroxidase (MnP) activity. Based on the ongoing P. ostreatus genome deciphering project we identified at least nine genes encoding for MnP gene family members (mnp 1-9), of which only four (mnp 1-4) were previously known. Relative real-time PCR quantification analysis confirmed that all the nine genes are transcribed, and that Mn(2+) amendment results in a drastic increase in the transcript levels of the predominantly expressed MnP genes (mnp 3 and mnp 9), while decreasing versatile peroxidase gene transcription (mnp 4). A reverse genetics strategy based on silencing the P. ostreatus mnp 3 gene by RNAi was implemented. Knock down of mnp 3 resulted in the reduction of fungal OII decolourization capacity, which was co-linear with marked silencing of the Mn(2+)-dependent peroxidase genes mnp 3 and mnp 9. This is the first direct genetic proof of an association between MnP gene expression levels and azo dye decolourization capacity in P. ostreatus, which may have significant implication on understanding the mechanisms governing lignin biodegradation. Moreover, this study has proven the applicability of RNAi as a tool for gene function studies in Pleurotus research. PMID- 21255311 TI - Sequence- and activity-based screening of microbial genomes for novel dehalogenases. AB - Dehalogenases are environmentally important enzymes that detoxify organohalogens by cleaving their carbon-halogen bonds. Many microbial genomes harbour enzyme families containing dehalogenases, but a sequence-based identification of genuine dehalogenases with high confidence is challenging because of the low sequence conservation among these enzymes. Furthermore, these protein families harbour a rich diversity of other enzymes including esterases and phosphatases. Reliable sequence determinants are necessary to harness genome sequencing-efforts for accelerating the discovery of novel dehalogenases with improved or modified activities. In an attempt to extract dehalogenase sequence fingerprints, 103 uncharacterized potential dehalogenase candidates belonging to the alpha/beta hydrolase (ABH) and haloacid dehalogenase-like hydrolase (HAD) superfamilies were screened for dehalogenase, esterase and phosphatase activity. In this first biochemical screen, 1 haloalkane dehalogenase, 1 fluoroacetate dehalogenase and 5 l-2-haloacid dehalogenases were found (success rate 7%), as well as 19 esterases and 31 phosphatases. Using this functional data, we refined the sequence-based dehalogenase selection criteria and applied them to a second functional screen, which identified novel dehalogenase activity in 13 out of only 24 proteins (54%), increasing the success rate eightfold. Four new L-2-haloacid dehalogenases from the HAD superfamily were found to hydrolyse fluoroacetate, an activity never previously ascribed to enzymes in this superfamily. PMID- 21255314 TI - Prokaryotic whole-transcriptome analysis: deep sequencing and tiling arrays. PMID- 21255315 TI - Sugar (ribose), spice (peroxidase) and all things nice (laccase hair-dyes). PMID- 21255316 TI - Paving the way for synthetic biology-based bioremediation in Europe. PMID- 21255318 TI - Production and biological function of volatile esters in Saccharomyces cerevisiae. AB - The need to understand and control ester synthesis is driven by the fact that esters play a key role in the sensorial quality of fermented alcoholic beverages like beer, wine and sake. As esters are synthesized in yeast via several complex metabolic pathways, there is a need to gain a clear understanding of ester metabolism and its regulation. The individual genes involved, their functions and regulatory mechanisms have to be identified. In alcoholic beverages, there are two important groups of esters: the acetate esters and the medium-chain fatty acid (MCFA) ethyl esters. For acetate ester synthesis, the genes involved have already been cloned and characterized. Also the biochemical pathways and the regulation of acetate ester synthesis are well defined. With respect to the molecular basis of MCFA ethyl ester synthesis, however, significant progress has only recently been made. Next to the characterization of the biochemical pathways and regulation of ester synthesis, a new and more important question arises: what is the advantage for yeast to produce these esters? Several hypotheses have been proposed in the past, but none was satisfactorily. This paper reviews the current hypotheses of ester synthesis in yeast in relation to the complex regulation of the alcohol acetyl transferases and the different factors that allow ester formation to be controlled during fermentation. PMID- 21255317 TI - Advances in the field of high-molecular-weight polycyclic aromatic hydrocarbon biodegradation by bacteria. AB - Interest in understanding prokaryotic biotransformation of high-molecular-weight polycyclic aromatic hydrocarbons (HMW PAHs) has continued to grow and the scientific literature shows that studies in this field are originating from research groups from many different locations throughout the world. In the last 10 years, research in regard to HMW PAH biodegradation by bacteria has been further advanced through the documentation of new isolates that represent diverse bacterial types that have been isolated from different environments and that possess different metabolic capabilities. This has occurred in addition to the continuation of in-depth comprehensive characterizations of previously isolated organisms, such as Mycobacterium vanbaalenii PYR-1. New metabolites derived from prokaryotic biodegradation of four- and five-ring PAHs have been characterized, our knowledge of the enzymes involved in these transformations has been advanced and HMW PAH biodegradation pathways have been further developed, expanded upon and refined. At the same time, investigation of prokaryotic consortia has furthered our understanding of the capabilities of microorganisms functioning as communities during HMW PAH biodegradation. PMID- 21255319 TI - pHg/pSILBAgamma vector system for efficient gene silencing in homobasidiomycetes: optimization of ihpRNA - triggering in the mycorrhizal fungus Laccaria bicolor. AB - pSILBAgamma silencing vector was constructed for efficient RNA silencing triggering in the model mycorrhizal fungus Laccaria bicolor. This cloning vector carries the Agaricus bisporus gpdII promoter, two multiple cloning sites separated by a L. bicolor nitrate reductase intron and the Aspergillus nidulans trpC terminator. pSILBAgamma allows an easy oriented two-step PCR cloning of hairpin sequences to be expressed in basidiomycetes. With one further cloning step into pHg, a pCAMBIA1300-based binary vector carrying a hygromycin resistance cassette, the pHg/pSILBAgamma plasmid is used for Agrobacterium-mediated transformation. The pHg/pSILBAgamma system results in predominantly single integrations of RNA silencing triggering T-DNAs in the fungal genome and the integration sites of the transgenes can be resolved by plasmid rescue. pSILBAgamma construct and two other pSILBA plasmid variants (pSILBA and pSILBAalpha) were evaluated for their capacity to silence Laccaria nitrate reductase gene. While all pSILBA variants tested resulted in up to 65-76% of transformants with reduced growth on nitrate, pSILBAgamma produced the highest number (65%) of strongly affected fungal strains. The strongly silenced phenotype was shown to correlate with T-DNA integration in transcriptionally active genomic sites. pHg/pSILBAgamma was shown to produce T-DNAs with minimum CpG methylation in transgene promoter regions which assures the maximum silencing trigger production in Laccaria. Methylation of the target endogene was only slight in RNA silencing triggered with constructs carrying an intronic spacer hairpin sequence. The silencing capacity of the pHg/pSILBAgamma was further tested with Laccaria inositol-1,4,5-triphosphate 5-phosphatase gene. Besides its use in silencing triggering, the herein described plasmid system can also be used for transgene expression in Laccaria. pHg/pSILBAgamma silencing system is optimized for L. bicolor but it should be highly useful also for other homobasidiomycetes, group of fungi currently lacking molecular tools for RNA silencing. PMID- 21255320 TI - Adaptation of anaerobically grown Thauera aromatica, Geobacter sulfurreducens and Desulfococcus multivorans to organic solvents on the level of membrane fatty acid composition. AB - The effect of different solvents and pollutants on the cellular fatty acid composition of three bacterial strains: Thauera aromatica, Geobacter sulfurreducens and Desulfococcus multivorans, representatives of diverse predominant anaerobic metabolisms was investigated. As the prevailing adaptive mechanism in cells of T. aromatica and G. sulfurreducens whose cellular fatty acids patterns were dominated by palmitic acid (C16:0) and palmitoleic acid (C16:1cis), the cells reacted by an increase in the degree of saturation of their membrane fatty acids when grown in the presence of sublethal concentrations of the chemicals. Next to palmitic acid C16:0, the fatty acid pattern of D. multivorans was dominated by anteiso-branched fatty acids which are characteristic for several sulfate-reducing bacteria. The cells responded to the solvents with an increase in the ratio of straight-chain saturated (C14:0, C16:0, C18:0) to anteiso-branched fatty acids (C15:0anteiso, C17:0anteiso, C17:1anteisoDelta9cis). The results show that anaerobic bacteria react with similar mechanisms like aerobic bacteria in order to adapt their membrane to toxic organic solvents. The observed adaptive modifications on the level of membrane fatty acid composition can only be carried out with de novo synthesis of the fatty acids which is strictly related to cell growth. As the growth rates of anaerobic bacteria are generally much lower than in the so far investigated aerobic bacteria, this adaptive response needs more time in anaerobic bacteria. This might be one explanation for the previously observed higher sensitivity of anaerobic bacteria when compared with aerobic ones. PMID- 21255321 TI - Adaptive evolution of baker's yeast in a dough-like environment enhances freeze and salinity tolerance. AB - We used adaptive evolution to improve freeze tolerance of industrial baker's yeast. Our hypothesis was that adaptation to low temperature is accompanied by enhanced resistance of yeast to freezing. Based on this hypothesis, yeast was propagated in a flour-free liquid dough model system, which contained sorbitol and NaCl, by successive batch refreshments maintained constantly at 12 degrees C over at least 200 generations. Relative to the parental population, the maximal growth rate (u(max)) under the restrictive conditions, increased gradually over the time course of the experiment. This increase was accompanied by enhanced freeze tolerance. However, these changes were not the consequence of genetic adaptation to low temperature, a fact that was confirmed by prolonged selection of yeast cells in YPD at 12 degrees C. Instead, the experimental populations showed a progressive increase in NaCl tolerance. This phenotype was likely achieved at the expense of others traits, since evolved cells showed a ploidy reduction, a defect in the glucose derepression mechanism and a loss in their ability to utilize gluconeogenic carbon sources. We discuss the genetic flexibility of S. cerevisiae in terms of adaptation to the multiple constraints of the experimental design applied to drive adaptive evolution and the technologically advantageous phenotype of the evolved population. PMID- 21255322 TI - Manipulation of charged residues within the two-peptide lantibiotic lacticin 3147. AB - Lantibiotics are antimicrobial peptides which contain a high percentage of post translationally modified residues. While most attention has been paid to the role of these critical structural features, evidence continues to emerge that charged amino acids also play a key role in these peptides. Here 16 'charge' mutants of the two-peptide lantibiotic lacticin 3147 [composed of Ltnalpha (2+, 2-) and Ltnbeta (2+)] were constructed which, when supplemented with previously generated peptides, results in a total bank of 23 derivatives altered in one or more charged residues. When examined individually, in combination with a wild-type partner or, in some instances, in combination with one another, these mutants reveal the importance of charge at specific locations within Ltnalpha and Ltnbeta, confirm the critical role of the negatively charged glutamate residue in Ltnalpha and facilitate an investigation of the contribution of positively charged residues to the cationic Ltnbeta. From these investigations it is also apparent that the relative importance of the overall charge of lacticin 3147 varies depending on the target bacteria and is most evident when strains with more negatively charged cell envelopes are targeted. These studies also result in, for the first time, the creation of a derivative of a lacticin 3147 peptide (LtnbetaR27A) which displays enhanced specific activity. PMID- 21255324 TI - Microbial Biotechnology: biofuels, genotoxicity reporters and robust agro ecosystems. PMID- 21255326 TI - Virulence regulation in Citrobacter rodentium: the art of timing. AB - The mouse enteric pathogen Citrobacter rodentium, like its human counterpart, enteropathogenic Escherichia coli, causes attaching and effacing lesions in the intestinal epithelium of its host. This phenotype requires virulence factors encoded by the locus for enterocyte effacement (LEE) pathogenicity island. For timely expression of these virulence determinants at the site of infection and for efficient delivery of some virulence factors into epithelial cells, C. rodentium utilizes a positive regulatory loop involving the LEE-encoded regulatory proteins Ler, GrlA and GrlR to control LEE expression. Several transcription factors not encoded by LEE, some of which respond to specific environmental signals, also participate in this regulatory loop. Recently, we identified a non-LEE encoded, AraC-like regulatory protein, RegA, which plays a key role in the ability of C. rodentium to colonize the intestine. RegA functions by activating the transcription of a number of horizontally acquired operons encoding virulence-associated factors, such as autotransporters, fimbriae, a dispersin-like protein and its transporter. In addition, RegA represses transcription of a number of housekeeping genes. Importantly, RegA requires a gut specific environmental signal, bicarbonate, to exert its effects on gene expression. In our proposed model, when C. rodentium senses bicarbonate ions in the gastrointestinal tract, RegA directs the bacterium to reduce the production of proteins involved in normal cellular functions, while enhancing the production of factors required for colonization and virulence. PMID- 21255325 TI - Advances in Campylobacter biology and implications for biotechnological applications. AB - Campylobacter jejuni is a major foodborne pathogen of animal origin and a leading cause of bacterial gastroenteritis in humans. During the past decade, especially since the publication of the first C. jejuni genome sequence, major advances have been made in understanding the pathobiology and physiology of this organism. It is apparent that C. jejuni utilizes sophisticated mechanisms for effective colonization of the intestinal tracts in various animal species. Although Campylobacter is fragile in the environment and requires fastidious growth conditions, it exhibits great flexibility in the adaptation to various habitats including the gastrointestinal tract. This high adaptability is attributable to its genetically, metabolically and phenotypically diverse population structure and its ability to change in response to various challenges. Unlike other enteric pathogens, such as Escherichia coli and Salmonella, Campylobacter is unable to utilize exogenous glucose and mainly depends on the catabolism of amino acids as a carbon source. Campylobacter proves highly mutable in response to antibiotic treatments and possesses eukaryote-like dual protein glycosylation systems, which modify flagella and other surface proteins with specific sugar structures. In this review we will summarize the distinct biological traits of Campylobacter and discuss the potential biotechnological approaches that can be developed to control this enteric pathogen. PMID- 21255327 TI - What heat is telling us about microbial conversions in nature and technology: from chip- to megacalorimetry. AB - The exploitation of microorganisms in natural or technological systems calls for monitoring tools that reflect their metabolic activity in real time and, if necessary, are flexible enough for field application. The Gibbs energy dissipation of assimilated substrates or photons often in the form of heat is a general feature of life processes and thus, in principle, available to monitor and control microbial dynamics. Furthermore, the combination of measured heat fluxes with material fluxes allows the application of Hess' law to either prove expected growth stoichiometries and kinetics or identify and estimate unexpected side reactions. The combination of calorimetry with respirometry is theoretically suited for the quantification of the degree of coupling between catabolic and anabolic reactions. New calorimeter developments overcome the weaknesses of conventional devices, which hitherto limited the full exploitation of this powerful analytical tool. Calorimetric systems can be integrated easily into natural and technological systems of interest. They are potentially suited for high-throughput measurements and are robust enough for field deployment. This review explains what information calorimetric analyses provide; it introduces newly emerging calorimetric techniques and it exemplifies the application of calorimetry in different fields of microbial research. PMID- 21255329 TI - Strategies for enhancing bioluminescent bacterial sensor performance by promoter region manipulation. AB - Bioluminescent bacterial sensors are based upon the fusion of bacterial bioluminescence (lux) genes, acting as a reporter element, to selected bacterial stress-response gene promoters. Depending upon the nature of the promoter, the resulting constructs react to diverse types of environmental stress, including the presence of toxic chemicals, by dose-dependant light emission. Two bacterial sensors, harbouring sulA::luxCDABE and grpE::luxCDABE fusions, activated by the model chemicals nalidixic acid (NA) and ethanol, respectively, were subjected to molecular manipulations of the promoter region, in order to enhance the intensity and speed of their response and lower their detection thresholds. By manipulating the length of the promoter-containing segment (both promoters), by introducing random or specific mutations in the promoter sequence or by duplicating the promoter sequence (sulA only), major improvements in sensor performance were obtained. Improvements included significantly enhanced sensitivity, earlier response times and an increase in signal intensity. The general approaches described herein may be of general applicability for optimizing bacterial sensor performance, regardless of the sensing or reporting elements employed. PMID- 21255328 TI - Regulation and compartmentalization of beta-lactam biosynthesis. AB - Penicillins and cephalosporins are beta-lactam antibiotics widely used in human medicine. The biosynthesis of these compounds starts by the condensation of the amino acids L-alpha-aminoadipic acid, L-cysteine and L-valine to form the tripeptide delta-L-alpha-aminoadipyl-l-cysteinyl-D-valine catalysed by the non ribosomal peptide 'ACV synthetase'. Subsequently, this tripeptide is cyclized to isopenicillin N that in Penicillium is converted to hydrophobic penicillins, e.g. benzylpenicillin. In Acremonium and in streptomycetes, isopenicillin N is later isomerized to penicillin N and finally converted to cephalosporin. Expression of genes of the penicillin (pcbAB, pcbC, pendDE) and cephalosporin clusters (pcbAB, pcbC, cefD1, cefD2, cefEF, cefG) is controlled by pleitropic regulators including LaeA, a methylase involved in heterochromatin rearrangement. The enzymes catalysing the last two steps of penicillin biosynthesis (phenylacetyl-CoA ligase and isopenicillin N acyltransferase) are located in microbodies, as shown by immunoelectron microscopy and microbodies proteome analyses. Similarly, the Acremonium two-component CefD1-CefD2 epimerization system is also located in microbodies. This compartmentalization implies intracellular transport of isopenicillin N (in the penicillin pathway) or isopenicillin N and penicillin N in the cephalosporin route. Two transporters of the MFS family cefT and cefM are involved in transport of intermediates and/or secretion of cephalosporins. However, there is no known transporter of benzylpenicillin despite its large production in industrial strains. PMID- 21255330 TI - Ribose utilization by the human commensal Bifidobacterium breve UCC2003. AB - Growth of Bifidobacterium breve UCC2003 on ribose leads to the transcriptional induction of the rbsACBDK gene cluster. Generation and phenotypic analysis of an rbsA insertion mutant established that the rbs gene cluster is essential for ribose utilization, and that its transcription is likely regulated by a LacI-type regulator encoded by rbsR, located immediately upstream of rbsA. Gel mobility shift assays using purified RbsR(His) indicate that the promoter upstream of rbsABCDK is negatively controlled by RbsR(His) binding to an 18 bp inverted repeat and that RbsR(His) binding activity is modulated by D-ribose. The rbsK gene of the rbs operon of B. breve UCC2003 was shown to specify a ribokinase (EC 2.7.1.15), which specifically directs its phosphorylating activity towards D ribose, converting this pentose sugar to ribose-5-phosphate. PMID- 21255331 TI - Laccase-catalysed polymeric dye synthesis from plant-derived phenols for potential application in hair dyeing: Enzymatic colourations driven by homo- or hetero-polymer synthesis. AB - Laccase efficiently catalyses polymerization of phenolic compounds. However, knowledge on applications of polymers synthesized in this manner remains scarce. Here, the potential of laccase-catalysed polymerization of natural phenols to form products useful in hair dyeing was investigated. All 15 tested phenols yielded coloured products after laccase treatment and colour diversity was attained by using mixtures of two phenolic monomers. After exploring colour differentiation pattern of 120 different reactions with statistical regression analysis, three monomer combinations, namely gallic acid and syringic acid, catechin and catechol, and ferulic acid and syringic acid, giving rise to brown, black, and red materials, respectively, were further characterized because such colours are commercially important for grey hair dyeing. Selected polymers could strongly absorb visible light and their hydrodynamic sizes ranged from 100 to 400 nm. Analyses of enzyme kinetic constants, liquid chromatography and electrospray ionization-mass spectrometry (ESI-MS) coupled with collision-induced dissociation MS/MS indicate that both monomers in reactions involving catechin and catechol, and ferulic acid and syringic acid, are coloured by heteropolymer synthesis, but the gallic acid/syringic acid combination is based on homopolymer mixture formation. Comparison of colour parameters from these three reactions with those of corresponding artificial homopolymer mixtures also supported the idea that laccase may catalyse either hetero- or homo-polymer synthesis. We finally used selected materials to dye grey hair. Each material coloured hair appropriately and the dyeing showed excellent resistance to conventional shampooing. Our study indicates that laccase-catalysed polymerization of natural phenols is applicable to the development of new cosmetic pigments. PMID- 21255332 TI - Isolation and characterization of Cupriavidus basilensis HMF14 for biological removal of inhibitors from lignocellulosic hydrolysate. AB - The formation of toxic fermentation inhibitors such as furfural and 5-hydroxy-2 methylfurfural (HMF) during acid (pre-)treatment of lignocellulose, calls for the efficient removal of these compounds. Lignocellulosic hydrolysates can be efficiently detoxified biologically with microorganisms that specifically metabolize the fermentation inhibitors while preserving the sugars for subsequent use by the fermentation host. The bacterium Cupriavidus basilensis HMF14 was isolated from enrichment cultures with HMF as the sole carbon source and was found to metabolize many of the toxic constituents of lignocellulosic hydrolysate including furfural, HMF, acetate, formate and a host of aromatic compounds. Remarkably, this microorganism does not grow on the most abundant sugars in lignocellulosic hydrolysates: glucose, xylose and arabinose. In addition, C. basilensis HMF14 can produce polyhydroxyalkanoates. Cultivation of C. basilensis HMF14 on wheat straw hydrolysate resulted in the complete removal of furfural, HMF, acetate and formate, leaving the sugar fraction intact. This unique substrate profile makes C. basilensis HMF14 extremely well suited for biological removal of inhibitors from lignocellulosic hydrolysates prior to their use as fermentation feedstock. PMID- 21255333 TI - Controlling biofilm formation, prophage excision and cell death by rewiring global regulator H-NS of Escherichia coli. AB - The global regulator H-NS of Escherichia coli controls genes related to stress response, biofilm formation and virulence by recognizing curved DNA and by silencing acquired genes. Here, we rewired H-NS to control biofilm formation using protein engineering; H-NS variant K57N was obtained that reduces biofilm formation 10-fold compared with wild-type H-NS (wild-type H-NS increases biofilm formation whereas H-NS K57N reduces it). Whole-transcriptome analysis revealed that H-NS K57N represses biofilm formation through its interaction with the nucleoid-associated proteins Cnu and StpA and in the absence of these proteins, H NS K57N was unable to reduce biofilm formation. Significantly, H-NS K57N enhanced the excision of defective prophage Rac while wild-type H-NS represses excision, and H-NS controlled only Rac excision among the nine resident E. coli K-12 prophages. Rac prophage excision not only led to the change in biofilm formation but also resulted in cell lysis through the expression of toxin HokD. Hence, the H-NS regulatory system may be evolved through a single-amino-acid change in its N terminal oligomerization domain to control biofilm formation, prophage excision and apoptosis. PMID- 21255335 TI - Struggling to get a universal meningococcal vaccine and novel uses for bacterial toxins in cancer treatment. PMID- 21255336 TI - Genome (re-)annotation and open-source annotation pipelines. PMID- 21255338 TI - The little bacteria that can - diversity, genomics and ecophysiology of 'Dehalococcoides' spp. in contaminated environments. AB - The fate and persistence of chlorinated organics in the environment have been a concern for the past 50 years. Industrialization and extensive agricultural activities have led to the accumulation of these pollutants in the environment, while their adverse impact on various ecosystems and human health also became evident. This review provides an update on the current knowledge of specialized anaerobic bacteria, namely 'Dehalococcoides' spp., which are dedicated to the transformation of various chlorinated organic compounds via reductive dechlorination. Advances in microbiology and molecular techniques shed light into the diversity and functioning of Dehalococcoides spp. in several different locations. Recent genome sequencing projects revealed a large number of genes that are potentially involved in reductive dechlorination. Molecular approaches towards analysis of diversity and expression especially of reductive dehalogenase encoding genes are providing a growing body of knowledge on biodegradative pathways active in defined pure and mixed cultures as well as directly in the environment. Moreover, several successful field cases of bioremediation strengthen the notion of dedicated degraders such as Dehalococcoides spp. as key players in the restoration of contaminated environments. PMID- 21255337 TI - Adhesion determinants of the Streptococcus species. AB - Streptococci are clinically important Gram-positive bacteria that are capable to cause a wide variety of diseases in humans and animals. Phylogenetic analyses based on 16S rRNA sequences of the streptococcal species reveal a clustering pattern, reflecting, with a few exceptions, their pathogenic potential and ecological preferences. Microbial adhesion to host tissues is the initial critical event in the pathogenesis of most infections. Streptococci use multiple adhesins to attach to the epithelium, and their expression is regulated in response to environmental and growth conditions. Bacterial adhesins recognize and bind cell surface molecules and extracellular matrix components through specific domains that for certain adhesin families have been well defined and found conserved across the streptococcal species. In this review, we present the different streptococcal adhesin families categorized on the basis of their adhesive properties and structural characteristics, and, when available, we focus the attention on conserved functional domains. PMID- 21255339 TI - Revolutionizing membrane protein overexpression in bacteria. AB - The bacterium Escherichia coli is the most widely used expression host for overexpression trials of membrane proteins. Usually, different strains, culture conditions and expression regimes are screened for to identify the optimal overexpression strategy. However, yields are often not satisfactory, especially for eukaryotic membrane proteins. This has initiated a revolution of membrane protein overexpression in bacteria. Recent studies have shown that it is feasible to (i) engineer or select for E. coli strains with strongly improved membrane protein overexpression characteristics, (ii) use bacteria other than E. coli for the expression of membrane proteins, (iii) engineer or select for membrane protein variants that retain functionality but express better than the wild-type protein, and (iv) express membrane proteins using E. coli-based cell-free systems. PMID- 21255341 TI - Streptomyces lividans inhibits the proliferation of the fungus Verticillium dahliae on seeds and roots of Arabidopsis thaliana. AB - Verticillium wilt, a vascular disease in more than 200 dicotyledonous plants, is due to the ascomycete fungus Verticillium dahliae. As documented by video microscopy, the soil bacterium Streptomyces lividans strongly reduces the germination of V. dahliae conidia, and the subsequent growth of hyphae. Quantification by the use of DNA-intercalating dyes and Calcofluor-staining revealed that during prolonged co-cultivation, bacterial hyphae proliferate to a dense network, provoke a poor development of V. dahliae vegetative hyphae and lead to an enormous reduction of conidia and microsclerotia. Upon individual application to seeds of the model plant Arabidopsis thaliana, either the bacterial spores or the fungal conidia germinate at or within the mucilage, including its volcano-shaped structures. The extension of hyphae from each individual strain correlates with the reduction of the pectin-containing mucilage layer. Proliferating hyphae then spread to roots of the emerging seedlings. Plants, which arise in the presence of V. dahliae within agar or soil, have damaged root cells, an atrophied stem and root, as well as poorly developed leaves with chlorosis symptoms. In contrast, S. lividans hyphae settle in bunches preferentially at the outer layer near tips and alongside roots. Resulting plants have a healthy appearance including an intact root system. Arabidopsis thaliana seeds, which are co-inoculated with V. dahliae and S. lividans, have preferentially proliferating bacterial hyphae within the mucilage, and at roots of the outgrowing seedlings. As a result, plants have considerably reduced disease symptoms. As spores of the beneficial S. lividans strain are obtainable in large quantity, its application is highly attractive. PMID- 21255340 TI - Bacterial genotoxicity bioreporters. AB - Ever since the introduction of the Salmonella typhimurium mammalian microsome mutagenicity assay (the 'Ames test') over three decades ago, there has been a constant development of additional genotoxicity assays based upon the use of genetically engineered microorganisms. Such assays rely either on reversion principles similar to those of the Ames test, or on promoter-reporter fusions that generate a quantifiable dose-dependent signal in the presence of potential DNA damaging compounds and the induction of repair mechanisms; the latter group is the subject of the present review. Some of these assays were only briefly described in the scientific literature, whereas others have been developed all the way to commercial products. Out of these, only one, the umu-test, has been fully validated and ISO- and OECD standardized. Here we review the main directions undertaken in the construction and testing of bacterial-based genotoxicity bioassays, including the attempts to incorporate at least a partial metabolic activation capacity into the molecular design. We list the genetic modifications introduced into the tester strains, compare the performance of the different assays, and briefly describe the first attempts to incorporate such bacterial reporters into actual genotoxicity testing devices. PMID- 21255342 TI - Microbial diagnostic microarray for food- and water-borne pathogens. AB - A microbial diagnostic microarray for the detection of the most relevant bacterial food- and water-borne pathogens and indicator organisms was developed and thoroughly validated. The microarray platform based on sequence-specific end labelling of oligonucleotides and the pyhylogenetically robust gyrB marker gene allowed a highly specific (resolution on genus/species level) and sensitive (0.1% relative and 10(4) cfu absolute detection sensitivity) detection of the target pathogens. Validation was performed using a set of reference strains and a set of spiked environmental samples. Reliability of the obtained data was additionally verified by independent analysis of the samples via fluorescence in situ hybridization (FISH) and conventional microbiological reference methods. The applicability of this diagnostic system for food analysis was demonstrated through extensive validation using artificially and naturally contaminated spiked food samples. The microarray-based pathogen detection was compared with the corresponding microbiological reference methods (performed according to the ISO norm). Microarray results revealed high consistency with the reference microbiological data. PMID- 21255343 TI - Impacts of Shewanella oneidensis c-type cytochromes on aerobic and anaerobic respiration. AB - Shewanella are renowned for their ability to utilize a wide range of electron acceptors (EA) for respiration, which has been partially accredited to the presence of a large number of the c-type cytochromes. To investigate the involvement of c-type cytochrome proteins in aerobic and anaerobic respiration of Shewanella oneidensis Mr -1, 36 in-frame deletion mutants, among possible 41 predicted, c-type cytochrome genes were obtained. The potential involvement of each individual c-type cytochrome in the reduction of a variety of EAs was assessed individually as well as in competition experiments. While results on the well-studied c-type cytochromes CymA(SO4591) and MtrC(SO1778) were consistent with previous findings, collective observations were very interesting: the responses of S. oneidensis Mr -1 to low and highly toxic metals appeared to be significantly different; CcoO, CcoP and PetC, proteins involved in aerobic respiration in various organisms, played critical roles in both aerobic and anaerobic respiration with highly toxic metals as EA. In addition, these studies also suggested that an uncharacterized c-type cytochrome (SO4047) may be important to both aerobiosis and anaerobiosis. PMID- 21255344 TI - The phage-driven microbial loop in petroleum bioremediation. AB - During the drilling process and transport of crude oil, water mixes with the petroleum. At oil terminals, the water settles to the bottom of storage tanks. This drainage water is contaminated with emulsified oil and water-soluble hydrocarbons and must be treated before it can be released into the environment. In this study, we tested the efficiency of a continuous flow, two-stage bioreactor for treating drainage water from an Israeli oil terminal. The bioreactor removed all of the ammonia, 93% of the sulfide and converted 90% of the total organic carbon (TOC) into carbon dioxide. SYBR Gold staining indicated that reactor 1 contained 1.7 * 10(8) bacteria and 3.7 * 10(8) phages per millilitre, and reactor 2 contained 1.3 * 10(8) bacteria and 1.7 * 10(9) phages per millilitre. The unexpectedly high mineralization of TOC and high concentration of phage in reactor 2 support the concept of a phage-driven microbial loop in the bioremediation of the drainage water. In general, application of this concept in bioremediation of contaminated water has the potential to increase the efficiency of processes. PMID- 21255347 TI - Editorial - preview. PMID- 21255345 TI - Studies with bioengineered Nisin peptides highlight the broad-spectrum potency of Nisin V. AB - Nisin A is the most thoroughly investigated member of the lantibiotic family of antimicrobial peptides. In addition to a long history of safe use as a food antimicrobial, its activity against multi-drug resistant pathogens has resulted in a renewed interest in applying nisin as a chemotherapeutic to treat bacterial infections. The wealth of Nisin-related information that has been generated has also led to the development of the biotechnological capacity to engineer novel Nisin variants with a view to improving the function and physicochemical properties of this already potent peptide. However, the identification of bioengineered Nisin derivatives with enhanced antimicrobial activity against Gram positive targets is a recent event. In this study, we created stable producers of the most promising derivatives of Nisin A generated to date [M21V (hereafter Nisin V) and K22T (hereafter Nisin T)] and assessed their potency against a range of drug-resistant clinical, veterinary and food pathogens. Nisin T exhibited increased activity against all veterinary isolates, including streptococci and staphylococci, and against a number of multi-drug resistant clinical isolates including MRSA, but not vancomycin-resistant enterococci. In contrast, Nisin V displayed increased potency against all targets tested including hVISA strains and the hyper-virulent Clostridium difficile ribotype 027 and against important food pathogens such as Listeria monocytogenes and Bacillus cereus. Significantly, this enhanced activity was validated in a model food system against L. monocytogenes. We conclude that Nisin V possesses significant potential as a novel preservative or chemotherapeutic compound. PMID- 21255348 TI - Exploiting biodiversity in the marine environment: a personal perspective. PMID- 21255349 TI - Intellectual Property: a powerful tool to develop biotech research. AB - Today biotechnology is perhaps the most important technology field because of the strong health and food implications. However, due to the nature of said technology, there is the need of a huge amount of investments to sustain the experimentation costs. Consequently, investors aim to safeguard as much as possible their investments. Intellectual Property, and in particular patents, has been demonstrated to actually constitute a powerful tool to help them. Moreover, patents represent an extremely important means to disclose biotechnology inventions. Patentable biotechnology inventions involve products as nucleotide and amino acid sequences, microorganisms, processes or methods for modifying said products, uses for the manufacture of medicaments, etc. There are several ways to protect inventions, but all follow the three main patentability requirements: novelty, inventive step and industrial application. PMID- 21255350 TI - Commercial product exploitation from marine microbial biodiversity: some legal and IP issues. AB - The biodiversity found in the marine environment is remarkable and yet largely unknown compared with the terrestrial one. The associated genetic resource, also wide and unrevealed, has raised a strong interest from the scientific and industrial community. However, despite this growing interest, the discovery of new compounds extracted from marine organisms, more precisely from microorganisms, is ruled by a complex legislation. The access and transfer of genetic resource are ruled by the Convention on Biological Diversity. One of the three core objectives of this convention is to ensure the fair and equitable sharing of benefits generated by the use of genetic resources and to split these benefits between the different stakeholders. From the discovery of a microorganism to the commercialization of a product, three main stakeholders are involved: providers of microorganisms, e.g. academic institutes, the scientists who will perform R&D on biodiversity, and the industrial companies which will commercialize the final product arising from the R&D results. This article describes how difficult and complex it might be to ensure a fair distribution of benefits of this research between the parties. PMID- 21255351 TI - Genomics of microalgae, fuel for the future? PMID- 21255352 TI - Bioactive compounds from marine bacteria and fungi. AB - Marine bacteria and fungi are of considerable importance as new promising sources of a huge number of biologically active products. Some of these marine species live in a stressful habitat, under cold, lightless and high pressure conditions. Surprisingly, a large number of species with high diversity survive under such conditions and produce fascinating and structurally complex natural products. Up till now, only a small number of microorganisms have been investigated for bioactive metabolites, yet a huge number of active substances with some of them featuring unique structural skeletons have been isolated. This review covers new biologically active natural products published recently (2007-09) and highlights the chemical potential of marine microorganisms, with focus on bioactive products as well as on their mechanisms of action. PMID- 21255353 TI - Culturing marine bacteria - an essential prerequisite for biodiscovery. AB - The potential for using marine microbes for biodiscovery is severely limited by the lack of laboratory cultures. It is a long-standing observation that standard microbiological techniques only isolate a very small proportion of the wide diversity of microbes that are known in natural environments from DNA sequences. A number of explanations are reviewed. The process of establishing laboratory cultures may destroy any cell-to-cell communication that occurs between organisms in the natural environment and that are vital for growth. Bacteria probably grow as consortia in the sea and reliance on other bacteria for essential nutrients and substrates is not possible with standard microbiological approaches. Such interactions should be considered when designing programmes for the isolation of marine microbes. The benefits of novel technologies for manipulating cells are reviewed, including single cell encapsulation in gel micro-droplets. Although novel technologies offer benefits for bringing previously uncultured microbes into laboratory culture, many useful bacteria can still be isolated using variations of plating techniques. Results are summarized for a study to culture bacteria from a long-term observatory station in the English Channel. Bacterial biodiversity in this assemblage has recently been characterized using high throughput sequencing techniques. Although Alphaproteobacteria dominated the natural bacterial assemblage throughout the year, Gammaproteobacteria were the most frequent group isolated by plating techniques. The use of different gelling agents and the addition of ammonium to seawater-based agar did lead to the isolation of a higher proportion of Alphaproteobacteria. Variation in medium composition was also able to increase the recovery of other groups of particular interest for biodiscovery, such as Actinobacteria. PMID- 21255354 TI - Expression of the inulinase gene from the marine-derived Pichia guilliermondii in Saccharomyces sp. W0 and ethanol production from inulin. AB - It has been confirmed that Saccharomyces sp. W0 can produce high concentration of ethanol. In this study, the INU1 gene cloned from the marine-derived Pichia guilliermondii was transformed into uracil mutant of Saccharomyces sp. W0. The positive transformant Inu-66 obtained could produce 34.2 U ml-1 of extracellular inulinase within 72 h of cultivation. It was found that 15.2 U of inulinase activity per one gram of inulin was suitable for inulin hydrolysis and ethanol production by the transformant Inu-66. During the small-scale fermentation, 13.7 ml of ethanol in 100 ml of medium was produced and 99.1% of the added inulin was utilized by the transformant. During the 2 l fermentation, 14.9% (v/v) of ethanol was produced from inulin and 99.5% of the added inulin was converted into ethanol, CO2 and cell mass. PMID- 21255355 TI - Life cycle analysis of the model organism Rhodopirellula baltica SH 1(T) by transcriptome studies. AB - The marine organism Rhodopirellula baltica is a representative of the globally distributed phylum Planctomycetes whose members exhibit an intriguing lifestyle and cell morphology. The analysis of R. baltica's genome has revealed many biotechnologically promising features including a set of unique sulfatases and C1 metabolism genes. Salt resistance and the potential for adhesion in the adult phase of the cell cycle were observed during cultivation. To promote the understanding of this model organism and to specify the functions of potentially useful genes, gene expression throughout a growth curve was monitored using a whole genome microarray approach. Transcriptional profiling suggests that a large number of hypothetical proteins are active within the cell cycle and in the formation of the different cell morphologies. Numerous genes with potential biotechnological applications were found to be differentially regulated, revealing further characteristics of their functions and regulation mechanisms. More specifically, the experiments shed light on the expression patterns of genes belonging to the organism's general stress response, those involved in the reorganization of its genome and those effecting morphological changes. These transcriptomic results contribute to a better understanding of thus far unknown molecular elements of cell biology. Further, they pave the way for the biotechnological exploitation of R. baltica's distinctive metabolic features as a step towards sourcing the phylum Planctomycetes at large. PMID- 21255356 TI - Genomic signatures of fifth autotrophic carbon assimilation pathway in bathypelagic Crenarchaeota. AB - Marine Crenarchaeota, ubiquitous and abundant organisms in the oceans worldwide, remain metabolically uncharacterized, largely due to their low cultivability. Identification of candidate genes for bicarbonate fixation pathway in the Cenarchaeum symbiosum A was an initial step in understanding the physiology and ecology of marine Crenarchaeota. Recent cultivation and genome sequencing of obligate chemoautotrophic Nitrosopumilus maritimus SCM1 were a major breakthrough towards understanding of their functioning and provide a valuable model for experimental validation of genomic data. Here we present the identification of multiple key components of 3-hydroxipropionate/4-hydroxybutyrate cycle, the fifth pathway in carbon fixation, found in data sets of environmental sequences representing uncultivated superficial and bathypelagic Crenarchaeota from Sargasso sea (GOS data set) and KM3 (Mediterranean Sea) and ALOHA (Atlantic ocean) stations. These organisms are likely to use acetyl-CoA/propionyl-CoA carboxylase(s) as CO2-fixing enzyme(s) to form succinyl-CoA, from which one molecule of acetyl-CoA is regenerated via 4-hydroxybutyrate cleavage and another acetyl-CoA to be the pathway product. The genetic distinctiveness and matching sympatric abundance imply that marine crenarchaeal genotypes from the three different geographic sites share similar ecophysiological properties, and therefore may represent fundamental units of marine ecosystem functioning. To couple results of sequence comparison with the dark ocean primary production, dissolved inorganic carbon fixation rates were measured at KM3 Station (3000 m depth, Eastern Mediterranean Sea), i.e. at the same site and depth used for metagenomic library construction. PMID- 21255357 TI - Short-term changes in the composition of active marine bacterial assemblages in response to diesel oil pollution. AB - The changes caused by diesel oil pollution in the metabolically active bacterioplankton from an oligotrophic coastal location were analysed in laboratory microcosms (44 l) using 16S ribosomal RNA (16S rRNA) as molecular marker. The aim was to simulate typical hydrocarbon pollution events in a coastal area exploited for seasonal touristic activities. The experiment consisted in addition of low amounts of diesel oil without nutrients to seawater collected at different times (winter and summer). Bacterial diversity was analysed by terminal restriction fragment length polymorphism (T-RFLP) profiling of 16S rRNAs after reverse transcription polymerase chain reaction (RT-PCR), and by generation of 16S rRNA clone libraries in control and diesel-polluted microcosms. Diesel addition caused a twofold increase in prokaryotic numbers in comparison with controls at the end of the experiment, both in winter and summer microcosms. Bacterioplankton composition, determined by 16S rRNA T-RFLP data, changed rapidly (within 17 h) in response to treatment. The resulting communities were different in microcosms with water collected in summer and winter. A reduction in diversity (Shannon index, calculated on the basis of T-RFLP data) was observed only in summer microcosms. This was due to the rapid increase of phylotypes affiliated to the Oceanospirillaceae, not observed in winter microcosms. After diesel treatment there was a reduction in the number of phylotypes related to SAR11, SAR86 and picocyanobacteria, while phylotypes of the Roseobacter clade, and the OMG group seemed to be favoured. Our results show that diesel pollution alone caused profound effects on the bacterioplankton of oligotrophic seawater, and explained many of the differences in diversity reported previously in pristine and polluted sites in this coastal area. PMID- 21255360 TI - Genomic tracing of epidemics and disease outbreaks. PMID- 21255363 TI - Mining bacterial genomes for novel arylesterase activity. AB - One hundred and seventy-one genes encoding potential esterases from 11 bacterial genomes were cloned and overexpressed in Escherichia coli; 74 of the clones produced soluble proteins. All 74 soluble proteins were purified and screened for esterase activity; 36 proteins showed carboxyl esterase activity on short-chain esters, 17 demonstrated arylesterase activity, while 38 proteins did not exhibit any activity towards the test substrates. Esterases from Rhodopseudomonas palustris (RpEST-1, RpEST-2 and RpEST-3), Pseudomonas putida (PpEST-1, PpEST-2 and PpEST-3), Pseudomonas aeruginosa (PaEST-1) and Streptomyces avermitilis (SavEST-1) were selected for detailed biochemical characterization. All of the enzymes showed optimal activity at neutral or alkaline pH, and the half-life of each enzyme at 50 degrees C ranged from < 5 min to over 5 h. PpEST-3, RpEST-1 and RpEST-2 demonstrated the highest specific activity with pNP-esters; these enzymes were also among the most stable at 50 degrees C and in the presence of detergents, polar and non-polar organic solvents, and imidazolium ionic liquids. Accordingly, these enzymes are particularly interesting targets for subsequent application trials. Finally, biochemical and bioinformatic analyses were compared to reveal sequence features that could be correlated to enzymes with arylesterase activity, facilitating subsequent searches for new esterases in microbial genome sequences. PMID- 21255362 TI - Comparative genome-wide analysis of small RNAs of major Gram-positive pathogens: from identification to application. AB - In the recent years, the number of drug- and multi-drug-resistant microbial strains has increased rapidly. Therefore, the need to identify innovative approaches for development of novel anti-infectives and new therapeutic targets is of high priority in global health care. The detection of small RNAs (sRNAs) in bacteria has attracted considerable attention as an emerging class of new gene expression regulators. Several experimental technologies to predict sRNA have been established for the Gram-negative model organism Escherichia coli. In many respects, sRNA screens in this model system have set a blueprint for the global and functional identification of sRNAs for Gram-positive microbes, but the functional role of sRNAs in colonization and pathogenicity for Listeria monocytogenes, Staphylococcus aureus, Streptococcus pyogenes, Enterococcus faecalis and Clostridium difficile is almost completely unknown. Here, we report the current knowledge about the sRNAs of these socioeconomically relevant Gram positive pathogens, overview the state-of-the-art high-throughput sRNA screening methods and summarize bioinformatics approaches for genome-wide sRNA identification and target prediction. Finally, we discuss the use of modified peptide nucleic acids (PNAs) as a novel tool to inactivate potential sRNA and their applications in rapid and specific detection of pathogenic bacteria. PMID- 21255361 TI - Plasmid addiction systems: perspectives and applications in biotechnology. AB - Biotechnical production processes often operate with plasmid-based expression systems in well-established prokaryotic and eukaryotic hosts such as Escherichia coli or Saccharomyces cerevisiae, respectively. Genetically engineered organisms produce important chemicals, biopolymers, biofuels and high-value proteins like insulin. In those bioprocesses plasmids in recombinant hosts have an essential impact on productivity. Plasmid-free cells lead to losses in the entire product recovery and decrease the profitability of the whole process. Use of antibiotics in industrial fermentations is not an applicable option to maintain plasmid stability. Especially in pharmaceutical or GMP-based fermentation processes, deployed antibiotics must be inactivated and removed. Several plasmid addiction systems (PAS) were described in the literature. However, not every system has reached a full applicable state. This review compares most known addiction systems and is focusing on biotechnical applications. PMID- 21255364 TI - Characterization of the RND family of multidrug efflux pumps: in silico to in vivo confirmation of four functionally distinct subgroups. AB - We have developed a generalized profile that identifies members of the root nodulation-cell-division (RND) family of efflux pumps and classifies them into four functional subfamilies. According to Z-score values, efflux pumps can be grouped by their metabolic function, thus making it possible to distinguish pumps involved in antibiotic resistance (group 1) from those involved in metal resistance (group 3). In silico data regarding efflux pumps in group 1 were validated after identification of RND efflux pumps in a number of environmental microbes that were isolated as resistant to ethidium bromide. Analysis of the Pseudomonas putida KT2440 genome identified efflux pumps in all groups. A collection of mutants in efflux pumps and a screening platform consisting of 50 drugs were created to assign a function to the efflux pumps. We validated in silico data regarding efflux pumps in groups 1 and 3 using 9 different mutants. Four mutants belonging to group 2 were found to be more sensitive than the wild type to oxidative stress-inducing agents such as bipyridyl and methyl viologen. The two remaining mutants belonging to group 4 were found to be more sensitive than the parental to tetracycline and one of them was particularly sensitive to rubidium and chromate. By effectively combining in vivo data with generalized profiles and gene annotation data, this approach allowed the assignment, according to metabolic function, of both known and uncharacterized RND efflux pumps into subgroups, thereby providing important new insight into the functions of proteins within this family. PMID- 21255365 TI - Hydrophobic substances induce water stress in microbial cells. AB - Ubiquitous noxious hydrophobic substances, such as hydrocarbons, pesticides and diverse industrial chemicals, stress biological systems and thereby affect their ability to mediate biosphere functions like element and energy cycling vital to biosphere health. Such chemically diverse compounds may have distinct toxic activities for cellular systems; they may also share a common mechanism of stress induction mediated by their hydrophobicity. We hypothesized that the stressful effects of, and cellular adaptations to, hydrophobic stressors operate at the level of water : macromolecule interactions. Here, we present evidence that: (i) hydrocarbons reduce structural interactions within and between cellular macromolecules, (ii) organic compatible solutes - metabolites that protect against osmotic and chaotrope-induced stresses - ameliorate this effect, (iii) toxic hydrophobic substances induce a potent form of water stress in macromolecular and cellular systems, and (iv) the stress mechanism of, and cellular responses to, hydrophobic substances are remarkably similar to those associated with chaotrope-induced water stress. These findings suggest that it may be possible to devise new interventions for microbial processes in both natural environments and industrial reactors to expand microbial tolerance of hydrophobic substances, and hence the biotic windows for such processes. PMID- 21255366 TI - Engineering global regulator Hha of Escherichia coli to control biofilm dispersal. AB - The global transcriptional regulator Hha of Escherichia coli controls biofilm formation and virulence. Previously, we showed that Hha decreases initial biofilm formation; here, we engineered Hha for two goals: to increase biofilm dispersal and to reduce biofilm formation. Using random mutagenesis, Hha variant Hha13D6 (D22V, L40R, V42I and D48A) was obtained that causes nearly complete biofilm dispersal (96%) by increasing apoptosis without affecting initial biofilm formation. Hha13D6 caused cell death probably by the activation of proteases since Hha-mediated dispersal was dependent on protease HslV. Hha variant Hha24E9 (K62X) was also obtained that decreased biofilm formation by inducing gadW, glpT and phnF but that did not alter biofilm dispersal. Hence, Hha may be engineered to influence both biofilm dispersal and formation. PMID- 21255368 TI - New molecular microbiology approaches in the study of Campylobacter fetus. AB - Campylobacter fetus infection is a substantial problem in herds of domestic cattle worldwide and a rising threat in human disease. Application of comparative and functional genomics approaches will be essential to understand the molecular basis of this pathogen's interactions with various hosts. Here we report recent progress in genome analyses of C. fetus ssp. fetus and C. fetus ssp. venerealis, and the development of molecular tools to determine the genetic basis of niche specific adaptations. Campylobacter research has been strengthened by the rapid advancements in imaging technology occurring throughout microbiology. To move forward in understanding the mechanisms underlying C. fetus virulence, current efforts focus on developing suitable in vitro models to reflect host- and tissue specific aspects of infection. PMID- 21255369 TI - Vaccine development against Neisseria meningitidis. AB - Meningococcal disease is communicable by close contact or droplet aerosols. Striking features are high case fatality rates and peak incidences of invasive disease in infants, toddlers and adolescents. Vaccine development is hampered by bacterial immune evasion strategies including molecular mimicry.As for Haemophilus influenzae and Streptococcus pneumoniae, no vaccine has therefore been developed that targets all serogroups of Neisseria meningitidis. Polysaccharide vaccines available both in protein conjugated and non-conjugated form, have been introduced against capsular serogroups A, C,W-135 and Y, but are ineffective against serogroup B meningococci, which cause a significant burden of disease in many parts of the world. Detoxified outer membrane vesicles are used since decades to elicit protection against epidemic serogroup B disease. Genome mining and biochemical approaches have provided astounding progress recently in the identification of immunogenic, yet reasonably conserved outer membrane proteins. As subcapsular proteins nevertheless are unlikely to immunize against all serogroup B variants, thorough investigation by surrogate assays and molecular epidemiology approaches are needed prior to introduction and post licensure of protein vaccines. Research currently addresses the analysis of life vaccines, meningococcus B polysaccharide modifications and mimotopes, as well as the use of N. lactamica outer membrane vesicles. PMID- 21255370 TI - Shiga toxin and its use in targeted cancer therapy and imaging. AB - Shiga and the Shiga-like toxins are related protein toxins produced by Shigella dysenteriae and certain strains of Escherichia coli. These toxins are composed of two non-covalently attached, modular parts: the A moiety (StxA) containing the enzymatically active A1 fragment, and the non-toxic, pentameric binding moiety (StxB). Stx binds specifically to the glycosphingolipid globotriaosylceramide (Gb3) at the surface of target cells and is then internalized by endocytosis. Subsequently, in toxin-sensitive cells, the Stx/Gb3 complex is transported in a retrograde manner via the Golgi apparatus to the endoplasmic reticulum, where the enzymatically active part of Stx is translocated to the cytosol, enabling it to irreversibly inhibit protein synthesis via modification of ribosomal 28S RNA. Whereas Gb3 shows a relatively restricted expression in normal human tissues, it has been reported to be highly expressed in many types of cancers. This review gives a brief introduction to Stx and its intracellular transport. Furthermore, after a description of Gb3 and the methods that are currently used to detect its cellular expression, we provide an updated overview of the published reports on Gb3 overexpression in human cancers. Finally, we discuss the possibility of utilizing Stx or StxB coupled to therapeutic compounds or contrast agents in targeted cancer therapy and imaging. PMID- 21255371 TI - The 'LipoYeasts' project: using the oleaginous yeast Yarrowia lipolytica in combination with specific bacterial genes for the bioconversion of lipids, fats and oils into high-value products. AB - The oleochemical industry is currently still dominated by conventional chemistry, with biotechnology only starting to play a more prominent role, primarily with respect to the biosurfactants or lipases, e.g. as detergents, or for biofuel production. A major bottleneck for all further biotechnological applications is the problem of the initial mobilization of cheap and vastly available lipid and oil substrates, which are then to be transformed into high-value biotechnological, nutritional or pharmacological products. Under the EU-sponsored LipoYeasts project we are developing the oleaginous yeast Yarrowia lipolytica into a versatile and high-throughput microbial factory that, by use of specific enzymatic pathways from hydrocarbonoclastic bacteria, efficiently mobilizes lipids by directing its versatile lipid metabolism towards the production of industrially valuable lipid-derived compounds like wax esters (WE), isoprenoid derived compounds (carotenoids, polyenic carotenoid ester), polyhydroxyalkanoates (PHAs) and free hydroxylated fatty acids (HFAs). Different lipid stocks (petroleum, alkane, vegetable oil, fatty acid) and combinations thereof are being assessed as substrates in combination with different mutant and recombinant strains of Y. lipolytica, in order to modulate the composition and yields of the produced added-value products. PMID- 21255372 TI - Development of a biomarker for Geobacter activity and strain composition; proteogenomic analysis of the citrate synthase protein during bioremediation of U(VI). AB - Monitoring the activity of target microorganisms during stimulated bioremediation is a key problem for the development of effective remediation strategies. At the US Department of Energy's Integrated Field Research Challenge (IFRC) site in Rifle, CO, the stimulation of Geobacter growth and activity via subsurface acetate addition leads to precipitation of U(VI) from groundwater as U(IV). Citrate synthase (gltA) is a key enzyme in Geobacter central metabolism that controls flux into the TCA cycle. Here, we utilize shotgun proteomic methods to demonstrate that the measurement of gltA peptides can be used to track Geobacter activity and strain evolution during in situ biostimulation. Abundances of conserved gltA peptides tracked Fe(III) reduction and changes in U(VI) concentrations during biostimulation, whereas changing patterns of unique peptide abundances between samples suggested sample-specific strain shifts within the Geobacter population. Abundances of unique peptides indicated potential differences at the strain level between Fe(III)-reducing populations stimulated during in situ biostimulation experiments conducted a year apart at the Rifle IFRC. These results offer a novel technique for the rapid screening of large numbers of proteomic samples for Geobacter species and will aid monitoring of subsurface bioremediation efforts that rely on metal reduction for desired outcomes. PMID- 21255373 TI - Comparison of the mesophilic cellulosome-producing Clostridium cellulovorans genome with other cellulosome-related clostridial genomes. AB - Clostridium cellulovorans, an anaerobic and mesophilic bacterium, degrades native substrates in soft biomass such as corn fibre and rice straw efficiently by producing an extracellular enzyme complex called the cellulosome. Recently, we have reported the whole-genome sequence of C. cellulovorans comprising 4220 predicted genes in 5.10 Mbp [Y. Tamaru et al., (2010) J. Bacteriol., 192: 901 902]. As a result, the genome size of C. cellulovorans was about 1 Mbp larger than that of other cellulosome-producing clostridia, mesophilic C. cellulolyticum and thermophilic C. thermocellum. A total of 57 cellulosomal genes were found in the C. cellulovorans genome, and they coded for not only carbohydrate-degrading enzymes but also a lipase, peptidases and proteinase inhibitors. Interestingly, two novel genes encoding scaffolding proteins were found in the genome. According to KEGG metabolic pathways and their comparison with 11 Clostridial genomes, gene expansion in the C. cellulovorans genome indicated mainly non-cellulosomal genes encoding hemicellulases and pectin-degrading enzymes. Thus, by examining genome sequences from multiple Clostridium species, comparative genomics offers new insight into genome evolution and the way natural selection moulds functional DNA sequence evolution. Our analysis, coupled with the genome sequence data, provides a roadmap for constructing enhanced cellulosome-producing Clostridium strains for industrial applications such as biofuel production. PMID- 21255374 TI - Diversity of aerobic anoxygenic phototrophic bacteria in paddy soil and their response to elevated atmospheric CO2. AB - Aerobic anoxygenic phototrophic bacteria (AAnPB) are recognized as an important group driving the global carbon cycling. However, the diversity of AAnPB in terrestrial environment remains largely unknown as well as their responses to the elevated atmospheric CO2. By using culture-independent techniques, the diversity of AAnPB in paddy soil and the changes in response to the rising atmospheric CO2 were investigated within China FACE (Free-air CO2 enrichment) platform. There was a phylogenetically diverse AAnPB community with large population size residing in paddy soil. The community structure of AAnPB in bulk and rhizospheric soils stayed almost identical, while the population size was higher in rhizospheric [2.0-2.5 x 108 copy number of pufM genes g-1 dry weight soil (d.w.s.)] than that in bulk (0.7-0.8 x 108 g-1 d.w.s.) soils. Elevated atmospheric CO2 appeared to significantly stimulate AAnPB abundance (up to 1.4-1.5 x 108 g-1 d.w.s.) and result in a higher AAnPB percentage in total bacterial community (from 0.5% up to 1.5%) in bulk soil, whereas no significant effect was observed in rhizospheric soil. Our results would extend the functional ecotypes of AAnPB and indicate that environmental changes associated with the rising atmospheric CO2 might affect AAnPB community in paddy soil. PMID- 21255375 TI - Monitoring of pathogenic and non-pathogenic Fusarium oxysporum strains during tomato plant infection. AB - Monitoring of pathogenic strains of Fusarium oxysporum (Fox), which cause wilt and rots on agricultural and ornamental plants, is important for predicting disease outbreaks. Since both pathogenic and non-pathogenic strains of Fox are ubiquitous and are able to colonize plant roots, detection of Fox DNA in plant material is not the ultimate proof of an ongoing infection which would cause damage to the plant. We followed the colonization of tomato plants by strains Fox f. sp. radicis-lycopersici ZUM2407 (a tomato foot and root rot pathogen), Fox f. sp. radiciscucumerinum V03-2g (a cucumber root rot pathogen) and Fox Fo47 (a well known non-pathogenic biocontrol strain). We determined fungal DNA concentrations in tomato plantlets by quantitative PCR (qPCR) with primers complementary to the intergenic spacer region (IGS) of these three Fox strains. Two weeks after inoculation of tomato seedlings with these Fox strains, the DNA concentration of Forl ZUM2407 was five times higher than that of the non-compatible pathogen Forc V03-2g and 10 times higher than that of Fo47. In 3-week-old plantlets the concentration of Forl ZUM2407 DNA was at least 10 times higher than those of the other strains. The fungal DNA concentration, as determined by qPCR, appeared to be in good agreement with data of the score of visible symptoms of tomato foot and root rot obtained 3 weeks after inoculation of tomato with Forl ZUM2407. Our results show that targeting of the multicopy ribosomal operon results in a highly sensitive qPCR reaction for the detection of Fox DNA. Since formae speciales of Fox cannot be distinguished by comparison of ribosomal operons, detection of Fox DNA is not evidence of plant infection by a compatible pathogen. Nevertheless, the observed difference in levels of plant colonization between pathogenic and non-pathogenic strains strongly suggests that a concentration of Fox DNA in plant material above the threshold level of 0.005% is due to proliferation of pathogenic Fox. PMID- 21255376 TI - Functionalization of whole-cell bacterial reporters with magnetic nanoparticle. AB - We developed a biocompatible and highly efficient approach for functionalization of bacterial cell wall with magnetic nanoparticles (MNPs). Three Acinetobacter baylyi ADP1 chromosomally based bioreporters, which were genetically engineered to express bioluminescence in response to salicylate, toluene/ xylene and alkanes, were functionalized with 18 3 nm iron oxide MNPs to acquire magnetic function. The efficiency of MNPs functionalization of Acinetobacter bioreporters was 99.96 0.01%. The MNPs-functionalized bioreporters (MFBs) can be remotely controlled and collected by an external magnetic field. The MFBs were all viable and functional as good as the native cells in terms of sensitivity, specificity and quantitative response. More importantly, we demonstrated that salicylate sensing MFBs can be applied to sediments and garden soils, and semiquantitatively detect salicylate in those samples by discriminably recovering MFBs with a permanent magnet. The magnetically functionalized cells are especially useful to complex environments in which the indigenous cells, particles and impurities may interfere with direct measurement of bioreporter cells and conventional filtration is not applicable to distinguish and harvest bioreporters. The approach described here provides a powerful tool to remotely control and selectively manipulate MNPs-unctionalized cells in water and soils. It would have a potential in the application of environmental microbiology, such as bioremediation enhancement and environment monitoring and assessment. PMID- 21255377 TI - Simple, fast and high-efficiency transformation system for directed evolution of cellulase in Bacillus subtilis. AB - Bacillus subtilis can serve as a powerful platform for directed evolution, especially for secretory enzymes. However, cloning and transformation of a DNA mutant library in B. subtilis are not as easy as they are in Escherichia coli. For direct transformation of B. subtilis, here we developed a new protocol based on supercompetent cells prepared from the recombinant B. subtilis strain SCK6 and multimeric plasmids. This new protocol is simple (restriction enzyme-, phosphatase- and ligase-free), fast (i.e. 1 day) and of high efficiency (i.e. ~107 or ~104 transformants per mg of multimeric plasmid or ligated plasmid DNA respectively). Supercompetent B. subtilis SCK6 cells were prepared by overexpression of the competence master regulator ComK that was induced by adding xylose. The DNA mutant library was generated through a two-round PCR: (i) the mutagenized DNA fragments were generated by error-prone PCR and linearized plasmids were made using high-fidelity PCR, and (ii) the multimeric plasmids were generated based on these two DNA templates by using overlap PCR. Both protein expression level and specific activity of glycoside hydrolase family 5 endoglucanse on regenerated amorphous cellulose were improved through this new system. To our limited knowledge, this study is the first report for enhancing secretory cellulase performance on insoluble cellulose. PMID- 21255381 TI - The clinical utility of testicular cancer risk loci. AB - Three recent genome-wide association studies of testicular germ cell tumors have uncovered predisposition alleles in or near several genes, including KITLG, BAK1, SPRY4, TERT, ATF7IP, and DMRT1. The calculated per-allele odds ratio for variants in the region of KITLG is the highest reported for any malignancy so far. These findings are in agreement with epidemiological data indicating that testicular cancer has a higher heritability than most other cancers. Here, we discuss the question of whether the newly identified risk polymorphisms can be used to guide patient care. PMID- 21255378 TI - Microbial sunscreens. PMID- 21255383 TI - A real-time PCR assay with improved specificity for detection and discrimination of all clinically relevant Bordetella species by the presence and distribution of three Insertion Sequence elements. AB - BACKGROUND: In Dutch laboratories molecular detection of B. pertussis and B. parapertussis is commonly based on insertion sequences IS481 and IS1001, respectively. Both IS elements are more widely spread among Bordetella species. Both Bordetella holmesii, and B. bronchiseptica can harbour IS481. Also, IS1001 is found among B. bronchiseptica. IS481, and IS1001 based PCR thus lacks specificity when used for detection of specific Bordetella spp. FINDINGS: We designed a PCR based on IS1002, another IS element that is present among Bordetella species, and exploited it as a template in combination with PCR for IS481, and IS1001. In combining the PCRs for IS481, IS1001, and IS1002, and including an inhibition control, we were able to detect and discriminate all clinically relevant Bordetella species. CONCLUSIONS: We developed an improved PCR method for specific detection of B. pertussis, B. parapertussis, B. holmesii, and B. bronchiseptica. PMID- 21255382 TI - Prevalence of visual impairment, cataract surgery and awareness of cataract and glaucoma in Bhaktapur district of Nepal: the Bhaktapur Glaucoma Study. AB - BACKGROUND: Cataract and glaucoma are the major causes of blindness in Nepal. Bhaktapur is one of the three districts of Kathmandu valley which represents a metropolitan city with a predominantly agrarian rural periphery. This study was undertaken to determine the prevalence of visual impairment, cataract surgery and awareness of cataract and glaucoma among subjects residing in this district of Nepal. METHODS: Subjects aged 40 years and above was selected using a cluster sampling methodology and a door to door enumeration was conducted for a population based cross sectional study. During the community field work, 11499 subjects underwent a structured interview regarding awareness (heard of) and knowledge (understanding of the disease) of cataract and glaucoma. At the base hospital 4003 out of 4800 (83.39%) subjects underwent a detailed ocular examination including log MAR visual acuity, refraction, applanation tonometry, cataract grading (LOCSIotaIota), retinal examination and SITA standard perimetry when indicated. RESULTS: The age-sex adjusted prevalence of blindness (best corrected <3/60) and low vision (best corrected <6/18 >= 3/60) was 0.43% (95%C.I. 0.25 - 0.68) and 3.97% (95% C.I. 3.40 - 4.60) respectively. Cataract (53.3%) was the principal cause of blindness. The leading causes of low vision were cataract (60.8%) followed by refractive error (12%). The cataract surgical coverage was 90.36% and was higher in the younger age group, females and illiterate subjects. Pseudophakia was seen in 94%. Awareness of cataract (6.7%) and glaucoma (2.4%) was very low. Among subjects who were aware, 70.4% had knowledge of cataract and 45.5% of glaucoma. Cataract was commonly known to be a 'pearl like dot' white opacity in the eye while glaucoma was known to cause blindness. Awareness remained unchanged in different age groups for cataract while for glaucoma there was an increase in awareness with age. Women were significantly less aware (odds ratio (OR): 0.63; 95%, confidence interval (CI): 0.54 - 0.74) for cataract and (OR: 0.64; 95% CI: 0.50 - 0.81) for glaucoma. Literacy was also correlated with awareness. CONCLUSION: The low prevalence of visual impairment and the high cataract surgical coverage suggests that cataract intervention programs have been successful in Bhaktapur. Awareness and knowledge of cataract and glaucoma was very poor among this population. Eye care programs needs to be directed towards preventing visual impairment from refractive errors, screening for incurable chronic eye diseases and promoting health education in order to raise awareness on cataract and glaucoma among this population. PMID- 21255384 TI - Targets downstream of Cdk8 in Dictyostelium development. AB - BACKGROUND: Cdk8 is a component of the mediator complex which facilitates transcription by RNA polymerase II and has been shown to play an important role in development of Dictyostelium discoideum. This eukaryote feeds as single cells but starvation triggers the formation of a multicellular organism in response to extracellular pulses of cAMP and the eventual generation of spores. Strains in which the gene encoding Cdk8 have been disrupted fail to form multicellular aggregates unless supplied with exogenous pulses of cAMP and later in development, cdk8- cells show a defect in spore production. RESULTS: Microarray analysis revealed that the cdk8- strain previously described (cdk8-HL) contained genome duplications. Regeneration of the strain in a background lacking detectable gene duplication generated strains (cdk8-2) with identical defects in growth and early development, but a milder defect in spore generation, suggesting that the severity of this defect depends on the genetic background. The failure of cdk8- cells to aggregate unless rescued by exogenous pulses of cAMP is consistent with a failure to express the catalytic subunit of protein kinase A. However, overexpression of the gene encoding this protein was not sufficient to rescue the defect, suggesting that this is not the only important target for Cdk8 at this stage of development. Proteomic analysis revealed two potential targets for Cdk8 regulation, one regulated post-transcriptionally (4 hydroxyphenylpyruvate dioxygenase (HPD)) and one transcriptionally (short chain dehydrogenase/reductase (SDR1)). CONCLUSIONS: This analysis has confirmed the importance of Cdk8 at multiple stages of Dictyostelium development, although the severity of the defect in spore production depends on the genetic background. Potential targets of Cdk8-mediated gene regulation have been identified in Dictyostelium which will allow the mechanism of Cdk8 action and its role in development to be determined. PMID- 21255385 TI - Shaping mechanisms of metal specificity in a family of metazoan metallothioneins: evolutionary differentiation of mollusc metallothioneins. AB - BACKGROUND: The degree of metal binding specificity in metalloproteins such as metallothioneins (MTs) can be crucial for their functional accuracy. Unlike most other animal species, pulmonate molluscs possess homometallic MT isoforms loaded with Cu(+) or Cd(2+). They have, so far, been obtained as native metal-MT complexes from snail tissues, where they are involved in the metabolism of the metal ion species bound to the respective isoform. However, it has not as yet been discerned if their specific metal occupation is the result of a rigid control of metal availability, or isoform expression programming in the hosting tissues or of structural differences of the respective peptides determining the coordinative options for the different metal ions. In this study, the Roman snail (Helix pomatia) Cu-loaded and Cd-loaded isoforms (HpCuMT and HpCdMT) were used as model molecules in order to elucidate the biochemical and evolutionary mechanisms permitting pulmonate MTs to achieve specificity for their cognate metal ion. RESULTS: HpCuMT and HpCdMT were recombinantly synthesized in the presence of Cd(2+), Zn(2+) or Cu(2+) and corresponding metal complexes analysed by electrospray mass spectrometry and circular dichroism (CD) and ultra violet visible (UV-Vis) spectrophotometry. Both MT isoforms were only able to form unique, homometallic and stable complexes (Cd(6)-HpCdMT and Cu(12)-HpCuMT) with their cognate metal ions. Yeast complementation assays demonstrated that the two isoforms assumed metal-specific functions, in agreement with their binding preferences, in heterologous eukaryotic environments. In the snail organism, the functional metal specificity of HpCdMT and HpCuMT was contributed by metal specific transcription programming and cell-specific expression. Sequence elucidation and phylogenetic analysis of MT isoforms from a number of snail species revealed that they possess an unspecific and two metal-specific MT isoforms, whose metal specificity was achieved exclusively by evolutionary modulation of non-cysteine amino acid positions. CONCLUSION: The Roman snail HpCdMT and HpCuMT isoforms can thus be regarded as prototypes of isoform families that evolved genuine metal-specificity within pulmonate molluscs. Diversification into these isoforms may have been initiated by gene duplication, followed by speciation and selection towards opposite needs for protecting copper-dominated metabolic pathways from nonessential cadmium. The mechanisms enabling these proteins to be metal-specific could also be relevant for other metalloproteins. PMID- 21255387 TI - Unusual cause of a painful right testicle in a 16-year-old man: a case report. AB - INTRODUCTION: Urgent surgical exploration of the scrotum of a child or teenager who presents with a painful and swollen testicle is paramount if testicular torsion is not to be missed. It is extremely rare for a non-scrotal pathology to present with acute scrotal signs. Here we present such a rare case and emphasize the importance of being aware of this potential clinical pitfall. CASE PRESENTATION: A 16-year-old Caucasian man presented as a surgical emergency with a five to six hour history of a painful, red, and swollen right hemiscrotum. He also complained of vague lower abdominal pain, vomiting, and watery diarrhea. He had a temperature of 38.5 degrees C and a tender, red, and swollen right hemiscrotum. The right testicle appeared elevated. He was mildly tender in his central and upper abdomen and less so in the lower abdomen. No convincing localizing abdominal signs were noted. He had an increased white cell count (15 * 109/L) and C-reactive protein (CRP; 300 mg/L). Urgent right hemiscrotal exploration revealed about 5 ml of pus in the tunica vaginalis and a normal testicle. A right iliac fossa incision identified the cause: a perforated retrocecal appendix. Appendectomy was performed, and both the abdomen and scrotum washed copiously with saline before closure. The patient made an uneventful recovery. CONCLUSION: Acute appendicitis presenting with scrotal signs due to a patent processus vaginalis is an extremely rare clinical entity. To date, fewer than five such cases have been reported in the medical literature. It is, therefore, extremely important to be aware of this unusual clinical scenario, as only a high index of suspicion will enable prompt, successful management of both the appendicitis and the scrotal abscess. PMID- 21255386 TI - Replicative phenotyping adds value to genotypic resistance testing in heavily pre treated HIV-infected individuals--the Swiss HIV Cohort Study. AB - BACKGROUND: Replicative phenotypic HIV resistance testing (rPRT) uses recombinant infectious virus to measure viral replication in the presence of antiretroviral drugs. Due to its high sensitivity of detection of viral minorities and its dissecting power for complex viral resistance patterns and mixed virus populations rPRT might help to improve HIV resistance diagnostics, particularly for patients with multiple drug failures. The aim was to investigate whether the addition of rPRT to genotypic resistance testing (GRT) compared to GRT alone is beneficial for obtaining a virological response in heavily pre-treated HIV infected patients. METHODS: Patients with resistance tests between 2002 and 2006 were followed within the Swiss HIV Cohort Study (SHCS). We assessed patients' virological success after their antiretroviral therapy was switched following resistance testing. Multilevel logistic regression models with SHCS centre as a random effect were used to investigate the association between the type of resistance test and virological response (HIV-1 RNA <50 copies/mL or >=1.5 log reduction). RESULTS: Of 1158 individuals with resistance tests 221 with GRT+rPRT and 937 with GRT were eligible for analysis. Overall virological response rates were 85.1% for GRT+rPRT and 81.4% for GRT. In the subgroup of patients with >2 previous failures, the odds ratio (OR) for virological response of GRT+rPRT compared to GRT was 1.45 (95% CI 1.00-2.09). Multivariate analyses indicate a significant improvement with GRT+rPRT compared to GRT alone (OR 1.68, 95% CI 1.31 2.15). CONCLUSIONS: In heavily pre-treated patients rPRT-based resistance information adds benefit, contributing to a higher rate of treatment success. PMID- 21255388 TI - Reverse transcription of the pFOXC mitochondrial retroplasmids of Fusarium oxysporum is protein primed. AB - BACKGROUND: The pFOXC retroplasmids are small, autonomously replicating DNA molecules found in mitochondria of certain strains of the filamentous fungus Fusarium oxysporum and are among the first linear genetic elements shown to replicate via reverse transcription. The plasmids have a unique clothespin structure that includes a 5'-linked protein and telomere-like terminal repeats, with pFOXC2 and pFOXC3 having iterative copies of a 5 bp sequence. The plasmids contain a single large open reading frame (ORF) encoding an active reverse transcriptase (RT). The pFOXC-RT is associated with the plasmid transcript in a ribonucleoprotein (RNP) complex and can synthesize full-length (-) strand cDNA products. In reactions containing partially purified RT preparations with exogenous RNAs, the pFOXC3-RT has been shown to initiate cDNA synthesis by use of snapped-back RNAs, as well as loosely associated DNA primers. RESULTS: The complete sequence of the distantly related pFOXC1 plasmid was determined and found to terminate in 3-5 copies of a 3 bp sequence. Unexpectedly, the majority of (-) strand cDNA molecules produced from endogenous pFOXC1 transcripts were attached to protein. In vitro experiments using partially purified pFOXC3-RT preparations having a single radiolabeled deoxyribonucleotide triphosphate (dNTP) generated a nucleotide-labeled protein that migrated at the size of the pFOXC-RT. The nucleotide preference of deoxynucleotidylation differed between pFOXC3 and pFOXC1 and showed complementarity to the respective 3' terminal repeats. In reactions that include exogenous RNA templates corresponding to the 3' end of pFOXC1, a protein-linked cDNA product was generated following deoxynucleotidylation, suggesting that reverse transcription initiates with a protein primer. CONCLUSIONS: The finding that reverse transcription is protein primed suggests the pFOXC retroplasmids may have an evolutionary relationship with hepadnaviruses, the only other retroelement family known to initiate reverse transcription via a protein primer. Moreover, the similarity to protein-primed linear DNA elements supports models in which the terminal repeats are generated and maintained by a DNA slideback mechanism. The ability of the pFOXC-RT to utilize RNA, DNA and protein primers is unique among polymerases and suggests that the pFOXC plasmids may be evolutionary precursors of a broad range of retroelements, including hepadnaviruses, non-long terminal repeat (non-LTR) retrotransposons and telomerase. PMID- 21255389 TI - Effector granules in human T lymphocytes: the luminal proteome of secretory lysosomes from human T cells. AB - BACKGROUND: Cytotoxic cells of the immune system have evolved a lysosomal compartment to store and mobilize effector molecules. In T lymphocytes and NK cells, the death factor FasL is one of the characteristic marker proteins of these so-called secretory lysosomes, which combine properties of conventional lysosomes and exocytotic vesicles. Although these vesicles are crucial for immune effector function, their protein content in T cells has so far not been investigated in detail. RESULTS: In the present study, intact membranous vesicles were enriched from homogenates of polyclonally activated T cells and initially characterized by Western blotting and electron microscopic inspection. The vesicular fraction that contained the marker proteins of secretory lysosomes was subsequently analyzed by 2D electrophoresis and mass spectrometry. The proteome analysis and data evaluation revealed that 70% of the 397 annotated proteins had been associated with different lysosome-related organelles in previous proteome studies. CONCLUSION: We provide the first comprehensive proteome map of T cell derived secretory lysosomes with only minor contaminations by cytosolic, nuclear or other proteins. This information will be useful to more precisely address the activation-dependent maturation and the specific distribution of effector organelles and proteins in individual T or NK cell populations in future studies. PMID- 21255390 TI - Folic acid supplementation before and during pregnancy in the Newborn Epigenetics STudy (NEST). AB - BACKGROUND: Folic acid (FA) added to foods during fortification is 70-85% bioavailable compared to 50% of folate occurring naturally in foods. Thus, if FA supplements also are taken during pregnancy, both mother and fetus can be exposed to FA exceeding the Institute of Medicine's recommended tolerable upper limit (TUL) of 1,000 micrograms per day (MUg/d) for adult pregnant women. The primary objective is to estimate the proportion of women taking folic acid (FA) doses exceeding the TUL before and during pregnancy, and to identify correlates of high FA use. METHODS: During 2005-2008, pre-pregnancy and pregnancy-related data on dietary supplementation were obtained by interviewing 539 pregnant women enrolled at two obstetrics-care facilities in Durham County, North Carolina. RESULTS: Before pregnancy, 51% of women reported FA supplementation and 66% reported this supplementation during pregnancy. Before pregnancy, 11.9% (95% CI = 9.2%-14.6%) of women reported supplementation with FA doses above the TUL of 1,000 MUg/day, and a similar proportion reported this intake prenatally. Before pregnancy, Caucasian women were more likely to take FA doses above the TUL (OR = 2.99; 95% = 1.28-7.00), compared to African American women, while women with chronic conditions were less likely to take FA doses above the TUL (OR = 0.48; 95%CI = 0.21-0.97). Compared to African American women, Caucasian women were also more likely to report FA intake in doses exceeding the TUL during pregnancy (OR = 5.09; 95%CI = 2.07-12.49). CONCLUSIONS: Fifty-one percent of women reported some FA intake before and 66% during pregnancy, respectively, and more than one in ten women took FA supplements in doses that exceeded the TUL. Caucasian women were more likely to report high FA intake. A study is ongoing to identify possible genetic and non-genotoxic effects of these high doses. PMID- 21255391 TI - Strabismus-mediated primary archenteron invagination is uncoupled from Wnt/beta catenin-dependent endoderm cell fate specification in Nematostella vectensis (Anthozoa, Cnidaria): Implications for the evolution of gastrulation. AB - BACKGROUND: Gastrulation is a uniquely metazoan character, and its genesis was arguably the key step that enabled the remarkable diversification within this clade. The process of gastrulation involves two tightly coupled events during embryogenesis of most metazoans. Morphogenesis produces a distinct internal epithelial layer in the embryo, and this epithelium becomes segregated as an endoderm/endomesodermal germ layer through the activation of a specific gene regulatory program. The developmental mechanisms that induced archenteron formation and led to the segregation of germ layers during metazoan evolution are unknown. But an increased understanding of development in early diverging taxa at the base of the metazoan tree may provide insights into the origins of these developmental mechanisms. RESULTS: In the anthozoan cnidarian Nematostella vectensis, initial archenteron formation begins with bottle cell-induced buckling of the blastula epithelium at the animal pole. Here, we show that bottle cell formation and initial gut invagination in Nematostella requires NvStrabismus (NvStbm), a maternally-expressed core component of the Wnt/Planar Cell Polarity (PCP) pathway. The NvStbm protein is localized to the animal pole of the zygote, remains asymmetrically expressed through the cleavage stages, and becomes restricted to the apical side of invaginating bottle cells at the blastopore. Antisense morpholino-mediated NvStbm-knockdown blocks bottle cell formation and initial archenteron invagination, but it has no effect on Wnt/beta-catenin signaling-mediated endoderm cell fate specification. Conversely, selectively blocking Wnt/beta-catenin signaling inhibits endoderm cell fate specification but does not affect bottle cell formation and initial archenteron invagination. CONCLUSIONS: Our results demonstrate that Wnt/PCP-mediated initial archenteron invagination can be uncoupled from Wnt/beta-catenin-mediated endoderm cell fate specification in Nematostella, and provides evidence that these two processes could have evolved independently during metazoan evolution. We propose a two-step model for the evolution of an archenteron and the evolution of endodermal germ layer segregation. Asymmetric accumulation and activation of Wnt/PCP components at the animal pole of the last common ancestor to the eumetazoa may have induced the cell shape changes that led to the initial formation of an archenteron. Activation of Wnt/beta-catenin signaling at the animal pole may have led to the activation of a gene regulatory network that specified an endodermal cell fate in the archenteron. PMID- 21255392 TI - Knowns and unknowns on burden of disease due to chemicals: a systematic review. AB - BACKGROUND: Continuous exposure to many chemicals, including through air, water, food, or other media and products results in health impacts which have been well assessed, however little is known about the total disease burden related to chemicals. This is important to know for overall policy actions and priorities. In this article the known burden related to selected chemicals or their mixtures, main data gaps, and the link to public health policy are reviewed. METHODS: A systematic review of the literature for global burden of disease estimates from chemicals was conducted. Global disease due to chemicals was estimated using standard methodology of the Global Burden of Disease. RESULTS: In total, 4.9 million deaths (8.3% of total) and 86 million Disability-Adjusted Life Years (DALYs) (5.7% of total) were attributable to environmental exposure and management of selected chemicals in 2004. The largest contributors include indoor smoke from solid fuel use, outdoor air pollution and second-hand smoke, with 2.0, 1.2 and 0.6 million deaths annually. These are followed by occupational particulates, chemicals involved in acute poisonings, and pesticides involved in self-poisonings, with 375,000, 240,000 and 186,000 annual deaths, respectively. CONCLUSIONS: The known burden due to chemicals is considerable. This information supports decision-making in programmes having a role to play in reducing human exposure to toxic chemicals. These figures present only a number of chemicals for which data are available, therefore, they are more likely an underestimate of the actual burden. Chemicals with known health effects, such as dioxins, cadmium, mercury or chronic exposure to pesticides could not be included in this article due to incomplete data and information. Effective public health interventions are known to manage chemicals and limit their public health impacts and should be implemented at national and international levels. PMID- 21255393 TI - When the human viral infectome and diseasome networks collide: towards a systems biology platform for the aetiology of human diseases. AB - BACKGROUND: Comprehensive understanding of molecular mechanisms underlying viral infection is a major challenge towards the discovery of new antiviral drugs and susceptibility factors of human diseases. New advances in the field are expected from systems-level modelling and integration of the incessant torrent of high throughput "-omics" data. RESULTS: Here, we describe the Human Infectome protein interaction Network, a novel systems virology model of a virtual virus-infected human cell concerning 110 viruses. This in silico model was applied to comprehensively explore the molecular relationships between viruses and their associated diseases. This was done by merging virus-host and host-host physical protein-protein interactomes with the set of genes essential for viral replication and involved in human genetic diseases. This systems-level approach provides strong evidence that viral proteomes target a wide range of functional and inter-connected modules of proteins as well as highly central and bridging proteins within the human interactome. The high centrality of targeted proteins was correlated to their essentiality for viruses' lifecycle, using functional genomic RNAi data. A stealth-attack of viruses on proteins bridging cellular functions was demonstrated by simulation of cellular network perturbations, a property that could be essential in the molecular aetiology of some human diseases. Networking the Human Infectome and Diseasome unravels the connectivity of viruses to a wide range of diseases and profiled molecular basis of Hepatitis C Virus-induced diseases as well as 38 new candidate genetic predisposition factors involved in type 1 diabetes mellitus. CONCLUSIONS: The Human Infectome and Diseasome Networks described here provide a unique gateway towards the comprehensive modelling and analysis of the systems level properties associated to viral infection as well as candidate genes potentially involved in the molecular aetiology of human diseases. PMID- 21255394 TI - Fluorescent dye labeled DNA size standards for molecular mass detection in visible/infrared range. AB - BACKGROUND: Targeting Induced Local Lesions in Genomes (TILLING) is a high throughput reverse genetics tool which detects mismatches (single point mutations or small indels) in large number of individuals of mutagenized populations. Currently, TILLING is intensively used for genomics assisted molecular breeding of several crop plants for desired traits. Most commonly used platform for mutation detection is Li-COR DNA Analyzer, where PCR amplified products treated with single strand mismatch specific nuclease are resolved on denaturing gels. The molecular size of any cut product can be easily estimated by comparing with IR dye labeled markers of known sizes. Similar fluorescent dye labeled size markers are also used for several genotyping experiments. Currently, commercially available size standards are expensive and are restricted up to only 700 bp which renders estimation of products of sizes greater than 700 bases inaccurate. FINDINGS: A simple protocol was developed for labeling 5' end of multiple DNA size markers with fluorescent dyes. This method involves cloning a pool of different size markers of DNA in a plasmid vector. PCR amplification of plasmid using IR dye labeled universal primers generates 5' fluorescent labeled products of various sizes. The size of products constituting the ladder can be customized as per the need. The generated size markers can be used without any further purification and were found to be stable up to one year at -20 degrees C. CONCLUSIONS: A simple method was developed for generating fluorescent dye labeled size standards. This method can be customized to generate different size standards as per experimental needs. The protocol described can also be adapted for developing labeled size standards for detection on platforms other than Li COR i.e. other than infra red range of the spectrum. PMID- 21255395 TI - Cerebral aneurysm exclusion by CT angiography based on subarachnoid hemorrhage pattern: a retrospective study. AB - BACKGROUND: To identify patients with spontaneous subarachnoid hemorrhage for whom CT angiography alone can exclude ruptured aneurysms. METHODS: An observational retrospective review was carried out of all consecutive patients with non-traumatic subarachnoid hemorrhage who underwent both CT angiography and catheter angiography to exclude an aneurysm. CT angiography negative cases (no aneurysm) were classified according to their CT hemorrhage pattern as "aneurismal", "perimesencephalic" or as "no-hemorrhage." RESULTS: Two hundred and forty-one patients were included. A CT angiography aneurysm detection sensitivity and specificity of 96.4% and 96.0% were observed. All 35 cases of perimesencephalic or no-hemorrhage out of 78 CT angiography negatives also had negative angiography findings. CONCLUSIONS: CT angiography is self-reliant to exclude ruptured aneurysms when either a perimesencephalic hemorrhage or no hemorrhage pattern is identified on the CT within a week of symptom onset. PMID- 21255396 TI - Glutathione Peroxidase 4 is associated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain. AB - BACKGROUND: Parkinson's disease is a neurodegenerative disorder characterized pathologically by the loss of nigrostriatal dopamine neurons that project from the substantia nigra in the midbrain to the putamen and caudate nuclei, leading to the clinical features of bradykinesia, rigidity, and rest tremor. Oxidative stress from oxidized dopamine and related compounds may contribute to the degeneration characteristic of this disease. RESULTS: To investigate a possible role of the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4) in protection from oxidative stress, we investigated GPX4 expression in postmortem human brain tissue from individuals with and without Parkinson's disease. In both control and Parkinson's samples, GPX4 was found in dopaminergic nigral neurons colocalized with neuromelanin. Overall GPX4 was significantly reduced in substantia nigra in Parkinson's vs. control subjects, but was increased relative to the cell density of surviving nigral cells. In putamen, GPX4 was concentrated within dystrophic dopaminergic axons in Parkinson's subjects, although overall levels of GPX4 were not significantly different compared to control putamen. CONCLUSIONS: This study demonstrates an up-regulation of GPX4 in neurons of substantia nigra and association of this protein with dystrophic axons in striatum of Parkinson's brain, indicating a possible neuroprotective role. Additionally, our findings suggest this enzyme may contribute to the production of neuromelanin. PMID- 21255397 TI - Patients with allergic rhinitis and allergic asthma share the same pattern of eosinophil and neutrophil degranulation after allergen challenge. AB - BACKGROUND: Patients with allergic rhinitis and allergic asthma demonstrate comparable local and systemic eosinophil inflammation, and yet they present with different clinical pictures. Less is even known about the contribution of neutrophil inflammation in allergic diseases. The aim of the study was to examine the propensity and selectivity of granule release from primed systemic eosinophils and neutrophils in allergic rhinitis and allergic asthma after seasonal and experimental allergen exposure. We hypothesize that the dissimilar clinical manifestations are due to diverse eosinophil and neutrophil degranulation. METHODS: Nine birch pollen allergic patients with rhinitis, eight with asthma and four controls were studied during pollen season and after nasal and bronchial allergen challenge. Eosinophils and neutrophils were incubated in vitro with assay buffer and opsonized Sephadex particles for spontaneous and C3b induced granule protein release. The released amount of eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) and myeloperoxidase (MPO) was measured by specific radioimmunoassay. RESULTS: C3b-induced degranulation resulted in increased release of ECP and MPO from primed blood eosinophils and neutrophils in both allergic rhinitis and allergic asthma during pollen season and after both nasal and bronchial challenge (p-values 0.008 to 0.043). After bronchial challenge, the ECP release was significantly higher in the rhinitic group compared to the asthmatic group [19.8 vs. 13.2%, (p = 0.010)]. The propensity for EPO release was weak in all challenge models but followed the same pattern in both allergic groups. CONCLUSIONS: Systemically activated eosinophils and neutrophils have similar patterns of degranulation after allergen exposure in allergic rhinitis and allergic asthma. The released amount of ECP, EPO and MPO was similar in all allergen challenge models in both allergic groups. Our results indicate that other mechanisms than the magnitude of eosinophil and neutrophil inflammation or the degranulation pattern of the inflammatory cells determines whether or not an allergic patient develops asthma. PMID- 21255398 TI - Enhanced RAD21 cohesin expression confers poor prognosis and resistance to chemotherapy in high grade luminal, basal and HER2 breast cancers. AB - INTRODUCTION: RAD21 is a component of the cohesin complex, which is essential for chromosome segregation and error-free DNA repair. We assessed its prognostic and predictive power in a cohort of in situ and invasive breast cancers, and its effect on chemosensitivity in vitro. METHODS: RAD21 immunohistochemistry was performed on 345 invasive and 60 pure in situ carcinomas. Integrated genomic and transcriptomic analyses were performed on a further 48 grade 3 invasive cancers. Chemosensitivity was assessed in breast cancer cell lines with an engineered spectrum of RAD21 expression. RESULTS: RAD21 expression correlated with early relapse in all patients (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.06 to 2.86, P = 0.029). This was due to the effect of grade 3 tumors (but not grade 1 or 2) in which RAD21 expression correlated with early relapse in luminal (P = 0.040), basal (P = 0.018) and HER2 (P = 0.039) groups. In patients treated with chemotherapy, RAD21 expression was associated with shorter overall survival (P = 0.020). RAD21 mRNA expression correlated with DNA copy number, with amplification present in 32% (7/22) of luminal, 31% (4/13) of basal and 22% (2/9) of HER2 grade 3 cancers. Variations in RAD21 mRNA expression in the clinical samples were reflected in the gene expression data from 36 breast cancer cell lines. Knockdown of RAD21 in the MDA-MB-231 breast cancer cell line significantly enhanced sensitivity to cyclophosphamide, 5-fluorouracil and etoposide. The findings for the former two drugs recapitulated the clinical findings. CONCLUSIONS: RAD21 expression confers poor prognosis and resistance to chemotherapy in high grade luminal, basal and HER2 breast cancers. RAD21 may be a novel therapeutic target. PMID- 21255399 TI - Randomised social-skills training and parental training plus standard treatment versus standard treatment of children with attention deficit hyperactivity disorder - the SOSTRA trial protocol. AB - BACKGROUND: Children with attention deficit hyperactivity disorder (ADHD) are hyperactive and impulsive, cannot maintain attention, and have difficulties with social interactions. Medical treatment may alleviate symptoms of ADHD, but seldom solves difficulties with social interactions. Social-skills training may benefit ADHD children in their social interactions. We want to examine the effects of social-skills training on difficulties related to the children's ADHD symptoms and social interactions. METHODS/DESIGN: The design is randomised two-armed, parallel group, assessor-blinded trial. Children aged 8-12 years with a diagnosis of ADHD are randomised to social-skills training and parental training plus standard treatment versus standard treatment alone. A sample size calculation estimated that at least 52 children must be included to show a 4-point difference in the primary outcome on the Conners 3rd Edition subscale for 'hyperactivity impulsivity' between the intervention group and the control group. The outcomes will be assessed 3 and 6 months after randomisation. The primary outcome measure is ADHD symptoms. The secondary outcome is social skills. Tertiary outcomes include the relationship between social skills and symptoms of ADHD, the ability to form attachment, and parents' ADHD symptoms. DISCUSSION: We hope that the results from this trial will show that the social-skills training together with medication may have a greater general effect on ADHD symptoms and social and emotional competencies than medication alone. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT00937469. PMID- 21255400 TI - Granulocytic sarcoma of the small bowel, greater omentum and peritoneum associated with a CBFbeta/MYH11 fusion and inv(16) (p13q22): a case report. AB - INTRODUCTION: Granulocytic sarcoma (GS) is an extramedullary disease which is composed of immature myeloid cells or myeloblasts and usually occurs in association with acute myeloid leukemia (AML), as an initial presentation or a relapse. GS has been associated with various cytogenetic abnormalities, particularly with the t(8;21) translocation and less frequently the inv(16) type. CASE PRESENTATION: We present a rare case of GS of the small bowel, greater omentum and peritoneum, which caused obstruction, in a patient with AML associated with a CBFbeta/MYH11 fusion gene and an inv(16) (p13q22). In this patient there was only mild myeloid hyperplasia in bone marrow aspiration but molecular analysis identified a CBFbeta-MYH11 fusion and inv(16) (p13;q22). CONCLUSION: Because of its nonspecific clinical and radiologic findings, this entity can be misdiagnosed and can mimic other solid neoplasms, making it a diagnostic challenge. In a GS with no or minimal morphological changes in bone marrow aspiration it is very important to perform a cytogenetic analysis to benefit from the diagnosis and therapeutic strategy. PMID- 21255401 TI - Modification of fatty acids composition in erythrocytes lipids in arterial hypertension associated with dyslipidemia. AB - BACKGROUND: Modification of fatty acids (FA) composition in erythrocytes lipids as an early indicator of the development of arterial hypertension (AH) and lipid disorders. METHODS: We included 34 patients with arterial hypertension and 11 healthy individuals. Each patient was examined the lipid composition of serum. From erythrocytes by gas chromatography were identified fatty acids. The quantitative composition of the erythrocyte lipids FA in patients with AH presented with saturated and polyunsaturated monoenic acids with carbon chain lengths from C12 to C22. RESULTS: In all hypertensive patients is disturbed lipid FA composition of erythrocytes. The patients with a normal level of serum lipids revealed deficiency of polyunsaturated acids n6-linoleic (18:2 n6), arachidonic (20:4 n6), dokozatetraenic 14.4% (22:4 n6). The patients with dislipidemia installed more profound restructuring of the lipid matrix of the membrane of erythrocytes. A decrease in polyunsaturated fatty acids family n3: dokozapentaenovoy (22:5 n3), docosahexaenoic PUFA (22:6 n3), the total value of n3 PUFA in 1,3 times was revealed. CONCLUSION: Thus, modification of erythrocyte FA are fairly subtle indicator of pathology of lipid metabolism, which manifest themselves much earlier than changes in the lipoprotein of blood plasma. PMID- 21255402 TI - Oil accumulation in the model green alga Chlamydomonas reinhardtii: characterization, variability between common laboratory strains and relationship with starch reserves. AB - BACKGROUND: When cultivated under stress conditions, many microalgae species accumulate both starch and oil (triacylglycerols). The model green microalga Chlamydomonas reinhardtii has recently emerged as a model to test genetic engineering or cultivation strategies aiming at increasing lipid yields for biodiesel production. Blocking starch synthesis has been suggested as a way to boost oil accumulation. Here, we characterize the triacylglycerol (TAG) accumulation process in Chlamydomonas and quantify TAGs in various wild-type and starchless strains. RESULTS: In response to nitrogen deficiency, Chlamydomonas reinhardtii produced TAGs enriched in palmitic, oleic and linoleic acids that accumulated in oil-bodies. Oil synthesis was maximal between 2 and 3 days following nitrogen depletion and reached a plateau around day 5. In the first 48 hours of oil deposition, a ~80% reduction in the major plastidial membrane lipids occurred. Upon nitrogen re-supply, mobilization of TAGs started after starch degradation but was completed within 24 hours. Comparison of oil content in five common laboratory strains (CC124, CC125, cw15, CC1690 and 11-32A) revealed a high variability, from 2 MUg TAG per million cell in CC124 to 11 MUg in 11-32A. Quantification of TAGs on a cell basis in three mutants affected in starch synthesis (cw15sta1-2, cw15sta6 and cw15sta7-1) showed that blocking starch synthesis did not result in TAG over-accumulation compared to their direct progenitor, the arginine auxotroph strain 330. Moreover, no significant correlation was found between cellular oil and starch levels among the twenty wild-type, mutants and complemented strains tested. By contrast, cellular oil content was found to increase steeply with salt concentration in the growth medium. At 100 mM NaCl, oil level similar to nitrogen depletion conditions could be reached in CC124 strain. CONCLUSION: A reference basis for future genetic studies of oil metabolism in Chlamydomonas is provided. Results highlight the importance of using direct progenitors as control strains when assessing the effect of mutations on oil content. They also suggest the existence in Chlamydomonas of complex interplays between oil synthesis, genetic background and stress conditions. Optimization of such interactions is an alternative to targeted metabolic engineering strategies in the search for high oil yields. PMID- 21255403 TI - Improved hatchability and efficient protection after in ovo vaccination with live attenuated H7N2 and H9N2 avian influenza viruses. AB - Mass in ovo vaccination with live attenuated viruses is widely used in the poultry industry to protect against various infectious diseases. The worldwide outbreaks of low pathogenic and highly pathogenic avian influenza highlight the pressing need for the development of similar mass vaccination strategies against avian influenza viruses. We have previously shown that a genetically modified live attenuated avian influenza virus (LAIV) was amenable for in ovo vaccination and provided optimal protection against H5 HPAI viruses. However, in ovo vaccination against other subtypes resulted in poor hatchability and, therefore, seemed impractical. In this study, we modified the H7 and H9 hemagglutinin (HA) proteins by substituting the amino acids at the cleavage site for those found in the H6 HA subtype. We found that with this modification, a single dose in ovo vaccination of 18-day old eggs provided complete protection against homologous challenge with low pathogenic virus in >= 70% of chickens at 2 or 6 weeks post hatching. Further, inoculation of 19-day old egg embryos with 106 EID50 of LAIVs improved hatchability to >= 90% (equivalent to unvaccinated controls) with similar levels of protection. Our findings indicate that the strategy of modifying the HA cleavage site combined with the LAIV backbone could be used for in ovo vaccination against avian influenza. Importantly, with protection conferred as early as 2 weeks post-hatching, with this strategy birds would be protected prior to or at the time of delivery to a farm or commercial operation. PMID- 21255404 TI - Comparision of nerve stimulator and ultrasonography as the techniques applied for brachial plexus anesthesia. AB - BACKGROUND: Brachial plexus block is useful for upper extremity surgery, and many techniques are available. The aim of our study was to compare the efficacy of axillary brachial plexus block using an ultrasound technique to the peripheral nerve stimulation technique. METHODS: 60 patients scheduled for surgery of the forearm or hand were randomly allocated into two groups (n = 30 per group). For Group 1; US, and for Group 2 PNS was applied. The quality and the onset of the sensorial and motor blockade were assessed. The sensorial blockade, motor blockade time and quality of blockade were compared among the cases. RESULTS: The time needed to perform the axillary brachial plexus block averaged is similar in both groups (p > 0.05). Although not significant statistically, it was observed that the sensory block had formed earlier in Group 1 (p > 0.05). But the degree of motor blockade was intenser in Group 1 than in Group 2 (p < 0.05). CONCLUSIONS: Ultrasound offers a new possibility for identifiying the nerves of the brachial plexus for regional anesthesia. The ultrasound-guided axillary brachial plexus block is a safe method with faster onset time and better quality of motor blockade compared to peripheral nerve stimulation technique. PMID- 21255405 TI - Defining mental disorder. Exploring the 'natural function' approach. AB - Due to several socio-political factors, to many psychiatrists only a strictly objective definition of mental disorder, free of value components, seems really acceptable. In this paper, I will explore a variant of such an objectivist approach to defining metal disorder, natural function objectivism. Proponents of this approach make recourse to the notion of natural function in order to reach a value-free definition of mental disorder. The exploration of Christopher Boorse's 'biostatistical' account of natural function (1) will be followed an investigation of the 'hybrid naturalism' approach to natural functions by Jerome Wakefield (2). In the third part, I will explore two proposals that call into question the whole attempt to define mental disorder (3). I will conclude that while 'natural function objectivism' accounts fail to provide the backdrop for a reliable definition of mental disorder, there is no compelling reason to conclude that a definition cannot be achieved. PMID- 21255406 TI - Induction of ovulation in Xenopus without hCG injection: the effect of adding steroids into the aquatic environment. AB - BACKGROUND: The African clawed frog, Xenopus laevis, is widely used in studies of oogenesis, meiotic cell cycle and early embryonic development. However, in order to perform such studies, eggs are normally collected after the injection of hCG into the dorsal lymph sac of fully-grown female frogs following pre-injection of PMSF. Although this protocol is established and used as standard laboratory approach, there are some concerns over whether the injections could cause the transmission of deleterious microorganisms. Moreover, these injection protocols require a competent skilled worker to carry out the procedure efficiently. METHODS: Recently, we established a novel method to induce fish ovulation by simply adding the natural maturation-inducing hormone of teleosts, 17 alpha, 20 beta-dihydroxy-4-pregnen-3-one (17,20 beta-DHP), into the surrounding water. In the present study, we demonstrate how we can induce ovulation in frogs using the same methodology. RESULTS: In frogs, progesterone was effective in the induction of oocyte maturation in vitro. We then examined the ability of progesterone to induce ovulation in frogs. However treatment of frogs with progesterone alone only occasionally induced ovulation in vivo. The number of oocytes and the frequency of ovulation were significantly lower than that induced by hCG injection. Thus, conditions were improved by using a combination of progesterone with estradiol and by pre-treating frogs with low concentrations of progesterone or estradiol. Finally, we established an efficient means of inducing ovulation in frogs which involved pre-treatment of frogs with salt solution followed by a mixture of estradiol and progesterone at high concentration. The frequency and numbers of oocytes obtained were identical to those resulting from PMSG-hCG induction. Fertilization rate of eggs ovulated by the new treatment method was comparable to eggs obtained by hCG-injection and juveniles developed normally. CONCLUSIONS: To conclude, we have successfully developed a novel method to induce ovulation in frogs but without the need for a potentially harmful injection strategy. PMID- 21255408 TI - Prevalence and risk factors accounting for true silent myocardial ischemia: a pilot case-control study comparing type 2 diabetic with non-diabetic control subjects. AB - BACKGROUND: Given the elevated risk of cardiovascular events and the higher prevalence of silent coronary artery disease (CAD) in diabetic versus non diabetic patients, the need to screen asymptomatic diabetic patients for CAD assumes increasing importance. The aims of the study were to assess prospectively the prevalence and risk factor predictors of true silent myocardial ischemia (myocardial perfusion defects in the absence of both angina and ST-segment depression) in asymptomatic type 2 diabetic patients. METHODS: Stress myocardial perfusion gated SPECT (single photon emission computed tomography) was carried out in 41 type 2 diabetic patients without history of cardiovascular disease (CVD) and 41 nondiabetic patients matched by age and gender. RESULTS: There were no significant differences between the two groups regarding either the classic CVD risk factors or left ventricular function. True silent ischemia was detected in 21.9% of diabetic patients but only in 2.4% of controls (p < 0.01). The presence of myocardial perfusion defects was independently associated with male gender and the presence of diabetic retinopathy (DR). The probability of having myocardial perfusion defects in an asymptomatic diabetic patient with DR in comparison with diabetic patients without DR was 11.7 [IC95%: 3.7-37]. CONCLUSIONS: True silent myocardial ischemia is a high prevalent condition in asymptomatic type 2 diabetic patients. Male gender and the presence of DR are the risk factors related to its development. PMID- 21255407 TI - Cross-talk between cd1d-restricted nkt cells and gammadelta cells in t regulatory cell response. AB - CD1d is a non-classical major histocompatibility class 1-like molecule which primarily presents either microbial or endogenous glycolipid antigens to T cells involved in innate immunity. Natural killer T (NKT) cells and a subpopulation of gammadelta T cells expressing the Vgamma4 T cell receptor (TCR) recognize CD1d. NKT and Vgamma4 T cells function in the innate immune response via rapid activation subsequent to infection and secrete large quantities of cytokines that both help control infection and modulate the developing adaptive immune response. T regulatory cells represent one cell population impacted by both NKT and Vgamma4 T cells. This review discusses the evidence that NKT cells promote T regulatory cell activation both through direct interaction of NKT cell and dendritic cells and through NKT cell secretion of large amounts of TGFbeta, IL-10 and IL-2. Recent studies have shown that CD1d-restricted Vgamma4 T cells, in contrast to NKT cells, selectively kill T regulatory cells through a caspase-dependent mechanism. Vgamma4 T cell elimination of the T regulatory cell population allows activation of autoimmune CD8+ effector cells leading to severe cardiac injury in a coxsackievirus B3 (CVB3) myocarditis model in mice. CD1d-restricted immunity can therefore lead to either immunosuppression or autoimmunity depending upon the type of innate effector dominating during the infection. PMID- 21255409 TI - Endoscopic procedures for removal of foreign bodies of the aerodigestive tract: The Bugando Medical Centre experience. AB - BACKGROUND: Foreign bodies in the aerodigestive tract continue to be a common problem that contributes significantly to high morbidity and mortality worldwide. This study was conducted to describe our own experience with endoscopic procedures for removal of foreign bodies in the aerodigestive tract, in our local setting and compare with what is described in literature. METHODS: This was a prospective descriptive study which was conducted at Bugando Medical Centre between January 2008 and December 2009. Data were collected using a structured questionnaire and analyzed using SPSS computer software version 15. RESULTS: A total of 98 patients were studied. Males outnumbered females by a ratio of 1.1:1. Patients aged 2 years and below were the majority (75.9%). The commonest type of foreign bodies in airways was groundnuts (72.7%) and in esophagus was coins (72.7%). The trachea (52.2%) was the most common site of foreign body's lodgment in the airways, whereas cricopharyngeal sphincter (68.5%) was the commonest site in the esophagus. Rigid endoscopy with forceps removal under general anesthesia was the main treatment modality performed in 87.8% of patients. The foreign bodies were successfully removed without complications in 90.8% of cases. Complication rate was 7.1% and bronchopneumonia was the most common complication accounting for 42.8% of cases. The mean duration of hospital stay was 3.4 days and mortality rate was 4.1%. CONCLUSION: Aerodigestive tract foreign bodies continue to be a significant cause of childhood morbidity and mortality in our setting. Rigid endoscopic procedures under general anesthesia are the main treatment modalities performed. Prevention is highly recommended whereby parents should be educated to keep a close eye on their children and keep objects which can be foreign bodies away from children's reach. PMID- 21255411 TI - Molecular mechanism of the schedule-dependent synergistic interaction in EGFR mutant non-small cell lung cancer cell lines treated with paclitaxel and gefitinib. AB - BACKGROUND: Chemotherapy combined concurrently with TKIs produced a negative interaction and failed to improve survival when compared with chemotherapy or TKIs alone in the treatment of non-small cell lung cancer (NSCLC). The present study investigated the sequence-dependent interaction between paclitaxel and gefitinib and clarified the underlying mechanism. METHODS: The effects on cell proliferation, EGFR signaling pathway, and TGFalpha expression were evaluated in a panel of human NSCLC cell lines harboring EGFR mutations with three different combination sequences: sequential treatment with paclitaxel followed by gefitinib (T->G), sequential treatment with gefitinib followed by paclitaxel (G->T), or concomitant treatment (T + G). RESULTS: The sequence-dependent anti-proliferative effects differed between EGFR-TKI-sensitive and -resistant cell lines carrying EGFR mutations. A synergistic anti-proliferative activity was obtained with paclitaxel treatment followed by gefitinib in all cell lines, with mean CI values of 0.63 in Hcc827, 0.54 in PC-9, 0.81 in PC-9/GR, and 0.77 in H1650 cells for the T->G sequence. The mean CI values for the G->T sequence were 1.29 in Hcc827, 1.16 in PC-9, 1.52 in PC-9/GR, and 1.5 in H1650 cells. The mean CI values for T+G concomitant treatment were 0.88 in Hcc827, 0.91 in PC-9, 1.05 in PC-9/GR, and 1.18 in H1650 cells. Paclitaxel produced a dose-dependent increase in EGFR phosphorylation. Paclitaxel significantly increased EGFR phosphorylation compared with that in untreated controls (mean differences: +50% in Hcc827, + 56% in PC-9, + 39% in PC-9/GR, and + 69% in H1650 cells; p < 0.05). The T->G sequence produced significantly greater inhibition of EGFR phosphorylation compared with the opposite sequence (mean differences: -58% in Hcc827, -38% in PC-9, -35% in PC 9/GR, and -30% in H1650 cells; p < 0.05). Addition of a neutralizing anti TGFalpha antibody abolished paclitaxel-induced activation of the EGFR pathway in PC-9 and H1650 cells. Sequence-dependent TGFalpha expression and release are responsible for the sequence-dependent EGFR pathway modulation. CONCLUSION: The data suggest that the sequence of paclitaxel followed by gefitinib is an appropriate treatment combination for NSCLC cell lines harboring EGFR mutations. Our results provide molecular evidence to support clinical treatment strategies for patients with lung cancer. PMID- 21255410 TI - The immunoregulatory mechanisms of carcinoma for its survival and development. AB - The immune system in patients detects and eliminates tumor cells, but tumors still progress persistently. The mechanisms by which tumor cells survive under the pressure of immune surveillance are not fully understood. This review is to present the evidence from clinical studies, showing a significant correlation of clinicopathological features of carcinoma with: (1) the loss of classical human leukocyte antigen class I, (2) the up-regulation of non-classical human leukocyte antigen class I, pro-apoptotic Fas ligand and receptor-binding cancer antigen expressed on SiSo cells I, and (3) the formation of immunosuppressive microenvironment by up-regulation of transforming growth factor-beta, Galectin-1, inhibitory ligand B7s, indoleamine 2,3-dioxygenase and arginase, as well as by recruitment of tumor-induced myeloid-derived suppressor cells and regulatory T cells. All of these factors may together protect carcinoma cells from the immune cytotoxicity. PMID- 21255412 TI - Development of a novel multiplex DNA microarray for Fusarium graminearum and analysis of azole fungicide responses. AB - BACKGROUND: The toxigenic fungal plant pathogen Fusarium graminearum compromises wheat production worldwide. Azole fungicides play a prominent role in controlling this pathogen. Sequencing of its genome stimulated the development of high throughput technologies to study mechanisms of coping with fungicide stress and adaptation to fungicides at a previously unprecedented precision. DNA-microarrays have been used to analyze genome-wide gene expression patterns and uncovered complex transcriptional responses. A recently developed one-color multiplex array format allowed flexible, effective, and parallel examinations of eight RNA samples. RESULTS: We took advantage of the 8 * 15 k Agilent format to design, evaluate, and apply a novel microarray covering the whole F. graminearum genome to analyze transcriptional responses to azole fungicide treatment. Comparative statistical analysis of expression profiles uncovered 1058 genes that were significantly differentially expressed after azole-treatment. Quantitative RT-PCR analysis for 31 selected genes indicated high conformity to results from the microarray hybridization. Among the 596 genes with significantly increased transcript levels, analyses using GeneOntology and FunCat annotations detected the ergosterol-biosynthesis pathway genes as the category most significantly responding, confirming the mode-of-action of azole fungicides. Cyp51A, which is one of the three F. graminearum paralogs of Cyp51 encoding the target of azoles, was the most consistently differentially expressed gene of the entire study. A molecular phylogeny analyzing the relationships of the three CYP51 proteins in the context of 38 fungal genomes belonging to the Pezizomycotina indicated that CYP51C (FGSG_11024) groups with a new clade of CYP51 proteins. The transcriptional profiles for genes encoding ABC transporters and transcription factors suggested several involved in mechanisms alleviating the impact of the fungicide. Comparative analyses with published microarray experiments obtained from two different nutritional stress conditions identified subsets of genes responding to different types of stress. Some of the genes that responded only to tebuconazole treatment appeared to be unique to the F. graminearum genome. CONCLUSIONS: The novel F. graminearum 8 * 15 k microarray is a reliable and efficient high-throughput tool for genome-wide expression profiling experiments in fungicide research, and beyond, as shown by our data obtained for azole responses. The array data contribute to understanding mechanisms of fungicide resistance and allow identifying fungicide targets. PMID- 21255413 TI - A novel neuron-enriched protein SDIM1 is down regulated in Alzheimer's brains and attenuates cell death induced by DNAJB4 over-expression in neuro-progenitor cells. AB - BACKGROUND: Molecular changes in multiple biological processes contribute to the development of chronic neurodegeneration such as late onset Alzheimer's disease (LOAD). To discover how these changes are reflected at the level of gene expression, we used a subtractive transcription-based amplification of mRNA procedure to identify novel genes that have altered expression levels in the brains of Alzheimer's disease (AD) patients. Among the genes altered in expression level in AD brains was a transcript encoding a novel protein, SDIM1, that contains 146 amino acids, including a typical signal peptide and two transmembrane domains. Here we examined its biochemical properties and putative roles in neuroprotection/neurodegeneration. RESULTS: QRT-PCR analysis of additional AD and control post-mortem human brains showed that the SDIM1 transcript was indeed significantly down regulated in all AD brains. SDIM1 is more abundant in NT2 neurons than astrocytes and present throughout the cytoplasm and neural processes, but not in the nuclei. In NT2 neurons, it is highly responsive to stress conditions mimicking insults that may cause neurodegeneration in AD brains. For example, SDIM1 was significantly down regulated 2 h after oxygen-glucose deprivation (OGD), though had recovered 16 h later, and also appeared significantly up regulated compared to untreated NT2 neurons. Overexpression of SDIM1 in neuro-progenitor cells improved cells' ability to survive after injurious insults and its downregulation accelerated cell death induced by OGD. Yeast two-hybrid screening and co-immunoprecipitation approaches revealed, both in vitro and in vivo, an interaction between SDIM1 and DNAJB4, a heat shock protein hsp40 homolog, recently known as an enhancer of apoptosis that also interacts with the mu opioid receptor in human brain. Overexpression of DNAJB4 alone significantly reduced cell viability and SDIM1 co overexpression was capable of attenuating the cell death caused DNAJB4, suggesting that the binding of SDIM1 to DNAJB4 might sequester DNAJB4, thus increasing cell viability. CONCLUSION: Taken together, we have identified a small membrane protein, which is down regulated in AD brains and neuronal cells exposed to injurious insults. Its ability to promote survival and its interaction with DNAJB4 suggest that it may play a very specific role in brain cell survival and/or receptor trafficking. PMID- 21255414 TI - Chasing the dragon - characterizing cases of leukoencephalopathy associated with heroin inhalation in British Columbia. AB - An association between leukoencephalopathy, a disease of the white matter of the brain, and smoking heroin is well recognized. This paper describes 27 cases of leukoencephalopathy identified in two cities in British Columbia, Canada 2001 2006; the largest number of geographically and temporally defined reported cases in North America.Twenty cases of leukoencephalopathy were identified in and around Vancouver with onset dates December 2001 to July 2003; seven further cases were identified in Victoria September 2005-August 2006. Twenty (74%) of all cases were male, two couples were reported and eleven cases (55%) had Asian ethnicity. One case reported smoking heroin on a single occasion and developed mild symptoms; all other cases were hospitalized. Thirteen (48%) cases died; all had smoked heroin for a minimum of 3 years. Testing of one available heroin sample identified no substance other than common cutting agents.Although a specific etiology was not identified our study supports the theory of an intermittent exposure to a toxic agent added to the heroin or a combustion by-product. It also suggests a dose response effect rather than genetic predisposition. Collaboration with public health, health professionals, law enforcement and persons who use illegal drugs, will facilitate the early identification of cases to enable timely and complete follow-up including obtaining samples. Testing of implicated heroin samples may allow identification of the contaminant and therefore prevent further cases. It is therefore important to ensure key stakeholders are aware of our findings. PMID- 21255415 TI - Skp2 and Skp2B team up against Rb and p53. AB - The Skp2 locus encodes two proteins, Skp2 and Skp2B. The role of Skp2 in the ubiquitin-dependent degradation of key regulators of the retinoblastoma protein pathway has been well established. More recent work from the McCormick's group suggested that Skp2 has an ubiquitin-independent function in the regulation of the p53 pathway. Adding to this observation, we reported that Skp2B also regulates the activity of p53 by degrading a distinct substrate, prohibitin. Since prohibitin has been implicated in the regulation of the Rb pathway, collectively, these observations suggest that Skp2 and Skp2B team up against p53 and Rb. PMID- 21255416 TI - Modeling RNA polymerase competition: the effect of sigma-subunit knockout and heat shock on gene transcription level. AB - BACKGROUND: Modeling of a complex biological process can explain the results of experimental studies and help predict its characteristics. Among such processes is transcription in the presence of competing RNA polymerases. This process involves RNA polymerases collision followed by transcription termination. RESULTS: A mathematical and computer simulation model is developed to describe the competition of RNA polymerases during genes transcription on complementary DNA strands. E.g., in the barley Hordeum vulgare the polymerase competition occurs in the locus containing plastome genes psbA, rpl23, rpl2 and four bacterial type promoters. In heat shock experiments on isolated chloroplasts, a twofold decrease of psbA transcripts and even larger increase of rpl23-rpl2 transcripts were observed, which is well reproduced in the model. The model predictions are in good agreement with virtually all relevant experimental data (knockout, heat shock, chromatogram data, etc.). The model allows to hypothesize a mechanism of cell response to knockout and heat shock, as well as a mechanism of gene expression regulation in presence of RNA polymerase competition. The model is implemented for multiprocessor platforms with MPI and supported on Linux and MS Windows. The source code written in C++ is available under the GNU General Public License from the laboratory website. A user-friendly GUI version is also provided at http://lab6.iitp.ru/en/rivals. CONCLUSIONS: The developed model is in good agreement with virtually all relevant experimental data. The model can be applied to estimate intensities of binding of the holoenzyme and phage type RNA polymerase to their promoters using data on gene transcription levels, as well as to predict characteristics of RNA polymerases and the transcription process that are difficult to measure directly, e.g., the intensity (frequency) of holoenzyme binding to the promoter in correlation to its nucleotide composition and the type of sigma-subunit, the amount of transcription initiation aborts, etc. The model can be used to make functional predictions, e.g., heat shock response in isolated chloroplasts and changes of gene transcription levels under knockout of different sigma-subunits or RNA polymerases or due to gene expression regulation. PMID- 21255417 TI - Coating carbon nanotubes with a polystyrene-based polymer protects against pulmonary toxicity. AB - BACKGROUND: carbon nanotubes (CNT) can have adverse effects on health. Therefore, minimizing the risk associated with CNT exposure is of crucial importance. The aim of this work was to evaluate if coating multi-walled CNT (MWCNT) with polymers could modify their toxicity, thus representing a useful strategy to decrease adverse health effects of CNT. We used industrially-produced MWCNT uncoated (NT1) or coated (50/50 wt%) with acid-based (NT2) or polystyrene-based (NT3) polymer, and exposed murine macrophages (RAW 264.7 cell line) or Balb/c mice by intratracheal administration. Biological experiments were performed both in vitro and in vivo, examining time- and dose-dependent effects of CNT, in terms of cytotoxicity, expression of genes and proteins related to oxidative stress, inflammation and tissue remodeling, cell and lung tissue morphology (optical and transmission electron microscopy), and bronchoalveolar lavage fluid content analysis. RESULTS: extensive physico-chemical characterization of MWCNT was performed, and showed, although similar dimensions for the 3 MWCNT, a much smaller specific surface area for NT2 and NT3 as compared to NT1 (54.1, 34 and 227.54 m(2)/g respectively), along with different surface characteristics. MWCNT induced cytotoxicity, oxidative stress, and inflammation were increased by acid based and decreased by polystyrene-based polymer coating both in vitro in murine macrophages and in vivo in lung of mice monitored for 6 months. CONCLUSIONS: these results demonstrate that coating CNT with polymers, without affecting their intrinsic structure, may constitute a useful strategy for decreasing CNT toxicity, and may hold promise for improving occupational safety and that of general the user. PMID- 21255418 TI - Breeding value prediction for production traits in layer chickens using pedigree or genomic relationships in a reduced animal model. AB - BACKGROUND: Genomic selection involves breeding value estimation of selection candidates based on high-density SNP genotypes. To quantify the potential benefit of genomic selection, accuracies of estimated breeding values (EBV) obtained with different methods using pedigree or high-density SNP genotypes were evaluated and compared in a commercial layer chicken breeding line. METHODS: The following traits were analyzed: egg production, egg weight, egg color, shell strength, age at sexual maturity, body weight, albumen height, and yolk weight. Predictions appropriate for early or late selection were compared. A total of 2,708 birds were genotyped for 23,356 segregating SNP, including 1,563 females with records. Phenotypes on relatives without genotypes were incorporated in the analysis (in total 13,049 production records).The data were analyzed with a Reduced Animal Model using a relationship matrix based on pedigree data or on marker genotypes and with a Bayesian method using model averaging. Using a validation set that consisted of individuals from the generation following training, these methods were compared by correlating EBV with phenotypes corrected for fixed effects, selecting the top 30 individuals based on EBV and evaluating their mean phenotype, and by regressing phenotypes on EBV. RESULTS: Using high-density SNP genotypes increased accuracies of EBV up to two-fold for selection at an early age and by up to 88% for selection at a later age. Accuracy increases at an early age can be mostly attributed to improved estimates of parental EBV for shell quality and egg production, while for other egg quality traits it is mostly due to improved estimates of Mendelian sampling effects. A relatively small number of markers was sufficient to explain most of the genetic variation for egg weight and body weight. PMID- 21255419 TI - Factors influencing nurses' compliance with Standard Precautions in order to avoid occupational exposure to microorganisms: A focus group study. AB - BACKGROUND: Nurses may acquire an infection during the provision of nursing care because of occupational exposure to microorganisms. Relevant literature reports that, compliance with Standard Precautions (a set of guidelines that can protect health care professionals from being exposed to microorganisms) is low among nurses. Additionally, high rates of exposure to microorganisms among nurses via several modes (needlesticks, hand contamination with blood, exposure to air transmitted microorganisms) occur. The aim of the study was to study the factors that influence nurses' compliance with Standard Precaution in order to avoid occupational exposure to pathogens, by employing a qualitative research design. METHOD: A focus group approach was used to explore the issue under study. Four focus groups (N = 30) were organised to elicit nurses' perception of the factors that influence their compliance with Standard Precautions. The Health Belief Model (HBM) was used as the theoretical framework and the data were analysed according to predetermined criteria. RESULTS: Following content analysis, factors that influence nurses' compliance emerged. Most factors could be applied to one of the main domains of the HBM: benefits, barriers, severity, susceptibility, cues to action, and self-efficacy. CONCLUSIONS: Changing current behavior requires knowledge of the factors that may influence nurses' compliance with Standard Precautions. This knowledge will facilitate in the implementation of programs and preventive actions that contribute in avoiding of occupational exposure. PMID- 21255420 TI - Study of multiparameter respiratory pattern complexity in surgical critically ill patients during weaning trials. AB - BACKGROUND: Separation from mechanical ventilation is a difficult task, whereas conventional predictive indices have not been proven accurate enough, so far. A few studies have explored changes of breathing pattern variability for weaning outcome prediction, with conflicting results. In this study, we tried to assess respiratory complexity during weaning trials, using different non-linear methods derived from theory of complex systems, in a cohort of surgical critically ill patients. RESULTS: Thirty two patients were enrolled in the study. There were 22 who passed and 10 who failed a weaning trial. Tidal volume and mean inspiratory flow were analyzed for 10 minutes during two phases: 1. pressure support (PS) ventilation (15-20 cm H2O) and 2. weaning trials with PS: 5 cm H2O. Sample entropy (SampEn), detrended fluctuation analysis (DFA) exponent, fractal dimension (FD) and largest lyapunov exponents (LLE) of the two respiratory parameters were computed in all patients and during the two phases of PS. Weaning failure patients exhibited significantly decreased respiratory pattern complexity, reflected in reduced sample entropy and lyapunov exponents and increased DFA exponents of respiratory flow time series, compared to weaning success subjects (p < 0.001). In addition, their changes were opposite between the two phases of the weaning trials. A new model including rapid shallow breathing index (RSBI), its product with airway occlusion pressure at 0.1 sec (P0.1), SampEn and LLE predicted better weaning outcome compared with RSBI, P0.1 and RSBI* P0.1 (conventional model, R(2) = 0.874 vs 0.643, p < 0.001). Areas under the curve were 0.916 vs 0.831, respectively (p < 0.05). CONCLUSIONS: We suggest that complexity analysis of respiratory signals can assess inherent breathing pattern dynamics and has increased prognostic impact upon weaning outcome in surgical patients. PMID- 21255421 TI - Tuberculosis infection among homeless persons and caregivers in a high tuberculosis-prevalence area in Japan: a cross-sectional study. AB - BACKGROUND: Tuberculosis (TB) is a major public health problem. The Airin district of Osaka City has a large population of homeless persons and caregivers and is estimated to be the largest TB-endemic area in the intermediate-prevalence country, Japan. However, there have been few studies of homeless persons and caregivers. The objective of this study is to detect active TB and to assess the prevalence and risk factors for latent TB infection among homeless persons and caregivers. METHODS: We conducted a cross-sectional study for screening TB infection (active and latent TB infections) using questionnaire, chest X-ray (CXR), newly available assay for latent TB infection (QuantiFERON-TB Gold In Tube; QFT) and clinical evaluation by physicians at the Osaka Socio-Medical Center Hospital between July 2007 and March 2008. Homeless persons and caregivers, aged 30-74 years old, who had not received CXR examination within one year, were recruited. As for risk factors of latent TB infection, the odds ratios (OR) and 95% confidence intervals (95% CI) for QFT-positivity were calculated using logistic regression model. RESULTS: Complete responses were available from 436 individuals (263 homeless persons and 173 caregivers). Four active TB cases (1.5%) among homeless persons were found, while there were no cases among caregivers. Out of these four, three had positive QFT results. One hundred and thirty-three (50.6%) homeless persons and 42 (24.3%) caregivers had positive QFT results. In multivariate analysis, QFT-positivity was independently associated with a long time spent in the Airin district: >=10 years versus <10 years for homeless (OR = 2.53; 95% CI, 1.39-4.61) and for caregivers (OR = 2.32; 95% CI, 1.05-5.13), and the past exposure to TB patients for caregivers (OR = 3.21; 95% CI, 1.30-7.91) but not for homeless persons (OR = 1.51; 95% CI, 0.71-3.21). CONCLUSIONS: Although no active TB was found for caregivers, one-quarter of them had latent TB infection. In addition to homeless persons, caregivers need examinations for latent TB infection as well as active TB and careful follow-up, especially when they have spent a long time in a TB-endemic area and/or have been exposed to TB patients. PMID- 21255422 TI - Exogenous glucagon-like peptide-1 attenuates the glycaemic response to postpyloric nutrient infusion in critically ill patients with type-2 diabetes. AB - INTRODUCTION: Glucagon-like peptide-1 (GLP-1) attenuates the glycaemic response to small intestinal nutrient infusion in stress-induced hyperglycaemia and reduces fasting glucose concentrations in critically ill patients with type-2 diabetes. The objective of this study was to evaluate the effects of acute administration of GLP-1 on the glycaemic response to small intestinal nutrient infusion in critically ill patients with pre-existing type-2 diabetes. METHODS: Eleven critically ill mechanically-ventilated patients with known type-2 diabetes received intravenous infusions of GLP-1 (1.2 pmol/kg/minute) and placebo from t = 0 to 270 minutes on separate days in randomised double-blind fashion. Between t = 30 to 270 minutes a liquid nutrient was infused intraduodenally at a rate of 1 kcal/min via a naso-enteric catheter. Blood glucose, serum insulin and C-peptide, and plasma glucagon were measured. Data are mean +/- SEM. RESULTS: GLP-1 attenuated the overall glycaemic response to nutrient (blood glucose AUC30-270 min: GLP-1 2,244 +/- 184 vs. placebo 2,679 +/- 233 mmol/l/minute; P = 0.02). Blood glucose was maintained at < 10 mmol/l in 6/11 patients when receiving GLP-1 and 4/11 with placebo. GLP-1 increased serum insulin at 270 minutes (GLP-1: 23.4 +/- 6.7 vs. placebo: 16.4 +/- 5.5 mU/l; P < 0.05), but had no effect on the change in plasma glucagon. CONCLUSIONS: Exogenous GLP-1 in a dose of 1.2 pmol/kg/minute attenuates the glycaemic response to small intestinal nutrient in critically ill patients with type-2 diabetes. Given the modest magnitude of the reduction in glycaemia the effects of GLP-1 at higher doses and/or when administered in combination with insulin, warrant evaluation in this group. TRIAL REGISTRATION: ANZCTR:ACTRN12610000185066. PMID- 21255423 TI - A Leu to Ile but not Leu to Val change at HIV-1 reverse transcriptase codon 74 in the background of K65R mutation leads to an increased processivity of K65R+L74I enzyme and a replication competent virus. AB - BACKGROUND: The major hurdle in the treatment of Human Immunodeficiency virus type 1 (HIV-1) includes the development of drug resistance-associated mutations in the target regions of the virus. Since reverse transcriptase (RT) is essential for HIV-1 replication, several nucleoside analogues have been developed to target RT of the virus. Clinical studies have shown that mutations at RT codon 65 and 74 which are located in beta3-beta4 linkage group of finger sub-domain of RT are selected during treatment with several RT inhibitors, including didanosine, deoxycytidine, abacavir and tenofovir. Interestingly, the co-selection of K65R and L74V is rare in clinical settings. We have previously shown that K65R and L74V are incompatible and a R->K reversion occurs at codon 65 during replication of the virus. Analysis of the HIV resistance database has revealed that similar to K65R+L74V, the double mutant K65R+L74I is also rare. We sought to compare the impact of L->V versus L->I change at codon 74 in the background of K65R mutation, on the replication of doubly mutant viruses. METHODS: Proviral clones containing K65R, L74V, L74I, K65R+L74V and K65R+L74I RT mutations were created in pNL4-3 backbone and viruses were produced in 293T cells. Replication efficiencies of all the viruses were compared in peripheral blood mononuclear (PBM) cells in the absence of selection pressure. Replication capacity (RC) of mutant viruses in relation to wild type was calculated on the basis of antigen p24 production and RT activity, and paired analysis by student t-test was performed among RCs of doubly mutant viruses. Reversion at RT codons 65 and 74 was monitored during replication in PBM cells. In vitro processivity of mutant RTs was measured to analyze the impact of amino acid changes at RT codon 74. RESULTS: Replication kinetics plot showed that all of the mutant viruses were attenuated as compared to wild type (WT) virus. Although attenuated in comparison to WT virus and single point mutants K65R, L74V and L74I; the double mutant K65R+L74I replicated efficiently in comparison to K65R+L74V mutant. The increased replication capacity of K65R+L74I viruses in comparison to K65R+L74V viruses was significant at multiplicity of infection 0.01 (p = 0.0004). Direct sequencing and sequencing after population cloning showed a more pronounced reversion at codon 65 in viruses containing K65R+L74V mutations in comparison to viruses with K65R+L74I mutations. In vitro processivity assays showed increased processivity of RT containing K65R+L74I in comparison to K65R+L74V RT. CONCLUSIONS: The improved replication kinetics of K65R+L74I virus in comparison to K65R+L74V viruses was due to an increase in the processivity of RT containing K65R+L74I mutations. These observations support the rationale behind structural functional analysis to understand the interactions among unique RT mutations that may emerge during the treatment with specific drug regimens. PMID- 21255424 TI - Engaging diverse underserved communities to bridge the mammography divide. AB - BACKGROUND: Breast cancer screening continues to be underutilized by the population in general, but is particularly underutilized by traditionally underserved minority populations. Two of the most at risk female minority groups are American Indians/Alaska Natives (AI/AN) and Latinas. American Indian women have the poorest recorded 5-year cancer survival rates of any ethnic group while breast cancer is the number one cause of cancer mortality among Latina women. Breast cancer screening rates for both minority groups are near or at the lowest among all racial/ethnic groups. As with other health screening behaviors, women may intend to get a mammogram but their intentions may not result in initiation or follow through of the examination process. An accumulating body of research, however, demonstrates the efficacy of developing 'implementation intentions' that define when, where, and how a specific behavior will be performed. The formulation of intended steps in addition to addressing potential barriers to test completion can increase a person's self-efficacy, operationalize and strengthen their intention to act, and close gaps between behavioral intention and completion. To date, an evaluation of the formulation of implementation intentions for breast cancer screening has not been conducted with minority populations. METHODS/DESIGN: In the proposed program, community health workers will meet with rural-dwelling Latina and American Indian women one-on-one to educate them about breast cancer and screening and guide them through a computerized and culturally tailored "implementation intentions" program, called Healthy Living Kansas-Breast Health, to promote breast cancer screening utilization. We will target Latina and AI/AN women from two distinct rural Kansas communities. Women attending community events will be invited by CHWs to participate and be randomized to either a mammography "implementation intentions" (MI2) intervention or a comparison general breast cancer prevention informational intervention (C). CHWs will be armed with notebook computers loaded with our Healthy Living Kansas-Breast Health program and guide their peers through the program. Women in the MI2 condition will receive assistance with operationalizing their screening intentions and identifying and addressing their stated screening barriers with the goal of guiding them toward accessing screening services near their community. Outcomes will be evaluated at 120-days post randomization via self-report and will include mammography utilization status, barriers, and movement along a behavioral stages of readiness to screen model. DISCUSSION: This highly innovative project will be guided and initiated by AI/AN and Latina community members and will test the practical application of emerging behavioral theory among minority persons living in rural communities. PMID- 21255425 TI - An ancient family of SelB elongation factor-like proteins with a broad but disjunct distribution across archaea. AB - BACKGROUND: SelB is the dedicated elongation factor for delivery of selenocysteinyl-tRNA to the ribosome. In archaea, only a subset of methanogens utilizes selenocysteine and encodes archaeal SelB (aSelB). A SelB-like (aSelBL) homolog has previously been identified in an archaeon that does not encode selenosysteine, and has been proposed to be a pyrrolysyl-tRNA-specific elongation factor (EF-Pyl). However, elongation factor EF-Tu is capable of binding archaeal Pyl-tRNA in bacteria, suggesting the archaeal ortholog EF1A may also be capable of delivering Pyl-tRNA to the ribosome without the need of a specialized factor. RESULTS: We have phylogenetically characterized the aSelB and aSelBL families in archaea. We find the distribution of aSelBL to be wider than both selenocysteine and pyrrolysine usage. The aSelBLs also lack the carboxy terminal domain usually involved in recognition of the selenocysteine insertion sequence in the target mRNA. While most aSelBL-encoding archaea are methanogenic Euryarchaea, we also find aSelBL representatives in Sulfolobales and Thermoproteales of Crenarchaea, and in the recently identified phylum Thaumarchaea, suggesting that aSelBL evolution has involved horizontal gene transfer and/or parallel loss. Severe disruption of the GTPase domain suggests that some family members may employ a hitherto unknown mechanism of nucleotide hydrolysis, or have lost their GTPase ability altogether. However, patterns of sequence conservation indicate that aSelBL is still capable of binding the ribosome and aminoacyl-tRNA. CONCLUSIONS: Although it is closely related to SelB, aSelBL appears unlikely to either bind selenocysteinyl-tRNA or function as a classical GTP hydrolyzing elongation factor. We propose that following duplication of aSelB, the resultant aSelBL was recruited for binding another aminoacyl-tRNA. In bacteria, aminoacylation with selenocysteine is essential for efficient thermodynamic coupling of SelB binding to tRNA and GTP. Therefore, change in tRNA specificity of aSelBL could have disrupted its GTPase cycle, leading to relaxation of selective pressure on the GTPase domain and explaining its apparent degradation. While the specific role of aSelBL is yet to be experimentally tested, its broad phylogenetic distribution, surpassing that of aSelB, indicates its importance. PMID- 21255426 TI - Arachnomelia syndrome in Simmental cattle is caused by a homozygous 2-bp deletion in the molybdenum cofactor synthesis step 1 gene (MOCS1). AB - BACKGROUND: Arachnomelia syndrome is an autosomal recessive inherited disease in cattle. Affected calves die around birth and show malformations of the skeleton mainly affecting the legs, the spinal column and the skull. A number of arachnomelia syndrome affected Simmental calves were recently detected by a surveillance system of anomalies with a peak of more than 120 recorded cases in the year 2006. The causative mutation was previously mapped to a 9 cM-region on bovine chromosome 23. We herein report the fine-mapping and identification of the gene causing arachnomelia syndrome in Simmental cattle. RESULTS: By using a dense set of markers, the arachnomelia syndrome linked region could be refined to 1.5 cM harbouring three protein coding genes. Comparative sequencing of these genes revealed a two-bp-deletion in the bovine MOCS1 gene resulting in a frame-shift and a premature termination codon. We genotyped affected calves and their ancestors and found that all affected were homozygous for the deletion whereas all carriers were heterozygous. Furthermore, cattle from the same population, but not directly related to known carriers mostly showed the wild type genotype. CONCLUSIONS: MOCS1 encodes two proteins that are involved in the first synthesis step of molybdenum cofactor. A non functional sulfite-oxydase, one of the enzymes requiring molybdenum cofactor, leads to a similar pathology in Brown Swiss cattle. In combination the perfect association of the mutation with the phenotype and the obvious disruption of protein translation provide strong evidence for the causality of the MOCS1 mutation. Our results are the first example for an oligogenic lethal inherited disease in cattle. Furthermore, they show the potential involvement of sulfite metabolism in aberrant bone development. PMID- 21255427 TI - Athletic humans and horses: comparative analysis of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) expression in peripheral blood mononuclear cells in trained and untrained subjects at rest. AB - BACKGROUND: Horses and humans share a natural proclivity for athletic performance. In this respect, horses can be considered a reference species in studies designed to optimize physical training and disease prevention. In both species, interleukin-6 (IL-6) plays a major role in regulating the inflammatory process induced during exercise as part of an integrated metabolic regulatory network. The aim of this study was to compare IL-6 and IL-6 receptor (IL-6R) mRNA expression in peripheral blood mononuclear cells (PBMCs) in trained and untrained humans and horses. RESULTS: Nine highly trained male swimmers (training volume: 21.6 +/- 1.7 h/wk in 10-12 sessions) were compared with two age-matched control groups represented by eight lightly trained runners (training volume: 6.4 +/- 2.6 h/wk in 3-5 sessions) and nine untrained subjects. In addition, eight trained horses (training volume: 8.0 +/- 2.1 h/wk in 3-4 sessions) were compared with eight age-matched sedentary mares. In humans, IL-6 mRNA levels in PBMCs determined by quantitative reverse transcription-polymerase chain reaction were significantly higher in highly trained subjects, whereas IL-6R expression did not differ among groups. In horses, transcripts of both IL-6 and IL-6R were significantly up-regulated in the trained group. CONCLUSIONS: Up-regulation of IL 6R expression in PBMCs in horses could reflect a mechanism that maintains an adequate anti-inflammatory environment at rest through ubiquitous production of anti-inflammatory cytokines throughout the body. These findings suggest that the system that controls the inflammatory response in horses is better adapted to respond to exercise than that in humans. PMID- 21255428 TI - Nucleosome resection at a double-strand break during Non-Homologous Ends Joining in mammalian cells - implications from repressive chromatin organization and the role of ARTEMIS. AB - BACKGROUND: The S. cerevisiae mating type switch model of double-strand break (DSB) repair, utilizing the HO endonuclease, is one of the best studied systems for both Homologous Recombination Repair (HRR) and direct ends-joining repair (Non-Homologous Ends Joining - NHEJ). We have recently transposed that system to a mammalian cell culture model taking advantage of an adenovirus expressing HO and an integrated genomic target. This made it possible to compare directly the mechanism of repair between yeast and mammalian cells for the same type of induced DSB. Studies of DSB repair have emphasized commonality of features, proteins and machineries between organisms, and differences when conservation is not found. Two proteins that stand out that differ between yeast and mammalian cells are DNA-PK, a protein kinase that is activated by the presence of DSBs, and Artemis, a nuclease whose activity is modulated by DNA-PK and ATM. In this report we describe how these two proteins may be involved in a specific pattern of ends processing at the DSB, particularly in the context of heterochromatin. FINDINGS: We previously published that the repair of the HO-induced DSB was generally accurate and occurred by simple rejoining of the cohesive 3'-overhangs generated by HO. During continuous passage of those cells in the absence of puromycin selection, the locus appears to have become more heterochromatic and silenced by displaying several features. 1) The site had become less accessible to cleavage by the HO endonuclease; 2) the expression of the puro mRNA, which confers resistance to puromycin, had become reduced; 3) occupancy of nucleosomes at the site (ChIP for histone H3) was increased, an indicator for more condensed chromatin. After reselection of these cells by addition of puromycin, many of these features were reversed. However, even the reselected cells were not identical in the pattern of cleavage and repair as the cells when originally created. Specifically, the pattern of repair revealed discrete deletions at the DSB that indicated unit losses of nucleosomes (or other protein complexes) before religation, represented by a ladder of PCR products reminiscent of an internucleosomal cleavage that is typically observed during apoptosis. This pattern of cleavage suggested to us that perhaps, Artemis, a protein that is believed to generate the internucleosomal fragments during apoptosis and in DSB repair, was involved in that specific pattern of ends-processing. Preliminary evidence indicates that this may be the case, since knock-down of Artemis with siRNA eliminated the laddering pattern and revealed instead an extensive exonucleolytic processing of the ends before religation. CONCLUSIONS: e have generated a system in mammalian cells where the absence of positive selection resulted in chromatin remodeling at the target locus that recapitulates many of the features of the mating-type switching system in yeast. Specifically, just as for yeast HML and HMR, the locus had become transcriptionally repressed; accessibility to cleavage by the HO endonuclease was reduced; and processing of the ends was drastically changed. The switch was from high-fidelity religation of the cohesive ends, to a pattern of release of internucleosomal fragments, perhaps in search of micro-homology stretches for ligation. This is consistent with reports that the involvement of ATM, DNA-PK and Artemis in DSB repair is largely focused to heterochromatic regions, and not required for the majority of IR induced DSB repair foci in euchromatin. PMID- 21255429 TI - Bologna Guidelines for Diagnosis and Management of Adhesive Small Bowel Obstruction (ASBO): 2010 Evidence-Based Guidelines of the World Society of Emergency Surgery. AB - BACKGROUND: There is no consensus on diagnosis and management of ASBO. Initial conservative management is usually safe, however proper timing for discontinuing non operative treatment is still controversial. Open surgery or laparoscopy are used without standardized indications. METHODS: A panel of 13 international experts with interest and background in ASBO and peritoneal diseases, participated in a consensus conference during the 1st International Congress of the World Society of Emergency Surgery and 9th Peritoneum and Surgery Society meeting, in Bologna, July 1-3, 2010, for developing evidence-based recommendations for diagnosis and management of ASBO. Whenever was a lack of high level evidence, the working group formulated guidelines by obtaining consensus. RECOMMENDATIONS: In absence of signs of strangulation and history of persistent vomiting or combined CT scan signs (free fluid, mesenteric oedema, small bowel faeces sign, devascularized bowel) patients with partial ASBO can be managed safely with NOM and tube decompression (either with long or NG) should be attempted. These patients are good candidates for Water Soluble Contrast Medium (WSCM) with both diagnostic and therapeutic purposes. The appearance of water soluble contrast in the colon on X-ray within 24 hours from administration predicts resolution. WSCM may be administered either orally or via NGT (50-150 ml) both immediately at admission or after an initial attempt of conservative treatment of 48 hours. The use of WSCM for ASBO is safe and reduces need for surgery, time to resolution and hospital stay.NOM, in absence of signs of strangulation or peritonitis, can be prolonged up to 72 hours. After 72 hours of NOM without resolution surgery is recommended.Patients treated non-operatively have shorter hospital stay, but higher recurrence rate and shorter time to re admission, although the risk of new surgically treated episodes of ASBO is unchanged. Risk factors for recurrences are age <40 years and matted adhesions. WSCM does not affect recurrence rates or recurrences needing surgery when compared to traditional conservative treatment.Open surgery is the preferred method for surgical treatment of strangulating ASBO as well as after failed conservative management. In selected patients and with appropriate skills, laparoscopic approach can be attempted using open access technique. Access in the left upper quadrant should be safe. Laparoscopic adhesiolysis should be attempted preferably in case of first episode of SBO and/or anticipated single band. A low threshold for open conversion should be maintained.Peritoneal adhesions should be prevented. Hyaluronic acid-carboxycellulose membrane and icodextrin can reduce incidence of adhesions. Icodextrin may reduce the risk of re-obstruction. HA cannot reduce need of surgery. PMID- 21255430 TI - Evaluation of signal transduction pathways after transient cutaneous adenoviral gene delivery. AB - BACKGROUND: Adenoviral vectors have provided effective methods for in vivo gene delivery in therapeutic applications. However, these vectors can induce immune responses that may severely affect the ability of vector re-application. There is limited information about the mechanisms and signal transduction pathways involved in adenoviral recognition. For optimization of cutaneous gene therapy it is necessary to investigate molecular mechanisms of virus recognition in epidermal cells. The aim of this study was to investigate the signal transduction of the innate immunity after adenoviral DNA internalization in keratinocytes. METHODS: In vitro, keratinocytes were transfected with DNA, in the presence and absence of inhibitors for signalling molecules. In vivo, immunocompetent and athymic mice (n = 3 per group) were twice transduced with an Ad-vector. RESULTS: The results show an acute induction of type-I-interferon after in vitro transfection. Inhibition of PI3K, p38 MAPK, JNK and NFkappaB resulted in a decreased expression of type-I-interferon. In contrast to immunocompetent mice, athymic mice demonstrated a constant transgene expression and reduced inflammatory response in vivo. CONCLUSION: The results suggest an induction of the innate immunity triggered by cytoplasm localised DNA which is mediated by PI3K-, p38 MAPK-, JNK-, NFkappaB-, JAK/STAT- and ERK1/2-dependent pathways. A stable transgene expression and a reduced inflammatory response in immunodeficient mice have been observed. These results provide potential for an effective adenoviral gene delivery into immunosupressed skin. PMID- 21255431 TI - A randomized controlled trial examining Iyengar yoga for young adults with rheumatoid arthritis: a study protocol. AB - BACKGROUND: Rheumatoid arthritis is a chronic, disabling disease that can compromise mobility, daily functioning, and health-related quality of life, especially in older adolescents and young adults. In this project, we will compare a standardized Iyengar yoga program for young people with rheumatoid arthritis to a standard care wait-list control condition. METHODS/DESIGN: Seventy rheumatoid arthritis patients aged 16-35 years will be randomized into either the 6-week Iyengar yoga program (12 - 1.5 hour sessions twice weekly) or the 6-week wait-list control condition. A 20% attrition rate is anticipated. The wait-list group will receive the yoga program following completion of the first arm of the study. We will collect data quantitatively, using questionnaires and markers of disease activity, and qualitatively using semi-structured interviews. Assessments include standardized measures of general and arthritis-specific function, pain, mood, and health-related quality of life, as well as qualitative interviews, blood pressure/resting heart rate measurements, a medical exam and the assessment of pro-inflammatory cytokines. Data will be collected three times: before treatment, post-treatment, and two months following the treatment. DISCUSSION: Results from this study will provide critical data on non-pharmacologic methods for enhancing function in rheumatoid arthritis patients. In particular, results will shed light on the feasibility and potential efficacy of a novel intervention for rheumatoid arthritis symptoms, paving the way for a larger clinical trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT01096823. PMID- 21255432 TI - Generation of genome-scale gene-associated SNPs in catfish for the construction of a high-density SNP array. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) have become the marker of choice for genome-wide association studies. In order to provide the best genome coverage for the analysis of performance and production traits, a large number of relatively evenly distributed SNPs are needed. Gene-associated SNPs may fulfill these requirements of large numbers and genome wide distribution. In addition, gene-associated SNPs could themselves be causative SNPs for traits. The objective of this project was to identify large numbers of gene-associated SNPs using high throughput next generation sequencing. RESULTS: Transcriptome sequencing was conducted for channel catfish and blue catfish using Illumina next generation sequencing technology. Approximately 220 million reads (15.6 Gb) for channel catfish and 280 million reads (19.6 Gb) for blue catfish were obtained by sequencing gene transcripts derived from various tissues of multiple individuals from a diverse genetic background. A total of over 35 billion base pairs of expressed short read sequences were generated. Over two million putative SNPs were identified from channel catfish and almost 2.5 million putative SNPs were identified from blue catfish. Of these putative SNPs, a set of filtered SNPs were identified including 342,104 intra-specific SNPs for channel catfish, 366,269 intra-specific SNPs for blue catfish, and 420,727 inter-specific SNPs between channel catfish and blue catfish. These filtered SNPs are distributed within 16,562 unique genes in channel catfish and 17,423 unique genes in blue catfish. CONCLUSIONS: For aquaculture species, transcriptome analysis of pooled RNA samples from multiple individuals using Illumina sequencing technology is both technically efficient and cost-effective for generating expressed sequences. Such an approach is most effective when coupled to existing EST resources generated using traditional sequencing approaches because the reference ESTs facilitate effective assembly of the expressed short reads. When multiple individuals with different genetic backgrounds are used, RNA-Seq is very effective for the identification of SNPs. The SNPs identified in this report will provide a much needed resource for genetic studies in catfish and will contribute to the development of a high-density SNP array. Validation and testing of these SNPs using SNP arrays will form the material basis for genome association studies and whole genome-based selection in catfish. PMID- 21255433 TI - Synthetic arylquinuclidine derivatives exhibit antifungal activity against Candida albicans, Candida tropicalis and Candida parapsilopsis. AB - BACKGROUND: Sterol biosynthesis is an essential pathway for fungal survival, and is the biochemical target of many antifungal agents. The antifungal drugs most widely used to treated fungal infections are compounds that inhibit cytochrome P450-dependent C14alpha-demethylase (CYP51), but other enzymes of this pathway, such as squalene synthase (SQS) which catalyses the first committed step in sterol biosynthesis, could be viable targets. The aim of this study was to evaluate the antifungal activity of SQS inhibitors on Candida albicans, Candida tropicalis and Candida parapsilopsis strains. METHODS: Ten arylquinuclidines that act as SQS inhibitors were tested as antiproliferative agents against three ATCC strains and 54 clinical isolates of Candida albicans, Candida tropicalis and Candida parapsilopsis. Also, the morphological alterations induced in the yeasts by the experimental compounds were evaluated by fluorescence and transmission electron microscopy. RESULTS: The most potent arylquinuclidine derivative (3-[1' {4'-(benzyloxy)-phenyl}]-quinuclidine-2-ene) (WSP1267) had a MIC50 of 2 MUg/ml for all species tested and MIC90 varying from 4 MUg/ml to 8 MUg/ml. Ultrathin sections of C. albicans treated with 1 MUg/ml of WSP1267 showed several ultrastructural alterations, including (a) loss of cell wall integrity, (b) detachment of the plasma membrane from the fungal cell wall, (c) accumulation of small vesicles in the periplasmic region, (d) presence of large electron-dense vacuoles and (e) significantly increased cell size and cell wall thickness. In addition, fluorescence microscopy of cells labelled with Nile Red showed an accumulation of lipid droplets in the cytoplasm of treated yeasts. Nuclear staining with DAPI revealed the appearance of uncommon yeast buds without a nucleus or with two nuclei. CONCLUSION: Taken together, our data demonstrate that arylquinuclidine derivatives could be useful as lead compounds for the rational synthesis of new antifungal drugs. PMID- 21255434 TI - Clinical, genetic, and pathological features of male pseudohermaphroditism in dog. AB - Male pseudohermaphroditism is a sex differentiation disorder in which the gonads are testes and the genital ducts are incompletely masculinized. An 8 years old dog with normal male karyotype was referred for examination of external genitalia abnormalities. Adjacent to the vulva subcutaneous undescended testes were observed. The histology of the gonads revealed a Leydig and Sertoli cell neoplasia. The contemporaneous presence of testicular tissue, vulva, male karyotype were compatible with a male pseudohermaphrodite (MPH) condition. PMID- 21255435 TI - Discovery pipeline for epigenetically deregulated miRNAs in cancer: integration of primary miRNA transcription. AB - BACKGROUND: Cancer is commonly associated with widespread disruption of DNA methylation, chromatin modification and miRNA expression. In this study, we established a robust discovery pipeline to identify epigenetically deregulated miRNAs in cancer. RESULTS: Using an integrative approach that combines primary transcription, genome-wide DNA methylation and H3K9Ac marks with microRNA (miRNA) expression, we identified miRNA genes that were epigenetically modified in cancer. We find miR-205, miR-21, and miR-196b to be epigenetically repressed, and miR-615 epigenetically activated in prostate cancer cells. CONCLUSIONS: We show that detecting changes in primary miRNA transcription levels is a valuable method for detection of local epigenetic modifications that are associated with changes in mature miRNA expression. PMID- 21255436 TI - GWAPower: a statistical power calculation software for genome-wide association studies with quantitative traits. AB - BACKGROUND: In designing genome-wide association (GWA) studies it is important to calculate statistical power. General statistical power calculation procedures for quantitative measures often require information concerning summary statistics of distributions such as mean and variance. However, with genetic studies, the effect size of quantitative traits is traditionally expressed as heritability, a quantity defined as the amount of phenotypic variation in the population that can be ascribed to the genetic variants among individuals. Heritability is hard to transform into summary statistics. Therefore, general power calculation procedures cannot be used directly in GWA studies. The development of appropriate statistical methods and a user-friendly software package to address this problem would be welcomed. RESULTS: This paper presents GWAPower, a statistical software package of power calculation designed for GWA studies with quantitative traits, where genetic effect is defined as heritability. Based on several popular one degree-of-freedom genetic models, this method avoids the need to specify the non centrality parameter of the F-distribution under the alternative hypothesis. Therefore, it can use heritability information directly without approximation. In GWAPower, the power calculation can be easily adjusted for adding covariates and linkage disequilibrium information. An example is provided to illustrate GWAPower, followed by discussions. CONCLUSIONS: GWAPower is a user-friendly free software package for calculating statistical power based on heritability in GWA studies with quantitative traits. The software is freely available at: http://dl.dropbox.com/u/10502931/GWAPower.zip. PMID- 21255437 TI - Clinical monitoring and correlates of nephropathy in SIV-infected macaques during high-dose antiretroviral therapy. AB - BACKGROUND: In many preclinical AIDS research studies, antiretroviral therapy (ART) is administered to experimentally simian immunodeficiency (SIV)-infected rhesus macaques for reduction of viral load to undetectable levels. Prolonged treatment of macaques with a high dose of PMPA (9-[2-(r)-(phosphonomethoxy) propyl] adenine or tenofovir; 30 mg/kg of body weight subcutaneously once daily) can result in proximal renal tubular dysfunction, a Fanconi-like syndrome characterized by glucosuria, aminoaciduria, hypophosphatemia, and bone pathology. In contrast, chronic administration of a low dose of PMPA (10 mg/kg subcutaneously once daily) starting at birth does not seem to be associated with any adverse health effects within 3 years of treatment. In contrast to PMPA, limited information on systemic toxicity in rhesus monkeys is available for FTC (5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine; emtricitabine) and stavudine (d4T). RESULTS: In this study, the clinical and biochemical correlates of tubular nephrosis in SIV-infected rhesus macaques associated with systemic administration of high-dose ART consisting of the three nucleoside analog inhibitors PMPA, FTC, and d4T were investigated. It was found that acute renal failure was uncommon (7.1% of treated animals) and that morphologic evidence of nephropathy, which persisted for more than 300 days following discontinuation of the drug cocktail, was more frequent (52.4% of treated animals). While parameters from single time points lacked predictive value, biochemical alterations in Blood Urea Nitrogen (BUN) and phosphorus were frequently identified longitudinally in the blood of ART-treated animals that developed evidence of nephropathy, and these longitudinal changes correlated with disease severity. CONCLUSIONS: Recommendations are proposed to limit the impact of drug-induced renal disease in future SIV macaque studies. PMID- 21255439 TI - How are the different specialties represented in the major journals in general medicine? AB - BACKGROUND: General practitioners and medical specialists mainly rely on one "general medical" journal to keep their medical knowledge up to date. Nevertheless, it is not known if these journals display the same overview of the medical knowledge in different specialties. The aims of this study were to measure the relative weight of the different specialties in the major journals of general medicine, to evaluate the trends in these weights over a ten-year period and to compare the journals. METHODS: The 14,091 articles published in The Lancet, the NEJM, the JAMA and the BMJ in 1997, 2002 and 2007 were analyzed. The relative weight of the medical specialities was determined by categorization of all the articles, using a categorization algorithm which inferred the medical specialties relevant to each article MEDLINE file from the MeSH terms used by the indexers of the US National Library of Medicine to describe each article. RESULTS: The 14,091 articles included in our study were indexed by 22,155 major MeSH terms, which were categorized into 81 different medical specialties. Cardiology and Neurology were in the first 3 specialties in the 4 journals. Five and 15 specialties were systematically ranked in the first 10 and first 20 in the four journals respectively. Among the first 30 specialties, 23 were common to the four journals. For each speciality, the trends over a 10-year period were different from one journal to another, with no consistency and no obvious explanatory factor. CONCLUSIONS: Overall, the representation of many specialties in the four journals in general and internal medicine included in this study may differ, probably due to different editorial policies. Reading only one of these journals may provide a reliable but only partial overview. PMID- 21255438 TI - Identification and characterization of seven new exon 11-associated splice variants of the rat MU opioid receptor gene, OPRM1. AB - BACKGROUND: The mouse mu opioid receptor (OPRM1) gene undergoes extensive alternative splicing at both the 3'- and 5'-ends of the gene. Previously, several C-terminal variants generated through 3' splicing have been identified in the rat OPRM1 gene. In both mice and humans 5' splicing generates a number of exon 11 containing variants. Studies in an exon 11 knockout mouse suggest the functional importance of these exon 11-associated variants in mediating the analgesic actions of a subset of mu opioids, including morphine-6beta-glucuronide (M6G) and heroin, but not others such as morphine and methadone. We now have examined 5' splicing in the rat. RESULTS: The current studies identified in the rat a homologous exon 11 and seven exon 11-associated variants, suggesting conservation of exon 11 and its associated variants among mouse, rat and human. RT-PCR revealed marked differences in the expression of these variants across several brain regions, implying region-specific mRNA processing of the exon 11-associated variants. Of the seven rat exon 11-associated variants, four encoded the identical protein as found in rMOR-1, two predicted 6 TM variants, and one, rMOR 1H2, generated a novel N-terminal variant in which a stretch of an additional 50 amino acids was present at the N-terminus of the previously established rMOR-1 sequence. When expressed in CHO cells, the presence of the additional 50 amino acids in rMOR-1H2 significantly altered agonist-induced G protein activation with little effect on opioid binding. CONCLUSION: The identification of the rat exon 11 and its associated variants further demonstrated conservation of 5' splicing in OPRM1 genes among rodents and humans. The functional relevance of these exon 11 associated variants was suggested by the region-specific expression of their mRNAs and the influence of the N-terminal sequence on agonist-induced G protein coupling in the novel N-terminal variant, rMOR-1H2. The importance of the exon 11 associated variants in mice in M6G and heroin analgesia revealed in the exon 11 knockout mouse implies that these analogous rat variants may also play similar roles in rat. The complexity created by alternative splicing of the rat OPRM1 gene may provide important insights of understanding the diverse responses to the various MU opioids seen in rats. PMID- 21255440 TI - Single amino acid change in gp41 region of HIV-1 alters bystander apoptosis and CD4 decline in humanized mice. AB - BACKGROUND: The mechanism by which HIV infection leads to a selective depletion of CD4 cells leading to immunodeficiency remains highly debated. Whether the loss of CD4 cells is a direct consequence of virus infection or bystander apoptosis of uninfected cells is also uncertain. RESULTS: We have addressed this issue in the humanized mouse model of HIV infection using a HIV variant with a point mutation in the gp41 region of the Env glycoprotein that alters its fusogenic activity. We demonstrate here that a single amino acid change (V38E) altering the cell-to-cell fusion activity of the Env minimizes CD4 loss in humanized mice without altering viral replication. This differential pathogenesis was associated with a lack of bystander apoptosis induction by V38E virus even in the presence of similar levels of infected cells. Interestingly, immune activation was observed with both WT and V38E infection suggesting that the two phenomena are likely not interdependent in the mouse model. CONCLUSIONS: We conclude that Env fusion activity is one of the determinants of HIV pathogenesis and it may be possible to attenuate HIV by targeting gp41. PMID- 21255441 TI - A nuclear export signal within the structural Gag protein is required for prototype foamy virus replication. AB - BACKGROUND: The Gag polyproteins play distinct roles during the replication cycle of retroviruses, hijacking many cellular machineries to fulfill them. In the case of the prototype foamy virus (PFV), Gag structural proteins undergo transient nuclear trafficking after their synthesis, returning back to the cytoplasm for capsid assembly and virus egress. The functional role of this nuclear stage as well as the molecular mechanism(s) responsible for Gag nuclear export are not understood. RESULTS: We have identified a leptomycin B (LMB)-sensitive nuclear export sequence (NES) within the N-terminus of PFV Gag that is absolutely required for the completion of late stages of virus replication. Point mutations of conserved residues within this motif lead to nuclear redistribution of Gag, preventing subsequent virus egress. We have shown that a NES-defective PFV Gag acts as a dominant negative mutant by sequestrating its wild-type counterpart in the nucleus. Trans-complementation experiments with the heterologous NES of HIV-1 Rev allow the cytoplasmic redistribution of FV Gag, but fail to restore infectivity. CONCLUSIONS: PFV Gag-Gag interactions are finely tuned in the cytoplasm to regulate their functions, capsid assembly, and virus release. In the nucleus, we have shown Gag-Gag interactions which could be involved in the nuclear export of Gag and viral RNA. We propose that nuclear export of unspliced and partially spliced PFV RNAs relies on two complementary mechanisms, which take place successively during the replication cycle. PMID- 21255442 TI - Immunohistochemical profiles of claudin-3 in primary and metastatic prostatic adenocarcinoma. AB - BACKGROUND: Claudins are integral membrane proteins that are involved in forming cellular tight junctions. One member of the claudin family, claudin-3, has been shown to be overexpressed in breast, ovarian, and pancreatic cancer. Here we use immunohistochemistry to evaluate its expression in benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), normal tissue adjacent to prostatic adenocarcinoma (NAC), primary prostatic adenocarcinoma (PCa), and metastatic prostatic adenocarcinoma (Mets). METHODS: Tissue microarrays were immunohistochemically stained for claudin-3, with the staining intensities subsequently quantified and statistically analyzed using a one-way ANOVA with subsequent Tukey tests for multiple comparisons or a nonparametric equivalent. Fifty-three cases of NAC, 17 cases of BPH, 35 cases of PIN, 107 cases of PCa, and 55 cases of Mets were analyzed in the microarrays. RESULTS: PCa and Mets had the highest absolute staining for claudin-3. Both had significantly higher staining than BPH (p < 0.05 in both cases) and NAC (p < 0.05 in both cases). PIN had a lower, but non-significant, staining score than PCa and Mets, but a statistically higher score than both BPH and NAC (p < 0.05 for both cases). No significant differences were observed between PCa, Mets, and PIN. CONCLUSIONS: To our knowledge, this represents one of the first studies comparing the immunohistochemical profiles of claudin-3 in PCa and NAC to specimens of PIN, BPH, and Mets. These findings provide further evidence that claudin-3 may serve as an important biomarker for prostate cancer, both primary and metastatic, but does not provide evidence that claudin-3 can be used to predict risk of metastasis. PMID- 21255443 TI - Clinical significance of retinal emboli during diagnostic and therapeutic cardiac catheterization in patients with coronary artery disease. AB - BACKGROUND: Cardiac catheterization may cause retinal embolization, a risk factor for cerebrovascular emboli and stroke. We describe the incidence of clinically silent and apparent retinal emboli following diagnostic and interventional coronary catheterization and associated risk factors. METHODS: Three hundred selected patients attending a tertiary referral center for diagnostic and therapeutic cardiac catheterization were studied. Retinal examination and examination of the visual field and acuity were done before and after catheterization by a retinal specialist. RESULTS: There were 5 case of retinal embolus before catheterization, and 19 patients (incidence 6.3%) developed new retinal arteriolar emboli after catheterization. Only 1 patient developed clinically apparent changes in vision. Two conventional risk factors (age and hypertension) were significantly associated with new retinal emboli. The risk of retinal emboli was also significantly associated with operator expertise. CONCLUSIONS: Retinal embolism was found after coronary catheterization in 6.3% of our patients. This finding indicates that the retinal, and possibly the cerebral circulation, may be compromised more frequently than is clinically apparent as a complication of coronary catheterization. Age and hypertension are independent predictors of retinal embolism. PMID- 21255445 TI - Endoscopic treatment of vesicoureteral reflux using calcium hydroxyl apatite in dogs. AB - BACKGROUND: Injection of biomaterial to suburetral region, using minimally invasive procedure, has become an interesting topic for urologists to treat vesicoureteral reflux. The objective of this study was to evaluate the feasibility of injecting newly introduced calcium hydroxyl apatite to suburetral region, for treating an experimentally induced vesicoureteral reflux in dogs. FINDINGS: Bilateral vesicoureteral refluxed (VUR) mixed breed dogs (n = 12; 10-15 kg live weight, 3-6 months of age) were selected for this study. The presence and grade of the reflux were determined using cystography. Accordingly, 6 dogs displayed grade 1 & 2 and the other 6 showed grade 3 & 4 bilateral VUR. Every single dog, with bilateral VUR, underwent endoscopic treatment and received an injection of calcium hydroxyl apatite (an Iranian made product) into the left (treated side) and an injection of the similar volume of normal saline in to the right (control side) subureteric space. One week, 3 and 6 months after treatment, cystography was performed. On each occasion, 4 dogs were euthanized by gas inhalation and biopsy samples were collected for histopathological study from ureter, bladder, kidney, lung and spleen in order to investigate the biomaterial migration into different organs. Data were analyzed using Chi-squared test. In control sides, radiographs confirmed the same grade of VUR, found at the initiation of the study. VUR was resolved in 100% (6/6) of Grade 1 & 2 and 83.33% (5/6) of Grade 3 & 4 in treated side. Therefore, the total success rate of this study was 91.67% (11/12). Macroscopic examination of the vesicouretral region of the treated side revealed a firm and consistent biomaterial mass at the site of injection. Histological findings confirmed inflammation at treated side. In contrast, there was no tissue reaction on control side. There was no evidence for biomaterial migration in macroscopic and microscopic observations in this study. CONCLUSION: In the present study, a new biocompatible material produced a firm, consist and sustainable biomaterial mass in the suburetral region for treating vesicouretral reflux without any evidence of biomaterial migration. PMID- 21255444 TI - Plasmodium falciparum liver stage antigen-1 is cross-linked by tissue transglutaminase. AB - BACKGROUND: Plasmodium falciparum sporozoites injected by mosquitoes into the blood rapidly enter liver hepatocytes and undergo pre-erythrocytic developmental schizogony forming tens of thousands of merozoites per hepatocyte. Shortly after hepatocyte invasion, the parasite starts to produce Liver Stage Antigen-1 (LSA 1), which accumulates within the parasitophorous vacuole surrounding the mass of developing merozoites. The LSA-1 protein has been described as a flocculent mass, but its role in parasite development has not been determined. METHODS: Recombinant N-terminal, C-terminal or a construct containing both the N- and C- terminal regions flanking two 17 amino acid residue central repeat sequences (LSA NRC) were subjected to in vitro modification by tissue transglutaminase-2 (TG2) to determine if cross-linking occurred. In addition, tissue sections of P. falciparum-infected human hepatocytes were probed with monoclonal antibodies to the isopeptide epsilon-(gamma-glutamyl)lysine cross-bridge formed by TG2 enzymatic activity to determine if these antibodies co-localized with antibodies to LSA-1 in the growing liver schizonts. RESULTS: This study identified a substrate motif for (TG2) and a putative casein kinase 2 phosphorylation site within the central repeat region of LSA-1. The function of TG2 is the post translational modification of proteins by the formation of a unique isopeptide epsilon-(gamma-glutamyl)lysine cross-bridge between glutamine and lysine residues. When recombinant LSA-1 protein was crosslinked in vitro by purified TG2 in a calcium dependent reaction, a flocculent mass of protein was formed that was highly resistant to degradation. The cross-linking was not detectably affected by phosphorylation with plasmodial CK2 in vitro. Monoclonal antibodies specific to the very unique TG2 catalyzed epsilon- lysine cross-bridge co-localized with antibodies to LSA-1 in infected human hepatocytes providing visual evidence that LSA-1 was cross-linked in vivo. CONCLUSIONS: While the role of LSA-1 is still unknown these results suggest that it becomes highly cross-linked which may aid in the protection of the parasite as it develops. PMID- 21255446 TI - The health workforce crisis in Bangladesh: shortage, inappropriate skill-mix and inequitable distribution. AB - BACKGROUND: Bangladesh is identified as one of the countries with severe health worker shortages. However, there is a lack of comprehensive data on human resources for health (HRH) in the formal and informal sectors in Bangladesh. This data is essential for developing an HRH policy and plan to meet the changing health needs of the population. This paper attempts to fill in this knowledge gap by using data from a nationally representative sample survey conducted in 2007. METHODS: The study population in this survey comprised all types of currently active health care providers (HCPs) in the formal and informal sectors. The survey used 60 unions/wards from both rural and urban areas (with a comparable average population of approximately 25 000) which were proportionally allocated based on a 'Probability Proportion to Size' sampling technique for the six divisions and distribution areas. A simple free listing was done to make an inventory of the practicing HCPs in each of the sampled areas and cross-checking with community was done for confirmation and to avoid duplication. This exercise yielded the required list of different HCPs by union/ward. RESULTS: HCP density was measured per 10 000 population. There were approximately five physicians and two nurses per 10 000, the ratio of nurse to physician being only 0.4. Substantial variation among different divisions was found, with gross imbalance in distribution favouring the urban areas. There were around 12 unqualified village doctors and 11 salespeople at drug retail outlets per 10 000, the latter being uniformly spread across the country. Also, there were twice as many community health workers (CHWs) from the non-governmental sector than the government sector and an overwhelming number of traditional birth attendants. The village doctors (predominantly males) and the CHWs (predominantly females) were mainly concentrated in the rural areas, while the paraprofessionals were concentrated in the urban areas. Other data revealed the number of faith/traditional healers, homeopaths (qualified and non-qualified) and basic care providers. CONCLUSIONS: Bangladesh is suffering from a severe HRH crisis--in terms of a shortage of qualified providers, an inappropriate skills-mix and inequity in distribution--which requires immediate attention from policy makers. PMID- 21255447 TI - HIV-1 Nef increases astrocyte sensitivity towards exogenous hydrogen peroxide. AB - BACKGROUND: HIV-1 infected individuals are under chronic exposure to reactive oxygen species (ROS) considered to be instrumental in the progression of AIDS and the development of HIV-1 associated dementia (HAD). Astrocytes support neuronal function and protect them against cytotoxic substances including ROS. The protein HIV-1 Nef, a progression factor in AIDS pathology is abundantly expressed in astrocytes in patients with HAD, and thus may influence its functions. RESULTS: Endogenous expressed HIV-1 Nef leads to increased sensitivity of human astrocytes towards exogenous hydrogen peroxide but not towards TNF-alpha. Cell death of nef expressing astrocytes exposed to 10 MUM hydrogen peroxide for 30 min occurred within 4 h. CONCLUSION: HIV-1 Nef may contribute to neuronal dysfunction and the development of HAD by causing death of astrocytes through decreasing their tolerance for hydrogen peroxide. PMID- 21255448 TI - Dietary energy density and adiposity: employing bias adjustments in a meta analysis of prospective studies. AB - BACKGROUND: Dietary studies differ in design and quality making it difficult to compare results. This study quantifies the prospective association between dietary energy density (DED) and adiposity in children using a meta-analysis method that adjusts for differences in design and quality through eliciting and incorporating expert opinion on the biases and their uncertainty. METHOD: Six prospective studies identified by a previous systematic literature search were included. Differences in study quality and design were considered respectively as internal and external biases and captured in bias checklists. Study results were converted to correlation coefficients; biases were considered either additive or proportional on this scale. The extent and uncertainty of the internal and external biases in each study were elicited in a formal process by five quantitatively-trained assessors and five subject-matter specialists. Biases for each study were combined across assessors using median pooling and results combined across studies by random-effects meta-analysis. RESULTS: The unadjusted combined correlation between DED and adiposity change was 0.06 (95%CI 0.01, 0.11; p = 0.013), but with considerable heterogeneity (I2 = 52%). After bias-adjustment the pooled correlation was 0.17 (95%CI - 0.11, 0.45; p = 0.24), and the studies were apparently compatible (I2 = 0%). CONCLUSIONS: This method allowed quantitative synthesis of the prospective association between DED and adiposity change in children, which is important for the development of evidence-informed policy. Bias adjustment increased the magnitude of the positive association but the widening confidence interval reflects the uncertainty of the assessed biases and implies that higher quality studies are required. PMID- 21255449 TI - Application of satellite precipitation data to analyse and model arbovirus activity in the tropics. AB - BACKGROUND: Murray Valley encephalitis virus (MVEV) is a mosquito-borne Flavivirus (Flaviviridae: Flavivirus) which is closely related to Japanese encephalitis virus, West Nile virus and St. Louis encephalitis virus. MVEV is enzootic in northern Australia and Papua New Guinea and epizootic in other parts of Australia. Activity of MVEV in Western Australia (WA) is monitored by detection of seroconversions in flocks of sentinel chickens at selected sample sites throughout WA. Rainfall is a major environmental factor influencing MVEV activity. Utilising data on rainfall and seroconversions, statistical relationships between MVEV occurrence and rainfall can be determined. These relationships can be used to predict MVEV activity which, in turn, provides the general public with important information about disease transmission risk. Since ground measurements of rainfall are sparse and irregularly distributed, especially in north WA where rainfall is spatially and temporally highly variable, alternative data sources such as remote sensing (RS) data represent an attractive alternative to ground measurements. However, a number of competing alternatives are available and careful evaluation is essential to determine the most appropriate product for a given problem. RESULTS: The Tropical Rainfall Measurement Mission (TRMM) Multi-satellite Precipitation Analysis (TMPA) 3B42 product was chosen from a range of RS rainfall products to develop rainfall-based predictor variables and build logistic regression models for the prediction of MVEV activity in the Kimberley and Pilbara regions of WA. Two models employing monthly time-lagged rainfall variables showed the strongest discriminatory ability of 0.74 and 0.80 as measured by the Receiver Operating Characteristics area under the curve (ROC AUC). CONCLUSIONS: TMPA data provide a state-of-the-art data source for the development of rainfall-based predictive models for Flavivirus activity in tropical WA. Compared to ground measurements these data have the advantage of being collected spatially regularly, irrespective of remoteness. We found that increases in monthly rainfall and monthly number of days above average rainfall increased the risk of MVEV activity in the Pilbara at a time-lag of two months. Increases in monthly rainfall and monthly number of days above average rainfall increased the risk of MVEV activity in the Kimberley at a lag of three months. PMID- 21255450 TI - Fever detection in under 5 children in a tertiary health facility using the infrared tympanic thermometer in the oral mode. AB - BACKGROUND: Monitoring of body temperature is an important clinical procedure in the care of sick children, especially the under-5 children, as many disease conditions present with fever. The oral mercury-in-glass thermometer which has relatively good accuracy cannot be used in children less than 5 years because it requires their cooperation. OBJECTIVE: This study was aimed at using the infrared tympanic thermometer (IRTT) in oral mode to measure temperature in febrile and afebrile children less than 5 years. METHODS: Rectal and tympanic temperatures were measured consecutively in 400 febrile and 400 afebrile under-5 children matched for age, using the mercury-in-glass thermometer and the IRTT in oral mode respectively. RESULTS: In the febrile children, the mean tympanic temperature was 38.6 +/- 0.9 degrees C, while the mean rectal temperature was 39.0 +/- 0.8 degrees C. In the afebrile group, the mean tympanic temperature was 37.0 +/- 0.4 degrees C, while the mean rectal temperature was 37.4 +/- 0.3 degrees C. The mean difference between rectal and tympanic temperatures in both groups was statistically significant. There was good correlation between the two temperatures. The tympanic thermometer used in the oral mode had a sensitivity of 87.3% and a specificity of 96.5%. CONCLUSION: The IRTT (oral mode) may not be reliable in estimating 'core' body temperature in children under the age of five years, but with a fairly good sensitivity and specificity, as well as its other advantages such as short duration of measurement, convenience and safety, it is a useful instrument for screening children with fever in a busy setup. PMID- 21255451 TI - Variant Plasmodium ovale isolated from a patient infected in Ghana. AB - Recent data have found that Plasmodium ovale can be separated in two distinct species: classic and variant P. ovale based on multilocus typing of different genes. This study presents a P. ovale isolate from a patient infected in Ghana together with an analysis of the small subunit RNA, cytochrome b, cytochrome c oxidase I, cysteine protease and lactate dehydrogenase genes, which show that the sample is a variant P. ovale and identical or highly similar to variant P. ovale isolated from humans in South-East Asia and Africa, and from a chimpanzee in Cameroon. The split between the variant and classic P. ovale is estimated to have occurred 1.7 million years ago. PMID- 21255452 TI - Persistent directional cell migration requires ion transport proteins as direction sensors and membrane potential differences in order to maintain directedness. AB - BACKGROUND: Ion transport proteins generate small electric fields that can induce directional cell motility; however, little is known about their mechanisms that lead to directedness. We investigated Na, K-ATPase (NaKA) and Na+/H+ exchanger isoforms (NHE1 and 3) in SaOS-2 and Calvarial osteoblasts, which present anode- and cathode- directed motility, during electrotaxis. RESULTS: Significant colocalizations of NaKA with vinculin and pNHE3 with beta-actin were observed to occur at the leading edges of cells. The directedness were attenuated when NaKA or NHE3 was inhibited, confirming their implication in directional sensing. Depending on the perceived direction, a divergent regulation in PIP2 levels as a function of NHE3 and NaKA levels was observed, suggesting that PIP2 may act as a spatiotemporal regulator of the cell membrane during electrotaxis. Moreover, at the same places where pNHE3 accumulates, bubble-shaped H+ clouds were observed, suggesting a physio-mechanical role for NHE3. The cell membrane becomes hyperpolarized at the front and depolarized at the back, which confirms NaKA activity at the leading edge. CONCLUSION: We suggest a novel role for both NaKA and NHE3 that extends beyond ion translocation and conclude that they can act as directional sensors and Vmem as a regulatory cue which maintain the persistent direction in electrotaxis. PMID- 21255453 TI - A population-based surveillance study on severe acute maternal morbidity (near miss) and adverse perinatal outcomes in Campinas, Brazil: the Vigimoma Project. AB - BACKGROUND: Auditing of sentinel health events based on best-practice protocols has been recommended. This study describes a population-based investigation on adverse perinatal events including severe acute maternal morbidity (near-miss), maternal and perinatal mortality, as a health intervention to help improve the surveillance system. METHODS: From October to December 2005, all cases of maternal death (MD), near-miss (NM), fetal deaths (FD), and early neonatal deaths (END), occurring in Campinas, Brazil, were audited by maternal mortality committees. RESULTS: A total of 4,491 liveborn infants (LB) and 159 adverse perinatal events (35.4/1000 LB) were revised, consisting of 4 MD (89/100.000 LB) and 95 NM (21.1/1000 LB), 23.7 NM for each MD. In addition, 32 FD (7.1/1000 LB) and 28 END (6.2/1000 LB) occurred. The maternal death/near miss rate was 23.7:1. Some delay in care was recognized for 34%, and hypertensive complications comprised 57.8% of the NM events, followed by postpartum hemorrhage. CONCLUSION: Auditing near miss cases expanded the understanding of the spectrum from maternal morbidity to mortality and the importance of promoting adhesion to clinical protocols among maternal mortality committee members. Hypertensive disorders and postpartum hemorrhage were identified as priority topics for health providers training, and organization of care. PMID- 21255454 TI - Optimization of glutathione production in batch and fed-batch cultures by the wild-type and recombinant strains of the methylotrophic yeast Hansenula polymorpha DL-1. AB - BACKGROUND: Tripeptide glutathione (gamma-glutamyl-L-cysteinyl-glycine) is the most abundant non-protein thiol that protects cells from metabolic and oxidative stresses and is widely used as medicine, food additives and in cosmetic industry. The methylotrophic yeast Hansenula polymorpha is regarded as a rich source of glutathione due to the role of this thiol in detoxifications of key intermediates of methanol metabolism. Cellular and extracellular glutathione production of H. polymorpha DL-1 in the wild type and recombinant strains which overexpress genes of glutathione biosynthesis (GSH2) and its precursor cysteine (MET4) was studied. RESULTS: Glutathione producing capacity of H. polymorpha DL-1 depending on parameters of cultivation (dissolved oxygen tension, pH, stirrer speed), carbon substrate (glucose, methanol) and type of overexpressed genes of glutathione and its precursor biosynthesis during batch and fed-batch fermentations were studied. Under optimized conditions of glucose fed-batch cultivation, the glutathione productivity of the engineered strains was increased from ~900 up to ~ 2300 mg of Total Intracellular Glutathione (TIG) or GSH+GSSGin, per liter of culture medium. Meantime, methanol fed-batch cultivation of one of the recombinant strains allowed achieving the extracellular glutathione productivity up to 250 mg of Total Extracellular Glutathione (TEG) or GSH+GSSGex, per liter of the culture medium. CONCLUSIONS: H. polymorpha is an competitive glutathione producer as compared to other known yeast and bacteria strains (Saccharomyces cerevisiae, Candida utilis, Escherichia coli, Lactococcus lactis etc.) with good perspectives for further improvement especially for production of extracellular form of glutathione. PMID- 21255455 TI - FASIMU: flexible software for flux-balance computation series in large metabolic networks. AB - BACKGROUND: Flux-balance analysis based on linear optimization is widely used to compute metabolic fluxes in large metabolic networks and gains increasingly importance in network curation and structural analysis. Thus, a computational tool flexible enough to realize a wide variety of FBA algorithms and able to handle batch series of flux-balance optimizations is of great benefit. RESULTS: We present FASIMU, a command line oriented software for the computation of flux distributions using a variety of the most common FBA algorithms, including the first available implementation of (i) weighted flux minimization, (ii) fitness maximization for partially inhibited enzymes, and (iii) of the concentration based thermodynamic feasibility constraint. It allows batch computation with varying objectives and constraints suited for network pruning, leak analysis, flux-variability analysis, and systematic probing of metabolic objectives for network curation. Input and output supports SBML. FASIMU can work with free (lp_solve and GLPK) or commercial solvers (CPLEX, LINDO). A new plugin (faBiNA) for BiNA allows to conveniently visualize calculated flux distributions. The platform-independent program is an open-source project, freely available under GNU public license at http://www.bioinformatics.org/fasimu including manual, tutorial, and plugins. CONCLUSIONS: We present a flux-balance optimization program whose main merits are the implementation of thermodynamics as a constraint, batch series of computations, free availability of sources, choice on various external solvers, and the flexibility on metabolic objectives and constraints. PMID- 21255456 TI - Memantine effects on liver and adrenal gland of rats exposed to cold stress. AB - BACKGROUND: Memantine attenuates heart stress due cold stress, however, no study focused its effects on liver and adrenal gland. We evaluated its effects on lipid depletion in adrenal gland and glycogen depletion in liver of rats exposed to cold stress. METHODS: Male rats divided into 4 groups: 1)Control (CON); 2)Memantine (MEM); 3)Induced cold stress (IH) and; 4)Induced cold stress memantine (IHF). Memantine were administrated by gavage (20 mg/kg/day) during eight days. Cold stress were performed during 4 hours once at - 8 degrees C. Lipid and glycogen depletion were presented as its intensity levels. RESULTS: Rats exposed to cold stress presented the highest glycogen (p < 0.001) and lipid depletion (p < 0.001) in liver and adrenal gland, respectively. We noted that memantine significantly reduced lipid depletion in adrenal gland and glycogen depletion in liver. CONCLUSION: Memantine prevented glycogen depletion in liver and lipid depletion in adrenal gland of rats under a cold stress condition. PMID- 21255457 TI - Policymakers and the example of smoking to children: A qualitative study. AB - BACKGROUND: The normality of smoking that children are exposed to is associated with increased risk of smoking uptake. To better understand policymaking that could address this issue, our aim was to identify and document the views of New Zealand policymakers regarding the example of smoking behaviour to children, and the policy responses they preferred. METHOD: We analysed public documents for relevant statements, and conducted semi-structured anonymous interviews with 62 purposively selected policymakers. We identified views of New Zealand policymakers regarding: the example to children of adult smoking behaviour, and the policy responses they preferred. RESULTS: In both public statements and anonymous interviews, policymakers demonstrated that they perceived a clear relationship between the example of smoking and children taking up smoking. However, they showed a general unwillingness to support further smokefree legislation in areas frequented by children. Rather, they preferred to educate adults about their impact as models for youth behaviour. CONCLUSIONS: Health advocates in New Zealand and elsewhere may require more evidence of the effect of relevant legislation and of public support, and wider alliances, to significantly move policies specifically to reduce the example of smoking. PMID- 21255458 TI - Validity of gait parameters for hip flexor contracture in patients with cerebral palsy. AB - BACKGROUND: Psoas contracture is known to cause abnormal hip motion in patients with cerebral palsy. The authors investigated the clinical relevance of hip kinematic and kinetic parameters, and 3D modeled psoas length in terms of discriminant validity, convergent validity, and responsiveness. METHODS: Twenty four patients with cerebral palsy (mean age 6.9 years) and 28 normal children (mean age 7.6 years) were included. Kinematic and kinetic data were obtained by three dimensional gait analysis, and psoas lengths were determined using a musculoskeletal modeling technique. Validity of the hip parameters were evaluated. RESULTS: In discriminant validity, maximum psoas length (effect size r = 0.740), maximum pelvic tilt (0.710), maximum hip flexion in late swing (0.728), maximum hip extension in stance (0.743), and hip flexor index (0.792) showed favorable discriminant ability between the normal controls and the patients. In convergent validity, maximum psoas length was not significantly correlated with maximum hip extension in stance in control group whereas it was correlated with maximum hip extension in stance (r = -0.933, p < 0.001) in the patients group. In responsiveness, maximum pelvic tilt (p = 0.008), maximum hip extension in stance (p = 0.001), maximum psoas length (p < 0.001), and hip flexor index (p < 0.001) showed significant improvement post-operatively. CONCLUSIONS: Maximum pelvic tilt, maximum psoas length, hip flexor index, and maximum hip extension in stance were found to be clinically relevant parameters in evaluating hip flexor contracture. PMID- 21255459 TI - Dutch randomized trial comparing standard catheter-directed thrombolysis versus ultrasound-accelerated thrombolysis for thromboembolic infrainguinal disease (DUET): design and rationale. AB - BACKGROUND: The use of thrombolytic therapy in the treatment of thrombosed infrainguinal native arteries and bypass grafts has increased over the years. Main limitation of this treatment modality, however, is the occurrence of bleeding complications. Low intensity ultrasound (US) has been shown to accelerate enzymatic thrombolysis, thereby reducing therapy time. So far, no randomized trials have investigated the application of US-accelerated thrombolysis in the treatment of thrombosed infra-inguinal native arteries or bypass grafts. The DUET study (Dutch randomized trial comparing standard catheter directed thrombolysis versus Ultrasound-accElerated Thrombolysis for thrombo embolic infrainguinal disease) is designed to assess whether US-accelerated thrombolysis will reduce therapy time significantly compared with standard catheter-directed thrombolysis. METHODS/DESIGN: Sixty adult patients with recently (between 1 and 7 weeks) thrombosed infrainguinal native arteries or bypass grafts with acute limb ischemia class I or IIa, according to the Rutherford classification for acute ischemia, will be randomly allocated to either standard thrombolysis (group A) or US-accelerated thrombolysis (group B). Patients will be recruited from 5 teaching hospitals in the Netherlands during a 2-year period. The primary endpoint is the duration of catheter-directed thrombolysis needed for uninterrupted flow in the thrombosed infrainguinal native artery or bypass graft, with outflow through at least 1 crural artery. DISCUSSION: The DUET study is a randomized controlled trial that will provide evidence of whether US-accelerated thrombolysis will significantly reduce therapy time in patients with recently thrombosed infrainguinal native arteries or bypass grafts, without an increase in complications. TRIAL REGISTRATION: Current Controlled Trials ISRCTN72676102. PMID- 21255460 TI - Effectiveness of trigger point dry needling for plantar heel pain: study protocol for a randomised controlled trial. AB - BACKGROUND: Plantar heel pain (plantar fasciitis) is a common and disabling condition, which has a detrimental impact on health-related quality of life. Despite the high prevalence of plantar heel pain, the optimal treatment for this disorder remains unclear. Consequently, an alternative therapy such as dry needling is increasingly being used as an adjunctive treatment by health practitioners. Only two trials have investigated the effectiveness of dry needling for plantar heel pain, however both trials were of a low methodological quality. This manuscript describes the design of a randomised controlled trial to evaluate the effectiveness of dry needling for plantar heel pain. METHODS: Eighty community-dwelling men and woman aged over 18 years with plantar heel pain (who satisfy the inclusion and exclusion criteria) will be recruited. Eligible participants with plantar heel pain will be randomised to receive either one of two interventions, (i) real dry needling or (ii) sham dry needling. The protocol (including needling details and treatment regimen) was formulated by general consensus (using the Delphi research method) using 30 experts worldwide that commonly use dry needling for plantar heel pain. Primary outcome measures will be the pain subscale of the Foot Health Status Questionnaire and "first step" pain as measured on a visual analogue scale. The secondary outcome measures will be health related quality of life (assessed using the Short Form-36 questionnaire - Version Two) and depression, anxiety and stress (assessed using the Depression, Anxiety and Stress Scale - short version). Primary outcome measures will be performed at baseline, 2, 4, 6 and 12 weeks and secondary outcome measures will be performed at baseline, 6 and 12 weeks. Data will be analysed using the intention to treat principle. CONCLUSION: This study is the first randomised controlled trial to evaluate the effectiveness of dry needling for plantar heel pain. The trial will be reported in accordance with the Consolidated Standards of Reporting Trials and the Standards for Reporting Interventions in Clinical Trials of Acupuncture guidelines. The findings from this trial will provide evidence for the effectiveness of trigger point dry needling for plantar heel pain. TRIAL REGISTRATION: Australian New Zealand 'Clinical Trials Registry'. ACTRN12610000611022. PMID- 21255461 TI - Inflammatory pseudo-tumor of the liver: a rare pathological entity. AB - Inflammatory pseudo-tumor (IPT) of the liver is a rare benign neoplasm and is often mistaken as a malignant entity. Few cases have been reported in the literature and the precise etiology of inflammatory pseudotumor remains unknown. Patients usually present with fever, abdominal pain and jaundice. The proliferation of spindled myofibroblast cells mixed with variable amounts of reactive inflammatory cells is characteristics of IPT. We reviewed the literature regarding possible etiology for IPT with a possible suggested etiology. PMID- 21255463 TI - "Risk homeostasis"or "teachable moment"? the interaction between smoking behavior and lung cancer screening in the Mayo Lung Project. AB - The chest X-ray lung cancer screening program of Mayo Lung Project (MLP) yielded mixed results of improved lung case survival but no improvement in lung cancer mortality. This paper analyzes the smoking patterns of study participants in order to examine possible behavioral ramifications of periodic lung cancer screening. Using a longitudinal difference-of-difference model, we compared the smoking behavior, in terms of current smoker status among all subjects and the intensity of smoking among those continuing smokers, between those who received periodic lung cancer screening and those who received usual-care. In both arms of this lung cancer screening trial, there was a sizable decline in cigarette smoking one year after participants received baseline prevalence screening. There was no significant difference in current smoker status between the intervention group receiving periodic X-ray screening and the control group receiving usual care. While we detect that the continuing smokers in the intervention group smoked more than their counterparts in the control group, the magnitude of the difference is not sufficient to explain a substantial difference in lung cancer incidence between the two groups. Our study shows that periodic lung screening in MLP did not decrease smoking behavior beyond the observed decline following the initial prevalence screening conducted at baseline for both the intervention and control groups. Our results also indicate, paradoxically, that participants assigned to the intervention group smoked more cigarettes per day on average than those in the control group. Lung cancer screening programs need additional cessation components to sustain the abstinence effect typically observed following initial lung screening. PMID- 21255462 TI - Finding a cure for HIV: will it ever be achievable? AB - Combination antiretroviral therapy (cART) has led to a major reduction in HIV related mortality and morbidity. However, HIV still cannot be cured. With the absence of an effective prophylactic or therapeutic vaccine, increasing numbers of infected people, emerging new toxicities secondary to cART and the need for life-long treatment, there is now a real urgency to find a cure for HIV.There are currently multiple barriers to curing HIV. The most significant barrier is the establishment of a latent or "silent" infection in resting CD4+ T cells. In latent HIV infection, the virus is able to integrate into the host cell genome, but does not proceed to active replication. As a consequence, antiviral agents, as well as the immune system, are unable to eliminate these long-lived, latently infected cells. Reactivation of latently infected resting CD4+ T cells can then re-establish infection once cART is stopped. Other significant barriers to cure include residual viral replication in patients receiving cART, even when the virus is not detectable by conventional assays. In addition, HIV can be sequestered in anatomical reservoirs, such as the brain, gastrointestinal tract and genitourinary tract.Achieving either a functional cure (long-term control of HIV in the absence of cART) or a sterilizing cure (elimination of all HIV infected cells) remains a major challenge. Several studies have now demonstrated that treatment intensification appears to have little impact on latent reservoirs. Some potential and promising approaches that may reduce the latent reservoir include very early initiation of cART and the use of agents that could potentially reverse latent infection.Agents that reverse latent infection will promote viral production; however, simultaneous administration of cART will prevent subsequent rounds of viral replication. Such drugs as histone deacetylase inhibitors, currently used and licensed for the treatment of some cancers, or activating latently infected resting cells with cytokines, such as IL-7 or prostratin, show promising results in reversing latency in vitro when used either alone or in combination. In order to move forward toward clinical trials that target eradication, there needs to be careful consideration of the risks and benefits of these approaches, agreement on the most informative endpoints for eradication studies and greater engagement of the infected community. PMID- 21255464 TI - Anti-proliferative effects of raw and steamed extracts of Panax notoginseng and its ginsenoside constituents on human liver cancer cells. AB - BACKGROUND: Panax notoginseng is a potential source of anticancer compounds. This study aims to investigate the effects of steaming on the chemical profile of P. notoginseng and the anti-proliferative effects of P. notoginseng on liver cancer cells. METHODS: Samples of powdered raw P. notoginseng roots were steamed for various durations. Extracts of the raw and steamed samples were subjected to ultra-high pressure liquid chromatography/mass spectrometry (UHPLC-MS) analysis for chemical profiling. The anti-proliferative effects on three human liver cancer cells, namely SNU449, SNU182 and HepG2, were evaluated using colorimetric WST-1 assay. RESULTS: Steaming changed chromatographic and pharmacological profiles of P. notoginseng, causing differences in activities such as inhibition of cancer growth. Steamed P. notoginseng exhibited greater anti-proliferative effects against liver cancer cells (SNU449, SNU182 and HepG2) than its raw form; steaming up to 24 hours increased bioactivities. Steaming increased the concentrations of ginsenoside Rh2, Rk1, Rk3 and 20S-Rg3 and enhanced growth inhibition of liver cancer cells. CONCLUSION: Steaming changes the chemical profile as well as anti-cancer biological activities of P. notoginseng. Steamed P. notoginseng contains potential compounds for the treatment of liver cancer. PMID- 21255466 TI - Parameter estimation in systems biology models using spline approximation. AB - BACKGROUND: Mathematical models for revealing the dynamics and interactions properties of biological systems play an important role in computational systems biology. The inference of model parameter values from time-course data can be considered as a "reverse engineering" process and is still one of the most challenging tasks. Many parameter estimation methods have been developed but none of these methods is effective for all cases and can overwhelm all other approaches. Instead, various methods have their advantages and disadvantages. It is worth to develop parameter estimation methods which are robust against noise, efficient in computation and flexible enough to meet different constraints. RESULTS: Two parameter estimation methods of combining spline theory with Linear Programming (LP) and Nonlinear Programming (NLP) are developed. These methods remove the need for ODE solvers during the identification process. Our analysis shows that the augmented cost function surfaces used in the two proposed methods are smoother; which can ease the optima searching process and hence enhance the robustness and speed of the search algorithm. Moreover, the cores of our algorithms are LP and NLP based, which are flexible and consequently additional constraints can be embedded/removed easily. Eight system biology models are used for testing the proposed approaches. Our results confirm that the proposed methods are both efficient and robust. CONCLUSIONS: The proposed approaches have general application to identify unknown parameter values of a wide range of systems biology models. PMID- 21255465 TI - Inhibition of spinal astrocytic c-Jun N-terminal kinase (JNK) activation correlates with the analgesic effects of ketamine in neuropathic pain. AB - BACKGROUND: We have previously reported that inhibition of astrocytic activation contributes to the analgesic effects of intrathecal ketamine on spinal nerve ligation (SNL)-induced neuropathic pain. However, the underlying mechanisms are still unclear. c-Jun N-terminal kinase (JNK), a member of mitogen-activated protein kinase (MAPK) family, has been reported to be critical for spinal astrocytic activation and neuropathic pain development after SNL. Ketamine can decrease lipopolysaccharide (LPS)-induced phosphorylated JNK (pJNK) expression and could thus exert its anti-inflammatory effect. We hypothesized that inhibition of astrocytic JNK activation might be involved in the suppressive effect of ketamine on SNL-induced spinal astrocytic activation. METHODS: Immunofluorescence histochemical staining was used to detect SNL-induced spinal pJNK expression and localization. The effects of ketamine on SNL-induced mechanical allodynia were confirmed by behavioral testing. Immunofluorescence histochemistry and Western blot were used to quantify the SNL-induced spinal pJNK expression after ketamine administration. RESULTS: The present study showed that SNL induced ipsilateral pJNK up-regulation in astrocytes but not microglia or neurons within the spinal dorsal horn. Intrathecal ketamine relieved SNL-induced mechanical allodynia without interfering with motor performance. Additionally, intrathecal administration of ketamine attenuated SNL-induced spinal astrocytic JNK activation in a dose-dependent manner, but not JNK protein expression. CONCLUSIONS: The present results suggest that inhibition of JNK activation may be involved in the suppressive effects of ketamine on SNL-induced spinal astrocyte activation. Therefore, inhibition of spinal JNK activation may be involved in the analgesic effects of ketamine on SNL-induced neuropathic pain. PMID- 21255467 TI - SMARCB1/INI1 germline mutations contribute to 10% of sporadic schwannomatosis. AB - BACKGROUND: Schwannomatosis is a disease characterized by multiple non-vestibular schwannomas. Although biallelic NF2 mutations are found in schwannomas, no germ line event is detected in schwannomatosis patients. In contrast, germline mutations of the SMARCB1 (INI1) tumor suppressor gene were described in familial and sporadic schwannomatosis patients. METHODS: To delineate the SMARCB1 gene contribution, the nine coding exons were sequenced in a series of 56 patients affected with a variable number of non-vestibular schwannomas. RESULTS: Nine variants scattered along the sequence of SMARCB1 were identified. Five of them were classified as deleterious. All five patients carrying a SMARCB1 mutation had more multiple schwannomas, corresponding to 10.2% of patients with schwannomatosis. They were also diagnosed before 35 years of age. CONCLUSIONS: These results suggest that patients with schwannomas have a significant probability of carrying a SMARCB1 mutation. Combined with data available from other studies, they confirm the clinical indications for genetic screening of the SMARCB1 gene. PMID- 21255468 TI - Saponin accumulation in the seedling root of Panax notoginseng. AB - BACKGROUND: Panax notoginseng is an important Chinese medicinal plant. Dammarene type triterpenoid saponins are main pharmacologically effective compounds in P. notoginseng. This study aims to investigate the formation and accumulation of saponins in P. notoginseng roots during germination and juvenile stage. METHODS: P. notoginseng seeds were collected and stored in wet sand. After germination, the seedlings were transplanted into a soil nursery bed and cultivated for one year. During this period, samples were collected every month and the concentrations of ginsengnosides Rg1, Re, Rb1, Rd and notoginsengnoside R1 were determined by HPLC. RESULTS: There was little saponin in the P. notoginseng seed. The chemical composition of seed was different from that of root. After germination, Rb1, Rg1, Re, Rd and R1 appeared successively in the seedling root. And in the five-month-old root, all these five main saponins came into existence. The accumulation of saponins in P. notoginseng root was affected by seasons. CONCLUSION: The accumulation of saponins showed a time-dependent increase after germination of P. notoginseng. PMID- 21255469 TI - Vitamins in the treatment of chronic viral hepatitis. AB - Hepatitis B virus (HBV)- and hepatitis C virus (HCV)-related chronic infections represent a major health problem worldwide. Although the efficacy of HBV and HCV treatment has improved, several important problems remain. Current recommended antiviral treatments are associated with considerable expense, adverse effects and poor efficacy in some patients. Thus, several alternative approaches have been attempted. To review the clinical experiences investigating the use of lipid and water-soluble vitamins in the treatment of HBV- and HCV-related chronic infections, PubMed, the Cochrane Library, MEDLINE and EMBASE were searched for clinical studies on the use of vitamins in the treatment of HBV- and HCV-related hepatitis, alone or in combination with other antiviral options. Different randomised clinical trials and small case series have evaluated the potential virological and/or biochemical effects of several vitamins. The heterogeneous study designs and populations, the small number of patients enrolled, the weakness of endpoints and the different treatment schedules and follow-up periods make the results largely inconclusive. Only well-designed randomised controlled trials with well-selected endpoints will ascertain whether vitamins have any role in chronic viral hepatitis. Until such time, the use of vitamins cannot be recommended as a therapy for patients with chronic hepatitis B or C. PMID- 21255470 TI - Metabolomics and human nutrition. AB - The present report summarises a workshop convened by the UK Food Standards Agency (Agency) on 25 March 2010 to discuss the current Agency's funded research on the use of metabolomics technologies in human nutrition research. The objectives of this workshop were to review progress to date, to identify technical challenges and ways of overcoming them, and to discuss future research priorities and the application of metabolomics in public health nutrition research and surveys. Results from studies nearing completion showed that by using carefully designed dietary and sampling regimens, it is possible to identify novel biomarkers of food intake that could not have been predicted from current knowledge of food composition. These findings provide proof-of-principle that the metabolomics approach can be used to develop new putative biomarkers of dietary intake. The next steps will be to validate these putative biomarkers, to develop rapid and inexpensive assays for biomarkers of food intake of high public health relevance, and to test their utility in population cohort studies and dietary surveys. PMID- 21255471 TI - Feeding sunflower oil to partially defaunate the rumen increases nitrogen retention, urea-nitrogen recycling to the gastrointestinal tract and the anabolic use of recycled urea-nitrogen in growing lambs. AB - The objective of the present study was to delineate how interactions between feeding sunflower oil (SFO) to partially defaunate the rumen and altering dietary ruminally fermentable carbohydrate may alter urea-N kinetics and N metabolism in lambs. In a 4 * 4 Latin square with a 2 * 2 factorial arrangement of treatments, four Suffolk ram lambs (61.5 (se 4.0) kg) were used. Treatments were 0 ( - SFO) v. 6 % (+SFO) SFO and dry-rolled barley (DRB) v. pelleted barley (PB). N balance was measured over 4 d, with concurrent measurement of urea-N kinetics using continuous intra-jugular infusions of [(15)N(15)N]urea. Feeding SFO decreased (P = 0.001) ruminal protozoa and NH3-N concentrations. Urinary N excretion was lower (P = 0.003), and retained N was higher (P = 0.002) in +SFO lambs compared with - SFO lambs. Endogenous production of urea-N (urea-N entry rate; UER) was similar across treatments. Urea-N transfer to the gastrointestinal tract (GIT) (GIT entry rate; GER), expressed as absolute amounts (16.4 v. 13.1 g/d) or as a proportion of the UER (0.693 v. 0.570), its anabolic use (9.0 v. 6.0 g/d) and microbial N supply (14.6 v. 10.9 g/d) were higher (P <= 0.001) in +SFO lambs compared with SFO lambs. As a proportion of the UER, GER was higher, whereas urinary urea-N loss was lower, in lambs fed PB compared with those fed DRB (P = 0.01). In summary, feeding SFO increased urea-N recycling to the GIT and microbial non NH(3)-N supply, thus providing new evidence that the improved efficiency of N utilization in partially defaunated ruminants could be partly mediated by an increase in urea-N recycling. PMID- 21255472 TI - Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides. AB - In vitro, both carbohydrate sugars and artificial sweeteners (AS) stimulate the secretion of glucagon-like peptide-1 (GLP-1). It has been suggested that the gut tastes sugars and AS through the same mechanisms as the tongue, with potential effects on gut hormone release. We investigated whether the human gut responds in the same way to AS and carbohydrate sugars, which are perceived by lingual taste as equisweet. We focused on the secretion of gastrointestinal (GI) satiety peptides in relation to appetite perception. We performed a placebo-controlled, double-blind, six-way, cross-over trial including twelve healthy subjects. On separate days, each subject received an intragastric infusion of glucose, fructose or an AS (aspartame, acesulfame K and sucralose) dissolved in 250 ml of water or water only (control). In a second part, four subjects received an intragastric infusion of the non-sweet, non-metabolisable sugar analogue 2-deoxy d-glucose. Glucose stimulated GLP-1 (P = 0.002) and peptide tyrosine tyrosine (PYY; P = 0.046) secretion and reduced fasting plasma ghrelin (P = 0.046), whereas fructose was less effective. Both carbohydrate sugars increased satiety and fullness (albeit not significantly) compared with water. In contrast, equisweet loads of AS did not affect gastrointestinal peptide secretion with minimal effects on appetite. 2-Deoxy-d-glucose increased hunger ratings, however, with no effects on GLP-1, PYY or ghrelin. Our data demonstrate that the secretion of GLP-1, PYY and ghrelin depends on more than the detection of (1) sweetness or (2) the structural analogy to glucose. PMID- 21255473 TI - An open study of the effectiveness of a multi-component weight-loss intervention for adults with intellectual disabilities and obesity. AB - Adults with intellectual disabilities experience high rates of obesity. Despite this higher risk, there is little evidence on the effectiveness of weight-loss interventions for adults with intellectual disabilities and obesity. The present study examined the effectiveness of the TAKE 5 multi-component weight-loss intervention. Adults with obesity were invited using specialist intellectual disability services to participate in the study. Obesity was defined as a BMI of 30 kg/m2 or greater. TAKE 5 included a daily energy-deficit diet of 2510 kJ (600 kcal), achieved via a personalised dietary prescription. Participants' body weight, BMI, waist circumference and levels of physical activity and sedentary behaviour were measured before and after the intervention. A total of fifty-four individuals consented to participate, of which forty-seven (87 %) completed the intervention in the study period. There was a significant decrease in body weight (mean difference - 4.47 (95 % CI - 5.91, - 3.03) kg; P < 0.0001), BMI (- 1.82 (95 % CI - 2.36, - 1.29) kg/m(2); P < 0.0001), waist circumference (- 6.29 (95 % CI - 7.85, - 4.73) cm; P < 0.0001) and daily sedentary behaviour of participants (- 41.40 (95 % CI - 62.45, - 20.35) min; P = 0.00 034). Of the participants who completed the intervention, seventeen (36.2 %) lost 5 % or more of their initial body weight. Findings from the study suggest that TAKE 5 is an effective weight loss intervention for adults with intellectual disabilities and obesity. The effectiveness of TAKE 5 should be examined further in a controlled study. PMID- 21255474 TI - Dietary resistant and butyrylated starches have different effects on the faecal bacterial flora of azoxymethane-treated rats. AB - Epidemiological studies have suggested that dietary fibre lowers the risk of colorectal cancer, which may be due to increased butyrate production from colonic fermentation of a type of fibre, resistant starch (RS). The present study investigated the effects of dietary RS and butyrylated RS on the faecal microbiota of rats treated with azoxymethane. A total of four groups of nine rats were fed diets containing either standard maize starch (low-amylose maize starch (LAMS), low RS), LAMS with 3 % tributyrin (LAMST), cooked 10 % high-amylose maize starch (HAMS, high RS) or cooked 10 % butyrylated HAMS (HAMSB). Faecal samples were examined by denaturing gradient gel electrophoresis (DGGE) of PCR-amplified 16S rRNA gene fragments. Multivariate analysis demonstrated no differences between faecal microbiota before treatment but revealed differences in DGGE patterns between diet groups, with the exception of the two low-RS groups (LAMS and LAMST). Subsequent analysis identified eleven DGGE bands contributing significantly to the differentiation between diets. These phylotypes belonged to Clostridiales (five), Lactobacillus (one) and Bacteroidetes (five) lineages. Rats fed HAMS had increased concentration of propionate in their distal colonic digesta and developed faecal populations containing Ruminococcus bromii-like bacteria. HAMSB increased propionate and butyrate concentrations in distal colonic digesta and was associated with the appearance of two non-butyrate producing bacteria, Lactobacillus gasseri and Parabacteroides distasonis. In conclusion, supplementation with specific dietary RS leads to changes in faecal microbiota profiles that may be associated with improved bowel health. PMID- 21255475 TI - The association of diabetes and BMI among Melanesian and Indian Fijians aged >= 40 years. AB - The present study examines the association of diabetes with BMI (kg/m(2)) in Asian-Indian and Melanesian Fijian populations sharing a common environment. A population-based survey was used to investigate the risk of diabetes (defined by glycosylated Hb concentration >= 6.5 % among participants who denied previous diagnosis of the disease by a medical practitioner) by sex, ethnicity and strata of BMI in a series of age-adjusted logistic regression models. Ethnicity and BMI interactions were compared using WHO and empirically derived BMI cut-off points. Indians had a greater risk (BMI and age adjusted) of undetected diabetes than Melanesians in both males (OR 2.99, 95 % CI 1.73, 5.17; P < 0.001) and females (OR 2.26, 95 % CI 1.56, 3.28; P < 0.001). BMI >= 25 to < 30 and >= 30 kg/m(2) conferred a higher risk of diabetes compared with a BMI >= 18.5 to < 25 kg/m(2). Risk was higher for males with a BMI >= 25 to < 30 kg/m(2) (OR 2.35, 95 % CI 1.24, 4.46; P = 0.007) and BMI >= 30 kg/m(2) (OR 6.08, 95 % CI 3.06, 12.07; P < 0.001) than for females with the same BMI (OR 1.85, 95 % CI 1.11, 3.08; P = 0.027 and OR 2.10, 95 % CI 1.28, 3.44; P = 0.002, respectively). However, the threshold that appeared to differentiate higher risk varied by ethnicity and sex. For Melanesians, BMI thresholds suggested were 25 kg/m(2) for males and 32 kg/m(2) for females. For Indo-Fijians, these were 24 and 22 kg/m(2) for males and females, respectively. Disaggregating by ethnicity and sex, and applying specific evidence-based thresholds, may render BMI a more discriminating tool for assessing the risk of developing diabetes among Fiji adults. PMID- 21255476 TI - Consumption of long-chain n-3 PUFA, alpha-linolenic acid and fish is associated with the prevalence of chronic kidney disease. AB - Due to the anti-inflammatory properties of PUFA, it has been suggested that they may protect against kidney damage in adults. However, relatively few epidemiological studies have examined this hypothesis in human subjects. We investigated the association between dietary intakes of PUFA (n-3, n-6 and alpha linolenic acid), fish and the prevalence of chronic kidney disease (CKD). A total of 2600 Blue Mountains Eye Study (1997-9) participants aged >= 50 years were analysed. Dietary data were collected using a semi-quantitative FFQ, and PUFA and fish intakes were calculated. Baseline biochemistry including serum creatinine was measured. Moderate CKD was defined as an estimated glomerular filtration rate of < 60 ml/min per 1.73 m2. Participants in the highest quartile of long-chain n 3 PUFA intake had a significantly reduced likelihood of having CKD compared with those in the lowest quartile of intake (multivariable-adjusted OR 0.69, 95 % CI 0.49, 0.99). alpha-Linolenic acid intake was positively associated with CKD (OR, per standard deviation increase in alpha-linolenic acid, 1.18, 95 % CI 1.05, 1.32). Total n-3 PUFA or total n-6 PUFA were not significantly associated with CKD. The highest compared with the lowest quartile of fish consumption was associated with a reduced likelihood of CKD (OR 0.68, 95 % CI 0.48, 0.97; P for trend = 0.02). The present study shows that an increased dietary intake of long chain n-3 PUFA and fish reduces the prevalence of CKD. Hence, a diet rich in n-3 PUFA and fish could have a role in maintaining healthy kidney function, in addition to roles of these nutrients in the prevention and modulation of other diseases. PMID- 21255477 TI - A Salmonella Typhimurium phage type (PT) U320 outbreak in England, 2008: continuation of a trend involving ready-to-eat products. AB - In March 2008, the Health Protection Agency in England conducted a retrospective case-control study to investigate the cause of 179 cases of the newly recognized, fully antimicrobial-sensitive Salmonella Typhimurium PT U320. Forty-three symptomatic laboratory-confirmed case-patients and 84 asymptomatic location matched controls were interviewed by telephone about exposures in the 3 days prior to illness or interview. Multivariate logistic analysis indicated consumption of pre-packaged egg sandwiches (odds ratio 3.29, 95% confidence interval 1.19-9.09) was independently associated with illness. Eight of the 15 case-patients who consumed egg sandwiches did so from retail chain A (53.3%) whereas none of the eight controls consumed similar sandwiches (chi2=7.20, P<=0.01). A review of the pre-packaged egg sandwich ingredients suggested this outbreak was probably caused by exposure to an ingredient common to pre-packaged sandwiches and prepared salads but we established a definitive epidemiological link with only the former. Short shelf-life, product diversity and investigation lag hinder epidemiological investigations of such popular products, providing continued challenges for food safety enforcement of freshly prepared produce. PMID- 21255478 TI - Malignant melanoma of nasal cavity and paranasal sinuses: report of 24 patients and literature review. AB - OBJECTIVE: To report our experience of the management of patients with primary sinonasal malignant melanoma, and to review the relevant medical literature. METHOD: Retrospective review examining treatment and outcomes. RESULTS: Twenty four patients were treated between 1982 and 2007. The mean age at presentation was 67.5 years. The overall five-year survival was 30 per cent; mean survival was three years and eight months. CONCLUSION: Sinonasal malignant melanoma is associated with a poor outcome, and survival statistics have not improved over the last 40 years. Treatment should include radical surgery wherever possible. Local recurrence is common; radiotherapy may help control this but does not appear to affect overall survival. The limited evidence available suggests that endoscopic removal of sinonasal malignant melanoma is as effective as other local surgical means, but that craniofacial resection remains the 'gold standard' for tumours that contact or traverse the skull base. Novel biological treatments are emerging and hold promise for the future. PMID- 21255479 TI - Nasal craniopharyngioma: case report and literature review. AB - OBJECTIVE: We report the first case in the English language literature of an adamantinomatous infrasellar craniopharyngioma, and we describe our management strategy. CASE REPORT: A 46-year-old woman presented with a six-month history of left-sided nasal obstruction and epistaxis. Rhinological examination revealed a left-sided, polypoidal lesion lying medial to the middle turbinate. An urgent examination under anaesthesia was organised; biopsies were considered characteristic of craniopharyngioma. Magnetic resonance imaging and computed tomography demonstrated a well defined, heterogeneous, infrasellar mass centred in the midline, extending anteriorly into the left nasal cavity and posteriorly encasing both internal carotid arteries. Craniofacial resection was performed via a midfacial degloving approach, with adjuvant radiotherapy. The patient was disease-free one year post-operatively. CONCLUSION: Craniopharyngiomas should be considered in the differential diagnosis of a unilateral nasal polyp. Although technically benign, they are locally aggressive. Therefore, we recommend complete excision with adjuvant radiotherapy if margins are involved or close. PMID- 21255480 TI - Diet cost, diet quality and socio-economic position: how are they related and what contributes to differences in diet costs? AB - OBJECTIVE: To examine diet costs in relation to dietary quality and socio economic position, and to investigate underlying reasons for differences in diet costs. DESIGN: Dietary intake was assessed by a 4 d food diary and evaluated using the 2005 Healthy Eating Index (HEI). National consumer food prices collected by Statistics Sweden and from two online stores/supermarkets were used to estimate diet costs. SETTING: Sweden. SUBJECTS: A nationally representative sample of 2160 children aged 4, 8 or 11 years. RESULTS: Higher scores on the HEI resulted in higher diet costs and, conversely, higher diet costs were linked to increased total HEI scores. Children who consumed the most healthy and/or expensive diets ate a more energy-dilute and varied diet compared with those who ate the least healthy and/or least expensive diets. They also consumed more fish, ready meals and fruit. Regression analysis also linked increased food costs to these food groups. There was a positive, but weak, relationship between HEI score and diet cost, parental education and parental occupation respectively. CONCLUSIONS: Healthy eating is associated with higher diet cost in Swedish children, in part because of price differences between healthy and less-healthy foods. The cheapest and most unhealthy diets were found among those children whose parents were the least educated and had manual, low-skill occupations. Our results pose several challenges for public health policy makers, as well as for nutrition professionals, when forming dietary strategies and providing advice for macro- and microlevels in society. PMID- 21255481 TI - An activated set point of T-cell and monocyte inflammatory networks in recent onset schizophrenia patients involves both pro- and anti-inflammatory forces. AB - We recently described a pro-inflammatory gene expression signature in the monocytes of 60% of patients with recent-onset schizophrenia (SCZ). Here we investigated whether the T-cell system is also in a pro-inflammatory state. A detailed fluorescence-activated cell sorting (FACS) analysis, e.g. of CD3+CD25+ T cells, IFN-gamma+, IL-4+, IL-17A+ (CD4+) lymphocytes and CD4+CD25highFoxP3+ regulatory T cells, was performed on peripheral blood of 26 patients with recent onset SCZ (in 19 of whom the inflammatory gene expression signature of the monocyte had been determined) and in age-/gender-matched healthy controls. Various relevant T-cell cytokines, e.g. sCD25, IFN-gamma, IL-17A and IL-4, were measured in serum by a multiplex assay. We detected: (a) not only higher percentages of pro-inflammatory-prone monocytes, activated CD3+CD25+ T cells and pro-inflammatory Th17 cells in patients, but also higher percentages of anti inflammatory CD4+CD25highFoxP3+ regulatory T cells and IL-4+ lymphocytes; (b) that this activated T-cell set point was reflected in significantly raised serum levels of sCD25; (c) that the up-regulation of IL-4+-containing lymphocytes was predominantly found in patients characterized by a monocyte pro-inflammatory set point; and (d) that regulatory T-cell and Th17-cell numbers were higher in patients irrespective of the pro-inflammatory state of the monocytes. Our data do not support the concept that the T-cell system is in a simple pro-inflammatory state in recent-onset SCZ, but do show that the monocyte and T-cell networks are activated and involve both pro- and anti-inflammatory forces. This suggests control within an activated inflammatory system. PMID- 21255482 TI - New insights into the mechanisms of the interactions between doxorubicin and the ion-exchange hydrogel DC BeadTM for use in transarterial chemoembolization (TACE). AB - Ion-exchange microspheres (IEMs) are widely employed in controlled drug delivery of ionic drugs due to their high loading capacity and the possibility to obtain the controlled release of the loaded drug(s) at a specific site. Among IEMs, DC Bead(TM) are embolic microdevices (100-300 MUm diameter) designed for transarterial chemoembolization (TACE) and composed of cross-linked poly(vinyl alcohol) (PVA) hydrogel, bearing anionic sulfonate moieties on the cross-links, and able to bind cationic drugs such as doxorubicin hydrochloride (Dox). Even if DC Bead(TM) were studied for their release and bulk characteristics, a thorough characterization of these devices is still lacking. In particular, the aim of this work was the determination of bound and free water, Dox distribution within the microdevices and drug-DC Bead(TM) interactions, in terms of transport features within the device. Compared with previous results, different Dox radial distributions in DC Bead(TM) were found, and related to bead microsctructure and ion exchange mechanism. Artifacts due to the self-quenching of Dox at high concentration were prevented and the diffusion coefficients of drug-polymer (Dox ionic sites) evaluated in different sections of the microspheres. Furthermore, DSC results indicated that in the hydrogel either free (bulk) or bound (non freezable) water could be found, and that no freezing-bound water was present. PMID- 21255483 TI - An improved approach to poly(ester-carbonate) conjugates. AB - A novel poly(ester-carbonate) (P(LA-co-NPC)) with activated pendant carboxyl groups was synthesized by ring-opening polymerization of L-lactide (LA) and 2 methyl-2-(4-nitrophenoxycarbonyl)-propylene carbonate (NPC) with diethyl zinc (ZnEt(2)) as catalyst. GPC and NMR studies confirmed the co-polymer structure. The pendant 4-nitrophenyl carboxylate groups can react with amino-containing molecules, such as 3,6,9-trioxa-1,11-undecanediamine, doxorubicin and chitosan under mild conditions. Therefore, any amino-containing molecules of biomedical interests can be conjugated to P(LA-co-NPC) efficiently and easily. The biocompatibility of the co-polymer was tested using L929 cell line, indicating that P(LA-co-NPC) is a promising biomedical material. PMID- 21255484 TI - Homogeneous chitosan/poly(L-lactide) composite scaffolds prepared by emulsion freeze-drying. AB - The combination between chitosan (CS)-based hydrophilic extracellular matrix polysaccharide and polylactide (PLA)-based hydrophobic biodegradable aliphatic polyester is a challenge in the biomaterials field. This study investigated the formation of homogeneous chitosan/poly(L-lactide) (CS/PLLA) porous composite scaffold using a novel emulsion freeze-drying technique. An oil-in-water (O/W) emulsification system was used in the presence of surfactant Tween-80, in which CS solution was used as the water phase and PLLA solution was used as the oil phase. The composite scaffolds showed well interconnected pore structures and homogenous distribution of CS and PLLA when the PLLA volume fraction was not higher than 50%. Once the PLLA content increased to 75%, SEM micrographs demonstrated that the two components present phase separation region. FT-IR analysis revealed that there are strong hydrogen bond interactions between CS and PLLA components. The porosity of the CS/PLLA composites was in the range of 85-90% and showed a slight decrease with increasing PLLA dose. The mechanical properties of the composites lay between that of the pure CS and the PLLA scaffold. The compressive strength increased from 0.17 to 0.21 MPa, while the compressive modulus increased from 2.37 to 3.38 MPa as the PLLA contents increased from 25 to 75%. In vitro cytotoxicity was evaluated by MTT assay. The results indicated that MC3T3-E1 cell viability and proliferation in the CS/PLLA scaffold were comparable to that in the CS scaffold, and much higher than that in the PLLA scaffold. The successful hydrophilic polysaccharide and hydrophobic polyester system offers a new delivery method of growth factors and a novel scaffold design for tissue engineering. PMID- 21255485 TI - The effect of layer-by-layer chitosan-hyaluronic acid coating on graft-to-bone healing of a poly(ethylene terephthalate) artificial ligament. AB - Surface coating with an organic layer-by-layer self-assembled template of chitosan and hyaluronic acid on a poly(ethylene terephthalate) (PET) artificial ligament was designed for the promotion and enhancement of graft-to-bone healing after artificial ligament implantation in a bone tunnel. The results of in vitro culturing of MC3T3-E1 mouse osteoblastic cells supported the hypothesis that the layer-by-layer coating of chitosan and hyaluronic acid could promote the cell compatibility of grafts and could promote osteoblast proliferation. A rabbit extra-articular tendon-to-bone healing model was used to evaluate the effect of this kind of surface-modified stainless artificial ligament in vivo. The final results proved that this organic compound coating could significantly promote and enhance new bone formation at the graft-bone interface histologically and, correspondingly, the experimental group with coating had significantly higher biomechanical properties compared with controls at 8 weeks (P < 0.05). PMID- 21255486 TI - Transcutaneous measurement of carbon dioxide tension during extended monitoring: evaluation of accuracy and stability, and an algorithm for correcting calibration drift. AB - BACKGROUND: When polysomnography is indicated in a patient with a presumed sleep disorder, continuous monitoring of arterial carbon dioxide tension (P(aCO(2))) is desirable, especially if nocturnal hypoventilation is suspected. Transcutaneous CO(2) monitors (P(tcCO(2))) provide a noninvasive correlate of P(aCO(2)), but their accuracy and stability over extended monitoring have been considered inadequate for the diagnosis of hypoventilation. We examined the stability and accuracy of P(tcCO(2)) measurements and the performance of a previously described linear interpolation technique designed to correct for calibration drift. METHODS: We compared the P(tcCO(2)) values from 2 TINA TCM-3 monitors to P(aCO(2)) values from arterial blood samples obtained at the beginning, every 15 min of the first hour, and then hourly over 8 hours of monitoring in 6 hemodynamically stable, male, intensive care patients (mean age 46 +/- 17 y). RESULTS: Time had a significant (P = .002) linear effect on the P(tcCO(2)) P(aCO(2)) difference, suggesting calibration drift over the monitoring period. We found no differences between monitor type or interaction between time and monitor type. For the 2 monitors the uncorrected bias was 3.6 mm Hg and the limits of agreement were -5.1 to 12.3 mm Hg. Our linear interpolation algorithm improved the bias and limits of agreement to 0.4 and -5.5 to 6.4 mm Hg, respectively. CONCLUSIONS: Following stabilization and correction for both offset and drift, P(tcCO(2)) tracks P(aCO(2)) with minimal residual bias over 8 hours of monitoring. Should future research confirm these findings, then interpolated P(tcCO(2)) may have an increased role in detecting sleep hypoventilation and assessing the efficacy of treatment. PMID- 21255487 TI - Critical-thinking ability in respiratory care students and its correlation with age, educational background, and performance on national board examinations. AB - BACKGROUND: Critical thinking is an important characteristic to develop in respiratory care students. METHODS: We used the short-form Watson-Glaser Critical Thinking Appraisal instrument to measure critical-thinking ability in 55 senior respiratory care students in a baccalaureate respiratory care program. We calculated the Pearson correlation coefficient to assess the relationships between critical-thinking score, age, and student performance on the clinical simulation component of the national respiratory care boards examination. We used chi-square analysis to assess the association between critical-thinking score and educational background. RESULTS: There was no significant relationship between critical-thinking score and age, or between critical-thinking score and student performance on the clinical-simulation component. There was a significant (P = .04) positive association between a strong science-course background and critical thinking score, which might be useful in predicting a student's ability to perform in areas where critical thinking is of paramount importance, such as clinical competencies, and to guide candidate-selection for respiratory care programs. PMID- 21255488 TI - Experience with a new device for clearing mucus from the endotracheal tube. AB - Partial or total obstruction of an endotracheal tube (ETT) by mucus can cause severe respiratory distress, hypoxemia, or death. Signs of an obstructed ETT include increased ventilation pressure, changes in the ventilator graphics, S(pO(2)) decrease, and cardiovascular changes. We present 3 patients whose ETTs were partially obstructed by mucus. In each case the patient displayed adverse effects from the obstruction, but once the obstruction was removed they showed dramatic improvement. In each case we used a new device (Rescue Cath, Omneotech, Tavernier, Florida) designed to remove mucus from the ETT lumen. The 3 cases demonstrate that the device is effective and capable of relieving the adverse effects of ETT mucus obstruction. PMID- 21255489 TI - Pulmonary cryptococcus infection after mono-chemotherapy with gemcitabine. AB - Mono-chemotherapy with gemcitabine (difluorodeoxycytidine) is an effective cancer chemotherapy, and is often used instead of a more effective but more toxic combination chemotherapy regimen. Infection associated with gemcitabine is very rare. We present a case of Cryptococcus neoformans pneumonia that developed after 5 courses of gemcitabine for advanced bladder carcinoma. Lung biopsy and antigens demonstrated C. neoformans. The pneumonia resolved after antifungal therapy. PMID- 21255490 TI - Tuberculosis-associated secondary pneumothorax: a retrospective study of 53 patients. AB - BACKGROUND: Pneumothorax is a well known complication of pulmonary tuberculosis (TB), particularly in patients with advanced TB. METHODS: At our national TB referral hospital, we compared the medical records of 53 TB patients with pneumothorax and 106 TB patients without pneumothorax, seen in 2003 to 2008. We analyzed data on demographics; TB type (smear-positive, smear-negative, extrapulmonary); patient type (new patient, relapse, treatment default, treatment failure); clinical and radiological manifestations; surgeries; and outcomes. RESULTS: Of the 53 pneumothorax patients, 34 (64%) were male. The pneumothorax group's mean age was 34 y (range 14-76 y). Thirty-six (68%) of the pneumothorax patients were new TB cases (ie, TB undiagnosed before they presented with pneumothorax). Pneumothorax was not significantly associated with sex, smoking, or drug use. Pneumothorax was significantly more common in patients < 30 years old (P < .001). In terms of radiological manifestations, 20 pneumothorax patients (38%) had cavitary lesions, and pulmonary infiltration and effusion were present in 19 (36%) and 17 (32%) patients, respectively. Cavitary lesion was significantly more common among the pneumothorax patients (P = .006). Overall, 47 (89%) of the pneumothorax patients were relieved with chest-tube insertion; the other pneumothorax patients were only observed. CONCLUSIONS: In patients < 30 years old or with cavitary lesions, worsening of the patient's respiratory condition should prompt consideration of pneumothorax. PMID- 21255491 TI - Glucose intolerance in patients with cystic fibrosis: sex-based differences in clinical score, pulmonary function, radiograph score, and 6-minute walk test. AB - OBJECTIVE: To determine the sex-specific relationships between glucose intolerance and Shwachman-Kulczycki clinical score, lung function, Brasfield chest-radiograph score, and exercise capacity in patients with cystic fibrosis (CF). METHODS: We used a cross-sectional study design and included CF patients >= 10 years old. All patients had clinical and nutritional evaluation, oral glucose tolerance test, spirometry, chest radiograph, and 6-min walk test (6MWT). Patients were classified as having normal glucose tolerance, impaired glucose tolerance, or CF-related diabetes mellitus. RESULTS: We included 88 patients: 59 with normal glucose tolerance, 15 with impaired glucose tolerance, and 14 with CF related diabetes. Shwachman-Kulczycki clinical score (P = .04), at-rest S(pO(2)) (P = .001), S(pO(2)) difference before versus after 6MWT (P = .001), and Brasfield chest-radiograph score (P = .01) were significantly lower in the impaired-glucose-tolerance group than in the normal-glucose-tolerance group, but did not differ from the CF-related-diabetes group. In female patients only, percent-of-predicted FEV(1) was significantly lower in the impaired-glucose tolerance group than in the normal-glucose-tolerance group (P = .02), but did not differ from the CF-related-diabetes group (P = .10). There was a significant relationship between glucose intolerance and sex when clinical score, 6-min walk distance, FEV(1), and radiograph score were combined in a multivariate analysis. CONCLUSIONS: In patients with CF, glucose intolerance was associated with poor clinical score, lower at-rest S(pO(2)), greater S(pO(2)) difference before versus after 6MWT, poor lung function, and lower radiograph score. Overall, multivariate analysis indicated poorer performance in the latter variables in female patients with glucose intolerance than in male patients with glucose intolerance. PMID- 21255492 TI - Classifying different types of double triggering based on airway pressure and flow deflection in mechanically ventilated patients. AB - BACKGROUND: Double-triggering (DT) is a frequent type of patient-ventilator asynchrony and has potentially severe consequences, such as alveolar overdistention or the generation of intrinsic PEEP. However, the first breath of DT could be patient-triggered (DT-P), auto-triggered (DT-A), or ventilator triggered (DT-V). OBJECTIVE: To differentiate DT-P, DT-A, and DT-V using airway pressure or flow changes during the trigger-delay phase in ventilated patients. METHODS: Fourteen mechanically ventilated patients with DT were included. All patients were on flow-triggered ventilation modes and received either continuous mandatory ventilation or pressure support ventilation. Breaths in which the first breath was associated with an esophageal pressure drop of > 1 cm H(2)O were categorized as DT-P. Breaths in which the first breath occurred at the ventilator set cycle were categorized as DT-V. Breaths in which the first breath occurred earlier than the ventilator set cycle without esophageal pressure drop were categorized as DT-A. The pressure drop and flow change at 0.13 s (PD(0.13) and F(0.13), respectively) in the trigger-delay phase were calculated from the nadir. RESULTS: There were 507 double-triggered breaths: 271 DT-V (53%), 50 DT-A (10%), and 186 DT-P (37%). The PD(0.13) for DT-V, DT-A, and DT-P were 0.16 +/- 0.12 cm H(2)O, 0.25 +/- 0.17 cm H(2)O, and 1.34 +/- 0.67 cm H(2)O, respectively. The F(0.13) for DT-V, DT-A, and DT-P were 2.11 +/- 2.31 L/min, 2.64 +/- 2.07 L/min, and 16.51 +/- 8.02 L/min, respectively. The best discriminatory criteria for differentiating DT-P from DT-V and DT-A, based on the Youden index (sensitivity + specificity - 1) was PD(0.13) >= 0.49 cm H(2)O, which had a Youden index of 95%. CONCLUSION: DT-P can be distinguished from DT-V and DT-A by using airway pressure deflections in the trigger-delay phase. PMID- 21255493 TI - Thrombolytic therapy in a patient with suspected pulmonary embolism despite a negative computed tomography pulmonary angiogram. AB - We report a case of a 62-year-old male who presented to our intensive care unit with hypoxemia 6 hours after retinal surgery. He had a negative computed tomography (CT) pulmonary angiogram, but an emergency echocardiogram revealed the McConnell sign. He was thrombolysed and had rapid improvement in oxygenation and hemodynamics. Thrombolysis in hemodynamically unstable pulmonary embolism is not controversial, but most algorithms require confirmation of the diagnosis. Our patient had a negative CT pulmonary angiogram but was thrombolysed based on the clinical picture. Autopsy confirmed the diagnosis of multiple pulmonary emboli and unexpectedly discovered a patent foramen ovale that explained paradoxical embolism to the brain. PMID- 21255494 TI - Tracheal glomus tumor: a multidisciplinary approach to management. AB - A 66-year-old man presented with acute respiratory distress due to a tracheal tumor involving the posterior wall of the upper trachea, with nearly complete airway obstruction. Partial debulking of the tumor's endoluminal component, via rigid bronchoscopy and yttrium-aluminum-perovskite laser, allowed timely and effective airway restoration. The diagnosis was benign tracheal glomus tumor. Two weeks later, elective tracheal sleeve resection with end-to-end anastomosis allowed complete resection of the lesion. No tumor recurrence was found at 21 month follow-up. We describe the multidisciplinary management of this extremely rare tracheal tumor, and review its features. PMID- 21255495 TI - Cardiac arrest following foreign-body aspiration. PMID- 21255496 TI - Neurally adjusted ventilatory assist: a ventilation tool or a ventilation toy? AB - Mechanical ventilation has, since its introduction into clinical practice, undergone a major evolution from controlled ventilation to various modes of assisted ventilation. Neurally adjusted ventilatory assist (NAVA) is the newest development. The implementation of NAVA requires the introduction of a catheter to measure the electrical activity of the diaphragm (EA(di)). NAVA relies, opposite to conventional assisted ventilation modes, on the EA(di) to trigger the ventilator breath and to adjust the ventilatory assist to the neural drive. The amplitude of the ventilator assist is determined by the instantaneous EA(di) and the NAVA level set by the clinician. The NAVA level amplifies the EA(di) signal and determines instantaneous ventilator assist on a breath-to-breath basis. Experimental and clinical data suggest superior patient-ventilator synchrony with NAVA. Patient-ventilator asynchrony is present in 25% of mechanically ventilated patients in the intensive care unit and may contribute to patient discomfort, sleep fragmentation, higher use of sedation, development of delirium, ventilator induced lung injury, prolonged mechanical ventilation, and ultimately mortality. With NAVA, the reliance on the EA(di) signal, together with an intact ventilatory drive and intact breathing reflexes, allows integration of the ventilator in the neuro-ventilatory coupling on a higher level than conventional ventilation modes. The simple monitoring of the EA(di) signal alone may provide the clinician with important information to guide ventilator management, especially during the weaning process. Although, until now, little evidence proves the superiority of NAVA on clinically relevant end points, it seems evident that patient populations (eg, COPD and small children) with major patient-ventilator asynchrony may benefit from this new ventilatory tool. PMID- 21255497 TI - Effects of mean arterial pressure and needle size on arterial sampler filling time. AB - BACKGROUND: Arterial blood sampling is subject to numerous pre-analytical errors, one of which is inadvertent venous blood sampling. Especially when assessing oxygenation and titrating ventilation, accidental venous blood sampling may lead to inappropriate respiratory care and repeated percutaneous punctures. OBJECTIVE: To determine the effects of mean systemic blood pressure and needle size on vented arterial sampler filling times, to distinguish venous and arterial sampling. METHODS: We constructed an extracorporeal laboratory model to circulate whole blood at 4 L/min. We used hemostats to create 6 pressures: 57 mm Hg (representing a patient in shock), 70 mm Hg (representing a patient with low normal blood pressure), 93 mm Hg (normal), 107 mm Hg (high-normal), 133 mm Hg (severe hypertension), and 14 (peripheral venous pressure). We simulated percutaneous punctures with vented arterial samplers preset to 2 mL, with 2 common sampling needles. We compared the filling times of each pressure/needle combination and determined the correlation between the mean pressure and filling time. RESULTS: For all the tested arterial pressures combined, the mean +/- SD sampler filling time was 15.8 +/- 0.4 s; for venous pressures the time was 51.4 +/- 1.4 s (P < .001). With the 22-gauge/1.5-inch needles the sampler filling time was 22.2 +/- 14.9 s. With the 23-gauge/1-inch needle the time was 21.4 +/- 13.1 s (difference not significant). The Pearson correlation coefficient between the mean blood pressures and the sampler filling times was r(2) = -0.86 (P = .01). CONCLUSIONS: Lower blood pressure increased the sampler filling time. Measuring the filling time may enable therapists to confirm successful arterial puncture in adult patients. Confirming successful arterial puncture prior to blood analysis would expedite appropriate patient care decisions. PMID- 21255498 TI - A preliminary randomized controlled trial to assess effectiveness of nasal high flow oxygen in intensive care patients. AB - OBJECTIVE: In a cardiothoracic and vascular intensive care unit, to compare nasal high-flow (NHF) oxygen therapy and standard high-flow face mask (HFFM) oxygen therapy in patients with mild to moderate hypoxemic respiratory failure. METHODS: In a prospective randomized comparative study, 60 patients with mild to moderate hypoxemic respiratory failure were randomized to receive NHF or HFFM. We analyzed the success of allocated therapy, noninvasive ventilation rate, and oxygenation. RESULTS: Significantly more NHF patients succeeded with their allocated therapy (P = .006). The rate of noninvasive ventilation in the NHF group was 3/29 (10%), compared with 8/27 (30%) in the HFFM group (P = .10). The NHF patients also had significantly fewer desaturations (P = .009). CONCLUSIONS: NHF oxygen therapy may be more effective than HFFM in treating mild to moderate hypoxemic respiratory failure. PMID- 21255499 TI - Symmetrical-waveform high-frequency oscillation increases artificial mucus flow without changing basal mucus transport in in vitro ovine trachea. AB - BACKGROUND: The efficacy of symmetrical-waveform high-frequency oscillating (HFO) air flow for airway secretion clearance is controversial and debated in the literature. METHODS: We conducted in vitro experiments with ovine tracheae to investigate the effects of symmetrical-waveform HFO on tracheal transport of artificial mucus. We mounted each trachea as an intact tube, with a 15(o) head down tilt, infused artificial mucus (10 mL over one hour) at the caudal end of the trachea, and measured mucus-transport velocity as the time between the beginning of infusion and the first appearance of artificial mucus over 2 near infrared sensors at the rostral end of the trachea and by measuring the amount of mucus emerging. In a second series of experiments we opened each trachea flat and with video microscopy we measured the transport velocity of plaques over the endogenous mucus sheet. RESULTS: In the intact-trachea preparation, HFO at 20 Hz and 50 cm H(2)O increased mucus-transport velocity from 5.8 mm/min to 7.8 mm/min. HFO led to nearly half the artificial mucus being cleared during the infusion period. In the opened-trachea experiments the mean control transport velocity was 8.7 mm/min, and HFO, at 14 Hz or 20 Hz (and 50 cm H(2)O), did not significantly alter that velocity. CONCLUSIONS: Symmetrical-waveform HFO increases mucus transport velocity and mucus clearance when a thick layer of mucus is present. This may be important when considering the mechanisms of mucus clearance and using HFO for secretion clearance. PMID- 21255500 TI - A risk tertiles model for predicting mortality in patients with acute respiratory distress syndrome: age, plateau pressure, and P(aO(2))/F(IO(2)) at ARDS onset can predict mortality. AB - BACKGROUND: Predicting mortality has become a necessary step for selecting patients for clinical trials and defining outcomes. We examined whether stratification by tertiles of respiratory and ventilatory variables at the onset of acute respiratory distress syndrome (ARDS) identifies patients with different risks of death in the intensive care unit. METHODS: We performed a secondary analysis of data from 220 patients included in 2 multicenter prospective independent trials of ARDS patients mechanically ventilated with a lung protective strategy. Using demographic, pulmonary, and ventilation data collected at ARDS onset, we derived and validated a simple prediction model based on a population-based stratification of variable values into low, middle, and high tertiles. The derivation cohort included 170 patients (all from one trial) and the validation cohort included 50 patients (all from a second trial). RESULTS: Tertile distribution for age, plateau airway pressure (P(plat)), and P(aO(2))/F(IO(2)) at ARDS onset identified subgroups with different mortalities, particularly for the highest-risk tertiles: age (> 62 years), P(plat) (> 29 cm H(2)O), and P(aO(2))/F(IO(2)) (< 112 mm Hg). Risk was defined by the number of coexisting high-risk tertiles: patients with no high-risk tertiles had a mortality of 12%, whereas patients with 3 high-risk tertiles had 90% mortality (P < .001). CONCLUSIONS: A prediction model based on tertiles of patient age, P(plat), and P(aO(2))/F(IO(2)) at the time the patient meets ARDS criteria identifies patients with the lowest and highest risk of intensive care unit death. PMID- 21255501 TI - Optimal PEEP guided by esophageal balloon manometry. AB - A 45-year-old female was admitted to our ICU with severe ascites, and septic shock due to an obstructive ureteric stone. Despite an F(IO(2)) of 1.0, high PEEP, and multiple recruitment maneuvers, it was challenging to obtain an S(pO(2)) > 85% after the patient was turned. We inserted an esophageal balloon to determine whether the abdominal pressure was affecting lung compliance. PEEP was guided to a level of 32 cm H(2)O to achieve a transpulmonary pressure of 0 cm H(2)O. Within 6 hours there was significant oxygenation improvement: P(aO(2))/F(IO(2)) increased from 80 mm Hg to 244 mm Hg, and oxygenation index decreased from 35 to 18. At 48 hours, P(aO(2))/F(IO(2)) was 382 mm Hg and oxygenation index was 7. Paracentesis of approximately 5 L assisted with weaning. Subsequent PEEP changes were guided by transpulmonary pressure. She was weaned from mechanical ventilation within 10 days, with no adverse sequelae associated with very high PEEP. PMID- 21255502 TI - Predicted postoperative product and diffusion heterogeneity index in the evaluation of candidates for lung resection. AB - OBJECTIVES: The primary objective of this retrospective study was to evaluate whether abnormal predicted postoperative variables and predicted postoperative product are useful in predicting postoperative complications. The secondary objective was to assess whether an abnormal diffusion heterogeneity index is associated with increased postoperative complications. METHODS: In this retrospective study we evaluated the medical records of 57 patients who underwent lung resection for lung cancer. Calculations of the predicted postoperative variables were done using preoperative testing data, including the extent of the resected lung segments. Predicted postoperative product was obtained by multiplying the predicted postoperative percent-of-predicted FEV(1) by the predicted postoperative percent-of-predicted single-breath diffusing capacity of the lung for carbon monoxide (D(LCO)). The measured product was obtained by multiplying FEV(1) by D(LCO). We derived diffusion heterogeneity index from measurements of the single-breath D(LCO) with the 3-equation method, as a measure of the heterogeneity of the distribution of gas exchange in the lung. RESULTS: Patients with complications had lower predicted postoperative FEV(1) (P < .001), lower predicted postoperative D(LCO) (P < .001), lower predicted postoperative maximal oxygen uptake (P < .001), lower predicted postoperative increase in percent-of-predicted D(LCO) at 70% work load from at-rest percent-of-predicted D(LCO) (DeltaD(LCO)%) (P < .001), lower predicted postoperative product (P < .001), and lower measured product (P = .004). Interestingly, diffusion heterogeneity index increased with exercise in [corrected] patients with complications but decreased with exercise in [corrected] patients without complications. CONCLUSIONS: The predicted postoperative variables, predicted postoperative product, measured product, and diffusion heterogeneity index are potentially useful predictors of complications in candidates for lung resection. PMID- 21255503 TI - Tiotropium for treatment of stable COPD: a meta-analysis of clinically relevant outcomes. AB - OBJECTIVE: To systematically review recent evidence on the effectiveness of tiotropium versus placebo, ipratropium, and long-acting beta(2) agonists on outcomes relevant to patients with stable COPD, including health-related quality of life, dyspnea, exacerbations and hospitalizations. METHODS: Our inclusion criteria for trials were: >= 12 weeks; compared tiotropium to placebo, ipratropium, or long-acting beta agonists; patients >= 40 y old and with stable COPD. Sixteen trials (16,301 patients) met the inclusion criteria. RESULTS: Tiotropium improved health-related quality of life (measured with St George's Respiratory Questionnaire) compared to placebo (odds ratio [OR] 1.61, 95% CI 1.38 1.88, P < .001) and ipratropium (OR 2.03, 95% CI 1.34-3.07, P = .001). Tiotropium also improved dyspnea (measured with the Transitional Dyspnea Index) compared to placebo (OR 1.96, 95% CI 1.58-2.44, P < .001) and ipratropium (OR 2.10, 95% CI 1.28-3.44, P = .003). Tiotropium decreased the likelihood of an exacerbation (OR 0.83, 95% CI 0.72-0.94, P = .004) and related hospitalizations (OR 0.89, 95% CI 0.80-0.98, P = .02) but not serious adverse events (OR 1.06, 95% CI 0.97-1.17, P = .19), compared to placebo. The cumulative incidence of dry mouth was 7.4% with tiotropium, compared to 3.9% with ipratropium, 1.6% with salmeterol, and 2.0% with placebo. CONCLUSIONS: In stable COPD, tiotropium showed superior efficacy in improving quality of life and dyspnea, compared to placebo and ipratropium. However, tiotropium's differences with salmeterol were less clear. PMID- 21255504 TI - Customization of an open-lung ventilation strategy to treat a case of life threatening acute respiratory distress syndrome. AB - The ARDS Network low-tidal-volume protocol is considered the standard of care for patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). The protocol is built on the foundation of low-tidal-volume ventilation, use of a combined PEEP and F(IO(2)) table, and managing alveolar end-inspiratory pressure by limiting the plateau airway pressure to <= 30 cm H(2)O. Although this strategy, to date, is the only method that significantly improves ALI/ARDS survival, alternative methods of improving hypoxemia and minimizing ventilator induced lung injury, in conjunction with low-tidal-volume ventilation, can be used for life-threatening ARDS. We present a case in which we customized the use of alveolar recruitment maneuvers by analyzing the hysteresis of the pressure volume curve to assess lung recruitability, decremental PEEP to sustain lung recruitment, and careful use of plateau pressure >= 30 cm H(2)O, which improved our patient's life-threatening hypoxemia within the first 36 min of arrival to our ICU. PMID- 21255505 TI - Electrocardiographic guidance for the placement of gastric feeding tubes: a pediatric case series. AB - BACKGROUND: The placement of nasal or oral gastric tubes is one of the most frequently performed procedures in critically ill children; tube malposition, particularly in the trachea, is an important complication. Neurally adjusted ventilatory assist (NAVA) ventilation (available only on the Servo-i ventilator, Maquet Critical Care, Solna, Sweden) requires a proprietary-design catheter (Maquet Critical Care, Solna, Sweden) with embedded electrodes that detect the electrical activity of the diaphragm (EA(di)). The EA(di) catheter has the potential benefit of confirming proper positioning of a gastric catheter, based on and the EA(di) waveforms. METHODS: In a case series study, our multidisciplinary team used EA(di) guidance for immediate, real-time confirmation of proper nasal or oral gastric tube placement in 20 mechanically ventilated pediatric patients who underwent 23 oral or nasal gastric tube placements. The catheters were placed with our standard practice, with the addition of a team member monitoring the EA(di) waveforms. As the tube passes down the esophagus and posterior to the heart, a characteristic EA(di) pattern is identified and the position of the atrial signal confirms correct placement of the gastric tube. If the EA(di) waveforms indicate incorrect placement, the tube is repositioned until the proper EA(di) waveform pattern is obtained. Then proper tube placement is reconfirmed via auscultation over the stomach while air is injected into the catheter, checking the pH of fluid suctioned from the catheter (gastric pH indicates correct positioning), and/or radiograph. RESULTS: The group's median age was 3 years (range 4 d to 16 y). All 20 patients had successful gastric catheter placement. The EA(di) catheter provided characteristic patterns for correctly placed tubes, tubes malpositioned above or below the gastroesophageal junction, and curled tubes. Proper catheter position was confirmed via radiograph and/or gastric pH in all 20 patients. CONCLUSIONS: EA(di) guidance helps confirm proper gastric catheter position, is equivalent to our standard practice for confirming gastric catheter placement, and may reduce the need for radiographs and improve patient safety by avoiding catheter malpositions. PMID- 21255506 TI - Acute respiratory failure in a patient with spontaneous esophageal rupture (Boerhaave syndrome). PMID- 21255507 TI - Hematologic abnormalities associated with lung carcinoma. PMID- 21255508 TI - Assessment of accuracy of the Vacu-Med 17053 calibrator for ventilation, oxygen uptake (V(O(2))), and carbon dioxide production (V(CO(2))). AB - BACKGROUND: Few have examined the accuracy of mechanical calibrators used to calibrate metabolic monitors. OBJECTIVE: To evaluate the Vacu-Med 17053 motorized syringe calibrator for accuracy against the accepted standard method: the Douglas bag. METHODS: We tested oxygen consumption values (V(O(2))) of 522-3,210 mL/min. We mixed room air and calibration gases in the pumping syringes of the Vacu-Med 17053 and evacuated those gases into a Douglas bag, measured the Douglas bag volumes and concentrations, and converted to pulmonary ventilation, V(O(2)), and carbon dioxide production (V(CO(2))). RESULTS: The Vacu-Med 17053 calibrator overestimated V(O(2)) by a mean 28.6 mL/min (1.3% error), underestimated V(CO(2)) by 6.9 mL/min (-1.7% error), and underestimated pulmonary ventilation by 0.98 L/min (-1.4% error). The V(O(2)) and V(CO(2)) differences between the calibrator and the Douglas bag were larger at higher V(O(2)) levels. CONCLUSIONS: The V(O(2)) and V(CO(2)) differences might be attributable to fluctuations of the calibrator settings. The Vacu-Med 17053 calibrator was accurate with the application of a mathematical correction. PMID- 21255509 TI - Effects on aerosol performance of mixing of either budesonide or beclomethasone dipropionate with albuterol and ipratropium bromide. AB - BACKGROUND: Mixing of nebulized drugs is common in real life, but its consequences on aerosol output and granulometry are poorly known. METHODS: In an in vitro study I evaluated the effects on aerosol output, drug output, and aerosol particle size characteristics of mixing either beclomethasone dipropionate or budesonide with albuterol and ipratropium bromide. I tested the SideStream and VentStream-Pro nebulizers, run with the AirClinic compressor. Using the same fill volume in all experiments, I nebulized and evaluated each studied drug alone, and 2 drug mixtures: beclomethasone plus albuterol plus ipratropium; and budesonide plus albuterol plus ipratropium. I measured aerosol output via gravimetrics. I measured drug delivery by collecting the aerosol on a filter in the inspiratory limb, and the residual solution in the reservoir and the circuit after nebulization, and assayed those liquids with chromatography. I measured particle size distribution via cascade impaction. RESULTS: Mixing tended to reduce drug output and to increase mass median aerodynamic diameter with the SideStream, but not always with the VentStream-Pro. However, the drug output always remained satisfactory and the mass median aerodynamic diameters were within the respirable range. When nebulized alone, the respirable mass of bronchodilators ranged from 18% to 40% of the nominal dose; when mixed, it ranged from 13% to 37%. When nebulized alone, the respirable mass of corticosteroids ranged from 10% to 24% of the nominal dose; when mixed, it ranged from 10% to 17%. CONCLUSIONS: Both the SideStream and VentStream-Pro have good aerosol performance in nebulizing budesonide or beclomethasone dipropionate alone, and when mixed with albuterol and ipratropium bromide. PMID- 21255510 TI - Diagnostic utility of plasma procalcitonin for nosocomial pneumonia in the intensive care unit setting. AB - BACKGROUND: Nosocomial pneumonia is a difficult diagnosis to establish in the intensive care unit setting, due to the non-specific nature of the clinical and radiographic findings. Procalcitonin is a circulating biomarker that may become elevated in the presence of bacterial infection. METHODS: We conducted a prospective single-center cohort study at Barnes-Jewish Hospital, a 1,200-bed urban teaching hospital in St Louis, Missouri. In medical and surgical intensive care unit patients with suspected nosocomial pneumonia we measured plasma procalcitonin with an enzyme-linked fluorescent assay. RESULTS: We evaluated 104 consecutive patients with suspected nosocomial pneumonia, 67 (64%) of whom met our predefined clinical and microbiologic criteria for definite nosocomial pneumonia. Though the mean procalcitonin concentration was greater in the 67 patients with definite nosocomial pneumonia (18.3 +/- 99.1 ng/mL, median 0.8 ng/mL, 5th percentile 0.0 ng/mL, 95th percentile 43.1 ng/mL) than in the 12 patients with definite absence of nosocomial pneumonia (1.7 +/- 2.0 ng/mL, median 1.0 ng/mL, 5th percentile 0.0 ng/mL, 95th percentile 6.7 ng/mL), this difference was not statistically significant (P = .66). A procalcitonin cutoff value of > 1 ng/mL yielded a diagnostic sensitivity of 50% and a specificity of 49% for definite nosocomial pneumonia. Receiver operating curve and multivariate logistic regression analyses demonstrated that procalcitonin is inferior to clinical variables for diagnosing nosocomial pneumonia. However, compared to patients with an initial procalcitonin > 1 ng/mL, those with lower procalcitonin had fewer total antibiotic days (13.0 +/- 10.3 d vs 19.7 +/- 12.0 d, P < .001) and fewer antibiotic days for treatment of nosocomial pneumonia (10.0 +/- 5.9 d vs 14.7 +/- 7.4 d, P < .001). CONCLUSIONS: Plasma procalcitonin has minimal diagnostic value for nosocomial pneumonia. PMID- 21255511 TI - Pilot study of a new device to titrate oxygen flow in hypoxic patients on long term oxygen therapy. AB - BACKGROUND: The O(2) Flow Regulator (Dima, Bologna, Italy) is a new automated oxygen regulator that titrates the oxygen flow based on a pulse-oximetry signal to maintain a target S(pO(2)). We tested the device's safety and efficacy. METHODS: We enrolled 18 subjects with chronic lung disease, exercise-induced desaturation, and on long-term oxygen therapy, in a randomized crossover study with 2 constant-work-load 15-min cycling exercise tests, starting with the patient's previously prescribed usual oxygen flow. In one test the oxygen flow was titrated manually by the respiratory therapist, and in the other test the oxygen flow was titrated by the O(2) Flow Regulator, to maintain an S(pO(2)) of 94%. We measured S(pO(2)) throughout each test, the time spent by the respiratory therapist to set the device or to manually regulate the oxygen flow, and the total number of respiratory-therapist titration interventions during the trial. RESULTS: There were no differences in symptoms or heart rate between the exercise tests. Compared to the respiratory-therapist-controlled tests, during the O(2) Flow Regulator tests S(pO(2)) was significantly higher (95 +/- 2% vs 93 +/- 3%, P = .04), significantly less time was spent below the target S(pO(2)) (171 +/- 187 s vs 340 +/- 220 s, P < .001), and the O(2) Flow Regulator tests required significantly less respiratory therapist time (5.6 +/- 3.7 min vs 2.0 +/- 0.1 min, P = .005). CONCLUSIONS: The O(2) Flow Regulator may be a safe and effective alternative to manual oxygen titration during exercise in hypoxic patients. It provided stable S(pO(2)) and avoided desaturations in our subjects. PMID- 21255512 TI - Capnography/Capnometry during mechanical ventilation: 2011. AB - We searched the MEDLINE, CINAHL, and Cochrane Library databases for articles published between January 1990 and November 2010. The update of this clinical practice guideline is based on 234 clinical studies and systematic reviews, 19 review articles that investigated capnography/capnometry during mechanical ventilation, and the 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. The following recommendations are made following the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) scoring system: (1) Continuous-waveform capnography is recommended, in addition to clinical assessment to confirm and monitor correct placement of an endotracheal tube. (2) If waveform capnography is not available, a non-waveform exhaled CO(2) monitor, in addition to clinical assessment, is suggested as the initial method for confirming correct tube placement in a patient in cardiac arrest. (3) End-tidal CO(2) (P(ETCO(2))) is suggested to guide ventilator management. (4) Continuous capnometry during transport of the mechanically ventilated patients is suggested. (5) Capnography is suggested to identify abnormalities of exhaled air flow. (6) Volumetric capnography is suggested to assess CO(2) elimination and the ratio of dead-space volume to tidal volume (V(D)/V(T)) to optimize mechanical ventilation. (7) Quantitative waveform capnography is suggested in intubated patients to monitor cardiopulmonary quality, optimize chest compressions, and detect return of spontaneous circulation during chest compressions or when rhythm check reveals an organized rhythm. PMID- 21255513 TI - [Overview of Revista Alergia Mexico and editorial farewell]. PMID- 21255514 TI - [For a new era]. PMID- 21255515 TI - [Atopic dermatitis in scholar children from Ciudad Guzman, Mexico. Prevalence and related factors]. AB - BACKGROUND: Atopic dermatitis is an ever more frequent disease in children; its etiology is unknown, although a genetic predisposition along with environment factors could be the origin. OBJECTIVE: To determine the prevalence of atopic dermatitis among school-children and the main associated risk factors. PATIENTS AND METHODS: A randomized, stratified and conglomerated sample of 6 to 12 year old school-children was obtained. Their parents answered the main ISAAC questionnaire, to which some variables were added, such as family and hereditary history, tobacco smoking exposure and nutritional condition according to the body mass index as associated risk factors. RESULTS: We found a prevalence of 3% for atopic dermatitis, and the presence of dermatitis symptoms during the last twelve months was found in 6.8% of the cases. Multivariate analysis demonstrated an elevated risk for atopic dermatitis in children of mothers with any type of allergic disease (OR 2.75, CI 95% 1.09 to 6.92, p = 0.031). CONCLUSIONS: The frequency of atopic dermatitis as well as that of the symptoms was low, similar to previous reports conducted in Mexico. Maternal atopy was the only factor associated with atopic dermatitis. PMID- 21255516 TI - [Adverse reactions to mosquito bites in scholars from Monterrey, Nuevo Leon, Mexico]. AB - BACKGROUND: Allergic reactions to insect bites are a global problem, the true incidence and prevalence of morbidity from adverse reactions to mosquito bites are unknown. OBJECTIVE: To describe the adverse reactions to mosquito bites in school-age children of Monterrey, Nuevo Leon. MATERIAL AND METHODS: A cross sectional descriptive study was made via a randomized application of questionnaires to children from public elementary schools in the metropolitan area of Monterrey, Nuevo Leon. RESULTS: A total of 11 public schools randomly selected were included in the study. One thousand questionnaires were submitted, of which 506 fulfilled the inclusion criteria; 55% were females. Seventy-six percent referred adverse reactions to mosquito bites, itching (75%) and rash (72%) being the most frequent ones, in the last 12 months. CONCLUSIONS: Adverse reactions to mosquito bites occur frequently. Early detection is important to establish a prompt treatment. PMID- 21255517 TI - [Non-allergic chronic rhinitis]. AB - OBJECTIVE: To review the existent literature regarding non-allergic rhinitis. DATA SOURCES: PubMed search was performed using the key words: non-allergic rhinitis, vasomotor rhinitis, irritant rhinitis, idiopathic rhinitis, chronic rhinopathy, nociceptive dysfunction, capsaicin, entopy. STUDY SELECTION: Articles were selected based on their relevance to this review. RESULTS: Chronic rhinitis affects up to 20% of the general population. The term rhinitis (inflammation of the nasal mucosal membrane) is used in daily practice for nasal dysfunction causing symptoms like nasal itching, sneezing, rhinorrhea, and or nasal blockage. When allergy, mechanical obstruction, and infections have been excluded as the cause of rhinitis, a number of poorly defined nasal conditions of partly unknown etiology and pathophysiology remain. The differential diagnosis of non-allergic noninfectious rhinitis is extensive. If the pathophysiology is unknown, the term idiopathic rhinitis is used as well as vasomotor rhinitis. This term has been recently questioned and the term non-allergic rhinopathy has been proposed with the subsequent definition and inclusion criteria delineated; other forms include irritative-toxic (occupational) rhinitis, hormonal rhinitis, drug-induced rhinitis, non-allergic rhinitis with eosinophilia syndrome, rhinitis due to physical and chemical factors, food-induced rhinitis, emotion-induced rhinitis, atrophic rhinitis. CONCLUSIONS: The number of patients with non-allergic, non infectious rhinitis as a known cause or precipitant factor has increased in the last years. Nevertheless, 50% of the patients have to be classified as non allergic rhinitis, known today as non-allergic rhinopathy. It's important for this group of patients to be evaluated by an expert in Rhinology and Allergy to determine the best possible treatment. PMID- 21255518 TI - [Keratoconus in allergic patients. A report of three cases]. AB - Keratoconus is a disease that causes variable degrees of vision loss. Some patients need to undergo corneal transplantation due to disease severity. The development of keratoconus has been strongly associated to allergic and dermatologic diseases such as atopic dermatitis. Keratoconus is a poorly diagnosed condition and as it is of utmost importance to identify it at an early stage, we present three cases of patients with the disease with multidisciplinary management. We emphasize the importance of referring these patients for their subsequent evaluation by specialists. PMID- 21255519 TI - Rapid desensitization to chemotherapy drugs in oncologic patients. A good and safe option. A two-case presentation. AB - Hypersensitivity reactions, and anaphylactic or anaphylactoid reactions to oncologic chemotherapy drugs, such as platinum, taxanes, monoclonal antibodies and others, limit their therapeutic use due to the fear of the treating physician to induce severe or deadly reactions in patients who have presented previous reactions to the same. This leads to the use of less effective or second line chemotherapy schemes for the sensitivity of the tumor. The rapid desensitization to such medications in patients who have presented previous reactions is a safe and proven effective procedure, which allows the use of the most effective chemotherapy drugs for the tumor sensitivity in oncologic patients even if they have presented hypersensitivity reactions to those drugs previously. In spite of the effectiveness, safety and tolerance demonstrated in fast desensitization to chemotherapy drug protocols in previous works, it remains an underutilized procedure, perhaps due to ignorance and/or fear of triggering a serious reaction in patients. Two successful cases of fast desensitization are hereby presented, one with trastuzumab (Herceptin), a monoclonal antibody, and another with docetaxel (Taxotere), a semisynthetic taxane, both products utilized for the treatment of breast cancer. The purpose of this presentation is to disseminate among oncologists, allergists, nurses applying chemotherapy and in general to all medical personnel related to cancer patients, the benefits of such rapid desensitization to chemotherapy drug protocols in patients with previous hypersensitivity reactions. The relative ease to accomplish them and the high percentage of success that is achieved encourage us to promote more frequent and universal use of these procedures. PMID- 21255520 TI - [Obituary: manuel romero herrera (1929-2010)]. PMID- 21255521 TI - [Ethics in medical journal reports]. PMID- 21255522 TI - [Basis to modify the immunotherapy regimen at the Allergy Service, General Hospital of Mexico]. AB - BACKGROUND: In Mexico, the way allergen immunotherapy is performed has remained without changes for many years. Here we present the modifications that have been performed in the General Hospital of Mexico to make immunotherapy more effective. OBJECTIVE: To show the changes implemented to make immunotherapy faster and more effective by changing the volume of allergy vaccines from 5 or 10 mL to 3 mL, and the theoretical and practical support for the change. MATERIAL AND METHOD: The amount of protein delivered in each immunotherapy shot was computed to show how they change along the treatment. Results for schedules for 3, 5 and 10 mL were compared. RESULTS: Results showed serial rises and falls in protein amount injected every time a new vaccine flask starts to be used. However, in the case for 3 mL vaccines schedules, those changes are less pronounced. CONCLUSIONS: Due to these results we suggest a schedule of immunotherapy with 3 mL vaccines that allow getting the maintenance doses in a shorter time and at lower cost. PMID- 21255523 TI - [Theophylline, a new look to an old drug]. AB - OBJECTIVES: To emphasize the safety and efficacy of theophylline in chronic inflammatory respiratory diseases. To mention its immunomodulatory effects. DATA SOURCES: PubMed search using the keywords: theophylline, histone deacetylase, antiinflammatory, asthma, chronic obstructive pulmonary disease (COPD), corticoresistance. RESULTS: Theophylline is a methylxantine, that inhibits phosphodiesterase (PDE), induces histone deacetylase and antagonizes adenosine. Its main effect is to relax airway smooth muscle. The immunomodulatory effects of theophylline are obtained at low plasma concentrations (less than 10 mg/L). The combination of inhaled corticoesteroids and theophylline exerts a synergistic antiinflammatory effect that improves asthma control and reduces COPD exacerbations. Histones are a group of transcriptional cofactors involved in chromatin remodeling. Histone deacetylases (HDACs) suppress inflammatory gene expression. In patients with COPD and severe asthma there is a reduction in HDAC 2 secondary to the increased oxidative and nitrative stress. HDAC-2 is required by corticosteroids to switch off activated inflammatory genes, then its reduction favors corticosteroid resistance. Theophylline via HDAC-2 induction and PDE inhibition, suppresses inflammatory gene expression, and inhibits free oxygen radicals production. CONCLUSIONS: Theophylline at low plasma concentrations exerts antiinflammatory effects, restoring corticosteroid sensitivity in COPD and severe asthma. PMID- 21255524 TI - Total control of asthma: an evaluation in patients of a tertiary hospital. AB - BACKGROUND: Asthma control is an important goal of international asthma guidelines, but in most reports total control is reached in a small proportion of cases. OBJECTIVE: To know the degree of asthma control, the percentage of ER visits and hospitalizations in the last month and in the last year, and the type of pharmacologic treatment for asthma in a tertiary hospital. PATIENTS AND METHOD: This is an observational study in asthmatic patients from 12 to 60 years old, with more than one year of treatment, who answered the questionnaire of Asthma Control Test (ACT). RESULTS: A total of 204 patients were included, 116 women and 88 men, with an average age of 24 years. We observed that 19 patients (9.3%) were in total control of asthma: scored 25 ACT points, 88 patients (43.1%) scored 20-24 points (non total control) and 97 patients (47.5%) less than 20 points (asthma not controlled). According to the asthma severity index, 125 patients had intermittent symptoms (61.3%), and persistent symptoms were present in 79 patients. In the previous month 8.3% of patients had ER visits and 2.9% were hospitalized; in the previous year the ER visits and hospitalizations percentages were 33.3% and 14.2%, respectively. Inhaled steroids were used by 12.2% of the patients, long-action beta2 agonists by 9.8% and daily short action beta2 agonists by 28%. CONCLUSIONS: Total control of asthma was observed in less than 10% of our patients-sample; the majority of them had intermittent asthma; the pattern of medication was inadequate, with misuse of inhaled steroids and an elevated use of inhaled rescue medications. PMID- 21255525 TI - [Hypersensitivity to metals in patients with orthopedic implants]. AB - All metals in contact with biological systems suffer corrosion, which is an electrochemical process that causes metallic ions formation, known as haptens, which link with endogenous or exogenous proteins, therefore inducing an immune response. A hypersensitivity response to an implanted material should be suspected when cutaneous lesions or inflammatory reactions occur proximal to or surrounding the site of the metallic orthopedic implant. At present there is no a reliable diagnostic test for the determination of hypersensitivity to implanted metallic devices. It has been shown that the products of corrosive degradation are associated with dermatitis, urticaria and vasculitis. Cutaneous lesions in patients with unsuccessful metallic implants are more frequent than in non rejected implants or the general population. Although the cellular and humoral hypersensitivity response in metallic orthopedic implants has been clearly identified, the risk is very low. Nowadays the importance of hypersensitivity to metals as a contributing factor in the failure of implants is unknown. PMID- 21255526 TI - Exenatide - pharmacokinetics, pharmacodynamics, safety and tolerability in patients >= 75 years of age with Type 2 diabetes. AB - OBJECTIVE: This study evaluated pharmacokinetics, pharmacodynamics,safety, and tolerability of single doses of exenatide in elderly Type 2 diabetes (T2D)patients. METHODS: This placebo-controlled,patient-blind, crossover study compared elderly patients (>= 75 y, n = 15) to controls( >= 45 to <= 65y, n = 15) with T2D. Patients were randomized to single subcutaneous doses of exenatide 5MUg, placebo or exenatide 10 MUg (Sequence 1) or placebo, exenatide 5 MUg or exenatide 10 MUg (Sequence 2) before a standardized breakfast over three consecutive days. Serial blood samples were collected for plasma exenatide and serum glucose concentrations.Pharmacokinetic data from this study were also integrated with those from six other clinical pharmacology studies to further evaluate the impact of age on plasma exenatide apparent clearance (CL/F) (139 controls ( <= 65 y); 28 elderly patients (> 65 y)). RESULTS: Mean +/- SD ages for control and elderly patients were 57 +/- 6 y and 78 +/- 3 y, respectively.All elderly patients had renal impairment at baseline, as compared with one third of controls. Dose-normalized plasma exenatide maximum concentration and exposure were greater in elderly patients, but between-age group differences were neither statistically significant nor considered clinically relevant. The integrated pharmacokinetic analysis showed a significant linear relationship between plasma exenatide CL/F and renal clearance (test of slope = 0, p < 0.001),with no additional effect from age. Exenatide dose-dependently blunted postprandial serum glucose excursions in both age groups. No hypoglycemia or serious adverse events were reported, and exenatide was generally well tolerated in both age groups. CONCLUSIONS: Exenatide dose adjustments should be determined by renal function rather than age in elderly T2D patients. PMID- 21255527 TI - A phase I, single-dose study of the disposition of 14C-radiolabeled gabapentin enacarbil in healthy male volunteers. AB - Gabapentin enacarbil (GEn) is a prodrug of gabapentin that is effective in restless legs syndrome (RLS) and has dose-proportional gabapentin exposure. OBJECTIVE: This Phase I, open-label, non-randomized, single-center study of 14C GEn in healthy male volunteers (XenoPort, Inc. protocol: XP065) characterized the mass balance, absorption, metabolism, and elimination pathways of GEn after oral administration of 14C-GEn. METHODS: Subjects received GEn 600 mg as two gelatin capsules containing 300 mg immediate release GEn solution each with approximately 50 uCi of 14C-GEn. Pharmacokinetic assessments included total radioactivity excreted in urine (Aeu(0-t)) and feces (Aef(0-t)), mean maximum concentration (Cmax), 14C-GEn-derived radioactivity in plasma and whole blood, and gabapentin area under the concentration-time curve extrapolated to infinity (AUC0-inf). Tolerability was assessed using adverse events (AEs), vital signs, clinical laboratory tests, and ECGs. Six male subjects aged 24 - 46 years were recruited to the study. RESULTS: Mean total recovery of 14C-GEn-derived radioactivity was 99.3% (94.1% in urine and 5.2% in feces). Mean Cmax and AUC for GEn-derived total radioactivity were similar in whole blood and plasma; the blood to plasma ratio for 14C-GEn-derived total radioactivity was 0.91. 14C-gabapentin was the only radioactive species present in blood. More than 85% of the radioactive dose was recovered in urine within 24 h of dosing. Eight treatment-emergent AEs were reported by 3 subjects; all were mild in intensity. There were no clinically relevant changes in vital signs, laboratory values, or ECGs. CONCLUSIONS: GEn was extensively absorbed and rapidly eliminated from plasma and whole blood. PMID- 21255528 TI - Controlling pain in the post-operative setting. AB - BACKGROUND AND AIMS: Post-operative pain (POP) is a form of acute, intense pain experienced in the period following surgery, whose adequate control is often problematic. This paper reviews determinants and characteristics of POP, together with rationale and current protocols for its management. DETERMINANTS/CONSEQUENCES OF POP: Main determinants of POP are the type of intervention and the disease motivating surgery, though other factors related to patient (age, pain threshold, socio-cultural factors, personality) and setting (pre-operative information, relationship with medical staff) may also influence its perception. POP control is essential to relieve suffering but also to prevent dangerous consequences on organ systems, e.g., reduced cough, atelectasis, increased myocardial oxygen consumption and ischemia, constipation, urinary retention, reduced musculoskeletal mobility and increased risk of deep venous thrombosis. MANAGEMENT OF POP: Constant assessment of pain intensity is recommended for optimal POP control. This is mostly achieved pharmacologically with monitoring of side-effects. Multi-modal analgesia is recommended, combining different drug classes, e.g., an opioid (morphine, pethidine, fentanyl, tramadol, codeine) with a non-opioid (NSAID; Cox-2 inhibitor), delivered through various routes, and including neuraxial use of local anesthetics (bupivacaine, ropivacaine) alone or in combination with other drugs, nerve blocks, antihyperalgesics (ketamine, dextromethorphan) and techniques such as patient controlled analgesia (PCA) and pre-emptive analgesia. An efficient organization of pain services is also recommended. CONCLUSION: Acute post-surgical pain represents a crucial problem, but the multimodal therapeutic approach has enhanced the efficacy of pain-control while minimizing side-effects of each modality. Further improvement of POP control will necessarily involve better organization of pain services. PMID- 21255529 TI - Steady state pharmacokinetics and dose equivalents of oral clodronate in renal failure. AB - OBJECTIVE: Clodronate is used in the treatment of osteoporosis, and malignancy associated bone disease. The steady state pharmacokinetics and the dose equivalents of oral clodronate were assessed in subjects with various degrees of renal failure. MATERIALS AND METHODS: 1,600 mg of clodronate was given orally mornings for 11 days to 14 healthy volunteers (creatinine clearance, CLCr, > 80 ml/min), and 18, 12 and 16 subjects with mild (50 - 80 ml/min), moderate (30 - 50 ml/min) and severe (< 30 ml/min) renal failure, respectively. Trough drug levels at 4, 7 and 11 days, and concentration-time curves for 72 h after the last dose were followed. RESULTS: In all study groups, the trough drug levels achieved the kinetic steady state within 11 days. The area under the 24-h concentration-time curve (AUC0-24) enlarged and the elimination half-life (t1/2elim) prolonged progressively when the renal function was impaired. The maximum drug level and the time to maximum were not changed significantly in the renal failure. In the steady state phase, the diurnal drug excretion (E0-24) was not changed by the kidney function, but the renal drug clearance (CLD) decreased in close correlation with CLCr. The normal-to-failed AUC0-24 ratios in mild, moderate, and severe renal failure were 0.53, 0.43 and 0.31, respectively, when the ideally matched counterpart was assumed as the normal reference to each renal failure group. CONCLUSIONS: In mild, moderate and severe renal failure, 53%, 43% and 31% oral clodronate doses, respectively, resulted in drug AUCs similar to those in controls with normal (> 80 ml/min) CLCR. PMID- 21255530 TI - Pharmacoepidemiological profiles of prescriptions for antihypertensive agents among ethnic Chinese patients. AB - OBJECTIVE: We compared the short- and long-term cumulative incidences of add-on therapy across the major anti-hypertensive drug classes among Chinese patients who had newly received an antihypertensive agent. MATERIALS AND METHODS: We analyzed 16,154 adult patients with uncomplicated hypertension who had newly received an antihypertensive monotherapy in one large territory of Hong Kong during January 2004 to June 2007. We compared the cumulative incidences of and factors associated with add-on therapy by drug classes at 180 days and 360 days using binary logistic regression analyses. RESULTS: The crude cumulative incidences of add-on therapy at 180 days were not statistically significantly different among those receiving thiazide diuretics (6.26%), b-blockers (5.99%), calcium channel blockers (CCB) (5.95%) or drugs acting on the renin angiotensin system (RAS) (4.41%), and these figures were similar at 360 days (both p = 0.213). The odds ratios of add-on therapy for RAS (0.72, 95% CI 0.49 - 1.06), thiazide diuretics (1.08, 95% CI 0.85 - 1.37) and beta-blockers (1.02, 95% CI 0.86 - 1.22) were not statistically significant compared to CCB at 180 days and 360 days. Male patients and younger subjects were more likely to receive an add on therapy in both time frames. CONCLUSIONS: This study suggested that the major antihypertensive drug classes had similar add-on rates in real-life clinical practice. PMID- 21255531 TI - Correlation between the pharmacological efficacy of cyclosporine and tacrolimus as evaluated by the lymphocyte immunosuppressant sensitivity test (LIST) and the MTT assay procedure in patients before and after renal transplantation. AB - OBJECTIVES: Cyclosporine and tacrolimus are calcineurin inhibitors that are used to prevent acute rejection in renal transplant recipients. The lymphocyte immunosuppressant sensitivity test (LIST) can predict the pharmacological efficacy of these immunosuppressive agents for renal transplant recipients. There is a correlation between cyclosporine and tacrolimus pharmacological efficacy as evaluated by LIST by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay procedure prior to renal transplantation. However, the LIST can also evaluate patients before and after the transplantation. MATERIALS AND METHODS: The present study examined the relationship between cyclosporine and tacrolimus pharmacological efficacy by LIST using the MTT assay in 16 renal transplant recipients at 1, 3 and 12 months after transplantation, as well as before the operation. RESULTS: The relationship of cyclosporine and tacrolimus pharmacological efficacy gave a significant Kendall and Spearman's coefficient correlation in these transplant recipients by the LIST using the MTT assay procedure immediately prior to renal transplantation (rk = 0.711, rs = 0.877, p < 0.01). Furthermore, correlations between the cyclosporine and tacrolimus IC50 values were also observed with a significant Kendall and Spearman's coefficient correlation at 1 and 12 months after transplantation (rk1month = 0.65, rs1month = 0.829, p < 0.01, and k12month = 0.433, rs12month = 0.603, p < 0.01, respectively). However, no statistically significant relationship was observed between the pharmacological efficacies of the calcineurin inhibitors at 3 months after transplantation (rk3month = 0.117, rs3month = 0.1, p > 0.05). CONCLUSIONS: Both cyclosporine and tacrolimus exhibit pharmacological efficacy by the inhibition of calcineurin. However, the correlation between cyclosporine and tacrolimus pharmacological efficacies may be altered, due to immunosuppressive therapy or clinical events at 3 months after renal transplantation. PMID- 21255532 TI - Safety, tolerability and pharmacokinetics of single escalating doses of indacaterol, a once-daily beta2-agonist bronchodilator, in subjects with COPD. AB - OBJECTIVES: To assess the safety and tolerability of 4 doses of indacaterol, a once-daily beta2-agonist, in subjects with chronic obstructive pulmonary disease (COPD). The 24-h bronchodilator effect and pharmacokinetics of indacaterol were also investigated. METHODS: 16 subjects aged 43 - 72 years with mild/moderate COPD were each given single doses of indacaterol of 400, 1,000, 2,000 and 3,000 ug, via a single-dose dry powder inhaler. RESULTS: Changes from predose (400, 1,000, 2,000, 3,000 ug doses, respectively) were as follows. Maximum mean decreases in fasting (up to 2 h post-dose) serum potassium were 0.12, 0.30, 0.38, 0.26 mmol/l; maximum mean increases (up to 2 h post-dose) in fasting serum glucose were 0.12, 0.40, 0.87, 1.01 mmol/l. The maximum increase in heart rate (by 3, 6, 12, 13 beats/min, respectively) was within 1 h post-dose. No clinically significant electrocardiogram abnormalities were reported. Most adverse events were mild or moderate, with none considered serious or leading to withdrawal. Indacaterol was rapidly absorbed and displayed multiphasic disposition kinetics. The terminal elimination phase with a half-life of 50 - 63 h could only be seen for doses of 1,000 ug or higher. Mean systemic exposure to indacaterol (AUC0-24) increased by ~ 9-fold from 400 to 3,000 ug. CONCLUSION: Even at doses far in excess of the therapeutic range, indacaterol had minimal systemic effects; such changes would be considered within safe limits for a single dose. PMID- 21255533 TI - Pharmacokinetic interaction between efavirenz and rifampicin in healthy volunteers. AB - OBJECTIVE: Rifampicin induces the metabolism of efavirenz in humans. This study evaluated efavirenz bioavailability after rifampicin administration to healthy volunteers. METHODS: A 3-week, before-and-after trial was performed on 8 healthy volunteers. The pharmacokinetic parameters were: plasma drug concentration-time profile from 0 to 72 h (AUC0-72), plasma drug concentration-time profile from 0 h to infinity (AUC0-inf), maximal drug concentration (Cmax), time to reach maximal drug concentration (tmax), and time to reach half the initial drug concentration in elimination phase (t1/2). After an overnight fast, the volunteers ingested one efavirenz 600 mg tablet, then blood samples were drawn to evaluate plasma efavirenz levels at 0, 2, 3, 4, 5, 6, 24, 72, 120, and 168 h. The procedure was repeated after a 1-week induction period of 450 mg/day. Paired-t test and Wilcoxon matched-pairs test were used for differences between mean concentrations. RESULTS: Baseline mean AUC0-72 was 46.80 +/- 9.27 ug/ml.h, AUC0 inf was 96.38 +/- 38.10 ug/ml.h, Cmax 2.19 +/- 0.68 ug/ml.h, tmax 4.50 +/- 0.93 h, and t1/2 96.60 +/- 42.38 h. Post-induction values were significantly increased: AUC0-72 9.53 +/- 11.26 ug/ml.h (p < 0.05; CI95% = 0.112 - 18.940), AUC0-inf 37.24 +/- 42.43 (p < 0.05; CI95% = 0.021 - 0.406) ug/ml.h, and tmax 1.13 +/- 0.99 h (p < 0.05; CI95% = 0.296 - 1.953). No significant reduction occurred in post-rifampicin induction means of Cmax and t1/2. CONCLUSION: Co administration of a single dose of efavirenz 600 mg/day with 1-week rifampicin 450 mg/day significantly reduced efavirenz bioavailability in healthy volunteers. PMID- 21255534 TI - Evaluation of bioequivalence between a single-capsule formulation of esomeprazole 40 mg and acetylsalicylic acid 325 mg and the monotherapies given separately in healthy volunteers. AB - OBJECTIVE: The aim of this study was to investigate the bioequivalence of a single oral dose of esomeprazole 40 mg and acetylsalicylic acid 325 mg when formulated as a single capsule, relative to the components given as separate monotherapies. METHODS: This was an open, randomized, single-center, single-dose, 2-stage group sequential design, 2-way crossover study (NCT00688428) in 49 healthy adult volunteers (29 women). In each treatment period, subjects received a single dose of esomeprazole 40 mg and ASA 325 mg formulated as a single capsule or as separate monotherapies given in combination. Treatment periods were separated by a washout period of at least 6 days. The bioequivalence of a single capsule formulation of esomeprazole 40 mg and ASA 325 mg relative to the monotherapies given individually was assessed by the geometric mean ratios of the area under the plasma concentration-time curve (AUC) and observed maximum plasma concentration (Cmax). If the 94% confidence interval (CI) of the geometric mean ratios of AUC and Cmax were within 0.80 - 1.25, bioequivalence would be established. A 94% CI was used to compensate for the multiple analyses of the study design, and to assure that the actual overall confidence level was 90%. RESULTS: The geometric mean ratios of the AUC for esomeprazole 40 mg and ASA 325 mg when administered in the single capsule formulation, relative to the monotherapies were 0.97 (94% CI, 0.90 - 1.04) and 1.04 (94% CI, 1.00 - 1.08). The corresponding mean geometric ratios for Cmax were 0.99 (94% CI, 0.90 - 1.09) and 1.02 (94% CI, 0.92 - 1.13). CONCLUSIONS: Treatment with esomeprazole 40 mg and ASA 325 mg formulated as a single capsule is bioequivalent to the separate monotherapies of esomeprazole 40 mg and ASA 325 mg when given in combination as separately-administered drugs in healthy adult subjects. PMID- 21255535 TI - Tolerability of quetiapine in children and adolescents with Tourette's syndrome. PMID- 21255537 TI - FOXP3+ regulatory T-cells in renal allografts: correlation with long-term graft function and acute rejection. AB - BACKGROUND: The interpretation of a cellular infiltrate as cytotoxic or tolerogen represents an unsolved challenge in current transplantation. The so-called regulatory CD4+ CD25+ T-cells which express the FOXP3 gene have received increasing interest with respect to this question. The existing studies concerning the role of FOXP3+ Tregs for transplant tolerance yielded contradictory results. METHODS: We examined the numbers of the FOXP3+ Tregs in two groups of renal allograft biopsies both showing cellular infiltration, but either without (n=29) or with signs of acute cellular rejection (n=26), by means of immunofluorescence and correlated the amount of FOXP3+ Tregs to renal function at the time of biopsy and after 1 and 2 years of follow up. RESULTS: The number of FOXP3+ Tregs within infiltrates in non-rejecting biopsies did not correlate with renal function after 1 and 2 years. There were no significant differences in the numbers of FOXP3+ Tregs between biopsies with or without borderline infiltrates. Increased numbers of FOXP3+ Tregs were not associated with an ameliorated severity of graft rejection and did not correlate with outcome after the rejection episode and renal function after 1 and 2 years. CONCLUSIONS: The identification of the FOXP3+ regulatory cells within the allograft cannot be considered as an appropriate marker for the interpretation of infiltrates as cytotoxic or tolerogenic or as a prognostic marker for later transplant function. PMID- 21255538 TI - Is monitoring of FOXP3 Treg cells in renal transplants during acute cellular rejection episodes useful? AB - BACKGROUND: The FOXP3 (forkhead Box p3) transcription factor is a marker for T regulatory cells (Treg). During cellular immune responses, Treg are expected to increase in number to ultimately control and limit this response. In renal transplants massive infiltration by T cells is often seen during rejection crises. This prompted us to examine changes in the numbers of FOXP3 positive T cells accompanying acute cellular rejection events. METHODS: A total of 32 transplant biopsies from 23 patients were studied retrospectively, these 16 protocol biopsies and 16 biopsies taken during rejection episodes included 9 serial pairs (protocol-rejection). To quantify FOXP3 positive T cells, frozen sections were double immunostained with anti-CD3 and anti-FOXP3 antibodies. Areas revealing T cell infiltrates were measured morphometrically and the number of FOXP3 positive cells per 1,000 um2 of CD3 positive cells was taken as an FOXP3 index. RESULTS: This index was 0.46 (median, range 0.00-1.00) in the 16 protocol biopsies and 0.48 (median, range 0.16-2.31) in rejection episode biopsies. The highest values were seen during rejection crises, exceeding 1.00 in 6/16 biopsies, whereas no protocol biopsies had values greater than 1.00 (0/16) (difference significant p<0.02). In serial biopsies no consistent behavior was observed; the FOXP3 index remained unchanged, fell slightly or rose to a maximum of 13 fold. Expression levels of FOXP3 could vary within weeks. No correlations were found between donor type, initial therapy, therapy at biopsy, serum creatinine at the time of biopsy, at 3 months or 1 year later, and any of the morphometric parameters (CD3 and FOXP3) studied. CONCLUSIONS: During rejection of renal allografts the fraction of FOXP3+ Treg cells within the infiltrating T-cell population can increase transiently. This phenomenon was not consistently seen in acute cellular rejection and the information does not appear to be of value for individual patient management in such cases. PMID- 21255539 TI - Ezetimibe is effective in the treatment of persistent hyperlipidemia of renal allograft recipients. AB - INTRODUCTION: Ezetimibe is a hypolipidemic agent acting via inhibition of cholesterol absorption from the small intestine. The effectiveness and safety of long-term administration of ezetimibe was evaluated in renal allograft recipients with persistent hyperlipidemia. PATIENTS AND METHODS: 67 renal allograft recipients with post-transplantation hyperlipidemia resistant to statins were included in the study; 11 were treated with ezetimibe (10 mg/day) alone and 56 with ezetimibe and statin. The effectiveness of ezetimibe was assessed by determination of total cholesterol (TC), LDL cholesterol (LDL-C), HDL cholesterol (HDL-C) and triglycerides (TR). Its safety was determined by liver enzymes (ALT, AST), LDH, CPK, serum creatinine and blood levels of immunosuppressive drugs (cyclosporine, tacrolimus, everolimus, sirolimus) over the follow-up period of 18+/-6 months. RESULTS: A significant reduction of TC and LDL-C blood levels by 25% and 34% respectively, was observed during the first month of treatment with ezetimibe (p<0.001). This reduction was maintained for the whole period of ezetimibe administration. Renal function remained stable over the follow-up period, while no changes of the blood levels of immunosuppressive drugs were observed. Liver enzymes, LDH and CPK remained normal in all patients except for one diabetic patient who developed rhabdomyolysis. Apart from gastrointestinal symptoms in 2 patients, no other side effects were observed. CONCLUSION: Combination of ezetimibe with statins represents an effective and safe regimen for treatment of persistent hyperlipidemia in renal allograft recipients. PMID- 21255540 TI - Arteriovenous access creation defers chronic hemodialysis initiation. AB - AIMS: This study evaluated whether arteriovenous access (AVA) creation before hemodialysis might affect the rate of decline of renal function. METHODS: This was a retrospective, case-control study comparing two groups of 80 patients each. The AVA group underwent AVA creation more than 2 months before initiation of chronic hemodialysis (CHD). The catheter group (i.e., the control group) commenced CHD through a temporary catheter. The catheter group patients were matched with AVA group patients in terms of age, gender, nature of underlying disease, and rate of decline in estimated glomerular filtration rate (eGFR) before AVA creation. The zero point (Z-point) was defined as the date of AVA creation for AVA patients, or the date on which the same eGFR was attained by each catheter group patient compared with a matched AVA patient. Time-to-dialysis was defined as the interval from the Z-point to the date of initiation of dialysis. The rates of change in eGFR before and after the Z-point were also measured. RESULTS: The AVA and catheter groups were similar in terms of baseline characteristics. The Z-point eGFR (ml/min/1.73 m2) was 11.4+/-3.1 in the AVA group and 11.3+/-3.2 in the catheter group. The eGFR at the time of dialysis was 6.4+/-2.0 in the AVA group and 6.1+/-1.9 in the catheter group. The mean and median dialysis-free time was longer in the AVA than in the catheter group (14.2+/-9.4 vs. 5.9+/-4.1 months, 13.1 (3-41) vs. 5.0 (2-17) months, p<0.001). Multivariate proportional Cox's hazard modeling showed that the AVA group and the Z-point eGFR were each independent predictors of the time to initiation of CHD. The mean changes in eGFR per month (delta eGFR) before the Z-point were similar for the two groups. For the AVA group, the mean delta eGFR was lower after the Z point compared to before (-0.63 vs. -0.21 ml/min/1.73 m2, p=0.002). For the catheter group, the mean delta eGFR was similar before and after the Z-point ( 0.63 vs. -0.67 ml/min/1.73 m2). The mean delta eGFR after the Z-point was less in the AVA group compared to the catheter group (-0.67 vs. -0.21 ml/min/1.73 m2, p=0.002). CONCLUSION: In this retrospective observational study, AVA creation appears to retard the rate of decline in eGFR and to defer CHD initiation. PMID- 21255541 TI - A new form of myeloma "kidney": shortened hemofilter survival and implications for membrane filtration plasmapheresis. AB - BACKGROUND: Despite rigorous focus on extracorporeal CRRT parameters such as access, blood flow, hemoconcentration, and anticoagulation, some patients have unexpected repetitive hemofilter clotting. We instead explored patient or disease related factors that could be responsible, and present a case of plasma cell dyscrasia in which paraproteins caused hollow fiber failure. METHODS: A patient with IgG kappa chain multiple myeloma complicated by sepsis and acute renal failure was started on CVVH with a regional citrate anticoagulation protocol that typically yields filter life of >50 h. Polysulfone hemofilters repetitively clotted every 2-4 h, even after excluding circuit-related problems. Failed filters were examined by light, electron (EM), and immunofluorescence (IF) microscopy. RESULTS: Imaging of the hemofilters revealed several ultrastructural features typical for myeloma-associated alterations in native human tissue. Red cell rouleaux formation occurred within the hollow fibers. There was extensive protein layering on the luminal surface of the fibers with some extension into their walls: these deposits were IF+ for IgG kappa, and had a fibrillary substructure on EM. CONCLUSION: Extracorporeal hollow fiber phenomena recapitulate many intra-corporeal paraprotein effects such as those described in the kidney with plasma cell dyscrasias. Rapid protein layering suggests fouling of the membrane, decreased solute clearance before total device failure, and raises the theoretical concern that this might also occur during filtration plasmapheresis: we thus suggest serial serum free light chain levels to confirm their removal when using that technique. These findings emphasize the importance of disease rather than circuit-related factors that are under-appreciated causes of premature hemofilter failure. PMID- 21255542 TI - Social support from health care providers is associated with reduced illness intrusiveness in hemodialysis patients. AB - BACKGROUND: End-stage renal disease (ESRD) disrupts patients' life styles, interests and activities negatively affecting their quality of life. Social support has been previously associated with favorable health outcomes. However, no study has examined the association of social support from health care providers with perceived health and ESRD intrusiveness on patients' lives. METHODS: A self-administered questionnaire was completed by 1,238 Italian hemodialysis patients. The Self-Rated Health (SRH) and the Illness Intrusiveness Rating Scale (IIRS) assessed disease burden. 10 items assessed social support from health care providers (SS-HC). The nursing staff of each center provided patients' clinical information. Linear regression was used to assess correlates of SRH and IIRS. Mediational analysis was used to assess direct and indirect associations of SS-HC with SRH through IIRS. RESULTS: Higher SS-HC was associated with smaller IIRS and higher SRH. Further correlates of better SRH were younger age, no post-dialysis hypotension, no diabetes and cardiovascular diseases, better sleep quality, and smaller burden of oral therapy. CONCLUSIONS: Our results suggest that social support might reduce illness burden and improve patients' perceived health. Further research should assess the efficacy and cost effectiveness of structured support programs for dialysis patients. PMID- 21255543 TI - Erectile dysfunction in male hemodialysis patients in China--one center experience. AB - OBJECTIVE: To evaluate the prevalence and the risk factors of erectile dysfunction in a Chinese cohort of hemodialysis (HD) patients. METHODS: 63 male hemodialysis patients were assigned to HD group and 47 health volunteers were recruited as controls. The International Index of Erectile Function (IIEF-5) was used to assess erectile dysfunction (ED). All data were obtained by patient interviews and medical chart review. We measured the blood sex hormone of all the patients and volunteers. We divided those under 50 years HD patients into two groups according to erectile function (EF) score, Group A: EF score>=12, no ED or mild ED; Group B: EF score<12, moderate or severe ED. RESULTS: The incidence of ED was significantly higher and the erectile function score was significantly lower in the HD group than that in the control group. The level of follicle stimulating hormone, luteinizing hormone, prolactin, estradiol, progesterone were significantly higher and the level of testosterone was significantly lower in the HD group than that in the control group. Patients in Group A were younger and duration of dialysis were shorter than patients in Group B. The level of high density lipoprotein was higher and FSH was lower in Group A than that in Group B. A significant negative correlation was found between the EF score and the age, duration of dialysis, the level of FSH and PRL in the HD group. There was a positive correlation trend between EF score and T level, but this did not reach statistical significance (p>0.05). More patients had hypertension in the HD group. CONCLUSION: The age, duration of dialysis, hypertension, lipid disorder, the abnormality of hypothalamic-pituitary-gonadal axis were risk factors for ED in HD patients. PMID- 21255544 TI - Metabolic syndrome loses its predictive power in late-stage chronic kidney disease progression--a paradoxical phenomenon. AB - BACKGROUND: Metabolic syndrome (MS) is a significant determinant of CKD. The aim of this study was to determine the possible impact of MS on CKD progression. METHODS: 746 CKD subjects were included. The presence of MS was determined according to the modified criteria proposed by the Adult Treatment Panel (ATP) III. The study endpoints were stage-to-stage CKD progression or starting renal replacement therapy during the study period. CKD Stages 1, 2 and 3 were defined as early-stage CKD, while CKD Stages 4 and 5 were defined as late-stage CKD. RESULTS: Early-stage CKD patients with MS had a higher risk of CKD progression than those without MS. Cox regression analysis showed that MS was a significant determinant of CKD progression in early-stage (HR: 1.60, p=0.041) but not late stage CKD patients (HR: 1.00, p=0.975). The results of subgroup analysis in non diabetic subjects also showed that only early-stage CKD subjects with MS had significant risks of CKD progression (HR: 2.21, p=0.010). In diabetic patients, the association between MS and CKD progression was not significant in both early- and late-stage CKD. CONCLUSIONS: Our findings suggested that the impact of MS on CKD progression might be prominent in non-diabetic early-stage CKD subjects, and became non-significant in diabetic late-stage CKD and diabetic CKD patients. PMID- 21255545 TI - Chronic kidney disease after orthotopic liver transplantation in recipients receiving tacrolimus. AB - INTRODUCTION: Chronic kidney disease (CKD) is common in liver transplant recipients receiving calcineurin inhibitors. METHOD AND POPULATION: The goals of this case-control study were to identify risk factors associated with CKD and its effect on mortality in 294 liver transplant recipients receiving calcineurin inhibition with tacrolimus. RESULTS: Hepatitis C virus (HCV) was the most common indication (42%) for transplantation. CKD 4 and 5 (estimated glomerular filtration rate (eGFR) of <=29 ml/min/1.73 m2) developed in 10.8% of recipients during a mean follow-up of 52 months. The incidence density of CKD was 2.56 per 100 patient-years. End-stage renal disease developed in 2.7%. By univariate analysis, CKD patients were older (mean+/-sd, 57+/-10 vs. 51+/-11, p<0.05) with hypertension (56 vs. 32%, p<0.05), had lower preoperative hematocrit (31+/-6 vs. 34+/-5, p<0.05), alanine aminotransferase (median (95% confidence limit) 46 (34 80) vs. 68 (56-77), <0.05) and eGFR (56+/-28 vs. 91+/-35 ml/ min/1.73 m2, p<0.05), had higher preoperative prothrombin time (16.1 (14.6-17.2) vs. 14.8 (14.5-15.1) seconds, p<0.05), and required more perioperative renal replacement therapy (RRT) (41% vs. 6.5%, p<0.05) compared to controls. Perioperative need for RRT (hazard ratio (95% CI) 2.72 (1.05-7.03)) and lower preoperative eGFR: 60-89 (4.08 (1.23-13.5)), 30-59 (4.26 (1.18-15.36)), and<=29 (5.91 ((1.28-27.19)) vs. eGFR>=90 ml/min/1.73 m2 were independently associated with development of CKD adjusting for important covariates. The development of CKD (2.36 (1.22-4.59)) was independently associated with late mortality with an attributable risk of 12.8%. CONCLUSION: Data demonstrate that CKD is an important clinical event associated with increased risk for death after primary liver transplantation. PMID- 21255546 TI - Glomerulocystic kidney disease in an adult with enlarged kidneys: a case report and review of the literature. AB - We report the case of a 31-year-old male with enlarged kidneys and glomerulocystic kidney disease (GCKD). The patient had no family history of renal disease or other diseases. On initial presentation he complained of poor eyesight, and hypertensive retinopathy and elevated serum creatinine (5.0 mg/dl) were found at that time. Renal biopsy showed cystic dilatation of Bowman's capsule and atrophy of the glomerular tuft. Thus, an adult case of sporadic GCKD was diagnosed. Based on previous reports, kidney size in patients with adult type GCKD varies from small to large. Our patient's kidneys are the largest ever reported (right kidney was 22 cm*10 cm, left kidney was 19 cm*10 cm). A review of the literature dealing with sporadic adult GCKD suggested that it is difficult to diagnose this disease early in its course. PMID- 21255547 TI - Successfully treated multicentric Castleman's disease with renal thrombotic microangiopathy using rituximab and corticosteroid. AB - Thrombotic microangiopathy (TMA) is a rare renal complication accompanied with Castleman's disease. We report the first case of TMA combined plasma cell type multicentric Castleman's disease (MCD) which was successfully treated with rituximab and corticosteroid. A previously healthy 60-year-old Korean man was admitted due to acute renal failure, thrombocytopenia, and multiple lymphadenopathies. The result of lymph node biopsy was plasma cell type Castleman's disease and TMA was revealed by kidney biopsy. After treatment with rituximab, prednisolone and temporary hemodialysis, complete remission was achieved. The combination of corticosteroid and rituximab was associated with improvement for this patient. PMID- 21255548 TI - Successful treatment of life-threatening pentoxifylline intoxication by high-flux hemodialysis. AB - High-flux hemodialysis is the method of choice for the treatment of many life threatening intoxications. Reports on intoxication with pentoxifylline are rare, and although pharmacokinetic properties of the drug suggest a potential role for hemodialysis, there are no published reports on extracorporeal treatment attempts. We report the first case of successful treatment of potentially life threatening pentoxifylline intoxication by high-flux hemodialysis. Based on this single case, dialysis should be considered, especially in anuric patients with pentoxifylline intoxication. PMID- 21255549 TI - Arteriovenous dialysis access-associated transvenous pacemaker infection. AB - Pacemaker (PM), implantable cardioverter defibrillator and cardiac resynchronization therapy devices also provide support to chronic hemodialysis patients with cardiac rhythm abnormalities. However, these devices can get infected. In general, device infection is either primary or metastatic spread from a distant source. Arteriovenous grafts are commonly used to provide dialysis therapy. Compared to a fistula an arteriovenous graft runs a higher risk of infection. In this analysis, we report 2 chronic hemodialysis patients who have been successfully receiving dialysis through an arteriovenous graft for approximately 2 years. Both had had a PM device for about the same duration. Access infection necessitated surgical removal of the arteriovenous graft in these patients. However, due to bacteremia (methicillin-resistant Staphylococcal aureus (MRSA)), infection spread to involve the transvenous PM leads in both patients. In 1 patient the infection also involved the PM pocket. Lead and wound culture confirmed MRSA in both patients. PM device and leads were removed in both patients. After the resolution of bacteremia, both patients received an epicardial pacemaker. None of the patients had valvular endocarditis. While dialysis was provided with a catheter, an arteriovenous fistula was planned. In conclusion, contamination of the transvenous PM device can occur due to hematogenous spread of infection from an infected arteriovenous graft. Epicardial instead of a transvenous PM might be the better option for such patients to provide long-term cardiac rhythm support. PMID- 21255550 TI - Early recurrence of Type 2 diabetic nephropathy after kidney transplantation. PMID- 21255551 TI - MMTV-Cre transgenes can adversely affect lactation: considerations for conditional gene deletion in mammary tissue. AB - CRE-loxP-mediated inactivation and activation of genes in mouse mammary epithelium have been widely used to study genetic pathways in normal development and neoplastic transformation in vivo. In 1997, we generated three distinct mouse lines carrying an identical MMTV-Cre transgene (lines A, D, and F). Because the presence of CRE recombinase can adversely affect the physiology of nonmammary cells, we explored whether transgenic females display lactational defects. Whereas dams from line D nurse their pups and display overtly normal mammary development, line A shows some impairment during lactation and females from line F completely fail to nurse their litters. The ability to nurse a litter correlates with the extent of alveolar development and differentiation. This study demonstrates the importance of including appropriate "Cre-only" controls and provides guidelines to avoid problems in data interpretation. PMID- 21255552 TI - Quantification of arginine and its metabolites in human erythrocytes using liquid chromatography-tandem mass spectrometry. AB - Erythrocytes may affect several physiological processes because they are scavengers, vehicles, and (as recently highlighted) a producer of nitric oxide (NO). NO bioavailability is linked to arginine, its metabolic products ornithine and citrulline, and methylarginines. Here we describe a liquid chromatography tandem mass spectrometry method for the simultaneous quantification of analytes involved in the Arg/NO metabolic pathway in erythrocytes. Calibration functions were linear, and the interday coefficients of variation were less than 10%. Limit of quantification values make this method suitable for low concentration samples. The method presented here allows easy sample preparation and provides a valuable tool for the evaluation of the Arg/NO metabolic pathway in erythrocytes. PMID- 21255553 TI - Automated in-solution protein digestion using a commonly available high performance liquid chromatography autosampler. AB - A completely automated peptide mapping liquid chromatography/mass spectrometry (LC/MS) system for characterization of therapeutic proteins in which a common high-performance liquid chromatography (HPLC) autosampler is used for automated sample preparation, including protein denaturation, reduction, alkylation, and enzymatic digestion, is described. The digested protein samples are then automatically subjected to LC/MS analysis using the same HPLC system. The system was used for peptide mapping of monoclonal antibodies (mAbs), known as a challenging group of therapeutic proteins for achieving complete coverage and quantitative representation of all peptides. Detailed sample preparation protocols, using an Agilent HPLC system, are described for Lys-C digestion of mAbs with intact disulfide bonds and tryptic digestion of mAbs after reduction and alkylation. The automated procedure of Lys-C digestion of nonreduced antibody, followed by postdigestion disulfide reduction, produces both the nonreduced and reduced digests that facilitate disulfide linkage analysis. The automated peptide mapping LC/MS system has great utility in preparing and analyzing multiple samples for protein characterization, identification, and quantification of posttranslational modifications during process and formulation development as well as for protein identity and quality control. PMID- 21255554 TI - Visualization of ceramide channels by transmission electron microscopy. AB - Functional studies have shown that the sphingolipid ceramide, self-assembles in phospholipid membranes to form large channels capable of allowing proteins to cross the membrane. Here these channels are visualized by negative stain transmission electron microscopy. The images contain features consistent with stain-filled pores having a roughly circular profile. There is no indication of tilt, and the results are consistent with the formation of right cylinders. The sizes of the pores range from 5 to 40nm in diameter with an asymmetric distribution indicating no apparent upper size limit. The size distribution matches well with the distribution of sizes calculated from electrophysiological measurements. PMID- 21255555 TI - Patch clamp analysis of the respiratory chain in Bacillus subtilis. AB - Bacillus subtilis is a representative Gram-positive bacterium. In aerobic conditions, this bacterium can generate an electrochemical potential across the membrane with aerobic respiration. Here, we developed the patch clamp method to analyze the respiratory chain in B. subtilis. First, we prepared giant protoplasts (GPs) from B. subtilis cells. Electron micrographs and fluorescent micrographs revealed that GPs of B. subtilis had a vacuole-like structure and that the intravacuolar area was completely separated from the cytoplasmic area. Acidification of the interior of the isolated and purified vacuole-like structure, due to H(+) translocation after the addition of NADH, revealed that they consisted of everted cytoplasmic membranes. We called these giant provacuoles (GVs) and again applied the patch clamp technique. When NADH was added as an electron donor for the respiratory system, a significant NADH-induced current was observed. Inhibition of KCN and 2-heptyl-4-hydroxyquinoline-N-oxide (HQNO) demonstrated that this current is certainly due to aerobic respiration in B. subtilis. This is the first step for more detailed analyses of respiratory chain in B. subtilis, especially H(+) translocation mechanism. PMID- 21255556 TI - Loss of lysophosphatidic acid receptor-3 enhances cell migration in rat lung tumor cells. AB - Lysophosphatidic acid (LPA) indicates several biological effects, such as cell proliferation, differentiation and migration. LPA interacts with G protein coupled transmembrane LPA receptors. In our previous report, we detected that loss of the LPA receptor-1 (Lpar1) expression is due to its aberrant DNA methylation in rat tumor cell lines. In this study, to assess an involvement of the other LPA receptor, Lpar3, in the pathogenesis of rat lung tumor cells, we measured the expression levels of the Lpar3 gene and its DNA methylation status by reverse transcription (RT)-polymerase chain reaction (PCR) and bisulfite sequencing analyses, respectively. RLCNR lung adenocarcinoma cells showed reduced expression of the Lpar3, compared with normal lung tissues. In the 5' upstream region of the Lpar3, normal lung tissues were unmethylated. By contrast, RLCNR cells were highly methylated, correlating with reduced expressions of the Lpar3. Based on these results, we generated the Lpar3-expressing RLCNR-a3 cells and measured the cell migration ability. Interestingly, the cell migration of RLCNR a3 cells was significantly lower than that of RLCNR cells. This study suggests that loss of the Lpar3 due to aberrant DNA methylation may be involved in the progression of rat lung tumor cells. PMID- 21255557 TI - The regulation of tooth morphogenesis is associated with epithelial cell proliferation and the expression of Sonic hedgehog through epithelial-mesenchymal interactions. AB - Ectodermal organs, such as the tooth, salivary gland, hair, and mammary gland, develop through reciprocal epithelial-mesenchymal interactions. Tooth morphologies are defined by the crown width and tooth length (macro morphologies), and by the number and locations of the cusp and roots (micro morphologies). In our current study, we report that the crown width of a bioengineered molar tooth, which was reconstructed using dissociated epithelial and mesenchymal cells via an organ germ method, can be regulated by the contact area between epithelial and mesenchymal cell layers. We further show that this is associated with cell proliferation and Sonic hedgehog (Shh) expression in the inner enamel epithelium after the germ stage has formed a secondary enamel knot. We also demonstrate that the cusp number is significantly correlated with the crown width of the bioengineered tooth. These findings suggest that the tooth micro-morphology, i.e. the cusp formation, is regulated after the tooth width, or macro-morphology, is determined. These findings also suggest that the spatiotemporal patterning of cell proliferation and the Shh expression areas in the epithelium regulate the crown width and cusp formation of the developing tooth. PMID- 21255558 TI - Effects of estrogen on the neuromuscular system in the embryonic zebrafish (Danio rerio). AB - Estrogen (E2) has been shown to play an important role in maintaining central nervous system (CNS) axonal growth, synapse formation, and neurotransmitter release; however, there is less direct evidence for a similar role in the peripheral nervous system (PNS). In a previous study we have shown that when E2 was removed from embryonic zebrafish (Danio rerio) system using the aromatase inhibiter (AI) 4-hydroxyandrostenedione (4-OH-A) fish did not developmentally express normal sensory-motor (S-M) functions such as tactile, vestibular, and swimming behaviors, creating a condition called 'listless.' These findings led to speculation that E2 deprivation, under these conditions, caused a neuromuscular like "denervation" resulting in the 'listless' condition. Morphometric data analysis reported in this study indicated that there was an absence of vesicular acetylcholine transporter (VAChT) staining in the primary motor neurons as a result of AI treatment compared to controls. In contrast, E2 co-treatment with AI (E2+AI) rescued a significant number of VAChT stained nerve endings and treatment of fish with E2 alone exhibited a significantly higher number of VAChT profiles than in control fish. In addition, in the AI treated group znp-1 antibody staining of the primary motor neurons demonstrated: 1) diminished axon branching; 2) shorter primary axons; and 3) an absence in the posterior trunk regions of fish. In turn, trunk muscles were significantly diminished in size and less organized when treated with AI when compared to controls and E2+AI treatment restored myotome width and height accompanied by some dramatic changes in the alpha-bungarotoxin-labeled ACh post-synaptic receptor elements of the trunk skeletal muscles. Data from this study suggest that treatment with the AI 4-OH-A essentially denervates the zebrafish trunk skeletal muscles, most likely by compromising the development of the vesicular transport system for ACh preventing it from acting at the synaptic terminals. These findings begin to demonstrate the prominent role that E2 plays in the developing zebrafish PNS, particularly at the neuromuscular level. PMID- 21255559 TI - Prenatal water deprivation alters brain angiotensin system and dipsogenic changes in the offspring. AB - OBJECTIVE: Central renin-angiotensin system (RAS) plays an important role in regulating body fluid balance. The present study determined the effect of maternal dehydration on brain expression levels of angiotensinogen, angiotensin II receptor subtypes, and dipsogenic responses in offspring. METHODS: Pregnant rats were deprived of water during late gestation. Expressions of brain angiotensinogen, angiotensin II receptors, and dipsogenic responses were determined. RESULTS: Maternal water deprivation significantly decreased fetal body and brain weight, and body and tail length. Fetal plasma sodium, osmolality, and hematocrit were increased. Both AT(1)R and AT(2)R protein abundance was significantly increased in the fetal brain, associating with increased mRNA levels of AT(1a)R and AT(2)R. Additionally, angiotensinogen mRNA was increased. In adult offspring, prenatal dehydration resulted in significant increases in AT(1)R protein and AT(1a)R mRNA, as well as angiotensinogen mRNA in the forebrain in both males and females. In contrast, AT(2)R mRNA and protein were increased only in males. Prenatal dehydration resulted in a significant increase in intracerebroventricular angiotensin II-induced water intake in male, but not female, offspring. CONCLUSION: The results provided new information that antenatal water deprivation induces a reprogramming of brain RAS and Ang II receptor expression patterns and alters the central Ang II-mediated dipsogenic response in offspring in a sex-dependent manner. PMID- 21255560 TI - Differential effects of intrauterine growth restriction on brain structure and development in preterm infants: a magnetic resonance imaging study. AB - Previous evidence suggests that preterm newborns with intrauterine growth restriction (IUGR) have specific neurostructural and neurodevelopmental anomalies, but it is unknown whether these effects persist in early childhood. We studied a sample of 18 preterm IUGR, 15 preterm AGA - born between 26 and 34 weeks of gestational age (GA) - and 15 healthy born-term infants. Infants were scanned at 12 months corrected age (CA), in a 3T scanner, without sedation. Analyses were made by automated lobar volumetry and voxel-based morphometry (VBM). The neurodevelopmental outcome was assessed in all subjects at 18 months CA with the Bayley Scale for Infant and Toddler Development, third edition. IUGR infants had reduced relative volumes for the insular and temporal lobes. According to VBM, IUGR infants had bilateral reduced gray matter (GM) in the temporal, parietal, frontal, and insular regions compared with the other groups. IUGR infants had increased white matter (WM) in temporal regions compared to the AGA group and in frontal, parietal, occipital, and insular regions compared to the term group. They also showed decreased WM in the cerebellum and a non significant trend in the hippocampus compared to term infants. IUGR infants had reduced neurodevelopmental scores, which were positively correlated with GM in various regions. These data suggest that the IUGR induces a distinct brain pattern of structural changes that persist at 1 year of life and are associated with specific developmental difficulties. PMID- 21255561 TI - Identification of SEC61beta and its autoantibody as biomarkers for colorectal cancer. AB - BACKGROUND: To identify novel serological biomarkers for human colorectal cancer (CRC), we analyzed CRC tissues using gel-assisted digestion and isobaric tags with related and absolute quantitation (iTRAQ) labeling mass spectrometry (MS). By comparing pairs of tumor tissues and matched normal tissues, we discovered the SEC61beta with expression changes 3.3-fold and a marginal statistical significance (p=0.052) previously. METHODS: SEC61beta expression in CRC tissues was further analyzed by western blotting and immunohistochemistry. We next assessed the putative diagnostic value of the SEC61beta autoantibody as a serum marker. RESULTS: Using western blotting analysis, SEC61beta expression was increased 1.9-fold in tumor tissues. Immunohistochemical analysis of 64 CRC specimens showed that SEC61beta was positively detected in 64% of the tumors, but weakly or not detected in >80% of the adjacent nontumor epithelial cells. Western blot analysis with plasma samples showed that the sensitivity and specificity of the SEC61beta autoantibody from patients with CRC were 79% and 75%, respectively. Importantly, the results of the SEC61beta autoantibody for early detection of colorectal cancer revealed a higher sensitivity of 77% than the carcinoembryonic antigen (CEA) assay. CONCLUSIONS: Measurement of SEC61beta autoantibody levels may provide an alternative detection indicator for CRC, particularly among early stage patients. PMID- 21255562 TI - The imbalance of Th17/Treg in patients with uterine cervical cancer. AB - BACKGROUND: Th17/Treg was reported to play critical roles in immunoregulation, and its imbalance may lead to autoimmune diseases and allergic reactions. Information on Th17/Treg in cancer bearing hosts is still limited. METHODS: We examined the expression of IL-17, Foxp3 and IL-10 in uterine cervical cancer (UCC) patients, cervical intraepithelial neoplasia (CIN) patients and healthy controls by flow cytometry and enzyme-linked immunosorbent assay. Interleukin (IL)-17-producing CD4+ cells as Th17 and CD4+CD25+Foxp3+ cells as Treg were expressed as a percentage of the total CD4+ cells. RESULTS: Compared with controls, patients with UCC or CIN had a higher proportion of Th17 cells. UCC patients also revealed a significant increase in Treg number and IL-17 and IL-10 concentrations in plasma, while CIN patients did not. Notably, in UCC patients, the increased Th17 prevalence was associated with clinical stage, lymph node metastases and vasoinvasion, while the increased Treg frequency was associated with tumor differentiation. Remarkably, an attractive imbalance of Th17/Treg was observed in UUC and CIN patients. Furthermore, in UCC patients with lymph node metastases or vasoinvasion, the ratio of Th17/Treg was significantly higher than that in negative patients respectively. CONCLUSIONS: Our results indicated a possible role of Th17 in UCC patients correlated to Treg cells, and the imbalance of Th17/Treg may be involved in the development and progression of UCC. PMID- 21255563 TI - Diagnostic utility of an anti-CCP point-of-care immunotest in Chinese patients with rheumatoid arthritis. AB - BACKGROUND: Early and accurate diagnosis of rheumatoid arthritis (RA) has become increasingly important. The clinical significance of anti-cyclic citrullinated peptide (CCP) antibody in Chinese RA adults was studied using an anti-CCP2 rapid test. METHODS: Anti-CCP antibody and rheumatoid factor (RF) were determined in 95 RA patients and 140 patients with rheumatic diseases other than RA. RESULTS: Two hundred and thirty five subjects were enrolled in this study. Both sensitivity and specificity of anti-CCP2 ELISA (78.9% & 95.7%) were higher than those of RF (67.4% & 84.3%). The area under the receiver operating characteristic curve for anti-CCP2 ELISA was 0.852 (95% CI: 0.792-0.913) which was larger than that for RF 0.775 (95% CI: 0.710-0.840). Both sensitivity and specificity (75.8% and 92.9%) of the anti-CCP2 rapid test were comparable to the ELISA. However, the sensitivity (62.1%) of a combined strategy by measuring anti-CCP antibody and RF was even lower than either marker alone although the specificity (98.6%) was slightly improved. CONCLUSIONS: Anti-CCP antibody is a valuable tool for diagnosis of RA in Chinese patients. With the use of the reliable and user friendly anti-CCP rapid test, it may have an important role in the design of therapeutic strategies in RA patients. PMID- 21255564 TI - Patient acuity exacerbates discrepancy between whole blood and plasma methods through error in molality to molarity conversion: "Mind the gap!". AB - OBJECTIVE: A mathematical constant factor is proposed to convert measured whole blood glucose molality to plasma-equivalent molarity. The objective of this study was to determine the distributions of conversion factors for groups of patients with different acuity and to assess the gap or error in plasma-equivalent glucose reporting that would occur when a mathematical constant conversion factor is used in patients. METHODS: Distributions of hematocrit, red blood cell water and plasma water were determined in patients from the community, hospital and adult intensive care unit. Volume displacement conversion factor distributions and glucose error were determined for each group. RESULTS: With increasing patient acuity the median hematocrit decreased, median plasma water increased and variation of these parameters increased. In hospital patients, the molality to molarity conversion factor distribution interval was 1.04-1.16, rather than a constant 1.11. Assuming direct electrode glucose devices only have error attributed to analytical imprecision (coefficient of variation of 5%), it is predicted that only 2% of community patients will have glucose results that exceed 10% of the target values. In the same device, due to variance in hematocrit and plasma water affecting the factor for conversion of molality to molarity, it is predicted that 8.2% of adult intensive care unit patients would have glucose results that exceed 10% of the target value. CONCLUSIONS: Changes in hematocrit and plasma water concentration are predicted to affect a gap or error between whole blood direct reading biosensors and central laboratory plasma methods. This error increases and becomes more variable as patient acuity increases. PMID- 21255565 TI - Non-cell-autonomous planar cell polarity propagation in the auditory sensory epithelium of vertebrates. AB - Sensory epithelia of the inner ear require a coordinated alignment of hair cell stereociliary bundles as an essential element of mechanoreceptive function. Hair cell bundle alignment is mediated by core planar cell polarity (PCP) proteins, such as Vangl2, that localize asymmetrically to the circumference of the cell near its apical surface. During early phases of cell orientation in the chicken basilar papilla (BP), Vangl2 is present at supporting cell junctions that lie orthogonal to the polarity axis. Several days later, there is a striking shift in the Vangl2 pattern associated with hair cells that reorient towards the distal (apical) end of the organ. How the localization of PCP proteins transmits planar polarity information across the developing sensory epithelium remains unclear. To address this question, the normal asymmetric localization of Vangl2 was disrupted by overexpressing Vangl2 in clusters of cells. The BP was infected with replication-competent retrovirus encoding Vangl2 prior to hair cell differentiation. Virus-infected cells showed normal development of individual stereociliary bundles, indicating that asymmetry was established at the cellular level. Yet, bundles were misoriented in ears infected with Vangl2 virus but not Wnt5a virus. Notably, Vangl2 misexpression did not randomize bundle orientations but rather generated larger variations around a normal mean angle. Cell clusters with excess Vangl2 could induce non-autonomous polarity disruptions in wild-type neighboring cells. Furthermore, there appears to be a directional bias in the propagation of bundle misorientation that is towards the abneural edge of the epithelium. Finally, regional bundle reorientation was inhibited by Vangl2 overexpression. In conclusion, ectopic Vangl2 protein causes inaccurate local propagation of polarity information, and Vangl2 acts in a non-cell-autonomous fashion in the sensory system of vertebrates. PMID- 21255567 TI - Human adipose derived stroma/stem cells grow in serum-free medium as floating spheres. AB - With the goal of obtaining clinically safe human adipose-derived stroma/stem cells (ASC) and eliminating the use of serum, we have developed a new culture system that allows the expansion of ASC as spheres in a defined medium. These spheres can be passaged several times. They are not only aggregated cells but rather originate from single cells as clonal spheres can be obtained after seeding at very low density and reform clonal spheres after dissociation. These spheres can also revert to monolayer growth when plated in medium containing human plasma and even generate fibroblast-like colonies (CFU-f). Under several differentiation-specific media, spheres-derived ASC maintain their capacity to differentiate into osteoblasts, endothelial cells and adipocytes. These results indicate that human ASC can be maintained in a serum-free 3D culture system, which is of great interest for the expansion in bioreactors of autologous ASC and their use in clinical trials. PMID- 21255566 TI - Two distinct origins for Leydig cell progenitors in the fetal testis. AB - During the differentiation of the mammalian embryonic testis, two compartments are defined: the testis cords and the interstitium. The testis cords give rise to the adult seminiferous tubules, whereas steroidogenic Leydig cells and other less well characterized cell types differentiate in the interstitium (the space between testis cords). Although the process of testis cord formation is essential for male development, it is not entirely understood. It has been viewed as a Sertoli-cell driven process, but growing evidence suggests that interstitial cells play an essential role during testis formation. However, little is known about the origin of the interstitium or the molecular and cellular diversity within this early stromal compartment. To better understand the process of mammalian gonad differentiation, we have undertaken an analysis of developing interstitial/stromal cells in the early mouse testis and ovary. We have discovered molecular heterogeneity in the interstitium and have characterized new markers of distinct cell types in the gonad: MAFB, C-MAF, and VCAM1. Our results show that at least two distinct progenitor lineages give rise to the interstitial/stromal compartment of the gonad: the coelomic epithelium and specialized cells along the gonad-mesonephros border. We demonstrate that both these populations give rise to interstitial precursors that can differentiate into fetal Leydig cells. Our analysis also reveals that perivascular cells migrate into the gonad from the mesonephric border along with endothelial cells and that these vessel-associated cells likely represent an interstitial precursor lineage. This study highlights the cellular diversity of the interstitial cell population and suggests that complex cell-cell interactions among cells in the interstitium are involved in testis morphogenesis. PMID- 21255568 TI - Impaired IFN-gamma production after stimulation with bacterial components by natural killer cells from gastric cancer patients. AB - Gastric adenocarcinoma is a major health problem world-wide, as this is the second most common cause of cancer death in the world. It has been estimated that infection by Helicobacter pylori cause at least half of the gastric cancers. Previously, we have demonstrated that H. pylori antigens directly activate NK cells to secrete IFN-gamma. There is also a marked synergistic effect in NK cells stimulated with bacterial lysate and low levels of IL-12, a cytokine which is produced by macrophages and dendritic cells in the H. pylori-infected stomach. The present study was designed to investigate whether NK cells from gastric cancer patients display an altered ability to respond to components from H. pylori and other bacteria. The results show that NK cells from peripheral blood of gastric cancer patients have a severely suppressed ability to produce IFN gamma after stimulation with H. pylori lysate and the synthetic bacterial lipoprotein FSL-1. Furthermore, the synergistic effect of IL-12 and lysate is absent in gastric cancer patients, unless the concentration of IL-12 is increased 10-fold. We also demonstrate that there is a similar lack of IFN-gamma production from NK cells isolated from the gastric mucosa of cancer patients. In addition, we propose that the observed suppression is due to tumour-derived TGF-beta and that increased expression of the transcription factor GATA-3 may be responsible for the TGF-beta induced suppression. PMID- 21255569 TI - Retinal pigment epithelial cells upregulate expression of complement factors after co-culture with activated T cells. AB - In this study we examined the effect of T cell-derived cytokines on retinal pigment epithelial (RPE) cells with respect to expression of complement components. We used an in vitro co-culture system in which CD3/CD28-activated human T cells were separated from the human RPE cell line (ARPE-19) by a membrane. Differential gene expression in the RPE cells of complement factor genes was identified using gene arrays, and selected gene transcripts were validated by q-RT-PCR. Protein expression was determined by ELISA and immunoblotting. Co-culture with activated T cells increased RPE mRNA and/or protein expression of complement components C3, factors B, H, H-like 1, CD46, CD55, CD59, and clusterin, in a dose-dependent manner. Soluble factors derived from activated T cells are capable of increasing expression of complement components in RPE cells. This is important for the further understanding of inflammatory ocular diseases such as uveitis and age-related macular degeneration. PMID- 21255570 TI - Molecular analysis of zinc transporters in Schistosoma japonicum. AB - Members of the zinc-regulated transporter/iron-regulated transporter-like protein (ZIP) family of proteins transport metal ions across cell membranes. Genes encoding ZIPs are present in the genomes of schistosomes. Here, we describe molecular characterisation of six ZIPs (SjZIPA-F) from Schistosoma japonicum. Quantitative PCR analyses of these ZIPs through the lifecycle showed that each is expressed predominantly during the intramammalian stage and are particularly enriched in adult females. Using laser microdissected tissue as template, SjZIPA D were transcriptionally enriched in female reproductive tissues, SjZIPE was not expressed in specific tissues and SjZIPF was expressed similarly in each tissue. Whole mount in situ hybridization revealed that SjZIPA and SjZIPB were localised to the oesophageal gland of adults and the vitellaria. We have shown that multiple ZIPs are expressed by schistosomes during the intramammalian parasitic phases and propose that the encoded products perform diverse cellular functions related to metal transport in different cells of S. japonicum. PMID- 21255571 TI - The tumor suppressor RECK interferes with HER-2/Neu dimerization and attenuates its oncogenic signaling. AB - Our previous study demonstrates that HER-2/Neu oncogene inhibits a matrix metalloproteinase inhibitor and tumor metastasis suppressor RECK to promote metastasis. Conversely, the effect of RECK on the oncogenic function of HER-2/Neu is unknown. Ectopic expression of RECK in 293T cells and HER-2/Neu-overexpressing breast cancer cells shows that RECK and HER-2/Neu are co-localized and these two proteins can be co-immunoprecipitated. RECK inhibits HER-2/Neu receptor dimerization and autophosphorylation, which causes reduction of ERK and AKT kinase activity and down-regulation of HER-2/Neu target genes. RECK expression is reduced in 58.8% of breast cancer tissues and is associated with lymph node invasion supporting its anti-metastatic role. Collectively, we provide the first evidence that RECK can negatively regulate oncogenic activity of HER-2/Neu by inhibiting receptor dimerization. PMID- 21255572 TI - The results of Phase III clinical trials with telaprevir and boceprevir presented at the Liver Meeting 2010: a new standard of care for hepatitis C virus genotype 1 infection, but with issues still pending. PMID- 21255573 TI - Targeted contrast-enhanced ultrasound: an emerging technology in abdominal and pelvic imaging. PMID- 21255574 TI - Sequence and phenotypic analysis for resistance monitoring in hepatitis C virus drug development: recommendations from the HCV DRAG. PMID- 21255575 TI - Corticosterone stress response and plasma metabolite levels during breeding and molt in a free-living migratory songbird, the wood thrush (Hylocichla mustelina). AB - Many birds face energetic trade-offs between different life history stages, such as reproductive effort, feather molt and the non-breeding period. Little is known about how physiological measures of condition (corticosterone, plasma metabolites) in free-living birds change from nesting stages to the post-breeding molt period or whether this is influenced by prior reproductive effort. We evaluated whether corticosterone (CORT) and plasma metabolite levels vary with date, nest stage and sex in a free-living migratory songbird, the wood thrush (Hylocichla mustelina). We also tested whether (1) baseline CORT levels early in the season were predictive of subsequent reproductive success and (2) whether prior reproductive effort influenced CORT levels and blood metabolites during molt. Baseline CORT levels decreased with date during both the incubation stage and nestling stage, but did not vary significantly across stage of breeding season. Stress-induced CORT declined with date during incubation and varied significantly across breeding stage, with lower levels during feather molt. Profiles of the metabolites of beta-hydroxybutyrate, glycerol, and triglyceride did not vary significantly with date or breeding stage. Only triglycerides varied significantly with sex, with females having higher levels than males. Reproductive output was highly variable (0-10 fledglings per season) but baseline CORT levels in females during the first incubation period of the season was not related to subsequent reproductive output. Prior reproductive effort, measured as the cumulative number of young hatched during the breeding season, was positively related to stress-induced CORT during molt. High reproductive effort in wood thrush appears to have physiological carry-over effects into the molt period which could potentially affect rate of molt and preparation for fall migration. PMID- 21255576 TI - Antibodies against the Trypanosoma cruzi ribosomal P proteins induce apoptosis in HL-1 cardiac cells. AB - High levels of antibodies (Abs) against the C-terminal end of the Trypanosoma cruzi ribosomal P2beta protein, defined by the R13 peptide, are detected in sera from patients with chronic Chagas heart disease (cChHD). These Abs can cross react with the beta1-adrenergic receptor (beta1-AR), inducing a functional response in cardiomyocytes. In this study, we report that a monoclonal Ab against the R13 peptide, called mAb 17.2, and its single-chain Fv fragment (scFv), C5, caused apoptosis of murine adult cardiac HL-1 cells, and this effect was inhibited by pre-incubation with the beta-blocker, propranolol. In addition, apoptosis induced by mAb 17.2 might involve the mitochondrial pathway evidenced by an increase in pro-apoptotic molecule, Bax/anti-apoptotic molecule, Bcl(XL), mRNA levels. HL-1 cells also underwent apoptosis after incubation with nine of 23 IgGs from cChHD patients (39.1%) that presented reactivity against R13 peptide and beta1-AR. The apoptotic effect caused by these IgGs was partially abolished by pre-incubation with R13 peptide or propranolol, suggesting the involvement of the C-terminal end of ribosomal P proteins and the beta-adrenergic pathway. Moreover, we observed high rates of cardiomyocyte apoptosis in two tissue samples from cChHD patients by using a TUNEL assay and staining of active caspase-3. Our data demonstrate that Abs developed during T. cruzi infection have a strong cardiomyocyte apoptosis inducing ability, which could contribute to the heart disease developed in patients with cChHD. PMID- 21255577 TI - Control of onchocerciasis in Africa: threshold shifts, breakpoints and rules for elimination. AB - Control of onchocerciasis in Africa is currently based on annual community directed treatment with ivermectin (CDTI) which has been assumed to be not efficient enough to bring about elimination. However, elimination has recently been reported to have been achieved by CDTI alone in villages of Senegal and Mali, reviving debate on the eradicability of onchocerciasis in Africa. We investigate the eradicability of onchocerciasis by examining threshold shifts and breakpoints predicted by a stochastic transmission model that has been fitted extensively to data. We show that elimination based on CDTI relies on shifting the threshold biting rate to a level that is higher than the annual biting rate. Breakpoints become relevant in the context of when to stop CDTI. In order for the model to predict a good chance for CDTI to eliminate onchocerciasis, facilitating factors such as the macrofilaricidal effect of ivermectin must be assumed. A chart predicting the minimum efficacy of CDTI required for elimination, dependent on the annual biting rate, is provided. Generalisable recommendations into strategies for the elimination of onchocerciasis are derived, particularly referring to the roles of vectors, the residual infection rate under control, and a low-spreader problem originating from patients with low parasite burdens. PMID- 21255578 TI - Impact of blood processing variations on natural killer cell frequency, activation, chemokine receptor expression and function. AB - Understanding the role of natural killer (NK) cells in human disease pathogenesis is crucial and necessitates study of patient samples directly ex vivo. Manipulation of whole blood by density gradient centrifugation or delays in sample processing due to shipping, however, may lead to artifactual changes in immune response measures. Here, we assessed the impact of density gradient centrifugation and delayed processing of both whole blood and peripheral blood mononuclear cells (PBMC) at multiple timepoints (2-24 h) on flow cytometric measures of NK cell frequency, activation status, chemokine receptor expression, and effector functions. We found that density gradient centrifugation activated the NK cells and modified the chemokine receptor expression. Delays in processing beyond 8h activated NK cells in PBMC but not in whole blood. Likewise, processing delays decreased chemokine receptor (CCR4 and CCR7) expression in both PBMC and whole blood. Finally, delays in processing PBMC were associated with a decreased ability of NK cells to degranulate (as measured by CD107a expression) or secrete cytokines (IFN-gamma and TNF-alpha). In summary, our findings suggest that density gradient centrifugation and delayed processing of PBMC can alter measures of clinically relevant NK cell characteristics including effector functions; and therefore should be taken into account in designing clinical research studies. PMID- 21255579 TI - Development of a genetically-modified novel T-cell receptor for adoptive cell transfer against renal cell carcinoma. AB - A novel alpha/beta T-cell clone with broad reactivity against human clear cell renal cell carcinomas (RCC) was generated from a patient with renal cancer. The T cell receptor (TCR) from this clone recognizes soluble TNF-related apoptosis inducing ligand bound to death receptor 4, a complex found on the surface of nearly all RCC. In this study, we modified this novel TCR by introducing amino acid (AA) substitutions in its complementarity determining region 2 (CDR2) and CDR3 regions of both chains, to increase its activity. We demonstrated that tumor recognition by PBL, retrovirally-transduced with these TCRs, was decreased or unchanged by substitutions in the TCR beta chain, and in the CDR2alpha region. Yet some AA substitutions in the CDR3alpha region at positions 109 and 112 could augment tumor recognition. Specifically, substituting phenylalanine for tyrosine at AA109 (109Y-F) and alanine or lysine for serine at AA112 (112S-K or 112 S-A) augmented tumor recognition. Increased benefit was seen on combining both AA substitutions and a retrovirus encoding the modified TCR 109Y-F/112S-K conferred the best tumor recognition to transduced PBL. This modified TCR retained the recognition pattern of parental clone HC/2G-1 against RCC lines, other tumors and normal tissues. These results document that CDR3alpha plays an important role in the interaction of the HC/2G-1 TCR and its novel ligand. A phase I/II clinical trial, adoptively transferring autologous PBL transduced with this modified TCR has just begun in patients with metastatic RCC. PMID- 21255580 TI - Determination of optimal incubation time for the production of acute phase cytokines ex vivo by peripheral blood mononuclear cells from renal transplant recipients. AB - Levels of acute phase cytokines secreted ex vivo by peripheral blood mononuclear cells (PBMCs) have been shown to be associated with clinical conditions or histologic lesions in renal transplant recipients. One of the limiting factors for the potential use of this assay as a diagnostic tool is the incubation time needed to measure adequate cytokine levels. Here, we validated that shorter time periods than the usual 48 h are sufficient for the production of acute phase cytokines. Cytokine levels were measured with the Luminex platform. We observed that, in contrast to cytokines associated with adaptive immunity, cytokines such as IL-1beta, IL-6 and TNF-alpha are measurable as early as 2 h following incubation at a concentration of 1.5 million PBMC/150 MUL. Levels obtained in the 2 h cultures have good correlations with the levels obtained after 48 h of culture for IL-1beta and TNF-alpha (R=0.79, P=0.004 and R=0.92, P<0.001 respectively). We conclude that same-day incubation of PBMCs and measurement of these cytokines following blood collection in transplant recipients is feasible. It provides a rationale for further studies using shorter incubation times for ex vivo cellular assay measuring acute phase cytokine levels. PMID- 21255581 TI - Pim-1 kinase inhibits pathological injury by promoting cardioprotective signaling. AB - Stem cells mediate tissue repair throughout the lifespan of an organism. However, the ability of stem cells to mitigate catastrophic damage, such as that sustained after major myocardial infarction is inadequate to rebuild the heart and restore functional capacity. However, capitalizing on the ability of these cells to attenuate damage in the myocardium, various maneuvers that enhance repair mechanisms to improve cardiac structure and function after injury are being investigated. These studies have led to discovery of various factors that mediate cardioprotection and enhance endogenous repair by 1) salvaging surviving myocardium, 2) promoting homing of stem cells and 3) increasing survival and proliferation of stem cell populations at the site of injury. Herein we report upon a downstream target of Akt kinase, named Pim-1, which promotes cardioprotective signaling and enhances cardiac structure and function after pathological injury. The compilation of studies presented here supports use of Pim-1 to enhance long-term myocardial repair after pathological damage. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure." PMID- 21255582 TI - Contribution of titin and extracellular matrix to passive pressure and measurement of sarcomere length in the mouse left ventricle. AB - It remains to be established to what degree titin and the extracellular matrix (ECM) contribute to passive pressure in the left ventricle (LV). Thus, we aimed to elucidate the contribution of major molecular determinants of passive pressure in the normal mouse LV. Furthermore, we determined the working sarcomere length (SL) range of the LV to bridge our findings to earlier work in skinned muscle fibers. We utilized Frank-Starling type protocols to obtain diastolic pressure volume relationships (PVR) in Langendorff perfused isolated LVs. To quantify the molecular contribution of titin and ECM, we innovated on methods of fiber mechanics to chemically permeabilize intact LVs and measure a fully passive PVR. To differentially dissect the contributions of the ECM and titin, we utilized myofilament extraction techniques in permeabilized LVs, measuring passive PVRs at each stage in the protocol. Myofilament extraction suggests that titin contributes ~80% of passive pressures in the heart. Langendorff perfusion was also used to chemically fix passive and BaCl(2) activated hearts at specific volumes to determine that the maximal working SL range of the midwall LV fibers is approximately 1.8-2.2 MUm. A model of the passive SL-volume relationship was then used to estimate the pressure-SL relationships, indicating that the ECM contribution does not exceed titin's contribution until large volumes with SLs >~2.2 MUm. In conclusion, within physiological volumes, titin is the dominant contributor to LV passive pressure, and ECM-based pressures dominate at larger volumes. PMID- 21255584 TI - The functional half-life of an mRNA depends on the ribosome spacing in an early coding region. AB - Bacterial mRNAs are translated by closely spaced ribosomes and degraded from the 5'-end, with half-lives of around 2 min at 37 degrees C in most cases. Ribosome free or "naked" mRNA is known to be readily degraded, but the initial event that inactivates the mRNA functionally has not been fully described. Here, we characterize a determinant of the functional stability of an mRNA, which is located in the early coding region. Using literature values for the mRNA half lives of variant lacZ mRNAs in Escherichia coli, we modeled how the ribosome spacing is affected by the translation rate of the individual codons. When comparing the ribosome spacing at various segments of the mRNA to its functional half-life, we found a clear correlation between the functional mRNA half-life and the ribosome spacing in the mRNA region approximately between codon 20 and codon 45. From this finding, we predicted that inserts of slowly translated codons before codon 20 or after codon 45 should shorten or prolong, respectively, the functional mRNA half-life by altering the ribosome density in the important region. These predictions were tested on eight new lacZ variants, and their experimentally determined mRNA half-lives all supported the model. We thus suggest that translation-rate-mediated differences in the spacing between ribosomes in this early coding region is a parameter that determines the mRNAs functional half-life. We present a model that is in accordance with many earlier observations and that allows a prediction of the functional half-life of a given mRNA sequence. PMID- 21255583 TI - Single-molecule studies of transcription: from one RNA polymerase at a time to the gene expression profile of a cell. AB - Single-molecule techniques have emerged as powerful tools for deciphering mechanistic details of transcription and have yielded discoveries that would otherwise have been impossible to make through the use of more traditional biochemical and/or biophysical techniques. Here, we provide a brief overview of single-molecule techniques most commonly used for studying RNA polymerase and transcription. We then present specific examples of single-molecule studies that have contributed to our understanding of key mechanistic details for each different stage of the transcription cycle. Finally, we discuss emerging single molecule approaches and future directions, including efforts to study transcription at the single-molecule level in living cells. PMID- 21255585 TI - Mating strategies in primates: a game theoretical approach to infanticide. AB - Infanticide by newly immigrated or newly dominant males is reported among a variety of taxa, such as birds, rodents, carnivores and primates. Here we present a game theoretical model to explain the presence and prevalence of infanticide in primate groups. We have formulated a three-player game involving two males and one female and show that the strategies of infanticide on the males' part and polyandrous mating on the females' part emerge as Nash equilibria that are stable under certain conditions. Moreover, we have identified all the Nash equilibria of the game and arranged them in a novel hierarchical scheme. Only in the subspace spanned by the males are the Nash equilibria found to be strict, and hence evolutionarily stable. We have therefore proposed a selection mechanism informed by adaptive dynamics to permit the females to transition to, and remain in, optimal equilibria after successive generations. Our model concludes that polyandrous mating by females is an optimal strategy for the females that minimizes infanticide and that infanticide confers advantage to the males only in certain regions of parameter space. We have shown that infanticide occurs during turbulent changes accompanying male immigration into the group. For changes in the dominance hierarchy within the group, we have shown that infanticide occurs only in primate groups where the chance for the killer to sire the next infant is high. These conclusions are confirmed by observations in the wild. This model thus has enabled us to pinpoint the fundamental processes behind the reproductive decisions of the players involved, which was not possible using earlier theoretical studies. PMID- 21255587 TI - On the Gause predator-prey model with a refuge: a fresh look at the history. AB - This article re-analyses a prey-predator model with a refuge introduced by one of the founders of population ecology Gause and his co-workers to explain discrepancies between their observations and predictions of the Lotka-Volterra prey-predator model. They replaced the linear functional response used by Lotka and Volterra by a saturating functional response with a discontinuity at a critical prey density. At concentrations below this critical density prey were effectively in a refuge while at a higher densities they were available to predators. Thus, their functional response was of the Holling type III. They analyzed this model and predicted existence of a limit cycle in predator-prey dynamics. In this article I show that their model is ill posed, because trajectories are not well defined. Using the Filippov method, I define and analyze solutions of the Gause model. I show that depending on parameter values, there are three possibilities: (1) trajectories converge to a limit cycle, as predicted by Gause, (2) trajectories converge to an equilibrium, or (3) the prey population escapes predator control and grows to infinity. PMID- 21255586 TI - Integrin organization: linking adhesion ligand nanopatterns with altered cell responses. AB - Integrin receptors bind to adhesion ligand (e.g. arginine-glycine-aspartic acid or RGD containing peptides) on extracellular matrix and organize into high density complexes which mediate many cell behaviors. Biomaterials with RGD nanopatterned into multivalent "islands" (~30-70 nm diameter) have been shown to alter cell responses, although the length scale of pattern features is orders of magnitude smaller than adhesion complexes. In this work, we employ together for the first time an extensive data set on osteoblast responses as a function of ligand nanopatterns, a computational model of integrin binding to ligand nanopatterns, and new measures of integrin organization on the cell surface. We quantify, at multiple length scales, integrin organization generated in silico as a function of RGD nanopattern parameters. We develop a correlative model relating these measures of in silico integrin organization and in vitro MC3T3 preosteoblast cell responses as functions of the same RGD nanopatterns: cell spreading correlates with the number of bound integrins, focal adhesion kinase (FAK) phosphorylation correlates with small, homogeneously distributed clusters of integrins, and osteogenic differentiation correlates with large, heterogeneously distributed integrin clusters. These findings highlight the significance of engineering biomaterials at the nanolevel and suggest new approaches to understanding the mechanisms linking integrin organization to cell responses. PMID- 21255588 TI - Tumour angiogenesis: the gap between theory and experiments. AB - A common experimental technique for viewing in vivo angiogenesis utilises tumours implanted into a test animal cornea. The cornea is avascular but the tumour promotes vascularisation from the limbus and the new blood vessels can be readily observed through the transparent cornea. Many of the early mathematical models for tumour angiogenesis used this scenario as their experimental template and as such assumed that there is a large gap, of the order of 2mm, between the tumour and neighbouring vasculature at the onset of angiogenesis. In this work we consider whether the assumption that there is a significant gap between the tumour and neighbouring vasculature is unique to intra-cornea tumour implants, or whether this characterises avascular tumour growth more generally. To do this we utilise a simple scaling argument, derive a multi-compartment model for tumour growth, and consider in vivo images. This analysis demonstrates that the corneal implant experiments and the corresponding mathematical models cannot generally be applied to a clinical setting. PMID- 21255589 TI - Accuracy evaluation of RBC velocity measurement in nail-fold capillaries. AB - Cutaneous red blood cell velocity in vivo can be measured by using capillaroscopy with image processing techniques. However, unlike simulated blood flow images, there is no standard to determine the accuracy of the techniques for computing blood flow velocities. In this paper, we quantitatively evaluated the accuracy of previously proposed optical flow method for measuring red blood cell velocity in nail-fold capillaries. Blood flow images of subjects under normal and occlusion release conditions were examined by a capillaroscope. To obtain velocity values, the images were further analyzed by using optical flow, cross-correlation and visual inspection methods, respectively. Visual inspection method was taken as the golden standard to determine the accuracy of blood flow velocity measurement using optical flow and cross-correlation techniques. Results showed that optical flow estimation provided superior accuracy to cross-correlation when assessing real blood flow velocity in nail-fold capillaries. Optical flow estimation is able to measure red blood cell velocity with a high accuracy of 91% and 86% when the observed velocity is less than 0.5mm/s under normal and occlusion-release conditions, respectively. In addition, optical flow method showed good agreement with visual inspection in determining blood flow velocity in both normal and occlusion-release conditions when the high-velocity zone is excluded. PMID- 21255590 TI - Vascular thalamic amnesia: a reappraisal. AB - In humans lacunar infarcts in the mesial and anterior regions of the thalami are frequently associated with amnesic syndromes. In this review paper, we scrutinized 41 papers published between 1983 and 2009 that provided data on a total of 83 patients with the critical ischemic lesions (i.e. 17 patients with right-sided lesions, 25 with left-sided lesions and 41 with bilateral lesions). We aimed to find answers to the following questions concerning the vascular thalamic amnesia syndrome: (i) Which qualitative pattern of memory impairment (and associated cognitive and behavioral deficits) do these patients present? (ii) Which lesioned intrathalamic structures are primarily responsible for the amnesic syndrome? (iii) Are the recollection and familiarity components of declarative memory underlain by the same or by different thalamic structures? Results of the review indicate that, similar to patients with amnesic syndromes due to mesio-temporal lobe damage, patients with vascular thalamic amnesia display a prevalent deficit of declarative anterograde long-term memory, a less consistent deficit of declarative retrograde long-term memory and substantially spared short-term and implicit memory. Unlike mesio-temporal lobe patients, however, vascular thalamic amnesics often present dysexecutive and behavioral deficits similar to those observed in patients with frontal damage. The presence of an amnesic syndrome in patients with thalamic lacunar infarcts is strongly predicted by involvement of the mammillo-thalamic tract, which connects the anterior nuclei complex to the hippocampus proper via the fornix and the mammillary bodies. Finally, data reported in a few single cases provide support for the hypothesis that thalamic regions connected to distinct areas of the mesio temporal lobe play differential roles in recollection and familiarity processes. The mammillo-thalamic tract/anterior nuclei axis seems primarily implicated in recollective processes, whereas the ventroamygdalofugal pathway/medio-dorsal axis primarily underlies familiarity processes. PMID- 21255591 TI - Neural and behavioral correlates of intentional actions. AB - An essential characteristic of human behavior is the ability to act out of intrinsic motivation to achieve desired goals. These kinds of actions have been classed as intentional or voluntary. They contrast with actions that are performed in response to external stimuli. Recent research has begun to explore the functional underpinnings of internally guided actions and how they differ from externally guided actions. From these studies, one can conclude that the two action modes differ with respect to their neural and behavioral correlates. Most importantly, functional neuroimaging and also lesion studies point to a crucial role of the frontomedian cortex in intentional actions. The present paper reviews the neuroanatomical, behavioral, electroencephalographical and functional neuroimaging findings related to intentional actions.The reviewed data suggest two dimensions for the control of action: First, a medial-lateral dimension with regard to intentional vs. stimulus-based action control. Second, an anterior posterior dimension related to more abstract vs. specific decisions of action parameters. PMID- 21255592 TI - A process-model based approach to prospective memory impairment in Parkinson's disease. AB - The present review discusses the current state of research on the clinical neuropsychology of prospective memory in Parkinson's disease. To do so the paper is divided in two sections. In the first section, we briefly outline key features of the (partly implicit) rationale underlying the available literature on the clinical neuropsychology of prospective memory. Here, we present a conceptual model that guides our approach to the clinical neuropsychology of prospective memory in general and to the effects of Parkinson's disease on prospective memory in particular. In the second section, we use this model to guide our review of the available literature and suggest some open issues and future directions motivated by previous findings and the proposed conceptual model. The review suggests that certain phases of the prospective memory process (intention formation und initiation) are particularly impaired by Parkinson's disease. In addition, it is argued that prospective memory may be preserved when tasks involve specific features (e.g., focal cues) that reduce the need for strategic monitoring processes. In terms of suggestions for future directions, it is noted that intervention studies are needed which target the specific phases of the prospective memory process that are impaired in Parkinson's disease, such as planning interventions. Moreover, it is proposed that prospective memory deficits in Parkinson's disease should be explored in the context of a general impairment in the ability to form an intention and plan or coordinate an appropriate series of actions. PMID- 21255593 TI - Substrate specificity and inhibitor analyses of human steroid 5beta-reductase (AKR1D1). AB - Human steroid 5beta-reductase (aldo-keto reductase 1D1) catalyzes the stereospecific NADPH-dependent reduction of the C4-C5 double bond of Delta(4) ketosteroids to yield an A/B cis-ring junction. This cis-configuration is crucial for bile acid biosynthesis and plays important roles in steroid metabolism. The biochemical properties of the enzyme have not been thoroughly studied and conflicting data have been reported, partially due to the lack of highly homogeneous protein. In the present study, we systematically determined the substrate specificity of homogeneous human recombinant AKR1D1 using C18, C19, C21, and C27 Delta(4)-ketosteroids and assessed the pH-rate dependence of the enzyme. Our results show that AKR1D1 proficiently reduced all the steroids tested at physiological pH, indicating AKR1D1 is the only enzyme necessary for all the 5beta-steroid metabolites present in humans. Substrate inhibition was observed with C18 to C21 steroids provided that the C11 position was unsubstituted. This structure activity relationship can be explained by the existence of a small alternative substrate binding pocket revealed by the AKR1D1 crystal structure. Non-steroidal anti-inflammatory drugs which are potent inhibitors of the related AKR1C enzymes do not inhibit AKR1D1. By contrast chenodeoxycholate and ursodeoxycholate were found to be potent non-competitive inhibitors suggesting that bile-acids may regulate their own synthesis at the level of AKR1D1 inhibition. PMID- 21255594 TI - A molecularly imprinted receptor for separation of testosterone and epitestosterone, based on a steroidal cross-linker. AB - A series of molecularly imprinted polymers have been prepared and investigated as stationary phases in high performance liquid chromatography for the separation of testosterone and epitestosterone using non-polar mobile phases. The polymers were imprinted using 5alpha-dihydrotestosterone as template, and all retain testosterone more strongly than its 17alpha-OH epimer. The best polymer was prepared using trifluoromethylacrylic acid as functional monomer (interacting with the template via hydrogen bonds), divinylbenzene as 'inert' cross-linker, and chloroform as porogen. It also included a steroid-based cross-linker, which may interact with the template via van der Waals interactions to lend additional 'shape selectivity'. A 250*4.6mm column packed with this polymer gave baseline resolution of testosterone and epitestosterone (15 MUg each) in under 20 min. Preparation of the steroid based cross-linker included the selective reduction of 5alpha-dihydrotestosterone (17beta-hydroxy-5alpha-androstan-3-one) to the 3alpha,17beta-diol using K-selectride. PMID- 21255595 TI - Is the PentaBDE replacement, tris (1,3-dichloro-2-propyl) phosphate (TDCPP), a developmental neurotoxicant? Studies in PC12 cells. AB - Organophosphate flame retardants (OPFRs) are used as replacements for the commercial PentaBDE mixture that was phased out in 2004. OPFRs are ubiquitous in the environment and detected at high concentrations in residential dust, suggesting widespread human exposure. OPFRs are structurally similar to neurotoxic organophosphate pesticides, raising concerns about exposure and toxicity to humans. This study evaluated the neurotoxicity of tris (1,3-dichloro 2-propyl) phosphate (TDCPP) compared to the organophosphate pesticide, chlorpyrifos (CPF), a known developmental neurotoxicant. We also tested the neurotoxicity of three structurally similar OPFRs, tris (2-chloroethyl) phosphate (TCEP), tris (1-chloropropyl) phosphate (TCPP), and tris (2,3-dibromopropyl) phosphate (TDBPP), and 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), a major component of PentaBDE. Using undifferentiated and differentiating PC12 cells, changes in DNA synthesis, oxidative stress, differentiation into dopaminergic or cholinergic neurophenotypes, cell number, cell growth and neurite growth were assessed. TDCPP displayed concentration-dependent neurotoxicity, often with effects equivalent to or greater than equimolar concentrations of CPF. TDCPP inhibited DNA synthesis, and all OPFRs decreased cell number and altered neurodifferentiation. Although TDCPP elevated oxidative stress, there was no adverse effect on cell viability or growth. TDCPP and TDBPP promoted differentiation into both neuronal phenotypes, while TCEP and TCPP promoted only the cholinergic phenotype. BDE-47 had no effect on cell number, cell growth or neurite growth. Our results demonstrate that different OPFRs show divergent effects on neurodifferentiation, suggesting the participation of multiple mechanisms of toxicity. Additionally, these data suggest that OPFRs may affect neurodevelopment with similar or greater potency compared to known and suspected neurotoxicants. PMID- 21255596 TI - Suppressive effects of acid-forming diet against the tumorigenic potential of pioglitazone hydrochloride in the urinary bladder of male rats. AB - Pioglitazone hydrochloride (PIO), a peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, was administered orally for 85 weeks at 16 mg/kg/day to male rats fed either a diet containing 1.5% ammonium chloride (acid-forming diet) or a control diet to investigate the effects of urinary acidification induced by the acid-forming diet on the tumorigenic potential of PIO in the urinary bladder. The surviving animals at the end of the administration period were followed to the end of the 2-year study period without changes in the diet and were subjected to terminal necropsy on Week 104. The number of urinary microcrystals, evaluated by manual counting with light microscopy and by an objective method with a laser diffraction particle size analyzer, was increased by PIO on Weeks 12 and 25 and the increases were markedly suppressed by urinary acidification. Urinary citrate was decreased by PIO throughout the study period, but no changes were seen in urinary oxalate at any timepoint. The incidences of PIO-treated males bearing at least one of the advanced proliferative changes consisting of papillary hyperplasia, nodular hyperplasia, papilloma or carcinoma were significantly decreased from 11 of 82 males fed the control diet to 2 of 80 males fed the acid-forming diet. The acid-forming diet did not show any effects on the toxicokinetic parameters of PIO and its metabolites. Microcrystalluria appears to be involved in the development of the advanced stage proliferative lesions in bladder tumorigenesis induced by PIO in male rats. PMID- 21255597 TI - On the venom system of centipedes (Chilopoda), a neglected group of venomous animals. AB - Centipedes are among the oldest extant terrestrial arthropods and are an ecologically important group of soil and leaf litter predators. Despite their abundance and frequent, often painful, encounters with humans, little is known about the venom and venom apparatus of centipedes, although it is apparent that these are both quite different from other venomous lineages. The venom gland can be regarded as an invaginated cuticle and epidermis, consisting of numerous epithelial secretory units each with its own unique valve-like excretory system. The venom contains several different enzymes, but is strikingly different to most other arthropods in that metalloproteases appear to be important. Myotoxic, cardiotoxic, and neurotoxic activities have been described, most of which have been attributed to high molecular weight proteins. Neurotoxic activities are also unusual in that G-protein coupled receptors often seem to be involved, either directly as targets of neurotoxins or indirectly by activating endogenous agonists. These relatively slow responses may be complemented by the rapid effects caused by histamines present in the venom and from endogenous release of histamines induced by venom cytotoxins. The differences probably reflect the ancient and independent evolutionary history of the centipede venom system, although they may also be somewhat exaggerated by the paucity of information available on this largely neglected group. PMID- 21255598 TI - A high-throughput venom-gland transcriptome for the Eastern Diamondback Rattlesnake (Crotalus adamanteus) and evidence for pervasive positive selection across toxin classes. AB - Despite causing considerable human mortality and morbidity, animal toxins represent a valuable source of pharmacologically active macromolecules, a unique system for studying molecular adaptation, and a powerful framework for examining structure-function relationships in proteins. Snake venoms are particularly useful in the latter regard as they consist primarily of a moderate number of proteins and peptides that have been found to belong to just a handful of protein families. As these proteins and peptides are produced in dedicated glands, transcriptome sequencing has proven to be an effective approach to identifying the expressed toxin genes. We generated a venom-gland transcriptome for the Eastern Diamondback Rattlesnake (Crotalus adamanteus) using Roche 454 sequencing technology. In the current work, we focus on transcripts encoding toxins. We identified 40 unique toxin transcripts, 30 of which have full-length coding sequences, and 10 have only partial coding sequences. These toxins account for 24% of the total sequencing reads. We found toxins from 11 previously described families of snake-venom toxins and have discovered two putative, previously undescribed toxin classes. The most diverse and highly expressed toxin classes in the C. adamanteus venom-gland transcriptome are the serine proteinases, metalloproteinases, and C-type lectins. The serine proteinases are the most abundant class, accounting for 35% of the toxin sequencing reads. Metalloproteinases are the most diverse; 11 different forms have been identified. Using our sequences and those available in public databases, we detected positive selection in seven of the eight toxin families for which sufficient sequences were available for the analysis. We find that the vast majority of the genes that contribute directly to this vertebrate trait show evidence for a role for positive selection in their evolutionary history. PMID- 21255599 TI - Case definitions for human poisonings postulated to palytoxins exposure. AB - A series of case reports and anecdotal references describe the adverse effects on human health ascribed to the marine toxin palytoxin (PLTX) after different exposure routes. They include poisonings after oral intake of contaminated seafood, but also inhalation and cutaneous/systemic exposures after direct contact with aerosolized seawater during Ostreopsis blooms and/or through maintaining aquaria containing cnidarian zoanthids. The symptoms commonly recorded during PLTX intoxication are general malaise and weakness, associated with myalgia, respiratory effects, impairment of the neuromuscular apparatus and abnormalities in cardiac function. Systemic symptoms are often recorded together with local damages whose intensity varies according to the route and length of exposure. Gastrointestinal malaise or respiratory distress is common for oral and inhalational exposure, respectively. In addition, irritant properties of PLTX probably account for the inflammatory reactions typical of cutaneous and inhalational contact. Unfortunately, the toxin identification and/or quantification are often incomplete or missing and cases of poisoning are indirectly ascribed to PLTXs, according only to symptoms, anamnesis and environmental/epidemiological investigations (i.e. zoanthid handling or ingestion of particular seafood). Based on the available literature, we suggest a "case definition of PLTX poisonings" according to the main exposure routes, and, we propose the main symptoms to be checked, as well as, hemato-clinical analysis to be carried out. We also suggest the performance of specific analyses both on biological specimens of patients, as well as, on the contaminated materials responsible for the poisoning. A standardized protocol for data collection could provide a more rapid and reliable diagnosis of palytoxin-poisoning, but also the collection of necessary data for the risk assessment for this family of toxins. PMID- 21255600 TI - Purification and characterization of a metalloproteinase, Porthidin-1, from the venom of Lansberg's hog-nosed pitvipers (Porthidium lansbergii hutmanni). AB - Porthidium lansbergii hutmanni is a small pit viper found on Margarita Island, Venezuela. Local tissue damage is one of the most obvious characteristics of P. l. hutmanni envenomation, which can lead to diverse pathological effects, such as hemorrhage, edema, blistering, necrosis, lymphatic vessel damage and degradation of extracellular matrix. Metalloproteinases are one of the major components in venoms responsible for these effects. To date, very little is known or has been reported on P. l. hutmanni venom. Crude P. l. hutmanni venom had a LD(50) of 2.5 mg/kg and was considered very hemorrhagic (minimal hemorrhagic dose [MHD]: 0.98 MUg) when compared to other hemorrhagic (Bothrops) venoms in Venezuela. Crude P. l. hutmanni venom also inhibited ADP-induced platelet aggregation. A metalloproteinase, Porthidin-1, from this venom was isolated by three chromatography steps (Sephadex G100, Superose 12 HR10/30 and Bioscale Q2). Porthidin-1 falls in the SVMP P-I class having a molecular weight of 23 kDa, verified by both SDS-PAGE and mass spectrometry. High-resolution mass spectrometry and a database search identified a peptide from Porthidin-1 (YNGDLDK) belonging to the SVMP family of proteins. Porthidin-1 contained hemorrhagic, fibrino(geno)lytic, caseinolytic and gelatinolytic activities, and these activities were capable of being neutralized by metalloproteinase inhibitors but not serine proteinase inhibitors. The peptide YNGDLDK shared similarities with five venom proteins with a BLAST e-value of <1. This work details the biochemical and pathophysiological effects that can result from envenomations, and highlights the importance and significance for characterizing unknown or poorly documented venoms from different geographical regions. PMID- 21255602 TI - Effects of sleep deprivation on retrieval and reconsolidation of morphine reward memory in rats. AB - Relapse induced by exposure to cues associated with drugs of abuse is a major challenge to the treatment of drug addiction. Drug seeking can be inhibited by manipulation of the reconsolidation of drug-related memory. Sleep has been proposed to be involved in various memory processes. However, the role of sleep in drug reward memory is not clear. The present study used conditioned place preference to examine the effects of total sleep deprivation on retrieval and reconsolidation of morphine reward memory in rats. Six-hour total sleep deprivation had no effect on the retrieval of morphine reward memory. However, sleep deprivation from 0-6 h, but not 6-12 h, after re-exposure disrupted the reconsolidation of morphine reward memory. This impairment was not attributable to the formation of an aversive associative memory between the drug-paired context and sleep deprivation. Our findings suggest that sleep plays a critical role in morphine reward memory reconsolidation, and sleep deprivation may be a potential non-pharmacotherapy for the management of relapse associated with drug related memory. PMID- 21255601 TI - Functional analysis of a recombinant PIII-SVMP, GST-acocostatin; an apoptotic inducer of HUVEC and HeLa, but not SK-Mel-28 cells. AB - Disintegrins and disintegrin-like peptides interact with integrins and interfere with cell-cell and cell-matrix interactions. A disintegrin-like snake venom gene, Acocostatin was cloned from the venom gland mRNA of Agkistrodon contortrix contortrix. Acocostatin belongs to the PIII-SVMP subfamily of disintegrin-like peptides. The recombinant acocostatin peptide was produced and purified as GST fusion. The GST-acocostatin peptide, at 44 MUg/mL, inhibited platelet aggregation by 30% in PRP and 18% in whole blood. In addition GST-acocostatin, at 220 MUg/mL, inhibited SK-Mel-28 cell migration by 48%, but did not inhibit T24 cell migration. The GST-acocostatin peptide ability to induce apoptosis on HUVEC, HeLa, and SK-Mel-28 cells was determined using Annexin V-FITC and chromatin fragmentation assays after 24 h of treatment. At 5 MUM GST-acocostatin peptide, 19.68%+/- 3.09 of treated HUVEC, and 35.86% +/- 2.05 of treated HeLa cells were in early apoptosis. The GST-acocostatin peptide also caused chromatin fragmentation of HUVEC and HeLa cells as determined by fluorescent microscopy and Hoechst staining. The GST-acocostatin peptide failed to induce apoptosis of SK Mel-28 cells. We characterized the HUVEC, HeLa, and T24 integrin expression by flow cytometry, as the first step in determining GST-acocostatin binding specificity. Our results indicate that HUVEC express alphav, alphavbeta3, alphavbeta5, alpha6, beta1, and beta3 integrin receptors. HeLa cells express alpha1, alpha2, alpha6, alphav, alphavbeta5, and beta1 integrin receptors. T24 cells express alpha1, alpha3, alpha6, alphav, alphavbeta3, alphavbeta5, beta1, beta3, and beta6 integrin receptors. PMID- 21255603 TI - (1->3)-beta-D-Glucan inhibits a dual mechanism of peroxynitrite stroke. AB - AIM: The antioxidative and antinitrative activities of (1->3)-beta-D-glucan (1 4MUg/ml) from the yeast cell walls of Saccharomyces cerevisiae in human plasma treated with strong oxidants - peroxynitrite (ONOO(-)) (0.1mM) and hydrogen peroxide (H(2)O(2)) (2mM) were studied in vitro. The main purpose of this study was to assess if (1->3)-beta-D-glucan, a well known strong immunostimulatory agent, possesses a protective function against dual mechanism of ONOO(-) stroke associated with nitrative and oxidative damages to human plasma biomolecules. SCOPE: The protein changes were determined in vitro by estimating the level of oxidative stress markers - carbonyl groups, and nitrative products - 3 nitrotyrosine residues. The plasma lipid peroxidation was also investigated. The obtained results show that (1->3)-beta-D-glucan inhibits in vitro ONOO(-)-induced oxidation and nitration of plasma proteins, even by 50% and 30%, respectively. The antioxidative activity of (1->3)-beta-D-glucan was confirmed by its inhibitory effect on plasma lipids peroxidation induced by ONOO(-) or by H(2)O(2). CONCLUSIONS: The obtained results demonstrate that (1->3)-beta-D-glucan from S. cerevisiae protects plasma components against toxic effects of ONOO(-) and H(2)O(2) due to its antioxidative and antinitrative activities. Therefore (1 >3)-beta-D-glucan supplementation during inflammatory may be beneficial not only regard for its ability to stimulate the immune system but also by antioxidative properties. PMID- 21255604 TI - Preparation of rich handles soft cellulosic fabric using amino silicone based softener. Part-I: Surface smoothness and softness properties. AB - A series of amino silicone based softeners with different emulsifiers were prepared and adsorbed onto the surfaces of cotton and blends of cotton/polyester fabrics. Factors affecting the performance properties of the finished substrate such as post-treatment with amino functional silicone based softener varying different emulsifiers in their formulations and its concentration on different processed fabrics were studied. Fixation of the amino-functional silicone softener onto/or within the cellulose structure is accompanied by the formation of semi-inter-penetrated network structure thereby enhancing both the extent of crosslinking and networking as well as providing very high softness. The results of the experiments indicate that the amino silicone can form a hydrophobic film on both cotton and blends of cotton/polyester fabrics and its coating reduces the surface roughness significantly. Furthermore, the roughness becomes lesser with an increase in the applied strength of amino silicone based softener. PMID- 21255605 TI - Fabrication of gelatin-hyaluronic acid hybrid scaffolds with tunable porous structures for soft tissue engineering. AB - The development of three-dimensional (3-D) scaffolds with highly open porous structure is one of the most important issues in tissue engineering. In this study, 3-D macroporous gelatin/hyaluronic acid (GE/HA) hybrid scaffolds with varying porous morphology were prepared by freeze-drying their blending solutions and subsequent chemical crosslinking by using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). The resulting scaffolds were characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Their swelling, in vitro degradation properties and compressive strength were also investigated. To evaluate in vitro cytocompatibility of scaffolds, mouse L929 fibroblasts were seeded onto the scaffolds for cell morphology and cell viability studies. It was found that the porous structure of scaffolds can be tailored by varying the ratios of gelatin to HA, both the swelling ratios and degradation rate increased with the increase of HA content in hybrid scaffolds, and crosslinking the scaffolds with EDC improved the degradation resistance of the scaffold in culture media and increased the mechanical strength of scaffolds. The in vitro results revealed that the prepared scaffolds do not induce cytotoxic effects and suitable for cell growth, especially in the case of scaffolds with higher gelatin content. The combined results of the physicochemical and biological studies suggested that the developed GE/HA hybrid scaffolds exhibit good potential and biocompatibility for soft tissue engineering applications. PMID- 21255606 TI - The 1.6A resolution structure of activated D138L mutant of catabolite gene activator protein with two cAMP bound in each monomer. AB - The X-ray crystal structure of the cAMP-liganded D138L mutant of Escherichia coli catabolite gene activator protein (CAP) was determined at a resolution of 1.66A. This high resolution crystal structure reveals four cAMP binding sites in the homodimer. Two anti conformations of cAMPs (anti-cAMP) locate between the beta barrel and the C-helix of each subunit; two syn conformations of cAMPs (syn-cAMP) bind on the surface of the C-terminal domain. With two syn-cAMP molecules bound, the D138L CAP is highly symmetrical with both subunits assuming a "closed" conformation. These differences make the hinge region of the mutant more flexible. Protease susceptibility measurements indicate that D138L is more susceptible to proteases than that of wild type (WT) CAP. The results of protein dynamic experiments (H/D exchange measurements) indicate that the structure of D138L mutant is more dynamic than that of WT CAP, which may impact the recognition of specific DNA sequences. PMID- 21255607 TI - Aromatic-Aromatic Interactions Database, A(2)ID: an analysis of aromatic pi networks in proteins. AB - The geometrical arrangement of the aromatic rings of phenylalanine, tyrosine, tryptophan and histidine has been analyzed at a database level using the X-ray crystal structure of proteins from PDB in order to find out the aromatic-aromatic (pi-pi) networks in proteins and to understand how these aromatic rings are connected with each-other in a specific pi-pi network. A stringent examination of the 7848 proteins indicates that close to 89% of the proteins have occurrence of at least a network of 2pi or a higher pi-pi network. The occurrence of pi-pi networks in various protein superfamilies based on SCOP, CATH and EC classifiers has also been probed in the present work. In general, we find that multidomain and membrane proteins as well as lyases show a more number of these networks. Analysis of the distribution of angle between planes of two proximal aromatic rings (phi) distribution indicates that at a larger cutoff distance (between centroid of two aromatic rings), above 5A, C-H?pi interactions (T-shaped orientation) are more prevalent, while pi-pi interactions (stacked orientation) are more prevalent at a smaller cutoff distance. The connectivity patterns of pi pi networks propose strong propensity of finding arrangement of aromatic residues as clusters rather than linear arrangement. We have also made a public domain database "Aromatic-Aromatic Interactions Database" (A(2)ID) comprising of all types of pi-pi networks and their connectivity pattern present in proteins. It can be accessed by url http://203.199.182.73/gnsmmg/databases/aidb/aidb.html. PMID- 21255608 TI - Comparative structural modeling and docking studies of oxalate oxidase: Possible implication in enzyme supplementation therapy for urolithiasis. AB - In humans oxalate is end product of protein metabolism, with no enzyme present to act on it. In conditions of its enhanced endogenous synthesis or increased absorption from the diet, oxalate accumulation leads to hyperoxaluria which can further lead to a number of pathological conditions including urolithiasis. Urolithiasis has been a perplexing problem due to its high incidence and rate of recurrence after treatment like Extracorporeal-shock wave lithotripsy (ESWL). Hence other prophylactic treatment becomes necessary. One of the newer approaches of curing such metabolic disorders is the enzyme supplementation therapy. Oxalate oxidase (OxOx) is a commonly occurring enzyme in plants, bacteria and fungi that catalyses oxidative cleavage of oxalate to CO(2) with reduction of dioxygen to H(2)O(2). Present study, used Hordeum vulgare OxOx crystal structure (PDB ID 2ET1A) as a template for constructing 3D models of OxOx from Triticum aestivum, Arabidopsis thaliana, Sclerotiana sclerotiarum. Similarly Homology models for isoforms Ceriporiopsis subvermispora 336, C. subvermispora 422 were constructed by using template Bacillus subtilis oxalate decarboxylase (Oxdc) (PDB ID 2UY8A) by comparative modeling approach in SWISS MODEL, MODELLER, 3D JIGSAW and GENO 3D program server. Based on overall stereochemical quality (PROCHECK, PROSA, VARIFY 3D), best models were selected, energy minimized, refined and characterized for active site in BioMed CaChe V 6.1 workspace. Selected models were further studied for structure function relationship with substrate (oxalate) and its analogue (glycolate) by using docking approach. Calculated interaction energy between the oxalate and constructed enzyme indicated that homology models for OxOx of T. aestivum, A. thaliana and S. sclerotiarum, can account for better regio specificity of this enzyme towards oxalate. That supports the interested metabolism and thus may further implement in enzyme supplementation therapy for urolithiasis. PMID- 21255609 TI - Characterization of pLP18, a novel cryptic plasmid of Lactobacillus plantarum PC518 isolated from Chinese pickle. AB - A cryptic plasmid of Lactobacillus plantarum PC518 isolated from Chinese pickle, designated pLP18, was sequenced and characterized. It is a 1806-bp circular molecule with a G+C content of 37.5%. Sequence analysis of pLP18 revealed three putative open reading frames (ORFs), in which ORF1 contained conserved motifs of pMV158-family Rep proteins and showed 60% similarity with the Rep protein of pPSC22, a member of rolling-circle replication (RCR) pMV158 family. The double strand origin (dso) of pMV158 family and the single strand origin A (ssoA) located upstream of the rep gene. The putative cop and rnaII genes were predicted to be regulatory genes controlling copy number of pLP18. The results of Southern hybridization suggested that pLP18 replicate via the RCR mechanism. Furthermore, the relative copy number of pLP18 was estimated to be about 24 copies per chromosome equivalent by quantitative PCR. PMID- 21255610 TI - Safety, pharmacokinetics, and antiviral activity of the cyclophilin inhibitor NIM811 alone or in combination with pegylated interferon in HCV-infected patients receiving 14 days of therapy. AB - BACKGROUND: Cyclophilin inhibitors have shown activity against a variety of viruses, including HCV. NIM811, a novel, non-immunosuppressive cyclophilin inhibitor was studied in ascending doses in a randomized, double-blind, placebo controlled 14-day trial in genotype 1 HCV patients. Doses of 10 up to 600 mg were given orally once or twice daily as monotherapy (9:3 randomization of NIM811:placebo). 600 mg or placebo bid for 14 days was then co-administered with pegylated interferon alpha (PEG-IFN-alpha) administered on days 1 and 8 to genotype 1 relapsers. RESULTS: NIM811 was well tolerated at all doses. Although lack of antiviral effect was noted in the monotherapy arms, liver transaminase normalization occurred at doses over 75 mg. Mild, clinically non-significant elevations of bilirubin, and significant declines in platelet numbers were observed in the 400 and 600 mg bid groups. In the combination group, the mean HCV RNA decline was 2.85 log, compared to a 0.56 log in the PEG-IFN alone arm. The mean ALT (alanine transaminase) declined significantly by day 14 in the combination, but was unchanged in the PEG-IFN alone group. In the combination therapy group, the mean platelets were 203*10(9)/L at baseline and fell to 105*10(9)/L by day 14; for patients treated with PEG-IFN the values were 177*10(9)/L and 139*10(9)/L. There was a significant increase in bilirubin, although this did not reach clinically concerning levels. There were no severe or serious adverse events. The pharmacokinetics in both monotherapy and combination arms were dose linear and not affected by PEG-INF. CONCLUSION: NIM811 monotherapy resulted in a normalization of liver transaminases in the absence of significant virological response. The combination of NIM811 and pegylated interferon alpha showed significant antiviral activity compared to interferon alone in genotype 1 HCV relapsers. The use of oral cyclophilin inhibitors as part of a combination regime for treatment of hepatitis C, especially to deter resistance, holds promise. PMID- 21255611 TI - Differences of acute versus chronic ethanol exposure on anxiety-like behavioral responses in zebrafish. AB - Zebrafish, a vertebrate model organism amenable to high throughput screening, is an attractive system to model and study the mechanisms underlying human diseases. Alcoholism and alcoholic medical disorders are among the most debilitating diseases, yet the mechanisms by which ethanol inflicts the disease states are not well understood. In recent years zebrafish behavior assays have been used to study learning and memory, fear and anxiety, and social behavior. It is important to characterize the effects of ethanol on zebrafish behavioral repertoires in order to successfully harvest the strength of zebrafish for alcohol research. One prominent effect of alcohol in humans is its effect on anxiety, with acute intermediate doses relieving anxiety and withdrawal from chronic exposure increasing anxiety, both of which have significant contributions to alcohol dependence. In this study, we assess the effects of both acute and chronic ethanol exposure on anxiety-like behaviors in zebrafish, using two behavioral paradigms, the Novel Tank Diving Test and the Light/Dark Choice Assay. Acute ethanol exposure exerted significant dose-dependent anxiolytic effects. However, withdrawal from repeated intermittent ethanol exposure disabled recovery from heightened anxiety. These results demonstrate that zebrafish exhibit different anxiety-like behavioral responses to acute and chronic ethanol exposure, which are remarkably similar to these effects of alcohol in humans. Because of the accessibility of zebrafish to high throughput screening, our results suggest that genes and small molecules identified in zebrafish will be of relevance to understand how acute versus chronic alcohol exposure have opposing effects on the state of anxiety in humans. PMID- 21255612 TI - Individual differences in maternal response to immune challenge predict offspring behavior: contribution of environmental factors. AB - Maternal infection during pregnancy elevates risk for schizophrenia and related disorders in offspring. Converging evidence suggests the maternal inflammatory response mediates the interaction between maternal infection, altered brain development, and behavioral outcome. The extent to which individual differences in the maternal response to immune challenge influence the development of these abnormalities is unknown. The present study investigated the impact of individual differences in maternal response to the viral mimic polyinosinic:polycytidylic acid (poly I:C) on offspring behavior. We observed significant variability in body weight alterations of pregnant rats induced by administration of poly I:C on gestational day 14. Furthermore, the presence or absence of maternal weight loss predicted MK-801 and amphetamine stimulated locomotor abnormalities in offspring. MK-801 stimulated locomotion was altered in offspring of all poly I:C treated dams; however, the presence or absence of maternal weight loss resulted in decreased and modestly increased locomotion, respectively. Adult offspring of poly I:C treated dams that lost weight exhibited significantly decreased amphetamine stimulated locomotion, while offspring of poly I:C treated dams without weight loss performed similarly to vehicle controls. Social isolation and increased maternal age predicted weight loss in response to poly I:C but not vehicle injection. In combination, these data identify environmental factors associated with the maternal response to immune challenge and functional outcome of offspring exposed to maternal immune activation. PMID- 21255613 TI - Effects of insulin and leptin in the ventral tegmental area and arcuate hypothalamic nucleus on food intake and brain reward function in female rats. AB - There is evidence for a role of insulin and leptin in food intake, but the effects of these adiposity signals on the brain reward system are not well understood. Furthermore, the effects of insulin and leptin on food intake in females are underinvestigated. These studies investigated the role of insulin and leptin in the ventral tegmental area (VTA) and the arcuate hypothalamic nucleus (Arc) on food intake and brain reward function in female rats. The intracranial self-stimulation procedure was used to assess the effects of insulin and leptin on the reward system. Elevations in brain reward thresholds are indicative of a decrease in brain reward function. The bilateral administration of leptin into the VTA (15-500 ng/side) or Arc (15-150 ng/side) decreased food intake for 72 h. The infusion of leptin into the VTA or Arc resulted in weight loss during the first 48 (VTA) or 24 h (Arc) after the infusions. The administration of insulin (0.005-5 mU/side) into the VTA or Arc decreased food intake for 24 h but did not affect body weights. The bilateral administration of low, but not high, doses of leptin (15 ng/side) or insulin (0.005 mU/side) into the VTA elevated brain reward thresholds. Neither insulin nor leptin in the Arc affected brain reward thresholds. These studies suggest that a small increase in leptin or insulin levels in the VTA leads to a decrease in brain reward function. A relatively large increase in insulin or leptin levels in the VTA or Arc decreases food intake. PMID- 21255614 TI - Inflammation modulates anxiety in an animal model of multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by inflammation, but also degenerative changes. Besides neurological deficits, the rate of affective disorders such as depression and anxiety is at least six fold increased. Many aspects of MS can be mimicked in the animal model of myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (MOG-EAE). Here we investigate behavioral changes in C57BL/6 mice suffering from mild MOG-EAE. In the later phase of the disease, mice were subjected to behavioral tests including the light-dark-box (LD Box), the acoustic startle response (SR) with a pre-pulse inhibition protocol as well as the learned helplessness (LH) paradigm. Behavioral data were correlated with the motor performance in an open field and rotarod test (RR). In the RR and open field, there was no significant difference in the motor performance between controls and mice suffering from mild MOG-EAE. Yet EAE mice displayed an increased anxiety like behavior with a 23% reduction of the time spent in the bright compartment of the LD Box as well as an increased SR. In the LH paradigm, mice suffering from MOG-EAE were twice as much prone to depressive-like behavior. These changes correlate with an increase of hippocampal tissue tumor necrosis factor alpha levels and neuronal loss in the hippocampus. Modulation of monoaminergic transmission by chronic application of the antidepressant amitriptyline resulted in a decreased startle reaction and increased hippocampal norepinephrine levels. These data imply that chronic inflammation in the CNS may impact on emotional responses in rodent models of anxiety. PMID- 21255615 TI - Crystal structures of three protozoan homologs of tryptophanyl-tRNA synthetase. AB - Tryptophanyl-tRNA synthetase (TrpRS) is an essential enzyme that is recognizably conserved across all forms of life. It is responsible for activating and attaching tryptophan to a cognate tRNA(Trp) molecule for use in protein synthesis. In some eukaryotes this original core function has been supplemented or modified through the addition of extra domains or the expression of variant TrpRS isoforms. The three TrpRS structures from pathogenic protozoa described here represent three illustrations of this malleability in eukaryotes. The Cryptosporidium parvum genome contains a single TrpRS gene, which codes for an N terminal domain of uncertain function in addition to the conserved core TrpRS domains. Sequence analysis indicates that this extra domain, conserved among several apicomplexans, is related to the editing domain of some AlaRS and ThrRS. The C. parvum enzyme remains fully active in charging tRNA(Trp) after truncation of this extra domain. The crystal structure of the active, truncated enzyme is presented here at 2.4A resolution. The Trypanosoma brucei genome contains separate cytosolic and mitochondrial isoforms of TrpRS that have diverged in their respective tRNA recognition domains. The crystal structure of the T. brucei cytosolic isoform is presented here at 2.8A resolution. The Entamoeba histolytica genome contains three sequences that appear to be TrpRS homologs. However one of these, whose structure is presented here at 3.0A resolution, has lost the active site motifs characteristic of the Class I aminoacyl-tRNA synthetase catalytic domain while retaining the conserved features of a fully formed tRNA(Trp) recognition domain. The biological function of this variant E. histolytica TrpRS remains unknown, but, on the basis of a completely conserved tRNA recognition region and evidence for ATP but not tryptophan binding, it is tempting to speculate that it may perform an editing function. Together with a previously reported structure of an unusual TrpRS from Giardia, these protozoan structures broaden our perspective on the extent of structural variation found in eukaryotic TrpRS homologs. PMID- 21255616 TI - Nuclear-encoded mitochondrial proteins and their role in cardioprotection. AB - During myocardial ischemia/reperfusion, mitochondria are both a source and a target of injury. In cardioprotective maneuvers such as ischemic and pharmacological pre- and postconditioning mitochondria have a decisive role. Since about 99% of the mitochondrial proteins are encoded in the nucleus, deleterious and protective mitochondrial effects most likely comprise the import of cytosolic proteins. The present review therefore discusses the role of mitochondria in myocardial ischemia/reperfusion injury and protection from it, focusing on some cytosolic proteins, which are translocated into mitochondria before, during, or following ischemia/reperfusion. Both morphological and functional alterations are discussed at the level of the heart, the cardiomyocyte and/or the mitochondrion itself. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. PMID- 21255617 TI - Heterotrimeric Galpha(i) proteins are regulated by lipopolysaccharide and are anti-inflammatory in endotoxemia and polymicrobial sepsis. AB - Previous studies have implicated a role of heterotrimeric Galpha(i) proteins in lipopolysaccharide (LPS)-induced inflammatory responses. We hypothesized that Toll-like receptor (TLR) signaling regulates Galpha(i) proteins, which are anti inflammatory in endotoxemia and polymicrobial sepsis. RAW 264.7 cells were stimulated with LPS and the Galpha(i)-GTP protein complex was immunoprecipitated with a Galpha(i) protein activation assay. In subsequent in vivo studies, the Galpha(i) protein inhibitor pertussis toxin (PTx) or G(i) protein agonist mastoparan (MP-7) were administrated prior to endotoxemia. LPS-induced pro inflammatory cytokines and mortality were determined. To examine the role of Galpha(i2) in sepsis, Galpha(i2) (-/-) and wildtype (WT) mice were subjected to cecal ligation and puncture (CLP) and monitored every 24 h for 120 h. Other mice were sacrificed 24 h after CLP. Peritoneal fluid, blood, and tissue samples were collected. Plasma pro-inflammatory cytokine production, bacterial load in peritoneal fluid, blood and lung tissue, myeloperoxidase (MPO) activity in lung and liver and different immune cell populations in spleen were studied. We found that Galpha(i) proteins are rapidly activated by LPS followed by rapid inactivation. These studies provide the first direct evidence that Galpha(i) proteins are modulated by TLR signaling. In following studies, PTx augmented LPS induced plasma TNFalpha, IL-6, whereas MP-7 suppressed LPS-induced TNFalpha and decreased LPS-induced mortality. In sepsis studies, the survival rate post-CLP was significantly decreased in the Galpha(i2) (-/-) mice compared to WT mice. CLP induced plasma TNFalpha, IL-6, bacterial load in peritoneal fluid, blood and lung tissue and lung and liver MPO activity were significantly increased in Galpha(i2) (-/-) compared to WT mice. Galpha(i2) (-/-) mice also exhibited increased Th1 and Th2 responses compared to WT mice. Taken together, Galpha(i) proteins are activated by LPS and negatively regulate endotoxemia and sepsis. Understanding the role of Galpha(i2) protein in regulation of the inflammatory response in sepsis may provide novel targets for treatment of sepsis. PMID- 21255618 TI - Lipid rafts are essential for the regulation of SOCE by plasma membrane resident STIM1 in human platelets. AB - STIM1 is a transmembrane protein essential for the activation of store-operated Ca2+ entry (SOCE), a major Ca2+ influx mechanism. STIM1 is either located in the endoplasmic reticulum, communicating the Ca2+ concentration in the stores to plasma membrane channels or in the plasma membrane, where it might sense the extracellular Ca2+ concentration. Plasma membrane-located STIM1 has been reported to mediate the SOCE sensitivity to extracellular Ca2+ through its interaction with Orai1. Here we show that plasma membrane lipid raft domains are essential for the regulation of SOCE by extracellular Ca2+. Treatment of platelets with the SERCA inhibitor thapsigargin (TG) induced Mn2+ entry, which was inhibited by increasing concentrations of extracellular Ca2+. Platelet treatment with methyl beta-cyclodextrin, which removes cholesterol and disrupts the lipid raft domains, impaired the inactivation of Ca2+ entry induced by extracellular Ca2+. Methyl beta-cyclodextrin also abolished translocation of STIM1 to the plasma membrane stimulated by treatment with TG and prevented TG-evoked co-immunoprecipitation between plasma membrane-located STIM1 and the Ca2+ permeable channel Orai1. These findings suggest that lipid raft domains are essential for the inactivation of SOCE by extracellular Ca2+ mediated by the interaction between plasma membrane located STIM1 and Orai1. PMID- 21255619 TI - Identify submitochondria and subchloroplast locations with pseudo amino acid composition: approach from the strategy of discrete wavelet transform feature extraction. AB - It is very challenging and complicated to predict protein locations at the sub subcellular level. The key to enhancing the prediction quality for protein sub subcellular locations is to grasp the core features of a protein that can discriminate among proteins with different subcompartment locations. In this study, a different formulation of pseudoamino acid composition by the approach of discrete wavelet transform feature extraction was developed to predict submitochondria and subchloroplast locations. As a result of jackknife cross validation, with our method, it can efficiently distinguish mitochondrial proteins from chloroplast proteins with total accuracy of 98.8% and obtained a promising total accuracy of 93.38% for predicting submitochondria locations. Especially the predictive accuracy for mitochondrial outer membrane and chloroplast thylakoid lumen were 82.93% and 82.22%, respectively, showing an improvement of 4.88% and 27.22% when other existing methods were compared. The results indicated that the proposed method might be employed as a useful assistant technique for identifying sub-subcellular locations. We have implemented our algorithm as an online service called SubIdent (http://bioinfo.ncu.edu.cn/services.aspx). PMID- 21255621 TI - Human MxA protein inhibits the replication of classical swine fever virus. AB - Classical swine fever virus (CSFV) has a spherical enveloped particle with a single stranded RNA genome, the virus belonging to a pestivirus of the family Flaviviridae is the causative agent of an acute contagious disease classical swine fever (CSF). The interferon-induced MxA protein has been widely shown to inhibit the life cycle of certain RNA viruses as members of the Bunyaviridae family and others. Interestingly, it has been reported that expression of MxA in infected cells was blocked by CSFV and whether MxA has an inhibitory effect against CSFV remains unknown to date until present. Here, we report that CSFV replicated poorly in cells stably transfected with human MxA. The proliferation of progeny virus in both PK-15 cell lines and swine fetal fibroblasts (PEF) continuously expressing MxA was shown significantly inhibited as measured by virus titration, indirect immune fluorescence assay and real-time PCR. PMID- 21255620 TI - Alpha-synuclein release by neurons activates the inflammatory response in a microglial cell line. AB - The neurodegenerative process in Parkinson's disease (PD) is accompanied by the presence of a neuroinflammatory response, which has been suggested as one of the principal components involved in PD progression. In this report we assessed the inflammatory potential of alpha-synuclein, a protein central to PD pathogenesis, released by neurons on the mouse microglia cell line BV-2. BV-2 cells were treated with conditioned medium isolated from normal SH-SY5Y cells and clones that over-express WT or mutant A53T alpha-synuclein. Conditioned medium isolated from over-expressing clones induced the transcription and release of pro inflammatory cytokines. Treatment of SH-SY5Y alpha-synuclein over-expressing cells with MPP+, the active metabolite of the neurotoxin MPTP, increased the inflammatory response in BV-2 cells. In contrast, the direct exposure of BV-2 cells to MPP+ failed to induce an inflammatory response. These results support the hypothesis that WT and A53T alpha-synuclein has an important role in the initiation and maintenance of inflammation in PD, through the activation of a pro inflammatory response in microglial cells. PMID- 21255622 TI - Identification of a linear epitope on the capsid protein of classical swine fever virus. AB - The capsid (C) protein of Classical swine fever virus (CSFV) is proposed to play an essential role in the replication and translation of the viral RNA. In this study, a monoclonal antibody (mAb) directed against the C protein was generated with the recombinant C protein expressed in Escherichia coli as immunogen. IFA and IPMA analysis showed that the native C protein of CSFV virions was reactive to the mAb. By truncating the C protein, we identified a linear epitope recognized by the mAb, corresponding to amino acids (61)TQDGLYHNKN(70) of the CSFV C protein, which is well conserved among pestiviruses. Laser confocal analysis showed that the C protein mainly locates in the cellular nucleoplasm and nucleolus of PK-15 cells. The results have implications for further study of CSFV replication. PMID- 21255623 TI - In situ apoptosis of adaptive immune cells and the cellular escape of rabies virus in CNS from patients with human rabies transmitted by Desmodus rotundus. AB - The aim of the current study was to investigate the apoptosis of neurons, astrocytes and immune cells from human patients that were infected with rabies virus by vampire bats bite. Apoptotic neurons were identified by their morphology and immune cells were identified using double immunostaining. There were very few apoptotic neurons present in infected tissue samples, but there was an increase of apoptotic infiltrating CD4+ and TCD8+ adaptive immune cells in the rabies infected tissue. No apoptosis was present in NK, macrophage and astrocytes. The dissemination of the human rabies virus within an infected host may be mediated by viral escape of the virus from an infected cell and may involve an anti apoptotic mechanism, which does not kill the neuron or pro-apoptosis of TCD4+ and TCD8+ lymphocytes and which allows for increased proliferation of the virus within the CNS by attenuation of the adaptive immune response. PMID- 21255624 TI - Regulation of STAT signaling in mouse bone marrow derived dendritic cells by respiratory syncytial virus. AB - BACKGROUND/AIMS: Dendritic cells (DCs) act as a portal for virus invasion as well as potent antigen-presenting cells (APCs) involved in the antiviral host response. Interferons (IFNs) are produced in response to bacterial and viral infection and activate innate immune responses to efficiently counteract and remove pathogenic invaders. Respiratory syncytial virus (RSV) could inhibit IFN mediated signaling pathway in epithelial cells; however, the effects of RSV on IFN signaling in the dendritic cells (DCs) are still unknown. METHODS: Mouse bone marrow derived DCs (BMDCs) were mock or infected with RSV at different multiplicity of infection (MOI) for 24h, and then treated with different cytokines such as interferon-beta (IFN-beta), IFN-gamma or interleukin-10 (IL 10). The mRNA expression of RSV nonstructural protein-1 (NS-1) and NS-2 was detected by RT-PCR. The expression of Janus family kinase-signal transducer and activator of transcription (JAK/STAT) signaling proteins was assessed by immunoblotting assays. The nuclear localization of specific signaling proteins was determined by immunofluorescence assay. RESULTS: Increasing amounts of NS-1 or NS-2 mRNA expression in BMDCs were observed with infected RSV at increasing MOI, suggesting BMDCs were permissive for viral gene expression. Further examination of the IFN-beta signaling cascade showed RSV infection increased the total cellular levels of STAT1 and STAT2 in BMDCs, but impaired the IFN-beta dependent phosphorylation and nuclear localization of STAT1 and STAT2. The inhibitory effects of RSV on STAT1 and STAT2 phosphorylation and translocation were abolished by UV inactivation. In contrast, RSV did not inhibit the IFN-gamma stimulated STAT1 phosphorylation and nuclear localization. IL-10-stimulated STAT3 phosphorylation was also unaffected by RSV. CONCLUSIONS: As well as RSV inhibiting STAT protein levels through degradation mechanisms in epithelial cells, these findings demonstrate that RSV also can specifically inhibit the type I interferon response in BMDCs through regulation of STAT1 and STAT2 phosphorylation and nuclear translocation. PMID- 21255625 TI - Full genome sequencing and analysis of human cytomegalovirus strain JHC isolated from a Korean patient. AB - Human cytomegalovirus (HCMV) is a ubiquitous human pathogen and contains double stranded DNA genome with approximately 230 kbp. Because of its huge size, comparative genomic studies of HCMV genome have been limited. In this study it was attempted to obtain and analyze the full genome sequence from clinical isolate from Korea. The strain JHC was isolated from Korean patient undergoing bone marrow transplantation who exhibited resistance to ganciclovir treatment (Lee et al., 2005). The virus was plaque-purified, and the full genome sequence was determined by pyrosequencing technique. The JHC genome was found to contain 235,476 bp and 165 open reading frames (ORFs). Comparison with the full genome nucleotide sequences of 11 other HCMV strains suggest that JHC is not closely related with any other strains at genome level. As expected, JHC lacked IRL sequences found in lab-adapted AD169-varUK strain and this region was replaced by ORFs UL133-UL150 as in other clinical isolates. Two ORFs (UL1 and UL119) of the strain JHC were found to be truncated due to early stop codons, and RL6 contains an unusual start codon TTG. The strain JHC contains all the genetic information for micro RNAs known to be present in HCMV. PMID- 21255626 TI - Intracellular organelle-targeted non-viral gene delivery systems. AB - Gene therapy is a rapidly growing approach for the treatment of various diseases. To achieve successful gene therapy, a gene delivery system is necessary to overcome several barriers in the extracellular and intracellular spaces. Polymers, peptides, liposomes and nanoparticles developed as gene carriers have achieved efficient cellular uptake of genes. Among these carriers, cationic polymers and peptides have been further developed as intracellular organelle targeted delivery systems. The cytoplasm, nucleus and mitochondria have been considered primary targets for gene delivery using targeting moieties or environment-responsive materials. In this review, we explore recently developed non-viral gene carriers based on reducible systems specialized to target the cytoplasm, nucleus and mitochondria. PMID- 21255627 TI - Low-dose whey protein-enriched water beverages alter satiety in a study of overweight women. AB - AIM: To determine the effect of low-dose whey protein-enriched water beverages on postprandial satiety and energy intake (EI). METHODS: Fifty overweight and mildly obese women were given 500 mL water-based beverages on 4 different occasions in a double blind, cross-over study. The beverages were reasonably matched for colour, flavour, sweetness and contained 0% (water control, 0 g, 8 kJ), 1% (5 g, 93 kJ), 2% (10 g, 178 kJ) and 4% (20 g, 348 kJ) whey protein by weight (ClearProtein8855TM). Following a standard evening meal and breakfast, beverages were consumed 120 min before an ad libitum lunch at which EI was measured. Feelings associated with hunger and fullness were also measured using visual analogue scales (VAS). RESULTS: 46 participants completed all 4 beverage conditions. There was a significant effect of beverage preload on hunger (beverage*time; P=0.0074), where each of the 1%, 2% and 4% w/w protein beverages decreased hunger compared to the water control (P<0.05). Suppression of hunger was also maintained for longer following the protein beverages (Friedman test, P=0.013). Fullness (beverage*time; P=0.0020) and satisfaction (beverage*time; P=0.0356) were both increased by the 1% and 4% protein beverages (P<0.05). EI at lunch decreased by up to 8 percent (control vs 4% protein, delta=-247 kJ, Tukey's post hoc, P>0.05) when escalating protein doses were added to the water preload (water control, 3028 kJ; 1%, 3080 kJ; 2%, 2924 kJ; 4%, 2781 kJ), only partial compensation for the added energy. CONCLUSIONS: These low-dose, whey protein enriched water beverages significantly altered short term postprandial satiety, however the effect was not sufficient to impact on food intake when assessed 2 h after consumption. PMID- 21255628 TI - Propionate. Anti-obesity and satiety enhancing factor? AB - Propionate is produced along with acetate and butyrate as a result of fermentative activity of gut microflora on dietary fiber. It has long been known to exhibit hypophagic effects in ruminants, however, its potential physiological roles in non-ruminants as well as humans remained unnoticed over the years. In view of various studies pointing towards the hypophagic as well as hypocholesterolemic effects of propionate in humans, it may act as an important factor in amelioration of obesity, a lifestyle disease arising due to energy imbalance and growing at a startling rate globally. Short chain fatty acids have recently been ascribed as ligands to G-protein coupled receptors (GPRs) 41 and 43. Thus, propionate along with acetate may also be involved in the regulation of adipogenesis and adipokine release mediated via GPRs. The present review summarizes the evidence which collectively raise the possibility of propionate as a dietary factor to depress appetite and combat the obesity epidemic. PMID- 21255629 TI - Differential toxicity profile of ricin isoforms correlates with their glycosylation levels. AB - Ricin is one of the most potent and deadly plant toxins from the seeds of Ricinus communis. In view of its high toxicity, ricin is being used as an immunotoxin in cancer therapy. Ricin also has several isoforms with differential glycosylation depending on the seed variety. Our study shows three isoforms designated 1, 2 and 3, which differed in their surface charge, resulting in a different behavior on cation exchange chromatography, two dimensional (pI 5.5-8.7) and native PAGE. The molecular masses of isoform-1, 2 and 3 were measured as 63.55 kDa, 64.03 kDa and 62.8 kDa, respectively, by MALDI-TOF/MS. In vitro studies with monkey kidney (Vero) cells showed a time dependent increase in cytotoxicity of the isoforms evaluated by extracellular lactate dehydrogenase activity and mitochondrial dehydrogenase assay. These isoforms also induce oxidative stress and DNA damage. Among the isoforms, isoform-3 was quick to generate reactive oxygen species (ROS), (in 90 min) and exhibited maximum cytotoxicity. Morphological changes, catalase activity and DNA fragmentation were significantly higher with isoform-3 treatment compared to others. The glycosylation studies by MALDI-TOF/MS showed that isoform-3 is highly glycosylated with high sugar levels containing more of hybrid/complex type glycopeptides with mannose as hexose units. These experimental evidences clearly suggest that isoform-3 is superior in its early ROS generation, potency to induce oxidative stress and cytotoxicity, that could be due to it's higher glycosylation levels which make isoform-3 as an ideal candidate for immunotoxin studies. PMID- 21255630 TI - New and translational perspectives of oestrogen deprivation in breast cancer. AB - Over the last 20 years, aromatase inhibitors have been developed to become a highly effective treatment strategy for treatment of hormone receptor positive breast cancer. Despite their success, poor response and resistance limit the effectiveness of these agents in up to 50% of patients. In recent years, studies using highly sensitive hormone assays have provided insight into the source of oestrogen production for the stimulation of oestrogen receptor positive breast cancer growth, suggesting that uptake from the circulation is likely to make a significant contribution to intratumoural oestradiol. To obtain insight into how tumours become resistant to oestrogen after aromatase inhibition, long term oestrogen deprivation of cultured cells has been used to mimic acquired resistance to aromatase inhibitors. This work has aided the selection of agents to rationally combine with aromatase inhibitors to combat resistance. Molecular profiling using genome-wide approaches has shed new light on the heterogeneity of responses to oestrogen deprivation and predictors of resistance in vivo. Testing new agents and combinations in short-term pre-surgical studies using biomarkers such as Ki67 is critical for increasing the rate at which new rational combinations can be assessed for efficacy. PMID- 21255631 TI - Localization of hypothalamic insulin receptor in neonatal chicks: evidence for insulinergic system control of feeding behavior. AB - Feeding behavior is managed by various neuropeptides and/or neurotransmitters within the central nervous system in vertebrates. It is proposed that central insulin acts as the negative-feedback regulator of appetite via the central melanocortin system in neonatal chicks. The present study investigated the localization of insulin receptors in the chick hypothalamus using immunohistochemistry. Immunostaining revealed hypothalamic neuron expressing insulin receptors in the paraventricular nucleus, ventromedial hypothalamus, lateral hypothalamus and infundibular nucleus, the avian equivalent of the mammalian arcuate nucleus. Additionally, double-staining immunohistochemistry in the infundibular nucleus revealed the presence of insulin receptors in both alpha melanocyto stimulating hormone and neuropeptide Y neurons. Immunohistological analysis indicates that the insulinergic system in the chick hypothalamus contributes to feeding behavior and this system regulates both anorexigenic and orexigenic neuropeptides. Furthermore, the mechanisms of central insulin induced feeding behavior contributes to the regulation of the melanocortin system in the chick infundibular nucleus. PMID- 21255632 TI - Analysis of metabotropic glutamate receptor 7 as a potential substrate for SUMOylation. AB - Group III metabotropic glutamate receptors (mGluRs) undergo post-translational modification by SUMO in in vitro assays but the SUMOylation of full-length mGluRs in mammalian cells has not been reported. Here we investigated SUMOylation of mGluR7 in HEK293 cells and primary cortical neurons in an attempt to confirm SUMOylation and define physiological effects on mGluR7 function. Using a recombinant bacterial expression assay we validated in vitro SUMOylation of the C terminal domain of mGluR7 by both SUMO-1 and SUMO-2 and show that a single lysine residue (K889) in mGluR7 is required for SUMOylation. However, using a range of approaches, we were unable to detect SUMOylation of full-length mGluR7 in either heterologous cells or neurons. Further, we observed no differences in receptor stability or surface expression between wild-type and a non-SUMOylatable point mutant mGluR7. Thus, our results question whether mGluR7, and by implication other group III mGluRs, are physiologically relevant neuronal SUMO substrates. PMID- 21255633 TI - Frontal activation and connectivity using near-infrared spectroscopy: verbal fluency language study. AB - Near infrared spectroscopy (NIRS) is an optical technique with high temporal resolution and reasonably good spatial resolution, which allows non invasive measurement of the blood oxygenation of tissue. The current work is focused in assessing and correlating brain activation, connectivity and cortical lateralization of the frontal cortex in response to language-based stimuli, using NIRS. Experimental studies were performed on 15 normal right-handed adults, wherein the participants were presented with a verbal fluency task. The hemodynamic responses in the pre- and anterior frontal cortex were assessed in response to a Word generation task in comparison to the baseline random Jaw movement and Rest conditions. The functional connectivity analysis was performed using zero-order correlations and the cortical lateralization was evaluated as well. An increase in oxy- and a decrease in deoxy-hemoglobin were observed during verbal fluency task in the frontal cortex. Unlike in the pre-frontal cortex, the hemodynamic response in the anterior frontal during verbal fluency task was not significantly different from that during random Jaw movement. Bilateral activation and symmetrical connectivity were observed in the pre-frontal cortex, independent of the stimuli presented. A left cortical dominance and asymmetry connectivity was observed in the anterior frontal during the verbal fluency task. The work is focused to target the pediatric epileptic populations in the future, where understanding the brain functionality (activation, connectivity, and dominance) in response to language is essential as a part of the pre-surgical evaluation in a clinical environment. PMID- 21255634 TI - Nitric oxide synthase expression in the medullary respiratory related nuclei and its involvement in CO-mediated central respiratory effects in neonatal rats. AB - The present study was conducted in order to observe the potential participation of the nitric oxide synthase-NO pathway in CO-mediated regulation of respiration of neonatal rats. An immunofluorescent histochemical technique was used to examine the existence of the neuronal nitric oxide synthase, a key enzyme of synthesizing NO, in medullary respiratory nuclei. The rhythmic respiratory-like discharges of hypoglossal rootlets of medullary slices were recorded to test the role of the nitric oxide synthase in CO-mediated respiratory effects. We observed neuronal nitric oxide synthase expressed in the medullary respiratory nuclei in conjunction with CO lengthened expiratory duration, decreased respiratory frequency, and increased inspiratory amplitude. These CO-mediated respiratory effects could be partially eliminated by prior treatment of the slices with Nomega-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. The results suggest that nitric oxide synthase-NO pathway might be involved in the CO mediated central regulation of respiration at the level of medulla oblongata in neonatal rats. PMID- 21255635 TI - Chronic, systemic treatment with a metabotropic glutamate receptor 5 antagonist produces anxiolytic-like effects and reverses abnormal firing activity of projection neurons in the basolateral nucleus of the amygdala in rats with bilateral 6-OHDA lesions. AB - Although 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective metabotropic glutamate receptor 5 antagonist, improves the motor symptoms of Parkinson's disease (PD), the effects of MPEP on the psychiatric symptom of PD and the mechanism involved are still unclear. In the present study, we examined the effects of MPEP in anxiolytic-like behavior and firing activity of projection neurons in the basolateral nucleus of the amygdala (BLA) in rats with 6 hydroxydopamine (6-OHDA) injected bilaterally into dorsal striatum. Rats were divided into three groups, sham-operated group, 6-OHDA lesion with vehicle treatment group and 6-OHDA lesion with MPEP treatment group. Injection of 6-OHDA (10.5 MUg) into the dorsal striatum produced 31.5% loss of tyrosine hydroxylase immunoreactive (TH-ir) neurons in the SNpc. The 6-OHDA-lesioned rats showed anxiety behavior and the firing rate of BLA projection neurons decreased significantly compared with sham-operated rats, and no difference was found in the firing pattern of these neurons. Whereas chronic, systemic treatment of MPEP (3 mg/kg/day, i.p.; 14 days) attenuated loss of TH-ir neurons, produced anxiolytic-like effect and normalized the abnormal firing rate of projection neurons of the BLA in rats with the bilateral lesions. Systemic administration of cumulative apomorphine (10-160 MUg/kg, i.v.) inhibited the firing rate of BLA projection neurons in sham-operated, 6-OHDA lesion with vehicle-treated and MPEP treated rats, but the 6-OHDA lesion decreased the response of BLA projection neurons to apomorphine stimulation, while MPEP reversed the reactivity of these neurons. These data demonstrate that the partial lesion of the nigrostriatal pathway causes anxiety symptom and decreases firing rate of BLA projection neurons in the rat. Furthermore, chronic, systemic MPEP treatment has the neuroprotective and anxiolytic-like effects, and reverses the abnormal firing rate of BLA projection neurons, suggesting that MPEP has important implication for the treatment of PD. PMID- 21255636 TI - The future is written: impact of scripts on the cognition, selection, knowledge and transmission of medicinal plant use and its implications for ethnobotany and ethnopharmacology. AB - AIM OF THE STUDY: Apart from empirically learned medicinal and pharmacological properties, the selection of medicinal plants is dependent on cognitive features, ecological factors and cultural history. In literate societies the transmission of medicinal plant knowledge through texts and, more recently, other media containing local as well as non-local knowledge has a more immediate and a more prolonged effect than oral transmission. Therefore, I try to visualize how field based studies in ethnobiology and especially medical ethnobotany and ethnopharmacology run the risk of repeating information and knowledge and illustrate the importance of differentiating and acknowledging the origin, transmission and rationale of plant use made by humans. MATERIALS AND METHODS: Reviewing literature dealing with the traditional parameters (e.g. hot/cold dichotomy, organoleptic properties, doctrine of signatures) influencing the selection and transmission of plant use in a juxtaposition to our recent finding of causal influence of text on local plant use. Discussing the passing down of knowledge by text as a special case of oblique/one-to-many knowledge transmission. RESULTS: Historical texts on materia medica, popular books on plant use, clinical studies, and informants of ethnobotanical field studies generate a circle of information and knowledge, which progressively conditions the results of ethnobotanical field studies. While text reporting on phytotherapeutical trends may cause innovation through the introduction of "new" applications to local customs, persistently repeating well established folk remedies leads to the consolidation of such uses adding a conservative dimension to a local pharmacopoeia, which might not actually be there to that extent. CONCLUSIONS: Such a "shaping" of what might appear to be the results of a field investigation is clearly outside the ordinary principles of scientific enquiry. The traditional pillars of ethnobotanical field studies - that is, "input to drug discovery" and "conservation of cultural heritage" - are also incompatible with this process. Ethnobotancial field studies aimed at a contribution to natural products research and/or the conservation of cultural heritage, as well as those aimed at an assessment and validation of local pharmacopoeias should differentiate between local plant use and widespread as well as modern knowledge reported in popular textbooks and scientific literature. PMID- 21255637 TI - Early biochemical effects after unilateral hypoxia-ischemia in the immature rat brain. AB - Perinatal hypoxia-ischemia (HI) gives rise to inadequate substrate supply to the brain tissue, resulting in damage to neural cells. Previous studies at different time points of development, and with different animal species, suggest that the HI insult causes oxidative damage and changes Na+, K+-ATPase activity, which is known to be very susceptible to free radical-related lipid peroxidation. The aim of the present study was to establish the onset of the oxidative damage response in neonatal Wistar rats subjected to brain HI, evaluating parameters of oxidative stress, namely nitric oxide production, lipoperoxidation by thiobarbituric acid reactive substances (TBA-RS) production and malondialdehyde (MDA) levels, reactive species production by DCFH oxidation, antioxidant enzymatic activities of catalase, glutathione peroxidase, superoxide dismutase as well as Na+, K+ ATPase activity in hippocampus and cerebral cortex. Rat pups were subjected to right common carotid ligation followed by exposure to a hypoxic atmosphere (8% oxygen and 92% nitrogen) for 90 min. Animals were sacrificed by decapitation 0, 1 and 2 h after HI and both hippocampus and cerebral cortex from the right hemisphere (ipsilateral to the carotid occlusion) were dissected out for further experimentation. Results show an early decrease of Na+, K+-ATPase activity (at 0 and 1 h), as well as a late increase in MDA levels (2 h) and superoxide dismutase activity (1 and 2 h after HI) in the hippocampus. There was a late increase in both MDA levels and DCFH oxidation (1 and 2 h) and an increase in superoxide dismutase activity (2 h after HI) in cortex; however Na+, K+-ATPase activity remained unchanged. We suggest that neonatal HI induces oxidative damage to both hippocampus and cortex, in addition to a decrease in Na+, K+-ATPase activity in hippocampus early after the insult. These events might contribute to the later morphological damage in the brain and indicate that it would be essential to pursue neuroprotective strategies, aimed to counteract oxidative stress, as early as possible after the HI insult. PMID- 21255638 TI - Crosstalk between platelet-derived growth factor-induced Nox4 activation and MUC8 gene overexpression in human airway epithelial cells. AB - Reactive oxygen species (ROS) contribute to chronic airway inflammation, and NADPH oxidase (Nox) is an important source of ROS. However, little is known of the role that ROS play in chronic upper respiratory tract inflammation. We investigated the mechanism of ROS generation and its association with mucin gene overexpression in the nasal epithelium. The level of platelet-derived growth factor (PDGF) expression was increased in sinusitis mucosa, and high-level PDGF expression induced intracellular ROS, followed by MUC8 gene overexpression in normal human nasal epithelial cells. Knockdown of Nox4 expression with Nox4 siRNA decreased PDGF-induced intracellular ROS and MUC8 expression. Infection with an adenovirus containing Nox4 cDNA resulted in Nox4 overexpression and increased intracellular levels of ROS and MUC8 expression. PDGF and Nox4 overexpression are essential components of intracellular ROS generation and may contribute to chronic inflammation in the nasal epithelium through induction of MUC8 overexpression. PMID- 21255639 TI - Glutathione modulates the toxicity of, but is not a biologically relevant reductant for, the Pseudomonas aeruginosa redox toxin pyocyanin. AB - Pyocyanin is an important redox toxin produced by the common human pathogen Pseudomonas aeruginosa. It generates reactive oxygen species (ROS) that alter intracellular redox status and cell function. Reducing equivalents for pyocyanin are provided by intracellular NAD(P)H and, it has been reported, glutathione (GSH). Cellular GSH levels are at least 1-2 orders of magnitude greater than NAD(P)H; therefore GSH should represent the major reductant for pyocyanin and potentiate its toxicity. Paradoxically, GSH has been found to inhibit pyocyanin toxicity in cellular models. This study was undertaken to evaluate the potential of GSH as a biologically relevant reductant for pyocyanin. As observed using spectrophotometry, under aerobic conditions pyocyanin readily oxidized NADPH, whereas oxidation of GSH could not be detected. Under anaerobic conditions pyocyanin was reduced by NADPH, but reduction by GSH could not be detected. Reduction of molecular oxygen and the formation of ROS readily proceeded in the presence of pyocyanin and NADPH, whereas GSH was without effect. Finally, exposure of normal human dermal fibroblasts to subcytotoxic concentrations of pyocyanin did not lead to depletion of endogenous GSH, but exogenous GSH provided protection against the senescence-inducing effects of the toxin. In summary, GSH does not reduce pyocyanin under physiologically relevant conditions or contribute to pyocyanin toxicity. However, GSH does provide protection against the deleterious effects of this important bacterial toxin on mammalian cells. PMID- 21255640 TI - Changes in reactive oxygen species begin early during replicative aging of Saccharomyces cerevisiae cells. AB - Increased reactive oxygen species (ROS) are a feature of aging cells, but little is known about when ROS generation begins as cells age. Here we show how ROS change in Saccharomyces cerevisiae cells throughout their early replicative life span using the fluorescent ROS indicator dihydroethidium (DHE), which has some specificity for the superoxide anion. Cells in a particular age range were heterogeneous with respect to their ROS burden. Surprisingly, some cells as young as 5-7 generations acquired a greatly increased level of ROS detected by DHE relative to virgin cells. By 12 generations 50% of cells had a substantial ROS burden despite being only halfway through their life span. In contrast to the wild type, cells of a sir2 mutant had lower levels of ROS reacting with DHE. Daughters from older mothers had low ROS levels, and this asymmetric distribution of ROS was SIR2-independent. Mitochondrial fragmentation also began to occur in cells after 4 generations and increased markedly as cells aged. Daughter cells regenerated normal tubular mitochondria despite the fragmentation of mitochondria in the mother cells, whereas daughters of the sir2 mutant had fragmented mitochondria at all ages. PMID- 21255641 TI - Akt activation through the phosphorylation of erythropoietin receptor at tyrosine 479 is required for myeloproliferative disorder-associated JAK2 V617F mutant induced cellular transformation. AB - The disruption of Janus kinase 2 (JAK2) signaling regulation by its point mutation, V617F, is involved in various myeloproliferative disorders (MPDs). JAK2 V617F mutant induced constitutive activation of Akt when erythropoietin receptor (EpoR) was coexpressed; however, the physiological role of Akt activation in MPDs has not been elucidated. LY294002, a phosphoinositide 3-kinase (PI3K) inhibitor, inhibited Akt activation and induced apoptotic cell death in cells expressing JAK2 V617F mutant and EpoR. Previously, it has been shown that the phosphorylation at Y479 in EpoR is critical for the interaction with PI3K, an upstream molecule of Akt. Hence, EpoR mutant with a point mutation of Y479F, which fails to activate Akt, is useful for addressing the role of Akt activation in JAK2 V617F mutant-induced tumorigenesis. Interestingly, under the expression of EpoR Y479F mutant, JAK2 V617F mutant failed to exhibit potent anti-apoptotic activity. In addition, JAK2 V617F mutant-induced phosphorylation of CREB and GSK 3beta was significantly decreased in cells expressing EpoR Y479F mutant, resulting in the downregulation of Bcl-XL and Mcl-1 expression. Furthermore, compared with when nude mice were inoculated with cells expressing JAK2 V617F mutant and EpoR, the lifespan of nude mice inoculated with cells expressing JAK2 V617F mutant and EpoR Y479F mutant was effectively prolonged. Taken together, it was clarified that PI3K-Akt activation through the phosphorylation of EpoR at Y479 is required for oncogenic signaling of JAK2 V617F mutant and that targeted disruption of this pathway has therapeutic utility. PMID- 21255642 TI - The PI3K-Akt pathway regulates calpain 6 expression, proliferation, and apoptosis. AB - The calpains are a family of cysteine proteases involved in some biological processes whose activities are highly dependent on Ca(2+). Calpain 6 (CAPN6), one member of the family, is unique in that it lacks the active-site cysteine residues for protease activity. According to the data that CAPN6 was up-regulated in the Akt transformed mouse embryonic fibroblast cells by cDNA chip, the mechanisms underlying elevated CAPN6 expression by PI3K-Akt signaling pathway and its biological functions were studied. The results showed that CAPN6 was down regulated on transcriptional and post-transcriptional levels by the PI3K inhibitor or Akt deletion. CAPN6 protein was stabilized by PI3K-GSK-3beta pathway. Deleted CAPN6 promoters activity were assessed by dual-luciferase reporter system, and the founding indicated that -93/+200 DNA fragment was the core promoter of it. Transcription factor binding sites in the CAPN6 promoter were mutated and the results showed that AP1, Oct-1, and FoxD3 were the critical transcription factors in regulation of CAPN6 expression. In addition, CAPN6 promoted cancer cell proliferation and inhibited its apoptosis. The finding demonstrates that CAPN6 is regulated by the PI3K-Akt signaling pathway and provides evidence that it may be a therapeutic target of cancer. PMID- 21255644 TI - O-GlcNAcylation is a novel regulator of lung and colon cancer malignancy. AB - O-GlcNAc is a monosaccharide attached to serine or threonine hydroxyl moieties on numerous nuclear and cytoplasmic proteins; O-GlcNAcylation is dynamically regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Although recent studies have shown that O-GlcNAcylation plays essential roles in breast cancer progression, it is also necessary to know whether O-GlcNAcylation is involved in other types of human cancer. In this study, O-GlcNAcylation levels and the expressions of OGT and OGA in human lung and colon cancer tissues were examined by immunohistochemistry analysis. We found that O-GlcNAcylation as well as OGT expression was significantly elevated in the cancer tissues compared with that in the corresponding adjacent tissues. Additionally, the roles of O-GlcNAcylation in the malignancy of lung and colon cancer were investigated in vitro. The results showed that O-GlcNAcylation markedly enhanced the anchorage-independent growth of lung and colon cancer cells; O-GlcNAcylation could also enhance lung and colon cancer invasion in a context-dependent manner. All together, this study suggests that O-GlcNAcylation might play important roles in lung and colon cancer formation and progression, and may be a valuable target for diagnosis and therapy of cancer. PMID- 21255645 TI - Fluid transport and cystogenesis in autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited nephropathy. The development and enlargement of cysts in ADPKD requires tubular cell proliferation, abnormalities in the extracellular matrix and transepithelial fluid secretion. Multiple studies have suggested that fluid secretion across ADPKD cyst-lining cells is driven by the transepithelial secretion of chloride, mediated by the apical CFTR channel and specific basolateral transporters. The whole secretory process is stimulated by increased levels of cAMP in the cells, probably reflecting modifications in the intracellular calcium homeostasis and abnormal stimulation of the vasopressin V2 receptor. This review will focus on the pathophysiology of fluid secretion in ADPKD cysts, starting with classic, morphological and physiological studies that were followed by investigations of the molecular mechanisms involved and therapeutic trials targeting these pathways in cellular and animal models and ADPKD patients. This article is part of a Special Issue entitled: Polycystic Kidney Disease. PMID- 21255646 TI - Microporous bilayer osmotic tablet for colon-specific delivery. AB - Microporous bilayer osmotic tablet bearing dicyclomine hydrochloride and diclofenac potassium was developed using a new oral drug delivery system for colon targeting. The tablets were coated with microporous semipermeable membrane and enteric polymer using conventional pan-coating process. The developed microporous bilayer osmotic pump tablet (OPT) did not require laser drilling to form the drug delivery orifice. The colon-specific biodegradation of pectin could form in situ delivery pores for drug release. The effect of formulation variables like inclusion of osmogen, amount of HPMC and NaCMC in core, amount of pore former in semipermeable membrane was studied. Scanning electron microscopic photographs showed formation of in situ delivery pores after predetermined time of coming in contact with dissolution medium. The number of pores was dependent on the amount of the pore former in the semipermeable membrane. In vitro dissolution results indicated that system showed acid-resistant, timed release and was able to deliver drug at an approximate zero order up to 24h. The developed tablets could be effectively used for colon-specific drug delivery to treat IBS. PMID- 21255643 TI - Adult human CD133/1(+) kidney cells isolated from papilla integrate into developing kidney tubules. AB - Approximately 60,000 patients in the United States are waiting for a kidney transplant due to genetic, immunologic and environmentally caused kidney failure. Adult human renal stem cells could offer opportunities for autologous transplant and repair of damaged organs. Current data suggest that there are multiple progenitor types in the kidney with distinct localizations. In the present study, we characterize cells derived from human kidney papilla and show their capacity for tubulogenesis. In situ, nestin(+) and CD133/1(+) cells were found extensively intercalated between tubular epithelia in the loops of Henle of renal papilla, but not of the cortex. Populations of primary cells from the renal cortex and renal papilla were isolated by enzymatic digestion from human kidneys unsuited for transplant and immuno-enriched for CD133/1(+) cells. Isolated CD133/1(+) papillary cells were positive for nestin, as well as several human embryonic stem cell markers (SSEA4, Nanog, SOX2, and OCT4/POU5F1) and could be triggered to adopt tubular epithelial and neuronal-like phenotypes. Isolated papillary cells exhibited morphologic plasticity upon modulation of culture conditions and inhibition of asymmetric cell division. Labeled papillary cells readily associated with cortical tubular epithelia in co-culture and 3-dimensional collagen gel cultures. Heterologous organ culture demonstrated that CD133/1(+) progenitors from the papilla and cortex became integrated into developing kidney tubules. Tubular epithelia did not participate in tubulogenesis. Human renal papilla harbor cells with the hallmarks of adult kidney stem/progenitor cells that can be amplified and phenotypically modulated in culture while retaining the capacity to form new kidney tubules. This article is part of a Special Issue entitled: Polycystic Kidney Disease. PMID- 21255647 TI - Evolution of a physiological pH 6.8 bicarbonate buffer system: application to the dissolution testing of enteric coated products. AB - The use of compendial pH 6.8 phosphate buffer to assess dissolution of enteric coated products gives rise to poor in vitro-in vivo correlations because of the inadequacy of the buffer to resemble small intestinal fluids. A more representative and physiological medium, pH 6.8 bicarbonate buffer, was developed to evaluate the dissolution behaviour of enteric coatings. The bicarbonate system was evolved from pH7.4 Hanks balanced salt solution to produce a pH 6.8 bicarbonate buffer (modified Hanks buffer, mHanks), which resembles the ionic composition and buffer capacity of intestinal milieu. Prednisolone tablets were coated with a range of enteric polymers: hypromellose phthalate (HP-50 and HP 55), cellulose acetate phthalate (CAP), hypromellose acetate succinate (HPMCAS-LF and HPMCAS-MF), methacrylic acid copolymers (EUDRAGIT(r) L100-55, EUDRAGIT(r) L30D-55 and EUDRAGIT(r) L100) and polyvinyl acetate phthalate (PVAP). Dissolution of coated tablets was carried out using USP-II apparatus in 0.1M HCl for 2h followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, the various enteric polymer coated products displayed rapid and comparable dissolution profiles. In pH 6.8 mHanks buffer, drug release was delayed and marked differences were observed between the various coated tablets, which is comparable to the delayed disintegration times reported in the literature for enteric coated products in the human small intestine. In summary, the use of pH 6.8 physiological bicarbonate buffer (mHanks) provides more realistic and discriminative in vitro release assessment of enteric coated formulations compared to compendial phosphate buffer. PMID- 21255648 TI - Zero-order release of 5-fluorouracil from PCL-based films featuring trilayered structures for stent application. AB - A trilayered Poly(epsilon-caprolactone) (PCL)-based film with a coating layer (CL), a drug-storing layer (DSL) loaded with antitumor drug 5-Fluorouracil (5-FU) and a backing layer (BL) are presented for film-based stent application in malignant stricture or stenosis. V-C diffusion cells were used to investigate the drug permeability of the CL, while scanning electron microscopy (SEM) was employed for observing the microscopic architectures and morphologies. Drug release from the trilayered films exhibited a zero-order pattern, and the release process followed an 'outer-to-inner' pattern. The formation mechanism and influencing factors of the zero-order drug release pattern were in-depth elucidated, and factors affecting the drug release were also investigated. The reduction of initial drug loading in DSL slowed the drug release and diminished the zero-order release pattern. Drug permeability of the CL depended significantly on CL thickness, but not significantly on PCL molecular weight. Besides, the addition of PEG porogen in the CL accelerated the drug release by elevation of the drug permeability of CL, and the action mechanism of PEG was revealed by the PEG release test and SEM. The loading of 5-FU in the CL could lead to a two-phased release profile. This study revealed the potential of the trilayered film in controlled drug delivery to intraluminal tumor due to its highly tunable zero-order drug release. PMID- 21255650 TI - Antiretroviral drugs in HIV-infected children. AB - Availability of highly active antiretroviral therapy has dramatically increased survival rates and substantially modified the course of HIV infection, which has now become a chronic disease both in adults and in children. Treatment strategies in paediatric patients have to face with specific challenges associated with selection of a successful antiretroviral drug regimen, long-lasting maintenance of adherence to therapy, short and long-term drug-related toxicities and emerging of extensive drug resistance. This review shows an up-to-date picture of the ultimate advances of antiretroviral therapy in HIV-infected children. PMID- 21255649 TI - Crystallization of alpha- and beta-carotene in the foregut of Spodoptera larvae feeding on a toxic food plant. AB - In the animal kingdom, carotenoids are usually absorbed from dietary sources and transported to target tissues. Despite their general importance, the uptake mechanism is still poorly understood. Here we report the "red crop" phenomenon, an accumulation of alpha- and beta-carotene in crystalline inclusions in the enlarged foregut of the polyphagous Spodoptera larvae feeding on some potentially toxic plant leaves. The carotene crystals give the insect foregut a distinctive orange-red color. The crystals are embedded in a homogenous lawn of the bacterium Enterococcus casseliflavus, but the carotene seems to be selectively taken from the food plant. Caterpillars which fail to develop these carotene crystals exhibit a high mortality or fail to develop to adulthood. The crystallization of carotene and the enlargement of the foregut thus appears to manifest a multiple step physiological adaptation of the insects to toxic food plants. PMID- 21255651 TI - A novel C-type lectin from bay scallop Argopecten irradians (AiCTL-7) agglutinating fungi with mannose specificity. AB - C-type lectins are a superfamily of proteins that can bind pathogen-associated molecular patterns (PAMPs) and microorganisms through the recognition of carbohydrates, thus they are directly involved in innate defense mechanisms as part of the acute-phase response to infection. In this study, the cDNA of a novel C-type lectin (designated as AiCTL-7) was cloned from bay scallop Argopecten irradians by expression sequence tag (EST) analysis and rapid amplification of cDNA ends (RACE) approach. The full-length cDNA of AiCTL-7 was of 651 bp containing a 525 bp open reading frame which encoded a signal peptide of 15 residues and a conserved carbohydrate-recognition domain (CRD) of 174 residues with the EPD and WSD motifs instead of the invariant EPN and WND motifs for determining the carbohydrate-binding specificity and constructing Ca(2+)-binding site 2 in vertebrates. The deduced amino acid sequence of AiCTL-7 CRD shared homology not only with the CRDs of C-type lectins in mollusks, but also with the fish lectin CRDs. The mRNA transcripts of AiCTL-7 were mainly detected in the tissue of hepatopancreas and also marginally detectable in kidney, gonad, hemocytes, heart and adductor of health scallop. After challenge with fungi Pichia pastoris GS115 and Gram-negative bacteria Listonella anguillarum, the relative expression level of AiCTL-7 was up-regulated significantly in hepatopancreas and hemocytes. The CRD of AiCTL-7 was recombined and expressed in Escherichia coli, and the recombinant protein (rAiCTL-7) aggregated P. pastoris remarkably in a Ca(2+)-dependent manner, and this agglutination could be inhibited by d-mannose, but not by d-galactose or beta-1,3-glucan. However, rAiCTL-7 displayed no obvious agglutinating activity against L. anguillarum. These results collectively indicated that AiCTL-7 was involved in the primitive acute-phase response to microbial invasion as an important pattern recognition receptor (PRR) in the innate immune system of scallops. PMID- 21255652 TI - Development of immunity in rainbow trout (Oncorhynchus mykiss, Walbaum) to Aeromonas hydrophila after the dietary application of garlic. AB - The development and duration of immune protection against Aeromonas hydrophila infections with garlic as an immunostimulant in rainbow trout Oncorhynchus mykiss was studied. Rainbow trout fingerlings of 14 g average weight were fed with 0 g (=Control), 0.5 g and 1.0 g of garlic 100 g(-1) of feed for 14 days. Physiological factors, biochemical, immunological, haematological parameters and electrolyte indices were evaluated after a further 14, 21 and 28 days before challenge with Aeromonas hydrophila. Fourteen days after the cessation of feeding with garlic, mortality rates of 12% (relative percent survival [RPS] = 86%) and 16% (RPS = 80%) were recorded in groups which received 0.5 g and 1.0 g of garlic 100 g(-1) of feed, respectively, compared to 84% mortalities in the controls. The corresponding RPS 21 days after ending the feeding regime was 75% and 68, respectively. One week later, the RPS had dropped to 55% and 46% in the groups fed with 0.5 g and 1.0 g garlic 100 g(-1) of feed, respectively. PMID- 21255653 TI - Evaluation of internal control genes for qRT-PCR normalization in tissues and cell culture for antiviral studies of grass carp (Ctenopharyngodon idella). AB - Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) has become one of the most commonly used techniques for RNA expression. To obtain more reliable results with biological significance, it requires data normalization using an appropriate internal control gene. Here, we cloned partial sequence of elongation factor 1alpha (EF1alpha) gene from grass carp (Ctenopharyngodon idella). The stabilities of four commonly used internal control genes encoding 18S rRNA, beta-actin, EF1alpha, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were integratedly assessed using the geNorm, NormFinder and BestKeeper programs. Integrative analyses of qRT-PCR data indicated that the stability ranking of the examined genes was 18S rRNA > EF1alpha > GAPDH > beta actin in gill, head kidney, heart, intestine, liver, muscle, skin, spleen, and trunk kidney tissues in untreated grass carp. When the same calculations were done in spleen tissue at different time points post grass carp reovirus (GCRV) infection, the gene ranking was 18S rRNA > beta-actin > GAPDH > EF1alpha. The rank ordering of expression stability was EF1alpha > beta-actin>18S rRNA > GAPDH in C. idella kidney (CIK) cell culture stimulated by poly(I:C). The recommended ranking was EF1alpha > GAPDH > beta-actin>18S rRNA in CIK cells infected by GCRV. The results indicated that 18S rRNA was the best invariant internal control gene in individual level in grass carp, EF1alpha was the most suitable in CIK cell culture stimulated by poly(I:C) or infected by GCRV. As an assay, EF1alpha was employed to examine the changes of Toll-like receptor 3 (TLR3) and melanoma differentiation associated gene 5 (MDA5) after virus infection in CIK cells. These data laid the foundation for more precise results in qRT-PCR studies of gene expression in grass carp. PMID- 21255654 TI - Alteration of brain functional network at rest and in response to YMCA physical stress test in concussed athletes: RsFMRI study. AB - There is still controversy in the literature whether a single episode of mild traumatic brain injury (mTBI) results in short- and/or long-term functional and structural deficits in the concussed brain. With the inability of traditional brain imaging techniques to properly assess the severity of brain damage induced by a concussive blow, there is hope that more advanced applications such as resting state functional magnetic resonance imaging (rsFMRI) will be more specific in accurately diagnosing mTBI. In this rsFMRI study, we examined 17 subjects 10+/-2 days post-sports-related mTBI and 17 age-matched normal volunteers (NVs) to investigate the possibility that the integrity of the resting state brain network is disrupted following a single concussive blow. We hypothesized that advanced brain imaging techniques may reveal subtle alterations of functional brain connections in asymptomatic mTBI subjects. There are several findings of interest. All mTBI subjects were asymptomatic based upon clinical evaluation and neuropsychological (NP) assessments prior to the MRI session. The mTBI subjects revealed a disrupted functional network both at rest and in response to the YMCA physical stress test. Specifically, interhemispheric connectivity was significantly reduced in the primary visual cortex, hippocampal and dorsolateral prefrontal cortex networks (p<0.05). The YMCA physical stress induced nonspecific and similar changes in brain network connectivity patterns in both the mTBI and NV groups. These major findings are discussed in relation to underlying mechanisms, clinical assessment of mTBI, and current debate regarding functional brain connectivity in a clinical population. Overall, our major findings clearly indicate that functional brain alterations in the acute phase of injury are overlooked when conventional clinical and neuropsychological examinations are used. PMID- 21255655 TI - Dissociating hippocampal and basal ganglia contributions to category learning using stimulus novelty and subjective judgments. AB - We identified factors leading to hippocampal and basal ganglia recruitment during categorization learning. Subjects alternated between blocks of a standard trial and error category learning task and a subjective judgment task. In the subjective judgments task subjects categorized the stimulus and then instead of receiving feedback they indicated the basis of their response using 4 options: Remember: Conscious episodic memory of previous trials. Know-Automatic: Automatic, rapid response accompanied by conscious awareness of category membership. Know-Intuition: A "gut feeling" without fully conscious knowledge of category membership. Guess: Guessing. In addition, new stimuli were introduced throughout the experiment to examine effects of novelty. Categorization overall recruited both the basal ganglia and posterior hippocampus. However, basal ganglia activity was found during Know judgments (both Automatic and Intuition), whereas posterior hippocampus activity was found during Remember judgments. Granger causality mapping indicated interactions between the basal ganglia and hippocampus, with the putamen exerting directed influence on the posterior hippocampus, which in turn exerted directed influence on the posterior caudate nucleus. We also found a region of anterior hippocampus that showed decreased activity relative to baseline during categorization overall, and showed a strong novelty effect. Our results indicate that subjective measures may be effective in dissociating basal ganglia from hippocampal dependent learning, and that the basal ganglia are involved in both conscious and unconscious learning. They also indicate a dissociation within the hippocampus, in which the anterior regions are sensitive to novelty, and the posterior regions are involved in memory based categorization learning. PMID- 21255657 TI - Relationships between cognitive function and frontal grey matter volumes and thickness in middle aged and early old-aged adults: the PATH Through Life Study. AB - The study examined the relationship of lateral frontal cortical volume and thickness with cognitive function in two samples of healthy middle aged (MA, 44 48 years old) and early old-age (OA, 64-68 years old) adults. T1-weighted magnetic resonance imaging scans were acquired in 400 MA and 397 OA adults from respective random community samples. Cortical volumes and thickness were measured with a surface-based segmentation procedure (http://surfer.nmr.mgh.harvard.edu). Volumes of lateral frontal grey matter were found to be significantly lower for OA than MA. Structure-function relationships were investigated using path analyses. In OA, smaller lateral frontal volumes were associated with better episodic memory (EM) (p<0.012, B=-0.117), and Symbol-Digit Modalities Test (SDM) (p<0.031, B=-0.118) performance. Smaller frontal cortical thickness was also associated with better EM (p<0.01) and SDM (p<0.01) performance in OA. However, in MA greater cortical thickness was associated with better EM and (p<0.01) and reaction time (RT) (p<0.01). OA cohort showed significant positive correlations between Total Brain Volume and SDM, Digit-Backwards span and RT. Possible explanations and implications of the relationships in the context of cognitive aging in healthy adults, and limitations of cross-sectional research are discussed. PMID- 21255656 TI - Detection of amyloid plaques targeted by USPIO-Abeta1-42 in Alzheimer's disease transgenic mice using magnetic resonance microimaging. AB - Amyloid plaques are one of the pathological hallmarks of Alzheimer's disease (AD). The visualization of amyloid plaques in the brain is important to monitor AD progression and to evaluate the efficacy of therapeutic interventions. Our group has developed several contrast agents to detect amyloid plaques in vivo using magnetic resonance microimaging (MUMRI) in AD transgenic mice, where we used intra-carotid mannitol to enhance blood-brain barrier (BBB) permeability. In the present study, we used ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, chemically coupled with Abeta1-42 peptide to detect amyloid deposition along with mannitol for in vivo MUMRI by femoral intravenous injection. A 3D gradient multi-echo sequence was used for imaging with a 100MUm isotropic resolution. The amyloid plaques detected by T2*-weighted MUMRI were confirmed with matched histological sections. Furthermore, two different quantitative analyses were used. The region of interest-based quantitative measurement of T2* values showed contrast-injected APP/PS1 mice had significantly reduced T2* values compared to wild-type mice. In addition, the scans were examined with voxel-based morphometry (VBM) using statistical parametric mapping (SPM) for comparison of contrast-injected AD transgenic and wild-type mice. The regional differences seen in VBM comparing USPIO-Abeta1-42 injected APP/PS1 and wild-type mice correlated with the amyloid plaque distribution histologically, contrasting with no differences between the two groups of mice without contrast agent injection in regions of the brain with amyloid deposition. Our results demonstrated that both approaches were able to identify the differences between AD transgenic mice and wild-type mice, after injected with USPIO-Abeta1-42. The feasibility of using less invasive intravenous femoral injections for amyloid plaque detection in AD transgenic mice facilitates using this method for longitudinal studies in the pathogenesis of AD. PMID- 21255658 TI - Transient haemodynamic events in neurologically compromised infants: a simultaneous EEG and diffuse optical imaging study. AB - We describe a series of novel simultaneous EEG and diffuse optical imaging studies of newborn infants. These experiments provide evidence of large, transient haemodynamic events which occur repeatedly and consistently within and across several infants with neurological damage, all of whom were diagnosed with seizures. A simple but independent process of rejecting artifacts and identifying events within diffuse optical imaging data is described, and this process is applied to data from 4 neurologically damaged neonates and from 19 healthy, age matched controls. This method results in the consistent identification of events in three out of four of the neurologically damaged infant group which are dominated by a slow (>30s) and significant increase in oxyhaemoglobin concentration, followed by a rapid and significant decrease before a slow return to baseline. No comparable events are found in any of our control data sets. The importance and physiological implications of our findings are discussed, as is the suitability of a combined EEG and diffuse optical imaging approach to the study and monitoring of neonatal brain injury. PMID- 21255659 TI - Impact of brain networks involved in vigilance on processing irrelevant visual motion. AB - The ability to sustain attention over prolonged periods of time is called vigilance. Vigilance is a fundamental component of attention which impacts on performance in many situations. We here investigate whether similar neural mechanisms are responsible for vigilant attention over long and short durations of time and whether neural activity in brain regions sensitive to vigilant attention is related to processing irrelevant information. Brain activity was measured by means of functional magnetic resonance imaging (fMRI) in a 32 min visual vigilance task with varying inter-target intervals and irrelevant peripheral motion stimuli. Changes in neural activity were analysed as a function of time on task to capture long-term aspects of vigilance and as a function of time between target stimuli to capture short-term aspects of vigilance. Several brain regions including the inferior frontal, posterior parietal, superior and middle temporal cortices and the anterior insular showed decreases in neural activity as a function of time on task. In contrast, increasing inter-target intervals resulted in increased neural activity in a widespread network of regions involving lateral and medial frontal areas, temporal areas, cuneus and precuneus, inferior occipital cortex (right), posterior insular cortices, the thalamus, nucleus accumbens and basal forebrain. A partial least square analysis revealed that neural activity in this latter network covaried with neural activity related to processing irrelevant motion stimuli. Our results provide neural evidence that two separate mechanisms are responsible for sustaining attention over long and short durations. We show that only brain areas involved in sustaining attention over short durations of time are related to processing irrelevant stimuli and suggest that these areas can be segregated into two functionally different networks, one possibly involved in motivation, the other in arousal. PMID- 21255660 TI - Quantification of light reflectance spectroscopy and its application: determination of hemodynamics on the rat spinal cord and brain induced by electrical stimulation. AB - Two quantification methods for light reflectance spectroscopy (LRS) were developed and validated to determine absolute and relative values of hemodynamic parameters and light scattering, followed by a specific application using in vivo animal experiments. A single-channel LRS system consisted of a light source, CCD array detector, and a computer along with a bifurcated, 2-mm-diameter optical probe; this system was utilized to perform laboratory tissue phantoms for validation of the algorithms. In the animal study, a multi-channel, multisite approach was used to measure several reflectance spectra from rat brain and spinal cord on both the ipsi-lateral and contra-lateral sides, using thin 800-MUm diameter optic probes. The neuro-hemodynamic changes were induced by 10-V electrical stimulation in rat hind paw. The LRS data of the animals were analyzed using both absolute and relative methods. The results show that the relative method is computation-efficient and offers a quick estimation of changes in oxy hemoglobin concentration for real-time monitoring. The absolute quantification method, on the other hand, provides us with an accurate computational tool to calculate absolute values of oxy-, deoxy-, total hemoglobin concentrations, and light scattering coefficients. We also observe that the hemodynamic responses in rat spinal cord were delayed with a few seconds and have an overall broader full width at half maximum, as compared to those from rat somatosensory cortex. LRS as a measurement system provides a robust method for studying local hemodynamic changes and a potential technique to investigate hemo-neural mechanisms in pain processing. PMID- 21255661 TI - Resting state fMRI reveals increased subthalamic nucleus-motor cortex connectivity in Parkinson's disease. AB - Parkinson's disease (PD) is associated with abnormal hypersynchronicity in basal ganglia-thalamo-cortical loops. The clinical effectiveness of subthalamic nucleus (STN) high frequency stimulation indicates a crucial role of this nucleus within the affected motor networks in PD. Here we investigate alterations in the functional connectivity (FC) profile of the STN using resting state BOLD correlations on a voxel-by-voxel basis in functional magnetic resonance imaging (fMRI). We compared early stage PD patients (n=31) during the medication-off state with healthy controls (n=44). The analysis revealed increased FC between the STN and cortical motor areas (BA 4 and 6) in PD patients in accordance with electrophysiological studies. Moreover, FC analysis of the primary motor cortex (M1) hand area revealed that the FC increase was primarily found in the STN area within the basal ganglia. These findings are in good agreement with recent experimental data, suggesting that an increased STN-motor cortex synchronicity mediated via the so called hyperdirect motor cortex-subthalamic pathway might play a fundamental role in the pathophysiology of PD. An additional subgroup analysis was performed according to the presence (n=16) or absence (n=15) of tremor in patients. Compared to healthy controls tremor patients showed increased STN FC specifically in the hand area of M1 and the primary sensory cortex. In non tremor patients, increased FC values were also found between the STN and midline cortical motor areas including the SMA. Taken together our results underline the importance of the STN as a key node for the modulation of BG-cortical motor network activity in PD patients. PMID- 21255663 TI - Robustness of intrinsic connectivity networks in the human brain to the presence of acoustic scanner noise. AB - Evoked responses in functional magnetic resonance imaging (fMRI) are affected by the presence of acoustic scanner noise (ASN). Particularly, stimulus-related activation of the auditory system and deactivation of the default mode network have repeatedly been shown to diminish. In contrast, little is known about the influence of ASN on the spontaneous fluctuations in brain activity that are crucial for network-related neuroimaging methods like independent component analysis (ICA) or functional and effective connectivity analysis (ECA). The present study assessed the robustness of intrinsic connectivity networks in the human brain to the presence of ASN by comparing 'silent' (sparse) and 'noisy' (continuous) acquisition schemes, both during task performance and during rest. In agreement with existing literature, ASN strongly diminished conventional evoked response levels. In contrast, ICA and ECA robustly identified similar functional networks regardless of the scanning method. ASN affected the strength of only few independent components, and effective connectivity was hardly sensitive to ASN overall. However, unexpectedly, ICA revealed notable differences in the underlying neurodynamics. In particular, low-frequency network oscillations dominated in the commonly used continuous scanning environment, but signal spectra were significantly flatter during the less noisy sparse scanning runs. We tentatively attribute these differences to the ubiquitous influence of ASN on alertness and arousal. PMID- 21255662 TI - Associations between cortical thickness and verbal fluency in childhood, adolescence, and young adulthood. AB - Neuroimaging studies of normative human brain development indicate that the brain matures at differing rates across time and brain regions, with some areas maturing into young adulthood. In particular, changes in cortical thickness may index maturational progressions from an overabundance of neuropil toward efficiently pruned neural networks. Developmental changes in structural MRI measures have rarely been examined in relation to discrete neuropsychological functions. In this study, healthy right-handed adolescents completed MRI scanning and the Controlled Oral Word Association Test (COWAT). Associations of task performance and cortical thickness were assessed with cortical-surface-based analyses. Significant correlations between increasing COWAT performances and decreasing cortical thickness were found in left hemisphere language regions, including perisylvian regions surrounding Wernicke's and Broca's areas. Task performance was also correlated with regions associated with effortful verbal processing, working memory, and performance monitoring. Structure-function associations were not significantly different between older and younger subjects. Decreases in cortical thicknesses in regions that comprise the language network likely reflect maturation toward adult-like cortical organization and processing efficiency. The changes in cortical thicknesses that support verbal fluency are apparent by middle childhood, but with regionally separate developmental trajectories for males and females, consistent with other studies of adolescent development. PMID- 21255664 TI - Nuclear-mitochondrial discordance and gene flow in a recent radiation of toads. AB - Natural hybridization among recently diverged species has traditionally been viewed as a homogenizing force, but recent research has revealed a possible role for interspecific gene flow in facilitating species radiations. Natural hybridization can actually contribute to radiations by introducing novel genes or reshuffling existing genetic variation among diverging species. Species that have been affected by natural hybridization often demonstrate patterns of discordance between phylogenies generated using nuclear and mitochondrial markers. We used Amplified Fragment Length Polymorphism (AFLP) data in conjunction with mitochondrial DNA in order to examine patterns of gene flow and nuclear mitochondrial discordance in the Anaxyrus americanus group, a recent radiation of North American toads. We found high levels of gene flow between putative species, particularly in species pairs sharing similar male advertisement calls that occur in close geographic proximity, suggesting that prezygotic reproductive isolating mechanisms and isolation by distance are the primary determinants of gene flow and genetic differentiation among these species. Additionally, phylogenies generated using AFLP and mitochondrial data were markedly discordant, likely due to recent and/or ongoing natural hybridization events between sympatric populations. Our results indicate that the putative species in the A. americanus group have experienced high levels of gene flow, and suggest that their North American radiation could have been facilitated by the introduction of beneficial genetic variation from admixture between divergent populations coming into secondary contact after glacial retreats. PMID- 21255665 TI - Phylogeny of Philippine slender skinks (Scincidae: Brachymeles) reveals underestimated species diversity, complex biogeographical relationships, and cryptic patterns of lineage diversification. AB - The spectacular, virtually endemic radiation of Philippine semi-fossorial skinks of the genus Brachymeles represent one of the few radiations of scincid lizards to possess both fully limbed and limbless species. And yet, nothing is known of the phylogenetic relationships of this exceptional group. Morphologically similar body plans have made it difficult to assess species-level diversity, and the genus has long been recognized as one of the more modest radiations of southeast Asian lizards. However, recent large-scale survey efforts have resulted in the discovery of numerous new species, and taxonomic studies indicate that the diversity within the genus Brachymeles is grossly underestimated. In this study we provide the first robust estimate of phylogenetic relationships within the genus Brachymeles using a multi-locus dataset and nearly complete taxonomic sampling. We provide statistical tests of monophyly for all polytypic species and two widespread limb-reduced species and our results indicate wholesale deviations from past summaries and taxonomic evaluations of the genus. With few exceptions, we are able to reject the monophyly of all polytypic and widespread species, thereby validating the need for large-scale taxonomic revisions. Our results reveal that the limbless, monotypic, genus Davewakeum is nested within Brachymeles. Mapping of body form on our preferred phylogenetic tree suggests that limb-reduction and digit loss has occurred on multiple occasions in the history of the genus. A Bayesian reconstruction of ancestral areas indicates strong statistical support for a minimum of five major dispersal events that have given rise to a major component of the observed species diversity on separate Pleistocene aggregate island platforms of the archipelago. PMID- 21255666 TI - Influence of lifetime hip joint force on the risk of self-reported hip osteoarthritis: a community-based cohort study. AB - OBJECTIVE: To investigate the influence of cumulative lifetime hip joint force on the risk of self-reported medically-diagnosed hip osteoarthritis (OA). DESIGN: Prospective cohort. SETTING: General population. PARTICIPANTS: Members of Canadian Association of Retired Persons, community-dwelling. MAIN OUTCOME: Health professional diagnosed hip OA, self-reported. METHODS: Exposure data on lifetime physical activity type (occupational, household, sport) and dose (frequency, intensity, duration) was collected in 2005. Subjects were ranked in terms of a 'cumulative peak force index' (CFPI), a measure of lifetime mechanical hip joint force. Multivariable survival analyses were performed to obtain adjusted effects for mean lifetime exposure and during 5-year age periods. RESULTS: Of 2918 subjects aged 45-85, 176 (6.03%) developed hip OA during the 2-year follow up (43 men, 133 women). The highest quintile of mean lifetime hip CPFI (HR 2.32; 95% CI 1.31-4.12), and high hip force in three age periods (35-39, 40-44, 45-49) were independently associated with hip OA. Previous hip injury was an approximate five fold risk for development of hip OA across all models. In analysis by activity domain (occupation, sport, household), there was a trend (non-significant) for the highest quintile of occupational force, but not sport or household, to be associated with hip OA. CONCLUSIONS: A newly proposed measure of lifetime mechanical hip force was used to estimate the risk of self-reported, medically diagnosed hip OA. While there are important limitations, this prospective study suggests that lifelong physical activity is generally safe. Very high levels of lifetime force from all domains combined, and in particular from occupational forces, may be important in the etiology of hip OA. PMID- 21255667 TI - Knee injury and Osteoarthritis Outcome Score (KOOS); reliability and validity in competitive athletes after anterior cruciate ligament reconstruction. AB - OBJECTIVE: To validate the Knee injury and Osteoarthritis Outcome Score (KOOS) for the assessment of competitive athletes with higher level sports activities after anterior cruciate ligament (ACL) reconstruction. METHODS AND MEASURES: Fifty-seven athletes (39 males and 18 females; age, 25.6 +/- 3.4 years; height, 179.6 +/- 7.4 cm; weight, 77.6 +/- 9.8 kg) after ACL reconstruction were asked to complete the Persian KOOS and Short Form-36 (SF-36) questionnaires in the test session. To evaluate test-retest reliability, all participants filled out the KOOS and SF-36, 6-8 days after the first visit. The properties of the KOOS in terms of reliability [Intraclass Correlation Coefficient (ICC)], internal consistency (Cronbach's alpha), dimensionality (item-scale correlation) and construct validity (Spearman's rank correlation) were evaluated. RESULTS: No floor or ceiling effect was observed. The ICCs (S.E.M.s) of the KOOS subscales were: Pain 0.93 (2.2), Symptoms 0.85 (3.1), Activities of Daily Living 0.91 (2.9), Function in Sport and Recreation 0.75 (2.1) and Knee-related Quality of Life 0.89 (2.6). The Cronbach's alphas of the KOOS subscales were: Pain 0.91, Symptoms 0.75, Activities of Daily Living 0.96, Function in Sport and Recreation 0.86 and Knee-related Quality of Life 0.74. Spearman's rank correlations between the subscales of the KOOS and representative subscales of the SF-36 ranged from 0.40 to 0.79. CONCLUSION: This study illustrates the validity and reliability of the KOOS in measuring the functional status and quality of life of athletes after ACL reconstruction. This study further validates the use of the KOOS in highly competitive athletes in research on knee injuries. PMID- 21255668 TI - Calcium/calmodulin-dependent protein kinases as potential targets of nitric oxide. AB - Nitric oxide (NO) synthesis is controlled by Ca(2+)/calmodulin (CaM) binding with and kinase-dependent phosphorylation of constitutive NO synthases, which catalyze the formation of NO and L-citrulline from L-arginine. NO operates as a mediator of important cell signaling pathways, such as cGMP signaling cascade. Another mechanism by which NO exerts biological effects is mediated via post translational modification of redox-sensitive cysteine thiols of proteins. The Ca(2+)/CaM-dependent protein kinases (CaM kinases) such as CaM kinase I, CaM kinase II, and CaM kinase IV, are a family of protein kinases which requires binding of Ca(2+)/CaM to and subsequent phosphorylation of the enzymes to initiate its activation process. We report other regulation mechanisms of CaM kinases, such as S-glutathionylation of CaM kinase I at Cys(179) and S nitrosylation of CaM kinase II at Cys(6/30). Such unique post-translational modification of CaMKs by NO shed light on a new area of mutual regulation of NO- and CaM kinases-signals. Based on the novel direct regulation of these kinases, we propose that CaM kinases/NO signaling would be good targets for understanding how they can participate in neuronal physiology and disease. PMID- 21255669 TI - Tacrolimus modulates liver and pancreas nitric oxide synthetase and heme oxygenase isoforms and cytokine production after endotoxemia. AB - Cytoprotective effects of tacrolimus are due to its unspecific anti-inflammatory and anti-oxidant properties. Neither the exact mechanisms nor if there is any organ-specificity or dose-dependent response have not been yet elucidated. Our aim was to evaluate the effect of tacrolimus on oxidative stress and mediator production in liver and pancreatic tissue secondary to endotoxemia. Wistar rats were pretreated with intraperitoneal injection of tacrolimus (0.07, 0.15, and 0.3mg/kg) 24h before Escherichia coli LPS was administrated. Animals were sacrificed 24h after LPS administration and iNOS, eNOS, and nNOS and type 1 and 2 heme-oxygenase (HO) expression were measured. TNF-alpha and IL-1 tissue expression and plasmatic NO, CO, TNF-alpha, and IL-1 were also determined. LPS exposure increased iNOS expression in both organs, eNOS did not show variations and liver nNOS expression was significantly lower. Tacrolimus diminished both pancreas and liver iNOS and nNOS expression. Both liver and pancreatic eNOS expression augmented when tacrolimus was administrated. High doses of tacrolimus were correlated with ameliorated liver HO-1 plus HO-2 and pancreas HO-1 expression after LPS stimulation. Tacrolimus treatment diminished TNF-alpha but not IL-1 expression increase after LPS challenge in hepatic tissue. Pancreatic TNF-alpha and IL-1 values diminished partially when high doses were employed. Plasmatic NO, CO, TNF-alpha, and IL-1 concentrations increase after LPS challenge was diminished when highest doses of tacrolimus were given. In conclusion, tacrolimus exerts a protective effect on commonly observed harmful phenomena after LPS stimulation by modulating liver and pancreas oxidative enzyme expression and cytokine production. PMID- 21255670 TI - Multiscale mathematical models of airway constriction and disease. AB - Loss of lung function in airway disease frequently involves many complex phenomena and interconnected underlying causes. In many conditions, such as asthmatic airway hyper-responsiveness, hypothesised underlying causes span multiple spatial scales. In cases like this, it is insufficient to take a reductionist approach, wherein each subsystem (at a given spatial scale) is considered in isolation and then the whole is taken to be merely the sum of the parts; this is because there can be significant and important interactions and synergies between spatial scales. Experimentally this can manifest as, for example, significant differences between behaviour in isolated tissue and that seen in vivo, while from a modelling perspective, it necessitates multiscale modelling approaches. Because it is precisely in these complex environs that models have the greatest potential to improve understanding of underlying behaviours, these multiscale models are of particular importance. This paper reviews several examples of multiscale models from the most important models in the literature, with a particular emphasis on those concerned with airway hyper responsiveness and airway constriction. PMID- 21255671 TI - New concepts in the management of chronic cough. AB - There has been significant progress in the field of cough in the past 10 years. Obstructive sleep apnoea, tonsillar enlargement and environmental fungi have recently been described as causes of chronic cough. The advances in the assessment of gastro-oesophageal reflux (GOR) have led to a greater understanding of the relationship between cough and GOR and are likely to change the approach to managing patients with GOR-cough. The investigation of the phenotype of patients with idiopathic chronic cough has provided novel insights. Patients with an idiopathic chronic are predominantly female, have an onset of cough around the menopause and have a high prevalence of organ specific autoimmune disease, particularly hypothyroidism. The presence of bronchoalveolar lymphocytosis suggests there is homing of inflammatory cells from primary sites of autoimmune inflammation to the lungs. A heightened cough reflex is a key feature of most patients with chronic cough and has led some investigators to suggest that chronic cough be recognised as a unique entity called Cough Hypersensitivity Syndrome (CHS). A number of subjective and objective tools have been developed recently to assess cough severity. Antitussive drug development is an emerging and exciting area of cough research. PMID- 21255672 TI - PDE4-inhibitors: a novel, targeted therapy for obstructive airways disease. AB - Roflumilast is a selective once daily, oral phosphodiesterase-4 inhibitor that has recently been registered in all European Union countries as novel targeted therapy for COPD, while FDA approval for the USA market is expected in 2011. In several phase III trials in patients with moderate to (very) severe COPD and in patients with symptoms of chronic bronchitis and recurrent exacerbations, roflumilast showed sustained clinical efficacy by improving lung function and by reducing exacerbation rates. These beneficial effects have also been demonstrated when added to long-acting bronchodilators (both LABA and LAMA), underscoring the anti-inflammatory activity of roflumilast in COPD. Pooled data analysis showed overall mild to moderate, mostly self-limiting adverse events, mainly consisting of nausea, diarrhea and weight loss. In this review we discuss the results of the 4 registration studies showing promising effects of roflumilast in COPD and provide an overview of the topics that still need to be addressed. PMID- 21255673 TI - Inflammation-induced airway smooth muscle responsiveness is strain dependent in mice. AB - Different mouse strains display different degrees of inflammation-induced airway hyperresponsiveness in vivo. It is not known whether these variations are attributable to distinct properties of the airway smooth muscle. Therefore, tracheal ring segments from C57BL/6 and BALB/c mice were exposed to three different pro-inflammatory stimuli for 4 days while maintained under tissue culture conditions: tumour necrosis factor alpha (100 ng/ml), the Toll-like receptor (TLR) 3 agonist polyI:C (10 MUg/ml), and the TLR4 agonist LPS (10 MUg/ml). The contractile responses to carbachol, 5-hydroxytryptamine (5-HT) and bradykinin were assessed after culture. In addition, gene expression of TLR1 TLR9, pivotal inflammatory signal transduction proteins (jun-kinase, p38 and p65) and critical negative regulators of inflammation (A20, Itch, Tax1bp1 and RNF11) were studied in tracheal smooth muscle strips, fresh and following treatment for 4 days with LPS, from both strains. No differences between the strains were detected regarding the response of freshly isolated preparations to carbachol, 5 HT and bradykinin. After stimulation with pro-inflammatory mediators, contractions in response to 5-HT and bradykinin, but not to carbachol, were up regulated. This up-regulation was markedly larger in BALB/c than in C57BL/6 segments and depended on the type of inflammatory stimulus. Expression of the genes investigated did not differ between the two strains. These findings indicate that strain differences in airway hyperresponsiveness can be linked to differences in the responsiveness of airway smooth muscle to pro-inflammatory mediators per se. The differences do not appear to be due to differential expression of TLR or common inflammatory transduction and repressor proteins. PMID- 21255674 TI - Biomarkers of genotoxicity and genomic instability in a non-human primate, Cebus libidinosus (Cebidae, Platyrrhini), exposed to nitroimidazole derivatives. AB - The genotoxicity of two nitroimidazole derivatives, ornidazole (ONZ) and metronidazole (MTZ) in the peripheral blood lymphocytes of Cebus libidinosus (CLI) (Primates, Cebidae) was assessed. Endpoints measured included sister chromatid exchange (SCE) frequency, cell proliferation kinetics (CPK), replication index (RI), mitotic index (MI), and damage incidence in or near CLI heterochromatin regions. MI and SCE values following ONZ or MTZ treatments were significantly different (p<0.001) from control. SCE frequency per chromosome was not proportional to chromosome length. The chromosomes most affected for SCE were 1, 2, 4, 6, 11-13, 17, and 18, many of which possess interstitial or terminal heterochromatin. In the CLI genome, chromosomes 11 and 17 showed higher susceptibility to damage RI was the only biomarker that did not show statistically significant differences between control and treated cultures. C. libidinosus bands 11q1.4 and 11q1.5 may be hot-spots in the context of nitroimidazole exposure. PMID- 21255675 TI - Workshop summary: Top concentration for in vitro mammalian cell genotoxicity assays; and report from working group on toxicity measures and top concentration for in vitro cytogenetics assays (chromosome aberrations and micronucleus). AB - The selection of maximum concentrations for in vitro mammalian cell genotoxicity assays was reviewed at the 5th International Workshop on Genotoxicity Testing (IWGT), 2009. Currently, the top concentration recommended when toxicity is not limiting is 10mM or 5mg/ml, whichever is lower. The discussion was whether to reduce the limit, and if so whether the 1mM limit proposed for human pharmaceuticals was appropriate for testing other chemicals. The consensus was that there was reason to consider reducing the 10mM limit, and many, but not all, attendees favored a reduction to 1mM. Several proposals are described here for the concentration limit. The in vitro cytogenetics expert working group also discussed appropriate measures and level of cytotoxicity. Data were reviewed from a multi-laboratory trial of the in vitro micronucleus (MN) assay with multiple cell types and several types of toxicity measurements. The group agreed on a preference for toxicity measures that take cell proliferation after the beginning of treatment into account (relative increase in cell counts, relative population doubling, cytokinesis block proliferation index or replicative index), and that this applies both to in vitro MN assays and to in vitro chromosome aberration assays. Since relative cell counts (RCC) underestimate toxicity, many group members favored making a recommendation against the use of RCC as a toxicity measure for concentration selection. All 14 chemicals assayed for MN induction in the multi-laboratory trial were detected without exceeding 50% toxicity by any measure, but some were positive only at concentrations with toxicity quite close to 50%. The expert working group agreed to accept the cytotoxicity range recommended by OECD guideline 487 (55+/-5% toxicity at the top concentration scored). This also reinforces the original intent of the guidance for the in vitro chromosome aberration assay, where ">50%" was intended to target the range close to 50% toxicity. PMID- 21255676 TI - A review of the genotoxicity of 1,2-dichloroethane (EDC). AB - 1,2-Dichloroethane (EDC, CAS#107-06-2) is a high production volume halogenated aliphatic hydrocarbon that is used mainly in the manufacture of vinyl chloride. EDC has been found in ambient and residential air samples, as well as in groundwater, surface water and drinking water. EDC has been well-studied in a variety of genotoxicity assays, and appears to involve the metabolic activation of the parent compound. We critically evaluated the genotoxicity data of EDC and its metabolites as part of an evaluation of carcinogenic mechanisms of action of EDC. EDC is genotoxic in multiple test systems via multiple routes of exposure. EDC has been shown to induce DNA adduct formation, gene mutations and chromosomal aberrations in the presence of key activation enzymes (including CYP450s and/or GSTs) in laboratory animal and in vitro studies. EDC was negative for clastogenesis as measured by the micronucleus assay in mice. In general, an increased level of DNA damage is observed related to the GSH-dependent bioactivation of EDC. Increased chromosomal aberrations with increased CYP450 expression were suggestive of a role for the oxidative metabolites of EDC in inducing chromosomal damage. Taken together, these studies demonstrate that EDC exposure, in the presence of key enzymes (including CYP450s and/or GSTs), leads to DNA adduct formation, gene mutations and chromosomal aberrations. PMID- 21255677 TI - To the Editor: Optimizing right ventricular lead position for defibrillation. PMID- 21255678 TI - Spinal cord stimulation effects on myocardial ischemia, infarct size, ventricular arrhythmia, and noninvasive electrophysiology in a porcine ischemia-reperfusion model. AB - BACKGROUND: Susceptibility to ventricular arrhythmias and sudden cardiac death can be reduced by modulation of autonomic tone. Spinal cord stimulation (SCS) presumably affects autonomic tone and reduces myocardial ischemia. OBJECTIVE: The purpose of this study was to investigate whether SCS could reduce myocardial ischemia, infarct size, and ventricular arrhythmias as well as repolarization alterations in a porcine ischemia-reperfusion model. METHODS: Anesthetized common Landrace pigs were randomized to SCS (n = 10) or sham treatment (n = 10) before, during, and after 45 minutes of coronary occlusion. Area at risk, infarct size, and spontaneous ventricular arrhythmias were analyzed. Continuous three dimensional vectorcardiograms was recorded and analyzed with respect to ECG intervals, ST-segment, and T-vector and T-vector-loop morphology. RESULTS: SCS was associated with significantly (P <.04) fewer episodes of nonsustained ventricular tachycardia (NSVT) and sustained ventricular tachycardia (SVT), particularly during mid-left anterior descending artery (LAD) occlusion (SCS vs non-SCS; NSVT, mid- and proximal LAD: 0 vs 22 and 45 vs 72; SVT, mid- and proximal LAD: 3 vs 15 and 5 vs 5). No difference in ventricular fibrillation episodes was observed. The SCS group had significantly less ST elevation (P <.03) but similar area at risk, infarct size, and ratio of infarct size/area at risk. Ischemia induced increases of T(amplitude) and T(area) suggesting increased repolarization gradients, which were significantly reduced by SCS (P <.01 for both). CONCLUSION: SCS appears to have an antiarrhythmic effect on spontaneous NSVT and SVT during ischemia-reperfusion in association with a reduction of repolarization alterations. Vectorcardiography signs of myocardial ischemia were reduced by SCS, but this intervention was not accompanied by any effect on infarct size. PMID- 21255679 TI - To the editor: End of the apex era? PMID- 21255680 TI - Ca2+-calmodulin-dependent protein kinase II regulation of cardiac excitation transcription coupling. PMID- 21255681 TI - Comparative study of the immune effect of an Edwardsiella tarda antigen in two forms: subunit vaccine vs DNA vaccine. AB - Edwardsiella tarda is a Gram-negative bacterial pathogen and the etiological agent of a systematic fish disease called edwardsiellosis, which affects a wide range of marine and freshwater fish. E. tarda vaccines in various forms have been reported by a number of research groups; however, comparative studies on the immune mechanisms of these vaccines are lacking. In this report, we identified a new E. tarda vaccine candidate, Eta2, and analyzed in a comparative manner the immune response induced by Eta2 in two different forms: purified recombinant subunit vaccine and DNA vaccine. Eta2 is a protein of 178 residues and shares high levels of sequence identities with the OmpH family of outer membrane protein chaperones of several bacterial species. Recombinant Eta2 (rEta2) purified from Escherichia coli was highly protective against E. tarda challenge in a Japanese flounder (Paralichthys olivaceus) model and produced relative percent of survival rates of 83% and 78%, respectively, at 4- and 8-week post-vaccination (p.v.). Eta2 as a DNA vaccine in the form of plasmid pCEta2 also induced strong protective immunity at 4- and 8-week p.v. Immunological analysis indicated that (i) rEta2 and pCEta2 enhanced head kidney macrophage activation at 1- and, for pCEta2, 7-day p.v.; (ii) rEta2 and pCEta2 induced similar patterns of serum antibody production, however, the antibodies induced by rEta2 were of much higher levels and afforded stronger passive immunoprotection upon naive flounder than those induced by pCEta2; (iii) both rEta2 and pCEta2 upregulated the expression of specific and nonspecific immune factors which include, in the case of pCEta2 but not rEta2, interferon, interferon-induced Mx protein, and CD8alpha; however, the induction patterns effected by rEta2 and pCEta2 were different. While high levels of interleukin 1beta (IL-1beta), natural killer cell enhancing factor, Mx, MHC Ialpha, and IgM inductions were observed in pCEta2-vaccinated fish, only IL 1beta, complement C3, and IgM inductions were highly induced in rEta2-vaccinated fish. Taken together, these results indicate that both rEta2 and pCEta2 induce specific and nonspecific immunities, however, pCEta2 induces both B cell and T cell responses, whereas rEta2 induces mainly humoral response. PMID- 21255682 TI - Trends in anal cancer in Australia, 1982-2005. AB - BACKGROUND: Most anal squamous cell carcinomas (SCCs) are caused by high risk types of human papillomavirus (HPV) and are potentially preventable by HPV vaccination. In order to understand the burden of potentially preventable anal cancer in Australia, we examine the incidence and survival from invasive anal SCC 1982-2005. METHODS: We reviewed data on invasive anal cancer cases notified to the National Cancer Statistics Clearing House. Age specific incidence rates of SCC were calculated by year of cancer diagnosis and by birth cohort, and rates of anal adenocarcinoma were included for comparison. Incidence rates were age standardised to the Australian 2001 standard population. Trends in relative survival of SCC were examined. RESULTS: During the study period, a total of 4615 invasive anal cancer cases were diagnosed and most (69.7%) were SCC. Annual incidence of SCC increased almost 50%, from 0.65 to 1.00/100,000. Incidence increased at all ages. The annual rate of increase was almost two-folder higher in men (3.42%, 95% CI 2.49-4.35) than in women (1.88%, 95% CI 1.18-2.58). Five year relative survival increased by nearly 10% from 58.9% to 68.3% over the last 20 years. Younger patients and women had better survival. For anal adenocarcinoma, increases of borderline significance were seen in men and women. CONCLUSION: There is an increasing burden of anal SCC in Australia. The group with the highest incidence - homosexual men - are not likely to be protected under the current vaccination policy. PMID- 21255683 TI - Kinetic study of the antibody response during the blood meal of Ixodes ricinus: implication on plasma cell maturation in vivo and for anti-Ixodes vaccination. AB - Anti-tick vaccination could be an ideal solution to prevent pathogen transmission, but none is currently available against Ixodes ticks. Recently, we showed that adult Ixodes ricinus infestation on mice decreases the specific antibody production to BSA injected during infestation. Here, a kinetic study of seric levels of BSA-specific antibodies was performed to evaluate the B memory cell differentiation in Balb/c mice and the capacity of specific B memory cells to respond to BSA during infestation. We concluded that the tick blood meal inhibits or impairs the local differentiation of mature B cells into plasma cells, but does not alter the formation of memory B cell. Accordingly, this mechanism should not be an impediment to anti-Ixodes vaccination. PMID- 21255684 TI - Guillain-Barre syndrome following receipt of influenza A (H1N1) 2009 monovalent vaccine in Korea with an emphasis on Brighton Collaboration case definition. AB - BACKGROUND: In 2009-2010 season, with ongoing of influenza A (H1N1), employment of mass vaccination has generated concerns in issue of adverse events following immunization (AEFI). This study investigates the clinical and laboratory data of reported cases of Guillain-Barre syndrome (GBS) and Fisher syndrome (FS) following receipt of influenza A (H1N1) 2009 monovalent vaccine to the National Vaccine Injury Compensation Program (NVICP) in Korea, with all cases reviewed under case definition developed by Brighton Collaboration GBS Working Group. METHOD: Retrospective review of medical records for all suspected cases of GBS ad FS following receipt of influenza A (H1N1) monovalent vaccine reported to NVICP from December 1, 2009, through April 28, 2010 was conducted. Additional analyses were performed for identification of levels of diagnostic certainty according to Brighton Collaboration case definition. RESULT: Of 29 reported cases, 22 were confirmed to meet Brighton criteria level 1, 2, or 3 for GBS (21) or FS (1). Of those, 2 (9.1%) met level 1, 9 (40.9%) met level 2, and 11 (50.0%) met level 3. The male to female ratio was 2:0 in cases with level 1, 8:1 in cases with level 2, and 3:8 in cases with level 3. The mean age was older in cases with level 1 (54.0 +/- 26.9) than that of cases with level 2 (25.6 +/- 22.8), and level 3 (13.6 +/- 2.4, P=0.005). The median onset interval was longer in cases with level 1 (16 days) than that of cases that met level 2 (12.44 days), and 3 (1.09 days, P=0.019). CONCLUSION: The Brighton case definition was used to improve the quality of AEFI data in Korea, and was applicable in retrospective review of medical records in cases with GBS and FS after influenza A (H1N1) vaccination. These findings suggest that standardized case definition was feasible in clarifying the AEFI data, and to further increase the understanding of possible relationship of influenza vaccine and GBS. PMID- 21255686 TI - Further interest of miniexon multiplex PCR for a rapid typing of Trypanosoma cruzi DTU groups. AB - In order to validate a rapid typing of Trypanosoma cruzi DTUs, the miniexon multiplex PCR was tested for the first time, on a large and diversified sample of 70 strains belonging to all current DTUs (TcI to TcVI). Three DTU groups have been distinguished by specific PCR molecular weight, TcI (200bp), TcII, V, VI (250bp) and TcIII and IV (150bp) with no incorrect grouping. These groups are epidemiologically and genetically relevant; moreover the method is easy and cheap and allows direct identification of parasites from triatomine faeces. PMID- 21255685 TI - Repeat revaccination with 23-valent pneumococcal polysaccharide vaccine among adults aged 55-74 years living in Alaska: no evidence of hyporesponsiveness. AB - BACKGROUND: Older adults are at highest risk of invasive pneumococcal disease (IPD) and are recommended to receive vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23). Antibody concentrations decline following vaccination. We evaluated the immunogenicity and reactogenicity of revaccination and repeat revaccination. METHODS: Adults aged 55-74 years were vaccinated with a 1st to 4th dose of PPV23. Participants were eligible for revaccination if a minimum of 6 years had passed since their last dose of PPV23. Blood collected on the day of vaccination and 30 days later was analyzed by ELISA for IgG to five serotypes. Functional antibody activity was measured using an opsonophagocytic killing (OPK) assay. Reactions to vaccination were documented. RESULTS: Subjects were vaccinated with a 1st dose (n=123), 2nd dose (n=121), or 3rd or 4th dose (n=71) of PPV23. The post-vaccination IgG geometric mean concentrations (GMCs) were similar among first-time vaccinees and re-vaccinees for all serotypes with the exception of a lower GMC for serotype 1 in re-vaccinees. The post-vaccination OPK geometric mean titers (GMTs) were similar among first-time vaccinees and re vaccinees with the exception of a higher GMT for serotype 6B in re-vaccinees. Compared to first-time vaccinees, re-vaccinees reported more joint pain (p=0.004), fatigue (p=0.019), headache (p=0.014), swelling (p=0.006), and moderate limitation in arm movement (p=0.025). CONCLUSIONS: Repeat revaccination with PPV23, administered 6 or more years after the prior dose, was immunogenic and generally well tolerated. PMID- 21255687 TI - Analysis of human P[4]G2 rotavirus strains isolated in Brazil reveals codon usage bias and strong compositional constraints. AB - The Rotavirus genus belongs to the family Reoviridae and its genome consist of 11 segments of double-stranded RNA. Group A rotaviruses (RV-A) are the main etiological agent of acute viral gastroenteritis in infants and young children worldwide. Understanding the extent and causes of biases in codon usage is essential to the understanding of viral evolution. However, the factors shaping synonymous codon usage bias and nucleotide composition in human RV-A are currently unknown. In order to gain insight into these matters, we analyzed the codon usage and base composition constraints on the two genes that codify the two outer capsid proteins (VP4 [VP8*] and VP7) of 58 P[4]G2 RV-A strains isolated in Brazil and investigated the possible key evolutionary determinants of codon usage bias. The results of these studies revealed that the frequencies of codon usage in both RV-A proteins studied are significantly different than the ones used by human cells. In order to observe if similar trends of codon usage are found when RV-A complete genomes are considered, we compare these results with results found using a dataset of 10 reference strains for whom the complete codes of the 11 segments are known. Similar results were obtained using capsid proteins or complete genomes. The general correlations found between the position of each sequence on the first axis generated by correspondence analysis and the relative dinucleotide abundances indicate that codon usage in RV-A can also be strongly influenced by underlying biases in dinucleotide frequencies. CpG and GpC containing codons are markedly suppressed. Thus, the results of this study suggest that RV-A genomic biases are the result of the evolution of genome composition in relation to host adaptation and the ability to escape antiviral cell responses. PMID- 21255688 TI - An emerging recombinant cluster of nephropathogenic strains of avian infectious bronchitis virus in Korea. AB - The infectious bronchitis virus (IBV) is continuously evolving through point mutation and recombination of their genome, subsequently the emergence of IBV variants complicates disease control. The objective of this study was to investigate genetic characterization of new IBV variants isolated from commercial chicken flocks in Korea collected between 2005 and 2010. Phylogenetic analysis revealed that all new IBV isolates belonged to Korean group II (K-II), which included the nephropathogenic IBV strains. However, the isolates formed a new gene cluster that was distinguished from the two distinct K-II subgroups (KM91 like and QX-like). Recombination events were identified in the S1 gene, with their putative parental strains being the KM91-like or QX-like subgroup. In addition, two crossover sites were observed in the S1 gene of IBV isolates. These results suggest that natural genetic recombination between heterologous strains classified into different genetic groups has occurred and may have caused the emergence of new IBV strains. This finding provides important information on IBV evolution and is essential for the effective control of IB in Korea. PMID- 21255689 TI - Management of autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus. AB - Autoimmune neutropenia, caused by neutrophil-specific autoantibodies is a common phenomenon in autoimmune disorders such as Felty's syndrome and systemic lupus erythematosus. Felty's syndrome is associated with neutropenia and splenomegaly in seropositive rheumatoid arthritis which can be severe and with recurrent bacterial infections. Neutropenia is also common in systemic lupus erythematosus and it is included in the current systemic lupus classification criteria. The pathobiology of the autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus is complex, and it could be a major cause of morbidity and mortality due to increased risk of sepsis. Treatment should be individualized on the basis of patient's clinical situation, and prevention or treatment of the infection. Recombinant human granulocyte colony-stimulating factor is a safe and effective therapeutic modality in management of autoimmune neutropenia associated with Felty's syndrome and systemic lupus erythematosus, which stimulates neutrophil production. There is a slight increased risk of exacerbation of the underlying autoimmune disorder, and recombinant human granulocyte colony stimulating factor dose and frequency should be adjusted at the lowest effective dose. PMID- 21255690 TI - Respiration-related control of abdominal motoneurons. AB - The abdominal muscles form part of the expiratory pump in cooperation with the other expiratory muscles, primarily the internal intercostal and triangularis sterni muscles. The discharge of abdominal muscles is divided into four main patterns: augmenting, plateau, spindle and decrementing. The patterns tend to be species-specific and dependent on the state of the central nervous system. Recent studies suggest that the abdominal muscles are more active than classically thought, even under resting conditions. Expiratory bulbospinal neurons (EBSN) in the caudal ventral respiratory group are the final output pathway to abdominal motoneurons in the spinal cord. Electrophysiological and anatomical studies indicated the excitatory monosynaptic inputs from EBSN to the abdominal motoneurons, although inputs from the propriospinal neurons seemed to be necessary to produce useful motor outputs. Respiration-related sensory modulation of expiratory neurons by vagal afferents that monitor the rate of change of lung volume and the end-expiratory lung volume (EELV) play a crucial role in modulating the drive to the abdominal musculature. Studies using in vitro and in situ preparations of neonatal and juvenile rats show bi-phasic abdominal activity, characterized by bursting at the end of expiration, a silent period during the inspiratory period, and another burst that occurs abruptly after inspiratory termination. Since the abdominal muscles rarely show these post inspiratory bursts in the adult rat, the organization of the expiratory output pathway must undergo significant development alterations. PMID- 21255691 TI - Elastic fibers in the aortic valve spongiosa: a fresh perspective on its structure and role in overall tissue function. AB - This study characterizes the elastic fiber structure within the aortic valve spongiosa, the middle layer of the tri-laminate leaflet. The layer is rich in glycosaminoglycans and proteoglycans, through which it resists compression and lubricates shear between the outer layers. Elastin in this layer forms a fine, interweaving structure, yet it is unclear how this particular structure, which uses elasticity to preload the leaflet, assists spongiosa function. In this study, immunohistochemistry (IHC) and scanning electron microscopy (SEM) are used to characterize spongiosa elastin, as well as investigate regional differences in structure. IHC for elastin highlights an intermediate structure which varies in thickness and density between regions. In particular, the spongiosa elastin is thicker in the hinge and coaptation region than in the belly. SEM of NaOH digested leaflets shows a rectilinear pattern of elastic fibers in the hinge and coaptation region, as opposed to a radially oriented stripe pattern in the belly. In conclusion, elastic fibers in the spongiosa connect the two outer layers and vary regionally in structure, while possibly playing a role in responding to regionally specific loading patterns. PMID- 21255692 TI - Mixed culture of oleaginous yeast Rhodotorula glutinis and microalga Chlorella vulgaris for lipid production from industrial wastes and its use as biodiesel feedstock. AB - A mixed culture of oleaginous yeast Rhodotorula glutinis and microalga Chlorella vulgaris was performed to enhance lipid production from industrial wastes. These included effluent from seafood processing plant and molasses from sugar cane plant. In the mixed culture, the yeast grew faster and the lipid production was higher than that in the pure cultures. This could be because microalga acted as an oxygen generator for yeast, while yeast provided CO(2) to microalga and both carried out the production of lipids. The optimal conditions for lipid production by the mixed culture were as follows: ratio of yeast to microalga at 1:1; initial pH at 5.0; molasses concentration at 1%; shaking speed at 200 rpm; and light intensity at 5.0 klux under 16:8 hours light and dark cycles. Under these conditions, the highest biomass of 4.63+/-0.15 g/L and lipid production of 2.88+/ 0.16 g/L were obtained after five days of cultivation. In addition, the plant oil like fatty acid composition of yeast and microalgal lipids suggested their high potential for use as biodiesel feedstock. PMID- 21255694 TI - Triptolide and its expanding multiple pharmacological functions. AB - Triptolide, a diterpene triepoxide, is a major active component of extracts derived from the medicinal plant Tripterygium wilfordii Hook F (TWHF). Triptolide has multiple pharmacological activities including anti-inflammatory, immune modulation, antiproliferative and proapoptotic activity. So, triptolide has been widely used to treat inflammatory diseases, autoimmune diseases, organ transplantation and even tumors. Triptolide cannot only induce tumor cell apoptosis directly, but can also enhance apoptosis induced by cytotoxic agents such as TNF-alpha, TRAIL and chemotherapeutic agents regardless of p53 phenotype by inhibiting NFkappaB activation. Recently, the cellular targets of triptolide, such as MKP-1, HSP, 5-Lox, RNA polymerase and histone methyl-transferases had been demonstrated. However, the clinical use of triptolide is often limited by its severe toxicity and water-insolubility. New water-soluble triptolide derivatives have been designed and synthesized, such as PG490-88 or F60008, which have been shown to be safe and potent antitumor agent. Importantly, PG490-88 has been approved entry into Phase I clinical trial for treatment of prostate cancer in USA. This review will focus on these breakthrough findings of triptolide and its implications. PMID- 21255693 TI - Suberoylanilide hydroxamic acid (SAHA; vorinostat) causes bone loss by inhibiting immature osteoblasts. AB - Histone deacetylase (Hdac) inhibitors are used clinically to treat cancer and epilepsy. Although Hdac inhibition accelerates osteoblast maturation and suppresses osteoclast maturation in vitro, the effects of Hdac inhibitors on the skeleton are not understood. The purpose of this study was to determine how the pan-Hdac inhibitor, suberoylanilide hydroxamic acid (SAHA; a.k.a. vorinostat or Zolinza(TM)) affects bone mass and remodeling in vivo. Male C57BL/6J mice received daily SAHA (100mg/kg) or vehicle injections for 3 to 4weeks. SAHA decreased trabecular bone volume fraction and trabecular number in the distal femur. Cortical bone at the femoral midshaft was not affected. SAHA reduced serum levels of P1NP, a bone formation marker, and also suppressed tibial mRNA levels of type I collagen, osteocalcin and osteopontin, but did not alter Runx2 or osterix transcripts. SAHA decreased histological measures of osteoblast number but interestingly increased indices of osteoblast activity including mineral apposition rate and bone formation rate. Neither serum (TRAcP 5b) nor histological markers of bone resorption were affected by SAHA. P1NP levels returned to baseline in animals which were allowed to recover for 4weeks after 4weeks of daily SAHA injections, but bone density remained low. In vitro, SAHA suppressed osteogenic colony formation, decreased osteoblastic gene expression, induced cell cycle arrest, and caused DNA damage in bone marrow-derived adherent cells. Collectively, these data demonstrate that bone loss following treatment with SAHA is primarily due to a reduction in osteoblast number. Moreover, these decreases in osteoblast number can be attributed to the deleterious effects of SAHA on immature osteoblasts, even while mature osteoblasts are resistant to the harmful effects and demonstrate increased activity in vivo, indicating that the response of osteoblasts to SAHA is dependent upon their differentiation state. These studies suggest that clinical use of SAHA and other Hdac inhibitors to treat cancer, epilepsy or other conditions may potentially compromise skeletal structure and function. PMID- 21255695 TI - Galactomannan from Caesalpinia spinosa induces phenotypic and functional maturation of human dendritic cells. AB - Plant polysaccharides present an interesting potential as immunomodulators, particularly in the induction of antitumoral responses, principally because of their molecular complexity and low in vivo toxicity. Activation of dendritic cells (DCs) could improve antitumoral responses usually diminished in cancer patients, and natural adjuvants provide a possibility of inducing this activation. Herein, we investigated the immunomodulatory activity of a neutral plant polysaccharide Galactomannan on human monocyte-derived DCs (MDDC). MDDCs were stimulated with Galactomannan (GLM) from Caesalpinia spinosa and both phenotypic and functional activities were assessed by flow cytometry and real time PCR. The phagocytic ability of MDDCs was determined by using E-coli pHrodo particles and induction of T-lymphocyte allostimulation was determined after T cell staining with carboxyfluorescein succinimidyl ester (CFSE). In MDDCs, purified Galactomannan induced phenotypic maturation revealed by increased expression of CD83, CD86, CD206, and HLA-DR. Functional experiments showed the loss of particulate antigen uptake in Galactomannan-stimulated DCs and increased alloantigen presentation capacity. Finally, Galactomannan increased protein and mRNA levels of pro-inflammatory cytokines including IL-1beta, IL-6, IL-8, IL 12p70, and TNF-alpha. These data reveal that Galactomannan obtained from Caesalpinia spinosa promotes effective activation of MDDCs. This adjuvant-like activity may have therapeutic applications in clinical settings where immune responses need boosting. PMID- 21255696 TI - Black tea polyphenol inhibits CXCL10 production in oncostatin M-stimulated human gingival fibroblasts. AB - CXC chemokine ligand 10 (CXCL10) plays an important role in the infiltration of Th1 cells and thus in the exacerbation of periodontal disease. Theaflavin-3,3' digallate (TFDG), polyphenol in black tea, has some beneficial effects but the effect of TFDG on CXCL10 production from human gingival fibroblasts (HGFs) is uncertain. In this study, we investigated the mechanisms by which TFDG may inhibit oncostatin M (OSM)-induced CXCL10 production in human gingival fibroblasts. TFDG prevented OSM-mediated CXCL10 production by HGFs in a dose dependent manner. TFDG significantly inhibited OSM-induced phosphorylation of c Jun N terminal kinase (JNK), protein kinase B (Akt) (Ser473) that are related to CXCL10 production from OSM-stimulated HGFs. In addition, TFDG suppressed OSM receptor (OSMR) beta expression on HGFs. These data provide a novel mechanism where the black tea flavonoid, theaflavin, could provide direct benefits in periodontal disease. PMID- 21255697 TI - Production of recombinant human HMGB1 and anti-HMGB1 rabbit serum. AB - High-mobility group box-1 (HMGB1) plays important roles in inflammation, immune responses, and tumor progression. Since HMGB1 and its components have been shown to be mediators of a number of diseases but several sources of recombinant HMGB1 showed controversial biological activity, it is important to obtain recombinant HMGB1 with properties that resemble the native protein. For this purpose, we cloned genes coding for human HMGB1 and its active components A box and B box by PCR and inserted the cloned genes into pET28a vectors for transformation of Escherichia coli BL21. The E. coli expressed proteins were then purified with a Ni(2+)-NTA column and the endotoxin content was removed. Recombinant human HMGB1 (rhHMGB1) and its B box thus obtained stimulated, but A box inhibited, the production of the chemokine CXCL8/IL-8 by THP-1 monocytic cell line. We also used purified rhHMGB1 to immunize rabbits and generated potent anti-sera, which was capable of neutralizing the activity of rhHMGB1 in vitro and detecting the increased HMGB1 expression in inflammatory tissues in mice and humans. Thus, we have established essential means to produce biologically active rhHMGB1 that will facilitate us to study its role in diseases and to explore its potential as a therapeutic agent. PMID- 21255698 TI - Sulfur-containing antioxidants increase in vitro several functions of lymphocytes from mice. AB - The in vitro effects of several sulfur-containing antioxidants, such as glutathione (GSH), N-acetylcysteine (NAC), thioproline (TP) and taurine (TAU), at different concentrations, on key functions of lymphocytes from axillary nodes, spleen, thymus and peritoneum from young-adult BALB/c mice have been investigated. The functions studied have been proliferation, both spontaneous and in response to the mitogen Concanavalin A, mobility both spontaneous and directed to a chemical attractant (chemotaxis) and adherence to substrate. The effect of these antioxidants on the viability of leukocytes was also investigated. The results show an antioxidant-induced stimulation of all the functions studied. The highest concentrations used of each antioxidant were the most effective in proliferation (5mM for GSH, 1mM for TP and NAC and 40 mM for TAU). These concentrations increase mobility significantly. The presence of TP+NAC enhances the chemotaxis of peritoneal lymphocytes more than each antioxidant separately. The adherence capacity of peritoneal lymphocytes also increased at 10 min of incubation with GSH, TP and NAC. All these antioxidants increase the viability of leukocytes in culture, especially in cells from spleen. In conclusion, the sulfur containing antioxidants studied in vitro improve the functional capacity of lymphocytes from young-adult mice and these results showing that the improvement of the immune response, and specifically of the lymphocyte functions, found after ingesting diet supplemented with the antioxidants studied, are due to a direct action of these compounds in the immune cells. PMID- 21255699 TI - Virtual reality for embryonic measurements requiring depth perception. AB - Two real-time three-dimensional images of first-trimester pregnancies visualized using virtual reality (VR) are presented. Inherently three-dimensional structures, like the umbilical cord and limbs, can be efficiently and accurately measured using VR. PMID- 21255700 TI - Millennium neonatology: building for the future. Introduction. PMID- 21255701 TI - The newborn intensive care unit environment of care: how we got here, where we're headed, and why. AB - The newborn intensive care unit (NICU) is a life-defining place for many infants, families, and caregivers. The place in which such events occur is often remembered for its sights, sounds, and smells, but the physical environment of the NICU is far more than a memory tag; it can directly influence the quality of the experience for all of its inhabitants. A growing body of evidence demonstrates the profound impact of the physical environment on growth and development of the neonatal brain. The value of skin-to-skin care is now established. Psychology, sociology, and occupational health provide additional insight into the effect of the NICU setting on families and caregivers. Together, these lines of evidence point to the need for individualized environments. Single family rooms are a growing trend in the NICU because they allow for individualized environments. Careful planning can avoid pitfalls and bring benefit to babies, families, and caregivers alike. PMID- 21255703 TI - Family support and family-centered care in the neonatal intensive care unit: origins, advances, impact. AB - Family-centered care (FCC) has been increasingly emphasized as an important and necessary element of neonatal intensive care. FCC is conceptualized as a philosophy with a set of guiding principles, as well as a cohort of programs, services, and practices that many hospitals have embraced. Several factors drive the pressing need for family-centered care and support of families of infants in NICUs, including the increase in the number of infants in NICUs; growth in diversity of the population and their concurrent needs; identification of parental and familial stress and lack of parenting confidence; and gaps in support for families, as identified by parents and NICU staff. We explore the origins of and advances in FCC in the NICU and identify various delivery methods and aspects of FCC and family support in the NICU. We examine the research and available evidence supporting FCC in the NICU and offer recommendations for increased dissemination and for future study. PMID- 21255702 TI - Infant neurobehavioral development. AB - The trend toward single-room neonatal intensive care units (NICUs) is increasing; however scientific evidence is, at this point, mostly anecdotal. This is a critical time to assess the impact of the single-room NICU on improving medical and neurobehavioral outcomes of the preterm infant. We have developed a theoretical model that may be useful in studying how the change from an open-bay NICU to a single-room NICU could affect infant medical and neurobehavioral outcome. The model identifies mediating factors that are likely to accompany the change to a single-room NICU. These mediating factors include family centered care, developmental care, parenting and family factors, staff behavior and attitudes, and medical practices. Medical outcomes that plan to be measured are sepsis, length of stay, gestational age at discharge, weight gain, illness severity, gestational age at enteral feeding, and necrotizing enterocolitis (NEC). Neurobehavioral outcomes include the NICU Network Neurobehavioral Scale (NNNS) scores, sleep state organization and sleep physiology, infant mother feeding interaction scores, and pain scores. Preliminary findings on the sample of 150 patients in the open-bay NICU showed a "baseline" of effects of family centered care, developmental care, parent satisfaction, maternal depression, and parenting stress on the neurobehavioral outcomes of the newborn. The single-room NICU has the potential to improve the neurobehavioral status of the infant at discharge. Neurobehavioral assessment can assist with early detection and therefore preventative intervention to maximize developmental outcome. We also present an epigenetic model of the potential effects of maternal care on improving infant neurobehavioral status. PMID- 21255704 TI - Outcomes of human milk-fed premature infants. AB - Significant benefits to infant host defense, sensory-neural development, gastrointestinal maturation, and some aspects of nutritional status are observed when premature infants are fed their mothers' own milk. A reduction in infection related morbidity in human milk-fed premature infants has been reported in nearly a dozen descriptive, and a few quasi-randomized, studies in the past 25 years. Human milk-fed infants also have decreased rates of rehospitalization for illness after discharge. Studies on neurodevelopmental outcomes have reported significantly positive effects for human milk intake in the neonatal period and long-term mental and motor development, intelligence quotient, and visual acuity through adolescence. Body composition in adolescence also is associated with human milk intake in the neonatal intensive care unit. Finally, human milk intake is less associated with the development of the metabolic syndrome than infant formula feeding. PMID- 21255706 TI - [Copayments: conclusions from the scientific evidence. SemFYC document, October 2010]. PMID- 21255707 TI - Introduction. A current update of the influence of genomics on cancer care. PMID- 21255705 TI - Microstructural and functional connectivity in the developing preterm brain. AB - Prematurely born children are at increased risk for cognitive deficits, but the neurobiological basis of these findings remains poorly understood. Because variations in neural circuitry may influence performance on cognitive tasks, recent investigations have explored the impact of preterm birth on connectivity in the developing brain. Diffusion tensor imaging studies demonstrate widespread alterations in fractional anisotropy, a measure of axonal integrity and microstructural connectivity, throughout the developing preterm brain. Functional connectivity studies report that preterm neonates, children and adolescents exhibit alterations in both resting state and task-based connectivity when compared with term control subjects. Taken together, these data suggest that neurodevelopmental impairment following preterm birth may represent a disease of neural connectivity. PMID- 21255708 TI - The biology of cancer: what do oncology nurses really need to know. AB - OBJECTIVES: To describe the impact of genetics and genomics on the biology of cancer and the implications for patient care. DATA SOURCES: Pubmed; CINAHL. CONCLUSIONS: Cancer research in genetics/genomics has identified new mechanisms influencing personalized risk assessment/management, early detection, cancer treatment, and long-term screening/surveillance. IMPLICATIONS FOR NURSING PRACTICE: Understanding the basics of genetics/genomics on the biology of cancer will facilitate patient education and care delivery, including the administration and monitoring of genetically targeted therapies whose toxicities may in part be mediated by the molecular pathways targeted by the specific agent. PMID- 21255709 TI - Genetic cancer risk assessment. AB - OBJECTIVES: To describe critical elements of cancer risk assessment as identified through professional standards. DATA SOURCES: Professional guidelines, policy statements, and other published literature. CONCLUSION: The continually increasing integration of genetics/genomics into oncology care mandates that oncology nurses be familiar with the cancer risk assessment process, complexities, and implications for personalized risk reduction and early detection recommendations and for cancer treatment, including targeted therapies. IMPLICATIONS FOR NURSING PRACTICE: Informed nurses can identify genetic cancer risk factors, educate patients about cancer risk and risk management/treatment strategies, and refer appropriate patients to a cancer genetics nurse or other genetics professional for comprehensive risk assessment. PMID- 21255710 TI - Germline mutations in cancer susceptibility genes: an overview for nurses. AB - OBJECTIVE: To provide an overview of hereditary cancer susceptibility genes and associated cancer risks. DATA SOURCES: Peer reviewed published research studies and review articles. CONCLUSIONS: Identifying deleterious mutations in cancer susceptibility genes allows for clarification of cancer risk in individual family members and risk-level appropriate screening, and risk management recommendations. Evolving knowledge of the role of germline mutations provides an unprecedented opportunity to reduce cancer incidence, morbidity, and morality. IMPLICATIONS FOR NURSING PRACTICE: To provide individuals/families with accurate cancer risk management information and guidance, oncology nurses must be familiar with scientific discoveries related to cancer susceptibility genes. PMID- 21255711 TI - Genetic tumor profiling and genetically targeted cancer therapy. AB - OBJECTIVES: To discuss how understanding and manipulation of tumor genetics information and technology shapes cancer care today and what changes might be expected in the near future. DATA SOURCES: Published articles, web resources, clinical practice. CONCLUSIONS: Advances in our understanding of genes and their regulation provide a promise of more personalized cancer care, allowing selection of the most safe and effective therapy in an individual situation. IMPLICATIONS FOR NURSING PRACTICE: Rapid progress in the technology of tumor profiling and targeted cancer therapies challenges nurses to keep up-to-date to provide quality patient education and care. PMID- 21255712 TI - Infusion of pharmacogenetics into cancer care. AB - OBJECTIVES: To review pharmacogenetics as it relates to cancer therapy and to describe pharmacogenetic tests that are clinically available and relevant to cancer drug selection or dosing or both. DATA SOURCES: Peer-reviewed, evidence based literature. CONCLUSIONS: Genetic predispositions and enzyme specific inhibitors and inducers are critical factors in patients' responses to cancer drugs. IMPLICATIONS FOR NURSING PRACTICE: Nurses need to incorporate knowledge about pharmacogenetics when administering cancer drugs and monitoring patients' responses. Nurses also have an important role in assuring that patients are informed about the purpose and limitations of pharmacogenetic testing. PMID- 21255713 TI - Ethical, legal, psychosocial, and cultural implications of genomics for oncology nurses. AB - OBJECTIVES: To summarize the role of oncology nurses in the ethical, legal, psychosocial, and cultural issues inherent in genetic testing for hereditary cancer risk and to describe the recent trend and implications of direct-to consumer genetic tests. DATA SOURCES: Published articles/books, legal rulings, professional organization statements. CONCLUSIONS: Ethical, legal, psychosocial, and cultural implications are inherent in the growing field of genetic science that is transforming modern health care. IMPLICATIONS FOR NURSING PRACTICE: Nurses have a duty to be knowledgeable about and advocate for the ethical integration of genetic/genomic information into their patient's health care. PMID- 21255714 TI - Essential genetic and genomic nursing competencies for the oncology nurse. AB - OBJECTIVES: To review the opportunities and possibilities for advancing oncology nursing competencies in genetic/genomics through the illustration of case scenarios in clinical care. DATA SOURCES: Literature; research reports. CONCLUSIONS: Oncology nurses have the potential to influence whether or not cutting edge research discoveries are utilized at the bedside. Clinical integration of genetic/genomic information has the potential to optimize health outcomes and lengthen patient lives. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses need to include genetics/genomics in their practice in order to impact quality patient care today and for the future. PMID- 21255715 TI - Appendix: genetic educational, health policy, research, and networking resources. PMID- 21255716 TI - Extravasation management: clinical update. AB - OBJECTIVE: To present a clinical update on the prevention, detection, and evidence-based management of vesicant chemotherapy extravasations. DATA SOURCES: Journal articles, published and unpublished case reports, personal experience. CONCLUSION: In the 4 years that have elapsed since the publication of the original article, much more is known about vesicant chemotherapy extravasation, and effective evidence-based treatments now are available. The antidotes sodium thiosulfate for mechlorethamine extravasations and hyaluronidase for plant alkaloid extravasations are recommended by the manufacturers of these vesicants and cited in nursing guidelines. The anthracycline extravasation treatment dexrazoxane for injection, the first and only extravasation treatment with proven effectiveness, is now available as Totect (dexrazoxane; TopoTarget USA, Rockaway, NJ, USA) in the US and Savene (SpePharm, Amsterdam, The Netherlands) in Europe. IMPLICATIONS FOR NURSING PRACTICE: Nurses who administer vesicant chemotherapy agents need to be aware of the most current evidence (or lack of evidence) for various types of extravasation treatment. Well-informed nurses are patient advocates and instrumental in detecting, managing, and documenting extravasations. Most importantly, nurses play a key role in preventing vesicant chemotherapy extravasations. PMID- 21255718 TI - Comparison of two self-rating instruments for medication adherence assessment in hypertension revealed insufficient psychometric properties. PMID- 21255720 TI - Re: Early failure of xenogenous de-cellularised pulmonary valve conduits: a word of caution! PMID- 21255721 TI - How one bad protein spoils the barrel: structural details of beta2-microglobulin amyloidogenicity. AB - In this issue, Eichner et al. (2011) describe at atomic resolution the structure of an amyloidogenic state of beta(2)-microglobulin and how it may corrupt a soluble counterpart in the pathological scenario that ensues when good proteins go to the "dark side'" and form infectious toxic amyloid. PMID- 21255722 TI - Regulator of Ras depalmitoylation and retrograde trafficking: a new hat for FKBP. AB - In this issue of Molecular Cell, Ahearn et al. (2011) identified FKBP12 as a novel regulator of Ras signaling through its modulation of depalmitoylation of H Ras and its recycling from plasma membrane to the Golgi. PMID- 21255723 TI - Many paths to the same end: histone transcripts recruit canonical initiation factors through unconventional interactions. AB - In this issue of Molecular Cell, Eriani and colleagues show that histone transcripts recruit translation initiation factors through an alternate pathway reminiscent of viral translation, suggesting a broader role for noncanonical translation initiation on cellular transcripts (Martin et al., 2011). PMID- 21255724 TI - A new role for miR-182 in DNA repair. AB - A role for miRNAs in modulating cellular responses to DNA damage and chemotherapy is emerging. In this issue of Molecular Cell, Moskwa and colleagues propose a novel function for miR-182 in the posttranscriptional regulation of BRCA1 expression and in DNA repair (Moskwa et al., 2011). PMID- 21255725 TI - Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. AB - Emerging evidence suggests that protein acetylation is a broad-ranging regulatory mechanism. Here we utilize acetyl-peptide arrays and metabolomic analyses to identify substrates of mitochondrial deacetylase Sirt3. We identified ornithine transcarbamoylase (OTC) from the urea cycle, and enzymes involved in beta oxidation. Metabolomic analyses of fasted mice lacking Sirt3 (sirt3(-/-)) revealed alterations in beta-oxidation and the urea cycle. Biochemical analysis demonstrated that Sirt3 directly deacetylates OTC and stimulates its activity. Mice under caloric restriction (CR) increased Sirt3 protein levels, leading to deacetylation and stimulation of OTC activity. In contrast, sirt3(-/-) mice failed to deacetylate OTC in response to CR. Inability to stimulate OTC under CR led to a failure to reduce orotic acid levels, a known outcome of OTC deficiency. Thus, Sirt3 directly regulates OTC activity and promotes the urea cycle during CR, and the results suggest that under low energy input, Sirt3 modulates mitochondria by promoting amino acid catabolism and beta-oxidation. PMID- 21255726 TI - The soluble form of Bax regulates mitochondrial fusion via MFN2 homotypic complexes. AB - In mammals, fusion of the mitochondrial outer membrane is controlled by two DRPs, MFN1 and MFN2, that function in place of a single outer membrane DRP, Fzo1 in yeast. We addressed the significance of two mammalian outer membrane fusion DRPs using an in vitro mammalian mitochondrial fusion assay. We demonstrate that heterotypic MFN1-MFN2 trans complexes possess greater efficacy in fusion as compared to homotypic MFN1 or MFN2 complexes. In addition, we show that the soluble form of the proapoptotic Bcl2 protein, Bax, positively regulates mitochondrial fusion exclusively through homotypic MFN2 trans complexes. Together, these data demonstrate functional and regulatory distinctions between MFN1 and MFN2 and provide insight into their unique physiological roles. PMID- 21255727 TI - Conformational conversion during amyloid formation at atomic resolution. AB - Numerous studies of amyloid assembly have indicated that partially folded protein species are responsible for initiating aggregation. Despite their importance, the structural and dynamic features of amyloidogenic intermediates and the molecular details of how they cause aggregation remain elusive. Here, we use DeltaN6, a truncation variant of the naturally amyloidogenic protein beta(2)-microglobulin (beta(2)m), to determine the solution structure of a nonnative amyloidogenic intermediate at high resolution. The structure of DeltaN6 reveals a major repacking of the hydrophobic core to accommodate the nonnative peptidyl-prolyl trans-isomer at Pro32. These structural changes, together with a concomitant pH dependent enhancement in backbone dynamics on a microsecond-millisecond timescale, give rise to a rare conformer with increased amyloidogenic potential. We further reveal that catalytic amounts of DeltaN6 are competent to convert nonamyloidogenic human wild-type beta(2)m (Hbeta(2)m) into a rare amyloidogenic conformation and provide structural evidence for the mechanism by which this conformational conversion occurs. PMID- 21255728 TI - FKBP12 binds to acylated H-ras and promotes depalmitoylation. AB - A cycle of palmitoylation/depalmitoylation of H-Ras mediates bidirectional trafficking between the Golgi apparatus and the plasma membrane, but nothing is known about how this cycle is regulated. We show that the prolyl isomerase (PI) FKBP12 binds to H-Ras in a palmitoylation-dependent fashion and promotes depalmitoylation. A variety of inhibitors of the PI activity of FKBP12, including FK506, rapamycin, and cycloheximide, increase steady-state palmitoylation. FK506 inhibits retrograde trafficking of H-Ras from the plasma membrane to the Golgi in a proline 179-dependent fashion, augments early GTP loading of Ras in response to growth factors, and promotes H-Ras-dependent neurite outgrowth from PC12 cells. These data demonstrate that FKBP12 regulates H-Ras trafficking by promoting depalmitoylation through cis-trans isomerization of a peptidyl-prolyl bond in proximity to the palmitoylated cysteines. PMID- 21255730 TI - Cap-assisted internal initiation of translation of histone H4. AB - In eukaryotes, a crucial step of translation initiation is the binding of the multifactor complex eIF4F to the 5' end of the mRNA, a prerequisite to recruitment of the activated small ribosomal 43S particle. Histone H4 mRNAs have short 5'UTRs, which do not conform to the conventional scanning-initiation model. Here we show that the ORF of histone mRNA contains two structural elements critical for translation initiation. One of the two structures binds eIF4E without the need of the cap. Ribosomal 43S particles become tethered to this site and directly loaded in the vicinity of the AUG. The other structure, 19 nucleotides downstream of the initiation codon, forms a three-way helix junction, which sequesters the m(7)G cap. This element facilitates direct positioning of the ribosome on the cognate start codon. This unusual translation initiation mode might be considered as a hybrid mechanism between the canonical and the IRES driven translation initiation process. PMID- 21255729 TI - Molecular and structural basis of ESCRT-III recruitment to membranes during archaeal cell division. AB - Members of the crenarchaeal kingdom, such as Sulfolobus, divide by binary fission yet lack genes for the otherwise near-ubiquitous tubulin and actin superfamilies of cytoskeletal proteins. Recent work has established that Sulfolobus homologs of the eukaryotic ESCRT-III and Vps4 components of the ESCRT machinery play an important role in Sulfolobus cell division. In eukaryotes, several pathways recruit ESCRT-III proteins to their sites of action. However, the positioning determinants for archaeal ESCRT-III are not known. Here, we identify a protein, CdvA, that is responsible for recruiting Sulfolobus ESCRT-III to membranes. Overexpression of the isolated ESCRT-III domain that interacts with CdvA results in the generation of nucleoid-free cells. Furthermore, CdvA and ESCRT-III synergize to deform archaeal membranes in vitro. The structure of the CdvA/ESCRT III interface gives insight into the evolution of the more complex and modular eukaryotic ESCRT complex. PMID- 21255731 TI - Structure of a preternary complex involving a prokaryotic NHEJ DNA polymerase. AB - In many prokaryotes, a specific DNA primase/polymerase (PolDom) is required for nonhomologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs). Here, we report the crystal structure of a catalytically active conformation of Mycobacterium tuberculosis PolDom, consisting of a polymerase bound to a DNA end with a 3' overhang, two metal ions, and an incoming nucleotide but, significantly, lacking a primer strand. This structure represents a polymerase:DNA complex in a preternary intermediate state. This polymerase complex occurs in solution, stabilizing the enzyme on DNA ends and promoting nucleotide extension of short incoming termini. We also demonstrate that the invariant Arg(220), contained in a conserved loop (loop 2), plays an essential role in catalysis by regulating binding of a second metal ion in the active site. We propose that this NHEJ intermediate facilitates extension reactions involving critically short or noncomplementary DNA ends, thus promoting break repair and minimizing sequence loss during DSB repair. PMID- 21255734 TI - Comment on: Adjustable gastric banding outcomes with and without gastrogastric imbrication sutures: a randomized controlled trial. PMID- 21255733 TI - Gastric plication: preclinical study of durability of serosa-to-serosa apposition. AB - BACKGROUND: Vertical gastric plication is a novel surgical approach for reducing the stomach capacity. Anterior surface plication and greater curvature plication are variations of vertical gastric plication that reduce the gastric capacity through infolding of the anterior surface or greater curvature of the stomach, respectively. These approaches have been tested, with positive results in a small number of preclinical and clinical trials. A key step toward greater investigation of vertical gastric plication as a viable bariatric procedure would be confirmation that the apposed serosal tissues can be securely and durably bonded. We compared the short-term durability of gastric plications and serosal bonds using a variety of fastening devices and techniques in a university hospital and private company setting. METHODS: A total of 30 anterior surface plication and 8 greater curvature plication procedures were performed using an open or a laparoscopic surgical technique in 38 hound dogs. The fastening devices used were T-tags, buttressed T-tags, 2 types of suture, and 4 types of staple based fasteners. The density of the fastening devices was varied among the dogs. With 3 exceptions (2 in keeping with the study design and 1 due to complications), the dogs were followed up for 8 weeks. Histologic examinations and tensile testing were performed postmortem. RESULTS: All fastening devices created durable plication folds, except for 1 technique. The only technique that did not produce durable serosa-to-serosa adhesions was a staple/suture combination. Intentional abrasion of the apposed sites had no demonstrable effect on the bonds between the tissues in any group. Increasing the fastener density and number of rows increased the adhesions within the folds. CONCLUSION: Our findings have confirmed the short-term durability and development of dense fibrous appositions of the serosal folds for fastening approaches that create fixed serosal apposition. Additional studies are needed to identify the optimal fastening modality for anterior surface plication, greater curvature plication, and, ultimately, clinical applications of this procedure. PMID- 21255732 TI - Activation-induced cytidine deaminase induces reproducible DNA breaks at many non Ig Loci in activated B cells. AB - After immunization or infection, activation-induced cytidine deaminase (AID) initiates diversification of immunoglobulin (Ig) genes in B cells, introducing mutations within the antigen-binding V regions (somatic hypermutation, SHM) and double-strand DNA breaks (DSBs) into switch (S) regions, leading to antibody class switch recombination (CSR). We asked if, during B cell activation, AID also induces DNA breaks at genes other than IgH genes. Using a nonbiased genome-wide approach, we have identified hundreds of reproducible, AID-dependent DSBs in mouse splenic B cells shortly after induction of CSR in culture. Most interestingly, AID induces DSBs at sites syntenic with sites of translocations, deletions, and amplifications found in human B cell lymphomas, including within the oncogene B cell lymphoma11a (bcl11a)/evi9. Unlike AID-induced DSBs in Ig genes, genome-wide AID-dependent DSBs are not restricted to transcribed regions and frequently occur within repeated sequence elements, including CA repeats, non CA tandem repeats, and SINEs. PMID- 21255735 TI - Patients who endorse more binge eating triggers before gastric bypass lose less weight at 6 months. AB - BACKGROUND: Patients presenting for gastric bypass surgery often demonstrate binge eating behaviors. The present study sought to determine whether binge eating triggers are predictive of weight loss outcomes in bariatric surgery patients at 6 months postoperatively in the setting of a university hospital. METHODS: A total of 48 patients presenting for gastric bypass surgery at an academic medical center in the Southeastern United States and who had returned for the 6-month follow-up visit were included in the present study. The patients were mostly women (85%), white (71%), and middle-aged (mean age 47 years), with an average weight of 100.9 kg. The patients completed the Inventory of Binge Eating Situations at baseline, and weight loss outcomes were assessed at 6 months. Weight loss success was indexed using 2 methods: the percentage of excess weight lost (continuous variable) and whether the patient was on track with their weight loss as defined by a >= 50% excess weight loss (dichotomous variable). RESULTS: A significant negative correlation (r = -.31, P = .03) was found between the preoperative Inventory of Binge Eating Situations scores and the percentage of excess weight loss at 6 months after gastric bypass surgery. Logistic regression analysis showed that "on track" status at 6 months was predicted by the Inventory of Binge Eating Situations score at baseline (Wald chi-square = 3.97, df = 1, P = .046). CONCLUSION: Careful assessment of binge eating situations could serve as a potential predictor of poor weight loss outcomes in patients seeking gastric bypass surgery. These findings support the baseline assessment of binge eating triggers and future research to examine the effectiveness of interventions for coping with binge eating triggers for gastric bypass surgery patients. PMID- 21255736 TI - Systematic literature review of reoperations after gastric banding: is a stepwise approach justified? PMID- 21255737 TI - Sanctions for authors of plagiarized Surgery for Obesity and Related Diseases article. PMID- 21255738 TI - A tribute to the Extramural Epidemiology Program, National Institute on Aging. PMID- 21255739 TI - A European perspective on population studies of dementia. AB - The change in the world's age demographics and the predicted rise in the incidence of age-related diseases, including dementia, is a source of major public health concern. Major research effort in both the United States and Europe has been targeted toward understanding the pathogenesis and epidemiology of dementia. This article presents a general overview of the history of dementia research in Europe and how it compares with that in the United States. The review highlights the common issues which both U.S. and European researchers have identified and attempted to tackle. To maximize information gained from studies across the world, better harmonization of methodology is needed, as informed from current research practice. PMID- 21255740 TI - Counting dementia: There is no one "best" way. AB - The growing societal and individual burden of dementia means that counting the cases of dementia is critical. There are several approaches and methods that can be used to identify dementia cases. The ascertainment can range from very detailed characterization of the individual (deep) to a brief standardized assessment (wide) that emphasizes individual functioning. The choice of going deep or wide depends on the goal of the ascertainment. These goals are discussed, as well as the emerging issues that may change the way dementia cases are classified. PMID- 21255741 TI - Operationalizing diagnostic criteria for Alzheimer's disease and other age related cognitive impairment-Part 1. AB - In this article, the challenges faced by several noted population studies for Alzheimer dementia in operationalizing current clinical diagnostic criteria for Alzheimer's disease (AD) have been reviewed. Differences in case ascertainment, methodological biases, cultural and educational influences on test performance, inclusion of special populations such as underrepresented minorities and the oldest old, and detection of the earliest symptomatic stages of underlying AD have been considered. Classification of Alzheimer dementia may be improved by the incorporation of biomarkers for AD if the sensitivity, specificity, and predictive value of the biomarkers are established and if they are appropriate for epidemiological studies, as may occur should a plasma biomarker be developed. Biomarkers for AD could also facilitate studies of the interactions of various forms of neurodegenerative disorders with cerebrovascular disease, resulting in "mixed dementia". PMID- 21255742 TI - Operationalizing diagnostic criteria for Alzheimer's disease and other age related cognitive impairment-Part 2. AB - This article focuses on the effects of operational differences in case ascertainment on estimates of prevalence and incidence of cognitive impairment and/or dementia of the Alzheimer type. Experience and insights are discussed by investigators from the Framingham Heart Study, the East Boston Senior Health Project, the Chicago Health and Aging Project, the Mayo Clinic Study of Aging, the Baltimore Longitudinal Study of Aging, and the Aging, Demographics, and Memory Study. There is a general consensus that the single most important factor determining prevalence estimates of Alzheimer's disease (AD) is the severity of cognitive impairment used as a threshold to define cases. Studies that require a level of cognitive impairment in which persons are unable to provide self-care will have much lower estimates than the studies aimed at identifying persons in the earliest stages of AD. There are limited autopsy data from the aforementioned epidemiological studies to address accuracy in the diagnosis of etiological subtype, namely the specification of AD alone or in combination with other types of pathology. However, other community-based cohort studies show that many persons with mild cognitive impairment and also some persons without dementia or mild cognitive impairment meet pathological criteria for AD, thereby suggesting that the number of persons who would benefit from an effective secondary prevention intervention is probably higher than the published prevalence estimates. Improved accuracy in the clinical diagnosis of AD is anticipated with the addition of molecular and structural biomarkers in the next generation of epidemiological studies. PMID- 21255743 TI - Passive case-finding for Alzheimer's disease and dementia in two U.S. communities. AB - Passive surveillance for disease is a public health approach that relies on documentation available within existing health records for the region or community being studied. Its two primary advantages over active case-finding are the lower cost of research and the lower burden on the population under study. The effectiveness of passive case-finding depends on the comprehensiveness of the healthcare coverage in a given community and the adequacy of the available medical records. The Rochester Epidemiology Project has permitted dementia case detection for Olmsted County, Minnesota, using a medical records-linkage system. These data were compared with case ascertainment using direct assessment of individuals in an epidemiological study of the same community. At the Group Health Research Institute, investigators compared dementia and Alzheimer's disease cases detected using an electronic medical record database search with those identified by a parallel active case-finding study. In this article, the advantages and disadvantages of passive case-finding were discussed, and the following conclusion was drawn: the purpose of the study being conducted should determine the case-finding approach that is to be used. PMID- 21255744 TI - National estimates of the prevalence of Alzheimer's disease in the United States. AB - Several methods of estimating prevalence of dementia are presented in this article. For both Brookmeyer and the Chicago Health and Aging project (CHAP), the estimates of prevalence are derived statistically, forward calculating from incidence and survival figures. The choice of incidence rates on which to build the estimates may be critical. Brookmeyer used incidence rates from several published studies, whereas the CHAP investigators applied the incidence rates observed in their own cohort. The Aging, Demographics, and Memory Study (ADAMS) and the East Boston Senior Health Project (EBSHP) were sample surveys designed to ascertain the prevalence of Alzheimer's disease and dementia. ADAMS obtained direct estimates by relying on probability sampling nationwide. EBSHP relied on projection of localized prevalence estimates to the national population. The sampling techniques of ADAMS and EBSHP were rather similar, whereas their disease definitions were not. By contrast, EBSPH and CHAP have similar disease definitions internally, but use different calculation techniques, and yet arrive at similar prevalence estimates, which are considerably greater than those obtained by either Brookmeyer or ADAMS. Choice of disease definition may play the larger role in explaining differences in observed prevalence between these studies. PMID- 21255745 TI - Sources of variability in estimates of the prevalence of Alzheimer's disease in the United States. AB - BACKGROUND: The prevalence of Alzheimer's disease (AD) in the United States was estimated at 2.3 million in 2002 by the Aging, Demographics, and Memory Study (ADAMS), which is almost 50% less than the estimate of 4.5 million in 2000 derived from the Chicago Health and Aging Project. METHODS: We considered how differences in diagnostic criteria may have contributed to these differences in AD prevalence. RESULTS: We identified several important differences in diagnostic criteria that may have contributed to the differing estimates of AD prevalence. Two factors were especially noteworthy. First, the Diagnostic and Statistical Manual of Mental Disorders III-R and IV criteria of functional limitation documented by an informant used in ADAMS effectively concentrated the diagnosis of dementia toward a relatively higher level of cognitive impairment. ADAMS separately identified a category of cognitive impairment not dementia and within that group there were a substantial number of cases with "prodromal" AD (a maximum of 1.95 million with upweighting). Second, a substantial proportion of dementia in ADAMS was attributed to either vascular disease (representing a maximum of 0.59 million with upweighting) or undetermined etiology (a maximum of 0.34 million), whereas most dementia, including mixed dementia, was attributed to AD in the Chicago Health and Aging Project. CONCLUSION: The diagnosis of AD in population studies is a complex process. When a diagnosis of AD excludes persons meeting criteria for vascular dementia, when not all persons with dementia are assigned an etiology, and when a diagnosis of dementia requires an informant report of functional limitations, the prevalence is substantially lower and the diagnosed cases most likely have a relatively higher level of impairment. PMID- 21255746 TI - Trends in the incidence and prevalence of Alzheimer's disease, dementia, and cognitive impairment in the United States. AB - Declines in heart disease and stroke mortality rates are conventionally attributed to reductions in cigarette smoking, recognition and treatment of hypertension and diabetes, effective medications to improve serum lipid levels and to reduce clot formation, and general lifestyle improvements. Recent evidence implicates these and other cerebrovascular factors in the development of a substantial proportion of dementia cases. Analyses were undertaken to determine whether corresponding declines in age-specific prevalence and incidence rates for dementia and cognitive impairment have occurred in recent years. Data spanning 1 or 2 decades were examined from community-based epidemiological studies in Minnesota, Illinois, and Indiana, and from the Health and Retirement Study, which is a national survey. Although some decline was observed in the Minnesota cohort, no statistically significant trends were apparent in the community studies. A significant reduction in cognitive impairment measured by neuropsychological testing was identified in the national survey. Cautious optimism appears justified. PMID- 21255747 TI - Reducing case ascertainment costs in U.S. population studies of Alzheimer's disease, dementia, and cognitive impairment-Part 1. AB - Establishing methods for ascertainment of dementia and cognitive impairment that are accurate and also cost-effective is a challenging enterprise. Large population-based studies often using administrative data sets offer relatively inexpensive and reliable estimates of severe conditions including moderate to advanced dementia that are useful for public health planning, but they can miss less severe cognitive impairment which may be the most effective point for intervention. Clinical and epidemiological cohorts, intensively assessed, provide more sensitive detection of less severe cognitive impairment but are often costly. In this article, several approaches to ascertainment are evaluated for validity, reliability, and cost. In particular, the methods of ascertainment from the Health and Retirement Study are described briefly, along with those of the Aging, Demographics, and Memory Study (ADAMS). ADAMS, a resource-intense sub study of the Health and Retirement Study, was designed to provide diagnostic accuracy among persons with more advanced dementia. A proposal to streamline future ADAMS assessments is offered. Also considered are algorithmic and Web based approaches to diagnosis that can reduce the expense of clinical expertise and, in some contexts, can reduce the extent of data collection. These approaches are intended for intensively assessed epidemiological cohorts where goal is valid and reliable case detection with efficient and cost-effective tools. PMID- 21255749 TI - A new technique for controlling the brain: optogenetics and its potential for use in research and the clinic. AB - The recent development of optogenetic techniques has generated considerable excitement in neuroscience research. Optogenetics uses light to control the activity of neurons which have been modified to express light-sensitive proteins. Some proteins, such as channelrhodopsin, are cation channels that produce depolarization of neurons when illuminated. In other cases, neuronal activity can be inhibited through illumination of proteins, such as the chloride pump halorhodopsin, that hyperpolarize neurons. Because these proteins can be selectively expressed in specific cell types and/or in specific locations, optogenetics avoids several of the non-specific effects of electrical or pharmacological brain stimulation. This short review will explain the physiology of this technique, describe the basic and technical aspects of the method, and highlight some of the research as well as the clinical potential of optogenetics. PMID- 21255748 TI - Reducing case ascertainment costs in U.S. population studies of Alzheimer's disease, dementia, and cognitive impairment-Part 2. AB - Dementia of the Alzheimer's type (DAT) is a major public health threat in developed countries where longevity has been extended to the eighth decade of life. Estimates of prevalence and incidence of DAT vary with what is measured, be it change from a baseline cognitive state or a clinical diagnostic endpoint, such as Alzheimer's disease. Judgment of what is psychometrically "normal" at the age of 80 years implicitly condones a decline from what is normal at the age of 30. However, because cognitive aging is very heterogeneous, it is reasonable to ask "Is 'normal for age' good enough to screen for DAT or its earlier precursors of cognitive impairment?" Cost containment and accessibility of ascertainment methods are enhanced by well-validated and reliable methods such as screening for cognitive impairment by telephone interviews. However, focused assessment of episodic memory, the key symptom associated with DAT, might be more effective at distinguishing normal from abnormal cognitive aging trajectories. Alternatively, the futuristic "Smart Home," outfitted with unobtrusive sensors and data storage devices, permits the moment-to-moment recording of activities so that changes that constitute risk for DAT can be identified before the emergence of symptoms. PMID- 21255750 TI - Electrodes in the brain--ethical criteria for research and treatment with deep brain stimulation for neuropsychiatric disorders. AB - BACKGROUND: Deep brain stimulation (DBS) has been used for neuropsychiatric disorders in clinical and research settings for almost 50 years now. Recent evidence demonstrates some efficacy in treating obsessive-compulsive disorder and major depression in patients refractory to other treatment modalities beyond single case reports. This has led to a considerable surge of clinical and commercial interest in DBS for psychiatric indications. Because of the high vulnerability of psychiatric patients, the lack of extensive short- and long-term data about effectiveness and the rapid spread of questionable indications this new field in psychiatry requires ethical criteria that can be applied to both research and clinical decision-making. OBJECTIVE AND METHODS: We here present an evidence-based systematic ethical analysis of psychiatric DBS using the criteria of beneficence, nonmaleficence, and autonomy. RESULTS AND CONCLUSIONS: The proposed criteria are helpful in analyzing empirical evidence, informing research investigations and guiding clinical decision-making. This will prepare the ground for ethically justified, empirically comprehensive DBS in this highly vulnerable population and allow stringent future societal discussions about its legitimation. PMID- 21255752 TI - Quantitative analysis of phosphenes induced by navigation-guided repetitive transcranial magnetic stimulation. AB - OBJECTIVE: Though a cortical visual prosthesis is a promising method for treating severe visual disturbances, long-term blindness is known to depress visual cortex activity. We examined the use of repetitive transcranial magnetic stimulation (rTMS) with a navigation system as a direct functional assessment tool for the visual cortex. METHODS: We performed rTMS of the occipital cortex at three different stimulus frequencies (1 Hz, 5 Hz, and 20 Hz), on five stimulus targets around the calcarine fissure in 10 healthy subjects and 3 patients with visual impairment. RESULTS: In the subjects with normal vision, phosphenes were mostly induced in the visual hemifield contralateral to the stimulation site, and stimulation on the targets inferior to the calcarine fissure predominantly induced phosphenes in the upper visual hemifield. High-frequency stimulation induced larger and complicated-shaped phosphenes at higher rates. The phosphenes induced rate and spatial distribution were altered in the blind patients. CONCLUSIONS: The rTMS has the ability to directly assess the regional visual function of the occipital cortex both in normal-sighted subjects and blind patients. Precise targeting with a navigation system appropriately stimulated the lingual gyri, which contributed to consistently inducing the phosphenes in the upper visual fields. Atypical representation of the phosphenes in patients with visual impairment suggests the alteration of regional cortical excitations and spatial representation due to the cortical reorganization after the loss of visual inputs. PMID- 21255753 TI - Reducing procedural pain and discomfort associated with transcranial direct current stimulation. AB - BACKGROUND: Transcranial direct current stimulation (tDCS) appears to have modulatory effects on the excitability of cortical brain tissue. Though tDCS as presently applied causes no apparent harm to brain structure or function, a number of uncomfortable sensations can occur beneath the electrodes during stimulation, including tingling, pain, itching, and burning sensations. Therefore, we investigated the effect of topically applied Eutectic mixture of local anesthetics (EMLA) on tDCS-related discomfort. METHODS: Nine healthy adults received both anodal and cathodal 2.0 mA tDCS for 5 minutes over the prefrontal cortex with the skin pretreated for 20 minutes with either EMLA or placebo cream. Participants rated procedural discomfort six times across eight dimensions of sensation. RESULTS: On average, the mean sensation ratings for EMLA-associated tDCS stimulation were significantly lower than placebo-associated stimulation for every cutaneous sensation evaluated. Cathodal stimulation was associated with higher ratings of "sharpness" and intolerability than anodal stimulation. CONCLUSIONS: Topical EMLA may reduce tDCS-related discomfort. PMID- 21255751 TI - Neuropsychologic effects of neuromodulation techniques for treatment-resistant depression: a review. AB - Electroconvulsive therapy (ECT) and ablative neurosurgical procedures are established interventions for treatment-resistant depression (TRD), but their use may be limited in part by neuropsychological adverse effects. Additional neuromodulation strategies are being developed that aim to match or exceed the efficacy of ECT/ablative surgery with a better neurocognitive side effect profile. In this review, we briefly discuss the neurocognitive effects of ECT and ablative neurosurgical procedures, then synthesize the available neurocognitive information for emerging neuromodulation therapies, including repetitive transcranial magnetic stimulation, magnetic seizure therapy, transcranial direct current stimulation, vagus nerve stimulation, and deep brain stimulation. The available evidence suggests these procedures may be more cognitively benign relative to ECT or ablative neurosurgical procedures, though further research is clearly needed to fully evaluate the neurocognitive effects, both positive and negative, of these novel neuromodulation interventions. PMID- 21255754 TI - Cardiovascular safety of the method of limits titration procedure for electroconvulsive therapy dosing: a retrospective study. PMID- 21255755 TI - Intensive high-frequency repetitive transcranial magnetic stimulation treatment in an electroconvulsive shock therapy-resistant bipolar I patient with mixed episode. AB - This case report describes a 52-year-old woman who received a diagnosis of bipolar I disorder of the mixed type, resistant to bilateral electroconvulsive shock therapy (ECT) and successfully treated with intensive left-sided high frequency repetitive transcranial magnetic stimulation (HF-rTMS). PMID- 21255756 TI - Fast estimation of transcranial magnetic stimulation motor threshold. AB - BACKGROUND: In Transcranial Magnetic Stimulation (TMS), the Motor Threshold (MT) is the minimum intensity required to evoke a liminal response in the target muscle. Because the MT reflects cortical excitability, the TMS intensity needs to be adjusted according to the subject's MT at the beginning of every TMS session. OBJECTIVE: Shorten the MT estimation process compared to existing methods without compromising accuracy. METHODS: We propose a Bayesian adaptive method for MT determination that incorporates prior MT knowledge and uses a stopping criterion based on estimation of MT precision. We compared the number of TMS pulses required with this new method with existing MT determination methods. RESULTS: The proposed method achieved the accuracy of existing methods with as few as seven TMS pulses on average when using a common prior and three TMS pulses on average when using subject-specific priors. CONCLUSIONS: Our adaptive Bayesian method is effective in reducing the number of pulses to estimate the MT. PMID- 21255757 TI - Fast estimation of transcranial magnetic stimulation motor threshold: is it safe? PMID- 21255758 TI - Including prior knowledge for accurate and fast motor threshold estimation. PMID- 21255760 TI - Three-year results of safety and efficacy of the everolimus-eluting coronary stent in women (from the SPIRIT III randomized clinical trial). AB - Women treated with the XIENCE V have improved 1-year clinical outcomes compared to women treated with TAXUS; whether benefits in women are sustained at 3 years is unknown. Three-year follow-up of the SPIRIT III trial revealed improved clinical outcomes of the XIENCE V everolimus-eluting stent compared to the TAXUS paclitaxel-eluting stent. One thousand two patients with coronary artery lesions <=28 mm in length in 2.5- to 3.75-mm diameter vessels were prospectively randomized to receive XIENCE V or TAXUS stents. A post hoc gender subset analysis was performed. Six hundred sixty-nine patients (30% women) received XIENCE V and 332 patients (34% women) received TAXUS. In the overall population, women had higher 3-year rates of major adverse cardiac events (16.0% vs 10.0%, p = 0.01) and target lesion revascularization (10.2% vs 5.3%, p = 0.008) compared to men. In women, those with XIENCE V continued to have lower major adverse cardiac event rates than those with TAXUS at 2 years (9.5% vs 18.3%, p = 0.03) and 3 years (12.2% vs 22.6%, p = 0.03). Although 1-year target vessel failure rates were similar, at 2- and 3-year follow-up women treated with XIENCE V had approximately 40% relative decreases in target vessel failure rates compared to those treated with TAXUS (12.7% vs 22.0%, p = 0.05; 16.0% vs 26.4%, p = 0.03, respectively). Stent thrombosis and bleeding complication rates were similar between treatment arms in the gender subgroups through 3 years. In conclusion, women in the SPIRIT III trial have sustained clinical benefits from XIENCE V implantation compared to TAXUS without increases in long-term complications. PMID- 21255761 TI - P wave duration and risk of longitudinal atrial fibrillation in persons >= 60 years old (from the Framingham Heart Study). AB - Long-term risk prediction is a priority for the prevention of atrial fibrillation (AF). P wave indices are electrocardiographic measurements describing atrial conduction. The role of P wave indices in the prospective determination of AF and mortality risk has had limited assessment. We quantified by digital caliper the P wave indices of maximum duration and dispersion in 1,550 Framingham Heart Study participants >= 60 years old (58% women) from single-channel electrocardiograms recorded from 1968 through 1971. We examined the association of selected P wave indices and long-term outcomes using Cox proportional hazards regression incorporating age, gender, body mass index, systolic blood pressure, treatment for hypertension, significant murmur, heart failure, and PR interval. Over a median follow-up of 15.8 years (range 0 to 38.7), 359 participants developed AF and 1,525 died. Multivariable-adjusted hazard ratios (HRs) per SD increase in maximum P wave duration were 1.15 (95% confidence interval [CI] 0.90 to 1.47, p = 0.27) for AF and 1.02 (95% CI 0.96 to 1.08, p = 0.18) for mortality. The upper 5% of P wave maximum duration had a multivariable-adjusted HR of 2.51 (95% CI 1.13 to 5.57, p = 0.024) for AF and an HR of 1.11 (95% CI 0.87 to 1.40, p = 0.20) for mortality. We found no significant associations between P wave dispersion with incidence of AF or mortality. In conclusion, maximum P wave duration at the upper fifth percentile was associated with long-term AF risk in an elderly community based cohort. P wave duration is an electrocardiographic endophenotype for AF. PMID- 21255763 TI - Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome. AB - An uncharacterized multisystemic mitochondrial cytopathy was diagnosed in two infants from consanguineous Palestinian kindred living in a single village. The most significant clinical findings were tubulopathy (hyperuricemia, metabolic alkalosis), pulmonary hypertension, and progressive renal failure in infancy (HUPRA syndrome). Analysis of the consanguineous pedigree suggested that the causative mutation is in the nuclear DNA. By using genome-wide SNP homozygosity analysis, we identified a homozygous identity-by-descent region on chromosome 19 and detected the pathogenic mutation c.1169A>G (p.Asp390Gly) in SARS2, encoding the mitochondrial seryl-tRNA synthetase. The same homozygous mutation was later identified in a third infant with HUPRA syndrome. The carrier rate of this mutation among inhabitants of this Palestinian isolate was found to be 1:15. The mature enzyme catalyzes the ligation of serine to two mitochondrial tRNA isoacceptors: tRNA(Ser)(AGY) and tRNA(Ser)(UCN). Analysis of amino acylation of the two target tRNAs, extracted from immortalized peripheral lymphocytes derived from two patients, revealed that the p.Asp390Gly mutation significantly impacts on the acylation of tRNA(Ser)(AGY) but probably not that of tRNA(Ser)(UCN). Marked decrease in the expression of the nonacylated transcript and the complete absence of the acylated tRNA(Ser)(AGY) suggest that this mutation leads to significant loss of function and that the uncharged transcripts undergo degradation. PMID- 21255762 TI - Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42. AB - By using homozygosity mapping in a consanguineous Pakistani family, we detected linkage of nonsyndromic hearing loss to a 7.6 Mb region on chromosome 3q13.31 q21.1 within the previously reported DFNB42 locus. Subsequent candidate gene sequencing identified a homozygous nonsense mutation (c.1135G>T [p.Glu379X]) in ILDR1 as the cause of hearing impairment. By analyzing additional consanguineous families with homozygosity at this locus, we detected ILDR1 mutations in the affected individuals of 10 more families from Pakistan and Iran. The identified ILDR1 variants include missense, nonsense, frameshift, and splice-site mutations as well as a start codon mutation in the family that originally defined the DFNB42 locus. ILDR1 encodes the evolutionarily conserved immunoglobulin-like domain containing receptor 1, a putative transmembrane receptor of unknown function. In situ hybridization detected expression of Ildr1, the murine ortholog, early in development in the vestibule and in hair cells and supporting cells of the cochlea. Expression in hair cell- and supporting cell-containing neurosensory organs is conserved in the zebrafish, in which the ildr1 ortholog is prominently expressed in the developing ear and neuromasts of the lateral line. These data identify loss-of-function mutations of ILDR1, a gene with a conserved expression pattern pointing to a conserved function in hearing in vertebrates, as underlying nonsyndromic prelingual sensorineural hearing impairment. PMID- 21255764 TI - The sparkle of the eye: the impact of ocular surface wetness on corneal light reflection. AB - PURPOSE: To measure the sparkle of the human eye evaluated by the intensity of corneal light reflection in normal subjects and dry eye patients to investigate whether ocular surface wetness has an impact on the sparkle of the eye. DESIGN: Prospective case-control study. METHODS: We examined a consecutive series of eight dry eye patients with Sjogren syndrome (SS, 15 eyes), as well as eight normal subjects (16 eyes). The specular corneal surface light reflection was quantitatively measured with an ophthalmic slit-lamp microscope and image capturing system under fixed conditions of light source, incident angle, and detector sensitivity. The intensity of images from subjects' corneal light reflection was quantified with image analysis software along with the measurement of grade of self-reported brilliancy of the eye, corneal fluorescein staining score, tear film break-up time, and Schirmer test value. The intensity of corneal light reflection was also compared before and after dry eye treatment. RESULTS: The mean intensity of corneal light reflection was significantly lower in dry eye patients (125.0 +/- 40.1) than normal subjects (167.6 +/- 36.6, P=.004). Grade of self-reported brilliancy of the eye, corneal fluorescein staining scores, tear film break-up time, and Schirmer test values showed good correlation to the intensity of corneal light reflection. After punctal plug treatment, the intensity of corneal light reflection significantly increased from 125.0 +/- 40.1 to 167.2 +/- 45.0 (P<.0001). CONCLUSIONS: The intensity of corneal light reflection representing the sparkle of the eye was significantly more intense in normal subjects compared to dry eye patients, and was increased after punctal plug treatment. The intensity of corneal light reflection appeared to correlate well with tear film stability, volume, and ocular surface desiccation. We showed that tears contributed not only to ocular surface wetness but also to the extent of the light reflection from the eye. PMID- 21255765 TI - Immunohistochemical expression of matrix metalloproteinases in squamous cell carcinoma of the tongue and lower lip. AB - OBJECTIVE: To evaluate the immunohistochemical expression of MMP-1, -2, -7, -9 and -26 in oral squamous cell carcinomas (SCCs) according to tumour site and histological grade of malignancy. STUDY DESIGN: Fifteen cases of SCC of the lower lip and 15 cases of tongue SCC were selected and divided into low grade malignancy (n = 17) and high grade malignancy (n = 13). RESULTS: Higher immunohistochemical expression of MMPs by neoplastic cells was observed in tongue SCCs, with a statistically significant difference for MMP-9 (P < 0.05). High grade SCCs showed a higher expression of MMPs, except for MMP-2, with a statistically significant difference for MMP-7 (P < 0.05) and MMP-26 (P < 0.05). In addition, a direct association was observed between morphological scores of malignancy and MMP immunoreactivity, with the association being significant for MMP-7 and MMP-26. CONCLUSION: The present results demonstrate the important role of MMPs in the development of SCCs of the lower lip and tongue. PMID- 21255766 TI - Depression after spinal cord injury: comorbidities, mental health service use, and adequacy of treatment. AB - OBJECTIVE: To provide data for depression rates and psychiatric comorbid conditions, mental health service use, and adequacy of depression treatment in depressed and nondepressed adults with spinal cord injury (SCI). DESIGN: Cross sectional survey as part of the Project to Improve Symptoms and Mood after SCI (PRISMS). SETTING: Community setting. PARTICIPANTS: Community-residing people with traumatic SCI (N=947). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patient Health Questionnaire-9 (PHQ-9) Depression Scale, psychiatric history questionnaire, Cornell Service Index (mental health service use), and current medication use. RESULTS: The prevalence of probable major depression (PHQ-9 score >=10) was 23%. There was a high lifetime prevalence of other psychiatric conditions, particularly anxiety disorders. In depressed participants, 29% currently were receiving any antidepressant and 11% were receiving guideline level antidepressant dose and duration, whereas 11% had been receiving any psychotherapy in the past 3 months and 6% had been receiving guideline-level psychotherapy in the past 3 months. Serotonergic antidepressants and individual psychotherapy were the most common types of treatment received, and there was a wide range of provider types and treatment settings. Demographic and clinical variables were not associated with receipt of mental health service or guideline level care. CONCLUSIONS: Findings from this study document the low rate of mental health treatment for persons with SCI and probable major depression. These findings have implications for improving the effectiveness of depression treatment in people with SCI. PMID- 21255767 TI - Internet-based treatment of social phobia: a randomized controlled trial comparing unguided with two types of guided self-help. AB - Internet-based self-help for social phobia with minimal therapist support via email have shown efficacy in several controlled trials by independent research teams. The role and necessity of therapist guidance is, however, still largely unclear. The present study compared the benefits of a 10-week web-based unguided self-help treatment for social phobia with the same intervention complemented with minimal, although weekly, therapist support via email. Further, a third treatment arm was included, in which the level of support was flexibly stepped up, from no support to email or telephone contact, on demand of the participants. Eighty-one individuals meeting diagnostic criteria for social phobia were randomly assigned to one of the three conditions. Primary outcome measures were self-report measures of symptoms of social phobia. Secondary outcome measures included symptoms of depression, interpersonal problems, and general symptomatology. Measures were taken at baseline, post-treatment, and at 6-month follow-up. Data from a telephone-administered diagnostic interview conducted at post-treatment were also included. Results showed significant symptom reductions in all three treatment groups with large effect sizes for primary social phobia measures (Cohen's d=1.47) and for secondary outcome measures (d=1.16). No substantial and significant between-groups effects were found on any of the measures (Cohen's d=00-.36). Moreover, no difference between the three conditions was found regarding diagnosis-free status, clinically significant change, dropout rates, or adherence measures such as lessons or exercises completed. These findings indicate that Internet-delivered treatment for social phobia is a promising treatment option, whether no support is provided or with two different types of therapist guidance. PMID- 21255768 TI - [Laparoscopic treatment of achalasia: analysis of results and reflections on the technique]. AB - INTRODUCTION: Heller myotomy using the laparoscopic approach is the best treatment that we can offer to patients with achalasia. On not acting on the cause of the disease, we can only alleviate the persistence of the symptoms, but not make them disappear. OBJECTIVE: To analyse the results of our group in the treatment of achalasia by laparoscopy. MATERIAL AND METHODS: The pre- and post operative results are analysed of a series of 20 patients intervened prospectively by laparoscopy of achalasia during a period from May 2003 to April 2010. For this we used a modification of the grading scale of pre- and post operative symptoms described by Velanovich for GER (a scale from 0-5). Data on the complications and the hospital stay were also collected. RESULTS: A wide Heller myotomy was performed using a Dor type antireflux mechanism. There were no oesophageal perforations or complications during the surgery. Two (10%) patients had postoperative complications. The mean hospital stay was 3.11 +/- 2.13 days. After a mean follow up of 55.8 +/- 14.1 months, the symptoms studied had significantly decreased after the surgery. Only 3 (15%) patients had clinical symptoms of GER after surgery. Nineteen patients (95%) said they were satisfied with the operation. CONCLUSIONS: The laparoscopic treatment of achalasia is a safe technique, reproducible and effective technique, which achieves very satisfactory control of the achalasia symptoms with a minimum of morbidity. PMID- 21255769 TI - [Accreditation and dedication in coloproctology is associated with good perioperative care]. AB - Complex data analysis methods require optimisation techniques such as evolutionary algorithms in order to generate reliable results. The objective of this study is to analyse the relationships of particular perioperative care in colorectal surgery (CRS) with surgeon epidemiological data, performing partition grouping to look for significant relationships. METHODS: Data were used from a survey of members of Spanish coloproctology associations on perioperative care in colorectal surgery, and analysing the responses associated with mechanical bowel preparation (MBP), nasogastric intubation (NGI), drainages (D), and early feeding (EF), over the existing scientific evidence (SE) which shows that the first ones are unnecessary and the importance of the last one. We applied a variant of particle swarm optimization (PSO), to group data conglomerates, optimising variables with statistical grouping criteria. RESULTS: A total of 130 surveys were analysed, finding 2 clear groups which included 21.5% and 78.5% of the sample, respectively. Sixty eight per cent of the surgeons in Group A belonged to the European Board in Coloproctology, compared to none in Group B, and the former performed 80% of the coloproctology activity, compared to 60% of the rest. A responded homogeneously to questions on MBP, NGI, D and EF, those of group A following the SE, while the others did it randomly and without following it. Age, work position or academic range were not significant in the grouping. CONCLUSIONS: The evolutionary algorithm was shown to be able to identify groups according to the use of perioperative care in CRS. Accreditation and dedication was associated with behaviour based on the SE. PMID- 21255770 TI - [Trocar site incisional hernia in laparoscopic surgery]. AB - Trocar site incisional hernias (TSIH) are the most common complications in laparoscopic surgery. We have carried out a review of the literature with the aim of establishing their incidence, the reasons for them happening, and their prevention. After a search in the MEDLINE PubMed and PubMed CENTRAL data bases from 1991 to 2009, combining the words: "hernia", "laparoscopy" and "trocar", we obtained 545 articles, of which we analysed 60 of them. The incidence of TSIH varies between 0.18% and 2.8%. The diameter of the trocar, obesity and age play a fundamental role when proceeding to close the fascia, a closure which is the most important factor to prevent these incisional hernias appearing. The appearance of new laparoscopic material and the increasing more common closure of defects of the fascia means that new and more extensive prospective studies should be performed. PMID- 21255771 TI - [Transanal endoscopic surgery with conventional laparoscopy materials: is it feasible?]. AB - INTRODUCTION: Transanal endoscopic surgery with conventional laparotomy materials may be an alternative to transanal endoscopic microsurgery (TEM) for the excision of rectal lesions susceptible to local resection. MATERIAL AND METHOD: We prospectively analysed 27 patients included consecutively between 1999 and 2009, on whom a Transanal endoscopic operation (TEO) was performed by total resection of the rectal wall. All procedures were performed with a 40mm rectoscope, initially designed by us and later with the Storz rectoscope, using conventional laparoscopic tools and material. RESULTS: We operated on 27 patients with a mean age of 69.4 years: 23 due to benign lesions and 4 malignant. The medium distance of the tumour to the anal margins was 8.2cm (range 5-15) and a mean tumour diameter of 3.38 +/- 1.2cm. There were 4 postoperative complications, 3 due to bleeding and one case of perforation. The mean hospital stay was 6 +/- 3.75 days. There was no perioperative mortality or recurrences.. CONCLUSION: Performing transanal endoscopic surgery with conventional laparoscopy material is feasible, with a reduction in costs and accessible to laparoscopy surgeons. PMID- 21255772 TI - [Choleperitoneum secondary to acute acalculous cholecystitis with Coxsackie virus infection involvement]. PMID- 21255773 TI - Divergent effects of different positive emotions on moral judgment. AB - Positive emotions are often treated as relatively similar in their cognitive behavioral effects, and as having unambiguously beneficial consequences. For example, Valdesolo and DeSteno (2006) reported that a humorous video made people more prone to choose a utilitarian solution to a moral dilemma. They attributed this finding to increased positive affect. To determine whether such results actually stem in general from positive affect or from other more specific properties of humor, we conducted an experiment with moral dilemmas presented during an interleaved emotion-induction procedure involving mirth and another positive emotion, elevation. Mirth increased permissiveness for deontological violations, whereas elevation had the opposite effect. Furthermore, affective valence had no apparent independent influence on these judgments. Our results suggest that mirth and elevation have distinct cognitive consequences whose properties reflect their respective social functions, not their shared positive valence. PMID- 21255774 TI - Localisation through operation for brain tumour: a reply to Karnath and Steinbach. PMID- 21255775 TI - A comprehensive gene mutation screen in men with asthenozoospermia. AB - OBJECTIVE: To find novel genetic causes of asthenozoospermia by comprehensively screening known candidate genes derived from mouse models. DESIGN: Case-control study. SETTING: A fertility center based in an academic hospital. PATIENT(S): Thirty men with isolated asthenozoospermia. INTERVENTION(S): Screening nine candidate genes for mutations: ADCY10, AKAP4, CATSPER1, CATSPER2, CATSPER3, CATSPER4, GAPDHS, PLA2G6, and SLC9A10. To account for a possible effect of heterozygous mutations, assessing imprinting of all candidate genes by studying the expression pattern of heterozygous SNPs in testis biopsies of five unrelated men. MAIN OUTCOME MEASURE(S): Mutations found in patients only. RESULT(S): We identified 10 heterozygous asthenozoospermia-specific mutations in ADYC10 (n = 2), AKAP4 (n =1), CATSPER1 (n = 1), CATSPER2 (n = 1), CATSPER3 (n = 1), CATSPER4 (n = 3), and PLA2G6 (n = 1). These mutations were distributed over six patients. In silico analysis showed that 8 of the 10 mutations either had a negative BLOSUM score, were located in conserved residues, and/or were located in a functional domain. Expression analysis demonstrated that CATSPER1 and CATSPER4 are imprinted. CONCLUSION(S): Given their putative effect on protein structure, their location in conserved sequences or functional domains, and their absence in controls, the identified mutations may be a cause of asthenozoospermia in humans. PMID- 21255776 TI - Urinary peptide profiling identifies a panel of putative biomarkers for diagnosing and staging endometriosis. AB - OBJECTIVE: To identify a potential diagnostic endometriosis marker using matrix enhanced laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS)-based urinary proteomics. DESIGN: Prospective randomized pilot study. SETTING: University hospital, tertiary referral center for endometriosis. PATIENT(S): 53 women undergoing laparoscopic surgery for pain and/or infertility comprising 30 women without endometriosis and 23 with endometriosis. INTERVENTION(S): Laparoscopy and urine specimens. MAIN OUTCOME MEASURE(S): Urinary peptide profiles. RESULT(S): We observed distinct patterns of peptide profiles in the urine samples of women presenting with typical clinical symptoms of endometriosis. Six statistically significant putative peptide markers were identified (four during the periovulatory phase and two during the luteal phase) by comparing controls with moderate/severe endometriosis patients. The periovulatory peptide mass of 1,767.1 Da and the luteal peptide mass of 1,824.3 Da both showed a sensitivity of 75% and a specificity of 85% and 71%, respectively. Also detected were seven peptide markers (two during the periovulatory phase and five during the luteal phase) by comparing the urinary peptide profiles of patients with minimal/mild to moderate/severe endometriosis. The periovulatory peptide mass of 3,280.9 Da and the luteal peptide mass of 1,933.8 Da showed a sensitivity of 82% and 75% and a specificity of 88% and 75%, respectively. CONCLUSION(S): Urinary proteomic analysis may provide a novel method of diagnosing and staging endometriosis. PMID- 21255777 TI - Partially migrated gastric ring after transected banded vertical gastric bypass. PMID- 21255778 TI - Clinical evaluation of the Trauma Outcome Profile (TOP) in the longer-term follow up of polytrauma patients. AB - BACKGROUND: No sufficiently validated disease-specific instrument is available to assess patient outcome after polytrauma. The aim of this investigation was to test the recently published Trauma Outcome Profile (TOP) in the longer-term outcome of multiply injured patients. METHODS: Single centre validation study on the TOP in comparison with objective and subjective measures of patient, injury or treatment characteristics and longer-term outcome (e.g. medical outcomes study Short Form-36, SF-36; Nottingham Health Profile, NHP; working capacity), at least 2 years following trauma in 117 survivors of polytrauma (injury severity score, ISS>16), using comparative analysis and correlation testing of prospectively collected data. RESULTS: Patients' mean weighted self-rating with regard to the 10 single TOP dimensions of Health Related Quality of Life (HRQoL, 0-100) ranged from lowest values for mental functioning (52.6+33.5) to highest values for daily activities (79.0+27.5). The rate of persons who indicated an abnormal level of function or pain increased significantly from pre-injury status (2% and 5%, resp.) to 46% for both values at longer-term follow-up (p<0.001). Observed associations between single dimensions or TOP component summary scores with the corresponding values from general HRQol instruments, such as the SF-36, resulted in R (Pearson) up to 0.85. Survivors of polytrauma who presented with a reduced working capacity (RWC) at longer-term follow-up in all TOP dimensions included a significantly higher rate of patients conspicuous for a relevantly reduced outcome compared with those with a non reduced working capacity (NRWC) (posttraumatic stress disease, PTSD: p<0.05; all other dimensions: p<0.001). Patients with a RWC were characterised by an almost fivefold probability of reduced outcome with regard to the TOP dimensions 'social interaction' or 'satisfaction' (odds ratio, OR 12.4 (95% CI 5.1-30.1) and 12.5 (4.0-39.0), resp.). CONCLUSIONS: This first clinical and methodological evaluation in a well defined cohort of polytrauma patients found the TOP to be a reliable and well discriminating score covering both relevant general and trauma-specific aspects of longer-term outcome. Despite these promising primary results, until further validation, the TOP should be used together with already accepted HRQoL measures to allow adequate international comparison of data in the future. PMID- 21255779 TI - Posttraumatic stress disorder, depression, and hopelessness in women who are victims of sexual violence. AB - OBJECTIVE: To evaluate posttraumatic stress disorder (PTSD), depression, and hopelessness in women 1 and 6 months after they experienced sexual violence. METHODS: This prospective study, in which the clinician-administered PTSD scale, the Beck depression inventory, and the Beck hopelessness scale were used, included 67 women at 1 month and 52 women at 6 months after they experienced sexual violence. RESULTS: Overall, 77.6% of the women were <= 24years of age, and 52% were adolescents; 15% had a history of drug abuse, and 13.5% had a history of previous sexual violence. The aggressor was unknown in 76% of cases, and there was more than 1 aggressor in 9% of cases. In the first month, 43% of the women had moderate or very severe PTSD; 52.2% had moderate or severe depression; and 22.4% had moderate or severe hopelessness, which decreased to 21%, 20% and 10%, respectively, at 6 months. In the first month, severity of PTSD was associated with moderate or severe depression, and at 6 months severity of PTSD was associated with multiple aggressors and previous psychiatric disorders. All scores decreased in the sixth month. CONCLUSION: Severe mental health disorders were still present 6 months after women had experienced sexual violence. PMID- 21255780 TI - Pioglitazone improves endothelial and adipose tissue dysfunction in pre-diabetic CAD subjects. AB - OBJECTIVE: To investigate the effect of pioglitazone on endothelial and adipose tissue dysfunction in newly detected IGT patients with CAD. METHODS AND DESIGN: Participants (n=25) were randomized to treatment with either placebo or pioglitazone (30 mg/day) for 12 weeks. Before and after treatment we evaluated endothelial function (flow-mediated dilation--FMD--of the brachial artery), circulating adipose and inflammatory markers (adiponectin isoforms, TNF-alpha, and high sensitivity-CRP), and insulin sensitivity (euglycemic hyperinsulinemic clamp). RESULTS: No significant changes were observed in subjects (n=12) treated with placebo. By contrast, subjects (n=13) treated with pioglitazone had significant improvement in FMD (10.8+/-5.3 vs 13.3+/-3.6%, p<0.01), accompanied by increased high molecular weight adiponectin (HMW-Ad) (1.7+/-1.2 vs 4.8+/-3.6 MUg/ml, p<0.05) and decreased TNF-alpha (4.3+/-1.9 vs 3.2+/-1.2 pg/ml, p<0.05) associated to an increased glucose disposal (4.8+/-1.9 vs 5.4+/-2.0 mg kg(-1) min(-1), p<0.05). A multiple regression analysis indicated that increasing of HMW Ad after pioglitazone predicted increased FMD. CONCLUSION: Pioglitazone significantly improves endothelial and adipose tissue dysfunction in pre-diabetic patients with CAD. PMID- 21255781 TI - Impurity profiling of pharmaceuticals by thin-layer chromatography. AB - Although there is a tendency in current pharmacopoeias for favouring HPLC, thin layer chromatography (TLC) is still a very popular and frequently used analytical method in the pharmaceutical industry. This paper highlights the possibilities of this method in the different areas of pharmaceutical analysis like in-process and intermediate control, illustrated by impurity testing of active ingredients and final products, as well as its application in pharmaceutical research and development, based on some examples reported mainly in the last five years. PMID- 21255782 TI - OFFGEL isoelectric focusing and polyacrylamide gel electrophoresis separation of platinum-binding proteins. AB - In this work a 2D electrophoretic separation procedure able to maintain the integrity of platinum-protein bonds has been developed. The method is based on the use of sequential OFFGEL isoelectric focussing (IEF) and PAGE. A systematic study of the reagents used for PAGE, for OFFGEL-IEF separation, and post separation treatment of gels (such as enzymatic digestion and sample preparation for MS analysis) was tackled regarding their suitability for the identification of platinum binding proteins using standard proteins incubated with cisplatin. The distribution of platinum in high and low molecular weight fractions (separated by cut-off filters) was determined by ICP-MS, which allows evaluating platinum-protein bond stability under the conditions studied. SDS-PAGE in the absence of beta-mercaptoethanol or dithiotreitol preserved the platinum-protein bonds. In addition, neither the influence of the electric field during the electrophoretic separation, nor the processes of fixing, staining and destaining of proteins in the gel did result in the loss of platinum from platinum binding proteins. SDS-PAGE under non-reducing conditions provides separation of platinum binding proteins in very narrow bands with quantitative recoveries. Different amounts of platinum-bound proteins covering the range 0.3-2.0 MUg were separated and mineralised for platinum determination, showing good platinum linearity. Limits of detection for a mixture of five standard proteins incubated with cisplatin were between the range of 2.4 and 13.9 pg of platinum, which were satisfactory for their application to biological samples. Regarding OFFGEL-IEF, a denaturing solution without thiourea and without dithiotreitol is recommended. The suitability of the OFFGEL-IEF for the separation of platinum binding proteins of a kidney cytosol was demonstrated. PMID- 21255783 TI - Comparison of different sample treatments for the analysis of quinolones in milk by capillary-liquid chromatography with laser induced fluorescence detection. AB - A simple and very sensitive capillary-liquid chromatography method coupled with laser induced fluorescence detection has been developed for the simultaneous determination of seven quinolones of veterinary use in milk. Moreover, a comparison between two different sample treatments (QuEChERS and molecularly imprinted polymer, MIP) has been carried out in terms of efficiency of the extraction (number of analytes to be analysed and absence of interferences), throughput, linear dynamic range in matrix-matches calibrations, detection and quantification limits and accuracy (trueness and precision, by means of recovery assays). The results showed that the QuEChERS procedure was more efficient and faster, showing good recoveries, sensitivity and precision for all the studied compounds. Employing this proposed method, very low detection limits, between 0.4 MUg/kg for danofloxacin, and 6 MUg/kg for sarafloxacin, have been obtained. PMID- 21255784 TI - Simultaneous effect of pH, temperature and mobile phase composition in the chromatographic retention of ionizable compounds. AB - The retention of 22 monoprotic acid-base solutes in 12 buffers (pH from 2 to 12) at 3 temperatures (25, 40 and 55 degrees C) and in 3 mobile phase compositions (20, 40 and 60% acetonitrile) was measured. The retention data for each solute, temperature and mobile phase compositions was fitted to pH by means of the common sigmoidal equation and the retention and acid-base parameters were obtained (logk(HA), logk(A) and pK(a)). The dependence of these parameters on temperature (van't Hoff plots), mobile phase composition (phi, volume fraction of acetonitrile) and mobile phase polarity (P(m)(N) parameter) was investigated. Linear plots of the parameter values against the reverse of the absolute temperature, on one hand, and phi or P(m)(N), in the other hand, were generally obtained. From this analysis we propose 6-parameter equations to relate retention to pH and T at constant mobile phase composition, and to pH and phi or P(m)(N) at constant temperature. A general 12 parameter equation is also proposed to relate retention simultaneously to pH, T and phi or P(m)(N). The general constancy of some terms of the equations allow to simplify the 12 parameter equation to a 8 parameter equation able to predict retention of the studied solutes. The accuracy of the proposed method provided excellent results with the advantage of modeling the effects of various optimization variables (modifier concentration, mobile phase pH and temperature) using a single equation, based on only eight fitting parameters. PMID- 21255785 TI - Characterization and modeling of nonlinear hydrophobic interaction chromatographic systems. AB - A general rate model was employed in concert with a preferential interaction quadratic adsorption isotherm for the characterization of HIC resins and the prediction of solute behavior in these separation systems. The results indicate that both pore and surface diffusion play an important role in protein transport in HIC resins. The simulated and experimental solute profiles were compared for two model proteins, lysozyme and lectin, for both displacement and gradient modes of chromatography. Our results indicate that a modeling approach using the generate rate model and preferential interaction isotherm can accurately predict the shock layer response in both gradient and displacement chromatography in HIC systems. While pore and surface diffusion played a major role and were limiting steps for proteins, surface diffusion was seen to play less of a role for the displacer. The results demonstrate that this modeling approach can be employed to describe the behavior of these non-linear HIC systems, which may have implications for the development of more efficient preparative HIC separations. PMID- 21255786 TI - Trace analysis of 28 steroids in surface water, wastewater and sludge samples by rapid resolution liquid chromatography-electrospray ionization tandem mass spectrometry. AB - A sensitive rapid resolution liquid chromatography-tandem mass spectrometry (RRLC MS/MS) method, combined with solid-phase extraction, ultrasonic extraction and silica gel cartridge cleanup, was developed for 28 steroids including 4 estrogens (estrone (E1), 17beta-estradiol (E2), 17alpha-ethynyl estradiol (EE2), diethylstilbestrol (DES)), 14 androgens (androsta-1,4-diene-3,17-dione (ADD), 17alpha-trenbolone, 17beta-trenbolone, 4-androstene-3,17-dione, 19 nortestoserone, 17beta-boldenone, 17alpha-boldenone, testosterone (T), epi androsterone (EADR), methyltestosterone (MT), 4-hydroxy-androst-4-ene-17-dione (4 OHA), 5alpha-dihydrotestosterone (5alpha-DHT), androsterone (ADR), stanozolol (S)), 5 progestagens (progesterone (P), ethynyl testosterone (ET), 19 norethindrone, norgestrel, medroxyprogesterone (MP)), and 5 glucocorticoids (cortisol, cortisone, prednisone, prednisolone, dexamethasone) in surface water, wastewater and sludge samples. The recoveries of surface water, influents, effluents and sludge samples were 90.6-119.0% (except 5alpha-DHT was 143%), 44.0 200%, 60.7-123% and 62.6-138%, respectively. The method detection limits for the 28 analytes in surface water, influents, effluents and freeze-dried sludge samples were 0.01-0.24 ng/L, 0.02-1.44 ng/L, 0.01-0.49 ng/L and 0.08-2.06 ng/g, respectively. This method was applied in the determination of the residual steroidal hormones in two surface water of Danshui River, 12 wastewater and 8 sludge samples from two wastewater treatment plants (Meihu and Huiyang WWTPs) in Guangdong (China). Ten analytes were detected in surface water samples with concentrations ranging between 0.4 ng/L (17beta-boldenone) and 55.3 ng/L (5alpha DHT); twenty analytes in the wastewater samples with concentrations ranging between 0.3 ng/L (P) and 621 ng/L (5alpha-DHT); and 12 analytes in the sludge samples with concentrations ranging between 1.6 ng/g (E1) and 372 ng/g (EADR). PMID- 21255787 TI - Achieving high peak capacity production for gas chromatography and comprehensive two-dimensional gas chromatography by minimizing off-column peak broadening. AB - By taking into consideration band broadening theory and using those results to select experimental conditions, and also by reducing the injection pulse width, peak capacity production (i.e., peak capacity per separation time) is substantially improved for one dimensional (1D-GC) and comprehensive two dimensional (GC*GC) gas chromatography. A theoretical framework for determining the optimal linear gas velocity (the linear gas velocity producing the minimum H), from experimental parameters provides an in-depth understanding of the potential for GC separations in the absence of extra-column band broadening. The extra-column band broadening is referred to herein as off-column band broadening since it is additional band broadening not due to the on-column separation processes. The theory provides the basis to experimentally evaluate and improve temperature programmed 1D-GC separations, but in order to do so with a commercial 1D-GC instrument platform, off-column band broadening from injection and detection needed to be significantly reduced. Specifically for injection, a resistively heated transfer line is coupled to a high-speed diaphragm valve to provide a suitable injection pulse width (referred to herein as modified injection). Additionally, flame ionization detection (FID) was modified to provide a data collection rate of 5kHz. The use of long, relatively narrow open tubular capillary columns and a 40 degrees C/min programming rate were explored for 1D-GC, specifically a 40m, 180MUm i.d. capillary column operated at or above the optimal average linear gas velocity. Injection using standard auto-injection with a 1:400 split resulted in an average peak width of ~1.5s, hence a peak capacity production of 40peaks/min. In contrast, use of modified injection produced ~500ms peak widths for 1D-GC, i.e., a peak capacity production of 120peaks/min (a 3-fold improvement over standard auto-injection). Implementation of modified injection resulted in retention time, peak width, peak height, and peak area average RSD%'s of 0.006, 0.8, 3.4, and 4.0%, respectively. Modified injection onto the first column of a GC*GC coupled with another high-speed valve injection onto the second column produced an instrument with high peak capacity production (500-800peaks/min), ~5-fold to 8-fold higher than typically reported for GC*GC. PMID- 21255788 TI - Improving precision of manual hydrodynamic injection in capillary electrophoresis with contactless conductivity detection. AB - Reproducible injection in capillary electrophoresis has been difficult to achieve with manual injection techniques using simple injection devices, such as gravity injection (siphoning) or hydrodynamic sample splitting. We demonstrate that the injection reproducibility can be improved using very simple means. With hydrodynamic sample splitter, a passive micro-metering valve can be inserted in line to regulate the sample flow rate through the splitter interface. A significant improvement of both reproducibility and repeatability was achieved. The reproducibility of RSD of the peak areas improved from 25.4% to 4.4%, while the repeatability was below 4.1% when micro-metering valve was used. Additional simple correction that can be used to further improve the variability of injected sample volumes in any hydrodynamic injection mode in CE with conductivity detection was proposed and verified. The measured EOF peak can serve as a simple indicator of the injected volume and can be effectively used for additional correction. By a linear function between the injection volume and the peak area of the EOF, the RSD values of peak areas for both manual gravity injection and hydrodynamic sample splitter were further improved below 2% RSD. The linearity of the calibration curve was also significantly improved. The proposed correction works even with slight differences in matrix composition, as demonstrated on the analysis aqueous soil extract of model mixture of five nerve agent degradation products. PMID- 21255789 TI - Influence of chemical treatments on adhesion properties of hemp fibres. AB - In addition to be an environmentally friendly material, hemp fibres are also inexpensive reinforcements in thermoplastics or concrete composites, due to their intrinsic mechanical, thermal and acoustic properties. The morphology of hemp fibres has been chemically modified in order to enhance the matrix/fibre interface and has been examined by Scanning Electron Microscopy (SEM). In this paper, Gas Chromatography (GC) and Atomic Force Microscopy (AFM) were used to investigate the influence of treatments on the composition of hemp fibres and also on the micro-adhesive interactions between a silica colloidal probe and the surface of the fibres using Chemical Force Microscopy (CFM). Microscopy studies and chemical analysis showed that each treatment tends to lead to a morphology of interconnected web-like structure of hemp fibres. It was found that on an average, the adhesion force, contribution of capillary force and Van der Waals' forces, is higher in the case of NaOH treatment. PMID- 21255790 TI - Investigation of the sorption properties of beta-cyclodextrin-based polyurethanes with phenolic dyes and naphthenates. AB - The sorption of p-nitrophenol (PNP), phenolphthalein (phth) and naphthenates (NAs) with beta-cyclodextrin (beta-CD) based polyurethane sorbents from aqueous solutions are reported. The copolymer sorbents were synthesized at various beta CD/diisocyanate monomer mole ratios (e.g., 1:1, 1:2, and 1:3) with diisocyanates of variable molecular size and hydrogen deficiency. The copolymer sorbents were characterized in the solid state using (13)C CP-MAS NMR spectroscopy, IR spectroscopy and elemental (C,H,N) analysis. The equilibrium sorption properties of the copolymer sorbents in aqueous solution were characterized using isotherm models at pH 4.6 and 9.0 for PNP, pH 9.0 for naphthenates and pH 10.5 for phth. UV-Vis spectroscopy was used to monitor the unbound fraction of the phenolic dyes in the aqueous phase, whereas, electrospray ionization mass spectrometry was used to monitor the unbound fraction of naphthenates. The sorption results of the copolymer sorbents were compared with a commercially available carbonaceous standard; granular activated carbon (GAC). The sorption properties and capacities of the copolymer sorbents (Q(m)) were estimated using the Sips isotherm. The sorption capacity for GAC was 2.15 mmol PNP/g, 0.0698 mmol phth/g, and 142 mg NAs/g, respectively, whereas the polymeric materials ranged from 0.471 to 1.60 mmol/g (PNP), 0.114 to 0.937 mmol/g (phth), and 0 to 75.5 mg/g (naphthenates), respectively, for the experimental conditions investigated. The observed differences in the sorption properties were attributed to the accessible surface areas and pore structure characteristics of the copolymer sorbents. The binding constant, K(eq), for copolymer materials for each sorbate is of similar magnitude to the binding affinity observed for native beta-CD. PNP showed significant binding onto the copolymer framework containing diisocyanate domains, whereas, negligible sorption to the sites was observed for phth and naphthenates. The beta CD inclusion sites in the copolymer framework are concluded to be the main sorption site for phth and naphthenates through the formation of well-defined inclusion complexes. PMID- 21255791 TI - Surface functionalization of SBA-15 and a nonordered mesoporous silica with a 1,4 diazabicyclo[2.2.2]octane derivative: study of CuCl2 adsorption from ethanol solution. AB - This work describes the preparation and characterization of postfunctionalized ordered (SBA-15) and nonordered (SMD) mesoporous silicas with n-propyl-1,4 diazoniabicycle[2.2.2]octane chloride (DbCl) moiety. The main interest is based on the fact that these materials are excellent adsorbents due to the ability of functional groups to retain copper chlorides on their surfaces as anionic complexes CuCl(2+n)(n-). The specific surface areas (S(BET)) and average pore diameters (d(pore)) for SBA-15 and SMD are SBA-15, S(BET)=944 m(2) g(-1), d(pore)=9.0 nm; SMD, S(BET)=710 m(2) g(-1), d(pore)=11 nm. On functionalization with DbCl, reductions in the specific surface areas of the resulting materials (SBA-15/DbCl and SMD/DbCl) are observed and the following functionalization degrees (phi) were determined: SBA-15/DbCl, S(BET)=247 m(2) g(-1), phi=0.95 mmol g(-1); SMD/DbCl, S(BET)=83 m(2) g(-1), phi=1.2 mmol g(-1). The adsorption equilibria of CuCl(2) in ethanol were characterized, and the heterogeneous stability constants, beta(1) and beta(2), corresponding to formation of CuCl(4)(2 ) and CuCl(3)(-) anionic species adsorbed on the surface were found. Also, the effective sorption capacities (t(Q)) were determined: SBA-15/DbCl, log beta(1)=4.46, log beta(2)=7.10, t(Q)=0.80 mmol g(-1); SMD/DbCl, log beta(1)=4.95, log beta(2)=7.52, t(Q)=0.75 mmol g(-1). Regeneration of the adsorbents requires a very simple procedure consisting of their immersion in aqueous solution followed by immediate release to the solution phase of the Cu(OH(2))(n)(2+) species, followed by chloride anions as the counterions. PMID- 21255792 TI - Role of AMP-activated protein kinase and adiponectin during development of hepatic steatosis in high-fat diet-induced obesity in rats. AB - Obesity, an abnormal condition of adipose tissue, has recently been recognized as a major cause of metabolic syndromes, especially non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to examine the possible involvement of adipokines in the development of fatty liver. Sprague-Dawley (SD) rats fed a high-fat (HF) diet for 15 weeks developed increased hepatocellular vacuolation, hepatic triglyceride (TG) content and serum TG, total cholesterol and free fatty acid levels, with increases in adipose tissue mass. The serum concentration of adiponectin decreased slightly in these animals. Western blotting analysis demonstrated a decrease in the levels of AMP-activated protein kinase (AMPK) and phosphorylated-AMPK in the livers of these rats. These results indicate similarities between the diet-induced obesity rat model of NAFLD and human NAFLD, thus making the rat a useful model for the further study of NAFLD, including the interactions between adipokines and hepatic fat metabolism. PMID- 21255793 TI - A nondimensional formulation of the passive bidomain equation. AB - Simulation studies of ST depression arising from subendocardial ischemia show a marked difference in the resulting epicardial potential distributions depending on which of the 3 common experimentally determined bidomain conductivity data sets is chosen. Here, the governing equation is rendered nondimensional by dividing by the difference in normal and ischemic transmembrane potentials during the ST segment and by the sum of the intracellular and extracellular conductivities in the transverse direction, yielding the ratio of the sum of the intracellular and extracellular longitudinal conductivities divided by the sum of the intracellular and extracellular transverse conductivities as a dimensionless group. Averaging this ratio over the 3 sets of experimentally determined data gives the value of 3.21 +/- 0.08. The effect of this narrow range means that the left-hand side of the governing equation can be considered, as a good approximation, to be the same for all these sets of conductivity data. Hence, the right hand of the nondimensional differential equation contains all the necessary information to compare the effect different conductivity data sets have on the epicardial potential distribution. As an example, an explanation is given as to why values from one data set give rise to epicardial distributions that are markedly different from those obtained from the other 2 data sets. PMID- 21255794 TI - Phenome-transcriptome correlation unravels anxiety and depression related pathways. AB - The identification of pathways pertinent to human diseases is critical for gaining a better understanding of their pathophysiology. Pathway knowledge in turn can provide disease marker information required for diagnosis, drug development and improved patient treatment. Psychiatric disorders including anxiety and depression are complex diseases and are caused by a combination of multiple genetic and environmental factors affecting certain brain circuits. Here we used a systems biology approach to identify molecular pathways that affect anxiety- and depression-like phenotypes. For this purpose we screened pathways for stable enrichment in a great number of publicly available transcriptome data from the Gene Expression Omnibus related to anxiety- and depression-like phenotypes. In case of anxiety our analysis implicate a dysregulation of carbohydrate metabolism, tight junction and the phosphatidylinositol signaling system, whereas for depression gap junction, gonadotropin-releasing hormone signaling and ubiquitin-mediated proteolysis pathways are affected. Furthermore, both anxiety and depression show a dysregulation of VEGF signaling, long term potentiation and the glycolysis pathway. Molecular entities that are part of the identified pathways can serve as biomarkers and potential therapeutic targets for diagnosis and treatment of depression and anxiety disorders. PMID- 21255795 TI - The -1082G/A polymorphism in IL-10 gene is associated with risk of Alzheimer's disease: a meta-analysis. AB - BACKGROUND: The -1082G/A polymorphism in IL-10 gene has been extensively investigated for association to Alzheimer's disease (AD), however, results of different studies have been inconsistent. The objective of this study is to assess the relationship of IL-10 -1082G/A polymorphism and AD risk by using meta analysis. METHODS: All eligible case-control studies were searched in Pubmed and Embase. Odds ratios (OR) with the 95% confidence intervals (CI) were used to assess the association. RESULTS: A total of 2158 cases and 2088 controls in 12 case-control studies were included. The results indicated that the A allele carriers (AA+AG) had a 27% increased risk of AD, when compared with the homozygote GG (OR=1.27, 95%CI=1.02-1.58 for AA+AG vs. GG). In the subgroup analysis by ethnicity, significant elevated risks were associated with A allele carriers in Europeans (OR=1.27 and 95%CI=1.01-1.59 for AA+AG vs. GG), but not in Asians (OR=1.37 and 95%CI=0.32-5.88 for AA+AG vs. GG). CONCLUSIONS: This meta analysis suggested that the -1082G/A polymorphism of IL-10 gene would be a risk factor for AD. To further evaluate gene-to-gene and gene-to-environmental interactions between polymorphisms of IL-10 gene and AD risk, more studies with large groups of patients are required. PMID- 21255796 TI - The Contegra bovine jugular vein graft versus the Shelhigh pulmonic porcine graft for reconstruction of the right ventricular outflow tract: a comparative study. AB - OBJECTIVES: Reconstruction of the right ventricular outflow tract plays a major role in congenital cardiac surgery. With the advent of the Contegra bovine jugular vein graft and the Shelhigh pulmonic xenograft, hopes were high that the lack of availability of homografts would be overcome. The present study evaluated both grafts and investigated the influence of known risk factors for premature graft failure. METHODS: From December 1999 to September 2008, 84 consecutive patients (mean age, 12 +/- 15 years) with a total of 100 implanted conduits (43 Contegra bovine jugular vein grafts and 57 Shelhigh pulmonic xenografts) were included in this study. Primary end points were reintervention, reoperation, and death. RESULTS: The rate of overall conduit replacement was 25% for the Shelhigh pulmonic xenograft versus 26% for the Contegra bovine jugular vein graft. The predominant mode of failure was conduit stenosis for both groups (23% for the Shelhigh pulmonic xenograft vs 19% for the Contegra bovine jugular vein graft), with a mean time to replacement of 18 +/- 9 months for the Shelhigh pulmonic xenograft versus 42 +/- 4 months for the Contegra bovine jugular vein graft (P = .25). Histopathological analysis revealed a similar chronic inflammatory reaction in both conduits, but it was significantly stronger in the Shelhigh pulmonic xenograft group. The Contegra bovine jugular vein graft showed frequently the formation of a stenotic membrane at the distal anastomosis site. Age of less than 1 year, body surface area, pulmonary stenosis, and conduit size of less than 14 mm could not be identified as risk factors for premature failure. CONCLUSIONS: Both conduits fail predominantly because of stenosis and are subject to a chronic inflammatory reaction, although this was stronger in the Shelhigh pulmonic xenograft group. Mean time to replacement was 18 +/- 9 months for the Shelhigh pulmonic graft group versus 42 +/- 4 months for the Contegra bovine graft group (P = .25). Because there is a trend toward earlier failure in the Shelhigh pulmonic xenograft group, we currently prefer to implant the Contegra bovine jugular vein graft for right ventricular outflow tract reconstruction. PMID- 21255797 TI - Two decades of pediatric lung transplant in the United States: have we improved? AB - OBJECTIVE: Since 1988, approximately 1100 pediatric lung transplants have been performed worldwide with consistent improvement in survival. Similarly, survival for pediatric heart transplant has increased over the years; however, in this cohort improvement in survival is exclusively a result of increased early (1 year) survival. To observe if this same phenomenon exists in pediatric lung transplants, the United Network for Organ Sharing database was analyzed to evaluate and characterize how pediatric lung transplant survival has changed in the past 2 decades. METHODS: The United Network for Organ Sharing database was queried for patients aged 18 years or less who underwent lung transplantation from May 1988 to May 2008. Analysis included 959 pediatric lung transplants. RESULTS: Age groups were infants (<=1 years) (n = 106 [11%]), children (2-12 years) (n = 299 [31%]), and adolescents (>=13 years) (n = 554 [58%]). A total of 546 (57%) were girls. Kaplan-Meier survival was significantly better in the late era (2002-2008) than in all other eras (1988-1994 and 1995-2001) (P < .05). The half-life for graft has increased significantly over the eras (early, 2.2 years; mid, 3.3 years; and late, 3.8 years). Conditional 1-year survival (ie, mid to late survival) was not significantly different (P = .3) among the eras. Gender, age, diagnosis, prolonged ischemic time, and cytomegalovirus mismatch did not significantly affect overall patient or graft survival. Chronic preoperative steroid dependence (P = .02), preoperative ventilatory dependence (P < .001), and retransplantation (P = .02) were associated with decreased survival. CONCLUSIONS: Survival in pediatric lung transplant has increased significantly over the years, but this improvement primarily reflects improvement in early survival. Survival in pediatric lung transplant after the first posttransplant year has not changed in more than 2 decades. PMID- 21255798 TI - Comparison of surgical techniques for early-stage thymoma: feasibility of minimally invasive thymectomy and comparison with open resection. AB - OBJECTIVE: The minimally invasive, video-assisted thoracoscopic surgical (VATS) approach to resection of the thymus is frequently practiced for benign disease; however, a VATS approach for thymoma remains controversial. The objective of the present study was to evaluate the feasibility of VATS thymectomy for the treatment of early-stage thymoma and to compare the outcomes with those after open resection. METHODS: A retrospective review of 40 patients who underwent surgical resection of early-stage thymoma during a 12-year period was conducted. Data on patient characteristics, morbidity, recurrence, and survival were collected. The primary endpoint studied was overall survival. RESULTS: Of the 40 patients, 14 underwent thymectomy for stage I and 26 for stage II thymoma; 19 were men and 21 were women (median age, 64 years; range, 35-86 years). Open thymectomy was performed in 22 patients, and VATS was performed in 18. The operative mortality rate was 0%. The tumor stage and number of patients undergoing adjuvant radiotherapy were comparable in both surgical groups. The median length of hospital stay was shorter in the VATS group (3 days) than in the open group (5 days) (P = .0001). The median follow-up was 36 months. No significant differences were found in the estimated recurrence-free and overall 5 year survival rates (83%-100%) between the 2 groups. CONCLUSIONS: VATS of early stage thymoma appears safe and feasible and was associated with a shorter hospital stay. The oncologic outcomes were comparable in the open and VATS groups during intermediate-term follow-up. Additional follow-up is required to evaluate the long-term results of thoracoscopic thymectomy for early-stage thymoma. PMID- 21255799 TI - A history and evolution of laparoscopic nephrectomy: perspectives from the past and future directions in the surgical management of renal tumors. AB - June 25, 2010 marks the twentieth anniversary of the first clinical laparoscopic nephrectomy. Since the advent of this procedure a paradigm shift toward minimally invasive options for urological surgery has been witnessed, resulting in rapid technological innovations and improved patient outcomes. A history of the minimally invasive surgical management of renal masses is presented with a focus on laparoscopic nephrectomy. PMID- 21255800 TI - Prognostic value of cyclooxygenase-2 expression in squamous cell carcinoma of the bladder. AB - PURPOSE: Inflammation is associated with the pathogenesis of carcinoma, including squamous cell carcinoma of the bladder. Cyclooxygenase-2 is an enzyme that is induced at inflammation sites. We assessed the expression pattern of cyclooxygenase-2 in patients with squamous cell carcinoma of the bladder and determined whether cyclooxygenase-2 expression is associated with clinical outcomes after radical cystectomy. MATERIALS AND METHODS: Immunohistochemical staining for cyclooxygenase-2 was done on archival bladder specimens from 152 patients treated with radical cystectomy for squamous cell carcinoma on the Autostainer (DakoCytomation, Carpinteria, California). Bright field microscopy imaging coupled with advanced color detection software was used. Cyclooxygenase-2 was defined as over expressed when greater than 20% cells were positive. We assessed the relationship of cyclooxygenase-2 expression with pathological parameters and clinical outcome. RESULTS: The study included 99 male and 53 female patients with a mean age of 52 years who had squamous cell carcinoma, including 80.9% with bilharziasis. Presenting stage was T2 or greater and presenting grade was GII or less in 93.4% of patients. Median followup was 63.2 months. Cyclooxygenase-2 was over expressed in 74 cystectomy specimens (48.7%) and associated with higher pathological stage (p=0.003) and grade (p=0.049). On multivariate Cox proportional hazards regression analysis cyclooxygenase-2 over expression was associated with disease recurrence (p=0.031) and bladder cancer specific mortality (p=0.046). CONCLUSIONS: Cyclooxygenase-2 over expression is associated with pathological stage, grade and worse outcomes after radical cystectomy, suggesting a role in bladder squamous cell carcinoma progression. Our findings support the need for further evaluation of cyclooxygenase-2 and inflammatory signaling pathways, and cyclooxygenase-2 targeted prevention or therapy in patients with bladder squamous cell carcinoma. PMID- 21255801 TI - Ultrastructural properties of interstitial cells of Cajal in the Guinea pig bladder. AB - PURPOSE: We investigated the ultrastructural characteristics of interstitial cells of Cajal in the guinea pig bladder. MATERIALS AND METHODS: Bladders were removed from guinea pigs and processed for transmission electron microscopy. Some sections were labeled with c-Kit antibodies and colloidal gold particles for positive identification of interstitial cells of Cajal. RESULTS: Kit positive cells, identified with 10 nm gold particles, were located on the periphery of detrusor smooth muscle bundles and in the interbundle spaces. Interstitial cells of Cajal in these regions contained mitochondria, rough and smooth endoplasmic reticulum, thin and intermediate filaments, caveolae, Golgi apparatus, free ribosomes, cytoplasmic vesicles and had a discontinuous basal lamina. They were distinct from smooth muscle cells by an absence of dense bodies, membrane attachment bands and thick filaments. The ultrastructure of interstitial cells of Cajal in all regions of the bladder wall examined were similar and the myofibroblast characteristic, fibronexus, was not evident in any of the cells examined. Interstitial cells of Cajal had lateral branches which extended toward other interstitial cells of Cajal, neighboring smooth muscle cells or nerves. Cells with the ultrastructural profile of interstitial cells of Cajal were associated with bladder microvessels and their branched processes were in close proximity to vascular smooth muscle cells. CONCLUSIONS: Bladder interstitial cells of Cajal have typical ultrastructural characteristics of interstitial cells of Cajal from other tissues and were immunopositive for the interstitial cell of Cajal marker Kit. They were closely associated with detrusor smooth muscle and often networked with other interstitial cells of Cajal. The observation of perivascular cells with interstitial cells of Cajal characteristics indicates that there may be more subtypes of these cells in the bladder than previously considered. PMID- 21255802 TI - Trophic factor and FR167653 supplementation during cold storage rescue chronic renal injury. AB - PURPOSE: The use of organs from deceased after cardiac death and extended criteria donors grew in the last decade. These organs are more sensitive to ischemia-reperfusion injury during transplantation and current preservation protocols do not protect them adequately. MATERIALS AND METHODS: In an autotransplanted, deceased after cardiac death donor pig kidney model we evaluated the benefits of supplementation with University of Wisconsin solution trophic factors and FR167653, an inhibitor of p38 mitogen-activated protein kinase. RESULTS: Supplemented solution improved renal recovery and limited ischemia-reperfusion injury, particularly when agents were used in conjunction. Long-term benefits were highlighted by decreased renal fibrosis, as determined by Picrosirius staining, and inflammation, as evaluated by renal cell infiltration. Mechanistic evaluation showed decreased expression of epithelial-to-mesenchymal transition markers, a process involved in renal fibrosis development. Tumor necrosis factor-alpha was markedly decreased in the treated experimental group. Apoptosis was also decreased, accompanied by decreased p38 mitogen-activated protein kinase phosphorylation. CONCLUSIONS: Supplementing the current gold standard kidney preservation protocol with trophic factors and p38 mitogen activated protein kinase inhibitors markedly increased the quality of grafts in our pig deceased after cardiac death donor model. Hence, this represents a strategy of interest to improve transplantation outcomes. PMID- 21255803 TI - Mesenchymal stem cell recruitment and improved bladder function after bladder outlet obstruction: preliminary data. AB - PURPOSE: Mesenchymal stem cells have various therapeutic benefits in various organ injury models. Bladder outlet obstruction causes smooth muscle hypertrophy and fibrosis, leading to lowered compliance, increased storage pressures and renal injury. Decreased blood flow and hypoxia may contribute to obstruction related bladder decompensation. We used a mouse model to determine whether mesenchymal stem cell recruitment occurred after bladder outlet obstruction and whether this was associated with changes in bladder hypoxia, histology and function. We also identified potential chemokines involved in mesenchymal stem cell recruitment. MATERIALS AND METHODS: A total of 20 female mice underwent bladder outlet obstruction. Three days later 2 million green fluorescent protein labeled mesenchymal stem cells were intravenously administered. After 4 weeks urodynamic and histological evaluation was performed. Quantitative reverse transcriptase-polymerase chain reaction was done to determine relative expression of the chemokines CCL2, CCL20, CCL25, CXCL9 and CXCL16. We simultaneously studied mice with bladder outlet obstruction only without mesenchymal stem cell injection and a control group. RESULTS: In 10 of 15 surviving mesenchymal stem cell injected mice mesenchymal stem cells were identified in the detrusor, and decreased hypoxia, hypertrophy and fibrosis was seen. Nine of 10 mice with mesenchymal stem cell engraftment had improved compliance compared to those without engraftment (mean+/-SD 9.6+/-5.1 vs 3.9+/-2.6 MUl/cm H2O, p=0.012). Polymerase chain reaction revealed a 2-fold increase in CCL2 expression but there were no significant changes in other chemokine levels. CONCLUSIONS: Mesenchymal stem cell recruitment to the bladder after bladder outlet obstruction appears to be associated with increased blood flow and decreased tissue hypoxia, which may contribute to improvement in histopathological and functional parameters. Mesenchymal stem cell recruitment may be related to CCL2 over expression. Additional studies in larger samples are needed but these initial results suggest a potential role for mesenchymal stem cell based therapy for bladder outlet obstruction related bladder injury. PMID- 21255804 TI - MicroRNA-100 expression is independently related to biochemical recurrence of prostate cancer. AB - PURPOSE: Abnormal miRNA expression has emerged as crucial factors in carcinogenesis and is important in the comprehension of prostate cancer behavior. We determined the correlation of miRNA expression profiles with prostate cancer progression. MATERIALS AND METHODS: We studied frozen specimens from 49 patients treated for prostate cancer with radical prostatectomy. We intentionally chose 28 men without and 21 with biochemical recurrence, defined as prostate specific antigen greater than 0.2 ng/ml. The expression of 14 miRNAs was determined by quantitative reverse transcriptase-polymerase chain reaction. All radical prostatectomy specimens were studied in toto to determine tumor volume, Gleason score and 2002 TNM pathological stage. Benign prostate tissue from benign prostatic hyperplasia served as a control. RESULTS: Four miRNAs were related to tumor recurrence. Using the Cox regression test the risk of recurrence was 3.0, 3.3, 2.7 and 3.4 for high levels of miR-100, miR-145, miR-191 and miR-let7c, respectively. When considering statistically significant clinical variables on univariate analysis of biochemical-free survival, prostate specific antigen and tumor volume, results revealed that miR-100 and tumor volume were independently related to tumor recurrence. CONCLUSIONS: A high level of miR-100 is related to biochemical recurrence of localized prostate cancer in patients treated with radical prostatectomy. The role of miR-100 during carcinogenesis must be resolved in future studies to better understand the molecular pathways in which miR-100 is involved. This may open the possibility of using it as a prognostic marker and inspire the development of a target drug. PMID- 21255805 TI - The histone deacetylase inhibitor trichostatin A synergistically resensitizes a cisplatin resistant human bladder cancer cell line. AB - PURPOSE: Cisplatin is the mainstay of treatment for advanced bladder cancer. However, intrinsic or acquired resistance to cisplatin is common, which severely limits its therapeutic potential. We determined the synergistic antitumor effect of cisplatin and the histone deacetylase inhibitor trichostatin A in cisplatin resistant human bladder cancer cells. MATERIALS AND METHODS: The cisplatin resistant human bladder cancer cell line T24R2 was exposed to cisplatin and/or trichostatin A. Tumor cell proliferation was examined by cell counting kit assay. Synergism between 2 drugs was examined by the combination index. Changes in cell cycle and apoptosis were determined by flow cytometry. We analyzed the expression of caspase-3, 8 and 9, poly(adenosine diphosphate-ribose) polymerase, p21WAF1/CIP1, cyclin A, B1 and D1, Cdc2c, p-Cdc2c, Cdc25c, p-Cdc25c, cytochrome c, p-Akt, t-Akt, Bcl-2, Bax, Bad, vascular endothelial growth factor and fetal liver kinase-1 by Western blot and colorimetric assay. RESULTS: Based on the combination index and isobole analysis of the Cell Counting Kit-8 assay we observed a strong synergistic antitumor effect between cisplatin and trichostatin A, allowing a 3.5 and 4.9-fold dose reduction in cisplatin and trichostatin A, respectively, while achieving an estimated 90% kill of T24R2 cells. The underlying mechanism could be synergistic cell cycle arrest, induction of caspase mediated apoptosis or up-regulated expression of pro-apoptotic Bad and Bax. CONCLUSIONS: Results indicate that trichostatin A may synergistically enhance the antitumor effect of cisplatin and resensitize cisplatin resistant bladder cancer cells. These findings suggest the potential use of histone deacetylase inhibitor as a combination agent to enhance the antitumor effect of cisplatin in patients with advanced bladder cancer. PMID- 21255806 TI - Modified scrotal (Bianchi) mid raphe single incision orchiopexy for low palpable undescended testis: early outcomes. AB - PURPOSE: We compared the results of low transscrotal mid raphe orchiopexy, high scrotal incision (Bianchi) and conventional inguinal approach in patients with palpable undescended testes. MATERIALS AND METHODS: Orchiopexies performed between January 2003 and September 2009 with a minimum 3-month followup were included. Low scrotal incision (group 1) and high scrotal incision (group 2) were compared to the traditional inguinal 2-incision technique (group 3). We retrospectively reviewed operative time, success as defined by mid or lower scrotal position of the testis, and complications at 12 weeks and 1 year postoperatively. RESULTS: A total of 286 orchiopexies were performed in 214 patients with palpable undescended testes. Group 1 included 81 patients with 125 undescended testes. Group 2 consisted of 44 patients with 60 undescended testes. Group 3 included 89 patients with 101 undescended testes. Postoperatively the testes were located in a good position within the scrotum in 99% of patients in group 1, 98% in group 2 and 100% in group 3. Mean+/-SD operative time for unilateral undescended testes was significantly shorter for low transscrotal compared to inguinal orchiopexy (28+/-10 vs 37+/-12 minutes, p<0.0001) but equivalent to a high scrotal incision (27+/-10 minutes, p=0.59). For all 160 children followed for 1 year no long-term atrophy or secondary reascent was observed. CONCLUSIONS: Low transscrotal mid raphe orchiopexy appears to be an excellent alternative to high scrotal incision or standard inguinal orchiopexy for low palpable undescended testes, especially bilateral cases. PMID- 21255807 TI - alpha-lipoic acid can improve endothelial dysfunction in subjects with impaired fasting glucose. AB - Several studies showed that impairment of endothelium-dependent arterial dilation (EDAD) exists in subjects with impaired fasting glucose (IFG). The crucial mechanism of this endothelial dysfunction remains unclear. We hypothesized that oxidative stress may be partially responsible for the impairment in EDAD in subjects with IFG. Thus, the present study was designed to assess whether the antioxidant alpha-lipoic acid can improve endothelial dysfunction in subjects with IFG. Sixty subjects with newly diagnosed IFG and 32 healthy individuals with normal glucose tolerance were enrolled. Subjects were randomized into 2 groups: untreated experimental group (n = 30) and alpha-lipoic acid treatment group (n = 30, alpha-lipoic acid 600 mg via intravenous infusion once a day for 3 weeks). We measured EDAD at baseline and after 3 weeks of intervention. At baseline, EDADs in alpha-lipoic acid and untreated experimental groups were 4.03% and 4.14%, respectively, which were significantly lower than that in controls (5.72%) (P < .001). After 3 weeks of intervention, there was a remarkable increase in EDAD (reaching 5.10%; DeltaEDAD, 26.5%) (P < .01) and a significant decrease in plasma thiobarbituric acid reactive substances (TBARS) (29.1%) (P < .05) in IFG subjects treated with alpha-lipoic acid. Endothelium-dependent arterial dilation and TBARS remained unchanged before and after intervention in the untreated experimental group. The absolute changes in EDAD showed a significant negative correlation with the changes in TBARS (r = -0.444, P = .014). Our data showed that IFG subjects have impaired endothelial function and that antioxidant alpha-lipoic acid can improve endothelial function through a decrease of oxygen-derived free radicals. PMID- 21255808 TI - Glucagon-like peptide-1 and candesartan additively improve glucolipotoxicity in pancreatic beta-cells. AB - Glucagon-like peptide-1 (GLP-1) and angiotensin II type 1 receptor blocker reduce beta-cell apoptosis in diabetes, but the underlying mechanisms are not fully understood. We examined the combination effects of GLP-1 and candesartan, an angiotensin II type 1 receptor blocker, on glucolipotoxicity-induced beta-cell apoptosis; and we explored the possible mechanisms of the antiapoptotic effects. The effects of GLP-1 and/or candesartan on glucolipotoxicity-induced apoptosis and the phosphorylation of insulin receptor substrate-2 (IRS-2), protein kinase B (PKB), and forkhead box O1 (FoxO1) were evaluated by using MIN6 cells and isolated mouse pancreatic islets. Although palmitate significantly enhanced the high-glucose-induced apoptosis in both islets and MIN6 cells, GLP-1 and candesartan significantly inhibited apoptosis; and combination treatment additively prevented apoptosis. Whereas palmitate significantly decreased the phosphorylation of IRS-2, PKB, and FoxO1 in MIN6 cells, these changes were significantly inhibited by treatment with GLP-1 and/or candesartan. In addition, wortmannin, an inhibitor of phosphoinositide 3-kinase, markedly inhibited GLP-1- and/or candesartan-mediated PKB and FoxO1 phosphorylation. The present results suggest that GLP-1 and candesartan additively prevent glucolipotoxicity-induced apoptosis in pancreatic beta-cells through the IRS-2/phosphoinositide 3 kinase/PKB/FoxO1 signaling pathway. PMID- 21255809 TI - Proteomic analysis of secreted proteins from aseptically grown rice. AB - Plants are known to secrete a variety of compounds into the rhizosphere. These compounds are thought to play important roles in the regulation of soil chemical properties and soil microorganisms. To determine the composition of proteins secreted from rice roots, aseptic hydro culture was performed, and the collected proteins were analyzed. Over 100 proteins were identified; most were identified using the rice database (RAP-DB), and about 60% of the identified proteins were suspected to have a signal peptide. Functional categorization suggested that most were secondary metabolism- and defense-related proteins. Pathogenesis- and stress related proteins were the major proteins found in the bathing solution under aseptic conditions. Thus, we propose that rice plants constitutively secrete a large variety of proteins to protect their roots against abiotic and/or biotic stresses in the environment. PMID- 21255810 TI - The reversal of hyperglycemia after transplantation of mouse embryonic stem cells induced into early hepatocyte-like cells in streptozotocin-induced diabetic mice. AB - Cellular replacement therapy is a potential therapeutic strategy for diabetes. In this study, we investigated the effect of transplantation of induced mouse embryonic stem cells (mESCs) into endoderm and early hepatocyte-like cells in streptozotocin (STZ)-diabetic mice. After embryoid body (EB) formation from mESC, the EBs were cultured in the presence of dexamethasone (DEX) and insulin for 4 days then was added acidic fibroblast growth factor (aFGF), hepatocyte growth factor (HGF) and oncostatin M (OSM) for 10 days, respectively. Blood glucose levels, intraperitoneal glucose tolerance (IGT) test and islet histology were assessed. The result revealed that transplantation of induced mESCs into early hepatocyte-like cells could repair pancreatic islets of control group. Blood glucose levels and intraperitoneal glucose tolerance test were significantly improved in test group compared to control group. Furthermore, there was significant increase in the number of islets in test group compared to control group. The findings declare that induced mESCs into endoderm and early hepatocyte like cells, are appropriate candidate for regenerative therapy of pancreatic islets in type I diabetes. PMID- 21255812 TI - Ultrasonically enhanced extraction of bioactive principles from Quillaja Saponaria Molina. AB - A study of ultrasonic enhancement in the extraction of bioactive principles from Quillaja Saponaria Molina (Quillay) is presented. The effects influencing the extraction process were studied through a two-level factorial design. The effects considered in the experimental design were: granulometry, extraction time, acoustic Power, raw matter/solvent ratio (concentration) and acoustic impedance. It was found that for aqueous extraction the main factors affecting the ultrasonically-assisted process were: granulometry, raw matter/solvent ratio and extraction time. The extraction ratio was increased by Ultrasonics effect and a reduction in extraction time was verified without any influence in the product quality. In addition the process can be carried out at lower temperatures than the conventional method. As the process developed uses chips from the branches of trees, and not only the bark, this research contributes to make the saponin exploitation process a sustainable industry. PMID- 21255813 TI - Measurements of coating density using ultrasonic reflection coefficient phase spectrum. AB - A nondestructive method to determine the density of coating has been proposed in this paper based on the ultrasonic reflection coefficient phase spectrum (URCPS). A model was set up first to represent the ultrasonic waves reflected from a coating system at normal incident, and the relation between the extremum of URCPS and the coating density was established to provide the principle of determining the density. The ultrasonic method was validated on a series of ZrO2-7wt.%Y2O3 (YSZ) coatings with various density. The specimens were prepared by electric beam physical vapor deposit (EB-PVD). After deposition, the specimens were irradiated using high-intensity pulsed ion beam (HIPIB) at different ion current density of 100 and 200A/cm2 to change coating density. The coating densities of as-deposited and post irradiation by HIPIB were derived to be 4940-5030, 5200-5320 and 5390 5470kg/m3, respectively. The relative error between the coating density measured by the ultrasonic method and Archimedean principle ranging from 2.53% to 6.11%, indicates that the proposed ultrasonic quantification method provides a reliable nondestructive way to determine coating density. PMID- 21255811 TI - Isolation, primary culture and morphological characterization of oenocytes from Aedes aegypti pupae. AB - Oenocytes are ectodermic cells that participate in a number of critical physiological roles such as detoxification and lipid storage and metabolism in insects. In light of the lack of information on oenocytes from Aedes aegypti and the potential role of these cells in the biology of this major yellow fever and dengue vector, we developed a protocol to purify and maintain Ae. aegypti pupa oenocytes in primary culture. Ae. aegypti oenocytes were cultured as clustered and as isolated ovoid cells with a smooth surface. Our results demonstrate that these cells remain viable in cell culture for at least two months. We also investigated their morphology in vivo and in vitro using light, confocal, scanning and transmission electron microscopes. This work is the first successful attempt in isolating and maintaining Ae. aegypti oenocytes in culture, and a significant step towards understanding the role of this cell type in this important disease vector. The purification and the development of primary cultures of insect oenocytes will allow future studies of their metabolism in producing and secreting compounds. PMID- 21255814 TI - Chimeric porcine reproductive and respiratory syndrome viruses reveal full function of genotype 1 envelope proteins in the backbone of genotype 2. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is classified into two genotypes, type 1 and type 2, which share only about 60% genetic identity. Here, we report viable chimeric viruses in which the envelope protein genes from ORF2a to ORF5 of vSHE (type 1) were swapped into the genetic backbone of vAPRRS (type 2). We found that the envelope proteins of genotype 1 were fully functional in genotype 2 PRRSV, and the rescued chimeric progeny viruses showed robust genetic stability and similar replication properties to the parental strains in vitro. To our knowledge, this is the first study to report the substitution of complete ORFs between different genotypes of porcine arterivirus. These findings pave the way to further elucidate the structure-function relationship of PRRSV envelope proteins, and may enable the development of novel marker vaccines that can be used to differentiate vaccinated from infected animals. PMID- 21255815 TI - Strong foreign promoters contribute to innate inflammatory responses induced by adenovirus transducing vectors. AB - E1-deleted adenovirus (FG Ad) transducing vectors are limited for use in vivo by their induction of strong innate and adaptive inflammatory responses. We have examined the contribution of the transgene cassette, particularly the foreign promoter driving transgene expression, in the induction of innate inflammation using a mouse ear model in which swelling is measured as a sensitive surrogate marker of the total innate inflammatory response. The commonly used cytomegalovirus major immediate early (CMV) promoter led to high-level swelling that was independent of transgene expression, while the Rous sarcoma virus and human ubiquitin C promoters led to intermediate levels of swelling and the Ad E1A promoter or no promoter led to equally low levels of swelling. Significant swelling was induced by a virus in which the E1A promoter directed pIX expression, supporting the possibility that activation of expression of Ad genes retained in the vector plays an important role in the inflammatory response. Taken together, our findings support the idea that strong foreign promoters likely play the limiting role in the induction of innate and adaptive immune responses that limit the duration of transgene expression after transduction by FG Ad vectors. PMID- 21255817 TI - Advanced oxidation processes coupled with electrocoagulation for the exhaustive abatement of Cr-EDTA. AB - Using Cr-EDTA as a model system, a two-step method has been investigated for the abatement of persistent chromium complexes in water. The treatment consists of an oxidative decomposition of the organic ligands by means of ozonization or electrochemical oxidation at a boron doped diamond (BDD) electrode, followed by removal of the metal via electrochemical coagulation. In the designed synthetic waste, EDTA has been used both as a chelating agent and as a mimic of the organic content of a typical wastewater provided by a purification leather plant. A crucial point evaluated is the influence of the oxidative pretreatment on the chemical modification of the synthetic waste and hence on the electrocoagulation efficacy. Because of the great stability of Cr complexes, such as Cr-EDTA, the classical coagulation methods, based on ligand exchange between Cr(III) and Fe(II) or Fe(III), are ineffective toward Cr abatement in the presence of organic substances. On the contrary, when advanced oxidation processes (AOPs), such as ozonization or electrooxidation at a BDD anode are applied in series with electrocoagulation (EC), complete abatement of the recalcitrant Cr fraction can be achieved. ECs have been carried out by using Fe sacrificial anodes, with alternating polarization and complete Cr abatement (over 99%) has been obtained with modest charge consumption. It has been found that Cr(III) is first oxidized to Cr(VI) in the AOP preceding EC. Then, during EC, Cr(VI) is mainly reduced back to Cr(III) by electrogenerated Fe(II). Thus, Cr is mainly eliminated as Cr(III). However, a small fraction of Cr(VI) goes with the precipitate as confirmed by XPS analysis of the sludge. PMID- 21255818 TI - Landscapes and their relation to hominin habitats: case studies from Australopithecus sites in eastern and southern Africa. AB - We examine the links between geomorphological processes, specific landscape features, surface water drainage, and the creation of suitable habitats for hominins. The existence of mosaic (i.e., heterogeneous) habitats within hominin site landscape reconstructions is typically explained using models of the riverine and gallery forest settings, or the pan or lake setting. We propose a different model: the Tectonic Landscape Model (TLM), where tectonic faulting and volcanism disrupts existing pan or river settings at small-scales (~10-25 km). Our model encompasses the interpretation of the landscape features, the role of tectonics in creating these landscapes, and the implications for hominins. In particular, the model explains the underlying mechanism for the creation and maintenance of heterogeneous habitats in regions of active tectonics. We illustrate how areas with faulting and disturbed drainage patterns would have been attractive habitats for hominins, such as Australopithecus, and other fauna. Wetland areas are an important characteristic of surface water disturbance by fault activity; therefore we examine the tectonically-controlled Okavango Delta (Botswana) and the Nylsvley wetland (South Africa) as modern examples of how tectonics in a riverine setting significantly enhance the faunal and floral biodiversity. While tectonic landscapes may not have been the only type of attractive habitats to hominins, we propose a suite of landscape, faunal, and floral indicators, which when recovered together suggest that site environments may have been influenced by tectonic and/or volcanic activity while hominins were present. For the fossil sites, we interpret the faulting and landscapes around australopithecine-bearing sites of the Middle Awash (Ethiopia) and Makapansgat, Taung, and Sterkfontein (South Africa) to illustrate these relationships between landscape features and surface water bodies. Exploitation of tectonically active landscapes may explain why the paleoenvironmental signals, anatomy, diets, as well as the fauna associated with Australopithecus appear largely heterogeneous through time and space. This hypothesis is discussed in light of potential preservation and time-averaging effects which may affect patterns visible in the fossil record. The model, however, offers insight into the landscape processes of how such habitats are formed. The landscape features and range of habitat conditions, specifically the wetter, down-dropped plains and drier, uplifted flanks persist in close proximity for as long as the fault motion continues. The Tectonic Landscape Model provides an alternative explanation of why mixed habitats may be represented at certain sites over longer timescales. PMID- 21255816 TI - Antibody-mediated neutralization of flaviviruses: a reductionist view. AB - Flaviviruses are a group of ~70 small RNA viruses responsible for significant morbidity and mortality across the globe. Efforts to develop effective vaccines for several clinically important flaviviruses are underway. Antibodies are a significant component of the host's protective response against flavivirus infection with the potential to contribute to immunity via several distinct mechanisms, including an ability to directly neutralize virus infection. Conversely, virus-reactive antibodies have been implicated in the increased risk of severe clinical manifestations following secondary dengue virus infection. In this review, we will discuss recent progress toward understanding the molecular basis of antibody-mediated neutralization of flaviviruses. Neutralization requires engagement of the virion with a stoichiometry that exceeds a required threshold. From this perspective, we will discuss viral and host factors that impact the number of antibody molecules bound to the virus particle and significantly modulate the potency of neutralizing antibodies. PMID- 21255819 TI - The Early-Middle Pleistocene faunal assemblages of Gesher Benot Ya'aqov: Inter site variability. AB - This study investigates faunal remains from the site of Gesher Benot Ya'aqov, analyzing how hominins may have utilized vertebrates and exploring paleoenvironments during the Early and Middle Pleistocene. Based on analyses of a range of vertebrates, results show that the species distribution of terrestrial vertebrates (microvertebrates and mammals) at the site of Gesher Benot Ya'aqov shows relative stasis above the Matuyama-Brunhes Boundary (MBB) (0.78 Ma). However, consistency in faunal remains at the site reflecting stasis does not seem to reflect accurately the paleoenvironment. Marked changes are demonstrable in the lake-margin sedimentary background, archaeological remains, and agents of accumulation and damage, as well as in the density of medium-large mammals. This study emphasizes the significance of studying assemblages as a whole rather than the species representation on its own. PMID- 21255820 TI - Land, lake, and fish: Investigation of fish remains from Gesher Benot Ya'aqov (paleo-Lake Hula). AB - The question of whether or not pre-modern hominins were responsible for the accumulation of fish remains is discussed through analyses of remains recovered from two lacustrine facies (I-4 and I-5) from Area A of the Acheulian site of Gesher Benot Ya'aqov (GBY) in the Jordan Rift Valley, Israel. The fish remains provide the first glimpse into the naturally accumulated fish assemblage from the fluctuating shores of a lake that had been continually exploited by early hominins some 780,000 years ago. Preliminary analysis of the remains show that thirteen of the seventeen species native to Lake Hula were identified at GBY. These represent three of the five freshwater fish families native to the lake: Cyprinidae (carps), Cichlidae (tilapini, St. Peter's fish), and Clariidae (catfish). From a taphonomical perspective, a significant difference is found between the two lithofacies (Layers I-4 and I-5) in terms of species composition, richness, diversity, and skeleton completeness. It appears that the fish remains recovered from Layer I-4 (clay) are better preserved than those from Layer I-5 (coquina). In both lithofacies, Cyprinidae are highly abundant while Cichlidae and Clariidae are rare and under-represented, especially when compared to the Lake Hula fishery report from the 1950s. All of these identified species may have contributed significantly to the diet of GBY hominins. PMID- 21255821 TI - Effects of various physicochemical characteristics on the toxicities of ZnO and TiO nanoparticles toward human lung epithelial cells. AB - Although novel nanomaterials are being produced and applied in our daily lives at a rapid pace, related health and environmental toxicity assessments are lagging behind. Recent reports have concluded that the physicochemical properties of nanoparticles (NPs) have a crucial influence on their toxicities and should be evaluated during risk assessments. Nevertheless, several controversies exist regarding the biological effects of NP size and surface area. In addition, relatively few reports describe the extents to which the physicochemical properties of NPs influence their toxicity. In this study, we used six self synthesized and two commercial ZnO and TiO2 nanomaterials to evaluate the effects of the major physicochemical properties of NPs (size, shape, surface area, phase, and composition) on human lung epithelium cells (A549). We characterized these NPs using transmission electron microscopy, X-ray diffraction, the Brunauer Emmett-Teller method, and dynamic laser scattering. From methyl thiazolyl tetrazolium (MTT) and Interleukin 8 (IL-8) assays of both rod- and sphere-like ZnO NPs, we found that smaller NPs had greater toxicity than larger ones--a finding that differs from those of previous studies. Furthermore, at a fixed NP size and surface area, we found that the nanorod ZnO particles were more toxic than the corresponding spherical ones, suggesting that both the size and shape of ZnO NPs influence their cytotoxicity. In terms of the effect of the surface area, we found that the contact area between a single NP and a single cell was more important than the total specific surface area of the NP. All of the TiO2 NP samples exhibited cytotoxicities lower than those of the ZnO NP samples; among the TiO2 NPs, the cytotoxicity increased in the following order: amorphous>anatase>anatase/rutile; thus, the phase of the NPs can also play an important role under size-, surface area-, and shape-controlled conditions. PMID- 21255822 TI - Neutrophil and monocyte activation markers have prognostic impact in disseminated intravascular coagulation: in vitro effect of thrombin on monocyte CD163 shedding. AB - Monocyte and neutrophil activation occur during microvascular disturbance of disseminated intravascular coagulation (DIC). This study investigated the diagnostic and prognostic value of circulating neutrophil elastase (NE) and neutrophil volume distribution width (NDW) as neutrophil activation markers and circulating soluble CD163 (sCD163) and monocyte volume distribution width (MDW) as monocyte activation markers in 168 patients suspected of having DIC. The sCD163 provided significant diagnostic value. The prognostic value of sCD163 was comparable to that of D-dimer, but was dependent on other coagulation markers. In vitro, thrombin significantly induced sCD163 from monocytes upregulated with IL 10 or dexamethasone. NDW was an independent and powerful prognostic marker. MDW and NE did not provide diagnostic and prognostic power. Excessive thrombin during ongoing DIC induces florid secretion of CD163; sCD163 might therefore be a potential diagnostic and prognostic marker for DIC. NDW, a convenient parameter measured by an automated hematology analyzer, may be an independent prognostic parameter for DIC. PMID- 21255823 TI - Searching robotic prostatectomy online: what information is available? AB - OBJECTIVES: To search online using the Google search engine to determine what information for robotic-assisted radical prostatectomy (RARP) is available and whether the claims made on the Internet are supported by the published peer reviewed urologic data. METHODS: The term "robotic prostatectomy" was searched using Google on September 29, 2009. The first 50 Web sites were reviewed for RARP specific outcomes, including oncologic outcomes, potency, continence, recovery, and blood loss. All claims were compared with the accepted standards supported by the existing published urologic data. RESULTS: Of the first 50 Web sites, 9 were rejected. Of the remaining 41, 29 were from academic practices and 8 from nonacademic practices; for 4, this distinction was not applicable. Also, 19 sites had direct links, photographs, or text from the Intuitive Surgical Web site, and 22 sites did not. Of the 41 Web sites, 20 made no mention of surgeon experience with RARP and 21 did, with an average experience of 1487 +/- 1206 cases. More than 60% of the sites claimed better potency outcomes with RARP than with radical retropubic prostatectomy, although 32% of sites omitted this information. Similarly, 63% of the Web sites claimed improved continence with RARP than with radical retropubic prostatectomy, and 29% of the sites made no mention of continence. Data on oncologic efficacy was missing from 22% of the Web sites, 22% suggested the cancer outcomes were equivalent between RARP and radical retropubic prostatectomy, and 56% suggested the cancer outcomes were better with RARP. Concerning postoperative recovery and blood loss, 85% of the sites stated that both were improved with RARP, and only 15% omitted these data. CONCLUSIONS: Overall, an online search using the Google search engine for robotic prostatectomy yielded many Web sites with unsubstantiated information of variable accuracy. PMID- 21255824 TI - The vaginal radical trachelectomy: an update of a series of 125 cases and 106 pregnancies. AB - OBJECTIVE: To review our first consecutive 125 vaginal radical trachelectomies (VRT) to assess the oncologic, fertility and obstetrical outcomes. METHODS: Data from our prospective database was used to identify all VRT planned between October 1991 to March 2010 in patients with early-stage cervical cancer (stages IA, IB and IIA). Chi-square test, Fisher's exact test and Student t-test were used to compare baseline characteristics and Kaplan-Meier survival curves were constructed and compared with the use of the log-rank test. RESULTS: During the study period, 140 VRT were planned and 125 were performed. The median age of the patients was 31 and 75% were nulliparous. The majority of the lesions were stage IA2 (21%) or IB1 (69%) and 41% were grade 1. In terms of histology, 56% were squamous and 37% were adenocarcinomas. Vascular space invasion was present in 29% of cases, and 88.5% of the lesions measured <=2cm. The mean follow-up was 93months (range: 4-225months). There were 6 recurrences (4.8%) and 2 deaths (1.6%) following VRT. The actuarial 5-year recurrence-free survival was 95.8% [95% CI: 0.90-0.98], whereas it was 79% [95% CI: 0.49-0.93] in the group where the VRT was abandoned (p=0.001). Higher tumor grade, LVSI and size >2cm appeared to be predictive of the risk of abandoning VRT (p=0.001, p=0.025 and p=0.03 respectively). Tumor size >2cm was statistically significantly associated with a higher risk of recurrence (p=0.001). In terms of obstetrical outcome, 58 women conceived a total of 106 pregnancies. The first and second trimester miscarriage rates were 20% and 3% respectively, and 77 (73%) of the pregnancies reached the third trimester, of which 58 (75%) delivered at term. Overall, 15 (13.5%) patients experienced fertility problems, 40% of which were due to cervical factor. Twelve (80%) were able to conceive, the majority with assisted reproductive technologies. CONCLUSION: VRT is an oncologically safe procedure in well-selected patients with early-stage disease. Lesion size >2cm appears to be associated with a higher risk of recurrence and a higher risk of abandoning the planned VRT. Fertility and obstetrical outcomes post VRT are excellent. PMID- 21255826 TI - Elsevier statement on Research4Life. PMID- 21255825 TI - The RNA exosome targets the AID cytidine deaminase to both strands of transcribed duplex DNA substrates. AB - Activation-induced cytidine deaminase (AID) initiates immunoglobulin (Ig) heavy chain (IgH) class switch recombination (CSR) and Ig variable region somatic hypermutation (SHM) in B lymphocytes by deaminating cytidines on template and nontemplate strands of transcribed DNA substrates. However, the mechanism of AID access to the template DNA strand, particularly when hybridized to a nascent RNA transcript, has been an enigma. We now implicate the RNA exosome, a cellular RNA processing/degradation complex, in targeting AID to both DNA strands. In B lineage cells activated for CSR, the RNA exosome associates with AID, accumulates on IgH switch regions in an AID-dependent fashion, and is required for optimal CSR. Moreover, both the cellular RNA exosome complex and a recombinant RNA exosome core complex impart robust AID- and transcription-dependent DNA deamination of both strands of transcribed SHM substrates in vitro. Our findings reveal a role for noncoding RNA surveillance machinery in generating antibody diversity. PMID- 21255827 TI - Valsalva haemorrhagic retinopathy after push-ups. PMID- 21255828 TI - Comparison of short-course multidrug treatment with standard therapy for visceral leishmaniasis in India: an open-label, non-inferiority, randomised controlled trial. AB - BACKGROUND: Improved treatment approaches are needed for visceral leishmaniasis. We assessed the efficacy and safety of three potential short-course combination treatments compared with the standard monotherapy in India. METHODS: Standard treatment (1 mg/kg amphotericin B infusion on alternate days for 30 days, total dose 15 mg/kg) was compared with three drug combinations (single injection of 5 mg/kg liposomal amphotericin B and 7-day 50 mg oral miltefosine or single 10-day 11 mg/kg intramuscular paromomycin; or 10 days each of miltefosine and paromomycin) in an open-label, parallel-group, non-inferiority, randomised controlled trial in two hospital sites in Bihar, India. Patients aged 5-60 years with parasitologically confirmed visceral leishmaniasis were randomly assigned one of the four treatments by the trial statistician by use of a computer generated list. Clinical assessments were done at the end of treatment (15 days on combination treatment; 31 days for standard treatment) and after 45 days and 6 months. The primary endpoint was definitive cure (defined as no sign or symptom of visceral leishmaniasis and parasitologically cured to the last follow-up). Analyses were done both by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00696969. FINDINGS: Between June, 2008, and July, 2009, 634 patients were assigned amphotericin B (n=157), liposomal amphotericin B with miltefosine (n=160) or paromomycin (n=158), or miltefosine and paromomycin (n=159). 618 patients were in the per-protocol population. There were two relapses in each group. The numbers with definitive cure at 6 months for the intention-to-treat population were 146 (cure rate 93.0%; CI 87.5-96.3) for amphotericin B, 156 (97.5%; 93.3-99.2) for liposomal amphotericin B and miltefosine, 154 (97.5%; 93.24-99.2) for liposomal amphotericin B and paromomycin, and 157 (98.7%; 95.1-99.8) for miltefosine and paromomycin. All combinations were non-inferior to the standard treatment, in both the intention-to-treat and per-protocol populations. Patients in the combination groups had fewer adverse events than did those assigned standard treatment. INTERPRETATION: Combination treatments for visceral leishmaniasis are efficacious and safe, and decrease the duration of therapy, thereby encouraging adherence and reducing emergence of drug-resistant parasites. FUNDING: Drugs for Neglected Diseases initiative and the Indian Council of Medical Research. PMID- 21255829 TI - Combination therapy for visceral leishmaniasis. PMID- 21255832 TI - Click assembly of magnetic nanovectors for gene delivery. AB - Functionalization of iron oxide nanoparticles with quaternary ammonium ion-based aminooxy and oxime ether substrates provides a flexible route for generating magnetic gene delivery vectors. Using the MCF-7 breast cancer cell line, our findings show that pDNA magnetoplexes derived from the lipid-coated nanoparticle formulation dMLP transfect in the presence of 10% serum with or without magnetic assistance at significantly higher levels than a commonly used cationic liposome formulation, based on luciferase assay. The present ion-pairing, click chemistry approach furnishes Fe(3)O(4) nanoparticles with lipid layers. The resultant magnetic nanovectors serve as transfection enhancers for otherwise transfection inactive materials. PMID- 21255834 TI - Correlation among nuclear localization of NuMA-RARalpha, deregulation of gene expression and leukemic phenotype of hCG-NuMA-RARalpha transgenic mice. AB - Acute promyelocytic leukemia (APL) is a model system of aberrant transcription in cancer. We sought to elucidate the mechanism of action of the variant fusion NuMA RARalpha in APL, using the hCG-NuMA-RARalpha transgenic model. We report that subcellular localization of NuMA-RARalpha in transgenic mice is dependent upon its protein expression and transgene dosage. Subcellular localization of the fusion is inversely correlated with extent of gene deregulation at the mRNA level for Cebpalpha, CebpE and Pu.1. Finally, we report that phenotype onset is correlated with NuMA-RARalpha copy number; mice with higher copy number developing disease later than those with lower copy number. PMID- 21255833 TI - The effect of internalizing human single chain antibody fragment on liposome targeting to epithelioid and sarcomatoid mesothelioma. AB - Immunoliposomes (ILs) anchored with internalizing human antibodies capable of targeting all subtypes of mesothelioma can be useful for targeted imaging and therapy of this malignant disease. The objectives of this study were to evaluate both the in vitro and in vivo tumor targeted internalization of novel internalizing human single chain antibody (scFv) anchored ILs on both epithelioid (M28) and sarcomatoid (VAMT-1) subtypes of human mesothelioma. ILs were prepared by post-insertion of mesothelioma-targeting human scFv (M1) onto preformed liposomes and radiolabeled with (111)In ((111)In-IL-M1), along with control non targeted liposomes ((111)In-CL). Incubation of (111)In-IL-M1 with M28, VAMT-1, and a control non-tumorigenic cell line (BPH-1) at 37 degrees C for 24 h revealed efficient binding and rapid internalization of ILs into both subtypes of tumor cells but not into the BPH-1 cells; internalization accounted for approximately 81-94% of total cell accumulation in mesothelioma cells compared to 37-55% in control cells. In tumor-bearing mice intravenous (i.v.) injection of (111)In-IL-M1 led to remarkable tumor accumulation: 4% and 4.7% injected dose per gram (% ID/g) for M28 and VAMT-1 tumors, respectively, 48 h after injection. Furthermore, tumor uptake of (111)In-IL-M1 in live xenograft animal models was verified by single photon emission computed tomography (SPECT/CT). In contrast, i.v. injection of (111)In-CL in tumor-bearing mice revealed very low uptake in both subtypes of mesothelioma, 48 h after injection. In conclusion, M1 scFv anchored ILs showed selective tumor targeting and rapid internalization into both epithelioid and sarcomatoid subtypes of human mesothelioma, demonstrating its potential as a promising vector for enhanced tumor drug targeting. PMID- 21255835 TI - Estimation of CML incidence: disagreement between national cancer registry and health claims data system in Taiwan. PMID- 21255837 TI - Whole-body and body-part-specific bioconcentration of explosive compounds in sheepshead minnows. AB - Sheepshead minnows (Cyprinodon variegatus) were exposed to radiolabeled isotopes of the explosives 2,4,6-trinitrotoluene (TNT), exahydro-1,3,5-trinitro-1,3,5 triazine (commonly known as RDX), and octahydro-1,3,5,7-tetranitro-1,3,5,7 tetrazocine (commonly known as HMX), yielding the bioconcentration factors (BCF) of 3.3, 0.7, and 0.1 L kg(-1), respectively. For TNT, the body residue of transformation product exceeded that of the parent compound by factors of 1, 8, and 16 for total aminonitrotoluenes, total extractable compounds, and total transformation products, respectively, with substantial bioaccumulation of both non-identified extractable and unextractable (i.e., tissue-bound), compounds. In comparison, the sum body residues of RDX and HMX transformation products were <4 times higher than for parent compounds. The concentrations of RDX and HMX and their transformation products were similar among liver, viscera (excluding liver), gills, and body remains (integument and muscles), while 46% of the TNT transformation products resided in the liver, and 64% of the parent compound was in the viscera. PMID- 21255838 TI - Using Pb-Al ratios to discriminate between internal and external deposition of Pb in feathers. AB - Feathers provide a potentially useful biomonitoring option in studies regarding pollution exposure in avian species. However, they must be used with care because the complex, fine structure is highly prone to accumulating surface contamination. This may therefore give a misleading indication of pollutant intake in the animal. Here, data are presented for 4 large scavenging raptor species collected in Spain, and analyses are undertaken on feather barbs and rachis for both Pb and Al concentrations. Aluminium levels are used as a marker of surface contamination by inorganic particulate material. Despite using a thorough washing technique, feather barbs showed significantly higher levels of Pb than did the rachis for all 4 species studied. We also observed a significant correlation (r=0.782, p<0.001) between Al and Pb levels in the barbs, whilst rachis Al levels were below our detection limit in all samples analysed. Results indicate that the rachis would provide more representative data as regards Pb (or other heavy metal) uptake and tissue deposition within bird tissues during the period of feather growth. As such, data would be more toxicologically relevant. PMID- 21255836 TI - Coexistence of meningeal infiltration and multiple lymphadenopathy as the initial presentation of de novo adult acute megakaryoblastic leukemia. PMID- 21255839 TI - Molecular identification and characterization of Mycobacterium avium subspecies paratuberculosis in free living non-human primate (Rhesus macaques) from North India. AB - In recent years, Mycobacterium avium subspecies paratuberculosis (MAP) has emerged as major animal pathogen with significant zoonotic concerns, worldwide. MAP infection is endemic in domestic and wild ruminant population in India. However, information on MAP infection in free ranging animal species and non human primates is limited. Present study aimed to estimate the status of MAP infection in free living Rhesus macaques suffering with multiple clinical conditions (coughing and loose stool). A total of 25 stool samples were collected from six colonies of Rhesus macaques from Mathura region (North India) and screened for the presence of MAP, using microscopic examination and IS900 PCR, directly from stool samples. PCR positive DNA samples were further genotyped using IS1311 PCR-restriction enzyme analysis. Of the 25 stool samples, 10 (40.0%) and 2 (8.0%) were positive for MAP using microscopic examination and direct IS900 PCR, respectively. IS900 PCR positive DNA samples were genotyped as 'Indian Bison type', which is a major MAP genotype infecting domestic and wild ruminant species and human beings in India. Prevalence of MAP in Rhesus macaques (Indian monkeys) was moderately high and confirmed interspecies sharing of MAP between domestic livestock and non-human primates. Presence of MAP in non-human primates, support the etiological role of MAP in inflammatory bowel disease patients. Indian monkeys may serve as model for understanding the role of non-human primates in sustenance, transmission and pathogenesis of MAP infection. PMID- 21255840 TI - Late onset of leucoencephalopathy with cerebral calcifications and cysts. PMID- 21255841 TI - Mechanical thrombectomy with the Penumbra recanalization device in acute ischemic stroke. AB - BACKGROUND AND PURPOSE: The aim of this study was to assess the clinical outcome of patients treated with the Penumbra system (PS) for acute ischemic stroke. A retrospective, monocentric matched-pair analysis in comparison with patients treated by intraarterial thrombolysis (IAT) with alteplase was designed for this purpose. METHODS: Twenty-two consecutive patients, (mean age 62), with acute ischemic stroke and National Institutes of Health Stroke Scale (NIHSS) scores >= 7 were treated with the PS. Twenty corresponding patients could be identified, treated with IAT. Matches were sought for initial NIHSS score and target vessels. Thrombolysis in myocardial infarction (TIMI) grades, mortality rates, NIHSS upon discharge, and modified Rankin scores (mRs) at 90 days were compared. RESULTS: A total of 32 vessels in 20 patients were treated in either arm of the study. Recanalization to TIMI 2/3 was successful in 25/32 (78%) of target vessels with the PS, and 17/32 (53%) of target vessels in the IAT group. Upon discharge, 2/20 patients treated with PS and 7/20 patients treated with IAT had a NIHSS score of 0 to 1 or an improvement greater or equal to 10-point on the NIHSS scale. All cause mortality at 90 days was 3/20 patients treated with PS, and 2/20 patients treated with IAT. Three out of twenty patients treated with PS and 7/20 patients treated with IAT had a mRS of <= 2 at 90 days. CONCLUSION: The Penumbra system is effective in re-opening occluded major arteries. Our data seems to indicate that not all patients benefit clinically from improved revascularization of occluded major arteries. PMID- 21255842 TI - Hypoglossal artery associated with homolateral internal carotid artery dissection. PMID- 21255843 TI - Dietary exposure of PBDEs resulting from a subsistence diet in three First Nation communities in the James Bay Region of Canada. AB - BACKGROUND: Concerns regarding the persistence, bioaccumulation, long-range transport, and adverse health effects of polybrominated dipheyl ethers (PBDEs) have recently come to light. PBDEs may potentially be of concern to indigenous (First Nations) people of Canada who subsist on traditional foods, but there is a paucity of information on this topic. OBJECTIVES AND METHODS: To investigate whether the traditional diet is a major source of PBDEs in sub-Arctic First Nations populations of the Hudson Bay Lowlands (James and Hudson Bay),Ontario, Canada, a variety of tissues from wild game and fish were analyzed for PBDE content (n=147) and dietary exposure assessed and compared to the US EPA reference doses (RfDs). In addition, to examine the effect of isolation/industrialization on PBDE body burdens, the blood plasma from three First Nations (Cree Nation of Ouje-Bougoumou, Quebec; Fort Albany First Nation, Ontario; and Weenusk First Nation [Peawanuck], Ontario, Canada) were collected (n=54) and analyzed using a log-linear contingency model. RESULTS AND CONCLUSIONS: The mean values of PBDEs in wild meats and fish adjusted for standard consumption values and body weight, did not exceed the US EPA RfD. Log linear modeling of the human PBDE body burden showed that PBDE body burden increases as access to manufactured goods increases. Thus, household dust from material goods containing PBDEs is likely responsible for the human exposure; the traditional First Nations diet appears to be a minor source of PBDEs. PMID- 21255844 TI - Lingual antimicrobial peptide and IL-8 expression are oppositely regulated by the antagonistic effects of NF-kappaB p65 and C/EBPbeta in mammary epithelial cells. AB - Pathogen contact induces quickly in Mammary Epithelial Cells (MEC) the expression of the proinflammatory cytokine IL-8 and delayed that of the bactericidal beta defensin LAP. Both genes encoding these factors feature on their proximal promoter a composite NF-kappaB/CEBP binding site. We compare here in MEC the role of NF-kappaB and C/EBP factors in regulating basal and pathogen-induced expression of both genes from cattle. Abrogating NF-kappaB binding to that site by introduction of a single point mutation blocks promoter activity of both genes in reporter gene assays. Chromatin accessibility PCR and Chromatin immunoprecipitation reveal that the chromatin of the resting LAP promoter is tightly packed and NF-kappaB p50 homodimer binding prevails. Infection results in chromatin decompaction accompanied by predominant recruitment of NF-kappaB p65 for promoter activation. Overexpression of transcription factors confirms a stimulatory role of NF-kappaB p65 but also a repressive function of C/EBPbeta for LAP promoter activity. These factors reverse roles to control IL-8 expression. NF kappaB p65 homodimers already reside on the resting IL-8 promoter and induction recruits NF-kappaB p50. Overexpression of both NF-kappaB factors represses the promoter in MEC, but not in HEK293 cells. Inhibitors of NF-kappaB activation and nuclear recruitment both tremendously increase basal and pathogen stimulated IL-8 mRNA concentrations in MEC. Mutation of the C/EBP-binding site blocks and overexpression of C/EBPbeta stimulates IL-8-promoter activity. Thus, the pathogen induced fast activation of diverse transcription factors acting through a common promoter binding site is gene specifically differentiated into opposite functional significance for swiftly (IL-8) or slowly (LAP) induced genes in MEC. PMID- 21255845 TI - Acoustic parameters of infant-directed singing in mothers with depressive symptoms. AB - The purpose of this study was to explore the relationship between mothers' depressive symptoms and the acoustic parameters of infant-directed (ID) singing. Participants included 80 mothers and their 3- to 9-month-old infants. A digital recording was made of each mother's voice while singing to her infant. Extraction and analyses of vocal data revealed a main effect of tempo, meaning that as mothers reported more depressive symptoms, they tended to sing faster to their infants. Additionally, an interaction effect indicated that mothers with depressive symptoms were more likely to sing with tonal key clarity to their male infants. These findings suggest that as mothers experience depressive symptoms, their ID singing may lack the sensitivity and emotional expression that infants need for affect regulation. An intervention that combines interaction coaching and ID singing may help mothers with depressive symptoms to engage in sensitive and emotionally synchronized interactions with their infants. PMID- 21255846 TI - Cytokine signalling in mammary gland development. AB - Mammary gland development occurs in three distinct stages during the lifetime of the female mammal: in embryonic, pubertal and reproductive life. At each of these developmental stages, different signalling molecules induce changes in both the epithelium and the surrounding stroma. However, it is during pregnancy that the most dramatic changes occur, resulting in a massive increase in the number of epithelial cells and in their function. Pregnancy initiates the development of a new epithelial lineage, the alveolar cells, which form the milk-producing lobuloalveolar structures. These cells become redundant at the end of lactation and are removed in an exquisitely controlled process of tissue remodelling coupled with extensive cell death. All of these events require not only steroid hormones but also sequential signalling by cytokines. A recent surprising discovery was that the signalling pathways and cytokines that regulate lineage determination in T helper cells are also involved in mammary gland development during pregnancy. PMID- 21255847 TI - Effects of inactivated parapoxvirus ovis on the cumulative incidence of pneumonia and cytokine secretion in foals on a farm with endemic infections caused by Rhodococcus equi. AB - The objectives of the present study were to determine if administration of inactivated parapoxvirus ovis (IPPVO) can decrease the cumulative incidence of pneumonia and increase the number of IFN-gamma- and IL-4-secreting cells among foals. Fifty-nine foals were randomly assigned to 2 treatment groups (IPPVO or placebo) prior to birth. At 24-48 h of age, foals received 2 ml of either IPPVO or a placebo by intramuscular injection. Injections were repeated 24h and 8 days later. The number of IFN-gamma- and IL-4-secreting cells was measured using a validated ELISPOT assay on blood mononuclear cells collected when the foals were 1-14 days old. Foals were monitored daily for clinical signs of pneumonia and biweekly for lung lesions by ultrasonography. The proportion of foals that developed clinical or ultrasonographic evidence of pneumonia was not significantly different between IPPVO (16 of 28) and placebo (14 of 31). IFN gamma- and IL-4-secreting cells were detected in only 22 and 15 foals, respectively. There was a significant effect of treatment with IPPVO on the number of IFN-gamma secreting cells in foals 7- to 14-days-old but not in younger foals. There was no significant effect of treatment with IPPVO on the number of IL-4-secreting cells. The odds of detecting IFN-gamma (5.1; 95% CI: 1.5-15) and IL-4 (3.5; 95% CI: 1.1-12) were significantly higher in foals 7-14 days than in younger foals regardless of treatment group. There was no significant association between IFN-gamma or IL-4 secretion early in life and subsequent development of pneumonia. PMID- 21255848 TI - Prognostic value of NT-pro BNP, left ventricular inotropic reserve and cardiopulmonary exercise test in patients with non-ischemic dilated cardiomyopathy. PMID- 21255849 TI - Epicardial adipose tissue is an independent predictor of coronary atherosclerotic burden. AB - INTRODUCTION: Epicardial adipose tissue (EAT) may play an active role in the development of coronary artery disease (CAD). The aim of this work was to study the relations between EAT, abdominal visceral fat (AVF), and coronary atherosclerotic burden as assessed by multislice computed tomography (MSCT). POPULATION AND METHODS: Two hundred fifteen patients without known CAD referred to 64-SCT during a 6-months period were included. All patients underwent a standardized protocol including quantification of AVF, EAT, coronary artery calcification (CAC), and coronary angiography by MSCT. RESULTS: Two hundred fifteen patients, with mean age of 58 +/- 11 years, in which 61% were males, with mean body mass index (BMI) of 28 +/- 4 kg/m(2) were included. EAT volume was directly associated with male sex, age, BMI, abdominal circumference, AVF, number of coronary segments with atherosclerotic plaques (p<0.01 for all), number of segments with significant stenoses, and presence of metabolic syndrome components (p<0.05). CAC increased by 14.7% per additional 10 ml of EAT volume. Adjusting for age, gender, and AVF changed this increase to 7.5%. After adjusting for all considered confounders, there was still an independent association, with a CAC increase of 3.7% per additional 10 ml of EAT. A significant interaction was found between EAT volume and gender and between EAT volume and obesity: an increase of EAT was associated with an increase of additional 8% of CAC in men, and additional increase of 5% in non-obese individuals (p<0.001 for both). CONCLUSION: EAT volume positively relates to coronary atherosclerotic burden, as assessed by CAC; this correlation was shown to be independent of AVF. PMID- 21255850 TI - Comparison of different body habitus between patients with mitral valve prolapse and normal populations in young Taiwanese females. PMID- 21255851 TI - E2-BSA activates caveolin-1 via PI3K/ERK1/2 and lysosomal degradation pathway and contributes to EPC proliferation. AB - BACKGROUND: The mechanism that estrogen (E(2)) increases the number of endothelial progenitor cells (EPC) is largely unknown. Here we used E(2) conjugated bovine serum albumin (E(2)-BSA, membrane impermeable) to investigate whether the membrane estrogen receptor (mER) and its related protein caveolin-1 (CAV-1) are involved in these processes. METHODS AND RESULTS: E(2)-BSA promoted [(3)H]-thymidine incorporation of EPC through increasing CAV-1 expression via mER (ERalpha, but not ERbeta or GPR30). Both cholesterol depletion and CAV-1 knockdown with use of CAV-1 siRNA significantly attenuated E(2)-BSA-induced [(3)H]-thymidine incorporation. Western blot showed that E(2)-BSA increased membrane CAV-1 protein expression 12h after treatment, whereas mRNA levels of CAV 1 were augmented until 24h after E(2)-BSA treatment. Furthermore, pre-incubated EPC with ICI 182780 (a specific ER antagonist), LY 294002 (a selective PI(3)K inhibitor) or PD 98059 (a specific ERK1/2 inhibitor) before E(2)-BSA inhibited the late-stage effect of E(2)-BSA (>=24 h) on up-regulation of CAV-1 mRNA and protein expression. Pulse chase results demonstrated that E(2)-BSA inhibited lysosome-mediated degradation of CAV-1 protein at the early stage (<=12 h), and then resulted in the increased CAV-1 protein. CONCLUSION: In the present work we demonstrated that E(2)-BSA promotes EPC proliferation through mER (ERalpha) in CAV-1-dependent manner: prolonging the stability of CAV-1 protein through quick inhibition of the lysosomal degradation pathway at the early stage (<=12 h) and up-regulating CAV-1 at transcription levels through PI(3)K/ERK1/2 signaling pathway at the late stage (>=24 h). These data indicated that a there is a novel mechanism of E(2)-BSA in the regulation of EPC proliferation through CAV-1. PMID- 21255852 TI - CA-125 and heart failure: Deja vu continues. PMID- 21255853 TI - Osteoprotegerin is associated with markers of atherosclerosis and body fat mass in type 2 diabetes patients. PMID- 21255854 TI - New developments in dry powder pulmonary vaccine delivery. AB - Pulmonary immunization has gained increased recognition as a means of triggering both a mucosal and systemic immune response without the use of needles. The appropriate formulation of antigens in a dry, solid state can result in improved stability, thereby removing cold-chain storage complications associated with conventional liquid-based vaccines. The particulate nature of dry powder vaccines could also induce a better immune response. This review describes our current understanding of pulmonary immunization, including possible barriers facing the development of pulmonary vaccines, and discusses recent advances in spray-drying technologies applicable to the production of dry powder formulations for pulmonary vaccine delivery. PMID- 21255855 TI - High-throughput process development for biopharmaceutical drug substances. AB - Quality by Design (QbD) is gaining industry acceptance as an approach towards development and commercialization of biotechnology therapeutic products that are expressed via microbial or mammalian cell lines. In QbD, the process is designed and controlled to deliver specified quality attributes consistently. To acquire the enhanced understanding that is necessary to achieve the above, however, requires more extensive experimentation to establish the design space for the process and the product. With biotechnology companies operating under ever increasing pressure towards lowering the cost of manufacturing, the use of high throughput tools has emerged as a necessary enabler of QbD in a time- and resource-constrained environment. We review this topic for those in academia and industry that are engaged in drug substance process development. PMID- 21255856 TI - Energy expenditure and enjoyment of small-sided soccer games in overweight boys. AB - When space is limited, it would be preferable to play multiple small-sided soccer games (SSG) simultaneously on small courts, rather than a single game, to maximise participation. Given that the layouts of most gymnasiums incorporate several badminton courts, we examined whether energy expenditure and enjoyment of SSG on a badminton court (6.1*13.4 m) were comparable to larger court dimensions (volleyball and basketball courts; 9*18 m and 14.2*26.5 m, respectively). Twelve overweight boys played 30 min three-a-side SSG on each court in a counterbalanced design. During SSG, energy expenditure was estimated via accelerometry, heart rate was monitored and ratings of perceived exertion (RPE) and enjoyment were obtained. Energy expenditure was similar between badminton and volleyball courts, but lower than the basketball court (p<.05). Mean% HR(max) was significantly lower on the badminton court than the volleyball and basketball courts (p<.05). There was no effect of court size on RPE or enjoyment (p>.05). These results suggest that it may be preferable to play SSG on a larger court when space is available. Alternatively, when space is limited the difference in energy expenditure between court sizes can be accounted for by an additional 2.3 min of play on a badminton court. PMID- 21255857 TI - Simplification of a complex microbial antilisterial consortium to evaluate the contribution of its flora in uncooked pressed cheese. AB - A complex microbial consortium derived from raw milk and composed of populations classified in 4 groups (lactic acid bacteria (A), Gram positive catalase positive bacteria (B), Gram negative bacteria (C) and yeasts (D)) can contribute to the inhibition of Listeria monocytogenes in the core of an uncooked pressed cheese. To identify what groups may be involved in the inhibition, the consortium was simplified by successively omitting one group at a time. Pasteurized milk was inoculated with these more or less complex consortia and their effects on L. monocytogenes count, pH, acids and volatile compounds in the core of uncooked pressed cheese were evaluated. The growth of L. monocytogenes was the highest in cheeses prepared with pasteurized milk and only St. thermophilus. Inhibition in other cheeses was expressed by comparison with growth in these ones. All the consortia containing both lactic acid bacteria (group A) and Gram positive catalase positive bacteria (group B)--ABCD, ABD, ABC, AB--were more inhibitory than those containing lactic acid bacteria on its own (A) or associated only with yeasts (AD) or/and Gram negative (ADC). Consortia without lactic acid bacteria were weakly inhibitory or had no effect. Gram positive catalase positive bacteria alone were not inhibitory although most of the species became established in the cheeses. The Lactobacillus population (Lb. casei, Lb. plantarum, Lb. curvatus and Lb. farciminis) was predominant in cheeses (9 log CFU/g) with a higher count than Leuconostoc (7 log CFU/g) and Enterococcus (7 log CFU/g). Lactobacillus counts were negatively correlated with those of L. monocytogenes (r=-0.84 at 18 days) and with the level of D-lactic acid. There was no correlation between L. monocytogenes and Leuconostoc or Enterococcus counts. Complex consortium ABCD and AB not only had a stronger inhibitory power in cheeses than consortium AD, they were also associated with the highest levels of L-lactic and acetic acids. All cheeses inoculated with lactic acid bacteria differed from those without by higher levels of ethyl formiate, pentane and alcohols (2-butanol, 2-pentanol), and lower levels of ketones (2-hexanone, 2,3-butanedione) and aldehydes (2-methyl butanal). Levels of 2-methyl-butanal, 2-butanol and 2-pentanol were higher in ABCD and AB cheeses than in AD cheeses. Beside their contribution to the inhibition, their effect on cheese flavour must be evaluated. PMID- 21255858 TI - Association of eNOS gene polymorphisms with renal disease in Caucasians with type 2 diabetes. AB - AIM: In this study we investigated if the -786T>C, the VNTR intron 4 a/b and the 894G>T (Glu298Asp) polymorphisms in the eNOS gene were associated with renal disease in 617 type 2 diabetic Caucasian-Brazilians. These polymorphisms were also examined in 100 Caucasian healthy blood donors. METHODS: Genotyping of eNOS polymorphisms was performed by PCR or PCR-RFLP and haplotype frequencies were estimated using a Bayesian method. Logistic regression analysis was done to test for association of eNOS polymorphisms with susceptibility to renal involvement (microalbuminuria, macroalbuminuria or end-stage renal disease). This analysis was carried out assuming three different genetic models for the minor allele, adjusting for possible effect modifiers. RESULTS: Genotype and allele frequencies in patients with renal disease were not significantly different from those of patients with normoalbuminuria and healthy blood donors for all eNOS polymorphisms. Likewise, there were no differences in haplotype frequencies among healthy blood donors and type 2 diabetic patients with or without renal involvement (P>0.05 for all comparisons). CONCLUSION: No associations between the -786T>C, the VNTR intron 4 a/b and the 894G>T (Glu298Asp) polymorphisms in the eNOS gene and renal disease were observed in type 2 diabetic Caucasian Brazilians. PMID- 21255859 TI - The redistributive effect of the move from age-based to income-based prescription drug coverage in British Columbia, Canada. AB - OBJECTIVES: To explore the redistributive impact of two different pharmaceutical financing policies (age-based versus income-based pharmacare) on the distribution of income in British Columbia (B.C.), Canada. METHODS: Using household-level data on all payments that are used to finance prescription drugs in B.C. (including taxation and private payments), we performed a redistributive analysis to indicate how much income inequality in the province changed as a result of payments made for prescription drugs. We also illustrated changes in vertical equity (different treatment according to ability-to-pay) and horizontal equity (equals, according to ability-to-pay, being treated equally) between the two years separately through a pre-post policy examination. RESULTS: We found that payments made to finance prescription drugs increased overall income inequality in the province. This negative impact was larger after the move to income-based pharmacare. Our results also show increasing horizontal inequity after the policy change, and suggest that the increased reliance on out-of-pocket payments was a major source of the negative impact on the B.C.'s overall income distribution. We also show that the consequences of the move to income-based pharmacare would have been less severe had the level of public financing not decreased substantially between the two years. CONCLUSIONS: The increase in income inequality in B.C. following the policy change was an unintended consequence of the move to income based pharmacare. This finding is worth consideration as countries and jurisdictions weigh pharmaceutical policy alternatives. PMID- 21255860 TI - Supporting adaptive clinical treatment processes through recommendations. AB - OBJECTIVES: Efficient clinical treatment processes is considered a key factor of medical quality control. Current IT solutions are far away from this perspective since they typically have difficulty supporting the variances occurring in clinical practices, and providing adequate flexible support of clinical processes. METHODS: This paper proposes a hybrid approach based on rough set theory and case-based reasoning to allow physicians to rapidly adjust patients' treatment processes to changes of patients' clinical states. In detail, the proposed approach recommends appropriate treatment plans in clinical process execution by adopting a similarity measure to select appropriate clinical treatment plans executed on patients who presented similar features to the current one. Such clinical treatment plans are then applied to suggest which actions to perform next in clinical treatment process execution. RESULTS: As a motivating scenario, this study performs the experiments of type 2 diabetes patient's treatment process. The results show that the proposed approach is feasible to recommend suitable clinical treatment plans in clinical process execution, which makes adaptive clinical treatment processes possible. PMID- 21255861 TI - Long term cardiovascular risk models' combination. AB - The correct diagnosis of cardiovascular disease is a key factor to reduce social and economic costs. In this context, cardiovascular disease risk assessment tools are of fundamental importance. This work addresses two major drawbacks of the current cardiovascular risk score systems: reduced number of risk factors considered by each individual tool and the inability of these tools to deal with incomplete information. To achieve these goals a two phase strategy was followed. In the first phase, a common representation procedure, based on a Naive-Bayes classifier methodology, was applied to a set of current risk assessment tools. Classifiers' individual parameters and conditional probabilities were initially evaluated through a frequency estimation method. In a second phase, a combination scheme was proposed exploiting the particular features of Bayes probabilistic reasoning, followed by conditional probabilities optimization based on a genetic algorithm approach. This strategy was applied to describe and combine ASSIGN and Framingham models. Validation results were obtained based on individual models, assuming their statistical correctness. The achieved results are very promising, showing the potential of the strategy to accomplish the desired goals. PMID- 21255862 TI - Natural history collections as sources of long-term datasets. AB - In the otherwise excellent special issue of Trends in Ecology and Evolution on long-term ecological research (TREE 25(10), 2010), none of the contributors mentioned the importance of natural history collections (NHCs) as sources of data that can strongly complement past and ongoing survey data. Whereas very few field surveys have operated for more than a few decades, NHCs, conserved in museums and other institutions, comprise samples of the Earth's biota typically extending back well into the nineteenth century and, in some cases, before this time. They therefore span the period of accelerated anthropogenic habitat destruction, climate warming and ocean acidification, in many cases reflecting baseline conditions before the major impact of these factors. PMID- 21255863 TI - Activity modulation of the bacterial Rho GAP YopE: an inspiration for the investigation of mammalian Rho GAPs. AB - The Yersinia enterocolitica Rho GTPase Activating Protein (Rho GAP) YopE belongs to a group of bacterial virulence factors that is translocated into infected target cells by a type three secretion system. Structurally and biochemically YopE resembles eukaryotic Rho GAPs which control various cellular functions by modulating the activity of Rho GTP binding proteins. Here we summarise the published information on cellular effects, Rho protein substrates, compartmentalisation and turnover of YopE. A fascinating picture evolves of how this virulence factor integrates in host cellular regulatory mechanisms to fine tune bacterial pathogenicity. PMID- 21255865 TI - Photosystem I: its biogenesis and function in higher plants. AB - Photosystem I (PSI), the plastocyanin-ferredoxin oxidoreductase of the photosynthetic electron transport chain, is one of the largest bioenergetic complexes known. It is composed of subunits encoded in both the chloroplast genome and the nuclear genome and thus, its assembly requires an intricate coordination of gene expression and intensive communication between the two compartments. In this review, we first briefly describe PSI structure and then focus on recent findings on the role of the two small chloroplast genome-encoded subunits PsaI and PsaJ in the stability and function of PSI in higher plants. We then address the sequence of PSI biogenesis, discuss the role of auxiliary proteins involved in cofactor insertion into the PSI apoproteins and in the establishment of protein-protein interactions during subunit assembly. Finally, we consider potential limiting steps of PSI biogenesis, and how they may contribute to the control of PSI accumulation. PMID- 21255864 TI - Yersinia enterocolitica outer protein T (YopT). AB - Pathogenic Yersinia strains evade the innate immune responses of the host by producing effector proteins (Yersinia outer proteins (Yops)), which are directly injected into mammalian cells by a type III secretion system (TTSS). One of these effector proteins (YopT) disrupts the actin cytoskeleton of the host cell. YopT is a cysteine protease which cleaves Rho proteins directly upstream of the post translationally modified cysteine. Thereby, it releases the GTPases from the membrane leading to their inactivation. Besides a biochemical characterisation of the molecular mechanism and substrate specificity also delivery into host cells with chaperone binding and guidance to the injection apparatus and the patho physiological role of YopT have been studied and are summarised in this review. PMID- 21255866 TI - [Bilateral retinal detachment in Hallermann-Streiff-Francois syndrome: a case report]. AB - We report the case of a patient with Hallermann-Streiff-Francois syndrome, with typical presentation of white bilateral cataract. The surgical treatment showed morphological retinal abnormalities, which resulted in an exudative retinal detachment. This case underscores the importance of paying special attention during surgical treatment of cataract in this type of patient. PMID- 21255867 TI - [Fusobacterium nucleatum isolated from a patient presenting lachrymal canaliculitis]. AB - A 68-year-old woman presented with a painless inflammation of the right superior eyelid that had started several weeks before. The clinical diagnosis concluded in canaliculitis and the solid concretions were surgically extracted from the superior canalicula. The anaerobic bacteria Fusobacterium nucleatum sp. nucleatum was isolated. Signs dramatically regressed two weeks after surgery followed by one course of oral amoxicillin and clavulanic acid associated with topical tobramycin. The clinical signs had disappeared two months later. PMID- 21255868 TI - A new American Joint Committee on Cancer staging system for cutaneous squamous cell carcinoma: creation and rationale for inclusion of tumor (T) characteristics. AB - BACKGROUND: The incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. Although most patients achieve complete remission with surgical treatment, those with advanced disease have a poor prognosis. The American Joint Committee on Cancer (AJCC) is responsible for the staging criteria for all cancers. For the past 20 years, the AJCC cancer staging manual has grouped all nonmelanoma skin cancers, including cSCC, together for the purposes of staging. However, based on new evidence, the AJCC has determined that cSCC should have a separate staging system in the 7th edition AJCC staging manual. OBJECTIVE: We sought to present the rationale for and characteristics of the new AJCC staging system specific to cSCC tumor characteristics (T). METHODS: The Nonmelanoma Skin Cancer Task Force of AJCC reviewed relevant data and reached expert consensus in creating the 7th edition AJCC staging system for cSCC. Emphasis was placed on prospectively accumulated data and multivariate analyses. Concordance with head and neck cancer staging system was also achieved. RESULTS: A new AJCC cSCC T classification is presented. The T classification is determined by tumor diameter, invasion into cranial bone, and high-risk features, including anatomic location, tumor thickness and level, differentiation, and perineural invasion. LIMITATIONS: The data available for analysis are still suboptimal, with limited prospective outcomes trials and few multivariate analyses. CONCLUSIONS: The new AJCC staging system for cSCC incorporates tumor-specific (T) staging features and will encourage coordinated, consistent collection of data that will be the basis of improved prognostic systems in the future. PMID- 21255869 TI - Nonablative 1550-nm fractional laser therapy versus triple topical therapy for the treatment of melasma: a randomized controlled pilot study. AB - BACKGROUND: Various treatments are currently available for melasma. However, results are often disappointing. OBJECTIVE: We sought to assess the efficacy and safety of nonablative 1550-nm fractional laser therapy and compare results with those obtained with triple topical therapy (the gold standard). METHODS: Twenty female patients with moderate to severe melasma and Fitzpatrick skin types II to V were treated either with nonablative fractional laser therapy or triple topical therapy (hydroquinone 5%, tretinoin 0.05%, and triamcinolone acetonide 0.1% cream) once daily for 8 weeks in a randomized controlled observer-blinded study. Laser treatment was performed every 2 weeks for a total of 4 times. Physician Global Assessment was assessed at 3 weeks, 3 months, and 6 months after the last treatment. RESULTS: Physician Global Assessment improved (P < .001) in both groups at 3 weeks. There was no difference in Physician Global Assessment between the two groups. Mean treatment satisfaction and recommendation were significantly higher in the laser group at 3 weeks (P < .05). However, melasma recurred in 5 patients in both groups after 6 months. Side effects in the laser group were erythema, burning sensation, facial edema, and pain; in the triple group side effects were erythema, burning, and scaling. LIMITATIONS: Limitations were: small number of patients; only one set of laser parameters; and a possible difference in motivation between groups. CONCLUSIONS: Nonablative fractional laser therapy is safe and comparable in efficacy and recurrence rate with triple topical therapy. It may be a useful alternative treatment option for melasma when topical bleaching is ineffective or not tolerated. Different laser settings and long-term maintenance treatment should be tested in future studies. PMID- 21255870 TI - Clinical and histologic features of incontinentia pigmenti in adults with nuclear factor-kappaB essential modulator gene mutations. AB - BACKGROUND: Incontinentia pigmenti (IP) is a multisystem disorder, in which cutaneous symptoms can be accompanied by dental, ocular, and central nervous system defects. In adults, the clinical diagnosis of IP is based principally on the late onset of stage 4 lesions and their association with dental, nail, ocular, or central nervous system anomalies. Nevertheless, these lesions are often unrecognized. OBJECTIVES: Our aim was assessment of IP manifestations in adults to clarify diagnostic criteria for mild forms of the disease, to help physicians detect adult IP in the presence of subtle lesions and avoid misdiagnosis. METHOD: We conducted clinical and histologic examination of 25 adults with IP and nuclear factor-kappaB essential modulator gene rearrangement or mutations. RESULTS: Linear atrophic, hypopigmented, and hairless lesions (stage 4) are constant in adults. Apoptotic keratinocytes in the epidermis or dermis and atrophic hair follicles, with absence of arrector pili muscles, are frequently observed. In contrast, nipple anomalies are rare. LIMITATIONS: We were unable to determine the age of the onset of IP stage 4 lesions. CONCLUSION: Skin manifestations are constant in adult patients with IP. Histology is characteristic and could be considered as a minor diagnostic criterion of IP. Nipple anomalies also may be considered as a minor criterion. Detection of such subtle manifestations can evoke IP in patients with repeated miscarriages or unexplained neurologic manifestations. PMID- 21255871 TI - Patients with drug-eluting stents and management of their anticoagulant therapy in cutaneous surgery. AB - Whether a patient has a drug-eluting stent (DES) implanted may not seem to be an immediate concern for a dermatologist. However, the clinician needs to consider a patient's risk of bleeding if a patient is to undergo a cutaneous surgical procedure. Patients with skin cancer are generally older with a higher risk of comorbidities such as cardiovascular disease with history of cardiac stent implantation. After DES placement, patients are typically on long-term dual antiplatelet therapy, which increases the risk of bleeding. However, stopping antiplatelet therapy prematurely can lead to serious thrombotic complications. Thus, when performing a dermatologic procedure in a patient with a DES, the physician must weigh the risks of bleeding complications with continuing antiplatelet therapy against the risk of thrombotic complications associated with stopping antiplatelet therapy. The aim of this review is to identify the issues for the dermatologist and the dermatologic surgeon surrounding the perioperative treatment of patients with a DES and to discuss the treatment of patients with an implanted DES. PMID- 21255872 TI - Pediatric "STUMP" lesions: evaluation and management of difficult atypical Spitzoid lesions in children. AB - Spitz nevi represent a distinct type of melanocytic nevi more commonly seen in childhood. Although typically benign, a subset of Spitz lesions raise concern and create a diagnostic dilemma as a result of confusing histology that involves characteristics of classic Spitz nevi intermixed with features of cutaneous melanoma. Such atypical Spitz lesions, or Spitzoid tumors of uncertain malignant potential, are difficult to classify and their biologic potential is uncertain. Nonetheless, these are critical tasks for both prognosis and clinical management. New tools, such as immunohistochemical stains, comparative genomic hybridization, and fluorescence in situ hybridization, have been used to provide further insight into these controversial lesions and to aid in their evaluation. In this review, we present our experience managing 6 cases of Spitzoid tumor of uncertain malignant potential and discuss the potential use of various diagnostic modalities, including sentinel lymph node biopsy, immunostaining, and molecular analysis. PMID- 21255873 TI - Surveillance Provinciale des Infections Nosocomiales (SPIN) Program: implementation of a mandatory surveillance program for central line-associated bloodstream infections. AB - BACKGROUND: In 2003, the Surveillance Provinciale des Infections Nosocomiales (SPIN) program was launched to gather data on incidence rates of central line associated bloodstream infections (CLABSIs) in intensive care units (ICUs) in the Province of Quebec. To improve the generalizability of SPIN benchmarks, in 2007 participation in SPIN became mandatory for all ICUs with >=10 beds. OBJECTIVE: To describe the implementation process, surveillance methods, and overall results of the SPIN program between 2003 and 2009. METHODS: SPIN surveillance methods are based on the National Healthcare Safety Network. Participation is open to all Quebec ICUs and as of January 2007 is mandatory for all units with >=10 beds. Data include CLABSI incidence rates for 2003-2009 and the epidemiology of CLABSI cases. RESULTS: Mandatory participation in the SPIN program increased the number of ICUs by 100% (from 30 to 60 units). For 2003-2009, the overall CLABSI incidence rates were 1.67 CLABSIs/1,000 catheter-days for adult ICUs, 2.24 CLABSIs/1,000 catheter-days for pediatric ICUs, and 4.40 CLABSIs/1,000 catheter days for neonatal ICUs. The patients with CLABSI were predominately female (60%), mean patient age was 44 +/- 32 years, and 64% of the patients had a regular central venous line in place. CONCLUSION: The implementation of mandatory participation was essential to increase the generalizability of SPIN CLABSI incidence rates, which also improved the quality of these data for use as provincial benchmarks. PMID- 21255874 TI - A method for evaluating health care workers' personal protective equipment technique. AB - BACKGROUND: Given the potential for the transfer of infectious diseases among patients in isolation, health care workers (HCWs), and other patients in the hospital environment, the proper use of personal protective equipment (PPE) is paramount. The literature is limited regarding studies of HCWs' use of PPE in patient care tasks. METHODS: A pilot study was conducted to examine the feasibility of using a simulated health care environment to assess HCWs' technique when implementing standard airborne and contact isolation precautions. The participants (n = 10) were assigned patient care tasks based on their specific professional roles. The encounters were digitally recorded during donning and doffing of PPE, as well as during interactions with the simulated patient. Powdered fluorescent marker was used as a measure of contamination. RESULTS: The pilot data show various inconsistencies in the HCWs' PPE technique. Each of the 10 participants committed at least one breach of standard airborne and contact isolation precautions. CONCLUSION: An expanded research study of HCW behaviors is needed to properly examine these contamination and exposure pathways. Training programs should be developed that emphasize the common errors in HCWs' PPE technique. PMID- 21255875 TI - Investigating the impact of the definition of previous antibiotic exposure related to isolation of extended spectrum beta-lactamase-producing Klebsiella pneumoniae. AB - BACKGROUND: Previous antibiotic exposure is a risk factor for extended spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae isolation, but the optimal definition of previous antibiotic exposure remains unclear. METHODS: This was a retrospective, case-control study comparing 88 patients with ESBL-producing K pneumoniae (cases) and 88 patients with non-ESBL-producing K pneumoniae (controls). Three previous antibiotic exposure definitions were analyzed, including durations of 30, 60, and 90 days prior to organism isolation. RESULTS: The mean cohort age was 63.6 +/- 16.9 years, 43% were male, and 86% were black. In bivariate analysis, third-generation cephalosporins and cefepime were associated with ESBL-producing K pneumoniae isolation, and the odds ratios (OR) were significant regardless of previous antibiotic exposure definition. However, for fluoroquinolones and ampicillin/sulbactam, the ORs varied as a function of previous antibiotic exposure definition. In multivariate analysis, third generation cephalosporin usage was a risk factor for ESBL-producing K pneumoniae isolation, whereas ampicillin/sulbactam usage was protective against these organisms, regardless of the time frame analyzed. Other independent predictors of ESBL-producing K pneumoniae included nursing home residence (OR, 9.30 [95% confidence interval: 3.69-23.43]) and hemodialysis (OR, 13.60 [95% confidence interval: 4.29-43.17]). CONCLUSION: Prior use of third-generation cephalosporins, nursing home residence, and hemodialysis were independent risk factors for isolation of an ESBL-producing K pneumoniae regardless of the time frame analyzed. PMID- 21255876 TI - Waning immunity and booster responses in nursing and medical technology students who had received plasma-derived or recombinant hepatitis B vaccine during infancy. AB - BACKGROUND: The national hepatitis B virus (HBV) vaccination program was launched in Taiwan in 1984. After November 1992, a recombinant HBV vaccine replaced the plasma-derived HBV vaccine. METHODS: A total of 1,812 nursing and medical technology freshman students was tested to evaluate their waning immunity toward hepatitis B. In the 2007 (2008) academic year, 438 (382) students testing nonprotective antibodies received 3 (1) booster doses of HBV vaccine according to suggestions from Taiwan's Center for Disease Control (CDC). RESULTS: The seroprevalences of hepatitis B surface antigen (+) were 0.8% and 0.7% in the plasma-derived and recombinant group, respectively; for antibody to hepatitis B surface antigen (anti-HBs) (+), they were 43.2% and 33.3% (P < .001), respectively. In the 2007 freshman group, 99.1% of the students previously vaccinated with plasma-derived HBV vaccine exhibited anti-HBs seroconversion. In the 2008 freshman group, the booster dose induced anti-HBs seroconversions of 92.1% and 95.9% in the students who had received the plasma-derived and recombinant HBV vaccine, respectively (P = .370). CONCLUSION: Most students exhibited signs of immune memory after receiving the booster, regardless of having received plasma-derived or recombinant HBV. Only a small number of vaccinees lost their immune memory after 16 years, suggesting that some students might benefit from boosting before proceeding to clinical practice. PMID- 21255877 TI - Effects of the fluoride on the central nervous system. AB - INTRODUCTION: Fluoride (F) is a toxic and reactive element, and exposure to it passes almost unnoticed, with the consumption of tea, fish, meat, fruits, etcetera and articles of common use such as: toothpaste additives; dental gels, non-stick pans and razor blades as Teflon. It has also been used with the intention of reducing the dental cares. DEVELOPMENT: Fluoride can accumulate in the body, and it has been shown that continuous exposure to it causes damaging effects on body tissues, particularly the nervous system directly without any previous physical malformations. BACKGROUND: Several clinical and experimental studies have reported that the F induces changes in cerebral morphology and biochemistry that affect the neurological development of individuals as well as cognitive processes, such as learning and memory. F can be toxic by ingesting one part per million (ppm), and the effects they are not immediate, as they can take 20 years or more to become evident. CONCLUSION: The prolonged ingestion of F may cause significant damage to health and particularly to the nervous system. Therefore, it is important to be aware of this serious problem and avoid the use of toothpaste and items that contain F, particularly in children as they are more susceptible to the toxic effects of F. PMID- 21255878 TI - Thiazolidione derivatives as novel antibiofilm agents: design, synthesis, biological evaluation, and structure-activity relationships. AB - Rational designed novel thiazolidiones were synthesized and evaluated for antibiofilm activity. The active derivatives were not only potent inhibitors of Staphylococcus epidermidis biofilm growth but also efficient antibacterial agents. 3f showed 4-fold higher activity (6.25 MUM) in the biofilms dispersal assay and significantly higher antibacterial activity (MIC 3.125 MUM) in comparison to the 3-(5-((6- (ethoxycarbonyl)-5-(benzo[1,3]dioxol-5-yl)-3-oxo-7 phenyl- thiazolo[3,2-a]pyrimidin-2(5H)-ylidene)methyl)furan-2-yl)benzoic acid (1). PMID- 21255879 TI - [Pulmonary and cutaneous lesions]. PMID- 21255880 TI - Effects of competitive computer-assisted learning versus conventional teaching methods on the acquisition and retention of knowledge in medical surgical nursing students. AB - PURPOSE: This paper presents a novel approach of computer-assisted learning for nursing education in university undergraduate courses. BACKGROUND: The most innovative aspect of the proposal is the design of nursing assignments as on-line competitions. The effects of competitive e-learning versus conventional teaching methods on the acquisition and retention of knowledge were compared in a course on medical-surgical nursing. METHOD: A total of 116 students of mixed gender, age, computer experience and educational background in a second-year course on medical-surgical nursing participated in the study. Data were collected from nursing students at four time points. The on-line activities were carried out using a web-based automatic evaluation system. RESULTS: The study revealed that the competitive e-learning method produced significant cognitive gains for the experimental group students in the immediate follow-up test. Nevertheless, both teaching methods resulted in similar knowledge retention in the 10-week follow-up test. CONCLUSION: Significant benefits were found following our approach. The work of the students could be evaluated along the course, the workload of instructors was reduced and students received immediate feedback by the on-line judge, which promoted both independent learning and reflective thinking. The approach is applicable to any other nursing educational institution. PMID- 21255881 TI - Characteristics of leadership that influence clinical learning: a narrative review. AB - Leadership has been consistently implied in fostering clinical learning. However there is a lack of clarity about the form leadership should take. Limited quantitative research indicated a narrative approach to review literature from a broad perspective. A framework to guide the synthesis was developed to ensure a rigorous review process. Preliminary reading and review of papers using search terms nursing and leadership and clinical learning and learning culture narrowed the inclusion criteria to 245 papers published between 2000 and 2010. Given the diversity of the papers' focus, aim and context, a refined screening process justified the inclusion of twenty-six papers in the review. A critical appraisal of these peer-reviewed quantitative, qualitative and commentary papers identified factors/elements integral to effective leadership. Across the literature leadership was discussed in relation to two broad themes: influence of leadership on organisational learning and development and; influence of leadership on undergraduate clinical education. The factors central to leadership emerged as transformative principles, the role of the nurse unit/ward manager, collaboration and relationship building and role-modelling. The review has raised some suggestions for future research aimed at examining the impact of a leadership capacity building intervention that supports clinical learning. PMID- 21255882 TI - The development and descriptions of an evidence-based case management educational program. AB - Educational preparation is the key to successful case management and better patient outcomes. Closer examination reveals that existing case management education programs often lack a theoretical underpinning. In order to address the issues, this paper describes the development process of using an expanded version of Donabedian's structure-process-outcome framework as a base and program itself. Four main stages were used in the development process. A systematic literature review and needs assessment provided relevant evidence for the program design. Then, a panel review was undertaken and pilot testing initiated with public health nurses. The expert panel review and the findings of the pilot test both supported the selection of the program content and the learning approaches adopted throughout the program. Sixteen hours of workshops provided detailed content on the case management process. Four main learning strategies were chosen based on transformative learning theory and the findings of the needs assessment. The paper provides an example of the development of a program based on existing theory and evidence. PMID- 21255883 TI - Modelling tritium flux from water to atmosphere: application to the Loire River. AB - Tritium (3H or T) is one of the major radionuclides released by nuclear power plants (NPP) into rivers. However, tritiated water (HTO) flux from water to air is seldom considered when assessing health effects of such releases. The aim of this paper is to present the result of a research program, called LORA, conducted on the Loire River (France). To improve our understanding of HTO flux from surface water to air, three field campaigns were organised during the NPP's radioactive releases to measure simultaneously the activity concentrations in air on the riverbank, using an innovative system, and in river water. The measurements showed that during radioactive releases, water vapour was enriched in 3H. These results were used to calibrate exchange velocities. The average of these estimated exchange velocities was more than one order of magnitude higher than those calculated in the literature from indoor experiments. The variability of these values was also larger, showing that outdoor studies cover a wide range of conditions influencing HTO flux. No correlation was observed between exchanges velocities and meteorological conditions. However, there was a significant difference between day and night with a higher value observed during the day. Two approaches used to calculate HTO evaporation from water (i.e. the approach based on water evaporation and the approach considering that HTO follows its own concentration gradient) were included in a hydrodynamic model, which was used to evaluate HTO air activity along the Loire River. In conclusion, only the approach considering that HTO follows its own gradient led to a good agreement between measurements and predictions. A one-year simulation was done to estimate the contribution of this process to the dose. Its contribution can be considered as negligible in this case compared to the other pathways such as ingestion of water or foodstuffs. PMID- 21255884 TI - Antlers of Cervus elaphus as biomonitors of 90Sr in the environment. AB - Adequate radioprotection of the environment requires the identification of biomonitors sensitive to the variation of its radionuclide content. Due to the chemical similarities between calcium and strontium, calcified tissues of mammals are considered to be good 90Sr biomonitors. This work considered Cervus elaphus antlers which, being shed annually, can give information about the importance of radiostrontium contamination in an ecosystem in the time period required for the growth of the antler. The samples were collected at various points of W and SW Spain. The mean value of their 90Sr content was (70 +/- 43 (S.D.)) Bq/kg d.w., range (16-218) Bq/kg d.w., and the radionuclide was evenly distributed in the different parts of the antler. There was a good correlation between the antlers' 90Sr content and the 90Sr deposited in the soil. The antlers' content of 226Ra (from the natural uranium series) and the contents of some stable elements (Ca, Mg, Sr, and K) were also determined. The values for these stable elements were practically constant in the analyzed samples, and the concentrations measured decreased in the following order: Ca " Mg > K > Sr " 90Sr > 226Ra. PMID- 21255885 TI - Comparative trends and seasonal variation of 7Be, 210Pb and 137Cs at two altitude sites in the central part of France. AB - The atmospheric concentrations of 137Cs, 210Pb, and 7Be were measured over a three-year period at two research stations located less than 12 km apart and at different altitudes (puy de Dome, 1465 m a.s.l. and Opme, 660 m a.s.l., France). Seasonal trends in all radionuclides were observed at both stations, with high concentration measured during the summer and low concentrations during the winter. The 210Pb concentrations at both stations were similar to each other. Higher concentrations of both 7Be and 137Cs were measured at puy de Dome than at Opme. These observations can be explained by the stratospheric and upper tropospheric sources of 7Be and the long-range transportation of 137Cs at high altitudes. Air mass origins during sampling periods were classified into several groups by their route to the stations (marine, marine modified, continental and mediterranean). We observed that 7Be concentrations were constant regardless of the air mass origins, unlike 137Cs and 210Pb concentrations that increased when influenced by continental air masses. Higher 7Be concentrations were observed when air masses were arriving from the upper troposphere than from the boundary layer, the opposite was observed for 137Cs. The temporal trend in concentrations of 7Be shows good agreement with previous modelling studies suggesting that there is a good understanding of its sources and the atmospheric vertical mixing of this radionuclide. The sources and mixing of 210Pb, however, seem to be more complex than it appeared to be in previous modelling studies. PMID- 21255886 TI - Aetiology and presentation of ankylosis of the temporomandibular joint: report of 23 cases from Abuja, Nigeria. AB - Several studies have reviewed the management of ankylosis of the temporomandibular joint (TMJ), but only a few focused on the aetiology and clinical features. We retrospectively studied the aetiology and clinical features of patients with ankylosis of the TMJ who presented to the Maxillofacial Unit, National Hospital, Abuja, Nigeria, between 2004 and 2009. There were 13 male and 10 female patients, M:F ratio 1.3:1, age range 6-62, mean (SD) 20 (13) years. The aetiological factors were trauma (n=11) that comprised falls (n=6), untreated fractures of the zygomatic arch (n=4) and myositis ossificans (n=1); infection (n=9), that comprised cancrum oris (n=3) and ear infection (n=6); congenital or unknown (n=2), and coronoid hyperplasia (n=1). The maximum interincisal distance at presentation ranged from 0 to 25 mm (mean (SD) 6.7 (7.2) mm). Seventeen had facial deformities. The diagnoses recorded were as follows: left extracapsular ankylosis, (n=8); right intracapsular bony ankylosis, (n=6); left intracapsular bony ankylosis, (n=4); bilateral intracapsular bony ankylosis, (n=4), and bilateral intracapsular fibrous ankylosis (n=1). Extreme poverty was the main predisposing factor. There is a need for a concerted effort among healthcare providers, policy makers, and the world in general to eradicate poverty and improve healthcare to limit the incidence of ankylosis of the TMJ. PMID- 21255887 TI - The use of Tie-LokTM Ties to secure endotracheal tube in challenging tracheostomy cases. PMID- 21255888 TI - Elastomer femoroplasty prevents hip fracture displacement In vitro biomechanical study comparing two minimal invasive femoroplasty techniques. AB - The purpose of this study was to test femur strength and the ability to prevent fracture displacement of two minimal invasive Elastomer femoroplasty techniques. METHODS: A total of sixteen fixed human cadaveric femur pairs were used. From each pair one femur was randomly assigned for Elastomer femoroplasty. In these femora we drilled a 3.5mm entrance in the lateral cortex. Cavities for the Elastomer were created by: group A, balloon and group B an excentric drill. All femora were fractured by simulating a fall on the greater trochanter. Neck-shaft angles on plain anterior posterior radiographs were measured to determine fracture displacement. FINDINGS: There was no significant difference in fracture load between controls and treated femora for group A, 2904N (SD 1091) versus 2803N (SD 627) and group B, 2773N (SD 747) versus 2597N (SD 834). In group A the mean displacement was 35 degrees (SD 14) for the control femora and 3 degrees (SD 2) for the treated femora (P<0.001). In group B the mean displacement was 38 degrees (SD 10) for the controls and 8 degrees (SD 13) for the treated femora (P<0.001). INTERPRETATION: The results of this study show that minimal invasive Elastomer femoroplasty prevents fracture displacement of the proximal femur. We found no significant compromise in load-to-fracture after minimal invasive balloon or excentric drill femoroplasty. PMID- 21255889 TI - Reduced ozone by air filtration consistently improved grain yield in wheat. AB - This study considered effects of reduced [O(3)] on wheat yield. Open-top chamber charcoal filtered air treatments were compared with non-filtered treatments for field-grown wheat. 30 experiments meeting requirements were found, representing nine countries in North America, Europe and Asia. 26 experiments reported improved yield and 4 experiments reduced yield by filtration, a significant positive effect. Average yield improvement was 9%. Average daytime [O(3)] was reduced by filtration from 35 to 13 nmol mol(-1). Filtration efficiency was 63% for O(3) and 56% for SO(2). For NO(x) it was observed that NO(2) was reduced and NO increased by filtration. Thus, filters convert NO(2) to NO. Most experiments reported low or very low [SO(2)] and [NO(x)]. Thus, O(3) can be concluded to be the main phytotoxic component in the experiments. Elevated [NO(2)] was observed in one experiment. The conclusion is that current [O(3)] over large parts of the world adversely affect wheat yield. PMID- 21255890 TI - Persistent organic pollutant in a fish community of a sub-alpine lake. AB - This study investigated the presence of organochlorine pollutants in abiotic and biotic samples from Lake Como (Italy). DDTs and PCBs were found to be the major contaminants, ranging from 0.04 to 4.25 and from 0.25 to 40.8 MUg/g lipid respectively. Evidence of biomagnification according to the trophic role of the investigated organisms was highlighted by means of Stable Isotope Analysis. A Trophic Magnification Factor (TMF) was calculated for the chemicals of interest and the applicability of the method for global use was confirmed. Statistically significant correlation has been found between the calculated trophic level and the concentrations of more lipophilic compounds, while for the less lipophilic (e.g., HCH, 3CBs) the relationship is no statistically significant and the TMF is close to 1. The role of the foraging area in affecting PCB and DDT concentrations within aquatic ecosystems has been highlighted by a Principal Component Analysis (PCA). PMID- 21255891 TI - A comparative study of violence risk assessment tools: a systematic review and metaregression analysis of 68 studies involving 25,980 participants. AB - There are a large number of structured instruments that assist in the assessment of antisocial, violent and sexual risk, and their use appears to be increasing in mental health and criminal justice settings. However, little is known about which commonly used instruments produce the highest rates of predictive validity, and whether overall rates of predictive validity differ by gender, ethnicity, outcome, and other study characteristics. We undertook a systematic review and meta-analysis of nine commonly used risk assessment instruments following PRISMA guidelines. We collected data from 68 studies based on 25,980 participants in 88 independent samples. For 54 of the samples, new tabular data was provided directly by authors. We used four outcome statistics to assess rates of predictive validity, and analyzed sources of heterogeneity using subgroup analysis and metaregression. A tool designed to detect violence risk in juveniles, the Structured Assessment of Violence Risk in Youth (SAVRY), produced the highest rates of predictive validity, while an instrument used to identify adults at risk for general offending, the Level of Service Inventory-Revised (LSI R), and a personality scale commonly used for the purposes of risk assessment, the Psychopathy Checklist-Revised (PCL-R), produced the lowest. Instruments produced higher rates of predictive validity in older and in predominantly White samples. Risk assessment procedures and guidelines by mental health services and criminal justice systems may need review in light of these findings. PMID- 21255892 TI - Trauma reminders and PTSD symptoms in children three years after a terrorist attack in Beslan. AB - As a consequence of a terrorist attack, children may experience trauma-related internal and external reminders that are directly linked to their physical and psychological health. We assessed PTSD and trauma reminders in 58 school-age children three years after the terrorist attack in Beslan, Russia in 2004, as well as their association with degree of exposure, psychological distress and coping. Findings revealed a prevalence of situational trauma reminders associated with high levels of distress in more exposed children. The presence of PTSD was predicted by level of exposure to the attack, frequency of exposure to trauma reminders, and support seeking as a coping strategy. Findings are discussed in light of the socio-political climate in Beslan and distress experienced by the population three years after the attack. PMID- 21255893 TI - Venous thromboembolism in oral and maxillofacial surgery: a review of the literature. PMID- 21255894 TI - Internal derangement of the temporomandibular joint with mouth-closing disturbance caused by a thickness of retrodiscal tissue: a case report. PMID- 21255895 TI - Analysis of the anatomy of the maxillary sinus septum using 3-dimensional computed tomography. AB - PURPOSE: Maxillary posterior teeth exhibit a high incidence of periodontal bone and tooth loss. After tooth loss, the edentulous alveolar process of the posterior maxilla is often affected by resorption, which results in loss of vertical bone volume. Moreover, progressive sinus pneumatization leads to a decrease in the alveolar process from the cranial side. The sinus elevation and augmentation surgical technique opened a new way of anchoring endosseous implants despite discernible bone reduction. However, the surgical interventions require in-depth knowledge of maxillary sinus anatomy such as sinus septum and potential variations. The purpose of this study was to investigate the prevalence, location, height, morphology, and orientation of maxillary sinus septa by use of computed tomography (CT) and 3-dimensional imaging. MATERIALS AND METHODS: Two hundred patients undergoing implant treatment at the Yonsei University College of Dentistry, Seoul, South Korea, were randomly selected for analysis of maxillary sinus septa. CT and DentaScan (GE Medical Systems, Milwaukee, WI)-reformatted data from 400 sinuses were analyzed with the Preview program (Infinitt, Seoul, South Korea). Three-dimensional images were rendered for measurement by use of the Accurex program (CyberMed, Seoul, South Korea). RESULTS: We found 111 septa in 400 maxillary sinuses (27.7%). This corresponded to 37% of the patients. Among total septa, 25 sinus septa (22.5%) were located in the anterior, 51 (45.9%) in the middle, and 35 (31.5%) in the posterior regions. The directional orientation analyses showed that 106 septa were buccopalatal, 4 were sagittal, and 1 was transverse type. The mean septal heights were 7.78 +/- 2.99 and 7.89 +/- 3.09 mm in the right and left sinuses, respectively. CONCLUSION: Three-dimensional CT image analyses may provide useful information that can avoid unnecessary complications during sinus augmentation procedures by facilitating adequate, timely identification of the anatomic structures inherent to the maxillary sinus. PMID- 21255896 TI - [The free groin flap utility. About 19 cases]. AB - INTRODUCTION: The pedicled groin flap, well known for the hand resurfacing, has first been described by Mac Gregor in 1972. But the free groin flap is unpopular because of its short (5mm) and small artery (caliber 1,5 to 2mm) and a bulky aspect. The purpose of this study is to show its interest by weighing up the pros and cons of its advantages and of its disadvantages. PATIENTS AND METHODS: This study concerns 19 cases of free groin flap for posttraumatic reconstruction of limbs between 1994 and 2009. The patients including six children, were 10 males and nine females, ages from 4 to 50 years old. The size flap ranged from 4*10 to 15*25cm. We reported the indications, the wound's size, the postoperative complications and the quality of life. RESULTS: We observed one total necrosis and three partial necrosis. One debulking was generally required. CONCLUSION: The free groin flap has a lot of valuable qualities: a good vascularisation, allowing a big size flap (20*30cm), with direct closing of the donor site, in only one surgical installation, without sacrifying a muscle. The scar of the donor site is easily hidden by underwear. The flap's skin has good quality, without hair, and the antifibrotic effect of the fat permits a good tendinous sliding. Compared to the pedicled groin flap, this free technique enables the reconstruction of the lower limbs, while upper limbs are free, without weaning time. The functional and aesthetic result of the reconstruction is good and we think that for a microsurgical team, this reliable flap should be more chosen for the posttraumatic reconstruction of limbs. PMID- 21255897 TI - Lymphangioleiomyomatosis. AB - Lymphangioleiomyomatosis (LAM) is a rare disease that mainly affects women, particularly at fertile age. It is sporadic or associated with tuberous sclerosis complex. It is characterised by an abnormal proliferation of immature smooth muscle cells (SMC), which grow aberrantly in the airway, parenchyma, lymphatics and pulmonary blood vessels and which can gradually lead to respiratory failure. It affects several systems, affecting the lymphatic ganglia and causing abdominal tumours. Given its very low prevalence, a difficult to establish early diagnosis, absence of curative treatment and the difficulty in obtaining information, places LAM under the heading of the so-called Rare Diseases. There is a growing interest in the study of this disease which has led to the setting up of patient registers and an exponential growth in LAM research, both at a clinical level and cellular level. PMID- 21255898 TI - One-week and 6-month cardiovascular magnetic resonance outcome of the pharmacoinvasive strategy and primary angioplasty for the reperfusion of ST segment elevation myocardial infarction. AB - INTRODUCTION AND OBJECTIVES: Pharmacoinvasive strategy represents an attractive alternative to primary angioplasty. Using cardiovascular magnetic resonance imaging we compared the left ventricular outcome of the pharmacoinvasive strategy and primary angioplasty for the reperfusion of ST-segment elevation myocardial infarction. METHODS: Cardiovascular magnetic resonance was performed 1 week and 6 months after infarction in two consecutive cohorts of patients included in a prospective university hospital ST-segment elevation myocardial infarction registry. During the period 2004-2006, 151 patients were treated with pharmacoinvasive strategy (thrombolysis followed by routine non-immediate angioplasty). During the period 2007-2008, 93 patients were treated with primary angioplasty. A propensity score matched population was also evaluated. RESULTS: At 1-week cardiovascular magnetic resonance, pharmacoinvasive strategy and primary angioplasty patients showed a similar extent of area at risk (29+/-15 vs. 29+/-17%, P=.9). Non-significant differences were detected by cardiovascular magnetic resonance at 1 week and at 6 months in infarct size, salvaged myocardium, microvascular obstruction, ejection fraction, end-diastolic volume index and end-systolic volume index (P>.2 in all cases). The same trend was observed in 1-to-1 propensity score matched patients. The rate of major adverse cardiac events (death and/or re-infarction) at 1 year was 6% in pharmacoinvasive strategy and 7% in primary angioplasty patients (P=.7). CONCLUSIONS: A pharmacoinvasive strategy including thrombolysis and routine non-immediate angioplasty represents a widely available and logistically attractive approach that yields identical short-term and long-term cardiovascular magnetic resonance derived left ventricular outcome compared to primary angioplasty. PMID- 21255899 TI - Recurrent ventricular fibrillation caused by left circumflex artery occlusion without ST-elevation on 12-lead ECG. PMID- 21255900 TI - Pain relief in office gynaecology: a systematic review and meta-analysis. AB - Hysteroscopy, hysterosalpingography (HSG), sonohysterography and endometrial ablation are increasingly performed in an outpatient setting. The primary reason for failure to complete these procedures is pain. The objective of this review was to compare the effectiveness and safety of different types of pharmacological intervention for pain relief in office gynaecological procedures. A systematic search of medical databases including PubMed, EMBASE, Cochrane Central register of controlled trials, PsychInfo and CINHAL was conducted in 2009. Randomised controlled trials (RCTs) investigating the use of local anaesthetics, opioid analgesics, non-opioid analgesics and intravenous sedation for pain relief during and after hysteroscopy, HSG, sonohysterography and endometrial ablation were reviewed. Secondary outcomes included adverse effects and failure to complete procedures. Where RCTs were not identified, the best available evidence was sought. Each study was assessed against inclusion criterion. Results for each study were expressed as a standardised mean difference (SMD) with 95% confidence intervals and combined for meta-analysis with Revman 5 software. Meta-analysis revealed beneficial effect of the use of local anaesthetics during and within 30 min after hysteroscopy; SMD -0.45 (95% CI -0.73, -0.17) and SMD -0.51 (95% CI 0.81, -0.21) respectively. No beneficial effect was noted during HSG. One RCT found evidence of benefit for pain relief during hysterosalpingo contrastsonography; SMD -1.04 [95% CI -1.44, -0.63]. There was no significant difference in failure to complete hysteroscopy due to cervical stenosis between the intervention and control groups (OR 1.31 (95% CI 0.66, 2.59)), but the incidence of failure to complete the procedure due to pain was significantly less in the intervention group (OR 0.29 (0.12, 0.69)). There is evidence of benefit for the use of local anaesthetics for outpatient hysteroscopy and hysterosalpingo contrastsonography. Local anaesthetics may be considered when performing hysteroscopy in postmenopausal women to reduce the failure rate. PMID- 21255901 TI - The history and usage of the vaginal pessary: a review. AB - It is expected that with the rising female life expectancy the prevalence of pelvic organ prolapse will increase. From ancient times mechanical devices have been used to reposition prolapsed organs. Given that surgical correction of prolapse is associated with high recurrence rates, pessaries offer a favorable alternative. In spite of the antiquity of pessary usage the evidence for its use, the effectiveness of symptom relief, and the nuances of clinical management with the pessary in situ have not been studied methodically. There is a need for controlled trials to assess the efficacy of pessaries as opposed to other non surgical and surgical methods of treating pelvic organ prolapse. Additionally, the long term effects and complications of pessary usage have not been assessed in trials, and knowledge about the potential complications caused by the pessary rests mainly on anecdotal data. This review provides a historical perspective and appraises the current knowledge regarding the indications, effectiveness and the potential complications associated with pessary use. Data were obtained from an electronic search of Medline (1966-2010) and by hand searching the citations which were not available online. Keywords used were pelvic organ prolapse, pelvic floor dysfunction, vaginal pessary and urinary incontinence. Textbooks are also quoted where relevant. Most studies report moderate success rates in the short term following insertion of a pessary for the management of prolapse and concur in the remission of almost all symptoms attributable to the prolapse. Reported success is variable in the remission of urinary and bowel symptoms. We conclude that based on the available evidence (mostly retrospective and prospective cohort studies), treatment with a vaginal pessary is a feasible option that can be offered in the short term to women with prolapse. There is a need for controlled trials to assess the long term efficacy. PMID- 21255902 TI - The conformational effect of para-substituted C8-arylguanine adducts on the B/Z DNA equilibrium. AB - The B form of DNA exists in equilibrium with the Z form and is mainly affected by sequence, electrostatic interactions, and steric effects. C8-purine substitution shifts the equilibrium toward the Z form though how this interaction overcomes the unfavorable electrostatic interactions and decrease in stacking in the Z form has not been determined. Here, a series of C8-arylguanine derivatives, bearing a para-substituent were prepared and the B/Z equilibrium determined. B/Z ratios were measured by CD and conformational effects of the aryl substitution determined by NMR spectroscopy and molecular modeling. The para-substituent was found to have a significant effect on the B/Z DNA equilibrium caused by altering base-pair stacking of the B form and modifying the hydration/ion shell of the B form. A unique melting temperature versus salt concentration was observed and provides evidence relevant to the mechanism of B/Z conformational interconversion. PMID- 21255903 TI - Applications of pressure perturbation calorimetry in biophysical studies. AB - Pressure perturbation calorimetry (PPC) is a relatively new and efficient technique, to study the volumetric properties of biomolecules in solution. In PPC, the coefficient of thermal expansion of the partial volume of the biomolecule is deduced from the heat consumed or produced after small isothermal pressure jumps (typically+/-5 bar). This strongly depends on the interaction of the biomolecule with the solvent or cosolvent as well as on its packing and internal dynamic properties. This technique, complemented by ultrasound velocity and densitometry, provides valuable insight into the basic thermodynamic properties of solvation and volume effects accompanying phase transitions and interactions of biomolecular systems. Here we review data on protein folding, ligand binding processes, and phospholipid phase transitions, together with discussion of interpretation and further significant applications. PMID- 21255904 TI - Determining advanced recycling fees and subsidies in "E-scrap" reverse supply chains. AB - Primarily due to environmental concerns and legislative mandates, the disposition of end-of-life (EOL) electronics products has attracted much attention. Advanced recycling fees (ARFs) and government subsidies may play important roles in encouraging or curtailing the flows of recycled items. We present a Stackelberg type model to determine ARFs and socially optimal subsidy fees in decentralized reverse supply chains where each entity independently acts according to its own interests. The model consists of one leader (the government) and two followers (a group of manufacturers, importers, and sellers (MISs) and a group of recyclers). To maximize social welfare, the government determines the ARFs paid by MIS and the subsidy fees for recyclers when MIS sells new products and recyclers process EOL products. We find that MIS and recyclers behave at the equilibrium status by choosing optimal selling quantity in the market and optimal reward money for customers bringing EOL products to recyclers. Under this approach the two fees achieve the maximum of social welfare at the equilibrium status, while both MIS and recyclers gain the maximum of profits. For comparative purposes, we also develop a conceptual model describing the current practice by which ARFs and the subsidy fees are determined on the basis of fund balance between revenues and costs along with recycling operations. We conclude that our results outperform current practice. PMID- 21255905 TI - Re: Claude C. Schulman, Jacques Irani, Juan Morote, et al. Androgen-deprivation therapy in prostate cancer: a European expert panel review. Eur Urol suppl 2010;9:675-91. PMID- 21255907 TI - Re: Nicola Nicolai, Rosalba Miceli, Andrea Necchi, et al. Retroperitoneal lymph node dissection with no adjuvant chemotherapy in clinical stage I nonseminomatous germ cell tumours: long-term outcome and analysis of risk factors of recurrence. Eur Urol 2010;58:912-8. PMID- 21255908 TI - Re: Ricardo L. Favaretto, Shahrokh F. Shariat, Daher C. Chade et al. The effect of tumor location on prognosis in patients treated with radical nephroureterectomy at Memorial Sloan-Kettering Cancer Center. Eur Urol 2010;58:574-80. PMID- 21255910 TI - Cluster headache patients are not affected by restless legs syndrome: an observational study. AB - OBJECTIVE: To investigate the presence of Restless Legs Syndrome (RLS) in Cluster Headache (CH) patients compared to headache-free controls. DESIGN AND SETTING: Cross-sectional case-control study of CH patients presenting at tertiary headache centers over the period January-December 2008. PATIENTS AND PARTICIPANTS: Fifty consecutive patients (6 women and 44 men) of mean age of 39.7 year (standard deviation 10.9) with episodic or chronic CH diagnosed according to ICHD-II criteria and 50 headache-free subjects matched by age and sex were recruited. RESULTS: None of the CH patients had RLS. Six (12%) headache-free controls had RLS. CONCLUSIONS: Our data indicate no probable relationship between CH and RLS. However, since both conditions have a circadian rhythm and are associated with altered melatonin secretion, we conjecture that reduced nocturnal melatonin in CH likely allows sustained dopaminergic activity which could be protective against RLS in CH patients. PMID- 21255911 TI - Cognitive deficits in patients with chronic fatigue syndrome compared to those with major depressive disorder and healthy controls. AB - OBJECT: Chronic fatigue syndrome (CFS) patients report usually cognitive complaints. They also have frequently comorbid depression that can be considered a possible explanation for their cognitive dysfunction. We evaluated the cognitive performance of patients with CFS in comparison with a control group of healthy volunteers and a group of patients with MDD. PATIENTS AND METHODS: Twenty five patients with CFS, 25 patients with major depressive disorder (MDD), and 25 healthy control subjects were given standardized tests of attention, working memory, and verbal and visual episodic memory, and were also tested for effects related to lack of effort/simulation, suggestibility, and fatigue. RESULTS: Patients with CFS had slower phasic alertness, and also had impaired working, visual and verbal episodic memory compared to controls. They were, however, no more sensitive than the other groups to suggestibility or to fatigue induced during the cognitive session. Cognitive impairments in MDD patients were strongly associated with depression and subjective fatigue; in patients with CFS, there was a weaker correlation between cognition and depression (and no correlation with fatigue). CONCLUSIONS: This study confirms the presence of an objective impairment in attention and memory in patients with CFS but with good mobilization of effort and without exaggerated suggestibility. PMID- 21255912 TI - Polypropylene-polyester cranial prostheses prepared with CAD/CAM technology. Report of first 15 cases. AB - OBJECTIVES: The authors described a new cranioplastic method where polypropylene polyester knitwear was shaped according to individual patient's skull 3D model. The material was formed in a customized manner and preoperatively adjusted to the patient needs with modern CAD/CAM techniques. PATIENTS AND METHODS: The procedure consisted of a CT scan with a simple but unorthodox protocol, 3D modeling of the bone defect and planned prosthesis, finally the preparation of the plate itself. Prostheses were used in the 15 cases of cranial defects. RESULTS: Sample cases were shown with preoperative and postoperative CT scans, patient pictures, and 3D models of the prostheses. The size of the defect ranged from 15 to 95 cm(2), and the observation period after the reconstructive operation ranged from 3 to 23 months. The results were very good in all cases of cranioplasties performed after craniectomies of various origins. CONCLUSION: CAD/CAM shaping gave better adjustment to requirements of specific defect than any standard preformed plate. Such method seemed to be a reasonable alternative to other cranioplastic solutions and can be recommended even for cases of large or complicated shape cranioplasties. PMID- 21255913 TI - Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer. AB - Aberrant DNA methylation is a common phenomenon in human cancer. The aims of this study were to investigate the methylation profiles of non-small cell lung cancer (NSCLC) in the Chinese population. Twenty tumor suppressor genes (TSGs) were determined of the methylation status using methylation-specific PCR in 78 paired NSCLC specimens and adjacent normal tissues, as well as in 110 Stage I/II NSCLC and 50 cancer-free plasmas. The results showed that, nine genes (APC, CDH13, KLK10, DLEC1, RASSF1A, EFEMP1, SFRP1, RARbeta and p16(INK4A)) demonstrated a significantly higher frequency of methylation in NSCLC compared with the normal tissues (P<=0.001), while the others (RUNX3, hMLH1, DAPK, BRCA1, p14(ARF), MGMT, NORE1A, FHIT, CMTM3, LSAMP and OPCML) showed relatively low sensitivity or specificity. Furthermore, methylation of multiple genes was more frequentin cancerous tissue, CpG island methylator phenotype positive (CIMP+) cases were detected in 65.38% of (51/78) NSCLC while only in 1.28% (1/78) of adjacent normal tissues (P<0.001), and CIMP+ was associated with advanced stage (P=0.017), lymphatic metastasis (P=0.001) and adverse 2-year progression-free survival (P=0.027). The nine genes validated in tissues also showed a significantly higher frequency of tumor-specific hypermethylation in NSCLC plasma, as compared with the cancer-free plasmas, and a 5-gene set (APC, RASSF1A, CDH13, KLK10 and DLEC1) achieved a sensitivity of 83.64% and a specificity of 74.0% for cancer diagnosis. Thus, the results indicated that methylated alteration of multiple genes plays an important role in NSCLC pathogenesis and a panel of candidate epigenetic biomarkers for NSCLC detection in the Chinese population was identified. PMID- 21255914 TI - Understanding removal of phosphate or arsenate onto water treatment residual solids. AB - Chemical and physical characterization methods were used to analyze ferric, alum, and lime water treatment residual solids (WTRSs) in order to describe why phosphate or arsenate adsorption occurred on the WTRSs, and why ferric WTRSs were the stronger adsorbent for both phosphate and arsenate. In total, five WTRSs, two ferric, two alum, and one lime, were analyzed. Elemental analysis of the WTRSs showed lime residuals contained the greatest molar amount of the primary element (7.04 mol Ca/kg solid), followed by the ferric residuals (4.86-4.96 mol Fe/kg solid) whereas alum residuals contained the least amount of primary element as compared to the ferric or alum residual solids (3.62-4.67 mol Al/kg solid). Mercury porosimetry identified more small pores (<0.006 MUm) in a ferric WTRSs when compared to an alum WTRSs, indicating that a more detailed pore structure allowing for intraparticle phosphate or arsenate diffusion might be present in the ferric solid. Similarly, SEM images at 1000 times magnification showed a porous surface in both ferric WTRSs, whereas the alum WTRSs showed a smooth surface at the same magnification. Several general equations to describe phosphate or arsenate adsorption on WTRSs were provided. PMID- 21255915 TI - Examination of competitive lanthanide sorption onto smectites and its significance in the management of radioactive waste. AB - The competitive effect of La and Lu (analogues of radionuclides appearing in radioactive waste) in the sorption in four smectites was examined. Sorption and desorption distribution coefficients (K(d); K(d,des)), and desorption rates (R(des)) were determined from batch tests in two media: deionized water and, to consider the influence of cement leachates, 0.02 mol L(-1) Ca. The competitive effect was lower when high-affinity sites were available, as in the water medium at the lowest range of initial lanthanide concentration, with high K(d) for La and for Lu (5-63*10(4) L kg(-1)). Lower K(d) was measured at higher initial concentrations and in the Ca medium, where Lu showed a stronger competitive effect. This was confirmed by fitting the sorption data to a two-solute Langmuir isotherm. The desorption data indicated that sorption was virtually irreversible for the scenarios with high sorption, with an excellent correlation between K(d) and K(d,des) (R(2) around 0.9 for the two lanthanides). Assuming that radioactive waste is a mixture of radionuclides, and that Ca ions will be provided by the cement leachates, this would reduce the retention capacity of clay engineered barriers. PMID- 21255916 TI - Elevated concentrations of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans and polybrominated diphenyl ethers in hair from workers at an electronic waste recycling facility in eastern China. AB - Hair samples collected from e-waste recycling workers (n=23 males, n=4 females) were analyzed to assess occupational exposures to polybrominated diphenyl ethers (PBDEs) and polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) at a large e-waste recycling facility in Taizhou, eastern China. Hair samples from a reference population composed of residents of Shanghai (n=11) were analyzed for comparison. The mean concentration of ?PBDEs (range, 22.8-1020 ng/g dw; mean, 157 ng/g dw) found in hair samples from e-waste recycling workers was approximately 3 times higher than the mean determined for the reference samples. The congener profiles of PBDEs in hair from e-waste recycling workers were dominated by BDE 209, whereas the profiles in the reference-population samples showed comparable levels of BDE 47 and BDE 209. Total PCDD/F concentrations in hair from e-waste workers (range, 126-5820 pg/g dw; mean, 1670 pg/g dw) were approximately 18-fold greater than the concentrations measured in hair from the reference population. Concentrations of PCDFs were greater than concentrations of PCDDs, in all of the hair samples analyzed (samples from e-waste and non-e-waste sites). Tetrachlorodibenzofurans (TCDFs) were the major homologues in hair samples. Overall, e-waste recycling workers had elevated concentrations of both PBDEs and PCDD/Fs, indicating that they are exposed to high levels of multiple persistent organic pollutants. PMID- 21255917 TI - Application of persulfate to remediate petroleum hydrocarbon-contaminated soil: feasibility and comparison with common oxidants. AB - In this study, batch experiments were conducted to evaluate the feasibility of petroleum-hydrocarbon contaminated soil remediation using persulfate oxidation. Various controlling factors including different persulfate and ferrous ion concentrations, different oxidants (persulfate, hydrogen peroxide, and permanganate), and different contaminants (diesel and fuel oil) were considered. Results show that persulfate oxidation is capable of treating diesel and fuel oil contaminated soil. Higher persulfate and ferrous ion concentrations resulted in higher diesel degrading rates within the applied persulfate/ferrous ion molar ratios. A two-stage diesel degradation was observed in the batch experiments. In addition, treatment of diesel-contaminated soil using in situ metal mineral activation under ambient temperature (e.g., 25 degrees C) may be a feasible option for site remediation. Results also reveal that persulfate anions could persist in the system for more than five months. Thus, sequential injections of ferrous ion to generate sulfate free radicals might be a feasible way to enhance contaminant oxidation. Diesel oxidation efficiency and rates by the three oxidants followed the sequence of hydrogen peroxide>permanganate>persulfate in the limited timeframes. Results of this study indicate that the application of persulfate oxidation is a feasible method to treat soil contaminated by diesel and fuel oil. PMID- 21255918 TI - Modeling the operation of a three-stage fluidized bed reactor for removing CO2 from flue gases. AB - A bubbling counter-current multistage fluidized bed reactor for the sorption of carbon dioxide (CO(2)) by hydrated lime particles was simulated employing a two phase model, with the bubble phase assumed to be in plug flow, and the emulsion phase in plug flow and perfectly mixed flow conditions. To meet prescribed permissible limit to emit carbon dioxide from industrial flue gases, dry scrubbing of CO(2) was realized. For the evaluation, a pilot plant was built, on which also the removal efficiency of CO(2) was verified at different solids flow rates. The model results were compared with experimental data in terms of percentage removal efficiency of carbon dioxide. The comparison showed that the EGPF model agreed well with the experimental data satisfactorily. The removal efficiency was observed to be mainly influenced by flow rates of adsorbent and CO(2) concentration. PMID- 21255919 TI - Adsorption of food dyes acid blue 9 and food yellow 3 onto chitosan: stirring rate effect in kinetics and mechanism. AB - Adsorption of food dyes acid blue 9 and food yellow 3 onto chitosan was studied. Stirring rate influence on kinetics and mechanism was verified. Infra-red analysis was carried out before and after adsorption in order to verify the adsorption nature. Adsorption experiments were carried out in batch systems with different stirring rates (15-400 rpm). Kinetic behavior was analyzed through the pseudo-first-order, pseudo-second-order and Elovich models. Adsorption mechanism was verified according to the film diffusion model and HSDM model. Pseudo-second order and Elovich models were satisfactory in order to represent experimental data in all stirring rates. For both dyes, adsorption occurred by film and intraparticle diffusion, and the stirring rate increase caused a decrease in film diffusion resistance. Therefore, the film diffusivity increased the adsorption capacity and, consequently, intraparticle diffusivity increased. In all stirring rates, the rate-limiting step was film diffusion. Adsorption of acid blue 9 and food yellow 3 onto chitosan occurred by chemiosorption. PMID- 21255920 TI - Perchlorate degradation using an indigenous microbial consortium predominantly Burkholderia sp. AB - An acclimatized mixed microbial consortium, predominantly Burkholderia sp., was isolated from an activated sludge and investigated for its potential to degrade perchlorate in batch shake flasks. The 16S rDNA analysis of the predominant strain in the mixed culture showed the closest homology (98%) with Burkholderia sp. ATSB16. For the first time mixed culture with predominantly Burkholderia sp., has been reported to be involved in perchlorate degradation. The substrate perchlorate was completely utilized within 10 days even at a high concentration of 1000 mg L(-1) utilizing succinate as the sole carbon-source. Compared to other carbon-sources tested in this study, succinate proved to be better for perchlorate degradation by the mixed consortium. The optimum conditions for perchlorate degradation by the enriched mixed culture were found to be 30 degrees C and pH 7.0. The effect of co-pollutants on perchlorate removal by the mixed culture was also investigated at a mixed perchlorate concentration of 500 mg L(-1). Results showed that the degradation of perchlorate was affected to different extent due to the presence of an equal concentration (500 mg L(-1)of each) of co-pollutants such as nitrate, nitrite, chlorate and phosphate. PMID- 21255921 TI - Photoredox pathways of Cr(III)-tartrate complexes and their impacting factors. AB - In the present study, exposure of Cr(III)-tar to full light of medium pressure mercury lamps and a xenon lamp was conducted in batch reaction systems at 25 degrees C and different pH values to predict the potential for Cr(III) oxidation. The results indicated that the more intense irradiation and higher pH facilitated Cr(III)-tar oxidation. It appears that a ligand-to-metal charge-transfer occurs for Cr(III)-tar after irradiation, leading to the generation of Cr(II) and tar. or .OH. The accompanying photochemical decomposition of tar./or tar, together with O(2), further caused the formation of .OH through multiple pathways, which ultimately converted Cr(II) to Cr(VI) step by step. H(2)O(2), a direct source of .OH under irradiation, significantly enhanced photooxidation of Cr(III)-tar, but not obviously of aqueous Cr(III) or Cr(III)-tar in dark, implying that Cr(II) acts as a precursor of Cr(III) oxidization to Cr(VI). PMID- 21255922 TI - Biotransformation of a highly chlorinated PCB mixture in an activated sludge collected from a Membrane Biological Reactor (MBR) subjected to anaerobic digestion. AB - The role of anaerobic digestion (AD) on the decontamination and biomethanization of a PCB-spiked sludge obtained from a Membrane Biological Reactor (MBR) pilot plant was investigated throughout a 10-month batch experiment. The study was carried out under mesophilic (35 degrees C) and thermophilic (55 degrees C) conditions and was monitored by means of an integrated chemical, microbiological and molecular biology strategy. Remarkable PCB depletions (higher than 50% of the overall spiked PCBs) and dechlorinations were achieved under methanogenic conditions. The process was not affected by yeast extract addition. Both acetoclastic and hydrogenotrophic methanogens, together with some fermentative eubacteria, were found to persist in all PCB biodegrading microcosms. This finding, together with those obtained from parallel microcosms where specific populations were selectively inhibited, suggested that native methanogens played a key role in the biodegradation and dechlorination of the spiked PCBs. Taken together, the results of this study indicate that AD is a feasible option for the decontamination and the efficient disposal (with the production of a CH(4)-rich biogas) of contaminated MBR sludge, which can be then employed as a fertilizer for agricultural purposes. PMID- 21255923 TI - Comparative modeling of biological nutrient removal from landfill leachate using a circulating fluidized bed bioreactor (CFBBR). AB - Steady state operational data from a pilot scale circulating fluidized bed bioreactor (CFBBR) during biological treatment of landfill leachate, at empty bed contact times (EBCTs) of 0.49, and 0.41 d and volumetric nutrients loading rates of 2.2-2.6 kg COD/(m(3)d), 0.7-0.8 kg N/(m(3)d), and 0.014-0.016 kg P/(m(3)d), was used to calibrate and compare developed process models in BioWin((r)) and AQUIFAS((r)). BioWin((r)) and AQUIFAS((r)) were both capable of predicting most of the performance parameters such as effluent TKN, NH(4)-N, NO(3)-N, TP, PO(4) P, TSS, and VSS with an average percentage error (APE) of 0-20%. BioWin((r)) underpredicted the effluent BOD and SBOD values for various runs by 80% while AQUIFAS((r)) predicted effluent BOD and SBOD with an APE of 50%. Although both calibrated models, confirmed the advantages of the CFBBR technology in treating the leachate of high volumetric loading and low biomass yields due to the long solid retention time (SRT), both BioWin((r)) and AQUIFAS((r)) predicted the total biomass and SRT of CFBBR based on active biomass only, whereas in the CFBBR runs both active as well as inactive biomass accumulated. PMID- 21255924 TI - Setting up High Gradient Magnetic Separation for combating eutrophication of inland waters. AB - To find new approaches to devise technologies for handling with eutrophication of inland waters is a global challenge. Separation of the P from water under conditions of continuous flow is proposed as an alternative and effective method. This work is based on using highly magnetic particles as the seeding adsorbent material and their later removal from solution by High Gradient Magnetic Separation (HGMS). Contrast to other methods based on batch conditions, large volumes of water can be easily handled by HGMS because of decreasing retention times. This study identifies the best working conditions for removing P from solution by investigating the effects of a set of four different experimental variables: sonication time, flow rate (as it determines the retention time of particles in the magnetic field), magnetic field strength and the iron (Fe) particles/P concentration ratio. Additionally, the change of P removal efficiency with time (build up effect) and the possibility of reusing magnetic particles were also studied. Our results evidenced that while flow rate does not significantly affect P removal efficiency in the range 0.08-0.36 mL s(-1), sonication time, magnetic field strength and the Fe particles/P concentration ratio are the main factors controlling magnetic separation process. PMID- 21255925 TI - Characterization of magnetic soluble starch-functionalized carbon nanotubes and its application for the adsorption of the dyes. AB - Soluble starch-functionalized multiwall carbon nanotube composites (MWCNT-starch) were prepared to improve the hydrophilicity and biocompatibility of MWCNTs. Characterization of the MWCNT-starch by Fourier transform infrared (FTIR) spectroscopy, ultraviolet-visible (UV-vis) spectroscopy, X-ray diffraction (XRD), transmission electron microscope (TEM) and thermogravimetric analysis (TG), showed that the starch component (about 14.3 wt%) was covalently grafted onto the surface of MWCNT. MWCNT-starch-iron oxide composites, intended for use as adsorbents for the removal of dyes from aqueous solutions, were prepared by synthesizing iron oxide nanoparticles at the surface of MWCNT-starch. Starch acts as a template for growth of iron oxide nanoparticles which are uniformly dispersed on the surface of the MWCNT-starch. MWCNT-starch-iron oxide exhibits superparamagnetic properties with a saturation magnetization (23.15 emu/g) and better adsorption for anionic methyl orange (MO) and cationic methylene blue (MB) dyes than MWCNT-iron oxide. PMID- 21255926 TI - Managing major chemical accidents in China: towards effective risk information. AB - Chemical industries, from their very inception, have been controversial due to the high risks they impose on safety of human beings and the environment. Recent decades have witnessed increasing impacts of the accelerating expansion of chemical industries and chemical accidents have become a major contributor to environmental and health risks in China. This calls for the establishment of an effective chemical risk management system, which requires reliable, accurate and comprehensive data in the first place. However, the current chemical accident related data system is highly fragmented and incomplete, as different responsible authorities adopt different data collection standards and procedures for different purposes. In building a more comprehensive, integrated and effective information system, this article: (i) reviews and assesses the existing data sources and data management, (ii) analyzes data on 976 recorded major hazardous chemical accidents in China over the last 40 years, and (iii) identifies the improvements required for developing integrated risk management in China. PMID- 21255927 TI - Binding strength-associated toxicity reduction by birnessite and hydroxyapatite in Pb and Cd contaminated sediments. AB - In situ stabilization of sediment-bound heavy metals has been proposed as an alternative to ex situ treatment due to the concerns on ecosystem disturbance and remediation cost. The present study was conducted to test the performance of birnessite, hydroxyapatite, and zeolite as stabilizing agents for Pb and Cd in sediment. The heavy metal binding capacity and strength of the stabilizing agents were determined by analyzing Langmuir model parameters. The three agents showed the similar binding capacity (i.e., maximum monolayer sorption constant, K(a)) ranging from 1.13 to 3.62*10(5) mg/kg for Pb and 1.07 to 1.33*10(5) mg/kg for Cd. In contrast, binding strength (i.e., binding energy constant, b) of birnessite and hydroxyapatite was about one order higher than that of zeolite. This is further supported by five-step sequential extraction data: more than 99 and 70% of freshly spiked Pb and Cd were present as not-readily extractable fractions in birnessite and hydroxyapatite, respectively while the fractions were 17.9 and 14.1% in zeolite. Toxicity Characteristic Leaching Procedure (TCLP) test was also conducted to verify the effectiveness of the heavy metal-stabilizing ability of birnessite and hydroxyapatite. Birnessite successfully retained both Pb and Cd against the leaching solution, satisfying the TCLP extract concentration limits (i.e., 5 and 1 mg/L, respectively). However, hydroxyapatite released about 223.7 mg/L of Cd into the solution, which greatly exceeded the limit. The toxicity test with Hyalella azteca showed that their survival rate increased by 92.5-100% when birnessite or hydroxyapatite was added to Pb- or Cd-spiked sediment as a stabilizing agent. Our data demonstrate the potential use of birnessite and hydroxyapatite as an effective in situ remediation means for heavy metal contaminated sediment with minimal risk to the aquatic ecosystem. PMID- 21255928 TI - Enduring prevention and transient reduction of postoperative pain by intrathecal resolvin D1. AB - Postoperative pain slows surgical recovery, impacting the return of normal function for weeks, months, or longer. Here we report the antihyperalgesic actions of a new compound, resolvin D1 (RvD1), known to reduce inflammation and to suppress pain after peripheral nerve injury, on the acute pain occurring after paw incision and the prolonged pain after skin-muscle retraction. Injection of RvD1 (20-40ng) into the L5-L6 intrathecal space 30minutes before surgery reduces the postincisional primary mechanical hypersensitivity, lowering the peak change by approximately 70% (with 40ng) and reducing the area under the curve (AUC) for the entire 10-day postincisional course by approximately 60%. Intrathecal injection of RvD1 on postoperative day (POD) 1 reduces the hyperalgesia to the same level as that from preoperative injection within a few hours, an effect that persists for the remaining PODs. Tactile allodynia and hyperalgesia following the skin/muscle incision retraction procedure, measured at the maximum values 12 to 14days, is totally prevented by intrathecal RvD1 (40ng) given at POD 2. However, delaying the injection until POD 9 or POD 17 results in RvD1 causing only transient and incomplete reversal of hyperalgesia, lasting for <1day. These findings demonstrate the potent, effective reduction of postoperative pain by intrathecal RvD1 given before or shortly after surgery. The much more limited effect of this compound on retraction-induced pain, when given 1 to 2weeks later, suggests that the receptors or pathways for resolvins are more important in the early than the later stages of postoperative pain. Single intrathecal injections of resolvin D1 in rats before or 1 to 2days after surgery strongly reduce postoperative pain for several weeks. PMID- 21255930 TI - Reprint of: Surface electronic structure of Ti-covered W(1 1 1) by photofield emission. AB - Photofield emission (PFE) measurements are employed to examine modifications of the surface electronic structure of the tungsten (1 1 1) facet upon deposition of thin films (1-3 monolayers) of titanium. With the help of DFT simulations, the observed PFE features are interpreted as adsorbate-induced resonance states with energies just below the Fermi level, localized predominantly at the exposed surface atoms. Comparison between the computed surface DOS distributions and the measured PFE spectra is also used to verify various possible arrangements of the Ti adatoms, supporting the DFT-favored model of Ti growth in registry with the W(1 1 1) substrate until a full physical overlayer of the adsorbate is completed. PMID- 21255929 TI - Attention to painful cutaneous laser stimuli evokes directed functional connectivity between activity recorded directly from human pain-related cortical structures. AB - Our previous studies show that attention to painful cutaneous laser stimuli is associated with functional connectivity between human primary somatosensory cortex (SI), parasylvian cortex (PS), and medial frontal cortex (MF), which may constitute a pain network. However, the direction of functional connections within this network is unknown. We now test the hypothesis that activity recorded from the SI has a driver role, and a causal influence, with respect to activity recorded from PS and MF during attention to a laser. Local field potentials (LFP) were recorded from subdural grid electrodes implanted for the treatment of epilepsy. We estimated causal influences by using the Granger causality (GRC), which was computed while subjects performed either an attention task (counting laser stimuli) or a distraction task (reading for comprehension). Before the laser stimuli, directed attention to the painful stimulus (counting) consistently increased the number of GRC pairs both within the SI cortex and from SI upon PS (SI>PS). After the laser stimulus, attention to a painful stimulus increased the number of GRC pairs from SI>PS, and SI>MF, and within the SI area. LFP at some electrode sites (critical sites) exerted GRC influences upon signals at multiple widespread electrodes, both in other cortical areas and within the area where the critical site was located. Critical sites may bind these areas together into a pain network, and disruption of that network by stimulation at critical sites might be used to treat pain. Electrical activity recorded from the somatosensory cortex drives activity recorded elsewhere in the pain network and may bind the network together; disruption of that network by stimulation at critical sites might be used to treat pain. PMID- 21255931 TI - Prior and concomitant dehydroepiandrosterone treatment affects immunologic response of cultured macrophages infected with Trypanosoma cruzi in vitro? AB - DHEA, a steroid hormone synthesized from cholesterol by cells of the adrenal cortex, plays an essential role in enhancing the host's resistance to different experimental infections. Receptors for this hormone can be found in distinct immune cells (especially macrophages) that are known to be the first line defense against Trypanosoma cruzi infection. These cells operate through an indirect pathway releasing nitric oxide (NO) and cytokines such TNF-alpha and IL-12 which in turn trigger an enhancement of natural killer cells and lymphocytes which finally secrete pro and anti-inflammatory cytokines. The effects of pre- and post infection DHEA treatment on production of IL-12, TNFalpha and NO were evaluated. T. cruzi infected macrophages post treated with DHEA displayed enhanced concentrations of TNF-alpha, IL-12 and NO. Probably, the mechanisms that induced the production of cytokines by infected cells are more efficient when the immune system has been stimulated first by parasite invasion, suggesting that the protective role of DHEA is greater when administered post infection. PMID- 21255932 TI - Comparative susceptibility of carp fingerlings to Lernaea cyprinacea infection. AB - Study was conducted to find out the comparative susceptibility of fingerlings of seven species of carps (Labeo fimbriatus, L. rohita, L. calbasu, Catla catla, Ctenopharyngodon idella, Cyprinus carpio and Hypophthamichthys molitrix) grown under both mono and polyculture to Lernaea cyprinacea infection. Under monoculture, C. carpio, L. rohita and L. calbasu, did not acquire Lernaea infection and were thus considered resistant, whereas C. idella, H. molitrix, C. catla and L. fimbriatus were susceptible. Even challenge with higher infective doses of copepodids under monoculture did not result in infection in the resistant fish species. The resistance of L. rohita and C. carpio to Lernaea infection under monoculture was not sustained when these two fish species were maintained in polyculture along with susceptible fish species. Labeo calbasu, even under polyculture, however, did not acquire Lernaea infection indicating that this fish species is the most resistant and least preferred host for this parasite. Similarly, C. carpio, L. rohita and L. calbasu when grown together in polyculture and exposed to a higher infective dose (120 copepodids/fish) also did not develop the infection. The possible reasons for differences in susceptibility shown by these carp species in monoculture and the loss of resistance by rohu and common carp while in polyculture with susceptible species are discussed. The ability of resistant fish species to prevent establishment of anchor worms on them under monoculture can be utilized to control this parasitic infection commonly encountered in culture ponds. PMID- 21255933 TI - Genotyping of Toxoplasma gondii isolates from free range chickens in the Pantanal area of Brazil. AB - The aim of this paper was to genetically characterize Toxoplasma gondii isolates from free range chickens in regions of Brazilian territory in the state of Mato Grosso do Sul (MS) where T. gondii strains have never been studied. In total, T. gondii isolates from 22 free range chickens were included in this study. Fifty chickens from Eldorado, thirty from Rio Verde and ten from Aquidauana were sampled between January and April 2007. In relation to the genetic diversity of T. gondii isolates from chickens in MS, the magnitude of the diversity in the isolates sampled in this study was comparable to the overall diversity in a composite data set. These 22 isolates in MS revealed 11 genotypes, whereas the 321 isolates ever genotyped in Brazil have revealed 95 genotypes. The values of Simpson's Diversity Index for the whole population of T. gondii isolates in Brazil, the whole population of T. gondii isolates from chickens in Brazil and the population surveyed in this study were 0.97, 0.95 and 0.90, respectively. Seven of the 11 genotypes revealed from chicken isolates from MS are newly described genotypes and six of them each have a single isolate. In conclusion, the results obtained from isolates in MS corroborate previous studies on T. gondii isolates in Brazil, thus confirming their diversity and atypicality. Nonetheless, the applicability of PCR-RFLP markers for epidemiological inferences remains controversial. PMID- 21255934 TI - Oxidative stress parameters in silver catfish (Rhamdia quelen) juveniles infected with Ichthyophthirius multifiliis and maintained at different levels of water pH. AB - The aim of this study was to determine oxidative stress parameters in the liver, gill and muscle of silver catfish juveniles infected with Ichthyophthirius multifiliis and maintained at pH 5.0 or 7.0 for three days. Juveniles were infected by adding one I. multifiliis-infected juvenile and water containing theronts to tanks. After the appearance of white spots on the skin, infected juveniles exposed to pH 5.0 and 7.0 showed significantly higher thiobarbituric acid reactive substances (TBARS) levels in the liver and gills compared to uninfected juveniles. Liver of infected juveniles exposed to pH 7.0 showed higher catalase (CAT) and lower glutathione-S-transferase (GST) activities, but those maintained at pH 5.0 showed significantly higher GST activity than uninfected juveniles. The gills of infected juveniles showed significantly higher CAT (day two) and GST activity at both pH 5.0 and 7.0 compared to uninfected juveniles. Muscle of infected juveniles showed significantly lower CAT and GST activity and TBARS levels (at day three) when maintained at both pH 5.0 and 7.0 compared to uninfected juveniles. In conclusion, I. multifiliis infection induces liver and gill damage via lipid peroxidation products in silver catfish, but higher antioxidant enzyme activity could indicate a greater degree of protection against this parasite. PMID- 21255935 TI - Biochemical and histological responses of Rattus novergicus (Wistar) infected by Echinostoma paraensei (Trematoda: Echinostomatidae). AB - Tests were performed to evaluate the biochemical alterations in Rattus norvegicus after infection by the intestinal trematode Echinostoma paraensei. The rodents received 150 metacercariae each, serum samples were collected and the parasite load was quantified weekly until the fifth week of infection. The levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALKP), gamma-glutamyl transferase (GGT), bilirubin, glucose, total proteins and fractions and hepatic glycogen were determined. All the animals exposed to the metacercariae were infected in the first week and worms were recovered up to the third week after infection. The levels of AST, ALT, GGT, bilirubin and globulin rose in the first and/or second week and declined thereafter to levels near those of the control group. In contrast, the level of total proteins in the plasma fell significantly in the first week while the ALKP activity went down only in the fourth and fifth weeks in relation to the control group. There was no significant difference in the levels of albumin, glycogen and glucose. Infection by E. paraensei in R. norvegicus causes changes in the hepatic function, possibly resulting from the cholestasis produced by the partial obstruction of the bile duct by the helminths. PMID- 21255936 TI - Use of an autologous bioengineered composite skin in extensive burns: Clinical and functional outcomes. A multicentric study. AB - OBJECTIVE: We report clinical and functional outcomes obtained after application of an autologous bioengineered composite skin (ABCS) produced in a single Spanish tissue-engineering unit. MATERIALS/METHODS: Twenty-five burned patients treated with ABCS from 1999 to 2007 in five burn centres were included in the study. Mean age was 29 years (SD 11), with mean total body surface area (TBSA) burned being 74% (SD 17) and mean full-thickness injury of 61% (SD 19) of TBSA. RESULTS: The mean area initially engrafted with ABCS was 24% (SD 13) of TBSA, with a final take of 49% (SD 30, range 0-100%). ABCS achieved permanent coverage of a mean of 11% (SD 8) of TBSA. In subset analyses, lack of pre- and post-application wound bed infection and lack of serious acute systemic complications at the time of engraftment were significantly associated with better ABCS take. CONCLUSIONS: Final take obtained with ABCS could be improved with the use of non-cytotoxic topical antibiotics following engraftment. The use of plasma to prepare ABCS reduces production costs: cost-effectiveness ratio is not a limitation for its use. In terms of patient satisfaction, cosmetic/functional outcomes (general appearance, texture, flexibility, sensitivity and colour) of ABCS and split thickness autografts are not different statistically. PMID- 21255938 TI - Neurobiological and behavioral stress reactivity in children prenatally exposed to tobacco. AB - This study examined neurobiological and behavioral stress reactivity in children who had been prenatally exposed to tobacco. Neurobiological stress reactivity was measured using salivary cortisol and alpha-amylase levels at five different time points throughout a stressful neuropsychological test session, which involved a competition against a videotaped opponent. Participants (mean age: 10.6 years, SD 1.3) were 14 prenatally exposed (PE) children, 9 children with disruptive behavior problems (DBD), and 15 normal controls (NC). For cortisol responses, no significant differences between the three groups were observed. Normal controls, however, had significantly higher alpha-amylase levels than PE-children throughout the test session, and their alpha-amylase levels also increased throughout the session, whereas these remained low and stable for PE-children. Alpha-amylase levels and trajectory of PE-children were similar to those observed for DBD-children. PE-children also showed significantly increased behavioral stress reactivity compared to NC-children, and neurobiological and behavioral stress reactivity were inversely related in PE-children, again similar to what was observed for DBD-children. These results support the hypothesis that prenatal smoking may lead to long-lasting neurobiological and behavioral changes in exposed offspring. PMID- 21255937 TI - Behavioral effects of peripheral corticotropin-releasing factor during maternal separation may be mediated by proinflammatory activity. AB - When guinea pig pups are separated from their mothers in a novel environment, an initial period of active behavior (vocalizing, locomotor activity) wanes after an hour or so and is replaced by a second, passive stage characterized by a crouched stance, closed eyes, and extensive piloerection. If pups are given a peripheral injection of 7-14MUg of corticotropin-releasing factor (CRF) prior to testing, the passive behaviors occur immediately upon separation. We found that intracerebroventricular infusion of 1-10MUg of CRF did not increase passive behavior relative to vehicle infusion, but that peripheral injection of the anti inflammatory cytokine, interleukin-10, attenuated the passive behavior induced by peripheral CRF injection. These results together with previous findings suggest that peripheral CRF administration affects behavior of separated guinea pig pups through a mechanism that involves peripheral proinflammatory activity. The possible role of endogenous peripheral CRF in the behavioral response of untreated pups during maternal separation is considered. PMID- 21255939 TI - Polyclonal antitumor immunoglobulin may play a role in ovarian cancer adjuvant therapy. AB - Currently, surgery plus adjuvant chemotherapy are the mainstay of care in the treatment of ovarian cancer. Although this therapeutic strategy has been considered as "golden standard" regimen with profound impact on survival improvement, several obstacles have been encountered, such as chemotherapy drug resistance and disease relapse. Residual cancer cells in the abdominal cavity and vessels are considered as the main cause of disease relapse. New treatment options attempt to yield higher survival rate in patients. Monoclonal antibodies such as Trastuzumab and Cetuximab showed promising effects on several solid tumors. But for epithelial ovarian cancer, modalities of intravenous monoclonal antibody monotherapy have not achieved expected results as they have in the treatments of breast and colorectal cancer. Relatively low expression of matched receptors on ovarian cancer cells, as well as the intravenous delivery with less efficacy of intra-abdominal antibody accumulation, may account for lack of efficacy of monoclonal antibody on ovarian cancer. So we hypothesize that polyvalent antibodies boosted from rabbit by inoculating human tumor cells could deplete ovarian cancer cells through intraperitoneal route. The mechanisms may include interrupting ligand-receptor binding and thus result in blockage of intracellular signaling pathways such as EGFR and HER2 signal transduction, and possibly may also involve antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. PMID- 21255940 TI - Impaired glucose tolerance and metabolic syndrome in idiopathic polyneuropathy: the role of pain and depression. AB - Chronic idiopathic axonal polyneuropathy (CIAP) is referred to as axonal neuropathy after an adequate workup fails to determine a cause. A subgroup of patients with CIAP has impaired glucose tolerance (IGT). These patients have been considered by some investigators to have a neuropathy as a result of IGT and/or metabolic syndrome (MetS). Patients with CIAP usually suffer from chronic pain and associated depression, both of which have been proposed to cause insulin resistance (IR) by such mechanisms as a sustained increase in the corticosteroids and catecholamines, and chronic low grade inflammation. In a pilot study of 14 patients with CIAP+IGT and eight normal controls, we found a correlation between the number of features of the MetS with scores of pain and depression. There was no increase in the frequency of retinopathy and nephropathy in these patients, contrary to what would have been expected if chronic hyperglycemia was the cause of the neuropathy. We hypothesize that neuropathy has an unclear cause in the majority of patients with CIAP+IGT/MetS--and IGT/MetS are a result of comorbidities of CIAP, including chronic pain and depression. PMID- 21255941 TI - Peptide p3 may play a neuroprotective role in the brain. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disease. The amyloid beta (Abeta) peptide is considered a major etiological factor in the development of AD. BACE1-deficient mice and forebrain-specific conditional presenilin1 and presenilin2 double knockout mice (presenilins cDKO mice) both lack Abeta, but exhibit completely different phenotypes. The peptide p3 may play a neuroprotective role. A lack of peptide p3 could trigger an inflammatory response in the brain of presenilins cDKO mice. PMID- 21255942 TI - Feasibility of helical tomotherapy in stereotactic body radiation therapy for centrally located early stage non-small-cell lung cancer or lung metastases. AB - PURPOSE: To investigate the ability of helical tomotherapy (HT) to spare critical organs immediately adjacent to the tumor target in stereotactic body radiation therapy (SBRT) for centrally located lung lesions. METHODS AND MATERIALS: HT SBRT plans for 10 patients with centrally located lesions or lesions immediately adjacent to a critical structure were generated. A total of 70 Gy in 10 fractions was prescribed to the planning target volume (PTV) to satisfy a target volume coverage of >=95% PTV receiving 70 Gy and an established set of dose constraints for the organs at risk (OARs). Quality assurance (QA) of the HT plans was performed with both ion chamber and film measurements. RESULTS: The PTV coverage criteria was met with 95% of the PTV receiving 70.68 +/- 0.33 Gy for all cases even though the OARs immediately adjacent to the PTV ranged from 0.38 to 0.85 cm away. The mean lung dose (MLD), and V(20) were 7.15 +/- 1.44 Gy, and 11.93 +/- 3.24 % for the total lung, respectively. The dose parameters of MLD, V(5), V(10), and V(20) for the contralateral lung were significantly lower than those for the ipsilateral lung (p < 0.05). An average dose fall off from the PTV periphery to the edge of the immediately adjacent OAR was 47.6% over an average distance of 4.87 mm. Comparison of calculated and measured doses with the ion chamber showed an average of 1.85% point dose error, whereas an average mean gamma and the area with a gamma larger than 1 of 0.20 and 0.94% were observed, respectively. CONCLUSION: HT allows the sparing of critical structures immediately adjacent to the tumor target, thus making SBRT for these centrally located lesions feasible. PMID- 21255943 TI - Radiotherapy breast boost with reduced whole-breast dose is associated with improved cosmesis: the results of a comprehensive assessment from the St. George and Wollongong randomized breast boost trial. AB - PURPOSE: To evaluate comprehensively the effect of a radiotherapy boost on breast cosmetic outcomes after 5 years in patients treated with breast-conserving surgery. METHODS: The St. George and Wollongong trial (NCT00138814) randomized 688 patients with histologically proven Tis-2, N 0-1, M0 carcinoma to the control arm of 50 Gy in 25 fractions (342 patients) and the boost arm of 45 Gy in 25 fractions to the whole breast followed by a 16 Gy in 8 fraction electron boost (346 patients). Five-year cosmetic outcomes were assessed by a panel subjectively in 385 patients and objectively using pBRA (relative breast retraction assessment). A subset of patients also had absolute BRA measurements. Clinician assessment and patient self-assessment of overall cosmetic and specific items as well as computer BCCT.core analysis were also performed. RESULTS: The boost arm had improved cosmetic overall outcomes as scored by the panel and BCCT.core software with 79% (p = 0.016) and 81% (p = 0.004) excellent/good cosmesis respectively compared with 68% in no-boost arm. The boost arm also had lower pBRA and BRA values with a mean difference of 0.60 and 1.82 mm, respectively, but was not statistically significant. There was a very high proportion of overall excellent/good cosmetic outcome in 95% and 93% in the boost and no-boost arms using patient self-assessment. However, no difference in overall and specific items scored by clinician assessment and patient self-assessment was found. CONCLUSION: The results show the negative cosmetic effect of a 16-Gy boost is offset by a lower whole-breast dose of 45 Gy. PMID- 21255944 TI - Interstitial fluid pressure and vascularity of intradermal and intramuscular human tumor xenografts. AB - PURPOSE: High interstitial fluid pressure (IFP) in tumors has been shown to be associated with poor prognosis. Mechanisms underlying the intertumor heterogeneity in IFP were investigated in this study. METHODS AND MATERIALS: A-07 melanoma xenografts were transplanted intradermally or intramuscularly in BALB/c nu/nu mice. IFP was measured in the center of the tumors with a Millar catheter. Tumor blood perfusion and extracellular volume fraction were assessed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The necrotic fraction, vascular density, and vessel diameters of the tumors were determined by image analysis of histological preparations. RESULTS: Significant intertumor heterogeneity in IFP, blood perfusion, and microvascular morphology was observed whether the tumors were transplanted intradermally or intramuscularly. High IFP was mainly a consequence of high resistance to blood flow caused by low vessel diameters in either transplantation site. IFP decreased with increasing blood perfusion in intradermal tumors and increased with increasing blood perfusion in intramuscular tumors, mainly because the morphology of the tumor microvasculature differed systematically between the two tumor models. CONCLUSION: The potential of DCE-MRI as a noninvasive method for assessing the IFP of tumors may be limited because any relationship between IFP and blood perfusion may differ with the tumor growth site. PMID- 21255945 TI - [Two cases of juvenile gigantomastia treated by reduction mammaplasty with nipple areola complex graft]. AB - Two cases of juvenile gigantomastia treated by reduction mammaplasty with nipple areola complex graft. Juvenile gigantomastia or virginal hypertrophy is a volume anomaly of breast of the teenager. It is unsightly. But often, it is pain, impaired spinal posture and the shoulder girdle and the psychological effects that bring the teenager to make an application for aesthetic surgery. We report two cases of juvenile and bilateral gigantomastia in adolescents aged 13 years old and unresolved. They have lost their hope before surgical procedure. In both cases, treatment consisted of a reduction mammaplasty with nipple-areola complex graft according to the technique of Thorek. The total resection was 3500 and 2900 g of breast tissue in one and 4000 g per breast in the other. Satisfaction regarding the shape, size and symmetry of the reconstructed breast was good. Although the effects on breastfeeding remain patent, the psychological impact was favorable in all cases. PMID- 21255946 TI - Microarray analyses of THP-1 cells infected with Streptococcus suis serotype 2. AB - Streptococcus suis serotype 2 (S. suis 2) is a pathogen responsible for several diseases in both pigs and humans. To gain more insight into the pathogenesis of this organism, an oligonucleotide (oligo)-based microarray was used to investigate gene expression changes in human monocytic cells (THP-1) in response to exposure to S. suis 2 strain SC19. A total of 328 differentially expressed genes were identified. These differentially expressed genes belonged to a variety of functional categories, including genes involved in apoptosis, immunity, signal transduction, chemokine production and the ubiquitin-proteasome system. Our findings can be of interest for future research. PMID- 21255947 TI - A review of the causes of poor fertility in high milk producing dairy cows. AB - Fertility in dairy cows has declined over the past five decades as milk production per cow has increased. Many hypotheses have been proposed to explain this including issues of genetics, physiology, nutrition and management, and these factors have been investigated at the animal, organ and cellular level at critical time points of the productive life of dairy cows. This paper reviews the physiological events and their causes and consequences affecting fertility in dairy cows and summarises these in a downloadable poster. We consider the following points to have the greatest negative impact on fertility and that they need to be prioritised in efforts to ameliorate the problem (others have been included in the review). Firstly, minimise negative energy balance and resolve any infection of the post partum uterus. Secondly, expression and detection of oestrus followed by insemination with high quality semen (day 0). Thirdly, ovulation and fertilisation of a high quality oocyte (day 1). Fourthly, an early increase in progesterone secretion from the corpus luteum (days 3-7). Fifthly, the uterine endometrium must produce an early and appropriate environment to stimulate embryo development (days 6-13). This leads to sixthly, a large embryo producing adequate quantities of interferon tau (days 14-18) that alters uterine prostaglandin secretion and signals maternal recognition of pregnancy (days 16 18). Future strategies to improve dairy cow fertility are needed for the benefit of the dairy industry and for cow welfare and should be based upon an integrative approach of these events. PMID- 21255948 TI - The bodies of two missing children in an enclosed underground environment. AB - Two young children, respectively 11 and 13 years old, originally from a small town of Southern Italy, were missing on 5 June 2006 (06:30 p.m.). Soon after their disappearance, the search for the missing children began. Broadcasters promptly transmitted a description of the missing children, pushing the entire community to assist in the search and safe recovery of the children. However, every effort was in vain, and the search went on for more than 1 year. During the missing-child search, the investigators collected enough evidence against the father, who was arrested 17 months after the children's disappearance. He was indicted for kidnapping, homicide and concealment of the two bodies. He never confessed to the crimes and claimed to be innocent. Three months after the conviction, a fireman found the two corpses in a subterranean, dry cistern next to a well over 20 m deep. The bodies were well preserved, almost mummified, with only few body-parts skeletonised. Based on dental records, they were identified as those of the two children, who had gone missing 1.5 years before. Signs of a very low insect activity were present, reasonably consistent with a rapid skin dehydration. The autopsy showed no signs of defence injuries or ligature consistent with strangulation or captivation, except for fractures of the axial skeleton at a number of points consistent with a fall from a low-medium height. The body of the elder brother presented major injuries with signs of recent haemorrhages and gut content analysis consistent with the last meal, which provided enough evidence to ascertain a very short survival time. The younger child showed minor injuries, signs of old haemorrhages and gastric- and intestine emptying time consistent with a longer survival time of approximately 3-4 days, spent alone in the dark and cold cistern. A long post-mortem interval (PMI) of approximately 20 months was estimated, mainly from the pattern of insect succession. Based on such physical evidence, on 4 March 2008, 4 months after conviction and 40 days after the recovery of the two bodies, the father was finally released from prison and exonerated from previous indictment of homicide. PMID- 21255949 TI - Management of cervical lymph node metastasis in tonsillar squamous cell carcinoma: Is it necessary to treat node-negative contralateral neck? AB - OBJECTIVE: To investigate the appropriate management of cervical lymph node metastasis in patients with tonsillar squamous cell carcinoma (SCC). METHODS: The medical records of 49 patients that were surgically treated for tonsillar SCC were evaluated. Preoperative and postoperative stages, clinical factors affecting the nodal metastasis, and its relationship with survival were examined. RESULTS: Among 49 ipsilateral neck dissection (ND) specimens, 34 neck specimens (69%) were pN+. Out of 17 cases that underwent ipsilateral elective NDs, 4 cases (24%) were found to have pN+ necks. The disease-specific survival of the 34 patients with pN+ necks and 4 patients with occult metastases was worse than that of the remaining patients with pN0 necks and without occult metastasis, respectively (p=0.049 and p=0.023, respectively). All cases (100%) that underwent contralateral therapeutic NDs had pN+ findings. Two out of the 21 cases (less than 10%) that underwent contralateral elective NDs turned out to have pN+ necks and did not show any difference in survival compared to the 19 cases with pN0 necks. The degree of differentiation was associated with contralateral nodal metastasis. CONCLUSION: Patients with tonsillar SCC require thorough ipsilateral neck treatment because of the high probability of nodal metastasis and the close association between lymph node metastasis and survival. The contralateral cN+ neck should also be treated; however, the contralateral cN0 neck might be preserved with caution on the cases with poorly differentiated primary tumors and/or ipsilateral cN+ necks. PMID- 21255950 TI - Neuropsychological status of children with newly diagnosed idiopathic childhood epilepsy. AB - We characterized the neuropsychological status of children with newly diagnosed idiopathic childhood epilepsy and measured differences in IQ between children with different types of epilepsy. The Korean Education Development Institute Wechsler Intelligence Scale for Children (KEDI-WISC) was administered to 72 patients (35 males and 37 females), of mean age 8.7+/-2.6 years, with newly diagnosed idiopathic childhood epilepsy. Of these patients, 22 (30.6%) had generalized epilepsy, 48 (66.7%) localization-related epilepsy, and 2 (2.8%) mixed epilepsy. Children with generalized epilepsy and benign childhood epilepsy with centro-temporal spikes (BCECTS) were of similar verbal IQ and full-scale IQ, although performance IQ was significantly lower in patients with generalized epilepsy. Among children with BCECTS, those with unilateral spikes had higher full-scale and performance IQ scores than those with bilateral spikes. Follow-up studies on large numbers of patients are needed to determine the effects of epilepsy per se, and antiepileptic drugs, on intelligence. PMID- 21255951 TI - E-learning and education in radiology. AB - PURPOSE: To evaluate current applications of e-learning in radiology. MATERIAL AND METHODS: A Medline search was performed using PubMed (National Library of Medicine, Bethesda, MD) for publications discussing the applications of e learning in radiology. The search strategy employed a single combination of the following terms: (1) e-learning, and (2) education and (3) radiology. This review was limited to human studies and to English-language literature. We reviewed all the titles and subsequent the abstract of 29 articles that appeared pertinent. Additional articles were identified by reviewing the reference lists of relevant papers. Finally, the full text of 38 selected articles was reviewed. RESULTS: Literature data shows that with the constant development of technology and global spread of computer networks, in particular of the Internet, the integration of multimedia and interactivity introduced into electronic publishing has allowed the creation of multimedia applications that provide valuable support for medical teaching and continuing medical education, specifically for radiology. Such technologies are valuable tools for collaboration, interactivity, simulation, and self-testing. However, not everything on the World Wide Web is useful, accurate, or beneficial: the quality and veracity of medical information on the World Wide Web is variable and much time can be wasted as many websites do not meet basic publication standards. CONCLUSION: E-learning will become an important source of education in radiology. PMID- 21255952 TI - Learning from diagnostic errors: a good way to improve education in radiology. AB - PURPOSE: To evaluate the causes and the main categories of diagnostic errors in radiology as a method for improving education in radiology. MATERIAL AND METHODS: A Medline search was performed using PubMed (National Library of Medicine, Bethesda, MD) for original research publications discussing errors in diagnosis with specific reference to radiology. The search strategy employed different combinations of the following terms: (1) diagnostic radiology, (2) radiological error and (3) medical negligence. This review was limited to human studies and to English-language literature. Two authors reviewed all the titles and subsequently the abstracts of 491 articles that appeared pertinent. Additional articles were identified by reviewing the reference lists of relevant papers. Finally, the full text of 75 selected articles was reviewed. RESULTS: Several studies show that the etiology of radiological error is multi-factorial. The main category of claims against radiologists includes the misdiagnoses. Radiologic "misses" typically are one of two types: either missed fractures or missed diagnosis of cancer. The most commonly missed fractures include those in the femur, the navicular bone, and the cervical spine. The second type of "miss" is failure to diagnose cancer. Lack of appreciation of lung nodules on chest radiographs and breast lesions on mammograms are the predominant problems. CONCLUSION: Diagnostic errors should be considered not as signs of failure, but as learning opportunities. PMID- 21255953 TI - Radiographic study of the hip joint to determine anthropometric parameters for Indian population. AB - Hip replacement surgeries are on the rise in India. However, for these surgeries, most of the implants used are imported and manufactured entirely to suit the geometrical considerations of the western population. Studies in the past have shown that there are anatomical variations in the hip joint for different ethnic backgrounds and geographical locations. There is paucity of anthropometric hip joint data related to Indian population and anthropometric variations in skeletal geometry between Asian and Western counterparts have not yet been thoroughly reviewed and considered for implant manufacturing. The purpose of this anthropometric study is to determine any anatomical variations in the normal hip joint among the Indian population and to statistically compare the mean values with the existing data on western population. 422 Hip radiographs of 211 individuals (141 males and 70 females) with normal and healthy hip joints were evaluated to obtain the horizontal offset, vertical offset and neck shaft angle. For males, mean neck shaft angle was 127.68 degrees (SD = 3.94), horizontal offset was 34.60mm (SD=6.55) and vertical offset was 39.17 mm (SD = 5.86). For females, mean neck shaft angle was 125.92 degrees (SD = 4.75), horizontal offset was 32.96 mm (SD = 7.04) and vertical offset was 36.38 mm (SD = 6.28). When these parameters were compared to the data available from western world, there were significant anatomical variations and it was evident that there is a need to evaluate existing implants in relation to this data and possibly design the implants suited and relevant to Indian population. PMID- 21255954 TI - More information in imaging examination. PMID- 21255955 TI - The CONNECT (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision) trial: the value of wireless remote monitoring with automatic clinician alerts. AB - OBJECTIVES: The primary objective was to determine if wireless remote monitoring with automatic clinician alerts reduces the time from a clinical event to a clinical decision in response to arrhythmias, cardiovascular (CV) disease progression, and device issues compared to patients receiving standard in-office care. A secondary objective was to compare the rates of CV health care utilization between patients in the remote and in-office arms. BACKGROUND: In addition to providing life-saving therapy, implantable cardioverter defibrillators collect advanced diagnostics on the progression of the patient's heart disease. Device technology has progressed to allow wireless remote monitoring with automatic clinician alerts to replace some scheduled in-office visits. METHODS: The CONNECT (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision) study was a multicenter, prospective, randomized evaluation involving 1,997 patients from 136 clinical sites who underwent insertion of an implantable cardioverter-defibrillator (including cardiac resynchronization therapy devices) and were followed up for 15 months. Health care utilization data included all CV-related hospitalizations, emergency department visits, and clinic office visits. RESULTS: The median time from clinical event to clinical decision per patient was reduced from 22 days in the in-office arm to 4.6 days in the remote arm (p < 0.001). The health care utilization data revealed a decrease in mean length of stay per CV hospitalization visit from 4.0 days in the in-office arm to 3.3 days in the remote arm (p = 0.002). CONCLUSIONS: Wireless remote monitoring with automatic clinician alerts as compared with standard in-office follow-up significantly reduced the time to a clinical decision in response to clinical events and was associated with a significant reduction in mean length of CV hospital stay. (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision [CONNECT]; NCT00402246). PMID- 21255956 TI - Apolipoprotein A-I therapy promise, challenges, and disappointment. PMID- 21255957 TI - Efficacy and safety of a novel oral inducer of apolipoprotein a-I synthesis in statin-treated patients with stable coronary artery disease a randomized controlled trial. AB - OBJECTIVES: The purpose of this study was to investigate the safety, tolerability, and efficacy of RVX-208, the first oral agent designed to enhance apolipoprotein (apo) A-I synthesis. BACKGROUND: No agent that selectively induces synthesis of apoA-I has reached an advanced stage of clinical development. METHODS: A total of 299 statin-treated patients with coronary artery disease were treated with placebo or with RVX-208 at a dose of 50, 100, or 150 mg twice daily for 12 weeks. Changes in lipid-related biomarkers, in addition to safety and tolerability, of RVX-208 were investigated. RESULTS: For each dose of RVX-208, individual pairwise comparisons of apoA-I changes with placebo, the primary end point, did not achieve statistical significance. However, treatment with RVX-208 was associated with a dose-dependent increase in apoA-I levels by up to 5.6% (p = 0.035 for trend). Administration of RVX-208 resulted in significant increases in levels of high-density lipoprotein cholesterol (HDL-C) ranging from 3.2% to 8.3% (p = 0.02), and large HDL particles increased by 11.1% to 21.1% (p = 0.003). ApoA I levels increased rapidly from 8 to 12 weeks, suggesting that peak pharmacological effect has not been achieved by the end of the 12-week study. Transient and reversible elevations in liver transaminases >3 times the upper limit of normal were observed in 18 patients treated with RVX-208, with no associated increase in bilirubin levels. CONCLUSIONS: Administration of RVX-208 for 12 weeks was associated with increases in apoA-I, HDL-C, and concentration of large HDL particles, consistent with facilitation of cholesterol mobilization. Maximal increases in apoA-I may require longer exposure. An increase in liver enzymes was observed with active treatment. (Clinical Trial for Dose Finding and Safety of RVX000222 in Subjects With Stable Coronary Artery Disease; NCT01058018). PMID- 21255958 TI - Patient navigation from the paired perspectives of cancer patients and navigators: a qualitative analysis. AB - OBJECTIVE: Patient navigation for cancer care assesses and alleviates barriers to health care services. We examined paired perspectives of cancer patients and their navigators to examine the process of patient navigation. We explored the strengths, limitations, and our own lessons learned about adopting the novel methodology of multiperspective analysis. METHODS: As part of a larger RCT, patients and navigators were interviewed separately. We reviewed interviews with 18 patient-navigator dyads. Dyad summaries were created that explicitly incorporated both patient and navigator perspectives. Emerging themes and verbatim quotations were reflected in the summaries. RESULTS: Paired perspectives were valuable in identifying struggles that arose during navigation. These were represented as imbalanced investment and relational amelioration. Patients and navigators had general consensus about important patient needs for cancer care, but characterized these needs differently. CONCLUSION: Our experience with multiperspective analysis revealed a methodology that delivers novel relational findings, but is best conducted de novo rather than as part of a larger study. PRACTICE IMPLICATIONS: Multiperspective analysis should be more widely adopted with clear aims and analytic strategy that strengthen the ability to reveal relational dynamics. Navigation training programs should anticipate navigator struggles and provide navigators with tools to manage them. PMID- 21255959 TI - Benefits of concurrent syringe exchange and substance abuse treatment participation. AB - Participation in syringe exchange programs (SEPs) is associated with many individual and public health benefits but may have little impact on reducing drug use without concurrent treatment engagement. This study evaluated rates of drug use, other risk behaviors, and illegal activities in newly registered SEP participants (N = 240) enrolled versus not enrolled in substance abuse treatment over a 4-month observation window and examined the effect of days in treatment on these outcomes. After controlling for baseline differences, SEP registrants enrolled in treatment (n = 113) reported less days of opioid and cocaine use, injection drug use, illegal activities, and incarceration than those not enrolled in treatment (n = 127). For those enrolled in treatment, days of treatment was strongly correlated with each of these outcomes. These findings provide good evidence for a dose-response effect of treatment in syringe exchangers and suggest that substance abuse treatment significantly expands the harm reduction benefits of SEP participation. PMID- 21255961 TI - Correlates of motivation to change in adolescents completing residential substance use treatment. AB - This research identified psychosocial correlates of motivation to change in adolescents being discharged from residential treatment for substance use disorders. Using a naturalistic longitudinal design, adolescents in a residential treatment program in southeast Ohio were assessed at intake and discharge using self-administered questionnaires. Surveys assessed motivation to change one's drug and alcohol use, ways of coping to avoid future alcohol/substance use, and social support. The 68 participants (mean age = 16.0, range = 12-18) were predominantly Caucasian (87%) and male (69%). Over the course of treatment, adolescents reported significant increases in active-cognitive coping, avoidant behavioral coping, and attachment and marginally significant increases in motivation to change and reliable alliance. Adolescents who reported higher discharge levels of motivation to change also reported greater levels of social integration at discharge. Strengthening adolescents' social integration may also increase their motivation to avoid using drugs and alcohol as they prepare to exit treatment and return to their home communities. PMID- 21255960 TI - Higher maternal doses of methadone does not increase neonatal abstinence syndrome. AB - OBJECTIVE: The purpose of this study is to assess the incidence of clinically significant neonatal abstinence syndrome (NAS) based on maternal antenatal methadone dosing in women with a history of narcotic dependence. STUDY DESIGN: A retrospective review of 174 pregnant women on methadone maintenance was performed. Data were stratified based on maternal methadone dose at delivery: low (0-50 mg/day, n = 59), medium (51-100 mg/day, n = 63), and high (>100 mg/day, n = 52). NAS was defined by Finnegan as score greater than 7 on two occasions. Outcome measures were rate and severity of NAS, birth weight, preterm birth rate, and neonatal morbidities and mortality. RESULTS: The rates of NAS (40.7% vs. 52.4% vs. 40.8%, p > .05), birth weight, and neonatal morbidities were similar regardless of the maternal methadone dose. Although there was a trend toward earlier delivery, the rate of preterm birth among the three groups (low dose, 17%; medium dose, 19%; high dose, 27%; p > .05) was not statistically significant. CONCLUSION: Higher maintenance dosing of methadone is not associated with increased rate or severity of NAS or other adverse perinatal outcomes. Concerns about NAS should not restrict the methadone dosing during pregnancy. Methadone dosing should not be restricted to lower dosing during pregnancy. PMID- 21255962 TI - Hemorrhagic shock worsens neuromuscular recovery in a porcine model of hind limb vascular injury and ischemia-reperfusion. AB - BACKGROUND: In order to advance beyond basic statistical limb salvage to improved functional or quality limb salvage, a better understanding of the ischemic threshold of the limb is required. To date, models of extremity ischemia and reperfusion involve small animals and few include survival with physiologic measures of nerve and muscle recovery. In addition, the effect of hemorrhagic shock on the ischemic threshold of the extremity is unknown. This study characterized the effect of class III hemorrhagic shock on the ischemic threshold of the extremity in a large-animal model of neuromuscular recovery. METHODS: Yorkshire/Landrace-cross swine (weight, 70-90 kg) were randomized to iliac artery repair either immediately or at 1, 3, or 6 hours after vessel loop occlusion and arteriotomy. A fifth group underwent excision of the arterial segment without repair to represent ligation. Class III shock was created by removing 35% of total blood volume using a variable rate model. Animals were monitored for 14 days to serially collect markers of functional recovery. RESULTS: Animals with <=1 hour ischemia (control) had clinically normal limb function by the end of the 2-week observation period, with minimal muscle and nerve changes on histology. Separate analysis of contralateral, nonexperimental limbs revealed normal histology and function. After 3 hours of ischemia, functional recovery was impaired, with moderate-to-severe degeneration of nerve and muscle noted on histology. Animals undergoing 6 hours of ischemia or ligation had minimal electromyelography response and severe systemic inflammation, which correlated with severe muscle and nerve degeneration. Concurrent class III hemorrhagic shock was associated with a decrement in neuromuscular recovery across all groups but was greatest in groups undergoing >=3 hours of extremity ischemia (P < .01). CONCLUSIONS: This study demonstrates the feasibility of combined hemorrhagic shock and extremity ischemia-reperfusion in a large-animal survival model. The presence of hemorrhagic shock compounds the effect of extremity ischemia, reducing the ischemic threshold of the limb to <3 hours. Strategies to improve functional salvage after extremity vascular injury in the setting of shock should include attempts at restoration of flow <=60 minutes. PMID- 21255965 TI - [Analysis of 379 drug prescriptions at a call Center 15]. AB - INTRODUCTION: Prescription of medicines by telephone (PMT) in the call Center 15 is a reality, but has never been studied. OBJECTIVE: The objective was a Qualitative and quantitative study of the PMT. METHOD: A monocentric and observational study of calls for a week of the center 15 of Besancon (France) was performed. MATERIAL: Computer records and dial center 15 recordings of telephone conversations were analyzed. Variables analyzed were characteristics of callers, context of the requirement, analysis of compliance with the summary of product characteristics and mode of access to medicines. RESULTS: Among 1183 appeals studied, a PMT was performed in 379 cases (32%). New and isolated prescriptions are the most frequent. 68% of PMT correspond to optional prescriptions. The 539 drugs prescribed belong to 4 main groups: analgesics, non steroidal anti inflammatory, anti spasmodic, anti-diarrheal. In 9 out of 10 cases these drugs are from the family pharmacy. CONCLUSION: The PMT at the center 15 is realized in one third of cases. This work helps highlight the shortcomings of the practice in terms of safety and security requirement of the proceedings against the recommendations of the French High Authority for Health. PMID- 21255964 TI - [Routine ankle brachial pressure index measurement for peripheral artery disease diagnosis in internal medicine department: Comparison with the recommendations of the Haute Autorite de Sante. Prospective descriptive study about 106 patients]. AB - PURPOSE: The ankle brachial pressure index (ABPI) makes it possible to diagnose peripheral artery disease (PAD) and identify patients with a vascular risk. Recently, the Haute Autorite de sante (HAS) issued guidelines. We wanted to determine the interest and impact of these guidelines when applied to patients hospitalised in an internal medicine department. METHODS: We systematically measured the ABPI in two internal medicine departments. We compared the results obtained with the screening criteria and the good practices recommended by the HAS. RESULTS: The screening criteria recommended by the HAS were already applied in 91% of our 97 patients. PAD was found in 37.1% of patients. In 83% of cases, the diagnosis was unknown (p = 0.02). The PAD was symptomatic in 83% of the known PAD cases, and 3.3% in newly-diagnosed cases (p < 0.001)). The sensitivity of the HAS screening criteria applied to our population was 100% but almost patients justifies ABPI screening. The specificity was 11.5%, the positive predictive value 40% and the negative predictive value 100%. The optimal treatment recommended was implemented in only 50% of patients with known arteriopathy and in 10% of newly-diagnose PAD (p = 0.04). CONCLUSION: PAD prevalence is high in internal medicine department and systematic measurement of ABPI is effective. Determining patients to screen with the HAS criteria has a poor impact in our patients. The optimal treatment is still extremely under-prescribed even in patients with known PAD. PMID- 21255966 TI - [A dermatosis that reveals another...]. PMID- 21255967 TI - [Pathophysiology of epilepsies: recent progresses]. AB - Epilepsy is often due to an initial aggression (brain trauma etc.). Decades can pass before the appearance of spontaneous recurrent seizures. It is therefore important to understand the mechanisms responsible for the construction of an epileptic brain. Understanding these mechanisms would open the way to preventive treatments.The probability of appearance of epilepsy after an initial insult is rather low. A preventive treatment can only be applied if predictive markers exist. The occurrence of interictal spikes and the presence of cognitive deficits could constitute early markers of epileptogenesis (the process leading to epilepsy). Epileptogenesis can be studied in animal models of epilepsy. In these models, the opening of the brain blood barrier, the neuro-inflammatory response, and the activation of some genes play a pivotal role in epileptogenesis. Therapeutical interventions targeting these candidates have beneficial effects, delaying epileptogenesis, but not preventing them. Future research directions for the early treatment of at-risk patients will be discussed. PMID- 21255968 TI - The role of echocardiography in the early diagnosis of the complications of endovascular repair of blunt aortic injury. AB - PURPOSE: Endovascular repair of traumatic aortic injury has been associated with severe procedural complications, including endoleaks, coverage of the left subclavian artery, stent collapse, access complications, and questionable durability. Echocardiography has proven to be a valuable tool in the intraoperative detection of these complications. In the current study, we report on the use of echocardiography as an early postoperative diagnostic technique for the evaluation of endovascular stent graft positioning in the intensive care setting. METHODS: From January 2005 to January 2009, 14 patients who underwent endovascular repair of a blunt aortic injury were admitted in our intensive care unit. Transesophageal and/or transthoracic echocardiography were used as first line diagnostic tools in the assessment of the endovascular graft position. RESULTS: Twenty-eight percent of patients (4 of 14) developed a pressure gradient between upper and lower limbs (greater than 50 mm Hg), which presented with persistent hypertension, requiring antihypertensive therapy in high doses and difficult weaning. In all 4 patients, stent graft malposition was identified using echocardiography. The diagnosis was verified by computed tomography and aortography. CONCLUSION: Noninvasive echocardiographic monitoring proved to be a valuable tool in the early diagnosis of postoperative stent graft malalignment. To our knowledge, this is the first time that echocardiography is described in the relevant literature as an early diagnostic technique in this setting. PMID- 21255969 TI - Prediction of stroke volume by global left ventricular longitudinal strain in patients undergoing assessment for cardiac transplantation. AB - PURPOSE: Speckle-tracking echocardiography (STE) is a novel technique that can be used for assessment of left ventricular (LV) longitudinal deformation dynamics. Using cardiac catheterization as the reference standard, the aim of this study was to evaluate the relation between LV global longitudinal strain (GLS) assessed by STE and LV stroke volume in patients undergoing assessment for cardiac transplantation. METHODS: Conventional echocardiography and STE were performed during right-sided cardiac catheterization in 51 patients referred for cardiac transplant assessment. Thermodilution LV stroke volume indexed (LVSVI) was used as the reference standard. Univariate regression analyses and receiver operating characteristics curves were used to test correlations between LVSVI and GLS by STE. RESULTS: Global longitudinal strain was obtained successfully in 95.5% of patients. Among all variables analyzed, GLS best predicted the LVSVI (r = 0.79; P < .0001). Minor correlations with the LVSVI were observed for tissue Doppler derived systolic mitral annular velocity (r = 0.51; P < .005) and for LV ejection fraction (r = 0.32; P < .05). CONCLUSIONS: In a group of patients referred for cardiac transplant assessment, LV longitudinal deformation analysis by STE closely correlates with LVSVI, suggesting that, in this particular clinical setting, this new parameter may help provide an accurate, noninvasive, and quantitative assessment of LV function. PMID- 21255970 TI - Admission hyperlactatemia: causes, incidence, and impact on outcome of patients admitted in a general medical intensive care unit. AB - PURPOSE: The aim of this study was to evaluate the causes, incidence, and impact on outcome of admission hyperlactatemia in patients admitted to a general medical intensive care unit (ICU). METHODS: A retrospective cohort study was done in an 8 bed general ICU of tertiary care hospital over 15 months. Data regarding patient demographics, probable cause of hyperlactatemia, presence of shock, need for organ support, and ICU outcome were recorded. Patients were divided into 2 groups based on admission lactate levels as follows: high lactate (>2 mmol/L) and normal lactate (<2 mmol/L). Patients were compared in terms of need for organ support and ICU mortality. RESULTS: Admission hyperlactatemia was present in 199 of 653 (30.47%) patients. Shock was the commonest cause, 53.3% patients, followed by respiratory and renal failure in 26 (13.1%) and 16 (8%) patients, respectively. Mean +/- SD lactate levels in survivors and nonsurvivors were 1.64 +/- 1.56 and 4.77 +/- 4.72 mmol/L, respectively (P = .000). Receiver operating characteristic curve for lactate was 0.803 (95% confidence interval [CI], 0.753-0.853). Sensitivity and specificity of lactate (>2 mmol/L) to predict ICU mortality was 74.8% and 77.8%, respectively. Odds ratio for dying in patients with hyperlactatemia was 10.39 (95% CI, 6.378-16.925) with a relative risk of 1.538 (95% CI, 1.374-1.721). On subgroup analysis, in patients without hypotension too, ICU mortality was significantly increased in patients with hyperlactatemia (1.3% vs 6.45%, P = .009). CONCLUSIONS: Admission hyperlactatemia is common in a general ICU and is associated with increased mortality, irrespective of presence of hypotension. Shock was the commonest cause for hyperlactatemia, followed by respiratory and renal failures. PMID- 21255971 TI - Failure to achieve euglycemia despite aggressive insulin control signals abnormal physiologic response to trauma. AB - PURPOSE: We hypothesize that a failure to normalize a patient's glucose on an automated euglycemia protocol signals an adverse response after trauma and that this response can identify patients with an increased mortality. MATERIALS AND METHODS: There were 1246 ventilated, critically ill trauma patients who were placed on an automated euglycemia. All glucose values collected both by laboratory serum measurements and by bedside arterial samples were included in the analysis. RESULTS: Forty six thousand two hundred eighteen data entries for glucose (mg/dL) were analyzed. Time to normalization, defined as the first value in the goal range of 80 to 110 mg/dL, was different between the 2 groups, survivors correcting significantly faster (396 vs 487 minutes; P = .003). Mortality in patients who normalized (80-110 mg/dL) in the first 6 hours of admission was 13.6% vs 18.3% in patients requiring greater than 6 hours (P = .02). Patients who never normalized also required significantly greater insulin doses despite there being no significant difference in demographic data between the 2 groups. CONCLUSIONS: A posttraumatic patient's response to tight glycemic control revealed important prognostic information about the patients' physiologic status. Patients who failed to reach euglycemia in the first 6 hours of admission had an increased hospital mortality. The time to normalization is significantly longer in those patients who died. Patients who did not correct rapidly required significantly higher insulin doses, suggesting insulin resistance. PMID- 21255972 TI - Predictors of stress-related growth in parents of children with ADHD. AB - This study was designed to investigate stress-related growth in 71 parents of children with ADHD, compared with 80 parents of non-clinical children. Adopting Tedeschi and Calhoun's (2004) theoretical framework for predicting personal growth, the study investigated the contribution of emotional intelligence (individual characteristics), social support (environmental factors), parental self-efficacy and perceptions of parenting as a challenge vs. a threat (cognitive processing). Results indicated that emotional intelligence was the main predictor of stress-related growth, particularly for parents of ADHD children, emphasizing that this personal trait is especially relevant to coping with on-going parental strain; whereas social support made a greater contribution to growth for the control group than for parents of children with ADHD. Path analysis confirmed our research model, suggesting that parents' sense of competence and of parenthood as a challenge vs. a threat mediates between emotional intelligence and social support on the one hand, and growth on the other. PMID- 21255973 TI - Effortful control in typically developing boys and in boys with ADHD or autism spectrum disorder. AB - Despite increased interest in the role of effortful control (EC) in developmental disorders, few studies have focused on EC in autism spectrum disorders (ASD) and no study so far has directly compared children with ASD and children with ADHD. A first aim of this study was to investigate whether typically developing (TD) boys, boys with ADHD and boys with ASD can be differentiated based on EC levels. A second aim was to evaluate the relationship between EC and symptoms of ADHD and ASD. We assessed EC in 27 TD boys, 27 boys with ADHD and 27 boys with ASD (age 10 15) using different EC questionnaires. Clinical groups scored lower than the TD group on all EC total scales, but could only be differentiated from each other by means of self-reported persistence, impulsivity and activation control. Our data suggest that although EC is useful in differentiating TD boys from clinical groups, it is less efficient in distinguishing ADHD from ASD. Also, results suggest that EC plays a role in the manifestation of symptoms of both ADHD and ASD and that high levels of EC enable children to function more adequate in daily situations. PMID- 21255974 TI - Determining histology-MRI slice correspondences for defining MRI-based disease signatures of prostate cancer. AB - Mapping the spatial disease extent in a certain anatomical organ/tissue from histology images to radiological images is important in defining the disease signature in the radiological images. One such scenario is in the context of men with prostate cancer who have had pre-operative magnetic resonance imaging (MRI) before radical prostatectomy. For these cases, the prostate cancer extent from ex vivo whole-mount histology is to be mapped to in vivo MRI. The need for determining radiology-image-based disease signatures is important for (a) training radiologist residents and (b) for constructing an MRI-based computer aided diagnosis (CAD) system for disease detection in vivo. However, a prerequisite for this data mapping is the determination of slice correspondences (i.e. indices of each pair of corresponding image slices) between histological and magnetic resonance images. The explicit determination of such slice correspondences is especially indispensable when an accurate 3D reconstruction of the histological volume cannot be achieved because of (a) the limited tissue slices with unknown inter-slice spacing, and (b) obvious histological image artifacts (tissue loss or distortion). In the clinic practice, the histology-MRI slice correspondences are often determined visually by experienced radiologists and pathologists working in unison, but this procedure is laborious and time consuming. We present an iterative method to automatically determine slice correspondence between images from histology and MRI via a group-wise comparison scheme, followed by 2D and 3D registration. The image slice correspondences obtained using our method were compared with the ground truth correspondences determined via consensus of multiple experts over a total of 23 patient studies. In most instances, the results of our method were very close to the results obtained via visual inspection by these experts. PMID- 21255975 TI - An analysis of the existing resources in relation to education and treatment of diabetes in four European countries: Estonia, Finland, Ireland, and Lithuania. AB - Diabetes has reached pandemic proportions worldwide. To address and assist health care professionals in maintaining and updating their knowledge base on diabetes care, a multilateral project within the framework of the Lifelong Learning Programme and the Erasmus Curriculum Development - sub programme was initiated in 2008. Four European countries are involved in the project - Estonia, Finland, Ireland and Lithuania. Across all four countries the prevalence of diabetes is rising rapidly. The project's (DIPRA - Counselling for Practice - a pilot of improving counselling quality of diabetes) main product will be an on-line study module on patient education and counselling for health care professionals. The management of diabetes demands a broad range of skills which include, communication, leadership, counselling, teaching and research to name but a few. While it is acknowledged that nurses can incorporate these skills into practice and so benefit the care of the patient there is no uniformity across the four countries studied as to what constitutes a specialist diabetes nurse. The study module and all the materials (databank, on-line lectures, and interactive exercises) will be developed in English and translated into partners' national languages (Estonian, Finnish, Lithuanian) to maximize the accessibility of all professionals in partner countries. PMID- 21255976 TI - A pilot study of QT interval analysis in overweight and obese youth. AB - This descriptive pilot study examined if manual corrected QT (QTc) interval measures obtained from a standard 12-lead electrocardiogram (ECG) correlated with automated 24-hour ambulatory Holter QTc measures in 30 overweight and obese youth aged 12-17 years. In addition, we sought to determine if a significant difference existed between the means of manual 12-lead ECG versus automated 24-hour ambulatory Holter measures. Spearman's rho correlation coefficient revealed there was little if any correlation between manual 12-lead ECG and automated 24-hour ambulatory Holter QTc measures (r = .179, p = .345). In addition, a significant difference existed between QTc measures obtained from the manual 12-lead ECG in comparison to the automated 24-hour ambulatory Holter measures (p = .01). The manual 12-lead ECG and automated 24-hour ambulatory Holter analysis methods should not be used for comparison of QTc measures in overweight and obese youth. PMID- 21255977 TI - Gastric emptying, glucose metabolism and gut hormones: evaluation of a common preoperative carbohydrate beverage. AB - OBJECTIVE: To study the gastric-emptying rate and gut hormonal response of two carbohydrate-rich beverages. A specifically designed carbohydrate-rich beverage is currently used to support the surgical patient metabolically. Fruit-based beverages may also promote recovery, due to natural antioxidant and carbohydrate content. However, gastric emptying of fluids is influenced by its nutrient composition; hence, safety of preoperative carbohydrate loading should be confirmed. Because gut hormones link carbohydrate metabolism and gastric emptying, hormonal responses were studied. METHODS: In eight volunteers, gastric emptying rates of both 400 mL of a ready-to-use beverage (A: Nutricia preOp; 50.4 g carbohydrates-mainly polysaccharides; 260 mOsm/kg) and 400 mL over-the-counter fruit-based lemonade (B: Roosvicee Original; 48 g carbohydrates--mainly fruit associated saccharides; 805 mOsm/kg) were determined scintigraphically (using hepatate Tc-99(m)) according to a crossover design. Plasma glucose, insulin, C peptide, glucagon-like peptide (GLP-1), peptide YY, total glucagon, and ghrelin were studied. RESULTS: Gastric emptying showed no differences in residual volumes. Earlier onset in emptying for beverage A versus B was observed (trend), with significantly higher glucose, insulin, C-peptide, and glucagon responses at 15-90 min. GLP-1 was inversely related to residual volume. CONCLUSION: Fruit based lemonade is a safe alternative for preoperative purposes. It induces a more limited glucose, insulin, and C-peptide response. Later onset in gastric emptying (B versus A: trend), lower glucagon release, and differences in beverage content and osmolarity may have contributed to those differences. Efficient emptying was reflected by early GLP-1 levels. PMID- 21255978 TI - Extraoral prostheses using extraoral implants. AB - The aim of this study was to evaluate extraoral prostheses and the use of extraoral implants in patients with facial defects. 10 cases were treated utilizing maxillofacial prostheses employing extraoral implants in five cases. 16 extraoral implants were installed. Seven implants were placed in irradiated sites in the orbital regions. Six implants were placed in mastoid regions and three in a zygoma region that was irradiated. Two implants failed before initial integration was achieved in irradiated areas. Using 14 extraoral implants as anchors, five extraoral prostheses were set. The other five cases were treated with extraoral prostheses without using extraoral implants due to cost and patient-related factors. The data included age, sex, primary disease, implant length, implant failure, prosthetic attachment, radiation therapy, and peri implant skin reactions. The use of extraoral implants for the retention of extraoral prostheses has simplified the placement, removal, and cleaning of the prosthesis by the patient. The stability of the prostheses was improved by anchors. Clinical and technical problems are presented with the techniques used for their resolution. Using extraoral implants resulted in a high rate of success in retaining facial prostheses and gave good stability and aesthetic satisfaction. PMID- 21255979 TI - Modification of the bilateral sagittal split osteotomy (BSSO) in a study using pig mandibles. AB - In a bilateral sagittal split osteotomy (BSSO) mechanical irritation of the inferior alveolar nerve (IAN) (e.g. by chiselling) should be avoided to prevent neural damage. A modification of the Obwegeser-Dal Pont operation technique was studied by splitting 100 pig mandibles ex vivo. An additional osteotomy at the caudal border of the mandible was used to facilitate the sagittal split by means of a locus of minor resistance. The chisel was inserted distal to the second molar and far away from the IAN. The mandible was split by torque. The modified technique reduced the required torque to split the mandible about 30% compared with the original technique (paired t-test, t(69)=-12.89; p<0.05). 75% of all mandibles split by the modified technique were classified as bad splits compared with 100% using the original technique using the same protocol without the additional osteotomy. PMID- 21255980 TI - Electroclinical features of absence seizures in sleep. AB - PURPOSE: To analyze electroclinical features of absence seizures during sleep. PRINCIPAL RESULTS: 30 children with genetic generalized epilepsy had 52 paroxysms of GSW >2s during sleep. 18/52 (35%) demonstrated a clinical sign. Ictal GSW lasted an average of 6.5s. CONCLUSION: Motor manifestations are seen during GSW>2s in sleep. 72% likely represent true ictal motor features while the rest may be serendipitous sleep phenomenon. PMID- 21255981 TI - Decrease in circulating Th17 cells correlates with increased levels of CCL17, IgE and eosinophils in atopic dermatitis. AB - BACKGROUND: Clinical significance of circulating CD4(+) T cell subsets, including T-helper (Th)1, Th2, Th17 and regulatory T (Treg) cells, in patients with atopic dermatitis (AD) remains unclear. No previous studies have simultaneously evaluated the four T cell subset profiles in AD. OBJECTIVE: The aim of the present study was to explore whether the percentage of these four subsets of CD4(+) T cells correlate to the severity parameters of AD patients. METHODS: Intracellular expression of interferon (IFN)-gamma, interleukin (IL)-4, IL-17 and forkhead box P3 (Foxp3) in CD4(+) T cells was evaluated in peripheral blood mononuclear cells from normal controls and patient with AD as well as with chronic eczema using a flow cytometer. Serum CCL17 levels were measured as an objective severity parameter of AD together with percentage of eosinophils and serum IgE levels. RESULTS: In AD patients, the number of Th1 (IFN-gamma(+)) and Th17 (IL-17(+)) subsets was significantly decreased, but that of Th2 (IL-4(+)) and Treg (Foxp3(+)) subsets was similar to that of normal controls. The T cell subset profiles of patients with chronic eczema were not different with those of normal controls. The frequency of Th17cells, particularly that of the IFN gamma(nega)IL-17(+) subset, showed a significant negative correlation with CCL17, IgE and eosinophil levels in AD patients. This was, however, not the case in Th1, Th2 and Treg cells. CONCLUSION: Decreased circulating Th17 cells might contribute to activity of AD. PMID- 21255982 TI - Predictors of response and remission in the acute treatment of first-episode schizophrenia patients--is it all about early response? AB - BACKGROUND: To evaluate the predictive validity of early response compared to other well-known predictor variables in acutely ill first-episode patients. METHODS: 112 patients were treated with a mean dosage of 4.14 mg (+/-1.70) haloperidol and 112 patients with a mean dosage of 4.17 mg (+/-1.55) risperidone for a mean inpatient treatment duration of 42.92 days (+/-16.85) within a double blind, randomized controlled trial. Early response was defined as a >= 30% improvement in the PANSS total score by week 2, response as a >= 50% reduction in the PANSS total score from admission to discharge and remission according to the consensus criteria. Univariate tests and logistic regression models were applied to identify significant predictors of response and remission. RESULTS: 52% of the patients were responders and 59% remitters at discharge. Non-remitters at discharge were hindered from becoming remitters mainly by the presence of negative symptoms. Univariate tests revealed several significant differences between responders/non-responders and remitters/non-remitters such as age, severity of baseline psychopathology as well as the frequency of early response. Both early response (p<0.0001) and a higher PANSS positive subscore at admission (p=0.0002) were identified as significant predictors of response at discharge, whereas a shorter duration of untreated psychosis (p=0.0167), a lower PANSS general psychopathology subscore (p<0.0001), and early treatment response (p=0.0002) were identified as significant predictors of remission. CONCLUSION: Together with the finding that early response is a significant predictor of response and remission, the relevance and predictive validity of negative and depressive symptoms for outcome is also highlighted. PMID- 21255983 TI - Electrochemical detection of anticancer drug topotecan using nano-acetylene black film. AB - Topotecan, a novel anticancer drug, has been widely used in the treatment of ovarian and cervical cancers. Herein, acetylene black (AB) nanoparticles were used to modify the electrode surface, and the electrochemical behavior of topotecan was examined. At the AB film surface, an irreversible oxidation peak was observed for topotecan, and the response signal greatly increased. The influences of pH value, amount of AB, accumulation potential and time were investigated. As a result, a novel electrochemical method with high sensitivity and rapid response was developed for the detection of topotecan. The linear range is from 2 MUg L(-1) to 0.4 mg L(-1), and the limit of detection is 1.45 MUg L(-1) (or 3.17*10(-9) M). The method was successfully used to detect topotecan in blood serum, and the results consisted with the values that obtained by high performance liquid chromatography. PMID- 21255985 TI - [Painless lump of the clavicle. Congenital pseudarthrosis of the clavicle]. PMID- 21255986 TI - [A lethal variant of Netherton syndrome in a large inbred family]. AB - Netherton syndrome is a rare autosomal recessive disorder characterized by the triad of ichthyosiform erythrodermia, typical hair dysplasia, and severe atopic features. The broad range of variable expression of this disease is well described and 20% of complications occur during the neonatal period such as hypernatremic dehydration, electrolyte imbalances, recurrent or severe infections, and failure to thrive. Mutation of the SPINK5 gene has been identified as disease-causing in Netherton syndrome, but the pathophysiology still remains unclear. Almost all SPINK5 mutations result in the absence of the serine-protease inhibitor LEKTI protein in both keratinocytes and lymphocytes. In this study, we report on a severe form of Netherton syndrome observed in three patients within a large inbred Rom family. All of them died in the first months of life despite early treatment. They were found to be homozygous for the c.1431 12G>A SPINK5 gene mutation, which has not been associated with a lethal form of the disease thus far. This family illustrates the extreme phenotype of Netherton disease of neonatal onset. Molecular diagnosis allowed further genetic counseling and prenatal testing during other pregnancies. PMID- 21255987 TI - [Rib fractures in the newborn]. PMID- 21255988 TI - [Gender-dependent differences in glutathione (GSH) metabolism in very preterm infants]. AB - BACKGROUND: Gender differences in mortality and morbidity are often reported in very preterm infants. In studies aiming to understand the underlying mechanisms, better protection against oxidative stress in baby girls has been suggested. OBJECTIVES: Shortly after birth, we compared glutathione (GSH) metabolism in female and male preterm infants and its relationship with prenatal and postnatal parameters. METHODS: We took the opportunity of a prospective randomised controlled trial evaluating the safety-efficacy balance of inhaled nitric oxide (Hamon and al., 2005) [12] to assess, in vivo, the antioxidant defences within the first 48 h of life in 240 premature infants less than 32 weeks gestational age (GA). We measured total plasmatic GSH level (nmol/L), intraerythrocyte glutathione peroxidase (GPX, MUmol/min/g haemoglobin) and intraerythrocyte glutathione reductase (GR, MUmol/min/g haemoglobin) from venous blood samples withdrawn through central lines. RESULTS: Expressed as mean +/- standard error of the mean: soon after birth (at 24h median), plasmatic GSH was not different between females (n=123) and males (n=117): 0.932 +/- 0.016 vs 0.956 +/- 0.012 nmol/L. However, at the same time, GPX, the enzyme involved in GSH synthesis, was at a significantly higher level in baby girls (p<0.001): 11.63 +/- 0.25 vs 10.21 +/- 0.24 MUmol/min/g haemoglobin, as was GR, the enzyme responsible for GSH regeneration (p=0.02): 12.18 +/- 0.23 vs 11.22 +/- 0.21 MUmol/min/g haemoglobin. We observed no significant correlation between GSH levels, GPX, or GR activities with prenatal steroids, GA, birth weight, severity of respiratory disease, and oxygen requirements for the entire population or between the two genders. CONCLUSION: Whereas the level of glutathione, a key molecule in the defence against oxidative stress in humans, appears to be identical in preterm females and males soon after birth, the enzymes involved in its synthesis (GPX) and regeneration (GR) are higher in females. SPECULATION: Study of the sequential progression of GSH, GPX, and GR with regard to prolonged oxidative stress exposure in preterm females and males is needed to better evaluate their potential clinical relevance. PMID- 21255989 TI - [Neonatal ABO incompatibility underlies a potentially severe hemolytic disease of the newborn and requires adequate care]. AB - ABO allo-immunization is the most frequent hemolytic disease of the newborn and ABO incompatibility is present in 15-25 % of pregnancies. True ABO alloimmunization occurs in approximately one out of 150 births. Intensity is generally lower than in RhD allo-immunization. We report on three cases showing that ABO allo-immunization can lead to severe hemolytic disease of the newborn with potentially threatening hyperbilirubinemia and complications. Early diagnosis and adequate care are necessary to prevent complications in ABO incompatibility. A direct antiglobulin test is the cornerstone of diagnosis and should be performed at birth on cord blood sampling in all group infants born to O mothers, especially if of African origin. Risk factor analysis and attentive clinical monitoring during the first days of life are essential. Vigilance is even more important for infants discharged before the age of 72 h. Every newborn should be assessed for the risk of developing severe hyperbilirubinemia and should be examined by a qualified healthcare professional in the first days of life. Treatment depends on the total serum bilirubin level, which may increase very rapidly in the first 48 h of life in cases of hemolytic disease of the newborn. Phototherapy and, in severe cases, exchange transfusion are used to prevent hyperbilirubinemia encephalopathy. Intravenous immunoglobulins are used to reduce exchange transfusion. Treatments of severe hemolytic disease of the newborn should be provided and performed by trained personnel in neonatal intensive care units. PMID- 21255990 TI - [Microcephaly and neonatal thrombocytopenia. Cerebral lesions in congenital cytomegalovirus infection]. PMID- 21255991 TI - Geographic disparity in COPD hospitalization rates among the Texas population. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality caused by cigarette smoking and other environmental exposures. While variation in exposures may affect COPD morbidity and mortality, little is known about geographic variation, a surrogate of exposures. The objective of this manuscript is to explore the geographic variation in COPD hospitalization rates among the Texas population in 2006. METHODS: The study population consisted of all Texas residents with COPD hospitalizations in the 2006 Texas Health Care Information Council (THCIC) data. County population estimates stratified by race, age, and gender were linked to THCIC data to calculate county level COPD hospitalization rates per 100,000 admissions. The data were merged with Urban Influence Codes by county, and metropolitan status was determined by United States Department of Agriculture (USDA) criteria. Variation in COPD hospitalization rates were analyzed using Poisson Regression. RESULTS: Overall, non Hispanic (NH) Whites had the highest rate of hospitalization, followed by NH Blacks (rate ratio=0.42) and Hispanics (RR=0.17), the 65+ age category had the highest rates of hospitalization. In the metropolitan counties COPD hospitalization rates were lower than non-metropolitan counties, however in metropolitan counties the rates of hospitalization were significantly higher (p<0.0001) in females compared to males. The rates were significantly higher in males in public health regions 10 and 11, which are predominantly non-metropolitan counties. CONCLUSIONS: In Texas there is substantial geographic variation in hospitalization rates associated with gender and race/ethnicity. Other factors that may contribute to the variation and require further investigation include differences in smoking and exposure to other environmental risk factors, access to primary care, medical practice patterns, and coding practices. PMID- 21255992 TI - Disposable biosensor based on graphene oxide conjugated with tyrosinase assembled gold nanoparticles. AB - A highly efficient enzyme-based screen printed electrode (SPE) was obtained by using covalent attachment between 1-pyrenebutanoic acid, succinimidyl ester (PASE) adsorbing on the graphene oxide (GO) sheets and amines of tyrosinase protected gold nanoparticles (Tyr-Au). Herein, the bi-functional molecule PASE was assembled onto GO sheets. Subsequently, the Tyr-Au was immobilized on the PASE-GO sheets forming a biocompatible nanocomposite, which was further coated onto the working electrode surface of the SPE. The characterization of obtained nanocomposite and modified SPE surface was investigated by atomic force microscopy (AFM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM). Attributing to the synergistic effect of GO-Au integration and the good biocompatibility of the hybrid-material, the fabricated disposable biosensor (Tyr-Au/PASE-GO/SPE) exhibited a rapid amperometric response (less than 6s) with a high sensitivity and good storage stability for monitoring catechol. This method shows a good linearity in the range from 8.3*10(-8) to 2.3*10(-5) M for catechol with a squared correlation coefficient of 0.9980, a quantitation limit of 8.2*10(-8) M (S/N=10) and a detection limit of 2.4*10(-8) M (S/N=3). The Michaelis-Menten constant was measured to be 0.027 mM. This disposable tyrosinase biosensor could offer a great potential for rapid, cost-effective and on-field analysis of phenolic compounds. PMID- 21255993 TI - Interface resistances of anion exchange membranes in microbial fuel cells with low ionic strength. AB - The interface resistances between an anion exchange membrane (AEM) and the solution electrolyte were measured for low buffer (or ionic strength) of electrolytes typical of microbial fuel cells (MFCs). Three AEMs (AFN, AM-1, and ACS) having different properties were tested in a flat-plate MFC to which 5-mM acetate was fed to the anode and an air-saturated phosphate buffer (PB) solution was fed to the cathode. Current density achieved in the MFCs was correlated inversely with independently measured membrane-only resistances. However, the total interfacial resistances measured by current-voltage plots were approximately two orders higher than those of the membrane-only resistances, although membranes had the same order as with the membrane-only resistance. EIS spectra showed that the resistances from electric-double layer and diffusion boundary layer were the main resistances not the membrane's resistance. The electric-double layer and diffusion boundary layer resistances of the AEMs were much larger in the 10 mM PB electrolyte, compared to 100 mM PB. EIS study also showed that the resistance of diffusion boundary layer decreased due to mechanical stirring. Therefore, the interface resistance that originates from the interaction between the membrane and the catholyte solution should be considered when designing and operating MFC processes with an AEM. The AEMs allowed transport of uncharged O(2) and acetate, but the current losses for both were low during normal MFC operation. PMID- 21255994 TI - Collection mode surface plasmon fibre sensors: a new biosensing platform. AB - Sensors based on surface plasmon resonance (SPR) allow rapid, label-free, highly sensitive detection, and indeed this phenomenon underpins the only label-free optical biosensing technology that is available commercially. In these sensors, the existence of surface plasmons is inferred indirectly from absorption features that correspond to the coupling of light into a thin metallic film. Although SPR is not intrinsically a radiative process, when the metallic coating which support the plasmonic wave exhibits a significant surface roughness, the surface plasmon can itself couple to the local photon states, and emit light. Here we show that using silver coated optical fibres, this novel SPR transducing mechanism offers significant advantages compare to traditional reflectance based measurements such as lower dependency on the metallic thickness and higher signal to noise ratio. Furthermore, we show that more complex sensor architectures with multiple sensing regions scattered along a single optical fibre enable multiplexed detection and dynamic self referencing of the sensing signal. Moreover, this alternative approach allows to combine two different sensing technologies, SPR and fluorescence sensing within the same device, which has never been demonstrated previously. As a preliminary proof of concept of potential application, this approach has been used to demonstrate the detection of the seasonal influenza A virus. PMID- 21255995 TI - 35 MHz quartz crystal microbalance and surface plasmon resonance studies on the binding of angiotensin converting enzyme with lisinopril. AB - Angiotensin converting enzyme (ACE) plays a pivotal role in blood pressure regulation, and its interaction with an ACE inhibitor (ACEI) is an important research topic for treatment of hypertension. Herein, a low reagent consumption, multiparameter and highly sensitive quartz crystal microbalance (QCM) at 35-MHz fundamental frequency was utilized to monitor in situ the binding process of solution lisinopril (LIS, a carboxylic third-generation ACEI) to ACE adsorbed at a 1-dodecanethiol (C12SH)-modified Au electrode. From the QCM data, the binding molar ratio (r) of LIS to adsorbed ACE was estimated to be 2.3:1, and the binding and dissociation rate constants (k(1) and k(-1)) and the binding equilibrium constant (K(a)) were estimated to be k(1)=4.1*10(6) L mol(-1) s(-1), k( 1)=7.3*10(-3) s(-1) and K(a)=5.62*10(8) L mol(-1), respectively. Comparable qualitative and quantitative results were also obtained from separate experiments of cyclic voltammetry, electrochemical impedance spectroscopy and surface plasmon resonance measurements. PMID- 21255996 TI - A versatile graphene-based fluorescence "on/off" switch for multiplex detection of various targets. AB - We have designed a versatile molecular beacon (MB)-like probe for the multiplex sensing of targets such as sequence-specific DNA, protein, metal ions and small molecule compounds based on the self-assembled ssDNA-graphene oxide (ssDNA-GO) architecture. The probe employs fluorescence "on/off" switching strategy in a single step in homogeneous solution. Compared to traditional molecular beacons, the proposed design is simple to prepare and manipulate and has little background interference, but still gives superior sensitivity and rapid response. More importantly, this ssDNA-GO architecture can serve as a universal beacon platform by simply changing the types of ssDNA sequences for the different targets. In this work, the ssDNA-GO architecture probe has been successfully applied in the multiplex detection of sequence-specific DNA, thrombin, Ag(+), Hg(2+) and cysteine, and the limit of detection was 1 nM, 5 nM, 20 nM, 5.7 nM and 60 nM, respectively. The results demonstrate that the ssDNA-GO architecture can be an excellent and versatile platform for sensing multiplex analytes, easily replacing the universal molecular beacon. PMID- 21255997 TI - Searching for synthetic lethality in cancer. AB - The incentive to develop personalised therapy for cancer treatment is driven by the premise that it will increase therapeutic efficacy and reduce toxicity. Understanding the underlying cellular and molecular basis of the disease has been extremely important in the design of these novel therapies; however, identifying new drug targets for personalised therapies remains problematic. This review describes how the biological concept of synthetic lethality has been successfully implemented to identify new therapeutic approaches and targets in models from yeast through to human cells. We also discuss how recent technical advances combined with an increased understanding of the complexity of cellular networks may facilitate therapeutic advances in the future. PMID- 21255999 TI - Cadherin-catenin adhesion complexes at the synapse. AB - Classic cadherins function as key organizers during the formation and remodeling of synapses in the vertebrate central nervous system. Cadherins are Ca2+ dependent homophilic adhesion molecules whose adhesive strength can be regulated by conformational changes, through cadherin's association with intracellular binding proteins, and by the regulation of cadherin turnover and internalization. In this mini-review, we will highlight recent studies on the role of cadherins and their associated partners in regulating synaptic architecture. Moreover, we will discuss molecular mechanisms underlying cadherin turnover and the subsequent impact on synaptic connections. PMID- 21255998 TI - Autophagy in tumorigenesis and energy metabolism: friend by day, foe by night. AB - Autophagy is the mechanism by which cells consume parts of themselves to survive starvation and stress. This self-cannibalization limits cell death and tissue inflammation, recycles energy and biosynthetic substrates and removes damaged proteins and organelles, accumulation of which is toxic. In normal tissues, autophagy-mediated damage mitigation may suppress tumorigenesis, while in advanced tumors macromolecular recycling may support survival by buffering metabolic demand under stress. As a result, autophagy-activation in normal cells may suppress tumorigenesis, while autophagy inhibition may be beneficial for the therapy of established tumors. The mechanisms by which autophagy supports cancer cell metabolism are slowly emerging. As cancer is being increasingly recognized as a metabolic disease, how autophagy-mediated catabolism impacts cellular and mammalian metabolism and tumor growth is of great interest. Most cancer therapeutics induce autophagy, either directly by modulating signaling pathways that control autophagy in the case of many targeted therapies, or indirectly in the case of cytotoxic therapy. However, the functional consequence of autophagy induction in the context of cancer therapy is not yet clear. A better understanding of how autophagy modulates cell metabolism under various cellular stresses and the consequences of this on tumorigenesis will help develop better therapeutic strategies against cancer prevention and treatment. PMID- 21256000 TI - Changes of bone resorption marker (NTX) in chemotherapy plus zoledronic acid versus chemotherapy alone for nasopharyngeal cancer patients with bone metastases. AB - BACKGROUND: Zoledronic acid (ZOL) is the only bisphosphonate with demonstrated efficacy for the prevention of skeletal-related events (SRE) in patients with bone metastases of diverse malignant tumours. A recent large, retrospective analysis reported that a reduction in N-telopeptide of type I collagen (NTX) provided a continuum of reduced SRE risk and survival benefit in patients with bone metastases. The present prospective, open-label, randomised, phase II trial sought to evaluate NTX changes after ZOL administration in nasopharyngeal cancer (NPC) patients with bone metastases (BM). METHODS: Newly diagnosed NPC patients (n = 60) with bone metastasis were randomised to the test group (n = 30), who received chemotherapy with cisplatin plus 5-fluorouracil (5-FU) (q3wks) and intravenous ZOL (4 mg, q4 wks) for 3 months, or a control group (n = 30), who received cisplatin plus 5-FU alone. Urinary NTX was measured by ELISA at baseline and 1, 2 and 3months after administration of ZOL. RESULTS: The median baseline NTX level was no different in both the test and control patients (75.4 and 94.6 nM bone collagen equivalent units/mM creatinine, respectively; p = 0.370). NTX decreased by 61.5% within 1month in the test group, but only by 6.6% in the control group (p < 0.01). After 3 months, the test group reached a maximum reduction (-85.9%) as compared to the other time points and to the control group (-51.5%) (p = 0.001). More patients in the test group achieved normal NTX than that in the control group (p=0.042). CONCLUSIONS: ZOL administered with chemotherapy immediately and consistently reduced NTX levels for NPC patients with bone metastasis. Larger prospective randomised trial to confirm the efficacy of ZOL in NPC patients with bone metastases is pending. PMID- 21256001 TI - The effects of four different pretreatments on enzymatic hydrolysis of sweet sorghum bagasse. AB - Four pretreatment processes including ionic liquids, steam explosion, lime, and dilute acid were used for enzymatic hydrolysis of sweet sorghum bagasse. Compared with the other three pretreatment approaches, steam-explosion pretreatment showed the greatest improvement on enzymatic hydrolysis of the bagasse. The maximum conversion of cellulose and the concentration of glucose obtained from enzymatic hydrolysis of steam explosion bagasse reached 70% and 25 g/L, respectively, which were both 2.5 times higher than those of the control (27% and 11 g/L). The results based on the analysis of SEM photos, FTIR, XRD and NMR detection suggested that both the reduction of crystallite size of cellulose and cellulose degradation from the Ialpha and Ibeta to the Fibril surface cellulose and amorphous cellulose were critical for enzymatic hydrolysis. These pretreatments disrupted the crystal structure of cellulose and increased the available surface area, which made the cellulose better accessible for enzymatic hydrolysis. PMID- 21256002 TI - Performance of enhanced biological SBR process for aniline treatment by mycelial pellet as biomass carrier. AB - Mycelial pellet of Aspergillus niger Y3 was used as a biomass carrier to immobilize the aniline-degrading bacterium, Acinetobacter calcoaceticus JH-9 and the mix culture of the COD rapid degradation bacteria. In order to investigate its removal effect on aniline and COD, the combined mycelial pellets were applied in the SBR. Comparison of the performances was conducted between another SBR inoculated with sole strain JH-9 and the above SBR. The results showed that the stable degradations of aniline and COD were observed in both reactors. In the SBR with combined mycelial pellet, the biological removal efficiency was about 0.9 mg aniline/(L.d). It was much higher than that in the activated sludge reactor. Meanwhile, the performances of the sedimentation velocity, liquid-solid phase separation and the effluent quality were better in the SBR. According to SEM images and PCR-DGGE analysis, the species immobilized on the biomass carrier were more predominant in this system. PMID- 21256003 TI - Homogeneous butyrylation and lauroylation of poplar wood in the ionic liquid 1 butyl-3-methylimidazolium chloride. AB - Wood meal was dissolved under identical conditions in the ionic liquid 1-butyl-3 methylimidazolium chloride ([C(4)mim]Cl) and homogeneously esterified with butyryl chloride and lauroyl chloride in the presence of triethylamine as a neutralizer. The effect of the molar ratio of reagent to the hydroxyl groups in wood on the properties of the esterified wood and the possible mechanism of the homogeneous esterification of wood in this reaction medium were studied. Furthermore, the physicochemical properties of the esterified wood were characterized by FTIR, solid-state CP/MAS (13)C NMR, TGA/DTG and SEM. The results confirmed that the homogeneous modifications were successfully processed and highly substituted wood esters could be obtained by reacting the dissolved wood in this homogeneous system. PMID- 21256004 TI - Evolution of organic matter in a full-scale composting plant for the treatment of sewage sludge and biowaste by respiration techniques and pyrolysis-GC/MS. AB - A full-scale composting plant treating in two parallel lines sewage sludge and the source-selected organic fraction of municipal solid waste (OFMSW or biowaste) has been completely monitored. Chemical routine analysis proved not to be suitable for an adequate plant monitoring in terms of stabilization and characterization of the process and final compost properties. However, the dynamic respiration index demonstrated to be the most feasible tool to determine the progression of the degradation and stabilization of organic matter for both sewage sludge and OFMSW lines. Both lines exhibited an important degree of stabilization of organic matter using rapid and cumulative respiration indices. Pyrolysis-GC/MS was applied to the most important inputs, outputs, and intermediate points of the plant. It proved to be a powerful tool for the qualitative characterization of molecular composition of organic matter present in solid samples. A full characterization of the samples considered is also presented. PMID- 21256005 TI - Conformationally constrained farnesoid X receptor (FXR) agonists: heteroaryl replacements of the naphthalene. AB - To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes. PMID- 21256006 TI - Structure and property based design, synthesis and biological evaluation of gamma lactam based HDAC inhibitors. AB - Histone deacetylases (HDACs) are involved in post-translational modification and gene expression. Cancer cells recruited amounts of HDACs for their survival by epi-genetic down regulation of tumor suppressor genes. HDACs have been the promising targets for treatment of cancer, and many HDAC inhibitors have been investigated nowadays. In previous study, we synthesized delta-lactam core HDAC inhibitors which showed potent HDAC inhibitory activities as well as cancer cell growth inhibitory activities. Through QSAR study of the delta-lactam based inhibitors, the smaller core is suggested as more active than larger one because it fits better in narrow hydrophobic tunnel of the active pocket of HDAC enzyme. The smaller gamma-lactam core HDAC inhibitors were designed and synthesized for biological and property optimization. Phenyl, naphthyl and thiophenyl groups were introduced as the cap groups. Hydrophobic and bulky cap groups increase potency of HDAC inhibition because of hydrophobic interaction between HDAC and inhibitors. In overall, gamma-lactam based HDAC inhibitors showed more potent than delta-lactam analogues. PMID- 21256007 TI - Improved synthesis of 5-hydroxymethyl-2'-deoxycytidine phosphoramidite using a 2' deoxyuridine to 2'-deoxycytidine conversion without temporary protecting groups. AB - 5-Hydroxymethylcytosine has recently been characterized as the 'sixth base' in human DNA. To enable research on this DNA modification, we report an improved method for the synthesis of 5-hydroxymethyl-2'-deoxycytidine ((5-HOMe)dC) phosphoramidite for site-specific incorporation into oligonucleotides. To minimize manipulations we employed a temporary protecting group-free 2' deoxyuridine to 2'-deoxycytidine conversion procedure that utilizes phase transfer catalysis. The desired (5-HOMe)dC phosphoramidite is obtained in six steps and 24% overall yield from 2'-deoxyuridine. PMID- 21256008 TI - Spirodiketopiperazine-based CCR5 antagonist: discovery of an antiretroviral drug candidate. AB - Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate. PMID- 21256009 TI - Discovery of new anti-depressants from structurally novel 5-HT3 receptor antagonists: design, synthesis and pharmacological evaluation of 3 ethoxyquinoxalin-2-carboxamides. AB - A novel series of 3-ethoxyquinoxalin-2-carboxamides were designed as per the pharmacophoric requirements of 5-HT(3) receptor antagonist using ligand-based approach. The desired carboxamides were synthesized from the key intermediate, 3 ethoxyquinoxalin-2-carboxylic acid by coupling with appropriate amines in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) and 1-hydroxybenzotriazole (HOBt). The 5-HT(3) receptor antagonism was evaluated in longitudinal muscle myenteric plexus preparation from guinea pig ileum against 5-HT(3) agonist, 2-methy-5-HT, which was expressed in the form of pA(2) values. Compound 6h (3-ethoxyquinoxalin-2-yl)(4-methylpiperazin-1-yl)methanone was found to be the most active compound, which expressed a pA(2) value of 7.7. In forced swim test, the compounds with higher pA(2) value exhibited good anti-depressant like activity and compounds with lower pA(2) value failed to show activity as compared to the vehicle-treated group. PMID- 21256010 TI - HIV-1 protease inhibition potential of functionalized polyoxometalates. AB - Polyoxometalates (POMs) are interesting biomedical agents due to their versatile anticancer and antiviral properties, such as remarkable anti-HIV activity. Although POMs are tunable and easily accessible inorganic drug prototypes in principle, their full potential can only be tapped by enhancing their biocompatibility, for example, through organic functionalization. We have therefore investigated the HIV-1 protease inhibition potential of functionalized Keggin- and Dawson-type POMs with organic side chains. Their inhibitory performance was furthermore compared to other POM types, and the buffer dependence of the results is discussed. In addition, chemical shift mapping NMR experiments were performed to exclude POM-substrate interactions. Whereas the introduction of organic side chains into POMs is a promising approach in principle, the influence of secondary effects on the reaction system also merits detailed investigation. PMID- 21256011 TI - Exploration of mild copper-mediated coupling of organotrifluoroborates in the synthesis of thiirane-based inhibitors of matrix metalloproteinases. AB - The copper-mediated and non-basic oxidative cross-coupling of organotrifluoroborates with phenols was applied to elaboration of the structures of thiirane-based inhibitors of matrix metalloproteinases. By revision of the synthetic sequence to allow this cross-coupling as the final step, and taking advantage of the neutral nature of organotrifluoroborate cross-coupling, a focussed series of inhibitors showing aryloxy and alkenyloxy replacement of the phenoxy substituent was prepared. This reaction shows exceptional promise as an alternative to the classic copper-mediated but strongly basic Ullmann reaction, for the diversification of ether segments within base-labile lead structures. PMID- 21256012 TI - Synthesis and biophysical characterization of R-6'-Me-alpha-L-LNA modified oligonucleotides. AB - The synthesis and biophysical properties of R-6'-Me-alpha-L-LNA, which has a methyl group in the (R) configuration on the 2',4'-bridging substituent of alpha L-LNA, is reported. The synthesis of the uracil nucleobase phosphoramidite was efficiently accomplished in 14 steps and 8 chromatographic purifications starting from a known sugar intermediate. Biophysical evaluation revealed that substitution along the edge of the major groove does not impair the high affinity duplex forming ability of alpha-L-LNA modified oligonucleotides. PMID- 21256013 TI - Chemical and biological explorations of the electrophilic reactivity of the bioactive marine natural product halenaquinone with biomimetic nucleophiles. AB - The electrophilic reactivity of the bioactive marine sponge natural product halenaquinone has been investigated by reaction with the biomimetic nucleophiles N-acetyl-L-cysteine and N(alpha)-acetyl-L-lysine. While cysteine reacted at the vacant quinone positions C-14 and C-15, lysine was found to react preferentially at the keto-furan position C-1. A small library of analogues was prepared by reaction of halenaquinone with primary amines, and evaluated against a range of biological targets including phospholipase A(2), farnesyltransferases (FTases) and Plasmodium falciparum. Geranylamine analogue 11 exhibited the most potent activity towards FTases (IC(50) 0.017-0.031 MUM) and malaria (IC(50) 0.53-0.62 MUM). PMID- 21256015 TI - Representation of others' action by neurons in monkey medial frontal cortex. AB - Successful social interaction depends on not only the ability to identify with others but also the ability to distinguish between aspects of self and others. Although there is considerable knowledge of a shared neural substrate between self-action and others' action, it remains unknown where and how in the brain the action of others is uniquely represented. Exploring such agent-specific neural codes is important because one's action and intention can differ between individuals. Moreover, the assignment of social agency breaks down in a range of mental disorders. Here, using two monkeys monitoring each other's action for adaptive behavioral planning, we show that the medial frontal cortex (MFC) contains a group of neurons that selectively encode others' action. These neurons, observed in both dominant and submissive monkeys, were significantly more prevalent in the dorsomedial convexity region of the MFC including the pre supplementary motor area than in the cingulate sulcus region of the MFC including the rostral cingulate motor area. Further tests revealed that the difference in neuronal activity was not due to gaze direction or muscular activity. We suggest that the MFC is involved in self-other differentiation in the domain of motor action and provides a fundamental neural signal for social learning. PMID- 21256014 TI - Myofibrillar myopathies. AB - Myofibrillar myopathies represent a group of muscular dystrophies with a similar morphologic phenotype. They are characterized by a distinct pathologic pattern of myofibrillar dissolution associated with disintegration of the Z-disk, accumulation of myofibrillar degradation products, and ectopic expression of multiple proteins and sometimes congophilic material. The clinical features of myofibrillar myopathies are more variable. These include progressive muscle weakness, that often involves or begins in distal muscles but limb-girdle or scapuloperoneal distributions can also occur. Cardiomyopathy and peripheral neuropathy are frequent associated features. EMG of the affected muscles reveals myopathic motor unit potentials and abnormal irritability often with myotonic discharges. Rarely, neurogenic motor unit potentials or slow nerve conductions are present. The generic diagnosis of myofibrillar myopathies is based on muscle biopsy findings in frozen sections. To date, all myofibrillar myopathy mutations have been traced to Z-disk-associated proteins, namely, desmin, alphaB crystallin, myotilin, ZASP, filamin C and Bag3. However, in the majority of the myofibrillar myopathy patients the disease gene awaits discovery. PMID- 21256016 TI - Redox-responsive zinc finger fidelity switch in homing endonuclease and intron promiscuity in oxidative stress. AB - It is well understood how mobile introns home to allelic sites, but how they are stimulated to transpose to ectopic locations on an evolutionary timescale is unclear. Here we show that a group I intron can move to degenerate sites under oxidizing conditions. The phage T4 td intron endonuclease, I-TevI, is responsible for this infidelity. We demonstrate that I-TevI, which promotes mobility and is subject to autorepression and translational control, is also regulated posttranslationally by a redox mechanism. Redox regulation is exercised by a zinc finger (ZF) in a linker that connects the catalytic domain of I-TevI to the DNA binding domain. Four cysteines coordinate Zn(2+) in the ZF, which ensures that I TevI cleaves its DNA substrate at a fixed distance, 23-25 nucleotides upstream of the intron insertion site. We show that the fidelity of I-TevI cleavage is controlled by redox-responsive Zn(2+) cycling. When the ZF is mutated, or after exposure of the wild-type I-TevI to H(2)O(2), intron homing to degenerate sites is increased, likely because of indiscriminate DNA cleavage. These results suggest a mechanism for rapid intron dispersal, joining recent descriptions of the activation of biomolecular processes by oxidative stress through cysteine chemistry. PMID- 21256017 TI - A Southern Hemisphere bathyal fauna is distributed in latitudinal bands. AB - The large-scale spatial distribution of seafloor fauna is still poorly understood. In particular, the bathyal zone has been identified as the key depth stratum requiring further macroecological research, particularly in the Southern Hemisphere. Here we analyze a large biological data set derived from 295 research expeditions, across an equator-to-pole sector of the Indian, Pacific, and Southern oceans, to show that the bathyal ophiuroid fauna is distributed in three broad latitudinal bands and not primarily differentiated by oceanic basins as previously assumed. Adjacent faunas form transitional ecoclines rather than biogeographical breaks. This pattern is similar to that in shallow water despite the order-of-magnitude reduction in the variability of environmental parameters at bathyal depths. A reliable biogeography is fundamental to establishing a representative network of marine reserves across the world's oceans. PMID- 21256018 TI - Observers exploit stochastic models of sensory change to help judge the passage of time. AB - Sensory stimulation can systematically bias the perceived passage of time, but why and how this happens is mysterious. In this report, we provide evidence that such biases may ultimately derive from an innate and adaptive use of stochastically evolving dynamic stimuli to help refine estimates derived from internal timekeeping mechanisms. A simplified statistical model based on probabilistic expectations of stimulus change derived from the second-order temporal statistics of the natural environment makes three predictions. First, random noise-like stimuli whose statistics violate natural expectations should induce timing bias. Second, a previously unexplored obverse of this effect is that similar noise stimuli with natural statistics should reduce the variability of timing estimates. Finally, this reduction in variability should scale with the interval being timed, so as to preserve the overall Weber law of interval timing. All three predictions are borne out experimentally. Thus, in the context of our novel theoretical framework, these results suggest that observers routinely rely on sensory input to augment their sense of the passage of time, through a process of Bayesian inference based on expectations of change in the natural environment. PMID- 21256019 TI - The Ndc80 loop region facilitates formation of kinetochore attachment to the dynamic microtubule plus end. AB - Proper chromosome segregation in mitosis relies on correct kinetochore microtubule (KT-MT) interactions. The KT initially interacts with the lateral surface of a single MT (lateral attachment) extending from a spindle pole and is subsequently anchored at the plus end of the MT (end-on attachment). The conversion from lateral to end-on attachment is crucial because end-on attachment is more robust and thought to be necessary to sustain KT-MT attachment when tension is applied across sister KTs upon their biorientation. The mechanism for this conversion is still elusive. The Ndc80 complex is an essential component of the KT-MT interface, and here we studied a role of the Ndc80 loop region, a distinct motif looping out from the coiled-coil shaft of the complex, in Saccharomyces cerevisiae. With deletions or mutations of the loop region, the lateral KT-MT attachment occurred normally; however, subsequent conversion to end on attachment was defective, leading to failure in sister KT biorientation. The Ndc80 loop region was required for Ndc80-Dam1 interaction and KT loading of the Dam1 complex, which in turn supported KT tethering to the dynamic MT plus end. The Ndc80 loop region, therefore, has an important role in the conversion from lateral to end-on attachment, a crucial maturation step of KT-MT interaction. PMID- 21256020 TI - Emotional and social behaviors elicited by electrical stimulation of the insula in the macaque monkey. AB - Evidence from a large number of brain imaging studies has shown that, in humans, the insula, and especially its anterior part, is involved in emotions and emotion recognition. Typically, however, these studies revealed that, besides the insula, a variety of other cortical and subcortical areas are also active. Brain imaging studies are correlative in nature, and, as such, they cannot give indications about the necessary contribution of the different centers involved in emotions. In the present study, we aimed to define more clearly the role of the insula in emotional and social behavior of the monkey by stimulating it electrically. Using this technique, one may determine whether direct activation of the insula can produce specific emotional or social behaviors and exactly which parts of this structure are responsible for these behaviors. The results showed that two emotional behaviors, a basic one (disgust) and a social one (affiliative state), were easily elicited by electrical stimulation of specific parts of the insula. Both behaviors were characterized by specific motor and vegetative responses and by a dramatic change in the monkey's responsiveness to external stimuli. PMID- 21256021 TI - Cell-to-cell variability in PI3K protein level regulates PI3K-AKT pathway activity in cell populations. AB - BACKGROUND: Cell-to-cell variability in populations has been widely observed in mammalian cells. This heterogeneity can result from random stochastic events or can be deliberately maintained through regulatory processes. In the latter case, heterogeneity should confer a selective advantage that benefits the entire population. RESULTS: Using multicolor flow cytometry, we have uncovered robust heterogeneity in phosphoinositide 3-kinase (PI3K) activity in MCF10A cell populations, which had been previously masked by techniques that only measure population averages. We show that AKT activity is bimodal in response to EGF stimulation and correlates with PI3K protein level, such that only cells with high PI3K protein can activate AKT. We further show that heterogeneity in PI3K protein levels is invariably maintained in cell populations through a degradation/resynthesis cycle that can be regulated by cell density. CONCLUSIONS: Given that the PI3K pathway is one of the most frequently upregulated pathways in cancer, we propose that heterogeneity in PI3K activity is beneficial to normal tissues by restricting PI3K activation to only a subset of cells. This may serve to protect the population as a whole from overactivating the pathway, which can lead to cellular senescence or cancer. Consistent with this, we show that oncogenic mutations in p110alpha (H1047R and E545K) partially evade this negative regulation, resulting in increased AKT activity in the population. PMID- 21256023 TI - A mechanical signal biases caste development in a social wasp. AB - Understanding the proximate mechanisms of caste development in eusocial taxa can reveal how social species evolved from solitary ancestors. In Polistes wasps, the current paradigm holds that differential amounts of nutrition during the larval stage cause the divergence of worker and gyne (potential queen) castes. But nutrition level alone cannot explain how the first few females to be produced in a colony develop rapidly yet have small body sizes and worker phenotypes. Here, we provide evidence that a mechanical signal biases caste toward a worker phenotype. In Polistes fuscatus, the signal takes the form of antennal drumming (AD), wherein a female trills her antennae synchronously on the rims of nest cells while feeding prey-liquid to larvae. The frequency of AD occurrence is high early in the colony cycle, when larvae destined to become workers are being reared, and low late in the cycle, when gynes are being reared. Subjecting gyne destined brood to simulated AD-frequency vibrations caused them to emerge as adults with reduced fat stores, a worker trait. This suggests that AD influences the larval developmental trajectory by inhibiting a physiological element that is necessary to trigger diapause, a gyne trait. PMID- 21256022 TI - Ndc80 internal loop interacts with Dis1/TOG to ensure proper kinetochore-spindle attachment in fission yeast. AB - The Ndc80 complex, a conserved outer kinetochore complex, comprising four components (Ndc80/Hec1, Nuf2, Spc24, and Spc25), constitutes one of the core microtubule-binding sites within the kinetochore. Despite this knowledge, molecular mechanisms by which this complex contributes to establishment of correct bipolar attachment of the kinetochore to the spindle microtubule remain largely elusive. Here we show that the conserved internal loop of fission yeast Ndc80 directly binds the Dis1/TOG microtubule-associated protein, thereby coupling spindle microtubule dynamics with kinetochore capture. Ndc80 loop mutant proteins fail to recruit Dis1 to kinetochores, imposing unstable attachment and frequent spindle collapse. In these mutants, mitotic progression is halted attributable to spindle assembly checkpoint activation, and chromosomes remain in the vicinity of the spindle poles without congression. dis1 deletion precisely phenocopies the loop mutants. Intriguingly, forced targeting of Dis1 to the Ndc80 complex rescues loop mutant's defects. We propose that Ndc80 comprises two microtubule-interacting interfaces: the N-terminal region directly binds the microtubule lattice, while the internal loop interacts with the plus end of microtubules via Dis1/TOG. Therefore, our results provide a crucial insight into how the Ndc80 complex establishes stable bipolar attachment to the spindle microtubule. PMID- 21256024 TI - Thai nurses' experience of caring for persons with life-sustaining technologies in intensive care settings: a phenomenological study. AB - Technological competency as caring in nursing is grounded in the viewpoint that health care technologies are used to know persons. This study described the experiences of eight Thai nurses caring for persons with life-sustaining technologies in adult intensive care settings. Using individual semi-structured interviews, Van Manen's hermeneutic phenomenological approach was used to analyse the data. Nine thematic categories formed the description of the experience of caring for. The experience of caring for is described as valuing competency to care despite differing insecurities in the use of technology. Influenced by relationships and compassion, the risk that technology prevented an appreciation of persons as wholes is embodied in the encouraging collaboration of fostering time to care regardless of being in a restricted space surrounded with technology. Locsin's theory of Technological Competency as Caring in Nursing serves as theoretical lens through which findings are discussed. These findings should assist nurses achieve quality human care in intensive care settings. PMID- 21256025 TI - Pressure-relieving properties of various shoe inserts in older people with plantar heel pain. AB - Plantar heel pain is one of the most common musculoskeletal conditions affecting the foot and it is commonly experienced by older adults. Contoured foot orthoses and some heel inserts have been found to be effective for plantar heel pain, however the mechanism by which they achieve their effects is largely unknown. The aim of this study was to investigate the effects of foot orthoses and heel inserts on plantar pressures in older adults with plantar heel pain. Thirty-six adults aged over 65 years with plantar heel pain participated in the study. Using the in-shoe Pedar((r)) system, plantar pressure data were recorded while participants walked along an 8 m walkway wearing a standardised shoe and 4 different shoe inserts. The shoe inserts consisted of a silicon heel cup, a soft foam heel pad, a heel lift and a prefabricated foot orthosis. Data were collected for the heel, midfoot and forefoot. Statistically significant attenuation of heel peak plantar pressure was provided by 3 of the 4 shoe inserts. The greatest reduction was achieved by the prefabricated foot orthosis, which provided a fivefold reduction compared to the next most effective insert. The contoured nature of the prefabricated foot orthosis allowed for an increase in midfoot contact area, resulting in a greater redistribution of force. The prefabricated foot orthosis was also the only shoe insert that did not increase forefoot pressure. The findings from this study indicate that of the shoe inserts tested, the contoured prefabricated foot orthosis is the most effective at reducing pressure under the heel in older people with heel pain. PMID- 21256026 TI - Aging modifies joint power and work when gait speeds are matched. AB - It is well known that ankle joint power generation (A2) is reduced in healthy older adults (OG) during gait. No general consensus exists, however, as to what fundamental compensatory actions are made at the knee and hip joints by the OG to compensate for this loss of power. The failure to control gait speed may account for this lack of agreement. This study investigated the effect of aging on lower limb joint power and work during gait. The gait patterns of eight old (OG: 66.8+/ 5.4 yr) and 12 young adults (YG: 26.6+/-2.9 yr) were recorded for a range of matched speeds (1.0 m s(-1), 1.3 m s(-1), 1.6 m s(-1)). Speed did not differ between the groups. Combining speeds, the OG generated 17% less A2 power and 21% less A2 work (p<0.05). Compared to the YG, the OG generated 46% more H1 work, 30% more H2 peak power, 16% more H3 peak power, 30% more K3 peak power and 19% more K4 peak power (p<0.05). These actions by the OG were associated with less ankle plantar-flexion, more hip flexion and anterior pelvic tilt (p<0.05). The OG adopted a different gait pattern at the faster speeds by generating more H3 work than A2 work. This shows the OG rely on hip flexors to propel the leg into swing when ankle plantar-flexor function is reduced. This may partly explain how gait changes emerge with aging. PMID- 21256027 TI - Postural deficits in Huntington's disease when performing motor skills involved in daily living. AB - Previous studies of Huntington's disease (HD) have reported motor control deficits for selected fine and gross motor skills. However, no studies have metrically assessed postural control in this clinical group when performing motor skills involved in daily living. Therefore, the purpose of the present study was to evaluate and compare postural control of individuals with confirmed Huntington's disease and non-gene carriers when completing three functional postural tasks. Eleven individuals with HD (mean age=47.1 years: UHDRS mean=34.5: mean age of HD onset 34.6 years: mean CAG repeat=44.1) and 17 non-gene carriers (NGC) (mean age=39.2 years: UHDRS mean=0.13: mean CAG repeat=20.5) completed three tests on a force plate interfaced with a computer. The tests were a step up and over an obstacle (SUO) test, a sit-to-stand (STS) test, and a step and turn (ST) test. Selected kinematic and kinetic variables were used to quantify postural control. Data were analyzed using MANOVA procedures and discriminant function analysis. HD patients were significantly slower in completing all three tests (HD SUO=2.3 s vs. NGC SUO=1.6 s; HD STS=0.8 s vs. NGC STS=0.5 s; HD ST=1.7 s vs. NGC ST=0.9 s) and developed less rising force during the step up and over test (HD=25.8% body weight vs. NGC=39.4% body weight) but not for the sit-to stand test. Additionally, sway velocity of the center of gravity (COG) was significantly higher for HD patients when performing the sit-to-stand (HD=4.1 degrees /s vs. NGC=2.9 degrees /s) and step and turn tests (HD=33.7 degrees /s vs. NGC=21.7 degrees /s). HD patients manifest significant postural control deficits when performing motor skills typical of daily living activities. PMID- 21256028 TI - Changes in balance, functional performance and fall risk following whole body vibration training and vitamin D supplementation in institutionalized elderly women. A 6 month randomized controlled trial. AB - Falls in the elderly constitute a growing public health problem. This randomized controlled trial investigated the potential benefit of 6 months of whole body vibration (WBV) training and/or vitamin D supplementation on balance, functionality and estimated fall risk in institutionalized elderly women. A total of 113 women (mean age: 79.6) were randomly assigned to either a WBV or a no training group, receiving either a conventional dose (880 IU/d) or a high dose (1600 IU/d) of vitamin D3. The WBV group performed exercises on a vibration platform 3*/week. Balance was evaluated by computerized posturography. Functionality was assessed by 10 m walk test, Timed up and Go (TUG) performance and endurance capacity (Shuttle Walk). Fall risk was determined with the Physiological Profile Assessment. Performance on the 10 m walk test and on TUG improved over time in all groups. For none of the parameters, high-dose vitamin D resulted in a better performance than conventional dosing. The improvements in the WBV group in endurance capacity, walking at preferred speed, and TUG were significantly larger than the changes with supplementation alone. No additional benefit of WBV training could be detected on fall risk and postural control, although sway velocity and maximal isometric knee extension strength improved only in the WBV group. This trial showed that a high-dose vitamin D supplementation is not more efficient than conventional dosing in improving functionality in institutionalized elderly. WBV training on top of vitamin D supplementation provided an added benefit with regard to walking, TUG performance, and endurance capacity. PMID- 21256029 TI - Factors affecting the accuracy of ventricular catheter placement. AB - Despite technological improvements, ventriculoperitoneal (VP) shunts are still often complicated by malfunction, predominantly with proximal catheter obstruction. There is evidence that accurate placement of the ventricular catheter is significantly related to shunt survival. To identify possible risk factors that might lead to suboptimal shunt placement, we retrospectively reviewed the demographic data and radiological scans of 141 patients who underwent a VP shunt operation from 2005 to 2008 at our institution. We developed and validated a novel scale to assess catheter placement. Almost half (47.9%) of the catheters were "excellently" placed with the entire tip located in the cerebrospinal fluid, and the position of 25% was considered "good". However, 26.8% were less than optimally placed ("poor", "fair" or "moderate"), with 8.5% ("poor") lying entirely outside the ventricular system. Statistical analysis demonstrated that the preoperative size of the ventricles and the age of the patient at shunt insertion were the most important predictors in determining the quality of ventricular catheter placement. Further studies are required to evaluate frameless stereotaxy in optimizing shunt placement in patients with smaller ventricles. PMID- 21256030 TI - Stent for temporary endovascular bypass and thrombectomy in major ischemic stroke. AB - Endovascular techniques for acute stroke have evolved from a pharmacological to a mechanical approach. We report illustrative cases of successful anterior circulation recanalization in patients with large arterial occlusions, using a stent-based technique to perform arterial recanalization and thrombectomy, without permanent stent implantation. Four patients (mean age 59 years), presented with National Institutes of Health Stroke Scale (NIHSS) scores of 18 to 24, from 2 hours to 6 hours after stroke onset, with middle cerebral artery (MCA), MCA branch, internal carotid artery (ICA) terminus, or tandem ICA-MCA occlusions. A closed-cell stent was temporarily inserted to achieve temporary endovascular bypass, and then used as a thrombectomy device during withdrawal. Rapid and complete recanalization with successful thrombectomy was achieved in all patients within 28 minutes to 52 minutes. One week after treatment patients achieved NIHSS scores of 2 to 5, with no hemorrhagic complications. This approach allowed rapid endovascular revascularization and thrombectomy, without permanent stent implant. Stent-based thrombectomy devices may become a valuable tool in the management of acute ischemic stroke. PMID- 21256031 TI - Nanoparticle silver ion coatings inhibit biofilm formation on titanium implants. AB - The formation of bacterial biofilm on the surface of implanted metal objects is a major clinical problem. The antibacterial and antifungal effect of silver ions has been long known, and seems to give silver the capability to inhibit biofilm formation. To test the effect of silver ions, 20 New Zealand rabbits had bacteria applied to a screw insertion site at the iliac crest, and were then randomly divided into two groups: Group I, which had silver-coated screws applied, and Group II, which had uncoated titanium screws. After the rabbits were sacrificed on day 28, we examined the screws, the bone adjacent to the screws, and the liver, kidneys, brain and corneas of both groups under transmission (TEM) and scanning electron microscopy (SEM). We also analysed microbiological samples from the screw holes. All silver-coated screws, but only 10% of uncoated titanium screws, were sterile. All tissue samples appeared ultrastructurally normal in both groups. Biofilm formation was inhibited on all silver-coated screws, but all uncoated screws developed a biofilm on their surfaces. Our findings suggest that nanoparticle silver ion-coated implants are as safe as uncoated titanium screws and that they can help prevent both biofilm formation and infection. PMID- 21256032 TI - Adenylylation: renaissance of a forgotten post-translational modification. AB - The stable post-translational modification of proteins by adenylylation or uridylylation was discovered more than four decades ago as a mechanism to regulate the activity of enzymes. Although many other processes involving the covalent transfer of an AMP residue to an amino acid side chain have been identified since then, these are transient adenylylation events that essentially use the free energy of ATP hydrolysis to activate specific processes. Recently, new examples of stable adenylylation of small GTPases involved in signal transduction and regulation of cellular events were discovered, which appear to modulate downstream processes such as cytoskeletal rearrangement and vesicular trafficking. We present a survey of the historical and modern phases of research in this area, focusing on the common and differing aspects of protein adenylylation. PMID- 21256033 TI - Synthesis and triplex-forming ability of oligonucleotides bearing 1-substituted 1H-1,2,3-triazole nucleobases. AB - Using the copper(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition, a post elongation modification of 1-ethynyl substituted nucleobases has been employed to construct 18 variations of oligonucleotides from a common oligonucleotide precursor. The triplex-forming ability of each oligonucleotide with dsDNA was evaluated by the UV melting experiment. It was found that triazole nucleobases generally tend to exhibit binding affinities in the following order: CG>TA>AT, GC base pairs. Among the triazole nucleobases examined, a 1-(4-ureidophenyl)triazole provided the best result with regard to affinity and selectivity for the CG base pair. PMID- 21256034 TI - Synthesis of 6,14-epoxymorphinan derivatives and their pharmacologies. AB - A novel 6,14-epoxymorphinan benzamide derivative (NS22) that was previously reported showed opioid kappa receptor agonistic activity and analgesic activity. The unsatisfactory kappa selectivity of NS22 led us to synthesize its derivatives to improve the opioid kappa receptor selectivity and the agonist activity. In the course of SAR of the various derivatives, 17-benzyl-6,14-epoxymorphinan derivatives (KNT-33, 53, 55, 80, 90, 133) were found to show high selectivities and affinities for the opioid kappa receptor. In addition, KNT-33, 53, 55 showed dose-dependent analgesic effects in acetic acid writhing tests. Therefore, 17 benzyl substituents may play an important role for developing kappa selectivity. PMID- 21256035 TI - Synthesis and SAR studies on azetidine-containing dipeptides as HCMV inhibitors. AB - SAR studies on an azetidine-containing dipeptide prototype inhibitor of HCMV are described. Three series of structurally modified analogues, involving substitutions at the N- and C-terminus, and at the C-terminal side-chain were synthesized and evaluated for antiviral activity. Aliphatic or no substituents at the C-carboxamide group, an aliphatic C-terminal side-chain, as well as a benzyloxycarbonyl moiety at the N-terminus were absolute requirements for anti HCMV activity. The conformational restriction induced by the 2-azetidine residue into the dipeptide derivatives, identified by (1)H NMR as a gamma-type reverse turn, seems to have influence on the activity of these molecules. PMID- 21256036 TI - Atomic Force Microscopy of bulk tendon samples: affect of location and fixation on tissue ultrastructure. AB - Atomic Force Microscopy (AFM) is a surface characterisation technique which analyses topology. To date, AFM studies of tissue ultrastructure have focussed on single collagen fibrils extracted from different tissues prior to analysis. Using sample preparation techniques used in electron microscopy studies, this work uses AFM to analyse the collagen ultrastructure of bulk samples from bovine deep digital flexor tendons (DDFTs). DDFT ultrastructure in regions of the tendon which experience different loading conditions are compared. Samples are analysed post-freezing and post-aldehyde fixation with either 10% formalin or 4% glutaraldehyde in order to investigate the affect of tissue preservation on tissue ultrastructure. The results demonstrate that both fibril diameter and repeat unit of the tendon vary between different regions in the dorsoventral plane, with regions subjected to both tensile and compressive forces exhibiting smaller fibril diameter and repeat unit compared to regions subjected to tensile forces alone. These differences are detectable regardless of the tissue preservation technique used. However these measured differences do vary with preservation techniques with aldehyde-fixed samples exhibiting smaller fibril diameters and larger repeat units compared to frozen samples. These results demonstrate that AFM is a highly suitable technique for the characterisation of different ultrastructures in bulk samples but that it is important to be consistent in the choice of preservation technique. PMID- 21256037 TI - Structure of the Rtt109-AcCoA/Vps75 complex and implications for chaperone mediated histone acetylation. AB - Yeast Rtt109 promotes nucleosome assembly and genome stability by acetylating K9, K27, and K56 of histone H3 through interaction with either of two distinct histone chaperones, Vps75 or Asf1. We report the crystal structure of an Rtt109 AcCoA/Vps75 complex revealing an elongated Vps75 homodimer bound to two globular Rtt109 molecules to form a symmetrical holoenzyme with a ~12 A diameter central hole. Vps75 and Rtt109 residues that mediate complex formation in the crystals are also important for Rtt109-Vps75 interaction and H3K9/K27 acetylation both in vitro and in yeast cells. The same Rtt109 residues do not participate in Asf1 mediated Rtt109 acetylation in vitro or H3K56 acetylation in yeast cells, demonstrating that Asf1 and Vps75 dictate Rtt109 substrate specificity through distinct mechanisms. These studies also suggest that Vps75 binding stimulates Rtt109 catalytic activity by appropriately presenting the H3-H4 substrate within the central cavity of the holoenzyme to promote H3K9/K27 acetylation of new histones before deposition. PMID- 21256038 TI - Radiosynthesis and biological evaluation of the (99m)Tc-tricarbonyl moxifloxacin dithiocarbamate complex as a potential Staphylococcus aureus infection radiotracer. AB - In the present investigation, radiosynthesis of the (99m)Tc-tricarbonyl moxifloxacin dithiocarbamate complex ((99m)Tc(CO)(3)-MXND) and its biological evaluation in male Wister rats (MWR) artificially infected with Staphylococcus aureus (S. aureus) was assessed. The (99m)Tc(CO)(3)-MXND complex was radiochemically examined in terms of stability in saline and in serum and biologically its in-vitro binding with S. aureus and percent absorption in MWR models. Radiochemically the (99m)Tc(CO)(3)-MXND complex showed more than 90% stability in saline up to 240 min and in serum 14.95% undesirable species was appeared within 16h. In-vitro the (99m)Tc(CO)(3)-MXND complex showed saturated binding with S. aureus. In MWR artificially infected with live S. aureus the complex showed about six fold higher uptakes in the infected muscle as compared to the normal muscle. However, insignificant change in the uptake of (99m)Tc(CO)(3)-MXND complex in the infected and inflamed or normal muscle was observed in the MWR infected with heat killed S. aureus. The (99m)Tc(CO)(3)-MXND complex disappeared from the circulatory system and appeared in the urinary system within 60-90 min followed by excretion through normal route of urinary system. Based on the elevated and stable radiochemical succumb in saline, serum, saturated in-vitro binding with S. aureus and higher accumulation in the target organ of the MWR, we recommend the (99m)Tc(CO)(3)-MXND complex for radio localization of the infection induced by S. aureus in human. PMID- 21256039 TI - Automated production of [11C]acetate and [11C]palmitate using a modified GE Tracerlab FX(C-Pro). AB - As researchers explore new applications for positron emission tomography radiopharmaceuticals, the demand for effective and readily available radiopharmaceuticals continues to increase. The syntheses of two such radiopharmaceuticals, [(11)C]acetate and [(11)C]palmitate, can be automated on the GE Tracerlab FX(C-Pro) by utilizing Grignard reactions. Radiochemical purities of the [(11)C]acetate and the [(11)C]palmitate products were high (>98% and >99.9%, respectively) with average non-corrected yields of 18% (n = 3) and 10% (n = 5), respectively. These data comprise the validation trials for site qualification of clinical production of both radiopharmaceuticals. PMID- 21256040 TI - The effectiveness of stilbenes in resistant Vitaceae: ultrastructural and biochemical events during Plasmopara viticola infection process. AB - Leaves of different Vitis vinifera L. cultivars, susceptible or resistant to downy mildew, Chasselas, Solaris, IRAC 2091 (cvs. Gamaret x Bronner) and Muscadinia rotundifolia were inoculated with Plasmopara viticola. Samples were then examined by scanning and transmission electron microscopy, by light microscopy and for their ability to synthesise stilbenes. These phytoalexins were strictly analysed at infection sites. In the susceptible Chasselas, P. viticola colonises, at 72h post-infection (hpi), all of the spongy mesophyll with functional haustoria and produces mainly the non toxic piceide. No necrotic zone was observed on Chasselas leaves. The ultrastructural response to downy mildew infection is different in each of the other three resistant grape cultivars. In Solaris, where leaf necrosis are rapidly induced, the infection is restricted to the upper part of the loose spongy mesophyll, and associated with a rapid cell wall disruption and the dispersion of cytoplasmic content along with the production of viniferins. In IRAC 2091, leaf necrosis are quite similar to those observed on Solaris but the infected plant cell, as well as the haustoria, show high electron dense cellular particles without any recognisable organelles, probably related to the effect of the toxic compound pterostilbene, which is synthesised in this grape cultivar. In M. rotundifolia leaf necrosis are much more scarce and smaller than in other cultivars, but pathogen and plant cells are both strongly affected, with concomitant expulsion of cytoplasmic materials through the stomata after P. viticola penetration. In this cultivar, the concentration of all identified stilbenes exceeds 1*103 MUmol mg(-1) FW. The critical role of stilbenes in the resistance of Vitis spp. is discussed. PMID- 21256041 TI - Abolition of photosystem I cyclic electron flow in Arabidopsis thaliana following thermal-stress. AB - Heat tolerance of Arabidopsis thaliana (WT) and its mutants, crr2-2, lacking NADPH-dehydrogenase (Ndh-pathway), and pgr5, deficient in proton gradient regulation and/or ferredoxin-quinone-reductase (FQR-pathway), was studied from 30 to 46 degrees C. Chlorophyll fluorescence revealed that thermal damage to photosystem II (PSII) was maximal in WT plants following short-term exposure of leaves to moderate or high temperature stress. Thermal stress impaired the photosynthetic electron flow at oxidizing and reducing sides of PSII. This was deduced from the transformation of temperature dependent OJIP to OKP patterns, changes in the relative amplitudes of K-step fluorescence rise and F(v)/F(o) ratio. The amplitude of the K-peak that corresponds to the magnitude of damage to the oxygen evolving complex (OEC) in crr2-2 mutants was about 50% of that observed in WT plants exposed to 46 degrees C. The damage to OEC in pgr5 mutants was relatively smaller and thus their PSII complexes were more heat tolerant. P700 oxidation-reduction kinetics following heat-stress revealed that photosystem I (PSI) complexes remained oxidizable either with 10-ms multiple turn-over flashes or far-red illumination but the complementary cyclic electron flow around PSI (CEF) was abolished in both mutants. With further increase in incubation temperature, CEF was fully suppressed even in WT. Thus, P700 turn-over was not enhanced following thermal stress. Furthermore, the experimental data predicts the onset of pseudocyclic electron transport with molecular oxygen as terminal acceptor in crr2-2 and pgr5 mutants but not in wild type Arabidopsis subjected to severe thermal-stress. PMID- 21256042 TI - Supportive psychotherapy for patients with heart transplantation or ventricular assist devices. AB - OBJECTIVE: Both heart transplant (HTX) candidates and patients on ventricular assist device (VAD) support suffer from severe heart failure and have to fear life-threatening complications. For both patient groups, the importance of screening for and treatment of psychosocial problems and mental disorders to optimize compliance and survival has been acknowledged. We compared the use of psychotherapeutic support by patients with primary HTX, on VAD support, either on destination therapy or to be transplanted, and successfully bridged to transplant. In addition, we evaluated the use for supportive psychotherapy for the families of our patients and present two typical cases. METHODS: Patients with primary HTX (HTX(prim), n=16), with VAD on destination therapy (VAD(dest), n=15), with VAD waiting for transplant (VAD(htx), n=9), and patients who have been successfully bridged on VAD to transplant (HTX(vad), n=11) were analyzed during the preoperative and the in-hospital postoperative period. International Classification of Diseases (ICD 10) diagnoses, number of contacts with the psychologist, time expenses for individual interventions, family interventions, and concomitant communication were assessed. RESULTS: Adjustment disorders were the most prevalent disturbances. HTX(vad) patients needed more psychotherapeutic interventions and required more time for individual support than HTX(prim) patients. Partners and families of almost one-half of all patients made use of supportive psychotherapy; there were no differences between the groups with regard to the needed time. Further, the groups did not differ in the time expenses for concomitant communication with the psychologist. At the latest contact with the psychologist, three VAD(dest) patients did not need further psychotherapy at this time; also, one VAD patient waiting for transplant and two after primary HTX were psychosocially stable. CONCLUSION: Our data reflect the high emotional distress, especially of HTX(vad) patients. Our data suggest further that patients on VAD support experience psychosocial and emotional stress as severe as HTX candidates and recipients do. Patients on destination therapy and those who are waiting for transplantation do not differ in this regard. The high complexity of the psychosocial problems of VAD and HTX patients warrants professional psychotherapeutic support. PMID- 21256043 TI - Use of donors who have suffered cardiopulmonary arrest and resuscitation in lung transplantation. AB - OBJECTIVES: Shortage of donors is one of the major limitations in lung transplantation (LuTX) and an aggressive expansion of criteria for donor selection has been proposed. This study evaluates the outcome of recipients of pulmonary grafts coming from resuscitated donors when compared with recipients of non-resuscitated donors. METHODS: We retrospectively analyzed the donor and recipient charts of all double LuTX performed at our institution between 2000 and 2008 with regard to the performance of donor-cardiopulmonary resuscitation (CPR). RESULTS: Out of 186 eligible transplants, 22 patients (11.8%) received lungs from donors who have suffered cardiac arrest (CA) and subsequent CPR. Mean duration of CPR was 15.2 +/- 11.3 min. Terminal laboratory profiles of CPR donors and non-CPR donors were similar as were ventilation time and paO(2)/FiO(2) ratio before organ harvesting or chest X-ray. CPR-donor status did not affect the following indices of graft function: length of postoperative ventilation, paO(2)/FiO(2) ratio up to 48 h and lung function up to 60 months. Length of intensive care and hospital stay, need for inotropic support and 30-day mortality were not significantly different for the transplantation of CPR or no-CPR donor lungs. One- and 3-year survival rates were comparable as well with 84.4% and 66.3% for CPR donors versus 88.5% and 69.8% no-CPR donors. CONCLUSIONS: This study indicates that transplantation of lungs from resuscitated donors may not affect outcome after LuTX. Therefore, donor history of CA should not automatically preclude LuTX. PMID- 21256044 TI - Trans-apical aortic valve implantation in patients with severe calcification of the ascending aorta. AB - OBJECTIVE: In patients with calcification of the ascending aorta, postoperative stroke and mortality rates remain high after conventional aortic valve replacement, but the results of trans-apical aortic valve implantation in these patients are not known. We evaluate the outcome of trans-apical aortic valve implantation in patients with severely calcified ascending aorta in a single center with expanded procedural experience. METHODS: Between April 2008 and July 2010, 258 patients underwent trans-apical aortic valve implantation using Edwards Sapien valve. By computed tomography (CT) scan, we identified 46 (18%) patients with severe calcification of the ascending aorta (16 with porcelain aorta and 30 with severe, but not complete, calcification). RESULTS: Of 46 patients (mean age 77 +/- 10 years, range 63-90 years; EuroSCORE (European System for Cardiac Operative Risk Evaluation) 45 +/- 22%; STS (Society of Thoracic Surgeons) score 23 +/- 13) with calcified aorta, 15 received 23-mm valves and 31 patients 26-mm valves. Primary valve implantation was successful in 44 patients and a second valve was implanted (valve-in-valve) in two. Six patients underwent concomitant interventions (three elective percutaneous coronary intervention (PCI), one off pump coronary artery bypass (OPCAB), one tricuspid valve reconstruction, and one left-ventricular (LV) aneurysmectomy). The final procedural results showed valve incompetence (trace or grade 1) in 17 (37%) patients and paravalvular leak in 15 (32.6%) (trace in 10 and grade 1 in five). There was no 30-day mortality. Postoperatively, cranial CT showed new cerebral ischemia areas in three patients (6.2%), but only one patient (2.1%) experienced postoperative neurological deficit (temporary aphasia). Survival at 6 and 12 months was 88% and 85.2%, respectively. CONCLUSIONS: Trans-apical aortic valve implantation can be performed safely in patients with aortic valve stenosis and severe calcification of the ascending aorta. PMID- 21256045 TI - Magnetic resonance imaging evaluation of cerebral embolization during percutaneous aortic valve implantation: comparison of transfemoral and trans apical approaches using Edwards Sapiens valve. AB - OBJECTIVE: Cerebral embolization during trans-catheter aortic valve implantation (TAVI) has not been assessed clearly in the literature. Therefore, we compared the rate of cerebral embolisms with diffusion-weighted magnetic resonance imaging (DWI) in transfemoral (TF) and trans-apical (TA) approaches. METHOD: Eighty patients benefited from TAVI between January 2008 and June 2010. Out of these, 35 were included in the study. Twenty-one were TF (group 1) and 14 TA (group 2). During the same period, 285 patients benefited from a conventional aortic valve surgery (aortic valve replacement (AVR)). Thirteen of these were also analyzed and considered as the control group (group 3). We systematically performed a DWI the day before the procedure and 48 h after. DWI studies were blindly analyzed by a neuroradiologist, and all patients had a clinical neurological assessment before and after the procedure, according the National Institutes of Health Stroke Scale (NIHSS). RESULTS: Thirty-two patients in the TAVI group had new cerebral lesions: 19 in the TF group and 13 in the trans-apical group (p=NS). Mean number of embolic lesions per patient was 6.6 in group I and 6.0 in group II (p=NS). Mean volume of embolic lesions was 475.0 mm3 in group I and 2170.5 mm3 in group II (p=NS). In group III, one patient had one new cerebral lesion (p<0.05 vs TAVI) of 36.5 mm3 (p=NS vs TAVI). All patients were neurologically asymptomatic. CONCLUSIONS: The incidence of silent cerebral embolic lesions after TAVI is significantly higher compared with the standard surgical AVR. The number of emboli is similar in the TF and TA groups but the volume tended to be higher in the TA group. However, there is no clinical impact of those lesions. PMID- 21256046 TI - Advanced gastric cancer (GC) and cancer of the gastro-oesophageal junction (GEJ): focus on targeted therapies. AB - Despite recent improvements in surgical techniques and chemotherapy treatments, locally advanced/metastatic gastroesophageal junction (GEJ) and gastric cancer (GC) are still associated with poor clinical outcome. However, increased understanding of molecular mechanisms underlying carcinogenesis and its implementation in the treatment of breast, colon, lung, and other cancers in recent years have spurred focus on the development and incorporation of targeted agents in current therapeutic options for this difficult-to-treat disease. Such agents have the ability to target a variety of cancer relevant targets, including epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) and its receptor. In this review, we describe the current status of targeted therapies in the treatment of advanced GC and GEJ cancer, focusing on pre-clinical and clinical data available on monoclonal antibodies and tyrosine kinase inhibitors acting in these pathways, including completed and ongoing phase III studies. PMID- 21256047 TI - Vastus lateralis oxygenation dynamics during maximal fatiguing concentric and eccentric isokinetic muscle actions. AB - The present study aimed to assess whether high intensity exhaustive eccentric (ECC) exercise was associated with a greater decrease in muscle oxygenation compared to high intensity exhaustive concentric (CON) exercise during maximal isokinetic knee extensions. On two separate days, ten recreationally active participants performed maximal isokinetic concentric (KE(CON)) and eccentric (KE(ECC)) knee extension exercises at 60 degrees s(-1) until exhaustion. Muscle oxygenation profile and activity were acquired continuously from the vastus lateralis (VL) muscle using near-infrared spectroscopy, along with surface electromyography (sEMG). The torque output was significantly greater during KE(ECC) (P<0.01). Total time to exhaustion was longer in ECC condition (P<0.01). The decrease in tissue oxygenation index observed between the beginning and end exercise values was significantly greater during KE(ECC) than during KE(CON) (P<0.05) while total haemoglobin volume did not differ significantly. KE(ECC) resulted in a significant increase in end-exercise integrated sEMG (P<0.05). We propose that the associated higher intramuscular pressure may have compressed blood vessels and led to a greater decrease in tissue oxygenation index. The observed end-exercise increase in neural drive during KE(ECC) may have occurred to prevent from muscle performance decrease. These results suggest that, over time, repeated maximal ECC actions induce a greater O(2) extraction compared to maximal CON actions. PMID- 21256049 TI - The proton pump inhibitor pantoprazole and its interaction with enteric-coated mycophenolate sodium in transplant recipients. AB - BACKGROUND: In this prospective study we investigated the impact of the proton pump inhibitor (PPI) pantoprazole on the bioavailability of mycophenolic acid (MPA) after oral administration of enteric-coated mycophenolate sodium (EC-MPS; Myfortic) in heart or lung transplant recipients. Previously we demonstrated that pantoprazole reduces the MPA exposure of mycophenolate mofetil (MMF; CellCept) by 34% in area under the concentration-time curve (AUC). Because gastrointestinal side-effects are common after organ transplantation, we investigated the effect of PPI on MPA levels in patients receiving EC-MPS. METHODS: MPA plasma concentrations and inosine monophosphate dehydrogenase (IMPDH) activity at baseline, 30 minutes and 1, 2, 3 and 4 hours were obtained from 21 patients. These patients were treated with pantoprazole 40 mg once daily and EC-MPS twice daily at a mean dose of 960 mg. Measurements were repeated after pantoprazole withdrawal. RESULTS: MPA concentrations and IMPDH activities did not reveal any significant difference during PPI treatment and after withdrawal. MPA AUC, MPA C(max) (maximal MPA concentration), the time until C(max) was reached (T(max)) and IMPDH activity AUC all showed no significant difference. CONCLUSION: We did not find an influence of pantoprazole on EC-MPS pharmacokinetics such as we did for MMF in our previous investigation. A further prospective, large, cross-over study is planned to support these preliminary results. Given that MPA exposure by AUC correlates with the incidence of acute rejection episodes and transplant vasculopathy, the present findings may have clinical implications. PMID- 21256048 TI - Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension. AB - BACKGROUND: Tadalafil 40 mg orally once daily, was shown to be well-tolerated and efficacious for pulmonary arterial hypertension in a 16-week, double-blind, placebo (PBO)-controlled trial. Inclusion criteria included the option for background bosentan. Analyses of tadalafil in treatment-naive patients and as add on to bosentan were pre-specified. Objectives were to provide safety and efficacy data for both groups. METHODS: Groups analyzed included: treatment-naive + PBO; treatment-naive + tadalafil; background bosentan + PBO; and background bosentan + tadalafil. Patients randomized to tadalafil or PBO (N = 405) were analyzed by bosentan use (yes = 216, no = 189). Treatment differences in 6-minute walk distance (6MWD, PBO-adjusted), functional class (FC), clinical worsening (CW) and adverse events were assessed. Hazard ratios (HRs) with 95% confidence intervals (CIs) are presented for FC and CW. RESULTS: At Week 16, PBO-adjusted 6MWD increases were 44 m (CI: 20 to 69 m; n = 37) for tadalafil 40 mg in treatment naive patients and 23 m (CI: -2 to 48 m; n = 42) for tadalafil 40 mg add-on to bosentan. The 6MWD for treatment-naive and background bosentan PBO patients decreased by 3 m and increased by 19 m, respectively, at Week 16 compared with baseline. Two (5%) treatment-naive patients had CW with tadalafil 40 mg vs 8 (22%) with PBO (HR = 3.3, CI: 1.1 to 10.0). Two (5%) background bosentan patients had CW with tadalafil 40 mg add-on vs 5 (11%) for PBO add-on (HR = 1.9, CI: 0.4 to 10.2). Adverse events for tadalafil monotherapy and as add-on were similar. CONCLUSION: Tadalafil 40 mg was well-tolerated and provided clinical benefit in patients as monotherapy. It was also well-tolerated when added to background bosentan, but data are insufficient to conclude additional benefit. PMID- 21256050 TI - Tolerance induction by hematopoietic cell transplantation: combined use of stem cells and progenitor cells. AB - BACKGROUND: Donor-specific hematopoietic cell transplantation (HCT) in the form of bone marrow transplantation has been long recognized experimentally as a means of inducing tolerance for subsequently transplanted organs. Clinical translation has been limited, however, due to HCT-associated complications. Unrelated myeloid progenitors (MP) can be administered simultaneously with hematopoietic stem cells (HSC). This reduces susceptibility to bacterial and fungal infections in neutropenic mice in laboratory studies. It is not known, however, if the addition of third-party MP interferes with tolerance induction. METHODS: BALB/c (H-2d) mice were irradiated and reconstituted with 4,000 AKR (H-2k) HSC or with 4,000 AKR HSC combined with 10(5) FVB (H-2q) MP. After 2 months, the mice received skin grafts from these three strains or from an unrelated strain, C57BL/6 (H-2b). Composition and origin of hematopoietic cells was analyzed using flow cytometry. RESULTS: Mice in both groups accepted all the host-type- and HSC-donor-matched grafts, and rejected unrelated grafts. Surprisingly, recipients of both HSC and MP also accepted MP-matched skin grafts (14 of 14), even with very low levels of MP-derived cells in circulation. The analysis revealed that, although most hematopoietic cells were derived from HSC donors, regulatory T cells were derived from both donors as well as the recipient. CONCLUSION: The addition of third party MP cells does not interfere with HCT-induced tolerance induction and, surprisingly, induces MP-specific tolerance. PMID- 21256052 TI - The aortic valve microenvironment and its role in calcific aortic valve disease. AB - In calcific aortic valve disease, fibrotic and calcific lesions form focally in the fibrosa layer of the valve leaflets. Layer-specific pathosusceptibility suggests that the fibrosa microenvironment is permissive to pathological development. The cellular microenvironment in the aortic valve is defined by a variety of biomechanical-, biochemical-, and extracellular-mediated factors, some of which are unique to the fibrosa. Growing evidence supports the role of these microenvironmental cues in the local regulation of side-specific valve cell phenotypes and focal pathological alterations, revealing new insights into the cellular and molecular processes that contribute to calcific aortic valve disease. PMID- 21256051 TI - Relating inter-individual differences in metacognitive performance on different perceptual tasks. AB - Human behavior depends on the ability to effectively introspect about our performance. For simple perceptual decisions, this introspective or metacognitive ability varies substantially across individuals and is correlated with the structure of focal areas in prefrontal cortex. This raises the possibility that the ability to introspect about different perceptual decisions might be mediated by a common cognitive process. To test this hypothesis, we examined whether inter individual differences in metacognitive ability were correlated across two different perceptual tasks where individuals made judgments about different and unrelated visual stimulus properties. We found that inter-individual differences were strongly correlated between the two tasks for metacognitive ability but not objective performance. Such stability of an individual's metacognitive ability across different perceptual tasks indicates a general mechanism supporting metacognition independent of the specific task. PMID- 21256053 TI - Development and pretesting multimedia HIV-prevention text messages for mobile cell phone delivery. PMID- 21256054 TI - Exploring decision-making of HIV-infected Hispanics and African Americans participating in clinical trials. AB - Underrepresentation of HIV-infected Hispanics and African Americans in clinical trials seriously limits our understanding of the benefits and risks of treatment in these populations. This qualitative study examined factors that racial/ethnic minority patients consider when making decisions regarding research participation. A total of 35 HIV-infected Hispanic and African American patients enrolled in clinical research protocols at the National Institutes of Health were recruited to participate in focus groups and in-depth interviews. The sample included mostly male participants (n = 22), had a mean age of 45, had nearly equal representation of race/ethnicity, and were diagnosed 2 to 22 years earlier. Baseline questionnaires included demographics and measures of social support and acculturation. Interviewers had similar racial/ethnic, cultural, and linguistic backgrounds as the participants. Four major themes related to the decisions of participants to enroll in clinical trials emerged, which are as follows: enhancers, barriers, beliefs, and psychosocial context. Results may help researchers develop strategies to facilitate inclusion of HIV-infected Hispanics and African Americans into clinical trials. PMID- 21256055 TI - Erythropoietin contrastingly affects bacterial infection and experimental colitis by inhibiting nuclear factor-kappaB-inducible immune pathways. AB - Erythropoietin (EPO) is the principal cytokine regulating erythropoiesis through its receptor, EPOR. Interestingly, EPORs are also found on immune cells with incompletely understood functions. Here, we show that EPO inhibits the induction of proinflammatory genes including tumor necrosis factor (TNF)-alpha and inducible nitric oxide (NO) synthase in activated macrophages, which is mechanistically attributable to blockage of nuclear factor (NF)-kappaB p65 activation by EPO. Accordingly, in systemic Salmonella infection, treatment of mice with EPO results in reduced survival and impaired pathogen clearance because of diminished formation of anti-microbial effector molecules such as TNF-alpha and NO. However, neutralization of endogenous EPO or genetic ablation of Epor promotes Salmonella elimination. In contrast, in chemically induced colitis, EPO EPOR interaction decreases the production of NF-kappaB-inducible immune mediators, thus limiting tissue damage and ameliorating disease severity. These immune-modulatory effects of EPO may be of therapeutic relevance in infectious and inflammatory diseases. PMID- 21256056 TI - Two-stage cooperative T cell receptor-peptide major histocompatibility complex CD8 trimolecular interactions amplify antigen discrimination. AB - The T cell receptor (TCR) and CD8 bind peptide-major histocompatibility complex (pMHC) glycoproteins to initiate adaptive immune responses, yet the trimolecular binding kinetics at the T cell membrane is unknown. By using a micropipette adhesion frequency assay, we show that this kinetics has two stages. The first consists of TCR-dominant binding to agonist pMHC. This triggers a second stage consisting of a step increase in adhesion after a one second delay. The second stage binding requires Src family kinase activity to initiate CD8 binding to the same pMHC engaged by the TCR. This induced trimeric-cooperative interaction enhances adhesion synergistically to favor potent ligands, which further amplifies discrimination. Our data reveal a TCR-CD8 positive-feedback loop involved in initial signaling steps that is sensitive to a single pMHC is rapid, reversible, synergistic, and peptide discriminative. PMID- 21256057 TI - T lymphocytes negatively regulate lymph node lymphatic vessel formation. AB - Lymph node lymphatic vessels (LNLVs) serve as a conduit to drain antigens from peripheral tissues to within the lymph nodes. LNLV density is known to be positively regulated by vascular endothelial growth factors secreted by B cells, macrophages, and dendritic cells (DCs). Here, we show that LNLV formation was negatively regulated by T cells. In both steady and inflammatory states, the density of LNLVs was increased in the absence of T cells but decreased when T cells were restored. Interferon-gamma secretion by T cells suppressed lymphatic specific genes in lymphatic endothelial cells and consequently caused marked reduction in LNLV formation. When T cells were depleted, recruitment of antigen carrying DCs to LNs was augmented, reflecting a compensatory mechanism for antigen presentation to T cells through increased LNLVs. Thus, T cells maintain the homeostatic balance of LNLV density through a negative paracrine action of interferon-gamma. PMID- 21256058 TI - Downregulation of remodelling enzymatic activity induced by an angiotensin converting enzyme inhibitor (perindopril) reduces the degeneration of experimental abdominal aortic aneurysms in a rat model. AB - AIMS: Angiotensin-converting enzyme (ACE) inhibitors have proven their ability to affect vascular wall remodelling, in addition to their anti-hypertensive effects. The aim of this study was to assess the impact of perindopril on the development of abdominal aortic aneurysm (AAA) in a rat model, and its correlation to enzyme activities involved in vascular wall remodelling. METHODS: The model of the decellularised aortic xenograft in Lewis rat was chosen. Rats were randomised to two groups: group P fed with 3 mg kg(-1) of perindopril daily during 30 days, or control group C (n = 15 per group)). Rats were euthanised at 30 days for analysis. AAA growth and histological changes in the aortic wall were measured by histomorphometry. Proteolytic activities were measured by gelatin zymography of conditioned medium for activematrix metalloproteinase 9/pro-matrix metalloproteinase 9 (MMP9/pro-MMP9) and activeMMP2/pro-MMP2, and by quantitative immunofluorescence tissue for elastase and plasmin. RESULTS: The mean maximal diameter of AAAs at 30 days was significantly lower in the treated group P compared with the control group C (2.5 +/- 1.0 vs. 4.9 +/- 2.1 mm; P < 0.01). The expansion rate of AAAs after 30 days was significantly reduced in group P compared with group C (36 +/- 14% vs. 67 +/- 23%; P < 0.01). Pro-MMP9 and MMP9 activities were significantly decreased in relative intensity (RI) in group P compared with group C (0.43 +/- 0.64 RI vs. 1.02 +/- 0.61 RI, P = 0.01; 0.18 +/- 0.57 RI vs. 0.66 +/- 1.19 RI, P = 0.004). The activation rate of MMP2 was also significantly lower in group P compared with group C (1.27 +/- 0.42 vs. 1.67 +/- 0.44; P = 0.002). Elastase and plasmin tissue activities were significantly lower in group P compared with group C, respectively (3.9 +/- 3.3 vs. 5.8 +/- 3.7 IF min(-1) g(-1),and 25.9 +/- 23.9 vs. 49.1 +/- 38.7 IF min(-1) g(-1); P < 0.05). CONCLUSION: After 30 days of treatment by perindopril, a significant decrease in aneurysmal degeneration of the decellularised aortic xenograft AAA model was observed. This phenomenon appears to be induced by a downregulation of enzymes involved in the aortic wall remodelling during aneurysmal degeneration. PMID- 21256059 TI - Glucocerebrosidase gene has an alternative upstream promoter, which has features and expression characteristic of housekeeping genes. AB - Database searches have shown that a part of glucocerebrosidase (GBA) transcripts may originate at an alternative upstream promoter (P2) located 2.6 kb upstream of the known (P1) GBA promoter. The putative alternative transcripts contained one or two extra exons (exon -2 or exons -2, -1, respectively), but the first ATG codon and predicted amino-acid sequence are the same as in the transcript from P1. Luciferase assays confirmed promoter activity of both sites in HepG2 cells: the P1 construct exhibited the highest activity of luciferase (17.82+/-1.10 relative luciferase units), while the P2 construct reached 3.01+/-0.43 relative luciferase units. Serial 5' deletions of P2 led to changes in reporter activity, the most prominent decreases were observed in deletion constructs carrying bases 353 to -658, and -353 to -920 (numbered as in NM_001005750.1), respectively. This suggests that the P2 core promoter is contained within the region of -920bp to 1311bp. Three P2 transcription initiation sites were found by 5' RACE at positions 347, 380, and 413bp upstream of the +1 ATG. The expression stability of transcripts from P2, P1 was studied in 20 human tissues and was higher than that of GAPDH and ACTB, which are commonly used as reference housekeeping genes. The P2 contains an unmethylated CpG island, multiple Sp-1 consensus binding sites and, unlike P1, does not contain a TATA box, features all common to the majority of housekeeping gene promoters. We have examined DNA samples from a phenotypically diverse group of twenty Ashkenazi Jewish Gaucher patients homozygous for the common mild mutation N370S. Both P1 and P2, as well as exons 2 and -1, did not contain any sequence variations, with the exception of the known polymorphism rs10908459 found on one allele. The phenotypical differences in the patients were thus not explained by nucleotide variations in both promoters. PMID- 21256060 TI - Variable angle NMR spectroscopy and its application to the measurement of residual chemical shift anisotropy. AB - The successful measurement of anisotropic NMR parameters like residual dipolar couplings (RDCs), residual quadrupolar couplings (RQCs), or residual chemical shift anisotropy (RCSA) involves the partial alignment of solute molecules in an alignment medium. To avoid any influence of the change of environment from the isotropic to the anisotropic sample, the measurement of both datasets with a single sample is highly desirable. Here, we introduce the scaling of alignment for mechanically stretched polymer gels by varying the angle of the director of alignment relative to the static magnetic field, which we call variable angle NMR spectroscopy (VA-NMR). The technique is closely related to variable angle sample spinning NMR spectroscopy (VASS-NMR) of liquid crystalline samples, but due to the mechanical fixation of the director of alignment no sample spinning is necessary. Also, in contrast to VASS-NMR, VA-NMR works for the full range of sample inclinations between 0 degrees and 90 degrees . Isotropic spectra are obtained at the magic angle. As a demonstration of the approach we measure 13C RCSA values for strychnine in a stretched PDMS/CDCl3 gel and show their usefulness for assignment purposes. In this context special care has been taken with respect to the exact calibration of chemical shift data, for which three approaches have been derived and tested. PMID- 21256061 TI - Diagonalization-free implementation of spin relaxation theory for large spin systems. AB - The Liouville space spin relaxation theory equations are reformulated in such a way as to avoid the computationally expensive Hamiltonian diagonalization step, replacing it by numerical evaluation of the integrals in the generalized cumulant expansion. The resulting algorithm is particularly useful in the cases where the static part of the Hamiltonian is dominated by interactions other than Zeeman (e.g. in quadrupolar resonance, low-field EPR and Spin Chemistry). When used together with state space restriction tools, the algorithm reported is capable of computing full relaxation superoperators for NMR systems with more than 15 spins. PMID- 21256062 TI - [A descriptive study of patients seen in a stroke unit in the Community of Extremadura]. AB - OBJECTIVES: To describe the activity in the stroke unit (SU) of the Hospital de Caceres as well as the demographic characteristics and cardiovascular risk factors in our patients. To determine the patient's functional status at discharge. MATERIAL AND METHODS: A descriptive study of 432 patients admitted consecutively in the SU of the Hospital de Caceres from October, 2008 to May, 2010 was carried out. The different study variables (demographic, risk factors, dependence) were determined and analyzed. RESULTS: The patient prototype was a 71 year old-man from the rural environment, with hypertension, hyperlipidemia, diabetes, who had an ischemic stroke. On medical discharge from the stroke unit (SU), the patient had a mild functional dependence, after and average stay of 2.8 days in the SU. CONCLUSIONS: All patients who suffers a stroke should be attended by and benefit from the care provided in a SU. These units are organizational models that improve patient care in the acute phase, this resulting in lower mortality and disability in these patients. PMID- 21256063 TI - [The nurse expert in the care of the critical patients according to Patricia Benner]. AB - INTRODUCTION: When discussing care, the individual cannot be considered separate from their most immediate context, that is, the family. Including the family in the cares for a critically ill patient requires a skill that is not developed until the nursing professional is competent in Benner's terms. The skill that a nurse can have to become involved in caring for patients and the family is acquired over time and through experience. OBJECTIVE: To explore the behavior and clinical judgment of a nurse qualified in areas of critical care, according to Patricia Benner, identifying the responses provided by the nurse for patient and family needs. METHOD: Maria, an expert nurse in an intensive care unit, was selected to report on a significant clinical episode related to caring for the family. Her narration was read, and analysis and conclusions were carried out, within the field of caring for the family and according to the six aspects of clinical judgment and expert behavior outlined by Benner. RESULTS: It reveals how the expert skills and know-how of the nurse bring about a significant change in the practice. CONCLUSIONS: Encouraging the family to take part in the care promotes union, decreases impotence and anxiety and helps to assimilate the loved one's situation, aspects which form part of the nursing skill to provide complete care. Using Maria's clinical practice as a base, aspects of the clinical judgment and behavior that Benner identifies in an expert nurse can be observed. PMID- 21256064 TI - [Intrahospital transportation of the seriously ill patient. The need for an action guideline]. AB - The basics caused by the transportation of a patient in serious condition within the same hospital are varied, all of them involving a risk to the patient's stability and a responsibility for the accompanying professionals. The care that supposes the appropriate attention to the patient and the need for coordination among the parties make it necessary to homogenize the transfer criteria and those of the necessary previous maneuvers. This work has been carried out based on the lack of an intervention system that guides this practice. This work describes the possible intrahospital itineraries, the transport of this kind of patient, the phases of this type of transport as well as the most frequent physiologic alterations. The purpose of all this is to develop an action algorithm for the serious patient's intrahospital transportation and to reduce the incidence of adverse events during this transfer. A classification system that makes it possible to calculate the level of risk and to anticipate the care needs that a patient may require during the transfer is presented. PMID- 21256065 TI - [Education in bioethics, a way for professionalism]. AB - One of the elements that have historically defined professions making them different from mere occupations is the fact that their responsibilities have been defined more in moral than juridical terms. Because it is not the due respect to the law but the tendency to moral excellence the fundamental characteristic of professions. Professionalism is the base of medicine's contract with society and it obliges to put patients' interests above the doctors' ones, supplying competence and integrity standards, and providing expert help to society in health matters. Education in bioethics is an appropriate instrument to reach this goal, as it promotes an interdisciplinary analysis of the problems created by the medical and biological progress and its correspondent technologies, to find what is most human in its practical application. PMID- 21256066 TI - [Regional pilot study to evaluate the laboratory turnaround time according to the client source]. AB - PURPOSE: To show turnaround time to client source in eight laboratories covering eight Health Areas (2,014,475 inhabitants) of the Valencian Community (Spain). MATERIAL AND METHODS: Internal Laboratory Information System (LIS) registers (test register and verification date and time), and daily LIS registers were used to design the indicators, These indicators showed the percentage of key tests requested (full blood count and serum glucose and thyrotropin) that were validated on the same day the blood was taken (inpatients and Primary Care and/or at 12 a.m. (inpatients). Urgent (stat) tests were also registered as key tests (serum troponin and potassium) and were recorded in minutes. Registers were collected and indicators calculated automatically through a Data Warehouse application and OLAP cube software. RESULTS: Long turnaround time differences were observed at 12 a.m. in inpatients, and in the day of sample extraction in primary care patients. The variability in turnaround of stat tests is related to hospital size, activity and validation by the laboratory physician. CONCLUSIONS: The study results show the large turnaround time disparity in eight Health Care Areas of Valencian Community. The various requesting sources covered by the laboratories create the need for continuous mapping processes redesign and benchmarking studies to achieve customer satisfaction. PMID- 21256067 TI - Ultrasonically-promoted synthesis of mandelic acid by phase transfer catalysis in an ionic liquid. AB - An efficient and facile process to synthesize mandelic acid through phase transfer catalysis (PTC; also phase transfer catalyst) using ultrasound in an ionic liquid has been developed. Mandelic acid was synthesized from benzaldehyde with chloroform in an 89.6% yield at 60 degrees C for 2h by using tetrabutyl ammonium bromide (TBAB) as a phase transfer catalyst. Effects of different factors, such as frequency of ultrasound, reaction temperature, kinds of PTC and solvents had been investigated to obtain the optimum condition. It was observed that the ultrasonically promoted synthesis of mandelic acid by PTC in the ionic liquid exhibited significant enhancement in reaction yields under ambient conditions. PMID- 21256068 TI - Evolved pseudo-wavelet function to optimally decompose sEMG for automated classification of localized muscle fatigue. AB - The purpose of this study was to develop an algorithm for automated muscle fatigue detection in sports related scenarios. Surface electromyography (sEMG) of the biceps muscle was recorded from ten subjects performing semi-isometric (i.e., attempted isometric) contraction until fatigue. For training and testing purposes, the signals were labelled in two classes (Non-Fatigue and Fatigue), with the labelling being determined by a fuzzy classifier using elbow angle and its standard deviation as inputs. A genetic algorithm was used for evolving a pseudo-wavelet function for optimising the detection of muscle fatigue on any unseen sEMG signals. Tuning of the generalised evolved pseudo-wavelet function was based on the decomposition of twenty sEMG trials. After completing twenty independent pseudo-wavelet evolution runs, the best run was selected and then tested on ten previously unseen sEMG trials to measure the classification performance. Results show that an evolved pseudo-wavelet improved the classification of muscle fatigue between 7.31% and 13.15% when compared to other wavelet functions, giving an average correct classification of 88.41%. PMID- 21256069 TI - The trajectory of apathy after deep brain stimulation: from pre-surgery to 6 months post-surgery in Parkinson's disease. AB - Deep brain stimulation (DBS) has been associated with increased apathy in patients with PD, yet studies lack longitudinal data and have not assessed differences between sites of implantation (i.e. STN versus GPi). We assessed apathy prior to surgery and 6 months post-surgery using a longitudinal design latent growth curve modeling. We hypothesized that apathy would increase post surgery, and be related to subthalamic nucleus (versus globus pallidus interna) implantation. Forty-eight PD patients underwent unilateral surgery to either GPi or STN and completed the Apathy Scale prior to surgery and 2, 4, and 6 months post-surgery. Forty-eight matched PD controls completed the Apathy Scale at a 6 month interval. Results indicated apathy increased linearly from pre- to 6-months post-DBS by .66 points bi-monthly, while apathy in the control group did not change. There was no relationship between apathy and DBS site. Higher baseline depression was associated with higher baseline apathy, but not with change in apathy. Middle-aged adults (<65) had a steeper trajectory of apathy than older adults (>= 65). Apathy trajectory was not related to motor severity, laterality of DBS, levodopa medication reduction, or motor changes after surgery. PMID- 21256070 TI - Measuring food deserts in New York City's low-income neighborhoods. AB - There has been growing interest in the environmental factors that contribute to poor health outcomes, particularly in areas where health disparities are pronounced. The locations of food deserts, or unhealthy food environments, correspond to areas with the highest proportions of African-American/Black residents, a population suffering from higher rates of many chronic conditions, including obesity and diabetes in our study area. This study seeks to enhance our understanding of the role of the neighborhood environment on residents' health, by examining neighborhood food availability and access in low-income and wealthier neighborhoods of New York City. We documented the neighborhood food environment and areas we call "food deserts" by creating methodological innovations. We calculated the lowest scores within East and Central Harlem and North and Central Brooklyn-areas with the highest proportions of Black residents and the lowest median household incomes. By contrast, the most favorable food desert scores were on the Upper East Side, a predominantly white, middle and upper-income area. PMID- 21256071 TI - Endurance and fatigue characteristics of the neck flexor and extensor muscles during isometric tests in patients with postural neck pain. AB - Sustained postural loading of the cervical spine during work or recreational tasks may contribute to the development of neck pain. The aim of this study was to compare neck muscle endurance and fatigue characteristics during sub-maximal isometric endurance tests in patients with postural neck pain, with asymptomatic subjects. Thirteen female patients with postural neck pain and 12 asymptomatic female control subjects completed timed sub-maximal muscle endurance tests for the neck flexor and extensor muscles. Muscle fatigue, defined as the time dependent decrease in median frequency electromyography (EMG), was examined using surface EMG analysis during the tests. The median extensor test holding time was lower but not significantly different in the neck pain group (165 s) that the control group (228 s) (p = 0.17). There was no difference between groups in the flexor test holding time (neck pain = 36 s, controls = 38 s) (p = 0.96). The neck pain group was characterised by greater variability in neck flexor (p = 0.03) and extensor (p = 0.006) muscle endurance. For both tests, the rate of decrease in median frequency EMG was highly variable within and between groups with no significant difference between groups for the flexor or extensor test (p = 0.05 0.82). Patients with postural neck pain did not have significant impairment of neck muscle endurance or accelerated fatigue compared to control subjects. However, the greater variability in these indices of muscle function may reflect patient-specific changes in muscle function associated with neck pain disorder. PMID- 21256072 TI - Risk factors and clinical features of craniocervical arterial dissection. AB - Craniocervical arterial dissection is one of the most common causes of ischaemic stroke in young people and is occasionally associated with neck manipulation. Identification of individuals at risk will guide risk management. Early recognition of dissection in progress will expedite medical intervention. Study aims were to identify risk factors and presenting features of craniocervical arterial dissection. Medical records of patients from the Hunter region of New South Wales, Australia aged <= 55 years with radiographically confirmed or suspected vertebral or internal carotid artery dissection, were retrospectively compared with matched controls with stroke from some other cause. Records were inspected for details of clinical features, presenting signs and symptoms and preceding events. Records of 47 dissection patients (27 males, mean age 37.6 years) and 43 controls (22 males, mean age 42.6 years) were inspected. Thirty (64%) dissection patients but only three (7%) controls reported an episode of mild mechanical trauma, including manual therapy, to the cervical spine within the preceding three weeks. Mild mechanical trauma to the head and neck was significantly associated with craniocervical arterial dissection (OR 23.53). Cardiovascular risk factors for stroke were less evident in the dissection group (<1 factor per case) compared to the controls (>3). PMID- 21256073 TI - Effect of classification-specific treatment on lumbopelvic motion during hip rotation in people with low back pain. AB - Increased and early lumbopelvic motion during trunk and limb movements is thought to contribute to low back pain (LBP). Therefore, reducing lumbopelvic motion could be an important component of physical therapy treatment. Our purpose was to examine the effects of classification-specific physical therapy treatment (Specific) based on the Movement System Impairment (MSI) model and non-specific treatment (Non-Specific) on lumbopelvic movement patterns during hip rotation in people with chronic LBP. We hypothesized that following treatment people in the Specific group would display decreased lumbopelvic rotation and achieve more hip rotation before lumbopelvic rotation began. We hypothesized that people in the Non-Specific group would display no change in these variables. Kinematic data collected before and after treatment for hip lateral and medial rotation in prone were analyzed. The Specific group (N = 16) demonstrated significantly decreased lumbopelvic rotation and achieved greater hip rotation before the onset of lumbopelvic rotation after treatment with both hip lateral and medial rotation. The Non-Specific group (N = 16) demonstrated significantly increased lumbopelvic rotation and no change in hip rotation achieved before the onset of lumbopelvic rotation. People who received treatment specific to their MSI LBP classification displayed decreased and later lumbopelvic motion with hip rotation, whereas people who received generalized non-specific treatment did not. PMID- 21256074 TI - The effect of neck torsion on postural stability in subjects with persistent whiplash. AB - Dysfunction of cervical receptors in neck disorders has been shown to lead to disturbances in postural stability. The neck torsion manoeuvre used in the smooth pursuit neck torsion (SPNT) test is thought to be a specific measure of neck afferent dysfunction on eye movement in those with neck pain. This study aimed to determine whether neck torsion could change balance responses in those with persistent whiplash-associated disorders (WADs). Twenty subjects with persistent WAD and 20 healthy controls aged between 18 and 50 years stood on a computerised force plate with eyes closed in comfortable stance under 5 conditions: neutral head, head turned to left and right and neck torsion to left and right. Root mean square (rms) amplitude of sway was measured in the anterior-posterior (AP) and medial-lateral (ML) directions. The whiplash group had significantly greater rms amplitude in the AP direction following neck torsion compared to the control group (p < 0.03). The results show that the neck torsion manoeuvre may lead to greater postural deficits in individuals with persistent WAD and provides further evidence of neck torsion to identify abnormal cervical afferent input, as an underlying cause of balance disturbances in WAD. Further research is warranted. PMID- 21256075 TI - Congenital ectropion uveae with iris coloboma and telecanthus. AB - Congenital ectropion uveae (CEU) is a rare, non progressive anomaly characterised by the presence of iris pigment epithelium on the anterior surface and is frequently associated with anterior iris insertion, dysgenesis of the drainage angle and glaucoma. This paper describes an unusual case of bilateral congenital ectropion uveae with iris coloboma and telecanthus. The anterior chamber angle was normal and there was no evidence of glaucoma. To the best of our knowledge, this association has not been reported previously. PMID- 21256076 TI - Multiplex reverse transcription PCR Luminex assay for detection and quantitation of viral agents of gastroenteritis. AB - BACKGROUND: Several viruses can cause diarrheal disease, a leading cause of morbidity and mortality worldwide. Existing diagnostic methods include ELISA and nucleic acid amplification, usually performed individually. OBJECTIVES: (1) To develop a multiplexed assay for simultaneous detection of major enteric viral pathogens. (2) Quantitation of viral load by normalizing with an extrinsic control. STUDY DESIGN: A simple protocol combining a one-step multiplex reverse transcription-polymerase chain reaction (RT-PCR) with microsphere-based fluorescence detection was developed for norovirus GI and GII, rotavirus, astrovirus, sapovirus, and adenovirus. An extrinsic control, bacteriophage MS2, was spiked into each fecal sample before nucleic acid extraction to normalize between samples for the efficiency of nucleic acid extraction and amplification. RESULTS: The fluorescent results were quantitative and nearly as sensitive as the corresponding singleplex real time RT-PCR (qRT-PCR) assay on analytic samples. Upon testing 229 fecal samples from inpatients with diarrhea in Tanzania the assay yielded between 88% and 100% sensitivity and specificity for all analytes. The difference in fluorescence intensities of MS2 between samples indicated variable extraction efficiency and was used to better refine the viral load of each specimen. CONCLUSIONS: This one-step nucleic acid-based assay enables rapid, sensitive and specific detection of the major viral causes of gastroenteritis. The quantitation yielded by the assay is informative for clinical research particularly in the context of mixed infections. PMID- 21256077 TI - Intuitive versus theory-based assessment of consciousness: the problem of low level consciousness. PMID- 21256078 TI - Relationship between training load and injury in professional rugby league players. AB - OBJECTIVES: To investigate the relationship between training load and injury in professional rugby league players; DESIGN: Prospective cohort study; METHODS: Seventy-nine professional rugby league players (mean+/-SD age, 23.3+/-3.8 years) participated in this four-year study. A periodized field, strength, and power training program was implemented, with training loads progressively increased in the general preparatory phase of the season and reduced during the competitive phase of the season. Training loads and injuries were recorded for each training session. RESULTS: Training load was significantly related (P<0.05) to overall injury (r=0.82), non-contact field injury (r=0.82), and contact field injury (r=0.80) rates. Significant relationships were also observed between the field training load and overall field injury (r=0.68), non-contact field injury (r=0.65), and contact field injury (r=0.63) rates. Strength and power training loads were significantly related to the incidence of strength and power injuries (r=0.63). There was no significant relationship between field training loads and the incidence of strength and power injuries. However, strength and power training loads were significantly (P<0.01) associated with the incidence of contact (r=0.75) and non-contact (r=0.82) field training injuries. CONCLUSIONS: These findings suggest that the harder rugby league players train, the more injuries they will sustain, and that high strength and power training loads may contribute indirectly to field injuries. Monitoring of training loads and careful scheduling of field and gymnasium sessions to avoid residual fatigue is warranted to minimize the effect of training-related injuries on professional rugby league players. PMID- 21256079 TI - Gender differences in predicting quality of life in cancer patients with pain. AB - PURPOSE: Numerous studies have identified several factors influencing quality of life (QOL) in cancer patients. However, studies on gender differences in cancer related physical symptoms and QOL levels have yielded inconsistent results. The present study examined common symptoms (i.e., pain intensity, fatigue, and depression) in regard to their ability to predict QOL in male and female oncology patients with cancer pain. METHOD: A total of 114 oncology outpatients, including 34 males and 80 females, with pain completed a demographic questionnaire, the Multidimensional Quality of Life Scale - Cancer, the Lee Fatigue Scale, the Center for Epidemiological Studies - Depression Scale, and a numeric rating scale for pain intensity. RESULTS: The female patients reported significantly lower psychological dimension of QOL than their male counterparts (p=0.009). Also for the females, a negative correlation was found between pain intensity and QOL (r= 0.504, p<0.0001), as well as positive correlations between pain intensity and fatigue (r=0.421, p<0.0001) and depression (r=0.368, p<0.0001). Stepwise linear regression analyses showed that among the females, QOL was significantly predicted by pain intensity as well as by depression (F((2,75))=52.62, p<0.0001, Adj. R(2)=0.57). However, among the males, depression was the only symptom found to predict QOL (F((2,30))=9.72, p<0.001, Adj. R(2)=0.39). CONCLUSION: Therefore, it is concluded that gender should be considered as an additional feature for further characterizing QOL. Gender differences in factors predicting QOL warrant different clinical approaches to male and female patients, and identifying these differences may assist health care providers in tailoring treatment modalities to individual patients for optimal outcomes. PMID- 21256080 TI - Development and validation of health beliefs model scale for prostate cancer screenings (HBM-PCS): evidence from exploratory and confirmatory factor analyses. AB - PURPOSE: Primary diagnostic tools for prostate cancer are prostate examination and detection of prostate specific antigen. It is important to know what factors affect individuals in their use of these tools. The aim of this study was to create a scale that combined the basic components of the health belief model with a focus on prostate cancer screening. METHOD: A total of 240 healthy men (mean age and standard deviation = 53.8 +/- 10.8) was selected by convenient sampling. In this methodological study, exploratory and confirmatory factor analyses were used for psychometric evaluation. Cronbach's alpha coefficient was used to evaluate the reliability of the scale. RESULTS: The scale was composed of 41 items and five subscales. The initial analysis extracted five factors. Confirmatory factor analysis showed that the data obtained were compatible with Health Beliefs Model (HBM) (chi(2) = 769 (n = 240) = 324.25, p > 0.05, GFI = 0.93, AGFI = 0.93, RMSA = 0.00, CFI = 1.00. Cronbach's alpha coefficient of the subscales ranged from 0.83 to 0.94. CONCLUSIONS: The scale was found to be appropriate for the measurement of health beliefs about prostate cancer screening. The scale may be used in prostate cancer screenings for males who are 40 years and older to measure perceived susceptibility, perceived seriousness, health motivation, perceived barriers and perceived benefits with regard to prostate cancer screenings. PMID- 21256082 TI - Personalised treatment for bladder cancer. PMID- 21256081 TI - A 20-gene model for molecular nodal staging of bladder cancer: development and prospective assessment. AB - BACKGROUND: Neoadjuvant chemotherapy before cystectomy confers a survival benefit in bladder cancer, but it has not been widely adopted since most patients do not benefit and we are at present unable to predict those that do. Since the most important predictor of recurrence after cystectomy is pathologically positive nodes, our aim was to assess techniques that define this stage for the selection of patients for neoadjuvant chemotherapy. METHODS: We developed a gene expression model (GEM) to predict the pathological node status in primary tumour tissue from three independent cohorts of patients who were clinically node negative. From a subset of transcripts detected faithfully by microarrays from both paired frozen and formalin-fixed tissues (32 pairs), we developed both the GEM and cutoffs that identified patient strata with raised risk of nodal involvement by use of two separate training cohorts (90 and 66 patients). We then assessed the GEM and cutoffs to predict node-positive disease in tissues from a phase 3 trial cohort (AUO-AB-05/95; 185 patients). FINDINGS: We developed a 20-gene GEM with an area under the curve of 0.67 (95% CI 0.60-0.75) for prediction of nodal disease at cystectomy in AUO-AB-05/95. The cutoff system identified patients with high relative risk (1.74, 95% CI 1.03-2.93) and low relative risk (0.70, 95% CI 0.51 0.96) of node-positive disease. Multivariate logistic regression showed the GEM predictor was independent of age, sex, pathological stage, and lymphovascular space invasion (coefficient 9.81, 95% CI 1.64-18.00; p=0.019). INTERPRETATION: Selecting patients for neoadjuvant chemotherapy on the basis of risk of node positive disease has the potential to benefit high-risk patients while sparing other patients toxic effects and delay to cystectomy. FUNDING: US National Cancer Institute (R01CA143971). PMID- 21256083 TI - Sweaty skin: an invitation to bite? AB - Anopheles gambiae sensu stricto and Aedes aegypti have a preference for human blood, which determines their importance as vectors of pathogens responsible for human diseases. Volatile organic chemicals are the principal cues by which humans are being located. Human sweat contains components that are attractive to anthropophilic mosquito species, and variation in sweat composition causes differential attractiveness to mosquitoes within and between individuals and also between humans and other mammals. Characteristics of skin glands and skin microbiota define the odorous organic compounds emitted by sweat, thereby the degree of attractiveness of the host to mosquitoes. Carboxylic acids in particular appear to characterize humans. Thus sweat-associated human volatiles are probably the primary determinant factor in the host preference of anthropophilic mosquitoes. PMID- 21256084 TI - Deciphering the role of IS6110 in a highly transmissible Mycobacterium tuberculosis Beijing strain, GC1237. AB - The capacity of infection and the ability of Mycobacterium tuberculosis strains belonging to the Beijing family to spread rapidly probably result from genetic advantages and unidentified mechanisms of virulence not yet thoroughly investigated. Among the mechanisms proposed to be responsible for the varying virulence phenotypes of M. tuberculosis strains we find IS6110 insertions, genetic reorganizations and deletions, which have strong influences on fitness. Beijing family is one of the lineages with the highest number of copies of IS6110. By studying genetic markers characteristic for this lineage, here we have characterized the clinical isolate M. tuberculosis GC1237 strain responsible for important epidemic outbreaks in the Gran Canary Island. We have identified and analyzed each point of insertion of IS6110 using a bacterial artificial chromosome (BAC) library of this strain, in addition to the use of other approximations. Nineteen copies of IS6110 have been localized in GC1237 genome of which, four copies of IS6110 can act as a promoter and we have focused in the characterization of one copy located 31 bp upstream of the essential gene Rv2179c and compared to the reference strain H37Rv. PMID- 21256085 TI - Allogeneic hematopoietic stem cell transplantation for childhood aplastic anemia: prospective trial in China. AB - We aim to investigate the efficacy and safety of the treatment with fully matched allogeneic hematopoietic stem cell transplants for children with severe aplastic anemia (SAA) in the first prospective trial in China. Six SAA children received allogeneic hematopoietic stem cell transplantation combined with chemotherapy. Five patients had successful engraftment while the sixth child regained normal peripheral blood counts consistent with spontaneous autologous hematopoiesis. Mean duration of follow-up was 2.75 years, and survival was 83%(5/6). The results indicated that allogeneic hematopoietic stem cell transplantation is a good option for the treatment of children with severe aplastic anemia. PMID- 21256086 TI - Implementation of guidelines for management of possible multidrug-resistant pneumonia in intensive care: an observational, multicentre cohort study. AB - BACKGROUND: The American Thoracic Society and Infectious Diseases Society of America provide guidelines for management of hospital-acquired, ventilator associated, and health-care-associated pneumonias, consisting of empirical antibiotic regimens for patients at risk for multidrug-resistant pathogens. We aimed to improve compliance with these guidelines and assess outcomes. METHODS: We implemented a performance-improvement initiative in four academic medical centres in the USA with protocol-based education and prospective observation of outcomes. Patients were assessed for severity of illness and followed up until death, hospital discharge, or day 28. We included patients in intensive-care units who were at risk for multidrug-resistant pneumonia and were treated empirically. FINDINGS: 303 patients at risk for multidrug-resistant pneumonia were treated empirically, and prescribed treatment was guideline compliant in 129 patients and non-compliant in 174 patients. 44 (34%) patients died before 28 days in the compliance group and 35 (20%) died in the non-compliance group. Five patients in the compliance group and seven in the non-compliance group were lost to follow-up after day 14. Kaplan-Meier estimated survival to 28 days was 65% in the compliance group and 79% in the non-compliance group (p=0.0042). This difference persisted after adjustment for severity of illness. Median length of stay and duration of mechanical ventilation did not differ between groups. Compliance failures included non-use of dual treatment for Gram-negative pathogens in 154 patients and absence of meticillin-resistant Staphylococcus aureus coverage in 24 patients. For patients in whom pathogens were subsequently identified, empirical treatment was active in 79 (81%) of 97 of patients receiving compliant therapy compared with 109 (85%) of 128 of patients receiving non-compliant therapy. INTERPRETATION: Because adherence with empirical treatment was associated with increased mortality, we recommend a randomised trial be done before further implementation of these guidelines. FUNDING: Pfizer, US Medical. PMID- 21256087 TI - Nosocomial pneumonia: de-escalation is what matters. PMID- 21256089 TI - Gynaecological surgery via vaginal route. PMID- 21256088 TI - Divergent effects of calcineurin Abeta on regulatory and conventional T-cell homeostasis. AB - Calcineurin (CN) is a phosphatase that activates nuclear factor of activated T cells (NFAT). While the CN inhibitors cyclosporine A (CsA) and tacrolimus (FK506) can prevent graft rejection, they also cause inflammatory diseases. We investigated the role of calcineurin using mice deficient in the CN catalytic subunit Abeta (CNAbeta). Cnab(-/-) mice exhibit defective thymocyte maturation, splenomegaly and hepatomegaly. Further, as Cnab(-/-) mice age, they exhibit spontaneous T-cell activation and enhanced production of proinflammatory cytokines (IL-4, IL-6, and IFNgamma). FOXP3(+) T(reg) cells were significantly decreased in Cnab(-/-) mice likely contributing to increased T-cell activation. Interestingly, we found that CNAbeta is critical for promotion of BCL-2 expression in FOXP3(+) T(reg) and for permitting TGFbeta signaling, as TGFbeta induces FOXP3 in control but not in Cnab(-/-) T-cells. Together, these data suggest that CNAbeta is important for the production and maintenance of T(reg) cells and to ensure mature T-cell quiescence. PMID- 21256090 TI - Nonalcoholic fatty liver disease in adolescents receiving valproic acid. AB - OBJECTIVE: The aim of this study was to investigate the association between the metabolic derangements induced by valproic acid (VPA) and ultrasound-diagnosed nonalcoholic fatty liver disease (NAFLD) in adolescents. METHODS: Using a cross sectional design, we evaluated 86 adolescents with epilepsy who had received VPA monotherapy. Subjects for comparison were 67 normal-weight and 43 weight-matched adolescents. Participants underwent hepatic ultrasound, anthropometric evaluations, and biochemical tests. RESULTS: Although the occurrence of ultrasound-diagnosed NAFLD was higher in VPA-treated patients than in normal weight controls (36.0% vs 7.5%, P<0.001), it was similar in VPA-treated patients and weight-matched controls (36.0% vs 34.9%, P>0.05). The identified predictors of NAFLD in VPA-treated patients were abdominal obesity (OR=3.2, 95% CI=2.1-6.8), insulin resistance (OR=2.8, 95% CI=1.7-5.2), metabolic syndrome (OR=2.6, 95% CI=1.4-4.8), and generalized obesity (OR=1.9, 95% CI=1.2-3.7). CONCLUSION: Valproic acid monotherapy is associated with NAFLD in a high percentage of adolescents with epilepsy who have typical VPA-related metabolic disturbances. PMID- 21256091 TI - Preliminary comparison of sertraline levels in postbariatric surgery patients versus matched nonsurgical cohort. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) is the most frequent bariatric procedure performed in the United States, with thousands performed. Because of the changes to the gastrointestinal tract, the potential exists for clinically significant alterations in the absorption/bioavailability of ingested medications. The purpose of the present pilot trial was to determine to what extent RYGB alters the area under the plasma concentration/time curve (AUC(0 10.5)) of the antidepressant, sertraline at a community research center. METHODS: After an overnight fast, 5 postbariatric surgery and 5 nonsurgical control subjects matched for body mass index, age, and gender received 100 mg of sertraline. Plasma samples were obtained for 10.5 hours. The mean AUC(0-10.5), maximal plasma concentration, and the interval to the peak plasma level were obtained for both groups. RESULTS: The mean AUC(0-10.5) was significantly smaller for the postbariatric surgery group (124.4 +/- 55.5 ng-hr/mL, range 62.0-198.1; P = .043) compared with the nonsurgical control group (314.8 +/- 129.6 ng-hr/mL, range 194.8-508.7). The maximal plasma concentration was also significantly smaller for the postbariatric surgery group than for the nonsurgical control group (P = .043). CONCLUSION: To our knowledge, this is the first reported study exploring antidepressant pharmacokinetics after bariatric surgery. In the present trial, the AUC(0-10.5) and maximal plasma concentration were significantly smaller in the subjects who had undergone RYGB than in the matched subjects who had not. Additional investigation of the effects of bariatric surgery (RYGB, sleeve gastrectomy, and gastric banding) on the antidepressant pharmacokinetic parameters is warranted. PMID- 21256092 TI - Does patient compliance with preoperative bariatric office visits affect postoperative excess weight loss? AB - BACKGROUND: The amount of excess weight loss (EWL) achieved after bariatric surgery has varied considerably. Reliable preoperative predictors of the postoperative %EWL do not exist. Patient compliance with the physician recommendations has generally been believed to be important for long-term success after bariatric surgery, especially after gastric banding. We hypothesized that poor preoperative patient compliance with office visits, a likely indicator of overall compliance, would be associated with lower %EWL after bariatric surgery at a teaching hospital in the United States. METHODS: We performed an institutional review board-approved review of prospectively collected data from all patients undergoing bariatric surgery from 2007 to 2009. The patients were categorized into 2 groups: those who had missed <25% of all preoperative appointments at our bariatric center and those who had missed >25%. The average %EWL at 12 months between the 2 groups was compared using the unpaired t test separately for the gastric bypass and gastric banding patients. RESULTS: The gastric band patients with >25% missed appointments had lost 23% EWL at 12 months compared with 32% EWL for the gastric band patients who had missed <25% of their appointments (P = .01). No difference was found in the %EWL for the gastric bypass patients according to the missed preoperative appointments. The postoperative compliance was significantly poorer than preoperatively. CONCLUSION: The patients with a greater percentage of missed preoperative appointments had a lower postoperative %EWL at 1 year after gastric banding but not after gastric bypass. This information could prove useful during patient selection or when counseling patients about the type of bariatric surgery to pursue. PMID- 21256093 TI - Competition between PARP-1 and Ku70 control the decision between high-fidelity and mutagenic DNA repair. AB - Affinity maturation of antibodies requires a unique process of targeted mutation that allows changes to accumulate in the antibody genes while the rest of the genome is protected from off-target mutations that can be oncogenic. This targeting requires that the same deamination event be repaired either by a mutagenic or a high-fidelity pathway depending on the genomic location. We have previously shown that the BRCT domain of the DNA-damage sensor PARP-1 is required for mutagenic repair occurring in the context of IgH and IgL diversification in the chicken B cell line DT40. Here we show that immunoprecipitation of the BRCT domain of PARP-1 pulls down Ku70 and the DNA-PK complex although the BRCT domain of PARP-1 does not bind DNA, suggesting that this interaction is not DNA dependent. Through sequencing the IgL variable region in PARP-1(-/-) cells that also lack Ku70 or Lig4, we show that Ku70 or Lig4 deficiency restores GCV to PARP 1(-/-) cells and conclude that the mechanism by which PARP-1 is promoting mutagenic repair is by inhibiting high-fidelity repair which would otherwise be mediated by Ku70 and Lig4. PMID- 21256094 TI - A sensitive LC-MS/MS method for determination of levamisole in human plasma: application to pharmacokinetic study. AB - A sensitive and rapid LC-MS/MS method was developed and validated for the determination of levamisole in human plasma. The assay was based on liquid-liquid extraction of analytes from human plasma with ethyl ether. Chromatographic separation was carried on an Agilent HC-C(8) column (150 mm * 4.6 mm, 5 MUm) at 40 degrees C, with a mobile phase consisting of acetonitrile-10 mM ammonium acetate (70:30, v/v), a flow rate of 0.5 mL/min and a total run time of 6 min. Detection and quantification were performed by mass spectrometry in the multiple reaction monitoring mode with positive electrospray ionization m/z at 205.1 >178.2 for levamisole, and m/z 296.1->264.1 for mebendazole (internal standard). The assay was linear over a concentration range of 0.1-30 ng/mL with a lower limit of quantification of 0.1 ng/mL. The coefficient of variation of the assay precision was less than 8.5%. The assay was successfully used to analyze human plasma samples in a pharmacokinetic study where levamisole was administered as a liniment. PMID- 21256095 TI - Purification of a lectin from Canavalia ensiformis using PEG-citrate aqueous two phase system. AB - A PEG/citrate aqueous two-phase system was tested in the partition of commercial Concanavalin A (Con A) and subsequently applied to the extraction and purification of Con A from the crude extract of Canavalia ensiformis seeds. Con A was successfully extracted to the bottom phase of a system composed of 22% (w/w) PEG8000 and 12% (w/w) citrate at pH 6.0. The obtained purification factor was 11.5 without any loss in the hemagglutinating activity. The purity of extracted lectin was confirmed by SDS-PAGE analysis. PMID- 21256096 TI - Multiscale approach in mathematical biology: comment on "Toward a mathematical theory of living systems focusing on developmental biology and evolution: a review and perspectives" by Bellomo and Carbonaro. PMID- 21256097 TI - Recommendations for the prevention, diagnosis, and treatment of chronic hepatitis B and C in special population groups (migrants, intravenous drug users and prison inmates). AB - The global spread of hepatitis B virus (HBV) and hepatitis C virus (HCV), their high chronicity rates and their progression to cirrhosis and hepatocellular carcinoma, are major public health problems. Research and intervention programmes for special population groups are needed in order to assess their infection risk and set up suitable prevention and control strategies. Aim of this paper is to give health care professionals information on HBV and HCV infections amongst migrants, drug users and prison inmates. The manuscript is an official Position Paper on behalf of the following Scientific Societies: Italian Association for the Study of the Liver (A.I.S.F.), Italian Society of Infectious and Tropical Diseases (S.I.M.I.T.), Italian Federation Department's Operators and Addiction Services (FederSerD), Italian Prison Medicine and Healthcare Society (S.I.M.S.Pe.). The considered population groups, having a high prevalence HBV and HCV infections, require specific interventions. In this context, the expression "special population" refers to specific vulnerable groups at risk of social exclusion, such as migrants, prison inmates, and intravenous drug users. When dealing with special population groups, social, environmental and clinical factors should be considered when selecting candidates for therapy as indicated by national and international guidelines. PMID- 21256098 TI - [Use of pacifiers and breastfeeding]. AB - Pacifiers are widely used in developed societies. They are used for soothing infants, reducing their stress and pain during procedures and to help them sleep. The use of pacifiers has been associated, however, with a shorter duration and exclusivity of breastfeeding, with higher rates of otitis media and dental problems, as well as a higher risk of accidents during infancy. Recent studies have also described a relationship between pacifier use and SIDS, especially when used during infants sleep. Other described benefits are analgesia and stimulation of non-nutritive sucking in preterm and term infants. There is, at present, wide debate and controversy on whether or not to recommend its use; thus it seems important for professionals and parents to be aware of the risks and benefits associated to its use, particularly related to breastfeeding. Due to the existing controversy of scientific findings, the Committee on Breastfeeding of the Spanish Paediatrics Society, publishes this review, trying to summarise present evidence with the objective of, after analysing scientific results and recommendations, making recommendations regarding the use of the pacifier in the breastfed infant. PMID- 21256099 TI - Structural characterization and primary in vitro cell culture of locust male germline stem cells and their niche. AB - The establishment of in vitro culture systems to expand stem cells and to elucidate the niche/stem cell interaction is among the most sought-after culture systems of our time. To further investigate niche/stem cell interactions, we evaluated in vitro cultures of isolated intact male germline-niche complexes (i.e., apical complexes), complexes with empty niche spaces, and completely empty niches (i.e., isolated apical cells) from the testes of Locusta migratoria and the interaction of these complexes with isolated germline stem cells, spermatogonia (of transit-amplifying stages), cyst progenitor cells, cyst progenitor cell-like cells, cyst cells, and follicle envelope cells. The structural characteristics of these cell types allow the identification of the different cell types in primary cultures, which we studied in detail by light and electron microscopy. In intact testes germline stem cells strongly adhere to their niche (the apical cell), but emigrate from their niche and form filopodia if the apical complex is put into culture with "standard media." The lively movements of the long filopodia of isolated germline stem cells and spermatogonia may be indicative of their search for specific signals to home to their niche. All other incubated cell types (except for follicle envelope cells) expressed rhizopodia and lobopodia. Nevertheless isolated germline stem cells in culture do not migrate to empty niche spaces of nearby apical cells. This could indicate that apical cells lose their germline stem cell attracting ability in vitro, although apical cells devoid of germline stem cells either by emigration of germline stem cells or by mechanical removal of germline stem cells are capable of surviving in vitro up to 56 days, forming many small lobopodia and performing amoeboid movements. We hypothesize that the breakdown of the apical complex in vitro with standard media interrupts the signaling between the germline stem cells and the niche (and conceivably the cyst progenitor cells) which directs the typical behavior of the male regenerative center. Previously we demonstrated the necessity of the apical cell for the survival of the germline stem cell. From these studies we are now able to culture viable isolated germline stem cells and all cells of its niche complex, although DNA synthesis stops after Day 1 in culture. This enables us to examine the effects of supplements to our standard medium on the interaction of the germline stem cell with its niche, the apical cell. The supplements we evaluated included conditioned medium, tissues, organs, and hemolymph of male locusts, insect hormones, mammalian growth factors, Ca(2+) ion, and a Ca(2+) ionophore. Although biological effects on the germline stem cell and apical cell could be detected with the additives, none of these supplements restored the in vivo behavior of the incubated cell types. We conclude that the strong adhesion between germline stem cells and apical cells in vivo is actively maintained by peripheral factors that reach the apical complex via hemolymph, since a hemolymph-testis barrier does not exist. The in vitro culture model introduced in this study provides a platform to scan for possible regulatory factors that play a key role in a feedback loop that keeps germline stem cell division and sperm disposal in equilibrium. PMID- 21256100 TI - Do French medical schools provide appropriate training on gait and gait disorders? AB - AIM: Evaluate the need for integrated teaching on normal and pathological gait at medical school. METHOD: A questionnaire filled out by 91 French general practitioners (GPs, 130 of whom were contacted) with an average of 19 years of practice and 56 sixth-year medical students. Assessment of the students' knowledge of normal and pathological gait. RESULTS: Seventy-two percent of the GPs and 82% of the students considered gait to be a frequent reason for consultation. Eighty-nine percent of the GPs and 98% of the students stated that they had difficulty analysing a gait disorder. Eighty percent of the GPs and 50% of the students considered that the teaching on gait and gait disorders at medical school was insufficient. The responses notably highlighted the poor coordination between teachers from the various disciplines involved. The students' knowledge of gait was poor (only 20% of their answers were correct). This was especially true for semiological questions, which were correctly answered by less than one student in 10. CONCLUSION: The results of the present study demonstrate that French medical schools need to provide better teaching on gait. We, therefore, propose the implementation of an integrated teaching programme with a sufficient focus on functional and semiological approaches. PMID- 21256101 TI - Retrospective study of the rhinoscleroma about 14 cases in ENT departments of university hospitals (Cote d'Ivoire). AB - PURPOSE OF STUDY: To report the epidemiological, clinical, therapeutic and evolutionary aspects of rhinoscleroma in ENT departments of university hospitals (Cote d'Ivoire). MATERIAL AND METHOD: Retrospective study of rhinoscleroma conducted in the ENT and head and neck surgery departments in Cote d'Ivoire from January 1980 to December 2008 including the cases of confirmed rhinoscleroma and the treated cases. RESULTS: Fourteen cases of rhinoscleroma were found in 28 years. The early manifestations were not specific enough so the patients were seen with clinical status with obvious disorders or physical discomfort. Treatment was medical and surgical. Medical therapy was based on streptomycin, thiopenicol or ciprofloxacin administration. Surgery consisted in removing the fibrous adhesions to correct the functional and aesthetic disorders. CONCLUSION: Rhinoscleroma has become a more and more rare disease because of the sensitivity to the new molecules. Diagnosis can be difficult and delayed because of its clinical polymorphism. PMID- 21256102 TI - Cardiac CT angiography compared with myocardial perfusion stress testing on downstream resource utilization. AB - BACKGROUND: Nuclear myocardial perfusion stress (MPS) testing and cardiac computed tomographic angiography (CCTA) are commonly used noninvasive tests. Limited studies exist comparing their clinical and cost outcomes. OBJECTIVES: We compared the clinical and cost outcomes of MPS with CCTA in a symptomatic cohort. METHODS: We retrospectively identified 241 symptomatic patients without known coronary artery disease (CAD) who underwent MPS between May 2006 and April 2008. A comparison group of 252 age- and sex-matched symptomatic patients without known CAD underwent 64-slice CCTA during the same period. The primary outcome was the per-patient rate of posttest clinical evaluations and cardiac testing for the presenting symptom. Total direct costs were also compared. RESULTS: The group consisted of 44% women of mean age 53 +/- 10 years. There were no differences in risk factors or pretest probability of obstructive CAD (83% intermediate risk) between groups. During mean follow-up of 30 +/- 7 months, we found no difference between CCTA and MPS in per-patient rates of any posttest evaluation or testing, 24.6% versus 27.7% (P = 0.44), respectively. CCTA patients had lower utilization of invasive angiography (3.3% vs 8.1%; P = 0.02) and a nonsignificant trend toward reduced downstream cardiac testing (11.5% vs 17.0%; P = 0.08). Including the evaluation of significant incidental findings (7.1% in CCTA), mean direct costs were significantly lower using CCTA ($808; 95% CI, $611-$1005) compared with MPS ($1315; 95% CI, $1105-$1525; P <0.001). CONCLUSIONS: Low-intermediate risk patients without known CAD who underwent CCTA, compared with MPS, had similar rates of posttest evaluations, fewer invasive catheterizations, and lower overall evaluation costs. PMID- 21256106 TI - A practical method for cell-free protein synthesis to avoid stable isotope scrambling and dilution. AB - During recent years, the targets of protein structure analysis using nuclear magnetic resonance spectroscopy have become larger and more complicated. As a result, a complete and precise stable isotope labeling technique has been desired. A cell-free protein synthesis system is appropriate for this purpose. In the current study, we achieved precise and complete (15)N and (2)H labeling using an Escherichia coli cell extract-based cell-free protein synthesis system by controlling the metabolic reactions in the system with their chemical inhibitors. The addition of aminooxyacetate, d-malate, l-methionine sulfoximine, S-methyl-l cysteine sulfoximine, 6-diazo-5-oxo-l-norleucine, and 5-diazo-4-oxo-l-norvaline was quite effective for precise amino acid-selective (15)N labeling even for aspartic acid, asparagine, glutamic acid, and glutamine, which generally suffer from severe isotope scrambling and dilution when using the conventional cell-free system. For (2)H labeling, the back-protonation of the H(alpha) and H(beta) positions, which commonly occurred in the conventional system, was dramatically suppressed by simply adding aminooxyacetate and d-malate to the cell-free system except for the H(alpha) positions in methionine and cysteine. PMID- 21256107 TI - Measuring protein synthesis using metabolic 2H labeling, high-resolution mass spectrometry, and an algorithm. AB - We recently developed a method for estimating protein dynamics in vivo with heavy water ((2)H(2)O) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) [16], and we confirmed that (2)H labeling of many hepatic free amino acids rapidly equilibrated with body water. Although this is a reliable method, it required modest sample purification and necessitated the determination of tissue-specific amino acid labeling. Another approach for quantifying protein kinetics is to measure the (2)H enrichments of body water (precursor) and protein-bound amino acid or proteolytic peptide (product) and to estimate how many copies of deuterium are incorporated into a product. In the current study, we used nanospray linear trap Fourier transform ion cyclotron resonance mass spectrometry (LTQ FT-ICR MS) to simultaneously measure the isotopic enrichment of peptides and protein-bound amino acids. A mathematical algorithm was developed to aid the data processing. The most notable improvement centers on the fact that the precursor/product labeling ratio can be obtained by measuring the labeling of water and a protein (or peptide) of interest, thereby minimizing the need to measure the amino acid labeling. As a proof of principle, we demonstrate that this approach can detect the effect of nutritional status on albumin synthesis in rats given (2)H(2)O. PMID- 21256108 TI - Characterization of photosystem II in transgenic tobacco plants with decreased iron superoxide dismutase. AB - Iron superoxide dismutases (FeSODs) play an important role in preventing the oxidative damage associated with photosynthesis. To investigate the mechanisms of FeSOD in protection against photooxidative stress, we obtained transgenic tobacco (Nicotiana tabacum) plants with severely decreased FeSOD by using a gene encoding tobacco chloroplastic FeSOD for the RNAi construct. Transgenic plants were highly sensitive to photooxidative stress and accumulated increased levels of O2*- under normal light conditions. Spectroscopic analysis and electron transport measurements showed that PSII activity was significantly reduced in transgenic plants. Flash-induced fluorescence relaxation and thermoluminescence measurements revealed that there was a slow electron transfer between Q(A) and Q(B) and decreased redox potential of Q(B) in transgenic plants, whereas the donor side function of PSII was not affected. Immunoblot and blue native gel analyses showed that PSII protein accumulation was also decreased in transgenic plants. PSII photodamage and D1 protein degradation under high light treatment was increased in transgenic plants, whereas the PSII repair was not affected, indicating that the stability of the PSII complex was decreased in transgenic plants. The results in this study suggest that FeSOD plays an important role in maintaining PSII function by stabilizing PSII complexes in tobacco plants. PMID- 21256109 TI - Acyl chain composition determines cardiolipin clustering induced by mitochondrial creatine kinase binding to monolayers. AB - It has been recently shown that mitochondrial creatine kinase (mtCK) organizes mitochondrial model membrane by modulating the state and fluidity of lipids and by promoting the formation of protein-cardiolipin clusters. This report shows, using Brewster angle microscopy, that such clustering is largely dependent on the acyl chain composition of phospholipids. Indeed, mtCK-cardiolipin domains were observed not only with unsaturated cardiolipins, but also with the cardiolipin precursor phosphatidylglycerol. On the other hand, in the case of saturated dimyristoylphosphatidylglycerol and tetramyristoylcardiolipin, mtCK was homogeneously distributed underneath the monolayer. However, an overall decrease in membrane fluidity was indicated by infrared spectroscopy as well as by extrinsic fluorescence spectroscopy using Laurdan as a fluorescent probe, both for tetramyristoylcardiolipin and bovine heart cardiolipin containing liposomes. The binding mechanism implicated the insertion of protein segments into monolayers, as evidenced from alternative current polarography, regardless of the chain unsaturation for the phosphatidylglycerols and cardiolipins tested. PMID- 21256110 TI - Vulnerability of the cysteine-less proton-coupled folate transporter (PCFT SLC46A1) to mutational stress associated with the substituted cysteine accessibility method. AB - The proton-coupled transporter (PCFT) mediates intestinal folate absorption and folate transport from blood across the choroid plexus. The membrane topology of PCFT has been defined using the substituted cysteine accessibility method; an intramolecular disulfide bond between the Cys 66 and 298 residues, in the first and fourth extracellular loops, respectively, is present but not essential for function. The current report describes Lys 422 mutations (K422C, K422E) that have no effect on transport activity when introduced into wild-type PCFT but result in a marked loss of activity when introduced into a Cys-less PCFT which is otherwise near-fully functional. The loss of activity of both mutant PCFTs was shown to be due to impaired protein stability and expression. Additional studies were conducted with the K422C mutation in Cys-less PCFT. The impact of re-introduction of one, two, three or five, Cys residues was assessed. While there were some differences in the impact of the different Cys residues re-introduced, restoration was attributed more to a cumulative effect rather than the specific role of individual Cys residues. Preservation of the Cys66-Cys298 intramolecular disulfide bond was not required for stability of the K422C protein. These observations are relevant to studies with Cys-less transporters utilized for the characterization of proteins with the substituted cysteine accessibility method and indicate that functional defects detected in a Cys-less protein, when the tertiary structure of the molecule is stressed, are not necessarily relevant to the wild-type protein. PMID- 21256111 TI - Calcineurin B subunit interacts with proteasome subunit alpha type 7 and represses hypoxia-inducible factor-1alpha activity via the proteasome pathway. AB - The calcineurin (CN) B subunit (CNB) is the regulatory subunit of CN, which is the only serine/threonine-specific protein phosphatase regulated by Ca2+/CaM. It has been shown to have potential as an anticancer agent, and has a positive effect on the phagocytic index and coefficient. We report here that CNB binds to proteasome subunit alpha type 7 (PSMA7) and inhibits the transactivation activity of hypoxia-inducible factor-1alpha (HIF-1alpha) via the proteasome pathway. In addition, we show that CNB represses the expression of vascular endothelial growth factor (VEGF), which is regulated by HIF-1alpha. These results indicate that CNB modulates cellular proteasome activity via a specific interaction with PSMA7. This may provide a molecular basis for its anticancer and antiviral activities. PMID- 21256112 TI - Apoptosis induces Bcl-XS and cleaved Bcl-XL in chronic lymphocytic leukaemia. AB - The Bcl-X gene has both pro-survival, Bcl-XL, and pro-apoptotic, Bcl-XS, gene products, which are produced by alternative splicing. The function of these proteins has previously been characterised in cell lines, often by transfecting expression constructs, and primary cell systems capable of dynamically regulating Bcl-XL and Bcl-XS have not been described. Such a system is potentially important to allow testing of agents that promote apoptosis by increasing the amount of Bcl XS at the expense of Bcl-XL. In this report we characterise Bcl-X gene products in primary human leukaemic B-cells in culture conditions associated with survival and apoptosis. We found that Bcl-XS was induced in spontaneous and drug-induced apoptosis and that apoptosis induced in cells cultured on mouse fibroblasts expressing CD40 ligand with IL-4 (CD154/IL-4), a condition mimicking the tissue microenvironment, additionally produced expression of cleavage products of Bcl XL. Both Bcl-XS and Bcl-XL were produced in a caspase dependent manner. We tested emetine, an agent previously reported to increase Bcl-XS but found that it did not have this effect in primary human B-cells. Therefore, there are two mechanisms-cleavage of Bcl-XL and production of Bcl-XS-by which Bcl-X gene products could enhance apoptosis in CLL but neither appeared to have a primary role in inducing leukaemic cell death. PMID- 21256113 TI - Temperature-dependent coaggregation of eye lens alphaB- and beta-crystallins. AB - Crystallin is essential not only for the maintenance of eye lens transparency, but also in the biology of other tissues. Eye lens alpha-crystallin exists as a heteropolymer composed of two homologous subunits, alphaA and alphaB. Despite the critical role of alpha-crystallin in many tissues, little is known regarding structural and functional significance of the two subunits. Herein, we describe a unique feature of alphaB-crystallin. At high temperatures (>70 degrees C) not only alphaB-crystallin aggregates but also enhances the aggregation of other lens proteins. Intriguingly, alphaB-crystallin-mediated coaggregation at and above 70 degrees C involves beta- but not gamma-crystallin. Further, alphaA-crystallin, but not a mutant (F71L) alphaA-crystallin, prevented aggregation of alphaB crystallin and also reduced coaggregation of alphaB- and beta-crystallin. These studies explain the rationale for the existence of alpha-crystallin heteropolymer with alphaA subunit as a major partner that is vital for lens transparency and provide insights into alphaB-crystallin-induced coaggregation which may have a bearing in some pathological conditions where alphaB-crystallin is overexpressed. PMID- 21256114 TI - A myomesin mutation associated with hypertrophic cardiomyopathy deteriorates dimerisation properties. AB - Myomesin plays an important structural and functional role in the M-band of striated muscles. The C-terminal domain 13 of myomesin dimerises and forms antiparallel strands which cross-link neighboring Myosin filaments and titin in the M-line of the sarcomeres. These interactions stabilise the contractile apparatus during striated muscle contraction. Since myomesin is an important component of the M-band we screened the myomesin gene for genetic variants in patients with hypertrophic cardiomyopathy (HCM). We identified the missense mutation V1490I in domain 12 of myomesin in a family with inherited HCM. Analytical ultracentrifugation experiments, circular dichroism spectra, and surface plasmon resonance spectroscopy of myomesin fragments were carried out to investigate the effects of the mutation V1490I on structure and function of myomesin domains 11-13 and 12-13. Both the wild type and mutated myomesin domains My11-13 revealed similar secondary structures and formed stable dimers. Mutated myomesin domains My11-13 and My12-13 dimers revealed a reduced thermal stability and a significantly decreased dimerisation affinity, showing disturbed functional properties of V1490I mutated myomesin. However, monomeric myomesin domains My11 12, i.e. without dimerisation domain 13 showed no difference in thermal stability between wild type and V1490I mutated myomesin. In conclusion, the V1490I mutation associated with HCM lead to myomesin proteins with abnormal functional properties which affect dimerisation properties of myomesin domain 13. These effects may contribute to the pathogenesis of HCM. PMID- 21256115 TI - Structure based discovery of small molecule suppressors targeting bacterial lysozyme inhibitors. AB - The production of lysozyme inhibitors, competitively binding to the lysozyme active site, is a bacterial strategy to prevent the lytic activity of host lysozymes. Therefore, suppression of the lysozyme-inhibitor interaction is an interesting new approach for drug development since restoration of the bacterial lysozyme sensitivity will support bacterial clearance from the infected sites. Using molecular modelling techniques the interaction of the Salmonella PliC inhibitor with c-type lysozyme was studied and a protein-protein interaction based pharmacophore model was created. This model was used as a query to identify molecules, with potential affinity for the target, and subsequently, these molecules were filtered using molecular docking. The retained molecules were validated as suppressors of lysozyme inhibitory proteins using in vitro experiments revealing four active molecules. PMID- 21256116 TI - Mild caloric restriction up-regulates the expression of prohibitin: a proteome study. AB - Caloric restriction (CR) is well known to expand lifespan in a variety of species and to retard many age-related diseases. The effects of relatively mild CR on the proteome profile in relation to lifespan have not yet been reported, despite the more extensive studies of the stricter CR conditions. Thus, the present study was conducted to elucidate the protein profiles in rat livers after mild CR for a relatively short time. Young growing rats were fed CR diets (10% and 30% CR) for 1month. We performed the differential proteomic analysis of the rat livers using two-dimensional electrophoresis combined with MALDI-TOF mass spectrometry. The most remarkable protein among the differentially expressed proteins was found to be prohibitin, the abundance of which was increased by 30% CR. Prohibitin is a ubiquitously expressed protein shown to suppress cell proliferation and to be related to longevity. The increase in prohibitin was observed both in 10% and 30% CR by Western blot analysis. Furthermore, induction of AMP-activated kinase (AMPK) protein, related to the actions of prohibitin in promoting longevity, was observed. The increased prohibitin level in response to subtle CR suggests that this increase may be one of the early events leading to the expansion of lifespan in response to CR. PMID- 21256117 TI - Cleaved caspase-3 expression after experimental stroke exhibits different phenotypes and is predominantly non-apoptotic. AB - Cleaved caspase-3 (CC3) is well known as an executioner protease of apoptosis following brain ischemia. However, an increasing body of evidence suggests several non-apoptotic functions of CC3. To improve our understanding of the relation between cell death-related and non-adverse effects of postischemic caspase-3 activation, we examined the spatiotemporal distribution and identity of CC3-positive cells at days 2, 3 and 4 after permanent middle cerebral artery occlusion in rats. The lacking colocalization of CC3 and TUNEL staining indicated, that CC3 expression was predominantly non-apoptotic. Nuclear CC3 expression was frequently found to be colocalized with GFAP-positive astrocytes within the tissue adjacent to the infarct, whereas cytoplasmatic CC3 expression occurred solely in the lesion. Multiple fluorescence labeling revealed costaining of cytoplasmatic CC3 with markers directed against astrocytes, macrophages/microglia and supposedly pericytes. Our findings suggest that CC3 expression was predominantly associated with cellular responses to stroke such as reactive astrogliosis and the infiltration of macrophages. PMID- 21256118 TI - Myelin damage of hippocampus and cerebral cortex in rat pentylenetetrazol model. AB - Epilepsy is a chronic neurological disorder characterized by spontaneous recurrent seizures, which also occur in demyelinating diseases of the central nervous system (CNS) with a higher prevalence. Meanwhile, demyelination occurrings have been occasionally observed in CNS of epilepsy patients, indicating an association between demyelination and epileptic seizures by an unknown mechanism. However, no confirmative experimental evidence has yet been given. Thus, by using a rat pentylenetetrazol model, electroencephalogram (EEG), Western blotting, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, the present study provided direct evidence that myelin sheath damage in rat hippocampus and cerebral cortex started in the early stage of epileptic seizures induction and lasted with no further increase in severity in the development of epileptic seizures. It was illustrated that myelin sheath damage was not the result of oligodendrocyte destruction, but the autoantibodies against myelin basic protein (MBP) produced in peripheral circulation accompanied by increased permeability of blood-brain barrier (BBB) formed in the development of epileptic seizures. This study firstly provided experimental evidence for myelin sheath damage in PTZ-induced rat's epileptic seizures and further demonstrated that its possible cause was autoimmunoreaction. PMID- 21256120 TI - Role of PI3K/Akt in diazoxide preconditioning against rat hippocampal neuronal death in pilocarpine-induced seizures. AB - Diazoxide (DZ), a highly selective opener of the mitochondrial ATP-sensitive potassium (mitoK(ATP)) channel, has neuroprotective effects. However, the mechanism of DZ protecting hippocampal neurons against cell death in pilocarpine induced seizures is unknown. In this study, we investigated DZ attenuating neuronal loss caused by pilocarpine-induced seizures in rat hippocampus. DZ inhibited seizure-induced change in phospho-Akt expression, translocation of apoptosis-inducing factor (AIF), release of cytochrome c (CytC) and caspase-3 activation, which could be abolished by preincubation with 5-hydroxydecanoic acid, an inhibitor of mitoK(ATP). In addition, wortmannin, an inhibitor of phosphatidylinositol-3-kinase (PI3K), attenuated the translocation of AIF, CytC release and caspase-3 activation after seizures. DZ could reduce neuronal death induced by seizures in hippocampus by suppressing the translocation of AIF, CytC release and the activation of caspase-3 via the PI3K/Akt pathway. PMID- 21256119 TI - Layer I neocortical ectopia: cellular organization and local cortical circuitry. AB - Focal cortical dysplasia (FCD) are associated with neurological disorders and cognitive impairments in humans. Molecular layer ectopia, clusters of misplaced cells in layer I of the neocortex, have been identified in patients with developmental dyslexia and psychomotor retardation. Mouse models of this developmental disorder display behavioral impairments and increased seizure susceptibility. Although there is a correlation between cortical malformations and neurological dysfunction, little is known about the morphological and physiological properties of cells within cortical malformations. In the present study we used electrophysiological and immunocytochemical analyses to examine the distribution of neuronal and non-neuronal cell types within and surrounding layer I neocortical ectopia in NXSMD/EiJ mice. We show that cells within ectopia have membrane properties of both pyramidal and a variety of non-pyramidal cell types, including fast-spiking cells. Immunocytochemical analysis for different interneuronal subtypes demonstrates that ectopia contain nonpyramidal cells immunoreactive for calbindin-D28K (CALB), parvalbumin (PARV), and calretinin (CR). Ectopia also contains astrocytes, positive for glial fibrillary acidic protein (GFAP) and oligodendrocyte precursor cells positive for NG2 proteoglycan (NG2). Lastly, we provide electrophysiological and morphological evidence to demonstrate that cells within ectopia receive input from cells within layers I, upper and deeper II/III, and V and provide outputs to cells within deep layer II/III and layer V, but not layers I and upper II/III. These results indicate that ectopia contain cells of different lineages with diverse morphological and physiological properties, and appear to cause disruptions in local cortical circuitry. PMID- 21256121 TI - Prevention and diminished expression of experimental autoimmune encephalomyelitis by low dose naltrexone (LDN) or opioid growth factor (OGF) for an extended period: Therapeutic implications for multiple sclerosis. AB - Endogenous opioids inhibit the onset and progression of experimental autoimmune encephalomyelitis (EAE) with 30days of treatment. This study examined the long term effects of the opioid growth factor (OGF, [Met(5)]-enkephalin) and a low dose of the opioid antagonist naltrexone (LDN) on expression of myelin oligodendrocyte glycoprotein (MOG)-induced EAE. C57BL/6 mice began receiving daily injections of 10mg/kg OGF (MOG+OGF), 0.1mg/kg naltrexone (MOG+LDN), or saline (MOG+Vehicle) at the time of EAE induction and continuing for 60days. In contrast to 100% of the MOG+Vehicle group with behavioral symptoms of EAE, 63% and 68% of the MOG+OGF and MOG+LDN mice expressed disease. Both severity and disease indices of EAE in OGF- and LDN-treated mice were notably decreased from MOG+Vehicle cohorts. By day 60, 6- and 3-fold more animals in the MOG+OGF and MOG+LDN groups, respectively, had a remission compared to MOG+Vehicle mice. Neuropathological studies revealed i) astrocyte activation and neuronal damage as early as day 10 (prior to behavioral symptoms) in all MOG-injected groups, ii) a significant reduction of activated astrocytes in MOG+OGF and MOG+LDN groups compared to MOG+Vehicle mice at day 30, and iii) no demyelination on day 60 in mice treated with OGF or LDN and not displaying disease symptoms. These results indicate that treatment with OGF or LDN had no deleterious long-term repercussions and did not exacerbate EAE, but i) halted progression of disease, ii) reversed neurological deficits, and iii) prevented the onset of neurological dysfunction across a considerable span of time. PMID- 21256122 TI - Human Polycomb protein 2 promotes alpha-synuclein aggregate formation through covalent SUMOylation. AB - Parkinson's disease (PD) manifests from the impairment of motor systems due to the specific loss of dopaminergic neurons and the appearance of intracellular filamentous inclusions called Lewy bodies (LBs). alpha-Synuclein, a major component of LBs, is known to contribute to the pathogenesis of PD. Although alpha-synuclein is known to be a target of diverse posttranslational modifications, the contribution of alpha-synuclein SUMOylation and its functional consequences have not yet been fully characterized. Here, we demonstrate that human Polycomb protein 2 (hPc2) binds to alpha-synuclein and may function as a SUMO E3 ligase to promote the SUMOylation of alpha-synuclein. In addition, hPc2 promotes the SUMOylation of alpha-synuclein in the presence of MG-132-induced proteasome inhibition, which consequently promotes alpha-synuclein aggregate formation. Furthermore, the increased formation of intracellular alpha-synuclein aggregates, which predominantly contain SUMOylated alpha-synuclein, significantly reduces the death of fibroblast cells in response to staurosporine. In summary, the results from this study demonstrate that the hPc2-induced SUMOylation of alpha-synuclein could function as a cytoprotector by increasing alpha-synuclein aggregate formation within fibroblast cells. PMID- 21256123 TI - Murine hepatic aldehyde dehydrogenase 1a1 is a major contributor to oxidation of aldehydes formed by lipid peroxidation. AB - Reactive lipid aldehydes are implicated in the pathogenesis of various oxidative stress-mediated diseases, including non-alcoholic steatohepatitis, atherosclerosis, Alzheimer's and cataract. In the present study, we sought to define which hepatic Aldh isoform plays a major role in detoxification of lipid derived aldehydes, such as acrolein and HNE by enzyme kinetic and gene expression studies. The catalytic efficiencies for metabolism of acrolein by Aldh1a1 was comparable to that of Aldh3a1 (V(max)/K(m)=23). However, Aldh1a1 exhibits far higher affinity for acrolein (K(m)=23.2 MUM) compared to Aldh3a1 (K(m)=464 MUM). Aldh1a1 displays a 3-fold higher catalytic efficiency for HNE than Aldh3a1 (218 ml/min/mg vs 69 ml/min/mg). The endogenous Aldh1a1 gene was highly expressed in mouse liver and a liver-derived cell line (Hepa-1c1c7) compared to Aldh2, Aldh1b1 and Aldh3a1. Aldh1a1 mRNA levels was 34-fold and 73-fold higher than Aldh2 in mouse liver and Hepa-1c1c7 cells respectively. Aldh3a1 gene was absent in mouse liver, but moderately expressed in Hepa-1c1c7 cells compared to Aldh1a1. We demonstrated that knockdown of Aldh1a1 expression by siRNA caused Hepa-1c1c7 cells to be more sensitive to acrolein-induced cell death and resulted in increased accumulation of acrolein-protein adducts and caspase 3 activation. These results indicate that Aldh1a1 plays a major role in cellular defense against oxidative damage induced by reactive lipid aldehydes in mouse liver. We also noted that hepatic Aldh1a1 mRNA levels were significantly increased (~3 fold) in acrolein-fed mice compared to control. In addition, hepatic cytosolic ALDH activity was induced by acrolein when 1mM NAD(+) was used as cofactor, suggesting an Aldh1a1-protective mechanism against acrolein toxicity in mice liver. Thus, mechanisms to induce Aldh1a1 gene expression may provide a useful rationale for therapeutic protection against oxidative stress-induced pathologies. PMID- 21256124 TI - The microRNA-processing enzyme Dicer is dispensable for somite segmentation but essential for limb bud positioning. AB - Dicer is an enzyme that processes microRNAs (miRNAs) to their mature forms. As miRNAs were first discovered for their role in the control of developmental timing, we investigated their potential requirement in mouse somitogenesis, an event with precise temporal periodicity. To address the collective role of miRNAs in mesoderm development including somite formation, we used T (Brachyury)-Cre mouse line to inactivate Dicer in most cells of the mesoderm lineage. This Dicer mutant exhibits a reduced anterior-posterior axis. Somite number remains normal in mutant embryos up until the death of the embryos more than two days after Dicer inactivation. Consistent with this, the molecular machineries required for establishing segmentation, including clock and wave front, are not perturbed. However, somite size is reduced and later-formed somites are caudalized, coincident with increased cell death. Outside of the paraxial mesoderm and prior to apparent reduction of the axis in the mutant, the position of the hindlimb bud, a lateral plate mesoderm-derived structure, is posteriorly shifted and the timing of hindlimb bud initiation is delayed accordingly. We observed changes in the expression of genes critical for limb positioning, which include a shifted and delayed downregulation of Hand2 and Tbx3, and shifted and delayed upregulation of Gli3 in the prospective limb bud field. The 3' UTRs of both Hand2 and Tbx3 harbor target sites for a seed sequence-sharing family of miRNAs mir 25/32/92/363/367. As an example of the family we show that mir-363, a miRNA with elevated expression in the prospective limb bud field, is capable of inhibiting Hand2/Tbx3 expression in vitro in a binding site-dependent manner. Together, our findings provide the first demonstration that in mouse embryonic mesoderm, while Dicer is dispensable for somite segmentation, it is essential for proper limb bud positioning. PMID- 21256125 TI - Vernolide-A inhibits tumour specific angiogenesis by regulating proinflammatory cytokines, VEGF, MMPs and TIMP. AB - Angiogenesis is the development of new blood vessels from the pre-existing vascular beds, and plays a pivotal role in tumour growth, invasion and metastasis. We studied the antiangiogenic activity of vernolide-A using in vivo as well as in vitro models. Vernolide-A significantly inhibited tumour directed capillary formation. The level of serum proinflammatory cytokines such as IL 1beta, IL-6, TNF-alpha, and GM-CSF, and also level of serum VEGF, a proangiogenic factor were found to be elevated in angiogenesis induced animals which were significantly reduced by the treatment of vernolide-A in C57BL/6 mice. Administration of vernolide-A significantly enhanced the production of antiangiogenic factors such as IL-2 and TIMP. In vitro studies using rat aortic ring assay showed that vernolide-A at non-toxic concentrations significantly inhibited microvessel sprouting and also exhibited a significant inhibition in the proliferation, migration, and tube formation of endothelial cells, which are key events in the process of angiogenesis. Vernolide-A significantly inhibited the invasion of the collagen matrix by HUVECs in a dose dependent manner and also showed an inhibition in the activation of procollagenase to active collagenase of metalloproteinases. Taken together, these results demonstrate that vernolide-A inhibits tumour-specific angiogenesis by downregulating the production of pro angiogenic factors like pro-inflammatory cytokines, VEGF, and MMPs and also upregulating the anti-angiogenic factors such as IL-2 and TIMP-1. PMID- 21256126 TI - Identification of T-cell factor-4 isoforms that contribute to the malignant phenotype of hepatocellular carcinoma cells. AB - The Wnt/beta-catenin signaling pathway is frequently activated in hepatocellular carcinoma (HCC). Downstream signaling events involving the Wnt/beta-catenin cascade occur through T-cell factor (TCF) proteins. The human TCF-4 gene is composed of 17 exons with multiple alternative splicing sites. However, the role of different TCF-4 isoforms in the pathogenesis of HCC is unknown. The purpose of this study was to identify and characterize TCF-4 isoforms in HCC. We identified 14 novel TCF-4 isoforms from four HCC cell lines. Functional analysis following transfection and expression in HCC cells revealed distinct effects on the phenotype. The TCF-4J isoform expression produced striking features of malignant transformation characterized by high cell proliferation rate, migration and colony formation even though its transcriptional activity was low. In contrast, the TCF-4K isoform displayed low TCF transcriptional activity; cell proliferation rate and colony formation were reduced as well. Interestingly, TCF-4J and TCF-4K differed by only five amino acids (the SxxSS motif). Thus, these studies suggest that conserved splicing motifs may have a major influence on the transcriptional activity and functional properties of TCF-4 isoforms and alter the characteristics of the malignant phenotype. PMID- 21256127 TI - The cation channel mucolipin-1 is a bifunctional protein that facilitates membrane remodeling via its serine lipase domain. AB - Phospholipase modulators have been shown to affect the topology of lipid bilayers and the formation of tubulo-vesicular structures, but the specific endogenous phospholipases involved have yet to be identified. Here we show that TRPML1 (MLN1), a Ca(2+)-permeable channel, contributes to membrane remodeling through a serine lipase consensus domain, and thus represents a novel type of bifunctional protein. Remarkably, this serine lipase active site determines the ability of MLN1 to generate tubulo-vesicular extensions in mucolipin-1-expressing oocytes, human fibroblasts and model membrane vesicles. Our demonstration that MLN1 is involved in membrane remodeling and the formation of extensions suggests that it may play a role in the formation of cellular processes linked to the late endosome/lysosome (LE/L) pathway. MLN1 is absent or mutated in patients with mucolipidosis IV (MLIV), a lysosomal disorder with devastating neurological and other consequences. This study provides potential insight into the pathophysiology of MLIV. PMID- 21256128 TI - Trypanosoma brucei brucei: endocytic recycling is important for mouse infectivity. AB - Endocytosis in the African trypanosome, Trypanosoma brucei, is intimately involved in maintaining homeostasis of the cell surface proteome, morphology of the flagellar pocket and has recently been demonstrated as a bona fide drug target. RNAi-mediated knockdown of many factors required for endocytic transport, including several small GTPases, the major coat protein clathrin and a clathrin associated receptor, epsinR, results in rapid cell death in vitro. Rapid loss of viability in vitro precludes meaningful investigation by RNAi of the roles of trypanosome endocytosis in vivo. Here we have sought to address this issue using strategies designed to produce milder effects on the endocytic system than complete functional ablation. We created a trypanosome clathrin heavy chain hemizygote and several lines expressing mutant forms of Rab5 and Rab11, described previously. All are viable in in vitro culture, with negligible impact to proliferative rates or cell cycle. Clathrin hemizygotes express clathrin heavy chain at ~50% of wild type levels, but despite this demonstrate no defect to growth in mice, while none of the Rab5 mutants affected proliferation in vivo, despite clear evidence for effects on endocytosis. By contrast we find that expressing a dominantly active Rab11 mutant led to compromised growth in mice. These data indicate that trypanosomes likely tolerate the effects of partly decreased clathrin expression and alterations in early endocytosis, but are more sensitive to alterations in the recycling arm of the pathway. PMID- 21256130 TI - Digestive physiology and characterization of digestive cathepsin L-like proteinase from the sugarcane weevil Sphenophorus levis. AB - Sugarcane is an important crop that has recently become subject to attacks from the weevil Sphenophorus levis, which is not efficiently controlled with chemical insecticides. This demands the development of new control devices for which digestive physiology data are needed. In the present study, ion-exchange chromatography of S. levis whole midgut homogenates, together with enzyme assays with natural and synthetic substrates and specific inhibitors, demonstrated that a cysteine proteinase is a major proteinase, trypsin is a minor one and chymotrypsin is probably negligible. Amylase, maltase and the cysteine proteinase occur in the gut contents and decrease throughout the midgut; trypsin is constant in the entire midgut, whereas a membrane-bound aminopeptidase predominates in the posterior midgut. The cysteine proteinase was purified to homogeneity through ion exchange chromatography. The purified enzyme had a mass of 37 kDa and was able to hydrolyze Z-Phe-Arg-MCA and Z-Leu-Arg-MCA with k(cat)/K(m) values of 20.0+/-1.1 MUM(-1)s(-1) and 30.0+/-0.5 MUM(-1)s(-1), respectively, but not Z-Arg-Arg-MCA. The combined results suggest that protein digestion starts in the anterior midgut under the action of a cathepsin L-like proteinase and ends on the surface of posterior midgut cells. All starch digestion takes place in anterior midgut. These data will be instrumental to developing S. levis-resistant sugarcane. PMID- 21256129 TI - The role of stress on physiologic responses and clinical symptoms in irritable bowel syndrome. PMID- 21256131 TI - Influence of mutagenesis and viral load on the sustained low-level replication of an RNA virus. AB - Lethal mutagenesis is an antiviral strategy that aims to extinguish viruses as a consequence of enhanced mutation rates during virus replication. The molecular mechanisms that underlie virus extinction by mutagenic nucleoside analogues are not well understood. When mutagenic agents and antiviral inhibitors are administered sequentially or in combination, interconnected and often conflicting selective constraints can influence the fate of the virus either towards survival through selection of mutagen-escape or inhibitor-escape mutants or towards extinction. Here we report a study involving the mutagenesis of foot-and-mouth disease virus (FMDV) by the nucleoside analogue ribavirin (R) and the effect of R mediated mutagenesis on the selection of FMDV mutants resistant to the inhibitor of RNA replication, guanidine hydrochloride (GU). The results show that under comparable (and low) viral load, an inhibitory activity by GU could not substitute for an equivalent inhibitory activity by R in driving FMDV to extinction. Both the prior history of R mutagenesis and the viral population size influenced the selection of GU-escape mutants. A sufficiently low viral load allowed continued viral replication without selection of inhibitor-escape mutants, irrespective of the history of mutagenesis. These observations imply that reductions of viral load as a result of a mutagenic treatment may provide an opportunity either for immune-mediated clearing of a virus or for an alternative antiviral intervention, even if extinction is not initially achieved. PMID- 21256132 TI - Characterization of a family of RanBP2-type zinc fingers that can recognize single-stranded RNA. AB - The recognition of single-stranded RNA (ssRNA) is an important aspect of gene regulation, and a number of different classes of protein domains that recognize ssRNA in a sequence-specific manner have been identified. Recently, we demonstrated that the RanBP2-type zinc finger (ZnF) domains from the human splicing factor ZnF Ran binding domain-containing protein 2 (ZRANB2) can bind to a sequence containing the consensus AGGUAA. Six other human proteins, namely, Ewing's sarcoma (EWS), translocated in liposarcoma (TLS)/FUS, RNA-binding protein 56 (RBP56), RNA-binding motif 5 (RBM5), RNA-binding motif 10 (RBM10) and testis expressed sequence 13A (TEX13A), each contains a single ZnF with homology to the ZRANB2 ZnFs, and several of these proteins have been implicated in the regulation of mRNA processing. Here, we show that all of these ZnFs are able to bind with micromolar affinities to ssRNA containing a GGU motif. NMR titration data reveal that binding is mediated by the corresponding surfaces on each ZnF, and we also show that sequence selectivity is largely limited to the GGU core motif and that substitution of the three flanking adenines that were selected in our original selection experiment has a minimal effect on binding affinity. These data establish a subset of RanBP2-type ZnFs as a new family of ssRNA-binding motifs. PMID- 21256133 TI - On the existence of a possible A2A-D2-beta-Arrestin2 complex: A2A agonist modulation of D2 agonist-induced beta-arrestin2 recruitment. AB - Given that coactivation of adenosine A(2A) (A(2A)R) and dopamine D(2) (D(2)R) receptors results in the coaggregation, cointernalization, and codesensitization of the A(2A)R and D(2)R and the role of scaffolding protein beta-arrestin2 in the desensitization, internalization, and signaling of G-protein-coupled receptors, in this study we explored the ability of the A(2A)R agonist CGS21680 in A(2A)R D(2)R-coexpressing cells to modulate the D(2)R agonist-induced recruitment of beta-arrestin2 to the D(2)R by means of proximity-based bioluminescence resonance energy transfer (BRET(2)) and co-trafficking analysis. We found evidence that CGS21680 can increase the maximal BRET(2) signal between beta-arrestin2(RLuc) and D(2L)R(GFP2) upon D(2)R activation, by increasing the potency of the D(2)R agonist to exert this action. In addition, this change was associated with an increased formation of cytoplasmic clusters containing beta-arrestin2(GFP2) and D(2L)R(YFP) as seen from the co-trafficking analysis. Furthermore, the A(2A)R agonist advanced the time for the increase in Akt phosphorylation obtained with the D(2)R agonist. Finally, using a novel bioinformatics approach to predict the protein-protein interface, we have also found that amino acid pro-triplets TNY, LLS, RAF, and VSR may be crucial for the -induced beta-arrestin2 recruitment by A(2A)R-D(2)R heteromers. Taken together, the results indicate that the antagonistic A(2A)R-D(2)R allosteric receptor-receptor interaction in A(2A)R D(2)R heteromers favors beta-arrestin2 recruitment to the D(2L)R protomer with subsequent cointernalization associated with a reduced time onset of Akt phosphorylation followed by a rapid dephosphorylation. Thus, beta-arrestin2 action becomes more rapid and short-lasting and, in this way, mimics G-protein mediated signaling. PMID- 21256134 TI - Association of neighboring beta-strands of outer membrane protein A in lipid bilayers revealed by site-directed fluorescence quenching. AB - We present a detailed study on the formation of neighboring beta-strands during the folding of a monomeric integral membrane protein of the beta-barrel type. beta-Strand and beta-barrel formations were investigated for the eight-stranded transmembrane domain of outer membrane protein A (OmpA) with single-tryptophan (W), single-cysteine (C) OmpA mutants. Based on the OmpA structure, W and C were introduced in two neighboring beta-strands oriented toward the hydrocarbon core of the membrane. Replaced residue pairs were closer to either the periplasmic turns (named cis-side) or the outer loops (named trans-side) of the strand. W(n)C(m) OmpA mutants containing W at position n and C at position m along the polypeptide chain were labeled at the C by a nitroxyl spin label, which is a short-range fluorescence quencher. To monitor the association of neighboring beta strands, we determined the proximity between fluorescent W and labeled C in OmpA folding experiments by intramolecular fluorescence quenching. Formation of native beta-strand contacts in folding experiments required the lipid membrane. Residues in the trans-side of strands beta(1), beta(2), and beta(3), represented by mutants W(15)C(35) (beta(1)beta(2), trans) and W(57)C(35) (beta(3)beta(2), trans), reached close proximity prior to residues in the N(beta(1))- and C(beta(8))-terminal strands as examined for mutants W(15)C(162) (beta(1)beta(8), trans) and W(7)C(170) (beta(1)beta(8), cis). Tryptophan and cysteine converged slightly faster in W(15)C(162) (beta(1)beta(8), trans) than in W(7)C(170) (beta(1)beta(8), cis). The last folding step was observed for residues at the cis ends of strands beta(1) and beta(2) for the mutant W(7)C(43) (beta(1)beta(2), cis). The data also demonstrate that the neighboring beta-strands associate upon insertion into the hydrophobic core of the lipid bilayer. PMID- 21256135 TI - Ligand bound structures of a glycosyl hydrolase family 30 glucuronoxylan xylanohydrolase. AB - Xylanases of glycosyl hydrolase family 30 (GH30) have been shown to cleave beta 1,4 linkages of 4-O-methylglucuronoxylan (MeGX(n)) as directed by the position along the xylan chain of an alpha-1,2-linked 4-O-methylglucuronate (MeGA) moiety. Complete hydrolysis of MeGX(n) by these enzymes results in singly substituted aldouronates having a 4-O-methylglucuronate moiety linked to a xylose penultimate from the reducing terminal xylose and some number of xylose residues toward the nonreducing terminus. This novel mode of action distinguishes GH30 xylanases from the more common xylanase families that cleave MeGX(n) in accessible regions. To help understand this unique biochemical function, we have determined the structure of XynC in its native and ligand-bound forms. XynC structure models derived from diffraction data of XynC crystal soaks with the simple sugar glucuronate (GA) and the tetrameric sugar 4-O-methyl-aldotetrauronate resulted in models containing GA and 4-O-methyl-aldotriuronate, respectively. Each is observed in two locations within XynC surface openings. Ligand coordination occurs within the XynC catalytic substrate binding cleft and on the structurally fused side beta-domain, demonstrating a substrate targeting role for this putative carbohydrate binding module. Structural data reveal that GA acts as a primary functional appendage for recognition and hydrolysis of the MeGX(n) polymer by the protein. This work compares the structure of XynC with a previously reported homologous enzyme, XynA, from Erwinia chrysanthemi and analyzes the ligand binding sites. Our results identify the molecular interactions that define the unique function of XynC and homologous GH30 enzymes. PMID- 21256136 TI - Probing cellular processes with oligo-mediated recombination and using the knowledge gained to optimize recombineering. AB - Recombination with single-strand DNA oligonucleotides (oligos) in Escherichia coli is an efficient and rapid way to modify replicons in vivo. The generation of nucleotide alteration by oligo recombination provides novel assays for studying cellular processes. Single-strand exonucleases inhibit oligo recombination, and recombination is increased by mutating all four known exonucleases. Increasing oligo concentration or adding nonspecific carrier oligo titrates out the exonucleases. In a model for oligo recombination, lambda Beta protein anneals the oligo to complementary single-strand DNA at the replication fork. Mismatches are created, and the methyl-directed mismatch repair (MMR) system acts to eliminate the mismatches inhibiting recombination. Three ways to evade MMR through oligo design include, in addition to the desired change (1) a C.C mismatch 6 bp from that change; (2) four or more adjacent mismatches; or (3) mismatches at four or more consecutive wobble positions. The latter proves useful for making high frequency changes that alter only the target amino acid sequence and even allows modification of essential genes. Efficient uptake of DNA is important for oligo mediated recombination. Uptake of oligos or plasmids is dependent on media and is 10,000-fold reduced for cells grown in minimal versus rich medium. Genomewide engineering technologies utilizing recombineering will benefit from both optimized recombination frequencies and a greater understanding of how biological processes such as DNA replication and cell division impact recombinants formed at multiple chromosomal loci. Recombination events at multiple loci in individual cells are described here. PMID- 21256138 TI - A compact result for the time-dependent probability of fixation at a neutral locus. AB - A result is derived, in the form of a sum, for the time-dependent probability of fixation of an unlinked neutral locus. The result captures many of the key features of the probability of fixation in a highly compact form. For 'small' times (t ? 4N(e)) a single term of the sum accurately determines the time dependent probability of fixation. This is in contrast to the well-known result of Kimura, which requires the contribution of many terms in a different sum, for 'small' times. Going beyond small times, an approximation is derived for the time dependent probability of fixation which applies for all times when the initial relative allele frequency is small. PMID- 21256137 TI - Structure of rhomboid protease in a lipid environment. AB - Structures of the prokaryotic homologue of rhomboid proteases reveal a core of six transmembrane helices, with the active-site residues residing in a hydrophilic cavity. The native environment of rhomboid protease is a lipid bilayer, yet all the structures determined thus far are in a nonnative detergent environment. There remains a possibility of structural artefacts arising from the use of detergents. In an attempt to address the effect of detergents on the structure of rhomboid protease, crystals of GlpG, an Escherichia coli rhomboid protease in a lipid environment, were obtained using two alternative approaches. The structure of GlpG refined to 1. 7-A resolution was obtained from crystals grown in the presence of lipid bicelles. This structure reveals well-ordered and partly ordered lipid molecules forming an annulus around the protein. Lipid molecules adapt to the surface features of protein and arrange such that they match the hydrophobic thickness of GlpG. Virtually identical two-dimensional crystals were also obtained after detergent removal by dialysis. A comparison of an equivalent structure determined in a completely delipidated detergent environment provides insights on how detergent substitutes for lipid. A detergent molecule is also observed close to the active site, helping to postulate a model for substrate binding and hydrolysis in rhomboids. PMID- 21256139 TI - Molecular distributions in gene regulatory dynamics. AB - Extending the work of Friedman et al. (2006), we study the stationary density of the distribution of molecular constituents in the presence of noise arising from either bursting transcription or translation, or noise in degradation rates. We examine both the global stability of the stationary density as well as its bifurcation structure. We have compared our results with an analysis of the same model systems (either inducible or repressible operons) in the absence of any stochastic effects, and shown the correspondence between behaviour in the deterministic system and the stochastic analogs. We have identified key dimensionless parameters that control the appearance of one or two stable steady states in the deterministic case, or unimodal and bimodal densities in the stochastic systems, and detailed the analytic requirements for the occurrence of different behaviours. This approach provides, in some situations, an alternative to computationally intensive stochastic simulations. Our results indicate that, within the context of the simple models we have examined, bursting and degradation noise cannot be distinguished analytically when present alone. PMID- 21256141 TI - Isolation rearing-induced reduction of brain 5alpha-reductase expression: relevance to dopaminergic impairments. AB - Isolation rearing (IR), a well-established rat model of early chronic psychosocial stress, engenders marked behavioral alterations related to changes of dopamine (DA) neurotransmission in cortical and subcortical brain regions. Stress-induced shifts in gamma-aminobutyric acid (GABA)-ergic signaling have been implicated in the dysregulation of DA release. The neurosteroid 3alpha-hydroxy 5alpha-pregnan-20-one (allopregnanolone/AP), synthesized from progesterone by the action of the rate-limiting enzyme 5alpha-reductase (5AR), is a potent positive allosteric modulator of GABA(A) receptor function. Thus, alterations of 5AR activity/expression may impact upon DA neurotransmission. We studied the effects of IR on the 5AR expression/function and extracellular concentrations of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC). Immediately after weaning, male rats were subjected to either IR or social rearing (SR) conditions for 5-8 weeks. Compared to SR, IR rats exhibited significantly lower protein expression of 5AR isoforms (1 and 2) in both brain regions and reduced brain, but not plasma, content of AP and allotetrahydrodeoxycorticosterone, the 5alpha-reduced metabolite of deoxycorticosterone. IR-exposed rats also exhibited higher levels of DA and DOPAC in the NAcc shell, but not in mPFC, when compared to SR rats. The 5AR inhibitor finasteride (FIN, 100 mg/kg, i.p.) enhanced DA and DOPAC content in the NAcc shell of SR, but not IR rats. FIN, however, elicited equivalent increases in DA and DOPAC levels in the mPFC of both groups. These results show that IR induces changes in expression/activity of brain 5AR which, in a brain region specific manner, may partially underlie the alterations in DA signaling induced by this manipulation. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'. PMID- 21256142 TI - Introduction to the Special Issue on the human amygdala and emotional function. PMID- 21256143 TI - Binding in visual working memory: the role of the episodic buffer. AB - The episodic buffer component of working memory is assumed to play a central role in the binding of features into objects, a process that was initially assumed to depend upon executive resources. Here, we review a program of work in which we specifically tested this assumption by studying the effects of a range of attentionally demanding concurrent tasks on the capacity to encode and retain both individual features and bound objects. We found no differential effect of concurrent load, even when the process of binding was made more demanding by separating the shape and color features spatially, temporally or across visual and auditory modalities. Bound features were however more readily disrupted by subsequent stimuli, a process we studied using a suffix paradigm. This suggested a need to assume a feature-based attentional filter followed by an object based storage process. Our results are interpreted within a modified version of the multicomponent working memory model. We also discuss work examining the role of the hippocampus in visual feature binding. PMID- 21256144 TI - Unconditioned and conditioned effects of intravenous insulin and glucose on heart rate variability in healthy men. AB - We examined whether an injection of intravenous insulin and intravenous glucose would affect frequency-domain measures of heart rate variability (HRV), i.e., the high-frequency (HF-) band and the ratio of the low frequency (LF-) to the HF-band in healthy humans. Using a classical conditioning protocol, we also assessed whether the measures of HRV are subject to classical conditioning. Thirty healthy men were divided into three groups, given a conditioned stimulus (CS) and an intravenous injection of either insulin (0.05IU/kg) in Group 1, glucose (15%, 0.5g/kg) in Group 2, or placebo (physiological saline [0.9%]) in Group 3 during the 4-day acquisition phase. All subjects were given an olfactory CS (rosewood peppermint smell) and placebo injection on day 5 (test). Due to their high inter individual variability, HF and LF/HF-ratio were analysed by intragroup comparisons, using a pre-injection baseline interval (min -15 to -5), and three functional post-injection intervals: a) the interval to the maximum insulin level, i. e. insulin peak (min 0-5) in Groups 1 and 2, b) the interval to the maximum of insulin-induced hypoglycaemia (min 20-25) in Group 1, and c) the end of the session (min 70-75). On days 1 to 4, we found significant increases of the HF-band from baseline to interval min 0-5 in Group 1, and an even more pronounced increase in the glucose-treated Group 2. At the test (Day 5), both experimental groups responded with an HF-increase in the interval of the former insulin peak, and also at the other measurement intervals, reflecting some general increase of vagal activity remaining as a conditioned response. On days 1 to 4, the HF-band was positively correlated with the change of peripheral insulin levels in Group 1, reaching statistical significance on days 3 and 4. This pattern only emerged in tendency on Day 4 in Group 2. In conclusion, insulin triggers an increase in parasympathetic tone at maximum hyperinsulinaemia, and our data support the notion that this response pattern can become classically conditioned. PMID- 21256140 TI - Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. AB - Serotonergic hallucinogens produce profound changes in perception, mood, and cognition. These drugs include phenylalkylamines such as mescaline and 2,5 dimethoxy-4-methylamphetamine (DOM), and indoleamines such as (+)-lysergic acid diethylamide (LSD) and psilocybin. Despite their differences in chemical structure, the two classes of hallucinogens produce remarkably similar subjective effects in humans, and induce cross-tolerance. The phenylalkylamine hallucinogens are selective 5-HT(2) receptor agonists, whereas the indoleamines are relatively non-selective for serotonin (5-HT) receptors. There is extensive evidence, from both animal and human studies, that the characteristic effects of hallucinogens are mediated by interactions with the 5-HT(2A) receptor. Nevertheless, there is also evidence that interactions with other receptor sites contribute to the psychopharmacological and behavioral effects of the indoleamine hallucinogens. This article reviews the evidence demonstrating that the effects of indoleamine hallucinogens in a variety of animal behavioral paradigms are mediated by both 5 HT(2) and non-5-HT(2) receptors. PMID- 21256145 TI - Depression and altered serum lipids in cynomolgus monkeys consuming a Western diet. AB - Research over the past 15 years has suggested a high comorbidity of depression and coronary heart disease (CHD). However the mechanisms responsible for this relationship are poorly understood. This study was designed to examine the relationships between depressive behaviors and concentrations of circulating lipids and lipid signaling molecules that may be common to both CHD and depression in a cohort of cynomolgus monkeys (Macaca fascicularis) consuming a 'Western' diet, enriched with saturated fat and cholesterol. Socially-housed adult female cynomolgus monkeys (n=36) were fed the Western diet for 27 months and depressive behavior was recorded weekly. Body weight, body mass index and circulating cholesterol profiles were measured in all animals, and fatty acids (FA) and FA-based signaling molecules were measured in the 6 least and 6 most depressed monkeys. Monkeys consuming the Western diet exhibited a broad range of percent time spent in depressive behavior. The percent time spent depressed was positively correlated with total plasma and LDL cholesterol and negatively correlated with HDL cholesterol. Despite being leaner, depressed monkeys had higher concentrations of monounsaturated fats (C16:1 and C17:1), a higher omega6/omega3 polyunsaturated fatty acid (PUFA) ratio and higher concentrations of omega-6 (omega6) PUFAs, particularly C18:2omega6 and C20:3omega6. FA ratios suggest that stearoyl CoA desaturase 1 activity was increased in depressed monkeys. Depressed female cynomolgus monkeys had elevated concentrations of serum lipids and lipid signaling molecules that are typically associated with obesity, insulin resistance and cardiovascular disease, which may account in part for the comorbidity of depression and CHD. PMID- 21256147 TI - The use of cognitive enhancers in animal models of fear extinction. AB - In anxiety disorders, such as posttraumatic stress disorders and phobias, classical conditioning pairs natural (unconditioned) fear-eliciting stimuli with contextual or discrete cues resulting in enduring fear responses to multiple stimuli. Extinction is an active learning process that results in a reduction of conditioned fear responses after conditioned stimuli are no longer paired with unconditioned stimuli. Fear extinction often produces incomplete effects and this highlights the relative permanence of bonds between conditioned stimuli and conditioned fear responses. The animal research literature is rich in its demonstration of cognitive enhancing agents that alter fear extinction. This review specifically examines the fear extinguishing effects of cognitive enhancers that act on gamma-aminobutyric acid (GABA), glutamatergic, cholinergic, adrenergic, dopaminergic, and cannabinoid signaling pathways. It also examines the effects of compounds that alter epigenetic and neurotrophic mechanisms in fear extinction. Of these cognitive enhancers, glutamatergic N-methyl d-aspartate (NMDA) receptor agonists, such as D-cycloserine, have enhanced fear extinction in a context-, dose- and time-dependent manner. Agents that function as glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor agonists, alpha2-adrenergic receptor antagonists (such as yohimbine), neurotrophic factors (brain derived neurotrophic factor or BDNF) and histone deacetylase inhibitors (valproate and sodium butyrate) also improve fear extinction in animals. However, some have anxiogenic effects and their contextual and temporal effects need to be more reliably demonstrated. Various cognitive enhancers produce changes in cortico-amygdala synaptic plasticity through multiple mechanisms and these neural changes enhance fear extinction. We need to better define the changes in neural plasticity produced by these agents in order to develop more effective compounds. In the clinical setting, such use of effective cognitive enhancers with cue exposure therapy, using compounds derived from animal model studies, provides great hope for the future treatment of anxiety disorders. PMID- 21256146 TI - How neural mediation of anticipatory and compensatory insulin release helps us tolerate food. AB - Learned anticipatory and compensatory responses allow the animal and human to maintain metabolic homeostasis during periods of nutritional challenges, either acutely within each meal or chronically during periods of overnutrition. This paper discusses the role of neurally-mediated anticipatory responses in humans and their role in glucoregulation, focusing on cephalic phase insulin and pancreatic polypeptide release as well as compensatory insulin release during the etiology of insulin resistance. The necessary stimuli required to elicit CPIR and vagal activation are discussed and the role of CPIR and vagal efferent activation in intra-meal metabolic homeostasis and during chronic nutritional challenges are reviewed. PMID- 21256148 TI - Icariin attenuates social defeat-induced down-regulation of glucocorticoid receptor in mice. AB - Icariin is a major constituent of flavonoids isolated from the herb Epimedium. It displays antidepressant-like activity in mice behavioral despair models and chronic mild stress models. In this study, a chronic social defeat protocol is used as a mouse model for depression, and the social avoidance effects of icariin administration are investigated. The data indicate that social defeat significantly reduces mice social interaction time and that icariin administered at 25 mg/kg and 50 mg/kg for 28 consecutive days produce remarkable increases in social interaction time. Impaired glucocorticoid receptor (GR) function is related to depression and normalization of GR function is closely associated with the recovery from depression. In this study, GR binding affinity and protein expression were evaluated by radioactive ligand and western blot, respectively. Our results demonstrate that both GR binding affinity and protein expression in the social defeat model are remarkably decreased and that icariin administration attenuates social defeat-induced GR down-regulation. In the present study, our data also show that icariin administration significantly inhibits social defeat induced increases of corticosterone and IL-6 levels. The potential mechanisms of icariin induced GR modulation, such as effects on HPA-axis function, proinflammatory signaling pathway and membrane steroid transporters, need further study. PMID- 21256149 TI - Race and response to colon cancer screening interventions. AB - OBJECTIVE: We report race-related differences in response to behavioral interventions in colorectal cancer (CRC) screening. METHODS: From 2002 through 2005, a total of 1430 primary care patients (578 whites and 852 African Americans) from Jefferson Family Medicine Associates, a large primary care practice affiliated with Thomas Jefferson University, completed a baseline survey and were randomized to 1 of 4 groups, as follows: control (usual care), standard intervention (SI), tailored intervention (TI), or tailored intervention plus phone (TIP). The SI group received a targeted print intervention by mail. The TI group received the targeted intervention and tailored message pages that addressed perceptions related to screening. The TIP group received the targeted intervention, tailored message pages, and a telephone reminder. RESULTS: CRC screening rates for whites and African Americans were comparable in usual care (33% versus 32%, respectively). In response to intervention, however, whites exhibited significantly higher (p=0.005) screening rates than African Americans (53% versus 43%, respectively; adjusted OR=1.44; 95% CI=1.12-1.86). This effect is largely explained by differential response to mailed print interventions. CONCLUSIONS: Whites and African Americans may respond differently to mailed interventions intended to increase CRC screening. Research is needed on methods that can both increase screening and racial equity in screening. PMID- 21256150 TI - Identification and functional characterization of Dicer2 and five single VWC domain proteins of Litopenaeus vannamei. AB - Dicer (Dcr) is the key protein of the RNA interference (RNAi) pathway. To investigate the role of the RNAi pathway in shrimp anti-viral immunity, Litopenaeus vannamei Dcr2 (designated as LvDcr2) was identified and characterized. The full-length cDNA of LvDcr2 was 5513bp long, with an open reading frame encoding a putative protein of 1502 amino acids. In addition, five proteins homologous to the single von Willebrand factor type C (VWC) domain protein (SVC) were also identified in L. vannamei and named LvSVC1-5. These LvSVCs were between 102 and 190 amino acids in length and all contained a motif similar to Drosophila melanogaster SVC proteins (DmSVCs). By co immunoprecipitation assays and pull-down assays, we demonstrated that LvDcr2, L. vannamei Argonaute 2 (LvAgo2), and L. vannamei transactivating response RNA binding protein isoform 1 (LvTRBP1) interacted with each other. A luciferase reporter assay indicated that the promoters of LvSVC1, LvSVC4, LvSVC5, and DmSVC Vago (DmVago) were activated by LvDcr2 as well as by Drosophila Dcr2 (DmDcr2). Real-time RT-PCR showed that LvDcr2 and LvSVCs were up-regulated in immune responses against Poly(C-G) or WSSV challenge. These results suggested that LvDcr2 formed complexes with LvAgo2 and LvTRBP1 to act as the cores of shrimp small interfering RNA (siRNA)-induced silencing complex (siRISC)/siRISC-loading complex (siRLC), role in shrimp siRNA pathway. Furthermore, these results also suggested that LvDcr2 may engage in non-specific activation of anti-viral immunity. PMID- 21256151 TI - Should polymyxin be used empirically to treat infections in patients under high risk for carbapenem-resistant Acinetobacter? PMID- 21256152 TI - Clinicopathological and microbiological characteristics of mycobacterial otitis media in a medical center, 2000 to 2009. PMID- 21256153 TI - Social and economic impact of school closure resulting from pandemic influenza A/H1N1. AB - OBJECTIVES: On May 23, 2009, a school was closed for one week plus mass chemoprophylaxis to contain the pandemic after a kindergartener tested positive for pandemic influenza A/H1N1. We evaluated the impact of school closure on the students, families, and the school. METHODS: Households were surveyed using a questionnaire to obtain information on adherence to, socio-economic impact by and inconveniences of school closure. The school principal was interviewed to assess the impact on the staff. Compliance and adverse events of chemoprophylaxis were assessed. RESULTS: Of the 232 (14%) households surveyed, 29 (13%) went to public places or gatherings at least once during the closure. Sixty-one (27%) of 229 respondents reported workplace absenteeism, and 42 (18%) of 231 respondents had wage loss. In total, 194 working days lost and 6433 US dollars wage lost were noted. The school put in 6573 h of manpower during the period. For chemoprophylaxis, 6 (6%) kindergartners missed at least one dose; and 6 (6%) reported adverse events, but none sought medical care. Overall, 169 (73%) families were at least moderately supportive of school closure. CONCLUSIONS: With assistance from the school, short-term school closure was supported by the majority of families despite economic inconvenience to the households. PMID- 21256155 TI - Dimers and beyond: The functional puzzles of class C GPCRs. AB - Our understanding of G protein-coupled receptor (GPCR) activation has evolved during the last ten years, both at a molecular level thanks to the resolution of several crystal structures, and at a cellular level with the characterization of complexes surrounding the receptor. Class C GPCRs, including receptors for glutamate, gamma-aminobutyric acid (GABA), taste compounds, amino acids and Ca(2+), have several structural features that make them unique in the GPCR family. First, they possess a large and structurally-defined extracellular domain, which is distal from the transmembrane core and bears the agonist binding site. Second, they form obligatory dimers providing a unique mode of activation compared to GPCRs of other classes. In this article, we aim to provide an overview of the molecular mechanisms of class C GPCR activation as dimeric entities. Furthermore, we discuss the possibility of modulating receptor function through the use of ligands or by association, direct or indirect, with other receptors (GPCRs or not) with the aim to better understand receptor function. Finally, we present the therapeutic scope for the class C GPCRs that highlights the need to fully characterize the functioning of these receptors in their native environment to develop better therapeutic molecules. PMID- 21256154 TI - MicroRNAs: Meta-controllers of gene expression in synaptic activity emerge as genetic and diagnostic markers of human disease. AB - MicroRNAs are members of the non-protein-coding family of RNAs. They serve as regulators of gene expression by modulating the translation and/or stability of messenger RNA targets. The discovery of microRNAs has revolutionized the field of cell biology, and has permanently altered the prevailing view of a linear relationship between gene and protein expression. The increased complexity of gene regulation is both exciting and daunting, as emerging evidence supports a pervasive role for microRNAs in virtually every cellular process. This review briefly describes microRNA processing and formation of RNA-induced silencing complexes, with a focus on the role of RNA binding proteins in this process. We also discuss mechanisms for microRNA-mediated regulation of translation, particularly in dendritic spine formation and function, and the role of microRNAs in synaptic plasticity. We then discuss the evidence for altered microRNA function in cognitive brain disorders, and the effect of gene mutations revealed by single nucleotide polymorphism analysis on altered microRNA function and human disease. Further, we present evidence that altered microRNA expression in circulating fluids such as plasma/serum can correlate with, and serve as, novel diagnostic biomarkers of human disease. PMID- 21256157 TI - Drug discovery and the human kinome: recent trends. AB - A major new trend in drugs targeted at protein kinases is the discovery of allosteric modulators. These compounds differ from ATP-centric drugs in that they do not compete with ATP for binding to the catalytic domain, generally acting by inducing conformational changes to modulate activity. They could provide a number of advantages over more classical protein kinase drugs. For example, they are likely to be more selective, since they bind to unique regions of the kinase and may be useful in overcoming resistance that has developed to drugs that compete with ATP. They offer the ability of activating the kinases either by removing factors that inhibit kinase activity or by simply producing changes to the enzyme to foster catalytic activity. Furthermore, they provide more subtle modulation of kinase activity than simply blocking ATP access to inhibit activity. One hurdle to overcome in discovering these compounds is that allosteric modulators may need to inhibit protein-protein interactions; generally difficult to accomplish with small molecules. Despite the technical problems of identifying allosteric modulators, major gains have been made in identifying allosteric inhibitors and activators of the growth factor receptors as well as soluble tyrosine and serine/threonine kinases and some of these drugs are now in various stages of clinical trials. This review will focus on the discovery of novel allosteric modulators of protein kinases and drug discovery approaches that have been employed to identify such compounds. PMID- 21256156 TI - Astrocyte elevated gene-1 (AEG-1): A multifunctional regulator of normal and abnormal physiology. AB - Since its initial identification and cloning in 2002, Astrocyte Elevated Gene-1 (AEG-1), also known as metadherin (MTDH), 3D3 and LYsine-RIch CEACAM1 co-isolated (LYRIC), has emerged as an important oncogene that is overexpressed in all cancers analyzed so far. Examination of a large cohort of patient samples representing diverse cancer indications has revealed progressive increase in AEG 1 expression with stages and grades of the disease and an inverse relationship between AEG-1 expression level and patient prognosis. AEG-1 functions as a bona fide oncogene by promoting transformation. In addition, it plays a significant role in invasion, metastasis, angiogenesis and chemoresistance, all important hallmarks of an aggressive cancer. AEG-1 is also implicated in diverse physiological and pathological processes, such as development, inflammation, neurodegeneration, migraine and Huntington's disease. AEG-1 is a highly basic protein with a transmembrane domain and multiple nuclear localization signals and it is present in the cell membrane, cytoplasm, nucleus, nucleolus and endoplasmic reticulum. In each location, AEG-1 interacts with specific proteins thereby modulating diverse intracellular processes the combination of which contributes to its pleiotrophic properties. The present review provides a snapshot of the current literature along with future perspectives on this unique molecule. PMID- 21256158 TI - Heat-killed Lactobacillus acidophilus La205 enhances NK cell cytotoxicity through increased granule exocytosis. AB - Heat-killed lactic acid bacteria (LAB) are known to be important immunomodulators that stimulate tumor necrosis factor-alpha (TNF-alpha) and nitric oxide (NO) production as well as increase phagocytic activity in macrophages. NK cells play a critical role in innate immune response and induce spontaneous killing of tumor cells and virus-infected cells. However, the effect of heat-killed LAB on NK cells is still unclear. In this study, we investigated the effect of heat-killed Lactobacillus acidophilus La205 (La205) on NK cytolytic activity. We found that heat-killed La205 directly stimulated NK cytolytic activity in dose- and time dependent manners. To determine the mechanism underlying heat-killed La205 enhanced NK cytotoxicity, the expression of NK activating receptors was tested. Heat-killed La205 did not affect the expression of NK activating receptors. To investigate whether NK degranulation is related to heat-killed La205-enhanced NK cytotoxicity, NK degranulation inhibitor concanamycin A (CMA) was used. CMA effectively blocked heat-killed La205-induced NK cytotoxicity, and an assay for detection of a degranulation marker, CD107a, showed that heat-killed La205 increased granule exocytosis approximately 2-fold in comparison to non-treated NK cells. In addition, heat-killed La205 dramatically elevated mRNA expression of granulysin, a component of the cytolytic granule contents, in NK cells. However, other granule contents, including perforin and granzymes, were not changed by heat-killed La205. From these data, we concluded that heat-killed La205 stimulated NK cytolytic activity through enhancement of granule exocytosis, and granulysin may be a critical mediator in heat-killed La205-induced granule exocytosis. PMID- 21256159 TI - Blockade of IL-6-signaling inhibits the pathogenesis of CD4+ T cell-mediated lethal graft-versus-host reaction against minor histocompatibility antigen. AB - Graft-versus-host reaction (GVHR) is considered as a problem in hematopoietic cell transplantation. We found that CD45RB(high) CD62L(+) naive CD4(+) T cells from wild-type B10D2 (H-2d MMTV6(-)) mice immediately differentiated into effector T cells producing high-levels of various cytokines after the transfer into BALB/c RAG2(-/-) (H-2d MMTV6(+)) mice. The expanded CD4(+) T cells, which have almost TCR Vbeta3 chain, recognized the minor antigen of recipient mice and brought typical severe GVHR symptoms such as eyelid irritation, diarrhea, and liver failure. Eventually, all of the recipient mice transferred CD4(+) T cells was dead within 10 days. We demonstrated here that blockade of IL-6 signaling by administration of anti-IL-6 receptor (IL-6R) monoclonal antibody (mAb) remarkably inhibited the CD4(+) T cell-mediated lethal GVHR. In addition, we confirmed that the in vivo injection of anti-IL-6R mAb prevented the generation of effector CD4(+) T cells which produce the inflammatory cytokines such as IFN-gamma, TNF alpha, and IL-17. These findings indicated that IL-6 was a critical factor in the CD4(+) T cell-dependent acute GVHR induced by a minor-antigen, suggesting that IL 6-mediated signaling pathway would be a strong therapeutic target in T cell mediated GVHR as well as other diseases including autoimmune and inflammation. PMID- 21256160 TI - Induction of heme oxygenase-1 expression by cilostazol contributes to its anti inflammatory effects in J774 murine macrophages. AB - The effects of cilostazol on stimulating heme oxygenase (HO)-1 expression including signal pathways and suppression of inflammatory cytokines and molecules were studied. Cilostazol stimulation time (1-8 h)- and concentration (1-30 MUM) dependently increased the HO-1 mRNA and protein expression associated with increased HO-1 activity, as did cobalt protoporphyrin IX (1-3 MUM) in J774 macrophages. In addition, cilostazol (1-30 MUM) concentration-dependently reduced lipopolysaccharide (LPS)-mediated nitrite and TNF-alpha production, in accordance with the inhibition of LPS-stimulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression in the J774 macrophages, as did CoPP (1 MUM). In parallel with these results, LPS-induced IkappaBalpha degradation and NF-kappaB nuclear translocation were significantly decreased after treatment with cilostazol as well as with CoPP. These effects of cilostazol and CoPP were significantly reversed by Zn protoporphyrin IX (ZnPP). The effects of cilostazol on IkappaBalpha expression and nitrite production were not manifested in the cells transfected with HO-1 small interfering RNA. In the J774 macrophages, cilostazol time (0-180min)- and concentration (1-100MUM)-dependently increased the nuclear expression of NF-E2 related factor (Nrf2) and antioxidant response element (ARE) activity (3.70+/-0.45 fold, P<0.01). PI3-kinase and Akt play a role in the major signal pathways with cilostazol-induced HO-1 expression. In summary, cilostazol suppressed production of anti-inflammatory cytokines and molecules via inhibition of NF-kappaB activation, through a mechanism involving up-regulation of cyclic AMP-dependent protein kinase activation-coupled Nrf2-linked HO-1 expression in J774A.1 macrophages. PMID- 21256161 TI - The RAG1 V(D)J recombinase/ubiquitin ligase promotes ubiquitylation of acetylated, phosphorylated histone 3.3. AB - Histone variant H3.3 is associated with transcriptionally active chromatin and accumulates at loci undergoing preparation for V(D)J recombination, a DNA rearrangement required for the assembly of antigen receptors and development of B and T lymphocytes. Here we demonstrate that the RAG1 V(D)J recombinase protein promotes ubiquitylation of H3.3 that has been heavily acetylated and phosphorylated on serine 31 (acetyl-H3.3 S31p). A fragment of RAG1 promoted formation of a mono-ubiquitylated H3 product that was identified using mass spectrometry as ubiquitylated acetyl-H3.3 S31p. H3 was ubiquitylated at multiple lysine residues, and correspondingly, di-, tri- and higher-order ubiquitylated products were detected at low levels. Ubiquitylation was dependent on an intact RAG1 RING finger/ubiquitin ligase domain and required additional regions of the RAG1 amino terminus that are likely to interact with H3. Acetylated residues within the H3 amino terminal tail were also required. Purified, recombinant H3.1 and H3.3 were not good substrates, suggesting that post-translational modifications enhance recognition by RAG1. A complex including damage-DNA binding protein has also been shown to ubiquitylate H3 in response to UV treatment, suggesting the H3 ubiquitylation may be a common step in multiple DNA repair pathways. PMID- 21256162 TI - Inhibition of T cell activation through down-regulation of TCR-CD3 expression mediated by an anti-CD90 Ab. AB - We are trying to develop new Abs that can manipulate CD4 T cell responses and are usable as immunosuppressive agents. To this end, we performed functional screening, in which we examined the effect of an Ab on the proliferation of mouse CD4 T cells upon activation. The Ab, LP5, inhibited the activation of CD4 T cells stimulated with an anti-CD3 Ab or peptide antigen. The Ab alone had no stimulatory effect on CD4 T cells. Biochemical experiments demonstrated that LP5 recognized the Thy-1 (CD90) molecule. Interestingly, the treatment of CD4 T cells with LP5 in vitro induced a temporary down-regulation of CD3 expression at the cell surface. TCR molecules were also affected. Other anti-CD90 Abs not inhibitory to CD4 T cell activation failed to induce a reduction in CD3. Experiments in vitro revealed that the down-regulation caused by LP5 is due to an accelerated endocytosis of cell surface CD3. In addition, it was shown that CD3 down-regulation before or in the early stages of T cell activation is critical for the induction of hyporesponsiveness. Experiments in vivo showed that pre treatment of CD4 T cells with LP5 inhibited the rejection of semi-allogeneic bone marrow transplants. Based on these observations, we propose that CD3 down regulation without any stimulatory activity against T cells could be one approach to inhibiting T cell activation, and CD90 would be an appropriate target. PMID- 21256164 TI - Targeting fatty acid and carbohydrate oxidation--a novel therapeutic intervention in the ischemic and failing heart. AB - Cardiac ischemia and its consequences including heart failure, which itself has emerged as the leading cause of morbidity and mortality in developed countries are accompanied by complex alterations in myocardial energy substrate metabolism. In contrast to the normal heart, where fatty acid and glucose metabolism are tightly regulated, the dynamic relationship between fatty acid beta-oxidation and glucose oxidation is perturbed in ischemic and ischemic-reperfused hearts, as well as in the failing heart. These metabolic alterations negatively impact both cardiac efficiency and function. Specifically there is an increased reliance on glycolysis during ischemia and fatty acid beta-oxidation during reperfusion following ischemia as sources of adenosine triphosphate (ATP) production. Depending on the severity of heart failure, the contribution of overall myocardial oxidative metabolism (fatty acid beta-oxidation and glucose oxidation) to adenosine triphosphate production can be depressed, while that of glycolysis can be increased. Nonetheless, the balance between fatty acid beta-oxidation and glucose oxidation is amenable to pharmacological intervention at multiple levels of each metabolic pathway. This review will focus on the pathways of cardiac fatty acid and glucose metabolism, and the metabolic phenotypes of ischemic and ischemic/reperfused hearts, as well as the metabolic phenotype of the failing heart. Furthermore, as energy substrate metabolism has emerged as a novel therapeutic intervention in these cardiac pathologies, this review will describe the mechanistic bases and rationale for the use of pharmacological agents that modify energy substrate metabolism to improve cardiac function in the ischemic and failing heart. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. PMID- 21256163 TI - Mitochondrial dysfunction in diabetic cardiomyopathy. AB - Cardiovascular disease is common in patients with diabetes and is a significant contributor to the high mortality rates associated with diabetes. Heart failure is common in diabetic patients, even in the absence of coronary artery disease or hypertension, an entity known as diabetic cardiomyopathy. Evidence indicates that myocardial metabolism is altered in diabetes, which likely contributes to contractile dysfunction and ventricular failure. The mitochondria are the center of metabolism, and recent data suggests that mitochondrial dysfunction may play a critical role in the pathogenesis of diabetic cardiomyopathy. This review summarizes many of the potential mechanisms that lead to mitochondrial dysfunction in the diabetic heart. This article is part of a Special Issue entitled: Mitochondria and Cardioprotection. PMID- 21256165 TI - The N-terminal region of RECQL4 lacking the helicase domain is both essential and sufficient for the viability of vertebrate cells. Role of the N-terminal region of RECQL4 in cells. AB - Rothmund-Thomson syndrome (RTS) is a rare genetic disorder characterized by premature aging, developmental abnormalities, and a predisposition to cancer. RTS is caused by mutations in the RECQL4 gene, which encodes one of the five human RecQ helicases. To identify the cellular functions of RECQL4, we generated a chicken DT40 cell line in which RECQL4 expression could be turned off by doxycycline (Dox). Upon exposure to Dox, cells stopped growing and underwent apoptosis. The cells could be rescued by expression of the N-terminal region of RECQL4 (amino acids 1-496), which lacks the helicase domain and has sequence similarity to yeast Sld2, which plays an essential function in the initiation of DNA replication in Saccharomyces cerevisiae. Smaller fragments of the N-terminal region of RECQL4 did not rescue the cells from lethality. RECQL4 gene knockout cells complemented with RECQL4 (1-496) showed relatively high sensitivity to DNA damaging agents that induce double strand breaks and cross-links, suggesting that the C-terminal region including the helicase domain of RECQL4 is involved in the repair of certain types of DNA lesions. PMID- 21256167 TI - The relation of self-efficacy and error-related self-regulation. AB - Relations between a modifiable psychosocial factor, self-efficacy (SE), and behavioral and neural indices of self-regulation, including post-error behavior, the error-related negativity (ERN), and error positivity (Pe) were examined in young adults during a flanker task emphasizing either accuracy or speed. SE was predicted to be associated with larger ERN and Pe amplitudes, as well as greater post-error behavioral performance during task conditions emphasizing accuracy, but not speed. Results showed that higher SE was associated with greater post error response accuracy during the accuracy condition, but not the speed condition, and higher SE was related with greater ERN amplitudes across instruction conditions. Further, ERN amplitude mediated the relationship between SE and post-error response accuracy in the accuracy condition. These findings emphasize the role of motivation and incentive on the self-regulatory system and suggest that SE is beneficially related to self-regulatory processes and outcomes. PMID- 21256168 TI - ERP signatures of cross-modal semantic fragment priming: early context effects in speech perception. AB - Research in speech perception and language comprehension has shown that the processing and recognition of a word (the target) is facilitated if a related word (the prime) precedes it. This effect is observable even if the prime only consists of a word-initial fragment (e.g. bor- facilitates the recognition of border). The fragment priming paradigm has gained an important role in ERP studies on lexical access, since it reliably shows a distinct deflection at around 350 ms after word-onset, taken as index for lexical activation. While previous studies concentrated on form-related prime-target pairs, we are interested in ERP fragment priming components elicited by meaning-related pairs. For that purpose, we designed a cross-modal priming experiment, in which primes were either the initial syllables of their following targets (e.g. bor[der] border; phonological condition) or the initial syllables of a semantic relative to these targets (e.g. mar[gin]-border; semantic condition). We found a reliable P350 effect in the phonological condition, but not in the semantic condition, and a N400 priming effect for the phonological condition. The phonological and the semantic condition differed from the control condition in an early negativity around 180 ms post onset. Our results are discussed with respect to ERP components that index form-based and meaning-based processing, possibly reflecting separate representations. PMID- 21256169 TI - Meat, morals, and masculinity. AB - Much research has demonstrated that people perceive consumers of "good," low-fat foods as more moral, intelligent, and attractive, and perceive consumers of "bad," high-fat foods as less intelligent, less moral, and less attractive. Little research has contrasted perceptions of omnivores and vegetarians, particularly with respect to morality and gender characteristics. In two between subject studies, we investigated people's perceptions of others who follow omnivorous and vegetarian diets, controlling for the perceived healthiness of the diets in question. In both studies, omnivorous and vegetarian participants rated vegetarian targets as more virtuous and less masculine than omnivorous targets. PMID- 21256166 TI - Karyopherins in nuclear transport of homeodomain proteins during development. AB - Homeodomain proteins are crucial transcription factors for cell differentiation, cell proliferation and organ development. Interestingly, their homeodomain signature structure is important for both their DNA-binding and their nucleocytoplasmic trafficking. The accurate nucleocytoplasmic distribution of these proteins is essential for their functions. We summarize information on (a) the roles of karyopherins for import and export of homeoproteins, (b) the regulation of their nuclear transport during development, and (c) the corresponding complexity of homeoprotein nucleocytoplasmic transport signals. This article is part of a Special Issue entitled: Regulation of Signaling and Cellular Fate through Modulation of Nuclear Protein Import. PMID- 21256170 TI - Responsiveness to healthy television (TV) food advertisements/commercials is only evident in children under the age of seven with low food neophobia. AB - Exposure to television advertisements for unhealthy foods has been shown to subsequently increase the amount of snack food consumed in children between the ages of five and eleven. However, it has yet to be elucidated whether healthy food television advertisements have a different effect on subsequent food intake in children. The current study explored the role of food neophobia in 'responsiveness' to food adverts in children between the ages of five and seven. Sixty-six children were exposed to unhealthy food adverts, healthy food adverts and toy adverts embedded into a cartoon in a counterbalanced order on three different occasions. Following the cartoon, children were offered a snack consisting of six food items (chocolate, jelly sweets, potato crisps, Snack-a Jacks, green seedless grapes and carrot sticks). Food advert exposure, irrespective of content (either unhealthy or healthy food items), increased food intake by 47 kcal (11%) in high food neophobic children. Children who scored lower on the food neophobia scale ate significantly more (63 kcal, 14%) following the unhealthy food adverts only. In the healthy advert condition low food neophobic children consumed less chocolate (p=0.003) but did not increase their consumption of fruit and vegetables. Presentation of healthy foods does not alter food preferences in the short-term. Children with low levels of food neophobia appear to respond to healthy food messages but children with higher levels of food neophobia do not. Instead, high food neophobic children will continue to consume more chocolate following exposure to food adverts irrespective of the healthy or unhealthy message they contain. PMID- 21256171 TI - Whey proteins as source of dipeptidyl dipeptidase IV (dipeptidyl peptidase-4) inhibitors. AB - Preclinical and clinical studies suggest that whey proteins can reduce postprandial glucose levels and stimulate insulin release in healthy subjects and in subjects with type 2 diabetes by reducing dipeptidyl peptidase-4 (DPP-4) activity in the proximal bowel and hence increasing intact incretin levels. Our aim was to identify DPP-4 inhibitors among short peptides occurring in hydrolysates of beta-lactoglobulin, the major whey protein found in the milk of ruminants. We proved that the bioactive peptide Ile-Pro-Ala can be regarded as a moderate DPP-4 inhibitor. PMID- 21256172 TI - Orexins/hypocretins increase the promoter activity of selective steroidogenic enzymes. AB - Orexins (hypocretins) regulate multiple physiological functions, including central regulation of energy homeostasis and sleep-wake behavior but also peripheral hormonal actions. Recent data suggest specific effects of orexins at adrenal glands. To further assess the mechanism by which orexins regulate steroidogenesis we analyzed the effect of orexin A and B on the transcriptional activity of the luciferase reporter gene driven by the human steroid 21 hydroxylase (CYP21), 3beta-hydroxysteroid dehydrogenase (HSD3B2), 11beta hydroxylase (CYP11B1), and aldosterone synthase (CYP11B2) gene promoter regions. After transient transfection of the reporter gene constructs into human NCI H295R cells, treatment with orexin A and B for 6 and 12h increased the promoter activity of the CYP11B2, HSD3B2 and, to a lesser extend, CYP21 genes. The activity of the CYP11B1 was increased by both orexins after 3h of treatment. Compared to the effects of forskolin or angiotensin II, however, the effect of orexins on the transcriptional activity of the steroidogenic enzyme genes was moderate. Our results suggest that orexins increase the expression of steroidogenic enzymes at the transcriptional level and that orexins play a role in the long term regulation of adrenal steroid production. PMID- 21256173 TI - Microcin J25-Ga induces apoptosis in mammalian cells by inhibiting mitochondrial RNA-polymerase. AB - MccJ25, an antimicrobial peptide, was unable to cause apoptosis of COS-7 cells in spite of inducing reactive-oxygen species overproduction as well as cytochrome c release from isolated mitochondria. Surprisingly, MccJ25-Ga, an amidated variant of MccJ25 that displays similar anti-mitochondrial effects, did induce apoptosis in COS-7. The only difference found between the activities of these peptides was the unpredicted inhibition of mitochondrial RNA synthesis by MccJ25-Ga. These results led us to hypothesize that both mitochondrial RNA polymerase and mitochondrial membrane might be the molecular targets of MccJ25-Ga in mitochondria and this combined effect may lead to apoptosis. PMID- 21256174 TI - Loss of the glutamate transporter splice-variant GLT-1b in inferior colliculus and its prevention by ceftriaxone in thiamine deficiency. AB - Downregulation of astrocytic glutamate transporters is a feature of thiamine deficiency (TD), the underlying cause of Wernicke's encephalopathy, and plays a major role in its pathophysiology. Recent investigations suggest that ceftriaxone, a beta-lactam antibiotic, stimulates GLT-1 expression and confers neuroprotection against ischemic and motor neuron degeneration. Thus, ceftriaxone treatment may be a protective strategy against excitotoxic conditions. In the present study, we examined the effects of ceftriaxone on the glutamate transporter splice-variant GLT-1b in rats with TD and in cultured astrocytes under TD conditions. Our results indicate that ceftriaxone protects against loss of GLT-1b levels in the inferior colliculus during TD, but with no significant effect in the thalamus and frontal cortex by immunoblotting and immunohistochemistry. Ceftriaxone also normalized the loss of GLT-1b in astrocyte cultures under conditions of TD. These results suggest that ceftriaxone has the ability to increase GLT-1b levels in astrocytes during TD, and may be an important pharmacological strategy for the treatment of excitotoxicity in this disorder. PMID- 21256175 TI - Arginine-vasopressin V1a receptor inhibition improves neurologic outcomes following an intracerebral hemorrhagic brain injury. AB - Cerebral edema is a devastating consequence of brain injury leading to cerebral blood flow compromise and worsening parenchyma damage. In the present study, we investigated the effects of arginine-vasopressin (AVP) V(1a) receptor inhibition following an intracerebral hemorrhagic (ICH) brain injury in mice and closely assessed the role it played in cerebral edema formation, neurobehavioral functioning, and blood-brain-barrier (BBB) disruption. To support our investigation, SR49059, an AVP V(1a) receptor competitive antagonist, and NC1900, an arginine-vasopressin analogue, were used. Male CD1 mice (n=205) were randomly assigned to the following groups: naive, sham, ICH, ICH with SR49059 at 0.5 mg/kg, ICH with SR49059 at 2mg/kg, ICH with NC1900 at 1 ng/kg, ICH with NC1900 at 10 ng/kg, and ICH with a combination of SR49059 at 2 mg/kg and NC1900 at 10 ng/kg. ICH was induced by using the collagenase injection model and treatment was given 1h after surgery. Post assessment was conducted at 6, 12, 24, and 72 h after surgery and included brain water content, neurobehavioral testing, Evans Blue assay, western blotting, and hemoglobin assay. The study found that inhibition of the AVP V(1a) receptor significantly reduced cerebral edema at 24 and 72 h post-ICH injury and improved neurobehavioral function while reducing BBB disruption at 72 h. Western blot analysis demonstrated increased protein expression of aquaporin 4 (AQP4) in vehicle, which was reduced with AVP V(1a) receptor inhibition. Our study suggests that blockage of the AVP V(1a) receptor, is a promising treatment target for improving ICH-induced brain injury. Further studies will be needed to confirm this relationship and determine future clinical direction. PMID- 21256176 TI - Weight gain and ghrelin level after olanzapine monotherapy. AB - BACKGROUND: The present study aimed to explore the association between weight gain and ghrelin among schizophrenic patients under olanzapine treatment. The relationships among weight gain and adiponectin, fasting glucose, and lipid profile were also investigated. METHODS: This case-control study recruited 66 schizophrenic patients from the Chung Shan Medical University Hospital in central Taiwan. All of them were undergoing olanzapine monotherapy and were categorized into weight gain (WG) and non-weight gain (NWG) groups. Subjects in the control group (CG) were recruited from a healthy community population based on a health survey (n=119). Multivariate logistic regression was used to explore the association of ghrelin with weight gain. RESULTS: The 66 schizophrenic patients had a mean age of 36.3+/-9.6 years, with 50% females. They received olanzapine treatment for a mean period of 8.3+/-7.5 years. The control group had a mean age of 38.9+/-9.3 years and 52.9% were females. Comparing fasting serum ghrelin levels, the WG group had the lowest mean value (822.3+/-253.1 pg/ml) while the control group had the highest mean value (1261.2+/-1639.7 pg/ml), with a significant difference between the two (p=0.01). In contrast, there was no difference in adiponectin levels among the three groups. The WG and NWG groups had higher diastolic blood pressure than the control group, but systolic blood pressure was the same in all three groups. There was no difference in the total cholesterol level although the WG and NWG groups had higher triglyceride (TG) and glucose levels than the control group. CONCLUSIONS: Weight gain after olanzapine treatment is associated with lower ghrelin level. Olanzapine is linked to elevated diastolic pressure, TG, and glucose, regardless of the weight gain. PMID- 21256177 TI - Serum haptoglobin levels in patients with melancholic and nonmelancholic major depression. AB - BACKGROUND: Major depression (MD) is accompanied by systemic immune activation or an inflammatory response with the involvement of phagocytic cells, T cell activation, B cell proliferation, and an acute phase response with increased levels of positive and decreased levels of negative acute-phase proteins. In this study, we aimed to determine any differences in serum haptoglobin (Hp) concentrations among patients with melancholic and nonmelancholic MD and the healthy controls. METHODS: This study involved 125 male patients who were admitted to the Department of Psychiatry, Gulhane Military Medical Academy (GMMA), in Ankara, Turkey. They were diagnosed with MD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and agreed to participate in the study. The melancholic group consisted of 37 patients and the nonmelancholic group had 45 patients. A healthy control group of 40 subjects was selected from the staff of GMMA. These subjects had not had any lifetime psychiatric diagnosis or psychiatric treatment in their medical histories. Peripheral venous blood samples were obtained from the patients and the control group for a complete blood count, routine biochemistry, and the detection of serum Hp levels. RESULTS: There was no statistically significant difference among the melancholic MD, the nonmelancholic MD, and the healthy control groups in terms of age, level of education, and gender. Serum Hp concentrations are significantly higher in melancholic patients as compared with non-melancholic depressed patients and controls. However, there was no statistically significant difference between the nonmelancholic MD and the control group in terms of Hp concentrations. CONCLUSION: The results of this study are important in terms of showing different serum Hp concentrations in patients with melancholic and nonmelancholic MD. PMID- 21256178 TI - Association study between Disrupted-in-Schizophrenia-1 (DISC1) and Japanese patients with treatment-resistant schizophrenia (TRS). AB - Treating the 20-30% of patients with schizophrenia whose symptoms are resistant to antipsychotic treatment, a condition known as treatment-resistant schizophrenia (TRS), can be problematic. Recently, an association between Disrupted-in-Schizophrenia-1 (DISC1), a candidate susceptibility gene for schizophrenia, and TRS was reported. Associations between three missense SNPs, rs3738401 (Q264R), rs6675281 (L607F), and rs821616 (S704C) in DISC1, especially rs3738401, showed strong significance. Thus, the main aim of our current study was to examine if the reported possible functional polymorphisms in DISC1 were related to Japanese TRS. First, DISC1 was re-investigated in 485 Japanese patients with schizophrenia and 660 healthy controls with a case-control study using four candidate SNPs, rs751229, rs3738401, rs821597, and rs821616. DISC1 was not associated with schizophrenia in the Japanese population. Second, we investigated whether these SNPs contributed to TRS in 127 inpatients with schizophrenia (35 patients; TRS and 92 patients; non-TRS). The genotypic distributions of these four SNPs were not significantly different between TRS and non-TRS in either genotypic or recessive models of minor alleles. In addition, clinical variables, such as improvement in clinical symptoms, duration of hospitalization, and total antipsychotics dose amounts, were not different among the genotypes of these SNPs. Taken together, results showed that DISC1 had no apparent degree of association with Japanese patients with schizophrenia as a candidate susceptibility gene for disease per se or TRS. PMID- 21256179 TI - Acetyl-l-Carnitine in the treatment of anhedonia, melancholic and negative symptoms in alcohol dependent subjects. AB - OBJECTIVE: Aim of this randomized, double-blind, placebo-controlled study was to evaluate the efficacy of Acetyl-l-Carnitine (ALC), at different dosages, on specific anhedonic symptoms in detoxified alcohol dependent subjects. Secondary endpoints were the effect of ALC on melancholic and negative symptoms. METHOD: Sixty-four anhedonic alcohol dependent patients with minor or absent withdrawal symptoms were randomized: 23 received ALC at a dosage of 3g/day, 21 received ALC at a dosage of 1g/day, and 20 were given placebo. ALC was given intravenously for 10days, followed by 80days of oral treatment plus a follow-up period of 45days. The presence of anhedonic symptoms was determined by the SHAPS (Snaith-Hamilton Pleasure Scale) and the VASa (Visual Analogue Scale for Anhedonia); negative and melancholic symptoms were evaluated by the SANS (Scale for the Assessment of Negative Symptoms), and the BRMS (Bech-Rafaelsen Melancholia Scale). RESULTS: The natural course of anhedonia in the placebo group showed a decline until day 30 and remains stable for the rest of the study. Intravenously ALC accelerated the improvement of anhedonia reaching constant low levels early, on day 10. At this step levels of anhedonia (SHAPS, VASa) and melancholic symptoms (BRMES) resulted significantly reduced (p<0.05) in both the ALC 3g and ALC 1g groups with respect to placebo; SANS scores significantly reduced only in the ALC 1g respect to placebo (p=0.014). During oral treatment with ALC, anhedonia scores did not differ from placebo. CONCLUSION: Intravenously ALC was effective in accelerating the abstinence-associated improvement of anhedonia, melancholic and negative symptoms, whereas oral ALC treatment starting on day 10 showed no further improvements. Accordingly, in alcohol dependent subjects, ALC may be considered as a new potentially useful drug for the treatment of anhedonia. PMID- 21256180 TI - Comparison of different finishing/polishing systems on surface roughness and gloss of resin composites. AB - OBJECTIVES: The aim of this study was to compare four finishing/polishing systems (F/P) on surface roughness and gloss of different resin composites. METHODS: A total of 40 disc samples (15 mm * 3 mm) were prepared from a nanofill - Filtek Supreme Plus (FS) and a micro-hybrid resin composite - Esthet-X (EX). Following 24h storage in 37 degrees C water, the top surfaces of each sample were roughened using 120-grit sandpaper. Baseline measurements of surface roughness (Ra, MUm) and gloss were recorded. Each composite group was divided into four F/P disk groups: Astropol[AP], Enhance/PoGo[EP], Sof-Lex[SL], and an experimental disk system, EXL-695[EXL] (n=5). The same operator finished/polished all samples. One sample from each group was evaluated under SEM. Another blinded-operator conducted postoperative measurements. Results were analysed by two-way ANOVA, two interactive MANOVA and Tukey's t-test (p<0.05). RESULTS: In surface roughness, the baseline of two composites differed significantly from each other whereas postoperatively there was no significance. The Sof-Lex F/P system provided the smoothest surface although there were no statistical significance differences between F/P systems (p>0.01). In gloss, FS composite with the EXL-695 system provided a significantly higher gloss (p<0.01). EX treated by Soflex revealed the least gloss (p<0.05). SEM images revealed comparable results for F/P systems but EX surfaces included more air pockets. CONCLUSIONS: Four different finishing/polishing systems provided comparable surface smoothness for both composites, whereas EXL with FS provided significantly higher gloss. SEM evaluations revealed that the EX surface contained more air pockets but F/P systems were compatible. PMID- 21256181 TI - Regulation of inducible nitric oxide synthase expression in bovine ovarian granulosa cells. AB - Nitric oxide (NO) is a potential regulator of ovarian follicle growth, and ovarian granulosa cells reportedly generate NO in response to gonadotrophins, suggesting that the regulated form of nitric oxide synthase (iNOS) is present. The objectives of the present study were to gain insight into the expression and role of iNOS in the follicle. Messenger RNA encoding iNOS was detected in granulosa cells, and abundance was higher in growing dominant follicles compared to subordinate follicles (P<0.01). FSH (P<0.05) and IGF1 (P<0.01) stimulated oestradiol secretion and iNOS mRNA abundance in granulosa cells in vitro, whereas FGF2 (P<0.05) and EGF (P<0.01) decreased oestradiol secretion and iNOS expression. The addition of an anti-oestrogen prevented FSH-induced iNOS mRNA accumulation. Inhibition of endogenous NO production did not affect steroidogenesis in granulosa cells, but increased FasL mRNA abundance, caspase-3 activation and the incidence of apoptotic cell death (P<0.05). These results demonstrate that iNOS is expressed in ruminant granulosa cells and is regulated by gonadotrophins and oestradiol. Physiological levels of NO may contribute to the survival of granulosa cells. PMID- 21256182 TI - Regulation of Sertoli cell activin A and inhibin B by tumour necrosis factor alpha and interleukin 1alpha: interaction with follicle-stimulating hormone/adenosine 3',5'-cyclic phosphate signalling. AB - Regulation of crucial events during spermatogenesis involves dynamic changes in cytokine production and interactions across the cycle of the seminiferous epithelium. Regulation of activin A and inhibin B production by the inflammatory cytokines, tumour necrosis factor alpha (TNFalpha) and interleukin 1alpha (IL1alpha), alone and in conjunction with FSH or a cAMP analogue (dibutyryl cAMP), was examined in cultures of Sertoli cells from 20-day old rats. Both TNFalpha and IL1alpha stimulated activin A secretion and expression of its subunit (beta(A)) mRNA, and suppressed inhibin B secretion and expression of its subunit (alpha and beta(B)) mRNAs. The actions of TNFalpha and IL1alpha were opposed by FSH and dibutyryl cAMP. Both cytokines inhibited FSH/dibutyryl cAMP stimulated inhibin B secretion and mRNA expression as well as stem cell factor mRNA expression. Both cytokines also inhibited FSH-induced cAMP production, and reduced baseline FSH receptor mRNA expression. These data highlight the reciprocal relationship that exists between FSH/cAMP signalling and inflammatory cytokine signalling pathways in the control of Sertoli cell function, and production of activin A/inhibin B in particular. It is anticipated that these interactions play important roles in the fine control of events during the cycle of the seminiferous epithelium and in the inhibition of spermatogenesis during inflammation. PMID- 21256183 TI - Stage-specific regulation of juvenile hormone biosynthesis by ecdysteroid in Bombyx mori. AB - In the penultimate (4th) instar larvae of Bombyx mori, juvenile hormone (JH) synthesis by corpora allata (CA) fluctuates. When diet containing 20 hydroxyecdysone (20E) was fed, JH synthetic activity of the CA was first stimulated as the ecdysteroid titer increased, then suppressed slightly by the higher molting concentration of ecdysteroids (>250 ng/ml). The overall JH biosynthetic activity was modulated by the expression of JH biosynthetic enzymes in the CA: primarily JH acid O-methyltransferase (JHAMT), isopentenyl diphosphate isomerase, and farnesyl diphosphate synthase 1. After the last (5th) larval ecdysis, the artificially increased high ecdysteroid level due to the 20E diet activated JH synthesis by the CA, which required intact nervous connections with the brain. A factor(s) from the 20E-activated brain controls mainly JHAMT and HMG Co-A reductase expression to stimulate the JH synthesis. In the normal last instar larvae, the ecdysteroid titer declines so that these activation mechanisms are absent; therefore the decline of the ecdysteroid titer after the final larval ecdysis is one of the factors which induces the cessation of the JH synthesis by CA. PMID- 21256184 TI - Effects of optimized-SopungSunkiwon on memory impairment and enhancement. AB - Optimized-SopungSunkiwon (OSS) is a multi-herbal formula that contains six medicinal herbs from SopungSunkiwon, a traditional medicine used for neurodegenerative disorders. In this study, we investigated the anti-amnesic effects of OSS in a dementia model. Acetylcholinesterase (AChE) inhibition assay was performed to investigate the cholinergic antagonistic effect of OSS. In addition, a step-through passive-avoidance test was performed with scopolamine induced memory impairment in mice, and immunohistochemistry was analyzed to investigate synaptic formation with synaptic proteins. OSS inhibited AChE activity, resulting in significant improvement of memory functions. In the passive-avoidance test, the latency time of OSS-treated mice was significantly longer than that of either the control or scopolamine-treated group. In the immunohistochemical analysis, synaptic proteins such as synaptophysin and PSD-95 were significantly increased in OSS-treated mice. These results demonstrate that OSS may affect impairment and enhancement of memory and increase synaptophysin and PSD-95 facilitating acetylcholine release and synaptic growth. PMID- 21256185 TI - Impaired dopamine release and uptake in R6/1 Huntington's disease model mice. AB - Huntington's disease (HD) is a progressive, neurodegenerative movement disorder. Here, we used fast-scan cyclic voltammetry to measure dopamine release and uptake in striatal brain slices from R6/1 HD model mice. Peak dopamine release ([DA](max)) was significantly diminished in R6/1 mice (52% of wild-type at 24 weeks of age). Similarly, dopamine released per locally applied electrical stimulus pulse ([DA](p)), which is [DA](max) corrected for uptake and electrode performance, was also diminished in R6/1 mice (43% of wild-type by 24 weeks of age). Moreover, V(max), the maximum rate of dopamine uptake, obtained by modeling the stimulated release plots, was decreased at 16 and 24 weeks of age in R6/1 mice (51 and 48% of wild-type, respectively). Thus, impairments in both dopamine release and uptake appear to progress in an age-dependent manner in R6/1 mice. PMID- 21256186 TI - Brain activity associated with recognition of appropriate action selection based on allocentric perspectives. AB - We investigated brain activity associated with recognition of appropriate action selection based on allocentric perspectives using functional magnetic resonance imaging. The participants observed video clips in which one person (responder) passed one of three objects after a request by a second person (requester). The requester was unable to see one of the three objects because it was occluded by another object. Participants were asked to judge the appropriateness of the responder's action selection based on the visual information from the requester's perspective (i.e., allocentric perspective), not the responder's perspective (i.e., egocentric perspective). The experimental factors included the congruency of request interpretation and the appropriateness of action selection. The results showed that brain regions including the right temporo-parieto-occipital (TPO) junction and the left inferior parietal lobule (IPL) were more activated when the interpretation of the requested object differed between the egocentric and allocentric perspectives than when it was the same (the effect of incongruency for consistency). On the other hand, greater activation was found in the right dorsolateral prefrontal cortex (DLPFC) when the incongruency effect was compared only between the conditions of appropriate action selection (the interaction effect). These results suggest that both the TPO junction and IPL are involved in obtaining visual information from the allocentric perspective when visual information based on only the egocentric perspective is insufficient to interpret another person's request. The right DLPFC is likely related to this process to override the interference of action selection based on the egocentric perspective. PMID- 21256187 TI - Dissociation between visual line bisection and mental number line bisection in schizophrenia. AB - Many studies of hemispatial neglect patients have indicated that spatial attention processes operate similarly in visual space and number space. However, some studies have indicated a dissociation of processing between visual line bisection and mental number bisection. A number of investigations have suggested that schizophrenic patients show a mild right pseudo-neglect on visual line bisection tasks. The present study was designed to determine if a functional link exists between performance of visual line and number line bisection in schizophrenic patients. Groups of 40 schizophrenic patients and 40 controls performed each bisection task. In the visual line bisection task, schizophrenic patients showed a significant leftward bias relative to the healthy controls for 9 different line lengths. No significant difference in bias was found between the 2 groups on the mental line bisection task. These results indicated that schizophrenic patients may exhibit attention deficit with respect to visual space but not number space, suggestive of the dissociation of processing between visual line bisection and mental number line bisection. These results provide more insight into the correlation between the visual line and number bisection tasks in schizophrenic patients. PMID- 21256188 TI - Adjuvant System AS03 containing alpha-tocopherol modulates innate immune response and leads to improved adaptive immunity. AB - AS03 is an Adjuvant System (AS) containing alpha-tocopherol and squalene in an oil-in-water (o/w) emulsion. AS03 has been considered for the development of pandemic and seasonal influenza vaccines. Key features of AS03's mode of action were investigated in vivo in mice and ex vivo in human cells. AS03's adjuvant activity was superior to that of aluminium hydroxide and required the spatio temporal co-localisation of AS03 with the antigen. This requirement coincided with AS03 triggering a transient production of cytokines at the injection site and in the draining lymph nodes (dLNs). The nature of the cytokines produced was consistent with the enhanced recruitment of granulocytes and of antigen-loaded monocytes in the dLNs. The presence of alpha-tocopherol in AS03 was required for AS03 to achieve the highest antibody response. The presence of alpha-tocopherol also modulated the expression of some cytokines, including CCL2, CCL3, IL-6, CSF3 and CXCL1; increased the antigen loading in monocytes; and increased the recruitment of granulocytes in the dLNs. Hence, AS03's promotion of monocytes as the principal antigen-presenting cells, and its effects on granulocytes and cytokines, may all contribute to enhancing the antigen-specific adaptive immune response. PMID- 21256189 TI - Ag85B-ESAT-6 adjuvanted with IC31(r) promotes strong and long-lived Mycobacterium tuberculosis specific T cell responses in volunteers with previous BCG vaccination or tuberculosis infection. AB - New TB vaccines are urgently needed because of the apparent lack of effect of the BCG vaccine on rates of adult contagious pulmonary tuberculosis and the risk of disseminated BCG disease in immunocompromised individuals. Since BCG appears to protect children, the primary target for vaccine development is a booster vaccine for adults but such vaccines ideally need to be able to efficiently prime mycobacterially naive individuals as well as boost individuals previously vaccinated with BCG and those latently infected with TB. Protective immunity against Mycobacterium tuberculosis depends mainly on the generation of a Th1-type cellular immune response characterized by interferon-gamma (IFN-gamma) production. In the present study, we monitored safety and IFN-gamma responses in healthy BCG-vaccinated and prior or latently TB-infected individuals receiving a novel vaccine composed of the fusion protein Ag85B-ESAT-6 combined with the adjuvant IC31((r)), administered at 0 and 2 months. Vaccination caused few local or systemic adverse effects besides transient soreness at the injection site, but it elicited strong antigen-specific T cell responses against Ag85B-ESAT-6 and both the Ag85B and ESAT-6 components, that could be augmented by second vaccination. The strong responses persisted through 32 weeks of follow-up, indicating the induction of a persistent memory response in the vaccine recipients. PMID- 21256190 TI - Hypertonicity-enhanced TNF-alpha release from activated human monocytic THP-1 cells requires ERK activation. AB - BACKGROUND: Hypertonic stress enhances tumor necrosis factor (TNF)-alpha expression in activated monocytes. However, the underlying mechanism is unknown. The produced TNF-alpha is primarily cleaved and released by TNF-alpha-converting enzyme (TACE), and the surface expression of TACE is down-regulated by endocytosis. As hypertonicity inhibits endocytosis, we evaluated the mechanism of hypertonicity-induced TNF-alpha release from activated human monocytic THP-1 cells. METHODS: THP-1 cells were stimulated with lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA) in the presence or absence of hypertonic agents (150 mM sucrose or 150-300 mM NaCl). The amount of TNF-alpha mRNA and protein, surface expression of TACE and activation of signaling pathways (mitogen activated protein kinase, Akt and NF-kappaB) were assayed. RESULTS: Hypertonic sucrose and NaCl significantly enhanced TNF-alpha release from THP-1 cells upon LPS or PMA stimulation. Hypertonic sucrose and other endocytosis inhibitors increased surface expression of TACE, but their effects on TNF-alpha release were inconsistent. This enhancement effect by hypertonicity was not attenuated by inhibition of TACE or IkappaB kinase, but it was blocked by cycloheximide and a MAP/ERK kinase inhibitor. The LPS- or PMA-induced TNF-alpha mRNA expression was not increased; rather, it was inhibited by hypertonicity. ERK1/2 was re-activated after sucrose treatment in LPS-stimulated THP-1 cells. CONCLUSIONS: Hypertonicity enhanced TNF-alpha protein synthesis from LPS- or PMA-activated THP-1 cells requires ERK activation and may proceed without TACE. GENERAL SIGNIFICANCE: A vast amount of TNF-alpha production was regulated by a crucial post transcriptional manner in activated human monocytic leukemia cells, and it may possibly be contributed to the cachexia condition. PMID- 21256191 TI - Redox regulation of ERK1/2 activation induced by sphingosine 1-phosphate in fibroblasts: involvement of NADPH oxidase and platelet-derived growth factor receptor. AB - BACKGROUND: Sphingosine 1-phosphate (S1P) is a sphingolipid metabolite synthesized after stimulation with growth factors or cytokines. S1P extracellular effects are mediated through specific Gi-protein coupled receptors (GPCRs). Recently, we demonstrated in NIH3T3 fibroblasts stimulated by platelet-derived growth factor (PDGF) or S1P the NADPH oxidase activation and the H(2)O(2) intracellular level increase trough the Gi protein involvement. METHODS: NIH3T3 fibroblast cell cultures were used. Western blot and quantitative analyses by Chemidoc-Quantity-One software were performed. H(2)O(2) level was assayed by fluorescence spectrophotometric analysis, and cell proliferation by counted manually or ELISA kit. RESULTS: This study demonstrates, in NIH 3T3 fibroblasts, a novel redox regulated mechanism of S1P-induced activation of ERK 1/2 related to NADPH oxidase activity and intracellular H(2)O(2) level increase with PDGF receptor tyrosine kinase involvement through a transactivation mechanism. This event is mediated by S1P(1) and S1P(3) receptors by Gi proteins and can contribute to S1P mitogenic signaling. CONCLUSION: These results can be related to mechanisms of cross-talk previously identified between receptor tyrosine kinase, including PDGFreceptor, and several GPCR ligands. GENERAL SIGNIFICANCE: The redox-sensitive ERK1/2 and PDGFr tyrosine kinase activity could be targets for therapies in diseases in which deregulation of intracellular oxidative status and the consequent alteration of S1P and/or PDGF signaling pathway are involved. PMID- 21256192 TI - Context-specific social behavior is altered by orbitofrontal cortex lesions in adult rhesus macaques. AB - Although the orbitofrontal cortex has been implicated in important aspects of social behavior, few studies have evaluated semi-naturalistic social behavior in nonhuman primates after discrete lesions of this cortical area. In the present report, we evaluated the behavior of adult rhesus monkeys during dyadic social interactions with novel animals following discrete lesions of the orbitofrontal cortex. In a constrained condition, in which animals could engage in only restricted social behaviors, there were no significant differences in social behavior between the lesion group and the sham-operated control group. When the experimental animals could freely interact with partner animals, however, lesioned animals differed from control animals in terms of social interest and fear-related behaviors. These alterations were contingent on the partner with which they interacted. The lesioned animals, when compared to the control animals, had a significantly greater propensity to approach some but not all of their social partners. They also grimaced more towards the partner animal that they did not approach. Behavioral alterations were more apparent during the initial interactions between animals. We discuss these findings in relation to the role of the orbitofrontal cortex in context dependent modulation of social behavior. PMID- 21256193 TI - N-methyl-D-aspartate receptor subunit composition in the rat trigeminal principal nucleus remains constant during postnatal development and following neonatal denervation. AB - N-methyl-D-aspartate receptors (NMDARs) play a major role in various forms of developmental and adult synaptic plasticity (Lopez de Armentia M, Sah P (2003) J Neurosci 23:6876-6883). Activity-dependent shifts in NR2 subunits of the NMDARs have been proposed to be the molecular basis of critical period plasticity. Several supporting examples have been reported; however it is not clear whether the relationship between NMDAR subunit changes and neural plasticity are correlative or causal, nor whether such a relationship is universal across all sensory pathways with developmental plasticity. In the present study, we used voltage-clamp recording techniques to investigate whether subunit composition of NMDARs changes during development and after neonatal denervation in the principal sensory nucleus (PrV) of the trigeminal nerve. Relative AMPA receptor contribution to synaptic transmission increased linearly by the second postnatal week in the normal PrV. Denervation by peripheral nerve damage did not alter this process. We took the weighted decay time constant (tauw) of NMDAR-mediated EPSCs as an index for NMDAR subunit composition. The tauw measurement and Western blot analysis revealed that NMDARs contained both NR2A and NR2B subunits. The NR2A/NR2B ratio did not change during postnatal development or after neonatal denervation. Thus, critical period plasticity-related pattern formation in the PrV does not depend on changes in subunit composition of NMDARs. The mechanism underlying developmental synaptic plasticity in the PrV differs from those in higher trigeminal centers and other brain structures. PMID- 21256194 TI - Selectively diminished corpus callosum fibers in congenital central hypoventilation syndrome. AB - Congenital central hypoventilation syndrome (CCHS), a condition associated with mutations in the PHOX2B gene, is characterized by loss of breathing drive during sleep, insensitivity to CO2 and O2, and multiple somatomotor, autonomic, neuropsychological, and ophthalmologic deficits, including impaired intrinsic and extrinsic eye muscle control. Brain structural studies show injury in peri callosal regions and the corpus callosum (CC), which has the potential to affect functions disturbed in the syndrome; however, the extent of CC injury in CCHS is unclear. Diffusion tensor imaging (DTI)-based fiber tractography procedures display fiber directional information and allow quantification of fiber integrity. We performed DTI in 13 CCHS children (age, 18.2+/-4.7 years; eight male) and 31 control (17.4+/-4.9 years; 18 male) subjects using a 3.0-Tesla magnetic resonance imaging scanner; CC fibers were assessed globally and regionally with tractography procedures, and fiber counts and densities compared between groups using analysis-of-covariance (covariates; age and sex). Global CC evaluation showed reduced fiber counts and densities in CCHS over control subjects (CCHS vs. controls; fiber-counts, 4490+/-854 vs. 5232+/-777, P<0.001; fiber-density, 10.0+/-1.5 vs. 10.8+/-0.9 fibers/mm2, P<0.020), and regional examination revealed that these changes are localized to callosal axons projecting to prefrontal (217+/-47 vs. 248+/-32, P<0.005), premotor (201+/-51 vs. 241+/-47, P<0.012), parietal (179+/-64 vs. 238+/-54, P<0.002), and occipital regions (363+/-46 vs. 431+/-82, P<0.004). Corpus callosum fibers in CCHS are compromised in motor, cognitive, speech, and ophthalmologic regulatory areas. The mechanisms of fiber injury are unclear, but may result from hypoxia or perfusion deficits accompanying the syndrome, or from consequences of PHOX2B action. PMID- 21256195 TI - Laminar-specific and developmental expression of aquaporin-4 in the mouse hippocampus. AB - Mice deficient in the water channel aquaporin-4 (AQP4) demonstrate increased seizure duration in response to hippocampal stimulation as well as impaired extracellular K+ clearance. However, the expression of AQP4 in the hippocampus is not well described. In this study, we investigated (i) the developmental, laminar and cell-type specificity of AQP4 expression in the hippocampus; (ii) the effect of Kir4.1 deletion on AQP4 expression; and (iii) performed Western blot and RT PCR analyses. AQP4 immunohistochemistry on coronal sections from wild-type (WT) or Kir4.1-/- mice revealed a developmentally-regulated and laminar-specific pattern, with highest expression in the CA1 stratum lacunosum-moleculare (SLM) and the molecular layer (ML) of the dentate gyrus (DG). AQP4 was colocalized with the glial markers glial fibrillary acidic protein (GFAP) and S100beta in the hippocampus, and was also ubiquitously expressed on astrocytic endfeet around blood vessels. No difference in AQP4 immunoreactivity was observed in Kir4.1-/- mice. Electrophysiological and postrecording RT-PCR analyses of individual cells revealed that AQP4 and Kir4.1 were co-expressed in nearly all CA1 astrocytes. In NG2 cells, AQP4 was also expressed at the transcript level. This study is the first to examine subregional AQP4 expression during development of the hippocampus. The strikingly high expression of AQP4 in the CA1 SLM and DG ML identifies these regions as potential sites of astrocytic K+ and H2O regulation. These results begin to delineate the functional capabilities of hippocampal subregions and cell types for K+ and H2O homeostasis, which is critical to excitability and serves as a potential target for modulation in diverse diseases. PMID- 21256196 TI - Methamphetamine-sensitized mice are accompanied by memory impairment and reduction of N-methyl-d-aspartate receptor ligand binding in the prefrontal cortex and hippocampus. AB - The aim of the present study was to investigate a causal relationship between low dose methamphetamine-induced (METH; 2 mg/kg, i.p. once every other day for 7 days) behavioral sensitization and memory function. We first investigated the spatial working memory (short-term memory) and long-term memory in mice behaviorally sensitized by repeated METH treatments. We also assessed changes in NMDA receptor binding in METH-treated mice. Acute METH administration induces hyperlocomotion but do not induce memory impairment of changes in NMDA receptor binding. However, repeated METH treatment in mice produced behavioral sensitization and showed memory impairment and a decrease in NMDA receptor binding in the prefrontal cortex, as well as in the CA1, CA2, and CA3 regions of the hippocampus. These results suggest that repeated METH-induced behavioral sensitization may be accompanied by memory impairment, characterized by decreased NMDA receptor binding in the prefrontal cortex and hippocampus. Our study shows clearly that repeated but not acute low dose METH treatment induces memory impairment in mice and the possible mechanism involves reduction of NMDA receptor binding in specific brain regions associated with learning and memory. PMID- 21256197 TI - Endocannabinoid 2-arachidonoylglycerol protects neurons against beta-amyloid insults. AB - While endocannabinoid modulation of both GABAergic and glutamatergic synaptic transmission and plasticity has been extensively investigated, our understanding of the role of endocannabinoids in protecting neurons from harmful insults remains limited. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous ligand and a full agonist for cannabinoid receptors, exhibits anti-inflammatory and neuroprotective effects via a CB1 receptor (CB1R)-mediated mechanism. However, it is still not clear whether 2-AG is also able to protect neurons from beta-amyloid (Abeta)-induced neurodegeneration. Here, we demonstrate that exogenous application of 2-AG significantly protected hippocampal neurons in culture against Abeta-induced neurodegeneration and apoptosis. This neuroprotective effect was blocked by SR141716 (SR-1), a selective CB1R antagonist, but not by SR144528 (SR-2), a selective CB2R antagonist, or capsazepine (CAP), a selective transient receptor potential cation channels, subfamily V, member 1 (TRPV1) receptor antagonist. To determine whether endogenous 2-AG is capable of protecting neurons from Abeta insults, hippocampal neurons in culture were treated with URB602 or JZL184, selective inhibitors of monoacylglycerol lipase (MAGL), the enzyme hydrolyzing 2-AG. MAGL inhibition that elevates endogenous levels of 2-AG also significantly reduced Abeta-induced neurodegeneration and apoptosis. The 2-AG-produced neuroprotective effects appear to be mediated via CB1R-dependent suppression of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and nuclear factor-kappaB (NF-kappaB) phosphorylation and cyclooxygenase-2 (COX-2) expression. Our results suggest that elevation of endogenous 2-AG by inhibiting its hydrolysis has potential as a novel efficacious therapeutic approach for preventing, ameliorating or treating Alzheimer's disease. PMID- 21256198 TI - The maturation of photoreceptors in the avian retina is stimulated by thyroid hormone. AB - During retinal development, the cell-fate of photoreceptors is committed long before maturation, which entails the expression of opsins and functional transduction of light. The mechanisms that delay the maturation of photoreceptors remain unknown. We have recently reported that immature photoreceptors express the LIM domain transcription factors Islet2 and Lim3, as well as the cell-surface glycoprotein axonin1 [Fischer et al., (2008a) J Comp Neurol 506:584-603]. As the photoreceptors mature to form outer segments and express photopigments, the expression of the Islet2, Lim3 and axonin1 is diminished. The purpose of this study was to investigate whether thyroid hormone (TH) influences the maturation of photoreceptors. We studied the maturation of photoreceptors across the gradient of maturity that exists in far peripheral regions of the post-natal chicken retina [Ghai et al., (2008) Brain Res 1192:76-89]. We found that intraocular injections of TH down-regulated Islet2, Lim3 and axonin1 in photoreceptors in far peripheral regions of the retina. By contrast, TH stimulated the up-regulation of red-green opsin, violet opsin, rhodopsin and calbindin in photoreceptors. We found a correlation between the onset of RLIM (RING finger LIM-domain binding protein) and down-regulation of Islet2 and Lim3 in maturing photoreceptors; RLIM is known to interfere with the transcriptional activity of LIM-domain transcription factors. We conclude that TH stimulates the maturation of photoreceptors in the avian retina. We propose that TH inhibits the expression of Islet2 and Lim3, which thereby permits photoreceptor maturation and the onset of photopigment-expression. PMID- 21256199 TI - Growth hormone improves hippocampal adult cell survival and counteracts the inhibitory effect of prolonged sleep deprivation on cell proliferation. AB - Sleep deprivation (SD) produces numerous deleterious changes in brain cells, including apoptosis. It has been demonstrated that growth hormone (GH) stimulates cell growth and counteracts apoptosis, although this anti-apoptotic effect has not been tested against SD. To determine the protective effect of GH administration on cell proliferation and survival in the dentate gyrus (DG) of the hippocampus after sleep deprivation; we injected Wistar adult rats with a low dose of recombinant human GH (rhGH 5 ng/kg) per seven days and then we gently sleep deprived the animals for 48 consecutive hours. 5-Bromodeoxiuridine (BrdU) was administered to assess cell proliferation after the GH treatment and NeuN was used as marker of cell fate. Our results indicate that GH produced a three fold increase in the number of BrdU positive cells within the DG [Control = 1044 +/- 106.38 cells, rhGH = 2952 +/- 99.84 cells, P<0.01]. In contrast, 48 h of SD significantly reduced cell proliferation but this effect was antagonized by the GH administration [SD = 540 +/- 18.3 cells, rhGH + SD = 1116 +/- 84.48 cells, P<0.004]. Paradoxically, SD and GH administration increased cell survival separately but no significantly compared with control animals. However, cell survival was increased in animals treated with rhGH+SD compared to rats injected with saline solution [P<0.04]. Within the survival cells, the percentage of neurons was higher in SD animals [95%] compared with saline group, while this percentage (NeuN positive cells) was increased in animals treated with rhGH+SD [120%] compared with rhGH [25%] alone. Our findings indicate that GH strongly promotes cell proliferation in the adult brain and also protects the hippocampal neuronal precursors against the deleterious effect of prolonged sleep loss. PMID- 21256201 TI - Comparative analyses of the Moraxella catarrhalis type-IV pilus structural subunit PilA. AB - Moraxella catarrhalis is a Gram-negative aerobic diplococcus that is a mucosal pathogen of the upper and lower respiratory tracts in humans. In order to colonize the human host and establish an infection, M. catarrhalis must be able to effectively attach to the respiratory mucosal epithelia. Although little is known about M. catarrhalis pathogenesis, our laboratory has previously shown that expression of type IV pili (TFP) contributes to mucosal colonization. TFP are filamentous surface appendages primarily composed of a single protein subunit termed pilin, which is encoded by pilA in M. catarrhalis. These surface structures play a crucial role in the initiation of disease by a wide range of pathogenic bacteria. Our studies also indicate that unlike the pilin of the pathogenic Neisseria species, which exhibit both phase and antigenic variation, the pilin subunit of M. catarrhalis appears to be more highly conserved as there are no major pilin variants produced by a single strain and only two major PilA antigenic variants, termed clade 1 and clade 2, have been observed between strains. Moreover, we have determined that these highly conserved bacterial surface structures are expressed by all M. catarrhalis clinical isolates evaluated. Therapeutic or vaccine-based interventions that prevent or diminish nasopharyngeal colonization will likely decrease acute and recurrent M. catarrhalis infections in prone populations. Thus, our data indicate that additional studies aimed at elucidating the role of PilA in the pathogenesis and host response to M. catarrhalis infections are warranted. PMID- 21256200 TI - High content imaging-based assay to classify estrogen receptor-alpha ligands based on defined mechanistic outcomes. AB - Estrogen receptor-alpha (ER) is an important target both for therapeutic compounds and endocrine disrupting chemicals (EDCs); however, the mechanisms involved in chemical modulation of regulating ER transcriptional activity are inadequately understood. Here, we report the development of a high content analysis-based assay to describe ER activity that uniquely exploits a microscopically visible multi-copy integration of an ER-regulated promoter. Through automated single-cell analyses, we simultaneously quantified promoter occupancy, recruitment of transcriptional cofactors and large-scale chromatin changes in response to a panel of ER ligands and EDCs. Image-derived multi parametric data was used to classify a panel of ligand responses at high resolution. We propose this system as a novel technology providing new mechanistic insights into EDC activities in a manner useful for both basic mechanistic studies and drug testing. PMID- 21256202 TI - Toxicokinetics, including saturable protein binding, of 4-chloro-2-methyl phenoxyacetic acid (MCPA) in patients with acute poisoning. AB - Human data on protein binding and dose-dependent changes in toxicokinetics for MCPA are very limited. 128 blood samples were obtained in 49 patients with acute MCPA poisoning and total and unbound concentrations of MCPA were determined. The Scatchard plot was biphasic suggesting protein binding to two sites. The free MCPA concentration increased when the total concentration exceeded 239mg/L (95% confidence interval 198-274mg/L). Nonlinear regression using a two-site binding hyperbola model estimated saturation of the high affinity binding site at 115mg/L (95%CI 0-304). Further analyses using global fitting of serial data and adjusting for the concentration of albumin predicted similar concentrations for saturable binding (184mg/L and 167mg/L, respectively) without narrowing the 95%CI. In 25 patients, the plasma concentration-time curves for both bound and unbound MCPA were approximately log-linear which may suggest first order elimination, although sampling was infrequent so zero order elimination cannot be excluded. Using a cut off concentration of 200mg/L, the half-life of MCPA at higher concentrations was 25.5h (95%CI 15.0-83.0h; n=16 patients) compared to 16.8h (95%CI 13.6-22.2h; n=10 patients) at lower concentrations. MCPA is subject to saturable protein binding but the influence on half-life appears marginal. PMID- 21256203 TI - A novel in vitro pancreatic carcinogenesis model. AB - Environmental factors (e.g., BaP) have been pointed out as one of the etiologies of pancreatic cancer. However, very limited experimental assays are available to identify pancreatic specific environmental mutagens or susceptibility genes. In this study, we have developed a simple in vitro cell culture model system that can be used to study the molecular and biochemical aspects of carcinogenesis in a near-normal immortalized pancreatic ductal epithelial cell lines. In order to demonstrate that xenobiotic stress response is intact in these cells, we employed standard molecular biology techniques. For examples, luciferase reporter and/or real-time quantitative PCR assays were used to determine stress-induced CYP1A1 and CYP1B1 gene expression. Western blotting and immunocytochemistry assays were used to demonstrate that TCDD or BaP could activate AhR signaling. For exploring the carcinogenesis mechanism, we incubated cells with [3H]BaP and determined BaP DNA binding activity by measuring its radioactivity. BaP-DNA adduct formation was further confirmed by [32P]-postlabeling assay. Finally, we demonstrated the effects of endogenous AhR or BRCA1 in BaP-DNA adduct accumulation in our cell system. As results, no apparent BaP-DNA adduct accumulation by [32P]-postlabeling assay was found in either control-siRNA or AhR-siRNA pretreated cells. On the other hand, a significant increase of BaP-DNA adduct accumulation was found in BRCA1 knockdown cells. In conclusion, we suggest that this in vitro model may provide the feasibility for future studies on the molecular basis of pancreatic ductal cell carcinogenesis caused by dietary mutagens. PMID- 21256204 TI - Cardioprotective effects of aqueous Schizandra chinensis fruit extract on ovariectomized and balloon-induced carotid artery injury rat models: effects on serum lipid profiles and blood pressure. AB - AIM OF THE STUDY: The fruit from Schizandra chinensis, a member of the Magnoliaceae family, has been used to treat menopause-related symptoms. We have previously reported that an aqueous extract of Schizandra chinensis fruit (ScEx) caused vascular relaxation via the production of endothelial nitric oxide. Estrogen-like molecules are known to play a protective role in cardiovascular diseases through several mechanisms, but the cardioprotective effects of ScEx have not been clearly demonstrated. Therefore, we investigated the vasculoprotective effects of ScEx on ovariectomized (OVX) and balloon-induced carotid artery injury rat models. MATERIALS AND METHODS: An aqueous extract of Schizandra chinensis (ScEx) was examined for its cardioprotective effects. To test the arterial response to injury, we applied the balloon-induced carotid artery model to OVX Sprague-Dawley (SD) rats. Rats were subcutaneously administered vehicle, 17beta-estradiol (E2; 0.02 or 0.2mg/kg/day), or ScEx (0.2 or 2.0mg/kg/day) over the course of the study. Vessel morphology was assessed two weeks after injury. To identify the cardioprotective effects after ScEx treatment, we measured serum lipid profiles and blood pressure levels in the OVX- and sham-operated normotensive and spontaneously hypertensive rats (SHR). Serum lipid profiles were measured in OVX rats after five weeks of treatment with vehicle, E2 (0.5mg/kg/day), or ScEx (0.5 or 5.0mg/kg/day). Tail systolic blood pressure in OVX SHR was measured weekly. RESULTS: In the balloon-induced carotid artery injury model, treatment with E2 (0.2mg/kg/day) or ScEx (2.0mg/kg/day) reduced the intimal area and the intima-to-media ratio compared to control animals. Injection of ScEx or E2 reduced body weight gain but did not inhibit the decrease in uterine weight. Treatment with ScEx (5.0mg/kg/day) or E2 (0.5mg/kg/day) in OVX SD rats reduced total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C), and TC-(HDL-C)/HDL-C compared to control animals. In OVX rats, treatment with ScEx or E2 also significantly reduced LDL-C compared with the OVX control rats, and systolic blood pressure was significantly attenuated compared to OVX control and the sham control rats. CONCLUSIONS: ScEx treatment restored endothelial function in rats that underwent balloon-induced carotid artery injury, and it reduced serum cholesterol levels in OVX rats. Similar to E2, ScEx exhibited hypotensive effects in OVX SHR. Therefore, ScEx and E2 exhibited similar cardioprotective effects, thereby suggesting that ScEx is a potential candidate to replace estradiol in the prevention and treatment of cardiovascular diseases. PMID- 21256205 TI - Validation of noninvasive quantification of bone marrow fat volume with microCT in aging rats. AB - Marrow fat infiltration is one of the hallmarks of age-related bone loss. This fat infiltration has been quantified by invasive and noninvasive methods. However, the validity of the noninvasive methods has not been correlated with a gold standard. In this study we aim to validate the usefulness of marrow fat quantification by correlating microCT (MUCT) images with histology analysis. Fat volume (FV) and bone volume (BV) of distal femora of young (4 months) and old (27 months) Louvain/c (LOU) rats (n=22) were quantified by histology and compared with MUCT images analyzed by an image analysis software (SliceOMatic). We found that for SliceOMatic/MUCT the intra-rater reliability for duplicate measurements was 0.94 (p<0.001) and the inter-rater reliability for FV/BV ratio in young and old rats was 98% and 99% respectively. Both methods showed a significant increase (~2 fold) in the FV/BV ratio in the old rats as compared with their young counterparts (p<0.001). A significantly higher correlation (r2=0.85) in the old rats was found between our noninvasive method and histology. Furthermore, our noninvasive method showed good agreement with histology. In conclusion, noninvasive quantification of FV/BV ratio using an image analysis software is as reliable as histology for identifying age related marrow fat changes with high inter and intra-rater reliability. These findings provide a new noninvasive method for quantifying marrow fat, which is useful and can be tested not only in animals but also in human studies. PMID- 21256206 TI - Aflatoxin B1 and fumonisin B1 affect the oxidative status of bovine peripheral blood mononuclear cells. AB - Mycotoxins are secondary metabolites having a high cytotoxic potential. They are produced by molds and released in food and feed. To date, the mechanisms underlying the mycotoxin-induced cytotoxicity have not been fully clarified. The induction of oxidative stress, as a possible mechanism, has been postulated. This in vitro study was focused on the effect of two widely occurring mycotoxins, aflatoxin B(1) (AFB(1)) and fumonisin B(1) (FB(1)), on the oxidative status of bovine peripheral blood mononuclear cells (PBMC) incubated for 2 and 7 days at different levels of AFB(1) (0, 5 and 20 MUg/ml) and FB(1) (0, 35 and 70 MUg/ml). Reactive oxygen metabolites (ROM), intracellular thiols (SH), malondialdehyde (MDA) and gene expression of cytoplasmic superoxide dismutase (SOD) and glutathione peroxidase (GSHPX-1) were measured on PBMC after incubation. The highest concentration of AFB(1) and all concentrations of FB(1) caused an increase (p<0.05) of intracellular ROM without any time dependent effect. Intracellular SH decreased with 20 MUg AFB(1)/ml (p<0.05) and the effect was particularly marked after 7 days of exposure. Intracellular SH were not affected by FB(1) even though a lower (p<0.05) SH level after 2 days exposure than after 7 days was observed. MDA increased (p<0.05) in AFB(1) or FB(1) treated PBMC. The exposure to FB(1) for 7 days increased MDA (p<0.05) only in cells treated with 70 MUg/ml. Exposure of PBMC to AFB(1) reduced SOD mRNA while FB(1) decreased both SOD and GSHPX-1 mRNA abundance. These results demonstrate that, even though by different mechanisms, AFB(1) and FB(1) may induce cytotoxicity through an impairment of the oxidative status of PBMC. PMID- 21256207 TI - A missense mutation in the 20S proteasome beta2 subunit of Great Danes having harlequin coat patterning. AB - Harlequin is a pigmentary trait of the domestic dog that is controlled by two autosomal loci: the melanosomal gene, SILV, and a modifier gene, harlequin (H), previously localized to chromosome 9. Heterozygosity for a retrotransposon insertion in SILV and a mutation in H causes a pattern of black patches on a white background. Homozygosity for H is embryonic lethal. Fine mapping of the harlequin locus revealed a 25 kb interval wherein all harlequin Great Danes are heterozygous for a common haplotype. This region contains one gene, PSMB7, which encodes the beta2 catalytic subunit of the proteasome. Sequence analysis identified a coding variant in exon 2 that segregates with harlequin patterning. The substitution predicts the replacement of a highly conserved valine with a glycine. Described herein is the identification of a naturally-occurring mutation of the ubiquitin proteasome system that is associated with a discernable phenotype of dogs. PMID- 21256209 TI - Neural distribution of the nuclear progesterone receptor in the tungara frog, Physalaemus pustulosus. AB - The gonadal steroid hormone progesterone plays an important role across all vertebrates in mediating female reproductive physiology and behavior. Many effects of progesterone are mediated by a nuclear progesterone receptor (PR), which is crucial for integration of external signals and internal physiological cues in the brain to produce an appropriate behavioral output. The tungara frog, Physalaemus pustulosus, is an excellent model system for the study of mechanisms by which sensory signals, such as auditory communication, are processed within neural circuits where mate choice decisions are made. To establish a framework for studying the neural basis of mate choice and social behavior in this species, we first describe the cytoarchitecture of the brain using Nissl-stained sections. Then, in order to better understand where progesterone acts to regulate social decisions, we determined the distribution of PR protein throughout the brain of P. pustulosus by immunohistochemistry. We found PR immunoreactivity in key brain regions known to modulate the processing of auditory cues and social behavior in other vertebrates. Due to its widespread distribution, PR likely also plays important roles in non-limbic brain regions that mediate non-social information processing. Further, we have colocalized PR with tyrosine hydroxylase, providing a functional context for the role of progesterone in mediating motivation and motor behavior. Our results significantly extend our understanding of hormonal modulation in the anuran brain and support the important role of the nuclear progesterone receptor in modulating female mate choice and receptivity in amphibians and across vertebrates. PMID- 21256210 TI - TRPV1 expression in acupuncture points: response to electroacupuncture stimulation. AB - The present study was to examine the distribution of transient receptor potential vanilloid type-1 (TRPV1) receptor immunoreactivity in the acupuncture points (acupoint), and determine the influences of electroacupuncture (EA) stimulation on TRPV1 expression. EA stimulation of BL 40 was conducted in two sessions of 20 min separated by an 80 min interval in anesthetized rats. Sections of skin containing BL 40, and its non-meridian control were examined by immunolabeling with antibodies directed against TRPV1. Without EA, the number of subepidermal nerve fibers expressing TRPV1 was higher in the acupoint than in non-acupoint control skin (p<0.01). The subepidermal nerve fibers showed the co-localization of TRPV1 with peripherine, a marker for the C-fibers and A-delta fibers. The expression of TRPV1 in nerve fibers is significantly increased by EA stimulation in acupoints (p<0.01). However the upregulation in the non acupoint meridian and the non-meridian control skin was short of statistical significance. Double immunostaining of TRPV1 and neuronal nitric oxide synthase (nNOS) revealed their co-localization in both the subepidermal nerve fibers and in the dermal connective tissue cells. These results show that a high expression of TRPV1 endowed with nNOS in subepidermal nerve fibers exists in the acupoints and the expression is increased by EA. We conclude that the higher expression of TRPV1 in the subepidermal nerve fibers and its upregulation after EA stimulation may play a key role in mediating the transduction of EA signals to the CNS, and its expression in the subepidermal connective tissue cells may play a role in conducting the local effect of the EA. PMID- 21256208 TI - Prenatal environmental exposures, epigenetics, and disease. AB - This review summarizes recent evidence that prenatal exposure to diverse environmental chemicals dysregulates the fetal epigenome, with potential consequences for subsequent developmental disorders and disease manifesting in childhood, over the lifecourse, or even transgenerationally. The primordial germ cells, embryo, and fetus are highly susceptible to epigenetic dysregulation by environmental chemicals, which can thereby exert multiple adverse effects. The data reviewed here on environmental contaminants have potential implications for risk assessment although more data are needed on individual susceptibility to epigenetic alterations and their persistence before this information can be used in formal risk assessments. The findings discussed indicate that identification of environmental chemicals that dysregulate the prenatal epigenome should be a priority in health research and disease prevention. PMID- 21256211 TI - A novel synthetic protoapigenone analogue, WYC02-9, induces DNA damage and apoptosis in DU145 prostate cancer cells through generation of reactive oxygen species. AB - The protoapigenone analogue WYC02-9, a novel synthetic flavonoid, has been shown to act against a variety of experimental tumors. However, its effects on prostate cancer and its mechanism of action are unknown. Thus, WYC02-9 was investigated for its cytotoxicity against DU145 prostate cancer cells, as was the underlying mechanisms by which WYC02-9 might induce DNA damage and apoptotic cell death through reactive oxygen species (ROS). WYC02-9 inhibited the cell growth of three prostate cancer cell lines, especially DU145 cells. In DU145 cells, WYC02-9 increased the generation of intracellular ROS, followed by induction of DNA damage and activation of the ATM-p53-H2A.X pathway and checkpoint-related signals Chk1/Chk2, which led to increased numbers of cells in the S and G2/M phases of the cell cycle. Furthermore, WYC02-9 induced apoptotic cell death through mitochondrial membrane potential decrease and activation of caspase-9, caspase-3, and PARP. The above effects were all prevented by the ROS scavenger N acetylcysteine. Administration of WYC02-9 in a nude mouse DU145 xenograft model further identified the anti-cancer activity of WYC02-9. These findings therefore suggest that WYC02-9-induced DNA damage and mitochondria-dependent cell apoptosis in DU145 cells are mediated via ROS generation. PMID- 21256212 TI - Multimerization-defective variants of dodecameric secretin PulD. AB - The C-terminal core domain of the secretin PulD from Klebsiella oxytoca forms heat-resistant dodecameric complexes within less than 10min in an Escherichia coli in vitro transcription-translation system containing liposomes, and is toxic when made in the cytoplasm without a signal peptide. Random mutagenesis of DNA encoding this region of PulD revealed that amino acid changes throughout almost its entire length abolished toxicity. Most of the amino acid substitutions engendered by the mutations retarded or abolished assembly of the dodecameric secretin complex in vitro and/or in the periplasm. Only one of the tested multimerization-defective variants could be rescued by co-production and mixed multimer formation with wild-type secretin in vitro. A three amino acid insertion specifically generated in a region of PulD that was not affected by the spontaneous mutations formed functional multimers that, unlike the wild-type protein, were dissociated by heating in SDS. PMID- 21256214 TI - Manufacturing recombinant proteins in kg-ton quantities using animal cells in bioreactors. AB - Mammalian cells in bioreactors as production host are the focus of this review. We wish to briefly describe today's technical status and to highlight emerging trends in the manufacture of recombinant therapeutic proteins, focusing on Chinese hamster ovary (CHO) cells. CHO cells are the manufacturing host system of choice for more than 70% of protein pharmaceuticals on the market [21]. The current global capacity to grow mammalian cells in bioreactors stands at about 0.5 million liters, whereby the largest vessels can have a working volume of about 20,000l. We are focusing in this article on the upstream part of protein manufacturing. Over the past 25 years, volumetric yields for recombinant cell lines have increased about 20-fold mainly as the result of improvements in media and bioprocess design. Future yield increases are expected to come from improved gene delivery methods, from improved, possibly genetically modified host systems, and from further improved bioprocesses in bioreactors. Other emerging trends in protein manufacturing that are discussed include the use of disposal bioreactors and transient gene expression. We specifically highlight here current research in our own laboratories. PMID- 21256213 TI - Zebrafish as a model to understand autophagy and its role in neurological disease. AB - In the past decade, the zebrafish (Danio rerio) has become a popular model system for the study of vertebrate development, since the embryos and larvae of this species are small, transparent and undergo rapid development ex utero, allowing in vivo analysis of embryogenesis and organogenesis. These characteristics can also be exploited by researchers interested in signaling pathways and disease processes and, accordingly, there is a growing literature on the use of zebrafish to model human disease. This model holds great potential for exploring how autophagy, an evolutionarily conserved mechanism for protein degradation, influences the pathogeneses of a range of different human diseases and for the evaluation of this pathway as a potential therapeutic strategy. Here we summarize what is known about the regulation of autophagy in eukaryotic cells and its role in neurodegenerative disease and highlight how research using zebrafish has helped further our understanding of these processes. PMID- 21256216 TI - Dimer-tetramer association equilibria of human adult hemoglobin and its mutants as observed by analytical ultracentrifugation. AB - Dimer-tetramer equilibrium of human adult hemoglobin in CO form (COHb A) and its mutants were measured by sedimentation velocity and sedimentation equilibrium. In sedimentation velocity, the association constants were estimated by measuring the concentration dependence of the weight average sedimentation coefficients at pH 6 and 7 and fitting the data to the theoretical binding isotherms with association constants as a parameter. Association constants of wild type Hb A and three mutant Hbs, Hb Hirose(betaW37S), recombinant (r)Hb(betaW37H) and rHb(alphaY42S), in which an amino acid was replaced at the alpha(1)beta(2) interface, were measured in the presence and absence of inositol hexaphosphate (IHP). All the three mutations lowered the value of association constants, but the presence of IHP shifted the equilibrium toward tetramer. Although the association constant between dimer and tetramer of rHb(betaW37H) and rHb(alphaY42S) were similar, sedimentation coefficient distribution function, c(s), analysis indicated that the association and dissociation rate constants of the former is higher than the latter. PMID- 21256215 TI - Age-dependent regulation of skeletal muscle mitochondria by the thrombospondin-1 receptor CD47. AB - CD47, a receptor for thrombospondin-1, limits two important regulatory axes: nitric oxide-cGMP signaling and cAMP signaling, both of which can promote mitochondrial biogenesis. Electron microscopy revealed increased mitochondrial densities in skeletal muscle from both CD47 null and thrombospondin-1 null mice. We further assessed the mitochondria status of CD47-null vs WT mice. Quantitative RT-PCR of RNA extracted from tissues of 3 month old mice revealed dramatically elevated expression of mRNAs encoding mitochondrial proteins and PGC-1alpha in both fast and slow-twitch skeletal muscle from CD47-null mice, but modest to no elevation in other tissues. These observations were confirmed by Western blotting of mitochondrial proteins. Relative amounts of electron transport enzymes and ATP/O(2) ratios of isolated mitochondria were not different between mitochondria from CD47-null and WT cells. Young CD47-null mice displayed enhanced treadmill endurance relative to WTs and CD47-null gastrocnemius had undergone fiber type switching to a slow-twitch pattern of myoglobin and myosin heavy chain expression. In 12 month old mice, both skeletal muscle mitochondrial volume density and endurance had decreased to wild type levels. Expression of myosin heavy chain isoforms and myoglobin also reverted to a fast twitch pattern in gastrocnemius. Both CD47 and TSP1 null mice are leaner than WTs, use less oxygen and produce less heat than WT mice. CD47-null cells produce substantially less reactive oxygen species than WT cells. These data indicate that loss of signaling from the TSP1-CD47 system promotes accumulation of normally functioning mitochondria in a tissue-specific and age-dependent fashion leading to enhanced physical performance, lower reactive oxygen species production and more efficient metabolism. PMID- 21256217 TI - Evaluating the stoichiometry of macromolecular complexes using multisignal sedimentation velocity. AB - Gleaning information regarding the molecular physiology of macromolecular complexes requires knowledge of their component stoichiometries. In this work, a relatively new means of analyzing sedimentation velocity (SV) data from the analytical ultracentrifuge is examined in detail. The method depends on collecting concentration profile data simultaneously using multiple signals, like Rayleigh interferometry and UV spectrophotometry. If the cosedimenting components of a complex are spectrally distinguishable, continuous sedimentation-coefficient distributions specific for each component can be calculated to reveal the molar ratio of the complex's components. When combined with the hydrodynamic information available from the SV data, a stoichiometry can be derived. Herein, the spectral properties of sedimenting species are systematically explored to arrive at a predictive test for whether a set of macromolecules can be spectrally resolved in a multisignal SV (MSSV) experiment. Also, a graphical means of experimental design and criteria to judge the success of the spectral discrimination in MSSV are introduced. A detailed example of the analysis of MSSV experiments is offered, and the possibility of deriving equilibrium association constants from MSSV analyses is explored. Finally, successful implementations of MSSV are reviewed. PMID- 21256219 TI - Analytical ultracentrifugation combined with X-ray and neutron scattering: Experiment and modelling. AB - Analytical ultracentrifugation and solution scattering provide different multi parameter structural and compositional information on proteins. The joint application of the two methods supplements high resolution structural studies by crystallography and NMR. We summarise the procedures required to obtain equivalent ultracentrifugation and X-ray and neutron scattering data. The constrained modelling of ultracentrifugation and scattering data is important to confirm the experimental data analysis and yields families of best-fit molecular models for comparison with crystallography and NMR structures. This modelling of ultracentrifugation and scattering data is described in terms of starting models, their conformational randomisation in trial-and-error fits, and the identification of the final best-fit models. Seven applications of these methods are described to illustrate the current state-of-the-art. These include the determination of antibody solution structures (the human IgG4 subclass, and oligomeric forms of human IgA and its secretory component), the solution structures of the complement proteins of innate immunity (Factor H and C3/C3u) and their interactions with macromolecular ligands (C-reactive protein), and anionic polysaccharides (heparin). Complementary features of joint ultracentrifugation and scattering experiments facilitate an improved understanding of crystal structures (illustrated for C3/C3u, C-reactive protein and heparin). If a large protein or its complex cannot be crystallised, the joint ultracentrifugation-scattering approach provides a means to obtain an overall macromolecular structure. PMID- 21256218 TI - Dual functional RNA nanoparticles containing phi29 motor pRNA and anti-gp120 aptamer for cell-type specific delivery and HIV-1 inhibition. AB - The potent ability of small interfering RNA (siRNA) to inhibit the expression of complementary RNA transcripts is being exploited as a new class of therapeutics for diseases including HIV. However, efficient delivery of siRNAs remains a key obstacle to successful application. A targeted intracellular delivery approach for siRNAs to specific cell types is highly desirable. HIV-1 infection is initiated by the interactions between viral glycoprotein gp120 and cell surface receptor CD4, leading to fusion of the viral membrane with the target cell membrane. Once HIV infects a cell it produces gp120 which is displayed at the cell surface. We previously described a novel dual inhibitory anti-gp120 aptamer siRNA chimera in which both the aptamer and the siRNA portions have potent anti HIV activities. We also demonstrated that gp120 can be used for aptamer mediated delivery of anti-HIV siRNAs. Here we report the design, construction and evaluation of chimerical RNA nanoparticles containing a HIV gp120-binding aptamer escorted by the pRNA of bacteriophage phi29 DNA-packaging motor. We demonstrate that pRNA-aptamer chimeras specifically bind to and are internalized into cells expressing HIV gp120. Moreover, the pRNA-aptamer chimeras alone also provide HIV inhibitory function by blocking viral infectivity. The Ab' pRNA-siRNA chimera with 2'-F modified pyrimidines in the sense strand not only improved the RNA stability in serum, but also was functionally processed by Dicer, resulting in specific target gene silencing. Therefore, this dual functional pRNA-aptamer not only represents a potential HIV-1 inhibitor, but also provides a cell-type specific siRNA delivery vehicle, showing promise for systemic anti-HIV therapy. PMID- 21256220 TI - fMRI of the brainstem using dual-echo EPI. AB - The brainstem is the part of the human brain that plays a pivotal role in the maintenance of many critical body functions. Due to the elevated level of cardiogenic noise, few fMRI studies have investigated the brainstem so far. Cardiac-gated echo-planar imaging with acquisition of two echoes per excitation (dual-echo EPI) is one method that significantly reduces cardiogenic noise and, thus, allows for fMRI measurements of the brainstem. As information on optimal preprocessing approaches for brainstem-fMRI data is still scarce, the goal of this study was to compare different combinations of normalization and smoothing procedures as implemented in standard fMRI software packages and to identify the combinations yielding optimal results for dual-echo EPI. 21 healthy subjects were measured while executing a simple motor paradigm to activate the facial and trigeminal motor nucleus in the brainstem. After motion correction and calculation of T(2)*-maps the data were preprocessed with 24 combinations of standard normalization (SPM classic, SPM unified, FSL, ABC) and smoothing procedures (pre-/post-smoothing with 3mm-, 4.5mm- and 6mm-kernel) before undergoing first- and second-level statistical analysis. Activation results were compared for first-level and second-level statistics using two anatomically defined regions of interest. Five methods were found to be sensitive for activation of both nuclei. These included FSL normalization with 3mm and 4.5mm pre-smoothing as well as 3mm post-smoothing, SPM unified normalization with 3mm pre-smoothing and ABC normalization with 4.5mm pre-smoothing. All these methods can be recommended for normalization and smoothing when analyzing fMRI data of the brainstem acquired by cardiac-gated dual-echo EPI. PMID- 21256221 TI - Quantitative evaluation of 10 tractography algorithms on a realistic diffusion MR phantom. AB - As it provides the only method for mapping white matter fibers in vivo, diffusion MRI tractography is gaining importance in clinical and neuroscience research. However, despite the increasing availability of different diffusion models and tractography algorithms, it remains unclear how to select the optimal fiber reconstruction method, given certain imaging parameters. Consequently, it is of utmost importance to have a quantitative comparison of these models and algorithms and a deeper understanding of the corresponding strengths and weaknesses. In this work, we use a common dataset with known ground truth and a reproducible methodology to quantitatively evaluate the performance of various diffusion models and tractography algorithms. To examine a wide range of methods, the dataset, but not the ground truth, was released to the public for evaluation in a contest, the "Fiber Cup". 10 fiber reconstruction methods were evaluated. The results provide evidence that: 1. For high SNR datasets, diffusion models such as (fiber) orientation distribution functions correctly model the underlying fiber distribution and can be used in conjunction with streamline tractography, and 2. For medium or low SNR datasets, a prior on the spatial smoothness of either the diffusion model or the fibers is recommended for correct modelling of the fiber distribution and proper tractography results. The phantom dataset, the ground truth fibers, the evaluation methodology and the results obtained so far will remain publicly available on: http://www.lnao.fr/spip.php?rubrique79 to serve as a comparison basis for existing or new tractography methods. New results can be submitted to fibercup09@gmail.com and updates will be published on the webpage. PMID- 21256222 TI - Functional motor-cortex mapping using corticokinematic coherence. AB - We present a novel method, corticokinematic coherence (CKC), for functional mapping of the motor cortex by computing coherence between cortical magnetoencephalographic (MEG) signals and the kinematics of voluntary movements. Ten subjects performed self-paced flexion-extensions of the right-hand fingers at about 3 Hz, with a three-axis accelerometer attached to the index finger. Cross correlogram and coherence spectra were computed between 306 MEG channels and the accelerometer signals. In all subjects, accelerometer and coherence spectra showed peaks around 3-5 Hz and 6-10 Hz, corresponding to the movement frequencies. The coherence was statistically significant (P<0.05) in all subjects, with sources at the hand area of the primary motor cortex contralateral to the movement. CKC appears to be a promising and robust method for reliable and convenient functional mapping of the human motor cortex. PMID- 21256223 TI - Two-detector Corrected Near Infrared Spectroscopy (C-NIRS) detects hemodynamic activation responses more robustly than single-detector NIRS. AB - In near-infrared spectroscopy (NIRS) of human cerebral hemodynamics, detection of stimulus-related responses is confounded by the presence of unrelated trends in both the brain and the overlying scalp. A proposed strategy for reducing hemodynamic noise has been to record "scalp only" trends simultaneously via a second shorter-separation detector (~5 mm rather than ~30 mm) and perform a subtraction (C-NIRS, for "corrected near-infrared spectroscopy"). To compare the single- and dual-detector strategies, a 21-volunteer study of visual stimulation responses (6 stimulation blocks and 8 recording channels per measurement run) has been conducted. Activation-flagged channels were defined based upon (a) the significance (p-value) of the average rise in oxyhemoglobin concentration and (b) the average signal-to-noise over 6 stimulation epochs. At reasonable thresholds (p<0.025, SNR>1), the C-NIRS method increased the number of activation-flagged channels from 47 to 66, an increase of 40%, adding 24 channels and eliminating only 5. Of the 71 channels that were activation-flagged by at least one modality, the C-NIRS time series exhibited more significant oxyhemoglobin rise in 80% of such channels, and better signal-to-noise in 73%. In addition, single-subject C NIRS stimulus responses were more consistent than NIRS over the six stimulation epochs, with significantly lower coefficients of variation in both amplitude and latency (i.e. time between stimulus onset and maximum hemoglobin rise). These results demonstrate that two-detector C-NIRS provides a straightforward way of (a) removing hemodynamic interference from NIRS data, (b) increasing the detection rate of cerebrally-unique responses, and (c) improving the quality of those recorded responses. Parallel insights regarding deoxyhemoglobin trends could not be drawn from this data set but should be attainable in future studies with higher signal to noise ratios. PMID- 21256224 TI - A new statistical test based on the wavelet cross-spectrum to detect time frequency dependence between non-stationary signals: application to the analysis of cortico-muscular interactions. AB - The study of the correlations that may exist between neurophysiological signals is at the heart of modern techniques for data analysis in neuroscience. Wavelet coherence is a popular method to construct a time-frequency map that can be used to analyze the time-frequency correlations between two time series. Coherence is a normalized measure of dependence, for which it is possible to construct confidence intervals, and that is commonly considered as being more interpretable than the wavelet cross-spectrum (WCS). In this paper, we provide empirical and theoretical arguments to show that a significant level of wavelet coherence does not necessarily correspond to a significant level of dependence between random signals, especially when the number of trials is small. In such cases, we demonstrate that the WCS is a much better measure of statistical dependence, and a new statistical test to detect significant values of the cross-spectrum is proposed. This test clearly outperforms the limitations of coherence analysis while still allowing a consistent estimation of the time-frequency correlations between two non-stationary stochastic processes. Simulated data are used to investigate the advantages of this new approach over coherence analysis. The method is also applied to experimental data sets to analyze the time-frequency correlations that may exist between electroencephalogram (EEG) and surface electromyogram (EMG). PMID- 21256225 TI - Comparing the similarity and spatial structure of neural representations: a pattern-component model. AB - In recent years there has been growing interest in multivariate analyses of neuroimaging data, which can be used to detect distributed patterns of activity that encode an experimental factor of interest. In this setting, it has become common practice to study the correlations between patterns to make inferences about the way a brain region represents stimuli or tasks (known as representational similarity analysis). Although it would be of great interest to compare these correlations from different regions, direct comparisons are currently not possible. This is because sample correlations are strongly influenced by voxel-selection, fMRI noise, and nonspecific activation patterns, all of which can differ widely between regions. Here, we present a multivariate modeling framework in which the measured patterns are decomposed into their constituent parts. The model is based on a standard linear mixed model, in which pattern components are considered to be randomly distributed over voxels. The model allows one to estimate the true correlations of the underlying neuronal pattern components, thereby enabling comparisons between different regions or individuals. The pattern estimates also allow us to make inferences about the spatial structure of different response components. Thus, the new model provides a theoretical and analytical framework to study the structure of distributed neural representations. PMID- 21256226 TI - The human amygdala plays a stimulus specific role in the detection of novelty. AB - The primary focus of research on the amygdala has been on the detection of and response to emotion but the amygdala also sometimes responds to new or unexpected stimuli without specific emotional content. Very little is currently known about why the amygdala responds to some new stimuli but not to others. Here we investigated the conditions that are necessary and sufficient for the expression of novelty specific amygdala responses by presenting novel and repeated images to human participants and varying the content of these images while measuring blood oxygenation level dependent (BOLD) responses. In Experiment 1 we presented novel and repeated emotional and neutral images. Both emotional and neutral images of humans evoked more amygdala activity when novel than when repeated. In Experiment 2 we presented novel and repeated images of humans and scenes. Images of humans but not scenes evoked more amygdala activity when novel than when repeated. Our results suggest that the amygdala plays a stimulus-specific role in the brain's novelty detection network. Surprisingly, emotion was not necessary for amygdalar novelty responses, but the presence of a human representation was important. Amygdala responses evoked by novel faces may reflect our need to use others' faces as clues for important events in the environment. PMID- 21256227 TI - Simple explanations before complex theories: Alternative interpretations of Sirotin and Das' observations. AB - We make a few additional points regarding our discussion with Sirotin and Das' 2009 Nature paper and their 2011 NeuroImage response to our commentary. While we find their data interesting in itself, we remain concerned with how the data are interpreted by the authors. We discuss two categories of methodological issues that limit the conclusions one can draw from their results. (1) The measures of fit quality between the optical and electrical data: kernel shape variation, variance of predicted/measured signals, and R(2), interact with each other and are confounded by the fact that one condition has a lower signal magnitude and therefore, lower signal-to-noise-ratio (SNR). (2) Hemodynamic responses to distinct events will be incorrectly or inefficiently estimated if the hemodynamic responses overlap across periodic trials that are not jittered and have an inter trial interval less than 15s. Most importantly, the overlapping responses across trials might cause transient effects that look similar to the anticipatory effects presented by Sirotin and Das. While their study demonstrates a potentially useful way to probe neurovascular coupling, we believe the current results have little practical relevance for interpreting hemodynamic measures of neural activity such as those used in fMRI. We conclude by making several suggestions for future analyses, which might help elucidate the mechanisms behind these observations and lead to a better understanding of how these observations relate to hemodynamic based measures of neural activation. PMID- 21256229 TI - An MRI based average macaque monkey stereotaxic atlas and space (MNI monkey space). AB - In studies of the human brain, a standard stereotaxic space such as the Montreal Neurological Institute (MNI space) is widely used to provide a common reference for the three-dimensional localization of functional activation foci and anatomical structures, enabling the comparison of results obtained across different studies. Here we present a standard macaque monkey brain MRI template that offers a common stereotaxic reference frame to localize anatomical and functional information in an organized and reliable way for comparison across individual monkeys and studies. We have used MRI volumes from a group of 25 normal adult macaque monkeys (18 cynomolgus and 7 rhesus) to create a common standard macaque monkey brain as well as atlases for each of these species separately. In addition, the digital macaque monkey volume was subjected to 3D volumetric analysis and comparison of brain structures between the individual brains and the average atlas. Furthermore, we provide a means of transforming any macaque MRI volume into MNI monkey space coordinates in 3D using simple web based tools. Coordinates in MNI monkey space can also be transformed into the coordinate system of a detailed neuroanatomical paper atlas (Paxinos et al., 2008), enabling researchers to identify and delineate cortical and subcortical structures in their individual macaque monkey brains. PMID- 21256230 TI - Real-time feedback optimization of z-shim gradient for automatic compensation of susceptibility-induced signal loss in EPI. AB - Signal loss in gradient-echo echo planar imaging (GE-EPI) due to susceptibility induced magnetic field inhomogeneity makes it difficult to assess the blood oxygenation level-dependent (BOLD) effect in fMRI investigations. The z-shim method that applies an additional gradient moment is one of the more popular methods of compensating for GE-EPI signal loss. However, this method requires a calibration sweep scan and post-processing to identify the optimal z-shim gradients, which slows down fMRI experiments. This study attempts to decrease the calibration time by introducing a real-time feedback framework. Creating a feedback loop between the image processing and the GE-EPI pulse sequence converts the calibration of z-shim gradients to an optimization problem, which can be accelerated by local search methods. This study proposes an interleaved scan that allows the simultaneous optimization of two z-shim gradient moments and allocates sufficient processing time for networking and computation. The z-shim compensated images obtained by the proposed real-time method are comparable to those created by the sweep method. The optimization procedure for obtaining negative and positive gradient moments generally requires about twenty GE-EPI repetitions. In conclusion, the proposed z-shim method includes an automated real-time framework to achieve a significant reduction in susceptibility-induced signal loss in GE EPI with a minimal increase in calibration time. The proposed procedure is fully automatic and compatible with conventional GE-EPI and can thus serve as a pre adjustment module in EPI-based fMRI researches. PMID- 21256228 TI - Solving future problems: default network and executive activity associated with goal-directed mental simulations. AB - Mental simulations are often focused on a goal in the future or a problem to be solved. Recent neuroimaging studies have associated mental simulations of the future with default network activity, but the simulations in these studies were not typically directed toward achieving a particular goal. Goal-directed simulation requires cognitive control to maintain information, make decisions, and coordinate abstract action sequences. Therefore, it should recruit not only the default network, but also executive regions. To investigate whether default network and executive regions can be coactive in the context of goal-directed simulation, we designed a problem-solving task in which participants simulated solving several specific problems in imaginary scenarios while in the MRI scanner. We analyzed brain activity during simulation relative to a semantic elaboration task and found that goal-directed simulation engaged core regions of the default network and executive dorsolateral prefrontal cortex. A functional connectivity analysis with posterior cingulate and dorsolateral prefrontal cortex seeds revealed that activity in these regions was coupled throughout the goal directed simulation period and associated with a distributed network of other default and executive regions, including medial prefrontal cortex, medial temporal, and parietal regions. PMID- 21256231 TI - Influences of negative BOLD responses on positive BOLD responses. AB - Understanding possible interactions between blood oxygenation level-dependent (BOLD) responses is critical for model-based analyses and the interpretation of experiments that deal with stimuli presented close together in time. Such interactions are well documented in the case of successive positive BOLD responses. However, the influence that a stimulus-induced, negative BOLD response exerts on a subsequent positive BOLD response has yet to be investigated and is the focus of the current study. We performed functional magnetic resonance imaging on 10 healthy subjects during bilateral electrical median nerve stimulation using five different time intervals between left- and right-sided stimuli. We found an acute interruption of the ongoing negative BOLD response at the onset of the positive BOLD response. Different parameters characterizing the positive BOLD response were estimated. There was no impact of the preceding negative BOLD response on the parameters describing the subsequent positive BOLD response. These findings indicate that the underlying mechanisms for negative and positive BOLD responses do not engage parallel processes. We hypothesize that the negative BOLD response is caused by a decreased release of the same vasodilatative agents that evoke the positive BOLD response. Additionally, our results demonstrate that there is no need to adjust the model of a positive BOLD response due to a preceding negative BOLD response in the same brain area. PMID- 21256232 TI - Is the semantic category effect in the lateral temporal cortex due to motion property differences? AB - Two specific areas within the posterior lateral temporal cortex (PLTC), the posterior superior temporal sulcus (pSTS) and the posterior middle temporal gyrus (pMTG), have been proposed to store different types of conceptual properties of motion: the pSTS encodes knowledge of articulated, biological motion, and the pMTG encodes knowledge about unarticulated, mechanical motion. We examined this hypothesis by comparing activation patterns evoked by verbs denoting biological motion (e.g., walk), mechanical motion (e.g., rotate), and low-motion events (e.g., ferment). Classical noun categories with different motion types (animals, tools, and buildings) were also tested and compared with previous findings of the categorical effects in PLTC. Replicating previous findings of different types of nouns, we observed stronger activation for animals than tools in the pSTS and stronger activation for tools compared to other types of nouns in the pMTG. However, such motion-type specific activation patterns only partly extended to verbs. Whereas the pSTS showed preferences for biological-motion verbs, no region within the pMTG was sensitive to verbs denoting mechanical motion. We speculate that the pMTG preference for tools is driven by properties other than mechanical motion, such as strong mappings between the visual form and motor-related representations. PMID- 21256233 TI - Neurobehavioral mechanisms of human fear generalization. AB - While much research has elucidated the neurobiology of fear learning, the neural systems supporting the generalization of learned fear are unknown. Using functional magnetic resonance imaging (fMRI), we show that regions involved in the acquisition of fear support the generalization of fear to stimuli that are similar to a learned threat, but vary in fear intensity value. Behaviorally, subjects retrospectively misidentified a learned threat as a more intense stimulus and expressed greater skin conductance responses (SCR) to generalized stimuli of high intensity. Brain activity related to intensity-based fear generalization was observed in the striatum, insula, thalamus/periacqueductal gray, and subgenual cingulate cortex. The psychophysiological expression of generalized fear correlated with amygdala activity, and connectivity between the amygdala and extrastriate visual cortex was correlated with individual differences in trait anxiety. These findings reveal the brain regions and functional networks involved in flexibly responding to stimuli that resemble a learned threat. These regions may comprise an intensity-based fear generalization circuit that underlies retrospective biases in threat value estimation and overgeneralization of fear in anxiety disorders. PMID- 21256234 TI - Neural mechanisms of brain-computer interface control. AB - Brain-computer interfaces (BCIs) enable people with paralysis to communicate with their environment. Motor imagery can be used to generate distinct patterns of cortical activation in the electroencephalogram (EEG) and thus control a BCI. To elucidate the cortical correlates of BCI control, users of a sensory motor rhythm (SMR)-BCI were classified according to their BCI control performance. In a second session these participants performed a motor imagery, motor observation and motor execution task in a functional magnetic resonance imaging (fMRI) scanner. Group difference analysis between high and low aptitude BCI users revealed significantly higher activation of the supplementary motor areas (SMA) for the motor imagery and the motor observation tasks in high aptitude users. Low aptitude users showed no activation when observing movement. The number of activated voxels during motor observation was significantly correlated with accuracy in the EEG-BCI task (r=0.53). Furthermore, the number of activated voxels in the right middle frontal gyrus, an area responsible for processing of movement observation, correlated (r=0.72) with BCI-performance. This strong correlation highlights the importance of these areas for task monitoring and working memory as task goals have to be activated throughout the BCI session. The ability to regulate behavior and the brain through learning mechanisms involving imagery such as required to control a BCI constitutes the consequence of ideo motor co-activation of motor brain systems during observation of movements. The results demonstrate that acquisition of a sensorimotor program reflected in SMR BCI-control is tightly related to the recall of such sensorimotor programs during observation of movements and unrelated to the actual execution of these movement sequences. PMID- 21256235 TI - Lateralized neural mechanisms underlying the modulation of response inhibition processes. AB - Functional cerebral asymmetries (FCAs) are an important modulator of cognitive functions. Here, we investigated the temporal and spectral dynamics as well as the cortical networks underlying the lateralized modulation of executive functions related to response inhibition. To this end, we recorded event-related potentials (ERPs) during tachistoscopic presentation of verbal 'Go' and 'Nogo' stimuli in the left (LVF) and the right visual field (RVF). Participants committed fewer false alarms to verbal Nogo stimuli presented in the RVF than to stimuli presented in the LVF. This asymmetry was paralleled by neurophysiological data. The Nogo-N2 and related delta frequency band power were stronger when response inhibition was driven by stimuli presented in the LVF, implying a stronger response conflict. This effect was mediated by stronger activations in bilateral medial-prefrontal and especially left parietal networks. This shows that asymmetries in behavioural performance do not necessarily reflect differences in the overall capability of one hemisphere to solve a task. Even though information is initially confined to one hemisphere after tachistoscopic presentation, this does not primarily cause behavioural asymmetries. Instead, hemispheric dominances in information processing can induce differences in demands on cognitive processes operating via bilateral networks that ultimately drive behavioural asymmetries. PMID- 21256237 TI - Speciation in tropical seas: allopatry followed by range change. AB - We investigated whether present distribution ranges in marine organisms are reliable indicators of the geographic pattern of past speciation events by assessing the level of geographic overlap (sympatric index) as a function of node age in four phylogenies of tropical marine species groups. The analyses led to remarkably similar results among the four groups examined with (1) most nodes associated with a sympatry index of either 0 (allopatry) or 1 (entire overlap) and (2) statistical support that sister species have an allopatric distribution significantly more frequently than sister clades (i.e. groups of species). Species divergences were expressed on a time scale and very similar times were needed for species range overlap to occur since sharp transitions from allopatry to sympatry occurred around 4 Ma in all groups. Present results supports that species range changes were not random as previous simulations results supports that species range probably evolve through occasional shifts of large amplitude. In front of the time needed for species range overlapping, our study suggests that species interaction and competitive exclusion can no longer be excluded as a driver of marine species distribution. PMID- 21256236 TI - DTI registration in atlas based fiber analysis of infantile Krabbe disease. AB - In recent years, diffusion tensor imaging (DTI) has become the modality of choice to investigate white matter pathology in the developing brain. To study neonate Krabbe disease with DTI, we evaluate the performance of linear and non-linear DTI registration algorithms for atlas based fiber tract analysis. The DTI scans of 10 age-matched neonates with infantile Krabbe disease are mapped into an atlas for the analysis of major fiber tracts - the genu and splenium of the corpus callosum, the internal capsules tracts and the uncinate fasciculi. The neonate atlas is based on 377 healthy control subjects, generated using an unbiased diffeomorphic atlas building method. To evaluate the performance of one linear and seven nonlinear commonly used registration algorithms for DTI we propose the use of two novel evaluation metrics: a regional matching quality criterion incorporating the local tensor orientation similarity, and a fiber property profile based metric using normative correlation. Our experimental results indicate that the whole tensor based registration method within the DTI-ToolKit (DTI-TK) shows the best performance for our application. PMID- 21256238 TI - Symbiodinium diversity among host clionaid sponges from Caribbean and Pacific reefs: Evidence of heteroplasmy and putative host-specific symbiont lineages. AB - Among the Porifera, symbiosis with Symbiodinium spp. (i.e., zooxanthellae) is largely restricted to members of the family Clionaidae. We surveyed the diversity of zooxanthellae associated with sponges from the Caribbean and greater Indo Pacific regions using chloroplast large subunit (cp23S) domain V sequences. We provide the first report of Clade C Symbiodinium harbored by a sponge (Cliona caesia), and the first report of Clade A Symbiodinium from an Indo-Pacific sponge (C. jullieni). Clade A zooxanthellae were also identified in sponges from the Caribbean, which has been reported previously. Sponges that we examined from the Florida Keys all harbored Clade G Symbiodinium as did C. orientalis from the Indo Pacific, which also supports earlier work with sponges. Two distinct Clade G lineages were identified in our phylogenetic analysis; Symbiodinium extracted from clionaid sponges formed a monophyletic group sister to Symbiodinium found in foraminiferans. Truncated and 'normal' length variants of 23S rDNA sequences were detected simultaneously in all three morphotypes of C. varians providing the first evidence of chloroplast-based heteroplasmy in a sponge. None of the other sponge species examined showed evidence of heteroplasmy. As in previous work, length variation in cp23S domain V sequences was found to correspond in a highly precise manner to finer resolution of phylogenetic topology among Symbiodinium clades. On a global scale, existing data indicate that members of the family Clionaidae that host zooxanthellae can form symbiotic associations with at least four Symbiodinium clades. The majority of sponge hosts appear to harbor only one cladal type of symbiont, but some species can harbor more than one clade of zooxanthellae concurrently. The observed differences in the number of partners harbored by sponges raise important questions about the degree of coevolutionary integration and specificity of these symbioses. Although our sample sizes are small, we propose that one of the Clade G lineages identified in this study is comprised of sponge-specialist zooxanthellae. These zooxanthellae are common in Caribbean sponges, but additional work in other geographic regions is necessary to test this idea. Sponges from the Indo-Pacific region harbor zooxanthellae from Clades A, C, and G, but more sponges from this region should be examined. PMID- 21256239 TI - Long noncoding RNAs in cell biology. AB - Whole genome transcriptomic analyses have identified large numbers of dynamically expressed long non-protein-coding RNAs (lncRNAs) in mammals and other animals whose functions are, as yet, largely unknown. Here we summarize the growing evidence that lncRNAs, like mRNAs, can be trafficked to and function in a wide variety of subcellular locations. Investigation of the subcellular distribution of lncRNAs has the potential to greatly expand our knowledge not only of the function of lncRNAs but also of cell biology by identifying previously unknown subcellular structures and novel constituents of known cellular organelles. PMID- 21256240 TI - Nitric oxide, reactive nitrogen species and associated enzymes during plant senescence. AB - Leaf senescence is often associated with increased oxidative damage to cellular macromolecules by reactive oxygen species. However, very little is known about other radicals: gaseous free radical nitric oxide and related molecules--reactive nitrogen species. This review brings a short survey of the questions. PMID- 21256241 TI - Gene expression profiles induced by Salmonella infection in resistant and susceptible mice. AB - Mouse models have been extensively used to investigate the mechanisms of salmonellosis. However, the role of the hosts' local intestinal responses during early stages of infection remain unclear. In this study, transcript array analysis was employed to investigate regulation of gene expression in the murine intestine following oral challenge with Salmonella enterica serovar Enteritidis. Salmonella resistant C3H/HeN mice elicited only weak transcription responses in the ileum even in the presence of bacterial replication and systemic infection. This poor response was surprising given previously published results using in vitro models. Susceptible TLR4-deficient C3H/HeJ mice displayed a stronger response, suggesting a role for TLR4 in dampening the response to Salmonella. Responses of susceptible BALB/c mice were also unremarkable. In contrast, in vitro infection of murine rectal epithelial cells induced a strong transcription response consistent with previous in vitro studies. Although the pattern of genes expressed by the ileal tissue upon in vivo infection were similar in all three mouse lines, the genes up-regulated during in vitro infection were different, indicating that the responses seen in vitro do not mimic those seen in vivo. Taken together these data indicate that in vivo responses to Salmonella, at the level of the intestine, are tightly regulated by the host. PMID- 21256242 TI - Putting the brakes on the anti-viral response: negative regulators of type I interferon (IFN) production. AB - Type I IFNs (IFNalpha/beta) are essential anti-viral cytokines produced in response to the detection of viral components by host pattern recognition receptors. IFNalpha/beta production is transient, and aberrant activation can be hazardous to the host. In this article, we review our current understanding of host negative regulatory mechanisms that control IFNalpha/beta production. PMID- 21256243 TI - Autophagosomes and human diseases. AB - The autophagosome is a double-membrane bound compartment that initiates macroautophagy, a degradative pathway for cytoplasmic material terminating in the lysosomal compartment. The discovery of ATG genes involved in the formation of autophagosomes has greatly increased our understanding of the molecular basis of macroautophagy, and its role in cell function. Macroautophagy plays a pivotal role in cell fitness by removing obsolete organelles and protein aggregates. Its stimulation is an adaptive response to stressful situations, such as nutrient deprivation, intended to maintain a level of ATP compatible with cell survival. Macroautophagy is central for organ homeostasis, embryonic development, and longevity. Malfunctioning autophagy is observed in many human diseases including cancer, neurodegenerative diseases, cardiac and muscular diseases, infectious and inflammatory diseases, diabetes, and obesity. Discovering potential drug therapies that can be used to modulate macroautophagy is a major challenge, and likely to enhance the therapeutic arsenal against many human diseases. PMID- 21256244 TI - Comet assay and analysis of micronucleus formation in patients with rheumatoid arthritis. AB - Oxidants play a significant role in causing oxidative stress, which underlies the pathogenesis of rheumatoid arthritis (RA). Genetic factors that predispose individuals to RA are considered to play an important role in the development of the disease. The aim of this study was to determine, by use of the comet assay and the micronucleus (MN) test, whether DNA damage has an effect on the pathogenesis of RA. Furthermore, our aim was to show if there is an association between oxidative stress and DNA damage in RA. This study was conducted between January and June 2010 in the Erzurum Training and Research Hospital. We analyzed lymphocytes from patients with RA (12 in active and 31 in inactive periods) and 30 healthy controls for effects in the comet assay and the MN test. In addition, the levels of malondialdehyde (MDA) and superoxide dismutase (SOD), the activity of glutathione peroxidase (GSH-Px), the erythrocyte sedimentation rate (ESR) and the high-sensitivity C-reactive protein (hs-CRP) rate were determined in all the subjects. The comet-tail length, the MN frequencies and the MDA levels were significantly higher in patients--both in the active and the inactive period- than in the controls. In contrast, the SOD and GSH-Px levels were significantly lower in both patient groups than in the controls. Our results suggest that an increased plasma MDA level and decreased plasma GSH-Px and SOD levels reflect the higher degree of oxidative stress in RA patients, a situation that may impair genetic stability in those patients. Thus, the results suggest that increased DNA damage may play an important role in the pathogenesis of RA. PMID- 21256245 TI - Assessing the cytotoxic and mutagenic effects of secondary metabolites produced by several fungal biological control agents with the Ames assay and the VITOTOX((r)) test. AB - The potential genotoxic effects of several pure secondary metabolites produced by fungi used as biological control agents (BCAs) were studied with the Ames Salmonella/microsome mutagenicity assay and the Vitotox test, with and without metabolic activation. A complete set of Salmonella tester strains was used to avoid false negative results. To detect possible mutagenic and/or cytotoxic effects of fungal secondary metabolites due to synergistic action, crude extracts and fungal cell extracts of the BCAs were also examined. Although the sensitivity of the methods varied depending on the metabolite used, clearly no genotoxicity was observed in all cases. The results of the two assays are discussed in the light of being used in a complementary fashion for a convincing risk-assessment evaluation of fungal BCAs and their secondary metabolites. PMID- 21256246 TI - Genotoxicity biomarkers in occupational exposure to formaldehyde--the case of histopathology laboratories. AB - Formaldehyde, classified by the IARC as carcinogenic in humans and experimental animals, is a chemical agent that is widely used in histopathology laboratories. The exposure to this substance is epidemiologically linked to cancer and to nuclear changes detected by the cytokinesis-block micronucleus test (CBMN). This method is extensively used in molecular epidemiology, since it provides information on several biomarkers of genotoxicity, such as micronuclei (MN), which are biomarkers of chromosomes breakage or loss, nucleoplasmic bridges (NPB), common biomarkers of chromosome rearrangement, poor repair and/or telomere fusion, and nuclear buds (NBUD), biomarkers of elimination of amplified DNA. The aim of this study is to compare the frequency of genotoxicity biomarkers, provided by the CBMN assay in peripheral lymphocytes and the MN test in buccal cells, between individuals occupationally exposed and non-exposed to formaldehyde and other environmental factors, namely tobacco and alcohol consumption. The sample comprised two groups: 56 individuals occupationally exposed to formaldehyde (cases) and 85 unexposed individuals (controls), from whom both peripheral blood and exfoliated epithelial cells of the oral mucosa were collected in order to measure the genetic endpoints proposed in this study. The mean level of TWA(8h) was 0.16+/-0.11 ppm (1.25 million versus 18% in communities <100,000, p < 0.03) were more common in larger communities (43.4% versus 37.7%, p < 0.001). Pneumonectomy was more common in smaller communities (14.5% vs 9.9%, p = 0.048, whereas more lobar (53.8 vs 45.2%, p = 0.01) and sublobar resections (44.9% vs 31.7%, p < 0.0001) were more common in larger communities. Thoracic surgeons provided the majority of formal resections (51% to 57%) compared with general surgeons (17% to 21%). CONCLUSIONS: Lung cancer incidence and surgical care vary significantly by health region, income level, and community size. These disparities require further evaluation to meet the needs of patients with lung cancer. PMID- 21256271 TI - Surgical management of endobronchial inflammatory myofibroblastic tumors. AB - BACKGROUND: Endobronchial myofibroblastic tumors are neoplasms composed of clonal populations of smooth muscle cells and a variable lymphocytic inflammatory component. They represent a challenge with respect to diagnosis, classification, and surgical resection due to their infrequent occurrence. METHODS: We retrospectively reviewed our experience with patients who had myofibroblastic tumors in the major airways over a 15-year period, in order to understand the incidence, natural biology, treatment, and long-term outcome of individuals with this type of neoplasm in an endobronchial location. RESULTS: Between 1995 and 2010, 11 patients (9 female, 2 male) underwent surgical resection of a myofibroblastic tumor arising within the tracheobronchial tree. The mean age was 39.6 years (range, 22.3 to 53.6 years). All patients were symptomatic, with cough and dyspnea as the most common presenting complaints. Rigid bronchoscopy with endobronchial biopsy was utilized to establish the diagnosis in 9 of 11 patients. Laser-mechanical debulking was performed to relieve airway obstruction prior to operation in 10 of 11 patients. Because of wide submucosal infiltration of the neoplasms, surgical resection for complete removal was required for all individuals. Tracheal resection was performed in 3 patients, carinal resection in 1 patient, mainstem bronchial resection in 2 patients, sleeve resection in 3 patients, bilobectomy in 1 patient, and right lower lobectomy in 1 patient. Resection with tumor-free margins was accomplished in all patients. Mean tumor size was 2.3 cm (range, 1.5 to 3.5 cm). There were no operative deaths, with all patients alive and disease-free at a mean of 6.1 +/- 3.7 years. CONCLUSIONS: Complete surgical resection of inflammatory myofibroblastic tumors presenting in a major airway is safe and leads to excellent survival for patients with this uncommon disease. PMID- 21256272 TI - Small cell carcinoma of the esophagus: a report of 16 cases from a single institution and literature review. AB - BACKGROUND: The optimum treatment for small cell carcinoma of the esophagus (SCEC) has not been established. We reviewed our experience in the management of patients with SCEC. METHODS: The clinical data from 16 patients with SCEC were retrospectively collected with regard to demographics, use of tobacco or alcohol, presenting symptoms, tumor characteristics, staging, treatment, response, outcome, and survival. RESULTS: Of the 16 patients, 4 of 8 patients with limited disease underwent curative resection followed by adjuvant chemotherapy. Three patients are still alive at 221, 75, and 34 months after treatment with no evidence of disease. The other 4 patients with limited disease received chemotherapy with or without surgery, and all died of disease within 21 months after treatment. The other 8 patients had extensive disease at presentation. One of these patients had chemotherapy followed by surgery. The prognosis for this group of patients was poor. The median survival of all patients was 13.5 months (range, 4 days to 221 months). The median survival of patients with limited disease was 20.5 months (range, 5 to 221), whereas it was 4.5 months for patients with extensive disease (range, 4 days to 44 months). CONCLUSIONS: Small-cell carcinoma of the esophagus is a rare and highly malignant tumor with dismal prognosis. The treatment strategies for SCEC varied. Systemic chemotherapy should always be part of multimodality treatment. For patients with limited disease, curative resection followed by chemotherapy can provide long-term survival and can be considered as primary treatment for select patients. PMID- 21256273 TI - Invited commentary. PMID- 21256274 TI - Decreased conduit perfusion measured by spectroscopy is associated with anastomotic complications. AB - BACKGROUND: Gastric conduit ischemia during esophagectomy likely contributes to high anastomotic complication rates, yet we lack a reliable method to assess gastric conduit perfusion. We hypothesize that optical fiber spectroscopy (OFS) can reliably assess conduit perfusion and that the degree of intraoperative gastric ischemia is associated with subsequent anastomotic complications. METHODS: During esophagectomy, OFS was used to measure oxygen saturation (SaO(2)) and blood volume fraction (BVF) in the distal gastric conduit at baseline and after gastric devascularization, conduit formation, and transposition. The SaO(2) and BVF readings were correlated to clinical outcomes. RESULTS: The OFS measurements were obtained in 23 patients during esophagectomy, four of whom previously underwent gastric ischemic conditioning. Eight patients developed anastomotic complications. Compared with baseline, conduit creation produced a 29.4% reduction in SaO(2) (p < 0.01), while BVF increased by 28% (p = 0.06). Patients with subsequent anastomotic complications demonstrated a 52.5% decrease in SaO(2) upon conduit creation compared with 15.1% in patients without complications (p = 0.01). Patients who underwent ischemic conditioning did not develop significant changes in SaO(2) (p = 0.72) or BVF (p = 0.5) upon gastric conduit creation. CONCLUSIONS: Intraoperative OFS demonstrates significant alterations in gastric conduit oxygenation during esophageal replacement, which may be tempered by gastric ischemic conditioning. The degree of intraoperative gastric ischemia resulting from gastric conduit creation is associated with the development of anastomotic complications, suggesting that OFS is useful for assessing changes in conduit oxygenation during esophagectomy. Further studies are needed to refine this technology and investigate the clinical utility of intraoperative conduit oxygenation data. PMID- 21256275 TI - Invited commentary. PMID- 21256276 TI - Evaluating the reliability and reproducibility of the Ottawa Thoracic Morbidity and Mortality classification system. AB - BACKGROUND: Minimizing adverse events after surgery is widely recognized as an important indicator of quality; yet no consensus has been reached on how to standardize the reporting of adverse events after surgical procedures. Our objectives were to develop a standardized classification system to monitor both the presence and severity of thoracic morbidity and mortality, and to evaluate its reliability and reproducibility among a national cohort of thoracic surgeons. METHODS: To assess the Thoracic Morbidity and Mortality classification system (based on the Clavien-Dindo classification of adverse events), a 31-item questionnaire was sent to all members of the Canadian Association of Thoracic Surgeons in August 2009, consisting of a general description of the Thoracic Morbidity and Mortality severity grades, 20 case-based questions of postoperative adverse events to be classified, and questions regarding personal judgments. We derived descriptive and quantitative information using weighted Kappa statistics. RESULTS: Fifty-two (54.7%) thoracic surgeons completed the questionnaire; 41 (78.8%) of the respondents were affiliated with an academic teaching hospital. A total of 1,326 individual weighted Kappa statistics were calculated for all distinct pairs of raters, of which 1,152 (87%) were greater than 0.81, a range that is interpreted as "almost perfect agreement." A further 174 (13%) were in the range between 0.61 and 0.8, interpreted as "substantial agreement." All results were statistically significant (p < 0.0001). The classification system was regarded as straightforward (98% of the respondents), reproducible (94%), logical (92%), and useful (98%). CONCLUSIONS: The modified classification system appears to offer objective, reliable, and reproducible reporting of thoracic morbidity and mortality, and thus may assist continuous quality improvement in thoracic surgery. PMID- 21256277 TI - Improving patient care in cardiac surgery using Toyota production system based methodology. AB - BACKGROUND: A new cardiac surgery program was developed in a community hospital setting using the operational excellence (OE) method, which is based on the principles of the Toyota production system. The initial results of the first 409 heart operations, performed over the 28 months between March 1, 2008, and June 30, 2010, are presented. METHODS: Operational excellence methodology was taught to the cardiac surgery team. Coaching started 2 months before the opening of the program and continued for 24 months. RESULTS: Of the 409 cases presented, 253 were isolated coronary artery bypass graft operations. One operative death occurred. According to the database maintained by The Society of Thoracic Surgeons, the risk-adjusted operative mortality rate was 61% lower than the regional rate. Likewise, the risk-adjusted rate of major complications was 57% lower than The Society of Thoracic Surgeons regional rate. Daily solution to determine cause was attempted on 923 distinct perioperative problems by all team members. Using the cost of complications as described by Speir and coworkers, avoiding predicted complications resulted in a savings of at least $884,900 as compared with the regional average. CONCLUSIONS: By the systematic use of a real time, highly formatted problem-solving methodology, processes of care improved daily. Using carefully disciplined teamwork, reliable implementation of evidence based protocols was realized by empowering the front line to make improvements. Low rates of complications were observed, and a cost savings of $3,497 per each case of isolated coronary artery bypass graft was realized. PMID- 21256278 TI - Invited commentary. PMID- 21256279 TI - Minimally invasive versus sternotomy approach for mitral valve surgery in patients greater than 70 years old: a propensity-matched comparison. AB - BACKGROUND: The goal of this study was to compare the outcome after mitral valve surgery through either standard sternotomy or right lateral minithoracotomy in elderly patients with higher perioperative risk. METHODS: All 1,027 elderly patients (>70 years) who received isolated mitral valve surgery (+/- tricuspid valve repair) between August 1999 and July 2009 were analyzed for outcome differences due to surgical approach using propensity score matching. The etiology of mitral valve disease was degenerative (83%), endocarditis (6%), rheumatic (10%), and acute ischemic (<1%). Isolated stenosis was rare (3%); most patients had mitral valve regurgitation (72%) or combined mitral valve disease (25%). RESULTS: The minimally invasive approach led to longer duration of surgery (186 +/- 61 vs 169 +/- 59 minutes, p = 0.01), cardiopulmonary bypass time (142 +/ 54 vs 102 +/- 45 minutes, p = 0.0001), and cross-clamp time (74 +/- 44 vs 64 +/- 28 minutes, p = 0.015). There were no differences between the matched groups in 30-day mortality (7.7% vs 6.3%, p = 0.82), combined major adverse cardiac and cerebrovascular events (11.2% vs 12.6%, p = 0.86), or other postoperative outcome. Only the number of postoperative arrhythmias and pacemaker implants was higher in the sternotomy group (65.7% vs 50.3%, p = 0.023 and 18.9% vs 10.5%, p = 0.059). Long-term survival was 66% +/- 5.6% vs 56 +/- 5.5% at 5 years and 35% +/- 12% vs 40% +/- 7.9% at 8 years, and did not show significant differences. CONCLUSIONS: Minimally invasive mitral valve surgery through a right lateral minithoracotomy is at least as good and safe as the standard sternotomy approach in elderly patients. PMID- 21256280 TI - Outcomes of minimally invasive valve surgery versus standard sternotomy in obese patients undergoing isolated valve surgery. AB - BACKGROUND: We hypothesize that composite in-hospital surgical complications are lower in obese patients who undergo minimally invasive valve surgery for aortic and (or) mitral valve disease, when compared with the standard median sternotomy approach. METHODS: We retrospectively reviewed 2,288 heart operations done at our institution between January 3, 2005 and January 10, 2010, and identified 160 consecutive obese patients, defined as patients with a body mass index of greater than 30 kg/m(2), who underwent isolated mitral and (or) aortic valve surgery. The outcomes of those who had minimally invasive valve surgery were compared with a matched control group who had valve surgery through a median sternotomy approach. RESULTS: Of the 160 patients, 64 underwent the minimally invasive approach and 96 had a median sternotomy. The mean age was 69.4 +/- 11 years for the minimally invasive group, and 64.7 +/- 11.5 for the median sternotomy group (p = 0.015). Composite postoperative complications occurred in 15 (23.49%) versus 49 (51.0%) patients (p = 0.034) in the minimally invasive group versus median sternotomy, respectively. The difference was driven by a lower incidence of acute renal failure (0 vs 6 patients [6.25%], p = 0.041), prolonged intubation (12 [18.7%] vs 33 [34.3%], p = 0.049), reintubation (3 [4.68%] vs 15 [15.6%], p = 0.032), deep wound infections (0 vs 4 [4.1%], p = 0.098), and death (0 vs 8 [8.3%], p = 0.041), respectively. All patients in the minimally invasive group were alive at 30 days. CONCLUSIONS: Minimally invasive surgery for isolated valve lesions in obese patients has a lower morbidity and mortality when compared with the standard median sternotomy approach. PMID- 21256281 TI - Outcome of patients with aortic stenosis referred to a multidisciplinary meeting for transcatheter valve. AB - BACKGROUND: Until recently, many elderly patients with symptomatic aortic stenosis and multiple risk factors were untreated due to perceived risks of surgery. With the advent of transcatheter aortic valve implantation there has been a surge in referral for treatment. We present the outcome of patients referred to a multidisciplinary meeting. METHODS: A total of 175 patients were reviewed between January 2008 and March 2010. Patients' characteristics, investigations, and their outcome designated for transcatheter aortic valve implantation, surgical aortic valve replacement, and medical therapy were studied. The decision making process was a combination of known risk factors accounted for in the European system for cardiac operative risk evaluation and factors unaccounted for in traditional scoring systems. RESULTS: Sixty-three patients underwent transcatheter implantation, 74 underwent surgical valve replacement, and 38 were treated medically. There were no deaths at 30 days in the transcatheter or surgical group. There were more strokes (6.3% vs 1.4%, p = 0.057) and pacemaker implantations (25% vs 0, p = 0.0001) in the transcatheter group compared with the surgical group. The patients in the transcatheter group had shorter ventilation and intensive care stays. Similar numbers were discharged home or to their original residence. At median follow-up of 466 days, more patients had paravalvular and central aortic valve regurgitation in the transcatheter group. At one year there were more deaths in the medically managed group (30%), compared with the transcatheter (17%) or surgical groups (4%). CONCLUSIONS: Symptomatic high-risk aortic valve patients have a good outcome after transcatheter aortic valve implantation or surgery. Forty-two percent of patients referred for transcatheter aortic valve implantation had surgery and did well. The medically managed group have a poor outcome. PMID- 21256282 TI - Performance of SynerGraft decellularized pulmonary homograft in patients undergoing a Ross procedure. AB - BACKGROUND: In the Ross aortic valve replacement (AVR), a pulmonary allograft normally replaces the autotransplanted pulmonary valve. Despite the Ross advantages vs other AVR procedures, there has been a small but unpredictable risk of early structural allograft valve deterioration, usually manifested by shrinkage and right ventricular outflow tract obstruction. This study analyzed our results of the Ross AVR using a new CryoValve SynerGraft (CryoLife Inc, Kennesaw, GA) decellularized pulmonary allograft (SGDPA) and compared it with the standard cryopreserved allograft (SCA) used during the same period. METHODS: Between 2000 and 2009, 29 patients received a SGDPA and 34 received the SCA during Ross AVR. Patients were a mean age at implant of 28.6 +/- 16.0 years (range, 4 months to 58 years). Retrospective data included reported adverse events, and the most recent hemodynamic data were collected. RESULTS: No early or late deaths or significant morbid events occurred during the mean follow-up of 4.9 +/- 2.7 years (range, 2 months to 9 years). No patient required conduit reoperation. The median peak gradient at discharge was 12 mm Hg and was not significant at last follow-up. No deterioration in conduit valve function occurred in the SGDPA group. Mild conduit regurgitation developed in several SCA patients, and one patient had moderate regurgitation. No patient reached our definition of conduit dysfunction (peak gradient: 40 mm Hg or >2+ regurgitation). CONCLUSIONS: The SGDPA conduit is an alternative to the SCA for the Ross AVR. The early clinical and hemodynamic results are encouraging but were not significantly different from the SCA. SynerGraft technology may provide a more durable option for patients who need right ventricular outflow tract reconstruction. Further long-term follow-up is needed to see if this decellularization process improves long-term allograft durability. PMID- 21256283 TI - Serial changes of hemodynamic performance with Medtronic Hall valve in aortic position. AB - BACKGROUND: The aim of this study was to evaluate the long-term hemodynamic performance of the Medtronic Hall valve by analyzing serial changes in echocardiographic outcomes in aortic position. METHODS: One hundred seventeen patients who underwent aortic valve replacement (AVR) using the Medtronic Hall valve between August 1997 and January 2004 were retrospectively studied. Fifty five patients underwent isolated AVR (AVR group), and 62 patients underwent AVR and mitral valve replacement (double valve replacement group). Mean age was 51.2 +/- 10.4 years (range, 26 to 67 years), and mean follow-up duration was 93.7 +/- 25.6 months (913.6 patient-years; range, 17 to 140 months). Serial echocardiographic data were analyzed. RESULTS: Overall mortality was 12.8% (15 of 117), but no early mortality occurred. A greater than 15 mm Hg increment of aortic transprosthetic mean pressure gradient at last follow-up occurred in 13 patients (11.1%). Redo AVR was performed in 7 patients, 6 of whom had subaortic pannus ingrowths. Group cumulative survival rates at 10 years were similar (90.4%, AVR group versus 88.4%, double valve replacement group; p = 0.580), but the AVR group showed better adverse cardiac event-free survival at 10 years (80.1% versus 53.8%; p = 0.025). Multivariate analysis showed that double valve replacement and a small-sized valve (20 mm) significantly predicted the increment of aortic transprosthetic mean pressure gradient at last follow up greater than 15 mm Hg (p = 0.013; odds ratio, 13.9; p = 0.019; odds ratio, 4.2, respectively). CONCLUSIONS: The transprosthetic mean pressure gradient of the Medtronic Hall valve in the aortic position frequently increased as a function of time, and this increase was more common in patients who had undergone double valve replacement, especially in those implanted with a small valve. PMID- 21256284 TI - Simultaneous hybrid revascularization versus off-pump coronary artery bypass for multivessel coronary artery disease. AB - BACKGROUND: This study sought to compare early and midterm clinical outcomes of a simultaneous hybrid coronary revascularization procedure with those in a propensity-matched subset of patients undergoing conventional off-pump coronary artery bypass grafting. METHODS: From June 2007 through December 2009, 104 consecutive patients (mean age 61.8 +/- 10.2 years) with multivessel coronary artery disease underwent elective simultaneous coronary revascularization at Fuwai Hospital. Using propensity score methodology, these patients were matched with 104 patients who had undergone off-pump coronary artery bypass grafting through median sternotomy during the same period. We compared these groups' in hospital clinical outcomes and freedom from major adverse cardiac or cerebrovascular events at a mean follow-up of 18 +/- 7.9 months. RESULTS: The hybrid procedure required longer operative time and incurred higher in-hospital costs, but had shorter median intubation time (11.6 +/- 6.3 vs 13.8 +/- 6.8 hours, p = 0.02), intensive care unit length of stay (34.5 +/- 35.6 vs 55.3 +/- 46.4 hours, p < 0.001), and postoperative in-hospital length of stay (8.2 +/- 2.6 vs 9.5 +/- 4.5 days, p = 0.01). The hybrid group had significantly less chest tube drainage (789 +/- 389 vs 834 +/- 285 mL, p = 0.005) and need for blood transfusion (28.8% vs 51.9%, p > 0.001). At a mean follow-up of 18 months, the freedom from major adverse cardiac or cerebrovascular events is in favor of the hybrid group (99.0% vs 90.4%; p = 0.03). CONCLUSIONS: Compared with conventional off-pump coronary artery bypass grafting, simultaneous hybrid coronary revascularization shortens recovery time and has superior outcomes at a mean follow-up of 18 months. Simultaneous hybrid coronary revascularization provides a safe and reproducible alternative for selected patients with multivessel coronary artery diseases. PMID- 21256285 TI - Invited commentary. PMID- 21256286 TI - Right gastroepiploic artery graft for myocardial revascularization: prevalence of atherosclerosis and availability as a conduit. AB - BACKGROUND: We evaluated prevalence of atherosclerosis and availability of right gastroepiploic artery graft in patients undergoing coronary artery bypass graft surgery. METHODS: Among the 1,579 patients who underwent isolated coronary artery bypass grafting between January 1999 and December 2008, we opened the peritoneum to examine the right gastroepiploic artery for use as a graft in 1,128 patients (71.4%). A computer-based patient database system was utilized for this retrospective study. RESULTS: Of 1,128 patients, 139 patients (12.3%) had atherosclerotic right gastroepiploic arteries at gross examination. Seventy-three of 139 atherosclerotic right gastroepiploic arteries had multiple or diffuse atherosclerotic lesions that precluded their use as a bypass graft; the remaining 66 right gastroepiploic arteries were used as a bypass graft including the atheromatous segment or after exclusion of the atherosclerotic segment. Another 60 nonatherosclerotic right gastroepiploic arteries were unavailable to use as a graft because of their short length, small caliber, and weak pulsation. Overall availability of the right gastroepiploic arteries as a graft was 88.2% (995 of 1,128). Multivariable logistic regression analysis showed older age (>=65 years; p < 0.001), insulin-treated diabetes mellitus (p = 0.001), and chronic renal failure (p < 0.001) as independent risk factors for atherosclerosis. CONCLUSIONS: The prevalence of atherosclerosis and availability of the right gastroepiploic artery graft in patients undergoing isolated coronary artery bypass grafting was 12.3% and 88.2%, respectively. Older age (>=65 years), insulin-treated diabetes mellitus, and chronic renal failure were identified as independent predictors for the atherosclerotic right gastroepiploic artery. PMID- 21256287 TI - Invited commentary. PMID- 21256288 TI - Extensive reconstruction of the left anterior descending coronary artery with an internal thoracic artery graft. AB - BACKGROUND: Revascularization of the diffusely diseased coronary artery is a big challenge for both cardiologists and cardiac surgeons. Long reconstruction of the diffusely diseased vessel may be a useful surgical option. The aim of this study is to assess clinical and angiographic outcomes of extensive reconstruction (>=4 cm) of the left anterior descending coronary artery (LAD) using an internal thoracic artery (ITA) graft with or without endarterectomy. METHODS: We retrospectively reviewed 213 patients who underwent extensive reconstruction of the LAD using an ITA graft between September 2004 and July 2009. The diffusely diseased LAD was extensively incised, additional endarterectomy was performed if necessary, and then the LAD was reconstructed with an ITA graft in a long on-lay fashion. Early and 1-year postoperative angiography was performed in 188 patients (88.3%) and 152 patients (71.4%), respectively. RESULTS: The mean length of the reconstructed LAD was 5.4 +/- 1.2 cm. Endarterectomy was performed in 46.0% of the patients. The operative mortality was 1.4%. Low cardiac output and perioperative myocardial infarction were observed in 3.3 and 5.2% of the patients, respectively. Freedom from death and other cardiac or cerebrovascular events was 91.5 +/- 2.2% at 3 years. The early and 1-year patency rates of the ITA to LAD grafting were 95.7% and 93.4%, respectively. CONCLUSIONS: Extensive reconstruction of the diffusely diseased LAD using an ITA graft could be performed safely. Early and 1-year angiographic outcome were excellent. This surgical revascularization is an useful option for revascularization of the diffuse coronary artery disease. PMID- 21256289 TI - Salvage of pacemakers and automatic implantable cardioverter-defibrillators using dermis grafts. AB - BACKGROUND: Thin patients with thoracic pacemakers and automatic implantable cardioverter-defibrillators often have minimal tissue over the devices, with erosion through the surface a major concern. This erosion can lead to device infection and need for removal, or primary device infection can, in turn, lead to erosion. Even worse is exposure and infection of the leads to the heart, with fatalities having occurred. Pressure symptoms, as with shoulder seatbelt straps, can occur, and the visible deformity may be objectionable. METHODS: To correct these problems without device removal, we used a novel surgical approach. Thirteen patients had 15 grafts, of either the acellular dermal graft AlloDerm (LifeCell Corp, Branchburg, NJ [n = 13 for threatened exposure or pressure symptoms, including two repeats]) or autogenous dermis (n = 2 for existing open wounds with chronic drainage) placed over the devices. RESULTS: After all graft procedures, there was no skin breakdown; exposure and extrusion were completely prevented. Follow-up was 3 to 68 months (mean 36.8). The 2 open wound patients treated with dermis autografts had no recurrence of wound breakdown. Most patients with pressure symptoms had reduction in tenderness and pain. Patients liked the visible softening of the device contour, but not the subtly increased forward projection. The only immediate complication was one rapidly expanding hematoma leading to graft removal. One late complication was a mild infection, treated successfully. CONCLUSIONS: Acellular human dermal allografts, or live dermis autografts, provided significant protection over cardiac pacing devices in 13 patients with 15 grafts, with no subsequent surface exposures or extrusions. PMID- 21256290 TI - Invited commentary. PMID- 21256291 TI - Pathogenesis of acute aortic dissection: a finite element stress analysis. AB - BACKGROUND: Type A and type B aortic dissections typically result from intimal tears above the sinotubular junction and distal to the left subclavian artery (LSA) ostium, respectively. We hypothesized that this pathology results from elevated pressure-induced regional wall stress. METHODS: We identified 47 individuals with normal thoracic aortas by electrocardiogram-gated computed tomography angiography. The thoracic aorta was segmented, reconstructed, and triangulated to create a geometric mesh. Finite element analysis using a systolic pressure load of 120 mm Hg was performed to predict regional thoracic aortic wall stress. RESULTS: There were local maxima of wall stress above the sinotubular junction in the ascending aorta and distal to the ostia of the supraaortic vessels, including the LSA, in the aortic arch. No local maximum of wall stress was found in the descending thoracic aorta. Comparison of the mean peak wall stress above the sinotubular junction (0.43 +/- 0.07 MPa), distal to the LSA (0.21 +/- 0.07 MPa), and in the descending thoracic aorta (0.06 +/- 0.01 MPa) showed a significant effect for wall stress by aortic region (p < 0.001). CONCLUSIONS: In the normal thoracic aorta, there are peaks in wall stress above the sinotubular junction and distal to the LSA ostium. This stress distribution may contribute to the pathogenesis of aortic dissections, given their colocalization. Future investigations to determine the utility of image-derived biomechanical calculations in predicting aortic dissection are warranted, and therapies designed to reduce the pressure load-induced wall stress in the thoracic aorta are rational. PMID- 21256292 TI - Invited commentary. PMID- 21256294 TI - Invited commentary. PMID- 21256293 TI - Arch debranching versus elephant trunk procedures for hybrid repair of thoracic aortic pathologies. AB - BACKGROUND: We compared outcomes of arch debranching (AD) and elephant trunk (ET) techniques when used with thoracic endovascular aortic repair. METHODS: A review was performed of consecutive patients with proximal thoracic aortic pathologies repaired with a hybrid approach. RESULTS: Between 2005 and 2009, 58 patients underwent first-stage ET (n = 21) or AD (n = 37). Cardiopulmonary bypass was utilized in 100% of ET procedures and 68% of AD procedures (p < 0.01). Circulatory arrest was used in 86% of ET and 27% of AD cases (p < 0.01). The second stage was completed in 76% of ET and 76% of AD patients. Rates of spinal cord ischemia (ET 0 of 21, AD 0 of 37, p = 1.0), stroke (ET 2 of 21, AD 4 of 37, p = 1.0), and 30-day mortality (ET 4 of 21, AD 6 of 37, p = 1.0) were similar. Each group had one major aortic complication between the two stages. Type Ia endovascular leak at 1 and 12 months occurred in 13% ET patients and 4% AD patients at 1 month (p = 0.54) and in 0% ET patients and 4% AD patients at 12 months (p = 1.0). Kaplan-Meier estimates of survival at 1 and 12 months were 90.5% +/- 6.4% and 73.1% +/- 10% in the ET group, and 86.5% +/- 5.6 and 71.6% +/- 8.5 in the AD group, respectively (p = 0.68). The risk of a secondary procedure at 1 and 12 months was 76.2% +/- 9.3% and 58.7% +/- 12% in the ET group, and 71.0% +/- 7.8% and 52.8% +/- 10% in the AD group, respectively (p = 0.86). CONCLUSIONS: Arch debranching achieves equivalent results to standard elephant trunk repair but with a decreased need for cardiopulmonary bypass and circulatory arrest. PMID- 21256295 TI - Minimizing cerebral embolism in resection of distal aortic arch aneurysm through a left thoracotomy. AB - BACKGROUND: In order to reduce the risk of cerebral embolism during aortic replacement through a left thoracotomy, we performed ascending or arch aortic cannulation (AAC) as well as early extracorporeal perfusion (EEP) under deep hypothermic circulatory arrest (DHCA). In this study we examined the effectiveness of these modifications in preventing cerebral embolism after distal arch replacement. METHODS: Between January 2006 and March 2010, 40 patients underwent distal arch replacement through a left thoracotomy, using 2 pieces of an artificial graft. In all patients, AAC, EEP, and the open technique for aortic anastomosis were performed under DHCA. The AAC resulted in the proximal aortic perfusion from the proximal site of the diseased aorta. The EEP was induced by aortic distal perfusion from the side branch of a distal graft. After completion of the proximal anastomosis under EEP and DHCA, anastomosis between the proximal and distal grafts was made during rewarming. Neurologic deficit in the brain and spinal cord, as well as early surgical results, were clinically evaluated. RESULTS: There was no permanent neurologic deficit after the surgery in the operative survivors. No patient had a stroke (0%). Temporary paraplegia and paraparesis occurred in 1 and 2 patients, respectively (7.7%); all 3 patients were able to walk prior to their discharge from hospital. Mortality in this series was 5.0% (2 of 40 patients); the cause of death was rupture of an esophageal ulcer and cardiogenic shock possibly due to myocardial infarction. CONCLUSIONS: The AAC and EEP, in addition to deep hypothermia and DHCA, minimized the risk of cerebral embolism after distal arch aortic replacement by the left lateral approach. PMID- 21256296 TI - Long-term results and cusp dynamics after aortic valve resuspension for aortic root aneurysms. AB - BACKGROUND: This study reports our 10-year experience with the David technique and technical modifications to create neosinuses. METHODS: From January 1996 to February 2009, the David procedure was performed in 151 consecutive patients in our department. Mean age was 59 +/- 13 years (range, 22 to 78 years). All patients had ascending aortic aneurysm (mean diameter, 6.0 +/- 1.1 cm); 59 patients had additional arch aneurysm. Fifty-four patients underwent the standard David procedure, with a pseudosinus created in 42 patients (28%) and neosinuses in 55 patients (36%) by plicating the base and sinotubular junction of the tube graft. Patients were followed up prospectively and had echocardiography studies before discharge and at follow-up. Mean follow-up was 5 years (584 patient years). RESULTS: There were 6 in-hospital and 16 late deaths. Reexploration for bleeding was necessary in 27 patients (17%). Three patients had perioperative neurologic events, and 2 patients experienced them during follow-up. Five patients required late aortic valve replacement. Cardiovascular events were the cause of late death in 6 patients. Valve gradients were low, with only 2 patients having significant valve incompetence remaining. Echocardiography results showed a more physiologic, reduced velocity of cusp movement in the neosinus group compared with the conventional technique. CONCLUSIONS: Aortic valve resuspension is a durable procedure. Only 4.8% experienced a relevant valve dysfunction. Other valve-related complications were minimal, with three observed neurologic events and one endocarditis. Creation of the neosinus lead to more physiologic leaflet dynamics and facilitated geometric adaptation. PMID- 21256297 TI - Invited commentary. PMID- 21256298 TI - Dynamic normal aortic root diameters: implications for aortic root reconstruction. AB - BACKGROUND: The main aim of this study is to determine the normal diameter and the relationship of aortic root components in healthy adults, and to provide a morphologic foundation for future clinical applications. METHODS: Echocardiography was performed in 314 normal subjects who were divided into five groups according to age. Dynamic aortic root diameters were measured and normalized to body surface area. Averages of these dynamic diameters were calculated for each age group and by gender, and differences between them were tested. Correlation coefficients were also determined between the dynamic diameters and age, body surface area, weight, and height. Aortic root diameters were also tested and compared between the end-diastole and the mid-systole. RESULTS: Normalized diameters for the dynamic aortic root varied among the age groups. There were apparent relationships between the dynamic diameters and age, body surface area, weight, and height (p < 0.01). The normalized diameters were similar between both genders within each age group (p > 0.05). Each part of the aortic root expanded and contracted proportionally and harmoniously during the cardiac cycle. The ratio of the aortic valve annulus to the sinus of Valsalva, the sinus-tube joint, and the proximal ascending aorta were 0.70, 0.85, and 0.78 at the end-diastole, respectively, and 0.71, 0.85 and 0.78 at the mid-systole, respectively. CONCLUSIONS: The dynamic diameters of aortic roots of healthy adults were augmented with an increase according to age, body surface area, weight, and height. The results are of applicable value to aortic valve repair. PMID- 21256299 TI - Invited commentary. PMID- 21256300 TI - Surgical ventricular restoration for patients with ischemic heart failure: determinants of two-year survival. AB - BACKGROUND: Surgical ventricular restoration (SVR) improves left ventricular (LV) systolic function by partially restoring the normal geometry of the left ventricle. However, the beneficial effects of this surgical procedure on long term clinical outcome remain controversial. The present study aimed to evaluate the independent determinants of 2-year morbidity and mortality rates after SVR. METHODS: Seventy-nine patients with ischemic heart disease and LV ejection fraction of 0.35 or less were included. All patients underwent SVR and additionally coronary artery bypass grafting or mitral valve surgery if clinically indicated. Clinical and echocardiographic examination was performed before SVR and at 6 months' follow-up. The primary end point was a composite of all-cause mortality and hospitalizations for heart failure. RESULTS: At 6 months' follow-up a significant improvement in heart failure symptoms was noted. In addition, LV ejection fraction increased from 0.27 +/- 0.07 to 0.36 +/- 0.10 (p < 0.001). During a median follow-up of 2.7 years, the primary end point was recorded in 22% of the patients. Baseline New York Heart Association functional class IV and a 6-month follow-up LV end-systolic volume index of at least 60 mL/m(2) were independently associated with worse outcome (hazard ratio, 5.4; 95% confidence interval, 1.9 to 15.2; p < 0.001; hazard ratio, 2.7; 95% confidence interval, 1.3 to 5.6; p < 0.001, respectively). CONCLUSIONS: Advanced heart failure status at baseline and large residual postsurgery LV end-systolic volume index were independently associated with increased mortality and heart failure hospitalization rates at 2 years' follow-up after SVR. PMID- 21256301 TI - Outcomes and cost of cardiac surgery in octogenarians is related to type of operation: a multiinstitutional analysis. AB - BACKGROUND: Given recent economic implications in caring for an aging population, we sought to determine if postoperative complications and costs for octogenarians differed based on the type of cardiac operation. METHODS: From 2003 to 2008, patients who underwent cardiac operations at 16 different centers were identified from the Virginia Cardiac Surgery Quality Initiative and selected into two cohorts (<80 years and >=80 years). Octogenarians (>=80 years) were stratified into isolated primary coronary bypass graft, aortic valve, mitral valve, or combined operation. Preoperative risks, outcomes, and costs were analyzed. Case mix adjusted models for mortality and major complication rate were developed. RESULTS: We examined 45,731 patients, of which 3,079 were octogenarians (82.7 +/- 2.5 years). Compared with younger patients, octogenarians incurred higher mortality (6.5% vs 3.1%, p < 0.001) and major complication rates (13.2% vs 8.4%, p < 0.001) with only incrementally higher total costs (p < 0.001). Among octogenarians mortality was similar despite the operation. Cross-clamp and cardiopulmonary bypass time (p < 0.001), hospital length of stay (p = 0.001), and major complication rate (p = 0.002) were highest for combined operation. Despite the fewest complications, mitral valve operation had the highest total costs (p < 0.001). Type of operation was not predictive of mortality or major complication rate. However, age, female gender, emergent status, and prolonged cardiopulmonary bypass time were independently associated with death despite risk-adjustment. CONCLUSIONS: Advanced age confers increased risks and incrementally higher costs in patients undergoing cardiac operations. Isolated mitral and combined procedures have the highest complications and costs. Any proposed cardiac operation in octogenarians mandates careful consideration of resource utilization. PMID- 21256302 TI - Twenty years of cardiac surgery in patients aged 80 years and older: risks and benefits. AB - BACKGROUND: Patients aged 80 years and older who require cardiac surgical procedures are an increasing population and usually present with considerable comorbidity. Detailed operative risk stratification versus long-term survival and quality of life after surgery is mandatory. METHODS: A retrospective analysis was performed on 1,003 patients aged 82.3 years (range, 80 to 94 years) who underwent aortic valve replacement (n = 303), coronary artery bypass grafting (n = 403), or aortic valve replacement with coronary artery bypass grafting (n = 297) between 1987 and 2006. Preoperative data, operative outcome, long-term survival, and predictors for early and late mortality were analyzed. Furthermore, the Short Form 36 Health Status questionnaire was used to evaluate the quality of life. RESULTS: Overall in-hospital mortality was 7.1%. Overall actuarial survival at 1, 5, and 10 years was 81.6% +/- 1.2%, 60.4% +/- 1.9%, and 23.3% +/- 2.6% (mean survival time, 6.25 +/- 0.2 years) and showed no significant difference compared with an age- and sex-matched general population. Multivariate analysis showed that preoperative creatinine concentration greater than 1.3 mg/dL (p < 0.001), preoperative atrial fibrillation (p < 0.005), and postoperative prolonged ventilation (p < 0.001) were independent predictors for poor long-term survival. The physical health summarized score of the Short Form 36 Health Status questionnaire was significantly increased in the study population compared with a German standard population aged 80 years and older (p < 0.05). CONCLUSIONS: Despite an increased operative mortality, octogenarians showed a considerable quality of life and an excellent long-term survival. To further improve surgical outcome in octogenarians, patient selection should be done with consideration of the identified independent preoperative risk factors. PMID- 21256303 TI - Predictors and outcomes of seizures after cardiac surgery: a multivariable analysis of 2,578 patients. AB - BACKGROUND: Limited data exist regarding the epidemiology and prognosis of seizures in adults after cardiac surgery. The aim of this study was to define preoperative predictors of seizures and impact on postoperative outcomes. METHODS: A prospective database of 2,578 consecutive adults who underwent cardiac surgery at a single institution between April 2007 and December 2009 was retrospectively analyzed to determine risk factors for postoperative seizures and prognostic impact. No patient received tranexamic acid or aprotinin. RESULTS: Seizures occurred in 31 patients (1%) at a median of 2 days postoperatively (1 patient had a preoperative diagnosis of seizure disorder). Seizures were classified as generalized tonic-clonic (71%), simple/complex partial (26%), or status epilepticus (3%). Incidence differed according to procedure (coronary bypass 0.1%, isolated valve 1%, valve/coronary bypass 3%, aorta 5%; p <0.001). Patients who experienced seizures had nearly a fivefold higher operative mortality than patients who did not (29% versus 6%, p <0.001). Head computed tomography was performed in 26 patients (84%), of whom ischemic strokes were identified in 14 cases (53%). These were embolic in 9 patients (34%), and watershed in 3 (12%). Hemorrhagic strokes were observed in 2 patients (8%). The occurrence of a new postoperative stroke in seizure patients did not significantly increase the likelihood of in-hospital death. Thirteen patients (41%) were discharged without neurologic deficit. Multivariable logistic regression analysis identified three risk factors for seizure: deep hypothermic circulatory arrest, aortic calcification or atheroma, and critical preoperative state. CONCLUSIONS: Seizures in adults after cardiac surgery are strong independent predictors of permanent neurologic deficit and increased operative mortality. Early head computed tomography may be indicated to identify treatable pathology. PMID- 21256304 TI - Invited commentary. PMID- 21256305 TI - Dose-dependent effect of statins on the incidence of acute kidney injury after cardiac surgery. AB - BACKGROUND: Acute kidney injury (AKI) after cardiac surgery is associated with increased morbidity and mortality. METHODS: We assessed whether statin treatment is associated with a lower incidence of postoperative AKI in 2,104 consecutive patients who underwent coronary artery bypass graft or valve surgery at the Minneapolis Veterans Administration Medical Center. Acute kidney injury was defined as absolute increase greater than 0.3 mg/dL or relative increase greater than 50% in serum creatinine from baseline, within 48 hours after surgery or requiring postoperative hemodialysis per AKI network. Propensity scores were utilized to adjust for the differences between the statin and the no-statin treatment groups. All statins were converted to equivalent-dose simvastatin and divided at the median to construct high-dose (>=40 mg) and low-dose (<40 mg) statin groups. RESULTS: Of the 2,104 patients, 1,435 (68%) were taking statins (638 high-dose) and 495 (24%) developed AKI (25% high-dose vs 40% low-dose vs 35% no-statin; p = 0.014). Estimated preoperative glomerular filtration rate (p = 0.003), diabetes mellitus (p=0.02), valve surgery with or without coronary artery bypass graft (p = 0.024), cardiopulmonary bypass time (p = 0.001), and intraaortic balloon pump (p = 0.055) were independent predictors of AKI. After propensity adjustment statin treatment was not associated with postoperative AKI (odds ratio 0.79; 95% confidence interval 0.59 to 1.06; p = 0.11 for high-dose v. no-statin). After full adjustment for all independent predictors of AKI, the results did not change. Statins also had no effect on the incidence of postoperative hemodialysis (0.8% high-dose vs 1.9% low-dose vs 1% no-statin; p = 0.15). CONCLUSIONS: Statin treatment is not associated with a lower incidence of AKI after cardiac surgery. PMID- 21256306 TI - Invited commentary. PMID- 21256307 TI - Artificial surface-induced inflammation relies on complement factor 5: proof from a deficient person. AB - BACKGROUND: Exposing blood to artificial surfaces results in an inflammatory response, including complement activation and cytokine release. The aim of this investigation was to study complement-dependency and independency in artificial surface-induced inflammation in human whole blood from a patient with a genetic deficiency of complement factor 5 (C5). METHODS: Whole blood from a C5-deficient patient, C5 protein reconstituted blood, and blood from a control subject was used. The complement inhibitor compstatin (C3 inhibitor) and a C5a receptor antagonist were used to block complement. Blood was circulated in closed loops of polyvinyl chloride tubing. Leukocyte CD11b expression and release of granule enzymes (myeloperoxidase, elastase, lactoferrin), cytokines (interleukins, chemokines, and growth factors; n = 27) as well as complement activation were measured after incubation. RESULTS: In C5-deficient blood, there was no formation of the terminal complement complex, as opposed to reconstituted or control blood. Release of granule enzymes was partly dependent on C3, revealed by a compstatin dependent effect in C5-deficient blood, and partly C5a-dependent as evident from the reconstitution and control blood. The chemokines interleukin-8 and monocyte chemoattractant protein-1 were also highly complement dependent, the effect being C5a-mediated, whereas platelet-derived and vascular endothelial growth factors were partly complement dependent. Interferon-gamma increased in a complement independent manner, whereas the rest of the cytokines did not respond to the surface. Leukocyte expression of CD11b was only marginally increased in deficient blood exposed to the surface, whereas reconstitution induced a considerable, C5a dependent increase, comparable with that of the control. CONCLUSIONS: The polyvinyl chloride surface induced a defined inflammatory response, which largely depended on C5. PMID- 21256308 TI - Leukocyte depletion during extracorporeal circulation allows better organ protection but does not change hospital outcomes. AB - BACKGROUND: Leukocyte filtration has been reported to reduce inflammatory damage during cardiopulmonary bypass. We evaluated the role of leukocyte filtration on hospital outcome and postoperative morbidity. METHODS: Eighty-two consecutive patients who underwent isolated coronary artery bypass grafting were randomly assigned (1:1) to receive leukocyte filters on both arterial and cardioplegia lines or standard arterial filters during cardiopulmonary bypass. Hospital outcome, postoperative markers of morbidity, and biochemical assays were compared. Data were collected preoperatively, intraoperatively, and postoperatively. Costs for patients receiving intraoperative leukofiltration were compared with control patients getting standard arterial filters. RESULTS: Hospital mortality and intensive care unit and hospital length of stay were similar. Although duration of ventilation and incidence of pneumonia were comparable, leukocyte-depleted patients showed a higher ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (p = 0.008) and lower need for postoperative noninvasive ventilation (p = 0.041). Control patients showed higher need for continuous furosemide infusion (p = 0.013) and for renal replacement therapy (p = 0.014), in association with higher serum creatinine (p = 0.038) and blood urea (p = 0.18) and lower glomerular filtration rate (p = 0.038). Leukocyte depleted patients required lower doses of inotropic agents (p = 0.56), whereas troponin I leakage and incidence of postoperative atrial fibrillation were comparable. No differences were found in terms of postoperative cerebral dysfunction or neutrophil and platelet counts, as well as postoperative bleeding and need for transfusions. Finally, leukodepletion proved significantly cost beneficial, with a 37% cost reduction. CONCLUSIONS: Although hospital outcomes were similar in terms of mortality and length of stay, the improvements in pulmonary, renal, and myocardial function, in association with the cost benefit, justify the use of leukocyte-depletion filters in the clinical practice. PMID- 21256309 TI - Invited commentary. PMID- 21256310 TI - Risk factors for preoperative and postoperative progression of aortic regurgitation in congenital ruptured sinus of Valsalva aneurysm. AB - BACKGROUND: We reviewed our experience with congenital ruptured sinus of Valsalva aneurysms (RSVA) to determine risk factors influencing occurrence and postoperative worsening of aortic regurgitation (AR). METHODS: Over an 11-year period, 210 patients (33 +/- 9.7 years old) underwent surgical repair of RSVA. Aneurysm originated from the right noncoronary sinus and other sinuses in 171, 35 and 4 patients, respectively; and ruptured into right ventricle outlet tract in 115 patients, right ventricle in 16, right atrium in 75, and other chambers in 4. Aortic regurgitation (111) and ventricular septal defect (108) were common coexisting anomalies. Patch closure of RSVA was performed in 61 patients, direct sutures in 18 patients, patch closure plus direct sutures in 88 patients, and repair simultaneous with aortic valve replacement in 43 patients. RESULTS: All but one patient survived the operation. In early postoperative periods, AR improved in 26 patients and worsened in 23. In 114 late follow-up patients with echocardiographic assessment, 18 showed deteriorated AR. By logistic regression analysis, RSVA ruptured into the right ventricle outlet tract and secondary changes of the aortic valve were risk factors for preoperative AR, and RSVA repaired with direct sutures had a significantly higher incidence of early worsening of AR. By Cox regression analysis, AR at discharge was an independent risk factor for late follow-up AR worsening. CONCLUSIONS: The RSVA can be repaired with a low mortality and excellent long-term result. An early, aggressive treatment should be recommended to prevent postoperative AR, and a direct-suture closure of RSVA should be avoided to prevent early worsening of AR. PMID- 21256311 TI - Anomalous origin of left coronary artery from pulmonary artery in older children and adults: direct aortic implantation. AB - BACKGROUND: Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) presents rarely in adulthood and is treated by different surgical techniques with varying results. This study was undertaken to evaluate the feasibility of reestablishment of a dual coronary system in older children and adults with emphasis on direct aortic implantation. METHODS: From 2002 to 2010, 10 patients aged 10 to 51 years (median age, 24 years) underwent surgical correction of ALCAPA. Median weight was 44.5 kg. All the patients except 2 were symptomatic. Two patients were in atrial fibrillation. Eight patients had varying degrees of mitral regurgitation, which was severe in 2. In all patients, the left coronary artery was arising from the facing sinus of the pulmonary artery. Direct left main coronary implantation into the aorta was feasible in all patients. Mitral valve replacement was done in 4 patients. RESULTS: At a median follow-up of 5.5 years there was no new angina or infarction. One patient died 3 months postsurgery due to intracerebral bleed. Echocardiography demonstrated normal antegrade flow in the transferred left coronary artery, with 2 patients having persistent moderate mitral regurgitation. Coronary angiography done on follow-up in one patient revealed a patent transferred left coronary artery with distal development of new atherosclerotic lesion. CONCLUSIONS: Direct reimplantation of the ALCAPA is considered technically more difficult and hazardous in adults. With increased experience with coronary transfer technique, direct aortic implantation is feasible in adult cases. This provides a more physiologic correction and reestablishment of a dual coronary system with a better outcome. PMID- 21256312 TI - Invited commentary. PMID- 21256313 TI - Late pulmonary valve replacement in patients with pulmonary atresia and intact ventricular septum: a case-matched study. AB - BACKGROUND: Pulmonary valve replacement (PVR) is a common therapy for chronic pulmonary regurgitation. However, the use of this strategy is mostly based on the studies performed on patients with tetralogy of Fallot (TOF) and not in patients with pulmonary atresia/intact ventricular septum (PA/IVS). The aim of this study is to evaluate our experience with PVR in patients with PA/IVS and compare them with a matched cohort of TOF patients. METHODS: Between 1995 and 2009, 13 patients with PA/IVS underwent a late PVR. Matched TOF control subjects were identified for 12 of these patients. Before and after PVR echocardiographic, magnetic resonance imaging, exercise test, Holter, and electrocardiographic data were compared between groups. RESULTS: There was no mortality in either group. The PVR improved pulmonary regurgitant fraction and right ventricular volumes in all patients. Patients with PA/IVS had more significant tricuspid regurgitation (TR [at least moderate]) by echocardiography and magnetic resonance imaging before PVR (n = 11 [85%] versus n = 1 [8%]; p = 0.003) and had more tricuspid valve repairs than TOF patients (n = 9 [69%] versus n = 1 [8%]; p = 0.004). Repair was undertaken by a combination of techniques. Although TR was improved early postoperatively, only 2 of 9 patients (22%) were free from significant TR at most recent follow-up (median 2.5 years; range, 0.1 to 10.9). No patient underwent reoperation at latest follow-up. CONCLUSIONS: Patients with PA/IVS can undergo a late PVR with excellent results. Significant TR and repair are more commonly observed among patients with PA/IVS compared with TOF patients. Although tricuspid valve repair improves regurgitation early, TR tends to recur, suggesting the need for further refinement of current surgical techniques. PMID- 21256314 TI - Invited commentary. PMID- 21256315 TI - Risk factors for prosthesis failure in pulmonary valve replacement. AB - BACKGROUND: After initial right ventricular outflow tract reconstruction, replacement of the pulmonary valve (PVR) with a bioprosthetic valve may be performed. Bioprosthetic valves fail (PVF) and require repeat replacement. Identification of risk factors for PVF would be useful for clinicians choosing among various options for the initial PVR. METHODS: We retrospectively analyzed outcomes of 169 consecutive patients (55% male) with repaired tetralogy of Fallot or pulmonary stenosis undergoing a first PVR. Data were abstracted from the medical records, including gender, diagnosis, indication for PVR, age at PVR (< 10 years or >= 10 years), type of valve, and time of PVF. Actuarial freedom from PVF was compared by log rank and parametric survival analysis. Risk factors for PVF were analyzed by univariate and multivariate methods. Prosthesis types for PVR were pulmonary homograft in 56, stented porcine valve in 16, stented porcine valve in Dacron (DuPont, Wilmington, DE) conduit in 26, and bovine pericardial valve in 71. RESULTS: Indication for PVR was pulmonary stenosis in 21% and insufficiency in 79%. Median follow-up for the entire cohort was 8 years. PVF occurred in 24 patients at a median time of 5.7 years. Actuarial freedom from PVF at 10 years was 72% for all valve types, 55% for porcine valve in Dacron conduit, 60% for homograft, 75% for porcine valve, and 78% for bovine pericardial valve (p = 0.36). By univariate analysis, young age (p < 0.0001), male gender (p = 0.0017), and indication of pulmonary stenosis (p = 0.015) were risk factors for PVF. In multivariate analysis, tetralogy of Fallot anatomy (p < 0.06), younger age (p < 0.02), and use of a homograft valve (p < 0.02) were risk factors for early PVF (<3 years). Young age (p < 0.0001) at time of PVR was associated with late PVF. CONCLUSIONS: Freedom from reoperation for PVR during 10 years of follow up is excellent. Younger age, tetralogy of Fallot, and use of a homograft valve were risk factors for early PVF. Only younger age at PVR was a significant risk factor for late PVF. PMID- 21256316 TI - Hybrid management strategy for percutaneous Fontan completion without surgery: early results. AB - BACKGROUND: We report early results of surgical preparation and subsequent percutaneous Fontan completion strategy for the treatment of single-ventricle defects. METHODS: Two hundred twenty-seven patients underwent bidirectional cavopulmonary connection (BDCPC) between 2002 and 2007. Thirty-four patients had lateral tunnel created at time of BDCPC, fenestrated with 10 to 14 mm openings with the cardiac superior vena cava end patched to maintain BDCPC physiology. At second stage, Fontan circulation was established by superior vena cava patch perforation, tunnel dilatation, and stenting plus fenestration device closure. RESULTS: Thirty-four patients underwent Fontan preparation with BDCPC. Median age was 7.7 months (5 to 51) and 29 patients (85%) had previous palliation. Mean bypass and ischemic times were 141 and 72 minutes, respectively. Median ventilation, intensive care, and hospital stay durations were 1, 5, and 10 days, respectively. There was one early death and two take-downs. Twenty-eight patients underwent Fontan procedure: surgical (n = 3), percutaneous (n = 25). None of the patients who underwent percutaneous Fontan completion required inotropes, chest tube insertion, or mechanical ventilation. Median intensive care and hospital stay durations were 1 and 6 days, respectively. There were no early mortalities after percutaneous Fontan but one late death and one surgical revision. Overall survival after BDCPC with Fontan preparation was 77%. CONCLUSIONS: Despite longer bypass and ischemic times, Fontan preparation at time of BDCPC is feasible and associated with encouraging early outcomes. Percutaneous Fontan completion is associated with short recovery, low morbidity and excellent early dynamics, and echocardiographic and clinical outcomes. Further follow-up is needed to confirm those favorable results. PMID- 21256317 TI - Lung retransplantation in children: appropriate when selectively applied. AB - BACKGROUND: Lung retransplantation (re-LTx) in children has been associated with lower survival rates compared with primary lung transplantation. However, improving survival for primary LTx has led to more patients presenting for re LTx. Therefore, an analysis of the UNOS (United Network of Organ Sharing) database to evaluate the effectiveness of pediatric lung retransplantation in the United States was completed. METHODS: The UNOS registry was queried for pediatric re-LTx patients from May 1988 to May 2008. There were 81 (10%) re-LTx out of a total 802 pediatric lung transplants. RESULTS: Median age and weight at re-LTx were 14 (range, 0 to 18) years and 32 (4 to 58) kg. Indications for re-LTx were obliterative bronchiolitis in 50 patients (62%), primary graft failure in 8 (10%), and other in 23 (28%). The Kaplan-Meier graft survival for re-LTx patients was worse than for primary transplant patients (p < 0.001, graft half-life 0.9 vs 4.0 years), especially if re-LTx was done less than 1 year after primary transplant (graft half-life 0.25 years). Graft survival in patients who underwent re-LTx greater than 1 year after primary transplant was not statistically different than for primary LTx patients (p = 0.21; graft half-life 2.8 vs 4.0 years), and if re-LTx greater than 1 year posttransplant occurred in patients who were not ventilator dependent, survival was further improved (p = 0.68; graft half-life 4.7 vs 4.0 years). CONCLUSIONS: Pediatric lung retransplantation within the first year after primary transplant does not appear advisable. Pediatric re LTx greater than 1 year after primary transplantation may be a reasonable strategy for end-stage graft failure. Patients greater than 1 year posttransplant and not ventilator dependent appear an even more compelling group in which to consider lung retransplantation. PMID- 21256318 TI - Superior chest drainage with an active tube clearance system: evaluation of a downsized chest tube. AB - PURPOSE: We developed a small-diameter (20-French [Fr]) chest drainage system that incorporates an active tube clearance (ATC) system, and we evaluated its efficacy in an acute hemothorax model. DESCRIPTION: The ATC system includes an internal guidewire that can be advanced into the lumen of the chest tube to keep the tube from clogging. In six pigs, a 20-Fr ATC tube was placed on one side and a 32-Fr standard tube on the other, and 120 mL of fresh blood was infused into each pleural space every 15 minutes for a total of 840 mL. EVALUATION: The amount of drainage for 2 hours with a 20-Fr ATC tube was significantly greater than that with the 32-Fr standard tube (525 +/- 179 mL vs 183 +/- 85 mL; p = 0.0032). CONCLUSIONS: This is the first time a smaller diameter tube has been shown to have better drainage in the setting of acute bleeding compared with larger diameter tubes. PMID- 21256319 TI - Sternal metastasis of breast cancer: ex vivo hypothermia and reimplantation. AB - Breast cancer frequently metastasizes to the bone. When the sternum is involved, it usually presents as a solitary lesion. In such cases, resection is indicated, including with the intention to cure. This case report describes a technique for a complete exeresis of the sternum, ex vivo repair under hypothermia, and reimplantation. Cryosurgery is a well-known technique to resect bone metastases and was the procedure used in our patient. The follow-up after 2 years shows no evidence of tumor recurrence, with excellent results on aesthetic levels. PMID- 21256320 TI - Combined free vascularized iliac osteocutaneous flap and pedicled pectoralis major myocutaneous flap for reconstruction of anterior chest wall full-thickness defect. AB - Large defects of the anterior chest wall lead to gross chest instability that can result in paradoxic respiration. Osteoradionecrosis of the lower sternum and multiple left ribs resulted in a huge, full-thickness defect of the left anterior chest wall in a 67-year-old woman. An iliac osteocutaneous flap (bone segment 3 * 14 cm) was harvested for reconstruction of the bone defect. The skin defect was covered by the skin paddle of the iliac osteocutaneous flap and a contralateral rotational pectoralis major muscle flap. Months postoperatively, the patient was physically active, the chest was stable, and the vascularized iliac bone was incorporated into the recipient bone. PMID- 21256321 TI - A clear cell tumor of the lung presenting as a rapidly growing coin lesion: is it really a benign tumor? AB - There are few reported cases of clear cell tumor of the lung, a very rare benign mesenchymal neoplasm. We describe a 41-year-old asymptomatic man who presented with a coin lesion in a routine chest roentgenogram that was absent in a roentgenogram performed a year earlier. After a thorough workup, including radionuclide scintigraphy, the diagnosis of cell tumor of the lung was established. Somatostatin receptor positivity was demonstrated, and this clear cell tumor of the lung had a rapid growth rate. Because of these features, the benign nature of such a tumor remains questionable. PMID- 21256322 TI - Aortic endostent followed by extended pneumonectomy for T4 lung cancer. AB - Pulmonary and aortic en bloc resection may be performed with cardiopulmonary bypass support, but is associated with high surgical morbidity and mortality. A 59-year-old man with left lower lobe cancer invading the aorta was considered to be unsuitable for such an extended operation because of previous myocardial infarction, coronary bypass grafts, and subsequent multiple coronary artery stenting. Pneumonectomy with en bloc resection of aortic adventitia and media was accomplished after thoracic aorta endovascular stent graft placement. The aortic defect was reinforced with an extrathoracic muscle flap. The postoperative course was uneventful, and the patient was faring well at the 23-month follow-up. An endovascular stent may be an alternative in selected patients with aortic involvement, avoiding the need for cardiopulmonary bypass. PMID- 21256323 TI - Life-threatening aortic hemorrhage during pectus bar removal. AB - This report presents an unusual case of late, aortic hemorrhage that occurred during the removal of the stabilizing bar 3 years after a Nuss operation. The primary reason for this complication was a rotation of the sternum bar, which caused chronic damage to the aorta and development of an aortomediastinal fistula. Cardiopulmonary bypass and implantation of an aortic prosthesis were required for successful treatment of this complication. PMID- 21256324 TI - Hemangioma of the rib. AB - An asymptomatic 48-year-old woman presented to our hospital with a tumor of the rib incidentally diagnosed on a chest roentgenogram. The patient was investigated and underwent tumor resection of the chest wall. The pathologic study revealed that it was cavernous hemangioma. This tumor of the bone is a distinctly uncommon benign vascular tumor, generally occurring in the spine or skull. Hemangiomas involving the rib are even more rare, with only 22 cases described in the literature. However, we suggest that this tumor of the rib should be considered in the differential diagnosis, principally in asymptomatic patients. PMID- 21256325 TI - Use of SternaLock plating system in acute treatment of unstable traumatic sternal fractures. AB - Optimal surgical treatment of unstable sternal fractures is controversial. Wiring provides suboptimal fixation and adaptations of existing non-sternum specific plating systems may be dangerous when rapid sternal reentry is required. We present our experience with the sternal specific fixation system, SternaLock (Biomet Microfixation Inc, Jacksonville, FL), in the acute treatment of transverse sternal body fractures in 2 patients who sustained significant blunt anterior chest wall trauma. SternaLock provides the rigid sternal fixation necessary for reliable fracture healing while offering advantages over other systems with regards to ease of use and safety. PMID- 21256326 TI - Combined heart and liver transplantation in a patient with situs ambiguous. AB - We report the case of 21-year-old man with Fontan circulation failure and end stage liver cirrhosis, along with situs ambiguous. Combined simultaneous heart and liver transplantation was successfully performed with technical modifications, including rotated implantation and bilateral venous reconstruction. PMID- 21256327 TI - An unusual case of a large cavernous hemangioma invading the left ventricular apex. AB - Cardiac hemangiomas are extremely rare benign vascular tumors of the heart. We present the unusual case of a 60-year-old man with a large cavernous hemangioma involving the left ventricular apex. The tumor was completely excised under cardiopulmonary bypass. The pertinent literature is reviewed and the technical steps, clinical presentation, and histopathologic findings are discussed. PMID- 21256328 TI - Late tamponade secondary to aortic root perforation by BioSTAR septal closure device. AB - We report a patient who presented with pericardial tamponade 9 months after percutaneous closure of a patent foramen ovale using a BioSTAR septal closure device (NMT Medical, Boston, MA). During the operation, bleeding was observed on the posterior aortic root caused by a nonendothelialized strut. The device was explanted, followed by pericardial patch aortoplasty and patch closure of the patent foramen ovale. This report presents a case of late tamponade related to the new-generation bioabsorbable BioSTAR device. Although late complications related with BioSTAR are rare, the presentation may be dramatic. A high index of suspicion and quick intervention is often lifesaving. PMID- 21256329 TI - 43.3-year durability of a Smeloff-Cutter ball-caged mitral valve. AB - Extended durability of mechanical heart valves has been documented for many years. We describe a case of a ball-caged mechanical valve implanted 43.3 years previous to developing valve dysfunction. The patient presented with both prosthetic valve stenosis and insufficiency. This Smeloff-Cutter valve (Cutter Laboratories, Berkeley, CA) in the mitral position was dysfunctional due to lipid absorption, which resulted in ball variance and concomitant pannus growth prevented optimal seating of the ball in its cage. This is the longest length of time in which a Smeloff-Cutter mechanical valve has been originally implanted. PMID- 21256330 TI - Successful on-pump coronary artery bypass without using protamine. AB - A 48-year-old woman presented with a history of angina and breathlessness on exertion. She was diagnosed to have critical left main stem coronary artery disease along with a blocked right coronary artery. She was also allergic to protamine. After multidisciplinary consultation, it was decided to use heparin without protamine for reversal. She underwent successful on-pump coronary artery bypass grafting (CABG) without excessive blood loss. The disadvantages were a longer total operating time and the use of blood products to achieve normal coagulation. This case report describes the successful management of this complex problem. PMID- 21256331 TI - Mixed-type total anomalous pulmonary venous connection in an adult. AB - Cardiac plus infracardiac mixed-type total anomalous pulmonary venous connection is an extremely rare congenital heart disease. We describe a case in which the pulmonary veins made a confluence and connected to a vertical vein running into the inferior vena cava by the way of the hepatic vein. Surgical correction was successfully obtained by deroofing the coronary sinus and using the pericardial patch to reconstruct the interatrial septum. The patient showed no signs of any complication at her 5-month follow-up. PMID- 21256332 TI - Pericardium-esophageal fistula. PMID- 21256333 TI - Prosthetic valve malfunction after Amplatzer closure of paravalvular leak. PMID- 21256334 TI - Aortic arch interruption with thoracic aortic dissection. PMID- 21256335 TI - Thoracoscopic extrapleural pneumonectomy for mesothelioma. AB - Mesothelioma is the most common primary pleural malignancy. Surgical therapy offers limited cure benefits at the cost of high morbidity. Although technically challenging and performed rarely, a less invasive approach to extrapleural pneumonectomy was developed with the intent to speed convalescence, hasten adjuvant therapies, improve quality of life, and reduce wound surface area for possible tumor contamination. PMID- 21256336 TI - Potassium-induced cardiac resetting technique for persistent ventricular tachycardia and fibrillation after aortic declamping. AB - We report a technique of injecting a high concentration of potassium chloride into the aorta root to resolve refractory ventricular tachycardia after aortic declamping, which occurs occasionally in open heart surgeries. Using this technique, normal sinus rhythm can be restored without the need for defibrillation and aortic clamping. PMID- 21256337 TI - Balloon catheter pulmonary embolectomy under direct visual control using a choledochoscope. AB - Acute massive pulmonary embolism has a high mortality rate despite advances in diagnosis and therapy. To salvage critically ill patients, complete clot extraction without arterial wall injury is essential. In this study, we performed balloon catheter embolectomy under direct visual control by using a flexible choledochoscope. For clear visualization, we introduced deep hypothermic circulatory arrest, and cold normal saline solution was flushed through the irrigation channel. From our experience, we believe that balloon catheter embolectomy with a choledochoscope allows easy access to the secondary and tertiary pulmonary branches and enables complete clot extraction. PMID- 21256338 TI - Circumflex right aortic arch with associated hypoplasia and coarctation: repair by aortic arch advancement and end-to-side anastomosis. AB - Right aortic arch with associated arch hypoplasia, coarctation, and an aberrant isolated left subclavian artery is a very uncommon variant of vascular rings, which itself accounts for fewer than 1% of all congenital cardiac defects. Several cases have been reported, and most commonly, extraanatomic grafts have been used for repair. We present a unique technique that involves the resection of the circumflex arch, aortic arch advancement, and end-to-side anastomosis to repair this rare aortic arch malformation. PMID- 21256339 TI - Primary complete repair of partial double aortic arch and Kommerell diverticulum. AB - Tracheal and esophageal stenosis caused by double aortic arch and Kommerell diverticulum is a rare but important pathologic entity in adult patients. Clinical symptoms are caused by esophageal or tracheal stenosis, or both. The present article describes a surgical method of complete repair with division of the rudimentary left arch, resection of the diverticulum, and transposition of the left subclavian artery. This method was transferred from pediatric patients and led to excellent clinical results in 2 consecutive adult patients compared with the previous technique with division of the left arch alone. PMID- 21256340 TI - Conversion and safety in off-pump coronary artery bypass: a system failure that needs re-emphasis. AB - Institution of cardiopulmonary bypass after commencement of "off-pump" coronary artery bypass surgery is known as conversion. This may be an emergency or elective process. The phenomenon of conversion, although widely reported, remains under-emphasized. Emergency conversion may lead to poorer patient outcomes and therefore warrants serious consideration. The rate of conversion may influence the results of randomized controlled trials, and be considered a surrogate performance indicator of surgical competence in off-pump coronary artery bypass. Several causes and predictors of conversion are reported in published literature. This article aims to examine the phenomenon of conversion in off-pump coronary artery bypass and proposes a framework for its prevention. PMID- 21256341 TI - Preoperative bevacizumab in combination with paclitaxel and carboplatin in surgically resectable non-small cell lung cancer. PMID- 21256342 TI - Avoiding sternotomy and cardiopulmonary bypass in type IV renal carcinoma: is it really worth it? PMID- 21256344 TI - Pulmonary instillation of activated charcoal: early findings on computed tomography. PMID- 21256345 TI - A simpler alternative to the Bentall operation using a stentless valve. PMID- 21256347 TI - Is the use of effective orifice area index calculator appropriate in definition of prosthesis-patient mismatch? PMID- 21256348 TI - Alternative technique for internal mammary artery. PMID- 21256351 TI - Partial homografts for atrioventricular valve repair. PMID- 21256352 TI - The pentacuspid aortic valve. PMID- 21256354 TI - The nurse scientist...A unique contribution to nursing's future. PMID- 21256355 TI - Diversity matters! Reframing the dialogue. PMID- 21256356 TI - Re: President's message: Making the case for nursing workforce diversity. PMID- 21256358 TI - The Doctor of Nursing Practice: a national workforce perspective. AB - In 2004, the American Association of Colleges of Nursing (AACN) adopted a position statement concerning the future of advanced practice nursing education. A target date of 2015 was articulated as the point by which master's preparation for advanced practice nurses would be replaced by doctoral level education. Seismic shifts in the realities surrounding nursing education and practice have occurred since the proposal to require a Doctor of Nursing Practice (DNP) degree for entry into advanced practice nursing was proposed. Unprecedented economic challenges have resulted in significant budget downturns for all sectors, including higher education. The consequent cutbacks, furloughs, and restructuring in educational operations of all types have placed enormous demands on faculty, staff, and students across the country. In addition, the growing incidence and earlier onset of chronic disease, a rapidly aging population, health care reform agendas, a shortage of primary care practitioners, and projected severe shortages of nursing faculty have raised fundamental questions about the capacity of nursing education to produce the numbers of advanced practice nurses needed. This article addresses the changing realities and growing concerns associated with the future of advanced practice nursing. Recommendations to ensure continuing development of advanced nursing practice that serves the interests and needs of the public now and in the future are presented within the context of a national workforce perspective. PMID- 21256359 TI - Impact factors in nursing journals. AB - Journal impact factors (IFs), a measure of citation frequency, are published annually in Journal Citation Reports (JCR). Journal IFs, although controversial because of the uses to which they have been put in academic arenas, remain a metric about which nurses should be informed. This paper discusses key issues in the controversy, explains how IFs are computed, and presents historical and 2009 IF data for nursing journals. The number of nursing journals indexed in JCR has grown from 35 in 2004 to 74 in 2009. The journals currently indexed are diverse in terms of focus (practice vs research), specialty areas, and country of publication. The median IF score for nursing journals (0.91 in 2009) is similar to that for several other health care categories. Given the controversies surrounding IFs, it may be useful for nurses to play a more active role in furthering the debate by undertaking research relating to IFs, including studies of how they affect nurses' scholarly pursuits and publication decisions. PMID- 21256361 TI - Evaluation of aging in place model with home care services and registered nurse care coordination in senior housing. AB - A state-sponsored evaluation of aging in place (AIP) as an alternative to assisted living and nursing home has been underway in Missouri. Cost, physical, and mental health assessment data reveal the cost-effectiveness and positive health measures of AIP. Findings of the first four years of the AIP evaluation of two long-term care settings in Missouri with registered nurse care coordination are compared with national data for traditional long-term care. The combined care and housing cost for any resident who received care services beyond base services of AIP and who qualified for nursing home care has never approached or exceeded the cost of nursing home care at either location. Both mental health and physical health measures indicate the health restoration and independence effectiveness of the AIP model for long-term care. PMID- 21256360 TI - Interdisciplinary research training in a school of nursing. AB - Although interdisciplinarity has become a favored model of scholarly inquiry, the assumption that interdisciplinary work is intuitive and can be performed without training is short-sighted. This article describes the implementation of an interdisciplinary research training program within a school of nursing. We describe the key elements of the program and the challenges we encountered. From 2007-2010, eleven trainees from 6 disciplines have been accepted into the program and 7 have completed the program; the trainees have published 12 manuscripts and presented at 10 regional or national meetings. The major challenge has been to sustain and "push the envelope" toward interdisciplinary thinking among the trainees and their mentors, and to assure that they do not revert to their "safer" disciplinary silos. This training program, funded by National Institute of Nursing Research (NINR), has become well-established within the school of nursing and across the entire University campus, and is recognized as a high quality research training program across disciplines, as exemplified by excellent applicants from a number of disciplines. PMID- 21256362 TI - Linking service-learning with community-based participatory research: an interprofessional course for health professional students. AB - Service-learning is a valued strategy for educating health professionals. Linking service-learning with community-based participatory research (CBPR) engages students with community stakeholders and faculty in a collaborative process to bring about social change and improved health. The purpose of this paper is to describe a strategy for involving interprofessional students in ongoing faculty CBPR in an underserved community. The process includes the design and implementation of a course that combines weekly seminars with field experiences in the targeted community, emphasizing community assessment, and working with community members to find solutions to health problems. Nursing, public health, and medical students were recruited to the initial course, and offered the opportunity to meet objectives of required components of their disciplinary curriculum. Community members became actively involved in educating students while working to solve identified health problems. Important principles of CBPR- trust, collaboration, excellence in science, and ethics--are emphasized throughout the initiative. This course is now a regular offering for interprofessional students, providing valuable learning experiences for students, faculty, and the community. Ongoing faculty CBPR continues a trusting community academic relationship and gives the community a voice in the solution for health problems. PMID- 21256363 TI - What evidence of evidence-based public policy? PMID- 21256364 TI - Healthcare reform in China and the challenges for public health education. PMID- 21256365 TI - Public health services in Shenzhen: a case study. AB - As one of the fastest growing cities in Pearl River Delta of southern China, Shenzhen accommodates a higher percentage and increasing number of internal migrants, mainly coming from the inland areas. The public health issues that challenge its local government include the special population structure, high incidence of infectious diseases, high prevalence of mental problems, rising chronic disease burdens, and maternal and children's health issues, although progress has been made in the past years. The health authority of Shenzhen has realized that provision of high quality equitable public health services to its residents, including migrants is of high priority, and should be supported by innovations in the health insurance system and establishment of community-based primary care networks. Making changes within the national-level health reform framework and learning from international experiences are necessary and important. PMID- 21256366 TI - Making the case for a 'fifth wave' in public health. AB - This paper will argue that the UK has seen several phases of public health improvement since the Industrial Revolution, and that each of these can be linked to major shifts in thinking about the nature of society and health itself. The authors are not, however, attempting to delineate firm sequences of events (or imply causality) as this would require a level of analysis of the relationship between economy, society and culture which is beyond the scope of this paper. Rather, it is suggested that each phase of health improvement can be thought of in metaphorical terms as a 'wave'. The first wave is associated with great public works and other developments arising from social responses to the profound disruptions which followed the Industrial Revolution. The second wave saw the emergence of medicine as science. The third wave involved the redesign of our social institutions during the 20th Century and gave birth to the welfare state. The fourth wave has been dominated by efforts to combat disease risk factors and the emergence of systems thinking. Although a trough of public health activity continues from each wave, none exerts the same impact as when it first emerged. This paper will discuss the complex challenges of obesity, inequality and loss of wellbeing, together with the broader problems of exponential growth in population, money creation and energy usage. As exponential growth is unsustainable on a finite planet, inevitable change looms. Taken together, these analyses suggest that a fifth wave of public health development is now needed; one which will need to differ radically from its forerunners. The authors invite others to join them in envisioning its nature and in furthering the debate about future public health. PMID- 21256367 TI - Involving community partners in the management of tuberculosis among drug users. PMID- 21256368 TI - Religion, organ transplantation, and the definition of death. PMID- 21256369 TI - Has artemisinin resistance spread already? PMID- 21256370 TI - Time to TEAM: exemestane, or tamoxifen then exemestane? PMID- 21256373 TI - Rethy Chhem: from war-torn Cambodia to the IAEA. PMID- 21256374 TI - India's Janani Suraksha Yojana: further review needed. PMID- 21256376 TI - Double-dose clopidogrel in patients undergoing PCI for ACS. PMID- 21256377 TI - Double-dose clopidogrel in patients undergoing PCI for ACS. PMID- 21256378 TI - Watch out for the even eviler cousin-sorbitol-fermenting E coli O157. PMID- 21256380 TI - Chilean miners: raising awareness of the plight of miners worldwide. PMID- 21256381 TI - Disseminating Japan's immunisation policy to the world. PMID- 21256382 TI - From paedophilia to gerontophilia. PMID- 21256383 TI - Family paralysis. PMID- 21256387 TI - [Wind of change]. PMID- 21256388 TI - [Nocturia is not associated with falls among the elderly: a population study in the city of Sao Paulo]. AB - INTRODUCTION: the present study aims to evaluate the association between nocturia and falls in a group of community-living elderly men in the city of Sao Paulo (Brazil). MATERIAL AND METHODS: under the coordination of the Pan American Health Organization and World Health Organization, a multicenter study named Health, Welfare and Aging (SABE Study) is being conducted to evaluate the living and health conditions of older people in Latin America and Caribbean. In Brazil, this study is evaluating the elderly population (60 years or more) in Sao Paulo since 2000. The presence of nocturia was taken as the response "yes" to the question "Do you need to void three times or more at night?" .The presence of falls was also taken as the response "yes" to the question "Did you have any fall during the last 12 months?" The intergroup analysis used was the logistic regression. RESULTS: total of 865 men was interviewed, mean age 68 years. It was observed high prevalence of nocturia and falls in all groups, with higher prevalence of both in the eldest group (p<0.001), however, the association of nocturia and falls was not statistically significant in any of the groups (p=0.45). CONCLUSION: this is one of the pioneering studies that assess only the male population, showing that nocturia was not significantly associated with falls. Nocturia and falls are highly prevalent conditions in the elderly, but no association was found between both, so that these variables may be correlated to age and other clinical conditions. PMID- 21256389 TI - [Does the criterion for prostate biopsy indication impact its accuracy? A prospective population-based outpatient clinical setting study]. AB - INTRODUCTION: Prostate specific antigen (PSA) and digital rectal examination (DRE) are the main tests for initial prostate investigation; there is no consensus about the best criterion for prostate biopsies. We aim to check the accuracy of different criteria in this context including PSA derivatives to detect prostate cancer. MATERIAL AND METHODS: Four different criteria for indication of prostate biopsy were compared: (A) PSA-density (>15 ng/ ml/ cc); (B) PSA > 2,5 ng/ml; (C) PSA-velocity (> 0.7 ng/ ml/ year); (D) free/total PSA ratio (<15%). All biopsies and histopathological examinations were performed by the same urologist and pathologist, respectively. RESULTS: The study was performed on 180 consecutive biopsies with 37.7% overall cancer detection rate: 29 (16.1%) performed following criterion A, 42 (23.3%) criterion B, 65 (36.1%) criterion C and 44 (24.4%) criterion D. Based on PSA criteria alone, the predictive positive value (PPV) was 37.9% for criterion A, 33.3% for B, 32.3% for C and 50.0% for criterion D, respectively, (p > 0.05). Associating positive DRE with changed PSA, the PPV increased to 50%, 50%, 43.9% and 68.2% for criteria A, B, C and D, respectively (p>0.05). In univariate analysis, DRE (positive versus negative), PSA level (>10 ng/ ml versus <4.0 ng/ ml), free/total PSA ratio (<10% versus >15%) and age were associated with PC. In multivariate analysis only positive DRE was associated with prostate cancer. CONCLUSIONS: All the criteria of PSA derivatives are complementary and useful predictors of cancer risk. However, a positive DRE increased the PPV of PSA derivatives. New tools are needed to improve the accuracy of prostate cancer detection. PMID- 21256390 TI - [Prostate specific antigen and NF-kB in prostatic disease: relation with malignancy]. AB - INTRODUCTION: NF-kB (p50/p65) is a transcription factor involved in TNF-alpha induced cell death resistance by promoting several antiapoptotic genes. We intend to relate the expression of NF-kB (p50 and p65) with serum levels of prostate specific antigen (PSA), both in normal males and in those with pathologic conditions of the prostate. MATERIALS AND METHODS: this study was carried out in 5 normal, 24 benign prostatic hyperplastic (BPH) and 19 patients with prostate cancer (PC). Immunohistochemical and Western blot analyses were performed on tissue and serum PSA was assayed by PSA DPC Immulite assays (Diagnostics Products Corporation, Los Angeles, CA). RESULTS: in controls, p65 NF-kB was not found and p50 was scantly detected in 60% normal samples in the cytoplasm of epithelial cells. Both p50 and p65 were expressed in 62.5% of the samples with BPH and in 63.2% of those with PC. Both increased its frequency of expression with higher PSA serum levels. CONCLUSIONS: Activation of NF-kB revealed by its nuclear translocation in prostate cancer could be related to cancer progression and elevated seric PSA levels. A better understanding of the biologic mechanism by which circulating PSA levels increase and its relation with NF-kB expression is needed. Possibly, NF-kB blockage could be used as a therapeutic target to counteract proliferation in prostate cancer. PMID- 21256391 TI - [Primary laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ-cell testis tumor]. AB - INTRODUCTION: this report is intended to retrospectively assess cancer control and morbidity of primary laparoscopic reproperitoneal lymphadenectomy (L-RPLND) in patients with clinical Stage I non seminomatous germ cell tumour (NSGCT). MATERIALS AND METHODS: one hundred and sixty-four patients with clinical Stage I NSGCT underwent primary diagnostic LRPLND between 1993 and 2006. Patients were operated unilaterally limiting the dissection to templates. Kaplan Meier curves were generated estimating time to recurrence. RESULTS: of the 164 patients, 82 (48%) had embryonal components and 35 (20%) lymphovascular invasion in the orchiectomy specimen. The median (IQR) age, operative time, length of hospital stay, blood loss and number of lymph nodes retrieved was 28 years (24-33), 135 minutes. (120- 180), 48 hours (24-48), 50 cc (20-100) and 14 (10-18) nodes, respectively. All patients had negative serum markers preoperatively. Presence of lymph node metastasis was identified in 32 (19.5%) patients. Follow-up was available in 15 of these. Fourteen received adjuvant chemotherapy and 2 of them had recurrence at 3 and 64 months. Absence of lymph node metastasis was diagnosed in 132 (80.5%) patients. Follow-up was available in 80 of these. Among them 7 recurred (5 retroperitoneum, 2 lung), one of them 33 months after L-RPLND. Median follow-up for patients without recurrence was 14 months (IQR:4-35). The cumulative 3-year recurrence free rate was 82% (95%CI: 64-91). Seventeen (10%) of 164 patients had intra or perioperative complications. CONCLUSIONS: this is the largest series of L-RPLND performed in a single institution. Both morbidity and oncologic safety of this technique needs to be prospectively evaluated in randomized trials. PMID- 21256392 TI - [Treatment of distal ureteral stricture by laparoscopic ureterovesical reimplantation]. AB - INTRODUCTION: to analyse the results achieved to treat iliac or pelvic ureteric stricture using laparoscopic reimplantation of the ureter in a psoic bladder. MATERIAL AND METHOD: in a four-year period, we performed laparoscopic ureteral reimplantation in a psoic bladder in 6 patients (right/left 1:1; male/female 1:2; mean age 59.2 years, range 47-87). In 4 cases the lesion was iatrogenic and in 2 cases idiopathic. Ureteral resection with bladder cuff and cystorraphy followed by ipsilateral lymph node dissection was performed in idiopathic cases or those with history of previous urothelial tumour (4 cases in total) before ureteral reimplantation. Bladder was extensively mobilized and fixed to minor psoas tendon before performing ureteroneocystostomy. Mixed intra and extravesical technique with submucosal tunnel (Politano) was used in a case and in the remaining 5 cases extravesical technique with submucosal tunnel (Goodwin) was used. Mean follow-up was 26 months (range 18-34). RESULTS: there was no need to convert to open surgery. Time of surgery was 230 minutes in the case treated with Politano ureteroneocystostomy and 120 (range 75-150) in those treated purely extravesically. The mean hospital stay was 3.2 days (range 2-5). There were no intra or postoperative complications. Histologic assessment always revealed ureteral fibrosis and in 2 cases accompanying granulomatous inflammation and dysplasia. No patient suffered re-stricture or impairment in renal function during follow-up. CONCLUSIONS: laparoscopic ureteral reimplantation is an effective and safe minimally invasive technique to treat benign distal stricture of the ureter. Simplicity of extravesical reimplantation has an advantage over its intravesical counterpart. PMID- 21256393 TI - [Diode laser enucleation of the prostate (Dilep): technique and initial results]. AB - INTRODUCTION: we present our preliminary experience and results of practising the prostate enucleation technique using a diode laser (DiLEP) and intravesical morcellation, following the same principles of holmium laser enucleation (HoLEP). MATERIALS AND METHOD: we endoscopically treated benign prostate hyperplasia with DiLEP in 17 patients over a period of five months. They were all followed up for three months with flowmetry and IPSS. We have described the prostate enucleation and morcellation technique in detail, as well as the materials required to perform them. We have also commented on the lessons learned having practised on more than 300 cases with HoLEP, with a view to applying this new technology. RESULTS: the mean age was 74.2 and the mean prostate volume was 61.26 (47-110) cc. The mean loss of haemoglobin was 2.1 (1.4-3.1) gr/dl. There were no major consequences or complications. All the patients were discharged from the hospital 24 hours after the operation. The improvement in the IPSS (22.3+/-4.1 vs. 7.1+/ 1.06) and in the Q max (7.14+/-2.6 vs. 21.4+/-3.6) was sustainable. CONCLUSIONS: It is the first description of the DiLEP technique for the surgical treatment of benign prostate hyperplasia. We believe the results obtained are promising and that they could signify some advantages as opposed to HoLEP. However, prospective randomized studies are required to confirm this opinion. PMID- 21256394 TI - [Renal retransplantation: risk factors and results]. AB - OBJECTIVE: to review our experience in renal retransplantations. MATERIALS AND METHODS: we carried out a retrospective study on 71 patients with retransplantation performed between 1980 and 2005. We studied: the characteristics of the recipient and graft, surgery data, causes of loss of the graft, number of rejects and transplantectomies and, survival of the graft. RESULTS: the most frequent cause of graft loss was chronic rejection. The causes of first graft loss were not associated with a greater loss of the second graft (p>0.05). The percentage of anti-HLA antibodies increased in the second transplant in comparison to the first (17.23+/-27.91% vs. 1.21+/-7.43%) (p=0.001), however, it was not correlated with a significant increase in loss of the second graft (p=0.320). There were no significant differences between the complications of the first and second transplants (p>0.05) and they were not associated with graft loss (p>0.05). The patients with a transplantectomy in the first transplant presented a risk 8.5 times higher of undergoing a second one (p=0.0001; OR: 8.54; CI: 95% 0.941 - 77.501). The most frequent cause of transplantectomies in the second transplant was acute rejection. Acute rejection as a cause for transplantectomy in the first transplant proved to be an independent risk factor of transplantectomy of the second transplant (p=0.009). The mean survival of the second graft was 5.08+/-4.81 years, higher than the first transplant (p=0.133). The survival of the graft at 1.5 and 10 years was 83%, 75% and 52%, respectively. CONCLUSIONS: the survival of the second transplant was not lower than the first, neither was there an increase in the number of complications. PMID- 21256395 TI - [Transumbilical single-incision laparoscopic ureterolithotomy]. AB - INTRODUCTION: laparoendoscopic single-site surgery (LESS) using transumbilical access and conventional laparoscopic instruments is a very attractive alternative to perform ureterolithotomy for ureteral stone with failed endourological management. MATERIAL AND METHOD: a 29-year-old woman presented with chronic right lumbar pain and a 1.2 cm impacted calculus localized at transition of abdominal to pelvic ureter. Semi-rigid ureteroscopy had failed to fragment the stone and shockwave lithotripsy was not available. Double-J ureteral catheter had been inserted preoperatively. We performed a transumbilical single-incision laparoscopic ureterolithotomy. Three conventional trocars were inserted in a single semi-circular umbilical incision. Right colon was detached and the ureter was identified. Calculus was extracted and the ureteral incision was closed with intracorporal sutures. RESULTS: ureterolithotomy was successfully completed, with all the operative steps performed transumbically. Operative time was 180 minutes. No single-port device or articulating and bent instruments were utilized. Estimated blood loss was less than 50 mL. No intraoperative, access-related and postoperative complications took place. The duration of hospitalization was 24 hours and scarless appearance was observed on postoperative day 15. CONCLUSION: transumbilical single-incision laparoscopic ureterolithotomy is feasible and safe. This approach offers an inherent cosmetic advantage and few postoperative discomfort. Additional experience and continued investigation are warranted. PMID- 21256396 TI - [Experience with sunitinib in hormone-resistant metastatic prostate cancer that is unresponsive to docetaxel]. AB - INTRODUCTION: systemic treatment options for patients with hormone-refractory prostate cancer (HRPC) that progress despite the use of Docetaxel are very limited. One of the options of compassionate use currently available is the use of Sunitinib. We present a joint preliminary experience with the use of Sunitinib in this clinical case. PATIENTS AND METHODS: a series of eight cases is presented, which sets forth a prospective multicentre experience with Sunitinib in patients with hormone-refractory metastatic and progressive prostate cancer, previously treated with at least a regime of Docetaxel-based chemotherapy. Other alternative chemotherapy regimes had already been tried in some patients. The primary objective of our study was the PSA response rate and our secondary objective was the progression-free period. We administered a dosage of 50mg/day for four-week cycles, followed by a two-week rest per cycle, until we reached a total of eight cycles or up to clinical progression or intolerable toxicity. RESULTS: in four cases, the PSA dropped to below 50% of the baseline level at the beginning of the treatment, and five patients presented some decrease in PSA. The progression-free time was 16.4 weeks. Toxicity arising from the treatment was moderate and manageable. CONCLUSIONS: despite the limits of this experience, we can say that Sunitinib appears to be an active and safe option in patients with hormone-refractory prostate cancer that is resistant to chemotherapy with Docetaxel. PMID- 21256397 TI - [Slings: why so many?]. PMID- 21256398 TI - [Benign prostate hyperplasia with fibro-fatty stromal metaplasia]. PMID- 21256399 TI - In vitro and in situ evidence supporting the utility of a bioadhesive fluoridated rinse in the management of dental erosion. PMID- 21256400 TI - An in vitro evaluation of a novel high fluoride daily mouthrinse using a combination of microindentation, 3D profilometry and DSIMS. AB - OBJECTIVES: Firstly, to evaluate the in vitro anti-erosion efficacy of a new mouthrinse formulation containing 450 ppm fluoride using profilometry and microindentation. Secondly, to compare fluoride uptake by erosive lesions from two mouthrinses containing different fluoride sources using dynamic secondary ion mass spectrometry (DSIMS). METHODS: Sound human enamel was treated (60s) with mouthrinses containing different fluoride concentrations, then immersed in 1.0% citric acid pH 3.8 for either 300 s or 30 min (Studies 1 & 2 respectively). Surface roughness and erosion depth were determined profilometrically in Study 1, and surface microhardness monitored as a function of time in Study 2. Lesion rehardening was monitored following a 60 s rinse and immersion in artificial saliva for 48 h (Study 3), whilst Study 4 employed DSIMS to quantify fluoride uptake by lesions treated (60s) with rinses containing either sodium fluoride (NaF) or a NaF/Olaflur/stannous chloride combination. RESULTS: The test rinse (450 ppm fluoride) suppressed surface roughening and bulk tissue loss versus all comparators (p< 0.0001), except in the latter measure for the rinse containing 112 ppm fluoride. The test rinse significantly inhibited enamel surface softening versus the three rinses containing <=112 ppm fluoride (as NaF) at 30 min (p<0.05), but was not statistically significantly different from the 225 ppm fluoride rinse. The test rinse conferred statistically superior lesion rehardening versus all comparators at both 24 and 48 h (p< 0.0001). DSIMS demonstrated statistically significantly higher fluoride uptake by incipient erosive lesions treated with the test rinse versus the NaF/Olaflur/stannous rinse. CONCLUSIONS: Anti-erosion efficacy was positively correlated with fluoride concentration. DSIMS showed significantly higher levels of fluoride uptake by incipient erosive lesions treated with the 450 ppm fluoride rinse versus the NaF/Olaflur/stannous rinse. PMID- 21256401 TI - A comparative evaluation of fluoridated and non-fluoridated mouthrinses using a 5 day cycling enamel erosion model. AB - OBJECTIVES: To assess the relative protective effect of commercial mouthrinses containing 0-450 ppm fluoride on erosion progression in enamel using a simulated 5-day in vitro cycling model with concurrent monitoring of surface microhardness (SMH) and bulk tissue loss. METHODS: Specimens were randomly assigned to six treatment groups (n=6). The model mimicked morning and evening use with rinse times (30 or 60 s) reflecting those prescribed on pack, interspersed with three cycles of demineralisation/remineralisation per simulated day. The latter comprised 1.0% citric acid monohydrate pH 3.2 for 300 s, with subsequent remineralisation in mucin-free artificial saliva pH7.0 for 120 min. SMH was determined by Vickers microindentation and bulk tissue loss using white-light interferometry. RESULTS: From the end of day 1, fluoride-containing mouthrinses conferred statistically significant reductions in bulk tissue loss versus fluoride-free rinses (p<0.05), with lesion depth inversely proportional to fluoride concentration. From day 3, the mean lesion depth of specimens treated with the 450 ppm rinse were statistically significantly lower than all comparator treatment groups (p<0.05). Two distinct trends were apparent when comparing SMH changes in groups treated with fluoride-free versus fluoride-containing mouthrinses. In the latter, SMH levelled out over the final three simulated days in contrast to the former whose SMH continued to fall; differences were statistically significant at day 5 (p< 0.05). CONCLUSIONS: Bulk tissue loss is inversely proportional to fluoride concentration in this cycling model. The plateau in SMH reflects stabilisation of mineral density as the study progresses and the number of fluoride binding sites and consequently uptake increases, in turn leading to enhanced lesion remineralisation. PMID- 21256402 TI - Evaluation of salivary fluoride retention from a new high fluoride mouthrinse. AB - OBJECTIVES: To evaluate salivary fluoride retention from a new high fluoride daily use mouthrinse over a 120 min period. METHODS: Sixteen subjects completed a randomised single-blind, four-treatment cross-over trial. Sensodyne(r) Pronamel(r) mouthrinse (A) contained 450 ppm fluoride; reference products were Colgate(r) Fluorigard(r) (B), Listerine(r) Total Care (C) and Listerine Softmint Sensation (D) containing 225, 100 and 0 ppm fluoride respectively. Salivary fluoride retention was monitored ex vivo after a single supervised use of test product (10 mL, 60 s). Samples were collected at 0, 1, 3, 5, 15, 30, 60 and 120 min post-rinse, generating fluoride clearance curves from which the area under the curve (AUC) was calculated. Differences in salivary fluoride concentrations for each product were analysed using ANCOVA at each time point using a 5% significance level, as well as lnAUC for the periods 0-120, 0-1, 1-15, 15-60 and 60-120 min. Pairwise comparisons between all treatment groups were performed. RESULTS: Salivary fluoride levels for A-C peaked immediately following use. Fluoride levels were statistically significantly higher for A versus B-D (p<= 0.004), linear dose responses were apparent. AUC(0-120) was statistically significantly greater for A than for B (p = 0.035), C (p< 0.0001) and D (p< 0.0001). Post-hoc comparisons of lnAUC for the remaining time domains showed fluoride retention from A was statistically significantly greater versus B-D (p< 0.0001). CONCLUSIONS: Single-use treatment with the new mouthrinse containing 450 ppm fluoride resulted in statistically significantly higher salivary fluoride levels throughout the 120 min test period. Total fluoride retention (AUC(0-120)) was also statistically significantly greater versus comparator rinse treatments. PMID- 21256403 TI - Evaluation of mouthrinse and dentifrice regimens in an in situ erosion remineralisation model. AB - OBJECTIVES: To compare the effectiveness of dentifrice/mouthrinse regimens in a clinical in situ erosion remineralisation model. METHODS: Thirty-six subjects completed a randomised single-blind cross-over trial of five treatment regimens. R1: Dentifrice A [1450 ppm fluoride as the sodium salt (NaF), 50000 ppm potassium nitrate (KNO(3))] plus 450 ppm fluoride (NaF) rinse; R2: Dentifrice A plus sterile water rinse; R3: Dentifrice B (fluoride-free Dentifrice A) plus sterile water rinse; R4: Dentifrice B plus 450 ppm fluoride (NaF) rinse; R5: Dentifrice C (1000 ppm fluorine as sodium monofluorophosphate, 450 ppm fluoride as NaF) plus sterile water rinse. Subjects wore a palatal appliance holding eight pre demineralised enamel blocks. A 60 min interval separated in vivo use of dentifrice and rinse with the appliance retained in situ for 4h. Efficacy endpoints were percentage surface microhardness recovery (%SMHR) following remineralisation, and percentage relative erosion resistance (%RER) of recovered specimens following a subsequent in vitro erosive challenge. Statistical analyses included ANOVA and selected twin-tailed t-tests. RESULTS: Mean %SMHR (+/-SE) was (a)42.14+/-1.39, (b)38.02+/-1.39, (c)30.57+/-1.39, (b)37.75+/-1.39 and (c)30.88+/ 1.39 for regimens R1-R5 respectively (different superscripts denote statistically significant differences (p<0.05) between treatment regimens). Mean %RER (+/-SE) was (a)-2.88+/-2.16, (b)-14.54+/-2.16, (c)-40.05+/-2.16, (a)-3.76+/-2.16 and (d) 29.48+/-2.16 for regimens R1-R5 respectively. R1 elicited statistically significantly greater %SMHR versus all comparator regimens (p<0.01), and conferred statistically significantly greater %RER than comparator regimens (p<0.0001) except R4 (p=0.70). CONCLUSIONS: The combination treatment of dentifrice A containing 1450 ppm fluoride with the 450 ppm fluoride mouthrinse elicited significant enhancements in rehardening of incipient enamel erosive lesions, and significantly increased their subsequent resistance to a second erosive challenge. PMID- 21256404 TI - Studies on a novel combination polymer system: in vitro erosion prevention and promotion of fluoride uptake in human enamel. AB - OBJECTIVES: Firstly, determine the effect of pre-treating sound human enamel with a hydrosoluble combination polymer system (TriHydraTM) comprising 0.20% carboxymethylcellulose, 0.010% xanthan gum and 0.75% copovidone, alone or in combination with fluoride, on in vitro erosion by citric acid. Secondly, investigate the effect of the polymers on fluoride uptake by incipient erosive lesions. METHODS: Study 1: Sound enamel specimens were treated (60s, 20 degrees C, 150 rpm) with either (i) deionised water, (ii) polymers in deionised water, (iii) 300 mg/L fluoride or (iv) polymers in 300 mg/L fluoride. Specimen groups (n=5) were then immersed in 1.0% citric acid (pH 3.8, 300 s, 20 degrees C, 50 rpm) and non-contact profilometry was used to determine surface roughness (Sa) and bulk tissue loss. Study 2: Incipient erosive lesions were similarly treated with (i)-(iv). Dynamic Secondary Ion Mass Spectrometry (DSIMS) was then used to determine the fluoride depth-distribution. RESULTS: Study 1: Mean+/-SD Sa and erosion depths for treatment groups (i)-(iv) were (a)657+/-243, (b)358+/-50, (c)206+/-72, (d)79+/-16 nm and (a)19.73+/-8.70, (b)2.52+/-1.34, (b)0.49+/-0.34 and (b)0.31+/-0.21 mm respectively (matching superscripts denote statistically equivalent groups). Study 2: Lesions treated with (iii) and (iv) exhibited similar fluoride penetration depths (~ 60 MUm). Mean fluoride intensity ratios based on F/(F+P) at 1 MUm for treatment groups (i)-(iv) were (a)0.010+/-0.004, (a)0.011+/-0.004, (b)0.803+/-0.148 and (c)0.994+/-0.004 respectively. CONCLUSIONS: The combination polymer system exhibited anti-erosion efficacy in its own right. The polymer/fluoride admixture statistically significantly reduced Sa, however suppression of bulk tissue loss was not statistically significantly different versus either treatment alone. The presence of polymer appears to promote fluoride uptake by erosive lesions most noticeably in the first 6 MUm. PMID- 21256405 TI - Resuscitation 2010 in review. PMID- 21256406 TI - The Institute of Pediatric Nursing: a unified voice. PMID- 21256407 TI - Comparison of arm and calf automatic noninvasive blood pressures in pediatric intensive care patients. AB - The purpose of this study was to compare upper arm and calf automatic blood pressures (BPs) in a convenience sample of 221 children, ages 1 to 8 years, admitted to a pediatric intensive care unit of a 180-bed teaching hospital in the Mid-Atlantic region of the United States. Subjects were positioned in bed, with the head of bed elevated 30 degrees and extremities resting on the bed. BP cuff size was based on arm and calf circumferences. BPs were measured simultaneously using bedside and portable Spacelabs monitors. Calf BPs were greater than arm BPs in approximately 73% of the sample. Paired t tests show statistically significant differences for systolic BPs and mean arterial pressures. Influence of demographics, agitation levels, medical diagnoses, and current medications was explored. Calf and arm BPs were not interchangeable in acutely ill children, ages 1 to 8 years. PMID- 21256409 TI - Asthma: a health disparity among African American children: the impact and implications for pediatric nurses. AB - Asthma is the most common chronic illness among children and is a significant health disparity for African American children and their families. This article provides current statistics that clearly define the problem of asthma and explains the relevance of this health problem for pediatric nurses. The Healthy People 2010 objectives for pediatric asthma care are discussed as outcome measures. The individual, sociocultural, and environmental characteristics of asthma are described. The impact and implications for pediatric nurses in the roles of (a) coordinator of care, (b) child/family advocate, and (c) evaluator of care are explained. PMID- 21256408 TI - Ensuring children eat a healthy diet: a theory-driven focus group study to inform communication aimed at parents. AB - The Theory of Planned Behavior (TPB) served as a framework for analyzing focus group transcripts (N = 43) focused on parents' perceptions of the challenges of ensuring their children eat a healthy diet. The results suggest that parents consider their beliefs and behaviors as individuals within a society, within families, within cultures, as inheritors of family traditions, and as parents who influence or fail to influence the attitudes and behaviors of their children. The results showed the particular salience of factors related to the TPB concepts of perceived norms and control. Approaches to building theory-driven nursing interventions are suggested. PMID- 21256410 TI - The effect of an educational session on pediatric nurses' perspectives toward providing spiritual care. AB - This study evaluated the effect of a spiritual education session on pediatric nurses' perspectives toward providing spiritual care. A one-group pretest and posttest design was used to evaluate the effectiveness of the educational session. Participants consisted of 41 pediatric and neonatal nurses that worked in a large university-affiliated children's hospital. Findings confirmed that the spiritual education session had a positive effect on nurses' perspectives toward providing spiritual care. In addition, a positive correlation was identified between the pediatric nurses' perception of their own spirituality and their perspective toward providing care. PMID- 21256411 TI - Addressing children's beliefs through Fowler's stages of faith. AB - Knowledge of child development, including faith development, is important in providing holistic care to the child. Pediatric nurses and nurse practitioners may be inadequately prepared to meet the spiritual needs of children in developmentally appropriate ways. This article demonstrates why it is necessary to asses a child's or an adolescent's religious and spiritual beliefs and when and how a nurse intervenes. Modeled here is one way in which pediatric nurses can effectively combine their knowledge of child development and Fowler's theory of faith development to address the child and adolescent's spiritual needs. PMID- 21256412 TI - Obesity risk knowledge and physical activity in families of adolescents. AB - Health risk knowledge has been identified as a key to making informed decisions regarding healthy lifestyle choices (J. Swift, C. Glazebrook, & I. Macdonald, 2005). This article describes a descriptive, correlation study conducted with adolescents and their parents to examine the relationship between obesity risk knowledge and physical activity levels in families of adolescents. A statistically significant inverse relationship is found between parental physical activities and the activity levels of adolescents (r = -.23, p<.05). Although a relationship between physical activity and obesity risk knowledge in parents is supported, the phenomenon is not found in adolescent participants. PMID- 21256413 TI - Parent-provider communication during hospitalization. AB - Parents and health care providers interact and communicate with each other during a child's hospitalization. The purpose of this study was to compare communication experiences of parents, nurses, and physicians. A unique aspect of this study involved combining three individual data sources into a collective unit of study (triad). Triads involved in the care of three children in the inpatient setting of an urban children's hospital served as the sample for this study (n = 10). Participants were asked semistructured questions during face-to-face interviews. Findings included (a) the importance of providing information by health care providers using a caring and inclusive approach, (b) the benefits of establishing interpersonal connections and nurturing relationships, and (c) the identification of specific behaviors in all members of the triad that contribute to and sustain positively perceived communication. Future research directions examining triadic interactions, communication, and relationships among parents, nurses, and physicians are recommended. PMID- 21256414 TI - Attitude of Israeli mothers with vaccination of their daughters against human papilloma virus. AB - The purpose of the study is to examine whether the model based on the Theory of Reasoned Action (TRA) succeeds in predicting mothers' intention to vaccinate their daughters against the human papilloma virus infection. Questionnaires were distributed among convenience sample of 103 mothers of daughters 18 years and younger. Approximately 65% of mothers intend to vaccinate their daughters. Behavioral beliefs, normative beliefs, and level of knowledge had a significant positive effect on mothers' intention to vaccinate their daughters. High levels of religiosity were found to negatively affect mothers' intention to vaccinate their daughters. The TRA combined with level of knowledge and level of religiosity succeeds in predicting mothers' behavioral intentions regarding vaccinating daughters. This indicates the significance of nurses' roles in imparting information and increasing awareness among mothers. PMID- 21256415 TI - Nonmedical out-of-pocket expenses: a hidden cost of hospitalization. AB - Health care reform has primarily focused on the costs incurred by the health care delivery system. Little attention has been placed on the magnitude of out-of pocket (OOP) costs imposed on families as caregivers. Nonmedical OOP expenses (NOOPEs) are usually overlooked. The economic burden created by NOOPEs significantly inflates the total costs families must bear. Health care workers and policy makers must gain a better understanding of these realities. This article will discuss NOOPEs, provide a case study for illustration, and discuss strategies for nurses to assist families. PMID- 21256416 TI - Recommendations for the use of intraosseous vascular access for emergent and nonemergent situations in various health care settings: a consensus paper. PMID- 21256417 TI - Warnings that signal serious illness in children. PMID- 21256418 TI - Simulation and debriefing: helping the pediatric nurse thrive. PMID- 21256419 TI - Pediatric nursing research: creating partnerships with parents to improve the health of children and adolescents. PMID- 21256420 TI - Parental response to a diagnosis of diabetes: how nurses can help. PMID- 21256421 TI - The 20th anniversary of the American Association of Hip and Knee Surgeons: introduction. PMID- 21256422 TI - Estimated effects of in utero cocaine exposure on language development through early adolescence. AB - The potential longitudinal effects of prenatal cocaine exposure (PCE) on language functioning were estimated from early childhood through early adolescence in a large, well-retained urban sample of 451 full-term children (242 cocaine-exposed, 209 non-cocaine-exposed) participating in the Miami Prenatal Cocaine Study (MPCS). The sample was enrolled prospectively at birth, with documentation of prenatal drug exposure status through maternal interview, and toxicology assays of maternal and infant urine, and infant meconium. Age-appropriate versions of the Clinical Evaluation of Language Fundamentals (CELF) were used to measure total, expressive, and receptive language at ages 3, 5, and 12years. Longitudinal latent growth curve (LLGC) modeling of the data revealed an association between PCE (measured dichotomously as yes/no) and lower functioning in expressive and total language scores, after considering other sources of variation including child's age at testing, sex, prenatal exposure to alcohol, marijuana, and tobacco, and additional medical and social-demographic covariates. Analyses of level of PCE showed a gradient, i.e. dose-dependent, relationship between PCE level and expressive, receptive, and total language scores in the models controlling for age, child's sex, and other prenatal drug exposures. With additional covariate control these findings were most stable for the total language score. The evidence supports an inference about an enduring stable cocaine-specific effect on children's language abilities, with no effect on language growth over time in the longitudinal trajectory of language development. PMID- 21256423 TI - Adolescents with and without gestational cocaine exposure: Longitudinal analysis of inhibitory control, memory and receptive language. AB - Preclinical studies of gestational cocaine exposure (GCE) show evidence of changes in brain function at the anatomical, physiological, and behavioral levels, to include effects on developing dopaminergic systems. In contrast, human studies have produced less consistent results, with most showing small effects or no effects on developmental outcomes. Important changes in brain structure and function occur through adolescence, therefore it is possible that prenatal cocaine exposure has latent effects on neurocognitive (NC) outcome that do not manifest until adolescence or young adulthood. We examined NC function using a set of 5 tasks designed to tap 4 different systems: inhibitory control, working memory, receptive language, and incidental memory. For each NC task, data were collected longitudinally at ages 12, 14.5 and 17 years and examined using generalized estimating equations. One hundred and nine children completed at least two of the three evaluations. Covariates included in the final model were assessment number, gender, participant age at first assessment, caregiver depression, and two composites from the Home Observation for Measurement of the Environment (HOME), Environmental Stimulation and Parental Nurturance. We found no cocaine effects on inhibitory control, working memory, or receptive language (p=0.18). GCE effects were observed on incidental face memory task (p=0.055), and GCE by assessment number interaction effects were seen on the incidental word memory task (p=0.031). Participant performance on inhibitory control, working memory, and receptive language tasks improved over time. HOME Environmental Stimulation composite was associated with better receptive language functioning. With a larger sample size smaller differences between groups may have been detected. This report shows no evidence of latent effects of GCE on inhibitory control, working memory, or receptive language. GCE effects were observed on the incidental face memory task, and GCE by assessment number interaction effects was seen on the incidental word memory task. PMID- 21256424 TI - Development of inhibitory control among prenatally cocaine exposed and non cocaine exposed youths from late childhood to early adolescence: The effects of gender and risk and subsequent aggressive behavior. AB - The goal of the present investigation was to characterize the development of inhibitory control, an aspect of executive functions, in a sample of prenatally cocaine exposed (CE; n=165) children compared to an at risk, but prenatally cocaine unexposed (NCE; n=119) sample across time (i.e. 7.5 to 11.5 years of age). Gender and cumulative risk, a combination of postnatal medical (i.e. low birth weight and APGAR scores) and demographic risk, indexed by maternal educational attainment, were examined as predictors of change in inhibitory control across time and aggression was modeled as an outcome when children reached 14 years of age. Multiple group latent growth models indicated that CE children made more errors at 7.5 years of age during a standard Stroop interference task, however, over time CE children had greater age-related improvements, narrowing the initial gap, with NCE children in the ability to inhibit errors. Gender effects at 7.5 years within the NCE group were identified with NCE boys making initially more errors than NCE girls; both NCE and CE girls improved faster across development compared to NCE and CE boys, respectively. Greater cumulative risk was associated with more errors at 7.5 years in the CE and NCE groups. No differences were observed between CE and NCE children on time to complete the Stroop task at 7.5 years. However, NCE children had greater age related improvements in their time to complete the Stroop interference task relative to their CE counterparts. NCE girls improved the fastest over time relative to NCE boys; a similar trend emerged (p<0.10) with CE girls improving faster over time than CE boys. Although all participants improved across development, higher cumulative risk in both groups was associated with slower age related improvements (i.e. higher slopes) in the time to complete the Stroop task across development. After accounting for gender and cumulative risk, findings in both groups indicated that those who made more errors at 7.5 years of age and/or who had slower age-related changes (i.e. higher slopes) of time to complete the Stroop task across development were more aggressive as rated by caregivers at 14 years of age. Although qualified by gender and cumulative risk, these findings are consistent with reduced cognitive processing efficiency and executive function difficulties in CE children relative to NCE children. Findings suggest that executive function difficulties in CE children may be subtle as development continues to unfold over time. Furthermore, these findings indicate that development of inhibitory control may be an important mechanism linking prenatal cocaine exposure, gender, and cumulative risk to later adverse outcomes. PMID- 21256425 TI - The effects of prenatal cocaine exposure and gender on inhibitory control and attention. AB - Children exposed prenatally to cocaine show deficits in emotion regulation and inhibitory control. While controlling for the measures of medical complication in the perinatal period, environmental risk, and prenatal polydrug exposure (alcohol, tobacco, and marijuana), we examined the effects of prenatal cocaine exposure and gender on attention and inhibitory control in 203 children at ages 6, 9, and 11. Cocaine exposure affected the performance of males, but not females. Heavily exposed males showed deficits in the attention and the inhibition tasks. In addition, a significantly greater proportion of heavily exposed males (21%) than unexposed males (7%) or heavily exposed females (7%) failed to complete the task (p<0.01). Even without those poorest performing subjects, the overall accuracy for heavily exposed males (81%) was significantly reduced (p<0.05) compared to lightly exposed males (87%) and unexposed males (89%). The findings highlight the importance of considering gender specificity in cocaine exposure effects. Processes by which cocaine effects may be specific to males are discussed. PMID- 21256426 TI - Maternal cocaine use and mother-infant interactions: Direct and moderated associations. AB - This study examined the associations between prenatal cocaine exposure and quality of mother-infant play interactions at 13 months of infant ages. We investigated whether maternal psychological distress and infant reactivity mediated or moderated this association. Participants consisted of 220 (119 cocaine exposed and 101 non-cocaine exposed) mother-infant dyads participating in an ongoing longitudinal study of prenatal cocaine exposure. Results indicated that mothers who used cocaine during pregnancy displayed higher negative affect and lower sensitivity toward their infant during play interactions at 13 months, and that their infants were less responsive toward them. Contrary to hypothesis, this association was not mediated by maternal psychological distress or by infant reactivity. However, results for both the cocaine and non-cocaine exposed infants were supportive of a transactional model where lower maternal sensitivity at 1 month was predictive of higher infant reactivity at 7 months, which in turn was predictive of lower maternal warmth/sensitivity at 13 months, controlling for potential stability in maternal behavior. Results also indicated that as hypothesized, infant reactivity moderated the association between maternal cocaine use during pregnancy and maternal warmth/sensitivity at 13 months of age. Cocaine-using mothers who experienced their infants as being more reactive in early infancy were less warm/sensitive toward them in later infancy. Results have implications for parenting interventions that may be targeted toward improving maternal sensitivity among cocaine-using mothers with more reactive infants. PMID- 21256427 TI - The effects of prenatal marijuana exposure on delinquent behaviors are mediated by measures of neurocognitive functioning. AB - We hypothesized that there would be an association between prenatal marijuana exposure (PME) and delinquency and that the effects of PME on neurocognitive development would mediate this association. Mothers and offspring enrolled in a longitudinal study of the effects of prenatal substance exposure on child development, were interviewed from the fourth prenatal month through 14 years. There were 580 mother/child dyads at the 14-year phase. A standardized protocol assessed psychological, neurocognitive, social, environmental, and demographic characteristics, and substance use at each phase. The Self Report Delinquency scale (Loeber et al., 1998) and the Child Behavior checklist (Achenbach, 1991) delinquency subscale were combined to represent delinquent behavior. First trimester PME was used as a dichotomous variable, daily use versus all other use. Offspring of heavier marijuana users were significantly more likely to report delinquent behavior at age 14. The odds ratio for delinquency among those who were exposed to one or more joints per day during gestation was 1.76 (C.I. 1.05 2.96). PME significantly predicted child depressive symptoms and attention problems at age 10, after controlling for other significant covariates. Child depressive symptoms and attention problems at age 10 significantly predicted delinquency at 14 years. The association between PME and delinquent behavior at 14 years was mediated by depressive symptoms and attention problems in the offspring at 10 years. PMID- 21256428 TI - Effects of prenatal cigarette smoke exposure on neurobehavioral outcomes in 10 year-old children of adolescent mothers. AB - In this prospective study, adolescent mothers (mean age=16; range=12-18; 70% African-American) were interviewed about their tobacco use during pregnancy. When their children were ten, mothers reported on their child's behavior and the children completed a neuropsychological battery. We examined the association between prenatal cigarette smoke exposure (PCSE) and offspring neurobehavioral outcomes on data from the 10-year phase (n=330). Multivariate regression analyses were conducted to test if PCSE predicted neurobehavioral outcomes, adjusting for demographic characteristics, maternal psychological characteristics, prenatal exposure to other substances, and exposure to environmental tobacco smoke. Independent effects of PCSE were found. Exposed offspring had more delinquent, aggressive, and externalizing behaviors (CBCL). They were more active (Routh, EAS, and SNAP) and impulsive (SNAP) and had more problems with peers (SNAP). On the Stroop test, deficits were observed on the more complex interference task that requires both selective attention and response inhibition. The significant effects of PCSE on neurobehavioral outcomes were found for exposure to as few as 10 cigarettes per day. Most effects were found from first trimester PCSE exposure. These results are consistent with results from an earlier assessment when the children were age 6, demonstrating that the effects of prenatal tobacco exposure can be identified early and are consistent through middle childhood. PMID- 21256429 TI - Unpacking the association: Individual differences in the relation of prenatal exposure to cigarettes and disruptive behavior phenotypes. AB - Prenatal exposure to cigarettes has been robustly associated with disruptive behavior in diverse samples and across developmental periods. In this paper we aim to elucidate exposure related behavioral phenotypes and developmental pathways by testing: (a) differential associations of exposure and four disruptive behavior dimensional phenotypes: Aggression, Noncompliance, Temper Loss and Low Concern for Others; and (b) moderation of these pathways including sex differences and moderation by parental responsive engagement. Participants were 211 teens and their parents from the East Boston Family Study (EBFS), an adolescent follow-up of a pregnancy cohort over-sampled for exposure. A best estimate serum cotinine corrected score was used to characterize exposure. In multivariate models controlling for parental antisocial behavior, family adversity and secondhand exposure, exposure uniquely predicted Aggression and Noncompliance. Paternal responsiveness moderated exposure effects on disruptive behavior. There were no sex differences in these patterns. Phenotypic findings suggest the possibility of specific neural mechanisms. In conjunction with prior research, protective effects of parental responsiveness occurring as late as adolescence point to the potential benefit of parenting-based prevention efforts to reduce risk to exposed offspring. PMID- 21256430 TI - A new look at quantifying tobacco exposure during pregnancy using fuzzy clustering. AB - BACKGROUND: Prenatal tobacco exposure is a risk factor for the development of externalizing behaviors and is associated with several adverse health outcomes. Because pregnancy smoking is a complex behavior with both daily fluctuations and changes over the course of pregnancy, quantifying tobacco exposure is a significant challenge. To better measure the degree of tobacco exposure, costly biological specimens and repeated self-report measures of smoking typically are collected throughout pregnancy. With such designs, there are multiple, and substantially correlated, indices that can be integrated via new statistical methods to identify patterns of prenatal exposure. METHOD: A multiple-imputation based fuzzy clustering technique was designed to characterize topography of prenatal exposure. This method leveraged all repeatedly measured maternal smoking variables in our sample data, including (a) cigarette brand; (b) Fagerstrom nicotine dependence item scores; (c) self-reported smoking; and (d) cotinine level in maternal urine and infant meconium samples. Identified exposure groups then were confirmed using a suite of clustering validation indices based on multiple imputed datasets. The classifications were validated against irritable reactivity in the first month of life and birth weight of 361 neonates (Male(_n)=185; Female(_n)=176; Gestational Age_(Mean)=39weeks). RESULTS: This proposed approach identified three exposure groups, non-exposed, lighter-tobacco exposed, and heavier-tobacco-exposed based on high-dimensional attributes. Unlike cut-off score derived groups, these groupings reflect complex smoking behavior and individual variation of nicotine metabolism across pregnancy. The identified groups predicted differences in birth weight and in the pattern of change in neonatal irritable reactivity, as well as resulted in increased predictive power. Multiple-imputation-based fuzzy clustering appears to be a useful method to categorize patterns of exposure and their impact on outcomes. PMID- 21256432 TI - Social cognition LabLinks. PMID- 21256433 TI - Aplysia. PMID- 21256431 TI - Motor and cognitive outcomes through three years of age in children exposed to prenatal methamphetamine. AB - BACKGROUND: Methamphetamine (MA) use among pregnant women is an increasing problem in the United States. The impact of prenatal MA exposure on development in childhood is unknown. OBJECTIVE: To examine the effects of prenatal MA exposure on motor and cognitive development in children at 1, 2, and 3 years of age. DESIGN/METHODS: IDEAL enrolled 412 mother-infant pairs at four sites (Tulsa OK, Des Moines IA, Los Angeles CA, and Honolulu HI). MA subjects (n=204) were identified by self report or GC/MS confirmation of amphetamine and metabolites in infant meconium. Comparison subjects (n=208) were matched (race, birth weight, maternal education, and type of insurance), denied amphetamine use, and had a negative meconium screen. Both groups included prenatal alcohol, tobacco and marijuana use, but excluded use of opiates, lysergic acid diethylamide, phencyclidine or cocaine only. The Peabody Developmental Motor Scales (PDMS-2) were administered to the infants at the 1 and 3 year visits. This analysis includes a subsample (n=350) of the IDEAL study with completed 1 and/or 3 year visits (n=330 and 281, respectively). At each annual visit we also conducted the Bayley Scales of Infant Development (BSID-II) as a general evaluation of mental and motor development. The BSID-II analysis includes a subsample (n=356) of the IDEAL study with completed 1, 2, and/or 3 year visits (n=331, 288, and 278 respectively). GLM analysis conducted on the PDMS-2 and BSID-II examined the effects of MA exposure and heavy MA exposure (>=3 days of use/week), with and without covariates. Longitudinal analyses were used to examine the effects of MA exposure on changes in motor and cognitive performance over time. RESULTS: Heavy MA exposure was associated with significantly lower grasping scores than some and no use at 1 year (P=0.018). In longitudinal analysis, lower grasping scores associated with any MA exposure and heavy exposure persisted to 3 years. There were no effects of MA exposure, including heavy exposure, on the Bayley Mental Development Index (MDI) or Psychomotor Development Index (PDI) at any or across age. CONCLUSIONS: There were no differences in cognition as assessed by the BSID II between the groups. There was a subtle MA exposure effect on fine motor performance at 1 year with the poorest performance observed in the most heavily exposed children. By 3 years, no differences in fine motor performance were observed. These findings suggest MA exposure has modest motor effects at 1 year that are mostly resolved by 3 years. PMID- 21256434 TI - Sexual selection. AB - Sexual selection is a concept that has probably been misunderstood and misrepresented more than any other idea in evolutionary biology, confusion that continues to the present day. We are not entirely sure why this is, but sexual politics seems to have played its role, as does a failure to understand what sexual selection is and why it was initially invoked. While in some ways less intuitive than natural selection, sexual selection is conceptually identical to it, and evolution via either mechanism will occur given sufficient genetic variation. Recent claims that sexual selection theory is fundamentally flawed are simply wrong and ignore an enormous body of evidence that provides a bedrock of support for this major mechanism of organic evolution. In fact it is partly due to this solid foundation that current research has largely shifted from documenting whether or not sexual selection occurs, to addressing more complex evolutionary questions. PMID- 21256435 TI - Actin-based motility: WAVE regulatory complex structure reopens old SCARs. AB - The SCAR/WAVE complex controls actin polymerization at the leading edges of moving cells, but its mechanism of regulation remains unclear. The recent determination of its crystal structure, and identification of the binding sites for upstream regulators, mean its workings can finally start to be revealed. PMID- 21256436 TI - Protein dynamics: Moore's law in molecular biology. AB - The millisecond barrier has been broken in molecular dynamics simulations of proteins. Such simulations are increasingly revealing the inner workings of biological systems by generating atomic-level descriptions of their behaviour that make testable predictions about key molecular processes. PMID- 21256437 TI - Motor memory: a declaration of non-independence. AB - A new study shows that the 'fast' component of motor adaptation is distinct from its 'slow' counterpart and shares critical resources with declarative memory. PMID- 21256438 TI - Pyroptosis: macrophage suicide exposes hidden invaders. AB - Caspase-1 plays a key role in host defense through its dual function in inducing a pro-inflammatory cell death termed pyroptosis and in promoting the secretion of pro-inflammatory cytokines. A new study now highlights the specific importance of pyroptosis in resistance to intracellular pathogens. PMID- 21256439 TI - Affective neuroscience: amygdala's role in experiencing fear. AB - A new neuropsychological study of a rare patient provides novel evidence that amygdala lesions can virtually abolish the experience of fear, illuminating neurobiological mechanisms of fear experience. PMID- 21256440 TI - Microtubule dynamics: Patronin, protector of the minus end. AB - It has long been surmised that cellular microtubules are capped at the minus ends to prevent their depolymerization. A recent study provides the first definitive identification of a minus-end-specific capping protein, termed Patronin, which protects the microtubule arrays of both mitotic and interphase cells. PMID- 21256441 TI - Neural control: closed-loop human brain reading. AB - Closed-loop experimental testing of single medial temporal lobe neurons in humans reveals top-down effects, opening new possibilities for describing neural representations at the highest level. PMID- 21256442 TI - Model systems of invertebrate allorecognition. AB - Nearly all colonial marine invertebrates are capable of allorecognition--the ability to distinguish between self and genetically distinct members of the same species. When two or more colonies grow into contact, they either reject each other and compete for the contested space or fuse and form a single, chimeric colony. The specificity of this response is conferred by genetic systems that restrict fusion to self and close kin. Two selective pressures, intraspecific spatial competition between whole colonies and competition between stem cells for access to the germline in fused chimeras, are thought to drive the evolution of extensive polymorphism at invertebrate allorecognition loci. After decades of study, genes controlling allorecognition have been identified in two model systems, the protochordate Botryllus schlosseri and the cnidarian Hydractinia symbiolongicarpus. In both species, allorecognition specificity is determined by highly polymorphic cell-surface molecules, encoded by the fuhc and fester genes in Botryllus, and by the alr1 and alr2 genes in Hydractinia. Here we review allorecognition phenomena in both systems, summarizing recent molecular advances, comparing and contrasting the life history traits that shape the evolution of these distinct allorecognition systems, and highlighting questions that remain open in the field. PMID- 21256443 TI - Return to sport--how do you deal with it? PMID- 21256444 TI - A return-to-sport algorithm for acute hamstring injuries. AB - Acute hamstring injuries are the most prevalent muscle injuries reported in sport. Despite a thorough and concentrated effort to prevent and rehabilitate hamstring injuries, injury occurrence and re-injury rates have not improved over the past 28 years. This failure is most likely due to the following: 1) an over reliance on treating the symptoms of injury, such as subjective measures of "pain", with drugs and interventions; 2) the risk factors investigated for hamstring injuries have not been related to the actual movements that cause hamstring injuries i.e. not functional; and, 3) a multi-factorial approach to assessment and treatment has not been utilized. The purpose of this clinical commentary is to introduce a model for progression through a return-to-sport rehabilitation following an acute hamstring injury. This model is developed from objective and quantifiable tests (i.e. clinical and functional tests) that are structured into a step-by-step algorithm. In addition, each step in the algorithm includes a treatment protocol. These protocols are meant to help the athlete to improve through each phase safely so that they can achieve the desired goals and progress through the algorithm and back to their chosen sport. We hope that this algorithm can serve as a foundation for future evidence based research and aid in the development of new objective and quantifiable testing methods. PMID- 21256445 TI - Plyometric training as an intervention to correct altered neuromotor control during running after cycling in triathletes: a preliminary randomised controlled trial. AB - BACKGROUND: Altered neuromotor control during running after cycling has been associated with exercise-related leg pain and may have performance implications for triathletes. OBJECTIVE: To investigate the effectiveness of adding plyometric training to regular endurance training on triathletes' neuromotor control and running economy in those in which it is aberrant. DESIGN: Randomised controlled trial. SETTING: Institutional. PARTICIPANTS: 15 moderately-trained triathletes. INTERVENTIONS: Eight-week endurance only (control group) or endurance plus plyometric (plyometric group) training program. MAIN OUTCOME MEASURES: Neuromotor control and running economy during running after cycling. RESULTS: Eight of the fifteen triathletes exhibited aberrant neuromotor control and were randomised to control or plyometric groups. Combined plyometric and endurance training produced favourable neuromotor adaptations during running after cycling beyond that of endurance training at 8 weeks (numbers needed to treat 2). There were significant differences between control and plyometric groups at eight weeks for the coefficient of multiple correlation (p=0.03) and root mean square error (p = 0.01) between control and transition runs. Running economy was not different between groups at follow-up. CONCLUSION: Our results provide some support for the utility of plyometrics as an intervention to correct altered neuromotor control in those triathletes in which it is aberrant. PMID- 21256446 TI - Kinematics during lower extremity functional screening tests--are they reliable and related to jogging? AB - PURPOSE: To investigate the within-day and between-day reliability of 3D lower extremity kinematics during five lower extremity functional screening tests and to assess the association between these kinematics and those recorded during jogging. METHODS: Peak three-dimensional lower extremity kinematics were quantified in 25 uninjured participants during five lower extremity functional tests and jogging. A nine camera motion analysis system (Qualysis Medical AB, Sweden) was used to capture three trials of all tests. All functional tests were repeated by 10 participants one to two days later. Visual 3D (C-Motion Inc, USA) and Labview were used to process all data. Intraclass correlation coefficients (ICC) and typical errors (TE) were used to assess within- and between-day reliability of all variables. Pearson correlation coefficients were used to evaluate the association between peak joint kinematics during the functional tests and jogging. RESULTS: For the majority of kinematic variables the within day reliability was excellent (ICC >= 0.92) and the between-day reliability was excellent to good (ICC >= 0.80). The correlation between kinematics of the functional tests and jogging was generally large to very large (r = 0.53 to 0.93). CONCLUSIONS: These results suggest these lower extremity functional screening tests should prove a useful clinical tool when assessing dynamic lower extremity alignment. PMID- 21256447 TI - A comparison in the muscle activity of the abductor hallucis and the medial longitudinal arch angle during toe curl and short foot exercises. AB - OBJECTIVE: To compare the muscle activity of the abductor hallucis (AbdH) and the medial longitudinal arch (MLA) angle during toe curl (TC) and short foot (SF) exercises while sitting or in one-leg standing position. DESIGN: Two-way repeated measures ANOVA was used to analyze the effects of exercise type and position on the muscle activity of the AbdH and the MLA angle. PARTICIPANTS: Twenty subjects with normal feet participated in this study. MAIN OUTCOME MEASURES: The muscle activity of the AbdH and the MLA angle were measured during TC and SF exercises while sitting or in one-leg standing position. RESULTS: The EMG activity of AbdH in SF exercise was significantly greater than during TC exercise in both exercise postural positions (p < 0.001). During the SF exercise, the EMG activity of the AbdH in the one-leg standing position was significantly higher than that while sitting (p < 0.001). The MLA angle in SF exercise was significantly smaller than during TC exercise in both postural positions (p < 0.001). CONCLUSIONS: These results suggest that SF exercise is a more useful strengthening exercise than TC exercise in activating the AbdH muscle. PMID- 21256448 TI - A review of return to sport concerns following injury rehabilitation: practitioner strategies for enhancing recovery outcomes. AB - OBJECTIVES: Evidence suggests that competitive athletes returning to sport following injury rehabilitation may experience a range of psychosocial concerns. The purpose of this paper is to review some of the psychosocial stresses common among returning athletes and to provide practitioner strategies for enhancing recovery outcomes. EVIDENCE ACQUISITION: Findings are based on a database search of Sport Discus, Psychinfo, and Medline using sport injury, fear of re-injury, return to full activity. RESULTS: Salient apprehensions among athletes' returning to sport following injury were found to include: anxieties associated with re injury; concerns about an inability to perform to pre-injury standards; feelings of isolation, a lack of athletic identity and insufficient social support; pressures to return to sport; and finally, self-presentational concerns about the prospect of appearing unfit, or lacking in skill in relation to competitors. CONCLUSIONS: The results suggest that athletes returning to sport from injury may experience concerns related to their sense of competence, autonomy and relatedness. Given its focus on competence, autonomy and relatedness issues, self determination theory (SDT) is offered as a framework for understanding athlete concerns in the return to sport from injury. Practical suggestions for sport medicine practitioners, researchers and applied sport psychology specialists seeking to address athlete issues are provided using an SDT perspective. PMID- 21256449 TI - Efficacy of an inertial resistance training paradigm in the treatment of patellar tendinopathy in athletes: a case-series study. AB - STUDY DESIGN: Case-series study with pre- vs. post-test measurements design. BACKGROUND: Strength training programs emphasizing eccentric muscle actions have received much attention in the treatment of tendinopathies. The current study reports on the efficacy of a novel strength training paradigm using inertial eccentric-concentric resistance to treat chronic patellar tendinopathy. CASE DESCRIPTION: Ten athletes with chronic patellar tendinopathy (15 tendons) volunteered for the study. Subjects completed a 6-week training program employing a leg press flywheel ergometer. Pre and post measurements assessed lower limb maximal strength and vertical counter-movement-jump (CMJ) height. Surface electromyography (SEMG) analysis of paraspinal, rectus femoris, biceps femoris and medial gastrocnemius muscles were collected. All measurements were performed one week before and after the training period. Clinical measures of pain and tendon function were assessed by means of a visual analogue scale (VAS) and a patellar tendinopathy questionnaire (VISA) at baseline, post-training and follow up (12 wk). The Wilcoxon signed-rank test was employed for data comparisons. RESULTS: Eccentric strength increased after training (90%, p < 0.05). Similarly, VAS and VISA scores improved after training as well (60% and 86%, respectively, p < 0.01). There were no changes in CMJ height. CONCLUSION: Short-term training using inertial eccentric overload, resulted in improved muscle function and reduced subjective pain in long-lasting patellar tendinopathy. PMID- 21256450 TI - Rare neurological diseases: a united approach is needed. PMID- 21256451 TI - The risky business of drug development in neurology. PMID- 21256452 TI - Gunther Deuschl: from mathematics to movement disorders. PMID- 21256454 TI - Treatment of patients with essential tremor. AB - Essential tremor is a common movement disorder. Tremor severity and handicap vary widely, but most patients with essential tremor do not receive a diagnosis and hence are never treated. Furthermore, many patients abandon treatment because of side-effects or poor efficacy. A newly developed algorithm, based on the logarithmic relation between tremor amplitude and clinical tremor ratings, can be used to compare the magnitude of effect of available treatments. Drugs with established efficacy (propranolol and primidone) produce a mean tremor reduction of about 50%. Deep brain stimulation (DBS) in the thalamic nucleus ventrointermedius or neighbouring subthalamic structures reduces tremor by about 90%. However, no controlled trials of DBS have been done, and the best target is still uncertain. Better drugs are needed, and controlled trials are required to determine the safety and efficacy of DBS in the nucleus ventrointermedius and neighbouring subthalamic structures. PMID- 21256455 TI - Mechanisms of epileptogenesis and potential treatment targets. AB - Prevention of epileptogenesis after brain trauma is an unmet medical challenge. Recent molecular profiling studies have provided an insight into molecular changes that contribute to formation of ictogenic neuronal networks, including genes regulating synaptic or neuronal plasticity, cell death, proliferation, and inflammatory or immune responses. These mechanisms have been targeted to prevent epileptogenesis in animal models. Favourable effects have been obtained using immunosuppressants, antibodies blocking adhesion of leucocytes to endothelial cells, gene therapy driving expression of neurotrophic factors, pharmacological neurostimulation, or even with conventional antiepileptic drugs by administering them before the appearance of genetic epilepsy. Further studies are needed to clarify the optimum time window and aetiological specificity of treatments. Questions related to adverse events also need further consideration. Encouragingly, the recent experimental studies emphasise that the complicated process of epileptogenesis can be favourably modified, and that antiepileptogenesis as a treatment indication might not be an impossible mission. PMID- 21256456 TI - Looks like a duck, quacks like a duck ... still behaves like a bone marrow stromal cell. PMID- 21256457 TI - Bone marrow stromal cells as replacement cells for Parkinson's disease: generation of an anatomical but not functional neuronal phenotype. AB - The focus of cell replacement therapies (CRTs) for Parkinson's disease has been on delivering dopamine-producing cells to the striatum. Fetal grafts have proven the feasibility of this approach, but an appropriate source of replacement cells has restricted the clinical translation. Bone marrow stromal cells (BMSCs) have been heralded as an ideal source of dopaminergic (DAergic) replacement cells, as they are viewed as ethically acceptable, easily procured, and readily expanded. It is known that they confer functional benefits, particularly in stroke models, through the release of neurotrophic factors, but their transdifferentiation into neurons is still under contention. We sought to evaluate the neuronal phenotype and functional capacity of adult rat BMSCs after exposure to a novel multistep in vitro differentiation protocol compared with cells exposed to other reported neuronal differentiation conditions. We employed a systematic, comprehensive method of assessment to determine the neuronal differentiation capacity of BMSCs. Our fluorescence-activated cell sorting, immunofluorescent and semiquantitative polymerase chain reaction results confirmed that undifferentiated BMSCs isolated based on their adherence to plastic are of mesenchymal origin and express a range of lineage markers. After exposure to preinduction and neuronal induction steps, BMSCs down-regulate markers of other lineages but fail, as assessed by patch clamp, to differentiate into functional neurons. Thus, for BMSCs to be considered a source of DAergic neuronal replacement cells, their ability to transdifferentiate terminally along a neuronal lineage first must be clarified before attempting to direct more complex specification process required for them to be used in Parkinson's-disease-focused CRTs. PMID- 21256458 TI - Synergistic induction of CX3CL1 by interleukin-1beta and interferon-gamma in human lung fibroblasts: involvement of signal transducer and activator of transcription 1 signaling pathways. AB - CX3CL1 (fractalkine), a membrane-bound chemokine that induces both the adhesion and the migration of leukocytes, is involved in the recruitment of cells into tissues undergoing inflammatory responses. To explore the regulation of CX3CL1 in pulmonary inflammation and fibrosis, CX3CL1 expression in lung fibroblasts was examined. Normal human fibroblasts were obtained from Promocell (Lonza Walkersville Inc, Md) and were incubated in the presence or absence of various inflammatory stimuli. Culture supernatants were collected, and the soluble CX3CL1 levels were determined with an enzyme-linked immunosorbent assay. The expression of CX3CL1 mRNA transcripts in lung fibroblasts was assessed using quantitative TaqMan real-time polymerase chain reaction. Interleukin (IL)-1beta or interferon (IFN)-gamma individually induced negligible soluble CX3CL1 secretion by human lung fibroblasts after 24 h. However, the combination of IL-1beta and IFN-gamma induced dramatic increases in both soluble CX3CL1 protein and mRNA transcripts in a dose- and time-dependent manner. Synergistic up-regulation of cell-associated CX3CL1 protein also was observed after treatment with IL-1beta and IFN-gamma. The secretion and expression of lung fibroblast-derived CX3CL1 were markedly reduced by specific inhibitors of the STAT-1 transcription factor. These findings suggest that lung fibroblasts are an important cellular source of CX3CL1 and may play a role in pulmonary inflammation and fibrosis. PMID- 21256459 TI - AVE4454B--a novel sodium-hydrogen exchanger isoform-1 inhibitor--compared less effective than cariporide for resuscitation from cardiac arrest. AB - We compared the efficacy of the novel sodium-hydrogen exchanger (NHE-1) inhibitor AVE4454B with cariporide for resuscitation from ventricular fibrillation (VF) assessing the effects on left ventricular myocardial distensibility during chest compression, myocardial function after the return of spontaneous circulation, and survival. Three groups of 10 rats each were subjected to 10 min of untreated VF and resuscitation attempted by providing chest compression for up to 8 min with the depth of compression adjusted to attain an aortic diastolic pressure between 26 and 28 mmHg (to secure a coronary perfusion pressure above 20 mmHg) followed by electrical shocks. Rats received AVE4454B (1 mg/kg), cariporide (1 mg/kg), or vehicle control immediately before chest compression. We observed that NHE-1 inhibition (NHEI) preserved left ventricular myocardial distensibility during chest compression evidenced by less depth of compression required to attain the target aortic diastolic pressure corresponding to (mean +/- standard deviation) 14.1 +/- 1.1 mm in the AVE4454B group (P < 0.001 versus control), 15.0 +/- 1.4 mm in the cariporide group (P < 0.01 versus control), and 17.0 +/- 1.2 mm in controls. When the depth of compression was related to the coronary perfusion pressure generated-an index of left ventricular distensibility-only the cariporide group attained statistical significance. Postresuscitation, both compounds ameliorated myocardial dysfunction evidenced by lesser reductions in mean aortic pressure and the maximal rate of left ventricular pressure increase as well as earlier normalization of left ventricular end-diastolic pressure increases. This effect was associated with improved survival corresponding to 55% in the AVE4454B group (not significant) and 70% in the cariporide group (P < 0.01 versus control by Gehan-Breslow analysis) at 240 min postresuscitation. An inverse correlation was found between plasma cytochrome c and indices of left ventricular function at 240 min postresuscitation suggesting that NHEI exerts beneficial effects in part by attenuating mitochondrial injury. We conclude that cariporide is more effective than AVE4454B for resuscitation from cardiac arrest given its more prominent effect on preserving left ventricular myocardial distensibility and promoting survival. PMID- 21256460 TI - A novel role for tamoxifen in the inhibition of human platelets. AB - Tamoxifen, a selective estrogen receptor (ER) modulator (SERM), is widely used therapeutically for the treatment and prevention of breast cancer, but its use is associated with an increased risk of thrombosis. The mechanism of this adverse effect is still unclear. Arterial thromboses mostly consist of platelets that are adherent to ruptured endothelial surfaces. Several lines of evidence reported that tamoxifen stimulates platelet activation using different methodologies. In our preliminary study, tamoxifen exhibited potent antiplatelet activity in washed human platelets. The aim of this study was to examine the signal transduction pathways of tamoxifen in platelet activation. In this study, tamoxifen (3~7 MUmol/L) exhibited more potent activity in inhibiting platelet aggregation stimulated by collagen than other agonists (ie, thrombin). Tamoxifen inhibited collagen-stimulated platelet activation accompanied by relative Ca(+2) mobilization, thromboxane A(2) (TxA(2)) formation, and phospholipase C (PLC)gamma2, protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) phosphorylation (ie, p38 MAPK and extracellular signal-regulated kinase 1/2), but not hydroxyl radical (OH(*)) formation. However, tamoxifen did not increase nitric oxide (NO) release or vasodilator-stimulated phosphoprotein (VASP) phosphorylation in washed platelets. Furthermore, neither ICI 182,780, a pure ER antagonist, nor ODQ, an inhibitor of guanylate cyclase, significantly reversed the tamoxifen-mediated inhibition of platelet aggregation. In conclusion, this study demonstrates for the first time that tamoxifen possesses potent antiplatelet activity, the mechanism of which may be involved in the inhibition of the PLCgamma2-PKC-p38 MAPK-TxA(2) cascade, thereby leading to the inhibition of platelet activation. In our study, the direct inhibition of platelet activation by tamoxifen possibly may provide new insights into understanding its cardiovascular effects. PMID- 21256461 TI - Interdependence of cardiac iron and calcium in a murine model of iron overload. AB - Iron cardiomyopathy in beta-thalassemia major patients is associated with a vitamin D deficiency. Stores of 25-OH-D3 are markedly reduced, whereas the active metabolite, 1-25-(OH)-D3, is normal or increased. Interestingly, the ratio of 25 OH-D3 to 1-25-(OH)-D3 (a surrogate for parathyroid hormone [PTH]) is the strongest predictor of cardiac iron. Increased PTH and 1-25-OH-D3 levels have been shown to up-regulate L-type voltage-gated calcium channels (LVGCC), the putative channel for cardiac iron uptake. Therefore, we postulate that a vitamin D deficiency increases cardiac iron by altering LVGCC regulation. Hemojuvelin knockout mice were calcitriol treated, PTH treated, vitamin D-depleted, or untreated. Half of the animals in each group received the Ca(2+)-channel blocker verapamil. Mn(2+) was infused to determine LVGCC activity. Hearts and livers were harvested for iron, calcium, and manganese measurements as well as histology. Cardiac iron did not differ among the treatment groups; however, liver iron was increased in vitamin D-depleted animals (P < 0.0003). Cardiac iron levels did not correlate with manganese uptake but were proportional to cardiac calcium levels (r(2) = 0.6; P < 0.0001). Verapamil treatment reduced both cardiac (P < 0.02) and hepatic (P < 0.003) iron levels significantly by 34% and 28%, respectively. The association between cardiac iron and calcium levels was maintained after verapamil treatment (r(2) = 0.3; P < 0.008). Vitamin D depletion is associated with an increase in liver, but not cardiac, iron accumulation. Cardiac iron uptake was strongly correlated with cardiac calcium stores and was significantly attenuated by verapamil, suggesting that cardiac calcium and iron are related. PMID- 21256462 TI - Effect of oxidative stress induced by paradoxical sleep deprivation on the activities of Na+, K+-ATPase and acetylcholinesterase in the cortex and hippocampus of rat. AB - Several studies revealed the importance of paradoxical sleep as a homeostatic mechanism by which the brain can control oxidative stress. The aim of the present study is to investigate the effect of 72 h of paradoxical sleep deprivation on the oxidative stress markers and its insults on the activities of Na(+), K(+) ATPase and acetylcholinesterase in the cortex and hippocampus of albino rat. Animals were subjected to paradoxical sleep deprivation for 72 h. At the end of the experiment, the rats were sacrificed, and catalase activity, levels of reduced glutathione, lipid peroxidation, and nitric oxide were assayed together with the activities of Na(+), K(+)-ATPase and acetylcholinesterase in the cortex and hippocampus. The present study revealed a significant increase in lipid peroxidation accompanied by a significant decrease in reduced glutathione in the cortex and hippocampus. Na(+), K(+)-ATPase decreased significantly in both areas. However, acetylcholinesterase showed a significant increase in the investigated brain regions. The present data showed that 72 h of paradoxical sleep deprivation induced oxidative stress in the cortex and hippocampus. It could be suggested that the inhibition of Na(+), K(+)-ATPase and the increased acetylcholinesterase activity may underlie memory impairment, increased brain excitability, and anxiety induced by paradoxical sleep deprivation. PMID- 21256463 TI - [Allergic contact dermatitis to footwear in children]. PMID- 21256464 TI - Quality of life in pediatric patients with implantable cardioverter defibrillators. AB - Psychosocial and quality-of-life (QOL) outcomes in adult patients with implantable cardioverter-defibrillators (ICDs) are well studied. Minimal research exists regarding pediatric adjustment, despite a potentially more challenging adjustment process. The purpose of the present study was to examine psychosocial and QOL functioning of pediatric ICD patients from patient and parent self reports. Children and primary caregiver dyads from several university hospitals were analyzed using the PedsQL, the Device Severity Index, the ICD and Avoidance Survey, and demographic information. Sixty children (25 female, 35 male) were enrolled. The present pediatric sample reported lower psychosocial and physical QOL scores than healthy children's normative scores. In comparison with a sample of chronically ill children, pediatric ICD patients reported lower physical QOL. Parent-observed QOL reports revealed lower psychosocial and physical QOL than parent-observed healthy norms and lower psychosocial and physical QOL than chronically ill norms. There were no QOL differences by ICD shocks or medical severity. Female patients reported lower psychosocial, physical, and cardiac QOL scores. Children reported better QOL than parent observations on psychosocial and physical health. Finally, 84.7% of children reported avoidance behaviors since ICD implantation, with female children avoiding places more than male children. In conclusion, pediatric ICD patients are comparable to children with other chronic illnesses with the exception of lower physical QOL. Similar to adult samples, female children reported poorer QOL and were more likely to engage in avoidance behaviors. Patients indicated better QOL perceptions than their parents' reports. ICD discharges and medical severity did not negatively affect QOL. PMID- 21256465 TI - Angiotensin II receptor blockers and risk of cancer in patients with systemic hypertension. AB - Recently, concerns have been raised that angiotensin II receptor blockers (ARBs) may be associated with an increased risk for cancer development. However, the relation between ARBs and cancer is still unclear. Therefore, a nationwide population-based study was conducted to investigate the possible influence of ARBs on the occurrence of new cancers in patients with hypertension by using the Taiwan National Health Insurance database. A total of 109,002 patients with newly diagnosed hypertension were identified from a cohort database of 1 million individuals from January 1, 1998, to December 31, 2006. Among them, 40,124 (36.8%) had received ARBs for hypertension. The end point was the development of any type of cancer before the end of 2007. During an average of 5.7 +/- 2.6 years of follow-up, a total of 9,067 cases of new cancer occurrence were observed. The log-rank test showed that the occurrence rate of newly diagnosed cancers in the subjects receiving ARBs was significantly lower than those receiving treatment without ARBs (ARBs vs controls 3,082 vs 5,985, p <0.001). After adjusting for age, gender, co-morbidities, and medications for hypertension control, ARB use was found to be independently associated with a decreased risk for cancer occurrence (hazard ratio 0.66, 95% confidence interval 0.63 to 0.68, p <0.001). In conclusion, long-term use of ARBs is associated with a lower incidence of cancer occurrence, thereby suggesting that ARBs may prevent cancer development. PMID- 21256466 TI - Effectiveness and safety of percutaneous coronary intervention after fibrinolytic therapy for ST-segment elevation acute myocardial infarction. AB - The goal of treatment of an acute ST-segment elevation myocardial infarction is the timely restoration of myocardial blood flow to decrease myocardial necrosis and thereby preserve cardiac tissue and overall function. Mainstays of reperfusion treatment include fibrinolytic therapy and/or primary percutaneous coronary intervention. In those patients who are treated with fibrinolysis, there is debate as to whether and when they should also undergo subsequent percutaneous coronary intervention. In conclusion, the investigators review the published reports on systematic percutaneous coronary intervention after fibrinolytic therapy in the treatment of ST-segment elevation myocardial infarction and discuss the rationale behind this treatment strategy. PMID- 21256467 TI - Survival by stress modality in patients with a normal myocardial perfusion study. AB - We sought to determine the differential prognosis of patients with a normal single-photon emission computed tomographic (SPECT) perfusion study by type of stress modality. Even with a normal SPECT perfusion study, patients selected for adenosine stress have a worse survival than those selected for exercise stress. In patients who are able, low-level treadmill exercise is commonly performed during adenosine infusion ("walking" adenosine). The adjusted differential prognosis of patients performing walking adenosine is unknown. Our historical cohort underwent adenosine or treadmill stress with SPECT imaging during 2003 and 2004. Adenosine studies were classified as walking or adenosine only (no low level exercise). Patients with an abnormal single-photon emission computed tomogram or missing demographic information were excluded. All-cause mortality was determined through July 2008. In total 3,479 patients were included, of which 1,451 (41.7%) were stressed with adenosine only, 201 (5.8%) with walking adenosine, and 1,827 (52.5%) with treadmill exercise. Over an average of 4.3 +/- 1.0 years of follow-up, 307 (8.8%) died. Mortality was greatest for adenosine only, intermediate for walking adenosine, and least for exercise (p <0.001 by log rank test), even after accounting for covariates (adjusted hazard ratio for walking adenosine 0.57, p = 0.044). In conclusion, patients with a normal SPECT perfusion scan who are able to undergo an adenosine protocol in conjunction with exercise have an intermediate prognosis between those who cannot perform low level exercise and patients able to undergo full treadmill exercise. This differential survival remains significant after adjustment, perhaps because of differences in baseline functional capacity. PMID- 21256468 TI - Hospital discharge risk score system for the assessment of clinical outcomes in patients with acute myocardial infarction (Korea Acute Myocardial Infarction Registry [KAMIR] score). AB - Assessment of risk at time of discharge could be a useful tool for guiding postdischarge management. The aim of this study was to develop a novel and simple assessment tool for better hospital discharge risk stratification. The study included 3,997 hospital-discharged patients with acute myocardial infarction who were enrolled in the nationwide prospective Korea Acute Myocardial Infarction Registry-1 (KAMIR-1) from November 2005 through December 2006. The new risk score system was tested in 1,461 hospital-discharged patients who were admitted from January 2007 through January 2008 (KAMIR-2). The new risk score system was compared to the Global Registry of Acute Coronary Events (GRACE) postdischarge risk model during a 12-month clinical follow-up. During 1-year follow-up, all cause death occurred in 228 patients (5.7%) and 81 patients (5.5%) in the development and validation cohorts, respectively. The new risk score (KAMIR score) was constructed using 6 independent variables related to the primary end point using a multivariable Cox regression analysis: age, Killip class, serum creatinine, no in-hospital percutaneous coronary intervention, left ventricular ejection fraction, and admission glucose based on multivariate-adjusted risk relation. The KAMIR score demonstrated significant differences in its predictive accuracy for 1-year mortality compared to the GRACE score for the developmental and validation cohorts. In conclusion, the KAMIR score for patients with acute myocardial infarction is a simpler and better risk scoring system than the GRACE hospital discharge risk model in prediction of 1-year mortality. PMID- 21256470 TI - Usefulness of platelet response to clopidogrel by point-of-care testing to predict bleeding outcomes in patients undergoing percutaneous coronary intervention (from the Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty-Bleeding Study). AB - Platelet reactivity predicts ischemic outcomes in patients who undergo percutaneous coronary intervention (PCI), but the correlation of heightened platelet response with bleeding has not been characterized. The aim of this study was to evaluate whether low platelet reactivity by point-of-care measurement after clopidogrel administration correlates with bleeding complications of PCI. A total of 310 patients receiving clopidogrel before PCI were prospectively enrolled. Platelet reactivity was measured with the VerifyNow P2Y12 assay. The primary end point was the 30-day incidence of major bleeding or entry-site complications according to quartile distribution of P2Y12 reaction units (PRU). The primary end point occurred more frequently in patients with preprocedural PRU levels in the lowest quartile compared to those in the highest quartile (10.1% vs 1.3%, p = 0.043), due mainly to entry-site hemorrhages. Absolute PRU levels were lower in patients with major bleeding (171 +/- 49 vs 227 +/- 68 in patients without, p = 0.002). On multivariate analysis, pre-PCI PRU levels in the first quartile were associated with a 4.5-fold increased risk for major bleeding (odds ratio 4.5, 95% confidence interval 1.9 to 25.9, p = 0.01). By receiver-operating characteristic curve analysis, the optimal cutoff for the primary end point was a pre-PCI PRU value <= 189 (area under the curve 0.76, 95% confidence interval 0.66 to 0.87, p = 0.001). In conclusion, this study suggests that an enhanced response to clopidogrel may be associated with higher risk for early major bleeding or entry-site complications in patients who undergo PCI. Point-of-care monitoring of platelet reactivity after clopidogrel administration may help identify patients in whom individualized strategies are indicated to limit bleeding complications after coronary intervention. PMID- 21256471 TI - Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease. AB - The occurrence of depression in patients with coronary heart disease (CHD) substantially increases the likelihood of a poorer cardiovascular prognosis. Although antidepressants are generally effective in decreasing depression, their use in patients with CHD is controversial. We carried out a meta-analysis to evaluate the health effects of selective serotonin reuptake inhibitors (SSRIs) versus placebo or no antidepressants in patients with CHD and depression. Observational studies and randomized controlled trials (RCTs) were searched in MEDLINE, EMBASE, PsycINFO, Cochrane Controlled Clinical Trial Register and other trial registries, and references of relevant articles. Primary outcomes were readmission for CHD (including myocardial infarction, unstable angina, and stroke) and all-cause mortality; the secondary outcome was severity of depression symptoms. Seven articles on 6 RCTs involving 2,461 participants were included. One study incorrectly randomized participants, and another was a reanalysis of RCT data. These were considered observational and analyzed separately. When only properly randomized trials were considered (n = 734 patients), patients on SSRIs showed no significant differences in mortality (risk ratio 0.39, 95% confidence interval 0.08 to 2.01) or CHD readmission rates (0.74, 0.44 to 1.23) compared to controls. Conversely, when all studies were included, SSRI use was associated with a significant decrease in CHD readmission (0.63, 0.46 to 0.86) and mortality rates (0.56, 0.35 to 0.88). A significantly greater improvement in depression symptoms was always apparent in patients on SSRIs with all selected indicators. In conclusion, in patients with CHD and depression, SSRI medication decreases depression symptoms and may improve CHD prognosis. PMID- 21256469 TI - Risk of death and myocardial infarction in patients with peripheral arterial disease undergoing percutaneous coronary intervention (from the National Heart, Lung and Blood Institute Dynamic Registry). AB - Patients with peripheral arterial disease (PAD) undergoing percutaneous coronary intervention (PCI) are at high risk for adverse cardiovascular events. Trends over time in outcomes with advances in PCI and medical therapy are unknown. We evaluated 866 patients with PAD in the National Heart, Lung, and Blood Institute (NHLBI) Dynamic Registry undergoing PCI according to treatment eras: the early bare metal stent (BMS) era (wave 1, 1997 to 1998, n = 180), the BMS era (waves 2 and 3, 1999 and 2001 to 2002, n = 339), and the drug-eluting stent (DES) era (waves 4 and 5, 2004 and 2006, n = 347). We compared in-hospital and 1-year outcomes by recruitment era. In-hospital coronary artery bypass graft surgery rates were significantly lower in the later eras (3.9%, 0.9%, and 0.6% for the early BMS, BMS, and DES eras, respectively, p for trend = 0.005), and an increasing percentage of patients were discharged on aspirin, beta blockers, statins, and thienopyridines (p for trend <0.001 for all comparisons). Cumulative 1-year event rates in patients with PAD in the early BMS era, BMS era, and DES era for death were 13.7%, 10.5%, and 9.8% (p for trend = 0.21), those for myocardial infarction (MI) were 9.8%, 8.8%, and 10.0% (p for trend = 0.95), and those for repeat revascularization were 26.8%, 21.0%, and 17.2% (p for trend = 0.008). The 1-year adjusted hazard ratios of adverse events in patients with PAD using the early BMS era as the reference were 0.84 for death in the BMS era (95% confidence interval [CI] 0.46 to 1.55, p = 0.58) and 1.35 in the DES era (95% CI 0.71 to 2.56, p = 0.36), 0.89 for MI in the BMS era (95% CI 0.48 to 1.66, p = 0.72) and 1.02 in the DES era (95% CI 0.55 to 1.87, p = 0.95), and 0.63 for repeat revascularization in the BMS era (95% CI 0.41 to 0.97, p = 0.04) and 0.46 in the DES era (95% CI 0.29 to 0.73, p = 0.001). In conclusion, despite significant improvements in medical therapy and a decrease in repeat revascularization over time, patients with PAD who undergo PCI have a persistent high rate of death and MI. PMID- 21256472 TI - Urinary dysfunction after colorectal resection for endometriosis: results of a prospective randomized trial comparing laparoscopy to open surgery. AB - OBJECTIVE: To evaluate urinary symptoms before and after colorectal resection for endometriosis using validated questionnaires. STUDY DESIGN: We randomly assigned 52 patients with colorectal endometriosis to undergo laparoscopically assisted or open colorectal resection. The median follow-up was 19 months. Urinary symptoms were evaluated using the International Prostate Score Symptom and the Bristol Female Low Urinary Tract Symptoms questionnaires. RESULTS: Dysuria was observed in 29% of cases postoperatively. Using Bristol Female Low Urinary Tract Symptoms and International Prostate Score Symptom scores, an alteration was observed for voiding symptoms (P = .01 and P = .006, respectively). No difference was observed between the laparoscopy and the open surgery group. An alteration of the International Prostate Score Symptom voiding symptoms was observed in the group that did not undergo nerve sparing surgery (P = .048). An alteration of the International Prostate Score Symptom voiding symptoms was observed for patients who underwent vaginal resection (P = .01) and parametrial resection (P = .02). CONCLUSION: Our findings confirm that colorectal resection for endometriosis is a source of urinary dysfunction whatever the surgical route. PMID- 21256473 TI - Aberrant fetal growth and early, late, and postneonatal mortality: an analysis of Milwaukee births, 1996-2007. AB - OBJECTIVE: The objective of the study was to ascertain the association between fetal growth (small- [SGA], appropriate- [AGA], and large-for-gestational-age [LGA]) and early, late, and postneonatal mortality. STUDY DESIGN: Birth certificate data for nonanomalous singletons, delivered from 1996 to 2007, were obtained for Milwaukee residents. Multivariate logistic regression analyses, adjusted for 19 covariates, determined the association between fetal growth and mortality. RESULTS: Among the 123,383 live births, SGA was 57% higher than LGA (11% vs 7%). The infant mortality rate for SGA was 11.0, AGA, 5.3, and LGA, 2.7/1000 live births. SGA was a significant risk factor for early (adjusted odds ratio, 2.66) and late (2.06) but not postneonatal mortality. The adjusted risk of mortality for LGA was not significantly different from AGA. Over 12 years, 3 types of mortality for aberrant fetal growth did not change significantly. CONCLUSION: In the city of Milwaukee, aberrant fetal growth was variably associated with early, late, and postneonatal mortality. PMID- 21256474 TI - Large parathyroid tumors have an increased risk of atypia and carcinoma. AB - BACKGROUND: Risk for atypia and carcinoma in large parathyroid tumors is not known. Atypia and carcinoma were determined in small (<2 g) and large (>=2 g) tumors in patients undergoing parathyroidectomy for primary hyperparathyroidism. METHODS: The study was a retrospective analysis of a 5-year prospective database. Tumor weight, histopathology, age, gender, calcium, and parathyroid hormone levels were registered. Patients with 4-gland disease were not included. RESULTS: Among 353 parathyroid tumors, 313 weighed <2 g and 40 weighed >=2 g. There was no difference in age between groups. Patients with large tumors were more frequently men and had higher calcium and parathyroid hormone levels. Atypia was found in 4 of 313 (1.3%) and 7 of 40 (17.5%) small and large tumors, respectively (P < .05). Corresponding figures for carcinoma were 1 of 313 (.3%) and 2 of 40 (5.0%) (P < .05). CONCLUSIONS: Large parathyroid tumors have increased risk for atypia and carcinoma. Even so, most large parathyroid tumors are benign. PMID- 21256476 TI - [TNM-7th edition 2009 (UICC/AJCC) and Japanese Classification 2010 in Gastric Cancer. Towards simplicity and standardisation in the management of gastric cancer]. AB - The 7th edition of the UICC/AJCC TNM, and a new revision of the Japanese Classification for Gastric Cancer and Treatment Guidelines (Japanese Gastric Cancer Association) have been available since the beginning of 2010. One of the most important changes consists on the redefining and simplification of type D1/D2 lymphadenectomy depending on the type of gastrectomy performed (previously it depended on the location of the primary tumour), and the adoption of numeric criteria of TNM-7th Edition to evaluate the level of lymph node involvement (before, according to the anatomical location of the groups as regards the primary tumour). These changes attempt to make therapeutic management easier and a more uniform comparison of results between countries. The importance of these modifications in both systems justifies this exhaustive analysis and update of the new concepts for a correct management of gastric cancer. PMID- 21256475 TI - Behavioral interventions may prolong remission in patients with inflammatory bowel disease. AB - Inflammatory Bowel Diseases (IBDs) are chronic, relapsing and remitting gastrointestinal conditions with no known cure. Previous studies have linked behavioral factors, including stress and medication adherence, to relapse. PURPOSE: We sought to determine the effect of participation in a behavioral self management program on incidence of flare within 12 months following behavioral intervention when compared to the natural history of flare incidence prior to program participation. RESULTS: Results from a 2-level regression model indicated that those participants in the treatment group were 57% less likely to flare in the following 12 months (compared to 18% in the control group). The decline in "flare odds" was about 2 times greater in treatment versus controls (OR=0.52, t(34)=2.07, p<0.05). Office visits, ER visits, and disease severity (all p<0.05) were identified as moderators of flare risk. CONCLUSIONS: We have demonstrated 1) a statistical model estimating the likelihood of flare rates in the 12 months following a behavioral intervention for IBD (compared to a control condition), and 2) that the introduction of a behavioral intervention can alter the natural course of a chronic, relapsing and remitting gastrointestinal condition such as IBD. PMID- 21256477 TI - [Intestinal malrotation in the adult]. PMID- 21256478 TI - [Biobanks and use of samples of human origin for surgical research. Current regulatory framework]. AB - In recent years, there has been a growing interest in the development of biological samples and biobanks that make it easier for investigators to have access to quality samples and their associated clinical and epidemiological data. Thus, biobanks have become indispensible technological platforms for the development of both basic and clinical research. The properties of the biological sample as a support medium of personal and family information require that they are treated in accordance with new ethical standards. For this reason, the Law on Biomedical Research, provides a new regulatory framework in the process of obtaining samples and their storage for research purposes, where the consent of the source subject, data protection, the favourable opinion of a Research Ethics Committee, the prior taking out of an insurance policy against possible adverse effects, and the quality and safety requirements in the handling and management of these materials are key elements. PMID- 21256479 TI - PM 2.5 collected in a residential area induced Th1-type inflammatory responses with oxidative stress in mice. AB - Epidemiologists have tried to establish an association between human health and exposure to particulate matter (PM). In addition, many researchers have investigated the adverse effects of PM as a trigger of cardiovascular and pulmonary diseases. It is known that a number of environmental contaminants are attached to PM and the toxicity of PM may depend on the sources. We investigated the effects of PM collected in a residential area of Seoul on the immunotoxic responses including cytokine production in BAL fluid and in blood after a single intratracheal instillation in mice with the characterization of physico-chemical properties of PM 2.5 samples. As results, pro-inflammatory cytokines (IL-1, TNF alpha, and IL-6), Th0-type cytokine (IL-2), and Th1-type cytokines (IL-12 and IFN gamma) were increased by a dose-dependent manner. Cell infiltration in the alveolar area and phagocytosis by macrophage was observed until day 28 after instillation. The expressions of oxidative stress-related genes (HSP 1a, HSP 8, and SOD) and tissue damage-related genes (MMP-15, -19, and Slpi) were time dependently increased. PM 2.5 also induced an increase of T cell distribution in lymphocyte and decreased the CD4+/CD8+ ratio. Based on the results, we suggest that PM 2.5 collected in a residential area of Seoul may induce Th1 type inflammatory responses with oxidative stress and trigger adverse effects in human health. PMID- 21256480 TI - Incidence of non-lung solid cancers in Czech uranium miners: a case-cohort study. AB - OBJECTIVES: Uranium miners are chronically exposed to radon and its progeny, which are known to cause lung cancer and may be associated with leukemia. This study was undertaken to evaluate risk of non-lung solid cancers among uranium miners in Pribram region, Czech Republic. METHODS: A retrospective stratified case-cohort study in a cohort of 22,816 underground miners who were employed between 1949 and 1975. All incident non-lung solid cancers were ascertained among miners who worked underground for at least 12 months (n=1020). A subcohort of 1707 subjects was randomly drawn from the same population by random sampling stratified on age. The follow-up period lasted from 1977 to 1996. RESULTS: Relative risks comparing 180 WLM (90th percentile) of cumulative lifetime radon exposure to 3 WLM (10th percentile) were 0.88 for all non-lung solid cancers combined (95% CI 0.73-1.04, n=1020), 0.87 for all digestive cancers (95% CI 0.69 1.09, n=561), 2.39 for gallbladder cancer (95% CI 0.52-10.98, n=13), 0.79 for larynx cancer (95% CI 0.38-1.64, n=62), 2.92 for malignant melanoma (95% CI 0.91 9.42, n=23), 0.84 for bladder cancer (95% CI 0.43-1.65, n=73), and 1.13 for kidney cancer (95% CI 0.62-2.04, n=66). No cancer type was significantly associated with radon exposure; only malignant melanoma and gallbladder cancer showed elevated but non-significant association with radon. CONCLUSIONS: Radon was not significantly associated with incidence of any cancer of interest, although a positive association of radon with malignant melanoma and gallbladder cancer cannot be entirely ruled out. PMID- 21256481 TI - The risk of dying on days of higher air pollution among the socially disadvantaged elderly. AB - RATIONALE: The estimated mortality rate associated with ambient air pollution based on general population studies may not be applicable to certain subgroups. OBJECTIVE: The objective of the present study was to determine the influence of age, education, employment status and income on the risk of mortality associated with ambient air pollution. METHODS: Daily time-series analyses tested the association between daily air pollution and daily mortality in seven Chilean urban centers during the period January 1997-December 2007. Results were adjusted for long-term trends, day-of-the week and humidex. RESULTS: Interquartile increases in particulate matter (PM(10) and PM(2.5)), sulphur dioxide, nitrogen dioxide, carbon monoxide, and elemental and organic carbon were associated with a 4-7% increase in mortality among those who did not complete primary school (p<0.05) vs. 0.5-1.5% among university graduates (p>0.05). Among those at least 85 years of age respective estimates were 2-7%. However, among the elderly who did not complete primary school, respective estimates were 11-19% (p<0.05). The degree of effect modification was less for income and employment status than education, and sex did not modify the results. CONCLUSION: The socially disadvantaged, especially if elderly appear to be especially susceptible to dying on days of higher air pollution. Concentrations deemed acceptable for the general population would not appear to protect this susceptible subgroup. PMID- 21256482 TI - The impact of different causal models on estimated effects of disinfection by products on preterm birth. AB - BACKGROUND: Previous epidemiologic studies of preterm birth and drinking water disinfection by-products (DBP) reported inconsistent results especially for third trimester exposures. These inconsistencies may have been due to differences in the underlying causal model assumed and methodological issues, including the method of analysis (cumulative vs. density-sampling of controls and matching on gestational age) and appropriate control of confounding. METHODS: We use data from previously published research to illustrate how different causal models, methods of analysis, and the choice of covariates to control impact results. RESULTS: Exposure at high measured TTHM levels (>= 60 MUg/l) during the last trimester - with cumulatively sampled controls - corresponded to negative effect estimates when comparing preterm to term births and averaging exposure over different length periods. In contrast, density-sampling of controls with an exposure truncated at 36 weeks gestation and adjustment for possible confounding by exposures experienced in prior trimesters led to moderate changes in risk at the highest level of exposure averaged over the four weeks prior to birth. CONCLUSIONS: We recommend that future research on an exposure to DBPs and risk of preterm birth explore the sensitivity of their findings to different model specifications, specifically: (1) cumulative vs. density-sampling of controls when evaluating third trimester or whole pregnancy exposures, taking into account exposure-averaging length; (2) short-term peak exposures vs. long-term exposures; and (3) adjustment for exposure during prior pregnancy periods when evaluating later trimester exposures to account for possible 'priming' effects of early exposures. PMID- 21256483 TI - Adhesion formation after intracapsular myomectomy with or without adhesion barrier. AB - OBJECTIVE: To show the prevention of adhesion formation by placing an absorbable adhesion barrier after intracapsular myomectomy. DESIGN: Prospective blinded observational study. SETTING: University-affiliated Hospitals. PATIENT(S): Patients >= 18 years old with single or multiple uterine fibroids removed by laparoscopic or abdominal intracapsular myomectomy. INTERVENTION(S): A total of 694 women undergoing laparoscopic or abdominal myomectomy were randomized for placement of oxidized regenerated cellulose absorbable adhesion barrier to the uterine incision or for control subjects without barriers. The presence of adhesions was assessed in 546 patients who underwent subsequent surgery. MAIN OUTCOME MEASURE(S): The primary and secondary outcomes of the analysis were the presence and severity of adhesions for four groups: laparotomy with barrier, laparotomy without barrier, laparoscopy with barrier, and laparoscopy without barrier. RESULT(S): There was a higher rate of adhesions in laparotomy without barrier (28.1%) compared with laparoscopy with no barrier (22.6%), followed by laparotomy with barrier (22%) and laparoscopy with barrier (15.9%). Additionally, the type of adhesions were different, filmy and organized were predominant with an adhesion barrier, and cohesive adhesions were more common without an adhesion barrier. CONCLUSION(S): Oxidized regenerated cellulose reduces postsurgical adhesions. Cohesive adhesions reduction was noted in laparoscopy. PMID- 21256484 TI - In vitro maturation and fertilization of vitrified immature human oocytes, subsequent vitrification of produced embryos, and embryo transfer after thawing. AB - OBJECTIVE: To report on the capability of vitrified immature human oocytes to undergo in vitro maturation, fertilization, and embryo development, and to report on the post-thaw survival of vitrified embryos. DESIGN: Case report. SETTING: University-based IVF unit. PATIENT(S): Two women (34 and 36 years old) undergoing IVF therapy. INTERVENTION(S): Immature oocytes, retrieved after ovarian stimulation, were vitrified. Post-thaw, they underwent in vitro maturation and fertilization by intracytoplasmic sperm injection (ICSI). The produced embryos were vitrified at day 2. In one case, the embryos were thawed and transferred. MAIN OUTCOME MEASURE(S): Post-thaw survival of vitrified immature oocytes, capability for in vitro maturation, fertilization, embryo development; post-thaw survival of vitrified embryos. RESULT(S): In the first case, six immature oocytes survived after thawing and matured after in vitro maturation. Five of them underwent ICSI, four fertilized, and three cleaved. The embryos were vitrified for future use. In the second case, two out of three immature oocytes survived after thawing. They were normally fertilized and cleaved, and the embryos were vitrified. Later, the embryos were thawed and transferred to the patient. CONCLUSION(S): These cases demonstrate that vitrified immature oocytes can undergo post-thaw in vitro maturation and fertilization. The produced embryos are capable to undergo vitrification and thawing. PMID- 21256485 TI - Genomic analysis using high-resolution single-nucleotide polymorphism arrays reveals novel microdeletions associated with premature ovarian failure. AB - OBJECTIVE: To analyze DNA from women with premature ovarian failure (POF) for genome-wide copy-number variations (CNVs), focusing on novel autosomal microdeletions. DESIGN: Case-control genetic association study. SETTING: Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas. PATIENT(S): Of 89 POF patients, eight experienced primary amenorrhea and 81 exhibited secondary amenorrhea before age 40 years. INTERVENTION(S): Genomic DNA from peripheral blood samples was analyzed for CNVs using high-resolution single-nucleotide polymorphism (SNP) arrays. MAIN OUTCOME MEASURE(S): Identification of novel CNVs in 89 POF cases, using the Database of Genomic Variants as a control population. RESULT(S): A total of 198 autosomal CNVs were detected by SNP arrays, ranging in size from 0.1 Mb to 3.4 Mb. These CNVs (>0.1 Mb) included 17 novel microduplications and seven novel microdeletions, six of which contained the coding regions 8q24.13, 10p15-p14, 10q23.31, 10q26.3, 15q25.2, and 18q21.32. Most of the novel CNVs were derived from autosomes rather than the X chromosome. CONCLUSION(S): The present pilot study revealed novel microdeletions/microduplications in women with POF. Two novel microdeletions caused haploinsufficiency for SYCE1 and CPEB1, genes known to cause ovarian failure in knockout mouse models. Chromosomal microarrays may be a useful adjunct to conventional karyotyping when evaluating genomic imbalances in women with POF. PMID- 21256486 TI - Pregnancy rate and outcome in Swedish women with Turner syndrome. AB - Pregnancies occurred in 57 (12%) of 482 Swedish women with Turner syndrome with a liveborn rate of 54% in 124 pregnancies. Spontaneous pregnancies occurred in 40%, mainly in women with 45,X/46,XX mosaicism, and oocyte donation in 53% where miscarriages were less frequent, odds ratio = 0.43 (95% confidence interval 0.17 1.04). PMID- 21256487 TI - Perinatal outcome of twice-frozen-thawed embryo transfers: a clinical follow-up study. AB - We evaluated our clinical data on refrozen-thawed ETs (92 cycles) and found that human embryos were capable of withstanding two freeze-thaw cycles, resulting in normal live births after transfer at a rate similar to that of primary frozen thawed embryos. This is the first follow-up study to present perinatal outcomes of children born after embryo re-cryopreservation, and our results should encourage clinicians to explore the possibility of performing the refreezing procedure. PMID- 21256488 TI - Risk factors that predict mortality in patients with blunt chest wall trauma: a systematic review and meta-analysis. AB - BACKGROUND: The risk factors for mortality following blunt chest wall trauma have neither been well established or summarised. OBJECTIVE: To summarise the risk factors for mortality in blunt chest wall trauma patients based on available evidence in the literature. DATA SOURCES: A systematic review of English and non English articles using MEDLINE, EMBASE and the Cochrane Library from their introduction until May 2010. Additional studies were identified by hand-searching bibliographies and contacting relevant clinical experts. Grey literature was sought by searching abstracts from all Emergency Medicine conferences. Broad search terms and inclusion criteria were used to reduce the number of missed studies. STUDY SELECTION: A two step study selection process was used. All published and unpublished observational studies were included if they investigated estimates of association between a risk factor and mortality for blunt chest wall trauma patients. DATA EXTRACTION: A two step data extraction process using pre-defined data fields, including study quality indicators. STUDY APPRAISAL AND SYNTHESIS: Each study was appraised using a previously designed quality assessment tool and the STROBE checklist. Where sufficient data were available, odds ratios with 95% confidence intervals were calculated using Mantel Haenszel method for the risk factors investigated. The I(2) statistic was calculated for combined studies in order to assess heterogeneity. RESULTS: Age, number of rib fractures, presence of pre-existing disease and pneumonia were found to be related to mortality in 29 identified studies. Combined odds ratio of 1.98 (1.86-2.11, 95% CI), 2.02 (1.89-2.15, 95% CI), 2.43 (1.03-5.72, 95% CI) and 5.24 (3.51-7.82) for mortality were calculated for blunt chest wall trauma patients aged 65 years or more, with three or more rib fractures, pre-existing conditions and pneumonia respectively. CONCLUSIONS: The risk factors for mortality in patients sustaining blunt chest wall trauma were a patient age of 65 years or more, three or more rib fractures and the presence of pre-existing disease especially cardiopulmonary disease. The development of pneumonia post injury was also a significant risk factor for mortality. As a result of the variable quality in the studies, the results of the selected studies should be interpreted with caution. PMID- 21256489 TI - Lung Organ Failure Score (LOFS): probability of severe pulmonary organ failure after multiple injuries including chest trauma. AB - BACKGROUND: Pulmonary complications are common in multiple trauma patients with chest injury. Factors predisposing these critically ill patients to respiratory organ failure are not fully understood. METHODS: Univariate and multivariate logistic regression analyses were used to assess the prognostic value of clinical and laboratory variables (2002-2008; n = 30,616) from the Trauma Registry of the German Trauma Society (DGU). Data from patients admitted to the ICU with lung contusion/lacerations, an Injury Severity Score >= 16 and age >= 18 were included in the study. Severe pulmonary organ failure was defined as PaO(2)/FiO(2)<200 for >= 3 days and based on the odds ratios (ORs) a simplified Lung Organ Failure Score (LOFS) was developed using integer values. RESULTS: 21.3% (1254) of the 5892 patients analysed developed severe pulmonary organ failure. We identified seven independent predictors with significant correlation: age, gender, head injury, fluid therapy, injury severity, degree of chest trauma and surgical interventions. The highest ORs were observed in cases of Abbreviated Injury Scale (AIS)(Thorax) = 5 (1.58), surgical intervention (1.71) and multiple surgeries (2.41). We found that patients with simplified score values >= 21 points were at a maximum risk (>30%) for developing severe pulmonary complications. CONCLUSION: This scoring method could help trauma surgeons determine which multiple trauma patients are at risk for pulmonary complications after trauma. Efficacy analyses of prophylactic PEEP ventilation or rotational bed therapy in subgroups with comparable risks for respiratory complication could be based on the LOFS. PMID- 21256490 TI - A new non-invasive method for detection of local inflammation in atherosclerotic plaques: experimental application of microwave radiometry. PMID- 21256491 TI - Investigation of hemodynamics in the development of dissecting aneurysm within patient-specific dissecting aneurismal aortas using computational fluid dynamics (CFD) simulations. AB - Aortic dissecting aneurysm is one of the most catastrophic cardiovascular emergencies that carries high mortality. It was pointed out from clinical observations that the aneurysm development is likely to be related to the hemodynamics condition of the dissected aorta. In order to gain more insight on the formation and progression of dissecting aneurysm, hemodynamic parameters including flow pattern, velocity distribution, aortic wall pressure and shear stress, which are difficult to measure in vivo, are evaluated using numerical simulations. Pulsatile blood flow in patient-specific dissecting aneurismal aortas before and after the formation of lumenal aneurysm (pre-aneurysm and post aneurysm) is investigated by computational fluid dynamics (CFD) simulations. Realistic time-dependent boundary conditions are prescribed at various arteries of the complete aorta models. This study suggests the helical development of false lumen around true lumen may be related to the helical nature of hemodynamic flow in aorta. Narrowing of the aorta is responsible for the massive recirculation in the poststenosis region in the lumenal aneurysm development. High pressure difference of 0.21 kPa between true and false lumens in the pre aneurismal aorta infers the possible lumenal aneurysm site in the descending aorta. It is also found that relatively high time-averaged wall shear stress (in the range of 4-8 kPa) may be associated with tear initiation and propagation. CFD modeling assists in medical planning by providing blood flow patterns, wall pressure and wall shear stress. This helps to understand various phenomena in the development of dissecting aneurysm. PMID- 21256492 TI - Kinetic performance limits of constant pressure versus constant flow rate gradient elution separations. Part I: theory. AB - We report on a general theoretical assessment of the potential kinetic advantages of running LC gradient elution separations in the constant-pressure mode instead of in the customarily used constant-flow rate mode. Analytical calculations as well as numerical simulation results are presented. It is shown that, provided both modes are run with the same volume-based gradient program, the constant pressure mode can potentially offer an identical separation selectivity (except from some small differences induced by the difference in pressure and viscous heating trajectory), but in a significantly shorter time. For a gradient running between 5 and 95% of organic modifier, the decrease in analysis time can be expected to be of the order of some 20% for both water-methanol and water acetonitrile gradients, and only weakly depending on the value of V(G)/V0 (or equivalently t(G)/t0). Obviously, the gain will be smaller when the start and end composition lie closer to the viscosity maximum of the considered water-organic modifier system. The assumptions underlying the obtained results (no effects of pressure and temperature on the viscosity or retention coefficient) are critically reviewed, and can be inferred to only have a small effect on the general conclusions. It is also shown that, under the adopted assumptions, the kinetic plot theory also holds for operations where the flow rate varies with the time, as is the case for constant-pressure operation. Comparing both operation modes in a kinetic plot representing the maximal peak capacity versus time, it is theoretically predicted here that both modes can be expected to perform equally well in the fully C-term dominated regime (where H varies linearly with the flow rate), while the constant pressure mode is advantageous for all lower flow rates. Near the optimal flow rate, and for linear gradients running from 5 to 95% organic modifier, time gains of the order of some 20% can be expected (or 25-30% when accounting for the fact that the constant pressure mode can be run without having to leave a pressure safety margin of 5-10% as is needed in the constant flow rate mode). PMID- 21256493 TI - A flexible loop-type flow modulator for comprehensive two-dimensional gas chromatography. AB - The present investigation is focused on a simple flow modulator (FM), for comprehensive two-dimensional gas chromatography (GC*GC). The interface is stable at high temperatures, and consists of a metallic disc (located inside the GC oven) with seven ports, which are connected to an auxiliary pressure source via two branches, to the first and second dimension, to a waste branch (linked to a needle valve) and to an exchangeable modulation loop (2 ports). The ports are connected via micro-channels, etched on one of the inner surfaces of the disc. Modulation is achieved using a two-way electrovalve, connected on one side to the additional pressure source, and to the two metal branches, on the other. An FM enantio-GC*polar-GC method (using a flame ionization detector) was optimized (a 40-MUL loop was employed), for the analysis of essential oils. As an example, an application on spearmint oil is shown; the method herein proposed was subjected to validation. Finally, an FM GC*GC diesel experiment was carried out, using an apolar-polar column combination, to demonstrate the effectiveness of the modulator in the analysis of a totally different sample-type. PMID- 21256494 TI - Doping control analysis of insulin and its analogues in equine urine by liquid chromatography-tandem mass spectrometry. AB - Insulin and its analogues have been banned in both human and equine sports owing to their potential for misuse. Insulin administration can increase muscle glycogen by utilising hyperinsulinaemic clamps prior to sports events or during the recovery phases, and increase muscle size by its chalonic action to inhibit protein breakdown. In order to control insulin abuse in equine sports, a method to effectively detect the use of insulins in horses is required. Besides the readily available human insulin and its synthetic analogues, structurally similar insulins from other species can also be used as doping agents. The author's laboratory has previously reported a method for the detection of bovine, porcine and human insulins, as well as the synthetic analogues Humalog (Lispro) and Novolog (Aspart) in equine plasma. This study describes a complementary method for the simultaneous detection of five exogenous insulins and their possible metabolites in equine urine. Insulins and their possible metabolites were isolated from equine urine by immunoaffinity purification, and analysed by nano liquid chromatography-tandem mass spectrometry (LC/MS/MS). Insulin and its analogues were detected and confirmed by comparing their retention times and major product ions. All five insulins (human insulin, Humalog, Novolog, bovine insulin and porcine insulin), which are exogenous in horse, could be detected and confirmed at 0.05ng/mL. This method was successfully applied to confirm the presence of human insulin in urine collected from horses up to 4h after having been administered a single low dose of recombinant human insulin (Humulin R, Eli Lilly). To our knowledge, this is the first identification of exogenous insulin in post-administration horse urine samples. PMID- 21256495 TI - Qualitative and quantitative determination of polyacetylenes in different Bupleurum species by high performance liquid chromatography with diode array detector and mass spectrometry. AB - Polyacetylenes are main toxic ingredients in Bupleurum longiradiatum, a poisonous plant that has ever been misused as substitutes for Chaihu (Bupleuri Radix). For the first time, a high-performance liquid chromatography method coupled with diode array detector and mass spectrometry (HPLC-DAD-MS) was developed for qualitative and quantitative analysis of nine polyacetylenes in Bupleurum species. All references, including two new polyacetylenes, were isolated from B. longiradiatum and purified using a semi-preparation HPLC chromatography. The analysis was performed on a TSKgel ODS-100V C18 column (3 MUm, 150 mm x 4.6 mm i.d.) using a gradient system of acetonitrile and water, with diode array detection (254 nm). The method was validated for linearity, precision, accuracy, limit of detection and quantification. A total of 27 Bupleurum samples were examined with this method, which showed a great variety in the distribution and contents of the polyacetylenes. It was found that polyacetylenes (1-8) were the main ingredients in B. longiradiatum, while a few kinds of polyacetylenes (5-8) were also identified in B. smithii, B. smithii var. parvifolium, B. bicaule and B. angustissimum. However, no polyacetylenes (1-9) were detected in the authentic Chaihu samples and the other Bupleurum species. The results indicated that the toxic B. longiradiatum could readily be distinguished from other medicinal Bupleurum species based on the polyacetylene profiles, and the guidelines and quality control of polyacetylenes for Chaihu are useful. The acute toxicity of the ethanol extract of B. longiradiatum and its fractions was also investigated. PMID- 21256496 TI - Analysis of wax esters in edible oils by automated on-line coupling liquid chromatography-gas chromatography using the through oven transfer adsorption desorption (TOTAD) interface. AB - An automated method for the direct analysis of wax esters in edible oils is presented. The proposed method uses the TOTAD (through oven transfer adsorption desorption) interface for the on-line coupling of normal phase liquid chromatography and gas chromatography. In this fully automated system, the oil with C32 wax ester as internal standard and diluted with heptane is injected directly with no sample pre-treatment step other than filtration. The proposed method allows analysis of different wax esters, and is simpler and faster than the European Union Official Method, which is tedious and time-consuming. The obtained results closely match the certified values obtained from the median of the analytical results of the inter-labs certification study. Relative standard deviations of the concentrations are less than 5%. The method is appropriate for routine analysis as it is totally automated. PMID- 21256497 TI - Kinetic performance limits of constant pressure versus constant flow rate gradient elution separations. Part II: experimental. AB - We report on a first series of experiments comparing the selectivity and the kinetic performance of constant flow rate and constant pressure mode gradient elution separations. Both water-methanol and water-acetonitrile mobile phase mixtures have been considered, as well as different samples and gradient programs. Instrument pressures up to 1200 bar have been used. Neglecting some small possible deviations caused by viscous heating effects, the experiments could confirm the theoretical expectation that both operation modes should lead to identical separation selectivities provided the same mobile phase gradient program is run in reduced volumetric coordinates. Also in agreement with the theoretical expectations, the cP-mode led to a gain in analysis time amounting up to some 17% for linear gradients running from 5 to 95% of organic modifier at ultra-high pressures. Gains of over 25% were obtained for segmented gradients, at least when the flat portions of the gradient program were situated in regions where the gradient composition was the least viscous. Detailed plate height measurements showed that the single difference between the constant flow rate and the constant pressure mode is a (small) difference in efficiency caused by the difference in average flow rate, in turn leading to a different intrinsic band broadening. Separating a phenone sample with a 20-95% water-acetonitrile gradient, the cP-mode leads to gradient plate heights that are some 20-40% smaller than in the cF-mode in the B-term dominated regime, while they are some 5 10% larger in the C-term dominated regime. Considering a separation with sub 2 MUm particles on a 350 mm long coupled column, switching to the constant pressure mode allowed to finish the run in 29 instead of in 35 min, while also a larger peak capacity is obtained (going from 334 in the cF-mode to 339 in the cP-mode) and the mutual selectivity between the different peaks is fully retained. PMID- 21256498 TI - On the no-field method for void time determination in flow field-flow fractionation. AB - Elution time measurements of colloidal particles injected in a symmetrical flow field-flow fractionation (flow FFF) system when the inlet and outlet cross-flow connections are closed have been performed. This no-field method has been proposed earlier for void time (and void volume) determination in flow FFF Giddings et al. (1977). The elution times observed were much larger than expected on the basis of the channel geometrical volume and the flow rate. In order to explain these discrepancies, a flow model allowing the carrier liquid to flow through the porous walls toward the reservoirs located behind the porous elements and along these reservoirs was developed. The ratio between the observed elution time and expected one is found to depend only on a parameter which is a function of the effective permeability and thickness of the porous elements and of the channel thickness and length. The permeabilities of the frits used in the system were measured. Their values lead to predicted elution times in reasonable agreement with experimental ones, taking into account likely membrane protrusion inside the channel on system assembly. They comfort the basic feature of the flow model, in the no-field case. The carrier liquid mostly bypasses the channel to flow along the system mainly in the reservoir. It flows through the porous walls toward the reservoirs near channel inlet and again through the porous walls from the reservoirs to the channel near channel outlet before exiting the system. In order to estimate the extent of this bypassing process, it is desirable that the hydrodynamic characteristics of the permeable elements (permeability and thickness) are provided by flow FFF manufacturers. The model applies to symmetrical as well as asymmetrical flow FFF systems. PMID- 21256499 TI - Synthesis of a novel restricted access chiral stationary phase based on atom transfer radical polymerization and click chemistry for the analysis of chiral drugs in biological matrices. AB - A novel chiral restricted access material was synthesized via a combination of atom transfer radical polymerization (ATRP) and click chemistry. Poly(2-methyl-3 butyn-2-ol methacrylate) (pMBMA) was grafted onto porous silica gel by a surface initiated ATRP in order to synthesize an inner layer for beta-cyclodextrin (beta CD) immobilization. The azide-modified beta-CD was bound to pMBMA by click chemistry. The results demonstrate that click chemistry provides an effective route for the immobilization of beta-CD for chiral discrimination. A second ATRP reaction was then used to graft external poly(glycidyl methacrylate) (pGMA) layer onto the silica gel. The external hydrophilic layer was subsequently created by hydrolysis of the epoxy groups of the pGMA. This bi-layer grafted material exhibited both enantioseparation and protein exclusion. It can be used for the efficient separation of chiral compounds in biological samples with direct injection into an HPLC system. PMID- 21256500 TI - The use of phospholipid modified column for the determination of lipophilic properties in high performance liquid chromatography. AB - A new chromatographic stationary phase obtained by coating a reversed phase amide column with phosphatidylcholine based liposomes solution to yield a phospholipid modified column (PLM). The modification is achieved by the dynamic coating method which recycles the coating solution through the column in a closed loop for a period of 24 h. The chromatographic properties of the new column have changed significantly as compared to the original amide column due to the phospholipid coating. A good correlation was observed between n-octanol/water logP values and the logarithm of the retention factor obtained on the PLM column for a large number of solutes. In addition the PLM column was characterized using the linear solvation energy relationship (LSER). The values of the LSER system constants for the PLM column were calculated and were found to be very close to those of the n octanol/water extraction system thus suggesting that the PLM column can be used for the estimation of n-octanol/water partition coefficient and serve as a possible alternative to the shake-flask method for lipophilicity determination. In addition, the results suggest that the PLM column can provide an alternative to other phospholipid-based column such as the IAM and the DPC columns. PMID- 21256501 TI - Simultaneous extraction and clean-up of polybrominated diphenyl ethers and polychlorinated biphenyls from sheep liver tissue by selective pressurized liquid extraction and analysis by gas chromatography-mass spectrometry. AB - We describe a selective pressurized liquid extraction (SPLE) method, followed by gas chromatography-mass spectrometry (GC-MS), for the simultaneous extraction and clean-up of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) in sheep liver tissue samples. The on-line clean-up of liver tissue by SPLE was tested using differing amount of acid-modified silica (sulphuric acid:silica gel, 1:2, w/w), the most effective amount being 20 g. Different extraction solvents (iso-hexane and dichloromethane), either alone or in various combinations, were used to extract these target compounds from spiked liver samples. Variables affecting the SPLE extraction efficiency, including temperature, pressure, number of extraction cycles and static extraction time were studied; the optimum parameters were 80 degrees C, 10.3 MPa, 2 cycles and 5 min, respectively. The SPLE based method was compared with more traditional Soxhlet, off-line PLE, ultrasonic and heating extraction methods. Overall the mean percentage recoveries for all target chemicals using SPLE were 86-103% (n=3, SD < 9%), and compared favourably with the Soxhlet (63-109%, n=3, SD < 8%), off line PLE (82-104%, n=3, SD < 18%), ultrasonic (86-99%, n=3, SD < 11%) and heating (72-102%, n=3, SD < 21%) extraction methods. The limits of detection of the proposed method were 5-96 pg g-1 and 2-29 pg g-1 for the different PBDE and PCB chemicals studied, respectively. The outputs of the proposed method were linear over the range from 0.02 to 30 ng g-1, for all PCB and PBDE congeners except for PBDE 100 and 153 (0.05-30 ng g-1) and PBDE 183 (0.1-30 ng g-1). The method was successfully applied to sheep liver samples for the determination of the target PBDE and PCB compounds. PMID- 21256502 TI - Consequences of the formation of 3,4-dimethyl-5-phenyl-1,3-oxazolidine on the analysis of ephedrines in urine by gas chromatography and a new method for confirmation as N-trifluoroacetyl-O-t-butyldimethylsilyl ether derivatives. AB - The compound 3,4-dimethyl-5-phenyl-1,3-oxazolidine can appear as an artifact during the gas chromatographic analysis of ephedrines. Its presence is a risk for doping control and forensic analyses. An evaluation about the consequences of its formation showed the possibility of a false positive for ephedrine, a false negative for pseudophedrine and increased uncertainty in the quantitative approach. Misinterpretations can be avoided with the observation of fragments m/z 56 and 71 in the ephedrine mass spectrum during GC-MS analysis and also by the formation of N-TFA-O-TBDMS derivatives prior to GC analysis. These N-TFA-O-TBDMS derivatives lead to an increase in the number and mass of diagnostic ions, meet the identification criteria, and provide an improvement in chromatographic resolution, allowing the separation of the ephedrines. PMID- 21256503 TI - Azithromycin as a new chiral selector in capillary electrophoresis. AB - In capillary electrophoresis (CE), separation of enantiomers of a chiral compound can be achieved through the chiral interactions and/or complex formation between the chiral selector and the enantiomeric analytes on leaving their diastereomeric forms with different stability constants and hence different mobilities. A great number of chiral selectors have been employed in CE and among them macrocyclic antibiotics exhibited excellent enantioselective properties towards a wide number of racemic compounds. The use of azithromycin (AZM) as a chiral selector has not been reported previously. This work reports the use of AZM as a chiral selector for the enantiomeric separations of five chiral drugs and one amino acid (tryptophan) in CE. The enantioseparation is carried out using polar organic mixtures of acetonitrile (ACN), methanol (MeOH), acetic acid and triethylamine as run buffer. The influences of the chiral selector concentration, ACN/MeOH ratio, applied voltage and capillary temperature on enantioseparation are investigated. The results show that AZM is a viable chiral selector in CE for the enantioseparation of the type of chiral drugs investigated. PMID- 21256504 TI - Preparation of perfluoro-1,3-propanedisulfonic acid/silica nanocomposites encapsulated low molecular weight aromatic compounds possessing a nonflammable characteristic. AB - Perfluoro-1,3-propanedisulfonic acid/silica [PFPS/SiO(2)] nanocomposites were prepared by the sol-gel reactions of the corresponding disulfonic acid [PFPS] with tetraethoxysilane and silica nanoparticles under alkaline conditions. These fluorinated nanocomposites thus obtained can exhibit no weight loss behavior corresponding to the contents of PFPS in the composites after calcination at 800 degrees C, although the parent PFPS can decompose completely around 270 degrees C. In addition, we succeeded in encapsulation of a variety of low molecular weight aromatic compounds such as bisphenol-A, bisphenol-AF, bisphenol-F, 4,4' biphenol and 1,1'-bi-2-naphthol into PFPS/SiO(2) nanocomposite cores. (1)H MAS NMR spectra, UV-vis spectra, fluorescence spectra and HPLC measurements of PFPS/SiO(2) nanocomposites-encapsulated bisphenol-A showed the presence of encapsulated bisphenol-A in the composites before and even after calcination at 800 degrees C. Interestingly, it was verified that fluorescence spectra of PFPS/SiO(2) nanocomposites-encapsulated bisphenol-A after calcination at 800 degrees C can exhibit an extremely red-shifted and enhanced fluorescence peak, compared to that before calcination or parent bisphenol-A. PMID- 21256505 TI - Growth and fire resistance of colloidal silica-polyelectrolyte thin film assemblies. AB - Thin films of colloidal silica were deposited on cotton fibers via layer-by-layer (LbL) assembly in an effort to reduce the flammability of cotton fabric. Negatively charged silica nanoparticles of two different sizes (8 and 27 nm) were paired with either positively charged silica (12 nm) or cationic polyethylenimine (PEI). PEI/silica films were thicker due to better (more uniform) deposition of silica particles that contributed to more than 90% of the film weight. Each coating was evaluated at 10 and 20 bilayers (BL). All coated fabrics retained their weave structure after being exposed to a vertical flame test, while uncoated cotton was completely destroyed. Micro combustion calorimetry confirmed that coated fabrics exhibited a reduced peak heat release rate, by as much as 20% relative to the uncoated control. The 10 BL PEI-8 nm silica recipe was the most effective because the coating is relatively thick and uniform relative to the other systems. Soaking cotton in basic water (pH 10) prior to deposition resulted in better assembly adhesion and flame-retardant behavior. These results demonstrate that LbL assembly is a useful technique for imparting flame retardant properties through conformal coating of complex substrates like cotton fabric. PMID- 21256506 TI - Influence of lipid composition on the thermotropic behavior and size distribution of mixed cationic liposomes. AB - Cationic liposomes are studied mainly as nonviral nucleic acid delivery systems and to a lesser extent as carriers/adjuvants of vaccines and as low-molecular weight drug carriers. It is well established that the performance and the biological activity of liposomes in general are strongly related to their physicochemical properties. We investigated the thermotropic behavior and the size distribution of mixed cationic liposomes formulated with different percentages of 1,2 dimyristoyl-sn-glycero-3-phosphatidylcholine and one of four cationic amphiphiles characterized by a pyrrolidinium headgroup with the aim of achieving a better understanding of how the molecular structure of the cationic amphiphile and its mole percentage affect the physicochemical properties of the liposomes. Multilamellar vesicles and large unilamellar vesicles were studied by differential scanning calorimetry and turbidity, respectively, to characterize the thermotropic behavior and lipid phase, whereas dynamic light scattering was used to determine size distribution. This study shows that subtle modifications in the cationic amphiphile's molecular structure and in liposome composition may have dramatic effects on the organization of the liposome bilayer and hence on the morphological and physicochemical features of the liposomes, thus being highly relevant to the biological features investigated previously. PMID- 21256507 TI - First report of a ranavirus associated with morbidity and mortality in farmed Chinese giant salamanders (Andrias davidianus). AB - From February to May 2010, an outbreak of disease occurred amongst farmed Chinese giant salamanders (Andrias davidianus) in Hanzhong County, Shanxi Province, China. Clinical signs included anorexia, lethargy, ecchymoses and swollen areas on the head and limbs, and skin ulceration. The aim of this study was to determine the cause of this disease. Necropsy examination revealed subcutaneous and intramuscular oedema, swollen and pale livers with multifocal haemorrhage, swollen kidneys with multifocal haemorrhage and distended fluid-filled intestines with areas of haemorrhage. Light microscopy revealed intracytoplasmic inclusions suggestive of a viral infection in a variety of organs, as well as degeneration and necrosis of these organs. Electron microscopy of ultrathin sections of the same tissues revealed iridovirus-like particles within the inclusions. Of the six specimens tested, all were positive for ranavirus major capsid protein (MCP) gene. Sequence alignments of the ranavirus MCP gene from these specimens showed 95-98% similarity with published ranavirus data. The virus, provisionally designated as Chinese giant salamander virus (CGSV), was isolated from tissue homogenates of diseased salamanders following inoculation of epithelioma papilloma cyprini cells. Sequence analysis of the MCP genes showed that the isolated virus was a ranavirus with marked sequence identity to other members of the genus Ranavirus. Koch's postulates were fulfilled by infecting healthy Chinese giant salamanders with the CGSV. These salamanders all died within 6-8 days. This is the first report of ranavirus infection associated with mass mortality in Chinese giant salamanders. PMID- 21256508 TI - Histopathological and immunohistochemical comparison of the brain of human patients with Alzheimer's disease and the brain of aged dogs with cognitive dysfunction. AB - Alzheimer's disease (AD) is the most common progressive form of dementia in aged people. Microscopical changes in the brains of AD patients include the formation of senile plaques (SPs), neurofibrillary tangles (NFTs) and granulovacuolar degeneration and the deposition of amyloid-beta (Abeta). Aged dogs are known to suffer from cognitive dysfunction and this state is associated with deposition of Abeta in the brain. The aim of the present study was to investigate tau phosphorylation of neurons and astrocytes in the brain of aged dogs with progressive cognitive impairment. Changes in the brain of aged dogs with cognitive dysfunction were compared with those in the brain of patients with AD of Braak stage V. Immunohistochemically, Abeta deposition, phosphorylated tau Ser396 (p-tau Ser396) and ubiquitin were observed in the parietal cortex and hippocampus of aged dogs with cognitive dysfunction. Astrocytes with expression of p-tau Ser396 and neurons with co-localization of p-tau Ser396 and ubiquitin were observed. Expression of p-tau Ser396 and accumulation of ubiquitin were significantly increased in the parietal cortex and dorsal part of the hippocampus of the brain of aged dogs when compared with expression of these molecules in human AD. PMID- 21256509 TI - Associations between maternal fever and influenza and congenital heart defects. AB - OBJECTIVE: To examine associations between maternal reports of prenatal fever or influenza and congenital heart defects (CHDs), and to evaluate whether those associations varied with antipyretic use. STUDY DESIGN: We analyzed case infants with CHD (n = 2361) and control infants without CHD (n = 3435) from the Baltimore Washington Infant Study (1981-1989). Participating mothers were asked whether they experienced a "fever of 101 degrees F or higher," had "influenza (flu)," or used an antipyretic agent (ie, acetaminophen, salicylate, or nonsteroidal anti inflammatory drug) during the period extending from 3 months before pregnancy through the end of the third month of pregnancy. We used logistic regression to compute ORs and 95% CIs while controlling for potential confounders. RESULTS: There were significant associations between fever and influenza and specific CHDs, namely right-sided obstructive defects (fever: OR, 2.04; 95% CI, 1.27 to 3.27; influenza: OR, 1.75; 95% CI, 1.16 to 2.62) and atrioventricular septal defects in infants with Down syndrome (fever: OR, 1.92; 95% CI, 1.10 to 3.38; influenza: OR, 1.66; 95% CI, 1.04 to 2.63). Maternal antipyretic use in the setting of fever or influenza tended to decrease these associations. CONCLUSIONS: Prenatal maternal fever or influenza may be associated with right-sided obstructive lesions in all infants and with atrioventricular septal defects in infants with Down syndrome. The use of antipyretics might attenuate such associations. PMID- 21256510 TI - Fucosyltransferase 2 non-secretor and low secretor status predicts severe outcomes in premature infants. AB - OBJECTIVE: To investigate secretor gene fucosyltransferase 2 (FUT2) polymorphism and secretor phenotype in relation to outcomes of prematurity. STUDY DESIGN: Study infants were <=32 weeks gestational age. Secretor genotype was determined from salivary DNA. Secretor phenotype was measured with H antigen, the carbohydrate produced by secretor gene enzymes, in saliva samples collected on day 9 +/- 5. The optimal predictive cutoff point in salivary H values was identified with Classification and Regression Tree analysis. Study outcomes were death, necrotizing enterocolitis (NEC, Bell's stage II/III), and confirmed sepsis. RESULTS: There were 410 study infants, 26 deaths, 30 cases of NEC, and 96 cases of sepsis. Analyzed by genotype, 13% of 95 infants who were non-secretors, 5% of 203 infants who were heterozygotes, and 2% of 96 infants who were secretor dominant died (P = .01). Analyzed by phenotype, 15% of 135 infants with low secretor phenotype died, compared with 2% of 248 infants with high secretor phenotype (predictive value = 76%, P < .001). Low secretor phenotype was associated (P < .05) with NEC, and non-secretor genotype was associated (P = .05) with gram negative sepsis. Secretor status remained significant after controlling for multiple clinical factors. CONCLUSIONS: Secretor genotype and phenotype may provide strong predictive biomarkers of adverse outcomes in premature infants. PMID- 21256511 TI - Re: 11Ccholine positron emission tomography/computerized tomography to restage prostate cancer cases with biochemical failure after radical prostatectomy and no disease evidence on conventional imaging. G. Giovacchini, M. Picchio, A. Briganti, C. Cozzarini, V. Scattoni, A. Salonia, C. Landoni, L. Gianolli, N. Di Muzio, P. Rigatti, F. Montorsi and C. Messa J Urol 2010; 184: 938-943. PMID- 21256512 TI - Re: Transplantation of nonhematopoietic adult bone marrow stem/progenitor cells isolated by p75 nerve growth factor receptor into the penis rescues erectile function in a rat model of cavernous nerve injury. M. Kendirci, L. Trost, B. Bakondi, M. J. Whitney, W. J. G. Hellstrom and J. L. Spees J Urol 2010; 184: 1560 1566. PMID- 21256513 TI - Surgical outcomes of mini laparoscopic herniorrhaphy in infants. AB - PURPOSE: We compared surgical outcomes of mini laparoscopic and open herniorrhaphy in infants. MATERIALS AND METHODS: We enrolled 55 infants undergoing herniorrhaphy, of whom 24 underwent mini laparoscopic herniorrhaphy (bilateral in 17, unilateral in 7) and 31 open herniorrhaphy (bilateral in 9, unilateral in 22). Mean+/-SD patient age was 7.17+/-4.21 months in the mini laparoscopic and 5.39+/-4.11 months in the open groups (p=0.37). During laparoscopy a contralateral patent processus vaginalis of 2 cm or greater was noted and repaired simultaneously in 13 of 20 infants (65%) initially diagnosed with unilateral hernia. RESULTS: Mean+/-SD followup was 22.9+/-10.5 months in the mini laparoscopic group and 20.2+/-10.5 months in the open group (p=0.20). Contralateral metachronous inguinal hernia manifested in 4 of 22 patients (18%) initially presenting with unilateral hernia in the open group and in no patient in the mini laparoscopic group (p<0.05). Recurrence was noted in 1 of the 40 open herniorrhaphy sites and in none of the 41 mini laparoscopic herniorrhaphy sites (p=0.49). For unilateral repair mean+/-SD operative time was significantly longer in the mini laparoscopic group (80.00+/-18.97 minutes) compared to the open group (51.15+/-23.27 minutes, p<0.05). For bilateral repair mean+/-SD operative time was comparable between the 2 groups (82.52+/-14.74 minutes for mini laparoscopy and 95.62+/-20.62 minutes for open repair, p=0.35). CONCLUSIONS: Mini laparoscopic herniorrhaphy in infants may prevent contralateral metachronous inguinal hernia, and is as safe and effective as open herniorrhaphy. The drawback of mini laparoscopic repair is the longer operative time for unilateral herniorrhaphy, which may be overcome by increased experience. PMID- 21256516 TI - Re: Location, extent and number of positive surgical margins do not improve accuracy of predicting prostate cancer recurrence after radical prostatectomy. A. J. Stephenson, D. P. Wood, M. W. Kattan, E. A. Klein, P. T. Scardino, J. A. Eastham and B. S. Carver j urol 2009; 182: 1357-1363. PMID- 21256517 TI - Catheterizable serous lined urinary outlet in children and adolescents: a choice when other treatments fail. AB - PURPOSE: We evaluated the functional outcome of continent catheterizable outlet using the serous lined extramural tunnel technique as a continence mechanism in children and adolescents. MATERIALS AND METHODS: We retrospectively studied all patients who underwent continent catheterizable stoma using the serous lined extramural technique between May 1993 and March 2008. Patient records were reviewed for age, sex, indication for surgery, surgical details and postoperative course. All patients were evaluated for continence with emphasis on frequency of clean intermittent catheterization. Urodynamic evaluation was done for patients with leaking stoma. Stoma related complications were also recorded. RESULTS: A total of 37 boys and 23 girls 3 to 18 years old underwent continent catheterizable stoma using the serous lined extramural technique. Total bladder substitution was performed in 13 patients using continent ileal W-shaped reservoir, and 47 patients underwent augmentation ileocystoplasty mounted with serous lined outlet. The outlet channel was appendix in 39 patients (65%), tapered ileal segment in 13 (21.5%) and Monti ileal tube in 8 (13.5%). After a median followup of 43 months (range 10 to 180) 55 patients (91.6%) achieved continence, with catheterization frequency of 3 to 5 times during the daytime and 1 to 2 times at night. Stoma related complications were leaking stoma in 5 patients (8.4%), stomal stenosis in 6 (10%), parastomal hernia in 2 (3.3%) and reservoir stones in 8 (13.3%). Reoperation rate was 18.3% (11 patients). CONCLUSIONS: The serous lined continent outlet seems to be a durable and efficient technique for treating children with incontinence, with an acceptable complication rate. PMID- 21256519 TI - Editorial comment. PMID- 21256520 TI - Critical outcome analysis of staged buccal mucosa graft urethroplasty for prior failed hypospadias repair in children. AB - PURPOSE: Although staged buccal mucosa graft urethroplasty is a well accepted technique for salvage urethroplasty, there are few reports on this procedure for redo hypospadias repair in children. MATERIALS AND METHODS: We reviewed patients who underwent staged buccal mucosa graft urethroplasty for redo hypospadias repair. Age, quality of graft before tubularization, meatal position, presence of balanitis xerotica obliterans and complications were recorded. RESULTS: A total of 30 patients underwent 32 repairs during a 5-year period. Mean age at first stage was 7 years (range 1 to 17) and mean interval between stages was 9.3 months (5 to 13). Mean followup after second stage was 25 months (range 10 to 46). Meatal position before first stage was proximal in 44% of patients, mid shaft in 39% and distal in 16%. Nine patients had biopsy proved balanitis xerotica obliterans. There were no donor site complications. Four patients underwent a redo grafting procedure. Complications after second stage occurred in 11 of 32 repairs (34%), consisting of urethral stenosis in 5, glanular dehiscence in 3 and urethrocutaneous fistula in 3. A third of the patients had some degree of graft fibrosis/induration after the first stage. These patients were prone to more complications at second stage (9 of 11, 82%), compared to patients without these unfavorable findings (4 of 21, 19%; p<0.001). Presence of balanitis xerotica obliterans and meatal position were not significant factors associated with adverse outcomes. CONCLUSIONS: Staged buccal mucosa graft urethroplasty is a suitable technique for salvage urethroplasty. Complications after second stage were seen in approximately a third of patients, mainly those with fibrotic/indurated grafts. PMID- 21256521 TI - Cystic angiomyolipoma mimicking cystic renal cell carcinoma. PMID- 21256523 TI - Primary melanoma of the bladder. PMID- 21256524 TI - Instituting a conservative management protocol for pediatric blunt renal trauma: evaluation of a prospectively maintained patient registry. AB - PURPOSE: Retrospective studies show that even high grade pediatric renal trauma can be safely managed conservatively. We evaluated a prospective patient registry at our level 1 pediatric trauma center, where patients with renal trauma were treated with an institutional review board approved conservative blunt renal trauma protocol. Standardized treatment included a trial of expectant management for all stable cases. MATERIALS AND METHODS: We identified 39 children with blunt renal trauma treated between 2003 and 2008. A strict conservative approach was used, ie nonoperative management in cases that were hemodynamically stable or had a favorable response with up to 2 units of blood transfused and no operative renal lesion on imaging. Adult imaging protocols were followed and exploratory laparotomy for nonrenal causes did not alter course of expectant renal management. Outcomes evaluated were injury grade, hematuria, operative management, length of stay and associated injuries. RESULTS: Based on the American Association for the Surgery of Trauma organ injury severity scale, 13 patients were considered to have grade I disease, 8 grade II, 11 grade III, 6 grade IV and 1 grade V. Conservative management resulted in a 97% nonoperative rate and a single renorrhaphy. CONCLUSIONS: Using a prospective patient registry, this study demonstrates that conservative treatment of blunt pediatric renal trauma is safe and effective. Also, serious renal injuries are not missed by applying adult diagnostic imaging protocols in children. PMID- 21256525 TI - Multiple metachronous fibroepithelial polyps in children. AB - PURPOSE: We present our experience with a new phenotype of fibroepithelial polyps recurring in the urinary tract in children after robotic or laparoscopic pyeloplasty, and discuss the most appropriate treatment for these multiple metachronous neoplasms. MATERIALS AND METHODS: At our institution 14 children had fibroepithelial polyps as the cause of ureteropelvic junction obstruction at pyeloplasty. Of the patients 12 had at least 1 additional polyp in the ureter, necessitating concomitant ureteroscopy at either robotic or laparoscopic pyeloplasty. Of these 12 patients 9 had followup of at least 1 year. RESULTS: In 6 patients with at least 1 year of followup neoplasms were seen on retrograde pyelography and ureteroscopy that were not present on ureteroscopy at pyeloplasty. At 6 months after stent removal following the first recurrence 2 patients (33%) showed a second recurrence on imaging at a different location in the upper tract requiring laser ablation. One of these patients had a third recurrence that required further intervention before all were disease-free. No major intraoperative or preoperative complications developed. CONCLUSIONS: We should always consider the possibility of recurrent fibroepithelial polyps in children with ureteropelvic junction obstruction, and recommend routine retrograde pyelography and ureteroscopy at stent removal after laparoscopic or robotic pyeloplasty. Although ureteroscopic management seems to be the most appropriate modality in children with multiple metachronous fibroepithelial polyps, larger studies are needed. PMID- 21256526 TI - Evaluation of the contamination of platinum in estuarine and coastal sediments (Tagus Estuary and Prodelta, Portugal). AB - Platinum contamination in estuarine and coastal sediments has been evaluated in three cores collected from the Tagus Estuary and Prodelta shelf sediments. Elevated concentrations, up to 25-fold enrichment compared to background values, were found in the upper layers of the estuarine sediments. The degree of Pt enrichment in the estuarine sediments varied depending on the proximity to vehicular traffic sources, with a maximum concentration of 9.5 ng g(-1). A considerable decrease of Pt concentrations with depth indicated the absence of significant contamination before the introduction of catalytic converters in automobiles. Platinum distribution in the Tagus Prodelta shelf sediment core showed no surface enrichment; instead a sub-surface maximum at the base of the mixed layer suggested the possibility of post-depositional mobility, thereby blurring the traffic-borne contamination signature in coastal sediments. PMID- 21256527 TI - The impact of dredge-fill on Posidonia oceanica seagrass meadows: regression and patterns of recovery. AB - Posidonia oceanica meadows can be severely damaged by dredge-fill operations. We report on the construction of gas pipelines that occurred between 1981 and 1993 in SW Sicily, Italy. A large portion of the meadow was mechanically removed, and the excavated trench was filled with a mosaic of substrates, ranging from sand to consolidated rock debris. Meadow loss and recovery were quantified over 7 years after the end of operations. We recorded an overall loss of 81.20 ha of meadow. Substrate strongly affected recovery as the percent cover by P. oceanica consistently increased on calcareous rubble, reaching values of 44.37 +/- 3.05% in shallow sites after 7 years, whereas no significant increase occurred on other substrates. As in the Mediterranean Sea exploitation of coastal areas continues to grow with consequent impacts on P. oceanica meadows, this case study illustrates how artificial rubble-like materials could be employed to support the restoration of damaged meadows. PMID- 21256528 TI - Environmental capacity of nitrogen and phosphorus pollutions in Jiaozhou Bay, China: modeling and assessing. AB - In recent years, with the development of society and economy of Qingdao, environment and ecosystem problems, for instance, red ties, become more and more serious in Jiaozhou Bay, China, because of the increasing pollutants discharged into it. In order to solve these problems, an eco-hydrodynamic model is constructed to estimate the marine environmental capacity of nitrogen and phosphorus nutrients in Jiaozhou Bay, whose simulation results are rational for the bay. According to the model, if the target is set to achieve water quality (grade II) in Jiaozhou Bay, the environmental capacity of dissolved inorganic nitrogen and phosphorus in one year are approximately 7800 and 840 tons, respectively. Thus our research offers necessary scientific foundation to the total loads control efforts in this area. PMID- 21256529 TI - Ectopic expression of apple fruit homogentisate phytyltransferase gene (MdHPT1) increases tocopherol in transgenic tomato (Solanum lycopersicum cv. Micro-Tom) leaves and fruits. AB - Homogentisate phytyltransferase (HPT) is an important enzyme in the biosynthesis of tocopherols (vitamin E). Herein, an HPT homolog (MdHPT1) was isolated from apple (Malus domestica Borkh. cv. Fuji) fruits, whose gene expression level gradually decreased during fruit ripening, reaching a background level in ripened apple fruits. The amounts of alpha- and gamma-tocopherols, two major tocopherols in plant organs, were 5- to 14-fold lower in the fruits than in the leaves and flowers of apple plants. Transgenic tomato plants (Solanum lycopersicum cv. Micro Tom) overexpressing MdHPT1 were next constructed. Transgenic independent T(1) leaves contained ~1.8- to 3.6-fold and ~1.6- to 2.9-fold higher levels of alpha tocopherol and gamma-tocopherol, respectively, than those in control plants. In addition, the levels of alpha-tocopherol and gamma-tocopherol in 35S:MdHPT1 T(1) fruits increased up to 1.7-fold and 3.1-fold, respectively, as compared to the control fruits, indicating that an increase in alpha-tocopherol in fruits (maximal 1.7-fold) was less evident than that in leaves (maximal 3.6-fold). This finding suggests that the apple MdHPT1 plays a role in tocopherol production in transgenic tomatoes. PMID- 21256530 TI - Third harmonic transmit phasing for SNR improvement in tissue harmonic imaging with Golay-encoded excitation. AB - BACKGROUND: Ultrasound tissue harmonic signal generally provides superior image quality as compared to the linear signal. However, since the generation of the tissue harmonic signal is based on finite amplitude distortion of the propagating waveform, the penetration and the sensitivity in tissue harmonic imaging are markedly limited because of the low signal-to-noise ratio (SNR). METHODS: The method of third harmonic (3f(0)) transmit phasing can improve the tissue harmonic SNR by transmitting at both the fundamental (2.25MHz) and the 3f(0) (6.75MHz) frequencies to achieve mutual enhancement between the frequency-sum and the frequency-difference components of the second harmonic signal. To further increase the SNR without excessive transmit pressure, coded excitation can be incorporated in 3f(0) transmit phasing to boost the tissue harmonic generation. RESULTS: Our analyses indicate that the phase-encoded Golay excitation is suitable in 3f(0) transmit phasing due to its superior transmit bandwidth efficiency. The resultant frequency-sum and frequency-difference components of tissue harmonic signal can be simultaneously Golay-encoded for SNR improvement. The increase of the main-lobe signal with the Golay excitation in 3f(0) transmit phasing are consistent between the tissue harmonic measurements and the simulations. B-mode images of the speckle generating phantom also demonstrate the increases of tissue harmonic SNR for about 11dB without noticeable compression artifacts. CONCLUSION: For tissue harmonic imaging in combination with the 3f(0) transmit phasing method, the Golay excitation can provide further SNR improvement. Meanwhile, the axial resolution can be effectively restored by pulse compression while the lateral resolution remains unchanged. PMID- 21256531 TI - Pathogenicity of different PR8 influenza A virus variants in mice is determined by both viral and host factors. AB - Experimental mouse models were used to compare virulence and reproduction rate of three mouse-adapted variants of the PR8 influenza A virus strain. We observed large differences in pathogenicity in two mouse strains. The PR8M variant was lethal in DBA/2J mice but not in C57BL/6J mice, whereas PR8F and hvPR8 variants were lethal in both mouse strains. High lethality of PR8M in DBA/2J correlated with high viral load at early time points after infection and spread of the virus into alveolar regions. Also, higher viral loads and mortality in mice infected with PR8F resulted in a higher number of infiltrating leukocytes. 3D-protein structure predictions of the HA indicated amino acid sequence alterations which may render the HA cleavage site in PR8F more accessible to host proteases. Infection of C57BL/6J mice with a re-assorted PR8 virus revealed that the HA gene is the main determinant of virulence of the PR8F variant. PMID- 21256532 TI - Molecular analysis of soybean dwarf virus isolates in the eastern United States confirms the presence of both D and Y strains and provides evidence of mixed infections and recombination. AB - Soybean dwarf virus (SbDV), first identified as an agricultural problem in Japan, has emerged as a growing problem in the Midwestern United States. The majority of research on SbDV had been limited to four lab maintained strains from Japan. SbDV had been found in clover in the eastern United States, but these isolates rarely emerged into soybeans. These isolates were analyzed by multiplex PCR and sequencing, revealing that some were infections of both Y and D components, including a recombinant subisolate. Phylogenetic analyses for the US isolates revealed a broad diversity of SbDV, with selection pressure greater on the movement protein than the coat protein. The field isolates from the Eastern United States showed differences in symptoms, aphid transmission and host range, demonstrating that a study of field isolates is an important complement to laboratory maintained strains in understanding the biology and evolution of plant viruses. PMID- 21256533 TI - Numerical modelling of sediment-bacteria interaction processes in surface waters. AB - Faecal bacteria exist in both free-living and attached forms in surface waters. The deposition of sediments can take faecal bacteria out of the water column and to the bed. The sediments can subsequently be re-suspended into the water column, which can then lead to the re-suspension of the faecal bacteria of the attached form back into the water column, where it may desorb from the sediments. Therefore, the fate and transport of faecal bacteria is highly related to the governing sediment transport processes, particularly where these processes are significant. However, little attempt has been made to model such processes in terms of predicting the impact of the sediment fluxes on faecal bacteria levels. Details are given of the refinement of a numerical model of faecal bacteria transport, where the sediment transport processes are significant. This model is based on the model DIVAST (Depth Integrated Velocities And Solute Transport). Analytical solutions for steady and uniform flow conditions were derived and used to test the sediment-bacteria interaction model. After testing the sediment bacteria interaction model favourably against known results, the model was then set up for idealized case studies to investigate the effects of sediment on bacteria concentrations in the water column. Finally the model was applied to a simplified artificial flooding study to investigate the impact of suspended sediment fluxes on the corresponding bacteria transport processes. The model predictions have proved to be encouraging, with the results being compared to field measurements. PMID- 21256534 TI - PBDE and PCB contamination of eels from the Gironde estuary: from glass eels to silver eels. AB - Since the 1980s, the eel population has been decreasing dangerously. Persistent Organic Pollutants (POPs) such as Polychlorinated Biphenyls (PCBs) are one of the suspected causes of this decline. A preliminary study of PCB contamination carried out on different fish from the Gironde estuary (southwest of France, Europe) has shown a relatively high level of contamination of eel muscles. In order to characterize the contamination level of PCBs and PBDEs (PolyBrominated Diphenyl-Ethers) in eels from this estuary more than 240 eels were collected during the years 2004-2005 in the Gironde estuarine system, from glass eels to silver eels. Individual European eels were grouped according to length and localization sites. The results have shown a low contamination level of glass eels: respectively 28+/-11 ng g(-1)dw for PCBs and 5+/-3 ng g(-1)dw for PBDEs. The contamination level in eels (expressed in ng g(-1)dw) increases from glass eels to silver eels up to 3399 ng g(-1)dw of PCBs for the most contaminated silver eel. Such levels of PCBs similar to those observed in Northern Europe, could raise sanitary problems connected with the World Health Organization (WHO) recommendations. These results are worrying for the local people who regularly eat eels caught in the Gironde estuary. PMID- 21256535 TI - Endothelial, platelet, and tissue factor-bearing microparticles in cancer patients with and without venous thromboembolism. AB - BACKGROUND: Cancer is a prothrombotic state, with an increased prevalence of venous thromboembolism (VTE). Microparticles (MPs) are sub-micron-sized vesicles derived from activated or apoptotic cells that may play a role in VTE, although evidence of this association is still limited. OBJECTIVES: To evaluate the hypothesis that elevated numbers of endothelial (EMPs), platelets (PMPs), and Tissue Factor-bearing MPs (TF(+)MPs) in plasma may contribute to cancer associated thrombosis. PATIENTS/METHODS: EMPs, PMPs and TF(+)MPs plasma levels were measured in 90 consecutive patients (cases) referred to our Department (30 with a first episode of unprovoked VTE; 30 with active cancer; 30 with a diagnosis of acute VTE associated with active cancer), and in a group of 90 healthy subjects (controls). MPs analyses were performed by flow-cytometry (Cytomics FC500). RESULTS: Cases showed statistically significant higher (mean +/ SD) circulating EMPs and PMPs plasma levels (920 +/- 341 and 1221 +/- 413 MP/MUL, respectively) than controls (299 +/- 102 and 495 +/- 241 MP/MUL; p<0.005). Moreover cancer patients (with and without VTE) showed higher (mean +/- SD) TF(+)MPs (927 +/- 415 MPs/MUL) than controls (204 +/- 112 MPs/MUL; p<0.001). The subgroup of cancer patients plus VTE showed statistically significant higher TF(+)MPs plasma levels (1019 +/- 656 MPs/MUL) than cancer patients without VTE (755 +/- 391 MPs/MUL, p = 0.002). Multivariate analysis failed to show a significant association between elevated TF(+)MPs and VTE in cancer patients. CONCLUSIONS: Our results suggest that MPs might be an important intermediate in the cascade of cellular injury and vascular dysfunctions underlying the process of thrombosis, particularly in cancer. Further clinical investigations are needed to confirm the precise role of MPs in predicting hypercoagulable state in patients with cancer. PMID- 21256536 TI - A common promoter variant of the gene encoding cyclooxygenase-1 (PTGS1) is related to decreased incidence of myocardial infarction in patients with coronary artery disease. PMID- 21256537 TI - Persistent mullerian duct syndrome in adult men diagnosed using laparoscopy. AB - Persistent mullerian duct syndrome is a rare disease that occurs in men with a completely normal phenotype and is characterized by the presence of mullerian duct structures. Diagnostic laparoscopy can reveal an appearance consistent with a uterus, fallopian tubes, or ovotestes. PMID- 21256538 TI - Shock wave lithotripsy associated with greater prevalence of hypertension. AB - OBJECTIVES: To determine whether shock wave lithotripsy (SWL) increases the prevalence of hypertension (HTN) at intermediate follow-up. METHODS: All patients were treated with the Medstone STS electrohydraulic lithotripter, and the data were recorded prospectively in a centralized database. The data on the development of HTN after SWL was obtained from a questionnaire mailed to the patients who had undergone SWL from November 1999 and January 2002. Controls matched for age, sex, and body mass index were obtained from the National Health and Nutrition Examination Survey, using the demographic, body measurements, medical conditions, and blood pressure data sets. Two sets of matching controls were used to compare the prevalence of HTN between our patients and the NHANES population at SWL and at the follow-up point. RESULTS: A total of 2041 patients responded to the questionnaire, with a median follow-up of 6 years. No statistically significant difference was found in the HTN prevalence between the patients and matched controls at SWL (26.7% vs 28.0%). At the follow-up point, the prevalence of HTN was greater in our patients (37.8%) than in the controls (32.5%, P=.0009). Of our patients, 15% have developed de novo HTN compared with the predicted rate of 6.25% from the matched controls. Male gender, age, and a greater body mass index were associated with the development of HTN, but none of the SWL parameters (number of shocks, bilateral vs unilateral, and multiple SWL sessions) were significantly associated with HTN. CONCLUSIONS: The results of our study have indicated a small, but significant, increase in the risk of developing HTN after SWL using a third-generation electrohydraulic lithotripter at intermediate follow-up. PMID- 21256540 TI - Ability of linear length of positive margin in radical prostatectomy specimens to predict biochemical recurrence. AB - OBJECTIVES: To determine whether the linear length of a positive margin (LLPM) in radical prostatectomy specimens is associated with the risk of biochemical recurrence (BCR). METHODS: A total of 294 patients with a positive margin in the radical prostatectomy specimen were assessed for the association between the LLPM and BCR (defined as a serum prostate-specific antigen level of >=0.2 ng/mL) using a Cox proportional hazards regression model. The concordance index on multivariate analysis was calculated without the LLPM, with LLPM as a continuous variable, and with the LLPM as a binary variable (<=1 mm vs >1 mm). RESULTS: The mean LLPM was 3.90 mm (median 2.0, range 0.1-30.5). The LLPM was an independent prognostic factor for BCR (P < .05) on both univariate and multivariate analysis. The concordance index was 0.6802 when the LLPM was not included and was 0.6865 and 0.7189 when the latter was modeled as a binary and continuous variable, respectively. When the patients were stratified according to their pathologic stage, the LLPM was an independent prognostic factor for BCR in the 185 patients with Stage pT2 tumors but not in the 109 patients with Stage pT3 tumors. CONCLUSIONS: The LLPM in the radical prostatectomy specimen was an independent predictive factor for BCR in patients with a positive margin. This association was stronger for Stage pT2 tumors with a positive margin. Reporting the actual LLPM could improve the predictive accuracy of BCR in patients whose radical prostatectomies had positive margins. We advocate reporting LLPM in radical prostatectomy, particularly for pT2 tumors. PMID- 21256539 TI - Initial patterns of care with oral targeted therapies for patients with renal cell carcinoma. AB - OBJECTIVES: To characterize the contemporary use of oral-targeted therapies (ie, sunitinib, sorafenib) among patients with renal cell carcinoma (RCC) and to assess the factors associated with short-term and sequential treatment. METHODS: We used an administrative claims database of privately insured patients to evaluate oral-targeted therapy use among patients with RCC from 2006 to 2007. After identifying patients with RCC who had received sunitinib and/or sorafenib, we determined the prevalence of patients treated with short-term and/or sequential therapy. We performed bivariate and multivariate analyses to estimate the associations between the patient characteristics and receipt of short-term and/or sequential treatment regimens. RESULTS: We identified 938 patients with RCC who had initially been treated with sunitinib (n = 554) or sorafenib (n = 384). In this group, 36% and 23% of patients had received short-term or sequential therapy, respectively. Most patients (61%) who had received sequential therapy had undergone short-term treatment with >=1 drugs, with second-line sorafenib more likely to be given as short-term therapy than sunitinib (63% vs 34%, P < .001). Short-term therapy was more common in female patients (odds ratio 1.53, 95% confidence interval 1.12-2.09) and patients in the Southern United States (odds ratio 1.71, 95% confidence interval 1.05-2.80). Sequential therapy was more common among patients receiving sorafenib first (odds ratio 2.30, 95% confidence interval 1.64-3.21). CONCLUSIONS: Short-term and sequential oral targeted therapy use was relatively prevalent among patients with RCC. For patients treated with sunitinib and sorafenib, the patterns of short-term use varied by the sequence of medications, suggesting differences in the effectiveness or tolerability of each regimen. These findings highlight the need for future studies to characterize the "real-world" clinical outcomes and economic effect associated with these treatment courses. PMID- 21256541 TI - Evaluation of viability and proliferative activity of human urothelial cells cultured onto xenogenic tissue-engineered extracellular matrices. AB - OBJECTIVES: To evaluate the viability and proliferative activity of human urothelial cells (HUCs) cultured on tissue-engineered extracellular matrix scaffolds and to assess the potential of extracellular matrixes to support the growth of HUCs in their expected in vivo urine environment. METHODS: HUCs were obtained by bladder biopsy and cultured onto the luminal and abluminal surfaces of decellularized porcine small intestinal submucosa (SIS) and porcine urinary bladder matrix (UBM). In addition, HUCs were cultured in optimal in vitro growth conditions and in their expected in vivo urine environment. The attachment, viability, and proliferative activity of HUCs were evaluated and compared using quantitative viability indicators and fluorescent markers for intracellular esterase activity and plasma membrane integrity. RESULTS: The luminal and abluminal surfaces of the UBM demonstrated significantly greater HUC viability and proliferative activity compared with the luminal and abluminal surfaces of the SIS grafts (P < .0001). Culture of HUCs in a simulated in vivo urine environment significantly affected cell viability (P < .0001). Proliferative activity was immeasurable on cell-seeded scaffolds that were cultured in a urine environment after 48 hours of growth (P < .0001). CONCLUSIONS: This is the first comparative report of UBM and SIS. Our results have demonstrated that UBM has significantly greater regenerative potential for HUCs compared with SIS. However, the perceived potential for extracellular matrixes in reconstructive urology might be limited by their inability to induce urothelial regeneration in a urine environment. PMID- 21256542 TI - Idiopathic infantile bladder lithiasis from Roman antiquity. PMID- 21256543 TI - Evaluation and management of the persistent/recurrent varicocele. AB - OBJECTIVE: To review outcomes in adolescent patients following redo varicocelectomy surgery. METHODS: The composite varicocele registry of a single surgeon was queried to identify patients who had undergone redo varicocelectomy. Variables of testicular asymmetry, testicular volume, presence and degree of retrograde venous flow, and incidence of postoperative hydrocele were evaluated. RESULTS: Nineteen boys were identified as having had a redo varicocelectomy (16 open, 1 laparoscopic, 2 radiographic embolization) with a minimum postoperative follow-up of 6 months (mean: 23.4; range: 6-53 months). No varicocele was palpable postoperatively among the 17 surgical redoes; one patient's testicle was significantly smaller after surgery, and 3 developed a hydrocele requiring repair. One of two boys who underwent radiographic embolization had a persistent varicocele. Eight of the nine boys who had asymmetry of 10% or greater before redo demonstrated catch-up growth after repair. The consistent intraoperative finding in all redo patients was the presence of large veins within the cord, just proximal to the junction with the vas and in continuity with the dilated veins distal to the internal ring. Post-redo retrograde venous flow was not identifiable in 16 and minimal in three. CONCLUSIONS: Redo varicocelectomy can be accomplished successfully and has a similar chance of achieving catch-up growth as does an initial repair. Postoperatively, there exists a small risk of testicular volume compromise and a significant risk of hydrocele development. Distal collateral veins may have a smaller role in varicocele formation and recurrence than previously thought. PMID- 21256544 TI - Effect of sildenafil citrate on penile weight and physiology of cavernous smooth muscle in a post-radical prostatectomy model of erectile dysfunction in rats. AB - OBJECTIVES: To evaluate the gross morphometric changes and in vitro responses of the corpus cavernosus of rats treated with sildenafil citrate after cavernous neurotomy. METHODS: The animals were divided into 3 groups. Group 1 consisted of sham-operated rats (n = 16); group 2 consisted of rats that underwent bilateral cavernous neurotomy (BCN) (n = 16); and group 3 consisted of rats that underwent unilateral cavernous neurotomy (UCN) (n = 16). Each group of rats was further classified into 2 subgroups according to whether or not they received sildenafil treatment. The rats were killed on postoperative day 14, and penectomy was performed. Apoptosis was assessed by terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate nick end labeling (TUNEL), and organ-bath studies were evaluated by Phenylephrine (Phe), acetylcholine (Ach), sodium nitroprusside (SNP), and electrical field stimulation (EFS) responses. RESULTS: Penile weight in the BCN group was significantly lower than that of sham-treated group. UCN allowed much more preservation of penile weight compared with that in the sham-treated group. Sildenafil citrate treatment had positive effects on penile weight of both BCN (P = .003) and UCN (P = .004) groups. BCN increased smooth muscle apoptosis when compared with the sham or UCN group. Sildenafil citrate had a positive effect on the apoptotic index. In the BCN group, responses to Phe, Ach, SNP, and EFS decreased significantly, and sildenafil treatment corrected the responses to Phe, Ach, and SNP. CONCLUSIONS: Our experimental study results support that early and daily sildenafil citrate treatment has a protective affect on the adrenergic and cholinergic systems, which play a role in erectile function. PMID- 21256545 TI - Retroperitoneal laparoscopic upper-pole nephroureterectomy for duplex kidney anomalies in adult patients. AB - OBJECTIVES: To present our surgical techniques and experience with retroperitoneal laparoscopic upper pole nephroureterectomy for a duplex kidney in adult patients without vesicoureteral reflux. METHODS: A total of 32 adult patients with a duplex kidney underwent laparoscopic upper pole nephroureterectomy. A 3-port, finger- and balloon-dissecting, retroperitoneal approach was used. The upper pole renal parenchyma was divided circumferentially between the upper and lower poles using a harmonic scalpel, maintaining a margin around the upper pole parenchyma to avoid any possible injury to the lower pole functioning moiety. The urothelium of the remnant upper pole parenchyma was stripped off, and the edges of the remnant upper pole parenchyma were approximated with figure-of-8 stitches. The distal upper pole ureter was mobilized and transected at the point at which the ureter crossed anterior to the iliac vessels. Intravenous urography and renal ultrasonography were performed at 3 and 6 months postoperatively. RESULTS: All laparoscopic operations were performed successfully without conversion to open surgery. The mean operative time was 83 minutes. The mean blood loss was 18 mL. The mean postoperative hospital stay was 7 days. No intraoperative or major postoperative complications occurred. The intravenous urography and renal ultrasound findings 3 and 6 months postoperatively demonstrated normal pyelography findings and renal function of the preserved lower pole in all patients. CONCLUSIONS: Retroperitoneal laparoscopic upper pole nephroureterectomy is a safe and effective procedure and an excellent minimally invasive treatment option for the adult patient with a duplex kidney. PMID- 21256546 TI - Intermittent docetaxel chemotherapy in patients with castrate-resistant prostate cancer. AB - OBJECTIVES: To determine whether intermittent docetaxel might control disease while limiting the toxicity and improving the quality-of-life parameters in patients with advanced, castrate-resistant prostate cancer. Intermittent docetaxel represents an appealing therapeutic approach. METHODS: We reviewed the records of 35 patients with chemotherapy-naive castrate-resistant prostate cancer who had received docetaxel 45 mg/m(2) every 2 weeks, with oral prednisone 5 mg twice daily. Treatment was held when the patients had reached a >50% prostate specific antigen reduction from baseline that was confirmed by a second measurement 4 weeks later, in the absence of disease progression. Docetaxel was resumed at a >25% prostate-specific antigen increase from the nadir level, also confirmed by a second measurement 4 weeks later, or in cases of documented disease progression. RESULTS: Of the 35 patients, 18 (51.42%) had entered the first chemotherapy-free interval (CFI) after a median of 6 infusions (range 2 12), 6 patients had entered a second CFI after a median of 4 months (range 2-12), and 1 patient, a third CFI at the last follow-up point. The median interval "off chemotherapy" was 4.5 months (range 1-16) for the first CFI. Two patients discontinued docetaxel because of Grade 4 nonhematologic toxicity. The median interval to treatment failure was 8.1 months (95% confidence interval 5.1-12.2) for the entire cohort and 12.2 months (95% confidence interval 8.3-25+) for the patients who had entered the first CFI. CONCLUSIONS: The results of our study have shown that intermittent docetaxel is a clinically active and likely more tolerable and less costly therapeutic strategy for patients with castrate resistant prostate cancer than continuous administration. Additional validation of this approach is warranted. PMID- 21256547 TI - Veiled right kidney sign in retroperitoneal duodenal perforation after endoscopic retrograde cholangiopancreatography. AB - Retropneumoperitoneum due to duodenal perforation after endoscopic retrograde cholangiopancreatography is rare. Recognizing the presence of free air, which outlines the right kidney, is essential for its early diagnosis and appropriate management. PMID- 21256548 TI - Three-dimensional imaging of ureter with endoscopic optical coherence tomography. AB - OBJECTIVES: To verify the ability to identify the layered structures of the ureteral wall and to image a segment of the ureter in 3 dimensions with high speed, endoscopic optical coherence tomography (EOCT). METHODS: We imaged a porcine ureter ex vivo using a spectral-domain EOCT with a specially designed circumferential scanning fiber catheter. The images were correlated with the histologic findings to identify the corresponding structures. Three-dimensional images and en face images at different depths from the luminal surface were reconstructed from the multiple cross-sectional images to visualize the layered structure of a segment of the ureter from different perspectives. RESULTS: The EOCT images clearly revealed all layers of the ureteral wall as shown in the histologic images. In particular, with the specially designed fiber catheter, the light beam was well centered during the rotation and pull back, allowing constant acquisition of high-fidelity images and unambiguous identification of the smooth muscle layers in all images. With high-speed EOCT, a segment of ureter (20 mm) can be imaged in <90 seconds at a high resolution. CONCLUSIONS: With its ability to visualize all layers of the ureteral wall, EOCT offers the potential to stage urothelial cancers that have infiltrated the muscular wall (Stage T2). This information will be complimentary to the diagnostic information obtained through ureteroscopic biopsy and computed tomography urogram. PMID- 21256549 TI - Acceptance and durability of surveillance as a management choice in men with screen-detected, low-risk prostate cancer: improved outcomes with stringent enrollment criteria. AB - OBJECTIVE: To analyze the acceptance rate and durability of surveillance among contemporary men with low-risk prostate cancer managed at a large, US academic institution. METHODS: Patients with low-risk parameters on initial and repeat biopsy were offered surveillance regardless of age. Regular clinical evaluation and repeat prostate biopsy were recommended every 1-2 years, and intervention was recommended based on adverse clinical and pathologic parameters on follow-up. Acceptance rate of active surveillance, freedom from intervention, and freedom from recommended intervention were measured. RESULTS AND LIMITATIONS: Of 202 low risk patients, 86 (43%) chose immediate treatment and 116 (57%) underwent repeat biopsy for consideration of surveillance. Intervention was recommended after initial repeat biopsy in 27 (23%) men because of higher-risk features, leaving a total of 89 men on surveillance. Over a median follow-up of 33 months, 16 men were ultimately treated and 8 were recommended to undergo treatment because of adverse clinical features on subsequent evaluations. Of the men on surveillance, the 3-year freedom from intervention and freedom from recommended intervention was 87% (95% CI, 78-93) and 93% (95% CI, 85-97), respectively. CONCLUSIONS: Acceptance of surveillance (57%) in low-risk patients in this series is substantially higher than previous reports, and approximately one-third of these patients are ultimately managed by surveillance using stringent criteria. The risk of reclassification to a more aggressive cancer over short-term follow-up in appropriately selected patients is low. PMID- 21256550 TI - The "7-flap" perineal urethrostomy. AB - OBJECTIVES: Perineal urethrostomy is a well-accepted reconstructive option for complex anterior urethral stricture disease. We present a novel technique for the construction of a perineal urethrostomy that allows the surgeon greater control when managing all levels of anterior urethral stricture disease. METHODS: A perineal urethrostomy is constructed by advancing a 7-shaped laterally based perineal skin flap to the amputated bulbar or membranous urethra. RESULTS: Ten men between the ages of 48 and 79 underwent the 7-flap perineal urethrostomy for advanced urethral stricture disease; one had 7-flap revision of an existing perineal urethrostomy. Each patient was treated in an outpatient setting without perioperative complications. Nine of ten patients (90%) are voiding spontaneously without the need for urethrostomy revision or proximal urinary diversion. CONCLUSIONS: The 7-flap perineal urethrostomy is versatile, safe, and effective. It allows the surgeon maximal flexibility in the management of complex anterior urethral stricture disease. PMID- 21256551 TI - Angiotensin type-1 receptor blocker candesartan inhibits calcium oxalate crystal deposition in ethylene glycol-treated rat kidneys. AB - OBJECTIVES: To investigate whether an angiotensin type-1 receptor blocker could inhibit calcium oxalate crystal deposition using ethylene glycol-treated rats. The renoprotective effect has been reported to be another role of angiotensin type-1 receptor blockers in addition to their role in lowering blood pressure. Recent research has suggested that inhibiting reactive oxidative species generation and tubulointerstitial inflammation is the major role of angiotensin type-1 receptor blockers. These 2 factors are also important in the mechanism of calcium oxalate stone formation. METHODS: We divided 28 rats, aged 7 weeks, into 4 groups: group 1, control rats; group 2, candesartan-treated rats; group 3, stone-forming rats; and group 4, candesartan-treated stone-forming rats. The kidney crystal deposits were examined, and the oxidative stress biomarker, nicotinamide adenine dinucleotide phosphate oxidase activity, general and urinary variables, and the transforming growth factor-beta level in kidney tissue were compared among the 4 groups. RESULTS: The candesartan-treated rats were healthy and had weight gain similar to that of the control rats, although a significant reduction in blood pressure was observed. The urinary components associated with calcium oxalate stone formation were not influenced by candesartan treatment; however, significantly fewer crystal deposits were observed in group 4. The oxidative biomarker and nicotinamide adenine dinucleotide phosphate oxidase activity decreased, and the level of transforming growth factor-beta was suppressed in group 4. CONCLUSIONS: Candesartan had substantial effects on crystal formation in the rat kidney by suppressing nicotinamide adenine dinucleotide phosphate oxidase and the transforming growth factor-beta levels. PMID- 21256552 TI - Surgical anatomy of urogenital diaphragm and course of its vessels in exstrophy epispadias. AB - OBJECTIVES: To report the surgical anatomy of the muscles of the urogenital diaphragm and the pattern of its vessels in the classic exstrophy bladder and incontinent epispadias. METHODS: A total of 11 patients, 9 with unoperated classic exstrophy and 2 with incontinent epispadias, who were >5 years old at presentation, were selected for the present study. Magnetic resonance imaging of the pelvis was performed using a 3.0 T magnetic resonance imaging scanner and an 8-channel coil. Computed tomography was performed for 5 patients using a multidetector row helical computed tomography scanner. Angiograms of the vessels of the urogenital diaphragm were also obtained using magnetic resonance imaging and computed tomography. RESULTS: A central perineal body was seen in all the patients, with attachment of the bulbospongiosus anteriorly, superficial transverse perinei laterally, and anal sphincter posteriorly. At the root of corpora, the ischiocavernosus muscle was also seen. The triangle among the ischiocavernosus, bulbospongiosus, and superficial transverse perinei muscle was accentuated and contained the perineal artery, indirectly indicating the course of the perineal nerve. The dorsal penile artery was nearer to the posterior edge of the ischiopubic ramus, before coursing on the lateral aspect of the anterior segment of the corpora. The deep transverse perinei muscle and laid open external urethral sphincter were also seen in the proximal planes of the urogenital diaphragm. CONCLUSIONS: First, all the muscles of the urogenital diaphragm, including the external urethral sphincter, were present in the exstrophy bladder. Second, the perineal artery and its sphincteric branches were in the triangular space between the ischiocavernosus, bulbospongiosus, and superficial transverse perinei muscle. Finally, the dorsal penile artery ran along the inner edge of the ischiopubic ramus before lying on lateral aspect of the corpora. PMID- 21256553 TI - Comparison of a reduced radiation fluoroscopy protocol to conventional fluoroscopy during uncomplicated ureteroscopy. AB - OBJECTIVES: Although the long-term effects of radiation exposure are not completely predictable, the principle of keeping radiation exposure "as low as reasonably achievable" should be used. The purpose of this study was to compare fluoroscopy times before and after the implementation of a protocol designed to reduce fluoroscopy usage during ureteroscopy. METHODS: A retrospective review was conducted of 300 consecutive ureteroscopy patients at a single institution. Patients undergoing simple ureteroscopy without ancillary procedures or balloon dilation were further evaluated to determine the effect of a reduced fluoroscopy protocol. The protocol included several measures, including use of a laser-guided C-arm, use of a designated fluoroscopy technician and substitution of visual for fluoroscopic cues during ureteroscopy. Fluoroscopy times were compared between groups using a paired t test with P < .05 considered significant. RESULTS: Ureteroscopy cases before protocol implementation (n = 30) were compared with procedures after implementation (n = 30). Stone size and location were similar between groups. Protocol implementation significantly reduced the mean fluoroscopy exposure from 86.1 seconds (range 30-300) to 15.5 seconds (range 0 54; P < .001). There was no difference in mean operative time (74.2 vs 65.1 minutes; P = .14), or complications (2 patients vs 2 patients; P = 1) between groups. No complication in either group could be ascribed to the fluoroscopic technique. CONCLUSIONS: The reduced fluoroscopy protocol resulted in an 82% reduction in fluoroscopy time without altering patient outcomes. These simple radiation-reducing techniques add no technical difficulty and improve safety for the patient, surgeon, and operating room staff by lowering radiation exposure. PMID- 21256554 TI - Role of nitric oxide synthase in bladder pathologic remodeling and dysfunction resulting from partial outlet obstruction. AB - OBJECTIVES: To investigate the relationship between nitric oxide synthase (NOS) and oxidative stress and pathologic remodeling in the partial obstructed bladder of a rat model. METHODS: We surgically established partial bladder outlet obstruction (PBOO) in 2 groups of rats and allowed it to persist for 3-6 weeks. Normal and sham-operated rats served as the controls. Each group contained 6 rats for a total of 24 rats. Cystometry was used to evaluate the bladder function. The bladders were removed, and histopathologic measurements were performed to evaluate bladder hypertrophy and fibrosis and NOS immunolocalization. Biochemical measurements were used to evaluated NOS mRNA and activity and the oxidative stress level. RESULTS: The obstructed rats experienced significant increases in bladder weight, muscle hypertrophy, and deposits of collagen fibers compared with the normal and sham-operated groups. PBOO debilitated bladder contractibility, increased the residual urine volume and voiding interval, decreased the voiding volume, and caused poor bladder emptying, with an increased residual urine volume and decompensated bladder in the PBOO rats at 6 weeks. The elevation in malondialdehyde and reduction in superoxide dismutase activity in the PBOO rats suggested that oxidative stress injury occurred in the obstructed bladder. Lower inducible NOS and endothelial NOS (eNOS) mRNA expression was demonstrated through quantitative polymerase chain reaction. In particular, eNOS was significantly downregulated in the PBOO rats compared with the normal and sham-operated rats. The normal and PBOO bladder tissues did not express detectable levels of neuronal NOS mRNA or exhibit neuronal NOS immunoreactivity. The total NOS activity had decreased progressively in the PBOO groups in conjunction with the significantly decreased eNOS activity compared with that in the normal and sham-operated groups. CONCLUSIONS: These findings suggest that decreases in NOS activity and expression (mainly of eNOS) concomitant with increases in reactive oxygen species generation represent the underlying pathogenic mechanism of obstructed bladder remodeling and dysfunction. PMID- 21256555 TI - The face of testicular pain: a surprising ultrasound finding. AB - A scrotal ultrasound scan of a patient with a painful inflammatory mass surprisingly revealed a face in the image, which looked like a man experiencing painful stimuli. PMID- 21256556 TI - Ureteral stents do not cause bacterial infections in children after ureteral reimplantation. AB - OBJECTIVES: To determine, in a prospective study, the incidence of bacterial colonization and the risk of bacterial infection of indwelling double-J stents in children undergoing ureteral reimplantation. In a balance between the safety and comfort of the child, the need for postoperative stenting of the reimplanted ureters has been discussed. It is unknown whether an indwelling double-J stent after ureteral reimplantation would be a risk factor for postoperative urinary tract infection. METHODS: From 2005 to 2010, 209 children (138 girls and 71 boys; median age 3.8 years) with vesicoureteral reflux underwent unilateral or bilateral cross-trigonal ureteral reimplantation (352 ureters). All children received a single dose of gentamicin (2 mg/kg body weight) and a preoperative bladder rinse with 10% polividone-saline solution. A transurethral catheter was also left postoperatively for 2 (unilateral) or 3 (bilateral) days. The ureter was stented with a 8-22 cm multilength catheter. At 3 weeks postoperatively, the ureteral catheters were removed and investigated for bacterial colonization. RESULTS: Of the 209 children, 10 (4.8%) developed a urinary tract infection within the first 6 weeks after ureteral reimplantation. Of the remaining 199 children without any symptoms, 13 (6.5%) had a positive urine culture at removal of the catheters. Of the 199 children without any symptoms, 90 (45.2%) had a positive culture of one or more segments of the double-J catheter. CONCLUSIONS: Although the colonization rate of ureteral stents in our study was 42.9%, the rate of urinary tract infection during the first 6 weeks after ureteral reimplantation using indwelling ureteral stents was only 4.6%. We have concluded that the clinical significance of bacterial colonization of an indwelling ureteral stent is low, and therefore, ureteral stents can be used safely. PMID- 21256557 TI - Extended lymphadenectomy "step by step" in patients undergoing radical prostatectomy. AB - OBJECTIVES: To describe a surgical technique of pelvic lymph node dissection (PLND) in prostate cancer patients. The idea was to standardize the procedure of PLND and to increase the significance of lymphadenectomy as a part of radical prostatectomy (RP). The best ways to achieve this are (1) to describe the surgical procedure in detail, (2) to improve the knowledge of metastatic spread, and (3) to improve the management of complications. METHODS: One-hundred six patients with localized prostate carcinoma were treated with RP, including extended PLND. The number of removed lymph nodes (LNs) was correlated with histology and compared with that reported in the literature. Our aim was to observe technical differences that probably accrue in clinical outcomes. We proposed a conceptual schema of PLND. RESULTS: LN metastases were detected in 15 of 106 patients (14.15%). Positive sentinel LNs were detected in 11 of these 15 patients (73.3%). The average number of removed LNs was 20.5 (range +5). In 4 of 15 patients (26.5%), positive LNs were found in the fossa obturatoria; in 4 patients (26.5%) in the region of the external iliac artery; in 3 patients (20%) in the internal LN region; in 2 patients (13%) in the region of the common iliac artery; in 1 patient (7%) in the presciatic area; and in 1 patient (7%) in the sacral region. CONCLUSIONS: The standard routine was: (1) dissection of LN tissue along the common iliac artery, (2) dissection of LN tissue in the presciatic area, (3) dissection of LN tissue parasacral, and (4) peritoneal fenestration. PMID- 21256558 TI - Surgical repair of traumatic amputation of the glans. AB - Traumatic amputation of the penis in the pediatric population is rare. We present the case of a 4-year-old boy who, shortly after a plastibell circumcision, with the ring still in situ, experienced trauma to his glans, resulting in complete amputation. We describe our technique and outcome after surgical repair. PMID- 21256559 TI - Prenatal diagnosis of spontaneous bladder rupture in a female fetus. AB - Spontaneous bladder rupture is a rare condition, with diagnosis more rare in the prenatal than postnatal period. To our knowledge, there have been 7 cases of prenatally diagnosed bladder ruptures and all have been males. We report the first case of prenatal diagnosis of spontaneous bladder rupture in a female fetus. After a primary Cesarean-section birth, a tear in the newborn infant bladder dome was identified and repaired in 2 layers. The cause of the bladder rupture remains unknown. PMID- 21256561 TI - Reconstructive surgery for penoscrotal filarial lymphedema: a decade of experience and follow-up. AB - OBJECTIVES: To present our experience of reconstructive surgery in patients with penoscrotal filarial lymphedema. METHODS: From January 2000 to December 2009, we treated 48 patients with penile and penoscrotal filarial lymphedema using reconstructive surgery. Isolated penile involvement was seen in 14 patients, and 34 patients had penoscrotal involvement. All the patients had taken multiple courses of antifilarial drug before surgery. For isolated penile involvement, the diseased penile skin was excised and covered with a split-thickness skin graft. In some patients, the inner prepucial skin was preserved and used to cover the penile shaft. For those with penoscrotal involvement, scrotoplasty was performed, after excising the diseased scrotal skin and underlying soft tissue, while sparing the testes and spermatic cords. RESULTS: The mean patient age was 38 years (range 25-52), and the median follow-up time was 48 months (range 10-120). All 48 patients reported a satisfactory cosmetic appearance after the procedure and noted improvement in their ability to void while standing. Also, all of them could ambulate better and resumed sexual activity. Local groin infection was present in 12 patients; all were cured after proper management. CONCLUSIONS: In filarial lymphedema of penis and/or scrotum, excision of the diseased tissue and covering with a split-thickness skin graft provided good results. If the inner prepucial skin is healthy, it should be used to cover the distal penile shaft. If the scrotum is involved, scrotoplasty with lateral and posterior mobilized flaps provides satisfactory results. PMID- 21256560 TI - Effect of A 7-F transurethral catheter on abdominal leak point pressure measurement in men with post-prostatectomy incontinence. AB - OBJECTIVES: To assess the quantitative effect of the 7-F catheter on resultant abdominal leak point pressure (ALPP). The numerical value of ALPP in men with post-prostatectomy incontinence (PPI) may have some utility in directing therapy for this condition. Yet, no standardized method of calculating this value has been agreed upon. It has been suggested that the presence and size of the transurethral urodynamic catheter may affect ALPP. METHODS: A retrospective chart review of 20 consecutive men with symptomatic PPI was conducted. Multichannel video-urodynamics were performed using a 7-F transurethral catheter and a rectal catheter. The presence of sphincteric incontinence was elicited using the Valsalva maneuver and ALPP recorded from both vesical and rectal transducers. The transurethral catheter was then removed and ALPP repeated in the absence of a vesical transducer, permitting rectal transducer measurements only. Statistical analysis was performed using Wilcoxon signed-rank test. RESULTS: The mean age of this cohort was 66.4 years (range 54-78). All men showed a decrease in ALPP when performed without the urethral catheter. Mean ALPP with and without the transurethral catheter was 66.1 cm H(2)O (95% CI, 50.4-81.8 cm H(2)O) and 35.7 cm H(2)O (95% CI, 20.0-51.4 cm H(2)O), respectively (P <.01). A strong correlation between mean ALPP with and without the transurethral catheter was noted (r = .83). CONCLUSIONS: A 7-F transurethral catheter can affect absolute ALPP measurements in men with PPI. In this study, removal of the transurethral catheter resulted in a significant linear decline in ALPP. This finding may have clinical importance in centers where ALPP is used as a factor in determining therapy for PPI. ALPP standardization is needed. PMID- 21256562 TI - Tubeless percutaneous nephrolithotomy is associated with less pain and shorter hospitalization compared with standard or small bore drainage: a meta-analysis of randomized, controlled trials. AB - OBJECTIVES: To assess the efficacy and safety of tubeless percutaneous nephrolithotomy (PCNL) compared with standard or small-bore PCNL with a meta analysis of randomized, controlled trials. METHODS: All eligible studies were searched on MEDLINE, Embase, and the Cochrane Library databases. Risk ratio (RR), mean difference, or standardized mean difference (SMD), with its 95% CI, was used to evaluate the size effect. RESULTS: Ten and 3 trials were identified for comparison I (tubeless PCNL vs standard PCNL, 320 cases and 323 controls) and comparison II (tubeless PCNL vs small-bore PCNL, 55 cases and 54 controls), respectively. Tubeless PCNL required significantly less analgesia relative to standard PCNL (SMD -1.72; 95% CI -2.30 to 1.13; P(heterogeneity) = 0.04) and small-pore PCNL (SMD -0.69; 95% CI -1.13 to 2.05; P(heterogeneity) = 0.94). Furthermore, there was a remarkably shorter hospital stay in comparison I (SMD 1.35; 95% CI -1.40 to 1.30; P(heterogeneity) = 0.60) and comparison II (SMD 0.49; 95% CI -0.76 to 0.21; P(heterogeneity) = 0.15). The return to normal activity days was also significantly decreased in comparison I (SMD -4.34; 95% CI -6.28 to 2.41; P(heterogeneity) = 0.02). However, no significant difference was observed in the analyses concerning stone-free blood transfusion and complications rate in both comparisons. In subgroup analyses by nephrostomy diameter (22-Fr) and drainage methods, most results were consistent with the overall findings except for that to evaluate the operative time in the double-J stent subgroup. CONCLUSIONS: Tubeless PCNL is associated with less pain and quicker recovery compared with standard or small-bore PCNL, in the management of uncomplicated renal calculi. PMID- 21256563 TI - Surgery-related complications of robot-assisted radical cystectomy with intracorporeal urinary diversion. AB - OBJECTIVES: To assess the surgery-related complications at robot-assisted radical cystectomy with total intracorporeal urinary diversion during our learning curve in treating 45 patients with bladder cancer. METHODS: A total of 45 patients were pooled in 3 consecutive groups of 15 cases each to evaluate the complications according to the Clavien classification. As a surrogate for our learning curve, the following parameters were assessed: operative time, blood loss, urinary diversion type, lymph node yield, surgical margin status, and length of hospital stay. RESULTS: Early surgery-related complications were noted in 40% of the patients and late complications in 30%. The early Clavien grade III complications remained significant (27%) and did not decline with time. Overall, fewer complications were observed between the groups over time, with a significant decrease in late versus early complications (P = .005 and P = .058). The mean operative times declined from the first group to the second and third groups (P = .005) and the hospital stays shortened (P = .006). No significant difference was observed between groups regarding the lymph node yield at cystectomy (P = .108), with a mean of 22.5 nodes (range 10-52) removed. More patients received an orthotopic bladder substitute (Studer) in each of the latter 2 groups than in the first. CONCLUSIONS: Although robot-assisted radical cystectomy with total intracorporeal urinary diversion is a complex procedure, we observed decreased surgery-related complications and improved outcomes over time in the present series. Our results need to be confirmed by others before robot-assisted radical cystectomy with totally intracorporeal urinary diversion can be accepted as a treatment option for patients with bladder cancer. PMID- 21256564 TI - Robotic-assisted bladder diverticulectomy: tips and tricks. AB - INTRODUCTION: The da Vinci Surgical System has become extremely popular in the field of urology for procedures requiring complex reconstructive maneuvers, such as radical prostatectomy and pyeloplasty. A natural extension of these procedures is the use of the da Vinci system for complex urinary tract reconstruction deep in the pelvis, such as bladder diverticulectomy. TECHNICAL CONSIDERATIONS: In our report and accompanying Video, we have demonstrated some technical tips and tricks with regard to patient selection, preoperative imaging, patient positioning, port placement, intraoperative diverticulum recognition/excision, and cystotomy repair that the surgeon might find beneficial for successful completion of robotic-assisted bladder diverticulectomy. CONCLUSIONS: The tips and tricks we have presented might aid in the successful completion of robotic bladder diverticulectomy. PMID- 21256565 TI - Young age as favorable prognostic factor for cancer-specific survival in localized renal cell carcinoma. AB - OBJECTIVES: To evaluate the prognostic effect of age in patients with localized renal cell carcinoma (RCC) and investigate the incidence of Xp11 translocation RCC in young patients who developed recurrence. METHODS: From 1990 to 2007, 2403 Japanese patients underwent nephrectomy for presumed RCC at 9 institutions. Of those, 1143 patients had localized RCC (Stage pT1-2N0M0). Their clinical data were retrospectively reviewed. In the present study, 131 patients (11%) were considered young (<=45 years at diagnosis). In the young patients with recurrence, the nephrectomy specimens were immunostained with TFE3 to determine the incidence of Xp11 translocation RCC. RESULTS: During the median follow-up of 47 months, 3 cancer deaths (2.2%) occurred among young patients and 51 (5.0%) among older patients. The 5-year cancer-specific survival (CSS) rate was significantly better for the younger patients than for the older patients (P = .049). Multivariate analysis showed that age was significantly associated with CSS, as were the pathologic T stage, tumor grade, and symptoms at diagnosis. The hazard ratio of young age was 0.31 (95% confidence interval 0.077-0.87). The recurrence-free survival curves revealed no difference between these 2 groups. Of the 74 patients with recurrence, the CSS after recurrence was significantly better in the younger patients than in the older patients (P = .0010). Of the 8 young patients with recurrence, 4 had Xp11 translocation RCC, and 3 survived for >5 years after recurrence. CONCLUSIONS: Compared with the older patients, the young patients with RCC had similar recurrence-free survival rates but better CSS rates. This might have been because significant numbers of the young patients had Xp11 translocation RCC. PMID- 21256566 TI - Laparoscopic radiofrequency ablation of renal tumors: 32-month mean follow-up results of 106 patients. AB - OBJECTIVE: To report our experience of laparoscopic radiofrequency ablation (RFA) on patients with renal tumors. RFA has been increasingly applied in the management of small renal tumors. However, it was performed mostly via percutaneous approach, with limited cases and a short follow-up period. METHODS: From February 2006 to March 2008, laparoscopic RFA was performed on 106 renal tumors (size range: 0.9-5.5 cm) in 106 selected patients (74 men and 32 women, age range: 25-81 years). Initial contrast-enhanced computed tomography (CT) examination was performed seven days after the procedure, with subsequent CT assessment at three months, six months, and every six months thereafter. Serum creatinine measurement was conducted along with each time CT examination. RESULTS: The mean follow-up period was 32 months (range: 12-48). All 106 tumors were biopsied before RFA, of which 90 were diagnosed as renal cell carcinoma (RCC) (84.90%). There was one incomplete ablation. One case with radiographic local recurrence was then proved by pathologic analysis of the nephrectomy specimen to have no cancer cells. The local tumor control rate was 98.1% (104/106). Of the 90 RCC cases, the disease-free survival rate was 97.8% (88/90); both the cancer-specific and the overall survival rate were 100%. No death or renal failure after the procedure has yet been found. CONCLUSIONS: Our results showed that the laparoscopic RFA on small renal mass was safe, with outcomes of patients comparable with those by partial nephrectomy and percutaneous RFA. Further research and a longer follow-up period are needed to confirm our results. PMID- 21256567 TI - The long-term effect of alfuzosin in patients with lower urinary tract symptoms suggestive of benign prostate hyperplasia: evaluation of voiding and storage function with respect to bladder outlet obstruction grade and contractility. AB - OBJECTIVES: To evaluate the efficacy of alfuzosin treatment on voiding and storage in patients with lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) with respect to bladder outlet obstruction and contractility. METHODS: A 12-month, multicenter, observational, prospective study was conducted at four university hospitals in Korea. Patients were divided into four groups: group 1 (bladder outlet obstruction index (BOOI) >=20, bladder contractility index (BCI) >=100), group 2 (BOOI >=20, BCI <100), group 3 (BOOI <20, BCI >=100), and group 4 (BOOI <20, BCI <100), with respect to BOOI and BCI evaluated by pressure-flow study. Treatment efficacy was analyzed by validated symptom scores. RESULTS: Two-hundred thirty-two men with LUTS/BPH were enrolled, and 165 (41, 50, 30, and 44 in groups 1-4, respectively) were followed to the end of the study. After 12 months of alfuzosin treatment, all International Prostate Symptom Score (IPSS) parameters improved in all four groups. Mean improvement in IPSS subscore for voiding was 4.0 points in group 1, 5.5 points in group 2, 5.5 points in group 3, and 3.0 points in group 4. Change in IPSS subscore for storage was 2.5 points in group 1, 3.6 points in group 2, 2.9 points in group 3, and 1.8 points in group 4. There was no difference among four groups in improvements seen in storage or voiding IPSS subscore. International Continence Society male questionnaire scores significantly improved in all four groups with no between-group differences. CONCLUSIONS: Alfuzosin treatment in men with LUTS indicative of BPH effectively improved voiding and storage symptoms regardless of BOOI or BCI. PMID- 21256568 TI - Perioperative mortality is significantly greater in septuagenarian and octogenarian patients treated with radical cystectomy for urothelial carcinoma of the bladder. AB - OBJECTIVES: To revisit whether the perioperative mortality differs between septuagenarian and octogenarian patients and younger patients in a large contemporary population-based cohort. The data from tertiary care centers have suggested that perioperative mortality after radical cystectomy is not considerably different in septuagenarian or octogenarian patients compared with younger patients. However, population-based data have stated otherwise. METHODS: From 1988 to 2006, 12,722 radical cystectomies were performed for urothelial carcinoma of the urinary bladder in 17 Surveillance, Epidemiology, and End Results registries. Of those 12,722 patients, 4480 (35.2%) were aged 70-79 years and 1439 (11.3%) were aged >=80 years. Univariate and multivariate logistic regression models tested the 90-day mortality after radical cystectomy. Covariates consisted of sex, race, year of surgery, Surveillance, Epidemiology, and End Results registry, and histologic grade and stage. RESULTS: The overall 90 day mortality rate was 4% for the entire population, 2% for patients aged <=69 years, 5.4% for septuagenarian patients, and 9.2% for octogenarian patients. In the multivariate logistic regression analyses, septuagenarian (odds ratio 2.80; P < .001) and octogenarian (odds ratio 5.02; P < .001) age increased the risk of 90 day mortality after radical cystectomy. CONCLUSIONS: In the present population based analysis, the perioperative mortality after radical cystectomy was three- and fivefold greater in the septuagenarian and octogenarian patients, respectively, which was greater than that in tertiary care centers. This information should be included in informed consent considerations. PMID- 21256569 TI - Is percutaneous nephrolithotomy suitable for patients with scoliosis: single center experience. AB - OBJECTIVES: To present our experience with percutaneous nephrolithotomy (PCNL) for treating urolithiasis in patients with scoliosis. METHODS: We retrospectively reviewed the records of 5 patients with congenital scoliosis who had undergone PCNL. The demographic data, number and location of access sites, hemoglobin values, stone analyses, and complications were studied. Of the 5 patients, 3 had a history of failed shock wave lithotripsy, and 2 had undergone stone intervention in same kidney. All procedures were performed with the patient in the prone position after retrograde ureteral catheterization. Tract dilation was accomplished using Amplatz dilators of <=24F or 28F. PCNL was accomplished using a rigid nephroscope with ultrasound and/or pneumatic lithotriptor with the patient under general anesthesia. RESULTS: Of the 5 patients, 2 were men and 3 were women, and the mean age was 36.8 years (range 32-44), and the mean stone burden was 475 mm2 (range 400-1350). The mean operative and fluoroscopic screening time was 62.2 minutes (range 50-90) and 3.1 minutes (range 2-5), respectively. Of the 5 patients, 3 were stone free after PCNL. Auxiliary procedures were required in 2 patients and included second-look PCNL in 1 and ureteroscopy in 1. Thus, all 5 patients were rendered completely stone free after the final procedure. No severe complications, either from anesthesia or the surgical procedure, were observed in the patients. Two of the patients had to stay for 24 hours to screen for pulmonary and cardiac signs in the intensive care unit after PCNL. CONCLUSIONS: Larger stones or shock wave lithotripsy-refractory stones can be managed safely and effectively with PCNL in patients with scoliosis when they have been appropriately assessed before PCNL. PMID- 21256570 TI - Urologist practice styles in the initial evaluation of elderly men with benign prostatic hyperplasia. AB - OBJECTIVES: To investigate the degree to which expenditures on symptom evaluations vary among urologists and the factors associated with such variation. As the medical and surgical specialists for men with lower urinary tract symptoms (LUTS), urologists provide testing to evaluate symptoms and determine therapy. METHODS: We developed a cohort of men with an initial urologist visit for benign prostatic hyperplasia (BPH) from a 5% sample of Medicare patients (1999-2007) and established a physician level factor, practice style, as a function of average per patient expenditures. We then determined which AUA BPH guideline elements explained variation in quantity and expenditures for BPH testing, and also examined the impact of patient and physician factors on practice style. RESULTS: A nearly 15-fold variation in urologists' average per-patient expenditures existed ($35 to $527 per month; Median $92). Practice styles were associated with physician (P < .01 all examined variables) and patient (P < .01 for comorbidity, race/ethnicity, and socioeconomic status) factors. Guideline recommended care was provided at lower rates by the lowest expenditure urologists compared with middle to highest-intensity urologists (P < .01). Practice style variations were attributable mainly to differences in tests characterized by the guidelines as optional and not-recommended (P < .01). CONCLUSIONS: Expenditures for BPH evaluations vary substantially by geography, practice setting, and experience and are accounted for largely by differences in the use of optional and not-routinely recommended tests. Greater standardization could enhance patient care and reduce health care costs. PMID- 21256571 TI - National community prevalence of overactive bladder in the United States stratified by sex and age. AB - OBJECTIVE: To estimate the prevalence of and bother associated with overactive bladder (OAB) in adults aged >=40 years in the United States, using current International Continence Society definitions. METHODS: Internet-based panel members were selected randomly to participate in EpiLUTS, a cross-sectional, population-representative survey. Participants used Likert scales to rate how often they experienced individual lower urinary tract symptoms during the previous 4 weeks and how much bother they experienced. Based on responses to questions regarding urgency and urgency urinary incontinence, OAB symptoms were categorized as occurring at least "sometimes" or at least "often." Symptom bother was categorized as at least "somewhat" or at least "quite a bit." RESULTS: The response rate was 59.6%, with a final sample of 9416 men and 10,584 women. Prevalence of OAB symptoms at least "sometimes" was 27.2% and 43.1% for men and women, respectively; prevalence of OAB at least "often" was 15.8% and 32.6%, respectively. Among men with OAB symptoms at least "sometimes," 60.0% were bothered at least "somewhat" and 27.8% were bothered at least "quite a bit." Among women, bother rates were 67.6% and 38.9%, respectively. Among respondents with OAB at least "often," 67.8% and 38.2% of men and 73.0% and 47.1% of women reported being bothered at least "somewhat" and at least "quite a bit," respectively. We estimate that 29.8 million adults aged >=40 years in the United States have bothersome OAB symptoms. CONCLUSIONS: Bothersome OAB symptoms are highly prevalent among men and women aged >=40 years in the United States. PMID- 21256572 TI - Comparison of effects of alpha receptor blockers on endothelial functions and coagulation parameters in patients with benign prostatic hyperplasia. AB - OBJECTIVE: To investigate the effects of alpha receptor blockers used in the treatment of benign prostatic hyperplasia (BPH) on endothelial functions, coagulation parameters, and arterial blood pressure. MATERIALS AND METHODS: One hundred fifteen patients admitted to the treatment protocol because of symptomatic BPH were included in this prospective study. Patients were given the following treatments: doxazosin 4 mg/d (n = 25), terazosin 5 mg/d (n = 26), alfuzosin 10 mg/d (n = 26), tamsulosin 0.4 mg/d (n = 21), and observation (n = 17). All cases were evaluated before treatment and in the 12th week of treatment, according to biochemical parameters, endothelial functions, and arterial blood pressure. Biochemical parameters were bleeding time, coagulation time, prothrombin time, activated partial thromboplastin time, total prostate-specific antigen (PSA), and free PSA. Endothelial functions were evaluated with ultrasonography of the brachial artery. RESULTS: When coagulation tests were evaluated, there were significant increases in bleeding and coagulation times in the groups using doxazosin and terazosin. Doxazosin and terazosin lowered arterial blood pressure significantly compared with other treatments. With regard to effects on endothelial function, there were significant differences in flow mediated dilation rates of the brachial artery at 60 and 90 seconds before and during treatment in the alfuzosin and terazosin groups. CONCLUSIONS: Alpha receptor blockers can decrease the risk of cardiovascular complications by both reducing platelet aggregation and protecting endothelial functions in patients with prostatic hyperplasia. The only drug with a favorable effect in all 4 areas of interest, including BPH symptoms, blood pressure, platelet aggregation, and endothelial functions, was terazosin. PMID- 21256573 TI - Ovarian pathology for the pediatric urologist. AB - OBJECTIVES: To report the breadth of ovarian conditions that pediatric urologists may encounter through diverse referral patterns. METHODS: Two regional pediatric centers reviewed cases from 2000 to 2010, yielding 13 females with gonad-related conditions. RESULTS: Six of 13 patients (46%) were referred for a presumed urological condition that was later discovered to be of ovarian origin or were already known to the urology clinic for a congenital urological anomaly. Six patients had tumor markers drawn, all of which were normal. Median age was 11.2 years. The most common presenting symptoms were pain (6/13), emesis (5/13), and precocious puberty (2/13). Median mass diameter was 7.5 cm with 2 patients having masses greater than 20 cm. Histologic diagnosis was mature teratoma (4/13), streak gonad (3/13), and hemorrhagic cyst (2/13). Two patients had potentially malignant tumors (immature teratoma and juvenile granulosa cell tumor). CONCLUSIONS: At our centers, an ovarian condition is encountered an average of 1.3 times per year. As management of pediatric ovarian cysts and masses is controversial, pediatric urologists should be familiar with the diagnosis and treatment of such conditions. PMID- 21256574 TI - Recurrent urinary retention due to imperforate hymen after hymenotomy failure: a rare case report and review of the literature. AB - Acute urinary retention (AUR) is unusual in children. We report for the first time a case of recurrent urinary retention due to massive hematocolpos resulting from an imperforate hymen in a 14-year-old girl. In case of AUR in adolescent girls, clinicians should keep in mind that imperforate hymen may be a causative factor and this condition may easily be treated surgically, but follow-up is still necessary to ensure that there is no recurrence. PMID- 21256575 TI - An assessment of new sperm tests for male infertility. AB - The routine semen analysis, although used for more than 50 years, fails to accurately distinguish between fertile and infertile men. As a consequence, many tests of sperm function (TSF) have been developed. This review discusses both older and newer diagnostic TSF. It outlines the principles underlying each assay and reviews aggregate clinical data to determine its current relevance and utility. It concludes that the relevance of many older TSF is questionable, with the wide acceptance of intracytoplasmic sperm injection (ICSI). Newer TSF have the potential to deliver more clinically relevant information but require more extensive study to better understand their predictive role in the ICSI era. PMID- 21256576 TI - Secondary endoscopic pyelotomy in children with failed pyeloplasty. AB - OBJECTIVES: To assess the results of secondary endopyelotomies (SEP) that were performed in our center in children who had earlier failed pyeloplasty. METHODS: Eleven secondary endopyelotomies were done between 2005 and 2010 in 10 patients (5 boys and 5 girls, mean age 6.8 years), with a follow-up time of >6 months. The primary procedure was an open/laparoscopic pyeloplasty (n = 10) or a ureterocalicostomy (n = 1). In all cases, endopyelotomy was done by means of a monopolar electrocautery hook using the standard pediatric resectoscope. In 10 patients, SEP was done percutaneously, and in 1 patient it was done in a retrograde fashion. The mean operation time was 69 minutes. RESULTS: After a mean follow-up of 20 months, 70% of patients were free of complaints (n = 7), which was defined as a resolution of complaints, resolution of hydronephrosis, and improvement of renal wash-out curve and function. In 4 renal units, reintervention had to be considered; in one of these, a re-pyeloplasty has already been performed. The mean postoperative hospital stay was 2.8 days. No intraoperative complications occurred. In 1 patient, postoperative leakage around the nephrostomy drain occurred but resolved spontaneously. CONCLUSIONS: SEP is a fairly safe method to treat recurrent ureteropelvic junction-stenosis after failed pyeloplasty in children. However, because it seems to be less affective than the open redo pyeloplasty, it cannot be considered as a gold standard procedure and as such should be thoroughly discussed with the patient and parents. PMID- 21256577 TI - Utility of a modality combining FISH and cytology in upper tract urothelial carcinoma detection in voided urine samples of Chinese patients. AB - OBJECTIVES: To evaluate a combined analysis approach that involves cytologic evaluation and fluorescence in situ hybridization analysis (FISH) for detecting urothelial carcinoma (UC) in the upper tract (UT). METHODS: By refining the UroVysion positive criteria, an analyzing modality (Cyto-FISH) combined urine cytology and FISH analysis (UroVysion probe set) was introduced and urine specimens from 71 patients with UT-UC and 45 controls were analyzed. Sensitivity and specificity of urine cytology, FISH, and Cyto-FISH were determined and compared, respectively. The features of chromosomal aberrations of malignant cells from UT-UC were also determined. RESULTS: Overall sensitivity of verified UT-UC by Cyto-FISH analysis was sharply higher than the single value for urine cytology (85.9% vs 45.1%, P <.001) and was slightly higher than FISH (85.9% vs 78.9%, P = .378). Sensitivities of cytology and Cyto-FISH by grade were 28.2% vs 74.4% for low-grade (P <.001), and 65.6% vs 96.9% for high-grade tumors (P = .003), respectively. The advantage maintains stably not only in the detection of nonmuscle-invasive tumors but in invasive tumors between cytology and Cyto-FISH (39.1% vs 76.1%, P = .001, and 53.8% vs 100%, P <.001, respectively). Specificities were 97.8%. In addition, polysomic chromosomal aberrations of the UT-UC cases could present a possible trend toward greater chromosome increased with tumor grades and progressive stages of invasion. CONCLUSIONS: Our results have shown that Cyto-FISH analysis for the presence of UC cells is a powerful tool, providing high sensitivity and specificity, and may offer a new scheme for the tough UT-UC diagnosis. PMID- 21256578 TI - Candidate molecule for premature ejaculation, DA-8031: in vivo and in vitro characterization of DA-8031. AB - OBJECTIVES: To evaluate the efficacy of DA-8031 against premature ejaculation, we performed in vitro and in vivo pharmacologic studies. METHODS: We used a monoamine transporter binding affinity assay, receptor binding affinity assay, monoamine reuptake inhibition assay, and serotonin uptake inhibition assay in platelets and chemically induced ejaculation models in rats. RESULTS: The present study reports on the pharmacologic profile of the putative antipremature ejaculation drug, DA-8031. DA-8031 exhibits high affinity and selectivity to the serotonin transporter (Ki value 1.94 nM for 5-hydroxytryptamine transporter, 22 020 nM for norepinephrine transporter, and 77 679 nM for dopamine transporter) and potency to inhibit serotonin reuptake into the rat brain synaptosome in vitro (half maximal inhibitory concentration 6.52 nM for 5-hydroxytryptamine, 30.2 MUM for norepinephrine, and 136.9 MUM for dopamine). In the platelet serotonin uptake study, DA-8031 exhibited significant inhibition at oral doses of 10 and 30 mg/kg in a dose-dependent manner. In the sexual response studies, after oral and intravenous administration of DA-8031, ejaculation was significantly inhibited in both para-chloroamphetamine- and meta-chlorophenylpiperazine-mediated ejaculation models in rats. CONCLUSIONS: The pharmacologic profiles observed in the present study suggest the potential for DA-8031 as a therapeutic agent useful in the treatment of premature ejaculation. PMID- 21256579 TI - Survival and reproductive outcomes in women treated for malignant ovarian germ cell tumors. AB - OBJECTIVE: The objective of this study is to review all malignant germ-cell tumors (MOGCTs) treated at our institution, focusing on reproductive outcomes and menstrual function of patients treated with fertility-sparing surgery and adjuvant chemotherapy. METHODS: We performed a retrospective chart review of patients treated for MOGCTs between January 1, 1979 and March 31, 2008. Charts of identified patients were abstracted and data were collected. Patients who had fertility-sparing surgery were contacted and a telephone questionnaire was performed to gather reproductive and menstrual history. RESULTS: Forty patients were treated for MOGCTs at our institution. Mean age at the time of diagnosis was 26.5years (range, 10-48years). Histologic subtypes were: immature teratoma (52.5%), dysgerminoma (27.5%), yolk sac tumor (10.0%), mixed germ cell tumor (7.5%), and choriocarcinoma (2.5%). Thirty-five percent of tumors were FIGO stages II-IV. Twenty-seven patients (67.5%) were treated with chemotherapy postoperatively, 23 (85%) of whom received bleomycin, etoposide and cisplatin (BEP). There were three recurrences, but no deaths. Fertility-sparing surgery was performed in 22 patients (55%), 16 of whom received adjuvant chemotherapy. Fourteen of these patients were contacted. Of the 10 remaining patients desiring pregnancy, 8 (80%) had 11 successful spontaneous pregnancies, one required in vitro fertilization, and the other required donor egg in-vitro fertilization, resulting in 14 live births. All 14 patients had normal menstrual cycles within one year of completing chemotherapy. CONCLUSIONS: Overall survival was 100% among patients with both local and advanced MOGCTs, including those who underwent fertility-sparing surgery. Fertility-sparing surgery plus adjuvant chemotherapy appeared to have little or no effect on fertility or menstrual cycles. PMID- 21256580 TI - Pelvic exenteration in the age of modern chemoradiation. AB - BACKGROUND: To examine outcomes after pelvic exenteration in women treated with modern chemoradiation and surgical techniques. METHODS: All patients at our institution with a diagnosis of gynecologic malignancy who underwent pelvic exenteration after treatment with chemoradiation between 1/90 and 6/08 were evaluated with a retrospective chart review. RESULTS: 44 women were identified, of whom 29 (66%) had cervical, 6 (14%) had uterine, 5 (11%) had vaginal, and 4 (9%) had vulvar cancer. The majority of patients (82%) were initially treated with external beam whole-pelvic radiation with concurrent cisplatin. 38 patients (86%) underwent exenteration for a central pelvic recurrence, and the remaining 6 patients (14%) for radiation necrosis. The most common surgical complication was transfusion requirement in 36 patients (82%), followed by wound infection in 15 (34%), small bowel obstruction in 8 (18%), and sepsis in 6 (14%). The median time spent in the ICU post-operatively was 2 days. One patient (2%) died during her post-operative hospital stay. The mean EBL overall was 2497 cc and the mean operative time was 544 min. Use of electrothermal bipolar coagulation, which was used in 64% of the exenterations, significantly reduced blood loss (3679 cc vs. 1836 cc, p=0.014). After exenteration, 21 patients (48%) were diagnosed with a recurrence of cancer, and the mean progression free survival was 31 months. Patients who received exenteration less than 2 years after their initial chemoradiation had a significantly shorter overall survival time (8 months vs. 33 months, p=0.016). CONCLUSIONS: Approximately 50% of women develop recurrence following exenterations done after chemoradiation. Survival is significantly longer in patients who necessitate exenteration greater than 2 years out from initial treatment. Electrothermal bipolar coagulation appears to significantly reduce blood loss during these surgeries. PMID- 21256581 TI - Surgical staging of early stage epithelial ovarian cancer: results from the CDC NPCR ovarian patterns of care study. AB - OBJECTIVES: The objectives of this study were to determine the adequacy of surgical staging performed on surgically treated epithelial ovarian cancer (EOC) patients with apparent early stage disease and to determine if receipt of surgical staging had an influence on survival. METHODS: Detailed surgical staging information was collected from medical records for 721 patients diagnosed between 1998 and 2000 with EOC. Patients resided in California or New York and were identified through population-based cancer registries. RESULTS: Nearly 90% of patients had removal of the omentum and evaluation of bowel serosa and mesentery but only 72% had assessment of retroperitoneal lymph nodes and the majority of patients did not receive biopsies of other peritoneal locations. Only lymph node assessment (as well as node assessment combined with washings and omentectomy) had a statistically significant association with improved survival. The 5-year survival for women with node sampling was 84.2% versus 69.6% for those without this surgical procedure, and patients who did not have lymph node assessment had nearly twice the risk of death as those who did. When patients were stratified by receipt of chemotherapy, lack of node sampling had an effect only on patients who also had no chemotherapy (adjusted HR=2.2, CI=1.0-4.5). CONCLUSIONS: The results of this population-based study confirm the prognostic importance of surgical staging for women with EOC, and the important role of gynecologic oncologists in treating these patients. Adjuvant chemotherapy does not appear to further improve survival for those women who receive adequate surgical staging. PMID- 21256583 TI - Folate mediated l-arginine modified oligo (alkylaminosiloxane) graft poly (ethyleneimine) for tumor targeted gene delivery. AB - Folate receptor mediated gene targeting provides several advantages such as delivery of high concentration of gene at specific tumor sites including brain, lung, ovary, uterus and kidney where folate receptors are over expressed. In the present study for both systemic stability and tumor targeting ability, poly (ethylene glycol)-folic acid (PEG-FA) conjugate was coupled with an arginine modified oligo (alkylaminosiloxane) graft poly (ethyleneimine) having enhanced transfection efficiency compared to poly (ethyleneimine). The resultant polymer P(SiDAAr)5FP2 complexed pDNA effectively and showed protection against nuclease degradation. The PEG group provided improved blood compatibility and cell viability. Uniformly oriented arginine moiety helped to enhance cellular and nuclear localisation, which led to improved transfection. The polymer was capable of releasing pDNA at the nucleus and being cleared from the cell after its purpose. Transfection in presence of cellular uptake inhibitors showed multiple pathways for cellular uptake of the targeted polymer, out of which folate receptor mediated uptake was more prominent. The folate mediated cellular uptake of P(SiDAAr)5FP2 was then confirmed by flow cytometric evaluation. The high accumulation of targeted polymers in the tumor tissues of tumor bearing mice from 2nd hour onwards proved the active targeting effect of the polymer. Besides tumor accumulation, the material showed capability to diffuse through the vascular endothelium. This property is expected to be beneficial for brain targeting experiments. PMID- 21256582 TI - Conduction aphasia, sensory-motor integration, and phonological short-term memory - an aggregate analysis of lesion and fMRI data. AB - Conduction aphasia is a language disorder characterized by frequent speech errors, impaired verbatim repetition, a deficit in phonological short-term memory, and naming difficulties in the presence of otherwise fluent and grammatical speech output. While traditional models of conduction aphasia have typically implicated white matter pathways, recent advances in lesions reconstruction methodology applied to groups of patients have implicated left temporoparietal zones. Parallel work using functional magnetic resonance imaging (fMRI) has pinpointed a region in the posterior most portion of the left planum temporale, area Spt, which is critical for phonological working memory. Here we show that the region of maximal lesion overlap in a sample of 14 patients with conduction aphasia perfectly circumscribes area Spt, as defined in an aggregate fMRI analysis of 105 subjects performing a phonological working memory task. We provide a review of the evidence supporting the idea that Spt is an interface site for the integration of sensory and vocal tract-related motor representations of complex sound sequences, such as speech and music and show how the symptoms of conduction aphasia can be explained by damage to this system. PMID- 21256584 TI - Multifunctional Pluronic P123/F127 mixed polymeric micelles loaded with paclitaxel for the treatment of multidrug resistant tumors. AB - The aim of this study was to exploit the possibility of combination of active targeting function of folic acid by folate receptor-mediated endocytosis and overcoming multidrug resistance (MDR) by Pluronic block copolymers to promote drug delivery to MDR tumor following intravenous administration with paclitaxel (PTX) as model drug. Folic acid functionalized Pluronic P123/F127 mixed micelles encapsulating PTX (FPF-PTX) was firstly developed and tested in vitro and in vivo, while PTX-loaded Pluronic P123/F127 mixed micelles (PF-PTX) and Taxol were used as control. FPF-PTX was about 20 nm in diameter with spherical shape and high encapsulation efficiency. Cellular uptake of FPF-PTX was found to be higher than that of PF-PTX due to the folate receptor-mediated endocytosis effect. In vitro cytotoxicity, cell apoptosis and cell cycle arrest studies also revealed that FPF-PTX was more potent than those of PF-PTX and Taxol. In vivo pharmacokinetic study in rats showed that the polymeric micelles significantly enhanced the bioavailability of PTX (~3 fold) than Taxol. Moreover, in BALB/c mice bearing KBv MDR tumor xenografts, stronger antitumor efficacy was shown in FPF-PTX group, with good correlation between in vitro and in vivo. In conclusion, folate-conjugated Pluronic micelles could be a potential vehicle for delivering hydrophobic chemotherapeutic drugs to MDR tumors. PMID- 21256585 TI - A graphene functionalized electrochemical aptasensor for selective label-free detection of cancer cells. AB - Here we report an electrochemical sensor that can realize label-free cancer cell detection using the first clinical trial II used aptamer AS1411 and functionalized graphene. By taking advantages of AS1411 high binding affinity and specificity to the overexpressed nucleolin on the cancer cell surface, our developed electrochemical aptasensor can distinguish cancer cells and normal ones and detect as low as one thousand cells. With DNA hybridization technique, this E DNA sensor can be regenerated and reusable for cancer cell detection. Our work gives a good example for label-free cancer cell detection based on aptamer and graphene-modified electrode. PMID- 21256586 TI - The glucose-lowering potential of exendin-4 orally delivered via a pH-sensitive nanoparticle vehicle and effects on subsequent insulin secretion in vivo. AB - Exendin-4 is a potent insulinotropic agent in diabetes patients; however, its therapeutic utility is limited due to the frequent injections required. In this study, an orally available exendin-4 formulation, using an enteric-coated capsule containing pH-responsive NPs, was developed. Following oral administration of (123)I-labeled-exendin-4 loaded NPs in rats, the biodistribution of the administered drug was investigated using a dual isotope dynamic SPECT/CT scanner. The results showed that the radioactivity of (123)I-exendin-4 propagated from the esophagus, stomach, and small intestine and then was absorbed into the systemic circulation; with time progressing, (123)I-exendin-4 was metabolized and excreted into the urinary bladder. In the in vivo dissolution study, it was found that the enteric-coated capsule remained intact while in the stomach; the capsule was completely dissolved in the proximal segment of the small intestine and the loaded contents were then released. Oral administration of the capsule containing exendin-4 loaded NPs showed a maximum plasma concentration at 5 h after treatment; the bioavailability, relative to its subcutaneous counterpart, was found to be 14.0 +/- 1.8%. The absorbed exendin-4 could then stimulate the insulin secretion and provide a prolonged glucose-lowering effect. The aforementioned results suggest that the orally available exendin-4 formulation developed warrants further exploration as a potential therapy for diabetic patients. PMID- 21256587 TI - Multifunctional gadolinium-based dendritic macromolecules as liver targeting imaging probes. AB - The quest for highly efficient and safe contrast agents has become the key factor for successful application of magnetic resonance imaging (MRI). The gadolinium (Gd) based dendritic macromolecules, with precise and tunable nanoscopic sizes, are excellent candidates as multivalent MRI probes. In this paper, a novel series of Gd-based multifunctional peptide dendritic probes (generation 2, 3, and 4) possessing highly controlled structures and single molecular weight were designed and prepared as liver MRI probes. These macromolecular Gd-ligand agents exhibited up to 3-fold increase in T(1) relaxivity comparing to Gd-DTPA complexes. No obvious in vitro cytotoxicity was observed from the measured concentrations. These dendritic probes were further functionalized with multiple galactosyl moieties and led to much higher cell uptake in vitro as demonstrated in T(1) weighted scans. During in vivo animal studies, the probes provided better signal intensity (SI) enhancement in mouse liver, especially at 60 min post-injection, with the most efficient enhancement from the galactosyl moiety decorated third generation dendrimer. The imaging results were verified with analysis of Gd content in liver tissues. The design strategy of multifunctional Gd-ligand peptide dendritic macromolecules in this study may be used for developing other sensitive MRI probes with targeting capability. PMID- 21256588 TI - Review: Genetic manipulation of the rodent placenta. AB - The principal role of the placenta is the maintenance of pregnancy and promotion of fetal growth and viability. The use of transgenic rodents has greatly enhanced our understanding of placental development and function. However, embryonic lethality is often a confounding variable in determining whether a genetic modification adversely affected placental development. In these cases, it is beneficial to specifically manipulate the placental genome. The purpose of this review is to summarize available methodologies for specific genetic modification of the rodent placenta. By restricting genetic alterations to the trophoblast lineage, it is possible to gain a deeper understanding of placental development that perhaps will lead to gene-targeted therapies to rescue irregular placentation in transgenic animals or in women at high-risk for placenta associated pregnancy complications. PMID- 21256590 TI - Prevalence and clinical characteristics of N-terminally truncated WT1 expression in acute myeloid leukemia. AB - Overexpression of the Wilms' tumor gene 1 (WT1) was observed in most leukemia cells. In addition to four major isoforms of WT1, an N-terminally truncated isoforms (sWT1) has been identified. We separately quantified the transcript levels of sWT1 and full-length WT1 (fWT1) in 237 patients with acute myeloid leukemia (AML). sWT1 expression was observed in 45 of 237 (19.0%) AML patients, particularly in acute promyelocytic leukemia (59.3%). Although sWT1 expression was not associated with other genetic mutations and prognosis, fWT1 expression level in sWT1-expressing AML was significantly higher than that in un-expressing AML. These results suggested the possible cooperation of sWT1 and fWT1 in the pathophysiology of AML, while further analysis is required. PMID- 21256589 TI - Urocortins are present in the rat testis. AB - The synthesis and release of testosterone (T) depends both on circulating luteinizing hormone (LH) and on an array of testicular factors whose role remains incompletely understood. Corticotropin-releasing factor (CRF) had been reported in the rat testes, where it was thought to inhibit T secretion. However, the discovery that the CRF-related peptides urocortins (Ucns), of which there are currently three subtypes (Ucn 1, 2 and 3), cross-react with many reagents previously used to detect CRF, has cast doubt on this concept. Here we show that while CRF was readily measurable in rat hypothalami (which served as controls), signals for this peptide were barely detectable in total RNA extracted from the testes. On the other hand, microarray, RT-PCR and real-time quantitative RT-PCR (qRT-PCR) analyses all indicated strong signals for Ucn 1 in the male gonads, with weaker levels of Ucn 2 and 3 mRNA gene expression. Results obtained for Ucn 1 gene expression were corroborated by immunohistochemical detection, which appeared restricted to Leydig cells. Finally, to investigate possible changes in testicular Ucn 1 levels induced by homeostatic challenges, we measured them in rats exposed to alcohol. We observed that indeed, the intragastric injection of this drug significantly increased testicular Ucn 1, but not Ucn 2, Ucn 3, CRF, CRFR1 or CRFR2 mRNA levels. Collectively, these results provide novel information regarding the presence of CRF-like peptides in the adult male rat testis. PMID- 21256591 TI - Sublethal toxic effects in a generic aquatic ecosystem. AB - The dynamical behaviour of an aquatic ecosystem stressed by limiting nutrients and exposure to a conservative toxicant is investigated. The ecosystem downstream of a pollution source consists of: nutrients, biotic pelagic and benthic communities, and detritus pools in the water body and on the sediment. The long term dynamic behaviour of this system is analysed using bifurcation theory. A reference state is defined and our aim is to quantify the effects of toxicological (toxic exposure), ecological (feeding, predation, competition) and environmental stressors (nutrient supply, dilution rate). To that end we calculate the ranges of stress levels where the long-term dynamics (equilibrium, oscillatory or chaotic behaviour) is qualitatively the same. In this way we obtain levels of toxicological loading where the abundances of all populations are the same as in the reference case, the no-effect region. We will also calculate toxic exposure levels that do not lead to a change in the composition of the ecosystem, and therefore its structure, with respect to the reference unexposed situation, but where population abundances and internal toxicant concentrations may have been changed quantitatively. The model predicts that due to indirect effects even low sublethal toxic exposure can lead to catastrophic changes in the ecosystem functioning and structure, and that the long-term sensitivities of oligotrophic and eutrophic systems to toxic stress are different. PMID- 21256592 TI - Conducting evaluation in contested terrain: challenges, methodology and approach in an American context. AB - Using case examples, the author describes circumstances under which violence and conflict, overt and covert, have impinged on his evaluation field work. When fear is pervasive, it constrains people's ability and willingness to participate in an evaluation and their candor if they do. It can also be dangerous. Safety and well being of participants and researchers in his view take priority over the evaluation's goals. Evaluation involving people who are survivors of violence, torture and conflict requires special sensitivity and examples are offered of appropriate methodologies. Stakeholders in evaluations presumably have beneficent interest in a program's success. However in conflict situations 'malevolent' stakeholders, who standing to gain from a project's failure, will actively try to thwart it. Undermining the evaluation as well and impugning the evaluator's objectivity, skill, knowledge and credibility are among the tactics they employ. Evaluators are urged to stay attuned to field conditions, consider alternative methods and locations for collecting data and be self-conscious and deliberate about how their study and role are defined and understood by contending parties. PMID- 21256593 TI - Three-dimensional rotational angiography in the assessment of the angioarchitecture of brain arteriovenous malformations. AB - BACKGROUND AND PURPOSE: The angioarchitecture of brain arteriovenous malformations (BAVM) still remains a complex subject of study despite advances in medical imaging techniques. For this reason, the present study aimed to assess whether or not 3D rotational angiography (3DXA) might improve the assessment of BAVM. PATIENTS AND METHODS: Included prospectively were 72 patients who had undergone conventional digital subtraction angiography (DSA) and 3DXA for pretherapeutic assessment of BAVM prior to radiosurgery. Dimensional criteria, arterial-feed patterns, venous drainage, points of weakness and vascular densities (VD) of the nidus and shunt zone were studied. RESULTS: 3DXA detected all arteriovenous shunts by revealing abnormal venous enhancement. Post processing tools similar to CT and MRI may also be used to make complex 3D reconstructions. In addition, the technique provided significant help for volumetric estimations, extraction of arterial feeders and origins of draining veins, and analysis of the 3D conformation of the nidus. Furthermore, 3DXA detected significantly more points of weakness, such as intranidus aneurysms and venous anomalies (P<0.005). In 65% of cases, a gradient of vascular enhancement intensity was found between the arteries and draining veins surrounding or comprising the nidus. VD, or the percentages of space occupied by the enhanced vascular elements, was evaluated in both the nidus and shunt zone. VD in the shunt zone was highest in untreated patients with no history of bleeding (P<0.005). CONCLUSION: 3DXA offers a useful approach to BAVM exploration and can improve our knowledge of lesional angioarchitecture, necessary for the planning of therapeutic strategies. PMID- 21256594 TI - A first evaluation of the usefulness of feathers of nestling predatory birds for non-destructive biomonitoring of persistent organic pollutants. AB - In previous studies, feathers of adult predatory birds have been evaluated as valid non-destructive biomonitor matrices for persistent organic pollutants (POPs). In this study, we assessed for the first time the usefulness of nestling raptor feathers for non-destructive biomonitoring of POPs. For this purpose, we collected body feathers and blood of nestlings from three avian top predators from northern Norway: northern goshawks (Accipiter gentilis), white-tailed eagles (Haliaeetus albicilla) and golden eagles (Aquila chrysaetos). We were able to detect a broad spectrum of legacy POPs in the nestling feathers of all three species (Sigma PCBs: 6.78-140ng g(-1); DDE: 3.15-145ng g(-1); Sigma PBDEs: 0.538 7.56ng g(-1)). However, these concentrations were lower compared to other studies on raptor species, probably due to the aspect of monitoring of nestlings instead of adults. Besides their analytical suitability, nestling feathers also appear to be biologically informative: concentrations of most POPs in nestling feathers showed strong and significant correlations with blood plasma concentrations in all species (p<0.050; 0.7751*10(-6)) for preschool children. PMID- 21256596 TI - Impact of methionine oxidation in human IgG1 Fc on serum half-life of monoclonal antibodies. AB - IgG monoclonal antibodies (mAbs) consist of two Fab fragments and one Fc fragment. The Fab fragments contain the variable regions and are responsible for drug specificity (via antigen binding); the Fc fragment contains constant regions and is responsible for effector functions (via interactions with Fcgamma receptors) and extended serum half-life (via interaction with the neonatal Fc receptor, FcRn). There are two conserved methionine (Met) residues located in the FcRn binding site of the Fc fragment. It has been shown previously that oxidation of these two Met residues decreases the binding affinity to FcRn. We have further evaluated the impact of Met oxidation on serum half-lives of two humanized IgG1 mAbs in transgenic mice with human FcRn. Variable oxidation levels were obtained by several procedures: exposure to an oxidizing agent, accumulation during extended refrigerated storage, or chromatographic separation. Our results show that Met oxidation can result in a significant reduction of the serum circulation half-life and the magnitude of the change correlates well with the extent of Met oxidation and changes in FcRn binding affinities. The relatively low levels of Met oxidation accumulated during 3 years of refrigerated storage had minimal impact on FcRn binding and no detectable impact on the serum half-life. PMID- 21256597 TI - Immune-related gene expression in response to H5N1 avian influenza virus infection in chicken and duck embryonic fibroblasts. AB - Chicken and ducks are important hosts in responses to highly pathogenic avian influenza virus (HPAIV) H5N1 infection. In ducks, avian influenza (AI) generally causes an asymptomatic and long-lasting infection, whereas clinical apparent and transient disease is often observed in chickens. Using real-time quantitative PCR, we examined the expression of immune-related genes in response to H5N1 infection in chicken embryo fibroblasts (CEF) and duck embryo fibroblasts (DEF). While in CEF IL-6 expressed at high levels similar to mammalian species, in DEF expression levels were minimal. Similarly, duck IFN-beta expression were slightly upregulated, whereas chicken expressions were highly upregulated. Chronologically, the mRNA levels of both IFN-alpha and IFN-gamma, which belong to type I and type II interferon, respectively, were unregulated in a similar fashion in chickens than in ducks. IL-2 and TLR-7 were elevated from the beginning of the infection in both CEF and DEF to the end of the experiment. Chicken MHC class I expression was almost unaffected while duck expression were downregulated. DEF and CEF MHC class II expression were downregulated. Chemokine IL-8 expression was upregulated in both species. The IL-8 levels closely parallel the IL-1beta induced IL-6 levels in the same samples. These results show distinct embryo fibroblasts expression patterns of pro-inflammatory cytokines and IFNs between species. PMID- 21256598 TI - Class-switched marginal zone B cells in spleen have relatively low numbers of somatic mutations. AB - The vast majority of rodent splenic marginal zone (MZ)-B cells are naive IgM(+) cells. A small fraction of these MZ-B cells carry mutated V-genes, and represent IgM(+) memory MZ-B cells. Here we reveal further heterogeneity of B cells with a MZ-B cell phenotype, by providing evidence for the existence of class-switched memory MZ-B cells in the rat. In essence, we observed IGHV5 encoded Cgamma transcripts, among FACS-purified MZ-B cells, defined as HIS24(low)HIS57(bright) cells. Furthermore, we found that most IgG encoding transcripts are mutated. There is no significant difference in IGHV5 repertoire and subclass usage of these IgG encoding transcripts collected from B cells with a MZ-B cell phenotype and B cells with a follicular (FO) B cell phenotype. However, the IGHV5 genes encoding for IgG antibodies of MZ-B cells exhibited significantly fewer mutations, compared to those with a FO-B cell phenotype. In one rat we found a clonally related set of IgG encoding sequences, of which one was derived from the MZ-B cell fraction and the other from the FO-B cell fraction. We speculate that these two subpopulations of class-switched B cells are both descendants from naive FO-B cells and are generated in germinal centers. Class-switched memory cells with a MZ-B cell phenotype may provide the animal with a population of IgG memory cells that can respond rapidly to blood-borne pathogens. PMID- 21256599 TI - Rose or black-coloured glasses? Altered neural processing of positive events during memory formation is a trait marker of depression. AB - BACKGROUND: Valence-specific memory enhancement is one of the core cognitive functions that causes and maintains Major Depressive Disorder (MDD). While previous neuroimaging studies have elucidated the neural underpinnings of this emotional enhancement effect in depressed patients, this study aimed at detecting processing biases that are maintained throughout remission while patients were euthymic. METHODS: Fourteen medication-free women remitted from unipolar MDD and 14 matched controls were scanned while learning negative, positive, and neutral words, which were subsequently tested with free recall. RESULTS: The two groups did not differ in memory performance and showed no neural differences during successful encoding of neutral or negative words. However, during successful encoding of positive words, patients exhibited a larger recruitment of a set of areas, comprising cingulate gyrus, right inferior- and left medial-frontal gyrus as well as the right anterior hippocampus/amygdala. LIMITATIONS: Restriction to female participants may limit the generalization of the findings. CONCLUSION: Female MDD patients in clinical remission exert greater neural recruitment of memory-related brain regions when successfully encoding positive words, suggesting that neural biases related to memory formation of positive information do not entirely normalize. Further research is needed to establish whether this processing bias during successful memory formation of positive information is predictive for future relapse thereby offering the possibility to develop more focused therapeutic interventions to specifically target these processes. PMID- 21256600 TI - Cortical mechanisms of the symptomatology in major depressive disorder: a resting EEG study. AB - BACKGROUND: Diagnosis and treatment rely on symptom criteria in modern psychiatry. However, the cortical mechanisms of symptomatology in major depressive disorder (MDD) are still not clear. This study examined neural correlates of symptom clusters of MDD by electroencephalography (EEG). METHODS: Resting state eye-closed EEG signals were recorded in 196 depressive patients. Quantitative EEG (qEEG) of regional power, coherence and power series correlation across delta, theta, alpha and beta frequencies were used to correlate with overall depression severity evaluated by the Hamilton Depression Rating Scale (HDRS). Further, statistical comparisons between patients with high vs. low qEEG indices (median-split) were undertaken regarding symptom severity of core depression, sleep, activity, psychic anxiety, somatic anxiety, and delusion. RESULTS: None of the qEEG indices significantly correlated with overall depression severity or differentiated symptom severity of core depression, sleep, activity and psychic anxiety. A higher symptom severity of somatic anxiety was associated with higher regional power over widespread cortical regions and lower strengths at bi-temporal, temporo-parietal and fronto-parietal connections. A higher symptom severity of delusion was associated with higher regional power in the frontal and temporal regions, and lower strengths at inter-hemispheric (frontal, temporal and parietal) and fronto-temporo-parietal connections. LIMITATIONS: Our EEG recording with sampling rate of 128Hz and 20 electrodes may provide restricted spatial and temporal precision. CONCLUSIONS: Our results suggest that cortical mechanisms play important roles in the symptom manifestation of cognitive distortion (sub-score of delusion) and somatic anxiety in MDD. Our findings further imply that psychic anxiety and somatic anxiety are distinct entities. PMID- 21256602 TI - Neuroprotective therapeutics for Alzheimer's disease: progress and prospects. AB - The number of people with Alzheimer's disease (AD) has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is therefore an urgent need for safe and effective pharmacotherapy to help combat the corresponding and substantial increase in disease burden. Increased understanding of disease aetiology and pathophysiology, particularly in relation to the loss of vulnerable neurons and the formation of plaques and tangles, has increased hope for medications that can slow (or perhaps even halt) the course of the disease. In this article I review the neurobiological basis of AD, current progress towards neuroprotective therapeutics, and prospects for the future. PMID- 21256601 TI - Immune reconstitution of the female reproductive tract of humanized BLT mice and their susceptibility to human immunodeficiency virus infection. AB - An HIV vaccine capable of providing sterilizing immunity from vaginal infection would reduce the spread of HIV to women. Unfortunately, only one of the four HIV 1 vaccine clinical trials has demonstrated any level of protection (31%) against HIV-1 transmission. Additionally, only one topical microbicide clinical trial has reported an overall reduction in HIV transmission (39%). Developing even more effective vaccines and microbicides will require a better understanding of the key events involved in HIV infection and dissemination at the site of exposure. Novel immunodeficient mice capable of being systemically reconstituted with human hematopoietic stem cells have provided new systems where HIV transmission studies can be performed. Specifically, a humanized mouse model of vaginal HIV transmission has been developed that utilizes the humanized bone marrow-liver thymus (BLT) mouse. The female reproductive tract (FRT) of humanized BLT mice is reconstituted with functional human immune cells rendering them susceptible to vaginal HIV-1 infection. In this review we focus on four aspects of BLT mice for the study of vaginal HIV-1 transmission: (1) we discuss methods for creating humanized BLT mice and their reconstitution with human hematopoietic cells, (2) we describe reconstitution of the BLT mouse FRT with human immune cells, (3) we highlight the work done regarding vaginal HIV-1 transmission and (4) we summarize the efficacy of systemic pre-exposure prophylaxis (PrEP) to prevent vaginal HIV-1 transmission in BLT mice. BLT mice are a highly relevant small animal model for studying vaginal HIV-1 transmission, prevention and therapy. PMID- 21256603 TI - Treatment of nicotine addiction: present therapeutic options and pipeline developments. AB - Tobacco use is a global pandemic that poses a substantial and costly health burden. There are some treatment options are available, but currently marketed smoking-cessation drugs lack high levels of efficacy, particularly in real-life settings. Consequently, there is a compelling need for more effective pharmacotherapies to aid smokers in maintaining long-term abstinence. Advances in the understanding of the mechanisms involved in nicotine dependence have recently been translated into new medications and vaccines that interfere with nicotine signaling, many of which are currently at an advanced stage of development. In the present article we review current and emerging pharmacotherapies for tobacco dependence, focusing on the mechanistic rationale for their potential anti addiction efficacy, major findings in preclinical and clinical studies, and future research directions. PMID- 21256605 TI - Association between retinal microcirculation and aortic stiffness in hypertensive patients. AB - BACKGROUND: The fundoscopic examination of hypertensive patients, an established hypertension-related target organ damage, tends to be underutilized in clinical practice. We sought to investigate the relationship between retinal alterations and aortic stiffness, an independent predictor of cardiovascular morbidity and mortality. METHODS: Our population consisted of 197 consecutive essential hypertensive patients (age 60 +/- 13 years, 115 females) without overt cardiovascular disease. All subjects underwent fundoscopy examination and were distributed to four groups according to Scheie's grading system. Aortic stiffness was evaluated by carotid-femoral pulse wave velocity with a validated device (Complior). RESULTS: The four groups (Scheie's grades 0-3: including 24, 75, 74, 24 patients respectively) did not differ with regard to age, gender and their metabolic profile. Patients with higher Scheie's category had higher values of pulse wave velocity (8.2 +/- 1.5, 8.9 +/- 1.7, 9.3 +/- 1.8, 9.8 +/- 2.1m/s respectively, p=0.001). Multivariable regression analysis showed that age, fundus classification and systolic arterial pressure were independent determinants of pulse wave velocity. CONCLUSION: Hypertensive subjects exhibit a progressive stiffening of the aorta in parallel with the progression of retinal alterations according to Scheie's scale. Further studies are needed to clarify involved pathophysiological mechanisms and explore possible causal relationships. PMID- 21256604 TI - Kainate receptors coming of age: milestones of two decades of research. AB - Two decades have passed since the first report of the cloning of a kainate-type glutamate receptor (KAR) subunit. The intervening years have seen a rapid growth in our understanding of the biophysical properties and function of KARs in the brain. This research has led to an appreciation that KARs play very distinct roles at synapses relative to other members of the glutamate-gated ion channel receptor family, despite structural and functional commonalities. The surprisingly diverse and complex nature of KAR signaling underlies their unique impact upon neuronal networks through their direct and indirect effects on synaptic transmission, and their prominent role in regulating cell excitability. This review pieces together highlights from the two decades of research subsequent to the cloning of the first subunit, and provides an overview of our current understanding of the role of KARs in the CNS and their potential importance to neurological and neuropsychiatric disorders. PMID- 21256606 TI - Effect of myocardial protection of intracoronary adenosine and nicorandil injection in patients undergoing non-urgent percutaneous coronary intervention: a randomized controlled trial. AB - BACKGROUND: Several studies have demonstrated that adenosine and nicorandil protect the myocardium against angioplasty-related myocardial injury. We conducted a prospective study to investigate the myocardial protective effects of combination therapy with intracoronary adenosine and nicorandil. METHODS: We enrolled 213 consecutive patients with stable or unstable angina who were scheduled for non-urgent PCI for de-novo coronary lesions. Patients were randomized into group I (control saline, n=55), group II (adenosine 50 MUg, n=54), group III (nicorandil 4 mg, n=54), or group IV (adenosine-nicorandil combination, n=50). Serial assessments of CK-MB were used to assess myocardial necrosis before and after PCI. The primary endpoint was the incidence of myocardial necrosis (elevation of CK-MB), and the secondary endpoints were the changes in serum CK-MB and cTnI levels and the incidence of post-procedural myocardial infarction (MI). RESULTS: No significant differences were observed among the four groups with regard to baseline or angiographic characteristics. No major adverse events related to adenosine and nicorandil were observed. There were no significant differences in the incidence of post-procedural myocardial necrosis among the four groups (10.9, 14.8, 14.8, and 14.0%, respectively, p=0.9). There were no significant differences in the incidence of post-procedural MI among groups (p=0.6). In multivariate regression analysis, multivessel stenting, median stent length, and the presence of a compromised side branch were independent predictors of myonecrosis. CONCLUSIONS: Pretreatment with intracoronary adenosine, nicorandil, or the combination of the two drugs did not reduce the incidences of myocardial necrosis or MI after non-urgent PCI in patients with low-risk angina pectoris. PMID- 21256607 TI - Experiences of air travel in patients with chronic heart failure. AB - AIM: To conduct a survey in a representative cohort of ambulatory patients with stable, well managed chronic heart failure (CHF) to discover their experiences of air travel. METHODS: An expert panel including a cardiologist, an exercise scientist, and a psychologist developed a series of survey questions designed to elicit CHF patients' experiences of air travel (Appendix 1). The survey questions, information sheets and consent forms were posted out in a self addressed envelope to 1293 CHF patients. RESULTS: 464 patients (response rate 39%) completed the survey questionnaires. 54% of patients had travelled by air since their heart failure diagnosis. 20% of all patients reported difficulties acquiring travel insurance. 65% of patients who travelled by air experienced no health-related problems. 35% of patients who travelled by air experienced health problems, mainly at the final destination, going through security and on the aircraft. 27% of all patients would not travel by air in the future. 38% of patients would consider flying again if there were more leg room on the aeroplane, if their personal health improved (18%), if they could find cheaper travel insurance (19%), if there were less waiting at the airport (11%), or if there were less walking/fewer stairs to negotiate at the airport (7%). CONCLUSION: For most patients in this sample of stable, well managed CHF, air travel was safe. PMID- 21256608 TI - Insulation of the phrenic nerve as an alternative to left ventricular lead repositioning in cardiac resynchronization therapy. PMID- 21256609 TI - Cell patterning technologies for organotypic tissue fabrication. AB - Bottom-up tissue engineering technologies address two of the main limitations of top-down tissue engineering approaches: the control of mass transfer and the fabrication of a controlled and functional histoarchitecture. These emerging technologies encompass mesoscale (e.g. cell sheets, cell-laden hydrogels and 3D printing) and microscale technologies (e.g. inkjet printing and laser-assisted bioprinting), which are used to manipulate and assemble cell-laden building blocks whose thicknesses correspond to the diffusion limit of metabolites, and present the capacity for cell patterning with microscale precision, respectively. Here, we review recent technological advances and further discuss how these technologies are complementary, and could therefore be combined for the biofabrication of organotypic tissues either in vitro, thus serving as realistic tissue models, or within a clinic setting. PMID- 21256610 TI - Depression related to (neo)adjuvant hormonal therapy for prostate cancer. AB - BACKGROUND: We studied whether hormonal therapy, (neo)adjuvant to radiotherapy for localized prostate cancer, is related to an increase in depression and whether this is caused by the hormonal therapy itself or by the relatively poor prognosis of patients who get (neo)adjuvant hormonal therapy. METHODS: Between 2002 and 2005, 288 patients, irradiated for prostate cancer (T1-3N0M0), were studied prospectively in two clinics. In one clinic almost all patients received (neo)adjuvant androgen deprivation (Bicalutamide+Gosereline). In a second clinic hormonal therapy was prescribed mainly for high risk patients. This allowed us to separate the effects of hormonal therapy and the patient's prognosis. RESULTS: During the course of hormonal therapy, depression was significantly heightened by both hormone use (p<0.001) and poor prognosis (p<0.01). After completion of hormonal therapy, poor prognosis continued to affect the depression score (p<0.01). The increase was, however, small. CONCLUSIONS: Depression was mildly increased in patients receiving hormonal therapy. The increase appeared to be related to both the hormone therapy itself and the high risk status of patients. High risk status, with the associated poor prognosis, had a more sustained effect on depression. The rise was statistically significant, but was too small, however, to bear clinical significance. PMID- 21256611 TI - Intentional control and biomechanical exploitation in preparatory handwriting. AB - In this study it was investigated how primary school children perform a graphomotor task which required them to simultaneously achieve multiple movement goals. Thirty-four 1st-grade primary school children were asked to produce with an electronic ink pen loop patterns varying in height (3, 6, 9 and 12 mm) on preprinted sheets of paper attached to a digitizer tablet. The task was paced by means of an acoustic signal of either 1, 2 or 3 Hz. The children were instructed to attain both the imposed amplitude and frequency. By focusing on how local parameter errors changed from one movement to the next, exploitation of biomechanics when the children respected the inverse relationship between movement amplitude and frequency was distinguished from deliberate, cognitive control when the children succeeded in overriding the inverse relationship between movement amplitude and frequency. The results show that children, like adults, exploit biomechanics to a considerable extent. Coupling strength between the acoustic pacing signal and the pen-tip movements increased with age, whereas the temporal errors decreased. The study shows that preparatory writers can pursue multiple movement goals simultaneously at lower speeds but at higher speeds their capacity to do so is reduced. PMID- 21256612 TI - Proprioception plays a different role for sensorimotor adaptation to different distortions. AB - If proprioceptive feedback is degraded by agonist-antagonist muscle vibration, then adaptation to rotated vision remains intact while adaptation to a velocity dependent force field worsens. Here we evaluate whether this differential effect of vibration is related to the physical nature of the distortion - visual versus mechanical - or to their kinematic coupling to the subjects' hand - velocity versus position dependent. Subjects adapted to a velocity-dependent visual distortion, to a position-dependent force, or to a velocity-dependent force; one half of the subjects adapted with, and the other half without agonist-antagonist vibration at the wrist, elbow, and shoulder. We found, as before, that vibration slowed down adaptation to a velocity-dependent force. However, vibration did not modify adaptation to the other two distortions, nor did it influence the aftereffects of any distortion. From this we conclude that intact proprioception supports strategic compensatory processes when proprioceptive signals agree with visual ones, and provide relevant (dynamic) information not available to the visual system. PMID- 21256613 TI - Critical evaluation of the EU-technical guidance on shelf-life studies for L. monocytogenes on RTE-foods: a case study for smoked salmon. AB - In November 2008, a technical guidance document on the challenge test protocol was published by the EU CRL (Community of Reference Laboratory) for L. monocytogenes. This document describes the practical aspects on the execution of a challenge test in order to comply to the EU Commission regulation N degrees 2073/2005 on microbiological criteria for foodstuff. In this guideline two approaches are specified. On the one hand challenge tests, based on actual data measurements at the beginning and end of the shelf-life of products stored under reasonably foreseen T-profile, are described. On the other hand, growth potential is calculated by predictive models using a validated maximum specific growth rate. The present study evaluates the two above mentioned approaches on cold smoked salmon, a typical risk product for L. monocytogenes. The focus is on: (i) the relative importance of intrabatch versus interbatch variability, (ii) the concept of a simple challenge test based on actual data at start and end of shelf life versus a modelling approach and (iii) the interpretation of challenge tests. Next to this, available tertiary models were used to estimate the growth potential of these products based on their initial physicochemical characteristics. From the results it could be concluded that in some batches considerable intrabatch variability was obtained. In general, however, the interbatch variability was significantly higher than intrabatch variability. Concerning the two above mentioned methods for challenge tests, it can be stated that the first approach (simple challenge test) can be set up rather rapidly and is cost-effective for SMEs (small and medium enterprises) but provides only a single isolated outcome. This implies that challenge tests should be redone if changes occur in composition or production process. The second (modelling) approach, using extended challenge tests to establish growth parameters needs larger set ups and more complicated data analysis, which makes them more expensive. Using available tertiary models has the major advantage that the most important intrinsic and extrinsic factors can be included for the prediction of the growth parameter. It was clear that product specific models, taking into account the interaction effects with background flora, performed the best. Regarding the challenge tests, it can be concluded that the best approach to choose will depend on the particular context as in the end both approaches will lead to the same conclusion. PMID- 21256614 TI - Endothelial nitric oxide synthase VNTR (intron 4 a/b) polymorphism association with type 2 diabetes and its chronic complications. AB - SUBJECT AND AIMS: Endothelial derived nitric oxide (eNOS) is involved in several functions playing important role in development of type 2 diabetes and insulin resistance. The aim of this study was to examine the association between eNOS intron 4 VNTR polymorphism and type 2 diabetes in an Iranian population. METHODS: A total of 220 patients with type 2 diabetes and 96 healthy control subjects were recruited from the same area. Genotyping was performed using PCR. RESULTS: A significant difference was found in genotype frequencies of eNOS polymorphism between patients and controls (aa+ab vs. bb p=0.02, OR 2.0 95% CI; 1.05-3.96). Also allele a frequency was significantly increased in patients with diabetes compared with controls (p=0.007, OR 2.1 95% CI; 1.19-4.08). We found that in patients with diabetic neuropathy the frequency of 'a' allele was significantly increased compared to the controls p=0.03, OR=1.8 95% CI (1.00-3.7). Both genotype and allele frequencies were significantly different between patients who were complication free compared to the controls [aa+ab vs. bb p=0.007, OR=2.6 95% CI (1.2-5.8) and p=0.001, OR=2.8 95% CI (1.4-5.9)] respectively with the a allele conferring the risk. CONCLUSION: The association between eNOS VNTR polymorphism and T2DM seems to be stronger in patients without diabetic complications indicating diverse effect of eNOS polymorphism on diabetes and diabetic microvascular complications. PMID- 21256615 TI - The cost of drug development: a systematic review. AB - OBJECTIVES: We aimed to systematically review and assess published estimates of the cost of developing new drugs. METHODS: We sought English language research articles containing original estimates of the cost of drug development that were published from 1980 to 2009, inclusive. We searched seven databases and used citation tracing and expert referral to identify studies. We abstracted qualifying studies for information about methods, data sources, study samples, and key results. RESULTS: Thirteen articles were found to meet our inclusion criteria. Estimates of the cost of drug development ranged more than 9-fold, from USD$92 million cash (USD$161 million capitalized) to USD$883.6 million cash (USD$1.8 billion capitalized). Differences in methods, data sources, and time periods explain some of the variation in estimates. Lack of transparency limits many studies. Confidential information provided by unnamed companies about unspecified products forms all or part of the data underlying 10 of the 13 studies. CONCLUSIONS: Despite three decades of research in this area, no published estimate of the cost of developing a drug can be considered a gold standard. Studies on this topic should be subjected to reasonable audit and disclosure of - at the very least - the drugs which authors purport to provide development cost estimates for. PMID- 21256616 TI - Direct effects of audio-visual stimulation on EEG. AB - In the course of 2 months, 25 repetitions of a 20 min audio-visual stimulation (AVS) program with stimulations at 17, 9, 4, and 2 Hz were applied to 6 volunteers. EEG data were recorded from 6 scalp locations prior, during and after AVS. In order to identify direct and transient changes in EEG under influence of AVS, total power, relative frequency band powers and magnitude-squared coherences were estimated. Intense brain wave entrainment as a direct reaction to AVS was significant through increase of spectral powers and coherences around the stimulating frequency bands in the occipital areas, spreading also to the central and frontal regions. However, these excitations were 'short-lived'. On the other hand some signs of interhemispheric cooperation (coherences in the narrow bands around 2, 4, and 17 Hz at parieto-occipital areas) remained increased during the investigated 3 min after AVS. As going through further AVS sessions the driving response progressively enhanced for 2 and 4 Hz stimulation in centro-parietal locations. Progress was also found in the left and right hemisphere synchronization examined by coherences. In perspective, the results contribute to deeper comprehension of photic stimulation approaches as a technique of guided entrainment of the brain waves or intermediate increase of hemispheres' synchronization. PMID- 21256617 TI - Efficient data management in a large-scale epidemiology research project. AB - This article describes the concept of a "Central Data Management" (CDM) and its implementation within the large-scale population-based medical research project "Personalized Medicine". The CDM can be summarized as a conjunction of data capturing, data integration, data storage, data refinement, and data transfer. A wide spectrum of reliable "Extract Transform Load" (ETL) software for automatic integration of data as well as "electronic Case Report Forms" (eCRFs) was developed, in order to integrate decentralized and heterogeneously captured data. Due to the high sensitivity of the captured data, high system resource availability, data privacy, data security and quality assurance are of utmost importance. A complex data model was developed and implemented using an Oracle database in high availability cluster mode in order to integrate different types of participant-related data. Intelligent data capturing and storage mechanisms are improving the quality of data. Data privacy is ensured by a multi-layered role/right system for access control and de-identification of identifying data. A well defined backup process prevents data loss. Over the period of one and a half year, the CDM has captured a wide variety of data in the magnitude of approximately 5terabytes without experiencing any critical incidents of system breakdown or loss of data. The aim of this article is to demonstrate one possible way of establishing a Central Data Management in large-scale medical and epidemiological studies. PMID- 21256619 TI - Actin regulation in the malaria parasite. AB - Many intracellular pathogens hijack host cell actin or its regulators for cell-to cell spreading. In marked contrast, apicomplexan parasites, obligate intracellular, single cell eukaryotes that are phylogenetically older than the last common ancestor of animals and plants, employ their own actin cytoskeleton for active motility through tissues and invasion of host cells. A hallmark of actin-based motility of the malaria parasite is a minimal set of proteins that potentially regulate microfilament dynamics. An intriguing feature of the Plasmodium motor machinery is the virtual absence of elongated filamentous actin in vivo. Despite this unusual actin regulation sporozoites, the transmission stages that are injected into the mammalian host by Anopheles mosquitoes, display fast (1-3 MUm/s) extracellular motility. Experimental genetics and analysis of recombinant proteins have recently contributed to clarify some of the cellular roles of apicomplexan actin monomer- and filament-binding proteins in parasite life cycle progression. These studies established that the malaria parasite employs multiple proteins that bind actin to form pools of readily polymerizable monomers, a prerequisite for fast formation of actin polymers. The motile extracellular stages of Plasmodium parasites are an excellent in vivo model system for functional characterization of actin regulation in single cell eukaryotes. PMID- 21256618 TI - Homeodomain-only protein HOP is a novel modulator of late differentiation in keratinocytes. AB - The homeodomain-only protein (HOP) contains an atypical homeodomain which is unable to bind to DNA due to mutations in residues important for DNA binding. Recently, HOP was reported to regulate proliferation/differentiation homeostasis in different cell types. In the present study, we performed transcriptional profiling of cultured primary human keratinocytes and noted a robust induction of HOP upon calcium-induced cell differentiation. Immunohistochemistry of human skin localized HOP to the granular layer in the epidermis. Overexpression of HOP using a lentiviral vector up-regulated FLG and LOR expression during keratinocyte differentiation. Conversely, decreasing HOP expression using small interfering RNA markedly reduced the calcium-induced expression of late markers of differentiation in vitro, with the most prominent effect on profilaggrin (FLG) mRNA. Moreover, mRNA levels of profilaggrin and loricrin were downregulated in the epidermis of HOP knockout mice. Analysis of skin disorders revealed altered HOP expression in lichen planus, psoriasis and squamous cell carcinoma (SCC). Our data indicate that HOP is a novel modulator of late terminal differentiation in keratinocytes. PMID- 21256620 TI - Improved measurements of Na+ fluxes in plants using calixarene-based microelectrodes. AB - Ion-selective microelectrodes are a powerful tool in studying adaptive responses of plant cells and tissues to various abiotic stresses. However, application of this technique in Na(+) flux measurements was limited due to poor selectivity for Na(+) ions of commercially available Na(+) cocktails. Often, these cocktails cannot discriminate between Na(+) and other interfering ions such as K(+) and Ca(2+), leading to inaccurate measurements of Na(+) concentration and, consequently, inaccurate Na(+) flux calculations. To overcome this problem, three Na(+)-selective cocktail mixtures were prepared using tetramethoxyethyl ester derivative of p-t-butyl calix[4]arene. These cocktail mixtures were compared with commercially available ETH 227-based Na(+) cocktail for selectivity for Na(+) ions over other ions (particularly K(+) and Ca(2+)). Among the three calixarene based Na(+) cocktails tested, cocktail 2 [in % w/w: Na(+) ionophore (4-tert butylcalix[4]arene-tetra acetic acid tetraethyl ester) 3.5, the plasticizer (2 nitrophenyl octyl ether) 95.9 and lipophilic anion (potassium tetrakis (4 chlorophenyl) borate) 0.6] showed the best selectivity for Na(+) ions over K(+) and Ca(2+) ions and was highly stable over time (up to 10h). Na(+) flux measurements under a wide range of NaCl concentrations (25-150 mM) using Na(+) cocktail 2 established a clear dose-response relationship between severity of salt stress and magnitude of Na(+) influx at the distal elongation and mature zones of Arabidopsis thaliana roots. Furthermore, Na(+) cocktail 2 was compared with commercially available ETH 227-based Na(+) cocktail by measuring Na(+) fluxes at the two Arabidopsis root zones in response to 100mM NaCl treatment. With calixarene-based Na(+) cocktail 2, a large decreasing Na(+) influx (0-15 min) followed by small Na(+) influx (15-45 min) was measured, whereas with ETH based Na(+) cocktail Na(+) influx was short-lived (1-3 min) and was followed by Na(+) efflux (3-45 min) that might have been due to K(+) and Ca(2+) efflux measured together with Na(+) influx. In conclusion, Na(+)-selective calixarene based microelectrodes have excellent potential to be used in real-time Na(+) flux measurements in plants. PMID- 21256621 TI - High temperature limits in vivo pollen tube growth rates by altering diurnal carbohydrate balance in field-grown Gossypium hirsutum pistils. AB - It has recently been reported that high temperature slows in vivo pollen tube growth rates in Gossypium hirsutum pistils under field conditions. Although numerous physical and biochemical pollen-pistil interactions are necessary for in vivo pollen tube growth to occur, studies investigating the influence of heat induced changes in pistil biochemistry on in vivo pollen tube growth rates are lacking. We hypothesized that high temperature would alter diurnal pistil biochemistry and that pollen tube growth rates would be dependent upon the soluble carbohydrate content of the pistil during pollen tube growth. G. hirsutum seeds were sown on different dates to obtain flowers exposed to contrasting ambient temperatures but at the same developmental stage. Diurnal pistil measurements included carbohydrate balance, glutathione reductase (GR; EC 1.8.1.7), soluble protein, superoxide dismutase (SOD; EC 1.15.1.1), NADPH oxidase (NOX; EC 1.6.3.1), adenosine triphosphate (ATP), and water-soluble calcium. Soluble carbohydrate levels in cotton pistils were as much as 67.5% lower under high temperature conditions (34.6 degrees C maximum air temperature; August 4, 2009) than under cooler conditions (29.9 degrees C maximum air temperature; August 14, 2009). Regression analysis revealed that pollen tube growth rates were highly correlated with the soluble carbohydrate content of the pistil during pollen tube growth (r2 = 0.932). Higher ambient temperature conditions on August 4 increased GR activity in the pistil only during periods not associated with in vivo pollen tube growth; pistil protein content declined earlier in the day under high temperatures; SOD and NOX were unaffected by either sample date or time of day; pistil ATP and water soluble calcium were unaffected by the warmer temperatures. We conclude that moderate heat stress significantly alters diurnal carbohydrate balance in the pistil and suggest that pollen tube growth rate through the style may be limited by soluble carbohydrate supply in the pistil. PMID- 21256622 TI - Water soluble chlorophyll binding protein of higher plants: a most suitable model system for basic analyses of pigment-pigment and pigment-protein interactions in chlorophyll protein complexes. AB - This short review paper describes spectroscopic studies on pigment-pigment and pigment-protein interactions of chlorophyll (Chl) a and b bound to the recombinant protein of class IIa water soluble chlorophyll protein (WSCP) from cauliflower. Two Chls form a strongly excitonically coupled open sandwich dimer within the tetrameric protein matrix. In marked contrast to the mode of excitonic coupling of Chl and bacterio-Chl molecules in light harvesting complexes and reaction centers of all photosynthetic organisms, the unique structural pigment array in the Chl dimer of WSCP gives rise to an upper excitonic state with a large oscillator strength. This property opens the way for thorough investigations on exciton relaxation processes in Chl-protein complexes. Lifetime measurements of excited singlet states show that the unusual stability towards photodamage of Chls bound to WSCP, which lack any protective carotenoid molecule, originates from a high diffusion barrier to interaction of molecular dioxygen with Chl triplets. Site selective spectroscopic methods provide a wealth of information on the interactions of the Chls with the protein matrix and on the vibronic structure of the pigments. The presented data and discussions illustrate the great potential of WSCP as a model system for systematic experimental and theoretical studies on the functionalizing of Chls by the protein matrix. It opens the way for further detailed analyses and a deeper understanding of the properties of pigment protein complexes. PMID- 21256623 TI - Sphingolipid base modifying enzymes in sunflower (Helianthus annuus): cloning and characterization of a C4-hydroxylase gene and a new paralogous Delta8-desaturase gene. AB - Sphingolipids are components of plant cell membranes that participate in the regulation of important physiological processes. Unlike their animal counterparts, plant sphingolipids are characterized by high levels of base C4 hydroxylation. Moreover, desaturation at the Delta8 position predominates over the Delta4 desaturation typically found in animal sphingolipids. These modifications are due to the action of C4-hydroxylases and Delta8-long chain base desaturases, and they are important for complex sphingolipids finally becoming functional. The long chain bases of sunflower sphingolipids have high levels of hydroxylated and unsaturated moieties. Here, a C4-long chain base hydroxylase was functionally characterized in sunflower plant, an enzyme that could complement the sur2Delta mutation when heterologously expressed in this yeast mutant deficient in hydroxylation. This hydroxylase was ubiquitously expressed in sunflower, with the highest levels found in the developing cotyledons. In addition, we identified a new Delta8-long base chain desaturase gene that displays strong homology to a previously reported desaturase gene. This desaturase was also expressed in yeast and was able to change the long chain base composition of the transformed host. We studied the expression of this desaturase and compared it with that of the other isoform described in sunflower. The desaturase form studied in this paper displayed higher expression levels in developing seeds. PMID- 21256624 TI - Emergency department ultrasonographic probe contamination and experimental model of probe disinfection. AB - STUDY OBJECTIVE: We evaluate the frequency of emergency department (ED) ultrasonographic probe contamination and the bacterial species involved and evaluate probe cleaning and disinfection methods. METHODS: This was a 3-part observational cross-sectional study. Surveillance cultures were taken of linear and curvilinear probes on 3 ultrasonographic machines between patient encounters. Cultures of uncovered probes were taken immediately after scanning of skin and soft tissue infections. After experimental probe contamination with methicillin resistant Staphylococcus aureus (MRSA), we assessed 3-step disinfection by sequential cleaning with a dry towel, saline solution-moistened towel, and quaternary ammonia germicidal wipe and 1-step disinfection by germicidal wipe alone. Cultures were obtained by applying the probe to a blood agar plate. RESULTS: In part 1, of 164 surveillance cultures obtained from 6 probes on 29 sampling days during 11 months, 111 (67%; 95% confidence interval [CI] 60% to 74%) grew normal skin flora or environmental flora, 52 had no growth (32%; 95% CI 25% to 39%), and 2 (1.2%; 95% CI 0.3% to 4.3%) grew a clinically important pathogen. In part 2, 14 of 20 (70%; 95% CI 48% to 85%) cultures taken after skin and soft tissue infection scanning produced heavy growth of a clinically important pathogen, including 13 S aureus (5 MRSA). In part 3, cleaning with a dry and moist towel reduced but did not eliminate MRSA. The germicidal wipe step resulted in no growth in 15 of 15 (100%; 95% CI 80% to 100%) cultures in 3-step disinfection and in 9 of 10 (90%; 95% CI 60% to 98%) when used alone. CONCLUSION: Skin and environmental flora are commonly present on ultrasonographic probes between patient encounters in our ED; however, clinically important pathogens are uncommon. S aureus (including MRSA) frequently contaminates uncovered probes during skin and soft tissue infection scanning, but in an experimental model, MRSA appears to be reliably removed by a quaternary ammonia germicidal wipe if the probe is partially cleaned first. PMID- 21256625 TI - Clinical practice guideline for emergency department ketamine dissociative sedation: 2011 update. AB - We update an evidence-based clinical practice guideline for the administration of the dissociative agent ketamine for emergency department procedural sedation and analgesia. Substantial new research warrants revision of the widely disseminated 2004 guideline, particularly with respect to contraindications, age recommendations, potential neurotoxicity, and the role of coadministered anticholinergics and benzodiazepines. We critically discuss indications, contraindications, personnel requirements, monitoring, dosing, coadministered medications, recovery issues, and future research questions for ketamine dissociative sedation. PMID- 21256626 TI - A randomized controlled trial of ketamine/propofol versus propofol alone for emergency department procedural sedation. AB - STUDY OBJECTIVE: We compare the frequency of respiratory depression during emergency department procedural sedation with ketamine plus propofol versus propofol alone. Secondary outcomes are provider satisfaction, sedation quality, and total propofol dose. METHODS: In this randomized, double-blind, placebo controlled trial, healthy children and adults undergoing procedural sedation were pretreated with intravenous fentanyl and then randomized to receive either intravenous ketamine 0.5 mg/kg or placebo. In both groups, this procedure was immediately followed by intravenous propofol 1 mg/kg, with repeated doses of 0.5 mg/kg as needed to achieve and maintain sedation. Respiratory depression was defined according to any of 5 predefined markers. Provider satisfaction was scored on a 5-point scale, sedation quality with the Colorado Behavioral Numerical Pain Scale, and propofol dose according to the total number of milligrams of propofol administered. RESULTS: The incidence of respiratory depression was similar between the ketamine/propofol (21/97; 22%) and propofol alone (27/96; 28%) groups, difference 6% (95% confidence interval -6% to 18%). With ketamine/propofol compared with propofol alone, treating physicians and nurses were more satisfied, less propofol was administered, and there was a trend toward better sedation quality. CONCLUSION: Compared with procedural sedation with propofol alone, the combination of ketamine and propofol did not reduce the incidence of respiratory depression but resulted in greater provider satisfaction, less propofol administration, and perhaps better sedation quality. PMID- 21256627 TI - Inactivation of surrogate coronaviruses on hard surfaces by health care germicides. AB - BACKGROUND: In the 2003 severe acute respiratory syndrome outbreak, finding viral nucleic acids on hospital surfaces suggested surfaces could play a role in spread in health care environments. Surface disinfection may interrupt transmission, but few data exist on the effectiveness of health care germicides against coronaviruses on surfaces. METHODS: The efficacy of health care germicides against 2 surrogate coronaviruses, mouse hepatitis virus (MHV) and transmissible gastroenteritis virus (TGEV), was tested using the quantitative carrier method on stainless steel surfaces. Germicides were o-phenylphenol/p-tertiary amylphenol) (a phenolic), 70% ethanol, 1:100 sodium hypochlorite, ortho-phthalaldehyde (OPA), instant hand sanitizer (62% ethanol), and hand sanitizing spray (71% ethanol). RESULTS: After 1-minute contact time, for TGEV, there was a log(10) reduction factor of 3.2 for 70% ethanol, 2.0 for phenolic, 2.3 for OPA, 0.35 for 1:100 hypochlorite, 4.0 for 62% ethanol, and 3.5 for 71% ethanol. For MHV, log(10) reduction factors were 3.9 for 70% ethanol, 1.3 for phenolic, 1.7 for OPA, 0.62 for 1:100 hypochlorite, 2.7 for 62% ethanol, and 2.0 for 71% ethanol. CONCLUSION: Only ethanol reduced infectivity of the 2 coronaviruses by >3-log(10) after 1 minute. Germicides must be chosen carefully to ensure they are effective against viruses such as severe acute respiratory syndrome coronavirus. PMID- 21256628 TI - Long-term surveillance of air quality in medical center operating rooms. AB - BACKGROUND: Maintenance of adequate indoor air quality (IAQ) in operating rooms (ORs) is critical to the prevention of nosocomial infection in hospitalized patients. This study evaluated the characteristics of IAQ in various ORs in a medical center. METHODS: Air temperature, relative humidity, carbon dioxide (CO(2)), particulate matter (PM), and bacterial concentrations were monitored in the ORs, and monthly variations were noted. RESULTS: The mean CO(2) concentrations in the ORs were lower than the suggested level (600 ppm average over 8 hours) set by Taiwan's Environmental Protection Agency. Positive relationships were found among the number of persons, temperature (Spearman's rho coefficient [r(s)] = 0.19; P < .01), and CO(2) concentration (r(s) = 0.34; P < .01) in the OR. Bacterial concentration was significantly associated with PM level when adjusted for OR category and the number of persons in the room. Gram positive bacteria (eg, Bacillus spp, Micrococcus spp, Staphylococcus spp) were frequently found in the monitored ORs. CONCLUSION: The IAQ in the ORs varied significantly from month to month. The number of persons in the OR affected IAQ, and a decreased PM level might indicate reduced microbial contamination in the OR. PMID- 21256629 TI - The effects of needleless connectors on catheter-related bloodstream infections. AB - Needleless connectors, including the standard split septum and the luer-activated mechanical valve connectors, have been introduced into clinical practice to eliminate the risk of needlestick injuries by avoiding the use of needles when accessing the intravascular catheters. Negative and positive displacement mechanical valves have been associated with increased rates of catheter-related bloodstream infections as compared with split septum connectors. Based on available data, split septum connectors should be preferentially used instead of mechanical valves. Adequate disinfection by scrubbing the access port preferably with chlorhexidine is recommended to minimize the risk of catheter microbial contamination along with proper infection control practices. Large prospective randomized clinical trials are needed to evaluate further the possible causes and effects of different types of mechanical valve needleless connectors on bloodstream infections. PMID- 21256630 TI - Central insulin resistance and synaptic dysfunction in intracerebroventricular streptozotocin injected rodents. AB - To better understand the role of insulin signaling in the development of Alzheimer's disease (AD), we utilized an animal model (intracerebroventricular injection of streptozotocin-ic-streptozotocin (STZ)) that displays insulin resistance only in the brain and exhibits AD pathology. In this model, deficits in hippocampal synaptic transmission and long-term potentiation (LTP) were observed. The decline in LTP correlated with decreased expression of NMDAR subunits NR2A and NR2B. The deficits in LTP were accompanied by changes in the expression and function of synaptic AMPARs. In ic-STZ animals, an alteration in integrin-linked kinase (ILK)-glycogen synthase kinase 3 beta (GSK-3-beta) signaling was identified (p < 0.05). Similarly, there was decreased expression (p < 0.05) of brain derived neurotropic factor (BDNF) and stargazin, an AMPAR auxiliary subunit; both are required for driving AMPA receptors to the surface of the postsynaptic membrane. Our data illustrate that altered ILK-GSK-3beta signaling due to impaired insulin signaling may decrease the trafficking and function of postsynaptic glutamate receptors; thereby, leading to synaptic deficits contributing to memory loss. PMID- 21256632 TI - [Atlas of practical diagnosis in urolithiasis]. PMID- 21256631 TI - [Testicular tumours in infancy and children]. AB - INTRODUCTION: prepubertal testicular tumours are different from those that appear during adulthood. Traditionally, they were considered to be malignant, however benign testicular tumours are actually more frequent at this age. MATERIALS AND METHODS: we analysed our experience in the treatment of testicular tumours in children <= 13, with the intention of evaluating the use of partial orchiectomy. From 1984 to 2008, we diagnosed and treated 15 testicular tumours in children at our centre. We examined the therapeutic approach employed, underlining the possibility of testicular conservation in selected patients and we have analysed the results. RESULTS: the clinical presentation in 80% of the cases was an increase in testicle size with palpable mass. We performed 4 radical orchiectomies (27%) and 11 tumourectomies (73%). All the benign lesions in the final pathological anatomy were treated with tumourectomy: four epidermoid cysts, one hemangioma, one lipoma, one fibrous hamartoma, one juvenile granulosa tumour and one splenogonadal fusion. We also successfully and conservatively treated two cases of teratoma. The cases that received radical treatment were a yolk sac tumour (Stage I), two mixed germ cell tumours and one gonadoblastoma. CONCLUSIONS: there are more cases of benign testicular tumours than malignant tumours during puberty. In the event of a palpable testicular mass with negative tumour markers, conservative treatment by means of a tumourectomy may be considered. However, the lesion must be removed completely to prevent recurrence. PMID- 21256633 TI - [Injection of botulinum toxin (BTX-A) in children with bladder dysfunction due to detrusor overactivity]. AB - INTRODUCTION: bladder dysfunction causes urinary incontinence and kidney damage in children. When treatment with anticholinergics and intermittent bladder catheterization fails, the alternative therapy is bladder augmentation. PATIENTS AND METHODS: between 2005 and 2009, a prospective study was carried out with Botox((r)) injected into the detrusor of children suffering from high-pressure bladder despite anticholinergic treatment. We assessed their urodynamic, clinical and radiological evolution prior to and at 4 weeks, 6 months and 1 year after the injection (10 u/kg of weight up to 300 u). Reinjection was indicated in the event of clinical or urodynamic worsening. We employed the Wilcoxom test to statistically analyze the urodynamic parameters. RESULTS: 12 patients were treated, 11 with neurogenic bladder (91.7%) and 1 with posterior urethral valves (8.4%). The mean age was 12.6 (4.3-17.8) years and follow-up took place after 40.8 (16.9-45-7) months. Bladder capacity, detrusor accommodation and pressure improved after 4 weeks in all the patients except in 2 (16.7%). This improvement decreased after 6 months, although successive injections produced similar changes. One patient (8.3%) received 1 dose, six (50%) two doses and five (41.7%) received three. Clinical and urodynamic improvement in 8 patients (66.7%) prevented bladder augmentation. CONCLUSIONS: repeated botulinum toxin injection in the detrusor is a therapeutic instrument for high pressure and low accommodation bladders in children. It could replace bladder augmentation in some cases, however further studies with long-term follow-up care are required to appropriately evaluate its safety and effectiveness. PMID- 21256634 TI - [Immunohistochemical expression of microvascular density and carbonic anhidrase IX in renal carcinoma. Relation to histological type and tumoral progression]. AB - PURPOSE: to correlate the immunohistochemical expression of microvascular density (MVD) and the carbonic anhydrase IX (CAIX) with the different histological subtypes of renal carcinoma and its progression. MATERIAL AND METHODS: we studied 93 patients with renal cell carcinoma operated between 1990 and 2008. Antibodies employed for immunohistochemistry (IHC); CD31 (1: 40, Dako) and CD34 (1: 50, Dako) for MVD and CAIX (1: 100, Santa Cruz). CAIX was validated semiquantitatively as: strongly positive (>85%); weakly positive (10% -85%); and negative (< 10%), independently of the intensity of the stain. MVD was validated with both anti-CD31 and anti-CD34 by means of a whole section, to select the microscopic field (x100) with highest density of stained vessels, counting the number of vessels in a photographic field of 0.53 mm(2). Results are expressed as the maximal number of vessels by mm(2) of tumour tissue. RESULTS: median follow up was 40 months (1-160). We found no differences of expression with any of the 3 IHC markers between tumours that progressed (49) and tumours that did not progress (44). The IHC expression of CAIX was strongly related to MVD, measured for both CD31 and CD34 (p<0.0001). MVD with both antibodies was inversely related to tumour size and Fuhrman grade and was also stronger in clear cell carcinomas compared to the rest of histological subtypes, measured by CD31 (p = 0.001) and CD34 (p = 0.003). CONCLUSIONS: neither MVD nor CAIX expressions were related to tumour progression, but were related to histological subtypes. This fact, added to their co-expression, could prompt the use of the CAIX expression, which is far more reproducible, as a quick and easy approximation to MVD. More research should be done to use it as marker for targeted therapy. PMID- 21256635 TI - [Gastrointestinal stromal tumour in the urinary bladder]. PMID- 21256636 TI - Rediscovering the essence of nursing: exploring the impact of in clinical experience in Thailand for undergraduate nursing students from Australia. AB - Cultural competence is now widely recognised as an essential characteristic for undergraduate nursing students. Clinical experience in foreign countries has become increasingly popular as a strategy to enhance cultural awareness and competence. However, published research articulating the experience and outcomes of these initiatives is relatively rare, particularly from an Australian perspective. This paper presents the findings of a qualitative, exploratory research project. Individual semi-structure interviews were conducted with eight undergraduate nursing students before, during and at the conclusion of a four week clinical placement in Surin, Thailand. Data analysis identified the following major themes: first interview - anticipation; second interview - making a difference; contrasting worlds; and part of the group; third interview - reality check and group dynamics. These findings suggest that international clinical experience has potential benefits beyond the development of cultural competence. The importance of caring in nursing and the importance of group dynamics were particularly valued by student participants. PMID- 21256637 TI - Taurolidine lock - experience from the West of Scotland. PMID- 21256639 TI - Clinical characteristics, treatment, and evolution in 14 cases of pediatric orofacial lymphangioma. AB - PURPOSE: To present the largest series of orofacial lymphangioma in children published to date, analyzing the clinical characteristics and evolution of, and the treatment used for, these lesions. MATERIALS AND METHODS: The clinical data from patients diagnosed with orofacial lymphangioma, who were treated from 1998 to 2008 at the Oral and Maxillofacial Surgery Unit, Children's Hospital La Fe of Valencia (age 0 to 14 years), were reviewed. All patients with a clinical, radiographic, or, in surgical cases, histopathologic, diagnosis of orofacial lymphangioma were included. RESULTS: A total of 14 patients (8 boys and 6 girls; mean age 4.6 years) were included in the present study. Of the 14 cases, 9 had been diagnosed before the patients were 2 years old and 2 of which were congenital; 8 cases were located on the dorsum of the tongue. The lesion diameter was 1 to 2 cm in 9 patients, with 1 less than 1 cm, and was larger than 2 cm in 5. For treatment, 4 lymphangiomas were monitored periodically and resolved spontaneously, 1 was treated with sclerotherapy, and 9 with surgical extirpation. After surgery, 2 patients developed a recurrence within 13 months. CONCLUSIONS: Most of the lymphangiomas diagnosed in children occurred before 2 years of age, were on the dorsum of the tongue, and had a mean size of 1 to 2 cm. Of those treated with surgical extirpation, 2 recurred. PMID- 21256638 TI - Refeeding hypophosphataemia is more common in enteral than parenteral feeding in adult in patients. AB - BACKGROUND & AIMS: Refeeding hypophosphataemia (RH) can result in sudden death. This study aimed to compare the incidence of RH between patients fed enterally and those fed parenterally. METHODS: The risk of RH in adult patients fed parenterally (PN) or nasogastrically (NG) was assessed by comparison of patient records with the UK NICE guidelines for refeeding syndrome, between December 2007 and December 2008. A fall in serum phosphate to less than 0.6 mmol/L was indicative of RH. RESULTS: Of 321 patients,92 were at risk of RH. Of these, 23 (25%) patients developed RH (p = 0.003). 18 (33%) of NG fed, 'at-risk' patients developed RH vs 5 (13%) fed parenterally (p = 0.03). Death within 7 days and RH were not associated. The sensitivity and specificity of the NICE criteria for defining patient's risk of RH was calculated: 0.76 and 0.50 respectively for NG feeding; 0.73 and 0.38 respectively for parenteral feeding. CONCLUSION: Patients fed by NG tube and deemed at risk of RH are more likely to develop RH than patients fed by PN. The higher risk with NG feeding may be due to the incretin effect from absorption of glucose. The UK guidelines lack specificity. PMID- 21256640 TI - Inferior alveolar nerve canal and branches detected with dental cone beam computed tomography in lower third molar region. AB - PURPOSE: To evaluate the course of the inferior alveolar nerve and its branches, the detectable branches were investigated with dental cone beam computed tomography (CBCT). MATERIALS AND METHODS: Patients in whom the lower third molar (M3) and inferior alveolar nerve canal showed overlapping in the initial panoramic image were included. One hundred twelve impacted lower M3s were extracted after examination with dental CBCT. The detection ratio, the course of the branches, and their relation with the M3 were retrospectively investigated. RESULTS: One hundred fifty-five branches were observed in 106 cases (94.6%, 106/112) around the M3. Most branches coursed under the M3 (55.5%, 86/155), and 85 branches (54.8%, 85/155) were in contact with the M3. The inferior alveolar nerve canal and branch(es) were mostly in contact with the M3 (57.5%, 61/106). CONCLUSIONS: Dental CBCT can detect most tubular structures representing branches in the impacted lower M3 region. PMID- 21256641 TI - Comparison of preoperative computed tomography and surgical findings in maxillofacial infections. AB - PURPOSE: To examine the accuracy of computed tomography (CT) in predicting the presence of surgically confirmed abscess in patients presenting with deep maxillofacial infections (DMIs). MATERIALS AND METHODS: The medical records of 36 patients with clinically suspected DMI were reviewed. All patients underwent preoperative CT scan to determine whether abscess or cellulitis was present. The operative reports of all patients were compared with their preoperative CT scan findings. RESULTS: Of 36 patients, 30 had abscess predicted by preoperative CT scan. The positive predictive value for DMI based on CT findings interpreted by an oral surgeon and confirmed as an abscess at operation was 90%, whereas the negative predictive value was 33%. When findings were interpreted by a radiologist, the positive predictive value was 94.1% whereas the negative predictive value was 26.3%. Thirty patients had abscess predicted by preoperative CT scan when interpreted by an oral surgeon, whereas seventeen had abscess predicted by a radiologist. At operation, 3 of 30 patients had cellulitis whereas 27 had abscess, for a false-positive rate of 60% and false-negative rate of 12.9%. On the basis of preoperative radiography, 1 of 17 patients had cellulitis whereas 16 had abscess, for a false-positive rate of 16.7% and a false-negative rate of 46.7%. The agreement between CT and operative findings in predicting abscess by an oral surgeon was 80.6% and by a radiologist was 58.3%. CONCLUSION: CT yielded high sensitivity for the detection of DMI abscess but poor specificity, likely because of the paucity of cellulitis. PMID- 21256642 TI - Biomechanical study of SonicWeld Rx pin in cortical bone graft layering technique. AB - PURPOSE: The purpose of this in vitro study was to determine the biomechanical values of the SonicWeld Rx pin system in comparison with titanium screws for use in onlay cortical bone grafting. MATERIALS AND METHODS: In this study, 2.1-mm SonicWeld Rx pins and 1.5-mm titanium screws, measuring 7 mm in length, were used. Sawbone blocks were positioned to simulate an onlay bone graft, and the pins and screws were used to replicate bicortical fixation. Four groups were designated for vertical load application, and failure of the fixation was determined when stability was compromised. Study groups consisted of fixation material types and number of fixation appliances. A Bose Electroforce 3300 system was used to deliver the force and to obtain data. RESULTS: Comparison of SonicWeld Rx 1-pin fixation with titanium 1-screw fixation showed similar peak resistance loads. Average peak loading resistance for SonicWeld Rx 1-pin fixation was 65.54 N and that for titanium 1-screw fixation was 59.37 N, with no significant difference (P = .9698). Average peak strength of SonicWeld Rx 2-pin and titanium 2-screw fixations was 110.24 and 97.3 N, respectively, with no significant difference (P = .1041). CONCLUSION: Based on the measured biomechanical values, SonicWeld Rx fixation can withstand similar peak load forces compared with that of titanium screw fixation. The SonicWeld Rx fixation can be an alternative method of fixation for onlay bone grafting in dentoalveolar ridge augmentation. PMID- 21256643 TI - Three-dimensional regional displacements after mandibular advancement surgery: one year of follow-up. AB - PURPOSE: To evaluate the association of 3-dimensional changes in the position of the condyles, rami, and chin at splint removal and 1 year after mandibular advancement surgery. PATIENTS AND METHODS: This prospective observational study used preoperative and postoperative scans of 27 subjects presenting with a skeletal Class II jaw relationship with a normal or deep overbite. An automatic technique of cranial base superimposition was used to assess the positional and/or remodeling changes in the anatomic regions of interest. The displacements were visually displayed and quantified using 3-dimensional color maps. The positive and negative values of surface distances in the color maps indicated the direction of the displacements. Pearson correlation coefficients and a linear model for correlated data were used to evaluate the association between the regional displacements. RESULTS: The postoperative adaptations in the chin position between splint removal and 1 year after surgery were significantly negatively correlated with changes in the borders of the posterior ramus (left, r = -0.73, P <= .0001; and right, r = -0.68, P = .00) and the condyles (left, r = 0.53, P = .01; and right, r = -0.46, P = .02), indicating that these structures tended to be displaced in the same direction. Even though the mean condylar displacement with surgery was less than 1 mm, individual displacements greater than 2 mm with surgery were observed for 24% of the condyles. The condylar displacements were maintained at 1 year after surgery for 17% of the condyles. CONCLUSIONS: The surface distance displacements indicated that the postoperative adaptations at different anatomic regions were significantly related. PMID- 21256644 TI - Effects of zoledronic acid on healing of mandibular fractures: an experimental study in rabbits. AB - PURPOSE: The purpose of the present study was to evaluate the effects of systemically administered zoledronic acid (ZA) on mandibular fracture healing in a rabbit model using radiodensitometric, biomechanical, histologic, and histomorphometric methods. MATERIALS AND METHODS: A total of 36 skeletally mature male New Zealand white rabbits were used. The rabbits were randomly divided into 2 groups. A mandibular corpus fracture was created experimentally in all 36 rabbits. The experimental group was administered an intravenous, single dose of 0.1 mg/kg ZA, and the control group was administered only saline infusion during the procedure. All rabbits were sacrificed on the 21st postoperative day. Digital radiodensitometric analysis, a 3-point bending test, and histologic and histomorphometric examinations were performed on the harvested hemimandibles. The data were analyzed statistically. RESULTS: Biomechanical testing data showed that ZA treatment resulted in a significant increase in the healed bone strength. This result was supported by the radiologic, histologic, and histomorphometric findings. CONCLUSIONS: The results of the present study have revealed that systemic administration of ZA accelerates and improves the bone healing of mandibular fractures. PMID- 21256645 TI - Effects of head-neck extension on abnormality of laryngeal mask airway function resulting from opening the mouth. AB - PURPOSE: This study investigated the effects of head-neck extension on abnormalities of laryngeal mask airway (LMA) function resulting from opening the mouth. PATIENTS AND METHODS: A single, experienced LMA user inserted the LMA in 15 patients scheduled for elective oral surgery. Oropharyngeal leak pressure and intracuff pressure were sequentially documented in 5 mouth conditions in order (0 minutes, mouth closed plus 0 degrees extension; 3 minutes, mouth open plus 0 degrees extension; 6 minutes, mouth open plus 15 degrees extension; 9 minutes, mouth open plus 30 degrees extension; and 12 minutes, mouth open plus 45 degrees extension). RESULTS: Oropharyngeal leak pressures with the mouth open plus 0 degrees extension (30.7 +/- 5.6 cm H(2)O, P < .001), mouth open plus 15 degrees extension (29.1 +/- 6.8 cm H(2)O, P < .001), and mouth open plus 30 degrees extension (25.7 +/- 6.1 cm H(2)O, P < .001) were significantly higher than with the mouth closed plus 0 degrees extension (19.7 +/- 2.8 cm H(2)O). Compared with the position with the mouth closed plus 0 degrees extension (60.0 +/- 0 cm H(2)O), intracuff pressures were also higher with the mouth open plus 0 degrees extension (84.5 +/- 14.1 cm H(2)O, P < .001), mouth open plus 15 degrees extension (77.4 +/- 11.0 cm H(2)O, P < .001), and mouth open plus 30 degrees extension (73.6 +/- 9.6 cm H(2)O, P < .001). Both measurement values returned to control levels when the position with the mouth open plus 45 degrees extension was assumed (oropharyngeal leak pressure, 64.5 +/- 6.5 cm H(2)O [P = .212]; intracuff pressure, 20.2 +/- 4.9 cm H(2)O [P = .969]). CONCLUSIONS: In procedures requiring the patient to have an open mouth under general anesthesia using LMA, 45 degrees head-neck extension achieves acceptable airway conditions. PMID- 21256647 TI - Phonetic damage related to unilateral functional inhibition of the lingual nerve. AB - PURPOSE: The aim of this study was to analyze the effects of unilateral functional inhibition of the lingual nerve in phonetic function by perceptual and acoustic analyses of speech, which was recorded before and after neurosensory modification of the lingual nerve, and a comparison of results of these evaluations with a subject's self-perception. PATIENTS AND METHODS: The sample consisted of 10 volunteers who had the lingual nerve of the right side anesthetized. The analyzed recordings consisted of terms directly dependent on the tongue for production. In the perceptual analysis, pitch and loudness behaviors were observed, in addition to coarticulation and intelligibility. The acoustic analysis of 5 vowels and sibilant /s/ was realized. A questionnaire about the discomfort level in speech production was applied. RESULTS: Perceptual/auditive and acoustic parameters showed no significant differences. Although 3 informants declared some kind of discomfort related to speech production, they presented no acoustic or perceptual modification in sound quality. CONCLUSIONS: Although inhibition of sensory function of the lingual nerve generated considerable annoyance, there was no specific damage to phonetic function in the group under study, because no differences were observed in the quality of the speech of subjects after applying anesthesia to the lingual nerve. PMID- 21256646 TI - Prognostic factors affecting the duration of disability after third molar removal. AB - PURPOSE: The purposes of this investigation were 1) to estimate the duration of disability after third molar removal and 2) to identify factors associated with prolonged recovery. MATERIALS AND METHODS: This was a prospective cohort study composed of subjects enrolled in the American Association of Oral and Maxillofacial Surgeons Age-Related Third Molar Study. The predictor variables were grouped as follows: demographic, health status, anatomic, pathologic, medications, and complications. The outcome variable was the duration of postoperative disability measured as the number of days the subject reported inability to perform normal daily activities after third molar removal. Bivariate and multiple linear regression analyses were used. The level of statistical significance was P < .05. RESULTS: The study sample included 4,004 subjects who had 8,748 third molars removed. The mean duration of postoperative disability was 1.4 +/- 1.8 days (range, 0-26; median, 1 day). In the multiple linear regression model, age, female gender, number of third molars removed, mandibular third molar removal, full-bony impaction, sum of antibiotics or pain medications, and complications were associated with prolonged recovery (P < .05). Erupted third molars, periodontal disease or other preoperative pathology, and use of chlorhexidine were associated with earlier return to normal daily activities (P < .05). CONCLUSION: The study results suggest that third molar removal is associated with a mean delay in returning to normal activities of less than 2 days. Several factors were statistically associated with time to return to normal activities. PMID- 21256648 TI - Comparison of progressive cephalometric changes and postsurgical stability of skeletal Class III correction with and without presurgical orthodontic treatment. AB - PURPOSE: This study compares 1) progressive dental and skeletal changes, 2) postsurgical stability, and 3) treatment efficacy of patients with skeletal Class III correction with and without presurgical orthodontic treatment. PATIENTS AND METHODS: The study includes 53 patients who underwent orthognathic surgery (OGS) to correct skeletal Class III malocclusion. The patient grouping is based on presurgical orthodontics: surgical-first (SF) approach (n = 18) and modified conventional (MC) approach (n = 35). This study divides the MC group into 2 groups based on whether patients underwent tooth extraction in the presurgical phase (Ext group) (n = 10) or not (Nxt group) (n = 25). Serial lateral cephalometric film measurements identify skeletal and dental changes before treatment (T1), before OGS (T2), 1 month after OGS (T3), and at completion of treatment (T4). This investigation reviews the medical charts for treatment progress and duration. RESULTS: In the presurgical phase, the Ext group showed mild retraction of the upper incisors and more proclination of the lower incisors than the Nxt group. The skeletal sagittal parameters were similar from T1 to T4 in both the SF and MC groups. In the SF group, SN/U1 decreased 6.2 degrees after surgery and was mildly proclined at T4; in the MC group, upper incisor inclination (SN/U1) increased 1.8 degrees from T1 to T4, being 9.4 degrees greater than that in the SF group at T4. The lower incisor inclination (MP/L1) was similar at T4 in both groups. In the MC group, the MP/L1 was shown to be proclined 4.5 degrees before surgery, retroclined 1.9 degrees after surgery, and further retroclined 4.5 degrees until T4. The relapse rate of the mandibular setback was 14.3% in the SF group and 15.7% in the MC group without significant differences. The percentage of sagittal relapse less than 2 mm was 50% in the SF group and 54% in the MC group. The ratio was greater in the MC group with a relapse between 2 and 4 mm but lesser with a relapse greater than 4 mm. The Ext group showed a 3-month longer treatment duration than the Nxt group. CONCLUSION: The amount of skeletal correction and postsurgical relapse, as well as treatment duration, were no different in Class III OGS patients with or without presurgical orthodontic treatment. The presurgical work of lower incisor proclination returned to an inclination similar to the initial status after completing treatment. The final outcome of patients evidenced no difference in lower incisor inclination, with or without presurgical orthodontics. PMID- 21256649 TI - Nicotine nasal spray as an adjuvant analgesic for third molar surgery. AB - PURPOSE: To determine the efficacy of preoperatively administered nicotine nasal spray (3 mg) for analgesia after third molar (TM) surgery. MATERIALS AND METHODS: A single-center, prospective, randomized, double-blind, crossover trial was conducted. The study population consisted of 20 nonsmoking patients referred to the Department of Oral and Maxillofacial Surgery of Columbia University College of Dental Medicine for extraction of all 4 TMs. Each patient received nicotine nasal spray or placebo spray before TM surgery. At a subsequent visit the contralateral TMs were removed with prior administration of the alternate treatment. For an hour postoperatively, subjects reported information on pain and nausea, and hemodynamic variables were recorded at 15-minute intervals. Telephone follow-up was recorded for 5 days postoperatively, where patients reported information on pain, nausea, and use of hydrocodone/acetaminophen as rescue analgesia. RESULTS: Nicotine treatment was associated with a highly significant decrease in pain reported during the 5 days after TM surgery. There was no difference in the amount of hydrocodone/acetaminophen used or amount of nausea reported. There was a small but significant increase in heart rate after nicotine treatment compared with placebo during the first hour after surgery. There was no difference in blood pressure between groups. CONCLUSION: Pain is well controlled by hydrocodone/acetaminophen in most patients after TM surgery. However, there is significant variability in pain reported. Nicotinic agonists represent a new class of analgesic that can be considered for patients who are expected to have significant opioid-resistant pain after TM surgery. Caution should be used with patients in whom a small increase in heart rate would be deleterious. PMID- 21256650 TI - Malondialdehyde levels in dental follicles of asymptomatic impacted third molars. AB - PURPOSE: Increased levels of reactive oxygen species lead to oxidative stress and tissue damage. Malondialdehyde (MDA) is one of many low-molecular-weight endproducts of lipid peroxidation that increases with oxidative stress. The aim of this study was to determine oxidative stress in dental follicles (DFs) of radiologically asymptomatic impacted third molars (ITMs) using MDA. MATERIALS AND METHODS: This study involved 40 DFs of 40 patients referred for clinically and radiographically asymptomatic ITMs. Forty healthy gingival tissues in the same patients were obtained during surgical removal of teeth as a control group. DF widths on periapical radiographs narrower than 2.5 mm were included in the study. All tissues samples were analyzed for MDA as an indicator of oxidative stress. RESULTS: Levels of MDA were significantly higher in DFs from ITMs than those from healthy gingival tissues of the same patients (P < .01). CONCLUSION: The results suggest that significant oxidative stress may occur in DFs of asymptomatic ITMs. The findings suggest that increased MDA may play an important role in oxidative stress in DFs. In light of these preliminary findings of the present study, further investigations and comprehensive studies are required to determine the role of antioxidants that scavenge free radicals in DFs. PMID- 21256652 TI - Polycystic parotid disease in a male child: report of a case and review of the literature. PMID- 21256651 TI - In vitro biomechanical comparison of the effect of pattern, inclination, and size of positional screws on load resistance for bilateral sagittal split osteotomy. AB - PURPOSE: The purpose of this in vitro investigation was to determine whether the pattern, angle of placement, or size of positional screws affected their ability to resist vertical loads resembling mastication in the bilateral sagittal split osteotomy system. MATERIALS AND METHODS: Standardized bone substitutes were secured with three 12- to 16 mm-long, 1.85-, 2.0-, 2.1-, and 2.4-mm outer diameter, self-tapping titanium screws (Synthes, Solothurn, Switzerland) in various patterns using a positional screw technique. These patterns included transbuccal triangular, intraoral triangular, and transbuccal linear patterns. The models were secured in a jig and subjected to vertical loads by a mechanical testing unit (1475 UPM; Zwick, Ulm, Germany) until failure. Loading test data analysis was based on peak load values resulting in mechanical deformation of the system (1-, 3-, and 5-mm displacement), maximal force, and stiffness (load/displacement slope curve) for each group. Means and standard deviations were derived and compared for statistical significance using univariate analysis of variance with a confidence level of 95% (P values < .05). RESULTS: The designed study demonstrated that 1.85- and 2.0-mm-diameter positional screws provided similar stability in all 3 setups. Three screws placed in an inverted L pattern at 90 degrees (simulating a transbuccal approach) showed significantly higher resistance to vertical forces for advancement movements at 1-, 3-, and 5 mm displacement when compared with the inverted L group of screws placed at an angle (intraoral approach) or 3 screws in a linear pattern placed at 90 degrees (transbuccal approach) (P < .01). CONCLUSIONS: Under the conditions tested in this in vitro study, differences in the load resistance of positional screws placed in a transbuccal or intraoral approach could be demonstrated depending on the fixation technique. The transbuccal group of 3 screws in an inverted L pattern showed significantly greater stability than the intraoral group of 3 screws placed in an inverted L pattern and the transbuccal group of 3 screws in a linear pattern. Resistance to vertical loads with 1.85-mm screws was similar to that with the standard 2.0-mm screws in all 3 setups. The results of this study suggest that the angle of screw placement (surgical approach) and pattern have a greater influence on the stability of the bilateral sagittal split osteotomy system than the screw size. PMID- 21256653 TI - Symptoms before periapical surgery related to histologic diagnosis and postoperative healing at 12 months for 178 periapical lesions. AB - PURPOSE: To compare the preoperative signs and symptoms with the histologic diagnosis and postoperative healing at 12 months for 178 periapical lesions. MATERIALS AND METHODS: A total of 152 patients who had undergone periapical surgery from 2005 to 2008 were studied. The study included patients presenting with signs and symptoms before periapical surgery with a sufficient tissue sample (periapical lesion) for histologic analysis and a minimal follow-up of 12 months. The signs and symptoms present in the soft tissues at the initial examination were recorded. The histologic analysis established the diagnosis as granuloma, cyst, or scar tissue. The postoperative healing at 12 months was evaluated according to the criteria of von Arx and Kurt. RESULTS: Of the 152 patients, 147, with 178 periapical lesions, were included in the present study. No significant relationship was found between the preoperative signs and symptoms, lesion type, and evolution. However, scar tissues were asymptomatic in 78.1%, and 36.4% of granulomas were painful. Of the 8 cysts, 50% were asymptomatic and 50% caused pain. Fibrous scars created no soft tissue alterations in 68.7%. Granulomas had fistulized in 31.7%, and 75% of cysts had produced no alterations. The lesions with swelling had worse healing, and those with no soft tissue alterations had better postoperative healing. CONCLUSIONS: Chronic periapical lesions (granuloma, cyst, and scar tissue) are usually asymptomatic and do not create soft tissue alterations. However, they can deteriorate, producing pain and fistulization. Worse postoperative healing was observed for lesions with swelling, although the difference was not significant. PMID- 21256654 TI - Diagnostic value of ultrasonography in temporomandibular disorders. AB - PURPOSE: The purpose of this study was to determine the diagnostic value of ultrasonographic imaging (USI) in temporomandibular disorders. PATIENTS AND METHODS: USI and magnetic resonance imaging (MRI) were performed in 182 temporomandibular joints (TMJs) of 91 patients who were referred for treatment. After a detailed clinical examination, patients who were clinically diagnosed with TMJ disc derangement were referred to the radiology department for MRI and USI examinations. USI and MRI diagnoses of disc displacement were compared, using clinical diagnosis as the golden standard. The overall agreement between USI and MRI results was evaluated. RESULTS: Compared with the clinical diagnosis, MRI showed a sensitivity of 85%, specificity of 62%, and an accuracy of 80% in the detection of internal derangements. The positive predictable value, negative predictive value, and likelihood ratio were 88%, 54%, and 2.29, respectively. Compared with the clinical diagnosis, USI showed a sensitivity of 69%, specificity of 80%, and accuracy of 71% in the detection of internal derangements. The positive predictable value, negative predictive value, and likelihood ratio were 92%, 42%, and 3.45, respectively. Comparing the agreements between the MRI and USI diagnoses of internal derangement, the kappa value was found to be 0.36, indicating poor reliability (P < .001). CONCLUSION: USI, a noninvasive and dynamic imaging method, is a reliable method in evaluating the position of the disc in TMJ disc derangements. Better visualization of joint structures and more reliable results with higher sensitivity and accuracy can be achieved with high-resolution devices (>=12 MHz). PMID- 21256655 TI - Sialolipoma of the salivary gland: two new cases, literature review, and histogenetic hypothesis. PMID- 21256656 TI - Dissecting online control in Developmental Coordination Disorder: a kinematic analysis of double-step reaching. AB - In a recent study, children with movement clumsiness (or Developmental Coordination Disorder-DCD) were shown to have difficulties making rapid online corrections when reaching, demonstrated by slower and less accurate movements to double-step targets (Hyde & Wilson, 2011). These results suggest that children with DCD have difficulty using predictive estimates of limb position when making rapid adjustments to movement, in-flight. However, chronometric data alone does not provide strong evidence for this hypothesis: it remains unclear whether early (and rapid) control parameters or post-correction stages of the movement trajectory are affected. Thus, the overarching aim of this study was to conduct a kinematic analysis of double-step reaching in order to isolate the different control parameters that might explain the slower and less accurate double-step reaching performance of children with DCD. Participants were a new sample of 13 children with DCD aged between 8-12 years and 13 age-matched controls. Children were required to reach and touch one of three possible targets presented at the coordinates -20 degrees , 0 degrees and 20 degrees on a 17 in. LCD touch screen. For most trials (80%) the target remained stationary for the duration of movement (non-jump trials), while for the remainder (20%), the target jumped randomly to one of two peripheral locations at movement onset (jump trials). Consistent with earlier work, children with DCD were slower to initiate reaching compared to controls and showed longer MT and more errors on jump trials. Kinematic data showed that while the two groups did not differ on time to peak velocity or acceleration, children with DCD were slower to correct reach trajectory on jump trials. No group differences were observed on late kinematic markers, e.g., post-correction time. The pattern of results support and extend earlier work showing deficits in ROC in DCD. From a computational perspective, delayed corrections to the reach trajectory suggests some difficulty integrating information about the target perturbation with a predictive (or forward) estimate of limb position relative to the initial target. These conclusions are discussed, along with directions for future research. PMID- 21256657 TI - Lung sparing surgery by means of extended broncho-angioplastic (sleeve) lobectomies. AB - OBJECTIVE: To determine the morbidity, mortality and survival of sleeve lobectomy procedures compared to simple broncho-angioplasty procedures. PATIENTS AND METHODS: A total of 535 patients diagnosed with bronchogenic cancer between September 2005 and May 2010 who fulfilled the criteria of clinical, oncological and functional operability were treated in our unit. Unresectable central tumours (n=95) using simple lobectomy were scheduled for broncho-angioplasty techniques and a pneumonectomy in those where this was impossible. RESULTS: A total of 58 (11%) were performed, 46 simple broncho-angioplastic lobectomies (SBAL) and 12 extended broncho-angioplastic lobectomies (EBAL). In the SBAL group there were 32 bronchial (70%) and 7 (15%) bronchovascular reconstructions and only vascular (15%). In the EBAL group, 8 (66.7%) were bronchial and 4 (33.3%) were bronchovascular reconstructions. The most common type of resection was the right upper lobe (RUL)+segment 6 in five (41%) cases, followed by RUL+middle lobe. There were 2 (3%) deaths in the SBAL group. There was 34% morbidity in the SBAL and 33% in the EBAL group (P>0.05). Fifteen patients received neoadjuvant chemo radiotherapy treatment, due to histologically confirmed cN2; however, the number of complications was not significantly higher. No risk factors were detected in any variable studied that would affect EBAL compared to the SBAL group (P>0.05). The patients in both groups with a higher morbidity were pN1, located in the left upper lobe and associated with vascular reconstruction (P<0.05). The overall survival at 5 years was 61.6%, SBAL (61%) and EBAL (68.9%) with no differences between groups (P>0.05). CONCLUSIONS: EBALs are technically more demanding procedures, but do not increase morbidity or mortality compared to simple broncho angioplasty techniques, and with a similar survival. PMID- 21256658 TI - Cardiac magnetic resonance imaging and endothelin-1: a step forward in the detection of microvascular obstruction. PMID- 21256659 TI - Entrapment of circular mapping catheter in the mitral subvalvular apparatus during segmental isolation of pulmonary veins. PMID- 21256660 TI - Biventricular cardioverter-defibrillator implantation in a patient with the Mustard operation: "a big challenge". PMID- 21256661 TI - Migration and percutaneous implantation of a second aortic prosthesis. PMID- 21256662 TI - Color Doppler myocardial imaging demonstrates reduced diastolic tissue velocity in growth retarded fetuses with flow redistribution. AB - OBJECTIVES: In fetuses suffering from intrauterine growth retardation with cerebroplacental redistribution (IUGR CPR), the diastolic heart function may be particularly susceptible to hypoxemia as described in postnatal pathological conditions. Using the newly introduced ultrasound technique, color Doppler myocardial imaging (CDMI), we investigated the correlation between diastolic tissue velocities and diastolic blood flow velocities and compared diastolic myocardial tissue velocities in fetuses with IUGR CPR and normal fetuses. STUDY DESIGN: Peak early and active atrial tissue velocities (E' and A') were acquired from both ventricular free walls in 18 fetuses with IUGR CPR and 42 normal fetuses. In 35 normal fetuses, blood flow across the atrio-ventricular valves was also recorded. Umbilical artery (UA), middle cerebral artery (MCA) and ductus venosus (DV) flows were obtained in all fetuses. Nonparametric tests were used for statistical analysis. RESULTS: There was a tendency towards increased E' and A' with fetal age in normal pregnancies. No correlation between tissue velocity and blood flow velocity was established. IUGR CPR fetuses had significantly lower E' and A', but when indexing to heart length, only A' remained significantly lower. E'/A' ratio was increased in the left ventricle but unchanged in the right. CONCLUSION: CDMI is easily applicable during standard fetal echocardiography and provides new information on the diastolic properties of the fetal myocardium. In fetuses with IUGR CPR, diastolic tissue velocities are abnormal and especially A' may be a marker of diastolic dysfunction. PMID- 21256663 TI - Evaluating the intra- and interobserver reliability of three-dimensional ultrasound and power Doppler angiography (3D-PDA) for assessment of placental volume and vascularity in the second trimester of pregnancy. AB - Three-dimensional (3-D) power Doppler angiography (3-D-PDA) allows visualisation of Doppler signals within the placenta and their quantification is possible by the generation of vascular indices by the 4-D View software programme. This study aimed to investigate intra- and interobserver reproducibility of 3-D-PDA analysis of stored datasets at varying gestations with the ultimate goal being to develop a tool for predicting placental dysfunction. Women with an uncomplicated, viable singleton pregnancy were scanned at 12, 16 or 20 weeks gestational age groups. 3 D-PDA datasets acquired of the whole placenta were analysed using the VOCAL software processing tool. Each volume was analysed by three observers twice in the A plane. Intra- and interobserver reliability was assessed by intraclass correlation coefficients (ICCs) and Bland Altman plots. At each gestational age group, 20 low risk women were scanned resulting in 60 datasets in total. The ICC demonstrated a high level of measurement reliability at each gestation with intraobserver values >0.90 and interobserver values of >0.6 for the vascular indices. Bland Altman plots also showed high levels of agreement. Systematic bias was seen at 20 weeks in the vascular indices obtained by different observers. This study demonstrates that 3-D-PDA data can be measured reliably by different observers from stored datasets up to 18 weeks gestation. Measurements become less reliable as gestation advances with bias between observers evident at 20 weeks. PMID- 21256664 TI - Real-time electro-mechano-acoustic imaging for monitoring interactions between trypsin and different inhibitors in articular cartilage. AB - The purpose of this study was to observe the real-time interactions between trypsin and various inhibitors in articular cartilage in vitro using a novel electro-mechano-acoustic imaging method. Monitored in real-time, articular cartilage specimens from bovine patellae were first treated with trypsin to reach half proteoglycan depletion (Phase I), then the trypsin solution was replaced with (i) physiological saline buffer (PS), (ii) fetal bovine serum (FBS), (iii) protease inhibitor cocktail (PI) and (iv) 10% formalin (F), respectively, to observe their effects on residual digestion (Phase II). Ultrasound radio frequency signals from the articular cartilage were used to form a M-mode image, where the interface between trypsin digested and intact cartilage tissues could be observed with an additional echo generated. The inhibition time, the digestion depth and digestion fraction were measured for each specimen. The results showed that the dilution of trypsin using saline solution was not sufficient to stop the enzyme action instantly. Although groups FBS and PI had a similar inhibition time of approximately 1.5 h, their digestion depth was obviously different (0.25+/ 0.03 and 0.06+/-0.06 mm, respectively). In contrast, formalin only took <30 min to stop the trypsin digestion with almost no further digestion. The results demonstrated that the current system was capable of monitoring the trypsin digestion and inhibition process in real time. Also, different chemicals affected the residual trypsin digestion to different degrees. PMID- 21256665 TI - Color Doppler twinkling artifact of calcified cardiac valves in vitro: a not well known phenomenon in echocardiography. AB - The color Doppler twinkling artifact manifests as a rapidly changing mixture of red and blue colors behind strongly reflective structures. The twinkling artifact occurs behind diseased cardiac valves, although the phenomenon is not well described. This study sought to determine the presence of the color Doppler twinkling artifact in calcified cardiac valves in vitro using soft tissue radiography for reference. Seventeen specimens of diseased cardiac valves from patients undergoing valve replacement surgery were studied. The overall sensitivity and specificity for the detection of calcifications using the presence of the twinkling artifact were 66.7% and 81.8%, respectively. If valves with only microcalcifications or smooth calcifications were eliminated from the analysis, all (100%) of the three valves with irregular macrocalcifications exhibited the twinkling artifact. It is important to recognize this artifact because it may lead to misdiagnosis of vascular flow in echocardiography. PMID- 21256666 TI - Gene therapy of carcinoma using ultrasound-targeted microbubble destruction. AB - When microbubble contrast agents are loaded with genes and systemically injected, ultrasound-targeted microbubble destruction (UTMD) facilitates focused delivery of genes to target tissues. A mouse model of squamous cell carcinoma was used to test the hypothesis that UTMD would specifically transduce tumor tissue and slow tumor growth when treated with herpes simplex virus thymidine kinase (TK) and ganciclovir. UTMD-mediated delivery of reporter genes resulted in tumor expression of luciferase and green fluorescent protein (GFP) in perivascular areas and individual tumor cells that exceeded expression in control tumors (p=0.02). The doubling time of TK-treated tumors was longer than GFP-treated tumors (p=0.02), and TK-treated tumors displayed increased apoptosis (p=0.04) and more areas of cellular drop-out (p=0.03). These data indicate that UTMD gene therapy can transduce solid tumors and mediate a therapeutic effect. UTMD is a promising nonviral method for targeting gene therapy that may be useful in a spectrum of tumors. PMID- 21256667 TI - A comparison of the imaging performance of high resolution ultrasound scanners for preclinical imaging. AB - Nine ultrasound transducers from six ultrasound scanners were assessed for their utility for preclinical ultrasound imaging. The transducers were: L8-16, L10-22 (Diasus; Dynamic Imaging Ltd., Livingston, UK); L17-5, L15-7io (iU22; Philips, Seattle, WA, USA), HFL38/13-6 (MicroMaxx; Sonosite Inc., Bothell, WA, USA); il3Lv (Vivid 5; GE, Fairfield, CT, USA), RMV 704 (Vevo 770; Visualsonics Inc., Toronto, Canada) and MS550S, MS550D (Vevo 2100; Visualsonics Inc.). A quantitative analysis of the ultrasound images from all nine transducers employed measurements of the resolution integral as an indication of the versatility and technology of the ultrasound scanners. Two other parameters derived from the resolution integral, the characteristic resolution and depth of field, were used to characterise imaging performance. Six of these transducers were also assessed qualitatively by ultrasonically scanning 59 female common marmosets (Callithrix jacchus) yielding a total of 215 scans. The quantitative measurements for each of the transducers were consistent with the results obtained in the qualitative in vivo assessment. Over a 0-10 mm imaging depth, the values of the resolution integral, characteristic resolution and depth of field, measured using the Edinburgh Pipe Phantom, ranged in magnitude from 7-72, 93-930 MUm and 3.3-9.2 mm respectively. The largest resolution integrals were obtained using the Vevo 770 and Vevo 2100 scanners. The Edinburgh Pipe Phantom provides a quantitative method of characterising the imaging performance of preclinical imaging scanners. PMID- 21256668 TI - Spatial-temporal mapping of bone structural and elastic properties in a sheep model following osteotomy. AB - The course of bone healing in animal models is conventionally monitored by morphologic approaches, which do not allow the determination of the material properties of the tissues involved. Mechanical characterization techniques are either dedicated to the macroscopic evaluation of the entire organ or to the microscopic evaluation of the tissue matrix. The latter provides insight to regionally specific alterations at the tissue level in the course of healing. In this study, quantitative scanning acoustic microscopy was used at 50 MHz to investigate microstructural and elastic alterations of mineralized callus and cortical tissue after transverse osteotomy in sheep tibiae. Analyses were performed after 2, 3, 6 and 9 weeks of consolidation with stabilization by either a rigid or a semi-rigid external fixator. Increased stiffness and decreased porosity were observed in the callus tissue over the course of the healing process, which was dependent on the fixator type. In the adjacent cortical tissue, stiffness decreased during the first 3 weeks. Cortical porosity increased over time but the time-dependence was different between the two fixator types. The changes of stiffness of cortical and callus tissues were measured with respect to the distance to the periosteal cortex-callus boundary. Stiffness of cortex and callus tissue smoothly decreased as a function of the distance from the inner cortical region. The data obtained in this study can help to understand the processes involved in tissue maturation during endogenous bone healing. PMID- 21256669 TI - Irrigation of continent catheterizable ileal pouches: tap water can replace sterile solutions because it is safe, easy, and economical. AB - BACKGROUND: Continent catheterizable ileal pouches require regular irrigations to reduce the risk of bacteriuria and urinary tract infections (UTIs). OBJECTIVE: Our aim was to compare the UTI rate, patient friendliness, and costs of standard sterile irrigation versus irrigation with tap water. DESIGN, SETTING, AND PARTICIPANTS: Twenty-three patients participated in a prospective randomized two arm crossover single-center trial. Aseptic intermittent self-catheterization (ISC) combined with sterile sodium chloride (NaCl) 0.9% irrigation was compared with clean ISC and irrigation with tap water (H(2)O) during two study periods of 90 d each. INTERVENTION: Patients underwent daily pouch irrigations with NaCl 0.9% solution or tap water. MEASUREMENTS: Urine nitrite dipstick tests were evaluated daily; urine culture (UC) and patient friendliness were evaluated monthly. Costs were documented. RESULTS AND LIMITATIONS: A total of 3916 study days with nitrite testing and irrigation were analyzed, 1876 (48%) in the NaCl arm and 2040 (52%) in the H(2)O arm. In the NaCl arm, 418 study days (22%) with nitrite-positive dipsticks were recorded, 219 d (11%) in the H(2)O arm, significantly fewer (p=0.01). Of the 149 UCs, 96 (64%) were positive, 48 in each arm, revealing a total of 16 different germs. All patients preferred the H(2)O method. Monthly costs were up to 20 times lower in the H(2)O arm. CONCLUSIONS: Pouch irrigation with sterile NaCl 0.9% solution and tap water had comparable rates of positive UC. Irrigation with tap water significantly lowered the incidence of nitrite-positive study days and was substantially less costly and more patient friendly than NaCl irrigation. We therefore recommend the use of tap water (or bottled water) instead of sterile NaCl 0.9% solution for daily irrigation of continent catheterizable ileal pouches. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12610000618055, http://www.ANZCTR.org.au/ACTRN12610000618055.aspx. PMID- 21256670 TI - Acupuncture versus paroxetine for the treatment of premature ejaculation: a randomized, placebo-controlled clinical trial. AB - BACKGROUND: Acupuncture therapy has been used by many researchers in both male and female sexual dysfunction studies. OBJECTIVE: To determine whether acupuncture is effective as a premature ejaculation (PE) treatment compared with paroxetine and placebo. DESIGN, SETTING, AND PARTICIPANTS: The study was conducted with methodologic rigor based on Consolidated Standards of Reporting Trials (CONSORT) criteria. Ninety patients referred to the urology clinic at a tertiary training and research hospital with PE were included in this randomized controlled trial and randomly assigned into paroxetine, acupuncture, and placebo groups. Heterosexual, sexually active men aged between 28 and 50 yr were included. Men with other sexual disorders, including erectile dysfunction; with chronic psychiatric or systemic diseases; with alcohol or substance abuse; or who used any medications were excluded. INTERVENTION: The medicated group received paroxetine 20 mg/d; the acupuncture or sham-acupuncture (placebo) groups were treated twice a week for 4 wk. MEASUREMENTS: Intravaginal ejaculation latency times (IELTs) and the Premature Ejaculation Diagnostic Tool (PEDT) were used to assess PE. IELTs were calculated by using a partner-held stopwatch. Data were analyzed statistically. RESULTS AND LIMITATIONS: Median PEDT scores of paroxetine, acupuncture, and placebo groups were 17.0, 16.0, and 15.5 before treatment, and 10.5, 11.0, and 16.0 after treatment, respectively (p=0.001, p=0.001, and p=0.314, respectively). Subscores after treatment were significantly lower than subscores before treatment in the paroxetine and acupuncture groups but remained the same in the placebo group. Significant differences were found between mean-rank IELTs of the paroxetine and placebo groups (p=0.001) and the acupuncture and placebo groups (p=0.001) after treatment. Increases of IELTs with paroxetine, acupuncture, and placebo acupuncture were 82.7, 65.7, and 33.1 s, respectively. Extent of ejaculation delay induced by paroxetine was significantly higher than that of acupuncture (p=0.001). The most important limitation of the study was the lack of follow-up. CONCLUSIONS: Although less effective than daily paroxetine, acupuncture had a significant stronger ejaculation-delaying effect than placebo. PMID- 21256671 TI - Consensus criteria for the use of magnetic resonance imaging in the diagnosis and staging of prostate cancer: not ready for routine use. PMID- 21256672 TI - Residues of bioenergy production chains as soil amendments: immediate and temporal phytotoxicity. AB - The current shift towards bioenergy production increases streams of bioenergy rest-products (RPs), which are likely to end-up as soil amendments. However, their impact on soil remains unclear. In this study we evaluated crop phytotoxicity of 15 RPs from common bioenergy chains (biogas, biodiesel, bioethanol and pyrolysis). The RPs were mixed into a sandy soil and the seedling root and shoot elongation of lettuce (Lactuca sativa L.), radish (Raphanus sativus L.), and wheat (Triticum aestivum L.) were measured. Immediate phytotoxic effects were observed with biodiesel and bioethanol RPs (root elongation reduced to 14-60% for the three crops; P<0.05). However, phytotoxicity was no longer significant after seven days. Digestates had no phytotoxic effect whereas biochars ranged from beneficial to detrimental depending on the original feedstock and temperature of pyrolysis. Biochar amendment alleviated phytotoxicity of bioethanol by-products for wheat and radish. Phytotoxicity assessment is critical for successful soil amendment with bioenergy RPs. PMID- 21256673 TI - Polyacrylamide-clinoptilolite/Y-zeolite composites: characterization and adsorptive features for terbium. AB - The composites of natural (clinoptilolite) and synthetic zeolite (Z and YZ) with polyacrylamide (PAAm) were synthesized and characterized by FT-IR, TGA, XRD, SEM and PZC analysis. The adsorptive features of the minerals and its composites were investigated for Tb analogues to the rare earth elements (REs) by isotopic tracer method, (160)Tb was the radiotracer. The composites were the hybrid formations of PAAm and Z or YZ. Tb adsorption capacities of the composites were higher than those of bare Z and YZ. The compatibility of Tb adsorption kinetics to the second order and Weber-Morris models implied that the sorption process was chemical via ion exchange. The values of enthalpy and entropy changes were positive and the negative free enthalpy change was evidence for the spontaneity of adsorption. The reusability tests for the composites for five uses demonstrated that the adsorbents could be reused after complete recovery of the loaded ion. Unlike PAAm YZ, PAAm-Z was resistant to acidic environment. The overall results eventually suggested that the composite of Z and PAAm was a potential cost effective adsorbent for Tb(3+) and REs. PMID- 21256674 TI - Gas-bubbled nano zero-valent iron process for high concentration arsenate removal. AB - In this study, batch experiments were performed to investigate a novel process for high concentration arsenate removal in the presence of air and/or CO(2) bubbling. The pretreatment step, CO(2) bubbling at 300 mL/min for 5 min, was taken to adjust the solution pH to an acidic environment, followed by air bubbling at 300 mL/min for 10 min to increase dissolved oxygen in the solution. In the treatment period, the nano-scale zero-valent iron was applied to remove aqueous arsenate of 3000 MUg/L, while the treatment system was continuously bubbled by 300 mL/min of air. Such a process resulted in outstanding performance in arsenate removal. Furthermore, in the field groundwater application, the arsenate removal rate for the proposed process was 5 times faster than the rate measured when the system was pretreated by acidic chemical species only. PMID- 21256675 TI - Behavioral indices of ongoing pain are largely unchanged in male mice with tissue or nerve injury-induced mechanical hypersensitivity. AB - Despite the impact of chronic pain on the quality of life in patients, including changes to affective state and daily life activities, rodent preclinical models rarely address this aspect of chronic pain. To better understand the behavioral consequences of the tissue and nerve injuries typically used to model neuropathic and inflammatory pain in mice, we measured home cage and affective state behaviors in animals with spared nerve injury, chronic constriction injury (CCI), or intraplantar complete Freund's adjuvant. Mechanical hypersensitivity is prominent in each of these conditions and persists for many weeks. Home cage behavior was continuously monitored for 16 days in a system that measures locomotion, feeding, and drinking, and allows for precise analysis of circadian patterns. When monitored after injury, animals with spared nerve injury and complete Freund's adjuvant behaved no differently from controls in any aspect of daily life. Animals with CCI were initially less active, but the difference between CCI and controls disappeared by 2 weeks after injury. Further, in all pain models, there was no change in any measure of affective state. We conclude that in these standard models of persistent pain, despite the development of prolonged hypersensitivity, the mice do not have significantly altered "quality of life." As alteration in daily life activities is the feature that is so disrupted in patients with chronic pain, our results suggest that the models used here do not fully reflect the human conditions and point to a need for development of a murine chronic pain model in which lifestyle changes are manifest. PMID- 21256676 TI - Serological profile of Toxoplasma gondii and Neospora caninum infection in commercial sheep from Sao Paulo State, Brazil. AB - Neosporosis and toxoplasmosis are two important infections in young and adult sheep, leading to low production and abortion. This study aimed to determine the frequency of antibodies to Toxoplasma gondii and Neospora caninum in sheep from the eastern region of Sao Paulo State, Brazil. Serum samples (382) were collected from the sheep and assayed for T. gondii through modified agglutination test (MAT) and indirect fluorescent antibody test (IFAT), and for N. caninum antibodies, through IFAT, with cut-off titers equal to 16 (T. gondii) and 25 (N. caninum). All frozen samples were sent to the Center for Zoonoses Research (NUPEZO), Department of Veterinary Hygiene and Public Health (DHSVP), FMVZ, UNESP, for serological tests. A total of 71/382 (18.6%) samples reacted to T. gondii, especially at titers 16 (28; 39.4%), 64 (15; 21.1%), 256 (21; 29.6%) and 1024 (6; 8.5%) by MAT, and 16 (34; 47.9%), 64 (18; 25.4%), 256 (14; 19.7%) and 1024 (5; 7%) by IFAT. As regards N. caninum, 49/382 (12.8%) samples reacted at titers 25 (17; 34.7%), 50 (11; 22.5%), 100 (11; 22.5%), and >= 200 (10; 20.4%). These animals presented infection but no clinical signs. Six and ten animals had high titers for toxoplasmosis and neosporosis. No significant association was observed between antibodies for both parasites (P=0.535) according to Fisher's exact test, and no correlation was found between T. gondii (MAT) and N. caninum antibody titers (r=-0.0068; P=0.895), T. gondii (IFAT) and N. caninum antibody titers (r=-0.0025; P=0.961). Thus, T. gondii and N. caninum infections were observed in farms located in Sao Paulo State, where sheep play an important economical role for the national and regional business. PMID- 21256677 TI - Re-establishing functionality and aesthetics after severe burns over the proximal interphalangeal joint using the cross-digital dorsal adipofascial flap. PMID- 21256678 TI - Estimating the usage of allograft in the treatment of major burns. AB - AIM: To assess the amount of allograft used in the past treatment of major burns and calculate a figure to guide estimation of the quantity of allograft required to treat future patients and aid resource planning. METHODS: A retrospective observational study. Records of 143 patients treated with major burns at a regional centre, from January 2004 to November 2008 were accessed with biometric data and quantity of allograft used being recorded. This data was used to calculate an allograft index (cm2 allograft used/burn surface area (cm2)) (AI) for each patient. RESULTS: 112 of the 143 patients had complete sets of data, of the 112, 89 patients survived the initial stay in hospital. For all data average AI=1.077 +/- 0.090. AI varied according to burn % area with burns < 40% requiring 0.490 cm2 allo/cm2burn, increasing in a logarithmic fashion (R2=0.995) for burn areas > 40%. CONCLUSIONS: The ability to estimate deceased donor skin requirements based on % body surface area affected is important in the care planning for patients with major burns. Our findings of 0.5 cm2 allograft/cm2 burn for injuries less than 40% TBSA, increasing to 1.82 cm2 allograft/cm2 burn for injuries up to 80% TBSA can be used for planning purposes for individual services and for burn disaster planning. PMID- 21256679 TI - Chronic pain therapy and hypothalamic-pituitary-adrenal axis impairment. AB - Opiates and/or nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most effective therapies for chronic pain, but their prolonged time of use can affect health conditions through physical and psychological side effects. They include the very common gastrointestinal effects and changes that can induce osteoporosis, depression, impaired cognition and a generally poor quality of life, which per se can induce and maintain a chronic painful condition. For this reason it is becoming imperative to expand our knowledge of the interaction of these substances with body functions apparently not directly involved in nociception and pain, such as neuroendocrine functions. The purpose of this study was to determine, in male and female patients suffering from chronic pain, the effect of conventional pain therapy (opiates, NSAIDs) on hypothalamic-pituitary adrenal (HPA) axis function. This was assessed by measuring the blood levels of adrenal-related hormones (adrenocorticotrophin hormone, ACTH; cortisol; dehydroepiandrosterone, DHEA and dehydroepiandrosterone sulfate, DHEAS). The second purpose of the study was to test the hypothesis that these hormones are associated with the psychological profile shown by the chronic pain patients. The results showed significant changes induced by pain therapy on the HPA axis: ACTH, cortisol, DHEA and DHEAS blood levels decreased in all subjects taking opiates or NSAIDs to treat pain. Moreover these changes showed significant correlations with psychological features of the subjects depending on age and sex. PMID- 21256680 TI - Endocrinological and psychological responses to job stressors: an experimental test of the job demand--control model. AB - The buffer hypothesis of the Job Demand-Control Model predicts that high levels of job control compensate for the negative effects of high job demands on well being and health. Several studies have tested this hypothesis, but the results are far from consistent. The objective of this study was to test the buffer hypothesis with respect to psychological (subjective well-being) and physiological (salivary cortisol) indicators of job strain, using an experimental study design. Seventy-seven men and women worked at a simulated computer workplace for more than two hours. Job demands and job control were manipulated in a 2 (job demands: high vs. low)*2 (job control: high vs. low)*7 (time of measurement) study design. Demands were operationalized in terms of workload, and pacing control (self-paced vs. machine-paced) was used as a job control manipulation. As dependent variables, subjective well-being and salivary cortisol were measured at seven time points during the experiment (T1-T7). In line with the buffer hypothesis, high control eliminated the impact of high demands on salivary cortisol responses. The hypothesis was supported by a predicted significant three-way interaction of demands, control and time of measurement (p<.001), qualified by the absence of significant effects of the independent variables at T1 and T2 due to lagged cortisol reactions, and significant two-way interactions of demands and control, as predicted by the model, at the five remaining times of measurement (T3-T7): high demands led to increased cortisol reactions only in the low control condition. In contrast, no main or interaction effects of the independent variables were found for subjective well-being. This discrepancy between physiological and psychological stress reactions might be due to the lack of specificity inherent in measures of subjective well-being, due to lagged psychological reactions, or due to self-report biases in the subjective measures. In sum, this study provides the first clear-cut experimental evidence for the idea that the negative impact of high job demands on endocrinological responses can be buffered by high levels of job control. PMID- 21256681 TI - Tumor-targeted delivery of TAT-Apoptin fusion gene using Escherichia coli Nissle 1917 to colorectal cancer. AB - In view of the high incidence and mortality of the colorectal cancer, the limited efficacy and serious adverse effect of the conventional treatment, a novel alternative treatment needs to be developed. Recent studies have demonstrated that the targeted therapy as an alternative treatment showed a promising prospect. We hypothesized that construct a recombination non-pathogenic Escherichia coli Nissle 1917 (EcN), inserting a fusion gene TAT-Apoptin into this probiotic vector, as a targeted therapy strategy for patients of colorectal cancer. Compared with conventional treatments for tumors, the recombination EcN containing TAT-Apoptin fusion gene is capable of tumor-specific colonization, secretary expression and efficient intracellular delivery and therefore able to reduce the incidence of side effect and promote the efficiency of treatment. PMID- 21256682 TI - Effect of prolonged heat treatment from 48 degrees C to 63 degrees C on toughness, cooking loss and color of pork. AB - The effect of low temperature long time (LTLT) heat treatment at 48 degrees C, 53 degrees C, 58 degrees C, and 63 degrees C for T(c) (time to reach a core temperature equal to the water bath), T(c)+5h holding time, and T(c)+17h holding time was studied in Longissimus dorsi and Semitendinosus muscles from slaughter pigs and sows. Meat toughness (Warner-Bratzler Shear Force), cooking loss and color (Minolta L*a*b*-values) was measured and in the cooking loss the amount of heat-soluble collagen and activity of cathepsin B+L was determined. Decreasing shear force and increasing cooking loss during LTLT treatment was observed between 53 degrees C and 58 degrees C. Furthermore, increasing temperature from 53 degrees C to 58 degrees C and increasing time from T(c) to T(c)+17h increased the solubility of collagen. Residual activity of cathepsin B+L in LTLT treated pork was mainly affected by temperature, showing the highest activity at 58 degrees C and 63 degrees C. PMID- 21256683 TI - Effects of iron deficiency on neonatal behavior at different stages of pregnancy. AB - Animal and human studies have shown that prenatal and postnatal iron deficiency is a risk factor for behavioral, emotional and cognitive development. The aim of this study was to determine the associations between iron status of pregnant women and the behavior of their newborn, taking into account the timing in which the deficit occurs. This study was conducted in Spain (developed country) where: the general population is well-nourished; during pregnancy routine obstetrical checks are carried out; and pregnant women are systematically iron supplemented. A total of 216 healthy and well-nourished pregnant women and their term, normal weight newborn participated in this study. The neonatal behavior was assessed by the Neonatal Behavior Assessment Scale (NBAS). The results showed that in the first and second trimesters of pregnancy, iron deficiency was a weak and significant predictor of the NBAS autonomous nervous system cluster score, and in the third trimester, this condition predicted the NBAS motor and state organization clusters score and the NBAS robustness and endurance supplementary item. In conclusion, iron deficiency during pregnancy is related to the neonate's general autonomous response, motor performance and self regulation capabilities. PMID- 21256684 TI - Influence of seminal plasma on fresh and post-thaw parameters of stallion epididymal spermatozoa. AB - Fresh and post-thaw parameters (motility, morphology and viability) of stallion epididymal spermatozoa that have been and have not been exposed to seminal plasma were evaluated, and directly compared to fresh and post-thaw parameters of ejaculated spermatozoa. Six sperm categories of each stallion (n=4) were evaluated for motility, morphology and viability. These categories were fresh ejaculated spermatozoa (Fr-E), fresh epididymal spermatozoa that had been exposed to seminal plasma (Fr-SP+), fresh epididymal spermatozoa that had never been exposed to seminal plasma (Fr-SP-), frozen-thawed ejaculated spermatozoa (Cr-E), frozen-thawed epididymal spermatozoa that had been exposed to seminal plasma prior to freezing (Cr-SP+) and frozen-thawed epididymal spermatozoa that had never been exposed to seminal plasma (Cr-SP-). Results show that seminal plasma stimulates initial motility of fresh epididymal stallion spermatozoa while this difference in progressive motility is no longer present post-thaw; and that progressive motility of fresh or frozen-thawed ejaculated stallion spermatozoa is not always a good indicator for post-thaw progressive motility of epididymal spermatozoa. This study shows that seminal plasma has a positive influence on the incidence of overall sperm defects, midpiece reflexes and distal cytoplasmic droplets in frozen-thawed stallion epididymal spermatozoa while the occurance of midpiece reflexes is likely to be linked to distal cytoplasmic droplets. Furthermore, seminal plasma does not have an influence on viability of fresh and frozen-thawed morphologically normal epididymal spermatozoa. We recommend the retrograde flushing technique using seminal plasma as flushing medium to harvest and freeze stallion epididymal spermatozoa. PMID- 21256685 TI - Ultrasonographic and endocrine aspects of follicle deviation, and acquisition of ovulatory capacity in buffalo (Bubalus bubalis) heifers. AB - The objectives of this study were to determine the interval from ovulation to deviation and the diameter of the dominant (DF) and largest subordinate (SF) follicles at deviation in buffalo (Bubalus bubalis) heifers. Two methods of evaluation (observed vs. calculated) were used. FSH and LH profiles encompassing follicle deviation (Experiment 1), and the follicular diameter when the DF acquired ovulatory capacity (Experiment 2) were also determined. The time of deviation and the diameter of the DF and the largest SF at deviation did not differ between observed and calculated methods. Overall, follicle deviation occurred 2.6 +/- 0.2d (mean +/- SEM) after ovulation, and the diameters of the DF and SF at deviation were 7.2 +/- 0.2 and 6.4 +/- 0.2mm, respectively. No changes in plasma levels of FSH or LH were observed (P=0.32 and P=0.96, respectively). Experiment 2 was conducted in two phases according to the diameter of the DF during the first wave of follicular development at the time of LH challenge (25mg of pLH). In the first phase, follicles ranging from 5.0 to 6.0mm (n=7), 6.1 to 7.0mm (n=11), or 7.1 to 8.0mm (n=9) were used, and in the second phase, follicles ranging from 7.0 to 8.4mm (n=10), 8.5 to 10.0mm (n=10), or 10.1 to 12.0mm (n=9) of diameter were used. After the pLH treatment, the DF was monitored by ultrasonography every 12h for 48h. No ovulations occurred in heifers in the first phase. However, in the second phase, an effect of follicular diameter was observed on ovulation rate [7.0-8.4mm (0.0%, 0/10), 8.5-10.0mm (50.0%, 5/10), and 10.0-12.0mm (55.6%, 5/9)]. In summary, follicle deviation occurred 2.6d after ovulation in buffalo (B. bubalis) heifers, when the diameters of the DF and SF were 7.2 and 6.4mm, respectively. No significant changes in plasma concentrations of FSH or LH were detected. Finally, the acquisition of ovulatory capacity occurred when the DF reached 8.5mm in diameter. PMID- 21256686 TI - Intraosseous cavernous hemangioma of the middle turbinate. AB - Hemangiomas mostly arise from the soft tissues, and intraosseous hemangiomas are uncommon. They usually occur in the vertebra and skull bones, and intraosseous hemangioma of the nasal cavity is exceedingly rare. We describe a 56-year-old woman who was referred to our hospital with a tumor in her right nasal cavity, without subjective symptoms such as epistaxis. The tumor was located at the front end of the right middle turbinate. Enhanced computed tomography demonstrated a 3 cm*2cm expansive bony tumor replacing the bottom of the right middle turbinate with some partial enhancement effects. The characteristic honeycomb appearance was observed. The tumor and right middle turbinate were excised en bloc by the endoscopic endonasal approach. No complications or severe bleeding occurred during the peri-operative period. Histological examination showed endothelium lined blood-filled vascular spaces within the bony trabeculae, which suggested the typical pattern of intraosseous cavernous hemangioma. To the best of our knowledge, this is the first case report of intraosseous cavernous hemangioma of the middle turbinate in the English literature. PMID- 21256687 TI - Developmental status of 5-year-old moderate low birth weight children. AB - BACKGROUND: Low birth weight (LBW or birth weight<2500 g) is one of the most serious children problems in today's world. The purpose of this study was to evaluate and compare developmental status of moderately LBW (birth weight: 1500 2499 g) children at the age of five to that of normal birth weight (NBW: birth weight: 2500-4000 g) ones. METHODS: In a case-control study, developmental status of five year old children referred for vaccination between December 2008 and June 2009 in Yazd-Iran, evaluated via Persian version of 60-month Ages and Stages Questionnaires (ASQ). NBW and MLBW children were selected as control and case groups, respectively. RESULTS: Frequency of developmental delay in gross motor, fine motor and problem solving domains were significantly higher in MLBW group and mean score in all developmental domains was statistically significant lower in case group. CONCLUSION: LBW is one of risk factors for developmental delay. So, evaluation and monitoring of development status of LBW should be emphasized for early and timely diagnosis, investigation, management and also rehabilitation. PMID- 21256688 TI - [Social inequalities in health from observational studies to intervention: can the patient navigator reduce social inequalities in cancer patients?]. AB - The impact of social factors on healthcare inequality is well-recognized in many industrialized countries and involves a wide range of pathological conditions (cardiovascular disease, cancer, etc.). In general, the poorest indicators of health are observed in socially disadvantaged populations. Beyond this observation is the question of actions taken to prevent the formation of social inequality in healthcare. The purpose of this work was to evaluate the potential contribution of an intervention tool called the "patient navigator", used in English-speaking countries and to determine its feasibility in France. PMID- 21256689 TI - [Prevention of unintended pregnancies: toward a dual protection at sexual debut?]. AB - BACKGROUND: Despite the expanded range of contraceptive options and the fact that the first acts of intercourse are well protected, abortion rates among young women in France have increased in the last 15 years. These contraceptive failures could result from the lower effectiveness of the condom compared with the pill, and/or the occurrence of contraceptive gaps when switching from the condom to the pill. Adding to the existing literature, this paper explores the conditions by which women and men discontinue using the condom. METHODS: The study sample was comprised of 1552 men and 1849 women under the age of 30, who participated in the National Survey on Sexual Health in France. Respondents answered questions on contraceptive use, duration of condom use, condom discontinuation and the switch to another method of contraception at the time of condom discontinuation in the context of their first and last sexual relationships. RESULTS: Condoms, used by a large majority of respondents during the first acts of intercourse, were rapidly discontinued in favor of other methods, particular the pill, for continuing relationships. However, one in ten respondents (women and men alike) had unprotected intercourse after condom discontinuation, when condom use was discontinued in the first trimester of their relationship. Abortions were more frequent among respondents who reported they did not use a condom at the start of a relationship or among women who did not switch to another form of contraception after discontinuing condom use. CONCLUSION: While condoms are widely used during the first acts of intercourse, the rising abortion rates among young people suggests frequent contraceptive failures, which partly result from unprotected intercourse following condom discontinuation. These results question the dichotomy between HIV campaigns based on condom use and campaigns to reduce unintended pregnancies, which promote use of other forms of contraception, such as the pill. To reduce the incidence of unprotected intercourse, it would be important to promote the use of condoms at sexual debut, both as a contraceptive and preventive method against STIs, and provide counseling about all available contraceptive options, including the use of emergency contraception as a backup option in case of errors of use of the condom. PMID- 21256690 TI - Use of rapid prototyping and three-dimensional reconstruction modeling in the management of complex fractures. AB - BACKGROUND: The production of a copy of the fracture or a deformity in a bone with a complex geometry can be one of the important applications of the integration between two modern computer-based technologies, reverse engineering (RE) and rapid prototyping (RP). METHODS: This article reviews recent development in this field and present a case series about the use of medical CT/MRI scanning, three-dimensional reconstruction, anatomical modeling, computer-aided design, RP and computer-aided implantation in treating a complex fracture of acetabulums, calcaneum, and medial condyle of femur (Hoffa's fracture). CONCLUSION: The use of RP technology helped us to understand the fracture configuration and to achieve near anatomical reduction. With this we believe, this technology will reduce the surgical time as was observed in our cases. This consequently, will lower the requirement of an anesthetic dosage and decrease the intraoperative blood loss.In summary, the merging of computational analysis, modeling, designing, and fabrication will serve as important means to treat conditions and fractures around joints, spine, acetabulum, and craniofacial region. LEVEL OF EVIDENCE: Level 4, case series. PMID- 21256691 TI - Extrapyramidal symptom masquerading as subarachnoid hemorrhage. PMID- 21256692 TI - Evaluation of the "Consultation and Relational Empathy" (CARE) measure by means of Rasch-analysis at the example of cancer patients. AB - OBJECTIVE: The aims of this study are: (1) analysis of unidimensionality of the German version of the "Consultation and Relational Empathy" (CARE) measure and (2) identification of moderating variables affecting the scale structure. METHODS: The CARE-measure was evaluated by means of Rasch-analysis in a sample of N=326 cancer patients. Association of diagnosis and treatment as well as patients' characteristics was analyzed by person-fit measures and Differential Item Functioning. RESULTS: Nine of the original 10 CARE items fit to the Rasch model. For breast and prostate cancer, as well as for patients taking complementary and alternative medicine treatment, item biases affect the scale structure. Furthermore, older patients and patients with higher social support exhibit substantial deviations from model predictions. CONCLUSIONS: Only the nine item version of the CARE-measure allows for the unidimensional assessment of physician empathy. Especially for specific diagnosis and treatment groups, the CARE-items indicate variations in the underlying latent construct of physician empathy. PRACTICE IMPLICATIONS: The CARER-measure provides a theory-based and psychometrically sound basis for the assessment of PE. It can be used to enhance the fairness of the assessment and to further identify valuable information about the influence of patient characteristics on the structure of the construct PE. PMID- 21256693 TI - Tumor necrosis factor-alpha inhibits the stimulatory effect of luteinizing hormone and prostaglandin E(2) on progesterone secretion by the bovine corpus luteum. AB - Tumor necrosis factor-alpha (TNF-alpha) is involved in the tissue remodeling that occurs in the corpus luteum (CL) during its development and regression. This cytokine is also implicated in the regulation of reproduction by its actions on ovarian steroidogenic cells. The aim of this study was to examine the influence of TNF-alpha on (1) progesterone (P(4)) output by the bovine CL and on (2) the responsiveness of the CL to LH or prostaglandin E(2) (PGE(2)) in vitro. In experiment 1, CL (days 8 to 10 of the estrous cycle) were perfused by using an in vitro microdialysis system with TNF-alpha (0.1, 0.5, or 1 MUg/mL) alone or with TNF-alpha (1 MUg/mL) followed by LH (1000 ng/mL) or PGE(2) (2 * 10(-5) M). Basal P(4) release (P < 0.05) was increased by TNF-alpha (0.5 or 1 MUg/mL). Moreover, TNF-alpha (1 MUg/mL) inhibited the stimulatory effect of LH or PGE(2) on P(4) output (P < 0.05). In experiment 2, 4 h after intrauterine infusion of TNF-alpha (0.01 MUg/mL or 1 MUg/mL), CL (days 8 to 10 of the estrous cycle) were collected by colpotomy, cultured, and stimulated with LH (10 ng/mL) or PGE(2) (10(-6) M). Intrauterine infusion of TNF-alpha at a concentration of 1 MUg/mL increased basal P(4) output by CL (P < 0.05). Moreover, the intrauterine infusion of TNF-alpha at a concentration of 0.01 MUg/mL inhibited the stimulatory effect of LH or PGE(2) on P(4) output (P < 0.05). These results indicate that TNF-alpha (1) does not have an effect on the autonomous, pulsatile release of P(4); (2) increases P(4) secretion by bovine CL with increasing doses, and (3) reduces in a dose-dependent manner the responsiveness of CL to luteotropic factors both directly (after infusion to CL) and indirectly (after intrauterine infusion). PMID- 21256694 TI - [Infections at risk for epidemic or biological threat. Importance of the initial management of suspect patients]. PMID- 21256695 TI - Outcomes of unicompartmental knee arthroplasty stratified by body mass index. AB - Patients who have high body mass indices can have disabling medial compartment knee osteoarthritis, which might benefit from unicompartmental knee arthroplasty (UKA). The purpose of this study was to compare clinical and radiographic outcomes of UKAs in patients with body mass indices (BMIs) greater and less than 35 kg/m(2). Thirty-four patients (40 knees) had BMIs of 35 kg/m(2) or greater, whereas the remaining 33 patients (40 knees) had BMIs below 35 kg/m(2), with 2 year minimum follow-up. In the high-BMI group, 5 knees were revised to total knee arthroplasty, compared with none in the lower BMI group. Knee Society scores were lower in the surviving high-BMI knees. All surviving components were radiographically stable. The results suggest that UKA should be approached with caution in patients who have high BMIs. PMID- 21256696 TI - A comparison between imageless navigated and manual freehand technique acetabular cup placement in total hip arthroplasty. AB - The purpose of this study was to compare acetabular component positioning using an imageless system to a matched control group using conventional techniques. Thirty procedures were performed using navigation. A multislice computed tomographic scan was used to assess cup position. There was no significant difference between mean inclination (P = .11) and anteversion (P = .24) but a statistical significant difference for mean deviation from the desired position for inclination (P = .003) and anteversion (P = .007). There was a significant difference in the percentages of correctly placed cups with inclination (P = .046) and with anteversion (P = .006). Combining both anteversion and inclination, there was a significant difference (P = .01). We demonstrated a significant increase in accuracy of placement of acetabular cups within the desired position and safe zone using imageless navigation. PMID- 21256697 TI - Effects of simvastatin on osseointegration in a canine total hip arthroplasty model: an experimental study. AB - Simvastatin was recently demonstrated to stimulate bone morphogenetic protein-2 expression, leading to bone formation. The present study was designed to evaluate whether simvastatin administered by injection could promote osseointegration in a canine total hip arthroplasty model. Fifteen dogs were divided into 3 groups of 5 dogs each: group 1 (high-dosage simvastatin, 6.0 mg/[kg d]), group 2 (low-dosage simvastatin, 3.0 mg/[kg d]), and a control group (isotonic saline, 3.0 mg/[kg d]). Osseointegration was assessed by using the push-out test, scanning electron microscopy, energy-dispersive spectrometer microanalysis, and histomorphometric examination. The results showed higher mechanical strength, greater area of bone covering the femoral component, and higher bone-implant contact in group 1 than in the other 2 groups. Our findings indicate that simvastatin administered by injection could contribute significantly to osseointegration in a canine total hip arthroplasty model. PMID- 21256698 TI - Prevalence and risk factors of thromboembolism after joint arthroplasty without chemical thromboprophylaxis in an Asian population. AB - Venous thromboembolism (VTE) is a serious complication after major orthopedic surgery. This study examined the prevalence and risk factors of VTE in patients undergoing arthroplasty without thromboprophylaxis. A total of 1608 patients who underwent elective knee or hip arthroplasty between 1996 and 2009 were evaluated. The incidence of VTE was 1.99% (n = 32). Of them, 0.24% (n = 4) were diagnosed with a pulmonary embolism. The risk factors associated with VTE were female sex, revision surgery, bilateral simultaneous procedure, CVA (cerebrovascular accident; thromboembolic stroke) history, and preoperative platelet count (all P > .05). There was an annual increase in the prevalence of VTE from 1996 to 2009 (P = .002). According to these results, thromboprophylaxis is strongly recommended in high-risk groups of Korean arthroplasty patients. PMID- 21256699 TI - Ten-year follow-up of avascular necrosis of femoral head treated with alendronate for 3 years. AB - Although all the recent reports of the use of bisphosphonates in avascular necrosis of femoral head (AVNFH) have been encouraging, none has studied long term effects of this novel therapy. We therefore performed a 10-year follow-up study of 40 patients (53 hips) of AVNFH treated with 3-year-long oral alendronate therapy. Rates of clinical failure defined as need for further surgical intervention, of radiologic progression for the Ficat-Arlet scale, and of collapse of femoral head showed marked reduction even at 10 years as compared to the historical data available for natural history of hips with untreated AVNFH. Alendronate given for 3 years maintains its beneficial effects for as long as 10 years and hence is a worthwhile option to postpone the need for arthroplasty in these young and active patients. PMID- 21256700 TI - Short-term coagulation complications following total knee arthroplasty: a comparison of patient-reported and surgeon-verified complication rates. AB - Data from 3278 patients from a prospective patient-centered total joint registry was used to investigate the rates of complications in the first 6 months following primary total knee arthroplasty. All patients reporting deep venous thrombosis (DVT), pulmonary embolism (PE), or major bleeding were identified through patient self-reporting. Complications were verified by a review of imaging records and direct communication with patients by a surgeon. Surgeon verified rates of DVT, PE, and major bleeding were 1.52%, 0.49%, and 0.34%, respectively. When compared with the complication rates as reported by patients, concordance was 86.2% for DVT, 84.2% for PE, and 36.7% for major bleeding. More than half (54.5%) of the complications were diagnosed and treated at the original operative hospital, and 45.5% were diagnosed and treated at other institutions. PMID- 21256701 TI - Anterior-posterior glide mobile-bearing total knee arthroplasty: complications related to prosthesis design. AB - The aim of this study was to evaluate complications related to prosthesis design in patients managed with cemented total knee arthroplasty using anterior posterior glide mobile-bearing prosthesis. One hundred eighty-three total knee arthroplasties were performed using this prosthesis on 146 patients, with a minimum of 7 years of follow-up. There were late dislocations of the bearing in 2 knees, anterior soft tissue impingements in 6 knees at an earlier follow-up, excessive anteroposterior translation in 5 knees, and a fracture of the femoral component induced by osteolysis in 1 knee. Design modifications in the restraint mechanisms of the anterior-posterior glide mobile-bearing prosthesis may be required to minimize the development of complications with regard to sagittal instability and to improve the prosthesis' longevity. PMID- 21256702 TI - A rare case of diffuse pigmented villonodular synovitis after total knee arthroplasty. AB - Pigmented villonodular synovitis is a benign, proliferative disorder of unknown etiology that mainly affects the synovium of the joint, bursa, and the tendon sheath. The most common joint affected is the knee. Pigmented villonodular synovitis presents in either of 2 distinct forms, localized or diffuse. In this report, we describe a case of diffuse pigmented villonodular synovitis that presented in the knee 18 months after total knee arthroplasty. The diagnosis was suggested by histologic analysis of bloody aspirate and by abnormal synovial proliferation noted at arthroscopy and confirmed by histologic analysis of the resected tissue. PMID- 21256703 TI - 'Delamination and adhesive wear behavior of alpha-tocopherol-stabilized irradiated ultrahigh-molecular-weight polyethylene". PMID- 21256704 TI - Noise, numbness, and kneeling difficulties after total knee arthroplasty: is the outcome affected? AB - The sensation of numbness, prosthesis noise production, and kneeling difficulties are generally considered, by most surgeons, minor issues after total knee arthroplasty, but their frequency and relationship to patient expectations and satisfaction have been seldom described. We analyzed 49 patient responses to both an Oxford Knee Score and a separate questionnaire with specific questions about numbness, kneeling, and noise. Of these patients, 69% reported noise production, 71% reported numbness, and 82% reported kneeling difficulties. The mean scores for the magnitude of numbness and kneeling difficulties improved between the time frames of less than 6 months and more than 6 months postoperation, whereas noise scores worsened. None of these changes were statistically significant at the 5% level. Combinations of these issues do affect patient satisfaction and are greater for patients more than 6 months postoperation. A preoperative patient education program, informing patients about these issues, may improve patient satisfaction. PMID- 21256705 TI - Hidden blood loss after total hip arthroplasty. AB - A prospective study was carried out to analyze the characteristics of hidden blood loss after total hip arthroplasty (THA) in a series of 1232 patients. The method of deducting the observed perioperative blood loss from the calculated total blood loss based on hematocrit changes was used to calculate the hidden blood loss of each patient. The reinfused and transfused bloods were also considered. We found that the amount of hidden blood loss after THA was much larger than we observed perioperatively and significantly different between differently diagnosed patients. We concluded that THA can cause a large amount of hidden blood loss, which should be monitored carefully. Retaining and repairing the articular capsule is recommended during the operation, which can significantly decrease hidden blood loss. PMID- 21256706 TI - Prescription sharing, alcohol use, and street drug use to manage pain among veterans. AB - CONTEXT: Efforts to promote awareness and management of chronic pain have been accompanied by a troubling increase in prescription medication abuse. At the same time, some patients may misuse substances in an effort to manage chronic pain. OBJECTIVES: This study examines self-reported substance misuse for pain management among veterans and identifies the contributing factors. METHODS: We analyzed cross-sectional data from the Help Veterans Experience Less Pain study. RESULTS: Of 343 veterans, 35.3% reported an aberrant pain management behavior (24% reported using alcohol, 11.7% reported using street drugs, and 16.3% reported sharing prescriptions to manage pain). Poorer mental health, younger age, substance use disorders (SUDs), number of nonpain symptoms, and greater pain severity and interference were associated with aberrant pain management behaviors. In multivariate analysis, SUDs (odds ratio [OR]: 3.9, 95% confidence interval [CI]: 2.3-6.7, P<0.000) and poorer mental health (OR: 2.3, 95% CI: 1.3 4.3, P=0.006) were associated with using alcohol or street drugs to manage pain; SUDs (OR: 2.4, 95% CI: 1.3-4.4, P=0.006) and pain interference (OR: 1.1, 95% CI: 1.0-1.2, P=0.047) were associated with prescription sharing; and SUDs (OR: 3.6, 95% CI: 2.2-6.1, P<0.000) and number of nonpain symptoms (OR: 6.5, 95% CI: 1.2 35.4, P=0.031) were associated with any aberrant pain management behavior. CONCLUSION: Veterans with a history of SUDs, greater pain interference, more nonpain symptoms, and mental health concerns should be carefully managed to deter substance misuse for pain management. PMID- 21256707 TI - Promoting mouth-drying responses to reduce drooling effects by persons with intellectual and multiple disabilities: a study of two cases. AB - This study assessed the use of microswitch technology to promote mouth-drying responses and thereby reduce the effects of drooling by two adults with severe intellectual and multiple disabilities. Mouth-drying responses were performed via a special napkin that contained pressure sensors, a microprocessor and an MP3 to monitor the responses and ensure positive stimulation contingent on them. Initially, the responses produced 10 or 15 s of preferred stimulation. Subsequently, preferred stimulation was supplemented with matching periods of lower-grade stimulation to extend the inter-response intervals. Results showed that both participants (a) learned to dry their mouth consistently and reduce their chin wetness during the intervention, (b) stabilized their responding at lower frequencies as the lower-grade stimulation was added to the preferred stimulation, and (c) maintained the latter levels at a 3-month follow-up. Procedure and response conditions and outcome implications are discussed. PMID- 21256708 TI - MRI anatomical and morphological differences in the vocal tract between dysphonic and normal adult women. AB - OBJECTIVE: To analyze the vocal tract morphometry of women with vocal nodules (VN) compared with normal subjects by means of magnetic resonance imaging (MRI) at rest position. STUDY DESIGN: Prospective study. METHODS: The present research included 20 young adult women, aged 18-40 years: 10 dysphonic patients with VN and 10 normal subjects. All participants were tested using MRI; 12 measurements of the vocal tract were performed: nine in median sagittal section and three in axial section. RESULTS: The 12 measurements were smaller in the dysphonic group; statistical significance was obtained for three parameters: in the sagittal plane, the laryngeal vestibule area was significantly smaller in the dysphonic group, with P=0.012* (* = statistical significance); in the axial section, the distance between the right and left vocal processes of the arytenoids' cartilages and the distance between the anterior commissure of the glottis and the laryngeal posterior wall were also significantly lower in the dysphonic group, with P=0.036* and 0.010*, respectively. Significant differences in the vocal tract morphometry of individuals with VN were observed compared with normal subjects, at rest position. CONCLUSIONS: Results obtained from this study suggest that patients with VN may present a constantly increased tension of the laryngeal muscles, even at rest; moreover, reduced anterior-posterior dimension of the larynx may be a morphological characteristic of patients with VN. PMID- 21256709 TI - A comparison of sung and spoken phonation onset gestures using high-speed digital imaging. AB - Phonation onset is important in the maintenance of healthy vocal production for speech and singing. The purpose of this preliminary study was to examine differences in vocal fold vibratory behavior between sung and spoken phonation onset gestures. Given the greater degree of precision required for the abrupt onset sung gestures, we hypothesize that differences exist in the timing and coordination of the vocal fold adductory gesture with the onset of vocal fold vibration. Staccato and German (a modified glottal plosive, so named for its occurrence in German classical singing) onset gestures were compared with breathy, normal, and hard onset gestures, using high-speed digital imaging. Samples were obtained from two subjects with no history of voice disorders (a female trained singer and a male nonsinger). Simultaneous capture of acoustical data confirmed the distinction among gestures. Image data were compared for glottal area configurations, degree of adductory positioning, number of small amplitude prephonatory oscillations (PPOs), and timing of onset gesture events, the latter marked by maximum vocal fold abduction, maximum adduction, beginning of PPOs, and beginning of steady-state oscillation. Results reveal closer adductory positioning of the vocal folds for the staccato and German gestures. The data also suggest a direct relationship between the degree of adductory positioning and the number of PPOs. Results for the timing of onset gesture events suggest a relationship between discrete adductory positioning and more evenly spaced PPOs. By contrast, the overlapping of prephonatory adductory positioning with vibration onset revealed more unevenly spaced PPOs. This may support an existing hypothesis that less well-defined boundaries interfere with normal modes of vibration of the vocal fold tissue. PMID- 21256710 TI - A modified possibilistic fuzzy c-means clustering algorithm for bias field estimation and segmentation of brain MR image. AB - A modified possibilistic fuzzy c-means clustering algorithm is presented for fuzzy segmentation of magnetic resonance (MR) images that have been corrupted by intensity inhomogeneities and noise. By introducing a novel adaptive method to compute the weights of local spatial in the objective function, the new adaptive fuzzy clustering algorithm is capable of utilizing local contextual information to impose local spatial continuity, thus allowing the suppression of noise and helping to resolve classification ambiguity. To estimate the intensity inhomogeneity, the global intensity is introduced into the coherent local intensity clustering algorithm and takes the local and global intensity information into account. The segmentation target therefore is driven by two forces to smooth the derived optimal bias field and improve the accuracy of the segmentation task. The proposed method has been successfully applied to 3 T, 7 T, synthetic and real MR images with desirable results. Comparisons with other approaches demonstrate the superior performance of the proposed algorithm. Moreover, the proposed algorithm is robust to initialization, thereby allowing fully automatic applications. PMID- 21256711 TI - WITHDRAWN: Abstracts from international literature. AB - The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1006/ijom.2003.0550. The duplicate article has therefore been withdrawn. PMID- 21256712 TI - WITHDRAWN: Book review. AB - The publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1006/ijom.2003.0514. The duplicate article has therefore been withdrawn. PMID- 21256714 TI - Detection of human herpes virus 6B in patients with mesial temporal lobe epilepsy in West China and the possible association with elevated NF-kappaB expression. AB - BACKGROUND: There has been a long-standing suspicion that an association exists between mesial temporal lobe epilepsy (MTLE) and the herpes virus. Evidence for HHV-6B involvement has been reported. However, no investigation has been performed in China. METHODS: We used nested PCR and immunohistochemistry to detect viral DNA of human herpes virus (HHV)-6B, HHV-6A, herpes simplex virus (HSV)-1 and HSV-2 in resected brain tissues from patients with MTLE and control. A principal transcription factor, NF-kappaB, that is associated with the inflammatory response was also investigated by real-time PCR, western blotting and immunohistochemistry. RESULTS: HHV-6B DNA was detected in hippocampal samples from 9 out of 32 (28.1%) patients with MTLE and in 1 of 12 (8.3%) control samples. Immunoreactivity for HHV-6B was consistently present in MTLE patients positive for HHV-6 detected by PCR. Significant staining for HHV-6B antigen was distributed mainly around or in the nucleus of cells that morphologically resembled astrocytes and microglia. HHV-6B positivity was related to febrile convulsion history of patients with MTLE. The expression of NF-kappaB was up regulated and distributed in the nucleus of glial cells in MTLE patients positive for HHV-6B. CONCLUSION: This study was first to find HHV-6B in MTLE patients from West China and demonstrate a possible association between HHV-6B positivity and activation of NF-kappaB. The detailed role of HHV-6B and its association with NF kappaB in the development of chronic MTLE requires further investigation. PMID- 21256715 TI - Laterality and temporal distribution of seizures in patients with bitemporal independent seizures during a trial of responsive neurostimulation. AB - We describe seizure laterality and temporal seizure patterns in six subjects with bilateral temporal lobe epilepsy (bTLE) implanted with bilateral hippocampal depth electrodes and the NeuroPace RNSTM system over 84 consecutive days. Seizures were disproportionate in laterality in three subjects and disproportionate in time for two subjects. Clustering of seizures did not clearly affect laterality. Some but not all subjects with bTLE displayed nonrandom temporal or lateral clustering of seizures. PMID- 21256716 TI - Cortical sulcal areas in baboons (Papio hamadryas spp.) with generalized interictal epileptic discharges on scalp EEG. AB - Brain MRI studies in people with idiopathic generalized epilepsies demonstrate regional morphometric differences, though variable in magnitude and location. As the baboon provides an excellent electroclinical and neuroimaging model for photosensitive generalized epilepsy in humans, this study evaluated MRI volumetric and morphometric differences between baboons with interictal epileptic discharges (IEDs) on scalp EEG and baboons with normal EEG studies. Seventy-seven baboons underwent high-resolution brain MRI and scalp EEG studies. The scans were acquired using an 8-channel primate head coil (Siemens TRIO 3T scanner, Erlangen, Germany). After spatial normalization, sulcal measurements were obtained by object-based-morphology methods. One-hour scalp EEG studies were performed in animals sedated with ketamine. Thirty-eight (22F/16M) baboons had normal EEGs (IED-), while 39 (22F/17M) had generalized IEDs (IED+). The two groups were compared for age, total brain volume, and sulcal areas (Hotelling's Trace) as well as between-subjects comparison of 11 individual sulcal areas (averaged between left and right hemispheres). There were no differences between IED- and IED+ groups with respect to age or total brain (gray or white matter) volume, and multivariate tests demonstrated a marginally significant decrease of sulcal areas in IED+ baboons (p=0.075). Tests of between-subjects effects showed statistically significant decreases in the intraparietal (p=0.002), central (p=0.03) and cingulate sulci (p=0.02), and marginal decreases involving the lunate (p=0.07) and superior temporal sulci (p=0.08). Differences in sulcal areas in IED+ baboons may reflect global developmental abnormalities, while decreases of areas of specific sulci reflect anatomical markers for potential generators or cortical nodes of the networks underlying spontaneous seizures and photosensitivity in the baboon. PMID- 21256717 TI - Topiramate pharmacokinetics in infants and young children: contribution of population analysis. AB - PURPOSE: To determine the range of topiramate (TPM) concentrations obtained in children under 4 with the recommended dosage regimen (3-9 mg/kg/day) and to compare them to adult target ranges. METHODS: The population pharmacokinetic model developed for TPM, with/without enzyme inducer antiepileptic drugs (EIAEDs) in children was used to determine dosage regimens providing AUC and trough concentrations (C(trough)s) within the adult ranges. RESULTS: TPM pharmacokinetics was described by a one-compartment model. EIAEDs increased the apparent clearance (CL/F) and age and body weight increased the apparent distribution volume (Vd/F). Mean population estimates (% CV interindividual variability) were 0.608/1.15 L/h (13%) for CL/F without/with EIAEDs, 28.6L (0.2%) for Vd/F and 1.4h(-1) (124%) for the absorption rate constant. Mean AUC(0-12h) reached with a 2mg/kg/day dosing regimen was within described range. A 6-16 mg/kg/day dose depending on age allowed reaching target C(trough) range with the highest probability. Combined EIAEDs led to a 2- and 3-fold decrease in AUC and C(trough), respectively. CONCLUSION: TPM dosage of 2/4 mg/kg/day (without/with EIEADs, respectively) provides the AUC reported in adults. In children under 4, alternative dosing regimen should be considered mainly when associated to EIAED to reach C(trough) comparable to adult values. PMID- 21256718 TI - KCC2 was downregulated in small neurons localized in epileptogenic human focal cortical dysplasia. AB - Focal cortical dysplasia (FCD), which is characterized histologically by disorganized cortical lamination and large abnormal cells, is one of the major causes of intractable epilepsies. gamma-aminobutyric acid (GABA)(A) receptor mediated synchronous depolarizing potentials have been observed in FCD tissue. Since alterations in Cl(-) homeostasis might underlie these depolarizing actions of GABA, cation-Cl(-) cotransporters could play critical roles in the generation of these abnormal actions. We examined the expression patterns of NKCC1 and KCC2 by in situ hybridization histochemistry and immunohistochemistry in FCD tissue obtained by surgery from patients with intractable epilepsy. KCC2 mRNA and protein were expressed not only in non-dysplastic neurons in histologically normal portions located in the periphery of the excised cortex, but also in dysplastic cells in FCD tissue. The levels of KCC2 mRNA and protein were significantly decreased in the neurons around large abnormal neurons (giant neurons), but not in giant neurons, compared with non-dysplastic neurons. The neurons localized only around giant neurons significantly smaller than non dysplastic neurons. However NKCC1 expression did not differ among these cell types. These results suggest that the intracellular Cl(-) concentration ([Cl( )](i)) of small neurons might increase, so that depolarizing GABA actions could occur in the FCD tissue of epileptic foci. PMID- 21256719 TI - Psychotic symptoms in young adults exposed to childhood trauma--a 20 year follow up study. AB - Childhood adversity has been shown to increase the risk of psychotic symptoms in adult life. However, there are no previous studies looking at the association between experiencing a natural disaster during childhood and the development of psychotic symptoms in young adulthood. Eight hundred and six bushfire-exposed children and 725 control children were evaluated following the 1983 South Australian bushfires. Five hundred and twenty nine (65.6%) of the bushfire group and 464 (64%) controls participated in a follow up study 20 years later. Childhood data on emotional and behavioural disorders and dysfunctional parenting was available. The adult assessment included the Australian National Health and Well-Being psychosis screen and detailed information about trauma, childhood adversity and alcohol and cannabis abuse. 5.6% of subjects responded positively to the psychosis screen and 2.6% responded positively to a further probe question. Psychotic symptoms were more common in subjects exposed to a greater number of traumas, and were associated with higher rates of childhood adversity, emotional and behavioural disturbance, dysfunctional parenting, and alcohol and cannabis abuse. Subjects exposed to bushfires as children did not have a greater risk of psychosis. Our results indicate that exposure to multiple traumas, rather than a single major trauma, increases the risk of later psychosis. PMID- 21256720 TI - Determination of isoproterenol and uric acid by voltammetric method using carbon nanotubes paste electrode and p-chloranil. AB - An electrochemical method is described for the voltammetric determination of isoproterenol in the presence of uric acid using p-chloranil-carbon nanotubes paste electrode. Cyclic voltammetric, chronoamperometric, and electrochemical impedance spectroscopic methods have used to investigate the suitability of p chloranil as a mediator for the electrocatalytic oxidation of isoproterenol at pH=10.5. Using differential pulse voltammetry, isoproterenol (ISPT) and uric acid (UA) in a mixture can be measured simultaneously and individually with a potential difference of 360 mV. The electrocatalytic currents increase linearly with ISPT and UA concentrations over the concentration ranges of 0.015-100 MUmol L(-1) ISPT and 3.0-310 MUmol L(-1) UA. The detection limits for ISPT and UA were equal to 0.009 and 2.3 MUmol L(-1), respectively. The diffusion coefficient and the kinetic parameters such as electron transfer coefficient and heterogeneous rate constant were determined for ISPT, using the electrochemical approaches. The proposed method was successfully applied to the determination of isoproterenol in both ampoule and urine samples. PMID- 21256721 TI - Bioinert surface to protein adsorption with higher generation of dendrimer SAMs. AB - Interactions between proteins and biomaterial surfaces correlate with many important phenomena in biological systems. Such interactions have been used to develop various artificial biomaterials and applications, in which regulation of non-specific protein adsorption has been achieved with bioinert properties. In this research, we investigated the protein adsorption behavior of polymer brushes of dendrimer self-assembled monolayers (SAMs) with other generations. The surface adsorption properties of proteins with different pI values were examined on gold substrates modified with poly(amidoamine) dendrimer SAMs. The amount of fibrinogen adsorption was greater than that of lysozyme, potentially because of the surface electric charge. However, as the generations increased, protein adsorption decreased regardless of the surface charge, suggesting that protein adsorption was also affected by density of terminal group. PMID- 21256722 TI - Improved GFP gene transfection mediated by polyamidoamine dendrimer functionalized multi-walled carbon nanotubes with high biocompatibility. AB - The multi-walled carbon nanotubes (MWCNTs)-polyamidoamine (PAMAM) hybrid was prepared by covalent linkage approach, and characterized by transmission electron microscopy, Fourier transform infrared spectroscopy and ultraviolet-visible spectrometry. The PAMAM dendrimers were present on the surface of MWCNTs in high density, and the MWCNT-PAMAM hybrid exhibited good dispersibility and stability in aqueous solution. The interaction between MWCNT-PAMAM with plasmid DNA of enhanced green fluorescence protein (pEGFP-N1), intracellular trafficking of the hybrid, transfection performance and cytotoxicity to HeLa cells were evaluated in detail. We found that the MWCNT-PAMAM hybrid possessed good pEGFP-N1 immobilization ability and could efficiently delivery GFP gene into cultured HeLa cells. The surface modification of MWCNTs with PAMAM improved the transfection efficiency 2.4 and 0.9 times, and simultaneously decreased cytotoxicity by about 38%, as compared with mixed acid-treated MWCNTs and pure PAMAM dendrimers. The MWCNT-PAMAM hybrid can be considered as a new carrier for the delivery of biomolecules into mammalian cells. Therefore, this novel system may have good potential applications in biology and therapy, including gene delivery systems. PMID- 21256723 TI - High-intensity focussed ultrasound. PMID- 21256724 TI - Amelioration of cisplatin-induced rat renal lesions by a cyclooxygenase (COX)-2 selective inhibitor. AB - Cyclooxygenase (COX)-2, an inducible form of COX, plays important roles in inflammatory lesions. We investigated effects of a COX-2 selective inhibitor, NS 398, on cisplatin (CDDP)-induced rat renal lesions. As compared with rats injected with a single dose of CDDP (6 mg/kg; CDDP group), rats who were treated everyday with NS-398 (3mg/kg) after the CDDP injection (inhibitor group), showed the declines of blood urea nitrogen and creatinine values, and the delay of the peak of regenerating renal epithelial cell number (demonstrable with 5'-bromo-2' deoxyuridine immunohistochemistry); these findings suggested cytoprotective effects of the inhibitor. Furthermore, the numbers of ED1-immunopositive macrophages and alpha-smooth muscle actin (alpha-SMA)-immunopositive myofibroblasts were lower in the inhibitor group than in the CDDP group; mRNA expression of transforming growth factor-beta1 (TGF-beta1) was also decreased in the inhibitor group. Because the fibrotic area seen after CDDP injection were tended to decrease in the inhibitor group compared with the CDDP group, it was considered that the decreased number of infiltrating macrophages by the inhibitor might lead to the decreased production of TGF-beta1, thereby resulting in the reduced number of alpha-SMA-positive myofibroblasts responsible for fibrosis. Collectively, although these differences between the CDDP and inhibitor groups were not always marked, the COX-2 inhibitor used in this study could ameliorate the CDDP-induced rat renal lesions. PMID- 21256725 TI - Structure, chemical composition and putative function of the postpharyngeal gland of the emerald cockroach wasp, Ampulex compressa (Hymenoptera, Ampulicidae). AB - The postpharyngeal gland (PPG) plays a major role in the social integration of ant colonies. It had been thought to be restricted to ants but was recently also described for a solitary wasp, the European beewolf (Philanthus triangulum). This finding posed the question whether the gland has evolved independently in the two taxa or has been inherited from a common ancestor and is hence homologous. The latter alternative would be supported if a PPG was found in more basal taxa. Therefore, we examined a species at the base of the Apoidea, the solitary ampulicid wasp Ampulex compressa, for the existence of a PPG. Both sexes of this species possess a cephalic gland that branches off the posterior part of the pharynx, is lined by a cuticular intima and surrounded by a monolayered epithelium with the epithelial cells bearing long hairs. Most of these morphological characteristics conform to those of the PPG of ants and beewolves. Chemical analysis of the gland content revealed that it contains mainly hydrocarbons and that there is a congruence of the pattern of hydrocarbons in the gland, on the cuticle, and in the hemolymph, as has also been reported for both ants and beewolves. Based on these morphological and chemical results we propose that the newly described cephalic gland is a PPG and discuss its possible function in A. compressa. The present study supports the view of a homologous origin of the PPG in the aculeate Hymenoptera. PMID- 21256726 TI - Immunomodulatory properties of a lemon-quince preparation (Gencydo(r)) as an indicator of anti-allergic potency. AB - INTRODUCTION: Gencydo(r), a combination of lemon (Citrus limon) juice and aqueous quince (Cydonia oblonga) extract has been used traditionally in anthroposophical medicine for treating patients with allergic rhinitis or asthma. Because there are no reports about the mode of action, we investigated the anti-allergic effects of this preparation in vitro by using cell lines and primary cells in various biological and immunological endpoints. MATERIALS AND METHODS: The release of soluble mediators from basophilic cells, mast cells and lung epithelial cells, which are essential for the initiation of early- and late-phase allergic reactions, was analyzed in relation to the synthetic anti-allergic drugs azelastine and dexamethasone. In addition, the impact of Gencydo(r) on the viability and activation of GM-CSF-activated eosinophil granulocytes was investigated. RESULTS AND DISCUSSION: Gencydo(r) reduced the degranulation and histamine release of IgE-activated basophilic cells and mast cells and inhibited the IgE- and PMA/A23187-induced increases in IL-8, TNF-alpha and GM-CSF production in mast cells. The effects were comparable to that of the used concentration of azelastine and dexamethasone. Furthermore, Gencydo(r) partially blocked eotaxin release from human bronchial epithelial cells, but has no impact on the viability and activation of GM-CSF-activated eosinophil granulocytes. In conclusion, these results give a rational base for the topical use of Gencydo(r) in treatment of allergic disorders through the down regulation of soluble mediators, which are essential for the initiation and maintenance of allergic reactions. PMID- 21256727 TI - QCM immunosensor detection of Escherichia coli O157:H7 based on beacon immunomagnetic nanoparticles and catalytic growth of colloidal gold. AB - In this paper, we describe a novel method for detecting Escherichia coli (E. coli) O157:H7 by using a quartz crystal microbalance (QCM) immunosensor based on beacon immunomagnetic nanoparticles (BIMPs), streptavidin-gold, and growth solution. E. coli O157-BIMPs were magnetic nanoparticles loaded with polyclonal anti-E. coli O157:H7 antibody (target antibody, T-Ab) and biotin-IgG (beacon antibody, B-Ab) at an optimized ratio of 1:60 (T-Ab:B-Ab). E. coli O157:H7 was captured and separated by E. coli O157-BIMPs in a sample, and the streptavidin gold was subsequently conjugated to E. coli O157-BIMPs by using a biotin-avidin system. Finally, the gold particles on E. coli O157-BIMPs were enlarged in growth solution, and the compounds containing E. coli O157:H7, E. coli O157-BIMPs, and enlarged gold particles were collected using a magnetic plate. The QCM immunosensor was fabricated with protein A from Staphylococcus aureus and monoclonal anti-E. coli O157:H7 antibody. The compounds decreased the immunosensor's resonant frequency. E. coli O157-BIMPs and enlarged gold particles were used as "mass enhancers" to amplify the frequency change. The frequency shift was correlated to the bacterial concentration. The detection limit was 23 CFU/ml in phosphate-buffered saline and 53 CFU/ml in milk. This method could successfully detect E. coli O157:H7 with high specificity and stability. The entire procedure for the detection of E. coli O157:H7 took only 4 h. PMID- 21256728 TI - Self-assembled monolayer-assisted silicon nanowire biosensor for detection of protein-DNA interactions in nuclear extracts from breast cancer cell. AB - The large number of estrogen receptor (ER) binding sites of various sequence patterns requires a sensitive detection to differentiate between subtle differences in ER-DNA binding affinities. A self-assembled monolayer (SAM) assisted silicon nanowire (SiNW) biosensor for specific and highly sensitive detection of protein-DNA interactions, remarkably in nuclear extracts prepared from breast cancer cells, is presented. As a typical model, estrogen receptor element (ERE, dsDNA) and estrogen receptor alpha (ERalpha, protein) binding was adopted in the work. The SiNW surface was coated with a vinyl-terminated SAM, and the termination of the surface was changed to carboxylic acid via oxidation. DNA modified with amine group was subsequently immobilized on the SiNW surface. Protein-DNA binding was finally investigated by the functionalized SiNW biosensor. X-ray photoelectron spectroscopy (XPS) and atomic force microscopy (AFM) were employed to characterize the stepwise functionalization of the SAM and DNA on bare silicon surface, and to visualize protein-DNA binding on the SiNW surface, respectively. We observed that ERalpha had high sequence specificity to the SiNW biosensor which was functionalized with three different EREs including wild-type, mutant and scrambled DNA sequences. We also demonstrate that the specific DNA-functionalized SiNW biosensor was capable of detecting ERalpha as low as 10 fM. Impressively, the developed SiNW biosensor was able to detect ERalpha-DNA interactions in nuclear extracts from breast cancer cells. The SAM assisted SiNW biosensor, as a label-free and highly sensitive tool, shows a potential in studying protein-DNA interactions. PMID- 21256729 TI - An electrochemical competitive biosensor for ochratoxin A based on a DNA biotinylated aptamer. AB - Ochratoxin A (OTA) is one of the most important mycotoxin contaminants of foods, particularly cereals and cereal products, with strict low regulatory levels (of ppb) in many countries worldwide. An electrochemical competitive aptamer-based biosensor for OTA is described. Paramagnetic microparticle beads (MBs) were functionalized with an aptamer specific to OTA, and were allowed to compete with a solution of the mycotoxin conjugated to the enzyme horseradish peroxidase (OTA HRP) and free OTA. After separation and washing steps helped with magnetic separations, the modified MBs were localized on disposable screen-printed carbon electrodes (SPCEs) under a magnetic field, and the product of the enzymatic reaction with the substrate was detected with differential-pulse voltammetry. In addition to magnetic separation assays, other competitive schemes (direct/indirect aptasensors performed on the SPCEs surface or using gold nanoparticles functionalized with the aptamer) were preliminary tested, optimized and compared. The magnetic aptasensor showed a linear response to OTA in the range 0.78-8.74 ng mL(-1) and a limit of detection of 0.07+/-0.01 ng mL(-1), and was accurately applied to extracts of certified and spiked wheat samples with an RSD lower than about 8%. PMID- 21256730 TI - Electrochemical cell-based chip for the detection of toxic effects of bisphenol-A on neuroblastoma cells. AB - A cell-based chip was fabricated for the electrochemical detection of the dose dependent effects of bisphenol-A (BPA) on neuroblastoma cells (SH-SY5Y), which showed dual-mode correlation as a standard curve. Toxicity assessment of BPA became very important in environmental toxicants detection since BPA can be reached out easily from various common plastic-based product and give negative cellular effects on living organism. Cell chip was fabricated by immobilizing cells on C(RGD)(4) peptide coated electrode to detect the cytotoxicity of BPA electrochemically. Redox properties in living cells were determined by cyclic voltammetry using a home-made three-electrode system, and the cathodic peak current (I(pc)) was used as a parameter for measurement of the effect of BPA on cell viability. The peak current, I(pc) value increased with the concentration of BPA up to 300 nM and then decreased because of the stimulation of cancer cell activity at the concentration of BPA below 300nM and cytotoxicity at the concentration of BPA above 300 nM, respectively. MTT (3-(4,5-dimethylthiazol-2 yl)-2,5-diphenyltetrazolium bromide) assay and optical microscopy-based morphological analysis confirmed the results of electrochemical study. This dual mode correlation between the concentration of BPA and voltammetric signal intensity should be firstly considered to analyze its dose-dependent stimulus and cytotoxic effects on neuroblastoma cells by cell chip. PMID- 21256731 TI - Signal enhancement of surface plasmon-coupled emission (SPCE) with the evanescent field of surface plasmons on a bimetallic paraboloid biochip. AB - We present a novel approach to the enhancement of surface plasmon-coupled emission (SPCE) using surface plasmon excitation in a bimetal (Ag/Au) layer and we validate the enhancement by presenting the results of a model human IgG immunoassay. Theoretical calculations using Fresnel's equations have been carried out to determine the optimum bimetallic composition and the resulting electric field enhancement. Signal enhancement of SPCE was confirmed using a range of bimetallic layers which were deposited on the surface of a high collection efficiency polymer array biochip and subsequently immobilized with Alexa Fluor 647 labeled anti-human IgG. The bimetallic film of Ag/Au (36/10nm) was determined as an optimum substrate for maximum SPCE signal which was a compromise between the long-term stability of the metal layer and the optimized evanescent field enhancement. An enhanced dose-dependent response was also demonstrated which was ~3 times greater than that detected with a pure gold layer. A human IgG immunoassay showed a dose-dependent response yielding a limit of detection of 1pg/ml by the 3sigma rule. The improved performance of the bimetal layer compared to that of an assay carried out on a pure gold layer is attributed to the enhanced evanescent field intensity of surface plasmons in the bimetal combination which excites more fluorescence hence producing an enhanced SPCE signal. This result demonstrates the potential of the SPCE-based array biochips as a sensitive and high-throughput analysis platform for biomolecular interactions. PMID- 21256732 TI - Sensing scaffolds to monitor cellular activity using impedance measurements. AB - Scaffolds are cell adhesive matrices for the realisation of tissue constructs. Here we describe how scaffolds for tissue engineering can also be used as sensors for monitoring cellular activity such as adhesion and spreading. Carbon nanotube polymer composites were fabricated into membranes and scaffolds with electro conductive properties. Impedance techniques were used to measure the effects of media and cell cultures on composite membranes and the results were analysed using lumped parameter models. We show that protein adhesion can be distinguished from cell adhesion as the impedance changes are much smaller for the latter (5%). In the presence of cells, impedance changes are of the order of 40% and can be correlated with adhesion, spreading and changes in cell density. PMID- 21256733 TI - Dynamics of the translational machinery. AB - The recent growth in single molecule studies of translation has provided an insight into the molecular mechanism of ribosomal function. Single molecule fluorescence approaches allowed direct observation of the structural rearrangements occurring during translation and revealed dynamic motions of the ribosome and its ligands. These studies demonstrated how ligand binding affects dynamics of the ribosome, and the role of the conformational sampling in large scale rearrangements intrinsic to translation elongation. The application of time resolved cryo-electron microscopy revealed new conformational intermediates during back-translocation providing an insight into ribosomal dynamics from an alternative perspective. Recent developments permitted examination of conformational and compositional dynamics of the ribosome in real-time through multiple cycles of elongation at the single molecule level. The zero-mode waveguide approach allowed direct observation of the compositional dynamics of tRNA occupancy on the elongating ribosome. The emergence of single molecule in vivo techniques provided insights into the mechanism and regulation of translation at the organismal level. PMID- 21256734 TI - Does pain intensity predict a poor opioid response in cancer patients? AB - AIM: The aim of this study was to test the hypothesis that initial pain intensity is not a predictive factor of poor opioid response in advanced cancer patients, as suggested by a recent work. METHODS: A secondary analysis of one-hundred-sixty seven patients referred for treatment of cancer-related pain was conducted. Pain intensity at admission was recorded and patients were divided in three categories of pain intensity: mild, moderate and severe. Patients were offered a treatment with opioid dose titration, according to department policy. Data regarding opioid doses and pain intensity were collected after dose titration was completed. Four levels of opioid response were considered: (a) good pain control, with minimal opioid escalation and without relevant adverse effects; (b) good pain control requiring more aggressive opioid escalation, for example doubling the doses in four days; (c) adequate pain control associated with the occurrence of adverse effects; (d) poor pain control with adverse effects. RESULTS: Seventy-six, forty four, forty-one and six patients showed a response a, b, c, and d, respectively. No correlation between baseline pain intensity categories and opioid response was found. Patients with response 'b' and 'd' showed higher values of OEImg. CONCLUSION: Baseline pain intensity does not predict the outcome after an appropriate opioid titration. It is likely that non-homogeneous pain treatment would have biased the outcome of a previous work. PMID- 21256735 TI - Treatment strategy for early gastric cancer. AB - Gastric cancer ranks the second leading cause of cancer-specific mortality worldwide. With a poor prognosis, 5-year survival rate of gastric cancer is less than 20%-25% in the USA, Europe, and China [1]. However, early gastric cancer(EGC) offers an excellent (over 90%) chance of cure based on surgical resection [2]. As the increasing detection of EGC, more treatment options have been developed both curatively and minimally invasively to maintain a good quality of life(QOL). One of the advanced therapeutic techniques is endoscopic dissection. Improvements in surgical treatment include minimizing lymph node dissection, reconstruction methods, laparoscopy-assisted surgery, and sentinel node navigation surgery(SNNS) [3]. With technological advances, even Natural Orifice Transluminal Endoscopy Surgery (NOTES) and robotic surgery are expected to represent the next revolution [4]. However, there still remains much dispute among these treatments, which arouses further clinical trials to verify. Update of the treatments, controversial indications, prognosis and current strategies for EGC are discussed in this review. PMID- 21256736 TI - The effect of high intensity mixing on the enzymatic hydrolysis of concentrated cellulose fiber suspensions. AB - Enzymatic hydrolysis of lignocellulosic biomass in a high shear environment was examined. The conversion of cellulose to glucose in samples mixed in a torque rheometer producing shear flows similar to those found in twin screw extruders was greater than that of unmixed samples. In addition, there is a synergistic effect of mixing and enzymatic hydrolysis; mixing increases the rate of cellulose conversion while the increased conversion facilitates mixing. The synergy appears to result in part from particle size reduction, which is more significant when hydrolysis occurs during intense mixing. PMID- 21256737 TI - Effect of organic loading rate on VFA production, organic matter removal and microbial activity of a two-stage thermophilic anaerobic membrane bioreactor. AB - This study focused on the VFA (volatile fatty acid) profile variation with organic loading rate (OLR) of a two stage thermophilic anaerobic membrane bioreactor (TAnMBR). The two stage TAnMBR treating high strength molasses-based synthetic wastewater was operated under a side-stream partial sedimentation mode at 55 degrees C. Reactor performances were studied at different OLR ranging from 5 to 12 kg COD m(-3) d(-1). Operational performance of TAnMBR was monitored by assessing biological activity, organic removal efficiency, and VFA. The major intermediate products of anaerobic digestion were identified as acetate, propionate, iso-butyrate, n-butyrate and valerate. Among them acetate and n butyrate were identified as the most abundant components. Increase of OLR changes the predominant VFA type from acetic acid to n-butyric acid and the total VFA concentration was increased with increased OLR. Moreover, increased OLR increased organic removal efficiency up to second loading rate and dropped in third loading rate while biological activity was increased continuously. PMID- 21256738 TI - Improved bio-energy yields via sequential ethanol fermentation and biogas digestion of steam exploded oat straw. AB - Using standard laboratory equipment, thermochemically pretreated oat straw was enzymatically saccharified and fermented to ethanol, and after removal of ethanol the remaining material was subjected to biogas digestion. A detailed mass balance calculation shows that, for steam explosion pretreatment, this combined ethanol fermentation and biogas digestion converts 85-87% of the higher heating value (HHV) of holocellulose (cellulose and hemicellulose) in the oat straw into biofuel energy. The energy (HHV) yield of the produced ethanol and methane was 9.5-9.8 MJ/(kg dry oat straw), which is 28-34% higher than direct biogas digestion that yielded 7.3-7.4 MJ/(kg dry oat straw). The rate of biogas formation from the fermentation residues was also higher than from the corresponding pretreated but unfermented oat straw, indicating that the biogas digestion could be terminated after only 24 days. This suggests that the ethanol process acts as an additional pretreatment for the biogas process. PMID- 21256739 TI - Rhizosphere dynamics during phytoremediation of olive mill wastewater. AB - The potential of phytoremediation as a treatment option for olive mill wastewater (OMW) was tested on five perennial tree species. Cupressus sempervirens and Quercus ilex proved tolerant to six-month OMW treatment followed by six-month water irrigation, whereas Salix sp. and Laurus nobilis and, later, Pinus mugo suffered from phytotoxic effects. Test plants were compared to controls after treatment and irrigation, by monitoring biochemical and microbiological variations in the rhizosphere soil. OMW-treated soils were exposed to 50-fold higher phenols concentrations, which, irrespective of whether the respective plants were OMW-resistant or susceptible, were reduced by more than 90% by the end of the irrigation cycle, owing to significantly increased laccase, peroxidase and beta-glucosidase activities, recovery/acquisition of bacterial culturability and transitory development of specialized fungal communities sharing the presence of Geotrichum candidum. Of all results, the identification of Penicillium chrysogenum and Penicillium aurantiogriseum as dominant rhizosphere fungi was distinctive of OMW-tolerant species. PMID- 21256740 TI - The isolation, characterization and effect of lignin isolated from steam pretreated Douglas-fir on the enzymatic hydrolysis of cellulose. AB - Douglas-fir was SO(2)-steam pretreated at different severities (190, 200, and 210 degrees C) to assess the possible negative effect of the residual and isolated lignins on the enzymatic hydrolysis of the steam pretreated substrates. When various isolated lignins were added to the Avicel hydrolysis reactions, the decrease in glucose yields ranged from 15.2% to 29.0% after 72 h. It was apparent that the better hydrolysis yields obtained at higher pretreatment severities were more a result of the greater accessibly of the cellulose rather than any specific change in the non-productive binding of the lignin to the enzymes. FTIR and (13)C NMR characterization indicated that the lignin in the steam pretreated substrates became more condensed with increasing severity, suggesting that the cellulases were adsorbed to the lignin by hydrophobic interactions. Electrostatic interactions were also involved as the positively charged cellulase components were preferentially adsorbed to the lignins. PMID- 21256741 TI - Biobleaching of Eucalyptus globulus kraft pulps: comparison between pulps obtained from exploded and non-exploded chips. AB - The aim of this work was to evaluate the response to biobleaching of steam exploded kraft pulps and to compare the results with the controls. For this end, a laccase-mediator treatment using commercial laccase (Novozyme 51003) and a natural mediator (acetosyringone) were assayed, followed by alkaline extraction and hydrogen peroxide stages. Our approach resulted in exploded biobleached pulps with lower kappa number and improved optical properties compared to controls, even after subjecting pulps to accelerated ageing. Additionally, use of hydrogen peroxide was reduced. The LMS (laccase-mediator system) had a smaller impact on the properties of the bleached pulps and on hydrogen peroxide consumption than the steam explosion process did. PMID- 21256742 TI - Continuous-flow biodiesel production using slit-channel reactors. AB - Slit-channel reactors are reactors whose active surface areas are orders of magnitude higher than those of micro-reactors but have low fabrication costs relative to micro-reactors. We successfully produced biodiesel with different degrees of conversion using homogeneous catalyst in the slit-channel reactor. The reactor performance shows that percent conversion of soybean oil to biodiesel increases with channel depth, as expected, due to more efficient mixing. Shallow slit-channels require short average residence times for complete product conversion. Present results show that the slit-channel reactor provides an improved performance over traditional batch reactors using homogeneous sodium alkoxide catalyst. It is aimed to couple the reactors with solid catalysts in converting soybean oil to biodiesel and implementation method is suggested. The cost advantages resulting from the ease of fabrication of slit-channel reactors over micro-reactors and how these factors relate to the oil conversion efficiency to biodiesel are briefly noted and discussed. PMID- 21256743 TI - Bioaugmentation as a tool for improving the start-up and stability of a pilot scale partial nitrification biofilm airlift reactor. AB - The effectiveness of bioaugmentation in the improvement of the start-up of a biofilm airlift reactor to perform partial nitrification was investigated. Two identical biofilm airlift reactors were inoculated. The non-bioaugmented reactor (NB-reactor) was inoculated with conventional activated sludge, whereas the bioaugmented reactor (B-reactor) was seeded with the same conventional activated sludge but bioaugmented with nitrifying activated sludge from a pilot plant performing full nitritation under stable conditions (100% oxidation of influent ammonium to nitrite). The fraction of specialized nitrifying activated sludge in the inoculum of the B-reactor was only 6% (measured as dry matter). To simplify comparison of the results, operational parameters were equivalent for both reactors. Partial nitrification was achieved significantly faster in the B reactor, showing a very stable operation. The results obtained by fluorescence in situ hybridization assays showed that the specialized nitrifying biomass added to the B-reactor remained in the biofilm throughout the start-up period. PMID- 21256744 TI - Cytotoxicity micropollutant removal in a crossflow membrane bioreactor. AB - The application of membrane bioreactor (MBR) technology was investigated with the aim of evaluating its potential for cytostatic drug and cytotoxicity bioremoval. The toxicity removal was assessed from biomarker test. CP removal of up to 80% was achieved under the operating conditions studied (HRT of 48 h and a SRT of 50 days). The increase of TMP was associated with an increase of supernatant toxicity as if fouling led to retention of the toxicity. Peaks of supernatant cytotoxicity were correlated with peaks in supernatant humic acid contents. It may suggest that molecules with a toxic effect may be adsorbed or entrapped in humic acids substances. Our study then points out that advances in wastewater treatment using an MBR can provide a suitable process for lowering CP concentrations before discharge into the aqueous environment. However, a tertiary treatment is necessary if complete elimination of toxicity is targeted. PMID- 21256745 TI - Effects of inorganic carbon limitation on anaerobic ammonium oxidation (anammox) activity. AB - Anammox bacteria are chemoautotrophic bacteria that oxidize ammonium with nitrite as the electron acceptor and with CO(2) as the main carbon source. The effects of inorganic carbon (IC) limitation on anammox bacteria were investigated using continuous feeding tests. In this study, a gel carrier with entrapped anammox sludge was used. It was clearly shown that the anammox activity deteriorated with a decrease in the influent IC concentration. The relationship between the influent IC concentration and the anammox activity was analyzed using Michaelis Menten kinetics, and the apparent K(m) was determined to be 1.2mg-C/L. The activity could be recovered by adding IC to the influent. The consumption ratio of IC to ammonium was not constant and mainly depended on the influent ratio of the IC to ammonium concentrations (inf.IC/inf.NH(4)-N). The results indicated that an inf.IC/inf.NH(4)-N ratio of 0.2 in the anammox reactor was ideal for the anammox process using gel cubes. PMID- 21256746 TI - High efficient expression of cellobiase gene from Aspergillus niger in the cells of Trichoderma reesei. AB - The cellobiase gene from Aspergillus niger was cloned and connected with the strong promoter Pcbh1 from Trichoderma reesei to construct a recombinant plasmid pHB9 with the hygromycin B resistance marker. The plasmid was transformed into conidia of T. reesei using the modified PEG-CaCl(2) method. Main factors effecting the transformation were discussed and about 99-113 transformants/MUg DNA could be obtained under optimal conditions. It was found that the molecular mass of the recombinant cellobiase was about 120 kDa by SDS-PAGE analysis. The activity of cellobiase could reach 5.3 IU/ml after 48 h fermentation, which was as high as 106 times compared with that of the host strain. Meanwhile, the filter paper activity of recombinant T. reesei was 1.44-fold of the host strain. Saccharification of corncob residue with the crude enzyme showed that the hydrolysis yield (84.2%) of recombinant T. reesei was 21% higher than that (69.5%) of the host strain. PMID- 21256747 TI - Improvement of catalytic activity of lipase from Candida rugosa via sol-gel encapsulation in the presence of calix(aza)crown. AB - Lipase from Candida rugosa (CRL) was encapsulated within a chemically inert sol gel support in the presence of calix(aza)crowns as the new additives. The catalytic activity of the encapsulated lipases was evaluated both in the hydrolysis of p-nitrophenyl palmitate (p-NPP) and the enantioselective hydrolysis of racemic Naproxen methyl ester. It has been observed that the percent activity yields of the calix(aza)crown based encapsulated lipases were higher than that of the free lipase. Improved enantioselectivity was observed with the calix(aza)crown-based encapsulated lipases as compared to encapsulated free lipase. The reaction of Naproxen methyl ester resulted in 48.4% conversion for 24h and 98% enantiomeric excess for the S-acid, corresponding to an E value of >300 (E=166 for the encapsulated free enzyme). Moreover, the encapsulated lipases were still retained about 18% of their conversion ratios after the sixth reuse in the enantioselective reaction. PMID- 21256748 TI - Furoxan nitric oxide donor coupled chrysin derivatives: synthesis and vasculoprotection. AB - A series of furoxan-based nitric oxide-releasing chrysin derivatives were synthesized. Pharmacological assays indicated that all chrysin derivatives exhibited in vitro inhibitory activities against aldose reductase and advanced glycation end-product formation. Some chrysin derivatives were also found to increase the glucose consumption of HepG2 cells. Furthermore, the compounds released a low amount of NO in the presence of L-cysteine (range from 0.20% to 1.89%). These hybrid furoxan-based NO donor chrysin derivatives offer a mutual prodrug design concept for the development of therapeutic or preventive agents for vascular complications due to diabetes. PMID- 21256749 TI - Conduction block and tonic pupils in Charcot-Marie-Tooth disease caused by a myelin protein zero p.Ile112Thr mutation. AB - We report a patient with Charcot-Marie-Tooth disease (CMT) due to the p.Ile112Thr mutation in myelin protein zero (MPZ) who presented with a patchy neuropathy with conduction block and tonic pupils. Conduction block is unusual in inherited neuropathies, while pupil abnormalities are recognised to occur in CMT especially due to MPZ mutations. This case highlights that patchy demyelinating neuropathy with conduction block may occur in p.Ile112Thr MPZ mutations. Involvement of the pupils, as in this case, may be a pointer towards a genetic rather than inflammatory cause of neuropathy. PMID- 21256750 TI - Bone is functionally impaired in dystrophic mice but less so than skeletal muscle. AB - The primary purpose of this study was to determine if tibial bone strength is compromised in dystrophic mice and if so, what geometric and material properties contribute. Results of three-point bending tests showed that tibia of mdx and dko (dystrophin- and utrophin-deficient) mice had up to 50% lower strength and stiffness compared to wild-type mice. Micro-computed tomography indicated that dystrophic tibia had reductions of 6-57% in cortical cross-sectional moment of inertia and cross-sectional area. Metaphyseal trabecular bone morphometry was also altered up to 78% in dystrophic mice. Bone-to-muscle functional ratios (i.e., three-point bending measures:muscle strength) indicated that bone strength was relatively high in 7-week-old dystrophic mice compared to muscle strength, but ratios were similar to wild-type mice by 24 months of age. Young dystrophic mice have compromised bone strength; these models may be useful for designing therapeutic regimens aimed at improving the skeleton. PMID- 21256751 TI - Levodopa effect on electromyographic activation patterns of tibialis anterior muscle during walking in Parkinson's disease. AB - Previous studies have reported that patients with Parkinson's disease (PD) show, in the "off medication" state, a reduced activation of tibialis anterior (TA) in the late swing-early stance phase of the gait cycle. In PD patients the pathophysiological picture may cause differences among the stride cycles. Our aims were to evaluate how frequently TA activity is reduced in the late swing early stance phase and if there is a relationship between the TA pattern and the clinical picture. Thirty PD patients were studied 2 h after Levodopa administration ("on-med") and 12 h after Levodopa wash-out ("off-med"). They were evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS III) and surface electromyography of TA and gastrocnemius medialis (GM). The root mean square (RMS) of the TA activity in late swing-early stance phase (RMS-A) was normalized as a percent of the RMS of the TA activity in late stance-early swing (RMS-B). RMS-A was reduced in 30% of patients in the "off-med" condition. Within these patients, the percentage of stride cycles with reduced RMS-A, ranged between 28% and 83%. After Levodopa intake, no stride cycle showed reduced RMS-A. Patients with reduced RMS-A had a lower UPDRS III total score in the "on-med" rather than in the "off-med" condition (p=0.02). Our data confirm and extend previous observations indicating that, in "off-med" the function of TA is impaired in those patients clinically more responsive to Levodopa. TA activation is reduced in a relatively high percent of gait cycles in the "off-med" state. Since the variability of TA activation disappears after Levodopa administration, this phenomenon could be the expression of an abnormal dopaminergic drive. PMID- 21256752 TI - Surgical treatment of os odontoideum. AB - Os odontoideum is a rare disease. There have been few reports of os odontoideum in the literature. In this study we retrospectively reviewed eight surgically treated patients. One patient underwent C1-2 transarticular screw fixation, five patients underwent C1-2 polyaxial screw and rod fixation and two patients with dystopic os odontoideum underwent occipito-cervical (O-C) fusion. Of the eight patients, neck pain was alleviated in seven (87.5%). Of the six patients who had neurological signs and symptoms, five (83.3%) exhibited neurological improvement. Radiologically, solid fusion was observed in seven patients (87.5%). Active surgical treatment should be considered even in patients with os odontoideum who exhibit mild symptoms. In most patients with os odontoideum, use of the C1-2 polyaxial screw and rod technique may be the most appropriate treatment. In patients with dystopic os odontoideum, O-C fusion should be considered. PMID- 21256753 TI - Clinicopathological profile of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes (POEMS) syndrome. AB - Patients with polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes (POEMS) syndrome caused by underlying plasma cell dyscrasias, although rare, may present with peripheral neuropathy. In this retrospective study we describe the clinical, electrophysiological and pathological profile of 29 patients (27 males and two females, with a mean age of 45.9+/-7.9 years) seen between 1983 to 2009 who satisfied the Dispenzieri criteria. Polyneuropathy with weakness and paresthesias of the limbs evolving over 8.3+/-9.1 months, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes were seen in all patients. Other features included pedal edema (25 patients), papilledema (24), weight loss (23), clubbing (20) and Castleman disease (three patients). We report the pathological features seen in nerve biopsies, osteosclerotic lesions, skin biopsies, lymph node biopsies and bone marrow aspirates. We report the method of a diagnosis confirmation and compare the clinicopathological features of our patients with other published series. Our findings highlight the importance of a meticulous systemic examination and systematic laboratory investigations in the diagnosis of POEMS syndrome. PMID- 21256754 TI - Spinal extradural arachnoid cyst: review of surgical techniques. AB - Extradural arachnoid cysts of the spine are a rare cause of spinal cord and nerve root compression, usually in the mid to lower thoracic spine and at the thoraco lumbar junction in a posterior position. Local pain and myelopathy occur predominantly in young adults, and MRI reveals a well-demarcated extradural lesion, iso-intense to cerebrospinal fluid. We report a 33-year-old woman with an extradural arachnoid cyst from T11 to L1 and review the surgical techniques reported in the literature. PMID- 21256755 TI - State-of-the-art reperfusion strategies for acute ischemic stroke. AB - Timely recanalization of the occluded artery is the only effective treatment for acute ischemic stroke. Intravenous tissue plasminogen activator (i.v. tPA), administered within 3 hours of symptom onset, is the only United States Food and Drug Administration-approved treatment. This short window often precludes effective intervention, and i.v. tPA often fails to recanalize major and mid sized arteries. Intra-arterial thrombolysis has been used for decades, but its safety and effectiveness in cerebrovascular occlusions is also limited. Recently, new mechanical neuroendovascular devices have shown high recanalization rates with acceptable safety in early studies. Multi-modal reperfusion therapy (MMRT)- including intra-arterial infusion of thrombolytics and/or antiplatelet agents, mechanical clot disruption and retrieval, and balloon angioplasty with stent placement--is the prevailing concept for the management of major acute stroke. Recent results suggest that MMRT results in higher chances for both recanalization of the occluded artery and reperfusion of the ischemic tissue. PMID- 21256756 TI - Synthetic approaches to the 2009 new drugs. AB - New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 21 NCEs marketed in 2009. PMID- 21256757 TI - Benzyl benzoates: New phlorizin analogs as mushroom tyrosinase inhibitors. AB - In our research, 14 benzyl benzoates with hydroxyl(s) (3-16) were synthesized and their inhibitory activity on mushroom tyrosinase was tested. Results indicated that among these compounds, 4-hydroxybenzyl 3,5-dihydroxybenzoate (3), 4 hydroxybenzyl 2,4-dihydroxybenzoate (5), 4-hydroxybenzyl 2,4,6-dihydroxybenzoate (7), 3-hydroxybenzyl 3,5-dihydroxybenzoate (8), 3-hydroxybenzyl 2,4 dihydroxybenzoate (10) exhibited inhibitory activity with their IC(50) less than 10MUM. Further studies showed these five compounds were competitive inhibitors of tyrosinase and their structure-activity relationships were investigated in this article. PMID- 21256758 TI - Synthesis of carbon-11-labeled bivalent beta-carbolines as new PET agents for imaging of cholinesterase in Alzheimer's disease. AB - Carbon-11-labeled bivalent beta-carbolines, 9,9'-(pentane-1,5-diyl)bis(2 [(11)C]methyl-9H-pyrido[3,4-b]indol-2-ium)iodide ([(11)C]2a), 9,9'-(nonane-1,9 diyl)bis(2-[(11)C]methyl-9H-pyrido[3,4-b]indol-2-ium)iodide ([(11)C]2b), 9,9' (dodecane-1,12-diyl)bis(2-[(11)C]methyl-9H-pyrido[3,4-b]indol-2-ium)iodide ([(11)C]2c) and 1,9-bis(2-[(11)C]methyl-3,4-dihydro-1H-pyrido[3,4-b]indol-9(2H) yl)nonane ([(11)C]3), were prepared by N-[(11)C]methylation of their corresponding amine precursors using [(11)C]CH(3)I and isolated by either a simplified solid-phase extraction (SPE) method or HPLC in 40-60% radiochemical yields based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 20-30min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 185-370 GBq/MUmol. PMID- 21256759 TI - Disposition of plutonium-239 via production of fission molybdenum-99. AB - A heritage of physical consequences of the U.S.-Soviet arms race has accumulated, the weapons-grade plutonium (WPu), which will become excess as a result of the dismantlement of the nuclear weapons under the arms reduction agreements. Disposition of Pu has been proposed by mixing WPu with high-level radioactive waste with subsequent vitrification into large, highly radioactive glass logs or fabrication into mixed oxide fuel with subsequent irradiation in existing light water reactors. A potential option may be the production of medical isotope molybdenum-99 by using Pu-239 targets. PMID- 21256760 TI - Conventional aortic valve replacement in patients with concomitant coronary artery disease and previous coronary artery bypass grafting in the era of interventional approaches. AB - OBJECTIVE: In patients with symptomatic aortic valve stenosis and a high estimated operative risk due to previous coronary artery bypass grafting (CABG) procedures, interventional aortic valve implantation techniques may ultimately prove superior. However, recent studies have revealed increased mortality and impaired survival in patients with concomitant coronary artery disease (CAD). METHODS: Between January 1996 and May 2010, 60 patients (73 +/- 6 years, 15 female (25%)) underwent conventional operation 9 +/- 6 years after CABG for symptomatic aortic valve stenosis (European System for Cardiac Operative Risk Evaluation, EuroSCORE) standard 11 +/- 3%, logistic 27 +/- 17%, Society of Thoracic Surgeons (STS) Score 19 +/- 8%). Coronary angiography revealed open grafts and no need for further revascularization in all patients. High-risk patients were identified (log. EuroSCORE>= 20%, n = 34) and divided by age (< 75 years, n=15; >= 75 years, n=19) for sub-group analysis. Follow-up for all 60 patients was performed according to the current guidelines: quality of life was assessed using the Minnesota Living with Heart Failure Questionnaire (MLHFQ). RESULTS: Thirty-day-mortality was 5% (n=3). During follow-up (100% complete), 18 patients died. Thus, 1-, 3- and 5-year survival was 91%, 77%, and 69%, respectively. No differences in survival could be detected between the two high risk groups. Quality of life revealed excellent results for the entire cohort, as well as both high-risk groups. CONCLUSIONS: Conventional surgery in patients with symptomatic aortic valve stenosis after previous CABG can be performed with excellent results despite a high calculated risk, independent of age. Although conventional surgery is technically more demanding and associated with substantial surgical trauma, it is justified by the excellent survival and high quality of life in this high-risk patient cohort. PMID- 21256762 TI - Repair of perivalvular leakage without re-replacement of prosthetic valves. AB - Perivalvular leakage after valve replacement is an awkward complication, and is liable to recur if re-replacement of a prosthetic valve is attempted. We describe an alternative way to repair perivalvular leakage by plastering the crack resulting from left-atrial degeneration around the prosthetic cuff using an equine pericardial roll. Our technique, which does not involve re-replacement of the prosthetic valve, is an easy, timesaving, and cost-effective method. The pericardium is useful for covering the crack between the prosthetic cuff and the hard left-atrial wall. PMID- 21256761 TI - Iatrogenic hypoglycemia secondary to tight glucose control is an independent determinant for mortality and cardiac morbidity. AB - OBJECTIVE: Evaluation of the effects of tight glycemia control in critically ill patients should include temporal as well as punctual glycemia data. METHODS: Insulin drip was used to target intensive care unit (ICU) glucose levels between 80 and 126 mg dl-1 in a consecutive series of adult cardiac surgery patients. ICU hourly glycemia was prospectively recorded. Glycemia standard deviation, hyperglycemia index (area under the curve for glycemia>126 mg dl-1 divided by total hours in ICU), and hypoglycemic episodes were recorded and analyzed, together with outcomes. RESULTS: A total of 596 patients were included. Hypoglycemia occurred in 21% of the patients. In-hospital mortality was 2.6%. There was a univariate correlation between mortality and glycemia standard deviation, and hypoglycemia occurrence. At multivariate analysis, hypoglycemia was a determinant for mortality (p=0.002; odds ratio (OR)=20.0), respiratory failure (p=0.0001; OR=1.4), requirement of a tracheostomy (p=0.0001; OR=21.6), and hemodynamic instability requiring intra-aortic balloon pump (IABP) (p=0.01; OR=1.5). To clarify the determinants of hypoglycemia, a second multivariate model was built. Diabetes (p=0.0001; OR=23) and chronic renal failure (p=0.01; OR=25) were the sole determinants for hypoglycemia occurrence. CONCLUSION: Iatrogenic hypoglycemia secondary to ICU tight glycemia control correlates with hospital mortality, respiratory, and cardiac morbidity in patients undergoing cardiac surgery. ICU hyperglycemia index and glycemia temporal variability have no independent correlation with outcomes. Higher glycemia targets should be advised in the perioperative management of patients with diabetes and renal failure, as both conditions independently increase the risk of hypoglycemia occurrence. PMID- 21256763 TI - Photogeneration of reactive oxygen species and photoinduced plasmid DNA cleavage by novel synthetic chalcones. AB - This paper describes the synthesis and photodynamic properties of six different chalcone derivatives. Using N,N-dimethyl-4-nitrosoaniline (RNO) bleaching assay, the singlet oxygen generating efficiencies of these chalcones are determined relative to rose bengal (RB). Superoxide dismutase (SOD) inhibitable cytochrome c reduction assay and electron magnetic resonance (EMR) spin trapping techniques are used to determine the superoxide anion radical (O2.-) yield upon photoirradiation. Photoinduced DNA scission studies show that O2.- is involved in the DNA strand break. In addition, antimicrobial activity of these chalcones is also investigated. Structure activity relationship accounts for the difference in the photogeneration of reactive oxygen species (ROS) by these sensitizers. Presence of electron releasing -OCH3 groups enhances the photogeneration of ROS. Cyclic voltammetry studies indicate a correlation between enzymatic O2.- generation efficiency and redox potential of chalcones. Both O2.- (Type I) and 1O2 (Type II) paths are involved in the photosensitization of chalcones. The LUMO energies obtained by molecular modeling correlate with the one-electron reduction potentials. PMID- 21256764 TI - C1q aggregate binding for the determination of anti-complementary activity of immunoglobulin products. AB - Aggregates in human immunoglobulin (Ig) products can develop due to employed manufacturing, formulation and storage conditions and can cause adverse reactions in patients. The test for anti-complementary activity (ACA) recommended by the European Pharmacopoeia (EP) is insensitive, variable and time consuming. We have optimised a commercial assay for the detection and quantitation of C1q binding aggregates in intravenous and intramuscular IgG preparations. The generation of C4d, iC3b and SC5b-9 induced by aggregates in vitro was measured by enzyme-linked immunosorbent assays (ELISA). In establishing the sensitivity of the C1q aggregate binding assay to detect IgG aggregates in comparison to turbidity and ACA, pure IgG at neutral and acidic pH was heated for various lengths of time to generate varying amounts of aggregates. The level of C1q binding aggregates was 7 fold greater in intramuscular samples. These aggregates were capable of activating complement in vitro and correlated with an increase in ACA. C1q aggregate binding was apparent before any quantifiable turbidity and ACA in the heat-treated samples. Furthermore, the C1q binding assay could discriminate between different levels of aggregates where ACA had reached a plateau. C1q aggregate binding is a sensitive, convenient, specific and robust means of detecting aggregates with a propensity for complement activation. PMID- 21256765 TI - Aortic valve closure associated with HeartMate left ventricular device support: technical considerations and long-term results. AB - BACKGROUND: Aortic valve integrity is crucial for optimal left ventricular assist device (LVAD) support. Pre-existing native aortic insufficiency, aortic valve incompetence acquired during support, as well as previously placed prosthetic aortic valves present unique problems for these patients. METHODS: We reviewed and analyzed data for 28 patients who underwent left ventricular outflow tract closure associated with HeartMate I (n =12) and HeartMate II (n = 16) LVAD insertion or exchange. Indications for valve closure, surgical technique, LVAD function, survival rates and complications were retrospectively analyzed. Survival rates were compared with those of HeartMate LVAD patients (n = 104) who did not undergo aortic valve closure. RESULTS: Indications for closure included native aortic valve insufficiency (10 patients), aortic valve deterioration after prolonged LVAD support (8 patients) and previously placed mechanical (9 patients) or bioprosthetic aortic prostheses (1 patient). There were 2 operative and 5 late deaths (mean 227 days post-operatively). Of the deaths, none were due to aortic valve closure. Actuarial survival was 78% at 1 year and 53% at 3 years, which was statistically better than for our patients with an intact aortic outflow (61% at 1 year, 45% at 3 years; p < 0.05). Five patients had transplants, 1 patient was successfully bridged to recovery, and 15 patients remain on LVAD support. No patient with outflow closure developed regurgitation, embolization or compromised LVAD support. CONCLUSION: Outflow tract closure in LVAD-supported patients is safe, often necessary and well tolerated. PMID- 21256767 TI - Differences between patients who do and do not adhere to antiretroviral therapy. AB - Nurses are often frustrated with HIV-infected patients who do not adhere to antiretroviral (ARV) therapy. To help patients adhere, it is first necessary to know the patient's stage of behavior change, and then to identify the specific factors determining that patient's behavior. The purpose of this study was to compare the health beliefs and behaviors of patients in the maintenance stage (optimum adherers) with those in the relapse stage (defaulters). Themes were extracted from open essay-type questions. The general profile for patients in the relapse stage was one of disempowerment, passiveness, and being a victim of ARVs. The profile for patients who achieved optimum ARV adherence levels illustrated empowerment, control, proactiveness, and being a victor rather than a victim of ARVs. Emerging themes were linked to the theoretical determinants of behavior change, and suggestions were made on how to help patients adhere to ARV regimens. PMID- 21256766 TI - Heart transplantation in children with markedly elevated pulmonary vascular resistance: impact of right ventricular failure on outcome. AB - BACKGROUND: Pulmonary hypertension causes increased morbidity and mortality in adults after heart transplantation. The effect of markedly elevated pulmonary vascular resistance (PVR) on post-transplant outcomes in children has not been well described. METHODS: Outcomes were compared in a retrospective study between 58 children with an elevated PVR index (PVRI) >= 6 U/m(2) and 205 children with a PVRI < 6 U/m(2). Patients who did and did not respond to acute vasodilator testing and patients who underwent transplant before (pre-1995) and after (post 1995) the availability of inhaled nitric oxide (iNO) were compared. RESULTS: The pre-transplant diagnoses, and cardiopulmonary bypass and donor ischemic times were similar between the high and low PVRI groups. High PVRI patients were older at transplant (12 +/- 6.2 vs 8 +/- 7.1 years, p = 0.002). The post-transplant inotrope score was higher in the high PVRI group (12 +/- 12 vs 2 +/- 2, p = 0.0001) and 1-year survival was worse (76% vs 81%, p = 0.03). The PVRI fell to < 6 U/m(2) with acute vasodilator testing in 21 of 49 (42%) high PVRI patients. RV failure occurred in 4 (19%) of the responders and in 14 (50%) of the non responders (p = 0.037). One responder (5%) and 4 non-responders (14%) died of RV failure. In the period after 1995, the year iNO became clinically available, the select group of high PVRI patients who received iNO preemptively had a lower incidence of post-transplant RV failure than the group that did not receive preemptive iNO (13% vs 54%, p = 0.04). CONCLUSIONS: Pre-transplant vasodilator testing identified patients at higher risk for RV failure. Patients who did not respond to vasodilator testing had an increased incidence of RV failure and death from RV failure. Preemptive use of iNO was associated with a decreased incidence of RV failure. PMID- 21256768 TI - Barriers to volunteer enrollment in HIV preventive vaccine clinical research trials: a review of the literature. PMID- 21256769 TI - Late HIV diagnosis and survival within 1 year following the first positive HIV test in a limited-resource region. PMID- 21256770 TI - A prospective open-labeled trial with levetiracetam in pediatric epilepsy syndromes: continuous spikes and waves during sleep is definitely a target. AB - Although LVT is currently extensively prescribed in childhood epilepsy, its effect on the panel of refractory epilepsy syndromes has not been entirely evaluated prospectively. In order to study the efficacy and safety of LVT as adjunctive therapy according to syndromes, we included 102 patients with refractory seizures (6 months to 15 years) in a prospective open-labeled trial. The responder rate was respectively 36% and 32% at 3 and 6 months with 6% and 7% patients becoming seizure free. Among the responders at 6 months (n=33), seizure frequency decreased by 66% and 79% at 3 and 6 months LVT compared to baseline. The highest benefit was for CSWS patients with 2/3 responders, 50% seizure free and no aggravation. LVT provided respectively 39% and 42% responders in focal and absence epilepsies. Infantile spasms and Dravet syndrome experienced the lowest efficacy. No patient with myoclonic-astatic epilepsy or Lennox-Gastaut syndrome was aggravated. LVT dose over 40 mg/kg/d was associated with a lower response rate. Tolerability was excellent. In spite of a small sample, we assume that CSWS is a good candidate for a randomized-controlled trial with LVT. PMID- 21256771 TI - Effects of intraperitoneal administration of the phenytoin on the skeletal system of rat fetus. AB - This study was conducted on determining the effects of phenytoin on the skeletal system of the fetuses of 13 Wistar Albino rats. The female rats were divided into two groups after the vaginal smear test: the group 1 (control group) included 6 individuals, whereas the group 2 (phenytoin group) comprised 7 animals. A dose of 25mg/kg/day phenytoin was administered intraperitoneally to pregnant rats on the 8th-10th days of pregnancy and fetuses were obtained by C-section on the 20th day. A number of 82 fetuses were observed by double staining technique. Their lengths and weights were measured, revealing the statistically significant differences between the two groups (p<0.001). The lengths of the fetuses in the group 2 were determined as to be 14% shorter and the weights 13% lower compared to those in the group 1. Similarly, number of the fetuses obtained in one gestation decreased 9% in the group 2. Ossification of the skull bones in the fetuses of the group 2 was observed eminently to be deteriorated through using dissection microscope and inspection. Costal separation anomaly was observed in the 10 fetuses of the group 2. The separated-laterally located costal components were not attached to the costal arch. Shape malformations in the last two ribs and wide angularity, particularly in the last six ribs, were also determined. This study has documented that intraperitoneal usage of the pheytoin during pregnancy may cause to different skeletal malformations, even with lower doses, in rat fetuses. PMID- 21256772 TI - Postictal sleep: syncope or seizure? AB - A 6-year-old boy presented with prolonged periods of unconsciousness (>60 min) following nausea and dizziness while standing. The application of EEG electrodes provoked a similar episode. These apparently long periods of unconsciousness could be explained by sleep. In view of the triggers (pain, distress, and prolonged standing), the prodromal features, and the transient sinus bradycardia during the EEG examination a diagnosis of vasovagal syncope was made. Sleep is an alternative explanation for delayed recovery after syncope in young children. Prompt recognition might avoid unnecessary investigations, distress, and an incorrect diagnosis. PMID- 21256773 TI - Safety and feasibility of ultrasound-accelerated catheter-directed thrombolysis in deep vein thrombosis. AB - OBJECTIVE: One in four patients with primary iliofemoral deep vein thrombosis (DVT) develops post-thrombotic syndrome (PTS) within 1 year despite optimal standard anticoagulant therapy. Removal of thrombus by thrombolytic drugs may prevent PTS. The aim of this study was to assess the short-term safety and efficacy of ultrasound-accelerated catheter-directed thrombolysis (US-accelerated CDT). DESIGN: This was a prospective non-randomised interventional study with US accelerated CDT for DVT. PATIENTS AND METHODS: Twelve patients with DVT (seven caval-iliofemoropopliteal, three iliofemoropopliteal, one femoropopliteal and one superior caval vein thrombosis) receiving standard anticoagulant and compression therapy, were treated with additional US-accelerated CDT (13 procedures) using the EKOS Endowave((r)) system (EKOS Corporation, Bothell, WA, USA) between October 2008 and January 2010. RESULTS: Thrombolysis was successful in 85% (11/13), with complete clot lysis (>90% restored patency) and in one case with partial clot lysis (50-90% restored patency). No pulmonary embolism and one bleeding at the catheter-insertion site were observed. In three patients, underlying lesions were successfully treated with balloon angioplasty and stent insertion. Four patients developed early recurrent thrombosis due to untreated residual venous obstruction. CONCLUSION: US-accelerated CDT is a safe and promising treatment in patients with DVT. Residual venous obstruction should be treated by angioplasty and stent insertion to avoid early re-thrombosis. PMID- 21256775 TI - Comments regarding 'Best medical therapy or wishful thinking in carotid disease? a single centre audit in Germany'. PMID- 21256776 TI - Plasma levels of pentraxin-3, an acute phase protein, are increased during sickle cell painful crisis. AB - The painful crisis accounts for the majority of sickle cell disease (SCD) related hospital admissions. The prototypic long pentraxin 3 (PTX3), an acute phase protein, is elevated in patients with inflammatory and ischemic states. As the sickle cell painful crisis is associated with both inflammation and tissue ischemia, we questioned whether plasma PTX3 levels are increased during and associated with painful crisis severity. Furthermore, since PTX3 up-regulates endothelial expression of tissue factor we studied PTX levels in relation to markers of endothelial and coagulation activation. Plasma levels of PTX3, ultra sensitive C-reactive protein (US-CRP), prothrombin fragment 1+2, thrombin antithrombin (TAT) complexes, von Willebrand Factor antigen and soluble vascular adhesion molecule-1 were determined in 105 asymptomatic sickle cell patients, 33 patients during painful crisis and 30 race matched healthy controls. Plasma PTX3 levels were comparable between patients in asymptomatic state and healthy controls, but significantly higher during painful crisis (P<0.01). US-CRP levels were higher in asymptomatic patients compared to controls (P<0.0001) and increased further during painful crisis (P<0.0001). PTX3 levels at presentation with painful crisis correlated significantly with the duration of subsequent hospital admission (r(s) = 0.43; P = 0.013), whereas US-CRP levels did not. PTX3 levels did not correlate with markers of hypercoagulability. The increase of PTX3 levels during painful crisis and their relation to the duration of subsequent hospital stay suggest that PTX3 might serve both as a diagnostic and severity marker of the painful sickle cell crisis. PMID- 21256777 TI - Career aspirations and pregnancy intentions in pregnant teens. AB - STUDY OBJECTIVE: To quantify the association between career aspirations and pregnancy intention in a cohort of pregnant adolescents seeking prenatal care. DESIGN: Pregnant adolescents presenting for their first prenatal visit between March 2002 and February 2005 participated in a 30-minute interview as part of a larger cohort study addressing pregnancy attitudes and outcomes. Pregnancy intention was assessed through direct questioning and career aspirations were assessed by categorizing career goal responses into three categories: those requiring less than a college education, those requiring at least a college education, and undecided. Associations between pregnancy intention and career aspirations were quantified using cross tabulations and multivariable logistic regression. SETTING: Hospital based prenatal clinic. PARTICIPANTS: Women aged 12 to 19 seeking prenatal care. MAIN OUTCOME MEASURE: Pregnancy intention. RESULTS: Of the 257 pregnant adolescents included in the study, 20% were 12-15 years old, 39% were 16-17 years old and 41% were 18-19 years old. The majority (85%) of the adolescents reported their pregnancies were unintended; 59% reported a career that requires at least a college education; 28% reported a career that requires less than a college education; and, 13% were undecided. Intended pregnancy was observed in 15% of those with career aspirations not requiring college and 17% of those with career aspirations and requiring college. CONCLUSIONS: The majority of adolescents in this study reported their pregnancy was unintended, had career aspirations requiring at least a college education, and reported plans to go back to school after the baby was born. Understanding pregnant adolescents' career aspirations may help inform pregnancy prevention and parenting support programs. PMID- 21256778 TI - STI testing information available to teens on the internet: what's missing? AB - STUDY OBJECTIVE: The purpose of this descriptive study is to provide baseline knowledge of the current internet content on STI testing available to adolescents on STI informational websites and to determine if barriers to STI testing are being addressed. DESIGN: A content analysis of eighteen structured STI informational websites was conducted. SETTING: The World Wide Web. PARTICIPANTS: STI informational websites. INTERVENTIONS: None. MAIN OUTCOME MEASURE: None. RESULTS: Findings suggest STI websites lack specific testing information for males. Few sites addressed consent and confidentiality or need for partner testing. Multiple statements portrayed pediatricians as poor communicators or unaware of adolescent healthcare needs. In contrast, only one statement portrayed pediatricians as a resource for teens. CONCLUSIONS: The internet has the potential to be an excellent resource for teens seeking information about STI testing. In our analysis, no single site stood out as accurate and comprehensive in addressing adolescent barriers to STI testing. PMID- 21256780 TI - Adolescent women and obesity. AB - The proportion of child and adolescent obesity in the United States has dramatically increased over the past few decades, challenging public health strategies and medical needs of the individual. The medical consequences of obesity include metabolic syndrome, polycystic ovary syndrome, and cardiovascular disease. There is no definite diagnostic criterion of metabolic syndrome in children and adolescents; commonly noted features are central adiposity, insulin resistance, dyslipidemia, and hypertension. To prevent negative health outcomes and early recognition for those at risk for overweight and obesity, healthcare providers should screen BMI in children and adolescents at least annually, as well as provide anticipatory guidance to all families during health maintenance visit. This review will address the epidemiology and consequences of obesity in children and adults, and issues for health care providers and public health officials to consider. These issues include increasing physical activity, decreasing sedentary activities, and promoting healthy eating behaviors. PMID- 21256779 TI - Congenital vaginal obstruction in neonates and infants: recognition and management. AB - BACKGROUND: Congenital vaginal obstruction commonly presents after puberty and presentation in infancy is uncommon. Due to lack of awareness, diagnosis may be missed in infants, sometimes with disastrous consequences. METHOD: A retrospective review of 9 neonates and infants treated for congenital vaginal obstruction in 16 years. RESULTS: The patients were aged 2 days to 4 months (median 28 days) at presentation. The main presenting feature was a lower abdominal mass, producing intestinal and urinary obstruction in 7 patients. In 2 patients, other conditions were suspected and diagnosis made only intraoperatively and in one patient, diagnosis was incidental during treatment for another condition. The cause of vaginal obstruction were low transverse vaginal septum 6, imperforate hymen 2, high transverse vaginal septum one. Associated anomalies were present in 5 patients (persistent cloaca 3, Hirschsprung disease 1, polydactyly 1). Low vaginal septum was treated by incision and drainage of hydrometrocolpos, imperforate hymen by hymenotomy and drainage of hydrometrocolpos and high vaginal septum by excision. There was recurrence of hydrometrocolpos in one patient who had low vaginal septum, requiring repeat surgery. One patient, in whom diagnosis was missed, died from overwhelming infection. Short term follow-up was good. CONCLUSION: Congenital vaginal obstruction is an uncommon presentation in this setting. Missing the diagnosis can lead to disastrous consequences. A high index of suspicion is required for prompt recognition and treatment. PMID- 21256781 TI - Acquired rectovaginal fistula in babies of unknown and asymptomatic retroviral positive mothers. AB - BACKGROUND: Acquired rectovaginal fistulae managed in three babies of asymptomatic mothers not known to be retroviral positive are presented to heighten clinician suspicion of HIV infection in babies with unexplained cause of acquired rectogenital fistula in regions where routine antenatal HIV screening is not adopted. CASES: Between 2004 and 2008, three babies aged 6, 10, and 11 months with rectovaginal fistula secondary to perinatal HIV transfer from unknown and asymptomatic positive mothers were managed at the University of Benin Teaching Hospital, Nigeria. Screening of the mothers confirmed the infection, and multidisciplinary approach to treatment, prompt antiretroviral regimen, use of broad spectrum antibiotics, and surgical management gave encouraging results. CONCLUSION: Routine antenatal screening and suspicion of HIV infection in babies with unexplained cause of acquired rectovaginal fistula is advocated. PMID- 21256782 TI - Hysteroscopic resection of uterine submucous leiomyoma protruding through hymen in a 16-year-old adolescent. AB - BACKGROUND: Uterine leiomyomas are rarely seen in adolescent and to date nine leiomyoma cases have been reported under age 17. Eight of these have been treated surgically via laparotomic myomectomy. CASE: A 16-year-old girl presented with a painless, lobulated necrotic mass protruding through the introitus. The mass originated from posterior uterine wall resected using hysteroscopy. Final pathology report revealed a submucous uterine leiomyoma. SUMMARY AND CONCLUSION: Submucous uterine leiomyomas may present as a vaginal mass in adolescents and can be safely treated using hysteroscopy. PMID- 21256783 TI - Novel homozygous insertion in SLC2A9 gene caused renal hypouricemia. AB - Renal hypouricemia is a heterogeneous inherited disorder characterized by impaired uric acid handling in the renal tubules. Patients are usually asymptomatic; however, some may experience urolithiasis and/or acute kidney injury. Most of the described patients (compound heterozygous and/or homozygous) are Japanese with mutations in the SLC22A12 gene (OMIM #220150). Four patients with renal hypouricemia caused by heterozygous defects and two families with homozygous mutations in the SLC2A9 gene have been recently described (OMIM #612076). We describe the clinical history, biochemical and molecular genetics findings of a Czech family with renal hypouricemia. The concentration of serum uric acid in the proband (16-year-old Czech girl with unrelated parents) was 0.17 +/- 0.05 mg/dl and expressed as an increase in the fractional excretion of uric acid (194 +/- 99%). The sequencing analysis of the coding region of uric acid transporters SLC22A12, SLC2A9, SLC17A3, ABCC4 and ABCG2, was performed. Analysis of genomic DNA revealed novel one nucleotide homozygote insertion in exon 3 in the SLC2A9 gene in proband and her brother resulting in a truncated protein (p.Ile118HisfsX27). No sequence variants in other candidate uric acid transporter were found. Homozygous loss-of-function mutations cause massive renal hypouricemia via total loss of uric acid absorption; however, they do not necessarily lead to nephrolithiasis and acute kidney injury. In contrast to previously reported heterozygous patients with renal hypouricemia type 2, we did not find even slight hypouricemia and found no decrease in the FE-UA of the heterozygous parents of the reported siblings. PMID- 21256784 TI - Unusual case of uterine stump pyometra in a cat. AB - This report describes an unusual case of uterine stump pyometra in a cat whose main clinical sign at presentation was abdominal straining. At the time of ovariohysterectomy, the surgeon reported that the uterine body had a purulent content. Nearly a month after the surgery the cat showed abdominal straining. The enlarged uterine stump, filled with purulent fluid, had caused a compression of the rectum and secondary intestinal sub-occlusion. Surgical revision consisted of draining the purulent content of the remnant of the uterine body and ablating as much of it as possible; checking of the ovarian pedicles revealed the presence of a small fragment of whitish tissue on the right side, which was shown to contain, by means of histological observation and immunohistochemical staining, ovarian tissue. Four months after surgical revision the queen did not show any pathological signs and 1 year later she is still in good health. PMID- 21256785 TI - [Assembly and management of helmet-CPAP in infants and children with acute respiratory insufficiency]. AB - Application of continuous positive airway pressure (CPAP) during respiratory insufficiency through a helmet interface is not well known in the Pediatric practice. The objective of this paper is to describe the necessary elements for it assembly, management and nursing care. The advantages and disadvantages of helmet compared to other interfaces are also discussed. PMID- 21256786 TI - [Prevention of mechanical ventilator-associated pneumonia: a comparison of two different oral hygiene methods]. AB - INTRODUCTION: Oral hygiene (OH) forms a part of the patient's safety in the prevention of mechanical ventilator-associated pneumonia (VAP). The dental plaque index (DP) is considered as a quality marker for OH. HYPOTHESIS: The association of electric toothbrush and conventional OH in intubated patients decreases the DP and incidence of VAP. OBJECTIVE: To verify the reduction of DP in patients receiving OH and electric toothbrush and its association with to the decrease of VAP incidence. MATERIALS AND METHODS: A 3-year long randomized, single blind and prospective study conducted in a 14-bed polyvalent intensive care unit. Patients were included when there was more than 48hours of mechanical ventilation and no expected respiratory infection. Patients were randomized into two groups: Standard (OH with chlorhexidine) (GS) and Raspall (Standard OH with electric dental brush) (GR). The VAP was identified following clinical, medical and microbiological criteria. The DP and halitosis were observed daily. Oral and pharyngeal swabs were collected during the first 5 days. RESULTS: 147 patients were included. Mean age was 53.9+/-17.5. No significant differences were found in the VAP incidence between the two groups (OR=0.78; 95% IC, 0.36-1.68; p=0.56). The relation between halitosis and DP was p=0.7. The dental plaque index on the 5th day was 1.98 (n=60) in GR and 2.04 (n=57) in GS (p=0.3). The dental plaque index on the 10th day was 1.68 (n=29) in GR and 1.91 (n=32) in GS (p=0.7). CONCLUSIONS: There is a tendency towards a decrease in the DP which is clearing in the GR group and no relation between VAP and greater DP or halitosis. PMID- 21256787 TI - [Ultrasound guided radial artery cannulation: procedure description and literature review]. AB - Arterial catheterization is the second most common invasive procedure performed in critical care units. These devices are essential in certain types of patients (the hemodinamically unstable or those who require regular evaluation of the gasometric values). Complications related to arterial cannulation are relatively scarce. However, there are no reliable indicators to predict the occurrence of radial artery occlusions or ischemic lesions in the hand after a radial cannulation procedure has been performed. Ultrasound-guided catheter insertion has been used for years to guide central venous cannulation in critical care, but its use has been more limited for arterial catheterization. This paper aims to describe the technique of ultrasound-guided radial artery catheterization and reviews the most important research papers that have evaluated the safety and efficacy of this procedure in the adult population. PMID- 21256788 TI - [Physical compatibility of sodium bicarbonate with other drugs often administered in the intensive care unit]. AB - INTRODUCTION: Acid-base disorders are associated with many diseases of the critically ill patient. Early treatment with sodium bicarbonate of these metabolic disorders is required for their normalization. This is an alkaline electrolyte solution administered by continuous or intermittent infusion. Its incompatibility due to its alkaline pH has been described, as it produces insoluble carbonate precipitation and causes carbon dioxide gas when mixed with acidic solutions. MATERIAL AND METHOD: An in vitro experimental study was performed. Bicarbonate was mixed with 13 drugs simulating Y-site administration. We combined 5 ml bicarbonate with 5 ml of every drug, at highest daily concentration used. The samples were visually examined to detect color changes, cloudiness, precipitation or gas formation, pH measurement and spectrophotometric analysis at 450 nm and 620 nm. The samples were evaluated at 0, 15, 30, 60 and 120 minutes. The compatibility criteria were absence of visual changes, pH changes<0.5 and variability of absorbance <0.01. RESULTS: We studied each drug individually and mixed with bicarbonate with 27 samples, and 135 measurements were performed. The incompatibilities did not always produce visual changes. Knowing the pH of drugs does not guarantee the compatibility of the mixture. Nitroglycerin with pH 4 is compatible with bicarbonate. Thiopental with pH 11 makes precipitation. Higher absorbances showed color changes, cloudiness and precipitation. CONCLUSIONS: Bicarbonate is physically compatible with esmolol, furosemide, heparin, insulin, morphine, nimodipine, nitroglycerin and urapidil and incompatible with amiodarone, cisatracurium, haloperidol, midazolam and thiopental. PMID- 21256789 TI - [Modulating variables of work disability in depressive disorders]. AB - OBJECTIVES: To describe the duration of sickness absence in unipolar depression and to determine the relationship of demographic, job-related and clinical variables with length of temporary work disability in depressive disorders. METHODS: Prospective observational study. A total of 1,292 subjects with depressive disorder diagnosis (ICD-9-CM) were selected claiming sick leave in an Occupational Diseases and Accident sat Work Insurance Scheme (sampling on successive occasions). Descriptive analyses of sickness absence duration, and bivariate (median test) and multivariate analysis (logistic regression) were performed to find relationships between demographic, job-related and clinical variables. RESULTS: Mean duration of sickness absence episodes due to a depressive disorder was 120 days. After multivariate analyses, female sex (p < 0.01), higher age (p < 0.01), lower educational level (p < 0.01), method of payment according to whether self-employed or unemployed workers (p < 0.01) and being referred to both psychiatrist and psychologist (p < 0.01) remained significantly associated with sick leave length. CONCLUSIONS: These findings confirm a strong association of depression with long periods of work disability and high absenteeism, and also suggest the need for improvements in functional ability assessment and promotion, treatment and referral of depressed patients. PMID- 21256790 TI - [Radiological diagnosis of hepatocellular carcinoma in 2010]. AB - The aim of diagnosis imaging is to detect hepatocellular carcinoma at an early stage, when a curative treatment is available. Biopsy is no longer required prior to treatment, and diagnosis of hepatocellular carcinoma is heavily dependent of imaging characteristics. Therefore, the purpose of this article is to describe the typical features of small (<20mm) and larger hepatocellular carcinomas with noninvasive diagnostic criteria, including ultrasound, computed tomography and MRI. Advances in these imaging modalities have greatly improved the detection of small hepatic nodules on liver cirrhosis, including the different steps of carcinogenesis, from regenerative to dysplastic nodules, and we emphasize the difficulties of radiological differentiation of precancerous lesions and small hepatocellular carcinomas. PMID- 21256791 TI - [Intracranial ependymomas: retrospective study of 16 cases]. AB - PURPOSE: To report the epidemiological, clinical aspects and therapeutic results of intracranial ependymomas in Morocco. PATIENTS AND METHODS: Our retrospective study concerned 16 cases of intracranial ependymomas, treated from January 1995 to December 2002 at the radiotherapy department of Ibn Rochd Hospital of Casablanca, Morocco. RESULTS: The average age was 15 years and complete surgery was possible in two cases. All the patients received cranial radiotherapy, combined with chemotherapy in six cases. Overall survival and progression-free survival at 5 years were respectively 50% and 31%. Eleven patients had local recurrence after an average period of 21 months. Progression-free survival at 5 years was better if complete resection: 100% vs. 28.6% in cases of incomplete resection, and depending on the histological type with 50% for classic ependymomas and 16.6% for anaplastic. CONCLUSION: Ependymomas are rare tumors and complete resection is the standard treatment followed by postoperative radiotherapy. The place of chemotherapy remains to be defined. PMID- 21256792 TI - Ultrasound irradiation promoted efficient solvent-free lipase-catalyzed production of mono- and diacylglycerols from olive oil. AB - This work reports the enzymatic production of mono- and diacylglycerols under the influence of ultrasound irradiation, in a solvent-free system, with and without the presence of surfactants at a constant temperature of 65 degrees C, glycerol to oil molar ratio of 2:1 and a commercial immobilized lipase (Novozym 435) as catalyst. For this purpose, two operation modes were adopted: the use of a sonotrode (ultrasonic probe), without agitation, varying reaction time, irradiation amplitude (25-45% of the total power) and type of surfactant, and a mechanically stirred reactor (600 rpm) under ultrasound irradiation in a water bath, testing different surfactants. Results show that very satisfactory MAG and DAG yields, above 50 wt.%, can be obtained without the use of surfactant, at mild irradiation power supply (~130 W), with no important enzyme activity losses verified, in a relatively short reaction time (2h), and low enzyme content (7.5 wt.%). Also, reaction kinetic results show that contents of MAG+DAG as high as ~65 wt.% can be achieved at longer times (6h), indicating a promising route for producing MAG and DAG using ultrasound irradiation. PMID- 21256793 TI - Rapid growth of magnetite nanoplates by ultrasonic irradiation at low temperature. AB - Two-dimensional plate-like Fe(3)O(4) nanocrystals were synthesized by a facile method using ultrasonic irradiation in aqueous solution at low temperature without protection from oxygen. The crystals were characterized by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, X ray photoelectron spectroscopy, and Fourier Transform infrared spectroscopy. The products subjected to ultrasound showed a two-dimensional morphology. The results obtained indicate that the morphologies of the magnetite crystals depend more on the ultrasonic irradiation than on the growth temperature. The thickness and width of the crystals increased with increasing temperature of the reaction medium. In addition, the magnetic hysteresis loop of the magnetite nanoplates was obtained at room temperature. PMID- 21256794 TI - New epicardial mapping electrode with warming/cooling function for experimental electrophysiology studies. AB - Cardiac electrical activity is influenced by temperature. In experimental models, the induction of hypothermia and/or hyperthermia has been used for the study of mechanisms of cardiac arrhythmia. A system that allows for localized, controlled induction, besides simultaneously recording electrical activity in the same induced area, needs to be developed ad hoc. This article describes the construction and application of a new system capable of locally modifying the epicardial temperature of isolated hearts and of carrying out cardiac mapping with sufficient spatial resolution. The system is based on a thermoelectric refrigerator and an array of 128 stainless steel unipolar electrodes in encapsulated epoxy of good thermal conductivity. The surface of the electrode is shaped to match the ventricular curvature. The electrode-device was tested on 7 isolated perfused rabbit hearts following the Langendorff technique. Quality recordings were obtained for the left ventricle at temperatures of 37 degrees C, 22 degrees C and 42 degrees C. The effects of temperature were explored in relation to two electrophysiological parameters: the QT interval during sinus rhythm and the VV interval during ventricular fibrillation. The results indicate that this is a suitable method for creating and analyzing electrophysiological heterogeneities induced by temperature in the experimental model. PMID- 21256795 TI - H-point standard additions method for simultaneous determination of sulfamethoxazole and trimethoprim in pharmaceutical formulations and biological fluids with simultaneous addition of two analytes. AB - The applicability of H-point standard additions method (HPSAM) to the resolving of overlapping spectra corresponding to the sulfamethoxazole and trimethoprim is verified by UV-vis spectrophotometry. The results show that the H-point standard additions method with simultaneous addition of both analytes is suitable for the simultaneous determination of sulfamethoxazole and trimethoprim in aqueous media. The results of applying the H-point standard additions method showed that the two drugs could be determined simultaneously with the concentration ratios of sulfamethoxazole to trimethoprim varying from 1:18 to 16:1 in the mixed samples. Also, the limits of detections were 0.58 and 0.37 MUmol L(-1) for sulfamethoxazole and trimethoprim, respectively. In addition the means of the calculated RSD (%) were 1.63 and 2.01 for SMX and TMP, respectively in synthetic mixtures. The proposed method has been successfully applied to the simultaneous determination of sulfamethoxazole and trimethoprim in some synthetic, pharmaceutical formulation and biological fluid samples. PMID- 21256796 TI - Effect of volitional relaxation and motor imagery on F wave and MEP: do these tasks affect excitability of the spinal or cortical motor neurons? AB - OBJECTIVE: To test if simple motor imagery, like thumb abduction, preferentially influences the excitability of the spinal or cortical motoneurons. METHODS: Ten healthy subjects underwent two separate experiments, each consisting of recording F waves and MEPs from abductor pollicis brevis (APB) in three consecutive sessions: (1) baseline, (2) after immobilizing APB for 3 h, and (3) after brief muscle exercise. During the immobilization, the subjects were instructed to volitionally relax APB in experiment 1 (relaxation task), and mentally simulate thumb abduction without actual movement in experiment 2 (imagery task). RESULTS: Relaxation task suppressed both MEPs and F waves. Motor imagery reduced this suppression, restoring F waves nearly completely (94%) and MEPs only partially (77%). Hence, the rest-induced decline of MEPs in part results from cortical modulation. In contrast, statistical analysis revealed no differences in imagery induced recovery of motoneuron excitabilities whether assessed by F wave or MEP. Thus, increased excitability of spinal motoneurons responsible for F-wave changes also accounts for recovery of MEPs. CONCLUSIONS: Volitional relaxation depresses the spinal and cortical motoneurons, whereas mental simulation counters rest induced suppression primarily by restoring spinal excitability. SIGNIFICANCE: The present findings help elucidate physiologic mechanisms underlying motor imagery. PMID- 21256797 TI - Nonlinear PD2i heart rate complexity algorithm detects autonomic neuropathy in patients with type 1 diabetes mellitus. AB - OBJECTIVE: The aim of this study was to test whether a new heart rate variability (HRV) complexity measure, the Point Correlation Dimension (PD2i), provides diagnostic information regarding early subclinical autonomic dysfunction in diabetes mellitus (DM). We tested the ability of PD2i to detect diabetic autonomic neuropathy (DAN) in asymptomatic young DM patients without overt neuropathy and compared them to age- and gender-matched controls. METHODS: HRV in DM type 1 patients (n=17, 10 female, 7 male) aged 12.9-31.5 years (duration of DM 12.4+/-1.2 years) was compared to that in a control group of 17 healthy matched probands. The R-R intervals were measured over 1h using a telemetric ECG system. RESULTS: PD2i was able to detect ANS dysfunction with p=0.0006, similar to the best discriminating MSE scale, with p=0.0002. CONCLUSIONS: The performance of PD2i to detect DAN in asymptomatic DM patients is similar to the best discriminative power of previously published complexity measures. SIGNIFICANCE: The PD2i algorithm may prove to be an easy to perform and clinically useful tool for the early detection of autonomic neuropathy in DM type 1 patients, especially given its minimal data requirements. PMID- 21256798 TI - Molecular structure of La3+-induced methanol dehydrogenase-like protein in Methylobacterium radiotolerans. AB - La(3+) and not Ca(2+) increases methanol dehydrogenase (MDH) activity in Methylobacterium radiotolerans NBRC15690. La(3+)- and Ca(2+)-MDH-like proteins were found to be homodimeric (alpha(2)) and heterotetrameric (alpha(2)beta(2)), respectively. N-terminal amino acid sequences of these proteins revealed that La(3+)- and Ca(2+)-MDH-like proteins were encoded by xoxF and mxaFI, respectively. PMID- 21256799 TI - Evaluation of painful sensory symptoms in restless legs syndrome: experience from two clinical trials. AB - BACKGROUND: Although "uncomfortable and unpleasant" limb sensations are a core symptom of restless legs syndrome (RLS), change in sensory symptomatology is usually not evaluated as a treatment outcome. METHODS: In two double-blind trials, patients with idiopathic RLS (n=357 in trial 615 and 398 in trial 604) were randomized to placebo or pramipexole (optimized at 0.125, 0.25, 0.50, or 0.75 mg/day). For entry, trial 604 also required at least moderate mood disturbance. In both trials, 12-week change in RLS-related limb pain was assessed using a 100-mm visual analogue scale (VAS). RESULTS: At baseline, approximately 75% of patients had limb-pain scores >30. Treatment with pramipexole yielded significant score reduction as early as day 5. At week 12, median score reduction for pramipexole relative to placebo was -33.5 vs. -11.0 (p<0.0001) in trial 615 and -31.0 vs. -11.0 (p<0.0001) in trial 604. CONCLUSIONS: Painful sensations may be more frequent in RLS than has previously been appreciated, and their amelioration may be a facet of pramipexole's benefit even in patients with concurrent mood disturbance. Limb pain assessment, e.g., by a VAS, is a useful measure of change in RLS symptom severity. PMID- 21256800 TI - A convenient expiratory positive airway pressure nasal device for the treatment of sleep apnea in patients non-adherent with continuous positive airway pressure. AB - BACKGROUND: While continuous positive airway pressure (CPAP) effectively treats obstructive sleep apnea (OSA), adherence to CPAP is suboptimal. The short-term efficacy of and adherence with a convenient expiratory positive airway pressure (EPAP) nasal device was evaluated in OSA patients non-adherent with CPAP. METHODS: Participants were OSA patients who refused CPAP or used CPAP less than 3 h per night. After demonstrating tolerability to the EPAP device during approximately 1 week of home use, patients underwent a screening/baseline polysomnogram (PSG1) and a treatment PSG (PSG2). Patients meeting prespecified efficacy criteria underwent PSG3 after about 5 weeks of EPAP treatment. RESULTS: Forty-seven of 59 eligible patients (80%) tolerated the device and underwent PSG1. Forty-three patients (27 m, 16f; 53.7+/-10.9 years) met AHI entry criteria and underwent PSG2. Mean AHI decreased from 43.3+/-29.0 at baseline to 27.0+/ 26.7 (p<0.001) at PSG2. Twenty-four patients (56%) met efficacy criteria; their mean AHI was 31.9+/-19.8, 11.0+/-7.9, 16.4+/-12.2 at PSG1, PSG2, and PSG3, respectively (p<0.001, PSG1 vs. both PSG2 and PSG3). Mean Epworth Sleepiness Scale (ESS) scores were 12.3+/-4.8 at baseline, 11.1+/-5.1 at PSG1, and 8.7+/-4.4 at PSG3 (p=0.001 compared to baseline). Device use was reported an average of 92% of all sleep hours. CONCLUSIONS: The improvements in AHI and ESS, combined with the high degree of treatment adherence observed, suggest that the convenient EPAP device tested may become a useful therapeutic option for OSA. PMID- 21256801 TI - REM sleep related bradyarrhythmia syndrome: Vagal overactivity or dysfunction of the cardiac conduction system? PMID- 21256802 TI - Sleep restriction over several days does not affect long-term recall of declarative and procedural memories in adolescents. AB - OBJECTIVES: There is broad evidence that sleep as opposed to waking facilitates the consolidation of both declarative and procedural memory. The current study addressed the question whether different extents of sleep restriction after learning would impair long-term memory consolidation in adolescents. METHODS: Eighty-eight healthy adolescents were randomized to five different sleep protocols with 9, 8, 7, 6 or 5 h of time in bed for four consecutive nights under controlled conditions that excluded daytime sleep. Declarative (word-pair task) and procedural memory (mirror tracing task) encoding was assessed prior to the sleep restriction protocol. Recall was assessed after two recovery nights following the sleep protocol and 4 weeks later. RESULTS: Sleep diaries and actigraphy data demonstrated that the participants closely followed the sleep protocols. There were no differences in demographic parameters or memory encoding at baseline. In contrast to the initial prediction, restriction of nocturnal sleep over four consecutive nights had no significant impact on declarative or procedural memory consolidation. Polysomnographic monitoring after sleep restriction demonstrated a high preservation of the amount of slow wave sleep in the restricted conditions. CONCLUSIONS: The results suggest that adolescents show a high resilience of memory consolidation to substantial sleep curtailment across four nights that might be promoted by increased sleep intensity under conditions of sleep restriction. PMID- 21256803 TI - Evaluation of subjective efficacy and safety of ramelteon in Japanese subjects with chronic insomnia. AB - OBJECTIVE: To assess patient-reported efficacy and safety of ramelteon in Japanese patients with chronic insomnia. METHODS: Randomized, double-blind, placebo-controlled, multicenter trial. After a placebo lead-in period, 987 adults with chronic insomnia received ramelteon 8 mg or placebo once daily for 2 weeks, followed by a placebo run-out period to monitor rebound insomnia. Patient reported sleep data were collected using sleep diaries. RESULTS: Ramelteon significantly reduced mean patient-reported sleep latency (primary endpoint) compared with placebo during week 1 (-4.54 min; p=0.001). Ramelteon maintained greater efficacy in sleep latency than placebo at week 2, but the difference did not achieve statistical significance. In a subset of patients who adhered to treatment and completed their diaries as instructed, a statistically significant reduction in subjective sleep latency was sustained through week 2. Compared with placebo, ramelteon also significantly improved mean total sleep time and mean sleep quality during week 1, the number of awakenings during week 2, and overall patient global impression scores. There was no evidence of rebound insomnia. Adverse events were generally mild and transient. CONCLUSIONS: In Japanese adults with chronic insomnia, ramelteon 8 mg significantly reduced patient-reported sleep latency, increased total sleep time and improved sleep quality after 1 week of treatment. Ramelteon was generally well tolerated with no rebound insomnia. PMID- 21256804 TI - Gender specificity of the slow wave sleep lost in chronic widespread musculoskeletal pain. AB - OBJECTIVES: The majority of patients suffering from musculoskeletal chronic widespread pain (CWP) are females, and they tend to report poor sleep. We tested the hypothesis that the poor sleep of female patients reporting CWP is gender specific for changes in (1) electroencephalograph (EEG) features and (2) heart rate variability (HRV). METHODS: Twenty-four normal sleepers were compared to 24 patients with CWP who complained of poor sleep. Patients were referred from general practice and were matched for age (41-47 years) and gender (25 W, 23 M). Sleep variables and spectral EEG activity analyses were performed during 1 night of sleep recording. Time-domain cardiac RR interval and spectral autoregressive analyses were also performed from the same data set. RESULTS: Compared to normal females, female patients with CWP had significantly shorter sleep duration (-68 min), lower sleep efficiency (-9.9%), twice the awakenings and a trend for more periodic limb movements per hour of sleep. Daytime napping was reported by 78% of CWPs. Compared to all controls, females with CWP had significantly less power in the EEG delta band in the first and second non-REM sleep cycle. Although RR interval analysis revealed that CWP patients had a faster heart rate, neither the sympathetic nor sympathovagal analysis reached statistical significance for gender or pain status comparisons. CONCLUSIONS: Female CWP patients have shorter sleep duration with many awakenings and lower sleep EEG delta activity without gender difference in HRV. PMID- 21256806 TI - Suppression of motor evoked potential during cataplexy. PMID- 21256805 TI - Pimavanserin tartrate, a 5-HT(2A) receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers. AB - OBJECTIVE: Determine the effects of pimavanserin tartrate [ACP-103; N-(4 flurophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2 methylpropyloxy)phenylmethyl)carbamide], a selective serotonin 5-HT(2A) receptor inverse agonist, on slow wave sleep (SWS), other sleep parameters, and attention/vigilance. METHODS: Forty-five healthy adults were randomized to pimavanserin (1, 2.5, 5, or 20 mg) or placebo in a double-blind fashion (n=9/group). Pimavanserin or placebo was administered once daily in the morning for 13 consecutive days. The effects of pimavanserin were measured after the first dose and again after 13 days. Sleep parameters were measured by polysomnography. Effects on attention/vigilance were measured by a continuous performance task. RESULTS: Compared to placebo, pimavanserin significantly increased SWS following single and multiple dose administration. Pimavanserin also decreased number of awakenings. PSG variables not affected by pimavanserin included sleep period time, total sleep time, sleep onset latency, number of stage shifts, total time awake, early morning wake, and microarousal index. Changes in sleep architecture parameters, sleep profile parameters, and spectral power density parameters were consistent with a selective increase in SWS. Pimavanserin did not adversely affect performance on the continuous performance test measured in the evening before or morning after polysomnography. CONCLUSIONS: These data suggest that pimavanserin selectively increases slow wave sleep and decreases awakenings, an effect that does not diminish with repeated administration. PMID- 21256807 TI - A compound belonging to traditional Chinese medicine improves nocturnal activity in Parkinson's disease. PMID- 21256808 TI - Adjuvant interferon: recommit or move on? PMID- 21256809 TI - Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial. AB - BACKGROUND: Adjuvant high-dose interferon alfa-2b improves relapse-free survival (RFS) in patients with high-risk melanoma, although benefits in overall survival are uncertain. Because of the toxic effects of high-dose regimens, intermediate doses are being explored. We investigated whether adjuvant therapy with intermediate-dose interferon alfa-2b for 1 or 2 years would improve outcomes in patients with stage IIB-IIC or III resected cutaneous melanoma. METHODS: This randomised, open-label, phase 3, parallel-group trial was undertaken between 1996 and 2004. 855 patients were randomly assigned at 35 centres in the Nordic countries by block randomisation to three groups: observation only (group A); 4 weeks of induction (interferon alfa-2b 10 million units flat dose subcutaneously 5 days per week) followed by 12 months of maintenance therapy (interferon alfa-2b 10 million units flat dose subcutaneously 3 days per week; group B); or 1 month of induction and 24 months of maintenance (group C). Neither investigators nor patients were masked to treatment assignment. Patients were stratified for country and tumour stage; patients with stage III disease were further stratified for presence of metastatic lymph nodes at primary diagnosis versus at relapse, palpable versus non-palpable lymph-node metastases, and number of metastatic lymph nodes. The primary endpoint was overall survival in the two interferon alfa 2b groups combined. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01259934. FINDINGS: 284 patients were assigned to group A, 285 to group B, and 286 to group C; all patients were analysed. The median follow-up time was 72.4 months (IQR 46.9-98.0). We recorded no significant improvement in overall survival in patients given interferon alfa-2b compared with observation: median overall survival was 56.1 months (IQR 22.3 to >120.0) in group A, 72.1 months (25.8 to >120) in group B, and 64.3 months (24.7 to >120) in group C (p=0.600). Hazard ratios (HR) for overall survival were 0.91 (95% CI 0.74 1.10; p=0.642) for groups B and C combined versus observation; 0.91 (0.72-1.14; p=0.652) for group B versus observation; and 0.91 (0.72-1.15; p=0.858) for group C versus observation. Median RFS was 23.2 months (IQR 5.6 to <120) in group A, 37.8 months (10.8 to >120) in group B, and 28.6 months (8.6 to >120) in group C (p=0.034). HRs for RFS were 0.80 (0.67-0.96; p=0.030) for groups B and C combined versus observation, 0.77 (0.63-0.96; p=0.034) for group B versus observation, and 0.83 (0.68-1.03; p=0.178) for group C versus observation. The most common grade 3 and 4 adverse events were fatigue (five in group A [1.8%], 28 in group B [9.8%], and 32 in group C [11.2%]), myalgia (three [1.1%], 15 [5.3%], 14 [4.9%], respectively), and thrombocytopenia (15 [5.3%], 23 [8.1%], eight [2.8%], respectively). INTERPRETATION: Adjuvant therapy with intermediate-dose interferon alfa-2b did not significantly improve overall survival. Interferon alfa-2b with 1 year maintenance therapy significantly improved RFS, but we recorded no significant effect for 2-year maintenance therapy. Further research is in progress to define the subgroup of patients who benefit from adjuvant interferon alfa-2b. FUNDING: Schering-Plough (now Merck); the Radiumhemmet Research Funds, Stockholm; the Stockholm County Council; and the Swedish Cancer Society. PMID- 21256810 TI - Commentary to "History and physical examination findings predictive of testicular torsion: an attempt to promote clinical diagnosis by house staff". PMID- 21256811 TI - The influence of labeling the vegetable content of snack food on children's taste preferences: a pilot study. AB - OBJECTIVE: This pilot study examined whether informing children of the presence of vegetables in select snack food items alters taste preference. METHODS: A random sample of 68 elementary and middle school children tasted identical pairs of 3 snack food items containing vegetables. In each pair, 1 sample's label included the food's vegetable (eg, broccoli gingerbread spice cake), and 1 sample's label did not (eg, gingerbread spice cake). Participants reported whether the samples tasted the same, or whether they preferred one sample. Frequency of vegetable consumption was also assessed. RESULTS: Taste preferences did not differ for the labeled versus the unlabeled sample of zucchini chocolate chip bread, chi(2) (2, n = 68) = 3.21, P = .20 or broccoli gingerbread spice cake chi(2) (2, n = 68) = 2.15, P = .34. However, students preferred the unlabeled cookies (ie, chocolate chip cookies) over the vegetable-labeled version (ie, chickpea chocolate chip cookies), chi(2) = (2, n = 68) 9.21, P = .01. Chickpeas were consumed less frequently (81% had not tried in past year) as compared to zucchini and broccoli. CONCLUSIONS AND IMPLICATIONS: Informing children of the presence of vegetables hidden within snack food may or may not alter taste preference and may depend on the frequency of prior exposure to the vegetable. PMID- 21256813 TI - Stillbirth in diabetic pregnancies. AB - Pregnancy in women with pregestational diabetes is associated with high perinatal morbidity and mortality. Stillbirth accounts for the majority of cases with perinatal death. Intrauterine growth restriction, pre-eclampsia, foetal hypoxia and congenital malformations may be contributing factors, but more than 50% of stillbirths are unexplained. Majority of stillbirths are characterised by suboptimal glycaemic control during pregnancy. Foetal hypoxia and cardiac dysfunction secondary to poor glycaemic control are probably the most important pathogenic factors in stillbirths among pregnant diabetic women. There is thus a need for new strategies for improving glycaemic control to near-normal levels throughout pregnancy and for preventing and treating hypertensive disorders in pregnancy. Antenatal surveillance tests including ultrasound examinations of the foetal growth rate, kick counting and non-stress testing of foetal cardiac function are widely used. However, future research should establish better antenatal surveillance tests to identify the infants susceptible to stillbirth before it happens. PMID- 21256814 TI - From the American Epilepsy Society 2009 Annual Course. Non-substrate-directed epilepsy and surgery: PRO and CON. AB - The surgical treatment of epilepsy is the most efficacious therapeutic modality for patients with a medically refractory partial seizure disorder. Epilepsy surgery has been demonstrated to be both effective and well tolerated in individuals with medial temporal lobe epilepsy associated with mesial temporal sclerosis. The identification of an MRI pathological substrate may be useful in identifying the epileptogenic zone and the appropriate operative strategy, and is predictive of the long-term seizure outcome. Patients with a non-substrate directed partial epilepsy often require a more rigorous presurgical evaluation because of issues regarding the lateralization and localization of the epileptic brain tissue. The surgical outcome may be most disappointing in individuals with localization-related epilepsy of extratemporal origin associated with a normal MRI study. The present discussion focuses on the selection of patients with extratemporal non-substrate-directed epilepsy for a presurgical evaluation. The important factors associated with an improved quality of life subsequent to epilepsy surgery include seizure remission and avoidance of operation-induced adverse effects. PMID- 21256815 TI - Factors contributing to Korean teachers' attitudes toward students with epilepsy. AB - We investigated factors contributing to teachers' attitudes toward students with epilepsy. Data were collected from 604 teachers in Korea. The questionnaire included the Scale of Attitudes Toward Persons with Epilepsy (ATPE) and a demographic and teaching experience survey. In stepwise linear regression analysis, ATPE Knowledge scores (P<0.001) and prior experience teaching a student with epilepsy (P=0.001) were identified as significant factors for ATPE Attitude scores. The ATPE Knowledge scores accounted for 50.1% of the variance in the Attitude scores, and experience teaching a student with epilepsy accounted only for 1.0%. Our finding that teachers' knowledge is the most important factor influencing teacher's attitudes toward epilepsy indicates that teachers should be provided with information about epilepsy universally, across geographic settings, educational levels, and experience levels. PMID- 21256812 TI - Anti-CD3 antibody ameliorates experimental autoimmune uveitis by inducing both IL 10 and TGF-beta dependent regulatory T cells. AB - Chronic/recurrent autoimmune (idiopathic) uveitis is difficult to treat and they account for approximately 10% of legal blindness in the Western world. As it has been reported that anti-CD3 antibody can enhance T cell regulatory function, we investigated its effects in vivo on experimental autoimmune uveitis (EAU), a model for autoimmune uveitis in humans. B10RIII mice immunized with an uveitogenic peptide were treated with the F(ab')(2) fragment of anti-CD3 mAb either before or at clinical disease onset. Evaluation of EAU and cellular responses showed that disease was inhibited and the activation and expansion of pathogenic T cells selectively reduced, whereas functions of Treg in vivo were enhanced. Moreover, mice treated with anti-CD3 mAb were resistant to a second challenge with antigen and thus protected from recurrence of disease. Our results demonstrate that anti-CD3 mAb is a potent inhibitor of autoimmune uveitis. PMID- 21256816 TI - Optimizing clinical performance and geometrical robustness of a new electrode device for intracranial tumor electroporation. AB - Current technology has limited applicability for electroporation based treatment of deep-seated tumors, and is in general, not optimized in terms of compliance with clinically relevant parameters. Here we present a novel electrode device developed for electrotransfer of antineoplastic drugs and genes to intracranial tumors in humans, and demonstrate a method to optimize the design (i.e. geometry) of the electrode device prototype to improve both clinical performance and geometrical tolerance (robustness). We have employed a semiempirical objective function based on constraints similar to those used in radiation oncology. The results show that small geometrical changes may yield a significant improvement. For example, a 2 mm displacement of 6 electrodes yields 14% better compliance with the clinical parameters, compared to the prototype, and additionally makes the electrode device less sensitive to random geometrical deviations. The method is readily applicable to other electrode configurations. PMID- 21256817 TI - Pharmacokinetics of kakkalide and its main metabolites in rat plasma determined by HPLC-DAD and LC-MSn. AB - This study was undertaken to assess the plasma pharmacokinetic profile of kakkalide (KA), the major isoflavone found in extracts from the dried flower of Pueraria lobata. The main metabolites were identified using HPLC-DAD or LC/MS/MS method, and a HPLC-UV method for simultaneous quantification of the metabolites as well as the parent compound in plasma was developed. Rat plasma contained three glucuronide metabolites, irisolidone-7-O-glucuronide (Ir-7G), tectorigenin 7-O-glucuronide (Te-7G) and 6-OH biochanin A-glucuronide (6-OH BiA-G), as well as KA and trace amount of irisolidone (Ir) after oral administration of 200 mg/kg KA. The pharmacokinetics of KA and three glucuronide conjugates in rat plasma was determined for the first time using a simple, selective and accurate HPLC method. The AUC(0-t) values of the glucuronide metabolites are significantly greater than that of KA. They were detectable in rat plasma at different time points, indicating that glucuronidation during KA metabolism in vivo may occur in different sites, first in intestine and then in liver. Moreover, enterohepatic recirculation may result in the slow elimination of these glucuronide metabolites. PMID- 21256818 TI - The transcriptomic profiles of adipose tissues are modified by feed deprivation in lactating goats. AB - A major function of ruminant adipose tissue is to store lipids for use in productive functions. Body fat mobilization is required during periods of negative energy balance such as lactation or undernutrition. Until now, gene expression profiling of ruminant adipose tissue in response to nutritional restriction has not been performed. To gain a better understanding of the molecular mechanisms in adipose tissue in response to dietary factors, microarray analysis was used to compare the effects of two extreme nutritional conditions (control diet vs. 48-h feed deprivation) in the omental and perirenal adipose tissues of lactating goats (Capra hircus). We observed the altered expression of 456 and 199 genes in omental and perirenal adipose tissues, respectively. Similar biological processes were altered by feed deprivation in these two sites, although twice as many genes were differentially expressed in the omental than in the perirenal adipose tissue. Taken together, the transcriptional changes involved in lipid metabolism (decreased lipid synthesis and triglyceride storage capacity as well as increased fatty acid oxidation) were consistent with reduced energy deposition in goat adipose tissues in response to a 48-h fast. An inflammatory state of the adipose tissue was observed following the 48-h fast. PMID- 21256819 TI - Vacuum-assisted closure therapy for patients with infected sternal wounds: a meta analysis of current evidence. AB - Acute and chronic wound infections are the main reasons for the observed increase in mortality rate and represent a significant risk factor in hospitalisation. From the patient's perspective, wound therapy is an uncomfortable, painful and long-term treatment. Modern sternal-wound-treatment systems would be expected to shorten wound healing and hospital stay periods. Vacuum-assisted closure (VAC) therapy is a system that promotes wound healing through the application of negative pressure by controlled suction to the wound surface. The application of controlled levels of negative pressure accelerates healing in many types of wounds. There are a number of scientific publications that have used meta analysis to compare VAC and traditional therapy, considering changes in wound size. This article surveys the research literature focussing on the management of wound infections. The objective of this study is to assess the impact of VAC compared with conventional therapy on length of stay (LOS) and mortality. Six articles were selected that included a total of 321 patients (169 for VAC therapy and 152 for conventional therapy). The meta-analysis showed that VAC therapy resulted in a decrease of 7.18 days in hospital LOS (confidence interval (CI) 95%: 10.82, 3.54), with no significant impact on mortality. Our data provide robust evidence of the effectiveness of VAC therapy. PMID- 21256820 TI - Augmentation mammaplasty for the secondary deformity after polyacrylamide hydrogel removal: delayed or immediate? PMID- 21256821 TI - Customised chest wall implant to correct pectus excavatum and bilateral breast reconstruction with muscle-sparing latissimus dorsi (MS-LD) flap in a single stage. PMID- 21256822 TI - Effects of taurine on reperfusion injury. AB - Taurine is an organic acid, which has a very important function in the human body. Recently, the antioxidant property of taurine has been much emphasised. In this study, the gracilis muscle flap model was used to investigate the effect of taurine in ischaemia/reperfusion injury in rats. Totally 32 Sprague-Dawley rats were divided into two groups: control group (n = 16) and the treatment group with taurine (n = 16). After elevation of the gracilis muscle flap, 4 h of ischaemia was performed in both groups. Thirty min before the reperfusion, taurine (200 mg kg(-1)) was injected intravenously. After 24 h of reperfusion, the amount of malondialdehyde (MDA), tissue water content and flap viability were evaluated. After 72 h of reperfusion, histological findings were evaluated. Amount of MDA and tissue water content were significantly lower (p < 0.005), and the flap viability was significantly higher (p < 0.005) in the treatment group 24 h after reperfusion. On comparing the outcomes of histological analysis between control and treatment groups, the amounts of collagen, fibroblast and angiogenesis in treatment group were significantly higher than those in the control group. However, the amount of polymorphonuclear leucocyte and tissue necrosis in the treatment group were significantly lower than in the control group. Our results showed that taurine played an important role in the process of ischaemia/reperfusion injury and presented certain protective effects with the improvement in flap survival after ischaemia/reperfusion injury. PMID- 21256823 TI - Acid sphingomyelinase regulates osteoclastogenesis by modulating sphingosine kinases downstream of RANKL signaling. AB - Acid sphingomyelinase (ASM) was identified as a gene induced by NFAT2 activation in osteoclasts. Suppression of ASM expression in bone marrow macrophages by knockdown enhanced c-Fos/NFAT2 expression, increasing the number of TRAP-positive multinucleated cells in vitro. SphK1 was upregulated during the late stage of osteoclastogenesis, while SphK2 expression remained constant. SphK1 was downregulated following ASM knockdown, while SphK2 levels were unchanged. Experiments using shRNA and catalytically-inactive form demonstrated inhibitory and stimulatory activities on osteoclast formation of SphK1 and SphK2, respectively. These results suggest that ASM regulates osteoclastogenesis by modulating the balance between SphK1 and SphK2 downstream of RANKL signaling. PMID- 21256824 TI - Biodegradable chitosan particles induce chemokine release and negligible arginase 1 activity compared to IL-4 in murine bone marrow-derived macrophages. AB - Alternatively activated macrophages have been implicated in the therapeutic activity of biodegradable chitosan on wound healing, however, the mechanisms of phenotypic differentiation are still unclear.In vitro, macrophages stimulated with high doses of chitosan (>= 500 MUg/mL) were reported to produce low-level markers associated with alternative activation (arginase-1) as well as classical activation (nitric oxide), and to undergo apoptosis. In this study, we tested the hypothesis that 40 kDa biodegradable chitosan (5-500 MUg/mL) is sufficient to polarize mouse bone marrow-derived macrophages (BMDM) in vitro to an alternatively activated phenotype. Control cultures were stimulated with IL-4 (alternative activation), IFN-gamma/LPS (classical activation), 1 MUm diameter latex beads (phagocytosis), or left untreated. After 48 h of in vitro exposure, BMDM phagocytosed fluorescent chitosan particles or latex beads, and remained viable and metabolically active, although some cells detached with increasing chitosan and latex bead dosage. Arginase-1 was over 100-fold more strongly induced by IL-4 than by chitosan, which induced only sporadic and weak arginase-1 activity over untreated BMDM, and no nitric oxide. IFN-gamma/LPS stimulated nitric oxide production and arginase-1 activity and high concentrations of inflammatory cytokines (IL-6, IL-1beta, TNF-alpha, MIP-1alpha/MIP-1beta), while latex beads stimulated nitric oxide and not arginase-1 activity. Chitosan or latex bead exposure, but not IL-4, tended to promote the release of several chemokines (MIP-1alpha/beta, GM-CSF, RANTES, IL-1beta), while all treatments promoted MCP-1 release. These data show that chitosan phagocytosis is not sufficient to polarize BMDM to the alternative or the classical pathway, suggesting that biodegradable chitosan elicits alternatively activated macrophages in vivo through indirect mechanisms. PMID- 21256825 TI - Insulin-like growth factor-binding protein-5 (IGFBP-5) inhibits TNF-alpha-induced NF-kappaB activity by binding to TNFR1. AB - IGFBP-5 is known to be involved in various cell phenomena such as proliferation, differentiation, and apoptosis. However, the exact mechanisms by which IGFBP-5 exerts its functions are unclear. In this study, we demonstrate for the first time that IGFBP-5 is a TNFR1-interacting protein. We found that ectopic expression of IGFBP-5 induced TNFR1 gene expression, and that IGFBP-5 interacted with TNFR1 in both an in vivo and an in vitro system. Secreted IGFBP-5 interacted with GST-TNFR1 and this interaction was blocked by TNF-alpha, demonstrating that IGFBP-5 might be a TNFR1 ligand. Furthermore, conditioned media containing secreted IGFBP-5 inhibited PMA-induced NF-kappaB activity and IL-6 expression in U-937 cells. Coimmunoprecipitation assays of TNFR1 and IGFBP-5 wild-type and truncation mutants revealed that IGFBP-5 interacts with TNFR1 through its N- and L-domains. However, only the interaction between the L-domain of IGFBP-5 and TNFR1 was blocked by TNF-alpha in a dose-dependent manner, suggesting that the L domain of IGFBP-5 can function as a TNFR1 ligand. Competition between the L domain of IGFBP-5 and TNF-alpha resulted in inhibition of TNF-alpha-induced NF kappaBeta activity. Taken together, our results suggest that the L-domain of IGFBP-5 is a novel TNFR1 ligand that functions as a competitive TNF-alpha inhibitor. PMID- 21256827 TI - Effects of a HP0859 (rfaD) knockout mutation on lipopolysaccharide structure of Helicobacter pylori 26695 and the bacterial adhesion on AGS cells. AB - Lipopolysaccharide (LPS) is considered as an important virulence factor of Helicobacter pylori, and contributes to infection persistence and disease severity. ADP-L-glycero-D-manno-heptose-6-epimerase is an enzyme essential for LPS synthesis and understanding of its biochemistry is critical for drug development. We cloned one putative ortholog of Escherichia colirfaD, HP0859, from H. pylori 26695. Determination of the native molecular weight of the recombinant HP0859 protein suggests that the protein is likely a hexamer. NADP+, instead of NAD+, was proved to be the physiological cofactor for HP0859 protein. Circular dichroism spectrum analysis demonstrated that the secondary structure of this protein is significantly altered when the cofactor is removed. We also constructed an HP0859 knockout mutant and examined its phenotypic properties. The HP0859 knockout mutant exhibited a severe truncation of LPS, a decreased growth rate, and a higher susceptibility to novobiocin. Disruption of HP0859 also reduced the adhesive capacity of H. pylori to AGS cells, and the infected cells failed to display the classic hummingbird phenotype. Complementation of the HP0859 knockout mutation restored these phenotypes completely. In conclusion, we demonstrate that HP0859 codes for a protein essential for the LPS inner core biosynthesis in H. pylori and an intact LPS structure contributes to the adherence ability of this bacterium. PMID- 21256826 TI - 2B4+ CD8+ T cells play an inhibitory role against constrained HIV epitopes. AB - Cytotoxic T cells play a critical role in the control of HIV and the progression of infected individuals to AIDS. 2B4 (CD244) is a member of the SLAM family of receptors that regulate lymphocyte development and function. The expression of 2B4 on CD8+ T cells was shown to increase during AIDS disease progression. However, the functional role of 2B4+ CD8+ T cells against HIV infection is not known. Here, we have examined the functional role of 2B4+ CD8+ T cells during and after stimulation with HLA B14 or B27 restricted HIV epitopes. Interestingly, IFN gamma secretion and cytotoxic activity of 2B4+ CD8+ T cells stimulated with HIV peptides were significantly decreased when compared to influenza peptide stimulated 2B4+ CD8+ T cells. The expression of the signaling adaptor molecule SAP was downregulated in 2B4+ CD8+ T cells upon HIV peptide stimulation. These results suggest that 2B4+ CD8+ T cells play an inhibitory role against constrained HIV epitopes underlying the inability to control the virus during disease progression. PMID- 21256829 TI - Functional characterization of the hypothalamic-pituitary-adrenal axis of the Wistar Audiogenic Rat (WAR) strain. AB - The Wistar Audiogenic Rat (WAR) strain is a genetic model of sound-induced reflex epilepsy which was selected starting from audiogenic seizures susceptible Wistar rats. Wistar resistant rats were used as WAR's control in this study. In the acute situation, audiogenic seizures (AS) in WARs mimic tonic-clonic seizures and, in the chronic protocol, mimic temporal lobe epilepsy. AS have been shown to evoke neuroendocrine responses; however, the hypothalamic-pituitary-adrenal activity in the WAR has not been established. The aim of this study was to evaluate the hypothalamic-pituitary-adrenal axis (HPA) responses to exogenous ACTH stimulation (8 ng/rat), fifteen minute restraint stress and circadian variation (8 am and 8 pm) under rest conditions in these animals through plasma measurements of ACTH and corticosterone concentrations. We also measured the body weight from birth to the 9th week of life and determined adrenal gland weight. We found that WARs are smaller than Wistar and presented a higher adrenal gland weight with a higher level of corticosterone release after intravenous ACTH injection. They also showed altered HPA axis circadian rhythms and responses to restraint stress. Our data indicate that, despite the lower body weight, WARs have increased adrenal gland weight associated with enhanced pituitary and adrenal responsiveness after HPA axis stimulation. Thus, we propose WARs as a model to study stress-epilepsy interactions and epilepsy-neuropsychiatry comorbidities. PMID- 21256828 TI - Inhibition of IkappaB kinase alpha (IKKalpha) or IKKbeta (IKKbeta) plus forkhead box O (Foxo) abolishes skeletal muscle atrophy. AB - Two transcription factor families that are activated during multiple conditions of skeletal muscle wasting are nuclear factor kappaB (NF-kappaB) and forkhead box O (Foxo). There is clear evidence that both NF-kappaB and Foxo activation are sufficient to cause muscle fiber atrophy and they are individually required for at least half of the fiber atrophy during muscle disuse, but there is no work determining the combined effect of inhibiting these factors during a physiological condition of muscle atrophy. Here, we determined whether inhibition of Foxo activation plus inhibition of NF-kappaB activation, the latter by blocking the upstream inhibitor of kappaB kinases (IKKalpha and IKKbeta), would prevent muscle atrophy induced by 7 days of cast immobilization. Results were based on measurements of mean fiber cross-sectional area (CSA) from 72 muscles transfected with 5 different mutant expression plasmids or plasmid combinations. Immobilization caused a 47% decrease in fiber CSA in muscles injected with control plasmids. Fibers from immobilized muscles transfected with dominant negative (d.n.) IKKalpha-EGFP, d.n. IKKbeta-EGFP or d.n. Foxo-DsRed showed a 22%, 57%, and 76% inhibition of atrophy, respectively. Co-expression of d.n. IKKalpha EGFP and d.n. Foxo-DsRed significantly inhibited 89% of the immobilization induced fiber atrophy. Similarly, co-expression of d.n. IKKbeta-EGFP and d.n. Foxo-DsRed inhibited the immobilization-induced fiber atrophy by 95%. These findings demonstrate that the combined effects of inhibiting immobilization induced NF-kappaB and Foxo transcriptional activity has an additive effect on preventing immobilization-induced atrophy, indicating that NF-kappaB and Foxo have a cumulative effect on atrophy signaling and/or atrophy gene expression. PMID- 21256830 TI - Studies on reduction of S-nitrosoglutathione by human carbonyl reductases 1 and 3. AB - Human carbonyl reductases 1 and 3 (CBR1 and CBR3) are monomeric NADPH-dependent enzymes of the short-chain dehydrogenase/reductase superfamily. Despite 72% identity in primary structure they exhibit substantial differences in substrate specificity. Recently, the endogenous low molecular weight S-nitrosothiol S nitrosoglutathione (GSNO) has been added to the broad substrate spectrum of CBR1. The current study initially addressed whether CBR3 could equally reduce GSNO which was not the case. Neither the introduction of residues which contribute to glutathione binding in CBR1, i.e. K106Q and S97V/D98A, nor the exchange C143S, which prevents a theoretical disulfide bond with C227 in CBR3, could engender activity towards GSNO. However, exchanging amino acids 236-244 in CBR3 to correspond to CBR1 was sufficient to engender catalytic activity towards GSNO. Catalytic efficiency was further improved by the exchanges Q142M, C143S, P230W and H270S. Hence, the same residues previously reported as important for reduction of carbonyl compounds appear to be key to CBR1-mediated reduction of GSNO. Furthermore, for CBR1-mediated reduction of GSNO, considerable substrate inhibition at concentrations >5 K(m) was observed. Treatment of CBR1 with GSNO followed by removal of low molecular weight compounds decreased the GSNO reducing activity, suggesting a covalent modification. Treatment with dithiothreitol, but not with ascorbic acid, could rescue the activity, indicating S-glutathionylation rather than S-nitrosation as the underlying mechanism. As C227 has previously been identified as the reactive cysteine in CBR1, the variant CBR1 C227S was generated, which, in comparison to the wild-type protein, displayed a similar k(cat), but a 30-fold higher K(m), and did not show substrate inhibition. Collectively, the results clearly argue for a physiological role of CBR1, but not for CBR3, in GSNO reduction and thus ultimately in regulation of NO signaling. Furthermore, at higher concentrations, GSNO appears to work as a suicide inhibitor for CBR1, probably through glutathionylation of C227. PMID- 21256831 TI - Hydroxyl containing seleno-imine compound exhibits improved anti-oxidant potential and does not inhibit thiol-containing enzymes. AB - Design and synthesis of organoselenium compounds with high thiol peroxidase (TPx) and low thiol oxidase (TOx) activities have been a difficult task and remains a synthetic-activity relationship dilemma. In this regard we are reporting for the first time a detail experimental data (both in vitro and in vivo) about the anti oxidant and toxicological profile of an Imine (-N) containing organoselenium compound (Compound A). The TPx activity of Compound A was significantly higher than diphenyl diselenide (DPDS). Both Compound A and DPDS protected sodium nitropruside (SNP) induced thiobarbituric acid reactive species (TBARS) production in rats tissue homogenate with significantly higher activity observed for Compound A than DPDS (p<0.05). The Compound A also exhibited strong antioxidant activity in the DPPH and ABTS radical scavenging assays. This study reveals that an imine group close to selenium atom drastically enhances the catalytic activities in the aromatic thiol (PhSH) assay systems. The oxidation of biologically significant thiols reflects the toxicity of the compounds. However, the present data showed that treatment with Compound A at 0, 10, 25 or 50mg/kg was not associated with mortality or body weight loss. Similarly it did not inhibit alpha-ALA-D and Na(+1)/K(+1) ATPase (sulfhydryl group containing enzymes) activities after acute oral treatment; rather it enhanced non-protein thiols (NPSH) concentration. The Compound A did not cause any oxidative stress as measured by TBARS production in rat's tissue preparation. Our data also indicate that exposure to Compound A did not affect plasma transaminase activities or levels of urea and creatinine in rats. Ascorbic acid is always considered a marker of oxidative stress and the reduction of its content may indicate an increase in oxidative stress. Treatment with Compound A did not alter Ascorbic acid levels in rats. The conducted in vitro and in vivo tests show the versatile therapeutic potential of this compound in the area of free radical induced damages, will undoubtedly enhance our understanding of the mechanism of model compounds and may ultimately yield insights that result in improved GPx mimics. PMID- 21256832 TI - Withaferin A enhances radiation-induced apoptosis in Caki cells through induction of reactive oxygen species, Bcl-2 downregulation and Akt inhibition. AB - Withaferin A (Wit A), a natural compound derived from the medicinal plant Withania somnifera, has been reported for the anti-tumor effects, including the inhibition of tumor cell growth, metastasis and angiogenesis. In this study, we investigated the effect of Wit A on radiation-induced apoptosis in human renal cancer cells (Caki cells). Our results showed that, compared with Wit A or radiation alone, the combination of both resulted in a significant enhancement of apoptosis, showing the increase in the cleavage of caspase-3 and PARP as well as sub-G1 cell population. In addition, reactive oxygen species (ROS) generation was correlated with the enhancement of radiation-induced apoptosis by Wit A. Wit A downregulated Bcl-2 protein levels and ectopic expression of Bcl-2 in Caki cells attenuated the apoptosis induced by Wit A plus radiation. Taken together, these results indicate that Wit A enhanced radiation-induced apoptosis in Caki cells through ROS generation, down-regulation of Bcl-2 and Akt dephosphorylation. Thus, our study shows that Wit A may be used as an effective radiosensitizer in cancer therapy. PMID- 21256833 TI - A high-performance liquid immunoaffinity chromatography method for determining transferrin-bound iron in serum. AB - BACKGROUND: The analyzed values in the ICSH reference method for serum iron analysis are affected by non-transferrin(Tf)-bound iron such as ferritin. Also, non-Tf-bound plasma iron (iron citrate) is present in iron-overloaded specimens from patients with hemochromatosis, which was measured as serum iron in previous methods. We developed a specific determination method for serum transferrin-bound iron (serum t Fe) by high-performance liquid immunoaffinity chromatography (HPLAC), and compared it with the ICSH method and a fully automated (FA) method. METHODS: Tf and t Fe were isolated from interferents in serum by HPLC using an immunoaffinity column. The concentration of t Fe isolated was determined by a colorimetric reaction using a highly sensitive chromogen. RESULTS: Interferents, except iron saccharate (detected at 5%), do not affect t Fe determination. Within run and between-run imprecisions were in the ranges of 0.2-0.4% and 0.4-1.0% CV. The results of the HPLAC method correlated well with those of the ICSH method (r=0.9993) and FA method (r=0.9984). CONCLUSIONS: In contrast to the ICSH and FA methods for determining serum iron, the HPLAC method is simple, highly precise and specific for serum t Fe, which can contribute to the measurement of iron status. PMID- 21256834 TI - Plasma HDL-cholesterol and triglyceride levels in familial hypercholesterolemia: data from the MedPed CZ database and the Czech population. AB - BACKGROUND: The aim of this study was to compare HDL-cholesterol and triglyceride levels in patients with familial hypercholesterolemia (FH) with a representative sample of the Czech population. METHODS: For the FH group: data of 1728 adult patients with FH (600 males and 1128 females) were taken from the MedPed CR database. The control group were 1995 individuals of the population sample of the Czech post-MONICA study (956 males and 1039 females). RESULTS: Compared with controls, FH males showed higher levels of HDL-cholesterol (1.35+/-0.35 mmol/l vs. 1.31+/-0.35 mmol/l; P<0.05) and triglycerides (1.98+/-1.00 vs. 1.81+/-1.45 mmol/l; P<0.01). After adjustment for age and BMI, the increase in triglycerides remained significant in the subgroup of non-FDB males only (2.22+/-0.06 vs. 1.74+/-0.04 mmol/l; P<0.001). Compared with controls, HDL-cholesterol was lower (1.55+/-0.40 mmol/l vs. 1.65+/-0.37 mmol/l; P<0.001), while triglycerides were higher (1.72+/-0.82 mmol/l vs. 1.28+/-0.75, P<0.001) in FH females. After adjustment for age and BMI, HDL-cholesterol remained lower in the subgroup of FH females without FDB (1.52+/-0.01 vs. 1.67+/-0.01 mmol/l, P<0.001) whereas triglycerides were higher in both female subgroups. CONCLUSIONS: A lower HDL-C in the group of FH patients compared with control subjects was demonstrated in FH females without FDB only. Elevated triglyceride levels were found in FH males and females, except for males with FDB. PMID- 21256835 TI - The dermatan sulfate-dependent anticoagulant pathway is mostly preserved in aneurysm and in severe atherosclerotic lesions while the heparan sulfate pathway is disrupted. AB - BACKGROUND: The pathogenesis of abdominal aortic aneurysm is associated with changes of several components of arterial wall. Vascular glycosaminoglycans contribute to the non-thrombogenic activity of blood vessels. We investigated whether modifications of glycosaminoglycans in human abdominal aortic aneurysm affect their anticoagulant properties. METHODS: Glycosaminoglycans were extracted from abdominal aortic aneurysms (n=11) derived from reconstitution surgeries, human abdominal aortas (n=9) from normal organ transplant donors and from preserved (n=10) and atherosclerotic (n=17) segments obtained from autopsy of an old patient. Glycosaminoglycan composition, concentration and anticoagulant activity were determined. RESULTS: Glycosaminoglycans extracted from aneurysms have a more potent anticoagulant activity than those from normal arteries of young adults, mostly due to a relative enrichment of dermatan sulfate, which potentiates heparin cofactor II inhibition of thrombin. Arterial segments of aged patient with severe atherosclerosis showed a glycosaminoglycan composition similar to aneurysms samples. Glycosaminoglycans extracted from these regions showed also a more potent heparin cofactor II-dependent anticoagulant activity than lesion-free areas due to the relative enrichment of dermatan sulfate. CONCLUSION: The anticoagulant activity from abdominal aortic aneurysms is preserved. No modifications particular to the aneurysms were dissociated from those observed in atherosclerosis. PMID- 21256836 TI - Screening and therapeutic management of lipoprotein(a) excess: review of the epidemiological evidence, guidelines and recommendations. AB - Lipoprotein(a) (Lp(a)) is a low density lipoprotein-like particle in which apolipoprotein B100 is covalently linked to the unique apolipoprotein(a). There is a mounting body of evidence suggesting a role of Lp(a) in the development and progression of several vascular diseases, such as coronary heart disease, ischemic stroke, abdominal aortic aneurysm and venous thromboembolism, so that prominent scientific societies have recently endorsed guidelines and recommendations that increasingly encourage the screening and the therapeutic management of Lp(a) excess. In this article, we review the epidemiologic evidence, guidelines and recommendations concerning the relationship between increased plasma Lp(a) levels and risk of cardiovascular disease or venous thromboembolism by systematically retrieving the most relevant articles from electronic databases. Although uncertainty still remains regarding the opportunity to screen for hyperlipoproteinemia(a), it seems inopportune as yet to measure plasma Lp(a) levels in asymptomatic persons, while its measurement might be of clinical significance in selected categories of patients at intermediate or high cardiovascular risk. The measurement of Lp(a) should be performed by using immunometric, harmonized and size-insensitive techniques and results reported in total lipoprotein mass rather than in traditional units. It is uncertain if Lp(a) genotyping or phenotyping add any additional information for the cardiovascular disease risk stratification. Although the optimal therapeutic management of Lp(a) excess is still controversial, a general agreement exists that very high Lp(a) levels should be lowered in patients with multiple cardiovascular risk factors, preferably with nicotinic acid therapy (e.g., 1.0-3.0 g/day). PMID- 21256837 TI - SOX2 expression levels distinguish between neural progenitor populations of the developing dorsal telencephalon. AB - The HMG-Box transcription factor SOX2 is expressed in neural progenitor populations throughout the developing and adult central nervous system and is necessary to maintain their progenitor identity. However, it is unclear whether SOX2 levels are uniformly expressed across all neural progenitor populations. In the developing dorsal telencephalon, two distinct populations of neural progenitors, radial glia and intermediate progenitor cells, are responsible for generating a majority of excitatory neurons found in the adult neocortex. Here we demonstrate, using both cellular and molecular analyses, that SOX2 is differentially expressed between radial glial and intermediate progenitor populations. Moreover, utilizing a SOX2(EGFP) mouse line, we show that this differential expression can be used to prospectively isolate distinct, viable populations of radial glia and intermediate cells for in vitro analysis. Given the limited repertoire of cell-surface markers currently available for neural progenitor cells, this provides an invaluable tool for prospectively identifying and isolating distinct classes of neural progenitor cells from the central nervous system. PMID- 21256838 TI - Wnt4 induces nephronic tubules in metanephric mesenchyme by a non-canonical mechanism. AB - Wnt4 and beta-catenin are both required for nephrogenesis, but studies using TCF reporter mice suggest that canonical Wnt signaling is not activated in metanephric mesenchyme (MM) during its conversion to the epithelia of the nephron. To better define the role of Wnt signaling, we treated rat metanephric mesenchymal progenitors directly with recombinant Wnt proteins. These studies revealed that Wnt4 protein, which is required for nephron formation, induces tubule formation and differentiation markers Lim1 and E-cadherin in MM cells, but does not activate a TCF reporter or up regulate expression of canonical Wnt target gene Axin-2 and has little effect on the stabilization of beta-catenin or phosphorylation of disheveled-2. Furthermore, Wnt4 causes membrane localization of ZO-1 and occludin in tight junctions. To directly examine the role of beta catenin/TCF-dependent transcription, we developed synthetic cell-permeable analogs of beta-catenin's helix C, which is required for transcriptional activation, in efforts to specifically inhibit canonical Wnt signaling. One inhibitor blocked TCF-dependent transcription and induced degradation of beta catenin but did not affect tubule formation and stimulated the expression of Lim1 and E-cadherin. Since a canonical mechanism appears not to be operative in tubule formation, we assessed the involvement of the non-canonical Ca(2+)-dependent pathway. Treatment of MM cells with Wnt4 induced an influx of Ca(2+) and caused phosphorylation of CaMKII. Moreover, Ionomycin, a Ca(2+)-dependent pathway activator, stimulated tubule formation. These results demonstrate that the canonical Wnt pathway is not responsible for mesenchymal-epithelial transition (MET) in nephron formation and suggest that the non-canonical calcium/Wnt pathway mediates Wnt4-induced tubulogenesis in the kidney. PMID- 21256839 TI - Stress and muscular dystrophy: a genetic screen for dystroglycan and dystrophin interactors in Drosophila identifies cellular stress response components. AB - In Drosophila, like in humans, Dystrophin Glycoprotein Complex (DGC) deficiencies cause a life span shortening disease, associated with muscle dysfunction. We performed the first in vivo genetic interaction screen in ageing dystrophic muscles and identified genes that have not been shown before to have a role in the development of muscular dystrophy and interact with dystrophin and/or dystroglycan. Mutations in many of the found interacting genes cause age dependent morphological and heat-induced physiological defects in muscles, suggesting their importance in the tissue. Majority of them is phylogenetically conserved and implicated in human disorders, mainly tumors and myopathies. Functionally they can be divided into three main categories: proteins involved in communication between muscle and neuron, and interestingly, in mechanical and cellular stress response pathways. Our data show that stress induces muscle degeneration and accelerates age-dependent muscular dystrophy. Dystrophic muscles are already compromised; and as a consequence they are less adaptive and more sensitive to energetic stress and to changes in the ambient temperature. However, only dystroglycan, but not dystrophin deficiency causes extreme myodegeneration induced by energetic stress suggesting that dystroglycan might be a component of the low-energy pathway and act as a transducer of energetic stress in normal and dystrophic muscles. PMID- 21256841 TI - Origin and function of the stalk-cell vacuole in Dictyostelium. AB - Large vacuoles are characteristic of plant and fungal cells, and their origin has long attracted interest. The cellular slime mould provides a unique opportunity to study the de novo formation of vacuoles because, in its life cycle, a subset of the highly motile animal-like cells (prestalk cells) rapidly develops a single large vacuole and cellulosic cell wall to become plant-like cells (stalk cells). Here we describe the origin and process of vacuole formation using live-imaging of Dictyostelium cells expressing GFP-tagged ammonium transporter A (AmtA-GFP), which was found to reside on the membrane of stalk-cell vacuoles. We show that stalk-cell vacuoles originate from acidic vesicles and autophagosomes, which fuse to form autolysosomes. Their repeated fusion and expansion accompanied by concomitant cell wall formation enable the stalk cells to rapidly develop turgor pressure necessary to make the rigid stalk to hold the spores aloft. Contractile vacuoles, which are rich in H(+)-ATPase as in plant vacuoles, remained separate from these vacuoles. We further argue that AmtA may play an important role in the control of stalk-cell differentiation by modulating the pH of autolysosomes. PMID- 21256840 TI - C. elegans ADAMTS ADT-2 regulates body size by modulating TGFbeta signaling and cuticle collagen organization. AB - Organismal growth and body size are influenced by both genetic and environmental factors. We have utilized the strong molecular genetic techniques available in the nematode Caenorhabditis elegans to identify genetic determinants of body size. In C. elegans, DBL-1, a member of the conserved family of secreted growth factors known as the Transforming Growth Factor beta superfamily, is known to play a major role in growth control. The mechanisms by which other determinants of body size function, however, is less well understood. To identify additional genes involved in body size regulation, a genetic screen for small mutants was previously performed. One of the genes identified in that screen was sma-21. We now demonstrate that sma-21 encodes ADT-2, a member of the ADAMTS (a disintegrin and metalloprotease with thrombospondin motifs) family of secreted metalloproteases. ADAMTS proteins are believed to remodel the extracellular matrix and may modulate the activity of extracellular signals. Genetic interactions suggest that ADT-2 acts in parallel with or in multiple size regulatory pathways. We demonstrate that ADT-2 is required for normal levels of expression of a DBL-1-responsive transcriptional reporter. We further demonstrate that adt-2 regulatory sequences drive expression in glial-like and vulval cells, and that ADT-2 activity is required for normal cuticle collagen fibril organization. We therefore propose that ADT-2 regulates body size both by modulating TGFbeta signaling activity and by maintaining normal cuticle structure. PMID- 21256842 TI - Comparison of mibefradil and derivative NNC 55-0396 effects on behavior, cytochrome P450 activity, and tremor in mouse models of essential tremor. AB - NNC 55-0396 [(1S,2S)-2-(2-(N-[(3-benzimidazol-2-yl)propyl]-N-methylamino)ethyl)-6 fluoro-1,2, 3,4-tetrahydro-1-isopropyl-2-naphtyl cyclopropanecarboxylate dihydrochloride], is a mibefradil derivative that retains potent in vitro T-type calcium channel antagonist efficacy. We compared the two compounds for behavioral toxicity, effects on cytochrome P450 activity, and efficacy against tremor in the gamma-aminobutyric acid type A (GABAA) receptor subunit alpha1-null mouse, and the harmaline tremor model of essential tremor in wild-type mice. NNC 55-0396 was better tolerated than mibefradil in the horizontal wire test of sedation/motor function, with 3/6 failing at 300 and 30mg/kg respectively. To assess for a potential interaction with harmaline, mice were given the drugs, followed by harmaline or vehicle, and tested 30min later in the inverted wire grid test. Mibefradil exacerbated, whereas NNC 55-0396 ameliorated harmaline-induced test deficits. In mouse liver microsomes, NNC 55-0396 was a less potent inhibitor of harmaline O-demethylation than mibefradil (Ki: 0.95 and 0.29MUM respectively), and also less potent at inhibiting testosterone 6-beta-hydroxylation (Ki: 0.71 and 0.12MUM respectively). In the GABAA alpha1-null model, NNC 55-0396 but not mibefradil, (each at 20mg/kg), suppressed tremor while NNC 55-0396 at 12.5mg/kg suppressed harmaline-induced tremor by half by 20-100min, whereas mibefradil at the same dose did not significantly affect tremor. In contrast to mibefradil, NNC 55-0396 is well tolerated and suppresses tremor, and exerts less cytochrome P450 inhibition. These results suggest potential clinical utility for NNC 55-0396 or similar derivatives as a T-type calcium antagonist. PMID- 21256843 TI - The immunoproteasome in steatohepatitis: its role in Mallory-Denk body formation. AB - Recently it has been shown that the expression of the immunoproteasome increased in proportion to the degree of chronic inflammation in both the liver cell cytoplasm and nuclei in liver biopsies from patients who had chronic active hepatitis or cirrhosis. In the present study, biopsies from patients with steatohepatitis, with or without Mallory-Denk body (MDB) formation, were studied by immunofluorescent staining. Normal liver showed colocalization of FAT10, LMP2, LMP7, and MECL-1 at the mitochondria. Only LMP2 and LMP7 were found in the cell nuclei. Liver biopsies from patients with steatohepatitis and MDB formation, and a case of hepatocellular carcinoma forming MDBs in the tumor cells, showed colocalization of FAT10 and ubiquitin with LMP2, LMP7 and MECL-1 within the MDB. This indicates involvement of the immunoproteasome in MDB formation in steatohepatitis cases and in a case of HCC forming MDBs. Prior studies have shown that the immunoproteasome was involved in drug-induced MDB formation using the same immunofluorescent colocalization approach as was used on these human liver biopsies. The increase in the immunoproteasome subunit proteins was made at the expense of the 26S proteasome. This indicates that the shift from the 26S to the immunoproteasome had occurred in the MDB positive hepatocytes. PMID- 21256845 TI - Can we use the "C" word with confidence? Cure for chronic hepatitis C. PMID- 21256844 TI - Rapid, cell-based toxicity screen of potentially therapeutic post-transcriptional gene silencing agents. AB - Post-transcriptional gene silencing (PTGS) agents such as antisense, ribozymes and RNA interference (RNAi) have great potential as therapeutics for a variety of eye diseases including retinal and macular degenerations, glaucoma, corneal degenerations, inflammatory and viral conditions. Despite their great potential and over thirty years of academic and corporate research only a single PTGS agent is currently approved for human therapy for a single disease. Substantial challenges exist to achieving both efficacious and safe PTGS agents. Efficacy, as measured in specific target mRNA and protein knockdown, depends upon a number of complex factors including the identification of rare regions of target mRNA accessibility, cellular co-localization of the PTGS agent in sufficient concentration with the target mRNA, and stability of the PTGS agent in the target cells in which it is delivered or expressed. Safety is commonly measured by lack of cytotoxicity or other deleterious cellular responses in cells in which the PTGS agent is delivered or expressed. To relieve major bottlenecks in RNA drug discovery novel, efficient, inexpensive, and rapid tools are needed to facilitate lead identification of the most efficacious PTGS agent, rational optimization of efficacy of the lead agent, and lead agent safety determinations. We have developed a technological platform using cell culture expression systems that permits lead identification and efficacy optimization of PTGS agents against arbitrary disease target mRNAs under relatively high throughput conditions. Here, we extend the technology platform to include PTGS safety determinations in cultured human cells that are expected to represent the common cellular housekeeping microenvironment. We developed a high throughput screening (HTS) cytotoxicity assay in 96-well plate format based around the SYTOX Green dye which is excluded from healthy viable cells and becomes substantially fluorescent only after entering cells and binding to nuclear DNA. In this format we can test a number of PTGS agents for cellular toxicity relative to control elements. We also developed an HTS 96-well plate assay that allows us to assess the impact of any given PTGS agent on stimulating a variety of common cellular stress signaling pathways (e.g. CRE, SRE, AP-1, NFkappaB, Myc, and NFAT) that could indicate possible deleterious effects of PTGS agents either dependent or independent of base pairing complementarity with target mRNAs. To this end we exploited the secreted alkaline phosphatase (SEAP) Pathway Profiling System where the expression of the secreted reporter protein is coupled to transcriptional activation of a variety of promoter elements involved in common cell signaling pathways. We found that a variety of lead hammerhead ribozyme (hhRz) and short hairpin (shRNA) expression constructs did not exert cytotoxicity in human cells when driven by highly active RNA Pol-III promoters. We also found that most of the cell signaling pathways tested (CRE, SRE, Myc, and NFAT) did not significantly couple through upregulation to expression of the set of PTGS agents tested. AP-1 and NFkappaB upregulation both appear to couple to the expression of some PTGS agents which likely reflect the known properties of these pathways to be stimulated by abundant small structured RNAs. PMID- 21256846 TI - Segmental sedimentation and counting technique (SSCT): an adaptable method for qualitative diagnosis of Echinococcus multilocularis in fox intestines. AB - A modified Segmental Sedimentation and Counting Technique (SSCT) to examine the presence of Echinococcus multilocularis helminths in segments of fox (Vulpes vulpes) intestine is described and compared to the "gold standard", SCT. Out of the 358 intestines collected, 117 were E. multilocularis positive. Using SSCT methods we compare the sensitivity of individual or pairs of segments to establish a tradeoff between saving time and the reliability of the diagnosis, especially in areas with low infection intensities. The results show that the analysis of segment S4 associated with segment S1 or S2 give 98.3% sensitivity, with specificity close to 100%. Based on our results and the time saved, we recommend using SSCT for routine examination of fox intestines for large epidemiological studies, particularly where the endemic prevalence of E. multilocularis is low or unknown. PMID- 21256848 TI - Up-regulation of calsyntenin-3 by beta-amyloid increases vulnerability of cortical neurons. AB - beta-Amyloid (Abeta) may play an important role in the pathogenesis of Alzheimer's disease. However, a causal relationship between Abeta oligomers and layer-specific neurodegeneration has not been clarified. Here we show up regulation of calsyntenin (Cst)-3 in cultured neurons treated with Abeta oligomers and in Tg2576 mice. Cst-3 is distributed in large neurons in layers 2-3 and 5 of the cerebral cortex, and accumulated in dystrophic neurites surrounding Abeta-plaques. Overexpression of Cst-3 accelerates neuronal death. These results indicate that up-regulation of Cst-3 in cortical neurons in layers 2-3 and 5 by Abeta oligomers may lead to increase in vulnerability of neurons. PMID- 21256847 TI - Characterization of inositol phospho-sphingolipid-phospholipase C 1 (Isc1) in Cryptococcus neoformans reveals unique biochemical features. AB - In this work, we biochemically characterized inositol phosphosphingolipid phospholipase C (Isc1) from the pathogenic fungus Cryptococcus neoformans. Unlike Isc1 from other fungi and parasites which hydrolyze both fungal complex sphingolipids (IPC-PLC) and mammalian sphingomyelin (SM-PLC), C. neoformans Isc1 only exerts IPC-PLC activity. Genetic mutations thought to regulate substrate recognition in other Isc1 proteins do not restore SM-PLC activity of the cryptococcal enzyme. C. neoformans Isc1 regulates the level of complex sphingolipids and certain species of phytoceramide, especially when fungal cells are exposed to acidic stress. Since growth in acidic environments is required for C. neoformans to cause disease, this study has important implications for understanding of C. neoformans pathogenicity. PMID- 21256849 TI - Curcumin induces a nuclear factor-erythroid 2-related factor 2-driven response against oxidative and nitrative stress after praziquantel treatment in liver fluke-infected hamsters. AB - Praziquantel has been used for the treatment of liver fluke infection, but an oxidative/nitrative stress may occur after a short-term treatment and participate in side effects. In an attempt to reduce the adverse effects, we administered curcumin, an anti-inflammatory agent, to Opisthorchis viverrini-infected hamsters treated with praziquantel. At 12h after treatment, curcumin decreased eosinophil infiltration and increased mononuclear cell infiltration in parallel with nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 expression at the transcriptional and protein levels. Curcumin also enhanced the expression of genes involved in the Nrf2-regulated stress pathway (Kelch-like ECH-associated protein 1, NAD(P)H:quinine oxidoreductase 1, glutamate cysteine ligase, and activating transcription factor 3, peroxiredoxin 3, peroxiredoxin 6, manganese superoxide dismutase, and catalase), leading to increased ferric antioxidant capacity in the plasma. In contrast, curcumin decreased the level of oxidative and nitrative stress markers such as urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine, plasma levels of malondialdehyde and nitrate/nitrite, and activity of plasma alanine transaminase, a liver injury marker. This correlated with the suppression of nuclear factor-kappaB (NF-kappaB) and related molecules (cyclooxygenase-2 and inducible nitric oxide synthase) and pro-inflammatory cytokines (IL-1beta and TNF alpha). In conclusion, curcumin may be an effective chemopreventive agent against oxidative and nitrative stress derived from praziquantel treatment during O. viverrini infection via induction of Nrf2 and suppression of NF-kappaB-mediated pathways. Nrf2 may also be a novel therapeutic target for not only parasitic diseases but other types of inflammation-mediated diseases. PMID- 21256850 TI - Molecular architecture of the human specialised atrioventricular conduction axis. AB - The atrioventricular conduction axis, located in the septal component of the atrioventricular junctions, is arguably the most complex structure in the heart. It fulfils a multitude of functions, including the introduction of a delay between atrial and ventricular systole and backup pacemaking. Like any other multifunctional tissue, complexity is a key feature of this specialised tissue in the heart, and this complexity is both anatomical and electrophysiological, with the two being inextricably linked. We used quantitative PCR, histology and immunohistochemistry to analyse the axis from six human subjects. mRNAs for ~50 ion and gap junction channels, Ca(2+)-handling proteins and markers were measured in the atrial muscle (AM), a transitional area (TA), inferior nodal extension (INE), compact node (CN), penetrating bundle (PB) and ventricular muscle (VM). When compared to the AM, we found a lower expression of Na(v)1.5, K(ir)2.1, Cx43 and ANP mRNAs in the CN for example, but a higher expression of HCN1, HCN4, Ca(v)1.3, Ca(v)3.1, K(ir)3.4, Cx40 and Tbx3 mRNAs. Expression of some related proteins was in agreement with the expression of the corresponding mRNAs. There is a complex and heterogeneous pattern of expression of ion and gap junction channels and Ca(2+)-handling proteins in the human atrioventricular conduction axis that explains the function of this crucial pathway. PMID- 21256852 TI - Further support for a hypothesis on the reported offspring sex ratios of hepatitis B carriers. PMID- 21256851 TI - Taking the heart failure battle inside the cell: small molecule targeting of Gbetagamma subunits. AB - Heart failure (HF) is devastating disease with poor prognosis. Elevated sympathetic nervous system activity and outflow, leading to pathologic attenuation and desensitization of beta-adrenergic receptors (beta-ARs) signaling and responsiveness, are salient characteristic of HF progression. These pathologic effects on beta-AR signaling and HF progression occur in part due to Gbetagamma-mediated signaling, including recruitment of receptor desensitizing kinases such as G-protein coupled receptor (GPCR) kinase 2 (GRK2) and phosphoinositide 3-kinase (PI3K), which subsequently phosphorylate agonist occupied GPCRs. Additionally, chronic GPCR signaling signals chronically dissociated Gbetagamma subunits to interact with multiple effector molecules that activate various signaling cascades involved in HF pathophysiology. Importantly, targeting Gbetagamma signaling with large peptide inhibitors has proven a promising therapeutic paradigm in the treatment of HF. We recently described an approach to identify small molecule Gbetagamma inhibitors that selectively block particular Gbetagamma functions by specifically targeting a Gbetagamma protein protein interaction "hot spot." Here we describe their effects on Gbetagamma downstream signaling pathways, including their role in HF pathophysiology. We suggest a promising therapeutic role for small molecule inhibition of pathologic Gbetagamma signaling in the treatment of HF. This article is part of a special issue entitled "Key Signaling Molecules in Hypertrophy and Heart Failure." PMID- 21256853 TI - Estimating gap lifetime and memory from a simple model of forest canopy dynamics. AB - Gap formation and closure represent important disturbance events in forests, but the processes involved are still poorly understood. We use models, which we and others previously developed, to make long-term predictions of tropical forest gap dynamics based on Barro Colorado Island data. We first fit the models to the data by comparing their discrete Fourier transforms, and we propose a definition for the lifetime of a gap and predict a large-gap lifetime typically to be less than 50 years. We find that the gap lifetime diverges logarithmically for large-gap sizes. We examine the 'memory' of spatial gap patterns via spatiotemporal correlations and find a correlation time of about 160 years, suggesting that present gap patterns could have long-lasting effects on forest spatial patterns. PMID- 21256854 TI - Perinatal lead exposure alters locomotion induced by amphetamine analogs in rats. AB - AIMS: The precise neurochemical perturbations through which perinatal (gestation/lactation) lead exposure modifies the reinforcement efficacy of various psychoactive drugs (e.g., cocaine, opiates) are unknown. The present study considers the role of altered serotonin and dopamine functionality in perinatal lead-psychostimulant interactions. MAIN METHODS: Female rats were administered a 16-mg lead or a control solution (p.o.) for 30days prior to breeding with non-exposed males. Lead exposure was discontinued at weaning (postnatal day [PND] 21). Starting at PND 120, male rats born to control or lead exposed dams were injected with either PAL-287 or PAL-353, at doses of 0, 2, 4, 8, or 16umol/kg (i.p.) with each dose given prior to an acute (45min) locomotion test. Whereas PAL-287 is a potent releaser of serotonin, PAL-353 is not. Each drug induces comparable release of norepinephrine (NE) and of dopamine (DA). KEY FINDINGS: Control and lead rats exhibited minimal locomotion to PAL-287. PAL-353 produced a dose-dependent activation of locomotion in control rats relative to the effects of PAL-287 in control rats. Lead-exposed rats exhibited a subsensitivity to PAL-353 at doses of 4 and 8umol/kg. SIGNIFICANCE: The subsensitivity of lead rats to PAL-353 is consistent with a lead-induced diminution of dopamine function, an effect noted earlier for the reuptake inhibitor cocaine (Nation et al. 2000). The similar response of lead and control rats to PAL-287 is inconsistent with diminished serotonin function. PMID- 21256855 TI - Cold perception and cutaneous microvascular response to local cooling at different cooling temperatures. AB - The aim of the present study was to investigate the effect of quantitatively measured cold perception (CP) thresholds on microcirculatory response to local cooling as measured by direct and indirect response of laser-Doppler (LD) flux during local cooling at different temperatures. The CP thresholds were measured in 18 healthy males using the Marstock method (thermode placed on the thenar). The direct (at the cooling site) and indirect (on contralateral hand) LD flux responses were recorded during immersion of the hand in a water bath at 20 degrees C, 15 degrees C, and 10 degrees C. The cold perception threshold correlated (linear regression analysis, Pearson correlation) with the indirect LD flux response at cooling temperatures 20 degrees C (r=0.782, p<0.01) and 15 degrees C (r=0.605, p<0.01). In contrast, there was no correlation between the CP threshold and the indirect LD flux response during cooling in water at 10 degrees C. The results demonstrate that during local cooling, depending on the cooling temperature used, cold perception threshold influences indirect LD flux response. PMID- 21256856 TI - Enhanced mental image mapping in autism. AB - The formation and manipulation of mental images represents a key ability for successfully solving visuospatial tasks like Wechsler's Block Design or visual reasoning problems, tasks where autistics perform at higher levels than predicted by their Wechsler IQ. Visual imagery can be used to compare two mental images, allowing judgment of their relative properties. To examine higher visual processes in autism, and their possible role in explaining autistic visuospatial peaks, we carried out two mental imagery experiments in 23 autistic and 14 age and IQ matched, non-autistic adolescents and adults. Among autistics, 11 had significantly higher Block Design scores than predicted by their IQ. Experiment 1 involved imagining a letter inside a circle, followed by a decision concerning which of two highlighted portions of the circle would contain the greater proportion of the letter. Experiment 2 involved four classic mental rotation tasks utilizing two- and three-dimensional geometric figures, hands and letters. Autistics were more accurate in the formation and comparison of mental images than non-autistics. Autistics with a Block Design peak outperformed other participants in both speed and accuracy of mental rotation. Also, Performance IQ and Block Design scores were better predictors of mental rotation accuracy in autistic compared to non-autistic participants. The ability to form, access and manipulate visual mental representations may be more developed in autistics. We propose two complementary mechanisms to explain these processing advantages: (1) a global advantage in perceptual processing, discussed in the framework of the enhanced perceptual functioning model, and (2) particular strengths in veridical mapping, the ability to efficiently detect isomorphisms among entities and then to use these mappings to process stimulus characteristics, thereby facilitating judgments about their differences. PMID- 21256857 TI - A novel platelet glycoprotein Ib-binding protein with human platelet aggregation inhibiting activity from Trimeresurus jerdonii venom. AB - Platelet glycoprotein Ib (GPIb) is a primary adhesion receptor and involved in platelet-related disorders. However, it is difficult to study GPIb-specific platelet stimulation using physiological ligands in vivo. GPIb-binding snake C type lectins (snaclecs) are useful tools for exploring GPIb in vitro because they act on platelets differently. In the present study, a novel GPIb-binding snaclec, named jerdonibitin, was purified, molecular cloned and characterized from Trimeresurus jerdonii venom. On SDS-polyacrylamide gel electrophoresis, it showed a single band with an apparent molecular weight of 25 kDa under non-reducing conditions and two distinct bands with apparent molecular weights of 15 kDa (alpha-subunit) and 13 kDa (beta-subunit) under reducing conditions. The cDNA sequences of each subunit of jerdonibitin were identified and both deduced amino acid sequences were confirmed by N-terminal protein sequencing and trypsin digested peptide mass fingerprinting of MALDI-TOF. Sequence alignment showed that jerdonibitin is a snaclec and has sequence similarity with TSV-GPIb-BP (a GPIb inhibitory snaclec). Jerdonibitin dose-dependently inhibited platelet aggregation induced by ristocetin or low-dose thrombin, but not by high-dose thrombin. The GPIbalpha was detected by affinity chromatography on jerdonibitin. In vivo, jerdonibitin also dose-dependently induced thrombocytopenia of mice and platelet counts remained at very low level after 18 h intravenous injection. In summary, a novel GPIb-inhibitory snaclec was molecular cloned and characterized, which might provide insights into investigation of how GPIb-inhibitory snaclecs work and development of new antiplatelet agents. PMID- 21256858 TI - The geometric horopter. AB - Two aspects of the geometric horopter, which here is based on the criterion of equality of angle, are clarified. The first is that in the fixation plane (containing the nodal points and the fixation point) the locus of points lying on the horopter is the larger arc of a circle, and not a full circle as has been previously accepted. The second is that elsewhere, the locus of these points is a straight line perpendicular to this plane and midway between the eyes. These rules hold for both symmetric and asymmetric convergence, and for fixation elevated or depressed from the horizontal. PMID- 21256859 TI - Acute effects of steroid hormones and neuropeptides on human social-emotional behavior: a review of single administration studies. AB - Steroids and peptides mediate a diverse array of animal social behaviors. Human research is restricted by technical-ethical limitations, and models of the neuroendocrine regulation of social-emotional behavior are therefore mainly limited to non-human species, often under the assumption that human social emotional behavior is emancipated from hormonal control. Development of acute hormone administration procedures in human research, together with the advent of novel non-invasive neuroimaging techniques, have opened up opportunities to systematically study the neuroendocrinology of human social-emotional behavior. Here, we review all placebo-controlled single hormone administration studies addressing human social-emotional behavior, involving the steroids testosterone and estradiol, and the peptides oxytocin and vasopressin. These studies demonstrate substantial hormonal control over human social-emotional behavior and give insights into the underlying neural mechanisms. Finally, we propose a theoretical model that synthesizes detailed knowledge of the neuroendocrinology of social-emotional behavior in animals with the recently gained data from humans described in our review. PMID- 21256860 TI - Innate immune response in the hemolymph of an ascidian, Halocynthia roretzi, showing soft tunic syndrome, using label-free quantitative proteomics. AB - Soft tunic syndrome of Halocynthia roretzi manifests as soft, weak, and rupturable tunics, causing mass mortality. Utilizing liquid chromatography-tandem mass spectrometry (LC-MS/MS), innate immune response was established by comparing hemolymph protein profiles of ascidians with healthy or softened tunics. Of 100 proteins in each individual ascidian, 59 proteins from healthy and 56 proteins from diseased ascidians were functionally classified. Proteins found only in diseased individuals included trypsin inhibitor and Hr-29, and with high exponentially modified protein abundance index (emPAI) values. From 41 proteins identified to be common to both healthy and diseased ascidians, 15 were associated with innate immune response. Ficolin 3, a component of the lectin complement system, was significantly decreased in diseased ascidians, but a cell surface protein, type II transmembrane serine protease-1 (TTSP), was considerably elevated. These results suggest that trypsin inhibitor, ficolin 3, and TTSP are probably involved in the innate immune response related to this tunic disease. Beside, Hr-29 could be suggested as a biomarker for soft tunic syndrome. PMID- 21256861 TI - Immunoglobulin light (IgL) chains in ectothermic vertebrates. AB - Four major ancesteral IgL isotypes have been identified kappa, lambda, sigma and sigma-cart. However, depending on the vertebrate class the genomic representation of these isotypes differs in regards to what is encoded in the germline and how these genes are organized. Also, the relative contribution of each isotype in immune responses varies. This review focuses on the IgL chains of ectothermic vertebrates, specifically the number of different isotypes, their phylogenetic relationship, genomic organizations and expression. PMID- 21256862 TI - Cardiovascular risk markers are increased in HIV-infected children with lipodystrophy syndrome. PMID- 21256863 TI - Animal models of traumatic brain injury: a critical evaluation. AB - Animal models are necessary to elucidate changes occurring after brain injury and to establish new therapeutic strategies towards a stage where drug efficacy in brain injured patients (against all classes of symptoms) can be predicted. In this review, six established animal models of head trauma, namely fluid percussion, rigid indentation, inertial acceleration, impact acceleration, weight drop and dynamic cortical deformation are evaluated. While no single animal model is entirely successful in reproducing the complete spectrum of pathological changes observed after injury, the validity of these animal models including face, construct, etiological and construct validity and how the models constitute theories about brain injury is addressed. The various types of injury including contact (direct impact) and non-contact (acceleration/deceleration) and their associated pathologies are described. The neuropathologic classifications of brain injury including primary and secondary, focal and diffuse are discussed. Animal models and their compatibility with microdialysis studies are summarised particularly regarding the role of excitatory and inhibitory amino acid neurotransmitters. This review concludes that the study of neurotransmitter interactions within and between brain regions can facilitate the development of novel compounds targeted to treat those cognitive deficits not limited to a single pharmacological class and may be useful in the investigation of new therapeutic strategies and pharmacological testing for improved treatment for traumatic head injury. PMID- 21256864 TI - A new ball launching system with controlled flight parameters for catching experiments. AB - Systematic investigations of sensorimotor control of interceptive actions in naturalistic conditions, such as catching or hitting a ball moving in three dimensional space, requires precise control of the projectile flight parameters and of the associated visual stimuli. Such control is challenging when air drag cannot be neglected because the mapping of launch parameters into flight parameters cannot be computed analytically. We designed, calibrated, and experimentally validated an actuated launching apparatus that can control the average spatial position and flight duration of a ball at a given distance from a fixed launch location. The apparatus was constructed by mounting a ball launching machine with adjustable delivery speed on an actuated structure capable of changing the spatial orientation of the launch axis while projecting balls through a hole in a screen hiding the apparatus. The calibration procedure relied on tracking the balls with a motion capture system and on approximating the mapping of launch parameters into flight parameters by means of polynomials functions. Polynomials were also used to estimate the variability of the flight parameters. The coefficients of these polynomials were obtained using the launch and flight parameters of 660 launches with 65 different initial conditions. The relative accuracy and precision of the apparatus were larger than 98% for flight times and larger than 96% for ball heights at a distance of 6m from the screen. Such novel apparatus, by reliably and automatically controlling desired ball flight characteristics without neglecting air drag, allows for a systematic investigation of naturalistic interceptive tasks. PMID- 21256865 TI - A sorting system with automated gates permits individual operant experiments with mice from a social home cage. AB - Behavioral experiments based on operant procedures can be time-consuming for small amounts of data. While individual testing and handling of animals can influence attention, emotion, and behavior, and interfere with experimental outcome, many operant protocols require individual testing. We developed an RFID technology- and transponder-based sorting system that allows removing the human factor for longer-term experiments. Identity detectors and automated gates route mice individually from their social home cage to an adjacent operant compartment with 24/7 operation. CD1-mice learnt quickly to individually pass through the sorting system. At no time did more than a single mouse enter the operant compartment. After 3 days of adjusting to the sorting system, groups of 4 mice completed about 50 experimental trials per day in the operant compartment without experimenter intervention. The automated sorting system eliminates handling, isolation, and disturbance of the animals, eliminates experimenter-induced variability, saves experimenter time, and is financially economical. It makes possible a new approach for high-throughput experimentation, and is a viable tool for increasing quality and efficiency of many behavioral and neurobiological investigations. It can connect a social home cage, through individual sorting automation, to diverse setups including classical operant chambers, mazes, or arenas with video-based behavior classification. Such highly automated systems will permit efficient high-throughput screening even for transgenic animals with only subtle neurological or psychiatric symptoms where elaborate or longer-term protocols are required for behavioral diagnosis. PMID- 21256866 TI - Long-term behavioral assessment of function in an experimental model for ischemic stroke. AB - Middle cerebral artery occlusion (MCAO) in rats is a well-studied experimental model for ischemic stroke leading to brain infarction and functional deficits. Many preclinical studies have focused on a small time window after the ischemic episode to evaluate functional outcome for screening therapeutic candidates. Short evaluation periods following injury have led to significant setbacks due to lack of information on the delayed effects of treatments, as well as short-lived and reversible neuroprotection, so called false-positive results. In this report, we evaluated long-term functional deficit for 90 days after MCAO in two rat strains with two durations of ischemic insult, in order to identify the best experimental paradigm to assess injury and subsequent recovery. Behavioral outcomes were measured pre-MCAO followed by weekly assessment post-stroke. Behavioral tests included the 18-point composite neurological score, 28-point neuroscore, rearing test, vibrissae-evoked forelimb placing test, foot fault test and the CatWalk. Brain lesions were assessed to correlate injury to behavior outcomes at the end of study. Our results indicate that infarction volume in Sprague-Dawley rats was dependent on occlusion duration. In contrast, the infarction volume in Wistar rats did not correlate with the duration of ischemic episode. Functional outcomes were not dependent on occlusion time in either strain; however, measurable deficits were detectable long-term in limb asymmetry, 18- and 28-point neuroscores, forelimb placing, paw swing speed, and gait coordination. In conclusion, these behavioral assays, in combination with an extended long-term assessment period, can be used for evaluating therapeutic candidates in preclinical models of ischemic stroke. PMID- 21256867 TI - Rapid identification viruses from nasal pharyngeal aspirates in acute viral respiratory infections by RT-PCR and electrospray ionization mass spectrometry. AB - Diagnosis of the etiologic agent of respiratory viral infection relies traditionally on culture or antigen detection. This pilot evaluation compared performance characteristics of the RT-PCR and electrospray ionization mass spectrometry (RT-PCR/ESI-MS) platform to conventional virologic methods for identifying multiple clinically relevant respiratory viruses in nasopharyngeal aspirates. The RT-PCR/ESI-MS respiratory virus surveillance kit was designed to detect respiratory syncytial virus, influenza A and B, parainfluenza types 1-4, adenoviridae types A-F, coronaviridae, human bocavirus, and human metapneumovirus. Patients (N=192) attending an emergency department during the 2007-2008 respiratory season consented, and "excess" frozen archived nasopharyngeal aspirates were analysed; 46 were positive by conventional virology and 69 by RT-PCR/ESI-MS, among which there were six samples with multiple viral pathogens detected. The sensitivity and specificity of the assay were 89.1% and 80.3%, respectively. Additional viruses that were not identified by conventional virology assays were detected (4 human bocaviruses and 7 coronaviruses). Samples in which the RT-PCR/ESI-MS results disagreed with conventional virology were sent for analysis by a third method using a commercial RT-PCR-based assay, which can identify viruses not detectable by conventional virologic procedures. Time to first result of RT-PCR/ESI-MS was 8h. RT-PCR/ESI-MS demonstrated capacity to detect respiratory viruses identifiable and unidentifiable by conventional methods rapidly. PMID- 21256868 TI - Real-time target-specific detection of loop-mediated isothermal amplification for white spot syndrome virus using fluorescence energy transfer-based probes. AB - Aiming to establish a target amplicon-specific detection system for loop-mediated isothermal amplification (LAMP), the fluorescent resonance energy transfer (FRET) probe technology was applied to develop the FRET LAMP platform. This report describes the development of the first FRET LAMP assay targeting white spot syndrome virus (WSSV) of penaeid shrimp. A successful accelerated WSSV LAMP was assembled first in a conventional oven and confirmed by gel electrophoresis and dot-blot hybridization. Subsequently, two additional FRET probes designed to target one loop region within WSSV LAMP amplicons were added to the same LAMP reaction. The reactions were carried out in a LightCycler (Roche) and significant FRET signals were detected in real time. Optimization of the reaction using plasmid DNA shortened the time for the detection of 10(2) copies of the target DNA to less than 70min. Cross reactivity was absent with WSSV-free or infectious hypodermal and hematopoietic necrosis virus-infected Penaeus vannamei samples. The performance of this system was comparable with that of a nested PCR assay from 21 WSSV-infected shrimp. Specifically detecting target amplicons and requiring no post-amplification manipulation, the novel FRET LAMP assay should allow indisputable detection of pathogens with minimized risks of amplicon contamination. PMID- 21256869 TI - Simultaneous and rapid detection of white spot syndrome virus and yellow head virus infection in shrimp with a dual immunochromatographic strip test. AB - A strip test for the dual detection of white spot syndrome virus (WSSV) and yellow head virus (YHV) was developed using monoclonal antibodies (MAbs) specific to the WSSV major envelope protein VP28 (W1 and W30) and the YHV nucleocapsid protein p20 (Y19 and Y21). The MAbs W30 and Y19 were conjugated with colloidal gold and sprayed onto a glass fiber pad that was placed adjacent to a sample chamber. The MAbs W1 and Y21 and the goat anti-mouse immunoglobulin G (GAM) antibody were sprayed onto a nitrocellulose membrane in strips at positions designated W, Y and C, respectively. These test strips were placed in plastic cases and stored desiccated in a plastic bag. The test strips were assessed for their ability to detect WSSV and YHV simultaneously using pleopods sampled from shrimp. A pleopod homogenate in application buffer 100MUl was applied to the sample chamber to flow through the nitrocellulose membrane strip, and antibody protein complexes could be observed within 15min. In sample from shrimp infected with WSSV and/or YHV, viral protein bound to the colloidal gold-conjugated MAbs. These complexes were captured by the MAbs at the W and/or Y test lines, resulting in the appearance of reddish-purple coloured bands. Any unbound colloidal gold conjugated MAbs migrated pass the W and Y lines would be captured by the GAM antibody, forming a band at position C. When samples not containing WSSV and YHV proteins or containing viral proteins at below the detection limit of the test, only the band at position C was observed. The sensitivity of the test was comparable to dot blot tests using single MAbs, and ~500-fold less sensitive than a 1-step PCR test for WSSV and 1000-fold less sensitive than an RT-PCR test for YHV. Despite this lower sensitivity, the dual strip test has advantages in speed and simplicity in not requiring sophisticated equipment or specialized skills. The ability to co-detect WSSV and YHV provides simultaneously cost savings. PMID- 21256870 TI - Highly sensitive capacitive biosensor for detecting white spot syndrome virus in shrimp pond water. AB - Water is one major pathways by which the white spot syndrome virus (WSSV) pathogen enters aquaculture facilities. This paper describes the production and use of a capacitive biosensor for the quantitative detection of as little as 1copy/MUl of WSSV in shrimp pond water. A glutathione-S-transferase tag for white spot binding protein (GST-WBP) was immobilized on a gold electrode through a self assembled monolayer. Binding between WSSV and the immobilized GST-WBP was directly detected by a capacitance measurement. Under optimum conditions, the capacitive biosensor detected WSSV over a wide linear range of between 1 and 1 * 10(5)copies/MUl. The system was highly selective for WSSV. One analysis cycle required only 20-25 min of analysis time and 25 min of regeneration time. The capacitive biosensor was applied to analyze WSSV concentration in eight shrimp pond water samples and the results were in good agreement with those obtained by a real time quantitative polymerase chain reaction (real-time PCR) method (P>0.05). The immobilized GST-WBP provided and could be reused for up to 39 analysis cycles for one electrode preparation with a relative standard deviation (RSD) of 2.4% and a good reproducibility of residual activity (95.8 +/- 2.3%). The appealing performance of this biosensor indicated that it had great potential for an accurate very sensitive, quantitative, detection method for WSSV. PMID- 21256871 TI - Comparative performance of three TSE rapid tests for surveillance in healthy sheep affected by scrapie. AB - Rapid tests specific for sheep and goats became part of European Union-wide active scrapie surveillance in 2006. Performance of three approved TSE rapid tests for the detection of sheep infected with scrapie in field cases in the pre clinical stage of the disease was compared. The medulla oblongata of 969 asymptomatic sheep of various genotype and breed aged over 18 months from 23 Italian flocks affected with scrapie, were tested by the Bio-Rad TeSeE Sheep/Goat (A), the IDEXX HerdChek BSE-Scrapie Antigen Test Kit, EIA (B) and the Prionics((r))-Check Western Small Ruminant (C) rapid tests. Of 136 positive samples of classical scrapie, as confirmed by Western blot assay, 132 were positive with test A (Se 97.06%, CI 95% 92.64-99.19); 135 with test B (Se 99.26%, 95% CI 95.97-99.98) and 128 with test C (Se 94.12%, 95% CI 88.74-97.43). Tests A and B showed the best performance on analytical sensitivity. All three systems demonstrated good reproducibility: being the intrarater and interrater kappa coefficients always over 0.83. The one available atypical scrapie sample was positive with tests A and B, negative with test C. Considering the discrepant results in the detection of low PrP(sc) concentrations and of the atypical case, differences can be expected in the efficacy of an active surveillance system, depending on the test adopted. PMID- 21256872 TI - GLP-1-derived nonapeptide GLP-1(28-36)amide targets to mitochondria and suppresses glucose production and oxidative stress in isolated mouse hepatocytes. AB - BACKGROUND: Uncontrolled hepatic glucose production (gluconeogenesis), and glycogenolysis, is a major contributor to the fasting hyperglycemia associated with type 2 diabetes. Here we report the discovery of a C-terminal nonapeptide (FIAWLVKGRamide) derived from GLP-1 that suppresses glucose production and oxidative stress in isolated mouse hepatocytes. The nonapeptide, GLP-1(28 36)amide, was reported earlier to be a major product derived from the cleavage of GLP-1 by the endopeptidase NEP 24.11. METHODS AND RESULTS: Hepatocytes were isolated from the livers of normal and diet-induced obese mice. We find that the GLP-1(28-36)amide nonapeptide rapidly enters isolated mouse hepatocytes by GLP-1 receptor-independent mechanisms, and targets to mitochondria where it inhibits gluconeogenesis and oxidative stress. CONCLUSIONS: These findings suggest that GLP-1 not only acts on a cell surface G-protein coupled receptor activating kinase-regulated signaling pathways, but a small C-terminal peptide derived from GLP-1 also enters cells, targets mitochondria, and exerts insulin-like actions by modulating oxidative phosphorylation. GLP-1(28-36)amide, or a peptide mimetic derived there from, might prove to be a useful treatment for fasting hyperglycemia and metabolic syndrome in type 2 diabetes. PMID- 21256873 TI - Excitatory regulation of angiotensin II on gastric motility and its mechanism in guinea pig. AB - In the present study, we investigated the effect of Ang II on gastric smooth muscle motility and its mechanism using intracellular recording and whole-cell patch clamp techniques. Ang II dose-dependently increased the tonic contraction and the frequency of spontaneous contraction in the gastric antral circular smooth muscles of guinea pig. ZD7155, an Ang II type 1 receptor (AT(1)R) blocker, completely blocked the effect of Ang II on the spontaneous contraction of gastric smooth muscle. In contrast, TTX, a sodium channel blocker, failed to block the effect. Furthermore, nicardipine, a voltage-gated Ca(2+)-channel antagonist, did not block the effect of Ang II on the tonic contraction of gastric smooth muscle, but external free-calcium almost completely blocked this effect. Both ryanodine, an inhibitor of calcium-induced Ca(2+) release (CICR) from ryanodine-sensitive calcium stores, and thapsigargin, which depletes calcium in calcium stores, almost completely blocked the effect of Ang II on tonic contraction. However, 2 APB, an inositol trisphosphate (IP(3)) receptor blocker, significantly, but not completely, blocked the Ang II effect on tonic contraction. We also determined that Ang II depolarized membrane potential and increased slow wave frequency in a dose-dependent manner. It also inhibited delayed rectifying potassium currents in a dose-dependent manner, but did not affect L-type calcium currents or calcium activated potassium currents. These results suggest that Ang II plays an excitatory regulation in gastric motility via AT(1)R-IP(3) and the CICR signaling pathway. The Ang II-induced inhibition of delayed rectifying potassium currents that depolarize membrane potential is also involved in the potentiation of tonic contraction and the frequency of spontaneous contraction in the gastric smooth muscle of guinea pig. PMID- 21256874 TI - WITHDRAWN: Involvement of Adenosine Signaling in Controlling the Release of Ghrelin from the Mouse Stomach. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 21256875 TI - Implication of Substance P in myocardial contractile function during ischemia in rats. AB - Evidence suggests that substance P (SP) participates in the pathology of acute myocardial ischemia and infarction but the profiles of the peptide in regulation of cardiac functions are still elusive. The aim of this study was to investigate the role of substance P in regulation of cardiac functions and its association with adrenergic mechanism in acute myocardial ischemia and infarction with rodent models. The experiments were carried out in Sprague-Dawley rats. SP and norepinephrine were significantly up-regulated in myocardium at 15min, 30min and 60min of coronary artery occlusion. Pretreatment of the rats with a specific antagonist of neurokinin-1 receptor, D-SP, significant increased+dp/dt and decreased -dp/dt, compared with the controls, pretreated with 0.9% saline. Pretreatment of the isolated CAO hearts with substance P (10(-7)mol/L) significantly increased left ventricular end diastolic pressure. SP producing no effects on cardiac functions when given alone to isolated (non-CAO) heart caused significant attenuation of the changes in the contractility and diastolic functions induced by norepinephrine, when given with norepinephrine. SP attenuated the increase in the activity of PKA provoked by norepinephrine in cultured myocytes. In conclusion, the findings may indicate SP regulates cardiac functions via modulation of adrenergic activity, through suppression of over activation of PKA. PMID- 21256876 TI - Immunogenicity, reactogenicity and safety of the human rotavirus vaccine RIX4414 (RotarixTM) oral suspension (liquid formulation) when co-administered with expanded program on immunization (EPI) vaccines in Vietnam and the Philippines in 2006-2007. AB - Evaluation of immunogenicity and safety of a 2-dose liquid formulation of human rotavirus vaccine, RIX4414 following WHO's Expanded Program on Immunization (EPI) schedule (0, 1, and 2 months; Month 0 indicates day of enrollment) in Vietnam and the Philippines. Infants aged 6-10 (mean=8.7 +/- 1.07 weeks Vietnam) and 5-10 weeks (mean=6.6 +/- 1.03 weeks Philippines) received two doses of RIX4414 vaccine (V) and one dose of placebo (PL) or three placebo doses concomitantly with commercially available diphtheria-tetanus-whole-cell pertussis, hepatitis B and oral poliovirus vaccines. The vaccination schedules were: V-V-PL, V-PL-V and PL PL-PL (Vietnam); PL-V-V, V-PL-V and PL-PL-PL (Philippines). Anti-rotavirus seroconversion rate was assessed pre-vaccination and post-vaccination (ELISA cut off=20 U/ml). 375 infants were enrolled in each country. Seroconversion rates at one month post-Dose 2 of RIX4414 were Vietnam 63.3% (95% CI: 54.3-71.6) in V-V-PL group and 81.5% (95% CI: 73.4-88) in V-PL-V group; Philippines 70% (95% CI: 61 78) in PL-V-V group and 59.2% (95% CI: 49.8-68) in V-PL-V group. Frequencies of solicited (8-day post-each dose) and unsolicited symptoms (31-day post-each dose) were similar. Two-doses of rotavirus vaccine administered within the WHO EPI offer flexibility in existing schedule, though both schedules provides good immune responses. PMID- 21256877 TI - Evaluation of humoral response and protective efficacy of two inactivated vaccines against bluetongue virus after vaccination of goats. AB - Bluetongue serotype 8 has become a major animal health issue in the European Union and the European member States have agreed on a vaccination strategy, which involves only inactivated vaccines. In this study, the efficacy of two inactivated vaccines against bluetongue virus serotype 8 (BTV-8) used in Europe since 2008, BTVPUR ALSAP((r)) 8 (MERIAL) and BOVILIS((r)) BTV8 (Intervet/SP-AH), was evaluated in goats immunized and challenged with BTV-8 field isolates under experimental conditions. Serological, virological and clinical examinations were conducted before and after challenge. Three groups of 10 goats each (groups A, B and C) were randomly constituted and 2 groups (A and C) were subcutaneously vaccinated twice with one dose of the two commercial vaccines BTVPUR ALSAP 8 (group A) or BOVILIS BTV8 (group C) respectively. Animals of the groups A, C and B (B: controls) were challenged with a virulent inoculum containing BTV-8. During the experiment, it was found out that the BTV-8 challenge inoculum was contaminated with another BTV serotype. However, results demonstrated that vaccination of goats with two injections of BTVPUR ALSAP 8 or BOVILIS BTV8 provided a significant clinical protection against a BTV-8 challenge and completely prevented BTV-8 viraemia in all vaccinated animals. Qualitative data showed no difference in the kinetics and levels of the humoral response induced by these two inactivated vaccines. PMID- 21256878 TI - Novel cost-efficient real-time PCR assays for detection and quantitation of Listeria monocytogenes. AB - Listeriosis is a serious food-borne infection with mortality rates approaching 30%. Therefore, the rapid, cost-effective, and automated detection of Listeria monocytogenes throughout the food chain continues to be a major concern. Here we describe three novel quantitative real-time PCR assays for L. monocytogenes based on amplification of a target hlyA gene with SYBR Green I chemistry and hydrolysis probe (TaqMan MGB probe). In order to offer sensitive, rapid and robust tool of additional economical value the real-time PCR assays were designed and optimized to only 5 MUl-reactions. All assays were evaluated by using different non reference Listeria strains isolated from various food matrices. Results demonstrated specificity to L. monocytogenes with accurate quantification over a dynamic range of 5-6 log units with R2 higher than 0.98 and amplification efficiencies reaching above 92%. The detection and quantification limits were as low as 165 genome equivalents. Comparison of novel assays to commercially available TaqMan(r) Listeria monocytogenes Detection Kit and previously published studies revealed similar specificity, sensitivity and efficiency, but greater robustness and especially cost-efficiency in the view of smaller reaction volumes and continuous increase in sample throughput. PMID- 21256879 TI - Inter-laboratory evaluation of the ISO standard 11063 "Soil quality - Method to directly extract DNA from soil samples". AB - Extracting DNA directly from micro-organisms living in soil is a crucial step for the molecular analysis of soil microbial communities. However, the use of a plethora of different soil DNA extraction protocols, each with its own bias, makes accurate data comparison difficult. To overcome this problem, a method for soil DNA extraction was proposed to the International Organization for Standardization (ISO) in 2006. This method was evaluated by 13 independent European laboratories actively participating in national and international ring tests. The reproducibility of the standardized method for molecular analyses was evaluated by comparing the amount of DNA extracted, as well as the abundance and genetic structure of the total bacterial community in the DNA extracted from 12 different soils by the 13 laboratories. High quality DNA was successfully extracted from all 12 soils, despite different physical and chemical characteristics and a range of origins from arable soils, through forests to industrial sites. Quantification of the 16S rRNA gene abundances by real time PCR and analysis of the total bacterial community structure by automated ribosomal intergenic spacer analysis (A-RISA) showed acceptable to good levels of reproducibility. Based on the results of both ring-tests, the method was unanimously approved by the ISO as an international standard method and the normative protocol will now be disseminated within the scientific community. Standardization of a soil DNA extraction method will improve data comparison, facilitating our understanding of soil microbial diversity and soil quality monitoring. PMID- 21256880 TI - Evaluation of a rapid and inexpensive liquid culture system for the detection of Mycobacterium avium subsp. paratuberculosis in bovine faeces. AB - Mycobacterium avium subsp. paratuberculosis (MAP) is the etiologic agent of paratuberculosis, a chronic granulomatous enteric disease of ruminants. MAP detection by faecal culture provides the definitive diagnosis of the infection. Automated liquid systems for MAP culture are more sensitive and rapid than culture on solid media, but they are expensive and require specialised equipment. In this study, a non-automated culture method using a modified Middlebrook 7H9 liquid medium (7H9+) was compared with Herrold's solid medium (HEYM) and direct real-time PCR on dairy cattle faeces. MAP growth in 7H9+ was monitored weekly by real-time PCR until the 12th week post-inoculation. The analytical sensitivity of the three methods was evaluated using faecal samples from a healthy cow spiked with ten-fold dilutions of MAP organisms (10(4)-10(-1)) and naturally MAP infected faeces serially diluted 1 to 10 in negative faecal samples. The limits of detection of the solid culture and direct real-time PCR were 10(2) and 10(3)MAP/g, respectively. In comparison, the 7H9+ culture revealed as few as 1MAP/g. A marked reduction in time to detection of the pathogen, compared with HEYM culture, was obtained. In addition, the three methods were applied to environmental faecal samples collected from a high- and a low-prevalence herd. The culture in 7H9+ showed to be the most sensitive test in the low-prevalence herd and provided faster results than HEYM. In the high-prevalence herd the three methods showed the same sensitivity and the real-time PCR had the shortest turnaround time. In conclusion, the use of 7H9+ for MAP-detection from cattle faeces maximizes diagnostic sensitivity and reduces turnaround time and, therefore, could replace culture in solid medium. Hence, we propose a two-step protocol for the assessment of MAP faecal excretion based on: 1) direct real-time PCR on all samples; and 2) inoculation of negative samples into 7H9+ and analysis after 3 and, if necessary, 6weeks by real-time PCR. PMID- 21256881 TI - Immunological detection of UV induced cyclobutane pyrimidine dimers and (6-4) photoproducts in DNA from reference bacteria and natural aquatic populations. AB - UV light-caused DNA damage is a widespread field of study. As UV light has the biological effect of inactivating or killing bacteria, it is used for water disinfection. Due to this application, it is important to study the DNA damage efficiencies and regeneration capacities in bacteria after UV irradiation. Two monoclonal antibodies, anti-CPD and anti-(6-4) PP, were applied for an immunoassay of UV-induced DNA modifications. Cyclobutane pyrimidine dimer (CPD) and 6-4 photoproduct (6-4 PP) were detected in the reference bacteria Pseudomonas aeruginosa and Enterococcus faecium, and in natural water communities. The antibody-mediated detection signals increased with the UV doses from 100 400J/m(2). Here, the CPD-specific signals were stronger than the (6-4) PP specific signals. These immunological results were in accordance with parallel cultivation experiments. All UV-irradiated bacteria showed a reduction of their growth rate depending on UV application by several orders of magnitudes. The immunoassay was also applied to three types of natural aquatic habitats with different cell densities. Besides artificial UV irradiation, it was possible to visualize natural sunlight effects on these natural bacterial communities. Light dependent and dark repair processes were distinguished using the established immunological assays. The antibody-mediated analyses presented are fast methods to detect UV-induced DNA lesions and repair capacities in selected bacterial species as well as in entire natural mixed populations. PMID- 21256882 TI - Screening of reducing agents for anaerobic growth of Candida albicans SC5314. AB - This study aimed to evaluate the influence of different redox potentials (Eh) on cell growth, whole-cell protein profile and cell surface hydrophobicity (CSH) of Candida albicans SC5314. The yeast was grown in YNB broth enriched with reducing (158mM sodium sulfite, 4mM sodium sulfite, 2.5mM sodium metabisulfite, 1.3mM 2 mercaptoethanol, 5.5mM thioglycolic acid, and 3.2mM l-cysteine hydrochloride) and oxidizing agents (15mM ammonium persulfate and 80mM potassium ferricyanide) and incubated in normoxic and anoxic atmospheres at 37 degrees C, for 48h. Pre- and post-incubation Eh values were determined and cytoplasm proteins were extracted. Proteins were parted by SDS-PAGE and their profiles were compared. 3.2mM l cysteine and 1.3mM 2-mercaptoethanol promoted and maintained negative Eh values during incubation. No differences were detected among SDS-PAGE profiles. CSH differences only were observed with 4mM sodium sulfite and 3.2mM l-cysteine. Results showed that 3.2mM l-cysteine is a reducing agent that allows maintenance of negative Eh in both anoxic and normoxic conditions and it seems not to interfere in the global expression of plasmatic proteins. PMID- 21256883 TI - Efficient insertional mutagenesis system for the dimorphic pathogenic fungus Sporothrix schenckii using Agrobacterium tumefaciens. AB - Sporothrix schenckii is a dimorphic pathogenic fungus that causes human and animal sporotrichosis globally. Here we developed and optimized an Agrobacterium tumefaciens-mediated transformation (ATMT) system of S. schenckii for insertional mutagenesis. The transformation efficiency reached more than 600 transformants per 10(6) conidia. Using this protocol enabled us to obtain a large number of T DNA insertional mutants within a short experimental period. Several mutants with altered phenotypes were obtained during the transformation experiments. The mutants displayed mitotic stability. Transferred DNA (T-DNA) flanking sequences were cloned by thermal asymmetric interlaced PCR (TAIL-PCR). Our results demonstrated that the ATMT system can be an effective tool for insertional mutagenesis in S. schenckii. This is the first report of a suitable mutagenesis system which may provide valuable mutants and information for both forward and reverse genetics research in the future for this medically important fungus. PMID- 21256884 TI - Evaluation of CHROMagarTM StrepB agar, an aerobic chromogenic medium for prepartum vaginal/rectal Group B Streptococcus screening. AB - An aerobic chromogenic medium, CHROMagarTM StrepB agar, designed for isolation of group B Streptococci, was evaluated on 285 prepartum vaginal/rectal swabs from pregnant women. After overnight enrichment in Todd-Hewitt broth containing 15MUg/ml nalidixic acid and 10MUg/ml colistin, sensitivities were respectively 79% on day 1 and 92% on day 2, and significantly higher than those achieved by blood agar (40% and 58%) and colimycin-nalidixic-acid agar (82% on day 2). PMID- 21256885 TI - A reliable method for storage of tailed phages. AB - A universal and effective method for long-term storage of bacteriophages has not yet been described. We show that randomly selected tailed phages could be stored inside the infected cells at -80 degrees C without a major loss of phage and host viability. Our results suggest the suitability of this method as a standard for phage preservation. PMID- 21256886 TI - High reliability transformation of the basal fungus Mucor circinelloides by electroporation. AB - Molecular approaches to study the biology of the zygomycete Mucor circinelloides depend mainly on the existence of a polyethylene glycol-based transformation method, which is one of the most efficient in zygomycete fungi. However, the poor reliability and low transformation rates of this method are major obstacles in the molecular study of a number of biological processes. This paper describes an easy and reliable method to transform M. circinelloides protoplasts by electroporation. A high-voltage pulse of 25MUF capacitance, 400Omega resistance, and 4kV/cm field strength were seen to be the optimal electrical conditions for delivering DNA into M. circinelloides protoplasts. Under these electrical conditions, successful transformations were carried out with several self replicative plasmid and strain combinations, producing up to more than 500 transformants per MUg DNA. Targeted DNA integration of a transgene (atfA gene of Acinetobacter baylyi) in a particular locus (carRP) was also achieved. This transformation method will considerably facilitate in-depth molecular genetic studies of the biology of this fungus. PMID- 21256887 TI - Improved protocol for the simultaneous extraction and column-based separation of DNA and RNA from different soils. AB - We developed an improved protocol, allowing the simultaneous extraction of DNA and RNA from soil using phenol-chloroform with subsequent column-based separation of DNA and RNA (PCS). We compared this new approach with the well established protocol published by Griffiths et al. (2000), where DNA and RNA are separated by selective enzymatic digestions and two commercial kits used for DNA or RNA extraction, respectively, using four different agricultural soils. We compared yield and purity of the nucleic acids as well as abundance and diversity profiles of the soil bacterial communities targeting the nosZ gene via quantitative real time PCR and terminal restriction fragment length polymorphism on DNA and RNA level. The newly developed protocol provided purer nucleic acid extracts compared to the used kit-based protocols. All protocols were suitable for DNA- and RNA based gene quantification, however high variations between replicates were obtained for RNA samples using the original Griffiths protocol. Diversity patterns of nosZ were highly influenced by the extraction protocol used both on the DNA and RNA level. Finally, our data showed that the new protocol allows a simultaneous and reproducible extraction and separation of DNA and RNA, which were suitable for reliable analyses of gene and transcript copy numbers and diversity pattern. PMID- 21256888 TI - Cinnamic acid, coumarin and vanillin: Alternative phenolic compounds for efficient Agrobacterium-mediated transformation of the unicellular green alga, Nannochloropsis sp. AB - The use of acetosyringone in Agrobacterium-mediated gene transfer into plant hosts has been favored for the past few decades. The influence of other phenolic compounds and their effectiveness in Agrobacterium-mediated plant transformation systems has been neglected. In this study, the efficacy of four phenolic compounds on Agrobacterium-mediated transformation of the unicellular green alga Nannochloropsis sp. (Strain UMT-M3) was assessed by using beta-glucuronidase (GUS) assay. We found that cinnamic acid, vanillin and coumarin produced higher percentages of GUS positive cells as compared to acetosyringone. These results also show that the presence of methoxy group in the phenolic compounds may not be necessary for Agrobacterium vir gene induction and receptor binding as suggested by previous studies. These findings provide possible alternative Agrobacterium vir gene inducers that are more potent as compared to the commonly used acetosyringone in achieving high efficiency of Agrobacterium-mediated transformation in microalgae and possibly for other plants. PMID- 21256889 TI - Validation of a seminested PCR approach for rapid detection of Salmonella enterica subsp. enterica serovar Gallinarum. AB - Salmonella enterica subsp. enterica serovar Gallinarum (S. Gallinarum) is the causative agent of fowl typhoid, one of the major causes of mortality and morbidity on poultry farms. Even though it has been substantially eradicated in many developed countries, the disease still remains endemic in Central and South America, in Africa and in the Mediterranean countries of Europe. This leads to the routine screening of flocks, mainly by cultivation and serological techniques, which are expensive, as well as time and labour-consuming. Here we describe a simple and specific PCR-based method for detecting S. Gallinarum. It relies on two seminested PCRs which use four pairs of primers designed on the basis of two genomic regions which appear to be exclusive to the pathogen. Furthermore, an internal positive control was devised in order to avoid any false negative results. We performed sensitivity and specificity tests, and our findings showed the cogency of the system and its potential effectiveness even for routine uses. PMID- 21256890 TI - Improving qPCR efficiency in environmental samples by selective removal of humic acids with DAX-8. AB - Quantitative PCR is becoming the method of choice for the detection of pathogenic microorganisms and other targets in the environment. A major obstacle when amplifying DNA is the presence of inhibiting substances like humic acids that decrease the efficiency of PCR. We combined the polymeric adsorbent SupeliteTM DAX-8 with a large-volume (10 mL) nucleic acid extraction method to decrease the humic acid content prior to qPCR quantification in water samples. The method was tested by spiking with humic acid standards and the bacterial surrogate Acinetobacter baylyi ADP1. Improvements in qPCR detection of ADP1 after application of DAX-8 resin (5 and 10 w/v%) were compared with the effects of added bovine serum albumin (BSA) (50, 100 and 200 ng/MUL). Both additions improved detection of ADP1 by counteracting inhibitory effects. There were no changes in mean cycle threshold difference (DeltaC(T)) after application of DAX-8 compared to the control despite some loss of DNA, whereas significant increases occurred for BSA, irrespective of BSA concentration applied. The use of DAX-8 leads to an increase in qPCR amplification efficiency in contrast to BSA. The commonly used method to calculate genomic sample concentrations by comparing measured CT values relative to standard curves is only valid if amplification efficiencies of both are sufficiently similar. DAX-8 can provide this efficiency by removing humic acids permanently from nucleic acid extracts and has the potential to significantly increase the reliability of reported non-detects and measured results obtained by qPCR in environmental monitoring. PMID- 21256891 TI - Gene expression analysis of monospecies Salmonella typhimurium biofilms using differential fluorescence induction. AB - Bacterial biofilm formation is an important cause of environmental persistence of food-borne pathogens, such as Salmonella Typhimurium. As the ensemble of bacterial cells within a biofilm represents different physiological states, even for monospecies biofilms, gene expression patterns in these multicellular assemblages show a high degree of heterogeneity. This heterogeneity might mask differential gene expression that occurs only in subpopulations of the entire biofilm population when using methods that average expression output. In an attempt to address this problem and to refine expression analysis in biofilm studies, we used the Differential Fluorescence Induction (DFI) technique to gain more insight in S. Typhimurium biofilm gene expression. Using this single cell approach, we were able to identify 26 genetic loci showing biofilm specific increased expression. For a selected number of identified genes, we confirmed the DFI results by the construction of defined promoter fusions, measurement of relative gene expression levels and construction of mutants. Overall, we have shown for the first time that the DFI technique can be used in biofilm research. The fact that this analysis revealed genes that have not been linked with Salmonella biofilm formation in previous studies using different approaches illustrates that no single technique, in casu biofilm formation, is able to identify all genes related to a given phenotype. PMID- 21256892 TI - SMM-system: A mining tool to identify specific markers in Salmonella enterica. AB - This report presents SMM-system, a software package that implements various personalized pre- and post-BLASTN tasks for mining specific markers of microbial pathogens. The main functionalities of SMM-system are summarized as follows: (i) converting multi-FASTA file, (ii) cutting interesting genomic sequence, (iii) automatic high-throughput BLASTN searches, and (iv) screening target sequences. The utility of SMM-system was demonstrated by using it to identify 214 Salmonella enterica-specific protein-coding sequences (CDSs). Eighteen primer pairs were designed based on eighteen S. enterica-specific CDSs, respectively. Seven of these primer pairs were validated with PCR assay, which showed 100% inclusivity for the 101 S. enterica genomes and 100% exclusivity of 30 non-S. enterica genomes. Three specific primer pairs were chosen to develop a multiplex PCR assay, which generated specific amplicons with a size of 180bp (SC1286), 238bp (SC1598) and 405bp (SC4361), respectively. This study demonstrates that SMM system is a high-throughput specific marker generation tool that can be used to identify genus-, species-, serogroup- and even serovar-specific DNA sequences of microbial pathogens, which has a potential to be applied in food industries, diagnostics and taxonomic studies. SMM-system is freely available and can be downloaded from http://foodsafety.sjtu.edu.cn/SMM-system.html. PMID- 21256893 TI - Fourier transform infrared spectroscopy as a tool to characterize molecular composition and stress response in foodborne pathogenic bacteria. AB - Vibrational spectroscopy techniques have shown capacity to provide non destructive, rapid, relevant information on microbial systematics, useful for classification and identification. Infrared spectroscopy enables the biochemical signatures from microbiological structures to be extracted and analyzed, in conjunction with advanced chemometrics. In addition, a number of recent studies have shown that Fourier Transform Infrared (FT-IR) spectroscopy can help understand the molecular basis of events such as the adaptive tolerance responses expressed by bacteria when exposed to stress conditions in the environment (e.g. those that cells confront in food and during food processing). The current review gives an overview of the published experimental techniques, data-processing algorithms and approaches used in FT-IR spectroscopy to assess the mechanisms of bacterial inactivation by food processing technologies and antimicrobial compounds, to monitor the spore and membrane properties of foodborne pathogens in changing environments, to detect stress-injured microorganisms in food-related environments, to assess dynamic changes in bacterial populations, and to study bacterial tolerance responses. PMID- 21256894 TI - Origin of microbial life: Nano- and molecular events, thermodynamics/entropy, quantum mechanisms and genetic instructions. AB - Currently, there are no agreed upon mechanisms and supporting evidence for the origin of the first microbial cells on the Earth. However, some hypotheses have been proposed with minimal supporting evidence and experimentation/observations. The approach taken in this article is that life originated at the nano- and molecular levels of biological organization, using quantum mechanic principles that became manifested as classical microbial cell(s), allowing the origin of microbial life on the Earth with a core or minimal, organic, genetic code containing the correct instructions for cell(s) for growth and division, in a micron dimension environment, with a local entropy range conducive to life (present about 4 billion years ago), and obeying the laws of thermodynamics. An integrated approach that explores all encompassing factors necessary for the origin of life, may bring forth plausible hypotheses (and mechanisms) with much needed supporting experimentation and observations for an origin of life theory. PMID- 21256895 TI - Development of a combined immunomagnetic separation and quantitative reverse transcription-PCR assay for sensitive detection of infectious rotavirus in water samples. AB - A quantitative and rapid detection method for rotavirus in water samples was developed using immunomagnetic separation combined with quantitative reverse transcription-polymerase chain reaction (IMS-RT-qPCR). Magnetic beads coated with antibodies against representative group A rotavirus were used to capture and purify intact rotavirus particles in both artificial and real environmental water sample matrix. Compared to extracting RNA using commercial kits and RT-qPCR assay, the developed IMS-RT-qPCR method increased the detection sensitivity by about one order of magnitude when applied in clean water, with a detection limit of 3.16 50% tissue culture infectious dose (TCID(50))/mL within 5h. This method was compatible with various commonly used virus eluants, including beef extract (BE), beef extract with 0.05M glycine (BEG) and urea arginine phosphate buffer (UAPB). The recovery efficiencies from various eluants using IMS-RT-qPCR are higher than that using direct RT-qPCR method, demonstrating the effectiveness of the IMS step for eliminating inhibitors in the eluant matrix. This method was also successfully applied to purify and detect rotavirus particles seeded in 10(3)-fold concentrated wastewater influent samples. It seemed to reduce the interference from complex sample background and increase the qPCR product reliability comparing to RT-qPCR method without the IMS step. The results indicated that IMS-RT-qPCR is a rapid, sensitive and reliable tool for detecting rotaviruses in complex water environments. PMID- 21256896 TI - Sensitive counting of viable Enterobacteriaceae in seawaters and relationship with fecal indicators. AB - A fluorescent in situ hybridization based assay was used to enumerate viable Enterobacteriaceae members in seawaters by solid phase cytometry. The method was specific, highly sensitive (1cell/100ml) and allowed the quantification of VNC Enterobacteriaceae cells during an osmotic stress. Investigations on contaminated coastal seawater revealed a strong correlation between Enterobacteriaceae counts and standard fecal indicators. PMID- 21256897 TI - Are salivary gonadal steroid concentrations influenced by acute psychosocial stress? A study using the Trier Social Stress Test (TSST). AB - It is well documented that acute stress activates the sympathetic nervous system (SNS) and the Hypothalamus-Pituitary-Adrenal (HPA) axis. Results regarding the hypothalamus pituitary gonadal (HPG) axis, in contrast, are less consistent. Stress-associated increases as well as decreases have been reported for testosterone and estradiol. In the present study, healthy young male (n=39) and female participants (n=44, all tested in the luteal phase) were randomly assigned to a well-evaluated psychosocial stress protocol ("Trier Social Stress Test", TSST) or to a non-stressful control condition ("Placebo-TSST"). Salivary concentrations of cortisol, alpha-amylase, testosterone, progesterone, and estradiol were measured immediately before and twice (10 and 25 min) after the treatment. As was to be expected, cortisol- and sAA-concentrations increased in response to the stressor. Stressed men showed a more pronounced increase of cortisol than stressed women. In contrast, acute stress did not affect testosterone-, progesterone-, and estradiol-concentrations. The results of the present study suggest that an acute psychosocial laboratory stress or has no strong rapid effects on salivary gonadal steroids. In line with several previous studies the findings might suggest that stress-induced changes in gonadal steroids occur in response to physical stressors, to competitive stressors or to more severe stressors only. PMID- 21256898 TI - Discrimination between mothers' infant- and adult-directed speech using hidden Markov models. AB - Infant-directed speech (IDS) has the important functions of capturing the infants' attention and maintaining communication between the mother and the infant. It is known that three acoustic components (F0, F0 range, and tempo) in IDS and adult-directed speech (ADS) are different. However, it is not easy to discriminate between IDS and ADS using procedural approaches due to the wide range of individual differences. In this paper, we propose a novel approach to discriminate between IDS and ADS that uses mel-frequency cepstral coefficient and a hidden Markov model-based speech discrimination algorithm; this approach is not based on the prosodic features of F0, F0 range, and tempo. The average discrimination accuracy of the proposed algorithm is 84.34%. The objective accuracy of the discrimination models have been confirmed using the head-turn preference procedure, which measures infants' listening duration to auditory stimuli of IDS and ADS. These results suggest that the proposed algorithm may enable a robust and reliable classification of mothers' speech and infant attention to the mothers' speech may depend on IDS clarity. PMID- 21256899 TI - Mechanism of alkalosis-induced constriction of rat cerebral penetrating arterioles. AB - Cerebral arterioles are in close contact with the supplied tissue and are strong regulators of cerebrovascular tone. Transient ischemia can cause brain intracellular alkalosis producing vasoconstriction. However, the mechanisms of alkalosis-induced cerebral arteriolar constriction are poorly understood. Here, we determined the vascular responses to alkalosis under different conditions by monitoring the internal diameter of pressurized penetrating arterioles isolated from the rat cerebrum with an operating microscope. The roles of Na+/H+ exchanger (NHE), Na+/Ca2+ exchanger (NCX), Na+/K+-adenosine triphosphatase (NKA), and potassium (K+) channels during alkalosis were examined using specific inhibitors. Our results indicated that the extent of constriction of the penetrating arterioles was dependent on alkaline pH. Moreover, the alkalosis-induced vasoconstriction was significantly attenuated by inhibitors of NHE, NCX, and NKA, but not K+ channel inhibitors. Therefore, we concluded that NHE, NKA, and NCX are important regulators involved in alkalosis-induced vasoconstriction of rat cerebral penetrating arterioles. PMID- 21256900 TI - The effects of long-term sleep deprivation on the long-term potentiation in the dentate gyrus and brain oxidation status in rats. AB - Some evidence suggests that sleep deprivation might impair synaptic plasticity and produce oxidative stress in the hippocampus. However it is not clear whether impairment of long-term potentiation depends on the oxidative stress evoked by sleep deprivation protocol. In this study we aimed to investigate the effects of a 21-day sleep deprivation period on long-term plasticity taking into account the stressful effect of sleep deprivation. Sleep deprivation was carried out using the multiple platforms method on adult male Wistar rats. Long-term potentiation was studied in the medial perforant pathway-dentate gyrus synapses. Elevated T test was applied, and blood corticosterone levels were measured. Lipid peroxidation products in whole brain and hippocampus were determined. No significant difference was found between the sleep deprived, pedestal and cage control groups at the end of the 21-day period when corticosterone levels were compared. The results of the elevated T test indicated that sleep deprivation did not change the anxiety-like behavior of the animals. When compared with cage or pedestal control groups, sleep deprived rats displayed elevated malondialdehyde levels, and decreased superoxide dismutase and glutathione peroxidase activities together with impaired long-term potentiation maintenance. It can be argued that 21-day SD may impair the maintenance of long-term potentiation evoked in the dentate gyrus, and the balance between oxidant and antioxidant defenses of the hippocampus. PMID- 21256901 TI - Metallochelating liposomes with associated lipophilised norAbuMDP as biocompatible platform for construction of vaccines with recombinant His-tagged antigens: preparation, structural study and immune response towards rHsp90. AB - Hsp90-CA is present in cell wall of Candida pseudohyphae or hyphae-typical pathogenic morphotype for both systemic and mucosal Candida infections. Heat shock protein from Candida albicans (hsp90-CA) is an important target for protective antibodies during disseminated candidiasis of experimental mice and human. His-tagged protein rHsp90 was prepared and used as the antigen for preparation of experimental recombinant liposomal vaccine. Nickel-chelating liposomes (the size around 100nm, PDI<=0.1) were prepared from the mixture of egg phosphatidyl choline and nickel-chelating lipid DOGS-NTA-Ni (molar ratio 95:5%) by hydration of lipid film and extrusion methods. New non-pyrogenic hydrophobised derivative of MDP (C18-O-6-norAbuMDP) was incorporated into liposomes as adjuvans. rHsp90 was attached onto the surface of metallochelating liposomes by metallochelating bond and the structure of these proteoliposomes was studied by dynamic light scattering, AF microscopy, TEM and GPC. The liposomes with surface exposed C18-O-6-norAbuMDP were well recognised and phagocyted by human dendritic cells in vitro. In vivo the immune response towards this experimental vaccine applied in mice (i.d.) demonstrated both TH1 and TH2 response comparable to FCA, but without any side effects. Metallochelating liposomes with lipophilic derivatives of muramyl dipeptide represent a new biocompatible platform for construction of experimental recombinant vaccines and drug-targeting systems. PMID- 21256902 TI - Development of efficient acid cleavable multifunctional prodrugs derived from dendritic polyglycerol with a poly(ethylene glycol) shell. AB - In an attempt to explore the potential of dendritic systems for the development of effective anticancer drug delivery systems, we explored a simple modular approach of preparing polyglycerol doxorubicin prodrugs, with flexibility for drug loading using an acid-sensitive hydrazone linker and further post modification with poly(ethylene glycol) shell. The resulting drug polymer conjugates showed optimal properties for in vitro and in vivo applications because of their high water solubility, an appropriate size for passive tumor targeting, a high stability at physiological conditions, pronounced acid sensitive properties, cellular internalization, and a favorable toxicity profile. Doxorubicin polyglycerol conjugates with a high drug loading ratio showed clearly improved antitumor efficacy over doxorubicin in an ovarian xenograft tumor model (A2780) inducing transient complete remissions thus demonstrating the potential of developing efficient multifunctional dendritic drug delivery using our modular approach. PMID- 21256903 TI - Noninvasive and efficient transdermal delivery of CpG-oligodeoxynucleotide for cancer immunotherapy. AB - Oligodeoxynucleotides containing unmethylated cytosine-phosphate-guanosine motifs (CpG-ODN) possess immunostimulatory effects and potential antitumor activity. Since the skin is an easily available site of administration of CpG-ODN due to its accessibility and the presence of abundant antigen presenting cells, it is expected that the application of CpG-ODN to the skin would induce systemic immune response and antitumor activity. However, it is difficult to deliver hydrophilic macromolecules including CpG-ODN through the skin. We have previously demonstrated that small interfering RNA (siRNA) was efficiently delivered into rat epidermis by iontophoresis. In this report, we investigate the effect of transdermal iontophoretic delivery of CpG-ODN on the induction of immune responses and antitumor activity against B16F1 melanoma in mice. Iontophoresis promoted CpG-ODN delivery into the epidermis and dermis. Furthermore, iontophoretic delivery of CpG-ODN to the skin induced the expression of proinflammatory and Th1-type cytokines in the skin and draining lymph node. Finally, transdermal iontophoretic delivery of CpG-ODN led to antitumor activity against B16F1 melanoma. Interestingly, the CpG-ODN administration site is not restricted to the tumor area. In conclusion, CpG-ODN delivered transdermally induced potent antitumor activity, and our system is expected to serve as a simple and noninvasive approach for cancer immunotherapy. PMID- 21256904 TI - Gamma-glutamyltransferase, general and cause-specific mortality in 19,000 construction workers followed over 20 years. AB - BACKGROUND & AIMS: Associations of serum gamma-glutamyltransferase levels with a variety of incident diseases and mortality have been suggested. The present study attempted to expand the body of evidence to especially relevant occupational cohorts in which exposure to established gamma-GT determinants may greatly differ from the general population. METHODS: The study was based on occupational health examinations conducted from 1986 to 1992 in 19,090 German male workers from the construction industry, aged 25-64years. Sociodemographics and other health related information were collected during the exam. Vital status follow-up was conducted through 2008. Associations of baseline gamma-GT levels (measurements at 25 degrees C) with all-cause and cause-specific mortality were examined by Kaplan Meier plotting and multiple adjusted Cox regression models. RESULTS: A total of 2170 deaths occurred during 303,198 person-years of follow-up. The risk of death due to any cause was 2.5-fold increased in subjects in the highest (?39U/L) versus lowest (<11U/L) gamma-GT quintile. To varying extents, elevated gamma-GT was associated with higher mortality due to cancer, circulatory, respiratory, and digestive causes, as well as accidents/poisoning. CONCLUSIONS: The findings in this cohort provide evidence for gamma-GT being associated with a broad range of causes of death, including less investigated outcomes. Some characteristics of the observed patterns need to be seen in the context of our cohort, featuring particularly high gamma-GT levels. PMID- 21256905 TI - Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK. AB - BACKGROUND & AIMS: Mechanisms underlying synergistic liver injury caused by alcohol and obesity are not clear. We have produced a mouse model of synergistic steatohepatitis by recapitulating the natural history of the synergism seen in patients for mechanistic studies. METHODS: Moderate obesity was induced in mice by 170% overnutrition in calories using intragastric overfeeding of high fat diet. Alcohol (low or high dose) was then co-administrated to determine its effects. RESULTS: Moderate obesity plus alcohol intake causes synergistic steatohepatitis in an alcohol dose-dependent manner. A heightened synergism is observed when a high alcohol dose (32g/kg/d) is used, resulting in plasma ALT reaching 392+/-28U/L, severe steatohepatitis with pericellular fibrosis, marked M1 macrophage activation, a 40-fold induction of iNos, and intensified nitrosative stress in the liver. Hepatic expression of genes for mitochondrial biogenesis and metabolism are significantly downregulated, and hepatic ATP level is decreased. Synergistic ER stress evident by elevated XBP-1, GRP78 and CHOP is accompanied by hyperhomocysteinemia. Despite increased caspase 3/7 cleavage, their activities are decreased in a redox-dependent manner. Neither increased PARP cleavage nor TUNEL positive hepatocytes are found, suggesting a shift of apoptosis to necrosis. Surprisingly, the synergism mice have increased plasma adiponectin and hepatic p-AMPK, but adiponectin resistance is shown downstream of p-AMPK. CONCLUSIONS: Nitrosative stress mediated by M1 macrophage activation, adiponectin resistance, and accentuated ER and mitochondrial stress underlie potential mechanisms for synergistic steatohepatitis caused by moderate obesity and alcohol. PMID- 21256906 TI - Induction of CXCR3- and CCR5-associated chemokines during acute hepatitis C virus infection. AB - BACKGROUND & AIMS: Characterization of inflammatory mediators, such as chemokines, during acute hepatitis C virus (HCV) infection might shed some light on viral clearance mechanisms. METHODS: Plasma levels of CXCR3 (CXCL9-11)- and CCR5 (CCL3-4)-associated chemokines, ALT, and HCV RNA were measured in nine injection drug users (median 26 samples/patient) before and during 10 acute (eight primary and two secondary) HCV infections. Using functional data analysis, we estimated smooth long-term trends in chemokine expression levels to obtain the magnitude and timing of overall changes. Residuals were analyzed to characterize short-term fluctuations. RESULTS: CXCL9-11 induction began 38-53days and peaked 72-83days after virus acquisition. Increases in ALT levels followed a similar pattern. Substantial negative auto-correlations of chemokine levels at 1 week lags suggested substantial week-to-week oscillations. Significant correlations were observed between CXCL10 and HCV RNA as well as ALT and CXCR3-associated chemokines measured in the preceding week, CCL3-4 expression levels did not change appreciably during acute HCV infection. CONCLUSIONS: Elevation of CXCR3 associated chemokines late during acute HCV infection suggests a role for cellular immune responses in chemokine induction. Week-to-week oscillations of HCV RNA, chemokines, and ALT suggest frequent, repeated cycles of gain and loss of immune control during acute hepatitis C. PMID- 21256907 TI - Noninvasive evaluation of hepatic fibrosis using acoustic radiation force-based shear stiffness in patients with nonalcoholic fatty liver disease. AB - BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease in developed countries, may progress to nonalcoholic steatohepatitis (NASH) in a minority of people. Those with NASH are at increased risk for cirrhosis and hepatocellular carcinoma. The potential risk and economic burden of utilizing liver biopsy to stage NAFLD in an overwhelmingly large at risk population are enormous; thus, the discovery of sensitive, inexpensive, and reliable noninvasive diagnostic modalities is essential for population-based screening. METHODS: Acoustic Radiation Force Impulse (ARFI) shear wave imaging, a noninvasive method of assessing tissue stiffness, was used to evaluate liver fibrosis in 172 patients diagnosed with NAFLD. Liver shear stiffness measures in three different imaging locations were reconstructed and compared to the histologic features of NAFLD and AST-to-platelet ratio indices (APRI). RESULTS: Reconstructed shear stiffnesses were not associated with ballooned hepatocytes (p=0.11), inflammation (p=0.69), nor imaging location (p=0.11). Using a predictive shear stiffness threshold of 4.24kPa, shear stiffness distinguished low (fibrosis stage 0-2) from high (fibrosis stage 3-4) fibrosis stages with a sensitivity of 90% and a specificity of 90% (AUC of 0.90). Shear stiffness had a mild correlation with APRI (R(2)=0.22). BMI>40kg/m(2) was not a limiting factor for ARFI imaging, and no correlation was noted between BMI and shear stiffness (R(2)=0.05). CONCLUSIONS: ARFI imaging is a promising imaging modality for assessing the presence or absence of advanced fibrosis in patients with obesity related liver disease. PMID- 21256908 TI - External eating, impulsivity and attentional bias to food cues. AB - Cognitive and behavioural responses to food reward, such as attentional biases and overeating, have been associated with individual differences in reward responsiveness and impulsivity. This study investigated relationships between external eating, impulsivity and attentional bias to food cues, assessed using the pictorial visual-probe task. As previously reported, attentional bias correlated positively with external eating. Additional novel findings were: (i) attentional bias for food cues was positively related to trait impulsivity, (ii) attentional bias remained related to attention impulsivity after controlling for external eating. Our findings highlight the relationship between the ability to control impulsive responding and selective attention to food cues. PMID- 21256909 TI - Neurite formation by neurons derived from adult rat hippocampal progenitor cells is susceptible to myelin inhibition. AB - Myelin-associated inhibitors expressed following injury to the adult central nervous system (CNS) induce growth cone collapse and retraction of the axonal cytoskeleton. Myelin-associated glycoprotein (MAG) is a bi-functional molecule that promotes neuritogenesis in some immature neurons during development then becomes inhibitory to neurite outgrowth as neurons mature. Progress is being made towards the elucidation of the downstream events that regulate myelin inhibition of regeneration in neuronal populations. However it is not known how adult derived neural stem cells or progenitors respond to myelin during neuronal differentiation and neuritogenesis. Here we examine the effect of MAG on neurons derived from an adult rat hippocampal progenitor cell line (AHPCs). We show that, unlike their developmental counterparts, AHPC-derived neurons are susceptible to MAG inhibition of neuritogenesis during differentiation and display a 57% reduction in neurite outgrowth when compared with controls. We demonstrate that this effect can be overcome (by up to 69%) by activation of the neurotrophin, cyclic AMP and protein kinase A pathways or by Rho-kinase suppression. We also demonstrate that combination of these factors enhanced neurite outgrowth from differentiating neurons in the presence of MAG. This work provides important information for the successful generation of new neurons from adult neural stem cell populations within compromised adult circuitry and is thus directly relevant to endogenous repair and regeneration of the adult CNS. PMID- 21256910 TI - Human leukocyte antigen (HLA)-E and HLA-G polymorphisms in human papillomavirus infection susceptibility and persistence. AB - Human leukocyte antigen (HLA)-E and HLA-G molecules act as powerful modulators of innate and adaptive immune responses. The study examined whether HLA-E and/or HLA G polymorphisms are associated with human papillomavirus (HPV) infection susceptibility and persistence in 636 female university students in Montreal. HLA G*01:01:02 and HLA-G*01:01:08 alleles were associated with increased risk of HPV 16 (odds ratio (OR) = 2.10, 95% confidence interval (CI), 1.11-3.96) and any infections with HPV types from alpha species 1, 8, 10, and 13 (OR = 2.72, 95% CI, 1.11-6.68). HLA-G*01:01:02 and HLA-G*01:03 alleles were associated with persistent HPV-16 (OR = 2.07, 95% CI, 1.16-3.68) and persistent infections with HPV types from alpha species 2, 3, 4, and 15 (OR = 2.99, 95% CI, 1.12-8.00). HLA E polymorphism was not associated with risk of acquisition or persistence of HPV infection. These results suggest that HLA-G molecules may play a role in mediating HPV infection risk. PMID- 21256912 TI - Butyrophilin-like 2 in pulmonary sarcoidosis: a factor for susceptibility and progression? AB - The aims of this study were to assess the association of BTNL2G16071A with the course of pulmonary sarcoidosis and to verify the association with disease predisposition. In addition, the linkage between BTNL2G16071A and certain human leukocyte antigen (HLA)-DRB1/DQB1 types was investigated. In a retrospective case control study BTNL2G16071A, HLA-DQB1, and HLA-DRB1 were typed in 632 sarcoidosis patients. These patients were classified into 304 patients with persistent sarcoidosis and 328 patients with nonpersistent sarcoidosis. The BTNL2 16071A variant allele was present significantly more often in patients with persistent disease (92.4%; 281/304) compared with patients demonstrating a nonpersistent course (86.6%; 284/328; odds ratio (OR) = 1.89 with 95% confidence interval (95% CI) 1.11-3.22). Furthermore, BTNL2 16071A variant allele carriers have an increased risk (OR = 1.85, 95% CI 1.19-2.88) of developing sarcoidosis. Moreover, the strong linkage between variant allele and HLA-DRB1*15 presence (OR = 8.43, 95% CI 3.02-23.5) was confirmed. The presence of a BTNL2G16071A variant allele almost doubles the risk of progressing to persistent pulmonary sarcoidosis in addition to increasing the risk of developing sarcoidosis. Presumably, these increased risks are caused by the strong linkage between BTNL2G16071A and DRB1*15. The choice between determining BTNL2G16071A SNP or the HLA-DRB1 type depends on the ability and/or availability to perform either test. PMID- 21256913 TI - Workshop report: identifying key issues underpinning the selection of linear or non-linear dose-response extrapolation for human health risk assessment of systemic toxicants. AB - The report of an Expert Panel convened by the National Research Council (NRC) of the National Academy of Sciences (NAS), entitled Science and Decisions: Advancing Risk Assessment (National Research Council, 2009a), includes a recommendation to use, as a default approach, low-dose linear extrapolation for systemic toxicity. This recommendation represents a significant departure from long-standing risk assessment practices for non-cancer toxicity, where the most appropriate No Observed Adverse Effect Level (NOAEL) or Benchmark Dose (BMD) of the critical effect in the key study is selected, and then a "safe exposure" level is derived by applying uncertainty factors to account for dataset completeness, potential greater sensitivity of humans when compared with experimental animals, and for potential variability of sensitivity in humans. A workshop was held to "frame" issues raised by the NAS report that needed further study. Workshop objectives included the following: (1) identify the issues raised by the 2009 NRC report and discuss the extent to which existing science may (or may not) align with the NAS analyses and recommendations, and (2) identify/develop possible actions to assist in advancing deeper and broader considerations of some of the critical issues presented by the 2009 NAS Panel. Experts invited to this "Framing" Workshop encompassed a full spectrum of toxicology and risk assessment disciplines; in particular, expertise in molecular interactions and dose-response of biological systems were well represented. The recommendations developed at this Framing Workshop provide specific ideas on possible further steps to facilitate deeper and broader consideration of the issues underpinning dose-response extrapolation in the risk assessment of systemic toxicants. PMID- 21256914 TI - Harm potential of magic mushroom use: a review. AB - In 2007, the Minister of Health of the Netherlands requested the CAM (Coordination point Assessment and Monitoring new drugs) to assess the overall risk of magic mushrooms. The present paper is an updated redraft of the review, written to support the assessment by CAM experts. It summarizes the literature on physical or psychological dependence, acute and chronic toxicity, risk for public health and criminal aspects related to the consumption of magic mushrooms. In the Netherlands, the prevalence of magic mushroom use was declining since 2000 (last year prevalence of 6.3% in 2000 to 2.9% in 2005), and further declined after possession and use became illegal in December 2008. The CAM concluded that the physical and psychological dependence potential of magic mushrooms was low, that acute toxicity was moderate, chronic toxicity low and public health and criminal aspects negligible. The combined use of mushrooms and alcohol and the quality of the setting in which magic mushrooms are used deserve, however, attention. In conclusion, the use of magic mushrooms is relatively safe as only few and relatively mild adverse effects have been reported. The low prevalent but unpredictable provocation of panic attacks and flash-backs remain, however, a point of concern. PMID- 21256915 TI - Association between caries location and restorative material treatment provided. AB - OBJECTIVES: This cross-sectional study by the Northwest PRECEDENT practitioners correlated the location of caries diagnosed in the past 12 months with treatment provided. METHODS: An oral health survey was conducted on up to 20 patients per practice for 101 practises in the Northwest PRECEDENT network. A total of 1943 eligible patients were randomly assessed for the location of and treatment provided for caries lesions diagnosed within the past 12 months. Regression analysis using generalized estimating equations (GEE) was performed to assess association of treatment to tooth location and surface characterization, adjusting for age, practice location (urban/rural), dentist gender, and experience level. The analysis accounts for clustering by practice using robust variance estimates. RESULTS: Overall, 55.4% of patients exhibited recent caries and 42.8% received treatment for at least one permanent tooth. 18% of treated teeth were treated with amalgam, and 72% were treated with composite. This percentage varied as a function of tooth surface characteristics, patient characteristics, and dentist characteristics. The results suggest that restoration selection does depend on tooth type and which surfaces are being restored. The odds of a molar receiving an amalgam restoration are 2.44 (95% CI=1.81-3.30) times higher as compared to a bicuspid, adjusting for all other covariates. When the restoration includes the occlusal surface of a tooth the odds are 0.42 (95% CI=0.20-0.89) times as great that amalgam will be placed. When the restoration includes the mesial or distal surface of the tooth the odds for amalgam restoration are 2.49 (95% CI=1.25-4.95) times higher compared to when it does not include these surfaces. CONCLUSION: Restorative material choice varied based on caries location and practitioner gender. PMID- 21256916 TI - Jack bean alpha-mannosidase digestion profile of hybrid-type N-glycans: effect of reaction pH on substrate preference. AB - Jack bean alpha-mannosidase (JBM) is a well-studied plant vacuolar alpha mannosidase, and is widely used as a tool for the enzymatic analysis of sugar chains of glycoproteins. In this study, the JBM digestion profile of hybrid-type N-glycans was examined using pyridylamino (PA-) sugar chains. The digestion efficiencies of the PA-labeled hybrid-type N-glycans Manalpha1,6(Manalpha1,3)Manalpha1,6(GlcNAcbeta1,2Manalpha1,3)Manbeta1,4GlcNAcbeta ,4GlcNAc-PA (GNM5-PA) and Manalpha1,6(Manalpha1,3)Manalpha1,6(Galbeta1,4GlcNAcbeta1,2Manalpha1,3)Manbeta1,4 lcNAcbeta1,4GlcNAc-PA (GalGNM5-PA) were significantly lower than that of the oligomannose-type N-glycan Manalpha1,6(Manalpha1,3)Manalpha1,6Manbeta1,4GlcNAcbeta1,4GlcNAc-PA (M4-PA), and the trimming pathways of GNM5-PA and GalGNM5-PA were different from that of M4 PA, suggesting a steric hindrance to the JBM activity caused by GlcNAcbeta1 2Man(alpha) residues of the hybrid-type N-glycans. We also found that the substrate preference of JBM for the terminal Manalpha1-6Man(alpha) and Manalpha1 3Man(alpha) linkages in the hybrid-type N-glycans was altered by the change in reaction pH, suggesting a pH-dependent change in the enzyme-substrate interaction. PMID- 21256917 TI - Transcellular movement of hydroxyurea is mediated by specific solute carrier transporters. AB - OBJECTIVE: Hydroxyurea has proven laboratory and clinical therapeutic benefits for sickle cell anemia and other diseases, yet many questions remain about its in vivo pharmacokinetic and pharmacodynamic profiles. Previous reports suggest that hydroxyurea passively diffuses across cells, but its observed rapid absorption and distribution are more consistent with facilitated or active transport. We investigated the potential role of solute carrier (SLC) transporters in cellular uptake and accumulation of hydroxyurea. MATERIALS AND METHODS: Passive diffusion of hydroxyurea across cell membranes was determined using the parallel artificial membrane permeability assay. SLC transporter screens were conducted using in vitro intracellular drug accumulation and transcellular transport assays in cell lines and oocytes overexpressing SLC transporters. Gene expression of SLC transporters was measured by real-time polymerase chain reaction in human tissues and cell lines. RESULTS: Hydroxyurea had minimal diffusion across a lipid bilayer but was a substrate for five different SLC transporters belonging to the organic cation/carnitine transporters and organic anion transporting polypeptides (OATP) families of transporters and urea transporters A and B. Further characterization of hydroxyurea transport revealed that cellular uptake by OATP1B3 is time- and temperature-dependent and inhibited by known substrates of OATP1B3. Urea transporters A and B are expressed differentially in human tissues and erythroid cells, and transport hydroxyurea bidirectionally via facilitated diffusion. CONCLUSIONS: These studies provide new insight into drug transport proteins that may be involved in the in vivo absorption, cellular distribution, and elimination of hydroxyurea. Elucidation of hydroxyurea transcellular movement should improve our understanding of its pharmacokinetics and pharmacodynamics, and may help explain some of the interpatient drug variability observed in patients with sickle cell anemia. PMID- 21256918 TI - Optimal parameter settings for information processing in gene regulatory networks. AB - Gene networks can often be interpreted as computational circuits. This article investigates the computational properties of gene regulatory networks defined in terms of the speed and the accuracy of the output of a gene network. It will be shown that there is no single optimal set of parameters, but instead, there is a trade-off between speed and accuracy. Using the trade-off it will also be shown how systems with various parameters can be ranked with respect to their computational efficiency. Numerical analysis suggests that the trade-off can be improved when the output gene is repressing itself, even though the accuracy or the speed of the auto-regulated system may be worse than the unregulated system. PMID- 21256919 TI - Compositional perspectives on human brain aging. AB - Using publicly available microarray data from the frontal cortex of 30 individuals, spanning the ages of 26-106 years old, we investigate the expression patterns of compositionally distinct genes during human brain aging. Our analyses revealed that at advance ages, GC-poor genes appear to be induced while GC-rich genes are repressed. Interestingly, investigations upon two different types of genes, named pivotal (permanently expressed genes) and non-pivotal (on-off regulated genes), revealed an induction of the GC-poor pivotal genes and a repression of the GC-richer non-pivotal genes at advanced ages. Summarizing, this study shows that genes with different compositional properties have opposite age related expression patterns, suggesting an implication of different regulation mechanisms related to their localization in different chromatin structure, which correlates with the GC level. Finally, an innovative approach on investigating human aging process is suggested, which involves the base composition of genes. PMID- 21256920 TI - Hypospadias: interactions between environment and genetics. AB - Hypospadias is one of the most common congenital malformations. It is considered to be a mild form of the 46,XY disorders of sex development (DSD), but its precise etiology remains to be elucidated. Compromised androgen synthesis or effects can cause this frequent malformation, although the mutational analyses of the genes involved in androgen actions have identified abnormalities in only a very small portion of patients. The overwhelming majority of cases remain unexplained and hypospadias may be a highly heterogeneous condition subject to multiple genetic and environmental factors. We here review the recent advances in this field and discuss the potential interactions between the environment and genetics. PMID- 21256921 TI - Endogenous biotin as a marker of adrenocortical cells with steroidogenic potential. AB - Interpretation of adrenal cortex phenotypes is greatly facilitated by simultaneous examination of multiple markers at single cell resolution. However, the availability of multiple appropriate antibodies can be rate limiting, while their cognate antigens are often subject to variable accessibility. Specific markers not subject to these constraints thus have obvious utility. Here we report that endogenous biotin, when detected in fixed, frozen tissue sections using fluorescent streptavidin, is a specific marker of apparently all cells with steroidogenic potential in the murine adrenal cortex. While streptavidin stains presteroidogenic and mature cortical cells, it does not label the adrenal capsule, medulla or vascular endothelium. Developmental profiles reveal adrenal endogenous biotin labeling from E13.5 through adulthood. Comparisons with zonal markers, hypothalamic-pituitary-adrenal (HPA) axis-remodeled tissue, transgenic Shh-nLacZ or Gli1-nLacZ animals, and Shh mutant embryos further demonstrate the utility of this approach. Fluorescent streptavidin applied using a simple one step staining protocol thus provides a potent counterstain for use in adrenal analyses. PMID- 21256922 TI - Serum brain-derived neurotrophic factor and clozapine daily dose in patients with schizophrenia: a positive correlation. AB - Brain-derived neurotrophic factor (BDNF) plays a critical role in neurodevelopment and neuroplasticity. Altered BDNF signaling is thought to contribute to the pathogenesis of schizophrenia (SZ) especially in relation to cognitive deficits. Clozapine (CLZ) has been shown a beneficial effect on cognition in SZ in some studies and a detrimental effect in others. To examine serum BDNF, two groups of chronically medicated DSM-IV SZ patients (n=44), on treatment with clozapine (n=31) and typical antipsychotics (n=13) had 5ml blood samples collected by venipuncture. Serum BDNF levels were significantly correlated with CLZ daily dose (r=0.394, p=0.028), but not with typical antipsychotic daily dose (r=0.208, p=0.496). This study suggests that serum BDNF levels are correlated with CLZ daily dose, and this may lead to the cognitive enhancement as seen in patients with SZ under CLZ. Despite the strong evidence that chronic administration of CLZ is effective for patients with SZ, it is still unknown whether atypical antipsychotic drugs regulate BDNF expression. Serum BDNF levels concentration in SZ merits further investigations with regard to the role of neurotrophins in the cognitive response to treatment with CLZ and other atypical antipsychotics. PMID- 21256923 TI - Electrophysiological correlates of visually processing subject's own name. AB - We investigated the electrophysiological correlates of the processing of subject's own name (SON) in comparison to familiar and unfamiliar names in the Chinese language. The three types of names were the deviants in an oddball paradigm among lexical and non-lexical phrases. All items consisted of three characters, and the non-lexical items were the targets. All names caused a clear N170 component of identical size which we take as a correlate of structural encoding. Only SON elicited a large N250 component, reflecting attentional capturing of SON. Additionally, SON caused a larger but later peaking P300 than the other two name stimuli which we interpret as a correlate of access to self reference information. PMID- 21256924 TI - KIF1A is the primary anterograde motor protein required for the axonal transport of dense-core vesicles in cultured hippocampal neurons. AB - Dense-core vesicles (DCVs) are responsible for transporting, processing, and secreting neuropeptide cargos that mediate a wide range of biological processes, including neuronal development, survival, and learning and memory. DCVs are synthesized in the cell body and are transported by kinesin motor proteins along microtubules to pre- and postsynaptic release sites. Due to the dependence on kinesin-based transport, we sought to determine if the kinesin-3 family member, KIF1A, transports DCVs in primary cultured hippocampal neurons, as has been described for invertebrate neurons. Two-color, live-cell imaging showed that the DCV markers, chromogranin A-RFP and BDNF-RFP, move together with KIF1A-GFP in both the anterograde and retrograde directions. To demonstrate a functional role for KIF1A in DCV transport, motor protein expression in neurons was reduced using RNA interference (shRNA). Fluorescently tagged DCV markers showed a significant reduction in organelle flux in cells expressing shRNA against KIF1A. The transport of cargo driven by motors other than KIF1A, including mitochondria and the transferrin receptor, was unaffected in KIF1A shRNA expressing cells. Taken together, these data support a primary role for KIF1A in the anterograde transport of DCVs in mammalian neurons, and also provide evidence that KIF1A remains associated with DCVs during retrograde DCV transport. PMID- 21256925 TI - 1-Hz low frequency repetitive transcranial magnetic stimulation in children with Tourette's syndrome. AB - The aim of the current study was to assess the efficacy of repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) of the cortex to children with Tourette's syndrome (TS), if rTMS over the SMA had positive effects on ameliorating tics. We designed a pilot open label 12 weeks cohort study to assess the efficacy of rTMS with TS at specific regions. We administered rTMS over SMA with slow frequency to children with TS. We examined 10 male children (mean age 11.2 +/- 2.0 years) diagnosed with TS according to the Diagnostic and Statistical Manual of Mental Disorders version IV and Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Children with TS were treated with active rTMS to the SMA for 10 daily sessions (1 Hz, 100% of motor threshold, and 1200 stimuli/day). All subjects completed the study with no side effects and no worsening of ADHD or depressive and anxiety symptoms. Tic symptoms improved significantly over the 12 weeks of the study. Statistically significant reductions were seen in the Yale Global Tourette's Syndrome Severity Scale (YGTSS) and Clinical Global Impression (CGI). Low-frequency rTMS over the SMA appears to be effective in children with TS. Further studies using repetitive transcranial magnetic stimulation in TS are warranted, using blinded, balanced, and parallel designs. rTMS over the SMA to children with TS might result in a significant clinical improvement and a normalization of both the hemisphere hyperexcitability. PMID- 21256926 TI - Effects of intragastric injection of glutamate on efferent sympathetic nerve activity in rats. AB - Niijima previously reported that intragastric infusion of glutamate has increased the activity of the efferent parasympathetic nerves that innervate the stomach and pancreas in urethane-anesthetized rats. In the present study, the effects of intragastric injection of glutamate on the efferent sympathetic nerve outflow to the kidney and the white adipose tissue in rats were analyzed. Although the sympathetic nerve activities of the renal and white adipose tissues were not affected after intragastric glutamate injection in rats that were fasted for 3h, these activities were significantly accelerated after intragastric glutamate injection in rats that were fasted for 48h. Moreover, to test the role of the afferent neural pathway on sympathoexcitation caused by glutamate injection, the effects of vagotomy, or sympathetic denervation, were also examined. In vagotomized rats, the sympathetic nerve activities of the renal and white adipose tissues were eliminated after glutamate injection, but these activities remained unaffected in rats that underwent sympathetic denervation. Thus, the stimulating effects of glutamate administration on the sympathetic nerve activities of the renal and white adipose tissues could depend on the length of the fast and the vagal afferent pathway. PMID- 21256927 TI - Increased neural response to trauma scripts in posttraumatic stress disorder following paroxetine treatment: A pilot study. AB - Neuroimaging studies of individuals with posttraumatic stress disorder (PTSD) have revealed altered patterns of activity in medial prefrontal brain regions, including the anterior cingulate cortex (ACC), an area implicated in affect regulation. Selective serotonin reuptake inhibitors (SSRIs) have been shown to effectively treat PTSD symptoms, but there remains a lack of functional neuroimaging research examining the effects of psychopharmacological treatment on brain function in PTSD. The purpose of this pilot study was to assess the effects of the SSRI paroxetine on neural responses to traumatic memories in a small sample of patients with PTSD, as measured with PET imaging; we hypothesized that paroxetine treatment would be associated with increased regional cerebral blood flow (rCBF) in the medial prefrontal cortex. Thirteen participants with PTSD were given controlled-release paroxetine (paroxetine CR) or placebo in a randomized, double-blind fashion for 12 weeks. Participants underwent brain imaging using positron emission tomography (PET) before and at the end of treatment in conjunction with exposure to neutral scripts and personalized trauma scripts. Participants treated with paroxetine CR and placebo both exhibited significantly increased rCBF in the ACC during trauma versus neutral script presentations; however, we noted an increase in function in the orbitofrontal cortex (OFC) in paroxetine-treated (but not placebo-treated) participants. Participants in both groups showed decreases in overall PTSD symptomatology following treatment; paroxetine-treated participants showed a slightly greater percentage decrease in symptoms. These preliminary findings indicate that increased ACC function represents a nonspecific response to treatment, whereas increased OFC function is specifically associated with paroxetine treatment in PTSD. These pilot data reveal putative mechanisms for SSRI treatment in PTSD and substantiate the need for large-scale placebo-controlled studies investigating these effects. PMID- 21256928 TI - Anxiety-like behavior and proinflammatory cytokine levels in the brain of C57BL/6 mice infected with Plasmodium berghei (strain ANKA). AB - Cerebral malaria (CM) is a severe complication resulting from Plasmodium falciparum infection. The underlying mechanisms of CM pathogenesis remain incompletely understood. The imbalance between the release of proinflammatory and anti-inflammatory cytokines has been associated with central nervous system dysfunction found in human and experimental CM. The current study investigated anxiety-like behavior, histopathological changes and release of brain cytokines in C57BL/6 mice infected with Plasmodium berghei strain ANKA (PbA). Anxiety-like behavior was assessed in control and PbA-infected mice using the elevated plus maze test. Histopathological changes in brain tissue were assessed by haematoxylin and eosin staining. Brain concentration of the cytokines IL-1beta, IL-4, IL-10, TNF-alpha and IFN-gamma was determined by ELISA. We found that PbA infected mice on day 5 post-infection presented anxiety symptoms, histopathological alterations in the brainstem, cerebrum and hippocampus and increased cerebral levels of proinflammatory cytokines IL-1beta and TNF-alpha. These findings suggest an involvement of central nervous system inflammatory mediators in anxiety symptoms found in CM. PMID- 21256929 TI - Painful laser stimuli induce directed functional interactions within and between the human amygdala and hippocampus. AB - The pathways by which painful stimuli are signaled within the human medial temporal lobe are unknown. Rodent studies have shown that nociceptive inputs are transmitted from the brainstem or thalamus through one of two pathways to the central nucleus of the amygdala. The indirect pathway projects from the basal and lateral nuclei of the amygdala to the central nucleus, while the direct pathway projects directly to the central nucleus. We now test the hypothesis that the human ventral amygdala (putative basal and lateral nuclei) exerts a causal influence upon the dorsal amygdala (putative central nucleus), during the application of a painful laser stimulus. Local field potentials (LFPs) were recorded from depth electrode contacts implanted in the medial temporal lobe for the treatment of epilepsy, and causal influences were analyzed by Granger causality (GRC). This analysis indicates that the dorsal amygdala exerts a pre stimulus causal influence upon the hippocampus, consistent with an attention related response to the painful laser. Within the amygdala, the analysis indicates that the ventral contacts exert a causal influence upon dorsal contacts, consistent with the human (putative) indirect pathway. Potentials evoked by the laser (LEPs) were not recorded in the ventral nuclei, but were recorded at dorsal amygdala contacts which were not preferentially those receiving causal influences from the ventral contacts. Therefore, it seems likely that the putative indirect pathway is associated with causal influences from the ventral to the dorsal amygdala, and is distinct from the human (putative) indirect pathway which mediates LEPs in the dorsal amygdala. PMID- 21256930 TI - Stimulation-mediated translocation of calmodulin and neurogranin from soma to dendrites of mouse hippocampal CA1 pyramidal neurons. AB - Calmodulin (CaM) and neurogranin (Ng) are two abundant neuronal proteins in the forebrain whose interactions are implicated in the enhancement of synaptic plasticity. To gain further insight into the actions of these two proteins we investigated whether they co-localize in principle neurons and whether they respond to high frequency stimulation in a coordinated fashion. Immunohistochemical staining of CaM and Ng in mouse hippocampal slices revealed that CaM was highly concentrated in the nucleus of CA1 pyramidal neurons, whereas Ng was more broadly localized throughout the soma and dendrites. The asymmetrical localization of CaM in the nucleus of pyramidal neurons was in sharp contrast to the distribution observed in pyramidal cells of the neighboring subiculum, where CaM was uniformly localized throughout the soma and dendrites. The somatic concentrations of CaM and Ng in CA1 pyramidal neurons were approximately 10- and two-fold greater than observed in the dendrites, respectively. High frequency stimulation (HFS) of hippocampal slices promoted mobilization of CaM and Ng from soma to dendrites. These responses were spatially restricted to the area close to the site of stimulation and were inhibited by the N-methyl-D-asparate receptor antagonist 2-amino-5-phosphonopentanoic acid. Furthermore, HFS failed to promote translocation of CaM from soma to dendrites of slices from Ng knockout mice, which also exhibited deficits in HFS-induced long-term potentiation. Translocated CaM and Ng exhibited distinct puncta decorating the apical dendrites of pyramidal neurons and appeared to be concentrated in dendritic spines. These findings suggest that mobilization of CaM and Ng to stimulated dendritic spines may enhance synaptic efficacy by increasing and prolonging the Ca2+ transients and activation of Ca2+/CaM-dependent enzymes. PMID- 21256931 TI - Calpain-mediated regulation of stargazin in adult rat brain. AB - Changes in AMPA receptors have been proposed to underlie changes in synaptic efficacy in hippocampus and other brain structures. Calpain activation has also been discussed as a potential mechanism to produce lasting modifications of synaptic structure and function. Stargazin is a member of the family of transmembrane AMPA receptor associated proteins (TARPs), which participates in trafficking of AMPA receptors and regulates their kinetic properties. We report here that preincubation of thin (20 MUm) frozen rat brain sections with calcium changes the immunological properties of stargazin, an effect totally blocked by a calpain inhibitor. Immunocytochemistry indicates that in situ calpain activation produces a decreased immunoreactivity for stargazin in the neuropil throughout the brain, and Western blots confirmed that a similar treatment decreased stargazin levels. Interestingly, the same treatment did not modify the immunoreactivity for another TARP member, gamma-8, although it increased immunoreactivity in cell bodies in hippocampus, an effect that was not blocked by calpain inhibition. These results strongly suggest the involvement of calpain in the regulation of AMPA receptor targeting and function through truncation of stargazin. PMID- 21256932 TI - Serum insulin like growth factor-1 is associated with working memory, executive function and selective attention in a sample of healthy, fit older adults. AB - The present study examined the association between serum insulin like growth factor-1 (IGF-1) concentrations and cognitive function in a sample of healthy, fit older adults (age: 70.8+/-9.3 years, body mass index (BMI): 27.3+/-5.7). Participants reported to the laboratory and basic anthropometric data were collected, followed by a fasted blood draw to quantify serum IGF-1. Participants then underwent cognitive testing that included the Mini-Mental Status Exam (MMSE), Trail Making Test A and B, Ruff's 2 and 7 test of selective attention and Letter Number Sequencing. Results showed the participants were generally cognitively intact (MMSE 27.6+/-1.8). Significant partial correlations (controlled for age, gender and years of education) emerged between serum IGF-1 concentrations and the total (r=0.381, P=0.030) and longest trial (r=0.455, P=0.011) on Letter Number Sequencing. Similar partial correlations yielded significant relationships between serum IGF-1 and Ruff's Automatic Detection Errors (r=-0.495, P=0.006), Controlled Speed Errors (r=-0.598, P=0.002) and errors made on the Trial Making Test part B (r=-0.466, P=0.010). These findings suggest that fasting levels of serum IGF-1 are related to higher levels of cognitive performance in healthy older adults, including working memory, selective attention and executive function. Further work is needed to more clearly determine possible mechanisms. PMID- 21256933 TI - Mediodorsal nucleus of the thalamus is critical for the expression of memory of methamphetamine-produced conditioned place preference in rats. AB - Methamphetamine (MA) is a powerful and highly addictive psychostimulant. However, the neural substrate mediating MA-induced conditioned effects, an essential part of addiction, remain unclear. The present study investigated the involvement of the anterior cingulate cortex (ACC), the lateral nucleus of amygdala (LNA), and the mediodorsal nucleus of the thalamus (MD) in MA-conditioned place preference (CPP). Rats underwent bilateral radio-frequency lesions of the ACC, LNA, or MD followed by MA CPP training. Lesions of the MD, but not the ACC or LNA, disrupted MA CPP learning. To clarify the role of the MD on the different stages of the MA CPP memory process, bilateral microinfusions of lidocaine into the MD were performed 5 min prior to each conditioning trial, immediately after the conditioning trial, or 5 min before the testing phase. Pretesting, but not pre- or post-conditioning, infusions of lidocaine into the MD impaired MA CPP. Furthermore, a clear preference for the previously conditioned MA paired cues was expressed when the rats were tested again 24 h after infusions of lidocaine. These results are interpreted as indicating that the MD is specifically involved in the memory retrieval process of MA associated memory which suggests the MD could have an important role in relapse in individuals suffering from MA addiction. PMID- 21256934 TI - The basolateral amygdala regulates adaptation to stress via beta-adrenergic receptor-mediated reductions in phosphorylated extracellular signal-regulated kinase. AB - The reactivity of physiological systems and behavior to psychological stress is reduced with increasing familiarity with a repeated stressor. This reduced reactivity, termed habituation, is a crucial adaptation limiting negative health consequences of stress and can be disrupted in psychopathology. We hypothesized that the ability to habituate physiologically and behaviorally to previously experienced stressors depends on beta-adrenergic receptor activation (beta-AR) in the basolateral amygdala (BLA), a specific neural substrate important for the consolidation of multiple types of memories. We observed that administration of the beta-AR antagonist propranolol into the BLA after each of four daily exposures to restraint stress prevented the normal development of neuroendocrine and behavioral habituation measured during the fifth restraint in adult male rats. In contrast, the beta-AR agonist clenbuterol administered into the BLA after each restraint on days 1-4 enhanced neuroendocrine habituation at the lowest dose but attenuated behavioral habituation at high doses. We then explored intracellular signaling mechanisms in the BLA that might be a target of beta-AR activation during stress. beta-AR activation post restraint is necessary for the alteration in basal phosphorylated ERK (pERK) levels, as daily post-stress beta AR blockade on days 1-4 prevented repeated stress from leading to decreased pERK in the BLA on day 5. Finally, we examined the effect of blocking ERK phosphorylation in the BLA after each restraint on days 1-4 with the MEK (MAPK/ERK kinase) inhibitor U0126, and found that this was sufficient to both mimic neuroendocrine habituation in stress-naive animals and to enhance it in repeatedly stressed animals during restraint on day 5. Together, the results suggest that an individual's ability to habituate to repeated stress is regulated by activation of BLA beta-AR, which may have these effects by transducing subsequent reductions in pERK. Individual variations in beta-AR activation and intracellular signaling in the BLA may contribute significantly to adaptation to psychological stress and consequent resilience to stress-related psychopathology. PMID- 21256935 TI - An abiotic stress response gene TaSnRK2.7-B in wheat accessions: genetic diversity analysis and gene mapping based on SNPs. AB - TaSnRK2.7, a SnRK2 (sucrose non-fermenting1-related protein kinase 2) member of wheat, confers enhanced multi-stress tolerance in carbohydrate metabolism. Here, the nucleotide diversity of TaSnRK2.7 was investigated in 60 wheat accessions with different stress-tolerant features. One copy, named TaSnRK2.7-B, was detected in 32 accessions, which mainly exhibited stress tolerance. The TaSnRK2.7 B evolutionary dynamics were examined in these cultivars, which have been subjected to population bottlenecks and intensive selection in breeding. Nucleotide diversity (pi) in the entire TaSnRK2.7-B region was 0.00148. Sliding window analysis demonstrated that 3932-4535bp was a variation-enriched region, covering the eighth intron, the ninth exon and the 3'-flanking region. As predicted, neutrality tests revealed that the TaSnRK2.7-B protein was relatively conservative, and population bottlenecks or purifying selection may have acted on TaSnRK2.7-B. Furthermore, linkage disequilibrium between SNP loci extends across the entire TaSnRK2.7-B region. A SNP marker of TaSnRK2.7-B was developed and mapped on chromosome 2AL flanked by WMC179.4 and WMC401, which were co-located in the same or adjacent chromosome intervals with QTLs for phosphorus utilization efficiency and accumulation efficiency of stem water-soluble carbohydrates. PMID- 21256936 TI - Effect of rare earth elements on beef cattle growth performance, blood clinical chemical parameters and mitogen stimulated proliferation of bovine peripheral blood mononuclear cells in vitro and ex vivo. AB - Rare earth elements (REE) are possible performance enhancers in animal production, but little is known about their effects on ruminants. Therefore a feeding trial was conducted with 40 fattening bulls who received 0, 100, 200 or 300mg REE-citrate/kg dry matter (DM), containing 34.30% La, 58.09% Ce and 7.61% other REE. DM intake was measured daily and live weight weekly. Ex vivo ConcanavalinA (ConA)-stimulated cell proliferation of peripheral blood mononuclear cells (PBMC) was tested by MTT and alamar blue (AB) assay. Serum was analysed for clinical chemical parameters, ion (Mg, Ca and P) and REE concentrations. The effects of LaCl(3), CeCl(3), NdCl(3) and YCl(3) on ConA stimulated proliferation of PBMC were tested in vitro, using MTT and AB assay. REE-citrate supplementation did affect DM intake, but not live weight gain, clinical chemical parameters, and ion concentrations significantly. In REE-300 group ex vivo proliferation of PBMC was significantly increased. In vitro ConA stimulated proliferation decreased with rising REE-chloride concentrations. At least at the highest tested concentration (approximately 290MUM) the inhibition reached significance. Proliferation of non-stimulated PBMC was not affected dose dependently. REE affect the proliferation of PBMC, thus an effect on the bovine immune system is possible. However, the great differences in effective doses in vitro and ex vivo (serum REE concentrations) might explain the different results from the experiments. PMID- 21256937 TI - The contribution of Raman spectroscopy to the analysis of phase transformations in pharmaceutical compounds. AB - We show in this paper the contribution of the whole Raman spectrum including the phonon spectrum, to detect, identify and characterize polymorphic forms of molecular compounds, and study their stability and transformation. Obtaining these kinds of information is important in the area of pharmaceutical compounds. Two different polymorphic systems are analyzed through investigations in indomethacin and caffeine exposed to variable environmental conditions and various stresses, as possibly throughout the production cycle of the active pharmaceutical ingredient. It is shown the capability of the low-frequency Raman spectroscopy to reveal disorder in the crystalline state, to detect small amorphous or crystalline material, and to elucidate ambiguous polymorphic or polyamorphic situations. PMID- 21256938 TI - Pretreatment effects of moxibustion on the skin permeation and skin and muscle concentrations of salicylate in rats. AB - The effect of moxibustion on the in vitro and in vivo skin permeation of salicylate was evaluated in rats. First, the effect of moxibustion pretreatment on the elimination pharmacokinetics of salicylate after i.v. injection in rats was determined: no clear difference was observed in the plasma profiles of salicylate (SA) with or without moxibustion pretreatment. However, much higher skin and muscle concentrations of salicylate were observed after its i.v. injection. Next, an in vitro skin permeation study of SA was performed after moxibustion pretreatment. Moxibustion pretreatment increased the skin permeation of SA, and the extent of the increase in SA skin permeation was related to the strength of moxibustion ignition. More intense treatments produced higher skin permeation. A similar enhancement effect on the skin permeation of SA was observed in in vivo studies. Interestingly, the skin/plasma and muscle/plasma ratios of SA were markedly increased by moxibustion pretreatment. These results were due to the induction of enhanced skin permeation and lower clearance into the cutaneous vessels by moxibustion ignition. Combination treatment involving moxibustion and the topical application of drugs such as NSAID may be useful for increasing local pharmaceutical effects by enhancing the drug concentration in the skin and muscle underneath the topical application site. PMID- 21256939 TI - Mechanistic modelling of drug release from polymer-coated and swelling and dissolving polymer matrix systems. AB - The time required for the design of a new delivery device can be sensibly reduced if the release mechanism is understood and an appropriate mathematical model is used to characterize the system. Once all the model parameters are obtained, in silico experiments can be performed, to provide estimates of the release from devices with different geometries and compositions. In this review coated and matrix systems are considered. For coated formulations, models describing the diffusional drug release, the osmotic pumping drug release, and the lag phase of pellets undergoing cracking in the coating due to the build-up of a hydrostatic pressure are reviewed. For matrix systems, models describing pure polymer dissolution, diffusion in the polymer and drug release from swelling and eroding polymer matrix formulations are reviewed. Importantly, the experiments used to characterize the processes occurring during the release and to validate the models are presented and discussed. PMID- 21256940 TI - Controlled release from hydrogel-based solid matrices. A model accounting for water up-take, swelling and erosion. AB - Design and realization of drug delivery systems based on polymer matrices could be greatly improved by modeling the phenomena which take place after the systems administration. Availability of a reliable mathematical model, able to predict the release kinetic from drug delivery systems, could actually replace the resource-consuming trial-and-error procedures usually followed in the manufacture of these latter. In this work, the complex problem of drug release from polymer (HPMC) based matrices systems was faced. The phenomena, previously observed and experimentally quantified, of water up-take, system swelling and erosion, and drug release were here described by transient mass balances with diffusion. The resulting set of differential equations was solved by using finite element methods. Two different systems were investigated: cylindrical matrices in which the transport phenomena were allowed only by lateral surfaces ("radial" case), and cylindrical matrices with the overall surface exposed to the solvent ("overall" case). A code able to describe quantitatively all the observed phenomena has been obtained. PMID- 21256941 TI - Applications of X-ray scattering in pharmaceutical science. AB - The use of X-ray scattering techniques in pharmaceutical science is increasing, in part through increased collaborations with the materials science community, and through increased availability of instrumentation, particularly synchrotron sources. The ability to understand not only the biopharmaceutical outcome, but also arguably, more importantly, the structural aspects of drugs and drug delivery systems, is essential to progressing pharmaceutical science; this review serves as an introduction to the major techniques and the wide range of areas in which X-ray scattering may be applied in understanding and controlling structure in pharmaceutical systems. PMID- 21256942 TI - Water state effect on drug release from an antibiotic loaded polyurethane matrix containing albumin nanoparticles. AB - Water mobility plays a crucial role in determining transport properties of small molecules in polymer matrices. In particular, in drug delivery systems, water state affects the pharmacokinetics, especially drug absorption, diffusion and release. In the present study, the state of water in an antibiotic-loaded composite consisting of albumin nanoparticles (BSA(np)) dispersed into a carboxylated polyurethane (PEUA) has been investigated and compared with that of the single drug-loaded components. The antibiotic cefamandole nafate was used as a model drug. DSC analysis, used to evaluate the freezing and non-freezing water fractions in the hydrated samples, showed that in BSA(np) water can adsorb both in the inter-particles regions and inside the particles. With increasing of total adsorbed water amount, the contribution of the freezing water fraction was higher than the non-freezing one. As for PEUA, the majority of water molecules absorbed is in a mobile freezing state (about 60% of the W(tot)). As for the PEUA/BSA(np) composite, the higher polyurethane phase segregation induced by the nanoparticles as well as the higher non-freezing water fraction significantly enhanced drug uptake with respect to PEUA. Moreover, the greater non-freezing water fraction allowed the drug to penetrate within BSA nanoparticles and to give rise then to a controlled drug release. Indeed, the diffusion barrier exerted by nanoparticles and the matrix prolonged the antimicrobial activity from 4 to 9 days. Finally, the higher polyurethane phase segregation also improved composite mechanical properties, as evidenced in stress-strain experiments and dynamic mechanical analysis. PMID- 21256943 TI - Deposition of aerosols delivered by nasal route with jet and mesh nebulizers. AB - PURPOSE: To quantify the amount of aerosol deposited in different parts of the airways with a commercially available nasal sonic jet nebulizer (NJN) using a sound effect, and to compare its performance with a new nasal mesh nebulizer (NMN). METHODS: Seven healthy non-smoking male volunteers aged 21-36 years with a mean weight of 77+/-10 kg were included in this single-center study. Both nebulizer systems were loaded with (99m)Tc-DTPA and scintigraphies were performed with a gamma camera. Particle size distribution of the aerosols produced by the two nebulizer systems was measured. RESULTS: There was no statistical difference between the two nebulizers in terms of fraction of particles smaller than 5 MUm (44+/-4% vs 45+/-2%) (p>0.9). Aerosol deposition in the nasal region was 73+/-10% (% of aerosol deposited in airways) with the NJN, and 99+/-3% with the NMN (p=0.01). Total nasal deposition was 9.6+/-1.9% of the nebulizer charge with the NJN and 28.4+/-8.9% with the NMN (p=0.01). 0.5+/-0.3% of the nebulizer charge was deposited in the maxillary sinuses with the NJN, compared to 2.2+/-1.6% with the NMN (p=0.01). CONCLUSION: Although the two nebulizers had the same particle size, NMN significantly improved aerosol deposition in nasal cavity and prevents deposition into the lungs. PMID- 21256944 TI - Hansen solubility parameter as a tool to predict cocrystal formation. AB - The objective of this study was to investigate whether the miscibility of a drug and coformer, as predicted by Hansen solubility parameters (HSPs), can indicate cocrystal formation and guide cocrystal screening. It was also our aim to evaluate various HSPs-based approaches in miscibility prediction. HSPs for indomethacin (the model drug) and over thirty coformers were calculated according to the group contribution method. Differences in the HSPs between indomethacin and each coformer were then calculated using three established approaches, and the miscibility was predicted. Subsequently, differential scanning calorimetry was used to investigate the experimental miscibility and cocrystal formation. The formation of cocrystals was also verified using liquid-assisted grinding. All except one of the drug-coformers that were predicted to be miscible were confirmed experimentally as miscible. All tested theoretical approaches were in agreement in predicting miscibility. All systems that formed cocrystals were miscible. Remarkably, two new cocrystals of indomethacin were discovered in this study. Though it may be necessary to test this approach in a wide range of different coformer and drug compound types for accurate generalizations, the trends with tested systems were clear and suggest that the drug and coformer should be miscible for cocrystal formation. Thus, predicting the miscibility of cocrystal components using solubility parameters can guide the selection of potential coformers prior to exhaustive cocrystal screening work. PMID- 21256945 TI - Nanoparticles for paclitaxel delivery: a comparative study of different types of dendritic polyesters and their degradation behavior. AB - The aim of this study was to formulate nanoparticles from three different hyperbranched polymers, namely an unmodified dendritic polyester (Boltorn H40TM), a lipophilic, fatty acid modified dendritic polymer (Boltorn U3000TM) and an amphiphilic dendritic polymer (Boltorn W3000TM) for drug delivery of paclitaxel and to investigate their properties. A solvent displacement method allowed preparation of nanoparticles from all three hyperbranched polymers. Nanoparticle sizes ranged from 70 to 170 nm. The lipophilic Boltorn U3000TM formed the biggest nanoparticles and the amphiphilic Boltorn W3000TM formed the smallest ones. Nanoparticles of amphiphilic Boltorn W3000TM displayed only a slightly negative zeta potential, while more negative zeta potentials were measured for nanoparticles based on the other two polymers. Degradation profiles were investigated by short time pH-stat titration. Boltorn H40TM showed a faster degradation rate then the two other fatty acid containing polymers. For Boltorn H40TM, degradation rate was also investigated in longer term mass loss studies resulting in 30% degradation during 3 weeks. Cytotoxicity of the nanoparticles was studied by MTT assay displaying low cytotoxicity for all three polymers. All three types of nanoparticles were loaded with paclitaxel and their release profiles were studied. Sizes and zeta potentials remained stable after loading and did not change significantly. These three types of hyperbranched polymers show potential as nanoparticulate delivery systems and should be further studied. Due to their high loading efficiency, Boltorn U3000 and W3000 represent the most interesting candidates. PMID- 21256946 TI - Enhanced permeation of fentanyl from supersaturated solutions in a model membrane. AB - The aim of the present study was to investigate the permeation of fentanyl from supersaturated formulations when applied to silicone membrane. Silicone was chosen in order to separate the effects of supersaturation from other possible influences of volatile formulation components on biological membranes. Supersaturated formulations containing either propylene glycol/water (PG/H(2)O) or propylene glycol/ethanol (PG/Et) were prepared containing varying degrees of saturation (DS) of fentanyl. Permeation of finite and infinite doses of the PG/H(2)O formulations, and finite doses of the PG/Et formulations was investigated using Franz-type diffusion cells. For the PG/H(2)O formulations a good correlation between the flux and the DS of the formulation up to 5 DS for infinite dose studies (r(2)=0.99), and up to 7 DS for finite dose studies (r(2)=0.98), was evident. Similarly, for the PG/Et formulations there is a good correlation between the mean flux and the theoretical DS of the formulation (r(2)=0.95). Except for the 2 DS formulations, no significant differences were seen in the mean flux between PG/H(2)O and PG/Et finite dose studies. The larger fluxes observed for infinite doses of the PG/H(2)O formulations versus finite doses reflect changes in the effective area of diffusion over the time of the experiment for the latter set of experiments. The permeation enhancement observed for PG/Et formulations confirms that enhanced drug thermodynamic activity was induced by ethanol evaporation. PMID- 21256947 TI - Why and how to prepare biodegradable, monodispersed, polymeric microparticles in the field of pharmacy? AB - Drug delivery via biodegradable microparticles benefits from both the protection of the encapsulated drug from hazardous conditions and the controlled release of the encapsulated drug, thereby reducing the administration frequency and improving patient compliance. Microsphere-size particle distribution is considered as being an important factor that affects the choice of the administration route and the drug-release rate. Significant research efforts have been directed towards the production of monodispersed "designer" particles. Amongst various techniques, some have been examined from lab-scale to industrial scale. This review provides a global overview of monodispersed microparticle production methods and then focuses on recent processes being used to produce biodegradable microparticles applied in the pharmaceutical field. Further discussion about the choice of process according to the microparticle objectives of use is suggested. PMID- 21256949 TI - Analysis and recordings of orally transmitted knowledge about medicinal plants in the southern mountainous region of Korea. AB - AIM OF THE STUDY: This study aims to analyze and record orally transmitted knowledge of medicinal plants from the indigenous people living in the southern mountainous region of Korea. This article is the first study of its kind. MATERIALS AND METHODS: Data was collected through the participatory rural appraisal (PRA) method involving interviews, informal meetings, open and group discussions, and overt observations with semi-structured questionnaires. RESULTS: The investigation reveals that the indigenous people have used 217 species of medicinal plants distributed in 177 genera belonging to 77 families with 691 different uses. The representative families were Asteraceae (13.5%) followed by Fabaceae (8.2%), Araliaceae (6.1%), Rosaceae (5.8%), Cucurbitaceae (4.1%), Poaceae (3.0%), Liliaceae (2.7%), and Apiaceae (2.6%). On the whole, 21 kinds of plant-parts were used and prepared in 26 various ways by the people for medicinal purposes. The informant consensus factor (ICF) values in the ailment categories were veterinary ailments (0.88), pains (0.84), cuts and wounds (0.77), and respiratory system disorders (0.76). In terms of fidelity levels, 41 plant species showed 100% of fidelities. CONCLUSION: In recent years, the Korean society has been a heavy loss of traditional practices due to a rapid decrease of the senior population. This pressing circumstance raises the level of urgency for the preservation of indigenous knowledge from extinction. A priority should be given first for collecting and recording indigenous knowledge from the natives inhabiting the national parks and environmental preservation areas. PMID- 21256948 TI - Dissecting the molecular basis of organ of Corti development: Where are we now? AB - This review summarizes recent progress in our understanding of the molecular basis of cochlear duct growth, specification of the organ of Corti, and differentiation of the different types of hair cells. Studies of multiple mutations suggest that developing hair cells are involved in stretching the organ of Corti through convergent extension movements. However, Atoh1 null mutants have only undifferentiated and dying organ of Corti precursors but show a near normal extension of the cochlear duct, implying that organ of Corti precursor cells can equally drive this process. Some factors influence cochlear duct growth by regulating the cell cycle and proliferation. Shortened cell cycle and premature cell cycle exit can lead to a shorter organ of Corti with multiple rows of hair cells (e.g., Foxg1 null mice). Other genes affect the initial formation of a cochlear duct with or without affecting the organ of Corti. Such observations are consistent with evolutionary data that suggest some developmental uncoupling of cochlear duct from organ of Corti formation. Positioning the organ of Corti requires multiple genes expressed in the organ of Corti and the flanking region. Several candidate factors have emerged but how they cooperate to specify the organ of Corti and the topology of hair cells remains unclear. Atoh1 is required for differentiation of all hair cells, but regulation of inner versus outer hair cell differentiation is still unidentified. In summary, the emerging molecular complexity of organ of Corti development demands further study before a rational approach towards regeneration of unique types of hair cells in specific positions is possible. PMID- 21256950 TI - Aged garlic extract inhibits homocysteine-induced scavenger receptor CD36 expression and oxidized low-density lipoprotein cholesterol uptake in human macrophages in vitro. AB - AIM OF THE STUDY: Expression of CD36 scavenger receptors on macrophages is involved in oxidized low-density lipoprotein (OxLDL) uptake and foam cell formation during atherosclerotic lesion development. It has been shown previously in vitro and in vivo that the atherosclerotic risk factor homocysteine (Hcy) stimulates macrophage CD36 expression and OxLDL uptake. We now examined the effects of aged garlic extract (AGE), a garlic preparation enriched in water soluble organic sulfur-containing compounds, on Hcy-induced CD36 expression and foam cell formation in human monocytes/macrophages. RESULTS: Incubation with Hcy (200 MUM for 72h) in THP-1-derived macrophages and primary human macrophages caused a 37.8+/-5.2% and 60.7+/-4.2% increase in CD36 expression compared to control, respectively. Coincubation with AGE (5mg/ml) significantly suppressed CD36 expression in THP-1 derived macrophages by 48.6+/-9.0% compared to Hcy incubated cells only. AGE (1-5mg/ml) dose dependently inhibited Hcy-induced CD36 expression in primary human macrophages, and decreased binding of nuclear proteins to a PPARgamma response element. Preincubation with AGE significantly inhibited DiI-labeled OxLDL uptake. CONCLUSIONS: These data indicate that AGE inhibits CD36 expression and OxLDL uptake in human macrophages by modulating the PPARgamma pathway, and suggest that the extract could be useful for the prevention of atherosclerotic lesions. PMID- 21256951 TI - Acute and subchronic oral toxicity assessment of the aqueous extract from the stem bark of Erythrina senegalensis DC (Fabaceae) in rodents. AB - AIM OF THE STUDY: The decoction of the stem bark of Erythrina senegalensis (EAES) is traditionally used in the Western region of Cameroon against liver disorders. The present study evaluated the potential toxicity of this decoction after acute and sub-chronic administration in rodents. MATERIALS AND METHODS: In acute study, a single administration of EAES was given orally to mice at doses ranging from 1.25 to 12.5 g/kg. General behaviour, adverse effects and mortality were determined for up to 14 days post treatment. In the sub-chronic study, EAES was given orally as a single administration to Wistar rats at doses of 300, 600 and 1,200 mg/kg/day for 28 days. Animal body weight was observed throughout the experimental period while haematological and biochemical parameters of blood and urine, as well as kidney and liver tissues histology were evaluated at the end of the experiment. RESULTS: In the acute study in mice, none of the doses used induced mortality or significant behavioural changes. In the sub-chronic study in rats, daily oral administration of EAES at the dose of 600 mg/kg resulted in a significant increase in the relative body weight at the last week of treatment. The relative weights of organs were not affected by the treatment. No haematological changes were observed a part of a significant increase in WBC count at the dose of 600 mg/kg. Serum AST, ALT, ALP, total protein, total cholesterol and triglycerides decreased significantly while total and conjugated bilirubin significantly increased. Renal function indices assay in blood showed significant modification in all the treated groups compared to control while, in urine, only urea excretion markedly reduced at a dose of 1,200 mg/kg. Histological analysis did no show any liver or kidney alteration. CONCLUSION: These results demonstrated that there is a wide margin of safety for the therapeutic use of EAES and further corroborated the traditional use of this extract as a hepatoprotective agent. PMID- 21256952 TI - Potent antiplasmodial extracts from Cameroonian Annonaceae. AB - AIM OF THE STUDY: In a search for new antimalarial leads, we have carried out a preliminary ethnopharmacological study with the aim of evaluating the in vitro antiplasmodial activity of extracts from thirteen Annonaceae species growing in Cameroon, and of assessing the acute toxicity of promising fractions in Swiss albino mice. MATERIALS AND METHODS: Plants were selected on the basis of an ethnobotanical survey carried out in four sites in centre and south regions of Cameroon (Yaounde neighbourhoods, Kon-Yambetta, Ngobayang and Mbalmayo) on Annonaceae plants locally used to treat malaria and related symptoms. The choice of the sites was mainly based on environmental factors enabling mosquito breeding, cosmopolitan areas regrouping people from different cultural origins, areas with limited access to health centers, and areas with people relying exclusively on traditional medical practices. Collected materials were extracted by maceration in 95% ethanol. The crude extract was partitioned using organic solvents and the fractions afforded were evaluated for antiplasmodial activity in culture against the W2 strain of Plasmodium falciparum. Promising fractions (methanol fractions) were assessed for their acute toxicity in Swiss albino mice. RESULTS: From the results achieved, 37 (31.3%) out of 118 extracts tested exhibited antiplasmodial activity, with IC(50) values ranging from 1.07 MUg/ml to 9.03 MUg/ml. Of the active extracts, 29 (78.4%) were methanol fractions, 21 (72.4%) of which inhibited the parasites with IC(50)<5 MUg/ml. The promising fractions proved to be safe through oral administration in mice. CONCLUSIONS: The activities and toxicity profiles of methanol fractions indicate that they deserve to be further investigated in detail for antimalarial lead discovery. PMID- 21256953 TI - Quorum sensing and c-di-GMP-dependent alterations in gene transcripts and virulence-associated phenotypes in a clinical isolate of Aeromonas hydrophila. AB - Recently, we demonstrated that the LuxS-based quorum sensing (QS) system (AI-2) negatively regulated the virulence of a diarrheal isolate SSU of Aeromonas hydrophila, while the ahyRI-based (AI-1) N-acyl-homoserine lactone system was a positive regulator of bacterial virulence. Thus, these QS systems had opposing effects on modulating biofilm formation and bacterial motility in vitro models and in vivo virulence in a speticemic mouse model of infection. In this study, we linked these two QS systems with the bacterial second messenger cyclic diguanosine monophosphate (c-di-GMP) in the regulation of virulence in A. hydrophila SSU. To accomplish this, we examined the effect of overproducing a protein with GGDEF domain, which increases c-di-GMP levels in bacteria, on the phenotype and transcriptional profiling of genes involved in biofilm formation and bacterial motility in wild-type (WT) versus its QS null mutants. We provided evidence that c-di-GMP overproduction dramatically enhanced biofilm formation and reduced motility of the WT A. hydrophila SSU, which was equitable with that of the DeltaluxS mutant. On the contrary, the ?ahyRI mutant exhibited only a marginal increase in the biofilm formation with no effect on motility when c-di GMP was overproduced. Overall, our data indicated that c-di-GMP overproduction modulated transcriptional levels of genes involved in biofilm formation and motility phenotype in A. hydrophila SSU in a QS-dependent manner, involving both AI-1 and AI-2 systems. PMID- 21256954 TI - Single and concerted effects of benzo[a]pyrene and flavonoids on the AhR and Nrf2 pathway in the human colon carcinoma cell line Caco-2. AB - As phytochemicals have the potential to counteract adverse effects of carcinogens we investigated the influence of the flavonoids quercetin and kaempferol on benzo[a]pyrene (BaP) mediated effects on human colon cancer cells, Caco-2. We focused on concerted effects on the expression of AhR and Nrf2 pathway components. In contrast to kaempferol, BaP and quercetin efficiently induced CYP1A1, CYP1A2 and CYP1B1-mRNA in Caco-2 cells. BaP not only acted via AhR activation but sustainably also by increasing AhR and by down-regulating AhRR mRNA. The flavonoids did not affect AhR expression but counteracted the BaP mediated AhRR repression. Only quercetin was found to induce AhRR mRNA. ARNT mRNA appeared to be slightly but significantly down-regulated by BaP as well as by flavonoids while expression of AIP was not or only slightly modulated. The Nrf2 pathway was activated by BaP and by the flavonoids shown by induction of Nrf2 and several of its target genes such as NQO1, GSTP1, GSTA1 and GCLC. Induction effects of 10 MUm BaP on Nrf2, GSTP1 and NQO1 were abolished by the flavonoids. In summary, we show that quercetin supports AhR mediated effects. Both flavonoids, however, may counteract the effects of BaP on expression of AhR, AhRR, Nrf2, GSTP1 and NQO1. In conclusion, quercetin appears to have two faces, a flavonoid-like one and a PAH-like one which supports Ahr-mediated effects while kaempferol acts "just like a flavonoid". Thus, flavonoids have to be treated individually with respect to their anti-adverse activity. PMID- 21256956 TI - Detection of aacA-aphD, qacEdelta1, marA, floR, and tetA genes from multidrug resistant bacteria: Comparative analysis of real-time multiplex PCR assays using EvaGreen((r)) and SYBR((r)) Green I dyes. AB - We have developed multiplex real-time PCR assays that utilize DNA-intercalating dyes, SYBR Green I (SG) and EvaGreen (EG), with two primer sets (set 1=qacEdelta1, tetA and aacA-aphD; set 2=tetA, marA, and floR) to simultaneously amplify the qacEdelta1, tetA, aacA-aphD, marA, and floR genes. Validity of the multiplex PCR assays was confirmed by testing 83 bacterial isolates, including Staphylococcus aureus (28 isolates), Enterococcus spp. (17 isolates), Salmonella enterica serovar Typhimurium (8 isolates), Citrobacter spp. (9 isolates), Escherichia coli (14 isolates) and Aeromonas veronii (7 isolates), and performing sequence analysis of representative PCR products. Agarose gel analysis revealed the presence of correct size PCR products, and the differences in their thermal melting (T(m)) curves were used to distinguish various PCR products. Although T(m) peaks of different amplicons after EG-based singleplex and multiplex PCR assays were resolved nicely, only one or two peaks were seen for SG-bound amplicons. EG-based multiplex real-time PCR assays provided better peak resolution. There was a good correlation with a better linear relationship between the C(t) and log input DNA concentration for the set 1 and set 2 genes in EG-based assays (R(EG)(2)=0.9813and0.9803) than in SG-based assays (R(SG)(2)=0.5276and0.6255). The sensitivities of detection were 2.5-25fg and 25 250fg of template DNA in EG and SG-based singleplex and multiplex PCR assays, respectively. The assays, which could be completed in less than 45min, offer sensitive and rapid detection of qacEdelta1, aacA-aphD, marA, floR, and tetA genes from a diverse group of multiple antibiotic-resistant bacterial strains. PMID- 21256955 TI - Stress- and glucocorticoid-induced priming of neuroinflammatory responses: potential mechanisms of stress-induced vulnerability to drugs of abuse. AB - Stress and stress-induced glucocorticoids (GCs) sensitize drug abuse behavior as well as the neuroinflammatory response to a subsequent pro-inflammatory challenge. Stress also predisposes or sensitizes individuals to develop substance abuse. There is an emerging evidence that glia and glia-derived neuroinflammatory mediators play key roles in the development of drug abuse. Drugs of abuse such as opioids, psychostimulants, and alcohol induce neuroinflammatory mediators such as pro-inflammatory cytokines (e.g. interleukin (IL)-1beta), which modulate drug reward, dependence, and tolerance as well as analgesic properties. Drugs of abuse may directly activate microglial and astroglial cells via ligation of Toll-like receptors (TLRs), which mediate the innate immune response to pathogens as well as xenobiotic agents (e.g. drugs of abuse). The present review focuses on understanding the immunologic mechanism(s) whereby stress primes or sensitizes the neuroinflammatory response to drugs of abuse and explores whether stress- and GC-induced sensitization of neuroimmune processes predisposes individuals to drug abuse liability and the role of neuroinflammatory mediators in the development of drug addiction. PMID- 21256957 TI - Maintenance of immune hyporesponsiveness to melanosomal proteins by DHICA mediated antioxidation: Possible implications for autoimmune vitiligo. AB - Melanocyte destruction in the skin of vitiligo patients has been considered to be a consequence of an autoimmune response against melanosomal proteins. However, little is known about the molecular mechanisms by which the immune system recognizes these sequestered intracellular self-proteins, which are confined in specialized organelles termed melanosomes, and is provoked into an autoimmune response to melanocytes. Here, we utilize a sucrose density-gradient ultracentrifugation protocol to enrich melanosomal components from dopachrome tautomerase (Dct)-mutant or wild-type melanocytes exposed to a pulse of hydrogen peroxide at a noncytotoxic concentration to evaluate their immunogenicity in mice challenged with the corresponding melanosomal proteins. The results demonstrate that enhanced humoral and cellular immune responses to a challenge with late stage melanosomal proteins, especially with those derived from Dct-mutant melanocytes, are found in the immunized mice. To elucidate whether a reduced 5,6 dihydroxyindole-2-carboxylic acid (DHICA) content in melanin might cause a loss in antioxidative protection to the proteins, we incubated these melanosomal proteins in vitro with synthetic 5,6-dihydroindole (DHI)-melanin or DHI/DHICA (1:1)-melanin and then used them to immunize mice. T cell proliferation and IgG antibody responsiveness to the challenges were significantly induced by melanosomal proteins treated with DHI-melanin, but not by those treated with DHI/DHICA (1:1)-melanin. Moreover, we observed that melanosomal proteins derived from Dct-mutant melanocytes are subject to oxidative modifications that alter their antigenic configurations to attain an enhanced immunogenicity compared with those derived from wild-type melanocytes. From these results, we conclude that DHICA-mediated antioxidation plays a critical role in the maintenance of immune hyporesponsiveness to melanosomal proteins. PMID- 21256958 TI - Inhibition of tubulin polymerization by hypochlorous acid and chloramines. AB - Protein thiol oxidation and modification by nitric oxide and glutathione are emerging as common mechanisms to regulate protein function and to modify protein structure. Also, thiol oxidation is a probable outcome of cellular oxidative stress and is linked to degenerative disease progression. We assessed the effect of the oxidants hypochlorous acid and chloramines on the cytoskeletal protein tubulin. Total cysteine oxidation by the oxidants was monitored by labeling tubulin with the thiol-selective reagent 5-iodoacetamidofluorescein; by reaction with Ellman's reagent, 5,5'-dithiobis(2-nitrobenzoic acid); and by detecting interchain tubulin disulfides by Western blot under nonreducing conditions. Whereas HOCl induced both cysteine and methionine oxidation of tubulin, chloramines were predominantly cysteine oxidants. Cysteine oxidation of tubulin, rather than methionine oxidation, was associated with loss of microtubule polymerization activity, and treatment of oxidized tubulin with disulfide reducing agents restored a considerable portion of the polymerization activity that was lost after oxidation. By comparing the reactivity of hypochlorous acid and chloramines with the previously characterized oxidants, peroxynitrite and the nitroxyl donor Angeli's salt, we have identified tubulin thiol oxidation, not methionine oxidation or tyrosine nitration, as a common outcome responsible for decreased polymerization activity. PMID- 21256959 TI - Effect of nitric oxide on neointimal hyperplasia based on sex and hormone status. AB - Nitric oxide (NO)-based therapies decrease neointimal hyperplasia; however, studies have been performed only in male animal models. Thus, we sought to evaluate the effect of NO on vascular smooth muscle cells (VSMC) in vitro and neointimal hyperplasia in vivo based on sex and hormone status. In hormone replete medium, male VSMC proliferated at greater rates than female VSMC. In hormone-depleted medium, female VSMC proliferated at greater rates than male VSMC. However, in both hormone environments, NO inhibited proliferation and migration to a greater extent in male compared to female VSMC. These findings correlated with greater G0/G1 cell cycle arrest and changes in cell cycle protein expression in male compared to female VSMC after exposure to NO. Next, the rat carotid artery injury model was used to assess the effect of NO on neointimal hyperplasia in vivo. Consistent with the in vitro data, NO was significantly more effective at inhibiting neointimal hyperplasia in hormonally intact males compared to females using weight-based dosing. An increased weight-based dose of NO in females was able to achieve efficacy equal to that in males. Surprisingly, NO was less effective at inhibiting neointimal hyperplasia in castrated animals of both sexes. In conclusion, these data suggest that NO inhibits neointimal hyperplasia more effectively in males compared to females and in hormonally intact compared to castrated rats, indicating that the effects of NO in the vasculature may be sex- and hormone-dependent. PMID- 21256960 TI - Dicer activity in neural crest cells is essential for craniofacial organogenesis and pharyngeal arch artery morphogenesis. AB - MicroRNAs (miRNAs) play important roles in regulating gene expression during numerous biological/pathological processes. Dicer encodes an RNase III endonuclease that is essential for generating most, if not all, functional miRNAs. In this work, we applied a conditional gene inactivation approach to examine the function of Dicer during neural crest cell (NCC) development. Mice with NCC-specific inactivation of Dicer died perinatally. Cranial and cardiac NCC migration into target tissues was not affected by Dicer disruption, but their subsequent development was disturbed. NCC derivatives and their associated mesoderm-derived cells displayed massive apoptosis, leading to severe abnormalities during craniofacial morphogenesis and organogenesis. In addition, the 4th pharyngeal arch artery (PAA) remodeling was affected, resulting in interrupted aortic arch artery type B (IAA-B) in mutant animals. Taken together, our results show that Dicer activity in NCCs is essential for craniofacial development and pharyngeal arch artery morphogenesis. PMID- 21256961 TI - A novel excipient, 1-perfluorohexyloctane shows limited utility for the oral delivery of poorly water-soluble drugs. AB - The applicability of the semi-fluorinated alkane 1-perfluorohexyloctane (F6H8) as a novel excipient in lipid based drug delivery systems was studied. Solubility studies of 11 poorly water soluble drugs (cinnarizine, danazol, estradiol, fenofibrate, griseofulvin, halofantrine, lidocaine, prednisolone, probucol, rolipram and siramesine) showed significantly lower equilibrium solubility in F6H8 compared to soy bean oil (long chain triglyceride). F6H8 was miscible with medium chain triglycerides (MCT) but not miscible with long chain triglycerides, neither was pure F6H8 nor the mixture F6H8:MCT (1:1) miscible with 7 commonly used surfactants (Cremophor EL, Span 20, Span 80, Labrasol, Softigen 767 and Gelucire 44/14, polysorbate 80). In vitro lipolysis studies confirmed that F6H8 was non-digestible. F6H8:MCT (1:1) showed initially faster lipolysis compared to pure MCT. Thus, final phase lipolysis was lower indicating that F6H8 may affect the lipolysis of MCT. However, in vivo bioavailability studies in rats showed the same plasma concentration-time profiles when dosing 10mg/kg halofantrine at two dose levels of F6H8, MCT or F6H8:MCT (1:1) (AUC ranged from 3058 to 3447hng/ml, T(max)~6.0h, C(max) ranged from 168 to 265mg/ml). Generally, the addition of polysorbate 80 shortened the time to reach C(max) (T(max) ranged 1.3-4.5h), but had limited effect on the bioavailability from F6H8 or MCT in combination with polysorbate 80 (4:1) (AUC ranged from 3807 to 4403 (hng/ml)). Although a synergistic effect was obtained with halofantrine in F6H8:MCT:polysorbate 80 (2:2:1) (AUC 5574+/-675hng/ml; mean+/-SEM), it was not superior to dosing halofantrine in pure polysorbarte 80 (AUC 7370+/-579hng/ml; mean+/-SEM). The applicability of F6H8 as an excipient for future use in lipid based formulations for poorly water soluble drugs is therefore considered to be very limited. PMID- 21256962 TI - Non-invasive imaging of skin physiology and percutaneous penetration using fluorescence spectral and lifetime imaging with multiphoton and confocal microscopy. AB - New multiphoton and confocal microscope technologies and fluorescence lifetime imaging techniques are now being used to non-invasively image, in space (three dimensions),in time, in spectra, in lifetime and in fluorescence anisotropy (total of 7 dimensions), fluorescent molecules in in situ and in vivo biological tissue, including skin. The process involves scanning a 2D area and measuring fluorescence at a given tissue depth below the surface after excitation by a laser beam with a wavelength within the one-photon or two-photon absorption band of the fluorophores followed by the stacking together of a series of 2D images from different depths to reconstruct the full spatial structure of the sample. Our aim in this work is to describe the principles, opportunities, limitations and applications of this new technology and its application in defining skin morphology, disease and skin penetration in vitro and in vivo by drugs, chemicals and nanoparticles. A key emphasis is in the use of fluorescence lifetime imaging to add additional specificity and quantitation to the detection of the various exogenous chemicals and nanoparticles that may be applied to the skin as well as endogenous fluorescent species in the skin. Examples given include equipment configuration; components in skin autofluorescence in various skin strata; imaging and quantification of coexisting drugs and their metabolites; skin pH; nanoparticle zinc oxide skin penetration; liposome delivery of drugs to deeper tissues; and observations in skin ageing and in various skin diseases. PMID- 21256964 TI - Separation and purification of Escherichia coli-expressed human thymosin-alpha1 using affinity chromatography and high-performance liquid chromatography. AB - In this study, a human thymosin-alpha1 (hTalpha1) fusion protein was overexpressed in Escherichia coli (E. coli). The hexahistidine-tagged hTalpha1 fusion protein was obtained in soluble form in cells of the engineered E. coli strain BL21 (DE3)/pET-28a-hTalpha1 that had been induced with isopropyl -D-1 thiogalactopyranoside (IPTG). The recombinant protein accounted for approximately 50-60% of the total protein. We then developed and validated a separation method for hTalpha1 from E. coli cells based on thermal denaturation, nickel-resin affinity chromatography and high-performance liquid chromatography. The purification method showed good reproducibility and was easy to operate. Purified recombinant hTalpha1 of high homogeneity was characterized and found to be of high purity (over 99%), as determined by high-voltage electrophoresis and high performance liquid chromatography analysis. Isoelectric focusing analysis indicated a pI of approximately 4.0, and full wavelength screening showed an optimal absorbance wavelength at around 214nm. PMID- 21256965 TI - Identification, molecular characterization and expression analysis of a mucosal C type lectin in the eastern oyster, Crassostrea virginica. AB - Lectins are well known to actively participate in the defense functions of vertebrates and invertebrates where they play an important role in the recognition of foreign particles. They have also been reported to be involved in other processes requiring carbohydrate-lectin interactions such as symbiosis or fertilization. In this study, we report a novel putative C-type lectin (CvML) from the eastern oyster Crassostrea virginica and we investigated its involvement in oyster physiology. The cDNA of this lectin is 610 bp long encoding for a 161 residue protein. CvML presents a signal peptide and a single carbohydrate recognition domain (CRD) which contains a YPD motif and two putative conserved sites, WID and DCM, for calcium binding. CvML transcripts were expressed in mucocytes lining the epithelium of the digestive gland and the pallial organs (mantle, gills, and labial palps) but were not detected in other tissues including hemocytes. Its expression was significantly up-regulated following starvation or bacterial bath exposure but not after injection of bacteria into oyster's adductor muscle. These results highlight the potential role of CvML in the interactions between oyster and waterborne microorganisms at the pallial interfaces with possible involvement in physiological functions such as particle capture or mucosal immunity. PMID- 21256967 TI - A wavelet-based method for measuring the oscillatory dynamics of resting-state functional connectivity in MEG. AB - Determining the dynamics of functional connectivity is critical for understanding the brain. Recent functional magnetic resonance imaging (fMRI) studies demonstrate that measuring correlations between brain regions in resting-state activity can be used to reveal intrinsic neural networks. To study the oscillatory dynamics that underlie intrinsic functional connectivity between regions requires high temporal resolution measures of electrophysiological brain activity, such as magnetoencephalography (MEG). However, there is a lack of consensus as to the best method for examining connectivity in resting-state MEG data. Here we adapted a wavelet-based method for measuring phase-locking with respect to the frequency of neural oscillations. This method employs anatomical MRI information combined with MEG data using the minimum norm estimate inverse solution to produce functional connectivity maps from a "seed" region to all other locations on the cortical surface at any and all frequencies of interest. We test this method by simulating phase-locked oscillations at various points on the cortical surface, which illustrates a substantial artifact that results from imperfections in the inverse solution. We demonstrate that normalizing resting state MEG data using phase-locking values computed on empty room data reduces much of the effects of this artifact. We then use this method with eight subjects to reveal intrinsic interhemispheric connectivity in the auditory network in the alpha frequency band in a silent environment. This spectral resting-state functional connectivity imaging method may allow us to better understand the oscillatory dynamics underlying intrinsic functional connectivity in the human brain. PMID- 21256966 TI - Stochastic tractography study of Inferior Frontal Gyrus anatomical connectivity in schizophrenia. AB - BACKGROUND: Abnormalities within language-related anatomical structures have been associated with clinical symptoms and with language and memory deficits in schizophrenia. Recent studies suggest disruptions in functional connectivity within the Inferior Frontal Gyrus (IFG) network in schizophrenia. However, due to technical challenges, anatomical connectivity abnormalities within this network and their involvement in clinical and cognitive deficits have not been studied. MATERIAL AND METHODS: Diffusion and anatomical scans were obtained from 23 chronic schizophrenia patients and 23 matched controls. The IFG was automatically segmented, and its white matter connections extracted and measured with newly developed stochastic tractography tools. Correlations between anatomical structures and measures of semantic processing were also performed. RESULTS: White Matter connections between the IFG and posterior brain regions followed two distinct pathways: dorsal and ventral. Both demonstrated left lateralization, but ventral pathway abnormalities were only found in schizophrenia. IFG volumes also showed left lateralization and abnormalities in schizophrenia. Further, despite similar laterality and abnormality patterns, IFG volumes and white matter connectivity were not correlated with each other in either group. Interestingly, measures of semantic processing correlated with white matter connectivity in schizophrenia and with gray matter volumes in controls. Finally, hallucinations were best predicted by both gray matter and white matter measures together. CONCLUSIONS: Our results suggest abnormalities within the ventral IFG network in schizophrenia, with white matter abnormalities better predicting semantic deficits. The lack of a statistical relationship between coexisting gray and white matter deficits might suggest their different origin and the necessity for a multimodal approach in future schizophrenia studies. PMID- 21256968 TI - Systematics and biogeography of Indo-Pacific ground-doves. AB - Ground-doves represent an insular bird radiation distributed across the Indo Pacific. The radiation comprises sixteen extant species, two species believed to be extinct and six species known to be extinct. In the present study, we present a molecular phylogeny for all sixteen extant species, based on two mitochondrial markers. We demonstrate that the Gallicolumba as currently circumscribed is not monophyletic and recommend reinstalling the name Alopecoenas for a monophyletic radiation comprising ten extant species, distributed in New Guinea, the Lesser Sundas and Oceania. Gallicolumba remains the name for six species confined to New Guinea the Philippines and Sulawesi. Although our phylogenetic analyses fail to support a single origin for the remaining Gallicolumba species, we suspect that the addition of nuclear sequence data may alter this result. Because a number of ground-dove taxa have gone extinct, it is difficult to assess biogeographical patterns. However, the Alopecoenas clade has clearly colonized many remote oceanic islands rather recently, with several significant water crossings. The Gallicolumba radiation(s), on the other hand, is significantly older and it is possible that diversification within that group may in part have been shaped by plate tectonics and corresponding re-arrangements of land masses within the Philippine and Sulawesi region. PMID- 21256969 TI - Chronic stress prior to hippocampal stroke enhances post-stroke spatial deficits in the ziggurat task. AB - Stress is one of the most important variables to determine recovery following stroke. We have previously reported that post-stroke exposure to either stress or corticosterone (CORT) alleviates hippocampal ischemic outcome. The present experiment expands previous findings by investigating the influence of exposure to stress prior to ischemic event. Rats received either daily restraint stress (1h/day; 16 consecutive days) or CORT (0.5mg/kg; 16 consecutive days) prior to focal ischemic stroke in the hippocampus induced by bilateral injection of endothelin-1 (ET-1). All experimental groups were then tested in the ziggurat task, a new task for spatial cognition. The stress+stroke group showed significant deficits in both hippocampal structure and function. No deleterious effect of pre-stroke exposure to CORT was found in the CORT+stroke group. Our results indicate that a history of chronic stress sensitizes hippocampal cells to the damaging consequences of focal ischemia. The opposing effects of CORT-related experiences in this study not only reflect the diversity of glucocorticoid actions in the stress response, but also provide evidence that elevated CORT in the absence of emotional disturbance is not sufficient to produce hippocampal deficit. PMID- 21256971 TI - Duplication of calsequestrin genes in teleosts: molecular characterization in the Senegalese sole (Solea senegalensis). AB - Calsequestrin is a moderate-affinity, high-capacity Ca(2+) binding protein in the sarcoplasmic reticulum of skeletal and cardiac muscle that seems to act as an intralumenal Ca(2+) buffer. Two different isoforms have been described in mammals, the skeletal and cardiac isoforms, encoded by CASQ1 and CASQ2 genes, respectively. In this study, we present molecular phylogenetic evidence of a gene duplication event of both calsequestrin genes in teleosts, referred to as casq1a/casq1b and casq2a/casq2b. We obtained the entire cDNAs encoding the four genes in the Senegalese sole (Solea senegalensis Kaup). Main features and sequence identities with other fish and mammalian calsequestrins are described. Expression profiles during larval development and in juvenile tissues were analyzed using a real-time PCR approach. In juvenile fish, casq1a and casq1b were highly expressed in skeletal muscle, whereas the highest casq2a and casq2b transcript levels were detected in heart and brain, respectively. During metamorphosis, casq2a and casq1b expression remained unchanged. In contrast, casq1a and casq2b mRNAs exhibited a continuous increase from the beginning of metamorphosis until post-metamorphosis. Transcriptional regulation of casq1 and casq2 genes by thyroid hormones (THs) was also evaluated. Larvae exposed to the goitrogen thiourea (TU) exhibited higher casq1a mRNA levels than untreated control, whereas expression of the remaining genes did not vary significantly. Moreover, addition of exogenous T4 hormone to TU-treated larvae increased the casq1a steady-state levels with respect to the untreated control at metamorphosis climax. Comprehensively, these results demonstrate the existence of four calsequestrin genes in teleosts differentially regulated by THs. PMID- 21256970 TI - Alcohol-related amnesia and dementia: animal models have revealed the contributions of different etiological factors on neuropathology, neurochemical dysfunction and cognitive impairment. AB - Chronic alcoholism is associated with impaired cognitive functioning. Over 75% of autopsied chronic alcoholics have significant brain damage and over 50% of detoxified alcoholics display some degree of learning and memory impairment. However, the relative contributions of different etiological factors to the development of alcohol-related neuropathology and cognitive impairment are questioned. One reason for this quandary is that both alcohol toxicity and thiamine deficiency result in brain damage and cognitive problems. Two alcohol related neurological disorders, alcohol-associated dementia and Wernicke Korsakoff syndrome have been modeled in rodents. These pre-clinical models have elucidated the relative contributions of ethanol toxicity and thiamine deficiency to the development of dementia and amnesia. What is observed in these models- from repeated and chronic ethanol exposure to thiamine deficiency--is a progression of both neural and cognitive dysregulation. Repeated binge exposure to ethanol leads to changes in neural plasticity by reducing GABAergic inhibition and facilitating glutamatergic excitation, long-term chronic ethanol exposure results in hippocampal and cortical cell loss as well as reduced hippocampal neurotrophin protein content critical for neural survival, and thiamine deficiency results in gross pathological lesions in the diencephalon, reduced neurotrophic protein levels, and neurotransmitters levels in the hippocampus and cortex. Behaviorally, after recovery from repeated or chronic ethanol exposure there is impairment in working or episodic memory that can recover with prolonged abstinence. In contrast, after thiamine deficiency there is severe and persistent spatial memory impairments and increased perseverative behavior. The interaction between ethanol and thiamine deficiency does not produce more behavioral or neural pathology, with the exception of reduction of white matter, than long-term thiamine deficiency alone. PMID- 21256973 TI - Noggin. AB - Metabologens initiate, promote and maintain morphogenesis and adult tissue homeostasis. Bone morphogenetic proteins (BMPs) which belong to the transforming growth factor-beta (TGF-beta) superfamily, represent a major class of metabologens that regulate ectoderm, mesoderm and endoderm derived tissue formation. In order to temporally and spatially control BMP initiated signaling cascades, a tight regulatory network is needed to maintain concinnity. There are a number of ways how BMP signaling can be inhibited or more likely be modified, among which the direct extracellular inhibition through cysteine-knot containing proteins from the DAN-, the twisted gastrulation-, chordin- and noggin-family is a classic. This review focuses on noggin and its impact on the vast array of BMP driven actions and thereby invites the ever-growing BMP research field to (re-) investigate noggin's function in detail. PMID- 21256974 TI - Role of quercetin on mitomycin C induced genotoxicity: analysis of micronucleus and chromosome aberrations in vivo. AB - Quercetin, a flavonol group of plant flavonoid, has generated immense interest because of its potential antioxidant, anti-proliferative, chemoprotective, anti inflammatory and gene expression modulating properties. However, the pro-oxidant chemistry of quercetin is important as it is related to the generation of mutagenic quinone-type metabolites. In the present study, 25mg/kg, 50mg/kg and 100mg/kg of quercetin given through the intra peritoneal (i.p.) route induced 2.31 +/- 0.27%, 4.72 +/- 0.58% and 6.38 +/- 0.68% (control value=0.67 +/- 0.30%) respectively, of cells with micronucleus (MN) in polychromatic erythrocytes in bone marrow cells and 10.93 +/- 0.98%, 10.00 +/- 0.89% and 14.27 +/- 3.94% (control 2.61 +/- 0.48) of cells with chromosome aberrations (CA) following 24h of the treatments. Higher frequencies of MN and CA were also observed after 48h of the treatments. To verify the effect of route of treatment on the quercetin induced damage, 100mg/kg b.w. was given through oral route which declined frequency of MN (P<0.001) as well as CA (P<0.05) as compared to the i.p. route for the same dose. Quercetin also induced higher frequency of metaphases with sticky chromosomes and C-mitosis. Pre-treatment with quercetin significantly reduced the frequency of mitomycin C (MMC) induced MN as well as CA, but no clear correlation between the dose and effect could be observed. Further studies are required to elucidate the possible interaction of quercetin with DNA as well as with other DNA damaging agents like MMC in vivo. The protective action of quercetin was not enhanced when given orally. Our findings suggest that quercetin may result in genomic instability in the tested dose range and significant reduction in MMC induced genotoxicity in the highest dose tested. These effects of quercetin are to be taken into consideration while evaluating the possible use of quercetin as a therapeutic agent. PMID- 21256972 TI - c-Yes regulates cell adhesion at the blood-testis barrier and the apical ectoplasmic specialization in the seminiferous epithelium of rat testes. AB - During spermatogenesis, extensive junction restructuring takes place at the blood testis barrier (BTB) and the Sertoli cell-spermatid interface known as the apical ectoplasmic specialization (apical ES, a testis-specific adherens junction) in the seminiferous epithelium. However, the mechanism(s) that regulates these critical events in the testis remains unknown. Based on the current concept in the field, changes in the phosphorylation status of integral membrane proteins at these sites can induce alterations in protein endocytosis and recycling, causing junction restructuring. Herein, c-Yes, a non-receptor protein tyrosine kinase, was found to express abundantly at the BTB and apical ES stage-specifically, coinciding with junction restructuring events at these sites during the seminiferous epithelial cycle of spermatogenesis. c-Yes also structurally associated with adhesion proteins at the BTB (e.g., occludin and N-cadherin) and the apical ES (e.g., beta1-integrin, laminins beta3 and gamma3), possibly to regulate phosphorylation status of proteins at these sites. SU6656, a selective c Yes inhibitor, was shown to perturb the Sertoli cell tight junction-permeability barrier in vitro, which is mediated by changes in the distribution of occludin and N-cadherin at the cell-cell interface, moving from cell surface to cytosol, thereby destabilizing the tight junction-barrier. However, this disruptive effect of SU6656 on the barrier was blocked by testosterone. Furthermore, c-Yes is crucial to maintain the actin filament network in Sertoli cells since a blockade of c-Yes by SU6656 induced actin filament disorganization. In summary, c-Yes regulates BTB and apical ES integrity by maintaining proper distribution of integral membrane proteins and actin filament organization at these sites. PMID- 21256975 TI - Two-dimensional immunoblot analysis of antigenic proteins of Spirometra plerocercoid recognized by human patient sera. AB - Sparganosis is caused by invasion of Spirometra plerocercoid into various tissues/organs. Subcutaneous sparganosis can be diagnosed and treated by worm removal, while visceral/cerebral sparganosis is not easy to diagnose. The diagnosis depends largely on the detection of specific antibodies circulating in the patients' sera. Previous studies demonstrated that 31 and 36kDa proteins of the sparganum invoked specific and sensitive antibody responses, but also showed cross reactions with cysticercosis sera. We enriched protein fractions containing 31-36kDa through gel filtration and examined immune recognition pattern against the patient sera by 2-dimensional electrophoresis (2-DE) followed by immunoblotting. Serum samples from sparganosis patients recognized 8-10 protein spots of 31 and 36kDa with different isoelectric point (pI) values with variable combinations, in which four spots of 31kDa with pIs 3.4, 3.9, 4.0 and 4.1, and one 36kDa spot (pI 3.5) appeared to be specifically reactive. One 31kDa protein spot with pI 3.3 and two spots of 36kDa with pIs 3.3 and 3.5 reacted crossly with neurocysticercosis sera. Neither sera from patients with other parasitic infections nor those from healthy controls showed positive reaction. Two DE/immunoblot analysis might be highly available in differential serodiagnosis of human sparganosis. PMID- 21256976 TI - Neuroarchitecture of the arcuate body in the brain of the spider Cupiennius salei (Araneae, Chelicerata) revealed by allatostatin-, proctolin-, and CCAP immunocytochemistry and its evolutionary implications. AB - Here we describe the neuronal organization of the arcuate body in the brain of the wandering spider Cupiennius salei. The internal anatomy of this major brain center is analyzed in detail based on allatostatin-, proctolin-, and crustacean cardioactive peptide (CCAP)-immunohistochemistry. Prominent neuronal features are demonstrated in graphic reconstructions. The stainings revealed that the neuroarchitecture of the arcuate body is characterized by several distinct layers some of which comprise nerve terminals that are organized in columnar, palisade like arrays. The anatomy of the spider's arcuate body exhibits similarities as well as differences when compared to the central complex in the protocerebrum of the Tetraconata. Arguments for and against a possible homology of the arcuate body of the Chelicerata and the central complex of the Tetraconata and their consequences for the understanding of arthropod brain evolution are discussed. PMID- 21256977 TI - AskHERMES: An online question answering system for complex clinical questions. AB - OBJECTIVE: Clinical questions are often long and complex and take many forms. We have built a clinical question answering system named AskHERMES to perform robust semantic analysis on complex clinical questions and output question-focused extractive summaries as answers. DESIGN: This paper describes the system architecture and a preliminary evaluation of AskHERMES, which implements innovative approaches in question analysis, summarization, and answer presentation. Five types of resources were indexed in this system: MEDLINE abstracts, PubMed Central full-text articles, eMedicine documents, clinical guidelines and Wikipedia articles. MEASUREMENT: We compared the AskHERMES system with Google (Google and Google Scholar) and UpToDate and asked physicians to score the three systems by ease of use, quality of answer, time spent, and overall performance. RESULTS: AskHERMES allows physicians to enter a question in a natural way with minimal query formulation and allows physicians to efficiently navigate among all the answer sentences to quickly meet their information needs. In contrast, physicians need to formulate queries to search for information in Google and UpToDate. The development of the AskHERMES system is still at an early stage, and the knowledge resource is limited compared with Google or UpToDate. Nevertheless, the evaluation results show that AskHERMES' performance is comparable to the other systems. In particular, when answering complex clinical questions, it demonstrates the potential to outperform both Google and UpToDate systems. CONCLUSIONS: AskHERMES, available at http://www.AskHERMES.org, has the potential to help physicians practice evidence-based medicine and improve the quality of patient care. PMID- 21256979 TI - Evaluation and application of a molecular method to assess the composition of strongylid nematode populations in sheep with naturally acquired infections. AB - We evaluated the performance of a PCR method for the diagnosis of naturally acquired strongylid nematode infections in sheep (n = 470; in a temperate climatic zone of south-eastern Australia), using a panel of 100 'negative control' samples from sheep known not to harbour parasitic helminths. We compared the diagnostic sensitivity (98%) and specificity (100%) of this assay against a conventional faecal flotation method and also established a system to rank the contribution of particular strongylid nematodes to the faecal egg counts (FECs) from 'mixed infections' in individual sheep. The testing of faecal samples herein revealed that Teladorsagia circumcincta (80%) and Trichostrongylus spp. (66%) were most prevalent, followed by Chabertia ovina (33%), Oesophagostomum venulosum (28%) and Haemonchus contortus (1%). For the majority of sheep in this study, T. circumcincta and Trichostrongylus spp. represented the largest proportion of strongylid eggs in faecal samples from individual sheep. This is the first large scale prevalence survey of gastrointestinal nematodes in live sheep using a molecular tool. The ability to rapidly rank strongylid nematodes according to their contribution to mixed infections represents a major advantage over routine coprological methods. This PCR tool has the potential to replace the conventional technique of larval culture. Future efforts will focus on enhancing and adapting this molecular method for high throughput application in routine, diagnostic settings. PMID- 21256978 TI - Diaphragmatic electromyography during cryoballoon ablation: a novel concept in the prevention of phrenic nerve palsy. AB - BACKGROUND: Hemidiaphragmatic paralysis is the most frequent complication associated with cryoballoon ablation for atrial fibrillation. To date, no preventive strategy has proved effective. OBJECTIVE: We sought to assess the feasibility of diaphragmatic electromyography during cryoballoon ablation, explore the relationship between altered signals and phrenic nerve palsy, and define characteristic changes that herald hemidiaphragmatic paralysis. METHODS: Cryoballoon ablation was performed in the right superior pulmonary vein or superior vena cava in 16 mongrel dogs weighing 37.7 +/- 2.4 kg, at sites determined by phrenic nerve capture. During ablation, the phrenic nerve was paced at 60 bpm from the superior vena cava while recording diaphragmatic compound motor action potentials (CMAPs) by esophageal decapolar catheters. Diaphragmatic excursion was monitored by fluoroscopy and abdominal palpation. RESULTS: Before ablation, the CMAP amplitude was 592 (interquartile range 504, 566) MUV, initial latency 21.5 +/- 4.2 ms, peak latency 64.7 +/- 21.1 ms, and duration 101.7 +/- 13.3 ms. Hemidiaphragmatic paralysis was obtained in all dogs 62 +/- 34 seconds into the cryoapplication. The CMAP amplitude decreased exponentially, with no patterned changes in latencies and duration. Discriminatory analyses by receiver operating curve characteristics identified a 30% reduction in CMAP amplitude as the most predictive cutoff value for hemidiaphragmatic paralysis (c-statistic 0.965; P<.0001). This criterion presaged diaphragmatic paralysis, as detected by abdominal palpation, by 31 +/- 23 seconds. CONCLUSION: Diaphragmatic electromyographic signals could be reliably recorded during cryoballoon ablation. An exponential decrease in CMAP amplitude precedes diaphragmatic paralysis, with a 30% reduction yielding the best discriminatory potential. A promising safety margin was detected, which merits prospective validation. PMID- 21256980 TI - Current status of the taxonomic position of Fusarium oxysporum formae specialis cubense within the Fusarium oxysporum complex. AB - Fusarium oxysporum is an asexual fungal species that includes human and animal pathogens and a diverse range of nonpathogens. Pathogenic and nonpathogenic strains of this species can be distinguished from each other with pathogenicity tests, but not with morphological analysis or sexual compatibility studies. Substantial genetic diversity among isolates has led to the realization that F. oxysporum represents a complex of cryptic species. F. oxysporum f. sp cubense (Foc), causal agent of Fusarium wilt of banana, is one of the more than 150 plant pathogenic forms of F. oxysporum. Multi-gene phylogenetic studies of Foc revealed at least eight phylogenetic lineages, a finding that was supported by random amplified polymorphic DNAs, restriction fragment length polymorphisms and amplified fragment length polymorphisms. Most of these lineages consist of isolates in closely related vegetative compatibility groups, some of which possess opposite mating type alleles, MAT-1 and MAT-2; thus, the evolutionary history of this fungus may have included recent sexual reproduction. The ability to cause disease on all or some of the current race differential cultivars has evolved convergently in the taxon, as members of some races appear in different phylogenetic lineages. Therefore, various factors including co-evolution the plant host and horizontal gene transfer are thought to have shaped the evolutionary history of Foc. This review discusses the evolution of Foc as a model formae specialis in F. oxysporum in relation to recent research findings involving DNA-based studies. PMID- 21256981 TI - Selective pressure for allelic diversity in SeM of Streptococcus equi does not affect immunoreactive proteins SzPSe or Se18.9. AB - Streptococcus equi, a clone or biovar of an ancestral Streptococcus zooepidemicus of Lancefield group C causes equine strangles, a highly contagious tonsillitis and lymphadenitis of the head and neck. At least 74 alleles based on N-terminal amino acid sequence of the anti-phagocytic SeM have been observed among isolates of S. equi from N. America, Europe and Japan. A d(N)/d(S) ratio of 5.93 for the 5' region of sem is indicative of positive selective pressure. The aim of this study was to determine whether variations in SeM were accompanied by variations in the surface exposed SzPSe and secreted Se18.9, both of which bind to equine tonsillar epithelium and, along with SeM, elicit strong nasopharyngeal IgA responses during convalescence. Sequences of genes for these proteins from 25 S. equi expressing 19 different SeM alleles isolated over 40 years in different countries were compared. No variation was observed in szpse, except for an Australian isolate with a deletion of a single repeat in the 3' end of the gene. Interestingly, only two SNP loci were detected in se18.9 compared to 93 and 55 in sem and szpse, respectively. The high frequency of nucleotide substitutions in szpse may be related to its mosaic structure since this gene in S. zooepidemicus exists in a variety of combinations of sequence segments and has a central hypervariable region that includes exogenous DNA sequence based on an atypical G C percentage. In summary, the results of this study document very different responses of streptococcal genes for 3 immunoreactive proteins to selection pressure of the nasopharyngeal mucosal immune response. PMID- 21256982 TI - Distinctive differences in long terminal repeat sequences between gamma1 endogenous retroviruses of African and Eurasian suid species. AB - Diversity of long terminal repeats (LTRs) from gamma1 endogenous retroviruses (ERVs) was analysed by DNA sequencing in 10 species of the family Suidae (suids, pigs and hogs). Phylogenetic analysis separated LTR sequences into two groups which correlated approximately with either the previously described cluster I and III, or the clusters II, IV and V. Interestingly, a specific LTR exhibiting a novel molecular rearrangement was identified exclusively within African host species when compared to LTRs previously reported from known ERVs in the domestic pig (Sus scrofa). Furthermore, other sections of LTRs appear to be unique to African suids as suggested by phylogenetic analysis. These differences between African and Eurasian ERV lineages show that these ERVs belong to different viral sub-populations, implying coevolution of endogenous viral sequences with their host species and providing no evidence of transfer of viral sequences between African and Eurasian suids. PMID- 21256983 TI - Efficient reduction of Cys110 thiyl radical by glutathione in human myoglobin. AB - Human myoglobin (hMb) possesses a cysteine (Cys) residue which is rare among mammalian Mbs. To investigate the effects of this unique Cys residue at the amino acid position 110 (Cys110) on hMb reactions, we studied the reactions of wild type (WT) methMb and its alanine mutant at Cys110 (C110A) with H(2)O(2), particularly in the presence of reduced glutathione (GSH) which is well known as a reducing agent. The formation rates of the ferryloxo (Fe(IV)=O) species by H(2)O(2) under air were about the same for WT and C110A methMbs, whereas the protein decomposed more in the case of WT than C110A hMb. With the addition of GSH, hMb consumed H(2)O(2) faster and decomposition of the protein decreased, where the effects were more prominent in WT than C110A hMb. The radicals produced by the reaction with H(2)O(2) decreased significantly due to the addition of 1mM GSH in the case of WT hMb, but not in the case of C110A hMb. These results show that GSH reduces H(2)O(2)-induced protein decomposition due to reduction of the C110-thiyl radical in WT hMb by electron transfer. PMID- 21256984 TI - Characterization of two novel nodule-enhanced alpha-type carbonic anhydrases from Lotus japonicus. AB - Two cDNA clones coding for alpha-type carbonic anhydrases (CA; EC 4.2.1.1) in the nitrogen-fixing nodules of the model legume Lotus japonicus were identified. Functionality of the full-length proteins was confirmed by heterologous expression in Escherichia coli and purification of the encoded polypeptides. The developmental expression pattern of LjCAA1 and LjCAA2 revealed that both genes code for nodule enhanced carbonic anhydrase isoforms, which are induced early during nodule development. The genes were slightly to moderately down-regulated in ineffective nodules formed by mutant Mesorhizobium loti strains, indicating that these genes may also be involved in biochemical and physiological processes not directly linked to nitrogen fixation/assimilation. The spatial expression profiling revealed that both genes were expressed in nodule inner cortical cells, vascular bundles and central tissue. These results are discussed in the context of the possible roles of CA in nodule carbon dioxide (CO(2)) metabolism. PMID- 21256985 TI - Ribosomal protein S18e as a putative molecular staple for the 18S rRNA 3'-major domain core. AB - Ribosomal protein S18e is a structural constituent of the 40S ribosomal subunit. We obtained recombinant human ribosomal protein S18e and studied its structural and functional properties. With the use of CD spectroscopy we showed that the protein secondary structure is mainly helical and stable in the neutral pH range and at low urea concentrations. Applying multiple sequence alignment, we revealed that the protein structure has characteristics of the eukaryotic members of the ribosomal protein S13p family with additional extensions in the N-terminal and central parts that contain alpha-helices according to our prediction. S18e binds specifically and independently to an RNA transcript corresponding to the evolutionary core of the 3'-major domain of 18S rRNA. Hydroxyl radical footprinting showed that the binding site of S18e on the 18S rRNA is similar in general to the binding site of S13p on the 16S rRNA in the 30S ribosomal subunit, albeit the rRNA regions attributed to binding of the eukaryote-specific extensions of S18e were also detected. With magnesium ion concentration close to cellular conditions (2mM), protein binding caused substantial rearrangements in the rRNA transcript making it compact in such a manner that helices H29/H30 and H41-H43 form a bundle resembling their arrangement in the ribosome. Thus, S18e seems to act as a molecular staple fixing the 18S rRNA 3'-major domain core. PMID- 21256986 TI - Solution structure of BTK-2, a novel hK(v)1.1 inhibiting scorpion toxin, from the eastern Indian scorpion Mesobuthus tamulus. AB - The three dimensional structure of a 32 residue three disulfide scorpion toxin, BTK-2, from the Indian red scorpion Mesobuthus tamulus has been determined using isotope edited solution NMR methods. Samples for structural and electrophysiological studies were prepared using recombinant DNA methods. Electrophysiological studies show that the peptide is active against hK(v)1.1 channels. The structure of BTK-2 was determined using 373 distance restraints from NOE data, 66 dihedral angle restraints from NOE, chemical shift and scalar coupling data, 6 constraints based on disulfide linkages and 8 constraints based on hydrogen bonds. The root mean square deviation (r.m.s.d) about the averaged co ordinates of the backbone (N, C(alpha), C') and all heavy atoms are 0.81 +/- 0.23A and 1.51 +/- 0.29A respectively. The backbone dihedral angles (phi and psi) for all residues occupy the favorable and allowed regions of the Ramachandran map. The three dimensional structure of BTK-2 is composed of three well defined secondary structural regions that constitute the alpha-beta-beta structural motif. Comparisons between the structure of BTK-2 and other closely related scorpion toxins pointed towards distinct differences in surface properties that provide insights into the structure-function relationships among this important class of voltage-gated potassium channel inhibiting peptides. PMID- 21256988 TI - Lipid substitution on low molecular weight (0.6-2.0 kDa) polyethylenimine leads to a higher zeta potential of plasmid DNA and enhances transgene expression. AB - Cationic polymers are desirable gene carriers because of their better safety profiles than viral delivery systems. Low molecular weight (MW) polymers are particularly attractive, since they display little cytotoxicity, but they are also ineffective for gene delivery. To create effective carriers from low MW polymers palmitic acid (PA) was substituted on 0.6-2.0 kDa polyethylenimines (PEIs) and their efficiency for plasmid DNA (pDNA) delivery was evaluated. The extent of lipid substitution was dependent on the lipid/PEI feed ratio and the polymer MW. While the hydrodynamic size of the polymer/pDNA complexes (polyplexes) increased or decreased depending on the extent of lipid substitution, the zeta potential of the assembled complexes was consistently higher as a result of lipid substitution. Lipid substitution generally increased the in vitro toxicity of the PEIs, but it was significantly lower than that of the 25 kDa branched PEI. The in vitro transfection efficiency of the lipid substituted polymers was higher than that of native PEIs, which were not at all effective. The delivery efficiency was proportional to the extent of lipid substitution as well as the polymer MW. This correlated with the increased uptake of lipid-substituted polyplexes, based on confocal microscopic investigations with FITC-labeled pDNA. The addition of chloroquine further increased the transfection efficiency of lipid-substituted PEIs, indicating that endosomal release was a limiting factor affecting the efficiency of these carriers. This study indicates that lipid substitution on low MW PEIs makes their assembly more effective, resulting in better delivery of pDNA into mammalian cells. PMID- 21256987 TI - Amelogenin-assisted ex vivo remineralization of human enamel: Effects of supersaturation degree and fluoride concentration. AB - The formation of organized nanocrystals that resemble enamel is crucial for successful enamel remineralization. Calcium, phosphate and fluoride ions, and amelogenin are important ingredients for the formation of organized hydroxyapatite (HAP) crystals in vitro. However, the effects of these remineralization agents on the enamel crystal morphology have not been thoroughly studied. The objective of this study was to investigate the effects of fluoride ions, supersaturation degree and amelogenin on the crystal morphology and organization of ex vivo remineralized human enamel. Extracted third molars were sliced thin and acid-etched to provide the enamel surface for immersion in different remineralization solutions. The crystal morphology and mineral phase of the remineralized enamel surface were analyzed by field emission-scanning electron microscopy, attenuated total reflection-Fourier transformed infrared and X-ray diffraction. The concentration of fluoride and the supersaturation degree of hydroxyapatite had significant effects on the crystal morphology and crystal organization, which varied from plate-like loose crystals to rod-like densely packed nanocrystal arrays. Densely packed arrays of fluoridated hydroxyapatite nanorods were observed under the following conditions: sigma(HAP)=10.2+/-2.0 with 1.5+/-0.5 mg l(-1) fluoride and 40+/-10 MUg ml(-1) amelogenin, pH 6.8+/-0.4. A phase diagram summarizes the conditions that form dense or loose hydroxyapatite nanocrystal structures. This study provides the basis for the development of novel dental materials for caries management. PMID- 21256989 TI - An in vitro study of two GAG-like marine polysaccharides incorporated into injectable hydrogels for bone and cartilage tissue engineering. AB - Natural polysaccharides are attractive compounds with which to build scaffolds for bone and cartilage tissue engineering. Here we tested two non-standard ones, HE800 and GY785, for the two-dimensional (2-D) and three-dimensional (3-D) culture of osteoblasts (MC3T3-E1) and chondrocytes (C28/I2). These two glycosaminoglycan-like marine exopolysaccharides were incorporated into an injectable silylated hydroxypropylmethylcellulose-based hydrogel (Si-HPMC) that has already shown its suitability for bone and cartilage tissue engineering. Results showed that, similarly to hyaluronic acid (HA) (the control), HE800 and GY785 significantly improved the mechanical properties of the Si-HPMC hydrogel and induced the attachment of MC3T3-E1 and C28/I2 cells when these were cultured on top of the scaffolds. Si-HPMC hydrogel containing 0.67% HE800 exhibited the highest compressive modulus (11kPa) and allowed the best cell dispersion, especially of MC3T3-E1 cells. However, these cells did not survive when cultured in 3-D within hydrogels containing HE800, in contrast to C28/I2 cells. The latter proliferated in the microenvironment or concentrically depending on the nature of the hydrogel. Among all the constructs tested the Si-HPMC hydrogels containing 0.34% HE800 or 0.67% GY785 or 0.67% HA presented the most interesting features for cartilage tissue engineering applications, since they offered the highest compressive modulus (9.5-11kPa) while supporting the proliferation of chondrocytes. PMID- 21256990 TI - Tissue plasminogen activator-containing polyurethane surfaces for fibrinolytic activity. AB - With the aim of minimizing thrombus formation in blood-contacting devices, tissue plasminogen activator (t-PA)-containing polyurethane (PU) materials have been developed. Cationic PU surfaces were prepared by grafting poly(dimethylaminoethyl methacrylate) and quaternizing the tertiary amino groups with iodomethane or 1,6 diiodohexane or alpha,alpha'-dichloro-p-xylene. The surfaces were characterized by water contact angles and X-ray photoelectron spectroscopy. The materials (PU CH(3)I, PU-I(CH(2))(6)I, PU-Cl) were treated with t-PA in Tris-buffered saline (pH 9.0) to give t-PA-loaded PU surfaces. The t-PA content of the surfaces was determined using radiolabeled t-PA. The quantities of t-PA taken up by the cationic surfaces were significantly greater than on the unmodified PU: approximately 14-fold greater for PU-Cl, 10-fold for PU-CH(3)I and 13-fold for PU I(CH(2))(6)I. The activity of the bound t-PA, as measured by a plasma clotting dissolution assay and a chromogenic substrate assay, was similar to that of normal, unbound t-PA. Release of t-PA from these materials in contact with plasma was measured using the labeled protein and was found to be the most rapid on the PU-CH(3)I material. This approach may have potential for the development of surfaces which can lyse clots that begin to form on them. PMID- 21256991 TI - Preoperative shock wave treatment enhances ischemic tissue survival, blood flow and angiogenesis in a rat skin flap model. AB - INTRODUCTION: Extracorporeal shock wave treatment (ESWT) has recently been shown to enhance skin flap survival. However, the bio-mechanisms operating during preoperative ESWT remain unclear. The aim of our study was to investigate whether preoperative ESWT can improve blood flow in ischemic skin flaps and to elucidate its possible mechanisms. METHODS: 14 male-rats were randomized into two groups and an oversized ventral random-pattern flap was raised. Experimental group received extracorporeal shock-wave treatment (ESWT) with an energy of 500 mJ/mm(2) seven days prior to total flap elevation, while control group received no treatment prior to total flap elevation. Seven days postoperatively, surviving flap area, perfused flap area, microvessel density and VEGF concentration were measured. RESULTS: Surviving flap area (59.43 +/- 14.72 % to 42.71 +/- 10.75 %, p = 0.026), perfused flap area (62.00 +/- 8.58 % to 45.14 +/- 10.50 %, p = 0.007), microvessel density (18.13 +/- 5.11 to 11.09 +/- 1.12, p = 0.016) and VEGF to total protein ratio (0.2107 +/- 0.0935 to 0.0123 +/- 0.0069, p = 0.008) were significantly elevated in the ESWT group. CONCLUSION: Preoperative ESWT can improve skin flap survival through enhanced topical blood perfusion and neovascularization via elevation of angio-active factors. PMID- 21256992 TI - Redox proteomics of fat globules unveils broad protein lactosylation and compositional changes in milk samples subjected to various technological procedures. AB - The Maillard reaction between lactose and proteins occurs during thermal treatment of milk and lactosylated beta-lactoglobulin, alpha-lactalbumin and caseins have widely been used to monitor the quality of dairy products. We recently demonstrated that a number of other whey milk proteins essential for nutrient delivery, defense against bacteria/virus and cellular proliferation become lactosylated during milk processing. The extent of their modification is associated with the harshness of product manufacturing. Since fat globule proteins are also highly important for the health-beneficial properties of milk, an evaluation of their lactosylation is crucial for a complete understanding of aliment nutritional characteristics. This is more important when milk is the unique dietary source, as in the infant diet. To this purpose, a sequential proteomic procedure involving an optimized milk fat globule (MFG) preparation/electrophoretic resolution, shot-gun analysis of gel portions for protein identification, selective trapping of lactosylated peptides by phenylboronate chromatography and their analysis by nanoLC-ESI-electron transfer dissociation (ETD) tandem MS was used for systematic characterization of fat globule proteins in milk samples subjected to various manufacturing procedures. Significant MFG protein compositional changes were observed between samples, highlighting the progressive adsorption of caseins and whey proteins on the fat globule surface as result of the technological process used. A significant lactosylation of MFG proteins was observed in ultra-high temperature sterilized and powdered for infant nutrition milk preparations, which well paralleled with the harshness of thermal treatment. Globally, this study allowed the identification of novel 157 non-redundant modification sites and 35 MFG proteins never reported so far as being lactosylated, in addition to the 153 ones ascertained here as present on other 21 MFG-adsorbed proteins whose nature was already characterized. Novel MFG proteins include components involved in nutrient delivery, defense response against pathogens and cellular proliferation/differentiation. Nutritional, biological and toxicological consequences of these findings are here discussed, highlighting their possible impact on children's diet. PMID- 21256993 TI - Digestion protocol for small protein amounts for nano-HPLC-MS(MS) analysis. AB - A miniaturized tryptic digestion protocol for protein analysis has been developed, which works well for small amounts of proteins using small volume of reagents. The protocol starts from 10MUL sample volume with total protein content in the low pmol or fmol range (alternatively expressed, in the low ng range). After adding various reagents the total volume of the tryptic digest will increase to 15MUL only. This is especially advantageous for nano-HPLC-MS or MALDI analysis which requires (and allows) analysis of few MUL aliquots only. Efficiency of the protocol was tested using nano-HLPC-MS(MS). The results show that the developed miniaturized digestion protocol performs at least as well, possibly even better, than conventional protocols using large sample amounts; and is far superior to digestion performed in larger volumes followed by solvent evaporation/resolvation. This is reflected both in signal intensities in MS and in the number of proteins identified by MS/MS. PMID- 21256994 TI - Simulations of trabecular remodeling and fatigue: is remodeling helpful or harmful? AB - Microdamage-targeted resorption is paradoxal, because it entails the removal of bone from a region that was already overloaded. Under continued intense loading, resorption spaces could potentially cause more damage than they remove. To investigate this problem, we incorporated damage algorithms in a computer simulation model for trabecular remodeling. We simulated damage accumulation and bone remodeling in a trabecular architecture, for two fatigue regimens, a 'moderate' regimen, and an 'intense' regimen with a higher number of loading cycles per day. Both simulations were also performed without bone remodeling to investigate if remodeling removed or exacerbated the damage. We found that remodeling tends to remove damage under the 'moderate' fatigue regimen, but it exacerbates damage under the 'intense' regimen. This harmful effect of remodeling may play a role in the development of stress fractures. PMID- 21256995 TI - Relation of aspirin failure to clinical outcome and to platelet response to aspirin in patients with acute myocardial infarction. AB - Aspirin failure, defined as occurrence of an acute coronary syndrome despite aspirin use, has been associated with a higher cardiovascular risk profile and worse prognosis. Whether this phenomenon is a manifestation of patient characteristics or failure of adequate platelet inhibition by aspirin has never been studied. We evaluated 174 consecutive patients with acute myocardial infarction. Of them, 118 (68%) were aspirin naive and 56 (32%) were regarded as having aspirin failure. Platelet function was analyzed after >=72 hours of aspirin therapy in all patients. Platelet reactivity was studied by light transmitted aggregometry and under flow conditions. Six-month incidence of major adverse coronary events (death, recurrent acute coronary syndrome, and/or stroke) was determined. Those with aspirin failure were older (p = 0.002), more hypertensive (p <0.001), more hyperlipidemic (p <0.001), and more likely to have had a previous cardiovascular event and/or procedure (p <0.001). Cumulative 6 month major adverse coronary events were higher in the aspirin-failure group (14.3% vs 2.5% p <0.01). Patients with aspirin failure had lower arachidonic acid induced platelet aggregation (32 +/- 24 vs 45 +/- 30, p = 0.003) after aspirin therapy compared to their aspirin-naive counterparts. However, this was not significant after adjusting for differences in baseline characteristics (p = 0.82). Similarly, there were no significant differences in adenosine diphosphate induced platelet aggregation and platelet deposition under flow conditions. In conclusion, our results suggest that aspirin failure is merely a marker of higher risk patient profiles and not a manifestation of inadequate platelet response to aspirin therapy. PMID- 21256996 TI - Comparison of thrombolysis in myocardial infarction, Global Registry of Acute Coronary Events, and Acute Physiology and Chronic Health Evaluation II risk scores in patients with acute myocardial infarction who require mechanical ventilation for more than 24 hours. AB - The ability to provide an accurate prognosis in an intensive care unit is of major importance. Numerous risk scores have been developed to predict hospital mortality based on demographic, physiologic, and clinical data. These scores were universally developed in general medical or surgical intensive care units. Patients admitted to a cardiac care unit differ in many aspects from those admitted to general medical intensive care units. Few patients require mechanical ventilation and prolonged intensive care. Performance of risk scores developed for patients with acute myocardial infarction (AMI) in this subgroup is unknown. We prospectively studied 51 consecutive patients who were admitted to a cardiac care unit from September 2006 to March 2008 for AMI and received mechanical ventilation for >24 hours. Acute Physiology and Chronic Health Evaluation II (APACHE II), Thrombolysis In Myocardial Infarction, and Global Registry of Acute Coronary Events risk scores were calculated for each patient. Mortality rates were extrapolated based on these 3 risk scores. Twenty-two of 51 patients (43%) died in hospital. Age, mean arterial pressure, urea, albumin, hemoglobin, need for vasopressors, and estimated glomerular filtration rate were predictive of mortality. APACHE II and Global Registry of Acute Coronary Events scores were higher in nonsurvivors but Thrombolysis In Myocardial Infarction risk score was not predictive of mortality. APACHE II score had the highest value for area under receiver operator characteristics curve for mortality prediction. In conclusion, patients with AMI requiring mechanical ventilation have a high mortality rate. This risk is predicted by co-morbidities better than by direct cardiac parameters. Consequently, conventional AMI risk scores do not perform well in this very sick population and the APACHE II score better predicts their short term outcome. PMID- 21256997 TI - A simple strategy improves prehospital electrocardiogram utilization and hospital treatment for patients with acute coronary syndrome (from the ST SMART Study). AB - Although the American Heart Association recommends a prehospital electrocardiogram (ECG) be recorded for all patients who access the emergency medical system with symptoms of acute coronary syndrome (ACS), widespread use of prehospital ECG has not been achieved in the United States. A 5-year prospective randomized clinical trial was conducted in a predominately rural county in northern California to test a simple strategy for acquiring and transmitting prehospital ECGs that involved minimal paramedic training and decision making. A 12-lead ECG was synthesized from 5 electrodes and continuous ST-segment monitoring was performed with ST-event ECGs automatically transmitted to the destination hospital emergency department. Patients randomized to the experimental group had their ECGs printed out in the emergency department with an audible voice alarm, whereas control patients had an ECG after hospital arrival, as was the standard of care in the county. The result was that nearly 3/4 (74%) of 4,219 patients with symptoms of ACS over the 4-year study enrollment period had a prehospital ECG. Mean time from 911 call to first ECG was 20 minutes in those with a prehospital ECG versus 79 minutes in those without a prehospital ECG (p <0.0001). Mean paramedic scene time in patients with a prehospital ECG was just 2 minutes longer than in those without a prehospital ECG (95% confidence interval 1.2 to 3.6, p <0.001). Patients with non-ST-elevation myocardial infarction or unstable angina pectoris had a faster time to first intravenous drug and there was a suggested trend for a faster door-to-balloon time and lower risk of mortality in patients with ST-elevation myocardial infarction. In conclusion, increased paramedic use of prehospital ECGs and decreased hospital treatment times for ACS are feasible with a simple approach tailored to characteristics of a local geographic region. PMID- 21256998 TI - 30-year trends in heart failure in patients hospitalized with acute myocardial infarction. AB - Despite significant advances in its treatment, acute myocardial infarction (AMI) remains an important cause of heart failure (HF). Contemporary data remain lacking, however, describing long-term trends in incidence rates, demographic and clinical profiles, and outcomes of patients who develop HF as a complication of AMI. Our study sample consisted of 11,061 residents of the Worcester (Massachusetts) metropolitan area hospitalized with AMI at all greater Worcester hospitals in 15 annual study periods from 1975 to 2005. Overall, 32.4% of patients (n = 3,582) with AMI developed new-onset HF during their acute hospitalization. Patients who developed HF were generally older, more likely to have pre-existing cardiovascular disease, and were less likely to receive cardiac medications or undergo revascularization procedures during their hospitalization than patients who did not develop HF (p <0.001). Incidence rates of HF remained relatively stable from 1975 to 1991 at 26% but decreased thereafter. Decreases were also noted in hospital and 30-day death rates in patients with acute HF (p <0.001). However, patients who developed new-onset HF remained at significantly higher risk for dying during their hospitalization (21.6%) than patients who did not develop this complication (8.3%, p <0.001). Our large community-based study of patients hospitalized with AMI demonstrates that incidence rates of and mortality attributable to HF have decreased over the previous 3 decades. In conclusion, HF remains a common and frequently fatal complication of AMI to which increased surveillance and treatment efforts should be directed. PMID- 21256999 TI - Predictive accuracy of SYNTAX score for predicting long-term outcomes of unprotected left main coronary artery revascularization. AB - The American College of Cardiology/American Heart Association recently updated recommendations for percutaneous coronary intervention (PCI) of unprotected left main coronary artery (ULMCA) disease from class III to II(b) according to the results of the SYNergy between percutaneous coronary intervention with TAXus and cardiac surgery (SYNTAX) trial. The SYNTAX score is an angiographic tool using solely the coronary anatomy. We studied the effect of co-morbidities (Parsonnet's score) on the ability of the SYNTAX score to predict long-term outcomes in patients with ULMCA disease treated by revascularization. A total of 328 patients underwent revascularization of ULMCA from April 2003 to February 2007. Of the 328 patients, 120 underwent PCI (median follow-up 973 days) and 208 underwent coronary artery bypass grafting (CABG) (median follow-up 1,298 days). The ability of the SYNTAX score to predict outcomes was assessed using the Cox proportional hazards model. The outcomes between the PCI and CABG groups were compared by propensity analysis. The median SYNTAX score was 26 in the PCI and 28 in the CABG group (p = 0.5). In the PCI group, greater quartiles were associated with worse survival (62.1% at SYNTAX score of >=36 vs 82.4% at SYNTAX score of <36, p = 0.03) and all-cause mortality, myocardial infarction, cerebrovascular events, and target vessel revascularization-free (MACCE) survival (47.7%, SYNTAX score >=20 vs 76.6%, SYNTAX score <20, p = 0.02). Using the Parsonnet score as a covariate, the SYNTAX score continued to be an independent predictor of MACCE and demonstrated a trend toward predicting mortality in the PCI group. In contrast, the SYNTAX score did not predict the outcomes for the CABG group. No difference was found in mortality between the PCI and CABG groups for ULMCA disease, regardless of coronary complexity; although greater SYNTAX scores were associated with increased MACCE rates with PCI compared to CABG. Both the coronary anatomy (SYNTAX score) and co-morbidities (Parsonnet's score) predicted long-term outcomes for PCI of ULMCA disease. In contrast, the SYNTAX score did not predict the outcomes after CABG. In conclusion, the ideal scoring system to guide an appropriate revascularization decision for ULMCA disease should take into account both the coronary anatomy and the co-morbidities. PMID- 21257000 TI - Effect of intravascular ultrasound findings on long-term repeat revascularization in patients undergoing drug-eluting stent implantation for severe unprotected left main bifurcation narrowing. AB - We studied the effect of the preprocedural intravascular ultrasound findings on stent expansion and the pre- and postprocedural findings on the long-term clinical outcomes in patients undergoing drug-eluting stent implantation for unprotected left main (LM) bifurcation disease. Using a left anterior descending (LAD) pullback, we evaluated the ostial LAD artery (3 mm distal to the carina), the polygon of confluence (POC; the confluent zone of the LAD artery and left circumflex artery), and the distal LM artery (3 mm just proximal to the POC). The measurements included the minimum lumen area (MLA) and minimum stent area within each segment. In 168 LM bifurcations, the preprocedural MLA and post-stenting minimum stent area within the LM artery were located within the POC in 41% and 70%, respectively. Independent predictors for the post-stent minimum stent area within the distal portion of LM artery above the LAD carina were the preprocedural lumen area of the LAD carina (beta = 0.253, 95% confidence interval [CI] 0.10 to 0.36, p = 0.001) and preprocedural MLA within the POC (beta = 0.205, 95% CI 0.04 to 0.23, p = 0.008). During the 41.8 +/- 18.0-month follow-up period, 26 patients experienced cardiac events. In the multivariate Cox model, female gender (adjusted hazard ratio 2.56, 95% CI 1.173 to 5.594, p = 0.018) and preprocedural MLA within the POC (adjusted hazard ratio 0.829, 95% CI 0.708 to 0.971, p = 0.020) were independent predictors for the occurrence of events at 3 years of follow-up. In conclusion, as assessed by the LAD pullback, the preprocedural MLA within the POC was a surrogate reflecting the overall severity of LM bifurcation disease, contributed to the post-stent minimum stent area within the distal segment of LM bifurcation, and was a predictor of clinical events during follow-up. PMID- 21257001 TI - Meta-analysis of randomized studies comparing intravascular ultrasound versus angiographic guidance of percutaneous coronary intervention in pre-drug-eluting stent era. AB - We conducted a formal meta-analysis of peer-reviewed, published, randomized studies comparing intravascular ultrasound (IVUS)-guidance and angiographic guided bare metal stent implantation. A total of 8 studies were identified. Because the Balloon Equivalent to Stent (BEST) study was a noninferiority trial designed to compare 2 very different percutaneous coronary intervention strategies-IVUS-guided aggressive balloon angioplasty (with bail-out stenting) and angiographic-guided deliberate bare metal stent implantation-it was eliminated. An unadjusted random-effects meta-analysis was used to compare the IVUS-guided and non-IVUS-guided stenting in the 7 remaining studies. A total of 2,193 patients were randomized in 5 multicenter and 2 single-center studies. IVUS guidance was associated with a significantly larger postprocedure angiographic minimum lumen diameter. The mean difference was 0.12 mm (95% confidence interval [CI] 0.06 to 0.18, p <0.0001). IVUS guidance was also associated with a significantly lower rate of 6-month angiographic restenosis (22% vs 29%, odds ratio 0.64, 95% CI 0.42 to 0.96, p = 0.02), a significant reduction in the revascularization rate (13% vs 18%, odds ratio 0.66, 95% CI 0.48 to 0.91, p = 0.004), and overall major adverse cardiac events (19% vs. 23%, odds ratio 0.69, 95% CI 0.49 to 0.97, p = 0.03). However, no significant effect was seen for myocardial infarction (p = 0.51) or mortality (p = 0.18). In conclusion, IVUS guidance for bare metal stent implantation improved the acute procedural results (angiographic minimum lumen diameter) and thereby reduced angiographic restenosis and repeat revascularization and major adverse cardiac events, with a neutral effect on death and myocardial infarction during a follow-up period of 6 months to 2.5 years. PMID- 21257002 TI - Effect of race on the frequency of postoperative atrial fibrillation following coronary artery bypass grafting. AB - Atrial fibrillation (AF) commonly complicates the postoperative course after coronary artery bypass grafting (CABG). Among the general population, African Americans have been shown to have a lower prevalence of AF than European Americans. Although many factors have been identified to predict risk for postoperative AF, race has not been examined. All patients aged >=18 years who underwent CABG at Henry Ford Hospital during a 5-year period from January 1, 2004, to December 31, 2008, were included. Patients were excluded for any previous diagnosis of AF or if they had concomitant valve surgery at the time of CABG. The incidence of AF was determined by International Classification of Diseases, Ninth Revision, coding from postoperative hospitalization records. Overall, 1,001 patients were eligible for analysis. Of these, 731 (73%) were European American and 270 (27%) were African American. The African American group had a higher prevalence of hypertension (75.6% vs 58.8%, p <0.001) and heart failure (22.6% vs 15.7%, p = 0.01) and a trend toward a higher prevalence of diabetes mellitus (38.1% vs 33.4%, p = 0.159). Postoperative AF was diagnosed in 214 European Americans (29.3%) and 50 African Americans (18.5%) (p = 0.001). In multivariate analysis adjusting for age strata, gender, hypertension, diabetes, and heart failure, African Americans had less postoperative AF than European Americans, with an adjusted odds ratio of 0.539 (95% confidence interval 0.374 to 0.777, p = 0.001). In conclusion, African Americans have a significantly reduced incidence of AF compared to European Americans after CABG. PMID- 21257003 TI - Effects of maximal atorvastatin and rosuvastatin treatment on markers of glucose homeostasis and inflammation. AB - Studies have reported an increased risk of developing diabetes in subjects receiving statins versus placebo. Our purpose was to compare the effects of maximum doses of rosuvastatin and atorvastatin on the plasma levels of the insulin, glycated albumin, adiponectin, and C-reactive protein compared to baseline in hyperlipidemic patients. We studied 252 hyperlipidemic men and women who had been randomized to receive atorvastatin 80 mg/day or rosuvastatin 40 mg/day during a 6-week period. Atorvastatin and rosuvastatin were both highly effective in lowering the low-density lipoprotein cholesterol and triglyceride levels, with rosuvastatin more effective than atorvastatin in increasing high density lipoprotein cholesterol. Atorvastatin and rosuvastatin at the maximum dosage both significantly (p <0.05) increased the median insulin levels by 5.2% and 8.7%, respectively, from baseline. However, only atorvastatin increased the glycated albumin levels from baseline (+0.8% for atorvastatin vs -0.7% for rosuvastatin, p = 0.002). Both atorvastatin and rosuvastatin caused significant (p <0.001) and similar median reductions in the C-reactive protein level of -40% and -26% compared to the baseline values. However, no statistically significant difference was found between the 2 groups in the adiponectin changes from baseline (-1.5% vs -4.9%, p = 0.15). In conclusion, our data have indicated that the maximum dosage of atorvastatin or rosuvastatin therapy significantly lower C reactive protein levels but also moderately increase insulin levels. PMID- 21257004 TI - Comparison of high-density lipoprotein cholesterol to apolipoprotein A-I and A-II to predict coronary calcium and the effect of insulin resistance. AB - High-density lipoprotein (HDL) cholesterol and its apolipoproteins each capture unique lipid and cardiometabolic information important to risk quantification. It was hypothesized that metabolic factors, including insulin resistance and type 2 diabetes, would confound the association of HDL cholesterol with coronary artery calcification (CAC) and that apolipoprotein A-I (apoA-I) and/or apolipoprotein A II (apoA-II) would add to HDL cholesterol in predicting CAC. Two community-based cross-sectional studies of white subjects were analyzed: the Penn Diabetes Heart Study (PDHS; n = 611 subjects with type 2 diabetes, 71.4% men) and the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA; n = 803 subjects without diabetes, 52.8% men) using multivariable analysis of apoA-I, apoA-II, and HDL cholesterol stratified by diabetes status. HDL cholesterol was inversely associated with CAC after adjusting for age and gender in whites with type 2 diabetes (tobit ratio for a 1-SD increase in HDL cholesterol 0.58, 95% confidence interval [CI] 0.44 to 0.77, p <0.001) as well as those without diabetes (tobit ratio 0.72, 95% CI 0.59 to 0.88, p = 0.001). In contrast, apoA-I was a weaker predictor in subjects with (tobit ratio 0.64, 95% CI 0.45 to 0.90, p = 0.010) and without (tobit ratio 0.79, 95% CI 0.66 to 0.94, p = 0.010) diabetes, while apoA II had no association with CAC. Control for metabolic variables, including triglycerides, waist circumference, and homeostasis model assessment of insulin resistance, attenuated these relations, particularly in subjects without diabetes. In likelihood ratio test analyses, HDL cholesterol added to apoA-I, apoA-II, and atherogenic apolipoprotein B lipoproteins but improved CAC prediction over metabolic factors only in subjects with diabetes. In conclusion, HDL cholesterol outperformed apoA-I and apoA-II in CAC prediction, but its association with CAC was attenuated by measures of insulin resistance. PMID- 21257005 TI - Comparison of estimated glomerular filtration rates and albuminuria in predicting risk of coronary heart disease in a population with high prevalence of diabetes mellitus and renal disease. AB - Improved accuracy in predicting coronary heart disease (CHD) risk in patients with diabetes and kidney disease is needed. The addition of albuminuria to established methods of CHD risk calculation was reported in the Strong Heart Study (SHS) cohort. In this study, the addition of estimated glomerular filtration rate (eGFR) was evaluated using data from 4,549 American Indian SHS participants aged 45 to 74 years. After adjustment for Framingham CHD risk factors, hazard ratios for eGFR as a predictor of CHD were 1.69 (95% confidence interval 1.34 to 2.13) in women and 1.41 (95% confidence interval 0.94 to 2.13) in men. Models including albuminuria, eGFR, or both scored higher in discriminatory power than models using conventional risk factors alone in women; in men, the improvement was seen only for albuminuria and the combination of albuminuria and eGFR. Hosmer-Lemeshow assessments showed good calibration for the models using eGFR alone in both genders, followed by models including albuminuria alone in both genders. Adding eGFR improved the net reclassification improvement (NRI) in women (0.085, p = 0.0004) but not in men (0.010, p = 0.1967). NRI and integrated discrimination improvement (IDI) were improved in both genders using albuminuria and eGFR (NRI 0.135, p <0.0001, and IDI 0.027, p <0.0001 in women; NRI 0.035, p <0.0196, and IDI 0.008, p <0.0156 in men). Therefore, a risk calculator including albuminuria enhances CHD prediction compared to a calculator using only standard risk factors in men and women. Including eGFR alone improves risk prediction in women, but for men, it is preferable to include eGFR and albuminuria. In conclusion, this enhanced calculator should be useful in estimating CHD risk in populations with high prevalence of diabetes and renal disease. PMID- 21257006 TI - Usefulness of insulin resistance estimation and the metabolic syndrome in predicting coronary atherosclerosis in type 2 diabetes mellitus. AB - Metabolic syndrome (MS) definitions predict cardiovascular events beyond traditional risk factors in patients with type 2 diabetes mellitus (DM) as well as subjects without DM. It has been shown that apolipoprotein B (apoB) and non high-density lipoprotein cholesterol are associated with coronary artery calcification in DM. However, the relative value of MS, apoB lipoproteins, and estimates of insulin resistance is unknown in predicting atherosclerosis in DM. Cross-sectional analyses of white subjects in 2 community-based studies were performed (n = 611 patients with DM, n = 803 subjects without DM) using multivariate analysis of traditional risk factors and then adding MS, apoB, and homeostasis model assessment of insulin resistance (HOMA-IR). Incremental value was tested using likelihood ratio testing. Beyond traditional risk, HOMA-IR (tobit regression ratio 1.86, p = 0.002), apoB (tobit regression ratio 1.55, p = 0.001), and MS (tobit regression ratio 2.37, p = 0.007) were independently associated with coronary artery calcification in DM. In nested models, HOMA-IR added value to apoB (tobit regression ratio 1.72, p = 0.008), MS (tobit regression ratio 1.72, p = 0.011), and apoB and MS (tobit regression ratio 1.64, p = 0.021). ApoB showed a similar pattern when added to HOMA-IR (tobit regression ratio 1.51, p = 0.004), MS (tobit regression ratio 1.46, p = 0.005), and HOMA-IR and MS (tobit regression ratio 1.48, p = 0.006). MS added to apoB (tobit regression ratio 1.99, p = 0.032) but not HOMA-IR (tobit regression ratio 1.54, p = 0.221) or apoB and HOMA-IR (tobit regression ratio 1.32, p = 0.434). In conclusion, insulin resistance estimates add value to MS and apoB in predicting coronary artery calcification scores in DM and warrant further evaluation in clinic for identification of patients with DM at higher risk for atherosclerotic cardiovascular disease. PMID- 21257007 TI - Effect of different obesity phenotypes on cardiovascular events in Tehran Lipid and Glucose Study (TLGS). AB - In this community-based study, 6,215 subjects aged >=30 years (43% men, mean age 47 years) free of cardiovascular disease (CVD) at baseline were followed for a mean of 8.1 years to assess risk for CVD stratified by body mass index and dysmetabolic status. Participants were stratified by body mass index categories (18.5 to 24.9 kg/m2 = normal, 25 to 29.9 kg/m2 = overweight, and >=30 kg/m2 = obese) and dysmetabolic status. Dysmetabolic status was defined as having metabolic syndrome according to the International Diabetes Federation's definition or diabetes. First CVD events occurred in 446 subjects. Multivariate adjusted hazard ratios for CVD events in normal-weight, overweight, and obese subjects without dysmetabolic status were 1.00 (reference), 1.10 (95% confidence interval [CI] 0.76 to 1.61), and 1.07 (95% CI 0.59 to 1.96), respectively, and for normal-weight, overweight and obese subjects with dysmetabolic status were 2.10 (95% CI 1.36 to 3.26), 2.35 (95% CI 1.71 to 3.22), and 2.35 (95% CI 1.71 to 3.22), respectively. There was an interaction between body mass index and metabolic abnormalities in predicting CVD. In conclusion, normal-weight subjects with dysmetabolic status had higher risk for future CVD compared to healthy obese subjects. PMID- 21257008 TI - Effect of elevated left ventricular diastolic filling pressure on the frequency of left atrial appendage thrombus in patients with nonvalvular atrial fibrillation. AB - We investigated the relation between left ventricular diastolic dysfunction and left atrial appendage (LAA) thrombus in patients with atrial fibrillation (AF). We performed transesophageal echocardiography to examine LAA thrombus or spontaneous echo contrast (SEC) and to measure LAA emptying flow velocity in consecutive 376 patients with AF. We estimated diastolic filling pressure as the ratio of early transmitral flow velocity (E) to mitral annular velocity (e') on transthoracic echocardiogram. E/e' ratio in 28 patients (7.4%) with LAA thrombi was higher than that in patients without thrombus (18.3 +/- 9.3 vs 11.4 +/- 5.9, p <0.0001). The fourth quartile of E/e' (>13.6) consisted of 19 patients with thrombi and had a higher prevalence of thrombi than the others (p <0.0001). Multivariate regression analysis selected E/e' >=13 as an independent predictor of LAA thrombus with an odds ratio of 3.50 (1.22 to 10.61) in addition to LA dimension and ejection fraction. Increased quartile of E/e' was negatively associated with LAA flow velocity and positively with rate of SEC. In conclusion, increased diastolic filling pressure is associated with a higher rate of LAA thrombus in AF, partly through blood stasis or impaired LAA function. PMID- 21257009 TI - Analysis of willingness to pay for implantable cardioverter-defibrillator therapy. AB - Despite being effective in the primary and secondary prevention of sudden cardiac arrest, the cost-effectiveness of implantable cardioverter-defibrillator (ICD) therapy remains debated. We attempted to estimate the value ICD recipients place on their ICD device. We used the contingent valuation method to evaluate the willingness to pay (WTP) and the cost benefit of ICD therapy in an unselected population of 237 recipients. A hypothetical scenario was presented to patients in which at the end of their current ICD no public reimbursement for the replacement would occur. Patients were asked to indicate their out-of-pocket WTP for a replacement ICD using a close-ended question format. Seven different "take it-or-leave-it" bids were randomly varied and assigned to patients. Median WTP was calculated with nonparametric methods, and multiple logistic regression models were generated to identify factors associated with WTP. Only cost of the device was considered. Median WTP was estimated at CAN $4,125, which corresponds to 21% of the cost of the device (CAN $20,000). In multiple logistic regression analysis, a higher bid (odds ratio [OR] 0.95, 95% confidence interval [CI] 0.91 to 0.99, per CAN $1,000 increase) was associated with a lower WTP, whereas a higher gross family income (OR 2.3, 95% CI 0.9 to 9.0) and higher education (OR 2.2, 95% CI 0.9 to 5.1) were associated with a trend for higher WTP. In conclusion, ICD recipients would be willing to pay a substantial amount for a replacement ICD. Considering the expensive price of the device, ICD recipients value favorably the benefits provided by the ICD. PMID- 21257010 TI - Usefulness of the Agatston score = 0 to exclude ischemic cardiomyopathy in patients with heart failure. AB - Quantification of coronary artery calcium has prognostic value and is commonly used in asymptomatic patients. Routine clinical use of coronary artery calcium in other populations remains uncertain. We sought to understand the potential application of the Agatston score in patients with heart failure (HF). For this purpose, 3 populations were identified: (1) patients with an Agatston score equal to 0, (2) patients with high-risk coronary artery disease (CAD) defined as 3 vessel, left main, or 2-vessel disease involving the proximal left anterior descending coronary artery, and (3) patients with HF symptoms and left ventricular (LV) ejection fraction <50%. Excluding patients with HF or LV dysfunction, 738 patients (mean age 52 +/- 10 years, 43% men) had an Agatston score equal to 0. Of these, 18 (2%) had obstructive CAD (diameter stenosis >=50%), 8 (1%) had diameter stenoses >=70%, and none had high-risk CAD. The 74 patients with high-risk CAD without LV dysfunction had high Agatston scores (mean 895 +/- 734, median 716, range 50 to 3,210). In total 153 patients with a history of HF and abnormal ejection fraction were identified. All 13 patients with ischemic cardiomyopathy had Agatston scores >0, whereas 46 of 140 patients (30.1%) with nonischemic causes had an Agatston score equal to 0. An Agatston score equal to 0 identified nonischemic causes with a specificity of 100% (confidence interval 90 to 100) and positive predictive value of 100% (confidence interval 90 to 100). Agatston score equal to 0 had incremental value to pretest probability for CAD. In conclusion, an Agatston score equal to 0 confers a very low likelihood of obstructive CAD, appears to rule out high-risk CAD, and thus may be used to rule out ischemic cardiomyopathy in patients with HF. PMID- 21257011 TI - Utility of the neutrophil to lymphocyte ratio in predicting long-term outcomes in acute decompensated heart failure. AB - Neutrophil-to-lymphocyte ratio (NLR) has been associated with poor outcomes in patients with acute coronary syndromes. However, its role for risk stratification in acute decompensated heart failure (ADHF) has not been well described. In this study, 1,212 consecutive patients admitted with ADHF who had total white blood cell and differential counts measured at admission were analyzed. The patients were divided into tertiles according to NLR. The association between NLR and white blood cell types with all-cause mortality was assessed using Cox regression analysis. During a median follow-up period of 26 months, a total of 284 patients (23.4%) had died, and a positive trend between death and NLR was observed; 32.8%, 23.2%, and 14.2% of deaths occurred in the higher, middle, and lower tertiles, respectively (p <0.001). After adjusting for confounding factors, multivariate analysis demonstrated that patients in the higher NLR tertile had the highest mortality (adjusted hazard ratio 2.23, 95% confidence interval (CI) 1.63 to 3.02, p <0.001), followed by those in the middle tertile (adjusted hazard ratio 1.62, 95% CI 1.16 to 2.23, p = 0.001). Furthermore, tertiles of NLR were superior in predicting long-term mortality compared with white blood cell, neutrophil, and relative lymphocyte counts. Patients in the higher NLR tertile (adjusted odds ratio 3.46, 95% CI 2.11 to 5.68, p <0.001) had a significantly higher 30-day readmission rate. In conclusion, higher NLR, an emerging marker of inflammation, is associated with an increased risk for long-term mortality in patients admitted with ADHF. NLR is a readily available inexpensive marker to aid in the risk stratification of patients with ADHF. PMID- 21257012 TI - Utility of comprehensive assessment of strain dyssynchrony index by speckle tracking imaging for predicting response to cardiac resynchronization therapy. AB - The strain delay index is reportedly a marker of dyssynchrony and residual myocardial contractility. The aim of this study was to test the hypothesis that a relatively simple version of the strain dyssynchrony index (SDI) can predict response to cardiac resynchronization therapy (CRT) and that combining assessment of radial, circumferential, and longitudinal SDI can further improve the prediction of responders. A total of 52 patients who underwent CRT were studied. The SDI was calculated as the average difference between peak and end-systolic strain from 6 segments for radial and circumferential SDI and 18 segments for longitudinal SDI. Conventional dyssynchrony measures were assessed by interventricular mechanical delay, the Yu index, and radial dyssynchrony by speckle tracking strain. Response was defined as a >=15% decrease in end-systolic volume after 3 months. Of the individual parameters, radial SDI >=6.5% was the best predictor of response to CRT, with sensitivity of 81%, specificity of 81%, and an area under the curve of 0.87 (p <0.001). Circumferential SDI >=3.2% and longitudinal SDI >=3.6% were also found to be predictive of response to CRT, with areas under the curve of 0.81 and 0.80, respectively (p <0.001). Moreover, radial, circumferential, and longitudinal SDI at baseline were correlated with reduction of end-systolic volume with CRT. In addition, the response rate in patients with 3 positive SDIs was 100%. In contrast, rates in patients with either 1 or no positive SDIs were 42% and 22%, respectively (p <0.005 and p <0.001 vs 3 positive SDIs). In conclusion, the SDI can successfully predict response to CRT, and the combined approach leads to more accurate prediction than using individual parameters. PMID- 21257013 TI - Relation of periodic leg movements during sleep and mortality in patients with systolic heart failure. AB - Periodic leg movements during sleep (PLMs) are a disorder characterized by regularly recurring movements of the legs during sleep. Although PLMs are common in patients with heart failure (HF), their clinical significance is unknown. The aim of this study was to determine whether, in patients with HF, PLMs are associated with increased mortality risk. In a prospective cohort study, 218 consecutive patients with systolic HF newly referred to an HF clinic from 1997 to 2004 who underwent overnight polysomnography, regardless of symptoms or signs of sleep disorders, were enrolled. The frequency of PLMs per hour of sleep was quantified as the PLM index (PLMI). Patients were classified as either normal (PLMI <5) or abnormal (PLMI >=5). Eighty-one of the patients (37%) had PLMIs >=5. During a mean follow-up period of 32.9 months, complete follow-up data were obtained in 95%. Patients with PLMIs >=5 were older and had lower left ventricular ejection fractions and higher New York Heart Association classes than patients with PLMIs <5. The mortality rate was significantly higher in patients with PLMIs >=5 than those with PMLIs <5 (10.4 vs 3.4 deaths/100 patient-years, p = 0.002). After adjusting for significant confounding factors, the presence of PLMI >=5 remained a significant independent risk for death (hazard ratio 2.42, 95% confidence interval 1.16 to 5.02, p = 0.018). In conclusion, in patients with systolic HF, the presence of PLMI >=5 is associated with an increased mortality risk, but these findings do not establish a cause-effect relation. PMID- 21257014 TI - Comparison of direct planimetry of mitral valve regurgitation orifice area by three-dimensional transesophageal echocardiography to effective regurgitant orifice area obtained by proximal flow convergence method and vena contracta area determined by color Doppler echocardiography. AB - Direct measurement of anatomic regurgitant orifice area (AROA) by 3-dimensional transesophageal echocardiography was evaluated for analysis of mitral regurgitation (MR) severity. In 72 patients (age 70.6 +/- 13.3 years, 37 men) with mild to severe MR, 3-dimensional transesophageal echocardiography and transthoracic color Doppler echocardiography were performed to determine AROA by direct planimetry, effective regurgitant orifice area (EROA) by proximal convergence method, and vena contracta area (VCA) by 2-dimensional color Doppler echocardiography. AROA was measured with commercially available software (QLAB, Philips Medical Systems, Andover, Massachusetts) after adjusting the first and second planes to reveal the smallest orifice in the third plane where planimetry could take place. AROA was classified as circular or noncircular by calculating the ratio of the medial-lateral distance above the anterior-posterior distance (<=1.5 compared to >1.5). AROA determined by direct planimetry was 0.30 +/- 0.20 cm2, EROA determined by proximal convergence method was 0.30 +/- 0.20 cm2, and VCA was 0.33 +/- 0.23 cm2. Correlation between AROA and EROA (r = 0.96, SEE 0.058 cm2) and between AROA and VCA (r = 0.89, SEE 0.105 cm2) was high considering all patients. In patients with a circular regurgitation orifice area (n = 14) the correlation between AROA and EROA was better (r = 0.99, SEE 0.036 cm2) compared to patients with noncircular regurgitation orifice area (n = 58, r = 0.94, SEE 0.061 cm2). Correlation between AROA and EROA was higher in an EROA >=0.2 cm2 (r = 0.95) than in an EROA <0.2 cm2 (r = 0.60). In conclusion, direct measurement of MR AROA correlates well with EROA by proximal convergence method and VCA. Agreement between methods is better for patients with a circular regurgitation orifice area than in patients with a noncircular regurgitation orifice area. PMID- 21257015 TI - Effect of ventricular volume before unloading in a systemic ventricle supporting the Fontan circulation. AB - The influence of volume overload on ventricular performance has been previously investigated but primarily with respect to the duration of overload. The aim of the present study was to elucidate whether the magnitude of the preoperative volume overload, represented by the ventricular volume, has any effect on ventricular performance long after the Fontan operation in patients with tricuspid atresia. We evaluated consecutive changes in hemodynamic catheterization data obtained at 1, 5, and 10 years after primary Fontan repair. The variables were compared between patients with larger (n = 20) and smaller (n = 21) ventricles (preoperative end-diastolic volume [percentage of predicted] 262 +/- 33%, maximum 320% vs 182 +/- 22%, minimum 133%, respectively). In a subgroup of patients (n = 33) who underwent symptom-limited exercise at 10.7 +/- 3.0 postoperative years, the peak oxygen uptake was measured, and the potential predictors were interrogated. The difference in ventricular contractility between the groups tended to increase with time, with those with a larger ventricle showing poorer contraction, irrespective of whether it was assessed in a load dependent (ejection fraction) or load-independent (end-systolic elastance) manner. The differences in these variables reached statistical significance at 10 years (p = 0.028 and p = 0.032). Multivariate analysis indicated a larger ventricle was an independent risk factor of poorer aerobic capacity (p = 0.047). In conclusion, ventricular performance was less preserved in those with a larger ventricle, which might result in suboptimal aerobic capacity. Our findings suggest not only early unloading, but also avoidance of excessive volume overload is of importance to minimize the deleterious effect of volume overload on an inherently susceptible ventricle. PMID- 21257016 TI - Complex congenital heart disease in unaffected relatives of adults with 22q11.2 deletion syndrome. AB - The 22.q11.2 deletion syndrome (22q11DS) is a common genetic condition associated with 22q11.2 microdeletions and classically has included congenital heart disease (CHD) as a part of the variable expression. Some evidence has shown that relatives of those with 22q11DS might be at an increased risk of CHD in the absence of 22q11.2 deletions. We obtained a detailed family history of CHD in the first- to third-degree relatives (n = 2,639) of 104 adult probands with 22q11DS. We compared the prevalence of CHD in the relatives without 22q11.2 deletions to the published general population prevalence. We also investigated the effect of CHD in the probands on prevalence of CHD in the relatives. Of the 104 probands with 22q11DS, 14 (13.5%) had 17 relatives (17 of 2,639, 0.6%) with CHD. Of 66 probands with CHD, 15 (0.9%) of their 1,663 relatives had CHD, a significantly greater prevalence than that for the relatives of probands without CHD (0.2%, 2 of 976, p = 0.041, odds ratio 4.43, 95% confidence interval 1.03 to 40.00). In relatives of probands with CHD, the prevalence of those with severe CHD (0.36%) was significantly elevated compared to population expectations (0.061%, p = 0.007, odds ratio 5.88, 95% confidence interval 2.16 to 12.85). In conclusion, these results support a heritable susceptibility to CHD in families of probands with 22q11DS, in addition to that imparted by microdeletion 22q11.2. The occurrence of CHD in relatives might be related to the expression of CHD in the proband with 22q11DS. These findings have potential implications for the genetic counseling of families of those with 22q11DS and support the notion that interacting genetic variants might contribute to the variable expression of 22q11DS. PMID- 21257017 TI - Left ventricular function assessed by two-dimensional speckle tracking echocardiography in long-term survivors of Hodgkin's lymphoma treated by mediastinal radiotherapy with or without anthracycline therapy. AB - Anthracycline therapy is well known for its adverse cardiac effects. However, few studies have been performed of the long-term follow-up of myocardial function in adult survivors of Hodgkin's lymphoma receiving anthracycline. Two-dimensional speckle tracking echocardiography is an accurate angle-independent modality for the quantification of left ventricular (LV) function. The aim of the present study was to investigate the long-term effect of anthracycline on LV systolic function. Echocardiography was performed in 47 survivors of Hodgkin's lymphoma 22 +/- 2 years after successful mediastinal radiotherapy with (n = 27) or without (n = 20) anthracycline (doxorubicin) treatment and in 20 healthy controls. LV function was assessed by the LV ejection fraction and global longitudinal and circumferential strain. Both patient groups had received a similar dosage of radiation, and doxorubicin was given at a total dose of 309 +/- 92 mg. The global longitudinal strain was reduced in patients receiving anthracycline with mediastinal radiotherapy compared to the other group receiving mediastinal radiotherapy alone or combined radiotherapy and regimens without anthracyclines ( 16.1 +/- 1.9% vs -17.5 +/- 1.7%, respectively, p <0.05). Both patient groups had reduced strain compared to the healthy controls (-20.4 +/- 1.7%, both p <0.001). The circumferential strain was also reduced in the treatment groups (-18.3 +/- 3.2% and -17.8 +/- 3.6% vs -22.5 +/- 2.1%, both p <0.001). The LV ejection fraction did not differ between the patient groups (55 +/- 8% vs 56 +/- 6%, p = 1.0) but was reduced compared to that of the controls (62 +/- 5%, both p <0.05). In conclusion, myocardial function was reduced in the survivors of Hodgkin's lymphoma 2 decades after successful treatment consisting of mediastinal radiotherapy with or without chemotherapy. Patients receiving anthracycline therapy had additional negative long-tem effects on LV systolic function. PMID- 21257018 TI - Usefulness of the myocardial performance index determined by tissue Doppler imaging m-mode for predicting mortality in the general population. AB - The objective of this study was to evaluate the prognostic value of the myocardial performance index (MPI), assessed by color-coded tissue Doppler imaging (TDI) M-mode through the anterior mitral leaflet. Color TDI M-mode through the mitral leaflet is an easy, very fast, and precise method to estimate cardiac intervals and thus obtain the MPI, but the diagnostic and prognostic values of this parameter are unknown. In a large population study, cardiac function was evaluated in 1,100 participants by conventional echocardiography and TDI. MPI was calculated from pulse-wave Doppler analyses of left ventricular in- and outflow using standard procedures (MPI(conv)) and by color-coded TDI M-mode through the mitral leaflet in the apical 4-chamber view (MPI(TDI)). MPI(TDI) was increased in subjects with coronary heart disease (CHD) compared to controls, even after multivariable adjustment (p <0.002). During follow-up (median 5.3 years), 90 participants died. MPI(TDI) was significantly associated with overall mortality, and risk of dying increased by 31% per 0.1 increase in MPI(TDI). In contrast to MPI(conv), MPI(TDI) provided independent prognostic information in a multivariable Cox proportional hazard model (adjusting for age, gender, body mass index, heart rate, mean arterial blood pressure, and CHD), with a hazard ratio of 1.18 (p = 0.01) per 0.1 increase in MPI(TDI). In conclusion, MPI(TDI) is a quick, simple, and reproducible measurement, which is increased in subjects with CHD and provides independent prognostic information in a low-risk population. PMID- 21257019 TI - Quantitative analysis of right ventricular function in patients with pulmonary hypertension using three-dimensional echocardiography and a two-dimensional summation method compared to magnetic resonance imaging. AB - Magnetic resonance imaging (MRI) is considered the clinical reference standard for measuring the right ventricular (RV) volume and ejection fraction, although real-time 3-dimensional echocardiography (RT3DE) would be a preferred method owing to its convenience and availability for repetitive examinations. However, the feasibility, accuracy, and reproducibility of RT3DE have not been fully examined. The present study sought to validate the correlation of RT3DE with a 2 dimensional summation method compared to MRI for assessing the function of the right ventricle and to evaluate the RV function in patients with pulmonary hypertension (PH). Thirty patients with PH underwent both RT3DE and MRI. The right ventricle was reconstructed with RT3DE using a 2-dimensional summation method to analyze the MRI measurements. The RV end-diastolic volume, RV end systolic volume, and RV ejection fraction were measured. Fifteen normal subjects underwent the same echocardiographic protocol for comparison. The RV end diastolic volume index, RV end-systolic volume index, and RV ejection fraction measured using RT3DE correlated well with those measured using MRI (R = 0.96, p <0.001; R = 0.96, p <0.001; p = 0.93, and p <0.001, respectively). All inter- and intraobserver variability values for the RV end-diastolic volume, RV end-systolic volume, and RV ejection fraction were <17%. Both the RV end-diastolic volume index and the RV end-systolic volume index were significantly enlarged in those with PH compared to those in the normal subjects (RVEDVI 123 +/- 42 ml/m2 vs 74 +/- 12 ml/m2; RVESVI 86 +/- 33 ml/m2 vs 26 +/- 5 ml/m2 in those with PH and the normal subjects, respectively, p <0.0001). In contrast, the RV ejection fraction was significantly reduced in the patients with PH compared to that in the normal subjects (30 +/- 12% vs 65 +/- 6%, respectively, p <0.01). Thus, RT3DE with a 2 dimensional summation method might provide comparable and feasible measurements of the RV volume in patients with PH compared to MRI. PMID- 21257020 TI - Hypertension, the J-Curve and the INVEST Trial. PMID- 21257022 TI - Cold pressor test safety-the incidence of vasovagal reactions. PMID- 21257023 TI - QRS duration as a predictor of permanent pacemaker implantation. PMID- 21257024 TI - Invited review: ruminating conscientiously: scientific and socio-ethical challenges for US dairy production. AB - Despite the predominantly positive depictions of dairy production, public concern about farm animal production practices in the United States is currently higher than at any point in recent history. Many standard industry practices, including some used by the US dairy industries, are increasingly challenged not just on scientific grounds, but also on ethical grounds. Concerns include the environmental impacts and sustainability of modern farm animal production practices, food safety and security, and the increasingly complex issue of animal welfare. As the impetus increases to achieve broad stakeholder engagement in discussions of US food policy, understanding and addressing the ethical concerns associated with contemporary dairy production is critically important to ensure the industry's autonomy and long-term viability. Animal welfare assessment or accountability tools such as the Ethical Matrix or Campbell's Ethics Assessment Process can provide a structured, transparent method of making appropriate ethical choices about the care and welfare of farm animals that are also scientifically grounded. PMID- 21257025 TI - Invited review: udder health of dairy cows in automatic milking. AB - Automatic milking (AM) is increasing in modern dairy farming, and over 8,000 farms worldwide currently use this technology. Automatic milking system is designed to replace conventional milking managed by a milker in a milking parlor or in tie stalls. Cows are generally milked more frequently in AM than in conventional milking, and milking is quarter-based instead of udder-based. Despite improvements in the milking process and often building of a new barn before the introduction of AM, udder health of the cows has not improved; on the contrary, problems may appear following conversion from conventional milking to AM. This review focuses on udder health of dairy cows in AM, and we discuss several aspects of cow and milking management in AM associated with udder health. Finally, adequate management methods in AM are suggested. According to several studies comparing udder health between automatic and conventional milking or comparing udder health before and after the introduction of automatic milking in the same herds, udder health has deteriorated during the first year or more after the introduction of AM. Automatic detection of subclinical and clinical mastitis and cleaning the teats before milking are challenges of AM. Failures in mastitis detection and milking hygiene pose a risk for udder health. These risk factors can partly be controlled by management actions taken by the farmer, but AM also needs further technical development. To maintain good udder health in AM, it is imperative that the barn is properly designed to keep the cows clean and the cow traffic flowing. Milking frequency must be maintained for every cow according to its stage of lactation and milk production. Careful observation of the cows and knowledge of how to use all data gathered from the system are also important. "Automatic" does not mean that the role of a competent herdsman is in any way diminished. PMID- 21257026 TI - Invited review: effect of udder health management practices on herd somatic cell count. AB - A systematic review of the scientific literature on relationships between management practices used on dairy farms and herd somatic cell count (SCC) was undertaken to distinguish those management practices that have been consistently shown to be associated with herd SCC from those lacking evidence of association. Relevant literature was identified using a combination of database searches (PubMed, Medline, CAB, Agricola, and Web of Science) and iterative screening of references. To be included in the review, a manuscript had to be published after 1979 in French, English, or Dutch; study design had to be other than case report or case series; herds studied had to be composed of >= 40 milking cows producing on average >= 7,000kg of milk in 305 d; interventions studied had to be management practices applied at the herd level and used as udder health control strategies; and SCC had to be measured using electronic cell counting methods. The 36 manuscripts selected were mainly observational cross-sectional studies; 8 manuscripts dealt exclusively with automatic milking systems and 4 with management of calves and heifers and its effect on SCC in early lactation heifers. Most practices having consistent associations with SCC were related to milking procedures: wearing gloves during milking, using automatic take-offs, using postmilking teat dipping, milking problem cows last, yearly inspection of the milking system, and use of a technique to keep cows standing following milking; all were consistently associated with lower herd SCC. Other practices associated with lower SCC were the use of a freestall system, sand bedding, cleaning the calving pen after each calving, surveillance of dry-cow udders for mastitis, use of blanket dry-cow therapy, parenteral selenium supplementation, udder hair management, and frequent use of the California Mastitis Test. Regarding SCC of heifers, most of the consistent associations reported were related to interventions made during the peripartum period. Studies on automatic milking systems have frequently reported elevation of the herd SCC following transition to the new system. These elevations seemed to be mediated both by the lack of monitoring of chronically infected cows and by an elevated incidence of intramammary infections. By assembling the results reported in many different studies, this review generates a more comprehensive understanding of the management practices influencing SCC and highlights areas of SCC control knowledge that lack evidence of effectiveness. PMID- 21257027 TI - Composition, yield, and functionality of reduced-fat Oaxaca cheese: effects of using skim milk or a dry milk protein concentrate. AB - The effect of adding either skim milk or a commercial dry milk protein concentrate (MPC) to whole milk on the composition, yield, and functional properties of Mexican Oaxaca cheese were investigated. Five batches of Oaxaca cheeses were produced. One batch (the control) was produced from whole milk containing 3.5% fat and 9% nonfat solids (SNF). Two batches were produced from milk standardized with skim milk to 2.7 and 1.8% fat, maintaining the SNF content at 9%. In the other 2 batches, an MPC (40% protein content) was used to standardize the milk to a SNF content of 10 and 11%, maintaining the milk fat content at 3.5%. The use of either skim milk or MPC caused a significant decrease in the fat percentage in cheese. The use of skim milk or MPC showed a nonsignificant tendency to lower total solids and fat recoveries in cheese. Actual, dry matter, and moisture-adjusted cheese yields significantly decreased with skim milk addition, but increased with MPC addition. However, normalized yields adjusted to milk fat and protein reference levels did not show significant differences between treatments. Considering skim milk-added and control cheeses, actual yield increased with cheese milk fat content at a rate of 1.34 kg/kg of fat (R=0.88). In addition, cheese milk fat and SNF:fat ratio proved to be strong individual predictors of cheese moisture-adjusted yield (r(2) ~ 0.90). Taking into account the results obtained from control and MPC-added cheeses, a 2.0-kg cheese yield increase rate per kg of milk MPC protein was observed (R=0.89), with TS and SNF being the strongest predictors for moisture adjusted yield (r(2) ~ 0.77). Reduced-fat Oaxaca cheese functionality differed from that of controls. In unmelted reduced-fat cheeses, hardness and springiness increased. In melted reduced-fat cheeses, meltability and free oil increased, but stretchability decreased. These changes were related to differences in cheese composition, mainly fat in dry matter and calcium in SNF. PMID- 21257028 TI - The whey fermentation product malleable protein matrix decreases triglyceride concentrations in subjects with hypercholesterolemia: a randomized placebo controlled trial. AB - Malleable protein matrix (MPM) is a unique whey-derived ingredient obtained through a fermentation process using proprietary lactic acid bacteria strains from the Lactobacillus kefiranofaciens species. Because evidence from animal models suggests that MPM decreases serum lipid concentrations, the purpose of the present trial was to assess the hypothesis that MPM exerts lipid-lowering effects in humans. A total of 161 subjects (50% male; age 54.5 +/- 9.8 yr, body mass index 26.3 +/- 3.6 kg/m(2)) with hypercholesterolemia with baseline low-density lipoprotein cholesterol (LDL-C) levels of 181 +/- 30 mg/dL and normal triglyceride (TG) levels (131 +/- 55 mg/dL) were randomized to receive MPM (2 * 15 g/d) or matching placebo. A 6-wk run-in phase was followed by a double-blind 12-wk treatment phase after randomization. The data were analyzed on an intention to-treat basis. The primary outcome measure was the percentage change of LDL-C. The secondary outcome measures were changes in TG and high-density lipoprotein cholesterol concentrations as well as changes in other cardiovascular risk factors. After 12 wk of treatment, the relative TG decrease from baseline reached 9.8%, whereas LDL-C was slightly decreased (by 1.5%) following MPM treatment compared with placebo in the intention-to-treat cohort. The treatment effect on TG reduction was much higher in the subset of subjects having TG levels at baseline of 150 mg/dL or above (n=42), reaching 20.0% compared with placebo. High density lipoprotein cholesterol concentrations, blood pressure, and fasting blood glucose remained unchanged, whereas a positive treatment effect was seen on hemoglobin A(1c). The MPM product was tolerated well without severe adverse events. In conclusion, MPM has significant TG-lowering properties in subjects with combined hypercholesterolemia and higher TG levels. Its effects on LDL-C concentrations and glucose metabolism deserve further investigation. PMID- 21257029 TI - Effect of kappa-casein B relative content in bulk milk kappa-casein on Montasio, Asiago, and Caciotta cheese yield using milk of similar protein composition. AB - The aim of this study was to investigate the effect exerted by the relative content of kappa-casein (kappa-CN) B in bulk milk kappa-CN on coagulation properties and cheese yield of 3 Italian cheese varieties (Montasio, Asiago, and Caciotta). Twenty-four cheese-making experiments were carried out in 2 industrial and 1 small-scale dairy plant. Detailed protein composition of bulk milk of 380 herds providing milk to these dairies was analyzed by reversed-phase HPLC. To obtain 2 experimental milks differing in the relative content of kappa-CN B in kappa-CN, herds were selected on the basis of bulk milk protein composition and relative content of kappa-CN genetic variants. Milk was collected and processed separately for the 2 groups of selected herds. A difference of 20% in the relative content of kappa-CN B in kappa-CN was obtained for the 2 experimental milks for Montasio and a difference of 15% for Asiago and Caciotta. The 2 experimental milks were of similar protein and CN content, casein number, pH, CN composition, and beta-CN genetic composition. For each cheese-making trial, amounts of milk, ranging from 2,000 to 6,000kg, were manufactured. Each vat contained milk collected at least from 4 dairy herds. Cheese yield after brining and at the end of the aging was recorded. Milk with a greater proportion of kappa CN B in kappa-CN (HIGHB) exhibited similar coagulation properties and greater cheese yield compared with milk with a lower proportion of kappa-CN B in kappa-CN (LOWB). The increased cheese yield observed for HIGHB when manufacturing Montasio cheese was ascribed to a greater fat content compared with LOWB. The probability of HIGHB giving a cheese yield 5% greater than that of LOWB ranged from 51 to 67% for Montasio cheese, but was less than 21% for Asiago and Caciotta cheeses. Variation in relative content of kappa-CN B in kappa-CN content did not relevantly affect industrial cheese yield when milks of similar CN composition were processed. An indirect effect due to the increased kappa-CN content of kappa CN B milk is thought to explain the favorable effects of kappa-CN B on cheese yield reported in the literature. PMID- 21257030 TI - Effect of oxidoreduction potential on aroma biosynthesis by lactic acid bacteria in nonfat yogurt. AB - The aim of this study was to investigate the effect of oxidoreduction potential (Eh) on the biosynthesis of aroma compounds by lactic acid bacteria in non-fat yogurt. The study was done with yogurts fermented by Lactobacillus bulgaricus and Streptococcus thermophilus. The Eh was modified by the application of different gaseous conditions (air, nitrogen, and nitrogen/hydrogen). Acetaldehyde, dimethyl sulfide, diacetyl, and pentane-2,3-dione, as the major endogenous odorant compounds of yogurt, were chosen as tracers for the biosynthesis of aroma compounds by lactic acid bacteria. Oxidative conditions favored the production of acetaldehyde, dimethyl sulfide, and diketones (diacetyl and pentane-2,3-dione). The Eh of the medium influences aroma production in yogurt by modifying the metabolic pathways of Lb. bulgaricus and Strep. thermophilus. The use of Eh as a control parameter during yogurt production could permit the control of aroma formation. PMID- 21257031 TI - Identification of lactic acid bacteria in Taiwanese ropy fermented milk and evaluation of their microbial ecology in bovine and caprine milk. AB - The purpose of this study was to identify species of lactic acid bacteria in Taiwanese ropy fermented milk and to study their microbial dynamics during the fermentation process through conventional microbiological cultivation and PCR denaturing gradient gel electrophoresis. Identification results indicated that Lactococcus lactis ssp. cremoris and Leuconostoc mesenteroides ssp. mesenteroides were the major lactic acid bacteria in Taiwanese ropy fermented milk. Interestingly, 3 groups were identified as Lc. lactis ssp. cremoris using 16S rDNA sequencing, but they showed different denaturing gradient gel electrophoresis patterns and assimilation of carbohydrates. In addition, the microbial dynamics study in different fermentation stages demonstrated that Lc. lactis ssp. cremoris was the most dominant bacterial species in the samples, followed by Leu. mesenteroides ssp. mesenteroides with no differences among the fermentation stages. Finally, the microbial distribution profiles showed that the microbial ecology was different in bovine, caprine, and reconstituted milk, which might further affect the characteristics of the product. PMID- 21257032 TI - Salty taste in dairy foods: can we reduce the salt? AB - Sodium can be found in many sources of the US diet. Dietary guidelines currently suggest a maximum intake of 2,300 mg of sodium (6g of sodium chloride) per day, whereas the average consumer intake is 3,600 mg of sodium (9 g of sodium chloride) per day. The main health concern with high consumption of sodium is hypertension. The objectives of this study were to identify the salty taste intensity of sodium chloride in water and various dairy food matrices, and to identify the just-noticeable difference in concentration at which consumers noticed a decrease in salty taste in these food products. Solutions and food products (water, cheese sauce, cottage cheese, and milk-based soup) were prepared with sodium chloride ranging in concentration from 0.008 to 0.06 M. Seventeen panelists evaluated the salty intensity of each product in triplicate using a magnitude estimation scale. In subsequent tests, panelists (n=50) evaluated salty intensity of these food products in separate sessions using an ascending force choice method to determine the just-noticeable difference. Consumer acceptance tests (n=75 consumers) were conducted with cottage cheeses with and without sodium reductions and under conditions with and without health benefits of sodium reduction. The magnitude estimation scale data were log-transformed, and all data were analyzed by ANOVA with Fisher's least significant difference for means separation. The linear proportion of the power function in the salty taste intensity curve for sodium chloride solutions and the 3 foods was between 0.03 and 0.20 M. Consumers were able to notice and correctly identify reductions in salt concentration of less than 20% in all products. When consumers were informed of sodium reduction and its health benefits before tasting cottage cheese with lower sodium (4-12%), overall liking scores for the lower sodium cottage cheeses were not different from higher sodium cottage cheeses. These results suggest that reducing sodium in cheese sauce, cottage cheese, and milk-based soups may be challenging and that exploration of sodium chloride alternatives in these foods is warranted. Appropriate product positioning or advertising may be beneficial to consumer acceptance of lower sodium types of products. PMID- 21257033 TI - Cooling causes changes in the distribution of lipoprotein lipase and milk fat globule membrane proteins between the skim milk and cream phase. AB - Lipoprotein lipase (LPL) activity and free fatty acid levels were studied in freshly milked, uncooled milk from individual Danish Holstein or Jersey cows, or after storage for up to 24h at either a cooling temperature (4 degrees C) or at the milking temperature (31 degrees C). Upon cooling for up to 24h, LPL activity increased in the cream phase, whereas the activity in the skim milk was steady, as observed for Jersey cows, or increased, as seen for the Holsteins. Storage at 31 degrees C decreased the LPL activity in both the cream phase and the skim milk phase. The increase in free fatty acid levels was found to depend on LPL activity, incubation temperature, substrate availability, and incubation time. Furthermore, the migration of milk proteins between the skim milk phase and the cream phase upon cooling of milk from Jersey cows or from Danish Holstein cows was studied using proteomic methods involving 2-dimensional gel electrophoresis and mass spectrometry. Proteins associated with the milk fat globules were isolated from all milk fractions and analyzed. Major changes in the distributions of proteins between the skim milk phase and the cream phase were observed after cooling at 4 degrees C for 4h, where a total of 29 proteins between the 2 breeds was found to change their association with the milk fat globule membrane (MFGM) significantly. Among these, the MFGM proteins adipophilin, fatty acid-binding protein, and lactadherin, as well as the non-MFGM proteins beta-casein, lactoferrin, and heat shock protein-71, were identified. Adipophilin, lactadherin, and lactoferrin were quantitatively more associated with the MFGM upon cold storage at 4 degrees C, whereas beta-casein, fatty acid-binding protein, and heat shock protein-71 were found to be less associated with the MFGM upon cold storage. PMID- 21257034 TI - Production and partial purification of proteases from Aspergillus oryzae grown in a medium based on whey protein as an exclusive nitrogen source. AB - Several attempts have been made to incorporate whey proteins into curd to increase cheese yield. For some types of cheese, degradation of whey proteins that have been incorporated into the curd would be required to obtain acceptable flavor and texture. On the basis of the high potential for protease synthesis in Aspergillus oryzae, sodium nitrate as a nitrogen source in a minimal medium for fungi, known as Czapek-Dox medium, was replaced with whey protein isolate to induce the protease to hydrolyze whey protein using A. oryzae AHU7146. A solid phase medium adjusted to pH 6 was suitable for this purpose when incubation was carried out at 25 degrees C for 2 wk. The application of column chromatography enabled the resolution of 3 proteolytic components (1, 2, and 3). With respect to optimal temperature and zymographic analysis, component 1 was similar to component 3. In contrast, component 2 was less abundant than the other components and exhibited activity in the alkaline pH region. The degradation of beta lactoglobulin and alpha-lactalbumin in whey protein isolate solution by the crude enzyme was primarily attributed to the action of components 1 and 3, based on HPLC analysis and the N-terminal amino acid sequences; however, zymography demonstrated evident proteolysis due to component 2. Because heat-denatured whey protein aggregates were digestible by the crude enzyme, the proteolytic system from A. oryzae has the potential as an additive to stimulate the ripening of cheese enriched with whey protein. PMID- 21257035 TI - Fat microstructure of yogurt as assessed by x-ray microtomography. AB - In this work, the x-ray microtomography (MUCT) technique was used for the analysis of fat microstructure and quantification of fat in 7 types of yogurts. The dynamic mechanical properties of the yogurt samples also were studied using a controlled-strain rotational rheometer and correlated to the fat microstructure. Five types of commercially produced and 2 homemade yogurts, chosen to exhibit variability in terms of visible structure of fat, were used for this experiment. Appropriate quantitative 3-dimensional parameters describing the fat structure were calculated. With regard to the microstructural and rheological relationship, results from the correlation carried out show that a correlation exists among some microstructural and rheological parameters of the yogurt samples. The results from this study also show that MUCT is a suitable technique for the microstructural analysis of fat as it not only quantifies the fat deposits present, but also determines the deposits' spatial distribution. PMID- 21257036 TI - Attenuating effect of casein glycomacropeptide on proliferation, differentiation, and lipid accumulation of in vitro Sprague-Dawley rat preadipocytes. AB - Food components with the ability to suppress preadipocyte proliferation and intracellular lipid accumulation may be helpful in the prevention of obesity, which is a worldwide health concern. Casein glycomacropeptide (GMP), which has pronounced gastric inhibitory activity, could potentially possess fat synthesis inhibition properties and an obesity-alleviating capacity. The objective of the present study was to investigate the effect of GMP on the proliferation and differentiation of preadipocytes as well as triglyceride accumulation and glycerol-3-phosphate dehydrogenase activity in preadipocytes isolated from Sprague-Dawley rats. Different dosages (0, 0.31, 0.625, 1.25, 2.5, and 5.0 mg/mL) of GMP were co-incubated with preadipocytes. The proliferation activity of preadipocytes significantly decreased in the GMP-treated group compared with that of the control group without GMP supplementation. The GMP exhibited an inhibitory effect against preadipocyte proliferation in a dose-dependent manner; the maximal antiproliferative effect was obtained with 2.5 mg/mL. The GMP also attenuated differentiation, as revealed by decreased lipid content, and the effect was more pronounced when cells were treated with GMP before or at the beginning of differentiation induction than at later stages of cell differentiation. Cultured preadipocytes treated with GMP accumulated fewer triglycerides and had lower glycerol-3-phosphate dehydrogenase activity than did the control cells without GMP supplementation. In conclusion, GMP can inhibit the proliferation, differentiation, and lipid accumulation of preadipocytes in vitro. PMID- 21257037 TI - Changes of protein content and its fractions in bovine milk from different breeds subject to somatic cell count. AB - Global milk production is undeniably dominated by 2 dairy breeds recognized worldwide: Holstein-Friesian and Jersey. A third breed, Simmental, serves as a dual-purpose breed. The objective of the present research was to establish potential changes in the fractional components of bovine milk protein (mainly whey) in relation to the health status of a dairy cow's mammary glands, which is closely determined by somatic cell count (SCC). The milk of 3 breeds was studied: Polish Holstein-Friesian (Black and Red-White varieties), Simmental, and Jersey. The cows were housed in freestall barns and fed according to the total mixed ration feeding system for both winter and summer periods. Milk samples were collected individually from each cow twice a year, in the winter and summer seasons. A total of 1,822 milk samples were evaluated (946 in winter and 876 in summer). The milk was examined for SCC, crude protein, casein, and whey fraction proteins (alpha-lactalbumin, beta-lactoglobulin, lactoferrin, BSA, and lysozyme). The research material for each breed was split into 4 groups based on SCC (group I: <=100,000 cells/mL; group II: 101,000 to 400,000 cells/mL; group III: 401,000 to 500,000 cells/mL; and group IV: 501,000 to 1,000,000 cells/mL). It was found that an increase of SCC promulgated a progressive decline in the daily yield of milk, which was significantly true for the Polish Holstein-Friesian. The level of crude protein decreased slightly as SCC increased, and casein concentration (r= 0.591) also followed this trend of decline. Elevation of SCC produced a decrease of major albumins (i.e., alpha-lactalbumin and beta-lactoglobulin). However, SCC increase induced an increase in the immunoactive proteins (lactoferrin and lysozyme) as well as BSA. The interactions of a breed with increased SCC, which can be measured based on the BSA content of the milk, has indicated various levels of susceptibility to the increase in different breeds. This is confirmed by different values of correlation coefficients for these relationships: 0.71 in the Holstein-Friesian, 0.58 in Simmental, and 0.47 in the Jersey cows. Holstein Friesian cows are more sensitive to mammary gland infections causing a greater decline of their daily milk yields, which, in turn, is reflected in an increase of the negative value of the correlation coefficients between SCC and milk efficiency (-0.24). In the other 2 breeds, the correlations were also negative, but substantially lower (-0.12 and -0.15). PMID- 21257038 TI - A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant. AB - The dry period is a critical time in the lactation cycle, offering the optimum time for cure of existing intramammary infection (IMI), while also encompassing the periods of highest susceptibility to new intramammary infection. Until recent years, intramammary infection in the dry period has been controlled with the use of antibiotic dry cow therapy. The aim of this study was to investigate 3 different dry cow therapy regimens, in low-somatic cell count (SCC; bulk milk SCC<250,000 cells/mL) herds in southwest England. A total of 489 cows was recruited to the study and randomly allocated to receive either the broad spectrum antibiotic cefquinome, a combination treatment comprising the narrow spectrum antibiotic cloxacillin and an internal teat sealant, or the narrow spectrum antibiotic cloxacillin alone. All quarters were sampled for bacteriology at drying off and again in the week immediately postcalving; 2 quarters were also sampled 2 wk before the estimated calving date to allow an assessment of infection dynamics during the dry period. Quarters were subsequently monitored for clinical mastitis for the first 100 d of lactation. Conventional multilevel (random effects) models were constructed to assess the efficacy of products in preventing IMI. Survival analysis was used to examine factors that influenced the risk of clinical mastitis using conventional Cox proportional hazards models. No differences were identified between the treatment groups in terms of cure of IMI caused by the major pathogens. Quarters in both the combination and cefquinome treated groups were more likely to be free of a major pathogen or enterobacterial pathogen postcalving. With respect to clinical mastitis, the cefquinome-treated group was less likely to develop clinical mastitis than was the cloxacillin treated group. PMID- 21257039 TI - Effects of flooring and restricted freestall access on behavior and claw health of dairy heifers. AB - Claw health, locomotion, feed intake, milk yield, body weight, activity, and lying and standing behavior of dairy heifers were monitored in a single dairy herd during the first 3 mo after calving. During the first 8 wk after calving, 2 treatments were applied: restricted freestall access by closing the stalls between 2300 h and 0500 h (yes or no) and alley flooring (concrete or rubber topped slatted floors). Apart from treatments, housing was identical. The animals were kept in small groups (n=4 to 6) in adjacent barn pens. Thereafter, the animals were kept in 1 group in a freestall section with concrete slatted floor and unrestricted access to the stalls for 5 wk. All animals were fed the same partial mixed ration. We hypothesized that (1) hard flooring causes high mechanical load of the claws and (2) restricted freestall access causes prolonged standing bouts and reinforced effects of hard flooring on claws. The heifers had only minor claw lesions before first calving, and the prevalence and severity of sole hemorrhages increased during the first 3 mo after calving (from 0.24 +/- 0.08 to 1.18 +/- 0.14 and from 0.04 +/- 0.01 to 0.24 +/- 0.02, respectively), particularly in the outer hind claws. Animals kept on rubber alley flooring had lower average hemorrhage scores in wk 9 (0.13 +/- 0.03 vs. 0.21 +/- 0.03) and wk 14 (0.20 +/- 0.03 vs. 0.27 +/- 0.03) after calving, had a slower feed intake (3.05 +/- 0.14 vs. 3.46 +/- 0.14 g/s) and spent more time feeding (7.3 +/- 0.3 vs. 6.6 +/- 0.3 min/h) than animals kept on hard concrete alley floors. Restricted freestall access resulted in fewer standing bouts per day (14.4 +/- 1.0 vs. 17.9 +/- 1.0) and more strides per hour (99.8 +/- 5.4 vs. 87.2 +/- 5.4) without changing overall standing time (15.0 +/- 0.3 vs. 14.7 +/- 0.3 h/d) and did not affect the occurrence of sole hemorrhages. The animals with no overnight freestall access spent more time standing (55.9 +/- 0.9 vs. 35.8 +/- 0.9 min/h) and feeding (7.8 +/- 0.3 vs. 4.3 +/- 0.3 min/h) between 2300 and 0500 h and less during the rest of the 24-h period (31.3 +/- 0.8 vs. 37.0 +/- 0.8 min/h and 6.8 +/- 0.3 vs. 7.6 +/- 0.3 min/h). Thus, the animals adapted to restricted freestall access, that caused increased overnight standing, by additional lying down during the day and used part of the extra standing time at night for feeding. The restrictions probably had only a minor effect on the mechanical load of their claws. Therefore, the first part of the hypothesis was confirmed and the second part was rejected. PMID- 21257040 TI - Modeling the retention of rumen boluses for the electronic identification of goats. AB - We constructed a regression model to estimate the retention of electronic boluses in goats. With this aim, 2,482 boluses were administered to goats from dairy (Murciano-Granadina, n=1,326; French Alpine, n=381) and meat (Blanca de Rasquera, n=532) breeds. A total of 19 bolus types made of materials (ceramic, plastic tubes filled with concrete or silicone, and ballasts) differing in their specific gravity (SG) were used, thereby obtaining a wide variation in bolus features: diameter (9 to 22 mm), length (37 to 84 mm), weight (5 to 111 g), volume (2.6 to 26 mL), and SG (1.0 to 5.5). Each bolus contained a half-duplex glass encapsulated transponder (32 * 3.8mm) and was administered using adapted balling guns. Murciano-Granadina and Blanca de Rasquera goats also wore 2 visual plastic ear tags: V1 (double flag, 5.1g) and V2 (flag-button, 4.2g). No data on ear tags in French Alpine goats was available. Bolus and ear tag retention [(retained/monitored) * 100] was recorded for at least 1 yr. Dynamic reading efficiency [(dynamic reading/static reading) * 100] was also evaluated from 1,496 bolus readings. No administration incidences or apparent negative behavior or performance effects were observed for any bolus type. Static reading efficiency of retained boluses was 100%, except for the prototypes with metal ballasts, which yielded a 93.3% reading efficiency. Retention of metal-ballasted boluses was confirmed using x-ray equipment. Excluding ballasted boluses, a 99.5% dynamic reading efficiency was obtained. Ear tag losses were 6.5% for V1 and 3.7% for V2, ranging from 3.2 to 7.8% depending on ear tag type and goat breed. Bolus retention varied (0 to 100%) according to their physical features. Obtained data allowed the fitting of a logistic model of bolus retention rate according to bolus volume and weight (R(2) = 0.98); the SG was implicitly considered. Estimated weight and SG to produce medium- (15 mL) and standard-sized (22 mL) boluses for 99.95% retention rate in goats were 73.0 and 94.1g, and 4.87 and 4.28, respectively. Mini-boluses are not recommended, as none of the available radio translucent materials reach the required SG. In conclusion, increase of SG was fundamental to optimize bolus retention. Medium-sized boluses (10 to 15 mL; SG 5.8 to 4.9) for early administration and efficient retention in adult goats could be produced, thereby addressing the problem of using proper boluses for goat identification. PMID- 21257041 TI - Periparturient effects of feeding a low dietary cation-anion difference diet on acid-base, calcium, and phosphorus homeostasis and on intravenous glucose tolerance test in high-producing dairy cows. AB - Feeding rations with low dietary cation-anion difference (DCAD) to dairy cows during late gestation is a common strategy to prevent periparturient hypocalcemia. Although the efficacy of low-DCAD rations in reducing the incidence of clinical hypocalcemia is well documented, potentially deleterious effects have not been explored in detail. The objective of the study presented here was to determine the effect of fully compensated metabolic acidosis on calcium and phosphorus homeostasis, insulin responsiveness, and insulin sensitivity as well as on protein metabolism. Twenty multiparous Holstein-Friesian dairy cows were assigned to 1 of 2 treatment groups and fed a low-DCAD ration (DCAD = -9 mEq/100g, group L) or a control ration (DCAD = +11 mEq/100g, group C) for the last 3 wk before the expected calving date. Blood and urine samples were obtained periodically between 14 d before to 14 d after calving. Intravenous glucose tolerance tests and 24-h volumetric urine collection were conducted before calving as well as 7 and 14 d postpartum. Cows fed the low-DCAD ration had lower urine pH and higher net acid excretion, but unchanged blood pH and bicarbonate concentration before calving. Protein-corrected plasma Ca concentration 1 d postpartum was higher in cows on the low-DCAD diet when compared with control animals. Urinary Ca and P excretion was positively associated with urine net acid excretion and negatively associated with urine pH. Whereas metabolic acidosis resulted in a 6-fold increase in urinary Ca excretion, the effect on renal P excretion was negligible. A more pronounced decline of plasma protein and globulin concentration in the periparturient period was observed in cows on the low-DCAD diets resulting in significantly lower total protein and globulin concentrations after calving in cows on low-DCAD diets. Intravenous glucose tolerance tests conducted before and after calving did not reveal group differences in insulin response or insulin sensitivity. Our results indicate that fully compensated metabolic acidosis increased the Ca flux resulting in increased urinary calcium excretion before calving and increased plasma Ca concentration on the day after calving, whereas the effect on P homeostasis was unlikely to be clinically relevant. The clinical relevance of the effect of metabolic acidosis on the plasma protein and globulin concentration is unclear but warrants further investigation. PMID- 21257042 TI - Behavior of cows during and after peak feeding time on organic and conventional dairy farms in the United Kingdom. AB - The behavior of groups of housed, lactating dairy cattle was observed over 2 winter housing periods on 20 organic farms and 20 conventional farms in the United Kingdom. Three methods were used: (1) 6 video-clips of 10 min duration were captured of cows feeding at sections of the feed-bunk face during the peak feeding period (0 to 90 min) and continuously observed for aggressive interactions among cows; (2) the proportion of cows at the feed-bunk face was scanned every 15 min for 4.5h to include the peak feeding period (0 to 255 min); and (3) all nonfeeding behaviors were scanned every 15 min for 2.5h after the peak feeding period (120 to 255 min). The latter scans were analyzed post hoc for measures of cow comfort (freestall farms only). Management and health data were collected on each farm. On farms with open-fronted feed-bunk faces, a greater number of aggressive interactions occurred at the feed-bunk face at peak feeding time on organic farms than on conventional farms (organic = 36.3 +/- 4.4; conventional = 29.1 +/- 3.0). Higher proportions of cows were at the feed-bunk face at peak feeding on organic farms than on conventional farms (organic=0.58 +/ 0.04; conventional=0.48 +/- 0.03). Housing type (freestall versus straw pen) explained most differences in postfeeding behavior (proportion of ruminating cow in alleyways: freestalls=0.16+/-0.06 vs. straw-pen=0.08 +/- 0.03), with few differences between organic and conventional herds. On freestall farms, the proportions of cows on organic farms lying down postfeeding was smaller than in conventional herds (organic=0.38 +/- 0.09 vs. conventional=0.43 +/- 0.07). Differences in behavior around peak feeding time could be associated with the reduction in food "quality" on organic farms compared with the energy requirement of the cows, with cows on organic farms being highly motivated to feed. A correlation was observed between farms that had high amounts of lying and farms that had high lameness prevalence (R(2)=55.3), suggesting a complex relationship between comfort and pain. Overall, the behavior of dairy cows on organic farms was not different from that of conventionally reared cows, and the results suggest that most behavioral welfare problems relating to housing could be alleviated by management practices. PMID- 21257043 TI - Associations between paratuberculosis milk ELISA result, milk production, and breed in Canadian dairy cows. AB - The 3 objectives of this study were (1) to quantify milk production differences among cows with different paratuberculosis (ParaTB) milk ELISA results; (2) to determine if production differences existed in lactations preceding the test among cows with different ParaTB milk ELISA results; and (3) to assess whether Channel Island breeds were more likely to test positive with the ParaTB milk ELISA than other dairy breeds. Current and completed lactation records from 35,591 dairy cows in Ontario and western Canada that had been tested with a commercial ParaTB milk ELISA were included in the analysis. The first occurrence of the highest categorical test result was used to classify the cow. Cows were then grouped by the lactation in which the first high-positive (HTP), low positive, or negative milk ELISA occurred, and comparisons were made within lactation groups. High test-positive cows were defined as those that had an optical density >= 1.0 on at least 1 ParaTB milk ELISA. The associations between ParaTB milk ELISA status and milk production, as measured by the 305-d milk yield, were assessed with a series of linear mixed models. The effect of breed on the likelihood of testing positive with the milk ELISA was assessed using a logistic mixed model for the lactation in which the first negative or positive ParaTB milk ELISA occurred. Test-positive cows produced on average 2.9 to 6.8% less milk than negative herdmates in the lactation in which they were tested. The HTP cows produced on average 466, 514, and 598 kg less milk than low-positive herdmates in lactations 1, 2, and 4, respectively. Cows testing low-positive in their second lactation had, on average, a 218-kg higher milk yield in their first lactation than their test-negative herdmates. Otherwise, no association was found between test result and milk production in preceding lactations. Differences in milk production among negative, test-positive, and HTP cows increased with increasing parity. Cows of the Channel Island breeds had 1.4 to 8.3 times the odds to test positive compared with other dairy breeds. The findings of this study are consistent with previous studies that have reported that milk production is lower in test-positive animals. The differences in milk production increased with increasing ELISA optical density scores and parity in which the animal tested positive. However, with the exception of second-lactation cows, no differences in milk production were observed in tests preceding lactations. The differences in milk ELISA status among dairy breeds support the need for further studies investigating the genetic component of ParaTB susceptibility. PMID- 21257044 TI - Cow-level and herd-level risk factors for subclinical endometritis in lactating Holstein cows. AB - The objectives of this study were to obtain prevalence estimates for subclinical endometritis (SCE), determine cow- and herd-level risk factors, and evaluate the reproductive consequences of SCE. A cross-sectional study was used to determine prevalence and risk factors with cows followed in a prospective study to determine reproductive outcomes. Lactating Holstein cows were sampled between 40 and 60 d in milk using low-volume uterine lavage, and cytology was evaluated to determine SCE status. In total, 779 cows from 38 herds were used in the analysis. The cow-level prevalence of SCE was 25.9%. Within-herd level prevalence ranged from 4.8 to 52.6% (median 26.3%, interquartile range 15.6 to 33.3%). Cow-level risk factors identified were ketosis [odds ratio (OR) 3.83; 95% confidence interval (CI) 1.82-8.07], acute metritis (OR 1.86; 95% CI 1.05-3.30], and the interaction between milk production and parity. Primiparous cows that produced more milk had increased odds of having SCE, whereas multiparous cows that produced more milk had decreased odds of having SCE. Herd-level risk factors identified were housing early postpartum cows on bedded packs (herd-level SCE=36.1%), which increased herd prevalence of SCE by 16.7% (SE 5.58) compared with early postpartum cows housed in freestalls (herd-level SCE=19.4%), and straw bedding in the calving pen, which decreased herd prevalence of SCE by 10.7% (SE 3.59) compared with herds that used other bedding material. In this study, primiparous cows with and without SCE had similar reproductive performance; however, multiparous cows with SCE had median days open 44 d longer (159 d; 95% CI 126-186 d) compared with unaffected multiparous cows (115 d; 95% CI 106-132 d). PMID- 21257045 TI - Structure and performance of Awassi and Assaf dairy sheep farms in northwestern Spain. AB - Data of 69 dairy sheep farms (70% Assaf and 30% Awassi crossbred), located in the Spanish Autonomous Community of Castilla y Leon and grouped for receiving technical advice, were used to study their structure and performance. Farm surface was 55.4ha, on average. Approximately 25% of the farms did not have cultivation land, and the other 75% had, on average, 73ha (from which 67% were devoted to forage). Farms used 2.1 annual work units (familiar, 90%), 493 ewes, and yielded 147,000 L/yr of milk. Farmers were tenant (84%), younger than 45 yr (70%), had new houses, and were grouped in cooperatives (83%). Sheep were fed indoors (occasional grazing only) in modern loose stalls and had machine milking. Planned mating (summer to fall) was done in 91% of farms (hormonal treatment, 54%) but artificial insemination was scarce (23%). Annual milk sales averaged 309 L/ewe (fat, 6.5%; protein, 5.3%; log(10) somatic cell count, 5.7), and milk was sent to local dairy industries for cheese production, and 1.35 lambs/ewe were harvested as milk-fed lambs (lechazo). Artificial lamb rearing was done in 38% of farms (automatic, 81%; manual, 19%). Total mixed rations were used in 33% of farms, and the rest used rationed concentrate (including self-produced cereals) according to physiological stage of the ewes (0.45 to 1.97 kg/d) and ad libitum forage (dehydrated, 70%; hay, 68%; fresh, 25%; silage, 12%). The concentrate-to forage ratio ranged between 32 and 61%. In total, 68% of farms bought more than half of the forage, and 87% of them bought more than half of the required concentrates. According to structural, productive, and managerial traits, 4 types of farms were differentiated by using multiple correspondence analysis and cluster analysis. Type groups were: 1) large-surface farms, devoted to cereal and forage production, predominantly with Awassi crossbreed sheep and a high level of self-consumed commodities (12% of the farms); 2) large flocks with intermediate farm surfaces devoted to forage production and predominantly with Assaf sheep (30% of the farms); 3) high-yielding farms, with intermediate sized flocks of Assaf sheep and very intensive management (42% of the farms); and, 4) no-land farms predominantly with Assaf sheep (16% of the farms). In conclusion, the dairy sheep farms studied showed more adoption of intensive production systems than traditional farms, which resulted in higher milk and lamb yields. Despite all of them being based on familiar units, as traditional farms, they were highly dependent on external resources and became more vulnerable, faced with future uncertainties of the market. PMID- 21257046 TI - Effects of high dietary crude protein on the characteristics of preovulatory follicles in dairy heifers. AB - The objectives were to examine the effect of high dietary crude protein on characteristics of preovulatory follicles in dairy heifers. Eight Israeli Holstein heifers, 4 fitted with rumen fistula and 4 intact, were assigned to 1 of 3 treatments in a replicated (n=2) 4 * 3 incomplete Latin square design with 39-d periods. Treatments were: low (6.0%; LP), moderate (13.0%; MP), and high (20.0%; HP) crude-protein diets, containing 1.27 Mcal NE(L)/kg dry matter. Diets were based on approximately 66% wheat straw and various proportions of ground corn grain and soybean meal. The estrous cycles of the heifers were synchronized, and 14 d after behavioral estrus, heifers received PGF(2 alpha) injections. After a further 40 h, at d 39 of each period, follicular fluid (FF) was aspirated from follicles of diameter >7 mm. The intake of the LP diet was 9% lower than that of MP and HP diets. Rumen ammonia and plasma urea nitrogen concentrations were highest in the HP and lowest in the LP, with intermediate levels in MP diets. No differences were found between treatments in plasma and FF concentrations of glucose and nonesterified fatty acids. High-protein diets increased urea concentrations very similarly in preovulatory FF and in plasma. No differences were observed between diets, in preovulatory follicle diameters and concentrations of androstenedione. However, higher estradiol and progesterone concentrations in FF were observed under the HP than under the MP diet, with no difference between diets in estrogen to progesterone ratio. It can be concluded that high concentrations of urea in plasma, caused by high dietary crude protein, penetrated into preovulatory follicles, but did not impair preovulatory characteristics. This lack of detrimental effects might be attributed to the use in this study of nonlactating heifers, which have fewer nutritional and physiological constraints and eliminate negative effects of potential interactions with high urea on dairy cows' reproductive systems. PMID- 21257047 TI - The use of plastic cover sheaths at the time of artificial insemination improved fertility of lactating dairy cows. AB - An adequate and clean artificial insemination (AI) technique is recommended to improve reproductive outcomes in dairy cattle. The objective of this study was to evaluate the effectiveness of using protective plastic sheaths (PS) to minimize contamination of the AI catheter (AIC) on pregnancies per AI (PAI) in lactating dairy cattle. Lactating cows housed in freestall barns on a commercial dairy farm were presynchronized with 2 injections of PGF(2alpha) given 14 d apart (starting at 26+/-3 d postpartum) followed by Ovsynch (GnRH-7 d-PGF(2alpha)-56 h-GnRH-16 h timed-AI; TAI) 12 d later. Cows presenting signs of standing heat any time during the protocol received AI, whereas the remaining animals were subjected to TAI 16h after second Ovsynch GnRH. At the time of AI (1 AI technician), 996 services from 773 lactating dairy cows were randomly assigned to 1 of the 2 groups; with (TRT, n=487) or without (CON, n=509) the use of disposable PS. In the TRT group, the AIC protected with a PS was introduced into the vagina; once in the cranial portion of the vagina adjacent to the cervical os, the PS was pulled back and only the AIC was manipulated through the cervix into the uterine body for semen deposition. In the CON group, cows were inseminated without the use of PS. Samples were taken with a sterile cotton swab from the tip of the AIC (n=51) after AI from both treatment groups. Pregnancy diagnosis was determined by ultrasonography 39+/-3 d after AI. Cultured swab samples revealed that the use of PS was effective in minimizing contamination of the AIC (positive bacterial growth: TRT=61.53% vs. CON=100%). Overall, the proportion of cows pregnant was greater for cows in TRT (42.7) compared with the CON group (36.1). For first services postpartum, PAI did not differ between CON (43.01%, n=194) and TRT (43.8%, n=182) groups. However, PAI for second or greater services were greater in TRT (43.8%, n=305) than in CON cows (32.3%, n=315). Results from this study provided evidence that the use of PS during AI improved PAI for second or greater services in lactating dairy cows. Performing a clean AI technique through the use of PS may be an effective strategy to improve reproductive outcomes in dairy cattle. PMID- 21257048 TI - Short communication: measures of weight distribution and frequency of steps as indicators of restless behavior. AB - Restless behavior, as measured by the steps taken or weight shifting between legs, may be a useful tool to assess the comfort of dairy cattle. These behaviors increase when cows stand on uncomfortable surfaces or are lame. The objective of this study was to compare 2 measures of restless behavior, stepping behavior and changes in weight distribution, on 2 standing surfaces: concrete and rubber. Twelve cows stood on a weighing platform with 1 scale/hoof for 1h. The platform was covered with either concrete or rubber, presented in a crossover design. Restlessness, as measured by both the frequency of steps and weight shifting (measured as the standard deviation of weight applied over time to the legs), increased over 1h of forced standing on either concrete or rubber. A positive relationship was found between the frequency of steps and the standard deviation of weight over 1h for both treatments and pairs of legs (r >= 0.66). No differences existed in the standard deviation of weight applied to the front (27.6 +/- 1.6 kg) or rear legs (33.5 +/- 1.4 kg) or the frequency of steps (10.2 +/- 1.6 and 20.8 +/- 3.2 steps/10 min for the front and rear pair, respectively) between rubber and concrete. Measures of restlessness are promising tools for assessing specific types of discomfort, such as those associated with lameness, but additional tools are needed to assess comfort of non-concrete standing surfaces. PMID- 21257049 TI - Short communication: influence of sampling interval on the accuracy of predicting bulk milk somatic cell count. AB - Although bulk milk somatic cell count (BMSCC) is, in most instances, not a good proxy for actual average herd somatic cell count (SCC), BMSCC is the only SCC parameter available to monitor trends in udder health for a large number of farms worldwide. The frequency of sampling BMSCC varies considerably between countries, and it is unknown to what extent the sampling interval of BMSCC or variation in BMSCC data itself influences the accuracy. The aim of this study was to assess the effect of sampling interval and variation of the BMSCC data on the accuracy to predict BMSCC. Because BMSCC is measured at regular time intervals, an artificial neural network (ANN) was used to determine both the effect of sampling interval and variation of the BMSCC data. The intervals examined in this study ranged from 4 to 14 d and were compared with the baseline of a standard 2-d sampling interval. The BMSCC data were collected every other day for a 24-mo period on 949 farms, and all series were created by exclusion of BMSCC data in between the original 2-d sampling interval series. The effect of variation of BMSCC was determined by comparing the error of the ANN model in 2 subsets of farms, those with the lowest SD (n=239) and those with a high SD of BMSCC data (n=236). No significant differences were found in any of the sampling intervals between the 2 cohorts of low and high SD in BMSCC. Overall, compared with the 2-d sampling interval, on average the error of the ANN model was 32,600 cells/mL for all farms included, ranging from 15,000 cells/mL (4-d interval) to 41,000 cells/mL (14-d sampling interval). Therefore, the length of the sampling interval greatly influences the usefulness of BMSCC data to monitor trends in udder health at the herd level. PMID- 21257050 TI - Effect of precalving and postcalving dietary energy level on performance and blood metabolite concentrations of dairy cows throughout lactation. AB - The effects of the level of energy intake (high E and low E) offered before and after calving on body condition score at calving, production performance, and energy status in the first 250 d of lactation were evaluated in a 2 * 2 factorial design experiment involving 80 Holstein-Friesian dairy animals (40 primiparous and 40 multiparous). From d 80 until d 21 precalving, primiparous animals were offered either high or low pasture allowances. Thereafter, these animals were housed and had ad libitum access to a high energy density diet (high E) or restricted access [6 kg of dry matter (DM) per d] to a low energy density diet (low E), respectively, until calving. From d 100 until d 42 precalving, multiparous animals were offered either ad libitum or restricted (10 kg of DM/d) access to a late lactation diet, and thereafter, had ad libitum access to a high E diet or restricted access (7 kg of DM complete diet/d) to a low E diet, respectively, until calving. The forage to concentrate (F:C) ratios (DM basis) of these high E and low E diets [d 42 (d 21 in primiparous animals) until calving] were 64:36 and 83:17, respectively. Cows offered high E and low E precalving diets were allocated to either a high E or low E postcalving diet [F:C ratio (DM basis) of 30:70 and 70:30, respectively] and remained on these diets until d 250 of lactation. Multiparous animals offered a high E diet precalving had a significantly higher body condition score at calving than those offered the low E diet precalving. This effect was not evident in primiparous animals. Precalving diet had no significant effect on plasma nonesterified fatty acid concentrations during the last 3 wk precalving in primi- or multiparous animals. Primiparous animals offered a high E diet precalving had significantly higher postcalving plasma concentrations of nonesterified fatty acid, suggesting greater mobilization of body reserves. Primi- and multiparous animals offered a high E diet postcalving had a significantly higher dry matter intake, milk yield, and energy status postcalving compared with animals offered a low E diet postcalving. Milk yields of primiparous animals offered high E and low E diets postcalving were 29.7 and 24.8 kg/d, respectively, and milk yield of multiparous animals offered high E and low E diets postcalving were 33.5 and 28.2 kg/d, respectively. It is concluded that altering body condition score during the dry period is difficult but that specific dietary regimens applied precalving can have a significant influence on postcalving production and energy-related parameters. PMID- 21257051 TI - The ensiling capability of a mixture of sodium benzoate, potassium sorbate, and sodium nitrite. AB - The objective of this study was to evaluate the effects of an additive comprising sodium benzoate, potassium sorbate, and sodium nitrite on the quality of silages fermented from various forage crops. Thirteen crops in 3 groups (differing in dry matter concentration and degree of ensilability) were treated with the additive mixture and compared with untreated control silages. The main focus was on yeast and Clostridia spp. activity in the silages, although other silage quality criteria also were measured. Treated silages from difficult-to-ensile crops at low dry matter were found to have significantly lower silage pH, fewer clostridial spores, and reduced concentrations of ammonia N, butyric acid, and ethanol. In addition, dry matter losses were reduced in treated silages compared with those receiving no additive. Similar results were observed in silages from easy or intermediate ensilable crops when the dry matter concentration was <300 g/kg. When the dry matter concentration was >350 g/kg, the treated silages contained less ammonia N, ethanol, and yeast for 3 out of 4 forages. All treated silages from all crops were aerobically stable during the examination time. The application of the tested additive mixture reduced the growth of undesirable microflora and thereby reduced silage losses and prolonged the aerobic stability of the silages. PMID- 21257052 TI - Effect of fibrolytic enzyme application to low- and high-concentrate diets on the performance of lactating dairy cattle. AB - The objective of this study was to examine the effect of applying a fibrolytic enzyme preparation to diets with high (48% of diet dry matter, DM) or low (33% of diet DM) proportions of concentrate on production performance of lactating dairy cows. Sixty lactating Holstein cows (589 kg +/- 20; 22 +/- 3 d in milk) were stratified according to milk production and parity and randomly assigned to 4 treatments with a 2 * 2 factorial arrangement. Dietary treatments included the following: 1) low-concentrate diet (LC); 2) LC plus enzyme (LCE); 3) high concentrate diet (HC); and 4) HC plus enzyme (HCE). The enzyme was sprayed at a rate of 3.4 mg of enzyme/g of DM on the total mixed ration daily and the trial lasted for 63 d. A second experiment with a 4 * 4 Latin square design used 4 ruminally fistulated cows to measure treatment effects on ruminal fermentation and in situ ruminal dry matter degradation during four 18-d periods. Enzyme application did not affect dry matter intake (DMI; 23.9 vs. 22.3 kg/d) or milk production (32.8 vs. 34.2 kg/d) but decreased estimated CH(4) production, increased total volatile fatty acid concentration (114.5 vs. 125.7 mM), apparent total tract digestibility of DM (69.8 vs. 72.6%), crude protein (CP; 69.2 vs. 73.3%), acid detergent fiber (50.4 vs. 54.8%), neutral detergent fiber (53.7 vs. 55.4%), and the efficiency of milk production (1.44 vs. 1.60 kg of milk/kg of DMI). Feeding more concentrates increased DMI (21.5 vs. 24.8 kg/d), milk yield (32.2 vs. 34.7 kg/d), milk protein yield (0.89 vs. 0.99 kg/d), and DM (69.9 vs. 72.6%), but decreased ruminal pH (6.31 vs. 6.06). Compared with cows fed HC, those fed LCE had lower DMI (20.8 vs. 25.7 kg/d) and CP intake (3.9 vs. 4.8 kg/d), greater ruminal pH (6.36 vs. 6.10), and similar milk yield (33.2 +/- 1.1 kg/d). Consequently, the efficiency of milk production was greater in cows fed LCE than those fed HC (1.69 vs. 1.42 kg of milk/kg of DMI). This fibrolytic enzyme increased the digestibility of DM, CP, neutral detergent fiber, and acid detergent fiber and the efficiency of milk production by dairy cows. Enzyme application to the low-concentrate diet resulted in as much milk production as that from cows fed the untreated high-concentrate diet. PMID- 21257053 TI - The use of a multivariate analysis to study between-goat variability in feeding behavior and associated rumen pH patterns. AB - This study examined feeding patterns and their relation to rumen pH. The measured variables were the cumulative time spent chewing (eating or ruminating) and the mean rumen pH, per 20-min intervals (46 intervals altogether). A total of 333 feeding patterns, defined as time-series of measurements for 1 animal and 1 given day during 15 h and 20 min following the afternoon feeding, were collected from 12 stall-housed dairy goats fed a total mixed ration twice daily. The first objective of this study was to analyze the within-day variability of feeding behavior to characterize different feeding patterns. The second objective was to analyze, for each goat, the between-day variability of its feeding behavior. The third objective was to study the influence of feeding behavior on rumen pH. A multivariate method (principal component analysis) was performed on the time spent eating or ruminating during each of the 46 intervals. The factor score plots generated by the principal component analysis highlighted the evolution in time of chewing activities. They also were used to determine 4 different types of feeding behavior in the extreme patterns of the first 2 axes. These feeding patterns were associated with different rumen pH patterns in goats with the same total dry matter intake and mean rumen pH. Some goats had a major eating period immediately after feeding, followed by a period of rumination; this pattern was associated with a marked decrease in rumen pH and a pH nadir below 6.0. Other goats performed alternate periods of eating and ruminating throughout the studied period. The latter feeding pattern was associated with a shorter total duration of rumination, but a more stable rumen pH than the feeding pattern described previously. Feeding pattern was quite constant between days for some goats, but highly variable for others. However, the continuum observed between these 4 groups shows that many intermediate types of behavior can be observed. In conclusion, characterizing animals according to their feeding behavior by using a principal component analysis may provide information on the animal's predisposition to rumen acidosis. PMID- 21257054 TI - Prevalence of gastrointestinal disorders recorded at postmortem inspection in white veal calves and associated risk factors. AB - The study aimed at assessing the prevalence of poor rumen development, presence of rumen plaques, rumen papillae hyperkeratinization, and abomasal lesions in veal calves and to investigate risk factors for their occurrence at the farm level. Within a wide cross-sectional study, a sample of 170 veal farms representative of the European veal meat production systems was considered in the 3 major producing countries (99 in the Netherlands, 47 in France, and 24 in Italy). An average of 59 +/- 10 (SD) rumens and abomasa belonging to calves from a single batch per farm were inspected at the abattoir by trained observers to assess the incidence of these gastrointestinal disorders. Potential risk factors for their occurrence related to farm management, housing, and to the feeding plan were obtained by a questionnaire submitted to the stockperson. Prevalence of poor rumen development (almost no papillae present), rumen plaques, and hyperkeratinization were 60.4, 31.4, and 6.1% of rumens, respectively, whereas abomasal lesions in the pyloric area were recorded in 74.1% of abomasa. Independent variables related to the feeding system confirmed to be the main risk factors for the occurrence of gastrointestinal disorders in veal calves. However, additional risk sources for each given problem were identified among housing and management variables. The provision of a low amount of solid feed (<= 50kg of dry matter/head per cycle) was a relevant risk for rumen underdevelopment. Rumen wall alterations (plaques and hyperkeratinization) and abomasal lesions were instead associated with the administration of large quantities of solids (151-300 kg of dry matter/head per cycle) in calves receiving milk replacer during the entire fattening cycle. Among the types of solid feed, cereal grain acted as a preventive measure for low rumen development, whereas it was a risk factor for the occurrence of rumen plaques, papillae hyperkeratinization, and abomasal lesions. Some housing and management options adopted to improve veal calf welfare (i.e., higher space allowance and use of heating) were associated with lower risk for gastrointestinal disorders. PMID- 21257055 TI - Deletion of arginine from an abomasal infusion of amino acids does not decrease milk protein yield in Holstein cows. AB - This study was undertaken to determine if a limited supply of Arg would alter milk and milk protein yields, as well as mammary uptake of AA and energetic substrates. Six lactating Holstein cows (199 +/- 5 d in milk) were used in a replicated 3 * 3 Latin square balanced for residual effects with 14-d periods. The diet was formulated to supply 100% of the National Research Council net energy requirement and 72% of the metabolizable protein requirement. The treatments were randomly distributed as abomasal infusions of (1) water (CTL), (2) a mixture of essential AA (EAA) excluding Arg (ARG-), or (3) a mixture of EAA including Arg (ARG+). The profile of EAA in the infusates was the same as that found in casein with the exception that methionine was increased to maintain a 3:1 ratio of digestible lysine:methionine (total dietary+infusion). Milk protein yield was increased by the ARG+ compared with the CTL treatment and deletion of Arg in the infusate (ARG-) did not impair this response. Deletion of Arg from the EAA mixture decreased the mammary uptake of Arg relative to that of the CTL treatment, and although the uptake:output ratio decreased from 2.52 (ARG+) to 2.12 (ARG-), it was still largely in excess of Arg secretion in milk protein. Otherwise, Arg deletion did not affect any of the measured parameters (no significant difference between ARG- and ARG+) except Arg and urea arterial concentrations. In support of the increased yields of milk protein and lactose, mammary uptake of the group 2 AA (Ile, Leu, Lys, and Val) increased and the uptake:output ratio tended to increase from 1.04 to 1.23. The mammary uptake:milk protein output ratio was not different from 1 and not different among treatments for the group 1 AA (His, Met, Phe+Tyr, Trp). Mammary uptake of energetic substrates did not vary across treatments, although milk lactose yield increased with the ARG+ treatment relative to CTL. These results indicate that deletion of Arg has minimal effects on milk and milk component yields when the remaining EAA are supplied in sufficient amounts despite decreased mammary Arg uptake and that group 2 AA seem to be involved in the mammary gland to support the lactose yield response to EAA infusion. PMID- 21257056 TI - Effects of feeding rapeseed oil, soybean oil, or linseed oil on stearoyl-CoA desaturase expression in the mammary gland of dairy cows. AB - Stearoyl-CoA desaturase (SCD) is an important enzyme in the bovine mammary gland, and it introduces a double bond at the Delta(9) location of primarily myristoyl-, palmitoyl-, and stearoyl-CoA. The main objective of this study was to compare the effects of various fatty acids (FA) typically present in dairy cow rations on the expression of SCD1 and SCD5 in the mammary gland of dairy cows. Twenty-eight Holstein-Friesian cows were randomly assigned to 1 of 4 dietary treatments. The dietary treatments were a basal diet supplemented (dry matter basis) with 2.7% rapeseed oil as a source of C18:1 cis-9; 2.7% soybean oil as a source of C18:2 cis-9,12; 2.7% linseed oil as a source of C18:3 cis-9,12,15; or 2.7% of a 1:1:1 mixture of the 3 oils. The oil supplements were included in the concentrate, which was fed together with corn silage and grass silage. In addition, cows were grazing on pasture, consisting mainly of perennial ryegrass, during the day. Biopsies from the mammary gland were taken and analyzed for mRNA expression of SCD1 and SCD5 by using quantitative real-time PCR. Milk yield as well as milk protein and fat contents did not differ among the 4 dietary treatments. Dietary supplementation with rapeseed oil and linseed oil increased proportions of C18:1 cis-9 and C18:3 cis-9,12,15 in blood plasma, respectively, compared with the other treatments. Supplementation with soybean oil and linseed oil increased milk FA proportions of C18:2 cis-9,12 and C18:3 cis-9,12,15, respectively, but supplementation with rapeseed oil did not increase C18:1 cis-9 in milk. Mammary SCD1 expression was reduced by supplementation of soybean oil compared with rapeseed oil and linseed oil. In contrast, SCD5 expression did not differ among the 4 treatments. The C16 and C18 desaturation indices, representing proxies for SCD activity, were lower for the soybean oil diet compared with the diet supplemented with a mixture of the 3 oils. In conclusion, our study shows that mammary SCD1 expression is significantly downregulated in dairy cows by feeding unprotected soybean oil compared with rapeseed oil or linseed oil, and this is partially reflected by the lower desaturase indices in the milk. Furthermore, mammary SCD5 expression appears to be differently regulated than expression of SCD1. PMID- 21257057 TI - Glucagon-like peptide-2 (GLP-2) increases small intestinal blood flow and mucosal growth in ruminating calves. AB - Glucagon-like peptide-2 (GLP-2) increases small intestinal mass and blood flow in nonruminants but its effect in ruminants is unknown. Eight Holstein calves with an ultrasonic flow probe around the superior mesenteric artery and catheters in the carotid artery and mesenteric vein were paired by age and randomly assigned to treatment of a control (0.5% of BSA in saline; n=4) or GLP-2 (50 MUg/kg of body weight of bovine GLP-2 in BSA; n=4) given subcutaneously every 12h for 10 d. Blood flow was measured on d 0 (acute) and d 10 (chronic) and included 3 periods: baseline (saline infusion), treatment (infusion of BSA or 1,000 pmol of GLP-2/kg of body weight per h), and recovery (saline infusion). On d 11, calves were killed 2h after injection of 5-bromo-2'-deoxyuridine (BrdU). Gastrointestinal tissues were weighed and epithelial samples were obtained to determine villus height, crypt depth, and BrdU staining. Infusion of GLP-2 increased superior mesenteric artery blood flow to 175% of baseline on d 0 but to only 137% of baseline after chronic treatment. Compared with that of the control, GLP-2 increased small intestinal mass by 24% by increasing epithelial mass in the jejunum and ileum. Additionally, GLP-2 increased villus height, crypt depth, and BrdU-labeling in small intestinal segments. These results demonstrate that GLP-2 induces similar increases in small intestinal blood flow and growth in ruminants to those observed in nonruminants. Furthermore, GLP-2 increases small intestinal blood flow in ruminants but this response is attenuated after 10 d of GLP-2 administration. In cattle, GLP-2 may be an important hormone in the regulation of intestinal blood flow and epithelial growth. PMID- 21257058 TI - Improved milk production efficiency in early lactation dairy cattle with dietary addition of a developmental fibrolytic enzyme additive. AB - A 3-part study was conducted to evaluate the effect of a developmental fibrolytic enzyme additive on the digestibility of selected forages and the production performance of early-lactation dairy cows. In part 1, 4 replicate 24-h batch culture in vitro incubations were conducted with alfalfa hay, alfalfa silage, and barley silage as substrates and ruminal fluid as the inoculum. A developmental fibrolytic enzyme additive (AB Vista, Marlborough, UK) was added at 5 doses: 0, 0.5, 1.0, 1.5, and 2.0 MUL/g of forage dry matter (DM). After the 24-h incubation, DM, neutral detergent fiber (NDF), and acid detergent fiber (ADF) disappearance were determined. For alfalfa hay, DM, NDF, and ADF disappearance was greater at the highest dosage compared with no enzyme addition. Barley silage NDF and ADF and alfalfa silage NDF disappearance tended to be greater for the highest enzyme dosage compared with no enzyme addition. In part 2, 6 ruminally cannulated, lactating Holstein dairy cows were used to determine in situ degradation of alfalfa and barley silage, with (1.0 mL/kg of silage DM) and without added enzyme. Three cows received a control diet (no enzyme added) and the other 3 received an enzyme-supplemented (1.0 mL/kg of diet DM) diet. Enzyme addition after the 24h in situ incubation did not affect the disappearance of barley silage or alfalfa silage. In part 3, 60 early-lactation Holstein dairy cows were fed 1 of 3 diets for a 10-wk period: (1) control (CTL; no enzyme), (2) low enzyme (CTL treated with 0.5 mL of enzyme/kg of diet DM), and (3) high enzyme (CTL treated with 1.0 mL of enzyme/kg of diet DM). Adding enzyme to the diet had no effect on milk yield, but dry matter intake was lower for the high enzyme treatment and tended to be lower for the low enzyme treatment compared with CTL. Consequently, milk production efficiency (kg of 3.5% fat-corrected milk/kg of DM intake) linearly increased with increasing enzyme addition. Cows fed the low and high enzyme diets were 5.3 (not statistically significant) and 11.3% more efficient, respectively, compared with CTL cows. This developmental fibrolytic enzyme additive has the potential to increase fiber digestibility of forages, which could lead to greater milk production efficiency for dairy cows in early lactation. PMID- 21257059 TI - Replacing corn with glycerol in diets for transition dairy cows. AB - Expansion of the biofuels industry has increased the availability of glycerol as an alternative feed for dairy cows. The objective of this study was to determine the effects of glycerol on feed intake, milk production, rumen volatile fatty acids, and metabolic parameters in transition dairy cows. Multiparous Holstein cows were fed diets containing either high-moisture corn (n=11) or glycerol (n=12) from -28 to +56 d relative to calving. Glycerol was included at 11.5 and 10.8% of the ration dry matter for the pre- and postpartum diets, respectively. Prepartum feed intake was not changed by glycerol feeding (14.9 vs. 14.6 kg/d, control vs. glycerol) nor did postpartum feed intake differ (19.8 vs. 20.7 kg/d, control vs. glycerol). Overall milk yield did not differ (35.8 vs. 37 kg/d, control vs. glycerol) and milk composition, milk urea nitrogen, somatic cells, and energy balance were not different with glycerol feeding. Blood glucose content was decreased in cows fed glycerol during the prepartum period (59.1 vs. 53.4 mg/dL), and beta-hydroxybutyrate concentration was increased (0.58 vs. 0.82 mmol/L, control vs. glycerol). Concentrations of blood nonesterified fatty acids did not differ between the treatment groups, and no response to glycerol for blood metabolites during the postpartum period was observed. Total rumen volatile fatty acid concentrations (mmol/L) did not differ between treatments, but proportions of rumen propionate and butyrate were greater for cows fed glycerol (22.7 vs. 28.6% of propionate, control vs. glycerol; and 11.5 vs. 15.3% of butyrate, control vs. glycerol) at the expense of acetate (61.4 vs. 51.5%, control vs. glycerol). These data indicate that glycerol is a suitable replacement for corn grain in diets for transition dairy cows. PMID- 21257060 TI - Peripartum responses of dairy cows to prepartal feeding level and dietary fatty acid source. AB - This experiment was conducted to investigate the effect of feeding level and oilseed supplementation during the close-up dry period on energy balance (EB), hepatic lipidosis, metabolic status, and productivity in early lactation. Seventy seven Holstein cows were blocked according to parity and expected calving date and then assigned randomly to 1 of 6 treatments in a 2 * 3 factorial allocation with 2 feeding levels: ad libitum (AL) or 30% feed restriction (FR), and 3 dietary fatty acid sources: canola seed, linola seed, or flaxseed at 8% of dietary dry matter (DM), to enrich the rations with oleic, linoleic, or linolenic acids, respectively during the last 4 wk of gestation. After parturition, all cows were fed a common lactation diet. Cows fed AL lost less body weight (-2.9 vs. -6.0%) and body condition score (+0.67 vs. -2.30%), and consequently were in more positive EB (+4.6 vs. -0.3 Mcal) during the prepartum period than cows subjected to FR. Postpartum, FR cows lost less body weight (-9.7 vs. -12.4%) and experienced less severe negative EB (-4.5 vs. -7.0 Mcal) than AL cows. Cows fed AL had higher plasma insulin (6.8 vs. 4.4 MUIU/mL) and lower nonesterified fatty acid concentrations (436 vs. 570 mEq/mL) during the close-up period than cows subjected to FR. Cows fed AL tended to have lower liver glycogen content in early lactation than cows subjected to FR (4.4 vs. 2.9 % of DM) [corrected], but had similar triglyceride content (13.1 +/- 1.2 MUg/g of DM). Fatty acid source did not influence response variables. In conclusion, eliminating intake depression by FR during the close-up period had positive carryover effects on EB and metabolic status during early lactation, but feeding linoleic and linolenic acids via unprotected oilseeds only had negligible effects on peripartum responses. PMID- 21257061 TI - The value of different fat supplements as sources of digestible energy for lactating dairy cows. AB - The effects of fat supplements that differed in fatty acid composition (chain length and degree of saturation) and chemical form (free fatty acids, Ca salts of fatty acids, and triacylglyceride) on digestible energy (DE) concentration of the diet and DE intake by lactating cows were measured. Holstein cows were fed a control diet [2.9% of dry matter (DM) as long-chain fatty acids] or 1 of 3 diets with 3% added fatty acids (that mainly replaced starch). The 3 fat supplements were (1) mostly saturated (C18:0) free fatty acids (SFA), (2) Ca-salts of fatty acids (CaFA), and (3) triacylglyceride high in C16:0 fatty acids (TAG). Cows fed CaFA (22.8 kg/d) consumed less DM than cows fed the control (23.6 kg/d) and TAG (23.8 kg/d) diets but similar to cows fed SFA (23.2 kg/d). Cows fed fat produced more fat-corrected milk than cows fed the control diet (38.2 vs. 41.1 kg/d), mostly because of increased milk fat percentage. No differences in yields of milk or milk components were observed among the fat-supplemented diets. Digestibility of DM, energy, carbohydrate fractions, and protein did not differ between diets. Digestibility of long-chain fatty acids was greatest for the CaFA diet (76.3%), intermediate for the control and SFA diets (70.3%), and least for the TAG diet (63.3%). Fat-supplemented diets had more DE (2.93 Mcal/kg) than the control diet (2.83 Mcal/kg), and DE intake by cows fed supplemented diets was 1.6 Mcal/d greater than by cows fed the control, but no differences were observed among the supplements. Because the inclusion rate of supplemental fats is typically low, large differences in fatty acid digestibility may not translate into altered DE intake because of small differences in DM intake or digestibility of other nutrients. PMID- 21257062 TI - Effect of the provision of a low-nutritive feedstuff on the behavior of dairy heifers limit fed a high-concentrate ration. AB - The objective of this study was to examine the behavioral and growth responses of dairy heifers when a low-nutritive feedstuff was provided with (either within or alongside) a limit-fed ration. Twenty-four Holstein dairy heifers (187 +/- 11.3 d of age, 231.1 +/- 12.0kg), divided in groups of 4, were exposed to each of 3 treatments in a replicated Latin square design with 28-d periods. The treatment rations were (1) total mixed ration (TMR) in a limited amount (TMR-L), (2) TMR in a limited amount with straw (1.8 kg of DM/d per heifer) offered as a choice (TMR SC), and (3) TMR in a limited amount with straw (1.8 kg of DM/d per heifer) mixed in (TMR-SM). The TMR was fed, once daily, at a restricted level (2.02% of body weight) and contained (on a DM basis) 19.0% alfalfa/grass haylage, 21% corn silage, 45% high moisture corn, and 15% protein supplement. Feeding behavior and unrewarded time at the feed bunk were recorded for the last 14 d of each period. Standing time was recorded for the last 7 d of each period. Rumination behavior was recorded twice weekly (during the fifth hour after feed delivery) in the last 14 d of each period. Body weight was recorded weekly and group DMI was recorded daily. Dry matter intake was lowest for the TMR treatment compared with the treatments with straw (5.7 vs. 7.3 kg/d). Heifer average daily gain tended to be lower on the TMR-SM treatment compared with the TMR-L and TMR-SC treatments (0.78 vs. 0.94 kg/d). Feed efficiency (DMI/ADG) was improved on the TMR-L (6.3) compared with TMR-SC (7.8) and TMR-SM (9.9) treatments. Daily feeding time differed between the TMR-L (76.1 min/d), TMR-SC (206.9 min/d), and TMR-SM (279.2 min/d) treatments. Unrewarded feeding time at the feed bunk differed between the TMR-L (38 min/d) compared with the TMR-SC (10.9 min/d) and TMR-SM (1.7 min/d) treatments. Inactive standing time differed among treatments, with TMR-L being the highest compared with TMR-SC and TMR-SM (556.4 vs. 409.9 vs. 340.1 min/d). There tended to be fewer heifers ruminating on the TMR-L compared with TMR-SM (14.0 vs. 21.9%). The results suggest that provision of straw as a choice alongside a limit-fed ration will allow heifer growth rates to be met, as well as provide a suitable foraging source that heifers can use to satisfy their natural feeding behavior patterns. PMID- 21257063 TI - Effect of exogenous phytase on feed inositol phosphate hydrolysis in an in vitro rumen fluid buffer system. AB - Three in vitro experiments using a rumen fluid buffer system were performed to investigate the effect of addition of 4 experimental phytases (Phy1, Phy2, Phy3, and Phy4) compared with no addition of phytase on feed inositol phosphate hydrolysis in wheat and rapeseed cake to determine which of the 4 phytases was most suitable under rumen-like conditions. The feedstuffs were incubated with a mixture of physiological buffer, ruminal fluid, and exogenous phytase at pH 6.2, after which the samples were incubated for different periods. Incubations were stopped using HCl, and the samples were analyzed for inositol phosphates via high performance ion chromatography. Addition of phytase (Phy1) resulted in enhanced degradation of myo-inositol hexakisphosphate (InsP(6)) in rapeseed cake, whereas addition of exogenous phytase did not improve the degradation of InsP(6) in wheat. Only rapeseed cake was therefore used subsequently. All 4 phytases increased degradation of InsP(6) in rapeseed cake in the in vitro system, and degradability of InsP(6) increased with higher incubation time and higher phytase dosages, independent of phytase. Addition of 2 units of phytase per gram of substrate of the phytases Phy1, Phy2, Phy3, and Phy4 led to an undegraded InsP(6) content of 56, 49, 70, and 18%, respectively, when incubated with rapeseed cake for 6h, indicating that Phy2 and Phy4 were the most effective phytases. However, Phy2 had a higher specific activity than Phy4, as 60% of the original InsP(6) content was remaining after 3h when 5mg of enzyme protein per gram of substrate of Phy2 was added to rapeseed cake, whereas 150 mg of enzyme protein per gram of substrate of Phy4 was necessary to achieve a similar result. Therefore, Phy2 appeared to be most applicable under rumen-like conditions. PMID- 21257064 TI - Genetic evaluations for measures of the milk-flow curve in the Italian Brown Swiss population. AB - The objective of this study was to estimate heritabilities and genetic correlations between milk-release parameters, somatic cell score, milk yield, and udder functional traits in the Italian Brown Swiss population. Data were available from 37,511 cows over a span of 12 yr (1997-2008) from 1,592 herds. Milking flows were recorded for each individual once during lactation. Three different analyses were performed to estimate variance components for all the traits of interest. The first analysis included single control data milk yield, somatic cell score, maximum milk flow, average milk flow, time of plateau, decreasing time, and total milking time, whereas the second analysis included milk-release parameters as well as total udder score, udder depth, and 305-d milk yield and somatic cell score as dependent variables. The third analysis included total milking time, 305-d milk yield and somatic cell score, total udder score, udder depth, and ratios of maximum milk flow over total milking time (R1), time of plateau (R2), and decreasing time (R3) to estimate the relationship between the shape of the milk-release curves and important milking traits. Results from the first and second analysis found similar heritabilities for milkability traits ranging from 0.05 to 0.41 with genetic correlations between production traits and flow traits ranging from low to moderate values. Positive genetic correlations were found among production, somatic cell score, and milkability traits. The third analysis showed that R1 had the greatest heritability of the ratio traits (0.37) with large genetic correlations with R2 and R3, a low correlation with 305 d somatic cell score, and no correlation with 305-d milk yield. Estimated responses to selection over 5 generations were also calculated using different indexes, which included either flow or ratio traits. The results of this study show that it is possible to use information collected through portable flowmeters to improve milkability traits. Using a set of variables or traits to describe the overall release of milk can be an advantageous selection strategy to decrease management costs while maintaining milk production. PMID- 21257065 TI - Quantitative trait loci affecting milk production traits on bovine chromosome 6 in zebuine Gyr breed. AB - Fourteen Brazilian dairy Gyr sire families with 657 daughters were analyzed for quantitative trait loci (QTL) on chromosome 6 by using a daughter design for 5 economic traits: milk, fat, and protein production, fat and protein percentage. The cows and sires were genotyped for 27 microsatellites with average spacing between markers of 4.9 cM. In the analyses across 14 families, for the largest significant families, and within family, a QTL was located for milk yield and fat yield close to marker BMS2508 at the 5% chromosome-wide significance level across families and 1% chromosome-wide within families. For fat percentage, a QTL near DIK4482 was identified at the 5% chromosome-wide significance level when all families were analyzed together and at the 1% chromosome-wide significance level within the largest significant families. The different analyses yielded results that were generally consistent for milk yield, fat yield, and fat percentage. The order of the markers in the derived map was consistent with that in the consensus map. Some QTL and candidate genes in dairy cattle for milk production traits are probably preserved in Bos taurus and Bos indicus. PMID- 21257066 TI - Effect of age and pregnancy status on adaptive immune responses of Canadian Holstein replacement heifers. AB - Selection for production traits with little or no emphasis on health traits has led to an increase in the incidence of disease in Canadian dairy herds. We describe here a patented protocol for estimating the breeding value for immune responsiveness in heifers that combines measures of both cell-mediated (CM) and antibody-mediated (AM) immune responses (IR). The ability of putative type 1 and type 2 antigens used to induce CMIR and AMIR, respectively, was assessed in replacement Holstein heifers, and the effects of age and pregnancy on type 1 and type 2 IR bias were estimated. Results demonstrated that the type 1 and type 2 antigens induced polarized type 1 and type 2 responses in heifers regardless of age and pregnancy status, and can therefore be used to identify animals with superior overall immune responsiveness. However, age and pregnancy status had significant effects on adaptive IR profiles, highlighting the need for appropriate statistical modeling of such effects when ranking animals on their ability to mount CM and AMIR. Responses became increasingly type 1 biased as heifers approached 12 mo of age, from which point, responses then became increasingly type 2 biased with age and length of gestation. Knowledge of how age and pregnancy influence the dynamics of type 1 and type 2 IR bias is expected to improve our ability to select animals with enhanced immune responsiveness and aid in the development of effective vaccines through strategic targeting of vaccine components to recipients. PMID- 21257067 TI - Effect of herd prevalence on heritability estimates of antibody response to Mycobacterium avium subspecies paratuberculosis. AB - Worldwide, classical control strategies based on hygiene and culling of infected animals have been implemented to eradicate Johne's disease. Breeding for disease resistance may be a useful additional tool to control the disease. The aim of this study was to estimate genetic parameters for the presence of a Mycobacterium avium ssp. paratuberculosis specific antibody response in milk of Dutch Holstein Friesian cows using subsets of data based on within-herd test prevalence. The analyzed data set consisted of milk samples of 684,364 animals from 12,077 herds collected during the routine milk production scheme. Milk samples were tested for antibodies specific for Johne's disease by an ELISA test. Heritability estimates were calculated for 4 different subsets of data to determine the sensitivity of heritability for within-herd test prevalence. Results expressed as percentage of the sample to positive ratio were analyzed with a sire-maternal grandsire model with fixed effects for parity, year of birth, lactation stage, and herd; a covariate for milk yield at test day; and random effects for sire, maternal grandsire, and error. The estimated heritability ranged from 0.031 for the complete data set to 0.097 for herds with a test prevalence of at least 10%. Cross-validation was applied to determine which of the subsets of data produced the most accurate estimated breeding values. Results showed that for genetic selection to contribute to disease control, breeding values were estimated most accurately from herds with at least 2 animals that tested positive. In this subset the heritability was 0.041. PMID- 21257068 TI - Goat milk allergenicity as a function of alphas1-casein genetic polymorphism. AB - Cow milk allergy is the most frequent allergy in the first years of life. Milk from other mammalian species has been suggested as a possible nutritional alternative to cow milk, but in several cases, the clinical studies showed a high risk of cross-reactivity with cow milk. In the goat species, alphaS1-casein (alphaS1-CN), coded by the CSN1S1 gene, is characterized by extensive qualitative and quantitative polymorphisms. Some alleles are associated with null (i.e., CSN1S1 0(1)) or reduced (i.e., CSN1S1 F) expression of the specific protein. The aim of this work was to obtain new information on goat milk and to evaluate its suitability for allergic subjects, depending on the genetic variation at alphas1 CN. Individual milk samples from 25 goats with different CSN1S1 genotypes were analyzed by sodium dodecyl sulfate PAGE and immunoblotting, using monoclonal antibodies specific for bovine alpha-CN and sera from children allergic to cow milk. A lower reaction was observed to 2 goat milk samples characterized by the CSN1S1 0(1)0(1) and 0(1)F genotypes. Moreover, a fresh food skin prick test, carried out on 6 allergic children, showed the lack of positive reaction to the 0(1)0(1) milk sample and only one weak reactivity to the 0(1)F sample. The risk of cross-reactivity between cow and goat milk proteins suggests the need for caution before using goat milk for infant formulas. However, we hypothesize that it can be used successfully in the preparation of modified formulas for selected groups of allergic patients. The importance of taking the individual goat CN genetic variation into account in further experimental studies is evident from the results of the present work. PMID- 21257069 TI - Potential consequences of selection to change gestation length on performance of Holstein cows. AB - Genetic evaluations for gestation length (GL) for Holstein service sires were studied to determine their effectiveness in predicting GL in an independent data set. Consequences of selection on GL were also assessed by examining correlated changes in milk and fitness traits. Holstein bulls with >= 300 calvings between 1998 and 2005 were stratified into the following 7 groups using predicted transmitting ability (PTA) for service sire GL: <-3.00, -3.00 to -2.01, ..., 1.00 to 1.99, and >= 2.00 d. An independent set of 261,598 first-parity cows mated later to the same bulls and calving between 2006 and 2009 were segregated by the service sire PTA GL groups (group had 8,317 to 73,324 gestations), and these mates' GL were examined to determine effectiveness of service sire PTA GL. The model included fixed effects for herd-year and service sire group, plus covariates for conception dates to account for time opportunity among mates. Mean GL for mates by service sire group (from lowest to highest PTA GL) were 275.3, 276.5, 277.8, 278.6, 279.5, 280.6, and 281.7 d. Thus, service sire PTA GL was effective in identifying bulls that modified GL. Subsequent yield and fitness traits were also examined for the (independent) mates with the same service sire groups. Intermediate service sire PTA GL was optimal for yield traits and days open; performance for productive life and culling generally became less favorable as service sire PTA GL increased. A second examination was made by replacing service sire PTA GL groups in the model with phenotypic cow GL groups. Relationships between GL and subsequent performance for milk yield and fitness traits were examined using 9 phenotypic cow GL groups: <= 271, 272-273, ..., 284 285, and >= 286 d. Performance generally improved for subsequent lactation yield as cow GL increased; however, intermediate GL was optimal for productive life, calving ease, stillbirth, culling, and days open. Results indicated that neither shortening nor increasing the mean for GL in the Holstein breed provided much overall benefit when all traits were considered. The same traits examined in the cows for the correlated effect from various GL were also examined in their offspring to determine whether the GL producing the calf had any influence on these same traits when the offspring reached their own productive period. Little carryover occurred from GL on the dam to the other traits observed on the offspring when examined a generation later. PMID- 21257070 TI - Evidence of biases in genetic evaluations due to genomic preselection in dairy cattle. AB - A genomic preselection step of young sires is now often included in dairy cattle breeding schemes. Young sires are selected based on their genomic breeding values. They have better Mendelian sampling contribution so that the assumption of random Mendelian sampling term in genetic evaluations is clearly violated. When these sires and their progeny are evaluated using BLUP, it is feared that estimated breeding values are biased. The effect of genomic selection on genetic evaluations was studied through simulations keeping the structure of the Holstein population in France. The quality of genetic evaluations was assessed by computing bias and accuracy from the difference and correlation between true and estimated breeding values, respectively, and also the mean square error of prediction. Different levels of heritability, selection intensity, and accuracy of genomic evaluation were tested. After only one generation and whatever the scenario, breeding values of preselected young sires and their daughters were significantly underestimated and their accuracy was decreased. Genomic preselection needs to be accounted for in genetic evaluation models. PMID- 21257071 TI - Short communication: milk fat composition of 4 cattle breeds in the Netherlands. AB - Milk fatty acid (FA) composition was compared among 4 cattle breeds in the Netherlands: Dutch Friesian (DF; 47 animals/3 farms), Meuse-Rhine-Yssel (MRY; 52/3), Groningen White Headed (GWH; 45/3), and Jersey (JER; 46/3). Each cow was sampled once between December 2008 and March 2009 during the indoor housing season, and samples were analyzed using gas chromatography. Significant breed differences were found for all traits including fat and protein contents, 13 major individual FA, 9 groups of FA, and 5 indices. The saturated fatty acid proportion, which is supposed to be unfavorable for human health, was smaller for GWH (68.9%) compared with DF (74.1%), MRY (72.3%), and JER (74.3%) breeds. The proportion of conjugated linoleic acid and the unsaturation index, which are associated positively with human health, were both highest for GWH. Differences in milk fat composition can be used in strategies to breed for milk with a FA profile more favorable for human health. Our results support the relevance of safeguarding the local Dutch breeds. PMID- 21257072 TI - Effect of complementation of cattle cooling systems with feedline soakers on lactating dairy cows in a desert environment. AB - Two experiments were conducted on a commercial dairy farm in eastern Saudi Arabia to investigate the effects of Korral Kool (KK; Korral Kool Inc., Mesa, AZ) cattle cooling systems complemented with feedline soakers on core body temperature (CBT) of dairy cows. In both experiments, cows had access to KK 24h/d. In the first experiment, 7 primiparous and 6 multiparous lactating Holstein dairy cows were assigned to 1 of 2 pens, which were assigned randomly to treatment sequence over 4 d in a switchback design. Soakers were on (ON24) or off (OFF24) for 24h/d. For the second experiment, 20 multiparous lactating Holstein cows were assigned randomly to 1 of 2 pens, which were assigned randomly to treatment sequence in a switchback design. This experiment lasted 4 d and feedline soakers alternately remained off or were on (ON12) for 12h/d. In experiment 1, average ambient temperature was 30 +/- 0.9 degrees C and average relative humidity was 44 +/- 14% (mean +/- SD). Feedline soakers complementing KK systems for 24 h/d decreased the mean CBT of lactating dairy cows compared with KK systems alone (38.80 vs. 38.98 +/- 0.061 degrees C, respectively). A significant treatment by time interaction was found. The greatest treatment effects occurred at 2100 h; treatment means at this time were 39.26 and 38.85 +/- 0.085 degrees C for OFF24 and ON24 treatments, respectively. In experiment 2, average ambient temperature was 35 +/- 1.5 degrees C and average relative humidity was 33 +/- 16%. Feedline soakers running for 12 h/d significantly decreased the mean 24-h CBT from 39.16 to 38.99 +/- 0.084 degrees C. Treatment by time interaction was also significant; the greatest treatment effects occurred at 1500 h, when ON12 reduced CBT from 39.38 to 38.81 +/- 0.088 degrees C. These results demonstrate that complementing the KK system with feedline soakers decreased the CBT of dairy cows housed in desert environments. However, the combined systems were not sufficient to lower CBT to normal temperatures in this extreme environment. PMID- 21257073 TI - A model of nitrogen efficiency in contrasting grass-based dairy systems. AB - Nitrogen (N) efficiency is one of the key drivers of environmentally and economically sustainable agricultural production systems. An N balance model was developed, evaluated, and validated to assess N use efficiency and N surplus and to predict N losses from contrasting grass-based dairy production systems in Ireland. Data from a 5-yr study were used to evaluate and validate the model. Grass-based and high-concentrate production systems combined with 3 divergent strains of Holstein-Friesian (HF) dairy cows-high-production North American (HP), high-durability North American (HD), and New Zealand (NZ)-were evaluated. As concentrate input increased, N surplus per hectare increased and N use efficiency per hectare decreased (23 and 10%, respectively). When the N required to rear replacement animals to maintain the production system was considered, the N surplus of the HP genetic strain was greater (156 kg of N/cow) than that of the HD (140 kg of N/cow) or the NZ (128 kg of N/cow). The model estimated N leaching of 8.1mg of NO(3)-N/L, similar to that measured by others at the same site. The model creates awareness of methods and indicators available to assess the most suitable and environmentally sustainable grass based dairy production systems. PMID- 21257074 TI - Sources of Klebsiella and Raoultella species on dairy farms: be careful where you walk. AB - Klebsiella spp. are a common cause of mastitis, milk loss, and culling on dairy farms. Control of Klebsiella mastitis is largely based on prevention of exposure of the udder to the pathogen. To identify critical control points for mastitis prevention, potential Klebsiella sources and transmission cycles in the farm environment were investigated, including oro-fecal transmission, transmission via the indoor environment, and transmission via the outdoor environment. A total of 305 samples was collected from 3 dairy farms in upstate New York in the summer of 2007, and included soil, feed crops, feed, water, rumen content, feces, bedding, and manure from alleyways and holding pens. Klebsiella spp. were detected in 100% of rumen samples, 89% of water samples, and approximately 64% of soil, feces, bedding, alleyway, and holding pen samples. Detection of Klebsiella spp. in feed crops and feed was less common. Genotypic identification of species using rpoB sequence data showed that Klebsiella pneumoniae was the most common species in rumen content, feces, and alleyways, whereas Klebsiella oxytoca, Klebsiella variicola, and Raoultella planticola were the most frequent species among isolates from soil and feed crops. Random amplified polymorphic DNA-based strain typing showed heterogeneity of Klebsiella spp. in rumen content and feces, with a median of 4 strains per 5 isolates. Observational and bacteriological data support the existence of an oro-fecal transmission cycle, which is primarily maintained through direct contact with fecal contamination or through ingestion of contaminated drinking water. Fecal shedding of Klebsiella spp. contributes to pathogen loads in the environment, including bedding, alleyways, and holding pens. Hygiene of alleyways and holding pens is an important component of Klebsiella control on dairy farms. PMID- 21257075 TI - Associations between several aspects of heifer development and dairy cow survivability to second lactation. AB - A data set from 7,768 Holstein heifers born between 2004 and 2006, including growth rates from birth until first calving; age and body weight at insemination; and incidence of diarrhea, navel infections, and bovine respiratory disease (BRD) was used to evaluate potential associations between these factors and the odds of completing the first lactation. All heifers were raised in a contract heifer operation (Rancho Las Nieves, Mallen, Spain) and returned to their herds of origin (133 herds in total) before calving. Dates of death were provided by the Subdireccion General de Explotaciones y Sistemas de Trazabilidad de los Recursos Agricolas y Ganaderos from the Ministry of Environment, and Rural and Marine Areas of the Spanish government. At the time of analysis, 2,571 (33.1%) animals out of the 7,768 considered had died. In total, 655 (8.4%) heifers did not finish first lactation, and 31.5% of these left the herd within the first 50 DIM. Also, 4.8% of heifers aborted and were rebred. Data were analyzed using a mixed-effects logistic regression and survival analysis for dichotomous variables and a mixed effects model for continuous ones. Incidence of diarrhea or navel infection was not associated with the chances of finishing the first lactation. Heifers that completed first lactation had a lesser average age at first calving (724 +/- 2 d) than those that did not (737 +/- 3 d). Heifers that reached second lactation grew (0.8 +/- 0.04 kg/d) more between 12 and 65 d of age than those that did not (0.7 +/- 0.04 kg/d). As conception rate decreased, chances of leaving the herd before completing the first lactation increased. The number of AI services needed per conception as a nulliparous heifer was negatively associated with survivorship to second lactation. Heifers that experienced an abortion were 2.73 +/- 0.52 times more likely to leave the herd before completing the first lactation (but also calved with a much older age at first calving). Heifers that experienced 4 or more BRD cases before first calving had 1.87 +/- 0.14 greater odds of not completing the first lactation than those that never experienced BRD. These results show potential to forecast future heifer success in finishing the first lactation based on average daily gain early in life, incidence of BRD, reproductive performance (conception and abortion rates), and age at first calving. PMID- 21257076 TI - Brown Swiss * Holstein crossbreds compared with pure Holsteins for calving traits, body weight, backfat thickness, fertility, and body measurements. AB - Brown Swiss * Holstein crossbred cows and pure Holstein cows were compared in a designed experiment. All cows were housed in a freestall barn at the experimental station of the federal state of Saxony-Anhalt, Germany, and calved from July 2005 to August 2008. Brown Swiss * Holstein crossbred cows were mated to Holstein AI bulls for first calving and mated to Fleckvieh artificial insemination (AI) bulls for second and third calvings. Pure Holstein cows were consistently mated to Holstein AI bulls. At first calving, Holstein-sired calves from Brown Swiss * Holstein crossbred dams (282 d) had longer gestation length than Holstein-sired calves from Holstein dams (280 d). For second and third calvings, gestation length was significantly longer for Fleckvieh-sired calves from Brown Swiss * Holstein crossbred dams (284 d) than for Holstein-sired calves from Holstein dams (278 d). Holstein-sired calves from Brown Swiss * Holstein crossbred dams (43 kg) and Holstein-sired calves from pure Holstein dams (42 kg) were not significantly different for calf weight at birth for first calving. For second and third calvings, Fleckvieh-sired calves from Brown Swiss * Holstein crossbred dams (50 kg) had significantly heavier calf weight at birth than Holstein-sired calves from pure Holstein dams (44 kg). For calving difficulty and stillbirth, Brown Swiss * Holstein crossbred cows were not different from pure Holstein cows at first calving or at second and third calving. Brown Swiss * Holstein crossbred cows (71 d) were not significantly different from pure Holstein cows (75 d) for days to first breeding during first lactation; however, Brown Swiss * Holstein crossbred cows (81 d) had significantly fewer days to first breeding than pure Holstein cows (89 d) during second lactation, and the crossbred cows (85 d) tended to have fewer days to first breeding than pure Holstein cows (92 d) during third lactation. For days open, Brown Swiss * Holstein crossbred cows were not significantly different than pure Holstein cows during any of the first 3 lactations. For body weight, Brown Swiss * Holstein crossbred cows were significantly heavier than pure Holstein cows during first lactation (621 kg versus 594 kg) and second lactation (678 kg versus 656 kg). Also, Brown Swiss * Holstein crossbred cows (18.20mm) had significantly more backfat thickness than pure Holstein cows (15.81 mm) during first lactation. Brown Swiss * Holstein crossbred cows (48 cm) had significantly greater chest width than pure Holstein cows (46 cm). Furthermore, Brown Swiss * Holstein crossbred cows had significantly longer front heel walls (5.2 cm versus 5.0 cm), significantly longer rear heel walls (4.2 cm versus 4.0 cm), and significantly more depth of the front heel (4.4 cm vs. 4.1cm) than pure Holstein cows. This study has shown that F(1) of Brown Swiss * Holstein cows are competitive with pure Holstein cows for all traits analyzed here. For fertility, crossbred Brown Swiss * Holstein cows exhibited fewer days to first breeding during second lactation than pure Holstein cows. PMID- 21257077 TI - Endometrial cancer. PMID- 21257078 TI - Development of early non-invasive markers and means for the diagnosis and progression monitoring of preeclampsia and tailoring putative therapies (project pregenesys 037244). PMID- 21257079 TI - Cell-free nucleic acids as potential markers for preeclampsia. AB - Preeclampsia is one of the leading causes of maternal and fetal/neonatal mortality and morbidity worldwide. Therefore, widely applicable and affordable tests are needed to make an early diagnosis before the occurrence of the clinical symptoms. Circulating cell-free nucleic acids in plasma and serum are novel biomarkers with promising clinical applications in different medical fields, including prenatal diagnosis. Quantitative changes of cell-free fetal (cff)DNA in maternal plasma as an indicator for impending preeclampsia have been reported in different studies, using real-time quantitative PCR for the male-specific SRY or DYS 14 loci. In case of early onset preeclampsia, elevated levels may be already seen in the first trimester. The increased levels of cffDNA before the onset of symptoms may be due to hypoxia/reoxygenation within the intervillous space leading to tissue oxidative stress and increased placental apoptosis and necrosis. In addition to the evidence for increased shedding of cffDNA into the maternal circulation, there is also evidence for reduced renal clearance of cffDNA in preeclampsia. As the amount of fetal DNA is currently determined by quantifying Y-chromosome specific sequences, alternative approaches such as the measurement of total cell-free DNA or the use of gender-independent fetal epigenetic markers, such as DNA methylation, offer a promising alternative. Cell free RNA of placental origin might be another potentially useful biomarker for screening and diagnosis of preeclampsia in clinical practice. Fetal RNA is associated with subcellular placental particles that protect it from degradation. Its levels are ten-fold higher in pregnant women with preeclampsia compared to controls. In conclusion, through the use of gender-independent sequences, the universal incorporation of fetal nucleic acids into routine obstetric care and into screening or diagnostic settings using combined markers may soon become a reality. Effort has now to be put into the establishment of standardized and simplified protocols for the analysis of these biomarkers in a clinical setting. PMID- 21257080 TI - Placenta-bound and body fluid PP13 and its mRNA in normal pregnancy compared to preeclampsia, HELLP and preterm delivery. AB - OBJECTIVES: To compare the distribution of placental protein 13 (PP13) in fetal and maternal blood and amnionic fluid and to correlate it with PP13 protein and mRNA in the placenta. METHODS: Umbilical arterial serum, amnionic fluid, maternal venous serum and placental tissues were collected from normal outcome pregnancies (N = 63) (GA>37), early onset preeclampsia (PE) (N = 12, GA: 26-33), and HELLP syndrome (N = 5, GA: 27-29). Because PE and HELLP cases delivered preterm, cases of preterm delivery (PTD) (N = 6, GA: 31-36) served as additional control. PP13 was determined by ELISA, Western blot, and immunohistochemistry. PP13 mRNA was measured by PCR (RT-PCR). Continuous parameters were compared by t-test, P < 0.05 was considered significant. RESULTS: In women with normal pregnancy outcome significantly higher PP13 levels were found in maternal serum compared to amnionic fluid and negligible amount was found in fetal serum. A similar pattern was identified in cases of PTD with concentrations similar to term control. In PE and HELLP cases PP13 levels in amnionic fluid level were more than twice compared to maternal serum (P < 0.001). Umbilical cord level was negligible in PE but high in HELLP corresponding to the much higher level of PP13 in this patient group compared to all others. In the placenta PP13 level in term controls was higher compared to PTD. In PE and HELLP (similar early delivery time as PTD) the level was significantly higher (P < 0.01) compared to PTD or term controls. PP13 mRNA levels in term control and PTD were similar while PP13 mRNA levels in PE and HELLP placentas were significantly lower compared to term controls or PTD or the two combined. Syncytiotrophoblast labeling appeared stronger in PE and HELLP compared to term controls and PTD. CONCLUSIONS: In all cases but HELLP, PP13 in fetal blood is very low indicating that routing of PP13 to fetal blood is limited and that the fetus is unlikely to generate PP13. PP13 mRNA is lower in the third trimester at the time of disease while protein level accumulates and become higher creating an unparallel change in the level of the mRNA and the corresponding protein. PMID- 21257081 TI - PP13 as a marker of pre-eclampsia: A two platform comparison study. AB - OBJECTIVE: To evaluate the role of PP13 as a marker for pre-eclampsia (PE) by comparing two different immunoassay platforms. METHODS: In this case-control study, first-trimester serum samples from 195 normal pregnancies and 37 pregnancies with PE were analysed for PP13 by using a manual DTL ELISA and the AutoDELFIA((r)) platform. RESULTS: Levels of PP13 in first-trimester pregnancies increased with gestational age in controls and pre-eclampsia cases using both methods of analysis, but at different rates. PP13 levels were decreased in women with PE. Levels of the marker are found to be more reduced in PE cases when measured using the DTL ELISA compared to AutoDELFIA((r)). CONCLUSION: Further studies are needed to compare the performance of the DTL ELISA and the AutoDELFIA((r)) PP13 assays in terms of reproducibility, robustness and clinical performance in predicting pre-eclampsia. PMID- 21257082 TI - Screening for pre-eclampsia--lessons from aneuploidy screening. AB - BACKGROUND: Antenatal screening for aneuploidy is an established routine clinical practice worldwide. The same statistical methodology, developed and refined over three decades, might be adapted to screening for pre-eclampsia. METHODS: The published literature is reviewed for evidence that the methodology is valid for pre-eclampsia using first trimester maternal serum PP13, PAPP-A, PlGF, ADAM12 and inhibin A, together with MAP and uterine artery Doppler PI. Risk is estimated for both early onset pre-eclampsia, requiring delivery before 34 weeks, or late onset disease. Prior risk from the background prevalence multiplied by likelihood ratios (LRs) for ethnicity, parity, adiposity and family history is multiplied by an LR from the screening marker profile. Markers are expressed in multiples of the gestation-specific median and adjusted for body mass, ethnicity and smoking status as appropriate. A standardized population with a fixed distribution of risk factors and a multi-variate Gaussian model of marker profiles is used to predict performance. RESULTS: There is sufficient published data to estimate individual risks reasonably well. Modeling predicts that using PAPP-A and one other serum marker, together with the physical markers more than two-thirds of early and one-third of late onset cases can be detected by classifying less than 2% of pregnancies as high risk; three-quarters of early case could be detected with a 5% high risk rate. CONCLUSION: Whilst more data on some markers is still required modeling so far suggests that extending first trimester aneuploidy screening programs to include pre-eclampsia screening would yield a high detection. However, prospective studies are needed to verify the model predictions. PMID- 21257083 TI - Placental and trophoblastic in vitro models to study preventive and therapeutic agents for preeclampsia. AB - In the field of preeclampsia, enormous efforts are ongoing to identify biomarkers predicting the syndrome already in the first trimester of pregnancy. At the same time, there is the need for in vitro models to test such biomarkers prior to their use in clinical trials. In addition, in vitro models may accelerate the development and evaluation of the benefit of any putative therapeutics. Therefore, in vitro systems have been established to evaluate the release of biomarkers and measure the effect of putative therapeutics using placental villous explants as well as the choriocarcinoma cell line BeWo. For explants, a cryogenic method to freeze, transport and thaw villous explants was developed to use such tissues for a multi-site tissue culture evaluation. Here we focus on three out of many in vitro models that have been established for human placental trophoblast. (1) Choriocarcinoma cell lines such as BeWo, Jeg-3 and Jar cells (2) isolated primary trophoblast cells, and (2) villous explants from normal placentas delivered at term. Cell lines were used to assess the effect of differentiation and fusion on the expression and release of a preeclampsia marker (placental protein 13; PP13) and beta-hCG. Moreover, cell lines were used to study the effect of putative preeclampsia therapeutics such as vitamins C and E, heparin and aspirin on marker release and viability. Cryopreservation of villous explants enabled shipment to a remote laboratory and testing of parameters in different countries using explants from one and the same placenta. Recently published data make it tempting to speculate that the choriocarcinoma cell line BeWo as well as fresh and cryogenically stored placental villous explants may well serve as in vitro models to study preventive and therapeutic agents in the field of preeclampsia. PMID- 21257084 TI - Cryogenic and low temperature preservation of human placental villous explants - a new way to explore drugs in pregnancy disorders. AB - BACKGROUND: A major handicap in cell culture studies using human tissues is the insufficient availability of fresh material on site. A method was developed for cryogenic storage and low temperature preservation of human placental villous explants, facilitating multi-site distribution for functional studies. METHODS: Explants from term placentas were incubated with cryoprotectant agents (dimethyl sulfoxide (DMSO), ethylene glycol, propanediol or Aedesta), frozen in liquid nitrogen, thawed and then cultured in-vitro. Viability was assessed by comparing frozen and thawed explants with non-frozen controls for morphological changes, lactate dehydrogenase (LDH) release, placenta protein 13 (PP13) secretion, and PCNA Western blotting. Functional studies determined the effect of oxygen and magnesium on explant viability. RESULTS: Cryoprotection by 3 M DMSO best maintained explants' viability, morphological integrity and PP13 release after freezing and thawing from liquid nitrogen. The effect of oxygen and magnesium was used to test the functional viability of cultured explants, after freezing in liquid nitrogen and transfer to dry ice for 1-5 days on site or for shipment to a remote lab. The tested parameters were similar between controls and cryogenically treated explants in the remote lab and the lab of origin, demonstrating the possibility of cryostoring explants for functional studies. CONCLUSION: Cryogenically stored placental villous explants shipped frozen can serve as a useful tool for comparative functional studies of placental villous tissues. The results of this pilot study also open the way for multi-site studies associated with drug tailoring for pregnancy disorders. PMID- 21257085 TI - [Idiopathic granulomatous mastitis with favorable outcome with medical treatment]. AB - Granulomatous mastitis is a rare inflammatory disorder. Its etiology remains unknown. We report a 42-year-old female who presented with an idiopathic granulomatous mastitis. Outcome was favourable with corticosteroids. The disease course of this entity is unpredictable and a consensual treatment is difficult. PMID- 21257086 TI - Guidance on reporting ultrasound exposure conditions for bio-effects studies. AB - This guidance is intended to encourage best practice among researchers into ultrasound bio-effects in terms of how they determine and report the exposure conditions used in their studies. It covers both diagnostic and therapeutic applications of ultrasound and is intended to be useful to the researchers themselves, to the review boards of ethical and funding committees and to the editors and reviewers of scientific journals. Recommendations are made for reporting formats, depending on the information available, and level of the study. PMID- 21257087 TI - Real-time elastography in differentiating metastatic from nonmetastatic liver nodules. AB - The study was designed to evaluate the role of real-time elastography in differentiating metastatic from nonmetastatic liver nodules, which include various benign lesions, hepatocellular carcinoma (HCC) nodules and lymphoma. Out of 1000 prospective patients who underwent abdominal ultrasound (US) examination, 48 patients had liver nodules. Nodule stiffness was determined by real-time elastography (ES) using color maps and shear wave velocity (SWV) and nodules having marked stiffness or SWV of more than 2.5 m/s were diagnosed as metastatic. The final diagnosis was made on fine needle aspiration cytology. No statistically significant differences were seen on elastomaps in the stiffness of metastatic and nonmetastatic nodules (p = 0.16) while SWV showed statistically significant differences in the strain velocities of benign, metastatic and heptocellular carcinoma nodules p < 0.0001 and < 0.008, respectively. At a cutoff value of SWV 2.5 m/s, the sensitivity, specificity and false positive to detect metastatic nodules by ES were 88%, 83% and 16%, respectively. When the SWV cut off value was set at 2.0 m/s the sensitivity, specificity and false positive were 94%, 70% and 29%, respectively. The study showed that estimation of SWV by ES at a cut off value of 2.5 m/s was a better and a more useful tool in diagnosing both solid and necrotic metastatic liver nodules compared with the color stiffness maps alone. PMID- 21257088 TI - Low-intensity pulsed ultrasound accelerated callus formation, angiogenesis and callus remodeling in osteoporotic fracture healing. AB - Osteoporotic fracture is a critical medico-social challenge leading to burdens in health care costs and hospital bed stays. Low-intensity pulsed ultrasound (LIPUS) was reported to accelerate normal fracture; however, its effect on osteoporotic fracture has not been previously addressed. We hypothesize that LIPUS can accelerate osteoporotic fracture healing and up-regulate the expression in the osteogenesis-, remodeling- and angiogenesis-related genes. Ovariectomy-induced osteoporotic fracture rat model was used to investigate the effects of LIPUS. Fractured rats were assigned to LIPUS or control group and healing was assessed by gene expression quantification, radiographic callus morphometry and histomorphometry. In the LIPUS group, Col-1 and bone morphogenetic protein-2 were up-regulated at earlier time points of week 2 to week 4 post-fracture; vascular endothelial growth factor was found to be up-regulated at week 4 to week 8; osteoprotegerin was up-regulated at week 2 post-fracture, followed by the surge of RANKL expression. Callus width and area measurements showed higher callus formation at weeks 2-4 in the LIPUS group and more rapid drop at weeks 6-8. Histomorphometry showed enhanced endochondral ossification in the callus at weeks 2-4, and lower at week 8. We conclude that LIPUS can accelerate osteoporotic fracture healing by enhancing callus formation, angiogenesis and callus remodeling. PMID- 21257089 TI - Acoustic radiation contrast in MR images for breast cancer diagnostics--initial phantom study. AB - Acoustic radiation contrast in magnetic resonance images is an approach to visualize the changes in ultrasonic loss and viscoelastic changes of the sample with the resolution of a magnetic resonance imaging (MRI) system. By irradiating ultrasound (US) into a tissue-mimicking sample, a displacement along the US beam path caused by the acoustic radiation force is obtained. This displacement varies with the US intensity, the duration of irradiation, the US attenuation and the viscoelastic properties of the sample. US pulses of 2.5 MHz with a duration of 20 ms and an intensity of <17 W/cm(2) are used. An MRI sequence was programmed to produce images in which the magnitude of the displacement is visualized by gray value changes. In addition, a finite element simulation of the measurements was performed to demonstrate the feasibility of the method. Through examination of the measurements and the simulations, information about viscoelastic changes was achieved. In this work, measurements on different breast phantoms are presented. PMID- 21257090 TI - Ultrasonic evaluation of dental implant biomechanical stability: an in vitro study. AB - Dental implants are widely used for oral rehabilitation. However, there remain risks of failure that are difficult to anticipate. The objective of this ex vivo study is to investigate the potentiality of quantitative ultrasound (QUS) to assess the amount of bone in contact with titanium prototype cylindrical implants. Four groups of 10 rabbit femurs each are considered, corresponding to different amounts of bone in contact with the implant. The 10 MHz ultrasonic response of the implant is processed to derive a quantitative indicator I, based on the temporal variation of the signal amplitude. Analysis of variance (ANOVA) (p < 10(-5)) tests revealed a statistical distribution of I significantly correlated with the amount of bone in contact with the cylinders. An analytical model considering the propagation of lateral waves allows the understanding of the physical origin of the echoes. QUS technique may be used to investigate the amount of bone in contact with a cylinder implant. PMID- 21257091 TI - Acoustic radiation force on a spherical contrast agent shell near a vessel porous wall--theory. AB - Contrast agent microshells (CAMSs) are under intensive investigation for their wide applications in biomedical imaging and drug delivery. In drug delivery applications, CAMSs are guided to the targeted site before fragmentation by high intensity ultrasound waves leading to the drug release. Prediction of the acoustic radiation force used to nondestructively guide a CAMS to the suspected site is becoming increasingly important and gaining attention particularly because it increases the system efficiency. The goal of this work is to present a theoretical model for the time-averaged (static) acoustic radiation force experienced by a CAMS near a blood vessel wall. An exact solution for the scattering of normal incident plane acoustic waves on an air-filled elastic spherical shell immersed in a nonviscous fluid near a porous and nonrigid boundary is employed to evaluate the radiation force function (which is the radiation force per unit energy density per unit cross-sectional surface). A particular example is chosen to illustrate the behavior of the time-averaged (static) radiation force on an elastic polyethylene spherical shell near a porous wall, with particular emphasis on the relative thickness of the shell and the distance from its center to the wall. This proposed model allows obtaining a priori information on the static radiation force that may be used to advantage in related as drug delivery and contrast agent imaging. This study should assist in the development of improved models for the evaluation of the time-averaged acoustic radiation force on a cluster of CAMSs in viscous and heat-conducting fluids. PMID- 21257092 TI - Are ECG premature complexes induced by ultrasonic cavitation electrophysiological responses to irreversible cardiomyocyte injury? AB - The objective of this study was to explore the relationship between premature complexes (PCs) in the electrocardiogram (ECG) and lethal injury of cardiomyocytes induced by ultrasound exposure of the heart with contrast-agent gas bodies in the circulation. Anesthetized rats were exposed in a heated water bath to 1.55 MHz focused ultrasound with bursts triggered at end systole during contrast agent infusion. PCs were detected in ECG recordings and cardiomyocyte necrosis was scored by identifying Evans blue-stained cells in multiple frozen sections. With 0.1 MUL/kg/min infusion of contrast agent for 5 min, both effects increased strongly for 2-ms bursts with increasing peak rarefactional pressure amplitude >1 MPa. At 8 MPa, statistically significant effects were found even for no agent infusion relative to sham tests. For 2-ms bursts at 2 MPa, the highly significant bioeffects seen for 10-, 1- and 0.1-MUL/kg/min infusion became marginally significant for 0.01 MUL/kg/min, which indicated a lower probability of cavitation nucleation. Burst duration variation from 0.2-20 ms produced no substantial trends in the results. Overall, the two effects were well correlated (r(2) = 0.88). The PCs occurring during contrast-enhanced ultrasound therefore appear to be electrophysiological responses to irreversible cardiomyocyte injury induced by ultrasonic cavitation. PMID- 21257093 TI - Characterization of DefinityTM ultrasound contrast agent at frequency range of 5 15 MHz. AB - The status of vasa vasorum, which can be imaged using ultrasound contrast agents, is an indication for the progression of atherosclerosis. The preferred ultrasound frequency for this purpose is between 5 and 15 MHz. Therefore, it is essential to have knowledge about the acoustic properties of microbubbles such as elasticity and viscosity to be able to implement the current models for lipid encapsulated microbubbles developed for frequencies used in precordial imaging. In this study, the shell parameters, stiffness S(p) and friction S(f), of DefinityTM microbubbles have been calculated at frequency range of 5-15 MHz by comparing the theoretical modeling of acoustic bubble response and experimental measurements. Derived parameters are in good agreement with previous estimations on SonoVueTM and SonazoidTM contrast agent. However, the value of S(f) is higher than previously estimated for DefinityTM between 12-28 MHz. PMID- 21257094 TI - Ohtahara syndrome and respiratory chain complex I deficiency. PMID- 21257095 TI - Diabetes and cardiovascular disease. Foreword. PMID- 21257096 TI - Preface cardiovascular disease prevention: the continuum of primary and secondary prevention. PMID- 21257097 TI - Prediction of cardiovascular disease events. AB - Observational studies with incidence of cardiovascular disease (CVD) events have typically provided the information that is used. Prediction of risk is dependent on accurate and precise baseline measurements in persons without coronary disease at baseline. Follow-up of 5 to 10 years is a typical interval of interest for the prediction of coronary disease events in adults who are asymptomatic at the baseline. Performance criteria for risk estimation include discrimination, calibration, and reclassification, and newer heart disease risk factors and biomarkers can be evaluated in the context of existing risk estimation approaches. PMID- 21257098 TI - Interventions for cardiovascular disease prevention. AB - Cardiovascular disease prevention is a continuum that encompasses the life course. This article discusses preventive strategies focusing on policy and clinical initiatives including primordial prevention (lifestyle changes involving smoking, diet and exercise), primary prevention (risk factor control), and secondary prevention (acute and chronic disease management). Combined use of all the three strategies can have an immediate and large impact on reducing CVD morbidity and mortality. PMID- 21257099 TI - Women and heart disease. AB - In the United States heart disease causes more than one-third of all deaths and most of these occur in women, not men, although women and health care professionals alike continue to view death from heart disease as a threat primarily to middle-aged men. The disparity between genders in the incidence of cardiovascular disease (CVD) may be the result of significant differences in both cardiovascular risk factors and presentation between men and women. This article reviews recent data regarding unique sex-specific characteristics of both risk for, and presentation of, CVD in women. PMID- 21257100 TI - Primary and secondary prevention strategy for cardiovascular disease in diabetes mellitus. AB - The majority of individuals with diabetes die from cardiovascular disease (CVD) and related complications. The risk of CVD is 2 to 4 fold greater in diabetes and largely magnified by co-morbidities that aggregate along with it. Sufficient evidence-based data now exist to support multifactorial risk intervention with specific targets for goal-directed therapy for both primary and secondary prevention. These interventions have shown survival benefit in addition to prevention of vascular complications. Prevention of diabetes and delaying its onset should also be an important aspect in future health care strategy and research to confront the oncoming tsunami of CVD related to diabetes. PMID- 21257101 TI - Antiplatelet therapy in coronary heart disease prevention. AB - Platelets are central to the pathogenesis of coronary heart disease (CHD). An ever-growing number of antiplatelet therapies used in different doses and combinations have helped manage atherothrombosis, both acutely and in primary and secondary prevention. Despite modern therapy, nearly 800,000 individuals suffer annually from an initial coronary event in the United States alone; almost 500,000 experience a recurrent event. This review provides a current appraisal of antiplatelet drug use in CHD prevention and discusses key barriers to achieving its full potential in real-world practice. PMID- 21257102 TI - Lipid-lowering therapy with statins for the primary and secondary prevention of cardiovascular disease. AB - Cardiovascular disease (CVD) still ranks as the top cause of mortality worldwide. Lipid-modifying therapy has revolutionized the treatment of the disease and is partly responsible for the recent decline in deaths due to CVD. Treatment strategies have evolved since the introduction of the earlier lipid-lowering agents (fibrates, niacin, bile acid resins) to the advent of statins, which have become the standard drugs in cholesterol therapy. The strategy of using high intensity statin therapy as the initial treatment approach in high-risk individuals, rather than focusing on specific cholesterol levels alone, remains a subject of debate. PMID- 21257103 TI - Focusing on high-density lipoprotein for coronary heart disease risk reduction. AB - A low level of high-density lipoprotein (HDL) is an acknowledged risk factor for coronary heart disease (CHD). HDL cholesterol (HDL-C) exerts its primary cardioprotective effect through a reverse cholesterol transport process, and suppression of this process has been the focus of the development of novel therapeutic agents for increasing HDL-C levels. Several strategies can be used to increase HDL-C levels to target cardiovascular risk reduction. This article presents a review of the biologic actions of HDL that can serve as a potential basis for antiatherosclerotic activity and discusses strategies for targeting HDL for CHD risk reduction. PMID- 21257104 TI - Emerging therapies for atherosclerosis prevention and management. AB - Atherosclerosis is a chronic immunoinflammatory disease involving medium and large arteries, resulting from a complex interaction between genetic and environmental risk factors. Acute atherosclerotic vascular disease largely results from thrombosis that supervenes on a disrupted atherosclerotic plaque. A healthy lifestyle coupled with management of modifiable risk factors reduces the adverse clinical consequences of atherothrombosis. Reducing low-density lipoprotein cholesterol levels using statins and other agents is the primary pharmacologic approach to stabilize atherosclerosis, but a large residual risk burden remains, stimulating the search for additional therapies for atherosclerosis management. This review focuses on new and emerging therapeutic strategies targeting atherosclerosis. PMID- 21257105 TI - Renin-angiotensin-aldosterone blockade for cardiovascular disease prevention. AB - The renin-angiotensin-aldosterone system (RAAS) plays a significant role in pathophysiology of multiple disease states. RAAS blockade is beneficial in patients with hypertension, acute myocardial infarction, chronic heart failure, stroke, and diabetic renal disease. RAAS blockade with the combination angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has demonstrated conflicting results in recent clinical trials. This article reviews the latest evidence of isolated ACEI or ARB use, their combination, and the role of aldosterone blockers and direct renin inhibitors in patients at risk, and makes recommendations for their use in the prevention of morbidity and mortality in cardiovascular disease. PMID- 21257106 TI - Role of medical versus interventional strategies to prevent coronary events in patients with stable coronary artery disease. AB - Chronic coronary artery disease (CAD) is a highly prevalent and complex health problem in the United States. The goals of treatment in patients with stable CAD are to reduce symptoms and thus improve quality of life, reduce myocardial ischemia, and, more importantly, reduce the risk of myocardial infarction and death. In this article, the authors review the evidence regarding the role of medical versus interventional strategies in reducing the risk of future coronary events in patients with stable CAD. PMID- 21257107 TI - The adolescence of the Web--from turbulence to enlightenment. PMID- 21257108 TI - Online aggression: a reflection of in-person victimization or a unique phenomenon? PMID- 21257109 TI - Online communication among adolescents: an integrated model of its attraction, opportunities, and risks. AB - Adolescents far outnumber adults in their use of e-communication technologies, such as instant messaging and social network sites. In this article, we present an integrative model that helps us to understand both the appeal of these technologies and their risks and opportunities for the psychosocial development of adolescents. We first outline how the three features (anonymity, asynchronicity, and accessibility) of online communication stimulate controllability of online self-presentation and self-disclosure among adolescents. We then review research on the risks and opportunities of online self-presentation and self-disclosure for the three components of adolescents' psychosocial development, including identity (self-unity, self-esteem), intimacy (relationship formation, friendship quality, cyberbullying), and sexuality (sexual self-exploration, unwanted sexual solicitation). Existing research suggests several opportunities of online communication, such as enhanced self esteem, relationship formation, friendship quality, and sexual self-exploration. It also yields evidence of several risks, including cyberbullying and unwanted sexual solicitation. We discuss the shortcomings of existing research, the possibilities for future research, and the implications for educators and health care professionals. PMID- 21257110 TI - Youth Internet victimization in a broader victimization context. AB - PURPOSE: To examine past-year and lifetime rates of online victimization and associations with offline victimizations, trauma symptomatology, and delinquency among adolescents. METHODS: Data were collected through telephone interviews from a nationally representative sample of 2,051 adolescents (ages, 10-17) as part of the National Survey of Children's Exposure to Violence. Data were collected between January and May, 2008. RESULTS: Six percent of youth reported a past-year online victimization and 9% a lifetime online victimization. Almost all youth reporting a past-year online victimization (96%) reported offline victimization during the same period. The offline victimizations most strongly associated to online victimization were sexual victimizations (e.g., sexual harassment, being flashed, rape) and psychological and emotional abuse. Online victims also reported elevated rates of trauma symptomatology, delinquency, and life adversity. CONCLUSIONS: Prevention and intervention should target a broader range of behaviors and experiences rather than focusing on the Internet component exclusively. Internet safety educators need to appreciate that many online victims may be at risk not because they are naive about the Internet, but because they face complicated problems resulting from more pervasive experiences of victimization and adversity. PMID- 21257111 TI - The neglected role of adolescent emotional well-being in national educational achievement: bridging the gap between education and mental health policies. AB - PURPOSE: Although child poverty is recognized as a critical determinant of poor educational achievement in the United States, policy discussions on raising academic achievement rarely include the importance of the effects of poverty on the mental health of adolescents. This article examines the role of adolescent emotional well-being (indicators of depression) as a mediator of the effects of poverty on differences in educational achievement at the national and U.S. state levels. METHODS: Differences in standardized adolescent academic achievement across 23 developed countries and 39 U.S. states were analyzed using path analytic techniques to test the hypothesis that indicators of adolescent emotional well-being mediate relations between child poverty rates and academic achievement. RESULTS: Child poverty rates were related to both adolescent emotional well-being and educational achievement across both U.S. states and developed countries. Path analyses showed that the status of a country's or state's adolescent emotional well-being is a strong predictor of its educational achievement and that emotional well-being mediates the relationship between poverty and educational achievement. CONCLUSION: Policies designed to ameliorate the adverse effects of poverty on mental health are critical as they are likely to improve both average educational achievement and student emotional well-being. Attention to improving mental health care not only has the potential to reduce societal and individual costs directly related to health but also to reduce the indirect costs of poor educational achievement. PMID- 21257112 TI - Gender differences and predictors of self-rated health development among Swedish adolescents. AB - PURPOSE: The purpose of the study was to evaluate the development of self-rated health among boys and girls during adolescence. METHODS: Longitudinal cohort study, involving 1,046 Swedish adolescents from the seventh (12-13 years old) to the ninth grade. Self-rated health (well-being) and health-related empowerment were measured using a questionnaire. RESULTS: In the seventh as well as in the ninth grade, the proportion of adolescents reporting a good health was lower in girls than in boys. In general, girls showed lower health-related empowerment as compared with boys and this difference remained between both the grades. In boys and girls belonging to both grades, a high empowerment score was related to a high self-rated health. For both boys and girls, self-rated health declined between the seventh and ninth grade. In girls, the proportion rating their health as "very good" declined from 47 % to 30%, and in boys the same proportion declined from 56% to 46%, indicating an increasing gender difference. Only a minor proportion of adolescents (16% of the boys and 13% of the girls) reported an improvement. A high self-rated health in grade nine was, in girls, predicted by positive school experiences in seventh grade and, in boys, by a good mood in the family. CONCLUSION: During adolescence, girls reported lower self-rated health than boys and this gender difference increased over the years. High empowerment is related to high self-rated health, and positive school experiences and a good mood in the family seem to be important predictors of a positive development of self-rated health. PMID- 21257113 TI - Relationship between adolescent risk preferences on a laboratory task and behavioral measures of risk-taking. AB - PURPOSE: The goal of the study was to assess individual differences among adolescents regarding risk-taking behavior in the laboratory. The second aim was to evaluate whether the laboratory-based risk-taking behavior is associated with other behavioral and psychological measures associated with risk-taking behavior. METHODS: A total of 82 adolescents with no personal history of psychiatric disorder completed a computerized decision-making task, the Wheel of Fortune. On the basis of the choices made between clearly defined probabilities and real monetary outcomes, this task assesses risk preferences when participants are confronted with potential rewards and losses. The participants also completed a variety of behavioral and psychological measures associated with risk-taking behavior. RESULTS: Performance on the task varied on the basis of probability and anticipated outcomes. In the winning sub-task, participants selected low probability-high-magnitude reward (high-risk choice) less frequently than high probability-low-magnitude reward (low-risk choice). In the losing sub-task, participants selected low-probability-high-magnitude loss more often than high probability-low-magnitude loss. On average, the selection of probabilistic rewards was optimal and similar to performance in adults. There were, however, individual differences in performance, and one-third of the adolescents made high risk choice more frequently than low-risk choice while selecting a reward. After controlling for sociodemographic and psychological variables, high-risk choice on the winning task predicted "real-world" risk-taking behavior and substance related problems. CONCLUSIONS: These findings highlight individual differences in risk-taking behavior. Regarding validity of the Wheel of Fortune task, the preliminary data suggest that it might be a valuable laboratory tool for studying behavioral and neurobiological processes associated with risk-taking behavior in adolescents. PMID- 21257114 TI - A parent-based intervention to reduce sexual risk behavior in early adolescence: building alliances between physicians, social workers, and parents. AB - PURPOSE: To evaluate the efficacy of a parent-based intervention to prevent sexual risk behavior among Latino and African American young adults. This was delivered to mothers while waiting for their adolescent child to complete an annual physical examination. METHODS: A randomized clinical trial was conducted with 264 mother-adolescent dyads in New York City. Adolescents were eligible for the study only if they were African American or Latino and aged 11-14 years, inclusive. Dyads completed a brief baseline survey and were then randomly assigned to one of the following two conditions: (1) a parent-based intervention (n = 133), or (2) a "standard care" control condition (n = 131). Parents and adolescents completed a follow-up survey nine months later. The primary outcomes included whether the adolescent had ever engaged in vaginal sexual intercourse, the frequency of sexual intercourse, and the frequency of oral sex. RESULTS: Relative to the control group, statistically significant reduced rates of transitioning to sexual activity and frequency of sexual intercourse were observed, with oral sex reductions nearly reaching statistical significance (p < .054). Specifically, sexual activity increased from 6% to 22% for young adults in the "standard of care" control condition, although it remained at 6% among young adults in the intervention condition at the 9-month follow-up. CONCLUSIONS: A parent-based intervention delivered to mothers in a pediatric clinic as they waited for their child to complete a physical examination may be an effective way to reduce sexual risk behaviors among Latino and African American middle-school young adults. PMID- 21257115 TI - Compounded effect of early adolescence depressive symptoms and impulsivity on late adolescence gambling: a longitudinal study. AB - PURPOSE: Depression and impulsivity have been positively correlated to problem gambling, but no study has focused on their combined effects on the onset of problem gambling. This study examined the possible synergistic effect of depressive symptoms and impulsivity in early adolescence on late adolescence gambling behaviors among a longitudinal cohort of 678 students from Baltimore, Maryland. METHODS: The South Oaks Gambling Screen-Revised for Adolescents, Teacher Observation of Classroom Adaptation-Revised, and Baltimore How I Feel Adolescent Version, were used to assess late adolescence gambling behaviors, early adolescence impulsivity, and depressive symptoms, respectively. Data analyses were conducted using analysis of variance and binary logistic regression models. RESULTS: Problem gamblers (PGs) were 12% of the sample (includes at-risk and PGs), 87.5% of whom were males and 12.5% were females (p < .001). Among males, there appeared to be a slight association between early adolescence depressive symptoms and late adolescence problem gambling. Compared with nongamblers and social gamblers, depressive symptoms increased the odds of problem gambling by four-fold (PGs vs. nongamblers: OR = 4.1, 95% CI = .73-22.47, p = .11; PGs vs. social gamblers: OR = 3.9, 95% CI = .78-19.31, p = .10). Among those with high depressive symptoms, increases in impulsivity decreased the odds of problem gambling while among those with high impulsivity, increases in depressive symptoms decreased the odds of problem gambling. CONCLUSIONS: Early adolescence depressive symptoms appear to be more positively associated with late adolescence problem gambling than early adolescence impulsivity, there seems to be a divisive interaction between depressive symptoms and impulsivity on problem gambling. PMID- 21257116 TI - Do parents have any influence over how young people appraise tobacco images in the media? AB - BACKGROUND: Socio-cultural factors, including media and family, play an important role in introducing and reinforcing pro-smoking intentions. Tendencies to appraise smokers in media in positive, negative, and empathic ways may play a role in the social and familial dynamics influencing smoking intentions. OBJECTIVE: This study assessed: (1) social group differences in appraisals of pro and antismoking imagery in media; (2) whether parental antismoking expectations are associated with less positive appraisals; and (3) whether these appraisal tendencies mediate the relationship between parental antismoking expectations and smoking intentions. METHODS AND MATERIALS: Adolescents (N = 515, ages 11-13, M = 11.5 years) from Auckland, New Zealand completed a multimedia, computer-based questionnaire assessing media exposure of smoking imagery in four media clips as well as media exposure, parental attitudes toward smoking, and smoking intentions. RESULTS: Appraisals of smoking imagery in the media clips and media consumption were patterned on the basis of gender, ethnic group, school economic status, and peer and parent smoking behaviors. Positive appraisals of the smoking images were found to mediate the relationship between weaker parental antismoking expectations and greater smoking intentions. CONCLUSION: Parents may have significant influence over how adolescents perceive smoking imagery in media by presenting clear and unambiguous expectations about tobacco use at home. These expectations may shape how adolescents respond to smoking images by effectively "tainting" the image. PMID- 21257117 TI - Predictors and sequelae of smoking topography over the course of a single cigarette in adolescent light smokers. AB - PURPOSE: The objective of this study was to determine whether adolescent smokers, who varied in their smoking histories and symptoms of nicotine dependence, exhibit any decrease in puff volume and duration similar to that typically seen in dependent adolescent and adult smokers. Moreover, we examined whether puffing trajectories were moderated by individual difference factors, as well as whether puffing topography over the course of smoking a single cigarette was predictive of an escalation in dependence symptoms. METHODS: We assessed smoking topography (puff number, duration, volume, maximum flow rate [velocity], and inter-puff interval) over the course of smoking a single cigarette in a sample of 78 adolescent light smokers, using hierarchical linear modeling. We examined moderators (anxiety, depression, nicotine dependence) of the topographic trajectories, as well as whether smoking topography predicted any change in dependence over a 2-year period. RESULTS: Puff volume and puff duration decreased over the course of smoking the cigarette, whereas puff velocity and inter-puff interval increased. Slopes for puff volume and duration were moderated by anxiety and depressive symptoms. Moreover, individuals with a less "typical" topography pattern (exhibited stable or increasing volume and duration over the course of smoking the cigarette) demonstrated a heightened dependence escalation in the subsequent 2 years. CONCLUSION: Our findings suggest that adolescent light smokers self-regulate nicotine during the course of smoking a single cigarette, similar to that reported in dependent adolescent and adult smokers. However, single cigarette self-regulation was influenced by certain affective factors. Implications of these findings and future directions for adolescent smoking research are discussed. PMID- 21257118 TI - Effects of a school-based prevention program on European adolescents' patterns of alcohol use. AB - PURPOSE: School-based substance abuse prevention programs are widespread but are rarely evaluated in Europe. We aimed to evaluate the effect of a new school-based prevention program against substance use on the frequency of alcohol consumption and alcohol-related problem behaviors among European students. METHODS: During the school year 2004-2005, a total of 7,079 students aged 12-14 years from 143 schools in seven European countries participated in this cluster randomized controlled trial. Schools were randomly assigned to either control (65 schools, 3,532 students) or to a 12-session standardized program based on the comprehensive social influence model (78 schools, 3,547 students). Alcohol use and frequency of alcohol-related problem behaviors were investigated through a self-completed anonymous questionnaire at baseline and 18 months thereafter. The association between intervention and changes in alcohol-related outcomes was expressed as odds ratio (OR), estimated by multilevel regression model. RESULTS: The preventive program was associated with a decreased risk of reporting alcohol related problems (OR = .78, 95% confidence intervals [CI] = .63-.98), although this reduction was not statistically significant in the subgroup of 743 current drinkers at baseline. The risk for alcohol consumption was not modified by exposure to the program (OR = .93, 95% CI = .79-1.09). In the intervention group, nondrinkers and occasional drinkers at baseline progressed toward frequent drinking less often than in the control group. CONCLUSIONS: School curricula based on the comprehensive social-influence model can delay progression to frequent drinking and reduce occurrence of alcohol-related behavioral problems in European students. These results, albeit moderate, have potentially useful implications at the population level. PMID- 21257119 TI - Obese adolescents are less active than their normal-weight peers, but wherein lies the difference? AB - BACKGROUND: Obese adolescents achieve less moderate to vigorous physical activity (MVPA) than normal-weight adolescents, but the nature and extent of the deficit is unclear. This study aimed to describe differences in MVPA across weight status categories by domain of activity (sport, play, and active transport) and specific activity-sets (e.g. team sports, playground games, and chores) using minutes of activity, estimated intensity, and estimated energy expenditure as metrics of MVPA. METHOD: Anthropometric, use-of-time, and pedometer data were collected on a random sample of 2,200 Australian children aged 9-16 years. Minutes of activity, intensity metabolic equivalents of tasks (METs), and energy expenditure (MET.min) within each domain were estimated using an energy cost compendium. RESULTS: Obese adolescents reported 174 MET.min/d lower MVPA energy expenditure than normal weight peers (p < .0001), more than accounting for the entire difference in total daily energy expenditure (154 MET.min/d). Of this difference, 121 MET.min/d was associated with lower sports participation (p < .0001) and 45 MET.min/d with less free play (p = .03). There were no differences in minutes of active transport or in reported activity intensity across weight status categories in sport, free play, or active transport. The differences in MVPA participation between obese and normal-weight adolescents were largely because of different levels of participation in team sports, cycling, partner sports (boys), and dancing (girls). CONCLUSION: More than two-thirds of the difference in energy expenditure between obese and normal-weight Australian adolescents was because of lower participation in sport. Strategies for engaging obese adolescents in sport may help to redress deficits in energy expenditure. PMID- 21257120 TI - Preliminary healthy eating outcomes of SNaX, a pilot community-based intervention for adolescents. AB - PURPOSE: We used principles of community-based participatory research to develop and pilot test a 5-week intervention for middle school students, Students for Nutrition and eXercise (SNaX). SNaX aimed to translate school obesity-prevention policies into practice with peer advocacy of healthy eating and school cafeteria changes. METHODS: A total 425 seventh graders (63% of all seventh graders) in the intervention school were surveyed at baseline regarding cafeteria attitudes and sugar-sweetened beverage consumption; of the 425 students, 399 (94%) were surveyed again at 1-month post-intervention. School cafeteria records were obtained from two schools: the intervention school and a nonrandomized selected comparison school with similar student socio-demographic characteristics. RESULTS: A total of 140 students in the intervention school were trained as peer advocates. In the intervention school, cafeteria attitudes among peer advocates significantly improved over time (approximately one-third of a standard deviation), whereas cafeteria attitudes of non-peer advocates remained stable; the improvement among peer advocates was significantly greater than the pre-post change for non-peer advocates (b = .71, p < .001). Peer advocates significantly reduced their sugar-sweetened beverage intake (sports and fruit drinks), from 33% before intervention to 21% after intervention (p = .03). Cafeteria records indicated that servings of fruit and healthier entrees (salads, sandwiches, and yogurt parfaits) significantly decreased in the comparison school and significantly increased in the intervention school; the magnitude of changes differed significantly between the schools (p < .001). CONCLUSIONS: As compared with the non-peer advocates, peer advocates appeared to benefit more from the intervention. Future research should consider engaging parents, students, and other key community stakeholders to determine acceptable and sustainable cafeteria changes. PMID- 21257121 TI - High frequency hearing sensitivity in adolescent females of a lower socioeconomic status over a period of 24 years (1985-2008). AB - PURPOSE: To examine annually over a period of 24 years, the high frequency hearing sensitivity in different groups of urban female adolescents with a low socioeconomic status (SES) and residential foster care. METHODS: Hearing screening (15 decibel [dB] hearing level ranging from 1,000 to 8,000 Hertz [Hz]) and threshold (>15 dB hearing level) records were obtained from 8,710 female adolescents (mean age, 15.8 years [range, 12-20 years]), predominantly Hispanic and African American from households with a low SES. Data related to the use of personal listening devices (PLDs), daily hours of usage, occurrence of tinnitus, and hearing thresholds between 1,000 and 8,000 Hz over an 8-year period (2001 2008) were obtained from the adolescents. RESULTS: High frequency hearing loss (HFHL) doubled over the 24-year period from 10.1% in 1985 to 19.2% in 2008. In comparison with the general adolescent population, this group of female adolescents presented with a higher percentage of bilateral mild or greater degrees of HFHL at two or more frequencies including 3,000, 4,000, and 6,000 Hz. Use of PLDs increased four-fold, from 18.3% (n = 68) in 2001 to 76.4% (n = 227) in 2008. Of the total number reporting tinnitus (n = 286), 99.7% (n = 285) also reported regular PLD use. A significant relationship was found between PLD use and reported tinnitus and HFHL irrespective of time of use of PLD. CONCLUSIONS: Increased incidence of HFHL, reported tinnitus, PLD use, and hours of daily use in at-risk female adolescents of a low SES was found. A frequency interval of 3,000-6,000 Hz should be included in hearing screening protocols to identify potentially disabling hearing loss. Hearing conservation strategies need to be developed and/or modified that target and reach at-risk children and adolescents. PMID- 21257122 TI - Association of provider scope of practice with successful transition for youth with special health care needs. AB - PURPOSE: Youth with special health care needs (YSHCN) encounter unique challenges in the transition from pediatric to adult healthcare. Although discussing transition with healthcare providers can be beneficial, it is unclear whether the providers' scope of practice (child-only vs. lifespan-oriented) drives these discussions. We examined the association between scope of practice and transition related services. METHODS: We used caregivers' responses in the 2005-2006 National Survey of Children with Special Healthcare Needs. We compared transition outcomes for youth whose providers treated only children, and youth whose providers also treated adults (lifespan-oriented). Individual and household-level demographic factors were applied to logistic regression models. RESULTS: Youth with lifespan-oriented providers were more likely than youth with child-only providers to have discussed changing health needs in adulthood (52% vs. 43%) and adult health insurance (24% vs. 21%). There was no difference in receiving encouragement toward self-responsibility (79% vs. 78%). These associations persisted after adjusting for demographics. CONCLUSIONS: YSHCN are more likely to report having discussed issues related to transition into adult healthcare if their providers treat adults as well as children. However, discussion involving adult health insurance in particular was lacking for all YSHCN. PMID- 21257123 TI - Adolescent alcohol intoxication in the Dutch hospital departments of pediatrics: a 2-year comparison study. AB - PURPOSE: To monitor the prevalence of, and the circumstances leading to, adolescent alcohol intoxication admissions in Dutch hospital departments of pediatrics. METHODS: Data were collected in 2007 and 2008, using the Dutch Pediatric Surveillance System, in which pediatricians received questionnaires on varying issues, including adolescent alcohol intoxication admissions. RESULTS: The adolescents treated in 2008, as in 2007, were average youth across proportion of gender, educational level, school performances, family structure, siblings, familiarity with medical or aid agencies, alcohol use, and other (illicit) drug use. In 2008, 13% more adolescents were treated. These adolescents showed a trend of having a younger average age, higher blood alcohol concentrations, and longer durations of mental impairment. About 45% of the adolescents who were treated for alcohol intoxication had purchased alcohol from a commercial place, despite that 51 times the specific adolescent had not reached the legal age of 16 years old. About one-third of the youngsters consumed alcohol at home or at a friend's home. CONCLUSIONS: The number of adolescents suffering from alcohol intoxication increased in 2008 compared with 2007. Parental (lack of) involvement and responsibilities of commercial sales personnel are discussed. PMID- 21257124 TI - Human papillomavirus vaccine: an updated position statement of the Society for Adolescent Health and Medicine. PMID- 21257125 TI - Defining physiatry: a tolerance for uncertainty. PMID- 21257126 TI - Is SHAQ the future of health care? PMID- 21257127 TI - Does neurologic examination during inpatient rehabilitation help predict global outcome after nonpenetrating traumatic brain injury? AB - OBJECTIVE: To determine whether combining basic neurologic examination measurements with posttraumatic amnesia (PTA) duration can enhance prediction accuracy in moderate-to-severe traumatic brain injury (TBI). DESIGN: A descriptive between-subjects study. SETTING: Multicenter: 4 Veterans Affairs Brain Injury Rehabilitation Centers within the Defense and Veterans Brain Injury Center network. PARTICIPANTS: A total of 210 patients (active duty, veteran, or military dependent) with moderate-to-severe nonpenetrating TBI who consented during acute rehabilitation for data collection and completed relevant baseline and 12-month follow-up evaluations. METHODS: Multivariate analysis on neurologic examination predictor variables (upper extremity paresis, lower extremity paresis, Romberg test, and Kurtzke Expanded Disability Status Scale [EDSS]) was performed with block logistic regression modeling that controlled for duration of PTA. MAIN OUTCOME MEASURE: Glasgow Outcome Score at 1 year. RESULTS: Glasgow Outcome Score prediction accuracy by using PTA duration was modestly improved with the included neurologic examination measurements. The most influential predictor among them was EDSS, a composite measurement of neurologic impairment. When EDSS was excluded, the simple measurements of upper limb paresis and the Romberg test also provided independent prognostic value. CONCLUSIONS: This study demonstrated that simple clinical measurements of neurologic impairment (limb paresis, imbalance, other neurologic deficits) are of value in refining the prediction of long-term global outcome from TBI. These measurements may serve as markers of focal injury not captured by PTA duration, a severity marker weighted toward diffuse injury. PMID- 21257128 TI - Landing mechanics during side hopping and crossover hopping maneuvers in noninjured women and women with anterior cruciate ligament reconstruction. AB - OBJECTIVE: To compare, landing mechanics and electromyographic activity of the lower extremities during side hopping and crossover hopping maneuvers, in noninjured women and women with anterior cruciate ligament (ACL) reconstruction. DESIGN: A case-control study. SETTING: A 3-dimensional motion analysis laboratory. PARTICIPANTS: Twenty-eight young women (range, 21-35 years) (15 control subjects and 13 subjects with ACL reconstruction). PATIENTS AND METHODS: All participants performed a side-to-side hopping task that consisted of hopping single-legged 10 times consecutively from side to side across 2 lines marked 30 cm apart on 2 individual force plates. The task was designated as a side hopping when the hop was to the opposite side of the stance leg and as crossover hopping when the hop was toward the side of the stance leg. MAIN OUTCOME MEASUREMENTS: Peak hip-/knee-joint angles; peak knee extension/abduction joint moments; electromyographic studies of the gluteus maximus, gluteus medius, rectus femoris, and hamstring muscles; and quadriceps/hamstring co-contraction ratio were compared between the groups by means of 2 * 2 multivariate analysis of variance tests (group * maneuver). RESULTS: Noninjured women and women with ACL reconstruction exhibited similar hip- and knee-joint angles during both types of hopping. Hip-joint angles were greater during the crossover hopping in both groups, and knee-joint angles did not differ between the groups or hops. Knee joint moments demonstrated a significant group * maneuver interaction. Greater knee extension and valgus moments were noted in the control group during crossover hopping, and greater knee abduction moments were noted in the ACL group during side hopping. Electromyographic data revealed no statistically significantly differences between the groups. CONCLUSIONS: Women with ACL reconstruction exhibited the restoration of functional biomechanical movements such as hip-/knee-joint angles and lower extremity neuromuscular activation during side-to-side athletic tasks. However, not all biomechanical strategies are restored years after surgery, and women who have undergone a procedure such as ACL reconstruction may continue to exhibit knee-joint abduction moments that increase the risk of additional knee injury. PMID- 21257129 TI - Reliability of bidirectional and variable-opening equipment for the measurement of pelvic floor muscle strength. AB - OBJECTIVE: In evaluating pelvic floor muscles, it is important to use reliable and accurate methods. Therefore the objective of this study was to verify the reliability of bidirectional and variable-opening equipment designed to measure anteroposterior and left-right strength of pelvic floor muscles. DESIGN: Test retest to assess reliability. SETTING: Academic institution, primary level of clinical care. PARTICIPANTS: Seventeen nulliparous women between 20 and 33 years of age participated in the procedure during 3 consecutive weeks. METHODS: A dynamometer was used to evaluate pelvic floor muscle strength. The reliability was tested in 3 sessions, with a 7-day interval between, excluding premenstrual and menstrual periods. On each day of data collection, 3 maximum voluntary contractions of pelvic floor muscles were measured. The abdominal and gluteus muscles were evaluated concomitantly to the assessment in an attempt to isolate the pelvic floor muscle contractions. MAIN OUTCOME MEASURES: To evaluate the test retest reliability with the intraclass correlation coefficient and the SEM. RESULTS: Intraclass correlation of pelvic floor muscle force values ranged from good to excellent. The SEM values for anteroposterior strength were 1.96 N and 1.86 N for left and right, respectively. CONCLUSIONS: Test-retest values demonstrated that the equipment we assessed to measure the anteroposterior and left-right force generated reliable pelvic floor muscle strength measurements. PMID- 21257130 TI - Natural history of scoliosis in nonambulatory spastic tetraplegic cerebral palsy. AB - OBJECTIVE: To analyze the development and progression of scoliosis in children and adolescents with nonambulatory spastic tetraplegic cerebral palsy. DESIGN: Retrospective longitudinal review. SETTING: Pediatric nursing home. PARTICIPANTS: A total of 110 children and adolescents <18 years of age, with scoliosis. INTERVENTIONS: N/A. MAIN OUTCOME MEASURES: Cobb angle, age, weight, height, history of hip dislocation, tracheostomy. RESULTS: The Cobb angle increased with age, weight, and height in a nonlinear fashion. A square root transformation of the Cobb angle was chosen to model the nonlinear relationship between the Cobb angle and predictors. Age, height, and weight were significant univariate predictors of the square root of the Cobb angle (slopes = 0.377, 0.067, and 0.06, respectively). In the multivariate mixed model, age remained a significant predictor of the Cobb angle (slope = 0.456), but height and weight did not. If the Cobb angle was > 40 degrees by age 12 years, scoliosis was more likely to progress than if the Cobb angle was <= 40 degrees . The effect of age was stronger for those with history of tracheostomy (age slope = 0.631 vs 0.281) than those without. The relationship of age and Cobb angle did not differ significantly between hip dislocated and non-hip-dislocated groups. CONCLUSIONS: Age was found to be the most significant predictor of Cobb angle, and the effect of age was greater in the tracheostomy group than in the nontracheostomy group. After adjustment for age, the weight and height were not significant predictors of Cobb angle. Cobb angles of > 40 degrees by the age of 12 years were associated with greater increases in Cobb angle with age. PMID- 21257131 TI - Does the location of low back pain predict its source? AB - OBJECTIVE: To evaluate the predictive utility of the pattern of low back pain (LBP) in detecting the source of LBP as internal disk disruption (IDD), facet joint pain (FJP), or sacroiliac joint pain (SIJP). DESIGN: Retrospective chart review. SETTING: University spine center. PATIENT SAMPLE: A total of 170 cases from 156 patients presenting with LBP whose low back disorder was definitively diagnosed. The mean age was 54.4 years (SD, 16.2) and median duration of LBP was 12 months (interquartile ranges, 6-32). METHODS: Charts of consecutive LBP patients who underwent definitive diagnostic spinal procedures including provocation diskography, facet joint blocks, and sacroiliac joint blocks were retrospectively reviewed. Each patient with LBP was queried as to the exact location of their LBP: midline, defined as in-line with the spinous processes, and/or paramidline, defined as lateral to 1 fingerbreadth adjacent to the midline. OUTCOME MEASURES: In patients with a definitive diagnosis for the source of LBP, the proportion of each diagnosed source of pain was calculated. chi(2) tests were used to identify differences in the percentages of midline and paramidline LBP among the groups of patients testing positive for IDD, FJP, or SIJP. Diagnostic measures of sensitivity, specificity, positive and negative predictive values, diagnostic accuracy, and likelihood ratios of positive and negative tests using the presence/absence of midline and paramidline pain for the diagnosis of IDD, FJP, and SIJP were estimated. RESULTS: With cases of IDD, significantly greater percentages of patients reported midline LBP (95.8%; chi(2) = 101.4, df = 2, P < .0001) as compared with cases of FJP (15.4%) or SIJP (12.9%). In cases of IDD, significantly lower percentages of patients reported paramidline pain (67.3%; chi(2) = 16.1, df = 2, P = .0003) as compared with cases of FJP (95.0%) or SIJ (96.0%). In cases of IDD, significantly greater percentages of patients reported midline LBP (95.8%; chi(2) = 101.4, df = 2, P < .0001) as compared with cases of FJP (15.4%) or SIJP (12.9%). The specificity of midline LBP for IDD, FJP, and SIJP was 74.8% (95% CI = 65.0%-82.9%), 28.0% (20.1%-37.0%), and 36.0% (28.0%-44.5%), respectively. The negative predictive value of paramidline LBP for IDD, FJP, and SIJP was 29.2% (95% CI = 12.6%-51.1%), 91.7% (73.0%-99.0%), and 95.8% (78.9%-99.9%). The diagnostic accuracy of midline LBP for IDD, FJP, and SIJP was 83.5%, 24.1%, and 31.8%, respectively. CONCLUSIONS: The presence of midline LBP increases the probability of lumbar IDD and reduces the probability of symptomatic FJ and SIJ dysfunction. The presence of isolated paramidline LBP increases the probability of symptomatic FJ or SIJ but mildly reduces the likelihood of lumbar IDD. PMID- 21257132 TI - Psychometrics of dominant right hand during the 9-hole PEG test: differences between PEG placement and removal. AB - OBJECTIVE: To assess psychometrics of hand dominance during the 9-Hole Peg Test. SUBJECTS: Sixteen healthy volunteers (23-40 years of age, 10 female and 6 male subjects, all fortuitously right handed). METHODS: As is conventional protocol, the total time to perform the task was recorded as a dexterity index. In addition, the relative distance between points (distal phalanges) on the index finger and thumb was continuously monitored by the use of a magnetic sensing system. Time required, mean values for peak distance, and cumulative total motion distance were analyzed separately for the peg-placement and peg-removal phases. Data for dominant and nondominant hands were compared by the use of paired t tests (P < .05). RESULTS: Total time to perform the 9-Hole Peg Test was shorter for the dominant hands (mean, 18.65 seconds) than the nondominant hands (mean, 20.11 seconds). During the peg-placement phase, lower values for peak distance, cumulative total motion distance, and time required were recorded for dominant hands, suggesting more efficient movement. By contrast, during peg-removal phase, no statistically significant differences between dominant- and nondominant-hand values were apparent. CONCLUSIONS: Although healthy subjects perform the 9-Hole Peg Test more efficiently using their dominant hands, the difference in measured dexterity was observed only during the peg-placement phase. This discrepancy between the peg-placement and peg-removal efficiency suggests the need for phase discrimination in future studies. PMID- 21257133 TI - Results from the 2009 Pediatric Rehabilitation Practice survey of the AAPM&R Pediatric Rehabilitation/Developmental Disabilities Council. AB - OBJECTIVE: To quantitatively describe the practices of pediatric physiatrists who are members of the Pediatric Rehabilitation/Developmental Disabilities Council of the American Academy of Physical Medicine and Rehabilitation (AAPM&R). DESIGN: Cross-sectional survey using the SurveyMonkey instrument. SETTING: The Pediatric Rehabilitation/Developmental Disabilities Council. PARTICIPANTS: Eighty-six members of the Pediatric Rehabilitation/Developmental Disabilities Council ListServ of the Pediatric Rehabilitation/Developmental Disabilities Council of the AAPM&R and pediatric physiatrists known to the author. METHODS: The link to the survey was embedded in an e-mail message that was distributed by the author to the members of the ListServ on August 14, 2009. Four reminder e-mail messages were sent. The survey was closed on October 2, 2009. All data were extracted into STATA for analysis. Basic practice data were tabulated by raw numbers and percentages. Summary statistics were calculated for salary data, and simple t tests and Mann-Whitney tests were used to determine if differences were statistically significant (alpha < 0.05) between subgroups. MAIN OUTCOME MEASUREMENTS: Location and style of practice, training, experience, and clinical productivity. Comparison of salary data was by experience, training, position, and gender. RESULTS: Women made up 71% of surveyed pediatric physiatrists. Forty percent of respondents practiced in the midwestern United States, and more than 50% practiced in academic settings. Twenty-eight percent of female respondents reported the title of medical director compared with 40% of the male respondents. Whereas 20% of responding practitioners had been in practice for more than 20 years, only 8% were full professors. Nearly 40% of respondents reported doing research, but only 8% had received federal funding for research. The average salary was $191,400. Salary differences were noted by title, experience, and academic rank. Female respondents earned, on average, 82% of what male respondents earned. CONCLUSIONS: This survey highlights important issues, including regional variations, a potential lack of academic competitiveness, limited engagement in externally funded research, and salary inequities. PMID- 21257134 TI - Pediatric rehabilitation medicine in the USA. PMID- 21257135 TI - Neural interfaces for control of upper limb prostheses: the state of the art and future possibilities. AB - Current treatment of upper limb amputation restores some degree of functional ability, but this ability falls far below the standard set by the natural arm. Although acceptance rates can be high when patients are highly motivated and receive proper training and care, current prostheses often fail to meet the daily needs of amputees and frequently are abandoned. Recent advancements in science and technology have led to promising methods of accessing neural information for communication or control. Researchers have explored invasive and noninvasive methods of connecting with muscles, nerves, or the brain to provide increased functionality for patients experiencing disease or injury, including amputation. These techniques offer hope of more natural and intuitive prosthesis control, and therefore increased quality of life for amputees. In this review, we discuss the current state of the art of neural interfaces, particularly those that may find application within the prosthetics field. PMID- 21257136 TI - Setting limits: the threat of violence in the health care setting. PMID- 21257137 TI - Should performance of interventional spine procedures be part of the core training for PM&R residency training programs? PMID- 21257138 TI - Inpatient rehabilitation in persons with multiple myeloma-associated fractures: an analysis of 8 consecutive inpatient admissions. PMID- 21257139 TI - Relief of radiation-induced xerostomia with acupuncture treatment: a case presentation. PMID- 21257140 TI - The relationship between divided attention and implicit memory: a meta-analysis. AB - This article reports a meta-analysis comparing the size of repetition priming in full and divided-attention (DA) conditions. The main analysis included 38 effect sizes (ES) extracted from 21 empirical studies, for a total of 2074 (full attention) and 2148 (divided-attention) participants. The mean weighted ES was 0.357 (95% CI=0.278-0.435), indicating that divided attention produced a small, but significant, negative effect on implicit memory. Overall, the distinction between identification and production priming provided the best fit to empirical data (with the effect of DA being greater for production tests), whereas there was no significant difference between perceptual and conceptual priming. A series of focused contrasts suggested that word-stem completion might be influenced by lexical-conceptual processes, and that perceptual identification might involve a productive component. Implications for current theories of implicit memory are discussed. PMID- 21257141 TI - Theory of non-equilibrium force measurements involving deformable drops and bubbles. AB - Over the past decade, direct force measurements using the Atomic Force Microscope (AFM) have been extended to study non-equilibrium interactions. Perhaps the more scientifically interesting and technically challenging of such studies involved deformable drops and bubbles in relative motion. The scientific interest stems from the rich complexity that arises from the combination of separation dependent surface forces such as Van der Waals, electrical double layer and steric interactions with velocity dependent forces from hydrodynamic interactions. Moreover the effects of these forces also depend on the deformations of the surfaces of the drops and bubbles that alter local conditions on the nanometer scale, with deformations that can extend over micrometers. Because of incompressibility, effects of such deformations are strongly influenced by small changes of the sizes of the drops and bubbles that may be in the millimeter range. Our focus is on interactions between emulsion drops and bubbles at around 100 MUm size range. At the typical velocities in dynamic force measurements with the AFM which span the range of Brownian velocities of such emulsions, the ratio of hydrodynamic force to surface tension force, as characterized by the capillary number, is ~10(-6) or smaller, which poses challenges to modeling using direct numerical simulations. However, the qualitative and quantitative features of the dynamic forces between interacting drops and bubbles are sensitive to the detailed space and time-dependent deformations. It is this dynamic coupling between forces and deformations that requires a detailed quantitative theoretical framework to help interpret experimental measurements. Theories that do not treat forces and deformations in a consistent way simply will not have much predictive power. The technical challenges of undertaking force measurements are substantial. These range from generating drop and bubble of the appropriate size range to controlling the physicochemical environment to finding the optimal and quantifiable way to place and secure the drops and bubbles in the AFM to make reproducible measurements. It is perhaps no surprise that it is only recently that direct measurements of non-equilibrium forces between two drops or two bubbles colliding in a controlled manner have been possible. This review covers the development of a consistent theory to describe non-equilibrium force measurements involving deformable drops and bubbles. Predictions of this model are also tested on dynamic film drainage experiments involving deformable drops and bubbles that use very different techniques to the AFM to demonstrate that it is capable of providing accurate quantitative predictions of both dynamic forces and dynamic deformations. In the low capillary number regime of interest, we observe that the dynamic behavior of all experimental results reviewed here are consistent with the tangentially immobile hydrodynamic boundary condition at liquid-liquid or liquid-gas interfaces. The most likely explanation for this observation is the presence of trace amounts of surface-active species that are responsible for arresting interfacial flow. PMID- 21257142 TI - Fetal responses to lipopolysaccharide-induced chorioamnionitis alter immune and airway responses in 7-week-old sheep. AB - OBJECTIVE: We hypothesized that fetal innate immune responses to lipopolysaccharide-induced chorioamnionitis would alter postnatal systemic immune and airway responsiveness. STUDY DESIGN: Ewes received intraamniotic injections with saline or lipopolysaccharide at 90, 100, and 110 days of gestation. Immune status and airway responsiveness were evaluated at term and at 7 weeks of age. RESULTS: At term, lymphocytes, monocytes, and neutrophils were significantly increased (respectively, 24-fold, 127-fold, and 31,000-fold) in lungs and blood monocytes became Toll-like receptor 2 responsive after lipopolysaccharide exposures. Furthermore, CD4 and CD4/CD25 lymphocytes were increased in thymus and lymph nodes. At 7 weeks, airway reactivity decreased and concentrations of CD8 cytotoxic T lymphocytes changed in the lungs and thymus relative to controls. CONCLUSION: Early gestational lipopolysaccharide exposure increased leukocyte responsiveness at term. Decreased airway reactivity and changes in lymphocytes at 7 weeks postnatal demonstrate persistent effects of fetal exposure to LPS. PMID- 21257143 TI - Effects of cocaine use during pregnancy on low birthweight and preterm birth: systematic review and metaanalyses. AB - OBJECTIVE: To review systematically maternal antenatal cocaine exposure and adverse perinatal outcomes. STUDY DESIGN: Medline, Embase, CINAHL and secondary references in relevant studies were searched. English language studies of antenatal cocaine exposure and pregnancy outcomes published from 1966 to July 2009 were included. Metaanalyses were performed using the random effects model. RESULTS: Thirty-one studies were included. Cocaine use during pregnancy was associated with significantly higher odds of preterm birth (odds ratio [OR], 3.38; 95% confidence interval [CI], 2.72-4.21), low birthweight (OR, 3.66; 95% CI, 2.90-4.63), and small for gestational age infants (OR, 3.23; 95% CI, 2.43 4.30), as well as shorter gestational age at delivery (-1.47 week; 95% CI, -1.97 to -0.98 week) and reduced birthweight (-492 g; 95% CI, -562 to -421 g). CONCLUSION: Prenatal cocaine exposure is significantly associated with preterm birth, low birthweight, and small for gestational age infants. PMID- 21257144 TI - Multilayered Gore-Tex patch for temporary coverage of deep noninfectious corneal defects: surgical procedure and clinical experience. AB - PURPOSE: To evaluate the multilayer Gore-Tex patch as temporary coverage of deep, noninfectious corneal defects. DESIGN: Retrospective, interventional case series. METHODS: SETTING: University Medical Center Schleswig-Holstein, Kiel, Germany. PATIENT POPULATION: Thirty-nine eyes of 38 patients with noninfectious, deep corneal defects. Underlying disorders included neurotrophic or immunologic ulcers in 37 eyes (94.9%) and traumatic defects in 2 eyes (5.1%). Intervention procedures: Corneal defects were covered with multiple Gore-Tex layers, of which the uppermost was sutured to the cornea. The Gore-Tex patch was kept in place until an appropriate corneal transplant was obtained and effective systemic immunosuppression was initiated. MAIN OUTCOME MEASURES: Long-term preservation of the eye, frequency of resuturing of the Gore-Tex patch, and best-corrected visual acuity. RESULTS: In 38 cases, the eye could be preserved. In 10 eyes, additional sutures were required. Before surgery, the mean best-corrected visual acuity (logMAR) was 1.14 +/- 0.45 (20/250), and that at final follow-up was 1.13 +/- 0.41 (20/250). The Gore-Tex patch remained in place 4 days to 32 months (mean, 6.4 +/- 8.3 months) until corneal transplantation (27 eyes) or until an alternative way of defect coverage could be performed. Three eyes did not require further coverage after explantation of the Gore-Tex patch. In 6 eyes, either the Gore-Tex patch was kept in place or the patients died. CONCLUSIONS: Temporary coverage of deep corneal defects with multilayer Gore-Tex patches allows time until an appropriate corneal transplant is obtained. The technique is particularly useful in patients with underlying autoimmune disorders, because an effective systemic immunosuppression can be initiated before corneal transplantation. PMID- 21257145 TI - Intralesional triamcinolone acetonide injection versus incision and curettage for primary chalazia: a prospective, randomized study. AB - PURPOSE: To compare treatment outcomes of intralesional triamcinolone acetonide (TA) injection with incision and curettage (I&C) for primary chalazia. DESIGN: Prospective, randomized clinical trial. METHODS: SETTING: Institutional. STUDY POPULATION: Ninety-four patients with primary chalazia after failed conservative treatment were randomized to either intralesional TA injection (4 mg) or I&C performed under local anesthesia. All patients underwent comprehensive eye examinations that included digital photography of the lesion. Complete resolution was defined as lesion regression of 95% to 100%. Treatment was considered a failure if no resolution was achieved after the first attempted I&C or TA injection. MAIN OUTCOME MEASURES: Lesion resolution measured as 95% to 100% regression. RESULTS: Ninety-four patients participated in the study: 42 underwent I&C and 52 underwent TA injection as the first treatment. Complete resolution was achieved in 33 (79%) of 42 patients in the I&C group and in 42 (81%) of 52 patients in the TA group (P=.8, chi-square analysis). The average time to resolution in the TA group was 5 days, with most patients (48/52; 92%) having received a single injection and 4 (8%) of 52 patients having received 2 injections. TA precipitates were detected in 6 (11.5%) of 52 patients and resolved spontaneously. There were no complications, such as eyelid depigmentation, increased intraocular pressure, or any loss of vision, in either group. CONCLUSIONS: Intralesional TA injection is as effective as I&C in primary chalazia. Injection may be considered as an alternative first-line treatment in cases where diagnosis is straightforward and no biopsy is required. PMID- 21257146 TI - A randomized trial of brimonidine versus timolol in preserving visual function: results from the Low-Pressure Glaucoma Treatment Study. AB - PURPOSE: To compare the alpha2-adrenergic agonist brimonidine tartrate 0.2% to the beta-adrenergic antagonist timolol maleate 0.5% in preserving visual function in low-pressure glaucoma. DESIGN: Randomized, double-masked, multicenter clinical trial. METHODS: Exclusion criteria included untreated intraocular pressure (IOP) >21 mm Hg, visual field mean deviation worse than -16 decibels, or contraindications to study medications. Both eyes received twice-daily monotherapy randomized in blocks of 7 (4 brimonidine to 3 timolol). Standard automated perimetry and tonometry were performed at 4-month intervals. Main outcome measure was field progression in either eye, defined as the same 3 or more points with a negative slope >=-1 dB/year at P<5%, on 3 consecutive tests, assessed by pointwise linear regression. Secondary outcome measures were progression based on glaucoma change probability maps (GCPM) of pattern deviation and the 3-omitting method for pointwise linear regression. RESULTS: Ninety-nine patients were randomized to brimonidine and 79 to timolol. Mean (+/- SE) months of follow-up for all patients was 30.0 +/- 2. Statistically fewer brimonidine treated patients (9, 9.1%) had visual field progression by pointwise linear regression than timolol-treated patients (31, 39.2%, log-rank 12.4, P=.001). Mean treated IOP was similar for brimonidine- and timolol-treated patients at all time points. More brimonidine-treated (28, 28.3%) than timolol-treated (9, 11.4%) patients discontinued study participation because of drug-related adverse events (P=.008). Similar differences in progression were observed when analyzed by GCPM and the 3-omitting method. CONCLUSION: Low-pressure glaucoma patients treated with brimonidine 0.2% who do not develop ocular allergy are less likely to have field progression than patients treated with timolol 0.5%. PMID- 21257147 TI - Determinants of image quality of Heidelberg Retina Tomography II and its association with optic disc parameters in a population-based setting. AB - PURPOSE: To assess the determinants of image quality of Heidelberg Retina Tomography II (HRT II) and its association with optic disc parameters in a population-based setting. DESIGN: Population-based, cross-sectional study involving 3280 (78.7% response) Asian Malays aged 40 to 80 years. METHODS: Three thousand fifty-six participants completed the HRT II test. Image quality was assessed using the mean pixel height standard deviation generated by the HRT II, with lower mean pixel height standard deviation indicating higher quality. Participants underwent an interviewer-administered questionnaire and a standardized ophthalmic examination, including visual acuity, applanation tonometry, gonioscopy, refraction, automated perimetry, and lens and fundus photography. RESULTS: The mean (standard deviation) and median of mean pixel height standard deviation in the study population were 34 (34) and 23 MUm respectively. In multivariate regression models, older age and the presence of visual impairment, blindness, high myopia, and cataract were significantly associated with greater mean pixel height standard deviation (P<.05 for all). People with a higher mean pixel height standard deviation were more likely to have smaller rim area and greater cup depth. CONCLUSION: People who are older or have high myopia, visual impairment, blindness, or cataract are more likely to have poor HRT II image quality. Poorer image quality is in turn associated with smaller optic rim area and greater cup depth. These data provide useful information when the HRT instrument is used for diagnosing glaucoma in the general population. PMID- 21257148 TI - Effects of green diode laser in the treatment of pediatric Coats disease. AB - PURPOSE: To review the effect of green diode laser ablation therapy on retinal structure and functional outcome in patients with advanced Coats disease. DESIGN: Retrospective, interventional case series. METHODS: Fourteen eyes of 13 patients with Coats disease were included in this study. Medical records, Retcam photographs (Clarity Medical Systems, Pleasanton, CA), and fluorescein angiograms were reviewed. All patients initially were treated with green diode laser (532 nm) ablation therapy to areas of the retinal telangiectasis associated with exudation. Main outcome measures included visual acuity, treatment outcome defined as complete resolution of telangiectatic lesions or exudative detachment, and macular status at the end of follow-up. RESULTS: Before treatment, 1 eye was at stage 2 (telangiectasis and exudation), 12 eyes were at stage 3 (exudative retinal detachment), and 1 eye was at stage 4 (total retinal detachment with glaucoma). Five eyes had highly detached retina of more than 4 mm. Median age at diagnosis was 51 months (range, 0.5 to 153 months). Median follow-up was 39.5 months (range, 15 to 70 months). Median number of green diode laser photocoagulation treatments was 2 (range, 1 to 5). After laser photocoagulation, 13 (93%) of 14 eyes had no active exudation. Functionally, 4 (29%) of 14 eyes had 20/50 or better visual acuity, 3 (21%) of 14 eyes had 20/60 to 20/200 visual acuity, 5 (36%) of 14 eyes had 20/400 to light perception visual acuity, and 2 (14%) of 14 eyes had no light perception visual acuity. No eye was phthisical or enucleated. CONCLUSIONS: Green diode laser therapy can be an effective treatment for advanced Coats disease, even in the presence of a moderate to severely elevated retinal detachment. PMID- 21257149 TI - Relationship between sleep-disordered breathing and iris and/or angle neovascularization in proliferative diabetic retinopathy cases. AB - PURPOSE: To investigate whether sleep-disordered breathing is a risk factor for iris and/or angle neovascularization in patients with proliferative diabetic retinopathy (PDR). DESIGN: Cross-sectional comparative case series. SUBJECTS AND METHODS: One hundred fifty-one consecutive patients with PDR who underwent surgery in our hospital were divided based on the presence of iris and/or angle neovascularization (NV group, 37 patients) or absence of NV (non-NV group, 114 patients). Pulse oximetry was conducted during the night and the mean SpO(2), 4% oxygen desaturation index (4% ODI times/hour), the lowest SpO(2)% during sleep (lowest SpO(2)), and the cumulative percentage of time at SpO(2) <90% in analysis times (CT90%) were calculated. When the 4% ODI exceeded 5 times/hour, sleep disordered breathing was diagnosed. The results were compared between the 2 groups. Preoperative systemic parameters also were analyzed by logistic regression to clarify risk factors for the NV group. RESULTS: A mean total of 50% (62% of the NV group and 46% of the non-NV group) was diagnosed with sleep disordered breathing. The mean SpO(2) and lowest SpO(2) did not differ significantly between the 2 groups; the 4% ODI (12.3 vs 6.6) and CT90% (3.8 vs 1.7) were significantly higher in the NV group (P=.02, for both comparisons). Logistic regression analysis identified insulin therapy (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.26~7.20; P=.01); and 4% ODI (OR, 1.09; CI, 1.01~1.16; P=.02) as risk factors for the NV group. CONCLUSIONS: In patients with PDR, nocturnal intermittent hypoxia/reoxygenation resulting from sleep-disordered breathing may be a risk factor for iris and/or angle neovascularization. PMID- 21257150 TI - Optical coherence tomography enhanced depth imaging of choroidal tumors. AB - PURPOSE: To describe the spectral-domain optical coherence tomography (SD-OCT) features of choroidal tumors imaged using enhanced depth imaging (EDI) technique. DESIGN: Prospective observational case series. METHODS: One tumor each from 23 eyes of 23 patients was included. All the patients underwent clinical fundus photography, ultrasonography, and EDI SD-OCT. Qualitative characteristics (tumor outline, reflectivity and/or shadowing of choroidal layers, and detection of inner sclera) and quantitative characteristics (measurement of maximum tumor thickness and the largest tumor diameter) were assessed. RESULTS: Patients (male=12) were categorized as: amelanotic choroidal nevus (4), melanotic choroidal nevus (9), choroidal melanoma (3), circumscribed choroidal hemangioma (3), and choroidal metastasis (4). In all cases, EDI SD-OCT was able to identify the tumor distinctly from the surrounding normal choroid. Qualitative analysis revealed: amelanotic nevi, homogenous and medium reflective band with visible choroidal vessels; melanotic nevi and choroidal melanomas, high reflective band in the anterior choroid with shadowing, and nonvisualization of choroidal vessels and inner sclera; choroidal hemangiomas, medium/low reflective band without shadowing; and choroidal metastasis, low reflective band in the deep choroid with enlargement of the suprachoroidal space. Maximum tumor diameter and thickness was measurable by EDI SD-OCT only in 10 cases that were <9.0 mm in diameter and <1.0 mm in thickness (undetectable by ultrasonography). CONCLUSIONS: It is possible to obtain cross-sectional views of a variety of choroidal tumors using EDI SD-OCT. Small choroidal tumors nondetectable by ultrasonography can be objectively measured by this technique. PMID- 21257151 TI - Pre-seasonal treatment with topical olopatadine suppresses the clinical symptoms of seasonal allergic conjunctivitis. AB - PURPOSE: To evaluate the effectiveness of pre-seasonal treatment with topical olopatadine on the reduction of clinical symptoms of seasonal allergic conjunctivitis (SAC). DESIGN: Prospective interventional case series. METHODS: Eleven patients with SAC received topical olopatadine in one eye at least two weeks before the onset of allergy symptoms, and the other eye served as the control. After the onset of allergic conjunctivitis, both eyes were treated with topical olopatadine. Visual analogue scale (VAS), which evaluated the subjective symptoms of ocular allergy, and the tear levels of histamine and substance P were measured up to six weeks. RESULTS: At the onset of allergy symptoms, the VAS score in the pretreatment eyes was statistically significantly lower than that in the control eyes. The VAS score in the control eyes decreased with time but did not decrease to the level seen in the pretreatment eyes until four weeks later. The tear level of substance P at the onset of allergy symptoms was significantly suppressed in the pretreatment eyes, while the level of histamine was not suppressed. Alteration of the VAS scores in the pretreatment eyes significantly correlated with the level of substance P, but not of histamine. CONCLUSIONS: To suppress clinical symptoms in patients with SAC, pre-seasonal treatment with topical olopatadine is effective. The effectiveness of treatment correlates with the tear level of substance P. PMID- 21257152 TI - Relation of intraocular concentrations of inflammatory factors and improvement of macular edema after vitrectomy in branch retinal vein occlusion. AB - PURPOSE: To investigate the association of intraocular concentrations of inflammatory factors and improvement of macular edema after vitrectomy for patients with macular edema in branch retinal vein occlusion (BRVO). DESIGN: Retrospective case-control study. METHODS: Seventeen patients with BRVO who underwent vitreous surgery for macular edema and 15 control patients were enrolled from Hachioji Medical Center of Tokyo Medical University. The concentrations of eight inflammatory factors were measured in vitreous and aqueous fluids obtained at the time of vitrectomy using a flow cytometer. Macular thickness was measured by optical coherence tomography before and one, three, and six months after surgery. Correlations between the concentrations of inflammatory factors and macular thickness were statistically analyzed. RESULTS: Higher aqueous and vitreous concentrations of vascular endothelial growth factor (VEGF) and interleukin (IL)-8 were significantly correlated with a greater difference in macular thickness between before and six months after surgery (vitreous VEGF, P=.047; aqueous VEGF, P=.032; vitreous IL-8, P=.016; and aqueous IL-8, P=.032). Higher intraocular concentrations of monokine induced by interferon gamma (Mig) were significantly correlated with a smaller degree of macular thickness six months after surgery (vitreous Mig, P=.038; aqueous Mig, P=.009). CONCLUSION: High preoperative VEGF, IL-8, and Mig concentrations were associated with improvement of macular edema six months after vitreous surgery in patients with macular edema attributable to BRVO. PMID- 21257153 TI - Fundus autofluorescence of elongated photoreceptor outer segments in central serous chorioretinopathy. AB - PURPOSE: To determine the origin of fundus autofluorescence (AF) patterns in central serous chorioretinopathy (CSC). DESIGN: Retrospective, observational case series. METHODS: We retrospectively studied 30 consecutive eyes of 30 patients with primary CSC using AF and spectral-domain optical coherence tomography (SD OCT). We measured the AF using the Heidelberg Retina Angiograph with a 488-nm excitation light and a 500-nm cutoff barrier filter and compared the AF patterns with ophthalmoscopy and SD-OCT. RESULTS: We observed a patchy increased AF in the macular area in 22 eyes (73%), in which the length of the photoreceptor outer segment at the central fovea tended to be longer than the other eyes (P=.06). The punctate increased AF corresponded to the ophthalmoscopic precipitates in 17 eyes with precipitates. AF significantly (P=.017) decreased in eyes with a prominent serous retinal detachment (SRD). Eight eyes (27%) had increased AF in the inferior SRD. CONCLUSIONS: The patchy increased AF appears to originate from elongated photoreceptor outer segments in the detached retina. The autofluorescent fluorophores from the photoreceptor outer segments may be concentrated in precipitates or have settled into the inferior SRD. PMID- 21257154 TI - Quality of image of grating target placed in model of human eye with corneal aberrations as observed through multifocal intraocular lenses. AB - PURPOSE: To evaluate the quality of the image of a grating target placed in a model eye viewed through multifocal intraocular lenses (IOLs). DESIGN: Laboratory investigation. METHODS: Refractive (NXG1 or PY60MV) or diffractive (ZM900 or SA60D3) multifocal IOLs were placed in a fluid-filled model eye with human corneal aberrations. A United States Air Force resolution target was placed on the posterior surface of the model eye. A flat contact lens or a wide-field contact lens was placed on the cornea. The contrasts of the gratings were evaluated under endoillumination and compared to those obtained through a monofocal IOL. RESULTS: The grating images were clear when viewed through the flat contact lens and through the central far-vision zone of the NXG1 and PY60MV, although those through the near-vision zone were blurred and doubled. The images observed through the central area of the ZM900 with flat contact lens were slightly defocused but the images in the periphery were very blurred. The contrast decreased significantly in low frequencies (P<.001). The images observed through the central diffractive zone of the SA60D3 were slightly blurred, although the images in the periphery were clearer than that of the ZM900. The images were less blurred in all of the refractive and diffractive IOLs with the wide-field contact lens. CONCLUSION: Refractive and diffractive multifocal IOLs blur the grating target but less with the wide-angle viewing system. The peripheral multifocal optical zone may be more influential on the quality of the images with contact lens system. PMID- 21257155 TI - Distance stereotest using a 3-dimensional monitor for adult subjects. AB - PURPOSE: To evaluate the validity and test-retest reliability of a contour-based 3-dimensional (3-D) monitor distance stereotest (distance 3-D stereotest) and to measure the maximum horizontal disparity that can be fused with disparity vergence for determining the largest measurable disparity of true stereopsis. DESIGN: Observational case series. METHODS: Sixty-four normal adult subjects (age range, 23 to 39 years) were recruited. Contour-based circles (crossed disparity, 5000 to 20 seconds of arc; Microsoft Visual Studio C(++) 6.0; Microsoft, Inc, Seattle, Washington, USA) were generated on a 3-D monitor (46-inch stereoscopic display) using polarization glasses and were presented to subjects with normal binocularity at 3 m. While the position of the stimulus changed among 4 possible locations, the subjects were instructed to press the corresponding position of the stimulus on a keypad. The results with the new distance 3-D stereotest were compared with those from the distance Randot stereotest. RESULTS: The results of the distance 3-D stereotest and the distance Randot stereotests were identical in 64% and within 1 disparity level in 97% of normal adults. Scores obtained with the 2 tests showed a statistically significant correlation (r = 0.324, P = .009). The half-width of the 95% limit of agreement was 0.47 log seconds of arc (1.55 octaves) using the distance 3-D stereotest--similar to or better than that obtained with conventional distance stereotests. The maximum binocular disparity that can be fused with vergence was 1828 +/- 794 seconds of arc (range, 4000 to 500). CONCLUSIONS: The distance 3-D stereotest showed good concordance with the distance Randot stereotest and relatively good test-retest reliability, supporting the validity of the distance 3-D stereotest. The normative data set obtained from the present study can serve as a useful reference for quantitative assessment of a wide range of binocular sensory abnormalities. PMID- 21257156 TI - Outcomes of a protocol-based management for zone 1 retinopathy of prematurity: the Indian Twin Cities ROP Screening Program report number 2. AB - PURPOSE: To report the outcomes of zone 1 aggressive posterior retinopathy of prematurity (ROP) treated with aggressive laser photocoagulation by a protocol based approach over a 10-year period. DESIGN: Prospective, interventional case series. METHODS: SETTING: Tertiary eye institute and neonatal intensive care units in the twin cities of Hyderabad and Secunderabad in South India. STUDY POPULATION: Babies screened under the Indian Twin Cities Retinopathy of Prematurity Screening (ITCROPS) program between January 1, 1997 and March 31, 2007. INTERVENTION: Multiple sessions of laser photocoagulation at any sign of plus disease with abnormal shunt vessels with or without neovascularization in zone 1. OUTCOME MEASURE: Based on the anatomic status of the retina at the final follow-up, the outcome was classified into good (completely regressed with no vitreoretinal changes), fair (regression with vitreoretinal distortion), or poor (progression into partial or total retinal detachment involving macula). Descriptive statistics (mean and range) were used for gestational age at birth, birth weight, and post-conceptional age at first presentation and at the first intervention. Trends in incidence of zone 1 ROP over 1 decade were analyzed. Outcomes were expressed in terms of proportions and 95% confidence interval (CI). RESULTS: Of the 3654 babies screened, 227 eyes of 115 babies were detected to have zone 1 aggressive disease, defined as zone 1 retinal vessels having abnormal closed-loop shunts, dilation and tortuosity, flat new vessels, or rapid progression. Laser was performed in 169 eyes. Disease regressed with good outcome in 142 eyes (84%) (95% CI, 77.6-89.2) and progressed to poor outcome in 13 eyes (7.69%) (95% CI, 4.1-12.8), while fair outcome was seen in 6 eyes (3.55%) (95% CI, 1.3-7.5). Thus 148 babies (87.5%) (95% CI, 81.6-92.14) had a favorable outcome. The outcomes in 8 treated eyes (4.7%) lost to follow-up were unknown. CONCLUSIONS: Zone 1 aggressive ROP has a good outcome if the screening is done early; intervention is prompt and adequate, with frequent follow-up until complete regression is achieved. PMID- 21257157 TI - Folding of the prefrontal cortex in schizophrenia: regional differences in gyrification. AB - BACKGROUND: Anatomy of prefrontal cortex in schizophrenia has been studied previously by quantifying the degree of gyrification. Conflicting results exist, with some studies showing hypergyria and others showing hypogyria. It is likely that regional variations in cortical folding exist within the prefrontal cortex that could be explored by studying the anatomical subdivisions formed by the sulci and gyri. With surface reconstructions from magnetic resonance imaging, we studied the gyrification within anatomically meaningful subdivisions of prefrontal cortex in schizophrenia. METHODS: Prefrontal cortex was studied with an automated method to obtain Local Gyrification Index, reflecting the degree of cortical folding in 57 patients with schizophrenia and 42 control subjects. Regional differences within prefrontal cortex were compared between the two groups with a sulcogyral atlas. Effects of hemisphere and age were subsequently assessed. RESULTS: Patients with schizophrenia had significant hypogyria in most prefrontal regions except the frontomarginal region, which showed hypergyria. The normal left > right pattern of prefrontal gyrification was reversed in schizophrenia. Patients with schizophrenia also showed significant age-related reduction in gyrification at the hypogyric regions. CONCLUSIONS: The differences between reported findings regarding prefrontal gyrification might reflect regional variation in the nature of the abnormal process of gyrification in schizophrenia. Prefrontal gyrification is significantly influenced by age in schizophrenia, in addition to the influence of neurodevelopmental factors. PMID- 21257158 TI - Increased amygdala response to positive social feedback in young people with major depressive disorder. AB - BACKGROUND: Studies of depressed patients have demonstrated increased amygdala activation to negative affective stimuli. In this study, we used a paradigm that employed personally relevant social stimuli, which are known to strongly activate the amygdala, to test whether the amygdala demonstrated aberrant activity in depressed participants as they responded to stimuli with positive valence. METHODS: Nineteen patients with major depressive disorder, aged 15 to 24 years, were matched with 20 healthy control participants. They completed a novel functional magnetic resonance imaging task in which they received social feedback from people who they believed had evaluated them. Voxelwise statistical parametric maps of brain response to positive social feedback and to a control feedback condition were compared to test the hypothesis that differences in neural response between depressed and control participants would arise in the amygdala. RESULTS: Depressed participants showed increased neural response to the positive- versus control-feedback condition in the amygdala (p < .05, corrected). An exploratory analysis showed that depressed participants responded to faces from both feedback conditions with increased activity in regions subserving social appraisal (ventrolateral prefrontal cortex and inferior parietal cortex) and affective processing (pregenual anterior cingulate cortex and anterior insular cortex; p < .001, uncorrected). CONCLUSIONS: Depressed patients responded to positive social feedback with increased amygdala activation, demonstrating that amygdala hyperresponsivity in depression is not restricted to negatively valenced stimuli. The heightened sensitivity of depressed participants to social evaluation may help explain symptoms of depression such as social withdrawal. PMID- 21257159 TI - Removing the A2 criteria will not rescue posttraumatic stress disorder. PMID- 21257160 TI - Synthesis of a protected trihydroxyindolizidine 3-carboxylate via a hetero-Diels Alder addition of ethyl 2-nitrosoacrylate to a D-ribose-derived exo-glycal. AB - A protected trihydroxyindolizidine 3-carboxylate was prepared by a 6-endo epoxide cleavage, which in turn was intermediately formed from the hetero-Diels-Alder adduct of ethyl 2-nitrosoacrylate to a D-ribose-derived exo-glycal. PMID- 21257161 TI - When global structure "Explains Away" local grammar: a Bayesian account of rule induction in tone sequences. AB - While many constraints on learning must be relatively experience-independent, past experience provides a rich source of guidance for subsequent learning. Discovering structure in some domain can inform a learner's future hypotheses about that domain. If a general property accounts for particular sub-patterns, a rational learner should not stipulate separate explanations for each detail without additional evidence, as the general structure has "explained away" the original evidence. In a grammar-learning experiment using tone sequences, manipulating learners' prior exposure to a tone environment affects their sensitivity to the grammar-defining feature, in this case consecutive repeated tones. Grammar-learning performance is worse if context melodies are "smooth" -- when small intervals occur more than large ones -- as Smoothness is a general property accounting for a high rate of repetition. We present an idealized Bayesian model as a "best case" benchmark for learning repetition grammars. When context melodies are Smooth, the model places greater weight on the small interval constraint, and does not learn the repetition rule as well as when context melodies are not Smooth, paralleling the human learners. These findings support an account of abstract grammar-induction in which learners rationally assess the statistical evidence for underlying structure based on a generative model of the environment. PMID- 21257162 TI - Distress tolerance moderates the relationship between negative affect intensity with borderline personality disorder levels. AB - A number of studies have suggested that negative emotionality and negative affect intensity play key roles in the development and maintenance of borderline personality disorder (BPD). However, more recent research indicates that one's response to affective discomfort may be an even more important variable in the pathogenesis of BPD than either negative emotionality or negative affect intensity per se. As such, the current study aimed to empirically test the moderating role of 2 well-validated laboratory measures of the ability to tolerate psychological distress (distress tolerance) in the relationship of negative emotionality and negative affect intensity with BPD levels. Results provide laboratory-based evidence for a moderating effect of distress tolerance on the relationship of negative emotionality and negative affect intensity with levels of BPD. Specifically, the 2 former variables were related to levels of BPD among those with low distress tolerance. The current results add support to existing developmental frameworks of BPD and suggest the importance of modifying one's response to affective distress along with levels of negative emotionality in treatment settings. PMID- 21257163 TI - Awareness and knowledge of methylmercury in fish in the United States. AB - In the 1970s several states in the Great Lakes region became concerned about mercury contamination in lakes and rivers and were the first to issue local fish consumption advisories. In 2001, the Food and Drug Administration (FDA) advised pregnant women, nursing mothers, young children, and women who may become pregnant not to consume shark, swordfish, king mackerel, and tilefish and recommended that these women not exceed 12 ounces of other fish per week. In 2004, FDA reissued this advice jointly with the U.S. Environmental Protection Agency (EPA) and modified it slightly to provide information about consumption of canned tuna and more details about consumption of recreationally caught fish. Though several studies have examined consumers' awareness of the joint FDA and EPA advisory as well as different state advisories, few used representative data. We examined the changes in awareness and knowledge of mercury as a problem in fish using the pooled nationally representative 2001 and 2006 Food Safety Surveys (FSS) with sample sizes of 4482 in 2001 and 2275 in 2006. Our results indicated an increase in consumers' awareness of mercury as a problem in fish (69% in 2001 to 80% in 2006, p<.001). In our regression models, we found that in both years, parents having children less than 5 years of age were more aware of mercury in fish and knowledgeable about the information contained in the national advisories about mercury in fish (p<.01) than other adults. In both 2001 and 2006, women of childbearing age (aged 18-45) were less aware and knowledgeable about this information than other women. However, women of all age groups had larger gains in awareness and knowledge than their male counterparts during this time. Participants' race, education, income, region, fish preparation experiences, having a foodborne illness in the past year, and risk perceptions about the safety of food were significant predictors of their awareness and knowledge. PMID- 21257164 TI - Leptin role in the rat prostate ventral lobe. AB - The involvement of leptin in prostate diseases is related to an increase in the gene expression of both a and b isoform leptin receptors, leptin itself, androgen receptor, and aromatase, as well as by a reduction in both estrogen isoform receptors. PMID- 21257165 TI - Long-term outcome of palliative therapy for malignant colorectal obstruction in patients with unresectable metastatic colorectal cancers: endoscopic stenting versus surgery. AB - BACKGROUND: Self-expandable metal stents (SEMSs) provide a promising alternative for initial palliation of malignant bowel obstruction. However, data on the long term outcomes of SEMSs are limited. OBJECTIVE: The aim of this study was to compare the long-term outcomes of endoscopic stenting with those of surgery for palliation in patients with incurable obstructive colorectal cancer. DESIGNS AND SETTING: A retrospective study. PATIENTS: From January 2000 to December 2008, patients with incurable obstructive colorectal cancer who were treated with SEMSs (n = 71) or palliative surgery (n = 73) were reviewed. INTERVENTIONS: SEMS placement by using through-the-endoscope methods or surgery. MAIN OUTCOME MEASUREMENTS: Success rates and complication rates. RESULTS: Early success rates in the SEMS group and those in the surgery group were not different (95.8% vs 100%, P = .12), and the SEMS group had fewer early complications than the surgery group (15.5% vs 32.9%, P = .015). Although the patency duration of the first stent in the SEMS group was shorter than that in the surgery group (P < .001), the median patency duration after a second stenting was comparable to that of the surgery group (P = .239). There were more late complications in the SEMS group than in the surgery group (P = .028), but the rates of major complications did not differ between the 2 groups (P = .074). LIMITATIONS: Retrospective and single center study. CONCLUSIONS: SEMSs were not only an effective and acceptable therapy for initial palliation of malignant colorectal obstruction, but they also showed long-term efficacy comparable to that with surgery. PMID- 21257166 TI - Argon plasma coagulation treatment of hemorrhagic radiation proctopathy: the optimal settings for application and long-term outcome. AB - BACKGROUND: No standard treatment exists for hemorrhagic radiation proctopathy (HRP). Recently it was reported that argon plasma coagulation (APC) is effective for HRP. However, previous studies documented complications such as ulcers, strictures, and perforations in as many as 20% of APC-treated patients. OBJECTIVE: The aim of this study was to determine the optimal parameters for APC by using swine rectum and to assess the safety and effectiveness of APC in HRP patients. DESIGN: Prospective case series. SETTING: University teaching hospital. PATIENTS: Sixty-five patients with HRP were prospectively enrolled between 2000 and 2010. INTERVENTIONS: APC for HRP. MAIN OUTCOME MEASUREMENTS: Optimal APC parameters, number of treatments, success rate, complications, clinical remissions. RESULTS: APC in swine rectal wall ex vivo was optimal with a 40-W current, 1.2-L/min gas flow rate, and 2-second application, which was sufficient to treat the submucosal telangiectasia but did not adversely affect the muscle layer. Sixty-five patients (46 men, 19 women; median age 72 years) with HRP occurring at a mean of 20 months after radiotherapy were studied. Proctopathy was classified as grade A (mild) in 7 patients (10.8%), grade B (moderate) in 41 (63.1%), and grade C (severe) in 17 (26.2%). The treatment success rate was 98.5% after a median of 2 (range 1-5) APC sessions. The median clinical score for rectal bleeding was significantly decreased after APC (P < .0001), and the hemoglobin level was significantly increased (P < .0001). APC was well tolerated, and no significant side effects or complications occurred. During a mean follow up of 34.6 months (range 3.6 -121.1 months), 4 patients (6.3%) had minor recurrent rectal bleeding and 60 (93.8%) remained in remission. LIMITATIONS: Nonrandomized study. CONCLUSIONS: HRP treatment with optimal APC settings yields a high success rate and long-lasting clinical remission with no significant complications. PMID- 21257167 TI - Comparison of different estimation techniques for biomass concentration in large scale yeast fermentation. AB - In this study, previously developed five different state estimation methods are examined and compared for estimation of biomass concentrations at a production scale fed-batch bioprocess. These methods are i. estimation based on kinetic model of overflow metabolism; ii. estimation based on metabolic black-box model; iii. estimation based on observer; iv. estimation based on artificial neural network; v. estimation based on differential evaluation. Biomass concentrations are estimated from available measurements and compared with experimental data obtained from large scale fermentations. The advantages and disadvantages of the presented techniques are discussed with regard to accuracy, reproducibility, number of primary measurements required and adaptation to different working conditions. Among the various techniques, the metabolic black-box method seems to have advantages although the number of measurements required is more than that for the other methods. However, the required extra measurements are based on commonly employed instruments in an industrial environment. This method is used for developing a model based control of fed-batch yeast fermentations. PMID- 21257168 TI - Prevalence and correlates of intimate partner violence among women attending HIV voluntary counseling and testing in northern Tanzania, 2005-2008. AB - OBJECTIVE: To investigate the prevalence and correlates of intimate partner violence (IPV) among women at an HIV voluntary counseling and testing (VCT) center in northern Tanzania. METHODS: In a cross-sectional study, the lifetime history of IPV experienced by women attending an HIV VCT center in Moshi, Tanzania, from June 2005 to January 2008 was assessed. Bivariate and ordered logistic regression analyses were performed to identify risk factors for IPV. RESULTS: Of 2436 enrolled women, 432 (17.7%) reported IPV during their lifetime. Older, unemployed, and less-educated women, and those with children were more likely to have experienced IPV (P<0.05). IPV exposure differed by marital status (P<0.001). Adjusting for sociodemographics, the odds ratio of IPV was 1.51 (95% confidence interval [CI] 1.10-2.07) for married women and 2.25 (95% CI 1.63-3.10) for divorced women, compared with single women. HIV prevalence did not differ by IPV exposure or severity; however, 22.4% of single women who had experienced IPV were HIV seropositive, compared with 15.1% of women with no experience of IPV (P=0.041). CONCLUSION: Given that IPV represents both a risk factor for and a consequence of HIV infection, VCT sites are an appropriate and accessible venue for IPV screening and counseling in resource-poor settings. PMID- 21257169 TI - Accuracy of visual inspection with acetic acid for cervical cancer screening. AB - OBJECTIVE: To provide an updated estimation of the accuracy of visual inspection with acetic acid (VIA) in detecting true disease. METHODS: A PubMed search provided original studies on VIA accuracy in which the gold standard for confirmatory testing was histology alone or colposcopy followed by biopsy. The numbers of true-positive, false-positive, false-negative, and true-negative results were extracted from each study. Meta-analyses were then performed with different categories of studies according to confirmatory diagnosis threshold, category of women who received confirmatory testing, and whether a medical condition that could affect VIA accuracy was present at screening. The reference category consisted of 26 studies in which VIA was performed on asymptomatic women who all underwent confirmatory testing and in which the disease threshold was cervical intraepithelial neoplasia grade 2. RESULTS: We report an 80% sensitivity (range, 79%-82%) and a 92% specificity (range, 91%-92%) for VIA. Study region, capacity of screener, or size of the study population did not modify VIA accuracy. The positive predictive value was 10% (range, 9%-10%). CONCLUSION: Screening for precancerous and cancerous cervical lesions using VIA is a simple, low-cost, and efficient alternative to cytologic testing in low-resource areas. PMID- 21257170 TI - A model for the transfer of new education methodologies to improve capacity development for low-income countries. PMID- 21257171 TI - Patients' level of satisfaction and self-reports of intention to comply following consultation with nurses and midwives with prescriptive authority: a cross sectional survey. AB - BACKGROUND: Prescriptive authority for nurses and midwives was introduced in Ireland in 2007. This allows nurses and midwives who have completed a prescribing preparation programme to independently prescribe a wide-range of medications. To date little is known of patient outcomes such as satisfaction with the consultation process and intention to comply as a consequence of the introduction of nurse and midwife prescribing. OBJECTIVES: There are four principal objectives within this study: (1) to measure the level of patients' satisfaction with education and advice received from a nurse or midwife with a prescribing remit; (2) to measure patients' satisfaction with the consultation process; (3) to measure patients' self-reports of their intention to comply with the prescriber's prescription and advice; and (4) to identify the variables that predict patients' intention to comply with the prescription and advice provided by a nurse or midwife with prescriptive authority. DESIGN: Cross-sectional descriptive survey. PARTICIPANTS AND SETTING: A total of one hundred and forty respondents completed the survey. Respondents consisted of adult patients who had received a prescription from a nurse prescriber in a general hospital, women who had received a prescription from a midwife in a maternity hospital and parents whose child received a prescription from a nurse in a children's hospital. METHODS: Instruments used to measure patient outcomes included the Consultation Satisfaction Questionnaire (CSQ) and the compliance intent subscale of the Medical Interview Satisfaction Scale (MISS). A linear multiple regression model was performed to identify the variables that predicted patients' intent to comply. RESULTS: Patients and parents surveyed were highly satisfied with the care they received from nurses and midwives with prescriptive authority. Respondents also reported that they received comprehensive education and advice. Predictors of compliance intent included patient satisfaction with the time spent with the nurse or midwife during the prescribing consultation, overall satisfaction with the consultation process and patients' health status. CONCLUSIONS: Extending a prescribing remit to nurses and midwives has been an effective addition to the provision of health care. Providing patients with time to address their questions and concerns during the consultation process impacts positively on patient outcomes and develops a philosophy of concordance between the patient and nurse/midwife prescriber. PMID- 21257172 TI - Job characteristics, organizational conditions, and distress/well-being among Italian and Dutch nurses: a cross-national comparison. AB - BACKGROUND: Among health care workers, nursing has been identified as particularly stressful. Several studies have shown cross-national differences in nurses' levels of occupational stress and burnout. OBJECTIVES: The purpose of the study was to compare job characteristics, organizational conditions, and strain reactions in Italian (N = 609) and Dutch (N = 873) nurses. It was also examined how and to what extent various job characteristics and organizational conditions explain occupational and general strain. DESIGN: The study was a cross-sectional questionnaire survey. METHOD: Based on the Job Demand-Control-Support Model and the Tripod accident causation model, respectively job characteristics and organizational conditions were assessed as independent variables. Strain was operationalized in terms of job satisfaction, burnout, and psychosomatic complaints. RESULTS: Italian nurses perceived their job characteristics, organizational conditions, and well-being as more unfavourable than their Dutch colleagues. Hierarchical regression analyses showed that high job demands, low skill discretion, and low social support from supervisor were the most consistent predictors of occupational and general strain across samples. Organizational conditions added significantly to the prediction of job satisfaction and burnout. Furthermore, lack of personnel was a stronger predictor of burnout in the Italian nurses than in the Dutch nurses. CONCLUSIONS: The study provides cross-national confirmation of the impact of job characteristics and organizational conditions on nurses' well-being. Differences in job characteristics partially explain the observed cross-national differences in distress/well-being. Furthermore, some evidence for crossnational differential effects of job characteristics and organizational conditions on well-being was found. PMID- 21257173 TI - Foot mechanics during the first six years of independent walking. AB - Recognition of the changes during gait that occur normally as a part of growth is essential to prevent mislabeling those changes from adult gait as evidence of gait pathology. Currently, in the literature, the definition of a mature age for ankle joint dynamics is controversial (i.e., between 5 and 10 years). Moreover, the mature age of the metatarsophalangeal (MP) joint, which is essential for the functioning of the foot, has not been defined in the literature. Thus, the objective of the present study explored foot mechanics (ankle and MP joints) in young children to define a mature age of foot function. Forty-two healthy children between 1 and 6 years of age and eight adults were measured during gait. The ground reaction force (GRF), the MP and ankle joint angles, moments, powers, and 3D angles between the joint moment and the joint angular velocity vectors (3D angle alpha(M.omega)) were processed and compared between four age groups (2, 3.5, 5 and adults). Based on statistical analysis, the MP joint biomechanical parameters were similar between children (older than 2 years) and adults, hinting at a quick maturation of this joint mechanics. The ankle joint parameters and the GRFs (except for the frontal plane) showed an adult-like pattern in 5-year-old children. Some ankle joint parameters, such as the joint power and the 3D angle alpha(M.omega) still evolved significantly until 3.5 years. Based on these results, it would appear that foot maturation during gait is fully achieved at 5 years. PMID- 21257174 TI - High performance liquid chromatography of slightly soluble brominated indigoids from Tyrian purple. AB - Attempts at identification of mollusc species producing Tyrian purple from archaeological material are usually done with high performance liquid chromatography in the reversed-phase system, but the peaks obtained are often wide and asymmetric. This is due to the low solubility of the indigoids and their brominated derivatives in the mobile phase, especially 6,6'-dibromoindigotin, which is soluble in only few, particular solvents. Our study focused on improving both symmetry and peak height for more precise quantification. The influence of various factors was evaluated: stationary phase characteristics, mobile phase composition, elution gradient parameters and temperature on the peak shape of the main components of Tyrian purple. The best results were obtained using highly retentive, but moderately bonded ODS stationary phases (about 2.8 MUmol m(-2)), percolated with gradient of acetonitrile with acidified aqueous mobile phases (0.1% strong acid) at elevated temperatures (70 degrees C). The upper quantification limit for 6,6'-dibromoindigotin was improved by over 350%, between standard and optimised systems. Using them, the detection and quantification of trace Tyrian purple components (less than 0.15%) aside from major indigoids becomes possible. Consequently, for the first time, the new analogues of brominated and unbrominated indirubins were found in the shellfish purple from Hexaplex trunculus. PMID- 21257175 TI - A reliable method to determine methylmercury and ethylmercury simultaneously in foods by gas chromatography with inductively coupled plasma mass spectrometry after enzymatic and acid digestion. AB - A reliable and sensitive method for determination simultaneously of monomethylmercury (MeHg) and monoethylmercury (EtHg) in various types of foods by gas chromatography inductively coupled plasma mass spectrometry (GC-ICP/MS) was developed and validated. Samples were digested with pancreatin and then hydrochloric acid. MeHg and EtHg in the extract were derivatized in an aqueous buffer with sodium tetraphenylborate. After phase separation, the extract was directly transferred to analysis. The analyses were conducted by GC-ICP/MS with monopropylmercury chloride (PrHgCl) as surrogate standard. Concentrations of 254+/-5.1, 13.7+/-0.69 and 162+/-6.2 MUg Hg kg(-1) (one standard deviation, n=3) were obtained for MeHg in NIST SRM 1947 (Superior Lake fish), SRM 1566b (oyster tissue) and NRC Tort-2 (lobster Hepatopancreas), respectively. These are in good agreement with the certified values of 233+/-10, 13.2+/-0.7 and 152+/-13 MUg Hg kg(-1) (as 95% confidence interval), respectively. The method detection limits (3sigma) for MeHg and EtHg are 0.3 MUg Hg kg(-1). The method detection limit was estimated by using a 0.5 g of subsample, sufficiently low for the risk assessment of MeHg and EtHg in foods. The spiked recoveries of MeHg and EtHg in different food matrices were between 87 and 117% and the RSDs were less than 15%. When isotopic dilution mass spectrometry (IDMS) analysis was performed with a commercial available (201)Hg-enriched monomethylmercury (Me(201)Hg) solution as internal standard, concentrations of 244+/-13.4, 13.9+/-0.25 and 161+/-1.3 MUg Hg kg(-1) were obtained for MeHg in NIST SRM 1947, SRM 1566b and NRC Tort-2, respectively. It shown clearly that IDMS analysis got improvement in precision and accuracy, however, EtHg cannot be analyze simultaneously and the cost of analysis is higher. PMID- 21257176 TI - Inhibition of bubble coalescence: effects of salt concentration and speed of approach. AB - Bubble coalescence experiments have been performed using a sliding bubble apparatus, in which mm-sized bubbles in an aqueous electrolyte solution without added surfactant rose toward an air meniscus at different speeds obtained by varying the inclination of a closed glass cylinder containing the liquid. The coalescence times of single bubbles contacting the meniscus were monitored using a high speed camera. Results clearly show that stability against coalescence of colliding air bubbles is influenced by both the salt concentration and the approach speed of the bubbles. Contrary to the widespread belief that bubbles in pure water are unstable, we demonstrate that bubbles formed in highly purified water and colliding with the meniscus at very slow approach speeds can survive for minutes or even hours. At higher speeds, bubbles in water only survive for a few seconds, and at still higher speeds they coalesce instantly. Addition of a simple electrolyte (KCl) removes the low-speed stability and shifts the transition between transient stability and instant coalescence to higher approach speeds. At high electrolyte concentration no bubbles were observed to coalesce instantly. These observations are consistent with recent results of Yaminsky et al. (Langmuir 26 (2010) 8061) and the transitions between different regions of behavior are in semi-quantitative agreement with Yaminsky's model. PMID- 21257177 TI - Synthesis of hierarchical rose bridal bouquet- and humming-top-like TiO2 nanostructures and their shape-dependent degradation efficiency of dye. AB - Novel hierarchical rose bridal bouquet- and humming-top-like nanostructured TiO(2) were successfully prepared by the simple process with the hydrothermal temperature as the morphology-controlling factor. The gradual transformation from layered titanate to brookite phase was well consistent with the formation mechanism of the hierarchical morphologies. The three-dimensional flower bouquets built from the bunches of roses with surrounding fern fronds displayed the best adsorptivity and completely degraded methylene blue within 60 min under UV irradiation, whereas the humming-top geometry composed of anisotropically elongated spindle-like crystallites was detrimental to the dye photodegradation. PMID- 21257178 TI - Organic crystallizable solvent served as template for constructing well-ordered PPE films. AB - Tuning the solidification of the crystallizable solvent naphthalene, well patterned conjugated polymer poly(phenyleneethynylene) (PPE) films with well defined nanostructures of 0D nanodots, 1D lamellas, and 2D texture nanostructures have been prepared by several strategies. The nanostructures have been characterized and the formation mechanisms for the morphologies have been discussed. PMID- 21257179 TI - Influence of interfacial rheology on the viscosity of concentrated emulsions. AB - New models are developed for the viscosity of concentrated emulsions taking into consideration the effects of interfacial rheology and Marangoni phenomenon. The interface is assumed to be viscous with non-zero surface-shear and surface dilational viscosities. The Marangoni effect is accounted for through non-zero Gibbs elasticity of the interface. The experimental viscosity data for a number of emulsion systems are interpreted in terms of the proposed models. PMID- 21257180 TI - The development of visual short-term memory for multifeature items during middle childhood. AB - Visual short-term memory (VSTM) research suggests that the adult capacity is limited to three or four multifeature object representations. Despite evidence supporting a developmental increase in capacity, it remains unclear what the unit of capacity is in children. The current study employed the change detection paradigm to investigate both the capacity and nature of the representations of VSTM in 7-year-olds, 10-year-olds, and adults. Two experimental conditions were used to compare memory performance for single-feature objects with that for multifeature objects. Results provided further and more convincing evidence for a developmental increase in VSTM. Furthermore, the "loading up" of features in the multifeature condition was found to incur no significant performance deficit in all age groups. These findings are explained in terms of a developmental increase in the number of integrated multifeature object representations in VSTM. PMID- 21257181 TI - Periodic limb movements during sleep and restless legs syndrome in patients with ASIA A spinal cord injury. AB - OBJECTIVE: To establish the occurrence of Periodic Leg Movements (PLM) and Restless Legs Syndrome (RLS) in Spinal Cord Injury (SCI) subjects. METHODS: In this study, twenty four patients were submitted to a full night polysomnography and were assessed with Epworth Sleepiness Scale and an adapted form of International Restless Legs Syndrome Scale Rating Scale (IRLS Rating Scale). Control Group (CG) was composed of 16 subjects, 50% of each sex, age: 24.38+/-4 years old. Spinal Cord Injury Group (SCIG) was composed of 8 subjects (29+/-5 years old) with a complete SCI (ASIA A) of about three and a half years of duration, 100% males. RESULTS: 100% of SCIG had RLS compared to 17% in CG (p<0.0001). SCIG had 18.11+/-20.07 of PLM index while CG had 5.96+/-11.93 (p=0.01). Arousals related to PLM were recorded in CG and SCIG. There was a positive moderate correlation between RLS and age (r=0.5; p=0.01), RLS and PLM (r=0.49; p=0.01), adapted IRLS Rating Scale and PLM index (r=0.64; p=0.03) and also a negative moderate correlation between Epworth Sleepiness Scale and PLM index (r=-0.4; p=0.04) in both groups. CONCLUSION: RLS and PLM are common findings in SCI patients with a complete injury. PMID- 21257182 TI - Progressive mitochondrial myopathy, deafness, and sporadic seizures associated with a novel mutation in the mitochondrial tRNASer(AGY) gene. AB - We sequenced the mitochondrial genome from a patient with progressive mitochondrial myopathy associated with deafness, sporadic seizures, and histological and biochemical features of mitochondrial respiratory chain dysfunction. Direct sequencing showed a heteroplasmic mutation at nucleotide 12262 in the tRNASer(AGY) gene. RFLP analysis confirmed that 63% of muscle mtDNA harboured the mutation, while it was absent in all the other tissues. The mutation is predicted to influence the functional behaviour of the aminoacyl acceptor stem of the tRNA. Several point mutations on mitochondrial tRNA genes have been reported in patients affected by encephalomyopathies, but between them only four were reported for tRNASer(AGY). PMID- 21257184 TI - Re: Use of cutaneous flap for continent cystostomy (Daoud technique) M. Pons, R. Messaoudi, C. Fiquet, C. Jolly, D. Chaouadi, F. Lefebvre, M. Belouadah, M. A. Bouche-pillon, S. Daoud and M. L. Poli-merol j urol 2010; 184: 1116-1121. PMID- 21257185 TI - [Trends in semen quality in a non-industrialized population from the Salamanca area, Spain, during the last 30 years]. AB - BACKGROUND AND OBJECTIVE: The objective was to analyze the secular trend in semen quality over the past 30 years (1978-2007) in a population-based study in Salamanca, Western Spain. Information about this issue in non-industrialized areas of Southern Europe is lacking. SUBJECTS AND METHODS: We analyzed semen quality in 612 consecutive healthy normospermic subjects derived to our unit for andrologic evaluation. The study was performed at a single Centre and a single highly experienced technician made all analyses at the same laboratory. RESULTS: The age of the subjects at diagnosis increased, while the time interval of childless relationships before consultation decreased over time. Semen volume and sperm counts decreased while sperm motility increased over this period. Motile density per ejaculate showed a clearly decreasing trend. CONCLUSIONS: Our results demonstrate a decrease in semen quality over the last 30 years in the area of Salamanca in western Spain, suggesting that non-industrial-related factors may be involved in decreasing semen quality. PMID- 21257186 TI - Proteome analysis of wheat leaf under salt stress by two-dimensional difference gel electrophoresis (2D-DIGE). AB - Salt stress is a major abiotic stress that limits agricultural productivity in many regions of the world. To understand the molecular basis of the salt stress response in wheat (Triticum aestivum L.), a proteomic approach was used to identify the salt stress-responsive proteins in an elite Chinese wheat cultivar, Zhengmai 9023, which exhibits a high yield, superior gluten quality and better biotic resistance. Three-week-old seedlings were treated with NaCl of four different concentrations (1.0%, 1.5%, 2.0%, and 2.5%). The total proteins from the leaves of untreated and NaCl-treated plants were extracted and separated by two-dimensional difference gel electrophoresis (2D-DIGE). A total of 2358 protein spots were detected on the gels, among which 125 spots showed a significant change in protein abundance, and 83 differentially expressed spots were localised on preparative gels. Using Q-TOF mass spectrometry, 52 salt-responsive spots were identified, which were classified into six functional categories that included transport-associated proteins, detoxifying enzymes, ATP synthase, carbon metabolism, protein folding, and proteins with unknown biological functions. Of the 52 differentially expressed proteins, 26 were up-regulated, 21 were down regulated, and five spots showed multi-expression patterns. In particular, some important proteins for salt tolerance were found to be up-regulated in Zhengmai 9023 under salt stress, such as H(+)-ATPases, glutathione S-transferase, ferritin and triosephosphate isomerase. PMID- 21257187 TI - [Autofluorescence for the detection of potentially malignant and malignant lesions of the oral cavity lining]. AB - INTRODUCTION: The sensitivity of visual examination for the diagnosis of oral cancers is estimated at 85% and its specificity at 97%. However, it is likely that numerous lesions remain undetected. The objective of this article was to review literature on the contribution of tissular autofluorescence to detect potentially malignant and malignant lesions of the oral cavity. MATERIAL AND METHOD: The Medline database was consulted using the following keywords: fluorescence and cancer; autofluorescence and cancer; fluorescence and oral cancer; autofluorescence and oral cancer; Velscope((r)) and oral cancer. Only original articles and clinical case reports on the oral cavity published in English since 1999 were considered. RESULTS: Twenty-three publications were analyzed. Twelve studies concerned spectroscopy and 14 direct autofluorescence. The specificity of AF ranged between 75 and 100% in spectroscopy and between 39 and 100% in direct vision. The sensibility of the AF varied between 78 and 100% in spectroscopy and between 50 and 100% in direct vision. DISCUSSION: The variability of results may be explained by selection bias. The main contribution of fluorescence is to highlight oral mucous membrane lesions and to help physicians to better locate them. The lack of AF specificity supports the contribution of histological examination which remains the reference examination for the diagnosis of potentially malignant lesions and cancers of the oral cavity. PMID- 21257188 TI - Life cycle assessment of vertical and horizontal flow constructed wetlands for wastewater treatment considering nitrogen and carbon greenhouse gas emissions. AB - Life cycle assessment (LCA) is used to compare the environmental impacts of vertical flow constructed wetlands (VFCW) and horizontal flow constructed wetlands (HFCW). The LCAs include greenhouse gas (N(2)O, CO(2) and CH(4)) emissions. Baseline constructed wetland designs are compared to different treatment performance scenarios and to conventional wastewater treatment at the materials acquisition, assembly and operation life stages. The LCAs suggest that constructed wetlands have less environmental impact, in terms of resource consumption and greenhouse gas emissions. The VFCW is a less impactful configuration for removing total nitrogen from domestic wastewater. Both wetland designs have negligible impacts on respiratory organics, radiation and ozone. Gaseous emissions, often not included in wastewater LCAs because of lack of data or lack of agreement on impacts, have the largest impact on climate change. Nitrous oxide accounts for the increase in impact on respiratory inorganic, and the combined acidification/eutrophication category. The LCAs were used to assess the importance of nitrogen removal and recycling, and the potential for optimizing nitrogen removal in constructed wetlands. PMID- 21257189 TI - Cationic substrates of soybean lipoxygenase-1. AB - Soybean lipoxygenase-1 (SBLO-1) catalyzes the oxygenation of 1,4-dienes to produce conjugated diene hydroperoxides. The best substrates are anions of fatty acids; for example, linoleate is converted to 13(S)-hydroperoxy-9(Z),11(E) octadecadienoate. The manner in which SBLO-1 binds substrates is uncertain. In the present work, it was found that SBLO-1 will oxygenate linoleyltrimethylammonium ion (LTMA) to give primarily13(S)-hydroperoxy 9(Z),11(E)-octadecadienyltrimethylammonium ion. The rate of this process is about the same at pH 7 and pH 9 and is about 30% of the rate observed with linoleate at pH 9. At pH 7, SBLO-1 oxygenates linoleyldimethylamine (LDMA) to give primarily 13(S)-hydroperoxy-9(Z),11(E)-octadecadienyldimethylamine. The oxygenation of LDMA occurs at about the same rate as LTMA at pH 7, but more slowly at pH 9. The results demonstrate that SBLO-1 will readily oxygenate substrates in which the carboxylate of linoleate is replaced with a cationic group, and the products of these reactions have the same stereo- and regiochemistry as the products obtained from fatty acid substrates. PMID- 21257190 TI - Impact of metals on histopathology and expression of HSP 70 in different tissues of Milk fish (Chanos chanos) of Kaattuppalli Island, South East Coast, India. AB - Histological and Immunohistochemical studies were carried out to document the possible impact of heavy metal contamination in different tissues of Chanos chanos. Heavy metals such as Cu, Pb, Zn, Cd, Mn and Fe were predominant in water, sediment and biota of Kaattuppalli Island and varied significantly between two different sites. Histological changes such as swelling of muscle fiber and break down of muscle bundles were noted in the muscle. Similarly gill filament cell proliferation, increase in intercellular spaces and primary and secondary lamellar epithelium were evident in gills. The hepatocytes showed damage of central vein and rupture of irregular hepatic plate with more number of vacuoles in the fish collected from polluted site compared to that from the less polluted site. The impact of pollution was also assessed in different tissues by immunohistochemistry using primary antibody (mouse monoclonal HSP70 antibody 1:2000) and secondary antibody (HRP conjugated antibody) for expression of stress protein. Immunostaining analysis showed expression of HSP70 with high intensity in the tissues of fish collected from polluted site compared to less polluted sites. Further, HSP70 positive cells were analyzed from six locations per fish tissue section. One-way analysis of variance (ANOVA) followed by least significant difference (LSD) was used to check if the expression was significant. Results indicate that the values are statistically significant at the two different sampling sites (P<0.05). PMID- 21257191 TI - Removal mechanism of elemental mercury by using non-thermal plasma. AB - The removal mechanism of elementary mercury (Hg(0)) by non-thermal plasma (NTP) has been investigated, where dielectric barrier discharge and O(3) injection methods as oxidation techniques are employed, together with the analysis of mercury species deposited on the reactor surface using temperature-programmed desorption and dissociation (TPDD) and scanning electron microscopy-energy dispersive spectroscopy. The removal of Hg(0) by NTP is found to be time dependent and proceed through three domains; the Hg(0) concentration just slightly decreases as soon as NTP is initiated and then becomes constant for several minutes (Region 1), thereafter starts to decrease rapidly for 1h (Region 2) and, after passing fall-off region, very slowly decreases for about 4h (Region 3). The deposited mercury species on the reactor surface were conglomerated like islands, rather than dispersed uniformly, and their ratio of Hg(0) to O composition is observed to be 1:2. Additionally, the new peak in TPDD spectra observed in the region of 260-380 degrees C is proposed as HgO(3). These results lead us to conclude that the deposited mercury species by NTP have extra O atoms to oxidize the adsorbed Hg(0), resulting in the acceleration of removal rate as the oxidation of Hg(0) proceeds. PMID- 21257192 TI - The impact of anthropogenic and biogenic emissions on surface ozone concentrations in Istanbul. AB - Surface ozone concentrations at Istanbul during a summer episode in June 2008 were simulated using a high resolution and urban scale modeling system coupling MM5 and CMAQ models with a recently developed anthropogenic emission inventory for the region. Two sets of base runs were performed in order to investigate for the first time the impact of biogenic emissions on ozone concentrations in the Greater Istanbul Area (GIA). The first simulation was performed using only the anthropogenic emissions whereas the second simulation was performed using both anthropogenic and biogenic emissions. Biogenic NMVOC emissions were comparable with anthropogenic NMVOC emissions in terms of magnitude. The inclusion of biogenic emissions significantly improved the performance of the model, particularly in reproducing the low night time values as well as the temporal variation of ozone concentrations. Terpene emissions contributed significantly to the destruction of the ozone during nighttime. Biogenic NMVOCs emissions enhanced ozone concentrations in the downwind regions of GIA up to 25ppb. The VOC/NO(x) ratio almost doubled due to the addition of biogenic NMVOCs. Anthropogenic NO(x) and NMVOCs were perturbed by +/-30% in another set of simulations to quantify the sensitivity of ozone concentrations to the precursor emissions in the region. The sensitivity runs, as along with the model-calculated ozone-to-reactive nitrogen ratios, pointed NO(x)-sensitive chemistry, particularly in the downwind areas. On the other hand, urban parts of the city responded more to changes in NO(x) due to very high anthropogenic emissions. PMID- 21257193 TI - Quantitative effects of composting state variables on C/N ratio through GA-aided multivariate analysis. AB - It is widely known that variation of the C/N ratio is dependent on many state variables during composting processes. This study attempted to develop a genetic algorithm aided stepwise cluster analysis (GASCA) method to describe the nonlinear relationships between the selected state variables and the C/N ratio in food waste composting. The experimental data from six bench-scale composting reactors were used to demonstrate the applicability of GASCA. Within the GASCA framework, GA searched optimal sets of both specified state variables and SCA's internal parameters; SCA established statistical nonlinear relationships between state variables and the C/N ratio; to avoid unnecessary and time-consuming calculation, a proxy table was introduced to save around 70% computational efforts. The obtained GASCA cluster trees had smaller sizes and higher prediction accuracy than the conventional SCA trees. Based on the optimal GASCA tree, the effects of the GA-selected state variables on the C/N ratio were ranged in a descending order as: NH4+-N concentration>Moisture content>Ash Content>Mean Temperature>Mesophilic bacteria biomass. Such a rank implied that the variation of ammonium nitrogen concentration, the associated temperature and the moisture conditions, the total loss of both organic matters and available mineral constituents, and the mesophilic bacteria activity, were critical factors affecting the C/N ratio during the investigated food waste composting. This first application of GASCA to composting modelling indicated that more direct search algorithms could be coupled with SCA or other multivariate analysis methods to analyze complicated relationships during composting and many other environmental processes. PMID- 21257194 TI - An evaluation of direct measurement techniques for mercury dry deposition. AB - In this project, several surrogate surfaces designed to directly measure Hg dry deposition were investigated. Static water surrogate surfaces (SWSS) containing deionized (DI), acidified water, or salt solutions, and a knife-edge surrogate surface (KSS) using quartz fiber filters (QFF), KCl-coated QFF and gold-coated QFF were evaluated as a means to directly measure mercury (Hg) dry deposition. The SWSS was hypothesized to collect deposited elemental mercury (Hg0), reactive gaseous/oxidized mercury (RGM), and mercury associated with particulate matter (Hg(p)) while the QFF, KCl-coated QFF, and gold-coated QFF on the KSS were hypothesized to collect Hg(p), RGM+Hg(p), and Hg0+RGM+Hg(p), respectively. The Hg flux measured by the DI water was significantly smaller than that captured by the acidified water, probably because Hg0 was oxidized to Hg2+ which stabilized the deposited Hg and decreased mass transfer resistance. Acidified BrCl, which efficiently oxidizes Hg0, captured significantly more Hg than other solutions. However, of all collection media, gold-coated QFFs captured 6 to 100 times greater Hg mass than the other surfaces, probably because there is no surface resistance for Hg0 deposition to gold surfaces. In addition, the Hg0 concentration is usually 100-1000 times higher than RGM and Hg(p). For all other media, co-located samples were not significantly different, and the combination of daytime plus nighttime results were comparable to 24-h samples, implying that Hg0, RGM and Hg(p) were not released after they deposited nor did the surfaces reach equilibrium with the atmosphere. Based on measured Hg ambient air concentrations and fluxes, dry deposition velocities of RGM and Hg0 to DI water and other surfaces were 5.6+/-5.4 and 0.005-0.68 cm s-1 in this study, respectively. These results suggest surrogate surfaces can be used to measure Hg dry deposition; however, extrapolating the results to natural surface can be challenging. PMID- 21257195 TI - Measurement of circulating cell-derived microparticles by flow cytometry: sources of variability within the assay. AB - INTRODUCTION: Circulating cell-derived microparticles (MPs) have been implicated in several disease processes and elevated levels are found in many pathological conditions. The detection and accurate measurement of MPs, although attracting widespread interest, is hampered by a lack of standardisation. The aim of this study was to establish a reliable flow cytometric assay to measure distinct subtypes of MPs in disease and to identify any significant causes of variability in MP quantification. MATERIALS AND METHODS: Circulating MPs within plasma were identified by their phenotype (platelet, endothelial, leukocyte and annexin-V positivity (AnnV+). The influence of key variables (i.e. time between venepuncture and centrifugation, washing steps, the number of centrifugation steps, freezing/long-term storage and temperature of thawing) on MP measurement were investigated. RESULTS: Increasing time between venepuncture and centrifugation leads to increased MP levels. Washing samples results in decreased AnnV+MPs (P=0.002) and platelet-derived MPs (PMPs) (P=0.002). Double centrifugation of MPs prior to freezing decreases numbers of AnnV+MPs (P=0.0004) and PMPs (P=0.0004). A single freeze thaw cycle of samples led to an increase in AnnV+MPs (P=0.0020) and PMPs (P=0.0039). Long-term storage of MP samples at -80 degrees resulted in decreased MP levels. CONCLUSIONS: This study found that minor protocol changes significantly affected MP levels. This is one of the first studies attempting to standardise a method for obtaining and measuring circulating MPs. Standardisation will be essential for successful development of MP technologies, allowing direct comparison of results between studies and leading to a greater understanding of MPs in disease. PMID- 21257196 TI - Safety assessment and pharmacodynamics of a novel ultra low molecular weight heparin (RO-14) in healthy volunteers--a first-time-in-human single ascending dose study. AB - INTRODUCTION: RO-14 is a novel ultra low molecular heparin. The purpose of this study was to evaluate the safety and pharmacodynamic profile of RO-14 in healthy males. MATERIALS AND METHODS: We conducted a two-stage, single-center, open label, randomized study. Two cohorts of 6 volunteers were randomly assigned to 12 single, ascending subcutaneous doses (1750-19950IU of anti-FXa activity) in an alternating crossover fashion. Safety was assessed by spontaneous/elicited adverse events, medical examination and laboratory tests. Anti-FXa activity and anti-FIIa activity were assessed throughout the 24hours after dosing. Dose proportionality and linearity of the anti-FXa activity were evaluated. RESULTS: All doses were well tolerated and there were no bleeding events. At the lowest dose, anti-FXa activity A(max) was 0.16 (+/-0.02) IU/mL and AUC(0-24) was 1.11 (+/-0.24) IU*h/mL, At the highest dose anti-FXa activity A(max) was 1.67 (+/ 0.15) IU/mL; AUC(0-24) was 21.48 (+/-4.46) IU*h/mL and t1/2 was 8.05h. Mean T(max) (all doses) was 2.86 (+/-0.39) h. RO-14 showed proportional and linear pharmacodynamics [normalized A(max) among doses (p=0.594) and normalized AUC(0 24) (p=0.092), correlations between A(max-)dose (R(2)=0.89, p<0.001) and AUC(0 24)-dose (R(2)=0.86, p<0.001)]. Anti-FIIa activity was below the detection limit (0.1IU/ml) at all dose levels. No clinically significant changes were observed in the platelet count, APTT, PT, TT, fibrinogen and antithrombin. CONCLUSIONS: In this phase I study, RO-14 exhibited a good safety profile, anti-FXa activity for either prophylaxis or treatment of venous thromboembolism, linear pharmacodynamics, a longer elimination half-life than currently marketed low molecular weight heparin and no anti-FIIa activity. PMID- 21257197 TI - Synergistic effects of the dual release of stromal cell-derived factor-1 and bone morphogenetic protein-2 from hydrogels on bone regeneration. AB - The objective of this study is to evaluate the activity of gelatin hydrogels incorporating combined stromal cell-derived factor-1 (SDF-1) and bone morphogenetic protein-2 (BMP-2) on the in vivo bone regeneration at an ulna critical-sized defect and subcutaneous site of rats, and compared with that of those incorporating either SDF-1 or BMP-2. The similar release profile of SDF-1 and BMP-2 from the hydrogels was observed with or without the combination of BMP 2 and SDF-1, respectively. An enhanced bone regeneration by the hydrogels incorporating combined SDF-1 and BMP-2 was observed. In addition, the implantation of hydrogels incorporating combined SDF-1 and BMP-2 enhanced the expression level of CXC chemokine cell-surface receptor-4 (Cxcr4), Runt-related factor-2 (Runx2), and Osteocalcin genes. The experiments with green fluorescent protein (GFP)-positive Chimeric mice revealed that the recruitment of bone marrow derived cells was promoted and a vascular-like structure together with strong accumulation of CD31- and CD34-positive cells was observed at the site of hydrogels incorporating combined SDF-1 and BMP-2 implanted. In addition, a large fraction of CD29- and CD44-positive non-hematopoietic cells was detected. It is concluded that the combined release of SDF-1 and BMP-2 enhanced the recruitment of osteogenic cells and angiogenesis, resulting in the synergistic effect on bone regeneration. PMID- 21257199 TI - A photopolymerized antimicrobial hydrogel coating derived from epsilon-poly-L lysine. AB - Hydrogels made from epsilon-poly-l-lysine-graft-methacrylamide (EPL-MA) have been found to have impressive wide spectrum antimicrobial activity against both bacteria (specifically Escherichia coli, Pseudomonas aeruginosa, Serratia marcescens and Staphylococcus aureus) and fungi (specifically Candida albicans and Fusarium solani). The EPL-MA hydrogel also possesses in vitro biocompatibility and EPL-MA solution is relatively non-hemolytic: the concentration needed for onset of human red blood cell (hRBC) hemolysis is 12,500 MUg/mL so that the selectivity for the pathogenic microorganisms over hRBCs is 230-1560. Further, EPL-MA hydrogel can be conveniently ultraviolet-immobilized onto plasma-treated plastic surfaces to form thin highly adherent antimicrobial hydrogel coatings for medical devices and implants. PMID- 21257198 TI - Recapitulation of the embryonic cardiovascular progenitor cell niche. AB - Stem or progenitor cell populations are often established in unique niche microenvironments that regulate cell fate decisions. Although niches have been shown to be critical for the normal development of several tissues, their role in the cardiovascular system is poorly understood. In this study, we characterized the cardiovascular progenitor cell (CPC) niche in developing human and mouse hearts, identifying signaling pathways and extracellular matrix (ECM) proteins that are crucial for CPC maintenance and expansion. We demonstrate that collagen IV (ColIV) and beta-catenin-dependent signaling are essential for maintaining and expanding undifferentiated CPCs. Since niches are three-dimensional (3D) structures, we investigated the impact of a 3D microenvironment that mimics the in vivo niche ECM. Employing electrospinning technologies, 3D in vitro niche substrates were bioengineered to serve as culture inserts. The three dimensionality of these structures increased mouse embryonic stem cell differentiation into CPCs when compared to 2D control cultures, which was further enhanced by incorporation of ColIV into the substrates. Inhibiting p300-dependent beta-catenin signals with the small molecule IQ1 facilitated further expansion of CPCs. Our study represents an innovative approach to bioengineer cardiac niches that can serve as unique 3D in vitro systems to facilitate CPC expansion and study CPC biology. PMID- 21257200 TI - Multimodal tumor imaging by iron oxides and quantum dots formulated in poly (lactic acid)-D-alpha-tocopheryl polyethylene glycol 1000 succinate nanoparticles. AB - This work developed a multimodal imaging system by co-encapsulating superparamagnetic iron oxides (IOs) and quantum dots (QDs) in the nanoparticles of poly (lactic acid) - d-alpha-tocopheryl polyethylene glycol 1000 succinate (PLA-TPGS) for concurrent imaging of the magnetic resonance imaging (MRI) and the fluorescence imaging to combine their advantages and to overcome their disadvantages as well as to promote a sustained and controlled imaging with passive targeting effects to the diseased cells. The QDs and IOs-loaded PLA-TPGS NPs were prepared by a modified nanoprecipitation method, which were then characterized for their size and size distribution, zeta potential and the imaging agent encapsulation efficiency. The transmission electron microscopy (TEM) images showed direct evidence for the well-dispersed distribution of the QDs and IOs within the PLA-TPGS NPs. The cellular uptake and the cytotoxicity of the PLA-TPGS NPs formulation of QDs and IOs were investigated in vitro with MCF-7 breast cancer cells, which were conducted in close comparison with the free QDs and IOs at the same agent dose. The Xenograft model was also conducted for biodistribution of the QDs and IOs-loaded PLA-TPGS NPs among the various organs, which showed greatly enhanced tumor imaging due to the passively targeting effects of the NPs to the tumor. Images of tumors were acquired in vivo by a 7T MRI scanner. Further ex vivo images of the tumors were obtained by confocal laser scanning microscopy. Such a multimodal imaging system shows great advantages of both contrast agents making the resultant probe highly sensitive with good depth penetration, which confirms the diagnosis obtained from each individual imaging. With therapeutics co-encapsulation and ligand conjugation, such nanoparticles system can realize a multi-functional system for medical diagnosis and treatment. PMID- 21257201 TI - Effects of chronic 2,4,6,-trinitrotoluene, 2,4-dinitrotoluene, and 2,6 dinitrotoluene exposure on developing bullfrog (Rana catesbeiana) tadpoles. AB - Chronic aqueous exposures were conducted using bullfrog (Rana catesbeiana) tadpoles (8 d old) exposed to TNT (0-4 mg/L), 2,4-DNT (0-4 mg/L), and 2,6-DNT (0 8 mg/L) for 90 d. Survival of tadpoles examined using Cox proportional hazard models was reduced at all concentrations tested. Percent of abnormal swimming and other morphological abnormalities after sublethal exposure to TNT, 2,4-DNT, and 2,6-DNT at 2 mg/L were also evaluated. The effects of TNT, 2,4-DNT, and 2,6-DNT on wet body mass, snout vent length (SVL), and developmental stage of surviving tadpoles were examined. Only 2,4-DNT did not have a significant effect on body mass or SVL, but all three compounds tested had significant effects on survival. Long-term continuous exposure to these compounds at concentrations of 0.25 mg/L could lead to significant changes in growth and survival of larval amphibians. PMID- 21257202 TI - Flow diverter stents in the treatment of intracranial aneurysms: Where are we? AB - Flow diverter stents are devices designed to treat complex aneurysms. According to preliminary series published in the literature, treatment of aneurysms with flow diverters is highly efficacious with acceptable morbidity and mortality. Delayed aneurysm ruptures have been reported but mechanisms are actually not completely elucidated. In-stent thrombosis or stenosis was also observed. Indications of flow diverters are complex aneurysms (fusiform, large and giant, wide neck, small aneurysms untreatable by conventional coiling) as well as recurrences. Several randomized studies and registries are actually in progress and will contribute to a more precise knowledge of the place of the flow diverters in the treatment of intracranial aneurysms. PMID- 21257203 TI - Embolization of a ruptured lenticulostriate artery aneurysm. AB - Aneurysms arising from the lenticulostriate artery (LSA) are rare. So far, only 23 cases have been reported in the literature (Ahn et al. 2007 [1], Gandhi et al. 2008 [2], Harreld et al. 2010 [3]). Early detection and treatment of these aneurysms is difficult because of their small size, deep location and complex surrounding vasculature. The majority of reported cases were treated surgically, and only two were treated with endovascular embolization (Harreld et al. 2010 [3], Larrazabal et al. 2001 [4]). We present here a case of an LSA aneurysm that was successfully embolized with n-butyl cyanoacrylate (n-BCA) with no recurrence after 1 year of follow-up. PMID- 21257204 TI - Sewage epidemiology--a real-time approach to estimate the consumption of illicit drugs in Brussels, Belgium. AB - The sewage epidemiology approach was applied to a one-year sampling campaign in the largest wastewater treatment plant (WWTP) in Belgium. The consumption of cocaine (COC), amphetamine (AMP), methylenedioxymethamphetamine (MDMA), methamphetamine (METH), methadone (MTD) and heroin (HER) was evaluated based on measured concentrations of the parent compound and/or metabolites in daily 24 hour composite influent wastewater samples. The inevitable back-calculations used in the sewage epidemiology approach were adapted to newly available information regarding the stability of the compounds in wastewater and the excretion pattern of illicit drugs. For COC, three different back-calculation approaches were evaluated. In addition, for the first time, efforts were made to calculate the number of inhabitants living in the catchment area of the WWTP in a real-time and dynamic way, based on concentrations of nitrogen, phosphorus and oxygen in the wastewater samples. Clear variations in the amount of inhabitants in the catchment area of the WWTP were observed. For COC, AMP and MDMA a significant higher weekend use was observed while for HER and MTD no significant daily variations could be found. METH consumption was negligible. Generally, the sewage epidemiology calculations were in agreement with official statistics. This manuscript shows that sewage epidemiology provides consistent and logical results and that it is a promising tool that can be used in addition to classical studies to estimate illicit drug use in populations. Therefore, efforts should be made to further optimize this approach in the future. PMID- 21257206 TI - Prophylactic vaccines mimic synthetic CpG oligonucleotides in their ability to modulate immune responses. AB - Synthetic oligonucleotide ligands that bind to toll-like receptors are known to modulate the immune response via the activation of antigen presenting cells, and were therefore proposed as a novel form of vaccine adjuvant. Clinical-grade they are, however, not readily available. Here, we show that commonly used prophylactic vaccines for infectious diseases like measles, mumps and tuberculosis exhibit the same immune modulating behavior as synthetic CpG oligonucleotides in terms of their ability to stimulate IFN-alpha production and plasmacytoid dendritic cell maturation. Featuring the additional advantages of low-cost and proven safety, these vaccines could therefore be attractive alternatives to CpG oligonucleotides as adjuvants for immunotherapy. This previously undiscovered characteristic of prophylactic vaccines also sheds new light on the mechanisms by which they operate and is extremely interesting for vaccine development. Moreover, the finding that prophylactic vaccines trigger TLRs like synthetic oligonucleotides opens the possibility to predict the immune response of new vaccines. PMID- 21257205 TI - The alternative pathway is required, but not alone sufficient, for retinal pathology in mouse laser-induced choroidal neovascularization. AB - Human genetic studies have demonstrated that polymorphisms in different complement proteins can increase the risk for developing AMD. There are three pathways of complement activation, classical (CP), alternative (AP), and lectin (LP), which all activate a final common pathway. Proteins encoded by the AMD risk genes participate in the AP (CFB), CP/LP (C2), or in the AP and final common pathway (C3). Here we tested which pathway is essential in mouse laser-induced CNV. CNV was analyzed using single complement pathway knockouts (i.e., eliminating one complement pathway at a time), followed by a double knockout in which only the AP is present, and the CP and LP are disabled, using molecular, histological and electrophysiological outcomes. First, single-gene knockouts were analyzed and compared to wild type mice; C1q(-/-) (no CP), MBL(-/-) (no LP), and CFB(-/-) (no AP). Six days after the laser-induced lesion, mice without a functional AP had reduced CNV progression (P<0.001) and preserved ERG amplitudes, whereas those without a functional CP or LP were indistinguishable from the wild type controls (P>0.3). Second, AP-only mice (C1q(-/-)MBL(-/-)) were as protected from developing CNV as the CFB(-/-) mice. The degree of pathology in each strain correlated with protein levels of the angiogenic and anti-angiogenic protein VEGF and PEDF, respectively, as well as levels of terminal pathway activation product C5a, and C9. The analysis of complement activation pathways in mouse laser induced CNV allows for the following conclusions. Comparing the single pathway knockouts with those having only a functional AP showed: (1) that AP activation is necessary, but not alone sufficient for injury; and (2) that initial complement activation proceeds via both the LP and CP. Thus, these data indicate an important role for the AP in the generation of complement-dependent injury in the RPE and choroid via amplification of CP- and LP-initiated complement activation. Improving our understanding of the local regulation of this pathway in the eye is essential for developing improved treatment approaches for AMD. PMID- 21257207 TI - Impairment not only in remembering but also in knowing previously seen faces and words in schizophrenia. AB - Patients with schizophrenia have pronounced deficits in face recognition memory that severely hamper their social skills. The functional mechanisms of these impairments remain unknown. According to the dual-process theory, recognition memory comprises two distinct components: recollection and familiarity. Studies using the Remember/Know procedure in patients with schizophrenia showed impairments in conscious recollection as measured by remember responses, but not in familiarity as measured by know responses. Unfortunately, none of these studies used face material. We investigated both recognition memory components using words and faces and the 'Remember/Know' procedure in 25 patients with schizophrenia and 24 control participants. In the same task, size congruency of stimuli was manipulated between the study and test phases to have a selective impact on know responses for faces. Patients reported fewer remember responses than controls. Size changes between the study and the test affected know responses in controls but not in patients. These results reveal that patients with schizophrenia are impaired in terms of their ability to recollect details about previously seen faces as they are for words. PMID- 21257208 TI - Schizophrenia patients with predominantly positive symptoms have more disturbed sleep-wake cycles measured by actigraphy. AB - Sleep disturbances are widespread in schizophrenia, and one important concern is to determine the impact of this disruption on self-reported sleep quality and quality of life (QoL). Our aim was to evaluate the sleep-wake cycle in a sample of patients with schizophrenia (SZ), and whether sleep patterns differ between patients with predominantly negative versus predominantly positive symptoms, as well as its impact on sleep quality and QoL. Twenty-three SZ outpatients were studied with 24 h continuous wrist-actigraphy during 7 days. The quality of sleep was assessed with the Pittsburgh Sleep Quality Index (PSQI), and the self reported QoL was evaluated with the World Health Organization Quality of Life - Abbreviated version (WHOQOL-Bref). About half of the studied population presented an irregular sleep-wake cycle. We found a trend for more disrupted sleep-wake patterns in patients with predominantly positive symptoms, who also had a trend self-reported worse quality of sleep and worse QoL in all domains. Overall, patients with worse self-reported QoL demonstrated worse sleep quality. Our findings suggest that SZ patients are frequently affected with sleep and circadian rhythm disruptions; these may have a negative impact on rehabilitation strategies. Moreover, poor sleep may play a role in sustaining poor quality of life in SZ patients. PMID- 21257209 TI - IRF-1 signaling in central nervous system glial cells regulates inflammatory demyelination. AB - The present study provides evidence that interferon regulatory factor 1 (IRF-1) signaling in glial cells is involved in the pathogenesis of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). Using a bone marrow chimera model of EAE, we demonstrated that CNS IRF-1 regulates inflammatory demyelination and disease severity independently of the peripheral immune cells. In addition, we identified Caspase 1, a pro-inflammatory and pro-apoptotic molecule, as an important transcriptional target of IRF-1. The findings of our study indicate that IRF-1 signaling in glial cells serves as a final common pathway of inflammatory demyelination and may have important clinical implications in MS. PMID- 21257210 TI - Tympanic membrane perforation: size, site and hearing evaluation. AB - OBJECTIVE: To assess different clinical scales of TM perforation size; to evaluate the effect of the size and the site of a perforation on the hearing level and frequencies. METHODS: Prospective study. Observers had subjectively estimated the size in millimeter and in percentage of a particular perforation; objectively computerized measures of TM perforations area were analyzed. Agreement between different measures was studied. Cases with postoperative intact TM and an air-bone gap (ABG) of 10 dB or less were studied. RESULTS: Global mean preoperative ABG was 21.8 +/- 17 dB. Preoperative ABG was different between small large and small-total perforations (p=0.001). Difference of the preoperative ABG was statistically significant between perforations filling up the four quadrants and perforation limited to one quadrant in the postero-inferior, antero-superior and antero-inferior site. No statistically difference between perforation sites was identified for each affected frequency. Difference is statistically significant (p=0.001) between the 250 Hz and the other frequencies for the medium, large and total perforations. After myringoplasty bone conduction improvement was statistically significant for the frequencies 500 (p=0.04), 1000 (p=0.04) and 2000 Hz (p=0.011). Agreement was large enough when TM perforation size was expressed in percentage and absent when expressed in millimeter. CONCLUSION: TM perforation can be clinically estimated quite precisely as a percentage of the TM area. Conductive hearing loss is frequency dependent; with the greatest loss occurring at the lowest sound frequencies. Hearing loss does not depend on the perforation's location. PMID- 21257211 TI - Prognostic significance of aortic stiffness index in acromegaly--results from a 4 year follow-up. PMID- 21257212 TI - The epidemiology of canine Babesia infections in Zambia. AB - This study of 1196 dogs over a period of 18 months determined the seasonal infection patterns of canine babesiosis in Lusaka, the capital city of Zambia. The work also describes a retrospective study of the prevalence of canine babesiosis in laboratory clinical blood samples submitted to the University of Zambia, School of Veterinary Medicine for routine haematological examination from the year 1994 to 2009. A cross-sectional study was also performed to determine the levels of Babesia in a low-income society (during the dry season and the wet season of the year), where 361 samples were collected from dogs presented for mass rabies vaccination campaigns. Morphology of the Babesia indicated that all were of the large-sized Babesia canis infection. Babesia-positive dogs had significantly higher rectal temperatures than negative ones, and dogs younger than 1 year were more likely to be Babesia positive followed by those between 2 and 5 years old. Seasonal trends indicate two peaks, one in the rainy season (November-March) and another in the cold dry season (June/July). Monthly prevalence rates of Babesia ranged from 0% to 2.4% in natural populations and from 0% to 28.6% in laboratory specimens. This study shows that Zambia has lower Babesia prevalence than reported in other African countries. PMID- 21257213 TI - Survey on management practices related to the prevention and control of bovine viral diarrhea virus on dairy farms in Indiana, United States. AB - The objective of this cross-sectional study was to describe the application of management practices known to be associated with the prevention of bovine viral diarrhea virus (BVDV) infection on Indiana dairy farms and to determine the extent of BVDV vaccine use within Indiana dairy herds. The population in this study was Indiana dairy producers enrolled under the Indiana Premise ID list by the Indiana State Board of Animal Health (n=1600). During the fall of 2008 a questionnaire was mailed to Indiana dairy producers. Returned questionnaires were entered into a database and descriptive statistics were performed. A total of 208 questionnaires were found useful for analysis. Small herds (<100 head) constituted 60% of the sample population, 33% farms were categorized as medium herds (100-499 head) and finally 7% were large herds (>500 head). Most of the herds (68%) acquired their replacements from external sources (open herds); however, preventive measures against the introduction of BVDV into the farm such as purchased animal history, quarantine and BVDV testing were not commonly performed. Even though producers commonly reported the use of BVDV vaccines, not all animals groups were vaccinated within herds. This study highlights the aspects of management practices of BVDV control on Indiana dairy farms that need reinforcement. In particular, dairy producers should be made aware that vaccination should be complementary to a comprehensive biosecurity program. PMID- 21257214 TI - Risk factors for calf mortality in large Swedish dairy herds. AB - The aim of this study was to identify possible risk factors for 1-90 day calf mortality in large Swedish dairy herds. Sixty herds with a herd size of >=160 cows were visited once between December 2005 and March 2006. Thirty herds were known to have low mortality (LM) and 30 were known high mortality herds (HM). Upon the visit, data about housing and management was collected from interviews with personnel responsible for the calves. The herd status regarding the calves' passive transfer (total protein), levels of alpha-tocopherol, beta-carotene and retinol, and excretion of faecal pathogens (Cryptosporidium spp., Escherichia coli F5, rota and corona virus) was evaluated based on targeted sampling of high risk calf groups; in each herd, blood and faecal samples were collected from calves 1-7 and 1-14 days old, respectively. Similarly, the herd status regarding clinical respiratory disease in calves and history of respiratory virus exposure was evaluated based on lung auscultations and blood samplings of calves 60-90 days old. The median calf mortality risk (in calves 1-90 days of age) among HM herds was 9% (Range: 6-24%) and among LM herds 1% (Range: 0-2%). LM and HM herds were compared using five logistic regression models, covering potential risk factors within different areas: "Disease susceptibility", "Factors affecting the gastrointestinal tract", "Factors related to transmission of infectious disease", "Hygiene" and "Labour management". The percentage of calves, 1-7 days old, with inadequate serum concentrations of alpha-tocopherol and beta-carotene were significantly higher in HM herds compared to LM herds and also associated with higher odds of being a HM herd (OR=1.02; p=0.023 and OR=1.05; p=0.0028, respectively). The variable "Average number of faecal pathogens in the sampled target group" was significantly associated with higher odds of being a HM herd (OR=4.65; p=0.015), with a higher average in HM herds. The percentage of calves with diarrhoea treated with antibiotics was significantly higher in HM herds and was associated with higher odds of being a HM herd (OR=1.08; p=0.021). The median age at death of calves in the age interval 1-90 days that died during a one-year period was significantly lower among HM herds (13 days) than in LM herds (24 days) (p=0.0013) The results indicate that gastrointestinal disorders may be an important cause of calf mortality in large Swedish dairy herds. Furthermore, our study provides additional indications that fat soluble vitamins might play an important role for calf health. PMID- 21257215 TI - Faecal incontinence following radiotherapy for prostate cancer: a systematic review. AB - BACKGROUND: Faecal incontinence (FI) after radiotherapy is a known phenomenon, but has received little attention to date. This article aimed to review current knowledge on faecal incontinence related to radiotherapy for prostate cancer. METHODS: PubMed was searched for English-language articles published from January 1966 to December 2009 using the primary keywords 'faecal incontinence', 'prostate cancer' and 'radiotherapy'. Prospective, retrospective and controlled trials reporting FI as a complication of radiotherapy for prostate cancer were included. The retrieved titles and abstracts were screened permissively and evaluated as to whether they satisfied the predefined inclusion and exclusion criteria. RESULTS: Nine hundred and ninety four articles were identified from the search. After step wise review, 213 papers were selected for full article review of which 40 were selected for this review. The incidence of faecal incontinence following radiotherapy for prostate cancer varied from 1.6% to 58%. The mechanism of faecal incontinence was not entirely clear but it is most likely due to injury to the nerve plexus of the rectal muscular layer. Correlation between rectal dose-volume parameters and incidence is equivocal, although some studies suggest parameters confined to the lower rectum and/or anal canal may be of value to predict the extent of the injury and could be used as constraints in the dose planning process. CONCLUSIONS: Interpretation of data is limited due to lack of large cohort studies with data on pre-treatment continence status and because variable instruments have been used to assess the severity of the condition. Well-designed prospective studies are needed to investigate dosimetric parameters focusing on the anal canal and sphincter apparatus. Considering the spatial distribution of radiation to the rectum may identify a more direct linkage between radiation damage and faecal incontinence. PMID- 21257216 TI - A methodology for the analysis of PSA response signatures. AB - BACKGROUND AND PURPOSE: Temporal distributions in PSA levels following therapeutic intervention for prostate cancer are known to contain characteristics prognostic of disease progression. An algorithm was developed for extracting such characteristics, specifically in the context of previous observations following radiotherapy. MATERIAL AND METHODS: Segmented regression methods were investigated for characterising the 'signatures' in log(PSA) descent patterns between intervention and nadir. RESULTS: The segmented regression method can automatically identify and parameterise features in a PSA distribution including failure points and doubling time patterns following nadir. The method has previously been applied to the analysis of descent patterns on a large clinical data series (Radiother Oncol 2009;90:382-8). Batch-processing of data using the method for all patients in a clinical trial would establish population parameter values and ranges. Subsequent application to an individual patient's PSA data would determine which resulting prognostic group they fall into. CONCLUSIONS: As more complete and higher-resolution PSA progression datasets become available, techniques such as presented here will allow flexible definition of the characteristics being examined and rapid extraction of parameters for correlation with clinical progression data. PMID- 21257217 TI - The evaluation of a deformable image registration segmentation technique for semi automating internal target volume (ITV) production from 4DCT images of lung stereotactic body radiotherapy (SBRT) patients. AB - PURPOSE: To evaluate a deformable image registration (DIR) segmentation technique for semi-automating ITV production from 4DCT for lung patients, in terms of accuracy and efficiency. METHODS: Twenty-five stereotactic body radiotherapy lung patients were selected in this retrospective study. ITVs were manually delineated by an oncologist and semi-automatically produced by propagating the GTV manually delineated on the mid-ventilation phase to all other phases using two different DIR algorithms, using commercial software. The two ITVs produced by DIR were compared to the manually delineated ITV using the dice similarity coefficient (DSC), mean distance between agreement and normalised DSC. DIR-produced ITVs were assessed for their clinical suitability and also the time savings were estimated. RESULTS: Eighteen out of 25 ITVs had normalised DSC>1 indicating an agreement with the manually produced ITV within 1mm uncertainty. Four of the other seven ITVs were deemed clinically acceptable and three would require a small amount of editing. In general, ITVs produced by DIR were smoother than those produced by manual delineation. It was estimated that using this technique would save clinicians on average 28 min/patient. CONCLUSIONS: ABAS was found to be a useful tool in the production of ITVs for lung patients. The ITVs produced are either immediately clinically acceptable or require minimal editing. This approach represents a significant time saving for clinicians. PMID- 21257218 TI - Treatment with Bifidobacterium bifidum 17 partially protects mice from Th1-driven inflammation in a chemically induced model of colitis. AB - Probiotics have been suggested as an alternative therapeutical approach in the intervention of inflammatory disorders of the gastrointestinal tract (GIT). Application of single strains or probiotic mixtures has shown promising results in animal models and patients of inflammatory bowel disease (IBD). We recently demonstrated potent inhibitory capacity of a Bifidobacterium bifidum S17 on LPS induced inflammatory events in cell culture models using intestinal epithelial cells and verified these anti-inflammatory effects in two mouse models of colitis. In the present study we analyze the anti-inflammatory effect of this potential probiotic strain in a chemically-induced model of colitis in C57BL/6 mice. This model is characterized by a strong type 1T helper (Th1) response resembling Crohn's disease, one of the two most prevalent forms of IBD. We performed macroscopic analysis and determined the effect of B. bifidum S17 on the cytokine balance in biopsies of the colonic mucosa. While treatment with B. bifidum S17 only had a marginal effect on weight loss, no difference was observed in the macroscopic parameters. However, a significant reduction in histology scores and the levels of pro-inflammatory cytokines interleukin 1beta (IL-1beta), interleukin 6 (IL-6), keratinocyte-derived chemokine (KC) and the inflammatory markers cyclooxigenase 2 (Cox-2) and myeloperoxidase (MPO) was observed. These results indicate that treatment with B. bifidum S17 is able to partially inhibit the strong Th1-driven intestinal inflammation induced in our model of colitis. PMID- 21257219 TI - Effects of glimepiride and glibenclamide on carotid atherosclerosis in type 2 diabetic patients. AB - We performed a 3-year observation study of type 2 diabetic patients treated with glibenclamide or glimepiride and found that the annual progression of the maximum carotid intima-media thickness was significantly attenuated in the subjects treated with glimepiride (n=20) as compared with those treated with glibenclamide (n=20) (-0.044+/-0.171 mm/year vs. 0.077+/-0.203 mm/year, p=0.0474). PMID- 21257221 TI - Automatic nevirapine concentration interpretation system using support vector regression. AB - Follow-up of human immunodeficiency virus (HIV) patients treated with Nevirapine (NVP) is a necessary process to evaluate the drug resistance and the HIV mutation. It is also usually tested by immunochromatographic (IC) strip test. However, it is difficult to estimate the amount of drug the patient gets by visually inspection of color. In this paper, we propose an automatic interpretation system using a commercialized optical scanner. Several IC strips can be placed at any direction as long as they are on the scanner plate. There are three steps in the system, i.e., light intensity normalization, image segmentation and NVP concentration interpretation. We utilized the Support Vector Regression to interpret the NVP concentration. From the results, we found out the performance of the system is promising and better than that of the linear and nonlinear regression. PMID- 21257220 TI - A twin approach to unraveling epigenetics. AB - The regulation of gene expression plays a pivotal role in complex phenotypes, and epigenetic mechanisms such as DNA methylation are essential to this process. The availability of next-generation sequencing technologies allows us to study epigenetic variation at an unprecedented level of resolution. Even so, our understanding of the underlying sources of epigenetic variability remains limited. Twin studies have played an essential role in estimating phenotypic heritability, and these now offer an opportunity to study epigenetic variation as a dynamic quantitative trait. High monozygotic twin discordance rates for common diseases suggest that unexplained environmental or epigenetic factors could be involved. Recent genome-wide epigenetic studies in disease-discordant monozygotic twins emphasize the power of this design to successfully identify epigenetic changes associated with complex traits. We describe how large-scale epigenetic studies of twins can improve our understanding of how genetic, environmental and stochastic factors impact upon epigenetics, and how such studies can provide a comprehensive understanding of how epigenetic variation affects complex traits. PMID- 21257222 TI - Computer-aided optimal design of custom scoliosis braces considering clinical and patient evaluations. AB - Scoliosis causes an abnormal three dimensional curvature of the spine that is often treated by an orthotic device called brace. The objective of this research was to develop a new approach to automatically identify the optimal design of custom-built brace, based on clinical and patient evaluations. In this approach, torso geometry of the scoliosis patient was achieved using a 3-D imaging system that generated a 3-D torso surface model, which was modified using a custom CAD system to design the 3-D brace surface model. Two design parameters, a translational correction factor and a rotational correction factor, were selected to design the brace geometry from the torso geometry. The 3-D digital brace was evaluated by three clinical evaluation measures (imbalance, rib hump and principal axis angle reduction) and one patient evaluation measure (discomfort). A multi-objective optimization method was employed to identify the optimal design parameters considering both clinical and patient evaluations. PMID- 21257223 TI - Genes as leaders and followers in evolution. AB - A major question for the study of phenotypic evolution is whether intra- and interspecific diversity originates directly from genetic variation, or instead, as plastic responses to environmental influences initially, followed later by genetic change. In species with discrete alternative phenotypes, evolutionary sequences can be inferred from transitions between environmental and genetic phenotype control, and from losses of phenotypic alternatives. From the available evidence, sequences appear equally probable to start with genetic polymorphism as with polyphenism, with a possible dominance of one or the other for specific trait types. We argue in this review that to evaluate the prevalence of each route, an investigation of both genetic and environmental cues for phenotype determination in several related rather than in isolated species is required. PMID- 21257224 TI - Endangered species and a threatened discipline: behavioural ecology. AB - Behavioural ecologists often see little connection between the current conservation crisis and the future of their discipline. This view is myopic because our abilities to investigate and interpret the adaptive significance and evolutionary histories of behaviours are increasingly being compromised in human dominated landscapes because of species extinctions, habitat destruction, invasive species, pollution, and climate change. In this review, we argue that many central issues in behavioural ecology will soon become prohibitively difficult to investigate and interpret, thus impeding the rapid progress that characterizes the field. To address these challenges, behavioural ecologists should design studies not only to answer basic scientific questions but also to provide ancillary information for protection and management of their study organisms and habitats, and then share their biological insights with the applied conservation community. PMID- 21257225 TI - IL-10 controls Th2-type cytokine production and eosinophil infiltration in a mouse model of allergic airway inflammation. AB - Interleukin-10 was originally described as a factor that inhibits cytokine production by murine Th1 clones. Recent studies have since shown that IL-10 can also downregulate Th2 clones and their production of IL-4 and IL-5. Because of its immuno-suppressive properties, IL-10 has been suggested as a potential therapy for allergic inflammation and asthma. However, the pathophysiological role of IL-10 in vivo has not been clearly elucidated. We investigated the effects of IL-10 administration on the production of IgE, cytokine and allergen induced Th2 cytokine production as well as its effects on eosinophilic inflammation. We established GATA-3/TCR double transgenic (GATA-3/TCR-Tg) mice by crossing GATA-3 transgenic mice with ovalbumin (OVA)-specific TCR transgenic mice; these mice were then sensitized using an intraperitoneal injection of OVA adsorbed to alum and challenged with the intratracheal instillation of an allergen. When GATA-3/TCR-Tg mice sensitized with OVA and alum were injected with C57-IL-10 cells before OVA inhalation, the levels of IL-5, IL-13, and IL-4 decreased by 40-85% and number of eosinophils decreased by 70% (P<0.03) in the murine bronchoalveolar lavage fluid (BALF). These results suggest that IL-10 plays an important role downstream of the inflammatory cascade in the Th2 response to antigens and in the development of BALF eosinophilia and cytokine production in a murine model of asthma. These immunosuppressive properties in animal models indicate that IL-10 could be a potential clinical therapy for the treatment of allergic inflammation. PMID- 21257226 TI - Phenotypic and functional characterization of pulmonary macrophages subpopulations after intratracheal injection of Paracoccidioides brasiliensis cell wall components. AB - A shift in the activation of pulmonary macrophages characterized by an increase of IL-1, TNF-alpha and IL-6 production has been induced in mice infected with Paracoccidioides brasiliensis. It is still unclear whether a functional shift in the resident alveolar macrophage population would be responsible for these observations due to the expression of cell surface molecules. We investigated pulmonary macrophages by flow cytometry from mice treated with P. brasiliensis derivatives by intratracheal route. In vivo labeling with the dye PKH26GL was applied to characterize newly recruited pulmonary macrophages from the bloodstream. Pulmonary macrophages from mice inflamed with P. brasiliensis derivatives showed a high expression of the surface antigens CD11b/CD18 and CD23 among several cellular markers. The expression of these markers indicated a pattern of activation of a subpopulation characterized as CD11b+ or CD23+, which was modulated in vitro by IFN-gamma and IL-4. Analysis of monocytes labelled with PKH26GL demonstrated that CD11b+ cells did infiltrate the lung exhibiting a proinflammatory pattern of activation, whereas CD23+ cells were considered to be resident in the lung. These findings may contribute to better understand the pathology of lung inflammation caused by P. brasiliensis infection. PMID- 21257227 TI - IgG against Plasmodium falciparum variant surface antigens and growth inhibitory antibodies in Mozambican children receiving intermittent preventive treatment with sulfadoxine-pyrimethamine. AB - This study aimed to evaluate whether intermittent preventive treatment in infants with sulfadoxine-pyrimethamine (IPTi-SP) had an effect on the acquisition of IgG against Plasmodium falciparum variant surface antigens (VSA) and growth inhibitory antibodies in Manhica, Mozambique. In addition, we assessed factors affecting the magnitude of these responses and the association between antibody levels and protection against malaria. IgG to VSA expressed by MOZ2, R29 and E8B parasite isolates were measured in plasma samples collected at 5, 9, 12 and 24 months of age by flow cytometry. Growth-inhibitory antibodies in dialyzed plasmas using GFP-D10 parasites were measured by flow cytometry at 12 and 24 months. IPTi SP did not significantly modify the levels of IgG against VSA nor the growth inhibitory capacity of antibodies up to 2 years of age. Age but not previous episodes of malaria influenced the magnitude of these responses. In addition, anti-VSA IgG levels were 7% higher in children with current P. falciparum infection and were associated with neighborhood of residence. Children aged 24 months had 10% less parasite growth than those aged 12 months (95% CI 0.88-0.93, P<0.0001). Growth-inhibitory antibodies correlated with levels of IgG against AMA 1, when evaluating the 10% (R(2)=0.444, P=0.049) and 20% (R(2)=0.230, P=0.037) highest inhibitory samples. None of the responses were associated with subsequent risk of malaria. In conclusion, IPTi-SP does not negatively affect the development of antibody responses thought to be major contributors to the acquisition of immunity to malaria in infancy. PMID- 21257228 TI - [Comparison between Lenstar LS 900 non-contact biometry and OcuScan RXP contact biometry for task delegation]. AB - INTRODUCTION: Non-contact biometers have many advantages including the delegation of tasks to orthoptists. This study analyses the reliability of measurements comparing contact and non-contacts techniques. PATIENTS AND METHODS: Comparative measurements were taken on 86 eyes of 45 patients (mean age: 74 years; 44.4 % males) in preoperative phacoemulsification by three orthoptists with experience in this task. Each patient had non-contact measurements (Lenstar LS 900, Haag Streit) and contact measurements (corneal biometry and ultrasound pachymetry with OcuScan RXP, Alcon) and a keratometry refractometer (TONOREF II, Nidek). The axial length data, pachymetry, power of the intraocular lens (SRK/T formula), anterior chamber depth, and the average keratometry were analyzed by paired comparisons. RESULTS: The non-contact biometer was ineffective in 5.8 % of cases (Parkinson's disease, two cases; dense posterior subcapsular cataracts, three cases). The non-contact pachymetry was statistically significantly higher (546.4 MUm vs. 538.6 MUm; p<0.001). The axial length was significantly longer for the non-contact measurement (23.21 mm vs. 23.05 mm; p<0.0001). In 25.9 % of patients, this difference was greater than or equal to 0.3mm and affected the power of the implant chosen. The anterior chamber depth measured on non-contact biometry was statistically greater (3.33 mm vs. 3.03 mm; p<0.0001). However, there was no significant difference regarding the average keratometry (43.82 D vs. 43.78 D; p=0327). CONCLUSION: Besides the infectious benefit for patients, absence of cleaning and decontamination of biometric probes, non-contact measurements using Lenstar are an example of a safe activity that can be delegated to assistants. This technique has been used to optimize the refractive outcome of 25.9 % of our patients undergoing refractive cataract surgery. PMID- 21257229 TI - Survey of intraoperative povidone-iodine application to prevent surgical site infection in a French region. PMID- 21257230 TI - Emergency department management and 1-year outcomes of patients with atrial flutter. AB - STUDY OBJECTIVE: Atrial flutter is a common arrhythmia seen in the emergency department (ED), yet there is little research describing its management and outcomes. We analyze the success and safety of treatment of ED patients with atrial flutter. METHODS: This was a retrospective cohort study obtained by searching the ED administrative database of 2 urban hospitals to identify consecutive patients with a primary discharge diagnosis of atrial flutter from April 1, 2006, to January 31, 2009. We linked each patient's unique provincial health number to the provincial vital statistics registry and the regional ED database to identify subsequent deaths and strokes within 1 year. Manual chart review was conducted to confirm rhythms and outcomes and to identify patient comorbidities. Patients were stratified into 5 groups based on initial ED presentation and management approach: electrocardioversion, chemical cardioversion, spontaneous cardioversion, rate control only, and no acute ED arrhythmia-specific treatment. Primary outcome was the combined 1-year rate of stroke or death, and secondary outcomes included the proportion of eligible patients with conversion to normal sinus rhythm in each group and discharged to home. RESULTS: Data from 122 consecutive patients with a primary ED diagnosis of atrial flutter were collected; there were 3 deaths and no strokes (2.5%; 95% confidence interval 0% to 5.1%) in the following year. Patients undergoing electrocardioversion achieved normal sinus rhythm 91% of the time, with 93% discharged home; patients undergoing oral or intravenous antiarrhythmic treatment achieved sinus rhythm 27% of the time, with 60% discharged home. Discharge rates of patients with spontaneous cardioversion, rate control, and no ED treatment were 93%, 58%, and 96%, respectively. CONCLUSION: In this 2-center cohort of ED patients with atrial flutter, patients eligible for rhythm control had a higher success and lower admission rate with electrocardioversion than patients treated with antiarrhythmic medications. Overall, the majority of patients were discharged home. Deaths were typically related to concurrent medical illness rather than atrial flutter. PMID- 21257231 TI - White matter hyperintensities and impaired choice stepping reaction time in older people. AB - White matter hyperintensities (WMHs) are associated with impaired mobility in older people, but no studies have identified neuropsychological and sensorimotor mediating factors for this association. Our objective was to determine whether neuropsychological and sensorimotor functions mediate the association of WMHs and choice stepping reaction time (CSRT) under standard and dual-task conditions using structural equation modeling. Two hundred fifty-four older community dwellers (77.8 +/- 4.5 years) underwent structural magnetic resonance imaging, CSRT tests, neuropsychological and sensorimotor assessments. WMH volumes were quantified using an automated method. WMH volumes were significantly associated with neuropsychological tests and dual task CSRT performance. All neuropsychological and sensorimotor variables were also significantly associated with standard and dual task CSRT. The structural equation modeling revealed that impaired sensorimotor function was the only factor influencing impaired stepping performances in the standard condition. In the dual task condition, the association between WMHs and CSRT was mediated through slowed cognitive processing and not through reduced sensorimotor functioning. The conclusion was that WMHs are associated with slowed performance on a dual task CSRT task and this relationship is explained primarily by underlying neuropsychological impairments. PMID- 21257232 TI - Age dependence of excitatory-inhibitory balance following stroke. AB - The mechanisms which mediate cortical map plasticity and functional recovery following stroke remain a matter of debate. Readjustment of the excitatory inhibitory balance may support cortical map plasticity in perilesional areas. Here we studied cortical net inhibition in the vicinity of photothrombotically induced cortical lesions in young adult (3 months) and aged (24 months) male rats. Field potentials were recorded in cortical layer II/III following application of paired-pulse stimulation at layer VI/white matter in coronal brain slices. Additionally, we analyzed the regional distribution of 5 major gamma aminobutyric acid A (GABA(A)) receptor subunits (alpha1, alpha2, alpha3, alpha5, and gamma2) by immunohistochemistry. Paired-pulse inhibition in the perilesional parietal cortex was decreased in young rats but was increased in aged rats. As a consequence of the diminished intrinsic net inhibition in aged control animals, the excitatory-inhibitory balance was readjusted to an age-independent similar level in young and aged lesioned rats in a homeostatic-like fashion. These physiological changes in neuronal activity were accompanied by age-specific laminar alterations of the gamma-aminobutyric acid A (GABA(A)) receptor subunit composition, most prominently of the subunit alpha5. The present study suggests that the mechanisms underlying functional reorganization in aged animals may be distinctly different from those in young animals. PMID- 21257233 TI - Frontotemporal lobar degeneration genome wide association study replication confirms a risk locus shared with amyotrophic lateral sclerosis. AB - Frontotemporal lobar degeneration (FTLD) is a common cause of dementia especially in patients under the age of 65. FTLD has a high incidence of heritability with as many as 40% of patients reporting a family history of disease. Recently, the first genome wide association study was performed using only FTLD patients with a pathologically confirmed TDP-43 pathology. Genome wide significance was detected for a single gene (TMEM106B) on chromosome 7, though several other loci on chromosomes 1, 8, 9, 10 and 11 reached nominal significance. Here we have undertaken an attempt to replicate the association of these loci in FTLD cohorts of British origin. We failed to detect any association of TMEM106B in the Manchester or London cohort either when analyzed individually or when combined. Genotyping of the Manchester cohort failed to replicate any of the loci on chromosome 1, 8 and 10 but did detect association of the single SNP (rs2015747) on chromosome 11. Association was also observed in the London cohort but in the opposite direction. Combining the 2 datasets yielded no association. Analysis of the chromosome 9 locus, revealed strong association in the London FTLD cohort and the Manchester FTLD+ALS cases. These data confirm that FTLD and amyotrophic lateral sclerosis (ALS) share a common genetic risk factor on chromosome 9p. PMID- 21257234 TI - Combination therapy prevents amyloid-dependent and -independent structural changes. AB - Neuropathological features of Alzheimer's disease (AD) are recapitulated in transgenic mice expressing familial AD-causing mutations, but ectopic transgene overexpression makes it difficult to relate these abnormalities to disease pathogenesis. Alternatively, the APP/PS-1 double knock-in (DKI) mouse produces mutant amyloid precursor protein (APP) and presenilin-1 (PS-1) with normal levels and regulatory controls. Here, we investigated effects of amyloid on brain structure and neuroplasticity by vaccinating DKI mice with amyloid-beta starting at 8 months of age. At 14 months, vaccination blocked cerebral amyloid deposition and its attendant microglial activation. Neuropil abnormalities were pronounced only within plaques, and included circumscribed loss and dysmorphology of axons, dendrites, terminals and spines. Blockade of amyloid deposition restored neuropil integrity. Amyloid removal did not rescue reductions in the hippocampal neural progenitor and neuroblast populations, but adding 1 month of voluntary exercise to amyloid-beta vaccination markedly stimulated hippocampal neurogenesis. These results identify amyloid-dependent and -independent structural changes in the DKI mouse model of AD. Combining exercise with amyloid-directed immunotherapy produces greater restoration of brain structure and neuroplasticity than is achieved with either maneuver alone. PMID- 21257235 TI - Coexistence of narcolepsy and Alzheimer's disease. AB - A recent publication suggested that hypocretin (Hcrt, orexin) may mediate the neuropathological process leading to Alzheimer's disease (AD) and that antagonism of hypocretin receptors decreases this process. Narcoleptics have an approximately 90% loss of Hcrt neurons and commensurate reductions in the levels of Hcrt in their cerebrospinal fluid beginning at disease onset, usually before the age of 30. If Hcrt mediates the disease process, narcoleptics should be protected against AD. We examined the postmortem neuropathology and clinical records of 12 sequentially encountered cases of human narcolepsy. We found that AD was present in 4 of these narcoleptics, a prevalence that is similar to that of the general population. PMID- 21257236 TI - Response to Hood et al. (2010): 'A story of scrutiny and fear: Australian midwives' experiences of an external review of obstetric services, being involved with litigation and the impact on clinical practice'. PMID- 21257237 TI - The comminuted midshaft clavicle fracture: a biomechanical evaluation of plating methods. AB - BACKGROUND: The optimal plate location and fixation method for midshaft fractures of the clavicle remains undetermined. The objective of this study was to develop a realistic biomechanical model with which to compare superior with inferior medial plate placement, and the failure resistance of locked and against non locked constructs. METHODS: We estimated implant loads for operated patients in early rehabilitation utilising 3-D mathematical model of the shoulder. During simulation of upper limb motion associated with eating, the fracture opened in an inferior and frontal direction. The peak X, Y, and Z loads from the simulation were reproduced using a materials testing machine. A one centimetre transverse osteectomy was created at the midshaft of forty composite clavicles. Each specimen was then fixed with either (1) non-locked superior plating (n=10), (2) locked superior plating (n=10), (3) non-locked inferior-medial plating (n=10), or (4) locked inferior-medial plating (n=10). Specimens were loaded at 20 N/s in four-point bending for 50 cycles to the peak X, Y, Z moment obtained from the computational model (-3.50, 2.46, and -1.00 N m), then loaded to failure at 20 N/s. FINDINGS: Inferior-medial unlocked plates were significantly stiffer than superior locked plates (P=0.046). INTERPRETATION: Operative fixation of midshaft clavicle fractures is controversial, though becoming more widely accepted. Few biomechanical data are available to assist surgical decision-making. Inferior plates may be better equipped to resist the in vivo loads experienced by the clavicle during early rehabilitation after internal fixation, particularly during the shoulder flexion motions associated with eating. PMID- 21257238 TI - Reversal of thrombocytopenia in a pregnant woman after changing hemodiafiltration membranes. PMID- 21257239 TI - Cardiac testing for coronary artery disease in potential kidney transplant recipients: a systematic review of test accuracy studies. AB - BACKGROUND: Cardiovascular disease is the leading cause of death after kidney transplant. Screening for coronary artery disease is integral to pretransplant evaluation, although the relative performance of different tests is uncertain. STUDY DESIGN: Systematic review of diagnostic test accuracy studies using hierarchical summary receiver operating characteristic analysis. SETTING & POPULATION: Kidney transplant candidates undergoing pretransplant assessment. SELECTION CRITERIA OF STUDIES: Studies evaluating the accuracy of screening tests for detecting coronary artery disease. INDEX TESTS: Any non- or minimally invasive test used to diagnose coronary artery disease. REFERENCE TEST: Coronary angiography. RESULTS: 11 studies (690 participants) evaluated dobutamine stress echocardiography; 7 (317 participants), myocardial perfusion scintigraphy; 2 (129 participants), exercise stress electrocardiography; and 2 (121 participants), other tests. Dobutamine stress echocardiography had pooled sensitivity of 0.80 (95% CI, 0.64-0.90) and specificity of 0.89 (95% CI, 0.79-0.94). Myocardial perfusion scintigraphy had pooled sensitivity of 0.69 (95% CI, 0.48-0.85) and specificity of 0.77 (95% CI, 0.59-0.89). Head-to-head comparison of dobutamine stress echocardiography and myocardial perfusion scintigraphy (2 studies; 116 participants) showed that dobutamine stress echocardiography had higher specificity and at least equivalent or higher sensitivity. Indirect comparison suggested dobutamine stress echocardiography may have improved accuracy over myocardial perfusion scintigraphy (P = 0.07). LIMITATIONS: Power to detect differences in accuracy between tests is limited due to sparse data. Absence of significant coronary artery disease may not necessarily correlate with cardiac event-free survival after transplant. CONCLUSIONS: Dobutamine stress echocardiography may perform better than myocardial perfusion scintigraphy; however, additional studies directly comparing dobutamine stress echocardiography and myocardial perfusion scintigraphy are needed. Further research should focus on assessing the ability of functional tests to predict postoperative outcome. PMID- 21257240 TI - Dextran removal by plasmapheresis in a kidney-pancreas transplant recipient with dextran 40-induced osmotic nephrosis. AB - Osmotic nephrosis with acute kidney injury can follow the administration of colloid volume expanders and other hypertonic solutions. In the kidney transplant setting, such agents may be used in the donor before organ procurement and in the recipient during the perioperative period. We report a case of acute lung and kidney injury after infusion of dextran 40 immediately after surgery in a kidney pancreas transplant recipient. Osmotic nephrosis was confirmed by kidney biopsy, and a spectrophotometric assay was used to measure dextran 40 levels in serial serum samples. Plasmapheresis was initiated to decrease dextran 40 levels. Post hoc analysis confirmed that a single session of apheresis was sufficient to rapidly decrease dextran 40 levels without rebound, consistent with a small volume of distribution in a single-compartment model. PMID- 21257241 TI - Urine microscopy in acute kidney injury: time for a change. PMID- 21257242 TI - Kidney involvement in a patient affected by placental site trophoblastic tumor. AB - We report a 42-year-old woman who presents a few days after a spontaneous incomplete abortion at the ninth week of pregnancy with hypertension and nephrotic syndrome. Curettage findings and increased values for the beta subunit of human chorionic gonadotrophin were suspicious for a trophoblastic disease. A uterine placental site trophoblastic tumor was diagnosed 2 months later after hysterectomy and treated successfully using chemotherapy. Kidney biopsy showed features consistent with an unusual form of thrombotic microangiopathy characterized by the presence of large thrombus-like structures occluding the capillary lumina and smaller aggregates in the mesangium and along glomerular basement membranes. These deposits were positive for immunoglobulin M, C4, C1q, kappa and lambda light chains, and fibrinogen. Electron microscopy showed fibrin deposits located primarily in the subendothelial space. The differential diagnosis of this presentation included pre-eclamptic nephropathy, Waldenstrom disease, lupus anticoagulant glomerulonephritis, systemic lupus erythematosus, and cryoglobulinemic glomerulonephritis. We review the pathogenic mechanisms involved in this case. PMID- 21257243 TI - The relationship between kidney function and long-term graft survival after kidney transplant. AB - BACKGROUND: Whether chronic kidney disease (CKD) staging provides a useful framework for predicting outcomes after kidney transplant is unclear. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: We used data from the Patient Outcomes in Renal Transplantation (PORT) Study, including 13,671 transplants from 12 centers during 10 years of follow-up. PREDICTOR: Estimated glomerular filtration rate (eGFR; in milliliters per minute per 1.73 m(2)) at 12 months posttransplant. OUTCOMES: All-cause graft failure (a composite end point consisting of return to dialysis therapy, pre-emptive retransplant, or death with function), death-censored graft failure, and death with a functioning graft. MEASUREMENTS: The relationship between 12-month eGFR and subsequent graft outcomes through 10 years posttransplant was assessed using Cox proportional hazards analyses. RESULTS: Stage 3 included 63% of patients and was subdivided into stages 3a (eGFR, 45-59 mL/min/1.73 m(2); 34%) and 3b (eGFR, 30-44 mL/min/1.73 m(2); 29%). Compared with stage 2 (eGFR, 60-89 mL/min/1.73 m(2); 24%), adjusted Cox proportional HRs for graft failure were 1.12 (95% CI, 1.01 1.24; P = 0.04) for stage 3a, 1.50 (95% CI, 1.35-1.66; P < 0.001) for stage 3b, 2.86 (95% CI, 2.53-3.22; P < 0.001) for stage 4 (eGFR, 15-29 mL/min/1.73 m(2); 9%), and 13.2 (95% CI, 10.7-16.4; P < 0.001) for stage 5 (eGFR <15 mL/min/1.73 m(2); 1%). For stage 1 (eGFR >= 90 mL/min/1.73 m(2); 3%), risk of graft failure was increased (1.41 [95% CI, 1.13-1.75]; P < 0.001), likely due to serum creatinine associations independent of kidney function. Similar associations were seen between CKD stages and mortality. LIMITATIONS: Retrospective study; lack of gold-standard measurements of true GFR; lack of measures of comorbidity, inflammation, muscle mass, proteinuria, and other noncreatinine markers of eGFR. CONCLUSIONS: CKD stages validated in the general population provide a useful framework for predicting outcomes after kidney transplant. PMID- 21257244 TI - Recognition and management of CKD in primary care. PMID- 21257245 TI - Morphometric and biological characterization of biofilm in tunneled hemodialysis catheters. AB - BACKGROUND: Bacterial biofilm formation on hemodialysis tunneled cuffed catheters is under-recognized. We studied biofilm characteristics in patients with and without catheter-related bloodstream infection, accounting for catheter locking solution (citrate 4% or heparin 1:1,000). STUDY DESIGN: Prospective observational study. SETTING & PARTICIPANTS: 30 HD patients for whom the tunneled cuffed catheter was removed for either noninfectious reasons (n = 19) or bacteremia (n = 11). PREDICTORS: Bacteremia and catheter locking solution. OUTCOMES & MEASUREMENTS: Bacteria density in the biofilm, catheter luminal surface covered by biofilm, biofilm thickness, and exopolysaccharide content. RESULTS: Biofilm was present in all catheters. Overall, bacteria density, catheter surface coverage, biofilm thickness, and exopolysaccharide content were significantly higher in catheters from patients with bacteremia (5.3 [95% CI, 3.4-7.2] colony forming unit [CFU]/mL; 47% [95% CI, 34%-60%]; 41 [95% CI, 26-55] MUm; and 29.4% [95% CI, 20.1%-38.6%], respectively) than from patients without bacteremia (3.7 [95% CI, 3.6-3.8] CFU/mL; 17% [95% CI, 16%-19%]; 8.6 [95% CI, 7.3-9.8] MUm; and 5.3% [95% CI, 3.7%-6.8%], respectively). However, all biofilm parameters were lower in catheters from patients with bacteremia when citrate was used as locking agent. Furthermore, bacteria density (0.08 [95% CI, 0.02-0.13] CFU/mL/3 cm), biofilm thickness (1.4 [95% CI, 0.8-2.1] MUm/3 cm), and surface coverage (2.2% [95% CI, 1.8%-2.7%]/3 cm) decreased across the length of the catheter from tip to hub. LIMITATIONS: Observational study design, small numbers of patients, use of prevalent catheters. CONCLUSION: Biofilms are present in all tunneled cuffed catheters. However, the extent of the biofilm varied by the presence of bacteremia and type of locking solution. This method could be used to explore preventative measures. PMID- 21257246 TI - Serum concentrations of aluminum in hemodialysis patients. PMID- 21257247 TI - On the validity of self-reports and indirect reports to ascertain malaria prevalence in settings of hypoendemicity. AB - Self-reports are commonly used to ascertain malaria prevalence in epidemiological studies conducted in settings where laboratory diagnosis is impractical. Most studies, however, do not use self-report per se, but indirect report, where one respondent provides responses for all household members. Studies also vary in terms of the time frame used for this ascertainment. The aim of our research was to determine the validity of self-report and indirect report in ascertaining malaria prevalence over six, eighteen and thirty-month time periods. Reports of malaria episodes collected through interviewer-administered questionnaires (193 self-reports, 614 indirect reports) were compared to microscopy-confirmed cases (principally Plasmodium vivax) registered at a government-run health post in the Peruvian Amazon. Test parameters were estimated using a Bayesian latent class approach for imperfect gold standards. Logistic regression analyses were performed to explore determinants associated with accurate responses. Malaria self-report for the thirty-month period prevalence had the highest sensitivity (91.0%). Specificity was maximized when malaria prevalence was measured over the last six months for both self-report (91.6%) and indirect report (96.7%). Accuracy was highest for the six-month period prevalence in both self-report (91.3%) and indirect report (96.4%). Respondents who were female, had more education, or who provided a report on behalf of a child <= 12 years of age, were generally more accurate. Both self-report and indirect report provides accurate estimates of malaria prevalence, especially over shorter periods of time. The choice between self-report and indirect report should ultimately depend on the research question and the target study population. PMID- 21257248 TI - How personal experiences feature in women's accounts of use of information for decisions about antenatal diagnostic testing for foetal abnormality. AB - There has been a striking growth in the availability of health-related information based on personal experience in recent years and internet users are often drawn towards other people's stories about their health. Accounts of other people's experiences might convey social and emotional information that is not otherwise available but little is known about how it is used or the implications of its use in practice. This paper examines how people refer to information about other people's experiences when accounting for decisions about antenatal diagnostic testing for foetal abnormality. We conducted a secondary analysis of 37 qualitative interviews undertaken across the UK with 36 women and nine of their male partners (eight couples were interviewed together) who talked about diagnostic testing for foetal abnormality in 55 pregnancies. When describing their decisions, respondents referred to examples of knowledge gleaned from their own and other individuals' experiences as well as information based on biomedical or clinical-epidemiological research (usually about the probabilities of having a child affected by health problems or the probability of diagnostic tests causing miscarriage). Both forms of knowledge were employed in people's accounts to illustrate the legitimacy and internal coherence of decisions taken. The analysis demonstrates the personally idiosyncratic ways that people reflect on and incorporate different types of information to add meaning to abstract ideas about risk, to imagine the consequences for their own lives and to help them to make sense of the decisions they faced. PMID- 21257249 TI - Surgery-first accelerated orthognathic surgery: orthodontic guidelines and setup for model surgery. AB - The surgery-first approach indicates that the orthognathic surgery precedes the orthodontic treatment, whereas the orthodontics-first approach indicates that the orthodontic treatment precedes the orthognathic surgery. The conventional approach is an orthodontics-first approach. The purposes of this article are to introduce the concept of the surgery-first approach and to report the guidelines for orthodontic management and model surgery without presurgical orthodontic decompensation. The surgery-first approach treats facial esthetics first and then occlusion, whereas the conventional approach treats occlusion first and then facial esthetics. The surgery-first approach uses osteotomy to solve both skeletal problems and dental compensation, and a "transitional" occlusion is set up postoperatively. Orthodontics in the surgery-first approach is a postoperatively adjunctive treatment to transfigure the transitional occlusion into the solid final occlusion. The advantages of the surgery-first approach are that 1) the patient's chief complaint, dental function, and facial esthetics are achieved and improved in the beginning of the treatment; 2) the entire treatment period is shortened to 1 to 1.5 years or fewer depending on the complexity of orthodontic treatment; and 3) the phenomenon of postoperatively accelerated orthodontic tooth movement reduces the difficulty and treatment time of orthodontic management in the surgery-first approach. PMID- 21257250 TI - New 3-dimensional cephalometric analysis for orthognathic surgery. AB - Two basic problems have been associated with traditional 2-dimensional cephalometry. First, many important parameters cannot be measured on plain cephalograms; and second, most 2-dimensional cephalometric measurements are distorted in the presence of facial asymmetry. Three-dimensional cephalometry, which has been facilitated by the introduction of cone-beam computed tomography, can solve these problems. However, before this can be realized, fundamental problems must be solved. These include the unreliability of internal reference systems and some 3-dimensional measurements, and the lack of tools to assess and measure the symmetry. In the present report, we present a new 3-dimensional cephalometric analysis that uses different geometric approaches to solve these fundamental problems. The present analysis allows the accurate measurement of the size, shape, position, and orientation of the different facial units and incorporates a novel method to measure asymmetry. PMID- 21257251 TI - Quality of resuscitation: flight attendants in an airplane simulator use a new mechanical resuscitation device--a randomized simulation study. AB - PURPOSE: Cardiopulmonary resuscitation (CPR) during flight is challenging and has to be sustained for long periods. In this setting a mechanical-resuscitation device (MRD) might improve performance. In this study we compared the quality of resuscitation of trained flight attendants practicing either standard basic life support (BLS) or using a MRD in a cabin-simulator. METHODS: Prospective, open, randomized and crossover simulation study. Study participants, competent in standard BLS were trained to use the MRD to deliver both chest compressions and ventilation. 39 teams of two rescuers resuscitated a manikin for 12 min in random order, standard BLS or mechanically assisted resuscitation. Primary outcome was "absolute hands-off time" (sum of all periods during which no hand was placed on the chest minus ventilation time). Various parameters describing the quality of chest compression and ventilation were analysed as secondary outcome parameters. RESULTS: Use of the MRD led to significantly less "absolute hands-off time" (164+/-33 s vs. 205+/-42 s, p<0.001). The quality of chest compression was comparable among groups, except for a higher compression rate in the standard BLS group (123+/-14 min(-1) vs. 95+/-11 min(-1), p<0.001). Tidal volume was higher in the standard BLS group (0.48+/-0.14 l vs. 0.34+/-0.13 l, p<0.001), but we registered fewer gastric inflations in the MRD group (0.4+/-0.3% vs. 16.6+/ 16.9%, p<0.001). CONCLUSION: Using the MRD resulted in significantly less "absolute hands-off time", but less effective ventilation. The translation of higher chest compression rate into better outcome, as shown in other studies previously, has to be investigated in another human outcome study. PMID- 21257252 TI - Pulmonary artery air embolism after blunt trauma. PMID- 21257253 TI - Training rates and willingness to perform CPR in King County, Washington: a community survey. AB - BACKGROUND: It has been hypothesized that high rates of cardiopulmonary resuscitation (CPR) training in a community will lead to improved survival for out-of-hospital cardiac arrest. However, factors to consider when designing a far reaching community CPR training program are not well defined. We explored factors associated with receiving CPR training in the survey community and characteristics contributing to willingness to perform CPR in an emergency. METHODS: A telephone survey was administered to 1001 randomly selected residents in September 2008 assessing CPR training history, demographics, and willingness to perform CPR. Characteristics of survey respondents were compared to examine factors that may be associated with reports of being trained compared to reports of never being trained. A stratified analysis compared characteristics of respondents who reported a high level of willingness to perform CPR in those trained compared to those never trained. RESULTS: The survey response rate was 39%. Seventy-nine percent of survey respondents reported ever attending a CPR training class. A majority of people (53%) attended their most recent class more than five years ago. People who had never been trained in CPR were older, were more likely to be men and were less likely to have at least a 2-year college degree than those who had ever been trained. Among those who had been trained, younger age, male gender, time of last training and number of times trained were all significantly associated with willingness to perform CPR and none of these factors were associated with willingness in those who had not been trained. CONCLUSIONS: Retraining rates, methods for reaching underserved populations and measures that will improve the likelihood that bystanders will perform CPR in an emergency should be considered when designing a community CPR education program. PMID- 21257254 TI - Evaluation of adrenocortical function in 3-7 aged asthmatic children treated with moderate doses of fluticasone propionate: reliability of dehydroepiandrosterone sulphate (dhea-s) as a screening test. AB - BACKGROUND: Inhaled corticosteroids (ICS) are the first-line therapy in the treatment of persistent asthma. At medium to high doses and prolonged usage, ICS can supresss the hypothalamic-pituitary-adrenal axis. Dehydroepiandrosterone sulphate (DHEA-S) is a corticotropin-dependent adrenal androgen precursor that is supressible in patients treated with ICS. OBJECTIVES: To evaluate the adrenal axis in asthmatic children treated with moderate doses of fluticasone propionate and to evaluate the DHEA-S as a possible marker for adrenal axis in preadrenarchal children. METHODS: Twenty-eight children with persistent asthma with a mean age of 4.4 years (median 4.2; range 2.5-7.1) on long term treatment (mean 6.16; median 6; range 4.5-9 months) with moderate doses (mean 250; median 253; range 158-347 (g/m(2)/day) of inhaled fluticasone propionate were evaluated with low-dose ACTH stimulation test to assess adrenal function, and DHEA-S levels were compared with the results. RESULTS: One out of 28 patients (3.57%) demonstrated an abnormal cortisol response to low-dose ACTH test. There was no correlation between DHEA-S and peak cortisol, morning cortisol and fasting blood glucose levels. However, mean inhaled corticosteroid dosages were inversely correlated with the DHEA-S. CONCLUSIONS: In most of the children with persistent asthma, mild to moderate fluticazone propionate doses supress the hypothalamic pituitary-adrenal axis rarely. Chronic moderate doses of ICS may suppress adrenal androgen levels without supression of cortisol production. DHEA-S levels may be used as a practical method to follow adrenal functions and may be an earlier indicator of adrenal dysfunction in children. PMID- 21257255 TI - De novo urgency after tension-free vaginal tape versus transobturator tape procedure for stress urinary incontinence. AB - OBJECTIVE: To determine the frequency of de novo urgency after tension-free vaginal tape (TVT) compared with the transobturator tape (TOT) procedure in women with stress urinary incontinence (SUI). STUDY DESIGN: Prospective study of all consecutive women with urodynamically confirmed SUI undergoing anti-incontinence surgery between January 2000 and January 2008. All procedures were performed by experienced urogynaecologists well trained in TVT and TOT surgery. Assessments were carried out at 1, 6, 12 and, 36 months after surgery. RESULTS: The study population included 366 women (mean age 59.5 years), 243 in the TVT group and 123 in the TOT group. The groups were similar in terms of demographics, preoperative data, and cure rates. De novo urgency occurred in 13.4% of patients at 6 months after surgery, in 19.3% at 12 months, and in 22.1% at 36 months. De novo urgency was significantly more frequent in the TVT group than in the TOT group at 12 (22.2% vs 11.2%, P=0.025), 24 (24.8% vs 12.3%, P=0.033), and 36 (0% vs 24.7%, P=0.034) months. Cure rates were similar in both groups. The final adjusted cure rate was 87.3% (319/366). CONCLUSION: Treatment of SUI using the TOT procedure was associated with a lower rate of de novo urgency. PMID- 21257256 TI - Use of peripartum ST analysis of fetal electrocardiogram without blood sampling: a large prospective cohort study. AB - OBJECTIVE: Fetal peripartum surveillance with ST analysis of fetal electrocardiogram (STAN) alone or in combination with fetal blood sampling (FBS) is a worldwide debate. STAN monitoring without FBS support was implemented in 2000 in the authors' department when it took part in a European multicentre project. The aim of this study was to evaluate neonatal outcomes associated with peripartum STAN monitoring without FBS support in a large prospective cohort of patients at high risk of peripartum fetal asphyxia. STUDY DESIGN: This prospective cohort study included all consecutive high-risk women monitored with STAN technology over a 77-month period, excluding fetuses with congenital anomalies. Outcome variables were fetal metabolic acidosis, umbilical pH<=7.05 and normal extracellular base deficit, transfer to a neonatal intensive care unit, neonatal encephalopathy and neonatal death related to peripartum asphyxia. Cases with metabolic acidosis were reviewed by a referent midwife and referent obstetricians to check whether or not labour management was consistent with the STAN guidelines. RESULTS: In total, 3112 women were included in the study. The caesarean section rate for suspected fetal distress was 9.5% [95% confidence interval (CI) 8.5-10.5]. Acid-base status was available for 3067 (98.5%) neonates. There were 14 cases of fetal metabolic acidosis (0.45%; 95% CI 0.2 0.7), 62 cases with umbilical pH <= 7.05 and normal extracellular base deficit (2%; 95% CI 1.5-2.5), 27 neonates with 5-min Apgar scores <= 7 (0.87%; 95% CI 0.54-1.20) and 16 neonates were transferred to the neonatal intensive care unit (0.51%; 95% CI 0.26-0.76) due to peripartum asphyxia. No cases of neonatal encephalopathy, or fetal or neonatal death occurred. Out of the 14 cases of fetal metabolic acidosis, 11 were not managed in accordance with the STAN guidelines. Specificity was 80.5% and the negative predictive value was 99.9%. Sensitivity was highly affected by medical staff interpretation, varying from 9.1% in the authors' experience to 90.9% with appropriate labour management according to the STAN guidelines. CONCLUSIONS: STAN monitoring without FBS support was associated with a low rate of fetal metabolic acidosis. Most cases of fetal metabolic acidosis were not managed in accordance with the STAN guidelines. This study not only supports STAN usage without FBS support, but also warns of possible guideline violations and subsequent adverse neonatal outcomes. PMID- 21257257 TI - Maximizing cure for muscle-invasive bladder cancer: integration of surgery and chemotherapy. AB - CONTEXT: The optimal treatment strategy for muscle-invasive bladder cancer remains controversial. OBJECTIVE: To determine optimal combination of chemotherapy and surgery aimed at preserving survival of patients with locally advanced bladder cancer. EVIDENCE ACQUISITION: We performed a critical review of the published abstract and presentation literature on combined modality therapy for muscle-invasive bladder cancer. We emphasized articles of the highest scientific level, combining radical cystectomy and perioperative chemotherapy with curative intent to affect overall and disease-specific survival. EVIDENCE SYNTHESIS: Locally invasive, regional, and occult micrometastases at the time of radical cystectomy lead to both distant and local failure, causing bladder cancer deaths. Neoadjuvant and adjuvant chemotherapy regimens have been evaluated, as well as the quality of cystectomy and pelvic lymph node dissection. CONCLUSIONS: Prospective, randomized clinical trials argue strongly for neoadjuvant cisplatin based chemotherapy followed by high-quality cystectomy performed by an experienced surgeon operating in a high-volume center. Adjuvant chemotherapy after surgery is also effective when therapeutic doses can be given in a timely fashion. Both contribute to improved overall survival; however, many patients receive only one or none of these options, and the barriers to receiving optimal, combined, systemic therapy and surgery remain to be defined. An aging, comorbid, and often unfit population increasingly affected by bladder cancer poses significant challenges in management of individual patients. PMID- 21257258 TI - Extent of pelvic lymph node dissection and the impact of standard template dissection on nomogram prediction of lymph node involvement. AB - BACKGROUND: Our current lymph node involvement (LNI) nomogram was created using patients receiving both limited and standard lymph node dissection (LND). Over time, refinements in technique could affect the diagnostic yield from LND. OBJECTIVE: Our aim was to validate our existing LNI nomogram or develop a new nomogram with updated prediction coefficients that reflect the current standard LND template during radical prostatectomy (RP). We hypothesized that the existing nomogram would demonstrate good discrimination but poor calibration in a contemporary series of standard LND. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of 4176 consecutive primary RP patients was performed, including open procedures (3097 patients from 2000 to 2008) and laparoscopic procedures (1079 patients from 2005 to 2008). After excluding 127 patients (3%) with limited LND, 10 (0.2%) with pretreatment prostate-specific antigen (PSA) >50 ng/ml, and 318 (8%) with incomplete data, the final cohort totaled 3721 patients. The nomograms were evaluated using receiver operating characteristic analysis, calibration plots, and decision-curve analysis. INTERVENTIONS: Patients received open or laparoscopic (conventional and robot-assisted) RP and standard LND in our center. MEASUREMENTS: Assessments were obtained using preoperative PSA, biopsy Gleason score, and clinical stage. RESULTS AND LIMITATIONS: The median number of nodes removed was 11, with ~60% of patients having at least 10 nodes removed (n=2224). Overall, 5.2% of patients (n=194) had positive lymph nodes. The new nomogram had very high discriminative accuracy (area under the curve: 0.862). The decision-curve analysis showed that the new nomogram had the highest clinical net benefit for all reasonable threshold probabilities. CONCLUSIONS: The new nomogram shows improved calibration when predicting lymph node invasion in a contemporary cohort of patients with prostate cancer exclusively treated with RP and standard LND. This nomogram will be used as the preferred predictive model for counseling patients and developing studies at our institution. PMID- 21257259 TI - Green tea epigallocatechin gallate enhances therapeutic efficacy of temozolomide in orthotopic mouse glioblastoma models. AB - The alkylating agent temozolomide, in combination with surgery and radiation, is the current standard of care for patients with glioblastoma. However, despite this extensive therapeutic effort, the inclusion of temozolomide extends survival only by a few short months. Among the factors contributing to chemoresistance is elevated expression of the endoplasmic reticulum (ER) chaperone GRP78 (glucose regulated protein 78; BiP), a key pro-survival component of the ER stress response system. Because the green tea component EGCG (epigallocatechin 3 gallate) had been shown to inhibit GRP78 function, we investigated whether this polyphenolic agent would be able to increase the therapeutic efficacy of temozolomide in preclinical models of glioblastoma. Mice with intracranially implanted human U87 (p53 wild type) or U251 (p53 mutant) glioblastoma cells were treated with temozolomide and EGCG, alone and in combination. We found that EGCG alone did not provide survival benefit, but significantly improved the existing therapeutic effect of temozolomide, i.e., life extension was substantially greater under combination therapy as compared to temozolomide therapy alone. Immunohistochemical analysis of tumor tissue revealed increased expression levels of GRP78 in temozolomide-treated animals, which was diminished when temozolomide was combined with EGCG. Parallel in vitro experiments with siRNA targeting GRP78 or its major pro-apoptotic antagonist CHOP (CCAAT/enhancer binding protein homologous protein/GADD153) further established a critical role of the ER stress response system, where si-GRP78 sensitized cells to treatment with temozolomide, and si-CHOP provided protection from drug-induced toxicity. Thus, ER stress regulatory components affect the chemotherapeutic response of glioblastoma cells to treatment with temozolomide, and inclusion of EGCG is able to increase the therapeutic efficacy of this DNA-damaging agent. PMID- 21257260 TI - Laboratory investigations of stormwater remediation via slag: Effects of metals on phosphorus removal. AB - The use of electric arc furnace (EAF) slag for the removal of phosphorus (P) from various simulated stormwater blends was investigated in the laboratory. The form of P measured was the inorganic orthophosphate (PO(4)-P). The stormwater solutions used in this preliminary study were synthesized as blends of P and typical concentrations of some of the most common and abundant metals in stormwater (e.g. cadmium, copper, lead and zinc), and contacted with EAF slag to determine P removal efficiency and sorptive competition. Results showed that the presence of cadmium, lead and zinc had minimal effect on the removal process; copper was a significant inhibitor of P uptake by the EAF slag media. P removal was greatest in the metal-free and multi-metal stormwater solutions. PMID- 21257261 TI - Potential risks of metal toxicity in contaminated sediments of Deule river in northern France. AB - The aim of this paper was to evaluate the potential sediment cumulative damage and toxicity due to metal contamination in a polluted zone of Deule river (in northern France) from nearby two smelters. Metal-enrichment factors and geoaccumulation indices measured with sediment depth revealed that--compared to background levels either in local reference soils or in world rivers sediments/suspended particulate matter--Cd contributed to the highest pollution levels, followed by Zn, Pb and to a much lesser extent Cu and Ni. A comparison of the vertical distribution of AVS (acid volatile sulfides), SEM (simultaneously extracted metals), TMC (total metal concentrations), TOC (total organic carbon) and interstitial water-metal concentrations in the sediment allowed us to highlight the extent of toxicity caused by Cd, Pb, Zn, Ni and Cu and to raise the possibility of their association with certain geochemical phases. To assess the actual environmental impacts of these metals in Deule river, numerical sediment quality guidelines were further used in the present work. Sedimentary Pb, Zn, and Cd contents largely exceeded PEC (probable effect concentration) values reported as consensus-based sediment quality guidelines for freshwater ecosystems. As for risks of toxicity from pore waters, metal concentrations reached their maxima at the surficial layers of the sediment (1-3 cm) and IWCTU (Interstitial Water Criteria Toxicity Unit) observed for Pb and to a lesser extent Cd, violated the corresponding water quality data recommended by USEPA. PMID- 21257262 TI - Photodegradation mechanism and kinetics of methyl orange catalyzed by Fe(III) and citric acid. AB - In this study, the photodegradation process of methyl orange (MO) catalyzed by Fe(III) and citric acid and the reaction kinetics were investigated in detail at pHs from 2 to 8. The results show that the photodegradation of MO is slow in the presence of Fe(III) or citric acid alone. However, it is markedly enhanced when Fe(III) and citric acid coexist. High initial citric acid or initial Fe(III) concentrations lead to increased photodegradation of MO. And Fe(III) citrate mediated photodegradation of MO is optimized at pH 6. The photoproduction of hydroxyl radicals (.OH) in different catalytic systems was determined by HPLC. And the concentrations of Fe(II) and citric acid concentration in the process of the reaction were analyzed. The photodegradation of MO obeys to pseudo-zero order kinetics with respect to MO and the degradation reaction occurs in two phases. At the initial initiation stage, degradation rate is relatively slow, and significantly increases at a later acceleration stage. PMID- 21257263 TI - A randomised, five-parallel-group, placebo-controlled trial comparing the efficacy and tolerability of analgesic combinations including a novel single tablet combination of ibuprofen/paracetamol for postoperative dental pain. AB - Combination analgesia is often recommended for the relief of severe pain. This was a double-blind, 5-arm, parallel-group, placebo-controlled, randomised, single dose study designed to compare the efficacy and tolerability of a novel single tablet combination of ibuprofen and paracetamol with that of an ibuprofen/codeine combination, and a paracetamol/codeine combination, using the dental impaction pain model. Subjects with at least 3 impacted third molars and experiencing moderate to severe postoperative pain were randomised to receive: 1 or 2 tablets of a single-tablet combination of ibuprofen 200mg/paracetamol 500mg; 2 tablets of ibuprofen 200 mg/codeine 12.8mg; 2 tablets of paracetamol 500mg/codeine 15mg; or placebo. Results for the primary endpoint, the sum of the mean scores of pain relief combined with pain intensity differences over 12hours, demonstrated that 1 and 2 tablets of the single-tablet combination of ibuprofen/paracetamol were statistically significantly more efficacious than 2 tablets of placebo (P<0.0001) and paracetamol/codeine (P?0.0001); furthermore, 2 tablets offered significantly superior pain relief to ibuprofen/codeine (P=0.0001), and 1 tablet was found noninferior to this combination. Adverse events were uncommon during this study and treatment emergent adverse events were statistically significantly less frequent in the groups taking the ibuprofen/paracetamol combination compared with codeine combinations. In conclusion, 1 or 2 tablets of a single-tablet combination of ibuprofen 200mg/paracetamol 500mg provided highly effective analgesia that was comparable with, or superior to, other combination analgesics currently indicated for strong pain. A single-tablet combination of ibuprofen 200mg/paracetamol 500mg provides highly effective analgesia, comparable or superior to other combination analgesics indicated for strong pain. PMID- 21257264 TI - Vaginal allodynia as the presentation of a thalamic tumor. AB - Central pain syndromes associated with damage to the thalamic sensory relay nuclei have been described predominantly in the stroke literature; however, pain syndromes associated with thalamic neoplasms are much less common. We describe a woman with dyspareunia secondary to vaginal allodynia as the presenting sign of a left thalamic juvenile pilocytic astrocytoma. Subsequent to an uneventful stereotactic biopsy, her vaginal allodynia progressed to hemi-body allodynia. We believe that this is the first reported case of isolated vaginal allodynia associated with a thalamic neoplasm or any other structural pathology of the central nervous system. Dyspareunia secondary to vaginal allodynia as the presenting sign of a left thalamic juvenile pilocytic astrocytoma is reported, in a rare case underscoring that thalamic pathology including neoplasms should be considered in evaluating patients with longstanding and unexplained pain syndromes. PMID- 21257265 TI - Using atom probe tomography to analyse MAX-phase materials. AB - Ti(2)AlC belongs to an interesting group of materials with both metallic and ceramic properties. This material is highly attractive as a candidate for corrosion resistant coatings. The process of fabrication of such coatings is in the investigation stage only and the detailed knowledge of the structure and chemistry of the produced coatings is important for optimisation of their properties. In this work the applicability of atom probe tomography for investigation of both Ti(2)AlC bulk materials and coatings was tested. We show that for the first time, Ti(2)AlC has successfully been analysed using laser pulsing mode in a local electrode atom probe and the results from analysis of both bulk Ti(2)AlC and Ti(2)AlC based spray deposited coatings are presented. It appears that, in this particular material system, it is difficult to obtain the accurate stoichiometry. This is due to the loss of detection because of unavoidable multiple events and due to the peak overlaps present. Methods of how to approach these problems are discussed. PMID- 21257267 TI - The process of decompression in acute burns. PMID- 21257268 TI - Changes in cutaneous innervation in patients with chronic pain after burns. AB - BACKGROUND: Chronic pain is a common occurrence for burn patients and has significant impact on quality of life. However, the etiology is not well understood. Understanding the mechanisms underlying the restoration of sensory function and the development of chronic pain after burn is critical to improving long-term outcomes. OBJECTIVE: To determine whether cutaneous innervation in burn patients with chronic pain is altered when compared to patients without chronic pain. METHODS: Twelve patients with unilateral injury and who reported chronic pain were recruited. Each patient underwent sensory function testing and both scar and matched site uninjured skin biopsy. Biopsies were analyzed for total nerve density and nociceptive C-fiber density using immunohistochemistry. Results were compared to a control group of 33 patients with unilateral injury and no reported long-term pain. RESULTS: Sensory function was significantly diminished in scar compared to uninjured tissue in both study groups, but chronic pain patients did not have significantly diminished function when compared to control. Total nerve density was not significantly different between scar and uninjured sites in either group, or between groups. However, the density of nociceptive nerve fibers was significantly elevated in both uninjured (p=0.0193) and scar sites (p=0.0316) of the patients with chronic pain when compared to the control group. CONCLUSIONS: This data suggests that differences in cutaneous innervation may contribute to chronic pain after burn. There also appears to be a systemic difference in cutaneous innervation extending to distal uninjured sites. Therefore efforts to affect cutaneous reinnervation after burn may lead to less patients experiencing chronic pain. PMID- 21257270 TI - Maintenance chemotherapy for non-small-cell lung cancer. AB - Currently, platinum-based combination chemotherapy is the standard first-line chemotherapy for non-small-cell lung cancer (NSCLC). Historically, platinum-based chemotherapy has been recommended for up to six cycles even for responders, and second-line chemotherapy has been considered when disease progression is confirmed. In spite of extensive investigations into maintenance chemotherapy, no positive data have been obtained; however, the results of recent clinical trials suggest both the safety and efficacy of maintenance chemotherapy in patients with NSCLC, although it is still controversial. In this review, we summarize the major clinical trials of maintenance chemotherapy in patients with NSCLC, and discuss its clinical validity and present future perspectives. PMID- 21257269 TI - Small cell carcinoma of the upper urinary tract (UUT-SCC): report of a rare entity and systematic review of the literature. AB - BACKGROUND: Primary small cell carcinoma of the upper urinary tract (UUT-SCC) is an extremely uncommon disease. The current knowledge of these rare tumors is mainly based on case reports or small series. METHODS: We reported two cases and performed a systematic literature search from 1970 to 2010 for articles on UUT SCC. Overall, 40 patients with UUT-SCC were reviewed, a database was generated to analyze clinical characteristics, pathological features and therapy outcomes and to attempt in identifying prognostic factors. RESULTS: For the 39 cases with available data, median age was 66.5 years and male-female ratio was 2:1. An Asian ethnic background was more common (59%). Surgery was the standard treatment given to all patients. In 67% of cases, SCC coexisted with another malignant component, including urothelial carcinoma in 62% of patients. Overall median survival was 15 months and the 1-, 2- and 3-year survival rates were 58.4%, 38.1% and 23.8%, respectively. Of all cases, 53.8% developed detectable metastasis in a median delay of 13 months. Pathological stage was the only significant prognostic factor found (p=0.01). Patients who received adjuvant chemotherapy seem to have a higher median survival comparatively to those who did not receive chemotherapy but this was not statistically significant (24 vs. 12 months, p=0.56). CONCLUSIONS: UUT SCC is an extremely rare tumor characterized by an aggressive clinical course. Local or distant metastases are frequent and survival is poor. Pathological stage appeared to be a prognostic factor for overall survival. PMID- 21257271 TI - Tryptophan hydroxylase-2 (TPH2) in disorders of cognitive control and emotion regulation: a perspective. AB - Based on genetic variation, there is accumulating evidence that altered function of tryptophan hydroxylase-2 (TPH2), the enzyme critical for synthesis of serotonin (5-HT) in the brain, plays a role in anxiety-, aggression- and depression-related personality traits and in the pathogenesis of disorders featuring deficits in cognitive control and emotion regulation. Here, we appraise the genetic and neurobiological evidence to illustrate the critical role of TPH2 in central 5-HT system function and in the pathophysiology of a wide spectrum of disorders of cognitive control and emotion regulation, ranging from depression to attention-deficit/hyperactivity disorder (ADHD), a phenotype commonly associated with difficulties in the control of emotion and with a high co-morbidity of depression. Findings from psychophysiological and functional imaging studies are indicative of various TPH2 polymorphisms directly influencing serotonergic function and thus impacting on mood disorders and on the response to antidepressant treatment. Especially a combination with uncontrollable stress seems to potentiate these effects linking gene-environment interaction directly with behavioral dysfunction in human and animal models. TPH2-deficient mice display alterations in anxiety-like behavior which is accompanied by adaptational changes of 5-HT(1A) receptors and its associated signaling pathway. Mouse models in conjunction with cognitive neuroscience approaches in humans are providing unexpected results and it may well be that future research on TPH2 will provide an entirely new view of 5-HT in brain development and function related to neuropsychiatric disorders. PMID- 21257272 TI - [Ogilvie's syndrome following cesarean section: Just think! Report of two cases and review of the literature]. AB - OBJECTIVES: To identify clinical and radiological signs of the post-cesarean Ogilvie's syndrome in order to establish the appropriate treatment. PATIENTS AND METHODS: Based on the Medline research, we listed 41 cases of Ogilvie's syndrome after cesarean section. We analyzed the patient's age, the clinical and radiological signs, the time to diagnosis, and the treatments and their efficiency. RESULTS: The clinical signs generally appear in the first 72 h after cesarean. Diagnosis of Ogilvie's syndrome is based on a clinical picture of acute obstruction of the large bowel and by X-ray showing a large caecum without pathological lesion. If the caecal diameter is under 12 cm, conservative treatment is done with colonoscopic decompression when necessary, however if there are signs of peritonitis surgery is recommended. CONCLUSION: Ogilvie's syndrome after cesarean section is uncommon. Diagnosis must be fast in order to avoid the caecum to burst causing faecal peritonitis, which carries slight mortality rate. PMID- 21257273 TI - [Assessment of anxiety, pain and its management in prenatal diagnosis procedures]. AB - Invasive prenatal diagnosis procedures are numerous and more or less painful and stressful. The purpose of this study was to investigate maternal perception of both anxiety and pain before and after amniocentesis (AC) or transabdominal chorionic villus sampling (CVS), to determine factors associated with pain and anxiety, and to evaluate the pain support. This is a prospective study evaluating the professional practices at CHRU of Lille between March and May 2009 with 132 AC and 22 CVS by aspiration. An original questionnaire has been elaborated in three parts: the first one fulfilled by patients before the procedure, the second one, after the procedure, and the last one by the medical team. Statistical comparisons have used the Chi(2) test, the Fisher exact test, the Student's t test and the U test of Mann Whitney. RESULTS: The anxiety level is high but does not differ between the two groups AC and CVS. CVS are more painful than AC (EVA 5.77 versus 3.07, P<0.0001). No predisposing factor for anxiety has been found. On the other side, procedures are more painful when they are long lasting, considered difficult by the medical team, when needles used are large, the number of needle insertions increases, puncture is performed along a side of the uterus, patients are anxious, and then procedure indication is an hygroma. Patients are satisfied in 98.7% of cases of the support of the medical team. Few drug treatments was prescribed (only 4.5%), however, patients are generally applicant. CONCLUSION: An analgesic, anxiolytic, or a relaxation technique can be proposed to anxious and applicant patients undergoing CVS. Technical conditions of the procedure are more difficult to improve, however, we should use if possible thinner needles, and avoid, wherever technically possible, the punctures on the lateral side of the uterus. Finally, further studies seem necessary for the evaluation of a treatment protocol. PMID- 21257274 TI - Standardized measures for substance use stigma. AB - Despite indications that the stigma associated with substance use is high and may play a role in discouraging treatment participation, there is limited research in this area and only a few psychometrically sound measures of substance use stigma exist. The purpose of this study was to formulate and evaluate the psychometric properties of three substance use stigma measures. College students (N=565) completed three measures of substance use stigma that were modified from three established measures of mental illness stigma. Two of the three modified measures (Social Distance Scale for Substance Users and Affect Scale for Substance Users) emerged as having acceptable psychometric properties, whereas one modified measure (Dangerousness Scale for Substance Users) had inadequate psychometric properties. In regard to sex differences, women had significantly higher substance use stigma on the two psychometrically sound measures (p<.01). Perhaps, with standardized measures, there can be greater progress towards better understanding the mechanisms leading to high levels of substance use stigma and ultimately address failures to seek out treatment due to stigma. PMID- 21257275 TI - Conducting a respondent-driven sampling survey with the use of existing resources in Sydney, Australia. AB - BACKGROUND: Respondent-driven sampling (RDS) is a form of chain-referral sampling that is increasingly being used for HIV behavioural surveillance. When used for surveillance purposes, a sampling method should be relatively inexpensive and simple to operate. This study examined whether an RDS survey of people who inject drugs (PWID) in Sydney, Australia, could be successfully conducted through the use of minimal and existing resources. METHOD: The RDS survey was conducted on the premises of a local needle and syringe program (NSP) with some adjustments to take into account the constraints of existing resources. The impact of the survey on clients and on staff was examined by summarizing NSP service data and by conducting post-survey discussions with NSP staff. RESULTS: From November 2009 till March 2010, 261 participants were recruited in 16 waves. A significant increase was found in the number of services provided by the NSP during and after data collection. Generally, staff felt that the survey had a positive impact by exposing a broader group of people to the NSP. However, conducting the survey may have led to privacy issues for NSP clients due to an increased number of people gathering around the NSP. CONCLUSIONS: This study shows that RDS can be conducted with the use of minimal and existing resources under certain conditions (e.g., use of a self-administered questionnaire and no biological samples taken). A more detailed cost-utility analysis is needed to determine whether RDS' advantages outweigh potential challenges when compared to simpler and less costly convenience methods. PMID- 21257276 TI - Surgical management of cervical chyloma following parathyroidectomy. AB - Although rare, chylomas can present as a neck mass, especially in the post operative setting. Here, we present a case of a persistent cervical chyloma following parathyroidectomy and propose a management algorithm for this clinical entity. PMID- 21257277 TI - [Schools meals in French secondary state schools: compliance to national recommendations and schools catering patterns]. AB - BACKGROUND: Recent reports on the lack of nutritional quality of meals served in schools have led public authorities to draft, in 1999, recommendations for restoring a balanced food supply. Following the survey carried out by the French food safety Agency in 2005-2006, which highlighted gaps in the implementation of these recommendations, a law passed in July 2010 plans to make these recommendations mandatory, as their 2007 revised version. Thus, the objective of this study was to assess initial school compliance with regard to this last revised version of the recommendations and to identify school patterns through their catering management and implication in a dietary project. METHODS: Seven hundred and seven secondary state schools were questioned (570 were administrated by the Ministry of Education and 137 by the Ministry of Agriculture) on their catering practices. Twenty consecutive menus from each school were also analyzed with a specific coding system to establish its nutritional composition for comparison with the 2007 recommendations. RESULTS: On average, schools complied with half of the recommendations. Good compliance was observed with the 2007 recommendations concerning fried products, starchy foods, fruits, and dairy products whereas very few schools were in compliance with recommendations concerning fish, cheeses and sweetened desserts containing less than 15 % fat and more than 20 g of sugar per portion. Furthermore, compliance with recommendations was significantly better for lunch meals, and even better for agricultural establishments. A 5-component meal was also associated with greater compliance with the recommendations. In addition, four school patterns were identified based on catering management practices. The first two categories of establishments had knowledge of the recommendations but exhibited different levels of application. The last two types of establishments had no knowledge of the recommendations and differed in their catering management practices. CONCLUSION: Compliance with recommendations was contrasted, with high adequacy for some guidelines and low for others. Nevertheless, application of the current guidelines and real implication of the school in a dietary project did improve the dietary offer in such schools. PMID- 21257278 TI - Classification and identification of the Burkholderia cepacia complex: Past, present and future. AB - The Burkholderia cepacia complex is a group of closely related species with conflicting biological properties. Triggered by the devastating effect of pulmonary infections in cystic fibrosis patients, the scientific community generated an unusually large amount of taxonomic data for these bacteria during the past 15 years. This review presents the polyphasic, multilocus and genomic methodology used for the classification and identification of these bacteria. The current state-of-the-art demonstrates that present day taxonomists can replace traditional DNA-DNA hybridizations for species level demarcation and 16S rRNA sequence analysis for studying phylogeny by superior whole genome sequence-based parameters within the framework of polyphasic taxonomic studies. PMID- 21257279 TI - Tracing the transition of methicillin resistance in sub-populations of Staphylococcus aureus, using SELDI-TOF Mass Spectrometry and Artificial Neural Network Analysis. AB - Strains (n=99) of Staphylococcus aureus isolated from a large number of clinical sources and tested for methicillin sensitivity were analysed by MALDI-TOF-MS using the Weak Cation Exchange (CM10) ProteinChip Array (designated SELDI-TOF MS). The profile data generated was analysed using Artificial Neural Network (ANN) Analysis modelling techniques. Seven key ions identified by the ANNs that were predictive of MRSA and MSSA were validated by incorporation into a model. This model exhibited an area under the ROC curve value of 0.9147 indicating the potential application of this approach for rapidly characterising MRSA and MSSA isolates. Nearly all strains (n=97) were correctly assigned to the correct group, with only two aberrant MSSA strains being misclassified. However, approximately 21% of the strains appeared to be in a process of transition as resistance to methicillin was being acquired. PMID- 21257280 TI - Sharing qualitative research findings with participants: study experiences of methodological and ethical dilemmas. AB - OBJECTIVE: Sharing qualitative research findings with participants, namely member check, is perceived as a procedure designed to enhance study credibility and participant involvement. It is rarely used, however, and its methodological usefulness and ethical problems have been questioned. This article explores benefits and risks in applying member-check when studying healthcare topics, questioning the way it should be performed. METHODS: We discuss researchers' experiences in applying member-check, using four examples from three different studies: healthcare-providers' experiences of working with sexual-abuse survivors; adolescents' exposure to domestic-violence, and delivering and receiving bad news. RESULTS: Methodological and ethical difficulties can arise when performing member-check, challenging the day-to-day researcher-participant experience, and potentially, the physician-patient relationship. CONCLUSION: Applying member-check in healthcare settings is complex. Although this strategy has good intentions, it is not necessarily the best method for achieving credibility. Harm can be caused to participants, researchers and the doctor patient relationship, risking researchers' commitment to ethical principles. PRACTICE IMPLICATIONS: Because participants' experience regarding member-check is difficult to predict, such a procedure should be undertaken cautiously. Prior to initiating member-check, researchers should ask themselves whether such a procedure is potentially risky for participants; and if anonymity cannot be guaranteed, use alternative procedures when needed. PMID- 21257281 TI - Burnout among the addiction counseling workforce: the differential roles of mindfulness and values-based processes and work-site factors. AB - Although work-site factors have been shown to be a consistent predictor of burnout, the importance of mindfulness and values-based processes among addiction counselors has been little examined. In this study, we explored how strongly experiential avoidance, cognitive fusion, and values commitment related to burnout after controlling for well-established work-site factors (job control, coworker support, supervisor support, salary, workload, and tenure). We conducted a cross-sectional survey among 699 addiction counselors working for urban substance abuse treatment providers in six states of the United States. Results corroborated the importance of work-site factors for burnout reduction in this specific population, but we found that mindfulness and values-based processes had a stronger and more consistent relationship with burnout as compared with work site factors. We conclude that interventions that target experiential avoidance, cognitive fusion, and values commitment may provide a possible new direction for the reduction of burnout among addiction counselors. PMID- 21257282 TI - Lessons from five states: public sector use of the Washington Circle performance measures. AB - Five states (Connecticut, Massachusetts, New York, North Carolina, and Oklahoma) have incorporated the Washington Circle (WC) substance abuse performance measures in various ways into their quality improvement strategies. In this article, we focus on what other states and local providers might learn from these states' experiences as they consider using WC performance measures. Using a case study approach, we report that the use of WC measures differs across these five states, although there are important common themes required for adoption and sustainability of performance measures, which include leadership, evaluation of specification and use of measures over time, state-specific adaptation of the WC measure specifications, collaboration with consultants and partners, inclusion of WC measures in the context of other initiatives, reporting to providers and the public, and data and resource requirements. As additional states adopt some of the WC measures, or adopt other performance measurement approaches, these states' experiences could help them to develop implementations based on their particular needs. PMID- 21257284 TI - Clinical outcomes and implications of failed infrainguinal endovascular stents. AB - OBJECTIVE: While the influence of initial TransAtlantic InterSociety Consensus (TASC) II classification has been clearly shown to influence the primary patency of infrainguinal stenting procedures, its effect on outcomes once stent failure has occurred is less well documented. It is the objective of this paper to determine whether clinical outcomes and implications of anatomic stent failure vary according to initial TASC II classification. METHODS: Results were analyzed by TASC II classification. Kaplan-Meier survival curves were plotted and differences between groups tested by log-rank method. A Cox proportional hazards regression model was used to perform the multivariate analysis. RESULTS: During a 5-year period, 239 angioplasties and stents were performed in 192 patients. Primary patency was lost in 69 stented arteries. Failure was due to one or more hemodynamically significant stenoses in 43 patients, and occlusion in 26 patients. After primary stenting, limbs initially classified as TASC C and D were more likely to fail with occlusion (P < .0001), require open operation (P = .032), or lose run-off vessels (P = .0034) than those classified as TASC A or B. In two patients initially classified as TASC C, stent failure changed the level of open operation to a more distal site. Percutaneous reintervention was performed on 35 limbs. Successful reintervention improved the patency of TASC A and B lesions to 92%, 85%, and 64% and TASC C and D lesions to 78%, 72%, and 50% at 12, 24, and 36 months, respectively. Initial TASC classification was highly predictive of first anatomic failure (P < .0001), but it did not predict the durability of subsequent catheter based reintervention (P = .32). Ten patients with stent failure required operation, and five underwent amputation; all had failed with occlusion. Overall limb salvage was 89% and peri-procedural mortality was 0.4%. CONCLUSIONS: Following primary stenting of the superficial femoral artery (SFA) and popliteal artery, lesions classified as TASC C or D are more likely to fail with occlusion, lose run-off vessels, and alter the site of subsequent open operation than their TASC A and B counterparts. Although these complications are infrequent, they may negatively impact later attempts at revascularization, and this must be considered when deciding upon the proper treatment strategy for patients with infrainguinal occlusive disease. PMID- 21257285 TI - The quantification of ADAMTS4 and 8 expression and selection of reference genes for quantitative real-time PCR analysis in myocardial infarction. AB - INTRODUCTION: ADAMTS4 and ADAMTS8 are proteases involved in ECM proteolysis and antiangiogenesis, but little is known about their expression and function in myocardial infarction (MI). We examined ADAMTS4 and ADAMTS8 expression in a rat MI model by quantitative real-time polymerase chain reaction (qPCR) and enzyme linked immunosorbent assay (ELISA). The expressions of glyseraldehyde-3-phosphate dehydrogenase (GAPDH), beta-actin (ACTB), acidic ribosomal phosphoprotein P0 (ARBP), and ribosomal protein L13A (RPL13A) were examined in order to validate the appropriate housekeeping genes after MI. METHODS: Male Wistar rats were subjected to MI, and infarcted myocardial tissue was collected at 3, 6, 12, 24h, 3, 7, 14 and 21days after MI. ADAMTS4, ADAMTS8, and the four housekeeping genes were quantified using qPCR and the expression stability of the four housekeeping genes was investigated using GeNorm software. The protein levels of ADAMTS4 were detected using ELISA kits. RESULTS: The M values of GAPDH, ACTB, ARBP and RPL13A were 0.721, 1.2, 0.812 and 0.812 respectively. GAPDH and ARBP were ranked the most stable genes. ADAMTS4 mRNA increased at 3h after MI, peaked at 6h, then decreased rapidly. ADAMTS8 mRNA increased at 6h, peaked at 24h, remained high at 3d, then decreased gradually. The protein levels of ADAMTS4 were significantly increased at 6h, 12h, 24h and 3d after MI. CONCLUSION: The results suggest that GAPDH and ARBP are two appropriate housekeeping genes for the rat MI model. Both ADAMTS4 and ADAMTS8 mRNA levels and ADAMTS4 protein level increased, but they exhibited different expression profiles. PMID- 21257286 TI - Status of body dysmorphic disorder in Argentina. AB - Although body dysmorphic disorder (BDD) has received recent attention, it remains misunderstood and under-studied. The Argentine population seeks out plastic surgery at a disproportionate rate and exhibits high rates of preoccupation with bodily dissatisfaction, yet BDD is unrecognized and research is limited. The current study describes the prevalence, quality of life, and presentation style of BDD in depressed adolescents, as depression is the most common symptom for which adolescents seek treatment in Argentina. Twenty-five depressed adolescents and 85 non-depressed students were initially assessed for depression and BDD and subdivided depending on BDD status. Participants were assessed on various constructs including obsessions and compulsions, overvalued ideas, and overall level of impairment. A 2*2 factorial design was employed, and multivariate analysis of variance (MANOVA) was used to analyze the data. Significant main effects were observed for all dependent measures (BDI, OVIS, YBOCS, and Sheehan Disability Scale) for depressed vs. non-depressed participants and BDD status; significant interactions were observed between independent variables for all dependent measures. Depressed adolescents had significantly higher scores on the YBOCS-BDD, OVIS, BDI, and the Sheehan Disability Scale compared to non-depressed participants; furthermore, individuals reporting BDD symptoms reported significantly higher scores on the YBOCS-BDD, OVIS, BDI, and Sheehan Disability Scale. Significant interactions are discussed according to BDD status and depression on dependent measures. Patients with BDD have poor quality of life and present with anxiety and depression, yet it still remains underdiagnosed. PMID- 21257287 TI - Discrimination between attention deficit hyperactivity disorder and reactive attachment disorder in school aged children. AB - We aimed to determine whether it is possible to discriminate between children with attention deficit hyperactivity disorder (ADHD) and children with reactive attachment disorder (RAD) using standardized assessment tools for RAD. The study involved 107 children: 38 with a diagnosis of RAD and 30 with ADHD were recruited through community child and adolescent mental health services (CAMHS) and specialist ADHD clinics. In addition, 39 typically developing children were recruited through family practice. Clinicians were trained to use a standardized assessment package for RAD using a DVD with brief follow-up support. Discriminant function analysis was used to identify the items in the standardized assessment package that best discriminated between children with ADHD and children with RAD. Clinicians' ratings of RAD symptoms were reliable, particularly when focusing on eight core DSM-IV symptoms of RAD. Certain parent-report symptoms were highly discriminatory between children with ADHD and children with RAD. These symptoms included "cuddliness with strangers" and "comfort-seeking with strangers". A semi structured interview with parents, observation of the child in the waiting room and teacher report of RAD symptoms aided diagnostic discrimination between the groups. Clinical diagnosis of RAD can be made reliably by clinicians, especially when focusing on eight core RAD symptoms. Clear discrimination can be made between children with RAD and children with ADHD. PMID- 21257288 TI - The attitudes of Belgian adolescents towards peers with disabilities. AB - This study aimed to explore Belgian adolescents' attitudes towards peers with disabilities and to explore factors associated with these attitudes. Based on the theory of persuasive communication, this study focused on receiver variables (the "whom"), characteristics of students with disabilities ("concerning who") and channel ("how"). An online survey was created and published on several popular websites for youngsters. Attitudes were assessed by means of the CATCH questionnaire among 167 adolescents between 11 and 20 years old. Univariate and multivariate regression analyses were conducted. Belgian adolescents had fairly tolerant attitudes towards peers with disabilities. Factors associated with more positive attitudes were being female, and viewing a video introduction of a peer with a disability before assessing attitudes. Factors such as having a parent, sibling or good friend with a disability and frequent contact with persons with disabilities did not remain significant in the overall model. The way in which students with disabilities are presented to their peers is very important. Further research is needed among larger samples, including more diverse variables, concerning the former mentioned categories, and also concerning the source (the "who") and message (the "what"). PMID- 21257289 TI - Phenotype-environment interactions in genetic syndromes associated with severe or profound intellectual disability. AB - The research literature notes both biological and operant theories of behavior disorder in individuals with intellectual disabilities. These two theories of genetic predisposition and operant reinforcement remain quite distinct; neither theory on its own is sufficient to explain challenging behavior in genetic syndromes and an integrated approach is required. This literature review integrates the two approaches by exploring how environmental factors can influence problem behavior in genetic syndromes associated with intellectual disability. Particular attention is paid to studies that describe evidence that problem behaviors in syndromes that are considered to be phenotypic are associated with other aspects of an established behavioral phenotype. The review highlights how the study of phenotype-environment interactions within syndromes can promote understanding of the aetiology of problem behaviors both within genetic syndromes and, ultimately, the wider population of individuals with severe intellectual disabilities. The review also evaluates the current status of research and the methods typically employed. Implications for intervention, future research and extending existing causal models of challenging behavior are discussed. PMID- 21257290 TI - Differences in self-peptide binding between T1D-related susceptible and protective DR4 subtypes. AB - HLA-DR0401, 0403 and 0405 are associated with variable T1D susceptibilities when linked with a common HLA-DQ8 (DQA1*0301/DQB1*0302). It is unknown how the modest differences within the peptide binding regions of DR4 subtypes lead to distinct autoimmune risks. Since all Class II HLA molecules share the same intracellular compartments during biosynthesis, it is possible that DQ and DR compete with one another to bind and present antigenic peptides. As such, it is reasonable to hypothesize that a strong DR4 self-peptide binder down-modulates DQ8 epitope presentation more than a weak one. In this study, we first examined the binding of the peptides derived from two putative beta-cell autoantigens - GAD65 and insulin. Protective DR0403 bound similar number of self-peptides as susceptible DR0401 while highly susceptible DR0405 bound substantially less self-peptides than rest two molecules. Kinetic assays were used to further compare the stability of peptide:DR complexes formed between DR0401, 0403 and selected GAD65 peptides, which also bound DQ8. Two peptides with naturally processed DQ8 epitopes bound protective DR0403 with longer half-life and lower dissociation rate than susceptible DR0401, confirming DR0403 as a better peptide competitor than DR0401. The distinguishing peptide binding features of DR0401, DR0403, and DR0405 highlighted in this study help to explain the hierarchy of genetic associations between T1D and these DR4 subtypes. The enhanced peptide competition of DR0403 leads to a down-modulation of DQ8 epitope presentation, as compared to weak competitors such as DR0401 and DR0405, and therefore contributes to disease protection. PMID- 21257291 TI - Neuroantigen-specific CD8+ regulatory T-cell function is deficient during acute exacerbation of multiple sclerosis. AB - Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS). MS is thought to be T-cell-mediated, with prior research predominantly focusing on CD4+ T-cells. There is a high prevalence of CNS specific CD8+ T-cell responses in MS patients and healthy subjects. However, the role of neuroantigen-specific CD8+ T-cells in MS is poorly understood, with the prevalent notion that these may represent pathogenic T-cells. We show here that healthy subjects and MS patients demonstrate similar magnitudes of CD8+ and CD4+ T-cell responses to various antigenic stimuli. Interestingly, CD8+ T-cells specific for CNS autoantigens, but not those specific for control foreign antigens, exhibit immune regulatory ability, suppressing proliferation of CD4+CD25- T-cells when stimulated by their cognate antigen. While CD8+ T-cell mediated immune suppression is similar between healthy subjects and clinically quiescent treatment-naive MS patients, it is significantly deficient during acute exacerbation of MS. Of note, the recovery of neuroantigen-specific CD8+ T-cell suppression correlates with disease recovery post-relapse. These studies reveal a novel immune suppressor function for neuroantigen-specific CD8+ T-cells that is clinically relevant in the maintenance of peripheral tolerance and the intrinsic regulation of MS immune pathology. PMID- 21257292 TI - Direct sac puncture and glue embolization of intraosseous AVM of the maxilla. AB - The authors report an intraosseous maxillary arteriovenous malformation (AVM) treated with direct sac injection of n-butyl-2-cyanoacrylate and transarterial embolization. The case is presented because of its rarity and the efficacy of direct puncture glue embolization. PMID- 21257293 TI - Osseous healing after a sagittal splitting ramus osteotomy. AB - The purpose of this study was to examine osseous healing in the cleavage between the bone fragments after sagittal splitting ramus osteotomy (SSRO) utilizing computed tomography (CT). The subjects were 13 patients with mandibular prognathism who underwent bilateral SSRO. CT was used to study the rami immediately after surgery, then 6 months, 1 year, and 2 years after surgery. Many concave type (the angle between the cleavage >90 degrees ) anterior borders developed into the stairway type (the angle between the cleavage <90 degrees ) 6 12 months after surgery. Few borders changed to the smooth type. Almost all of the stairway and concave posterior borders changed to the smooth type in the 6-12 months after surgery. Regarding the posterior borders 1 year after surgery, the cleavage of distal and proximal bone fragments demonstrated stable osseous healing (smooth type) in cases where the length and width between the bone fragments were large. In conclusion, the authors successfully demonstrated detailed osseous healing in the cleavage between the bone fragments after SSRO. Remodelling between bone fragments is a major mechanism of osseous healing after this procedure. PMID- 21257294 TI - Oral versus depot antipsychotic drugs for schizophrenia--a critical systematic review and meta-analysis of randomised long-term trials. AB - OBJECTIVE: Non-adherence is a major problem in the treatment of schizophrenia. Depot antipsychotic drugs are thought to reduce relapse rates by improving adherence, but a systematic review of long-term studies in outpatients is not available. METHOD: We searched the Cochrane Schizophrenia Group's register, ClinicalTrials.gov, Cochrane reviews on depot medication, and the reference sections of included studies for randomised controlled trials lasting at least 12 months in outpatients that compared depot with oral antipsychotics in schizophrenia. Data on relapse (primary outcome), rehospitalisation, non adherence, and dropout due to any reason, inefficacy of treatment and adverse events were summarised in a meta-analysis using a random-effects model. Study quality was assessed with the Cochrane collaboration's risk of bias tool, and publication bias with funnel plots. RESULTS: Ten studies with 1700 participants met the inclusion criteria. Depot formulations significantly reduced relapses with relative and absolute risk reductions of 30% and 10%, respectively (RR 0.70, CI 0.57-0.87, NNT 10, CI 6-25, P=0.0009), and dropout due to inefficacy (RR 0.71, CI 0.57-0.89). Limited data on non-adherence, rehospitalisation and dropout due to any reason and adverse events revealed no significant differences. There were several potential sources of bias such as limited information on randomisation methods, problems of blinding and different medications in the depot and oral groups. Other studies reduced a potential superiority of depot by excluding non adherent patients. DISCUSSION: Depot antipsychotic drugs significantly reduced relapse. Due to a number of methodological problems in the single trials the evidence is, nonetheless, subject to possible bias. PMID- 21257295 TI - [Neonatal appendicitis: a diagnostic trap. A case report]. AB - Neonatal appendicitis is an uncommon disease characterized by high mortality and morbidity. We report the case of a full-term newborn with infectious syndrome. The nonresponse to antibiotic therapy despite good clinical status led to a search for an etiology. Appendicitis with focal peritonitis was discovered on sonography. In each newborn, presenting with unexplained febrile inflammatory syndrome with or without gastrointestinal symptoms, a routine abdominal sonography should be performed to search for intraperitoneal sepsis, including appendicitis. PMID- 21257296 TI - [Prevention of cerebral palsy using magnesium sulfate in pre-term newborns]. AB - This review concentrates on the best evidence emerging in recent years on cerebral palsy prevention by administration of magnesium sulfate in mothers at risk of pre-term birth before 33-34 weeks' gestation. It was shown in the Cochrane database and in 3 meta-analyses of 5 randomized trials (Magpie Trial [neuroprotection of the pre-eclamptic mother], MagNet [neuroprotection/other intent: tocolysis], ActoMgSO(4) [neuroprotection], PreMag [neuroprotection], and Beam [neuroprotection]) that prenatal low-dose magnesium sulfate given to mothers at risk of pre-term birth has no severe deleterious effects in mothers and does not increase pediatric mortality in very pre-term infants. Moreover, it has significant neuroprotective effects on the occurrence of cerebral palsy at 2 years of age (relative risk, 0.69; 95% confidence interval, 0.54-0.87) and, in the neuroprotection subgroup, on the combined outcome of pediatric mortality or cerebral palsy (relative risk: 0.85; 95% confidence interval: 0.74-0.98). The number needed to treat (NTT) to prevent 1 case of cerebral palsy was 63 (95% CI, 39-172) and the NTT for an extra survivor free of cerebral palsy in the neuroprotection subgroup was 42 (95% CI, 22-357), justifying that magnesium sulfate should be discussed as a stand-alone treatment or as part of a combination treatment. PMID- 21257298 TI - Differentially expressed cDNAs in Alternaria alternata treated with 2-propenyl isothiocyanate. AB - The molecular mechanism of the fungal tolerance phenotype to fungicides is not completely understood. This knowledge would allow for the development of environmentally friendly strategies for the control of fungal infection. With the goal of determining genes induced by 2p-ITC, a forward suppressive subtractive hybridization was performed using cDNAs from ITC-treated Alternaria alternata as a "tester" and from untreated fungus as a "driver." Using this approach, a library containing 102 ESTs was generated that resulted in 50 sequences after sequence assembly (17 contigs and 33 singletons). Blastx analysis revealed that 38% and 40% of the sequences showed significant similarity with known and hypothetical proteins, respectively, whereas 18% were not similar to known genes. These last sequences could represent novel genes that play an unknown role in the molecular responses of fungi during adaptation to 2p-ITC. Clones similar to opsins, ABC transporters, calmodulin, ATPases and SNOG proteins were identified. Using real-time RT-PCR analysis, significant inductions of an ABC transporter and a Ca(++) ATPase during 2p-ITC treatment were discovered. These results suggest that the fungal resistance phenotype to 2p-ITC involves calcium ions and 2p-ITC efflux via an ABC transporter. PMID- 21257299 TI - Development of PLZF-expressing innate T cells. AB - Recent studies have shown that the transcriptional regulator promyelocytic leukemia zinc finger (PLZF) controls the development of essentially all of the innate-like features of invariant Natural Killer T (NKT) cells. For example, PLZF deficient NKT cells do not acquire an 'activated' phenotype nor do they acquire the capacity to secrete multiple cytokines upon primary stimulation. The function of a subset of gammadelta T cells has now also been shown to be dependent upon expression of PLZF. Furthermore, IL-4 produced by PLZF-expressing cells causes some CD8 T cells to acquire innate-like features. Therefore, it is becoming clear that PLZF has a broad impact on the immune response. Here we discuss the current understanding of how expression of PLZF, the innate T cell determinant, is initiated during T cell development. PMID- 21257300 TI - Hepatitis B virus infection, its sequelae, and prevention by vaccination. AB - Hepatitis B virus (HBV) infection is a global health problem. There are >350 million of people chronically infected with this virus worldwide. Hepatitis B vaccines are effective in preventing the infection. Humoral immunity is the key factor in conferring the protection. Hepatitis B surface antibody titers of >=10mIU/mL are protective. Chronic carriage of HBV is related to the age when the infection occurs, the younger the age the higher the chronicity rate. Hence, vaccination should be given in early childhood. People vaccinated in infancy have a protection of >20 years, and hepatocellular carcinoma decreases in them. Although the vaccine-conferred immunity wanes by time, a universal booster is not recommended at present. PMID- 21257301 TI - Biodegradable kinetics of plastics under controlled composting conditions. AB - This study models and evaluates the kinetics of C-CO(2) evolution during biodegradation of plastic materials including Polyethylene (PE), PE/starch blend (PE/starch), microcrystalline cellulose (MCE), and Polylactic acid (PLA). The aerobic biodegradation under controlled composting conditions was monitorated according to ISO 14855-1, 2004. The kinetics model was based on first order reaction in series with a flat lag phase. A non-linear regression technique was used to analyze the experimental data. SEM studies of the morphology of the samples before and after biodegradation testing were used to confirm the biodegradability of plastics and the accuracy of the model. The work showed that MCE and PLA produced the high amounts of C-CO(2) evolution, which gave readily hydrolysable carbon values of 55.49% and 40.17%, respectively with readily hydrolysis rates of 0.338 day(-1) and 0.025 day(-1), respectively. Whereas, a lower amount of C-CO(2) evolution was found in PE/starch, which had a high concentration of moderately hydrolysable carbon of 97.74% and a moderate hydrolysis rate of 0.00098 day(-1). The mineralization rate of PLA was 0.500 day( 1) as a lag phase was observed at the beginning of the biodegradability test. No lag phase was observed in the biodegradability testing of the PE/starch and MCE. The mineralization rates of the PE/starch and MCE were found to be 1.000 day(-1), and 1.234 day(-1), respectively. No C-CO(2) evolution was observed during biodegradability testing of PE, which was used for reference as a non biodegradable plastics sample. PMID- 21257302 TI - A contact lens with embedded sensor for monitoring tear glucose level. AB - We report the design, construction, and testing of a contact lens with an integrated amperometric glucose sensor, proposing the possibility of in situ human health monitoring simply by wearing a contact lens. The glucose sensor was constructed by creating microstructures on a polymer substrate, which was subsequently shaped into a contact lens. Titania sol-gel film was applied to immobilize glucose oxidase, and Nafion(r) was used to decrease several potential interferences (ascorbic acid, lactate, and urea) present in the tear film. The sensor exhibits a fast response (20s), a high sensitivity (240 MUA cm(-2) mM(-1)) and a good reproducibility after testing a number of sensors. It shows good linearity for the typical range of glucose concentrations in the tear film (0.1 0.6 mM), and acceptable accuracy in the presence of interfering agents. The sensor can attain a minimum detection of less than 0.01 mM glucose. PMID- 21257303 TI - A novel chemiluminescence paper microfluidic biosensor based on enzymatic reaction for uric acid determination. AB - In this work, chemiluminescence (CL) method was combined with microfluidic paper based analytical device (MUPAD) to establish a novel CL MUPAD biosensor for the first time. This novel CL MUPAD biosensor was based on enzyme reaction which produced H(2)O(2) while decomposing the substrate and the CL reaction between rhodanine derivative and generated H(2)O(2) in acid medium. Microchannels in MUPAD were fabricated by cutting method. And the possible CL assay principle of this CL MUPAD biosensor was explained. Rhodanine derivative system was used to reach the purpose of high sensitivity and well-defined signal for this CL MUPAD biosensor. And the optimum reaction conditions were investigated. The quantitative determination of uric acid could be achieved by this CL MUPAD biosensor with accurate and satisfactory result. And this biosensor could provide good reproducible results upon storage at 4 degrees C for at least 10 weeks. The successful integration of MUPAD and CL reaction made the final biosensor inexpensive, easy-to-use, low-volume, and portable for uric acid determination, which also greatly reduces the cost and increases the efficiency required for an analysis. We believe this simple, practical CL MUPAD biosensor will be of interest for use in areas such as disease diagnosis. PMID- 21257304 TI - Production-related petroleum microbiology: progress and prospects. AB - Microbial activity in oil reservoirs is common. Methanogenic consortia hydrolyze low molecular weight components to methane and CO2, transforming light oil to heavy oil to bitumen. The presence of sulfate in injection water causes sulfate reducing bacteria to produce sulfide. This souring can be reversed by nitrate, stimulating nitrate-reducing bacteria. Removing biogenic sulfide is important, because it contributes to pitting corrosion and resulting pipeline failures. Increased water production eventually makes oil production uneconomic. Microbial fermentation products can lower oil viscosity or interfacial tension and produced biomass can block undesired flow paths to produce more oil. These biotechnologies benefit from increased understanding of reservoir microbial ecology through new sequence technologies and help to decrease the environmental impact of oil production. PMID- 21257305 TI - Economic evaluation of four follow-up strategies after curative treatment for breast cancer: results of an RCT. AB - BACKGROUND: An economic evaluation was performed alongside a randomised controlled trial (ISRCTN 74071417) investigating the cost-effectiveness of nurse led telephone follow-up instead of hospital visits, and of a short educational group programme (EGP) in the first year after breast cancer treatment. METHOD: This economic evaluation (n = 299) compared the one-year costs and the effects of four follow-up strategies: (1) hospital follow-up; (2) nurse-led telephone follow up; (3) hospital follow-up plus EGP; and (4) nurse-led telephone follow-up plus EGP. Costs were measured using cost diaries and hospital registrations. Quality adjusted life years (QALYs) were measured using the EQ-5D. Outcomes were expressed in incremental cost-effectiveness ratios (ICERs) and cost-effectiveness acceptability curves. RESULTS: Hospital follow-up plus EGP yielded most QALYs (0.776), but also incurred the highest mean annual costs (?4914). The ICER of this strategy versus the next best alternative, nurse-led telephone follow-up plus EGP (0.772 QALYs and ?3971), amounted to ?235.750/QALY. Hospital and telephone follow-up without EGP both incurred higher costs and less QALYs than telephone follow-up plus EGP and were judged inferior. Hospital follow-up plus EGP was not considered cost-effective, therefore, telephone follow-up plus EGP was the preferred strategy. The probability of telephone follow-up plus EGP being cost-effective ranged from 49% to 62% for different QALY threshold values. Secondary and sensitivity analyses showed that results were robust. CONCLUSION: Nurse-led telephone follow-up plus EGP seems an appropriate and cost-effective alternative to hospital follow-up for breast cancer patients during their first year after treatment. PMID- 21257306 TI - Two or three year disease-free survival (DFS) as a primary end-point in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, C-06, C-07 and C89803. AB - BACKGROUND: The ACCENT group previously established disease-free survival (DFS) with 2 or 3 years median follow-up to predict 5 year overall survival (5 year OS) in stage II and III colon cancer. ACCENT further proposed (1) a stronger association between DFS and OS in stage III than II, and (2) 6 or 7 years necessary to demonstrate DFS/OS surrogacy in recent trials. The relationship between end-points in trials with oral fluoropyrimidines, oxaliplatin and irinotecan is unknown. METHODS: Associations between the treatment effect hazard ratios (HRs) on 2 and 3 years DFS, and 5 and 6 years OS were examined in 6 phase III trials not included in prior analyses from 1997 to 2002. Individual data for 12,676 patients were analysed; two trials each tested oxaliplatin, irinotecan and oral treatment versus 5-FU/LV. FINDINGS: Overall association between 2/3 year DFS and 5/6 year OS HRs was modest to poor (simple R2 measures: 0.58-0.76, model based R2: 0.17-0.49). In stage III patients, the association increased (model based R2 >= 0.79). Observed treatment effects on 2 year DFS accurately 5/6 year OS effects overall and in stage III patients. INTERPRETATION: In recent trials of cytotoxic chemotherapy, 2 or 3 years DFS HRs are highly predictive of 5 and 6 years OS HRs in stage III but not stage II patients. In all patients the DFS/OS association is stronger for 6 year OS, thus at least 6 year follow-up is recommended to assess OS benefit. These data support DFS as the primary end-point for stage III colon cancer trials testing cytotoxic agents. PMID- 21257307 TI - Improved tolerance to bile salts of aggregated Bifidobacterium longum produced during continuous culture with immobilized cells. AB - The effect of cell immobilization and continuous culture was studied on selected physiological and technological characteristics of Bifidobacterium longum NCC2705 cultivated for 20 days in a two stage continuous fermentation system. Continuous immobilized cell (IC) cultures with and without glucose limitation exhibited formation of macroscopic cell aggregates after 12 and 9 days, respectively. Auto aggregation resulted in underestimation of viable cell counts by plate counts by more than 2 log units CFU/ml compared with qPCR method. Modifications of cell membrane composition might partially explain aggregate formation in IC cultures. Decreases in the ratio of unsaturated to saturated fatty acid content from 1.74 to 0.58 might also contribute to the enhanced tolerance of IC cells to porcine bile salts and aminoglycosidic antibiotics compared with free cells from batch cultures. The enhanced resistance against bile salts in combination with auto aggregation may confer an advantage to probiotic bacteria produced by IC technology. PMID- 21257308 TI - High concentration electrophysiology-based fragment screen: discovery of novel acid-sensing ion channel 3 (ASIC3) inhibitors. AB - The Merck Fragment Library was screened versus acid-sensing ion channel 3 (ASIC3), a novel target for the treatment of pain. Fragment hits were optimized using two strategies, and potency was improved from 0.7 mM to 3 MUM with retention of good ligand efficiency and incorporation of reasonable physical properties, off-target profile, and rat pharmacokinetics. PMID- 21257310 TI - Hedgehog morphogen: from secretion to reception. AB - A major challenge of developmental biology is to understand how cells coordinate developmental behaviors with their neighbors. To achieve this, cells often employ signaling molecules that emanate from a local source and act at a distance on target cells. The Hedgehog morphogen is an essential signaling molecule required for numerous processes during animal development. Emphasizing the importance of this molecule for both growth control and patterning, Hedgehog signaling activity is often deregulated during cancer formation and progression. The secretion and spread of Hedgehog are not passive processes, but require accessory molecules involved in Hedgehog processing, release, spread and reception. In this review, I focus on the factors that are required to control the spread and activity of Hedgehog, highlighting recent data that have shed light on these processes. PMID- 21257309 TI - Discovery of a potent series of non-steroidal non alpha-trifluoromethyl carbinol glucocorticoid receptor agonists with reduced lipophilicity. AB - A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFkappaB pIC(50) 8.3 (100%), clogP 1.9). Certain analogues in this series also display evidence for modulated pharmacology. PMID- 21257311 TI - Do cranial subdural hematomas migrate to the lumbar spine? AB - We report a patient with minor head trauma-related bilateral hemispheric subdural hematoma (SDH) and subsequent delayed spinal SDH or presumed migration to the lumbar spine. An acutely confused 88-year-old man presented to the Emergency Department after minor head trauma. Head CT scan revealed a small hemispheric SDH. The patient was admitted for observation. CT scan 6 hours later showed bilateral SDH with extension to the tentorium. Three days later SDH had resolved leaving bilateral subdural hygromas. Local leg weakness localized to the lumbar spine developed on day 6; spinal CT scan and MRI revealed a posterior L5-S1 collection. A pure subacute subdural hematoma compressing the cauda equina was drained after an L5 laminectomy. His lower leg weakness improved. The patient was discharged to rehabilitation two weeks after surgery. Patients with traumatic SDH who develop late-onset neurological deterioration attributable to any region of the spine should be evaluated for spinal SDH. PMID- 21257312 TI - Intrameatal aneurysm of the anterior inferior cerebellar artery. AB - Aneurysms of the distal part of the anterior-inferior cerebellar artery (AICA) are rare, with an incidence of 0.1% to 0.5%. We report a 55-year-old woman suffering from a subarachnoid hemorrhage resulting from a ruptured intrameatal aneurysm of the AICA. A left retrosigmoid craniotomy was performed and the aneurysm was clipped without post-operative deficits. Follow-up angiography demonstrated exclusion of the aneurysm, confirming preservation of the distal AICA. We review the pertinent literature and discuss clinical presentation, radiological findings and surgical management of this patient. PMID- 21257313 TI - Role of the anterior intermeniscal ligament in tibiofemoral contact mechanics during axial joint loading. AB - The anterior intermeniscal ligament (AIML) is an anatomically distinct structure that connects the anterior horns of the medial and lateral menisci. We hypothesized that both menisci work together as a unit in converting axial joint loading into circumferential hoop stresses, due to intermeniscal attachments. Therefore, loss of the AIML could lead to increased tibiofemoral contact stress and predispose to arthritic change. In this cadaveric study, we compared tibiofemoral contact pressures on axial loading, before and after sectioning of the AIML. Five fresh frozen human cadaveric knees were mounted on a linear x-y motion table and loaded in extension under axial compression of 1800N (about 2.5 times body weight for a 70kg individual), using a materials testing machine. Tibiofemoral contact pressures before and after sectioning of the AIML were measured using resistive pressure sensors. Contrary to our hypothesis, sectioning of the AIML produced no statistically significant increase in mean contact pressure, peak contact pressure or change in contact area, in either the medial or lateral compartment of the knees. This implies that the menisci work independently in converting axial loads into circumferential hoop stresses, and is probably due to their individual root attachments to the tibia. Based on this study, inadvertent sectioning of the AIML during knee surgery, e.g., arthroscopy, anterograde tibia nailing, anterior cruciate ligament reconstruction, meniscus transplantation and unicondylar knee replacement, is functionally insignificant. PMID- 21257314 TI - Evaluation of endogenous fatty acid amides and their synthetic analogues as potential anti-inflammatory leads. AB - A series of endogenous fatty acid amides and their analogues (1-78) were prepared, and their inhibitory effects on pro-inflammatory mediators (NO, IL 1beta, IL-6, and TNF-alpha) in LPS-activated RAW264.7 cells were evaluated. Their inhibitory activity on the pro-inflammatory chemokine MDC in IFN-gamma-activated HaCaT cells was also examined. The results showed that the activity is strongly dependent on the nature of the fatty acid part of the molecules. As expected, the amides derived from enone fatty acids showed significant activity and were more active than those derived from other types of fatty acids. A variation of the amine headgroup also altered bioactivity profile remarkably, possibly by modulating cell permeability. Regarding the amine part of the molecules, N-acyl dopamines exhibited the most potent activity (IC(50) ~2 MUM). This is the first report of the inhibitory activity of endogenous fatty acid amides and their analogues on the production of nitric oxide, cytokines (IL-1beta, IL-6, and TNF alpha) and the chemokine MDC. This study suggests that the enone fatty acid derived amides (such as N-acyl ethanolamines and N-acyl amino acids) and N-acyl dopamines may be potential anti-inflammatory leads. PMID- 21257315 TI - Absolute contraindications to percutaneous tracheostomy due to anomaly of aortic arch branches origin and running. PMID- 21257316 TI - Management of less-than-severe mitral regurgitation: should guidelines recommend earlier surgical intervention? AB - OBJECTIVE: It is well accepted that patients with severe mitral regurgitation (MR) benefit from mitral valve repair; however, the management of those with less than severe leakage is controversial. Watchful waiting is often advocated and considered safe, but the risk of developing left ventricular (LV) dysfunction under medical management is unknown. METHODS: Using a population-based County wide study database, we analyzed echocardiograms during clinical follow-up and medical management of 204 patients with mitral valve prolapse and less-than severe MR. LV dysfunction was defined per American Heart Association guidelines as an ejection fraction (EF) <60% or LV end-systolic dimension > 40 mm. RESULTS: At index examination, mean age was 57 years and 121 (59%) were women. The mean EF was 62%, and 62 (30%) had evidence of LV dysfunction. MR severity was mild in 121 (59%), mild-moderate in 23 (11%), moderate in 36 (18%) and moderate-severe in 24 (12%). During follow-up (mean 8.6 years), 79 patients (39%) demonstrated progression of MR by at least one grade. Greater degrees of regurgitation at index echocardiogram were associated with greater progression during follow-up (P=0.0001). After adjusting for age, sex, body surface area (BSA), and baseline regurgitation grade, multivariable modeling revealed that larger LV end-diastolic dimension (odds ratio (OR)=1.14; P=0.0018) and greater diastolic septal thickness (OR=1.40; P=0.0211) predicted greater progression of MR with time. From initial diagnosis to follow-up echocardiography, EF declined, while left-heart dimensions and pulmonary arterial pressure increased. Of the 142 patients with normal baseline LV function, 52% developed either worsening MR or de novo LV dysfunction. Importantly, even in the 87 patients with stable regurgitation, 18 (21%) developed new LV dysfunction during follow-up. Fifty-two patients (25%) eventually underwent mitral valve repair. Following surgery, there were significant decreases in EF, LV end-diastolic dimensions and LV mass; while 11 developed de novo LV dysfunction. CONCLUSIONS: Over half of patients with chronic persistent, but sub-severe MR due to mitral leaflet prolapse develop LV dysfunction or worsening regurgitation despite optimal medical management. LV deterioration can occur even in the absence of MR progression. These data advocate for the development of detailed guidelines supporting frequent echocardiographic monitoring and the identification of earlier triggers for surgical consideration prior to the development of LV dysfunction in this patient population. PMID- 21257317 TI - The CCAAT/enhancer (C/EBP) family of basic-leucine zipper (bZIP) transcription factors is a multifaceted highly-regulated system for gene regulation. AB - The C/EBP family of proteins represents an important group of bZIP transcription factors that are key to the regulation of essential functions such as cell cycle, hematopoiesis, skeletal development, and host immune responses. They are also intimately associated with tumorigenesis and viral disease. These proteins are regulated at multiple levels, including gene induction, alternative translational initiation, post-translational modification, and protein-protein interaction. This review attempts to integrate recent reports with more than 20 years of previous effort focused on this fascinating collection of regulators. PMID- 21257318 TI - Serum transforming growth factor beta-1 post hip fracture repair in elderly patients. AB - BACKGROUND: To determine the kinetics of serum transforming growth factor beta-1 (TGF-beta1) in aged hip fracture patients during a month post-op. and determine its relationship to complications and cognitive status. METHODS: Forty-one elderly patients were prospectively followed. Serum TGF-beta1 was obtained during the first 10h post-fracture (baseline) and pre-surgery, 48-60 h post-op., 7 and 30 days post-op. RESULTS: Mean age was 81.8+/-7.7, range 68-97 years. A significant increase in serum TGF-beta1 (from baseline) was observed on the seventh day post-op., lasting for at least 1 month (p = 0.004). Sixteen patients experienced post-op. complications. Serum TGF-beta1 of patients with complications was significantly higher compared to patients without complications (p = 0.039). More complications were found in impaired mental status (IMS) patients (9/12) compared to cognitively normal patients (10/29), (p = 0.037). However, no differences were found in serum TGF-beta1 between IMS and normal patients, nor was a correlation found between age and TGF-beta1 production. No differences were found between genders. CONCLUSIONS: There is a distinct increase in serum TGF-beta1, a week post hip fracture repair, lasting for at least a month, which is significantly higher in patients with post-op. complications. TGF beta1 seems to be essential to the healing process post hip fracture repair; still its clinical applications have as yet to be determined. PMID- 21257319 TI - Genetic polymorphisms in chitinase 3-like 1 (CHI3L1) are associated with circulating YKL-40 levels, but not with angiographic coronary artery disease in a Chinese population. AB - BACKGROUND: We sought to examine if polymorphisms in the promoter region of YKL 40 gene (CHI3L1) are associated with serum YKL-40 levels and coronary artery disease (CAD) in Chinese patients. METHODS: Three single nucleotide polymorphisms (SNPs) (-329G>A, rs10399931; -247C>T, rs10399805; -131G>C, rs4950928) in the CHI3L1 promoter were determined in 213 consecutive patients with angiographically documented CAD (luminal diameter stenosis >=50%) and 248 normal controls. Coronary cumulative obstruction score and number of diseased vessels represent the severity of CAD. Serum YKL-40 levels were assessed using an ELISA kit. RESULTS: Patients with CAD had remarkably higher serum YKL-40 levels compared to controls (p<0.001). There was no difference in the allele, genotype and haplotype distribution of these three SNPs between controls and CAD patients. The minor alleles of CHI3L1-329G>A and -131G>C were significantly associated with decreased serum YKL-40 levels in both controls (p = 0.001 and p<0.001, respectively) and CAD patients (p = 0.007 and p<0.001, respectively), whereas CHI3L1-247C>T had no appreciable effect. None of these genetic variants and haplotypes was associated with severity of angiographic CAD. CONCLUSIONS: CHI3L1-329G>A and -131G>C polymorphisms are associated with serum YKL-40 levels, but not with the prevalence or severity of CAD. PMID- 21257320 TI - Local tolerance and stability up to 24 months of a new 20% proline-stabilized polyclonal immunoglobulin for subcutaneous administration. AB - Subcutaneous administration of human IgG is an alternative to intravenous replacement therapy that is associated with more stable serum IgG levels and fewer systemic adverse events. Highly concentrated IgG solutions are most convenient to minimize infusion volume, but their preparation and stability presents substantial technical difficulties. We report on the stability and local tolerance of IgPro20, an l-proline-stabilized, 20% polyvalent human IgG developed for subcutaneous administration. Stability was tested according to ICH guidelines. Local tolerance and vasoactivity were examined in rabbit and rat models, respectively. The presence of l-proline in IgPro20 reduced viscosity and addition of Polysorbate 80 and inert gassing improved the appearance of the solution. After storage at 25 degrees C for 24 months, monomer + dimer content, aggregates, and fragments were within specification (>= 90.0%, <= 4.0%, and <= 10.0%, respectively), and Fc function and antibody activities were maintained. In rats, intravenous injection of IgPro20 produced mild and transient hypotension comparable to that seen with intravenous IgG products. Local tolerance of IgPro20 in rabbits was comparable to that of a marketed subcutaneous IgG, Beriglobin P. Functionality and quality of IgPro20 are maintained during storage at 25 degrees C for at least 24 months. The product is well tolerated as assessed in animal models. PMID- 21257321 TI - Comparison of outcomes in women versus men using a continuous-flow left ventricular assist device as a bridge to transplantation. AB - BACKGROUND: The use of large, pulsatile left ventricular assist devices (LVADs) has been limited in women because of their small body size. METHODS: We compared the survival outcomes, quality of life, and adverse events in 465 patients (104 women, 361 men) with advanced systolic heart failure in their first 18 months of support with the HeartMate II (Thoratec Corp, Pleasanton, CA) continuous-flow LVAD for bridge to transplantation. RESULTS: During the first 18 months, there were no differences in survival between women and men while on LVAD support (73% +/- 3% vs 73% +/- 5%, p = 0.855) but fewer women (40%) underwent heart transplantation than did men (55%; p = 0.001). More women continued on support after 18 months (p = 0.007). Median duration of support was 238 days for women and 184 days for men (p = 0.003). Mortality was 20% for women and 19% for men (p = 0.89). Adverse events were similar, with the exception of hemorrhagic stroke, which occurred more frequently in women (0.10 vs 0.04 events/patient-year, p = 0.02), and device-related infections, which occurred less frequently in women (0.23 vs 0.44, p = 0.006). Functional capacity and quality of life at 6 months improved significantly in women and men. CONCLUSIONS: Continuous-flow left ventricular assistance as a bridge to transplantation is associated with similar survival rates in women and men. Differences observed in higher stroke rates and fewer infections among women require further study. PMID- 21257322 TI - Incidental finding of cor triatriatum sinister in an adult post-myocardial infarction. AB - We report a case of a 51-year-old man who was transferred from a community hospital to our institution in cardiogenic shock after thrombolytic therapy for myocardial infarction. At autopsy, a cor triatriatum sinister was found. This may have contributed to his poor outcome post infarction. PMID- 21257324 TI - The safety and efficacy of add-on levetiracetam in elderly patients with focal epilepsy: a one-year observational study. AB - PURPOSE: The long-term safety and efficacy of levetiracetam (LEV) was evaluated as add-on therapy in focal epilepsy patients (n=491) aged at least 65 years who failed at least one monotherapy. METHODS: Patients (n=491) with focal epilepsy treated with at least one antiepileptic drug in monotherapy with insufficient seizure control were included in this prospective open-label study. The recommended LEV dose range was 1000-3000 mg per day. Follow-up visits were done approximately after 3, 6 and 12 months. Safety and efficacy was analysed based on all patients who received LEV (safety population, n=491) and all patients who were seen at all visits and completed the trial (per protocol population, n=364). RESULTS: Patients (53% men, median age 71 years) had a total of 97 adverse events (AEs) reported in 53 patients. The most common AEs were fatigue and restlessness (9.7% each of all AEs). A total of 35 serious AEs occurred in 19 patients (3.9% of the safety population), all but one unrelated to the study medication. Mean monthly seizure frequency dropped significantly from 7.0 (SD 8.7, range 1-85, median 4) at baseline to 1.7 (SD 2.9, range 0-29, median 1) at 3 month, 1.2 (SD 2.6, range 0-30, median 0) at 6, and 1.4 (SD 6.6, range 0-99, median 0) at 12 months, corresponding to a reduction of 75.7%, 82.9%, and 80.0% relative to baseline. Seizure freedom was reported by 42%, 57.7%, and 58% of patients during the previous period at 3, 6 and 12 months follow-up, respectively. CONCLUSIONS: Add-on treatment with LEV in elderly patients with focal epilepsy was safe and efficient. Levetiracetam might be considered as a suitable drug in the elderly. PMID- 21257323 TI - Bicuspid aortic valve disease: the role of oxidative stress in Lrp5 bone formation. AB - The bicuspid aortic valve is a common congenital cardiac anomaly, having a prevalence of 0.9% to 1.37% in the general population and a male preponderance ratio of 2:1. The recognition of a bicuspid aortic valve is clinically relevant because of its association with aortic stenosis or regurgitation, aortic aneurysm or dissection, and infective endocarditis. Although some patients with a bicuspid aortic valve may go undetected without clinical complications for a lifetime, the vast majority will require intervention, most often surgery, at some point. In fact, the natural history of bicuspid aortic valve is that of valve calcification and progressive stenosis that typically occur at a faster rate than in tricuspid aortic valves. This pattern of presentation supports the hypothesis that shear stress in patients with congenitally abnormal aortic valves may contribute to an earlier leaflet calcification. However, there is emerging research data showing that the valve calcification process might have a similar pathophysiologic process to that of vascular atherosclerosis. This review focuses on the current knowledge of the cellular mechanisms of bicuspid aortic valve. PMID- 21257325 TI - Morphometric dimensions of the caudal cervical vertebral column in clinically normal Doberman Pinschers, English Foxhounds and Doberman Pinschers with clinical signs of disk-associated cervical spondylomyelopathy. AB - Client-owned, clinically normal Doberman Pinschers (n=20), English Foxhounds (n=17), and Doberman Pinschers with clinical signs of disk-associated cervical spondylomyelopathy (DA-CSM) (n=17) were prospectively studied. All dogs underwent magnetic resonance imaging (MRI) of the cervical vertebral column. To evaluate vertebral canal stenosis, the canal occupying ratios of the spinal cord and cerebrospinal fluid (CSF)-column were calculated from C5 to C7. To evaluate the degree of spinal cord compression and the amount of canal compromise, the compression ratio, remaining spinal cord and CSF-column area, and vertebral canal and dorsoventral vertebral canal compromise ratios were calculated at the site of most severe compression. For each canal occupying ratio, there was a significant higher value (implicating less space available for the spinal cord in the vertebral canal) at the level of C7 for clinically affected Doberman Pinschers compared with clinically normal English Foxhounds. The remaining spinal cord area was significantly smaller in dogs with clinically relevant spinal cord compression compared to dogs with clinically irrelevant spinal cord compression. Relative stenosis of the caudal cervical vertebral canal occurred more often in Doberman Pinschers with DA-CSM compared to English Foxhounds and a critical degree of spinal cord compression should be reached to result in clinical signs. PMID- 21257326 TI - The impact of Alzheimer's disease on the functional connectivity between brain regions underlying pain perception. AB - Patients with Alzheimer's disease (AD) are administered fewer analgesics and report less clinical pain compared with their cognitively-intact peers, prompting much speculation about the likely impact of neurodegeneration on pain perception and processing. This study used functional connectivity analysis to examine the impact of AD on the integrated functioning of brain regions mediating the sensory, emotional, and cognitive aspects of pain. Fourteen patients with AD and 15 controls attended two experimental sessions. In an initial psychophysical testing session, a random staircase procedure was used to assess sensitivity to noxious mechanical pressure applied to the thumbnail. In a subsequent brain imaging session, fMRI data were collected as participants received noxious or innocuous thumbnail pressure, delivered at intensities corresponding with previously identified subjective pain thresholds. Two approaches to functional connectivity analysis were utilised. A seed-based correlation method was first used to identify regions showing significant functional connectivity with the right dorsolateral prefrontal cortex (DLPFC). Functional connectivity between a network of 17 predefined pain processing regions was then assessed. Between-group comparisons revealed enhanced functional connectivity between the DLPFC and the anterior mid cingulate cortex, periaqueductal grey, thalamus, hypothalamus, and several motor areas in patients with AD compared with control group. Likewise, inter-regional functional connectivity across most regions of the predefined pain network was shown to be greater in the patient group, with the enhanced functional connectivity centred on three nodes: the DLPFC-R, hypothalamus, and PAG. The results of this study support previous research suggesting an interplay between pain and cognitive processes in patients with AD. PMID- 21257327 TI - A fully integrated IQ-receiver for NMR microscopy. AB - We present a fully integrated CMOS receiver for micro-magnetic resonance imaging together with a custom-made micro-gradient system. The receiver is designed for an operating frequency of 300 MHz. The chip consists of an on-chip detection coil and tuning capacitor as well as a low-noise amplifier and a quadrature downconversion mixer with corresponding low-frequency amplification stages. The design is realized in a 0.13 MUm CMOS technology, it occupies a chip area of 950 * 800 MUm2 and it draws 50 mA from a supply voltage of 1.8 V. The achieved time domain spin sensitivity is 5*10(14)spins/Hz. Images of phantoms obtained in our custom-made gradient system with 8 MUm isotropic resolution are reported. PMID- 21257328 TI - Accumulation and distribution of alpha-synuclein and ubiquitin in the CNS of Gaucher disease mouse models. AB - Gaucher disease, a prevalent lysosomal storage disease, is caused by insufficient activity of acid beta-glucosidase (GCase) and resultant glucosylceramide accumulation. Recently in Parkinson disease (PD) patients, heterozygous mutations in GCase have been associated with earlier onset and more progressive PD. To understand the pathogenic relationships between GCase variants and Parkinsonism, alpha-synuclein and ubiquitin distributions and levels in the brains of several mouse models containing GCase variants were evaluated by immunohistochemistry. Progressive alpha-synuclein and ubiquitin aggregate accumulations were observed in the cortex, hippocampus, basal ganglia, brainstem, and some cerebellar regions between 4 and 24 weeks in mice that were homozygous for GCase [D409H (9H) or V394L (4L)] variants and also had a prosaposin hypomorphic (PS-NA) transgene. In 4L/PS-NA and 9H/PS-NA mice, this was coincident with progressive neurological manifestations and brain glucosylceramide accumulation. Ultrastructural studies showed electron dense inclusion bodies in neurons and axons of 9H/PS-NA brains. alpha-synuclein aggregates were also observed in ventricular, brainstem, and cerebellar regions of older mice (>42-weeks) with the GCase variant (D409H/D409H) without overt neurological disease. In a chemically induced GCase deficiency, alpha-synuclein aggregates and glucosylceramide accumulation also occurred. These studies demonstrate a relationship between glucosylceramide accumulation and alpha-synuclein aggregates, and implicate glucosylceramide accumulation as risk factor for the alpha-synucleinopathies. PMID- 21257329 TI - Exposure in utero to maternal diabetes leads to glucose intolerance and high blood pressure with no major effects on lipid metabolism. AB - AIM: Recent evidence shows that adult metabolic disease may originate from an adverse fetal environment that can alter organ development and function in postnatal life. This study aimed to analyze the effect of exposure in utero to maternal diabetes on the development of the metabolic syndrome in the offspring. METHODS: Pregnant rats were made diabetic (blood glucose was 20mM) with a single streptozotocin injection on day 0 of gestation. Offspring from diabetic mothers (DMO) and control mothers (CMO) were followed from birth to 12 months of age. In these animals, metabolic parameters, such as glucose tolerance, insulin sensitivity and plasma lipid levels, as well as pancreatic insulin and morphology were studied. RESULTS: Compared with controls, DMO offspring had normal birth weights, but impaired postnatal growth that persisted throughout life. Metabolic tests revealed that DMO offspring also showed impaired glucose tolerance at six months associated with decreased insulin sensitivity and low insulin secretion. In older animals (12 months old), this phenotype persisted, but to a lesser extent. The DMO offspring also presented with high blood pressure and decreased levels of fasting plasma triglycerides, but normal plasma NEFA, and HDL and total cholesterol. CONCLUSION: Altogether, these results show that our model of exposure in utero to maternal diabetes led to normal birth weights, and induced transient glucose intolerance and increased blood pressure with no major effects on lipid metabolism. It also suggests that a hyperglycaemic fetal environment may be able to 'programme' hypertension and glucose intolerance, but not alter lipid metabolism. PMID- 21257330 TI - [Radiological treatment of hepatocellular carcinoma in 2010]. AB - Several radiological techniques have been used for treating hepatocellular carcinoma. These include transcatheter arterial chemoembolization (TACE) and percutaneous therapy, such as radiofrequency (RF). The treatment efficacy of radiofrequency for hepatocellular carcinoma has been confirmed by several randomized and non randomized studies, with a benefit in terms of morbidity comparatively to surgery when cirrhosis is present. Radiofrequency ablation treatment is based on tumour size, shape and location, with a defined strategy and a proper patient selection. We will also review indications and technical aspects of transcatheter arterial chemoembolization (TACE). It is an accepted worldwide and effective treatment for patients with unresectable large or multinodular hepatocellular carcinoma. It improves significantly survival for adequate selected patients with preservation of liver function. PMID- 21257331 TI - Sonodynamic therapy using water-dispersed TiO2-polyethylene glycol compound on glioma cells: comparison of cytotoxic mechanism with photodynamic therapy. AB - Sonodynamic therapy is expected to be a novel therapeutic strategy for malignant gliomas. The titanium dioxide (TiO(2)) nanoparticle, a photosensitizer, can be activated by ultrasound. In this study, by using water-dispersed TiO(2) nanoparticles, an in vitro comparison was made between the photodynamic and sonodynamic damages on U251 human glioblastoma cell lines. Water-dispersed TiO(2) nanoparticles were constructed by the adsorption of chemically modified polyethylene glycole (PEG) on the TiO(2) surface (TiO(2)/PEG). To evaluate cytotoxicity, U251 monolayer cells were incubated in culture medium including 100 MUg/ml of TiO(2)/PEG for 3h and subsequently irradiated by ultraviolet light (5.0 mW/cm(2)) or 1.0MHz ultrasound (1.0 W/cm(2)). Cell survival was estimated by MTT assay 24h after irradiation. In the presence of TiO(2)/PEG, the photodynamic cytotoxic effect was not observed after 20 min of an ultraviolet light exposure, while the sonodynamic cytotoxicity effect was almost proportional to the time of sonication. In addition, photodynamic cytotoxicity of TiO(2)/PEG was almost completely inhibited by radical scavenger, while suppression of the sonodynamic cytotoxic effect was not significant. Results of various fluorescent stains showed that ultrasound-treated cells lost their viability immediately after irradiation, and cell membranes were especially damaged in comparison with ultraviolet-treated cells. These findings showed a potential application of TiO(2)/PEG to sonodynamic therapy as a new treatment of malignant gliomas and suggested that the mechanism of TiO(2)/PEG mediated sonodynamic cytotoxicity differs from that of photodynamic cytotoxicity. PMID- 21257332 TI - Intermediate alleles at the FRAXA and FRAXE loci in Parkinson's disease. AB - BACKGROUND: It is debatable whether the size of triplet repeats of the fragile X mental retardation genes FMR1 and FMR2 (found at the FRAXA and FRAXE loci) is associated with Parkinson's disease (PD). The aims of the current study were to investigate the relationship between these genes and PD and to determine whether these genes affected clinical manifestations of PD. METHODS: We recruited 206 PD patients and 227 control subjects from southern Spain. All subjects were screened for the size of CGG and CCG repeats at the FRAXA and FRAXE loci, respectively. Clinical features of each patient were examined in detail to study possible association between these features and genotype. RESULTS: Frequencies of FRAXA and FRAXE intermediate alleles were similar between PD and control groups. Clinical characteristics in PD patients, including severity of the disease, motor and non-motor symptoms, and motor complications and fluctuations were not affected by intermediate alleles at either locus. Two patients carrying FRAXA premutation alleles were identified showing clinical manifestations indistinguishable from idiopathic PD. CONCLUSIONS: FRAXA and FRAXE intermediate alleles do not seem to affect the risk for PD or modify clinical features in PD patients. PMID- 21257333 TI - Relationship between the physical environment and physical activity in older adults: a systematic review. AB - Previous reviews on children, adolescents and adults have reported consistent relationships between several physical environmental characteristics and physical activity (PA). This systematic review aims to provide a comprehensive overview of the literature concerning the relationship between the physical environment and PA in older adults. A systematic literature search resulted in the inclusion of 31 articles. Results were inconsistent but most of the studied environmental characteristics were reported not to be related to PA. More studies in different contexts utilizing longitudinal designs, standardized, reliable and validated PA and environmental measurements and investigating possible moderating effects are definitely warranted. PMID- 21257334 TI - Reducing harm in drinking environments: a systematic review of effective approaches. AB - Drinking environments, including bars, nightclubs and their surrounds are associated with high levels of acute alcohol-related harms. This systematic review examined the effectiveness of interventions implemented in drinking environments to reduce alcohol use and associated harms. The findings of the review were limited by the methodological shortcomings of the included studies. However, three studies indicated that multicomponent programmes combining community mobilisation, RBS training, house policies and stricter enforcement of licensing laws may be effective in reducing assaults, traffic crashes, and underage sales depending on the focus of the intervention. The effectiveness of other intervention approaches was limited. Future studies of interventions in drinking environments should focus on using appropriate and robust study designs. PMID- 21257335 TI - Can a deterministic spatial microsimulation model provide reliable small-area estimates of health behaviours? An example of smoking prevalence in New Zealand. AB - Models created to estimate neighbourhood level health outcomes and behaviours can be difficult to validate as prevalence is often unknown at the local level. This paper tests the reliability of a spatial microsimulation model, using a deterministic reweighting method, to predict smoking prevalence in small areas across New Zealand. The difference in the prevalence of smoking between those estimated by the model and those calculated from census data is less than 20% in 1745 out of 1760 areas. The accuracy of these results provides users with greater confidence to utilize similar approaches in countries where local-level smoking prevalence is unknown. PMID- 21257336 TI - Ancient and essential: the assembly of iron-sulfur clusters in plants. AB - In plants iron-sulfur (Fe-S) proteins are found in the plastids, mitochondria, cytosol and nucleus, where they are essential for numerous physiological and developmental processes. Recent mutant studies, mostly in Arabidopsis thaliana, have identified three pathways for the assembly of Fe-S clusters. The plastids harbor the SUF (sulfur mobilization) pathway and operate independently, whereas cluster assembly in the cytosol depends on the emerging CIA (cytosolic iron sulfur cluster assembly) pathway and mitochondria. The latter organelles use the ISC (iron-sulfur cluster) assembly pathway. In all three pathways the assembly process can be divided into a first stage where S and Fe are combined on a scaffold protein, and a second stage in which the Fe-S cluster is transferred to a target protein. The second stage might involve different carrier proteins with specialized functions. PMID- 21257337 TI - Compartmental tongue surgery: Long term oncologic results in the treatment of tongue cancer. AB - Compartmental tongue surgery (CTS) is a surgical technique that removes the compartments (anatomo-functional units) containing the primary tumor, eliminating the disease and potential muscular, vascular, glandular and lymphatic pathways of spread and recurrence. Compartment boundaries are defined as each hemi-tongue bounded by the lingual septum, the stylohyoid ligament and muscle, and the mylohyoid muscle. In this non-randomized retrospective study we evaluated the oncologic efficacy of CTS in patients with squamous cell carcinoma (SCCA) of the tongue treated from 1995 to 2008. We evaluated 193 patients with primary, previously untreated cT2-4a, cN0, cN+, M0 SCCA with no contraindication to anesthesia and able to give informed consent. Fifty patients treated between October 1995 and July 1999 received standard surgery (resection margin >1cm); 143 patients treated between July 1999 and January 2008 received CTS. Study endpoints were: 5-year local disease-free, locoregional disease-free and overall survival. After 5years, local disease control was achieved in 88.4% of CTS patients (16.8% improvement on standard surgery); locoregional disease control in 83.5% (24.4% improvement) and overall survival was 70.7% (27.3% improvement). The markedly improved outcomes in CTS patients, compared to those treated by standard surgery, suggest CTS as an important new approach in the surgical management of tongue cancer. PMID- 21257338 TI - Surgery alone provides long-term survival rates comparable to those of surgery plus postoperative radiotherapy for patients with adenoid cystic carcinoma of the palate. AB - We compared the outcomes and rates of survival provided by surgery alone and surgery combined with postoperative radiotherapy for patients with adenoid cystic carcinoma of the palate (ACP), a rare, low-grade malignant tumor arising within the salivary glands. Fifty-eight patients with ACP were included in this retrospective study. ACP at stages T(1), T(2), T(3,) and T(4) was found in 11, 32, 5, and 10 patients, respectively. The patients were treated with surgery alone or underwent surgery combined with postoperative radiotherapy. The 5, 10, and 15year survival rates were 75%, 37.5%, and 25%, respectively, among the 24 patients who underwent surgery alone. These were not significantly different from the rates of 70.6%, 35.3%, and 20.8%, respectively, among the 34 patients who underwent surgery plus postoperative radiotherapy (P=0.21). The 5 and 10year survival rates were significantly greater among patients receiving ?60Gy of radiotherapy than those among patients receiving <60Gy of radiotherapy (83.3% and 45.8% vs. 40.0% and 10.0%, respectively) (P=0.04). ACP exhibited good long-term survival rates when treated with surgery alone. Addition of postoperative radiotherapy at doses of ?60Gy had no effect on survival, but postoperative radiotherapy at doses of <60Gy reduced survival. Recurrence within the palate was the main cause of treatment failure. PMID- 21257339 TI - Quantum chemical simulations of solvent influence on UV-vis spectra and orbital shapes of azoderivatives of diphenylpropane-1,3-dione. AB - The DFT modeling of novel synthesized azoderivatives of beta-diketones - 2-(2-(2 hydroxyphenyl)hydrazono)-1,3-diphenylpropane-1,3-dione (1), 2-(2-(2-hydroxy-4 nitrophenyl)hydrazono)-1,3-diphenylpropane-1,3-dione (2), 3-(2-(1,3-dioxo-1,3 diphenylpropan-2-ylidene)hydrazinyl)-2-hydroxy-5-nitrobenzene sulfonic acid (3), 2-(2-(1,3-dioxo-1,3-diphenylpropan-2-ylidene)hydrazinyl)benzenesulfonic acid (4), 2-(2-(1,3-dioxo-1,3-diphenylpropan -2-ylidene)hydrazinyl)benzoic acid (5), 2-(2 (2-hydroxy-4-nitrophenyl)hydrazono)-1-phenylbutane-1,3-dione (6) were performed. The collected information confirms that 1-5 exist in hydrazo form, being stabilized by the intramolecular hydrogen bonds in DMSO solution and solid phase, while 6 exists in mixed enol-azo and hydrazo tautomeric forms, the latter dominating in more polar solvents. The relative stability of various tautomeric and izomeric forms of the symmetric 1-5 and unsymmetric 6 azoderivatives of beta diketones is calculated based on the density functional theory (DFT). Polarizable Continuum Model was used to simulate solvatochromic effects. Solvents of different polarities were used to collect experimental spectra, and the same solvents were chosen for the PCM calculations. The optical properties of 1-6 have been investigated by density functional theory and its electronic absorption bands have been assigned by time-dependent density functional theory (TD-DFT). PMID- 21257340 TI - Classification of the biological material with use of FTIR spectroscopy and statistical analysis. AB - Rapid detection and discrimination of dangerous biological materials such as bacteria and their spores has become a security aim of considerable importance. Various analytical methods, including FTIR spectroscopy combined with statistical analysis have been used to identify vegetative bacteria, bacterial spores and background interferants. The present work discusses the application of FTIR technique performed in reflectance mode using Horizontal Attenuated Total Reflectance accessory (HATR) to the discrimination of biological materials. In comparison with transmission technique the HATR is more rapid and do not require the sample destruction, simultaneously giving similar absorbance bands. HATR-FTIR results combined with statistical analysis PCA and HCA demonstrate that this combination provides novel and accurate microbial identification technique. PMID- 21257341 TI - Vibrational spectra and structures of the anions of urazole and 4-methylurazole: DFT calculations of the normal modes and the influence of hydrogen bonding. AB - Solid state IR and Raman as well as aqueous solution state Raman spectra are reported for the anions of urazole and 4-methylurazole, and their N-deuterated derivatives. DFT calculations, at the B3-LYP/cc-pVTZ level, established that the structures and vibrational spectra of both anions can be interpreted using a model that incorporates hydrogen-bonded water molecules, in conjunction with the polarizable continuum solvation method. In the case of the urazole anion it is shown that deprotonation occurs primarily at N1 rather than N4, but there is also evidence for the second tautomer both in the solid state and in aqueous solution. The vibrational spectra were computed at the optimised molecular geometry in each case, enabling normal coordinate analysis, which yielded satisfactory agreement with the experimental IR and Raman data. Computed potential energy distributions of the normal modes provided detailed vibrational assignments. PMID- 21257342 TI - Highly sensitive sensing of zinc(II) by development and characterization of a PVC based fluorescent chemical sensor. AB - A sensor membrane with excellent performance based on 1-methyl-1-phenyl-3-[1 hydroxyimino-2-(succinimido)ethyl]cyclobutane has been developed for the determination of zinc(II) ions. The sensing membrane is capable of determining zinc(II) with an outstanding high selectivity over a dynamic range between 8.0*10(-8) and 1.6*10(-4) mol L(-1) with a limit of detection of 2.5*10(-8) mol L(-1) (1.6 MUg L(-1)). It can be easily and completely regenerated by using 0.1 mol L(-1) EDTA solution. The optical sensor developed here was found to be stable, cost effective, easy to prepare, and has unique selectivity towards Zn(2+) ion with respect to common metal ions. The proposed sensor was then applied for the determination of zinc in tap water and hair samples with satisfactory results. PMID- 21257343 TI - Enhancement of xylose uptake in 2-deoxyglucose tolerant mutant of Saccharomyces cerevisiae. AB - Chemical mutation of Saccharomyces cerevisiae using ethyl methane sulfonate was performed to enhance its ability of xylose uptake for ethanol production from lignocellulose under microaerobic condition. Among the appeared mutants, the mutant no. 2 (M2) strain screened using inhibitory effects of 2-deoxyglucose (DOG) showed more than 4-fold high ability in xylose uptake compared with the wild type strain, under the presence of glucose. The catabolite repression by glucose was sufficiently reduced in M2 strain due to its tolerance to the high concentration of DOG (0.5%, wt./vol.). Metabolomic analyses of various sugars in the cell revealed that some of xylose was reduced to xylitol in M2 cell, providing the concentration gradient of xylose and more uptake of xylose. Xylulose-5-phosphate was significantly detected in the crude cell extract from M2 strain, indicating higher metabolic activity in pentose phosphate pathway. This was also confirmed by in vitro analyses of key enzymes involved in glucose and xylose metabolism, such as hexokinase, glucose-6-phosphate dehydrogenase and xylose reductase. Glucose uptake was moderately suppressed in the presence of trehalose-6-phosphate inhibiting the activation of hexokinase, resulting in more uptake of xylose through hexose transport system. To our knowledge, this study is the first report verifying that the mutation technique successfully enhances the xylose uptake by S. cerevisiae, particularly under the presence of glucose. PMID- 21257344 TI - Recent worldwide sleep patterns and problems during adolescence: a review and meta-analysis of age, region, and sleep. AB - Adolescent sleep health is becoming increasingly recognized internationally as a significant concern, with many countries reporting high incidences of sleep disturbance in our youth. Notwithstanding the value of findings obtained from each large-scale survey of adolescent sleep performed within individual countries, the field lacks synthesis and analysis of adolescent sleep studies into a single review. This review presents findings from a meta-analysis of 41 surveys of worldwide adolescent sleep patterns and problems published in the last decade (1999-2010). Sleep patterns tended to delay with increasing age, restricting school-night sleep. Notably, Asian adolescents' bedtimes were later than peers from North America and Europe, resulting in less total sleep time on school nights and a tendency for higher rates of daytime sleepiness. Weekend sleep data were generally consistent worldwide, with bedtimes 2+ hours later and more total sleep time obtained. We note a worldwide delayed sleep-wake behavior pattern exists consistent with symptoms of Delayed Sleep Phase Disorder, which may be exacerbated by cultural factors. Recommendations for future surveys of adolescent sleep patterns are discussed and provided in light of current methodological limitations and gaps in the literature. PMID- 21257345 TI - Hypoxic challenge assessment in individuals with obstructive sleep apnea. AB - BACKGROUND: The degree of arterial hypoxemia during air travel in individuals with obstructive sleep apnea (OSA) is not known. The Aerospace Medical Association considers a ground level arterial oxygen tension (PaO2) above 9.3 kPa as safe before air travel. METHODS: Fifteen subjects with untreated OSA (mean apnea-hypopnea index [AHI] 43/h) and 14 with treated OSA (mean AHI on CPAP 1.9/h) completed an assessment including hypoxic challenge test (HCT). The groups had similar mean age, mean BMI and pre-treatment OSA severity. RESULTS: Four subjects, all in the untreated group and with resting PaO2 >9.3 kPa and oxygen saturation (SpO2) >95%, had a positive HCT (PaO2 <6.6 kPa and/or SpO2 <85%). The PaO2 at the end of the HCT was significantly correlated with the minimum overnight SpO2 (r=.754, p=.002) but not with the daytime PaO2 and SpO2. Using a cut off value of 65%, the minimum overnight SpO2 had positive and negative predictive values of 57% and 100% respectively. CONCLUSIONS: OSA can be an additional risk factor for developing significant arterial hypoxemia during HCT. Baseline PaO2 and SpO2 did not predict arterial hypoxemia during the HCT. Minimum overnight SpO2 <65% may be used as a cut off to advise further assessment. Effective treatment of OSA seems to be the best option before air travel. PMID- 21257346 TI - Attendance at chlorinated indoor pools and risk of asthma in adult recreational swimmers. AB - To study a potential correlation between attendance at chlorinated indoor pools and the onset of asthma in adult leisure swimmers. 1136 adult swimmers attending indoor pools in the city of Verona completed a modified ECRHS questionnaire. The cumulative time spent in the pools was calculated on the basis of the mean frequency and duration of weekly swim activity for every year of attendance. The median value (320 h) was used to divide participants into 2 groups. Other questions concerned the family history of allergies, the medical diagnosis and the onset of asthma. The prevalence of respiratory symptoms in the study group was compared with that of a general population sample. New-onset asthma, first identified at least 12 months after the start of regular pool attendance, was more prevalent among swimmers characterized by a higher cumulative pool attendance (23/514, 4.5%) than in swimmers who were attending indoor pools less frequently (2/508, 0.4%; ratio 11.1, 95% CI 2.6-47.4). The statistical analysis revealed an independent association between the cumulative lifetime hours spent in indoor swimming pools and new onset asthma (relative risk 1.05, 95% CI 1.02 1.07). Respiratory symptoms were less frequent in the study population versus a general population sample (prevalence ratio 0.26-0.68). Attendance at chlorinated indoor pools may constitute a risk factor for developing asthma in leisure adult swimmers. Future research and efforts should aim at improving disinfection techniques, hygiene and ventilation in indoor swimming pools in order to provide an unobjectionable ambient for salubrious swim activities. PMID- 21257348 TI - Understanding the laminated layer of larval Echinococcus I: structure. AB - Echinococcus larvae are protected by a massive carbohydrate-rich acellular structure, called the laminated layer. In spite of being widely considered the crucial element of these host-parasite interfaces, the laminated layer has been historically poorly understood. In fact, it is still often called 'chitinous', 'hyaline' or 'cuticular' layer, or said to be composed of polysaccharides. However, over the past few years the laminated layer was found to be comprised of mucins bearing defined galactose-rich carbohydrates, and accompanied, in the case of Echinococcus granulosus, by calcium inositol hexakisphosphate deposits. In this review, the architecture and biosynthesis of this unusual structure is discussed at depth in terms of what is known and what needs to be discovered. PMID- 21257347 TI - Angiotensin II and angiotensin-1-7 redox signaling in the central nervous system. AB - Reactive oxygen species (ROS) are important intra-neuronal signaling intermediates in angiotensin II (AngII)-related neuro-cardiovascular diseases associated with excessive sympathoexcitation, including hypertension and heart failure. ROS-sensitive effector mechanisms, such as modulation of ion channel activity, indicate that elevated levels of ROS increase neuronal activity. Nitric oxide, which may work to counter the effects of ROS, particularly superoxide, has been identified as a signaling molecule in angiotensin-1-7 (Ang-(1-7)) stimulated neurons. This review focuses on recent studies that have revealed details on the AngII-activated sources of ROS, the downstream redox-sensitive effectors, Ang-(1 7)-stimulated increase in nitric oxide, and the neuro-cardiovascular (patho)physiological responses modulated by these reactive species. Understanding these intra-neuronal signaling mechanisms should provide insight for the development of new redox-based therapeutics for the improved treatment of angiotensin-dependent neuro-cardiovascular diseases. PMID- 21257349 TI - HELP LDL-apheresis in two cases of familial hypercholesterolemic pregnant women. AB - We report our experience with selective LDL-apheresis in two women affected by autosomal recessive hypercholesterolemia and heterozygous familial hypercholesterolemia respectively, during pregnancy. To date only a few cases have been reported, because of the rarity of pregnancy in these patients and a hesitation of physicians to perform extracorporeal treatment. One of the patients had severe coronary artery disease, an absolute contraindication for pregnancy. Both patients had extremely elevated lipoprotein values because of their primary dyslipidemia, pregnancy-related modification of their lipid profile, and mandatory discontinuation of lipid-lowering drugs. In both cases the use of the Heparin-induced Extracorporeal Lipoprotein Precipitation (HELP) therapy improved the clinical situation and resulted in a good outcome for both mother and fetus. PMID- 21257351 TI - Presurgical epilepsy localization with interictal cerebral dysfunction. AB - Localization of interictal cerebral dysfunction with 2-[(18)F]fluoro-2-D deoxyglucose (FDG) positron emission tomography (PET) and neuropsychological examination usefully supplements electroencephalography (EEG) and brain magnetic resonance imaging (MRI) in planning epilepsy surgery. In MRI-negative mesial temporal lobe epilepsy, correlation of temporal lobe hypometabolism with extracranial ictal EEG can support resection without prior intracranial EEG monitoring. In refractory localization-related epilepsies, hypometabolic sites may supplement other data in hypothesizing likely ictal onset zones in order to intracranial electrodes for ictal recording. Prognostication of postoperative seizure freedom with FDG PET appears to have greater positive than negative predictive value. Neuropsychological evaluation is critical to evaluating the potential benefit of epilepsy surgery. Cortical deficits measured with neuropsychometry are limited in lateralizing and localizing value for determination of ictal onset sites, however. Left temporal resection risks iatrogenic verbal memory deficits and dysnomia, and neuropsychological findings are useful in predicting those at greatest risk. Prognostication of cognitive risks with resection at other sites is less satisfactory. PMID- 21257350 TI - DNA-based methods in the immunohematology reference laboratory. AB - Although hemagglutination serves the immunohematology reference laboratory well, when used alone, it has limited capability to resolve complex problems. This overview discusses how molecular approaches can be used in the immunohematology reference laboratory. In order to apply molecular approaches to immunohematology, knowledge of genes, DNA-based methods, and the molecular bases of blood groups are required. When applied correctly, DNA-based methods can predict blood groups to resolve ABO/Rh discrepancies, identify variant alleles, and screen donors for antigen-negative units. DNA-based testing in immunohematology is a valuable tool used to resolve blood group incompatibilities and to support patients in their transfusion needs. PMID- 21257352 TI - An overview of international literature from cystic fibrosis registries. Part 3. Disease incidence, genotype/phenotype correlation, microbiology, pregnancy, clinical complications, lung transplantation, and miscellanea. AB - This is the third article related to a review of the literature based on data from national cystic fibrosis (CF) patient registries up to June 2008 and covering a total of 115 published studies. It focuses on several topics: CF incidence, genotype/phenotype correlation, microbiology, pregnancy/paternity, clinical complications, lung transplantation, and others. Seventy seven papers meeting the inclusion criteria were found to be related to the topics listed above. Another seven studies, already evaluated in previous papers of this series, were recalled for specific topics. Incidence is described by several studies, results being quite different from one country to another and quite inhomogeneous among regions within the same country. Studies on genetics address the genotype/phenotype correlation and look for a predictive value of CFTR mutations in terms of clinical outcome, with controversial results. Papers on microbiology describe the clinical relevance of different pathogens and their role in the progress of CF lung disease. A few articles give information on the features of CF women undergoing a pregnancy and try to identify the ones associated with a better outcome. Studies on clinical complications discuss prevalence and the role of haemoptysis, pneumothorax, CF related diabetes, ABPA and cancer. Papers on lung transplantation focus on models able to improve the selection criteria for transplantation candidates and the factors linked to post transplantation survival. Finally, several studies deal with a number of interesting topics related to CF epidemiology: clinical trial methodology, quality of care comparison among countries and centers, relationship between diagnosis and age/gender, and evaluation of pharmacological therapy. On the whole, CF Registries have already contributed to important advances in the knowledge of the natural history of CF, establishing the foundations for future improvement in CF research and care. PMID- 21257353 TI - Modeling the impact of global warming on vector-borne infections. AB - Global warming will certainly affect the abundance and distribution of disease vectors. The effect of global warming, however, depends on the complex interaction between the human host population and the causative infectious agent. In this work we review some mathematical models that were proposed to study the impact of the increase in ambient temperature on the spread and gravity of some insect-transmitted diseases. PMID- 21257354 TI - Embodied cognition and the perception-action link. AB - Perception is interpreted as a set of capabilities that facilitate two functions necessary for survival; learning about the environment and controlling real-time behavioral interactions with it. Perceptual capabilities evolve in the context of an organism and its environment, adapted to an organism's ecological niche. The relation between embodied perception and action can be studied in the context of the only muscles that serve only to enable perception--the eye muscles. The only eye movements under cognitive control are saccades, the rapid jumps of binocular fixation from one target to another. The world is perceived as stable while the retinal image, and the corresponding projections inside the brain, are displaced with each saccade. This space constancy forms the stable platform for all other visual functions and requires an explanation that involves visual short-term memory. This memory, and the change detection that it makes possible, is enhanced when there is a physical interaction between the observer and the visual stimulus. Perception is something you do, not something that happens to you. PMID- 21257355 TI - A stomach carpeted red. PMID- 21257356 TI - The anti-deamidated gliadin peptide antibodies unmask celiac disease in small children with chronic diarrhoea. AB - OBJECTIVES: To assess the usefulness of a new class of antibodies, the anti deamidated gliadin peptides, in the diagnostic approach to children less than 2 years with suspected celiac disease. PATIENTS AND METHODS: We investigated 40 children (median age: 16.8 months; age range: 4-24 months), with symptoms and signs of chronic enteropathy and high serum levels of conventional anti-gliadin antibodies, but normal values of anti-transglutaminase and anti-endomysial antibodies; all underwent measurement of anti-deamidated gliadin peptides serum levels, upper gastrointestinal endoscopy with biopsies and HLA typing; 40 subjects served as controls. RESULTS: In 29 patients (group A) serum levels of anti-deamidated gliadin peptides were normal and duodenal histology showed a spectrum of abnormalities ranging from mucosal inflammatory infiltrates to villous damage (in almost all cases compatible with Marsh 1-to-2 lesions). All improved on a cow's and soy milk free diet containing gluten. In 11 patients (group B) there were high serum levels of anti-deamidated gliadin peptides and histology showed features suggestive of celiac disease (Marsh 2-to-3 lesions) in all; furthermore, human leucocyte antigen typing was consistent with a celiac disease genetic pattern in all. Group B patients significantly improved on a gluten free diet containing cow's and soy milk proteins. None of the control group was anti-deamidated gliadin peptides positive. CONCLUSIONS: In children younger than 2 years with signs of chronic enteropathy and normal values of classical serum markers of celiac disease, the latter can be predicted by high serum levels of anti-deamidated gliadin peptides. PMID- 21257357 TI - Variations of plantar thermographic patterns in normal controls and non-ulcer diabetic patients: novel classification using angiosome concept. AB - Thermometry of the plantar skin temperature has been one of the important parameters for assessing ulceration risks in diabetic patients. Recent progress of infrared thermographic technology allows us to obtain imaging of temperature distribution of the whole plantar skin. However, it has not been fully elucidated to what extent the individual variation of the plantar thermographic patterns shows different trends between normal controls and diabetics. In this study, we made a novel framework of conceptual classification with 20 different categories of plantar thermographic patterns according to the foot angiosome concept. The thermographic images from 32 normal volunteers and 129 non-ulcer diabetic patients, recruited from Diabetes Foot Outpatient Clinic of the University of Tokyo Hospital, were allocated to the above-mentioned framework categories. In the normal group, thermographic patterns of more than 65% of feet were allocated to the two typical categories, including the 'butterfly pattern' among the 20 categories, whereas 225 feet (87.2%) of the diabetic groups were variously allocated to 18 out of the 20 categories. This is the first study, which describes detailed plantar thermographic patterns, showing wider variations in the diabetic patients than in the normal subjects. Thermography will be one of the screening options to assess circulatory status in both daily foot care and surgical intervention. PMID- 21257358 TI - Diversity of 15 human X chromosome microsatellite loci in Polish population. AB - X-STR analysis is a powerful tool in both phylogeny reconstruction and forensic investigation. Hereby, we provide new population data concerning 15 X-STR loci (included in commercially available typing kit Mentype Argus X-8 (Biotype AG, Dresden, Germany) (DXS10135, DXS8378, DXS7132, DXS10074, HPRTB, DXS10101, DXS10134 and DXS7423) and another seven (DXS6807, DXS9898, DXS101, DXS7424, DXS7133, DXS8377 and DXS10011) that were previously described by Poetsch et al. [1] obtained from a sample of 311 individuals from Poland and compared to the results previously obtained from other populations of European, Asian and African origin [2-4]. Numerous experiments seem to prove that X-STRs are valuable markers for human identification, kinship testing and even phylogenetic research - thus serving as a complement for autosomal microsatellites, Y-STRs and mtDNA [5-7]. PMID- 21257359 TI - Paraneoplastic dermatomyositis accompanying nasopharyngeal carcinoma: diagnosis, treatment and prognosis. AB - Dermatomyositis (DM) is a multisystem inflammatory disorder primarily affecting the skin and muscles. Its pathophysiology is still very poorly understood, but humoral and cellular immune dysregulation is apparent. Diagnosis of DM is based on five criteria: proximal limb muscle weakness, serum muscle enzyme elevation, histopathologic muscle abnormalities on muscle biopsy, electromyographic abnormalities, and clinical inflammatory dermatological manifestations (heliotrope rash, poikiloderma, and inflammatory lesions on the hands and facing joints). DM is frequently associated with certain cancers, and may appear before, concurrent with, or after diagnosis of cancer. DM has been reported to be associated with approximately one per 1000 cases of nasopharyngeal carcinoma. Treatment is based on long-course nonselective immunosuppression, particularly corticosteroids, by general route, even when malignancy is present, but new targeted therapies may modify the treatment strategy in the near future. Despite iatrogenic immunosuppression, the prognosis of nasopharyngeal cancer is not worse in patients with paraneoplastic DM. We report one case as an illustration of this paraneoplastic course (evolving in parallel with the cancer), and to make an update on the state of knowledge on paraneoplastic DM in such cancers. PMID- 21257360 TI - Automatic extraction of inferior alveolar nerve canal using feature-enhancing panoramic volume rendering. AB - Dental implant surgery, which involves the surgical insertion of a dental implant into the jawbone as an artificial root, has become one of the most successful applications of computed tomography (CT) in dental implantology. For successful implant surgery, it is essential to identify vital anatomic structures such as the inferior alveolar nerve (IAN), which should be avoided during the surgical procedure. Due to the ambiguity of its structure, the IAN is very elusive to extract in dental CT images. As a result, the IAN canal is typically identified in most previous studies. This paper presents a novel method of automatically extracting the IAN canal. Mental and mandibular foramens, which are regarded as the ends of the IAN canal in the mandible, are detected automatically using 3-D panoramic volume rendering (VR) and texture analysis techniques. In the 3-D panoramic VR, novel color shading and compositing methods are proposed to emphasize the foramens and isolate them from other fine structures. Subsequently, the path of the IAN canal is computed using a line-tracking algorithm. Finally, the IAN canal is extracted by expanding the region of the path using a fast marching method with a new speed function exploiting the anatomical information about the canal radius. In experimental results using ten clinical datasets, the proposed method identified the IAN canal accurately, demonstrating that this approach assists dentists substantially during dental implant surgery. PMID- 21257361 TI - Spectral estimation of nonstationary EEG using particle filtering with application to event-related desynchronization (ERD). AB - This paper proposes non-Gaussian models for parametric spectral estimation with application to event-related desynchronization (ERD) estimation of nonstationary EEG. Existing approaches for time-varying spectral estimation use time-varying autoregressive (TVAR) state-space models with Gaussian state noise. The parameter estimation is solved by a conventional Kalman filtering. This study uses non Gaussian state noise to model autoregressive (AR) parameter variation with estimation by a Monte Carlo particle filter (PF). Use of non-Gaussian noise such as heavy-tailed distribution is motivated by its ability to track abrupt and smooth AR parameter changes, which are inadequately modeled by Gaussian models. Thus, more accurate spectral estimates and better ERD tracking can be obtained. This study further proposes a non-Gaussian state space formulation of time varying autoregressive moving average (TVARMA) models to improve the spectral estimation. Simulation on TVAR process with abrupt parameter variation shows superior tracking performance of non-Gaussian models. Evaluation on motor-imagery EEG data shows that the non-Gaussian models provide more accurate detection of abrupt changes in alpha rhythm ERD. Among the proposed non-Gaussian models, TVARMA shows better spectral representations while maintaining reasonable good ERD tracking performance. PMID- 21257362 TI - Automatic detection of pathological voices using complexity measures, noise parameters, and mel-cepstral coefficients. AB - This paper proposes a new approach to improve the amount of information extracted from the speech aiming to increase the accuracy of a system developed for the automatic detection of pathological voices. The paper addresses the discrimination capabilities of 11 features extracted using nonlinear analysis of time series. Two of these features are based on conventional nonlinear statistics (largest Lyapunov exponent and correlation dimension), two are based on recurrence and fractal-scaling analysis, and the remaining are based on different estimations of the entropy. Moreover, this paper uses a strategy based on combining classifiers for fusing the nonlinear analysis with the information provided by classic parameterization approaches found in the literature (noise parameters and mel-frequency cepstral coefficients). The classification was carried out in two steps using, first, a generative and, later, a discriminative approach. Combining both classifiers, the best accuracy obtained is 98.23% +/- 0.001. PMID- 21257363 TI - Ambulatory estimation of knee-joint kinematics in anatomical coordinate system using accelerometers and magnetometers. AB - Knee-joint kinematics analysis using an optimal sensor set and a reliable algorithm would be useful in the gait analysis. An original approach for ambulatory estimation of knee-joint angles in anatomical coordinate system is presented, which is composed of a physical-sensor-difference-based algorithm and virtual-sensor-difference-based algorithm. To test the approach, a wearable monitoring system composed of accelerometers and magnetometers was developed and evaluated on lower limb. The flexion/extension (f/e), abduction/adduction (a/a), and inversion/extension (i/e) rotation angles of the knee joint in the anatomical joint coordinate system were estimated. In this method, since there is no integration of angular acceleration or angular velocity, the result is not distorted by offset and drift. The three knee-joint angles within the anatomical coordinate system are independent of the orders, which must be considered when Euler angles are used. Besides, since there are no physical sensors implanted in the knee joint based on the virtual-sensor-difference-based algorithm, it is feasible to analyze knee-joint kinematics with less numbers and types of sensors than those mentioned in some others methods. Compared with results from the reference system, the developed wearable sensor system is available to do gait analysis with fewer sensors and high degree of accuracy. PMID- 21257364 TI - Reduced conductivity dependence method for increase of dipole localization accuracy in the EEG inverse problem. AB - The EEG is a neurological diagnostic tool with high temporal resolution. However, when solving the EEG inverse problem, its localization accuracy is limited because of noise in measurements and available uncertainties of the conductivity value in the forward model evaluations. This paper proposes the reduced conductivity dependence (RCD) method for decreasing the localization error in EEG source analysis by limiting the propagation of the uncertain conductivity values to the solutions of the inverse problem. We redefine the traditional EEG cost function, and in contrast to previous approaches, we introduce a selection procedure of the EEG potentials. The selected potentials are, as low as possible, affected by the uncertainties of the conductivity when solving the inverse problem. We validate the methodology on the widely used three-shell spherical head model with a single electrical dipole and multiple dipoles as source model. The proposed RCD method enhances the source localization accuracy with a factor ranging between 2 and 4, dependent on the dipole location and the noise in measurements. PMID- 21257365 TI - Challenges and opportunities for next-generation intracortically based neural prostheses. AB - Neural prosthetic systems aim to help disabled patients by translating neural signals from the brain into control signals for guiding computer cursors, prosthetic arms, and other assistive devices. Intracortical electrode arrays measure action potentials and local field potentials from individual neurons, or small populations of neurons, in the motor cortices and can provide considerable information for controlling prostheses. Despite several compelling proof-of concept laboratory animal experiments and an initial human clinical trial, at least three key challenges remain which, if left unaddressed, may hamper the translation of these systems into widespread clinical use. We review these challenges: achieving able-bodied levels of performance across tasks and across environments, achieving robustness across multiple decades, and restoring able bodied quality proprioception and somatosensation. We also describe some emerging opportunities for meeting these challenges. If these challenges can be largely or fully met, intracortically based neural prostheses may achieve true clinical viability and help increasing numbers of disabled patients. PMID- 21257366 TI - Detection of vesicoureteral reflux using microwave radiometry-system characterization with tissue phantoms. AB - Microwave (MW) radiometry is proposed for passive monitoring of kidney temperature to detect vesicoureteral reflux (VUR) of urine that is externally heated by a MW hyperthermia device and thereafter reflows from the bladder to kidneys during reflux. Here, we characterize in tissue-mimicking phantoms the performance of a 1.375 GHz radiometry system connected to an electromagnetically (EM) shielded microstrip log spiral antenna optimized for VUR detection. Phantom EM properties are characterized using a coaxial dielectric probe and network analyzer (NA). Power reflection and receive patterns of the antenna are measured in layered tissue phantom. Receiver spectral measurements are used to assess EM shielding provided by a metal cup surrounding the antenna. Radiometer and fiberoptic temperature data are recorded for varying volumes (10-30 mL) and temperaturesg (40-46 degrees C) of the urine phantom at 35 mm depth surrounded by 36.5 degrees C muscle phantom. Directional receive pattern with about 5% power spectral density at 35 mm target depth and better than -10 dB return loss from tissue load are measured for the antenna. Antenna measurements demonstrate no deterioration in power reception and effective EM shielding in the presence of the metal cup. Radiometry power measurements are in excellent agreement with the temperature of the kidney phantom. Laboratory testing of the radiometry system in temperature-controlled phantoms supports the feasibility of passive kidney thermometry for VUR detection. PMID- 21257367 TI - Continuous intra-arterial blood pH monitoring by a fiber-optic fluorosensor. AB - Continuous intra-arterial blood pH monitoring is highly desirable in clinical practice. However, devices with appreciable accuracy are still not commercially available to date. In this study, we present a fiber-optic fluorosensor that can be used to continuously and accurately measure blood pH changes. The pH sensor is developed based on a proton-sensitive fluorescence dye, N-allyl-4-(4'-methyl piperazinyl)-1,8-naphthalimide, which is bonded covalently to an optical fiber through heat polymerization. Fluorescence intensity was recorded after the sensor was exposed to different pH buffer solutions or intra-arterial blood in rabbits. Fluorescence intensity with emission peak at 510 nm decreased immediately as the blood pH increased. Linear and reproducible responses were observed when pH ranges from 6.8 to 8.0 with resolution of 0.03 pH units. The correlation coefficient between the pH sensor and the conventional blood gas analyzer was 0.93 in vivo ( n=75, p<0.001) with a bias and precision of -0.02 +/- 0.08 pH units. The pH sensor was stable during measurement for at least 72 h. The pH sensor is not sensitive to fluctuations of various ions' concentrations and plasma osmosis at pathophysiological limits, suggesting that it is useful for the continuous measurement of blood pH at various clinical settings. PMID- 21257368 TI - Personalization of a cardiac electrophysiology model using optical mapping and MRI for prediction of changes with pacing. AB - Computer models of cardiac electrophysiology (EP) can be a very efficient tool to better understand the mechanisms of arrhythmias. Quantitative adjustment of such models to experimental data (personalization) is needed in order to test their realism and predictive power, but it remains challenging at the organ scale. In this paper, we propose a framework for the personalization of a 3-D cardiac EP model, the Mitchell-Schaeffer (MS) model, and evaluate its volumetric predictive power under various pacing scenarios. The personalization was performed on ex vivo large porcine healthy hearts using diffusion tensor MRI (DT-MRI) and optical mapping data. The MS model was simulated on a 3-D mesh incorporating local fiber orientations, built from DT-MRI. The 3-D model parameters were optimized using features such as 2-D epicardial depolarization and repolarization maps, extracted from the optical mapping. We also evaluated the sensitivity of our personalization framework to different pacing locations and showed results on its robustness. Further, we evaluated volumetric model predictions for various epi- and endocardial pacing scenarios. We demonstrated promising results with a mean personalization error around 5 ms and a mean prediction error around 10 ms (5% of the total depolarization time). Finally, we discussed the potential translation of such work to clinical data and pathological hearts. PMID- 21257369 TI - Real-time adaptive microstimulation increases reliability of electrically evoked cortical potentials. AB - Cortical neuroprostheses that employ repeated electrical stimulation of cortical areas with fixed stimulus parameters, are faced with the problem of large trial by-trial variability of evoked potentials. This variability is caused by the ongoing cortical signal processing, but it is an unwanted phenomenon if one aims at imprinting neural activity as precisely as possible. Here, we use local field potentials measured by one microelectrode, located at a distance of 200 microns from the stimulation site, to drive the electrically evoked potential toward a desired target potential by real-time adaptation of the stimulus intensity. The functional relationship between ongoing cortical activity, evoked potential, and stimulus intensity was estimated by standard machine learning techniques (support vector regression with problem-specific kernel function) from a set of stimulation trials with randomly varied stimulus intensities. The smallest deviation from the target potential was achieved for low stimulus intensities. Further, the observed precision effect proved time sensitive, since it was abolished by introducing a delay between data acquisition and stimulation. These results indicate that local field potentials contain sufficient information about ongoing local signal processing to stabilize electrically evoked potentials. We anticipate that adaptive low intensity microstimulation will play an important role in future cortical prosthetic devices that aim at restoring lost sensory functions. PMID- 21257370 TI - Bubbly cavitating flow generation and investigation of its erosional nature for biomedical applications. AB - This paper presents a study that investigates the destructive energy output resulting from hydrodynamic bubbly cavitation in microchannels and its potential use in biomedical applications. The research performed in this study includes results from bubbly cavitation experiments and findings showing the destructive effects of bubbly cavitating flow on selected solid specimens and live cells. The bubbles generated by hydrodynamic cavitation are highly destructive at the surfaces of the target medium on which they are carefully focused. The resulting destructive energy output could be effectively used for biomedical treatments, such as destroying kidney stones (renal calculi) or killing cancer cells. Motivated by this potential, the cavitation damage to cancerous cells and material removal from chalk pieces (which possess similar material properties as some kidney stones) was investigated. Our results showed that cavitation could induce damage both on chalk pieces and leukemia/lymphoma cells. We discovered that hydrodynamic cavitation exposure had early and delayed effects on cancer cell survival. Hence, the potential of hydrodynamic bubbly cavitation generated at the microscale for biomedical treatments was revealed using the microchannel configuration as a microorifice (with an inner diameter of 147 MUm and a length of 1.52 cm), which acts as the source of bubbly cavitating flows. PMID- 21257371 TI - Model-based human circadian phase estimation using a particle filter. AB - We present a method for tracking an individual's circadian phase that integrates dynamic models of circadian physiology with physiological measurements in a Bayesian statistical framework. A model of the circadian pacemaker's response to light exposure is transformed into a nonlinear state-space model with a circadian phase state. The probability distribution of the circadian phase is estimated by a particle filter that predicts changes over time based on the model, and performs updates with information gained from physiological measurements. Simulations demonstrate how probability distributions allow flexible initialization of model states and enable statistical quantification of entrainment and divergence properties of the circadian pacemaker. The combined use of sleep-wake scheduling data and physiological measurements is demonstrated in a case study highlighting advantages for addressing the challenge of noninvasive ambulatory monitoring of circadian physiology. PMID- 21257372 TI - Finite-element modeling of soft tissue rolling indentation. AB - We describe a finite-element (FE) model for simulating wheel-rolling tissue deformations using a rolling FE model (RFEM). A wheeled probe performing rolling tissue indentation has proven to be a promising approach for compensating for the loss of haptic and tactile feedback experienced during robotic-assisted minimally invasive surgery (H. Liu, D. P. Noonan, B. J. Challacombe, P. Dasgupta, L. D. Seneviratne, and K. Althoefer, "Rolling mechanical imaging for tissue abnormality localization during minimally invasive surgery, " IEEE Trans. Biomed. Eng., vol. 57, no. 2, pp. 404-414, Feb. 2010; K. Sangpradit, H. Liu, L. Seneviratne, and K. Althoefer, "Tissue identification using inverse finite element analysis of rolling indentation," in Proc. IEEE Int. Conf. Robot. Autom. , Kobe, Japan, 2009, pp. 1250-1255; H. Liu, D. Noonan, K. Althoefer, and L. Seneviratne, "The rolling approach for soft tissue modeling and mechanical imaging during robot-assisted minimally invasive surgery," in Proc. IEEE Int. Conf. Robot. Autom., May 2008, pp. 845-850; H. Liu, P. Puangmali, D. Zbyszewski, O. Elhage, P. Dasgupta, J. S. Dai, L. Seneviratne, and K. Althoefer, "An indentation depth-force sensing wheeled probe for abnormality identification during minimally invasive surgery," Proc. Inst. Mech. Eng., H, vol. 224, no. 6, pp. 751-63, 2010; D. Noonan, H. Liu, Y. Zweiri, K. Althoefer, and L. Seneviratne, "A dual-function wheeled probe for tissue viscoelastic property identification during minimally invasive surgery," in Proc. IEEE Int. Conf. Robot. Autom. , 2008, pp. 2629-2634; H. Liu, J. Li, Q. I. Poon, L. D. Seneviratne, and K. Althoefer, "Miniaturized force indentation depth sensor for tissue abnormality identification," IEEE Int. Conf. Robot. Autom., May 2010, pp. 3654-3659). A sound understanding of wheel-tissue rolling interaction dynamics will facilitate the evaluation of signals from rolling indentation. In this paper, we model the dynamic interactions between a wheeled probe and a soft tissue sample using the ABAQUS FE software package. The aim of this work is to more precisely locate abnormalities within soft tissue organs using RFEM and hence aid surgeons to improve diagnostic ability. The soft tissue is modeled as a nonlinear hyperelastic material with geometrical nonlinearity. The proposed RFEM was validated on a silicone phantom and a porcine kidney sample. The results show that the proposed method can predict the wheel-tissue interaction forces of rolling indentation with good accuracy and can also accurately identify the location and depth of simulated tumors. PMID- 21257373 TI - BELM: Bayesian extreme learning machine. AB - The theory of extreme learning machine (ELM) has become very popular on the last few years. ELM is a new approach for learning the parameters of the hidden layers of a multilayer neural network (as the multilayer perceptron or the radial basis function neural network). Its main advantage is the lower computational cost, which is especially relevant when dealing with many patterns defined in a high dimensional space. This brief proposes a bayesian approach to ELM, which presents some advantages over other approaches: it allows the introduction of a priori knowledge; obtains the confidence intervals (CIs) without the need of applying methods that are computationally intensive, e.g., bootstrap; and presents high generalization capabilities. Bayesian ELM is benchmarked against classical ELM in several artificial and real datasets that are widely used for the evaluation of machine learning algorithms. Achieved results show that the proposed approach produces a competitive accuracy with some additional advantages, namely, automatic production of CIs, reduction of probability of model overfitting, and use of a priori knowledge. PMID- 21257374 TI - Efficient sparse generalized multiple kernel learning. AB - Kernel methods have been successfully applied in various applications. To succeed in these applications, it is crucial to learn a good kernel representation, whose objective is to reveal the data similarity precisely. In this paper, we address the problem of multiple kernel learning (MKL), searching for the optimal kernel combination weights through maximizing a generalized performance measure. Most MKL methods employ the L(1)-norm simplex constraints on the kernel combination weights, which therefore involve a sparse but non-smooth solution for the kernel weights. Despite the success of their efficiency, they tend to discard informative complementary or orthogonal base kernels and yield degenerated generalization performance. Alternatively, imposing the L(p)-norm (p > 1) constraint on the kernel weights will keep all the information in the base kernels. This leads to non-sparse solutions and brings the risk of being sensitive to noise and incorporating redundant information. To tackle these problems, we propose a generalized MKL (GMKL) model by introducing an elastic-net type constraint on the kernel weights. More specifically, it is an MKL model with a constraint on a linear combination of the L(1)-norm and the squared L(2)-norm on the kernel weights to seek the optimal kernel combination weights. Therefore, previous MKL problems based on the L(1)-norm or the L(2)-norm constraints can be regarded as special cases. Furthermore, our GMKL enjoys the favorable sparsity property on the solution and also facilitates the grouping effect. Moreover, the optimization of our GMKL is a convex optimization problem, where a local solution is the global optimal solution. We further derive a level method to efficiently solve the optimization problem. A series of experiments on both synthetic and real-world datasets have been conducted to show the effectiveness and efficiency of our GMKL. PMID- 21257375 TI - MDS-based multiresolution nonlinear dimensionality reduction model for color image segmentation. AB - In this paper, we present an efficient coarse-to-fine multiresolution framework for multidimensional scaling and demonstrate its performance on a large-scale nonlinear dimensionality reduction and embedding problem in a texture feature extraction step for the unsupervised image segmentation problem. We demonstrate both the efficiency of our multiresolution algorithm and its real interest to learn a nonlinear low-dimensional representation of the texture feature set of an image which can then subsequently be exploited in a simple clustering-based segmentation algorithm. The resulting segmentation procedure has been successfully applied on the Berkeley image database, demonstrating its efficiency compared to the best existing state-of-the-art segmentation methods recently proposed in the literature. PMID- 21257376 TI - Interval-valued fuzzy sets applied to stereo matching of color images. AB - Stereo matching problem attempts to find corresponding locations between pairs of displaced images of the same scene. Correspondence estimation between pixels suffers from occlusions, noise, and bias. This paper introduces a novel approach to represent images by means of interval-valued fuzzy sets. These sets allow one to overcome the uncertainty due to the aforementioned problems. The aim is to take advantage of the new representation to develop a stereo matching algorithm. The interval-valued fuzzification process for images that is proposed here is based on image segmentation. Interval-valued fuzzy similarities are introduced to compare windows whose pixels are represented by intervals. To make use of color information, the similarities of the RGB channels were aggregated using the luminance formula. The experimental analysis makes a comparison with other methods. The new representation that is proposed together with the new similarity measure show a better overall behavior, providing more accurate correspondences, mainly near depth discontinuities and for images with a large amount of color. PMID- 21257377 TI - Least-squares luma-chroma demultiplexing algorithm for Bayer demosaicking. AB - This paper addresses the problem of interpolating missing color components at the output of a Bayer color filter array (CFA), a process known as demosaicking. A luma-chroma demultiplexing algorithm is presented in detail, using a least squares design methodology for the required bandpass filters. A systematic study of objective demosaicking performance and system complexity is carried out, and several system configurations are recommended. The method is compared with other benchmark algorithms in terms of CPSNR and S-CIELAB ?E* objective quality measures and demosaicking speed. It was found to provide excellent performance and the best quality-speed tradeoff among the methods studied. PMID- 21257378 TI - Curvature interpolation method for image zooming. AB - We introduce a novel image zooming algorithm, called the curvature interpolation method (CIM), which is partial-differential-equation (PDE)-based and easy to implement. In order to minimize artifacts arising in image interpolation such as image blur and the checkerboard effect, the CIM first evaluates the curvature of the low-resolution image. After interpolating the curvature to the high resolution image domain, the CIM constructs the high-resolution image by solving a linearized curvature equation, incorporating the interpolated curvature as an explicit driving force. It has been numerically verified that the new zooming method can produce clear images of sharp edges which are already denoised and superior to those obtained from linear methods and PDE-based methods of no curvature information. Various results are given to prove effectiveness and reliability of the new method. PMID- 21257379 TI - Autocorrelation-driven diffusion filtering. AB - In this paper, we present a novel scheme for anisotropic diffusion driven by the image autocorrelation function. We show the equivalence of this scheme to a special case of iterated adaptive filtering. By determining the diffusion tensor field from an autocorrelation estimate, we obtain an evolution equation that is computed from a scalar product of diffusion tensor and the image Hessian. We propose further a set of filters to approximate the Hessian on a minimized spatial support. On standard benchmarks, the resulting method performs favorable in many cases, in particular at low noise levels. In a GPU implementation, video real-time performance is easily achieved. PMID- 21257380 TI - Hybrid diversification operator-based evolutionary approach towards tomographic image reconstruction. AB - The proposed algorithm introduces a new and efficient hybrid diversification operator (HDO) in the evolution cycle to improve the tomographic image reconstruction and diversity in the population by using simulated annealing (SA), and the modified form of decreasing law of mutation probability. This evolutionary approach has been used for parallel-ray transmission tomography with the head and lung phantoms. The algorithm is designed to address the observation that the convergence of a genetic algorithm slows down as it evolves. The HDO is shown to yield a higher image quality as compared with the filtered back projection (FBP), the multiscale wavelet transform, the SA, and the hybrid continuous genetic algorithm (HCGA) techniques. Various crossover operators including uniform, block, and image-row crossover operators have also been analyzed, and the latter has been generally found to give better image quality. The HDO is shown to yield improvements of up to 92% and 120% when compared with FBP in terms of PSNR, for 128 * 128 head and lung phantoms, respectively. PMID- 21257381 TI - Fuzzy Optimal Control for Multistage Fuzzy Systems. AB - In the case that a system is affected by fuzzy factors, a fuzzy optimal-control problem is proposed. A fuzzy optimal-control problem for a multistage fuzzy system is considered to optimize the expected value of a fuzzy objective function subject to a multistage fuzzy system where, at every stage, the system is disturbed by a fuzzy variable. Based on Bellman's Principle of Optimality, a recurrence equation for the problem is presented. A linear quadratic fuzzy optimal-control problem is shown to have an exact solution by the recurrence equation if the system is affected by triangular fuzzy variables. For general cases, two methods, the hybrid intelligent algorithm and the finite-search method, are established to approximate the solutions of the problem. Finally, an example is used to show that these two methods are effective to solve a fuzzy optimal-control problem for a multistage fuzzy system. PMID- 21257382 TI - Semisupervised Metric Learning by Maximizing Constraint Margin. AB - Distance-metric learning is an old problem that has been researched in the supervised-learning field for a very long time. In this paper, we consider the problem of learning a proper distance metric under the guidance of some weak supervisory information. Specifically, this information is in the form of pairwise constraints which specify whether a pair of data points is in the same class ( must-link constraints) or in different classes ( cannot-link constraints). Given those constraints, our algorithm aims to learn a distance metric under which the points with must-link constraints are pushed as close as possible, while simultaneously, the points with cannot-link constraints are pulled away as far as possible. The kernelized version of our algorithm is also derived to tackle the nonlinear problem. Moreover, since in many cases, the data objects, such as images and videos, are more naturally represented as higher order tensors than vectors, we also extend our algorithm to learn the metrics directly from the tensors. Finally, experimental results are presented to show the effectiveness of our method. PMID- 21257383 TI - Fault Detection for T-S Fuzzy Discrete Systems in Finite-Frequency Domain. AB - This paper investigates the problem of fault detection for Takagi-Sugeno (T-S) fuzzy discrete systems in finite-frequency domain. By means of the T-S fuzzy model, both a fuzzy fault detection filter system and the dynamics of filtering error generator are constructed. Two finite-frequency performance indices are introduced to measure fault sensitivity and disturbance robustness. Faults are considered in a middle frequency domain, while disturbances are considered in another certain finite-frequency domain interval. By using the generalized Kalman Yakubovic-Popov Lemma in a local linear system model, the design methods are presented in terms of solutions to a set of linear matrix inequalities, which can be readily solved via standard numerical software. The design problem is formulated as a two-objective optimization algorithm. A numerical example is given to illustrate the effectiveness and potential of the developed techniques. PMID- 21257384 TI - Simulation of an instrumental childbirth for the training of the forceps extraction: control algorithm and evaluation. AB - This paper presents the control algorithm implanted on the childbirth simulator BirthSIM in order to provide training to novice obstetricians. The forceps extraction is an obstetric manipulation learned by experience. However, nowadays the training is mainly provided during real childbirths. This kind of training could lead to dramatic consequences due to the lack of experience of some operators. This paper explains the approach that has been used to simulate the dynamic process of a childbirth on the BirthSIM simulator. We especially focus on one procedure that reproduces a difficult instrumental delivery. The recorded tractive force to extract the fetus corresponds to the literature results that confirm the realism of the simulator. The novice results emphasize the need of a childbirth simulator in order to gain initial experience without any risks. PMID- 21257385 TI - 3-D pain drawings and seating pressure maps: relationships and challenges. AB - Mobility impaired people constitute a significant portion of the adult population, which often experience back pain at some point during their lifetime. Such pain is usually characterized by severe implications reflected on both their personal lives, as well as on a country's health and economic systems. The traditional 2-D representations of the human body often used can be limited in their ability to efficiently visualize such pain for diagnosis purposes. Yet, patients have been shown to prefer such drawings. However, considering that pain is a feeling or emotion that is subjective in nature, the pain drawings could be consequently regarded as a subjective means of communicating such pain. As a result, the study described in this paper proposes an alternative, which encompasses a 3-D pain visualization solution, developed in a previous work of ours. This alternative is complemented with the upcoming technique of pressure mapping for more objectivity in the pain data collection. The results of this study have shown that the proposed approach is a promising solution for the purpose intended, and it could generally prove to be a significant complementary method in the area of medical practice for the mobility impaired community. PMID- 21257386 TI - Addressing mental health epidemic among university students via web-based, self screening, and referral system: a preliminary study. AB - The prevalence and severity of mental health problems in college and university communities are alarming. However, the majority of students with mental disorders do not seek help from professionals. To help students assess their mental conditions and encourage them to take an active role in seeking care, we developed a web-based self-screening, referral, and secure communication system and evaluated it at the University of Washington for 17 months. The system handled more than 1000 screenings during the study period. Of the subjects who used the system, 75% noted that the system helped them to make a decision to receive help from professionals. The system was able to provide outreach to students with mental health concerns effectively, allow them to self-screen their conditions, and encourage them to receive professional assistance. The system provided students with 24/7 web-based access to the clinic, and more than 50% of the system use was made during off-hours. The system was well received by patients, referral managers, and care providers, and it was transferred to the clinic for daily clinical use. We believe that a web-based system like ours could be used as one way to tackle the growing epidemic of mental health problems among college and university students. PMID- 21257390 TI - Scotland launches a BVD eradication programme. PMID- 21257387 TI - A subspace approach to learning recurrent features from brain activity. AB - This paper introduces a novel technique to address the instability and time variability challenges associated with brain activity recorded on different days. A critical challenge when working with brain signal activity is the variability in their characteristics when the signals are collected in different sessions separated by a day or more. Such variability is due to the acute and chronic responses of the brain tissue after implantation, variations as the subject learns to optimize performance, physiological changes in a subject due to prior activity or rest periods and environmental conditions. We propose a novel approach to tackle signal variability by focusing on learning subspaces which are recurrent over time. Furthermore, we illustrate how we can use projections on those subspaces to improve classification for an application such as brain machine interface (BMI). In this paper, we illustrate the merits of finding recurrent subspaces in the context of movement direction decoding using local field potential (LFP). We introduce two methods for using the learned subspaces in movement direction decoding and show a decoding power improvement from 76% to 88% for a particularly unstable subject and consistent decoding across subjects. PMID- 21257391 TI - Looking out for canine lungworm. PMID- 21257392 TI - FAWC under threat? PMID- 21257393 TI - Scanner creates a stir in Rwanda. PMID- 21257394 TI - Status dogs: a reflection of a wider problem in society. AB - The issue of 'status' or 'intimidation' dogs and possible approaches to the problem were considered in one of the 'contentious issues' debates at this year's BVA Congress, which was held in Glasgow from September 23 to 25. Arianwen Morris reports. PMID- 21257395 TI - Trends in bovine viral diarrhoea in Scottish cattle. AB - Review of bovine viral diarrhoea virus-related disease, 1996 to 2009. Diverse range of respiratory diseases diagnosed in cattle. Caseous lymphadenitis confirmed in a Suffolk ram lamb aged only four months. Extramedullary haematopoiesis of unknown cause in a pig. Coccidiosis diagnosed frequently in pheasants and partridges. These are among matters discussed in the disease surveillance report for July from SAC Consulting: Veterinary Services (SAC C VS). PMID- 21257396 TI - Haemoperitoneum in horses: a retrospective review of 54 cases. AB - This retrospective study was conducted in the UK and identifies the most frequent causes, diagnoses, treatment and prognoses for short- and long-term survival in 54 cases of horses with haemoperitoneum. Clinical signs of haemorrhagic shock and colic were common, and abdominal ultrasound was very useful for the identification of haemoperitoneum. Causes of haemoperitoneum included uterine injury (22 per cent), involvement of specific blood vessels (20 per cent), splenic injury (19 per cent), neoplasia (13 per cent) and other (4 per cent). No source was identified in 22 per cent of cases. Fifty-seven per cent of cases underwent exploratory laparotomy. Of the surgical cases, a diagnosis was made in 65 per cent, with 42 per cent surviving to discharge. It was felt that exploratory laparotomy had both diagnostic and therapeutic implications. Twenty eight per cent of cases died, and 33 per cent were euthanased, whereas 39 per cent survived to be discharged from the hospital, with 35 per cent of these surviving in the long term. Idiopathic haemoperitoneum was associated with the best outcome for long-term survival. PMID- 21257397 TI - Effect of storage time on automated cell count and cytological interpretation of body cavity effusions. AB - The effect of 24- and 48-hour storage at room temperature on automated total nucleated cell count (TNCC), differential cell count (DCC) and cell morphology was assessed, and the effect of initial total protein concentration on canine and feline body cavity effusion samples (2 to 5 ml) was evaluated. At 24 and 48 hours, TNCC and absolute numbers of neutrophils, macrophages and small lymphocytes were significantly decreased and numbers of unrecognisable cells were significantly increased. Neoplastic cells and intracellular bacteria identified in fresh samples were missed at 24 and 48 hours. The initial total protein concentration was associated with an effect on percentage of unrecognisable cells and small lymphocytes over time. Change in TNCC over time would have resulted in misclassification of the effusion type in four of 47 samples. PMID- 21257398 TI - Teladorsagia circumcincta resistance to moxidectin and multiple anthelmintic groups in ewes following use of the persistent drug before lambing. AB - This paper describes the nematode control strategy adopted by a Scottish hill sheep farmer. It provides an example of the limited use of anthelmintic drugs, targeted towards control of the periparturient rise in faecal nematode egg output in ewes and exploitation of grazing management, resulting in limited exposure of naive sheep to infective larvae on pasture. Resistance to benzimidazole, imidazothiazole and macrocyclic lactone anthelmintics, and to a combination of a macrocyclic lactone and imidazothiazole anthelmintic drugs was diagnosed. The targeted use of a persistent anthelmintic drug to control a periparturient rise in faecal nematode egg output in ewes may be unnecessary and selects strongly for resistance when the reservoir of anthelmintic-susceptible nematodes in refugia is small at the time of treatment. However, the use of a persistent anthelmintic drug in a selective proportion of ewes can be important and probably does not select strongly for resistance when the reservoir of anthelmintic-susceptible nematodes in refugia is large at the time of treatment. The former circumstances might arise on many Scottish hill sheep farms, whereas the latter may occur on upland and lowground farms, depending on previous grazing management, anthelmintic use and winter weather conditions. These factors must be taken into account when preparing sustainable health plans for nematode parasite control in individual sheep flocks. PMID- 21257399 TI - Technical and financial evaluation of assays for progesterone in canine practice in the UK. AB - The concentration of progesterone was measured in 60 plasma samples from bitches at various stages of the oestrous cycle, using commercially available quantitative and semi-quantitative ELISA test kits, as well as by two commercial laboratories undertaking radioimmunoassay (RIA). The RIA, which was assumed to be the 'gold standard' in terms of reliability and accuracy, was the most expensive method when analysing more than one sample per week, and had the longest delay in obtaining results, but had minimal requirements for practice staff time. When compared with the RIA, the quantitative ELISA had a strong positive correlation (r=0.97, P<0.05) and a sensitivity and specificity of 70.6 per cent and 100.0 per cent, respectively, and positive and negative predictive values of 100.0 per cent and 71.0 per cent, respectively, with an overall accuracy of 90.0 per cent. This method was the least expensive when analysing five or more samples per week, but had longer turnaround times than that of the semi-quantitative ELISA and required more staff time. When compared with the RIA, the semi-quantitative ELISA had a sensitivity and specificity of 100.0 per cent and 95.5 per cent, respectively, and positive and negative predictive values of 73.9 per cent and 77.8 per cent, respectively, with an overall accuracy of 89.2 per cent. This method was more expensive than the quantitative ELISA when analysing five or more samples per week, but had the shortest turnaround time and low requirements in terms of staff time. PMID- 21257400 TI - Comparison of two formulations of chlorhexidine for treating canine superficial pyoderma. PMID- 21257401 TI - Effect of lameness on milk production in a flock of dairy sheep. PMID- 21257402 TI - Neurological dysfunction and caudal fossa overcrowding in a young cheetah with hypovitaminosis A. PMID- 21257403 TI - Risk factors for culling Holstein-Friesian cows. PMID- 21257404 TI - Cost-effectiveness of bovine TB control. PMID- 21257405 TI - Sustaining dairy cow health. PMID- 21257416 TI - Prevalence of Pasteurella multocida and other respiratory pathogens in the nasal tract of Scottish calves. AB - The prevalence of Pasteurella multocida, a cause of bovine respiratory disease, was studied in a random sample of beef suckler and dairy farms throughout Scotland, by means of a cross-sectional survey. A total of 637 calves from 68 farms from six geographical regions of Scotland were sampled between February and June 2008. Deep nasal swabs were taken, and samples that were culture-positive for P multocida were confirmed by PCR. Prevalence of P multocida was 17 per cent (105 of 616 calves); 47 per cent of farms had at least one positive animal. A higher prevalence was detected in dairy calves than beef calves (P=0.04). It was found that P multocida was associated with Mycoplasma-like organisms (P=0.06) and bovine parainfluenza type 3 virus (BPI-3) (P=0.04), detected by culture and quantitative PCR of nasal swabs, respectively. Detection of P multocida was not associated with bovine respiratory syncytial virus (BRSV), bovine herpesvirus type 1 (BoHV-1) or bovine viral diarrhoea virus (BVDV). Mycoplasma-like organisms, BPI-3, BRSV, BoHV-1 and BVDV were detected in 58, 17, four, 0 and eight calves, on 25, five, two, 0 and five of the 68 farms, respectively. PMID- 21257417 TI - Salmonella infection in cattle in Great Britain, 2003 to 2008. AB - Surveillance data for clinical disease in cattle in Great Britain due to Salmonella infections were analysed for the period 2003 to 2008 in order to describe seasonality and to investigate possible associations between Salmonella diagnoses and other variables such as region, climate, age and production type. A clear seasonal pattern was shown for Salmonella infection, coinciding with the second half of the year. The incidence of Salmonella Dublin and Salmonella Typhimurium was highest in the west of the country, which has the greatest cattle density, but this was not a feature of diagnoses with other serovars. Abortion was a more common clinical sign of S Dublin infections, but was relatively unusual in the case of S Typhimurium. The observed clinical picture and age of affected animals were largely determined by the seasonality of dairy cattle calving in Great Britain. PMID- 21257418 TI - Eradication programme for bovine viral diarrhoea virus in Orkney 2001 to 2008. AB - The strategies used and the results obtained in Orkney's bovine viral diarrhoea virus (BVDV) eradication programme over eight years (2001 to 2008) are presented and discussed. The venture was undertaken by local veterinary practices and the Orkney Livestock Association (OLA) with the financial support of the Orkney Islands Council. Participation is voluntary; the programme comprises screening of youngstock, a whole-herd test if required, elimination of persistently infected animals and strict biosecurity measures and/or vaccination. BVDV-free herds are certified, and certification is updated annually by retesting the youngstock. The programme aims to minimise economic losses, thereby increasing the competitiveness of the Orcadian cattle industry and to improve animal health and welfare by eliminating virus circulation. Information from databases of the Scottish Agricultural College, Biobest Laboratories and OLA show that despite a significant reduction in the overall prevalence of BVDV on Orkney during the initial stages of the eradication programme, there has been little progress made since 2006 and that some difficulties have been encountered, with herd BVDV breakdowns following initial eradication. These results highlight the need for continued motivation of farmers, strict application of biosecurity measures and/or systematic vaccination of all seronegative breeding animals. PMID- 21257419 TI - Tropical liver fluke-induced stress in experimentally infected and immunised buffaloes. AB - Disease-related stress associated with Fasciola gigantica infection was investigated in 16 male, yearling Murrah buffaloes. The animals were randomly assigned to one of four groups. Animals in groups 1 and 2 were vaccinated subcutaneously with 4.8 mg of excretory-secretory antigen (group 1) or 1300 MUg infection-specific antigen (group 2), in three doses. Subsequently, all the animals in groups 1, 2 and 3 were infected orally with 800 viable F gigantica metacercariae (bubaline origin) on week 6 of the experiment. The animals in group 4 served as healthy controls. The clinical progress of the disease with respect to the adrenocortical response to infection was assessed periodically. The infected animals in group 3 developed characteristic signs of the disease and had the highest in situ fluke population (mean [se] 331.8 [19.5] ). One of the four animals in group 3 died on day 110 postinfection (PI). Animals that had been immunised before infection (groups 1 and 2) acquired adequate levels of immunity, were comparatively healthier and had significantly lower (P<0.05) fluke populations (mean [se] 194.3 [11.8] in group 1 and 164.5 [9.2] in group 2). Throughout the course of the disease, the group 3 animals had significantly higher cortisol levels than those in groups 1 and 2 (P<0.01) from week 4 PI onward. Although animals in the immunised groups (groups 1 and 2) had increased hormone levels, they were not significantly different from those in the control animals in group 4. Cortisol levels were higher during the early prepatency phase (weeks 1 to 6 PI) than during the late prepatency and/or patency phases of the disease. Cortisol levels in the healthy control animals in group 4 remained within the normal range. PMID- 21257420 TI - Failure of injectable ivermectin to control psoroptic mange in cattle. PMID- 21257421 TI - Seroprevalence of Mycobacterium avium subspecies paratuberculosis in cows in Umbria, Italy. PMID- 21257422 TI - Oesophageal paresis associated with bluetongue virus serotype 8 in cattle. PMID- 21257423 TI - Guarding the welfare of farm animals. PMID- 21257424 TI - Impact of climate change on human and animal health. PMID- 21257425 TI - Use of palatable medicines. PMID- 21257426 TI - Controlling bovine TB. PMID- 21257427 TI - Horse or hound? PMID- 21257428 TI - Communication in relation to equine infectious anaemia in Devon. PMID- 21257429 TI - Use of monepantel. PMID- 21257430 TI - Time to 'get real' on responsible antimicrobial use in animals. PMID- 21257434 TI - Farm animal welfare--changing the veterinary focus. PMID- 21257436 TI - EFSA updates its position on cloning. PMID- 21257437 TI - Tissue donation leads to transplant success. PMID- 21257438 TI - Equine disease surveillance, April to June 2010. AB - Recent outbreaks of equine infectious anaemia and equine viral arteritis in the UK. Update on the equine infectious anaemia situation in Europe. West Nile virus reported in several Mediterranean countries. Current and future approaches to equine viral arteritis control in the UK. These are among matters discussed in the quarterly equine disease surveillance report for April to June 2010, prepared by Defra, the Animal Health Trust and the British Equine Veterinary Association. PMID- 21257439 TI - Control of canine leptospirosis in Europe: time for a change? AB - Changes in the formulation of the Leptospira components of dog vaccines are being considered in Europe, following changes in North America. This article discusses the options for change and recommends the continued inclusion of serovars Icterohaemorrhagiae and Canicola plus the inclusion of serovars Bratislava and Grippotyphosa (for mainland Europe only). If other serovars, such as Pomona, are to be considered in the future, then there is a need for additional clinical, cultural and serological studies across Europe to support their inclusion. PMID- 21257440 TI - Investigation of farmers' perspectives on the disposal of fallen livestock and animal by-products in Great Britain. AB - Two questionnaires were completed by a selection of farms in Great Britain during 2008 and 2009 to ascertain the role of the National Fallen Stock Company (NFSCo) in fallen livestock disposal, the current disposal methods used for fallen livestock and other animal by-products (ABPs), and factors determining use of a particular method. The results demonstrated a significant difference (P<0.001) in NFSCo membership in relation to geographical location and a significant difference (P<0.001) in disposal choice. Farmers' perceptions as to why they did or did not join NFSCo, and why they used particular disposal methods are discussed. Disposal methods of other ABPs (aborted fetuses/stillborn animals and placentas) demonstrated the illegal disposal of aborted fetuses/stillborn animals (19.5 per cent of respondents) and placentas (57.6 per cent of respondents). Overall, 13.7 per cent of respondents used a variety of illegal disposal methods for fallen livestock carcases and other ABPs. PMID- 21257441 TI - European field study of the efficacy and safety of the novel anthelmintic monepantel in sheep. AB - During 2007, a large-scale controlled, multicentre, blinded and randomised field study was conducted in Scotland, England and France to assess the efficacy and safety of monepantel, the first molecule to be developed from the recently discovered amino-acetonitrile derivatives class of anthelmintics, in sheep. Monepantel was administered orally, at a minimum dose of 2.5 mg/kg bodyweight, for the control of gastrointestinal nematodes in sheep maintained at pasture in a range of commercial production systems. Efficacy was measured by faecal egg count (FEC) reduction tests seven days after treatment and was demonstrated to be over 98 per cent against mixed-genus infections. The reduction in FEC of monepantel treated sheep was statistically significantly greater than in untreated control sheep (P<0.0001). The efficacy of monepantel against mixed-genus natural field infections of the major gastrointestinal nematodes was in agreement with similar studies conducted in Australia and New Zealand. There were no treatment-related adverse events during the study, which included the use of a range of concomitant treatments. PMID- 21257442 TI - Diagnosis of feline polycystic kidney disease by a combination of ultrasonographic examination and PKD1 gene analysis. AB - Persian-related and non-Persian-related cats were examined by ultrasonography and/or molecular testing to determine the prevalence of feline polycystic kidney disease (PKD) and the presence of a PKD1 gene mutation. PCR was used to amplify exon 29 of the PKD1 gene using genomic DNA extracted from blood samples, and the PCR products were analysed by direct DNA sequencing. Among the 111 cats included in the study, 54 were examined by both ultrasonography and gene testing for a point mutation in exon 29 of the PKD1 gene. The prevalence of PKD diagnosed by ultrasonography was 25.9 per cent in all the cats and 24.2 per cent in Persian related cats. The prevalence of the transversion mutation in exon 29 of the PKD1 gene was 13.5 per cent in all cats and 15.7 per cent in Persian-related cats. Three cats that were diagnosed with PKD by ultrasonography did not have the mutation within exon 29. Nucleotide analysis of exon 29 indicated that male cats had a higher point mutation rate than female cats. PMID- 21257443 TI - Sacrococcygeal intervertebral disc extrusion in a dachshund. PMID- 21257444 TI - Experimental infection of lambs with Border disease virus isolated from a Pyrenean chamois. PMID- 21257445 TI - Eimeria prionotemni-associated coccidiosis in a Bennett's wallaby (Macropus rufogriseus). PMID- 21257446 TI - Establishing the plasma copper reference range in Boer goats. PMID- 21257447 TI - Use of xylocaine spray in cats. PMID- 21257448 TI - Use of xylocaine spray in cats. PMID- 21257449 TI - Dangerous Dogs Act and the problem of 'status' dogs. PMID- 21257450 TI - Maintenance of Leptospira infection in cattle under tropical conditions. PMID- 21257453 TI - Rinderpest eradication: official declaration moves closer. PMID- 21257456 TI - WHO highlights 'crucial role' for vets. PMID- 21257458 TI - Charities unite to send supplies to Hungary. PMID- 21257459 TI - Where do you draw the line on treatment? AB - With euthanasia a legitimate treatment option in veterinary medicine, at what point does treatment become overtreatment? The issues were discussed in a 'contentious issues' debate at the BVA Congress, which was held in Glasgow from September 23 to 25. PMID- 21257460 TI - Reporting animal abuse: a vet's responsibility to society? AB - There is evidence of a link between animal and human abuse so there may be value in cross-reporting between the authorities responsible for investigating suspected cases. A debate called 'Turning a blind eye to abuse?' at this year's BVA Congress considered vets' ability to recognise non-accidental injury in animals and discussed protocols for reporting it. PMID- 21257462 TI - Fasciolosis prevalent among cattle in England and Wales. PMID- 21257463 TI - Indications of a relationship between buying-in policy and infectious diseases on dairy farms in Wales. AB - During the period February to May 2008, bulk milk samples were collected from 57 dairy farms throughout Wales in the framework of a voluntary somatic cell count project. Bulk milk samples were tested for antibodies to bovine viral diarrhoea virus (BVDV), bovine herpesvirus type 1 (BHV-1) and Leptospira Hardjo, and samples were also tested for the presence of BVDV antigen by PCR. A questionnaire was used to determine whether the herd was open or closed, what the vaccination status was, and to obtain general farm information such as the herd size and average milk yield. Vaccination against BVD, infectious bovine rhinotracheitis and leptospirosis was practised on 37, 12 and 35 per cent of the farms, respectively. The presence of bulk milk antibodies on farms that did not use vaccination was 75 per cent for BVDV, 54 per cent for BHV-2 and 76 per cent for L Hardjo. Open herds had 10 times the odds (95 per cent confidence interval [CI] 1.7 to 59.4)of having bulk milk antibodies for BVDV and 16.7 times the odds (95 per cent CI 2.0 to 49.7) of having bulk milk antibodies to BHV-1 compared with closed herds. A farm with bulk milk antibodies to one disease had significantly higher odds of having bulk milk antibodies to a second disease (P<0.05). PMID- 21257464 TI - Efficacy, safety and palatability of a new broad-spectrum anthelmintic formulation in dogs. AB - The efficacy, safety and palatability of a new flavoured chewable anthelmintic tablet were investigated in dogs. The efficacy, based on worm counts, of a single recommended therapeutic dose (RTD) of 5 mg pyrantel + 20 mg oxantel + 5 mg praziquantel/kg bodyweight was assessed in experimental infections (EI) and natural infections (NI) with Trichuris vulpis, Echinococcus granulosus and Toxocara canis. For T vulpis, the efficacy of the treatment was 99.3 per cent in EI (comparing groups of six treated and six control dogs) and 100 per cent in NI (nine treated and nine control dogs). For E granulosus, the efficacy was more than 99.9 per cent in EI (11 treated and 11 control dogs). For T canis, the efficacy was 94.3 per cent in EI (10 treated and 10 control dogs) and 100 per cent in NI (12 treated and 13 control dogs). In a field study, Ancylostoma caninum (11 dogs) and T canis (11 dogs) faecal egg counts were reduced by more than 99 per cent, and in eight dogs with Dipylidium caninum proglotides in the faeces the efficacy was 100 per cent. The tablets were readily consumed by 56 of 64 (87.5 per cent) privately owned dogs. Safety was assessed in groups of six dogs treated either once with twice the RTD, once with six times the RTD, with twice the RTD on three consecutive days, or untreated. There were no significant differences in blood parameters between the groups, and no abnormal clinical findings. Two dogs treated with six times the RTD vomited, but no vomiting was observed when administration was repeated two days later. PMID- 21257465 TI - Clinical assessment and outcome of a single-layer technique for anastomosis of the small intestine in horses. AB - In order to assess postoperative outcome in horses undergoing end-to-end anastomosis of the small intestine, performed using a one-layer technique, 15 horses that underwent exploratory coeliotomy, resection of the small intestine and end-to-end anastomosis using a continuous Lembert pattern were studied. Information on the age, breed, sex, diagnosis, treatment, complications and outcome of each case were obtained from medical records. Follow-up information was obtained via telephone conversations with clients and trainers. Five of the horses had short-term postoperative complications: one had postoperative ileus (POI), colic and peritonitis, one had POI and colic, two had POI only and one had diarrhoea only. A second exploratory coeliotomy was recommended in two of the 15 horses (13 per cent). The short-term survival rate, defined as survival up to the time of discharge from the hospital, was 93.3 per cent (14 of 15 horses). The long-term survival rate, defined as survival for at least 12 months after the surgery, was 84.6 per cent (11 of 13 horses followed up). PMID- 21257466 TI - Isosporoid coccidiosis in translocated cirl buntings (Emberiza cirlus). AB - Four of 17 cirl buntings (Emberiza cirlus) involved in a trial translocation in 2004 for conservation purposes died and were examined postmortem. Two of the cirl buntings showed intestinal and hepatic lesions, including necrotising enteritis, consistent with isosporoid coccidiosis, and a third had an intestinal infestation of isosporoid coccidia. Sporulated oocysts from faecal samples from the birds were identified as Isospora normanlevinei, a parasite previously detected in cirl bunting populations in continental Europe. In a subsequent translocation of 75 cirl buntings from Devon to Cornwall in 2006, each brood of birds was placed in strict quarantine at low stocking density, with improved hygienic precautions and detailed health surveillance, and each bird was treated prophylactically with toltrazuril in an attempt to control the disease but not eliminate the I normanlevinei parasites. Seventy-two of the 75 birds were successfully reared and released, and there were no apparent clinical or pathological signs of isosporoid coccidiosis in any bird. I normanlevinei was detected in the released population, an indication that it had been successfully conserved. PMID- 21257467 TI - Identification of cattle persistently infected with BVDV by ear-notch testing in Saudi Arabia. PMID- 21257468 TI - Prevalence of Actinobacillus pleuropneumoniae serovars in England and Wales. PMID- 21257469 TI - Orbital myositis associated with Lyme disease in a dog. PMID- 21257470 TI - Controlling bovine TB. PMID- 21257471 TI - Sarcoptic mange in badgers in the UK. PMID- 21257472 TI - Controlling bovine TB. PMID- 21257473 TI - Horse or hound? PMID- 21257474 TI - Gold IIP status for Norfolk practice. PMID- 21257475 TI - Wales moves to tighten dog breeding rules. PMID- 21257476 TI - Unravelling the costs of animal health. PMID- 21257477 TI - Nurse communication and client satisfaction. PMID- 21257478 TI - Government cuts and the challenges of partnership. PMID- 21257479 TI - Helping to avert 'a tragedy of the commons'. PMID- 21257482 TI - International disease monitoring, July to September. PMID- 21257483 TI - Mycobacterium bovis genotypes in Northern Ireland: herd-level surveillance (2003 to 2008). AB - Surveillance genotyping (variable number tandem repeat profiling and spoligotyping) of Mycobacterium bovis isolates from culture-confirmed bovine tuberculosis (TB)-affected herds in Northern Ireland is presented for the years 2003 to 2008 inclusive. A total of 175 M bovis genotypes were identified in 8630 isolates from 6609 herds. On average, 73 genotypes were identified each year, with 29 genotypes present in all six years. Highly significant differences (P<0.0001) were observed between the relative frequency of some genotypes in the years 2003 to 2008. The spatial distribution of M bovis genotypes was not random (P<0.0001). Significant geographical localisation of M bovis genotypes was evident, suggesting that sources tended to be local. Despite regions being dominated by geographically localised genotypes, substantial and exploitable local diversity was still evident. Genotypes were also translocated significant distances from their normal geographical location. PMID- 21257484 TI - Epidemiological study of pasture-associated laminitis and concurrent risk factors in the South of England. AB - A retrospective study of laminitis was carried out to identify risk factors associated with this disease on an East Anglian farm with approximately 1000 animals living in an area of 1000 acres. Medical records between January 1997 and May 2000 and between April 2005 and March 2008 were reviewed, and the age, sex, weight (kg), height (inches [in] and hands [H]) and weight-to-height ratio (kg/in) was recorded. The prevalence, incidence and seasonality of laminitis were determined and their relationship to the monthly temperature, rainfall and hours of sunshine was evaluated. Averaged over the six years, the highest prevalence (2.6 per cent) and incidence (16 cases/1000 animals) of laminitis occurred in May. The findings of a multivariate analysis revealed that females (P=0.007, odds ratio [OR] 1.46, 95 per cent confidence interval [CI] 1.1053 to 1.9646) and light animals (P <= 0.001, OR=0.995, 95 per cent CI =0.9932 to 0.9963) had the greatest risk of developing laminitis. A positive association was found between hours of sunshine and incidence (P=0.007, relative risk [RR] 1.009, 95 per cent CI 1.001 to 1.012) and prevalence (P=0.002, RR 1.008, 95 per cent CI 1.003 to 1.012) of laminitis. The data suggest that there is a relationship between season, sex of the animal and the development of laminitis. PMID- 21257485 TI - Use of a tetanus toxoid marker to allow differentiation of infected from vaccinated poultry without affecting the efficacy of a H5N1 avian influenza virus vaccine. AB - Tetanus toxoid (TT) was assessed as a positive marker for avian influenza (AI) virus vaccination in chickens, in a vaccination and challenge study. Chickens were vaccinated twice with inactivated AI H5N2 virus vaccine, and then challenged three weeks later with highly pathogenic AI H5N1 virus. Vaccinated chickens were compared with other groups that were either sham-vaccinated or vaccinated with virus with the TT marker. All sham-vaccinated chickens died by 36 hours postinfection, whereas all vaccinated chickens, with or without the TT marker, were protected from morbidity and mortality following exposure to the challenge virus. Serological testing for H5-specific antibodies identified anamnestic responses to H5 in some of the vaccinated birds, indicating active virus infection. PMID- 21257486 TI - Comparative use of CO2 laser, diode laser and monopolar electrocautery for resection of the soft palate in dogs with brachycephalic airway obstructive syndrome. AB - Clinical results, complications and the outcome of using either a carbon dioxide (CO2) laser, diode laser or electrocautery (ELEC) for resection of the soft palate with an extended palatoplasty technique in brachycephalic dogs with upper airway obstructive syndrome were compared. Dogs were randomly allocated into three groups (n=20 in each group): ELEC, diode and CO2 groups. The palatoplasty was made at the rostral aspect of the tonsils. A respiratory clinical score, ranging from 0 (normal) to 4 (cyanosis), was attributed to each dog before surgery and at 0 hours, 24 hours, two weeks and six months after surgery. A favourable outcome was defined as a one point or greater decrease in score 24 hours after surgery. The proportion of dogs with a favourable outcome was significantly higher in the CO2 (n=15) and ELEC groups (n=15) in comparison with the diode group (n=7) (OR=5.6, 95 per cent confidence interval 1.4 to 21.9). Surgical time was significantly shorter (P<0.001; mean [sd] 510 [178] seconds), and bleeding was less common (P<0.001; 30 per cent of cases) in the CO2 group. Complications were most frequent with the diode group (two cases of death and two cases of tracheostomy). The final outcome for all groups (n=57) was considered excellent in 79 per cent of cases and was considered good in 21 per cent. PMID- 21257487 TI - Antibodies to influenza A virus (H1 and H3) in companion animals in Iowa, USA. PMID- 21257488 TI - Selenium toxicosis in sheep associated with excessive sodium selenite in a commercial supplement. PMID- 21257489 TI - Intracardiac ectopic thyroid adenoma in a dog. PMID- 21257490 TI - More for less: dairy production in the 21st century. PMID- 21257491 TI - Controlling bovine TB. PMID- 21257492 TI - Controlling bovine TB. PMID- 21257493 TI - National dog walking survey. PMID- 21257494 TI - Long service on BVA Council. PMID- 21257495 TI - Status of dogs. PMID- 21257496 TI - Views sought on evidence-based veterinary medicine. PMID- 21257500 TI - AHT appeals for help in investigating mystery dog illness. PMID- 21257504 TI - WSAVA embraces 'one health'. PMID- 21257505 TI - Veterinary medicines: product update. PMID- 21257506 TI - Disease due to Salmonella diagnosed in cattle and pigs in Scotland. AB - Salmonellosis in cattle due to S Dublin and S Typhimurium, and in pigs due to S Typhimurium. Blue-green algae (cyanobacterium) toxicity suspected on a dairy farm. Outbreaks of parasitic pneumonia diagnosed in grazing cattle across Scotland. Parasitic gastroenteritis in lambs seen in association with deficiencies of trace elements. Viral insult suspected in outdoor sows affected by hindlimb paresis and paralysis. These are among matters discussed in the disease surveillance report for August from SAC Consulting: Veterinary Services (SAC C VS). PMID- 21257507 TI - Evaluation of suicide awareness programmes delivered to veterinary undergraduates and academic staff. AB - In an effort to increase suicide awareness skills among veterinary undergraduates, a three-hour suicide awareness workshop (safeTALK) was delivered to third-year Royal (Dick) School of Veterinary Studies undergraduates as part of their professional development curriculum. Students were able to opt out of the session by contacting the course organisers. A total of 26 of 151 (17 per cent) third-year students attended the workshop, and 17 completed a feedback questionnaire. The vast majority of the students reported that after completing the workshop they were more likely or much more likely to recognise the signs of a person at risk of suicide, approach a person at risk of suicide, ask a person about suicide, and connect a person at risk of suicide with help. Five veterinary academics attended a two-day Applied Suicide Intervention Skills Training (ASIST) course, and all reported that the course was effective in improving suicide awareness and intervention skills. PMID- 21257508 TI - Owners' observations of domestic cats after limb amputation. AB - Questionnaires were distributed to owners of cats that had undergone limb amputation in the UK, through 1000 veterinary clinics or publications relating to companion cats, or online. Between July 2009 and February 2010, responses were received relating to 234 cats, and data for 204 of these were included in subsequent analyses. The responses received provided data on signalment, aetiology, quality of life, behavioural changes and pain observed in cats after partial or total amputation of a limb. Young male domestic shorthair cats were over-represented in the sample; the most common reason for amputation was a fractured bone, and the hindlimb was almost twice as likely to be amputated as the forelimb. Although 89 per cent of the cats received analgesics/anti inflammatories after discharge, the owners of 35 per cent of the animals observed some signs of pain during recovery. Eighty-nine per cent of the cats were thought to have regained a 'normal' quality of life as defined by the owner and 94 per cent of the owners stated that they would agree with the decision to amputate the affected limb in a pet if faced with the same decision again. PMID- 21257509 TI - Elimination of small ruminant lentivirus infection from sheep flocks and goat herds aided by health schemes in Great Britain. AB - Over a period of 11 years, 33 sheep or goat holdings lost their maedi-visna or caprine arthritis-encephalitis accredited status (mean 2.8 per year [0.09 per cent] of the accredited holdings in Great Britain). Of these, 22 sheep flocks and two goat herds eradicated the infection and regained their accredited status. In addition, 10 sheep flocks and two goat herds managed to eradicate infection, having joined the scheme with infected animals. In flocks and herds with a high initial prevalence of infection, the adoption of an indirect ELISA, with greater sensitivity than the agar gel immunodiffusion test, improved success rates. A strategy was devised to interpret the ELISA results depending upon the prevalence of infection at the time. Eighteen of the 33 flocks/herds (54.5 per cent) that had introductions of infection also owned non-accredited stock. PMID- 21257510 TI - Thirteen-week dose-intensifying simultaneous combination chemotherapy protocol for malignant lymphoma in dogs. AB - This prospective study aimed to record the toxicity profile of a dose intensifying simultaneous chemotherapy (DISC) protocol for lymphoma in dogs. Remission rates and the duration of the protocol were also evaluated. Twenty-one dogs were studied. Diagnosis was based on cytological or histological assessments. The DISC protocol is a 13-week maintenance-free protocol. L Asparaginase (400 iu/kg) was administered subcutaneously on day 1, followed by weekly simultaneous intravenous administration of vincristine (0.7 mg/m(2) = 100 per cent), cyclophosphamide (200 mg/m(2) = 100 per cent) and doxorubicin (30 mg/m(2) = 100 per cent) at a starting dose level of 33 per cent. Dose levels were given twice and then increased by 5 to 7 per cent if grade 0 or I toxicities were seen, to a maximum dose level of 60 per cent. Two dogs experienced a grade IV toxicity (asymptomatic neutropenia in one dog and sepsis in the other). Two episodes of asymptomatic grade III thrombocytopenia and one episode of neutropenia were recorded. Other toxic events were infrequent and mild. Only one dog required hospitalisation for less than 72 hours. Seventeen dogs (80.9 per cent) achieved complete remission, one (4.8 per cent) achieved partial remission, two (9.5 per cent) had stable disease and in one (4.8 per cent) disease progressed. PMID- 21257511 TI - Acute phase proteins and heterophil:lymphocyte ratio in laying hens in different housing systems. PMID- 21257512 TI - Prevalence of inherited junctional epidermolysis bullosa in German shorthaired pointers bred in Italy. PMID- 21257513 TI - Unexpected production loss caused by helminth parasites in weaned beef calves. PMID- 21257514 TI - Possible preventive strategy for bovine neonatal pancytopenia. PMID- 21257515 TI - Suspected lack of efficacy of a live IBR marker vaccine in two dairy herds. PMID- 21257516 TI - Supporting the VBF. PMID- 21257517 TI - Faecal egg count reduction test to detect lack of efficacy of triclabendazole. PMID- 21257518 TI - Function of the panniculus carnosus--a hypothesis. PMID- 21257519 TI - Clinical trial on the efficacy of masitinib in canine IBD. PMID- 21257521 TI - New approval system for online retailers of veterinary medicines. PMID- 21257522 TI - Welsh code of practice for gamebird welfare. PMID- 21257523 TI - New year honours 2011. PMID- 21257525 TI - Research highlights of Moredun's anniversary year. PMID- 21257526 TI - Busy year for the IVSA's development fund. PMID- 21257527 TI - Veterinary medicines: product update. PMID- 21257528 TI - Vet to be suspended for certification offences. PMID- 21257529 TI - DNA testing man's best friend. PMID- 21257530 TI - Increase in the prevalence of Johne's disease in sheep in Scotland. AB - Increased prevalence of Johne's disease in sheep; abomasal damage in young cattle due to ostertagiosis; parasitic gastroenteritis in young sheep due to Nematodirus, Teladorsagia and Chabertia species; Streptococcus suis serotype 2 associated with a range of clinical signs in pigs; respiratory cryptosporidiosis confirmed in wild red grouse. These are among matters discussed in the disease surveillance report for October 2010 from SAC Consulting: Veterinary Services (SAC C VS). PMID- 21257531 TI - Idiopathic headshaking in horses: understanding the pathophysiology. PMID- 21257532 TI - Use of a gonadotrophin-releasing hormone vaccine in headshaking horses. AB - The aim of this study was to investigate the use of a gonadotrophin-releasing hormone (GnRH) vaccine in the treatment of headshaking in horses. Fifteen geldings received two doses of the GnRH vaccine four weeks apart. Serum was collected before and after vaccination to measure concentrations of luteinising hormone (LH) (10 horses) and follicle-stimulating hormone (FSH) (six horses). Owners recorded the frequency of seven common headshaking behaviours using a visual analogue scale (VAS) before vaccination and at two, four, eight, 12, 16 and 20 weeks after vaccination. Serum LH (P=0.008) and FSH (P=0.03) concentrations decreased significantly following vaccination. Although approximately one-third of the owners reported a subjective improvement in headshaking, serial scoring did not indicate a reduction in headshaking behaviours following vaccination with a commercial GnRH vaccine. Vaccination reactions were observed in four of 15 horses (27 per cent), including one case of severe, presumed immune-mediated, myositis. PMID- 21257533 TI - Diagnostic performance of PCR and ELISA on blood and milk samples and serological survey for small ruminant lentiviruses in central Spain. AB - The diagnostic performance of an ELISA for the detection of antibodies to the small ruminant lentiviruses (SRLVs) maedi-visna virus and caprine arthritis encephalitis virus in milk and corresponding blood samples was evaluated in 50 sheep. The agreement between ELISA results in blood and milk was 90 per cent, and the kappa value was 0.79. In addition, a serological survey in the central zone of Spain was performed using milk samples from 413 animals (250 sheep and 163 goats) from 12 flocks/herds. All flocks/herds had some animals that were positive for SRLV. Among the animals, 60.0 per cent of the sheep and 8.0 per cent of the goats tested were seropositive. Each sample was also tested using a PCR technique, which increased the percentage of positive animals detected. Using a combination of ELISA and PCR gave a total of 72.2 per cent of sheep and 28.8 per cent of goats positive for SRLV. PMID- 21257535 TI - Amnion nodosum in a Belgian draught horse. PMID- 21257534 TI - Associations between the prevalence of Mollicutes and Mycoplasma bovis and health and performance in stocker calves. AB - A longitudinal cross-sectional time-series study was carried out to determine the prevalence of nasal mycoplasma carriage, serostatus and seroconversion, and to evaluate the associations between these parameters and health and performance in weaned beef calves during a 42-day feeding period. Nasal swabs and serum were collected on days 0 (arrival), 10, 42 and at the first incidence of bovine respiratory disease complex. The samples were evaluated for Mollicutes (by culture), Mycoplasma bovis (by PCR) and serum antibody to M. bovis. On day 0, 90.4 per cent of the calves were Mollicutes nasal culture-positive. The seroprevalence of M. bovis was 26.6 per cent on day 0 and 98.2 per cent by day 42 (P<0.05). Seroconversion to M. bovis between days 0 and 42 was significantly associated (P=0.04) with lower weight gain. Weight gain was greater in calves that were PCR-negative for M. bovis on day 10 (P=0.01). The percentage of calves seropositive to M. bovis increased throughout the study, indicating exposure and an immunological response to the organism. Although associations with health outcomes were not identified, seroconversion to M. bovis was associated with a decreased rate of weight gain during the study period. PMID- 21257537 TI - Requirement for extramural studies. PMID- 21257536 TI - Serum antioxidant capacity of dairy cows with subclinical ketosis. PMID- 21257539 TI - Registration of bitches undergoing repeat caesareans. PMID- 21257540 TI - A veterinary surgeons' standards scheme? PMID- 21257541 TI - Self-certification for medicines compliance? PMID- 21257550 TI - Supply of injectable ACP. PMID- 21257551 TI - Veterinary health check to be introduced for Kennel Club shows. PMID- 21257553 TI - Demonstrating 'real pig welfare'. PMID- 21257554 TI - Improving horse welfare during long-distance transport. PMID- 21257555 TI - Wildlife management: from control to rehabilitation. PMID- 21257556 TI - Animal health economics network formed. PMID- 21257557 TI - Equine disease surveillance: quarterly summary. PMID- 21257558 TI - Vets and conservation: helping to restore the balance. PMID- 21257559 TI - Sterilisation of hybrid Galapagos tortoises (Geochelone nigra) for island restoration. Part 1: endoscopic oophorectomy of females under ketamine medetomidine anaesthesia. AB - An endoscopic sterilisation technique for use in Galapagos tortoises (Geochelone nigra) was developed as part of a conservation and ecosystem restoration project. Fifteen female giant Galapagos tortoises were anaesthetised, intubated and positioned in dorsal recumbency. A bilateral prefemoral approach was made and the ovaries were identified using a 5 mm * 33 cm rigid telescope. In the case of endoscope-assisted oophorectomy, the ovaries were exteriorised through the same incision, the vasculature was ligated and the mesovarium was transected. Two tortoises had immature ovaries that could not be exteriorised. In these animals, endoscopic oophorectomy was performed using radiosurgery. Closure of the incisions was routine. All tortoises except one recovered well from surgery. There were no reported complications six weeks and six months postoperatively, and all were successfully released on to Pinta Island in May 2010. PMID- 21257560 TI - Mediolateral hoof balance in relation to the handedness of apprentice farriers. AB - Horses that had been trimmed and shod by apprentice farriers were sourced from the Royal School of Military Engineering, Melton Mowbray (37 horses) and from the Household Cavalry, Knightsbridge (54 horses). The lateral and medial hoof wall angles of both forelimbs were measured using a Ruidoso hoof gauge by the same operator. The difference between the lateral and medial hoof wall angles for each horse was calculated and the results were compared between right-handed and left handed farriers using the Mann-Whitney U test (P<0.05). There was a significant difference in the mediolateral hoof balance obtained between right-handed and left-handed farriers for each forelimb (P<0.001). Right-handed farriers were shown to create an imbalance in 47 per cent of left forelimbs and 46 per cent of right forelimbs assessed, while left-handed farriers created an imbalance in 41 per cent of left forelimbs and 71 per cent of right forelimbs. The tendency was for right-handed farriers to over-trim the medial (inner) aspect of the left forelimb and the lateral (outer) aspect of the right forelimb; the reverse was demonstrated for left-handed farriers. Performing a risk ratio confirmed these findings. PMID- 21257561 TI - Evaluation of the toxicity of Adonis aestivalis in sheep. AB - To determine the toxicity of Adonis aestivalis (adonis) in sheep, adult Suffolk ewes were administered 1 per cent bodyweight adonis via surgically placed rumen cannulas in an acute, high-dose toxicity study, and 0.2 per cent bodyweight daily in a two-week, low-dose toxicity study. The ewes received cardiac examinations before dosing, 24 and 48 hours after dosing with 1 per cent bodyweight adonis, and after continuous low-dose administration. All the ewes administered adonis had transient sinus arrhythmias after receiving 1 per cent bodyweight adonis. Two of the three ewes had transient reduced fractional shortening after administration with 1 per cent bodyweight adonis; the same two ewes had reduced fractional shortening after the low-dose treatment regimen. No gross or microscopic lesions were seen when the ewes were examined postmortem at the end of the study. PMID- 21257562 TI - Axial sesamoid fracture causing deep digital flexor tendon damage in a horse. PMID- 21257563 TI - Outbreak of polyarthritis in lambs attributed to Pasteurella multocida. PMID- 21257564 TI - Tackling the welfare issues of dog breeding. AB - Sheila Crispin is chair of the new Advisory Council on the Welfare Issues of Dog Breeding. Here, she describes the background to the Council, outlines its priorities and offers some thoughts on the issues that need to be addressed. PMID- 21257565 TI - Treatment of diarrhoea in cats caused by Tritrichomonas foetus. PMID- 21257566 TI - Sheep welfare and provision of CPD. PMID- 21257567 TI - Autumn Nematodirus helvetianus infections in calves. PMID- 21257568 TI - Is this a record? PMID- 21257569 TI - Dealing with the new Veterinary Nurse training system. PMID- 21257570 TI - Welfare during transport: EFSA assesses the scientific evidence. PMID- 21257571 TI - British animal charity awarded Lavin Cup. PMID- 21257572 TI - German farms still restricted after dioxin contamination. PMID- 21257574 TI - Haiti - a year after the earthquake. PMID- 21257575 TI - Antimicrobials: industry welcomes decision on advertising to farmers. PMID- 21257576 TI - BSAVA invites VNs to join. PMID- 21257577 TI - Striking vet off 'the only appropriate sanction'. PMID- 21257580 TI - Gaining an insight into nurses' salaries and other benefits. PMID- 21257581 TI - Assessing the feasibility of a community animal health worker project in Rajasthan. PMID- 21257583 TI - Infectious bovine rhinotracheitis outbreaks in dairy cows. AB - Outbreaks of infectious bovine rhinotracheitis in dairy cattle. Louping ill in cattle and sheep. Vitamin A, D and E deficiency in fattening cattle. Dosing gun injuries in sheep. Large outbreak of lameness in sheep caused by a strawberry footrot-like condition. These are among matters discussed in the Veterinary Laboratories Agency's (VLA's) disease surveillance report for November 2010. PMID- 21257584 TI - Leg health in chickens: assessing the assessment. PMID- 21257585 TI - Assessing leg health in chickens using a force plate and gait scoring: how many birds is enough? AB - Meat chickens from experimental flocks were tested repeatedly from three to six weeks of age using gait score (GS) and force plate (FP) techniques, and the findings were related to postmortem results for leg health. This initial study indicated that five weeks was the optimal age to test birds using the FP to indicate abnormalities and pathologies. Birds (n=492) with a range of walking styles were then selected at five weeks of age from three commercial flocks, gait scored and tested using a FP. A subsample of these birds (n=191) was examined postmortem, and relationships between leg abnormalities and pathologies, GS and FP results were investigated. Models of leg abnormalities and pathologies with GS or FP measurements as covariates left much variation unexplained; hence, the number of birds that would need to be tested using these methods to assess the flock prevalence of leg abnormalities or pathologies is high. PMID- 21257586 TI - Sterilisation of hybrid Galapagos tortoises (Geochelone nigra) for island restoration. Part 2: phallectomy of males under intrathecal anaesthesia with lidocaine. AB - Lidocaine intrathecal anaesthesia was used to perform phallectomies in 15 hybrid Galapagos tortoises (Geochelone nigra) in a field setting as part of a conservation and ecosystem restoration project in the Galapagos Islands. The intrathecal injection was performed in the dorsal intercoccygeal region of the tail. Once the tail and hindlimbs were relaxed and the phallus was easily exteriorised, phallectomy was performed in a routine manner. All the animals recovered well from the procedure and were walking 30 to 60 minutes after surgery. No adverse effects were noted as a result of lidocaine intrathecal anaesthesia. One of the larger animals had evidence of haemorrhage from the surgical site 48 hours postoperatively. All tortoises continued to make full recoveries and were released on to the island of Pinta in May 2010. PMID- 21257587 TI - Prevalence of Coxiella burnetii infection in Dutch dairy herds based on testing bulk tank milk and individual samples by PCR and ELISA. AB - A study using an ELISA and a real-time PCR assay based on the detection of the repetitive transposon-like gene of Coxiella burnetii revealed that infection with the bacterium was widespread among Dutch dairy herds, with antibodies detected in bulk tank milk (BTM) from 268 of 341 herds (78.6 per cent) and bacterial DNA detected in 193 of 341 herds (56.6 per cent). The BTM samples were taken in November and December 2007. Serological and molecular studies in young and adult cattle selected from 100 herds showed that antibodies were present in the blood of 470 of 2936 (16.0 per cent) lactating cows but only in 19 of 1831 (1.0 per cent) young animals. Bacterial DNA was detected in the milk of 254 of 2925 (8.7 per cent) lactating cows; bacterial DNA was not detected in any of the faecal samples obtained from youngstock. The blood and milk samples were taken from the cattle in the period January to April 2008. PMID- 21257588 TI - Mandibular lymphoma in a three-year-old thoroughbred filly. PMID- 21257589 TI - Rare VTEC serotypes of potential zoonotic risk isolated from bovine hides and carcases. PMID- 21257590 TI - Zinc toxicity in two dogs associated with the ingestion of identification tags. PMID- 21257591 TI - Registration of bitches undergoing repeat caesareans. PMID- 21257592 TI - Bovine neonatal pancytopenia, and anaemia in lambs caused by feeding cow colostrum. PMID- 21257593 TI - Polymyositis and DNA collection in the Hungarian vizsla dog. PMID- 21257594 TI - Sheep abortion testing service. PMID- 21257595 TI - Poxvirus identified in a red squirrel (Sciurus vulgaris) from Spain. PMID- 21257596 TI - Prevalence of obesity in a population of horses in the UK. PMID- 21257597 TI - What makes a Salmonella strain epidemic? An expert opinion workshop. AB - An expert opinion workshop was held on the subject of the cause, identification and control of new and emerging Salmonella strains. Experts were invited to complete questionnaires, contribute to structured discussions and take part in cluster group tasks. Outputs of the workshop included that, with current surveillance methods, it might take up to 2.5 years from the first introduction of a new strain into the UK livestock population to its identification as a human epidemic strain. In order to reduce the time to detection and provide more effective control options, several recommendations were made, including better back-tracing of human cases to their source, which would require more effective communication between those responsible for human and veterinary surveillance. PMID- 21257598 TI - Acquired antimicrobial resistance in equine Rhodococcus equi isolates. PMID- 21257599 TI - Biopsy wound healing in long-finned pilot whales (Globicephala melas). PMID- 21257600 TI - Cross-reaction of a Campylobacter fetus subspecies venerealis real-time PCR. PMID- 21257601 TI - A genome-wide scan in affected sibling pairs with idiopathic recurrent miscarriage suggests genetic linkage. AB - Previously, siblings of patients with idiopathic recurrent miscarriage (IRM) have been shown to have a higher risk of miscarriage. This study comprises two parts: (i) an epidemiological part, in which we introduce data on the frequency of miscarriage among 268 siblings of 244 patients with IRM and (ii) a genetic part presenting data from a genome-wide linkage study of 38 affected sibling pairs with IRM. All IRM patients (probands) had experienced three or more miscarriages and affected siblings two or more miscarriages. The sibling pairs were genotyped by the Affymetrix GeneChip 50K XbaI platform and non-parametric linkage analysis was performed via the software package Merlin. We find that siblings of IRM patients exhibit a higher frequency of miscarriage than population controls regardless of age at the time of pregnancy. We identify chromosomal regions with LOD scores between 2.5 and 3.0 in subgroups of affected sibling pairs. Maximum LOD scores were identified in four occurrences: for rs10514716 (3p14.2) when analyzing sister-pairs only; for rs10511668 (9p22.1) and rs341048 (11q13.4) when only analyzing families where the probands have had four or more miscarriages; and for rs10485275 (6q16.3) when analyzing one sibling pair from each family only. We identify no founder mutations. Concluding, our results imply that IRM patients and their siblings share factors which increase the risk of miscarriage. In this first genome-wide linkage study of affected sibling pairs with IRM, we identify regions on chromosomes 3, 6, 9 and 11 which warrant further investigation in order to elucidate their putative roles in the genesis of IRM. PMID- 21257602 TI - Protein phosphatase 1 complexes modulate sperm motility and present novel targets for male infertility. AB - Infertility is a growing concern in modern society, with 30% of cases being due to male factors, namely reduced sperm concentration, decreased motility and abnormal morphology. Sperm cells are highly compartmentalized, almost devoid of transcription and translation consequently processes such as protein phosphorylation provide a key general mechanism for regulating vital cellular functions, more so than for undifferentiated cells. Reversible protein phosphorylation is the principal mechanism regulating most physiological processes in eukaryotic cells. To date, hundreds of protein kinases have been identified, but significantly fewer phosphatases (PPs) are responsible for counteracting their action. This discrepancy can be explained in part by the mechanism used to control phosphatase activity, which is based on regulatory interacting proteins. This is particularly true for PP1, a major serine/threonine PP, for which >200 interactors (PP1 interacting proteins-PIPs) have been indentified that control its activity, subcellular location and substrate specificity. For PP1, several isoforms have been described, among them PP1gamma2, a testis/sperm-enriched PP1 isoform. Recent findings support our hypothesis that PP1gamma2 is involved in the regulation of sperm motility. This review summarizes the known sperm-specific PP1-PIPs, involved in the acquisition of mammalian sperm motility. The complexes that PP1 routinely forms with different proteins are addressed and the role of PP1/A-kinase anchoring protein complexes in sperm motility is considered. Furthermore, the potential relevance of targeting PP1 PIPs complexes to infertility diagnostics and therapeutics as well as to male contraception is also discussed. PMID- 21257603 TI - Cohort profile: the KPSC Children's Health Study, a population-based study of 920 000 children and adolescents in southern California. PMID- 21257604 TI - MACCHI-BOU 2 is required for early embryo patterning and cotyledon organogenesis in Arabidopsis. AB - The phytohormone auxin is a key regulator of organogenesis in plants and is distributed asymmetrically via polar transport. However, the precise mechanisms underlying auxin-mediated organogenesis remain elusive. Here, we have analyzed the macchi-bou 2 (mab2) mutant identified in a pinoid (pid) enhancer mutant screen. Seedlings homozygous for either mab2 or pid showed only mild phenotypic effects on cotyledon positions and/or numbers. In contrast, mab2 pid double mutant seedlings completely lacked cotyledons, indicating a synergistic interaction. We found that mab2 homozygous embryos had defective patterns of cell division and showed aberrant cotyledon organogenesis. Further analysis revealed that the mab2 mutation affected auxin response but not auxin transport in the embryos, suggesting the involvement of MAB2 in auxin response during embryogenesis. MAB2 encodes an Arabidopsis ortholog of MED13, a putative regulatory module component of the Mediator complex. Mediator is a multicomponent complex that is evolutionarily conserved in eukaryotes and its regulatory module associates with Mediator to control the interaction of Mediator and RNA polymerase II. MAB2 interacts with a regulatory module component in yeast cells. Taken together, our data suggest that MAB2 plays a crucial role in embryo patterning and cotyledon organogenesis, possibly through modulating expression of specific genes such as auxin-responsive genes. PMID- 21257605 TI - From organelle to organ: ZRIZI MATE-Type transporter is an organelle transporter that enhances organ initiation. AB - Plant architecture is a predictable but flexible trait. The timing and position of organ initiation from the shoot apical meristem (SAM) contribute to the final plant form. While much progress has been made recently in understanding how the site of leaf initiation is determined, the mechanism underlying the temporal interval between leaf primordia is still largely unknown. The Arabidopsis ZRIZI (ZRZ) gene belongs to a large gene family encoding multidrug and toxic compound extrusion (MATE) transporters. Unique among plant MATE transporters identified so far, ZRZ is localized to the membrane of a small organelle, possibly the mitochondria. Plants overexpressing ZRZ in initiating leaves are short, produce leaves much faster than wild-type plants and show enhanced growth of axillary buds. These results suggest that ZRZ is involved in communicating a leaf-borne signal that determines the rate of organ initiation. PMID- 21257606 TI - Photosynthesis-dependent and -independent responses of stomata to blue, red and green monochromatic light: differences between the normally oriented and inverted leaves of sunflower. AB - The effects of growth light environment on stomatal light responses were analyzed. We inverted leaves of sunflower (Helianthus annuus) for 2 weeks until their full expansion, and measured gas exchange properties of the adaxial and abaxial sides separately. The sensitivity to light assessed as the increase in stomatal conductance was generally higher in the abaxial stomata than in the adaxial stomata, and these differences could not be completely changed by the inversion treatment. We also treated the leaves with DCMU to inhibit photosynthesis and evaluated the photosynthesis-dependent and -independent components of stomatal light responses. The red light response of stomata in both normally oriented and inverted leaves relied only on the photosynthesis-dependent component. The blue light response involved both the photosynthesis-dependent and photosynthesis-independent components, and the relative contributions of the two components differed between the normally oriented and inverted leaves. A green light response was observed only in the abaxial stomata, which also involved the photosynthesis-dependent and photosynthesis-independent components, strongly suggesting the existence of a green light receptor in sunflower leaves. Moreover, acclimation of the abaxial stomata to strong direct light eliminated the photosynthesis-independent component in the green light response. The results showed that stomatal responses to monochromatic light change considerably in response to growth light environment, although some of these responses appear to be determined inherently. PMID- 21257607 TI - Arabidopsis 3-ketoacyl-CoA thiolase-2 (KAT2), an enzyme of fatty acid beta oxidation, is involved in ABA signal transduction. AB - The phytohormone ABA plays an important role in plant development and adaptation to diverse environmental stresses. Many of the components involved in ABA signaling remain to be discovered, and knowledge of these is needed to understand fully the highly complex ABA signaling network. Here, we report that an enzyme catalyzing beta-oxidation of fatty acids, 3-ketoacyl-CoA thiolase-2 (KAT2/PED1/PKT3) (EC 2.3.1.16), is involved in ABA signaling. We provide genetic evidence that KAT2 positively regulates ABA signaling in all the major ABA responses, including ABA-induced inhibition of seed germination and post germination growth arrest, and ABA-induced stomatal closure and stomatal opening inhibition in Arabidopsis thaliana. KAT2 was shown to be important for reactive oxygen species (ROS) production in response to ABA, suggesting that KAT2 regulates ABA signaling at least partly through modulating ROS homeostasis in plant cells. Additionally, we provide data suggesting that KAT2 may function downstream of an important WRKY transcription repressor WRKY40, which may link KAT2 with the ABA receptor ABAR/CHLH-mediated signaling. PMID- 21257608 TI - Graphics processing unit implementations of relative expression analysis algorithms enable dramatic computational speedup. AB - SUMMARY: The top-scoring pair (TSP) and top-scoring triplet (TST) algorithms are powerful methods for classification from expression data, but analysis of all combinations across thousands of human transcriptome samples is computationally intensive, and has not yet been achieved for TST. Implementation of these algorithms for the graphics processing unit results in dramatic speedup of two orders of magnitude, greatly increasing the searchable combinations and accelerating the pace of discovery. AVAILABILITY: http://www.igb.illinois.edu/labs/price/downloads/. PMID- 21257609 TI - OrthoNets: simultaneous visual analysis of orthologs and their interaction neighborhoods across different organisms. AB - MOTIVATION: Protein interaction networks contain a wealth of biological information, but their large size often hinders cross-organism comparisons. We present OrthoNets, a Cytoscape plugin that displays protein-protein interaction (PPI) networks from two organisms simultaneously, highlighting orthology relationships and aggregating several types of biomedical annotations. OrthoNets also allows PPI networks derived from experiments to be overlaid on networks extracted from public databases, supporting the identification and verification of new interactors. Any newly identified PPIs can be validated by checking whether their orthologs interact in another organism. AVAILABILITY: OrthoNets is freely available at http://wodaklab.org/orthonets/. PMID- 21257610 TI - Cyclin-dependent kinase 5 phosphorylates mammalian HMGB1 protein only if acetylated. AB - High mobility group box 1 (HMGB1) protein is the most abundant chromatin associated non-histone protein expressed in all nucleated eukaryotic cells. We examined the phosphorylation of mammalian HMGB1 by testing the ability of the cyclin-dependent kinase 5 (Cdk5) to use as substrates native protein, either unmodified or in vivo acetylated and recombinant HMGB1. It turned out that Cdk5 was active on the in vivo acetylated HMGB1 only. We studied the effect of the phosphorylation on the 'architectural' properties of the acetylated HMGB1. The treatment with Cdk5 of the acetylated HMGB1 inhibited its capacity to induce DNA end-joining but had no effect on its ability to recognize distorted DNA structures. PMID- 21257611 TI - Differential effects on inhibition of cholesterol absorption by plant stanol and plant sterol esters in apoE-/- mice. AB - AIMS: 'Functional foods' supplemented with plant sterol esters (PSE) and plant stanol esters (PSA) are therapeutic options for the management of hypercholesterolaemia. However, their effects on blood monocytes, endothelial function, atherogenesis, and sterol tissue concentrations are poorly understood. METHODS AND RESULTS: Male apoE-/- mice (n= 30) were randomized to three different diets for 6 weeks (n= 10 per group): high-cholesterol (1.25%) western-type diet (WTD), WTD + 2% PSE, and WTD + 2% PSA. Both supplements reduced serum cholesterol. WTD + PSE resulted in increased plant sterol serum concentrations and increased inflammatory Ly-6C(high) monocyte numbers. WTD + PSA increased plant stanol serum concentrations and Ly-6C-monocyte numbers, but decreased vascular superoxide release, lipid hydroperoxides, and inflammatory cytokines in aortic tissue, in plasma, and in circulating monocytes. Despite reduced serum cholesterol concentrations, both supplements impaired endothelial vasodilation compared with WTD. WTD + PSA reduced the development of atherosclerotic lesions compared with WTD alone (12.7 +/- 3.7 vs. 28.3 +/- 3.5%), and WTD + PSE was less effective (17.5 +/- 3.7%). WTD + PSE and WTD + PSA reduced the cholesterol content in the liver, but not in the brain. However, WTD + PSE and WTD + PSA increased plant sterol and plant stanol concentrations in the liver as well as in the brain. CONCLUSION: PSE and PSA supplementation reduced serum cholesterol, but increased plant sterol and plant stanol concentrations. Elevated levels of PSE and PSA were associated with endothelial dysfunction and increased central nervous system depositions. Atherosclerotic lesion retardation was more pronounced in WTD + PSA, coinciding with higher regenerative monocyte numbers, decreased oxidative stress, and decreased inflammatory cytokines compared with WTD + PSE. PMID- 21257612 TI - Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy. AB - Cardiac hypertrophy is a stereotypic response of the heart to increased workload. The nature of the workload increase may vary depending on the stimulus (repetitive, chronic, pressure, or volume overload). If the heart fully adapts to the new loading condition, the hypertrophic response is considered physiological. If the hypertrophic response is associated with the ultimate development of contractile dysfunction and heart failure, the response is considered pathological. Although divergent signalling mechanisms may lead to these distinct patterns of hypertrophy, there is some overlap. Given the close relationship between workload and energy demand, any form of cardiac hypertrophy will impact the energy generation by mitochondria, which are the key organelles for cellular ATP production. Significant changes in the expression of nuclear and mitochondrially encoded transcripts that impact mitochondrial function as well as altered mitochondrial proteome composition and mitochondrial energetics have been described in various forms of cardiac hypertrophy. Here, we review mitochondrial alterations in pathological and physiological hypertrophy. We suggest that mitochondrial adaptations to pathological and physiological hypertrophy are distinct, and we shall review potential mechanisms that might account for these differences. PMID- 21257613 TI - Placental stem cells pre-treated with a hyaluronan mixed ester of butyric and retinoic acid to cure infarcted pig hearts: a multimodal study. AB - AIMS: Pre-treating placenta-derived human mesenchymal stem cells (FMhMSCs) with a hyaluronan mixed ester of butyric and retinoic acid (HBR) potentiates their reparative capacity in rodent hearts. Our aim was to test FMhMSCs in a large animal model by employing a novel combination of in vivo and ex vivo analyses. METHODS AND RESULTS: Matched regional quantifications of myocardial function and viability were performed by magnetic resonance imaging (MRI) and positron emission tomography (PET) 4 weeks after myocardial infarction combined with intramyocardial injection of FMhMSCs (n = 7), or HBR-pre-treated FMhMSCs (HBR FMhMSCs, n = 6), or saline solution (PBS, n = 7). Sham-operated pigs (n = 4) were used as control animals. Despite no differences in the ejection fraction and haemodynamics, regional MRI revealed, in pigs treated with HBR-FMhMSCs compared with the other infarcted groups, a 40% smaller infarct scar size and a significant improvement of the end-systolic wall thickening and circumferential shortening of the infarct border zone. Consistently, PET showed that myocardial perfusion and glucose uptake were, respectively, 35 and 23% higher in the border zone of pigs treated with HBR-FMhMSCs compared with the other infarcted groups. Histology supported in vivo imaging; the delivery of HBR-FMhMSCs significantly enhanced capillary density and decreased fibrous tissue by approximately 68%. Moreover, proteomic analysis of the border zone in the HBR-FMhMSCs group and the FMhMSCs group indicated, respectively, 45 and 30% phenotypic homology with healthy tissue, while this homology was only 26% in the border zone of the PBS group. CONCLUSION: Our results support a more pronounced reparative potential of HBR-pre-treated FMhMSCs in a clinically relevant animal model of infarction and highlight the necessity of using combined diagnostic imaging to avoid underestimations of stem cell therapeutic effects in the heart. PMID- 21257614 TI - EULAR recommendations for calcium pyrophosphate deposition. Part II: management. AB - OBJECTIVES: To develop evidence-based recommendations for management of calcium pyrophosphate deposition (CPPD). METHODS: A multidisciplinary guideline development group of 15 experts, representing 10 European countries, generated key propositions for management of CPPD using a Delphi consensus approach. For each recommendation research evidence was searched systematically. Whenever possible, the effect size and number needed to treat for efficacy and RR or OR for side effects were calculated for individual treatment modalities. Strength of recommendation was assessed by the European League Against Rheumatism visual analogue scale. RESULTS: Nine key recommendations were generated, including topics for general management, treatment of acute attacks, prophylaxis against recurrent acute attacks and management of chronic symptoms. It was recommended that optimal treatment requires both non-pharmacological and pharmacological treatments. For acute CPP crystal arthritis, cool packs, temporary rest and joint aspiration combined with steroid injection are often sufficient. For prophylaxis or chronic inflammatory arthritis with CPPD, oral non-steroidal anti-inflammatory drugs with gastroprotective treatment and/or low-dose colchicine 0.5-1.0 mg daily may be used. Other recommendations included parenteral or oral corticosteroid for acute CPP arthritis in those unresponsive or unsuited to other measures, and low dose corticosteroid, methotrexate or hydroxychloroquine for chronic inflammatory arthritis with CPPD. Asymptomatic CPPD requires no treatment. Strength of recommendations varies from 79% to 95%. CONCLUSION: Nine key recommendations for management of CPP crystal associated arthritis were developed using both research evidence and expert consensus. Strength of recommendations was provided to assist the application of these recommendations. PMID- 21257615 TI - European League Against Rheumatism recommendations for the inclusion of patient representatives in scientific projects. AB - OBJECTIVE: To develop recommendations to enable successful inclusion of the patient perspective in European League Against Rheumatism (EULAR)-funded scientific research projects. METHODS: The EULAR standardised operational procedures for guideline development were followed. A systematic literature review was presented during a first task force meeting, including 3 rheumatologists, 1 rheumatologist/epidemiologist, 2 allied health professionals, 2 representatives of arthritis research organisations and 7 patient representatives, resulting in 38 statements. A Delphi method was carried out to reduce and refine the statements and agree on a set of eight. Next, a survey among a wider group of experts, professionals and patient representatives (n=42), was completed. Feedback from this wider group was discussed at the second meeting and integrated in the final wording of the recommendations. Subsequently, the level of agreement of the group of experts (n=81) was re-evaluated. RESULTS: The project resulted in a definition of patient research partner and agreement on a set of eight recommendations for their involvement in research projects. These recommendations provide practical guidance for organising patient participation, capturing (1) the role of patient research partners, (2) phase of involvement, (3) the recommended number, (4) recruitment, (5) selection, (6) support, (7) training and (8) acknowledgement. CONCLUSION: Collaboration between patients and professionals in research is relatively new. Trials or effectiveness studies are not yet available. Nevertheless, it is possible to define recommendations for the inclusion of patients in research following a solid expert opinion based consensus process. PMID- 21257617 TI - Association of polymorphisms/haplotypes of the genes encoding vascular endothelial growth factor and its KDR receptor with recurrent pregnancy loss. AB - BACKGROUND Vascular endothelial growth factor (VEGF) and its kinase insert domain receptor (KDR) play an important role in angiogenesis, and their gene expression patterns also suggest a close relationship with early pregnancy. However, limited information is available regarding the role of the VEGF system, especially its KDR receptor, in recurrent pregnancy loss (RPL). This study was conducted to investigate a genetic association between VEGF and its receptor gene (KDR) with idiopathic RPL. METHODS In this case-control study, 115 women who had experienced at least two consecutive spontaneous miscarriages (n= 62 women with two miscarriages, n= 53 with three or more) and 170 controls were included. A total of 14 tag single-nucleotide polymorphisms (SNPs) of VEGF and KDR were selected from the HapMap Web site and three functional SNPs [rs1570360 (-1154G/A) of VEGF; rs2305948 (V297I) and rs1870377 (Q472H) of the KDR gene] were genotyped using primer extension analysis. We further used multifactor dimensionality reduction analysis to evaluate gene-gene interactions. RESULTS One tag SNP (rs6838752) and the functional SNP (Q472H) of the KDR gene were in complete linkage and showed significant differences between patients and controls (P< 0.05). The frequencies of haplotypes of VEGF (A-T-G haplotype) and KDR (A-C-A-T-G haplotype) showed significant differences in patients versus controls (P< 0.05). All comparisons with controls remained significant when the subgroup of women with three or more miscarriages was analyzed. CONCLUSIONS VEGF and its receptor gene (KDR) are associated with idiopathic RPL. The VEGF/KDR system jointly contributes to recurrent miscarriage in Taiwanese Han women. PMID- 21257618 TI - Barriers to providing palliative care for older people in acute hospitals. AB - BACKGROUND: the need for access to high-quality palliative care at the end of life is becoming of increasing public health concern. The majority of deaths in the UK occur in acute hospitals, and older people are particularly likely to die in this setting. However, little is known about the barriers to palliative care provision for older people within acute hospitals. OBJECTIVE: to explore the perspectives of health professionals regarding barriers to optimal palliative care for older people in acute hospitals. METHODS: fifty-eight health professionals participated in eight focus groups and four semi-structured interviews. RESULTS: participants identified various barriers to palliative care provision for older people, including attitudinal differences to the care of older people, a focus on curative treatments within hospitals and a lack of resources. Participants also reported differing understandings of whose responsibility it was to provide palliative care for older people, and uncertainly over the roles of specialist and generalist palliative care providers in acute hospitals. CONCLUSIONS: numerous barriers exist to the provision of high quality palliative care for older people within acute hospital settings. Additional research is now required to further explore age-related issues contributing to poor access to palliative care. PMID- 21257619 TI - General practitioner-led commissioning in the NHS: progress, prospects and pitfalls. AB - The latest NHS reforms in England will require all general practices to become members of general practitioner (GP) consortia. These organisations will have responsibility for commissioning the majority of health care for their local populations. This article reviews the history and evidence on impact of the previous models of GP commissioning that have been introduced in the NHS with the aim of distilling key lessons for the design, implementation and evaluation of the latest reforms. GP commissioning has the potential to generate a variety of benefits for the NHS and patients, including lowering elective and non-elective referrals, reducing waiting times, improved coordination of primary and community support services and better financial risk management. GP commissioning has also the potential to reduce patient satisfaction, increase inequalities between geographical areas and may generate substantial management and transaction costs. The GP community will need to display strong directive leadership as well as nurture a culture of collaboration and group camaraderie among practices if the GP consortia model of commissioning is to deliver the desired improvements in quality and performance. The implementation of the new GP consortia model of commissioning needs to be monitored and evaluated to ensure that the benefits are maximized and any unintended and dysfunctional effects mitigated. PMID- 21257620 TI - The concise argument. PMID- 21257621 TI - Hurts, insults and stigmas: a comment on Murphy. PMID- 21257623 TI - Protein microarrays for systems biology. AB - Systems biology holds the key for understanding biological systems on a system level. It eventually holds the key for the treatment and cure of complex diseases such as cancer, diabetes, obesity, mental disorders, and many others. The ' omics' technologies, such as genomics, transcriptomics, proteomics, and metabonomics, are among the major driving forces of systems biology. Featured as high-throughput, miniaturized, and capable of parallel analysis, protein microarrays have already become an important technology platform for systems biology. In this review, we will focus on the system level or global analysis of biological systems using protein microarrays. Four major types of protein microarrays will be discussed: proteome microarrays, antibody microarrays, reverse-phase protein arrays, and lectin microarrays. We will also discuss the challenges and future directions of protein microarray technologies and their applications for systems biology. We strongly believe that protein microarrays will soon become an indispensable and invaluable tool for systems biology. PMID- 21257624 TI - Four-way ligation for construction of a mammalian cell-based full-length antibody display library. AB - A unique four-way ligation strategy was developed for rapid construction of a full-length antibody library. A mammalian expression vector was constructed that contained dual mammalian expression cassettes and sequences recognized by the unique restriction enzymes BsmBI, BstXI, and SfiI. Both full-length light-chain and variable domain of heavy-chain genes were inserted into the vector in one step by four-way ligation, and full-length bivalent antibodies were displayed on mammalian cell surfaces. Using this strategy, only 2 weeks were required to successfully construct high-quality, full-length human antibody libraries. PMID- 21257625 TI - Arsenic trioxide promotes senescence and regulates the balance of adipogenic and osteogenic differentiation in human mesenchymal stem cells. AB - Arsenic trioxide (ATO) as an anti-tumor drug could induce differentiation and apoptosis in tumor cells. Mesenchymal stem cells (MSCs) play important roles in the hematogenesis of bone marrow. Many reports have shown that the disorder of MSC adipogenic and osteogenic differentiation occurs in some diseases. However, reports about the effects of ATO on MSCs are limited. In this study, we found that 1 MUM ATO promoted MSC senescence mainly through p21, although it had no effect on apoptosis at this dose. Furthermore, ATO promoted adipogenic differentiation, but inhibited osteogenic differentiation in MSCs. Our study also showed that CCAAT/enhancer-binding protein alpha C/EBPalpha and peroxisome proliferator-activated receptor gamma PPARgamma might be involved in the regulation of adipogenic and osteogenic differentiation induced by ATO. Our results indicated that ATO may exert an anti-tumor effect by influencing bone marrow micro-environment. Moreover, it may regulate the adipogenic and osteogenic differentiation of MSCs. PMID- 21257626 TI - Optimization of myocardial deformation imaging in term and preterm infants. AB - AIMS: Myocardial deformation imaging is now used to assess regional ventricular function in infants but their small size presents particular technical challenges. We therefore investigated the determinants of reproducibility of myocardial longitudinal strain (epsilon) in term and preterm infants, in order to determine optimal technical settings. METHODS AND RESULTS: Repeated longitudinal epsilon measurements of the mid-segments of the septum, and the left and right ventricular free walls, were performed using five different computation distances (CDs; also called strain length) in 20 infants. The coefficients of variation (CV) were calculated for each CD. Overall, epsilon measurements were most reproducible with a CD of 6 mm (CV 11.7%). In preterm infants (<34 weeks gestation; mean +/- SD diastolic LV length, 20.3 +/- 3.5 mm), epsilon measurements were most reproducible with CD of 6 mm (CV 7.2%); in term infants (>37 weeks gestation; mean +/- SD diastolic LV length, 29.6 +/- 3.0 mm), epsilon measurements were most reproducible with CD of 10 mm (CV 13.2%). The reproducibility of measuring epsilon increased with higher frame rates, from CV of 17.3% at frame rates <180 per s to 11.7% for frame rates >180 per s and 9.6% for rates >248 per s. CONCLUSION: In newborn infants, tissue Doppler loops should be acquired at frame rates above 180 per s. Myocardial deformation analysis of preterm infants should be performed using a CD of 6 mm, whereas a CD of 10 mm is more reproducible in term infants. PMID- 21257627 TI - What intensivists need to know about hemophagocytic syndrome: an underrecognized cause of death in adult intensive care units. AB - Hemophagocytic syndrome, also known as hemophagocytic lymphohistiocytosis (HLH), is a rare and frequently fatal disorder caused by an uncontrollable and ineffective systemic immune response. Patients initially present with fever, cytopenia, and hepatosplenomegaly, and subsequently develop multiorgan failure (MOF). Hemophagocytosis can be found on biopsy specimen but is not required. Acquired forms of HLH can occur in apparently healthy adults, while children present more often with an inherited form of the disease. Since HLH often presents with sepsis-like symptoms and organ dysfunction, patients are usually treated for presumed sepsis, which inevitably leads to delayed diagnosis and treatment. Intensivists need to have a low threshold for suspecting this disorder when previously healthy individuals present with a fulminant sepsis-like syndrome, which are unresponsive to conventional treatment. We present 3 patients with HLH who were admitted to our adult medical intensive care unit (MICU) over a 2-year period with fatal outcomes and emphasize the diagnostic importance of markedly elevated serum ferritin levels and the need for tissue biopsy in making an accurate diagnosis in a timely manner. PMID- 21257628 TI - Posterior reversible encephalopathy syndrome. AB - Posterior reversible encephalopathy syndrome (PRES) is characterized by headache, altered mental status, visual disturbances, and seizures. Radiological features typically include edema of the posterior cerebral regions, especially of the parietooccipital lobes. Atypical imaging features, such as involvement of anterior cerebral regions, deep white matter, and the brain stem are also frequently seen. Vasoconstriction is common in vascular imaging. Different conditions have been associated with PRES, but toxemia of pregnancy, solid organ or bone marrow transplantation, immunosuppressive treatment, cancer chemotherapy, autoimmune diseases, and hypertension are most commonly described. The pathophysiology of PRES is unclear and different hypotheses are being discussed. Posterior reversible encephalopathy syndrome is best managed by monitoring and treatment in the setting of a neurointensive care unit. The prognosis is usually benign with complete reversal of clinical symptoms within several days, when adequate treatment is immediately initiated. Treatment of severe hypertension, seizures, and withdrawal of causative agents represent the hallmarks of specific therapy in PRES. Delay in diagnosis and treatment may lead to permanent neurological sequelae. Therefore, awareness of PRES is of crucial importance for the intensivist. PMID- 21257629 TI - Short-term outcomes in premature neonates adhering to the philosophy of supportive care allowing for weight gain and organ maturation prior to cardiac surgery. AB - BACKGROUND: Prematurity is a recognized risk factor for morbidity and mortality following cardiac surgery. The purpose of this study was to examine short-term outcomes following cardiac surgery in premature neonates adhering to our institutional philosophy of supportive care allowing for weight gain and organ maturation. METHODS: Retrospective review of all neonates undergoing cardiac surgery from January 2002 to May 2008. A total of 810 neonates (<30 days of age) were identified. Prematurity defined as less than 36 weeks of gestation. Neonates undergoing ductus arteriosus ligation alone were excluded. In all, 63 neonates comprised the premature group. Term group comprised 244 randomly selected term neonates in a 1:4 ratio. Outcome variables were compared between the 2 groups. RESULTS: Median gestation 34 weeks, range 24 to 35 weeks. Defects: 2 ventricle, normal arch (41% premature vs 44% term; P = .7), 2 ventricle, abnormal arch (24% vs 22%; P = .8), single ventricle, normal arch (21% vs 15%; P = .2), single ventricle, abnormal arch (14% vs 19%; P = .4). Premature neonates were older and smaller at surgery. Cardiopulmonary bypass procedures were performed less frequently in premature neonates (49% vs 69%; P = .004). Length of mechanical ventilation at our institution (6 days [0.5-54) vs 4 days [0.5-49); P = .06); postoperative hospital stay at our institution (17 days [1-161) vs 15 days [0 153); P = .06); and mortality (16% vs 11%; P = .2) was not different between the 2 groups. CONCLUSION: Early outcome seems independent of weight, prematurity, cardiopulmonary bypass, and type of first intervention. Importantly, there was no statistical difference in mortality between the 2 groups, regardless of how they were treated. Further long-term follow-up is needed in this patient population. PMID- 21257630 TI - Review of a large clinical series: once- versus twice-daily enoxaparin for venous thromboembolism prophylaxis in high-risk trauma patients. AB - BACKGROUND: Consensus guidelines support the use of low-molecular-weight heparin for venous thromboembolism (VTE) prophylaxis in high-risk trauma patients but do not recommend a specific regimen. The current study compared the effectiveness and safety of enoxaparin 40 mg once-daily versus enoxaparin 30 mg twice-daily for VTE prophylaxis in high-risk trauma patients. METHODS: A retrospective chart review was conducted of all trauma patients older than 18 years of age admitted to Shands at the University of Florida between July 1, 2005 and June 30, 2007, who received either dosing regimen. Excluded were patients with Injury Severity Score <9, surviving <2 days, hospital length of stay <2 days, receipt of >1 agent, and/or dosing regimen for VTE prophylaxis during hospitalization, interruption in therapy, pregnancy, or diagnosis of a VTE within 24 hours of admission. RESULTS: A total of 409 patients were treated with once-daily dosing and 278 patients were treated with twice-daily dosing. The overall rate of VTE was 2.9% (95% confidence interval, 1.52, 5.07) in the once-daily group and 1.1% in the twice-daily group (95% confidence interval, 0.22, 3.12; P = .118). Major bleeding occurred in 11 patients in the once-daily group and 5 patients in the twice-daily group (1.8% vs 2.7%; P = .608). CONCLUSION: Enoxaparin 30 mg twice daily may be more effective than enoxaparin 40 mg once-daily for prevention of VTE in high-risk trauma patients; however, statistical significance was not achieved. There were no statistically significant differences observed in clinically significant bleeding. Further study is needed to clarify which dosing regimen of enoxaparin is superior with regard to safety and effectiveness. PMID- 21257631 TI - Risk factors and outcome of changes in adrenal response to ACTH in the course of critical illness. AB - BACKGROUND: To evaluate the concept of critical illness-related corticosteroid insufficiency (CIRCI) by studying the clinical significance, in terms of risk factors and outcome, of changes in the cortisol response to repeated adrenocorticotropic hormone (ACTH) testing in the course of critical illness. PATIENTS AND METHODS: In a retrospective study in a medical-surgical intensive care unit (ICU) of a university hospital, we retrospectively included 54 consecutive patients during a 3-year period, who underwent 2 conventional 250 MUg ACTH tests at an interval >24 hours, because of >=6 hours hypotension requiring repeated fluid challenges or vasopressor/inotropic treatment, while corticosteroid treatment was not (yet) initiated. Serum cortisol was measured immediately before and 30 and 60 minutes after intravenous injection of 250 MUg of ACTH. Patients were divided into those with an increase (>=0, n = 27) or a decrease (n = 27) in time in delta (Delta) cortisol in response to ACTH and with a Deltacortisol <100 (n = 11) and >=100 nmol/L (n = 43) at the second ACTH test. RESULTS: Changes in Deltacortisol in time were paralleled by changes in Deltacortisol/albumin, with a higher frequency of septic shock, persistently high disease severity, increased renal replacement therapy, and decreased platelet counts in the course of disease with a decrease in Deltacortisol in time. Similar trends in increased disease severity were observed when Deltacortisol remained or fell to <100 nmol/L. A decrease in Deltacortisol between the 2 tests, particularly to <100 nmol/L, was associated with increased mortality (18 nonsurvivors in the ICU). CONCLUSIONS: The findings favor the concept of dynamic adrenal function rather than poor reproducibility of the ACTH test, so that development of CIRCI, particularly in complicated septic shock and indicated by a fall in Deltacortisol (to <100 nmol/L) upon ACTH, correlates to a poor prognosis, independently of baseline cortisol, cortisol binding in blood, and disease severity. PMID- 21257632 TI - To Treat or to Palliate? A Case of Endocarditis, Severe Sepsis, and Advanced Cancer. PMID- 21257633 TI - Computerized physician order entry in the critical care environment: a review of current literature. AB - The implementation of health information technology (HIT) is accelerating, driven in part by a growing interest in computerized physician order entry (CPOE) as a tool for improving the quality and safety of patient care. Computerized physician order entry could have a substantial impact on patients in intensive care, where the potential for medical error is high, and the clinical workflow is complex. In 2009, only 17% of hospitals had functional CPOE systems in place. In intensive care unit (ICU) settings, CPOE has been shown to reduce the occurrence of some medication errors, but evidence of a beneficial effect on clinical outcomes remains limited. In some cases, new error types have arisen with the use of CPOE. Intensive care unit workflow and staff relationships have been affected by CPOE, often in unanticipated ways. The design of CPOE software has a strong impact on user acceptance. Intensive care unit-specific order sets lessen the cognitive workload associated with the use of CPOE and improve user acceptance. The diffusion of new technological innovations in the ICU can have unintended consequences, including changes in workflow, staff roles, and patient outcomes. When implementing CPOE in critical care areas, both organizational and technical factors should be considered. Further research is needed to inform the design and management of CPOE systems in the ICU and to better assess their impact on clinical end points, cost-effectiveness, and user satisfaction. PMID- 21257634 TI - A 24-year-old man with cough, rhabdomyolysis, and pneumomediastinum. AB - BACKGROUND: Community-acquired methicillin-resistant Staphylococcus aureus (CA MRSA) frequently causes severe necrotizing pneumonia in young patients. CASE: We present the case of a 24-year-old male, who was brought to the emergency department with persistent fevers, confusion, and severe cough. He was found to have necrotizing pneumonia, pneumomediastinum, and rhabdomyolysis with renal failure. Cultures were positive for influenza A and CA-MRSA. After a prolonged intensive care unit (ICU) stay, he made a complete recovery. CONCLUSION: Community-acquired MRSA pneumonia is a growing health threat that typically presents in young adults after, or in conjunction with, a flu-like illness. It is characterized by a rapidly progressive deteriorating clinical course. PMID- 21257635 TI - Analgesia and sedation in the intensive care of burn patients: results of a European survey. AB - OBJECTIVE: A variety of agents and techniques are employed in different countries, settings, and medical specialities in order to provide analgesia and sedation in intensive care. Several national guidelines have been published in recent years regarding sedation and analgesia in a general intensive care patient population; however, to date no data exist for patients with burn injuries. The aim of the study was to evaluate analgesia and sedation practice in the intensive care of burn patients in Europe. DESIGN: A postal survey was sent to 188 burn centers in Europe. The addresses were provided by the European Burn Association. The heads of the intensive care units were asked to fill in a structured questionnaire concerning the use of analgesia and sedation in their units. RESULTS: The overall response rate was 27.04%; 63% of European burn centers reported standard operating procedures for sedation and analgesia. A regular score-based assessment of sedation, analgesia, and delirium is carried out by 58%, 60%, and 5%, respectively, of the units. Propofol is the sedative most frequently used for short-term sedation and the weaning phase, whereas benzodiazepines are the preferred substances for medium- and long-term sedation. alpha2-agonists are widely used during weaning. Opioids are the analgesics of choice for approximately two thirds of the patients. Ketamine is preferred for analgesia in 12% and for sedation in 13% of all substances used. For painful procedures (eg, dressing changes), a large variety of different combinations of analgesics and sedatives are used. Half of the responding intensive care units use neuromuscular blocking agents and supportive nonpharmacological techniques. Two thirds of the European burn centers perceive the need for change in their concepts of analgesia and sedation. CONCLUSION: A wide variety of drugs are used for analgesia and sedation in European burn centers. This would appear to be due to lack of guidelines or scientific evidence. The implementation of regular assessment of sedation, analgesia, and delirium must be improved. The widespread use of neuromuscular blocking agents should be restricted or even abandoned. Two thirds of the units identify a need for change in their concepts. Valid scientific data are needed to develop guidelines for sedation and analgesia of burn patients. PMID- 21257636 TI - Perspectives of physicians and nurses regarding end-of-life care in the intensive care unit. AB - CONTEXT: The delivery of end-of-life care (EOLC) in the intensive care unit (ICU) varies widely among medical care providers. The differing opinions of nurses and physicians regarding EOLC may help identify areas of improvement. OBJECTIVE: To explore the differences of physicians and nurses on EOLC in the ICU and how these differences vary according to self-reported proficiency level and primary work unit. DESIGN: Cross-sectional survey of 69 ICU physicians and 629 ICU nurses. SETTING: Single tertiary care academic medical institution. RESULTS: A total of 50 physicians (72%) and 331 nurses (53%) participated in the survey. Significant differences between physicians and nurses were noted in the following areas: ability to safely raise concerns, do not resuscitate (DNR) decision making, discussion of health care directives, timely hospice referral, spiritual assessment documentation, utilization of social services, and the availability of EOLC education. In every domain of EOLC, physicians reported a more positive perception than nurses. Additional differences were noted among physicians based on experience, as well as among nurses based on their primary work unit and self reported proficiency level. CONCLUSIONS: Even with an increased focus on improving EOLC, significant differences continue to exist between the perspectives of nurses and physicians, as well as physicians among themselves and nurses among themselves. These differences may represent significant barriers toward providing comprehensive, consistent, and coordinated EOLC in the ICU. PMID- 21257637 TI - TAR DNA-binding protein 43 (TDP-43) regulates stress granule dynamics via differential regulation of G3BP and TIA-1. AB - TAR deoxyribonucleic acid-binding protein 43 (TDP-43) is a multifunctional protein with roles in transcription, pre-messenger ribonucleic acid (mRNA) splicing, mRNA stability and transport. TDP-43 interacts with other heterogeneous nuclear ribonucleoproteins (hnRNPs), including hnRNP A2, via its C-terminus and several hnRNP family members are involved in the cellular stress response. This relationship led us to investigate the role of TDP-43 in cellular stress. Our results demonstrate that TDP-43 and hnRNP A2 are localized to stress granules (SGs), following oxidative stress, heat shock and exposure to thapsigargin. TDP 43 contributes to both the assembly and maintenance of SGs in response to oxidative stress and differentially regulates key SGs components, including TIA-1 and G3BP. The controlled aggregation of TIA-1 is disrupted in the absence of TDP 43 resulting in slowed SG formation. In addition, TDP-43 regulates the levels of G3BP mRNA, a SG nucleating factor. The disease-associated mutation TDP-43(R361S) is a loss-of-function mutation with regards to SG formation and confers alterations in levels of G3BP and TIA-1. In contrast, a second mutation TDP 43(D169G) does not impact this pathway. Thus, mutations in TDP-43 are mechanistically divergent. Finally, the cellular function of TDP-43 extends beyond splicing and places TDP-43 as a participant of the central cellular response to stress and an active player in RNA storage. PMID- 21257638 TI - The N-terminal region of centrosomal protein 290 (CEP290) restores vision in a zebrafish model of human blindness. AB - The gene coding for centrosomal protein 290 (CEP290), a large multidomain protein, is the most frequently mutated gene underlying the non-syndromic blinding disorder Leber's congenital amaurosis (LCA). CEP290 has also been implicated in several cilia-related syndromic disorders including Meckel-Gruber syndrome, Joubert syndrome, Senor-Loken syndrome and Bardet-Biedl syndrome (BBS). In this study, we characterize the developmental and functional roles of cep290 in zebrafish. An antisense oligonucleotide [Morpholino (MO)], designed to generate an altered cep290 splice product that models the most common LCA mutation, was used for gene knockdown. We show that cep290 MO-injected embryos have reduced Kupffer's vesicle size and delays in melanosome transport, two phenotypes that are observed upon knockdown of bbs genes in zebrafish. Consistent with a role in cilia function, the cep290 MO-injected embryos exhibited a curved body axis. Patients with LCA caused by mutations in CEP290 have reduced visual perception, although they present with a fully laminated retina. Similarly, the histological examination of retinas from cep290 MO-injected zebrafish revealed no gross lamination defects, yet the embryos had a statistically significant reduction in visual function. Finally, we demonstrate that the vision impairment caused by the disruption of cep290 can be rescued by expressing only the N terminal region of the human CEP290 protein. These data reveal that a specific region of the CEP290 protein is sufficient to restore visual function and this region may be a viable gene therapy target for LCA patients with mutations in CEP290. PMID- 21257640 TI - Effect of progesterone on phosphamidon-induced impairment of memory and oxidative stress in rats. AB - Progesterone (a neurosteroid) is an important modulator of the nervous system functioning. Organophosphorus pesticides like phosphamidon have been shown to adversely affect memory and induce oxidative stress on both acute and chronic exposure. The present study was therefore designed to investigate the effects of progesterone (PROG) on phosphamidon-induced modulation of cognitive function and oxidative stress in rats. Cognitive function was assessed using step-down latency (SDL) on a passive avoidance apparatus and transfer latency (TL) on an elevated plus maze. Oxidative stress was assessed by examining the levels of thiobarbituric acid reactive species (TBARS) and non-protein thiols (NP-SH) in isolated homogenized whole brain samples. The results showed a significant reduction in SDL and prolongation of TL in the phosphamidon (1.74 mg/kg/d; p.o.) treated group at weeks 6 and 8 as compared to the control group. Two weeks treatment with PROG (15 mg/kg/d; i.p.) antagonized the effect of phosphamidon on SDL as well as TL. Phosphamidon alone produced a significant increase in the brain TBARS levels and decrease in the brain NP-SH levels. Treatment with PROG (15 mg/kg/d; i.p.) attenuated the effect of phosphamidon on oxidative stress. Together, the results showed that progesterone attenuated the cognitive dysfunction and increased oxidative stress induced by phosphamidon in the brain. PMID- 21257639 TI - Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage. AB - The purpose of our study was to determine the relationship between mutant huntingtin (Htt) and mitochondrial dynamics in the progression of Huntington's disease (HD). We measured the mRNA levels of electron transport chain genes, and mitochondrial structural genes, Drp1 (dynamin-related protein 1), Fis1 (fission 1), Mfn1 (mitofusin 1), Mfn2 (mitofusin 2), Opa1 (optric atrophy 1), Tomm40 (translocase of outermembrane 40) and CypD (cyclophilin D) in grade III and grade IV HD patients and controls. The mutant Htt oligomers and the mitochondrial structural proteins were quantified in the striatum and frontal cortex of HD patients. Changes in expressions of the electron transport chain genes were found in HD patients and may represent a compensatory response to mitochondrial damage caused by mutant Htt. Increased expression of Drp1 and Fis1 and decreased expression of Mfn1, Mfn2, Opa1 and Tomm40 were found in HD patients relative to the controls. CypD was upregulated in HD patients, and this upregulation increased as HD progressed. Significantly increased immunoreactivity of 8-hydroxy guanosine was found in the cortical specimens from stage III and IV HD patients relative to controls, suggesting increased oxidative DNA damage in HD patients. In contrast, significantly decreased immunoreactivities of cytochrome oxidase 1 and cytochrome b were found in HD patients relative to controls, indicating a loss of mitochondrial function in HD patients. Immunoblotting analysis revealed 15, 25 and 50 kDa mutant Htt oligomers in the brain specimens of HD patients. All oligomeric forms of mutant Htt were significantly increased in the cortical tissues of HD patients, and mutant Htt oligomers were found in the nucleus and in mitochondria. The increase in Drp1, Fis1 and CypD and the decrease in Mfn1 and Mfn2 may be responsible for abnormal mitochondrial dynamics that we found in the cortex of HD patients, and may contribute to neuronal damage in HD patients. The presence of mutant Htt oligomers in the nucleus of HD neurons and in mitochondria may disrupt neuronal functions. Based on these findings, we propose that mutant Htt in association with mitochondria imbalance and mitochondrial dynamics impairs axonal transport of mitochondria, decreases mitochondrial function and damages neurons in affected brain regions of HD patients. PMID- 21257641 TI - Correlation of testicular toxicity and oxidative stress induced by chlorpyrifos in rats. AB - Effect of chlorpyrifos pesticide on testicular oxidative damage was studied in Sprague-Dawley rats at varying doses. At lower doses (5 and 10 mg/kg body weight/30 days), reduction in plasma levels of testosterone and follicular stimulating hormone (FSH) and luteinizing hormone (LH) along with significant shrinkage of seminiferous tubules and drastic changes in germ cells were seen. But these adverse changes of testes were restored with the revival of serum testosterone and FSH and LH at higher doses (20 and 30 mg/kg body weight/30 days). Similarly, levels of testicular lipid peroxidation and diene conjugates were elevated whereas activities of antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase), steroidogenic (Delta(5), 3beta-HSD and Delta(5), 17beta-HSD) enzymes and angiotensinogen-converting enzyme and glutathione content including lipid-protein content of testes were decreased at low doses. But at higher doses, reductions in level of lipid peroxidation (as revealed by malondialdehyde [MDA] value) and conjugated dienes were found and on the contrary, revivals of testicular antiperoxidative/antioxidant enzymes defense systems, angiotensinogen-converting enzyme (ACE), steroidogenic enzymes, lipid protein and antioxidant glutathione content were observed. Therefore, the present study indicated from the results that chlorpyrifos had a dual effect at both doses on oxidative stress changes, but at higher doses, the cells were triggering its natural defense mechanism to combat the insult of lower doses of chlorpyrifos and became operative possibly through corrective measure of antioxidant enzymes defense system and pituitary gonadotropins hormones feedback mechanisms on testes. PMID- 21257642 TI - Metabolism of ethanol to acetaldehyde by rat uterine horn subcellular fractions. AB - Controversial studies from others suggested that alcohol intake could be associated with some deleterious effects in the uterus. Not all the effects of alcohol drinking on female reproductive organs can be explained in terms of endocrine disturbances. Deleterious effect of alcohol or its metabolites in situ could also play a role. Accordingly, we found a metabolism of alcohol to acetaldehyde in the rat uterine horn tissue cytosolic fraction mediated by xanthine oxidoreductase, requiring a purine cosubstrate and inhibited by allopurinol. This activity was detected by histochemistry in the epithelium and aldehyde dehydrogenase activity was detected in the muscular layer and in the serosa. There was a microsomal process, not requiring NADPH and of enzymatic nature, oxygen-dependent and inhibited by diethyldithiocarbamate, diphenyleneiodonium and partially sensitive to esculetin and nordihydroguaiaretic acid. The presence of metabolic pathways in the uterine horn able to generate acetaldehyde, accompanied by a low capacity to destroy it through aldehyde dehydrogenase, led to acetaldehyde accumulation in the uterus during ethanol exposure. Results suggest that any acetaldehyde produced in situ or arriving to the uterine horn via blood would remain in this organ sufficiently to have the opportunity to react with critical molecules to cause deleterious effects. PMID- 21257643 TI - Infectivity period of mice inoculated with human adenoviruses. AB - Due to non-productive infections, mice are not a good model to study some human adenoviruses. However, mice provide an excellent model to study the metabolic effects of human adenovirus, Ad36. Research interest in Ad36 is increasing rapidly, and consequently an increase in the use of mice as a model is anticipated. However, little is known about the transmission potential of Ad36 from infected mice to other laboratory animals or personnel. While underestimating the infectivity could promote inadvertent spread of Ad36, overstating it could drain valuable laboratory resources and animals. Therefore, we determined the duration of infectivity in female C57BL/6J mice that were experimentally infected with human adenoviruses Ad36 or Ad2. Other uninfected mice were co-housed for one week with the experimentally-infected animals, four or eight weeks postinfection. Additionally, uninfected mice were housed in the cages of mice that were infected with Ad36, 12 weeks earlier. The presence of viral DNA in tissues was used to indicate infection of mice. Although experimentally-infected mice harboured viral DNA at least up to 12 weeks, the horizontal transmission of infection was observed in co-housed mice only up to four weeks postinfection. Thus, Ad36-infected mice should be considered potentially infective for eight weeks and appropriate handling and barrier containment should be used. After eight week postinfection, horizontal transmission appears unlikely. This information may provide guidelines for animal handling, and experimental design using Ad36, which may increase safety for laboratory personnel and reduce the number of mice required for experiments. PMID- 21257644 TI - SKARP--A population-based cohort study of childhood food-associated symptoms perceived by parents and food allergies diagnosed by physicians: design, methods and participation. AB - BACKGROUND: Few epidemiological studies exist on food-associated symptoms and allergies in large unselected child populations. AIMS: To describe the design, methods and participation rate of the South Karelian Allergy Research Project (SKARP), a population-based epidemiological study on food-associated symptoms and physician-diagnosed food allergies. METHODS: The study population of 5,973 children born between 2001 and 2006 and resident in the province of South Karelia, Finland, was identified from the nationwide population register. The parents received a questionnaire to be returned at their child's annual visit to the child health clinic, where supplementary interviews were performed. Results of allergy tests (skin prick tests, immunoglobulin E antibodies and open food challenges) performed on participants and non-participants were collected from the relevant health care units in the area. RESULTS: Participation rates in the questionnaire study were 54% (644/1,194) among the parents of neonates and 69% (3308/4,779) among those of the children aged 1 to 4 years. Cooperation with the child health clinics and mailing of a reminder questionnaire improved participation by 8 and 10 percentage points, respectively. The final participation rate seemed to be unaffected by whether the child had or had not been tested for suspected allergy. CONCLUSIONS: A reasonably good participation rate and almost complete coverage of allergy tests were achieved thanks to successful cooperation with the child health clinics and test laboratories. This baseline study forms a representative database to estimate the occurrence of food associated symptoms, physician-diagnosed food allergies and allergy testing in the general population. PMID- 21257645 TI - The Danish Health Examination Survey 2007-2008 (DANHES 2007-2008). AB - AIMS: The Danish Health Examination Survey (DANHES 2007-2008) was carried out by the National Institute of Public Health, University of Southern Denmark, in 13 Danish municipalities in 2007-2008. The focus of the survey was diet, smoking, alcohol, and physical activity. The aim of the survey was to establish a research database for future cross-sectional and follow-up studies. METHODS: DANHES 2007 2008 included internet-based questionnaires and a health examination. There were two different questionnaires: a basic questionnaire on socio-demography, health behaviour, self-reported health status, and living conditions, and a supplementary food frequency questionnaire. The health examination contained measurements of blood pressure, resting heart rate, height, weight, fat percentage, waist and hip circumference, blood and hair samples, spirometry, bone mineral density, physical performance, muscle strength, and aerobic fitness. RESULTS: A total of 76,484 people completed the basic questionnaire, and 18,065 adult individuals participated in the health examination, corresponding to a response rate of 14% and a participation rate of 10%, respectively. CONCLUSIONS: The database from DANHES 2007-2008 is unique in its size and diversity of measurements and questionnaire contents. Data can be linked to various registers through the Danish civil registration system, and blood samples are stored in a biobank allowing for genetic analyses. Hence, DANHES 2007-2008 forms the basis for future research projects with a focus on health behaviour and prevention of lifestyle-related diseases. PMID- 21257646 TI - Health-related quality of life in Chinese people: a population-based survey of five cities in China. AB - AIMS: The current study aimed at undertaking an investigation to describe health related quality of life (HRQL) in Chinese people, with a Mandarin version of the 36-item short-form health survey (SF-36) validated. METHODS: A total of 3,219 respondents were successfully interviewed under a randomized stratified multi stage sampling design from April 2007 to January 2008 in five cities of mainland China. Self-finished interview method was applied and the Mandarin version of SF 36 was used for assessing HRQL. RESULTS: As a result, the reliability and validity of SF-36 were acceptable, although some deviations from the hypothesized model still existed. The Chinese population scored higher than other populations in five of the eight SF-36 scales and Chinese men scored higher than women in six of the eight SF-36 scales. CONCLUSIONS: Basically, the Mandarin version of SF-36 is a reliable instrument, although minor modifications are needed. The health related quality of life in Chinese people were quite high based on the sample of five cities in China; further research is needed to establish the countrywide norm of health-related quality of life in mainland China. PMID- 21257647 TI - Use of medical resources and indirect costs of otitis media in Sweden. AB - AIMS: To estimate the use of medical resources and the societal impact of otitis media (OM) in children less than five years of age in Sweden. METHODS: An internet survey questionnaire was administered to a sample of parents with children <5 years of age. The survey covered socio-demographic data, characteristics of the OM episode, use of medical resources, productivity loss by the caregivers, and travel-related costs. Medical doctor confirmed OM (MD-OM) was defined as symptoms of earache or ''running'' ear, and/or a diagnosis of OM provided by a medical doctor. RESULTS: Of all MD-OM episodes (n = 91), in 47% a general practitioner had been consulted, in 21% a paediatrician, and in 23% an emergency department had been visited. Hospital admission occurred in one case. The MD prescribed antibiotics in 85% and over the counter drugs were bought in 69% of the episodes. In 57% of the MD-OM episodes the caregivers lost days from a paid job (mean 30.3 hours per episode, SD 19.6). In 30% of the episodes, parents reported productivity loss at work during their child's illness (mean 9.0 hours per episode, SD 12.4). The mean costs were estimated to be 6,385 SEK (575) per episode of MD-OM resulting in an economic burden to Sweden of 743,570,000 SEK (66,920,866). Fifty eight per cent of the costs were indirect non-medical costs. CONCLUSIONS: The medical and economic burden of OM is considerable to individual families as well as to society in Sweden. This study has filled a gap in the knowledge base on the impact of OM on society. PMID- 21257648 TI - Do guidelines recommending pharmacogenetic testing of psychiatric patients affect treatment costs and the use of healthcare services? AB - AIM: To identify the effects of local recommendations of pharmacogenetic testing in psychiatry with respect to treatment costs. METHODS: Based on Danish patient registers, individual treatment costs within a 365-day period at three psychiatric hospitals recommending and using pharmacogenetic testing is compared retrospectively with treatment costs at other Danish psychiatric hospitals using alternate treatment strategies. Primary outcome of interest is total direct costs analyzed by multilevel modelling. Secondary outcome measures are healthcare consumption within specific sectors analyzed by Tobitregressions. RESULTS: Costs among patients treated at hospitals recommending and using pharmacogenetic testing were not found to be statistically significantly different from costs among patients treated at sites using alternate treatment strategies. In spite of recommendations to test all patients the uptake of the test was, however, low (26 31 %). Treatment practice using routine therapeutic drug monitoring (in Arhus) shows a trend towards lower costs. CONCLUSIONS: Based on this natural experiment we were not able to document statistically significant differences in total costs between treatment sites that had guidelines recommending pharmacogenetic testing, relative to sites without such guidelines, over a period of one year. However, guidelines of pharmacogenetic testing and possibly also therapeutic drug monitoring seem to lead to reductions in costs for primary care services. In the case of the former, reductions do, however, seem to be outweighed by increases in costs for psychiatric and non-psychiatric inpatient stays. In conclusion, no statistically significant differences in total direct costs across sites with different treatment strategies were found. PMID- 21257649 TI - How music may promote healthy behaviour. AB - INTRODUCTION: Using music to promote healthy behaviour may enhance coping mechanisms in spite of illness. AIMS: 1) To explore the role and significance of music and musicking in the life of men and women with long-term illnesses in or through different life phases, situations, events, issues and contexts. 2) To increase knowledge on how participants, through exposure to and exchange of new musical materials and practices, may learn to use music as a ''technology of self '' in relation to health promotion and rehabilitation. METHODS: This exploratory study sought to instigate narratives about music's role in supporting health through a pragmatic synthesis of elements of action-research, ethnography and grounded theory. Music CDs were conceived as an interactive and dialectical tool. This longitudinal study involved eight in-depth ethnographic interviews per participant, involving nine men and 13 women, aged between 35 and 65 with long term illnesses. RESULTS: Music is a motivational device for moving our bodies, releasing anger or aggression and even transcending pain. Personal preferences in music seemed to be important for these participants while exercising, substantiated in the importance of well-being and pleasure in everyday activities and situations. CONCLUSIONS: This study has contributed to an increase in self awareness and consciousness, well-being and health for the majority of the participants in the study. It has brought to the level of consciousness forms of ''expert'' practice that may otherwise have occurred tacitly. Implementation of future health promotion and rehabilitation programmes ought to strengthen their focus on musical, cultural and physical activity both at an individual level and within local communities. PMID- 21257650 TI - Result verification, code verification and computation of support values in phylogenetics. AB - Verification in phylogenetics represents an extremely difficult subject. Phylogenetic analysis deals with the reconstruction of evolutionary histories of species, and as long as mankind is not able to travel in time, it will not be possible to verify deep evolutionary histories reconstructed with modern computational methods. Here, we focus on two more tangible issues that are related to verification in phylogenetics (i) the inference of support values on trees that provide some notion about the 'correctness' of the tree within narrow limits and, more importantly; (ii) issues pertaining to program verification, especially with respect to codes that rely heavily on floating-point arithmetics. Program verification represents a largely underestimated problem in computational science that can have fatal effects on scientific conclusions. PMID- 21257651 TI - Brain microbleeds and Alzheimer's disease: innocent observation or key player? AB - Brain microbleeds are small dot-like lesions appearing as hyposignals on gradient echo magnetic resonance sequences. In Alzheimer's disease, brain microbleeds are of special interest as they may play a crucial role in the pathophysiology. They may be a missing link between two important theories on the neuropathogenesis of Alzheimer's disease-the amyloid cascade hypothesis and the vascular hypothesis. Moreover, they may affect the clinical course of the disease and may have therapeutic consequences. The aim of this article is to review available data to understand the meaning of brain microbleeds in clinical terms and underlying pathology in the context of Alzheimer's disease. We also review the available evidence and highlight the pitfalls of our current knowledge on brain microbleeds in the setting of clinical trials design. PMID- 21257652 TI - Community-based provision of injectable contraceptives in Madagascar: 'task shifting' to expand access to injectable contraceptives. AB - INTRODUCTION: Injectable contraceptives are now the most popular contraceptive methods in sub-Saharan Africa. Injectables have not been an option for African women lacking convenient access to health facilities, however, since very few family planning programmes permit community-based distribution (CBD) of injectables by non-medically trained workers. Committed to reducing unmet contraceptive need among remote, rural populations, the Ministry of Health and Family Planning (MOHFP) of Madagascar sought evidence regarding the safety, effectiveness and acceptability of CBD of injectables. METHODS: The MOHFP joined implementing partners in training 61 experienced CBD agents from 13 communities in provision of injectables. Management mechanisms for injectables were added to the CBD programme's pre-existing systems for record keeping, commodity management and supervision. After 7 months of service provision, an evaluation team reviewed service records and interviewed CBD workers and their supervisors and clients. RESULTS: CBD workers demonstrated competence in injection technique, counselling and management of clients' re-injection schedule. CBD of injectables appeared to increase contraceptive use, with 1662 women accepting injectables from a CBD worker. Of these, 41% were new family planning users. All CBD agents wished to continue providing this service, and most supervisors indicated the programme should continue. Nearly all clients interviewed said they intended to return to the CBD worker for re-injection and would recommend this service to a friend. CONCLUSIONS: This experience from Madagascar is among the first evidence from sub Saharan Africa documenting the feasibility, effectiveness and acceptability of CBD services for injectable contraceptives. This evidence influenced national and global policy makers to recommend expansion of the practice. CBD of injectables is an example of effective task shifting of a clinical practice as a means of extending services to underserved populations without further burdening clinicians. PMID- 21257654 TI - Republicans win vote in House of Representatives to repeal health reform bill. PMID- 21257655 TI - Strengths and weaknesses of hospital standardised mortality ratios. PMID- 21257656 TI - Healthcare in Turkey: from laggard to leader. PMID- 21257657 TI - Monitoring adherence to drug treatment by using change in cholesterol concentration: secondary analysis of trial data. AB - OBJECTIVE: To estimate the accuracy of monitoring cholesterol concentration for detecting non-adherence to lipid lowering treatment. DESIGN: Secondary analysis of data on cholesterol concentration in the LIPID (long term intervention with pravastatin in ischaemic disease) study by using three measures of non-adherence: discontinuation of treatment, allocation to placebo arm, less than 80% of pills taken. SETTING: Randomised placebo controlled trial in Australia and New Zealand. PARTICIPANTS: 9014 patients with previous coronary heart disease. INTERVENTIONS: Pravastatin 40 mg or placebo daily. MAIN OUTCOME MEASURES: Sensitivity, specificity, area under the receiver operating characteristics (ROC) curve, post test probability. RESULTS: Monitoring of cholesterol concentration had modest ability for detecting complete non-adherence. One year after the start of treatment, half (1957/3937) of the non-adherent patients and 6% (253/3944) of adherent patients had a rise in concentration of low density lipoprotein cholesterol. Accuracy was reasonable (area under the curve 0.89). Cholesterol monitoring, however, had weak ability for detecting partial non-adherence. One year after the start of treatment, 16% (34/213) of partially adherent and 4% (155/3585) of fully adherent patients had a rise in concentration of low density lipoprotein cholesterol. Accuracy was poor (area under the curve 0.65). For typical pre-test probabilities of non-adherence ranging from low (25%) to high (75%), the post-test probabilities indicate continuing uncertainty after lipid testing. A patient with no change in low density lipoprotein cholesterol concentration has a post-test probability of being completely non-adherent of between 67% and 95% and a post-test probability of being partially non-adherent of between 48% and 89%. A patient with a decrease in concentration of 1.0 mmol/L has a post-test probability of being completely non-adherent of between 7% and 40% and a post-test probability of being partially non-adherent of between 21% and 71%. CONCLUSIONS: Monitoring concentration of low density lipoprotein (or total) cholesterol has modest ability to detect complete non-adherence or non persistence with pravastatin treatment and weak ability to detect partial non adherence. Results of monitoring should be considered as no more than an adjunct to careful discussion with patients about adherence. PMID- 21257658 TI - Islet transplantation in type 1 diabetes. PMID- 21257659 TI - Dr Lansley's monster. PMID- 21257660 TI - New hygiene law aims to reduce infections in German hospitals. PMID- 21257662 TI - Food and drink industry rejects claims of irresponsibility over obesity and alcoholism. PMID- 21257664 TI - Astrocytes as brain interoceptors. AB - Astrocytes form a vascular-neuronal interface and provide CNS neural networks with essential structural and metabolic support. They embrace all penetrating arterioles and capillaries, enwrap multiple neuronal somata, thousands of individual synapses, and upon activation release gliotransmitters (ATP, glutamate and D-serine) capable of modulating neuronal activity. The aim of this brief report is to review recent data implicating astrocytes in the brain mechanisms responsible for the detection of different sensory modalities and transmitting sensory information to the relevant neural networks controlling vital behaviours. The concept of astrocytes as brain interoceptors is strongly supported by our recent data obtained from studies of the central nervous mechanisms underlying the chemosensory control of breathing. At the level of the medulla oblongata, astrocytes indeed act as functional central respiratory chemoreceptors, sensing changes in the arterial blood and brain levels of /pH and then imparting these changes on the activity of the respiratory network to induce adaptive changes in lung ventilation. PMID- 21257665 TI - Bidirectional control of arteriole diameter by astrocytes. AB - Astrocytes are the most numerous cells in the CNS. It is a defining feature of brain anatomy that every astrocyte has at least one contact with the vasculature, termed an endfoot. Collectively, all endfeet completely circumscribe all vessels in the brain. This unique anatomical feature has profound functional significance, as astrocyte endfeet have been discovered to release diffusible messengers that communicate directly with underlying smooth muscle cells to change arterial diameter and thereby regulate cerebral blood flow. A growing body of data now demonstrates that astrocytes serve as a bridge, relaying information on the level of neural activity to blood vessels in order to co-ordinate oxygen and glucose delivery with the energy demands of the tissue. In particular, astrocytes respond to elevations in extracellular glutamate as a consequence of synaptic transmission through the activation of group 1 metabotropic glutamate receptors. These Gq-coupled receptors elevate intracellular calcium via IP(3) signalling, which activates phospholipase A2 and generates arachidonic acid. Arachidonic acid acts as a signalling molecule or is converted to several lipid derivates, including prostaglandin E(2) and epoxyeicosatrienoic acids. Each of these lipids acts on vascular smooth muscle cells via different mechanisms to affect vessel diameter. Arachidonic acid initiates the production of 20 hydroxyeicosatetraenoic acid to cause vasoconstriction, whereas prostaglandin E(2) and epoxyeicosatrienoic acids cause vasodilatation. Factors that determine whether constrictor or dilatory pathways predominate involve nitric oxide and brain metabolic elements, such as oxygen, lactate and adenosine. Thus, astrocytes are thought to be capable of bidirectional control of arterial diameter, and the type of influence depends on the state of brain activity. PMID- 21257666 TI - Dose-response relationship of resistance training in older adults: a meta analysis. PMID- 21257667 TI - Challenges moving forward with economic evaluations of exercise intervention strategies aimed at combating cognitive impairment and dementia. PMID- 21257668 TI - Injuries and illnesses of football players during the 2010 FIFA World Cup. AB - BACKGROUND: The incidence and characteristics of football injuries during matches in top-level international tournaments are well documented, but training injuries and illnesses during this period have rarely been studied. AIM: To analyse the incidence and characteristics of injuries and illnesses incurred during the 2010 Federation Internationale de Football Association (FIFA) World Cup. METHODS: The chief physicians of the 32 finalist teams reported daily all newly incurred injuries and illnesses of their players on a standardised medical report form. RESULTS: Out of 229 injuries reported, 82 match and 58 training injuries were expected to result in time loss, equivalent to an incidence of 40.1 match and 4.4 training injuries per 1000 h. Contact with another player was the most frequent cause of match (65%) and of training (40%) injuries. The most frequent diagnoses were thigh strain and ankle sprain. 99 illnesses of 89 (12%) players were reported. Illnesses were mainly infections of the respiratory or the digestive system. Most illnesses did not result in absence from training or match. The incidence of time-loss illnesses was 3.0 per 1000 player days. CONCLUSION: The incidence of match injuries during the 2010 FIFA World Cup was significantly lower than in the three proceeding World Cups. This might be a result of more regard to injury prevention, less foul play and stricter refereeing. Tackling skills and fair play need to be improved to prevent contact injuries in training and matches. Prevention of illness should focus on reducing the risk of infections by considering the common modes of transmission and environmental conditions. PMID- 21257669 TI - The influence of game scheduling on medical encounters at the USA Cup soccer tournament. AB - OBJECTIVEL To investigate the influence of playing multiple games on multiple days on youth soccer medical encounter rates. DESIGN: Prospective cohort survey study. SETTING: Medical facility at the 2008 Schwan's USA Cup soccer tournament. PARTICIPANTS: Players presenting to the medical facility for game-related medical evaluation. ASSESSMENT OF RISK FACTORS: Date, game and half of game for each medical encounter. MAIN OUTCOME MEASURES: Game play-related medical encounters per 1000 match hours (MH). RESULTS: 211 players surveyed with 195 eligible and completed questionnaires. There were 4.06, 5.14 and 3.92 medical encounters/1000 MH on 11, 12 and 13 July, respectively, with no significant difference in injury incidence. There was no difference in medical encounter rates of second games compared with first games of the day (p=0.126). Daily medical encounter rates were 5.65, 8.95, 7.83, 6.94 and 4.62/1000 MH on 15, 16, 17, 18 and 19 July, respectively, with statistically significant differences on 16 July (p<0.001) and 17 July (p=0.022) compared with 15 July. Encounter rates of second games compared with first games of the day showed no difference (p=0.385). A linear test for trend from 15 to 19 July was not significant (p=0.092). CONCLUSIONS: The USA Cup format did not show either increased medical encounter rates from the cumulative total of games played or a consistently increased rate in the second game of the day compared with the first. Players, coaches, parents and administrators can feel confident that this tournament format does not pose an additional risk of injury. PMID- 21257670 TI - Characteristics of people with recurrent ankle sprains: a systematic review with meta-analysis. AB - OBJECTIVE: To examine whether people with recurrent ankle sprain, have specific physical and sensorimotor deficits. DESIGN: A systematic review of journal articles in English using electronic databases to September 2009. Included articles compared physical or sensorimotor measures in people with recurrent (>=2) ankle sprains and uninjured controls. MAIN OUTCOME GROUPS: Outcome measures were grouped into: physical characteristics, strength, postural stability, proprioception, response to perturbation, biomechanics and functional tests. A meta-analysis was undertaken where comparable results within an outcome group were inconsistent. RESULTS: Fifty-five articles met the inclusion criteria. Compared with healthy controls, people with recurrent sprains demonstrated radiographic changes in the talus, changes in foot position during gait and prolonged time to stabilisation after a jump. There were no differences in ankle range of motion or functional test performance. Pooled results showed greater postural sway when standing with eyes closed (SMD=0.9, 95% CI 0.4 to 1.4) or on unstable surfaces (0.5, 0.1 to 1.0) and decreased concentric inversion strength (1.1, 0.2 to 2.1) but no difference in evertor strength, inversion joint position sense or peroneal latency in response to a perturbation. CONCLUSION: There are specific impairments in people with recurrent ankle sprain but not necessarily in areas commonly investigated. PMID- 21257671 TI - Significance of smoking history and FDG uptake for pathological N2 staging in clinical N2-negative non-small-cell lung cancer. AB - BACKGROUND: This study was conducted to evaluate whether smoking history and the standardized uptake value (SUV) of 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) uptake are associated with unexpected pathological N2 status (pN2) in non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We analyzed the data of 220 patients who underwent surgical resection with clinical N2-negative status on computed tomography (CT) and positron emission tomography (PET)-CT. The maximum SUV of primary tumor was chosen for logistic analysis. RESULTS: Seventy-two patients (33%) had never smoked. The SUV ranged from 1.0 to 29.0 (median 9.1). In univariate analysis, adenocarcinomas (P = 0.019), female gender (P = 0.010), N1 on CT (P = 0.025), and N1 PET-CT (P = 0.001) were associated with a high probability of pN2. The proportion of pN2 in never smokers was higher than in ever smokers (26% versus 10% respectively; P = 0.002). The SUV remained on a multivariate logistic model (odds ratio 1.1; 95% confidence interval 1.0-1.2; P = 0.010) and it had a better predictive value in never smokers than in ever smokers (P = 0.017). CONCLUSIONS: This study indicates an association between smoking history and pN2 in clinically negative N2 NSCLC. The different roles of FDG uptake were also suggested based on smoking history. PMID- 21257672 TI - Phase II study of bendamustine in combination with rituximab as first-line treatment in patients 80 years or older with aggressive B-cell lymphomas. AB - BACKGROUND: Rituximab plus combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is widely recommended for the treatment of aggressive B-cell lymphomas. However, there is very little information regarding the management of elderly patients. PATIENTS AND METHODS: We initiated a phase II study of first-line treatment with rituximab and bendamustine in elderly patients (>=80 years) with aggressive B-cell lymphomas who were not eligible for R-CHOP or who did not agree to aggressive treatment. The treatment decision on eligibility for R-CHOP was left to discretion of the physicians. RESULTS: Fourteen patients with a median age of 85 years (range 80-95 years) were included. The age-adjusted international prognostic index was zero in five patients, one in three patients, and two in six patients. Thirteen patients were assessable for response. Seven patients (54%) had a complete response, two (15%) a partial response, and four (31%) progressive disease. The median overall survival was 7.7 months, and the median progression-free survival 7.7 months; however, six patients (43%) were alive without disease at 20-72 months from the start of treatment. Major toxicity was neutropenia (17% grade 3 and 6% grade 4). All other grade 3 and 4 hematotoxicities and non-hematological toxic effects ranged between 2% and 11% CONCLUSIONS: Because of its efficacy and low toxicity, bendamustine in combination with rituximab may be an alternative treatment for aggressive lymphomas in old patients not eligible for R-CHOP. These results, however, need to be confirmed in larger studies. PMID- 21257674 TI - Life-threatening cardiac arrhythmia after a single dose of nebulized epinephrine in pediatric emergency department. AB - Cardiac adverse effects are not commonly reported complications of nebulized epinephrine therapy. We present a case of critical cardiac arrhythmia developed at the Pediatric Emergency Department in an otherwise healthy infant after receiving 3 mg of L-epinephrine (1:1000) nebulization over a 90 min period for a diagnosis of bronchiolitis. Unstable ventricular tachycardia was found after the nebulization therapy that required chemical cardioversion. Frequent premature ventricular contractions (PVCs) were found initially following the cardiac insult that was controlled with oral amiodarone, and disappeared during follow-up. Although epinephrine inhalation is generally safe, adverse life-threatening events could be unpredictable and may evolve even after a single dose of nebulized epinephrine. PMID- 21257673 TI - "What" precedes "which": developmental neural tuning in face- and place-related cortex. AB - Although category-specific activation for faces in the ventral visual pathway appears adult-like in adolescence, recognition abilities for individual faces are still immature. We investigated how the ability to represent "individual" faces and houses develops at the neural level. Category-selective regions of interest (ROIs) for faces in the fusiform gyrus (FG) and for places in the parahippocampal place area (PPA) were identified individually in children, adolescents, and adults. Then, using an functional magnetic resonance imaging adaptation paradigm, we measured category selectivity and individual-level adaptation for faces and houses in each ROI. Only adults exhibited both category selectivity and individual-level adaptation bilaterally for faces in the FG and for houses in the PPA. Adolescents showed category selectivity bilaterally for faces in the FG and houses in the PPA. Despite this profile of category selectivity, adolescents only exhibited individual-level adaptation for houses bilaterally in the PPA and for faces in the "left" FG. Children only showed category-selective responses for houses in the PPA, and they failed to exhibit category-selective responses for faces in the FG and individual-level adaptation effects anywhere in the brain. These results indicate that category-level neural tuning develops prior to individual-level neural tuning and that face-related cortex is disproportionately slower in this developmental transition than is place-related cortex. PMID- 21257675 TI - Sensitivity of cytology in the diagnosis of paediatric malignancies in Nigeria. AB - BACKGROUND: Prompt and accurate diagnosis of solid malignant childhood neoplasms requires ancillary diagnostic techniques to supplement clinical acumen. This study aims to assess the role and sensitivity of Fine Needle Aspiration Cytology (FNAC) as a tool to meet these needs in a developing country like Nigeria. MATERIALS AND METHODS: Primary working diagnosis and cytological reports for all solid malignant neoplasms in children over a 4-year period were extracted from archives. These were then compared with histological diagnosis and/or response to therapy and clinical versus cytological sensitivity calculated. RESULTS: Clinical sensitivity for head/neck vs. abdominal cavity malignancies was (83% vs. 46%) compared with cytological sensitivity (100% vs. 90%). Cytological positive predictive value for malignancy at all sites was 100%. CONCLUSION: This study concludes that FNAC should be included in the routine investigation of these tumours in view of its high sensitivity and positive predictive value for malignancy. PMID- 21257676 TI - Using computer technology for HIV prevention among African-Americans: development of a tailored information program for safer sex (TIPSS). AB - New prevention options are urgently needed for African-Americans in the United States given the disproportionate impact of HIV/AIDS on this group. This combined with recent evidence supporting the efficacy of computer technology-based interventions in HIV prevention led our research group to pursue the development of a computer-delivered individually tailored intervention for heterosexually active African-Americans--the tailored information program for safer sex (TIPSS). In the current article, we discuss the development of the TIPSS program, including (i) the targeted population and behavior, (ii) theoretical basis for the intervention, (iii) design of the intervention, (iv) formative research, (v) technical development and testing and (vi) intervention delivery and ongoing randomized controlled trial. Given the many advantages of computer-based interventions, including low-cost delivery once developed, they offer much promise for the future of HIV prevention among African-Americans and other at risk groups. PMID- 21257677 TI - An HIV/AIDS knowledge scale for adolescents: item response theory analyses based on data from a study in South Africa and Tanzania. AB - A 14-item human immunodeficiency virus/acquired immunodeficiency syndrome knowledge scale was used among school students in 80 schools in 3 sites in Sub Saharan Africa (Cape Town and Mankweng, South Africa, and Dar es Salaam, Tanzania). For each item, an incorrect or don't know response was coded as 0 and correct response as 1. Exploratory factor analyses based on polychoric correlations showed two separate factors for all sites. Two-parameter item response theory (IRT) analysis (bifactorial multiple indicators multiple causes confirmatory factor analysis models) consistently showed a general first factor and a second 'method' factor. One single global latent variable seemed to sufficiently well capture most of the systematic variation in knowledge. Some items did not discriminate well between levels of the underlying knowledge latent variable and information values were highest for low levels of knowledge. The scale might be improved by adding items, in particular items that are more difficult to answer. Some differential item functioning effects related to site and socioeconomic status were identified. Scores on the latent knowledge variable were particularly low among females in Dar es Salaam and Mankweng, and were negatively associated with socioeconomic status. This study illustrates advantages of using IRT analysis instead of more conventional approaches to examining psychometric properties of knowledge scales. PMID- 21257678 TI - Social Adaptability Index: application and outcomes in a dialysis population. AB - BACKGROUND: Patient groups associated with disparities in health care are usually defined on the basis of race, gender or geographic location. Social Adaptability Index (SAI), calculated based on education, marital status, income, employment and substance abuse, has been strongly associated with clinical outcome in other patient populations and may be used to identify individuals at risk. We used data from the United States Renal Data System to evaluate the role of SAI in survival of patients on dialysis. METHODS: We used Cox model analyses to study the association between SAI and patient survival in patients with ESRD on dialysis, as well as in the subgroups based on age, race, sex, comorbidites and diabetic status. RESULTS: We analyzed 3396 patients (age of ESRD onset 56.9 +/- 16.1 years, 54.2% males, 64.2% white, 30.3% African-American). Mean SAI of the entire population was 7.1 +/- 2.5 (range 0-12 points). SAI was higher in whites (7.4 +/- 2.4) than in African-Americans (6.5 +/- 2.5) (analysis of variance, P <0.001) and greater in men (7.4 +/- 2.4) than in women (6.7 +/- 2.5) (t-test, P <0.001). In a Cox model adjusted for potential confounders, SAI was associated with decreased mortality [hazards ratio of 0.97 (95% confidence interval 0.95-0.99), P = 0.006]. Subgroup analysis demonstrated an association of SAI with survival in most of the subgroups. Potential limitations of the study include reverse causality, possible misclassification and retrospective design. CONCLUSION: We demonstrated that SAI is significantly associated with mortality in dialysis patients. SAI could be used to identify individuals at risk for inferior clinical outcomes. PMID- 21257679 TI - Urinary neutrophil gelatinase-associated lipocalin as a marker of acute kidney injury after orthotopic liver transplantation. AB - BACKGROUND: Urinary neutrophil gelatinase-associated lipocalin (NGAL) is a novel, sensitive and specific biomarker that is rapidly released after kidney injury. It predicts acute kidney injury (AKI) in multiple clinical scenarios. We hypothesized that urinary NGAL can predict AKI after liver transplantation. METHODS: Urine was collected in 92 patients undergoing liver transplantation (18 living-related and 74 deceased) before surgery, after reperfusion of the liver graft and then 3, 18 and 24 h later. NGAL was analyzed with enzyme-linked immunosorbent assay and corrected for dilution/concentration by calculating urinary NGAL/urine creatinine ratios. AKI was defined by Risk-Injury-Failure-Loss Endstage stage kidney disease (RIFLE)-risk criteria (increase of serum creatinine by >50%). RESULTS: Urinary NGAL/urine creatinine ratio was low prior to surgery and increased immediately after reperfusion, peaked 3 h later and remained elevated at 18 and 24 h. Urinary NGAL/urine creatinine ratios were higher in patients with post-operative (post-OP) AKI defined by RIFLE--risk criteria 3 and 18 h after reperfusion. The area under the curve of the receiver operator characteristics curve of urinary NGAL/urine creatinine ratio to predict AKI was 0.800 (95% CI: 0.732-0.869, P < 0.0001) 3 h and 0.636 (95% CI: 0.551-0.720, P < 0.005) 18 h after reperfusion. CONCLUSIONS: We conclude that urinary NGAL/urine creatinine ratio is able to predict post-OP AKI 3 and 18 h after transplantation with good discrimination. PMID- 21257680 TI - Non-fatal conductive energy device-related injuries treated in US emergency departments, 2005-2008. AB - This paper provides the first US estimates and rates of non-fatal conductive energy device (CED)-related (eg, Taser) injuries relative to other types of legal intervention injuries treated in hospital emergency departments (EDs). The data used for this study were from the National Electronic Injury Surveillance System (NEISS), including the Firearm Injury Surveillance Study (NEISS-FISS) and the All Injury Program (NEISS-AIP). Of an average annual 75,000 suspects treated for non fatal legal intervention injuries, 11% had injuries that were associated with the use of a CED or Taser. Of the suspects with non-fatal CED-related injuries, 90.1% were males, 72.6% were 20-44 years of age, and 55.2% were injured to the trunk. Most suspects with CED-related injuries (93.6%) were treated and released from the hospital ED. The authors conclude that NEISS is a useful data source for CED related injuries in the US; estimates from NEISS emphasise the importance of implementing CED safety guidelines by law enforcement officers and training of medical personnel to help reduce the risk of severe injury and potential adverse health consequences. PMID- 21257681 TI - Actinophytocola xinjiangensis sp. nov., isolated from virgin forest soil. AB - An aerobic, non-motile actinobacterium, strain QAIII60(T), was isolated from virgin forest soil of Kanas Nature Reserve, Xinjiang, north-west China. The isolate produced a very scant aerial mycelium that fragmented into cylindrical spores and a non-fragmented substrate mycelium with occasional septa. Whole-cell hydrolysates contained meso-diaminopimelic acid, arabinose, galactose, glucose, ribose and rhamnose (trace). The diagnostic polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, hydroxyphosphatidylethanolamine and ninhydrin-positive phosphoglycolipids. The major cellular fatty acids were iso-C(16:0), iso-C(14:0), iso-C(16:1) H and C(17:1)omega6c. The isoprenoid quinones consisted of MK-9(H(4)) and MK-10(H(2)). The G+C content of the genomic DNA was 72.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain QAIII60(T) formed a distinct phyletic line that was most closely, albeit loosely, associated with the genus Actinophytocola. A number of physiological characteristics differentiated the isolate from members of the genus Actinophytocola. On the basis of these data, we propose that strain QAIII60(T) (=CGMCC 4.4663(T) =NBRC 106673(T)) be assigned as the type strain of a novel species, Actinophytocola xinjiangensis sp. nov. PMID- 21257682 TI - Bradyrhizobium cytisi sp. nov., isolated from effective nodules of Cytisus villosus. AB - Several strains isolated from Cytisus villosus nodules have been characterized based on their diverse genetic, phenotypic and symbiotic characteristics. According to 16S rRNA gene sequence analysis, the isolates formed a group that was closely related to Bradyrhizobium canariense BTA-1(T) with 99.4% similarity. Analysis of three housekeeping genes, recA, atpD and glnII, suggested that the C. villosus strains represent a novel Bradyrhizobium species most closely related to B. canariense BTA-1(T) with similarities of 94.2, 96.7 and 94.5%, respectively. All these differences were congruent with DNA-DNA hybridization analysis, which revealed 31% relatedness between a representative strain (CTAW11(T)) isolated from C. villosus nodules and B. canariense BTA-1(T). Phenotypic differences among the strains isolated from C. villosus and B. canariense were based on assimilation of carbon and nitrogen sources. The nodC and nifH genes of strain CTAW11(T) were phylogenetically related to those of strains belonging to bv. genistearum and divergent from those of bv. glycinearum and, accordingly, they do not nodulate soybean. Based on the genotypic and phenotypic data obtained in this study, our strains should be classified as representatives of a novel species for which the name Bradyrhizobium cytisi sp. nov. is proposed; the type strain is CTAW11(T) (=LMG 25866(T)=CECT 7749(T)). PMID- 21257683 TI - Pedobacter boryungensis sp. nov., isolated from soil. AB - A Gram-negative, non-sporulating, non-flagellated rod, designated BR-9(T), was isolated from soil collected on the Korean peninsula. Strain BR-9(T) grew optimally at pH 6.0-7.0, at 30 degrees C and in the absence of NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain BR 9(T) belonged to the genus Pedobacter and clustered with Pedobacter insulae DS 139(T) and Pedobacter koreensis WPCB189(T). Strain BR-9(T) exhibited 98.2 and 97.5% 16S rRNA gene sequence similarity with P. insulae DS-139(T) and P. koreensis WPCB189(T), respectively, and <96.7% sequence similarity with the type strains of other species in the genus Pedobacter. Strain BR-9(T) contained MK-7 as the predominant menaquinone and iso-C(15:0) and summed feature 3 (C(16:1)omega7c and/or iso-C(15:0) 2-OH) as the major fatty acids. The DNA G+C content of strain BR-9(T) was 38.5 mol%. DNA-DNA relatedness between strain BR 9(T) and P. insulae DS-139(T) and P. koreensis KCTC 12536(T) was 3.4-4.2%, which indicated that the isolate was genetically distinct from these type strains. Strain BR-9(T) was also distinguishable by differences in phenotypic properties. On the basis of the data presented, strain BR-9(T) is considered to represent a novel species of the genus Pedobacter, for which the name Pedobacter boryungensis sp. nov. is proposed. The type strain is BR-9(T) (=KCTC 23344(T) =CCUG 60024(T)). PMID- 21257684 TI - Tenacibaculum geojense sp. nov., isolated from seawater. AB - A Gram-negative, non-flagellated, non-spore-forming bacterium, designated YCS 6(T), that was motile by gliding, was isolated from seawater on the southern coast of Korea. Strain YCS-6(T) grew optimally at 30 degrees C and with 2% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain YCS-6(T) fell within the genus Tenacibaculum and was most closely associated with Tenacibaculum litopenaei B-I(T), with which the isolate exhibited 95.9% 16S rRNA gene sequence similarity. Sequence similarity between strain YCS-6(T) and other members of the genus Tenacibaculum was 93.8-95.7%. Strain YCS-6(T) contained menaquinone-6 (MK-6) as the predominant respiratory quinone and iso-C(15:0), summed feature 3 (iso-C(15:0) 2-OH and/or C(16:1)omega7c), iso-C(15:0) 3-OH and iso-C(15:1) G as the major fatty acids. The DNA G+C content was 32.7 mol%. Differential phenotypic properties and phylogenetic distinctiveness distinguished strain YCS-6(T) from all other members of the genus Tenacibaculum. On the basis of our phenotypic, chemotaxonomic and phylogenetic data, strain YCS-6(T) is considered to represent a novel species of the genus Tenacibaculum, for which the name Tenacibaculum geojense sp. nov. is proposed. The type strain is YCS-6(T) (=KCTC 23423(T) =CCUG 60527(T)). PMID- 21257685 TI - Olivibacter oleidegradans sp. nov., a hydrocarbon-degrading bacterium isolated from a biofilter clean-up facility on a hydrocarbon-contaminated site. AB - A novel hydrocarbon-degrading, Gram-negative, obligately aerobic, non-motile, non sporulating, rod-shaped bacterium, designated strain TBF2/20.2(T), was isolated from a biofilter clean-up facility set up on a hydrocarbon-contaminated site in Hungary. It was characterized by using a polyphasic approach to determine its taxonomic position. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolate is affiliated with the genus Olivibacter in the family Sphingobacteriaceae. It was found to be related most closely to Olivibacter ginsengisoli Gsoil 060(T) (93.3% 16S rRNA gene sequence similarity). Strain TBF2/20.2(T) grew at pH 6-9 (optimally at pH 6.5-7.0) and at 15-42 degrees C (optimally at 30-37 degrees C). The major fatty acids were iso-C(15:0) (39.4%), summed feature 3 (iso-C(15:0) 2-OH and/or C(16:1)omega7c; 26.0%), iso-C(17:0) 3 OH (14.5%) and C(16:0) (4.5%). The major menaquinone was MK-7 and the predominant polar lipid was phosphatidylethanolamine. The DNA G+C content of strain TBF2/20.2(T) was 41.2 mol%. Physiological and chemotaxonomic data further confirmed the distinctiveness of strain TBF2/20.2(T) from recognized members of the genus Olivibacter. Thus, strain TBF2/20.2(T) is considered to represent a novel species of the genus Olivibacter, for which the name Olivibacter oleidegradans sp. nov. is proposed. The type strain is TBF2/20.2(T) (=NCAIM B 02393(T) =CCM 7765(T)). PMID- 21257686 TI - Pedobacter rhizosphaerae sp. nov. and Pedobacter soli sp. nov., isolated from rhizosphere soil of Chinese cabbage (Brassica campestris). AB - Two bacterial strains, 01-96(T) and 15-51(T), isolated from rhizosphere soil of Chinese cabbage (Brassica campestris) were characterized by using a polyphasic approach. 16S rRNA gene sequence analysis showed that strain 01-96(T) was phylogenetically related most closely to Pedobacter suwonensis 15-52(T) and Pedobacter roseus CL-GP80(T) (96.7 and 96.7% similarity, respectively), and strain 15-51(T) to Pedobacter borealis G-1(T) and P. suwonensis 15-52(T) (97.2 and 97.1%, respectively). However, levels of DNA-DNA relatedness between strain 15-51(T) and P. borealis KACC 14287(T) and P. suwonensis KACC 11317(T) were low (<50%). The G+C content of the genomic DNA was 37.8 mol% for strain 01-96(T) and 38.6 mol% for strain 15-51(T). The major fatty acids of the two strains were iso C(17:0) 3-OH, iso-C(15:0) and summed feature 3 (iso-C(15:0) 2-OH and/or C(16:1)omega7c). The results of DNA-DNA hybridization and phenotypic data showed that strains 01-96(T) and 15-51(T) could be distinguished from their closest phylogenetic relatives, and that these strains represented two novel species of the genus Pedobacter, for which the names Pedobacter rhizosphaerae sp. nov. (type strain 01-96(T) =KACC 14938(T) =NBRC 107690(T)) and Pedobacter soli sp. nov. (type strain 15-51(T) =KACC 14939(T) =NBRC 107691(T)) are proposed. PMID- 21257687 TI - Sunxiuqinia elliptica gen. nov., sp. nov., a member of the phylum Bacteroidetes isolated from sediment in a sea cucumber farm. AB - Three novel aerobic, elliptic bacteria, designated DQHS4(T), DQHS8 and DQHS15, were isolated from sediment of a seashore pond for sea cucumber culture in Jimo, Qingdao, on the east coast of China. Cells were Gram-, oxidase- and catalase negative. All three strains grew at 15-42 degrees C, pH 5-9 and NaCl concentrations between 0.5 and 10%. DNA-DNA hybridization experiments revealed high (>85%) relatedness among the three novel isolates and suggested that the strains constitute a single species. Comparative 16S rRNA gene sequence analysis indicated that these bacteria had less than 90% similarity to all described species of the phylum Bacteroidetes; the closest relative of the three isolates was Prolixibacter bellariivorans F2(T), sharing only 89.6% sequence similarity. The major cellular fatty acids were iso-C(17:0) 3-OH (19.8-20.0%), iso-C(15:0) (16.9-17.3%), anteiso-C(17:1) B and/or iso-C(17:1) I (7.4-8.7%), C(17:0) 2-OH (8.4%), anteiso-C(15:0) (8.2-8.6%) and C(17:1)omega6c (5.6-6.0%). The major respiratory quinone was menaquinone-7 (MK-7) and the DNA G+C content was 41.8 43.5 mol%. Based on the distinct phylogenetic position and the combination of genotypic, phenotypic and chemotaxonomic characteristics, these three strains were considered to represent a novel species of a new genus in the phylum Bacteroidetes, for which the name Sunxiuqinia elliptica gen. nov., sp. nov. is proposed. The type strain of Sunxiuqinia elliptica is DQHS4(T) (=CGMCC 1.9156(T) =NCCB 100301(T) =LMG 25367(T)). PMID- 21257688 TI - Cryptococcus yokohamensis sp. nov., a basidiomycetous yeast isolated from trees and a Queensland koala kept in a Japanese zoological park. AB - Three strains were isolated from the nostrils of a koala and the surrounding environment in a Japanese zoological park. Sequence analysis of the nuclear rDNA internal transcribed spacer (ITS) region and the large subunit rDNA D1/D2 domains in addition to physiological and morphological studies indicated that the isolates represent a single novel species belonging to the basidiomycetous genus Cryptococcus (Tremellales, Tremellomycetes, Agaricomycotina). Phylogenetic analysis based on D1/D2 and ITS regions revealed that the novel species belongs to the Fuciformis clade. The name Cryptococcus yokohamensis sp. nov. is proposed to accommodate these isolates with strain JCM 16989(T) (=TIMM 10001(T)=CBS 11776(T)=DSM 23671(T)) as the type strain. PMID- 21257689 TI - Sphaerisporangium krabiense sp. nov., isolated from soil. AB - A Gram-staining-positive, filamentous bacterial strain, designated A-T 0308(T), was isolated from soil of a tropical mangrove forest in Thailand. Strain A-T 0308(T) developed spherical sporangia containing non-motile spores on aerial mycelium. The novel strain contained meso-diaminopimelic acid, N-acetyl-type peptidoglycan and madurose, mannose, ribose, galactose and glucose as whole-cell sugars. The predominant menaquinones were MK-9(H(4)) and MK-9(H(6)); a small amount of MK-9(H(2)) and MK-9 was also detected. Mycolic acids were not detected. The diagnostic phospholipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol, phosphatidylinositol mannoside and phosphoglycolipid. The predominant cellular fatty acids were iso-C(16:0) and 10 methylated C(17:0). The G+C content of the DNA was 72 mol%. Phenotypic and chemotaxonomic analyses showed that the novel isolate had characteristics typical of members of the genus Sphaerisporangium. 16S rRNA gene sequence analysis also indicated that the strain belongs to the genus Sphaerisporangium and that it represents a clade distinct from other members of the genus with sequence similarities ranging from 96.3 to 97.8% between the novel strain and its closest relatives. Based on the results of phenotypic, chemotaxonomic and phylogenetic studies, strain A-T 0308(T) (=BCC 21702(T) =NBRC 107571(T)) represents a novel species of the genus Sphaerisporangium, for which the name Sphaerisporangium krabiense sp. nov. is proposed. PMID- 21257690 TI - Algoriphagus faecimaris sp. nov., isolated from coastal sediment. AB - A Gram-negative, non-motile, non-sporulating bacterial strain, designated LYX05(T), was isolated from coastal sediment of Qingdao, China, on the coast of the Yellow Sea. Strain LYX05(T) was aerobic and heterotrophic. The strain grew optimally at 37 degrees C and pH 7.5 and in the presence of 2% (w/v) NaCl. Colonies were 1-2 mm in diameter, circular, reddish orange and shiny with entire edges on marine agar medium. Cells were rods (0.3-0.5 um wide and 0.8-1.6 um long). The dominant fatty acids were iso-C(15:0) (40.82%) and C(16:0) (10.45%). The DNA G+C content was 42.5 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain LYX05(T) was phylogenetically related to the members of the genus Algoriphagus and the closest relative was Algoriphagus hitonicola 7-UAH(T) (95.8% 16S rRNA gene sequence similarity). On the basis of phenotypic, chemotaxonomic and phylogenetic data, strain LYX05(T) was considered to represent a novel species of the genus Algoriphagus, for which the name Algoriphagus faecimaris sp. nov. is proposed. The type strain is LYX05(T) (=JCM 16561(T) =DSM 23095(T) =LMG 25474(T)). PMID- 21257691 TI - Catenovulum agarivorans gen. nov., sp. nov., a peritrichously flagellated, chain forming, agar-hydrolysing gammaproteobacterium from seawater. AB - A novel Gram-negative, strictly aerobic, agar-hydrolysing bacterium, designated YM01(T), was isolated from seawater samples collected from the Yellow Sea (coastal region of Qingdao, PR China). Cells were rod-shaped, peritrichously flagellated and formed long chains end-to-end. The isolate had an absolute requirement for Na(+) ions, but not seawater, for growth and grew optimally at about 28 degrees C, in 2% NaCl and at pH 8.0-9.0. The isolate could not be cultured in marine broth 2216, but grew well on marine agar 2216. YM01(T) was able to hydrolyse cellulose, starch, aesculin and Tween 80, but not egg yolk, gelatin, urea or casein. 16S rRNA gene sequence analysis demonstrated that this isolate was unique, showing only 88.4-91.0% sequence similarity to its closest neighbours, including members of the genera Glaciecola (88.4-91.0%), Alteromonas (88.7-89.6%), Aestuariibacter (89.3-90.4%), Salinimonas (89.0%), Bowmanella (90.1 90.3%) and Agarivorans (88.5-89.9%). Phylogenetic analyses demonstrated that strain YM01(T) formed a distinct clade closely related to species of the family Alteromonadaceae within the group of Alteromonas-like gammaproteobacteria. It contained menaquinone MK-7 as the predominant isoprenoid quinone and C(16:0) (38.3%), C(16:1)omega7c and/or iso-C(15:0) 2-OH (29.0%), C(18:1)omega7c (9.3%) and C(10:0) 3-OH (8.2%) as major cellular fatty acids. Phosphatidylethanolamine, phosphatidylglycerol and an aminophospholipid were the major phospholipid constituents. The DNA G+C content was 44.8 mol%. Based on its phenotypic, chemotaxonomic and phylogenetic distinctiveness, strain YM01(T) is considered to represent a novel species in a new genus in the Gammaproteobacteria, for which the name Catenovulum agarivorans gen. nov., sp. nov. is proposed; the type strain of Catenovulum agarivorans is YM01(T) (=CGMCC 1.10245(T) =DSM 23111(T) =JCM 16580(T)). PMID- 21257692 TI - Description of Spongiibacter borealis sp. nov., isolated from Arctic seawater, and reclassification of Melitea salexigens Urios et al. 2008 as a later heterotypic synonym of Spongiibacter marinus Graeber et al. 2008 with emended descriptions of the genus Spongiibacter and Spongiibacter marinus. AB - A Gram-negative, rod-shaped and motile strain, designated CL-AS9(T), was isolated from polar seawater of the Arctic. Analysis of the 16S rRNA gene sequence of the strain showed an affiliation with the genus Spongiibacter, sharing 93.9% and 93.7% sequence similarities with the type strains of Spongiibacter tropicus CL CB221(T) and Spongiibacter marinus HAL40b(T), respectively. Phylogenetic analyses revealed that strain CL-AS9(T) formed a separate branch that was distinct from a clade comprising Spongiibacter marinus HAL40b(T), Spongiibacter tropicus CL CB221(T) and Melitea salexigens 5IX/A01/131(T). Cells of the strain grew optimally at 20-25 degrees C and pH 6.6-8.0 in the presence of 3-4% (w/v) sea salts. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol and an unidentified aminophospholipid. The major quinone was ubiquinone 8. The major cellular fatty acids were C(16:1)omega7c and/or iso-C(15:0) 2-OH (23.1%), C(17:1)omega8c (22.1%) and C(18:1)omega7c (15.6%). The genomic DNA G+C content was 53.6 mol%. Based on the phylogenetic, chemotaxonomic and phenotypic data presented, we propose the name Spongiibacter borealis sp. nov. with the type strain CL-AS9(T) (=KCCM 90094(T) =JCM 17304(T)) and the reclassification of Melitea salexigens as a later heterotypic synonym of Spongiibacter marinus. We also provide emended descriptions of the genus Spongiibacter and Spongiibacter marinus. PMID- 21257693 TI - Oceanisphaera ostreae sp. nov., isolated from seawater of an oyster farm, and emended description of the genus Oceanisphaera Romanenko et al. 2003. AB - A Gram-stain-negative, motile, non-spore-forming and short rod- or rod-shaped bacterial strain, T-w6(T), was isolated from seawater of an oyster farm in the South Sea, Korea. Strain T-w6(T) grew optimally at 25 degrees C and in the presence of 2% (w/v) NaCl. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain T-w6(T) joined the cluster comprising Oceanisphaera species with a bootstrap resampling value of 90.8%, and this cluster joined the clade comprising members of the genera Oceanimonas and Zobellella with a bootstrap resampling value of 100%. Strain T-w6(T) exhibited 16S rRNA gene sequence similarity of 95.9 and 96.6% to the type strains of Oceanisphaera litoralis and Oceanisphaera donghaensis, respectively. Strain T-w6(T) and the type strains of Oceanisphaera litoralis and Oceanisphaera donghaensis had Q-8 as the predominant ubiquinone and iso-C(15:0) 2-OH and/or C(16:1)omega7c, C(18:1)omega7c and C(16:0) as the major fatty acids. The major polar lipids were phosphatidylglycerol and phosphatidylethanolamine. The DNA G+C content of strain T-w6(T) was 56.6 mol%. Mean DNA-DNA relatedness of strain T-w6(T) with Oceanisphaera litoralis DSM 15406(T) and Oceanisphaera donghaensis KCTC 12522(T) was 13 and 10%, respectively. Phenotypic properties of strain T-w6(T) demonstrated that this strain could be distinguished from the other Oceanisphaera species. On the basis of the data presented, strain T-w6(T) is considered to represent a novel species of the genus Oceanisphaera, for which the name Oceanisphaera ostreae sp. nov. is proposed; the type strain is T-w6(T) (=KCTC 23422(T) =CCUG 60525(T)). An emended description of the genus Oceanisphaera is also presented. PMID- 21257694 TI - Thalassobius maritimus sp. nov., isolated from seawater. AB - A Gram-stain-negative, aerobic, motile, rod-shaped bacterial strain, GSW-M6(T), was isolated from seawater of Geoje island, Korea, and was subjected to a polyphasic taxonomic study. Strain GSW-M6(T) grew optimally at pH 7.0-8.0, at 30 degrees C and in the presence of 2% (w/v) NaCl. In the neighbour-joining phylogenetic tree based on 16S rRNA gene sequences, strain GSW-M6(T) clustered with Thalassobius aestuarii, Thalassobius gelatinovorus and Thalassobius mediterraneus. Strain GSW-M6(T) exhibited 96.2-96.9% 16S rRNA gene sequence similarity to the type strains of these three Thalassobius species. Strain GSW M6(T) contained Q-10 as the predominant ubiquinone and C(18:1)omega7c as the major fatty acid. The polar lipid profiles of strain GSW-M6(T) and the type strains of the three Thalassobius species were similar, with phosphatidylcholine, phosphatidylglycerol, phosphatidylethanolamine and an unidentified lipid as common major components. The DNA G+C content of strain GSW-M6(T) was 57 mol%. The mean level of DNA-DNA relatedness between strain GSW-M6(T) and the type strain of Thalassobius gelatinovorus was 17%. Differential phenotypic properties, together with the phylogenetic and genetic distinctiveness, enabled strain GSW-M6(T) to be differentiated from recognized species of the genus Thalassobius. On the basis of the data presented, strain GSW-M6(T) is considered to represent a novel species of the genus Thalassobius, for which the name Thalassobius maritimus sp. nov. is proposed. The type strain is GSW-M6(T) (=KCTC 23347(T) =CCUG 60021(T)). PMID- 21257695 TI - Morphology and molecular evaluation of Iphinoe spelaeobios gen. nov., sp. nov. and Loriellopsis cavernicola gen. nov., sp. nov., two stigonematalean cyanobacteria from Greek and Spanish caves. AB - Caves have generally been found to host phototrophic micro-organisms from various taxonomic groups, with cyanobacteria comprising an important group that have adapted to these stable and highly specific environments. A polyphasic study based on aspects of classical morphology and molecular data revealed two new monospecific genera from fresh material of Greek and Spanish caves. Both taxa are characterized by obligatory true branching (T-type, V-type and false branching), the presence of heterocysts, and reproduction by hormocysts and akinetes. They shared some similarities in their morphological characteristics as revealed by light, scanning electron and transmission electron microscopy, but phylogenetic analysis based on 16S rRNA gene sequences showed that the two phylotypes were different (89.8% similarity); this represents an example of shared morphology in genetically different strains of cave-adapted species. Phenotypic and genetic traits strongly support classification of the phylotypes as independent taxa in the order Stigonematales (the most differentiated and complicated group of cyanobacteria), family Loriellaceae Geitl 1925. Hence, the names Iphinoe spelaeobios Lamprinou and Pantazidou gen. nov., sp. nov. and Loriellopsis cavernicola Hernandez-Marine and Canals gen. nov., sp. nov. are proposed. PMID- 21257696 TI - Pusillimonas harenae sp. nov., isolated from a sandy beach, and emended description of the genus Pusillimonas. AB - A Gram-stain-negative, motile bacterium with two lateral flagella, designated strain B201(T), was isolated from beach sand from the Taean coast in South Korea. Cells were ovoid rods and positive for catalase and oxidase. Growth of strain B201(T) was observed between 15 and 45 degrees C (optimum, 30 degrees C) and between pH 5.0 and 9.0 (optimum, pH 6.0-7.5). Strain B201(T) contained ubiquinone Q-8 as the major isoprenoid quinone, but MK-6 was also present as a minor quinone. The major fatty acids of strain B201(T) were C(17:0) cyclo, C(16:0), summed feature 2 (iso-C(16:1) I/C(14:0) 3-OH and/or C(12:0) ALDE), C(12:0) and C(19:0) cyclo omega8c. The major cellular polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidylethanolamine, an unidentified phospholipid and three aminolipids. The genomic DNA G+C content was 53.1 mol%. Phylogenetic analysis based on 16S rRNA gene sequences showed that the strain formed a phyletic lineage with Pusillimonas ginsengisoli DCY25(T) within the genus Pusillimonas. Strain B201(T) was most closely related to P. ginsengisoli DCY25(T) and Pusillimonas soli MJ07(T) with similarities of 98.6 and 97.5%, respectively. However, DNA-DNA relatedness values of strain B201(T) with P. ginsengisoli DCY25(T) and P. soli MJ07(T) were 30.2+/-5.4 and 4.9+/-1.8%, respectively. On the basis of chemotaxonomic data and molecular properties, strain B201(T) represents a novel species of the genus Pusillimonas, for which the name Pusillimonas harenae sp. nov. is proposed; the type strain is B201(T) (=KACC 14927(T)=JCM 16917(T)). An emended description of the genus Pusillimonas is given. PMID- 21257697 TI - Descriptions of Actinoplanes ianthinogenes nom. rev. and Actinoplanes octamycinicus corrig. comb. nov., nom. rev. AB - Phylogenetic analysis of 'Actinoplanes ianthinogenes' Coronelli et al. 1974 and 'Actinoplanes ianthinogenes subsp. octamycini' Gauze et al. 1979 based on 16S rRNA gene sequencing data revealed that these organisms form a clade in the family Micromonosporaceae. Morphological and chemotaxonomic characteristics of strains of these species were consistent with those of members of the genus Actinoplanes. Morphological, DNA-DNA hybridization, physiological, biochemical and chemotaxonomic data showed that 'A. ianthinogenes' and 'A. ianthinogenes subsp. octamycini' can be easily differentiated from each other and that they merit separate species status. On the basis of morphological, physiological, biochemical, chemotaxonomic and DNA-DNA hybridization data, it is concluded that 'A. ianthinogenes' and 'A. ianthinogenes subsp. octamycini' should be assigned the status of two novel species: Actinoplanes ianthinogenes nom. rev. (type strain NBRC 13996(T)=A/1668(T)=ATCC 21884(T)=BCRC 13611(T)=DSM 43864(T)=IMSNU 20032(T)=JCM 3249(T)=KCTC 9347(T)=KCTC 9592(T)=NCIMB 12639(T)=NRRL B-16720(T)) and Actinoplanes octamycinicus corrig. comb. nov., nom. rev. (type strain NBRC 14524(T)=INA 4041(T)=ATCC 43632(T)=JCM 9649(T)=KCTC 9593(T)), respectively. PMID- 21257698 TI - The enigma of ENIGMA-I. PMID- 21257699 TI - Intravascular volume expansion: which surrogate markers could help the clinician to assess improved tissue perfusion? PMID- 21257700 TI - Using an anesthesia information management system to improve case log data entry and resident workflow. PMID- 21257701 TI - A survey of practice of neuromuscular block in the United States and Europe. PMID- 21257702 TI - The highlight technique: airway exchange catheters with a colored marking may improve safety of airway management. PMID- 21257703 TI - Guidelines for managing neuromuscular block: not only Czech beer deserves a taste. PMID- 21257704 TI - Imaging during pregnancy: computed tomography pulmonary angiography versus ventilation perfusion scintigraphy. PMID- 21257705 TI - A comparison of 3% saline and mannitol for brain relaxation during elective supratentorial brain tumor surgery. PMID- 21257706 TI - Syndrome of inappropriate secretion of antidiuretic hormone found by preoperative electrolyte analysis. PMID- 21257707 TI - Intrinsic position uncertainty explains detection and localization performance in peripheral vision. AB - Efficient performance in visual detection tasks requires excluding signals from irrelevant spatial locations. Indeed, researchers have found that detection performance in many tasks involving multiple potential target locations can be explained by the uncertainty the added locations contribute to the task. A similar type of Location Uncertainty may arise within the visual system itself. Converging evidence from hyperacuity and crowding studies suggests that feature localization declines rapidly in peripheral vision. This decline should add inherent position uncertainty to detection tasks. The current study used a modified detection task to measure how intrinsic position uncertainty changes with eccentricity. Subjects judged whether a Gabor target appeared within a cued region of a noisy display. The eccentricity and size of the region varied across blocks. When subjects detected the target, they used a mouse to indicate its location. This allowed measurement of localization as well as detection errors. An ideal observer degraded with internal response noise and position noise (uncertainty) accounted for both the detection and localization performance of the subjects. The results suggest that position uncertainty grows linearly with visual eccentricity and is independent of target contrast. Intrinsic position uncertainty appears to be a critical factor limiting search and detection performance. PMID- 21257708 TI - Effect of chronic and intermittent calorie restriction on serum adiponectin and leptin and mammary tumorigenesis. AB - The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum adiponectin and leptin levels was investigated in relation to mammary tumorigenesis. 10-wks old MMTV-TGF-alpha female mice were assigned to ad libitum fed (AL; AIN-93M diet), ICR (3-week 50% caloric restriction, AIN-93M-mod diet, 2* protein, fat, vitamins, and minerals followed by 3-wks 100% AL consumption of AIN 93M), and CCR (calorie and nutrient intake matched for each 6-wks ICR cycle, ~ 75% of AL) groups. Mice were sacrificed at 79 (end of restriction) or 82 (end of refeeding) wks of age. Serum was obtained in cycles 1, 3, 5, 8, 11, and terminal. Mammary tumor incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice, respectively. Serum adiponectin levels were similar among groups with no impact of either CCR or ICR. Serum leptin level rose in AL mice with increasing age but was significantly reduced by long-term CCR and ICR. The ICR protocol was also associated with an elevated adiponectin/leptin ratio. In addition, ICR-restricted mice had increased mammary tissue AdipoR1 expression and decreased leptin and ObRb expression compared with AL mice. Mammary fat pads from tumor-free ICR-mice had higher adiponectin expression than AL and CCR mice whereas all tumor-bearing mice had weak adiponectin signal in mammary fat pad. Although we did not show an association of either adiponectin or leptin with individual mice in relation to mammary tumorigenesis, we did find that reduced serum leptin and elevated adiponectin/leptin ratio were associated with the protective effect of intermittent calorie restriction. PMID- 21257709 TI - Oncogenic synergism between ErbB1, nucleolin, and mutant Ras. AB - Alterations in the ErbB family of growth factor receptors, their signaling components, and mutational activation of Ras proteins are major contributors to malignant transformation. Recently, mutant Ras was shown to be capable of activating ErbB receptors in a ligand-independent manner. Furthermore, it was observed that nucleolin, a transcriptional regulator and ribosome biogenesis factor, can bind both K-Ras and the cytoplasmic tail of ErbB receptors to enhance ErbB receptor activation. However, the functional significance of these interactions to cancer pathogenesis has not been probed. Here, we show that endogenous nucleolin interacts simultaneously in vivo with endogenous Ras and ErbB1 (EGFR) in cancer cells. The C-terminal 212 amino acids of nucleolin were determined to be sufficient to interact with ErbB1 and all Ras protein isoforms (H-, N-, and K-Ras). Nucleolin partially colocalizes with Ras at the plasma membrane. Moreover, activated but not wild-type Ras facilitates nucleolin interaction with ErbB1 and stabilizes ErbB1 receptor levels. Most importantly, these three oncogenes synergistically facilitate anchorage-independent cell growth in vitro and tumor growth in vivo. Our findings suggest strategies to target nucleolin as a general approach to inhibiting ErbB- and Ras-driven cancers. PMID- 21257710 TI - Novel role for STAT3 in transcriptional regulation of NK immune cell targeting receptor MICA on cancer cells. AB - The role of natural killer group 2, member D receptor (NKG2D)-expressing natural killer (NK) cells in tumor immunosurveillance is now well established. Nevertheless, tumor progression occurs despite tumor immunosurveillance, leading to cancer persistence in immunocompetent hosts. STAT3 plays a pivotal role both in oncogenic functions and in immunosuppression. In this study, we investigated the role of STAT3 in suppressing NK cell-mediated immunosurveillance. Using a colorectal cancer cell line (HT29) that can poorly activate NK, we neutralized STAT3 with pharmacologic inhibitors or siRNA and found that this led to an increase in NK degranulation and IFN-gamma production in a TGF-beta1-independent manner. Exposure to NKG2D-neutralizing antibodies partially restored STAT3 activity, suggesting that it prevented NKG2D-mediated NK cell activation. On this basis, we investigated the expression of NKG2D ligands after STAT3 activation in HT29, mesenchymal stem cells, and activated lymphocytes. The NK cell recognition receptor MHC class I chain-related protein A (MICA) was upregulated following STAT3 neutralization, and a direct interaction between STAT3 and the MICA promoter was identified. Because cross-talk between DNA damage repair and NKG2D ligand expression has been shown, we assessed the influence of STAT3 on MICA expression under conditions of genotoxic stress. We found that STAT3 negatively regulated MICA expression after irradiation or heat shock, including in lymphocytes activated by CD3/CD28 ligation. Together, our findings reveal a novel role for STAT3 in NK cell immunosurveillance by modulating the MICA expression in cancer cells. PMID- 21257711 TI - An EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. AB - Invasive carcinoma cells use specialized actin polymerization-driven protrusions called invadopodia to degrade and possibly invade through the extracellular matrix (ECM) during metastasis. Phosphorylation of the invadopodium protein cortactin is a master switch that activates invadopodium maturation and function. Cortactin was originally identified as a hyperphosphorylated protein in v-Src transformed cells, but the kinase or kinases that are directly responsible for cortactin phosphorylation in invadopodia remain unknown. In this study, we provide evidence that the Abl-related nonreceptor tyrosine kinase Arg mediates epidermal growth factor (EGF)-induced cortactin phosphorylation, triggering actin polymerization in invadopodia, ECM degradation, and matrix proteolysis-dependent tumor cell invasion. Both Src and Arg localize to invadopodia and are required for EGF-induced actin polymerization. Notably, Arg overexpression in Src knockdown cells can partially rescue actin polymerization in invadopodia while Src overexpression cannot compensate for loss of Arg, arguing that Src indirectly regulates invadopodium maturation through Arg activation. Our findings suggest a novel mechanism by which an EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Furthermore, they identify Arg as a novel mediator of invadopodia function and a candidate therapeutic target to inhibit tumor invasion in vivo. PMID- 21257712 TI - Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation. AB - Aquaporin-4 (AQP4) deficiency in mice reduces neuroinflammation in experimental autoimmune encephalomyelitis (EAE) produced by active immunization with myelin oligodendrocyte glycoprotein peptide (MOG). Potential mechanisms for the protective effect of AQP4 deficiency were investigated, including AQP4-dependent leukocyte and microglia cell function, immune cell entry in the central nervous system (CNS), intrinsic neuroinflammation, and humoral immune response. As we found with active-immunization EAE, neuroinflammation was greatly reduced in AQP4 knockout mice in adoptive-transfer EAE. AQP4 was absent in immune cells, including activated T lymphocytes. The CNS migration of fluorescently labeled, MOG-sensitized T lymphocytes was comparable in wild-type and AQP4-knockout mice. Microglia did not express AQP4. Serum anti-AQP4 antibodies were absent in EAE. Remarkably, intracerebral injection of LPS produced much greater neuroinflammation in wild-type than in AQP4-knockout mice, and cytokine (TNF alpha and IL-6) secretion was reduced in astrocyte cultures from AQP4-knockout mice. Adenovirus-mediated expression of AQP4, or of an unrelated aquaporin, AQP1, increased cytokine secretion in astrocyte and nonastrocyte cell cultures, supporting the involvement of aquaporin water permeability in cytokine secretion. Our data suggest an intrinsic proinflammatory role of AQP4 involving AQP4 dependent astrocyte swelling and cytokine release. Reduction in AQP4 water transport may be protective in neuroinflammatory CNS diseases. PMID- 21257713 TI - Noninvasive molecular imaging reveals role of PAF in leukocyte-endothelial interaction in LPS-induced ocular vascular injury. AB - Uveitis is a systemic immune disease and a common cause of blindness. The eye is an ideal organ for light-based imaging of molecular events underlying vascular and immune diseases. The phospholipid platelet-activating factor (PAF) is an important mediator of inflammation, the action of which in endothelial and immune cells in vivo is not well understood. The purpose of this study was to investigate the role of PAF in endothelial injury in uveitis. Here, we use our recently introduced in vivo molecular imaging approach in combination with the PAF inhibitors WEB 2086 (WEB) and ginkgolide B (GB). The differential inhibitory effects of WEB and GB in reducing LPS-induced endothelial injury in the choroid indicate an important role for PAF-like lipids, which might not require the PAF receptor for their signaling. P-selectin glycoprotein ligand-1-mediated rolling of mouse leukocytes on immobilized P-selectin in our autoperfused microflow chamber assay revealed a significant reduction in rolling velocity on the cells' contact with PAF. Rolling cells that came in contact with PAF rapidly assumed morphological signs of cell activation, indicating that activation during rolling does not require integrins. Our results show a key role for PAF in mediating endothelial and leukocyte activation in acute ocular inflammation. Our in vivo molecular imaging provides a detailed view of cellular and molecular events in the complex physiological setting. PMID- 21257714 TI - Local cholesterol increase triggers amyloid precursor protein-Bace1 clustering in lipid rafts and rapid endocytosis. AB - Amyloid peptide (Abeta) is generated by sequential cleavage of the amyloid precursor protein (APP) by beta-secretase (Bace1) and gamma-secretase. Abeta production increases after plasma membrane cholesterol loading through unknown mechanisms. To determine how APP-Bace1 proximity affects this phenomenon, we developed a fluorescence lifetime imaging microscopy-Forster resonance energy transfer (FLIM-FRET) technique for visualization of these molecules either by epifluorescence or at the plasma membrane only using total internal reflection fluorescence. Further, we used fluorescence correlation spectroscopy to determine the lipid rafts partition of APP-yellow fluorescent protein (YFP) and Bace1-green fluorescent protein (GFP) molecules at the plasma membrane of neurons. We show that less than 10 min after cholesterol exposure, Bace1-GFP/APP-mCherry proximity increases selectively at the membrane and APP relocalizes to raft domains, preceded by rapid endocytosis. After longer cholesterol exposures, APP and Bace1 are found in proximity intracellularly. We demonstrate that cholesterol loading does not increase Abeta production by having a direct impact on Bace1 catalytic activity but rather by altering the accessibility of Bace1 to its substrate, APP. This change in accessibility is mediated by clustering in lipid rafts, followed by rapid endocytosis. PMID- 21257715 TI - High clonal diversity in threatened peripheral populations of the yellow bird's nest (Hypopitys monotropa; syn. Monotropa hypopitys). AB - BACKGROUND AND AIMS: Peripheral populations of plant species are often characterized by low levels of genetic diversity as a result of genetic drift, restricted gene flow, inbreeding and asexual reproduction. These effects can be exacerbated where range-edge populations are fragmented. The main aim of the present study was to assess the levels of genetic diversity in remnant populations of Hypopitys monotropa (syn. Monotropa hypopitys; yellow bird's nest) at the edge of the species' European range in Northern Ireland, since these remnant populations are small and highly fragmented. METHODS: Every plant found through surveys of 21 extant populations was genotyped for eight microsatellite loci to estimate levels and patterns of genetic diversity and clonality. KEY RESULTS: Levels of genetic diversity were relatively high in the populations studied, and the incidence of clonal reproduction was generally low, with a mean of only 14.45 % of clonal individuals. Clones were small and highly spatially structured. Levels of inbreeding, however, were high. CONCLUSIONS: The observed low levels of clonality suggest that the majority of genets in the populations of H. monotropa studied are fertile and that reproduction is predominantly sexual. As the species is highly self-compatible, it is likely that the high levels of inbreeding observed in the populations in the present study are the result of self-pollination, particularly given the small numbers of individuals in most of the patches. Given this extent of inbreeding, further genetic monitoring would be advisable to ensure that genetic diversity is maintained. PMID- 21257716 TI - Nuclear DNA amounts in angiosperms: targets, trends and tomorrow. AB - BACKGROUND AND AIMS: The amount of DNA in an unreplicated gametic chromosome complement is known as the C-value and is a key biodiversity character of fundamental significance with many practical and predictive uses. Since 1976, Bennett and colleagues have assembled eight compilations of angiosperm C-values for reference purposes and subsequently these have been pooled into the Angiosperm DNA C-values Database (http://data.kew.org/cvalues/). Since the last compilation was published in 2005, a large amount of data on angiosperm genome size has been published. It is therefore timely to bring these data together into a ninth compilation of DNA amounts. Scope The present work lists DNA C-values for 2221 species from 151 original sources (including first values for 1860 species not listed in previous compilations). Combining these data with those published previously shows that C-values are now available for 6287 angiosperm species. KEY FINDINGS: Analysis of the dataset, which is by far the largest of the nine compilations published since 1976, shows that angiosperm C-values are now being generated at the highest rate since the first genome sizes were estimated in the 1950s. The compilation includes new record holders for the smallest (1C = 0.0648 pg in Genlisea margaretae) and largest (1C = 152.23 pg in Paris japonica) genome sizes so far reported, extending the range encountered in angiosperms to nearly 2400-fold. A review of progress in meeting targets set at the Plant Genome Size meetings shows that although representation for genera, geographical regions and some plant life forms (e.g. island floras and parasitic plants) has improved, progress to increase familial representation is still slow. In terms of technique it is now clear that flow cytometry is soon likely to become the only method available for plant genome size estimations. Fortunately, this has been accompanied by numerous careful studies to improve the quality of data generated using this technique (e.g. design of new buffers, increased awareness and understanding of problems caused by cytosolic inhibitors). It is also clear that although the speed of DNA sequencing continues to rise dramatically with the advent of next-generation and third-generation sequencing technologies, 'complete genome sequencing' projects are still unable to generate accurate plant genome size estimates. PMID- 21257717 TI - What do prostate cancer patients die of? AB - BACKGROUND: A recent rise in the incidence of prostate cancer and a more favorable outcome have increased the proportions of other causes of death in affected men. Extending the survival of prostate cancer patients thus requires knowledge of all causes of death. METHODS: Data on the population, cancers, and causes of death were gathered from the nationwide Swedish Family-Cancer Database. A Cox regression model, comparing prostate cancer patients with all other men, was applied. Hazard ratios (HR) were calculated both for the underlying cause and for dying with a specific cause listed among multiple causes of death. FINDINGS: Among 686,500 observed deaths, 62,500 were prostate cancer patients. For underlying causes other than prostate cancer, the highest cause-specific HRs were found for external causes (HR, 1.24; 95% confidence interval [CI], 1.16-1.31), diseases of the pulmonary circulation (HR, 1.22; 95% CI, 1.09-1.37), and heart failure (HR, 1.18; 95% CI, 1.11-1.24). For specific multiple causes, the highest HRs were found for anemia (HR, 2.28; 95% CI, 2.14-2.42), diseases of the pulmonary circulation (HR, 1.61; 95% CI, 1.55-1.68), and urinary system disease (HR, 1.90; 95% CI, 1.84-1.96). INTERPRETATIONS: Prostate cancer patients have a higher risk for dying from various causes other than prostate cancer, including external causes and heart failure. Mechanisms have been proposed linking these elevated risks to both cancer and treatment. More attention should be paid to comorbidities in men with prostate cancer. The present study fulfills a gap in the knowledge of death causes in prostate cancer patients. PMID- 21257718 TI - Genotoxicity, cytotoxicity and gene expression in patients undergoing elective surgery under isoflurane anaesthesia. AB - There are numerous studies reporting on the effects of inhalation anaesthesia in cells of exposed individuals but not much is known about the ability of isoflurane (ISF) to induce oxidative DNA damage. However, surgery is often associated with a temporary perioperative immunological alteration, and some volatile anaesthetics seem to contribute to a transient lymphocytopenia after surgery. We conducted a study to evaluate a possible genotoxic effect, including oxidative DNA damage, and apoptosis in peripheral lymphocytes of 20 patients American Society of Anaesthesiologists physical status I undergoing minor elective surgery lasting at least 120 min, under anaesthesia with ISF. We also investigated the expression of several genes in blood cells. Blood samples were collected at three time points: before anaesthesia (T(1)), 2 h after the beginning of anaesthesia (T(2)) and on the first post-operative day (T(3)). General DNA damage and oxidised bases (Fpg and endo III-sites) in blood lymphocytes were evaluated using the comet assay. Lymphocytes were phenotyped and apoptosis was evaluated by flow cytometry. In addition, expressions of hOGG1 and XRCC1, genes involved in DNA repair, and BCL2, a gene related to apoptosis, were assessed by quantitative real-time polymerase chain reaction. Results showed no statistically significant difference in the level of DNA damage and oxidised bases among the three sampling times. Anaesthesia with ISF did not increase the percentage of cells in early or late apoptosis in cytotoxic or helper T lymphocytes. Lower hOGG1 and BCL2 expressions were detected at T(3) in comparison to the other two previous time points, and there was significantly lower expression of XRCC1 at T(3) in relation to T(2). In conclusion, the exposure to ISF did not result in genotoxicity and cytotoxicity in lymphocytes and in toxicogenomic effect in leukocytes, although DNA repair and apoptosis-related genes were down-regulated on the first post-operative day. PMID- 21257719 TI - Abnormalities of the TITF-1 lineage-specific oncogene in NSCLC: implications in lung cancer pathogenesis and prognosis. AB - PURPOSE: Emerging evidence suggests that aberrant expression of oncogenes contributes to development of lung malignancy. The thyroid transcription factor 1 (TITF-1) gene functions as a lineage survival gene abnormally expressed in a significant fraction of non-small cell lung cancers (NSCLC), in particular lung adenocarcinomas. EXPERIMENTAL DESIGN: To better characterize TITF-1 abnormality patterns in NSCLC, we studied TITF-1's gene copy number using FISH and quantitative PCR, as well as its protein expression by immunohistochemistry analysis in a tissue microarray comprising surgically resected NSCLC (N = 321) including 204 adenocarcinomas and 117 squamous cell carcinomas (SCC). TITF-1 copy number and protein expression were correlated with patients' clinicopathologic characteristics, and in a subset of adenocarcinomas with EGFR and KRAS mutation status. RESULTS: We found that increased TITF-1 protein expression was prevalent in lung adenocarcinomas only and was significantly associated with female gender (P < 0.001), never-smokers (P = 0.004), presence of EGFR mutations (P = 0.05), and better overall survival (all stages, P = 0.0478; stages I and II, P = 0.002). TITF-1 copy number gain(CNG) was detected by FISH analysis in both adenocarcinomas (18.9%; high CNG, 8.3%) and SCCs (20.1%; high CNG, 3.0%), and correlated significantly with the protein product (P = 0.004) and presence of KRAS mutations (P = 0.008) in lung adenocarcinomas. Moreover, multivariate analysis revealed that TITF-1 copy number gain was an independent predictor of poor survival of NSCLC (P = 0.039). CONCLUSIONS: Our integrative study demonstrates that the protein versus genomic patterns of TITF-1 have opposing roles in lung cancer prognosis and may occur preferentially in different subsets of NSCLC patients with distinct oncogene mutations. PMID- 21257721 TI - Pentraxin-3 is a novel biomarker of lung carcinoma. AB - PURPOSE: Our objective was to validate the performance of three new candidate lung cancer biomarkers, pentraxin-3 (PTX3), human kallikrein 11 (KLK11), and progranulin. EXPERIMENTAL DESIGN: We analyzed by commercial ELISA, and with a blinded protocol, 422 samples from 203 patients with lung carcinoma, 180 individuals with high risk for lung cancer (heavy smokers), and 43 individuals with cancers other than lung. All samples were obtained from the Early Detection Research Network (Reference set A). RESULTS: We found that progranulin and KLK11 were not informative lung cancer biomarkers, with areas under the receiver operating characteristic curve (AUC; ROC), close to 0.50. However, PTX3 was an informative lung cancer biomarker, with considerable ability to separate lung cancer patients from high-risk controls. At 90% and 80% specificity, the sensitivities versus the high-risk control group were 37% and 48%, respectively. The discriminatory ability of PTX3 was about the same with all major subtypes and histotypes of lung cancer. The AUC of the ROC curves increased according to the disease stage, from 0.64 (stage I) to 0.72 (stage IV). CONCLUSION: PTX3, but not KLK11 or progranulin, is a new serum biomarker for lung carcinoma. Its diagnostic sensitivity and specificity is similar to other clinically used lung cancer biomarkers. More studies are needed to establish if PTX3 has clinical utility for lung cancer diagnosis and management. PMID- 21257720 TI - SST0001, a chemically modified heparin, inhibits myeloma growth and angiogenesis via disruption of the heparanase/syndecan-1 axis. AB - PURPOSE: Heparanase promotes myeloma growth, dissemination, and angiogenesis through modulation of the tumor microenvironment, thus highlighting the potential of therapeutically targeting this enzyme. SST0001, a nonanticoagulant heparin with antiheparanase activity, was examined for its inhibition of myeloma tumor growth in vivo and for its mechanism of action. EXPERIMENTAL DESIGN: The ability of SST0001 to inhibit growth of myeloma tumors was assessed using multiple animal models and a diverse panel of human and murine myeloma cell lines. To investigate the mechanism of action of SST0001, pharmacodynamic markers of angiogenesis, heparanase activity, and pathways downstream of heparanase were monitored. The potential use of SST0001 as part of a combination therapy was also evaluated in vivo. RESULTS: SST0001 effectively inhibited myeloma growth in vivo, even when confronted with an aggressively growing tumor within human bone. In addition, SST0001 treatment causes changes within tumors consistent with the compound's ability to inhibit heparanase, including downregulation of HGF, VEGF, and MMP-9 expression and suppressed angiogenesis. SST0001 also diminishes heparanase induced shedding of syndecan-1, a heparan sulfate proteoglycan known to be a potent promoter of myeloma growth. SST0001 inhibited the heparanase-mediated degradation of syndecan-1 heparan sulfate chains, thus confirming the antiheparanase activity of this compound. In combination with dexamethasone, SST0001 blocked tumor growth in vivo presumably through dual targeting of the tumor and its microenvironment. CONCLUSIONS: These results provide mechanistic insight into the antitumor action of SST0001 and validate its use as a novel therapeutic tool for treating multiple myeloma. PMID- 21257722 TI - A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors. AB - PURPOSE: Sphingosine 1-phosphate (S1P) is an important mediator of cancer cell growth and proliferation. Production of S1P is catalyzed by sphingosine kinase 1 (SphK). Safingol, (l-threo-dihydrosphingosine) is a putative inhibitor of SphK. We conducted a phase I trial of safingol (S) alone and in combination with cisplatin (C). EXPERIMENTAL DESIGN: A 3 + 3 dose escalation was used. For safety, S was given alone 1 week before the combination. S + C were then administered every 3 weeks. S was given over 60 to 120 minutes, depending on dose. Sixty minutes later, C was given over 60 minutes. The C dose of 75 mg/m(2) was reduced in cohort 4 to 60 mg/m(2) due to excessive fatigue. RESULTS: Forty-three patients were treated, 41 were evaluable for toxicity, and 37 for response. The maximum tolerated dose (MTD) was S 840 mg/m(2) over 120 minutes C 60 mg/m(2), every 3 weeks. Dose-limiting toxicity (DLT) attributed to cisplatin included fatigue and hyponatremia. DLT from S was hepatic enzyme elevation. S pharmacokinetic parameters were linear throughout the dose range with no significant interaction with C. Patients treated at or near the MTD achieved S levels of more than 20 MUmol/L and maintained levels greater than and equal to 5 MUmol/L for 4 hours. The best response was stable disease in 6 patients for on average 3.3 months (range 1.8-7.2 m). One patient with adrenal cortical cancer had significant regression of liver and lung metastases and another had prolonged stable disease. S was associated with a dose-dependent reduction in S1P in plasma. CONCLUSIONS: Safingol, the first putative SphK inhibitor to enter clinical trials, can be safely administered in combination with cisplatin. Reversible dose-dependent hepatic toxicity was seen, as expected from preclinical data. Target inhibition was achieved with downregulation of S1P. The recommended phase II dose is S 840 mg/m(2) and C 60 mg/m(2), every 3 weeks. PMID- 21257724 TI - Evaluation of the respective influence of thyroid hormones and TSH on blood coagulation parameters after total thyroidectomy. AB - BACKGROUND: Several hemostatic abnormalities have been described in hypothyroidism, such as modification of coagulation proteins and bleeding tendency. Although thyroid hormone deficiency is considered to be responsible for these changes, the underlying mechanisms have not yet been established. OBJECTIVE: To evaluate the respective influence of peripheral thyroid hormones (free thyroxine) and TSH on blood clotting by assessing coagulation parameters in patients with a history of total thyroidectomy for thyroid cancer, under three different conditions: induced hypothyroidism, euthyroid state, and following recombinant human TSH (rhTSH) administration. METHODS: Coagulation parameters (platelet count, fibrinogen, international normalized ratio, prothrombin time, thrombin time, activated partial thromboplastin time (APTT), factor VIII activity ((FVIII:C), as well as von Willebrand factor antigen (VWF:Ag) and VWF activity using collagen binding assay (VWF:CBA)) were measured in patients with severe hypothyroidism following withdrawal of thyroid hormone replacement therapy, and in the same patients with euthyroidism after restoring replacement treatment (group A), and before and after administering rhTSH (group B). RESULTS: FVIII:C, VWF:Ag, and VWF:CBA were significantly decreased (P<0.001), whereas APTT was significantly increased (P<0.001) in patients with severe hypothyroidism compared with patients in the euthyroid state. No changes in clotting parameters were observed in patients who received rhTSH therapy. CONCLUSION: This prospective study shows that severe short-term hypothyroidism is associated with significantly lower levels of VWF:Ag, VWF:CBA, and FVIII:C. Administration of exogenous TSH has no effect on coagulation parameters. These findings suggest that thyroid hormone deficiency is likely to be the main cause of coagulation alterations in patients with hypothyroidism. PMID- 21257723 TI - 18FDG-PET predicts pharmacodynamic response to OSI-906, a dual IGF-1R/IR inhibitor, in preclinical mouse models of lung cancer. AB - PURPOSE: To evaluate 2-deoxy-2-[(18)F]fluoro-d-glucose positron emission tomography imaging ((18)FDG-PET) as a predictive, noninvasive, pharmacodynamic (PD) biomarker of response following administration of a small-molecule insulin like growth factor-1 receptor and insulin receptor (IGF-1R/IR) inhibitor, OSI 906. EXPERIMENTAL DESIGN: In vitro uptake studies of (3)H-2-deoxy glucose following OSI-906 exposure were conducted evaluating correlation of dose with inhibition of IGF-1R/IR as well as markers of downstream pathways and glucose metabolism. Similarly, in vivo PD effects were evaluated in human tumor cell line xenografts propagated in athymic nude mice by (18)FDG-PET at 2, 4, and 24 hours following a single treatment of OSI-906 for the correlation of inhibition of receptor targets and downstream markers. RESULTS: Uptake of (3)H-2-deoxy glucose and (18)FDG was significantly diminished following OSI-906 exposure in sensitive tumor cells and subcutaneous xenografts (NCI-H292) but not in an insensitive model lacking IGF-1R expression (NCI-H441). Diminished PD (18)FDG-PET, collected immediately following the initial treatment agreed with inhibition of pIGF 1R/pIR, reduced PI3K (phosphoinositide 3-kinase) and MAPK (mitogen activated protein kinase) pathway activity, and predicted tumor growth arrest as measured by high-resolution ultrasound imaging. CONCLUSION: (18)FDG-PET seems to serve as a rapid, noninvasive PD marker of IGF-1R/IR inhibition following a single dose of OSI-906 and should be explored clinically as a predictive clinical biomarker in patients undergoing IGF-1R/IR-directed cancer therapy. PMID- 21257725 TI - FABP 4 is associated with inflammatory markers and metabolic syndrome in morbidly obese women. AB - OBJECTIVE: The adipocyte/macrophage fatty acid-binding protein 4 (FABP4) has been described as a biomarker for adiposity and metabolic syndrome (MS). The aims of this study were to assess the relationship between FABP4 and inflammatory cytokines related to obesity, and to evaluate FABP4 mRNA expression in visceral and subcutaneous adipose tissue in non-diabetic morbidly obese women versus healthy lean women. METHODS: We analyzed circulating levels of FABP4 in 81 Spanish women: 38 lean (body mass index (BMI)<25 kg/m(2)) and 43 morbidly obese (BMI>40 kg/m(2)). We took 30 follow-up blood samples at 6 and 12 months after bariatric surgery. We assessed FABP4 gene expression in samples of subcutaneous abdominal and visceral adipose tissue. Adipose tissue mRNA expression was determined by real-time RT-PCR. RESULTS: In morbidly obese women, plasma FABP4 levels were significantly higher than in non-obese patients. These levels positively correlated with BMI, homeostasis model assessment of insulin resistance (HOMA2-IR), and plasma glucose and insulin levels. Post-operative FABP4 levels decreased by a maximum of 30% after 12 months. We also found an inverse association between FABP4 and adiponectin levels, and positive correlations between FABP4 and circulating leptin, tumor necrosis factor (TNF) receptors, C-reactive protein (CRP) and interleukin 6 levels. Linear regression analysis revealed that FABP4 was more closely related to HOMA2-IR than adiponectin, CRP, TNF-RI, or leptin. Furthermore, high circulating FABP4 levels were associated with the presence of MS. FABP4 mRNA expression in visceral adipose tissue was related to its circulating levels in morbidly obese women. CONCLUSIONS: Our results indicate that serum FABP4 is associated with inflammatory factors related to obesity and MS in non-diabetic morbidly obese women. PMID- 21257726 TI - High prevalence of vertebral fractures despite normal bone mineral density in patients with long-term controlled acromegaly. AB - OBJECTIVE: To establish the prevalence of osteoporosis, vertebral fractures (VFs), and non-VFs in acromegaly patients with long-term controlled disease and factors potentially influencing fracture risk. DESIGN: Case-control study. Patients and measurements Eighty-nine patients (46% male, mean age: 58 years) were included. We studied VFs and non-VFs, bone mineral density (BMD), and markers of bone turnover. In 48 patients, BMD assessment was also obtained 7 years prior to the current study. To compare VF prevalence, data from a sample of the Dutch population (n=3469) were used. RESULTS: VF prevalence was 59% (men 64% and women 54%), significantly increased when compared with controls (odds ratio up to 6.5), and independent of the duration of disease control, BMD, markers of bone turnover, and acromegalic disease characteristics. Mean number of VFs per patient was 3.4+/-0.3 (range 1-8). There was no relationship between the number and severity of fractures, parameters of bone turnover, and follow-up BMD measurements. BMD did not change during prolongation of follow-up by 7 years of controlled acromegaly. CONCLUSION: There is a very high prevalence of VFs in acromegaly patients with long-term controlled disease, independently of BMD. In view of the significant morbidity and mortality associated with VFs in general and the inability of BMD to predict fracture risk in acromegalic patients, we propose to include VF assessment, for example by lateral conventional radiographs of the spine in the screening of patients with acromegaly, both at diagnosis and during follow-up after establishment of disease control. PMID- 21257727 TI - Relationship between cardioscopic images and histological changes in the left ventricle of patients with idiopathic myocarditis. AB - AIMS: Endomyocardial biopsy is essential for definite diagnosis of idiopathic myocarditis. However, since endomyocardial biopsy is guided by fluoroscopy, whether or not the diseased myocardium is biopsied depends on chance, and this may lead to misdiagnosis. If the endocardial surface represents changes indicative of stages of myocarditis, staging of myocarditis and targeted cardioscope-guided biopsy could be used for accurate histological diagnosis. METHODS AND RESULTS: The relationship between left ventricular endocardial surface colour observed by cardioscopy and biopsy findings were examined in 78 patients with suspected idiopathic myocarditis. Of these, 59 patients were diagnosed histologically as idiopathic myocarditis. Endocardial colour was classified into red, milky white, purple, yellowish brown, or white. Biopsied specimens with red and milky white wall segments exhibited histological changes compatible with acute myocarditis; purple segments, active chronic myocarditis; and yellowish brown and white segments, inactive chronic myocarditis. The sensitivity, specificity, and predictive value of red and milky white colours for detecting acute myocarditis were 100, 100, and 100%, respectively; of purple for detecting active chronic myocarditis were 83, 92, and 78%, respectively; and yellowish brown and white for detecting inactive chronic myocarditis were 82, 74, and 53, respectively. CONCLUSION: Red and milky white endocardial surface colours predicted histological acute myocarditis, and purple predicted active chronic myocarditis. However, yellowish brown and white colours did not predict inactive chronic myocarditis. PMID- 21257728 TI - Mouse LSECtin as a model for a human Ebola virus receptor. AB - The biochemical properties of mouse LSECtin, a glycan-binding receptor that is a member of the C-type lectin family found on sinusoidal endothelial cells, have been investigated. The C-type carbohydrate-recognition domain of mouse LSECtin, expressed in bacteria, has been used in solid-phase binding assays, and a tetramerized form has been used to probe a glycan array. In spite of sequence differences near the glycan-binding sites, the mouse receptor closely mimics the properties of the human receptor, showing high affinity binding to glycans bearing terminal GlcNAcbeta1-2Man motifs. Site-directed mutagenesis has been used to confirm that residues near the binding site that differ between the human and the mouse proteins do not affect this binding specificity. Mouse and human LSECtin have been shown to bind Ebola virus glycoprotein with equivalent affinities, and the GlcNAcbeta1-2Man disaccharide has been demonstrated to be an effective inhibitor of this interaction. These studies provide a basis for using mouse LSECtin, and knockout mice lacking this receptor, to model the biological properties of the human receptor. PMID- 21257729 TI - Hypoxia increases transepithelial electrical conductance and reduces occludin at the plasma membrane in alveolar epithelial cells via PKC-zeta and PP2A pathway. AB - During pulmonary edema, the alveolar space is exposed to a hypoxic environment. The integrity of the alveolar epithelial barrier is required for the reabsorption of alveolar fluid. Tight junctions (TJ) maintain the integrity of this barrier. We set out to determine whether hypoxia creates a dysfunctional alveolar epithelial barrier, evidenced by an increase in transepithelial electrical conductance (G(t)), due to a decrease in the abundance of TJ proteins at the plasma membrane. Alveolar epithelial cells (AEC) exposed to mild hypoxia (Po(2) = 50 mmHg) for 30 and 60 min decreased occludin abundance at the plasma membrane and significantly increased G(t). Other cell adhesion molecules such as E cadherin and claudins were not affected by hypoxia. AEC exposed to hypoxia increased superoxide, but not hydrogen peroxide (H(2)O(2)). Overexpression of superoxide dismutase 1 (SOD1) but not SOD2 prevented the hypoxia-induced G(t) increase and occludin reduction in AEC. Also, overexpression of catalase had a similar effect as SOD1, despite not detecting any increase in H(2)O(2) during hypoxia. Blocking PKC-zeta and protein phosphatase 2A (PP2A) prevented the hypoxia-induced occludin reduction at the plasma membrane and increase in G(t). In summary, we show that superoxide, PKC-zeta, and PP2A are involved in the hypoxia-induced increase in G(t) and occludin reduction at the plasma membrane in AEC. PMID- 21257731 TI - Endocytic response of type I alveolar epithelial cells to hypertonic stress. AB - We present plasma membrane (PM) internalization responses of type I alveolar epithelial cells to a 50 mosmol/l increase in tonicity. Our research is motivated by interest in ATI repair, for which endocytic retrieval of PM appears to be critical. We validated pharmacological and molecular tools to dissect the endocytic machinery of these cells and used these tools to test the hypothesis that osmotic stress triggers a pathway-specific internalization of PM domains. Validation experiments confirmed the fluorescent analogs of lactosyl-ceramide, transferrin, and dextran as pathway-specific cargo of caveolar, clathrin, and fluid-phase uptake, respectively. Pulse-chase experiments indicate that hypertonic exposure causes a downregulation of clathrin and fluid-phase endocytosis while stimulating caveolar endocytosis. The tonicity-mediated increase in caveolar endocytosis was associated with the translocation of caveolin-1 from the PM and was absent in cells that had been transfected with dominant-negative dynamin constructs. In separate experiments we show that hypertonic exposure increases the probability of PM wound repair following micropuncture from 82 +/- 4 to 94 +/- 2% (P < 0.01) and that this effect depends on Src pathway activation-mediated caveolar endocytosis. The therapeutic and biological implications of our findings are discussed. PMID- 21257730 TI - Proteolytic release of the receptor for advanced glycation end products from in vitro and in situ alveolar epithelial cells. AB - Although the receptor for advanced glycation end products (RAGE) has been used as a biological marker of alveolar epithelial cell injury in clinical studies, the mechanism for release of soluble RAGE from lung epithelial cells has not been well studied. Therefore, these studies were designed to determine the mechanism for release of soluble RAGE after lipopolysaccharide (LPS) challenge. For these purposes, alveolar epithelial cells from rat lungs were cultured on Transwell inserts, and LPS was added to the apical side (500 MUg/ml) for 16 h on day 7. On day 7, RAGE was expressed predominantly in surfactant protein D-negative cells, and LPS challenge induced release of RAGE into the medium. This response was partially blocked by matrix metalloproteinase (MMP) inhibitors. Transcripts of MMP-3 and MMP-13 were upregulated by LPS, whereas RAGE transcripts did not change. Proteolysis by MMP-3 and MMP-13 resulted in soluble RAGE expression in the bronchoalveolar lavage fluid in the in situ rat lung, and this reaction was inhibited by MMP inhibitors. In human studies, both MMP-3 and -13 antigen levels were significantly correlated with the level of RAGE in pulmonary edema fluid samples. These results support the conclusion that release of RAGE is primarily mediated by proteolytic damage in alveolar epithelial cells in the lung, caused by proteases in acute inflammatory conditions in the distal air spaces. PMID- 21257732 TI - Incentivising innovation or supporting other interests? European regulation of orphan medicinal products. PMID- 21257733 TI - Lewy bodies and olfactory dysfunction in old age. AB - As part of a clinical-pathologic project, older people completed a standard odor identification test at study entry. During a mean of 3.5 years of observation, 201 people died and underwent brain autopsy and neuropathologic examination (6 with a history of Parkinson's disease were excluded). Lewy bodies were identified with antibodies to alpha-synuclein and classified as nigral, limbic, or neocortical based on their distribution in 6 brain regions. Plaques and tangles in 5 regions were summarized with a previously established composite measure, and neuron loss in the substantia nigra was rated on 6-point scale. Odor identification scores ranged from 0 to 12 correct (mean = 8.0, standard deviation = 2.6). On neuropathologic examination, 26 persons had Lewy bodies (13 neocortical, 9 limbic, and 4 nigral). In an analysis adjusted for age, sex, education, and time from olfactory testing to death, limbic (estimate = -2.47, standard error [SE] = 0.73, P < 0.001) and neocortical (estimate = -4.36, SE = 0.63, P < 0.001) Lewy body subgroups were associated with impaired olfaction. Results were comparable in analyses that controlled for dementia or parkinsonism during the study or postmortem measures of plaques and tangles or nigral cell loss. A final set of analyses suggested that impaired olfactory performance may aid detection of underlying Lewy body disease. The findings indicate that Lewy body disease impairs late life olfactory function even in otherwise asymptomatic individuals. PMID- 21257734 TI - The K+-H+ exchanger, nigericin, modulates taste cell pH and chorda tympani taste nerve responses to acidic stimuli. AB - The relationship between acidic pH, taste cell pH(i), and chorda tympani (CT) nerve responses was investigated before and after incorporating the K(+)-H(+) exchanger, nigericin, in the apical membrane of taste cells. CT responses were recorded in anesthetized rats in vivo, and changes in pH(i) were monitored in polarized fungiform taste cells in vitro. Under control conditions, stimulating the tongue with 0.15 M potassium phosphate (KP) or 0.15 M sodium phosphate (NaP) buffers of pHs between 8.0 and 4.6, KP or NaP buffers did not elicit a CT response. Post-nigericin (500 * 10(-6) M), KP buffers, but not NaP buffers, induced CT responses at pHs <= 6.6. The effect of nigericin was reversed by the topical lingual application of carbonyl cyanide 3-chloro-phenylhydrazone, a protonophore. Post-nigericin (150 * 10(-6) M), KP buffers induced a greater decrease in taste cell pH(i) relative to NaP buffers and to NaP and KP buffers under control conditions. A decrease in pH(i) to about 6.9 induced by KP buffers was sufficient to elicit a CT response. The results suggest that facilitating apical H(+) entry via nigericin decreases taste cell pH(i) and demonstrates directly a strong correlation between pH(i) and the magnitude of the CT response. PMID- 21257735 TI - Direct imaging of pH1N1 2009 influenza virus replication in alveolar pneumocytes in fatal cases by transmission electron microscopy. AB - Human influenza virus pandemics constitute a major global public health issue. Although studies on autopsy specimens from the recent pandemic by the 2009 influenza A (H1N1) virus have revealed a broad spectrum of pathologic findings, direct electron microscopic studies of the lung tissue from influenza fatalities are few. In this study, we examined five well-preserved pulmonary necropsy specimens from fatal cases of laboratory-confirmed pH1N1 from India. The novel observations in comparison with earlier reports included direct imaging of influenza virus budding within dilated cisternae of pneumocytes, cell-free virus emerging from the cell membrane of a pneumocyte in the alveolar lumen, presence of polymorphonuclear cells with red blood cells as inflammatory exudates close to hyaline membranes and extensive cytoplasmic degeneration of epithelial cells of the alveolar lining. These observations are in consistent with the earlier findings and emphasize the possible role of this virus directly infecting cells of the lower respiratory tract as a key event in the rapid pathogenesis of pH1N1 disease process. PMID- 21257737 TI - Persistence of concurrent infections with multiple human papillomavirus types: a population-based cohort study. AB - The presence of more than one human papillomavirus (HPV) genotype may influence the duration of prevalently detected infections. This analysis included 1,646 infections detected at enrollment in 980 women from the Guanacaste, Costa Rica, cohort who were actively followed up every 6-12 months for up to 8 years. We categorized HPV infections as single or multiple types. Persistence of infections was estimated using discrete-time survival analysis. The difference between the duration of single and that of concurrent multiple type-specific prevalent HPV infections was not significant (P = .9; log-rank test). Concurrent, prevalent detection of additional HPV types did not change the likelihood of viral persistence. PMID- 21257736 TI - Strong hepatitis C virus (HCV)-specific cell-mediated immune responses in the absence of viremia or antibodies among uninfected siblings of HCV chronically infected children. AB - BACKGROUND: Cell-mediated immune (CMI) responses to hepatitis C virus (HCV) antigens in adults without seroconversion or viremia are biomarkers for prior transient infection. We investigated HCV-specific CMI responses in seronegative children living with HCV-infected siblings. METHODS: Children 3-18 years of age living with HCV-infected siblings were screened for HCV antibodies and HCV RNA. Peripheral blood mononuclear cells (PBMCs) were evaluated for HCV-specific CMI responses by interferon gamma (IFN-gamma) enzyme-linked immunospot assay using 3 recombinant HCV protein antigens. Flow cytometry phenotypically characterized IFN gamma-secreting cells. RESULTS: Forty-five seronegative children and 5 seropositive viremic siblings had functionally viable PBMCs. Among the 45 seronegative siblings, 15 (33.3%) had positive HCV-specific IFN-gamma responses, and subsequent RNA testing revealed that 3 were viremic. Compared with the 5 seropositive viremic children, the median number of HCV-specific spot-forming units was significantly higher in the 12 seronegative aviremic children (P = .002) and in the 3 seronegative viremic children (P = .025). Flow cytometric analysis revealed that IFN-gamma was synthesized mainly by CD4(+) T cells. CONCLUSION: Strong HCV-specific CD4(+) T cell responses were detectable in higher frequency among seronegative, aviremic children compared with persistently infected siblings. Further studies are needed to determine whether these immune responses are protective against HCV infection. PMID- 21257738 TI - Genetic variation in IL28B and treatment-induced clearance of hepatitis C virus in HIV-positive patients with acute and chronic hepatitis C. AB - Recently, a IL28B (rs 12979860) gene polymorphism was identified as a predictor for response to hepatitis C virus-specific treatment in human immunodeficiency virus (HIV)-uninfected and -infected patients with chronic hepatitis C. In an analysis of HIV-infected patients with acute hepatitis C, we found that the IL28B genotype was associated with serum levels of hepatitis C virus RNA, g-GT, and CD4 cell count. In contrast to HIV-infected patients with chronic hepatitis C, the IL28B genotype was not significantly associated with treatment response rates in patients with acute hepatitis C. Thus, effects of the IL28B single-nucleotide polymorphism may differ in HIV-infected patients with chronic and acute hepatitis C. PMID- 21257739 TI - Possession of HLA class II DRB1*1303 associates with reduced viral loads in chronic HIV-1 clade C and B infection. AB - BACKGROUND: The HLA class II molecules play a central role in the generation of human immunodeficiency virus (HIV)-specific CD4(+) T-helper cells, which are critical for the induction of cytotoxic CD8(+) T cell responses. However, little is known about the impact of HLA class II alleles on HIV disease progression. METHODS: In this study we investigated the effect of HLA class II alleles on HIV disease outcome and HIV-specific T cell responses in a cohort of 426 antiretroviral therapy-naive, HIV-1 clade C-infected, predominantly female black South Africans. RESULTS: The HLA class II allele DRB1*1303 was independently associated with lower plasma viral loads in this population (P = .02), an association that was confirmed in a second cohort of 1436 untreated, HIV-1 clade B-infected, male European Americans, suggesting that DRB1*1303-mediated protection is independent of ethnicity, sex, and viral clade. Interestingly, DRB1*1303 carriage was not associated with an increased frequency of interferon (IFN) gamma-positive HIV-specific CD4(+) T cell responses. CONCLUSIONS: These data demonstrate the independent effect of an HLA class II allele, DRB1*1303, on HIV disease progression, in the absence of increased IFN-gamma-positive HIV specific CD4(+) T cell frequencies, suggesting that the protective activity of DRB1*1303 may be mediated via an alternative mechanism. PMID- 21257740 TI - Comparison of a live attenuated 2009 H1N1 vaccine with seasonal influenza vaccines against 2009 pandemic H1N1 virus infection in mice and ferrets. AB - The role of seasonal influenza vaccination in pandemic influenza A H1N1 disease is important to address, because a large segment of the population is vaccinated annually. We administered 1 or 2 doses of pandemic H1N1 vaccine (CA/7 ca), a seasonal trivalent inactivated (s-TIV), or live attenuated influenza vaccine (s LAIV) to mice and ferrets and subsequently challenged them with a pandemic H1N1 virus. In both species, CA/7 ca was immunogenic and conferred complete protection against challenge. s-TIV did not confer protection in either animal model, and s LAIV did not confer any protection in ferrets. In mice, 2 doses of s-LAIV led to complete protection in the upper respiratory tract and partial protection in the lungs. Our data indicate that vaccination with the seasonal influenza vaccines did not confer complete protection in the lower respiratory tract in either animal model, whereas the CA/7 ca vaccine conferred complete protection in both animal models. PMID- 21257741 TI - Detection of low-level K65R variants in nucleoside reverse transcriptase inhibitor-naive chronic and acute HIV-1 subtype C infections. AB - To substantiate reports of greater emergence of the K65R nucleoside reverse transcriptase inhibitor (NRTI) mutation in human immunodeficiency virus type 1 (HIV-1) subtype C, we examined natural low-level K65R expression in subtype C relative to subtypes B and AE. We used allele-specific polymerase chain reaction to screen HIV-1 amplified by reverse-transcription high-fidelity polymerase chain reaction from subtype C-infected South African women and infants and CRF01(subtype AE) from Thailand; all subjects were NRTI naive. We found low-level K65R of unknown clinical significance in NRTI-naive subtype C-infected women and infants at frequencies above the natural occurrence in subtypes B and AE. The frequent appearance of subtype C frameshift deletions at codon 65 supports a propensity for transcription error in this region. PMID- 21257742 TI - Protecting respiratory health: what should be the constituents of an effective RPE programme? AB - Although personal respiratory protection is widely recognized as having a lower priority than reduction of any risk at source, respiratory protective equipment (RPE) is a major part of risk management for many employers. We have identified the key elements of what constitutes an effective risk control programme involving RPE, through a 3-fold approach involving (i) a review of the published scientific literature, (ii) exploring the issue through >40 years of research publications from the Institute of Occupational Medicine (IOM) (in which the ergonomics of personal protection equipment has been a significant thread), and (iii) a series of interviews and discussions with IOM and Health and Safety Executive staff with experience in the testing, prescription, or use of RPE. We have used the findings to formulate a series of recommendations for the constituents of an effective RPE programme. The role of management is paramount in recognizing the need for and providing appropriate RPE, which is both technically and ergonomically effective. Only then does any focus on the role of the employee, in wearing the RPE correctly at the appropriate times, becomes viable. PMID- 21257743 TI - Validation of the analysis of respirable crystalline silica (quartz) in foams used with CIP 10-R samplers. AB - Sampling the respirable fraction to measure exposure to crystalline silica is most often carried out using cyclones. However, low flow rates (<4 l min(-1)) and continuing improvement in workplace hygiene means less and less material is sampled for analysis, resulting in increased analytical uncertainty. Use of the CIP 10-R sampler, working at a flow rate of 10 l min(-1), is one attempt to solve current analytical difficulties. To check the ability of the analysis of quartz sampled on foams, known amounts of quartz associated with a matrix have been injected into foams. The results obtained show that the proposed protocol, with prior acid attack and ashing of the foams, satisfies the recommendations of EN 482 Standard [CEN. (2006) Workplace atmospheres-general requirements for the performance of procedures for the measurements of chemical agents. Brussels, Belgium: EN 482 Comite Europeen de normalization (CEN).], namely an expanded uncertainty of <50% for quartz weights between 0.1 and 0.5 times the 8-h exposure limit value and <30% for quartz weights between 0.5 and 2 times the 8-h exposure limit value, assuming an exposure limit value equal to 0.1 mg m(-3). Results obtained show that the 101 reflection line allows a quartz quantity of the order of 25 MUg to be satisfactorily measured, which corresponds to a 10th of the exposure limit value, assuming an exposure limit value of 0.05 mg m(-3). In this case, the 100 and 112 reflection lines with expanded uncertainties of ~50% would also probably lead to satisfactory quantification. Particular recommendations are also proposed for the preparation of calibration curves to improve the method. PMID- 21257744 TI - Proposed modification to the inhalable aerosol convention applicable to realistic workplace wind speeds. AB - The current convention for sampling inhalable aerosols was based on several mannequin studies performed in wind tunnels at wind speeds between 0.5 and 4 m s( 1). In reality, as we now know, the wind speed in most modern indoor working environments is generally at or below ~0.2 m s(-1). Inhalability studies performed in calm air aerosol chambers have shown that human aspiration efficiency at essentially zero wind speed is not consistent with the existing inhalable aerosol convention, calling into question the universal applicability of the current standard. More recently, experiments were carried out in a new hybrid wind tunnel-calm air chamber at more representative workplace wind speeds, between ~0.1 and 0.5 m s(-1), to fill in this knowledge gap. Comparing these new data to both the existing inhalable aerosol convention and a recently proposed alternative for low wind movement suggests that, while the existing inhalable aerosol convention remains appropriate for wind speeds above ~0.2 m s(-1), the modified version is more appropriate for the range below ~0.2 m s(-1). PMID- 21257745 TI - Structure-based search reveals hammerhead ribozymes in the human microbiome. AB - Deep sequencing of viral or bacterial nucleic acids monitors the presence and diversity of microbes in select populations and locations. Metagenomic study of mammalian viromes can help trace paths of viral transmissions within or between species. High throughput sequencing of patient and untreated sewage microbiomes showed many sequences with no similarity to genomic sequences of known function or origin. To estimate the distribution of functional RNAs in these microbiomes, we used the hammerhead ribozyme (HHR) motif to search for sequences capable of assuming its three-way junction fold. Although only two of the three possible natural HHR topologies had been known, our analysis revealed highly active ribozymes that terminated in any of the three stems. The most abundant of these are type II HHRs, one of which is the fastest natural cis-acting HHR yet discovered. Altogether, 13 ribozymes were confirmed in vitro, but only one showed sequence similarity to previously described HHRs. Sequences surrounding the ribozymes do not generally show similarity to known genes, except in one case, where a ribozyme is immediately preceded by a bacterial RadC gene. We demonstrate that a structure-based search for a known functional RNA is a powerful tool for analysis of metagenomic datasets, complementing sequence alignments. PMID- 21257746 TI - Identification of macrodomain proteins as novel O-acetyl-ADP-ribose deacetylases. AB - Sirtuins are a family of protein lysine deacetylases, which regulate gene silencing, metabolism, life span, and chromatin structure. Sirtuins utilize NAD(+) to deacetylate proteins, yielding O-acetyl-ADP-ribose (OAADPr) as a reaction product. The macrodomain is a ubiquitous protein module known to bind ADP-ribose derivatives, which diverged through evolution to support many different protein functions and pathways. The observation that some sirtuins and macrodomains are physically linked as fusion proteins or genetically coupled through the same operon, provided a clue that their functions might be connected. Indeed, here we demonstrate that the product of the sirtuin reaction OAADPr is a substrate for several related macrodomain proteins: human MacroD1, human MacroD2, Escherichia coli YmdB, and the sirtuin-linked MacroD-like protein from Staphylococcus aureus. In addition, we show that the cell extracts derived from MacroD-deficient Neurospora crassa strain exhibit a major reduction in the ability to hydrolyze OAADPr. Our data support a novel function of macrodomains as OAADPr deacetylases and potential in vivo regulators of cellular OAADPr produced by NAD(+)-dependent deacetylation. PMID- 21257747 TI - Conserved stress-protective activity between prion protein and Shadoo. AB - Shadoo (Sho) is a neuronally expressed glycoprotein of unknown function. Although there is no overall sequence homology to the cellular prion protein (PrP(C)), both proteins contain a highly conserved internal hydrophobic domain (HD) and are tethered to the outer leaflet of the plasma membrane via a C-terminal glycosylphosphatidylinositol anchor. A previous study revealed that Sho can reduce toxicity of a PrP mutant devoid of the HD (PrPDeltaHD). We have now studied the stress-protective activity of Sho in detail and identified domains involved in this activity. Like PrP(C), Sho protects cells against physiological stressors such as the excitotoxin glutamate. Moreover, both PrP(C) and Sho required the N-terminal domain for this activity; the stress-protective capacity of PrPDeltaN as well as ShoDeltaN was significantly impaired. In both proteins, the HD promoted homodimer formation; however, deletion of the HD had different effects. Although ShoDeltaHD lost its stress-protective activity, PrPDeltaHD acquired a neurotoxic potential. Finally, we could show that the N-terminal domain of PrP(C) could be functionally replaced by that of Sho, suggesting a similar function of the N termini of Sho and PrP(C). Our study reveals a conserved physiological activity between PrP(C) and Sho to protect cells from stress-induced toxicity and suggests that Sho and PrP(C) might act on similar signaling pathways. PMID- 21257748 TI - Inflammation of the hypothalamus leads to defective pancreatic islet function. AB - Type 2 diabetes mellitus results from the complex association of insulin resistance and pancreatic beta-cell failure. Obesity is the main risk factor for type 2 diabetes mellitus, and recent studies have shown that, in diet-induced obesity, the hypothalamus becomes inflamed and dysfunctional, resulting in the loss of the perfect coupling between caloric intake and energy expenditure. Because pancreatic beta-cell function is, in part, under the control of the autonomic nervous system, we evaluated the role of hypothalamic inflammation in pancreatic islet function. In diet-induced obesity, the earliest markers of hypothalamic inflammation are present at 8 weeks after the beginning of the high fat diet; similarly, the loss of the first phase of insulin secretion is detected at the same time point and is restored following sympathectomy. Intracerebroventricular injection of a low dose of tumor necrosis factor alpha leads to a dysfunctional increase in insulin secretion and activates the expression of a number of markers of apoptosis in pancreatic islets. In addition, the injection of stearic acid intracerebroventricularly, which leads to hypothalamic inflammation through the activation of tau-like receptor-4 and endoplasmic reticulum stress, produces an impairment of insulin secretion, accompanied by increased expression of markers of apoptosis. The defective insulin secretion, in this case, is partially dependent on sympathetic signal induced peroxisome proliferator receptor-gamma coactivator Deltaalpha and uncoupling protein-2 expression and is restored after sympathectomy or following PGC1alpha expression inhibition by an antisense oligonucleotide. Thus, the autonomic signals generated in concert with hypothalamic inflammation can impair pancreatic islet function, a phenomenon that may explain the early link between obesity and defective insulin secretion. PMID- 21257749 TI - Synthesis, maturation, and trafficking of human Na+-dicarboxylate cotransporter NaDC1 requires the chaperone activity of cyclophilin B. AB - Renal excretion of citrate, an inhibitor of calcium stone formation, is controlled mainly by reabsorption via the apical Na(+)-dicarboxylate cotransporter NaDC1 (SLC13A2) in the proximal tubule. Recently, it has been shown that the protein phosphatase calcineurin inhibitors cyclosporin A (CsA) and FK 506 induce hypocitraturia, a risk factor for nephrolithiasis in kidney transplant patients, but apparently through urine acidification. This suggests that these agents up-regulate NaDC1 activity. Using the Xenopus laevis oocyte and HEK293 cell expression systems, we examined first the effect of both anti-calcineurins on NaDC1 activity and expression. While FK-506 had no effect, CsA reduced NaDC1 mediated citrate transport by lowering heterologous carrier expression (as well as endogenous carrier expression in HEK293 cells), indicating that calcineurin is not involved. Given that CsA also binds specifically to cyclophilins, we determined next whether such proteins could account for the observed changes by examining the effect of selected cyclophilin wild types and mutants on NaDC1 activity and cyclophilin-specific siRNA. Interestingly, our data show that the cyclophilin isoform B is likely responsible for down-regulation of carrier expression by CsA and that it does so via its chaperone activity on NaDC1 (by direct interaction) rather than its rotamase activity. We have thus identified for the first time a regulatory partner for NaDC1, and have gained novel mechanistic insight into the effect of CsA on renal citrate transport and kidney stone disease, as well as into the regulation of membrane transporters in general. PMID- 21257750 TI - Manipulations in the peripheral stalk of the Saccharomyces cerevisiae F1F0-ATP synthase. AB - The Saccharomyces cerevisiae F(1)F(0)-ATP synthase peripheral stalk is composed of the OSCP, h, d, and b subunits. The b subunit has two membrane-spanning domains and a large hydrophilic domain that extends along one side of the enzyme to the top of F(1). In contrast, the Escherichia coli peripheral stalk has two identical b subunits, and subunits with substantially altered lengths can be incorporated into a functional F(1)F(0)-ATP synthase. The differences in subunit structure between the eukaryotic and prokaryotic peripheral stalks raised a question about whether the two stalks have similar physical and functional properties. In the present work, the length of the S. cerevisiae b subunit has been manipulated to determine whether the F(1)F(0)-ATP synthase exhibited the same tolerances as in the bacterial enzyme. Plasmid shuffling was used for ectopic expression of altered b subunits in a strain carrying a chromosomal disruption of the ATP4 gene. Wild type growth phenotypes were observed for insertions of up to 11 and a deletion of four amino acids on a nonfermentable carbon source. In mitochondria-enriched fractions, abundant ATP hydrolysis activity was seen for the insertion mutants. ATPase activity was largely oligomycin-insensitive in these mitochondrial fractions. In addition, very poor complementation was seen in a mutant with an insertion of 14 amino acids. Lengthier deletions yielded a defective enzyme. The results suggest that although the eukaryotic peripheral stalk is near its minimum length, the b subunit can be extended a considerable distance. PMID- 21257751 TI - Signal transduction of pregnenolone sulfate in insulinoma cells: activation of Egr-1 expression involving TRPM3, voltage-gated calcium channels, ERK, and ternary complex factors. AB - The neurosteroid pregnenolone sulfate acts on the nervous system by modifying neurotransmission and receptor functions, thus influencing synaptic strength, neuronal survival, and neurogenesis. Here we show that pregnenolone sulfate induces a signaling cascade in insulinoma cells leading to enhanced expression of the zinc finger transcription factor Egr-1 and Egr-1-responsive target genes. Pharmacological and genetic experiments revealed that influx of Ca(2+) ions via transient receptor potential M3 and voltage-gated Ca(2+) channels, elevation of the cytosolic Ca(2+) level, and activation of ERK are essential for connecting pregnenolone sulfate stimulation with enhanced Egr-1 biosynthesis. Expression of a dominant-negative mutant of Elk-1, a key regulator of gene transcription driven by a serum response element, attenuated Egr-1 expression following stimulation, indicating that Elk-1 or related ternary complex factors connect the transcription of the Egr-1 gene with the pregnenolone sulfate-induced intracellular signaling cascade elicited by the initial influx of Ca(2+). The newly synthesized Egr-1 was biologically active and bound under physiological conditions to the regulatory regions of the Pdx-1, Synapsin I, and Chromogranin B genes. Pdx-1 is a major regulator of insulin gene transcription. Accordingly, elevated insulin promoter activity and increased mRNA levels of insulin could be detected in pregnenolone sulfate-stimulated insulinoma cells. Likewise, the biosynthesis of synapsin I, a synaptic vesicle protein that is found at secretory granules in insulinoma cells, was stimulated in pregnenolone sulfate-treated INS 1 cells. Together, these data show that pregnenolone sulfate induces a signaling cascade in insulinoma cells that is very similar to the signaling cascade induced by glucose in beta-cells. PMID- 21257752 TI - Signaling and myosin-binding protein C. AB - Myosin-binding protein C (MyBP-C) is a thick filament protein consisting of 1274 amino acid residues (149 kDa) that was identified by Starr and Offer over 30 years ago as a contaminant present in a preparation of purified myosin. Since then, numerous studies have defined the muscle-specific isoforms, the structure, and the importance of the proteins in normal striated muscle structure and function. Underlying the critical role the protein plays, it is now apparent that mutations in the cardiac isoform (cMyBP-C) are responsible for a substantial proportion (30-40%) of genotyped cases of familial hypertrophic cardiomyopathy. Although generally accepted that MyBP-C can interact with all three filament systems within the sarcomere (the thick, thin, and titin filaments), the exact nature of these interactions and the functional consequences of modified binding remain obscure. In addition to these structural considerations, cMyBP-C can serve as a point of convergence for signaling processes in the cardiomyocyte via post translational modifications mediated by kinases that phosphorylate residues in the cardiac-specific isoform sequence. Thus, cMyBP-C is a critical nodal point that has both important structural and signaling roles and whose modifications are known to cause significant human cardiac disease. PMID- 21257753 TI - Redox signaling and cardiac sarcomeres. AB - Oxidative stress is common in many clinically important cardiac disorders, including ischemia/reperfusion, diabetes, and hypertensive heart disease. Oxidative stress leads to derangements in pump function due to changes in the expression or function of proteins that regulate intracellular Ca(2+) homeostasis. There is growing evidence that the cardiodepressant actions of reactive oxygen species (ROS) also are attributable to ROS-dependent signaling events in the sarcomere. This minireview focuses on myofilament protein post translational modifications induced by ROS or ROS-activated signaling enzymes that regulate cardiac contractility. PMID- 21257754 TI - Mne1 is a novel component of the mitochondrial splicing apparatus responsible for processing of a COX1 group I intron in yeast. AB - Saccharomyces cerevisiae cells lacking Mne1 are deficient in intron splicing in the gene encoding the Cox1 subunit of cytochrome oxidase but contain wild-type levels of the bc(1) complex. Thus, Mne1 has no role in splicing of COB introns or expression of the COB gene. Northern experiments suggest that splicing of the COX1 aI5beta intron is dependent on Mne1 in addition to the previously known Mrs1, Mss116, Pet54, and Suv3 factors. Processing of the aI5beta intron is similarly impaired in mne1Delta and mrs1Delta cells and overexpression of Mrs1 partially restores the respiratory function of mne1Delta cells. Mrs1 is known to function in the initial transesterification reaction of splicing. Mne1 is a mitochondrial matrix protein loosely associated with the inner membrane and is found in a high mass ribonucleoprotein complex specifically associated with the COX1 mRNA even within an intronless strain. Mne1 does not appear to have a secondary function in COX1 processing or translation, because disruption of MNE1 in cells containing intronless mtDNA does not lead to a respiratory growth defect. Thus, the primary defect in mne1Delta cells is splicing of the aI5beta intron in COX1. PMID- 21257755 TI - Transcriptional regulation of ATP-binding cassette transporter A1 expression by a novel signaling pathway. AB - ATP-binding cassette transporter A1 (ABCA1) is a membrane-bound protein that regulates the efflux of cholesterol derived from internalized lipoproteins. Using a mouse macrophage cell line, this report studied the impact of low-density lipoproteins (LDL) on ABCA1 expression and the signaling pathway responsible for lipoprotein-induced ABCA1 expression. Our data demonstrated that treatment of macrophages with LDL increased ABCA1 mRNA and protein levels 4.3- and 3.5-fold, respectively. LDL also induced an ~2-fold increase in macrophage surface expression of ABCA1 and a 14-fold-increase in apolipoprotein AI-mediated cholesterol efflux. In addition, LDL significantly increased the level of phosphorylated specificity protein 1 (Sp1) and the amount of Sp1 bound to the ABCA1 promoter without alteration in total Sp1 protein level. Mutation of the Sp1 binding site in the ABCA1 promoter and inhibition of Sp1 DNA binding with mithramycin A suppressed the ABCA1 promoter activity and reduced the ABCA1 expression level induced by LDL. LDL treatment also elevated protein kinase C zeta (PKC-zeta) phosphorylation and induced PKC-zeta binding with Sp1. Inhibition of PKC-zeta with kinase inhibitors or overexpression of kinase-dead PKC-zeta attenuated Sp1 phosphorylation and ABCA1 expression induced by LDL. These results demonstrate for the first time that activation of the PKCzeta-Sp1 signaling cascade is a mechanism for regulation of LDL-induced ABCA1 expression. PMID- 21257756 TI - Thematic minireview series on signaling in cardiac sarcomeres in health and disease. PMID- 21257757 TI - Cardiac Z-disc signaling network. AB - During the last 15 years, the perception of the cardiac z-disc has undergone substantial changes. Initially viewed as a structural component at the lateral boundaries of the sarcomere, the cardiac z-disc has increasingly become recognized as a nodal point in cardiomyocyte signal transduction and disease. This minireview thus focuses on novel components and recent developments in z disc biology and their role in cardiac signaling and disease. PMID- 21257758 TI - Signaling to myosin regulatory light chain in sarcomeres. AB - Myosin regulatory light chain (RLC) phosphorylation in skeletal and cardiac muscles modulates Ca(2+)-dependent troponin regulation of contraction. RLC is phosphorylated by a dedicated Ca(2+)-dependent myosin light chain kinase in fast skeletal muscle, where biochemical properties of RLC kinase and phosphatase converge to provide a biochemical memory for RLC phosphorylation and post activation potentiation of force development. The recent identification of cardiac-specific myosin light chain kinase necessary for basal RLC phosphorylation and another potential RLC kinase (zipper-interacting protein kinase) provides opportunities for new approaches to study signaling pathways related to the physiological function of RLC phosphorylation and its importance in cardiac muscle disease. PMID- 21257759 TI - Tearin' up my heart: proteolysis in the cardiac sarcomere. AB - Proteolysis within the cardiac sarcomere is a constantly evolving area of research. Three major pathways of proteolysis have been identified as being active within the cardiac sarcomere, namely the ubiquitin-proteasome system, autophagy, and the calpain system. The role of ubiquitin-proteasome system mediated proteolysis in cardiovascular health and disease has been known for some time; however, it is now apparent that other proteolytic systems also aid in the stabilization of cardiac sarcomere structure and function. This minireview focuses on the individual as well as cooperative involvement of each of these three major pathways of proteolysis within the cardiac sarcomere. PMID- 21257760 TI - Protein phosphorylation and signal transduction in cardiac thin filaments. PMID- 21257761 TI - The giant protein titin: a regulatory node that integrates myocyte signaling pathways. AB - Titin, the largest protein in the human body, is well known as a molecular spring in muscle cells and scaffold protein aiding myofibrillar assembly. However, recent evidence has established another important role for titin: that of a regulatory node integrating, and perhaps coordinating, diverse signaling pathways, particularly in cardiomyocytes. We review key findings within this emerging field, including those related to phosphorylation of the titin springs, and also discuss how titin participates in hypertrophic gene regulation and protein quality control. PMID- 21257762 TI - Reconstitution and organization of Escherichia coli proto-ring elements (FtsZ and FtsA) inside giant unilamellar vesicles obtained from bacterial inner membranes. AB - We have incorporated, for the first time, FtsZ and FtsA (the soluble proto-ring proteins from Escherichia coli) into bacterial giant unilamellar inner membrane vesicles (GUIMVs). Inside the vesicles, the structural organization and spatial distribution of fluorescently labeled FtsZ and FtsA were determined by confocal microscopy. We found that, in the presence of GDP, FtsZ was homogeneously distributed in the lumen of the vesicle. In the presence of GTP analogs, FtsZ assembled inside the GUIMVs, forming a web of dense spots and fibers. Whereas isolated FtsA was found adsorbed to the inner face of GUIMVs, the addition of FtsZ together with GTP analogs resulted in its dislodgement and its association with the FtsZ fibers in the lumen, suggesting that the FtsA-membrane interaction can be modulated by FtsZ polymers. The use of this novel in vitro system to probe interactions between divisome components will help to determine the biological implications of these findings. PMID- 21257763 TI - Lipooligosaccharide of Campylobacter jejuni: similarity with multiple types of mammalian glycans beyond gangliosides. AB - Campylobacter jejuni is well known for synthesizing ganglioside mimics within the glycan component of its lipooligosaccharide (LOS), which have been implicated in triggering Guillain-Barre syndrome. We now confirm that this pathogen is capable of synthesizing a much broader spectrum of host glycolipid/glycoprotein mimics within its LOS. P blood group and paragloboside (lacto-N-neotetraose) antigen mimicry is exhibited by RM1221, a strain isolated from a poultry source. RM1503, a gastroenteritis-associated strain, expresses lacto-N-biose and sialyl-Lewis c units, the latter known as the pancreatic tumor-associated antigen, DU-PAN-2 (or LSTa). C. jejuni GC149, a Guillain-Barre syndrome-associated strain, expresses an unusual sialic acid-containing hybrid oligosaccharide with similarity to both ganglio and Pk antigens and can, through phase variation of its LOS biosynthesis genes, display GT1a or GD3 ganglioside mimics. We show that the sialyltransferase CstII and the galactosyltransferase CgtD are involved in the synthesis of multiple mimic types, with LOS structural diversity achieved through evolving allelic substrate specificity. PMID- 21257765 TI - Draft genome sequence of a dominant, multidrug-resistant Neisseria gonorrhoeae strain, TCDC-NG08107, from a sexual group at high risk of acquiring human immunodeficiency virus infection and syphilis. AB - Neisseria gonorrhoeae infection is the second major cause of sexually transmitted diseases worldwide. Development of resistance to multiple classes of antimicrobials in N. gonorrhoeae has compromised treatment and disease control. Herein, we report the availability of the draft genome sequence of a multidrug resistant N. gonorrhoeae isolate, TCDC-NG08107, which spread in groups of men who have sex with men (MSM) in Taiwan. PMID- 21257764 TI - Dual transport properties of anion exchanger 1: the same transmembrane segment is involved in anion exchange and in a cation leak. AB - Previous results suggested that specific point mutations in human anion exchanger 1 (AE1) convert the electroneutral anion exchanger into a monovalent cation conductance. In the present study, the transport site for anion exchange and for the cation leak has been studied by cysteine scanning mutagenesis and sulfhydryl reagent chemistry. Moreover, the role of some highly conserved amino acids within members of the SLC4 family to which AE1 belongs has been assessed in AE1 transport properties. The results suggest that the same transport site within the AE1 spanning domain is involved in anion exchange or in cation transport. A functioning mechanism for this transport site is proposed according to transport properties of the different studied point mutations of AE1. PMID- 21257766 TI - Genome sequence of Lactobacillus farciminis KCTC 3681. AB - Lactobacillus farciminis is one of the most prevalent lactic acid bacterial species present during the manufacturing process of kimchi, the best-known traditional Korean dish. Here, we present the draft genome sequence of the type strain Lactobacillus farciminis KCTC 3681 (2,498,309 bp, with a G+C content of 36.4%), which consists of 5 scaffolds. PMID- 21257767 TI - Regulation of catalase-peroxidase KatG is OxyR dependent and Fur independent in Caulobacter crescentus. AB - Most organisms that grow in the presence of oxygen possess catalases and/or peroxidases, which are necessary for scavenging the H(2)O(2) produced by aerobic metabolism. In this work we investigate the pathways that regulate the Caulobacter crescentus katG gene, encoding the only enzyme with catalase peroxidase function in this bacterium. The transcriptional start site of the katG gene was determined, showing a short 5' untranslated region. The katG regulatory region was mapped by serial deletions, and the results indicate that there is a single promoter, which is responsible for induction at stationary phase. An oxyR mutant strain was constructed; it showed decreased katG expression, and no KatG protein or catalase-peroxidase activity was detected in stationary-phase cell extracts, implying that OxyR is the main positive regulator of the C. crescentus katG gene. Purified OxyR protein bound to the katG regulatory region between nucleotides -42 and -91 from the transcription start site, as determined by a DNase I footprinting assay, and a canonical OxyR binding site was found in this region. Moreover, OxyR binding was shown to be redox dependent, given that only oxidized proteins bound adjacent to the -35 sequence of the promoter and the katG P1 promoter was activated by OxyR in an H(2)O(2)-dependent manner. On the other hand, this work showed that the iron-responsive regulator Fur does not regulate C. crescentus katG, since a fur mutant strain presented wild-type levels of katG transcription and catalase-peroxidase production and activity, and the purified Fur protein was not able to bind to the katG regulatory region. PMID- 21257768 TI - Domain analysis of protein P30 in Mycoplasma pneumoniae cytadherence and gliding motility. AB - The cell wall-less prokaryote Mycoplasma pneumoniae causes bronchitis and atypical pneumonia in humans. Mycoplasma attachment and gliding motility are required for colonization of the respiratory epithelium and are mediated largely by a differentiated terminal organelle. P30 is a membrane protein at the distal end of the terminal organelle and is required for cytadherence and gliding motility, but little is known about the functional role of its specific domains. In the current study, domain deletion and substitution derivatives of P30 were engineered and introduced into a P30 null mutant by transposon delivery to assess their ability to rescue P30 function. Domain deletions involving the extracellular region of P30 severely impacted protein stability and adherence and gliding function, as well as the capacity to stabilize terminal organelle protein P65. Amino acid substitutions in the transmembrane domain revealed specific residues uniquely required for P30 stability and function, perhaps to establish correct topography in the membrane for effective alignment with binding partners. Deletions within the predicted cytoplasmic domain did not affect P30 localization or its capacity to stabilize P65 but markedly impaired gliding motility and cytadherence. The larger of two cytoplasmic domain deletions also appeared to remove the P30 signal peptide processing site, suggesting a larger leader peptide than expected. We propose that the P30 cytoplasmic domain may be required to link P30 to the terminal organelle core, to enable the P30 extracellular domain to achieve a functional conformation, or perhaps both. PMID- 21257769 TI - Genome sequence of Paracoccus sp. Strain TRP, a Chlorpyrifos Biodegrader. AB - Paracoccus sp. strain TRP, isolated from activated sludge, could completely biodegrade chlorpyrifos and 3,5,6-trichloro-2-pyridinol. Here we report the draft genome sequence of Paracoccus sp. strain TRP, which could be used to predict genes for xenobiotic biodegradation and metabolism. PMID- 21257770 TI - A selenium-dependent xanthine dehydrogenase triggers biofilm proliferation in Enterococcus faecalis through oxidant production. AB - Selenium has been shown to be present as a labile cofactor in a small class of molybdenum hydroxylase enzymes in several species of clostridia that specialize in the fermentation of purines and pyrimidines. This labile cofactor is poorly understood, yet recent bioinformatic studies have suggested that Enterococcus faecalis could serve as a model system to better understand the way in which this enzyme cofactor is built and the role of these metalloenzymes in the physiology of the organism. An mRNA that encodes a predicted selenium-dependent molybdenum hydroxylase (SDMH) has also been shown to be specifically increased during the transition from planktonic growth to biofilm growth. Based on these studies, we examined whether this organism produces an SDMH and probed whether selenoproteins may play a role in biofilm physiology. We observed a substantial increase in biofilm density upon the addition of uric acid to cells grown in a defined culture medium, but only when molybdate (Mo) and selenite (Se) were also added. We also observed a significant increase in biofilm density in cells cultured in tryptic soy broth with 1% glucose (TSBG) when selenite was added. In-frame deletion of selD, which encodes selenophosphate synthetase, also blocked biofilm formation that occurred upon addition of selenium. Moreover, mutation in the gene encoding the molybdoenzyme (xdh) prevented the induction of biofilm proliferation upon supplementation with selenium. Tungstate or auranofin addition also blocked this enhanced biofilm density, likely through inhibition of molybdenum or selenium cofactor synthesis. A large protein complex labeled with (75)Se is present in higher concentrations in biofilms than in planktonic cells, and the same complex is formed in TSBG. Xanthine dehydrogenase activity correlates with the presence of this labile selenoprotein complex and is absent in a selD or an xdh mutant. Enhanced biofilm density correlates strongly with higher levels of extracellular peroxide, which is produced upon the addition of selenite to TSBG. Peroxide levels are not increased in either the selD or the xdh mutant upon addition of selenite. Extracellular superoxide production, a phenomenon well established to be linked to clinical isolates, is abolished in both mutant strains. Taken together, these data provide evidence that an SDMH is involved in biofilm formation in Enterococcus faecalis, contributing to oxidant production either directly or alternatively through its involvement in redox-dependent processes linked to oxidant production. PMID- 21257771 TI - Enterococcus faecalis virulence regulator FsrA binding to target promoters. AB - The FsrABDC signal transduction system is a major virulence regulator in Enterococcus faecalis. The FsrC sensor histidine kinase, upon activation by the gelatinase biosynthesis-activating pheromone (GBAP) peptide encoded by the fsrBD genes, phosphorylates the FsrA response regulator required for the transcription of the fsrBDC and the gelE-sprE genes from the fsrB promoter and the gelE promoter, respectively. FsrA belongs to the LytTR family of proteins, which includes other virulence regulators, such as AgrA of Staphylococcus aureus, AlgR of Pseudomonas aeruginosa, and VirR of Clostridium perfringens. The LytTR DNA binding domain that characterizes these proteins generally binds to two imperfect direct repeats separated by a number of bases that place the repeats on the same face of the DNA helix. In this study, we demonstrated that FsrA also binds to two imperfect direct repeats separated by 13 bp, based on the consensus sequence of FsrA, T/AT/CAA/GGGAA/G, which is consistent with the binding characteristics of LytTR domains. PMID- 21257772 TI - Participation of chromosome segregation protein ParAI of Vibrio cholerae in chromosome replication. AB - Vibrio cholerae carries homologs of plasmid-borne parA and parB genes on both of its chromosomes. The par genes help to segregate many plasmids and chromosomes. Here we have studied the par genes of V. cholerae chromosome I. Earlier studies suggested that ParBI binds to the centromeric site parSI near the origin of replication (oriI), and parSI-ParBI complexes are placed at the cell poles by ParAI. Deletion of parAI and parSI caused the origin-proximal DNA to be less polar. Here we found that deletion of parBI also resulted in a less polar localization of oriI. However, unlike the deletion of parAI, the deletion of parBI increased the oriI number. Replication was normal when both parAI and parBI were deleted, suggesting that ParBI mediates its action through ParAI. Overexpression of ParAI in a parABI-deleted strain also increased the DNA content. The results are similar to those found for Bacillus subtilis, where ParA (Soj) stimulates replication and this activity is repressed by ParB (SpoOJ). As in B. subtilis, the stimulation of replication most likely involves the replication initiator DnaA. Our results indicate that control of chromosomal DNA replication is an additional function of chromosomal par genes conserved across the Gram-positive/Gram-negative divide. PMID- 21257773 TI - Unusual heme-binding PAS domain from YybT family proteins. AB - YybT family proteins (COG3887) are functionally unknown proteins that are widely distributed among the firmicutes, including the human pathogens Staphylococcus aureus and Listeria monocytogenes. Recent studies suggested that YybT family proteins are crucial for the in vivo survival of bacterial pathogens during host infection. YybT family proteins contain an N-terminal domain that shares minimum sequence homology with Per-ARNT-Sim (PAS) domains. Despite the lack of an apparent residue for heme coordination, the putative PAS domains of BsYybT and GtYybT, two representative members of the YybT family proteins from Bacillus subtilis and Geobacillus thermodenitrificans, respectively, are found to bind b type heme with 1:1 stoichiometry. Heme binding suppresses the catalytic activity of the DHH/DHHA1 phosphodiesterase domain and the degenerate GGDEF domain. Absorption spectroscopic studies indicate that YybT proteins do not form stable oxyferrous complexes due to the rapid oxidation of the ferrous iron upon O(2) binding. The ferrous heme, however, forms a hexacoordinated complex with carbon monoxide (CO) and a pentacoordinated complex with nitric oxide (NO). The coordination of NO, but not CO, to the heme stimulates the phosphodiesterase activity. These results suggest that YybT family proteins function as stress signaling proteins for monitoring cellular heme or the NO level by using a heme binding PAS domain that features an unconventional heme coordination environment. PMID- 21257774 TI - The ColR/ColS two-component system plays multiple roles in the pathogenicity of the citrus canker pathogen Xanthomonas citri subsp. citri. AB - Bacterial citrus canker disease, which is caused by Xanthomonas citri subsp. citri, is one of the most devastating diseases of citrus plants. In this study, we characterized the role of the two-component regulatory system ColR/ColS in the pathogenicity of X. citri subsp. citri. colS mutants (256A10 and 421E7), colR mutants (386C6 and 417E10), and a colR colS double mutant (306DSR) all lost pathogenicity and produced no symptoms on grapefruit leaves inoculated by either pressure infiltration or the spray method. The pathogenicity defect of the colS, colR, and colR colS mutants could be complemented using the wild-type colS, colR, and colR colS genes, respectively. Mutation of colS or colR significantly reduced X. citri subsp. citri growth in planta. The ColR/ColS system also played important roles in bacterial biofilm formation in glass tubes and on leaf surfaces, lipopolysaccharide (LPS) production, catalase activity, and tolerance of environmental stress, including phenol, copper, and hydrogen peroxide. Furthermore, quantitative reverse transcription-PCR assays demonstrated that the ColR/ColS system positively regulated the expression of important virulence genes, including hrpD6, hpaF, the O-antigen LPS synthesis gene rfbC, and the catalase gene katE. Overall, our data indicate that the two-component regulatory system ColR/ColS is critical for X. citri subsp. citri virulence, growth in planta, biofilm formation, catalase activity, LPS production, and resistance to environmental stress. PMID- 21257775 TI - Combinatorial regulation of fmgD by MrpC2 and FruA during Myxococcus xanthus development. AB - Upon starvation, a dense population of rod-shaped Myxococcus xanthus bacteria coordinate their movements to construct mounds in which some of the cells differentiate to spherical spores. During this process of fruiting body formation, short-range C-signaling between cells regulates their movements and the expression of genes important for sporulation. C-signaling activates FruA, a transcription factor that binds cooperatively with another transcription factor, MrpC2, upstream of the fmgA and fmgBC promoters, activating transcription. We have found that a third C-signal-dependent gene, herein named fmgD, is subject to combinatorial control by FruA and MrpC2. The two proteins appear to bind cooperatively upstream of the fmgD promoter and activate transcription. FruA binds proximal to the fmgD promoter, as in the fmgBC promoter region, whereas MrpC2 binds proximal to the fmgA promoter. A novel feature of the fmgD promoter region is the presence of a second MrpC2 binding site partially overlapping the promoter and therefore likely to mediate repression. The downstream MrpC2 site appears to overlap the FruA site, so the two transcription factors may compete for binding, which in both cases appears to be cooperative with MrpC2 at the upstream site. We propose that binding of MrpC2 to the downstream site represses fmgD transcription until C-signaling causes the concentration of active FruA to increase sufficiently to outcompete the downstream MrpC2 for cooperative binding with the upstream MrpC2. This would explain why fmgD transcription begins later during development and is more dependent on C-signaling than transcription of fmgA and fmgBC. PMID- 21257776 TI - Corynebacterium glutamicum as a host for synthesis and export of D-Amino Acids. AB - A number of d-amino acids occur in nature, and there is growing interest in their function and metabolism, as well as in their production and use. Here we use the well-established l-amino-acid-producing bacterium Corynebacterium glutamicum to study whether d-amino acid synthesis is possible and whether mechanisms for the export of these amino acids exist. In contrast to Escherichia coli, C. glutamicum tolerates d-amino acids added extracellularly. Expression of argR (encoding the broad-substrate-specific racemase of Pseudomonas taetrolens) with its signal sequence deleted results in cytosolic localization of ArgR in C. glutamicum. The isolated enzyme has the highest activity with lysine (100%) but also exhibits activity with serine (2%). Upon overexpression of argR in an l-arginine, l ornithine, or l-lysine producer, equimolar mixtures of the d- and l-enantiomers accumulated extracellularly. Unexpectedly, argR overexpression in an l-serine producer resulted in extracellular accumulation of a surplus of d-serine (81 mM d serine and 37 mM l-serine) at intracellular concentrations of 125 mM d-serine plus 125 mM l-serine. This points to a nonlimiting ArgR activity for intracellular serine racemization and to the existence of a specific export carrier for d-serine. Export of d-lysine relies fully on the presence of lysE, encoding the exporter for l-lysine, which is apparently promiscuous with respect to the chirality of lysine. These data show that d-amino acids can also be produced with C. glutamicum and that in special cases, due to specific carriers, even a preferential extracellular accumulation of this enantiomer is possible. PMID- 21257777 TI - The MreB-like protein Mbl of Streptomyces coelicolor A3(2) depends on MreB for proper localization and contributes to spore wall synthesis. AB - Most bacteria with a rod-shaped morphology contain an actin-like cytoskeleton consisting of MreB polymers, which form helical spirals underneath the cytoplasmic membrane to direct peptidoglycan synthesis for the elongation of the cell wall. In contrast, MreB of Streptomyces coelicolor is not required for vegetative growth but has a role in sporulation. Besides MreB, S. coelicolor encodes two further MreB-like proteins, Mbl and SCO6166, whose function is unknown. Whereas MreB and Mbl are highly similar, SCO6166 is shorter, lacking the subdomains IB and IIB of actin-like proteins. Here, we showed that MreB and Mbl are not functionally redundant but cooperate in spore wall synthesis. Expression analysis by semiquantitative reverse transcription-PCR revealed distinct expression patterns. mreB and mbl are induced predominantly during morphological differentiation. In contrast, sco6166 is strongly expressed during vegetative growth but switched off during sporulation. All genes could be deleted without affecting viability. Even a DeltamreB Deltambl double mutant was viable. Deltasco6166 had a wild-type phenotype. DeltamreB, Deltambl, and DeltamreB Deltambl produced swollen, prematurely germinating spores that were sensitive to various kinds of stress, suggesting a defect in spore wall integrity. During aerial mycelium formation, an Mbl-mCherry fusion protein colocalized with an MreB enhanced green fluorescent protein (MreB-eGFP) fusion protein at the sporulation septa. Whereas MreB-eGFP localized properly in the Deltambl mutant, Mbl-mCherry localization depended on the presence of a functional MreB protein. Our results revealed that MreB and Mbl cooperate in the synthesis of the thickened spore wall, while SCO6166 has a nonessential function during vegetative growth. PMID- 21257778 TI - Cholesterol is not an essential source of nutrition for Mycobacterium tuberculosis during infection. AB - Rv1106c (hsd; 3beta-hydroxysteroid dehydrogenase) is required by Mycobacterium tuberculosis for growth on cholesterol as a sole carbon source, whereas Rv3409c is not. Mutation of Rv1106c does not reduce Mycobacterium tuberculosis growth in infected macrophages or guinea pigs. We conclude that cholesterol is not required as a nutritional source during infection. PMID- 21257779 TI - Beta-adrenergic receptor activation rescues theta frequency stimulation-induced LTP deficits in mice expressing C-terminally truncated NMDA receptor GluN2A subunits. AB - Through protein interactions mediated by their cytoplasmic C termini the GluN2A and GluN2B subunits of NMDA receptors (NMDARs) have a key role in the formation of NMDAR signaling complexes at excitatory synapses. Although these signaling complexes are thought to have a crucial role in NMDAR-dependent forms of synaptic plasticity such as long-term potentiation (LTP), the role of the C terminus of GluN2A in coupling NMDARs to LTP enhancing and/or suppressing signaling pathways is unclear. To address this issue we examined the induction of LTP in the hippocampal CA1 region in mice lacking the C terminus of endogenous GluN2A subunits (GluN2ADeltaC/DeltaC). Our results show that truncation of GluN2A subunits produces robust, but highly frequency-dependent, deficits in LTP and a reduction in basal levels of extracellular signal regulated kinase 2 (ERK2) activation and phosphorylation of AMPA receptor GluA1 subunits at a protein kinase A site (serine 845). Consistent with the notion that these signaling deficits contribute to the deficits in LTP in GluN2ADeltaC/DeltaC mice, activating ERK2 and increasing GluA1 S845 phosphorylation through activation of beta-adrenergic receptors rescued the induction of LTP in these mutants. Together, our results indicate that the capacity of excitatory synapses to undergo plasticity in response to different patterns of activity is dependent on the coupling of specific signaling pathways to the intracellular domains of the NMDARs and that abnormal plasticity resulting from mutations in NMDARs can be reduced by activation of key neuromodulatory transmitter receptors that engage converging signaling pathways. PMID- 21257781 TI - Effects of diet type and metabolizable energy intake on tympanic temperature of steers fed during summer and winter seasons. AB - A summer study and a winter study were conducted using an incomplete factorial structure in a complete randomized design. Within season, the factors studied were 1) type of diet, which included 2 levels of ME, classified as either concentrate (3.04 Mcal of ME/kg) or roughage (2.63 Mcal of ME/kg) diets, and 2) daily ME intakes (MEI) of 11, 18, and 25 Mcal of ME/d for the roughage diets and 18, 25, and 32 Mcal of ME/d for the concentrate diets. In Exp. 1 (summer study), 30 steers (5 steers/treatment combination) were used to collect tympanic temperatures (TT). In Exp. 2 (winter study), 24 steers (4 steers/treatment combination) were used to collect TT. Mean TT was 0.3 degrees C greater for summer than winter (38.9 vs. 38.6 degrees C, respectively; P < 0.05). Steers fed diets based on concentrate tended to display greater TT than steers fed diets based on roughage. Season * diet * hour interactions were found for TT (P = 0.01). In the winter, greater TT (P < 0.05) were found from 0900 to 1400 h when an equal amount of MEI was derived from a concentrate-based vs. roughage-based diet. In cattle fed roughage-based diets during the summer, TT = 38.63 + 0.0114*MEI, whereas for cattle fed concentrate-based diets, TT = 38.69 + 0.0114*MEI. During the winter, for cattle fed a roughage-based diet, TT = 37.65 + 0.0856*MEI - 0.0018*MEI(2), whereas for cattle fed a concentrate-based diet, TT = 35.37 + 0.2635*MEI - 0.0051*MEI(2). In summary, results demonstrate that increases in the energy of the diet resulted in increases in TT. However, the response was dependent on season of the year, with a linear response in TT for summer and a quadratic response during winter. PMID- 21257782 TI - Usefulness of molecular-based methods for estimating effective population size in livestock assessed using data from the endangered black-coated Asturcon pony. AB - Empirical evidence of the usefulness of different molecular-based methods to estimate the effective population size (N(e)) for conservation purposes in endangered livestock populations is reported. The black-coated Asturcon pony pedigree (1,981 individuals) was available. Additionally, a total of 267 Asturcon individuals born in 1998, 2002, and 2008 were typed for 15 microsatellites. These yearly cohorts (cohort(1998, 2002, 2008)) included almost all individuals kept for reproduction at the end of the corresponding foaling season. The genealogical realized N(e) was estimated for each cohort by using the individual increase in inbreeding. Molecular N(e) was computed by using 1) linkage disequilibrium [N(e)(()(D)())], 2) a temporal method based on F-statistics [N(e)(()(T)())], 3) an unbiased temporal method [N(e)(()(JR)())], and 4) a Bayesian temporal method [N(e)(()(B)())]. Estimates of increased from cohort(1998) (18.8 +/- 5.1) to cohort(2008) (24.9 +/- 5.2), illustrating the history of the population and its breeding policy of avoiding matings between close relatives. The estimates of N(e)(()(D)()) were highly biased upward, with the maximum N(e)(()(D)()) value obtained for cohort(2002) (137.0). The estimates of N(e)(()(T)()), N(e)(()(JR)()), and N(e)(()(B)()) showed similar performance. However, N(e)(()(JR)()) estimates were very consistent across cohorts, varying from 14.9 to 15.5 after correcting for the effect of overlapping generations. When the drift signal was not strong (pair cohort(1998)-cohort(2002)), estimates of N(e)(()(T)()) and N(e)(()(B)()) were not realistic. Estimates of N(e)(()(B)()) tended to be biased downward (being 9.0 or below for the sampling pairs including cohort(2008)). Results of N(e)(()(D)()) are more likely to be estimates of the effective number of breeders producing the sample, rather than the effective size for a generation. The temporal methods were strongly affected by a weak drift signal, particularly when samplings were not spaced a sufficient number of generations or a sufficient time apart. The use of molecular-based estimates of N(e) is not straightforward, and their use in livestock conservation programs should be carried out with caution. Sampling strategies (including sampling sizes, sampling periods, and the age structure of the sampled individuals) must be carefully planned to ensure that robust estimates of N(e) are obtained. PMID- 21257780 TI - Coup d'Etat: an orphan takes control. AB - Chicken ovalbumin upstream promoter transcription factors (COUP-TFs) belong to the steroid/thyroid hormone receptor superfamily. Cloning of their cDNAs demonstrated the existence of two distinct but related genes: COUP-TFI (EAR-3, NR2F1) and COUP-TFII (ARP-1, NR2F2). They are referred to as orphan receptors because ligands for COUP-TFs have yet to be identified. Since 1998, extensive studies have demonstrated their physiological importance in cell-fate specification, organogenesis, angiogenesis, and metabolism, as well as a variety of diseases. In this article, we will comprehensively review the biological functions of COUP-TFII and its underlying mechanism in various developmental processes and diseases. In addition, we will briefly summarize some of the current findings of COUP-TFI. PMID- 21257783 TI - Lactulose as a marker of intestinal barrier function in pigs after weaning. AB - Intestinal barrier function in pigs after weaning is almost exclusively determined in terminal experiments with Ussing chambers. Alternatively, the recovery in urine of orally administered lactulose can be used to assess intestinal permeability in living animals. This experiment was designed to study the barrier function of the small intestine of pigs over time after weaning. The aim was to relate paracellular barrier function (measured by lactulose recovery in the urine) with macromolecular transport [measured by horseradish peroxidase (HRP) using Ussing chambers] and bacterial translocation to assess whether lactulose recovery is related to possible causes of infection and disease. Forty gonadectomized male pigs (6.7 +/- 0.6 kg) were weaned (d 0) at a mean age of 19 d, fitted with urine collection bags, and individually housed. Pigs were dosed by oral gavage with a marker solution containing lactulose (disaccharide) and the monosaccharides l-rhamnose, 3-O-methylglucose, and d-xylose at 2 h and at 4, 8, and 12 d after weaning. The recovery of sugars in the urine was determined over 18 h after each oral gavage. The day after each permeability test, the intestines of 10 pigs were dissected to determine bacterial translocation to the mesenteric lymph nodes and jejunal permeability for HRP in Ussing chambers. Recovery of l rhamnose in urine was affected by feed intake and by the time after weaning (P <= 0.05). Recovery of lactulose from the urine was greater (P <= 0.05) at 4, 8, and 12 d after weaning compared with the first day after weaning and was negatively correlated with feed intake (r = -0.63, P <= 0.001). The mean translocation of aerobic bacteria to the mesenteric lymph nodes was greater at 5 and 13 d after weaning compared with d 1 (P <= 0.05). Lactulose recovery showed no correlation with permeability for HRP nor with bacterial translocation (P > 0.05). Although both lactulose recovery and bacterial translocation increased over time after weaning, lactulose recovery did not correlate with the permeability for HRP nor bacterial translocation within a pig (P > 0.05). Therefore, we conclude that lactulose recovery in the urine of pigs after weaning is not associated with risk factors for infections. However, it appears to be possible to measure paracellular barrier function with orally administered lactulose in pigs shortly after weaning. Further studies will reveal whether this variable is relevant for the long-term performance or health of pigs after weaning. PMID- 21257784 TI - Effects of tryptophan supplementation on aggression among group-housed gestating sows. AB - The objective of this study was to determine the effects of dietary Trp supplementation on mixing-induced aggression and the associated stress, and on reproductive performance in gestating sows. After weaning, sows were mixed in pens with electronic sow feeders on concrete-slatted floors. Each pen housed 21 +/- 2.8 sows, with approximately 2.7 +/- 0.43 m(2)/sow of floor space allowance. Multiparous sows (n = 168) from 8 breeding groups were used, with 4 groups assigned to a control diet and 4 groups assigned to a high-Trp diet. Control sows received corn- and soybean meal-based diets throughout gestation (0.15% Trp) and lactation (0.21% Trp). Three days before and after mixing, sows assigned to the high-Trp treatment received approximately 2.3 times the dietary Trp (0.35% in the gestation diet and 0.48% in the lactation diet) fed to control sows. Six focal sows (2 sows from each of parity 1, 2, and 3 or greater) in each pen were designated and videotaped for 72 h after mixing to determine the type and number of aggressive interactions among sows. Before and 48 h after mixing, saliva samples were collected from focal sows, and scratches were assessed on all sows. Data were analyzed using the FREQ and GLIMMIX procedures (SAS Inst. Inc., Cary, NC). Aggression among sows was intense during the initial 6 h and decreased between 6 and 72 h after mixing. The initial aggression caused scratches and increased cortisol concentrations (P < 0.05). Mature sows tended to fight for longer periods (112 vs. 52 s/h per sow, SE = 23.8; P < 0.10) but had fewer scratches caused by aggression (injury score = 4.3 vs. 6.5, SE = 1.13; P < 0.01) than parity-1 sows. Supplementation of dietary Trp reduced the total duration of head-to-head knocking (P < 0.05) but did not affect other aggressive behaviors. There was no difference between dietary treatments in injury scores or saliva cortisol concentrations. Sows in the high-Trp treatment had more total piglets born (12.5 vs. 10.5 pigs/litter, SE = 0.55; P < 0.05) and more stillborn piglets (1.5 vs. 0.8 pigs/litter, SE = 0.20; P < 0.05), but had no significant change (P = 0.12) in piglets born alive (10.8 vs. 9.7 pigs/litter, SE = 0.42) compared with control sows. The results indicate that the initial aggression after mixing caused more injuries in young sows than in mature sows. Supplementation of dietary Trp at 2.3 times the control amount for a short period did not effectively reduce aggression and the associated stress in sows at mixing. PMID- 21257785 TI - Amino acid digestibility and energy content of deoiled (solvent-extracted) corn distillers dried grains with solubles for swine and effects on growth performance and carcass characteristics. AB - A study with 3 experiments was conducted to determine the AA digestibility and energy concentration of deoiled (solvent-extracted) corn distillers dried grains with solubles (dDGS) and to evaluate its effect on nursery pig growth performance, finishing pig growth performance, and carcass traits. In Exp. 1, a total of 5 growing barrows (initial BW = 30.8 kg) were fitted with a T-cannula in the distal ileum and allotted to 1 of 2 treatments: 1) a diet with dDGS as the sole protein source, or 2) a N-free diet for determining basal endogenous AA losses in a crossover design at 68.0 kg of BW. Apparent and standardized (SID) ileal digestibility of AA and energy concentration of dDGS were determined. In Exp. 2, a total of 210 pigs (initial BW = 9.9 kg) were used in a 28-d experiment to evaluate the effect of dDGS on nursery pig performance. Pigs were allotted to 5 dietary treatments (0, 5, 10, 20, or 30% dDGS) formulated to contain equal ME (increased added fat with increasing dDGS) and SID Lys concentrations based on the values obtained from Exp. 1. In Exp. 3, a total of 1,215 pigs (initial BW = 29.6 kg) were used in a 99-d experiment to determine the effect of dDGS on growth and carcass characteristics of finishing pigs. Pigs were allotted to dietary treatments similar to those used in Exp. 2 and were fed in 4 phases. The analyzed chemical composition of dDGS in Exp. 1 was 35.6% CP, 5.29% ash, 4.6% fat, 18.4% ADF, and 39.5% NDF on a DM basis. Apparent ileal digestibility values of Lys, Met, and Thr in dDGS were 47.2, 79.4, and 64.1%, respectively, and SID values were 50.4, 80.4, and 68.9%, respectively. The determined GE and DE and the calculated ME and NE values of dDGS were 5,098, 3,100, 2,858, and 2,045 kcal/kg of DM, respectively. In Exp. 2, nursery pig ADG, ADFI, and G:F were similar among treatments. In Exp. 3, increasing dDGS reduced (linear; P < 0.01) ADG and ADFI but tended to improve (linear; P = 0.07) G:F. Carcass weight and yield were reduced (linear; P < 0.01), loin depth tended to decrease (linear; P = 0.09), and carcass fat iodine values increased (linear; P < 0.01) as dDGS increased. No difference was observed in backfat, percentage of lean, or fat-free lean index among treatments. In conclusion, dDGS had greater CP and AA but less energy content than traditional distillers dried grains with solubles. In addition, when dietary fat was added to diets to offset the reduced ME content, feeding up to 30% dDGS did not affect the growth performance of nursery pigs but did negatively affect the ADG, ADFI, and carcass fat quality of finishing pigs. PMID- 21257786 TI - Behavioral and structural differences in migrating peripheral neutrophils from patients with chronic obstructive pulmonary disease. AB - RATIONALE: There are increased neutrophils in the lungs of patients with chronic obstructive pulmonary disease (COPD), but it is unclear if this is due to increased inflammatory signal or related to the inherent behavior of the neutrophils. This is critical, because inaccurate or excessive neutrophil chemotaxis could drive pathological accumulation and tissue damage. OBJECTIVES: To assess migratory dynamics of neutrophils isolated from patients with COPD compared with healthy smoking and nonsmoking control subjects and patients with alpha(1)-antitryspin deficiency. METHODS: Migratory dynamics and structure were assessed in circulating neutrophils, using phase and differential interference contrast microscopy and time-lapse photography. The effect of COPD severity was studied. Surface expression of receptors was measured using flow cytometry. The in vitro effects of a phosphoinositide 3-kinase inhibitor (LY294002) were studied. MEASUREMENTS AND MAIN RESULTS: COPD neutrophils moved with greater speed than cells from either control group but with reduced migratory accuracy, in the presence of IL-8, growth-related oncogene alpha, formyl-methionyl-leucyl phenylalanine, and sputum. This was present across all stages of COPD. Structurally, COPD neutrophils formed fewer pseudopods during migration. There were no differences in surface expression of the receptors CXCR1, CXCR2, or FPR1. LY294002 reduced COPD neutrophil migratory speed while increasing chemotactic accuracy, returning values to normal. The inhibitor did not have these effects in healthy control subjects or patients with a similar degree of lung disease. CONCLUSIONS: COPD neutrophils are intrinsically different than cells from other studied populations in their chemotactic behavior and migratory structure. Differences are not due to surface expression of chemoattractant receptors but instead appear to be due to differences in cell signaling. PMID- 21257787 TI - An air filter intervention study of endothelial function among healthy adults in a woodsmoke-impacted community. AB - RATIONALE: Particulate air pollution is associated with cardiovascular morbidity. One hypothesized mechanism involves oxidative stress, systemic inflammation, and endothelial dysfunction. OBJECTIVES: To assess an intervention's impact on particle exposures and endothelial function among healthy adults in a woodsmoke impacted community. We also investigated the underlying role of oxidative stress and inflammation in relation to exposure reductions. METHODS: Portable air filters were used in a randomized crossover intervention study of 45 healthy adults exposed to consecutive 7-day periods of filtered and nonfiltered air. MEASUREMENTS AND MAIN RESULTS: Reactive hyperemia index was measured as an indicator of endothelial function via peripheral artery tonometry, and markers of inflammation (C-reactive protein, interleukin-6, and band cells) and lipid peroxidation (malondialdehyde and 8-iso-prostaglandin F(2alpha)) were quantified. Air filters reduced indoor fine particle concentrations by 60%. Filtration was associated with a 9.4% (95% confidence interval, 0.9-18%) increase in reactive hyperemia index and a 32.6% (4.4-60.9%) decrease in C-reactive protein. Decreases in particulate matter and the woodsmoke tracer levoglucosan were associated with reduced band cell counts. There was limited evidence of more pronounced effects on endothelial function and level of systemic inflammation among males, overweight participants, younger participants, and residents of wood-burning homes. No associations were noted for oxidative stress markers. CONCLUSIONS: Air filtration was associated with improved endothelial function and decreased concentrations of inflammatory biomarkers but not markers of oxidative stress. Our results support the hypothesis that systemic inflammation and impaired endothelial function, both predictors of cardiovascular morbidity, can be favorably influenced by reducing indoor particle concentrations. PMID- 21257788 TI - From intensive care to critical care medicine: a historical perspective. AB - The evolution of Critical Care Medicine is traced in relationship to its predecessors, namely Intensive Care and Intensive Therapy. This commentary documents the initial physical care rendered by professional nurses in hospitals of the 19th century in locations close to the nursing stations. The development of incubators for newborns and life-support devices to support ventilation and renal function or to reverse fatal arrhythmias characterized Intensive Therapy of the early 20th century. In the most recent 50 years, Critical Care evolved for comprehensive, largely electronic monitoring and automated laboratory measurements to guide intensive therapy of multiorgan failures by critical care physicians and nurse specialists, pharmacists, and respiratory therapists using multiple life-support methodologies and devices. PMID- 21257789 TI - Excess ventilation during exercise and prognosis in chronic heart failure. AB - Excess ventilation during exercise with accompanying dyspnea is characteristic of chronic heart failure (CHF), and these patients often exhibit increased Ve relative to the Vco(2) compared with normal subjects. This can be measured in several ways, including using such variables as the slope of Ve versus Vco(2), the lowest ratio of Ve/Vco(2), and the ratio of Ve/Vco(2) at the lactic acidosis threshold or peak exercise. There is now considerable evidence that the degree of excess ventilation during exercise in patients with CHF is a robust predictor of outcome and identifies higher-risk patients requiring aggressive treatment, including heart transplantation. The mechanism of excess ventilation in patients with CHF during exercise is not completely understood. It may be related to enhanced output of chemoreceptors or peripheral muscle ergoreceptors, increased dead space/Vt ratio due to increased contribution of high ventilation-perfusion lung regions or rapid shallow breathing caused by earlier onset of lactic acidosis, or likely resulting from a combination of these causes. PMID- 21257790 TI - ANGPT2 genetic variant is associated with trauma-associated acute lung injury and altered plasma angiopoietin-2 isoform ratio. AB - RATIONALE: Acute lung injury (ALI) acts as a complex genetic trait, yet its genetic risk factors remain incompletely understood. Large-scale genotyping has not previously been reported for ALI. OBJECTIVES: To identify ALI risk variants after major trauma using a large-scale candidate gene approach. METHODS: We performed a two-stage genetic association study. We derived findings in an African American cohort (n = 222) using a cardiopulmonary disease-centric 50K single nucleotide polymorphism (SNP) array. Genotype and haplotype distributions were compared between subjects with ALI and without ALI, with adjustment for clinical factors. Top performing SNPs (P < 10(-4)) were tested in a multicenter European American trauma-associated ALI case-control population (n = 600 ALI; n = 2,266 population-based control subjects) for replication. The ALI-associated genomic region was sequenced, analyzed for in silico prediction of function, and plasma was assayed by ELISA and immunoblot. MEASUREMENTS AND MAIN RESULTS: Five SNPs demonstrated a significant association with ALI after adjustment for covariates in Stage I. Two SNPs in ANGPT2 (rs1868554 and rs2442598) replicated their significant association with ALI in Stage II. rs1868554 was robust to multiple comparison correction: odds ratio 1.22 (1.06-1.40), P = 0.0047. Resequencing identified predicted novel splice sites in linkage disequilibrium with rs1868554, and immunoblots showed higher proportion of variant angiopoietin 2 (ANG2) isoform associated with rs1868554T (0.81 vs. 0.48; P = 0.038). CONCLUSIONS: An ANGPT2 region is associated with both ALI and variation in plasma angiopoietin-2 isoforms. Characterization of the variant isoform and its genetic regulation may yield important insights about ALI pathogenesis and susceptibility. PMID- 21257791 TI - Lung regional metabolic activity and gas volume changes induced by tidal ventilation in patients with acute lung injury. AB - RATIONALE: During acute lung injury (ALI), mechanical ventilation can aggravate inflammation by promoting alveolar distension and cyclic recruitment derecruitment. As an estimate of the intensity of inflammation, metabolic activity can be measured by positron emission tomography imaging of [(18)F]fluoro 2-deoxy-D-glucose. OBJECTIVES: To assess the relationship between gas volume changes induced by tidal ventilation and pulmonary metabolic activity in patients with ALI. METHODS: In 13 mechanically ventilated patients with ALI and relatively high positive end-expiratory pressure, we performed a positron emission tomography scan of the chest and three computed tomography scans: at mean airway pressure, end-expiration, and end-inspiration. Metabolic activity was measured from the [(18)F]fluoro-2-deoxy-D-glucose uptake rate. The computed tomography scans were used to classify lung regions as derecruited throughout the respiratory cycle, undergoing recruitment-derecruitment, and normally aerated. MEASUREMENTS AND MAIN RESULTS: Metabolic activity of normally aerated lung was positively correlated both with plateau pressure, showing a pronounced increase above 26 to 27 cm H(2)O, and with regional Vt normalized by end-expiratory lung gas volume. This relationship did not appear to be caused by a higher underlying parenchymal metabolic activity in patients with higher plateau pressure. Regions undergoing cyclic recruitment-derecruitment did not have higher metabolic activity than those collapsed throughout the respiratory cycle. CONCLUSIONS: In patients with ALI managed with relatively high end-expiratory pressure, metabolic activity of aerated regions was associated with both plateau pressure and regional Vt normalized by end-expiratory lung gas volume, whereas no association was found between cyclic recruitment-derecruitment and increased metabolic activity. PMID- 21257792 TI - The Arabidopsis mutant jason produces unreduced first division restitution male gametes through a parallel/fused spindle mechanism in meiosis II. AB - In plants, whole-genome doubling (polyploidization) is a widely occurring process largely contributing to plant evolution and diversification. The generation and fusion of diploid gametes is now considered the major route of plant polyploidization. The parallel arrangement or fusion of meiosis II MII spindles (ps) is one of the most frequently reported mechanisms generating triploid offspring. Through a forward genetics screen of an Arabidopsis (Arabidopsis thaliana) ethyl methanesulfonate population, we identified Arabidopsis thaliana Parallel Spindles1 (AtPS1), which was recently reported as a major gene implicated in the control of the ps meiotic defect. In addition, we describe the isolation and characterization of a novel allele of JASON, involved in male gametophytic ploidy regulation in plants. Similar to atps1 mutants, jason produces more than 25% 2n pollen grains and spontaneously forms triploid offspring. By combining both cytological and genetic approaches, we demonstrate that loss of JASON causes the formation of parallel arranged and fused spindles in male MII, resulting in the production of unreduced first division restitution 2n spores. Although JASON encodes a protein of unknown function, we additionally show that the meiotic ps defect in jason is caused by a reduction in AtPS1 transcript levels, indicating that JASON positively regulates AtPS1 expression, allowing the proper organization and orientation of metaphase II spindle plates in MII. PMID- 21257793 TI - A novel sterol desaturase-like protein promoting dealkylation of phytosterols in Tetrahymena thermophila. AB - The gene TTHERM_00438800 (DES24) from the ciliate Tetrahymena thermophila encodes a protein with three conserved histidine clusters, typical of the fatty acid hydroxylase superfamily. Despite its high similarity to sterol desaturase-like enzymes, the phylogenetic analysis groups Des24p in a separate cluster more related to bacterial than to eukaryotic proteins, suggesting a possible horizontal gene transfer event. A somatic knockout of DES24 revealed that the gene encodes a protein, Des24p, which is involved in the dealkylation of phytosterols. Knocked-out mutants were unable to eliminate the C-24 ethyl group from C(29) sterols, whereas the ability to introduce other modifications, such as desaturations at positions C-5(6), C-7(8), and C-22(23), were not altered. Although C-24 dealkylations have been described in other organisms, such as insects, neither the enzymes nor the corresponding genes have been identified to date. Therefore, this is the first identification of a gene involved in sterol dealkylation. Moreover, the knockout mutant and wild-type strain differed significantly in growth and morphology only when cultivated with C(29) sterols; under this culture condition, a change from the typical pear-like shape to a round shape and an alteration in the regulation of tetrahymanol biosynthesis were observed. Sterol analysis upon culture with various substrates and inhibitors indicate that the removal of the C-24 ethyl group in Tetrahymena may proceed by a mechanism different from the one currently known. PMID- 21257794 TI - Functional study of genes essential for autogamy and nuclear reorganization in Paramecium. AB - Like all ciliates, Paramecium tetraurelia is a unicellular eukaryote that harbors two kinds of nuclei within its cytoplasm. At each sexual cycle, a new somatic macronucleus (MAC) develops from the germ line micronucleus (MIC) through a sequence of complex events, which includes meiosis, karyogamy, and assembly of the MAC genome from MIC sequences. The latter process involves developmentally programmed genome rearrangements controlled by noncoding RNAs and a specialized RNA interference machinery. We describe our first attempts to identify genes and biological processes that contribute to the progression of the sexual cycle. Given the high percentage of unknown genes annotated in the P. tetraurelia genome, we applied a global strategy to monitor gene expression profiles during autogamy, a self-fertilization process. We focused this pilot study on the genes carried by the largest somatic chromosome and designed dedicated DNA arrays covering 484 genes from this chromosome (1.2% of all genes annotated in the genome). Transcriptome analysis revealed four major patterns of gene expression, including two successive waves of gene induction. Functional analysis of 15 upregulated genes revealed four that are essential for vegetative growth, one of which is involved in the maintenance of MAC integrity and another in cell division or membrane trafficking. Two additional genes, encoding a MIC-specific protein and a putative RNA helicase localizing to the old and then to the new MAC, are specifically required during sexual processes. Our work provides a proof of principle that genes essential for meiosis and nuclear reorganization can be uncovered following genome-wide transcriptome analysis. PMID- 21257796 TI - A second mitochondrial DNA primase is essential for cell growth and kinetoplast minicircle DNA replication in Trypanosoma brucei. AB - The mitochondrial DNA of trypanosomes contains two types of circular DNAs, minicircles and maxicircles. Both minicircles and maxicircles replicate from specific replication origins by unidirectional theta-type intermediates. Initiation of the minicircle leading strand and also that of at least the first Okazaki fragment involve RNA priming. The Trypanosoma brucei genome encodes two mitochondrial DNA primases, PRI1 and PRI2, related to the primases of eukaryotic nucleocytoplasmic large DNA viruses. These primases are members of the archeoeukaryotic primase superfamily, and each of them contain an RNA recognition motif and a PriCT-2 motif. In Leishmania species, PRI2 proteins are approximately 61 to 66 kDa in size, whereas in Trypanosoma species, PRI2 proteins have additional long amino-terminal extensions. RNA interference (RNAi) of T. brucei PRI2 resulted in the loss of kinetoplast DNA and accumulation of covalently closed free minicircles. Recombinant PRI2 lacking this extension (PRI2DeltaNT) primes poly(dA) synthesis on a poly(dT) template in an ATP-dependent manner. Mutation of two conserved aspartate residues (PRI2DeltaNTCS) resulted in loss of enzymatic activity but not loss of DNA binding. We propose that PRI2 is directly involved in initiating kinetoplast minicircle replication. PMID- 21257797 TI - Standardized visual predictive check versus visual predictive check for model evaluation. AB - The visual predictive check (VPC) is a commonly used approach in model evaluation. However, it may not be feasible to conduct a VPC, or the results of a VPC could be misleading in certain situations. The objectives of the present study were to (1) examine the performance and applicability of the VPC and (2) propose the standardized visual predictive check (SVPC) as an alternative/complementary approach to the VPC. The difference between the SVPC and normalized prediction distribution error (npde) as visual tools for model evaluation is also discussed. The results of the simulation studies demonstrate that the VPC is not appropriate when stratification of covariate(s) in a model is difficult or arbitrary and may not be feasible when study design varies during a study/among participants. The SVPC addresses these issues by displaying the percentiles (P(i,j)) of each participant's observations in the marginal distribution of the corresponding model-simulated endpoints as a function of time (or any covariate of interest) based on that participant's own design template. Since the calculation of P(i,j) factors out subject-specific design features, the difference between observation and simulated values is only caused by misspecification of the structure model and/or inadequate estimation of random effect. Thus, the SVPC can be used in any situation. PMID- 21257795 TI - G1/S transcription factor orthologues Swi4p and Swi6p are important but not essential for cell proliferation and influence hyphal development in the fungal pathogen Candida albicans. AB - The G(1)/S transition is a critical control point for cell proliferation and involves essential transcription complexes termed SBF and MBF in Saccharomyces cerevisiae or MBF in Schizosaccharomyces pombe. In the fungal pathogen Candida albicans, G(1)/S regulation is not clear. To gain more insight into the G(1)/S circuitry, we characterized Swi6p, Swi4p and Mbp1p, the closest orthologues of SBF (Swi6p and Swi4p) and MBF (Swi6p and Mbp1p) components in S. cerevisiae. The mbp1Delta/Delta cells showed minor growth defects, whereas swi4Delta/Delta and swi6Delta/Delta yeast cells dramatically increased in size, suggesting a G(1) phase delay. Gene set enrichment analysis (GSEA) of transcription profiles revealed that genes associated with G(1)/S phase were significantly enriched in cells lacking Swi4p and Swi6p. These expression patterns suggested that Swi4p and Swi6p have repressing as well as activating activity. Intriguingly, swi4Delta/Delta swi6Delta/Delta and swi4Delta/Delta mbp1Delta/Delta strains were viable, in contrast to the situation in S. cerevisiae, and showed pleiotropic phenotypes that included multibudded yeast, pseudohyphae, and intriguingly, true hyphae. Consistently, GSEA identified strong enrichment of genes that are normally modulated during C. albicans-host cell interactions. Since Swi4p and Swi6p influence G(1) phase progression and SBF binding sites are lacking in the C. albicans genome, these factors may contribute to MBF activity. Overall, the data suggest that the putative G(1)/S regulatory machinery of C. albicans contains novel features and underscore the existence of a relationship between G(1) phase and morphogenetic switching, including hyphal development, in the pathogen. PMID- 21257798 TI - The pharmacokinetics, pharmacodynamics, and safety of orally dosed INCB018424 phosphate in healthy volunteers. AB - INCB018424 phosphate, a potent inhibitor of JAK enzymes with selectivity for JAK1&2, is in development for the treatment of myelofibrosis (MF). The oral dose pharmacokinetics, pharmacodynamics, safety, and tolerability of INCB018424 were evaluated in healthy volunteers in 2 double-blind, randomized, and placebo controlled studies. The first study evaluated single ascending doses of 5 to 200 mg INCB018424 and the effect of food, whereas the second study evaluated multiple ascending doses, including both once- and twice-daily dosing for 10 days. As a Biopharma-ceutical Classification System class I drug, INCB018424 exhibited good oral bioavailability and dose-proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3 hour plasma half-life and insignificant accumulation following repeat dosing. A high-fat meal reduced INCB018424 C(max) by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. INCB018424 was generally safe and well tolerated, with 25 mg bid and 100 mg qd established as the maximum tolerated doses in healthy volunteers. PMID- 21257799 TI - Absence of pharmacokinetic interaction between roflumilast and digoxin in healthy adults. AB - Numerous interactions are known for digoxin, which is a drug with a narrow therapeutic index and a substrate of P-glycoprotein (P-gp). This study investigated potential effects of coadministration on pharmacokinetics and safety of both drugs when a single dose of digoxin was concomitantly administered with roflumilast under steady-state conditions. Sixteen healthy male and female adults were randomly assigned in an open-label, crossover study to either of 2 treatment sequences that consisted of 2 treatment periods separated by a washout phase. Treatments were oral daily doses of roflumilast for 14 days given concomitantly on days 1 and 14 with a single oral dose of digoxin or an oral dose of digoxin once on day 1. Plasma samples for pharmacokinetic evaluations of digoxin and roflumilast concentrations with and without concomitant treatment were taken. The rate of digoxin absorption was slightly (15%) but statistically insignificantly increased, whereas the extent of absorption was not altered by concomitant medication with roflumilast. Concomitant medication with digoxin did not significantly affect steady-state pharmacokinetics of either roflumilast or its active metabolite roflumilast N-oxide. Roflumilast is not an inhibitor of P-gp. No safety or tolerability concerns were detected with coadministration of roflumilast and digoxin. PMID- 21257800 TI - Comparative bioavailability of a premixed, ready-to-use formulation of intravenous amiodarone with traditional admixture in healthy subjects. AB - Intravenous amiodarone is an effective agent for the treatment of recurrent ventricular fibrillation and hemodynamically unstable ventricular tachycardia. PM101 Premixed Injection is a new formulation of intravenous amiodarone that uses a cyclodextrin to maintain amiodarone in the aqueous phase. Eighty-eight subjects were enrolled in this randomized, single-blind, crossover, bioequivalence clinical study and were treated with single doses (150 mg) of PM101 Premixed Injection and intravenous amiodarone separated by a washout period of at least 42 days. Venous blood samples were taken periodically during the first 72 hours after dosing to determine standard pharmacokinetic parameters. The geometric ratio of the area under the concentration-time curve for time 0-72 hours (AUC0 72hr ) for amiodarone was 0.96 (95% confidence interval [CI], 0.94-0.99). The geometric ratio of the maximum concentration (Cmax ) for amiodarone was 0.87 (95% CI, 0.84-0.91). Because these ratios and their CI fell between the limits of 0.8 and 1.25, bioequivalence of these 2 formulations was established. No safety concerns unique to the PM101 Premixed Injection, ready-to-use formulation were identified. PMID- 21257801 TI - Human intravenous immunoglobulin-induced aseptic meningitis: a case report. PMID- 21257802 TI - A review of psychophysiological stressors on pharmacokinetics. AB - We conducted a comprehensive literature review on the effects of psychophysiological stressors on the pharmacokinetics of drugs commonly used by the Canadian Forces. These stressors may change the physiological status of an individual and subsequently may alter the drug's pharmacokinetics. The effects of isolated physical activities on pharmacokinetics have been well documented. However, the findings are inconsistent due to variations in the intensity and duration of the activity, and the routes and timing of drug administration. The effects of other environmental stressors, such as temperature extremes, hypobaric, hyperbaric, hyperoxic conditions, and the effects of multiple stressors are less well known. There are limited studies describing the effects of psychological stressors on drug pharmacokinetics. Further studies are necessary to understand the clinical implications of pharmacokinetic changes. We also discussed the advantage of using a physiologically based pharmacokinetic model to predict the effects of a single or multiple stressors. PMID- 21257803 TI - Prevalence and genetic diversity of Aichi viruses in wastewater and river water in Japan. AB - Aichi virus (AiV) genomes were detected in 12 (100%) influent and 11 (92%) effluent wastewater and 36 (60%) river water samples. Among 260 strains identified, 255 were genotype A and 5 were genotype B. This is the first report describing the molecular characterization of AiVs in aquatic environments in Japan. PMID- 21257804 TI - Microarray analysis and barcoded pyrosequencing provide consistent microbial profiles depending on the source of human intestinal samples. AB - Large-scale and in-depth characterization of the intestinal microbiota necessitates application of high-throughput 16S rRNA gene-based technologies, such as barcoded pyrosequencing and phylogenetic microarray analysis. In this study, the two techniques were compared and contrasted for analysis of the bacterial composition in three fecal and three small intestinal samples from human individuals. As PCR remains a crucial step in sample preparation for both techniques, different forward primers were used for amplification to assess their impact on microbial profiling results. An average of 7,944 pyrosequences, spanning the V1 and V2 region of 16S rRNA genes, was obtained per sample. Although primer choice in barcoded pyrosequencing did not affect species richness and diversity estimates, detection of Actinobacteria strongly depended on the selected primer. Microbial profiles obtained by pyrosequencing and phylogenetic microarray analysis (HITChip) correlated strongly for fecal and ileal lumen samples but were less concordant for ileostomy effluent. Quantitative PCR was employed to investigate the deviations in profiling between pyrosequencing and HITChip analysis. Since cloning and sequencing of random 16S rRNA genes from ileostomy effluent confirmed the presence of novel intestinal phylotypes detected by pyrosequencing, especially those belonging to the Veillonella group, the divergence between pyrosequencing and the HITChip is likely due to the relatively low number of available 16S rRNA gene sequences of small intestinal origin in the DNA databases that were used for HITChip probe design. Overall, this study demonstrated that equivalent biological conclusions are obtained by high throughput profiling of microbial communities, independent of technology or primer choice. PMID- 21257805 TI - Naringenin regulates expression of genes involved in cell wall synthesis in Herbaspirillum seropedicae. AB - Five thousand mutants of Herbaspirillum seropedicae SmR1 carrying random insertions of transposon pTnMod-OGmKmlacZ were screened for differential expression of LacZ in the presence of naringenin. Among the 16 mutants whose expression was regulated by naringenin were genes predicted to be involved in the synthesis of exopolysaccharides, lipopolysaccharides, and auxin. These loci are probably involved in establishing interactions with host plants. PMID- 21257806 TI - Prevalence and characterization of non-O157 shiga toxin-producing Escherichia coli isolates from commercial ground beef in the United States. AB - Escherichia coli O157:H7 is a Shiga toxin (stx)-producing E. coli (STEC) strain that has been classified as an adulterant in U.S. beef. However, numerous other non-O157 STEC strains are associated with diseases of various severities and have become an increasing concern to the beef industry, regulatory officials, and the public. This study reports on the prevalence and characterization of non-O157 STEC in commercial ground beef samples (n = 4,133) obtained from numerous manufacturers across the United States over a period of 24 months. All samples were screened by DNA amplification for the presence of Shiga toxin genes, which were present in 1,006 (24.3%) of the samples. Then, culture isolation of an STEC isolate from all samples that contained stx(1) and/or stx(2) was attempted. Of the 1,006 positive ground beef samples screened for stx, 300 (7.3% of the total of 4,133) were confirmed to have at least one strain of STEC present by culture isolation. In total, 338 unique STEC isolates were recovered from the 300 samples that yielded an STEC isolate. All unique STEC isolates were serotyped and were characterized for the presence of known virulence factors. These included Shiga toxin subtypes, intimin subtypes, and accessory virulence factors related to adherence (saa, iha, lifA), toxicity (cnf, subA, astA), iron acquisition (chuA), and the presence of the large 60-MDa virulence plasmid (espP, etpD, toxB, katP, toxB). The isolates were also characterized by use of a pathogenicity molecular risk assessment (MRA; based on the presence of various O-island nle genes). Results of this characterization identified 10 STEC isolates (0.24% of the 4,133 total) that may be considered a significant food safety threat, defined by the presence of eae, subA, and nle genes. PMID- 21257807 TI - Cupriavidus taiwanensis bacteroids in Mimosa pudica Indeterminate nodules are not terminally differentiated. AB - The beta-rhizobium Cupriavidus taiwanensis forms indeterminate nodules on Mimosa pudica. C. taiwanensis bacteroids resemble free-living bacteria in terms of genomic DNA content, cell size, membrane permeability, and viability, in contrast to bacteroids in indeterminate nodules of the galegoid clade. Bacteroid differentiation is thus unrelated to nodule ontogeny. PMID- 21257808 TI - Ecophysiology of uncultured filamentous anaerobes belonging to the phylum KSB3 that cause bulking in methanogenic granular sludge. AB - A filamentous bulking of a methanogenic granular sludge caused by uncultured filamentous bacteria of the candidate phylum KSB3 in an upflow anaerobic sludge blanket (UASB) system has been reported. To characterize the physiological traits of the filaments, a polyphasic approach consisting of rRNA-based activity monitoring of the KSB3 filaments using the RNase H method and substrate uptake profiling using microautoradiography combined with fluorescence in situ hybridization (MAR-FISH) was conducted. On the basis of rRNA-based activity, the monitoring of a full-scale UASB reactor operated continuously revealed that KSB3 cells became active and predominant (up to 54% of the total 16S rRNA) in the sludge when the carbohydrate loading to the system increased. Batch experiments with a short incubation of the sludge with maltose, glucose, fructose, and maltotriose at relatively low concentrations (approximately 0.1 mM) in the presence of yeast extract also showed an increase in KSB3 rRNA levels under anaerobic conditions. MAR-FISH confirmed that the KSB3 cells took up radioisotopic carbons from [(14)C]maltose and [(14)C]glucose under the same incubation conditions in the batch experiments. These results suggest that one of the important ecophysiological characteristics of KSB3 cells in the sludge is carbohydrate degradation in wastewater and that high carbohydrate loadings may trigger an outbreak of KSB3 bacteria, causing sludge bulking in UASB systems. PMID- 21257809 TI - [NiFe] hydrogenase from Alteromonas macleodii with unusual stability in the presence of oxygen and high temperature. AB - Hydrogenases are enzymes involved in the bioproduction of hydrogen, a clean alternative energy source whose combustion generates water as the only end product. In this article we identified and characterized a [NiFe] hydrogenase from the marine bacterium Alteromonas macleodii "deep ecotype" with unusual stability toward oxygen and high temperature. The A. macleodii hydrogenase (HynSL) can catalyze both H(2) evolution and H(2) uptake reactions. HynSL was expressed in A. macleodii under aerobic conditions and reached the maximum activity when the cells entered the late exponential phase. The higher level of hydrogenase activity was accompanied by a greater abundance of the HynSL protein in the late-log or stationary phase. The addition of nickel to the growth medium significantly enhanced the hydrogenase activity. Ni treatment affected the level of the protein, but not the mRNA, indicating that the effect of Ni was exerted at the posttranscriptional level. Hydrogenase activity was distributed ~30% in the membrane fraction and ~70% in the cytoplasmic fraction. Thus, HynSL appears to be loosely membrane-bound. Partially purified A. macleodii hydrogenase demonstrated extraordinary stability. It retained 84% of its activity after exposure to 80 degrees C for 2 h. After exposure to air for 45 days at 4 degrees C, it retained nearly 100% of its activity when assayed under anaerobic conditions. Its catalytic activity in the presence of O(2) was evaluated by the hydrogen deuterium (H-D) exchange assay. In 1% O(2), 20.4% of its H-D exchange activity was retained. The great stability of HynSL makes it a potential candidate for biotechnological applications. PMID- 21257810 TI - Characterization of a T5-like coliphage, SPC35, and differential development of resistance to SPC35 in Salmonella enterica serovar typhimurium and Escherichia coli. AB - The potential of bacteriophage as an alternative biocontrol agent has recently been revisited due to the widespread occurrence of antibiotic-resistant bacteria. We isolated a virulent bacteriophage, SPC35, that can infect both Salmonella enterica serovar Typhimurium and Escherichia coli. Morphological analysis by transmission electron microscopy and analysis of its 118,351-bp genome revealed that SPC35 is a T5 group phage belonging to the family Siphoviridae. BtuB, the outer membrane protein for vitamin B(12) uptake, was found to be a host receptor for SPC35. Interestingly, resistant mutants of both E. coli and S. Typhimurium developed faster than our expectation when the cultures were infected with SPC35. Investigation of the btuB gene revealed that it was disrupted by the IS2 insertion sequence element in most of the resistant E. coli isolates. In contrast, we could not detect any btuB gene mutations in the resistant S. Typhimurium isolates; these isolates easily regained sensitivity to SPC35 in its absence, suggesting phase-variable phage resistance/sensitivity. These results indicate that a cocktail of phages that target different receptors on the pathogen should be more effective for successful biocontrol. PMID- 21257811 TI - Diverse Borrelia burgdorferi strains in a bird-tick cryptic cycle. AB - The blacklegged tick Ixodes scapularis is the primary vector of the most prevalent vector-borne zoonosis in North America, Lyme disease (LD). Enzootic maintenance of the pathogen Borrelia burgdorferi by I. scapularis and small mammals is well documented, whereas its "cryptic" maintenance by other specialist ticks and wildlife hosts remains largely unexplored because these ticks rarely bite humans. We quantified B. burgdorferi infection in a cryptic bird-rabbit-tick cycle. Furthermore, we explored the role of birds in maintaining and moving B. burgdorferi strains by comparing their genetic diversity in this cryptic cycle to that found in cycles vectored by I. scapularis. We examined birds, rabbits, and small mammals for ticks and infection over a 4-year period at a focal site in Michigan, 90 km east of a zone of I. scapularis invasion. We mist netted 19,631 birds that yielded 12,301 ticks, of which 86% were I. dentatus, a bird-rabbit specialist. No resident wildlife harbored I. scapularis, and yet 3.5% of bird derived ticks, 3.6% of rabbit-derived ticks, and 20% of rabbit ear biopsy specimens were infected with B. burgdorferi. We identified 25 closely related B. burgdorferi strains using an rRNA gene intergenic spacer marker, the majority (68%) of which had not been reported previously. The presence of strains common to both cryptic and endemic cycles strongly implies bird-mediated dispersal. Given continued large-scale expansion of I. scapularis populations, we predict that its invasion into zones of cryptic transmission will allow for bridging of novel pathogen strains to humans and animals. PMID- 21257813 TI - Mutational analysis of residues in the helical region of the class IIa bacteriocin pediocin PA-1. AB - A 15-mer fragment that is derived from the helical region in the C-terminal half of pediocin PA-1 inhibited the activity of pediocin PA-1. Of 13 other pediocin like (hybrid) bacteriocins, only the hybrid bacteriocin Sak/Ped was markedly inhibited by the 15-mer fragment. Sak/Ped was the only one of these bacteriocins that had a sequence (in the C-terminal helix-containing half) identical to that of the 15-mer fragment, indicating that the fragment inhibits pediocin-like bacteriocins in a sequence-dependent manner. By replacing (one at a time) all 15 residues in the fragment with Ala or Leu, five residues (K1, A2, T4, N8, and A15) were identified as being especially important for the inhibitory action of the fragment. The results suggest that the corresponding residues (K20, A21, T23, N27, and A34, respectively) in pediocin PA-1 might be involved in interactions between pediocin PA-1 and its receptor. To characterize the environment surrounding these five residues when pediocin PA-1 interacts with target cells, these residues were replaced (one at a time) with a hydrophobic large (Leu) residue, a hydrophilic charged (Asp or Arg) residue, and a small (Ala or Gly) residue. The results revealed that residues A21 and A34 are in a spatially constrained environment, since the replacement with a small (Gly) residue was the only substitution that did not markedly reduce the bacteriocin activity. The positive charge in K20 and the polar amide group in N27 appeared to interact with electronegative groups, since the replacement of these two residues with a positive (Arg) residue was well tolerated, while replacement with a negative (Asp) residue was detrimental to the bacteriocin activity. K20 was in a less constrained environment than N27, since the replacement of K20 with a large hydrophobic (Leu) residue was tolerated fairly well and to a greater extent than N27. T23 seemed to be in an environment that was not restricted with respect to size, polarity, and charge, since replacements with large (Leu) and small (Ala) hydrophobic residues and a hydrophilic negative (Asp) residue were tolerated fairly well (2- to 6-fold reduction in activity). Moreover, the replacement of T23 with a large positive (Arg) residue resulted in wild-type or better-than-wild type activity. PMID- 21257812 TI - Microbial community composition and function in permanently cold seawater and sediments from an arctic fjord of svalbard. AB - Heterotrophic microbial communities in seawater and sediments metabolize much of the organic carbon produced in the ocean. Although carbon cycling and preservation depend critically on the capabilities of these microbial communities, their compositions and capabilities have seldom been examined simultaneously at the same site. To compare the abilities of seawater and sedimentary microbial communities to initiate organic matter degradation, we measured the extracellular enzymatic hydrolysis rates of 10 substrates (polysaccharides and algal extracts) in surface seawater and bottom water as well as in surface and anoxic sediments of an Arctic fjord. Patterns of enzyme activities differed between seawater and sediments, not just quantitatively, in accordance with higher cell numbers in sediments, but also in their more diversified enzyme spectrum. Sedimentary microbial communities hydrolyzed all of the fluorescently labeled polysaccharide and algal extracts, in most cases at higher rates in subsurface than surface sediments. In seawater, in contrast, only 5 of the 7 polysaccharides and 2 of the 3 algal extracts were hydrolyzed, and hydrolysis rates in surface and deepwater were virtually identical. To compare bacterial communities, 16S rRNA gene clone libraries were constructed from the same seawater and sediment samples; they diverged strongly in composition. Thus, the broader enzymatic capabilities of the sedimentary microbial communities may result from the compositional differences between seawater and sedimentary microbial communities, rather than from gene expression differences among compositionally similar communities. The greater number of phylum- and subphylum level lineages and operational taxonomic units in sediments than in seawater samples may reflect the necessity of a wider range of enzymatic capabilities and strategies to access organic matter that has already been degraded during passage through the water column. When transformations of marine organic matter are considered, differences in community composition and their different abilities to access organic matter should be taken into account. PMID- 21257814 TI - Integrative expression system for delivery of antibody fragments by lactobacilli. AB - A series of expression cassettes which mediate secretion or surface display of antibody fragments was stably integrated in the chromosome of Lactobacillus paracasei. L. paracasei producing surface-anchored variable domain of llama heavy chain (VHH) (ARP1) directed against rotavirus showed efficient binding to rotavirus and protection in the mouse model of rotavirus infection. PMID- 21257815 TI - General suppression of Escherichia coli O157:H7 in sand-based dairy livestock bedding. AB - Sand bedding material is frequently used in dairy operations to reduce the occurrence of mastitis and enhance cow comfort. One objective of this work was to determine if sand-based bedding also supported the microbiologically based suppression of an introduced bacterial pathogen. Bedding samples were collected in summer, fall, and winter from various locations within a dairy operation and tested for their ability to suppress introduced populations of Escherichia coli O157:H7. All sources of bedding displayed a heat-sensitive suppressiveness to the pathogen. Differences in suppressiveness were also noted between different samples at room temperature. At just 1 day postinoculation (dpi), the recycled sand bedding catalyzed up to a 1,000-fold reduction in E. coli counts, typically 10-fold greater than the reduction achieved with other substrates, depending on the sampling date. All bedding substrates were able to reduce E. coli populations by over 10,000-fold within 7 to 15 dpi, regardless of sampling date. Terminal restriction fragment length polymorphism (T-RFLP) analysis was used to identify bacterial populations potentially associated with the noted suppression of E. coli O157:H7 in sand bedding. Eleven terminal restriction fragments (TRFs) were overrepresented in paired comparisons of suppressive and nonsuppressive specimens at multiple sampling points, indicating that they may represent environmentally stable populations of pathogen-suppressing bacteria. Cloning and sequencing of these TRFs indicated that they represent a diverse subset of bacteria, belonging to the Cytophaga-Flexibacter-Bacteroidetes, Gammaproteobacteria, and Firmicutes, only a few of which have previously been identified in livestock manure. Such data indicate that microbial suppression may be harnessed to develop new options for mitigating the risk and dispersal of zoonotic bacterial pathogens on dairy farms. PMID- 21257816 TI - Single-nucleotide-polymorphism genotyping of Coxiella burnetii during a Q fever outbreak in The Netherlands. AB - Coxiella burnetii is the etiological agent of Q fever. Currently, the Netherlands is facing the largest Q fever epidemic ever, with almost 4,000 notified human cases. Although the presence of a hypervirulent strain is hypothesized, epidemiological evidence, such as the animal reservoir(s) and genotype of the C. burnetii strain(s) involved, is still lacking. We developed a single-nucleotide polymorphism (SNP) genotyping assay directly applicable to clinical samples. Ten discriminatory SNPs were carefully selected and detected by real-time PCR. SNP genotyping appeared to be highly suitable for discrimination of C. burnetii strains and easy to perform with clinical samples. With this new method, we show that the Dutch outbreak is caused by at least 5 different C. burnetii genotypes. SNP typing of 14 human samples from the outbreak revealed the presence of 3 dissimilar genotypes. Two genotypes were also present in livestock at 9 farms in the outbreak area. SNP analyses of bulk milk from 5 other farms, commercial cow milk, and cow colostrum revealed 2 additional genotypes that were not detected in humans. SNP genotyping data from clinical samples clearly demonstrate that at least 5 different C. burnetii genotypes are involved in the Dutch outbreak. PMID- 21257817 TI - Shifting the fermentative/oxidative balance in Saccharomyces cerevisiae by transcriptional deregulation of Snf1 via overexpression of the upstream activating kinase Sak1p. AB - With the aim to reduce fermentation by-products and to promote respiratory metabolism by shifting the fermentative/oxidative balance, we evaluated the constitutive overexpression of the SAK1 and HAP4 genes in Saccharomyces cerevisiae. Sak1p is one of three kinases responsible for the phosphorylation, and thereby the activation, of the Snf1p complex, while Hap4p is the activator subunit of the Hap2/3/4/5 transcriptional complex. We compared the physiology of a SAK1-overexpressing strain with that of a strain overexpressing the HAP4 gene in wild-type and sdh2 deletion (respiratory-deficient) backgrounds. Both SAK1 and HAP4 overexpressions led to the upregulation of glucose-repressed genes and to reduced by-product formation rates (ethanol and glycerol). SAK1 overexpression had a greater impact on growth rates than did HAP4 overexpression. Elevated transcript levels of SAK1, but not HAP4, resulted in increased biomass yields in batch cultures grown on glucose (aerobic and excess glucose) as well as on nonfermentable carbon sources. SAK1 overexpression, but not the combined overexpression of SAK1 and HAP4 or the overexpression of HAP4 alone, restored growth on ethanol in an sdh2 deletion strain. In glucose-grown shake flask cultures, the sdh2 deletion strain with SAK1 and HAP4 overexpression produced succinic acid at a titer of 8.5 g liter(-1) and a yield of 0.26 mol (mol glucose)(-1) within 216 h. We here report for the first time that a constitutively high level of expression of SAK1 alleviates glucose repression and shifts the fermentative/oxidative balance under both glucose-repressed and derepressed conditions. PMID- 21257818 TI - An image-based, high-throughput screening assay for molecules that induce excess DNA replication in human cancer cells. AB - Previous studies have shown DNA re-replication can be induced in cells derived from human cancers under conditions in which it is not possible for cells derived from normal tissues. Because DNA re-replication induces cell death, this strategy could be applied to the discovery of potential anticancer therapeutics. Therefore, an imaging assay amenable to high-throughput screening was developed that measures DNA replication in excess of four genomic equivalents in the nuclei of intact cells and indexes cell proliferation. This assay was validated by screening a library of 1,280 bioactive molecules on both normal and tumor-derived cells where it proved more sensitive than current methods for detecting excess DNA replication. This screen identified known inducers of excess DNA replication, such as inhibitors of microtubule dynamics, and novel compounds that induced excess DNA replication in both normal and cancer cells. In addition, two compounds were identified that induced excess DNA replication selectively in cancer cells and one that induced endocycles selectively in cancer cells. Thus, this assay provides a new approach to the discovery of compounds useful for investigating the regulation of genome duplication and for the treatment of cancer. PMID- 21257819 TI - Mouse snail is a target gene for HIF. AB - The transcriptional inhibitor Snail is a critical regulator for epithelial mesenchymal transition (EMT). Although low oxygen induces Snail transcription, thereby stimulating EMT, a direct role of hypoxia-inducible factor (HIF) in this process remains to be demonstrated. Here we show that hypoxia induces the expression of Snail via HIF. In silico analysis identified a potential hypoxia response element (HRE) close to the minimal promoter of the human and mouse genome of the snail gene. Gel shift assays demonstrated that a specific hypoxia inducible complex is formed with the putative HRE and that the complex contains HIF proteins. ChIP assays confirmed the interaction of HIF proteins with the putative HRE in vivo. Reporter gene analyses showed that the putative HRE responds to hypoxia in its natural position as well as in front of a heterologous promoter and that the HRE is directly activated by HIF-1alpha or HIF-2alpha. HIF knockdown with siRNA at 2% oxygen and overexpression of an oxygen-insensitive HIF (HIF-DeltaODD) mutant at 21% oxygen showed that HIF regulates Snail activation and subsequent cell migration. Our findings identify snail as a HIF target gene and provide novel insights into the regulation of snail and hypoxia-induced EMT. PMID- 21257820 TI - Race and gender differences in 1-year outcomes for community-dwelling stroke survivors with family caregivers. AB - BACKGROUND AND PURPOSE: Previous research has reported worse outcomes after stroke for women and for African Americans, but few prospective population-based studies have systematically examined demographic differences on long-term stroke outcomes. Race and gender differences in 1-year stroke outcomes were examined using an epidemiologically derived sample of first-time stroke survivors from the national REasons for Geographic and Racial Differences in Stroke (REGARDS) study. METHODS: Participants of REGARDS who reported a first-time stroke event during regular surveillance calls were interviewed by telephone and then completed an in home evaluation approximately 1 year after the verified first-time stroke event (N=112). A primary family caregiver was also enrolled and interviewed for each stroke survivor. Measures from the in-home evaluation included previously validated stroke outcomes assessments of neurological deficits, functional impairments, and patient-reported effects of stroke in multiple domains. Results- African American stroke survivors were less likely to be living with their primary family caregivers than white participants. Analyses that controlled for age, education, and whether the stroke survivors lived with their primary family caregivers indicated that African Americans and women showed significantly greater deficits on multiple 1-year outcome measures compared to whites and men, respectively. CONCLUSIONS: Among community-dwelling stroke survivors with family caregivers, women and African Americans are at heightened risk for poor long-term outcomes 1 year after first-time stroke events. Rehabilitation services and public health policies aimed at enhancing stroke recovery rates should address these disparities in poststroke outcomes. PMID- 21257821 TI - Associations of retinal microvascular signs and intracranial large artery disease. AB - BACKGROUND AND PURPOSE: Intracranial large artery disease (ICLAD) is a major cause of ischemic stroke. Retinal microvascular changes are associated with stroke, including small vessel cerebral disease and extracranial carotid disease. We examined the relationship between ICLAD and retinal microvascular changes. METHODS: This is a prospective cohort of 802 acute ischemic stroke patients. Retinal changes were assessed from photographs by graders masked to clinical data. ICLAD was evaluated using prespecified criteria. RESULTS: ICLAD was not associated with ipsilateral retinal arteriolar/venular caliber, focal arteriolar narrowing, or arteriovenous nicking. Severe enhanced arteriolar light reflex was independently associated with any ICLAD (P=0.006) and severe ICLAD (P<0.001). CONCLUSIONS: Enhanced arteriolar light reflex, but not retinal vessel caliber, was related to ICLAD. These data suggest that retinal microvascular signs have specific associations with large cerebral vessel disease. PMID- 21257822 TI - A candidate gene study revealed sex-specific association between the OLR1 gene and carotid plaque. AB - BACKGROUND AND PURPOSE: Sex differences have been recognized in stroke risk; however, the sex-dependent genetic contribution to stroke is unclear. We sought to examine the sex-dependent associations between genes involved in lipid metabolism and carotid atherosclerotic plaque, a subclinical precursor of stroke. METHODS: For the Genetic Determinant of Subclinical Carotid Disease study, 287 Dominicans ascertained through the Northern Manhattan Study were examined for carotid plaque using high-resolution ultrasound. Sixty-four single nucleotide polymorphisms (SNPs) in 11 lipid-related genes were genotyped. Plaque presence and plaque subphenotypes, including multiple, thick, irregular, and calcified plaque, were analyzed. First, the interaction between each SNP and sex was evaluated for association with each plaque phenotype using multiple logistic regression and controlling for age, smoking, and the main effects of sex and SNP. For SNPs with suggestive evidence for interaction with sex (P<0.1 for the interaction term), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and plaque phenotypes. RESULTS: The most compelling finding is with the missense SNP rs11053646 (K167N) in the OLR1 gene, which encodes lectin-like oxidized low-density lipoprotein receptor. Stratification analysis revealed a strong association between rs11053646 and all plaque phenotypes in women (OR, 2.44 to 5.86; P=0.0003 to 0.0081) but not in men (OR, 0.85 to 1.22; P=0.77 to 0.92). CONCLUSIONS: Genetic variation in genes involved in lipid metabolism may have sex-dependent effects on carotid plaque burden. Our findings provide a plausible biological basis underlying the sex difference in cardiovascular risk. PMID- 21257823 TI - Quantitative analysis of hemorrhage volume for predicting delayed cerebral ischemia after subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: Delayed cerebral ischemia (DCI) is an important complication after subarachnoid hemorrhage and appears to be associated with clot burden on CT. Quantification of hemorrhage on digitized images may be a more accurate method for predicting DCI than qualitative scales. METHODS: Quantitative analysis of clot burden on CT was performed in 160 subarachnoid hemorrhage patients who were scanned within 24 hours from the symptom onset between June 25, 2005 and July 19, 2009. Cisternal plus intraventricular hemorrhage volumes (CIHV) were classified into quartiles to evaluate their association with DCI. DCI was defined as neurological deterioration or cerebral infarction, or both attributable to vasospasm. RESULTS: DCI occurred in 25% of the patients included (age, 55.4+/-14.5; male, 36.3%). Compared to the lowest quartile of CIHV (<9.6 mL), the higher quartile (9.6 mL-16.5 mL, 16.5 mL-31.0 mL, and >=31.0 mL) was associated with a greater risk of DCI (odds ratio, 2.6, 4.1, and 6.1, respectively; P=0.01). Receiver-operating characteristic curve analysis showed that quantitative CIHV performed equivalently to the modified Fisher scale. Patients who had DCI develop in a specific vascular territory had higher amounts of blood volume in the corresponding cisterns. Patients in the highest quartile of CIHV also had a higher risk of death or severe disability at 3 months (71%) compared to other groups (23%, 19%, and 40% for first, second, and third quartiles, respectively). CONCLUSIONS: CIHV is a reasonable predictor for DCI and 3-month functional outcome in subarachnoid hemorrhage patients. PMID- 21257824 TI - Granulocyte colony-stimulating factor enhances arteriogenesis and ameliorates cerebral damage in a mouse model of ischemic stroke. AB - BACKGROUND AND PURPOSE: Enhancing collateral artery growth is a potent therapeutic approach to treat cardiovascular ischemic disease from occlusive artery. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has gained attention for its ability to promote arteriogenesis, ameliorating brain damage, by the mechanisms involving monocyte upregulation. However, the recent clinical study testing its efficacy in myocardial ischemia has raised the question about its safety. We tested alternative colony-stimulating factors for their effects on collateral artery growth and brain protection. METHODS: Brain hypoperfusion was produced by occluding the left common carotid artery in C57/BL6 mice. After the surgery, granulocyte colony-stimulating factor, macrophage colony-stimulating factor, or GM-CSF (100 MUg/kg/day) was administered daily for 5 days. The angioarchitecture for leptomeningeal anastomoses and the circle of Willis were visualized after the colony-stimulating factor treatment. Circulating blood monocytes and Mac-2-positive cells in the dorsal surface of the brain were determined. A set of animals underwent subsequent ipsilateral middle cerebral artery occlusion and infarct volume was assessed. RESULTS: Granulocyte colony stimulating factor as well as GM-CSF promoted leptomeningeal collateral growth after common carotid artery occlusion. Both granulocyte colony-stimulating factor and GM-CSF increased circulating blood monocytes and Mac-2-positive cells in the dorsal brain surface, suggesting the mechanisms coupled to monocyte upregulation might be shared. Infarct volume after middle cerebral artery occlusion was reduced by granulocyte colony-stimulating factor, similarly to GM-CSF. Macrophage colony-stimulating factor showed none of theses effects. CONCLUSIONS: Granulocyte colony-stimulating factor enhances collateral artery growth and reduces infarct volume in a mouse model of brain ischemia, similarly to GM-CSF. PMID- 21257825 TI - Stromal-derived factor-1[alpha] correlates with circulating endothelial progenitor cells and with acute lesion volume in stroke patients. AB - BACKGROUND AND PURPOSE: Endothelial progenitor cells (EPC) are important participants of neovascularization and are mobilized through signaling with stromal-derived factor (SDF-1alpha), vascular endothelial growth factor (VEGF), granulocyte colony-stimulating factor, and stem cell factor. The association between EPC levels and these growth factors (GF) in acute stroke has not been previously established. We aimed to determine the association between EPC and these GF, and to elucidate a relationship between these GF and stroke severity in acute stroke patients. METHODS: Seventeen patients were selected from 175 patients with imaging-confirmed acute ischemic stroke. EPC were quantified using CD34, CD133, and VEGF-R2 markers. Plasma VEGF, SDF-1alpha, granulocyte colony stimulating factor, and stem cell factor were determined by enzyme-linked immunosorbent assay on days 1 and 3, and brain MRI was performed at baseline and on days 1 and 5 after the stroke onset. RESULTS: Levels of SDF-1alpha strongly (r=0.6) correlated with the numbers of EPC subsets CD133(+)VEFG-R2(+) (P<0.004), CD34(+)VEGF-R2(+) (P<0.01), and CD34(+)CD133(+)VEGF-R2(+) (P<0.01) on day 1. Stem cell factor strongly (r=0.5) correlated with CD133(+)VEGF-R2(+) (P<0.05). SDF 1alpha moderately inversely (r=-0.49) correlated with baseline diffusion-weighted imaging lesion volumes (P<0.04). Median levels of SDF-1alpha (1561 pg/mL) increased (P<0.04) on day 3 compared to day 1 (1379 pg/mL). Similarly, VEGF at day 3 (95 pg/mL) increased (P<0.03) compared to day 1 (64 pg/mL). CONCLUSIONS: These results indicate that SDF-1alpha and stem cell factor correlate with an increase in EPC early in ischemic stroke patients. PMID- 21257826 TI - Pharmacological deep vein thrombosis prophylaxis does not lead to hematoma expansion in intracerebral hemorrhage with intraventricular extension. AB - BACKGROUND AND PURPOSE: Patients with intracerebral hemorrhage (ICH) are at high risk for development of deep venous thrombosis. Current guidelines state that low dose subcutaneous low molecular weight heparin or unfractionated heparin may be considered at 3 to 4 days from onset. However, insufficient data exist on hematoma volume in patients with ICH before and after pharmacological deep venous thrombosis prophylaxis, leaving physicians with uncertainty regarding the safety of this practice. METHODS: We identified patients from our stroke registry (June 2003 to December 2007) who presented with ICH only or ICH+intraventricular hemorrhage and received either low molecular weight heparin subcutaneously or unfractionated heparin within 7 days of admission and had a repeat CT scan performed within 4 days of starting deep venous thrombosis prophylaxis. We calculated the change in hematoma volume from the admission and posttreatment CTs. Hematoma volume was calculated using the ABC/2 method and intraventricular hemorrhage volumes were calculated using a published method of hand drawn regions of interest. RESULTS: We identified 73 patients with a mean age of 63 years and median National Institutes of Health Stroke Scale score 11.5. The mean baseline total hematoma volume was 25.8 mL+/-23.2 mL. There was an absolute change in hematoma volume from pre- and posttreatment CT of -4.3 mL+/-11.0 mL. Two patients developed hematoma growth. Repeat analysis of patients given pharmacological deep venous thrombosis prophylaxis within 2 or 4 days after ICH found no increase in hematoma size. CONCLUSIONS: Pharmacological deep venous thrombosis prophylaxis given subcutaneously in patients with ICH and/or intraventricular hemorrhage in the subacute period is generally not associated with hematoma growth. PMID- 21257827 TI - High frequency of silent pulmonary embolism in patients with cryptogenic stroke and patent foramen ovale. AB - BACKGROUND AND PURPOSE: Deep vein thrombosis and pulmonary embolism (PE) prove venous embolic activity and enforce the suspicion of paradoxical embolism in patients with stroke with patent foramen ovale. Because it has implications in secondary prevention, we investigated the frequency of silent PE in such a cohort of patients. METHODS: Patients with cryptogenic stroke or transient ischemic attack and patent foramen ovale who underwent a ventilation perfusion scintigraphy were identified from a stroke registry. Blinded from clinical data, ventilation perfusion scintigraphy scans were re-evaluated independently by 2 experts. Patients showing at least a subsegmental defect were considered as having silent PE. Factors potentially associated with PE were analyzed. RESULTS: The evaluation included 151 patients. Median age was 55.2 years and 59.9% were male. In 56 (37%) patients, silent PE was found; a deep vein thrombosis was evident in 11 (7%) patients. Atrial septal aneurysm was identified in 39 patients and hypermobile atrial septum in 37 patients. Atrial septal aneurysm and hypermobile atrial septum were independently associated with PE. In females, intake of oral contraceptives showed certain association with PE (6 of 25 versus 3 of 40; P=0.07). CONCLUSIONS: Silent PE frequently occurs in patients with cryptogenic stroke and patent foramen ovale, particularly when atrial septal aneurysm or hypermobile atrial septum are present. PMID- 21257828 TI - Selectin-mediated recruitment of bone marrow stromal cells in the postischemic cerebral microvasculature. AB - BACKGROUND AND PURPOSE: The therapeutic potential of bone marrow stromal cells (BMSCs) has been demonstrated in different models of stroke. Although it is well established that BMSCs selectively migrate to the site of brain injury, the mechanisms underlying this process are poorly understood. This study addresses the hypothesis that selectins mediate the recruitment of BMSCs into the postischemic cerebral microvasculature. METHODS: Focal ischemic stroke was induced by middle cerebral artery occlusion and reperfusion. Cell recruitment was monitored using either fluorescent- or radiolabeled BMSCs detected by intravital microscopy or tissue radioactivity. Mice were treated with either a blocking antibody against P- or E-selectin or with the nonselective selectin antagonist, fucoidin. The role of CD44 in cell recruitment was evaluated using BMSCs from CD44 knockout mice. RESULTS: Middle cerebral artery occlusion and reperfusion was associated with a significantly increased adhesion of BMSCs in cerebral venules compared with sham mice. Immunoneutralization of either E- or P-selectin blocked the middle cerebral artery occlusion and reperfusion-induced recruitment of adherent BMSCs. An attenuated recruitment response in the postischemic hemisphere was also noted after fucoidin treatment or administration of CD44-deficient BMSCs. CONCLUSIONS: Cerebral vascular endothelium assume a proadhesive phenotype after ischemic stroke that favors the recruitment of BMSCs, which use both P- and E-selectin to home into the infarct site. CD44 may serve as the critical ligand for selectin-mediated BMSC recruitment. PMID- 21257829 TI - Clopidogrel versus dipyridamole in addition to aspirin in reducing embolization detected with ambulatory transcranial Doppler: a randomized trial. AB - BACKGROUND AND PURPOSE: After stroke and transient ischemic attack there is a high early risk of recurrent stroke, particularly in large artery disease. It has been suggested more intensive antiplatelet regimens are required, but trial data are lacking. Treatment efficacy can be evaluated using transcranial Doppler detection of embolic signals. Ambulatory transcranial Doppler has recently been developed; prolonged recording may reduce subject numbers required to determine therapeutic efficacy. In a randomized trial (ISRCTN68019845) with blinded end point evaluation, we determined whether treatment with dipyridamole or clopidogrel, in addition to aspirin, was more effective at reducing embolization. METHODS: Consecutive patients with recent symptomatic carotid stenosis were recruited. Ambulatory transcranial Doppler and platelet aggregometry were performed at baseline and 48 hours. Patients, all on aspirin, were randomized to dipyridamole or clopidogrel. Recordings were analyzed offline masked to subject identity. RESULTS: Sixty patients were recruited, 30 in each arm. The primary end point of change in embolic signal frequency did not differ between groups (P=0.36). In patients with embolic signals at baseline, there was no difference in reduction in embolic signal frequency: dipyridamole (75.5; SD 17.7%) versus clopidogrel (77.5; SD 20.5%; P=0.77). Baseline platelet aggregation was not different between regimens, but at 48 hours, adenosine 5'-diphosphate aggregation rate (but not collagen) was lower with clopidogrel (P<0.001). CONCLUSIONS: Both dipyridamole and clopidogrel reduced embolization to a similar extent. Embolic signals are strong predictors of future stroke rate in this patient group. Our results suggest these 2 treatment regimens have similar efficacy in early secondary prevention of stroke, although this now needs testing in large Phase III trials. PMID- 21257830 TI - Recanalisation of the internal carotid artery via the vasa vasorum after coil occlusion. AB - Antegrade recanalisation of a completely occluded internal carotid artery (ICA) via the vasa vasorum is extremely rare. Here, we report such a case after proximal endovascular coiling in a case of dissected (i.e. non-atherosclerotic) ICA. A 42-year-old man presented with thromboembolic stroke of the left frontal lobe owing to pseudo-occlusion of the left ICA manifesting as motor aphasia and right hemiparesis. There were abundant floating thrombi in the petrous portion of the left ICA. Because of good collateral flow in the left middle cerebral artery territory through the anterior communicating artery and external carotid artery system, endovascular coil embolisation of the left ICA was performed for prevention of further thromboembolic stroke. The patient showed progressive recovery following endovascular treatment, and was discharged with mild right hemiparesis 1 month later. He maintained a regimen of aspirin and physical rehabilitation. At follow-up, 38 months later, the patient was asymptomatic. Angiography demonstrated occlusion of the left ICA and multiple serpiginous vessels originating from the proximal internal and external carotid arteries and which filled the ICA distal to the occlusion. This case suggests that an ICA occluded by proximal coil embolisation-even in a non-atherosclerotic case-might be recanalised via the vasa vasorum. PMID- 21257831 TI - Lymphocoele of the thoracic duct: a cause of left supraclavicular fossa. AB - Lymphocoele of the thoracic duct, alternatively referred to as thoracic duct cyst, is an uncommon abnormality that can present occasionally as a left supraclavicular fossa mass. Recognition of the origin of such a neck mass on imaging is crucial to avert unnecessary intervention. A case of such a mass is presented with discussion of the fascinating variable anatomy of the thoracic duct. PMID- 21257832 TI - Imaging findings of calcifying fibrous tumour of the liver. AB - Calcifying fibrous tumour (CFT) is a recently recognised rare benign lesion characterised by dense hyalinised collagenous tissue, psammomatous or dystrophic calcifications and a lymphoplasmacytic infiltrate. The usual locations of the lesion are the soft tissues of the extremities, but rarely it occurs in the abdomen. Recently, we experienced a case of CFT found in the liver of a 29-year old woman. Here, we describe the characteristic radiological and histopathological findings, along with a review of the relevant literature. PMID- 21257833 TI - Left ventricular true and false aneurysms identified by cardiovascular magnetic resonance. AB - Left ventricular aneurysms are uncommon complications of myocardial infarction. However, it is important to identify them because they are associated with increased morbidity and mortality. True aneurysms tend to be managed conservatively whereas false aneurysms, because of the risk of rupture, are usually treated with urgent surgery. Distinguishing these two subtypes is therefore critical and cardiovascular magnetic resonance (MR) is being used more frequently to characterise the type of aneurysm as well as to provide clear three dimensional images of aneurysm morphology. We present a very rare case of a true and a false aneurysm of the left ventricle in the same patient. MR enabled accurate delineation of both aneurysms and the late gadolinium-enhancement images provided evidence confirming both true and false aneurysms to be present. PMID- 21257834 TI - Blind-ending branch of a bifid ureter: multidetector CT imaging findings. AB - A bifid ureter with a blind-ending branch is a rare congenital anomaly. Although typically found incidentally, this anomaly can be symptomatic and radiologists should be aware of this important variant. To our knowledge, there has been no previous report of this anomaly as seen on multidetector CT urography. We present a patient with haematuria and review the clinical significance, radiological findings and embryological aetiology of this anomaly. PMID- 21257835 TI - MRI appearance of massive renal replacement lipomatosis in the absence of renal calculus disease. AB - Renal replacement lipomatosis is a rare benign entity in which extensive fibrofatty proliferation of the renal sinus is associated with marked renal atrophy. In this report, we present a case of massive renal replacement lipomatosis demonstrated on MRI. The presentation was atypical given an absence of associated renal calculus disease, and an initial CT scan was interpreted as suspicious for a liposarcoma. The differential diagnosis and key MRI findings that served to establish this specific diagnosis are reviewed. Histopathological correlation is also presented, as the patient underwent nephroureterectomy. PMID- 21257836 TI - MR defecography in patients with dyssynergic defecation: spectrum of imaging findings and diagnostic value. AB - OBJECTIVES: We describe the spectrum of findings and the diagnostic value of MR defecography in patients referred with suspicion of dyssynergic defecation. METHODS: 48 patients (34 females, 14 males; mean age 48 years) with constipation and clinically suspected dyssynergic defecation underwent MR defecography. Patients were divided into patients with dyssynergic defecation (n = 18) and constipated patients without dyssynergic defecation (control group, n = 30). MRIs were analysed for evacuation ability, time to initiate evacuation, time of evacuation, changes in the anorectal angle (ARA-change), presence of paradoxical sphincter contraction and presence of additional pelvic floor abnormalities. Sensitivity, specificity, positive and negative predictive values and accuracy for the diagnosis of dyssynergic defecation were calculated. RESULTS: The most frequent finding was impaired evacuation, which was seen in 100% of patients with dyssynergic defecation and in 83% of the control group, yielding a sensitivity for MR defecography for the diagnosis of dyssynergic defecation of 100% (95% confidence interval (CI) 97-100%), but a specificity of only 23% (95% CI 7-40%). A lower sensitivity (50%; 95% CI 24-76%) and a high specificity (97%; 95% CI 89 100%) were seen with abnormal ARA-change. The sensitivity of paradoxical sphincter contraction was relatively high (83%; 95% CI 63-100%). A combined analysis of abnormal ARA-change and paradoxical sphincter contraction allowed for the detection of 94% (95% CI 81-100%) of the patients with dyssynergic defecation. CONCLUSION: MR defecography detects functional and structural abnormal findings in patients with clinically suspected dyssynergic defecation. Impaired evacuation is seen in patients with functional constipation owing to other pelvic floor abnormalities than dyssynergic defecation. PMID- 21257837 TI - Comparison of conventional and three-dimensional conformal CT planning techniques for preoperative chemoradiotherapy for locally advanced rectal cancer. AB - OBJECTIVES: We assessed the impact of three-dimensional (3D) conformal planning vs conventional planning of preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) on small bowel and bladder sparing and in optimising coverage of tumour target volume. METHODS: Conformal and conventional plans were created for 50 consecutive patients. The conformal plan delineated a gross tumour volume (GTV), a clinical target volume (CTV) 1 to cover potential subclinical disease spread, a CTV2 to outline the mesorectum and lymph node areas at risk, and a planning target volume (PTV) to cover set-up error and organ movement. The conventional plan was created using digitally reconstructed radiographs (DRRs). Patients were treated with a dose of 45 Gy in 25 fractions with concurrent chemotherapy over 5 weeks. Dose-volume histograms (DVHs) were created and compared for GTV, PTV, small bowel and bladder. The GTV was covered by the conventional plan in all patients. RESULTS: Significant differences were shown for median PTV coverage with conformal planning compared with conventional planning: 99.2% vs 94.2% (range 95.9-100% vs 75.5-100%); p<0.05. The median volume of irradiated small bowel was significantly lower for CT plans at all DVH levels. Median bladder doses did not differ significantly. CONCLUSION: 3D conformal CT planning is superior to conventional planning in terms of coverage of the tumour volume. It significantly reduces the volume of small bowel irradiated with no decrease in the rate of R0 resection compared with published data, and at the present time should be considered as the standard of care for rectal cancer planning. PMID- 21257838 TI - Use of the triaxial microcatheter method in super-selective transcatheter arterial chemoembolisation for hepatocellular carcinoma. AB - OBJECTIVES: Transcatheter arterial chemoembolisation (TACE) has been widely used for inoperable hepatocellular carcinoma (HCC). Super-selective TACE is preferable to non-selective therapy, because it maximises the impact of treatment on the tumour while minimising damage to tumour-free liver parenchyma. It is therefore important to advance the catheter tip as close as possible in the feeding artery. There is now a new microcatheter with a 1.9-Fr tip with no taper, which can be inserted into a 2.7-Fr microcatheter. In this study we describe the new technique of using the two microcatheters called the triaxial microcatheter method. METHODS: We evaluated 30 TACE procedures to investigate whether or not the catheter tip could be advanced closer to HCC with the triaxial microcatheter method than with previous TACE using a conventional microcatheter. RESULTS: With conventional microcatheters, the level of embolisation was a lobar artery in 4 cases, segmental in 8 cases, subsegmental in 15 cases and sub-subsegmental in only 1 case. TACE could not be performed in two cases. When using the triaxial microcatheter method the level of embolisation was subsegmental in 8 cases, including 2 in which the level was the same as that with a conventional microcatheter, sub-subsegmental in 13 cases and more distal in 7 cases. In the two cases in which TACE could not be performed with the conventional microcatheter, it could be performed sufficiently using the new method. As a whole, in 28 of the 30 procedures (93%) we could successfully advance a catheter tip closer than with the previous TACE. CONCLUSION: The triaxial microcatheter method appears to be useful. PMID- 21257839 TI - Hepatitis and a rash in an immunocompromised patient. PMID- 21257840 TI - Subacute onset of abnormal gait and head drop in a 3-year-old with history of extreme prematurity. AB - A 3-year-old boy who had been a 23-week premature infant had subacute onset of abnormal gait, which progressed to generalized weakness with severe weakness of neck extensors. He had U waves on electrocardiography. His serum potassium was 1.8 mmol/L. The patient had a gastrostomy tube due to chronic feeding issues and was treated with inhaled albuterol for chronic lung disease. When his oral intake regressed, his family administered one of his oral supplements through the gastrostomy tube; the supplement was low in potassium. This feeding regression continued for several months. He had no additional gastrointestinal or renal loss of potassium. He had frequent exacerbations of his bronchopulmonary dysplasia. His history suggested he had chronic potassium depletion and that albuterol may have led to further potassium redistribution, exacerbating his hypokalemia. As more extremely premature infants survive with chronic feeding and respiratory issues, this presentation may become more common. PMID- 21257841 TI - Biomechanical comparison of coracoclavicular reconstructive techniques. AB - BACKGROUND: Acromioclavicular joint dislocations are common orthopaedic injuries. Numerous operative techniques have been described, but the gold standard has yet to be defined. The goal of fixation is to create a stiff and strong reconstruction of the coracoclavicular ligaments to provide optimal stability. The modified Weaver-Dunn is the traditional surgical procedure. However, due to the high rate of recurrent instability with this technique, a shift toward a more anatomic repair has occurred. PURPOSE: To evaluate the biomechanical performance of multiple types of coracoclavicular ligament reconstruction. STUDY DESIGN: Controlled laboratory study. METHODS: Thirty fresh-frozen human cadaveric shoulders were assigned to 1 of 5 reconstruction groups or a control group: modified Weaver-Dunn, nonanatomic allograft, anatomic allograft, anatomic suture, and GraftRope. A type III acromioclavicular joint dislocation was simulated in all specimens. The 5 techniques were completed, and a cyclic preload and a load to-failure protocol were performed. RESULTS: The control had an average load to failure of 1330.6 +/- 447.0 N. Compared with all techniques, the anatomic allograft had the highest load to failure, 948 +/- 148 N. It had a significantly higher load to failure than the modified Weaver-Dunn (523.2 +/- 98.6 N, P = .001), the anatomic suture (578.2 +/- 195.3 N, P = .01), the nonanatomic allograft (591.2 +/- 65.6 N, P = .003), and the GraftRope (646 +/- 167.4, P = .016). No significant difference in load to failure was found between the remaining techniques. CONCLUSION: The anatomic allograft reconstruction has superior initial biomechanical properties compared with the modified Weaver-Dunn, nonanatomic allograft, anatomic suture, and GraftRope techniques. CLINICAL RELEVANCE: Anatomic reconstruction of the coracoclavicular ligaments with allograft may provide a stronger biological solution for acromioclavicular joint dislocations. This reconstruction may minimize recurrent subluxation and pain and permit earlier rehabilitation when compared with current techniques. PMID- 21257842 TI - Local administration of autologous synovium-derived cells improve the structural properties of anterior cruciate ligament autograft reconstruction in sheep. AB - BACKGROUND: The structural properties of a tendon autograft deteriorate during the remodeling phase after anterior cruciate ligament (ACL) reconstruction. HYPOTHESIS: A local application of autologous synovium-derived cells cultured in medium supplemented with transforming growth factor beta (TGFbeta) may inhibit the deterioration of structural properties of the tendon graft after ACL reconstruction. STUDY DESIGN: Controlled laboratory study. METHODS: Fifty-two mature sheep were used. In each animal, the right knee underwent ACL reconstruction using the semitendinosus tendon autograft; then, the animals were divided into 5 groups of 10. No additional treatments were applied in group 1, whereas fibrin sealant was applied around the graft in group 2. In group 3, autologous synovium-derived cells cultured in standard medium were applied around the graft with fibrin sealant, whereas autologous synovium-derived cells cultured in TGFbeta-supplemented medium were applied with fibrin sealant in group 4. In group 5, fibrin sealant containing 20 ng of TGFbeta was applied around the graft. Each animal was sacrificed at 12 weeks after the surgery. In each group, 7 and 3 sheep were used for biomechanical and histologic evaluations, respectively. The remaining 2 sheep were used to confirm whether the applied cells infiltrated the graft at 1 week after surgery. RESULTS: Confocal microscope observations showed that the applied cells that were labeled before implantation infiltrated into the superficial portion of the graft at 1 week. Biomechanically, the maximum load and the stiffness of groups 4 and 5 were significantly greater than those of groups 1, 2, and 3. Histologically, necrotic lesions were observed in the core portion of the midsubstance in groups 1 and 2. In groups 3, 4, and 5, no necrotic lesions were found in the midsubstance. CONCLUSION: A local application of autologous synovium-derived cells cultured in TGFbeta-supplemented medium or a fibrin sealant containing TGFbeta significantly inhibits the natural deterioration of the structural properties of the tendon graft after ACL reconstruction. CLINICAL RELEVANCE: Administration of autologous synovium-derived cells cultured in TGFbeta-supplemented medium or TGFbeta and fibrin glue alone can be a potential cell-based therapy to prevent graft deterioration after transplantation or accelerate mechanical restoration of the deteriorated graft. PMID- 21257843 TI - Arthroscopic soft tissue tenodesis versus bony fixation anchor tenodesis of the long head of the biceps tendon. AB - BACKGROUND: Currently there are no prospective data available that compare the different tenodesis techniques of the long head of the biceps tendon with regard to their clinical and structural results. HYPOTHESIS: Soft tissue tenodesis provides clinical and structural results equivalent to those of bony fixation anchor tenodesis. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Fifty-seven patients with arthroscopically proven lesions of the long head of the biceps tendon (LHB) were prospectively included in this study. Thirty patients (7 women, 23 men; mean age, 57.9 years) were treated with an arthroscopic soft tissue tenodesis (STT) and 27 patients (8 women, 19 men; mean age, 61 years) with an arthroscopic bony fixation anchor tenodesis (BFAT). The clinical evaluation included the Constant score as well as a newly developed LHB score (maximum 100 points) that includes evaluation of pain and cramps (maximum 50 points), the patient- and examiner-dependent grading of the cosmetic result (maximum 30 points), and the measurement of elbow flexion strength (maximum 20 points). The integrity of the tenodesis construct was evaluated indirectly by detecting the position of the LHB using magnetic resonance imaging. A proximal intertubercular location of the tendon was judged as an intact tenodesis construct (3 points), a distal intertubercular location as a failure of tenodesis followed by autotenodesis in the sulcus (2 points), and an extratubercular location as a complete failure (1 point). RESULTS: Twenty-four patients (5 women, 19 men; mean age, 58.6 years; mean follow-up, 19.6 months) in the STT group and 20 patients (5 women, 15 men; mean age, 59.1 years; mean follow-up, 22.4 months) in the BFAT group could be evaluated. The overall Constant score did not reveal any significant difference in the STT group (mean, 75.0 points) compared with the BFAT group (mean, 78.3 points) (P > .05). However, the BFAT group showed significantly better results in the LHB score (BFAT mean, 91.8 points vs STT mean, 80.9 points), the examiner-dependent evaluation of the cosmetic result (BFAT mean, 11.3 points vs STT mean, 8.0 points), as well as in the evaluation of the structural integrity of the tenodesis construct (BFAT mean, 2.7 points vs STT mean, 2.2 points) (P < .05). CONCLUSION: When arthroscopic tenodesis of the LHB is indicated, the authors recommend a bony fixation over soft tissue fixation because anchor fixation provides significant advantages concerning the clinical and structural outcome. PMID- 21257844 TI - Can magnetic resonance imaging predict posterior drawer laxity at the time of surgery in patients with knee dislocation or multiple-ligament knee injury? AB - BACKGROUND: Previous studies indicate that isolated posterior cruciate ligament injuries demonstrate magnetic resonance imaging (MRI) and clinical evidence of healing when treated nonoperatively; however, the authors are unaware of any other study that has looked at whether initial MRI can predict posterior cruciate ligament stability at the time of surgery in patients with knee dislocation. HYPOTHESIS: An MRI grading system will predict laxity on posterior drawer testing at the time of surgery in patients with knee dislocations. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: Forty-two consecutive patients with knee dislocation or multiple-ligament knee injury evaluated by MRI were included in the study. An assignment of grade 0 (intact), grade I (injured/fibers intact), grade II (partial tearing of ligament), or grade III (complete tear) was made after each reading on 2 separate occasions by 3 surgeons. Posterior laxity of the knee was graded by the magnitude of excursion on the posterior drawer test by the senior author at the time of surgery. Interobserver and intraobserver reliability of the MRI grading scheme expressed by the kappa statistic kappa, as well as the predictive value of MRI grade in determining stability of the posterior cruciate ligament at the time of surgery, was assessed. RESULTS: The posterior cruciate ligament injury grading scheme tested demonstrated moderate to substantial intraobserver agreement (kappa = 0.66, kappa = 0.53, and kappa = 0.52, respectively, for all raters). Interobserver reliability demonstrated only moderate agreement (kappa = 0.49). If the grading scheme was changed to group both grades 0 and I (intact) and grades II and III (disrupted), intraobserver reliability demonstrated substantial to almost perfect agreement (kappa = 0.83, kappa = 0.80, and kappa = 0.75), and interobserver reliability demonstrated substantial agreement (kappa = 0.70). If the posterior cruciate ligament was classified as intact (grade 0 [intact] or grade I [injured]) on initial MRI, the injured knee was judged clinically stable (tibia anterior to or flush with the femoral condyles on posterior drawer testing) at the time of surgery 98.5% (95% confidence interval, 93%-100%) of the time. When the posterior cruciate ligament was classified as disrupted (grade II [partial tear] or grade III [complete tear]), the injured knee was judged unstable (tibia posterior to the femoral condyles on posterior drawer testing) 57.5% (95% confidence interval, 40%-73%) of the time. CONCLUSION: The presented system of grading posterior cruciate ligament injury in patients with knee dislocation on initial MRI demonstrates moderate to substantial interobserver and intraobserver reliability that increases if the grading scheme is modified. An initial MRI scan read as grade I may predict stability to posterior drawer at the time of surgery. Even with MRI evidence of disruption in the posterior cruciate ligament (grade II and grade III injuries), posterior cruciate ligament reconstruction may not be clinically indicated at the time of reconstruction and/or repair of other associated injuries. PMID- 21257845 TI - Humeral avulsion of the inferior glenohumeral ligament in college female volleyball players caused by repetitive microtrauma. AB - BACKGROUND: Humeral avulsion of the inferior glenohumeral ligament is a rare injury resulting from hyperabduction and external rotation, and it is most commonly seen with sports-related injuries, including those from volleyball. The anterior band of the inferior glenohumeral ligament is most commonly injured (93%), whereas the posterior band is infrequently injured. The axillary pouch humeral avulsion of the inferior glenohumeral ligament as a result of repetitive microtrauma has not been yet described in the English literature. HYPOTHESIS: Humeral avulsions of the inferior glenohumeral ligaments are identifiable in volleyball players without acute injuries, and they have a unique pathologic pattern in these athletes. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Four female college volleyball players with pain in their dominant shoulder and with inferior capsular laxity and/or instability-without a known history of trauma or dislocation of the same shoulder-were referred by an experienced sports medicine orthopaedic surgeon for the magnetic resonance arthrogram procedure of the same shoulder. The imaging findings were retrospectively correlated with the initial interpretation and arthroscopic findings. RESULTS: All 4 patients had an axillary pouch humeral avulsion of the inferior glenohumeral ligament. Three had articular surface partial-thickness rotator cuff tear, and 3 had a labral tear. All were outside hitters or middle blockers who consequently performed multiple hitting maneuvers in practice and games. CONCLUSION: Repetitive microtrauma from overhead hitting in volleyball generates forces on the inferior capsule of the shoulder joint that may cause inferior capsular laxity and subsequent failure of the humeral side of the axillary pouch portion of the inferior glenohumeral ligament. PMID- 21257846 TI - Clinical and magnetic resonance imaging-based outcomes to 5 years after matrix induced autologous chondrocyte implantation to address articular cartilage defects in the knee. AB - BACKGROUND: The availability remains limited of midterm clinical and radiologic results into matrix-induced autologous chondrocyte implantation (MACI). Outcomes are required to validate the efficacy of MACI as a suitable surgical treatment option for articular cartilage defects in the knee. HYPOTHESIS: A significant improvement in clinical and magnetic resonance imaging-based (MRI-based) outcomes after MACI will exist throughout the postoperative timeline to 5 years after surgery. Furthermore, patient demographics, cartilage defect parameters, and injury/surgery history will be associated with patient and graft outcome, whereas a significant correlation will exist between clinical and MRI-based outcomes at 5 years after surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A prospective evaluation was undertaken to assess clinical and MRI-based outcomes to 5 years in 41 patients (53 grafts) after MACI to the knee. After MACI surgery and a 12-week structured rehabilitation program, patients underwent clinical assessments (Knee injury and Osteoarthritis Outcome Score, SF-36, 6-minute walk test, knee range of motion) and MRI assessments at 3, 12, and 24 months, as well as 5 years after surgery. The MRI evaluation assessed 8 previously defined pertinent parameters of graft repair, as well as a combined MRI composite score. RESULTS: A significant improvement (P < .05) was demonstrated for all Knee injury and Osteoarthritis Outcome Score and SF-36 subscales over the postoperative timeline, as well as the 6-minute walk test and active knee extension. A significant improvement (P < .0001) was observed for the MRI composite score, as well as several individual graft scoring parameters. At 5 years after surgery, 67% of MACI grafts demonstrated complete infill, whereas 89% demonstrated good to excellent filling of the chondral defect. Patient demographics, cartilage defect parameters, and injury/surgery history demonstrated no significant pertinent correlations with clinical or MRI-based outcomes at 5 years, and no significant correlations existed between clinical and MRI-based outcome measures. At 5 years after surgery, 98% of patients were satisfied with the ability of MACI surgery to relieve knee pain; 86%, with improvement in their ability to perform normal daily tasks; and 73%, with their ability to participate in sport 5 years after MACI. CONCLUSION: These results suggest that MACI provides a suitable midterm treatment option for articular cartilage defects in the knee. Long-term follow-up is essential to confirm whether the repair tissue has the durability required to maintain long-term patient quality of life. PMID- 21257847 TI - Improving injection accuracy of the elbow, knee, and shoulder: does injection site and imaging make a difference? A systematic review. AB - BACKGROUND: Joint injections and aspirations are used to reduce joint pain and decrease inflammation. The efficacy of these injections is diminished when they are placed inadvertently in the wrong location or compartment. The purpose of this study was to determine whether the use of varying sites or imaging techniques affects the rate of accurate needle placement in aspiration and injection in the shoulder, elbow, and knee. HYPOTHESES: (1) Accuracy rates of different joint injection sites will demonstrate variability. (2) Injection accuracy rates will be improved when performed with concomitant imaging. STUDY DESIGN: Systematic review of the literature. METHODS: Studies reporting injection accuracy based on image verification were identified through a systematic search of the English literature. Accuracy rates were compared for currently accepted injection sites in the shoulder, elbow, and knee. In addition, accuracy rates with and without imaging of these joints were compared. RESULTS: In the glenohumeral joint, there is a statistically higher accuracy rate with the posterior approach when compared with the anterior approach (85% vs 45%). Injection site selection did not affect accuracy for the subacromial space, acromioclavicular joint, elbow, or knee. The use of imaging improved injection accuracy in the glenohumeral joint (95% vs 79%), subacromial space (100% vs 63%), acromioclavicular joint (100% vs 45%), and knee (99% vs 79%). CONCLUSION: Injection accuracy rates are significantly higher for the posterior approach compared with the anterior approach for the glenohumeral joint. Similarly, the accuracy rates are also higher when imaging is used in conjunction with injection of the glenohumeral joint, subacromial space, acromioclavicular joint, and knee. PMID- 21257848 TI - Biomechanical evaluation of pediatric anterior cruciate ligament reconstruction techniques. AB - BACKGROUND: Anterior cruciate ligament (ACL) reconstruction rates in skeletally immature patients have risen recently because of increased injury frequency combined with growing awareness of the importance of treating them in an acute setting. Concerns over potential growth disturbances caused by traditional tunnel placement have prompted the description of several partial and complete physeal sparing techniques. HYPOTHESIS: Native knee kinematics will most closely be restored by the all-epiphyseal technique because it best re-creates the intra articular ACL anatomy. STUDY DESIGN: Controlled laboratory study. METHODS: Six cadaveric knees were subjected to static anteroposterior, varus, and internal rotation forces at 0 degrees ,15 degrees , 30 degrees , 45 degrees , 60 degrees , and 90 degrees of flexion. Displacement and rotation of the tibia with respect to the femur were measured in the intact knee, after ACL disruption, and again after ACL reconstruction using all-epiphyseal, transtibial over-the-top, and iliotibial band physeal-sparing techniques. RESULTS: Peak anteroposterior translation in the ACL intact and deficient states was 2.8 +/- 1.4 mm and 7.2 +/- 2.7 mm, respectively, at 30 degrees . The all-epiphyseal reconstruction had a peak translation of 5.1 +/- 2.3 mm at 30 degrees , and the transtibial over-the top reconstruction had a peak of 4.8 +/- 1.8 mm at 30 degrees , both significantly greater than the ACL intact state. The iliotibial band technique had a peak anteroposterior translation of 1.7 +/- 1.1 mm at 45 degrees , which was significantly less than the ACL-deficient state. Internal rotation was significantly increased in the all-epiphyseal reconstruction compared with the ACL intact state and significantly decreased at all flexion angles except 0 degrees in the iliotibial band reconstruction. The only technique to affect varus rotation was the iliotibial band reconstruction, which significantly decreased varus rotation from the ACL-deficient state at flexion angles greater than 30 degrees . CONCLUSION: All physeal-sparing reconstruction techniques restored some stability to the knee. The iliotibial band reconstruction best restored anteroposterior stability and rotational control, although it appeared to overconstrain the knee to rotational forces at some flexion angles. CLINICAL RELEVANCE: This study provides orthopaedic surgeons with objective knee kinematic data to help guide them in making more informed decisions on the optimal technique for ACL reconstruction in skeletally immature patients. PMID- 21257849 TI - Adrenal imaging: why, when, what, and how? Part 3. The algorithmic approach to definitive characterization of the adrenal incidentaloma. PMID- 21257850 TI - United States Preventive Services Task Force screening mammography recommendations: science ignored. AB - OBJECTIVE: The purpose of this article is to examine the scientific evidence considered by the United States Preventive Services Task Force (USPSTF) in recommending against screening mammography in women 40-49 years old and against annual screening mammography in women 50 and older. We use evidence made available to the USPSTF to estimate the benefits and "harms" of screening mammography in women 40 years old and older. We use Cancer Intervention and Surveillance Modeling Network modeling to compare lives saved by different screening scenarios and the summary of evidence prepared for the USPSTF to estimate the frequency of harms of screening mammography by age. CONCLUSION: Averaged over the six Cancer Intervention and Surveillance Modeling Network models of benefit, screening mammography shows greatest benefit--a 39.6% mortality reduction--from annual screening of women 40-84 years old. This screening regimen saves 71% more lives than the USPSTF-recommended regimen of biennial screening of women 50-74 years old, which had a 23.2% mortality reduction. For U.S. women currently 30-39 years old, annual screening mammography from ages 40-84 years would save 99,829 more lives than USPSTF recommendations if all women comply, and 64,889 more lives with the current 65% compliance rate. The potential harms of a screening examination in women 40-49 years old, on average, consist of the risk of a recall for diagnostic workup every 12 years, a negative biopsy every 149 years, a missed breast cancer every 1,000 years, and a fatal radiation-induced breast cancer every 76,000-97,000 years. Evidence made available to the USPSTF strongly supports the mortality benefit of annual screening mammography beginning at age 40 years, whereas potential harms of screening with this regimen are minor. PMID- 21257851 TI - Image quality and radiation exposure in pediatric cardiovascular CT angiography from different injection sites. AB - OBJECTIVE: The purpose of this article is to evaluate the effect of different injection sites (i.e., head, arm, or leg vein) on image quality and radiation exposure in pediatric cardiovascular CT angiography (CTA) with 64-MDCT. MATERIALS AND METHODS: CTA was performed in 61 children with suspected extracardiac abnormalities. Patients were assigned to three groups according to the different injection sites: head, arm, or leg vein. Enhancement of heart chamber and great vessels and background noise were quantified. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), dose-length product (DLP), and effective dose (ED) were calculated. Subjective image quality was assessed by two radiologists in consensus. RESULTS: There was no significant difference among all groups in the mean attenuation of the heart chamber, pulmonary artery (PA), and aorta. There was also no significant difference in their mean attenuation, background noise, SNR, and CNR. However, there were significant differences among the three groups for aorta image quality (p = 0.006), despite the nonsignificant differences in heart chamber and PA image quality. There also were significant differences among the three groups for total DLP and ED (p = 0.01 for both), with prescanning DLPs of 17.6%, 20.2%, and 24.5%, respectively, of the total DLP for each group. CONCLUSION: Although all injection sites can yield diagnostic-quality images with a low radiation dose in pediatric cardiovascular CTA, the injection site has a slight impact on the image quality of different targeted areas with a significantly different radiation dose. The optimization of a prescanning protocol may open an avenue to reduce the radiation dose associated with cardiovascular CTA. PMID- 21257852 TI - Contrast-enhanced ultrasound with perflubutane microbubble agent: evaluation of differentiation of hepatocellular carcinoma. AB - OBJECTIVE: The aim of this study was to evaluate the effectiveness of contrast enhanced ultrasound with a perflubutane microbubble agent in the assessment of cellular differentiation of hepatocellular carcinoma (HCC). SUBJECTS AND METHODS: Continuous harmonic imaging with a low mechanical index (0.21-0.30) was performed 1, 5, and 10 minutes after i.v. contrast injection (0.0075 mL/kg). Tumor enhancement was evaluated by both subjective reading and objective intensity analysis based on the signal distribution in the nontumor parenchyma. Tumor vascularity was assessed with CT during hepatic arteriography. RESULTS: Sixty four patients with 77 histologically proved HCCs (mean greatest dimension, 19.1 +/- 5.3 mm)--six poorly differentiated HCCs, 45 moderately differentiated HCCs, and 26 well-differentiated HCCs--were enrolled in this prospective study. Among 64 hyperenhancing lesions on peak enhancement sonograms, four poorly differentiated HCCs and eight moderately differentiated HCCs exhibited washout within 1 minute. In addition to these 12 lesions, 36 lesions exhibited washout 5 minutes after injection, resulting in a total of 48 washout lesions. Fifty-four lesions exhibited washout 10 minutes after contrast injection (six poorly differentiated, 38 moderately differentiated, and 10 well-differentiated HCCs). Washout was more frequent in poorly than in moderately differentiated HCC (p = 0.0117) and well-differentiated HCC (p = 0.0003) in the 1-minute phase and was more frequent in moderately differentiated than in well-differentiated HCC in the 5-minute (p = 0.0026) and 10-minute (p = 0.0117) phases. Thirteen lesions were isoenhancing or hypoenhancing on peak enhancement sonograms (three moderately differentiated and 10 well-differentiated HCCs). Contrast-enhanced ultrasound and CT during hepatic arteriography did not differ significantly with respect to rate of detection of hyperenhancing lesions. CONCLUSION: The findings at contrast enhanced ultrasound with the perflubutane microbubble agent may be predictive of cellular differentiation of HCC without needle biopsy. PMID- 21257853 TI - Solitary fibrous tumor of the genitourinary tract. AB - OBJECTIVE: The purpose of this article is to describe the imaging features of solitary fibrous tumors involving the kidney, bladder, adrenal gland, retroperitoneum, or pelvis and other rare locations. CONCLUSION: Although clear radiologic differentiation of solitary fibrous tumors from malignancy is not possible, we suggest that familiarity with the manifestations of solitary fibrous tumors can help to avoid unnecessary radical surgery before histopathologic proof of malignancy is obtained. PMID- 21257854 TI - Incidence of immediate gadolinium contrast media reactions. AB - OBJECTIVE: Our objective was to determine the incidence of immediate adverse events for gadolinium-based contrast agents. MATERIALS AND METHODS: All gadolinium-based contrast agent adverse events reported to radiology quality assurance committees were graded according to American College of Radiology criteria and divided by the total number of injections to determine incidence during the past 10 years. For each event, an age- and examination-matched control patient was identified to compare sex, weight, creatinine, eosinophil count, allergic history and gadolinium-based contrast agent dose differences. The U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (AERS) database was analyzed to compare local experience to national trends. RESULTS: Abdominal MRI had the highest rates of adverse events, 0.013% compared with brain (0.0045%, p < 0.001) or spine (0.0034%, p < 0.001). Adverse events were more likely in women, with a female to male ratio of 3.3, and in patients with history of prior allergic reactions (p < 0.001). Immediate adverse events rates were 0.2, 0.5, 1.2, and 3.3 per 1,000 injections for gadodiamide, gadopentetate dimeglumine, gadobenate dimeglumine, and gadoteridol, respectively. Gadobenate dimeglumine had more severe patient reactions, including three patients who arrested (defined as the patient becoming unresponsive and the code team being called), one of whom died. From 2004 to 2009, the FDA received reports on 40 gadolinium-based contrast agent U.S. deaths unrelated to nephrogenic systemic fibrosis, with an incidence per million doses of 0.15, 0.19, 0.97, 2.7, and 0.7 for gadodiamide, gadoversetimide, gadopentetate dimeglumine, gadobenate dimeglumine, and gadoteridol, respectively. CONCLUSION: This limited retrospective analysis shows that gadolinium-based contrast agents are very safe, with only rare reports of death, and raises the possibility that nonionic linear gadolinium-based contrast agents and gadopentetate dimeglumine may have fewer severe immediate adverse events compared with gadobenate dimeglumine. PMID- 21257855 TI - A CT acquisition technique to generate images at various dose levels for prospective dose reduction studies. AB - OBJECTIVE: The purpose of this article is to determine whether the average of N CT images acquired at a particular dose (D) has image noise equivalent to that of a single image acquired at a dose of N * D. MATERIALS AND METHODS: An electron density phantom, an image quality phantom, and an adult anthropomorphic phantom were scanned multiple times on a 16-MDCT scanner at five effective tube current rotation time product (mAs) settings (130 kVp; 12, 24, 48, 72, and 144 mAs). Lower-mAs images were averaged to simulate higher-mAs images. Differences in CT number and image noise between simulated and acquired images were quantified using the electron density phantom. Image quality phantom images were scored by three physicists to investigate differences in low- and high-contrast resolution. A forced-choice observer study was performed with three radiologists using anthropomorphic phantom images to evaluate differences in overall image quality. RESULTS: The CT number was, on average, reproduced to within 1 HU, and image noise was reproduced to within 4%, which is below the threshold for visibly perceptible differences in noise. Low- and high-contrast resolution were not degraded, and simulated images were visually indistinguishable from acquired images. CONCLUSION: For the dose range studied, it was concluded that the image quality of a CT image produced by averaging multiple low-mAs CT images is identical to that of a high-mAs image acquired at equivalent effective dose, when all other acquisition and reconstruction parameters are held constant. Prospective CT dose-reduction studies may be feasible by acquiring multiple low dose scans instead of a single high-dose scan. Simulated high-dose images could be interpreted clinically, whereas lower-dose images would be available for an observer study. PMID- 21257856 TI - Direct quantification of breast dose during coronary CT angiography and evaluation of dose reduction strategies. AB - OBJECTIVE: The purpose of this study was to quantify the absorbed radiation dose received by the adult female breast during coronary CT angiography (CTA) and to evaluate the effectiveness of various dose reduction strategies. MATERIALS AND METHODS: An adult female thoracic anthropomorphic phantom was scanned using eight different clinical coronary CTA protocols that varied in detector configuration (320 * 0.5 mm or 64 * 0.5 mm), x-ray tube activation (full R-R, 65% R-R, or 70 80% R-R), use of tube current modulation, and use of breast shields. Direct dosimetry measurements were performed using Gafchromic film to determine the absorbed breast dose. RESULTS: Retrospective helical data acquisition using a 64 detector array and a full cardiac cycle without dose modulation or breast shielding is associated with an average absorbed breast dose of 82.9 mGy. Optimization of coronary CTA technique using a 320-detector array and a 70-80% cardiac phase reduces the absorbed breast dose by 78.9% to 17.5 mGy, whereas breast shields used in isolation reduces breast dose by up to 46.8%. CONCLUSION: The implementation of clinically validated coronary CTA protocols using large area detector acquisition and prospective ECG gating with limited x-ray tube activation results in substantial breast dose savings of up to 78.9% and should be used whenever possible in combination with bismuth breast shields to achieve further dose reduction. PMID- 21257857 TI - Radiation-related cancer risks in a clinical patient population undergoing cardiac CT. AB - OBJECTIVE: The purpose of our study was to estimate cancer induction risk and generate risk conversion factors in cardiac CT angiography. MATERIALS AND METHODS: Under an institutional review board waiver and in compliance with HIPAA, we collected characteristics for a consecutive cohort of 100 patients (60 men and 40 women; mean age, 59 +/- 11 years) who had previously undergone ECG-gated cardiac CT angiography on a 64-slice CT scanner. The volume CT Dose Index (CTDI(vol)) and dose-length product (DLP) were recorded and used with the ImPACT CT Patient Dosimetry Calculator to compute organ and effective doses in a standard 70 kg phantom. Patient-specific organ and effective doses were obtained by applying a weight-based correction factor. Radiation doses to radiosensitive organs were converted to risks using age- and sex-specific data published in BEIR VII. RESULTS: Median values were 62 mGy for CTDI(vol), 1,084 mGy-cm for DLP, and 17 cm for scan length. Effective doses ranged from 20 mSv (10th percentile) to 31 mSv (90th percentile). Median cancer induction risks in sensitive organs for men and women were 0.065% and 0.17%, respectively. For men and women, the range of risks was about a factor of 2. In men and women, about three quarters of the cancer risk was from lung cancer. Inclusion of the remaining less sensitive organs exposed during cardiac CT angiography examinations would likely increase the cancer induction risk by ~20%. CONCLUSION: The average cancer induction risk in sensitive organs from cardiac CT angiography for our patient cohort was 0.13%, with a female to male cancer induction risk ratio of 2.6. PMID- 21257858 TI - The art and science of straight lines in radiology. AB - OBJECTIVE: The purpose of this article is to review the physical basis for straight radiographic lines, identify the possible components that may form a straight line interface in the body, provide illustrative examples across multiple organ systems and modalities, and explore how the detection of these interfaces can support specific diagnoses. CONCLUSION: Detection of a straight line interface can help the radiologist recognize otherwise difficult or subtle pathologic processes, and identification of its components can provide valuable clues to diagnosis. PMID- 21257859 TI - Comparison of T1rho measurements in agarose phantoms and human patellar cartilage using 2D multislice spiral and 3D magnetization prepared partitioned k-space spoiled gradient-echo snapshot techniques at 3 T. AB - OBJECTIVE: The purpose of this article is to compare in vitro T1rho measurements in agarose phantoms and articular cartilage specimens using 2D multislice spiral and 3D magnetization prepared partitioned k-space spoiled gradient-echo snapshot MRI sequences. MATERIALS AND METHODS: Six phantoms (agarose concentration, 2%, 3%, and 4%; n = 2 each) and 10 axially sliced patellar specimens from five cadaveric donors were scanned at 3 T. T1rho-weighted images were acquired using 2D spiral and 3D magnetization prepared partitioned k-space spoiled gradient-echo snapshot sequences. Regions of interest were analyzed to measure T1rho values centrally within phantoms, to evaluate effects of pulse sequence and agarose concentration. In patellar specimens, regions of interest were analyzed to measure T1rho values with respect to anatomic location (the medial and lateral facets and the median ridge in deep and superficial halves of the cartilage) as well as location that exhibited magic angle effect in proton density-weighted images, to evaluate the effects of pulse sequence, anatomic location, and magic angle. RESULTS: In phantoms, T1rho values were similar (p = 0.9) between sequences but decreased significantly (p < 0.001), from ~55 to ~29 milliseconds, as agarose concentration increased from 2% to 4%. In cartilage specimens, T1rho values were also similar between sequences (p = 0.3) but were significantly higher (p < 0.001) in the superficial layer (95-120 milliseconds) compared with the deep layer (45-75 milliseconds). CONCLUSION: T1rho measurements of human patellar cartilage specimens and agarose phantoms using 2D spiral and 3D magnetization prepared partitioned k-space spoiled gradient-echo snapshot sequences gave similar values. Lower T1rho values for phantoms with higher agarose concentrations and proteoglycan concentrations that are higher in deeper layers of cartilage than in superficial layers suggest that our method is sensitive to concentration of macromolecules in biologic tissues. PMID- 21257860 TI - Association of parameniscal cysts with underlying meniscal tears as identified on MRI and arthroscopy. AB - OBJECTIVE: Although patients with parameniscal cysts usually have underlying meniscal tears, we noted that this association was less common with anterior lateral cysts. We wished to determine whether the frequency of a meniscal tear underlying a parameniscal cyst varied with cyst location. MATERIALS AND METHODS: We reviewed a database of 7,771 knee MR examinations and identified 134 patients with an MR diagnosis of 138 parameniscal cysts and correlative arthroscopy in 78 patients. We reviewed their medical records and MR studies to determine the location of the cysts and presence of an underlying meniscal tear as determined by MRI or arthroscopy. RESULTS: There were 50 lateral and 88 medial parameniscal cysts. Medial meniscal tears were found underlying a cyst in 96% of arthroscopy patients and 86% of patients who had only MR examinations without a location difference in tears (p = 0.68). Meniscal tears were found on MRI or arthroscopy in all 28 patients with a lateral cyst overlying the body or posterior horn of the lateral meniscus, whereas a tear was found on MRI or arthroscopy in only 14 (64%) of 22 patients with cysts adjacent to or extending to the lateral meniscus anterior horn (p = 0.006). Anterior lateral cysts extended medially either into the root or into Hoffa fat-pad, but the type of extension did not correlate with the presence of an underlying meniscal tear. CONCLUSION: In contrast to medial parameniscal cysts or cysts at other locations adjacent to the lateral meniscus, anteriorly located lateral parameniscal cysts are less likely to have underlying meniscal tears. PMID- 21257861 TI - Rosai-Dorfman disease in neuroradiology: imaging findings in a series of 10 patients. AB - OBJECTIVE: Rosai-Dorfman disease is a rare disorder characterized histologically by lymphatic sinus dilatation due to histiocyte proliferation. Our goal was to describe the CT, MRI, and (18)F-FDG (FDG) PET findings in a series of patients with this diagnosis. MATERIALS AND METHODS: We retrospectively reviewed the imaging studies of 10 patients with pathologically confirmed Rosai-Dorfman disease who were treated in our institution between January 2004 and December 2007. RESULTS: We found the following areas of general involvement: three intracranial, seven head and neck, and three spinal, with some patients having more than one site. Specific sites of involvement included the following: intracranial meninges, n = 2; pituitary, n = 2; lacrimal gland, n = 1; paranasal sinus, n = 3; neck lymph nodes, n = 6; salivary gland, n = 3; tonsil, n = 1; skin, n = 1; spinal meninges, n = 2; vertebral body, n = 1; and thymus, n = 1. The MRI characteristics of the involved areas were generally T1 isointense, T2 isointense, diffusion isointense to gray matter, and intensely enhancing with gadolinium chelate contrast agents. CT images generally showed the lesions were hyperdense to gray matter and intensely enhancing. FDG PET showed variable uptake, with nodal and lacrimal disease generally being FDG avid and other sites not. CONCLUSION: Rosai-Dorfman disease has a protean imaging appearance but most frequently presents as neck lymphadenopathy. The disease is frequently multifocal, and a diagnosis in one area should prompt suspicion that other sites may be involved also. PMID- 21257862 TI - Pediatric CT sedation: comparison of dexmedetomidine and pentobarbital. AB - OBJECTIVE: Our institution replaced pentobarbital with dexmedetomidine for pediatric CT sedation. The purpose of this study was to compare the efficacy, incidence of adverse events, and cardiovascular and respiratory profiles of these two sedatives. MATERIALS AND METHODS: Quality assurance data were accessed for a review of demographics, outcome parameters, and adverse events among all children who received either pentobarbital or dexmedetomidine. RESULTS: From January 2004 through June 2009 there were 388 pentobarbital sedations and 1,274 dexmedetomidine sedations. Age, sex, weight, and duration of imaging study were similar in the two groups. Average time to achieve sedation was 12 +/- 4 minutes with dexmedetomidine and 6 +/- 3 minutes with pentobarbital (p < 0.001). Recovery time was 32 +/- 18 minutes with dexmedetomidine and 95 +/- 28 minutes with pentobarbital (p < 0.001). There were no differences between groups in incidence of oxygen desaturation and need for brief positive pressure ventilation. The odds of needing additional sedative agents to complete the study were significantly higher with pentobarbital than with dexmedetomidine (odds ratio, 4.0; 95% CI, 2.0 8.4; p < 0.001). There was a significantly lower incidence of agitation and rage with dexmedetomidine (p < 0.01) but higher risk of hypotension (p < 0.01). There was one failed sedation in each group (p = 0.99). CONCLUSION: Dexmedetomidine is a safe and effective alternative to pentobarbital for pediatric CT, being associated with a much shorter recovery time and less need for adjuvant sedatives. PMID- 21257863 TI - Bronchial and nonbronchial systemic artery embolization in patients with major hemoptysis: safety and efficacy of N-butyl cyanoacrylate. AB - OBJECTIVE: The purpose of this study was to evaluate the safety and efficacy of N butyl cyanoacrylate for bronchial and nonbronchial systemic artery embolization in the management of major hemoptysis. MATERIALS AND METHODS: From March 2004 through March 2006, 108 patients with major hemoptysis underwent embolization with N-butyl cyanoacrylate. The common conditions causing hemoptysis were bronchiectasis (n = 34), sequelae of tuberculosis (n = 31), active tuberculosis (n = 18), lung cancer (n = 8), and aspergilloma (n = 6). A retrospective analysis of postprocedure outcomes, including immediate success, recurrence of hemoptysis, cause of recurrence, and complications, was performed. RESULTS: Immediate success was achieved in 105 patients (97.2%). During the follow-up period (range, 5 days 63 months; median, 28.5 months), recurrent hemoptysis was found in 21 of the 105 patients (20%). Repeat angiograms (n = 14) revealed incomplete embolization during the initial procedure in seven patients with early recurrence (< 3 months) and revascularization of nonbronchial systemic collateral arteries in seven patients with late recurrence (> 3 months). No recanalization of embolized arteries was found on repeat angiograms or at follow-up CT. The cumulative nonrecurrence rates were 91.4% 1 month, 83.4% 1 year, 76.7% 3 years, and 56.8% 5 years after the initial procedure. The procedure-related complications included transient chest pain (n = 21) and denudation of the bronchial mucosa (n = 3), which was clinically silent but found at bronchoscopy. CONCLUSION: N-butyl cyanoacrylate is a safe and effective agent for embolization in patients with major hemoptysis. PMID- 21257864 TI - Radiofrequency ablation for the treatment of primary intrahepatic cholangiocarcinoma. AB - OBJECTIVE: We present the results of percutaneous radiofrequency ablation (RFA) in patients with unresectable primary intrahepatic cholangiocarcinoma. MATERIALS AND METHODS: From 2000 to 2009, 13 patients with 17 primary intrahepatic cholangiocarcinomas underwent RFA at our institution. Intrahepatic cholangiocarcinoma was unresectable because of poor hepatic reserve due to liver cirrhosis in nine patients, extrahepatic extension in two, atrophy of the left hepatic lobe in one, and underlying comorbidities in one. Ten tumors had a diameter of less than 3 cm, five were between 3 and 5 cm, and two were larger than 5 cm. Technical effectiveness was defined as the complete ablation of the tumor, shown by imaging follow-up 1 month later. Local progression-free survival, overall survival periods, and complications after RFA were also evaluated. RESULTS: Technical effectiveness of RFA was achieved for 15 of the 17 tumors (88%), all smaller than 5 cm in diameter. Treatment failure occurred in two patients with large tumors (7 and 8 cm). After the 17 RFA sessions, one major complication (6%), a liver abscess, occurred 1 month later. During follow-up (median, 19.5 months; range, 3.3-82.1 months), nine patients died and four remain alive. Median local progression-free survival and overall survival periods were 32.2 and 38.5 months, respectively. The 1-, 3-, and 5-year survival rates were 85%, 51%, and 15%, respectively. CONCLUSION: RFA may provide successful local tumor control in patients with primary intrahepatic cholangiocarcinomas of intermediate (3-5 cm) or small (< 3 cm) diameter. RFA for unresectable primary intrahepatic cholangiocarcinoma resulted in a median overall survival period of 38.5 months. PMID- 21257865 TI - Optimum first-line treatment technique for benign cystic thyroid nodules: ethanol ablation or radiofrequency ablation? AB - OBJECTIVE: The purpose of this article is to compare the efficacy and safety of ethanol ablation and radiofrequency ablation (RFA) used as treatment of benign cystic thyroid nodules. MATERIALS AND METHODS: Fifty-seven patients (44 women and 13 men) with benign cystic nodules (cystic portions > 90%) inducing pressure symptoms or cosmetic problems were treated with ethanol ablation (n = 36) or RFA (n = 21). Ethanol ablation was performed using 16- or 18-gauge needles with 95 99% ethanol, and RFA used a cooled-electrode RFA system and 17- or 18-gauge internally cooled electrodes. Of nine viscous nodules, five were treated with ethanol ablation and four with RFA, with all except for one nodule in the RFA group being treated only after evacuation of internal colloid material. Nodule volume, symptom score (0-10), cosmetic score (1-4), and complications were evaluated before and after treatment. RESULTS: Both ethanol ablation and RFA resulted in significant decreases in nodule volume (p < 0.001), symptom score (p < 0.001), and cosmetic score (p < 0.001). There were no between-group differences in mean volume reduction (p = 0.15), decreases in symptoms (p = 0.53), cosmetic scores (p = 0.69), or therapeutic success rate (p = 0.61). However, the mean number of treatment sessions was significantly lower in the ethanol ablation than in the RFA group (p = 0.026). No serious complications were encountered in either group. CONCLUSION: Ethanol ablation yielded similar results with fewer treatment sessions compared with RFA. Because ethanol ablation is also less expensive and simpler to perform than RFA, our findings suggest that ethanol ablation, rather than RFA, should be the first-line treatment technique for benign predominantly cystic thyroid nodules. PMID- 21257866 TI - Liability for typographical errors. PMID- 21257867 TI - To order or not to order a CT examination because of radiation exposure: that is the question. PMID- 21257868 TI - Is this appropriate: will CT take my life? PMID- 21257869 TI - Overall survival after transarterial lipiodol infusion chemotherapy with or without embolization for unresectable hepatocellular carcinoma: propensity score analysis. PMID- 21257870 TI - Abdominopelvic CT increases diagnostic certainty and guides management decisions: a prospective investigation of 584 patients in a large academic medical center. AB - OBJECTIVE: The objective of our study was to prospectively determine how CT affects physicians' diagnostic certainty and management decisions in the setting of patients with nontraumatic abdominal complaints presenting to the emergency department. SUBJECTS AND METHODS: We included 584 patients presenting with nontraumatic abdominal complaints to the emergency department from November 2006 through February 2008. Emergency department clinicians were prospectively surveyed both before abdominal CT (pre-CT) and after abdominal CT (post-CT) to determine the leading diagnosis, the diagnostic certainty, and the management decisions. Changes were assessed by Fisher's exact test and the log likelihood ratio. RESULTS: The most common diagnoses were renal colic (119/584, 20.4%) and intestinal obstruction (80/584, 13.7%). CT altered the leading diagnosis in 49% of the patients (284/584, p < 0.00001) and increased mean physician diagnostic certainty from 70.5% (pre-CT) to 92.2% (post-CT) (p < 0.001; log likelihood ratio, 2.48). The management plan was changed by CT in 42% (244/583) (p < 0.0001). Physicians planned to admit 75.3% of the patients (440/584) to the hospital before CT; that plan was changed to hospital discharge with follow-up in 24.1% of patients (106/440) after CT. Surgery was planned for 79 patients before CT, whereas hospital discharge was planned for 25.3% of these patients (20/79) after CT. CONCLUSION: In the management of patients presenting to the emergency department with nontraumatic abdominal complaints, CT changes the leading diagnosis, increases diagnostic certainty, and changes potential patient management decisions. PMID- 21257871 TI - Preventable and self-inflicted disease in women: Hippocrates redux. PMID- 21257872 TI - Microbubble contrast-enhanced ultrasound for sentinel lymph node detection: ready for prime time? PMID- 21257873 TI - Preoperative sentinel node identification with ultrasound using microbubbles in patients with breast cancer. AB - OBJECTIVE: Sentinel lymph node (SLN) biopsy is the standard procedure for axillary staging in early breast cancer. Lymphatic imaging after peritumoral microbubble injection has been described in animal models. The aim of this study was to identify and localize SLNs preoperatively by contrast-enhanced sonography after intradermal injection of microbubbles in patients with breast cancer. SUBJECTS AND METHODS: Eighty consecutive consenting patients with primary breast cancer were recruited. Patients received a periareolar intradermal injection of microbubble contrast agent. Breast lymphatics were visualized by sonography and followed to the axilla to identify SLNs. A guidewire was deployed to localize the SLN. The next day, patients underwent standard tumor excision and SLN biopsy. RESULTS: In 71 (89%) of the 80 patients, SLNs were identified and guidewires were inserted. In these patients, operative findings using conventional radioisotope and blue dye techniques confirmed that the wired nodes were SLNs. Fourteen patients were found to have metastases in SLNs. In these patients, the SLNs were identified correctly and were localized with guidewires before surgery. CONCLUSION: SLNs may be identified and localized before surgery using contrast enhanced sonography after injection of microbubbles. PMID- 21257874 TI - Women's health, accountable care organizations, and radiology practice: maximizing radiology's value under health care reform. PMID- 21257875 TI - Noninvasive risk assessment for stroke: special emphasis on carotid atherosclerosis, sex-related differences, and the development of an effective screening strategy. AB - OBJECTIVE: Stroke accounts for a significant degree of morbidity, mortality, and health care expenditure in this nation despite the many medical and surgical preventive measures we have in place. This article discusses how developing a universally accepted effective screening examination will help decrease this health care burden. Risk factors for the development of cardiovascular disease are explored. Special attention is given to the pathogenesis and diagnosis of carotid atherosclerosis because it accounts for a large percentage of both embolic and ischemic strokes. Current diagnostic testing, in particular duplex carotid sonography, and proposed screening strategies for the detection of carotid atherosclerosis and other risk factors are reviewed. Sex-related differences proposed in the current literature are also explored in this article because they may affect how we screen for and prevent stroke. CONCLUSION: Developing an accurate, cost-effective, and universally acknowledged screening test will allow us to maximize the preventive medical and surgical measures we already have in place. Doing so will in turn lead to a significant decrease in the morbidity, mortality, and health care expenditure associated with stroke. PMID- 21257876 TI - Cardiovascular disease and stroke in women: role of radiology. AB - OBJECTIVE: The purposes of this review are to describe the clinical presentation and diagnostic test characteristics in the care of women with cardiovascular and cerebrovascular disease and to discuss the role of newer imaging modalities in improving diagnostic accuracy in the detection of these diseases. CONCLUSION: Despite major advances in both diagnostics and therapeutics, cardiovascular and cerebrovascular diseases remain two of the leading causes of morbidity and mortality among women worldwide. More research is needed into sex differences in these diseases, particularly to discern whether accurate imaging can lead to early diagnosis, change in clinical management, and overall improvement in patient outcomes. PMID- 21257877 TI - Diabetes revealed: multisystem danger. AB - OBJECTIVE: The purpose of this article is to review the role of diagnostic imaging in the evaluation of women with diabetes. CONCLUSION: Diabetic patients present a challenging population for the performance of various imaging studies and special considerations need to be made to obtain adequate studies. Imaging plays a significant role in assessing the multisystem morbidity of diabetes. Furthermore, diabetes in women may have some unique features and consequences and imaging studies can aid in the correct management of these patients. PMID- 21257878 TI - Epidemiology of lung cancer in women: risk factors, survival, and screening. AB - OBJECTIVE: Lung cancer remains the leading cause of cancer mortality in both men and women. Tobacco use causes the vast majority of lung cancer in women but does not explain all cases, because about one in five women who develop lung cancer have never smoked. CONCLUSION: Environmental exposures, genetic predisposition, hormonal factors, and viral infection may all play a role in lung cancer in women. A better understanding may provide an avenue to more effective screening, diagnosis, and therapy. PMID- 21257879 TI - Breast imaging and intervention in the overweight and obese patient. AB - OBJECTIVE: This article comments on the challenges and coping mechanisms for evaluating overweight and obese patients with breast imaging and diagnostic techniques. With the prevalence of obesity in society, the obstacles that arise regarding patients' adherence to screening guidelines are important to address. CONCLUSION: This article discusses social factors and physical limitations that influence these patients' desires and ability to seek health care, specifically breast care and the problems that arise during imaging and interventional procedures. PMID- 21257880 TI - Colorectal cancer screening in women: an underutilized lifesaver. AB - OBJECTIVE: Colorectal cancer (CRC) represents the third most common cancer diagnosed and a major cause of cancer-related deaths in women. Despite strong evidence that early screening decreases colorectal cancer incidence and mortality rates, colorectal cancer screening rates in women still lag significantly behind screening rates for breast and cervical cancers. Additionally, women have been found to be less likely than men to undergo CRC screening. This is despite the fact that the overall lifetime risk for the development of colorectal carcinoma is similar in both sexes. Barriers to screening have been found to be different for women compared with men. Screening adherence in women also appears to be associated with various social and demographic factors. CONCLUSION: CT colonography (CTC) is an accurate, minimally invasive, and well-tolerated examination that is newly endorsed by the American Cancer Society, U.S. Multisociety Task Force, and the American College of Radiology. Improved screening compliance may occur in women with further dissemination of CTC. PMID- 21257881 TI - Imaging and obesity: a perspective during pregnancy. AB - OBJECTIVE: Obesity is a rapidly growing global pandemic that has surpassed all other risk factors in obstetric care, converting 40% of pregnant women into a high-risk category, with the attendant increased burden on our health care systems. This article will review the role of the imaging specialist in understanding the determinants of poor pregnancy outcome in the mother and her baby. We will also review how obesity affects the quality of patient care in terms of the limitation in completion of fetal anatomic surveys, ergonomic risks to the imaging specialist, and techniques that may improve imaging quality and ensure patient safety. We urgently need refinement in our ability to detect those fetuses at greatest risk for stillbirth and growth restriction, macrosomia, and congenital anomalies, and to understand the potentially multigenerational impact of maternal obesity on the incidence of obesity and the metabolic syndrome for the future. Utilization of emerging technologies such as laser Doppler, evolving MRI technology, and expanded roles for ultrasound such as ultrasound guidance for placement of labor anesthesia will become increasingly important. CONCLUSION: The far-reaching implications of obesity on the mother and her children will continue have a progressive impact on our health care systems and resources. PMID- 21257882 TI - Detection and classification of calcifications on digital breast tomosynthesis and 2D digital mammography: a comparison. AB - OBJECTIVE: The purpose of this article is to compare the ability of digital breast tomosynthesis and full field digital mammography (FFDM) to detect and characterize calcifications. MATERIALS AND METHODS: One hundred paired examinations were performed utilizing FFDM and digital breast tomosynthesis. Twenty biopsy-proven cancers, 40 biopsy-proven benign calcifications, and 40 randomly selected negative screening studies were retrospectively reviewed by five radiologists in a crossed multireader multimodal observer performance study. Data collected included the presence of calcifications and forced BI-RADS scores. Receiver operator curve analysis using BI-RADS was performed. RESULTS: Overall calcification detection sensitivity was higher for FFDM (84% [95% CI, 79-88%]) than for digital breast tomosynthesis (75% [95% CI, 70-80%]). [corrected] In the cancer cohort, 75 (76%) of 99 interpretations identified calcification in both modes. Of those, a BI-RADS score less than or equal to 2 was rendered in three (4%) and nine (12%) cases with FFDM and digital breast tomosynthesis, respectively. In the benign cohort, 123 (62%) of 200 interpretations identified calcifications in both modes. Of those, a BI-RADS score greater than or equal to 3 was assigned in 105 (85%) and 93 (76%) cases with FFDM and digital breast tomosynthesis, respectively. There was no significant difference in the nonparametric computed area under the receiver operating characteristic curves (AUC) using the BI-RADS scores (FFDM, AUC = 0.76 and SD = 0.03; digital breast tomosynthesis, AUC = 0.72 and SD = 0.04 [p = 0.1277]). CONCLUSION: In this small data set, FFDM appears to be slightly more sensitive than digital breast tomosynthesis for the detection of calcification. However, diagnostic performance as measured by area under the curve using BI-RADS was not significantly different. With improvements in processing algorithms and display, digital breast tomosynthesis could potentially be improved for this purpose. PMID- 21257883 TI - CT and MRI of early intrauterine pregnancy. AB - OBJECTIVE: The objective of this article is to describe the CT and MRI findings of early intrauterine pregnancy. CONCLUSION: Early pregnancy should be considered when CT or MRI shows a fluid-filled cystlike structure in the uterus of a woman of reproductive age especially if there is a coexistent ovarian corpus luteum cyst. PMID- 21257884 TI - The role of the radiologist when encountering osteoporosis in women. AB - OBJECTIVE: This article describes the extent and potentially devastating consequences of osteoporosis in adult women. There is discussion of the importance of radiologists in the correct diagnosis and reporting of probable osteoporotic vertebral fractures on medical imaging studies. CONCLUSION: The Genant semiquantitative method for diagnosing osteoporotic vertebral fractures is presented. The importance of dual-energy x-ray absorptiometry reproducibility is also briefly discussed. PMID- 21257885 TI - Improved detection of subendocardial hyperenhancement in myocardial infarction using dark blood-pool delayed enhancement MRI. AB - OBJECTIVE: Delayed enhancement MRI using fast segmented k-space inversion recovery (IR) gradient-echo imaging is a well established "bright-blood" technique for identifying myocardial infarction and is used as the reference standard sequence in this study. The purpose of this study was to validate a recently developed dark blood-pool delayed enhancement technique in a porcine animal model, evaluate its performance in human patients, and quantify its performance compared with the reference standard in both. SUBJECTS AND METHODS: In an animal study, the reference standard and dark blood-pool delayed enhancement were assessed in three pigs with induced myocardial infarction. In a human study, 26 patients, 31-81 years old (19 men and seven women), with a known history of myocardial infarction were imaged using the reference standard and dark blood-pool delayed enhancement. Contrast-to-noise ratio (CNR), signal intensity ratio, signal-to-noise ratio (SNR), and qualitative scores of hyperenhancement were recorded. Measurements were compared using paired samples t test and Wilcoxon's signed rank test. RESULTS: In the animal study, the mean CNR of infarct to blood pool was 11 times higher for dark blood-pool delayed enhancement than for the reference standard. The mean SNR was 4.4 times higher for the reference standard. In the human study, the mean CNR and signal intensity ratio of hyperenhancing myocardium to the blood pool were 1.9 (p = 0.04) and 5.5 (p < 0.01) times higher, respectively, for dark blood-pool delayed enhancement compared with reference standard. The mean CNR and signal intensity ratio of hyperenhancing myocardium to normal myocardium and SNR were 2.8 (p < 0.01), 1.3 (p = 0.07), and 2.8 (p < 0.01) higher, respectively, for the reference standard. Qualitative analysis identified seven extra segments with grade 1 scars using dark blood-pool delayed enhancement (p < 0.01). CONCLUSION: Dark blood-pool delayed enhancement is complementary to the reference standard. It can detect more subendocardial foci of hyperenhancement, thus potentially identifying more infarcts and changing patient management. PMID- 21257886 TI - Thoracic CT findings in Birt-Hogg-Dube syndrome. AB - OBJECTIVE: Birt-Hogg-Dube syndrome manifests in the thorax as lung cysts. The purpose of this article is to describe the CT characteristics of cysts in patients with Birt-Hogg-Dube syndrome and to note other thoracic findings. MATERIALS AND METHODS: The thoracic CT examinations of 17 patients with Birt-Hogg Dube syndrome were reviewed retrospectively for the presence, anatomic distribution (upper lung predominant, lower lung predominant, or diffuse), extent (size, number), and morphology (shape, wall thickness) of cysts. Any additional thoracic findings were also noted. RESULTS: The study population consisted of 13 women (76%) and four men (24%) with a mean age of 50.2 +/-15.2 years. Two patients (12%) had normal findings on CT. Fifteen patients had cystic lung disease, all of whom had more than one cyst. Most patients had bilateral (13/15, 87%) and lower lung-predominant cysts (13/15, 87%). The cysts varied in size from 0.2 to 7.8 cm. The largest cysts were located in the lower lobes of 14 of 15 patients (93%). Of the nine patients with large cysts, most had at least one multiseptated cyst (7/9, 78%). Five of 15 patients (33%) had more than 20 cysts. Cyst shape varied among the 15 patients and also within individual patients (10/15, 67%) ranging from round to oval, lentiform, and multiseptated. Cysts showed no central or peripheral predominance. CONCLUSION: Discrete thin-walled cysts in patients with Birt-Hogg-Dube syndrome are more numerous and larger in the lower lobes and vary in size and shape. Large lung cysts are frequently multiseptated. These features may aid in differentiating Birt-Hogg-Dube syndrome from other more common cystic lung diseases. PMID- 21257887 TI - Comprehensive evaluation of patients with suspected prosthetic heart valve disorders using MDCT. AB - OBJECTIVE: Early diagnosis of prosthetic valve disorders is very important in reducing morbidity and mortality of patients with a replaced heart valve. Recently, MDCT has become an important noninvasive problem-solving tool in clinical practice. This article will introduce the scanning technique, interpretation algorithm, and image findings of many valvular and extravalvular diagnoses. CONCLUSION: With proper scanning technique and interpretation, MDCT can be a powerful technique for prosthetic heart valve evaluation. PMID- 21257888 TI - Training the next generation in luminal gastrointestinal radiology: a call to arms. PMID- 21257889 TI - Splenic volume model constructed from standardized one-dimensional MDCT measurements. AB - OBJECTIVE: The purposes of this study were to construct a model for estimation of splenic volume from standardized one-dimensional diameters of the spleen and to compare that model with the ellipsoid model for estimation of splenic volume. MATERIALS AND METHODS: In this retrospective study, segmentation software was used for semiautomated quantification of splenic volume by counting CT voxels in 193 consecutively registered patients. For standardization of one-dimensional measurements, the software was used to measure transaxial diameter in the slice with the largest splenic cross-sectional area. By incorporation of splenic volume and the product of width, thickness, and length into the linear regression equation, a model for estimation of splenic volume was constructed, and its performance was externally assessed. Splenic volume also was calculated with the formula for a prolate ellipsoid. The ellipsoid volume and best-fit volumes were compared with segmented splenic volume by use of Bland-Altman plot and Lin concordance correlation. A value of p < 0.05 denoted statistical significance. RESULTS: Splenic width was the best one-dimensional predictor of splenic volume (r = 0.84, p < 0.05). The linear regression fitted model for estimation of splenic volume (V(R)) in the initial 100 patients was V(R) = (0.36 * W * T * L) + 28, where W is width, T is thickness, and L is length (R(2) = 0.91, p < 0.05) and was externally validated by estimation of splenic volume in the other 93 patients. Compared with that observed with use of the ellipsoid formula, mean bias decreased from 22.57% to 0.93%, and the Lin coefficient increased from 0.81 to 0.96 with application of the best-fit model for calculation of splenic volume. CONCLUSION: The best-fit model V(R) = (0.36 * W * T * L) + 28 is more optimized than the ellipsoid formula and is associated with less bias for estimation of splenic volume. PMID- 21257890 TI - Assessment of aggressiveness of prostate cancer: correlation of apparent diffusion coefficient with histologic grade after radical prostatectomy. AB - OBJECTIVE: The purpose of this article is to evaluate the relationship between apparent diffusion coefficient (ADC) values, tumor volume, and total Gleason grade in patients with prostate cancer before radical prostatectomy. MATERIALS AND METHODS: A total of 110 patients with prostate cancer who had undergone endorectal prostate MRI at 1.5 T before radical prostatectomy were included. ADC values were derived by drawing a region of interest on the histologically confirmed tumors. Tumor volume was obtained by manual segmentation on T2-weighted images (T2WIs) and ADC maps. The relationship between the ADC value or tumor volume and the Gleason grade was assessed by using multivariate mixed linear and effect models. Multivariate analysis was performed to evaluate the accuracy of ADC and tumor volume in determining the aggressiveness of prostate cancer. RESULTS: A total of 197 tumors were studied; 128 (65%) tumors were found in the peripheral zone and 69 (35%) were found in the central gland. The ADC value was found to be negatively correlated with the Gleason grade (r = -0.39 for peripheral zone cancer). Higher ADC values were found to be associated with lower Gleason grades in the peripheral zone prostate cancers. No association was found in the central zone prostate cancers. Both ADC values and tumor volumes were found to significantly predict tumor aggressiveness, specifically in the peripheral zone (area under the curve, 0.78). CONCLUSION: ADC values were found to be negatively correlated with the postsurgical Gleason grade in patients with prostate cancer. Our results show that ADC values might help to predict prostate cancer, especially for tumors in the peripheral zone. Given the substantial overlap in the ADC values, the addition of other MR parameters, such as volumetry, and technical improvements in diffusion-weighted imaging might improve accuracy in the stratification of patients. PMID- 21257891 TI - Imaging findings after radiofrequency ablation of adrenal tumors. AB - OBJECTIVE: The purpose of this study was to describe the imaging findings after radiofrequency ablation of adrenal tumors. MATERIALS AND METHODS: We retrospectively reviewed the imaging findings of all patients with adrenal tumors treated with radiofrequency ablation in our department from January 2001 through August 2009. The studies were reviewed in consensus by two attending abdominal imaging radiologists and an abdominal imaging fellow. Imaging findings before, immediately after, and at short- and long-term follow-up after ablation were recorded. RESULTS: Fourteen patients (seven men, seven women; mean age, 56 +/- 8.4 years) underwent radiofrequency ablation of adrenal tumors. One case of small pneumothorax and one case of small hemothorax were the only minor complications (complication rate, 14%). The expected side effects of radiofrequency ablation were found in 35% of patients: in two patients adjacent liver parenchyma was ablated, in two patients the diaphragmatic crus was injured, and in two patients local hematoma occurred (in one patient, both adjacent liver and diaphragmatic crus were ablated). Immediate soft-tissue findings after radiofrequency ablation included air bubbles in 12 patients (86%) and fat stranding around the adrenal gland in 13 patients (93%). A fat rim sign was found in 60% of patients at long term follow-up. The attenuation of the tumor immediately after the procedure increased an average of 7 HU (median, 5 HU; range, -2 to 18 HU) and tended to decrease in long-term follow-up. At long-term follow-up, most (75%) of the tumors had decreased in size and attenuation. CONCLUSION: Air bubbles and fat stranding are frequently seen immediately after radiofrequency ablation of adrenal tumors. A fat rim sign is a common finding at long-term follow-up. Attenuation of the ablated zone increases immediately after the procedure and decreases in long-term follow-up. The volume of the ablated zone has a variable size response, suggesting the need for baseline imaging. PMID- 21257892 TI - MRI of patients with cardiac pacemakers: a review of the medical literature. AB - OBJECTIVE: Numerous studies testing the use of pacemakers with MRI have been published. Our aim was to analyze these trials to determine the safety of MRI for patients with cardiac pacemakers. We performed a systematic search of peer reviewed databases. A total of 31 articles were reviewed. CONCLUSION: The data are heterogeneous with regard to MRI being considered for patients with pacemakers, and the benefits of the imaging should outweigh the risks. PMID- 21257893 TI - Hybrid convolution kernel: optimized CT of the head, neck, and spine. AB - OBJECTIVE: Conventional CT requires generation of separate images utilizing different convolution kernels to optimize lesion detection. Our goal was to develop and test a hybrid CT algorithm to simultaneously optimize bone and soft tissue characterization, potentially halving the number of images that need to be stored, transmitted, and reviewed. MATERIALS AND METHODS: CT images generated with separate high-pass (bone) and low-pass (soft tissue) kernels were retrospectively combined so that low-pass algorithm pixels less than -150 HU or greater than 150 HU are substituted with corresponding high-pass kernel reconstructed pixels. A total of 38 CT examinations were reviewed using the hybrid technique, including 20 head, eight spine, and 10 head and neck scans. Three neuroradiologists independently reviewed all 38 hybrid cases, comparing them to both standard low-pass and high-pass kernel convolved images for characterization of anatomy and pathologic abnormalities. The conspicuity of bone, soft tissue, and related anatomy were compared for each CT reconstruction technique. RESULTS: For the depiction of bone, in all 38 cases, the three neuroradiologists scored the hybrid images as being equivalent to high-pass kernel reconstructions but superior to the low-pass kernel. For depiction of extracranial soft tissues and brain, the hybrid kernel was rated equivalent to the low-pass kernel but superior to that of the high-pass kernel. CONCLUSION: The hybrid convolution kernel is a promising technique affording optimized bone and soft tissue evaluation while potentially halving the number of images needed to be transmitted, stored, and reviewed. PMID- 21257894 TI - Prospective gating with 320-MDCT angiography: effect of volume scan length on radiation dose. AB - OBJECTIVE: The purpose of this study was to evaluate the relation between radiation dose reduction and volume scan length for prospectively ECG-gated 320 MDCT angiography in the diagnosis of coronary artery disease. MATERIALS AND METHODS: MDCT with prospective ECG gating was performed at one of the three volume scan lengths depending on heart length. Of 175 patients, 95 (55%; body mass index, 29 +/- 5.9; mean heart rate, 59 +/- 7 beats/min) underwent scanning at 160 mm; 46 (26%; body mass index, 30 +/- 4.1; mean heart rate, 56 +/- 5.74 beats/min) at 140 mm; and 34 (19%; body mass index, 30 +/- 3.71; mean heart rate, 58 +/- 3.96 beats/min) at 120 mm. RESULTS: The median radiation doses were 6.5 mSv (95% CI, 6.03-7.2 mSv) for the 95 patients who underwent scanning at a volume scan length of 160 mm, 4.33 mSv (95% CI, 4.06-6.62 mSv) for the 46 patients who underwent scanning at 140 mm, and 3.47 mSv (95% CI, 3.15-3.62 mSv) for the 34 patients who underwent scanning at 120 mm. The reduction in scan length from 160 to 140 mm represented a reduction in scan length of 12.5% and the reduction to 120 mm a reduction of 25%. The median radiation dose was reduced 33% when volume scan length was changed to 140 mm and 47% when the length was changed to 120 mm. CONCLUSION: Dose optimization remains an important concern in cardiac CT, and for 320-MDCT angiography, substantial dose reduction can be achieved by reducing volume scan length so that it is in concert with the patient's heart length. PMID- 21257895 TI - Utility of CT-guided biopsy of suspicious skeletal lesions in patients with known primary malignancies. AB - OBJECTIVE: Patients with a known primary malignancy and one or more suspicious skeletal lesions are often assumed to have skeletal involvement by the known malignancy. We set out to determine how often one would be correct in making this assumption. MATERIALS AND METHODS: All CT-guided bone biopsies performed at our institution between January 2006 and January 2009 in patients with a history of a single biopsy-proven malignancy were retrospectively reviewed. Pathology results were assigned to one of three outcomes: skeletal involvement by known malignancy, newly diagnosed malignancy, or no malignancy identified. Patients categorized as no malignancy identified required repeat biopsy or stability on follow-up imaging for confirmation. RESULTS: Of 104 patients with a known primary malignancy, 11 were excluded. Of the 93 included patients, there was skeletal involvement by the known malignancy in 82 (88%), a newly diagnosed malignancy in seven (8%), and no malignancy identified in four (4%). CONCLUSION: Biopsy of a suspicious skeletal lesion in a patient with a solitary known malignancy reveals a newly diagnosed malignancy or no evidence of malignancy in 12% of patients, emphasizing the importance of biopsy. PMID- 21257896 TI - MRI features of cortical desmoid in acute knee trauma. AB - OBJECTIVE: The purpose of this study was to describe the MRI features of cortical desmoids associated with acute trauma. CONCLUSION: Marrow edema, periostitis, and adjacent soft-tissue edema can be seen in cases of cortical desmoid associated with acute trauma. PMID- 21257897 TI - Carotid plaque vulnerability: quantification of neovascularization on contrast enhanced ultrasound with histopathologic correlation. AB - OBJECTIVE: The purpose of this research is to develop a computerized method to quantify carotid plaque neovascularization on contrast-enhanced ultrasound images and to compare the results with the histopathologic analysis of the plaque. SUBJECTS AND METHODS: Twenty-seven patients (age range, 48-84 years; mean [+/- SD] age, 68.4 +/- 9.72 years) were recruited before endarterectomy. Contrast enhanced ultrasound examination of the carotid artery was performed by applying low mechanical index and harmonics with pulse inversion. An algorithm was developed that implemented several image processing methods to automatically quantify neovascularization and reconstruct the vascular tree in the atheromatous plaque. Neovascularization and the number of inflammatory cells seen on histopathologic analysis of the plaque after endarterectomy were compared with neovascularization determined by the computerized method. The mean (+/- SD) ratios of the ultrasound and histopathologic measurements were calculated. RESULTS: In five patients, heavy calcification of the plaque prevented visualization of plaque texture. Intraplaque neovascularization on contrast enhanced ultrasound images was significant in 19 patients and low in three patients. The ratio of the neovascularization area to the total plaque area on contrast-enhanced ultrasound images was well correlated with the same histopathologic ratio (R(2) = 0.7905) and with the number of inflammatory cells present in the plaque (R(2) = 0.6109). The histopathologic ratio and the number of intraplaque inflammatory cells also were well correlated (R(2) = 0.7034). CONCLUSION: The newly developed method allowed quantification of the intraplaque neovascularization as a feature of vulnerability in the carotid plaque and proved to be highly correlated with histopathologic results. PMID- 21257898 TI - Spinal cord stimulators: typical positioning and postsurgical complications. AB - OBJECTIVE: Implantation of a spinal cord stimulator (SCS) is one option for pain control in individuals with chronic lumbosacral radicular or axial lumbar pain. The expected positioning of SCSs based on the location of pain, the types of electrodes (percutaneous vs surgical paddle), and the types of electrode arrays and the potential complications have not been described to date in the radiology literature. MATERIALS AND METHODS: A 5-year retrospective review of the radiology information system at our institution revealed 24 patients with images of 36 SCSs. Those images were reviewed to identify the location and type of electrodes as well as the location of the lead within the spinal canal. Not all implantable pulse generators were within the radiologic field of view. Complications identified by reviewing medical records were correlated with imaging findings. RESULTS: Fourteen different types of electrodes were identified. Most were placed in the thoracic spine only, but six thoracolumbar and two cervical spine electrodes were also present. We measured the position of the electrodes within the spinal canal on 26 CT studies of the 24 patients. On 22 of 26 CT studies, the electrodes were placed in the epidural space in the posterior one third of the spinal canal. Complications included misplaced, retained, and broken leads; puncture of the thecal sac; infection; and hematoma. CONCLUSION: Radiologists should be familiar with the different types of electrodes and typical spinal locations of electrodes, leads, and implantable pulse generators. Improper placement of electrodes may lead to ineffective pain relief or to other complications. PMID- 21257899 TI - Diagnosis of peritoneal dissemination: comparison of 18F-FDG PET/CT, diffusion weighted MRI, and contrast-enhanced MDCT. AB - OBJECTIVE: The purpose of this study was to compare the diagnostic performance of (18)F-FDG PET/CT, MRI with and without diffusion-weighted imaging (DWI), and contrast-enhanced MDCT in the detection of peritoneal dissemination of malignant tumors. MATERIALS AND METHODS: We retrospectively evaluated the cases of 107 patients who underwent PET/CT and 130 patients who underwent MRI and contrast enhanced MDCT. Twenty-six patients who underwent PET/CT and 23 who underwent MRI and contrast-enhanced MDCT were found to have peritoneal dissemination. All images were independently evaluated by two radiologists using a 5-point grading system. The results of PET/CT, T1- and T2-weighted MRI without DWI, MRI with DWI (b = 1,000 s/mm(2)), and contrast-enhanced MDCT were compared patient by patient and lesion by lesion by use of receiver operating characteristics analysis. Sensitivity, specificity, and positive predictive value were calculated and compared by use of the chi-square test. RESULTS: Patient by patient, the area under the receiver operating characteristics curve of MRI without DWI (0.88) was significantly less than that of the other modalities (contrast-enhanced MDCT, 0.91; MRI with DWI, 0.93; PET/CT, 0.97). The sensitivity of PET/CT (94%) was significantly higher than that of MRI without DWI (70%). The specificities of the modalities were not significantly different. In lesion-by-lesion analysis, MRI without DWI had significantly lower sensitivity (56%) than the other modalities (contrast-enhanced MDCT, 76%; MRI with DWI, 84%; PET/CT, 89%). The positive predictive value of PET/CT (93%) was significantly higher than that of the other three modalities (contrast-enhanced MDCT, 73%; MRI without DWI, 70%; MRI with DWI, 72%). CONCLUSION: PET/CT is the most useful technique for pathologic staging in the care of patients with malignant disease. If PET/CT is not available, DWI can be used as a screening tool. PMID- 21257900 TI - Cardiovascular anomalies in Turner syndrome: spectrum, prevalence, and cardiac MRI findings in a pediatric and young adult population. AB - OBJECTIVE: Turner syndrome affects one in 2,500 girls and women and is associated with cardiovascular anomalies. Visualizing the descending thoracic aorta in adults with Turner syndrome with echocardiography is difficult. Therefore, cardiac MRI is the preferred imaging modality for surveillance. Our goals were to use cardiac MRI describe the spectrum and frequency of cardiovascular abnormalities and to evaluate aortic dilatation and associated abnormalities in pediatric patients with Turner syndrome. MATERIALS AND METHODS: The cases of 51 patients with Turner syndrome (median age, 18.4 years; range, 6-36 years) were evaluated with cardiac MRI. The characteristics assessed included aortic structure, elongation of the transverse aortic arch, aortic diameter at multiple locations, and coarctation of the aorta (CoA). Additional evaluations were made for presence of bicuspid aortic valve (BAV), and partial anomalous pulmonary venous return (PAPVR). Associations between the cardiac MRI data and the following factors were assessed: age, karyotype, body surface area, blood pressure, and ventricular sizes and function. RESULTS: Sixteen patients (31.4%) had elongation of the transverse aortic arch, eight (15.7%) had CoA, 20 (39.2%) had BAV, and eight (15.7%) had PAPVR. Aortic dilatation was most common at the aortic sinus (30%). Elongation of the transverse aortic arch was associated with CoA (p < 0.01) and BAV (p < 0.05). Patients with elongation of the transverse aortic arch had dilated aortic sinus (p < 0.05). Patients with PAPVR had increased right heart mass (p < 0.05), increased ratio of main pulmonary artery to aortic valve blood flow (p = 0.0014), and increased right ventricular volume (p < 0.05). CONCLUSION: Cardiovascular anomalies in pediatric patients with Turner syndrome include aortic abnormalities and PAPVR. The significant association between elongation of the transverse aortic arch and CoA, BAV, and aortic sinus dilatation may contribute to increased risk of aortic dissection. The presence of PAPVR can be hemodynamically significant. These findings indicate that periodic cardiac MRI screening of persons with Turner syndrome is beneficial. PMID- 21257901 TI - The radiologist as a palliative care subspecialist: providing symptom relief when cure is not possible. AB - OBJECTIVE: The purpose of this study was to determine the percentage of patients referred to an interventional radiology (IR) practice who need palliative care and to examine the training required for a diplomate of the American Board of Radiology (ABR) to qualify for the hospice and palliative medicine certifying examination. MATERIALS AND METHODS: This retrospective study reviewed all patient referrals to an academic vascular and IR practice during the month of August 2009. The demographics, underlying diagnosis, and the type of procedures performed were ascertained from the electronic medical record. The requirements for a diplomate of the ABR to obtain certification as a hospice and palliative medicine subspecialist were evaluated and summarized. RESULTS: Two-hundred eighty two patients were referred to the IR service and underwent a total of 332 interventional procedures. Most of the patients (229 [81.2%]) had underlying diagnoses that would warrant consultation with a hospice and palliative medicine subspecialist; these patients were significantly older (58.5 vs 44.7 years; p < 0.01) and underwent more procedures (1.21 vs 1.02; p < 0.01). To obtain a subspecialty certification in hospice and palliative medicine, a radiologist needs certification by the ABR, an unrestricted medical license, 2 years of subspecialty training in hospice and palliative medicine, 100 hours of interdisciplinary hospice and palliative medicine team participation, active care of 50 terminally ill adult patients, and successful performance on the certification examination. CONCLUSION: Procedures related to palliative care currently compose the majority of our IR cases. Certification in hospice and palliative medicine can be achieved with a modest investment of time and clinical training. PMID- 21257902 TI - Radioembolization as salvage therapy for hepatic metastasis of uveal melanoma: a single-institution experience. AB - OBJECTIVE: The purpose of this study was to assess the safety and efficacy of radioembolization in the management of hepatic metastasis of uveal melanoma after failure of immunoembolization or chemoembolization. MATERIALS AND METHODS: From January 2007 through April 2009, 32 patients underwent radioembolization therapy for hepatic metastasis of uveal melanoma. Pretreatment tumor burdens were divided into three categories: less than 25% (n = 25), 25-50% (n = 5), and greater than 50% (n = 2). Toxicity, extrahepatic disease, and hepatic tumor response were assessed 1 month and then every 3 months after treatment. Best radiographic response of hepatic metastasis was determined with the Response Evaluation Criteria in Solid Tumors criteria. Overall survival and progression-free survival of hepatic metastasis were estimated by Kaplan-Meier analysis. Differences in survival between subgroups were evaluated by log-rank test in univariate analysis. RESULTS: The clinical follow-up period ranged from 1.0 to 29.0 months (median, 10.0 months). The median overall survival was 10.0 months, and the progression-free survival of hepatic metastasis, 4.7 months. Twenty-two patients died 1.0-29.0 months (median, 5.8 months) after treatment owing to progression of liver disease (n = 13), extrahepatic disease (n = 4), or both (n = 5). Patients who had a pretreatment tumor burden less than 25% had longer median overall survival (10.5 vs 3.9 months, p = 0.0003) and progression-free survival (6.4 vs 3.0 months, p = 0.03) than patients who had a pretreatment tumor burden of 25% or greater. Patients who had a complete response (n = 1), partial response (n = 1), or stable disease (n = 18) had longer median overall survival (14.7 vs 4.9 months, p = 0.0006) and progression-free survival of hepatic metastasis (7.9 vs 3.1 months, p < 0.0001) than patients with tumor progression (n = 12). Self limiting grade 1-2 systemic toxicity included tiredness (n = 9), indigestion (n = 2), and abdominal discomfort (n = 5). Grade 3-4 hepatic toxicity was attributed to tumor progression. CONCLUSION: Radioembolization is safe and effective salvage therapy for limited metastasis of uveal melanoma. PMID- 21257903 TI - Localization of magnetic pills. AB - Numerous therapeutics demonstrate optimal absorption or activity at specific sites in the gastrointestinal (GI) tract. Yet, safe, effective pill retention within a desired region of the GI remains an elusive goal. We report a safe, effective method for localizing magnetic pills. To ensure safety and efficacy, we monitor and regulate attractive forces between a magnetic pill and an external magnet, while visualizing internal dose motion in real time using biplanar videofluoroscopy. Real-time monitoring yields direct visual confirmation of localization completely noninvasively, providing a platform for investigating the therapeutic benefits imparted by localized oral delivery of new and existing drugs. Additionally, we report the in vitro measurements and calculations that enabled prediction of successful magnetic localization in the rat small intestines for 12 h. The designed system for predicting and achieving successful magnetic localization can readily be applied to any area of the GI tract within any species, including humans. The described system represents a significant step forward in the ability to localize magnetic pills safely and effectively anywhere within the GI tract. What our magnetic pill localization strategy adds to the state of the art, if used as an oral drug delivery system, is the ability to monitor the force exerted by the pill on the tissue and to locate the magnetic pill within the test subject all in real time. This advance ensures both safety and efficacy of magnetic localization during the potential oral administration of any magnetic pill-based delivery system. PMID- 21257904 TI - The complex that inserts lipopolysaccharide into the bacterial outer membrane forms a two-protein plug-and-barrel. AB - The cell surfaces of Gram-negative bacteria are composed of lipopolysaccharide (LPS). This glycolipid is found exclusively in the outer leaflet of the asymmetric outer membrane (OM), where it forms a barrier to the entry of toxic hydrophobic molecules into the cell. LPS typically contains six fatty acyl chains and up to several hundred sugar residues. It is biosynthesized in the cytosol and must then be transported across two membranes and an aqueous intermembrane space to the cell surface. These processes are required for the viability of most Gram negative organisms. The integral membrane beta-barrel LptD and the lipoprotein LptE form an essential complex in the OM, which is necessary for LPS assembly. It is not known how this complex translocates large, amphipathic LPS molecules across the OM to the outer leaflet. Here, we show that LptE resides within the LptD beta-barrel both in vitro and in vivo. LptD/E associate via an extensive interface; in one specific interaction, LptE contacts a predicted extracellular loop of LptD through the lumen of the beta-barrel. Disrupting this interaction site compromises the biogenesis of LptD. This unprecedented two-protein plug-and barrel architecture suggests how LptD/E can insert LPS from the periplasm directly into the outer leaflet of the OM to establish the asymmetry of the bilayer. PMID- 21257905 TI - Enforced hematopoietic cell E- and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells. AB - According to the multistep model of cell migration, chemokine receptor engagement (step 2) triggers conversion of rolling interactions (step 1) into firm adhesion (step 3), yielding transendothelial migration. We recently reported that glycosyltransferase-programmed stereosubstitution (GPS) of CD44 on human mesenchymal stem cells (hMSCs) creates the E-selectin ligand HCELL (hematopoietic cell E-selectin/L-selectin ligand) and, despite absence of CXCR4, systemically administered HCELL(+)hMSCs display robust osteotropism visualized by intravital microscopy. Here we performed studies to define the molecular effectors of this process. We observed that engagement of hMSC HCELL with E-selectin triggers VLA-4 adhesiveness, resulting in shear-resistant adhesion to ligand VCAM-1. This VLA-4 activation is mediated via a Rac1/Rap1 GTPase signaling pathway, resulting in transendothelial migration on stimulated human umbilical vein endothelial cells without chemokine input. These findings indicate that hMSCs coordinately integrate CD44 ligation and integrin activation, circumventing chemokine-mediated signaling, yielding a step 2-bypass pathway of the canonical multistep paradigm of cell migration. PMID- 21257906 TI - Multiple strategies in structured populations. AB - Many specific models have been proposed to study evolutionary game dynamics in structured populations, but most analytical results so far describe the competition of only two strategies. Here we derive a general result that holds for any number of strategies, for a large class of population structures under weak selection. We show that for the purpose of strategy selection any evolutionary process can be characterized by two key parameters that are coefficients in a linear inequality containing the payoff values. These structural coefficients, sigma(1) and sigma(2), depend on the particular process that is being studied, but not on the number of strategies, n, or the payoff matrix. For calculating these structural coefficients one has to investigate games with three strategies, but more are not needed. Therefore, n = 3 is the general case. Our main result has a geometric interpretation: Strategy selection is determined by the sum of two terms, the first one describing competition on the edges of the simplex and the second one in the center. Our formula includes all known weak selection criteria of evolutionary games as special cases. As a specific example we calculate games on sets and explore the synergistic interaction between direct reciprocity and spatial selection. We show that for certain parameter values both repetition and space are needed to promote evolution of cooperation. PMID- 21257907 TI - Regulation of imprinted gene expression in Arabidopsis endosperm. AB - Imprinted genes are expressed primarily or exclusively from either the maternal or paternal allele, a phenomenon that occurs in flowering plants and mammals. Flowering plant imprinted gene expression has been described primarily in endosperm, a terminal nutritive tissue consumed by the embryo during seed development or after germination. Imprinted expression in Arabidopsis thaliana endosperm is orchestrated by differences in cytosine DNA methylation between the paternal and maternal genomes as well as by Polycomb group proteins. Currently, only 11 imprinted A. thaliana genes are known. Here, we use extensive sequencing of cDNA libraries to identify 9 paternally expressed and 34 maternally expressed imprinted genes in A. thaliana endosperm that are regulated by the DNA demethylating glycosylase DEMETER, the DNA methyltransferase MET1, and/or the core Polycomb group protein FIE. These genes encode transcription factors, proteins involved in hormone signaling, components of the ubiquitin protein degradation pathway, regulators of histone and DNA methylation, and small RNA pathway proteins. We also identify maternally expressed genes that may be regulated by unknown mechanisms or deposited from maternal tissues. We did not detect any imprinted genes in the embryo. Our results show that imprinted gene expression is an extensive mechanistically complex phenomenon that likely affects multiple aspects of seed development. PMID- 21257908 TI - Structural plasticity within highly specific neuronal populations identifies a unique parcellation of motor learning in the adult brain. AB - Cortical networks undergo adaptations during learning, including increases in dendritic complexity and spines. We hypothesized that structural elaborations during learning are restricted to discrete subsets of cells preferentially activated by, and relevant to, novel experience. Accordingly, we examined corticospinal motor neurons segregated on the basis of their distinct descending projection patterns, and their contribution to specific aspects of motor control during a forelimb skilled grasping task in adult rats. Learning-mediated structural adaptations, including extensive expansions of spine density and dendritic complexity, were restricted solely to neurons associated with control of distal forelimb musculature required for skilled grasping; neurons associated with control of proximal musculature were unchanged by the experience. We further found that distal forelimb-projecting and proximal forelimb-projecting neurons are intermingled within motor cortex, and that this distribution does not change as a function of skill acquisition. These findings indicate that representations of novel experience in the adult motor cortex are associated with selective structural expansion in networks of functionally related, active neurons that are distributed across a single cortical domain. These results identify a distinct parcellation of cortical resources in support of learning. PMID- 21257909 TI - Lipoprotein LptE is required for the assembly of LptD by the beta-barrel assembly machine in the outer membrane of Escherichia coli. AB - Most Gram-negative bacteria contain lipopolysaccharide (LPS), a glucosamine-based phospholipid, in the outer leaflet of the outer membrane (OM). LPS is unique to the bacterial OM and, in most cases, essential for cell viability. Transport of LPS from its site of synthesis to the cell surface requires eight essential proteins, MsbA and LptABCDEFG. Although the key players have been identified, the mechanism of LPS transport and assembly is not clear. The stable LptD/E complex is present at the OM and functions in the final stages of LPS assembly. Here, we have identified the mutant allele lptE6, which causes a two-amino-acid deletion in the lipoprotein LptE that affects its interaction with LptD. Highly specific suppressor mutations were isolated not only in lptD but also in bamA, which encodes the central component of the beta-barrel assembly machine. We show that lptE6 and both suppressor mutations affect the assembly of the LptD/E complex and suggest that the lipoprotein LptE interacts with LptD while this protein is being assembled by the beta-barrel assembly machine. PMID- 21257910 TI - Decreased stability and increased formation of soluble aggregates by immature superoxide dismutase do not account for disease severity in ALS. AB - Protein aggregation is a hallmark of many diseases, including amyotrophic lateral sclerosis (ALS), where aggregation of Cu/Zn superoxide dismutase (SOD1) is implicated in causing neurodegeneration. Recent studies have suggested that destabilization and aggregation of the most immature form of SOD1, the disulfide reduced, unmetallated (apo) protein is particularly important in causing ALS. We report herein in depth analyses of the effects of chemically and structurally diverse ALS-associated mutations on the stability and aggregation of reduced apo SOD1. In contrast with previous studies, we find that various reduced apo SOD1 mutants undergo highly reversible thermal denaturation with little aggregation, enabling quantitative thermodynamic stability analyses. In the absence of ALS associated mutations, reduced apo SOD1 is marginally stable but predominantly folded. Mutations generally result in slight decreases to substantial increases in the fraction of unfolded protein. Calorimetry, ultracentrifugation, and light scattering show that all mutations enhance aggregation propensity, with the effects varying widely, from subtle increases in most cases, to pronounced formation of 40-100 nm soluble aggregates by A4V, a mutation that is associated with particularly short disease duration. Interestingly, although there is a correlation between observed aggregation and stability, there is minimal to no correlation between observed aggregation, predicted aggregation propensity, and disease characteristics. These findings suggest that reduced apo SOD1 does not play a dominant role in modulating disease. Rather, additional and/or multiple forms of SOD1 and additional biophysical and biological factors are needed to account for the toxicity of mutant SOD1 in ALS. PMID- 21257911 TI - Enlargement of catheter ablation lesions in infant hearts with cryothermal versus radiofrequency energy: an animal study. AB - BACKGROUND: Radiofrequency catheter ablation in immature hearts has been associated with marked enlargement of lesions over time, with potential for related late adverse events. It remains unknown whether cryothermal ablation lesions display a similar pattern of growth. METHODS AND RESULTS: Ablation lesions (n=384) were performed in 32 infant miniature swine in right and left atria, ventricles, and atrioventricular (AV) grooves preselected by a randomized factorial design devised to compare radiofrequency and cryothermal lesions produced by 7F 4-mm electrode-tip catheters. Animals were euthanized acutely or at 1, 6, or 12 months, according to the randomization scheme. The miniature swine weighed 8.8+/-1.2 kg and were 63+/-13 days of age at time of ablation. The minimum temperature during cryoablation was -79.8+/-3.4 degrees C and the average temperature during radiofrequency ablation was 54.4+/-5.5 degrees C. On morphometric analyses, no differences in the rate of growth of ablation lesions were noted between the 2 energy modalities in atria (P=0.44), ventricles (P=0.57), or AV grooves (P=0.69). Lesion volumes increased 3.3-fold in atria (95% confidence interval [CI], 2.3 to 4.3; P=0.001) and 2.2-fold in ventricles (95% CI, 1.4 to 3.0; P<0.0001), with the difference between chambers being nonsignificant (P=0.22). Whereas the depth of AV groove lesions increased over time (1.9-fold; 95% CI, 1.5 to 2.3; P<0.0001), lesion volumes did not enlarge significantly (1.5-fold; 95% CI, 0.4 to 2.6; P=0.45). CONCLUSIONS: Ablation lesions produced by cryothermal energy in immature atrial and ventricular myocardium enlarge to a similar extent to radiofrequency ablation. In contrast, AV groove lesion volumes do not increase significantly with either energy modality. PMID- 21257912 TI - Functional mathematical model of dual pathway AV nodal conduction. AB - Dual atrioventricular (AV) nodal pathway physiology is described as two different wave fronts that propagate from the atria to the His bundle: one with a longer effective refractory period [fast pathway (FP)] and a second with a shorter effective refractory period [slow pathway (SP)]. By using His electrogram alternance, we have developed a mathematical model of AV conduction that incorporates dual AV nodal pathway physiology. Experiments were performed on five rabbit atrial-AV nodal preparations to develop and test the presented model. His electrogram alternances from the inferior margin of the His bundle were used to identify fast and slow wave front propagations. The ability to predict AV conduction time and the interaction between FP and SP wave fronts have been analyzed during regular and irregular atrial rhythms (e.g., atrial fibrillation). In addition, the role of dual AV nodal pathway wave fronts in the generation of Wenckebach periodicities has been illustrated. Finally, AV node ablative modifications have been evaluated. The model accurately reproduced interactions between FP and SP during regular and irregular atrial pacing protocols. In all experiments, specificity and sensitivity higher than 85% were obtained in the prediction of the pathway responsible for conduction. It has been shown that, during atrial fibrillation, the SP ablation significantly increased the mean HH interval (204 +/- 39 vs. 274 +/- 50 ms, P < 0.05), whereas FP ablation did not produce significant slowing of ventricular rate. The presented mathematical model can help in understanding some of the intriguing AV node mechanisms and should be considered as a step forward in the studies of AV nodal conduction. PMID- 21257913 TI - Pressure-induced myogenic tone and role of 20-HETE in mediating autoregulation of cerebral blood flow. AB - While myogenic force in response to a changing arterial pressure has been described early in the 20th century, it was not until 1984 that the effect of a sequential increase in intraluminal pressure on cannulated cerebral arterial preparations was found to result in pressure-dependent membrane depolarization associated with spike generation and reduction in lumen diameter. Despite a great deal of effort by different laboratories and investigators, the identification of the existence of a mediator of the pressure-induced myogenic constriction in arterial muscle remained a challenge. It was the original finding by our laboratory that demonstrated the capacity of cerebral arterial muscle cells to express the cytochrome P-450 4A enzyme that catalyzes the formation of the potent vasoconstrictor 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid, the production of which in cerebral arterial muscle cells increases with the elevation in intravascular pressure. 20-HETE activates protein kinase C and causes the inhibition of Ca(2+)-activated K(+) channels, depolarizes arterial muscle cell membrane, and activates L-type Ca(2+) channel to increase intracellular Ca(2+) levels and evoke vasoconstriction. The inhibition of 20-HETE formation attenuates pressure-induced arterial myogenic constriction in vitro and blunts the autoregulation of cerebral blood flow in vivo. We suggest that the formation and action of cytochrome P-450-derived 20-HETE in cerebral arterial muscle could play a critically important role in the control of cerebral arterial tone and the autoregulation of cerebral blood flow under physiological conditions. PMID- 21257914 TI - Pulsatile to-fro flow induces greater and sustained expression of tissue factor RNA in HUVEC than unidirectional laminar flow. AB - Tissue factor (TF) is expressed in atherosclerotic lesions. Since mechanical forces influence endothelial cell (EC) function and are thought to account for the unique distribution of atherosclerosis in areas exposed to disturbed flow, we hypothesized that disturbed to-fro flow (TFF) and unidirectional pulsatile forward flow (PFF) would have different effects on TF expression in EC. TF RNA expression in HUVEC exposed to mechanical stress in the presence or absence of chemical stimulation with thrombin was determined. TFF induced a significantly higher TF expression than PFF that was sustained for 8 h. Combination of mechanical and chemical stimuli induced significantly higher TF expression than only mechanical stresses, and this effect was synergistic in both TFF and PFF. The MAPK p38 inhibitor SB-203580 significantly inhibited TF expression induced by mechanical and chemical stimulations, but the MEK inhibitor PD-98059 did not inhibit TF induced by TFF. Immunoblotting revealed that ERK1/2 phosphorylation induced by TFF was sustained for 120 min, whereas that induced by PFF was not. We conclude that disturbed flow induced greater and sustained amplification of TF expression, and this synergistic effect may be regulated by p38 MAPK and ERK1/2. These results provide added insight into the mechanism of atherosclerosis in areas of disturbed flow. PMID- 21257915 TI - Soluble guanylate cyclase-alpha1 is required for the cardioprotective effects of inhaled nitric oxide. AB - Reperfusion injury limits the benefits of revascularization in the treatment of myocardial infarction (MI). Breathing nitric oxide (NO) reduces cardiac ischemia reperfusion injury in animal models; however, the signaling pathways by which inhaled NO confers cardioprotection remain uncertain. The objective of this study was to learn whether inhaled NO reduces cardiac ischemia-reperfusion injury by activating the cGMP-generating enzyme, soluble guanylate cyclase (sGC), and to investigate whether bone marrow (BM)-derived cells participate in the sGC mediated cardioprotective effects of inhaled NO. Wild-type (WT) mice and mice deficient in the sGC alpha(1)-subunit (sGCalpha(1)(-/-) mice) were subjected to cardiac ischemia for 1 h, followed by 24 h of reperfusion. During ischemia and for the first 10 min of reperfusion, mice were ventilated with oxygen or with oxygen supplemented with NO (80 parts per million). The ratio of MI size to area at risk (MI/AAR) did not differ in WT and sGCalpha(1)(-/-) mice that did not breathe NO. Breathing NO decreased MI/AAR in WT mice (41%, P = 0.002) but not in sGCalpha(1)(-/-) mice (7%, P = not significant). BM transplantation was performed to restore WT BM-derived cells to sGCalpha(1)(-/-) mice. Breathing NO decreased MI/AAR in sGCalpha(1)(-/-) mice carrying WT BM (39%, P = 0.031). In conclusion, these results demonstrate that a global deficiency of sGCalpha(1) does not alter the degree of cardiac ischemia-reperfusion injury in mice. The cardioprotective effects of inhaled NO require the presence of sGCalpha(1). Moreover, our studies suggest that BM-derived cells are key mediators of the ability of NO to reduce cardiac ischemia-reperfusion injury. PMID- 21257916 TI - Ivabradine reduces heart rate while preserving metabolic fluxes and energy status of healthy normoxic working hearts. AB - Heart rate reduction (HRR) is an important target in the management of patients with chronic stable angina. Most available drugs for HRR, such as beta-blockers, have adverse effects, including on cardiac energy substrate metabolism, a well recognized determinant of cardiac homeostasis. This study aimed at 1) testing whether HRR by ivabradine (IVA) alters substrate metabolism in the healthy normoxic working heart and 2) comparing the effect of IVA with that of the beta blocker metoprolol (METO). This was assessed using our well-established model of ex vivo mouse heart perfusion in the working mode, which enables concomitant evaluation of myocardial contractility and metabolic fluxes using (13)C-labeled substrates. Hearts were perfused in the absence (controls; n = 10) or presence of IVA (n = 10, 3 MUM) with or without atrial pacing to abolish HRR in the IVA group. IVA significantly reduced HR (35 +/- 5%) and increased stroke volume (39 +/- 9%) while maintaining similar cardiac output, contractility, power, and efficiency. Effects of IVA on HR and stroke volume were reversed by atrial pacing. At the metabolic level, IVA did not impact on substrate selection to citrate formation, rates of glycolysis, or tissue levels of high-energy phosphates. In contrast, METO, at concentrations up to 40 MUM, decreased markedly cardiac function (flow: 25 +/- 6%; stroke volume: 30 +/- 10%; contractility: 31 +/- 9%) as well as glycolysis (2.9-fold) but marginally affected HR. Collectively, these results demonstrate that IVA selectively reduces HR while preserving energy substrate metabolism of normoxic healthy working mouse hearts perfused ex vivo, a model that mimics to some extent the denervated transplanted heart. Our results provide the impetus for testing selective HRR by IVA on cardiac substrate metabolism in pathological models. PMID- 21257917 TI - Relation between QT interval variability and cardiac sympathetic activity in hypertension. AB - Elevated QT interval variability is a predictor of malignant ventricular arrhythmia, but the underlying mechanisms are incompletely understood. A recent study in dogs with pacing-induced heart failure suggests that QT variability is linked to cardiac sympathetic nerve activity. The aim of this study was to determine whether increased cardiac sympathetic activity is associated with increased beat-to-beat QT interval variability in patients with essential hypertension. We recorded resting norepinephrine (NE) spillover into the coronary sinus and single-lead, short-term, high-resolution, body-surface ECG in 23 patients with essential hypertension and 9 normotensive control subjects. To assess beat-to-beat QT interval variability, we calculated the overall QT variability (QTVN) as well as the QT variability index (QTVi). Cardiac NE spillover (12.2 +/- 6.5 vs. 20.7 +/- 14.7, P = 0.03) and QTVi (-1.75 +/- 0.36 vs. -1.42 +/- 0.50, P = 0.05) were significantly increased in hypertensive patients compared with normotensive subjects. QTVN was significantly correlated with cardiac NE spillover (r(2) = 0.31, P = 0.001), with RR variability (r(2) = 0.20, P = 0.008), and with systolic blood pressure (r(2) = 0.16, P = 0.02). Linear regression analysis identified the former two as independent predictors of QTVN. In conclusion, elevated repolarization lability is directly associated with sympathetic cardiac activation in patients with essential hypertension. PMID- 21257918 TI - Cardiac myocyte remodeling mediated by N-cadherin-dependent mechanosensing. AB - Cell-to-cell adhesions are crucial in maintaining the structural and functional integrity of cardiac cells. Little is known about the mechanosensitivity and mechanotransduction of cell-to-cell interactions. Most studies of cardiac mechanotransduction and myofibrillogenesis have focused on cell-extracellular matrix (ECM)-specific interactions. This study assesses the direct role of intercellular adhesion, specifically that of N-cadherin-mediated mechanotransduction, on the morphology and internal organization of neonatal ventricular cardiac myocytes. The results show that cadherin-mediated cell attachments are capable of eliciting a cytoskeletal network response similar to that of integrin-mediated force response and transmission, affecting myofibrillar organization, myocyte shape, and cortical stiffness. Traction forces mediated by N-cadherin were shown to be comparable to those sustained by ECM. The directional changes in predicted traction forces as a function of imposed loads (gel stiffness) provide the added evidence that N-cadherin is a mechanoresponsive adhesion receptor. Strikingly, the mechanical sensitivity response (gain) in terms of the measured cell-spread area as a function of imposed load (adhesive substrate rigidity) was consistently higher for N-cadherin-coated surfaces compared with ECM protein-coated surfaces. In addition, the cytoskeletal architecture of myocytes on an N-cadherin adhesive microenvironment was characteristically different from that on an ECM environment, suggesting that the two mechanotransductive cell adhesion systems may play both independent and complementary roles in myocyte cytoskeletal spatial organization. These results indicate that cell-to-cell-mediated force perception and transmission are involved in the organization and development of cardiac structure and function. PMID- 21257919 TI - Androgen stimulates endothelial cell proliferation via an androgen receptor/VEGF/cyclin A-mediated mechanism. AB - Growing evidences support that androgen displays beneficial effects on cardiovascular functions although the mechanism of androgen actions remains to be elucidated. Modulation of endothelial cell growth and function is a potential mechanism of androgen actions. We demonstrated in the present study that androgens [dihydrotestosterone (DHT) and testosterone], but not 17beta-estradiol, produced a time- and dose-dependent induction of cell proliferation in primary human aortic endothelial cells (HAECs) as evident by increases in viable cell number and DNA biosynthesis. Real-time qRT-PCR analysis showed that DHT induced androgen receptor (AR), cyclin A, cyclin D1, and vascular endothelial growth factor (VEGF) gene expression in a dose- and time-dependent manner. The addition of casodex, a specific AR antagonist, or transfection of a specific AR siRNA blocked DHT-induced cell proliferation and target gene expression, indicating that the DHT effects are mediated via AR. Moreover, coadministration of SU5416 to block VEGF receptors, or transfection of a specific VEGF-A siRNA to knockdown VEGF expression, produced a dose-dependent blockade of DHT induction of cell proliferation and cyclin A gene expression. Interestingly, roscovitine, a selective cyclin-dependent kinase inhibitor, also blocked the DHT stimulation of cell proliferation with a selective inhibition of DHT-induced VEGF-A expression. These results indicate that androgens acting on AR stimulate cell proliferation through upregulation of VEGF-A, cyclin A, and cyclin D1 in HAECs, which may be beneficial to cardiovascular functions since endothelial cell proliferation could assist the repair of endothelial injury/damage in cardiovascular system. PMID- 21257920 TI - Narrowing a region on rat chromosome 13 that protects against hypertension in Dahl SS-13BN congenic strains. AB - Transfer of chromosome 13 from the Brown Norway (BN) rat onto the Dahl salt sensitive (SS) genetic background attenuates the development of hypertension, but the genes involved remain to be identified. The purpose of the present study was to confirm by telemetry that a congenic strain [SS.BN-(D13Hmgc37-D13Got22)/Mcwi, line 5], carrying a 13.4-Mb segment of BN chromosome 13 from position 32.4 to 45.8 Mb, is protected from the development of hypertension and then to narrow the region of interest by creating and phenotyping 11 additional subcongenic strains. Mean arterial pressure (MAP) rose from 118 +/- 1 to 186 +/- 5 mmHg in SS rats fed a high-salt diet (8.0% NaCl) for 3 wk. Protein excretion increased from 56 +/- 11 to 365 +/- 37 mg/day. In contrast, MAP only increased to 152 +/- 9 mmHg in the line 5 congenic strain. Six subcongenic strains carrying segments of BN chromosome 13 from 32.4 and 38.2 Mb and from 39.9 to 45.8 Mb were not protected from the development of hypertension. In contrast, MAP was reduced by ~30 mmHg in five strains, carrying a 1.9-Mb common segment of BN chromosome 13 from 38.5 to 40.4 Mb. Proteinuria was reduced by ~50% in these strains. Sequencing studies did not identify any nonsynonymous single nucleotide polymorphisms in the coding region of the genes in this region. RT-PCR studies indicated that 4 of the 13 genes in this region were differentially expressed in the kidney of two subcongenic strains that were partially protected from hypertension vs. those that were not. These results narrow the region of interest on chromosome 13 from 13.4 Mb (159 genes) to a 1.9-Mb segment containing only 13 genes, of which 4 are differentially expressed in strains partially protected from the development of hypertension. PMID- 21257921 TI - Skeletal muscle blood flow and oxygen uptake at rest and during exercise in humans: a pet study with nitric oxide and cyclooxygenase inhibition. AB - The aim of the present study was to determine the effect of nitric oxide and prostanoids on microcirculation and oxygen uptake, specifically in the active skeletal muscle by use of positron emission tomography (PET). Healthy males performed three 5-min bouts of light knee-extensor exercise. Skeletal muscle blood flow and oxygen uptake were measured at rest and during the exercise using PET with H(2)O(15) and (15)O(2) during: 1) control conditions; 2) nitric oxide synthase (NOS) inhibition by arterial infusion of N(G)-monomethyl-L-arginine (L NMMA), and 3) combined NOS and cyclooxygenase (COX) inhibition by arterial infusion of L-NMMA and indomethacin. At rest, inhibition of NOS alone and in combination with indomethacin reduced (P < 0.05) muscle blood flow. NOS inhibition increased (P < 0.05) limb oxygen extraction fraction (OEF) more than the reduction in muscle blood flow, resulting in an ~20% increase (P < 0.05) in resting muscle oxygen consumption. During exercise, muscle blood flow and oxygen uptake were not altered with NOS inhibition, whereas muscle OEF was increased (P < 0.05). NOS and COX inhibition reduced (P < 0.05) blood flow in working quadriceps femoris muscle by 13%, whereas muscle OEF and oxygen uptake were enhanced by 51 and 30%, respectively. In conclusion, by specifically measuring blood flow and oxygen uptake by the use of PET instead of whole limb measurements, the present study shows for the first time in humans that inhibition of NO formation enhances resting muscle oxygen uptake and that combined inhibition of NOS and COX during exercise increases muscle oxygen uptake. PMID- 21257923 TI - Involvement of NK 1.1-positive gammadeltaT cells in interleukin-18 plus interleukin-2-induced interstitial lung disease. AB - Interstitial lung disease (ILD) is induced by various factors in humans. However, the exact mechanism of ILD remains elusive. This study sought to determine the role of natural killer (NK) 1.1(+) gammadeltaT cells in ILD. The injection of IL 18 plus IL-2 (IL-18/IL-2) into C57BL6 (B6) mice induced acute ILD that resembled early-stage human ILD. An accumulation of NK1.1(+) gammadeltaT cells similar to NK cells was evident in the lungs. The T Cell Receptor (TCR) Vgamma and Vdelta repertoires of NK1.1(+) gammadeltaT cells indicated polyclonal expansion. The expression of IL-2 receptor beta (Rbeta) and IL-18Rbeta in NK1.1(+) gammadeltaT cells was higher than in NK1.1(-) gammadeltaT cells. IL-18/IL-2 stimulated the proliferation of NK1.1(+) gammadeltaT cells, but not NK1.1(-) gammadeltaT cells. The IL-18/IL-2-stimulated NK1.1(+) gammadeltaT cells produced higher concentrations of IFN-gamma than did NK1.1(-) gammadeltaT cells. Moreover, NK1.1(+) gammadeltaT and NK1.1(-) gammadeltaT cells constituted completely different cell populations. The IL-18/IL-2-induced ILD was milder in TCRdelta(-/ ) and IFN-gamma(-/-) mice, compared with B6 mice. Furthermore, cell-transfer experiments demonstrated that NK1.1(+) gammadeltaT cells could induce the expansion of NK cells and IFN-gamma mRNA in the lung by IL-18/IL-2. Our results suggest that NK1.1(+) gammadeltaT cells function as inflammatory mediators in the early phase of IL-18/IL-2-induced ILD. PMID- 21257924 TI - Antioxidants prevent the RhoA inhibition evoked by crocidolite asbestos in human mesothelial and mesothelioma cells. AB - Asbestos is a naturally occurring fibrous silicate, whose inhalation is highly related to the risk of developing malignant mesothelioma (MM), and crocidolite is one of its most oncogenic types. The mechanism by which asbestos may cause MM is unclear. We have previously observed that crocidolite in human MM (HMM) cells induces NF-kappaB activation and stimulates the synthesis of nitric oxide by inhibiting the RhoA signaling pathway. In primary human mesothelial cells (HMCs) and HMM cells exposed to crocidolite asbestos, coincubated or not with antioxidants, we evaluated cytotoxicity and oxidative stress induction (lipid peroxidation) and the effect of asbestos on the RhoA signaling pathway (RhoA GTP binding, Rho kinase activity, RhoA prenylation, hydroxy-3-methylglutharyl-CoA reductase activity). In this paper we show that the reactive oxygen species generated by the incubation of crocidolite with primary HMCs and three HMM cell lines mediate the inhibition of 3-hydroxy-3-methylglutharyl-CoA reductase (HMGCR). The coincubation of HMCs and HMM cells with crocidolite together with antioxidants, such as Tempol, Mn-porphyrin, and the association of superoxide dismutase and catalase, prevented the cytotoxicity and lipoperoxidation caused by crocidolite alone as well as the decrease of HMGCR activity and restored the RhoA/RhoA-dependent kinase activity and the RhoA prenylation. The same effect was observed when the oxidizing agent menadione was administrated to the cells in place of crocidolite. Such a mechanism could at least partly explain the effects exerted by crocidolite fibers in mesothelial cells. PMID- 21257922 TI - Expression profiling identifies Klf15 as a glucocorticoid target that regulates airway hyperresponsiveness. AB - Glucocorticoids (GCs), which activate GC receptor (GR) signaling and thus modulate gene expression, are widely used to treat asthma. GCs exert their therapeutic effects in part through modulating airway smooth muscle (ASM) structure and function. However, the effects of genes that are regulated by GCs on airway function are not fully understood. We therefore used transcription profiling to study the effects of a potent GC, dexamethasone, on human ASM (HASM) gene expression at 4 and 24 hours. After 24 hours of dexamethasone treatment, nearly 7,500 genes had statistically distinguishable changes in expression; quantitative PCR validation of a 40-gene subset of putative GR-regulated genes in 6 HASM cell lines suggested that the early transcriptional targets of GR signaling are similar in independent HASM lines. Gene ontology analysis implicated GR targets in controlling multiple aspects of ASM function. One GR regulated gene, the transcription factor, Kruppel-like factor 15 (Klf15), was already known to modulate vascular smooth and cardiac muscle function, but had no known role in the lung. We therefore analyzed the pulmonary phenotype of Klf15(-/ ) mice after ovalbumin sensitization and challenge. We found diminished airway responses to acetylcholine in ovalbumin-challenged Klf15(-/-) mice without a significant change in the induction of asthmatic inflammation. In cultured cells, overexpression of Klf15 reduced proliferation of HASM cells, whereas apoptosis in Klf15(-/-) murine ASM cells was increased. Together, these results further characterize the GR-regulated gene network in ASM and establish a novel role for the GR target, Klf15, in modulating airway function. PMID- 21257925 TI - Cytoprotective-selective activated protein C attenuates Pseudomonas aeruginosa induced lung injury in mice. AB - Inhibition of the small GTPase RhoA attenuates the development of pulmonary edema and restores positive alveolar fluid clearance in a murine model of Pseudomonas aeruginosa pneumonia. Activated protein C (aPC) blocks the development of an unfavorably low ratio of small GTPase Rac1/RhoA activity in lung endothelium through endothelial protein C receptor (EPCR)/protease-activated receptor-1 (PAR 1)-dependent signaling mechanisms that include transactivating the sphingosine-1 phosphate (S1P) pathway. However, whether aPC's cytoprotective effects can attenuate the development of pulmonary edema and death associated with P. aeruginosa pneumonia in mice remains unknown. Thus, we determined whether the normalization of a depressed ratio of activated Rac1/RhoA by aPC would attenuate the P. aeruginosa-mediated increase in protein permeability across lung endothelial and alveolar epithelial barriers. Pretreatment with aPC significantly reduced P. aeruginosa-induced increases in paracellular permeability across pulmonary endothelial cell and alveolar epithelial monolayers via an inhibition of RhoA activation and a promotion of Rac1 activation that required the EPCR-PAR 1 and S1P pathways. Furthermore, pretreatment with aPC attenuated the development of pulmonary edema in a murine model of P. aeruginosa pneumonia. Finally, a cytoprotective-selective aPC mutant, aPC-5A, which lacks most of aPC's anticoagulant activity, reproduced the protective effect of wild-type aPC by attenuating the development of pulmonary edema and decreasing mortality in a murine model of P. aeruginosa pneumonia. Taken together, these results demonstrate a critical role for the cytoprotective activities of aPC in attenuating P. aeruginosa-induced lung vascular permeability and mortality, suggesting that cytoprotective-selective aPC-5A with diminished bleeding risks could attenuate the lung damage caused by P. aeruginosa in critically ill patients. PMID- 21257926 TI - Hyaluronan fragments promote inflammation by down-regulating the anti inflammatory A2a receptor. AB - The tissue microenvironment plays a critical role in regulating inflammation. Chronic inflammation leads to an influx of inflammatory cells and mediators, extracellular matrix turnover, and increased extracellular adenosine. Low molecular weight (LMW) fragments of hyaluronan (HA), a matrix component, play a critical role in lung inflammation and fibrosis by inducing inflammatory gene expression at the injury site. Adenosine, a crucial negative regulator of inflammation, protects tissues from immune destruction via the adenosine A2a receptor (A2aR). Therefore, these two extracellular products of inflammation play opposing roles in regulating immune responses. As such, we wanted to determine the effect of LMW HA on A2aR function. In this article, we demonstrate that LMW HA causes a rapid, significant, and sustained down-regulation of the A2aR. CD44 was found to be necessary for LMW HA to down-modulate the A2aR as was protein kinase C signaling. We also demonstrate that LMW HA induces A2aR down-regulation during inflammation in vivo, and that this down-regulation can be blocked by treatment with an HA-blocking peptide. Because adenosine plays a critical role in limiting inflammation, our data provide a novel mechanism whereby LMW HA itself may further augment inflammation. By defining the pro- and anti-inflammatory properties of extracellular matrix components, we will be better able to identify specific pharmacologic targets as potential therapies. PMID- 21257927 TI - Fas activation in alveolar epithelial cells induces KC (CXCL1) release by a MyD88 dependent mechanism. AB - Activation of the Fas/Fas ligand (FasL) system is associated with activation of apoptotic and proinflammatory pathways that lead to the development of acute lung injury. Previous studies in chimeric mice and macrophage-depleted mice suggested that the main effector cell in Fas-mediated lung injury is not a myeloid cell, but likely an epithelial cell. The goal of this study was to determine whether epithelial cells release proinflammatory cytokines after Fas activation, and to identify the relevant pathways. Incubation of the murine alveolar epithelial cell line, MLE-12, with the Fas-activating monoclonal antibody, Jo2, resulted in release of the CXC chemokine, KC, in a dose-dependent manner. KC release was not prevented by the pan-caspase inhibitor, zVAD.fmk. Silencing of the adaptor protein, MyD88, with small interfering (si)RNA resulted in attenuation of KC release in response to Jo2. Fas activation resulted in phosphorylation of the mitogen-activated kinases extracellular signal-regulated kinase (ERK) and c-Jun-N terminal kinase (JNK), and pharmacologic inhibition of ERK and JNK attenuated KC release in a dose-response manner. Similarly, primary human small airways epithelial cells released IL-8 in response to soluble FasL, and this was abrogated by inhibition of JNK and ERK. In vivo confirmatory studies showed that MyD88-null mice are protected from Fas-induced acute lung injury. In summary, we conclude that Fas induces KC release in MLE-12 cells by a mechanism requiring MyD88, mitogen-activated protein kinases, and likely activator protein-1. PMID- 21257928 TI - Informatics in radiology: Efficiency metrics for imaging device productivity. AB - Acute awareness of the costs associated with medical imaging equipment is an ever present aspect of the current healthcare debate. However, the monitoring of productivity associated with expensive imaging devices is likely to be labor intensive, relies on summary statistics, and lacks accepted and standardized benchmarks of efficiency. In the context of the general Six Sigma DMAIC (design, measure, analyze, improve, and control) process, a World Wide Web-based productivity tool called the Imaging Exam Time Monitor was developed to accurately and remotely monitor imaging efficiency with use of Digital Imaging and Communications in Medicine (DICOM) combined with a picture archiving and communication system. Five device efficiency metrics-examination duration, table utilization, interpatient time, appointment interval time, and interseries time were derived from DICOM values. These metrics allow the standardized measurement of productivity, to facilitate the comparative evaluation of imaging equipment use and ongoing efforts to improve efficiency. A relational database was constructed to store patient imaging data, along with device- and examination related data. The database provides full access to ad hoc queries and can automatically generate detailed reports for administrative and business use, thereby allowing staff to monitor data for trends and to better identify possible changes that could lead to improved productivity and reduced costs in association with imaging services. (c) RSNA, 2011. PMID- 21257930 TI - Differential diagnosis for bilateral abnormalities of the basal ganglia and thalamus. AB - The basal ganglia and thalamus are paired deep gray matter structures that may be involved by a wide variety of disease entities. The basal ganglia are highly metabolically active and are symmetrically affected in toxic poisoning, metabolic abnormalities, and neurodegeneration with brain iron accumulation. Both the basal ganglia and thalamus may be affected by other systemic or metabolic disease, degenerative disease, and vascular conditions. Focal flavivirus infections, toxoplasmosis, and primary central nervous system lymphoma may also involve both deep gray matter structures. The thalamus is more typically affected alone by focal conditions than by systemic disease. Radiologists may detect bilateral abnormalities of the basal ganglia and thalamus in different acute and chronic clinical situations, and although magnetic resonance (MR) imaging is the modality of choice for evaluation, the correct diagnosis can be made only by taking all relevant clinical and laboratory information into account. The neuroimaging diagnosis is influenced not only by detection of specific MR imaging features such as restricted diffusion and the presence of hemorrhage, but also by detection of abnormalities involving other parts of the brain, especially the cerebral cortex, brainstem, and white matter. Judicious use of confirmatory neuroimaging investigations, especially diffusion-weighted imaging, MR angiography, MR venography, and MR spectroscopy during the same examination, may help improve characterization of these abnormalities and help narrow the differential diagnosis. PMID- 21257931 TI - Best cases from the AFIP: Balamuthia mandrillaris amebic meningoencephalitis. PMID- 21257932 TI - Articular cartilage in the knee: current MR imaging techniques and applications in clinical practice and research. AB - Magnetic resonance (MR) imaging is the most important imaging modality for the evaluation of traumatic or degenerative cartilaginous lesions in the knee. It is a powerful noninvasive tool for detecting such lesions and monitoring the effects of pharmacologic and surgical therapy. The specific MR imaging techniques used for these purposes can be divided into two broad categories according to their usefulness for morphologic or compositional evaluation. To assess the structure of knee cartilage, standard spin-echo (SE) and gradient-recalled echo (GRE) sequences, fast SE sequences, and three-dimensional SE and GRE sequences are available. These techniques allow the detection of morphologic defects in the articular cartilage of the knee and are commonly used in research for semiquantitative and quantitative assessments of cartilage. To evaluate the collagen network and proteoglycan content in the knee cartilage matrix, compositional assessment techniques such as T2 mapping, delayed gadolinium enhanced MR imaging of cartilage (or dGEMRIC), T1rho imaging, sodium imaging, and diffusion-weighted imaging are available. These techniques may be used in various combinations and at various magnetic field strengths in clinical and research settings to improve the characterization of changes in cartilage. PMID- 21257933 TI - Pitfalls that may mimic injuries of the triangular fibrocartilage and proximal intrinsic wrist ligaments at MR imaging. AB - Diagnosis of injuries to the ligamentous structures of the wrist can be a challenge, particularly when there is involvement of the small, complex structures of the proximal wrist. Recent advances in magnetic resonance (MR) imaging, especially in spatial and contrast resolution, have facilitated more precise visualization of these structures. However, there are a number of pitfalls that may cause difficulty in diagnosis of injuries to the triangular fibrocartilage complex (TFCC), lunotriquetral ligament, and scapholunate ligament. Use of inappropriate MR imaging sequences and MR imaging artifacts may decrease the accuracy of diagnosis of injuries to the TFCC and wrist ligaments, whereas variant anatomy of the proximal wrist structures may mimic disease of the TFCC and wrist ligaments. Knowledge of the detailed anatomy of the wrist, as well as variant patterns of structure morphology and signal intensity, can help differentiate actual disease from normal or variant appearances at assessment with MR imaging. PMID- 21257934 TI - Multidetector CT evaluation of calcaneal fractures. AB - As the largest tarsal bone and the most inferior bone in the body, the calcaneus is responsible for supporting the axial load from the weight of the body. It is most commonly fractured after a fall from a height in which axial loads exceed its support capacity. Calcaneal fractures account for 60% of all tarsal fractures. Conventional radiography is commonly used for initial evaluation of calcaneal injury but has the typical disadvantages of two-dimensional imaging. Modern assessment of calcaneal fractures relies heavily on multidetector computed tomography (CT), which allows better visualization and characterization of fracture lines and fragment displacement. Calcaneal fractures observed at CT have been divided into intra- and extraarticular fractures on the basis of subtalar joint involvement. The Sanders classification system for intraarticular fractures is the most commonly used system because it correlates with clinical outcomes and involves less interobserver variability. The classification of extraarticular fractures has been less controversial and makes use of anatomic landmarks on the calcaneus to divide the bone into anterior, middle, and posterior areas. Soft tissue involvement is an important aspect of calcaneal fracture assessment because it has been linked with poor functional outcomes. Familiarity with the normal anatomy of the calcaneus, the classification of calcaneal fractures, and the various complications of these fractures is essential for treatment assessment, especially if surgical intervention is required. PMID- 21257935 TI - Best cases from the AFIP: Necrotic giant cell tumor of bone manifesting with pathologic fracture. PMID- 21257936 TI - Adenomyosis: usual and unusual imaging manifestations, pitfalls, and problem solving MR imaging techniques. AB - Adenomyosis is a common nonneoplastic gynecologic disease characterized by the presence of ectopic endometrium within the myometrium. On T2-weighted magnetic resonance (MR) images, typical adenomyosis appears as an ill-demarcated low signal-intensity lesion with uterine enlargement. However, various physiologic or pathologic states such as amount of functional endometrial tissue, phase of the menstrual cycle, endogenous hormonal abnormality, and exogenous hormonal stimulation may affect the MR imaging appearance of adenomyosis and may result in a tumorlike appearance. Problem-solving MR imaging techniques used in diagnosis of adenomyosis include diffusion-weighted imaging, susceptibility-weighted imaging, hydrogen 1 MR spectroscopy, cine MR imaging, and high-resolution MR imaging at 3 T. Adenomyotic lesions that show high signal intensity relative to the outer myometrium on T2-weighted images mimic malignancies such as leiomyosarcoma and endometrial stromal sarcoma. In these cases, a relatively high apparent diffusion coefficient at diffusion-weighted imaging and a low choline peak at MR spectroscopy are suggestive of a benign lesion. Small hemorrhagic foci suggestive of an adenomyotic lesion are well demonstrated as signal voids at susceptibility-weighted imaging. Cine MR imaging is useful in differentiating transient myometrial contraction from focal adenomyosis. High-resolution MR imaging at 3 T demonstrates anatomically detailed structures and may improve diagnostic accuracy in differentiating adenomyosis from its mimics, such as low grade endometrial stromal sarcoma. PMID- 21257937 TI - Supraglottic larynx and hypopharynx: an important anatomic distinction. PMID- 21257938 TI - Pathways of extrapelvic spread of pelvic disease: imaging findings. AB - The complex extraperitoneal anatomy of the pelvis includes various outlets for the transit of organs and neurovascular structures to the rest of the body. These outlets include the greater sciatic foramen, lesser sciatic foramen, inguinal canal, femoral triangle, obturator canal, anal and genitourinary hiatuses of the pelvic floor, prevesical space, and iliopsoas compartment. All of these structures serve as conduits for the dissemination of malignant and benign inflammatory diseases from the pelvic cavity and into the soft-tissue structures of the abdominal wall, buttocks, and upper thigh. Knowledge of the pelvic anatomy is crucial to understand these patterns of disease spread. Cross-sectional imaging provides important anatomic information and depicts the extent of disease and its involvement of surrounding extrapelvic structures, information that is important for planning surgery and radiation therapy. PMID- 21257939 TI - Pathways of lymphatic spread in male urogenital pelvic malignancies. AB - Regional lymph node involvement in urogenital malignancies (category N in the TNM classification system) is a significant radiologic finding, with important implications for treatment and prognosis. Male urogenital pelvic cancers commonly spread to iliopelvic or retroperitoneal lymph nodes by following pathways of normal lymphatic drainage from the pelvic organs. The most likely pathway of nodal spread (superficial inguinal, pelvic, or paraaortic) depends on the tumor location in the prostate, penis, testis, or bladder and whether surgery or other therapy has disrupted normal lymphatic drainage from the tumor site; knowledge of both factors is needed for accurate disease staging. At present, lymph node status is most often assessed with standard anatomic imaging techniques such as multidetector computed tomography or magnetic resonance (MR) imaging. However, the detection of nodal disease with these techniques is reliant on lymph node size and morphologic characteristics, criteria that provide limited diagnostic specificity. Functional imaging techniques, such as diffusion-weighted MR imaging performed with or without a lymphotropic contrast agent and positron emission tomography, may allow a more accurate nodal assessment based on molecular or physiologic activity. PMID- 21257940 TI - Doppler US of the liver made simple. AB - Doppler ultrasonography (US) is usually the first-line modality for evaluating flow in native liver vessels and transjugular intrahepatic portosystemic shunts (TIPS). Waveforms, which represent flow in each of the major vessels and in TIPS, have been well described. The appearance of these waveforms should be recognized, and the mechanisms behind their generation should be understood by those interpreting these examinations. Understanding how waveforms are formed--that is, their mechanisms for generation--is predicated on knowing basic vascular Doppler concepts and established nomenclature. This article is a review of these basic concepts and nomenclature as applied to the interpretation of liver Doppler US waveforms. PMID- 21257941 TI - Evaluation of early gastric cancer at multidetector CT with multiplanar reformation and virtual endoscopy. AB - Early gastric cancer (EGC) is defined as a carcinoma in which invasion is limited to the mucosa and submucosa, regardless of lymph node status and distant metastasis. Recent advances in multidetector computed tomography (CT) with multiplanar reformation (MPR) provide a powerful tool for identifying gastric wall invasion and the perigastric extent of gastric cancer. In addition, MPR images confer advantages in the assessment of both intra- and extraluminal processes of the gastric wall and the evaluation of more distant regions, such as the paraaortic lymph nodes and other abdominal organs. Virtual endoscopy performed after air distention of the stomach can aid in the evaluation of gastric endoluminal morphologic features and the extent of EGC. Moreover, virtual endoscopy helps in detecting subtle mucosal changes and differentiating them from submucosal lesions in the same way as conventional endoscopy. Virtual endoscopy can depict abnormal endoluminal lesions within a wider field of view than can conventional endoscopy, and there are no "blind spots" because retrospective image reformation is available, which provides useful information for preoperative mapping. Multidetector CT with MPR and virtual endoscopy is a powerful, noninvasive tool for the early detection and accurate preoperative staging of EGC. PMID- 21257942 TI - Therapeutic response to radiofrequency ablation of neoplastic lesions: FDG PET/CT findings. AB - Ablation of neoplastic lesions by using radiofrequency energy is gaining popularity in clinical practice because of the minimally invasive nature of radiofrequency ablation (RFA). Primary and secondary tumors of the liver and lung are treated with RFA when surgery is precluded because of comorbidity. Benign bone tumors are also treated with RFA to relieve pain and prevent further tumor growth. Differentiation between postablation tissue changes and residual disease is difficult with morphologic imaging modalities such as ultrasonography, computed tomography (CT), and magnetic resonance (MR) imaging, thus limiting the use of these modalities to detection of residual disease early after RFA. Fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) is a functional imaging modality that can be used to study the effects and efficacy of RFA. Lesions that show increased FDG uptake at PET become completely photopenic immediately after RFA, a finding that is suggestive of the completeness of ablation. Focal areas of increased FDG uptake within the ablated zone are suggestive of residual disease. Reactive tissue changes such as inflammation are depicted in the periphery of the ablated lesion and show a uniform low-grade FDG uptake, which can be differentiated from the focal, nodular intense uptake in areas of residual disease. Use of combined FDG PET/CT to detect residual disease early after RFA allows ablation to be repeated, if necessary, to obtain the maximum therapeutic benefit. Note that FDG uptake in the complications sometimes associated with RFA can be a cause of potential false-positive PET results. PMID- 21257943 TI - Revisions to the TNM staging of non-small cell lung cancer: rationale, clinicoradiologic implications, and persistent limitations. AB - The International Association for the Study of Lung Cancer proposed changes to the 7th edition of the Tumor, Node, and Metastasis (TNM) staging manual of non small cell lung cancer (NSCLC) to improve the prognostic relevance of its descriptors. These changes include the subdivision of T1 and T2 disease according to size cut points; reassignment of the T and M categories of same-lobe, ipsilateral, and contralateral malignant pulmonary nodules; reassignment of pleural disease to metastatic disease; and introduction of intra- and extrathoracic metastatic disease. Because of movement between T and M descriptors and resultant stage migration, new stage groupings that contain TNM subsets different from those of the previous edition were created. The new staging classification was created on the basis of statistical analysis of a large international database of cases of NSCLC. The new classification has many advantages; however, limitations remain. Problems with routine radiologic staging of NSCLC have not been addressed, the varied survival rates for patients with the different histologic subtypes is not reflected, the new classification is not compatible with the previous system, and application of treatment algorithms on the basis of evidence from the previous edition is less clear. PMID- 21257944 TI - Evaluation of left ventricular diastolic function with cardiac MR imaging. AB - Assessment of left ventricular (LV) function with cardiac magnetic resonance (MR) imaging is often limited to evaluation of systolic function, including analysis of regional wall motion, measurement of mass and volume, and estimation of ejection fraction. However, diastolic dysfunction is present in various heart diseases, particularly in heart failure with preserved ejection fraction, which is increasingly prevalent and is associated with a poor prognosis. In daily practice, the assessment of diastolic function is mainly performed with transthoracic echocardiography. Evaluation of diastolic function with cardiac MR imaging is seldom performed in clinical practice. However, basic assessment of LV relaxation and stiffness abnormalities can be achieved with MR imaging by using a combination of left atrium size measurement and phase-contrast evaluation of transmitral flow. In addition, assessment of pulmonary venous flow and the LV filling curve can also be performed. Furthermore, MR imaging with late gadolinium enhancement sequences provides insight into the extent of myocardial fibrosis, which strongly influences LV stiffness. Finally, phase-contrast evaluation of tissue velocities, myocardial tagging, MR spectroscopy, and MR elastography are promising tools for a better understanding of LV diastolic function but require further evaluation. PMID- 21257945 TI - Imaging of cancer predisposition syndromes in children. AB - The term cancer predisposition syndrome (CPS) encompasses a multitude of familial cancers in which a clear mode of inheritance can be established, although a specific gene defect has not been described in all cases. Advances in genetics and the development of new imaging techniques have led to better understanding and early detection of these syndromes and offer the potential for preclinical diagnosis of any associated tumors. As a result, imaging has become an essential component of the clinical approach to management of CPSs and the care of children suspected of having a CPS or with a confirmed diagnosis. Common CPSs in children include neurofibromatosis type 1, Beckwith-Wiedemann syndrome, multiple endocrine neoplasia, Li-Fraumeni syndrome, von Hippel-Lindau syndrome, and familial adenomatous polyposis. Radiologists should be familiar with these syndromes, their common associated tumors, the new imaging techniques that are available, and current screening and surveillance recommendations to optimize the assessment of affected children. PMID- 21257946 TI - European Journal of Cardio-thoracic Surgery/Interactive CardioVascular and Thoracic Surgery--Reach out for the next decade! PMID- 21257947 TI - eComment: Negative pressure vacuum assisted closure therapy following cardiac surgery: safe and effective. PMID- 21257948 TI - eComment: Early discharge post cardiac surgery: the gold standard or a false economy? PMID- 21257949 TI - eComment: Intrathoracic esophagogastric anastomotic leakage following esophageal surgery. PMID- 21257950 TI - eComment: Treatment of thoracic anastomotic leaks after esophagectomy. PMID- 21257951 TI - eComment: Video-assisted thymectomy for thymoma. PMID- 21257952 TI - eComment: Bicuspid aortic valve and acute aortic dissection in the young--is long term surveillance beneficial? PMID- 21257953 TI - eComment: Endovascular treatment of chronic aortic dissection: is an uncovered stent the way to go? PMID- 21257954 TI - eComment: Continued postoperative left ventricle remodeling affects the initial good outcome of the restrictive mitral valve annuloplasty. PMID- 21257955 TI - eComment: Re: What is the best treatment of postpneumonectomy empyema? PMID- 21257956 TI - eComment: Re: Staged biventricular repair for persistent truncus arteriosus with aortic arch obstruction following bilateral pulmonary artery banding. PMID- 21257957 TI - eComment: Re: Thrombosis of a large saphenous vein graft aneurysm leading to acute myocardial infarction 21 years after coronary artery bypass grafting: role of cardiac multi-slice computed tomography. PMID- 21257958 TI - DAP12 promotes IRAK-M expression and IL-10 production by liver myeloid dendritic cells and restrains their T cell allostimulatory ability. AB - Freshly isolated hepatic dendritic cells (DC) are comparatively immature, relatively resistant to maturation, and can downmodulate effector T cell responses. Molecular mechanisms that underlie these properties are ill defined. DNAX-activating protein of 12 kDa (DAP12) is an ITAM-bearing transmembrane adaptor protein that integrates signals through several receptors, including triggering receptor expressed on myeloid cells-1, -2, and CD200R. Notably, DC propagated from DAP12-deficient mice exhibit enhanced maturation in response to TLR ligation. Given the constitutive exposure of liver DC to endotoxin draining from the gut, we hypothesized that DAP12 might regulate liver DC maturation. We show that DAP12 is expressed by freshly isolated liver, spleen, kidney, and lung myeloid DC. Moreover, inhibition of DAP12 expression by liver DC using small interfering RNA promotes their phenotypic and functional maturation, resulting in enhanced TNF-alpha, IL-6, and IL-12p70 production, reduced secretion of IL-10, and enhanced CD4(+) and CD8(+) T cell proliferation. Furthermore, DAP12 silencing correlates with decreased STAT3 phosphorylation in mature liver DC and with diminished expression of the IL-1R-associated kinase-M, a negative regulator of TLR signaling. These findings highlight a regulatory role for DAP12 in hepatic DC maturation, and suggest a mechanism whereby this function may be induced/maintained. PMID- 21257959 TI - NF-kappaB- and AP-1-mediated DNA looping regulates osteopontin transcription in endotoxin-stimulated murine macrophages. AB - Osteopontin (OPN) is expressed by various immune cells and modulates both innate and adaptive immune responses. However, the molecular mechanisms that control opn gene expression, especially at the chromatin level, remain largely unknown. We have previously demonstrated many specific cis- and trans-regulatory elements that determine the extent of endotoxin (LPS)-mediated induction of OPN synthesis in murine macrophages. In the present study, we confirm that NF-kappaB also plays an important role in the setting of LPS-stimulated OPN expression through binding to a distal regulatory element. Importantly, we demonstrate that LPS stimulates chromosomal loops in the OPN promoter between NF-kappaB binding site and AP-1 binding site using chromosome conformation capture technology. The crucial role of NF-kappaB and AP-1 in LPS-stimulated DNA looping was confirmed, as small interfering RNA knock-down of NF-kappaB p65 and AP-1 c-Jun exhibited decreased levels of DNA looping. Furthermore, we demonstrate that p300 can form a complex with NF-kappaB and AP-1 and is involved in DNA looping and LPS-induced OPN expression. Therefore, we have identified an essential mechanism to remodel the local chromatin structures and spatial conformations to regulate LPS-induced OPN expression. PMID- 21257960 TI - Limiting the amount and duration of antigen exposure during priming increases memory T cell requirement for costimulation during recall. AB - Donor-reactive memory T cells (Tmem) can play an important role in mediating graft rejection after transplantation. Transplant recipients acquire donor reactive Tmem not only through prior sensitization with alloantigens but also through previous exposure to environmental pathogens that are cross-reactive with allogeneic peptide-MHC complexes. Current dogma suggests that most, if not all, Tmem responses are independent of the requirement for CD28 and/or CD154/CD40 mediated costimulation to mount a recall response. However, heterogeneity among Tmem is increasingly being appreciated, and one important factor known to impact the function and phenotype of Ag-specific T cell responses is the amount/duration of Ag exposure. Importantly, the impact of Ag exposure on development of costimulation independence is currently unknown. In this study, we interrogated the effect of decreased Ag amount/duration during priming on the ability of donor reactive Tmem to mediate costimulation blockade-resistant rejection during a recall response after transplantation in a murine model. Recipients possessing donor-reactive Tmem responses that were generated under conditions of reduced Ag exposure exhibited similar frequencies of Ag-specific T cells at day 30 postinfection, but, strikingly, failed to mediate costimulation blockade resistant rejection after challenge with an OVA-expressing skin graft. Thus, these data demonstrate the amount/duration of Ag exposure is a critical factor in determining Tmem's relative requirement for costimulation during the recall response after transplantation. PMID- 21257962 TI - Rhesus macaque inhibitory and activating KIR3D interact with Mamu-A-encoded ligands. AB - Specific interactions between killer cell Ig-like receptors (KIRs) and MHC class I ligands have not been described in rhesus macaques despite their importance in biomedical research. Using KIR-Fc fusion proteins, we detected specific interactions for three inhibitory KIRs (3DLW03, 3DL05, 3DL11) and one activating KIR (3DS05). As ligands we identified Macaca mulatta MHC (Mamu)-A1- and Mamu-A3 encoded allotypes, among them Mamu-A1*001:01, which is well known for association with slow progression to AIDS in the rhesus macaque experimental SIV infection model. Interactions with Mamu-B or Mamu-I molecules were not found. KIR3DLW03 and KIR3DL05 differ in their binding sites to their shared ligand Mamu-A1*001:01, with 3DLW03 depending on presence of the alpha1 domain, whereas 3DL05 depends on both the alpha1 and alpha2 domains. Fine-mapping studies revealed that binding of KIR3DLW03 is influenced by presence of the complete Bw4 epitope (positions 77, 80 83), whereas that of KIR3DL05 is mainly influenced by amino acid position 77 of Bw4 and positions 80-83 of Bw6. Our findings allowed the successful prediction of a further ligand of KIR3DL05, Mamu-A1*002:01. These functional differences of rhesus macaque KIR3DL molecules are in line with the known genetic diversification of lineage II KIRs in macaques. PMID- 21257961 TI - Enhanced and sustained CD8+ T cell responses with an adenoviral vector-based hepatitis C virus vaccine encoding NS3 linked to the MHC class II chaperone protein invariant chain. AB - Potent and broad cellular immune responses against the nonstructural (NS) proteins of hepatitis C virus (HCV) are associated with spontaneous viral clearance. In this study, we have improved the immunogenicity of an adenovirus (Ad)-based HCV vaccine by fusing NS3 from HCV (Strain J4; Genotype 1b) to the MHC class II chaperone protein invariant chain (Ii). We found that, after a single vaccination of C57BL/6 or BALB/c mice with Ad-IiNS3, the HCV NS3-specific CD8(+) T cell responses were significantly enhanced, accelerated, and prolonged compared with the vaccine encoding NS3 alone. The AdIiNS3 vaccination induced polyfunctional CD8(+) T cells characterized by coproduction of IFN-gamma, TNF alpha and IL-2, and this cell phenotype is associated with good viral control. The memory CD8(+) T cells also expressed high levels of CD27 and CD127, which are markers of long-term survival and maintenance of T cell memory. Functionally, the AdIiNS3-vaccinated mice had a significantly increased cytotoxic capacity compared with the AdNS3 group. The AdIiNS3-induced CD8(+) T cells protected mice from infection with recombinant vaccinia virus expressing HCV NS3 of heterologous 1b strains, and studies in knockout mice demonstrated that this protection was mediated primarily through IFN-gamma production. On the basis of these promising results, we suggest that this vaccination technology should be evaluated further in the chimpanzee HCV challenge model. PMID- 21257963 TI - Class IA phosphoinositide 3-kinase beta and delta regulate neutrophil oxidase activation in response to Aspergillus fumigatus hyphae. AB - An effective immune response to the ubiquitous fungus Aspergillus fumigatus is dependent upon production of reactive oxygen species (ROS) by the NADPH oxidase. This is evidenced by the acute sensitivity of oxidase-deficient humans and mice to invasive aspergillosis. Neutrophils are recruited to the lungs shortly postinfection and respond by phagocytosing conidia and mediating extracellular killing of germinated hyphae in a ROS-dependent manner. However, the signaling mechanisms regulating the generation of ROS in response to hyphae are poorly understood. PI3Ks are important regulators of numerous cellular processes, with much recent work describing unique roles for the different class I PI3K isoforms. We showed by live-cell imaging that the lipid products of class I PI3Ks accumulated at the hyphal-bound neutrophil plasma membrane. Further, we used pharmacological and genetic approaches to demonstrate essential, but overlapping, roles for PI3Kbeta and PI3Kdelta in the ROS and spreading responses of murine neutrophils to Aspergillus hyphae. Hyphal-induced ROS responses were substantially inhibited by deletion of the common beta2-integrin subunit CD18, with only a minor, redundant role for Dectin-1. However, addition of soluble algal glucans plus the genetic deletion of CD18 were required to significantly inhibit activation of the PI3K-effector protein kinase B. Hyphal ROS responses were also totally dependent on the presence of Syk, but not its ITAM-containing adaptor proteins FcRgamma or DAP12, and the Vav family of Rac-guanine nucleotide exchange factors. These results start to define the signaling network controlling neutrophil ROS responses to A. fumigatus hyphae. PMID- 21257964 TI - A single nucleotide polymorphism in NF-kappaB inducing kinase is associated with mortality in septic shock. AB - We tested the hypothesis that single nucleotide polymorphisms (SNPs) within genes of the NF-kappaB pathway are associated with altered clinical outcome of septic shock patients. We genotyped 59 SNPs in the NF-kappaB pathway in a discovery cohort of septic shock patients (St. Paul's Hospital [SPH], N = 589), which identified the C allele of rs7222094 T/C within MAP3K14 (NF-kappaB inducing kinase; NIK) associated with increased 28-d mortality (uncorrected p = 0.00024, Bonferroni corrected p = 0.014). This result was replicated in a second cohort of septic shock patients (Vasopressin and Septic Shock Trial [VASST; N = 616]) in which the CC genotype of rs7222094 was associated with increased 28-d mortality (Cox regression: SPH cohort hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.12-1.64; p = 0.002 Caucasian only; and VASST cohort HR, 1.24; 95% CI, 1.00-1.52; p = 0.048 Caucasian only). Patients having the CC genotype of rs7222094 in SPH experienced more renal and hematological dysfunction (p = 0.003 and p = 0.011), while patients of the VASST cohort with the rs7222094 CC genotype showed the same trend toward more renal dysfunction. In lymphoblastoid cell lines, we found the rs7222094 genotype most strongly associated with mRNA expression of CXCL10, a chemokine regulated by NF-kappaB. Accordingly, we measured CXCL10 protein levels and found that the CC genotype of rs7222094 was associated with significantly lower levels than those of the TT genotype in lymphoblastoid cell lines (p < 0.05) and in septic shock patients (p = 0.017). This suggests that the CC genotype of NIK rs7222094 is associated with increased mortality and organ dysfunction in septic shock patients, perhaps due to altered regulation of NF-kappaB pathway genes, including CXCL10. PMID- 21257965 TI - Two unique human decidual macrophage populations. AB - Several important events occur at the maternal-fetal interface, including generation of maternal-fetal tolerance, remodeling of the uterine smooth muscle and its spiral arteries and glands, and placental construction. Fetal-derived extravillous trophoblasts come in direct contact with maternal decidual leukocytes. Macrophages represent ~20% of the leukocytes at this interface. In this study, two distinct subsets of CD14(+) decidual macrophages (dMs) are found to be present in first-trimester decidual tissue, CD11c(HI) and CD11c(LO). Gene expression analysis by RNA microarray revealed that 379 probes were differentially expressed between these two populations. Analysis of the two subsets revealed several clusters of coregulated genes that suggest distinct functions for these subsets in tissue remodeling, growth, and development. CD11c(HI) dMs express genes associated with lipid metabolism and inflammation, whereas CD11c(LO) dMs express genes associated with extracellular matrix formation, muscle regulation, and tissue growth. The CD11c(HI) dMs also differ from CD11c(LO) dMs in their ability to process protein Ag and are likely to be the major APCs in the decidua. Moreover, these populations each secrete both proinflammatory and anti-inflammatory cytokines that may contribute to the balance that establishes fetal-maternal tolerance. Thus, they do not fit the conventional M1/M2 categorization. PMID- 21257966 TI - Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection. AB - CD4 T cell help plays an important role in promoting CD8 T cell immunity to pathogens. In models of infection with vaccinia virus (VV) and Listeria monocytogenes, CD4 T cell help is critical for the survival of activated CD8 T cells during both the primary and memory recall responses. Still unclear, however, is how CD4 T cell help promotes CD8 T cell survival. In this study, we first showed that CD4 T cell help for the CD8 T cell response to VV infection was mediated by IL-21, a cytokine produced predominantly by activated CD4 T cells, and that direct action of IL-21 on CD8 T cells was critical for the VV-specific CD8 T cell response in vivo. We next demonstrated that this intrinsic IL-21 signaling was essential for the survival of activated CD8 T cells and the generation of long-lived memory cells. We further revealed that IL-21 promoted CD8 T cell survival in a mechanism dependent on activation of the STAT1 and STAT3 pathways and subsequent upregulation of the prosurvival molecules Bcl-2 and Bcl x(L). These results identify a critical role for intrinsic IL-21 signaling in CD8 T cell responses to an acute viral infection in vivo and may help design effective vaccine strategies. PMID- 21257967 TI - Lung effector memory and activated CD4+ T cells display enhanced proliferation in surfactant protein A-deficient mice during allergen-mediated inflammation. AB - Although many studies have shown that pulmonary surfactant protein (SP)-A functions in innate immunity, fewer studies have addressed its role in adaptive immunity and allergic hypersensitivity. We hypothesized that SP-A modulates the phenotype and prevalence of dendritic cells (DCs) and CD4(+) T cells to inhibit Th2-associated inflammatory indices associated with allergen-induced inflammation. In an OVA model of allergic hypersensitivity, SP-A(-/-) mice had greater eosinophilia, Th2-associated cytokine levels, and IgE levels compared with wild-type counterparts. Although both OVA-exposed groups had similar proportions of CD86(+) DCs and Foxp3(+) T regulatory cells, the SP-A(-/-) mice had elevated proportions of CD4(+) activated and effector memory T cells in their lungs compared with wild-type mice. Ex vivo recall stimulation of CD4(+) T cell pools demonstrated that cells from the SP-A(-/-) OVA mice had the greatest proliferative and IL-4-producing capacity, and this capability was attenuated with exogenous SP-A treatment. Additionally, tracking proliferation in vivo demonstrated that CD4(+) activated and effector memory T cells expanded to the greatest extent in the lungs of SP-A(-/-) OVA mice. Taken together, our data suggested that SP-A influences the prevalence, types, and functions of CD4(+) T cells in the lungs during allergic inflammation and that SP deficiency modifies the severity of inflammation in allergic hypersensitivity conditions like asthma. PMID- 21257968 TI - Differential expression of NLRP3 among hematopoietic cells. AB - Although the importance of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in health and disease is well appreciated, a precise characterization of NLRP3 expression is yet undetermined. To this purpose, we generated a knock-in mouse in which the Nlrp3 coding sequence was substituted for the GFP (enhanced GFP [egfp]) gene. In this way, the expression of eGFP is driven by the endogenous regulatory elements of the Nlrp3 gene. In this study, we show that eGFP expression indeed mirrors that of NLRP3. Interestingly, splenic neutrophils, macrophages, and, in particular, monocytes and conventional dendritic cells showed robust eGFP fluorescence, whereas lymphoid subsets, eosinophils, and plasmacytoid dendritic cells showed negligible eGFP levels. NLRP3 expression was highly inducible in macrophages, both by MyD88- and Trif dependent pathways. In vivo, when mice were challenged with diverse inflammatory stimuli, differences in both the number of eGFP-expressing cells and fluorescence intensity were observed in the draining lymph node. Thus, NLRP3 levels at the site of adaptive response initiation are controlled by recruitment of NLRP3 expressing cells and by NLRP3 induction. PMID- 21257970 TI - CD4 and CD8 T cell immune activation during chronic HIV infection: roles of homeostasis, HIV, type I IFN, and IL-7. AB - Immune activation plays an important role in the pathogenesis of HIV disease. Although the causes are not fully understood, the forces that lead to immune dysfunction differ for CD4 and CD8 T cells. In this study, we report that the molecular pathways that drive immune activation during chronic HIV infection are influenced by differences in the homeostatic regulation of the CD4 and CD8 T cell pools. Proliferation of CD4 T cells is controlled more tightly by CD4 T cell numbers than is CD8 T cell proliferation. This difference reflects the importance of maintaining a polyclonal CD4 T cell pool in host surveillance. Both pools of T cells were found to be driven by viral load and its associated state of inflammation. In the setting of HIV-induced lymphopenia, naive CD4 T cells were recruited mainly into the proliferating pool in response to CD4 T cell depletion, whereas naive CD8 T cell proliferation was driven mainly by levels of HIV RNA. RNA analysis revealed increased expression of genes associated with type I IFN and common gamma chain cytokine signaling in CD4 T cell subsets and only type I IFN-associated genes in CD8 T cell subsets. In vitro studies demonstrated enhanced STAT1 phosphorylation in response to IFN-alpha and increased expression of the IFNAR1 transcripts in naive and memory CD4 T cells compared with that observed in CD8 T cells. CD4 T cell subsets also showed enhanced STAT1 phosphorylation in response to exogenous IL-7. PMID- 21257969 TI - Marginal zone B cells regulate antigen capture by marginal zone macrophages. AB - The marginal zone (MZ) of the mouse spleen contains macrophages that express receptors that trap pathogens, including the scavenger receptor macrophage receptor with a collagenous structure and the C-type lectin specific intracellular adhesion molecule-grabbing nonintegrin receptor 1 (SIGN-R1). We previously reported that expression of SIGN-R1 was decreased in CD19-deficient mice. In this study, we demonstrate that SIGN-R1 is expressed on a subset of macrophage receptor with a collagenous structure (MARCO)(+) macrophages. This subset is diminished when MZ B cells are absent due to either genetic developmental defects or following transient migration of B cells out of the MZ. When B cells return to the MZ, there is a delay in recovery of SIGN-R1-expressing macrophages. During this period, capture of Ficoll, which for the macrophages requires SIGN-R1, remains defective not only by the macrophages, but also by the B cells. Thus, MZ B cells regulate expression of molecules on macrophages that are important for trapping Ag, which, in turn, is required for Ag capture by the B cells. PMID- 21257971 TI - A novel human IgA monoclonal antibody protects against tuberculosis. AB - Abs have been shown to be protective in passive immunotherapy of tuberculous infection using mouse experimental models. In this study, we report on the properties of a novel human IgA1, constructed using a single-chain variable fragment clone (2E9), selected from an Ab phage library. The purified Ab monomer revealed high binding affinities for the mycobacterial alpha-crystallin Ag and for the human FcalphaRI (CD89) IgA receptor. Intranasal inoculations with 2E9IgA1 and recombinant mouse IFN-gamma significantly inhibited pulmonary H37Rv infection in mice transgenic for human CD89 but not in CD89-negative littermate controls, suggesting that binding to CD89 was necessary for the IgA-imparted passive protection. 2E9IgA1 added to human whole-blood or monocyte cultures inhibited luciferase-tagged H37Rv infection although not for all tested blood donors. Inhibition by 2E9IgA1 was synergistic with human rIFN-gamma in cultures of purified human monocytes but not in whole-blood cultures. The demonstration of the mandatory role of FcalphaRI (CD89) for human IgA-mediated protection is important for understanding of the mechanisms involved and also for translation of this approach toward development of passive immunotherapy of tuberculosis. PMID- 21257972 TI - Recognition of cytoplasmic RNA results in cathepsin-dependent inflammasome activation and apoptosis in human macrophages. AB - dsRNA is an important pathogen-associated molecular pattern that is primarily recognized by cytosolic pattern-recognition receptors of the innate-immune system during virus infection. This recognition results in the activation of inflammasome-associated caspase-1 and apoptosis of infected cells. In this study, we used high-throughput proteomics to identify secretome, the global pattern of secreted proteins, in human primary macrophages that had been activated through the cytoplasmic dsRNA-recognition pathway. The secretome analysis revealed cytoplasmic dsRNA-recognition pathway-induced secretion of several exosome associated proteins, as well as basal and dsRNA-activated secretion of lysosomal protease cathepsins and cysteine protease inhibitors (cystatins). Inflammasome activation was almost completely abolished by cathepsin inhibitors in response to dsRNA stimulation, as well as encephalomyocarditis virus and vesicular stomatitis virus infections. Interestingly, Western blot analysis showed that the mature form of cathepsin D, but not cathepsin B, was secreted simultaneously with IL-18 and inflammasome components ASC and caspase-1 in cytoplasmic dsRNA-stimulated cells. Furthermore, small interfering RNA-mediated silencing experiments confirmed that cathepsin D has a role in inflammasome activation. Caspase-1 activation was followed by proteolytic processing of caspase-3, indicating that inflammasome activation precedes apoptosis in macrophages that had recognized cytoplasmic RNA. Like inflammasome activation, apoptosis triggered by dsRNA stimulation and virus infection was effectively blocked by cathepsin inhibition. In conclusion, our results emphasize the importance of cathepsins in the innate immune response to virus infection. PMID- 21257973 TI - Social marketing, stages of change, and public health smoking interventions. AB - As a "thought experiment," the authors used a modified stages of change model for smoking to define homogeneous segments within various hypothetical populations. The authors then estimated the population effect of public health interventions that targeted the different segments. Under most assumptions, interventions that emphasized primary and secondary prevention, by targeting the Never Smoker, Maintenance, or Action segments, resulted in the highest nonsmoking life expectancy. This result is consistent with both social marketing and public health principles. Although the best thing for an individual smoker is to stop smoking, the greatest public health benefit is achieved by interventions that target nonsmokers. PMID- 21257974 TI - Depression and hypothalamic-pituitary-adrenal activation: a quantitative summary of four decades of research. AB - OBJECTIVES: To summarize quantitatively the literature comparing hypothalamic pituitary-adrenal (HPA) axis function between depressed and nondepressed individuals and to describe the important sources of variability in this literature. These sources include methodological differences between studies, as well as demographic or clinical differences between depressed samples. METHODS: The current study used meta-analytic techniques to compare 671 effect sizes (cortisol, adrenocorticotropic hormone, or corticotropin-releasing hormone) across 361 studies, including 18,454 individuals. RESULTS: Although depressed individuals tended to display increased cortisol (d = 0.60; 95% confidence interval [CI], 0.54-0.66) and adrenocorticotropic hormone levels (d = 0.28; 95% CI, 0.16-0.41), they did not display elevations in corticotropin-releasing hormone (d = 0.02; 95% CI, -0.47-0.51). The magnitude of the cortisol effect was reduced by almost half (d = 0.33; 95% CI, 0.21-0.45) when analyses were limited to studies that met minimal methodological standards. Gender did not significantly modify any HPA outcome. Studies that included older hospitalized individuals reported significantly greater cortisol differences between depressed and nondepressed groups compared with studies with younger outpatient samples. Important cortisol differences also emerged for atypical, endogenous, melancholic, and psychotic forms of depression. CONCLUSIONS: The current study suggests that the degree of HPA hyperactivity can vary considerably across patient groups. Results are consistent with HPA hyperactivity as a link between depression and increased risk for conditions, such as diabetes, dementia, coronary heart disease, and osteoporosis. Such a link is strongest among older inpatients who display melancholic or psychotic features of depression. PMID- 21257975 TI - Symptom dimensions of depression and anxiety and the metabolic syndrome. AB - OBJECTIVE: To investigate the association between depression and anxiety symptoms and the metabolic syndrome (MetSyn), using a dimensional approach. The association between depression and anxiety, on the one hand, and the MetSyn as a cluster or its individual components, on the other hand, is equivocal. The categorical nature of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition might partly explain the inconsistent findings. METHODS: In 2,433 Netherlands Study of Depression and Anxiety participants (mean age, 42.3 years; 33.1% male), three symptoms dimensions-lack of positive affect (PA, depression specific); negative affect (NA, aspecific); and somatic arousal (SA, anxiety specific)-were assessed by a shortened adaptation of the Mood and Anxiety Symptom Questionnaire. The association between symptom dimensions and MetSyn components (waist circumference, triglycerides, high-density lipoprotein cholesterol, glucose, and mean blood pressure) was analyzed, using linear regression analysis. RESULTS: The occurrence rate of the MetSyn was 20.1% (n = 490). SA, but not PA and NA, was strongly associated with four out of five MetSyn components, especially waist circumference, triglycerides, and blood pressure (beta = 0.046, p = .01; beta = 0.077, p < .001; and beta = 0.069, p < .001, respectively), and with the total number of MetSyn components (beta = 0.098, p < .001). CONCLUSIONS: Our results demonstrate a strong association of most of the MetSyn components with the SA dimension, but not with the NA and PA scales. PMID- 21257976 TI - Does disturbed sleeping precede symptoms of anxiety or depression in toddlers? The generation R study. AB - OBJECTIVE: To examine whether sleep problems in infancy and early toddlerhood precede symptoms of anxiety or depression at 3 years. METHODS: Data on specific sleep problems at 2 months and 24 months were available for 4,782 children participating in a population-based cohort in The Netherlands. The Child Behavior Checklist for toddlers containing the Anxious/Depressed syndrome scale was assessed at 36 months. We adjusted the logistic regression analyses for several confounding factors; the analyses with sleep problems at 24 months were additionally adjusted for preexisting anxiety or depressive symptoms (at 18 months). RESULTS: Dyssomnia and parental presence during sleep onset at 2 months and 24 months were associated with anxiety or depressive symptoms at 3 years (e.g., parental presence: odds ratio(2 months), 1.22; 95% confidence interval, 1.04-1.44; odds ratio(24 months), 1.58; 95% confidence interval, 1.30-1.92). Parasomnia, short sleep duration, and absence of set bedtime at 24 months, but not at 2 months, also preceded anxiety or depressive symptoms. These significant associations were not due to children's anxiety or depressive symptoms at 18 months. Rhythmicity and co-sleeping were not associated with later anxiety or depressive symptoms. Additional analyses provided little evidence for a bidirectional association with anxiety or depressive symptoms preceding later sleep problems. CONCLUSIONS: Our findings highlight the importance of sleep problems early in life, because different sleep problems are associated with the frequency of anxiety or depressive symptoms. Therefore, healthcare practitioners must be particularly attentive to these problems in young children. Future research should address possible mechanisms underlying the association between disturbed sleeping and anxiety or depressive symptoms. PMID- 21257977 TI - Presurgical stress management improves postoperative immune function in men with prostate cancer undergoing radical prostatectomy. AB - OBJECTIVE: To assess whether stress management (SM) improved immune outcomes in men undergoing surgery for prostate cancer. METHODS: A total of 159 men were assigned randomly to a two-session presurgical SM intervention, a two-session supportive attention (SA) group, or a standard care (SC) group. Men in the SM group discussed their concerns about the upcoming surgery and were taught diaphragmatic breathing, guided imagery; they had an imaginal exposure to the day of surgery and learned adaptive coping skills. Men in the SA group discussed their concerns about the upcoming surgery and had a semistructured medical interview. Blood samples were collected at baseline (1 month before surgery) and 48 hours after surgery. Measures of mood (Profile of Mood States) were collected at baseline, 1 week pre surgery, and the morning of surgery. RESULTS: Men in the SM group had significantly higher levels of natural killer cell cytotoxicity (p = .04) and higher levels of circulating proinflammatory cytokines (interleukin [IL] 12p70, p = .02; IL-1beta, p = .02; tumor necrosis factor-alpha, p = .05) 48 hours post surgery than men in the SA group and higher levels of natural killer cell cytotoxicity (p = 0.02) and IL-1beta (p = .05) than men in the SC group. Immune parameters increased for the SM group and decreased or stayed the same for the SA and SC groups. The SM group had significantly lower Profile of Mood States scores than the SC group (p = .006), with no other group differences between SA and SC groups. Changes in mood were not associated with immune outcomes. CONCLUSIONS: The finding that SM leads to decreased presurgical mood-disturbance and increased immune parameters after surgery reveals the potential psychological and biological benefits of presurgical SM. PMID- 21257978 TI - Diagnostic crossover and outcome predictors in eating disorders according to DSM IV and DSM-V proposed criteria: a 6-year follow-up study. AB - OBJECTIVE: To evaluate in a 6-year follow-up study the course of a large clinical sample of patients with eating disorders (EDs) who were treated with individual cognitive behavior therapy. The diagnostic crossover, recovery, and relapses were assessed, applying both Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and the DSM-V proposed criteria. Patients with EDs move in and out of illness states over time, display frequent relapses, show a relevant lifetime psychiatric comorbidity, and migrate between different diagnoses. METHOD: A total of 793 patients (including anorexia nervosa, bulimia nervosa, binge eating disorder, and EDs not otherwise specified) were evaluated on the first day of admission, at the end of treatment, 3 years after the end of treatment, and 3 years after the first follow-up. Clinical data were collected through a face-to-face interview; diagnosis was performed by means of the Structured Clinical Interview for DSM-IV and the Eating Disorder Examination Questionnaire was applied. RESULTS: A consistent rate of relapse and crossover between the different diagnoses over time was observed. Mood disorders comorbidity has been found to be an important determinant of diagnostic instability, whereas the severity of shape concern represented a relevant outcome modifier. Using the DSM-V proposed criteria, most patients of EDs not otherwise specified were reclassified, so that the large majority of ED patients seeking treatment would be included in full-blown diagnoses. CONCLUSIONS: Among EDs, there are different subgroups of patients displaying various courses and outcomes. The diagnostic instability involves the large majority of patients. An integration of categorical and dimensional approaches could improve the psychopathological investigation and the treatment choices. PMID- 21257979 TI - Impact of aerobic training on cardiovascular reactivity to and recovery from challenge. AB - OBJECTIVE: To test the hypothesis that aerobic, but not strength, training would lead to attenuated reactivity to and more rapid recovery from cognitive and orthostatic challenge and that deconditioning would reverse this effect. METHODS: We conducted a randomized controlled trial contrasting the effects of aerobic versus strength training on heart rate, four indices of RR interval variability, and blood pressure reactivity to and recovery from psychological and orthostatic challenge in 149 healthy, young, sedentary adults. Subjects were randomized to 12 week aerobic or strength training programs and studied before and after training and again after 4 weeks of sedentary deconditioning. The data were analyzed by performing a Group (aerobic versus strength) by Session (study entry, post training, and deconditioning), by Period (baseline, speech, Stroop, math, tilt) three-way analysis of variance with prespecified contrasts of the effect of group assignment on reactivity and recovery. RESULTS: Aerobic capacity increased in response to conditioning and decreased after deconditioning in the aerobic, but not the strength, training group. However, the two groups did not differ on heart rate, RR interval variability, or blood pressure reactivity to or recovery from laboratory challenge. CONCLUSIONS: These findings, from the largest randomized controlled trial to address this matter to date, raise doubts about attenuation of reactivity or enhancement of recovery as a putative mechanism underlying the cardioprotective effects of aerobic exercise. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00365196. PMID- 21257980 TI - Differentiation in the momentary rating of somatic symptoms covaries with trait emotional awareness in patients at risk for sudden cardiac death. AB - OBJECTIVES: Somatic symptom ratings covary with neuroticism. Yet, people vary from one another in their ability to report their own emotions and differentiate them from bodily sensations. We hypothesized that stressed individuals with greater emotional awareness would experience somatic symptoms in a more differentiated way independent of neuroticism. METHODS: Over 3 days, ecological momentary assessments were completed in 161 patients (72.6% female; mean age, 35 years) with Long QT Syndrome, a genetic disorder associated with increased risk for sudden cardiac death. Patients were paged randomly ten times per day to report their momentary experience of nine somatic symptoms (e.g., headache, sore throat, tiredness) as well as other variables. We examined the intercorrelation between somatic symptom ratings, reasoning that greater intercorrelation among ratings indicated less differentiation. Subjects completed measures of neuroticism, depression, and the Levels of Emotional Awareness Scale, a trait measure of the tendency to experience emotions in a complex and differentiated way. RESULTS: Higher Levels of Emotional Awareness Scale-Self scores were associated with greater differentiation in the momentary rating of somatic symptoms (p < .001) in men and women independently. This association did not change after removing variance due to neuroticism, depression, or symptom intensity. CONCLUSIONS: Among individuals stressed by having a life-threatening condition, those who are more emotionally aware report somatic symptoms in a more differentiated way. These findings regarding symptoms largely unrelated to the disorder are consistent with other evidence that medically unexplained physical symptoms, which tend to be nonspecific, may be accompanied by relatively undifferentiated negative affect. PMID- 21257981 TI - Disability, distress and unemployment in neurology outpatients with symptoms 'unexplained by organic disease'. AB - OBJECTIVES: To determine the disability, distress and employment status of new neurology outpatients with physical symptoms unexplained by organic disease and to compare them with patients with symptoms explained by organic disease. METHODS: As part of a cohort study (the Scottish Neurological Symptoms Study) neurologists rated the extent to which each new patient's symptoms were explained by organic disease. Patients whose symptoms were rated as 'not at all' or only 'somewhat' explained by disease were considered cases, and those whose symptoms were 'largely' or 'completely' explained by disease were considered controls. All patients completed self-ratings of disability, health status (Medical Outcomes Study Short Form 12-Item Scale (SF-12)) and emotional distress (Hospital Anxiety and Depression Scale) and also reported their employment and state financial benefit status. RESULTS: 3781 patients were recruited: 1144 (30%) cases and 2637 (70%) controls. Cases had worse physical health status (SF-12 score 42 vs 44; difference in means 1.7 (95% CI -2.5 to 0.9)) and worse mental health status (SF 12 score 43 vs 47; difference in means -3.5 (95% CI -4.3 to to 2.7)). Unemployment was similar in cases and controls (50% vs 50%) but cases were more likely not to be working for health reasons (54% vs 37% of the 50% not working; OR 2.0 (95% CI 1.6 to 2.4)) and also more likely to be receiving disability related state financial benefits (27% vs 22%; (OR 1.3, 95% CI 1.1 to 1.6)). CONCLUSIONS: New neurology patients with symptoms unexplained by organic disease have more disability-, distress- and disability-related state financial benefits than patients with symptoms explained by disease. PMID- 21257982 TI - Variant Creutzfeldt-Jakob disease occurring in mother and son. PMID- 21257984 TI - Further corroboration of the asthmagenicity of 5-aminosalicylic acid. PMID- 21257983 TI - Impact of pesticide exposure misclassification on estimates of relative risks in the Agricultural Health Study. AB - BACKGROUND: The Agricultural Health Study (AHS) is a prospective study of licensed pesticide applicators and their spouses in Iowa and North Carolina. We evaluate the impact of occupational pesticide exposure misclassification on relative risks using data from the cohort and the AHS Pesticide Exposure Study (AHS/PES). METHODS: We assessed the impact of exposure misclassification on relative risks using the range of correlation coefficients observed between measured post-application urinary levels of 2,4-dichlorophenoxyacetic acid (2,4 D) and a chlorpyrifos metabolite and exposure estimates based on an algorithm from 83 AHS pesticide applications. RESULTS: Correlations between urinary levels of 2,4-D and a chlorpyrifos metabolite and algorithm estimated intensity scores were about 0.4 for 2,4-D (n=64), 0.8 for liquid chlorpyrifos (n=4) and 0.6 for granular chlorpyrifos (n=12). Correlations of urinary levels with kilograms of active ingredient used, duration of application, or number of acres treated were lower and ranged from -0.36 to 0.19. These findings indicate that a priori expert derived algorithm scores were more closely related to measured urinary levels than individual exposure determinants evaluated here. Estimates of potential bias in relative risks based on the correlations from the AHS/PES indicate that non differential misclassification of exposure using the algorithm would bias estimates towards the null, but less than that from individual exposure determinants. CONCLUSIONS: Although correlations between algorithm scores and urinary levels were quite good (ie, correlations between 0.4 and 0.8), exposure misclassification would still bias relative risk estimates in the AHS towards the null and diminish study power. PMID- 21257985 TI - Microbial aetiology of community-acquired pneumonia and its relation to severity. AB - BACKGROUND: The distribution of the microbial aetiology and mortality of community-acquired pneumonia (CAP) was investigated in relation to the clinical setting and severity scores (pneumonia severity index (PSI) and confusion, blood urea nitrogen, respiratory rate, blood pressure, age (CURB-65)). METHODS: 3523 patients with CAP were included (15% outpatients, 85% inpatients). The distribution of the microbial aetiology in relation to the clinical setting and severity scores (PSI, CURB-65) and the relative mortality of different aetiologies across the severity scores were analysed. RESULTS: The aetiology was established in 1463 patients (42%), of whom 257 died (7%). The ranking of aetiologies varied according to site of care, with increasing frequency of Streptococcus pneumoniae and mixed aetiologies and decreasing frequency of atypical pathogens in hospitalised patients and those in ICUs. The distribution of aetiologies according to severity scores showed corresponding patterns; however, the severity scores were more sensitive to Gram-negative enteric bacilli (GNEB) and Pseudomonas aeruginosa and less sensitive in identifying mixed aetiologies as moderate- and high-risk conditions. Mortality rates according to aetiology and severity scoring showed increasing mortality rates for all pathogens except atypical pathogens. S pneumoniae had the highest number of deaths while GNEB, P aeruginosa, Staphylococcus aureus and mixed aetiologies had the highest mortality rates. Legionella pneumophila was similarly distributed according to site of care and prognostic scores. CONCLUSIONS: CAP due to atypical bacterial pathogens is recognised both clinically and by severity scoring as a low-risk condition. Severity scores are more sensitive in identifying patients with GNEB and P aeruginosa as moderate- and high-risk aetiologies whereas mixed aetiologies may be underestimated. PMID- 21257986 TI - Randomised vitamin E supplementation and risk of chronic lung disease in the Women's Health Study. AB - BACKGROUND: The oxidant/antioxidant balance in lung tissue is hypothesised to contribute to the risk of chronic obstructive pulmonary disease (COPD). Observational studies consistently report higher antioxidant status associated with lower COPD risk, but few randomised studies have been reported. METHODS: A post hoc analysis of 38,597 women without chronic lung disease at baseline was conducted in the Women's Health Study (WHS) to test the effect of vitamin E on the risk of incident chronic lung disease. The WHS is a randomised double-blind placebo-controlled factorial trial of vitamin E (600 IU every other day) and aspirin (100 mg every other day) in female health professionals aged>=45 years. Using Cox proportional hazards models, the effect of randomised vitamin E assignment on self-reported physician-diagnosed chronic lung disease was evaluated. RESULTS: During 10 years of follow-up (376,710 person-years), 760 first occurrences of chronic lung disease were reported in the vitamin E arm compared with 846 in the placebo arm (HR 0.90; 95% CI 0.81 to 0.99; p=0.029). This 10% reduction in the risk of incident chronic lung disease was not modified by cigarette smoking, age, randomised aspirin assignment, multivitamin use or dietary vitamin E intake (minimum p for interaction=0.19). Current cigarette smoking was a strong predictor of chronic lung disease risk (HR 4.17; 95% CI 3.70 to 4.70; vs. never smokers). CONCLUSIONS: In this large randomised trial, assignment to 600 IU vitamin E led to a 10% reduction in the risk of chronic lung disease in women. PMID- 21257987 TI - Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn's disease. AB - OBJECTIVE: External fistulas represent a disabling manifestation of Crohn's disease with a difficult curability and a high relapse rate despite a large therapeutic armamentarium. Stem cell therapy is a novel and promising approach for treatment of chronic inflammatory conditions. We therefore investigated the feasibility, safety and efficacy of serial intrafistular injections of autologous bone marrow-derived mesenchymal stromal cells (MSCs) in the treatment of fistulising Crohn's disease. PATIENTS AND METHODS: We enrolled 12 consecutive outpatients (eight males, median age 32 years) refractory to or unsuitable for current available therapies. MSCs were isolated from bone marrow and expanded ex vivo to be used for both therapeutic and experimental purposes. Ten patients (two refused) received intrafistular MSC injections (median 4) scheduled every 4 weeks, and were monitored by surgical, MRI and endoscopic evaluation for 12 months afterwards. The feasibility of obtaining at least 50*106 MSCs from each patient, the appearance of adverse events, and the efficacy in terms of fistula healing and reduction of both Crohn's disease and perianal disease activity indexes were evaluated. In addition, the percentage of both mucosal and circulating regulatory T cells expressing FoxP3, and the ability of MSCs to influence mucosal T cell apoptosis were investigated. RESULTS: MSC expansion was successful in all cases; sustained complete closure (seven cases) or incomplete closure (three cases) of fistula tracks with a parallel reduction of Crohn's disease and perianal disease activity indexes (p < 0.01 for both), and rectal mucosal healing were induced by treatment without any adverse effects. The percentage of mucosal and circulating regulatory T cells significantly increased during the treatment and remained stable until the end of follow up (p < 0.0001 and p < 0.01, respectively). Furthermore, MSCs have been proven to affect mucosal T cell apoptotic rate. CONCLUSIONS: Locally injected MSCs represent a feasible, safe and beneficial therapy in refractory fistulising Crohn's disease. PMID- 21257988 TI - Does it all ADA up? Adalimumab for ulcerative colitis. PMID- 21257990 TI - Effectiveness of AFP and ultrasound tests on hepatocellular carcinoma mortality in HCV-infected patients in the USA. AB - BACKGROUND AND AIMS: The effectiveness of surveillance for hepatocellular carcinoma (HCC) in the USA is largely unknown. The objective of this study was to evaluate the effectiveness of HCC surveillance in a national Veterans Administration (VA) practice setting, using the national VA hepatitis C virus (HCV) Clinical Case Registry. METHOD: The cohort consisted of 1480 HCV-infected patients who developed HCC during 1998-2007. The timing and intensity of receiving alpha-fetoprotein (AFP) and abdominal ultrasound (US) for HCC surveillance were evaluated. Overall mortality risk was examined using Cox proportional hazards regression models adjusting for demographics, clinical features and receipt of HCC-specific treatment. RESULTS: The mean survival was 1.8 years following the HCC diagnosis date. Surveillance AFP or US were recorded in 77.8% of patients within 2 years prior to HCC diagnosis. Annual surveillance with both AFP and US was observed in only 2% of patients. The presence of either AFP or US surveillance during both 0-6 month and 7-24 month periods before HCC diagnosis was associated with a lower mortality risk (HR 0.71, 95% CI 0.62 to 0.82) compared with no surveillance. Receipt of two or more surveillance tests in the 0-6 months (HR 0.76 95% CI 0.66 to 0.88) and to a lesser extent in the 7-12 months (HR 0.81 95% CI 0.1 to 0.99) prior to HCC diagnosis was also associated with reduced mortality risk. CONCLUSIONS: Most patients with HCV-related cirrhosis do not receive regular imaging-based surveillance. The effectiveness of HCC surveillance tests in current clinical practice is rather modest in reducing HCC-related mortality. PMID- 21257989 TI - Variants in ZNF365 isoform D are associated with Crohn's disease. AB - OBJECTIVE: Genome-wide association studies have identified multiple Crohn's disease (CD) susceptibility loci, including association with non-coding intergenic single-nucleotide polymorphisms (SNPs) at 10q21. DESIGN: To fine-map the 10q21 locus, the authors genotyped 86 SNPs in 1632 CD cases and 961 controls and performed single-marker and conditional analyses using logistic regression. RESULTS: Association with CD risk spanning 11 SNPs (p<0.001) was observed. The most significant association observed was at the non-synonymous SNP, rs7076156 (Ala62Thr), in ZNF365. The alanine allele was over-represented in CD (p=5.23*10 7; OR=1.39 (95% CI 1.22 to 1.58)); allele frequency of 76% in CD and 69.7% in controls). Conditional analysis on rs7076156 nullified all other significant associations, suggesting that this is the causative variant at this locus. Four isoforms of ZNF365 have previously been identified, and rs7076156 is located in an exon unique to ZNF365 isoform D. The authors demonstrated, using reverse transcription-PCR, expression of ZNF365D in intestinal resections from both CD subjects and controls. Markedly reduced mean expression levels of ZNF365D were identified in Epstein-Barr virus-transformed lymphoblastoid cell lines from CD subjects homozygous for the risk allele (Ala). A whole-genome microarray expression study further suggested that the Ala62Thr change in ZNF365 isoform D is related to differential expression of the genes ARL4A, MKKS, RRAGD, SUMF2, TDR1 and ZNF148 in CD. CONCLUSIONS: Collectively, these data support the hypothesis that the non-synonymous Ala62Thr SNP, rs7076156, underlies the association between 10q21 and CD risk and suggest that this SNP acts by altering expression of genes under the control of ZNF365 isoform D. PMID- 21257991 TI - Idiopathic chronic pancreatitis in India: looking for a name! Futile or fruitful exercise? PMID- 21257992 TI - Acute presentations of HIV are still missed in low prevalence areas. AB - OBJECTIVES: To evaluate missed opportunities and delays in the diagnosis of HIV in a low prevalence setting over a 24 year period. METHODS: Patients with acute presentations of HIV were included in a retrospective note based review. Data were compared from acute presentations in 1985-2001 (88/241 new patients) with 2005-2007 (99/136 new patients). The number of recorded clinical and laboratory clues to infection and subsequent time delays to diagnosis of HIV were evaluated. RESULTS: The findings reflect the shifting demographics of HIV in the UK over the past two decades, exemplified by an eightfold increase in tuberculosis at presentation. Despite recording clinical stigmata of HIV (clues) in the notes, the number of missed clues increased, and many clinicians failed to request HIV testing. The median delay between presentation and diagnosis reduced from 5 to 1 day (p<0.001), and mortality dropped from 14% to 4% among patients presenting with acute symptoms. However, there was still a delay of more than 30 days before diagnosis for almost one in five patients. CONCLUSIONS: Despite some improvement and better awareness, there are still significant delays before hospital doctors consider the diagnosis of HIV for patients in low prevalence areas, even among some patient groups with high risk. Hospitals should consider moving to opt-out routine HIV testing of all medical admissions. PMID- 21257993 TI - Clinical risk scores to guide perioperative management. AB - Perioperative morbidity is associated with reduced long term survival. Comorbid disease, cardiovascular illness, and functional capacity can predispose patients to adverse surgical outcomes. Accurate risk stratification would facilitate informed patient consent and identify those individuals who may benefit from specific perioperative interventions. The ideal clinical risk scoring system would be objective, accurate, economical, simple to perform, based entirely on information available preoperatively, and suitable for patients undergoing both elective and emergency surgery. The POSSUM (Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity) scoring systems are the most widely validated perioperative risk predictors currently utilised; however, their inclusion of intra- and postoperative variables precludes validation for preoperative risk prediction. The Charlson Index has the advantage of consisting exclusively of preoperative variables; however, its validity varies in different patient cohorts. Risk models predicting cardiac morbidity have been extensively studied, despite the relatively uncommon occurrence of postoperative cardiac events. Probably the most widely used cardiac risk score is the Lee Revised Cardiac Risk Index, although it has limited validity in some patient populations and for non-cardiac outcomes. Bespoke clinical scoring systems responding to dynamic changes in population characteristics over time, such as those developed by the American College of Surgeons National Surgical Quality Improvement Program, are more precise, but require considerable resources to implement. The combination of objective clinical variables with information from novel techniques such as cardiopulmonary exercise testing and biomarker assays, may improve the predictive precision of clinical risk scores used to guide perioperative management. PMID- 21257994 TI - Bald aortic arch in Takayasu arteritis. PMID- 21257995 TI - Chilaiditi's syndrome: colonic interposition in a young patient with abdominal pain. PMID- 21257996 TI - Quality control in upper gastrointestinal endoscopy: detection rates of gastric cancer in Oxford 2005-2008. AB - BACKGROUND: Gastric cancer (GC) represents the sum of advanced gastric cancer (AGC) and early gastric cancer (EGC). Endoscopy (with biopsies) is the gold standard for detection of GC, but a false-negative rate of up to 19% is reported. AIM: To determine whether patients with GC had had an oesophagogastroduodenoscopy (OGD) in the year preceding diagnosis that might reasonably have been expected to detect the cancer, as a measure of quality assurance of endoscopic practice. METHODS: Patients with histologically proven GC were identified from pathology records. Endoscopy reports and case notes were examined to identify any OGD before diagnosis, the interval and endoscopic findings. A false-negative OGD was defined as one where GC was neither suspected nor shown at pathology, but where a diagnosis of GC was made within 12 months. RESULTS: Between January 2005 and February 2008, 9764 OGDs were performed. GC was diagnosed in 74 patients (male/female ratio 2.89; median age 76, range 38-95). Nine (12%) patients had EGC. There were no differences in age, sex or symptoms between the EGC and AGC group. Sixty-eight of the 74 patients with GC (92%) presented with alarm symptoms. Ten of the 74 had had an OGD within 12 months before definitive diagnosis; all these were planned because of suspicious lesions. Significantly fewer biopsies were performed at OGDs preceding definitive diagnosis (median 2 (0 10) vs 6 (2-12); p=0.002). CONCLUSION: False-negative rates of 0% (within 12 months) and 8% (within 3 years) for diagnosis of GC are reassuring, but an inadequate number of biopsies compromises the quality assurance of endoscopy. GC presents without alarm symptoms in <10%. PMID- 21257997 TI - The dissenting opinion: can simulation-based multi-professional training reduce 'groupthink'? PMID- 21257998 TI - Infective endocarditis: diagnosis delayed during swine flu pandemic. PMID- 21257999 TI - The impact of poloxamer 407 on the ultrastructure of the liver and evidence for clearance by extensive endothelial and kupffer cell endocytosis. AB - Poloxamer 407 (P407) is a non-ionic detergent that is used widely in pharmaceutical formulations and personal care products. In animals, P407 causes hyperlipidaemia. P407 is taken up by the liver and causes loss of fenestrations in liver sinusoidal endothelial cells (LSEC), which contributes to the pathogenesis of hyperlipidaemia. Here the short-term (1-15 days) effects of P407 on all liver cells were investigated in mice using electron and light microscopy. As expected, P407 was associated with hyperlipidaemia. Kupffer cells became massively engorged with vacuoles and took on a marked honeycomb morphology. LSECs also became engorged with vacuoles and endocytosis was activated. The diameter of lipoproteins in the space of Disse was less than those in the lumen, consistent with a filtering effect of fenestrations. Defenestration of the LSEC was noted. Hepatocyte endocytosis of lipoproteins and P407 particles was also noted; however, hepatocyte steatosis was not evident. Hepatic stellate cells did not appear to be abnormal. In conclusion, P407 is taken up by the liver mostly through endocytosis by LSECs and Kupffer cells. PMID- 21258000 TI - Racial and ethnic differences in subclinical myocardial function: the Multi Ethnic Study of Atherosclerosis. AB - BACKGROUND: Racial/ethnic differences in the incidence and severity of heart failure (HF) are not well understood, but may be related to pre-existing variations in myocardial function. OBJECTIVE: To examine racial/ethnic differences in regional myocardial function among asymptomatic individuals free of known cardiovascular disease. DESIGN, SETTING AND PATIENTS: The Multi-Ethnic Study of Atherosclerosis is a prospective, observational study of individuals without baseline cardiovascular disease, representing four major racial/ethnic groups. A total of 1099 study participants underwent cardiac MRI with tissue tagging; for each study, peak systolic strain (Ecc) and strain rate (SRs) were determined in four left ventricular (LV) regions. MAIN OUTCOME MEASURES: Multiple linear regression was used to analyse the relationship between race/ethnicity and regional strain (Ecc and SRs) while adjusting for cardiovascular risk factors. RESULTS: Compared with other racial/ethnic groups, Chinese-Americans had the greatest magnitude of Ecc in a majority of LV regions (-19.60+/-3.78, p<0.05); Chinese-Americans also had the greatest absolute values for SRs in all regions, reflecting higher rate of systolic contraction (-2.01+/-0.76, p<0.05). Conversely, African-Americans had the lowest Ecc values (-17.50+/-4.00, p<0.05) in the majority of wall regions while Hispanics demonstrated the lowest rate of contractility in all wall regions (-1.44+/-0.50, p<=0.001) in comparison with the other racial/ethnic groups. These race-based differences remained significant in the majority of LV wall regions after adjusting for multiple variables, including hypertension and LV mass. CONCLUSIONS: Important race-based differences in regional LV systolic function in a large cohort of asymptomatic individuals have been demonstrated. Further research is needed to investigate the possible mechanisms related to the race/ethnicity-based variations found in this study. PMID- 21258001 TI - Generalised muscle weakness in young adults with congenital heart disease. AB - BACKGROUND: In patients with heart failure from acquired cardiomyopathy, respiratory and skeletal muscle weakness is common and is an independent predictor for adverse events. Despite a different underlying pathology, many young adults with congenital heart disease (CHD) develop a syndrome comparable to heart failure from acquired cardiomyopathy and may be at risk for a similar skeletal muscle weakness. OBJECTIVES: To assess respiratory and skeletal muscle strength in adults with complex CHD. METHODS: Respiratory and skeletal muscle function was assessed in 51 adults; 41 with complex CHD (16 tetralogy of Fallot, 11 univentricular anatomy with Fontan operation and 14 with subaortic right ventricles) and 10 controls. Maximal inspiratory (MIPs) and expiratory (MEPs) pressures, handgrip strength, lung volumes and aerobic capacity (peak VO2) were measured. Results In patients with CHD (age 34 +/- 13 years), average% predicted MIPs, MEPs and handgrip strength were lower than in controls (77 +/- 27% vs 106 +/- 28%, 85 +/- 32% vs 116 +/- 41% and 72 +/- 15% vs 93 +/- 14%, respectively, p <= 0.01). There was no significant difference in muscle weakness between CHD subgroups. In 39% of patients with CHD, the handgrip strength, and in 22%, respiratory muscle strength was <70% predicted. These patients had a significantly lower peak VO2 (50 +/- 12% vs 64 +/- 14% predicted, p=0.008). CONCLUSION: Respiratory and skeletal muscle weakness is common in young adults with complex CHD and similar to that found in older adults with advanced heart failure from acquired heart disease. PMID- 21258002 TI - Arabidopsis floral initiator SKB1 confers high salt tolerance by regulating transcription and pre-mRNA splicing through altering histone H4R3 and small nuclear ribonucleoprotein LSM4 methylation. AB - Plants adapt their growth and development in response to perceived salt stress. Although DELLA-dependent growth restraint is thought to be an integration of the plant's response to salt stress, little is known about how histone modification confers salt stress and, in turn, affects development. Here, we report that floral initiator Shk1 kinase binding protein1 (SKB1) and histone4 arginine3 (H4R3) symmetric dimethylation (H4R3sme2) integrate responses to plant developmental progress and salt stress. Mutation of SKB1 results in salt hypersensitivity, late flowering, and growth retardation. SKB1 associates with chromatin and thereby increases the H4R3sme2 level to suppress the transcription of FLOWERING LOCUS C (FLC) and a number of stress-responsive genes. During salt stress, the H4R3sme2 level is reduced, as a consequence of SKB1 disassociating from chromatin to induce the expression of FLC and the stress-responsive genes but increasing the methylation of small nuclear ribonucleoprotein Sm-like4 (LSM4). Splicing defects are observed in the skb1 and lsm4 mutants, which are sensitive to salt. We propose that SKB1 mediates plant development and the salt response by altering the methylation status of H4R3sme2 and LSM4 and linking transcription to pre-mRNA splicing. PMID- 21258003 TI - Evolution and diverse roles of the CUP-SHAPED COTYLEDON genes in Arabidopsis leaf development. AB - CUP-SHAPED COTYLEDON2 (CUC2) and the interacting microRNA miR164 regulate leaf margin dissection. Here, we further investigate the evolution and the specific roles of the CUC1 to CUC3 genes during Arabidopsis thaliana leaf serration. We show that CUC2 is essential for dissecting the leaves of a wide range of lobed/serrated Arabidopsis lines. Inactivation of CUC3 leads to a partial suppression of the serrations, indicating a role for this gene in leaf shaping. Morphometric analysis of leaf development and genetic analysis provide evidence for different temporal contributions of CUC2 and CUC3. Chimeric constructs mixing CUC regulatory sequences with different coding sequences reveal both redundant and specific roles for the three CUC genes that could be traced back to changes in their expression pattern or protein activity. In particular, we show that CUC1 triggers the formation of leaflets when ectopically expressed instead of CUC2 in the developing leaves. These divergent fates of the CUC1 and CUC2 genes after their formation by the duplication of a common ancestor is consistent with the signature of positive selection detected on the ancestral branch to CUC1. Combining experimental observations with the retraced origin of the CUC genes in the Brassicales, we propose an evolutionary scenario for the CUC genes. PMID- 21258004 TI - Cell-specific vacuolar calcium storage mediated by CAX1 regulates apoplastic calcium concentration, gas exchange, and plant productivity in Arabidopsis. AB - The physiological role and mechanism of nutrient storage within vacuoles of specific cell types is poorly understood. Transcript profiles from Arabidopsis thaliana leaf cells differing in calcium concentration ([Ca], epidermis <10 mM versus mesophyll >60 mM) were compared using a microarray screen and single-cell quantitative PCR. Three tonoplast-localized Ca(2+) transporters, CAX1 (Ca(2+)/H(+)-antiporter), ACA4, and ACA11 (Ca(2+)-ATPases), were identified as preferentially expressed in Ca-rich mesophyll. Analysis of respective loss-of function mutants demonstrated that only a mutant that lacked expression of both CAX1 and CAX3, a gene ectopically expressed in leaves upon knockout of CAX1, had reduced mesophyll [Ca]. Reduced capacity for mesophyll Ca accumulation resulted in reduced cell wall extensibility, stomatal aperture, transpiration, CO(2) assimilation, and leaf growth rate; increased transcript abundance of other Ca(2+) transporter genes; altered expression of cell wall-modifying proteins, including members of the pectinmethylesterase, expansin, cellulose synthase, and polygalacturonase families; and higher pectin concentrations and thicker cell walls. We demonstrate that these phenotypes result from altered apoplastic free [Ca(2+)], which is threefold greater in cax1/cax3 than in wild-type plants. We establish CAX1 as a key regulator of apoplastic [Ca(2+)] through compartmentation into mesophyll vacuoles, a mechanism essential for optimal plant function and productivity. PMID- 21258006 TI - A three-dimensional RNA motif in Potato spindle tuber viroid mediates trafficking from palisade mesophyll to spongy mesophyll in Nicotiana benthamiana. AB - Cell-to-cell trafficking of RNA is an emerging biological principle that integrates systemic gene regulation, viral infection, antiviral response, and cell-to-cell communication. A key mechanistic question is how an RNA is specifically selected for trafficking from one type of cell into another type. Here, we report the identification of an RNA motif in Potato spindle tuber viroid (PSTVd) required for trafficking from palisade mesophyll to spongy mesophyll in Nicotiana benthamiana leaves. This motif, called loop 6, has the sequence 5'-CGA 3'...5'-GAC-3' flanked on both sides by cis Watson-Crick G/C and G/U wobble base pairs. We present a three-dimensional (3D) structural model of loop 6 that specifies all non-Watson-Crick base pair interactions, derived by isostericity based sequence comparisons with 3D RNA motifs from the RNA x-ray crystal structure database. The model is supported by available chemical modification patterns, natural sequence conservation/variations in PSTVd isolates and related species, and functional characterization of all possible mutants for each of the loop 6 base pairs. Our findings and approaches have broad implications for studying the 3D RNA structural motifs mediating trafficking of diverse RNA species across specific cellular boundaries and for studying the structure function relationships of RNA motifs in other biological processes. PMID- 21258007 TI - Low doses of natural killer T cells provide protection from acute graft-versus host disease via an IL-4-dependent mechanism. AB - CD4(+) natural killer T (NKT) cells, along with CD4(+)CD25(+) regulatory T cells (Tregs), are capable of controlling aberrant immune reactions. We explored the adoptive transfer of highly purified (> 95%) CD4(+)NKT cells in a murine model of allogeneic hematopoietic cell transplantation (HCT). NKT cells follow a migration and proliferation pattern similar to that of conventional T cells (Tcons), migrating initially to secondary lymphoid organs followed by infiltration of graft-versus-host disease (GVHD) target tissues. NKT cells persist for more than 100 days and do not cause significant morbidity or mortality. Doses of NKT cells as low as 1.0 * 10(4) cells suppress GVHD caused by 5.0 * 10(5) Tcons in an interleukin-4 (IL-4)-dependent mechanism. Protective doses of NKT cells minimally affect Tcon proliferation, but cause significant reductions in interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) production by donor Tcons and in skin, spleen, and gastrointestinal pathology. In addition, NKT cells do not impact the graft-versus-tumor (GVT) effect of Tcons against B-cell lymphoma-1 (BCL-1) tumors. These studies elucidate the biologic function of donor-type CD4(+)NKT cells in suppressing GVHD in an allogeneic transplantation setting, demonstrating clinical potential in reducing GVHD in HCT. PMID- 21258009 TI - IL-7R-dependent survival and differentiation of early T-lineage progenitors is regulated by the BTB/POZ domain transcription factor Miz-1. AB - T cells originate from early T lineage precursors that have entered the thymus and differentiate through well-defined steps. Mice deficient for the BTB/POZ domain of zinc finger protein-1 (Miz-1) almost entirely lack early T lineage precursors and have a CD4(-)CD8(-) to CD4(+)CD8(+) block causing a strong reduction in thymic cellularity. Miz-1(DeltaPOZ) pro-T cells cannot differentiate in vitro and are unable to relay signals from the interleukin-7R (IL-7R). Both STAT5 phosphorylation and Bcl-2 up-regulation are perturbed. The high expression levels of SOCS1 found in Miz-1(DeltaPOZ) cells probably cause these alterations. Moreover, Miz-1 can bind to the SOCS1 promoter, suggesting that Miz-1 deficiency causes a deregulation of SOCS1. Transgenic overexpression of Bcl-2 or inhibition of SOCS1 restored pro-T cell numbers and their ability to differentiate, supporting the hypothesis that Miz-1 is required for the regulation of the IL 7/IL-7R/STAT5/Bcl-2 signaling pathway by monitoring the expression levels of SOCS1. PMID- 21258010 TI - The importance of neovascularization and its inhibition for allogeneic hematopoietic stem cell transplantation. AB - GVHD and tumor relapse are fundamental problems in allogeneic HSCT. Recent research has linked neovascularization to GVHD, tumor growth, and graft-versus tumor (GVT) activity. Damage of the endothelium by the conditioning regimen provides the initiation stimulus for recruitment of donor-derived endothelial cells and their progenitors. During the early inflammatory phase of GVHD there is considerable neovascularization facilitating migration of inflammatory cells to target organs. In the course of GVHD, however, the vasculature itself becomes a target of alloreactive donor T cells. As a consequence, later stages of GVHD are characterized by fibrosis and rarefaction of blood vessels. Importantly, the inhibition of tumor-neovascularization by activated donor T cells that release antiangiogenic substances contributes to GVT and may be enhanced by pharmacologic inhibition of neovascularization. Furthermore, the therapeutic inhibition of neovascularization may improve immunotherapy for cancer by enhancing leukocyte infiltration in tumor tissue because of normalization of tumor vessels and stimulation of leukocyte-vessel wall interactions. These insights identify important mechanisms underlining the importance of neovascularization for allogeneic immune responses and move therapeutic approaches targeting neovascularization into the spotlight. This perspective covers current knowledge of the role of neovascularization during GVHD as well as GVT and its implications for HSCT. PMID- 21258008 TI - Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities. AB - Pulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34(+)CD133(+) proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 alpha (HIF-1alpha). Here, CD34(+)CD133(+) progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 alpha (SDF-1alpha) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process. PMID- 21258011 TI - Association between serum high-molecular-weight adiponectin level and the severity of chronic graft-versus-host disease in allogeneic stem cell transplantation recipients. AB - Recently, a growing body of evidence has suggested that adiponectin, which is secreted by adipose tissues, plays a critical role in obesity-related and autoimmune diseases. We compared the concentrations of adiponectin among 26 normal subjects and 34 allogeneic stem cell transplantation recipients. The concentrations of adiponectin were significantly higher in recipients with chronic graft-versus-host disease (cGVHD) than those in subjects without cGVHD (21.7 +/- 11.0 vs 9.1 +/- 6.1 MUg/mL in females, P < .001; and 10.1 +/- 6.8 vs 4.3 +/- 2.9 MUg/mL in males, P = .003). Multivariate analysis revealed that a higher concentration of adiponectin was associated with female sex (beta coefficient 8.2, P < .0001) and the severity of cGVHD (beta-coefficient 6.6, 12.7, and 15.6, P < .01, each for mild, moderate, and severe cGVHD, respectively). In addition, adiponectin levels increased as cGVHD progressed, decreased as cGVHD improved, and did not change with stable cGVHD. In conclusion, adiponectin was associated with the severity of cGVHD and might play a role in the pathophysiology of cGVHD. PMID- 21258012 TI - Effects of repeated use of the American Osteopathic Association's Clinical Assessment Program on measures of care for patients with diabetes mellitus. AB - CONTEXT: The American Osteopathic Association developed its Clinical Assessment Program (AOA-CAP) for Residencies to provide a mechanism for osteopathic residency programs to measure and improve their quality of patient care. OBJECTIVE: To compare program performance in processes of care and intermediate outcomes for patients with diabetes mellitus in residency programs that contributed data to the AOA-CAP for the first time vs residency programs that contributed data repeatedly. METHODS: Osteopathic family medicine residency programs that entered data into the AOA-CAP diabetes registry between July 1, 2005, and December 31, 2007, were included in the present study. Residency programs were separated into those that entered data into the registry for the first time during the 2005-2007 cycle (ie, first-time programs) and those that also entered data into the registry during the previous cycle (2003-2005) (ie, repeat programs). Measures of processes of care were annual foot examination, annual referral for ophthalmologic examination, annual microalbuminuria screening, use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) if albuminuria is present, use of ACE inhibitors or ARBs if hypertension is present, glycosylated hemoglobin (HbA(1c)) test in the previous year, and low-density lipoprotein cholesterol (LDL-C) test in the previous year. Measures of intermediate outcomes were control of blood pressure, HbA(1c), and LDL-C. Processes of care and outcome composite scores were also computed. RESULTS: Data from 52 osteopathic family medicine residency programs consisting of 2568 patient cases were analyzed. Twenty-three first-time programs with 992 cases and 29 repeat programs with 1576 cases entered data into the registry in the 2005-2007 cycle. Repeat programs had statistically significant better performance than first-time programs in the composite measure of processes of care (P=.0023)-largely the result of increased use of ACE inhibitors and ARBs in patients with albuminuria (P=.0087). The difference in the composite measure of intermediate outcomes was not statistically significant between the 2 groups. CONCLUSION: Repeated participation in the AOA-CAP registry was associated with improved residency program performance on the composite process of care measure but not on intermediate outcome measures for patients with diabetes mellitus. This finding suggests that osteopathic residency programs need to provide better training on adjusting patient care according to performance results. PMID- 21258013 TI - Implementation of a stroke alert protocol in the emergency department: a pilot study. AB - CONTEXT: Although tissue plasminogen activator (tPA) is an effective treatment for stroke patients, it typically must be administered within 3 hours of symptom onset to substantially reduce morbidity and mortality. Because of this limited treatment window, it is essential for healthcare professionals to properly identify and quickly triage stroke patients. OBJECTIVE: To determine if implementation of a stroke alert protocol coupled with a limited education program will reduce arrival time to computed tomography scan time and treatment time for stroke patients in the emergency department (ED). METHODS: This prospective pilot study took place at Geisinger Medical Center in Danville, Pennsylvania, and included a formal stroke protocol based partly on The Joint Commission's stroke center recommendations. The major feature was integration of various hospital departments to quickly and accurately identify and triage stroke patients; included was a limited education program for residents and attending staff. Patients who presented between November 1, 2007, to October 31, 2008, comprised the study group (ie, after protocol implementation). A retrospective analysis of patient records from November 1, 2006, to October 31, 2007, for stroke morbidity, mortality, and tPA administration was employed as a control group (ie, prior to protocol implementation). Inclusion criteria consisted of patients aged 18 years or older who arrived at the ED with stroke-like symptoms. Exclusion criteria consisted of previous hemorrhagic stroke, seizure at stroke onset, internal bleeding, intracranial hemorrhage, recent surgery, platelet count of less than 100 * 10(3)/MUL, untreated blood pressure greater than 185/110 mm Hg, symptoms lasting for longer than 6 hours, and vascular malformation. Patients with a history of ischemic stroke were included in the study. RESULTS: The study included a total of 233 stroke patients, 132 of whom presented to the ED prior to stroke protocol implementation and 101 of whom presented after stroke protocol implementation. For patients who arrived at the ED within 3 hours from symptom onset, median time to completion of a computed tomography (CT) scan was reduced from 65.5 minutes (interquartile range, 41.0-101.0) prior to the new protocol to 54.0 minutes (interquartile range, 25.0-54.0) after implementation (P<.004). Regarding patients who arrived in the ED 3 to 6 hours after symptom onset, median time from ED arrival to CT time decreased from 94.5 minutes (interquartile range, 68.0-136.0) before the new protocol to 48.5 minutes (interquartile range, 33.0 89.0) following implementation (P<.002). Of the 79 patients who arrived at the ED within 3 hours of symptom onset in the year after protocol implementation, 12 were treated with tPA, compared to 4 out of 86 treated in the year prior to protocol implementation. Mean time from ED arrival to tPA treatment was reduced from 85.5 minutes in the preprotocol group to 48.9 minutes in the postprotocol group. CONCLUSION: By coupling a formal stroke protocol with a limited education program, door-to-treatment time of stroke patients was reduced. PMID- 21258014 TI - Diagnosis and management of hereditary angioedema. AB - Hereditary angioedema (HAE) is characterized by sudden attacks of deep tissue swelling caused by C1 inhibitor deficiency. Swelling severity can vary from mild to severe, and some patients are at risk for disability and death from either asphyxiation or hypovolemic shock. Many HAE attacks are precipitated by trauma or stress. The extremities, genitalia, trunk, bowels, face, and larynx are commonly affected areas, but swelling can affect any single part of the body or multiple sites. Symptoms typically worsen over 24 to 36 hours and resolve within 48 hours. Because many symptoms of HAE overlap with those of other medical conditions, diagnosis may be delayed. A thorough family history can identify the signature symptoms of HAE, which include a family history of HAE, recurrent edema without urticaria, and symptomatic worsening during puberty. The author presents two hypothetical cases of HAE and reviews the clinical hallmarks of this condition, diagnostic tests, and available treatments. PMID- 21258016 TI - Osteopathic manipulative treatment for the treatment of hospitalized premature infants with nipple feeding dysfunction. AB - Premature newborns and infants are usually required to successfully transition from gavage to nipple feeding using breast or bottle before discharge from the hospital. This transition is frequently the last discharge skill attained. Delayed acquisition of this skill may substantially prolong hospital length of stay. The authors describe a case of hospitalized premature twins who had considerable delays in attaining nipple-feeding skills. Because of their inability to take all feedings by nipple, preparation for surgical placement of gastrostomy tubes was initiated. Before the surgeries were scheduled, the inpatient osteopathic manipulative medicine service was consulted, and the twins received a series of evaluations and osteopathic manipulative treatment (OMT) sessions. During the OMT course, the twins' nipple feeding skills progressed to full oral feeding, which allowed them to be discharged to home without placement of gastrostomy tubes. The authors also review the literature and discuss the development of nipple feeding in premature newborns and infants and the use of OMT in the management of nipple feeding dysfunction. PMID- 21258015 TI - Relationship between encounter time and candidate performance on COMLEX-USA Level 2-PE. AB - BACKGROUND: The National Board of Osteopathic Medical Examiners uses a standardized timing format for all osteopathic medical candidates across all stations in the Comprehensive Osteopathic Medical Licensing Examination-USA Level 2-Performance Evaluation (COMLEX-USA Level 2-PE). Examination standardization, and therefore validity, is weakened if time administered affects student performance. OBJECTIVE: To investigate the relationship between the amount of time students spent with standardized patients (SPs) and their clinical skill component scores. METHODS: Data were analyzed from 249 candidates in 21 test sessions from the 2007-2008 testing cycle. Trained SPs recorded the time each examinee entered and exited each encounter. Outcome measures of the examination included pass (1 if pass; 0 if fail) performance outcome, pass by domain (biomedical/biomechanical and humanistic), and pass by component scores (data gathering, osteopathic manipulative treatment, and patient note scores). Analysis of variance (ANOVA), followed by pairwise comparisons, was used to compare encounter times across cases. RESULTS: A total of 2988 SP encounters were analyzed. Examinees spent an average 12.1 minutes in each patient encounter. Candidates spent less time with cases classified as health promotion and disease prevention than with cases that primarily involved a problem visit, but amount of time spent with cases representing various content areas was not significantly different (P>.05). On average, candidates spent the least amount of time (11.95 minutes) with gastrointestinal cases and the most time (12.26 minutes) with patients who had complaints relating to the neuromusculoskeletal system. A trivial relationship was shown between the continuous variable encounter time as the average amount of time a student spends in the encounter and the dichotomous clinical skill outcome of the examination (r=.03). The relationship between these 2 variables was consistent when examined separately for the humanistic domain (r= .10) and the biomedical/biomechanical domain (r=.12). The strongest correlation was between encounter time and the data-gathering component score (r=.28). CONCLUSION: Time spent in the encounter was not influential in overall candidate performance in the COMLEX-USA Level 2-PE. Candidates spent a similar amount of time with cases of different content areas. This finding suggests that 14 minutes is sufficient for this osteopathic high-stakes performance evaluation. PMID- 21258017 TI - Management of suppurative cervical lymphadenitis in a healthy 24-year-old man. AB - Unilateral suppurative cervical lymphadenitis is characterized by acute onset of 1 or more tender cervical lymph nodes and can lead to fever, cellulitis, abscess formation, and bacteremia. This form of lymphadenitis is usually caused by gram positive bacteria. The present case details the treatment of a previously healthy 24-year-old man who presented with an acutely inflamed cervical lymph node. The patient did not respond to antibiotic monotherapy or combination antibiotics but recovered rapidly after methylprednisolone and osteopathic manipulative treatment were added to his care. PMID- 21258018 TI - Student abstracts and poster competitions: encouraging research. PMID- 21258021 TI - New drug and biological product approvals, 2010. PMID- 21258022 TI - Medicare demonstration shows accountability can save money. PMID- 21258023 TI - Lessons from a service learning trip to Haiti. PMID- 21258024 TI - Redesigning the workflow of central pharmacy operations. PMID- 21258025 TI - Formulary and database synchronization. PMID- 21258026 TI - Induction immunosuppressive therapies in renal transplantation. AB - PURPOSE: Induction immunosuppressive therapies for patients undergoing renal transplantation are reviewed. SUMMARY: The goal of induction therapy is to prevent acute rejection during the early posttransplantation period by providing a high degree of immunosuppression at the time of transplantation. Induction therapy is often considered essential to optimize outcomes, particularly in patients at high risk for poor short-term outcomes. All of the induction immunosuppressive agents currently used are biological agents and are either monoclonal (muromonab-CD3, daclizumab, basiliximab, alemtuzumab) or polyclonal (antithymocyte globulin [equine] or antithymocyte globulin [rabbit]) antibodies. Although antithymocyte globulin (rabbit) is not labeled for induction therapy, it is used for this purpose more than any other agent. Basiliximab is not considered as potent an immunosuppressive agent but has a much more favorable adverse-effect profile compared with antithymocyte globulin (rabbit) and is most commonly used in patients at low risk for acute rejection. Rituximab is being studied for use as induction therapy but to date has not demonstrated any significant benefits over placebo. While head-to-head data are available comparing most induction agents, the final decision on the most appropriate induction therapy for a transplant recipient is highly dependent on preexisting medical conditions, donor characteristics, and the maintenance immunosuppressive regimen to be used. CONCLUSION: No standard induction immunosuppressive regimen exists for patients undergoing renal transplantation. Antithymocyte globulin (rabbit) is the most commonly used agent, whereas basiliximab appears safer. The choice of regimen depends on the preferences of clinicians and institutions. PMID- 21258027 TI - Effectiveness of pharmacologic therapy for smoking cessation in adolescent smokers: Meta-analysis of randomized controlled trials. AB - PURPOSE: The effectiveness of pharmacologic therapy for smoking cessation in adolescent smokers was evaluated. METHODS: In this meta-analysis, the medical literature was searched for randomized controlled trials (RCTs) investigating the effect of pharmacologic therapy for smoking cessation in smokers age 20 years or younger. The overall effect of pharmacologic therapy was based on the longest follow-up data available in each study. The effects of pharmacologic therapy by follow-up period, type of pharmacologic therapy, and type of strategy analysis were also compared among RCTs. Secondary outcome measures were adverse events reported from each study. RESULTS: Six RCTs involving 816 smokers age 12-20 years were included in the final analysis. No significant increase in abstinence rates was detected with pharmacologic therapy (relative risk [RR], 1.38; 95% confidence interval [CI], 0.92-2.07; I(2) = 0.0%) in a fixed-effects meta-analysis. Similarly, no significant increase in abstinence rates was found in subgroup meta analyses of studies with both short-term (<= 12 weeks) (RR, 1.23; 95% CI, 0.92 1.65) and mid-term (26 weeks) follow-up periods (RR, 1.60; 95% CI, 0.90-2.82). Although few serious adverse events were reported, there was no evidence directly linking these effects to the pharmacologic therapy used. CONCLUSION: A meta analysis found that pharmacologic therapy for smoking cessation among adolescent smokers did not have a significant effect on abstinence rates at short-term and mid-term follow-up times of <26 weeks, and the RCTs examined found few adverse events. However, the results may have been affected by the limited number of participants in published trials. PMID- 21258028 TI - Systematic review of medication safety assessment methods. AB - PURPOSE: The accuracy, efficiency, and efficacy of four commonly recommended medication safety assessment methodologies were systematically reviewed. METHODS: Medical literature databases were systematically searched for any comparative study conducted between January 2000 and October 2009 in which at least two of the four methodologies-incident report review, direct observation, chart review, and trigger tool-were compared with one another. Any study that compared two or more methodologies for quantitative accuracy (adequacy of the assessment of medication errors and adverse drug events) efficiency (effort and cost), and efficacy and that provided numerical data was included in the analysis. RESULTS: Twenty-eight studies were included in this review. Of these, 22 compared two of the methodologies, and 6 compared three methods. Direct observation identified the greatest number of reports of drug-related problems (DRPs), while incident report review identified the fewest. However, incident report review generally showed a higher specificity compared to the other methods and most effectively captured severe DRPs. In contrast, the sensitivity of incident report review was lower when compared with trigger tool. While trigger tool was the least labor intensive of the four methodologies, incident report review appeared to be the least expensive, but only when linked with concomitant automated reporting systems and targeted follow-up. CONCLUSION: All four medication safety assessment techniques-incident report review, chart review, direct observation, and trigger tool-have different strengths and weaknesses. Overlap between different methods in identifying DRPs is minimal. While trigger tool appeared to be the most effective and labor-efficient method, incident report review best identified high severity DRPs. PMID- 21258029 TI - Pharmacist interventions to enhance blood pressure control and adherence to antihypertensive therapy: Review and meta-analysis. AB - PURPOSE: Pharmacist interventions to enhance blood pressure (BP) control and adherence to antihypertensive therapy in adults with essential hypertension were reviewed. METHODS: A literature search was conducted to identify relevant articles describing pharmacist interventions intended to improve adherence to antihypertensive medications. Studies were included if they described a pharmacist intervention to improve medication adherence and analyzed adherence to therapy and BP control as outcomes. A fixed-effects model was used to combine data from randomized controlled trials. RESULTS: A total of 15 studies were identified, testing 16 different interventions and containing data on 3280 enrolled patients. Although 87.5% of the interventions resulted in significant improvements in treatment outcomes, only 43.8% of the interventions were associated with significant increases in medication adherence. All interventions that increased antihypertensive medication adherence also significantly reduced BP. Almost all the interventions that were effective in increasing adherence to medication were complex, including combinations of different strategies. Meta analysis of 2619 patients in 8 studies found that pharmacist interventions significantly reduced systolic blood pressure (SBP) (p < 0.001) and diastolic blood pressure (DBP) (p = 0.002) and that the meta-analytic differences in SBP and DBP changes from baseline to endpoint in intervention and control groups were -4.9 +/- 0.9 mm Hg (p < 0.001) and -2.6 +/- 0.9 mm Hg (p < 0.001), respectively. CONCLUSION: A literature review and meta-analysis showed that pharmacist interventions can significantly improve medication adherence, SBP, DBP, and BP control in patients with essential hypertension. Interventions were complex and multifaceted and included medication management in all analyzed studies. PMID- 21258030 TI - Medication adherence in combat veterans with traumatic brain injury. AB - PURPOSE: Medication adherence in combat veterans with traumatic brain injury (TBI) was evaluated. METHODS: Patients with a diagnosis of TBI were identified by a computer search of veterans enrolled in the Operation Enduring Freedom/Operation Iraqi Freedom or TBI/polytrauma clinics at Durham Veterans Affairs Medical Center (VAMC) between September 15, 2007, and September 15, 2008. Patients were included if they were at least 18 years old, received medical care and medications at the VAMC for at least 12 continuous months, and were taking at least one maintenance medication. A randomly selected age-matched comparator group without TBI was obtained through a computer-generated convenience sample. A composite adherence score for each patient was calculated using the medication possession ratio (MPR). The most commonly prescribed medications and indicators of increased adherence among the TBI group were also identified. RESULTS: The composite MPR did not significantly differ between groups. The most commonly prescribed medications were selective serotonin-reuptake inhibitors and serotonin norepinephrine-reuptake inhibitors and other antidepressants; however, these classes were associated with the lowest adherence rates. Factors associated with increased adherence included taking more than five maintenance medications (78%), living with a spouse or significant other (77%), owning a memory-assistance device (74%), and comorbid diagnosis of posttraumatic stress disorder (PTSD) (74%). CONCLUSION: Medication adherence rates were similar among combat veterans with a diagnosis of TBI and an age-matched comparator group. Factors associated with increased adherence included taking more than five maintenance medications, living with a spouse or significant other, owning a memory-assistance device, and a comorbid diagnosis of PTSD. PMID- 21258031 TI - Making a case for a patient-centered integrated pharmacy practice model. PMID- 21258032 TI - CUSUM for monitoring competency: computer software is useful for bootstrapping and real-time CUSUM plotting. PMID- 21258033 TI - The role of multifunctional M1 metallopeptidases in cell cycle progression. AB - BACKGROUND: Metallopeptidases of the M1 family are found in all phyla (except viruses) and are important in the cell cycle and normal growth and development. M1s often have spatiotemporal expression patterns which allow for strict regulation of activity. Mutations in the genes encoding M1s result in disease and are often lethal. This family of zinc metallopeptidases all share the catalytic region containing a signature amino acid exopeptidase (GXMXN) and a zinc binding (HEXXH[18X]E) motif. In addition, M1 aminopeptidases often also contain additional membrane association and/or protein interaction motifs. These protein interaction domains may function independently of M1 enzymatic activity and can contribute to multifunctionality of the proteins. SCOPE: A brief review of M1 metalloproteases in plants and animals and their roles in the cell cycle is presented. In animals, human puromycin-sensitive aminopeptidase (PSA) acts during mitosis and perhaps meiosis, while the insect homologue puromycin-sensitive aminopeptidase (PAM-1) is required for meiotic and mitotic exit; the remaining human M1 family members appear to play a direct or indirect role in mitosis/cell proliferation. In plants, meiotic prophase aminopeptidase 1 (MPA1) is essential for the first steps in meiosis, and aminopeptidase M1 (APM1) appears to be important in mitosis and cell division. CONCLUSIONS: M1 metalloprotease activity in the cell cycle is conserved across phyla. The activities of the multifunctional M1s, processing small peptides and peptide hormones and contributing to protein trafficking and signal transduction processes, either directly or indirectly impact on the cell cycle. Identification of peptide substrates and interacting protein partners is required to understand M1 function in fertility and normal growth and development in plants. PMID- 21258034 TI - Mutations in INF2 are a major cause of autosomal dominant focal segmental glomerulosclerosis. AB - The recent identification of mutations in the INF2 gene, which encodes a member of the formin family of actin-regulating proteins, in cases of familial FSGS supports the importance of an intact actin cytoskeleton in podocyte function. To determine better the prevalence of INF2 mutations in autosomal dominant FSGS, we screened 54 families (78 patients) and detected mutations in 17% of them. All mutations were missense variants localized to the N-terminal diaphanous inhibitory domain of the protein, a region that interacts with the C-terminal diaphanous autoregulatory domain, thereby competing for actin monomer binding and inhibiting depolymerization. Six of the seven distinct altered residues localized to an INF2 region that corresponded to a subdomain of the mDia1 diaphanous inhibitory domain reported to co-immunoprecipitate with IQ motif-containing GTPase-activating protein 1 (IQGAP1). In addition, we evaluated 84 sporadic cases but detected a mutation in only one patient. In conclusion, mutations in INF2 are a major cause of autosomal dominant FSGS. Because IQGAP1 interacts with crucial podocyte proteins such as nephrin and PLCepsilon1, the identification of mutations that may alter the putative INF2-IQGAP1 interaction provides additional insight into the pathophysiologic mechanisms linking formin proteins to podocyte dysfunction and FSGS. PMID- 21258035 TI - Predicting the risk for dialysis or death in IgA nephropathy. AB - For the individual patient with primary IgA nephropathy (IgAN), it remains a challenge to predict long-term outcomes for patients receiving standard treatment. We studied a prospective cohort of 332 patients with biopsy-proven IgAN patients followed over an average of 13 years. We calculated an absolute renal risk (ARR) of dialysis or death by counting the number of risk factors present at diagnosis: hypertension, proteinuria >=1 g/d, and severe pathologic lesions (global optical score, >=8). Overall, the ARR score allowed significant risk stratification (P < 0.0001). The cumulative incidence of death or dialysis at 10 and 20 years was 2 and 4%, respectively, for ARR=0; 2 and 9% for ARR=1; 7 and 18% for ARR=2; and 29 and 64% for ARR=3, in adequately treated patients. When achieved, control of hypertension and reduction of proteinuria reduced the risk for death or dialysis. In conclusion, the absolute renal risk score, determined at diagnosis, associates with risk for dialysis or death. PMID- 21258036 TI - TRPC6 enhances angiotensin II-induced albuminuria. AB - Mutations in the canonical transient receptor potential cation channel 6 (TRPC6) are responsible for familial forms of adult onset focal segmental glomerulosclerosis (FSGS). The mechanisms by which TRPC6 mutations cause kidney disease are not well understood. We used TRPC6-deficient mice to examine the function of TRPC6 in the kidney. We found that adult TRPC6-deficient mice had BP and albumin excretion rates similar to wild-type animals. Glomerular histomorphology revealed no abnormalities on both light and electron microscopy. To determine whether the absence of TRPC6 would alter susceptibility to hypertension and renal injury, we infused mice with angiotensin II continuously for 28 days. Although both groups developed similar levels of hypertension, TRPC6 deficient mice had significantly less albuminuria, especially during the early phase of the infusion; this suggested that TRPC6 adversely influences the glomerular filter. We used whole-cell patch-clamp recording to measure cell membrane currents in primary cultures of podocytes from both wild-type and TRPC6 deficient mice. In podocytes from wild-type mice, angiotensin II and a direct activator of TRPC6 both augmented cell-membrane currents; TRPC6 deficiency abrogated these increases in current magnitude. Our findings suggest that TRPC6 promotes albuminuria, perhaps by promoting angiotensin II-dependent increases in Ca(2+), suggesting that TRPC6 blockade may be therapeutically beneficial in proteinuric kidney disease. PMID- 21258037 TI - Breast arterial calcification: a marker of medial vascular calcification in chronic kidney disease. AB - BACKGROUND AND OBJECTIVES: Because previous studies have not distinguished between intimal (atherosclerotic) and medial vascular calcification, the prevalence and clinical significance of either condition in chronic or end-stage kidney disease (CKD or ESKD) are unknown. We hypothesized that breast arterial calcification (BAC) is exclusively medial and that mammography can serve as a useful marker of generalized medial calcification in CKD and ESKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Arterial calcification was identified histologically in breast tissue or visually in mammograms and radiographs of extremities from patients with CKD or ESKD. RESULTS: Medial calcification but no intimal calcification was present in all 16 specimens from patients with CKD or ESKD. In 71 women with ESKD, BAC was present on mammograms in 63% compared with 17% in women without renal insufficiency matched for age, race, and diabetes (P<0.001). Age and ESKD duration were significant, independent predictors of BAC. BAC was also present in 36% of mammograms from the same patients performed 5.5+/ 0.7 years before the onset of ESKD (P<0.05 versus control) but in only 14% of patients with stage 3 CKD. Comparison of mammograms and extremity radiographs revealed that BAC was present in over 90% of patients with peripheral arterial calcification (PAC), and PAC was observed in less than 6% of patients without BAC. CONCLUSIONS: BAC is a specific and useful marker of medial vascular calcification in CKD, and its prevalence is markedly increased in ESKD and advanced CKD. PMID- 21258038 TI - A validation study of the Canadian Organ Replacement Register. AB - BACKGROUND AND OBJECTIVES: Accurate and complete documentation of patient characteristics and comorbidities in renal registers is essential to control bias in the comparison of outcomes across groups of patients or dialysis facilities. The objectives of this study were to assess the quality of data collected in the Canadian Organ Replacement Register (CORR) compared with the patient's medical charts. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cohort study of a representative sample of adult, incident patients registered in CORR in 2005 to 2006 examined the prevalence, sensitivity, specificity, positive and negative predictive values, and kappa of comorbid conditions and agreement in coding of patient demographics and primary renal disease between CORR and the patient's medical record. The effect of coding variation on patient survival was evaluated. RESULTS: Medical records on 1125 patients were reviewed. Agreement exceeded 97% for health card number, date of birth, and sex and 71% (range 46.6 to 89.1%) for the primary renal disease. Comorbid conditions were under-reported in CORR. Sensitivities ranged from 0.89 (95% confidence interval 0.80, 0.92) for hypertension to 0.47 (0.38, 0.55) for peripheral vascular disease. Specificity was >0.93 for all comorbidities except hypertension. Hazard ratios for death were similar whether calculated using data from CORR or the medical record. CONCLUSIONS: Comorbid conditions are under-reported in CORR; however, the associated risks of mortality were similar whether using the CORR data or the medical record data, suggesting that CORR data can be used in clinical research with minimal concern for bias. PMID- 21258039 TI - Randomized, double-blind study with glycerol and paraffin in uremic xerosis. AB - BACKGROUND AND OBJECTIVES: Uremic xerosis is a bothersome condition that is poorly responsive to moisturizing and emollient therapy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A randomized, double-blind, intraindividual (left versus right comparison), multicentric clinical study was performed on 100 patients with moderate to severe uremic xerosis for 7 days, during which the patients applied twice daily an emulsion combining glycerol and paraffin (test product) on one allocated lower leg, and the emulsion alone (comparator) on the other lower leg. This was followed by an open-labeled use of the test product on all of the xerotic areas for 49 days. The main efficacy parameter was treatment response on each lower leg, as defined by a reduction from baseline of at least two grades in a five-point clinical score on day 7. RESULTS: Among the 99 patients analyzed, the test product was highly effective with a treatment response in 72 patients (73%), whereas 44 patients (44%) responded to the comparator (P<0.0001, intergroup analysis). This was associated with an objective reduction in the density and thickness of the scales on day 7 (P<0.0001 compared with the comparator) and a substantial improvement of the uremic pruritus (75%) and quality of life of the patients at study end (P<0.001, intragroup analysis). The test product was very well tolerated, with product-related local intolerance (exacerbated pruritus, local burning, or erythema) occurring in only five patients (5%). CONCLUSIONS: Uremic xerosis can be managed successfully when an appropriate emollient therapy is used. PMID- 21258040 TI - Tacrolimus-induced neutropenia in renal transplant recipients. AB - Tacrolimus has become an important cornerstone in the prevention of rejection after kidney transplantation. However, its use has been complicated by several side effects, including chronic allograft nephropathy, diabetes mellitus, arterial hypertension, and neurotoxicity. Tacrolimus-induced neutropenia is a less recognized, but potentially harmful complication. Three patients with severe neutropenia developing within 3 months after kidney transplantation are described. After having excluded other well known causes, tacrolimus was considered the most probable culprit. Definitive proof of this hypothesis was obtained by discontinuation of tacrolimus and switching to cyclosporine, which led to recovery of white blood cell count in all three patients. PMID- 21258041 TI - Plasma S100A12 level is associated with cardiovascular disease in hemodialysis patients. AB - BACKGROUND AND OBJECTIVES: S100A12 is an endogenous receptor ligand for advanced glycation end products. Cardiovascular disease remains a major cause of morbidity and mortality in patients with chronic kidney disease. In this study, we report cross-sectional data on 550 hemodialysis patients and assess the relationship between plasma S100A12 level and cardiovascular disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A cross-sectional study of 550 maintenance hemodialysis patients was conducted. We investigated the past history of cardiovascular disease and quantified the plasma level of S100A12 protein in all participants. RESULTS: Plasma S100A12 level was higher in hemodialysis patients with cardiovascular disease (n=197; 33.8 +/- 28.1 ng/ml) than in those without it (n=353; 20.2 +/- 16.1 ng/ml; P<0.001). In multivariate logistic regression analysis, the plasma S100A12 level (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.13 to 1.44; P<0.001) was identified as an independent factor associated with the prevalence of cardiovascular disease. The other factors associated with the prevalence of cardiovascular diseases were the presence of diabetes mellitus (OR, 2.81; 95% CI, 1.79 to 4.41; P < 0.001) and high sensitivity CRP level (OR, 1.02; 95% CI, 1.00 to 1.05; P=0.046). Furthermore, the plasma S100A12 level (OR, 1.30; 95% CI, 1.09 to 1.54; P=0.004) was significantly associated with cardiovascular disease even in hemodialysis patients without diabetes mellitus (n=348). CONCLUSIONS: These results suggest that the plasma S100A12 protein level is strongly associated with the prevalence of cardiovascular disease in hemodialysis patients. PMID- 21258042 TI - 6,7,4'-trihydroxyisoflavone inhibits HCT-116 human colon cancer cell proliferation by targeting CDK1 and CDK2. AB - Colon cancer is a common epithelial malignancies worldwide. Epidemiologic evidence has shown that nutrition and dietary components are important environmental factors involved in the development of this disease. We investigated the biological activity of 6,7,4'-trihydroxyisoflavone (6,7,4'-THIF, a metabolite of daidzein) in in vitro and in vivo models of human colon cancer. 6,7,4'-THIF suppressed anchorage-dependent and -independent growth of HCT-116 and DLD1 human colon cancer cells more effectively than daidzein. In addition, 6,7,4' THIF induced cell cycle arrest at the S and G2/M phases in HCT-116 human colon cancer cells. Western blot analysis revealed that 6,7,4'-THIF effectively suppressed the expression of cyclin-dependent kinase (CDK) 2, but had no effect on other S- or G2/M-phase regulatory proteins such as cyclin A, cyclin B1 or CDK1. Daidzein did not affect the expression of any of these proteins. In kinase and pull-down assays, 6,7,4'-THIF, but not daidzein, inhibited CDK1 and CDK2 activities in HCT-116 cells by directly interacting with CDK1 and CDK2. In a xenograft mouse model, 6,7,4'-THIF significantly decreased tumor growth, volume and weight of HCT-116 xenografts. 6,7,4'-THIF bound directly to CDK1 and CDK2 in vivo, resulting in the suppression of CDK1 and CDK2 activity in tumors corresponding with our in vitro results. Collectively, these results suggest that CDK1 and CDK2 are potential molecular targets of 6,7,4'-THIF to suppress HCT-116 cell proliferation in vitro and in vivo. These findings provide insight into the biological actions of 6,7,4'-THIF and might establish a molecular basis for the development of new cancer therapeutic agents. PMID- 21258043 TI - Dopamine D1 receptor associations within and between dopaminergic pathways in younger and elderly adults: links to cognitive performance. AB - Age-related dopamine (DA) losses have been extensively demonstrated for the D2 receptor subtype. Comparatively little is known about adult age changes regarding D1 receptors. In this study, we demonstrate marked age-related D1 receptor losses in striatal, limbic, and cortical areas using positron emission tomography and the radioligand [(11)C]SCH23390 in humans. Interregional correlations of binding potential (BP) values were high for areas within DA pathways in younger and elderly adults alike. Furthermore, interregional correlations in D1 BP between DA pathways were uniformly high in younger adults, indicating that D1 receptor densities in striatal, limbic, and cortical areas are not regulated independently, despite dopaminergic innervation from different midbrain areas. For elderly adults, between-pathway correlations of D1 receptor densities were preserved only between mesolimbic and mesocortical areas, whereas striatal BPs were weakly related to those in limbic and neocortical regions. Importantly, weak between-pathway correlations in elderly adults were found only for the slower half of the sample when BP was estimated during a cognitive interference task. These results suggest that D1 receptor densities in different pathways are not regulated independently in younger adults, but segregate in older age, and that this segregation of D1 receptor systems may be related to age-related cognitive slowing. PMID- 21258044 TI - Estradiol decreases cortical reactive astrogliosis after brain injury by a mechanism involving cannabinoid receptors. AB - The neuroactive steroid estradiol reduces reactive astroglia after brain injury by mechanisms similar to those involved in the regulation of reactive gliosis by endocannabinoids. In this study, we have explored whether cannabinoid receptors are involved in the effects of estradiol on reactive astroglia. To test this hypothesis, the effects of estradiol, the cannabinoid CB1 antagonist/inverse agonist AM251, and the cannabinoid CB2 antagonist/inverse agonist AM630 were assessed in the cerebral cortex of male rats after a stab wound brain injury. Estradiol reduced the number of vimentin immunoreactive astrocytes and the number of glial fibrillary acidic protein immunoreactive astrocytes in the proximity of the wound. The effect of estradiol was significantly inhibited by the administration of either CB1 or CB2 receptor antagonists. The effect of estradiol may be in part mediated by alterations in endocannabinoid signaling because the hormone increased in the injured cerebral cortex the messenger RNA levels of CB2 receptors and of some of the enzymes involved in the synthesis and metabolism of endocannabinoids. These findings suggest that estradiol may decrease reactive astroglia in the injured brain by regulating the activity of the endocannabinoid system. PMID- 21258045 TI - In the loop: long range chromatin interactions and gene regulation. AB - Enhancers, silencer and insulators are DNA elements that play central roles in regulation of the genome that are crucial for development and differentiation. In metazoans, these elements are often separated from target genes by distances that can reach 100 Kb. How regulation can be accomplished over long distances has long been intriguing. Current data indicate that although the mechanisms by which these diverse regulatory elements affect gene transcription may vary, an underlying feature is the establishment of close contacts or chromatin loops. With the generalization of this principle, new questions emerge, such as how the close contacts are formed and stabilized and, importantly, how they contribute to the regulation of transcriptional output at target genes. This review will concentrate on examples where a functional role and a mechanistic understanding has been explored for loops formed between genes and their regulatory elements or among the elements themselves. PMID- 21258046 TI - Meet the neighbours: tools to dissect nuclear structure and function. AB - The eukaryotic cell nucleus displays a high degree of spatial organization, with discrete functional subcompartments that provide microenvironments where specialized processes take place. Concordantly, the genome also adopts defined conformations that, in part, enable specific genomic regions to interface with these functional centers. Yet the roles of many subcompartments and the genomic regions that contact them have not been explored fully. More fundamentally, it is not entirely clear how genome organization impacts function, and vice versa. The past decade has witnessed the development of a new breed of methods that are capable of assessing the spatial organization of the genome. These stand to further our understanding of the relationship between genome structure and function, and potentially assign function to various nuclear subcompartments. Here, we review the principal techniques used for analyzing genomic interactions, the functional insights they have afforded and discuss the outlook for future advances in nuclear structure and function dynamics. PMID- 21258048 TI - Antibodies to heterogeneous nuclear ribonucleoprotein H1 are directed to RNA recognition motif 3. PMID- 21258047 TI - Dynamics of epigenetic modifications in leukemia. AB - Chromatin modifications at both histones and DNA are critical for regulating gene expression. Mis-regulation of such epigenetic marks can lead to pathological states; indeed, cancer affecting the hematopoietic system is frequently linked to epigenetic abnormalities. Here, we discuss the different types of modifications and their general impact on transcription, as well as the polycomb group of proteins, which effect transcriptional repression and are often mis-regulated. Further, we discuss how chromosomal translocations leading to fusion proteins can aberrantly regulate gene transcription through chromatin modifications within the hematopoietic system. PML-RARa, AML1-ETO and MLL-fusions are examples of fusion proteins that mis-regulate epigenetic modifications (either directly or indirectly), which can lead to acute myeloblastic leukemia (AML). An in-depth understanding of the mechanisms behind the mis-regulation of epigenetic modifications that lead to the development and progression of AMLs could be critical for designing effective treatments. PMID- 21258050 TI - CC chemokine receptor 5 polymorphism in chronic periaortitis. AB - OBJECTIVE: Chronic periaortitis (CP) is a rare disease characterized by a fibro inflammatory tissue surrounding the abdominal aorta, and includes non-aneurysmal [idiopathic retroperitoneal fibrosis (IRF)] and aneurysmal forms [inflammatory abdominal aortic aneurysm (IAAA)]. We investigated whether CC chemokine receptor 5 (CCR5)Delta32 polymorphism confers susceptibility to CP. METHODS: One hundred CP patients and 180 healthy controls were genotyped for CCR5Delta32 polymorphism by molecular methods. The patients were subgrouped according to the type of CP (IRF or IAAA) and the presence of established atherosclerotic disease (ischaemic heart disease, cerebrovascular disease and peripheral arterial disease). RESULTS: The distribution of the CCR5Delta32 genotype differed between CP patients and controls (P = 0.01). The CCR5Delta32 allele was more frequent in CP patients than in controls [P = 0.02, odds ratio (OR) 2.8 (95% CI 1.2, 6.4)]. The distribution of the CCR5Delta32 genotype did not differ significantly between IRF patients and controls, whereas the CCR5Delta32 allele was more frequent in IAAA patients than in controls [P = 0.0001, OR 10.0 (95% CI 3.7, 27.3)]. Furthermore, the CCR5Delta32 allele occurred more frequently in IAAA than in IRF patients [P = 0.001, OR 6.4 (95% CI 2.1, 19.1)]. The CCR5Delta32 allele frequency was higher in IAAA patients without established atherosclerotic disease compared with controls [66.7 vs 5.6%, P = 0.00001, OR 34.0 (95% CI 7.4, 156.3)], but not in IAAA patients with atherosclerotic disease and IRF patients with or without atherosclerotic disease. CONCLUSIONS: The CCR5Delta32 polymorphism might be associated with an increased risk of developing the aneurysmal form of CP, IAAA, particularly in patients without established atherosclerotic disease. Chemokines may have a role in the pathophysiology of CP. PMID- 21258049 TI - Distinct in vitro binding properties of the anti-CD20 small modular immunopharmaceutical 2LM20-4 result in profound and sustained in vivo potency in cynomolgus monkeys. AB - OBJECTIVES: To characterize the in vitro binding and effector function properties of CD20-directed small modular immunopharmaceutical (SMIP) 2LM20-4, and to compare its in vivo B-cell depletion activity with the mutated 2LM20-4 P331S [no in vitro complement-dependent cytotoxicity (CDC)] and rituximab in cynomolgus monkeys. METHODS: Direct binding is examined in flow cytometry, confocal microscopy, scatchard and lipid raft assays. Effector function assays include CDC and Fc-mediated cellular toxicity. In the 6-month-long in vivo B-cell depletion study, single i.v. dosages of 1 or 10 mg/kg of anti-CD20 proteins were administered to monkeys and B-cell counts were monitored in peripheral blood, bone marrow and lymph nodes. RESULTS: 2LM20-4 has lower saturation binding to human primary B cells and recruits fewer CD20 molecules into lipid rafts compared with rituximab; however, it induces higher in vitro CDC. In competitive binding, 2LM20-4 only partially displaces rituximab, suggesting that it binds to a fraction of CD20 molecules within certain locations of the plasma membrane as compared with rituximab. In monkeys, 2LM20-4 had more sustained B-cell depletion activity than rituximab in peripheral blood and had significantly more profound and sustained activity than 2LM20-4 P331S and rituximab in the lymph nodes. CONCLUSIONS: SMIP 2LM20-4, which binds to a fraction of CD20 molecules as compared with rituximab, has more potent in vitro CDC, and more potent and sustained B-cell depletion activity in cynomolgus monkeys. Our work has considerable clinical relevance since it provides novel insights related to the emerging B-cell depletion therapies in autoimmune diseases. PMID- 21258051 TI - The long-term impact of early treatment of rheumatoid arthritis on radiographic progression: a population-based cohort study. AB - OBJECTIVE: To measure the long-term rate of radiographic progression in a cohort of patients treated early vs late with conventional DMARDs. METHODS: The long term rate of radiographic progression in patients included in the Swiss clinical quality management in rheumatoid arthritis (SCQM-RA) registry who initiated treatment with conventional DMARDs within the first year of symptom onset (early DMARD) vs patients who initiated treatment 1-5 years after symptom onset (late DMARD). Radiographic progression was assessed in 38 joints using a validated score (Ratingen Score). The rate of progression was calculated using a multivariate regression model for longitudinal data, adjusting for potential confounders. RESULTS: A total of 970 RA patients were included. The 368 patients in the early DMARD group started therapy after a median symptom duration of 6 months, whereas the 602 patients in the late DMARD group initiated therapy after median 2.5 years. RF, MTX use and other risk factors for erosive disease progression were similar between the two groups. However, the estimated rate of radiographic progression at baseline was higher in the early DMARD vs the late DMARD group (1.8 vs 0.6, P < 0.01). In spite of this, the long-term rate of radiographic progression was significantly lower in the early DMARD group after adjustment for confounding factors (-0.35 at 5 years, P = 0.012). CONCLUSION: This result supports the concept of a therapeutic window of opportunity early in the disease course and suggests that early initiation of DMARD therapy results in a long-lasting reduction of radiographic damage. PMID- 21258052 TI - Patients with systemic inflammatory and autoimmune diseases are at risk of vaccine-preventable illnesses. AB - OBJECTIVE: To evaluate vaccine coverage and humoral immunity to tetanus, diphtheria and poliomyelitis in adults followed for systemic inflammatory and/or autoimmune diseases (SIADs). METHODS: A cross-sectional study was conducted between June and August 2006 in a monocentric cohort of adults with SIAD. A standardized questionnaire was administered to collect medical, therapeutic and vaccine coverage data. Blood samples were collected in order to measure antibody titres against diphtheria, tetanus and poliomyelitis (DTP). RESULTS: One hundred and eighty-six patients, 32% males, mean (s.d.) age 51 (16) years, 79% receiving CSs and/or immunosuppressants, were included. The vaccine coverage was 29% for diphtheria, 48% for tetanus and 33% for poliomyelitis. The percentages of patients with no humoral immunity against DTP were 44, 21 and 12%, respectively, decreasing to 37.5, 10 and 0%, respectively, for those who had received a vaccine booster in the last 10 years. In a multivariate analysis, age and CS treatment were associated with the absence of humoral immunity against diphtheria and female sex, CD4(+) T cell <200/mm(3) and an absence of tetanus vaccine booster in the last 10 years with the absence of humoral immunity to tetanus. CONCLUSION: Vaccine coverage against tetanus, diphtheria and poliomyelitis is low in patients with SIAD despite the risk in this population of severe infection, especially when receiving immunosuppressants. A significant proportion of them had no humoral immunity against diphtheria or tetanus. Specific immunization schedules need to be optimized in these patients. PMID- 21258053 TI - Association between nail-fold capillary findings and disease activity in dermatomyositis. AB - OBJECTIVE: Although findings of nail-fold capillary changes and reduced red blood cell velocity in SSc patients are well established, studies in adult-onset DM patients are scarce. Our objective was to assess the changes and red blood cell velocity in finger nail-fold capillaries using nail-fold video capillaroscopy (NVC) in patients with adult-onset DM. METHODS: This study included 50 patients with adult-onset DM and 20 healthy subjects. A semi-quantitative rating scale was used to score capillaroscopy changes. Red blood cell velocity was evaluated using frame-to-frame determination of the position of capillary plasma gaps. RESULTS: Thirty-seven (74%) patients showed the scleroderma NVC pattern. Patients with the scleroderma pattern exhibited elevated serum creatine kinase levels more frequently and increased visual analogue scale of muscle disease activity. Scores of loss of capillaries were associated with muscle and global disease activity, whereas scores of haemorrhages were associated with skin disease activity. However, NVC findings were not significantly associated with lung involvement. The scores of irregularly enlarged capillaries, haemorrhages and loss of capillaries were reduced after stabilization of disease activity by treatment. The mean red blood cell velocity was not significantly reduced in DM patients compared with healthy controls and was not changed by treatment. CONCLUSION: Our results suggest that changes in nail-fold capillaries reflect disease activity in DM. Furthermore, the differences found in red blood cell velocity may reflect somewhat distinct microcirculation injuries in DM and SSc. PMID- 21258054 TI - Carbimazole embryopathy: implications for the choice of antithyroid drugs in pregnancy. AB - Maternal thyrotoxicosis, predominantly secondary to Graves' disease, affects 0.2% of all pregnancies. The Endocrine Society guidelines recommend the use of propylthiouracil as a first-line drug for thyrotoxicosis in pregnancy because of associations between carbimazole or methimazole and congenital anomalies. However, recent studies have highlighted the risk of severe liver injury with propylthiouracil. Here, we report another case with multiple congenital anomalies following in utero exposure to carbimazole and review the literature to consider the risks and benefits of available pharmacological treatments for thyrotoxicosis in pregnancy. PMID- 21258055 TI - Clinical characteristics and outcomes of critically ill cancer patients with septic shock. AB - OBJECTIVE: To evaluate the clinical characteristics and outcomes of critically ill cancer patients with septic shock. DESIGN: Prospective, observational cohort study. METHODS: Medical-surgical intensive care unit (ICU) at the Instituto Nacional de Cancerologia located in Mexico City from January 2008 to February 2010. There were no interventions. Eighty-two consecutive cancer patients with septic shock aged over 18 years were prospectively included and evaluated. RESULTS: During the study period, 620 critically ill cancer patients were admitted to ICU. Ninety-four patients were evaluated for septic shock at the request of ward onco-hematologists or surgeon oncologist responsible for the patient. After being evaluated by the intensivists, 82 patients were admitted to the ICU. Of the 82 patients, 56 (68.3%) had solid tumours and 26 (31.7%) had hematological malignancy. The most frequent sites of infection were: abdominal (57.3%) and respiratory (35.8%). Cultures were positive in 41 (50%) patients. The 63.4% of the patients had three or more organ dysfunctions on the day of their admission to the ICU. Cox multivariate analysis identified the Sequential Organ Failure Assessment (SOFA) score [hazard ratio (HR): 1.11; 95% confidence interval (95% CI): 1.02-1.19, P=0.008) and performance status (PS)>=2 (HR: 1.84; 95% CI: 1.03-3.29, P=0.040) as independent predictors of death to 3 months. The ICU mortality rate was 41.5% (95% CI: 31-52%). CONCLUSION: The variables associated with increased mortality were the degree of organ dysfunction determined by SOFA score at ICU admission and PS>=2. PMID- 21258056 TI - Rituximab in anti-glomerular basement membrane disease. PMID- 21258057 TI - Ruptured sinus of valsalva masquerading as infective endocarditis: importance of imaging with transoesophageal echocardiography. PMID- 21258058 TI - Bisphosphonates for post-menopausal osteoporosis: are they all the same? AB - The primary goal of treatment for post-menopausal osteoporosis (PMO) is reduction in fracture risk. Therefore, clinicians must recommend therapies that are safe and have proven anti-fracture efficacy. Bisphosphonates have long been established as first-line therapy for osteoporosis and several of these drugs significantly reduce osteoporotic fracture risk. However, choosing among different bisphosphonates can represent a difficult clinical decision. This review outlines the pharmacology of various bisphosphonates, discusses how their pharmacological characteristics affect their efficacy, and summarizes clinical safety and efficacy data. Clinical trial data and the opinions of expert bodies suggest that alendronate, risedronate, ibandronate and zoledronic acid all provide fracture protection for patients with PMO. However, there are differences among these agents. For example, all four agents have demonstrated efficacy in preventing vertebral fractures, but only zoledronic acid and risedronate significantly reduce non-vertebral fracture risk in pivotal trials. Moreover, reduction in hip fracture risk has only been established for alendronate, risedronate and zoledronic acid. Current data suggest that ibandronate and zoledronic acid have the most persistent antifracture effect. Bisphosphonates have been associated with a number of side effects, the evidence for which is summarized in this review. The most pertinent of these when choosing a bisphosphonate for a particular patient are the well-documented associations between gastrointestinal adverse events and oral administration, and between acute phase reactions and intravenous administration. Ultimately, selection of a specific bisphosphonate for treatment of PMO should be based on efficacy, risk profile, cost-effectiveness and patient preference. PMID- 21258059 TI - The changing pattern of referral in acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) is not only managed by nephrologists, but also by several other subspecialists. The referral rate to nephrologists and the factors influencing it are unknown. AIMS: To determine the referral rate, factors affecting referral and outcomes across the spectrum of AKI in a population based study. METHODS: We identified all patients with serum creatinine concentrations >=150 umol/l (male) or >=130 umol/l (female) over a 6-month period. AKI was defined according to the RIFLE classification (risk, injury, failure, loss, end stage renal disease [ESRD]). Clinical information and outcomes were obtained from each patient's case records. RESULTS: A total of 562 patients were identified as having AKI (incidence 2147 per million population/year [pmp/y]). One hundred and sixty-four patients (29%) were referred to nephrologists-referral rate 627 pmp/y. Forty-nine percent of patients whose serum creatinine rose to >300 umol/l were referred compared with 22% in our previous study of 1997. Forty-eight patients required renal replacement therapy-incidence 184 pmp/y in comparison to 50 pmp/y in our previous study of 1997. Patients had higher odds of referral if they were male, of younger age and were in the F category of the RIFLE classification. Patients had lower odds of referral if they had multiple co-morbid conditions or if they were managed in a hospital without a nephrology service. CONCLUSION: There has been a significant rise in the referral rate of patients with AKI to nephrologists but even during our period of study only one-third of such patients were being referred. With rising incidence and increased awareness, the referral rate will certainly rise putting a significant burden on the nephrology services. PMID- 21258060 TI - WIST: toolkit for rapid, customized LIMS development. AB - Workflow Information Storage Toolkit (WIST) is a set of application programming interfaces and web applications that allow for the rapid development of customized laboratory information management systems (LIMS). WIST provides common LIMS input components, and allows them to be arranged and configured using a flexible language that specifies each component's visual and semantic characteristics. WIST includes a complete set of web applications for adding, editing and viewing data, as well as a powerful setup tool that can build new LIMS modules by analyzing existing database schema. AVAILABILITY AND IMPLEMENTATION: WIST is implemented in Perl and may be obtained from http://vimss.sf.net under the BSD license. PMID- 21258061 TI - Recovering key biological constituents through sparse representation of gene expression. AB - MOTIVATION: Large-scale RNA expression measurements are generating enormous quantities of data. During the last two decades, many methods were developed for extracting insights regarding the interrelationships between genes from such data. The mathematical and computational perspectives that underlie these methods are usually algebraic or probabilistic. RESULTS: Here, we introduce an unexplored geometric view point where expression levels of genes in multiple experiments are interpreted as vectors in a high-dimensional space. Specifically, we find, for the expression profile of each particular gene, its approximation as a linear combination of profiles of a few other genes. This method is inspired by recent developments in the realm of compressed sensing in the machine learning domain. To demonstrate the power of our approach in extracting valuable information from the expression data, we independently applied it to large-scale experiments carried out on the yeast and malaria parasite whole transcriptomes. The parameters extracted from the sparse reconstruction of the expression profiles, when fed to a supervised learning platform, were used to successfully predict the relationships between genes throughout the Gene Ontology hierarchy and protein protein interaction map. Extensive assessment of the biological results shows high accuracy in both recovering known predictions and in yielding accurate predictions missing from the current databases. We suggest that the geometrical approach presented here is suitable for a broad range of high-dimensional experimental data. PMID- 21258062 TI - HTSanalyzeR: an R/Bioconductor package for integrated network analysis of high throughput screens. AB - MOTIVATION: High-throughput screens (HTS) by RNAi or small molecules are among the most promising tools in functional genomics. They enable researchers to observe detailed reactions to experimental perturbations on a genome-wide scale. While there is a core set of computational approaches used in many publications to analyze these data, a specialized software combining them and making them easily accessible has so far been missing. RESULTS: Here we describe HTSanalyzeR, a flexible software to build integrated analysis pipelines for HTS data that contains over-representation analysis, gene set enrichment analysis, comparative gene set analysis and rich sub-network identification. HTSanalyzeR interfaces with commonly used pre-processing packages for HTS data and presents its results as HTML pages and network plots. AVAILABILITY: Our software is written in the R language and freely available via the Bioconductor project at http://www.bioconductor.org. PMID- 21258063 TI - Automated validation of genetic variants from large databases: ensuring that variant references refer to the same genomic locations. AB - SUMMARY: Accurate annotations of genomic variants are necessary to achieve full genome clinical interpretations that are scientifically sound and medically relevant. Many disease associations, especially those reported before the completion of the HGP, are limited in applicability because of potential inconsistencies with our current standards for genomic coordinates, nomenclature and gene structure. In an effort to validate and link variants from the medical genetics literature to an unambiguous reference for each variant, we developed a software pipeline and reviewed 68 641 single amino acid mutations from Online Mendelian Inheritance in Man (OMIM), Human Gene Mutation Database (HGMD) and dbSNP. The frequency of unresolved mutation annotations varied widely among the databases, ranging from 4 to 23%. A taxonomy of primary causes for unresolved mutations was produced. AVAILABILITY: This program is freely available from the web site (http://safegene.hms.harvard.edu/aa2nt/). PMID- 21258064 TI - Computational inference of grammars for larger-than-gene structures from annotated gene sequences. AB - MOTIVATION: Larger than gene structures (LGS) are DNA segments that include at least one gene and often other segments such as inverted repeats and gene promoters. Mobile genetic elements (MGE) such as integrons are LGS that play an important role in horizontal gene transfer, primarily in Gram-negative organisms. Known LGS have a profound effect on organism virulence, antibiotic resistance and other properties of the organism due to the number of genes involved. Expert compiled grammars have been shown to be an effective computational representation of LGS, well suited to automating annotation, and supporting de novo gene discovery. However, development of LGS grammars by experts is labour intensive and restricted to known LGS. OBJECTIVES: This study uses computational grammar inference methods to automate LGS discovery. We compare the ability of six algorithms to infer LGS grammars from DNA sequences annotated with genes and other short sequences. We compared the predictive power of learned grammars against an expert-developed grammar for gene cassette arrays found in Class 1, 2 and 3 integrons, which are modular LGS containing up to 9 of about 240 cassette types. RESULTS: Using a Bayesian generalization algorithm our inferred grammar was able to predict > 95% of MGE structures in a corpus of 1760 sequences obtained from Genbank (F-score 75%). Even with 100% noise added to the training and test sets, we obtained an F-score of 68%, indicating that the method is robust and has the potential to predict de novo LGS structures when the underlying gene features are known. AVAILABILITY: http://www2.chi.unsw.edu.au/attacca. PMID- 21258065 TI - Computational refinement of post-translational modifications predicted from tandem mass spectrometry. AB - MOTIVATION: A post-translational modification (PTM) is a chemical modification of a protein that occurs naturally. Many of these modifications, such as phosphorylation, are known to play pivotal roles in the regulation of protein function. Henceforth, PTM perturbations have been linked to diverse diseases like Parkinson's, Alzheimer's, diabetes and cancer. To discover PTMs on a genome-wide scale, there is a recent surge of interest in analyzing tandem mass spectrometry data, and several unrestrictive (so-called 'blind') PTM search methods have been reported. However, these approaches are subject to noise in mass measurements and in the predicted modification site (amino acid position) within peptides, which can result in false PTM assignments. RESULTS: To address these issues, we devised a machine learning algorithm, PTMClust, that can be applied to the output of blind PTM search methods to improve prediction quality, by suppressing noise in the data and clustering peptides with the same underlying modification to form PTM groups. We show that our technique outperforms two standard clustering algorithms on a simulated dataset. Additionally, we show that our algorithm significantly improves sensitivity and specificity when applied to the output of three different blind PTM search engines, SIMS, InsPecT and MODmap. Additionally, PTMClust markedly outperforms another PTM refinement algorithm, PTMFinder. We demonstrate that our technique is able to reduce false PTM assignments, improve overall detection coverage and facilitate novel PTM discovery, including terminus modifications. We applied our technique to a large-scale yeast MS/MS proteome profiling dataset and found numerous known and novel PTMs. Accurately identifying modifications in protein sequences is a critical first step for PTM profiling, and thus our approach may benefit routine proteomic analysis. AVAILABILITY: Our algorithm is implemented in Matlab and is freely available for academic use. The software is available online from http://genes.toronto.edu. PMID- 21258067 TI - Discovery of genome-wide DNA polymorphisms in a landrace cultivar of Japonica rice by whole-genome sequencing. AB - Molecular breeding approaches are of growing importance to crop improvement. However, closely related cultivars generally used for crossing material lack sufficient known DNA polymorphisms due to their genetic relatedness. Next generation sequencing allows the identification of a massive number of DNA polymorphisms such as single nucleotide polymorphisms (SNPs) and insertions deletions (InDels) between highly homologous genomes. Using this technology, we performed whole-genome sequencing of a landrace of japonica rice, Omachi, which is used for sake brewing and is an important source for modern cultivars. A total of 229 million reads, each comprising 75 nucleotides of the Omachi genome, was generated with 45-fold coverage and uniquely mapped to 89.7% of the Nipponbare genome, a closely related cultivar. We identified 132,462 SNPs, 16,448 insertions and 19,318 deletions between the Omachi and Nipponbare genomes. An SNP array was designed to validate 731 selected SNPs, resulting in validation rates of 95 and 88% for the Omachi and Nipponbare genomes, respectively. Among the 577 SNPs validated in both genomes, 532 are entirely new SNP markers not previously reported between related rice cultivars. We also validated InDels on a part of chromosome 2 as DNA markers and successfully genotyped five japonica rice cultivars. Our results present the methodology and extensive data on SNPs and InDels available for whole-genome genotyping and marker-assisted breeding. The polymorphism information between Omachi and Nipponbare is available at NGRC_Rice_Omachi (http://www.nodai-genome.org/oryza_sativa_en.html). PMID- 21258068 TI - Conformational analysis of human serum albumin and its non-enzymatic glycation products using monoclonal antibodies. AB - Monoclonal antibodies (mAbs) were prepared to analyse the conformation of human serum albumin (HSA) and its non-enzymatic glycation (NEG) products. We first determined the epitopes of the mAbs using HSA subdomains expressed on the surface of yeast. Each mAb was classified as belonging to one of two groups; Type I mAbs which recognized a single subdomain structure and Type II mAbs which bound to plural subdomains. We analysed the pH-dependent conformational change in HSA. We found that one Type II mAb, HAy2, detected the normal to base form (N-B) transition while the other did not, suggesting that N-B transition occurred around Domain I accompanied by topological isomerization of subdomains without changing the subdomain structure itself. Next, we analysed the conformations of the NEG products. Since all mAbs reacted with the early NEG products, no structural change was thought to have occurred in the early NEG products. On the other hand, only a Type I mAb, HAy1, had full binding activity with the advanced glycation end products (AGE) while the other mAbs had lost or had diminished activity, suggesting that the over-all tertiary structure of HSA was altered except for a subdomain, sDOM Ia, in AGE. PMID- 21258066 TI - TOMATOMA: a novel tomato mutant database distributing Micro-Tom mutant collections. AB - The tomato is an excellent model for studies of plants bearing berry-type fruits and for experimental studies of the Solanaceae family of plants due to its conserved genetic organization. In this study, a comprehensive mutant tomato population was generated in the background of Micro-Tom, a dwarf, rapid-growth variety. In this and previous studies, a family including 8,598 and 6,422 M(2) mutagenized lines was produced by ethylmethane sulfonate (EMS) mutagenesis and gamma-ray irradiation, and this study developed and investigated these M(2) plants for alteration of visible phenotypes. A total of 9,183 independent M(2) families comprising 91,830 M(2) plants were inspected for phenotypic alteration, and 1,048 individual mutants were isolated. Subsequently, the observed mutant phenotypes were classified into 15 major categories and 48 subcategories. Overall, 1,819 phenotypic categories were found in 1,048 mutants. Of these mutants, 549 were pleiotropic, whereas 499 were non-pleiotropic. Multiple different mutant alleles per locus were found in the mutant libraries, suggesting that the mutagenized populations were nearly saturated. Additionally, genetic analysis of backcrosses indicated the successful inheritance of the mutations in BC(1)F(2) populations, confirming the reproducibility in the morphological phenotyping of the M(2) plants. To integrate and manage the visible phenotypes of mutants and other associated data, we developed the in silico database TOMATOMA, a relational system interfacing modules between mutant line names and phenotypic categories. TOMATOMA is a freely accessible database, and these mutant recourses are available through the TOMATOMA (http://tomatoma.nbrp.jp/index.jsp). PMID- 21258069 TI - Conformation of the calmodulin-binding domain of metabotropic glutamate receptor subtype 7 and its interaction with calmodulin. AB - Calmodulin (CaM), a Ca(2+)-binding protein, is a well-known regulator of various cellular functions. One of the targets of CaM is metabotropic glutamate receptor 7 (mGluR7), which serves as a low-pass filter for glutamate in the pre-synaptic terminal to regulate neurotransmission. Surface plasmon resonance (SPR), circular dichroism (CD) spectroscopy and nuclear magnetic spectroscopy (NMR) were performed to study the structure of the peptides corresponding to the CaM-binding domain of mGluR7 and their interaction with CaM. Unlike well-known CaM-binding peptides, mGluR7 has a random coil structure even in the presence of trifluoroethanol. Moreover, NMR data suggested that the complex between Ca(2+)/CaM and the mGluR7 peptide has multiple conformations. The mGluR7 peptide has been found to interact with CaM even in the absence of Ca(2+), and the binding is directed toward the C-domain of apo-CaM rather than the N-domain. We propose a possible mechanism for the activation of mGluR7 by CaM. A pre-binding occurs between apo-CaM and mGluR7 in the resting state of cells. Then, the Ca(2+)/CaM-mGluR7 complex is formed once Ca(2+) influx occurs. The weak interaction at lower Ca(2+) concentrations is likely to bind CaM to mGluR7 for the fast complex formation in response to the elevation of Ca(2+) concentration. PMID- 21258070 TI - Biochemical properties of Caenorhabditis elegans HMG-5, a regulator of mitochondrial DNA. AB - Caenorhabditis elegans HMG-5, which is encoded by F45E4.9, contains two high mobility group (HMG) box domains and shows sequence similarity with mammalian mitochondrial transcription factor A (TFAM). In this study, using soaking RNA interference, we found that knockdown of HMG-5 reduced the amount of mtDNA in P0 hermaphrodites, suggesting it as functional orthologue of mammalian TFAM. We also examined the biochemical property of HMG-5 in mammalian cells and in vitro. We found that HMG-5 localized to the mitochondria in human cultured cells and was included in the NP-40-insoluble fraction in which mtDNA and TFAM were enriched. By immunoprecipitation analysis, HMG-5 was found to associate with human mitochondrial DNA (mtDNA) in the cells. In vitro binding experiment also showed that HMG-5 binds to C. elegans mtDNA and plasmid DNA, indicating its feature as a non-specific DNA-binding protein. Furthermore, it was found that HMG-5 can interact with itself. These results demonstrate that HMG5 shares similar biochemical properties with mammalian TFAM as a nucleoid factor. HMG-5 could be a good candidate for investigating mtDNA metabolism in multicellular organisms. PMID- 21258071 TI - Structural basis of species differences between human and experimental animal CYP1A1s in metabolism of 3,3',4,4',5-pentachlorobiphenyl. AB - Coplanar polychlorinated biphenyls included in dioxin-like compounds are bio accumulated and adversely affect wildlife and human health. Although many researchers have studied the metabolism of PCBs, there have been few reports of the in vitro metabolism of 3,3',4,4',5-pentachlorobiphenyl (PCB126), despite the fact that it has the highest toxicity among PCB congeners. Cytochrome P450 (CYP) 1A1 proteins can metabolize some dioxins and PCBs by hydroxylation, but the activities of human and rat CYP1A1 proteins are very different. The mechanism remains unclear. From our results, rat CYP1A1 metabolized PCB126 into 4-OH 3,3',4',5-tetrachlorobiphenyl and 4-OH-3,3',4',5,5'-pentachlorobiphenyl, but human CYP1A1 did not metabolize. Homology models of the two CYP proteins, and docking studies, showed that differences in the amino acid residues forming their substrate-binding cavities led to differences in the size and shape of the cavities; only the cavity of rat CYP1A1 allowed PCB126 close enough to the haem to be metabolized. Comparison of the amino acid residues of other mammalian CYP1A1 proteins suggested that rats have a unique metabolism of xenobiotics. Our results suggest that it is necessary to be careful in human extrapolation of toxicity data estimated by using the rat as an experimental animal, especially in the case of compounds metabolized by CYP1A1. PMID- 21258072 TI - h-Indices in a university department of anaesthesia: an evaluation of their feasibility, reliability, and validity as an assessment of academic performance. AB - BACKGROUND: The h-index is a tool that is increasingly used to measure individual research productivity. It is unknown whether its use as an evaluation of individual research impact is reliable and valid within the context of anaesthesia. METHODS: We calculated the h-indices of 268 faculty members of a university department of anaesthesia using ScopusTM and Web of Science((r)). Agreement between the databases was investigated with a Bland-Altman plot. The construct validity was examined by comparing the h-indices for faculty grouped by academic rank. RESULTS: The mean bias between the ScopusTM and Web of Science((r)) h-indices was 0.09 but 1.96 sd limits of agreement were -5.7 to 5.9. The Web of Science((r))-derived h-indices showed a statistically significant difference between the different academic ranks (P<0.001): median h-indices were 0 for lecturers, 2 for assistant professors, 9 for associate professors, and 16 for full professors. The ScopusTM-derived h-indices also showed a statistically significant difference between the different academic ranks (P<0.001): median h indices were 0 for lecturers, 1 for assistant professors, 9 for associate professors, and 17 for full professors. Post hoc testing found statistically significant differences in all comparisons between academic ranks (all P<0.01). Ignoring self-citations did not affect construct validity of the h-index. We found no evidence that the h-index is superior to counting the total number of publications. CONCLUSIONS: Agreement between the two databases was problematic. There was evidence of construct validity; however, the overlap between academic ranks limits the discriminative power of a low h-index. PMID- 21258073 TI - Peripheral venous pressure as an alternative to central venous pressure in patients undergoing laparoscopic colorectal surgery. AB - BACKGROUND: Peripheral venous pressure (PVP) is strongly correlated with central venous pressure (CVP) during various surgeries. Laparoscopic surgery in the Trendelenburg position with pneumoperitoneum typically increases CVP. To determine whether PVP convincingly reflects changes in CVP, we evaluated the correlation between PVP and CVP in patients undergoing laparoscopic colorectal surgery. METHODS: Both CVP and PVP were measured simultaneously at predetermined time intervals during elective laparoscopic colorectal surgery in 42 patients without cardiac disease. The pairs of venous pressure measurements were analysed for correlation, and the Bland-Altman plots of repeated measures were used to evaluate the agreement between CVP and PVP. RESULTS: A total of 420 data pairs were obtained. The overall mean CVP was 11.3 (sd 4.5) mm Hg, which was significantly lower than the measured PVP of mean 12.1 (4.5) mm Hg (P=0.005). There was a strong positive correlation between overall CVP and PVP (correlation coefficient=0.96, P<0.0001). The mean bias (PVP-CVP) corrected for repeated measurements using random-effects modelling was 0.9 mm Hg [95% confidence interval (CI) 0.54-1.19 mm Hg] with 95% limits of agreement of -1.2 mm Hg (95% CI -1.75 to -0.62 mm Hg) to 2.9 mm Hg (95% CI 2.35-3.48 mm Hg). CONCLUSIONS: PVP displays a strong correlation and agreement with CVP under the increased intrathoracic pressure of pneumoperitoneum in the Trendelenburg position and may be used as an alternative to CVP in patients without cardiac disease undergoing laparoscopic colorectal surgery. PMID- 21258074 TI - Does an objective system-based approach improve assessment of perioperative risk in children? A preliminary evaluation of the 'NARCO'. AB - BACKGROUND: This study evaluated whether an objective tool would provide a more reliable and valid assessment of perioperative risk compared with the ASA physical status (ASA-PS) in children. METHODS: A system-based risk assessment tool was developed using these categories: Neurological, Airway, Respiratory, Cardiovascular, and Other (NARCO) with a subcomponent grading surgical severity (SS). Anaesthesiologists reviewed the preoperative assessments and assigned NARCO, SS, and ASA-PS scores independently. Perioperative outcomes were recorded by trained observers. Validity and reliability of the tools were evaluated. RESULTS: NARCO correlated with ASA-PS (rho=0.664; P<0.01) supporting its criterion validity. Inter-rater reliability of the measures was supported (intraclass correlation coefficients 0.71-0.96; kappa 0.43-0.87) except for the Airway category. Measures of exact agreement were slightly better for NARCO compared with ASA-PS. NARCO, SS, and ASA-PS scores correlated significantly with perioperative escalation of care, adverse events (AE), hospital length of stay, and admission status. Correlations between NARCO and ASA-PS and outcomes improved when SS was factored into their coding. There were significant, but low, correlations between all measures and mortality. The odds of having escalation of care, AE, and mortality were 5-47 times greater among children with higher risk scores. CONCLUSIONS: Findings suggest that all measures of outcome have acceptable to excellent reliability with a slight improvement in agreement for the NARCO compared with the ASA-PS. This study supports the validity of both the NARCO and the ASA-PS in predicting perioperative risk in children with a slight improvement in correlations when combined with the SS score. PMID- 21258075 TI - Preoperative levosimendan infusion in combined aortic valve and coronary bypass surgery. AB - BACKGROUND: Cardiopulmonary bypass may have detrimental effects on intestinal function and decrease the concentrations of the active, long-acting metabolites of levosimendan, an inodilator used to improve cardiac function. The aim of this study was to evaluate the haemodynamic effects of preoperative levosimendan in patients undergoing high-risk cardiac surgery. METHODS: Twenty-four patients were randomized to receive levosimendan (12 ug bolus followed by an infusion of 0.2 ug kg(-1) min(-1)) or a placebo 24 h before surgery. The inclusion criteria were left ventricular ejection fraction (LVEF) <50% or LV hypertrophy indicated by a wall thickness of >12 mm. Haemodynamics were recorded every hour for 24 h (pulmonary artery catheter) and daily until postoperative day 4 (whole-body impedance cardiography). Doppler echocardiography with tissue Doppler imaging was used to assess systolic and diastolic cardiac function. RESULTS: The cardiac index (CI) and stroke volume index (SI) were higher in the levosimendan group (LG) for the 4 day postoperative period (P<0.05); on the fourth postoperative day, the CI was 3.0 litre m(-2) min(-1) in the LG compared with 2.4 litre m(-2) min(-1) in the control group (CG) and the SI was 30 vs 25 ml m(-2), respectively. The LVEF measured at baseline and on the fourth postoperative morning decreased in the CG, but was maintained in the LG. CONCLUSIONS: Levosimendan improved haemodynamics compared with a placebo in patients undergoing high-risk cardiac surgery. The concentrations of levosimendan's metabolites were higher compared with earlier studies using perioperative dosing. PMID- 21258076 TI - Texture analysis of liver fibrosis microscopic images: a study on the effect of biomarkers. AB - Chronic hepatic injury results in liver fibrosis with eventual progression to irreversible cirrhosis. Liver fibrogenesis involves the activation of the quiescent hepatic stellate cell into an activated myofibroblast that is characterized by alpha-smooth muscle actin (alpha-SMA) expression and the production of collagens (types I and III). In the present study, rats were randomly divided into three groups: (i) control group, where rats were only treated with a vehicle; (ii) fibrosis group, where rats were treated with carbon tetrachloride (CCl(4)) to induce liver fibrosis; and (iii) silymarin group, where rats were protected with silymarin during CCl(4) treatment. Rats were sacrificed and sections of liver tissue were counterstained with hematoxylin and eosin and Masson's trichrome. Other sections were immunostained using collagens and alpha SMA primary antibodies. Fibrosis was confirmed using serum marker measurements. Microscopic images of the stained sections were acquired and digitized. The Biomarker Index of Fibrosis (BIF) was calculated from the images by quantifying the percentage of stained fibers. Statistical methods of texture analysis (TA), namely co-occurrence and run-length matrices, were applied on the digital images followed by classification using agglomerative hierarchical clustering and linear discriminant analysis with cross validation. TA applied on different biomarkers was successful in discriminating between the groups, showing 100% sensitivity and specificity for classification between the control and fibrosis groups using any biomarker. Some classification attempts showed dependence on the biomarker used, especially for classification between the silymarin and fibrosis groups, which showed optimal results using Masson's trichrome. TA results were consistent with both BIF and serum marker measurements. PMID- 21258077 TI - 24-Hour intraocular pressure phasing remains an important tool in glaucoma diagnostics. PMID- 21258078 TI - Anatomical utility of ultrasound biomicroscopy in the lacrimal drainage system. AB - BACKGROUND: Ultrasound biomicroscopy (UBM) is a safe and non-invasive auxiliary diagnostic tool. UBM evaluation of the lacrimal drainage system (LDS) can be limited by obstacles, such as keratinised epithelium of the skin coverage and difficulty with positioning the eye cup, owing to irregularities of the medial canthus area wherein the LDS is located. AIM: To evaluate LDS in normal individuals and in different pathological conditions using UBM. METHODS: UBM evaluation was carried out using a modified technique using swimming goggles with the front eye piece removed as an adjunctive device to overcome the difficulties of UBM evaluation of LDS. RESULTS: A total of 24 normal LDS were evaluated in 12 volunteers with an age range of 14 to 54 years (mean 31.17 +/- 14.09). The lacrimal sac (LS) longitudinal diameter was always greater than the screen limits (>= 15 mm), and the width varied from 1.87 mm to 3.36 mm (mean 2.56 +/- 0.43). Horizontal scanning of the LS revealed a mean cross-sectional area of 5.74 (+/- 2.61) mm2. The cross-section diameter of the canaliculi varied from 0.52 mm to 0.88 mm. LDS was also evaluated with UBM for the following disorders: chronic dacryocystitis, LS fistula, mucocoele, dacryolith, LDS with silicon tube, congenital and acquired canalicular obstruction, punctal plugs, Down's syndrome and Sjogren syndrome after permanent punctal occlusion. CONCLUSIONS: UBM is a valuable tool in the assessment of both normal and diseased LDS. It is a valuable tool in the evaluation of LDS distal to the site of complete obstruction. PMID- 21258079 TI - Thyroxin substitution and open-angle glaucoma: a nationwide register-based study on filled prescriptions. PMID- 21258080 TI - Persistence of glaucoma medical therapy in the Glasgow Glaucoma Database. AB - AIMS: To report the persistence of glaucoma medical therapy in a database of 1006 patients with ocular hypertension (OHT), normal tension glaucoma (NTG) and primary open-angle glaucoma (POAG) attending the Glaucoma Clinic at Glasgow Royal Infirmary, Glasgow, UK. METHOD: Analyses have been carried out using specially written queries to generate reports relating to initial treatment choice and persistence for individual drugs. Queries were investigated in the database time period from 16 February 1982 to 11 February 2009. When investigating drug persistence, the results from the database were split into two distinct time periods from 1997 to 2001 and from 2002 to 2009 to reflect the available treatment options used. RESULTS: The number of patients with each diagnosis was as follows: POAG 608; OHT 246; NTG 152. The Kaplan-Meier estimate for mean persistence from 1997 to 2001 (time to treatment discontinuation) of latanoprost was 58.8 +/- 1.95 months, timolol was 41.8 +/- 3.94 months, brimonidine was 24.1 +/- 3.05 months, and betaxolol was 22.9 +/- 2.04 months. The Kaplan-Meier estimate for mean persistence from 2002 to 2009 of latanoprost (time to treatment discontinuation) was 52.0 +/- 2.26 months, bimatoprost was 25.8 +/- 2.89 months, and travoprost was 23.0 +/- 1.27 months. The Kaplan-Meier estimate for mean persistence of latanoprost (time to treatment change) was 37.5 +/- 2.47 months, travoprost was 30.2 +/- 2.70 months, and bimatoprost was 17.5 +/- 2.88 months. CONCLUSION: The introduction of the first prostaglandin analogue, latanoprost, dramatically improved treatment persistence for glaucoma patients. In the current prostaglandin-rich treatment environment, these data do not show any significant differences between prostaglandins with respect to treatment persistence. PMID- 21258081 TI - Patients experience different types of visual sensations during cataract surgery. PMID- 21258083 TI - A phase II study of neoadjuvant and adjuvant chemotherapy with 5 fluorodeoxyuridine, leucovorin, oxaliplatin and docetaxel in the treatment of previously untreated advanced esophageal adenocarcinoma. AB - OBJECTIVE: A complete pathologic response to neoadjuvant chemotherapy, without the use of radiation, has infrequently been reported in operable chemo-naive stage III esophageal adenocarcinoma patients. METHODS: Twenty-nine eligible patients were enrolled in the study. Neoadjuvant therapy consisted of 5 fluorodeoxyuridine, leucovorin, oxaliplatin and docetaxel and was administered in two 4-week cycles. Following therapy, patients underwent surgical resection. Those patients having residual disease were offered adjuvant chemotherapy. Patients having a complete pathologic response were not offered any further chemotherapy. RESULTS: Twenty-four out of 29 patients finished neoadjuvant therapy and underwent curative esophagectomy. Two patients were declared inoperable after treatment, and three patients died prior to surgery. The median follow-up on all patients was 20.2 months. Median progression-free survival and median overall survival were 13.6 and 21.4 months, respectively. Clinical response to neoadjuvant chemotherapy was seen in 21 out of 29 patients (72.4%). Complete pathologic response with neoadjuvant chemotherapy was seen in 4 out of 24 patients (16.7%). Those four patients have been alive and progression-free for 20-37 months. Grade 3-4 toxicities occurred in 16 of the 29 patients during neoadjuvant therapy. Grade 3-4 toxicities were seen in 6 out of 14 patients during adjuvant therapy. (18)F-fluorodeoxyglucose-positron emission tomography standardized uptake values of >=8 correlated with better progression-free survival. CONCLUSION: 5-Fluorodeoxyuridine, leucovorin, oxaliplatin and docetaxel regimen is active in patients with esophageal adenocarcinoma. Toxicity profiles are manageable. Neoadjuvant chemotherapy allowed achievement of complete pathologic response without radiation. (18)F-fluorodeoxyglucose-positron emission tomography standardized uptake values might be prognostic. PMID- 21258084 TI - Impact of ischaemia and scar on the therapeutic benefit derived from myocardial revascularization vs. medical therapy among patients undergoing stress-rest myocardial perfusion scintigraphy. AB - AIMS: Although pre-revascularization ischaemia testing is recommended, the interaction between the extent of ischaemia and myocardial scar with performance of revascularization on patient survival is unclear. METHODS AND RESULTS: We identified 13 969 patients who underwent adenosine or exercise stress SPECT myocardial perfusion scintigraphy (MPS). The percent myocardium ischaemic (%I) and fixed (%F) were calculated using 5 point/20-segment MPS scoring. Patients lost to follow-up (2.8%) were excluded leaving 13 555 patients [35% with history (Hx) of known coronary artery disease (CAD), 65% exercise stress, 61% male, age 66 +/- 12]. Follow-up was performed at 12-18 months for early revascularization and at >7 years for all-cause death (ACD) (mean follow-up 8.7 +/- 3.3 years). All cause death was modelled using Cox proportional hazards modelling adjusting for logistic-based propensity scores, MPS, revascularization, and baseline characteristics. During FU, 3893 ACD (29%, 3.3%/year) and 1226 early revascularizations (9.0%) occurred. After risk-adjustment, a three-way interaction was present between %I, early revascularization, and HxCAD, such that %I identified a survival benefit with early revascularization in patients without prior myocardial infarction (MI), whereas no such benefit was present in patients with prior MI (overall model chi(2)= 3932, P < 0.001; interaction P < 0.021). Further modelling revealed that after excluding patients with scar >10% total myocardium, %I identified a survival benefit in all patients. CONCLUSION: In this large observational series with long-term follow-up, patients with significant ischaemia and without extensive scar were likely to realize a survival benefit from early revascularization. In contrast, the survival of patients with minimal ischaemia was superior with medical therapy without early revascularization. PMID- 21258085 TI - Cyclin-G-associated kinase modifies alpha-synuclein expression levels and toxicity in Parkinson's disease: results from the GenePD Study. AB - Although family history is a well-established risk factor for Parkinson's disease (PD), fewer than 5% of PD cases can be attributed to known genetic mutations. The etiology for the remainder of PD cases is unclear; however, neuronal accumulation of the protein alpha-synuclein is common to nearly all patients, implicating pathways that influence alpha-synuclein in PD pathogenesis. We report a genome wide significant association (P = 3.97 * 10(-8)) between a polymorphism, rs1564282, in the cyclin-G-associated kinase (GAK) gene and increased PD risk, with a meta-analysis odds ratio of 1.48. This association result is based on the meta-analysis of three publicly available PD case-control genome-wide association study and genotyping from a new, independent Italian cohort. Microarray expression analysis of post-mortem frontal cortex from PD and control brains demonstrates a significant association between rs1564282 and higher alpha synuclein expression, a known cause of early onset PD. Functional knockdown of GAK in cell culture causes a significant increase in toxicity when alpha synuclein is over-expressed. Furthermore, knockdown of GAK in rat primary neurons expressing the A53T mutation of alpha-synuclein, a well-established model for PD, decreases cell viability. These observations provide evidence that GAK is associated with PD risk and suggest that GAK and alpha-synuclein interact in a pathway involved in PD pathogenesis. The GAK protein, a serine/threonine kinase, belongs to a family of proteins commonly targeted for drug development. This, combined with GAK's observed relationship to the levels of alpha-synuclein expression and toxicity, suggests that the protein is an attractive therapeutic target for the treatment of PD. PMID- 21258086 TI - The FRA2C common fragile site maps to the borders of MYCN amplicons in neuroblastoma and is associated with gross chromosomal rearrangements in different cancers. AB - Common fragile sites (cFS) represent chromosomal regions that are prone to breakage after partial inhibition of DNA synthesis. Activation of cFS is associated with various forms of DNA instability in cancer cells, and is thought to be an initiating event in the generation of DNA damage in early-stage tumorigenesis. Only a few cFS have been fully characterized despite the growing interest in cFS instability in cancer genomes. In this study, six-color fluorescence in situ hybridization revealed that FRA2C consists of two cFS spanning 747 kb FRA2Ctel and 746 kb FRA2Ccen at 2p24.3 and 2p24.2, respectively. Both cFS are separated by a 2.8 Mb non-fragile region containing MYCN. Fine tiling array comparative genomic hybridization of MYCN amplicons from neuroblastoma (NB) cell lines and primary tumors revealed that 56.5% of the amplicons cluster in FRA2C. MYCN amplicons are either organized as double minutes or as homogeneously stained regions in addition to the single copy of MYCN retained at 2p24. We suggest that MYCN amplicons arise from extra replication rounds of unbroken DNA secondary structures that accumulate at FRA2C. This hypothesis implicates cFS in high-level gene amplification in cancer cells. Complex genomic rearrangements, including deletions, duplications and translocations, which originate from double-strand breaks, were detected at FRA2C in different cancers. These data propose a dual role for cFS in the generation of gross chromosomal rearrangements either after DNA breakage or by inducing extra replication rounds, and provide new insights into the highly recombinogenic nature of cFS in the human cancer genome. PMID- 21258087 TI - Increasing prevalence of dementia among very old people. AB - BACKGROUND: it is unknown whether the age-specific prevalence of dementia among the very old changes over time. METHODS: this study compares the prevalence of dementia in two population-based cross-sectional samples of very old people in northern Sweden in 2000-02 and in 2005-07. In total, 430 individuals aged 85 and older (mean age 89.5 years, 71.4% women) were evaluated for dementia in the first cross-section and 465 individuals (mean age 90.2 years, 70.9% women) in the second. Trained assessors performed assessments and interviews during home visits and collected information from carers, relatives and medical records. Dementia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition criteria. RESULTS: the prevalence of dementia in the total sample was 26.5% in 2000-02 and 37.2% in 2005-07 (P = 0.001). There was also an increase in the prescription of different antihypertensive agents, antilipemic agents and choline esterase inhibitors, and more people had had heart surgery in the later sample. CONCLUSIONS: in this sample of very old people, an increase in the age-specific prevalence of dementia was detected over 5 years. Possible reasons for this may be extended survival among individuals with risk factors for dementia and among individuals with established dementia. PMID- 21258088 TI - Assessment of biomarkers of drug-induced kidney injury in cynomolgus monkeys treated with a triple reuptake inhibitor. AB - Drug-induced kidney injury (DIKI) results in attrition during drug development; new DIKI urinary biomarkers offer potential to detect and monitor DIKI progression and regression, but frequently only in rats. The triple reuptake inhibitor (TRI) PRC200-SS represents a new class of antidepressants that elevate synaptic levels of serotonin, norepinephrine, and dopamine and is expected to produce more rapid onset and better antidepressant efficacy than single or dual inhibitors. Although preclinical studies and recent clinical trials lend support to this concept of superior efficacy for TRIs, there is little information on the safety profile of this class of compounds. Using histopathology and DIKI biomarkers, in single- and repeat dose toxicological studies in cynomolgus monkeys, PRC200-SS demonstrated dose-proportional kidney toxicity. Characterization of the histopathological lesions, using a combination of immunohistochemistry (IHC) and urinary biomarker analysis, indicated that the compound is a distal tubule and collecting duct toxicant. Segment specificity for the lesions was shown using a newly developed triple IHC combination method with antibodies against calbindin D28, aquaporin 2, and aquaporin 1. Urinary biomarker analyses, using multiplex immunoassays, confirmed a dose-proportional increase in the excretion of calbindin D28 and clusterin in compound-treated monkeys with levels returning to baseline during the drug-free recovery period. These results constitute the validation of distal nephron DIKI biomarkers in the cynomolgus monkey and demonstrate the utility of calbindin D28 and clusterin to monitor the progression of distal nephron DIKI, representing potential early biomarkers of DIKI for the clinic. PMID- 21258089 TI - KRAS mutation analysis in genomic DNA isolated from formalin-fixed paraffin embedded ovarian tissue: evaluation of a strip-based reverse-hybridisation assay. AB - AIMS: To evaluate a reverse-hybridisation assay (strip assay) designed for the sensitive detection of 10 mutations in codons 12 and 13 of the KRAS gene. The strip assay relies on mutant-enriched PCR followed by reverse-hybridisation of biotinylated amplification products to oligonucleotide probes immobilised as an array of parallel lines on nitrocellulose test strips. METHODS: The strip assay was used to analyse genomic DNA isolated from 120 formalin-fixed paraffin embedded (FFPE) ovarian tissue samples. The samples were analysed in parallel using a biochip-based protocol (biochip assay) covering the same mutation spectrum, and results were compared with respect to sensitivity, specificity and operational input. RESULTS: The strip assay identified 19 (16%) of 120 FFPE samples to carry a KRAS mutation; results were in agreement with those obtained by biochip hybridisation. Both assays had an analytical sensitivity of 1% when performed on FFPE-extracted DNA with approximately the same operational input needed for post-PCR processing. In contrast to the biochip assay, strip assay hybridisation may be automated to a large extent. CONCLUSIONS: The strip assay is an accurate and sensitive tool for the low to medium throughput detection of KRAS mutation in genomic DNA isolated from FFPE tissue. PMID- 21258090 TI - Investigation of the child with an acute metabolic disorder. AB - Inherited biochemical defects may present with acute life-threatening illness with a high mortality and morbidity. Some are treatable and have a good outcome with early appropriate intervention. However, because of their rarity, diagnosis is often delayed; they are not considered or investigated appropriately. This is especially likely in those presenting in previously healthy adults. The collection of acute samples is crucial. There are numerous disorders, and front line tests must cast a wide net. A small core of emergency tests generally indicates which metabolic pathway is defective and provides a working diagnosis and basis for treatment. Later confirmation and identification of the precise defect are essential for long-term management and for genetic counselling and prenatal diagnosis of future pregnancies. An escalating number of specialist tests and mutation analyses are undertaken by metabolic laboratories worldwide, but they are not widely available, are expensive, and must be requested selectively. Guidelines are presented here for the front-line investigation of acutely ill children with hypoglycaemia, metabolic acidosis, encephalopathy and intractable seizures, and for a dying child with a suspected, undiagnosed, inherited metabolic defect. With modification, these are also applicable to adults with a metabolic defect. In order to guide further investigation, selected disorders are described briefly along with their diagnostic work-up. Information about sample collection and processing is provided. PMID- 21258091 TI - Inappropriate calibration and optimisation of pan-keratin (pan-CK) and low molecular weight keratin (LMWCK) immunohistochemistry tests: Canadian Immunohistochemistry Quality Control (CIQC) experience. AB - AIMS: Pan-cytokeratin (pan-CK) and low molecular weight cytokeratin (LMWCK) tests are the most common immunohistochemistry (IHC) tests used to support evidence of epithelial differentiation. Canadian Immunohistochemistry Quality Control (CIQC), a new provider of proficiency testing for Canadian clinical IHC laboratories, has evaluated the performance of Canadian IHC laboratories in two proficiency testing challenges for both pan-CK and LMWCK. METHODS: CIQC has designed a 70-sample tissue microarray (TMA) for challenge 1 and a 30-sample TMA for challenge 2. There were 13 participants in challenge 1, and 62 in challenge 2. All results were evaluated and scored by CIQC assessors and compared with reference laboratory results. RESULTS: Participating laboratories often produced false negative results that ranged from 20% to 80%. False-positive results were also detected. About half of participating clinical laboratories have inappropriately calibrated IHC tests for pan-CK and LMWCK, which are the most commonly used markers for demonstration of epithelial differentiation. The great majority of laboratories were not aware of the problem with calibration of pan-CK and LMWCK tests because of inappropriate selection of external positive controls and samples for optimisation of these tests. Benign liver and kidney are the most important tissues to include as positive controls for both pan-CK and LMWCK. CONCLUSIONS: Participation in external quality assurance is important for peer comparison and proper calibration of IHC tests, which is also helpful for appropriate selection of positive control material and material for optimisation of the tests. PMID- 21258092 TI - Axillary fine needle aspiration cytology for pre-operative staging of patients with screen-detected invasive breast carcinoma. AB - INTRODUCTION: Fine needle aspiration cytology (FNAC) of radiologically abnormal axillary lymph nodes in patients with breast cancer can identify patients suitable for primary axillary clearance (AC) rather than sentinel node biopsy, enabling surgical axillary staging by a single operation. This study assessed the accuracy of FNAC in predicting positive axillary lymph nodes. METHODS: 161 patients with screen-detected invasive carcinoma and who had pre-operative FNAC of a radiologically abnormal axillary lymph node were identified from two screening units, The axillary FNAC reports were correlated with sentinel node biopsy and AC reports, and sensitivity, specificity, positive (PPV) and negative (NPV) predictive values were calculated. RESULTS: FNAC had a moderate sensitivity (66.3%) and NPV (71.8%), and a high specificity (98.7%) and PPV (98.3%). Most patients (86%) had a single axillary operation. The sensitivity was highest in grade 3 (81.8%) and ductal type (77.8%) tumours. The sensitivity was lower in tumours of special type (34.8%), grade 1 tumours (50%) and those without lymphovascular invasion (LVI) (55.9%). The NPV was highest in pT1 (86.7%) and in grade 1 (84.5%) tumours, and lowest (44%) in tumours with LVI. The PPV was 100% in grade 1 and 3 tumours, stage pT2 and pT3 tumours and those without LVI, and was high (>96%) in all other groups. In lymph-node-positive patients, the mean number of lymph nodes involved was higher in the case of a positive (6.4) than negative FNAC (4.4). CONCLUSIONS: FNAC of ultrasonically abnormal axillary lymph nodes achieved surgical staging by a single operation in most patients with screen-detected invasive breast carcinoma, with moderate sensitivity and high specificity. PMID- 21258093 TI - Modulating the processing of emotional stimuli by cognitive demand. AB - Emotional processing is influenced by cognitive processes and vice versa, indicating a profound interaction of these domains. The investigation of the neural mechanisms underlying this interaction is not only highly relevant for understanding the organization of human brain function. Rather, it may also help in understanding dysregulated emotions in affective disorders and in elucidating the neurobiology of cognitive behavioural therapy (e.g. in borderline personality disorder), which aims at modulating dysfunctional emotion processes by cognitive techniques, such as restructuring. In the majority of earlier studies investigating the interaction of emotions and cognition, the main focus has been on the investigation of the effects of emotional stimuli or, more general, emotional processing, e.g. instituted by emotional material that needed to be processed, on cognitive performance and neural activation patterns. Here we pursued the opposite approach and investigated the modulation of implicit processing of emotional stimuli by cognitive demands using an event-related functional magnetic resonance imaging--study on a motor short-term memory paradigm with emotional interferences. Subjects were visually presented a finger sequence consisting either of four (easy condition) or six (difficult condition) items, which they had to memorize. After a short pause positive, negative or neutral International affective picture system pictures or a green dot (as control condition) were presented. Subjects were instructed to reproduce the memorized sequence manually as soon as the picture disappeared. Analysis showed that with increasing cognitive demand (long relative to short sequences), neural responses to emotional pictures were significantly reduced in amygdala and orbitofrontal cortex. In contrast, the more difficult task evoked stronger activation in a widespread frontoparietal network. As stimuli were task-relevant go-cues and hence had to be processed perceptually, we would interpret this as a specific attenuation of affective responses by concurrent cognitive processing- potentially reflecting a relocation of resources mediated by the frontoparietal network. PMID- 21258094 TI - Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. AB - This document updates and expands the initial Infectious Diseases Society of America (IDSA) Fever and Neutropenia Guideline that was published in 1997 and first updated in 2002. It is intended as a guide for the use of antimicrobial agents in managing patients with cancer who experience chemotherapy-induced fever and neutropenia. Recent advances in antimicrobial drug development and technology, clinical trial results, and extensive clinical experience have informed the approaches and recommendations herein. Because the previous iteration of this guideline in 2002, we have a developed a clearer definition of which populations of patients with cancer may benefit most from antibiotic, antifungal, and antiviral prophylaxis. Furthermore, categorizing neutropenic patients as being at high risk or low risk for infection according to presenting signs and symptoms, underlying cancer, type of therapy, and medical comorbidities has become essential to the treatment algorithm. Risk stratification is a recommended starting point for managing patients with fever and neutropenia. In addition, earlier detection of invasive fungal infections has led to debate regarding optimal use of empirical or preemptive antifungal therapy, although algorithms are still evolving. What has not changed is the indication for immediate empirical antibiotic therapy. It remains true that all patients who present with fever and neutropenia should be treated swiftly and broadly with antibiotics to treat both gram-positive and gram-negative pathogens. Finally, we note that all Panel members are from institutions in the United States or Canada; thus, these guidelines were developed in the context of North American practices. Some recommendations may not be as applicable outside of North America, in areas where differences in available antibiotics, in the predominant pathogens, and/or in health care-associated economic conditions exist. Regardless of venue, clinical vigilance and immediate treatment are the universal keys to managing neutropenic patients with fever and/or infection. PMID- 21258095 TI - Interleukin-12 receptor beta1 deficiency predisposing to disseminated Coccidioidomycosis. PMID- 21258098 TI - Increasing rates of gastroenteritis hospital discharges in US adults and the contribution of norovirus, 1996-2007. AB - BACKGROUND: Diarrhea remains an important cause of morbidity, but until the mid 1990s, hospital admissions for diarrhea in the US adult population were declining. We aimed to describe recent trends in gastroenteritis hospitalizations and to determine the contribution of norovirus. METHODS: We analyzed all gastroenteritis-associated hospital discharges during 1996-2007 from a nationally representative data set of hospital inpatient stays. Annual rates of discharges by age were calculated. Time-series regression models were fitted using cause specified discharges as explanatory variables; model residuals were analyzed to estimate norovirus- and rotavirus-associated discharges. We then calculated the annual hospital charges for norovirus-associated discharges. RESULTS: Sixty-nine percent of all gastroenteritis discharges were cause-unspecified and rates increased by >= 50% in all adult and elderly age groups (>= 18 years of age) from 1996 through 2007. We estimate an annual mean of 71,000 norovirus-associated hospitalizations, costing $493 million per year, with surges to nearly 110,000 hospitalizations per year in epidemic seasons. We also estimate 24,000 rotavirus hospitalizations annually among individuals aged >= 5 years. CONCLUSIONS: Gastroenteritis hospitalizations are increasing, and we estimate that norovirus is the cause of 10% of cause-unspecified and 7% of all-cause gastroenteritis discharges. Norovirus should be routinely considered as a cause of gastroenteritis hospitalization. PMID- 21258099 TI - Single nucleotide polymorphisms in TLR9 are highly associated with susceptibility to bacterial meningitis in children. AB - BACKGROUND: Bacterial meningitis (BM) is a severe infection mainly caused by Streptococcus pneumoniae and Neisseria meningitidis (NM). However, genetically determined susceptibility to develop severe infections by these microorganisms is variable between individuals. Toll-like receptor 9 (TLR9) recognizes bacterial DNA leading to intracellular inflammatory signaling. Single nucleotide polymorphisms (SNPs) within the TLR9 gene are associated with susceptibility to several diseases, no such association with meningitis has been described. METHODS: We studied the role of TLR9 SNPs in host defense against BM. Two TLR9 SNPs and 4 TLR9 haplotypes were determined in 472 survivors of BM and compared to 392 healthy controls. RESULTS: Carriage of the TLR9+2848-A mutant was significantly decreased in meningococcal meningitis (MM) patients compared with controls (p: .0098, odds ratio [OR]: .6, 95% confidence interval [CI]: .4-.9). TLR9 haplotype I was associated with an increased susceptibility to MM (p: .0237, OR 1.3, 95% CI: 1.0-1.5). In silico analysis shows a very strong immunoinhibitory potential for DNA of NM upon recognition by TLR9 (CpG index of -106.8). CONCLUSIONS: We report an association of TLR9 SNPs with susceptibility to BM, specifically MM indicating a protective effect for the TLR9+2848-A allele. We hypothesize that the TLR9+2848-A mutant results in an up-regulation of TLR9 induced immune response compensating the strong inhibitory potential of NM CpG DNA. PMID- 21258100 TI - Carbapenem resistance in Klebsiella pneumoniae due to the New Delhi Metallo-beta lactamase. AB - Carbapenem resistance in Klebsiella pneumoniae is most notably due to the K. pneumoniae carbapenemase (KPC) beta-lactamase. In this report, we describe the occurrence of a newly described mechanism of carbapenem resistance, the NDM-1 beta-lactamase, in a patient who received medical attention (but was not hospitalized) in India. PMID- 21258101 TI - New Delhi metallo-beta-lactamase and multidrug resistance: a global SOS? PMID- 21258102 TI - Outbreak of Mycobacterium haemophilum infections after permanent makeup of the eyebrows. AB - We report a Mycobacterium haemophilum outbreak after permanent make-up of the eyebrows performed by the same freelance artist. Twelve patients presented an eyebrow lesion and cervical lymphadenitis. All were treated with antibiotics. Surgery was required in 10 cases. M. haemophilum DNA was identified in the make up ink. PMID- 21258103 TI - Persistent nausea, vomiting, and diarrhea in an immunocompetent elderly man. PMID- 21258104 TI - A research framework for reducing preventable patient harm. AB - Programs to reduce central line-associated bloodstream infections (CLABSIs) have improved the safety of hospitalized patients. Efforts are underway to disseminate these successes broadly to reduce other types of hospital-acquired infectious and noninfectious preventable harms. Unfortunately, the ability to broadly measure and prevent other types of preventable harms, especially infectious harms, needs enhancement. Moreover, an overarching research framework for creating and integrating evidence will help expedite the development of national prevention programs. This article outlines a 5-phase translational (T) framework to develop robust research programs that reduce preventable harm, as follows: phase T0, discover opportunities and approaches to prevent adverse health care events; phase T1, use T0 discoveries to develop and test interventions on a small scale; phase T2, broaden and strengthen the evidence base for promising interventions to develop evidence-based guidelines; phase T3, translate guidelines into clinical practice; and phase T4, implement and evaluate T3 work on a national and international scale. Policy makers should use this framework to fill in the knowledge gaps, coordinate efforts among federal agencies, and prioritize research funding. PMID- 21258107 TI - Quality HIV Care to the End of life. PMID- 21258105 TI - Induction therapy with protease-inhibitors modifies the effect of nevirapine resistance on virologic response to nevirapine-based HAART in children. AB - BACKGROUND: Nevirapine resistance after failed prophylaxis to prevent mother-to child human immunodeficiency virus (HIV) transmission can compromise subsequent nevirapine-based highly active antiretroviral therapy (HAART). METHODS: Nevirapine-exposed children who achieved virologic suppression with lopinavir/ritonavir-based induction HAART before switch to nevirapine-based HAART or who continued the lopinavir/ritonavir regimen were studied. Nevirapine resistant HIV was quantified (>= 1% frequency) in plasma before therapy and archived in peripheral blood mononuclear cells after induction HAART with ultradeep pyrosequencing. The primary endpoint was virologic failure (confirmed viremia >= 1000 copies/mL by 52 weeks) on nevirapine-based HAART, and Receiver operating characteristic analysis identified threshold levels of resistance associated with failure. RESULTS: Nevirapine resistance mutations were detected in plasma at a median frequency of 25.6% in 41 (33%) of 124 children starting HAART at median 9 months of age. After a median nine months of induction HAART, nevirapine-resistant HIV remained archived in cells in 59 (61%) of 96 children (median 13.6% of cells). The threshold frequency of nevirapine resistance in plasma most predictive of virologic failure on nevirapine-based HAART was 25%. Children maintaining resistance before therapy at or above this threshold frequency had a 3.5 fold higher risk of failure (95% confidence interval, 1.1 10.8) than children without detectable plasma resistance. In contrast, virologic failure was not independently associated with age, resistance in plasma below 25% frequencies, or archived in cells. CONCLUSIONS: Virologic suppression with lopinavir/ritonavir-based HAART in nevirapine-exposed children raises the threshold level of resistance at which reuse of nevirapine-based therapy is compromised. Standard genotyping may allow identification of children likely to benefit from an induction-switch approach. PMID- 21258108 TI - Serial acid fast bacilli smear and culture conversion rates over 26 weeks in a cohort of 93 sputum culture-positive tuberculosis (TB). PMID- 21258110 TI - The complexity, relative value, and financial worth of curbside consultations in an academic infectious disease unit. PMID- 21258112 TI - Dual pneumococcal and influenza vaccination: severe concerns about the composition of the control groups. PMID- 21258113 TI - Dual pneumococcal and influenza vaccination in elderly patients with chronic illnesses: protective benefits overestimated? PMID- 21258115 TI - Reduction in disparity for pneumonia hospitalisations between Australian Indigenous and non-Indigenous children. AB - BACKGROUND: In the 1990s pneumonia hospitalisation rates in Western Australia (WA) were 13 times higher in Indigenous children than in non-Indigenous children. Rates of invasive pneumococcal disease in Indigenous children declined following the introduction in 2001 of 7-valent pneumococcal conjugate vaccine (7vPCV) in a 2-4-6 month schedule with an 18-month pneumococcal polysaccharide booster (PPV). We investigated population trends for pneumonia hospitalisations between 1996 and 2005. METHODS: Population-based retrospective data linkage cohort study of singleton live births from 1996-2005. Hospitalisations for acute lower respiratory infections in Indigenous and non-Indigenous children less than 5 years of age were extracted and trends in age-specific incidence rates were examined using log-linear modelling. RESULTS: From 245 249 births (7.1% Indigenous), there were 7727 pneumonia episodes. Between 1996 and 2000 and 2001 and 2005 all-cause pneumonia hospitalisations fell by 28-44% in Indigenous children aged 6-35 months with no equivalent decline in non-Indigenous children or for other acute lower respiratory infections. Incidence rate ratios for pneumonia comparing Indigenous with non-Indigenous children aged 6-11 months fell from 14.6 (95% CI 12.3 to 17.2) in 1996-2000 to 9.9 (8.4 to 11.6) in 2001-2005. Log-linear modelling showed a steady decline in Indigenous children of 9%/annum (5-12%) at age 12-23 months for all-cause pneumonia and 37%/annum (20-50%) at age 6-11 months for pneumococcal pneumonia from 1996 to 2005, including the years prior to introduction of pneumococcal vaccines. CONCLUSIONS: Pneumonia hospitalisations and the disparity between Indigenous and non-Indigenous children has declined by a third. The unique Australian pneumococcal vaccine programme is likely to have had a significant effect but changes in socioeconomic factors have also contributed to the declines. PMID- 21258116 TI - Cell phone use and behavioural problems: indications of unobserved heterogeneity in Divan et al's study. PMID- 21258117 TI - New year resolutions. PMID- 21258118 TI - Metabolic modulation in heart failure: high time for a definitive clinical trial. PMID- 21258119 TI - Current applications and limitations of coronary computed tomography angiography in stable coronary artery disease. PMID- 21258120 TI - A single level of plasma troponin-I predicts left ventricular remodelling after primary angioplasty. PMID- 21258121 TI - Clinical applications of two-dimensional speckle tracking. PMID- 21258123 TI - Unification of the copper(I) binding affinities of the metallo-chaperones Atx1, Atox1, and related proteins: detection probes and affinity standards. AB - Literature estimates of metal-protein affinities are widely scattered for many systems, as highlighted by the class of metallo-chaperone proteins, which includes human Atox1. The discrepancies may be attributed to unreliable detection probes and/or inconsistent affinity standards. In this study, application of the four Cu(I) ligand probes bicinchoninate, bathocuproine disulfonate, dithiothreitol (Dtt), and glutathione (GSH) is reviewed, and their Cu(I) affinities are re-estimated and unified. Excess bicinchoninate or bathocuproine disulfonate reacts with Cu(I) to yield distinct 1:2 chromatophoric complexes [Cu(I)L(2)](3-) with formation constants beta(2) = 10(17.2) and 10(19.8) m(-2), respectively. These constants do not depend on proton concentration for pH >=7.0. Consequently, they are a pair of complementary and stable probes capable of detecting free Cu(+) concentrations from 10(-12) to 10(-19) m. Dtt binds Cu(I) with K(D) ~10(-15) m at pH 7, but it is air-sensitive, and its Cu(I) affinity varies with pH. The Cu(I) binding properties of Atox1 and related proteins (including the fifth and sixth domains at the N terminus of the Wilson protein ATP7B) were assessed with these probes. The results demonstrate the following: (i) their use permits the stoichiometry of high affinity Cu(I) binding and the individual quantitative affinities (K(D) values) to be determined reliably via noncompetitive and competitive reactions, respectively; (ii) the scattered literature values are unified by using reliable probes on a unified scale; and (iii) Atox1-type proteins bind Cu(I) with sub-femtomolar affinities, consistent with tight control of labile Cu(+) concentrations in living cells. PMID- 21258124 TI - Hypothyroidism: detecting and treating early symptoms as the body's energy rheostat is slowly turned down. PMID- 21258125 TI - A randomized double-blind crossover trial to investigate the efficacy of screening for adult hypothyroidism. AB - OBJECTIVE: To assess the value of population screening for adult hypothyroidism. SETTING: Healthy people attending for a general health assessment. METHODS: A thyroid-stimulating hormone (TSH) measurement was performed on people attending for a general health assessment (women aged 50-79 [35-49 with a family history of thyroid disease] and men aged 65-79). Those with TSH levels above 4.0 mU/L were invited to join a randomized double-blind crossover trial of thyroxine and placebo, each given in random order for four months. On entry a second blood sample was collected for a TSH measurement after the end of the trial to determine whether this would help select individuals for thyroxine treatment. The daily thyroxine dose started at 50 ug and if necessary was increased to achieve a TSH level of 0.6-2.0 mU/L. RESULTS: There were 341 (8%) people with a TSH level above 4.0 mU/L, 110 met eligibility criteria (64 agreed to participate), and 56 (49 women, 7 men) completed the trial. Among the 15 individuals with a repeat TSH measurement above 4.5 mU/L, 11 reported feeling better on thyroxine than placebo and none reported feeling better on placebo (P = 0.001; four felt no different), indicating that in this group 73% benefitted (i.e. 11/15; 95% CI 45-92%). The main symptoms relieved were tiredness and loss of memory. There was no indication of harm. In the 41 individuals with a repeat serum TSH of 4.5 mU/L or less: 10 reported feeling better on thyroxine than placebo and 16 better on placebo (P = 0.42, 15 felt no different). Thus about 8% of men and women in the specified age groups had a TSH above 4.0 mU/L, and of these about a quarter had a repeat TSH above 4.5 mU/L, of whom about half would benefit from thyroxine treatment. CONCLUSION: The results indicate that screening for hypothyroidism would be worthwhile. Approximately 1% of people screened would have a better quality of life. Pilot screening programmes for adult hypothyroidism are justified. PMID- 21258126 TI - Down's syndrome: screening and antenatal diagnosis regionally in England and Wales 1989-2008. AB - OBJECTIVE: To illustrate regional changes that occurred in screening for Down's syndrome (trisomy 21) in England and Wales from 1989 to 2008. METHODS: The National Down Syndrome Cytogenetic Register has collected data on all ante- and postnatal diagnoses of Down's syndrome in England and Wales since 1989 (n = 27,954). The percentages of (i) diagnoses made antenatally, (ii) antenatal diagnoses that had nuchal translucency (NT) measured, and (iii) antenatal diagnoses in mothers aged 37 and over with advanced maternal age as the sole recorded indication for diagnosis are presented according to where the mother lived (Government Office Region), year of diagnosis (1989-1994, 1995-2000, 2001 2006, 2007-2008), and maternal age (<37 years, >=37 years). RESULTS: The percentage of cases diagnosed antenatally has increased in younger women but varies between regions. It remained relatively constant at approximately 70% in older women. The use of NT measurement in antenatal screening has expanded rapidly but varies regionally, being most common in London and the South East where, in 2007-2008, over 75% of antenatal diagnoses in older women had NT measured. The sole indication of advanced maternal age has substantially reduced, and was less than 10% in older mothers in all regions in 2007-2008. CONCLUSIONS: There are regional and maternal age variations in Down's syndrome screening and diagnosis. Some regions used NT measurements, and eliminated advanced maternal age as sole reason for antenatal diagnostic testing more quickly than others. The reasons for variations need to be identified and addressed to ensure that when new screening techniques become available, regional differences are minimized. PMID- 21258127 TI - Women's preferences for the delivery of the National Health Service Breast Screening Programme: a cross-sectional survey. AB - OBJECTIVE: To elicit women's preferences for delivery of the National Health Service (NHS) Breast Screening Programme. DESIGN: Interview survey. SETTING: Private households in the UK. POPULATION: Five hundred and ninety-seven women aged 45-75 interviewed as part of the National Statistics Omnibus Survey, December 2008 and January 2009. OUTCOMES: Preferred setting (hospital or community) and preferred type of screening unit (mobile or permanent). Rated importance of distance, time, convenience and cost of travelling to a screening unit. RESULTS: Forty per cent of women did not mind whether the screening unit was based in a community or hospital setting, and 52% did not mind whether the unit was permanent or mobile. Among those who expressed a preference, 59% preferred a hospital to a community setting, and 62% preferred a permanent to a mobile unit. Many women (63%) said distance to a breast screening unit was an important factor, as was time to travel (58%). Among those with access to a car, 80% regarded the availability of parking as important, but only 40% regarded the cost of car travel as important. Among women with no access to a car, there was a similar pattern for ease of public transport (76%) and cost of public transport (48%). CONCLUSIONS: Many women were unconcerned about the type and setting of breast screening units. Among those who were concerned, most preferred hospital over community settings and permanent over mobile units, but nonetheless most women said time and distance were important. Well-situated units with advanced publicity about public transport links and parking facilities may encourage greater uptake. PMID- 21258128 TI - Is human papillomavirus screening preferable to current policies in vaccinated and unvaccinated women? A cost-effectiveness analysis. AB - OBJECTIVES: Italy was the first European nation to offer free vaccination against human papillomavirus (HPV) types 16 and 18. The vaccination is actively encouraged and is available free of charge to 11-year-old girls. The introduction of new technologies such as HPV DNA testing and HPV vaccination requires cost effectiveness analysis of cervical cancer strategies in Italy for both vaccinated and unvaccinated women. METHODS: A calibrated Markov model was developed to describe the natural history of HPV infection and cervical carcinogenesis. We performed a microsimulation generating the life histories of 10 million women. Changes in these life histories occur as consequences of prevention strategies. We estimated costs of screening activities using an activity-based costing analysis. We assessed lifetime risk due to cervical cancer, lifetime costs and quality-adjusted life-expectancy (QALE) for 18 scenarios. Strategies varied by screening interval (three and five years), primary and triage test (Pap test and HPV DNA test), and HPV 16 and 18 vaccination. RESULTS: The current screening policy (Pap test every three years) is more costly and less effective than HPV DNA test and Pap test triage every five years. For unvaccinated women an HPV DNA test every five years with a Pap test triage was cost-effective (ICER ?5753/QALE). Vaccination followed by the same screening strategy was cost effective (ICER ?23,951/QALE) for women who are eligible to be vaccinated. CONCLUSIONS: Our findings strongly support changing the Pap screening policy to the use of HPV DNA as a primary test with Pap test triage for both vaccinated and unvaccinated women. PMID- 21258129 TI - Implementing the national invasive cervical cancer audit: correlation between local and regional classification. AB - OBJECTIVE: To determine the accuracy of information recorded regionally and locally on the screening classification of cervical cancer cases using the national invasive cervical cancer audit categories. METHODS: Comparison of the audit categorization of all cervical cancer cases diagnosed at the University Hospital of North Staffordshire (UHNS) between January 2003 and December 2006 with the classification assigned by the West Midlands Cervical Screening Quality Assurance Reference Centre (WMQARC). RESULTS: Eighty-seven cases of cervical cancer were diagnosed during the three-year study period. There was agreement between the UHNS and WMQARC classification of cases in 52 cases (59.7%), moderate agreement kappa = 0.51 (95% CI 0.39-0.63). The greatest disparity was seen in the classification of lapsed attenders, with nine of the 26 cases categorized as 'lapsed' by the UHNS being assigned to the 'lost to follow-up' category by WMQARC. Three cases were deemed unclassifiable by WMQARC using the national classification since the women were over the age of 70 years but had previously been enrolled in the screening programme, and currently there is no national category for these women. CONCLUSIONS: Accurate and consistent classification of invasive cervical cancer cases is essential in order to obtain useful information on the efficiency of the national screening programme at a local, regional and national level. The use of a national algorithm would provide reassurance that all data used in the national evaluation of the NHS Cervical Screening Programme are consistent, meaning that robust conclusions could then be drawn from the data. PMID- 21258131 TI - Disease-specific mortality may underestimate the total effect of prostate cancer screening. AB - OBJECTIVES: To study the difference between the disease-specific and excess mortality rate in the European Randomized Study of Screening for Prostate Cancer section Rotterdam. METHODS: A total of 42,376 men were randomized to systematic screening or usual care. The excess number of deaths was defined as the difference between the observed number of deaths in the prostate cancer (PC) patients and the expected number of deaths up to 31 December 2006. The expected number was derived from mortality of all study participants before a possible diagnosis with PC. The disease-specific mortality rate was based on the number of men who died from PC. The excess mortality rate based on the arm-specific excess number of deaths and the disease-specific mortality rate were compared between the two study arms. RESULTS: The overall mortality rate was not significantly different between the intervention and the control arms of the study: RR 1.02 (95% CI 0.98-1.07). The disease-specific mortality rate was 0.42 men per 1000 person-years in the intervention and 0.48 men per 1000 person-years in the control arm: RR 0.86 (95% CI 0.64-1.17). The excess mortality rate was 0.40 per 1000 person-years in the intervention arm and 0.61 men per 1000 person-years in the control arm, and the RR for excess mortality was 0.66 (95% CI 0.39-1.13). CONCLUSIONS: In contrast to the disease-specific mortality rates an increased difference in the excess mortality rates was observed between the two arms. This observation may be due to a systematic underestimation of the disease-specific deaths, and/or an additional disease-related mortality that is measured by an excess mortality analysis but not by a disease-specific mortality. PMID- 21258130 TI - Optional screening strategies for cervical cancer using standalone tests and their combinations among low- and medium-income populations in Latin America and Eastern Europe. AB - BACKGROUND: The performance of cervical cancer (CC) screening can be improved by combining Pap smear with human papillomavirus (HPV) testing or visual methods, addressing local demographic, clinical and economic characteristics. OBJECTIVES: To examine the performance of standalone and combined screening tools in populations with variable prevalence of cervical intraepithelial neoplasia (CIN) and CC. METHODS: Merged data-sets from the Latin American Screening Study and New Independent States cohorts provided results for 15,000 women, screened using Pap smear, HPV testing and visual inspection with acetic acid, in Brazil, Argentina, Russia, Belarus and Latvia. Bayesian correction for verification bias was used. RESULTS: At CIN2+ cut-off, HPV detection alone was the most sensitive technique. There was an improvement (88.5% to 92.7%) in Hybrid Capture 2 (HC2) sensitivity among women >=35 years old. Using HPV detection alone was the least specific screening tool, regardless of the age group (69.9% [95% CI 66.5-72.8%] and 86.4% [95% CI 84.6-88.2%], in < or >=35 years, respectively). Of the test combinations, Pap smear (LSIL threshold) with HC2 had the highest specificity (98.7%; 95% CI 98.3-99.0%). However, in women >=35 years, the sensitivity of Pap alone was superior to that of the combination. CONCLUSIONS: The Pap test is a highly specific screening option in populations with medium-range CC prevalence. Combined testing for HPV in this scenario may yield slightly better positive predictive values in women >=35 years of age with LSIL, but at a high incremental cost. PMID- 21258132 TI - Experience with a wipe guaiac-based faecal occult blood test as an alternative test in a bowel screening programme. AB - The format of the traditional guaiac faecal occult blood test (gFOBT), particularly the collection technique, might cause difficulties for some. A multistage evaluation of alternative tests was performed. Firstly, four tests with different faecal collection approaches were assessed: a focus group recommended further investigation of a wipe gFOBT. Secondly, 100 faecal samples were analysed using two wipe tests and the routine gFOBT: no differences were found. Thirdly, a wipe gFOBT was introduced. Over 21 months, 400 requests were made and 311 wipe kit sets were submitted for analysis: 153 (49.2%) were negative, 21 (6.8%) positive (all 3 kits positive), 96 (30.9%) weak positive (1 or 2 positive) and 41 (13.2%) un-testable. Forty-three participants were referred for colonoscopy. Outcome data were provided on 39 participants: nine declined colonoscopy, two were judged unsuitable, two did not attend, two were already in follow-up, 13 had normal colonoscopy and two normal barium enema, two had diverticular disease, two had a metaplastic polyp, four had a low-risk adenoma and one had a high-risk adenoma. No participant had cancer. Detection of significant neoplasia was small. The use of the wipe gFOBT was ceased: it cannot be recommended as a screening test for bowel cancer. PMID- 21258133 TI - Age-specific frequency of screen-detected hepatitis C virus seropositivity in men from the Punjab province of Pakistan. AB - Pakistan is a South Asian country with a high population seroprevalence of anti hepatitis C virus (anti-HCV) antibody. In administrative districts of its most populous province, Punjab, the frequency of seropositivity for HCV in different age groups of adult men, the usual bread winners for their families, is not known. This study describes the frequency and age-distribution of seropositivity for anti-HCV antibodies in 58,680 clinically healthy, adult men, from nine districts of the Punjab province in Pakistan, undergoing pre-employment health screening. Laboratory records belonging to these men, screened by enzyme-linked immunosorbent assay 3 for antiHCV antibodies in serum, were analysed and frequencies were calculated. A total of 4034 (6.9%) were seropositive for HCV. The highest frequency of HCV seropositivity was noted in men from Multan (9.6%), followed by Lahore (9.4%) district. The lowest (5.0%) was noted among men residing in Bahawalpur district. There was a progressive increase in seroprevalence with increasing age in men from all districts. Further research needs to be initiated to describe differential HCV risk factor distribution in various districts and sustainability of relatively low seroprevalence noted in younger men. PMID- 21258134 TI - Reversible high affinity inhibition of phosphofructokinase-1 by acyl-CoA: a mechanism integrating glycolytic flux with lipid metabolism. AB - The enzyme phosphofructokinase-1 (PFK-1) catalyzes the first committed step of glycolysis and is regulated by a complex array of allosteric effectors that integrate glycolytic flux with cellular bioenergetics. Here, we demonstrate the direct, potent, and reversible inhibition of purified rabbit muscle PFK-1 by low micromolar concentrations of long chain fatty acyl-CoAs (apparent Ki~1 MUM). In sharp contrast, short chain acyl-CoAs, palmitoylcarnitine, and palmitic acid in the presence of CoASH were without effect. Remarkably, MgAMP and MgADP but not MgATP protected PFK-1 against inhibition by palmitoyl-CoA indicating that acyl CoAs regulate PFK-1 activity in concert with cellular high energy phosphate status. Furthermore, incubation of PFK-1 with [1-(14)C]palmitoyl-CoA resulted in robust acylation of the enzyme that was reversible by incubation with acyl protein thioesterase-1 (APT1). Importantly, APT1 reversed palmitoyl-CoA-mediated inhibition of PFK-1 activity. Mass spectrometric analyses of palmitoylated PFK-1 revealed four sites of acylation, including Cys-114, Cys-170, Cys-351, and Cys 577. PFK-1 in both skeletal muscle extracts and in purified form was inhibited by S-hexadecyl-CoA, a nonhydrolyzable palmitoyl-CoA analog, demonstrating that covalent acylation of PFK-1 was not required for inhibition. Tryptic footprinting suggested that S-hexadecyl-CoA induced a conformational change in PFK-1. Both palmitoyl-CoA and S-hexadecyl-CoA increased the association of PFK-1 with Ca2+/calmodulin, which attenuated the binding of palmitoylated PFK-1 to membrane vesicles. Collectively, these results demonstrate that fatty acyl-CoA modulates phosphofructokinase activity through both covalent and noncovalent interactions to regulate glycolytic flux and enzyme membrane localization via the branch point metabolic node that mediates lipid flux through anabolic and catabolic pathways. PMID- 21258135 TI - Cellular proteome, coregulators, endocrine system and the human brain: the Regulatory biology of humanism. PMID- 21258137 TI - A population-based model to describe geometrical uncertainties in radiotherapy: applied to prostate cases. AB - Local motions and deformations of organs between treatment fractions introduce geometrical uncertainties into radiotherapy. These uncertainties are generally taken into account in the treatment planning by enlarging the radiation target by a margin around the clinical target volume. However, a practical method to fully include these uncertainties is still lacking. This paper proposes a model based on the principal component analysis to describe the patient-specific local probability distributions of voxel motions so that the average values and variances of the dose distribution can be calculated and fully used later in inverse treatment planning. As usually only a very limited number of data for new patients is available; in this paper the analysis is extended to use population data. A basic assumption (which is justified retrospectively in this paper) is that general movements and deformations of a specific organ are similar despite variations in the shapes of the organ over the population. A proof of principle of the method for deformations of the prostate and the seminal vesicles is presented. PMID- 21258138 TI - Registration of 2D x-ray images to 3D MRI by generating pseudo-CT data. AB - Spatial and soft tissue information provided by magnetic resonance imaging can be very valuable during image-guided procedures, where usually only real-time two dimensional (2D) x-ray images are available. Registration of 2D x-ray images to three-dimensional (3D) magnetic resonance imaging (MRI) data, acquired prior to the procedure, can provide optimal information to guide the procedure. However, registering x-ray images to MRI data is not a trivial task because of their fundamental difference in tissue contrast. This paper presents a technique that generates pseudo-computed tomography (CT) data from multi-spectral MRI acquisitions which is sufficiently similar to real CT data to enable registration of x-ray to MRI with comparable accuracy as registration of x-ray to CT. The method is based on a k-nearest-neighbors (kNN)-regression strategy which labels voxels of MRI data with CT Hounsfield Units. The regression method uses multi spectral MRI intensities and intensity gradients as features to discriminate between various tissue types. The efficacy of using pseudo-CT data for registration of x-ray to MRI was tested on ex vivo animal data. 2D-3D registration experiments using CT and pseudo-CT data of multiple subjects were performed with a commonly used 2D-3D registration algorithm. On average, the median target registration error for registration of two x-ray images to MRI data was approximately 1 mm larger than for x-ray to CT registration. The authors have shown that pseudo-CT data generated from multi-spectral MRI facilitate registration of MRI to x-ray images. From the experiments it could be concluded that the accuracy achieved was comparable to that of registering x-ray images to CT data. PMID- 21258136 TI - Health and function of participants in the Long Life Family Study: A comparison with other cohorts. AB - Individuals from families recruited for the Long Life Family Study (LLFS) (n= 4559) were examined and compared to individuals from other cohorts to determine whether the recruitment targeting longevity resulted in a cohort of individuals with better health and function. Other cohorts with similar data included the Cardiovascular Health Study, the Framingham Heart Study, and the New England Centenarian Study. Diabetes, chronic pulmonary disease and peripheral artery disease tended to be less common in LLFS probands and offspring compared to similar aged persons in the other cohorts. Pulse pressure and triglycerides were lower, high density lipids were higher, and a perceptual speed task and gait speed were better in LLFS. Age-specific comparisons showed differences that would be consistent with a higher peak, later onset of decline or slower rate of change across age in LLFS participants. These findings suggest several priority phenotypes for inclusion in future genetic analysis to identify loci contributing to exceptional survival. PMID- 21258139 TI - Surface dosimetry for breast radiotherapy in the presence of immobilization cast material. AB - Curative breast radiotherapy typically leaves patients with varying degrees of cosmetic damage. One problem interfering with cosmetically acceptable breast radiotherapy is the external contour for large pendulous breasts which often results in high doses to skin folds. Thermoplastic casts are often employed to secure the breasts to maintain setup reproducibility and limit the presence of skin folds. This paper aims to determine changes in surface dose that can be attributed to the use of thermoplastic immobilization casts. Skin dose for a clinical hybrid conformal/IMRT breast plan was measured using radiochromic film and MOSFET detectors at a range of water equivalent depths representative of the different skin layers. The radiochromic film was used as an integrating dosimeter, while the MOSFETs were used for real-time dosimetry to isolate the contribution of skin dose from individual IMRT segments. Strips of film were placed at various locations on the breast and the MOSFETs were used to measure skin dose at 16 positions spaced along the film strips for comparison of data. The results showed an increase in skin dose in the presence of the immobilization cast of up to 45.7% and 62.3% of the skin dose without the immobilization cast present as measured with Gafchromic EBT film and MOSFETs, respectively. The increase in skin dose due to the immobilization cast varied with the angle of beam incidence and was greatest when the beam was normally incident on the phantom. The increase in surface dose with the immobilization cast was greater under entrance dose conditions compared to exit dose conditions. PMID- 21258140 TI - Prior image constrained scatter correction in cone-beam computed tomography image guided radiation therapy. AB - X-ray scatter is a significant problem in cone-beam computed tomography when thicker objects and larger cone angles are used, as scattered radiation can lead to reduced contrast and CT number inaccuracy. Advances have been made in x-ray computed tomography (CT) by incorporating a high quality prior image into the image reconstruction process. In this paper, we extend this idea to correct scatter-induced shading artifacts in cone-beam CT image-guided radiation therapy. Specifically, this paper presents a new scatter correction algorithm which uses a prior image with low scatter artifacts to reduce shading artifacts in cone-beam CT images acquired under conditions of high scatter. The proposed correction algorithm begins with an empirical hypothesis that the target image can be written as a weighted summation of a series of basis images that are generated by raising the raw cone-beam projection data to different powers, and then, reconstructing using the standard filtered backprojection algorithm. The weight for each basis image is calculated by minimizing the difference between the target image and the prior image. The performance of the scatter correction algorithm is qualitatively and quantitatively evaluated through phantom studies using a Varian 2100 EX System with an on-board imager. Results show that the proposed scatter correction algorithm using a prior image with low scatter artifacts can substantially mitigate scatter-induced shading artifacts in both full-fan and half-fan modes. PMID- 21258141 TI - Simultaneous in vivo dynamic contrast-enhanced magnetic resonance and scintigraphic imaging. AB - In this study, we investigated the in vivo application of an integrated small animal magnetic resonance (MR) and gamma-ray imaging system that consists of a semiconductor-based radiation detector, a parallel-hole collimator, and a specialized radiofrequency coil. Gadodiamide and (99m)Tc sestimibi agents were injected simultaneously into a mouse, and simultaneous dynamic contrast-enhanced MR and scintigraphic images of the kidneys were acquired. The time curves of both the MR signal intensity and radioactivity indicate a rapid uptake of the agents followed by a more gradual excretion, consistent with the previously reported literature. Our results demonstrate the feasibility of measuring multiple biological processes at the same time using both MR contrast agents and radiotracers. PMID- 21258142 TI - Combined micro- and nano-scale surface textures for enhanced near-infrared light harvesting in silicon photovoltaics. AB - As silicon photovoltaics evolve towards thin-wafer technologies, efficient optical absorption for the near-infrared wavelengths has become particularly challenging. In this work, we present a solution that employs combined micro- and nano-scale surface textures to increase light harvesting in the near-infrared for crystalline silicon photovoltaics, and discuss the associated antireflection and scattering mechanisms. The surface textures are achieved by uniformly depositing a layer of indium-tin-oxide nanowhiskers on micro-grooved silicon substrates using electron-beam evaporation. The nanowhiskers facilitate optical transmission in the near-infrared by functioning as impedance matching layers with effective refractive indices gradually varying from 1 to 1.3. Materials with such unique refractive index characteristics are not readily available in nature. As a result, the solar cell with combined textures achieves over 90% external quantum efficiencies for a broad wavelength range of 460-980 nm, which is crucial to the development of advanced thin-substrate silicon solar cells. PMID- 21258143 TI - Lognormal switching times for titanium dioxide bipolar memristors: origin and resolution. AB - We measured the switching time statistics for a TiO(2) memristor and found that they followed a lognormal distribution, which is a potentially serious problem for computer memory and data storage applications. We examined the underlying physical phenomena that determine the switching statistics and proposed a simple analytical model for the distribution based on the drift/diffusion equation and previously measured nonlinear drift behavior. We designed a closed-loop switching protocol that dramatically narrows the time distribution, which can significantly improve memory circuit performance and reliability. PMID- 21258144 TI - Spin-wave interference patterns created by spin-torque nano-oscillators for memory and computation. AB - Magnetization dynamics in nanomagnets has attracted broad interest since it was predicted that a dc current flowing through a thin magnetic layer can create spin wave excitations. These excitations are due to spin momentum transfer, a transfer of spin angular momentum between conduction electrons and the background magnetization, that enables new types of information processing. Here we show how arrays of spin-torque nano-oscillators can create propagating spin-wave interference patterns of use for memory and computation. Memristic transponders distributed on the thin film respond to threshold tunnel magnetoresistance values, thereby allowing spin-wave detection and creating new excitation patterns. We show how groups of transponders create resonant (reverberating) spin wave interference patterns that may be used for polychronous wave computation and information storage. PMID- 21258145 TI - Evidence for surface states in pristine and Co-doped ZnO nanostructures: magnetization and nonlinear optical studies. AB - An unexpected presence of ferromagnetic (FM) ordering in nanostructured ZnO has been reported previously. Recently, from our detailed magnetization studies and ab initio calculations, we attributed this FM ordering in nanostructured ZnO to the presence of surface states, and a direct correlation between the magnetic properties and crystallinity of ZnO was observed. In this study, through a systematic sample preparation of both pristine and Co-doped ZnO nanostructures, and detailed magnetization and nonlinear optical (NLO) measurements, we confirm that the observed FM ordering is due to the presence of surface states. PMID- 21258146 TI - Facile one-pot synthesis of near-infrared luminescent gold nanoparticles for sensing copper (II). AB - Novel near-infrared luminescent gold nanoparticles (NIRL-AuNPs) were synthesized by a simple, rapid and one-pot procedure. The driving force for the formation of these NIRL-AuNPs was attributed to the heat-assisted reduction of a gold(I)-thiol complex. These gold nanoparticles were characterized by TEM, DLS, FT-IR and XPS. Luminescence studies indicated that these NIRL-AuNPs exhibited strong emission with peak maximum at 810 nm, microsecond-range photoluminescence lifetime, large Stokes shifts (>400 nm) and stabilities towards photobleaching and chemical oxidation. The sensing application for Cu(2+) ions of these NIRL-AuNPs was demonstrated. These as-synthesized gold nanoparticles will provide a new NIRL nanomaterial for in vitro and in vivo applications. PMID- 21258147 TI - The importance of cellular internalization of antibody-targeted carbon nanotubes in the photothermal ablation of breast cancer cells. AB - Single-walled carbon nanotubes (CNTs) convert absorbed near infrared (NIR) light into heat. The use of CNTs in the NIR-mediated photothermal ablation of tumor cells is attractive because the penetration of NIR light through normal tissues is optimal and the side effects are minimal. Targeted thermal ablation with minimal collateral damage can be achieved by using CNTs attached to tumor specific monoclonal antibodies (MAbs). However, the role that the cellular internalization of CNTs plays in the subsequent sensitivity of the target cells to NIR-mediated photothermal ablation remains undefined. To address this issue, we used CNTs covalently coupled to an anti-Her2 or a control MAb and tested their ability to bind, internalize, and photothermally ablate Her2(+) but not Her2(-) breast cancer cell lines. Using flow cytometry, immunofluorescence, and confocal Raman microscopy, we observed the gradual time-dependent receptor-mediated endocytosis of anti-Her2-CNTs whereas a control MAb-CNT conjugate did not bind to the cells. Most importantly, the Her2(+) cells that internalized the MAb-CNTs were more sensitive to NIR-mediated photothermal damage than cells that could bind to, but not internalize the MAb-CNTs. These results suggest that both the targeting and internalization of MAb-CNTs might result in the most effective thermal ablation of tumor cells following their exposure to NIR light. PMID- 21258148 TI - Colloidal domain lithography for regularly arranged artificial magnetic out-of plane monodomains in Au/Co/Au layers. AB - Regularly arranged magnetic out-of-plane patterns in continuous and flat films are promising for applications in data storage technology (bit patterned media) or transport of individual magnetic particles. Whereas topographic magnetic structures are fabricated by standard lithographical techniques, the fabrication of regularly arranged artificial domains in topographically flat films is difficult, since the free energy minimization determines the existence, shape, and regularity of domains. Here we show that keV He(+) ion bombardment of Au/Co/Au layer systems through a colloidal mask of hexagonally arranged spherical polystyrene beads enables magnetic patterning of regularly arranged cylindrical magnetic monodomains with out-of-plane magnetization embedded in a ferromagnetic matrix with easy-plane anisotropy. This colloidal domain lithography creates artificial domains via periodic lateral anisotropy variations induced by periodic defect density modulations. Magnetization reversal of the layer system observed by magnetic force microscopy shows individual disc switching indicating monodomain states. PMID- 21258149 TI - Calcium dependent formation of tubular assemblies by recombinant S-layer proteins in vivo and in vitro. AB - Surface layer proteins have the appealing property to self-assemble in nanosized arrays in solution and on solid substrates. In this work, we characterize the formation of assembly structures of the recombinant surface layer protein SbsC of Geobacillus stearothermophilus ATTC 12980, which was tagged with enhanced green fluorescent protein and expressed in the yeast Saccharomyces cerevisiae. The tubular structures formed by the protein in vivo are retained upon bursting the cells by osmotic shock; however, their average length is decreased. During dialysis, monomers obtained by treatment with chaotropic chemicals recrystallize again to form tube-like structures. This process is strictly dependent on calcium (Ca(2+)) ions, with an optimal concentration of 10 mM. Further increase of the Ca(2+) concentration results in multiple non-productive nucleation points. We further show that the lengths of the S-layer assemblies increase with time and can be controlled by pH. After 48 h, the average length at pH 9.0 is 4.13 um compared to 2.69 um at pH 5.5. Successful chemical deposition of platinum indicates the potential of recrystallized mSbsC-eGFP structures for nanobiotechnological applications. PMID- 21258150 TI - Evidence for altered Numb isoform levels in Alzheimer's disease patients and a triple transgenic mouse model. AB - The cell fate determinant Numb exists in four alternatively spliced variants that differ in the length of their PTB (phosphotyrosine-binding domain, either lacking or containing an 11 amino acid insertion) and PRR (proline-rich region, either lacking or containing a 48 amino acid insertion). We previously reported that Numb switches from isoforms containing the PTB insertion to isoforms lacking this insertion in neural cultures subjected to stress induced by trophic factor withdrawal. The switch in Numb isoforms enhances the generation of amyloid-beta peptide (Abeta), the principle component of senile plaques in Alzheimer's disease (AD). Here we examine the expression of the Numb isoforms in brains from AD patients and triple transgenic (3xTg) AD mice. We found that levels of the Numb isoforms lacking the PTB insertion are significantly elevated in the parietal cortex but not in the cerebellum of AD patients when compared to control subjects. Levels of Numb isoforms lacking the PTB insertion were also elevated in the cortex but not cerebellum of 12 month-old 3xTg AD mice with Abeta deposits compared to younger 3xTg-AD mice and to non-transgenic mice. Exposure of cultured neurons to Abeta resulted in an increase in the levels of Numb isoforms lacking the PTB domain, consistent with a role for Abeta in the aberrant expression of Numb in vulnerable brain regions of AD patients and mice. Collectively, the data show that altered expression of Numb isoforms in vulnerable neurons occurs during AD pathogenesis and suggest a role for Numb in the disease process. PMID- 21258151 TI - The amyloid-beta42 proxy, amyloid-beta(25-35), induces normal human cerebral astrocytes to produce amyloid-beta42. AB - Astrocytes in amyloid-beta (Abeta)42-accumulating human brains afflicted with Alzheimer's disease (AD) upregulate vascular endothelial growth factor (VEGF)-A synthesis and also become loaded with Abeta42. We have already shown that Abeta(25-35) (surrogate of Abeta42)-induced VEGF-A production in 'normoxic' cultures of early passage normal human cerebral astrocytes (NAHAs) is mediated by the stabilization of VEGF gene-stimulating hypoxia-inducible factor (HIF)-1alpha and nuclear translocation of HIF-1alpha*HIF-1beta complexes. We have now found that treating these NAHAs with Abeta(25-35) also stimulates them to make Abeta42 (appearing in immunoblots as several bands with M(r)'s from 8 kDa upwards), whose levels peak at 48 h (2.8-fold versus 0 h, p < 0.001) and then start falling slowly. This rise of Abeta42 peptide production coincides with a transiently increased flow of HIF-1alpha (therefore HIF-1alpha*HIF-1beta complexes; at 24 h, 1.5-fold versus 0 h, p < 0.001) into the nucleus and transient surges first of beta-secretase (BACE-1/beta-S) mRNA expression (1.2-fold versus 0 h, p = 0.013) and activity peaking at 24-h (1.4-fold versus 0 h, p = 0.001), and then of gamma secretase (gamma-S) activity cresting at 48 h (1.6-fold versus 0 h, p < 0.001) that cleave the Abeta42 peptides from amyloid-beta protein precursor. Since the genes encoding components of these two secretases have the same HIF-1alpha*HIF 1beta-responsive elements in their promoters as the VEGF gene, these observations suggest that the Abeta42 released from neurons in the AD brain can recruit associated astrocytes via HIF-1alpha*HIF-1beta signaling into the pool of Abeta42 producing cells. In other words, Abeta42 begets Abeta42 in NAHAs. PMID- 21258152 TI - Phenotypic heterogeneity of the GRN Asp22fs mutation in a large Italian kindred. AB - The Asp22fs(g.63_64insC) mutation in progranulin gene (GRN) has been so far reported in one patient who developed frontotemporal dementia (FTD) at the age of 65. Here, we describe the clinical heterogeneity associated with the GRN Asp22fs mutation in a large Italian family. Clinical and instrumental workup of two symptomatic carriers in two generations has been carried out, together with genetic analysis of probands and of nine asymptomatic family members. The first proband was a 47-year old male clinically diagnosed with FTD. Family history was positive and suggestive of an autosomal dominant pattern of inheritance. Evaluation of plasma GRN levels was consistent with the presence of a mutation in its encoding gene, that was demonstrated by sequencing [Asp22fs(g.63_64insC)]. Brain MRI showed multiple T2 and FLAIR hyperintense areas in the frontal lobe white matter and right hemisphere cortical atrophy. The second proband was his 79 year old uncle, presenting with mild cognitive impairment. Brain MRI showed small T2 hyperintense lesions and widespread cortical atrophy. Cerebrospinal fluid amyloid-beta, tau, and phosphotau protein levels were in both cases in the range of normality. Additional nine asymptomatic family members were studied. This family's description expands the spectrum of clinical presentations of frontotemporal lobar degeneration caused by GRN mutations, suggesting that the diagnosis could be missed in some individuals with an atypical presentation, and points up the importance of GRN plasma level evaluation. PMID- 21258154 TI - Cardiac biomarkers in the diagnosis, prognosis and management of coronary artery disease: a primer for internists. AB - Initially coined in 1989, biomarkers have become a cornerstone of modern cardiovascular medicine. The past decade has borne witness to the rapid transition of cardiac biomarkers from bench to bedside in the management of patients with coronary artery disease. The implementation of cardiac biomarkers has transformed the internists' approach to cardiovascular patients. This article reviews several cardiac biomarkers in the context of diagnosis, prognosis, risk assessment and management of patients at risk of adverse cardiovascular outcomes. Biomarkers are presented according to their relevant role in the atherosclerotic cascade, a pathologic classification of particular value for internists, as it defines the role of these agents in the pathogenesis of heart disease. Where pertinent, limitations of cardiac biomarkers are discussed, thus allowing the discerning practitioner to remain cognizant of situations that may lead to spurious marker elevation or suppression. The review concludes with highlights on novel avenues of biomarker research that promise an exciting future for these entities. PMID- 21258155 TI - Hemi brain demyelination--a variant of acute disseminated encephalomyelitis. PMID- 21258153 TI - Effects of AZD3480 on cognition in patients with mild-to-moderate Alzheimer's disease: a phase IIb dose-finding study. AB - AZD3480 is a selective agonist of the central alpha4beta2 and alpha2beta2 neuronal nicotinic cholinergic receptors (NNRs). Its effects on cognition were investigated in 567 patients with mild-to-moderate Alzheimer's disease (AD) (Mini Mental State Examination [MMSE] 12-26). Mean baseline MMSE was 21 (SD +/- 3.7), with 61% of patients having mild disease (MMSE 21-26). Mean age was 74 (range 58 85) years. Patients were randomized to one of 5 treatment groups: AZD3480 5 mg, 20 mg or 35/100 mg, donepezil 10 mg (active comparator) or placebo, and treated once daily for 12 weeks. The primary outcome measure was change from baseline at Week 12 on the AD Assessment Scale-Cognitive Subscale (ADAS-Cog). Neither AZD3480 nor donepezil showed a statistically significant improvement versus placebo on ADAS-Cog. Improvements in a number of secondary outcome measures (MMSE, AD Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) and Disability Assessment for Dementia [DAD]) were observed for AZD3480 and for donepezil. A post-hoc analysis on ADAS-Cog, excluding patients with very mild AD (MMSE 25-26) indicated improvement versus placebo for AZD3480 20 mg (-1.4, 95% CI: -3.0; 0.2) and donepezil (-1.0, 95% CI: -2.3; 0.3). AZD3480 was well tolerated. The study did not meet proof of concept criteria: since neither AZD3480 nor donepezil were statistically significantly superior to placebo on ADAS-Cog and was considered to be inconclusive. Further studies are required to determine the therapeutic potential of stimulating alpha4beta2 receptors with NNRs in AD patients. PMID- 21258156 TI - Intracystic papillary carcinoma in the male breast: a rare presentation. PMID- 21258157 TI - Ceftriaxone resistant Shigella flexneri, an emerging problem. AB - Shigellosis is a disease of public health importance in developing countries. It may cause self-limited diarrhea to severe dysentery. Emergence of multi drug resistant (MDR) strains is a growing concern globally. Ceftriaxone and ciprofloxacin are the drugs of choice for MDR cases. Here, we report a case of MDR Shigella flexneri from an immunocompromised patient. The strain was resistant to ceftriaxone [minimum inhibitory concentration (MIC) >= 64 MUg/ml], limiting the treatment option. Simultaneously, the strain was also found to be resistant to ciprofloxacin (MIC >= 4 MUg/ml). However, it was susceptible to ceftazidime (MIC 4 MUg/ml). This is the first case of ceftriaxone resistant Shigella spp. reported from our hospital. PMID- 21258158 TI - 2009H1N1 Infection in a 1-day-old neonate. AB - A full-term female neonate was delivered with meconium stained amniotic fluid by cesarean section by a 2009H1N1 positive 22-year-old second gravida mother, who developed symptoms 8 days prior to delivery. The neonate was completely and immediately isolated from the mother after delivery. Oseltamivir was started at birth to the neonate who had a potential possibility of 2009H1N1 infection. At 5 hours of life, the neonate developed respiratory distress. The neonate's throat swab sent for 2009H1N1 by real-time polymerase chain reaction (RT-PCR) assay was positive. The neonate required oxygen by hood for 3 days and made an uneventful recovery. The mother developed acute respiratory distress syndrome after delivery, requiring ventilatory care for 14 days and was discharged after 25 days stay in hospital. 2009H1N1 infection, although rare, needs a high index of suspicion and prompt therapy in neonates. Clinicians should be alert about the possibility of perinatal transmission of 2009H1N1. PMID- 21258159 TI - The epinet data of four Indian hospitals on incidence of exposure of healthcare workers to blood and body fluid: a multicentric prospective analysis. AB - BACKGROUND: Sharps injury (SI) and blood and body fluid exposure are occupational hazards to healthcare workers (HCWs). Although data from the developed countries have shown the enormity of the problem, data from developing countries, such as India, arelacking. Purpose : The purpose of this study was to cumulate data from fourmajor hospitals in India and analyze the incidence of SI and blood and body fluid exposure in HCWs. MATERIALS AND METHODS: Four Indian hospitals (hospital A, B, C and D) from major cities of India participated in this multicentric study. Data ranging from 6 to 26 months were collected from these hospitals using Exposure Prevention Information network (EPINet) which is the database created by International Healthcare Worker Safety Research and Resource Center, University of Virginia. RESULTS: Two hundred and forty-three sharp injuries and 22 incidents of blood or body fluid exposure were encountered in the cumulated 50 months of our study. The incidence of SIswas thehighestamong nurses (55%) of allthe HCWs, akin to the global data. An injury rate of nearly 20% among housekeeping staff seems to be specific to the Indian data. Patient's room followed by operation theater appeared to be common locations of injury in our study. The source of the injury was identified in majority (64%) of the injuries. A major part of the group was not the primary users of the sharp (38%). Disposable needles caused nearly half of the injuries. Suture needles contributed to a reasonable number of injuries in one of the hospitals. CONCLUSIONS: The incidence of SI is the highest among nurses and the housekeeping staff (>30% each). A substantial number of injuries are avoidable. PMID- 21258160 TI - A simplified acute physiology score in the prediction of acute aluminum phosphide poisoning outcome. AB - BACKGROUND: Aluminum phosphide (AlP) is used as a fumigant. It produces phosphine gas, which is a mitochondrial poison. Unfortunately, there is no known antidote for AlP intoxication, and also, there are few data about its prognostic factors. AIMS: The aim of this study was to determine the impact of the Simplified Acute Physiology Score II (SAPS II ) in the prediction of outcome in patients with acute AlP poisoning requiring admission to the Intensive Care Unit (ICU). MATERIALS AND METHODS: This was a prospective study in patients with acute AlP poisoning, admitted to the ICU over a period of 12 months. The demographic data were collected and SAPSII was recorded. The patients were divided into survival and non-survival groups due to outcome. STATISTICAL ANALYSIS: The data were expressed as mean +/- SD for continuous or discrete variables and as frequency and percentage for categorical variables. The results were compared between the two groups using SPSS software. Results : During the study period, 39 subjects were admitted to the ICU with acute AlP poisoning. All 39 patients required endotracheal intubation and mechanical ventilation in addition to gastric decontamination with sodium bicarbonate, permanganate potassium, and activated charcoal, therapy with MgSO 4 and calcium gluconate and adequate hydration. Among these patients, 26 (66.7%) died. SAPSII was significantly higher in the non survival group than in the survival group (11.88 +/- 4.22 vs. 4.31 +/- 2.06, respectively) (P < 0.001). CONCLUSION: SAPSII calculated within the first 24 hours was recognized as a good prognostic indicator among patients with acute AlP poisoning requiring ICU admission. PMID- 21258161 TI - Speculative mechanisms for very late stent thrombosis after drug-eluting stent implantation. PMID- 21258162 TI - Clinical outcomes and the risk factors of coronary artery aneurysms that developed after drug-eluting stent implantation. AB - BACKGROUND: There is only limited data on coronary artery aneurysms (CAA) after drug-eluting stent (DES) implantation. METHODS AND RESULTS: Two hundred-fifty one patients who had 2 angiographic follow-ups at 8 months and 28-36 months, respectively, after the index procedure with DES from 2003 to 2007 were enrolled. A CAA was defined as a localized dilatation exceeding 1.5 times the diameter of the adjacent artery. The independent risk factors and major adverse cardiac events (MACE) were determined, including cardiac death, myocardial infarction (MI) and target-vessel revascularization (TVR), between the patients with CAA (n=35) and without them (n=216). On multivariate analysis, a lesion in an infarct related artery (IRA) (odds ratio (OR): 6.1, P=0.001), a lesion in the left anterior descending artery (OR: 4.9, P=0.005), a lesion length >33 mm (OR: 3.9, P=0.022), and a lesion with chronic total occlusion (CTO) (OR: 3.4, P=0.044) were the independent risk factors for CAA. Follow-up duration was 1,046+/-516 days. Although most patients (71.4%) were asymptomatic, MACE was found in 10 patients (28.6%). No deaths occurred. MI with stent thrombosis occurred in 5 patients (14.3%) and TVR occurred in 10 patients (28.6%). CONCLUSIONS: The risk factors for the development of CAA after DES are a long lesion over 33 mm, a lesion in the left anterior descending artery, a lesion in an IRA, and CTO. Long-term follow-up and large clinical trials are warranted for patients with CAA. PMID- 21258163 TI - A new angle on classifying coronary artery bifurcation stenoses. The DINO system. PMID- 21258164 TI - Clinical perspective of coronary computed tomographic angiography in diagnosis of coronary artery disease. AB - Since a 4-detector row coronary computed tomographic angiography (CCTA) was launched in 1998, CCTA has experienced rapid improvement of imaging qualities with the ongoing evolution of computed tomography (CT) technology. The diagnostic accuracy of CCTA to detect coronary artery stenosis is well established, whereas improvements are still needed to reduce the overestimation of coronary artery disease (CAD) and assess plaque composition. CCTA has been used to evaluate CAD in various clinical settings. For example, CCTA could be an efficient initial triage tool at emergency departments for patients with acute chest pain with low to-intermediate risk because of its high negative predictive value. In patients with suspected CAD, CCTA could be a cost-effective alternative to myocardial perfusion imaging and exercise electrocardiogram for the initial coronary evaluation of patients with intermediate pre-test likelihood suspected CAD. However, in asymptomatic populations, there is a lack of studies that show an improved prognostic power of CCTA over other modalities. Therefore, the clinical use of CCTA to detect CAD for purposes of risk stratification in asymptomatic individuals should be discouraged. As CT technology evolves, CCTA will provide better quality coronary imaging and non-coronary information with lower radiation exposure. Future studies should cover these ongoing technical improvements and evaluate the prognostic power of CCTA in various clinical settings of CAD in large, well-designed, randomized trials. PMID- 21258165 TI - Artificial compounds differentially control Dictyostelium chemotaxis and cell differentiation. AB - Differentiation-inducing factor-1 and -2 (DIF-1 and DIF-2) are small lipophilic signal molecules that control both cell differentiation and chemotaxis in the cellular slime mold Dictyostelium discoideum. In this study, we examined the effects of four amide derivatives of DIF-1 on stalk cell differentiation and chemotaxis. The DIF derivatives differentially affected cell differentiation and chemotaxis, suggesting the possible existence of at least three receptors for DIFs: one receptor responsible for stalk cell induction, and two receptors responsible for chemotaxis modulation. Furthermore, our results indicate that DIF derivatives can be utilized to analyze the DIF-signaling pathways. PMID- 21258166 TI - Use of doubly labeled water to validate a physical activity questionnaire developed for the Japanese population. AB - BACKGROUND: No study has attempted to use the doubly labeled water (DLW) method to validate a physical activity questionnaire administered to a Japanese population. The development and refinement of such questionnaires require that physical activity components related to physical activity level be examined. METHODS: Among 226 Japanese men and women 20 to 83 years of age, total energy expenditure (TEE) was assessed using the Japan Arteriosclerosis Longitudinal Study Physical Activity Questionnaire (JALSPAQ), and the results were compared with TEE measured by the DLW method as a gold standard. Resting metabolic rate (RMR) was measured using the Douglas Bag method. RESULTS: The median TEE by DLW and physical activity level (PAL: TEE/RMR) were 11.21 MJ/day and 1.88, respectively, for men, and 8.42 MJ/day and 1.83 for women. JALSPAQ slightly underestimated TEE: the differences in mean and standard error were -1.15 +/- 1.92 MJ/day. JALSPAQ and DLW TEE values were moderately correlated (Spearman correlation = 0.742, P < 0.001; intraclass correlation coefficient = 0.648, P < 0.001), and the 95% limit of agreement was -4.99 to 2.69 MJ. Underestimation of TEE by JALSPAQ was greater in active subjects than in less active subjects. Moderate and vigorous physical activity and physical activity during work (ie, occupational tasks and housework) were strongly related to physical activity level. However, the physical activity components that differentiated sedentary from moderately active subjects were not clear. CONCLUSIONS: Physical activity level values on JALSPAQ and DLW were weakly correlated. In addition, estimation of TEE in active subjects should be improved, and the use of a questionnaire to differentiate activity in sedentary and moderately active subjects must be reassessed. PMID- 21258167 TI - Manassantin A and B from Saururus chinensis inhibit interleukin-6-induced signal transducer and activator of transcription 3 activation in Hep3B cells. AB - Inhibition of interleukin-6 (IL-6) has been postulated to be an effective therapy in the pathogenesis of several inflammatory diseases. The current study was performed to examine potential effects of manassantin A and B isolated from Saururus chinensis on the IL-6-induced response to human hepatoma cells. We found that manassantin A and B inhibit signal transducer and activator of transcription 3 (Stat3) activity stimulated by IL-6. We also found that both compounds decreased IL-6-induced Stat3 phosphorylation and nuclear translocation. Both compounds blocked suppressor of cytokine signaling 3 (SOCS-3)-mRNA expression induced by IL-6. In addition, we found that Stat3 inhibitory effects of these compounds could be related to protein tyrosine phosphatase. These findings suggest that manassantin A and B could be useful remedies for treatment of inflammatory diseases by inhibiting IL-6 action. PMID- 21258168 TI - Nobiletin, a polymethoxy flavonoid, suppresses bone resorption by inhibiting NFkappaB-dependent prostaglandin E synthesis in osteoblasts and prevents bone loss due to estrogen deficiency. AB - Nobiletin, a polymethoxy flavonoid, prevents cancer and inflammation, but the roles of nobiletin in bone are unclear. We examined the effects of nobiletin on bone resorption in vitro and on bone mass in ovariectomized (OVX) mice in vivo. In vitro, nobiletin suppressed osteoclast formation and bone resorption induced by interleukin (IL)-1. Nobiletin suppressed the expression of cyclooxygenase-2, NFkappaB-dependent transcription, and prostaglandin E (PGE) production induced by IL-1 in osteoblasts. OVX mice showed severe bone loss in the femur by increased bone resorption due to estrogen deficiency, and nobiletin significantly restored the bone mass. Nobiletin could be beneficial to bone health in postmenopausal women. PMID- 21258169 TI - Microminipig, a non-rodent experimental animal optimized for life science research: in vivo proarrhythmia models of drug-induced long QT syndrome: development of chronic atrioventricular block model of microminipig. AB - A new in vivo proarrhythmia model of drug-induced long QT syndrome was developed using the Microminipig, an incredibly small minipig established by Fuji Micra Inc. (Shizuoka). The atrioventricular (AV) node of the Microminipig of either sex weighing approximately 6 - 7 kg was ablated under halothane anesthesia, and proper care was taken for them. Proarrhythmic effects of drugs were assessed at >2 months after the onset of AV block using a Holter recording system. Oral administration of dl-sotalol (10 mg/kg) to the AV-block Microminipig prolonged the QT interval; moreover, it frequently induced dangerous ventricular premature beats, whereas no arrhythmia was detected after the vehicle administration (n = 4). Such dl-sotalol-induced ventricular arrhythmias were not detected in the intact Microminipig with sinus rhythm, although significant QT prolongation was observed (n = 4). Thus, the sensitivity and specificity of the AV-block Microminipig for detecting the drug-induced long QT syndrome can be considered to be comparable to previously established AV-block animal models of dogs and monkeys. PMID- 21258170 TI - Microminipig, a non-rodent experimental animal optimized for life science research:novel atherosclerosis model induced by high fat and cholesterol diet. AB - Atherosclerotic lesions were observed in male and ovariectomized female Microminipig (MMP) fed a high fat and cholesterol diet with sodium cholate (HFCD/SC) for 3 months. HFCD/SC induced hypercholesterolemia accompanied by an increase in serum total cholesterol (T-Cho), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and cholesterol ester (CE). Unlike the mouse or rabbit, a dominant LDL-C fraction in the intact MMP, similar to that in humans, was observed by serum lipoprotein analysis. HFCD/SC increased body weight gain. At the end of the experiment, computed tomography scans of conscious animals showed that HFCD/SC had decreased liver attenuation values (Hounsfield unit) and increased subcutaneous and abdominal fat, suggesting the induction of fatty liver and obesity. HFCD/SC induced atherosclerotic lesions in systemic arteries, including the external and internal iliac arteries, abdominal aorta, coronary artery, and cerebral arterial circle. Atherosclerosis and pathological findings induced by HFCD/SC in MMP were similar to those in humans. The MMP is a potentially suitable tool for investigating human atherosclerosis. PMID- 21258171 TI - Microminipig, a non-rodent experimental animal optimized for life science research: preface. AB - Fuji Micra Inc. has recently achieved success in a challenging and prospective project that produces the smallest pig in the world, the "Microminipig", at a breeding farm at the foothills of Mt. Fuji in Japan. Microminipigs weigh approximately 7.0 kg at 6 months of age when they are mature. Microminipigs have been provided to several research organizations in Japan as a non-rodent experimental animal optimized for life science research. PMID- 21258172 TI - Sensory stimulation to improve swallowing reflex and prevent aspiration pneumonia in elderly dysphagic people. AB - Morbidity and mortality from aspiration pneumonia continues to be a major health problem in the elderly. A swallowing disorder, such as a delayed triggering of the swallowing reflex, exists in patients with aspiration pneumonia. We found that the swallowing reflex in elderly people was temperature-sensitive. The swallowing reflex was delayed when the temperature of the food was close to body temperature. The actual swallowing time shortened when the temperature difference increases. The improvement of swallowing reflex by temperature stimuli could be mediated by the temperature-sensitive transient receptor potential (TRP) channel. The administration of a pastille with capsaicin as an agonist stimulus of TRPV1, a warm-temperature receptor, decreased the delay in swallowing reflex. Food with menthol, an agonist of TRPM8, a cold-temperature receptor, also decreased the delay in swallowing reflex. Olfactory stimulation such as black pepper was useful to improve the swallowing reflex for people with low activity of daily living (ADL) levels or with decreased consciousness. Oral care also shortened the latent time of swallowing reflex presumably due to stimulating the nociception of the oral cavity. A combination of these sensory stimuli may improve the swallowing disorders and prevent aspiration pneumonia. PMID- 21258173 TI - Effect of orexin-A on post-ischemic glucose intolerance and neuronal damage. AB - Orexin-A is a newly identified neuropeptide expressed in the lateral areas of the hypothalamus that plays a role in various physiological functions, including regulation of glucose metabolism. We have previously reported that the development of post-ischemic glucose intolerance is one of the triggers of ischemic neuronal damage. Therefore, the aim of this study was to determine the effects of orexin-A on the development of post-ischemic glucose intolerance and ischemic neuronal damage. Male ddY mice were subjected to middle cerebral artery occlusion (MCAO) for 2 h. Neuronal damage was estimated by histological and behavioral analysis after MCAO. Intracerebroventricular administration of orexin A (2.5, 25, or 250 pmol/mouse) significantly and dose-dependently suppressed the development of post-ischemic glucose intolerance on day 1 after MCAO and neuronal damage on day 3 after MCAO. In the liver and skeletal muscle, the expression levels of insulin receptor were decreased, whereas those of gluconeogenic enzymes were increased on day 1 after MCAO. Furthermore, these expressions were completely recovered to normal levels by orexin-A and were reversed by the administration of SB334867, a specific orexin-1 receptor antagonist. These results suggest that regulation of post-ischemic glucose intolerance by orexin-A suppressed cerebral ischemic neuronal damage. PMID- 21258174 TI - Electrophysiological and pharmacological characteristics of triggered activity elicited in guinea-pig pulmonary vein myocardium. AB - The pulmonary vein is known as an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation. We analyzed electrophysiological and pharmacological characteristics of triggered activity elicited in the isolated pulmonary vein from the guinea pig. Immediately after the termination of train stimulation (pacing cycle length of 100 ms), spontaneous activities accompanied with phase-4 depolarization were detected in 43 out of 45 pulmonary vein preparations. Such triggered activities were not observed in the isolated left atrium. The incidence of triggered activity was higher at a shorter pacing cycle length (100 - 200 ms), and the coupling interval was shorter at a shorter pacing cycle length. Verapamil (1 uM), ryanodine (0.1 uM), and pilsicainide (10 uM) suppressed the occurrence of triggered activities. The resting membrane potential of the pulmonary vein myocardium was more positive than that of the left atrium. Carbachol (0.3 uM) hyperpolarized the resting membrane potential and completely inhibited the occurrence of triggered activities. These results suggest that the pulmonary veins have more arrhythmogenic features than the left atrium, possibly through lower resting membrane potential. The electrophysiological and pharmacological characteristics of triggered activity elicited in the pulmonary vein myocardium were similar to those previously reported using ventricular tissues. PMID- 21258175 TI - The effect of pantothenic acid deficiency on keratinocyte proliferation and the synthesis of keratinocyte growth factor and collagen in fibroblasts. AB - It has been reported that pantothenic acid (vitamin B5) and panthenol, an alcohol derivative of pantothenic acid, have beneficial moisturizing effects on the skin. However, few studies have investigated the mechanism of action of pantothenic acid on skin tissues. We tried to clarify the role of pantothenic acid on skin function by using keratinocytes and fibroblasts. The depletion of pantothenic acid from the culture medium suppressed keratinocyte proliferation and promoted differentiation. Moreover, pantothenic acid depletion decreased the synthesis of keratinocyte growth factor and procollagen 4a2 in fibroblasts. These results suggest that pantothenic acid is essential for maintaining keratinocyte proliferation and differentiation. PMID- 21258176 TI - Involvement of protein kinase C and RhoA in protease-activated receptor 1 mediated F-actin reorganization and cell growth in rat cardiomyocytes. AB - Protease-activated receptor 1 (PAR1) that can be activated by serine proteinases such as thrombin has been demonstrated to contribute to the development of cardiac remodeling and hypertrophy after myocardial injury. Here, we investigated the mechanisms by which PAR1 leads to hypertrophic cardiomyocyte growth using cultured rat neonatal ventricular myocytes. PAR1 stimulation with thrombin (1 U/ml) or a synthetic agonist peptide (TFLLR-NH(2), 50 uM) for 48 h induced an increase in cell size and myofibril formation associated with BNP (brain natriuretic peptide) production. This actin reorganization assessed by fluorescein isothiocyanate (FITC)-conjugated phalloidin staining appeared at 1 h after PAR1 stimulation, and this response was reduced by a protein kinase C (PKC) inhibitor, chelerythrine, inhibitors of Rho (simvastatin) and Rho-associated kinase (ROCK) (Y-27632), but not by pertussis toxin (PTX). By Western blot analysis, translocation of PKCalpha or PKCepsilon from the cytosol to membrane fractions was observed in cells stimulated with thrombin or TFLLR-NH(2) for 2 - 5 min. In addition, PAR1 stimulation for 3 - 5 min increased the level of active RhoA. Furthermore, inhibitors of PKC and ROCK and Rho abrogated PAR1-mediated increase in cell size. Depletion of PKCalpha or PKCepsilon by specific small interfering RNA also suppressed both actin reorganization and cell growth. These results suggest that PAR1 stimulation of cardiomyocytes induces cell hypertrophy with actin cytoskeletal reorganization through activation of PKCalpha and PKCepsilon isoforms and RhoA via PTX-insensitive G proteins. PMID- 21258177 TI - Bladder contractility is mediated by different K+ channels in the urothelium and detrusor smooth muscle. AB - The roles played by K(+) channels in the urothelium (UE) and detrusor smooth muscle (DSM) in regulating agonist-induced bladder contraction is not known at present. Thus, the effects in carbachol (CCh)-induced contraction in UE-intact (+UE) and UE-denuded (-UE) rat detrusor strips pretreated with K(+)-channel blockers were investigated here. The K(+)-channel blockers used were 4 aminopyridine (4-AP), glibenclamide (Glib), iberiotoxin (IbTx), charybdotoxin (ChTx), and apamin. In the absence of K(+)-channel blockers, control CCh-induced contractions were more potent in -UE than +UE strips. Treatment with IbTx and apamin resulted in more potent CCh-induced contractions in +UE strips. In -UE strips, CCh potency was increased by ChTx and Glib, but decreased by 4-AP. Different K(+) channels in the UE and DSM were thus involved in regulating bladder contractions. Contractile mediatory function of these channels, specific to the UE or DSM, may be potential drug targets in the management of bladder disorders. PMID- 21258178 TI - Sperm migration in pigs after deep intrauterine and intraperitoneal insemination. AB - Deep intrauterine insemination in pigs allows sperm deposition only into one uterine horn, but bilateral fertilization of oocytes occurs. How the sperm reach the contralateral oviduct remains disputable. The aim of this experiment was to study possible transperitoneal and/or transuterine sperm migration ways. Follicle growth and ovulation were induced in 24 peripubertal gilts with eCG and hCG 72 h after eCG. Endoscopic intrauterine insemination (IUI) was performed 32 h after hCG with 20 ml of extended semen (60 * 10(6) spermatozoa) as follows: Group CONTROL (n=8) received IUI into the right horn, and the left horn served as non treated control; Group LIGATURE (n=8) received IUI into the right horn, and the left horn was closed by endoscopic double ligature close to the bifurcation; Group INTRAPERITONEAL (IPI; n=8) received IUI into the right uterine horn, the left horn was closed by double ligature and semen was deposited intraperitoneally at the surface of the left ovary. Genital tracts were removed 65-66 h after hCG, the oviducts were flushed and ova (n=299) were analyzed for fertilization and cleavage. Furthermore, the accessory spermatozoa count/oocyte was graded as 0, without spermatozoa, 1, <5 spermatozoa, 2, 5-50 spermatozoa, 3, 50-100 spermatozoa and 4, >100 spermatozoa. The results indicate that low dose IUI into one horn provides a lower grade of accessory spermatozoa in the contra-lateral side (1.6 vs. 2.8). No spermatozoa were found in ova flushed from oviducts of the ligated uterine horn, even after intraperitoneal insemination (P<0.05), and no fertilization occurred, respectively. Our results clearly indicate that after low dose IUI into one uterine horn, spermatozoa reach the contralateral oviduct via transuterine migration. PMID- 21258179 TI - Intratesticular expression of mRNAs of both interferon gamma and tumor necrosis factor alpha is significantly increased in experimental autoimmune orchitis in mice. AB - Experimental autoimmune orchitis (EAO) is one of the models of immunological male infertility. Murine EAO is CD4+T cell-dependent and classically induced by immunization with a testicular homogenate and adjuvants. We previously established that immunization with viable syngeneic testicular germ cells (TGC) can also induce murine EAO with no use of any adjuvant. Analyses of this EAO model have already revealed that cultured spleen cells of immunized mice secreted interferon (IFN)-gamma and that treatment of the immunized mice with anti-IFN gamma monoclonal antibodies significantly suppressed the EAO. It is known that both IFN-gamma and tumor necrosis factor (TNF)-alpha are representative cytokines of Th1 cells and exhibit local toxicity toward the seminiferous epithelium in vivo. However, changes in these two cytokines in EAO-affected testes have not yet been investigated. Therefore, in the present study, we investigated the expression of intratesticular IFN-gamma and TNF- alpha mRNAs in TGC-induced EAO using real-time RT-PCR. The results demonstrated that the intratesticular mRNAs for both IFN-gamma and TNF-alpha significantly increased, while other cytokines such as IL-1alpha, IL-1beta, IL-6 and TGF-beta did not show dramatic changes in the immunized mice. These results suggest that secretion of significant amounts of IFN-gamma and TNF-alpha in situ contributes to the spermatogenic disturbance in EAO. PMID- 21258180 TI - In vitro development and postvitrification survival of cloned feline embryos derived from preadipocytes. AB - The aim of the present study was to optimize the conditions for in vitro development and postvitrification survival of somatic cell cloned feline embryos. To determine the effects of cell cycle synchronization of the nuclear donor cells, we cultured preadipocytes under serum starvation or conventional conditions. After two days in serum starvation culture, the proportion of synchronized donor cells at the G0/G1 phase was 91.6%. This was significantly higher than the proportion of non-synchronized cells in the proliferative phase (72.6%, P<0.05). The in vitro development of somatic cell nuclear transfer (SCNT) embryos reconstructed using donor cells treated under serum starvation conditions (normal cleavage rate of 65.7%, 46/70, and blastocyst formation rate of 20.0%, 14/70) was comparable to that of the serum supplemented group (52.5%, 31/59, and 20.3%, 12/59). Use of in vitro or in vivo matured oocytes as recipient cytoplasts equally supported development of the SCNT embryos to the blastocyst stage (11.9%, 5/42, vs. 9.5%, 2/21). SCNT-derived blastocysts were vitrified using the original minimum volume cooling (MVC) or the modified (stepwise) MVC method. Although none (n=10) of the SCNT blastocysts survived following vitrification by the original MVC method, the stepwise MVC method resulted in 100% survival after rewarming (n=11). In conclusion, we demonstrated that feline somatic cell cloned embryos with a high developmental ability can be produced irrespective of cell cycle synchronization of donor cells using either in vivo or in vitro matured oocytes. Furthermore, by utilizing a stepwise vitrification method, we showed that it is possible to cryopreserve cloned feline blastocysts. PMID- 21258181 TI - Expressions of lipid oxidation markers, N(epsilon)-hexanoyl lysine and acrolein in cisplatin-induced nephrotoxicity in rats. AB - The purpose of this study was to evaluate whether N(epsilon)-hexanoyl lysine (N(epsilon)-HEL) and acrolein reflect the severity of cisplatin-induced nephrotoxicity. Immunoexpression of N(epsilon)-HEL and acrolein in kidneys and their urinary concentration were examined up to day 4 post-cisplatin injection in rats. Cisplatin-induced tubular injury was observed histopathologically on days 2 4 after injection and became more severe time-dependently. On days 2-4, N(epsilon)-HEL and acrolein were immunostained in the cytoplasm of damaged tubular cells. Their immunostaining intensity and urinary levels increased as tubular injury became more severe. These results suggest that expressions of N(epsilon)-HEL and acrolein were associated with the pathogenesis of cisplatin induced nephrotoxicity. PMID- 21258182 TI - Involvement of a phosphorylation-mediated pathway to regulate the function of NSPL1 in exercise. AB - Skeletal-type neuroendocrine-specific protein like 1 (sk-NSPL1) has been demonstrated to be physiologically important in regulating the membrane translocation of glucose transporter 4 (GLUT4) in skeletal muscles. We investigated the levels of phosphorylation in proteins that are thought to be involved in exercise in wild-type and sk-NSPL1-deficient muscles with specific antibodies and phosphate-metal affinity chromatography resin (p-resin). In both normal skeletal muscle and sk-NSPL1-deficient muscle, adenosine monophosphate (AMP)-dependent kinase (AMPK) and acetyl-CoA carboxylase (ACC) were phosphorylated and adsorbed onto p-resin at high levels after exercise. On the other hand, the effect of 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), which is an activator of AMPK, in blood glucose was greatly diminished in mutant mice. P-resin adsorbed sk-NSPL1 in the membrane fraction from wild-type muscle after exercise and AICAR administration. Isolated sk-NSPL1 from wild-type also had increased adsorption onto p-resin after treatment with Ca(2+) and adenosine triphosphate (ATP). After long-term incubation of sk-NSPL1-containing membrane without ATP, sk-NSPL1 adsorption onto anion-exchange resin was drastically reduced. These results suggest that the function of sk-NSPL1 is regulated by a [Ca(2+)](i)- and AMPK-mediated pathway under exercise, and support the hypothesis that sk-NSPL1 is an important factor in the downstream of the exercise-dependent pathway in GLUT4 translocation. PMID- 21258183 TI - [Prognostic significance of Skp2 and p27(kip) in diffuse large B cell lymphoma]. PMID- 21258184 TI - [Significance of monitoring WT1 mRNA levels of peripheral blood and bone marrow in acute myeloid leukemia]. AB - This study investigated the clinical value of monitoring peripheral blood (PB) WT1 mRNA levels in acute myeloid leukemia (AML) patients. We evaluated the correlation between PB and bone marrow (BM) WT1 mRNA levels in the follow-up period of the clinical course of 17 AML patients. The levels of fusion gene transcripts in PB were also monitored when detected before chemotherapy. Patients with sustained complete remission (CR) showed a trend toward a higher WT1 mRNA reduction rate by induction therapy than patients who relapsed after CR (p=0.09). Correlation between the WT1 levels of PB and BM samples obtained on the same day was relatively strong (R=0.87). Among the four fusion transcript-positive patients, the levels of fusion transcripts and WT1 showed a similar transition pattern. These findings suggest that WT1 mRNA is a useful marker to improve risk stratification for post-induction therapy and to guide management of individual AML patients by monitoring minimal residual disease, especially for patients with no disease-specific marker. Since WT1 monitoring via PB sampling is simple and less invasive than BM sampling, the use of this marker also improves patient management. PMID- 21258185 TI - [ABVD chemotherapy for Hodgkin lymphoma at a single institute]. AB - Fifty-eight newly diagnosed patients with Hodgkin lymphoma were treated with ABVD chemotherapy at Yokohama City University Hematology group from October 1996 to June 2005. The median age of patients age was 41 years old and ranged from 15 to 75. Thirty-eight patients were in the early stage and 20 patients were in the advanced stage. Patients in the early stage received 3 cycles of ABVD chemotherapy and involved-field radiation therapy, while those in the advanced stage received 6 cycles of ABVD chemotherapy. The overall response rate in patients was 100% (CR 87%, PR 13%) in the early stage and 95% in the advanced stage. With a median follow-up of 44 months, the 3-year progression-free survival and overall survival were 89% and 95% in the early stage, and 70% and 81% in the advanced stage, respectively. The results of this study were similar to those previously reported in Western countries. PMID- 21258186 TI - [Therapeutic choice for the chronic myeloid leukemia patients in chronic phase showing late suboptimal response to imatinib]. AB - The response criteria proposed by European Leukemia Net are useful to predict the prognosis of de novo chronic myeloid leukemia (CML) patients in the chronic phase (CP) treated with imatinib. However, the clinical significance of late suboptimal response, which is defined as the achievement of CCgR without MMR after 18 months, is controversial. In this study, we retrospectively analyzed the clinical courses of 16 CML-CP patients, who satisfied the criteria for late suboptimal response. The median duration of imatinib treatment was 62 (25~87) months. The median starting dose of imatinib was 400 mg/day. Imatinib dose was escalated to 600~800 mg/day in 10 patients for various reasons. Among 4 patients who continued high-dose imatinib for late suboptimal response, 2 patients subsequently achieved MMR, and BCR-ABL mRNA transcript levels were decreasing in 2 patients. However, imatinib was kept at 300 or 400 mg/day in 6 patients. Among these six patients, 4 patients achieved MMR, while 2 failed to achieve MMR. None of 16 patients progressed to the acute phase or blast phase. Imatinib dose escalation was effective for late suboptimal response. Furthermore, a second tyrosine kinase inhibitor such as nilotinib may be more potent to reduce the risk of disease progression by achieving earlier MMR. PMID- 21258187 TI - [Chronic myeloid leukemia complicated with cerebellar hemorrhage and acute hydrocephalus successfully treated with imatinib and intensive supportive care]. AB - We report a case of a 46-year-old female demonstrating general fatigue and visual disturbances with retinal bleeding. She had a white blood cell count of 419,300/mm. Thereafter, she developed vomiting associated with vertigo caused by cerebellar hemorrhage, deteriorating to acute hydrocephalus secondary to obstruction of the cerebral aqueduct. Emergency procedures for cerebral protection, such as hyperventilation, administration of mannitol, and barbiturate coma, were performed. Bone marrow examination showed a positive BCR ABL/t(9;22)(q34;q11) chromosomal translocation detected by FISH and RT-PCR (masked Ph) and she was diagnosed as having chronic myeloid leukemia (CML) in the chronic phase (CP). She was administered Ara-C, together with imatinib 600 mg/d through a nasogastric tube. Eight days later, she underwent successful extubation and recovered without any neurological defect. She was maintained on imatinib 400 mg/d and demonstrated a major molecular response at 15 months. Physicians need to be aware that brain hemorrhage may develop as an initial symptom of CML patients in CP. PMID- 21258188 TI - [Epstein-Barr virus-associated post-transplant lymphoproliferative disorder diagnosed by the episode of intestinal perforation following allogeneic hematopoietic stem cell transplantation]. AB - A 64-year-old man was diagnosed as having acute myeloid leukemia. We performed sequential treatment with chemotherapy and reduced-intensity stem cell transplantation from an unrelated donor while the patient was in partial remission. After engraftment, he developed acute graft-versus-host disease of the gut on day 42 and steroid therapy was started. Despite transient aggravation of diarrhea, his symptoms slowly improved and the dose of steroid was tapered. On day 159, he complained of acute left lower abdominal pain. A CT scan showed perforation of the digestive tract and ileectomy was performed. At surgery, multiple ulcers of the intestine were found and one of the ulcers was perforated. Pathologically, transmural and diffuse proliferation of atypical cells in the ulcer were confirmed. Since these cells were positive for CD20 and Epstein-Barr virus (EBV) encoded RNA, we made a diagnosis of EBV-associated post-transplant lymphoproliferative disorder (PTLD). Reduction in the dose of immunosuppressive agents and rituximab led to complete remission of PTLD. PTLD after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is relatively rare, and the development of gastrointestinal perforation after allo-HSCT is very rare. PMID- 21258189 TI - [Repetition of Helicobacter cinaedi infections during chemotherapy for malignant lymphoma]. AB - A 70-year-old male, who had undergone resection of gastric malignant lymphoma in 1992, presented with cervical lymph node swelling in January 2008. Pathological examination of the lymph node biopsy demonstrated recurrence of malignant lymphoma, and he was treated with the R-CHOP regimen. Although he did not develop fever during the first through third course of R-CHOP, from the fourth course, he repeatedly demonstrated fever over 38 degrees C for about one week after each course of chemotherapy, despite the absence of neutropenia. Helicobacter cinaedi infection was confirmed by blood culture each time. Although it is difficult to diagnose Helicobacter cinaedi infection by the standard culture method, increased numbers of recent reports especially in immunocompromised patients have emphasized the importance of diagnosing Helicobacter cinaedi infection. PMID- 21258190 TI - [Progressive multifocal leukoencephalopathy after rituximab therapy in a patient with mantle cell lymphoma]. AB - A 74-year-old man, who had mantle cell lymphoma treated with several anticancer drugs including rituximab, was admitted to our hospital because of gait disturbance and progressive paralysis of the right lower limb. T2-weighted MR image showed multiple high intensity lesions in the left parietal lobe. Suspected of being cerebral invasion of lymphoma, high-dose methotrexate was begun, but the patient died of sepsis without neurological improvement. At autopsy, it was proven that neurological symptoms had been caused by progressive multifocal leukoencephalopathy (PML). PML should be considered as a possible complication of heavily treated lymphoma. PMID- 21258191 TI - [Massive hepatic infarction occurred during the myelosuppression after re induction chemotherapy for acute myeloid leukemia]. AB - Since the liver has a duplicate blood supply through the hepatic artery and portal vein, hepatic infarction is considered a rare disease. A 51-year-old male with acute myeloid leukemia and diabetes mellitus developed fulminant hepatic infarction only a few days after administration of FLAGM chemotherapy. Our case was considered to have been caused by the almost complete obstruction of both the hepatic artery and portal vein by thrombi during a short period. Hepatic infarction should be recognized as a complication that may develop after salvage chemotherapy such as FLAGM inducing marked myelosuppression. Hepatic infarction after chemotherapy requires further analysis by evaluating a larger number of cases. PMID- 21258192 TI - Aortic arch calcification and clinical outcome in patients with end-stage renal disease. AB - Vascular calcification is very common in end-stage renal disease, especially in hemodialysis patients. Vascular calcification is associated with poor prognosis in hemodialysis patients. The transformation of vascular smooth muscle cells into osteoblast-like cells seems to be a key element in the pathogenesis of vascular calcification. In addition to traditional risk factors including hypertension and dyslipidemia, hemodialysis patients possess a number of non-traditional cardiovascular risk factors, which may be associated with the pathogenesis of vascular calcification, such as duration of dialysis and imbalance of mineral metabolism. The severity of vascular calcification can be assessed with computed tomography (CT), but a simple technique is required as a routine practice. In an attempt to evaluate the extent of vascular calcification, we have proposed a simple non-invasive technique for estimating aortic arch calcification (AoAC) in hemodialysis patients. The present review summarizes the following aspects: (i) a method of estimating AoAC and the correlation between AoAC score estimated by chest X-ray and AoAC volume evaluated by multi-detector CT as a gold standard, (ii) relation of the presence of AoAC to the prevalence of cardiovascular diseases, and (iii) Kaplan-Meier analysis in terms of cardiovascular mortality in patients with AoAC compared to those without AoAC. We suggest that screening patients undergoing dialysis for the presence of AoAC is a cost-effective, efficient way to identify those patients at the highest risk of cardiovascular events and will allow for the treatment strategies to prevent vascular calcification. PMID- 21258193 TI - [Effect of acid pump antagonist (Revaprazan, Revanex(R)) on the result of 13C urea breath test in the patients with Helicobacter pylori associated peptic ulcer disease]. PMID- 21258194 TI - [The role of NF-kappaB in colon cancer]. AB - Colon cancer is the 3rd common malignancy and 4th common cause of cancer death in Korea. Recent studies have shown that abnormal inflammatory response plays a critical role in colon carcinogenesis. A striking example of connection between inflammation and cancer is NF-kappaB, in which key regulator of inflammation and immune response is associated with target for colon cancer treatment. Constitutive NF-kappaB expression in colon cancer is 40-80% in vivo as well as in vitro, and the inactivation of IKKbeta subunit can reduce tumor multiplicity. The possible mechanisms by which NF-kappaB can contribute to colon carcinogenesis include the activator of antiapoptotic gene expression, enhanced cell survival and proliferation, regulation of angiogenesis and promotion of metastasis of cancer cells. Recent insights into the role of NF-kappaB involved in colon cancer development as well as their relevance as therapeutic targets are herein discussed. PMID- 21258195 TI - [Effect of acid pump antagonist (Revaprazan, Revanex(R)) on result of 13C urea breath test in patients with Helicobacter pylori associated peptic ulcer disease]. AB - BACKGROUND/AIMS: Revaprazan (Revanex(R)) is a novel proton pump inhibitor (PPI) that has a somewhat different effect on proton pump compared with the other PPI's, also (called as 'acid pump antagonist'). We aimed to examine the false negative rate of 13C-urea breath test (UBT) in the patients with Helicobacter pylori (H. pylori) associated peptic ulcer disease who were treated with revaprazan and evaluate the anti-urease activity of revaprazan. METHODS: Total 55 patients were enrolled in this study. They received EGD examination between January 2009 and December 2009 and diagnosed histologically as H. pylori associated peptic ulcer disease. All patients took revaprazan only. Three patients were excluded because of underlying chronic disease and inappropriate breath sampling. The remaining 52 patients had UBT at 0, 2 and 4 weeks of revaprazan use. After 2 weeks of the cessation of revaprazan, they had the fourth UBT. RESULTS: At 2 and 4 weeks, the false negative rates of UBT were 5.8% and 23.1%, respectively (p=0.05). After 2 weeks of the cessation, the cases of the false negative result were five. Four out of five patients had prolonged negative results on two or three successive tests, and baseline 13C difference value did not predict the false negative results. CONCLUSIONS: False negative results of UBT were common and increased with prolonged use of acid pump antagonist. As PPI, it had also anti-urease activity and most patients (47/52, 90.4%) reverted to positive results by 2 weeks after the cessation of taking the medication. PMID- 21258196 TI - [The prevalence of Yersinia infection in adult patients with acute right lower quadrant pain]. AB - BACKGROUND/AIMS: Clinical manifestations of intestinal yersiniosis include enterocolitis, mesenteric adenitis, and terminal ileitis presenting with fever, right lower quadrant pain, and leukocytosis. According to a previous Korean study in 1997, Yersinia was revealed in two among 15 adult patients with mesenteric adenitis (13%). However, recent reports on the prevalence of Yersinia infection in adult patients are few. The aim of this study was to investigate the prevalence of Yersinia infection in adult patients with acute right lower quadrant pain. METHODS: Adult patients (>18 years) who visited Eulji medical center, due to acute right lower quadrant pain were enrolled prospectively from December 2007 to July 2009. Abdominal CT, stool culture, serologic test for Yersinia, and Widal test were performed. RESULTS: Among 115 patients, 5 patients were excluded due to positive Widal test or salmonella culture. In 110 patients, abdominal CT showed right colitis in 20 (18.2%), terminal ileitis in 16 (14.5%), mesenteric adenitis in 13 (11.8%), acute appendicitis in 10 (9.1%), acute diverticulitis in 7 (6.4%), non specific mucosal edema in 36 (32.7%) and no specific lesion in 8 (7.3%). Two (1.8%) of the 110 patients had antibodies to Yersinia. One patient showed acute enteritis and the other patient was diagnosed with acute appendicitis and underwent appendectomy. No Yersinia species were grown on stool or tissue culture. CONCLUSIONS: Nowadays, among adult Korean patients presenting with acute right lower quadrant pain, there have been few incidences of Yersinia infection. PMID- 21258197 TI - Validation of P2/MS and other noninvasive fibrosis scoring systems in the Korean population with nonalcoholic fatty liver disease. AB - BACKGROUND/AIMS: P2/MS is a noninvasive marker for detecting hepatic fibrosis in patients with viral hepatitis. However, the applicability of P2/MS in patients with nonalcoholic fatty liver disease (NAFLD) has not yet been validated. This study aimed to validate P2/MS and compare it to other noninvasive fibrosis scoring systems in Korean patients with NAFLD. METHODS: Consecutive patients who underwent liver biopsy between January 2002 and December 2009 at Seoul National University Hospital, Seoul, Korea were enrolled in this study. Fibrosis stage was determined using the METAVIR scoring system. RESULTS: A total of 235 patients were included in the study: advanced fibrosis (METAVIR F3-F4) was present in 7 patients. No patient was over-staged among 162 patients with a P2/MS score above the high cut-off (95), resulting in a high negative predictive value (NPV) of 100% (95% confidence interval, 97.1-100). There was no significant difference between the area under the receiver-operating characteristic curve (AUROC) of the FIB-4 (0.964) and the AUROC of the NAFLD fibrosis score (0.964) or P2/MS (0.940) for detecting advanced fibrosis. If P2/MS was implemented in the Korean patients with NAFLD, 68.9% of liver biopsies might be avoided. CONCLUSIONS: P2/MS has a high NPV for excluding advanced fibrosis in Korean patients with NAFLD, and can reduce the burden of liver biopsy in the majority of cases. Since there were few patients with advanced fibrosis, further studies are warranted in a cohort including more patients with advanced fibrosis to validate the low cut-off value. PMID- 21258198 TI - [Efficacy of a self-designed protective lead shield in reduction of radiation exposure dose during endoscopic retrograde cholangiopancreatography]. AB - BACKGROUND/AIMS: The increasing use of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP) calls for greater consideration of radiation exposure risk to endoscopists and assistants, and emphasizes the proper system of radiation protection. This study was designed to assess the effect of a newly developed, self-designed, protective lead shield. METHODS: A curtain-shaped protective shield composed of seven movable lead plates was developed, each with the following dimensions: depth, 0.1 cm; width, 15 cm; length, 70 cm. The curtain shaped protective shield was designed to be located between the patient and the endoscopist. Twenty-nine patients (11 men and 18 women) undergoing ERCP between January 2010 and March 2010 were selected for this study. The dose of radiation exposure was recorded with or without the protective lead shield at the level of the head, chest, and pelvis. The measurement was made at 50 cm and 150 cm from the radiation source. RESULTS: The mean patient age was 64 years. The mean patient height and weight was 161.7+/-6.9 cm and 58.9+/-9.9 kg, respectively. The mean body mass index (BMI) was 22.5+/-3.0 kg/m2. Endoscopists received 1522.2+/ 537.0 mR/hr without the protective lead shield. At the same distance, radiation exposure was significantly reduced to 68.8+/-88.0 mR/hr with the protective lead shield (p-value>0.0001). The radiation exposure to endoscopists and assistants was significantly reduced by the use of a protective lead shield (p value >0.0001). The amount of radiation exposure during ERCP was related to the patient's BMI (r=0.749, p=0.001). CONCLUSIONS: This self-designed, protective lead shield is effective in protecting endoscopists and assistants from radiation exposure. PMID- 21258199 TI - [A case of superior mesenteric venous thrombosis due to protein C deficiency in a patient with duodenal ulcer bleeding]. AB - Mesenteric venous thrombosis is a clinically very rare disease, and may cause bowel infarction and gangrene. Difficulty in the diagnosis the disease due to its non-specific symptoms and low prevalence can cause a clinically fatal situation. Mesenteric venous thrombosis may be caused by both congenital and acquired factors, and protein C deficiency, which is a very rare genetic disorder, is one of many causes of mesenteric thrombosis. The authors experienced a case of mesenteric venous thrombosis caused by protein C deficiency in a patient with duodenal ulcer bleeding, so here we report a case together with literature review. PMID- 21258200 TI - [Spontaneous dissolution of isolated superior mesenteric vein thrombosis in acute pancreatitis]. AB - Acute pancreatitis can result in many vascular complications in both artery and vein. Venous complication usually occurs as a form of splenic or portal vein thrombosis, and also can simultaneously occur in superior mesenteric vein as well. Rarely, isolated superior mesenteric vein thrombosis occurs as a venous complication. Although it is uncommon, mesenteric vein thrombosis is an important clinical entity because of the possibility of mesenteric ischemia and infarction of small bowel. The treatments of mesenteric venous thrombosis include anticoagulation therapy, transcatheter therapy and surgical intervention. We report a case of 45-year- old man who had acute pancreatitis with isolated superior mesenteric vein thrombosis, which was spontaneously dissolved with the resolution of underlying inflammation without anticoagulation or surgical intervention. PMID- 21258201 TI - [A case of liver abscess caused by Fusobacterium nucleatum in a patient with recurrent periodontal diseases]. AB - Fusobacteria are anaerobic gram-negative, non-spore forming bacilli found in normal flora of the oral cavity, urogenital tract, and gastrointestinal tract. Fusobacterium nucleatum has been seldom reported as a cause of liver abscess, particularly in immunocompetent hosts. A 55-year-old man with frequent periodontal disease visited our hospital with intermittent fever and headache for 2 months. Abdominal CT scan revealed an 8.2 * 6 cm mass in the right hepatic lobe with central low density. Abscess culture revealed F. nucleatum as the causative organism. Percutaneous abscess drainage and intravenous administration of antibiotics for 4 weeks improved symptoms and decreased the abscess size. We report a rare case of liver abscess due to F. nucleatum in an immunocompetent man with periodontal disease. PMID- 21258202 TI - Malignant solitary fibrous tumor of retroperitoneum mimicking gastric submucosal tumor. AB - Solitary fibrous tumors (SFTs) are an uncommon neoplasm characterized by the proliferation of spindle cells. The diagnostic criteria of malignant solitary fibrous tumors (MSFTs) include high cellularity, high mitotic activity (4>10 HPF), pleomorphism, hemorrhage and necrosis. This tumor frequently involves the pleura and MSFTs of retroperitoneum mimicking gastric submucosal tumor are very rare. We report a rare case of MSFT that presented as a gastric submucosal tumor. A gastroscopic examination showed a large bulging mucosa in the gastric body. Abdominal computed tomography revealed a well-defined heterogeneous enhancing mass between the left hepatic lobe and gastric body. Surgical resection was performed and histologic features were consistent with a MSFT. PMID- 21258203 TI - [Caroli syndrome with autosomal recessive polycystic kidney disease]. PMID- 21258205 TI - The autophagosome is overrated! PMID- 21258206 TI - Phase I clinical study of combination therapy with microwave ablation and cellular immunotherapy in hepatocellular carcinoma. AB - BACKGROUND AND AIMS: To observe safety and influence on viral load and peripheral T lymphocyte subsets of combination therapy with percutaneous microwave ablation (PMWA) and adoptive immunotherapy in hepatocellular carcinoma (HCC) with hepatitis B. RESULTS: No adverse effects of grade III/IV were observed. Viral load was decreased in 57.14% (four of seven) of patients and was undetectable in two (28.6%) patients without antiviral therapy. The percentage of CD4(+)CD25(high) regulatory T lymphocytes decreased significantly, and the percentage of CD8(+)CD28(-) effector cells increased significantly 1 month after therapy. However, 6 months after therapy, there was no significant difference. METHODS: Ten HCC (D<=5 cm, fewer than 3 tumors) patients were treated with radical PMWA and three courses of immunotherapy, which were started with PMWA, 2 weeks post-PMWA, and 3 months after PMWA. Peripheral blood mononuclear cells were differentiated into phenotypically confirmed DCs and effector cells. Immature DCs, cytokine-induced killer cells (CIK) and cytotoxic T lymphocytes (CTL) were injected into the marginal area of ablated tumors under contrast-enhanced sonographic guidance. Under sonographic guidance, tumor lysate-pulsed DC was injected into groin lymph nodes, while DC-CIK and CTL were injected into the abdominal cavity. CIK was infused intravenously. CONCLUSION: Adoptive immunotherapy prescribed soon after PMWA for HCC patients was safe and ameliorated the percentage of peripheral lymphocytes. PMID- 21258208 TI - Changes in rupture formation and zonary region stained with Evans blue during the recovery process from aluminum toxicity in the pea root apex. AB - We investigated how the pea (Pisum sativum cv. Harunoka) root, upon return to an Al-free condition, recovers from injury caused by exposure to Al. Elongation and re-elongation of the root during the recovery process from Al injury occurred only in the apical 5-mm region of the pea root. With the model system of the pea root for recovery from Al injury, images of the root characterized by zonal staining with Evans blue showed the existence of two regions in the root apex consisting of rupture and zonary stained regions. Ruptures enlarged by increase in their depth but without widening of the intervals among zonary stained regions in the roots treated with Al continuously. On the other hand, intervals of the zonary stained regions were widened due to re-elongation of the root and were narrow in the rupture region in the recovery root. PMID- 21258207 TI - A role for SR proteins in plant stress responses. AB - Members of the SR (serine/arginine-rich) protein gene family are key players in the regulation of alternative splicing, an important means of generating proteome diversity and regulating gene expression. In plants, marked changes in alternative splicing are induced by a wide variety of abiotic stresses, suggesting a role for this highly versatile gene regulation mechanism in the response to environmental cues. In support of this notion, the expression of plant SR proteins is stress-regulated at multiple levels, with environmental signals controlling their own alternative splicing patterns, phosphorylation status and subcellular distribution. Most importantly, functional links between these RNA-binding proteins and plant stress tolerance are beginning to emerge, including a role in the regulation of abscisic acid (ABA) signaling. Future identification of the physiological mRNA targets of plant SR proteins holds much promise for the elucidation of the molecular mechanisms underlying their role in the response to abiotic stress. PMID- 21258209 TI - Is cell polarity under mechanical control in plants? AB - Plant cells experience a tremendous amount of mechanical stress caused by turgor pressure. Because cells are glued to their neighbors by the middle lamella, supracellular patterns of physical forces are emerging during growth, usually leading to tension in the epidermis. Cortical microtubules have been shown to reorient in response to these mechanical stresses, and to resist them, indirectly via their impact on the anisotropic structure of the cell wall. In a recent study, we show that the polar localization of the auxin efflux carrier PIN1 can also be under the control of physical forces, thus linking cell growth rate and anisotropy by a common mechanical signal. Because of the known impact of auxin on the stiffness of the cell wall, this suggests that the mechanical properties of the extracellular matrix play a crucial signaling role in morphogenesis, notably controlling the polarity of the cell, as observed in animal systems. PMID- 21258210 TI - The plant cell nucleus: a true arena for the fight between plants and pathogens. AB - Communication between the cytoplasm and the nucleus is a fundamental feature shared by both plant and animal cells. Cellular factors involved in the transport of macromolecules through the nuclear envelope, including nucleoporins, importins and Ran-GTP related components, are conserved among a variety of eukaryotic systems. Interestingly, mutations in these nuclear components compromise resistance signalling, illustrating the importance of nucleocytoplasmic trafficking in plant innate immunity. Indeed, spatial restriction of defence regulators by the nuclear envelope and stimulus-induced nuclear translocation constitute an important level of defence-associated gene regulation in plants. A significant number of effectors from different microbial pathogens are targeted to the plant cell nucleus. In addition, key host factors, including resistance proteins, immunity components, transcription factors and transcriptional regulators shuttle between the cytoplasm and the nucleus, and their level of nuclear accumulation determines the output of the defence response, further confirming the crucial role played by the nucleus during the interaction between plants and pathogens. Here, we discuss recent findings that situate the nucleus at the frontline of the mutual recognition between plants and invading microbes. PMID- 21258211 TI - Nestin is a novel target for suppressing pancreatic cancer cell migration, invasion and metastasis. AB - Nestin, is a class VI intermediate filament (IF) that is expressed in 30% of pancreatic ductal adenocarcinoma (PDAC) cases, and its expression in PDAC positively correlates with peripancreatic invasion. An expression vector carrying a short hairpin RNA (shRNA) targeting nestin was stably transfected into PANC-1 and PK-45H human pancreatic cancer cells, which express high nestin levels. Alterations in morphology and alignment of actin filaments and alpha-tubulin were examined by phase-contrast and immunocytochemistry. Effects on cell growth, migration in scratch and Boyden chamber assays, invasion, cell adhesion, and in vivo growth were determined. Differences in mRNA levels were examined by arrays. Nestin shRNA-transfected cells exhibited decreased nestin expression, a sheet like appearance with tight cell-cell adhesion, increased expression of filamentous F-actin and E-cadherin, and attenuated migration and invasion, both of which were enhanced following nestin re-expression. Expression of alpha tubulin, and in vitro cell growth and adhesion were not altered by nestin down regulation, whereas hepatic metastases were decreased. Thus, nestin plays important roles in pancreatic cancer cell migration, invasion and metastasis by selectively modulating the expression of actin and cell adhesion molecules, and may therefore be a novel therapeutic target in PDAC. PMID- 21258214 TI - Antitumor activity of sphingosine kinase 2 inhibitor ABC294640 and sorafenib in hepatocellular carcinoma xenografts. AB - The balance between the pro-apoptotic lipids ceramide and sphingosine and the pro survival lipid sphingosine 1-phosphate (S1P) is termed the "sphingosine rheostat". Two isozymes, sphingosine kinase 1 and 2 (SK1 and SK2), are responsible for phosphorylation of pro-apoptotic sphingosine to form pro-survival S1P. We have previously reported the antitumor properties of an SK2 selective inhibitor, ABC294640, alone or in combination with the multikinase inhibitor sorafenib in mouse models of kidney carcinoma and pancreatic adenocarcinoma. Here we evaluated the combined antitumor effects of the aforementioned drug combination in two mouse models of hepatocellular carcinoma. Although combining the SK2 inhibitor, ABC294640, and sorafenib in vitro only afforded additive drug drug effects, their combined antitumor properties in the mouse model bearing HepG2 cells mirrored effects previously observed in animals bearing kidney carcinoma and pancreatic adenocarcinoma cells. Combining ABC294640 and sorafenib led to a decrease in the levels of phosphorylated ERK in SK-HEP-1 cells, indicating that the antitumor effect of this drug combination is likely mediated through a suppression of the MAPK pathway in hepatocellular models. We also measured levels of S1P in the plasma of mice treated with two different doses of ABC294640 and sorafenib. We found decreases in the levels of S1P in plasma of mice treated daily with 100 mg/kg of ABC294640 for 5 weeks, and this decrease was not affected by co-administration of sorafenib. Taken together, these data support combining ABC294640 and sorafenib in clinical trials in HCC patients. Furthermore, monitoring levels of S1P may provide a pharmacodynamic marker of ABC294640 activity. PMID- 21258215 TI - The role of vascular risk factors in the development of DED syndrome among an elderly community sample. AB - OBJECTIVES: To clarify the role of vascular risk factors in the development of depression-executive dysfunction (DED) syndrome and to investigate the distinct clinical presentation of DED syndrome. SETTING: A cross-sectional community-based study in South Korea. PARTICIPANTS: : A total of 2,007 participants age 65 or older. MEASUREMENTS: Depression was diagnosed with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) criteria using a questionnaire based on the Korean version of the Composite International Diagnostic Interview. Executive dysfunction was evaluated by the Initiation/Perseveration subscale of the Korean version of the Dementia Rating Scale. Information about demography and vascular risk factors was assessed using questionnaires. RESULTS: A total of 88 depressed elderly participants were identified. Previous cerebrovascular attack was found to increase the risk of DED syndrome, whereas hypertension, hyperlipidemia, and heart disease did not. A trend (p = 0.024) emerged, although it did not reach significance, suggesting an association between diabetes and DED. Depression without executive dysfunction was not associated with any vascular risk factors. In participants who reported two or more symptoms related to DSM-IV depression criteria (N = 335), executive dysfunction was associated with psychomotor retardation, feelings of worthlessness, and feelings of guilt. CONCLUSION: These findings suggest that the concept of DED syndrome is useful for identifying geriatric depression patients with a high risk of vascular risk factors. Attention to executive dysfunction in depressive elderly patients may help clinicians identify patients who need early intervention and careful follow-up for vascular risk factors. PMID- 21258213 TI - Virulence of serotype M3 Group A Streptococcus strains in wax worms (Galleria mellonella larvae). AB - Group A Streptococcus (GAS) causes human infections that range in severity from pharyngitis ("strep-throat") to necrotizing fasciitis ("flesh-eating disease"). To facilitate investigation of the molecular basis of host-pathogen interactions, infection models capable of rapidly screening for differences in GAS strain virulence are needed. To this end, we developed a Galleria mellonella larvae (wax worm) model of invasive GAS infection and used it to compare the virulence of serotype M3 GAS strains. We found that GAS causes severe tissue damage and kills wax worms in a dose-dependent manner. The virulence of genetically distinct GAS strains was compared by Kaplan-Meier survival analysis and determining 50% lethal doses (LD 50). Host-pathogen interactions were further characterized using quantitative culture, histopathology and TaqMan assays. GAS strains known to be highly pathogenic in mice and monkeys caused significantly lower survival and had significantly lower LD 50s in wax worms than GAS strains associated with attenuated virulence or asymptomatic carriage. Furthermore, isogenic inactivation of proven virulence factors resulted in a significantly increased LD 50 and decreased lesion size compared to the wild-type strain, a finding that also strongly correlates with animal studies. Importantly, survival analysis and LD 50 determination in wax worms supported our hypothesis that a newly emerged GAS subclone that is epidemiologically associated with more human necrotizing fasciitis cases than its progenitor lineage has significantly increased virulence. We conclude that GAS virulence in wax worms strongly correlates with the data obtained in vertebrate models, and thus, the Galleria mellonella larva is a useful host organism to study GAS pathogenesis. PMID- 21258212 TI - Cortactin: a multifunctional regulator of cellular invasiveness. AB - Branched actin assembly is critical for a variety of cellular processes that underlie cell motility and invasion, including cellular protrusion formation and membrane trafficking. Activation of branched actin assembly occurs at various subcellular locations via site-specific activation of distinct WASp family proteins and the Arp2/3 complex. A key branched actin regulator that promotes cell motility and links signaling, cytoskeletal and membrane trafficking proteins is the Src kinase substrate and Arp2/3 binding protein cortactin. Due to its frequent overexpression in advanced, invasive cancers and its general role in regulating branched actin assembly at multiple cellular locations, cortactin has been the subject of intense study. Recent studies suggest that cortactin has a complex role in cellular migration and invasion, promoting both on-site actin polymerization and modulation of autocrine secretion. Diverse cellular activities may derive from the interaction of cortactin with site-specific binding partners. PMID- 21258220 TI - Journal of Thoracic Imaging. In with the new! PMID- 21258222 TI - Expert opinion: Radiation dose management in cardiopulmonary imaging. PMID- 21258219 TI - ACR Appropriateness Criteria(r) screening for pulmonary metastases. AB - Screening for pulmonary metastatic disease is an important step for staging a patient with a known or recently discovered malignancy. Here we present our recommendations for screening for metastatic disease based on recommendations from the literature and experiences of pulmonary radiologists. In short, chest computed tomographic (CT) screening is the most appropriate tool for evaluation of pulmonary metastasis in the majority of cases. Chest computed tomographic screening is also recommended for follow-up and to determine response to therapy. Other modalities such as chest radiography, magnetic resonance imaging, and scintigraphy will also be discussed. Please note that this study is a summary of the complete version of this topic, which is available on the ACR website at www.acr.org. Practitioners are encouraged to refer to the complete version. PMID- 21258223 TI - Is CT screening for lung cancer ready for prime time? PMID- 21258224 TI - Is CT screening for lung cancer ready for prime time? PMID- 21258226 TI - Evidence-based medicine in cardiothoracic imaging. PMID- 21258227 TI - Quality management in cardiopulmonary imaging. AB - Increased scrutiny of the practice of medicine by government, insurance providers, and individual patients has led to a rapid growth of quality management programs in health care. Radiology is no exception to this trend, and quality management has become an important issue for individual radiologists as well as their respective practices. Quality control has been a mainstay of the practice of radiology for many years, with quality assurance and quality improvement both relative newcomers. This article provides an overview of quality management in the context of cardiopulmonary imaging and describes specific areas of cardiopulmonary radiology in which the components of a quality management program can be integrated. Specific quality components are discussed, and examples of quality initiatives are provided. PMID- 21258228 TI - Is the "golden age" of internal medicine dead? Revisiting a conversation with Frederic C. Bartter. PMID- 21258229 TI - Physician assistants in mental health. PMID- 21258230 TI - Risk factors for the acquisition of nosocomial infection with carbapenem resistant Klebsiella pneumoniae. AB - OBJECTIVES: Carbapenem-resistant Klebsiella pneumoniae (CRKP) has been increasingly reported all over the world. In this study, we aimed to investigate the risk factors for the acquisition of nosocomial CRKP infections. METHODS: We conducted a case-control study with data collected from thirty-nine patients with nosocomially acquired CRKP infection between July 2006 and July 2008. Controls were selected at a ratio of 1:2 from patients with nosocomial carbapenem susceptible Klebsiella pneumoniae (CSKP) infection and were matched with CRKP cases for site of infection and the date of hospital admission (+/- within 5 days). T test, chi-square test, and logistic regression were used for statistical analysis. RESULTS: Bivariable analysis showed that the age of the patients (P=0.038), days of hospital stay prior to isolation of Klebsiella pneumoniae (K. pneumoniae) (P=0.043), altered consciousness (P=0.007), intensive care unit (ICU) admission within two weeks (P=0.003), tracheal intubation (P=0.027), mechanical ventilation (P=0.009), number of changes in antibiotics>=4 (P=0.001), exposure to carbapenems (P = 0.002), exposure to fourth-generation cephalosporins (P=0.027), and exposure to piperacillin-tazobactams/cefoperazone-sulbactams (P=0.043) and glycopeptides (P=0.042) were related to CRKP infection. The multivariable analysis showed that ICU admission (within two weeks) [odds ratio (OR):4.68, 95% confidence intervals (CI):1.15-19.09, P=0.031], exposure to carbapenems (OR: 12.69, 95% CI: 2.09-77.10, P=0.006) and exposure to glycopeptides (OR: 3.57, 95% CI: 1.11-11.42, P=0.032) were independent risk factors for nosocomial CRKP infections. CONCLUSION: Several factors are related to CRKP infections. ICU admission (within two weeks) or prior exposure to carbapenems or glycopeptides are independent risk factors for the acquisition of nosocomial CRKP infections. PMID- 21258231 TI - Nephrolithiasis: evaluation and management. AB - Nephrolithiasis is a major cause of morbidity involving the urinary tract. The prevalence of this disease in the United States has increased from 3.8% in the 1970s to 5.2% in the 1990s. There were nearly two million physician-office visits for nephrolithiasis in the year 2000, with estimated annual costs totaling $2 billion. New information has become available on the clinical presentation, epidemiologic risk factors, evaluative approach, and outcome of various therapeutic strategies. In this report, we will review the epidemiology and mechanisms of kidney-stone formation and outline management aimed at preventing recurrences. Improved awareness and education in both the general population and among health-care providers about these modifiable risk factors has the potential to improve general health and decrease morbidity and mortality secondary to renal stone disease. PMID- 21258232 TI - Perioperative fluid administration: another form of "work-life balance". PMID- 21258233 TI - Pick up the pieces: depth of anesthesia and long-term mortality. PMID- 21258234 TI - Latex sensitization: a special risk for the obstetric population? AB - BACKGROUND: Previous studies have reported a greater frequency of sensitization to latex in the female population and a higher incidence of anaphylactic reactions to latex during cesarean section. In this study, the authors investigated the prevalence of latex sensitization in obstetric patients compared with nonpregnant subjects. METHODS: Two hundred ninety-four healthy pregnant women who were at term with a singleton fetus and scheduled for caesarean section (group A) were compared with 294 healthy nulliparous women with childbirth potential undergoing gynecologic surgery (group B). Before surgery, patients completed a questionnaire, and venous blood samples were collected to measure specific immunoglobulin E serum concentrations with a fluorescent enzyme immunoassay test. Skin-prick tests were performed if adverse reactions occurred during surgery. Latex allergy was diagnosed on the basis of immunoglobulin E results and/or positive skin-prick tests. RESULTS: The prevalence of latex sensitization was higher in group A than in group B (15/294, 5.1% vs. 5/294, 1.7%; P < 0.05). A significant difference in specific immunoglobulin E serum concentration was noted between pregnant and nonpregnant patients who had a positive fluorescent enzyme immunoassay test (median serum concentration: 1.93 kilounits/l; interquartile range = 2.28 vs. 0.78 kilounits/l; interquartile range = 1.07; P less than 0.05). Two patients in group A experienced an anaphylactic reaction to latex. Statistical analysis disclosed no association between latex sensitization and accepted risk factor for latex allergy. CONCLUSIONS: The authors report a higher prevalence of latex sensitization in the obstetric population than in nonpregnant subjects undergoing gynecologic surgery. PMID- 21258235 TI - Hepcidin and anemia of the critically ill patient: bench to bedside. PMID- 21258236 TI - Remifentanil degradation in umbilical cord blood of preterm infants. AB - BACKGROUND: No pharmacokinetic data about remifentanil in preterm infants exist, although remifentanil is increasingly used in this especially vulnerable subgroup of pediatric patients. Unfortunately, ethical restrictions in the volume of blood that can be withdrawn for kinetic sampling nearly prohibit pharmacokinetic studies in preterm infants. METHODS: Because remifentanil is rapidly metabolized by nonspecific blood esterases, we collected umbilical cord serum of preterm and term infants to investigate whether the activity of nonspecific blood esterases depends on gestational age. Umbilical cord serum, buffer solution, ascorbic acid, and remifentanil were mixed in a glass vial placed in a shaking water bath at 37 degrees C. Subsequently, serum samples were subjected to liquid chromatography mass spectrometry-based analysis of remifentanil and its metabolite GR90291 after 0, 30, 60, 100, and 150 min. RESULTS: We analyzed umbilical cord serum samples of 34 preterm infants (24-36 gestational weeks) and six term infants. The degradation rates of remifentanil to its major metabolite GR90291 were comparable in preterm and term infants. The overall median degradation half-life of remifentanil was 143 +/- (interquartile range) 47 min (minimum, 76 min; maximum, 221 min) without significant differences between very preterm infants (less than 28 gestational weeks) and term infants. The remifentanil concentration remained stable in control runs without serum. CONCLUSIONS: Our study demonstrates that very preterm infants exhibit a high nonspecific esterase activity in umbilical cord blood that is comparable with that of term infants. These results support clinical experiences that remifentanil is rapidly metabolized by preterm infants without prolonged side effects. PMID- 21258237 TI - Impact of applying the more stringent validation criteria of the revised European Society of Hypertension International Protocol 2010 on earlier validation studies. AB - OBJECTIVE: Since 2002 when the European Society of Hypertension International Protocol (ESH-IP) was published it has become the preferred protocol for validating blood pressure monitors worldwide. In 2010, a revised version of the ESH-IP with more stringent criteria was published. This study assesses the impact of applying the revised ESH-IP criteria. METHODS: A systematic literature review of ESH-IP studies reported between 2002 and 2010 was conducted. The impact of applying the ESH-IP 2010 criteria retrospectively on the data reported in these studies was investigated. The performance of the oscillometric devices in the last decade was also investigated on the basis of the ESH-IP criteria. RESULTS: Among 119 published studies, 112 with sufficient data were analyzed. According to ESH-IP 2002, the test device failed in 19 studies, whereas by applying the ESH-IP 2010 criteria in 28 additional studies increased the failure rate from 17 to 42%. Of these 28 studies, in 20 (71%) the test device failed at part 1 (accuracy per measurement) and in 22 (79%) at part 2 (accuracy per subject). Most of the failures involved the '5 mmHg or less' criterion. In the last decade there has been a consistent trend toward improved performance of oscillometric devices assessed on the basis of the ESH-IP criteria. CONCLUSION: This retrospective analysis shows that the stricter revised ESH-IP 2010 criteria will noticeably increase the failure rate of devices being validated. Oscillometric devices are becoming more accurate, and the revised ESH-IP by acknowledging this trend will allow more accurate devices to enter the market. PMID- 21258238 TI - Speech intelligibility as a predictor of cochlear implant outcome in prelingually deafened adults. AB - OBJECTIVES: Among adult patients with prelingual deafness, interindividual variability in speech perception outcome after cochlear implantation is generally large. It was hypothesized that the intelligibility of the patient's own speech may be predictive of speech perception with a cochlear implant. The objectives were (1) to provide a validation of a new test battery as a measurement tool for intelligibility using a group of prelingually deafened patients; (2) to investigate the validity of the test battery as a predictor of postimplant speech perception, based on preliminary data with a cochlear implant from a subgroup of patients; and (3) to investigate the validity of the test battery as a predictor of postimplant health-related quality of life (HRQoL) for the same subgroup of patients. DESIGN: Twenty-five adult cochlear implant candidates with prelingual deafness participated in this study. Average age at onset of deafness was 8 mos (range 0 to 4 yrs). Speech samples from the participants were recorded and presented to two normal-hearing listeners. Results from the seven intelligibility tests in the battery were subjected to analyses of reliability and validity. Furthermore, the multiple test outcomes were submitted to a Principal Component Analysis to investigate the possibility of summarizing the data. Subsequently, from the group of 25 participants, 9 participants with above-average intelligibility were selected for implantation. Speech perception data with a cochlear implant from the nine implantees were collected at 12 mos postimplantation, as well as HRQoL data. Predictive validity of the intelligibility test battery was determined, using the postimplant data as the criterion. RESULTS: Results from the 25 participants averaged over listeners showed that all tests in the battery had good reliability and validity as measures of intelligibility. Principal Component Analysis showed that the multiple test outcomes could be summarized by a single underlying variable. Despite the early age at onset of deafness, the subgroup of nine participants who received a cochlear implant included several good performers in terms of speech perception with the implant. The intelligibility test battery summary score had good validity as a predictor of postimplant outcome: the more intelligible the participant's speech, the better his or her speech perception outcome with the cochlear implant. Availability of effective auditory input in early life may be the fundamental factor underlying the potential for speech perception with a cochlear implant in later life. The intelligibility test battery can be reduced to a single test to minimize testing time without negatively affecting its predictive validity. Predictive validity of the intelligibility test battery can be generalized to HRQoL outcomes of cochlear implantation, provided these outcomes are concerned with speech processing abilities. CONCLUSIONS: The new test battery (or its reduced version), used as a measure of intelligibility, is a promising tool for guiding cochlear implant candidacy decisions and counseling for individual patients with prelingual deafness. Because intelligibility has superior predictive power in comparison to age at onset of deafness, the latter should be discarded as an exclusion criterion for cochlear implantation. PMID- 21258239 TI - Impact of hepatitis C virus infection on the course and outcome of patients with acute alcoholic hepatitis. AB - BACKGROUND AND AIMS: Limited information is available on the impact of hepatitis C virus (HCV) infection on the clinical course and outcome of acute alcoholic hepatitis (AH), a condition with a significant mortality. We designed this retrospective study to assess effect of HCV on the outcome of patients with AH. METHODS: Medical charts of patients with a discharge diagnosis of AH (defined using rigorous clinical criteria) were reviewed. Patients were stratified based on the presence or absence of concomitant HCV infection. The disease severity was estimated at admission and at day 7 using model for end-stage disease and discriminant function index scores. Patient survival at 6 months was confirmed with the county death registry. RESULTS: A total of 76 (29 HCV positive) AH cases were analyzed. At admission, disease severity was similar in both groups with severe disease in 53% (49% of AH alone and 59% of AH+HCV; P = 0.18). Although severity scores at day 7 were not available for all patients, disease severity tended to be worse for patients with AH+HCV. Kaplan-Meier survival curves showed a poor survival for AH+HCV compared with AH alone (69 vs. 91%; log-rank P = 0.015). Although patients with AH+HCV were treated less often compared with AH alone (27 vs. 54%; P = 0.05), HCV emerged as an independent risk factor for a poor outcome at 6 months (Cox proportional hazard ratio 8.45; P = 0.01) after controlling for patient demographics, disease severity at admission, and treatment. CONCLUSION: HCV may be a risk factor for patients with AH with a worse outcome at 6 months. If our findings are confirmed in larger databases, prospective studies are needed to examine mechanisms for this effect of HCV on the outcome of AH. PMID- 21258240 TI - Treatment patterns in paediatric patients with a new diagnosis of gastroesophageal reflux disease. AB - OBJECTIVE: Few data exist on the treatment of gastroesophageal reflux disease (GERD) in paediatrics. The objective of this study was to examine treatment patterns of GERD in paediatrics in the primary care. METHODS: Incident GERD cases among paediatric patients were identified using The Health Improvement Network UK primary care database. We assessed prescription treatments in 30 days before and any time after the date of diagnosis. Initial treatment was defined as that received in 30 days either side of diagnosis. Odds ratios and 95% confidence intervals of receiving the treatment were calculated by multiple logistic regressions. RESULTS: The incident GERD cohort comprised 1700 paediatric patients aged 1-17 years. Antacids were initially prescribed in 49.2% of patients. Similar proportions of patients (23.3 and 22.9%) received histamine-2 receptor antagonists (H(2)RAs) and proton pump inhibitors (PPIs); 7.5% were prescribed prokinetics and 19.3% received no prescribed treatment. Overall, 24.7% of initial H(2)RA users switched to PPIs, and 9.8% of those using PPIs switched to H(2)RAs. The likelihood of the use of PPI increased with age and was lower in girls than in boys (odds ratio: 0.7; 95% confidence interval: 0.5-0.9). CONCLUSIONS: Antacids are the drugs most frequently prescribed by primary care physicians to paediatric patients with GERD, and approximately half receive an initial course of antisecretory treatment with H(2)RAs or PPIs. This study suggests that treatment patterns in paediatrics differ from those in adults. PMID- 21258241 TI - Characteristics of the home health practice setting that attract and retain physical therapists: results of a survey and implications for home health. AB - An electronic survey of the home health (HH) section members of the American Physical Therapy Association (APTA) found that physical therapists (PTs) are attracted to HH for flexible work hours, the ability to work one on one with a patient, the functional setting, and salary, in that order. They continue to practice in HH because they take pride in their work, the relationships they have with their patients/caregivers, their ability to make autonomous work decisions, their control over their schedule, the relationships they have within the home health agency (HHA), salary, the relationships they have with peers, their benefits, and their ability to handle documentation demands, in that order. PMID- 21258242 TI - Comparisons of the effects of biological membrane (amnion) and silver sulfadiazine in the management of burn wounds in children. AB - This prospective study was conducted on 102 children with second-degree thermal burns to assess qualitative differences between topical silver sulfadiazine (SD) and oven-dried, radiation-sterilized human amnion as wound dressing. The patients were divided into silver SD and amniotic membrane (AM) group by random sampling technique. The variables compared 1) the number of days admitted in the hospital, 2) the number of dressing changes, 3) time needed for epithelialization, 4) comfort and pain of the patients during dressing, 5) comfort and pain of the patients between dressings, 6) activities during treatment, 7) acceptability of the modules by the patients or attending guardians, and 8) comfort of the doctor during application. Patients' ages ranging from 1 day to 12 years and admitted to inpatient burn unit within 72 hours of occurrence were included in this study. Fifty-one burned children enrolled in each group. The mean hospital stay is significantly lower in AM group (P < .01). The number of dressing changes in AM group was significantly low (P < .001). The mean time taken for epithelial coverage of superficial second-degree burns is significantly lower in AM than in SD group (P < .001) and also those of deep second-degree burns (P < .001). Application was painless in AM than SD group (P < .001). State of pain in-between application shows significant difference (P < .001). Application of AM was comfortable to the attending doctor (P < .001). Significant activity of the patients was observed during treatment (P < .01) with AM. AM was accepted by the patients or parents (P < .001). This study indicates that radiation-sterilized, oven-dried AM is a better treatment option because its use reduces hospital stay and the number of dressing changes. Epithelialization of the wound is quicker. The use of AM is painless and odorless. The procedure is easy and comfortable to the doctor, and it is well accepted. Most of the patients remain ambulatory during treatment. PMID- 21258243 TI - Treatment of the elderly when cure is the goal: the influence of age on treatment selection and efficacy for stage III non-small cell lung cancer. AB - BACKGROUND: : Treatment of elderly patients with stage III NSCLC is controversial. Limited data exist, as the elderly are underrepresented in clinical trials. METHODS: : After ethics approval, we performed a retrospective review of 1372 stage III NSCLC patients treated at our institution during the period 1997-2007. Patients with malignant effusions and microscopic N2 discovered only postoperatively were excluded, leaving 740 who were classified by treatment plan: palliative (palliative chemotherapy or radiation [<=40 Gy]); nonsurgical multimodality (>40 Gy radiation +/- chemotherapy); or surgical multimodality (chemotherapy, radiation, and surgery). Demographics, treatment, toxicity, and survival were analyzed by age, 0 to 65 years, n = 384; 66 to 75 years, n = 256; 76+ years, n = 100, and compared using log-rank, univariate, and multivariate statistical tests. RESULTS: : Patients older than 65 years were more likely to have poor performance status (p < 0.0001), multiple comorbidities (p < 0.0001), and to receive palliative therapy only (p < 0.0001). Older and younger patients treated with curative intent with nonsurgical bimodality therapy or trimodality therapy including surgery had similar rates of grade 3/4 toxicity (0-65 years, 39%; 66-75 years, 43%; 76+ years, 5%; p = 0.18) and toxic death (0-65 years, 4%; 66-75 years, 4%; 76+ years, 0%; p = 0.76). Survival was worse with increasing age (p < 0.0001), likely due to greater use of palliative treatment in the elderly. When survival was analyzed for patients treated with curative intent, there was no difference between age groups for nonsurgical (p = 0.32) or surgical (p = 0.53) therapy. CONCLUSION: : In select fit elderly patients, combined modality therapy is tolerable and is associated with survival similar to that of younger patients. PMID- 21258244 TI - Tumor regression and positional changes in non-small cell lung cancer during radical radiotherapy. AB - INTRODUCTION: We have used respiratory-correlated cone beam computed tomography (rcCBCT) imaging to study the volumetric and positional changes that occur throughout the course of radical radiotherapy in non-small cell lung cancer (NSCLC). METHODS: Tumor volumes and centers of mass were recorded and analyzed on weekly serial rcCBCT images of NSCLC patients treated with radical radiotherapy to a dose >=45 Gy with concurrent chemotherapy. RESULTS: Sixty patients with locally advanced NSCLC were included; in 31 patients, the primary tumor was peripheral and thus suitable for contouring. There was a mean percent decrease of 40.2% by fraction 15 and 51.1% by treatment completion. Among all 60 patients, 19 patients (32%) had more than 30% regression by fraction 15 and 25 patients (81%) by treatment completion. Statistically significant tumor migration in at least one direction between the first and the last 2 weeks was demonstrated in 14 of 27 patients. Clinically relevant changes (atelectasis and effusions) were noted in 11 of 29 visually assessed patients. CONCLUSIONS: Current rcCBCT image quality allows assessment of tumors located more peripherally. Significant tumor regression was documented in the majority of patients. In view of these observations, the suitability of adaptive radiotherapy in radical lung cancer treatment should be further investigated. PMID- 21258245 TI - Causes and consequences of deviation from multidisciplinary care in thoracic oncology. AB - BACKGROUND: Multidisciplinary decision making is advocated in thoracic oncology because of the multiplicity of management options. This approach is difficult to implement, and its benefits are empirical and likely depend on compliance with recommendations. We evaluated patient outcomes after discussion in a multidisciplinary thoracic oncology conference (MTOC). METHODS: Retrospective review of all cases presented at a weekly MTOC from February 1, 2006 to October 30, 2009. Patients were separated into cohorts based on concordance between MTOC recommendations and actual clinical care. Patient characteristics, MTOC recommendations, clinical care, and outcomes were compared between the two cohorts using appropriate statistical methods. RESULTS: Three hundred seventy-six patients were discussed at MTOC, and 454 sets of recommendations were made. Thirty-seven percent of patients received discordant care. Health insurance status and race were the only demographic factors significantly associated with receipt of discordant care. The likelihood of concordance with specific recommendations varied significantly. Patients who received concordant care had significantly shorter delay to onset of definitive therapy (p < 0.002), longer overall (p < 0.004), and progression-free survival (p < 0.02). The stage-adjusted hazard ratio for overall and progression-free survival in the concordant care cohort was 1.7 and 1.4, respectively. Sixty percent of all discordant care could be attributed to clinicians' decision. CONCLUSIONS: Deviation from multidisciplinary recommendations may be associated with significantly worse outcomes in patients discussed in an MTOC. Further investigation into the causes of discordant care is warranted. PMID- 21258246 TI - Accuracy of fine needle aspiration cytology in the pathological typing of non small cell lung cancer. AB - BACKGROUND: Histological typing of non-small cell lung cancer (NSCLC) has an increasing clinical relevance due to the emerging differences in medical treatment between squamous and nonsquamous tumors. However, most NSCLCs are diagnosed in an advanced stage, and the diagnosis is often obtained exclusively by cytology either exfoliative or following fine needle aspiration. We investigated the accuracy of fine needle aspiration cytology (FNAC) in NSCLC typing as compared with histology. METHODS: Over the period 2000-2009, 1182 transbronchial needle aspirate or transthoracic needle aspirate samples were obtained from patients with suspicious thoracic lesions. In 474 patients, a cytological diagnosis of primary NSCLC was obtained, and 186 (39%) of them (108 transbronchial needle aspirates and 78 transthoracic needle aspirates) received a parallel or subsequent histologic diagnosis on endoscopic biopsy (112) or surgery (74). RESULTS: At cytology, 158 (85%) NSCLC cases were typed (89 adenocarcinoma and 69 squamous cell carcinoma), while 28 (15%) were classified as NSCLC not otherwise specified. At histology, 183 (98%) cases were typed (109 adenocarcinoma, 69 squamous cell carcinoma, 3 adenosquamous carcinoma, and 2 large cell carcinoma), and only 3 (2%) were classified as NSCLC not otherwise specified. Cytological and histological typing was concordant in 137 of 156 (88%) cases (K = 0.755; p < 0.001). The positive predictive value of FNAC in typing NSCLC was 92% for adenocarcinoma and 82% for squamous cell carcinoma. CONCLUSION: FNAC in expert hands is fairly accurate for typing NSCLC and can be regarded as an acceptable procedure for diagnostic and medical treatment planning purposes in most NSCLC cases, especially when more invasive approaches are unfeasible. In poorly differentiated and doubtful cases, the use of ancillary techniques, such as immunocytochemistry, may be required to improve the diagnostic yield. PMID- 21258247 TI - Screening of anaplastic lymphoma kinase rearrangement by immunohistochemistry in non-small cell lung cancer: correlation with fluorescence in situ hybridization. AB - BACKGROUND: The use of a standard immunohistochemistry (IHC) assay to detect the anaplastic lymphoma kinase (ALK) protein in lung cancer is challenging. There are no universally accepted, evidence-based guidelines on identifying patients with ALK-rearranged lung cancer using IHC. METHODS: We retrospectively reviewed 465 resected specimens of non-small cell lung cancer using a tissue microarray as a test set. ALK protein expression using IHC with 5A4 monoclonal antibody (Novocastra) and ALK gene rearrangement using fluorescence in situ hybridization (FISH) with dual-color break-apart probes (Abbott molecular) were examined. Immunoreactivity was scored as 0, 1, 2, or 3, and the results were compared with the FISH results. A diagnostic algorithm was derived from the correlation of the IHC and FISH results and applied to an additional 187 adenocarcinoma samples used as a validation set. RESULTS: In the test set, ALK protein expression was detected in 40 patients (40/465, 8.6%), consisting of IHC scores of 1 (n = 14), 2 (n = 10), and 3 (n = 16), whereas 19 patients (19/453, 4.2%) were FISH-positive. All the FISH-positive patients were assigned IHC scores of 2 or 3. All the patients with ALK IHC scores of 3 were FISH-positive, those with scores of 0 or 1 were FISH-negative, and those with scores of 2 were FISH variable. In the validation set, ALK protein expression was detected in 14 patients (scores of 1, n = 2; scores of 2, n = 6; and scores of 3, n = 6), of which nine patients (9/187, 4.8%) were FISH-positive. All the patients with IHC scores of 0 or 1 were FISH-negative, and those with scores of 3 were FISH- positive. Among the patients with IHC scores of 2, three (3/6, 50%) were FISH-positive. CONCLUSIONS: The sensitivity and specificity of IHC was 100% and 95.8%, respectively. These data supported an IHC scoring algorithm in which ALK IHC scores of 0, 1, or 3 were highly compatible with FISH results, and IHC scores of 2 were variable. Based on these findings, the IHC assay using the 5A4 antibody reliably detected non-small cell lung cancer with ALK rearrangement and may be useful as a screening method to identify these tumors. PMID- 21258248 TI - Foxp3(+) regulatory T cells and natural killer cells distinctly infiltrate primary tumors and draining lymph nodes in pulmonary adenocarcinoma. AB - INTRODUCTION: Regulatory T cells (Tregs) can play a key role in suppressing T cell-mediated immunity in patients with cancer. In this study, the immune cell composition of the lung tissue and draining lymph nodes from patients with non small cell lung cancer was analyzed. METHODS: Samples (solid tumor, tumor border, and tumor-free lung tissue, as well as intrapulmonal N1 and mediastinal N2 lymph nodes) from 30 patients subjected to curative resection were analyzed by immunohistochemistry and flow cytometry. RESULTS: Immunohistochemistry showed the presence of Foxp3(+) Tregs in tumor-infiltrated lung tissue, scattered Tregs in tumor-free lung samples, and a large number of these cells in metastatic lymph nodes. Using flow cytometry, we observed a significant enhancement of CD4(+) T cells and Foxp3(+) Tregs in the tumor center of adenocarcinoma samples, when compared with tumor-free lung tissues and tumor periphery. This enrichment was associated with a drastic decrease in natural killer cell amounts. Metastatic lymph nodes also showed higher Treg numbers than tumor-free ones in patients with lung adenocarcinomas. In contrast, patients with squamous cell carcinomas displayed less profound accumulation of Tregs. CONCLUSION: Accumulation of Tregs in the center of lung tumors and in metastatic lymph nodes in combination with a decrease in the natural killer cell numbers suggests a critical role of Treg in the formation of immunosuppressive tumor microenvironment. Therefore, lung cancer immunotherapy may be improved by a specific Treg elimination or suppression. PMID- 21258249 TI - Lovastatin sensitizes lung cancer cells to ionizing radiation: modulation of molecular pathways of radioresistance and tumor suppression. AB - INTRODUCTION: In this study, we investigated the effect of the 3-hydroxy-3 methylgutaryl-CoA reductase inhibitor lovastatin, as a sensitizer of lung cancer cells to ionizing radiation (IR). METHODS: A549 lung adenocarcinoma cells were treated with 0 to 50 MUM lovastatin alone or in combination with 0 to 8 Gy IR and subjected to clonogenic survival and proliferation assays. To assess the mechanism of drug action, we examined the effects of lovastatin and IR on the epidermal growth factor (EGF) receptor and AMP-activated kinase (AMPK) pathways and on apoptotic markers and the cell cycle. RESULTS: Lovastatin inhibited basal clonogenic survival and proliferation of A549 cells and sensitized them to IR. This was reversed by mevalonate, the product of 3-hydroxy-3-methylgutaryl-CoA reductase. Lovastatin attenuated selectively EGF-induced phosphorylation of EGF receptor and Akt, and IR-induced Akt phosphorylation, in a mevalonate-sensitive fashion, without inhibition on extracellular signal-regulated kinase 1/2 phosphorylation by either stimulus. IR phosphorylated and activated the metabolic sensor and tumor suppressor AMPK, but lovastatin enhanced basal and IR-induced AMPK phosphorylation. The drug inhibited IR-induced expression of p53 and the cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1), but caused a redistribution of cells from G1-S phase (control and radiated cells) and G2-M phase (radiated cells) of cell cycle into apoptosis. The latter was also evident by induction of nuclear fragmentation and cleavage of caspase 3 by lovastatin in both control and radiated cells. CONCLUSIONS: We suggest that lovastatin inhibits survival and induces radiosensitization of lung cancer cells through induction of apoptosis, which may be mediated by a simultaneous inhibition of the Akt and activation of the AMPK signaling pathways. PMID- 21258250 TI - Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. AB - BACKGROUND: Specific mutations of the epidermal growth factor receptor (EGFR) gene are predictive for favorable response to tyrosine kinase inhibitors (TKIs) and are associated with a good prognosis. In contrast, Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation has been shown to predict poor response to such therapy. Nevertheless, tumor that initially responds to EGFR-TKIs almost inevitably becomes resistant later. Other mechanisms of resistance to EGFR inhibitors could involve activating mutations of the other main EGFR effector pathway, i.e., the phosphoinositide-3-kinase/phosphate and tensin homologue deleted from chromosome 10 (PTEN)/alpha serine/threonine protein kinase (AKT) pathway. The aim of this study was to investigate the role of phosphoinositide-3 kinase catalytic alpha (PIK3CA), EGFR, and KRAS gene mutations in predicting response and survival in patients with non-small cell lung cancer (NSCLC) treated with EGFR-TKIs. PATIENTS AND METHODS: A total of 166 patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. PIK3CA, EGFR, and KRAS mutations were analyzed using polymerase chain reaction based sequencing. RESULTS: EGFR mutation was detected in 25.3% of patients, PIK3CA mutation in 4.1%, and KRAS mutation in 6.7%. PIK3CA mutation correlated with shorter median time to progression (TTP) (p = 0.01) and worse overall survival (OS) (p < 0.001). EGFR mutation (p < 0.0001) correlated with favorable response to TKIs treatment and longer TTP (p < 0.0001). KRAS mutation correlated with progressive disease (p = 0.05) and shorter median TTP (p = 0.003) but not with OS. Cox multivariate analysis including histology and performance status showed that PIK3CA mutation was an independent factor to predict worse OS (p = 0.0001) and shorter TTP (p = 0.03), while KRAS mutation to predict shorter TTP (p = 0.01). CONCLUSION: PIK3CA and KRAS mutations seem to be indicators of resistance and poor survival in patients with NSCLC treated with EGFR-TKIs. PMID- 21258251 TI - Variation in comorbidity and clinical management in patients newly diagnosed with lung cancer in four Scottish centers. AB - BACKGROUND: Treatment and survival rates within Scotland for patients with lung cancer seem lower than in many other European countries. No study of lung cancer has attempted to specifically investigate the association between variation in investigation, comorbidity, and treatment and outcome between different centers. METHODS: Patient demographics, World Health Organization/Eastern Cooperative Oncology Group performance status, and primary treatment modality were recorded. In addition to recording the comorbidities present in each patient, the severity of each comorbidity was graded on a 4-point scale (0-3) using validated severity scales. Data were collected as the patient was investigated and entered in an anonymized format into a database designed for the study. RESULTS: Prospectively collected data from 882 patients diagnosed with lung cancer in four Scottish centers. A number of statistically significant differences were identified between centers. These included investigation, treatment between centers (i.e., surgical rates), age, tumor histology, smoking history, socioeconomic profile, ventilatory function, and performance status. Predictors of declining performance status included increasing severity of a number of comorbidities, age, lower socioeconomic status, and specific centers. CONCLUSIONS: This study has identified many significant intercenter differences within Scotland. We believe this to be the first study to identify nontumor factors independent of performance status that together limit the ability to deliver radical, possibly curative, therapy to our lung cancer population. It is only by identifying such factors that we can hope to improve on the relatively poor outlook for the majority of Scottish patients with lung cancer. PMID- 21258252 TI - miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non small cell lung cancer. AB - INTRODUCTION: The ability to diagnose non-small cell lung cancer (NSCLC) at an early stage may lead to improved survival. The aim of this study was to identify differentially expressed serum-based microRNAs (miRNAs) between patients with early-stage NSCLC and controls. These miRNAs may serve as biomarkers for NSCLC early detection. METHODS: miRNA profiling was performed on total RNA extracted from serum obtained from 22 individuals (11 controls and 11 patients with early stage NSCLC). Quantitative polymerase chain reaction (qPCR) was used to validate the profiling results in the discovery set and in a validation set of 31 controls and 22 patients with early-stage NSCLC. Additionally, six matched plasma samples (four NSCLC cases and two controls) and three serum mesothelioma samples were analyzed by qPCR. Receiver operating characteristic curves were generated for each possible combination of the miRNAs measured by qPCR. RESULTS: The expression of hsa-miR-1254 and hsa-miR-574-5p was significantly increased in the early-stage NSCLC samples with respect to the controls. Receiver operating characteristic curves plotting these two miRNAs were able to discriminate early-stage NSCLC samples from controls with 82% and 77% of sensitivity and specificity, respectively, in the discovery cohort and with 73% and 71% of sensitivity and specificity, respectively, in the validation cohort. The mesothelioma and plasma samples did not seem to classify into either NSCLC or control groups. CONCLUSIONS: Serum miRNAs are differentially expressed between patients with early-stage NSCLC and controls. The utility of miR-1254 and miR-574-5p serum based biomarkers as minimally invasive screening and triage tools for subsequent diagnostic evaluation warrants additional validation. PMID- 21258253 TI - Clinical outcome of small cell lung cancer with pericardial effusion but without distant metastasis. AB - BACKGROUND: Pericardial effusion is defined as M1a in the Union Internationale Contre le Cancer seventh tumor, node, metastasis edition for lung cancer. The clinical course of small cell lung cancer (SCLC) with pericardial effusion but without distant metastasis (M1a) has not been adequately investigated. METHODS: The medical records of patients with SCLC treated at the National Cancer Center Hospital East between July 1992 and December 2007 were reviewed. During this period, 766 patients were newly diagnosed as having SCLC. Thirty-three of the 416 patients with limited disease (LD) SCLC (8%) had pericardial effusion. Seventy nine patients with LD-SCLC (19%) had ipsilateral pleural effusion or dissemination. Of these, 16 patients had both pericardial and ipsilateral pleural effusion. We divided the 96 M1a patients into two subgroups: group A (n = 33) included patients with pericardial effusion, and group B (n = 63) included patients with ipsilateral pleural effusion or disseminated pleural nodules but without pericardial effusion. RESULTS: The median survival time among the patients with LD-M1a was 13.4 months (95% confidence interval: 10.7-16.6 months), and the 1-, 2-, 3-, and 5-year survival rates were 56%, 18%, 9%, and 8%, respectively. The survival of the patients with LD-M1a was intermediate between those of the patients with LD-M0 and patients with extensive disease M1b (p < 0.0001). The overall survival period was not statistically different between groups A and B (p = 0.5182). Nineteen patients in group A received chemoradiotherapy, but only two patients survived for more than 2 years (2- and 5 year survival rate: 11% both). Twenty-six patients in group B received chemoradiotherapy, and four patients survived for more than 5 years (5-year survival rate: 18%). CONCLUSIONS: Long-term survival was achieved among patients with SCLC with pericardial effusion but without distant metastasis who successfully underwent chemoradiotherapy, although 5-year survival rate in these patients was relatively lower than in patients with SCLC with ipsilateral pleural effusion but without pericardial effusion or distant metastasis. PMID- 21258254 TI - The prognostic impact of cigarette smoking on patients with non-small cell lung cancer. AB - INTRODUCTION: The purposes of this study are to investigate the association between cigarette smoking and clinicopathological characteristics of patients with non-small cell lung cancer (NSCLC) and to evaluate its significance as a predictor of recurrence after resection. METHODS: A total of 2295 consecutive patients with NSCLC underwent complete resection with systematic node dissection between August 1992 and December 2006 at the National Cancer Center Hospital East. RESULTS: A statistically significant difference in the 5-year overall survival rate was observed between never and ever smokers in patients with stage I (92% and 76%, respectively, p < 0.001) NSCLC, whereas no difference was observed in stage II (57% and 52%, respectively, p = 0.739) and stage III (30% and 33%, respectively, p = 0.897). In patients with stage I NSCLC, 5-year recurrence-free proportions (RFPs) for never and ever smokers were 89% and 80%, respectively (p < 0.001). In contrast, the 5-year RFPs for never smokers were lower than those for ever smokers in stage II (44% and 60%, respectively, p = 0.049) and stage III (17% and 31%, respectively, p = 0.004). In stage I patients, significant difference in 5-year RFP was observed between never and ever smokers (89% and 83%, respectively) in patients with adenocarcinoma, but not in patients with nonadenocarcinoma (82% and 76%, respectively). CONCLUSIONS: Smoking history showed different impact on postoperative recurrence in patients with NSCLC between stage I and stages II and III, and depending on histology in stage I patients. Disease stages should be considered while evaluating smoking history as a predictor of recurrence. PMID- 21258255 TI - Spontaneous smoking cessation before lung cancer diagnosis. AB - INTRODUCTION: We have observed that many patients with lung cancer stop smoking before diagnosis, usually before clinical symptoms, and often without difficulty. This led us to speculate that spontaneous smoking cessation may be a presenting symptom of lung cancer. METHODS: Patients from the Philadelphia Veterans Affairs Medical Center with lung cancer and for comparison, prostate cancer and myocardial infarction underwent a structured interview about their smoking habits preceding diagnosis. Severity of nicotine addiction was graded using the Fagerstrom Test for Nicotine Dependence. Among former smokers, dates of cessation, onset of symptoms, and diagnosis were recorded. Difficulty quitting was rated on a scale of 0 to 10. Distributions of intervals from cessation to diagnosis were compared between groups. RESULTS: All 115 patients with lung cancer had been smokers. Fifty-five (48%) quit before diagnosis, and only six of these (11%) were symptomatic at quitting. Patients with lung cancer who quit were as dependent on nicotine, when smoking the most, as those who continued to smoke, unlike the other groups. Despite this, 31% quit with no difficulty. The median interval from cessation to diagnosis was 2.7 years for lung cancer, 24.3 years for prostate cancer, and 10.0 years for patients with myocardial infarction. CONCLUSIONS: These results challenge the notion that patients with lung cancer usually quit smoking because of disease symptoms. The hypothesis that spontaneous smoking cessation may be a presenting symptom of lung cancer warrants further investigation. PMID- 21258256 TI - Thoracoscopic assessment of pleural tumor burden in patients with malignant pleural effusion: prognostic and therapeutic implications. AB - BACKGROUND: Malignant pleural effusion (MPE) is encountered at an advanced stage of disease progression and often heralds a poor prognosis. The most reliable predictive factor of survival in such patients is the primary tumor. Thoracoscopy is often performed for accurate diagnosis and/or thoracoscopic talc insufflation as a therapeutic modality. It remains unknown whether pleural tumor burden, as visualized on thoracoscopy, has potential prognostic value. The objective of this study was to determine the prognostic accuracy of pleural tumor extent and localization (parietal, visceral, or diaphragmatic involvement), as assessed during medical thoracoscopy. METHODS: Medical records of all patients who underwent thoracoscopy for suspicion of MPE between 2001 and 2008 at a tertiary care referral hospital were reviewed. Patients were included if pleural metastatic invasion was confirmed on tissue biopsy and survival status ascertained. RESULTS: Four hundred twenty-one patients underwent diagnostic or therapeutic medical thoracoscopy at our referral center. Among them, 122 had confirmed metastatic pleural spread, but survival data were lacking in 15. Primary tumor consisted of non-mall cell lung cancer in 56, breast cancer in 23, melanoma in eight, and other malignancies in 20. Median survival of the entire population was 9.4 months. On univariate analysis, the following variables were significantly associated with reduced median overall survival: pleural metastatic melanoma, age less than 60 years, bloody MPE, extensive pleural adhesions, and widespread visceral pleural nodules (p < 0.05). On multivariate analysis, only melanoma as a primary tumor, pleural fluid appearance and extent of pleural adhesions remained independent and significant predictors of survival. CONCLUSION: No significant association was found between the extent or localization of pleural tumor burden and overall survival. PMID- 21258257 TI - Computed tomography-guided interstitial high-dose-rate brachytherapy in the local treatment of primary and secondary intrathoracic malignancies. AB - INTRODUCTION: Image-guided interstitial (IRT) brachytherapy (BRT) is an effective treatment option as part of a multimodal approach to the treatment of isolated lung tumors. In this study, we report our results of computed tomography-guided IRT high-dose-rate (HDR) BRT in the local treatment of inoperable primary and secondary intrathoracic malignancies. METHODS: Between 1997 and 2007, 55 patients underwent a total of 68 interventional procedures for a total of 60 lung lesions. The median tumor volume was 160 cm3 (range, 24-583 cm3). Thirty-seven patients were men and 18 were women, with a median age of 64 years (range, 31-93 years). The IRT-HDR-BRT delivered a median dose of 25.0 Gy (range, 10.0-32.0 Gy) in twice daily fractions of 4.0 to 15.0 Gy in 27 patients and 10.0 Gy (range, 7.0-32.0 Gy) in once-daily fractions of 4.0 to 20.0 Gy in 28 patients. RESULTS: The median follow-up was 14 months (range, 1-49 months). The overall survival rate was 63% at 1 year, 26% at 2 years, and 7% at 3 years. The local control rate for metastatic tumors was 93%, 82%, and 82% and for primary intrathoracic cancers 86%, 79%, and 73% at 1, 2, and 3 years, respectively. Pneumothoraces occurred in 11.7% of interventional procedures, necessitating postprocedural drainage in one (1.8%) patient. CONCLUSIONS: In patients with inoperable intrathoracic malignancies, computed tomography-guided IRT-HDR-BRT is a safe and effective alternative to other locally ablative techniques. PMID- 21258258 TI - Antagonism between gefitinib and cisplatin in non-small cell lung cancer cells: why randomized trials failed? AB - INTRODUCTION: Four phase III randomized trials adding epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors to standard chemotherapeutics in patients with advanced non-small cell lung cancer (NSCLC) have failed to show benefits. The mechanism of these failures was examined. METHODS: Fifteen previously untreated NSCLC cell lines were simultaneously treated with gefitinib plus cisplatin. Three exhibited sensitizing-EGFR mutations. Three selected lines were further tested with paclitaxel/cisplatin, paclitaxel/gefitinib, and paclitaxel/cisplatin/gefitinib combinations. The tetrazolium colorimetric assay with application of the classic isobole method was used, and dose-versus-log response curves (DRCs) were analyzed to evaluate possible resistance mechanisms. RESULTS: Of the 15 cell lines tested, combined gefitinib/cisplatin was significantly antagonistic in 10 wild-type and three sensitizing-EGFR mutant cell lines (group mean combination index = 1.184, 95% confidence interval = 1.12-1.24, p = 0.001). The mean combination index values of paclitaxel/cisplatin/gefitinib were higher than or comparable with those of paclitaxel/cisplatin and paclitaxel/gefitinib. DRC analysis consistently showed nonsaturable passive resistance, suggesting that gefitinib at 0.001 to 0.3 MUM can interfere with cisplatin cell entry (at concentrations >1-3 MUM) in a dose-dependent manner and lead to antagonism. This antagonism may or may not be schedule dependent in different cell lines. CONCLUSIONS: In most EGFR wild-type or sensitizing-mutant NSCLC cells, the concomitant gefitinib/cisplatin combination showed antagonism, likely because gefitinib interfered with cisplatin entry into the cell. The findings that three-drug combination was not better than the two-drug combinations are in accordance with the results of the randomized trials. The EGFR-tyrosine kinase inhibitor/platinum antagonism is a possible reason for the failure of those randomized trials. PMID- 21258259 TI - Early indicators of enduring symptoms in high school athletes with multiple previous concussions. AB - BACKGROUND: Despite recent findings of cognitive, emotional, physical, and behavioral symptomatology in retired professional athletes with a history of multiple concussions, there is little systematic research examining these symptoms in high school athletes with a history of concussion. OBJECTIVE: To identify cognitive, emotional, and physical symptoms at baseline in nonconcussed high school athletes based on concussion history. METHODS: A multicenter sample of 616 high school athletes who completed baseline evaluations were assigned to groups based on history of concussion (none, 1, 2, or more previous concussions). The Post-Concussion Symptom Scale was administered as part of a computerized neuropsychological test battery during athletes' preseason baseline evaluations. Cross-sectional analyses were used to examine symptoms reported at the time of baseline neuropsychological testing. RESULTS: High school athletes with a history of 2 or more concussions showed significantly higher ratings of concussion related symptoms (cognitive, physical, sleep difficulties) than athletes with a history of one or no previous concussions. CONCLUSION: It appears that youth athletes who sustain multiple concussions experience a variety of subtle effects, which may be possible precursors of the future onset of concussion-related difficulties. PMID- 21258260 TI - Peripheral refraction profiles in subjects with low foveal refractive errors. AB - PURPOSE: To study the variability of peripheral refraction in a population of 43 subjects with low foveal refractive errors. METHODS: A scan of the refractive error in the vertical pupil meridian of the right eye of 43 subjects (age range, 18 to 80 years, foveal spherical equivalent, < +/- 2.5 diopter) over the central +/- 45 degrees of the visual field was performed using a recently developed angular scanning photorefractor. Refraction profiles across the visual field were fitted with four different models: (1) "flat model" (refractions about constant across the visual field), (2) "parabolic model" (refractions follow about a parabolic function), (3) "bi-linear model" (linear change of refractions with eccentricity from the fovea to the periphery), and (4) "box model" ("flat" central area with a linear change in refraction from a certain peripheral angle). Based on the minimal residuals of each fit, the subjects were classified into one of the four models. RESULTS: The "box model" accurately described the peripheral refractions in about 50% of the subjects. Peripheral refractions in six subjects were better characterized by a "linear model," in eight subjects by a "flat model," and in eight by the "parabolic model." Even after assignment to one of the models, the variability remained strikingly large, ranging from -0.75 to 6 diopter in the temporal retina at 45 degrees eccentricity. CONCLUSIONS: The most common peripheral refraction profile (observed in nearly 50% of our population) was best described by the "box model." The high variability among subjects may limit attempts to reduce myopia progression with a uniform lens design and may rather call for a customized approach. PMID- 21258261 TI - Perspective: how might emmetropization and genetic factors produce myopia in normal eyes? AB - Substantial evidence has emerged over the past decades for a role of genetics in the development of human refractive error. There is also an emmetropization mechanism that uses visual signals to match the axial length to the focal plane. There has been little discussion of how these two important factors might interact. We explore here ways in which genetic factors driving axial growth may interact with the emmetropization mechanism, mostly to produce emmetropic eyes but often to produce myopia. An important factor may be a normal, yet reduced ability of juvenile eyes to use myopia to restrain genetically driven axial elongation. Reduced ability to respond to myopia by slowing axial elongation may contribute to the development of myopia in cases where genetics alone would make the axial length longer than the focal plane. PMID- 21258262 TI - Blood levels of vitamin D in teens and young adults with myopia. AB - PURPOSE: Longitudinal data suggest that time outdoors may be protective against myopia onset. We evaluated the hypothesis that time outdoors might create differences in circulating levels of vitamin D between myopes and non-myopes. METHODS: Subjects provided 200 MUl of peripheral blood in addition to survey information about dietary intakes and time spent in indoor or outdoor activity. The 22 subjects ranged in age from 13 to 25 years. Myopes (n = 14) were defined as having at least -0.75 diopter of myopia in each principal meridian and non myopes (n = 8) had +0.25 diopter or more hyperopia in each principal meridian. Blood level of vitamin D was measured using liquid chromatography/mass spectroscopy. RESULTS: Unadjusted blood levels of vitamin D were not significantly different between myopes (13.95 +/- 3.75 ng/ml) and non-myopes (16.02 +/- 5.11 ng/ml, p = 0.29) nor were the hours spent outdoors (myopes = 12.9 +/- 7.8 h; non-myopes = 13.6 +/- 5.8 h; p = 0.83). In a multiple regression model, total sugar and folate from food were negatively associated with blood vitamin D, whereas theobromine and calcium were positively associated with blood vitamin D. Myopes had lower levels of blood vitamin D by an average of 3.4 ng/ml compared with non-myopes when adjusted for age and dietary intakes (p = 0.005 for refractive error group, model R = 0.76). Gender, time outdoors, and dietary intake of vitamin D were not significant in this model. CONCLUSIONS: The hypothesis that time outdoors might create differences in vitamin D could not be evaluated fully because time outdoors was not significantly related to myopia in this small sample. However, adjusted for differences in the intake of dietary variables, myopes appear to have lower average blood levels of vitamin D than non myopes. Although consistent with the hypothesis above, replication in a larger sample is needed. PMID- 21258264 TI - Noninvasive MRI measures of microstructural and cerebrovascular changes during normal swine brain development. AB - The swine brain is emerging as a potentially valuable translational animal model of neurodevelopment and offers the ability to assess the impact of experimentally induced neurological disorders. The goal for this study was to characterize swine brain development using noninvasive MRI measures of microstructural and cerebrovascular changes. Thirteen pigs at various postnatal ages (2.3-43.5 kg) were imaged on a 1.5-Tesla MRI system. Microstructural changes were assessed using diffusion tensor imaging measures of mean diffusivity and fractional anisotropy. Cerebrovascular changes were assessed using arterial spin labeling measures of baseline cerebral blood flow (CBF) and the cerebrovascular reactivity (CVR) of the blood-oxygen level dependent (BOLD) MRI signal to CO2. We found a positive logarithmic relationship for regional tissue volumes and fractional anisotropy with body weight, which is similar to the pattern reported in the developing human brain. Unlike in the maturing human brain, no consistent changes in mean diffusivity or baseline CBF with development were observed. Changes in BOLD CVR exhibited a positive logarithmic relationship with body weight, which may impact the interpretation of functional MRI results at different stages of development. This animal model can be validated by applying the same noninvasive measures in humans. PMID- 21258263 TI - Necrotizing enterocolitis is associated with ureaplasma colonization in preterm infants. AB - The study objective was to determine whether Ureaplasma respiratory tract colonization of preterm infants <33 wk gestation is associated with an increased risk for necrotizing enterocolitis (NEC). One or more tracheal or nasopharyngeal aspirates for Ureaplasma culture and PCR were obtained during the first week of life from 368 infants <33 wk gestation enrolled from 1999 to 2003 or from 2007 to 2009. NEC Bell stage >= 2 was confirmed by radiological criteria, and pathology, if available. Cord serum samples were analyzed for IL-6 and IL-1beta concentrations, and placentas were reviewed for histological chorioamnionitis in the first cohort. NEC was confirmed in 29 of 368 (7.9%) of the combined cohorts. The incidence of NEC was 2.2-fold higher in Ureaplasma-positive (12.3%) than Ureaplasma-negative (5.5%) infants <33 wk (OR, 2.43; 95% CI, 1.13-5.2; p = 0.023) and 3.3-fold higher in Ureaplasma-positive (14.6%) than Ureaplasma-negative (4.4%) infants <= 28 wk (OR, 3.67; 95% CI, 1.36-9.93; p = 0.01). Age of onset, hematologic parameters at onset, and NEC severity were similar between Ureaplasma positive and negative infants. Cord serum IL-6 and IL-1beta concentrations were significantly higher in Ureaplasma-positive than in Ureaplasma-negative NEC affected infants. Ureaplasma may be a factor in NEC pathogenesis in preterm infants by contributing to intestinal mucosal injury and/or altering systemic or local immune responses. PMID- 21258265 TI - Neonatal leptin administration alters regional brain volumes and blocks neonatal growth restriction-induced behavioral and cardiovascular dysfunction in male mice. AB - Premature delivery is often complicated by neonatal growth restriction (GR) and neurodevelopmental impairment. Because global overnutrition increases the risk of adult metabolic syndrome, we sought a targeted intervention. Premature delivery and perinatal GR decrease circulating levels of the neurotrophic hormone leptin. We hypothesized that leptin supplementation would normalize the outcomes of mice with incipient neonatal GR. Pups were fostered into litters of 6 or 12 to elicit divergent growth patterns. Pups in each litter received injections of saline or leptin from d 4 to 14. At 4 mo, mice underwent tail cuff blood pressure measurement, behavioral testing, and MRI. Mice fostered in litters of 12 had decreased weanling weights and leptin levels. Neonatal leptin administration normalized plasma leptin levels without influencing neonatal growth. Leptin replacement also normalized the hypertension, stress-linked immobility, conditioned fear, and amygdala enlargement seen in neonatal growth restricted male mice. In control males, neonatal leptin administration led to hypothalamic enlargement, without overt neurocardiovascular alterations. Female mice were less susceptible to the effects of neonatal GR or leptin supplementation. In conclusion, the effects of neonatal leptin administration are modulated by concurrent growth and gender. In growth restricted male mice, physiologic leptin replacement improves adult neurocardiovascular outcomes. PMID- 21258266 TI - Rapid assessment of cerebral autoregulation by near-infrared spectroscopy and a single dose of phenylephrine. AB - Rapid bedside determination of cerebral blood pressure autoregulation (AR) may improve clinical utility. We tested the hypothesis that cerebral Hb oxygenation (HbDiff) and cerebral Hb volume (HbTotal) measured by near-infrared spectroscopy (NIRS) would correlate with cerebral blood flow (CBF) after single dose phenylephrine (PE). Critically ill patients requiring artificial ventilation and arterial lines were eligible. During rapid blood pressure rise induced by i.v. PE bolus, DeltaHbDiff and DeltaHbTotal were calculated by subtracting values at baseline (normotension) from values at peak blood pressure elevation (hypertension). With the aid of NIRS and bolus injection of indocyanine green, relative measures of CBF, called blood flow index (BFI), were determined during normotension and during hypertension. BFI during hypertension was expressed as percentage from BFI during normotension (BFI%). Autoregulation indices (ARIs) were calculated by dividing BFI%, DeltaHbDiff, and DeltaHbTotal by the concomitant change in blood pressure. In 24 patients (11 newborns and 13 children), significant correlations between BFI% and DeltaHbDiff (or DeltaHbTotal) were found. In addition, the associations between Hb-based ARI and BFI%-based ARI were significant with correlation coefficients of 0.73 (or 0.72). Rapid determination of dynamic AR with the aid of cerebral Hb signals and PE bolus seems to be reliable. PMID- 21258267 TI - Angiotensin-converting enzyme tag single nucleotide polymorphisms in patients with intracerebral hemorrhage. AB - OBJECTIVES: Studies investigating the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and the risk of intracerebral hemorrhage (ICH) have provided conflicting results. Moreover, it is possible that the ACE I/D polymorphism may not represent the functional variant of the gene. The objective of this study was to clarify the influence of the ACE gene region on the risk of ICH by genotyping tag polymorphisms along ACE gene in two independent ethnically different cohorts. METHODS: We included 250 Greek and 169 Polish unrelated patients with ICH and 250 Greek and 322 Polish normal controls in the study. To cover the majority of the genetic variability across the extended ACE gene region, we identified five tag single nucleotide polymorphisms (rs4343, rs4461142, rs7221780, rs8066276, rs8066114) from the HapMap using a pairwise tagging approach and an r2 greater than or equal to 0.8. Single nucleotide polymorphisms and haplotypes were analyzed for associations with ICH risk, ICH subtype (lobar/nonlobar), and age of disease onset using logistic and Cox regression models. Correction for multiple comparisons was carried out. RESULTS: In the Polish cohort, we observed a trend toward an association between the rs4461142 and the age of ICH onset (hazard ratio 0.50, 95% confidence interval 0.27-0.90, P=0.02). A common haplotype (GTCTC) also showed a trend for increased ICH risk in the Polish cohort (odds ratio 0.19, 95% confidence interval 0.04-0.85, P=0.02). These results were not replicated in the Greek cohort. CONCLUSIONS: Our results did not provide clear evidence for a role of ACE gene in the development of ICH. PMID- 21258268 TI - Concurrent sexual partnerships and human immunodeficiency virus risk among South African youth. AB - BACKGROUND: To estimate the prevalence of concurrency (more than 1 sex partner overlapping in time), the attitudes/behaviors of those engaged in concurrency, length of relationship overlap, and the association between concurrency and human immunodeficiency virus (HIV) among South Africans aged 15 to 24 years. METHODS: A cross-sectional, nationally representative, household survey of HIV infection, and sexual attitudes and behaviors was conducted among 11,904 15 to 24 year old South Africans in 2003. Analyses were conducted among sexually experienced youth. RESULTS: Men were more likely to report having concurrent (24.7%) than serial partners (5.7%) in the past 12 months, but concurrency was not associated with HIV. Among women, concurrency and serial monogamy were equally common (4.7%), and concurrency, defined by respondent reports of multiple ongoing partners, was associated with HIV in multivariate analysis (odds ratio, 3.4; 95% confidence interval, 1.8-6.5). Median length of relationship overlap was approximately 4 months for women and 3 months for men. Compared to serial monogamists, concurrents reported less consistent condom use, and female concurrents were more likely to report transactional sex and problems negotiating condoms and refusing intercourse. CONCLUSIONS: Concurrency is a common partnership pattern among those youth with multiple partners, especially men. For women, having concurrent relationships may be associated with relationship power imbalances and less ability to protect against HIV. Given the prevalence and likely significance of concurrency in the spread of HIV throughout a sexual network, our findings underscore the need for prevention efforts targeting fidelity. PMID- 21258270 TI - Concurrent sexual partnerships and sexually transmitted diseases in Russia. AB - BACKGROUND: Sexual concurrency is associated with higher prevalence of sexually transmitted diseases (STDs) including HIV. However, most studies have focused only on the concurrency of the individual participant (individual concurrency) and not on concurrency of their sexual partners (partner concurrency). Furthermore, limited concurrency information is available in Russia where HIV epidemic is growing rapidly. We therefore examine the prevalence and correlates of individual and partner concurrency, and determine whether either type of concurrency is associated with diagnosed STDs among STD clinic attendees in St. Petersburg, Russia. METHODS: In total, 799 attendees were recruited into a cross sectional study between 2006 and 2008. A questionnaire collected information on demographics, medical history, sexual behaviors, and up to 3 sexual partners during the preceding year. RESULTS: The prevalence of individual and partner concurrency was 24.7% and 45.4%, respectively. Both were correlated with marital status, weekly alcohol consumption, age at first sex, and number of lifetime sexual partners. Partner concurrency was significantly associated with diagnosed STDs (odds ratio = 2.06; 95% confidence interval = 1.35-3.15). No significant association between individual concurrency and STDs was observed. CONCLUSIONS: Partner concurrency, not individual concurrency, is independently associated with increased odds of having an STD in the studied population. PMID- 21258269 TI - Mediators of the relation between partner violence and sexual risk behavior among women attending a sexually transmitted disease clinic. AB - BACKGROUND: Intimate partner violence (IPV) is associated with a wide range of negative outcomes, including sexual risk behavior. This cross-sectional study explored mediators of the relationship between IPV and risky sexual behavior in 717 women recruited from a sexually transmitted disease (STD) clinic. METHODS: Participants were recruited from a public STD clinic in upstate New York as part of a randomized controlled trial that was designed to evaluate several sexual risk reduction interventions. They completed an audio computer-assisted self interview in a private room. RESULTS: Among these women, 18% reported IPV in the past 3 months and 57% reported lifetime experience of IPV. Recent IPV was associated with greater sexual risk, as measured by more episodes of unprotected sex (overall and with a steady partner). Although IPV was associated with depressive symptoms and drug use before sex, these variables did not mediate the relationship between IPV and sexual risk behavior. CONCLUSIONS: The results indicate that IPV is common among women who attend an STD clinic and warrants increased attention. Research is needed to better understand the pathways linking IPV and HIV risk in women, to optimize the design of effective interventions. PMID- 21258271 TI - Axial loading during magnetic resonance imaging in patients with lumbar spinal canal stenosis: does it reproduce the positional change of the dural sac detected by upright myelography? AB - STUDY DESIGN: We compared the sizes of the dural sac among conventional magnetic resonance imaging (MRI), axial loaded MRI, and upright myelography in patients with lumbar spinal canal stenosis (LSCS). OBJECTIVE: To determine whether axial loaded MRI can demonstrate similar positional changes of the dural sac size as were detected by upright myelography in LSCS. SUMMARY OF BACKGROUND DATA: In patients with LSCS, constriction of the dural sac is worsened and symptoms are aggravated during standing or walking. To disclose such positional changes, upright myelography has been widely used. Recently, axial loaded MRI, which can simulate a standing position, has been developed. However, there has been no study to compare the dural sac size between axial loaded MRI and upright myelography. METHODS: Forty-four patients underwent conventional MRI, axial loaded MRI, and myelography. Transverse and anteroposterior diameters and the cross-sectional areas of the dural sac from L2-L3 to L5-S1 were compared. Pearson correlations of the diameters between the MRIs and the myelograms were analyzed. On the basis of the myelograms, all disc levels were divided into severe and nonsevere constriction groups. In each group, the diameters and the cross sectional areas were compared. Sensitivity and specificity to detect severe constriction were calculated for the conventional and axial loaded MRI. RESULTS: Transverse and anteroposterior diameters at L4-L5 in the axial loaded MRI and myelogram were significantly smaller than those observed in the conventional MRI (P < 0.001). Cross-sectional areas in the axial loaded MRI were significantly smaller than those in the conventional MRI at L2-L3, L3-L4, and L4-L5 (P < 0.001). Between the axial loaded MRI and the myelography, Pearson correlation coefficients of the transverse and anteroposterior diameters were 0.85 and 0.87, respectively (P < 0.001), which were higher than those for conventional MRI. Reductions of the dural sac sizes in the axial loaded MRI were more evident in the severe constriction group. The axial loaded MRI detected severe constriction with a higher sensitivity (96.4%) and specificity (98.2%) than the conventional MRI. CONCLUSION: The axial loaded MRI demonstrated a significant reduction in the dural sac size and significant correlations of the dural sac diameters with the upright myelogram. Furthermore, the axial loaded MRI had higher sensitivity and specificity than the conventional MRI for detecting the severe constriction observed in the myelogram. Therefore, the axial loaded MRI can be used to represent positional changes of the dural sac size detected by the upright myelography in patients with LSCS. PMID- 21258273 TI - The Oxford classification of IgA nephropathy: single centre experience. AB - The Oxford classification for the pathological classification of a glomerular disease in IgA nephropathy was established and published in 2009. Four of the pathological variables: 1) mesangial hypercellularity score, 2) segmental glomerulosclerosis, 3) endocapillary hypercellularity and 4) tubular atrophy/interstital fibrosis were presented as having value in predicting renal outcome in this glomerular disease. These features were recommended to be taken into account for predicting the outcome. In our study, we correlated these four variables with the outcome of the disease in 40 adult patients with IgA nephropathy. Standard histopathologic procedure was used to determine four variables as 0/1. The results were compared with renal outcome, clinical data were obtained from the out-patient files of the patients. The whole follow-up period was 3-27 years. The average survival of the whole group was 10.8+/-7.47 years (M+/-SD). Mesangial hypercellularity was confirmed to be associated with the renal outcome (p=0.047), as well as glomerular sclerosis (p=0.009), endocapillary hypercellularity (p=0.001) and tubular atrophy/interstitial fibrosis (p=0.045). When we analysed only patients with a severe form of the disease (nephrotic syndrome; patients treated with immunosuppression), the survival of the patients was associated only with the degree of tubulointerstitial changes (p=0.018). Analysing separately patients with mild clinical form, we found only a predictive value of segmental glomerulosclerosis on renal survival. PMID- 21258272 TI - Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. AB - BACKGROUND: The effect of islet cell transplantation (ICT) on the progression of diabetic microvascular complications is not well understood. METHODS: We have conducted a prospective, crossover, cohort study comparing ICT with intensive medical therapy on the progression of diabetic nephropathy, retinopathy, and neuropathy. RESULTS: The rate of decline in glomerular filtration rate is slower after ICT than on medical therapy. There was significantly more progression of retinopathy in medically treated patients than post-ICT. There was a nonsignificant trend for improved nerve conduction velocity post-ICT. CONCLUSIONS: ICT is associated with less progression of microvascular complications than intensive medical therapy. Multicenter, randomized trials are needed to further study the role of ICT in slowing the progression of diabetic complications. PMID- 21258274 TI - Risk factors and outcome of Preeclampsia. AB - AIM: To determine differences between groups with hypertension in pregnancy and assess risk factors associated with preeclampsia. PATIENTS AND METHODS: In the period 2008-10 at the Department of Nephrology in Skopje, Macedonia, a prospective and a longitudinal study study comprising 134 pregnant women was carried out. They had regular monthly check-ups in pregnancy and after delivery (1-8), when groups were defined as gestational hypertension, pre-existing hypertension, superimposed preeclampsia, and preeclampsia. A total of 134 women were regularly controlled by 24-hour ambulatory monitoring of blood pressure (24ABPM), blood and urine, D-dimers, and a resistance index of the Doppler of the umbilical artery (RI a.umb), and a questionnaire on risk factors was filled in for every pregnant woman. RESULTS: Superimposed preeclampsia was found in 22 (16.4%) and preeclampsia was found in 20 women (14.9%). Daily diastolic blood pressure of 24-hour blood pressure monitoring at the last check-up before delivery was significantly higher in the group with superimposed preeclampsia (SP) 87.6+/-9.5 and in the group with preeclampsia (PE) 87.9+/-7.7 mm Hg. Previous preeclampsia (OR=3.28), primiparity (OR=2.35), methyldopa (OR=3.76), number of check-ups (OR=2.3), positive family history (OR=1.4) and in vitro fertilisation (OR=1.15) were found as risk factors associated with the occurrence of preeclampsia and preeclampsia superimposed on preexisting hypertension. CONCLUSIONS: Early determination of risk factors should prompt more frequent check-ups in hypertensive pregnancies in order to determine timely delivery and avoid adverse outcomes in the mother and child. PMID- 21258275 TI - Atypical atrioventricular nodal reentry tachycardia with eccentric retrograde left-sided activation of coronary sinus. AB - BACKGROUND: Recent anatomical and electrophysiological studies have demonstrated that in the human atrioventricular node there are two main extensions, the rightward and leftward posterior nodal extension (LPNE). The occurrence of eccentric retrograde atrial activation has been demonstrated in several previous reports to be from 6 to 8% in patients with AVNRT. OBJECTIVES: The study was performed to confirm that standard right atrium ablation is effective and successful for atrioventricular node reentry tachycardia (AVNRT) with eccentric retrograde left-sided activation, masquerading as a tachycardia which looks like a tachycardia, using the left accessory pathway. METHODS AND RESULTS: During a 7 years period (from 2002 to 2008), 865 consecutive patients underwent electrophysiological study. In the group with atrioventricular node reentry tachycardia (AVNRT) there were 178 patients. In the group with typical fast-slow AVNRT (162 pts) there was concentric retrograde activation of both the atria. The 16 patients had atypical AVNRT (10 pts with slow-slow AVNRT and 6 pts with LPNE). The ablation was performed, in all patients in the Koch's triangle on the slow pathway of the atrioventricular node. The successful rate of ablation was 99.4% (177/178 pts). The incidence of AVNRT with eccentric retrograde activation was 3.4%. In the follow-up period (16+/-12 months), there was no recurrence of AVNRT in the group with LPNE. CONCLUSIONS: This study demonstrated the different electrophysiologic characteristics between the AVNRT patients with eccentric and concentric retrograde atrial activation. Standard ablation, but a little bit higher in the Koch's triangle, closer to the fast pathway, in the right atrium is effective and successful for AVNRT with retrograde left eccentric conduction in the coronary sinus. PMID- 21258276 TI - Osteonecrosis of the jaw in patients with multiple myeloma treated with bisphosphanates. AB - Bisphosphonates are pyrophosphate analogues which inhibit osteoclastic activity. Long term use of bisphosphonates has recently been associated with osteonecrosis of the jaw (ONJ) defined as a three month non-healing defect in the jaw. ONJ is commonly precipitated by a tooth extraction or other stomatological procedure in patients treated with long-term, potent, high dose intravenous bisphosphonates for the management of myeloma, breast or prostate cancer. The aim of this study was to evaluate the incidence of ONJ in patients with MM treated with bisphosphonates during the last 8 years in our institution and to pre-sent the first two cases. We have analysed 247 myeloma patients diagnosed in our institution in the period 2002-09. Only 190/247 patients (76.9%) were treated with bisphosphonates. The incidence of ONJ in our group of patients treated with bisphosphonates was 2/190 (1%). The most commonly used bisphosponate was i.v. pamidronate (17.8%) and 46.6% were treated with two or more types of bisphosphonates. Sixty-five patients (34.2%) received oral forms of bisphosphonates; 42.1% patients were treated with i.v. forms of pamidronate, ibondronate or clodronate, and 45 patients (23.7%) received a combination of oral and i.v. forms of bisphosphonates. The mean duration of bisphosphonates therapy was 24.7+/-17.7 months. The low incidence of ONJ in our institution could be explained by the rare use of zolendronate, which is the most commonly referred bisphosphonate causing ONJ, and by a relatively shorter duration of bisphosphonates treatment in patients with MM. Despite the fact that ONJ is a rare complication in our institution, preventive measures must be considered. PMID- 21258277 TI - Prevalence of thyroid dysfunction and autoimmunity in pregnant women with gestational diabetes and diabetes type 1. AB - OBJECTIVE: The aim of the present study was to determine the prevalence of abnormal thyroid function and antithyroid antibodies during pregnancy in women with diabetes type 1 and gestational diabetes mellitus (GDM). METHODS: The study group included 83 pregnant women who attended the Outpatient Department of the Endocrinology, Diabetes and Metabolic Disorders Clinic in the period from 05.2009 to 11.2009. The one hundred-g. oral glucose tolerance test (OGTT) was conducted on the pregnant women except for women with diabetes type 1. Thyroid functions were evaluated in all the pregnant women. After routine screening for GDM, thirty of the pregnant women were healthy and GDM was diagnosed in forty of them. The rest, thirteen women, had diabetes type 1. RESULTS: The women who developed GDM showed a mean free thyroxin concentration (fT4) significantly lower than that observed in the healthy pregnant women and women with diabetes type 1. Among the pregnant women with GDM, 10 women or 25% had fT4 concentrations below the lower cut-off with normal thyroid-stimulating hormone concentrations (TSH). A statistically significant difference was found in the prevalence of antithyroid antibodies (anti-TPO) between the (30%) women with diabetes type 1 and (10%) healthy pregnant women (p<0.05). In the women positive for anti-TPO, TSH was significantly higher (p<0.05). CONCLUSION: The significantly higher prevalence of hypothyroxinemia in GDM pregnancies and anti-TPO titres in pregnancies with diabetes type 1, than in healthy pregnant women warrants routine screening for thyroid abnormalities in these groups of pregnant women. PMID- 21258278 TI - Indications for VATS or open decortication in the surgical treatment of fibrino purulent stage of parapneumonic pleural empyema. AB - Open and Video-Assisted Thoracoscopycal pleural decortications are proved and effective surgical procedure in the surgical treatment of pleural empyema in the fibrinopurulent stage. Early referral to surgery gives a better chance of success in VATS pleural decortications than open decortications. Pleural morphology, biochemistry and biology can also affect the outcome of the surgical treatment of pleural empyema. The aim of this paper is to compare the results of VATS and open decortications of the pleura according to the preoperative morphological and biochemical conditions of the pleura and the pleural cavity as well as postoperative morphological and functional improvement in patients with parapneumonic, fibrinopurulent pleural empyema. Two different approaches (VATS and open pleural decortications) were analyzed in 37 patients divided into two groups. The biochemical analysis of pleural fluid (LDH, glucose, pH and albumins) and the pleural thickness of the chest CT scan were measured. The success of the operations was measured by plain chest X-ray and functional tests after 3 months postoperatively. The group with VATS pleural decortications showed a significantly (p<0.001) lower pleural LDH level and pleural thickness and significantly higher levels (p<0.001) of glucose and albumins than the group with opened pleural decortications. The differrences in the pleural pH were not significant. Postoperative chest X-rays at discharge were significantly better in VATS pleural decortications. FEV1 and FVC, predicted and 3 months after operation, were not significantly different between the two groups. VATS and open decortications are safe and effective for the majority of patients. When VATS pleural decortications cannot be performed due to an obliterated pleural space, open pleural decortication still remains an effective procedure that allows acceptable functional and morphological results. Preoperative determination of pleural LDH, glucose, and albumins, as well as the thickness of pleural peel on CT scan, enables better evaluation of the pleural condition and a more exact indication of the right procedure. PMID- 21258279 TI - Detected heterozygotes during the molecular analysis of the common CYP21A2 point mutations in Macedonian patients with congenital adrenal hyperplasia and their relatives. AB - BACKGROUND: Deficiency of 21-hydroxylase is present in 90-95% cases of congenital adrenal hyperplasia (CAH), an autosomal recessive disorder. Eleven common pseudogene-derived mutations account for approximately 95% of all affected CYP21A2 alleles in all three clinical forms of the disease. OBJECTIVE: To analyse the detected heterozygotes during the molecular analysis of eleven CYP21A2 common pseudogene-derived point mutations in Macedonian CAH patients and their relatives, using the PCR-ACRS protocol. MATERIAL AND METHODS: We performed direct molecular detection of CYP21A2 mutations: p.P30L, IVS2-655 C/A->G, G110Delta8nt, p.I172N, p.I236N, p.V237E, p.M239K, p.F306+t, p.V281L, p.Q318X and p.R356W, in 51 CAH Macedonian patients and their 70 healthy relatives (parents and siblings), using the differential PCR-ACRS protocol. RESULTS: Six of the analysed mutations were detected in 29.4% (15/51) of the patients, in the heterozygous state, with the following distribution: IVS2-655 C/A->G (13.7%), p.P30L (11.8%), p.Q318X (9.8%), p.I172N (3.9%), p.R356W (3.9%) and p.V281L (1.96%). Six cases (6/15) were compound heterozygotes and nine (9/15) were simple heterozygotes. Genotype phenotype correlation was observed in all of our detected compound heterozygote patients. Their clinical presentation was correlated with the less severely mutated allele. Four of the analysed mutations (p.P30L 20%, IVS2-655 C/A->G 12.9%, p.Q318X 7.1% and p.R356W 2.9%) appeared in thirty healthy relatives (42.9%), in the heterozygous state. CONCLUSION: Distribution of the analysed CYP21A2 mutations among CAH patients and their relatives is comparable to studies from other populations. As expected, high carrier frequency of alleles causing 21 hydroxylase deficiency was observed in relatives of CAH patients. PMID- 21258280 TI - Kinematic radiographic measurements of the wrist in the healthy population in the Republic of Macedonia. AB - Many diseases of the wrist can be recognized by radiographic changes and quantified by radiographic measurements. The kinematic radiographic measurements are the basis for kinematic studies of the wrist as well as a diagnostic, prognostic and follow- up tool for many conditions of the wrist. We undertook this study to identify the normal variations in the longitudinal and transverse dimensions of the wrist, and measure several indices on posteroanterior roentgenograms of the wrists of the healthy population in the Republic of Macedonia. There were 100 healthy subjects (47 men and 53 women), 41 left and 59 right hands. The mean age of the subjects was 42 years+/-12.42 (range 20 to 60 years). Measurements were made of the third metacarpal, the carpal height, the length of the capitate and the carpal- ulnar distance. The indices, expressed as ratios, included the carpal height ratios (we used two methods--CHR by Youm and Revised CHR as described by Natrass) and the Carpal-Ulnar Distance Ratio. The results we obtained are similar to those we find in the literature (CHR--0.53+/ 0.01; RCHR--1.56+/-0.02; Carpal-Ulnar Distance Ratio--0.30+/-0.01). This study shows that these methods are reproducible and the values represent normal reference values that can be used in further kinematic studies of the wrist in our population. Also, these measurements can be used in determining the degree of kinematic dysfunction present in people with wrist abnormalities, and in evaluation of the kinematic effectiveness of real and hypothetical treatment modalities, thus making them exceptionally valuable for the orthopaedic surgeons. PMID- 21258281 TI - Survival of pulmonary cancer patients treated surgically. AB - The aim of the study is to investigate the survival of patients treated surgically for lung cancer. 151 cases treated during the years 2000-03 are reviewed. The average age was 56.6+/-9.9 years (from 19 to 83 years old). The histological type was: 80 (53%) Squamous-cell carcinoma, 27 (17.9%) adenocarcinoma, 10 (6.6%) bronchioalveolar carcinoma, 5 (3.3%) small-cell carcinoma, and others--29 (19.2%). The post-surgical stage was often advanced; 92 (63%) of the patients were at stage IIIA. With 5 (3.3% of total operated cases) of the patients had limited disease of SCLC. Most of the patients had lobectomy (64.9%) and pneumonectomy (16.6%) Performed. Neoadjuvant treatment was carried out on 37 (24.5%) of the patients. Only half of the patients were alive after 1 year, and 11.9% after 2 years of the postoperative period. Survival was highly significantly better in patients with an early stage of the disease. Survival resulted decreasingly with the extent of the surgical intervention; lower survival resulted in the patients treated with pneumonectomy, but this was not statistically significant. Significantly better results of survival were seen in correlation with higher values of pre-surgical FEV1. There are significant differences in survival (p<0.05) in relation to diagnosis, group-age, histology, and highly significant differences (p<0.01) regarding definition N, M, stage of disease, FEV1. There were no significant differences in the survival of patients according to sex, type of intervention, site of intervention, FVC, definition T. PMID- 21258282 TI - Clinical correlates of MRI white matter abnormalities in schizophrenia. AB - Schizophrenia is a severe psychiatric illness that can be accompanied by positive symptoms, negative symptoms, and cognitive dysfunctions in most cognitive domains. Neuroimaging studies have focused on understanding the relationship between schizophrenia and brain abnormalities. Most of these have focused on the well-documented gray matter abnormalities. However, emphasis has recently been placed on white matter abnormalities associated with the disorder. A number of studies have found reduced white matter volumes in schizophrenia and abnormalities in genes associated with white matter. The clinical significance of these abnormalities is just beginning to be understood. The advent of diffusion tensor imaging (DTI) has been particularly important in this regard, as it allows us to draw inferences regarding the organization of white matter in the brain. In this article, I will review recent work showing clinical correlates of neuroimaging-based white matter abnormalities in schizophrenia. PMID- 21258283 TI - Spiral chemical shift imaging at 3T using 32 channel receive array and online reconstruction. AB - Magnetic resonance spectroscopic imaging (MRSI) is an imaging technique where one obtains a spectrum of signals, e.g. brain metabolites in vivo, from particular spatial locations of interest. Conventional MRSI suffers from intrinsically long acquisition times, making this technique suitable for in vivo acquisitions only for modest spatial resolutions. Spiral MRSI is a fast encoding algorithm that plays spiral-shaped k-space trajectories repeatedly within one repetition period (TR), therefore sampling the (kx,ky,kf) space simultaneously. This offers two orders of magnitude decrease in acquisition time compared to the conventional MRSI, at no SNR cost. In this work we show implementation of the spiral MRSI algorithm on Siemens' MRI platform, and present results from in vivo experiments on healthy volunteers. PMID- 21258284 TI - Single chain ferritin chimera as an improved MRI gene reporter. AB - Imaging gene expression non-invasively and deep into opaque tissues has been a long-standing goal of molecular science. Optical gene reporters such as green fluorescent protein and luciferase have revolutionized cellular and molecular biology, however their in vivo application is limited, due to poor tissue penetration of visible light. The iron storage protein ferritin forms a paramagnetic ferrihydrite core that affects the relaxation rate of surrounding nuclear spins. Ferritin has recently emerged as an MRI gene reporter for molecular applications, however its detection with MRI still has relatively low sensitivity. In this work we present an improved ferritin chimera, genetically engineered to exhibit stronger paramagnetic properties. PMID- 21258285 TI - Determination of EMF influence on a human exposed to EMF--modeling and methodology. AB - The wide use of electric energy in every segment of everyday living demands specific attention be paid to investigations connected with biological effects from the influence of electromagnetic fields on humans and the environment. Investigations connected with electromagnetic influence assessment on human health emphasize the influences of electromagnetic fields in a wide frequency range. Here, the interest in knowing the mechanisms of these interactions and ways of determining them is obvious. The parameters and quantities that describe such influence depend on the frequency of the electromagnetic field source that underlines the importance of their appropriate definition. Induced currents and charges as well as electric field distribution, or SAR, are quantities that represent this influence. Their determination is important for the formulation of norms and standards for human protection from exposure to electromagnetic fields. In this paper, a developed procedure for the determination of electric field distribution in the human body when exposed to EMF influence is presented. Several issues emerge in the course of this, such as finding representative parameters for problem description, modeling of the incident field source, which is obvious in various forms and in a wide frequency range, modeling of the human body, which is complex in geometric aspect and has a wide range of electric characteristics in its parts, developing an appropriate calculation methodology and a suitable presentation of the results. Modeling the incident field form and the human body are in direct correlation with the calculation method developed for determining the electric field distribution. Developed methodology enables the electric field in the humans to be determined, and other parameters such as SAR to be calculated. Having those values, we can discuss the biological effects on humans from such exposure. PMID- 21258286 TI - ADHD as an executive dysfunction. AB - Attention-deficit/hyperactivity disorder [ADHD] is a neuropsychiatric disorder characterized by inattention, hyperactivity and impulsivity that affects from 3 5% of school-aged children. In some cases it may persist into adulthood. Prominent theories about ADHD suggest that inattention, hyperactivity and impulsivity may be due to underlying deficits of the components of attention, including alerting, orienting and executive control. The aim of this study was to investigate neuropsychological characteristics of ADHD children, especially their executive functions [EFs]. The sample is comprised of 30 ADHD children from 6 to 14 years old [10, 45+/-22, 2], only boys, diagnosed at the department of psychophysiology, University Children's Hospital. The diagnosis was established according to ICD-10 criteria. All children had an IQ over 90 and were medication free. Psychological assessment of the children was performed with the Wechsler Intelligence Scale for Children [WISC-IV] and ADD-H Comprehensive Parent Rating Scale [ASTeRS]. Neuropsychological assessment was performed with the Stroop test and the Wisconsin Card Sorting Test [WCST]. Results showed an average IQ, manifested symptoms of hyperactivity and executive dysfunction, confirmed by the Stroop test and WCST. PMID- 21258287 TI - Some characteristics of patients with schizophrenia who attempted suicide. AB - OBJECTIVES: The aim of this study was to determinate some characteristics of schizophrenia patients who attempted suicide at the Skopje Psychiatric Hospital, Skopje, with respect to clinical, ethical and legal context. METHODS: The study included 80 patients with schizophrenia, 17.5% (n=14) of whom attempted suicide. The psychiatric diagnosis of schizophrenia was based on ICD-10 criteria. Sociodemographic and clinical data are presented descriptively as percentages. RESULTS: Based on the characteristics of patients with schizophrenia who attempted suicide, we obtained a typical profile as follows: middle-aged persons (average age 44.8), single (71.4% were not married and 35.7% lived alone), (87.5%) unemployed, repeatedly hospitalized and had a history of suicide attempts (50%), attempting suicide using a violent method (poisoning 64.3%, drowning 21.4%, slashing their wrists 14.3%, jumped from a height 7.1% etc.) after more than three weeks of hospital treatment, and out of hospital. The success of psychiatric treatment is the perception of the legal and medical aspects of suicide as well as their efficient balancing. PMID- 21258288 TI - Assessment of the criminal recidivism among individuals with mental disorders. AB - Epidemiological studies conducted in various regions through the world point to an increased risk of violence among individuals with mental disorders. Violent behaviour occurs in a certain social system that involves a whole person with a certain history of life, with a certain state of health or disease, and interaction with other socal circumastances. There are different methods of risk assessment, but basically two broad categories of methods determine assessment of the risk: clinical and statistical. The main purpose of the investigation is by using the statistical scale to determine risk factors of a psychopathological and social nature as well as individual traits that determine violent behaviour. The investigation has been conducted in psychiatric hospitals in Macedonia. The experimental group--perpetrators of a criminal act (PCA)--encompasses 89 patients, admitted to psychiatric hospitals in Macedonia as forensic patients. These patients have committed criminal acts. According to the forensic expertise they have had a diagnosis of psychiatric disorders (ICD 10). The control group- patients with mental disorders who had not committed a criminal act and had not expressed violent behavior--the control group without violence (CG WV) encompasses 60 patients. Methodologically is the: VRAG (Violence Risk Assessment Guide) was the instrument used in the investigation Psychiatric disorder does not have a predictive value per se, but assossiated with other factors such as comorbidity with antisocial personality disorder, alcohol abuse, violent behaviour during the developmental period of life and life in an incomplete family is a considerable predictive basis for prevention and management of further violence among individuals with mental disorders. PMID- 21258289 TI - Personal and social functioning in patients with schizophrenia. AB - AIM OF THE PAPER: To monitor personal and social functioning in patients with schizophrenia and to find out the difference regarding sociodemographic characteristics and out-patient or day hospital treatment. MATERIAL AND METHODS: The investigation included 120 subjects divided into two groups of 60 patients each with a diagnosis F20 according to MKD 10 criteria. Patients from the first group received out-patient care whereas those from the second group had day hospital treatment. Patients were of different age and gender, receiving regular antipsychotic therapy. They were included in individual and group psychosocial therapeutic procedures during the day hospital treatment. The investigation utilized the following diagnostic instruments: standardized clinical interview and PSP scale, Personal and social performance scale, Morosini, Magliano et al. 2000, and a non-standardized questionnaire of sociodemographic data, family support and existence of mental disorder in other family members. RESULTS: The results obtained have shown better personal and social functioning in patients who had family support, in those who are employed, in those with no mental disorder in other family members and in patients on day hospital treatment as opposed to patients receiving out-patient care. CONCLUSION: Day hospital psychosocial therapeutic treatment in combination with regular antipsychotic therapy, family and social support helps in more rapid reintegration and resocialization and a better quality of life in patients with schizophrenia. PMID- 21258290 TI - Family relationships as a risk factor for late life depression. AB - AIM: To explore the association between depression in older adults and marital status, marital quality and relationships with close family members. METHODS: This study is cross-sectional, carried out at the Department of Geriatric Psychiatry of Skopje Psychiatric Hospital. We studied 120 subjects, 60 patients with unipolar depression and 60 subjects without depression. There is no significant difference in the sex proportion and the average age between the two groups. Data were taken by questionnaire designed for the study. The Geriatric Depression Scale was used to measure depressive symptoms. RESULTS: The patients with late life depression reported significantly more dissatisfaction with marital relationships in their life (p=0.048). The difference between the two groups in regard to living arrangements was statistically significant, because more patients lived in a geriatric institution (p<0.01). The quality of family relations was confirmed with a significant difference (p<0.001). Harmoniousness and toleration are considerably present in the families of the control group, while lack of interest, dislike and permanent conflictual relationships considerably predominate in the families of the experimental group. High significance was confirmed with regard to the feeling of emotional neglect and a feeling of being an unloved member of the family in the patients with depression. CONCLUSION: Dissatisfaction with marital relationships was associated with a considerable risk of late life depression. The patients with late life depression reported significantly more conflictual family relations, a feeling of poor attention and neglect and the sense of not being a loved member of the family. PMID- 21258291 TI - The influence of peers over adolescents' sexual conduct in Macedonia. AB - The main objective of the study was to investigate the influence of peers on the main determinants of adolescents' sexual conduct in Macedonia, in order to identify both risk and protective factors. METHODOLOGY: Data were obtained through a quantitative cross-sectional survey using a standardized paper-and pencil self-administered questionnaire prepared for the WHO "Health Behaviour in School-aged Children" study. The study was conducted among 1226 secondary school students aged 15 and 17 (1st and 3rd year) from 10 different secondary schools in Macedonia. Peer contact frequency and peer group activities were examined as independent explanatory variables, and prevalence of sexual activity, age of onset of sexual activity, number of sexual partners and use of contraception during the first and recent sexual intercourse as dependent variables. RESULTS: Peer contact frequency has shown to be a protective factor with regard to the age of onset of sexual activity and use of contraception during the first and recent sexual intercourse, a risk factor with regard to the prevalence of sexual activity, whereas it has no influence on the number of sexual partners. Peer group activities have no influence on the prevalence of sexual activity and the use of contraception, but direct 'face to face' conversation is a protective factor regarding the age of onset of sexual activity and the number of different sexual partners. Chatting over the Internet has shown to be a risk factor regarding the number of sexual partners, while 'hanging out' has no impact on the determinants of sexual conduct. CONCLUSIONS: Friends may protect adolescents from risk activities and peer influence may be used in public health interventions aimed to improve adolescent sexual and reproductive health. PMID- 21258292 TI - Four generations in a family with neurofibromatosis 1: precocious puberty and optic nerve tumor (OPT). AB - Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with varied clinical manifestations. The proband is a 6-year-old boy with signs of precocious puberty. His penis was 10 cm, testicles 8 ml, pubic hair P2-3, and the genital skin was hyperpigmented. Multiple cafe au lait spots well above 5 mm were noticeable on his skin, as well as hard subcutaneous nodules, mostly on his trunk. His intelligence and hearing are normal. He has no history of seizures. Laboratory analysis showed: LH LH 1.4 mIU/ml, FSH 6.2 mIU/ml, testosterone 183 ng/ml. Bone age was 9 years. LHRH stimulation was characteristic of true precocious puberty (LH 9.8 mIU/ml and FSH 8.9 mIU/ml after 30 minutes). The MRI of the brain showed a tumor of the suprasellar region with compression of the pituitary stalk. At present the boy is 6 years old and has been treated with triptoreline acetate for 3 months. The volume of the testicles has decreased to 7 ml and a slight loss of pubic hair was noted. In addition, his mother and his grandfather exhibited dermal masses, and focal cutaneous and subcutaneous growths. The great-grand father had had the same cutaneous changes and died at the age of 75 from unrelated causes. It has already been well documented that NF is associated with an increased risk of malignancy and precocious puberty. Hence, we emphasize the need for a close and regular clinical follow-up of the OPT, puberty and patterns of growth. PMID- 21258293 TI - Inherited alleles revealing an incestuous paternity. AB - Some rape cases result in the pregnancy of the victim and if the case is not reported to the police after the act with a subsequent gynaecological examination of the girl and the taking of a vaginal swab, there is no way of connecting the rape case with the perpetrator, except by parentage determination using DNA (deoxyribonucleic acid) analysis after abortion or induced delivery. In order to solve the rape case of a minor girl of 14 years which resulted with pregnancy, where a 60-year-old man was accused of the rape, DNA was extracted from blood samples from the girl and the putative assailant and from the foetus after its induced delivery. The autosomal short tandem repeats (STR) typing for 15 different loci showed differences in 6 STR loci between the putative assailant as a father and the foetus, thus excluding the tested paternity. A large number of identical loci between the mother's and the child's genotype led us to consider the possibility of incestuous paternity. Analysis of DNA samples from the girl's father and brother clarified the case as brother-sister incest. PMID- 21258294 TI - The first seminar for magnetic resonance imaging in the Republic of Macedonia (Meeting Report). AB - The First Seminar for Magnetic Resonance Imaging in the Republic of Macedonia was held in August 2008 in the city of Ohrid. 150 professionals from 5 Balkan countries had an opportunity to hear over 30 lectures on MR given by renowned scientists from the US, Canada, Germany, Italy and Russia. A workshop on white matter in schizophrenia was held on the second day of the seminar, while the last day was reserved for young scientists from the region who presented their research in the field of MR. PMID- 21258295 TI - Peptide phage display as a tool for drug discovery: targeting membrane receptors. AB - Ligands selected from phage-displayed random peptide libraries tend to be directed to biologically relevant sites on the surface of the target protein. Consequently, peptides derived from library screenings often modulate the target protein's activity in vitro and in vivo and can be used as lead compounds in drug design and as alternatives to antibodies for target validation in both genomics and drug discovery. This review discusses the use of phage display to identify membrane receptor modulators with agonistic or antagonistic activities. Because isolating or producing recombinant membrane proteins for use as target molecules in library screening is often impossible, innovative selection strategies such as panning against whole cells or tissues, recombinant receptor ectodomains, or neutralizing antibodies to endogenous binding partners were devised. Prominent examples from a two-decade history of peptide phage display will be presented, focusing on the design of affinity selection experiments, methods for improving the initial hits, and applications of the identified peptides. PMID- 21258296 TI - Lipophilic toxin profile in Mytilus galloprovincialis during episodes of diarrhetic shellfish poisoning (DSP) in the N.E. Adriatic Sea in 2006. AB - Dinophysis spp. blooms and related shellfish toxicity events of diarrhetic shellfish poisoning (DSP) have been the most reported toxicity event through the Croatian National monitoring program. With the aim to characterize the DSP toxin profile in shellfish farmed in Croatia, for the first time a complete analysis of the toxin profile of Croatian mussels has been carried out using the LC-MS/MS technique. The obtained results showed okadaic acid (OA) as the main toxin contaminating Croatian mussels at that time. The maximum concentration of OA in shellfish tissue was recorded 12 days after the Dinophysis fortii bloom, thus suggesting that rapid growth of the toxin level in the shellfish occurred in the first week after the bloom while it was slower in the second week. Furthermore, the presence of only OA at concentrations which could endanger human health suggests D. fortii as the main organism responsible for the toxic event that occurred in Lim Bay. The presence of gymnodimine and spirolides in Croatian mussel has been detected for the first time, while the presence of yessotoxin and pectenotoxin-2 is confirmed. PMID- 21258297 TI - Efficient in vivo selection of a novel tumor-associated peptide from a phage display library. AB - We developed a screening procedure to identify ligands from a phage display random peptide library that are selective for circulating bone marrow derived cells homing to angiogenic tumors. Panning the library on blood outgrowth endothelial cell suspension in vitro followed by in vivo selection based on homing of bone marrow-bound phage to angiogenic tumors, yielded the peptide QFPPKLTNNSML. Upon intravenous injection phage displaying this peptide homed to Lewis lung carcinoma (LLC) tumors in vivo whereas control phage did not localize to tumor tissue. Phage carrying the QFPPKLTNNSML peptide labeled with 64Cu radionuclide when administered intravenously into a tumor bearing mouse was detected noninvasively with positron emission tomography (PET) around the tumor. These proof-of-principle experiments demonstrate the ability of the QFPPKLTNNSML peptide to deliver payload (radiolabeled phage conjugates) in vivo to sites of ongoing angiogenesis and point to its potential clinical utility in a variety of physiologic and pathologic processes where neovascular growth is a critical component. PMID- 21258298 TI - X-ray supramolecular structure, NMR spectroscopy and synthesis of 3-methyl-1 phenyl-1H-chromeno[4,3-c]pyrazol-4-ones formed by the unexpected cyclization of 3 [1-(phenyl-hydrazono)ethyl]-chromen-2-ones. AB - The molecular structures of nine 3-methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4 one isomers, obtained by the oxidative cyclization of the corresponding 1 phenylhydrazono chromen-2-ones with copper acetate as catalyst, are reported. The molecular and supramolecular structures of the 8-chloro, 8-bromo- and 8-nitro isomers 2b-d, were established by X-ray diffraction. The halogenated isomers 2b and 2c are isomorphs, they crystallize as a triclinic system, space group P-1 with two molecules in the asymmetric unit. Compound 2d crystallizes as a monoclinic system, space group P21/m with two molecules in the unit cell. The 1 phenyl ring [Cg(4)] is almost perpendicularly positioned to the chromene-pyrazole ring system. This conformation is in agreement with the anisotropic NMR shielding effect exerted by the phenyl ring over H-9 in solution. The supramolecular architecture is almost controlled by C-H...A (A = O, p) and face to face p stacking interactions. The observed p-stacking trend between chromene and pyrazole rings is given by the overlapping between the best donor and acceptor rings in each compound. PMID- 21258299 TI - Preparation of polyester-based metal-cross linked polymeric composites as novel materials resistant to bacterial adhesion and biofilm formation. AB - Bacterial biofilms constitute an extremely resistant form of bacterial colonization with dire health and economical implications. Towards achieving polymeric composites capable of resisting bacterial adhesion and biofilm formation, we prepared five 2,6-pyridinedicarboxylate-based polyesters employing five different diol monomers. The resulting polyesters were complexed with copper (II) or silver (I). The new polymers were characterized by proton and carbon nuclear magnetic resonance spectroscopy, inherent viscosity, infrared spectroscopy, differential scanning calorimetry and thermogravimetric analysis. The corresponding metal complexes were characterized by differential scanning calorimetry and infrared spectroscopy. The amounts of complexed copper and silver were determined by atomic absorption spectrophotometry. Finally, the resulting composites were tested for their antibacterial potential and were found to effectively resist bacterial attachment and growth. PMID- 21258300 TI - Palladium catalyzed allylic C-H alkylation: a mechanistic perspective. AB - The atom-efficiency of one of the most widely used catalytic reactions for forging C-C bonds, the Tsuji-Trost reaction, is limited by the need of preoxidized reagents. This limitation can be overcome by utilization of the recently discovered palladium-catalyzed C-H activation, the allylic C-H alkylation reaction which is the topic of the current review. Particular emphasis is put on current mechanistic proposals for the three reaction types comprising the overall transformation: C-H activation, nucleophilic addition, and re oxidation of the active catalyst. Recent advances in C-H bond activation are highlighted with emphasis on those leading to C-C bond formation, but where it was deemed necessary for the general understanding of the process closely related C-H oxidations and aminations are also included. It is found that C-H cleavage is most likely achieved by ligand participation which could involve an acetate ion coordinated to Pd. Several of the reported systems rely on benzoquinone for re oxidation of the active catalyst. The scope for nucleophilic addition in allylic C-H alkylation is currently limited, due to demands on pK(a) of the nucleophile. This limitation could be due to the pH dependence of the benzoquinone/hydroquinone redox couple. Alternative methods for re-oxidation that does not rely on benzoquinone could be able to alleviate this limitation. PMID- 21258301 TI - Recent advances in the application of chiral phosphine ligands in Pd-catalysed asymmetric allylic alkylation. AB - One of the most powerful approaches for the formation of simple and complex chiral molecules is the metal-catalysed asymmetric allylic alkylation. This reaction has been broadly studied with a great variety of substrates and nucleophiles under different reaction conditions and it has promoted the synthesis of new chiral ligands to be evaluated as asymmetric inductors. Although the mechanism as well as the active species equilibria are known, the performance of the catalytic system depends on the fine tuning of factors such as type of substrate, nucleophile nature, reaction medium, catalytic precursor and type of ligand used. Particularly interesting are chiral phosphines which have proved to be effective asymmetric inductors in several such reactions. The present review covers the application of phosphine-donor ligands in Pd-catalysed asymmetric allylic alkylation in the last decade. PMID- 21258302 TI - [The specifities of the HPV-genital infections in males]. AB - Anogenital infections caused by Human papillomavirus (HPV) are the most frequently diagnosed sexually transmitted infections of viral origin and up to 150 HPV DNA types have been recognized so far. Anogenital warts (condylomata acuminata) are the most common lesions presented in men, however, during the last decade the other HPV-associated exaggerated lesions such as condylomata plana, penile, scrotal, and anal intraepithelial neoplasias, as well as the penile, urine bladder and prostate cancer have been studied somewhat more extensively. The clinical variations might range from clinically invisible, asymptomatic lesions to the bizarre forms of giant condyloma of Buschke-Lowenstein type, including Bowenoid papulosis, Mb. Bowen, different kinds of eryhtroplasia both in men and women and a large spectrum of HPV-induced dermatovenereological entities in genital region including high-grade intraepithelial genital neoplasias, such as penile, anal, scrotal, vulvar, vaginal etc. (thus not only cervical), and, last but not least - the anogenital warts. A prophylactic vaccine that targets these types should thus substantially reduce the burden of HPV-associated clinical diseases. Ultimately, within the spectrum of therapeutic options for condylomata, no method is really superior to others; recurrences occurred in 30 70% of cases. We definitely need the HPV vaccination programme to eliminate one of the oldest and up to now unsolved problems of the mankind. Since HPV is transmitted by sexual intercourse, treatment of both partners is necessary in order to eliminate the virus from the population. Approaches to this include prophylactic vaccines such as quadrivalent HPV vaccine for both men and women. PMID- 21258303 TI - Surveillance of wildlife zoonotic diseases in the Balkans Region. AB - The countries of the Balkan Peninsula have become the region with frequent outbreaks of the emerging and re-emerging diseases during the last decade of the 20th and the first decade of the 21st century. The majority of outbreaks were wildlife zoonotic, and vector-borne diseases, such as brucellosis, leptospirosis, listeriosis, tularemia, Q-fever, Lyme disease, anthrax, rabies, viral hemorrhagic fevers, sandfly fever, tick-borne encephalitis and leishmainiasis. Epidemiological factors determined by ecology of causative agents are often the most useful diagnostic clues. The recognition of evolving problems of emerging and re-emerging diseases emphasizes the need for the development of better laboratory diagnostic methods for the surveillance and tracking of the diseases, and for continued research of factors contributing to the transmission of the organisms. The continuous occurrence of previously unidentified infections requires prospective national strategies for timely recognition of the syndromes, causative agent identification, establishment of criteria and methods for the diagnosis, optimization of the treatment regime, and determination of successful approaches to prevention and control. Wildlife diseases surveillance in the most of the Balkan countries has been coordinated by the WHO since 1992. Although new technology and communication have extremely improved in the last decade, there is a need for optimal communication lines among the Balkan countries, better exploitation of communication technologies like the Internet and other media in the field of emerging diseases. PMID- 21258304 TI - Beginnings and success in preventing anophelism by means of gambusia fish on the island of Krk in Croatia from 1922 to 1927. AB - The introductory part has summarized the role of malaria in the course of history and various attempts of its eradication in Croatia before the World War I. Furthemore, there is a list of activities and results accomplished between 1922 and 1927 on the island of Krk by Dr. Otmar Trausmiller. After a systematic sanitation of all anopheles habitats, primarily natural and artificial bodies of still water, and introduction of imported gambusia to those bodies of water, anopheles was virtually eradicated on the island. What followed was an evident decrease of new malaria incidents, and in the campaign against malaria there was still major concern in the form of chronic patients and intensive quinine therapy. Today, about eighty years after it was introduced to Krk, gambusia still abides in ponds across the island and it represents one of the main factors in the protection against potential revival of indigenous malaria. PMID- 21258305 TI - Emanuel Edward Klein, a diligent and industrious plodder or the father of British microbiology. AB - Emanuel Edward Klein (Osijek, 1844 - Hove, 1925) was a British microbiologist of Croatian origin. He completed his medical studies in Vienna in 1869. In 1869 he was sent to England to determine terms for the translation of Samuel Stricker's manual Handbuch von den Geweben des Menchen und der Tiere. During his visit he made a good impression on John Burdon Sanderson and John Simon, which was the main reason why he was invited to London in 1871 to conduct investigations under their guidance. In 1873 Klein began his collaboration with the Saint Bartholomew's Hospital, where he was appointed as a Joint Professor of General Anatomy and Physiology. His researches were in the fields of anatomy, histology, pathology, embryology, physiology, and especially microbiology. He did a great deal to its development in Britain. He has written about 260 scientific papers on a broad range of different topics. Despite all the aforementioned facts, his work was never properly studied, and he is almost unknown outside academic circles. For that reason, attitudes towards him still range between the extremes of calling him the father of British microbiology on one side, and attributing him as a diligent and industrious plodder on the other. In this paper we will try to prove the first attitude. We will put his researches in a general context. Finally we will highlight his original achievements in the isolation of new microbes. PMID- 21258306 TI - Efficiency of hypertonic and isotonic seawater solutions in chronic rhinosinusitis. AB - BACKGROUND: To compare the efficiency of isotonic and hypertonic seawater solutions used for nasal lavage and quality of life of the patients with chronic rhinosinusitis. METHODS: A random and controlled clinical study was performed. The study included 60 patients with history of chronic rhinosinusitis. At the beginning of the study, each subject was given a Patient Logbook, which needed to be filled out daily during the 15-day study period. There were three visits per each patient during the study. RESULTS: Results Patient Logbook notes showed significant statistical differences in all symptoms in the group of patients using hypertonic seawater solution. However, while the notes showed significant statistical differences in congestion and rhinorrhea, in the group of patients using isotonic seawater solution, other symptoms showed no major changes during the study period. CONCLUSIONS: Hypertonic seawater solution has been proven to be better than isotonic seawater solution in eliminating the symptoms of nasal congestion, rhinorrhea, cough, headache and waking up during the night. PMID- 21258307 TI - [Changes in the structure and clinical significance of the positive results of pretransfusion testing during the switching from tube test agglutination to gel microcolumn technique]. AB - AIM: To investigate the changes in pretransfusion testing during the switch from the agglutination tube test to the gel test. METHODS: Clinical significance of positive results has been analyzed in 7667 pretransfusion tests (with 16610 cross matches) performed by the tube test in 2005-2006, and in 7372 pretransfusion tests (with 17294 cross-matches) performed in 2007-2008 by the gel test. RESULTS: In both analyzed periods antibody detection was positive in 1.3% and cross matching in 0.3% cases. At least one test was positive in 1.4% pretransfusions tested by the tube test and in 1.3% by the gel test, with >75% positive results in women. Analyzing cases with positive cross-matching but negative antibody detection, eight of ten such cases found by the tube test were caused by 'cold antibodies' whereas 'warm non-specific antibodies' caused all three cases found by the gel test. The gel test detected higher proportion of immune antibodies than the tube test (69.8% vs 41.3%, p < 0.001), with a double increase in anti-K and Rh antibodies. The tube test detected 24 cases of clinically non-significant antibodies, as compared with no cases found by the gel test (p < 0,001). 'Non specific antibodies' more often caused positive cross-matches than antibody detection (42.6% vs. 29.9% by the tube test, 28.9% vs. 18.3% by the gel test). Despite of being close in the detection of irregular antibodies (p=0.062), the difference between the tube and gel test was not significant. 'Non-specific antibodies' were found by both tests more often in women, while clinical departments were of no significance. CONCLUSIONS: The gel test has proved to be a more optimal technique of pretransfusion testing. The detection of irregular antibodies is recommended as an obligatory part of pretransfusion testing. PMID- 21258308 TI - [Etiology of lymphadenopathy in childhood]. AB - BACKGROUND: To establish etiology and level of prevalence of lymphadenopathy in children. METHODS: One hundred and fifteen children aged 0-15 years with diagnosed lymphadenopathy at the Pediatric Clinic in Sarajevo during 2008 were included in the study. It analyzed age, sex, etiology and distribution and prevalence of lymphadenopathy. RESULTS: There was no statistically significant difference (p > 0,05) according to gender and age of children with lymphadenopathy. Leading etiological causes of lymphadenopathy were infections in 95% (62,7 %) and malignancies in 20 (13,3 %) cases. The most frequent isolated microorganisms were viruses in 65 children (65 %) and bacteria in 26 (28%) of children. Most frequent causes of malignant lymphadenopathy were acute lymphoblastic leukemia in 11 children (55 %) and acute myeloid leukemia in two (10%) children. Regional lymphadenopathy was more frequent than generalized lymphadenopathy, in 103 children (68,7%) and 47 (31,3 %) children, respectively. Most frequent localizations of regional lymphadenopathy were neck, axillae and groin, in 83, 8, and 5 (80,5 %, 7,8%, 4,8%) children. CONCLUSIONS: The regional and generalized lymphadenopathies in children depend on their etiology and have significant prognostic value for the disease. PMID- 21258309 TI - [The lunar cycle and seizures in children]. AB - AIM: To analyze the annual trend of hospitalization and potential influence of the lunar cycle of children treated for seizures METHODS: The data of the patients treated for seizures (convulsions, epileptic seizures, disturbance of consciousness and epileptic seizures in children with neurodevelopmental disability) in the Pediatrics Clinic of the University Clinical Center of Tuzla were retrospectively analyzed during 2008 in relation to seasonal distribution, admission time (month, week, admission moment, day in a week, time of the day) and the lunar cycle. RESULTS: Out f the total of 234 treated children, 55 (23,5%) were infants, 101 (43,1%) were under six years of age and 78 (33,3%) were of school age. The most common type of seizures were convulsions, 123 (42,6%). The seizures were numerous in the midst of the week, as opposed to weekends. The highest number of children was treated in January, February, July and August, that it, in the fourth, seventh, twenty-seventh and thirty-first week of the year. Seizures occured during the day in 149 patients (63,7%) and during the night in 84 (35,9%) patients (p < 0,0034). The number of treated patients was significantly larger in the third and fourth lunar phases (p < 0,018). CONCLUSIONS: The results suggested seasonal and weekly trends of hospitalization of patients with seizures and their relation with circadian and lunar cycles. There is a need for further prospective studies in order to get better understanding of the influence of the lunar cycle on health. PMID- 21258310 TI - Increased P wave dispersion in patients with liver steatosis. AB - AIM: Hepatic steatosis is associated with metabolic and hemodynamic abnormalities induced by insulin resistance and inflammatory state. Since abnormalities of P wave dispersion may be accompanied with latter issues we evaluated this subject in patients with hepatic steatosis. METHODS: Total of 106 patients and 56 healthy subjects were enrolled and performed hepatic ultrasonography, echocardiography, electrocardiogram, and biochemistry tests. Clinical features, laboratory and echocardiographic parameters, P wave dispersion were compared between groups and analyzed for any correlation among parameters. RESULTS: Body mass index (BMI), waist circumference, systolic and diastolic blood pressure, levels of total and LDL cholesterol, and fasting blood glucose (FBG), and left atrial diameter were significantly higher in patients with hepatic steatosis. Peak velocities of mitral E and A waves and their ratio were abnormally changed in patients compared to normals. In multiple linear regression analysis, approximately all of the variables previously correlated within Pearsons' correlation test were found to be significantly correlated with P wave dispersion [ waist circumference (beta=0.151, p=0.048), LDL cholesterol (beta=0.234, p=0.000), FBG (beta=0.402, p= 0.000), alanine aminotransferase (ALT) (beta=0.205, p= 0.006), alkaline phosphatase (ALP) (beta=0.277, p=0.000), gamma-glutamyl transferase (gamma-GT) (beta=0.240, p=0.000), left atrial diameter (beta=0.204, p=0.003), heart rate (beta=0.123, p=0.037)]. CONCLUSIONS: Increased P wave dispersion may indicate a risk of atrial arrhythmia which may be complicated with disabling symptoms and thromboembolism in patients with hepatic steatosis. Consequently, hepatic steatosis is associated with increased risk for cardiovascular disease due to metabolic and hemodynamic abnormalities probably induced by insulin resistance and inflammaory state. PMID- 21258311 TI - Impact of reversionary and other etiological factors on prognosis and course of schizophrenia. AB - BACKGROUND: To identify the presence of schizophrenia among patients and their relatives, factors affecting duration and prognosis of the disease and other etiological factors related to schizophrenia. METHODS: This retrospective, descriptive, analytical and epidemiological research, which was conducted at the Psychiatric hospital of the Clinical Center of the University of Sarajevo during 2007, covered randomly selected 100 hospitalized patients with schizophrenia according to diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Diagnosis of schizophrenia among relatives was based on anamnesis- Structural Clinical Interview (SCID) and it was applied to confirm DSM-IV diagnosis of schizophrenia. RESULTS: The presence of schizophrenia among patient relatives was the most important in etiology of schizophrenia (62%), and etiological factors were represented in 38 % of examinees (p=0,0001). Among relatives of examinees aged 20 - 30 years, schizophrenia was present in 37 (59.7%) cases. Schizophrenia among relatives caused earlier appearance of the disease. Duration of hospitalization of over 60 days was in the group of examinees which have the relatives with schizophrenia, 18 (29.0%); multiple hospitalizations were noted in the group of relatives in 40 (64.5%) cases; in one case (8.3%) traumatic experience was noted, in three (42.8%) acute stress, and in four 4 cases (28.6%) non-adequate living conditions. CONCLUSIONS: The results of this study show that reversionary factors are responsible for inducing schizophrenia, which leads towards chronic course of the disease and worsened prognosis. PMID- 21258312 TI - [Intrauterine growth standards for Tuzla region]. AB - AIM: To evaluate normal fetal growth and create a normogram for the population of the Tuzla Canton. METHODS: In the period 2002-2005 we evaluated fetal growth by ultrasound measurements (biparietal diameter - BPD, head circumpherency -HC, abdominal diameter -ABD, abdominal circumpherency -AC, femur length - FL) according to the criteria of FIGO (1986) in 100 healthy pregnant women with normal singleton pregnancy. All of them had spontaneous vaginal delivery between the 38th and 41st week. These measurements were done once per month starting from 12 to 41 weeks. RESULTS: Mean birth weight value in 38th week was 3280 +/- 345g, in 39th week 3360 +/- 280g, in 40th week 3596 +/- 320g and in 41st week 3732 +/- 38 g. These standards have shown lower values of all examined parameters in all the gestation weeks. Values of BPD and FL were very similar but differences between our values of HC and AC in the last four weeks were very high. CONCLUSIONS: We found significant differences between our standards and others (Hadlock, 1983 i Latin, 2000) especially in the last four weeks of gestation. Now, when we have standards of fetal growth for our population we expect better evaluation of gestational age and lower perinatal mortality in Bosnia and Herzegovina. PMID- 21258313 TI - [Stereological analysis of syncytiotrophoblast in resorption villi of placentas of young and older pregnant women]. AB - AIM: To determine quantitative parameters of volume density and absolute volume of syncytiotrophoblast in resorption villi of control and experimental group, compare the results and search for correlation between structural parameters of resorption villi and pregnancy age. METHODS: The research was performed on 60 human placentas of term pregnancy: 30 placentas of pregnant women of age 20 - 34 (control group), and 30 placentas of pregnant women of age 35 and older (experimental group). Stereological analysis was performed on multipurpose testing system M42 with 40 times objective magnification. RESULTS: Average volume density of syncytiotrophoblast in resorption villi of experimental and control group was Vvss = (0,489 +/- 0,032) mm0 and Vvsm = (0,389 +/- 0,078) mm0 , respectively. Statistical analysis of results using Student t-test indicated a significantly higher volume density of syncytiotrophoblast of resorption villi in the experimental than in the control group (p < 0,001). Absolute volume of syncytiotrophoblast in resorption villi of the experimental and control groups was Vss = (205,250+/-40,894) cm3 and Vsm = (178,386 +/- 44,413) cm3, respectively. We have found a significantly higher absolute volume of syncytiotrophoblast in resorption villi in the experimental than in the control group (p < 0,005). CONCLUSIONS: Statistically significant higher values of volume density and absolute volume of syncytiotrophoblast in resorption villi of placentas in older pregnant women represent a compensatory mechanism as a response to decreased metabolic exchange between a mother and a fetus. PMID- 21258314 TI - [Operative treatment of endometriosis in the Clinical Centre of Kragujevac during the period 2004-2008]. AB - In this retrospective research parameters connected to the pathogenesis and treatment of pelvic endometriosis have been analyzed (surgical operation, age, surgical approach and conservativeness of the operation, spreading of the endometrioses to the surrounding pelvic organs) at Gynecology and Obstetric Clinic of Clinical Centre in Kragujevac during a five year period. The total number of observed patients was 88. They all had ovary cysts and a high value of the Ca 125 tumor marker and pathological verification of endometrioses. The greatest number of patients were in the age group 26-35 (56,8%). The most common procedure was radical surgical operation adnexectomy in 53 (60,2%) and hysterectomy in 24 (45,83%) patients (p < 0,01). With almost equal probability both laparotomy and laparoscopy were performed (p > 0,01). Ovary endometriosis was often joined with other pelvic organs endometriosis. PMID- 21258315 TI - Emerging risk for viral hepatitis A in Croatian adults. AB - An objective of the study was to determine the changes in the risk of developing hepatitis A in the 30-years period and discuss the need for vaccination against HAV infection in Croatia and the city of Rijeka comparing incidence of hepatitis A between 1970-1974 and 2000-2004 periods. Hepatitis A declined in both populations and affected more prominently older population groups. Improvement of hygiene and sanitary conditions appears to have decreased hepatitis A incidence among children and adults, but only a seroepidemiological study can give more accurate data as a basis for discussion on the necessity of vaccination as a further measure in reducing hepatitis A incidence. PMID- 21258316 TI - [Intact twin tubal pregnancy]. AB - A case of a unilateral eight-week twin ectopic pregnancy diagnosed with transvaginal sonography is presented here. This ectopic pregnancy was found in the right Fallopian tube of a 35-year old woman. After the surgical procedure conducted by the method of transversal laparotomy, we removed the right Fallopian tube with two gestational sacs So far only a hundred of such cases of ectopic twin pregnancy have been described worldwide. PMID- 21258317 TI - Obstruction of left ventricular outflow tract by a calcified mass at mitral valve. AB - A case of an unusual left ventricular outflow tract obstruction by mitral valve pathology in a 35-year old female with diabetes and end-stage renal disease is presented in the study. The patient suffered from fever of an unknown origin after lower-leg amputation. Although the wound healed well, fever persisted for three weeks despite a triple antibiotic treatment until the infection was resolved with vancomycin. Three months later echocardiography displayed a floating mass attached to mitral valve, producing a newly developed systolic murmur and a mild haemodynamic obstruction of the left ventricular outflow tract. The calcified vegetation was probably formed during an unrecognized subacute infective endocarditis. PMID- 21258318 TI - Laparoscopic treatment of achalasia--first case in Croatia. AB - Esophageal achalasia is a primary esophageal motility disorder. Commonly used treatments are botulinum toxin injections, endoscopic balloon dilation and surgical myotomy with or without fundoplication. We are hereby presenting the first case of laproscopic myotomy with fundoplication performed in Croatia. A 32 year old female was admitted to the hospital due to the symptoms of dysphagia, regurgitation, chest pain and weight loss. Upper gastrointestinal tract radiography with contrast and flexible endoscopy confirmed the clinical diagnosis of achalasia. She was treated by the Heller laparoscopic procedure and Dor anterior fundoplication. The patient had a successful recovery and was discharged on the fifth postoperative day. This case shows that laparoscopic treatment of achalasia is a feasibile and safe procedure which can be performed even in a small country hospital, but it requires great technical care and experience of the surgeon. PMID- 21258319 TI - Localizing protein in 3D neural stem cell culture: a hybrid visualization methodology. AB - The importance of 3-dimensional (3D) topography in influencing neural stem and progenitor cell (NPC) phenotype is widely acknowledged yet challenging to study. When dissociated from embryonic or post-natal brain, single NPCs will proliferate in suspension to form neurospheres. Daughter cells within these cultures spontaneously adopt distinct developmental lineages (neurons, oligodendrocytes, and astrocytes) over the course of expansion despite being exposed to the same extracellular milieu. This progression recapitulates many of the stages observed over the course of neurogenesis and gliogenesis in post-natal brain and is often used to study basic NPC biology within a controlled environment. Assessing the full impact of 3D topography and cellular positioning within these cultures on NPC fate is, however, difficult. To localize target proteins and identify NPC lineages by immunocytochemistry, free-floating neurospheres must be plated on a substrate or serially sectioned. This processing is required to ensure equivalent cell permeabilization and antibody access throughout the sphere. As a result, 2D epifluorescent images of cryosections or confocal reconstructions of 3D Z-stacks can only provide spatial information about cell position within discrete physical or digital 3D slices and do not visualize cellular position in the intact sphere. Here, to reiterate the topography of the neurosphere culture and permit spatial analysis of protein expression throughout the entire culture, we present a protocol for isolation, expansion, and serial sectioning of post-natal hippocampal neurospheres suitable for epifluorescent or confocal immunodetection of target proteins. Connexin29 (Cx29) is analyzed as an example. Next, using a hybrid of graphic editing and 3D modelling softwares rigorously applied to maintain biological detail, we describe how to re-assemble the 3D structural positioning of these images and digitally map labelled cells within the complete neurosphere. This methodology enables visualization and analysis of the cellular position of target proteins and cells throughout the entire 3D culture topography and will facilitate a more detailed analysis of the spatial relationships between cells over the course of neurogenesis and gliogenesis in vitro. PMID- 21258320 TI - Cell-type-specific replication initiation programs set fragility of the FRA3B fragile site. AB - Common fragile sites have long been identified by cytogeneticists as chromosomal regions prone to breakage upon replication stress. They are increasingly recognized to be preferential targets for oncogene-induced DNA damage in pre neoplastic lesions and hotspots for chromosomal rearrangements in various cancers. Common fragile site instability was attributed to the fact that they contain sequences prone to form secondary structures that may impair replication fork movement, possibly leading to fork collapse resulting in DNA breaks. Here we show, in contrast to this view, that the fragility of FRA3B--the most active common fragile site in human lymphocytes--does not rely on fork slowing or stalling but on a paucity of initiation events. Indeed, in lymphoblastoid cells, but not in fibroblasts, initiation events are excluded from a FRA3B core extending approximately 700 kilobases, which forces forks coming from flanking regions to cover long distances in order to complete replication. We also show that origins of the flanking regions fire in mid-S phase, leaving the site incompletely replicated upon fork slowing. Notably, FRA3B instability is specific to cells showing this particular initiation pattern. The fact that both origin setting and replication timing are highly plastic in mammalian cells explains the tissue specificity of common fragile site instability we observed. Thus, we propose that common fragile sites correspond to the latest initiation-poor regions to complete replication in a given cell type. For historical reasons, common fragile sites have been essentially mapped in lymphocytes. Therefore, common fragile site contribution to chromosomal rearrangements in tumours should be reassessed after mapping fragile sites in the cell type from which each tumour originates. PMID- 21258321 TI - Mice carrying a knock-in mutation of Aicda resulting in a defect in somatic hypermutation have impaired gut homeostasis and compromised mucosal defense. AB - To elucidate the specific role of somatic hypermutation (SHM) in mucosal immunity, we generated mice carrying a knock-in point mutation in Aicda, which encodes activation-induced cytidine deaminase (AID), an enzyme essential to SHM and class-switch recombination (CSR). These mutant AID(G23S) mice had much less SHM but had normal amounts of immunoglobulin in both serum and intestinal secretions. AID(G23S) mice developed hyperplasia of germinal center B cells in gut-associated lymphoid tissues, accompanied by expansion of microflora in the small intestine. Moreover, AID(G23S) mice had more translocation of Yersinia enterocolitica into mesenteric lymph nodes and were more susceptible than wild type mice to oral challenge with cholera toxin. Together our results indicate that SHM is critical in maintaining intestinal homeostasis and efficient mucosal defense. PMID- 21258322 TI - Genome-wide identification of Ago2 binding sites from mouse embryonic stem cells with and without mature microRNAs. AB - MicroRNAs (miRNAs) are 19-22-nucleotide noncoding RNAs that post transcriptionally regulate mRNA targets. We have identified endogenous miRNA binding sites in mouse embryonic stem cells (mESCs), by performing photo-cross linking immunoprecipitation using antibodies to Argonaute (Ago2) followed by deep sequencing of RNAs (CLIP-seq). We also performed CLIP-seq in Dicer-/- mESCs that lack mature miRNAs, allowing us to define whether the association of Ago2 with the identified sites was miRNA dependent. A significantly enriched motif, GCACUU, was identified only in wild-type mESCs in 3' untranslated and coding regions. This motif matches the seed of a miRNA family that constitutes ~68% of the mESC miRNA population. Unexpectedly, a G-rich motif was enriched in sequences cross linked to Ago2 in both the presence and absence of miRNAs. Expression analysis and reporter assays confirmed that the seed-related motif confers miRNA-directed regulation on host mRNAs and that the G-rich motif can modulate this regulation. PMID- 21258323 TI - Crystal structure of XMRV protease differs from the structures of other retropepsins. AB - Using energy and density guided Rosetta refinement to improve molecular replacement, we determined the crystal structure of the protease encoded by xenotropic murine leukemia virus-related virus (XMRV). Despite overall similarity of XMRV protease to other retropepsins, the topology of its dimer interface more closely resembles those of the monomeric, pepsin-like enzymes. Thus, XMRV protease may represent a distinct branch of the aspartic protease family. PMID- 21258324 TI - Dynamic local unfolding in the serpin alpha-1 antitrypsin provides a mechanism for loop insertion and polymerization. AB - The conformational plasticity of serine protease inhibitors (serpins) underlies both their activities as protease inhibitors and their susceptibility to pathogenic misfolding and aggregation. Here, we structurally characterize a sheet opened state of the serpin alpha-1 antitrypsin (alpha1AT) and show how local unfolding allows functionally essential strand insertion. Mutations in alpha1AT that cause polymerization-induced serpinopathies map to the labile region, suggesting that the evolution of serpin function required sampling of high risk conformations on a dynamic energy landscape. PMID- 21258325 TI - Transcriptome-wide sequencing reveals numerous APOBEC1 mRNA-editing targets in transcript 3' UTRs. AB - Apolipoprotein B-editing enzyme, catalytic polypeptide-1 (APOBEC1) is a cytidine deaminase initially identified by its activity in converting a specific cytidine (C) to uridine (U) in apolipoprotein B (apoB) mRNA transcripts in the small intestine. Editing results in the translation of a truncated apoB isoform with distinct functions in lipid transport. To address the possibility that APOBEC1 edits additional mRNAs, we developed a transcriptome-wide comparative RNA sequencing (RNA-Seq) screen. We identified and validated 32 previously undescribed mRNA targets of APOBEC1 editing, all of which are located in AU-rich segments of transcript 3' untranslated regions (3' UTRs). Further analysis established several characteristic sequence features of editing targets, which were predictive for the identification of additional APOBEC1 substrates. The transcriptomics approach to RNA editing presented here dramatically expands the list of APOBEC1 mRNA editing targets and reveals a novel cellular mechanism for the modification of transcript 3' UTRs. PMID- 21258326 TI - Temporary disruption of fear-potentiated startle following PKMzeta inhibition in the amygdala. AB - We examined whether protein kinase M zeta (PKMzeta) inhibition in the amygdala permanently disrupts fear memory by testing retention at various intervals after PKMzeta blockade. Although the expression of fear memory was disrupted when the inhibitor was applied shortly before testing, it had no effect when rats were tested with longer retention intervals. These results suggest that PKMzeta inhibition does not erase memory, but temporarily disrupts expression of memory. PMID- 21258327 TI - Labile or stable: opposing consequences for memory when reactivated during waking and sleep. AB - Memory consolidation is a dynamic process. Reconsolidation theory assumes that reactivation during wakefulness transiently destabilizes memories, requiring them to reconsolidate in order to persist. Memory reactivation also occurs during slow wave sleep (SWS) and is assumed to underlie the consolidating effect of sleep. Here, we tested whether the same principle of transient destabilization applies to memory reactivation during SWS. We reactivated memories in humans by presenting associated odor cues either during SWS or wakefulness. Reactivation was followed by an interference task to probe memory stability. As we expected, reactivation during waking destabilized memories. In contrast, reactivation during SWS immediately stabilized memories, thereby directly increasing their resistance to interference. Functional magnetic resonance imaging revealed that reactivation during SWS mainly activated hippocampal and posterior cortical regions, whereas reactivation during wakefulness primarily activated prefrontal cortical areas. Our results show that reactivation of memory serves distinct functions depending on the brain state of wakefulness or sleep. PMID- 21258328 TI - Calmodulin as a direct detector of Ca2+ signals. AB - Many forms of signal transduction occur when Ca(2+) enters the cytoplasm of a cell. It has been generally thought that there is a fast buffer that rapidly reduces the free Ca(2+) level and that it is this buffered level of Ca(2+) that triggers downstream biochemical processes, notably the activation of calmodulin (CaM) and the resulting activation of CaM-dependent enzymes. Given the importance of these transduction processes, it is crucial to understand exactly how Ca(2+) activates CaM. We have determined the rate at which Ca(2+) binds to CaM and found that Ca(2+) binds more rapidly to CaM than to other Ca(2+)-binding proteins. This property of CaM and its high concentration support a new view of signal transduction: CaM directly intercepts incoming Ca(2+) and sets the free Ca(2+) level (that is, it strongly contributes to fast Ca(2+) buffering) rather than responding to the lower Ca(2+) level set by other buffers. This property is crucial for making CaM an efficient transducer. Our results also suggest that other Ca(2+) binding proteins have a previously undescribed role in regulating the lifetime of Ca(2+) bound to CaM and thereby setting the gain of signal transduction. PMID- 21258329 TI - NMR analysis demonstrates immunoglobulin G N-glycans are accessible and dynamic. AB - The N-glycan at Asn297 of the immunoglobulin G Fc fragment modulates cellular responses of the adaptive immune system. However, the underlying mechanism remains undefined, as existing structural data suggest the glycan does not directly engage cell surface receptors. Here we characterize the dynamics of the glycan termini using solution NMR spectroscopy. Contrary to previous conclusions based on X-ray crystallography and limited NMR data, our spin relaxation studies indicate that the termini of both glycan branches are highly dynamic and experience considerable motion in addition to tumbling of the Fc molecule. Relaxation dispersion and temperature-dependent chemical shift perturbations demonstrate exchange of the alpha1-6Man-linked branch between a protein-bound and a previously unobserved unbound state, suggesting the glycan samples conformational states that can be accessed by glycan-modifying enzymes and possibly glycan recognition domains. These findings suggest a role for Fc-glycan dynamics in Fc-receptor interactions and enzymatic glycan remodeling. PMID- 21258330 TI - Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells. AB - Glycosyltransferases are ubiquitous enzymes that catalyze the assembly of glycoconjugates throughout all kingdoms of nature. A long-standing problem is the rational design of probes that can be used to manipulate glycosyltransferase activity in cells and tissues. Here we describe the rational design and synthesis of a nucleotide sugar analog that inhibits, with high potency both in vitro and in cells, the human glycosyltransferase responsible for the reversible post translational modification of nucleocytoplasmic proteins with O-linked N acetylglucosamine residues (O-GlcNAc). We show that the enzymes of the hexosamine biosynthetic pathway can transform, both in vitro and in cells, a synthetic carbohydrate precursor into the nucleotide sugar analog. Treatment of cells with the precursor lowers O-GlcNAc in a targeted manner with a single-digit micromolar EC(50). This approach to inhibition of glycosyltransferases should be applicable to other members of this superfamily of enzymes and enable their manipulation in a biological setting. PMID- 21258331 TI - Label-free single-molecule detection of DNA-hybridization kinetics with a carbon nanotube field-effect transistor. AB - Single-molecule measurements of biomolecules can provide information about the molecular interactions and kinetics that are hidden in ensemble measurements. However, there is a requirement for techniques with improved sensitivity and time resolution for use in exploring biomolecular systems with fast dynamics. Here, we report the detection of DNA hybridization at the single-molecule level using a carbon nanotube field-effect transistor. By covalently attaching a single stranded probe DNA sequence to a point defect in a carbon nanotube, we are able to measure two-level fluctuations in the conductance of the nanotube in the presence of a complementary DNA target. The kinetics of the system are studied as a function of temperature, allowing the measurement of rate constants, melting curves and activation energies for different sequences and target concentrations. The kinetics demonstrate non-Arrhenius behaviour, in agreement with DNA hybridization experiments using fluorescence correlation spectroscopy. This technique is label-free and could be used to probe single-molecule dynamics at microsecond timescales. PMID- 21258332 TI - A recyclable supramolecular membrane for size-selective separation of nanoparticles. AB - Most practical materials are held together by covalent bonds, which are irreversible. Materials based on noncovalent interactions can undergo reversible self-assembly, which offers advantages in terms of fabrication, processing and recyclability, but the majority of noncovalent systems are too fragile to be competitive with covalent materials for practical applications, despite significant attempts to develop robust noncovalent arrays. Here, we report nanostructured supramolecular membranes prepared from fibrous assemblies in water. The membranes are robust due to strong hydrophobic interactions, allowing their application in the size-selective separation of both metal and semiconductor nanoparticles. A thin (12 um) membrane is used for filtration (~5 nm cutoff), and a thicker (45 um) membrane allows for size-selective chromatography in the sub-5 nm domain. Unlike conventional membranes, our supramolecular membranes can be disassembled using organic solvent, cleaned, reassembled and reused multiple times. PMID- 21258333 TI - Statistical analysis of nanoparticle dosing in a dynamic cellular system. AB - The delivery of nanoparticles into cells is important in therapeutic applications and in nanotoxicology. Nanoparticles are generally targeted to receptors on the surfaces of cells and internalized into endosomes by endocytosis, but the kinetics of the process and the way in which cell division redistributes the particles remain unclear. Here we show that the chance of success or failure of nanoparticle uptake and inheritance is random. Statistical analysis of nanoparticle-loaded endosomes indicates that particle capture is described by an over-dispersed Poisson probability distribution that is consistent with heterogeneous adsorption and internalization. Partitioning of nanoparticles in cell division is random and asymmetric, following a binomial distribution with mean probability of 0.52-0.72. These results show that cellular targeting of nanoparticles is inherently imprecise due to the randomness of nature at the molecular scale, and the statistical framework offers a way to predict nanoparticle dosage for therapy and for the study of nanotoxins. PMID- 21258334 TI - Plasmonic Luneburg and Eaton lenses. AB - Plasmonics takes advantage of the properties of surface plasmon polaritons, which are localized or propagating quasiparticles in which photons are coupled to the quasi-free electrons in metals. In particular, plasmonic devices can confine light in regions with dimensions that are smaller than the wavelength of the photons in free space, and this makes it possible to match the different length scales associated with photonics and electronics in a single nanoscale device. Broad applications of plasmonics that have been demonstrated to date include biological sensing, sub-diffraction-limit imaging, focusing and lithography and nano-optical circuitry. Plasmonics-based optical elements such as waveguides, lenses, beamsplitters and reflectors have been implemented by structuring metal surfaces or placing dielectric structures on metals to manipulate the two dimensional surface plasmon waves. However, the abrupt discontinuities in the material properties or geometries of these elements lead to increased scattering of surface plasmon polaritons, which significantly reduces the efficiency of these components. Transformation optics provides an alternative approach to controlling the propagation of light by spatially varying the optical properties of a material. Here, motivated by this approach, we use grey-scale lithography to adiabatically tailor the topology of a dielectric layer adjacent to a metal surface to demonstrate a plasmonic Luneburg lens that can focus surface plasmon polaritons. We also make a plasmonic Eaton lens that can bend surface plasmon polaritons. Because the optical properties are changed gradually rather than abruptly in these lenses, losses due to scattering can be significantly reduced in comparison with previously reported plasmonic elements. PMID- 21258335 TI - Designed ultrafast optical nonlinearity in a plasmonic nanorod metamaterial enhanced by nonlocality. AB - All-optical signal processing enables modulation and transmission speeds not achievable using electronics alone. However, its practical applications are limited by the inherently weak nonlinear effects that govern photon-photon interactions in conventional materials, particularly at high switching rates. Here, we show that the recently discovered nonlocal optical behaviour of plasmonic nanorod metamaterials enables an enhanced, ultrafast, nonlinear optical response. We observe a large (80%) change of transmission through a subwavelength thick slab of metamaterial subjected to a low control light fluence of 7 mJ cm( 2), with switching frequencies in the terahertz range. We show that both the response time and the nonlinearity can be engineered by appropriate design of the metamaterial nanostructure. The use of nonlocality to enhance the nonlinear optical response of metamaterials, demonstrated here in plasmonic nanorod composites, could lead to ultrafast, low-power all-optical information processing in subwavelength-scale devices. PMID- 21258336 TI - Hyperglycemia-induced cerebral hematoma expansion is mediated by plasma kallikrein. AB - Hyperglycemia is associated with greater hematoma expansion and poor clinical outcomes after intracerebral hemorrhage. We show that cerebral hematoma expansion triggered by intracerebral infusion of autologous blood is greater in diabetic rats and mice compared to nondiabetic controls and that this augmented expansion is ameliorated by plasma kallikrein (PK) inhibition or deficiency. Intracerebral injection of purified PK augmented hematoma expansion in both diabetic and acutely hyperglycemic rats, whereas injection of bradykinin, plasmin or tissue plasminogen activator did not elicit such a response. This response, which occurs rapidly, was prevented by co-injection of the glycoprotein VI agonist convulxin and was mimicked by glycoprotein VI inhibition or deficiency, implicating an effect of PK on inhibiting platelet aggregation. We show that PK inhibits collagen-induced platelet aggregation by binding collagen, a response enhanced by elevated glucose concentrations. The effect of hyperglycemia on hematoma expansion and PK-mediated inhibition of platelet aggregation could be mimicked by infusing mannitol. These findings suggest that hyperglycemia augments cerebral hematoma expansion by PK-mediated osmotic-sensitive inhibition of hemostasis. PMID- 21258337 TI - Brown adipose tissue activity controls triglyceride clearance. AB - Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold and has recently been shown to be present in humans. Triglyceride-rich lipoproteins (TRLs) transport lipids in the bloodstream, where the fatty acid moieties are liberated by the action of lipoprotein lipase (LPL). Peripheral organs such as muscle and adipose tissue take up the fatty acids, whereas the remaining cholesterol-rich remnant particles are cleared by the liver. Elevated plasma triglyceride concentrations and prolonged circulation of cholesterol-rich remnants, especially in diabetic dyslipidemia, are risk factors for cardiovascular disease. However, the precise biological role of BAT for TRL clearance remains unclear. Here we show that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice. Cold exposure drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, a process crucially dependent on local LPL activity and transmembrane receptor CD36. In pathophysiological settings, cold exposure corrected hyperlipidemia and improved deleterious effects of insulin resistance. In conclusion, BAT activity controls vascular lipoprotein homeostasis by inducing a metabolic program that boosts TRL turnover and channels lipids into BAT. Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans. PMID- 21258338 TI - A multistage tuberculosis vaccine that confers efficient protection before and after exposure. AB - All tuberculosis vaccines currently in clinical trials are designed as prophylactic vaccines based on early expressed antigens. We have developed a multistage vaccination strategy in which the early antigens Ag85B and 6-kDa early secretory antigenic target (ESAT-6) are combined with the latency-associated protein Rv2660c (H56 vaccine). In CB6F1 mice we show that Rv2660c is stably expressed in late stages of infection despite an overall reduced transcription. The H56 vaccine promotes a T cell response against all protein components that is characterized by a high proportion of polyfunctional CD4(+) T cells. In three different pre-exposure mouse models, H56 confers protective immunity characterized by a more efficient containment of late-stage infection than the Ag85B-ESAT6 vaccine (H1) and BCG. In two mouse models of latent tuberculosis, we show that H56 vaccination after exposure is able to control reactivation and significantly lower the bacterial load compared to adjuvant control mice. PMID- 21258339 TI - Micropilot: automation of fluorescence microscopy-based imaging for systems biology. AB - Quantitative microscopy relies on imaging of large cell numbers but is often hampered by time-consuming manual selection of specific cells. The 'Micropilot' software automatically detects cells of interest and launches complex imaging experiments including three-dimensional multicolor time-lapse or fluorescence recovery after photobleaching in live cells. In three independent experimental setups this allowed us to statistically analyze biological processes in detail and is thus a powerful tool for systems biology. PMID- 21258340 TI - miRNA regulation of Sdf1 chemokine signaling provides genetic robustness to germ cell migration. AB - microRNAs (miRNAs) function as genetic rheostats to control gene output. Based on their role as modulators, it has been postulated that miRNAs canalize development and provide genetic robustness. Here, we uncover a previously unidentified regulatory layer of chemokine signaling by miRNAs that confers genetic robustness on primordial germ cell (PGC) migration. In zebrafish, PGCs are guided to the gonad by the ligand Sdf1a, which is regulated by the sequestration receptor Cxcr7b. We find that miR-430 regulates sdf1a and cxcr7 mRNAs. Using target protectors, we demonstrate that miR-430-mediated regulation of endogenous sdf1a (also known as cxcl12a) and cxcr7b (i) facilitates dynamic expression of sdf1a by clearing its mRNA from previous expression domains, (ii) modulates the levels of the decoy receptor Cxcr7b to avoid excessive depletion of Sdf1a and (iii) buffers against variation in gene dosage of chemokine signaling components to ensure accurate PGC migration. Our results indicate that losing miRNA-mediated regulation can expose otherwise buffered genetic lesions leading to developmental defects. PMID- 21258341 TI - TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum. AB - Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ~5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders. PMID- 21258342 TI - Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. AB - Development, differentiation and response to environmental stimuli are characterized by sequential changes in cellular state initiated by the de novo binding of regulated transcriptional factors to their cognate genomic sites. The mechanism whereby a given regulatory factor selects a limited number of in vivo targets from a myriad of potential genomic binding sites is undetermined. Here we show that up to 95% of de novo genomic binding by the glucocorticoid receptor, a paradigmatic ligand-activated transcription factor, is targeted to preexisting foci of accessible chromatin. Factor binding invariably potentiates chromatin accessibility. Cell-selective glucocorticoid receptor occupancy patterns appear to be comprehensively predetermined by cell-specific differences in baseline chromatin accessibility patterns, with secondary contributions from local sequence features. The results define a framework for understanding regulatory factor-genome interactions and provide a molecular basis for the tissue selectivity of steroid pharmaceuticals and other agents that intersect the living genome. PMID- 21258343 TI - Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome. AB - 3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome. PMID- 21258345 TI - Transparency in peer review. AB - Would the publication of anonymous referee reports and editorial decision letters of published papers benefit the scientific debate? Results from a trial seem to suggest this. PMID- 21258344 TI - Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes. AB - The development of selective histone deacetylase (HDAC) inhibitors with anti cancer and anti-inflammatory properties remains challenging in large part owing to the difficulty of probing the interaction of small molecules with megadalton protein complexes. A combination of affinity capture and quantitative mass spectrometry revealed the selectivity with which 16 HDAC inhibitors target multiple HDAC complexes scaffolded by ELM-SANT domain subunits, including a novel mitotic deacetylase complex (MiDAC). Inhibitors clustered according to their target profiles with stronger binding of aminobenzamides to the HDAC NCoR complex than to the HDAC Sin3 complex. We identified several non-HDAC targets for hydroxamate inhibitors. HDAC inhibitors with distinct profiles have correspondingly different effects on downstream targets. We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. Our approach enables the discovery of novel targets and inhibitors and suggests that the selectivity of HDAC inhibitors should be evaluated in the context of HDAC complexes and not purified catalytic subunits. PMID- 21258347 TI - Protein polymer: Gene libraries open up. PMID- 21258348 TI - Protein folding: To knot or not to knot? PMID- 21258349 TI - Material witness: Carbon tailoring. PMID- 21258350 TI - Tribology: Sliding on vacuum. PMID- 21258351 TI - Metallic glasses: Damage tolerance at a price. PMID- 21258352 TI - Single dopants in semiconductors. AB - The sensitive dependence of a semiconductor's electronic, optical and magnetic properties on dopants has provided an extensive range of tunable phenomena to explore and apply to devices. Recently it has become possible to move past the tunable properties of an ensemble of dopants to identify the effects of a solitary dopant on commercial device performance as well as locally on the fundamental properties of a semiconductor. New applications that require the discrete character of a single dopant, such as single-spin devices in the area of quantum information or single-dopant transistors, demand a further focus on the properties of a specific dopant. This article describes the huge advances in the past decade towards observing, controllably creating and manipulating single dopants, as well as their application in novel devices which allow opening the new field of solotronics (solitary dopant optoelectronics). PMID- 21258354 TI - A heteroepitaxial perovskite metal-base transistor. AB - 'More than Moore' captures a concept for overcoming limitations in silicon electronics by incorporating new functionalities in the constituent materials. Perovskite oxides are candidates because of their vast array of physical properties in a common structure. They also enable new electronic devices based on strongly-correlated electrons. The field effect transistor and its derivatives have been the principal oxide devices investigated thus far, but another option is available in a different geometry: if the current is perpendicular to the interface, the strong internal electric fields generated at back-to-back heterojunctions can be used for oxide electronics, analogous to bipolar transistors. Here we demonstrate a perovskite heteroepitaxial metal-base transistor operating at room temperature, enabled by interface dipole engineering. Analysis of many devices quantifies the evolution from hot-electron to permeable-base behaviour. This device provides a platform for incorporating the exotic ground states of perovskite oxides, as well as novel electronic phases at their interfaces. PMID- 21258353 TI - A highly parallel method for synthesizing DNA repeats enables the discovery of 'smart' protein polymers. AB - Robust high-throughput synthesis methods are needed to expand the repertoire of repetitive protein-polymers for different applications. To address this need, we developed a new method, overlap extension rolling circle amplification (OERCA), for the highly parallel synthesis of genes encoding repetitive protein-polymers. OERCA involves a single PCR-type reaction for the rolling circle amplification of a circular DNA template and simultaneous overlap extension by thermal cycling. We characterized the variables that control OERCA and demonstrated its superiority over existing methods, its robustness, high-throughput and versatility by synthesizing variants of elastin-like polypeptides (ELPs) and protease-responsive polymers of glucagon-like peptide-1 analogues. Despite the GC-rich, highly repetitive sequences of ELPs, we synthesized remarkably large genes without recursive ligation. OERCA also enabled us to discover 'smart' biopolymers that exhibit fully reversible thermally responsive behaviour. This powerful strategy generates libraries of repetitive genes over a wide and tunable range of molecular weights in a 'one-pot' parallel format. PMID- 21258355 TI - The value of testicular 'mapping' in men with non-obstructive azoospermia. AB - As the field of assisted reproduction has advanced, many previously untreatable men are now biological fathers. Although finding sperm in men with obstructive azoospermia is not difficult, locating and retrieving spermatozoa in men with non obstructive azoospermia remains a clinical challenge, largely because sperm production in these men can be patchy or focal in nature. In response to this challenge, strategies such as fine-needle aspiration (FNA) mapping have been developed to find spermatozoa. This review discusses the history, evolution and current clinical utility and findings with FNA mapping for male infertility). Review of the current literature in the English language on FNA (diagnostic or therapeutic) with a keyword focuses on sperm detection, retrieval, safety and complications. FNA was described in human medicine over 100 years ago. Testis FNA was described 45 years ago and FNA 'mapping' of spermatozoa was described in 1997. This comparative review of the literature on sperm detection and complication rates with FNA and open testis biopsy or microdissection procedures suggests that FNA is highly informative, minimally invasive and is associated with fewer complications than other commonly used approaches to sperm detection in non-obstructive azoospermic patients. FNA mapping has gained considerable traction as an informative, 'testis sparing' technique for sperm detection in non obstructive azoospermia. With knowledge of sperm presence and location prior to sperm retrieval, FNA maps can help clinicians tailor sperm retrieval to optimize time, effort and extent of procedures needed to procure spermatozoa in these difficult cases. PMID- 21258356 TI - Electrophysiological mechanisms of sophocarpine as a potential antiarrhythmic agent. AB - AIM: To examine the electrophysiological effects of sophocarpine on action potentials (AP) and ionic currents of cardiac myocytes and to compare some of these effects with those of amiodarone. METHODS: Langendorff perfusion set-up was used in isolated guinea pig heart, and responses to sophocarpine were monitored using electrocardiograph. Conventional microelectrode, voltage clamp technique and perforated patch were employed to record fast response AP (fAP), slow response AP (sAP) and ionic currents in guinea pig papillary muscle or rabbit sinus node cells. RESULTS: Tachyarrhythmia produced by isoprenaline (15 MUmol/L) could be reversed by sophocarpine (300 MUmol/L). Sophocarpine (10 MUmol/L) decreased the amplitude by 4.0%, maximal depolarization velocity (V(max)) of the fAP by 24.4%, and Na(+) current (I(Na)) by 18.0%, while it prolonged the effective refractory period (ERP) by 21.1%. The same concentration of sophocarpine could also decrease the amplitude and V(max) of the sAP, by 26.8% and 25.7%, respectively, and attenuated the Ca(2+) current (I(CaL)) and the K(+) tail current substantially. Comparison of sophocarpine with amiodarone demonstrated that both prolonged the duration and the ERP of fAP and sAP, both decreased the amplitude and V(max) of the fAP and sAP, and both slowed the automatic heart rate. CONCLUSION: Sophocarpine could reverse isoprenaline-induced arrhythmia and inhibit I(Na), I(CaL), and I(Kr) currents. The electrophysiological effects of sophocarpine are similar to those of amiodarone, which might be regarded as a prospective antiarrhythmic agent. PMID- 21258357 TI - Combined prostaglandin E1 and lithium exert potent neuroprotection in a rat model of cerebral ischemia. AB - AIM: To examine the effects of a mixed formulation composed of prostaglandin E1 and lithium (PGE1+Li mixture) on brain damage after cerebral ischemia. The effects of the mixture on protein expression of heat shock proteins (HSPs), p53, and Bcl-2 were also determined. METHODS: Brain ischemia was induced with a permanent middle cerebral artery occlusion (pMCAO) in rats. Rats were treated with a single intravenous administration of PGE1, lithium or a PGE1+Li mixture immediately after the ischemic insult. The infarct volume and motor behavior deficits were analyzed 24 h after the ischemic insult. The protein levels of HSP70, glucose-regulated protein 78 (GRP78), HSP60, Bcl-2, and p53 in the striatum of the ipsilateral hemisphere were examined using immunoblotting. RESULTS: The mixture (PGE1 22.6 nmol/kg+Li 0.5 mmol/kg) reduced infarct volume and neurological deficits induced by focal cerebral ischemia. Moreover, the mixture had a greater neuroprotective effect against cerebral ischemia compared with PGE1 or lithium alone. The mixture was effective even if it was administered 3 h after ischemia. PGE1+Li also significantly upregulated cytoprotective HSP70, GRP78, HSP60, and Bcl-2 protein levels, while decreasing p53 expression. CONCLUSION: These results demonstrated a PGE1+Li mixture with a therapeutic window of up to 3 h for clinical treatment of cerebral ischemia. The PGE1+Li mixture potentially exerts a protective effect after stroke through the induction of HSPs and Bcl-2 proteins. PMID- 21258358 TI - Synaptic vesicle recycling at the calyx of Held. AB - Efficient endocytosis is crucial for maintaining synaptic transmission because of its role in retrieving constituent membrane and associated proteins. In the past three decades three modes of endocytosis have been proposed involving the central nervous system: clathrin-mediated endocytosis, kiss-and-run endocytosis and bulk endocytosis. These forms of endocytosis can be induced under different conditions, but their detailed molecular mechanisms and functions are largely unknown. Here, we review the existence and initiation of all three modes of endocytosis at a giant glutamatergic synapse, the calyx of Held. The possibility of direct electrophysiology recording in this synapse allows for accurate tracking of exocytosis and endocytosis via capacitance measurements. Future aims will be focused on identifying the molecules that undergo the different mechanisms of endocytosis and the conditions under which different forms of endocytosis predominate. PMID- 21258359 TI - The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond. AB - Nucleotide-binding oligomerization domain (NOD)-containing protein-like receptors (NLRs) are a recently discovered class of innate immune receptors that play a crucial role in initiating the inflammatory response following pathogen recognition. Some NLRs form the framework for cytosolic platforms called inflammasomes, which orchestrate the early inflammatory process via IL-1beta activation. Mutations and polymorphisms in NLR-coding genes or in genetic loci encoding inflammasome-related proteins correlate with a variety of autoinflammatory diseases. Moreover, the activity of certain inflammasomes is associated with susceptibility to infections as well as autoimmunity and tumorigenesis. In this review, we will discuss how identifying the genetic characteristics of inflammasomes is assisting our understanding of both autoinflammatory diseases as well as other immune system-driven disorders. PMID- 21258360 TI - Application of a novel inhibitor of human CD59 for the enhancement of complement dependent cytolysis on cancer cells. AB - Many monoclonal antibodies (mAbs) have been extensively used in the clinic, such as rituximab to treat lymphoma. However, resistance and non-responsiveness to mAb treatment have been challenging for this line of therapy. Complement is one of the main mediators of antibody-based cancer therapy via the complement-dependent cytolysis (CDC) effect. CD59 plays a critical role in resistance to mAbs through the CDC effect. In this paper, we attempted to investigate whether the novel CD59 inhibitor, recombinant ILYd4, was effective in enhancing the rituximab-mediated CDC effect on rituximab-sensitive RL-7 lymphoma cells and rituximab-induced resistant RR51.2 cells. Meanwhile, the CDC effects, which were mediated by rituximab and anti-CD24 mAb, on the refractory multiple myeloma (MM) cell line ARH-77 and the solid tumor osteosarcoma cell line Saos-2, were respectively investigated. We found that rILYd4 rendered the refractory cells sensitive to the mAb-mediated CDC effect and that rILYd4 exhibited a synergistic effect with the mAb that resulted in tumor cells lysis. This effect on tumor cell lysis was apparent on both hematological tumors and solid tumors. Therefore, rILYd4 may serve as an adjuvant for mAb mediated-tumor immunotherapy. PMID- 21258361 TI - Do viral infections protect from or enhance type 1 diabetes and how can we tell the difference? AB - Virus infections have been implicated in both initiation of and protection from autoimmune diseases, such as type 1 diabetes (T1D). In this review we intend to reflect on recent evidence how viruses might on the one hand be involved in the pathogenesis of T1D and on the other hand induce a state of protection from autoimmune-mediated damage. It is important to acknowledge that human individuals encounter more than just one virus infection in their lifetime. Therefore, it is important to integrate more than just one possible environmental triggering factor for autoimmune diseases to occur. PMID- 21258362 TI - CD47: a new player in phagocytosis and xenograft rejection. AB - Organ transplantation is limited by the availability of human donor organs. The transplantation of organs and tissues from other species (xenotransplantation) would supply an unlimited number of organs and offer many other advantages for which the pig has been identified as the most suitable source. However, the robust immune responses to xenografts remain a major obstacle to clinical application of xenotransplantation. The more vigorous xenograft rejection relative to allograft rejection is largely accounted for by the extensive genetic disparities between the donor and recipient. Xenografts activate host immunity not only by expressing immunogenic xenoantigens that provide the targets for immune recognition and rejection, but also by lacking ligands for the host immune inhibitory receptors. This review is focused on recent findings regarding the role of CD47, a ligand of an immune inhibitory receptor, signal regulatory protein alpha (SIRPalpha), in phagocytosis and xenograft rejection. PMID- 21258363 TI - Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immunosuppressive factors. AB - Immunosuppressive mediators in tuberculosis pleurisy (pleural fluid (PF)) are associated with the course of disease, but they remain poorly defined. To study the local immune status of patients with tuberculosis pleurisy, we examined the effect of PF on the functions of T cells and the differentiation of Th1 cells. PF could inhibit the ability of T cells to produce cytokines. However, tumor necrosis factor (TNF)-alpha derived from non-T cells was not impaired. Further analysis indicated that cell activation and cell cycle progression were also suppressed. Moreover, PF could inhibit Th1 cell differentiation. Importantly, we found that inhibitors of indoleamine 2,3-dioxygenase (IDO) and adenosine and neutralizing antibodies against IL-10 and transforming growth factor (TGF)-beta could reverse cytokine production, suggesting that IDO, adenosine, IL-10 and Transforming growth factor-beta1 in PF might take part in impairing T-cell functions. Taken together, our data demonstrate for the first time that several immunopathological factors participate in the downregulation of T-cell functions in local PF. PMID- 21258364 TI - TNFR2 expression on non-bone marrow-derived cells is crucial for lipopolysaccharide-induced septic shock and downregulation of soluble TNFR2 level in serum. AB - Persistently high serum levels of soluble tumor-necrosis factor (TNF) receptor 2 (sTNFR2) have been observed in septic shock and many inflammatory diseases. However, its origin and regulation during these pathological processes are still largely unknown. In this study, murine bone marrow (BM) chimeras selectively expressing TNFR2 on either BM-derived or non-BM-derived cells were generated and challenged with lipopolysaccharide (LPS). The results show that TNFR2 expression on non-BM-derived cells is crucial for both the sensitivity of mice to LPS and the downregulation of sTNFR2 in serum. Most importantly, sTNFR2 was released from both BM- and non-BM-derived cells. Non-BM TNFR1 expression influenced the sensitivity of mice to LPS challenge but not the level of serum sTNFR2. These results provide the first in vivo evidence for the origin and regulation of sTNFR2 in serum and could aid in the development of novel anti-TNF strategies against septic shock. PMID- 21258365 TI - In situ mass spectrometry of autoimmune liver diseases. AB - Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are the major forms of autoimmune liver diseases each characterized by the destruction of a specific liver cell type and the presence of differing auto-antibodies. We took a proteomic approach utilizing in situ matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) to obtain profiles directly from liver samples of patients with PBC, PSC, AIH and controls. The ability to precisely localize the region for acquisition of MALDI MS allowed us to obtain profiles from bile ducts, inflammatory infiltrates and hepatocytes from each biopsy sample. Analysis tools developed to identify peaks and compare peaks across diseases and cell types were used to develop models to classify the samples. Using an initial set of testing samples from PBC patients and controls, we identified unique peaks present in bile ducts, inflammatory infiltrates and hepatocytes that could classify samples in a validation cohort with 88-91% accuracy. Interestingly, profiles of PSC and AIH did not differ significantly from PBC. Identification of proteins in these peaks may represent novel autoantigens or effector molecules. These findings illustrate the potential of a proteomic approach to autoimmune diseases with in situ MALDI MS. PMID- 21258366 TI - Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. AB - Epidermal growth factor receptor (EGFR) can undergo post-translational modifications, including phosphorylation, glycosylation and ubiquitylation, leading to diverse physiological consequences and modulation of its biological activity. There is increasing evidence that methylation may parallel other post translational modifications in the regulation of various biological processes. It is still not known, however, whether EGFR is regulated by this post-translational event. Here, we show that EGFR Arg 1175 is methylated by an arginine methyltransferase, PRMT5. Arg 1175 methylation positively modulates EGF-induced EGFR trans-autophosphorylation at Tyr 1173, which governs ERK activation. Abolishment of Arg 1175 methylation enhances EGF-stimulated ERK activation by reducing SHP1 recruitment to EGFR, resulting in augmented cell proliferation, migration and invasion of EGFR-expressing cells. Therefore, we propose a model in which the regulatory crosstalk between PRMT5-mediated Arg 1175 methylation and EGF-induced Tyr 1173 phosphorylation attenuates EGFR-mediated ERK activation. PMID- 21258367 TI - AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. AB - Autophagy is a process by which components of the cell are degraded to maintain essential activity and viability in response to nutrient limitation. Extensive genetic studies have shown that the yeast ATG1 kinase has an essential role in autophagy induction. Furthermore, autophagy is promoted by AMP activated protein kinase (AMPK), which is a key energy sensor and regulates cellular metabolism to maintain energy homeostasis. Conversely, autophagy is inhibited by the mammalian target of rapamycin (mTOR), a central cell-growth regulator that integrates growth factor and nutrient signals. Here we demonstrate a molecular mechanism for regulation of the mammalian autophagy-initiating kinase Ulk1, a homologue of yeast ATG1. Under glucose starvation, AMPK promotes autophagy by directly activating Ulk1 through phosphorylation of Ser 317 and Ser 777. Under nutrient sufficiency, high mTOR activity prevents Ulk1 activation by phosphorylating Ulk1 Ser 757 and disrupting the interaction between Ulk1 and AMPK. This coordinated phosphorylation is important for Ulk1 in autophagy induction. Our study has revealed a signalling mechanism for Ulk1 regulation and autophagy induction in response to nutrient signalling. PMID- 21258368 TI - Oct4 kinetics predict cell lineage patterning in the early mammalian embryo. AB - Transcription factors are central to sustaining pluripotency, yet little is known about transcription factor dynamics in defining pluripotency in the early mammalian embryo. Here, we establish a fluorescence decay after photoactivation (FDAP) assay to quantitatively study the kinetic behaviour of Oct4, a key transcription factor controlling pre-implantation development in the mouse embryo. FDAP measurements reveal that each cell in a developing embryo shows one of two distinct Oct4 kinetics, before there are any morphologically distinguishable differences or outward signs of lineage patterning. The differences revealed by FDAP are due to differences in the accessibility of Oct4 to its DNA binding sites in the nucleus. Lineage tracing of the cells in the two distinct sub-populations demonstrates that the Oct4 kinetics predict lineages of the early embryo. Cells with slower Oct4 kinetics are more likely to give rise to the pluripotent cell lineage that contributes to the inner cell mass. Those with faster Oct4 kinetics contribute mostly to the extra-embryonic lineage. Our findings identify Oct4 kinetics, rather than differences in total transcription factor expression levels, as a predictive measure of developmental cell lineage patterning in the early mouse embryo. PMID- 21258369 TI - Spatially restricted activation of RhoA signalling at epithelial junctions by p114RhoGEF drives junction formation and morphogenesis. AB - Signalling by the GTPase RhoA, a key regulator of epithelial cell behaviour, can stimulate opposing processes: RhoA can promote junction formation and apical constriction, and reduce adhesion and cell spreading. Molecular mechanisms are thus required that ensure spatially restricted and process-specific RhoA activation. For many fundamental processes, including assembly of the epithelial junctional complex, such mechanisms are still unknown. Here we show that p114RhoGEF is a junction-associated protein that drives RhoA signalling at the junctional complex and regulates tight-junction assembly and epithelial morphogenesis. p114RhoGEF is required for RhoA activation at cell-cell junctions, and its depletion stimulates non-junctional Rho signalling and induction of myosin phosphorylation along the basal domain. Depletion of GEF-H1, a RhoA activator inhibited by junctional recruitment, does not reduce junction associated RhoA activation. p114RhoGEF associates with a complex containing myosin II, Rock II and the junctional adaptor cingulin, indicating that p114RhoGEF is a component of a junction-associated Rho signalling module that drives spatially restricted activation of RhoA to regulate junction formation and epithelial morphogenesis. PMID- 21258370 TI - PP2A activates brassinosteroid-responsive gene expression and plant growth by dephosphorylating BZR1. AB - When brassinosteroid levels are low, the GSK3-like kinase BIN2 phosphorylates and inactivates the BZR1 transcription factor to inhibit growth in plants. Brassinosteroid promotes growth by inducing dephosphorylation of BZR1, but the phosphatase that dephosphorylates BZR1 has remained unknown. Here, using tandem affinity purification, we identified protein phosphatase 2A (PP2A) as a BZR1 interacting protein. Genetic analyses demonstrated a positive role for PP2A in brassinosteroid signalling and BZR1 dephosphorylation. Members of the B' regulatory subunits of PP2A directly interact with BZR1's putative PEST domain containing the site of the bzr1-1D mutation. Interaction with and dephosphorylation by PP2A are enhanced by the bzr1-1D mutation, reduced by two intragenic bzr1-1D suppressor mutations, and abolished by deletion of the PEST domain. This study reveals a crucial function for PP2A in dephosphorylating and activating BZR1 and completes the set of core components of the brassinosteroid signalling cascade from cell surface receptor kinase to gene regulation in the nucleus. PMID- 21258371 TI - Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells. AB - The repressor element 1-silencing transcription factor (REST) functions as a master regulator to maintain neural stem/progenitor cells (NPCs). REST undergoes proteasomal degradation through beta-TrCP-mediated ubiquitylation during neuronal differentiation. However, reciprocal mechanisms that stabilize REST in NPCs are undefined. Here we show that the deubiquitylase HAUSP counterbalances REST ubiquitylation and prevents NPC differentiation. HAUSP expression declines concordantly with REST on neuronal differentiation and reciprocally with beta TrCP levels. HAUSP knockdown in NPCs decreases REST and induces differentiation. In contrast, HAUSP overexpression upregulates REST by overriding beta-TrCP mediated ubiquitylation. A consensus site (310-PYSS-313) in human REST is required for HAUSP-mediated REST deubiquitylation. Furthermore, REST overexpression in NPCs rescues the differentiation phenotype induced by HAUSP knockdown. These data demonstrate that HAUSP stabilizes REST through deubiquitylation and antagonizes beta-TrCP in regulating REST at the post translational level. Thus, HAUSP-mediated deubiquitylation represents a critical regulatory mechanism involved in the maintenance of NPCs. PMID- 21258372 TI - Interpretation of the FGF8 morphogen gradient is regulated by endocytic trafficking. AB - Forty years ago, it was proposed that during embryonic development and organogenesis, morphogen gradients provide positional information to the individual cells within a tissue leading to specific fate decisions. Recently, much insight has been gained into how such morphogen gradients are formed and maintained; however, which cellular mechanisms govern their interpretation within target tissues remains debated. Here we used in vivo fluorescence correlation spectroscopy and automated image analysis to assess the role of endocytic sorting dynamics on fibroblast growth factor 8 (Fgf8) morphogen gradient interpretation. By interfering with the function of the ubiquitin ligase Cbl, we found an expanded range of Fgf target gene expression and a delay of Fgf8 lysosomal transport. However, the extracellular Fgf8 morphogen gradient remained unchanged, indicating that the observed signalling changes are due to altered gradient interpretation. We propose that regulation of morphogen signalling activity through endocytic sorting allows fast feedback-induced changes in gradient interpretation during the establishment of complex patterns. PMID- 21258376 TI - Nitrogen reduction: Molybdenum does it again. PMID- 21258377 TI - Vibronic coupling: Cage-breaking cascade. PMID- 21258378 TI - Biomaterials: Silyl ether linkers. PMID- 21258379 TI - Atmospheric chemistry: The reaction that wouldn't quit. PMID- 21258380 TI - Hydrocarbon synthesis: Ringing the chains. PMID- 21258382 TI - Dynamic DNA nanotechnology using strand-displacement reactions. AB - The specificity and predictability of Watson-Crick base pairing make DNA a powerful and versatile material for engineering at the nanoscale. This has enabled the construction of a diverse and rapidly growing set of DNA nanostructures and nanodevices through the programmed hybridization of complementary strands. Although it had initially focused on the self-assembly of static structures, DNA nanotechnology is now also becoming increasingly attractive for engineering systems with interesting dynamic properties. Various devices, including circuits, catalytic amplifiers, autonomous molecular motors and reconfigurable nanostructures, have recently been rationally designed to use DNA strand-displacement reactions, in which two strands with partial or full complementarity hybridize, displacing in the process one or more pre-hybridized strands. This mechanism allows for the kinetic control of reaction pathways. Here, we review DNA strand-displacement-based devices, and look at how this relatively simple mechanism can lead to a surprising diversity of dynamic behaviour. PMID- 21258383 TI - Cis-dicarbonyl binding at cobalt and iron porphyrins with saddle-shape conformation. AB - Diatomic molecules attached to complexed iron or cobalt centres are important in many biological processes. In natural systems, metallotetrapyrrole units carry respiratory gases or provide sensing and catalytic functions. Conceiving synthetic model systems strongly helps to determine the pertinent chemical foundations for such processes, with recent work highlighting the importance of the prosthetic groups' conformational flexibility as an intricate variable affecting their functional properties. Here, we present simple model systems to investigate, at the single molecule level, the interaction of carbon monoxide with saddle-shaped iron- and cobalt-porphyrin conformers, which have been stabilized as two-dimensional arrays on well-defined surfaces. Using scanning tunnelling microscopy we identified a novel bonding scheme expressed in tilted monocarbonyl and cis-dicarbonyl configurations at the functional metal-macrocycle unit. Modelling with density functional theory revealed that the weakly bonded diatomic carbonyl adduct can effectively bridge specific pyrrole groups with the metal atom as a result of the pronounced saddle-shape conformation of the porphyrin cage. PMID- 21258384 TI - A molybdenum complex bearing PNP-type pincer ligands leads to the catalytic reduction of dinitrogen into ammonia. AB - The synthesis of transition metal-dinitrogen complexes and the stoichiometric transformation of their coordinated dinitrogen into ammonia and hydrazine have been the subject of considerable research, with a view to achieving nitrogen fixation under ambient conditions. Since a single example in 2003, no examples have been reported of the catalytic conversion of dinitrogen into ammonia under ambient conditions. The dimolybdenum-dinitrogen complex bearing PNP pincer ligands was found to work as an effective catalyst for the formation of ammonia from dinitrogen, with 23 equiv. of ammonia being produced with the catalyst (12 equiv. of ammonia are produced based on the molybdenum atom of the catalyst). This is another successful example of the catalytic and direct conversion of dinitrogen into ammonia under ambient reaction conditions. We believe that the results described in this Article provide valuable information with which to develop a more effective nitrogen-fixation system under mild reaction conditions. PMID- 21258385 TI - Interrogating viral capsid assembly with ion mobility-mass spectrometry. AB - Most proteins fulfil their function as part of large protein complexes. Surprisingly, little is known about the pathways and regulation of protein assembly. Several viral coat proteins can spontaneously assemble into capsids in vitro with morphologies identical to the native virion and thus resemble ideal model systems for studying protein complex formation. Even for these systems, the mechanism for self-assembly is still poorly understood, although it is generally thought that smaller oligomeric structures form key intermediates. This assembly nucleus and larger viral assembly intermediates are typically low abundant and difficult to monitor. Here, we characterised small oligomers of Hepatitis B virus (HBV) and norovirus under equilibrium conditions using native ion mobility mass spectrometry. This data in conjunction with computational modelling enabled us to elucidate structural features of these oligomers. Instead of more globular shapes, the intermediates exhibit sheet-like structures suggesting that they are assembly competent. We propose pathways for the formation of both capsids. PMID- 21258386 TI - Carbon oxidation state as a metric for describing the chemistry of atmospheric organic aerosol. AB - A detailed understanding of the sources, transformations and fates of organic species in the environment is crucial because of the central roles that they play in human health, biogeochemical cycles and the Earth's climate. However, such an understanding is hindered by the immense chemical complexity of environmental mixtures of organics; for example, atmospheric organic aerosol consists of at least thousands of individual compounds, all of which likely evolve chemically over their atmospheric lifetimes. Here, we demonstrate the utility of describing organic aerosol (and other complex organic mixtures) in terms of average carbon oxidation state, a quantity that always increases with oxidation, and is readily measured using state-of-the-art analytical techniques. Field and laboratory measurements of the average carbon oxidation state, using several such techniques, constrain the chemical properties of the organics and demonstrate that the formation and evolution of organic aerosol involves simultaneous changes to both carbon oxidation state and carbon number. PMID- 21258387 TI - Visible-light-mediated conversion of alcohols to halides. AB - The development of new means of activating molecules and bonds for chemical reactions is a fundamental objective for chemists. In this regard, visible-light photoredox catalysis has emerged as a powerful technique for chemoselective activation of chemical bonds under mild reaction conditions. Here, we report a visible-light-mediated photocatalytic alcohol activation, which we use to convert alcohols to the corresponding bromides and iodides in good yields, with exceptional functional group tolerance. In this fundamentally useful reaction, the design and operation of the process is simple, the reaction is highly efficient, and the formation of stoichiometric waste products is minimized. PMID- 21258389 TI - Supramolecular fishing for plasma membrane proteins using an ultrastable synthetic host-guest binding pair. AB - Membrane proteomics, the large-scale global analysis of membrane proteins, is often constrained by the efficiency of separating and extracting membrane proteins. Recent approaches involve conjugating membrane proteins with the small molecule biotin and using the receptor streptavidin to extract the labelled proteins. Despite the many advantages of this method, several shortcomings remain, including potential contamination by endogenously biotinylated molecules and interference by streptavidin during analytical stages. Here, we report a supramolecular fishing method for membrane proteins using the synthetic receptor ligand pair cucurbit[7]uril-1-trimethylammoniomethylferrocene (CB[7]-AFc). CB[7] conjugated beads selectively capture AFc-labelled proteins from heterogeneous protein mixtures, and AFc-labelling of cells results in the efficient capture of membrane proteins by these beads. The captured proteins can be recovered easily at room temperature by treatment with a strong competitor such as 1,1' bis(trimethylammoniomethyl)ferrocene. This synthetic but biocompatible host-guest system may be a useful alternative to streptavidin-biotin for membrane proteomics as well as other biological and biotechnological applications. PMID- 21258388 TI - A biomolecule-compatible visible-light-induced azide reduction from a DNA-encoded reaction-discovery system. AB - Using a system that accelerates the serendipitous discovery of new reactions by evaluating hundreds of DNA-encoded substrate combinations in a single experiment, we explored a broad range of reaction conditions for new bond-forming reactions. We discovered reactivity that led to a biomolecule-compatible, Ru(II)-catalysed azide-reduction reaction induced by visible light. In contrast to current azide reduction methods, this reaction is highly chemoselective and is compatible with alcohols, phenols, acids, alkenes, alkynes, aldehydes, alkyl halides, alkyl mesylates and disulfides. The remarkable functional group compatibility and mild conditions of the reaction enabled the azide reduction of nucleic acid and oligosaccharide substrates, with no detectable occurrence of side reactions. The reaction was also performed in the presence of a protein enzyme without the loss of enzymatic activity, in contrast to two commonly used azide-reduction methods. The visible-light dependence of this reaction provides a means of photouncaging functional groups, such as amines and carboxylates, on biological macromolecules without using ultraviolet irradiation. PMID- 21258390 TI - Strained endotaxial nanostructures with high thermoelectric figure of merit. AB - Thermoelectric materials can directly generate electrical power from waste heat but the challenge is in designing efficient, stable and inexpensive systems. Nanostructuring in bulk materials dramatically reduces the thermal conductivity but simultaneously increases the charge carrier scattering, which has a detrimental effect on the carrier mobility. We have experimentally achieved concurrent phonon blocking and charge transmitting via the endotaxial placement of nanocrystals in a thermoelectric material host. Endotaxially arranged SrTe nanocrystals at concentrations as low as 2% were incorporated in a PbTe matrix doped with Na(2)Te. This effectively inhibits the heat flow in the system but does not affect the hole mobility, allowing a large power factor to be achieved. The crystallographic alignment of SrTe and PbTe lattices decouples phonon and electron transport and this allows the system to reach a thermoelectric figure of merit of 1.7 at ~800 K. PMID- 21258391 TI - Catalytic dehydroaromatization of n-alkanes by pincer-ligated iridium complexes. AB - Aromatic hydrocarbons are among the most important building blocks in the chemical industry. Benzene, toluene and xylenes are obtained from the high temperature thermolysis of alkanes. Higher alkylaromatics are generally derived from arene-olefin coupling, which gives branched products--that is, secondary alkyl arenes--with olefins higher than ethylene. The dehydrogenation of acyclic alkanes to give alkylaromatics can be achieved using heterogeneous catalysts at high temperatures, but with low yields and low selectivity. We present here the first catalytic conversion of n-alkanes to alkylaromatics using homogeneous or molecular catalysts--specifically 'pincer'-ligated iridium complexes--and olefinic hydrogen acceptors. For example, the reaction of n-octane affords up to 86% yield of aromatic product, primarily o-xylene and secondarily ethylbenzene. In the case of n-decane and n-dodecane, the resulting alkylarenes are exclusively unbranched (that is, n-alkyl-substituted), with selectivity for the corresponding o-(n-alkyl)toluene. PMID- 21258392 TI - Ion mobility-mass spectrometry reveals a conformational conversion from random assembly to beta-sheet in amyloid fibril formation. AB - Amyloid cascades that lead to peptide beta-sheet fibrils and plaques are central to many important diseases. Recently, intermediate assemblies of these cascades were identified as the toxic agents that interact with cellular machinery. The location and cause of the transformation from a natively unstructured assembly to the beta-sheet oligomers found in all fibrils is important in understanding disease onset and the development of therapeutic agents. Largely, research on this early oligomeric region was unsuccessful because all the traditional techniques measure only the average oligomer properties of the ensemble. We utilized ion-mobility methods to deduce the peptide self-assembly mechanism and examined a series of amyloid-forming peptides clipped from larger peptides or proteins associated with disease. We provide unambiguous evidence for structural transitions in each of these fibril-forming peptide systems and establish the potential of this method for the development of therapeutic agents and drug evaluation. PMID- 21258393 TI - Give silver a shine. AB - Katharina M. Fromm explains how, as well as catalysis and jewellery, silver serves a myriad of medicinal applications--some of which are even behind poetic traditions such as throwing coins in wishing wells. PMID- 21258394 TI - Regulation of cancer cell metabolism. AB - Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology. PMID- 21258395 TI - DNA polymerases and cancer. AB - There are 15 different DNA polymerases encoded in mammalian genomes, which are specialized for replication, repair or the tolerance of DNA damage. New evidence is emerging for lesion-specific and tissue-specific functions of DNA polymerases. Many point mutations that occur in cancer cells arise from the error-generating activities of DNA polymerases. However, the ability of some of these enzymes to bypass DNA damage may actually defend against chromosome instability in cells, and at least one DNA polymerase, Pol zeta, is a suppressor of spontaneous tumorigenesis. Because DNA polymerases can help cancer cells tolerate DNA damage, some of these enzymes might be viable targets for therapeutic strategies. PMID- 21258397 TI - Mouse models of advanced spontaneous metastasis for experimental therapeutics. AB - An enduring problem in cancer research is the failure to reproduce highly encouraging preclinical therapeutic findings using transplanted or spontaneous primary tumours in mice in clinical trials of patients with advanced metastatic disease. There are several reasons for this, including the failure to model established, visceral metastatic disease. We therefore developed various models of aggressive multi-organ spontaneous metastasis after surgical resection of orthotopically transplanted human tumour xenografts. In this Opinion article we provide a personal perspective summarizing the prospect of their increased clinical relevance. This includes the reduced efficacy of certain targeted anticancer drugs, the late emergence of spontaneous brain metastases and the clinical trial results evaluating a highly effective therapeutic strategy previously tested using such models. PMID- 21258396 TI - Contribution of platelets to tumour metastasis. AB - Extensive experimental evidence shows that platelets support tumour metastasis. The activation of platelets and the coagulation system have a crucial role in the progression of cancer. Within the circulatory system, platelets guard tumour cells from immune elimination and promote their arrest at the endothelium, supporting the establishment of secondary lesions. These contributions of platelets to tumour cell survival and spread suggest platelets as a new avenue for therapy. PMID- 21258398 TI - Cancer-related direct-to-consumer advertising: a critical review. AB - The direct-to-consumer advertising (DTCA) phenomenon has received attention because of its attempt to reach out to consumers by bypassing important gatekeepers such as physicians. The emergence of new information platforms and the introduction of genetic tests directly to the consumer have heightened the concern with DTCA and its potential consequences. These effects of DTCA are particularly important given the communication inequalities among social groups, with class, race and ethnicity influencing how people access, seek, process and act on information. This Science and Society article reviews the major issues regarding general and cancer-related DTCA and also offers data from a national survey in the United States as an example of the communication inequalities in genetic testing awareness. PMID- 21258399 TI - Essential role of microphthalmia transcription factor for DNA replication, mitosis and genomic stability in melanoma. AB - Malignant melanoma is an aggressive cancer known for its notorious resistance to most current therapies. The basic helix-loop-helix microphthalmia transcription factor (MITF) is the master regulator determining the identity and properties of the melanocyte lineage, and is regarded as a lineage-specific 'oncogene' that has a critical role in the pathogenesis of melanoma. MITF promotes melanoma cell proliferation, whereas sustained supression of MITF expression leads to senescence. By combining chromatin immunoprecipitation coupled to high throughput sequencing (ChIP-seq) and RNA sequencing analyses, we show that MITF directly regulates a set of genes required for DNA replication, repair and mitosis. Our results reveal how loss of MITF regulates mitotic fidelity, and through defective replication and repair induces DNA damage, ultimately ending in cellular senescence. These findings reveal a lineage-specific control of DNA replication and mitosis by MITF, providing new avenues for therapeutic intervention in melanoma. The identification of MITF-binding sites and gene-regulatory networks establish a framework for understanding oncogenic basic helix-loop-helix factors such as N-myc or TFE3 in other cancers. PMID- 21258400 TI - ATR mediates cisplatin resistance in a p53 genotype-specific manner. AB - The protein kinase encoded by the ataxia telangiectasia and Rad3-related (ATR) gene is activated by DNA-damaging agents that are frequently used as anticancer therapeutics. Inhibition of ATR expression in cultured cancer cells has been demonstrated to increase sensitivity to chemotherapeutic drugs, including the DNA crosslinking agent cisplatin. Cisplatin is a widely used and effective drug, but its use is associated with significant toxicity. Here, we demonstrate that genetic inhibition of ATR expression selectively enhanced cisplatin sensitivity in human colorectal cancer cells with inactivated p53. A knock-in strategy was used to restore wild-type p53 in cells harboring wild-type or mutant ATR alleles. Knock-in of functional p53 in ATR-deficient cells restored checkpoint function, suppressed apoptotic pathways and markedly increased clonogenic survival after cisplatin treatment. These results suggest that a strategy that combines specific inhibitors of ATR and conventional therapies might promote synthetic lethality in p53-deficient tumors, and thus minimize toxicity to normal tissues. PMID- 21258401 TI - IL-6 promotes prostate tumorigenesis and progression through autocrine cross activation of IGF-IR. AB - As an established mediator of inflammation, interleukin-6 (IL-6) is implicated to facilitate prostate cancer progression to androgen independence through transactivation of the androgen receptor. However, whether IL-6 has a causative role in de novo prostate tumorigenesis was never investigated. We now provide the first evidence that IL-6 can induce tumorigenic conversion and further progression to an invasive phenotype of non-tumorigenic benign prostate epithelial cells. Moreover, we find that paracrine IL-6 stimulates the autocrine IL-6 loop and autocrine activation of insulin-like type I growth factor receptor (IGF-IR) to confer the tumorigenic property and also that activation of signal transducer and activator of transcription 3 (STAT3) is critical in these processes. Inhibition of STAT3 activation or IGF-IR signaling suppresses IL-6 mediated malignant conversion and the associated invasive phenotype. Inhibition of STAT3 activation suppresses IL-6-induced upregulation of IGF-IR and its ligands, namely IGF-I and IGF-II. These findings indicate that IL-6 signaling cooperates with IGF-IR signaling in the prostate microenvironment to promote prostate tumorigenesis and progression to aggressiveness. Our findings suggest that STAT3 and IGF-IR may represent potential effective targets for prevention or treatment of prostate cancer. PMID- 21258402 TI - Regulation of transcription of hypoxia-inducible factor-1alpha (HIF-1alpha) by heat shock factors HSF2 and HSF4. AB - Hypoxia-inducible factor-1alpha (HIF-1alpha) is a principal regulator of angiogenesis and other cellular responses to hypoxic stress in both normal and tumor cells. To identify novel mechanisms that regulate expression of HIF-1alpha, we designed a genome-wide screen for expressed sequence tags (ESTs) that when transcribed in the antisense direction increase production of the HIF-1alpha target, vascular endothelial growth factor (VEGF), in human breast cancer cells. We discovered that heat shock factor (HSF) proteins 2 and 4-which previously have been implicated in the control of multiple genes that modulate cell growth and differentiation and protect against effects of environmental and cellular stresses-function together to maintain a steady state level of HIF-1alpha transcription and VEGF production in these cells. We show both HSFs bind to discontinuous heat shock element (HSE) sequences we identified in the HIF-1alpha promoter region and that downregulation of either HSF activates transcription of HIF-1alpha. We further demonstrate that HSF2 and HSF4 displace each other from HSF/HSE complexes in the HIF-1alpha promoter so that HIF-1alpha transcription is also activated by overexpression of either HSFs. These results argue that HSF2 and HSF4 regulate transcription of HIF-1alpha and that a critical balance between these HSF is required to maintain HIF-alpha expression in a repressed state. Our findings reveal a previously unsuspected role for HSFs in control of VEGF and other genes activated by canonical HIF-1alpha-mediated signaling. PMID- 21258403 TI - EAPP: gatekeeper at the crossroad of apoptosis and p21-mediated cell-cycle arrest. AB - We previously identified and characterized E2F-associated phospho-protein (EAPP), a nuclear phosphoprotein that interacts with the activating members of the E2F transcription factor family. EAPP levels are frequently elevated in transformed human cells. To examine the biological relevance of EAPP, we studied its properties in stressed and unstressed cells. Overexpression of EAPP in U2OS cells increased the fraction of G1 cells and lead to heightened resistance against DNA damage- or E2F1-induced apoptosis in a p21-dependent manner. EAPP itself becomes upregulated in confluent cells and after DNA damage and stimulates the expression of p21 independently of p53. It binds to the p21 promoter and seems to be required for the assembly of the transcription initiation complex. RNAi-mediated knockdown of EAPP expression brought about increased sensitivity towards DNA damage and resulted in apoptosis even in the absence of stress. Our results indicate that the level of EAPP is critical for cellular homeostasis. Too much of it results in G1 arrest and resistance to apoptosis, which, paradoxically, might favor cellular transformation. Too little EAPP seems to retard the expression not only of the p21 gene, but also of a number of other genes and ultimately results in apoptosis. PMID- 21258405 TI - Galectin-3 regulates MUC1 and EGFR cellular distribution and EGFR downstream pathways in pancreatic cancer cells. AB - MUC1 is a transmembrane glycoprotein which is typically expressed at the apical membrane of normal epithelial cells. In cancer cells, the over-expression of MUC1 and its aberrant localization around the cell membrane and in the cytoplasm favours its interaction with different protein partners such as epidermal growth factor receptor (EGFR) and can promote tumour proliferation through the activation of oncogenic signalling pathways. Our aims were to study the mechanisms inducing MUC1 cytoplasmic localization in pancreatic cancer cells, and to decipher their impact on EGFR cellular localization and activation. Our results showed that galectin-3, an endogenous lectin, is co-expressed with MUC1 in human pancreatic ductal adenocarcinoma, and that it favours the endocytosis of MUC1 and EGFR. Depletion of galectin-3 by RNA interference increased the interaction between MUC1 and EGFR, EGFR and ERK-1,2 phosphorylation, and translocation of EGFR to the nucleus. On the contrary, silencing of galectin-3 led to a decrease of cyclin-D1 levels and of cell proliferation. The galectin-3 dependent regulation of MUC1/EGFR functions may represent an interesting mechanism modulating the EGFR-stimulated cell growth of pancreatic cancer cells. PMID- 21258406 TI - p70 S6 kinase in the control of actin cytoskeleton dynamics and directed migration of ovarian cancer cells. AB - Ovarian cancer is highly metastatic with a poor prognosis. The serine/threonine kinase, p70 S6 kinase (p70(S6K)), which is a downstream effector of phosphatidylinositol 3-kinase/Akt pathway, is frequently activated in ovarian cancer. Here, we show that p70(S6K) is a critical regulator of the actin cytoskeleton in the acquisition of the metastatic phenotype. This regulation is through two important activities: p70(S6K) acts as an actin filament cross linking protein and as a Rho family GTPase-activating protein. Ectopic expression of constitutively active p70(S6K) in ovarian cancer cells induced a marked reorganization of the actin cytoskeleton and promoted directional cell migration. Using cosedimentation and differential sedimentation assays, p70(S6K) was found to directly bind to and cross-link actin filaments. Immunofluorescence studies showed p70(S6K) colocalized with cytochalasin D-sensitive actin at the leading edge of motile cells. The p70(S6K) did not affect the kinetics of spontaneous actin polymerization, but could stabilize actin filaments by the inhibition of cofilin-induced actin depolymerization. In addition, we showed that p70(S6K) stimulated the rapid activation of both Rac1 and Cdc42, and their downstream effector p21-activated kinase (PAK1), but not RhoA. Depletion of p70(S6K) expression or inhibition of its activity resulted in significant inhibition of actin cytoskeleton reorganization and reduced migration, with a concomitant reduction in Rac1, Cdc42 and PAK1 activation, confirming that the effect was p70(S6K) specific. Similarly, the actin cytoskeleton reorganization/migratory phenotype could be reversed by expression of dominant negative Rac1 and Cdc42, or inhibition of PAK1. These results reveal a new direction for understanding the oncogenic roles of p70(S6K) in tumor progression. PMID- 21258404 TI - Virus-specific mechanisms of carcinogenesis in hepatitis C virus associated liver cancer. AB - The development of hepatocellular carcinoma (HCC) in persons who are persistently infected with hepatitis C virus (HCV) is a growing problem worldwide. Current antiviral therapies are not effective in many patients with chronic hepatitis C, and a greater understanding of the factors leading to progression of HCC will be necessary to design novel approaches to prevention of HCV-associated HCC. The lack of a small animal model of chronic HCV infection has hampered understanding of these factors. As HCV is an RNA virus with little potential for integration of its genetic material into the host genome, the mechanisms underlying HCV promotion of cancer are likely to differ from other models of viral carcinogenesis. In patients persistently infected with HCV, chronic inflammation resulting from immune responses against infected hepatocytes is associated with progressive fibrosis and cirrhosis. Cirrhosis is an important risk factor for HCC independent of HCV infection, and a majority of HCV-associated HCC arises in the setting of cirrhosis. However, a significant minority arises in the absence of cirrhosis, indicating that cirrhosis is not a prerequisite for cancer. Other lines of evidence suggest that direct, virus-specific mechanisms may be involved. Transgenic mice expressing HCV proteins develop cancer in the absence of inflammation or immune recognition of the transgene. In vitro studies have revealed multiple interactions of HCV-encoded proteins with cell cycle regulators and tumor suppressor proteins, raising the possibility that HCV can disrupt control of cellular proliferation, or impair the cell's response to DNA damage. A combination of virus-specific, host genetic, environmental and immune-related factors are likely to determine the progression to HCC in patients who are chronically infected with HCV. Here, we summarize current knowledge of the virus specific mechanisms that may contribute to HCV-associated HCC. PMID- 21258407 TI - Loss of the Birt-Hogg-Dube tumor suppressor results in apoptotic resistance due to aberrant TGFbeta-mediated transcription. AB - Birt-Hogg-Dube (BHD) syndrome is an inherited cancer susceptibility disease characterized by skin and kidney tumors, as well as cystic lung disease, which results from loss-of-function mutations in the BHD gene. BHD is also inactivated in a significant fraction of patients with sporadic renal cancers and idiopathic cystic lung disease, and little is known about its mode of action. To investigate the molecular and cellular basis of BHD tumor suppressor activity, we generated mutant Bhd mice and embryonic stem cell lines. BHD-deficient cells exhibited defects in cell-intrinsic apoptosis that correlated with reduced expression of the BH3-only protein Bim, which was similarly observed in all human and murine BHD-related tumors examined. We further demonstrate that Bim deficiency in Bhd(-/ ) cells is not a consequence of elevated mTOR or ERK activity, but results instead from reduced Bim transcription associated with a general loss of TGFbeta mediated transcription and chromatin modifications. In aggregate, this work identifies a specific tumor suppressive mechanism for BHD in regulating TGFbeta dependent transcription and apoptosis, which has implications for the development of targeted therapies. PMID- 21258408 TI - Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer. AB - Myeloid cell leukaemia-1 (Mcl-1) is an anti-apoptotic member of the Bcl-2 family that is elevated in a variety of tumour types including breast cancer. In breast tumours, increased Mcl-1 expression correlates with high tumour grade and poor patient survival. We have previously demonstrated that Her-2 levels correspond to increased Mcl-1 expression in breast tumours. Epidermal growth factor (EGF) receptor signalling is frequently deregulated in breast cancer and leads to increased proliferation and survival. Herein, we determined the critical downstream signals responsible for the EGF mediated increase of Mcl-1 and their role in cell survival. We found that both Mcl-1 mRNA and protein levels are rapidly induced upon stimulation with EGF. Promoter analysis revealed that an Elk 1 transcription factor-binding site is critical for EGF activation of the Mcl-1 promoter. Furthermore, we found that knockdown of Elk-1 or inhibition of the Erk signalling pathway was sufficient to block EGF upregulation of Mcl-1 and EGF mediated cell survival. Using chromatin immunoprecipitation and biotin labelled probes of the Mcl-1 promoter, we found that Elk-1 and serum response factor are bound to the promoter after EGF stimulation. To determine whether Mcl-1 confers a survival advantage, we found that knockdown of Mcl-1 expression increased apoptosis whereas overexpression of Mcl-1 inhibited drug induced cell death. In human breast tumours, we found a correlation between phosphorylated Elk-1 and Mcl 1 protein levels. These results indicate that the EGF induced activation of Elk-1 is an important mediator of Mcl-1 expression and cell survival and therefore a potential therapeutic target in breast cancer. PMID- 21258409 TI - miR-495 is upregulated by E12/E47 in breast cancer stem cells, and promotes oncogenesis and hypoxia resistance via downregulation of E-cadherin and REDD1. AB - MicroRNAs (miRNAs) are involved in tumorigenecity by regulating specific oncogenes and tumor suppressor genes, and their roles in breast cancer stem cells (BCSCs) are becoming apparent. Distinct from the CD44(+)/CD24(-/low) sub population, we have isolated a novel PROCR(+)/ESA(+) BCSC sub-population. To explore miRNA-regulatory mechanisms in this sub-population, we performed miRNA expression profiling and found miR-495 as the most highly upegulated miRNA in PROCR(+)/ESA(+) cells. Coincidently, high upregulation of miR-495 was also found in CD44(+)/CD24(-/low) BCSCs, reflecting its potential importance in maintaining common BCSC properties. Ectopic expression of miR-495 in breast cancer cells promoted their colony formation in vitro and tumorigenesis in mice. miR-495 directly suppressed E-cadherin expression to promote cell invasion and inhibited REDD1 expression to enhance cell proliferation in hypoxia through post transcriptional mechanism. miR-495 expression was directly modulated by transcription factor E12/E47, which itself is highly expressed in BCSCs. These findings reveal a novel regulatory pathway centered on miR-495 that contributes to BCSC properties and hypoxia resistance. PMID- 21258410 TI - Selective targeting of activating and inhibitory Smads by distinct WWP2 ubiquitin ligase isoforms differentially modulates TGFbeta signalling and EMT. AB - Ubiquitin-dependent mechanisms have emerged as essential regulatory elements controlling cellular levels of Smads and TGFbeta-dependent biological outputs such as epithelial-mesenchymal transition (EMT). In this study, we identify a HECT E3 ubiquitin ligase known as WWP2 (Full-length WWP2-FL), together with two WWP2 isoforms (N-terminal, WWP2-N; C-terminal WWP2-C), as novel Smad-binding partners. We show that WWP2-FL interacts exclusively with Smad2, Smad3 and Smad7 in the TGFbeta pathway. Interestingly, the WWP2-N isoform interacts with Smad2 and Smad3, whereas WWP2-C interacts only with Smad7. In addition, WWP2-FL and WWP2-C have a preference for Smad7 based on protein turnover and ubiquitination studies. Unexpectedly, we also find that WWP2-N, which lacks the HECT ubiquitin ligase domain, can also interact with WWP2-FL in a TGFbeta-regulated manner and activate endogenous WWP2 ubiquitin ligase activity causing degradation of unstimulated Smad2 and Smad3. Consistent with our protein interaction data, overexpression and knockdown approaches reveal that WWP2 isoforms differentially modulate TGFbeta-dependent transcription and EMT. Finally, we show that selective disruption of WWP2 interactions with inhibitory Smad7 can stabilise Smad7 protein levels and prevent TGFbeta-induced EMT. Collectively, our data suggest that WWP2 N can stimulate WWP2-FL leading to increased activity against unstimulated Smad2 and Smad3, and that Smad7 is a preferred substrate for WWP2-FL and WWP2-C following prolonged TGFbeta stimulation. Significantly, this is the first report of an interdependent biological role for distinct HECT E3 ubiquitin ligase isoforms, and highlights an entirely novel regulatory paradigm that selectively limits the level of inhibitory and activating Smads. PMID- 21258411 TI - TGF-beta1 signaling targets metastasis-associated protein 1, a new effector in epithelial cells. AB - In spite of a large number of transforming growth factor beta1 (TGF-beta1) regulated genes, the nature of its targets with roles in transformation continues to be poorly understood. Here, we discovered that TGF-beta1 stimulates transcription of metastasis-associated protein 1 (MTA1), a dual master coregulator, in epithelial cells, and that MTA1 status is a determinant of TGF beta1-induced epithelial-to-mesenchymal transition (EMT) phenotypes. In addition, we found that MTA1/polymerase II/activator protein-1 (AP-1) co-activator complex interacts with the FosB-gene chromatin and stimulates its transcription, and FosB in turn, utilizes FosB/histone deacetylase 2 complex to repress E-cadherin expression in TGF-beta1-stimulated mammary epithelial cells. These findings suggest that TGF-beta1 regulates the components of EMT via stimulating the expression of MTA1, which in turn, induces FosB to repress E-cadherin expression and thus, revealed an inherent function of MTA1 as a target and effector of TGF beta1 signaling in epithelial cells. PMID- 21258412 TI - The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling. AB - The liver kinase B1 (LKB1)/adenosine mono-phosphate-activated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the Peutz-Jeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general. PMID- 21258413 TI - Colon cancer cells produce immunoregulatory glucocorticoids. AB - Glucocorticoids (GC) have important anti-inflammatory and pro-apoptotic activities. Initially thought to be exclusively produced by the adrenal glands, there is now increasing evidence for extra-adrenal sources of GCs. We have previously shown that the intestinal epithelium produces immunoregulatory GCs and that intestinal steroidogenesis is regulated by the nuclear receptor liver receptor homolog-1 (LRH-1). As LRH-1 has been implicated in the development of colon cancer, we here investigated whether LRH-1 regulates GC synthesis in colorectal tumors and whether tumor-produced GCs suppress T-cell activation. Colorectal cancer cell lines and primary tumors were found to express steroidogenic enzymes and regulatory factors required for the de novo synthesis of cortisol. Both cell lines and primary tumors constitutively produced readily detectable levels of cortisol, as measured by radioimmunoassay, thin-layer chromatography and bioassay. Whereas overexpression of LRH-1 significantly increased the expression of steroidogenic enzymes and the synthesis of cortisol, downregulation or inhibition of LRH-1 effectively suppressed these processes, indicating an important role of LRH-1 in colorectal tumor GC synthesis. An immunoregulatory role of tumor-derived GCs could be further confirmed by demonstrating a suppression of T-cell activation. This study describes for the first time cortisol synthesis in a non-endocrine tumor in humans, and suggests that the synthesis of bioactive GCs in colon cancer cells may account as a novel mechanism of tumor immune escape. PMID- 21258414 TI - Mutations of the von Hippel-Lindau gene confer increased susceptibility to natural killer cells of clear-cell renal cell carcinoma. AB - The tumor suppressor gene von Hippel-Lindau (VHL) is involved in the development of sporadic clear-cell renal cell carcinoma (RCC). VHL interferes with angiogenesis and also controls cell adhesion and invasion. Therapies that target VHL-controlled genes are currently being evaluated in RCC patients. RCC is a immunogenic tumor and treatment with interleukin-2 (IL2) or interferon (IFN) alpha results in regression in some patients. We used two renal tumor cell lines (RCC6 and RCC4) carrying VHL loss-of-function mutations to investigate the role of mutant VHL in susceptibility to natural killer (NK) cell-mediated lysis. The RCC6 and RCC4 cell lines were transfected with the wild-type gene to restore the function of VHL. The presence of the gene in RCC cells downregulated hypoxia inducible factor (HIF)-1alpha and subsequently decreased vascular endothelial growth factor (VEGF) production. Relative to control transfectants and parental cells, pVHL-transfected cell lines activated resting and IL2-activated NK cells less strongly, as assessed by IFNgamma secretion, NK degranulation and cell lysis. NKG2A, a human leukocyte antigen (HLA)-I-specific inhibitory NK receptor, controls the lysis of tumor targets. We show that HLA-I expression in RCC-pVHL cells is stronger than that in parental and controls cells, although the expression of activating receptor NK ligands remains unchanged. Blocking NKG2A/HLA-I interactions substantially increased lysis of RCC-pVHL, but had little effect on the lysis of VHL-mutated RCC cell lines. In addition, in response to IFNalpha, the exponential growth of RCC-pVHL was inhibited more than that of RCC-pE cells, indicating that VHL mutations may be involved in IFNalpha resistance. These results indicate that a decreased expression of HLA-I molecules in mutated VHL renal tumor cells sensitizes them to NK-mediated lysis. These results suggest that combined immunotherapy with anti-angiogenic drugs may be beneficial for patients with mutated VHL. PMID- 21258415 TI - The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. AB - Heat shock protein 90 (Hsp90) is an emerging target for cancer therapy due to its important role in maintaining the activity and stability of key oncogenic signaling proteins. We show here that the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion protein, presumed to be the oncogenic driver in about 5% of patients with non-small cell lung cancer (NSCLC), is associated with Hsp90 in cells and is rapidly degraded upon exposure of cells to IPI-504. We find EML4-ALK to be more sensitive to Hsp90 inhibition than either HER2 or mutant epidermal growth factor receptor (EGFR) with an inhibitory concentration (IC)(50) for protein degradation in the low nanomolar range. This degradation leads to a potent inhibition of downstream signaling pathways and to the induction of growth arrest and apoptosis in cells carrying the EML4-ALK fusion. To generate a causative link between the expression of EML4-ALK and sensitivity to IPI-504, we introduced an EML4-ALK cDNA into HEK293 cells and show that the expression of the fusion protein sensitizes cells to IPI-504 both in vitro and in vivo. In a xenograft model of a human NSCLC cell line containing the ALK rearrangement, we observe tumor regression at clinically relevant doses of IPI-504. Finally, cells that have been selected for resistance to ALK kinase inhibitors retain their sensitivity to IPI-504. We have recently observed partial responses to administration of IPI-504 as a single agent in a phase 2 clinical trial in patients with NSCLC, specifically in patients that carry an ALK rearrangement. This study provides a molecular explanation for these clinical observations. PMID- 21258416 TI - TAZ is a novel oncogene in non-small cell lung cancer. AB - Transcriptional coactivator with PDZ-binding motif (TAZ) is a transcriptional coactivator involved in the differentiation of stem cell as well as the development of multiple organs. Recently, TAZ has also been identified as a major component of the novel Hippo-LATS tumor suppressor pathway and to function as an oncogene in breast cancer. We show for the first time that TAZ is an oncogene in non-small cell lung cancer (NSCLC). Our results show that TAZ is overexpressed in NSCLC cells and that lentivirus-mediated overexpression of TAZ in HBE135 immortalized human bronchial epithelial cells causes increased cell proliferation and transformation, which can be restored back to its original levels by knockdown of TAZ. In addition, short-hairpin RNA (shRNA)-mediated knockdown of TAZ expression in NSCLC cells suppresses their proliferation and anchorage independent growth in vitro, and tumor growth in mice in vivo, which can be reversed by re-introduction of shRNA-resistant TAZ into TAZ-knockdown NSCLC cells. These results indicate that TAZ is an oncogene and has an important role in tumorigenicity of NSCLC cells. Therefore, TAZ may present a novel target for the future diagnosis, prognosis and therapy of lung cancer. PMID- 21258417 TI - IC261 induces cell cycle arrest and apoptosis of human cancer cells via CK1delta/E and Wnt/beta-catenin independent inhibition of mitotic spindle formation. AB - Casein kinase 1 delta and epsilon (CK1delta/E) are key regulators of diverse cellular growth and survival processes including Wnt signaling, DNA repair and circadian rhythms. Recent studies suggest that they have an important role in oncogenesis. RNA interference screens identified CK1E as a pro-survival factor in cancer cells in vitro and the CK1delta/E-specific inhibitor IC261 is remarkably effective at selective, synthetic lethal killing of cancer cells. The recent development of the nanomolar CK1delta/E-selective inhibitor, PF670462 (PF670) and the CK1E-selective inhibitor PF4800567 (PF480) offers an opportunity to further test the role of CK1delta/E in cancer. Unexpectedly, and unlike IC261, PF670 and PF480 were unable to induce cancer cell death. PF670 is a potent inhibitor of CK1delta/E in cells; nanomolar concentrations are sufficient to inhibit CK1delta/E activity as measured by repression of intramolecular autophosphorylation, phosphorylation of disheveled2 proteins and Wnt/beta-catenin signaling. Likewise, small interfering RNA knockdown of CK1delta and CK1E reduced Wnt/beta-catenin signaling without affecting cell viability, further suggesting that CK1delta/E inhibition may not be relevant to the IC261-induced cell death. Thus, while PF670 is a potent inhibitor of Wnt signaling, it only modestly inhibits cell proliferation. In contrast, while sub-micromolar concentrations of IC261 neither inhibited CK1delta/E kinase activity nor blocked Wnt/beta-catenin signaling in cancer cells, it caused a rapid induction of prometaphase arrest and subsequent apoptosis in multiple cancer cell lines. In a stepwise transformation model, IC261-induced killing required both overactive Ras and inactive p53. IC261 binds to tubulin with an affinity similar to colchicine and is a potent inhibitor of microtubule polymerization. This activity accounts for many of the diverse biological effects of IC261 and, most importantly, for its selective cancer cell killing. PMID- 21258418 TI - A parainfluenza-3 outbreak in a SCT unit: sepsis with multi-organ failure and multiple co-pathogens are associated with increased mortality. AB - The estimated frequency of parainfluenza virus 3 (PIV-3) infections following haematopoietic SCT (HSCT) is 2-7%, whereas reported mortality ranges from 18 to 33%. We report a retrospective outcome analysis following an outbreak of PIV-3 infection in our transplant unit. A total of 16 HSCT patients developed PIV-3 infection. All patients had upper respiratory tract infection, whereas lower respiratory tract infection occurred in 8 patients. Overall, 13 patients were treated with aerosolised Ribavirin (2 g t.d.s. for 5 days) and i.v. Ig (0.5 g/kg) as per standard protocol. One patient refused treatment, whereas two patients with full immune reconstitution were not treated. Overall mortality was 62.5%. Sepsis with multi-organ failure and the presence of pulmonary co-pathogens were both significantly associated with PIV-3-related mortality. Our series confirms that high mortality is associated with PIV-3 infection in HSCT recipients. In patients who develop PIV-3 infection, despite strict enforcement of infection control policies, the best strategy might be careful risk assessment, with effective broad-spectrum anti-microbials in those who are at risk of secondary infection. PMID- 21258419 TI - Clonally identical Hodgkin's disease develops after allogeneic hematopoietic cell transplant for CLL. PMID- 21258421 TI - Alemtuzumab as salvage therapy for steroid and ATG/etanercept-refractory acute GVHD. PMID- 21258420 TI - (90)Y-ibritumomab tiuxetan followed by reduced-intensity conditioning and allo SCT in patients with advanced follicular lymphoma. AB - Reduced-intensity conditioning (RIC) hematopoietic SCT (HSCT) is a potentially curative therapeutic option for patients with advanced follicular lymphoma (FL), but disease relapse remains the most common cause of failure. Radioimmunoconjugates administered before RIC allo-HSCT may enhance cytoreduction and allow more time for GVL effect to develop without the associated toxicity of a myeloablative HSCT. We performed a retrospective study to describe the outcomes of patients with relapsed, refractory or transformed FL who received yttrium-90 ((90)Y)-ibritumomab tiuxetan followed by fludarabine and low-dose BU RIC allogeneic HSCT at the Dana-Farber Cancer Institute between 2006 and 2009, inclusively. Twelve patients were identified with a median age of 55 (40-66) years and a median number of lines of therapy of 5 (2-10). Two patients (17%) had transformed to a more aggressive histology and five (42%) had chemorefractory FL. Cumulative incidences of grade II-IV acute GVHD at 100 days were 17% (+/-11%) and chronic GVHD at 12 months were 63% (+/-19%). Two-year non-relapse mortality was 18% (+/-12%). Two-year OS and PFS were 83% (+/-11%) and 74% (+/-13%), respectively. This treatment is associated with favorable outcomes including acceptable rates of GVHD and relapse in advanced FL patients, and warrants prospective studies. PMID- 21258422 TI - Apheresis days required for harvesting CD34+ cells predicts hematopoietic recovery and survival following autologous transplantation. AB - We sought to determine whether patients requiring more aphereses to obtain adequate numbers of CD34+ cells had delayed hematopoietic recovery following autologous transplantation. We identified 496 consecutive individuals with lymphoma who underwent hematopoietic stem cell mobilization using etoposide and G CSF and first autologous transplantation. In multivariate analysis, increased apheresis days as a continuous and as a categorical variable at >=5/<5 days significantly predicted neutrophil recovery. Apheresis days fell just short of significance (P=0.06) as a predictor of platelet recovery in multivariate analysis. Increased apheresis days (as both continuous and categorical variables) were also predictive of treatment-related myelodysplastic syndrome/AML. Patients who underwent >=5 days of pheresis had significantly worse survival (P=0.001) than patients with less pheresis days owing to significantly higher relapse mortality (P=0.001). PMID- 21258423 TI - Lack of IL-21 signal attenuates graft-versus-leukemia effect in the absence of CD8 T-cells. AB - Previously, we have shown that IL-21R(-/-) splenocytes ameliorate GVHD as compared with wild-type splenocytes. Here, we investigated whether or not IL-21R( /-) splenocytes diminish the graft-versus-leukemia (GVL) effect. Surprisingly, IL 21R(-/-) splenocytes efficiently eliminate leukemic cells as well as wild-type splenocytes, suggesting the retention of GVL effects in the absence of IL-21 signaling. To compare the GVL effect between IL-21R(-/-) and wild-type cells, we titrated the number of splenocytes required for the elimination of leukemic cells and found that the threshold of GVL effect was obtained between 5 * 10(5) and 5 * 10(6) with both types of splenocytes. Cotransplantation with CD8-depleted splenocytes but not with purified CD8 T-cells resulted in a significant reduction in anti-leukemic effect of IL-21R(-/-) cells compared with wild-type cells, suggesting that the lack of IL-21 signaling primarily impairs CD4 T-cell rather than CD8 T-cell function and the comparable GVL effect with IL-21R(-/-) bulk splenocytes results from cooperative compensation by CD8 T-cells. PMID- 21258424 TI - Successful reduced-intensity SCT from unrelated cord blood in three patients with X-linked SCID. AB - We describe three males with X-linked SCID (X-SCID) who were successfully treated by reduced-intensity SCT from unrelated cord blood (CB). Mean age at transplant was 5.7 months (range, 3-9 months). Pre-transplant conditioning for all patients consisted of fludarabine (FLU) (30 mg/m(2) per day) from day -7 to day -2 (total dose 180 mg/m(2)) and BU 4 mg/kg per day from day -3 to day -2 (total dose 8 mg/kg). All CB units were serologically matched at HLA-A, B and DR loci. Although two patients had suffered from fungal or bacterial pneumonia before transplantation, there were no other infectious complications during transplantation. All patients engrafted and achieved 100% donor chimerism. We also confirmed full donor chimerism of both T and B cells. Only one patient developed acute GVHD grade III, which was resolved by increasing the dose of oral corticosteroid. None of the patients has developed chronic GVHD during follow up for 21-77 months. None of the patient received i.v. Ig replacement post transplant, or showed delay in psychomotor development. Reduced-intensity conditioning consisting of FLU and BU and transplantation from unrelated CB was an effective and safe treatment for these patients with X-SCID. PMID- 21258426 TI - Participation as Post-Fordist Politics: Demos, New Labour, and Science Policy. AB - In recent years, British science policy has seen a significant shift 'from deficit to dialogue' in conceptualizing the relationship between science and the public. Academics in the interdisciplinary field of Science and Technology Studies (STS) have been influential as advocates of the new public engagement agenda. However, this participatory agenda has deeper roots in the political ideology of the Third Way. A framing of participation as a politics suited to post-Fordist conditions was put forward in the magazine Marxism Today in the late 1980s, developed in the Demos thinktank in the 1990s, and influenced policy of the New Labour government. The encouragement of public participation and deliberation in relation to science and technology has been part of a broader implementation of participatory mechanisms under New Labour. This participatory program has been explicitly oriented toward producing forms of social consciousness and activity seen as essential to a viable knowledge economy and consumer society. STS arguments for public engagement in science have gained influence insofar as they have intersected with the Third Way politics of post Fordism. PMID- 21258425 TI - An inverse approach for elucidating dendritic function. AB - We outline an inverse approach for investigating dendritic function-structure relationships by optimizing dendritic trees for a priori chosen computational functions. The inverse approach can be applied in two different ways. First, we can use it as a "hypothesis generator" in which we optimize dendrites for a function of general interest. The optimization yields an artificial dendrite that is subsequently compared to real neurons. This comparison potentially allows us to propose hypotheses about the function of real neurons. In this way, we investigated dendrites that optimally perform input-order detection. Second, we can use it as a "function confirmation" by optimizing dendrites for functions hypothesized to be performed by classes of neurons. If the optimized, artificial, dendrites resemble the dendrites of real neurons the artificial dendrites corroborate the hypothesized function of the real neuron. Moreover, properties of the artificial dendrites can lead to predictions about yet unmeasured properties. In this way, we investigated wide-field motion integration performed by the VS cells of the fly visual system. In outlining the inverse approach and two applications, we also elaborate on the nature of dendritic function. We furthermore discuss the role of optimality in assigning functions to dendrites and point out interesting future directions. PMID- 21258427 TI - The Challenges of Community Engagement. AB - Lyons and Whelan provide a useful list of recommendations as to how community engagement on nanotechnology could be improved, which very few people working in community engagement could disagree with. However, as the conclusions of any study are dependent on the data obtained, if more data had been obtained and analysed then different conclusions might have been reached. Addressing the key issues in the paper and providing more data, also allows an opportunity to expand on current issues relating to community engagement on nanotechnology and the challenges it provides for practitioners. PMID- 21258428 TI - Amphiregulin mediates estrogen, progesterone, and EGFR signaling in the normal rat mammary gland and in hormone-dependent rat mammary cancers. AB - Both estrogen (E) and progesterone (P) are implicated in the etiology of human breast cancer. Defining their mechanisms of action, particularly in vivo, is relevant to the prevention and therapy of breast cancer. We investigated the molecular and cellular mechanisms of E and/or P-induced in vivo proliferation, in the normal rat mammary gland and in hormone-dependent rat mammary cancers which share many characteristics with the normal human breast and hormone-dependent breast cancers. We show that E+P treatment induced significantly greater proliferation in both the normal gland and mammary cancers compared to E alone. In both the normal gland and tumors, E+P-induced proliferation was mediated through the increased production of amphiregulin (Areg), an epidermal growth factor receptor (EGFR) ligand, and the activation of intracellular signaling pathways (Erk, Akt, JNK) downstream of EGFR that regulate proliferation. In vitro experiments using rat primary mammary organoids or T47D breast cancer cells confirmed that Areg and the synthetic progestin, R5020, synergize to promote cell proliferation through EGFR signaling. Iressa, an EGFR inhibitor, effectively blocked this proliferation. These results indicate that mediators of cross talk between E, P, and EGFR pathways may be considered as relevant molecular targets for the therapy of hormone-dependent breast cancers, especially in premenopausal women. PMID- 21258429 TI - Challenges and pitfalls in the management of parathyroid carcinoma: 17-year follow-up of a case and review of the literature. AB - A 29-year-old man presented to his primary care physician with nausea, severe weight loss and muscle weakness. He had a hard, fixed neck swelling. He was severely hypercalcaemic with 10-fold increased parathyroid hormone (PTH) concentrations. A diagnosis of primary hyperparathyroidism was established and the patient was referred for parathyroidectomy. At neck exploration, an enlarged parathyroid gland with invasive growth into the thyroid gland was found and removed, lymph nodes were cleared and hemithyroidectomy was performed. A suspected diagnosis of parathyroid carcinoma was confirmed histologically. Serum calcium and PTH levels normalised post-operatively, but hyperparathyroidism recurred within 3 years of surgery. Over the following 17 years, control of hypercalcaemia represented the most difficult challenge despite variable success achieved with repeated surgical interventions, embolisations, radiofrequency ablation of metastases and treatment with calcimimetics, bisphosphonates and haemodialysis using low-dialysate calcium. In this paper, we report the challenges and pitfalls we encountered in the management of our patient over nearly two decades of follow-up and review recent literature on the topic. PMID- 21258430 TI - The history of attention deficit hyperactivity disorder. AB - The contemporary concept of attention deficit hyperactivity disorder (ADHD) as defined in the DSM-IV-TR (American Psychiatric Association 2000) is relatively new. Excessive hyperactive, inattentive, and impulsive children have been described in the literature since the nineteenth century. Some of the early depictions and etiological theories of hyperactivity were similar to current descriptions of ADHD. Detailed studies of the behavior of hyperactive children and increasing knowledge of brain function have changed the concepts of the fundamental behavioral and neuropathological deficits underlying the disorder. This article presents an overview of the conceptual history of modern-day ADHD. PMID- 21258431 TI - Less discontinuation of ADHD drug use since the availability of long-acting ADHD medication in children, adolescents and adults under the age of 45 years in the Netherlands. AB - Treatment options for ADHD in the Netherlands have increased with the introduction of the extended-release formulations of methylphenidate (MPH ER, Concerta((r))) in 2003 and atomoxetine (ATX, Strattera((r))) in 2005, but data on the effect on drug usage patterns are scarce. The objective of the present study was to describe changes in the patterns of ADHD medication use and determinants thereof among children, adolescents and adults (<45 years) starting ADHD medication since the introduction of MPH ER and ATX. Data were obtained from Dutch community pharmacies as collected by the Foundation for Pharmaceutical Statistics, covering 97% of all dispenses for prescription medicines to outpatients in the Netherlands. Usage patterns (continuation, discontinuation, switching and addition) of ADHD drugs were evaluated at 3, 6 and 12 months after initiation for three separate time cohorts (patients starting ADHD medication in Jan-Dec 2002, Jan 2003-June 2004, respectively July 2004-Dec 2005). It was found that between 2002 and 2006, most ADHD drug users were initiated on methylphenidate IR. Discontinuation of any ADHD drug treatment decreased over time partly in favour of switching and addition. Discontinuation at 3 months decreased from around 33% to around 25%, at 6 months from less than 50% to almost 35%, and at 12 months from just fewer than 60% to less than 45%. Discontinuation was higher among females and in adults >18 years. After the introduction of MPH ER and ATX (time cohort III), 16.5% of the incident ADHD drug users switched their medication and almost 9% added an ADHD drug to the prior ADHD drug. In conclusion, discontinuation of incident ADHD drug use is high after 3, 6 and 12 months. During the study period, the incidence of discontinuation decreased because of the availability of extended-release methylphenidate and atomoxetine. PMID- 21258433 TI - Conserving Conflict? Transfrontier Conservation, Development Discourses and Local Conflict Between South Africa and Lesotho. AB - This paper describes and analyses how discourses of conservation and development as well as migrant labour practices can be understood as transnational dynamics that both cement and complicate transnational relations. It also looks into how these dynamics articulate with, shape and are being shaped by 'the local'. Focusing on the north-eastern boundary of Lesotho in the area of the 'Maloti Drakensberg transfrontier conservation and development project', we show how conflictual situations put the ethnographic spotlight on the ways in which 'local people' in Lesotho deal with dual forces of localisation and transnationalisation. We argue that they accommodate, even appropriate, these dual pressures by adopting an increasingly flexible stance in terms of identity, alliances, livelihood options and discourses. PMID- 21258432 TI - Dispositional Mindfulness, Meditation, and Conditional Goal Setting. AB - Conditional goal setting (CGS, the tendency to regard high order goals such as happiness, as conditional upon the achievement of lower order goals) is observed in individuals with depression and recent research has suggested a link between levels of dispositional mindfulness and conditional goal setting in depressed patients. Since interventions which aim to increase mindfulness through training in meditation are used with patients suffering from depression it is of interest to examine whether such interventions might alter CGS. Study 1 examined the correlation between changes in dispositional mindfulness and changes in CGS over a 3-4 month period in patients participating in a pilot randomised controlled trial of Mindfulness-Based Cognitive Therapy (MBCT). Results indicated that increases in dispositional mindfulness were significantly associated with decreases in CGS, although this effect could not be attributed specifically to the group who had received training in meditation. Study 2 explored the impact of brief periods of either breathing or loving kindness meditation on CGS in 55 healthy participants. Contrary to expectation, a brief period of meditation increased CGS. Further analyses indicated that this effect was restricted to participants low in goal re-engagement ability who were allocated to loving kindness meditation. Longer term changes in dispositional mindfulness are associated with reductions in CGS in patients with depressed mood. However initial reactions to meditation, and in particular loving kindness meditation, may be counterintuitive and further research is required in order to determine the relationship between initial reactions and longer-term benefits of meditation practice. PMID- 21258434 TI - Uptake of Hydrocarbon by Pseudomonas fluorescens (P1) and Pseudomonas putida (K1) Strains in the Presence of Surfactants: A Cell Surface Modification. AB - The objective of this research was the evaluation of the effects of exogenous added surfactants on hydrocarbon biodegradation and on cell surface properties. Crude oil hydrocarbons are often difficult to remove from the environment because of their insolubility in water. The addition of surfactants enhances the removal of hydrocarbons by raising the solubility of these compounds. These surfactants cause them to become more vulnerable to degradation, thereby facilitating transportation across the cell membrane. The obtained results showed that the microorganism consortia of bacteria are useful biological agents within environmental bioremediation. The most effective amongst all, as regards biodegradation, were the consortia of Pseudomonas spp. and Bacillus spp. strains. The results indicated that the natural surfactants (rhamnolipides and saponins) are more effective surfactants in hydrocarbon biodegradation as compared to Triton X-100. The addition of natural surfactants enhanced the removal of hydrocarbon and diesel oil from the environment. Very promising was the use of saponins as a surfactant in hydrocarbon biodegradation. This surfactant significantly increases the organic compound biodegradation. In the case of those surfactants that could be easily adsorbed on cells of strains (e.g., rhamnolipides), a change of hydrophobicity to ca. 30-40% was noted. As the final result, an increase in hydrocarbon biodegradation was observed. PMID- 21258435 TI - Growth and Lead Accumulation Capacity of Lemna minor and Spirodela polyrhiza (Lemnaceae): Interactions with Nutrient Enrichment. AB - A study to understand the biological effects of samples prepared with lead and the effects of lead were conducted on Lemna minor L. and Spirodela polyrhiza (L.) Schleid. This study was intended to test the hypothesis that nutrient enrichment (P, NO(3) (-)-N and SO(4) (2-)) enhances the metal tolerance of floating macrophytes. The plants were exposed to Pb concentrations 0, 1, 5, 10, 25, and 50 mg l(-1) for a period of 1, 3, 5, and 7 days. L. minor accumulated 561 mg g(-1) dry weight (dw) Pb, and S. polyrhiza accumulated 330 mg g(-1) dw Pb after 7 days, whereas in the groups enriched with nutrients, L. minor accumulated 128.7 mg g( 1) Pb and S. polyrhiza accumulated 68.7 mg g(-1) dw Pb after 7 days. Relative growth rates and photosynthetic pigments (chlorophyll a, b, and carotenoid) were measured in L. minor and S. polyrhiza exposed to different Pb concentrations under laboratory conditions. Relative growth rates were negatively correlated with metal exposure, but nutrient addition was found to suppress this effect. Photosynthetic pigment levels were found negatively correlated with metal exposure, and nutrient addition attenuated chlorophyll decrease in response to metal exposure. Metal and nutrient concentration in water decreased throughout the experiments. The study concluded that nutrient enrichment increases the tolerance of L. minor and S. polyrhiza to metals, that L. minor and S. polyrhiza are suitable candidates for the phytoremediation of low-level lead pollution, and that L. minor was more effective in extracting lead than was S. polyrhiza. PMID- 21258436 TI - Medicinal Plant Use and Health Sovereignty: Findings from the Tajik and Afghan Pamirs. AB - Medicinal plants are indicators of indigenous knowledge in the context of political volatility and sociocultural and ecological change in the Pamir Mountains of Afghanistan and Tajikistan. Medicinal plants are the primary health care option in this region of Central Asia. The main objective of this paper is to demonstrate that medicinal plants contribute to health security and sovereignty in a time of instability. We illustrate the nutritional as well as medicinal significance of plants in the daily lives of villagers. Based on over a decade and half of research related to resilience and livelihood security, we present plant uses in the context of mountain communities. Villagers identified over 58 cultivated and noncultivated plants and described 310 distinct uses within 63 categories of treatment and prevention. Presence of knowledge about medicinal plants is directly connected to their use. PMID- 21258437 TI - Non-destructive Analysis of Oil-Contaminated Soil Core Samples by X-ray Computed Tomography and Low-Field Nuclear Magnetic Resonance Relaxometry: a Case Study. AB - Non-destructive measurements of contaminated soil core samples are desirable prior to destructive measurements because they allow obtaining gross information from the core samples without touching harmful chemical species. Medical X-ray computed tomography (CT) and time-domain low-field nuclear magnetic resonance (NMR) relaxometry were applied to non-destructive measurements of sandy soil core samples from a real site contaminated with heavy oil. The medical CT visualized the spatial distribution of the bulk density averaged over the voxel of 0.31 * 0.31 * 2 mm(3). The obtained CT images clearly showed an increase in the bulk density with increasing depth. Coupled analysis with in situ time-domain reflectometry logging suggests that this increase is derived from an increase in the water volume fraction of soils with depth (i.e., unsaturated to saturated transition). This was confirmed by supplementary analysis using high-resolution micro-focus X-ray CT at a resolution of ~10 MUm, which directly imaged the increase in pore water with depth. NMR transverse relaxation waveforms of protons were acquired non-destructively at 2.7 MHz by the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence. The nature of viscous petroleum molecules having short transverse relaxation times (T2) compared to water molecules enabled us to distinguish the water-saturated portion from the oil-contaminated portion in the core sample using an M(0)-T2 plot, where M(0) is the initial amplitude of the CPMG signal. The present study demonstrates that non-destructive core measurements by medical X-ray CT and low-field NMR provide information on the groundwater saturation level and oil-contaminated intervals, which is useful for constructing an adequate plan for subsequent destructive laboratory measurements of cores. PMID- 21258438 TI - Managing Disagreement: A Defense of "Regime Bias" AB - Stein Ringen's theory of democratic purpose cannot do the work expected of it. Ringen's own criteria oscillate between being too vague to be useful (i.e. "freedom") or, when specified more fully, conflicting, so that almost all democracies will seem to be potentially at cross-purposes with themselves rather than their purposes or sub-purposes being mutually reinforcing. This reflects a bigger and more theoretical problem. Disagreement about the purpose of democracy is built into democracy itself. The whole point of many (perhaps all) of our democratic institutions is to arrive at conditionally legitimate decisions in spite of such disagreement. So-called regime bias, i.e. the tendency to assess democracies according to the form and stability of their institutions rather than their results or their ability to serve certain purposes, does not in fact arise from bias. It arises on the contrary from a determination to avoid the bias inherent in giving some-inevitably partisan-ideals of what democracies should do pride of place over others in a scheme of measurement or evaluation. And even a regime-based definition of democracy must itself make simplifying assumptions that elide possible normative controversies over how the democratic game is best played. Vindicating one's preferred set of democratic ideals against alternatives is a completely legitimate enterprise and lends richness to debates within and across democracies. But it is an inherently ideological and political enterprise, not a neutral or scholarly one. PMID- 21258439 TI - Charles Tilly as a Theorist of Nationalism. AB - This paper considers Charles Tilly as an important but underappreciated theorist of nationalism. Tilly's theory of nationalism emerged from the "bellicist" strand of his earlier work on state-formation and later incorporated a concern with performance, stories, and cultural modeling. Yet despite the turn to culture in Tilly's later work, his theory of nationalism remained state-centered, materialist, and instrumentalist-a source of both its power and its limitations. PMID- 21258440 TI - Welcome to Biomedical Optics Express. PMID- 21258441 TI - Depth resolved photothermal OCT detection of macrophages in tissue using nanorose. AB - Application of photothermal Optical Coherence Tomography (OCT) to detect macrophages in ex vivo rabbit arteries which have engulfed nanoclusters of gold coated iron oxide (nanorose) is reported. Nanorose engulfed by macrophages associated with atherosclerotic lesions in rabbit arteries absorb incident laser (800nm) energy and cause optical pathlength (OP) variation which is measured using photothermal OCT. OP variation in polydimethyl siloxane tissue phantoms containing varying concentrations of nanorose match values predicted from nanoparticle and material properties. Measurement of OP variation in rabbit arteries in response to laser excitation provides an estimate of nanorose concentration in atherosclerotic lesions of 2.5x10(9) particles/ml. OP variation in atherosclerotic lesions containing macrophages taking up nanorose has a different magnitude and profile from that observed in control thoracic aorta without macrophages and is consistent with macrophage presence as identified with RAM-11 histology staining. Our results suggest that tissue regions with macrophages taking up nanorose can be detected using photothermal OCT. PMID- 21258442 TI - Fiber-optic Raman probe couples ball lens for depth-selected Raman measurements of epithelial tissue. AB - In this study, we present a fiber-optic ball lens Raman probe design for improving depth-selected Raman measurements of epithelial tissue. The Monte Carlo simulation results show that tissue Raman collection efficiency can be improved by properly selecting the refractive index and the diameter of the ball lens for the Raman probe design and the depth-selectivity of Raman measurements can also be improved by either increasing the refractive index or reducing the diameter of the ball lens. An appropriate arrangement of the Raman probe-tissue distance can also optimize the collection efficiency for depth-resolved Raman measurements. Experimental evaluation of a ball lens Raman probe design on a two-layer tissue phantom confirms the potential of the ball lens Raman probe design for efficient depth-selected measurement on epithelial tissue. This work suggests that the fiber-optic Raman probe coupled with a ball lens can facilitate the depth selected Raman measurements of epithelial tissue, which may improve the diagnosis of epithelial precancer and early cancer at the molecular level. PMID- 21258443 TI - Tracking features in retinal images of adaptive optics confocal scanning laser ophthalmoscope using KLT-SIFT algorithm. AB - With the use of adaptive optics (AO), high-resolution microscopic imaging of living human retina in the single cell level has been achieved. In an adaptive optics confocal scanning laser ophthalmoscope (AOSLO) system, with a small field size (about 1 degree, 280 MUm), the motion of the eye severely affects the stabilization of the real-time video images and results in significant distortions of the retina images. In this paper, Scale-Invariant Feature Transform (SIFT) is used to abstract stable point features from the retina images. Kanade-Lucas-Tomasi(KLT) algorithm is applied to track the features. With the tracked features, the image distortion in each frame is removed by the second order polynomial transformation, and 10 successive frames are co-added to enhance the image quality. Features of special interest in an image can also be selected manually and tracked by KLT. A point on a cone is selected manually, and the cone is tracked from frame to frame. PMID- 21258444 TI - Pseudo-random single photon counting: a high-speed implementation. AB - Pseudo-random single photon counting (PRSPC) is a new time-resolved optical measurement method which combines the spread spectrum time-resolved method with single photon counting. A pseudo-random bit sequence is used to modulate a continuous wave laser diode, while single photon counting is used to build up the optical signal in response to the modulated excitation. Periodic cross correlation is performed to obtain the temporal profile of the subject of interest. Compared with conventional time-correlated single photon counting (TCSPC), PRSPC enjoys many advantages such as low cost and high count rate without compromising the sensitivity and time-resolution. In this paper, we report a PRSPC system that can be used for high-speed acquisition of the temporal point spread function of diffuse photons. It can reach a photon count rate as high as 3 Mcps (counts per second). Phantom experiments have been conducted to demonstrate the system performance. PMID- 21258445 TI - A practical method of measuring the human ?temporal contrast sensitivity function. AB - One of the more significant indicators of neural age-related loss and disease is reduced temporal processing speed. It would, therefore, be useful to have an accurate and practical device that measures the full range of an individual's temporal processing abilities (characterized as the temporal contrast sensitivity function, TCSF). 70 subjects (15-84 yrs) were tested. A small tabletop device utilizing electronic control of light-emitting diodes (LEDs) was constructed that delivered a 1-degree, 660 nm test (the modulation depth of which could be adjusted directly by the subject) centered within a 10-degree 660 nm surround. The method provided a TCSF that had a shape consistent with past studies (peaking around 8 Hz). Also consistent with past work, the largest age-decline was found at the highest frequencies and for the central fovea (r = 0.47, p<0.0001, ~2 Hz per decade). Psychophysical assessment of temporal vision offers an easy and dynamic measure of central visual function. PMID- 21258446 TI - Differentiating atherosclerotic plaque burden in arterial tissues using femtosecond CARS-based multimodal nonlinear optical imaging. AB - A femtosecond CARS-based nonlinear optical microscope was used to simultaneously image extracellular structural proteins and lipid-rich structures within intact aortic tissue obtained from myocardial infarction-prone Watanabe heritable hyperlipidemic rabbits (WHHLMI). Clear differences in the NLO microscopic images were observed between healthy arterial tissue and regions dominated by atherosclerotic lesions. In the current ex-vivo study, we present a single parameter based on intensity changes derived from multi-channel NLO image to classify plaque burden within the vessel. Using this parameter we were able to differentiate between healthy regions of the vessel and regions with plaque, as well as distinguish plaques relative to the age of the WHHLMI rabbit. PMID- 21258447 TI - Image-guided optical spectroscopy in diagnosis of osteoarthritis: a clinical study. AB - This goal of this study was to clinically evaluate the potential of a novel hybrid imaging techniques, called x-ray guided multispectral diffuse optical tomography, for identifying physiological parameters of joint tissues that can be used to distinguish between osteoarthritic and healthy joints in the hand. Between 2006 and 2009, the distal interphalangeal (DIP) finger joints from 40 subjects including 22 osteoarthritis patients and 18 healthy controls were examined clinically and scanned by the hybrid imaging platform that integrated a C-arm based x-ray tomosynthetic system with a mutlispectral diffuse optical imaging system. Based on the reconstructed results from the 40 subjects, it was observed that oxygen saturation and water content were two statistically most significant physiological discriminators for differentiation of the healthy joints from the osteoarthritic ones. PMID- 21258448 TI - Correction for specimen movement and rotation errors for in-vivo Optical Projection Tomography. AB - The application of optical projection tomography to in-vivo experiments is limited by specimen movement during the acquisition. We present a set of mathematical correction methods applied to the acquired data stacks to correct for movement in both directions of the image plane. These methods have been applied to correct experimental data taken from in-vivo optical projection tomography experiments in Caenorhabditis elegans. Successful reconstructions for both fluorescence and white light (absorption) measurements are shown. Since no difference between movement of the animal and movement of the rotation axis is made, this approach at the same time removes artifacts due to mechanical drifts and errors in the assumed center of rotation. PMID- 21258449 TI - Non-invasive surface-stripping for epifluorescence small animal imaging. AB - Non-invasive near-infrared fluorescence (NIRF) imaging is a powerful tool to study pathophysiology in a wide variety of animal disease models including brain diseases. However, especially in NIRF imaging of the brain or other deeper laying target sites, background fluorescence emitted from the scalp or superficial blood vessels can impede the detection of fluorescence in deeper tissue. Here, we introduce an effective method to reduce the impact of fluorescence from superficial layers. The approach uses excitation light at two different wavelengths generating two images with different depth sensitivities followed by an adapted subtraction algorithm. This technique leads to significant enhancement of the contrast and the detectability of fluorochromes located in deep tissue layers in tissue simulating phantoms and murine models with stroke. PMID- 21258450 TI - Efficient and facile delivery of gold nanoparticles in vivo using dissolvable microneedles for contrast-enhanced optical coherence tomography. AB - Obtaining sufficient contrast is an indispensable requirement for detecting early stage cancer using optical coherence tomography (OCT), an emerging diagnostic tool that detects abnormal lesions with micrometer resolutions in real time. PEGylated gold nanoparticles (Au NPs; 87 nm in diameter) were formulated in aqueous dissolvable microneedles (dMNs; 200 MUm height) for efficient, precisely controlled, and convenient delivery of Au NPs into hamster oral tissue in vivo. The Au NPs were then further briefly dissipated by ultrasound (US). The results showed 33% and 20% increase in average optical scattering intensity (contrast level) in dysplastic and normal tissues, respectively, and pinpointed pathological structures of early stage oral cancer were also identified by the highly convenient and efficient administration of Au NPs in a novel delivery platform. PMID- 21258451 TI - Direct evidence of lymphatic function improvement after advanced pneumatic compression device treatment of lymphedema. AB - Lymphedema affects up to 50% of all breast cancer survivors. Management with pneumatic compression devices (PCDs) is controversial, owing to the lack of methods to directly assess benefit. This pilot study employed an investigational, near-infrared (NIR) fluorescence imaging technique to evaluate lymphatic response to PCD therapy in normal control and breast cancer-related lymphedema (BCRL) subjects. Lymphatic propulsion rate, apparent lymph velocity, and lymphatic vessel recruitment were measured before, during, and after advanced PCD therapy. Lymphatic function improved in all control subjects and all asymptomatic arms of BCRL subjects. Lymphatic function improved in 4 of 6 BCRL affected arms, improvement defined as proximal movement of dye after therapy. NIR fluorescence lymphatic imaging may be useful to directly evaluate lymphatic response to therapy. These results suggest that PCDs can stimulate lymphatic function and may be an effective method to manage BCRL, warranting future clinical trials. PMID- 21258452 TI - Improved detection limits using a hand-held optical imager with coregistration capabilities. AB - Optical imaging is emerging as a non-invasive and non-ionizing method for breast cancer diagnosis. A hand-held optical imager has been developed with coregistration facilities towards flexible imaging of different tissue volumes and curvatures in near real-time. Herein, fluorescence-enhanced optical imaging experiments are performed to demonstrate deeper target detection under perfect and imperfect (100:1) uptake conditions in (liquid) tissue phantoms and in vitro. Upon summation of multiple scans (fluorescence intensity images), fluorescent targets are detected at greater depths than from single scan alone. PMID- 21258453 TI - Gold nanorod light scattering labels for biomedical imaging. AB - Gold nanorods can be used as extremely bright labels for differential light scattering measurements using two closely spaced wavelengths, thereby detecting human disease through several centimeters of tissue in vivo. They have excellent biocompatibility, are non-toxic, and are not susceptible to photobleaching. They have narrow, easily tunable plasmon spectral lines and thus can image multiple molecular targets simultaneously. Because of their small size, gold nanorods can be transported to various tissues inside the human body via the vasculature and microvasculature, and since they are smaller than vascular pore sizes, they can easily cross vascular space and enter individual cells. PMID- 21258454 TI - Development of an optical imaging platform for functional imaging of small animals using wide-field excitation. AB - The design and characterization of a time-resolved functional imager using a wide field excitation scheme for small animal imaging is described. The optimal operation parameters are established based on phantom studies. The performance of the platform for functional imaging and the simultaneous 3D reconstruction of absorption and scattering coefficients is investigated in vitro. PMID- 21258455 TI - Rapid spectral analysis for spectral imaging. AB - Spectral imaging requires rapid analysis of spectra associated with each pixel. A rapid algorithm has been developed that uses iterative matrix inversions to solve for the absorption spectra of a tissue using a lookup table for photon pathlength based on numerical simulations. The algorithm uses tissue water content as an internal standard to specify the strength of optical scattering. An experimental example is presented on the spectroscopy of portwine stain lesions. When implemented in MATLAB, the method is ~100-fold faster than using fminsearch(). PMID- 21258456 TI - Quantitative comparison of the OCT imaging depth at 1300 nm and 1600 nm. AB - One of the present challenges in optical coherence tomography (OCT) is the visualization of deeper structural morphology in biological tissues. Owing to a reduced scattering, a larger imaging depth can be achieved by using longer wavelengths. In this work, we analyze the OCT imaging depth at wavelengths around 1300 nm and 1600 nm by comparing the scattering coefficient and OCT imaging depth for a range of Intralipid concentrations at constant water content. We observe an enhanced OCT imaging depth for 1600 nm compared to 1300 nm for Intralipid concentrations larger than 4 vol.%. For higher Intralipid concentrations, the imaging depth enhancement reaches 30%. The ratio of scattering coefficients at the two wavelengths is constant over a large range of scattering coefficients and corresponds to a scattering power of 2.8 +/- 0.1. Based on our results we expect for biological tissues an increase of the OCT imaging depth at 1600 nm compared to 1300 nm for samples with high scattering power and low water content. PMID- 21258457 TI - A dual-modality optical coherence tomography and fluorescence lifetime imaging microscopy system for simultaneous morphological and biochemical tissue characterization. AB - Most pathological conditions elicit changes in the tissue optical response that may be interrogated by one or more optical imaging modalities. Any single modality typically only furnishes an incomplete picture of the tissue optical response, hence an approach that integrates complementary optical imaging modalities is needed for a more comprehensive non-destructive and minimally invasive tissue characterization. We have developed a dual-modality system, incorporating optical coherence tomography (OCT) and fluorescence lifetime imaging microscopy (FLIM), that is capable of simultaneously characterizing the 3 D tissue morphology and its biochemical composition. The Fourier domain OCT subsystem, at an 830 nm center wavelength, provided high-resolution morphological volumetric tissue images with an axial and lateral resolution of 7.3 and 13.4 um, respectively. The multispectral FLIM subsystem, based on a direct pulse-recording approach (upon 355 nm laser excitation), provided two-dimensional superficial maps of the tissue autofluorescence intensity and lifetime at three customizable emission bands with 100 um lateral resolution. Both subsystems share the same excitation/illumination optical path and are simultaneously raster scanned on the sample to generate coregistered OCT volumes and FLIM images. The developed OCT/FLIM system was capable of a maximum A-line rate of 59 KHz for OCT and a pixel rate of up to 30 KHz for FLIM. The dual-modality system was validated with standard fluorophore solutions and subsequently applied to the characterization of two biological tissue types: postmortem human coronary atherosclerotic plaques, and in vivo normal and cancerous hamster cheek pouch epithelial tissue. PMID- 21258458 TI - Quantitative Photoacoustic Image Reconstruction using Fluence Dependent Chromophores. AB - In biomedical photoacoustic imaging the images are proportional to the absorbed optical energy density, and not the optical absorption, which makes it difficult to obtain a quantitatively accurate image showing the concentration of a particular absorbing chromophore from photoacoustic measurements alone. Here it is shown that the spatially varying concentration of a chromophore whose absorption becomes zero above a threshold light fluence can be estimated from photoacoustic images obtained at increasing illumination strengths. This technique provides an alternative to model-based multiwavelength approaches to quantitative photoacoustic imaging, and a new approach to photoacoustic molecular and functional imaging. PMID- 21258459 TI - Corrections to linear methods for diffuse optical tomography using approximation error modelling. AB - Linear reconstruction methods in diffuse optical tomography have been found to produce reasonable good images in cases in which the variation in optical properties within the medium is relatively small and a reference measurement with known background optical properties is available. In this paper we examine the correction of errors when using a first order Born approximation with an infinite space Green's function model as the basis for linear reconstruction in diffuse optical tomography, when real data is generated on a finite domain with possibly unknown background optical properties. We consider the relationship between conventional reference measurement correction and approximation error modelling in reconstruction. It is shown that, using the approximation error modelling, linear reconstruction method can be used to produce good quality images also in situations in which the background optical properties are not known and a reference is not available. PMID- 21258461 TI - Practical implementation of log-scale active illumination microscopy. AB - Active illumination microscopy (AIM) is a method of redistributing dynamic range in a scanning microscope using real-time feedback to control illumination power on a sub-pixel time scale. We describe and demonstrate a fully integrated instrument that performs both feedback and image reconstruction. The image is reconstructed on a logarithmic scale to accommodate the dynamic range benefits of AIM in a single output channel. A theoretical and computational analysis of the influence of noise on active illumination feedback is presented, along with imaging examples illustrating the benefits of AIM. While AIM is applicable to any type of scanning microscope, we apply it here specifically to two-photon microscopy. PMID- 21258460 TI - Compositional-prior-guided image reconstruction algorithm for multi-modality imaging. AB - The development of effective multi-modality imaging methods typically requires an efficient information fusion model, particularly when combining structural images with a complementary imaging modality that provides functional information. We propose a composition-based image segmentation method for X-ray digital breast tomosynthesis (DBT) and a structural-prior-guided image reconstruction for a combined DBT and diffuse optical tomography (DOT) breast imaging system. Using the 3D DBT images from 31 clinically measured healthy breasts, we create an empirical relationship between the X-ray intensities for adipose and fibroglandular tissue. We use this relationship to then segment another 58 healthy breast DBT images from 29 subjects into compositional maps of different tissue types. For each breast, we build a weighted-graph in the compositional space and construct a regularization matrix to incorporate the structural priors into a finite-element-based DOT image reconstruction. Use of the compositional priors enables us to fuse tissue anatomy into optical images with less restriction than when using a binary segmentation. This allows us to recover the image contrast captured by DOT but not by DBT. We show that it is possible to fine-tune the strength of the structural priors by changing a single regularization parameter. By estimating the optical properties for adipose and fibroglandular tissue using the proposed algorithm, we found the results are comparable or superior to those estimated with expert-segmentations, but does not involve the time-consuming manual selection of regions-of-interest. PMID- 21258462 TI - Quantitative imaging of ischemic stroke through thinned skull in mice with Multi Exposure Speckle Imaging. AB - Laser Speckle Contrast Imaging (LSCI) has become a widely used technique to image cerebral blood flow in vivo. However, the quantitative accuracy of blood flow changes measured through the thin skull has not been investigated thoroughly. We recently developed a new Multi Exposure Speckle Imaging (MESI) technique to image blood flow while accounting for the effect of scattering from static tissue elements. In this paper we present the first in vivo demonstration of the MESI technique. The MESI technique was used to image the blood flow changes in a mouse cortex following photothrombotic occlusion of the middle cerebral artery. The Multi Exposure Speckle Imaging technique was found to accurately estimate flow changes due to ischemia in mice brains in vivo. These estimates of these flow changes were found to be unaffected by scattering from thinned skull. PMID- 21258463 TI - Actin-driven cell dynamics probed by Fourier transform light scattering. AB - We applied the newly developed Fourier transform light scattering (FTLS) to study dynamic light scattering in single live cells, at a temporal scale of seconds to hours. The nanoscale cell fluctuations were measured with and without the active actin contribution. We found experimentally that the spatio-temporal signals rendered by FTLS reveal interesting cytoskeleton dynamics in glial cells (the predominant cell type in the nervous system). The active contribution of actin cytoskeleton was obtained by modulating its dynamic properties via Cytochalasin D, a drug that inhibits actin polymerization/depolymerization. PMID- 21258464 TI - Signal attenuation and box-counting fractal analysis of optical coherence tomography images of arterial tissue. AB - The sensitivity of optical coherence tomography images to sample morphology is tested by two methods. The first method estimates the attenuation of the OCT signal from various regions of the probed tissue. The second method uses a box counting algorithm to calculate the fractal dimensions in the regions of interest identified in the images. Although both the attenuation coefficient as well as the fractal dimension correlate very well with the anatomical features of the probed samples; the attenuation method provides a better sensitivity. Two types of samples are used in this study: segments of arteries collected from atherosclerosis-prone Watanabe rabbits (WHHL-MI) and healthy segments of porcine coronary arteries. PMID- 21258465 TI - Deeply penetrating in vivo photoacoustic imaging using a clinical ultrasound array system. AB - Using a hand-held photoacoustic probe integrated with a clinical ultrasound array system, we successfully imaged objects deeply positioned in biological tissues. The optical contrasts were enhanced by methylene blue with a concentration of ~30 mM. The penetration depth reached ~5.2 cm in chicken breast tissue by using 650 nm wavelength, which is ~4.7 times the 1/e optical penetration depth. This imaging depth was achieved using a laser fluence on the tissue surface of only 3 mJ/cm(2), which is 1/7 of the American National Standards Institute (ANSI) safety limit (20 mJ/cm(2)). The noise equivalent sensitivity at this depth was ~11 mM. Further, after intradermal injection of methylene blue in a rat, a sentinel lymph node was easily detected in vivo, beneath a 2-cm thick layer of chicken breast. Also, blood located 3.5 cm deep in the rat was clearly imaged with intrinsic contrast. We have photoacoustically guided insertion of a needle into a rat sentinel lymph node with accumulated methylene blue. These results highlight the clinical potential of photoacoustic image-guided identification and needle biopsy of sentinel lymph nodes for axillary staging in breast cancer patients. PMID- 21258466 TI - Wound healing monitoring using near infrared fluorescent fibrinogen. AB - We demonstrate a method for imaging the wound healing process with near infrared fluorescent fibrinogen. Wound healing studies were performed on a rat punch biopsy model. Fibrinogen was conjugated with a near infrared fluorescent dye and injected into the tail vein. Fibrinogen is a useful protein for tracking wound healing because it is involved in fibrin clot formation and formation of new provisional matrix through transglutaminase's crosslinking activity. Strong fluorescence specific to the wound was observed and persisted for several days, indicating that the fibrinogen is converted to crosslinked fibrin. Administration of contrast agent simultaneously with wound creation led to primary labeling of the fibrin clot, indicating that the wound was in its early phase of healing. Administration on the following day showed labeling on the wound periphery, indicating location of formation of a new provisional matrix. This method may prove to be useful as a diagnostic for basic studies of the wound healing process, in drug development, or in clinical assessment of chronic wounds. PMID- 21258467 TI - Near infrared transillumination imaging of breast cancer with vasoactive inhalation contrast. AB - Inhalation of vasoactive gases such as carbon dioxide and oxygen can provide strong changes in tissue hemodynamics. In this report, we present a preliminary clinical study aimed at assessing the feasibility of inhalation-based contrast with near infrared continuous wave transillumination for breast imaging. We describe a method for fitting the transient absorbance that provides the wavelength dependence of the optical pathlength as parametrized by tissue oxygenation and scatter power as well as the differential changes in oxy- and deoxy-hemoglobin. We also present a principal component analysis data reduction technique to assess the dynamic response from the tissue that uses coercion to provide single temporal eigenvalues associated with both oxy- and deoxy hemoglobin changes. PMID- 21258468 TI - Assessing hemoglobin concentration using spectroscopic optical coherence tomography for feasibility of tissue diagnostics. AB - Hemoglobin (Hb) concentration and oxygen saturation levels are important biomarkers for various diseases, including cancer. Here, we investigate the ability to measure these parameters for tissue using spectroscopic optical coherence tomography (SOCT). A parallel frequency domain OCT system is used with detection spanning the visible region of the spectrum (450 nm to 700 nm). Oxygenated and deoxygenated Hb absorbing phantoms are analyzed. The results show that Hb concentrations as low as 1.2 g/L at 1 mm can be retrieved indicating that both normal and cancerous tissue measurements may be obtained. However, measurement of oxygen saturation levels may not be achieved with this approach. PMID- 21258469 TI - Scanning acoustic-photoacoustic microscopy using axicon transducers. AB - A dual mode scanning acoustic microscope is investigated, yielding simultaneously images with optical and acoustical contrast. Short laser pulses are used to excite acoustic waves in a sample for the photoacoustic imaging mode. At the same time the pulses irradiate a conical target generating limited diffraction acoustic waves (X-waves) for large depth of field ultrasound imaging. For photoacoustic as well as for ultrasound imaging a focusing, ring shaped detector is applied. First phantom experiments demonstrate the possibility to acquire data for both imaging modes in a single scan, by separating images due to their different time of flight. PMID- 21258470 TI - Resting state functional connectivity of the whole head with near-infrared spectroscopy. AB - Resting state connectivity aims to identify spontaneous cerebral hemodynamic fluctuations that reflect neuronal activity at rest. In this study, we investigated the spatial-temporal correlation of hemoglobin concentration signals over the whole head during the resting state. By choosing a source-detector pair as a seed, we calculated the correlation value between its time course and the time course of all other source-detector combinations, and projected them onto a topographic map. In all subjects, we found robust spatial interactions in agreement with previous fMRI and NIRS findings. Strong correlations between the two opposite hemispheres were seen for both sensorimotor and visual cortices. Correlations in the prefrontal cortex were more heterogeneous and dependent on the hemodynamic contrast. HbT provided robust, well defined maps, suggesting that this contrast may be used to better localize functional connectivity. The effects of global systemic physiology were also investigated, particularly low frequency blood pressure oscillations which give rise to broad regions of high correlation and mislead interpretation of the results. These results confirm the feasibility of using functional connectivity with optical methods during the resting state, and validate its use to investigate cortical interactions across the whole head. PMID- 21258471 TI - Synchronous radiation with Er:YAG and Ho:YAG lasers for efficient ablation of hard tissues. AB - Er:YAG and Ho:YAG laser beams were combined to irradiate hard tissues to achieve highly efficient ablation with low laser power. The delay time between pulses of the two lasers was controlled to irradiate alumina ceramic balls used as hard tissue models. With optimized delay time, the combined laser beam perforated the sample 40% deeper than independent radiation by either an Er:YAG or Ho:YAG laser. An ultra-high-speed camera and an infrared thermography camera were used to observe and investigate the ablation mechanisms. PMID- 21258472 TI - Biomedical applications of a real-time terahertz color scanner. AB - A real-time THz color scanner has the potential to further expand the application scope of THz spectral imaging based on its rapid image acquisition rate. We demonstrated three possible applications of a THz color scanner in the biomedical field: imaging of pharmaceutical tablets, human teeth, and human hair. The first application showed the scanner's potential in total inspection for rapid quality control of pharmaceutical tablets moving on a conveyor belt. The second application demonstrated that the scanner can be used to identify a potential indicator for crystallinity of dental tissue. In the third application, the scanner was successfully used to visualize the drying process of wet hairs. These demonstrations indicated the high potential of the THz color scanner for practical applications in the biomedical field. PMID- 21258473 TI - Depth-resolved imaging and detection of micro-retroreflectors within biological tissue using Optical Coherence Tomography. AB - A new approach to in vivo biosensor design is introduced, based on the use of an implantable micron-sized retroreflector-based platform and non-invasive imaging of its surface reflectivity by Optical Coherence Tomography (OCT). The possibility of using OCT for the depth-resolved imaging and detection of micro retroreflectors in highly turbid media, including tissue, is demonstrated. The maximum imaging depth for the detection of the micro-retroreflector-based platform within the surrounding media was found to be 0.91 mm for porcine tissue and 1.65 mm for whole milk. With further development, it may be possible to utilize OCT and micro-retroreflectors as a tool for continuous monitoring of analytes in the subcutaneous tissue. PMID- 21258474 TI - Metallic nanoparticle on micro ring resonator for bio optical detection and sensing. AB - We have numerically investigated the unique effects of metallic nanoparticle on the ring resonator, especially multiple Au nanoparticles on the micro ring resonator with the 4-port configuration on chip. For the Au nanoparticle, because it has smaller real refractive index than air and large absorption refractive index, we found that there is a blue shift for the ring resonance wavelength, instead of red shift normally observed for dielectric nanoparticles. The drop port intensity is strongly dependent on both number and size of nanoparticles, while relatively independent on position of nanoparticles. The correlation between the penetration depth of Au and the resonance mode evanescent tail is also discussed to reveal the unique properties of Au nanoparticle to be used for detection, sensing and nano medicine. PMID- 21258475 TI - SPLASSH: Open source software for camera-based high-speed, multispectral in-vivo optical image acquisition. AB - Camera-based in-vivo optical imaging can provide detailed images of living tissue that reveal structure, function, and disease. High-speed, high resolution imaging can reveal dynamic events such as changes in blood flow and responses to stimulation. Despite these benefits, commercially available scientific cameras rarely include software that is suitable for in-vivo imaging applications, making this highly versatile form of optical imaging challenging and time-consuming to implement. To address this issue, we have developed a novel, open-source software package to control high-speed, multispectral optical imaging systems. The software integrates a number of modular functions through a custom graphical user interface (GUI) and provides extensive control over a wide range of inexpensive IEEE 1394 Firewire cameras. Multispectral illumination can be incorporated through the use of off-the-shelf light emitting diodes which the software synchronizes to image acquisition via a programmed microcontroller, allowing arbitrary high-speed illumination sequences. The complete software suite is available for free download. Here we describe the software's framework and provide details to guide users with development of this and similar software. PMID- 21258476 TI - Quantitative phase study of the dynamic cellular response in femtosecond laser photoporation. AB - We use Digital Holographic Microscopy to study dynamic responses of live cells to femtosecond laser cellular membrane photoporation. Temporal and spatial characteristics of morphological changes as well as dry mass variation are analyzed and compared with conventional fluorescent assays for viability and photoporation efficiency. With the latter, the results provide a new insight into the efficiency and toxicity of this novel optical method of drug delivery. In addition, quantitative phase maps reveal photoporation related sub-cellular dynamics of cytoplasmic vesicles. PMID- 21258477 TI - A tissue equivalent phantom for simultaneous near-infrared optical tomography and EEG. AB - We describe a phantom which enables EEG and near-infrared optical tomography to be performed simultaneously over the same volume. The phantom provides a surface electrical contact impedance comparable to that of the human scalp, whilst also possessing an optical scattering coefficient and electrical conductivity equivalent to that of brain tissue. The construction of the phantom is described, as is the resulting simultaneous EEG and near infrared optical tomography experiment, which, to our knowledge, is the first performed on a scale comparable to that of the infant human brain. This imaging experiment successfully shows the suitability of this phantom construction for the assessment of simultaneous EEG and near infrared optical tomography systems. PMID- 21258478 TI - Interlaced spectrally encoded confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography. AB - Scanning laser ophthalmoscopy (SLO) and spectral domain optical coherence tomography (SDOCT) have become essential clinical diagnostic tools in ophthalmology by allowing for video-rate noninvasive en face and depth-resolved visualization of retinal structure. Current generation multimodal imaging systems that combine both SLO and OCT as a means of image tracking remain complex in their hardware implementations. Here, we combine a spectrally encoded confocal scanning laser ophthalmoscope (SECSLO) with an ophthalmic SDOCT system. This novel implementation of an interlaced SECSLO-SDOCT system allows for video-rate SLO fundus images to be acquired alternately with high-resolution SDOCT B-scans as a means of image aiming, guidance, and registration as well as motion tracking. The system shares the illumination source, detection system, and scanning optics between both SLO and OCT as a method of providing a simple multimodal ophthalmic imaging system that can readily be implemented as a table top or hand-held device. PMID- 21258479 TI - Algorithmic depth compensation improves quantification and noise suppression in functional diffuse optical tomography. AB - Accurate depth localization and quantitative recovery of a regional activation are the major challenges in functional diffuse optical tomography (DOT). The photon density drops severely with increased depth, for which conventional DOT reconstruction yields poor depth localization and quantitative recovery. Recently we have developed a depth compensation algorithm (DCA) to improve the depth localization in DOT. In this paper, we present an approach based on the depth compensated reconstruction to improve the quantification in DOT by forming a spatial prior. Simulative experiments are conducted to demonstrate the usefulness of this approach. Moreover, noise suppression is a key to success in DOT which also affects the depth localization and quantification. We present quantitative analysis and comparison on noise suppression in DOT with and without depth compensation. The study reveals that appropriate combination of depth-compensated reconstruction with the spatial prior can provide accurate depth localization and improved quantification at variable noise levels. PMID- 21258480 TI - Folate receptor targeting silica nanoparticle probe for two-photon fluorescence bioimaging. AB - Narrow dispersity organically modified silica nanoparticles (SiNPs), diameter ~30 nm, entrapping a hydrophobic two-photon absorbing fluorenyl dye, were synthesized by hydrolysis of triethoxyvinylsilane and (3-aminopropyl)triethoxysilane in the nonpolar core of Aerosol-OT micelles. The surface of the SiNPs were functionalized with folic acid, to specifically deliver the probe to folate receptor (FR) over-expressing Hela cells, making these folate two-photon dye doped SiNPs potential candidates as probes for two-photon fluorescence microscopy (2PFM) bioimaging. In vitro studies using FR over-expressing Hela cells and low FR expressing MG63 cells demonstrated specific cellular uptake of the functionalized nanoparticles. One-photon fluorescence microscopy (1PFM) imaging, 2PFM imaging, and two-photon fluorescence lifetime microscopy (2P-FLIM) imaging of Hela cells incubated with folate-modified two-photon dye-doped SiNPs were demonstrated. PMID- 21258481 TI - Polarization response measurement and simulation of rigid endoscopes. AB - Polarized light can reveal diagnostic information about tissue morphology. To promote easy adoption of polarization imaging techniques in the clinic it would be beneficial if they can be used with standard medical imaging instruments such as rigid endoscopes. We have characterized the polarization properties of two commercial laparoscopes and observed birefringence effects that complicate polarization imaging. Possible solutions are discussed that may be of interest to other tissue polarization imaging researchers. PMID- 21258482 TI - Fast 3D optical reconstruction in turbid media using spatially modulated light. AB - A method to perform fast 3-D optical reconstruction, based on structured light, in thick samples is demonstrated and experimentally validated. The experimental and reconstruction procedure, based on Finite Elements Method, used to reconstruct absorbing heterogeneities, with arbitrary arrangement in space, is discussed. In particular we demonstrated that a 2D sampling of the source Fourier plane is required to improve the imaging capability. PMID- 21258483 TI - Linear diode laser bar optical stretchers for cell deformation. AB - To investigate the use of linear diode laser bars to optically stretch cells and measure their mechanical properties, we present numerical simulations using the immersed boundary method (IBM) coupled with classic ray optics. Cells are considered as three-dimensional (3D) spherical elastic capsules immersed in a fluid subjected to both optical and hydrodynamic forces in a periodic domain. We simulate cell deformation induced by both single and dual diode laser bar configurations and show that a single diode laser bar induces significant stretching but also induces cell translation of speed < 10 um/sec for applied 6.6 mW/um power in unconfined systems. The dual diode laser bar configuration, however, can be used to both stretch and optically trap cells at a fixed position. The net cell deformation was found to be a function of the total laser power and not the power distribution between single or dual diode laser bar configurations. PMID- 21258484 TI - Analysis of pressure, angle and temporal effects on tissue optical properties from ?polarization-gated spectroscopic probe measurements. AB - Noninvasive optical techniques for tissue characterization, in particular, light scattering properties and blood supply quantification of mucosa, is useful in a wide variety of applications. However, fiber-optic probes that require contact with the tissue surface can present a challenging problem in the variability of in vivo measurements due the nature of interactions, for example affects due to variations in pressure applied to the probe tip. We present an in vivo evaluation of pressure, angle, and temporal effects on tissue properties for polarization gated spectroscopy at superficial depths (within 100 to 200 microns of tissue surface) for oral mucosa. PMID- 21258485 TI - Effects of muscle fiber motion on diffuse correlation spectroscopy blood flow measurements during exercise. AB - The influence of muscle fiber motion during exercise on diffuse correlation spectroscopy (DCS) measurements of skeletal muscle blood flow is explored. Isotonic (with muscle fiber motion) and isometric (without muscle fiber motion) plantar flexion exercises were performed at 30% of maximal force on a dynamometer, and muscle blood flow was continuously monitored on the medial gastrocnemius (calf) muscle of a healthy volunteer using DCS. During exercise, dynamometer recordings including footplate position, footplate angular velocity, and plantar flexion torque were obtained. Muscle fiber motions introduced artifacts into the DCS signals, causing an overestimation of blood flow changes. We show how proper co-registration of dynamometer recordings and DCS measurements enables separation of the true blood flow responses during exercise from those affected by the motion artifacts. PMID- 21258486 TI - Algorithms for bioluminescence tomography incorporating anatomical information and reconstruction of tissue optical properties. AB - Reconstruction algorithms are presented for a two-step solution of the bioluminescence tomography (BLT) problem. In the first step, a priori anatomical information provided by x-ray computed tomography or by other methods is used to solve the continuous wave (cw) diffuse optical tomography (DOT) problem. A Taylor series expansion approximates the light fluence rate dependence on the optical properties of each region where first and second order direct derivatives of the light fluence rate with respect to scattering and absorption coefficients are obtained and used for the reconstruction. In the second step, the reconstructed optical properties at different wavelengths are used to calculate the Green's function of the system. Then an iterative minimization solution based on the L1 norm shrinks the permissible regions where the sources are allowed by selecting points with higher probability to contribute to the source distribution. This provides an efficient BLT reconstruction algorithm with the ability to determine relative source magnitudes and positions in the presence of noise. PMID- 21258487 TI - Optical injection of mammalian cells using a microfluidic platform. AB - The use of a focused laser beam to create a sub-micron hole in the plasma membrane of a cell (photoporation), for the selective introduction of membrane impermeable substances (optical injection) including nucleic acids (optical transfection), is a powerful technique most commonly applied to treat single cells. However, particularly for femtosecond photoporation, these studies have been limited to low throughput, small-scale studies, because they require sequential dosing of individual cells. Herein, we describe a microfluidic photoporation system for increased throughput and automated optical injection of cells. Hydrodynamic focusing is employed to direct a flow of single-file cells through a focused femtosecond laser beam for photoporation. Upon traversing the beam, a number of transient pores potentially open across the extracellular membrane, which allows the uptake of the surrounding fluid media into the cytoplasm, also containing the chosen injection agent. The process is entirely automated and a rate of 1 cell/sec could readily be obtained, enabling several thousand cells to be injected per hour using this system. The efficiency of optically injecting propidium iodide into HEK293 mammalian cells was found to be 42 +/- 8%, or 28 +/- 4% taking into account the requirement of post-injection viability, as tested using Calcein AM. This work now opens the way for combining photoporation with microfluidic analyses, sorting, purification or on-chip cell culture studies. PMID- 21258488 TI - Doppler imaging with dual-detection full-range frequency domain optical coherence tomography. AB - Most of full-range techniques for Frequency Domain Optical Coherence Tomography (FD-OCT) reported to date utilize the phase relation between consecutive axial lines to reconstruct a complex interference signal and hence may exhibit degradation in either mirror image suppression performance or detectable velocity dynamic range or both when monitoring a moving sample such as flow activity. We have previously reported a technique of mirror image removal by simultaneous detection of the quadrature components of a complex spectral interference called a Dual-Detection Frequency Domain OCT (DD-FD-OCT) [Opt. Lett. 35, 1058-1060 (2010)]. The technique enables full range imaging without any loss of acquisition speed and is intrinsically less sensitive to phase errors generated by involuntary movements of the subject. In this paper, we demonstrate the application of the DD-FD-OCT to a phase-resolved Doppler imaging without degradation in either mirror image suppression performance or detectable velocity dynamic range that were observed in other full-range Doppler methods. In order to accommodate for Doppler imaging, we have developed a fiber-based DD-FD-OCT that more efficiently utilizes the source power compared with the previous free-space DD-FD-OCT. In addition, the velocity sensitivity of the phase-resolved DD-FD-OCT was investigated, and the relation between the measured Doppler phase shift and set flow velocity of a flow phantom was verified. Finally, we demonstrate the Doppler imaging using the DD-FD-OCT in a biological sample. PMID- 21258489 TI - Validation of diffuse correlation spectroscopy measurements of rodent cerebral blood flow with simultaneous arterial spin labeling MRI; towards MRI-optical continuous cerebral metabolic monitoring. AB - Cerebral blood flow (CBF) during stepped hypercapnia was measured simultaneously in the rat brain using near-infrared diffuse correlation spectroscopy (DCS) and arterial spin labeling MRI (ASL). DCS and ASL CBF values agree very well, with high correlation (R=0.86, p< 10(-9)), even when physiological instability perturbed the vascular response. A partial volume effect was evident in the smaller magnitude of the optical CBF response compared to the MRI values (averaged over the cortical area), primarily due to the inclusion of white matter in the optically sampled volume. The 8.2 and 11.7 mm mid-separation channels of the multi-distance optical probe had the lowest partial volume impact, reflecting ~75 % of the MR signal change. Using a multiplicative correction factor, the ASL CBF could be predicted with no more than 10% relative error, affording an opportunity for real-time relative cerebral metabolism monitoring in conjunction with MR measurement of cerebral blood volume using super paramagnetic contrast agents. PMID- 21258490 TI - An automatic image processing algorithm for initiating and terminating intracoronary ?OFDI pullback. AB - Intracoronary optical frequency domain imaging (OFDI) provides high resolution, three-dimensional views of coronary artery microstructure, but requires a non occlusive saline/contrast purge to displace blood for clear artery views. Recent studies utilized manual pullback initiation/termination based on real-time image observation. Automated pullback initiation/termination by real-time OFDI signal analysis would enable more efficient data acquisition. We evaluate the use of simple imaging parameters to automatically and robustly differentiate between diagnostic-quality clear artery wall (CAW) versus blood-obstructed fields (BOF). Algorithms are tested using intracoronary OCT human data retrospectively and intracoronary OFDI swine and human data prospectively. In prospective analysis of OFDI swine data, the sensitivity and specificity of the ratio of second and first moments (contrast parameter) were 99.6% and 97.2%, respectively. In prospective analysis of OFDI clinical data, the contrast parameter yielded 96.0% sensitivity and 94.5% specificity. Accuracy improved further by analyzing sequential frames. These results indicate the algorithm may be utilized with intracoronary OFDI for initiating and terminating automated pullback and digital data recording. PMID- 21258491 TI - Instrumentation to rapidly acquire fluorescence wavelength-time matrices of biological tissues. AB - A fiber-optic system was developed to rapidly acquire tissue fluorescence wavelength-time matrices (WTMs) with high signal-to-noise ratio (SNR). The essential system components (473 nm microchip laser operating at 3 kHz repetition frequency, fiber-probe assemblies, emission monochromator, photomultiplier tube, and digitizer) were assembled into a compact and clinically-compatible unit. Data were acquired from fluorescence standards and tissue-simulating phantoms to test system performance. Fluorescence decay waveforms with SNR > 100 at the decay curve peak were obtained in less than 30 ms. With optimized data transfer and monochromator stepping functions, it should be feasible to acquire a full WTM at 5 nm emission wavelength intervals over a 200 nm range in under 2 seconds. PMID- 21258492 TI - Influence of laser parameters and staining on femtosecond laser-based intracellular nanosurgery. AB - Femtosecond (fs) laser-based intracellular nanosurgery has become an important tool in cell biology, albeit the mechanisms in the so-called low-density plasma regime are largely unknown. Previous calculations of free-electron densities for intracellular surgery used water as a model substance for biological media and neglected the presence of dye and biomolecules. In addition, it is still unclear on which time scales free-electron and free-radical induced chemical effects take place in a cellular environment. Here, we present our experimental study on the influence of laser parameters and staining on the intracellular ablation threshold in the low-density plasma regime. We found that the ablation effect of fs laser pulse trains resulted from the accumulation of single-shot multiphoton induced photochemical effects finished within a few nanoseconds. At the threshold, the number of applied pulses was inversely proportional to a higher order of the irradiance, depending on the laser repetition rate and wavelength. Furthermore, fluorescence staining of subcellular structures before surgery significantly decreased the ablation threshold. Based on our findings, we propose that dye molecules are the major source for providing seed electrons for the ionization cascade. Consequently, future calculations of free-electron densities for intracellular nanosurgery have to take them into account, especially in the calculations of multiphoton ionization rates. PMID- 21258493 TI - Implementation of a continuous scanning procedure and a line scan camera for ?thin-sheet laser imaging microscopy. AB - We report development of a continuous scanning procedure and the use of a time delay integration (TDI) line scan camera for a light-sheet based microscope called a thin-sheet laser imaging microscope (TSLIM). TSLIM is an optimized version of a light-sheet fluorescent microscope that previously used a start/stop scanning procedure to move the specimen through the thinnest portion of a light sheet and stitched the image columns together to produce a well-focused composite image. In this paper, hardware and software enhancements to TSLIM are described that allow for dual sided, dual illumination lasers, and continuous scanning of the specimen using either a full-frame CCD camera and a TDI line scan camera. These enhancements provided a ~70% reduction in the time required for composite image generation and a ~63% reduction in photobleaching of the specimen compared to the start/stop procedure. PMID- 21258494 TI - Parallel phase-shifting digital holographic microscopy. AB - We propose parallel phase-shifting digital holographic microscopy (PPSDHM) which has the ability of three-dimensional (3-D) motion measurement using space division multiplexing technique. By the PPSDHM, instantaneous information of both the 3-D structure and the phase distributions of specimens can be simultaneously acquired with a single-shot exposure. We constructed a parallel phase-shifting digital holographic microscope consisting of an optical interferometer and an image sensor on which micro polarizers are attached pixel by pixel. The validity of the PPSDHM was experimentally verified by demonstrating the single-shot 3-D imaging and phase-imaging ability of the constructed microscope. PMID- 21258495 TI - Shifted-excitation Raman difference spectroscopy for in vitro and in vivo biological samples analysis. AB - The contamination of the Raman scattering signal with luminescence is a well known problem when dealing with biological media excited by visible light. The viability of the shifted-excitation Raman difference spectroscopy (SERDS) technique for luminescence suppression on Raman spectra of biological samples was studied in this work. A tunable Lithrow-configuration diode laser (lambda = 785 and 830 nm) coupled (directly or by optical fiber) to a dispersive Raman spectrometer was employed to study two sets of human tissues (tooth and skin) in order to determine the set of experimental parameters suitable for luminescence rejection. It was concluded that systematic and reproducible spectra of biological interest can be acquired by SERDS. PMID- 21258496 TI - Wide-field fluorescence lifetime imaging of cancer. AB - Optical imaging of tissue autofluorescence has the potential to provide rapid label-free screening and detection of surface tumors for clinical applications, including when combined with endoscopy. Quantitative imaging of intensity-based contrast is notoriously difficult and spectrally resolved imaging does not always provide sufficient contrast. We demonstrate that fluorescence lifetime imaging (FLIM) applied to intrinsic tissue autofluorescence can directly contrast a range of surface tissue tumors, including in gastrointestinal tissues, using compact, clinically deployable instrumentation achieving wide-field fluorescence lifetime images of unprecedented clarity. Statistically significant contrast is observed between cancerous and healthy colon tissue for FLIM with excitation at 355 nm. To illustrate the clinical potential, wide-field fluorescence lifetime images of unstained ex vivo tissue have been acquired at near video rate, which is an important step towards real-time FLIM for diagnostic and interoperative imaging, including for screening and image-guided biopsy applications. PMID- 21258497 TI - Repeatability of tissue fluorescence measurements for the detection of cervical intraepithelial neoplasia. AB - We examined intensity and shape differences in 378 repeated spectroscopic measures of the cervix. We examined causes of variability such as presence of precancer or cancer, pathologic tissue type, menopausal status, hormone or oral contraceptive use, and age; as well as technology related variables like generation of device and provider making exam. Age, device generation, and provider were statistically significantly related to intensity differences. Provider and device generation were related to shape differences. We examined the order of measurements and found a decreased intensity in the second measurement due to hemoglobin absorption. 96% of repeat measurements had classification concordance of cervical intraepithelial neoplasia. PMID- 21258498 TI - Next-generation acceleration and code optimization for light transport in turbid media using GPUs. AB - A highly optimized Monte Carlo (MC) code package for simulating light transport is developed on the latest graphics processing unit (GPU) built for general purpose computing from NVIDIA - the Fermi GPU. In biomedical optics, the MC method is the gold standard approach for simulating light transport in biological tissue, both due to its accuracy and its flexibility in modelling realistic, heterogeneous tissue geometry in 3-D. However, the widespread use of MC simulations in inverse problems, such as treatment planning for PDT, is limited by their long computation time. Despite its parallel nature, optimizing MC code on the GPU has been shown to be a challenge, particularly when the sharing of simulation result matrices among many parallel threads demands the frequent use of atomic instructions to access the slow GPU global memory. This paper proposes an optimization scheme that utilizes the fast shared memory to resolve the performance bottleneck caused by atomic access, and discusses numerous other optimization techniques needed to harness the full potential of the GPU. Using these techniques, a widely accepted MC code package in biophotonics, called MCML, was successfully accelerated on a Fermi GPU by approximately 600x compared to a state-of-the-art Intel Core i7 CPU. A skin model consisting of 7 layers was used as the standard simulation geometry. To demonstrate the possibility of GPU cluster computing, the same GPU code was executed on four GPUs, showing a linear improvement in performance with an increasing number of GPUs. The GPU-based MCML code package, named GPU-MCML, is compatible with a wide range of graphics cards and is released as an open-source software in two versions: an optimized version tuned for high performance and a simplified version for beginners (http://code.google.com/p/gpumcml). PMID- 21258499 TI - Ultrahigh resolution photoacoustic microscopy via transient absorption. AB - We have developed a novel, hybrid imaging modality, Transient Absorption Ultrasonic Microscopy (TAUM), which takes advantage of the optical nonlinearities afforded by transient absorption to achieve ultrahigh-resolution photoacoustic microscopy. The theoretical point spread function for TAUM is functionally equivalent to confocal and two-photon fluorescence microscopy, potentially enabling cellular/subcellular photoacoustic imaging. A prototype TAUM system was designed, built, and used to image a cross-section through several capillaries in the excised cheek pouch of a Syrian Hamster. The well-resolved capillaries in the TAUM image provided experimental evidence of the spatial resolution. These results suggest that TAUM has excellent potential for producing volumetric images with cellular/subcellular resolution in three dimensions deep inside living tissue. PMID- 21258500 TI - Measurement of two-photon excitation spectrum used to photoconvert a fluorescent protein (Kaede) by nonlinear Fourier-transform spectroscopy. AB - We demonstrate the measurement of two-photon excitation (TPE) spectra, used not only for fluorescence but also for photoconversion in green-to-red photoconvertible Kaede, using nonlinear Fourier-transform spectroscopy. It was found that in unphotoconverted Kaede, the TPE spectrum for photoconversion is much different to that for green-fluorescence. This is similar to the difference between the one-photon excitation of photoconversion in the neutral form and that of green-fluorescence in the ionized form. PMID- 21258501 TI - Integrated optical transfection system using a microlens fiber combined with microfluidic gene delivery. AB - Optical transfection is a promising technique for the delivery of foreign genetic material into cells by transiently changing the permeability of the cell membrane. Of the different optical light sources that have been used, femtosecond laser based transfection has been one of the most effective methods for optical transfection which is generally implemented using a free space bulk optical setup. In conventional optical transfection methods the foreign genetic material to be transfected is homogenously mixed in the medium. Here we report the first realization of an integrated optical transfection system which can achieve transfection along with localized drug delivery by combining a microlens fiber based optical transfection system with a micro-capillary based microfluidic system. A fiber based illumination system is also incorporated in the system in order to achieve visual identification of the cell boundaries during transfection. A novel fabrication method is devised to obtain easy and inexpensive fabrication of microlensed fibers, which can be used for femtosecond optical transfection. This fabrication method offers the flexibility to fabricate a microlens which can focus ultra-short laser pulses at a near infrared wavelength to a small focal spot (~3 um) whilst keeping a relatively large working distance (~20 um). The transfection efficiency of the integrated system with localized plasmid DNA delivery, is approximately 50%, and is therefore comparable to that of a standard free space transfection system. Also the use of integrated system for localized gene delivery resulted in a reduction of the required amount of DNA for transfection. The miniaturized, integrated design opens a range of exciting experimental possibilities, including the dosing of tissue slices, targeted drug delivery, and targeted gene therapy in vivo. PMID- 21258502 TI - Whole-cell-analysis of live cardiomyocytes using wide-field interferometric phase microscopy. AB - We apply wide-field interferometric microscopy techniques to acquire quantitative phase profiles of ventricular cardiomyocytes in vitro during their rapid contraction with high temporal and spatial resolution. The whole-cell phase profiles are analyzed to yield valuable quantitative parameters characterizing the cell dynamics, without the need to decouple thickness from refractive index differences. Our experimental results verify that these new parameters can be used with wide field interferometric microscopy to discriminate the modulation of cardiomyocyte contraction dynamics due to temperature variation. To demonstrate the necessity of the proposed numerical analysis for cardiomyocytes, we present confocal dual-fluorescence-channel microscopy results which show that the rapid motion of the cell organelles during contraction preclude assuming a homogenous refractive index over the entire cell contents, or using multiple-exposure or scanning microscopy. PMID- 21258503 TI - Quantifying subcellular dynamics in apoptotic cells with two-dimensional Gabor filters. AB - We demonstrate an optical Fourier filtering method which can be used to characterize subcellular morphology during dynamic cellular function. In this paper, our Fourier filters were based on two-dimensional Gabor elementary functions, which can be tuned to sense directly object size and orientation. We utilize this method to quantify changes in mitochondrial and nuclear structure during the first three hours of apoptosis. We find that the technique is sensitive to a decrease in particle orientation consistent with apoptosis-induced mitochondrial fragmentation. The scattering signal changes were less pronounced in the nucleus and the remainder of the cytoplasm. Particles in these regions were less oriented than mitochondria and did not change orientation significantly. PMID- 21258504 TI - Dual-point dual-wavelength fluorescence monitoring of DNA separation in a lab on a chip. AB - We present a simple approach in electrophoretic DNA separation and fluorescent monitoring that allows to identify the insertion or deletion of base-pairs in DNA probe molecules from genetic samples, and to perform intrinsic calibration/referencing for highly accurate DNA analysis. The principle is based on dual-point, dual-wavelength laser-induced fluorescence excitation using one or two excitation windows at the intersection of integrated waveguides and microfluidic channels in an optofluidic chip and a single, color-blind photodetector, resulting in a limit of detection of ~200 pM for single-end labeled DNA molecules. The approach using a single excitation window is demonstrated experimentally, while the option exploiting two excitation windows is proposed theoretically. PMID- 21258505 TI - Detection of early colorectal cancer development in the azoxymethane rat carcinogenesis model with Fourier domain low coherence interferometry. AB - Fourier domain low coherence interferometry (fLCI) is an emerging optical technique used to quantitatively assess cell nuclear morphology in tissue as a means of detecting early cancer development. In this work, we use the azoxymethane rat carcinogenesis model, a well characterized and established model for colon cancer research, to demonstrate the ability of fLCI to distinguish between normal and preneoplastic ex-vivo colon tissue. The results show highly statistically significant differences between the measured cell nuclear diameters of normal and azoxymethane-treated tissues, thus providing strong evidence that fLCI may be a powerful tool for non-invasive, quantitative detection of early changes associated with colorectal cancer development. PMID- 21258506 TI - Investigation of spectral interferences on the accuracy of broadband CW-NIRS tissue SO(2) determination. AB - An accurate SO(2) prediction method for using broadband continuous-wave diffuse reflectance near infrared (NIR) spectroscopy is proposed. The method fitted the NIR spectra to a Taylor expansion attenuation model, and used the simulated annealing method to initialize the nonlinear least squares fit. This paper investigated the effect of potential spectral interferences that are likely to be encountered in clinical use, on SO(2) prediction accuracy. The factors include the concentration of hemoglobin in blood, the volume of blood and volume of water in the tissue under the sensor, reduced scattering coefficient, u(s)', of the muscle, fat thickness and the source-detector spacing. The SO(2) prediction method was evaluated on simulated muscle spectra as well as on dual-dye phantoms which simulate the absorbance of oxygenated and deoxygenated hemoglobin. PMID- 21258507 TI - Bacteria detection with thin wetting ?film lensless imaging. AB - Lensless on-chip imaging is a promising technique to count and monitor cells and micro-objects in liquid sample. In this paper we apply this technique to the observation of uL sample containing bacteria evaporated onto a microscope slide. Compared with previously reported techniques, a large improvement in signal to noise ratio is obtained due to the presence of a few MUm thick wetting film creating a micro-lens on top of each bacteria. In these conditions, standard CMOS sensor are able to detect micro-objects as small as few MUm, e.g. E.coli and Bacillus subtilis bacteria and 1 MUm polymer beads with a large signal to noise ratio of 45 +/- 10. An overall detection efficiency of 85 +/- 7% and a co localization error of sigma(1D) = 1.1MUm compared with reference fluorescence microscopy images are achieved. This novel technique will be used as a pre positioning tool prior to other optical identification methods, e.g. Raman spectroscopy. PMID- 21258508 TI - Optical characterization of cutaneous transilluminators for eye safety. AB - Cutaneous transilluminators are light-emitting devices used to localize blood vessels for various medical procedures. They are often used in populations that may be at increased risk for skin burns, such as neonates and the elderly. While there is a known potential for skin burns, little is known about the ophthalmic risk from the use of these devices. This paper will report on the laboratory evaluation of the potential ocular hazards from transilluminators (TIs). Our results indicate that transilluminators which incorporate white-light LEDs have emissions that have the potential for producing injury to the retina, especially in patients who may have a reduced aversion response. PMID- 21258509 TI - Fiber-optic and articulating arm implementations of laminar optical tomography for clinical applications. AB - Laminar optical tomography (LOT) is a recently developed technique for depth resolved in vivo imaging of absorption and fluorescence contrast. Until now, LOT has been implemented in a benchtop configuration, limiting accessibility to tissues and restricting imaging applications. Here we report on LOT implemented through an articulating arm and a fiber optic image bundle allowing flexible imaging for a range of clinical applications. We quantify the performance of these two implementations by imaging a tissue mimicking phantom. PMID- 21258510 TI - High-resolution fluorescence microscopy based on a cyclic sequential multiphoton process. AB - We demonstrate high-resolution fluorescence microscopy based on a cyclic sequential multiphoton (CSM) process, which gives rise to fluorescence emission following a sequence of cyclic transitions between the bright and dark states of a fluorophore induced by pump and reverse light. By temporally modulating the reverse intensity, we can extract the fluorescence signal generated through the CSM process. We show that the demodulated fluorescence signal is nonlinearly proportional to the excitation intensities and it gives a higher spatial resolution than that of a confocal microscope. PMID- 21258511 TI - PDE-constrained multispectral imaging of tissue chromophores with the equation of radiative transfer. AB - We introduce a transport-theory-based PDE-constrained multispectral model for direct imaging of the spatial distributions of chromophores concentrations in biological tissue. The method solves the forward problem (boundary radiance at each wavelength) and the inverse problem (spatial distribution of chromophores concentrations), in an all-at-once manner in the framework of a reduced Hessian sequential quadratic programming method. To illustrate the code's performance, we present numerical and experimental studies involving tumor bearing mice. It is shown that the PDE-constrained multispectral method accelerates the reconstruction process by up to 15 times compared to unconstrained reconstruction algorithms and provides more accurate results as compared to the so-called two step approach to multi-wavelength imaging. PMID- 21258512 TI - Image analysis for classification of dysplasia in Barrett's esophagus using endoscopic optical coherence tomography. AB - Barrett's esophagus (BE) and associated adenocarcinoma have emerged as a major health care problem. Endoscopic optical coherence tomography is a microscopic sub surface imaging technology that has been shown to differentiate tissue layers of the gastrointestinal wall and identify dysplasia in the mucosa, and is proposed as a surveillance tool to aid in management of BE. In this work a computer-aided diagnosis (CAD) system has been demonstrated for classification of dysplasia in Barrett's esophagus using EOCT. The system is composed of four modules: region of interest segmentation, dysplasia-related image feature extraction, feature selection, and site classification and validation. Multiple feature extraction and classification methods were evaluated and the process of developing the CAD system is described in detail. Use of multiple EOCT images to classify a single site was also investigated. A total of 96 EOCT image-biopsy pairs (63 non dysplastic, 26 low-grade and 7 high-grade dysplastic biopsy sites) from a previously described clinical study were analyzed using the CAD system, yielding an accuracy of 84% for classification of non-dysplastic vs. dysplastic BE tissue. The results motivate continued development of CAD to potentially enable EOCT surveillance of large surface areas of Barrett's mucosa to identify dysplasia. PMID- 21258513 TI - Formation and characterization of an ideal excitation beam geometry in an optofluidic device. AB - An optimal excitation beam shape is necessary to perform reliable flow cytometric analysis but has so far not been implemented in a photonic-microfluidic integrated (i.e. optofluidic) device. We have achieved this feature by integrating a 1D lens system with planar waveguides and microfluidic channel on a substrate using one patterning material via a one-shot process. In this paper, we report the method of design and the performance of specifically formed excitation regions shaped to be ideal for reducing double detections, improving SNR, and for reliable detection in a flow cytometry application. Demonstration of different sizes via changes to lens design shows the ability to control the width of the shaped beam according to a targeted detection. PMID- 21258514 TI - Implementation of the equation of radiative transfer on block-structured grids for modeling light propagation in tissue. AB - We present the first algorithm for solving the equation of radiative transfer (ERT) in the frequency domain (FD) on three-dimensional block-structured Cartesian grids (BSG). This algorithm allows for accurate modeling of light propagation in media of arbitrary shape with air-tissue refractive index mismatch at the boundary at increased speed compared to currently available structured grid algorithms. To accurately model arbitrarily shaped geometries the algorithm generates BSGs that are finely discretized only near physical boundaries and therefore less dense than fine grids. We discretize the FD-ERT using a combination of the upwind-step method and the discrete ordinates (S(N)) approximation. The source iteration technique is used to obtain the solution. We implement a first order interpolation scheme when traversing between coarse and fine grid regions. Effects of geometry and optical parameters on algorithm performance are evaluated using numerical phantoms (circular, cylindrical, and arbitrary shape) and varying the absorption and scattering coefficients, modulation frequency, and refractive index. The solution on a 3-level BSG is obtained up to 4.2 times faster than the solution on a single fine grid, with minimal increase in numerical error (less than 5%). PMID- 21258515 TI - Effect of temporal location of correction of monochromatic aberrations on the dynamic accommodation response. AB - Dynamic correction of monochromatic aberrations of the eye is known to affect the accommodation response to a step change in stimulus vergence. We used an adaptive optics system to determine how the temporal location of the correction affects the response. The system consists of a Shack-Hartmann sensor sampling at 20 Hz and a 37-actuator piezoelectric deformable mirror. An extra sensing channel allows for an independent measure of the accommodation level of the eye. The accommodation response of four subjects was measured during a +/- 0.5 D step change in stimulus vergence whilst aberrations were corrected at various time locations. We found that continued correction of aberrations after the step change decreased the gain for disaccommodation, but increased the gain for accommodation. These results could be explained based on the initial lag of accommodation to the stimulus and changes in the level of aberrations before and after the stimulus step change. Future considerations for investigations of the effect of monochromatic aberrations on the dynamic accommodation response are discussed. PMID- 21258516 TI - Differential microscopy for fluorescence-detected nonlinear absorption linear anisotropy based on a staggered two-beam femtosecond Yb:KGW oscillator. AB - We present a new laser system and nonlinear microscope, designed for differential nonlinear microscopy. The microscope features time-correlated single photon counting of multiphoton fluorescence generated by an alternating pulse-train of orthogonally polarized pulses. The generated nonlinear signal is separated using home-built electronics. Results are presented on fluorescence-detected nonlinear absorption linear anisotropy (FDNALA) of chloroplasts in Asparagus Sprengerii Regel and of Congo Red-stained cellulose. PMID- 21258517 TI - Sentinel lymph node detection by an optical method using scattered photons. AB - We present a new near infrared optical probe for the sentinel lymph node detection, based on the recording of scattered photons. A two wavelengths setup was developed to improve the detection threshold of an injected dye: the Patent Blue V dye. The method used consists in modulating each laser diode at a given frequency. A Fast Fourier Transform of the recorded signal separates both components. The signal amplitudes are used to compute relative Patent Blue V concentration. Results on the probe using phantoms model and small animal experimentation exhibit a sensitivity threshold of 3.2 umol/L, which is thirty fold better than the eye visible threshold. PMID- 21258518 TI - High-resolution fiber optic microscopy with fluorescent contrast enhancement for the identification of axillary lymph node metastases in breast cancer: a pilot study. AB - This prospective pilot study evaluates the potential of high-resolution fiber optic microscopy (HRFM) to identify lymph node metastases in breast cancer patients. 43 lymph nodes were collected from 14 consenting breast cancer patients. Proflavine dye was topically applied to lymph nodes ex vivo to allow visualization of nuclei. 242 images were collected at 105 sites with confirmed histopathologic diagnosis. Quantitative statistical features were calculated from images, assessed with one-way ANOVA, and were used to develop a classification algorithm with the goal of objectively discriminating between normal and metastatic tissue. A classification algorithm using mean image intensity and skewness achieved sensitivity of 79% (27/34) and specificity of 77% (55/71). This study demonstrates the technical feasibility and diagnostic potential of HRFM with fluorescent contrast in the ex vivo evaluation of lymph nodes from breast cancer patients. PMID- 21258519 TI - Spectral and spatial dependence of?diffuse optical signals in response to?peripheral nerve stimulation. AB - Using non-invasive, near-infrared spectroscopy we have previously reported optical signals measured at or around peripheral nerves in response to their stimulation. Such optical signals featured amplitudes on the order of 0.1% and peaked about 100 ms after peripheral nerve stimulation in human subjects. Here, we report a study of the spatial and spectral dependence of the optical signals induced by stimulation of the human median and sural nerves, and observe that these optical signals are: (1) unlikely due to either dilation or constriction of blood vessels, (2) not associated with capillary bed hemoglobin, (3) likely due to blood vessel(s) displacement, and (4) unlikely due to fiber-skin optical coupling effects. We conclude that the most probable origin of the optical response to peripheral nerve stimulation is from displacement of blood vessels within the optically probed volume, as a result of muscle twitch in adjacent areas. PMID- 21258520 TI - Diffuse optical signals in response to peripheral nerve stimulation reflect skeletal muscle kinematics. AB - Previously we have reported a near-infrared optical response in the region occupied by a peripheral nerve that is distal to the site of electrical stimulation of that peripheral nerve. This "intermediate" signal is vascular in nature but its biological origin not been elucidated. In the present study, an animal model of the signal has been created and our human studies expanded to directly investigate the contribution of non-artifactual vascular motion induced by muscle contraction to the biological origin of this signal. Under non-invasive conditions during stimulation of the exposed sciatic nerve of the Sprague-Dawley rat, optical responses are robust. These signals can be abolished both pharmacologically and surgically using methods that eliminate muscle motion while leaving the electrophysiological health of the nerve intact. In human studies, signals that are elicited on stimulation of nerves containing motor axons, both within and outside the predicted imaging volume of the spectrometer, have similar temporal characteristics of those previously observed. Moreover, stimulation of sensory nerves alone does not elicit an optical response. These results strongly suggest that the intermediate signals are derived from stimulus-induced muscle contraction (whether via an innervating nerve or by direct stimulation) causing translational vascular motion within the optically interrogated region. PMID- 21258521 TI - Swept-source based, single-shot, multi-detectable velocity range Doppler optical coherence tomography. AB - Phase-Resolved Doppler Optical Coherence Tomography (PR-DOCT) allows visualization and characterization of the location, direction, velocity, and profile of flow activity embedded in a static sample structure. The detectable Velocity Dynamic Range (VDR) of each particular PR-DOCT system is governed by a detectable Doppler phase shift, a flow angle, and an acquisition time interval used to determine the Doppler phase shift. In general, the lower boundary of the detectable Doppler phase shift is limited by the phase stability of the system, while the upper boundary is limited by the pi phase ambiguity. For a given range of detectable Doppler phase shift, shortening the acquisition duration will increase not only the maximum detectable velocity but unfortunately also the minimum detectable velocity, which may lead to the invisibility of a slow flow. In this paper, we present an alternative acquisition scheme for PR-DOCT that extends the lower limit of the velocity dynamic range, while maintaining the maximum detectable velocity, hence increasing the overall VDR of PR-DOCT system. The essence of the approach is to implement a technique of multi-scale measurement to simultaneously acquire multiple VDRs in a single measurement. We demonstrate an example of implementation of the technique in a dual VDR DOCT, where two Doppler maps having different detectable VDRs were simultaneously detected, processed, and displayed in real time. One was a fixed VDR DOCT capable of measuring axial velocity of up to 10.9 mm/s without phase unwrapping. The other was a variable VDR DOCT capable of adjusting its detectable VDR to reveal slow flow information down to 11.3 MUm/s. The technique is shown to effectively extend the overall detectable VDR of the PR-DOCT system. Examples of real time Doppler imaging of an African frog tadpole are demonstrated using the dual-VDR DOCT system. PMID- 21258522 TI - Terahertz pulsed imaging of knee cartilage. AB - Osteoarthritis (OA) is a common form of arthritis caused by cartilage degeneration. In this paper, we investigate the potential use of terahertz (THz) pulsed imaging to quantitatively measure the early symptoms of OA in an animal model. THz images of excised rabbit femoral condyles were taken. We observe THz waves reflected off different layers within samples and demonstrate that the optical delay between reflections can give a quantitative measure of the thicknesses of particular tissues within cartilage. PMID- 21258523 TI - Cancer field effects in normal tissues revealed by Raman spectroscopy. AB - It has been demonstrated that the presence of cancer results in detectable changes to uninvolved tissues, collectively termed cancer field effects (CFE). In this study, we directly assessed the ability of Raman microspectroscopy to detect CFE via in-vitro study of organotypic tissue rafts approximating human skin. Raman spectra were measured from both epidermis and dermis after transfer of the rafts to dishes containing adherent cultures of either normal human fibroblasts or fibrosarcoma (HT1080) cells. Principal components analyses allowed discrimination between the groups with 86% classification accuracy in the epidermis and 94% in the dermis. These results encourage further study to evaluate the Raman capacity for detecting CFE as a possible tool for noninvasive screening for tumor presence. PMID- 21258524 TI - Mass-transport limitations in spot-based microarrays. AB - Mass transport of analyte to surface-immobilized affinity reagents is the fundamental bottleneck for sensitive detection in solid-support microarrays and biosensors. Analyte depletion in the volume adjacent to the sensor causes deviation from ideal association, significantly slows down reaction kinetics, and causes inhomogeneous binding across the sensor surface. In this paper we use high resolution molecular interferometric imaging (MI2), a label-free optical interferometry technique for direct detection of molecular films, to study the inhomogeneous distribution of intra-spot binding across 100 micron-diameter protein spots. By measuring intra-spot binding inhomogeneity, reaction kinetics can be determined accurately when combined with a numerical three-dimensional finite element model. To ensure homogeneous binding across a spot, a critical flow rate is identified in terms of the association rate k(a) and the spot diameter. The binding inhomogeneity across a spot can be used to distinguish high affinity low-concentration specific reactions from low-affinity high concentration non-specific binding of background proteins. PMID- 21258525 TI - Fluorescence lifetime optical tomography with Discontinuous Galerkin discretisation scheme. AB - We develop discontinuous Galerkin framework for solving direct and inverse problems in fluorescence diffusion optical tomography in turbid media. We show the advantages and the disadvantages of this method by comparing it with previously developed framework based on the finite volume discretization. The reconstruction algorithm was used with time-gated experimental dataset acquired by imaging a highly scattering cylindrical phantom concealing small fluorescent tubes. Optical parameters, quantum yield and lifetime were simultaneously reconstructed. Reconstruction results are presented and discussed. PMID- 21258526 TI - Detection of colonic inflammation with Fourier transform infrared spectroscopy using a flexible silver halide fiber. AB - Persistent colonic inflammation increases risk for cancer, but mucosal appearance on conventional endoscopy correlates poorly with histology. Here we demonstrate the use of a flexible silver halide fiber to collect mid-infrared absorption spectra and an interval model to distinguish colitis from normal mucosa in dextran sulfate sodium treated mice. The spectral regime between 950 and 1800 cm( 1) was collected from excised colonic specimens and compared with histology. Our model identified 3 sub-ranges that optimize the classification results, and the performance for detecting inflammation resulted in a sensitivity, specificity, accuracy, and positive predictive value of 92%, 88%, 90%, and 88%, respectively. PMID- 21258527 TI - High-speed focal modulation microscopy using acousto-optical modulators. AB - Focal Modulation Microscopy (FMM) is a single-photon excitation fluorescence microscopy technique which effectively rejects the out-of-focus fluorescence background that arises when imaging deep inside biological tissues. Here, we report on the implementation of FMM in which laser intensity modulation at the focal plane is achieved using acousto-optic modulators (AOM). The modulation speed is greatly enhanced to the MHz range and thus enables real-time image acquisition. The capability of FMM is demonstrated by imaging fluorescence labeled vasculatures in mouse brain as well as self-made tissue phantom. PMID- 21258528 TI - A predictive model of backscattering at subdiffusion length scales. AB - We provide a methodology for accurately predicting elastic backscattering radial distributions from random media with two simple empirical models. We apply these models to predict the backscattering based on two classes of scattering phase functions: the Henyey-Greenstein phase function and a generalized two parameter phase function that is derived from the Whittle-Matern correlation function. We demonstrate that the model has excellent agreement over all length scales and has less than 1% error for backscattering at subdiffusion length scales for tissue relevant optical properties. The presented model is the first available approach for accurately predicting backscattering at length scales significantly smaller than the transport mean free path. PMID- 21258529 TI - Stable absolute flow estimation with Doppler OCT based on virtual circumpapillary scans. AB - Doppler optical coherence tomography has the capability to measure blood flow quantitatively and in vivo. As only the axial component of the velocity can be assessed, the measurements have to be corrected for the angle of the vessels. We present a novel approach to extract quantitative flow data from circumpapillary scans in vivo on the human retina by registering the circular scan to a reference volume scan and extracting the angle directly from the volume. In addition, we perform phase unwrapping and interpolation of the flow under the assumption of a parabolic flow profile. We demonstrate the repeatability of the methods by applying it to different retinal vessels, achieving coefficients of variation of the average velocity of 3 to 8%. Results on the pulsatility and resistance index are also presented. PMID- 21258530 TI - Characterizing the localized surface plasmon resonance behaviors of Au nanorings and tracking their diffusion in bio-tissue with optical coherence tomography. AB - The characterization results of the localized surface plasmon resonance (LSPR) of Au nanorings (NRs) with optical coherence tomography (OCT) are first demonstrated. Then, the diffusion behaviors of Au NRs in mouse liver samples tracked with OCT are shown. For such research, aqueous solutions of Au NRs with two different localized surface plasmon resonance (LSPR) wavelengths are prepared and characterized. Their LSPR-induced extinction cross sections at 1310 nm are estimated with OCT scanning of solution droplets on coverslip to show reasonably consistent results with the data at individual LSPR wavelengths and at 1310 nm obtained from transmission measurements of Au NR solutions and numerical simulations. The resonant and non-resonant Au NRs are delivered into mouse liver samples for tracking Au NR diffusion in the samples through continuous OCT scanning for one hour. With resonant Au NRs, the average A-mode scan profiles of OCT scanning at different delay times clearly demonstrate the extension of strong backscattering depth with time. The calculation of speckle variance among successive OCT scanning images, which is related to the local transport speed of Au NRs, leads to the illustrations of downward propagation and spreading of major Au NR motion spot with time. PMID- 21258531 TI - Two-photon fluorescence correlation spectroscopy with high count rates and low background using dielectric microspheres. AB - Two-photon excitation fluorescence is a powerful technique commonly used for biological imaging. However, the low absorption cross section of this non-linear process is a critical issue for performing biomolecular spectroscopy at the single molecule level. Enhancing the two-photon fluorescence signal would greatly improve the effectiveness of this technique, yet current methods struggle with medium enhancement factors and/or high background noise. Here, we show that the two-photon fluorescence signal from single Alexa Fluor 488 molecules can be enhanced up to 10 times by using a 3 um diameter latex sphere while adding almost no photoluminescence background. We report a full characterization of the two photon fluorescence enhancement by a single microsphere using fluorescence correlation spectroscopy. This opens new routes to enhance non-linear optical signals and extend biophotonic applications. PMID- 21258532 TI - Hierarchical Bayesian regularization of reconstructions for diffuse optical tomography using multiple priors. AB - Diffuse optical tomography (DOT) is a non-invasive brain imaging technique that uses low-levels of near-infrared light to measure optical absorption changes due to regional blood flow and blood oxygen saturation in the brain. By arranging light sources and detectors in a grid over the surface of the scalp, DOT studies attempt to spatially localize changes in oxy- and deoxy-hemoglobin in the brain that result from evoked brain activity during functional experiments. However, the reconstruction of accurate spatial images of hemoglobin changes from DOT data is an ill-posed linearized inverse problem, which requires model regularization to yield appropriate solutions. In this work, we describe and demonstrate the application of a parametric restricted maximum likelihood method (ReML) to incorporate multiple statistical priors into the recovery of optical images. This work is based on similar methods that have been applied to the inverse problem for magnetoencephalography (MEG). Herein, we discuss the adaptation of this model to DOT and demonstrate that this approach provides a means to objectively incorporate reconstruction constraints and demonstrate this approach through a series of simulated numerical examples. PMID- 21258533 TI - Non-invasive optical interferometry for the assessment of biofilm growth in the middle ear. AB - Otitis media (OM) is the most common illness in children in the United States. Three-fourths of children under the age of three have OM at least once. Children with chronic OM, including OM with effusion and recurrent OM, will often have conductive hearing loss and communication difficulties, and need surgical treatment. Recent clinical studies provide evidence that almost all chronic OM cases are accompanied by a bacterial biofilm behind the tympanic membrane (eardrum) and within the middle ear. Biofilms are typically very thin, and cannot be recognized using a regular otoscope. Here we demonstrate how optical low coherence interferometry (LCI) noninvasively depth-ranges into the middle ear to detect and quantify biofilm microstructure. A portable diagnostic system integrating LCI with a standard video otoscope was constructed and used to detect and quantify the presence of biofilms in a newly-developed pre-clinical animal model for this condition. Using a novel classification algorithm for acquired LCI data, the system identified the presence of a biofilm with 86% sensitivity and 90% specificity, compared to histological findings. This new information on the presence of a biofilm, its structure, and its response to antibiotic treatment, will not only provide better understanding of fundamental principles that govern biofilm formation, growth, and eradication, but may also provide much needed clinical data to direct and monitor protocols for the successful management of otitis media. PMID- 21258534 TI - Photoacoustic tomography: a potential new tool for prostate cancer. AB - The feasibility of photoacoustic tomography (PAT) for noninvasive imaging of prostate cancer was explored through the study on a canine model in vivo. Imaging of blood-rich lesions mimicking prostate tumors was achieved using a commercial medical ultrasound (US) system without affecting its original imaging functions. Based on the optical contrast between hemoglobin and other tissues, PAT has demonstrated good sensitivity and high contrast-to-noise ratio in visualizing deep lesions; while US has presented the morphological features including the boundary and the urethral of the prostate. PAT of prostate cancer may facilitate improved tumor localization, staging of disease, and detection of recurrences. PMID- 21258535 TI - Non-invasive in vivo measurement of the tear film using spatial autocorrelation in a live mammal model. AB - Tear film stability and its interaction with the corneal surface play an important role in maintaining ocular surface integrity and quality of vision. We present a non-invasive technique to quantify the pre-corneal tear film thickness. A cMOS camera is used to record the interference pattern produced by the reflections from multiple layers of the tear film Principles of spatial autocorrelation are applied to extract the frequency of the periodic patterns in the images. A mathematical model is developed to obtain the thickness of the tear film from the spatial autocorrelation image. The technique is validated using micro-fabricated thin parylene films. We obtained repeatable and precise measurement on a live rabbit model (N = 6). We obtained an average value of 10.2um and standard deviation of, SD = 0.3 (N = 4). We measured one rabbit infected with HSV-1 virus that had a baseline tear film thickness of 4.7um. PMID- 21258536 TI - Detection of doxorubicin-induced apoptosis of leukemic T-lymphocytes by laser tweezers Raman spectroscopy. AB - Laser tweezers Raman spectroscopy (LTRS) was used to acquire the Raman spectra of leukemic T lymphocytes exposed to the chemotherapy drug doxorubicin at different time points over 72 hours. Changes observed in the Raman spectra were dependent on drug exposure time and concentration. The sequence of spectral changes includes an intensity increase in lipid Raman peaks, followed by an intensity increase in DNA Raman peaks, and finally changes in DNA and protein (phenylalanine) Raman vibrations. These Raman signatures are consistent with vesicle formation, cell membrane blebbing, chromatin condensation, and the cytoplasm of dead cells during the different stages of drug-induced apoptosis. These results suggest the potential of LTRS as a real-time single cell tool for monitoring apoptosis, evaluating the efficacy of chemotherapeutic treatments, or pharmaceutical testing. PMID- 21258537 TI - A Bayesian method for single molecule, fluorescence burst analysis. AB - There is currently great interest in determining physical parameters, e.g. fluorescence lifetime, of individual molecules that inform on environmental conditions, whilst avoiding the artefacts of ensemble averaging. Protein interactions, molecular dynamics and sub-species can all be studied. In a burst integrated fluorescence lifetime (BIFL) experiment, identification of fluorescent bursts from single molecules above background detection is a problem. This paper presents a Bayesian method for burst identification based on model selection and demonstrates the detection of bursts consisting of 10% signal amplitude. The method also estimates the fluorescence lifetime (and its error) from the burst data. PMID- 21258538 TI - Development of a versatile two-photon endoscope for biological imaging. AB - We describe a versatile, catheter-type two-photon probe, designed for in vivo and ex vivo imaging of the aqueous outflow pathway in the eye. The device consists of a silica double cladding fiber used for laser delivery and fluorescence collection, a spiral fiber scanner driven by a miniature piezoelectric tube, and an assembly of three micro-size doublet achromatic lenses used for focusing the laser and collecting the two-photon excitation signal. All the components have a maximum diameter of 2 mm and are enclosed in a length of 12-gauge stainless steel hypodermic tubing having an outer diameter of 2.8 mm. The lateral and axial resolutions of the probe are measured to be 1.5 MUm and 9.2 MUm, respectively. Different lens configurations and fibers are evaluated by comparing their spatial resolutions and fluorescence signal collection efficiencies. Doublet achromatic lenses and a double cladding fiber with a high inner cladding numerical aperture are found to produce a high signal collection efficiency, which is essential for imaging live tissues. Simple methods for reducing image distortions are demonstrated. Images of human trabecular meshwork tissue are successfully obtained with this miniature two-photon microscope. PMID- 21258540 TI - Comparison of intensity-modulated continuous-wave lasers with a chirped modulation frequency to pulsed lasers for photoacoustic imaging applications. AB - Using a Green's function solution to the photoacoustic wave equation, we compare intensity-modulated continuous-wave (CW) lasers with a chirped modulation frequency to pulsed lasers for photoacoustic imaging applications. Assuming the same transducer is used in both cases, we show that the axial resolution is identical and is determined by the transducer and material properties of the object. We derive a simple formula relating the signal-to-noise ratios (SNRs) of the two imaging systems that only depends on the fluence of each pulse and the time-bandwidth product of the chirp pulse. We also compare the SNR of the two systems assuming the fluence is limited by the American National Standards Institute (ANSI) laser safety guidelines for skin. We find that the SNR is about 20 dB to 30 dB larger for pulsed laser systems for reasonable values of the parameters. However, CW diode lasers have the advantage of being compact and relatively inexpensive, which may outweigh the lower SNR in many applications. PMID- 21258539 TI - Hemodynamic and metabolic diffuse optical monitoring in a mouse model of hindlimb ischemia. AB - Murine hindlimb ischemia is a useful model for investigation of the mechanisms of peripheral arterial disease and for understanding the role of endothelial cells and generic factors affecting vascular regeneration or angiogenesis. To date, important research with these models has explored tissue reperfusion following ischemia with Laser Doppler methods, methods which provide information about superficial (~mm) vascular regeneration. In this work, we employ diffuse correlation spectroscopy (DCS) and diffuse optical spectroscopy (DOS) in mice after hindlimb ischemia. We hypothesize that vascular re-growth is not uniform in tissue, and therefore, since diffuse optical methods are capable of probing deep tissues, that the diffuse optics approach will provide a more complete picture of the angiogenesis process throughout the whole depth profile of the limb. Besides increased depth penetration, the combined measurements of DCS and DOS enable all optical, noninvasive, longitudinal monitoring of tissue perfusion and oxygenation that reveals the interplay between these hemodynamic parameters during angiogenesis. Control mice were found to reestablish 90% of perfusion and oxygen consumption during this period, but oxygen saturation in the limb only partially recovered to about 30% of its initial value. The vascular recovery of mice with endothelial cell-specific deletion of HIF-2alpha was found to be significantly impaired relative to control mice, indicating that HIF-2alpha is important for endothelial cell functions in angiogenesis. Comparison of DOS/DCS measurements to parallel measurements in the murine models using Laser Doppler Flowmetry reveal differences in the reperfusion achieved by superficial versus deep tissue during neoangiogenesis; findings from histological analysis of blood vessel development were further correlated with these differences. In general, the combination of DCS and DOS enables experimenters to obtain useful information about oxygenation, metabolism, and perfusion throughout the limb. The results establish diffuse optics as a practical noninvasive method to evaluate the role of transcription factors, such as the endothelial cell-specific HIF-2alpha, in genetic ally modified mice. PMID- 21258541 TI - Depth-resolved measurement of mucosal microvascular blood content using ?low coherence enhanced backscattering spectroscopy. AB - Low-coherence enhanced backscattering (LEBS) spectroscopy is a light scattering technique which uses partial spatial coherence broadband illumination to interrogate the optical properties at sub-diffusion length scales. In this work, we present a post-processing technique which isolates the hemoglobin concentration at different depths within a sample using a single spectroscopic LEBS measurement with a fixed spatial coherence of illumination. We verify the method with scattering (spectralon reflectance standard and polystyrene microspheres) and absorbing (hemoglobin) phantoms. We then demonstrate the relevance of this method for quantifying hemoglobin content as a function of depth within biological tissue using the azoxymethane treated animal model of colorectal cancer. PMID- 21258542 TI - Direct and instantaneous observation of intravenously injected substances using intravital confocal micro-videography. AB - We describe the development and application of intravital confocal micro videography to visualize entrance, distribution, and clearance of drugs within various tissues and organs. We use a Nikon A1R confocal laser scanning microscope system attached to an upright ECLIPSE FN1. The Nikon A1R allows simultaneous four channel acquisition and speed of 30 frames per second while maintaining high resolution of 512 * 512 scanned points. The key techniques of our intravital imaging are (1) to present a flat and perpendicular surface to the objective lens, and (2) to expose the subject with little or no bleeding to facilitate optical access to multiple tissues and organs, and (3) to isolate the subject from the body movement without compressing the blood vessels, and (4) to insert a tail vein catheter for timed injection without moving the subject. Ear lobe dermis tissue was accessible without surgery. Liver, kidney, and subcutaneous tumor were accessed following exteriorization through skin incision. In order to image initial extravasations of compounds into tissue following intravenous injection, movie acquisition was initialized prior to drug administration. Our technique can serve as a powerful tool for investigating biological mechanisms and functions of intravenously injected drugs, with both spatial and temporal resolution. PMID- 21258543 TI - Measuring micro-interactions between coagulating red blood cells using optical tweezers. AB - Agents that alter the dynamics of hemostasis form an important part in management of conditions such as atherosclerosis, cerebrovascular disease, and bleeding diatheses. In this study, we explored the effects of heparin and tranexamic acid on the efficiency of blood coagulation. Using optical tweezers, we evaluated the pN-range micro-interaction between coagulating red blood cells (RBCs) by measuring the minimum power required to trap them. By observing the mobility of RBCs and the intensity of cellular interactions, we found that the coagulation process can be separated into three phases. The effects of heparin and tranexamic acid were examined by observing variations in cellular interaction during the coagulation phases. Heparin attenuated the interaction between RBCs and prolonged the first phase whereas the samples containing tranexamic acid bypassed the first two phases and immediately proceeded to the final one. PMID- 21258544 TI - Towards robust cellular image classification: theoretical foundations for wide angle ?scattering pattern analysis. AB - Clinical analysis of light scattering from cellular organelle distributions can help identify disease and predict a patient's response to treatment. This work presents a theoretical basis for the identification of important intracellular distributions from scattering patterns even in the presence of optical and structural variability, and examines how the geometry of an organelle distribution affects key properties of wide-angle (two-dimensional) scattering patterns. Specifically, this work demonstrates how organelle arrangement relates to the size and shape of intensity peaks within simulated scattering images, and how this relationship can affect cell identification when using standard image classification methods. PMID- 21258545 TI - Combined influences of chromatic aberration and scattering in depth-resolved two photon fluorescence endospectroscopy. AB - The influence of chromatic aberration of an objective lens in two-photon fluorescence (TPF) endospectroscopy of scattering media has been systematically investigated through both experiments and numerical simulations. Experiments were carried out on a uniform 3D scattering gelatin phantom embedded with TiO(2) granules (to mimic tissue scattering) and fluorescein-tagged polystyrene beads. It was found that fluorescence spectral intensity and lineshape varied as a function of depth when measured with a gradient-index (GRIN) lens which has severe chromatic aberration. The spectral distortion caused by the chromatic aberration became diminishing as the imaging depth increased. Ray tracing analysis and Monte Carlo simulations were carried out to study the interplay of chromatic aberration and scattering in the depth-resolved TPF spectra. The simulation results suggest that the collected fluorescence signals from deeper layers included more out-of-focus photons that experienced a few or multiple scatterings, which diminish the influence of chromatic aberration on the measured TPF spectra. The simulated collection efficiencies of TPF at different wavelengths and depths can be used to properly recover the true depth-resolved TPF spectra of a relatively uniform scattering medium. PMID- 21258546 TI - Characterizing dual wavelength polarimetry through the eye for monitoring glucose. AB - Diabetes is an insidious disease that afflicts millions of people worldwide and typically requires the person with the disease to monitor their blood sugar level via finger or forearm sticks multiple times daily. Therefore, the ability to noninvasively measure glucose would be a significant advancement for the diabetic community. The use of optically polarized light passed through the anterior chamber of the eye is one proposed noninvasive approach for glucose monitoring. However, the birefringence of the cornea and the difficulty in coupling the light across the eye have been major drawbacks toward realizing this approach. A dual wavelength optical polarimetric approach has been proposed as a means to potentially overcome the birefringence noise but has never been fully characterized. Therefore, in this paper an optical model has been developed along with experiments performed on New Zealand White rabbit eyes for characterizing the light path and corneal birefringence at two different wavelengths as they are passed through the anterior chamber of the eye. The results show that, without index matching, it is possible to couple the light in and out of the eye but only across a very limited range otherwise the light does not come back out of the eye. It was also shown that there is potential to use a dual wavelength approach to accommodate the birefringence noise of the cornea in the presence of eye motion. These results will be used to help guide the final design of the polarimetric system for use in noninvasive monitoring of glucose in vivo. PMID- 21258547 TI - Bioluminescence tomography with Gaussian prior. AB - Parameterizing the bioluminescent source globally in Gaussians provides several advantages over voxel representation in bioluminescence tomography. It is mathematically unique to recover Gaussians [Med. Phys. 31(8), 2289 (2004)] and practically sufficient to approximate various shapes by Gaussians in diffusive medium. The computational burden is significantly reduced since much fewer unknowns are required. Besides, there are physiological evidences that the source can be modeled by Gaussians. The simulations show that the proposed model and algorithm significantly improves accuracy and stability in the presence of Gaussian or non- Gaussian sources, noisy data or the optical background mismatch. It is also validated through in vivo experimental data. PMID- 21258548 TI - Photoacoustic imaging based on MEMS mirror scanning. AB - A microelectromechanical systems (MEMS)-based photoacoustic imaging system is reported for the first time. In this system, the MEMS-based light scanning subsystem and a ring-shaped polyvinylidene fluoride (PVDF) transducer are integrated into a miniaturized probe that is capable of three-dimensional (3D) photoacoustic imaging. It is demonstrated that the imaging system is able to image small objects embedded in phantom materials and in chicken and to in vivo visualize blood vessels under the skin of a human hand. PMID- 21258549 TI - Fundamentals of negative refractive index optical trapping: forces and radiation pressures exerted by focused Gaussian beams using the generalized Lorenz-Mie theory. AB - Based on the generalized Lorenz-Mie theory (GLMT), this paper reveals, for the first time in the literature, the principal characteristics of the optical forces and radiation pressure cross-sections exerted on homogeneous, linear, isotropic and spherical hypothetical negative refractive index (NRI) particles under the influence of focused Gaussian beams in the Mie regime. Starting with ray optics considerations, the analysis is then extended through calculating the Mie coefficients and the beam-shape coefficients for incident focused Gaussian beams. Results reveal new and interesting trapping properties which are not observed for commonly positive refractive index particles and, in this way, new potential applications in biomedical optics can be devised. PMID- 21258550 TI - Fluorescence lifetime biosensing with DNA microarrays and a CMOS-SPAD imager. AB - Fluorescence lifetime of dye molecules is a sensitive reporter on local microenvironment which is generally independent of fluorophores concentration and can be used as a means of discrimination between molecules with spectrally overlapping emission. It is therefore a potentially powerful multiplexed detection modality in biosensing but requires extremely low light level operation typical of biological analyte concentrations, long data acquisition periods and on-chip processing capability to realize these advantages. We report here fluorescence lifetime data obtained using a CMOS-SPAD imager in conjunction with DNA microarrays and TIRF excitation geometry. This enables acquisition of single photon arrival time histograms for a 320 pixel FLIM map within less than 26 seconds exposure time. From this, we resolve distinct lifetime signatures corresponding to dye-labelled HCV and quantum-dot-labelled HCMV nucleic acid targets at concentrations as low as 10 nM. PMID- 21258551 TI - High-speed spectral domain optical coherence tomography using non-uniform fast Fourier transform. AB - The useful imaging range in spectral domain optical coherence tomography (SD-OCT) is often limited by the depth dependent sensitivity fall-off. Processing SD-OCT data with the non-uniform fast Fourier transform (NFFT) can improve the sensitivity fall-off at maximum depth by greater than 5dB concurrently with a 30 fold decrease in processing time compared to the fast Fourier transform with cubic spline interpolation method. NFFT can also improve local signal to noise ratio (SNR) and reduce image artifacts introduced in post-processing. Combined with parallel processing, NFFT is shown to have the ability to process up to 90k A-lines per second. High-speed SD-OCT imaging is demonstrated at camera-limited 100 frames per second on an ex-vivo squid eye. PMID- 21258552 TI - Feasibility of using multiphoton excited tissue autofluorescence for in vivo human histopathology. AB - Rapid and direct imaging of microscopic tissue morphology and pathology can be achieved by multiphoton imaging of intrinsic tissue fluorophores and second harmonic signals. Engineering parameters for developing this technology for clinical applications include excitation levels and collection efficiencies required to obtain diagnostic quality images from different tissue types and whether these levels are mutagenic. Here we provide data on typical average powers required for high signal-to-noise in vivo tissue imaging and assess the risk potential of these irradiance levels using a mammalian cell gene mutation assay. Exposure times of ~16 milliseconds per cell to 760 nm, ~200 fs raster scanned laser irradiation delivered through a 0.75 NA objective produced negligible mutagenicity at powers up to about 50 mW. PMID- 21258553 TI - Distortions of the posterior surface in optical coherence tomography images of the isolated crystalline lens: effect of the lens index gradient. AB - We quantify the posterior surface distortions in optical coherence tomography (OCT) images of isolated crystalline lenses. The posterior radius of curvature and asphericity obtained from OCT images acquired with the beam incident first on the anterior, and then the posterior, surface were compared. The results were compared with predictions of a ray-tracing model which includes the index gradient. The results show that the error in the radius of curvature is within the measurement reproducibility and that it can be corrected by assuming a uniform refractive index. However, accurate asphericity values require a correction algorithm that takes into account the gradient. PMID- 21258554 TI - Full-color skin imaging using RGB LED and floating lens in optical coherence tomography. AB - The cosmetic industry has witnessed significant growth in recent years. Conventional hand-held skin cameras allow for 2D inspection of the skin surface. This paper proposes a new model for full-color 3D imaging of the skin tissue using fiber-based optical coherence tomography (OCT). Compared to laser or LD sources, RGB LED was found more suitable and thus chosen in the low-coherence interferometry due to its wider bandwidth. A floating objective lens was used to confocalize the R, G and B imaging planes and to derive a full-color image of the capillary system in the skin tissue. The skin imaging system can be miniaturized to form a new hand-held model using an RGB integrated source, a micro interferometer module and a high-speed beam steering device. Non-invasive, full color and hand-held skin imaging contributes to advances in the fields of skin science, dermatology and cosmetology. PMID- 21258555 TI - Multimodal CARS microscopy of structured carbohydrate biopolymers. AB - We demonstrate the utility of multimodal coherent anti-Stokes Raman scattering (CARS) microscopy for the study of structured condensed carbohydrate systems. Simultaneous second-harmonic generation (SHG) and spectrally-scanned CARS microscopy was used to elucidate structure, alignment, and density in cellulose cotton fibers and in starch grains undergoing rapid heat-moisture swelling. Our results suggest that CARS response of the O-H stretch region (3000 cm(-1)-3400 cm(-1)), together with the commonly-measured C-H stretch (2750 cm(-1)-2970 cm( 1)) and SHG provide potentially important structural information and contrast in these materials. PMID- 21258556 TI - Retinal Nerve Fiber Layer Segmentation on FD-OCT Scans of Normal Subjects and Glaucoma Patients. AB - Automated measurements of the retinal nerve fiber layer thickness on circular OCT B-Scans provide physicians additional parameters for glaucoma diagnosis. We propose a novel retinal nerve fiber layer segmentation algorithm for frequency domain data that can be applied on scans from both normal healthy subjects, as well as glaucoma patients, using the same set of parameters. In addition, the algorithm remains almost unaffected by image quality. The main part of the segmentation process is based on the minimization of an energy function consisting of gradient and local smoothing terms. A quantitative evaluation comparing the automated segmentation results to manually corrected segmentations from three reviewers is performed. A total of 72 scans from glaucoma patients and 132 scans from normal subjects, all from different persons, composed the database for the evaluation of the segmentation algorithm. A mean absolute error per A Scan of 2.9 um was achieved on glaucomatous eyes, and 3.6 um on healthy eyes. The mean absolute segmentation error over all A-Scans lies below 10 um on 95.1% of the images. Thus our approach provides a reliable tool for extracting diagnostic relevant parameters from OCT B-Scans for glaucoma diagnosis. PMID- 21258558 TI - Detection of nanoscale structural changes in bone using random lasers. AB - We demonstrate that the unique characteristics of random lasing in bone can be used to assess nanoscale structural alterations as a mechanical or structural biosensor, given that bone is a partially disordered biological nanostructure. In this proof-of-concept study, we conduct photoluminescence experiments on cortical bone specimens that are loaded in tension under mechanical testing. The ultra high sensitivity, the large detection area, and the simple detection scheme of random lasers allow us to detect prefailure damage in bone at very small strains before any microscale damage occurs. Random laser-based biosensors could potentially open a new possibility for highly sensitive detection of nanoscale structural and mechanical alterations prior to overt microscale changes in hard tissue and biomaterials. PMID- 21258557 TI - Intrinsic optical biomarkers associated with the invasive potential of tumor cells in engineered tissue models. AB - This report assesses the ability of intrinsic two-photon excited fluorescence (TPEF) and second harmonic generation (SHG) imaging to characterize features associated with the motility and invasive potential of epithelial tumor cells engineered in tissues. Distinct patterns of organization are found both within the cells and the matrix that depend on the adhesive properties of the cells as well as factors attributed to adjacent fibroblasts. TPEF images are analyzed using automated algorithms that reveal unique features in subcellular organization and cell spacing that correlate with the invasive potential. We expect that such features have significant diagnostic potential for basic in vitro studies that aim to improve our understanding of cancer development or response to treatments, and, ultimately can be applied in prognostic evaluation. PMID- 21258559 TI - High-throughput FCS using an LCOS spatial light modulator and an 8 * 1 SPAD array. AB - We present a novel approach to high-throughput Fluorescence Correlation Spectroscopy (FCS) which enables us to obtain one order of magnitude improvement in acquisition time. Our approach utilizes a liquid crystal on silicon spatial light modulator to generate dynamically adjustable focal spots, and uses an eight pixel monolithic single-photon avalanche photodiode array. We demonstrate the capabilities of this system by showing FCS of Rhodamine 6G under various viscosities, and by showing that, with proper calibration of each detection channel, one order of magnitude improvement in acquisition speed is obtained. More generally, our approach will allow higher throughput single-molecule studies to be performed. PMID- 21258560 TI - Estimation of biological chromophores using diffuse optical spectroscopy: benefit of extending the UV-VIS wavelength range to include 1000 to 1600 nm. AB - With an optical fiber probe, we acquired spectra from swine tissue between 500 and 1600 nm by combining a silicon and an InGaAs spectrometer. The concentrations of the biological chromophores were estimated by fitting a mathematical model derived from diffusion theory. The advantage of our technique relative to those presented in previous studies is that we extended the commonly-used wavelength ranges of 500 and 1000 nm to include the range of 1000 to 1600 nm, where additional water and lipid absorption features exist. Hence, a more accurate estimation of these two chromophores is expected when spectra are fitted between 500 and 1600 nm than between 500 and 1000 nm. When extending the UV-VIS wavelength range, the estimated total amount of chromophores approached 100% of the total as present in the probed volume. The confidence levels of the water and lipid related parameters increases by a factor of four. PMID- 21258561 TI - Effects of acetazolamide on the micro- and macro-vascular cerebral hemodynamics: a diffuse optical and transcranial doppler ultrasound study. AB - Acetazolamide (ACZ) was used to stimulate the cerebral vasculature on ten healthy volunteers to assess the cerebral vasomotor reactivity (CVR). We have combined near infrared spectroscopy (NIRS), diffuse correlation spectroscopy (DCS) and transcranial Doppler (TCD) technologies to non-invasively assess CVR in real-time by measuring oxy- and deoxy-hemoglobin concentrations, using NIRS, local cerebral blood flow (CBF), using DCS, and blood flow velocity (CBFV) in the middle cerebral artery, using TCD. Robust and persistent increases in oxy-hemoglobin concentration, CBF and CBFV were observed. A significant agreement was found between macro-vascular (TCD) and micro-vascular (DCS) hemodynamics, between the NIRS and TCD data, and also within NIRS and DCS results. The relative cerebral metabolic rate of oxygen, rCMRO(2), was also determined, and no significant change was observed. Our results showed that the combined diffuse optics ultrasound technique is viable to follow (CVR) and rCMRO(2) changes in adults, continuously, at the bed-side and in real time. PMID- 21258562 TI - Interfaces detection after corneal refractive surgery by low coherence optical interferometry. AB - The detection of refractive corneal surgery by LASIK, during the storage of corneas in Eye Banks will become a challenge when the numerous operated patients will arrive at the age of cornea donation. The subtle changes of corneal structure and refraction are highly suspected to negatively influence clinical results in recipients of such corneas. In order to detect LASIK cornea interfaces we developed a low coherence interferometry technique using a broadband continuum source. Real time signal recording, without moving any optical elements and without need of a Fourier Transform operation, combined with good measurement resolution is the main asset of this interferometer. The associated numerical processing is based on a method initially used in astronomy and offers an optimal correlation signal without the necessity to image the whole cornea that is time consuming. The detection of corneal interfaces - both outer and inner surface and the buried interface corresponding to the surgical wound - is then achieved directly by the innovative combination of interferometry and this original numerical process. PMID- 21258563 TI - Two-parameter angular light scatter collection for microfluidic flow cytometry by unique waveguide structures. AB - Waveguide numerical aperture restrictions and light-blocking elements are used to create a microfluidic cytometer with both illumination and two-parameter light scatter collection systems integrated on-chip. Good forward scatter coefficients of variation (9.7-18.3%) are achieved for polystyrene beads under a reasonably high flow rate (28 cm/s) using a greatly simplified optical system. PMID- 21258564 TI - Full-range imaging of eye accommodation by high-speed long-depth range optical frequency domain imaging. AB - We describe a high-speed long-depth range optical frequency domain imaging (OFDI) system employing a long-coherence length tunable source and demonstrate dynamic full-range imaging of the anterior segment of the eye including from the cornea surface to the posterior capsule of the crystalline lens with a depth range of 12 mm without removing complex conjugate image ambiguity. The tunable source spanned from 1260 to 1360 nm with an average output power of 15.8 mW. The fast A-scan rate of 20,000 per second provided dynamic OFDI and dependence of the whole anterior segment change on time following abrupt relaxation from the accommodated to the relaxed status, which was measured for a healthy eye and that with an intraocular lens. PMID- 21258565 TI - Diffusing-wave spectroscopy with dynamic contrast variation: disentangling the effects of blood flow and extravascular tissue shearing on signals from deep tissue. AB - We investigate the effects of blood flow and extravascular tissue shearing on diffusing-wave spectroscopy (DWS) signals from deep tissue, using an ex vivo porcine kidney model perfused artificially at controlled arterial pressure and flow. Temporal autocorrelation functions g((1))(tau) of the multiply scattered light field show a decay which is described by diffusion for constant flow, with a diffusion coefficient scaling linearly with volume flow rate. Replacing blood by a non-scattering fluid reveals a flow-independent background dynamics of the extravascular tissue. For a sinusoidally driven perfusion, field autocorrelation functions g((1))(tau, t') depend on the phase t' within the pulsation cycle and are approximately described by diffusion. The effective diffusion coefficient D(eff)(t') is modulated at the driving frequency in the presence of blood, showing coupling with flow rate; in the absence of blood, D(eff)(t') is modulated at twice the driving frequency, indicating shearing of extravascular tissue as the origin of the DWS signal. For both constant and pulsatile flow the contribution of extravascular tissue shearing to the DWS signal is small. PMID- 21258566 TI - Singular value decomposition metrics show limitations of detector design in diffuse fluorescence tomography. AB - The spatial resolution and recovered contrast of images reconstructed from diffuse fluorescence tomography data are limited by the high scattering properties of light propagation in biological tissue. As a result, the image reconstruction process can be exceedingly vulnerable to inaccurate prior knowledge of tissue optical properties and stochastic noise. In light of these limitations, the optimal source-detector geometry for a fluorescence tomography system is non-trivial, requiring analytical methods to guide design. Analysis of the singular value decomposition of the matrix to be inverted for image reconstruction is one potential approach, providing key quantitative metrics, such as singular image mode spatial resolution and singular data mode frequency as a function of singular mode. In the present study, these metrics are used to analyze the effects of different sources of noise and model errors as related to image quality in the form of spatial resolution and contrast recovery. The image quality is demonstrated to be inherently noise-limited even when detection geometries were increased in complexity to allow maximal tissue sampling, suggesting that detection noise characteristics outweigh detection geometry for achieving optimal reconstructions. PMID- 21258567 TI - Experimental models of duchenne muscular dystrophy: relationship with cardiovascular disease. AB - Almost every boy that has Duchenne Muscular Dystrophy (DMD) will develop cardiac problems. Whereas, it used to be respiratory problems that was the main cause of death in these DMD boys; with the advent of better respiratory care it is now the cardiac involvement that is becoming the most common cause of their death. Once the heart is affected, there is progressive deterioration in the function of the heart over time. The main problem is the death of the cardiomyocytes. The cause of the cardiomyocyte death is due to the loss of dystrophin, this makes the sarcolemma more susceptible to damage, and leads to a cascade of calcium influx, calcium activated proteases and ultimately the death of the cardiomyocyte. The dead cardiomyocytes are replaced by fibrotic tissue, which results in a dilated cardiomyopathy (DCM) developing, which begins in the base of the left ventricle and progresses to involve the entire left ventricle. The treatments used for the DMD cardiomyopathy are based on ones designed for other forms of cardiac weakness and include ACE-inhibitors and beta-blockers. New therapies based around the pathophysiology in DMD are now being introduced. This review will look at the pathophysiology of the cardiac problems in DMD and how the various animal models that are available can be used to design new treatment options for DMD boys. PMID- 21258569 TI - Mycobacterium Avium Complex (MAC) Lung Disease in Two Inner City Community Hospitals: Recognition, Prevalence, Co-Infection with Mycobacterium Tuberculosis (MTB) and Pulmonary Function (PF) Improvements After Treatment. AB - INTRODUCTION: The purpose of this study was to separate MAC lung disease from colonization and to define indications for treatment. MATERIALS AND METHODOLOGY: Over 4 years, we evaluated patients who had positive MAC cultures, MAC infection and coinfection with MTB. In the first study, 42 immunocompetent patients with sputum or BAL culture positive only for MAC during a single year (2004) were reviewed. On clinical and radiographic review, they were classified as disease related to MAC, likely related to MAC or unrelated to MAC. In the second study, we reviewed all immunocompetent patients, during two years (2004-2005), whose respiratory secretions cultured both MTB and nontuberculous mycobacteria (NTM). In the last study, we evaluated pulmonary function (PF) in patients with MAC infection before and after therapy (2006- 2007). PF was evaluated in patients following ATS guidelines. RESULTS: Lung disease was related/likely related to MAC in 21 patients (50%) and not related in 21 (50%). In patients with MAC-related lung disease, the primary physician did not consider the diagnosis except when that physician was a pulmonologist. Half of those with MAC-related lung disease were smokers, white and US-born. There were 12 immunocompetent patients with MTB and NTM cultures. Eleven were non-white and all were foreign-born. Presentation and clinical course were consistent with MTB. All 8 patients with abnormal PF improved. CONCLUSIONS: The prevalence of MAC lung infection in two inner city hospitals was four times higher than that of TB. The indication for treatment of MAC infection should also rely heavily on clinical and radiological evidence when there is only one positive sputum culture. The diagnosis was considered only when the admitting physician was a pulmonologist. Most patients with combined infection were clinically consistent with MTB and responded to anti MTB treatment alone. Treatment with anti-MAC therapy improved PF in those patients whose PF was abnormal to begin with. PMID- 21258568 TI - Animal models of cardiac disease and stem cell therapy. AB - Animal models that mimic cardiovascular diseases are indispensable tools for understanding the mechanisms underlying the diseases at the cellular and molecular level. This review focuses on various methods in preclinical research to create small animal models of cardiac diseases, such as myocardial infarction, dilated cardiomyopathy, heart failure, myocarditis and cardiac hypertrophy, and the related stem cell treatment for these diseases. PMID- 21258570 TI - Effect of Maternal HIV-1 Status and Antiretroviral Drugs on Haematological Profiles of South African Infants in Early Life. AB - Maternal HIV-1 status and antiretroviral drug exposure may influence the haematological profiles of infants. We recruited infants from 118 uninfected control women and from 483 HIV-1 infected women who received no antiretroviral drugs (n=28), or received single-dose Nevirapine (sdNVP) (n=424) or triple-drug combination therapy (n=31) to reduce HIV-1 transmission. Blood was drawn from infants within 24 hours of delivery or 6-12 weeks post-delivery and full blood counts performed using a fully automated AcT-5-diff haematology analyser and reference controls. Exposed uninfected (EU; no NVP) differed from control infants only in having lower basophil counts and percentages. In all infant groups, leukocyte profiles showed characteristic quantitative changes with age in the first 6 weeks of life. HIV-1 infected infants displayed by 6 weeks elevations in white blood cells, lymphocyte, monocyte and basophil counts, and monocyte and basophil percentages, when compared to EU infants. At birth EU NVP-treated infants exhibited elevated monocyte percentages and counts and basophil counts that did not persist at 6 weeks. Interestingly, EU newborns of mothers with high CD4 counts (> 500 cells/MUl) that had taken sdNVP had significantly elevated white blood cell, monocyte and basophil counts when compared to newborn infants of mothers with similar CD4 counts that had not taken sdNVP; this was not evident in infants of mothers with CD4 counts <200 cells/MUl. These previously undescribed features may affect immune response capability in early life and clinical consequences of such changes need to be further investigated. PMID- 21258572 TI - Remission of hypnic headache associated with idiopathic cyclic edema with the use of aminaphtone. AB - Headache is one of the chief complaints among patients visiting primary care physicians. The aim of the current study is to report on a case of daily intermittent headaches in a patient with idiopathic cyclic edema. Over three years the patient suffered from headaches that started and improved at specific times. They began at about 5 to 6 o'clock in the morning and spontaneously disappeared 3 to 4 hours after getting up and thus were directly associated to sleep. The patient complained of generalized edema and had weight differences of about two kilograms between 7 a.m. and 5 p.m. A hypothesis of idiopathic cyclic edema was reached and the patient was prescribed aminaphtone which cured the headaches within two days after initiating treatment. PMID- 21258571 TI - Autonomic dysfunction and risk stratification assessed from heart rate pattern. AB - The modulation of the autonomic nervous system (ANS) under physiological and pathophysiological conditions is in focus of recent research. Many patients with cardio- and cerebrovascular diseases display features of sympathovagal dysregulation. Measuring specific ANS parameters could improve risk stratification. Thus, the early diagnosis of ANS dysfunction in these patients poses a great challenge with high prognostic relevance.The most relevant methods and measures of Heart Rate Variability (HRV) analysis and HRV monitoring will be described in detail in this chapter. The grown importance of these easily obtainable heart rate patterns in stratifying the risk of patients with myocardial infarction and heart failure as well as ischemic stroke will be demonstrated based on recent clinical studies. In order to perspectively improve clinical management of these patients further large scale clinical investigations on the role of ANS dysfunction will be useful. PMID- 21258573 TI - An Unusual Presentation of Endocarditis Caused by Staphylococcus warneri. AB - Staphylococcus warneri does not generally cause serious infections in humans. We report a case of endocarditis in a healthy individual with no known past medical history. S. warneri was identified in her blood cultures and echocardiographic evidence confirmed the diagnosis of bacterial endocarditis. There was no apparent cause for her infection, and risk factors such as invasive treatment or medical implant were not present. This rare clinical presentation illustrates the importance of not overlooking low virulence species of Staphylococcus, as they can potentially serve as opportunistic etiological agents for endocarditis, especially among the elderly population. PMID- 21258574 TI - Disease modifying agents for multiple sclerosis. AB - OBJECTIVE: To summarize major clinical trials which evaluate the efficacy and safety data of approved disease modifying agents for the treatment of various types of multiple sclerosis. DATA SOURCES: A MEDLINE (1966 to August 2008) search of clinical trials using the terms multiple sclerosis, interferon, glatiramer, mitoxantrone and natalizumab was performed. A manual bibliographic search was also conducted. English-language articles identified from the searches were evaluated. New agents under investigation in phase 3 clinical trials were identified using www.clinicaltrials.gov. STUDY SELECTION #ENTITYSTARTX00026; DATA EXTRACTION: Relevant information was identified and selected based on clinical relevance and evidence-based strength. Prescribing information leaflets were used to provide usual dosage, contraindications, precautions, monitoring parameters and other relevant drug-specific information. DATA SYNTHESIS: Interferon beta products are more efficacious for the treatment of relapsing-remitting multiple sclerosis. Interferon beta 1-b also delayed the time to diagnosis of definite multiple sclerosis and reduced brain lesion burden in patients with clinical isolated syndrome. Glatiramer and natalizumab have both established efficacy in relapsing forms of multiple sclerosis; whereas mitoxantrone is more commonly used in patients with advanced disease. There are limited data the comparative efficacy among different disease modifying agents. New agents currently under investigation have showed promising results and may offer more treatment options in the future. CONCLUSIONS: MS is a complex and devastating disease with challenging treatment considerations and approaches. Interferon beta products continue to be the mainstay of therapy in many patients, however, other treatments are proving to be at least as effective in the management of various types of MS. Newer compounds are being developed and studied with much anticipation and promise for the clinical management of the disease. PMID- 21258575 TI - Evaluation of Computerized Free Text Sign-Out Notes: Baseline Understanding and Recommendations. AB - BACKGROUND: Standardization of sign-out, the transfer of patient information and responsibility between inpatient providers at shift change, is a Joint Commission National Patient Safety Goal intended to improve communication and reduce risk of error. Computerized systems with free text data entry and limited structure allow clinicians to generate sign-out notes in a variety of ways. OBJECTIVES: The literature lacks a systematic exploration of the range of content generated by users of computerized sign-out systems. The goal of this study was to determine if and how clinicians record standardized sign-out information using a system with free text data entry and limited structure. METHODS: Using qualitative methods, we reviewed free text sign-out notes for 730 patient cases across 39 hospital units at an academic medical center. RESULTS: Two categories of information expression emerged from analysis: patient treatment-comprised of patient summaries, awareness items, and action items-and care team coordination consisting of discharge information, contact information, and social concerns. A third category describing the format of sign-out note content, presentation of information, also emerged. Location and structure of information varied, but sign out note content for some hospital units exhibited specific characteristics and was relatively standardized. CONCLUSIONS: Findings provide a baseline understanding of computerized free text sign-out note content. Sign-out notes contained a synthesis of data from disparate sources. We recommend formalizing existing unit-specific content standardization and system use patterns to reduce sign-out note variability and improve communication. PMID- 21258576 TI - A Response to Recent Reanalyses of the National Reading Panel Report: Effects of Systematic Phonics Instruction Are Practically Significant. AB - The authors examine the reassessments of the National Reading Panel (NRP) report (National Institute of Child Health and Human Development, 2000) by G. Camilli, S. Vargas, and M. Yurecko (2003); G. Camilli, P. M. Wolfe, and M. L. Smith (2006); and D. D. Hammill and H. L. Swanson (2006) that disagreed with the NRP on the magnitude of the effect of systematic phonics instruction. Using the coding of the NRP studies by Camilli et al. (2003, 2006), multilevel regression analyses show that their findings do not contradict the NRP findings of effect sizes in the small to moderate range favoring systematic phonics. Extending Camilli et al. (2003, 2006), the largest effects are associated with reading instruction enhanced with components that increase comprehensiveness and intensity. In contrast to Hammill and Swanson, binomial effect size displays show that effect sizes of the magnitude found for systematic phonics by the NRP are meaningful and could result in significant improvement for many students depending on the base rate of struggling readers and the size of the effect. Camilli et al. (2003, 2006) and Hammill and Swanson do not contradict the NRP report, concurring in supporting comprehensive approaches to reading instruction. PMID- 21258579 TI - Rapid identification of mycobacterium species with the aid of multiplex polymerase chain reaction (PCR) from clinical isolates. AB - Mycobacteria are aerobic, nonspore forming, non-motile,single-cell bacteria.Of more than 40 currently recognized species of mycobacteria, Mycobacterium tuberculosis, the causative agent of human TB is the commonest pathogen for pulmonary and extra pulmonary tuberculosis cases. The other members of the Mycobacterium tuberculosis complex (MTC) or the nontubercular mycobacterium (NTM) produces similar diseases which cannot be differentiated from tuberculosis by clinical symptoms and signs. But this differentiation is important as the chemotherapy varies widely according to the strain of mycobacterium. The burden of morbidity and mortality of tuberculosis is rapidly growing worldwide, particularly with the HIV/AIDS epidemic. The strain identification of Mycobacterium remains a cumbersome, labor intensive and expensive procedure, which requires 3 to 12 weeks of time. The conventional methods of strain identification lack proper standardization and precise diagnosis. The prime objective of this study is to overcome these problems.A multiplex PCR using 3 amplicons of 165,365, and 541 base pair target sequences was done with a total number of 165 clinical isolates of suspected Koch's patients. Strain identification was compared both by conventional methods and multiplex PCR. The results of the study show that this multiplex PCR is supposed to be less complicated, less time consuming, cost-effective and superior to the conventional methods. It is also applicable for culture negative samples where strain identification is not possible by conventional approach. PMID- 21258578 TI - Experimental models of renal disease and the cardiovascular system. AB - Cardiovascular disease is a leading cause of death among patients with end stage renal failure. Animal models have played a crucial role in teasing apart the complex pathological processes involved. This review discusses the principles of using animal models, the history of their use in the study of renal hypertension, the controversies arising from experimental models of non-hypertensive uraemic cardiomyopathy and the lessons learned from these models, and highlights important areas of future research in this field, including de novo cardiomyopathy secondary to renal transplantation. PMID- 21258577 TI - Uner tan syndrome: history, clinical evaluations, genetics, and the dynamics of human quadrupedalism. AB - This review includes for the first time a dynamical systems analysis of human quadrupedalism in Uner Tan syndrome, which is characterized by habitual quadrupedalism, impaired intelligence, and rudimentary speech. The first family was discovered in a small village near Iskenderun, and families were later found in Adana and two other small villages near Gaziantep and Canakkale. In all the affected individuals dynamic balance was impaired during upright walking, and they habitually preferred walking on all four extremities. MRI scans showed inferior cerebellovermian hypoplasia with slightly simplified cerebral gyri in three of the families, but appeared normal in the fourth. PET scans showed a decreased glucose metabolic activity in the cerebellum, vermis and, to a lesser extent the cerebral cortex, except for one patient, whose MRI scan also appeared to be normal. All four families had consanguineous marriages in their pedigrees, suggesting autosomal recessive transmission. The syndrome was genetically heterogeneous. Since the initial discoveries more cases have been found, and these exhibit facultative quadrupedal locomotion, and in one case, late childhood onset. It has been suggested that the human quadrupedalism may, at least, be a phenotypic example of reverse evolution. From the viewpoint of dynamic systems theory, it was concluded there may not be a single factor that predetermines human quadrupedalism in Uner Tan syndrome, but that it may involve self organization, brain plasticity, and rewiring, from the many decentralized and local interactions among neuronal, genetic, and environmental subsystems. PMID- 21258580 TI - Quantitative modeling of forces in electromagnetic tweezers. AB - This paper discusses numerical simulations of the magnetic field produced by an electromagnet for generation of forces on superparamagnetic microspheres used in manipulation of single molecules or cells. Single molecule force spectroscopy based on magnetic tweezers can be used in applications that require parallel readout of biopolymer stretching or biomolecular binding. The magnetic tweezers exert forces on the surface-immobilized macromolecule by pulling a magnetic bead attached to the free end of the molecule in the direction of the field gradient. In a typical force spectroscopy experiment, the pulling forces can range between subpiconewton to tens of piconewtons. In order to effectively provide such forces, an understanding of the source of the magnetic field is required as the first step in the design of force spectroscopy systems. In this study, we use a numerical technique, the method of auxiliary sources, to investigate the influence of electromagnet geometry and material parameters of the magnetic core on the magnetic forces pulling the target beads in the area of interest. The close proximity of the area of interest to the magnet body results in deviations from intuitive relations between magnet size and pulling force, as well as in the force decay with distance. We discuss the benefits and drawbacks of various geometric modifications affecting the magnitude and spatial distribution of forces achievable with an electromagnet. PMID- 21258581 TI - Editor's note--about this supplement. PMID- 21258582 TI - Work-related cerebro-cardiovascular diseases in Korea. AB - Cerebro-cardiovascular disease (CVD) is one of compensable occupational diseases in Korea as in Japan or Taiwan. However, most countries accept only cardiovascular diseases (ischemic heart diseases) as compensable occupational diseases if any, but not cerebrovascular diseases. Korea has a prescribed list of compensable occupational diseases. CVD was not included in the list until 1993. In the early 1990s, a case of cerebral infarction was accepted as occupational disease by the Supreme Court. The decision was based on the concept that workers' compensation system is one of the social security systems. In 1994, the government has established a diagnostic criterion of CVD. The crude rate of compensated cerebrovascular disease decreased by 60.0% from 18.5 in 2003 to 7.4 in 2008 per 100,000 workers, and that of compensated coronary heart disease decreased by 60.5% from 3.8 in 2003 to 1.5 in 2008 per 100,000 workers. The compensated cases of CVD dramatically increased and reached its peak in 2003. Since many preventive activities were performed by the government and employers, the compensated cases have slowly decreased since 2003 and sharply decreased after 2008 when the diagnostic criterion was amended. The strategic approach is needed essentially because CVDs are common, serious and preventable diseases which lead to economic burden. PMID- 21258583 TI - Disease prevalence and mortality among agricultural workers in Korea. AB - The aim of this paper was to provide an overview of mortality and disease prevalence related to occupational diseases among agricultural workers in Korea. We evaluated the age-standardized mortality rates and the prevalence of chronic diseases and compared them with those of other populations using death registration data from 2004 through 2008 and the 2005 Korean National Health and Nutrition Examination Survey. In addition, we conducted a literature review on published articles examining the health status of farmers in Korea. Agricultural workers have a significantly higher mortality of cancer, tuberculosis, chronic respiratory diseases, liver diseases, suicide, motor and non-motor vehicle accidents. Compared to other populations, farmers have higher prevalence rates of arthritis and intervertebral disc disorders. The literature review revealed a number of work-related diseases among farmers, such as musculoskeletal diseases, pesticide poisoning, infections, and respiratory and neurologic diseases. Korean farmers demonstrate a distinct pattern of mortality and disease prevalence compared to other populations. Although lifestyle factors remain important contributors to those deaths and diseases, our study suggests that occupation is a major determinant as well. Intensive programs such as surveillance systems, therefore, should be developed in order to identify and prevent work-related diseases among agricultural workers in Korea. PMID- 21258584 TI - Management system of occupational diseases in Korea: statistics, report and monitoring system. AB - The management system of occupational diseases in Korea can be assessed from the perspective of a surveillance system. Workers' compensation insurance reports are used to produce official statistics on occupational diseases in Korea. National working conditions surveys are used to monitor the magnitude of work-related symptoms and signs in the labor force. A health examination program was introduced to detect occupational diseases through both selective and mass screening programs. The Working Environment Measurement Institution assesses workers' exposure to hazards in the workplace. Government regulates that the employer should do health examinations and working conditions measurement through contracted private agencies and following the Occupational Safety and Health Act. It is hoped that these institutions may be able to effectively detect and monitor occupational diseases and hazards in the workplace. In view of this, the occupational management system in Korea is well designed, except for the national survey system. In the future, national surveys for detection of hazards and ill health outcomes in workers should be developed. The existing surveillance system for occupational disease can be improved by providing more refined information through statistical analysis of surveillance data. PMID- 21258585 TI - Current status of pneumoconiosis patients in Korea. AB - This study identifies the number of pneumoconiosis patients after eliminating deceased patients between 2003 and 2008 as of January 1st and estimates it for the next five years. From 2003 to 2008, the pneumoconiosis patients were 16,929, 17,224, 17,366, 17,566, 17,542, and 17,546, respectively. The number of pneumoconiosis patients will have increased by 1,014 from 2008 to 18,560 in 2013 after applying the average change rates taken from 2003 to 2007. It takes 15-20 yr to develop coal workers' pneumoconiosis (the main cause in Korea) and patients will continue to be diagnosed with pneumoconiosis for some years to come since it has only been 20 yr since the decline of the coal mining industry in Korea. In addition, pneumoconiosis patients are increasing in industries in which the risk of pneumoconiosis was relatively low shows the necessity to improve dust-exposed workplace environments. PMID- 21258586 TI - Occupational asthma in Korea. AB - Occupational asthma (OA) is the leading occupational respiratory disease. Cases compensated as OA by the Korea Workers' Compensation and Welfare Service (COMWEL) (218 cases), cases reported by a surveillance system (286 cases), case reports by related scientific journals and cases confirmed by the Occupational Safety and Health Research Institute (OSHRI) over 15 yr from 1992 to 2006 were analyzed. Annual mean incidence rate was 1.6 by compensation and 3.5 by surveillance system, respectively. The trend appeared to increase according to the surveillance system. Incidence was very low compared with other countries. The most frequently reported causative agent was isocyanate followed by reactive dye in dyeing factories. Other chemicals, metals and dust were also found as causative agents. OA was underreported according to compensation and surveillance system data. In conclusion, a more effective surveillance system is needed to evaluate OA causes and distribution, and to effectively prevent newly developing OA. PMID- 21258587 TI - Occupational neurological disorders in Korea. AB - The purpose of this article was to provide a literature review of occupational neurological disorders and related research in Korea, focusing on chemical hazards. We reviewed occupational neurological disorders investigated by the Occupational Safety and Health Research Institute of Korean Occupational Safety and Health Agency between 1992 and 2009, categorizing them as neurological disorders of the central nervous system (CNS), of the peripheral nervous system (PNS) or as neurodegenerative disorders. We also examined peer-reviewed journal articles related to neurotoxicology, published from 1984 to 2009. Outbreaks of occupational neurological disorder of the CNS due to inorganic mercury and carbon disulfide poisoning had helped prompt the development of the occupational safety and health system of Korea. Other major neurological disorders of the CNS included methyl bromide intoxication and chronic toxic encephalopathy. Most of the PNS disorders were n-hexane-induced peripheral neuritis, reported from the electronics industry. Reports of manganese-induced Parkinsonism resulted in the introduction of neuroimaging techniques to occupational medicine. Since the late 1990s, the direction of research has been moving toward degenerative disorder and early effect of neurotoxicity. To understand the early effects of neurotoxic chemicals in the preclinical stage, more follow-up studies of a longer duration are necessary. PMID- 21258588 TI - Occupational hepatic disorders in Korea. AB - Occupational hepatic disorders are classified into toxic hepatitis, viral hepatitis, and chemical-induced malignancy in Korea. Toxic hepatitis cases were reported in workers who were exposed to dimethylformamide, dimethylacetamide, or trichloroethylene. Pre-placement medical examination and regular follow-up are necessary to prevent the development of toxic hepatitis. Viral hepatitis was chiefly reported among health care workers such as doctors, nurses and clinical pathology technicians who could easily be exposed to blood. Preventive measures for these groups therefore include vaccination and serum monitoring programs. Hepatic angiosarcoma caused by vinyl chloride monomer (VCM) exposure is a very well known occupational disease and it has not been officially reported in Korea yet. Some cases of hepatocellular carcinoma were legally approved for compensation as an occupational disease largely by overwork and stress, but not supported by enough scientific evidence. Effort to find the evidence of its causal relationship is needed. PMID- 21258589 TI - Occupational diseases in Korea. AB - Korea has industrialized since the 1970s. Pneumoconiosis in coal miners was the most common occupational disease in the 1970s to 1980s. With the industrialization, the use of many chemicals have increased since the 1970s. As a consequence, there were outbreaks of occupational diseases caused by poisonous chemicals, such as heavy metal poisoning, solvent poisoning and occupational asthma in the late 1980s and early 1990s with civil movement for democracy. Many actions have been taken for prevention by the government, employers and employees or unions. In the 1990s most chemical related diseases and pneumoconiosis have rapidly decreased due to improving work environment. In the late 1990s, cerebro cardiovascular diseases related to job stress or work overloads have abruptly increased especially after the economic crisis in 1998. After the year 2000, musculoskeletal disorders became a major problem especially in assembly lines in the manufacturing industry and they were expanded to the service industry. Mental diseases related to job stress have increased. Infectious diseases increased in health care workers and afforestation workers. Occupational cancers are increasing because of their long latency, although the use of carcinogenic substances are reduced, limited, and even banned. PMID- 21258590 TI - Occupational reproductive function abnormalities and bladder cancer in Korea. AB - The purpose of this study was to review occupational reproductive abnormalities and occupational bladder cancer in Korea and to discuss their toxicological implications. Reproductive dysfunction as a result of 2-bromopropane poisoning was first reported in Korean workers. In 1995, 23 of the 33 workers (25 female and 8 male workers) who were exposed to 2-bromopropane during the assembly of tactile switch parts developed reproductive and/or hematopoietic disorders. A total of 17 (68%) workers were diagnosed with ovarian failure. Two of the eight male workers experienced azoospermia and four workers experienced some degree of oligospermia or reduced sperm motility. In summary, 2-bromopropane poisoning caused severe reproductive effects in Korean workers. The prognosis was poor for reproductive dysfunction. A few cases of occupational bladder cancer have been reported in Korea, whereas other cancers of the urinary tract have not been reported after occupational exposure. A few cases of benzidine-induced cancer have been reported in Korea and 592 workers in Japan have received compensation for benzidine and beta-naphthylamine-induced cancer. In conclusion, a few cases of benzidine-induced occupational bladder cancer have been reported in Korea. However, benzidine-induced bladder cancer will likely be an important occupational health issue in Korea in the coming years. PMID- 21258591 TI - Occupational skin diseases in Korea. AB - Skin disease is the most common occupational disease, but the reported number is small in Korea due to a difficulty of detection and diagnosis in time. We described various official statistics and data from occupational skin disease surveillance system, epidemiological surveys and cases published in scientific journals. Until 1981, 2,222 cases of occupational skin disease were reported by Korean employee's regular medical check-up, accounting for 4.9% of the total occupational diseases. There was no subsequent official statistics to figure out occupational skin diseases till 1998. From 1999, the Korea Occupational Safety and Health Agency (KOSHA) published the number of occupational skin diseases through the statistics of Cause Investigation for Industrial Accidents. A total of 301 cases were reported from 1999 to 2007. Recent one study showed the figures of compensated occupational skin diseases. Many of them belonged to daily-paid workers in the public service, especially forestry workers. Also, it described the interesting cases such as vitiligo and trichloroethylene-induced Stevens Johnson Syndrome. Skin diseases are still important though the number of cases has decreased, and therefore it is recommended to grasp the status of occupational skin diseases through continuous surveillance system and to make policy protecting high-risk group. PMID- 21258592 TI - Occupational infection in Korea. AB - Occupational infection is a human disease caused by work-associated exposure to microbial agents through human and environmental contact. According to the literature, occupational infection was the third leading cause of occupational disease (861 cases, 8.0%), and health care, agricultural, forestry, and fishery workers were risk groups in Korea. In addition, most high-risk groups have not been protected by workers' compensation, which could lead to underestimation of the exact spectrum and magnitude of the problem, and may also result in a lack of development and implementation of occupational infection management. Through a review of national guidelines and documentations on prevention and control of occupational infection, a management strategy would promote adherence to worker safety regulations if it is explicit with regard to the agent and mode of infection in each of the high-risk groups. PMID- 21258593 TI - Occupational hearing loss in Korea. AB - In this article, current status of noise exposure in workplaces, trend of workers with noise-induced hearing loss (NIHL), and prevalence of NIHL in workers by industry and job category in Korea were reviewed. In addition, trends of research on the audiological effects such as hearing loss from noise and occupational hearing loss from non-noise in Korea were addressed through reports in industrial audiology. Though noise exposure level has improved, noise still shows the highest rate of cases exceeding exposure limit among workplace hazards. NIHL is the most common occupational disease except work-related disease such as musculoskeletal disorders and cerebrovascular diseases, and NIHL prevalence is thought to be much higher than reported in official publications. Noise affecting hearing comes from various sources such as workplaces, military settings, areas with exposure to high noise, and specific noise sources. There is also occupational hearing loss by non-noise including chemicals such as organic solvents and heavy metals, barotrauma, and trauma due to welding spark. Noise affects daily life through audiological effects such as hearing loss and tinnitus, non-audiological physical effects (e.g., cardiovascular), and psychosocial and behavioral effects. Development of systematic and comprehensive hearing conservation programs for lowering the noise level in workplaces and preventing the NIHL, and preparation of technological, administrative system for its settlement at workplace are urgently needed. PMID- 21258594 TI - Ionizing radiation-induced diseases in Korea. AB - Radiation risk has become well known through epidemiological studies of clinically or occupationally exposed populations, animal experiments, and in vitro studies; however, the study of radiation related or induced disease has been limited in Korea. This study is to find the level of occupational radiation exposure for various kinds of accidents, compensated occupational diseases, related studies, and estimations on future occupational disease risks. Research data of related institutions were additionally investigated. About 67% of 62,553 radiation workers had no exposure or less than 1.2 mSv per year. The 5 reported cases on radiation accident patients in Korea occurred during nondestructive testing. According to the recent rapid increase in the number of workers exposed to radiation, a higher social recognition of cancer, and an increasing cancer mortality rate, it is expected that occupational disease compensation will rapidly increase as well. Therefore, it is important to develop scientific and objective decision methods, such as probability of causation and screening dose in the establishment of an exposure and health surveillance system. PMID- 21258595 TI - Characteristics of work-related musculoskeletal disorders in Korea and their work relatedness evaluation. AB - Work-related musculoskeletal disorders (WMSDs) can be compensated through the Industrial Accident Compensation Insurance Act. We looked at the characteristics of WMSDs in worker's compensation records and the epidemiological investigation reports from the Occupational Safety and Health Research Institute (OSHRI). Based on the records of compensation, the number of cases for WMSDs decreased from 4,532 in 2003 to 1,954 in 2007. However the proportion of WMSDs among the total approved occupational diseases increased from 49.6% in 2003 to 76.5% in 2007, and the total cost of WMSDs increased from 105.3 billion won in 2004 to 163.3 billion won in 2007. The approval rate of WMSDs by the OSHRI accounted for 65.6%. Ergonomic and clinical characteristics were associated with the approval rate; however, the degenerative changes had a minimal affect. This result was in discordance between OSHRI and the Korea Workers' Compensation & Welfare Service. We presumed that there were perceptional gaps in work-relatedness interpretation that resulted from the inequality of information in ergonomic analyses. We propose to introduce ergonomic analysis to unapproved WMSDs cases and discuss those results among experts that will be helpful to form a consensus among diverse groups. PMID- 21258596 TI - Occupational psychiatric disorders in Korea. AB - We searched databases and used various online resources to identify and systematically review all articles on occupational psychiatric disorders among Korean workers published in English and Korean before 2009. Three kinds of occupational psychiatric disorders were studied: disorders related to job stress and mental illness, psychiatric symptoms emerging in victims of industrial injuries, and occupational psychiatric disorders compensated by Industrial Accident Compensation Insurance (IACI). Korea does not maintain official statistical records for occupational psychiatric disorders, but several studies have estimated the number of occupational psychiatric disorders using the Korea Workers' Compensation and Welfare Service (COMWEL, formerly KLWC) database. The major compensated occupational psychiatric disorders in Korea were "personality and behavioral disorders due to brain disease, damage, and dysfunction", "other mental disorders due to brain damage and dysfunction and to physical diseases", "reactions to severe stress and adjustment disorders", and "depressive episodes". The most common work-related psychiatric disorders, excluding accidents, were "neurotic, stress-related, and somatoform disorders" followed by "mood disorders". PMID- 21258597 TI - Occupational respiratory cancer in Korea. AB - Malignant mesothelioma and lung cancer are representative examples of occupational cancer. Lung cancer is the leading cause of cancer death, and the incidence of malignant mesothelioma is expected to increase sharply in the near future. Although information about lung carcinogen exposure is limited, it is estimated that the number of workers exposed to carcinogens has declined. The first official case of occupational cancer was malignant mesothelioma caused by asbestos exposure in the asbestos textile industry in 1992. Since then, compensation for occupational respiratory cancer has increased. The majority of compensated lung cancer was due to underlying pneumoconiosis. Other main causative agents of occupational lung cancer included asbestos, hexavalent chromium, and crystalline silica. Related jobs included welders, foundry workers, platers, plumbers, and vehicle maintenance workers. Compensated malignant mesotheliomas were associated with asbestos exposure. Epidemiologic studies conducted in Korea have indicated an elevated risk of lung cancer in pneumoconiosis patients, foundry workers, and asbestos textile workers. Occupational respiratory cancer has increased during the last 10 to 20 yr though carcinogen-exposed population has declined in the same period. More efforts to advance the systems for the investigation, prevention and management of occupational respiratory cancer are needed. PMID- 21258598 TI - Occupational lymphohematopoietic cancer in Korea. AB - The purpose of this study was to review the existing studies on lymphohematopoietic (LHP) cancer in Korea, estimate the prevalence of workers exposed to carcinogens, and determine the population attributable fraction (PAF) of leukemia. Two case series and 4 case reports were reviewed. Using official statistics, the prevalence of benzene exposure and ionizing radiation exposure was estimated. Based on the prevalence of exposure and the relative risk, The PAF of leukemia was calculated. Between 1996 and 2005, 51 cases of LHP cancer were reported from the compensation system. Greater than 50% of occupational LHP cancer was leukemia, and the most important cause was benzene. In a cohort study, the standardized incidence ratio was 2.71 (95% CI, 0.56-7.91). The prevalence of exposure was 2.5% and 2.2% in 1995 and 2000, respectively. Using the 1995 prevalence, 3.6-4.8% and 0.1% of cases with leukemia were attributable to benzene and ionizing radiation exposure, respectively, which resulted in 39.7-51.4 cases per year. Benzene is the most important cause of occupational leukemia in Korea. Considering the estimated PAF in this study, the annual number of occupational LHP cancer (51 cases during 10-yr period), might be underreported within the compensation system. PMID- 21258599 TI - Endoscopic diagnosis of pancreaticobiliary maljunction. AB - Pancreaticobiliary maljunction (PBM) is a congenital anomaly defined as a junction of the pancreatic and bile ducts located outside the duodenal wall, usually forming a markedly long common channel. As the action of the sphincter of Oddi does not functionally affect the junction in PBM patients, continuous pancreatobiliary reflux occurs, resulting in a high incidence of biliary cancer. PBM can be divided into PBM with biliary dilatation (congenital choledochal cyst) and PBM without biliary dilatation (maximal diameter of the bile duct <= 10 mm). The treatment of choice for PBM is prophylactic surgery before malignant changes can take place. Endoscopic retrograde cholangiopancreatography (ERCP) is the most effective examination method for close observation of the pattern of the junction site. When the communication between the pancreatic and bile ducts is maintained, despite contraction of the sphincter on ERCP, PBM is diagnosed. In these patients, levels of pancreatic enzymes in the bile are generally elevated, due to continuous pancreatobiliary reflux via a long common channel. Magnetic resonance cholangiopancreatography and 3D-computed tomography can diagnose PBM, based on findings of an anomalous union between the common bile duct and the pancreatic duct, in addition to a long common channel. Endoscopic ultrasonography and intraductal ultrasonography can demonstrate the junction outside the duodenal wall, and are useful for the diagnosis of associated biliary cancer. Gallbladder wall thickness on ultrasonography can be a screening test for PBM. PMID- 21258600 TI - Mini-laparoscopy in the endoscopy unit: Safety and outcomes in over one thousand patients. AB - AIM: To investigate the safety of consecutive mini-laparoscopy guided liver biopsies for the diagnosis and staging of liver diseases. METHODS: In this study we retrospectively analyzed the safety of mini-laparoscopic liver biopsy performed in an endoscopy unit in 1071 patients. We measured the incidence of bleeding and evaluated the management and outcome of bleeding interventions. RESULTS: The most common etiologies of liver injury were viral hepatitis and autoimmune liver disease. 250 patients had macroscopically and histologically proven cirrhosis. 13 patients had no pathological findings. 33% of all patients had bleeding that required argon plasma coagulation of the puncture site during laparoscopy. Significant bleeding occurred more often in patients with liver cirrhosis compared to non-cirrhotic liver diseases but was effectively treated with laparoscopic coagulation. CONCLUSION: In conclusion, mini-laparoscopy liver biopsy can be performed safely and effectively in high risk patients with advanced liver disease; mini-laparoscopy with liver biopsy can be done safely in an endoscopy unit. PMID- 21258601 TI - Ultraslim endoscopy with flexible spectral imaging color enhancement for upper gastrointestinal neoplasms. AB - AIM: To conduct a preliminary study on the effect of flexible spectral imaging color enhancement (FICE) used in combination with ultraslim endoscopy by focusing on the enhanced contrast between tumor and non-tumor lesions. METHODS: We examined 50 lesions of 40 patients with epithelial tumors of the upper gastrointestinal tract before endoscopic submucosal dissection using ultraslim endoscopy with conventional natural color imaging and with FICE imaging. We retrospectively investigated the effect of the use of FICE on endoscopic diagnosis in comparison with normal light. RESULTS: Visibility of the epithelial tumors of the upper gastrointestinal tract with FICE was superior to normal light in 54% of the observations and comparable to normal light in 46% of the observations. There was no lesion for which visibility with FICE was inferior to that with normal light. FICE visualized 69.6% of hyperemic lesions and 58.8% of discolored lesions better than conventional endoscopy with natural color imaging. FICE significantly improved the visibility of lesions with hyperemia or discoloration compared with normocolored lesions. CONCLUSION: This study suggests that the use of FICE would improve the ability of ultraslim endoscopy to detect epithelial tumors of the upper gastrointestinal tract. PMID- 21258602 TI - Duodenal tuberculosis presenting as gastric outlet obstruction: A case report. AB - Gastric outlet obstruction is commonly associated with malignancies and peptic ulcer disease. However, when no malignancy is seen and the patient is non responsive to conventional peptic ulcer treatment, other etiologies need to be explored. We report a case of gastric outlet obstruction due to duodenal tuberculosis. The patient is a 31 year old male who presented with 1 year history of recurrent epigastric pain and an acute episode of vomiting. Endoscopy revealed duodenal stricture. Computed tomography scan showed pyloroantral thickening. The patient was referred to the surgery service and underwent an exploratory laparotomy and gastrojejunostomy. A duodenal mass and calcified lymph nodes were noted on exploration and biopsy revealed a tuberculous origin. The patient was started on anti-tuberculosis medications and had improved on discharge. Gastroduodenal tuberculosis is rare and pyloric stenosis resulting from tuberculosis is even rarer. This, however, should be considered in patients who come from areas where the disease is endemic. PMID- 21258603 TI - Endoscopic retrieval of a gastric trichobezoar. AB - A 9-year-old girl presented with a chief complaint of abdominal pain. Esophagogastroduodenal endoscopy (EGD) identified a long and large gastric trichobezoar extending into the duodenum. We attempted endoscopic retrieval after informed consent was obtained from the patient's mother. Initially, a gasper with 5-prolongs, commonly used for retrieval of endoscopically excised polyps, failed to remove the whole trichobezoar. When a net was used instead, it proved impossible to remove the trichobezoar completely. Therefore, we withdrew the scope from the mouth, leaving the net grasping the tricobezoar firmly in the stomach. Subsequently, we were able to retrieve about 70% of the trichobezoar manually by grasping the snare part of the net directly. A second pass found no deep laceration or perforation endoscopically. The remaining trichobezoar was completely retrieved with the net. The procedure was completed within 15 min. The retrieved specimens were 34 cm in length and 100 g in weight. The patient was discharged uneventfully 5 d thereafter. She was advised to visit a psychiatrist to avoid suffering from a relapse. Follow-up EGD showed no trichobezoar, and the patient's frontal hair grew back. PMID- 21258604 TI - New Dendrimers: Synthesis and Characterization of Popam - Pamam Hybrid Dendrimers. AB - Recently developed multifunctional cancer therapeutic nano-device production is based on poly(amidoamine) PAMAM generation 5 (G5) dendrimer as a carrier 1-5. Scale up synthesis of this nano-device is limited because of long reaction sequence (12 reaction steps) and long and not easy work up of the products after each reaction step. Combination of poly(propyle-imine) and poly(amidoamine) synthesis can improve the production of the drug carrier.In this paper we give a general overview of the synthesis and characterization of a series of novel hybrid dendrimers which we coined as novel POMAM hybrid dendrimers, constructed from poly(propylene-imine) (PPI or POPAM) core and poly(amidoamine) PAMAM shells. The synthesis was accomplished by a divergent reiterating method involving repeating subsequent Michael addition and amidation reactions. Each generation of the newly synthesized dendrimer was characterized by using HPLC, GPC, NMR and AFM. PMID- 21258605 TI - Biomedical applications of thermally activated shape memory polymers. AB - Shape memory polymers (SMPs) are smart materials that can remember a primary shape and can return to this primary shape from a deformed secondary shape when given an appropriate stimulus. This property allows them to be delivered in a compact form via minimally invasive surgeries in humans, and deployed to achieve complex final shapes. Here we review the various biomedical applications of SMPs and the challenges they face with respect to actuation and biocompatibility. While shape memory behavior has been demonstrated with heat, light and chemical environment, here we focus our discussion on thermally stimulated SMPs. PMID- 21258606 TI - The prediction of Fe Mossbauer parameters by the density functional theory: a benchmark study. AB - We report the performance of eight density functionals (B3LYP, BPW91, OLYP, O3LYP, M06, M06-2X, PBE, and SVWN5) in two Gaussian basis sets (Wachters and Partridge-1 on iron atoms; cc-pVDZ on the rest of atoms) for the prediction of the isomer shift (IS) and the quadrupole splitting (QS) parameters of Mossbauer spectroscopy. Two sources of geometry (density functional theory-optimized and X ray) are used. Our data set consists of 31 iron-containing compounds (35 signals), the Mossbauer spectra of which were determined at liquid helium temperature and where the X-ray geometries are known. Our results indicate that the larger and uncontracted Partridge-1 basis set produces slightly more accurate linear correlations of electronic density used for the prediction of IS and noticeably more accurate results for the QS parameter. We confirm and discuss the earlier observation of Noodleman and co-workers that different oxidation states of iron produce different IS calibration lines. The B3LYP and O3LYP functionals have the lowest errors for either IS or QS. BPW91, OLYP, PBE, and M06 have a mixed success whereas SVWN5 and M06-2X demonstrate the worst performance. Finally, our calibrations and conclusions regarding the best functional to compute the Mossbauer characteristics are applied to candidate structures for the peroxo and Q intermediates of the enzyme methane monooxygenase hydroxylase (MMOH), and compared to experimental data in the literature. PMID- 21258607 TI - Optical Properties of Single-Walled Carbon Nanotubes Separated in a Density Gradient; Length, Bundling, and Aromatic Stacking Effects. AB - Single-walled carbon nanotubes (SWNTs) are promising materials for in vitro and in vivo biological applications due to their high surface area and inherent near infrared photoluminescence and Raman scattering properties. Here, we use density gradient centrifugation to separate SWNTs by length and degree of bundling. Following separation, we observe a peak in photoluminescence quantum yield (PL QY) and Raman scattering intensity where SWNT length is maximized and bundling is minimized. Individualized SWNTs are found to exhibit high PL QY and high resonance-enhanced Raman scattering intensity. Fractions containing long, individual SWNTs exhibit the highest PL QY and Raman scattering intensities, compared to fractions containing single, short SWNTs or SWNT bundles. Intensity gains of approximately ~1.7 and 4-fold, respectively, are obtained compared with the starting material. Spectroscopic analysis reveals that SWNT fractions at higher displacement contain increasing proportions of SWNT bundles, which causes reduced optical transition energies and broadening of absorption features in the UV-Vis-NIR spectra, and reduced PL QY and Raman scattering intensity. Finally, we adsorb small aromatic species on "bright," individualized SWNT sidewalls and compare the resulting absorption, PL and Raman scattering effects to that of SWNT bundles. We observe similar effects in both cases, suggesting aromatic stacking affects the optical properties of SWNTs in an analogous way to SWNT bundles, likely due to electronic structure perturbations, charge transfer, and dielectric screening effects, resulting in reduction of the excitonic optical transition energies and exciton lifetimes. PMID- 21258608 TI - Providers' views concerning family planning service delivery to HIV-positive women in Mozambique. AB - This study explores challenges and obstacles in providing effective family planning services to HIV-positive women as described by staff of maternal and child health (MCH) clinics. It draws upon data from a survey of service providers carried out from late 2008 to early 2009 in 52 MCH clinics in southern Mozambique, some with and some without HIV services. In all clinics, surveyed providers reported that practical, financial, and social barriers made it difficult for HIV-positive clients to follow protocols to prevent mother-to-child transmission of the virus. Likewise, staff were skeptical of their seropositive clients' ability to adhere to recommendations to cease childbearing and to use condoms consistently. Providers' recommendations to HIV-positive clients and their assessment of barriers to adherence did not depend on availability of HIV services. Although integration of HIV and reproductive health services is advancing in Mozambique, service providers do not feel that they can influence the behaviors of HIV-positive women effectively. PMID- 21258609 TI - Automatically-Activated Attitudes as Mechanisms for Message Effects: The Case of Alcohol Advertisements. AB - Alcohol advertisements may influence impulsive, risky behaviors indirectly, via automatically-activated attitudes toward alcohol. Results from an experiment in which participants were exposed to either four alcohol advertisements, four control advertisements, or four drunk driving public service advertisements, suggested that alcohol advertisements had more measurable effects on implicit, than on explicit attitude measures. Moreover, there were significant indirect paths from alcohol advertisement exposure through automatically-activated alcohol attitudes on willingness to engage in risky alcohol-related behaviors, notably drinking and driving. A mechanism that may explain how these advertisements activate automatic, non-deliberative alcohol attitudes was investigated. Associative evidence was found supportive of an evaluative conditioning mechanism, in which positive responses to an alcohol advertisement may lead to more positive automatically-activated attitudes toward alcohol itself. PMID- 21258610 TI - Semiparametric regression models and sensitivity analysis of longitudinal data with nonrandom dropouts. AB - We propose a family of regression models to adjust for nonrandom dropouts in the analysis of longitudinal outcomes with fully observed covariates. The approach conceptually focuses on generalized linear models with random effects. A novel formulation of a shared random effects model is presented and shown to provide a dropout selection parameter with a meaningful interpretation. The proposed semiparametric and parametric models are made part of a sensitivity analysis to delineate the range of inferences consistent with observed data. Concerns about model identifiability are addressed by fixing some model parameters to construct functional estimators that are used as the basis of a global sensitivity test for parameter contrasts. Our simulation studies demonstrate a large reduction of bias for the semiparametric model relatively to the parametric model at times where the dropout rate is high or the dropout model is misspecified. The methodology's practical utility is illustrated in a data analysis. PMID- 21258614 TI - DESIGN AND PRELIMINARY VALIDATION OF A RAPID AUTOMATED BIODOSIMETRY TOOL FOR HIGH THROUGPUT RADIOLOGICAL TRIAGE. AB - This paper presents design, hardware, software, and parameter optimization for a novel robotic automation system. RABiT is a Rapid Automated Biodosimetry Tool for high throughput radiological triage. The design considerations guiding the hardware and software architecture are presented with focus on methods of communication, ease of implementation, and need for real-time control versus soft time control cycles. The design and parameter determination for a non-contact PVC capillary laser cutting system is presented. A novel approach for lymphocyte concentration estimation based on computer vision is reported. Experimental evaluations of the system components validate the success of our prototype system in achieving a throughput of 6,000 samples in a period of 18 hours. PMID- 21258612 TI - Reading, writing, and phonological processing skills of adolescents with 10 or more years of cochlear implant experience. AB - OBJECTIVES: This study had three goals: (1) to document the literacy skills of deaf adolescents who received cochlear implants (CIs) as preschoolers; (2) to examine reading growth from elementary grades to high school; (3) to assess the contribution of early literacy levels and phonological processing skills, among other factors, to literacy levels in high school. DESIGN: A battery of reading, spelling, expository writing, and phonological processing assessments were administered to 112 high school (CI-HS) students, ages 15.5 to 18.5 yrs, who had participated in a reading assessment battery in early elementary grades (CI-E), ages 8.0 to 9.9 yrs. The CI-HS students' performance was compared with either a control group of hearing peers (N = 46) or hearing norms provided by the assessment developer. RESULTS: Many of the CI-HS students (47 to 66%) performed within or above the average range for hearing peers on reading tests. When compared with their CI-E performance, good early readers were also good readers in high school. Importantly, the majority of CI-HS students maintained their reading levels over time compared with hearing peers, indicating that the gap in performance was, at the very least, not widening for most students. Written expression and phonological processing tasks posed a great deal of difficulty for the CI-HS students. They were poorer spellers, poorer expository writers, and displayed poorer phonological knowledge than hearing age-mates. Phonological processing skills were a critical predictor of high school literacy skills (reading, spelling, and expository writing), accounting for 39% of variance remaining after controlling for child, family, and implant characteristics. CONCLUSIONS: Many children who receive CIs as preschoolers achieve age appropriate literacy levels as adolescents. However, significant delays in spelling and written expression are evident compared with hearing peers. For children with CIs, the development of phonological processing skills is not just important for early reading skills, such as decoding, but is critical for later literacy success as well. PMID- 21258613 TI - Disposition of cannabichromene, cannabidiol, and Delta9-tetrahydrocannabinol and its metabolites in mouse brain following marijuana inhalation determined by high performance liquid chromatography-tandem mass spectrometry. AB - A liquid chromatography-tandem mass spectrometry (LC-MS-MS)method was developed for the analysis of marijuana cannabinoids in mouse brain tissue using an Applied Biosystems 3200 Q trap with a turbo V source for TurbolonSpray attached to a Shimadzu SCL HPLC system. The method included cannabichromene (CBC),cannabidiol (CBD), Delta9-tetrahydrocannabinol (THC), 11-hydroxytetrahydrocannabinol (11-OH THC), and 11-nor-Delta9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH). These compounds were isolated by liquid-liquid extraction using cold acetonitrile. The following transition ions were monitored by multiple reaction monitoring (MRM): m/z 315>193, 315>259 for THC/CBD/CBC; m/z 331>193, 331>105 for 11-OH-THC; m/z 345>299, 345>193 for THC-COOH; m/z 318>196 for THC-d3; m/z 334>196 for 11-OH-THC d3, and m/z 348>302 for THC-COOH-d3. Linearity for THC, 1-OH-THC, and THC-COOH was 1-200 ng/g; for CBC and CBD, it was 0.5-20 ng/g. Within-run and between-run precisions for all the analytes yielded coefficients of variation of < 20%. Four C57BL6 mice were sacrificed 20 min after nose-only exposure to the smoke of 200 mg of marijuana containing 0.44 mg CBC, 0.93 mg CBD, and 8.81 mg THC. The mean brain concentrations were 3.9 +/- 1.5 ng/g CBC, 21 +/- 3.9 ng/g CBD, 364 +/- 74 ng/g THC, and 28 +/- 5.9 ng/g 11-OH-THC. THC-COOH was not detected. The relative mean brain cannabinoid concentrations correlated to the amounts of the cannabinoids in the inhaled marijuana. PMID- 21258615 TI - Nonparametric Inference of Doubly Stochastic Poisson Process Data via the Kernel Method. AB - Doubly stochastic Poisson processes, also known as the Cox processes, frequently occur in various scientific fields. In this article, motivated primarily by analyzing Cox process data in biophysics, we propose a nonparametric kernel-based inference method. We conduct a detailed study, including an asymptotic analysis, of the proposed method, and provide guidelines for its practical use, introducing a fast and stable regression method for bandwidth selection. We apply our method to real photon arrival data from recent single-molecule biophysical experiments, investigating proteins' conformational dynamics. Our result shows that conformational fluctuation is widely present in protein systems, and that the fluctuation covers a broad range of time scales, highlighting the dynamic and complex nature of proteins' structure. PMID- 21258611 TI - Pharmaceutical intervention for myopia control. AB - Myopia is the result of a mismatch between the optical power and the length of the eye, with the latter being too long. Driving the research in this field is the need to develop myopia treatments that can limit axial elongation. When axial elongation is excessive, as in high myopia, there is an increased risk of visual impairment and blindness due to ensuing pathologies such as retinal detachments. This article covers both clinical studies involving myopic children, and studies involving animal models for myopia. Atropine, a nonselective muscarinic antagonist, has been studied most extensively in both contexts. Because it remains the only drug used in a clinical setting, it is a major focus of the first part of this article, which also covers the many shortcomings of topical ophthalmic atropine. The second part of this article focuses on in vitro and animal-based drug studies, which encompass a range of drug targets including the retina, retinal pigment epithelium and sclera. While the latter studies have contributed to a better understanding of how eye growth is regulated, no new antimyopia drug treatments have reached the clinical setting. Less conservative approaches in research, and in particular, the exploration of new bioengineering approaches for drug delivery, are needed to advance this field. PMID- 21258616 TI - Cellular and Synaptic Localization of EAAT2a in Human Cerebral Cortex. AB - We used light and electron microscopic immunocytochemical techniques to analyze the distribution, cellular and synaptic localization of EAAT2, the main glutamate transporter, in normal human neocortex. EAAT2a-immunoreactivity (ir) was in all layers and consisted of small neuropilar puncta and rare cells. In white matter EAAT2a+ cells were numerous. Electron microscopic studies showed that in gray matter ~77% of immunoreactive elements were astrocytic processes, ~14% axon terminals, ~2.8% dendrites, whereas ~5% were unidentifiable. In white matter, ~81% were astrocytic processes, ~17% were myelinated axons, and ~2.0% were unidentified. EAAT2a-ir was never in microglial cells and oligodendrocytes. Pre embedding electron microscopy showed that ~67% of EAAT2a expressed at (or in the vicinity of) asymmetric synapses was in astrocytes, ~17% in axon terminals, while ~13% was both in astrocytes and in axons. Post-embedding electron microscopy studies showed that in astrocytic processes contacting asymmetric synapses and in axon terminals, gold particle density was ~25.1 and ~2.8 particles/MUm(2), respectively, and was concentrated in a membrane region extending for ~300 nm from the active zone edge. Besides representing the first detailed description of EAAT2a in human cerebral cortex, these findings may contribute to understanding its role in the pathophysiology of neuropsychiatric diseases. PMID- 21258617 TI - Altered auditory and multisensory temporal processing in autism spectrum disorders. AB - Autism spectrum disorders (ASD) are characterized by deficits in social reciprocity and communication, as well as by repetitive behaviors and restricted interests. Unusual responses to sensory input and disruptions in the processing of both unisensory and multisensory stimuli also have been reported frequently. However, the specific aspects of sensory processing that are disrupted in ASD have yet to be fully elucidated. Recent published work has shown that children with ASD can integrate low-level audiovisual stimuli, but do so over an extended range of time when compared with typically developing (TD) children. However, the possible contributions of altered unisensory temporal processes to the demonstrated changes in multisensory function are yet unknown. In the current study, unisensory temporal acuity was measured by determining individual thresholds on visual and auditory temporal order judgment (TOJ) tasks, and multisensory temporal function was assessed through a cross-modal version of the TOJ task. Whereas no differences in thresholds for the visual TOJ task were seen between children with ASD and TD, thresholds were higher in ASD on the auditory TOJ task, providing preliminary evidence for impairment in auditory temporal processing. On the multisensory TOJ task, children with ASD showed performance improvements over a wider range of temporal intervals than TD children, reinforcing prior work showing an extended temporal window of multisensory integration in ASD. These findings contribute to a better understanding of basic sensory processing differences, which may be critical for understanding more complex social and cognitive deficits in ASD, and ultimately may contribute to more effective diagnostic and interventional strategies. PMID- 21258618 TI - Type 7 Adenylyl Cyclase is Involved in the Ethanol and CRF Sensitivity of GABAergic Synapses in Mouse Central Amygdala. AB - The GABAergic system in the central amygdala (CeA) plays a major role in ethanol dependence and in the anxiogenic response to ethanol withdrawal. Previously, we found that both ethanol and corticotropin releasing factor (CRF) increase GABAergic transmission in mouse and rat CeA neurons, in part by enhancing the release of GABA via activation of presynaptic CRF1 receptors. CRF1 receptors are coupled to the enzyme adenylyl cyclase (AC), which produces the second messenger cyclic AMP. There are nine isoforms of AC, but we recently found that CRF1 receptors in the pituitary were coupled to the Type 7 AC (AC7). Therefore, using an in vitro electrophysiological approach in brain slices, here we have investigated a possible role of the AC7 signaling pathway in ethanol and CRF effects on CeA GABAergic synapses of genetically modified mice with diminished brain Adcy7 activity (HET) compared to their littermate male wild-type (WT) mice. We found no significant differences in basal membrane properties, mean baseline amplitude of evoked GABA(A) receptor-mediated inhibitory postsynaptic potentials (IPSPs), or paired-pulse facilitation (PPF) of GABA(A)-IPSPs between HET and WT mice. In CeA neurons of WT mice, ethanol superfusion significantly augmented (by 39%) GABAA-IPSPs and decreased PPF (by 25%), suggesting increased presynaptic GABA release. However, these effects were absent in HET mice. CRF superfusion also significantly augmented IPSPs (by 38%) and decreased PPF (by 23%) in WT CeA neurons, and still elicited a significant but smaller (by 13%) increase of IPSP amplitude, but no effect on PPF, in HET mice. These electrophysiological data suggest that AC7 plays an important role in ethanol and CRF modulation of presynaptic GABA release in CeA and thus may underlie ethanol-related behaviors such as anxiety and dependence. PMID- 21258619 TI - Functional roles of distributed synaptic clusters in the mitral-granule cell network of the olfactory bulb. AB - Odors are encoded in spatio-temporal patterns within the olfactory bulb, but the mechanisms of odor recognition and discrimination are poorly understood. It is reasonable to postulate that the olfactory code is sculpted by lateral and feedforward inhibition mediated by granule cells onto the mitral cells. Recent viral tracing and physiological studies revealed patterns of distributed granule cell synaptic clusters that provided additional clues to the possible mechanisms at the network level. The emerging properties and functional roles of these patterns, however, are unknown. Here, using a realistic model of 5 mitral and 100 granule cells we show how their synaptic network can dynamically self-organize and interact through an activity-dependent dendrodendritic mechanism. The results suggest that the patterns of distributed mitral-granule cell connectivity may represent the most recent history of odor inputs, and may contribute to the basic processes underlying mixture perception and odor qualities. The model predicts how and why the dynamical interactions between the active mitral cells through the granule cell synaptic clusters can account for a variety of puzzling behavioral results on odor mixtures and on the emergence of synthetic or analytic perception. PMID- 21258620 TI - Calcium messenger heterogeneity: a possible signal for spike timing-dependent plasticity. AB - Calcium concentrations as well as time courses have been used to model the signaling cascades leading to changes in the strength of synaptic connections. Previous models consider the dendritic spines as uniform compartments regarding calcium signaling. However, calcium concentrations can vary drastically on distances much smaller than typical spine sizes, and downstream targets of calcium signals are often found exactly in these calcium nanodomains. Even though most downstream targets are activated by calcium via calmodulin, which is a diffusive molecule, the capacity of calmodulin to bind to its targets even when it is not fully loaded with calcium allows its downstream cascade to be highly local. In this study, a model is proposed which uses the heterogeneity of calcium concentrations as a signal for spike-timing-dependent plasticity (STDP). The model is minimalistic and includes three sources of calcium in spines: NMDA receptors (NMDARs), voltage gated calcium channels (VGCCs) and IP3 receptors (IP3Rs). It is based on the biochemical cascades and assumption of spatial locations of four calcium-dependent enzymes: calcium/calmodulin-dependent protein kinase II located near NMDARs, calcineurin located near VGCCs, cyclic nucleotide phosphodiesterase (PDE) located near IP3Rs or NMDARs and adenylyl cyclase, located between VDCCs and NMDARs. To quantify the changes in synaptic weights the model also includes a simple description of AMPA receptor insertion in the membrane and docking to the postsynaptic density. Two parameters of the model are tuned such that weight changes produced by either pre or postsynaptic firing alone are minimal. The model reproduces the typical shape of STDP for spike doublets. If PDE is located near IP3Rs, the behavior for spike triplets is consistent with that observed in hippocampal cell culture; if near NMDAR, the behavior is similar to that observed in cortical L2/3 slices. PMID- 21258622 TI - Mycosporine-like amino acids in planktonic organisms living under different UV exposure conditions in Patagonian lakes. AB - Mycosporine-like amino acids (MAAs) were studied in zooplankton from 13 Argentinian lakes covering a broad range in altitude, maximum depth and physico chemical properties of the water. Four to nine different MAAs (predominantly porphyra-334 and shinorine) were found in the copepods Boeckella gibbosa, B. gracilipes, B. meteoris and Parabroteas sarsi, and in the ciliate Stentor amethystinus, while MAAs were undetectable in the cladoceran Daphnia middendorffiana. Among the different copepods, maximum MAA concentrations accounted for 0.25-1.31% of the dry weight, and contents were generally about three to seven times (up to 43 times) higher in the animals living in the clearest lakes compared to those occurring in low-UV systems. This variability in the content of MAAs was related to the lake altitude (r(2) = 0.71), and the fraction of the water column to which 1% of the surface UV radiation at 320 nm penetrated (r(2) = 0.57). Our data therefore underscore the role of MAAs as sunscreens to decrease the potential negative effects of solar radiation, but they also indicate that other environmental factors besides UV transparency play a role in determining MAA concentrations. One lake was selected to obtain additional information on the qualitative composition of MAAs in seston of <100 MUm between two sampling sites and over a 2 month study period (austral summer). Six different MAAs were detected in the samples, with porphyra-334 and palythine being predominant. In the copepods collected simultaneously, there was low variation in MAA concentrations between the two sites and over time. Thus, our results suggest that under similar UV exposure conditions MAA contents of planktonic organisms show low temporal variation. PMID- 21258623 TI - Sublethal stress: Impact of solar UV radiation on protein synthesis in the copepod Acartia tonsa. AB - Aquatic organisms respond to environmental challenges such as thermal stress with the rapid induction of highly conserved polypeptides known as stress proteins or heat shock proteins (Hsps). Solar ultraviolet radiation (UVR, 280-400 nm) is an important environmental stressor in marine ecosystems. Here, we present results of experiments conducted with the marine copepod Acartia tonsa to follow the de novo protein synthesis and measure the level of constitutive and inducible isoforms of the Hsp70 gene family of stress proteins after UV exposure. Animals were collected from Tampa Bay, Florida (USA), and exposed to solar radiation (full spectrum), UV-A (320-400 nm) and PAR (400-700 nm), or PAR only, for periods of 0.5-4 h. Controls were kept in the dark. Protein synthesis was robust under all treatments when the copepods were exposed to low solar radiation intensities. Conversely, high solar radiation intensities (both UV-B and UV-A) caused an overall suppression in the protein synthesis of the copepods with no detectable induction of stress-inducible isoforms of Hsps. Immunochemical assays (western blotting) showed that UVR increased levels (3.5-4-fold increase compared to the dark control) of the constitutively expressed 70 kDa heat-shock (Hsc70) protein in A. tonsa, without indication of inducible isoform upregulation. PMID- 21258624 TI - Seasonal and ontogenetic changes of mycosporine-like amino acids in planktonic organisms from an alpine lake. AB - We studied the quantitative and qualitative mycosporine-like amino acid (MAA) composition in phytoplankton and the copepod Cyclops abyssorum tatricus from an alpine lake over a 15-month period. Up to eight MAAs were identified in the samples, with shinorine being predominant. The MAAs occurred year round and showed a strong seasonal pattern. Compared with ice-cover periods, concentrations during the summer were on average 3.6 and 3.0 times higher in phytoplankton and C. abyssorum tatricus, respectively. During the summer, the contents of MAAs in phytoplankton decreased with depth, suggesting their photoprotective role. Chlorophyll a-specific concentrations of MAAs in phytoplankton correlated significantly with the incident solar radiation and ultraviolet (UV) water transparency (r(2) <= 0.36), however, the strongest relationship was found with water temperature (r(2) = 0.67). In zooplankton, highest contents of MAAs were found in eggs, nauplii, and young copepodids, presumably providing a high level of photoprotection for progeny. Proportions of the dominant MAAs in the copepod showed seasonal and ontogenetic variations, which were consistent with relative changes in the predominant MAA, but not other abundant MAAs, in phytoplankton. Considering a time lag of approximately 1 month between the synthesis and subsequent accumulation of these compounds, MAA concentrations in late copepodid to adult life stages were significantly correlated to those in phytoplankton. Annual patterns in MAAs with high concentrations during periods of elevated environmental stress are consistent with the idea that these compounds play an important role in protecting aquatic organisms against UV damage. PMID- 21258625 TI - Dyscalculia: neuroscience and education. AB - BACKGROUND: Developmental dyscalculia is a heterogeneous disorder with largely dissociable performance profiles. Though our current understanding of the neurofunctional foundations of (adult) numerical cognition has increased considerably during the past two decades, there are still many unanswered questions regarding the developmental pathways of numerical cognition. Most studies on developmental dyscalculia are based upon adult calculation models which may not provide an adequate theoretical framework for understanding and investigating developing calculation systems. Furthermore, the applicability of neuroscience research to pedagogy has, so far, been limited. PURPOSE: After providing an overview of current conceptualisations of numerical cognition and developmental dyscalculia, the present paper (1) reviews recent research findings that are suggestive of a neurofunctional link between fingers (finger gnosis, finger-based counting and calculation) and number processing, and (2) takes the latter findings as an example to discuss how neuroscience findings may impact on educational understanding and classroom interventions. SOURCES OF EVIDENCE: Finger-based number representations and finger-based calculation have deep roots in human ontology and phylogeny. Recently, accumulating empirical evidence supporting the hypothesis of a neurofunctional link between fingers and numbers has emerged from both behavioural and brain imaging studies. MAIN ARGUMENT: Preliminary but converging research supports the notion that finger gnosis and finger use seem to be related to calculation proficiency in elementary school children. Finger-based counting and calculation may facilitate the establishment of mental number representations (possibly by fostering the mapping from concrete non-symbolic to abstract symbolic number magnitudes), which in turn seem to be the foundations for successful arithmetic achievement. CONCLUSIONS: Based on the findings illustrated here, it is plausible to assume that finger use might be an important and complementary aid (to more traditional pedagogical methods) to establish mental number representations and/or to facilitate learning to count and calculate. Clearly, future prospective studies are needed to investigate whether the explicit use of fingers in early mathematics teaching might prove to be beneficial for typically developing children and/or might support the mapping from concrete to abstract number representations in children with and without developmental dyscalculia. PMID- 21258621 TI - Genetic Variations in Telomere Maintenance, with Implications on Tissue Renewal Capacity and Chronic Disease Pathologies. AB - Premature loss of telomere repeats underlies the pathologies of inherited bone marrow failure syndromes. Over the past decade, researchers have mapped genetic lesions responsible for the accelerated loss of telomere repeats. Haploinsufficiencies in the catalytic core components of the telomere maintenance enzyme telomerase, as well as genetic defects in telomerase holoenzyme components responsible for enzyme stability, have been linked to hematopoietic failure pathologies. Frequencies of these disease-associated alleles in human populations are low. Accordingly, the diseases themselves are rare. On the other hand, single nucleotide polymorphisms of telomerase enzyme components are found with much higher frequencies, with several non-synonymous SNP alleles observed in 2-4% of the general population. Importantly, recent advents of molecular diagnostic techniques have uncovered links between telomere length maintenance deficiencies and an increasing number of pathologies unrelated to the hematopoietic system. In these cases, short telomere length correlates to tissue renewal capacities and predicts clinical progression and disease severity. To the authors of this review, these new discoveries imply that even minor genetic defects in telomere maintenance can culminate in the premature failure of tissue compartments with high renewal rates. In this review, we discuss the biology and molecules of telomere maintenance, and the pathologies associated with an accelerated loss of telomeres, along with their etiologies. We also discuss single nucleotide polymorphisms of key telomerase components and their association with tissue renewal deficiency syndromes and other pathologies. We suggest that inter individual variability in telomere maintenance capacity could play a significant role in chronic inflammatory diseases, and that this is not yet fully appreciated in the translational research of pharmacogenomics and personalized medicine. PMID- 21258626 TI - Knowledge Brokering: The missing link in the evidence to action chain? AB - Transferring health care research into policy and practice is a messy and complex process which both policymakers and researchers can struggle with. A potential solution is to use individuals or organisations as knowledge brokers. Using a range of literature, this paper explains the theory behind knowledge brokering, identifies three models of brokering and explores the challenges of brokering. We suggest that clarifying these factors is a significant step towards planning well designed and rigorously evaluated brokering interventions. We also suggest that a clearly defined theoretical framework could help us to find out more about how brokering works and its effectiveness. PMID- 21258628 TI - Controlling Platinum, Ruthenium and Osmium Reactivity for Anticancer Drug Design. PMID- 21258629 TI - Effect of Speaking Environment on Speech Production and Perception. AB - Environments affect speaking and listening performance. This contribution reviews some of the main ways in which all sounds are affected by the environment they propagate into. These influences are used to assess how environments affect speakers and listeners. The article concludes with a brief consideration of factors that designers may wish to take into account to address the effects. PMID- 21258627 TI - Production of recombinant allergens in plants. AB - A large percentage of allergenic proteins are of plant origin. Hence, plant-based expression systems are considered ideal for the recombinant production of certain allergens. First attempts to establish production of plant-derived allergens in plants focused on transient expression in Nicotiana benthamiana infected with recombinant viral vectors. Accordingly, allergens from birch and mugwort pollen, as well as from apple have been expressed in plants. Production of house dust mite allergens has been achieved by Agrobacterium-mediated transformation of tobacco plants. Beside the use of plants as production systems, other approaches have focused on the development of edible vaccines expressing allergens or epitopes thereof, which bypasses the need of allergen purification. The potential of this approach has been convincingly demonstrated for transgenic rice seeds expressing seven dominant human T cell epitopes derived from Japanese cedar pollen allergens. Parallel to efforts in developing recombinant-based diagnostic and therapeutic reagents, different gene-silencing approaches have been used to decrease the expression of allergenic proteins in allergen sources. In this way hypoallergenic ryegrass, soybean, rice, apple, and tomato were developed. PMID- 21258630 TI - Estrogen induced breast cancer is the result in the disruption of the asymmetric cell division of the stem cell. AB - There is evidence that in the human breast there is a stem cell population that can give rise to many different cell types and have the unique potential to divide asymmetrically. In this way stem cells maintain the stem cell pool and simultaneously generate committed cells that reconstitute the organ for example for preparing the breast for a new pregnancy after the involution from a previous pregnancy and lactation process. In addition to the in vivo models of mammary morphogenesis there are in vitro systems that are more amenable to study in critically determined conditions the ductulogenic pattern of growth of the breast epithelia. Primary mammary epithelial cells grown in collagen matrix are able to form tree-like structures resembling in vivo ductulogenesis. The human breast epithelial cells MCF-10F formed tubules when grown in type I collagen and we demonstrated that treatment of these cells with 17beta-estradiol (E(2)) induces phonotypical changes indicative of neoplastic transformation. The transformation of MCF-10F by E(2) is associated with impaired ductal morphogenesis by altering the stem cells unique potential to divide asymmetrically inducing formation of solid masses mimicking intraductal carcinoma that progress to invasive and tumorigenic phenotype. In the present work we present evidence for the mechanism of cell asymmetry leading to normal ductulogenesis and how the normal stem cell is transformed to cancer stem cell by altering this process. Furthermore, we demonstrate that the carcinogenic agent, in this case E(2), induces a defect in the asymmetric cell division program of the normal mammary stem cell. PMID- 21258632 TI - Sphingosine-1-phosphate aggravates antigen-induced airway inflammation in mice. AB - Recent investigations suggest an involvement of sphingosine-1-phosphate (S1P) in the pathogenesis of allergic bronchial asthma. However, the role of S1P in the development of asthma is still controversial. Our aim was to investigate the effects of intranasal application of S1P on antigen-induced airway inflammation in a mouse model of allergic bronchial asthma. METHODOLOGY: Male BALB/c mice were actively sensitized with ovalbumin antigen, and were repeatedly challenged with aerosolized antigen. Animals also received an intranasal administration of S1P (10-5 M, 20 uL) or its vehicle (1% methanol in sterile PBS, 20 uL) 30 min prior to each antigen challenge. Histological examinations of the lungs and determination of cell number in the bronchoalveolar lavage fluids (BALFs) were studied. RESULTS: The airway inflammation induced by antigen exposure was significantly augmented by the intranasal administration of S1P: the cell number in BALFs of the S1P-treated, antigen-challenged mice (S1P-Challenged, 48.9+/-4.8 x 10(4)/mL BALF) was significantly increased as compared with those of the vehicle-treated, antigen-challenged ones (Vehicle-Challenged, 26.3+/-5.7 x 10(4)/mL BALF, P<0.01). CONCLUSION: In mice, the intranasal administration of S1P might aggravate the antigen-induced airway inflammation. PMID- 21258631 TI - Epigenetic targets of bioactive dietary components for cancer prevention and therapy. AB - The emergent interest in cancer epigenetics stems from the fact that epigenetic modifications are implicated in virtually every step of tumorigenesis. More interestingly, epigenetic changes are reversible heritable changes that are not due to the alteration in DNA sequence but have potential to alter gene expression. Dietary agents consist of many bioactive ingredients which actively regulate various molecular targets involved in tumorigenesis. We present evidence that numerous bioactive dietary components can interfere with various epigenetic targets in cancer prevention and therapy. These agents include curcumin (turmeric), genistein (soybean), tea polyphenols (green tea), resveratrol (grapes), and sulforaphane (cruciferous vegetables). These bioactive components alter the DNA methylation and histone modifications required for gene activation or silencing in cancer prevention and therapy. Bioactive components mediate epigenetic modifications associated with the induction of tumor suppressor genes such as p21(WAF1/CIP1) and inhibition of tumor promoting genes such as the human telomerase reverse transcriptase during tumorigenesis processes. Here, we present considerable evidence that bioactive components and their epigenetic targets are associated with cancer prevention and therapy which should facilitate novel drug discovery and development. In addition, remarkable advances in our understanding of basic epigenetic mechanisms as well as the rapid progress that is being made in developing powerful new technologies, such as those for sensitive and quantitative detection of epigenetic and epigenomic changes in cancer biology, hold great promise for novel epigenetic approaches to cancer prevention and therapy. PMID- 21258634 TI - Democratic Quality in Stable Democracies. AB - The major predecessor to Ringen's and my own efforts to measure democratic quality in terms of the purpose of democracy is Robert Dahl's seminal book Polyarchy (1971). Measuring the quality of democracy requires two prior judgments: (1) making sure that, in terms of institutional characteristics, a country is sufficiently democratic, and that, as a minimum, it has universal suffrage, and (2) that its democracy has been uninterrupted for a minimum number of years. To an important extent, higher democratic quality can be attributed to institutional characteristics of consensus democracy, especially proportional representation. PMID- 21258635 TI - Enduring Legacy? Charles Tilly and Durable Inequality. AB - This article assesses Charles Tilly's Durable Inequality and traces its influence. In writing Durable Inequality, Tilly sought to shift the research agenda of stratification scholars. But the book's initial impact was disappointing. In recent years, however, its influence has grown, suggesting a more enduring legacy. PMID- 21258633 TI - Retinal vein occlusions: The potential impact of a dysregulation of the retinal veins. AB - A retinal vein occlusion (RVO) is a sight threatening disease. It can be divided into central vein occlusion and branch retinal vein occlusion. The pathogenesis of the condition remains to be solved. Mechanical compression of the vessel wall or thrombotic occlusion of the vessel lumen, sometimes combined with rheological disorders, are often assumed pathomechanisms. Accordingly, the therapy relies either on mechanical decompression, lyses of thrombi or improvement of rheology. A number of observations however, such as the relationship of RVO to atherosclerotic risk factors, spontaneous reversibility particularly in young patients, rest flow observed in angiography, occlusion despite anticoagulation or thrombocytopenia and finally the positive effect of anti-VEGF therapy are not explained by the present pathogenetic concept. As a new concept we propose a local venous constriction induced by vasoconstrictive molecules diffusing from neighbouring diseased arteries and/or from other neighbouring (hypoxic) tissues. Recognizing these postulated conditions might lead to an earlier identification of impending vein occlusions as well as to a treatment more tailored to the risk factor constellation of the particular patient. PMID- 21258636 TI - The effects of migrant remittances on population-environment dynamics in migrant origin areas: international migration, fertility, and consumption in highland Guatemala. AB - International migration impacts origin regions in many ways. As examples, remittances from distant migrants may alter consumption patterns within sending communities, while exposure to different cultural norms may alter other behaviors. This paper combines these insights to offer a unique lens on migration's environmental impact. From an environmental perspective, we ask the following question: is the likely rise in consumption brought about by remittances counterbalanced by a reduction in fertility in migrant households following exposure to lower fertility cultures? Based on ethnographic case studies in two western highland Guatemalan communities, we argue that the near term rise in consumption due to remittances is not counterbalanced by rapid decline in migrant household fertility. However, over time, the environmental cost of consumption may be mitigated at the community level through diffusion of contraception and family planning norms yielding lower family size. PMID- 21258637 TI - Baseline observations from the POSSIBLE EU(r) study: characteristics of postmenopausal women receiving bone loss medications. AB - SUMMARY: Prospective Observational Scientific Study Investigating Bone Loss Experience in Europe (POSSIBLE EU(r)) is an ongoing longitudinal cohort study that utilises physician- and patient-reported measures to describe the characteristics and management of postmenopausal women on bone loss therapies. We report the study design and baseline characteristics of 3,402 women recruited from general practice across five European countries. PURPOSE: The POSSIBLE EU(r) is a study describing the characteristics and management of postmenopausal women receiving bone loss medications. METHODS: Between 2005 and 2008, general practitioners enrolled postmenopausal women initiating, switching or continuing treatment with bone loss treatment in France, Germany, Italy, Spain and the UK. Patients and physicians completed questionnaires at study entry and at 3-month intervals, for 1 year. RESULTS: Of 3,402 women enrolled (mean age 68.2 years [SD] 9.83), 96% were diagnosed with low bone mass; 55% of these using dual energy X ray absorptiometry. Most women (92%) had comorbidities. Mean minimum T score (hip or spine) at diagnosis was -2.7 (SD 0.89; median -2.7 [interquartile range, -3.2, -2.2]) indicating low bone mineral density. Almost 40% of the women had prior fractures in adulthood, mostly non-vertebral, non-hip in nature, 30% of whom had at least two fractures and more than half experienced moderate/severe pain or fatigue. Bisphosphonates were the most common type of bone loss treatment prescribed in the 12 months preceding the study. CONCLUSIONS: POSSIBLE EU(r) characterises postmenopausal women with low bone mass, exhibiting a high rate of prevalent fracture, substantial bone fragility and overall comorbidity burden. Clinical strategies for managing osteoporosis in this population varied across the five participating European countries, reflecting their different guidelines, regulations and standards of care. PMID- 21258638 TI - Vital Rates from the Action of Mutation Accumulation. AB - New models for evolutionary processes of mutation accumulation allow hypotheses about the age-specificity of mutational effects to be translated into predictions of heterogeneous population hazard functions. We apply these models to questions in the biodemography of longevity, including proposed explanations of Gompertz hazards and mortality plateaus. PMID- 21258639 TI - Mixed-radix Algorithm for the Computation of Forward and Inverse MDCT. AB - The modified discrete cosine transform (MDCT) and inverse MDCT (IMDCT) are two of the most computational intensive operations in MPEG audio coding standards. A new mixed-radix algorithm for efficient computing the MDCT/IMDCT is presented. The proposed mixed-radix MDCT algorithm is composed of two recursive algorithms. The first algorithm, called the radix-2 decimation in frequency (DIF) algorithm, is obtained by decomposing an N-point MDCT into two MDCTs with the length N/2. The second algorithm, called the radix-3 decimation in time (DIT) algorithm, is obtained by decomposing an N-point MDCT into three MDCTs with the length N/3. Since the proposed MDCT algorithm is also expressed in the form of a simple sparse matrix factorization, the corresponding IMDCT algorithm can be easily derived by simply transposing the matrix factorization. Comparison of the proposed algorithm with some existing ones shows that our proposed algorithm is more suitable for parallel implementation and especially suitable for the layer III of MPEG-1 and MPEG-2 audio encoding and decoding. Moreover, the proposed algorithm can be easily extended to the multidimensional case by using the vector radix method. PMID- 21258640 TI - Disentangling true shape differences and experimenter bias: are dextral and sinistral snail shells exact mirror images? AB - IN THEORY, SNAILS CAN COME IN TWO ENANTIOMORPHS: either dextral (coiling clockwise) or sinistral (coiling counter-clockwise). In snail species where both forms are actually present, coiling direction is determined by a single gene with delayed maternal inheritance; there is no predictable relationship between a snail's own coiling genotype and its actual coiling direction. Because of this genetic decoupling, it might be expected that dextral and sinistral individuals would be exact mirror images of one another. However, indications exist that there is a subtle but detectable shape difference between dextral and sinistral individuals that derive from the same gene pool. In this paper, we attempt to detect such differences in 50 dextral and 50 sinistral individuals of Amphidromus inversus, a species of land snail that is consistently chirally dimorphic. Four out of 18 volunteers who measured the shells with Vernier calipers found that sinistrals are stouter to a significant degree. A similar result was found by one out of five volunteers who measured the shells from photographs. These results do not allow distinguishing between real shape differences and a handling bias of sinistral as compared with dextral shells. However, when the same set of shells was subjected to a geometric morphometric analysis, we were able to show that sinistrals indeed exhibit a slight but significant widening and twisting of the shell near the palatal and parietal apertural areas. This result is surprising because species of the subgenus Amphidromus s. str. share a long history of chiral dimorphism, and the species would be expected to have been purged from disadvantageous interactions between direction of coil and general shell shape. We conclude that selection on the shape differences is either very weak or constrained by the fact that the pleiotropic effects of the chirality gene are of importance very early in development only. PMID- 21258642 TI - Behavioral characterization of individual olfactory memory retrieval in Drosophila melanogaster. AB - Memory performance depends not only on effective learning and storage of information, but also on its efficient retrieval. In Drosophila, aversive olfactory conditioning generates qualitatively different forms of memory depending on the number and spacing of conditioning trials. However, it is not known how these differences are reflected at the retrieval level, in the behavior of individual flies during testing. We analyzed conditioned behaviors after one conditioning trial and after massed and spaced repeated trials. The single conditioning produces an early memory that was tested at 1.5 h. Tested at 24 h after training, the spaced and the massed protocols generate two different forms of consolidated memory, dependent, or independent of de novo protein-synthesis. We found clearly distinct patterns of locomotor activity in flies trained with either spaced or massed conditioning protocols. Spaced-trained flies exhibited immediate and dynamic choices between punished and unpunished odors during the test, whereas massed-trained flies made a delayed choice and showed earlier disappearance of the conditioned response. Flies trained with single and spaced trials responded to the punished odor by decreasing their resting time, but not massed-trained flies. These findings demonstrate that genetically and pharmacologically distinct forms of memory drive characteristically different forms of locomotor behavior during retrieval, and they may shed light on our previous observation that memory retrieval in massed-trained flies is socially facilitated. Social interactions would enhance exploratory activity, and then reduce the latency of their conditioned choice and delay its extinction. PMID- 21258641 TI - A compositionality machine realized by a hierarchic architecture of synfire chains. AB - The composition of complex behavior is thought to rely on the concurrent and sequential activation of simpler action components, or primitives. Systems of synfire chains have previously been proposed to account for either the simultaneous or the sequential aspects of compositionality; however, the compatibility of the two aspects has so far not been addressed. Moreover, the simultaneous activation of primitives has up until now only been investigated in the context of reactive computations, i.e., the perception of stimuli. In this study we demonstrate how a hierarchical organization of synfire chains is capable of generating both aspects of compositionality for proactive computations such as the generation of complex and ongoing action. To this end, we develop a network model consisting of two layers of synfire chains. Using simple drawing strokes as a visualization of abstract primitives, we map the feed-forward activity of the upper level synfire chains to motion in two-dimensional space. Our model is capable of producing drawing strokes that are combinations of primitive strokes by binding together the corresponding chains. Moreover, when the lower layer of the network is constructed in a closed-loop fashion, drawing strokes are generated sequentially. The generated pattern can be random or deterministic, depending on the connection pattern between the lower level chains. We propose quantitative measures for simultaneity and sequentiality, revealing a wide parameter range in which both aspects are fulfilled. Finally, we investigate the spiking activity of our model to propose candidate signatures of synfire chain computation in measurements of neural activity during action execution. PMID- 21258643 TI - Neural substrates of attentive listening assessed with a novel auditory Stroop task. AB - A common explanation for the interference effect in the classic visual Stroop test is that reading a word (the more automatic semantic response) must be suppressed in favor of naming the text color (the slower sensory response). Neuroimaging studies also consistently report anterior cingulate/medial frontal, lateral prefrontal, and anterior insular structures as key components of a network for Stroop-conflict processing. It remains unclear, however, whether automatic processing of semantic information can explain the interference effect in other variants of the Stroop test. It also is not known if these frontal regions serve a specific role in visual Stroop conflict, or instead play a more universal role as components of a more generalized, supramodal executive-control network for conflict processing. To address these questions, we developed a novel auditory Stroop test in which the relative dominance of semantic and sensory feature processing is reversed. Listeners were asked to focus either on voice gender (a more automatic sensory discrimination task) or on the gender meaning of the word (a less automatic semantic task) while ignoring the conflicting stimulus feature. An auditory Stroop effect was observed when voice features replaced semantic content as the "to-be-ignored" component of the incongruent stimulus. Also, in sharp contrast to previous Stroop studies, neural responses to incongruent stimuli studied with functional magnetic resonance imaging revealed greater recruitment of conflict loci when selective attention was focused on gender meaning (semantic task) over voice gender (sensory task). Furthermore, in contrast to earlier Stroop studies that implicated dorsomedial cortex in visual conflict processing, interference-related activation in both of our auditory tasks was localized ventrally in medial frontal areas, suggesting a dorsal-to ventral separation of function in medial frontal cortex that is sensitive to stimulus context. PMID- 21258644 TI - Word wins over face: emotional Stroop effect activates the frontal cortical network. AB - The prefrontal cortex (PFC) has been implicated in higher order cognitive control of behavior. Sometimes such control is executed through suppression of an unwanted response in order to avoid conflict. Conflict occurs when two simultaneously competing processes lead to different behavioral outcomes, as seen in tasks such as the anti-saccade, go/no-go, and the Stroop task. We set out to examine whether different types of stimuli in a modified emotional Stroop task would cause similar interference effects as the original Stroop-color/word, and whether the required suppression mechanism(s) would recruit similar regions of the medial PFC (mPFC). By using emotional words and emotional faces in this Stroop experiment, we examined the two well-learned automatic behaviors of word reading and recognition of face expressions. In our emotional Stroop paradigm, words were processed faster than face expressions with incongruent trials yielding longer reaction times and larger number of errors compared to the congruent trials. This novel Stroop effect activated the anterior and inferior regions of the mPFC, namely the anterior cingulate cortex, inferior frontal gyrus as well as the superior frontal gyrus. Our results suggest that prepotent behaviors such as reading and recognition of face expressions are stimulus dependent and perhaps hierarchical, hence recruiting distinct regions of the mPFC. Moreover, the faster processing of word reading compared to reporting face expressions is indicative of the formation of stronger stimulus-response associations of an over-learned behavior compared to an instinctive one, which could alternatively be explained through the distinction between awareness and selective attention. PMID- 21258645 TI - The impact of disappointment in decision making: inter-individual differences and electrical neuroimaging. AB - Disappointment, the emotion experienced when faced to reward prediction errors (RPEs), considerably impacts decision making (DM). Individuals tend to modify their behavior in an often unpredictable way just to avoid experiencing negative emotions. Despite its importance, disappointment remains much less studied than regret and its impact on upcoming decisions largely unexplored. Here, we adapted the Trust Game to effectively elicit, quantify, and isolate disappointment by relying on the formal definition provided by Bell's in economics. We evaluated the effects of experienced disappointment and elation on future cooperation and trust as well as the rationality and utility of the different behavioral and neural mechanisms used to cope with disappointment. All participants in our game trusted less and particularly expected less from unknown opponents as a result of disappointing outcomes in the previous trial but not necessarily after elation indicating that behavioral consequences of positive and negative RPEs are not the same. A large variance in the tolerance to disappointment was observed across subjects, with some participants needing only a small disappointment to impulsively bias their subsequent decisions. As revealed by high-density EEG recordings the most tolerant individuals - who thought twice before making a decision and earned more money - relied on different neural generators to contend with neutral and unexpected outcomes. This study thus provides some support to the idea that different neural systems underlie reflexive and reflective decisions within the same individuals as predicted by the dual-system theory of social judgment and DM. PMID- 21258646 TI - Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy. AB - Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histone-modifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects. PMID- 21258647 TI - Self-interaction chromatography of proteins on a microfluidic monolith. AB - A novel miniaturized system has been developed for measuring protein-protein interactions in solution with high efficiency and speed, and minimal use of protein. A chromatographic monolith synthesized in a capillary is used in the method to make interaction measurements by self-interaction chromatography (SIC) in a manner that, compared to column methods, is more efficient as well as more readily practicable even if only small amounts of protein are available. The microfluidic monolith requires much less protein for both column synthesis and the chromatographic measurements than a conventional SIC system, and in addition offers improved mass transfer and hence higher chromatographic efficiency than for previous SIC miniaturization systems. Protein self-interactions for catalase as a model protein, quantified by measurement of second virial coefficients, B(22), were determined by SIC and follow trends that are consistent with previously reported values. Different column derivatization conditions were studied in order to optimize the chromatographic behavior of the microfluidic system for SIC measurements. Chromatographic sensitivity can be further increased by using different column synthesis conditions. PMID- 21258648 TI - Design and Control of Concentric-Tube Robots. AB - A novel approach toward construction of robots is based on a concentric combination of precurved elastic tubes. By rotation and extension of the tubes with respect to each other, their curvatures interact elastically to position and orient the robot's tip, as well as to control the robot's shape along its length. In this approach, the flexible tubes comprise both the links and the joints of the robot. Since the actuators attach to the tubes at their proximal ends, the robot itself forms a slender curve that is well suited for minimally invasive medical procedures. This paper demonstrates the potential of this technology. Design principles are presented and a general kinematic model incorporating tube bending and torsion is derived. Experimental demonstration of real-time position control using this model is also described. PMID- 21258650 TI - Where does the alignment score distribution shape come from? AB - Alignment algorithms are powerful tools for searching for homologous proteins in databases, providing a score for each sequence present in the database. It has been well known for 20 years that the shape of the score distribution looks like an extreme value distribution. The extremely large number of times biologists face this class of distributions raises the question of the evolutionary origin of this probability law.WE INVESTIGATED THE POSSIBILITY OF DERIVING THE MAIN PROPERTIES OF SEQUENCE ALIGNMENT SCORE DISTRIBUTIONS FROM A BASIC EVOLUTIONARY PROCESS: a duplication-divergence protein evolution process in a sequence space. Firstly, the distribution of sequences in this space was defined with respect to the genetic distance between sequences. Secondly, we derived a basic relation between the genetic distance and the alignment score. We obtained a novel score probability distribution which is qualitatively very similar to that of Karlin Altschul but performing better than all other previous model. PMID- 21258651 TI - Cost-effective cloud computing: a case study using the comparative genomics tool, roundup. AB - BACKGROUND: Comparative genomics resources, such as ortholog detection tools and repositories are rapidly increasing in scale and complexity. Cloud computing is an emerging technological paradigm that enables researchers to dynamically build a dedicated virtual cluster and may represent a valuable alternative for large computational tools in bioinformatics. In the present manuscript, we optimize the computation of a large-scale comparative genomics resource-Roundup-using cloud computing, describe the proper operating principles required to achieve computational efficiency on the cloud, and detail important procedures for improving cost-effectiveness to ensure maximal computation at minimal costs. METHODS: Utilizing the comparative genomics tool, Roundup, as a case study, we computed orthologs among 902 fully sequenced genomes on Amazon's Elastic Compute Cloud. For managing the ortholog processes, we designed a strategy to deploy the web service, Elastic MapReduce, and maximize the use of the cloud while simultaneously minimizing costs. Specifically, we created a model to estimate cloud runtime based on the size and complexity of the genomes being compared that determines in advance the optimal order of the jobs to be submitted. RESULTS: We computed orthologous relationships for 245,323 genome-to-genome comparisons on Amazon's computing cloud, a computation that required just over 200 hours and cost $8,000 USD, at least 40% less than expected under a strategy in which genome comparisons were submitted to the cloud randomly with respect to runtime. Our cost savings projections were based on a model that not only demonstrates the optimal strategy for deploying RSD to the cloud, but also finds the optimal cluster size to minimize waste and maximize usage. Our cost-reduction model is readily adaptable for other comparative genomics tools and potentially of significant benefit to labs seeking to take advantage of the cloud as an alternative to local computing infrastructure. PMID- 21258652 TI - A Response to the Influence of Observer Presence on Baboon (Papio spp.) and Rhesus Macaques (Macaca mulatta) Behavior: A Comment On. PMID- 21258653 TI - From Early Childhood to Adolescence: Linking Family Functioning and School Behavior. AB - The present study uses observational assessment of 66 two-parent families working and playing together when their eldest child is in kindergarten and again in 9(th) grade to identify distinct patterns of family functioning derived from structural family systems theory. Whereas concurrent assessment of the relationship between family type and adolescents' school behavior were not significant, significant prospective longitudinal relationships between family type assessed in early childhood and 9(th) grade school behavior were indicated. Kindergarteners whose families were primarily characterized by a strong mother child alliance were less academically competent, more aggressive/inattentive, and more anxious/depressed/withdrawn at school nine years later when they were in 9(th) grade, than their peers in more cohesive or father-child allied families. PMID- 21258654 TI - Electrically Triggered Release of a Small Molecule Drug from a Polyelectrolyte Multilayer Coating. AB - Electrically triggered drug delivery represents an attractive option for actively and remotely controlling the release of a therapeutic from an implantable device (e.g., a "pharmacy-on-a-chip"). Here we report the fabrication of nanoscale thin films that can release precise quantities of a small molecule drug in response to application of a small, anodic electric potential of at least +0.5 V versus Ag/AgCl. Films containing negatively charged Prussian Blue (PB) nanoparticles and positively charged gentamicin, a small hydrophilic antibiotic, were fabricated using layer-by-layer (LbL) assembly. When oxidized, the PB nanoparticles shift from negatively charged to neutral, inducing dissolution of the film. Films with thicknesses in the range 100-500 nm corresponding to drug loadings of 1-4 MUg/cm(2) were characterized. We demonstrate control over the drug dosage by tuning the film thickness as well as the magnitude of the applied voltage. Drug release kinetics ranging from triggered burst release to on/off, or pulsatile release, were achieved by applying different electric potential profiles. Finally, the in vitro efficacy of the released drug was confirmed against Staphylococcus aureus bacteria. Given the versatility of an external electrical stimulus and the ability of LbL assembly to conformally coat a variety of substrates regardless of size, shape, or chemical composition, we maintain that electrically controlled release of a drug from an LbL-coated surface could have applications in both implantable medical devices and transdermal drug delivery systems. PMID- 21258655 TI - Repetitive peroxide exposure reveals pleiotropic mitogen-activated protein kinase signaling mechanisms. AB - Oxidative stressors such as hydrogen peroxide control the activation of many interconnected signaling systems and are implicated in neurodegenerative disease etiology. Application of hydrogen peroxide to PC12 cells activated multiple tyrosine kinases (c-Src, epidermal growth factor receptor (EGFR), and Pyk2) and the serine-threonine kinase ERK1/2. Peroxide-induced ERK1/2 activation was sensitive to intracellular calcium chelation and EGFR and c-Src kinase inhibition. Acute application and removal of peroxide allowed ERK1/2 activity levels to rapidly subside to basal serum-deprived levels. Using this protocol, we demonstrated that ERK1/2 activation tachyphylaxis developed upon repeated peroxide exposures. This tachyphylaxis was independent of c-Src/Pyk2 tyrosine phosphorylation but was associated with a progressive reduction of peroxide induced EGFR tyrosine phosphorylation, EGFR interaction with growth factor receptor binding protein 2, and a redistribution of EGFR from the plasma membrane to the cytoplasm. Our data indicates that components of peroxide-induced ERK1/2 cascades are differentially affected by repeated exposures, indicating that oxidative signaling may be contextually variable. PMID- 21258656 TI - Ethanol impairs glucose uptake by human astrocytes and neurons: protective effects of acetyl-L-carnitine. AB - Alcohol consumption causes neurocognitive deficits, neuronal injury, and neurodegeneration. At the cellular level, alcohol abuse causes oxidative damage to mitochondria and cellular proteins and interlink with the progression of neuroinflammation and neurological disorders. We previously reported that alcohol inhibits glucose transport across the blood-brain barrier (BBB), leading to BBB dysfunction and neurodegeneration. In this study, we hypothesized that ethanol (EtOH)-mediated disruption in glucose uptake would deprive energy for human astrocytes and neurons inducing neurotoxicity and neuronal degeneration. EtOH may also have a direct effect on glucose uptake in neurons and astrocytes, which has not been previously described. Our results indicate that ethanol exposure decreases the uptake of D-(2-(3)H)-glucose by human astrocytes and neurons. Inhibition of glucose uptake correlates with a reduction in glucose transporter protein expression (GLUT1 in astrocytes and GLUT3 in neurons). Acetyl-L-carnitine (ALC), a neuroprotective agent, suppresses the effects of alcohol on glucose uptake and GLUT levels, thus reducing neurotoxicity and neuronal degeneration. These findings suggest that deprivation of glucose in brain cells contributes to neurotoxicity in alcohol abusers, and highlights ALC as a potential therapeutic agent to prevent the deleterious health conditions caused by alcohol abuse. PMID- 21258649 TI - Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases. AB - Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are the most common human adult-onset neurodegenerative diseases. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of AD, PD, and ALS are inherited, and genes causing these diseases have been identified. Nevertheless, the mechanisms of the neuronal cell death are unresolved. Morphological, biochemical, genetic, as well as cell and animal model studies reveal that mitochondria could have roles in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations, triggering neurodegeneration according to a cell death matrix theory. In AD, alterations in enzymes involved in oxidative phosphorylation, oxidative damage, and mitochondrial binding of Abeta and amyloid precursor protein have been reported. In PD, mutations in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review summarizes how mitochondrial pathobiology might contribute to neuronal death in AD, PD, and ALS and could serve as a target for drug therapy. PMID- 21258657 TI - Towards a dynamical network view of brain ischemia and reperfusion. Part II: a post-ischemic neuronal state space. AB - The general failure of neuroprotectants in clinical trials of ischemic stroke points to the possibility of a fundamental blind spot in the current conception of ischemic brain injury, the "ischemic cascade". This is the second in a series of four papers whose purpose is to work towards a revision of the concept of brain ischemia by applying network concepts to develop a bistable model of brain ischemia. We here build the bistable network model of brain ischemia. The central concept is that of a post-ischemic state space. Ischemia, as a quantitative perturbation, is envisioned to push the brain through a series of four phenotypes as a function of the amount of ischemia: the homeostatic, preconditioned, delayed neuronal death and necrotic phenotypes. The phenotypes are meta-stable attractors in the landscape of the post-ischemic state space. The sequence of the phenotypes derives from the mutual antagonism between damage mechanisms and stress responses, each conceived as aggregate ensemble variables. The competition between damage mechanisms and stress responses is posited to have the form of a bistability. Application of bistability to brain ischemia is grounded in the incontrovertible fact that post-ischemic neurons face the mutually exclusive decision to either live or die. PMID- 21258659 TI - Human Activity Recognition and Pattern Discovery. PMID- 21258658 TI - Current Concepts of HBV/HCV Coinfection: Coexistence, but Not Necessarily in Harmony. AB - Hepatitis B and hepatitis C are important causes of chronic liver disease globally. Although HBV/HCV coinfection is not uncommon, its epidemiology is poorly defined. Numerous studies provided evidence that coinfection accelerates liver disease progression and increases the risk of hepatocellular carcinoma. By applying new cell culture models to examine the interaction of both viruses, investigators concluded that HBV and HCV replicate in the same hepatocyte without interference. The roles of innate and adaptive immunity in determining the viral replication and disease outcomes still need rigorous investigation. To date, no standard-of-care recommendation exists for HBV/HCV coinfection. Pegylated interferon and ribavirin combination therapy demonstrated similar efficacy in suppressing HCV RNA in coinfection and HCV monoinfection. However, HBV reactivation during therapy can be a challenge. Future clinical trials evaluating the addition of a nucleoside/nucleotide analog for selective patients with HBV/HCV coinfection are essential for successful management of HBV/HCV coinfection. PMID- 21258660 TI - A permutation test for determining significance of clusters with applications to spatial and gene expression data. AB - Hierarchical clustering is a common procedure for identifying structure in a data set, and this is frequently used for organizing genomic data. Although more advanced clustering algorithms are available, the simplicity and visual appeal of hierarchical clustering has made it ubiquitous in gene expression data analysis. Hence, even minor improvements in this framework would have significant impact. There is currently no simple and systematic way of assessing and displaying the significance of various clusters in a resulting dendrogram without making certain distributional assumptions or ignoring gene-specific variances. In this work, we introduce a permutation test based on comparing the within-cluster structure of the observed data with those of sample datasets obtained by permuting the cluster membership. We carry out this test at each node of the dendrogram using a statistic derived from the singular value decomposition of variance matrices. The p-values thus obtained provide insight into the significance of each cluster division. Given these values, one can also modify the dendrogram by combining non significant branches. By adjusting the cut-off level of significance for branches, one can produce dendrograms with a desired level of detail for ease of interpretation. We demonstrate the usefulness of this approach by applying it to illustrative data sets. PMID- 21258661 TI - A memorable beginning, a rich history and a promising future. PMID- 21258662 TI - Practice audit in gastroenterology--the route to improving quality and safety. PMID- 21258663 TI - Point-of-care, peer-comparator colonoscopy practice audit: The Canadian Association of Gastroenterology Quality Program--Endoscopy. AB - BACKGROUND: Point-of-care practice audits allow documentation of procedural outcomes to support quality improvement in endoscopic practice. OBJECTIVE: To evaluate a colonoscopists' practice audit tool that provides point-of-care data collection and peer-comparator feedback. METHODS: A prospective, observational colonoscopy practice audit was conducted in academic and community endoscopy units for unselected patients undergoing colonoscopy. Anonymized colonoscopist, patient and practice data were collected using touchscreen smartphones with automated data upload for data analysis and review by participants. The main outcome measures were the following colonoscopy quality indicators: colonoscope insertion and withdrawal times, bowel preparation quality, sedation, immediate complications and polypectomy, and biopsy rates. RESULTS: Over a span of 16 months, 62 endoscopists reported on 1279 colonoscopy procedures. The mean cecal intubation rate was 94.9% (10th centile 84.2%). The mean withdrawal time was 8.8 min and, for nonpolypectomy colonoscopies, 41.9% of colonoscopists reported a mean withdrawal time of less than 6 min. Polypectomy was performed in 37% of colonoscopies. Independent predictors of polypectomy included the following: endoscopy unit type, patient age, interval since previous colonoscopy, bowel preparation quality, stable inflammatory bowel disease, previous colon polyps and withdrawal time. Withdrawal times of less than 6 min were associated with lower polyp removal rates (mean difference -11.3% [95% CI -2.8% to -19.9%]; P=0.01). DISCUSSION: Cecal intubation rates exceeded 90% and polypectomy rates exceeded 30%, but withdrawal times were frequently shorter than recommended. There are marked practice variations consistent with previous observations. CONCLUSION: Real-time, point-of-care practice audits with prompt, confidential access to outcome data provide a basis for targeted educational programs to improve quality in colonoscopy practice. PMID- 21258664 TI - Azathioprine metabolite measurements are not useful in following treatment of autoimmune hepatitis in Alaska Native and other non-Caucasian people. AB - BACKGROUND: In autoimmune hepatitis (AIH) patients treated with azathioprine, the utility of measuring thiopurine methyltransferase (TPMT) and azathioprine metabolites has been limited. OBJECTIVE: To evaluate the association between TPMT genotype and enzyme activity, and the impact of TPMT enzyme activity on levels of azathioprine metabolites and leukopenia to assess the clinical utility of monitoring azathioprine metabolites in Alaska Native and other non-Caucasian AIH patients. METHODS: Individuals with AIH were recruited at the Alaska Native Medical Center (Alaska, USA) and the University of Texas Southwestern Medical Center (Texas, USA). Identification of TPMT genotype and measurement of enzyme activity were performed. The metabolites 6-thioguanine nucleotides (6-TGN) and 6 methylmercaptopurine (6-MMP) were measured in participants who were on azathioprine, and the associations with disease remission and leukopenia were assessed. RESULTS: Seventy-one patients with AIH were included. The distribution of TPMT genotypes was similar to that reported in other populationbased studies. TPMT genotype and phenotype were strongly associated (P<0.0001). Levels of 6-TGN and 6-MMP correlated with azathioprine dose only in individuals with normal TPMT enzyme activity. Patients with leukopenia due to azathioprine were no more likely to have abnormal TPMT enzyme levels than those without leukopenia (P=1.0). No specific level of 6-TGN metabolites was associated with remission or leukopenia. DISCUSSION: Results of the present study were consistent with previous studies in Caucasian populations. TPMT genotype and phenotype correlated well, and levels of 6-TGN and 6-MMP metabolites were not associated with remission of AIH or toxicity of azathioprine. CONCLUSIONS: The present study confirmed the limited utility of monitoring levels of azathioprine metabolites in AIH patients. PMID- 21258665 TI - The impact of sirolimus on hepatitis C recurrence after liver transplantation. AB - BACKGROUND: While some immunosuppression strategies may accelerate hepatitis C virus (HCV) recurrence after liver transplantation (LT), the impact of sirolimus (SRL) is not known. OBJECTIVE: To assess the risk of biopsy-proven HCV recurrence and patient survival using known and suspected risk factors for HCV recurrence as covariates. METHODS: A retrospective analysis of 141 consecutive patients, including 88 who received de novo SRL therapy, who had undergone a first LT for HCV cirrhosis was conducted. Known and suspected risk factor covariates including transplant era, donor and recipient age, Model for End-stage Liver Disease score, cold ischemia time, immunosuppressive drugs and steroid treatment rejection rates were used in the assessment. RESULTS: Overall, 72.3% of the cohort developed biopsy-proven HCV recurrence. The incidence of HCV recurrence was not significantly different for patients treated with SRL (75% versus 69.8%; P=0.5). There was no difference found for time to recurrence, nor did mean activity or fibrosis scores differ at the time of initial recurrence. However, on follow-up using serial biopsies in patients with recurrence, the mean activity and fibrosis scores were significantly lower in the SRL group. Donor age and acute rejection episodes were the only factors affecting the HCV recurrence rate (expB 1.02 [95% CI 1.01 to 1.03]); P=0.03; and expB 2.8 [95% CI 1.8 to 4.3]; P<0.01], respectively). SRL treatment did not alter patient survival rates. Among patients treated with SRL-based immunosuppression, higher drug area under the curve levels were associated with a trend to lower disease activity and fibrosis at diagnosis; however, higher SRL levels were associated with shorter recurrence-free survival (P=0.038). CONCLUSION: Results of the present analysis suggest that de novo SRL based immunosuppression can be safely used in patients undergoing LT for HCV associated liver disease; however, SRL-based immunosuppression did not significantly affect the timing or severity of post-transplant HCV recurrence. HCV recurrence in SRL-treated patients had lower progressive activity and fibrosis levels on serial biopsy. PMID- 21258666 TI - What is nonacid reflux disease? AB - Proton pump inhibitors (PPIs) are the gold standard treatment for gastroesophageal reflux disease. In clinical practice, failure of PPIs occurs frequently, and may affect up to 30% of patients in a typical gastroenterology practice. Multichannel impedance monitoring combined with pH monitoring helps to detect nonacid reflux, and if symptoms correlate with these nonacid reflux episodes, nonacid reflux disease can be diagnosed. In contrast to PPIs, reflux inhibitors target transient lower esophageal sphincter relaxations, which are involved in the pathophysiology of reflux disease and may be the appropriate future treatment for nonacid reflux disease. The present article discusses the current understanding of nonacid reflux disease, its diagnosis and treatment. PMID- 21258667 TI - Chiropractic treatment for gastrointestinal problems: a systematic review of clinical trials. AB - Many chiropractors believe that chiropractic treatments are effective for gastrointestinal disorders. The aim of the present systematic review was to critically evaluate the evidence from controlled clinical trials supporting or not supporting this notion. Six electronic databases were searched for relevant studies. No limits were applied to language or publication date. Prospective, controlled, clinical trials of any type of chiropractic treatment for any type of gastrointestinal problem, except infant colic, were included. Only two trials were found--one was a pilot study, and the other had reached a positive conclusion; however, both had serious methodological flaws. There is no supportive evidence that chiropractic is an effective treatment for gastrointestinal disorders. PMID- 21258668 TI - Diagnosis and pharmacological management of small intestinal bacterial overgrowth in children with intestinal failure. AB - The present article provides a general overview of the possible diagnostic procedures available for the management of small intestinal bacterial overgrowth in pediatric patients with intestinal failure. The focus is to address current diagnostic tools and understand their associated advantages and disadvantages based on a literature search. Culture of small intestinal aspirates, noninvasive breath tests and an emerging interest in quantitative bacterial DNA fingerprinting are discussed. Proper management is critical for preventing the recurrence of small intestinal bacterial overgrowth and its related complications. Antibiotic prophylaxis is one approach to the treatment of bacterial overgrowth in intestinal failure patients. Although treatment trials can be challenging in such a vulnerable population, more investigative clinical studies examining early diagnosis, more effective control of recurrence and the prevention of associated complications must be conducted. PMID- 21258669 TI - Influence of gold nanoparticle size (2-50 nm) upon its electrochemical behavior: an electrochemical impedance spectroscopic and voltammetric study. AB - The electrochemical behavior of different size gold nanoparticles (AuNPs) was investigated. AuNPs with 2, 5, 10, 15, 20 and 50 nm diameters were immobilized onto a screen printed carbon electrode surface by physical adsorption. The impedimetric response was measured for different diameter AuNPs at a fixed value of their surface area, at the same content of gold (Au) and at the same concentration. In a further experiment, the impedimetric response toward AuNP concentration was measured for each diameter. Impedimetric results were compared with results obtained for the detection of Au by stripping voltammetry. Additionally, variability of active surface area and roughness of different electrodes before and after immobilization of AuNPs were carefully evaluated by means of cyclic voltammetry and laser scanning microscopy. Electrochemical impedance spectroscopy (EIS) is a sensitive technique capable of differentiating the signal generated by AuNPs of different sizes, thus providing useful information for the employment of AuNPs in electrochemical biosensors. PMID- 21258670 TI - The initiation mechanisms for surface hydrosilylation with 1-alkenes. AB - Hydrosilylation provides a route to form substituted silanes in solution. A similar reaction has been observed in the formation of covalent organic monolayers on a hydrogen-terminated silicon surface and is called thermal hydrosilylation. In solution, the mechanism requires a catalyst to add the basal silicon and saturating hydrogen to the C=C double bond. On the silicon surface, however, the reaction proceeds efficiently at 200 degrees C, initiated by visible light, and more slowly at room temperature in the dark. Such low activation energy barriers for the reactions on a surface relative to that required for solution hydrosilylation are remarkable, and although many explanations have been suggested, controversy still exists. In this work using a constrained molecular dynamics approach within the density functional theory framework, we show that the free energy activation barrier for abstraction of a hydrogen from silicon by an alkene molecule can be overcome by visible light or thermal excitation. Furthermore, we show that by concerted transfer of a hydrogen from the alpha-carbon to the beta-carbon, a 1-alkene can insert its alpha-carbon into a surface Si-H bond to accomplish hydrosilylation. PMID- 21258671 TI - Nanoaggregate shapes at the air/water interface. AB - Chiral interfaces and molecular recognition phenomena are of special interest not only for the understanding of biological recognition processes but also for the potential application in material science. Langmuir monolayers at the air-water interface have successfully been used as simple models to mimic biological phenomena. Recent experimental studies revealed that both chirality and molecular recognition processes of amphiphiles are controlling the features of the nano aggregates at the air/water interface. The objective of experimental studies has been to gain information about the properties of mesoscopic length scale aggregates obtained on the basis of chiral discrimation effects and the formation of supramolecular entities by molecular recognition of non-surface active species dissolved in the aqueous subphase. Differences in the two-dimensional morphology and lattice structures of the nano-aggregates cannot be explained by macroscopic theories and needed information about the detailed orientation and distance dependence of the intermolecular interaction within the aggregates. First new bottom-up studies have been directed toward understanding the driving forces for the aggregation processes of monolayers. Different types of interactions have been successfully considered using semi-empirical quantum chemical methods. The possibilities of Langmuir-Blodgett (LB) patterning to be an alternative paradigm for large-area patterning with mesostructured features are discussed. PMID- 21258672 TI - The temperature dependence of radiationless transition rates from ab initio computations. AB - The calculation of radiationless transition rates and of their temperature dependence from first principles is addressed by combining reliable electronic computations of the normal modes of the two electronic states with Kubo's generating function approach for the evaluation of the Franck-Condon weighted density of states. The whole sets of normal modes of the involved cofactors have been employed, taking into account the effects of nuclear equilibrium position displacements, of vibrational frequency changes, and of mixing of the normal modes. Application to the case of the elementary electron transfer step between bacteriopheophytin and ubiquinone cofactors of bacterial photosynthetic reaction centers yields a temperature dependence of the electron transfer rates in very good agreement with the experimental data. PMID- 21258673 TI - Influence of deuteration on lithium acetate dihydrate studied by inelastic X-ray scattering, density functional theory, thermal expansion, elastic and thermodynamic measurements. AB - The influence of deuteration on the properties of lithium acetate dihydrate has been investigated by thermal expansion measurements, ultrasound spectroscopy and calorimetry. Inelastic X-ray scattering has been employed to investigate if the low temperature structural phase transition can be detected by a change in the vibrational spectrum. Density functional theory, DFT, calculations have been employed to complement the experimental investigations. The thermal expansion coefficients and the specific heat of the deuterated compound differ significantly from the protonated form. The differences in the elastic stiffness coefficients are just above the detection limit of the technique employed here. Temperature dependent inelastic X-ray spectroscopic measurements show no significant change of the vibrational spectrum when crossing the transition temperature. The DFT calculations show that the methyl group dynamics are best described in the framework of coupled rotators of opposing methyl groups. One of the coupled rotational modes corresponds to a hindered rotator with a barrier of 15 meV, while the other is a free rotator. PMID- 21258674 TI - Synthesis of glycerol carbonate from glycerol and urea with gold-based catalysts. AB - The reaction of glycerol with urea to form glycerol carbonate is mostly reported in the patent literature and to date there have been very few fundamental studies of the reaction mechanism. Furthermore, most previous studies have involved homogeneous catalysts whereas the identification of heterogeneous catalysts for this reaction would be highly beneficial. This is a very attractive reaction that utilises two inexpensive and readily available raw materials in a chemical cycle that overall, results in the chemical fixation of CO(2). This reaction also provides a route to up-grade waste glycerol produced in large quantities during the production of biodiesel. Previous reports are largely based on the utilisation of high concentrations of metal sulfates or oxides, which suffer from low intrinsic activity and selectivity. We have identified heterogeneous catalysts based on gallium, zinc, and gold supported on a range of oxides and the zeolite ZSM-5, which facilitate this reaction. The addition of each component to ZSM-5 leads to an increase in the reaction yield towards glycerol carbonate, but supported gold catalysts display the highest activity. For gold-based catalysts, MgO is the support of choice. Catalysts have been characterised by XRD, TEM, STEM and XPS, and the reaction has been studied with time-on-line analysis of products via a combination of FT-IR spectroscopy, HPLC, (13)C NMR and GC-MS analysis to evaluate the reaction pathway. Our proposed mechanism suggests that glycerol carbonate forms via the cyclization of a 2,3-dihydroxypropyl carbamate and that a subsequent reaction of glycerol carbonate with urea yields the carbamate of glycerol carbonate. Stability and reactivity studies indicate that consecutive reactions of glycerol carbonate can limit the selectivity achieved and reaction conditions can be selected to avoid this. The effect of the catalyst in the proposed mechanism is discussed. PMID- 21258675 TI - GPS-YNO2: computational prediction of tyrosine nitration sites in proteins. AB - The last decade has witnessed rapid progress in the identification of protein tyrosine nitration (PTN), which is an essential and ubiquitous post-translational modification (PTM) that plays a variety of important roles in both physiological and pathological processes, such as the immune response, cell death, aging and neurodegeneration. Identification of site-specific nitrated substrates is fundamental for understanding the molecular mechanisms and biological functions of PTN. In contrast with labor-intensive and time-consuming experimental approaches, here we report the development of the novel software package GPS-YNO2 to predict PTN sites. The software demonstrated a promising accuracy of 76.51%, a sensitivity of 50.09% and a specificity of 80.18% from the leave-one-out validation. As an example application, we predicted potential PTN sites for hundreds of nitrated substrates which had been experimentally detected in small scale or large-scale studies, even though the actual nitration sites had still not been determined. Through a statistical functional comparison with the nitric oxide (NO) dependent reversible modification of S-nitrosylation, we observed that PTN prefers to attack certain fundamental biological processes and functions. These prediction and analysis results might be helpful for further experimental investigation. Finally, the online service and local packages of GPS-YNO2 1.0 were implemented in JAVA and freely available at: . PMID- 21258676 TI - Spray desorption collection: an alternative to swabbing for pharmaceutical cleaning validation. AB - Spray Desorption Collection (SDC) allows for much larger areas of surfaces to be sampled compared to traditional swabbing techniques, providing a valuable pre concentration advantage. Closely related to desorption electrospray ionization (DESI), analytes from the sample surface are collected onto a selected collection surface, which in a second step can be analyzed directly. Here we demonstrate the application of SDC as a large surface area sampling tool coupled with paper spray MS (PS-MS) and demonstrate its capabilities for cleaning validation of pharmaceutical equipment for both acidic and basic active ingredients from an aluminium surface. PMID- 21258677 TI - Distinction of Fusarium oxysporum fungal isolates (strains) using FTIR-ATR spectroscopy and advanced statistical methods. AB - Fusarium is a large fungi genus of a large variety of species and strains which inhabits soil and vegetation. It is distributed worldwide and affiliated to both warm and cold weather. Fusarium oxysporum species, for instance, cause the Fusarium wilt disease of plants, which appears as a leaf wilting, yellowing and eventually plant death. Early detection and identification of these pathogens are very important and might be critical for their control. Previously, we have managed to differentiate among different fungi genera (Rhizoctonia, Colletotrichum, Verticillium and Fusarium) using FTIR-ATR spectroscopy methods and cluster analysis. In this study, we used Fourier-transform infrared (FTIR) attenuated total reflection (ATR) spectroscopy to discriminate and differentiate between different strains of F. oxysporum. The result obtained was of spectral patterns distinct to each of the various examined strains, which belong to the same species. These differences were not as significant as those found between the different genera species. We applied advanced statistical techniques: principal component analysis (PCA) and linear discriminant analysis (LDA) on the FTIR-ATR spectra in order to examine the feasibility of distinction between these fungi strains. The results are encouraging and indicate that the FTIR-ATR methodology can differentiate between the different examined strains of F. oxysporum with a high success rate. Based on our PCA and LDA calculations performed in the regions [900-1775 cm(-1), 2800-2990 cm(-1), with 9 PCs], we were able to classify the different strains with high success rates: Foxy1 90%, Foxy2 100%, Foxy3 100%, Foxy4 92.3%, Foxy5 83.3% and Foxy6 100%. PMID- 21258678 TI - Nanoparticle-based strategies for detection and remediation of environmental pollutants. AB - Sensitive detection and efficient removal of an increasing number of persistent and emerging environmental pollutants are major challenges in our industrialized world. Now these challenges can be better answered by utilizing the advantages of nanotechnology in addition to traditional methods. Due to unique features of nanomaterials, such as size, surface area, adsorptivity, photoelectronic, and photocatalytic properties, they have emerged to be important materials in the analytical detection and remediation of environmental pollutants. PMID- 21258679 TI - Rapid, quantitative, and site specific synthesis of biomolecular radicals from a simple photocaged precursor. AB - Novel p-iodobenzoate-based labelling reagents are shown to be effective photocaged precursors for synthesizing biomolecular radicals site-selectively in the gaseous and condensed phases. In vacuo, a single pulse of UV photons (266 nm) is sufficient to quantitatively photolyse the C-I bond. In aqueous solutions, the photolysis half-life is estimated to be 2.5 minutes when irradiating with a 15 W compact fluorescent lamp (254 nm). PMID- 21258680 TI - An unprecedented 3D 8-connected pure inorganic framework based on nanosized {[Na12PO16H24]?[P4Mo6O31H6]4}15- clusters and zinc cations. AB - The first 3D uninodal eight-connected {P(4)Mo(6)O(31)H(6)}-based pure inorganic framework linked by transition metal ions has been synthesized and its electrochemical behavior and diffuse reflectance UV-Vis spectrum were investigated. PMID- 21258681 TI - Solid-state dye-sensitized solar cells fabricated by coupling photoelectrochemically deposited poly(3,4-ethylenedioxythiophene) (PEDOT) with silver-paint on cathode. AB - A PEDOT-based dye-sensitized solar cell (DSC) is successfully improved by coupling photoelectrochemically deposited PEDOT layer with an Ag paste-paint on the cathode. With a 9.3 MUm thick mesoscopic nanocrystalline TiO(2) film, a maximum cell performance of 3.2% with relatively high V(oc) of around 780 mV is achieved. PMID- 21258682 TI - Determining excitation temperature of fragmented C60 via momentum distributions of fragments. AB - Hot C(60) molecules under nanosecond laser excitation decay by a variety of fragmentation channels. An experimental search has been made to determine the excitation temperature of fragmented C(60)via analyzing the momentum distributions of the prompt ionic fragments C(n)(+) (n <= 58). It was found that all the C(60) precursors appearing as these ionic fragments have almost the same temperature and the temperature shows little variation with the laser fluences in our limited range. The results provide a clear evidence that a first-order phase transition in the fragmented C(60) is occurring at this temperature. The value of phase transition temperature is found to be about 6050 +/- 250 K, which is in a good agreement with the most recent estimations based on the molecular dynamics simulation. This approach offers an experimental opportunity for studying the fragmentation thermodynamics of more complex polyatomic molecules under excitation temperature determined conditions. PMID- 21258683 TI - Oxygen adsorption on small PtNi nanoalloys. AB - The adsorption of an oxygen molecule on nanoclusters of Pt and PtNi, in the size range between 13 and 55 atoms, has been studied using first-principle simulations. The structures have been obtained as a function of size and chemical composition of the clusters by means of the parallel excitable-walkers basin hopping method. O(2) preferentially adsorbs along the edge between two (111) facets due to a massive distortion of the Pt-Pt bond length. This bond elongation favours the adsorption in such a way that the binding energy of oxygen on a pure 55-atom cluster is still twice the value on the clean Pt(111). On the other hand, on 55-Pt(shell)Ni(core) nanoparticles, the O(2) binding energy is slightly lower than on Pt(111), because nickel core inhibits the stretching of the Pt-bond because of their size mismatch. However, as soon as its concentration is increased, Ni appears at the surface and its oxyphilic nature contributes to bind the oxygen molecule stronger. PMID- 21258684 TI - Trajectory analysis of single molecules exhibiting non-brownian motion. AB - Four techniques for analyzing single molecule tracking data--confinement level analysis, time series analysis and statistical analysis of lateral diffusion, multistate kinetics, and a newly developed method, radius of gyration evolution analysis--are compared using a set of sample fluorophore trajectories obtained from the lipophilic carbocyanine dye 1,1'-dioctadecyl-3,3,3'3' tetramethylindocarbocyanine, DiIC(18), partitioned into surface tethered poly(n isopropylacrylamide). The purpose here is two-fold: first to test that these techniques can be applied to single molecules trajectories, which typically contain a smaller total number of frames than those obtained from other particles, e.g. quantum dots or gold nanoparticles; and second to critically compare the information obtained from each method against the others. A set of five SMT trajectories, ranging in length from 41 to 273 steps with a 30 ms frame transfer exposure, were all successfully analyzed by all four techniques, provided two important criteria were met: enough steps to define the motion were acquired in the trajectory, generally on the order of 50 steps, and the fast and slow diffusion coefficients differ by at least a factor of 5. Beyond that the four trajectory analysis methods studied provide partially confirmatory and partially complementary information. SMT data resulting from more complex physical behavior may well benefit from using these techniques in succession to identify and sort populations. PMID- 21258686 TI - Determination of the temperature dependence of the dynamic nuclear polarisation enhancement of water protons at 3.4 Tesla. AB - It is shown that the temperature dependence of the DNP enhancement of the NMR signal from water protons at 3.4 T using TEMPOL as a polarising agent can be obtained provided that the nuclear relaxation, T(1I), is sufficiently fast and the resolution sufficient to measure the (1)H NMR shift. For high radical concentrations (~100 mM) the leakage factor is approximately 1 and, provided sufficient microwave power is available, the saturation factor is also approximately 1. In this situation the DNP enhancement is solely a product of the ratio of the electron and nuclear gyromagnetic ratios and the coupling factor enabling the latter to be directly determined. Although the use of high microwave power levels needed to ensure saturation causes rapid heating of the sample, this does not prevent maximum DNP enhancements, epsilon(0), being obtained since T(1I) is very much less than the characteristic heating time at these concentrations. It is necessary, however, to know the temperature variation of T(1I) to allow accurate modelling of the behaviour. The DNP enhancement is found to vary linearly with temperature with epsilon(0)(T) = -2 +/- 2 - (1.35 +/- 0.02)T for 6 degrees C <= T <= 100 degrees C. The value determined for the coupling factor, 0.055 +/- 0.003 at 25 degrees C, agrees very well with the molecular dynamics simulations of Sezer et al. (Phys. Chem. Chem. Phys., 2009, 11, 6626) who calculated 0.0534, however the experimental values increase much more rapidly with increasing temperature than predicted by these simulations. Large DNP enhancements (|epsilon(0)| > 100) are reported at high temperatures but it is also shown that significant enhancements (e.g.~40) can be achieved whilst maintaining the sample temperature at 40 degrees C by adjusting the microwave power and irradiation time. In addition, short polarisation times enable rapid data acquisition which permits further enhancement of the signal, such that useful liquid state DNP-NMR experiments could be carried out on very small samples. PMID- 21258685 TI - Competitive adsorption of macromolecules and real-time dynamics of Vroman-like effects. AB - Quasi-elastic light scattering (QELS) and quartz crystal microbalance (QCM) non equilibrium and equilibrium studies of competitive interactions of pairs of polymers and proteins with fumed silica and ceramic coatings deposited on QCM crystals show complex interfacial behaviour. The effects observed depend on the adsorption sequence of co-adsorbates, their chemical structure and the morphology and chemical structure of the adsorbent. The equilibrium adsorption and dynamics of interactions of macromolecules with bare adsorbent surface and surface covered with pre-adsorbed polymer or protein, are compared in terms of the distribution functions of the Gibbs free energy of adsorption, which varied from -25 kJ mol( 1) on a bare surface to almost 0 kJ mol(-1) on a polymer or protein coated surface. PMID- 21258687 TI - The structure and catalytic activity of anatase and rutile titania supported manganese oxide catalysts for selective catalytic reduction of NO by NH3. AB - The structure and catalytic properties of anatase and rutile supported manganese oxide catalysts prepared by impregnation method have been studied by using X-ray diffraction (XRD), laser Raman spectroscopy (LRS), X-ray photoelectron spectroscopy (XPS), H(2) temperature-programmed reduction (H(2)-TPR) and BET surface area measurements combined with activity testing of selective catalytic reduction (SCR) of NO by NH(3). It has been shown that the manganese oxide loadings on the two TiO(2) supports exert great influences on the SCR activity. For the rutile supported manganese oxide catalysts, increasing manganese oxide loading leads to the increase of reducibility of dispersed manganese oxide species and the rate constant k, which reaches a maximum around 9.6 * 10(-6) mol g(Mn)(-1) s(-1) at 0.5 mmol Mn per 100 m(2) TiO(2). When the manganese oxide loading is beyond this value, the existence of amorphous MnO(x) multiple layers will certainly reduce the ratio of manganese oxide species exposed on the surface and the reducibility of dispersed manganese oxide species, resulting in the rapid decrease of rate constant k. The LRS and XPS results have revealed that for the anatase supported manganese oxide catalysts manganese oxide species exist in Mn(+4) as a major species with Mn(+3) species and partially undecomposed Mn nitrate as the minor species. Under the SCR reaction conditions, Mn(+3) species on anatase are oxidized to Mn(+4) species, inserting in the surface of anatase and promoting the anatase-to-rutile transformation in the surface layers of the anatase support. Since these Mn(4+) cations are actually dispersed on the support with a rutile shell-anatase core structure and its concentration is very near to that of MnO(x)/TiO(2) (R) catalyst, the relation between the rate constant k and the MnO(x) loading on the anatase support is similar to that on the rutile support, and that the rate constant k values for anatase and rutile supported manganese oxide catalysts are very close at the same MnO(x) loading. PMID- 21258688 TI - Comment on "Theoretical investigations into the enantiomeric and racemic forms of alpha-(trifluoromethyl)lactic acid" by R. Tonner, V. A. Soloshonok and P. Schwerdtfeger, Phys. Chem. Chem. Phys., 2011, 13, 811-817. AB - It is argued that differences between homo- and heterochiral dimers of the title compound in the gas phase cannot be responsible for the different sublimation behaviour of racemic and enantiomerically pure crystals near room temperature. PMID- 21258690 TI - Characterization of oxides obtained by heating a mixture of peroxoniobic acid and peroxotitanic acid. AB - Nb-doped TiO(2) particles were prepared by heating a mixture of peroxotitanic acid and peroxoniobic acid in air. When the heating temperature was more than 1173 K, the dominant phase obtained was rutile TiO(2), along with a small amount of TiNb(2)O(7). The relationship between the lattice parameters of the obtained rutile TiO(2) depended on the molar fraction of Nb/(Ti + Nb). In the case where peroxo compounds were used as a precursor, a change in the lattice parameters of the rutile TiO(2) was observed within the lower X(Nb) range, as compared to the alkoxide method. The results indicate that a homogeneous dispersion of doped Nb(5+) ions in the obtained rutile TiO(2) lattice was achieved by using peroxo compounds. Furthermore, the oxide particles obtained by using peroxo compounds had a lower activation energy of the carrier electrons (E(a)) and oxygen vacancies, even though the heating procedure was carried out in air. The UV-vis absorption spectra and Raman spectra of the obtained oxide particles indicated that the dominant reaction of the decomposition of O(2)(2-) ions in the TiO(2) lattice was O(2)(2-)-> O(2) + 2e(-) as a reducing agent. PMID- 21258691 TI - Monoalkyl and monoanilide yttrium complexes containing tridentate pyridyl-1 azaallyl dianionic ligands. AB - A series of pyridyl-1-azaallyl ligand precursors (HL1-HL5) were synthesized via condensation of pyridine ketones with anilines. The alkane elimination reactions between Y(CH(2)SiMe(3))(3)(THF)(2) and HL4 or HL5 gave the monoalkyl complexes (L4-H)YCH(2)SiMe(3)(THF) (1) and (L5-H)YCH(2)SiMe(3)(THF) (2) supported by new tridentate pyridyl-1-azaallyl dianionic ligands. The reactions of monoalkyl complexes, 1 and 2, with one equivalent of 2,6-diisopropylaniline produced the corresponding monoanilide complexes, (L4-H)YNHAr(THF) (3) and (L5-H)YNHAr(THF) (4) (Ar = 2,6-((i)Pr)(2)C(6)H(3)), via highly selective protonolysis of the terminal alkyl Y-CH(2)SiMe(3) bond. Complexes 1-4 are active for intramolecular hydroamination of aminoalkenes. PMID- 21258692 TI - Cupredoxins--a study of how proteins may evolve to use metals for bioenergetic processes. AB - Cupredoxins are small proteins that contain type I copper centers, which are ubiquitous in nature. They function as electron transfer shuttles between proteins. This review of the structure and properties of native cupredoxins, and those modified by site-directed mutagenesis, illustrates how these proteins may have evolved to specifically bind copper, develop recognition sites for specific redox partners, tune redox potential for a particular function, and allow for efficient electron transfer through the protein matrix. This is relevant to the general understanding of the roles of metals in energy metabolism, respiration and photosynthesis. PMID- 21258693 TI - Fabrication of hybrids based on graphene and metal nanoparticles by in situ and self-assembled methods. AB - In this work, we developed two novel strategies to attach metal nanoparticles (Au and Ag) to the surface of graphene nanosheets, in which graphene oxide was first modified by the linking molecule (3-mercaptopropyl)triethoxysilane and then subjected to different treatments including in situ and self-assembled techniques. The synthesis processes and the resulting hybrids were investigated by ultraviolet-visible measurements, scanning electron microscopy, transmission electron microscopy, and X-ray photoelectron spectroscopy. It was found that both approaches could effectively immobilize metal nanoparticles onto a graphene surface, and that better distribution and size control of metal nanoparticles were obtained by the self-assembled method. Moreover, we prepared poly(vinylidene fluoride)/graphene-Ag nanocomposites by a solution blending method. The AC conductivity of the resulting nanocomposites could be increased significantly when the loading amount of graphene-Ag was only 2 wt%. We expect that such graphene-metal nanoparticle hybrids may be potentially useful in composite reinforcement, sensors, and electronic devices. PMID- 21258694 TI - A facile synthetic route for the preparation of gold nanostars with magnetic cores and their reusable nanohybrid catalytic properties. AB - A facile synthetic route under mild conditions to the preparation of gold nanostars (GNSs) with Fe3O4 cores (Fe3O4@GNSs), possessing magnetization and tunable optical properties from the visible to near-infrared (NIR) region, was developed. Additionally, the resulting Fe3O4@GNSs described here show good catalytic activity for the reduction of potassium ferricyanide as a model reaction. Importantly, the catalyst, Fe3O4@GNSs, can be easily recycled with an external magnet and exhibits long-life, good reusability and stability. We also anticipated that Fe3O4@GNSs may provide a platform for broad potential diagnostic and therapeutic biomedical applications due to its magnetization and tunable optical properties from the visible to NIR region. PMID- 21258695 TI - Nanoscale coordination polymers exhibiting luminescence properties and NMR relaxivity. AB - This article presents the first example of ultra-small (3-4 nm) magneto luminescent cyano-bridged coordination polymer nanoparticles Ln0.33(3+)Gdx3+/[Mo(CN)8]3- (Ln=Eu (x=0.34), Tb (x=0.35)) enwrapped by a natural biocompatible polymer chitosan. The aqueous colloidal solutions of these nanoparticles present a luminescence characteristic of the corresponding lanthanides (5D0->7F0-4 (Eu3+) or the 5D4->7F6-2 (Tb3+)) under UV excitation and a green luminescence of the chitosan shell under excitation in the visible region. Magnetic Resonance Imaging (MRI) efficiency, i.e. the nuclear relaxivity, measurements performed for Ln0.33(3+)Gdx3+/[Mo(CN)8]3- nanoparticles show r1p and r2p relaxivities slightly higher than or comparable to the ones of the commercial paramagnetic compounds Gd-DTPA(r) or Omniscan(r) indicating that our samples may potentially be considered as a positive contrast agent for MRI. The in vitro studies performed on these nanoparticles show that they maybe internalized into human cancer and normal cells and well detected by fluorescence at the single cell level. They present high stability even at low pH and lack of cytotoxicity both in human cancer and normal cells. PMID- 21258696 TI - Significant enhancement of yellow-green light emission of ZnO nanorod arrays using Ag island films. AB - Surface plasmon (SP) mediated emission from ZnO nanorod arrays (NRAs)/Ag/Si structures has been investigated. The ratio of visible emission to UV emission can be increased by over 30 times via coupling with SP without deterioration of the crystal quality. The fact that the effect of SP crucially depends on the size of Ag island films provides the feasibility to significantly enhance the yellow green emission of the ZnO nanostructures without sacrificing the crystallinity of ZnO. PMID- 21258697 TI - Confirmation of the electrostatic self-assembly of nanodiamonds. AB - A reliable explanation for the underlying mechanism responsible for the persistent aggregation and self-assembly of colloidal 5 nm diamond nanoparticles is critical to the development of nanodiamond-based technologies. Although a number of mechanisms have been proposed, validation has been hindered by the inherent difficulty associated with the identification and characterisation of the inter-particle interfaces. In this paper we present results of high resolution aberration corrected electron microscopy and complementary computer simulations to explicate the features involved, and confirm the electrostatic interaction mechanism as the most probable cause for the formation of agglutinates and agglomerates of primary particles. PMID- 21258698 TI - A rational approach to tuning the pKa values of rhodamines for living cell fluorescence imaging. AB - A novel strategy to systematically tune the pK(a) values of rhodamines is described. This strategy was applied to rationally develop compound 1e with a pK(a) of 6.5, the highest among rhodamine amide derivatives, and it could be employed to detect acidic pH variations in living cells with a turn-on signal. PMID- 21258699 TI - Highly efficient asymmetric vinylogous Mannich reaction induced by O-pivaloylated D-galactosylamine as the chiral auxiliary. AB - The diastereospecific formation of beta-N-glycoside-linked alpha-amino-2(5H) furanone has been achieved with high yield via a vinylogous Mannich reaction. The reaction was performed by using O-pivaloylated galactosylamine 1 as a chiral template and ZnCl(2).Et(2)O as a promoter in Et(2)O. Imines 3 of aromatic compounds and trimethylsiloxyfuran 4 were converted to N-galactosyl alpha-amino 2(5H)-furanone 5, giving ratios of diastereomers higher than 20:1. This procedure provides rapid access to biologically important gamma-butenolide derivatives. PMID- 21258701 TI - Anomalous oriented attachment growth behavior on SnO2 nanocrystals. AB - This work reports a detailed characterization of an anomalous oriented attachment behaviour for SnO(2) nanocrystals. Our results evidenced an anisotropic growth for two identical <110> directions, which are equivalent according to the SnO(2) crystallographic structure symmetry. A hypothesis is proposed to describe this behaviour. PMID- 21258700 TI - Synthesis and photochromic properties of imidazole-based diarylethenes. AB - A series of symmetrical imidazole- and N-methylated imidazole-based diarylethenes were synthesized, and the structures have been well characterized by NMR spectroscopy and mass spectrometry. Their photochromism were investigated upon UV/vis light irradiation in DMF solution. A significant red-shift of UV absorption was observed after irradiation with UV light when substituents on the benzene ring (such as methoxyl group) were introduced. But N-methylation on the two imidazole rings will result in a blue-shift of UV absorption. The photophysical properties can be adjusted by changing the substituents, which provides a new strategy for the design of diarylethenes with excellent properties. PMID- 21258702 TI - Tuning the light absorption of a molecular vanadium oxide system for enhanced photooxidation performance. AB - A new mechanism for enhancing the visible light absorption of a homogeneous polyoxovanadate system is described. The photoactive pentanuclear {V(5)} isopolyoxovanadate cluster is formed in situ by a thermally-induced condensation reaction starting from a tetranuclear {V(4)} precursor. Upon irradiation with visible light, {V(5)} undergoes a light induced reduction reaction resulting in the formation of a 2-electron reduced {V(10)} cluster. Simultaneously, the oxidant methanol is selectively oxidized to formaldehyde. The {V(10)} cluster can subsequently be re-oxidized using H(2)O(2) or O(2). PMID- 21258703 TI - Modelling of synchrotron SAXS patterns of silicalite-1 zeolite during crystallization. AB - Synchrotron small angle X-ray scattering (SAXS) was used to characterize silicalite-1 zeolite crystallization from TEOS/TPAOH/water clear sol. SAXS patterns were recorded over a broad range of length scales, enabling the simultaneous monitoring of nanoparticles and crystals occurring at various stages of the synthesis. A simple two-population model accurately described the patterns. Nanoparticles were modeled by polydisperse core-shell spheres and crystals by monodisperse oblate ellipsoids. These models were consistent with TEM images. The SAXS results, in conjunction with in situ light scattering, showed that nucleation of crystals occurred in a short period of time. Crystals were uniform in size and shape and became increasingly anisotropic during growth. In the presence of nanoparticles, crystal growth was fast. During crystal growth, the number of nanoparticles decreased gradually but their size was constant. These observations suggested that the nanoparticles were growth units in an aggregative crystal growth mechanism. Crystals grown in the presence of nanoparticles developed a faceted habit and intergrowths. In the final stages of growth, nanoparticles were depleted. Concurrently, the crystal growth rate decreased significantly. PMID- 21258704 TI - Periodic ab initio estimates of the dispersive interaction between molecular nitrogen and a monolayer of hexagonal BN. AB - The ab initio determination of the leading long-range term of pairwise additive dispersive interactions, based on the independent analysis of the response properties of the interacting objects, is here considered in the case where these are part of a periodic system. The interaction of a nitrogen molecule with a thin film of hexagonal BN has been chosen as a case study for identifying some of the problems involved, and for proposing techniques for their solution. In order to validate the results so obtained, the interaction energy between N(2) and a BN monolayer at different distances has been estimated following a totally different approach, namely by performing post-Hartree-Fock (MP2) supercell calculations using the Crystal+Cryscor suite of programs. The results obtained with the two approaches closely agree over a long range, while the limit of validity of the purely dispersive regime can be clearly assessed. PMID- 21258705 TI - Rayleigh scattering study and particle density determination of a high refractive index TiO2 nanohybrid polymer. AB - We have experimentally carried out a Rayleigh scattering study of a high refractive index TiO(2) nanohybrid polymer. By employing the Rayleigh scattering technique with at least three different wavelengths, we can obtain the Rayleigh ratio of the TiO(2) nanohybrid polymer at each utilized wavelength. These measured Rayleigh ratios are then used to estimate the size of the nanoparticle and determine the number of nanoparticles per unit volume or particle density. Furthermore, this technique can be used to evaluate the dominant size of nanoparticles in the nanohybrid polymer mainly contributed to Rayleigh scattering. PMID- 21258706 TI - On the nature of OH-stretching vibrations in hydrogen-bonded chains: pump frequency dependent vibrational lifetime. AB - Two-dimensional infrared spectroscopy was carried out on stereoselectively synthesized polyalcohols. Depending upon the stereochemical orientation of their hydroxyl groups, the polyols can either feature linear chains of hydrogen bonds that are stable for extended periods of time or they can display ultrafast dynamics of hydrogen-bond breakage and formation. In the former case, the OH stretching vibrations and their transition dipoles are substantially coupled, hence prior to vibrational relaxation, the initial OH-stretching excitation is rapidly redistributed among the set of hydroxyl-groups constituting the hydrogen bonded chain. This redistribution is responsible for an ultrafast loss of memory regarding the frequency of initial excitation and as a result, a pump-frequency independent vibrational lifetime is observed. In contrast, in the latter case, the coupling of the OH-groups and their transition dipoles is much weaker. Therefore, the OH-stretching excitation remains localized on the initially excited oscillator for the time scale of vibrational energy relaxation. As a result inhomogeneous relaxation dynamics with a pump-frequency-dependent lifetime are observed. PMID- 21258707 TI - Role of humidity on indium and tin migration in organic photovoltaic devices. AB - The stability of a common interface used in organic photovoltaic cells, between the transparent electrode of Indium Tin Oxide (ITO) and a buffer layer of poly(3,4-ethylenedioxythiophene):poly(4-styrenesulfonate) (PEDOT:PSS) is strongly influenced by the presence of humidity during processing, leading to significant migration of indium and tin species into the PEDOT:PSS layer. The interface was studied using neutral impact collision ion scattering spectroscopy (NICISS) and X ray photoelectron spectroscopy (XPS), to determine migration of indium and tin into the polymer layer. It was found that the migration starts almost instantly after spin coating of the aqueous PEDOT:PSS solution and it reaches a saturation level within twenty four hours. The indium and tin were found always uniformly distributed over the sampling depth of almost one-third of the thickness of the PEDOT:PSS layer. Exposure to humidity following annealing resulted in the highest concentration (1.8 * 10(-3) mol cm(-3)) of indium or tin species, corresponding to about one indium or tin moiety per 4.7 monomer units in the PEDOT:PSS. The maximum bulk concentration of indium is about two orders of magnitude higher after exposure to humid conditions compared to vacuum dried conditions. XPS measurements confirm the presence of both indium and tin in the PEDOT:PSS and the formation of salts with the metal ions as cations. PMID- 21258708 TI - Is the methanation reaction over Ru single crystals structure dependent? AB - The influence of monoatomic steps and defects on the methanation reaction over ruthenium has been investigated. The experiments are performed on a Ru(0 1 54) ruthenium single crystal, which contains one monoatomic step atom for each 27 terrace atoms. The methanation activity is measured at one bar of hydrogen and CO in a high pressure cell, which enables simultaneous measurements of the local reactivity of the well defined single crystal surface and the global reactivity of the entire crystal and its auxiliary support. By adding sulfur we observe that the measured activity from the well defined stepped front-side of the crystal is poisoned faster than the entire crystal containing more defects. We also observe that additional sputtering of the well-defined front-side increases the reactivity measured on the surface. Based on this, we conclude that the methanation reaction takes place on undercoordinated sites, such as steps and kinks, and that the methanation reaction is extremely structure dependent. Simulations of the flow, temperature, and product distributions in the high pressure cell are furthermore presented as supplementary information. PMID- 21258709 TI - Effect of the chemical composition on the work function of gold substrates modified by binary self-assembled monolayers. AB - This study demonstrated that the work function (Phi) of Au substrates can be fine tuned by using series ratios of binary self-assembled monolayers (SAMs). By using pure amine- and carboxylic acid-bearing alkanethiol SAM on gold substrates, Phi of Au changed from 5.10 to 5.16 and 5.83, respectively, as determined by ultra violet photoelectron spectrometry (UPS). The shift in Phi due to the use of different functional groups was rationalized by considering the dipole moments of the molecules anchored on the Au surface. A series of binary SAMs were fabricated by mixing carboxylic acid- and amine-terminated alkanethiols in the deposition solution. By mixing these functional groups in SAMs, a linear correlation between Phi with respect to chemical composition (hence the effective dipole moment on the Au surface) was observed. It was found that arbitrary Phi between extremes (5.16 and 5.83) controlled by respective functional groups can be obtained by changing the chemical composition of SAMs. The Scanning Kelvin Probe (SKP) was also used to measure the contact potential difference (CPD) between SAMs and referencing Au on a patterned substrate prepared by photo-lithography. It was found that the CPD of SAMs with different chemical compositions correlates to their Phi. However, the magnitude of the CPD was smaller than the difference in Phi measured by UPS that was possibly due to the adsorption of contaminants in air. PMID- 21258711 TI - Dynamics of scattering and dissociative adsorption on a surface alloy: H2/W(100) c(2 * 2)Cu. AB - H(2) scattering and dissociative adsorption on the W(100)-c(2 * 2)Cu surface alloy is studied based on DFT calculations. A strongly site dependent reactivity is observed in line with results obtained for the density of states projected onto the W and Cu atoms of the topmost layer. H(2) dissociation on a defect free terrace of W(100)-c(2 * 2)Cu is found to be a non-activated process like on W(100), despite the reduction of the number of energetically accessible dissociation pathways at low impact energies due to the presence of Cu atoms. A prominence of dynamic trapping and a reduction of the efficacy of trapping to promote dissociation is also verified, leading to a decrease of the initial sticking probability as a function of the molecular impact energy, in qualitative agreement with experimental findings. The heterogeneous reactivity is also evidenced by two different kinds of reflection events at low energies. Its combination gives rise to a broad specular peak superimposed on a cosine-like angular distribution of scattered molecules which is in good agreement with available experimental data. PMID- 21258710 TI - Towards biochemical filters with a sigmoidal response to pH changes: buffered biocatalytic signal transduction. AB - We realize a biochemical filtering process by introducing a buffer in a biocatalytic signal-transduction logic system based on the function of an enzyme, esterase. The input, ethyl butyrate, is converted into butyric acid--the output signal, which in turn is measured by the drop in the pH value. The developed approach offers a versatile "network element" for increasing the complexity of biochemical information processing systems. Evaluation of an optimal regime for quality filtering is accomplished in the framework of a kinetic rate-equation model. PMID- 21258712 TI - Computational design approaches and tools for synthetic biology. AB - A proliferation of new computational methods and software tools for synthetic biology design has emerged in recent years but the field has not yet reached the stage where the design and construction of novel synthetic biology systems has become routine. To a large degree this is due to the inherent complexity of biological systems. However, advances in biotechnology and our scientific understanding have already enabled a number of significant achievements in this area. A key concept in engineering is the ability to assemble simpler standardised modules into systems of increasing complexity but it has yet to be adequately addressed how this approach can be applied to biological systems. In particular, the use of computer aided design tools is common in other engineering disciplines and it should eventually become centrally important to the field of synthetic biology if the challenge of dealing with the stochasticity and complexity of biological systems can be overcome. PMID- 21258713 TI - Metabolomic anatomy of an animal model revealing homeostatic imbalances in dyslipidaemia. AB - Metabolomics is an emerging technology that reveals homeostatic imbalances in biological systems. Global determination of metabolite concentrations in body fluid and tissues provides novel anatomical aspects of pathological conditions that cannot be obtained from target-specific measurements. Here, we characterised metabolic imbalance in Watanabe heritable hyperlipidaemic rabbits as a model of hypercholesterolaemia. Using a mass spectrometry-based system, we measured a total of 335 metabolites in plasma and tissues (liver, aorta, cardiac muscle, and brain) from WHHL and healthy control rabbits. From the comparison between two metabolomic profiles, pathophysiological features including glutathione and phosphatidylcholine metabolism indicated the occurrence of oxidative stress in several tissues. Especially for the liver, imbalanced purine catabolism shed light on the transcriptional activation of xanthine oxidase, which is thought to act in absorbing or possibly triggering oxidative stress. We also applied this system to assess the therapeutic effects of simvastatin administration. After the treatment, a portion of the metabolomic features in pathological conditions showed alterations suggesting restoration of metabolism to the healthy condition. These changes were considered to be due to the pleiotropic action of statin, including antioxidant effects, rather than its main inhibitory action on cholesterol biosynthesis. PMID- 21258714 TI - A facile synthesis of mesoporous crystalline tin oxide films involving a base triggered formation of sol-gel building blocks. AB - We have developed a new facile procedure for manufacturing crystalline thin films of SnO2 with a uniform mesoporous architecture and full crystallinity of the walls. The procedure is based on the evaporation-induced self-assembly (EISA) of prehydrolyzed tin oxide precursor directed by a commercially available Pluronic polymer. The formation of the tin oxide precursor, which can be self-assembled into a mesoporous structure, is achieved by an addition of ammonium hydroxide to a tin tetrachloride solution. The relative concentration of ammonium hydroxide as well as the duration and temperature of the hydrolysis reaction influence significantly the properties of hydrolyzed tin oxide species and the mesostructure assembled from them. The films coated from these precursor solutions and calcined at 300 degrees C to 400 degrees C exhibit a well developed worm-like porosity with a wall to wall distance of ca. 18 nm, a surface area of up to 50 cm2 cm(-2) (corresponding to 55+/-5 m2 g(-1)), and high crystallinity. PMID- 21258715 TI - Stabilisation of SWNTs by alkyl-sulfate chitosan derivatives of different molecular weight: towards the preparation of hybrids with anticoagulant properties. AB - We have previously demonstrated that chitosan derivative N-octyl-O-sulfate chitosan (NOSC), which presents important pharmacological properties, can suspend single walled carbon nanotubes (SWNTs) up to 20 times more effectively than other chitosan derivatives in an aqueous environment. In an attempt to further investigate the impact of different molecular weights of chitosan to the solubilization and anticoagulant properties of these hybrids an array of NOSC derivatives varying their molecular weight (low, medium and high respectively) was synthesised and characterised by means of FT-IR spectroscopy, NMR spectroscopy and thermal gravimetric analysis (TGA). Microwave and nitric acid purified SWNTs, characterised by FT-IR spectroscopy, transmission electron microscopy (TEM) and Raman spectroscopy, were colloidally stabilised by these polymers and their anticoagulant activity was assessed. The results revealed that the low molecular weight NOSC coated SWNTs exhibit the highest activity when 0.5 mg mL(-1) NOSC solutions are used, activity which is similar to that of the free polymer. Preliminary studies by exposure of these hybrids to Brine Shrimp (Artemia) cysts revealed no effect on the viability of sub-adult Artemia. Our findings suggest the possibility of tailoring these nanomaterials to bear the required properties for application as biocompatible building blocks for nanodevices including biosensors and biomaterials. PMID- 21258716 TI - Synthesis of the four stereoisomers of 2,3-epoxy-4-hydroxynonanal and their reactivity with deoxyguanosine. AB - 2,3-Epoxy-4-hydroxynonanal (EHN) is a potential product of lipid peroxidation that gives rise to genotoxic etheno adducts. We have synthesized all four stereoisomers of EHN and individually reacted them with 2'-deoxyguanosine. In addition to 1,N(2)-etheno-2'-deoxyguanosine, 12 stereoisomeric products were isolated and characterized by (1)H NMR and circular dichroism spectroscopy. The stereochemical assignments were consistent with selective NOE spectra, vicinal coupling constants, and molecular mechanics calculations. Reversed-phase HPLC conditions were developed that could separate most of the adduct mixture. PMID- 21258717 TI - DAMPs and PDT-mediated photo-oxidative stress: exploring the unknown. AB - Damage-associated molecular patterns (DAMPs) or cell death associated molecular patterns (CDAMPs) are a subset of endogenous intracellular molecules that are normally hidden within living cells but become either passively released by primary and secondary necrotic cells or actively exposed and secreted by the dying cells. Once released, DAMPs are sensed by the innate immune system and act as activators of antigen-presenting cells (APCs) to stimulate innate and adaptive immunity. Cancer cells dying in response to a subset of conventional anticancer modalities exhibit a particular composition of DAMPs at their cell surface, which has been recently shown to be vital for the stimulation of the host immune system and the control of residual disease. Photodynamic therapy (PDT) for cancer has long been shown to be capable of killing malignant cells and concomitantly stimulate the host immune system, properties that are likely linked to its ability of inducing exposure/release of certain DAMPs. PDT, by evoking oxidative stress at specific subcellular sites through the light activation of organelle associated photosensitizers, may be unique in incorporating tumour cells destruction and antitumor immune response in one therapeutic paradigm. Here we review the current knowledge about mechanisms and signalling cascades leading to the exposure of DAMPs at the cell surface or promoting their release, the cell death mechanism associated to these processes and its immunological consequences. We also discuss how certain PDT paradigms may yield therapies that optimally stimulate the immune system and lead to the discovery of new DAMPs. PMID- 21258718 TI - Antitumor immunity promoted by vascular occluding therapy: lessons from vascular targeted photodynamic therapy (VTP). AB - The development of cancer is tightly related to the successful evasion of neoplastic tissue from immune system surveillance, which represents a key obstacle in tumor therapy. Most conventional therapies (surgery, chemotherapy and radiation) target the tumor cells directly or indirectly, while immunotherapy attempts to enhance host anti-tumor response. In a manner similar to surgery, photodynamic therapy (PDT), also a local tumor therapy, aims at tumor ablation in its initial acute phase. Treatment success is mainly determined by tumor eradication and the absence of local recurrences. However, experience gained over several decades of therapeutic application has repeatedly hinted at long term therapeutic effects of PDT, suggesting activation of the immune system by this treatment modality. Such contribution of the immune system to treatment success was widely confirmed in many laboratories in various preclinical and some clinical studies. In this present short review, we wish to present our modest contribution to this potential therapeutic trend describing the immune response upon application of a novel photosensitizing methodology: vascular targeted photodynamic therapy (VTP) developed in our laboratories. This modality differs from classical PDT in most aspects (sensitizer: Pd-bacteriochlorophyll and consequent spectral wavelength in the near infrared, the generated photochemistry, the treatment target, treatment objective, treatment protocol and more). For example in contrast to the tumor cells that constitute the target of classical PDT, the targets of VTP are the tumor-feeding arteries and draining veins whose almost instant occlusion (minutes) leads to tumor blood stasis and eradication. Some of the mechanistic features of the induced immune response, such as innate and acquired cellular and humoral mediators, induction of new antigens, resulting from oxidative modifications and implications for anti-tumor vaccination in this different treatment environment, are discussed. VTP is about to enter phase III clinical trials for the therapy of prostate cancer and the potential involvement of the immune system may contribute an interesting aspect for the understanding and future development of this treatment modality. PMID- 21258719 TI - Longer-range distances by spinning-angle-encoding solid-state NMR spectroscopy. AB - A new spinning-angle-encoding spin-echo solid-state NMR approach is used to accurately determine the dipolar coupling corresponding to a C-C distance over 4 A in a fully labelled dipeptide. The dipolar coupling dependent spin-echo modulation was recorded off magic angle, switching back to the magic angle for the acquisition of the free-induction decay, so as to obtain optimum sensitivity. The retention of both ideal resolution and long-range distance sensitivity was achieved by redesigning a 600 MHz HX MAS NMR probe to provide fast angle switching during the NMR experiment: for 1.8 mm rotors, angle changes of up to ~5 degrees in ~10 ms were achieved at 12 kHz MAS. A new experimental design that combines a reference and a dipolar-modulated experiment and a master-curve approach to data interpretation is presented. PMID- 21258720 TI - A variable series resistance mechanism to explain the negative capacitance observed in impedance spectroscopy measurements of nanostructured solar cells. AB - A simple model for conductivity modulation in a recombination diode is discussed to explain the observation of negative capacitance at forward bias observed in many optoelectronic devices. We formulate the basic recombination-modulation model in terms of an equivalent circuit for small ac perturbation and discuss the application of the results in measurements of impedance spectroscopy of dye sensitized solar cells, organic solar cells and related systems. PMID- 21258721 TI - Exploring the energy landscape of a molecular engineered analog of a tumor-homing peptide. AB - Recently a new non-coded amino acid was designed as a replacement for Arg, to protect the tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) from proteases. This constrained Arg analog, denoted c(5)Arg, was engineered to also promote the stability of the CREKA bioactive conformation. The conformational profile of the CREKA analog obtained by replacing Arg by c(5)Arg has been extensively investigated in this work. Two molecular dynamics simulations-based strategies have been employed: a modified simulated annealing and replica exchange. Results obtained using both techniques show that the conformational features of the new analog fulfill the purpose of its design. The new CREKA analog not only preserves the main structural attributes found for the bioactive conformation of the parent peptide but also shows lower flexibility. Moreover, the conformational profile of the mutated peptide narrows towards the most stable structures previously observed for the parent CREKA peptide. PMID- 21258723 TI - Diverse structures and adsorption properties of quasi-Werner-type copper(II) complexes with flexible and polar axial bonds. AB - The quasi-Werner-type copper(II) complex, [Cu(PF(6))(2)(4-mepy)(4)] (1), in which 4-mepy is the 4-methylpyridine ligand, has flexible and polar axial bonds of Cu PF(6). Flexibility of the Cu-PF(6) bonds induces diverse and unprecedented guest inclusion structures, such as {[Cu(PF(6))(2)(4-mepy)(4)][Cu(PF(6))(4 mepy)(4)(acetone)].PF(6).4acetone} (gamma-1?2.5acetone), {[Cu(PF(6))(2)(4 mepy)(4)][Cu(PF(6))(4-mepy)(4)(2-butanone)].PF(6).3.5(2-butanone)} (gamma 1?2.25(2-butanone)), {[Cu(PF(6))(2)(4-mepy)(4)][Cu(PF(6))(4 mepy)(4)(H(2)O)].PF(6).4benzene} (gamma-1?0.5H(2)O.2benzene), and {[Cu(PF(6))(2)(4-mepy)(4)].2benzene} (gamma-1?2benzene). Exposure of the dense form, alpha-1, to benzene vapor affords the benzene-inclusion complex {[Cu(PF(6))(2)(4-mepy)(4)].2benzene} (gamma-1?2benzene), all benzene guests of which are easily removed by vacuum drying, reforming guest-free, dense alpha-1' with smaller sized crystals than alpha-1. In contrast to alpha-1, which shows almost no CO(2) adsorption, alpha-1' adsorbs CO(2) gas with structural transformations, this being the first example that exhibits adsorption of gas in a dense Werner-type complex and a drastic change in adsorption properties depending on the size of the crystals. PMID- 21258722 TI - Spectroscopic and computational characterization of CuII-OOR (R = H or cumyl) complexes bearing a Me6-tren ligand. AB - A copper(II)-hydroperoxo complex, [Cu(Me(6)-tren)(OOH)](+) (2), and a copper(ii) cumylperoxo complex, [Cu(Me(6)-tren)(OOC(CH(3))(2)Ph)](+) (3), were synthesized by reacting [Cu(Me(6)-tren)(CH(3)CN)](2+) (1) with H(2)O(2) and cumyl-OOH, respectively, in the presence of triethylamine. These intermediates, 2 and 3, were successfully characterized by various physicochemical methods such as UV vis, ESI-MS, resonance Raman and EPR spectroscopies, leading us to propose structures of the Cu(II)-OOR species with a trigonal-bipyramidal geometry. Density functional theory (DFT) calculations provided geometric and electronic configurations of 2 and 3, showing trigonal bipyramidal copper(II)-OOR geometries. These copper(II)-hydroperoxo and -cumylperoxo complexes were inactive in electrophilic and nucleophilic oxidation reactions. PMID- 21258724 TI - Electronic and photophysical properties of adducts of [Ru(bpy)3]2+ and Dawson type sulfite polyoxomolybdates alpha/beta-[Mo18O54(SO3)2]4-. AB - The spectroscopic and photophysical properties of [Ru(bpy)(3)](2)[[Mo(18)O(54)(SO(3))(2)], where bpy is 2,2'-bipyridyl and [Mo(18)O(54)(SO(3))(2)](4-) is either the alpha or beta-sulfite containing polyoxomolybdate isomer, have been measured and compared with those for the well known but structurally distinct sulfate analogue, alpha-[Mo(18)O(54)(SO(4))(2)](4 ). Electronic difference spectroscopy revealed the presence of new spectral features around 480 nm, although they are weak in comparison with the [Ru(bpy)(3)](2)[Mo(18)O(54)(SO(4))(2)] analogue. Surprisingly, Stern-Volmer plots of [Ru(bpy)(3)](2+) luminescence quenching by the polyoxometallate revealed the presence of both static and dynamic quenching for both alpha and beta [Mo(18)O(54)(SO(3))(2)](4-). The association constant inferred for the ion cluster [Ru(bpy)(3)](2)alpha-[Mo(18)O(54)(SO(4))(2)] is K = 5.9 +/- 0.56 * 10(6) and that for [Ru(bpy)(3)](2)beta-[Mo(18)O(54)(SO(4))(2)] is K = 1.0 +/- 0.09 * 10(7). Unlike the sulfate polyoxometalates, both sulfite polyoxometalate ruthenium adducts are non-luminescent. Despite the strong electrostatic association in the adducts resonance Raman and photoelectrochemical studies suggests that unlike the sulfato polyoxometalate analogue there is no sensitization of the polyoxometalate photochemistry by the ruthenium centre for the sulfite anions. In addition, the adducts exhibit photochemical lability in acetonitrile, attributable to decomposition of the ruthenium complex, which has not been observed for other [Ru(bpy)(3)](2+) -polyoxometalate adducts. These observations suggest that less electronic communication exists between the [Ru(bpy)(3)](2+) and the sulfite polyoxoanions relative to their sulfate polyoxoanion counterparts, despite their structural and electronic analogy. The main distinction between sulfate and sulfite polyoxometalates lies in their reversible reduction potentials, which are more positive by approximately 100 mV for the sulfite anions. This suggests that the capacity for [Ru(bpy)(3)](2+) or analogues to sensitize photoreduction in the adducts of polyoxometalates requires very sensitive redox tuning. PMID- 21258725 TI - Integration of high volume portable aerosol-to-hydrosol sampling and qPCR in monitoring bioaerosols. AB - In this study, the integration of a high volume, portable aerosol-to-hydrosol sampling technique and quantitative polymerase chain reaction (qPCR) was investigated for bioaerosol monitoring by adapting the RCS High Flow to sample air with mineral-oil-strips. Bacillus subtilis var niger and Pseudomonas fluorescens were aerosolized and collected by the RCS High Flow loaded with mineral-oil-strips for 1, 2 and 5 min. In addition, the adapted aerosol-to hydrosol sampler was also tested for sampling environmental bacterial aerosols in four different environments (a back yard, a student dorm, a dining hall, and a play ground). The performances of the RCS High Flow with mineral-oil-strips were compared with the use of agar strips under similar conditions in all experiments. Air samples collected by the RCS High Flow were cultured, and in addition those collected with mineral-oil-strips were also quantified using qPCR. When sampling B. subtilis var niger aerosols, the use of mineral-oil-strips was shown to report significantly higher culturable concentrations than those obtained by agar strips regardless of the sampling time tested (p-value = 0.04). In contrast, the differences between the two methods when sampling P. fluorescens aerosols were not statistically significant (p-value = 0.5). When coupled with qPCR, the RCS High Flow loaded with mineral-oil-strips obtained significantly higher bacterial aerosol concentrations than those detected by the culturing method. The sampling time was observed to have negligible effects on the efficiency of the technology developed here. When sampling in different environments, the use of mineral-oil strip was observed to yield significantly higher, about 4-12 times, culturable bacterial aerosol concentration levels compared to the use of agar. This study demonstrated a high volume (100 L min-1) portable aerosol-to-hydrosol sampling technique, holding broad promise in monitoring airborne biological threats when coupled with qPCR technology. Yet, caution should be taken in relating the bioaerosol concentrations to health risks as qPCR detects both culturable and non culturable cells including inactivated ones. PMID- 21258726 TI - Ruthenium(III)-catalysed phenylselenylation of allyl acetates by diphenyl diselenide and indium(I) bromide in neat: isolation and identification of intermediate. AB - A fast and efficient phenylselenylation of allyl acetates by diphenyl diselenide and indium(I) bromide has been achieved in neat under the catalysis of Ru(acac)(3). The intermediate complex of diphenyl diselenide and indium has been isolated and identified as a polymeric pentacoordinated In(III) selenolate complex, [In(SePh)(3)](n). PMID- 21258727 TI - PDT-induced inflammatory and host responses. AB - Photodynamic therapy (PDT) is used in the management of neoplastic and nonmalignant diseases. Its unique mechanisms of action include direct cytotoxic effects exerted towards tumor cells, destruction of tumor and peritumoral vasculature and induction of local acute inflammatory reaction. The latter develops in response to (1) damage to tumor and stromal cells that leads to the release of cell death-associated molecular patterns (CDAMs) or damage associated molecular patterns (DAMPs), (2) early vascular changes that include increased vascular permeability, vascular occlusion, and release of vasoactive and proinflammatory mediators, (3) activation of alternative pathway of complement leading to generation of potent chemotactic factors, and (4) induction of signaling cascades and transcription factors that trigger secretion of cytokines, matrix metalloproteinases, or adhesion molecules. The majority of studies indicate that induction of local inflammatory response contributes to the antitumor effects of PDT and facilitates development of systemic immunity. However, the degree of PDT-induced inflammation and its subsequent contribution to its antitumor efficacy depend on multiple parameters, such as chemical nature, concentration and subcellular localization of the photosensitizers, the spectral characteristics of the light source, light fluence and fluence rate, oxygenation level, and tumor type. Identification of detailed molecular mechanisms and development of therapeutic approaches modulating PDT-induced inflammation will be necessary to tailor this treatment to particular clinical conditions. PMID- 21258728 TI - Cancer vaccines generated by photodynamic therapy. AB - The development of photodynamic therapy (PDT)-generated cancer vaccines is potentially one of the most significant achievements in the field of PDT. Employing vaccine protocols optimizes the capacity of PDT of inducing a strong immune response against treated tumor due to the establishment of highly favourable conditions for maximizing the avidity of the immune reaction while sustaining and prolonging its tumor-destroying attack. While the introduction of PDT vaccines into the clinics and testing on patients is still in a very early phase, much work can still be done on further improvement of the potency of PDT vaccines. Considerable advances can be expected by identifying the most effective adjuvants to be used with PDT vaccines, which will most likely be different with different types of cancerous lesions. PMID- 21258729 TI - A strong support-effect on the catalytic activity of gold nanoparticles for hydrogen peroxide decomposition. AB - Catalytic activity of gold nanoparticle (NP)-loaded metal oxide semiconductors (Au/MOs) for H(2)O(2) decomposition and chemoselective oxidation of cinnamyl alcohol to cinnamaldehyde strongly depends on both the kind of the MO-supports and the Au particle size, and Au/SrTiO(3) exhibits an extraordinary high level of activity for the H(2)O(2) decomposition exceeding that of Pt/TiO(2). PMID- 21258730 TI - Dimerization of pentanuclear clusters [Fe3Q(AsMe)(CO)9] (Q = Se, Te) as a conversion pathway to novel cubane-like aggregates. AB - The first examples of carbonyl heterocubane-type clusters, [Fe(4)(MU(3) Q)(2)(MU(3)-AsMe)(2)(CO)(12)] (2, Q = Se (a), Te (b)), which simultaneously contain elements of group 15 and 16, were obtained by thermolysis of [Fe(3)(MU(3) Q)(MU(3)-AsMe)(CO)(9)] (1) in acetonitrile. The clusters 2 possess a cubic Fe(4)Q(2)As(2) core with alternating Fe and Q/As atoms. The coordination environment of the Fe atoms is close to octahedral, and those of Q or As atoms are tetrahedral, which determines the distorted cubic cluster core geometry. The second main products of thermolysis are the clusters [Fe(6)(MU(3)-Q)(MU(4) Q)(MU(4)-AsMe)(2)(CO)(12)] (3a,b), whose core contains double the elemental composition of the initial cluster 1. In the case of the Se-containing cluster two other minor products [Fe(4)(MU(4)-Se)(MU(4)-SeAsMe)(CO)(12)] (4) and [Fe(3)(MU(3)-AsMe)(2)(CO)(9)] (5) are formed. Based on the structures and properties of the products, a reaction route for the conversion of 1 into 2 is proposed, which includes the associative formation of the clusters 3 as intermediates, unlike the dissociative pathways previously known for the transformations of similar clusters of the type [Fe(3)Q(2)(CO)(9)]. PMID- 21258731 TI - An unexpected dependence on the SnII base; reactions of Sn(NR2)2 with aromatic dithiols. AB - Unexpectedly, the reactions of the Sn(II) base Sn(NMe(2))(2) with 1,2 benzodithiols [L(SH)(2)] do not give the stannylenes, L(S)(2)Sn, which are generated with Sn{N(SiMe(3))(2)}(2), instead the ion-separated Sn(IV) compounds [Sn{L(S)(2)}](2-) 2[R(2)NH(2)](+) are formed in high yields. PMID- 21258732 TI - Catalytic insights into acid/base conjugates: highly selective bifunctional catalysts for the ring-opening polymerization of lactide. AB - Herein, we report the use of acid/base complexes for the ring opening polymerization of (L)-lactide. The salt formed from an equimolar reaction of benzoic acid and DBU produced a catalyst capable of controlled polymerizations allowing for targeted molecular weights and narrow polydispersities. The use of computational analysis suggests a bifunctional catalytic mechanism wherein both the monomer and propagating hydroxyl group are activated toward polymerization. PMID- 21258733 TI - Label-free DNAzyme-based fluorescing molecular switch for sensitive and selective detection of lead ions. AB - We developed a label-free fluorescent Pb(2+) sensor utilizing a DNAzyme-based fluorescing molecular switch, which enables fluorescence detection of Pb(2+) in aqueous solution with high sensitivity and selectivity. PMID- 21258734 TI - A concise total synthesis of (+/-)-cipadonoid B from synthetic azedaralide. AB - The tetranortriterpene cipadonoid B was efficiently constructed from synthetic azedaralide in a one-pot cascade, via the underutilised ketal-Claisen rearrangement. PMID- 21258736 TI - Metal-free catalysts for hydrogenation of both small and large imines: a computational experiment. AB - This study extends our previous work of using pi-FLP strategy to develop metal free hydrogenation catalysts. Using small MeN=CMe(2) imine (im1) as a model, we previously designed cat1 and cat2 catalysts. But it is unclear whether they are capable of catalyzing the hydrogenations of bulky imines. Using tBuN=C(H)Ph (im2) as a representative of large imines, we assessed the energetics of the cat1- and cat2-catalyzed im2 hydrogenations. The predicted energetics indicates that they can still catalyze large imine hydrogenations with experimentally accessible kinetic barriers, although the energetics becomes less favorable. To improve the catalysis, we proposed new catalysts (cat3 and cat4) by tailoring cat1 and cat2. The study indicates that cat3 and cat4 could have better performance for the hydrogenation of the bulky im2 than cat1 and cat2. Remarkably, cat3 and cat4 are also found suitable for small imine (im1) hydrogenation. Examining the hydrogen transfer substeps in the eight hydrogenations involved in this study, we observed that the mechanism for the hydrogen transfer step in the catalytic cycles depends on the steric effect between catalyst and substrate. The mechanism can be switched from stepwise one in the case of large steric effect (e.g.im2/cat2) to the concerted one in the case of small steric effect (e.g.im1/cat3). The new catalysts could be better targets for experimental realization because of their simpler constructions. PMID- 21258735 TI - Non-covalent ruthenium polypyridyl complexes-carbon nanotubes composites: an alternative for functional dissolution of carbon nanotubes in solution. AB - The dispersion of single-walled carbon nanotubes (SWCNTs) in the presence of water soluble polypyridyl complexes of the general formula [Ru(x)(bpy)(y)L](2+) (L = dppz, dppn, tpphz) is reported. These ligands have extended planar pi systems, which aid in the solubilization of SWCNTs via pi-pi interactions. PMID- 21258737 TI - High cytotoxicity of dihalo-substituted 8-quinolinolato-lanthanides. AB - Three new lanthanide complexes with dihalo-substituted 8-quinolinol: [Gd(BrQ)(3)(H(2)O)(2)].1.33EtOH.0.33H(2)O (1), [Dy(ClQ)(3)(H(2)O)(2)].1.33EtOH.0.33H(2)O (2), [Er(ClQ)(3)(H(2)O)(2)].1.33EtOH.0.33H(2)O (3) (H-BrQ = 5,7-dibromo-8-quinolinol, H-ClQ = 5,7-dichloro-8-quinolinol) have been synthesized and characterized by elemental analysis, IR, ESI-MS, single-crystal X-ray diffraction and TGA. The single-crystal X-ray diffraction analyses reveal that complexes 1-3 are mononuclear and isostructural. Each metal centre is coordinated by three dihalo substituted 8-quinolinol and two aqua ligands. The in vitro cytotoxicity of dihalo-substituted 8-quinolinol and complexes 1-3 against liver cancer BEL7404 was evaluated. The IC(50) values of 1-3 to BEL7404 were 47.2 +/- 2.6, 18.3 +/- 1.0 and 31.5 +/- 1.2 nM, respectively. The lanthanide complexes 1-3 exhibited significantly enhanced cytotoxicity vs. free substituted 8-quinolinol. The binding properties of dihalo-substituted 8-quinolinol and complexes 1 and 2 to DNA were investigated by UV-vis, fluorescence, CD spectroscopy and viscosity measurements, as well as agarose gel electrophoresis experiments. Both complexes 1 and 2 interact more strongly with DNA than the free quinolinol ligand. Intercalation is the most probable binding mode for both the complexes and the quinolinol ligands. PMID- 21258739 TI - A luminescent coordination polymer based on bisterpyridyl ligand containing o carborane: two tunable emission modes. AB - We designed a novel ditopic bisterpyridyl ligand containing o-carborane that can construct a coordination polymer by complexation with metal ions. Through the use of Sonogashira-Hagihara coupling, the desired ligand molecule was successfully synthesized. Addition of Zn(II) ions rapidly underwent the generation of a fluorescent coordination polymer, which was confirmed by (1)H NMR, UV-vis, and fluorescent titration experiments. Furthermore, the electronic structure of the bisterpyridyl ligand molecules was drastically changed upon the complexation with metal ions. The obtained coordination polymer showed light blue emission derived from the intraligand charge transfer (ILCT) state, whereas a bare ligand molecule exhibited yellowish-green aggregation-induced emission (AIE) in a poor solvent such as water, because of the variable C-C bond in o-carborane. PMID- 21258740 TI - A self-assembled molecular team of boronic acids at the gold surface for specific capture of cis-diol biomolecules at neutral pH. AB - We report a single-step strategy called self-assembled molecular team to generate boronate affinity ligands that can specifically capture cis-diol biomolecules at neutral pH, which provides three significant advantages: a simple procedure, high affinity and high specificity. PMID- 21258741 TI - Bio-functionalisation to enzymatically control the solution properties of a self supporting polymeric material. AB - Molecular self-assembly permits the spontaneous aggregation of a variety of low molecular weight amino acid subunits into highly ordered aggregates. Functionalisation of water soluble poly(allylamine) with acetyl protected dialanine enables the formation of a biopolymer self-supporting material (SSM). The presence of an enzyme cleavable dipeptide linker renders the SSM responsive to disruption by a targeted proteolytic enzyme. PMID- 21258742 TI - Modulation of an RNA-branching deoxyribozyme by a small molecule. AB - We have engineered an RNA-branching deoxyribozyme to respond positively to ATP, resulting in modulated control of ligation activity that may be applicable to sensor and nanotechnology applications. PMID- 21258738 TI - Isolation and analysis of ginseng: advances and challenges. AB - Ginseng occupies a prominent position in the list of best-selling natural products in the world. Because of its complex constituents, multidisciplinary techniques are needed to validate the analytical methods that support ginseng's use worldwide. In the past decade, rapid development of technology has advanced many aspects of ginseng research. The aim of this review is to illustrate the recent advances in the isolation and analysis of ginseng, and to highlight new applications and challenges. Emphasis is placed on recent trends and emerging techniques. PMID- 21258743 TI - A nanoporous metal-organic framework with accessible Cu2+ sites for the catalytic Henry reaction. AB - A novel 3D porous metal-organic framework containing 1D nanoscale opening channels was constructed from two kinds of pyridine carboxylates and copper(II) nodes with reachable copper sites located in the channel walls, which can be subsequently used to prompt the Henry reaction of benzaldehydes and nitroalkanes with remarkable catalytic activity compared with homogeneous copper cations. PMID- 21258744 TI - Assembly of F0F1-ATPase into solid state nanoporous membrane. AB - A novel ATPase/nanoporous membrane system was prepared. In this system, the activity of F(0)F(1)-ATPase was preserved. The two sides of F(0)F(1)-ATPase were successfully separated macroscopically, and the chemical environments of the two sides could be manipulated in situ individually and freely. Furthermore, this system was also provided with mobility and reusage. PMID- 21258745 TI - Synthesis of quadruped-shaped polyfunctionalized o-carborane synthons. AB - o-Carborane derivatives with precisely defined patterns of substitution have been prepared from 8,9,10,12-I(4)-1,2-closo-C(2)B(10)H(8) by replacing the iodine atoms, bonded to four adjacent boron vertices in the cluster, with allyl, and subsequently 3-hydroxypropyl groups. The resulting structures, comprising four pendant arms and two reactive vertices located on opposite sides of a central o carborane core, can be envisaged as versatile precursors for dendritic growth. PMID- 21258746 TI - Potential molecular targets in chemopreventative action of celecoxib: a proteomics analysis of J774.A1 macrophage-like cell line. AB - The overexpression of cyclooxygenase-2 (COX-2) enzyme has been strongly contributed to tumorigenesis. The efficacy of celecoxib as a selective COX-2 inhibitor has been shown in many studies, but the underlying mechanism as a chemopreventative agent has not yet been well known. For better understanding the chemopreventative molecular mechanisms, we used a comparative proteomics analysis of lipopolysaccharide (LPS) treated and untreated J774.A1 macrophage-like cell lines before and after treatment with celecoxib. Our findings define the contribution of several interesting proteins, including ferritin heavy chain, glyoxalase-1, cofilin, vimentin, and galectin-1, which could extend our understanding of the chemopreventative effects of celecoxib and provide new valuable tools for further anticancer research. PMID- 21258747 TI - A robust high resolution reversed-phase HPLC strategy to investigate various metabolic species in different biological models. AB - Recent advancements in the field of omics sciences have paved the way for further expansion of metabolomics. Originally tied to NMR spectroscopy, metabolomic disciplines are constantly and growingly involving HPLC and mass spectrometry (MS)-based analytical strategies and, in this context, we hereby propose a robust and efficient extraction protocol for metabolites from four different biological sources which are subsequently analysed, identified and quantified through high resolution reversed-phase fast HPLC and mass spectrometry. To this end, we demonstrate the elevated intra- and inter-day technical reproducibility, ease of an MRM-based MS method, allowing simultaneous detection of up to 10 distinct features, and robustness of multiple metabolite detection and quantification in four different biological samples. This strategy might become routinely applicable to various samples/biological matrices, especially for low availability ones. In parallel, we compare the present strategy for targeted detection of a representative metabolite, L-glutamic acid, with our previously proposed chemical-derivatization through dansyl chloride. A direct comparison of the present method against spectrophotometric assays is proposed as well. An application of the proposed method is also introduced, using the SAOS-2 cell line, either induced or non-induced to express the TAp63 isoform of the p63 gene, as a model for determination of variations of glutamate concentrations. PMID- 21258748 TI - Transition metal catalysed dehydrogenation of amine-borane fuel blends. AB - Mixtures containing ammonia-borane and sec-butylamine-borane remain liquid throughout the hydrogen release process that affords tri(N-sec-butyl)borazine and polyborazylene. Concentrated solutions with metal catalysts afford >5 wt% H(2) in 1 h at 80 degrees C and addition of (EMIM)EtSO(4) ionic liquid co-solvent eliminates competing formation of insoluble linear poly(aminoborane) (EMIM = 1 ethyl-3-methyl-imidazolium). PMID- 21258749 TI - Assembly of folate-polyoxometalate hybrid spheres for colorimetric immunoassay like oxidase. AB - Folate-functionalized polyoxometalate nanoparticles have unique oxidase-like activity, which can facilitate the fast oxidation of organic dyes without using any oxidizing agents or peroxidases especially at neutral pH conditions. This nanoparticle could be used as an agent in colorimetric multiplexed immunoassays. PMID- 21258750 TI - Fabrication of ionic liquid-functionalized polypyrrole nanotubes decorated with platinum nanoparticles and their electrocatalytic oxidation of methanol. AB - Polypyrrole nanotubes (PPyNTs)/Pt nanoparticle hybrids were synthesized by using covalently attached imidazolium-type ionic liquids (ILs) as linkers. The resultant Pt/ILs/PPyNTs hybrids exhibited high electrocatalytic activity in electrocatalytic oxidation of methanol. PMID- 21258751 TI - Spontaneous enrichment of one-handed helices by dissolution of quasiracemic crystals of a tetranuclear single helical complex. AB - The left-handed isomer of the helical complex [LZn(3)La(OAc)(3)] was spontaneously enriched from 50 : 50 to 87 : 13 when the quasiracemate crystals were dissolved. The invertible helicity of [LZn(3)La(OAc)(3)] (global chirality) helps the quasiracemate formation and the fixed point chirality of the R,R cyclohexanediamine moiety (local chirality) effectively controls the global chirality in solution. PMID- 21258752 TI - Pyridine-based coordination polymeric hydrogel with Cu2+ ion and its encapsulation of a hydrophobic molecule. AB - We report the formation of a coordination polymeric hydrogel of a pyridine derivative with Cu(2+) and its efficiency as a delivery system for curcumin as a model hydrophobic drug. PMID- 21258754 TI - Cleavage of RNA phosphodiester bonds by small molecular entities: a mechanistic insight. AB - RNA molecules participate in many fundamental cellular processes either as a carrier of genetic information or as a catalyst, and hence, RNA has received increasing interest both as a chemotherapeutic agent and as a target of chemotherapy. In addition the dual nature of RNA has led to the RNA-world concept, i.e. an assumption that the evolution at an early stage of life was based on RNA-like oligomers that were responsible for the storage and transfer of information and as catalysts maintained primitive metabolism. Accordingly, the kinetics and mechanisms of the cleavage of RNA phosphodiester bonds have received interest and it is hoped they will shed light on the mechanisms of enzyme action and on the development of artificial enzymes. The major mechanistic findings concerning the cleavage by small molecules and ions and their significance for the development of efficient and biologically applicable artificial catalysts for RNA hydrolysis are surveyed in the present perspective. PMID- 21258753 TI - Lyngbyoic acid, a "tagged" fatty acid from a marine cyanobacterium, disrupts quorum sensing in Pseudomonas aeruginosa. AB - Quorum sensing (QS) is a mechanism of bacterial gene regulation in response to increases in population density. Perhaps most studied are QS pathways mediated by acylhomoserine lactones (AHLs) in Gram-negative bacteria. Production of small molecule QS signals, their accumulation within a diffusion-limited environment and their binding to a LuxR-type receptor trigger QS-controlled gene regulatory cascades. In Pseudomonas aeruginosa, for example, binding of AHLs to their cognate receptors (LasR, RhlR) controls production of virulence factors, pigments, antibiotics and other behaviors important for its interactions with eukaryotic hosts and other bacteria. We have previously shown that marine cyanobacteria produce QS-inhibitory molecules, including 8-epi-malyngamide C (1), malyngamide C (2) and malyngolide (3). Here we isolated a new small cyclopropane containing fatty acid, lyngbyoic acid (4), as a major metabolite of the marine cyanobacterium, Lyngbya cf. majuscula, collected at various sites in Florida. We screened 4 against four reporters based on different AHL receptors (LuxR, AhyR, TraR and LasR) and found that 4 most strongly affected LasR. We also show that 4 reduces pyocyanin and elastase (LasB) both on the protein and transcript level in wild-type P. aeruginosa, and that 4 directly inhibits LasB enzymatic activity. Conversely, dodecanoic acid (9) increased pyocyanin and LasB, demonstrating that the fused cyclopropane "tag" is functionally relevant and potentially confers resistance to beta-oxidation. Global transcriptional effects of 4 in some ways replicate the gene expression changes of P. aeruginosa during chronic lung infections of cystic fibrosis patients, with reduced lasR signaling, increased biofilm and expression of the virulence locus HSI-I. Compound 4 may therefore prove to be a useful tool in the study of P. aeruginosa adaption during such chronic infections. PMID- 21258755 TI - Intracavitary and endobronchial tuberculosis. PMID- 21258756 TI - Evaluation of hemostatic AIDS in laparoscopic nephron-sparing surgery. AB - Partial nephrectomy is considered the standard of care for the management of small renal masses, and laparoscopic techniques are becoming popular for multiple reasons, one of which is minimal invasiveness. On the other hand, kidneys are extremely vascular organs, and renal hemorrhage is a major cause of morbidity after laparoscopic partial nephrectomies. Control of bleeding and management of calyceal injuries can be difficult and make the procedure technically challenging. This review looks at the various energy sources and hemostatic agents that are available to reduce bleeding during laparoscopic partial nephrectomies. PMID- 21258757 TI - Sacral neuromodulation for refractory urge incontinence is less effective following spinal surgery. AB - Patients with neurogenic disorders and voiding dysfunction have been reported to respond poorly to sacral neuromodulation. We report on our experience in treating voiding symptoms with sacral neuromodulation after spinal surgery. The medical charts of patients evaluated for sacral neuromodulation from 2000-2008 were retrospectively reviewed. Indications, need for explantation, and clinical success (>50% symptom improvement) were recorded. The cohort of patients who had undergone prior spinal surgery was compared to patients with no history of spinal surgery or neurological disease. Thirty-two patients with a history of spinal surgery and 136 with no history of neurologic disease underwent sacral neuromodulation testing. Twenty men and women (62.5%) from the spinal surgery group ultimately underwent permanent implantation. Seventeen of the 32 patients were diagnosed with urge incontinence, of whom 52.9% reported a successful outcome at a mean of 2.3 years of follow-up, compared to an 80.3% success rate in patients with no history of spinal surgery (p=0.018). Sixteen of 32 carried a diagnosis of urgency/frequency with 62.5% success at last follow-up, compared 73.9% (p=0.35) of those without a history of spinal surgery or neurological disease. Thirteen of 32 patients diagnosed with urinary retention experienced a 61.5% long-term success rate, compared with 63.6% for those without spinal surgery and urinary retention. Six of 20 (30.0%) in the spinal surgery group were explanted at a mean time of 2.9 years, compared with 27 of 102 (26.5%) of the non neurologic patients. Clinical success can be achieved using sacral neuromodulation in patients with voiding dysfunction and a history of spinal surgery; however, those with urge incontinence are less likely to report significant improvement. PMID- 21258758 TI - Using large institutional or national databases to evaluate prostate cancer outcomes and patterns of care: possibilities and limitations. AB - Prostate cancer is the most common non-skin-related cancer in men. With advances in technology, the care and treatment for men with this disease continues to become more complex. Large databases offer researchers a unique opportunity to conduct prostate cancer research in various areas, and provide important information that helps patients and providers determine prognosis after treatment. Furthermore, the studies using these databases may provide information on how side effects from various treatments can affect one's quality of life. Finally, information from these datasets can help to identify factors that determine why patients receive the treatments they do. Despite this, these databases are not without limitations. In this review, we discuss various available, national, multicenter, and institutional databases in the context of prostate cancer research, citing numerous important studies that have impacted on our understanding of prostate cancer outcomes. PMID- 21258759 TI - Practical aspects of allogeneic hematopoietic cell transplantation for patients with poor-risk chronic lymphocytic leukemia. AB - Allogeneic hematopoietic cell transplantation has become a viable option for younger patients with poor-risk chronic lymphocytic leukemia. The results obtained with either conventional or reduced-intensity conditioning regimens have been recently evaluated and compared with alternative nontransplant strategies. This manuscript deals with practical aspects of the procedure, including patient and donor selection, conditioning regimen, GVHD prophylaxis, disease monitoring, infectious and noninfectious complications, and timing of the procedure. Finally, we speculate on how we could improve the results obtained with the procedure and new advances currently in clinical trials. PMID- 21258760 TI - Vesicles generated during storage of red blood cells enhance the generation of radical oxygen species in activated neutrophils. AB - Erythrocytes are known to shed vesicles in vivo, under various conditions in vitro, and, with impact for transfusion medicine, during storage of red blood cell concentrates (Vsto vesicles). Vsto vesicles of blood transfusions have been shown to deliver glycosylphosphatidylinositol-linked proteins to recipient erythrocytes, to display prothrombotic activity, and to have an inhibitory effect on macrophages. The interaction of Vsto vesicles with and their effect on neutrophilic granulocytes has not yet been studied in detail. Fluorescently labeled Vsto and calcium-induced vesicles were prepared in order to study the uptake of labeled vesicular components by neutrophils as compared to the process of phagocytosis of zymosan using flow cytometry and confocal microscopy. The activating effect of Vsto vesicles on neutrophils was addressed by a luminometric assay for stimulated radical oxygen species (ROS) generation.Coincubation of vesicles and neutrophils results in a transfer of vesicular components to the cells. This uptake is different from a phagocytotic process and is enhanced upon interference with the cellular actin cytoskeleton. Preincubation of neutrophils with Vsto vesicles results in an enhanced ROS generation by neutrophils,which is further increased upon fMLP stimulation and during zymosan phagocytosis. The activating effect of Vsto vesicles on neutrophils might be due to the specific accumulation of lysophospholipids in Vsto vesicles and should be considered as a possible contributor to the pathogenesis of transfusion-related acute lung injury. PMID- 21258761 TI - Ossification vesicles with calcium phosphate in the eyes of the insect Copium teucrii (Hemiptera: Tingidae). AB - Arthropod eyes are built of repeating units named ommatidia. Each single ommatidium unit contains a cluster of photoreceptor cells surrounded by support cells and pigment cells. The insect Copium eye ommatidia include additional calcium-phosphate deposits, not described in insects to date, which can be examined today using a combined set of modern microscopy and spectroscopy techniques. Teucrium gnaphalodes L'Her plants, growing in central Spain, develop galls induced by Copium insects. A survey of C. teucrii adult specimens resulted in surprising environmental scanning electron microscopy (ESEM) images, showing that their bright red eyes contain a calcium-phosphate mineralization. A complete survey of Copium eye specimens was performed by ESEM using energy-dispersive spectroscopy, backscattered electron detector and cathodoluminescence (CL) probes, field emission scanning electron microscopy, micro-Raman spectroscopy, and confocal laser scanning microscopy in order to learn ommatidia features, such as chemical composition, molecular structure, cell membrane, and internal ommatidium eye fluids and calcium-phosphate distribution deposits. The CL panchromatic images distinguish between the calcium-phosphate ommatidium and calcium-phosphate setae, which are more apatite rich. They show Raman bands attributable to bone tissue apatite biomaterials, such as bone, collagen, lipids, and blood, i.e., peptides, amide-S, amide-II, amide-III, and cytochrome P-450 scc. The chemical composition of both galls and leaves of T. gnaphalodes was determined by gas chromatography-mass spectrometry (GC-MS) of their extracts. The spectrometric and microscopic images reveal that the calcium-phosphate mineralization is formed and constrained to Copium ommatidia, which are both matrix vesicles generating mixtures of apatite collagen and operational compound eyes of the insect. PMID- 21258762 TI - Sustained spatial attention in touch: modality-specific and multimodal mechanisms. AB - Sustained attention to a body location results in enhanced processing of tactile stimuli presented at that location compared to another unattended location. In this paper, we review studies investigating the neural correlates of sustained spatial attention in touch. These studies consistently show that activity within modality-specific somatosensory areas (SI and SII) is modulated by sustained tactile-spatial attention. Recent evidence suggests that these somatosensory areas may be recruited as part of a larger cortical network,also including higher level multimodal regions involved in spatial selection across modalities. We discuss, in turn, the following multimodal effects in sustained tactile-spatial attention tasks. First, cross-modal attentional links between touch and vision, reflected in enhanced processing of task-irrelevant visual stimuli at tactually attended locations, are mediated by common (multimodal) representations of external space. Second, vision of the body modulates activity underlying sustained tactile-spatial attention, facilitating attentional modulation of tactile processing in between-hand (when hands are sufficiently far apart) and impairing attentional modulation in within-hand selection tasks. Finally, body posture influences mechanisms of sustained tactile-spatial attention, relying, at least partly, on remapping of tactile stimuli in external, visually defined, spatial coordinates. Taken together, the findings reviewed in this paper indicate that sustained spatial attention in touch is subserved by both modality-specific and multimodal mechanisms. The interplay between these mechanisms allows flexible and efficient spatial selection within and across sensory modalities. PMID- 21258763 TI - Spinal cord injury and bladder dysfunction: new ideas about an old problem. AB - Control of the lower urinary tract (LUT) requires complex neuronal circuits that involve elements located at the peripheral nervous system and at different levels of the central nervous system. Spinal cord injury (SCI) interrupts these neuronal circuits and jeopardizes the voluntary control of bladder function. In most cases, SCI results in a period of bladder areflexia, followed by the emergence of neurogenic detrusor overactivity (NDO). Only recently, researchers have started to have a clearer vision of the mechanisms of SCI-induced changes affecting LUT control. For example, changes in the urothelium have recently been described and proposed to play a role in NDO. As such, a better understanding of NDO has generated new opportunities to investigate novel therapeutic approaches for NDO. In the present paper, we aim to update recent data concerning SCI-induced LUT dysfunction and therapeutic approaches commonly used to deal with NDO. We make a brief description of LUT control and changes occurring after SCI, and refer to new therapeutic options, including vanniloids and botulinum toxin. Finally, we discuss mechanisms of spinal cord repair, an interesting and very active area of investigation that has obtained some promising results in the recovery of LUT control. PMID- 21258764 TI - Lipoxins: a novel regulator in embryo implantation. AB - Embryo implantation is essential for mammalian pregnancy, which involves intricate cross-talk between the blastocyst and the maternal endometrium. Recent advances have identified various molecules crucial to implantation and endometrial receptivity, including leukemia inhibitory factor, calcitonin, and homeobox A10. There is a close relationship between implantation and inflammation. Lipoxins, important in the resolution of inflammation, may be a potential regulator in implantation. Here we discuss the hypothesis that lipoxins may work as a novel regulator in embryo implantation and the possible molecular mechanisms. PMID- 21258765 TI - Intracellular glutathione levels are involved in carbonyl cyanide p (trifluoromethoxy) phenylhydrazone-induced apoptosis in As4.1 juxtaglomerular cells. AB - Carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone (FCCP) is an uncoupler of mitochondrial oxidative phosphorylation in eukaryotic cells. In the present study, we investigated the involvement of reactive oxygen species (ROS) and glutathione (GSH) in FCCP-induced As4.1 juxtaglomerular cell death. Intracellular ROS levels were decreased by FCCP at the early time points (10-150 min) and increased at 48 h. FCCP inhibited the activity of Mn-superoxide dismutase (Mn SOD) via down-regulating its protein expression. Ebselen (an antioxidant) significantly attenuated ROS levels in FCCP-treated cells, but did not prevent FCCP-induced cell death. Moreover, intracellular GSH content was rapidly diminished within 10 min of FCCP treatment, which was accompanied by a reduction of the mitochondrial membrane potential [MMP (?psim)]. L-buthionine sulfoximine (BSO, a GSH synthesis inhibitor) significantly augmented As4.1 cell death by FCCP. However, N-acetylcysteine (NAC, a GSH precursor and antioxidant) attenuated GSH depletion, MMP (?psim) loss and cell death in FCCP-treated As4.1 cells. In addition, NAC increased Mn-SOD activity and decreased ROS levels in FCCP-treated As4.1 cells. In conclusion, these results suggest that compared to ROS levels, intracellular GSH levels are more closely linked to FCCP-induced apoptosis in As4.1 juxtaglomerular cells. PMID- 21258766 TI - Expression of calbindin-D28k is inversely correlated with proapototic gene expression in hydrogen peroxide-induced cell death in endometrial cancer cells. AB - Calbindin-D28k (CaBP-28k) is a calcium binding protein important for intracellular Ca2+ buffering and known to have anti-apoptotic properties in neurons, osteoblasts and male germ cells. Although endometrial cancer is a common invasive gynecologic malignancy, the involvement of uterine CaBP-28k in apoptotic signaling of endometrial cancer is poorly understood. The present study investigates the role of CaBP-28k in hydrogen peroxide (H2O2)-induced apoptotic signaling in human endometrial Ishikawa cells. The dose- and time-dependent effect of H2O2 on Bax, p53 and Bcl-2 expression was assessed by Western blot analysis. Treatment of cells with 1 mM H2O2 for 1 h induced an increase in Bax and p53 expression, but the expression of Bcl-2 was not affected by H2O2 treatment. Interestingly, overexpression of CaBP-28k inhibited cell death and caused a decrease in Bax, p53 and caspase 3 expression during H2O2-induced apoptosis, suggesting that CaBP-28k blocks the up-regulation of apoptosis-related gene expression. siRNA knockdown of CaBP-28k resulted in an elevation of H2O2 induced cell death and an increase in Bax, p53 and caspase 3, providing additional evidence that induction of the CaBP-28k gene might be associated with survival signaling during H2O2-mediated cell death. Overall, these results suggest that CaBP-28k expression is inversely correlated with pro-apoptotic gene expression in human endometrial Ishikawa cells. PMID- 21258767 TI - Involvement of epithelial-mesenchymal transition in adenoid cystic carcinoma metastasis. AB - The high frequencies of recurrence and distant metastasis of adenoid cystic carcinoma (AdCC) are significant obstacles for the long-term cure of patients with AdCC and emphasize the need for better understanding of the biological factors associated with these outcomes. To identify proteins that mediate AdCC metastasis, we established three AdCC cell lines expressing green fluorescent protein (GFP) from the ACCS cell line using orthotopic transplantation and in vivo selection in nude mice: Parental ACCS-GFP, highly tumorigenic ACCS-T GFP and metastatic ACCS-M GFP. ACCS-GFP and ACCS-M GFP were subjected to DNA microarray analysis and the results were used for data mining studies. DNA microarray analysis revealed significantly altered biological processes in the ACC-M GFP cells, including events related to cell adhesion (three categories) and signaling (three categories). In particular, a significant down-regulation of cell adhesion molecules, such as cadherins and integrin subunits was observed. The loss of E cadherin and integrins and the gain of vimentin in ACCS-M GFP cells were confirmed by immunoblotting. These results suggest that epithelial-mesenchymal transition (EMT) is a putative event in AdCC metastasis that induces tumor cell dissemination from the primary tumor site. In summary, in this study we established a useful nude mouse metastasis model which will enable further AdCC metastasis research and clinical treatment trials and we also provide evidence that EMT is significantly involved in the AdCC metastatic process. PMID- 21258768 TI - Promoter methylation of heat shock protein B2 in human esophageal squamous cell carcinoma. AB - Hypermethylation of gene promoters and the corresponding loss of gene expression are recognized as a hallmark of human cancer, and DNA methylation has emerged as a promising biomarker for the detection of human esophageal squamous cell carcinoma (ESCC). To identify novel genes methylated in ESCC, we screened 35 candidate genes identified from an oligonucleotide microarray. Among them, the heat shock protein B2 (HSPB2) was methylated in 95.7% (67/70) of primary ESCCs, whereas no methylation was found in normal esophageal tissues from ESCC patients (0%, 0/20). RT-PCR analysis revealed that HSPB2 expression was silenced or weakly expressed in most ESCC cell lines, and re-activated by the demethylating agent 5 aza-2'-deoxy-cytidine. These results indicate that promoter methylation of HSPB2 is one of the causal factors for loss or down-regulation of HSPB2 expression. mRNA expression of HSPB2 in ESCC tissues was significantly down-regulated compared to normal tissues. Our data suggest that promoter methylation of HSPB2 deserves further attention as a novel molecular biomarker in human ESCC. PMID- 21258769 TI - Restoration of miR-145 expression suppresses cell proliferation, migration and invasion in prostate cancer by targeting FSCN1. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression, primarily at the post-transcriptional level. Growing evidence suggests that miRNAs function as oncogenes or tumor suppressors in human cancers. The down regulation of miR-145 has been reported in many types of human cancer, including prostate cancer (PC), suggesting that miR-145 functions as a tumor suppressor. Using the PC cell lines, PC3 and DU145, gain-of-function assays revealed that miR 145 transfection inhibited cell proliferation, migration and invasion. Fascin homolog 1 (FSCN1), an actin-bundling protein, is a candidate target gene of miR 145 based on genome-wide gene expression analysis. A luciferase reporter assay showed a significantly decreased signal at two miR-145 target sites at the 3'UTR of FSCN1, suggesting that miR-145 directly regulates FSCN1. In FSCN1 loss-of function assays, cell growth, migration and invasion were all inhibited, implying that FSCN1 is associated with the progression of PC. The identification of tumor suppressive miRNAs and their target genes could provide new insights into the potential mechanisms of prostate carcinogenesis. PMID- 21258770 TI - Ets-1 is implicated in the regulation of androgen co-regulator FHL2 and reveals specificity for migration, but not invasion, of PC3 prostate cancer cells. AB - Different members of the Ets-family of transcription factors are involved in TMPRSS-2-Ets translocations frequently found in human prostate cancers. We previously reported that Ets-1, which is the prototype of Ets-family members, promotes both migration and invasion of melanoma, Hela and glioma cells. Here, we examined whether Ets-1 has a similar effect upon migration and invasion of PC3 prostate cancer cells, and whether it is implicated in the regulation of the androgen co-regulator four and a half LIM only protein-2 (FHL2). Two stable PC3 cell cultures were established by transfection with either an Ets-1 inverse antisense expression vector or a mock control vector. Western blot analysis confirmed presence of Ets-1 in mock and absence in Ets-1 inverse cells. Microarray and qRT-PCR revealed an up-regulation of FHL2 in Ets-1 blocked cells, compared to mock. To examine the effects of Ets-1 upon cell migration, a wound assay was performed, and demonstrated that wounds were completely colonized by mock compared to Ets-1 blocked cells after 55 h. Evaluation of the effect upon invasion was examined using the Boyden chamber, which revealed no significant difference between mock and Ets-1 blocked cells. In conclusion, our study demonstrated for the first time that Ets-1 is implicated in the regulation of the androgen co-regulator FHL2, and reveals specificity of action for migration, but not invasion of PC3 prostate cancer cells. PMID- 21258771 TI - Clinicopathological parameters and biological markers predicting non-sentinel node metastasis in sentinel node-positive breast cancer patients. AB - The value of complete axillary lymph node dissection (ALND) has been questioned in invasive breast cancer (IBC) patients with positive sentinel lymph nodes (SLNs) who have no non-sentinel lymph node (NSLN) metastases. Because biological markers have not been systematically studied in this setting, we sought to identify clinicopathological characteristics and biological markers for predicting NSLN metastases in SLN-positive IBC patients. Two hundred and five IBC patients who had at least one positive SLN and received SLN biopsy and ALND were included in our study. We examined the clinicopathological characteristics of their primary tumors, SLNs and NSLNs. We also evaluated the biological markers of the primary tumors by tissue microarray and immunohistochemistry. Of the 205 patients with SLN metastases, 89 patients (43.4%) had additional metastases in NSLNs. The following factors were found to be associated with NSLN metastases: peritumoral lymphovascular invasion (p=0.01), two or more metastatic SLNs (p<0.01), SLN metastasis >2.0 mm (p<0.01) and extra-nodal extension (p<0.01). Primary tumors >2.0 cm showed more NSLN metastases, but the association was statistically insignificant (p=0.08). In contrast, NSLN metastases were not associated with histologic grade, histologic type, presence of extensive intraductal component, presence of high grade ductal carcinoma in situ and number of harvested SLNs. Biological markers such as E-cadherin, CD44, cyclin D1, p21, ER, PR, c-erbB2, p53, Ki-67, luminal (CK7, CK18, CK19) and basal (CK5, p63) markers were not useful predictors of NSLN metastasis in IBC patients with SLN metastases. Multivariate analysis revealed that SLN metastasis >2.0 mm (p=0.01), two or more metastatic SLNs (p=0.03) and extranodal extension (p<0.01) were independent predictors of NSLN metastasis. For the prediction of NSLN metastasis in IBC patients with SLN metastases, light microscopic evaluation of the number, size and extranodal extension of metastatic SLNs by hematoxylin and eosin staining appeared to be critical. However, the biological markers of primary tumor characterized by immunohistochemical staining, such as luminal and basal markers, hormone receptors, E-cadherin, CD44, cyclin D1, p21, c-erb-B2, p53 and Ki-67, did not appear to be helpful predictors. PMID- 21258772 TI - [Squamous cell carcinoma of the colon. A rare histological entity]. AB - Squamous cell carcinoma of the colon is an extremely rare histopathological entity accounting for less than 0.025% of all colonic malignancies. Mucosal metaplasia is believed to be the leading cause of this form of carcinoma and the presentation and diagnosis is the same as for adenocarcinoma. Surgery is the treatment method of choice and adjuvant radiation and chemotherapy are recommended in advanced stages of the disease. Advanced squamous cell carcinoma seems to have a poorer prognosis compared to advanced adenocarcinoma. PMID- 21258773 TI - [Evidence-based antibiotic prophylaxis in general and visceral surgery]. AB - The use of prophylactic perioperative antibiotic therapy if indicated could successfully and safely prevent surgical wound infections. The current guidelines (S1) for prophylactic perioperative antibiotic therapy of the Study Group of the Scientific Medical Associations (AWMF) of 2004 was replaced by a recommendation of the study group of the Paul-Ehrlich-Gesellschaft for Chemotherapy (PEG) in 2010. This recommendation includes recent research data from 2000 to 2008. Indications and choice of antibiotic agent depend on specific risk factors of the patient and the operation performed. The aim of this article is to describe the current recommendations of the PEG for general and visceral surgery. PMID- 21258774 TI - [Long-term results in total knee arthroplasty. A meta-analysis of revision rates and functional outcome]. AB - BACKGROUND: Total knee arthroplasty (TKA) is one of the most common procedures in orthopedic surgery and clinical success can be characterized by the revision rate and improvement of function. To quantify both characteristics two independent meta-analyses have been performed. MATERIALS AND METHODS: A search in Medline provided a total of 96 studies on revision rates and 63 studies with functional results with a minimum follow-up of 5 years. RESULTS: A total of 911 revisions among 20,873 TKAs were identified corresponding to a meta-revision rate of 4.4% after a mean follow-up of 10.7 years. Most common causes for revision were aseptic loosening (31%), infection (23%), polyethylene wear (16%) and patellar problems (14%). Revision rates were higher in younger patients (7.0% <60 years at time of operation, 5.0% between 60 to 70 years and 2.2% >70 years), after cementless TKA (8.3% cementless versus 3.6% cemented) and in studies with a higher rate of patients with rheumatoid arthritis. The second meta-analysis revealed a meta-improvement based on the Knee Society Knee Score of 51.3%, for the Knee Society Function Score of 30.6%, for the Hospital for Special Surgery Score of 36.1% and for the New Jersey Orthopedic Hospital Knee Evaluation System of 33.6%. CONCLUSION: TKA is a successful treatment for osteoarthritis of the knee with an expectable revision rate of less than 5% within 10 years and a long lasting functional improvement of more than 30% in any assessment score. PMID- 21258775 TI - [Mixed tumor of the skin]. AB - An 81-year-old woman presented with a skin-colored, slowly growing tumor on her right lower eyelid. The diagnosis of mixed tumor of the skin was confirmed after excision and histologic examination of the tissue, which demonstrated a characteristic histology and immunohistochemistry. The mixed tumor of the skin is a usually benign neoplasm believed to originate in sweat glands. It is composed of epithelial cells set in a mesenchymal matrix, showing apocrine differentiation. Immunohistochemical staining is positive for cytokeratin, CEA, EMA and S100. PMID- 21258776 TI - Toxicity of trichloroethylene (TCE) on some algae and cyanobacteria. AB - The toxicity of trichloroethylene was tested in both glass enclosures and in polystyrene immunological plates, and resulted in insignificant correlation of EC50 (evaluated as OD 750 nm). In enclosures, EC50 evaluated as O2 evolution and as pH increment was highly significant. The optimal time for the assay of TCE in enclosures was 48-72 h; and in plates ca 200 h. After a longer time (e.g. 300 h) TCE diffused from the plates and growth was revived. TCE in low concentrations (ca. 0.1-0.2 g/L) stimulated the growth of some tested organisms, both in plates and in enclosures. Toxicity occurred from ca. 0.35-0.6 g/L (EC50). The testing procedure in enclosures was a suitable method for some volatile substances, giving rapid results. PMID- 21258777 TI - Effects of the metals lead and zinc on the growth, development, and reproduction of Pardosa astrigera (Araneae: Lycosidae). AB - Metal pollution is a serious environmental problem worldwide, and severely threatens biological diversity and human health. In order to investigate the effects of metals on a potential indicator species of wolf spider, Pardosa astrigera (Araneae: Lycosidae), 3rd-instar spiderlings were exposed to metals by using sublethal concentrations of PbCl2 and ZnCl2 solutions as their drinking water. The total durations of development of P. astrigera from the 3rd to 6th instars were significantly longer than that of the control group, and females showed a sharp reduction in total egg number. Body weights were significantly decreased in the mature spiders exposed to PbCl2 solutions and ZnCl2 solutions of high concentration (100 mM). These results suggest that detoxifying strategies deployed by P. astrigera against metal intoxication incur the costs of delayed development, and reduced growth and reproduction. PMID- 21258778 TI - Geochemical modeling of high fluoride concentration in groundwater of Pokhran area of Rajasthan, India. AB - The groundwater is the only major source of drinking water in western part of Rajasthan, India. The study was carried out to locate and decipher hydrogeochemical reactions responsible for elevated concentration of fluoride. The concentration of fluoride ranged from 0.6 to 4.74 ppm in groundwater of study area. Since the area is a desertic terrain and no industries are present thus possibility of anthropogenic input of fluoride is all most negligible thus the enrichment of fluoride in groundwater is only possible due to rock-water interaction. The highly alkaline conditions indicated fluorite dissolution as major process responsible for high concentration of fluoride in Pokhran. PMID- 21258779 TI - A comparison of early versus delayed repair of traumatic rotator cuff tears. AB - PURPOSE: The purpose of this study was to compare the clinical and magnetic resonance imaging (MRI) results between early and delayed operative treatment in patients with traumatic rotator cuff tears (RCT). METHODS: Thirty-five patients with a traumatic RCT who have been treated surgically during a 4-year period were included in the study. The results of early versus delayed repair of traumatic rotator RCT were assessed using the Constant and UCLA scores. In addition, all patients underwent a postoperative MRI to evaluate repair integrity. Early repair (within 3 weeks) was performed in 15 patients (group I) and delayed repair (after 3 weeks) in the rest 20 patients (group II). The time interval between injury and operation was 12 and 131 days on average for group I and II, respectively. RESULTS: Follow-up time was 34 and 38 months for group I and II, respectively. Postoperatively, the UCLA score was 31 and 26 (P < 0.05) for group I and II, respectively. The Constant score was 82 and 70 (P < 0.05) for group I and II, respectively. Range of motion was significantly better in group I. According to MRI, 5 patients (33%) in the group I and 7 patients (35%) in the group II had a retear. CONCLUSIONS: Early repair of a traumatic RCT provides better results in terms of shoulder function in comparison with a delayed repair. A delayed diagnosis of a traumatic RCT leads to difficulties in surgery and less good results. LEVEL OF EVIDENCE: Level III, therapeutic, retrospective, comparative study. PMID- 21258780 TI - Inter- and intraobserver reliability of the clock face representation as used to describe the femoral intercondylar notch. AB - PURPOSE: To validate the use of the clock face reference as a reliable means of communicating femoral intercondylar notch position. METHODS: A single red mark was made on ten identical left Sawbones femurs in the intercondylar notch at variable locations. Ten surgeons, who routinely perform ACL reconstructions, were presented the femurs in random order and asked to state the position of the mark to the nearest 30-min interval. Responses were recorded and then repeated 3 weeks later. The same 10 surgeons were presented with 30 actual arthroscopic photographs of the intercondylar notch, performed at 90 degrees of knee flexion, with a probe pointing at various locations (10 knees; 3 photographs/knee) along the lateral aspect of the notch. The results were then analyzed with an ICC, Cronbach's alpha test, and descriptive statistics. RESULTS: For the Sawbones, the ICC was 0.996 while individual physician's Cronbach's alpha test ranged from 0.954 to 0.999, indicating a very high interobserver and intraobserver reliability. The mean range of responses among the 10 surgeons was 1.6 h, SD 0.6. For the photographs, the ICC was also high at 0.997. There was a mean range of 1.1 h, SD 0.4, among surgeons. CONCLUSIONS: The clock face method is commonly utilized for both placement of the femoral tunnel during ACL reconstruction as well as describing the location of the ACL femoral tunnel between communicating surgeons. Despite a high statistical interobserver correlation, there is significant range among different surgeons' responses. The present study questions the reliability of the clock face method for use between surgeons as a stand alone tool. Other methods also utilizing anatomic landmarks may be more accurate for describing intercondylar notch anatomy. LEVEL OF EVIDENCE: III. PMID- 21258781 TI - ACL reconstruction with "the original all-inside technique". AB - With the improvement of knee arthroscopy during the past decades anterior cruciate ligament reconstruction has become a common procedure, with several surgical techniques described. The "original all-inside technique" for ACL reconstruction with manually drilled double half tunnels, allowing the use of one single tendon triplicated or quadruplicated and hopefully improving the quality of the contact area between graft and bone. PMID- 21258782 TI - A biomechanical comparison of the Delta screw and RetroScrew tibial fixation on initial intra-articular graft tension. AB - PURPOSE: The purpose of this study is to determine the effect of bioabsorbable interference screw (BIS) tibial fixation with the Delta screw (antegrade) and RetroScrew (retrograde) on initial (time zero) intra-articular graft tension in soft tissue anterior cruciate ligament (ACL) reconstruction in a cadaveric model. METHODS: Ten matched pairs of cadaveric tibias received one of two tibial fixation constructs using quadrupled hamstring grafts, Delta screw (antegrade) or the RetroScrew (retrograde). Each specimen was mounted to the materials testing device with the displacement force vector in line with the tibial tunnel. The construct was pre-tensioned (10-30 N, 0.1 Hz, 10 cycles), a baseline tension of 25 N was introduced, and the change in intra-articular graft tension before and after screw insertion was recorded. RESULTS: Segmental (proximal, middle, distal) BMD was utilized to assess BMD using quantitative computed tomography (qCT). The Delta screw had a higher maximum insertion torque (P = 0.03) and exhibited a larger increase in intra-articular graft tension as compared to the RetroScrew (38.3 +/- 17.9 N, 7.6 N +/- 14.4, P = 0.004), respectively. There were no significant correlations between intra-articular graft tension increase to maximum insertion torque (P = NS) or corresponding segmental BMD (P = NS). CONCLUSIONS: Delta screw tibial fixation (antegrade) in soft tissue ACL reconstruction significantly increases the initial intra-articular graft tension as compared to RetroScrew screw fixation (retrograde) in this cadaveric model. Delta screw (antegrade) tibial fixation may increase initial quadrupled hamstring graft intra-articular tension with currently accepted insertion techniques. PMID- 21258783 TI - Zirconium oxide aerogel for effective enrichment of phosphopeptides with high binding capacity. AB - In this study, zirconium oxide (ZrO(2)) aerogel was synthesized via a green sol gel approach, with zirconium oxychloride, instead of the commonly used alkoxide with high toxicity, as the precursor. With such material, phosphopeptides from the digests of 4 pmol of beta-casein with the coexistence of 100 times (mol ratio) BSA could be selectively captured, and identified by MALDI-TOF MS. Due to the large surface area (416.0 m(2) g(-1)) and the mesoporous structure (the average pore size of 10.2 nm) of ZrO(2) aerogel, a 20-fold higher loading capacity for phosphopeptide, YKVPQLEIVPN[pS]AEER (MW 1952.12), was obtained compared to that of commercial ZrO(2) microspheres (341.5 vs. 17.87 mg g(-1)). The metal oxide aerogel was further applied in the enrichment of phosphopeptides from 100 ng nonfat milk, and 17 phosphopeptides were positively identified, with a 1.5-fold improvement in phosphopeptide detection compared with previously reported results. These results demonstrate that ZrO(2) aerogel can be a powerful enrichment material for phosphoproteome study. PMID- 21258784 TI - Analysis of perfluorinated alkyl substances in Spanish sewage sludge by liquid chromatography-tandem mass spectrometry. AB - The present article describes the development of an analytical method for the determination of 13 perfluorinated alkyl substances (PFAS), as well as its application to real sewage sludge samples to confirm the presence of these compounds. The isolation of the analytes was performed by agitation, sonication and centrifugation techniques, followed by EnviCarb cleanup and weak anion exchange solid-phase extraction. Sensitive and selective determination was carried out by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Six mass-labelled internal standards were used to ensure the accuracy of the analytical results following isotopic dilution method. Several mobile phases (acetonitrile, methanol, mixtures of both and water with ammonium acetate or acetic acid) have been tested to reach the best resolution and reproducibility results. Other parameters related to MS/MS conditions were optimized. The reliability of the method was confirmed by the evaluation of linearity (R(2) = 0.995-0.999), accuracy (84-99%) and injection repeatability and reproducibility (relative standard deviation below 19 and 23%, respectively). Limits of detection ranged from 0.007 to 2.217 pg. Recoveries show values higher than 80% for most of the target compounds. The application of this method to twenty real samples demonstrates its efficiency and accuracy, as well as provides for the first time to our knowledge, PFAS levels in sewage sludges from Spain. PMID- 21258785 TI - New fluorescent perylene bisimide indicators--a platform for broadband pH optodes. AB - Asymmetric perylene bisimide (PBI) dyes are prepared and are shown to be suitable for the preparation of fluorescence chemosensors for pH. They carry one amino functional substituent which introduces pH sensitivity via photoinduced electron transfer (PET) while the other one increases solubility. The luminescence quantum yields for the new indicators exceed 75% in the protonated form. The new indicators are non-covalently entrapped in polyurethane hydrogel D4 and poly(hydroxyalkylmethacrylates). Several PET functions including aliphatic and aromatic amino groups were successfully used to tune the dynamic range of the sensor. Because of their virtually identical spectral properties, various PBIs with selected PET functions can easily be integrated into a single sensor with enlarged dynamic range (over 4 pH units). PBIs with two different substitution patterns in the bay position are investigated and possess variable spectral properties. Compared with their tetrachloro analogues, tetra-tert-butyl substituted PBIs yield more long-wave excitable sensors which feature excellent photostability. Cross-sensitivity to ionic strength was found to be negligible. The practical applicability of the sensors may be compromised by the long response times (especially in case of tetra-tert-butyl-substituted PBIs). PMID- 21258786 TI - Overexpression of Runx2 and MKP-1 stimulates transdifferentiation of 3T3-L1 preadipocytes into bone-forming osteoblasts in vitro. AB - Runx2, a transcription factor, is essential for osteoblastic differentiation, bone formation, and maintenance. We examined the effect of Runx2 on transdifferentiation of 3T3-L1 preadipocytes into functional, mature osteoblasts. Forced expression of exogenous Runx2 using a retroviral gene-delivery system showed increases of alkaline phosphatase (ALP) activity and expression of the osteoblastic marker genes osteocalcin (OC), bone sialoprotein (BSP), and osterix (Osx), accompanied by low-level matrix mineralization. In contrast, adipocytic differentiation was completely blocked with downregulation of adipogenic transcription factors PPARgamma2, C/EBPalpha, and C/EBPdelta. Treatment of dexamethasone (Dex), a synthetic glucocorticoid, stimulated the formation of mineralized nodules in Runx2-overexpressing 3T3-L1 cells with increases of ALP, OC, BSP, and Osx expression. Here, we focused on a dual specific phosphatase, mitogen-activated protein kinase (MKP-1), since Dex significantly increased MKP-1 expression in Runx2-overexpressing 3T3-L1 cells. Forced expression of exogenous MKP-1 resulted in accumulation of robust matrix mineralization in parallel with induction of ALP activity and expression of OC, BSP, and Osx in Runx2 overexpressing 3T3-L1 cells. These results suggest that simultaneous overexpression of Runx2 and MKP-1 is effective for transdifferentiation of preadipocytes into fully differentiated bone-forming osteoblasts and provide a novel strategy for cell-based therapeutic applications requiring significant numbers of osteogenic cells to synthesize mineralized constructs for the treatment of large bone defects. PMID- 21258787 TI - Microsatellite-based quantification method to estimate biomass of endophytic Phialocephala species in strain mixtures. AB - Fungi of the Phialocephala fortinii sensu lato-Acephala applanata species complex (PAC) are ubiquitous endophytic colonizers of tree roots in which they form genotypically diverse communities. Measurement of the colonization density of each of the fungal colonizers is a prerequisite to study the ecology of these communities. Up to now, there is no method readily available for the quantification of PAC strains co-colonizing the same root. The new DNA quantification method presented here is based on the amplification of microsatellites by competitive polymerase chain reaction (PCR). The method proved to be suitable to detect and quantify at least two strains within one single sample by the addition of a known amount of mycelium of a reference strain before DNA extraction. The method exploits the correlation between the reference/target ratio of light emitted during microsatellite detection (peak ratio) and the reference/target ratio of mycelial weights to determine the biomass of the target strain. Hence, calibration curves were obtained by linear regression of the peak ratios on the weight ratios for different mixtures of reference and target strains. The slopes of the calibration curves and the coefficients of determination were close to 1, indicating that peak ratios are good predictors of weight ratios. Estimates of fungal biomass in mycelial test mixtures of known composition laid within the 95% prediction interval and deviated on average by 16% (maximally 50%) from the true biomass. On average, 3-6% of the root biomass of Norway spruce seedlings consisted of mycelial biomass of either one of two inoculated PAC strains. Biomass estimates obtained by real-time quantitative PCR were correlated with the estimates obtained by the microsatellite-based method, but variation between the two estimates from the same root was high in some samples. The microsatellite-based DNA quantification method described here is currently the best method for strainwise estimation of endophytic biomass of PAC fungi in small root samples. PMID- 21258788 TI - The marine isolate Novosphingobium sp. PP1Y shows specific adaptation to use the aromatic fraction of fuels as the sole carbon and energy source. AB - Novosphingobium sp. PP1Y, isolated from a surface seawater sample collected from a closed bay in the harbour of Pozzuoli (Naples, Italy), uses fuels as its sole carbon and energy source. Like some other Sphingomonads, this strain can grow as either planktonic free cells or sessile-aggregated flocks. In addition, this strain was found to grow as biofilm on several types of solid and liquid hydrophobic surfaces including polystyrene, polypropylene and diesel oil. Strain PP1Y is not able to grow on pure alkanes or alkane mixtures but is able to grow on a surprisingly wide range of aromatic compounds including mono, bi, tri and tetracyclic aromatic hydrocarbons and heterocyclic compounds. During growth on diesel oil, the organic layer is emulsified resulting in the formation of small biofilm-coated drops, whereas during growth on aromatic hydrocarbons dissolved in paraffin the oil layer is emulsified but the drops are coated only if the mixtures contain selected aromatic compounds, like pyrene, propylbenzene, tetrahydronaphthalene and heterocyclic compounds. These peculiar characteristics suggest strain PP1Y has adapted to efficiently grow at the water/fuel interface using the aromatic fraction of fuels as the sole carbon and energy source. PMID- 21258789 TI - Insights into the mechanism of HIV-1 envelope induced membrane fusion as revealed by its inhibitory peptides. AB - HIV-1 fusion with its target cells is mediated by the glycoprotein 41 (gp41) transmembrane subunit of the viral envelope glycoprotein (ENV). The current models propose that gp41 undergoes several conformational changes between the apposing viral and cell membranes to facilitate fusion. In this review we focus on the progress that has been made in revealing the dynamic role of the N terminal heptad repeat (NHR) and the C-terminal heptad repeat (CHR) regions within gp41 to the fusion process. The involvement of these regions in the formation of the gp41 pre-hairpin and hairpin conformations during an ongoing fusion event was mainly discovered by their derived inhibitory peptides. For example, the core structure within the hairpin conformation in a dynamic fusion event is suggested to be larger than its high resolution structure and its minimal boundaries were determined in situ. Also, inhibitory peptides helped reveal the dual contribution of the NHR to the fusion process. Finally, we will also discuss several developments in peptide design that has led to a deeper understanding of the mechanism of viral membrane fusion. PMID- 21258791 TI - The benefit of wire cerclage stabilisation of the medial hinge in intramedullary nailing for the treatment of subtrochanteric femoral fractures: a biomechanical study. AB - PURPOSE: Reduction and intramedullary fixation of subtrochanteric fractures is often challenging. Osteosynthesis frequently fails and a higher rate of non unions is found. The aim of this study was to evaluate the benefit of an additional cerclage to anatomically reduce and support the medial hinge. The application is based on the experience of the surgeon; as yet no biomechanical data are available. METHODS: Ten pairs of human cadaveric femora were used to determine the biomechanical and clinical advantage of an additional cerclage. All femora were tested in a materials testing system after osteotomy, osteosynthesis with the Gamma III nail and randomisation into two groups with or without additional cerclage. RESULTS: After cyclic loading the compressive load to reach plastic deformation of 5 mm was 2,160 N on average in the group without cerclage vs 2,330 N on average in the group with cerclage. This biomechanical advantage showed no statistical significance (p = 0.2). Radiological examination when the abort criterion was reached revealed that use of the additional wire cerclage could significantly decrease the failure of osteosynthesis (100 vs 10%) after intramedullary nailing of subtrochanteric fractures (p < 0.05). CONCLUSION: In view of the more invasive operative approach with additional soft tissue injuries, application of an additional cerclage should still be considered carefully. Nevertheless, a mini-open approach to difficult fractures could be helpful in reducing the fracture with a clamp and is sometimes essential. The damage to the soft tissue must be weighed against the benefits of the procedure. An additional cerclage in oblique subtrochanteric fractures is a good option to ensure the reposition and cortical medial support if appropriate and to decrease osteosynthesis failure and rates of non-unions. PMID- 21258790 TI - Monocyte-derived DC maturation strategies and related pathways: a transcriptional view. AB - Ex vivo production of highly stimulator mature dendritic cells (DCs) for cellular therapy has been used to treat different pathological conditions with the aim of inducing a specific immune response. In the last decade, several protocols have been developed to mature monocyte-derived DCs: each one has led to the generation of DCs showing different phenotypes and stimulatory abilities, but it is not yet known which one is the best for inducing effective immune responses. We grouped several different maturation protocols according to the downstream pathways they activated and reviewed the shared features at a transcriptomic level to reveal the potential of DCs matured by each protocol to develop Th-polarized immune responses. PMID- 21258792 TI - Stakeholder opinions on the assessment of MPA effectiveness and their interests to participate at Pacific Rim National Park Reserve, Canada. AB - As the number of marine protected areas (MPAs) is globally increasing, information is needed on the effectiveness of existing sites. Many protected area agencies however have limited resources and are unable to evaluate MPA effectiveness. An evaluation conducted entirely by the managing agency may also lack credibility. Long-term monitoring and evaluation programs should ideally offer opportunities for participation of diverse groups in the selection of evaluation indicators and their assessment. A participatory approach has the potential to enhance evaluation capacity, to increase credibility and acceptance of results, to strengthen relationships between managers and local stakeholders, and to address more locally relevant information. Using a case study approach, this paper investigates diverse stakeholder groups' opinions on the design of an evaluation and their interest to participate in an assessment. Respondents were most interested in the assessment of MPA achievements and outcome indicators. Most groups identified a range of government agencies and stakeholders that should participate in an assessment but only half of all respondents were interested to participate in monitoring activities. Most frequently mentioned limitations for more participation were a lack of time and money, but also governance shortcomings such as limited participation possibilities and not paying enough credit to stakeholders' input. Participation interest was also influenced by occupation, place of residency, and familiarity with the marine environment. Differences exist among stakeholders about suitable evaluators and preferred monitoring partners, which could affect the credibility of evaluation results and affect monitoring activities. PMID- 21258793 TI - CD44 in hematological neoplasias. AB - The CD44 protein family spans a large group of transmembrane glycoproteins acquired by alternative splicing and post-translational modifications. The great heterogeneity in molecular structure is reflected in its various important functions: CD44 mediates (1) interaction between cell and extracellular matrix, (2) signal submission, e.g., by acting as co-receptor for membrane-spanning receptor tyrosine kinases or by association with intracellular molecules initiating several signaling pathways, and (3) anchor function connecting to the cytoskeleton via the ezrin-radixin-moesin protein family. The expression pattern of the different CD44 isoforms display strong variations dependent on cell type, state of activation, and differentiation stage. In hematopoietic cells, CD44 mediates interaction of progenitor cells and bone marrow stroma during hematopoiesis, regulates maturation, and activation-induced cell death in T cells, influences neutrophil and macrophage migration as well as cytokine production, and participates in lymphocyte extravasation and migration. CD44 is involved in development and progress of hematological neoplasias by enhancement of apoptotic resistance, invasiveness, as well as regulation of bone marrow homing, and mobilization of leukemia-initiating cells into the peripheral blood. Thereby altered CD44 expression functions as marker for worse prognosis in most hematological malignancies. Additionally, CD44 expression levels can be used to distinguish between different hematological neoplasias and subtypes. Concerning new treatment strategies, CD44 displays promising potential either by direct targeting of CD44 expressed on the malignant cells or reversing an acquired resistance to primary treatment mediated through altered CD44 expression. The former can be achieved by antibody or hyaluronan-based immunotherapy. PMID- 21258794 TI - Necrosis of mesenteric lymph nodes in Henoch-Schonlein purpura. PMID- 21258795 TI - Interstitial cystitis: a rare manifestation of primary Sjogren's syndrome, successfully treated with low dose cyclosporine. AB - Chronic interstitial cystitis (IC), mostly affecting middle-aged women, is a very rare manifestation of primary Sjogren's syndrome (pSS). Hereby, we report a 42 year-old woman with pSS, presenting with dysuria, urinary frequency, and suprapubic pain. She was diagnosed to have chronic IC, based upon the cystoscopic biopsy finding of chronic inflammation in the bladder wall. Systemic corticosteroid and azathioprine treatments together with local intravesical therapies were not effective. Therefore, cyclosporine (CSA) therapy was initiated. Initial low dose of CSA (1.5 mg/kg/d) improved the symptoms of the patient, with no requirement for dose increment. After 4 months of therapy, control cystoscopic biopsy showed that bladder inflammation regressed and IC improved. This case suggests that even low doses of CSA may be beneficial for treating chronic IC associated with pSS syndrome. PMID- 21258796 TI - Gastric dysmotility after liquid bolus ingestion in systemic sclerosis: an ultrasonographic study. AB - Gastric involvement appears quite commonly in systemic sclerosis (SSc). The aim of this study was to evaluate gastric wall motility using ultrasonography, a noninvasive method able to track both filling and emptying of fundus and antrum. The study was performed in 20 SSc patients and 20 healthy control subjects. Gastric filling and emptying were evaluated by transabdominal ultrasonography, measuring changes in fundus and antral areas over a 1-h period after ingestion of a liquid bolus (500 ml of mineral water). Areas of both gastric fundus and antrum at basal evaluation were found to be smaller in SSc patients than in healthy controls. Gastric filling was significantly reduced after ingestion of liquid bolus. Gastric emptying was delayed both in fundus and antrum. No significant differences of gastric wall motility have been observed in different subsets of SSc patients. Our findings show that gastric dysmotility is frequent and severe in SSc patients, contributing to the gastrointestinal disturbances which are very common in this disease. PMID- 21258797 TI - A single-nucleotide polymorphism of the STAT4 gene is associated with systemic lupus erythematosus (SLE) in female Chinese population. AB - Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease with complex genetic inheritance. Genetic association of signal transducer and activator of transcription 4 (STAT4) with SLE susceptibility has been convincingly established in multiple populations including Asians, whereas studies of genetic relations between STAT4 polymorphisms and subphenotypes of SLE were rarely conducted. In this study, we selected Chinese female population and investigated genetic association between a polymorphism of STAT4 gene (rs7582694) and SLE. Furthermore, genetic association tests based on different subsets classified by 11 clinical manifestations were also performed. A total of 675 SLE female patients and 678 healthy controls were enrolled into this study, and SNP genotyping was performed using Sequenom's MassArray system (Sequenom iPLEX assay). Our study showed strong evidence for genetic predisposition of rs7582694 to SLE (X ( 2 ) = 23.7, OR = 0.68, 95% CI: 0.58-0.79, P = 1.13 * 10(-6)), while no association was observed between rs7582694 and any clinical presentations. The results of our study demonstrated that STAT4 rs7582694 SNP was significantly associated with SLE, and these results were in accordance with previous studies. PMID- 21258798 TI - Increased serum RANTES in patients with systemic lupus erythematosus. AB - The aim of this study was to investigate the serum RANTES (regulated on activation, normal T-cell expressed and secreted) level in patients with systemic lupus erythematosus (SLE), and the associations with disease activity and clinical laboratory indexes. Twenty-seven SLE patients and 27 normal controls were enrolled in this study. Serum RANTES was measured by enzyme-linked immunosorbent assay (ELISA). The clinical and laboratory parameters of the patients were also recorded. Results showed that serum RANTES level was significantly elevated in SLE patients when compared with normal controls. Serum RANTES level was correlated with C3, ANA, anti-dsDNA antibodies, anti-Sm antibodies, and anti-SSB antibodies. Nevertheless, no association of serum RANTES level with SLEDAI was found. Taken together, serum RANTES level was significantly higher in SLE patients, suggesting that RANTES might be involved in the pathogenesis of SLE. PMID- 21258799 TI - Concomitant rheumatoid arthritis and amyotrophic lateral sclerosis: report of two new cases and review of literature. AB - To describe a rare association between rheumatoid arthritis (RA) and amyotrophic lateral sclerosis (ALS). Two new cases of patients with RA who developed amyotrophic lateral sclerosis (ALS), one receiving anti-TNFalpha agents, were reported. Only other five cases of this rare association have been previously described in literature. The simultaneous presence of the two diseases represents a difficult diagnostic challenge because RA may mimic some musculoskeletal symptoms of ALS. There is no evidence in favor of a common pathophysiologic mechanism, and thus the possibility of a fortuitous association must be raised. A neurotoxic side effect of various drugs for RA treatment could be considered. Casual or causal association remains a difficult choice. The possibility of a coincidental association must be raised but neurologic side effects of TNFalpha blockers lead to discussion. PMID- 21258800 TI - Diabetic muscular infarct: an unusual cause of extremity pain and dysfunction. AB - Diabetic muscular infarct (DMI) is a rare condition, which begins with acute onset of extremity pain and swelling. Patients usually have long-standing disease and poorly controlled diabetes mellitus (DM). Thigh muscle group is the most commonly involved side, while lower leg involvement is rare. We represent herein a 22-year-old patient with type I DM who admitted to our outpatient clinic due to painful swelling of the left leg. In physical examination, anterior left leg was painful and firm on palpation; there was diffuse swelling extending to the knee and ankle with mild local fever and redness. T2-weighted MRI demonstrated hyperintensity in left leg muscles. A biopsy confirmed the diagnosis of DMI. She was treated with glucose regulation, analgesics, antiplatelet treatment and rest. At her 6 months, recurrence of DMI was observed. DMI should be considered in diabetic patients with extremity pain and swelling. Treatment plan should include the regulation of the blood glucose and evaluation of end-organ complications, analgesia, and bed rest. PMID- 21258801 TI - Long-term efficacy of anti-CD20 antibodies in refractory lupus nephritis. AB - Eight patients with refractory lupus nephritis received rituximab after failing standard sequential therapy and were followed for 104 weeks after the infusion. One patient died secondary to a complicated pregnancy but had stable renal function. Three patients received a re-infusion of rituximab approximately 12 months apart due to a renal flare; during the second year of follow-up, those patients progressed toward ESRD. The four remaining patients demonstrated improvements in SLEDAI score, CrCl, and proteinuria with maintenance of their standard immunosuppressive therapy and did not require a re-infusion of rituximab. Although rituximab as induction therapy for refractory lupus nephritis has been shown to have a good response, its efficacy in long-term assessments demonstrates disappointing results. PMID- 21258802 TI - Hypopituitarism due to primary empty sella and uncommon muscular symptoms. PMID- 21258803 TI - Systemic lupus erythematosus in the elderly. AB - Onset of the disease above the age of 65 years is unusual. This study was undertaken to determine retrospectively the clinical and laboratory features in SLE patients aged over 65 years. It is a retrospective study about 18 elderly patients with SLE out of 342 diagnosed between 1994 and 2009 in the center of Tunisia. All patients had at least 4 of 11 revised ACR criteria of SLE. The frequency of SLE in the elderly was 5.3%. The median age was 70 years (range 66 and 78 years). The sex ratio F/M was 5. The most frequent clinical signs were anemia (83.3%), arthralgia (55.5%), arthritis (38.9%), and malar rash (33.3%). The proteinuria and the neuropsychiatric troubles were present in 27.8% of cases. The pericarditis was present in 16.7% of cases. Antibodies to double stranded DNA (anti-dsDNA) were detected in 66.7%, anti-nucleosome in 50%, anti-SSA and anti RNP in 27.8%, anti-Sm in 22%, and anti-SSB in 11%. Elderly patients with SLE exhibit distinct clinical and biological manifestations from the classic form. Thus, greater attention should be given for this particular subgroup of SLE patients to avoid delays in diagnosis or misdiagnosis. PMID- 21258804 TI - The effect of mud pack therapy on serum YKL-40 and hsCRP levels in patients with knee osteoarthritis. AB - The aim of this study was to evaluate the efficacy of treatment with mud pack in knee osteoarthritis (OA) and to determine whether mud pack effects serum levels of YKL-40 and high-sensitivity C-reactive protein (hsCRP) which are reported to be biological markers for articular damage or inflammation in patients with OA. Forty-four patients with the diagnosis of knee OA assigned into two groups were treated with local natural mineral-rich mud pack or hot pack. Treatments were applied for 6 days a week for 2 weeks as a total of 12 sessions. Patients were assessed at baseline, post-treatment, and 3 months after the treatment. VAS, range of motion, 15-m walking time, WOMAC index, Nottingham Health Profile, serum YKL-40, and hsCRP levels were the outcome measures. Pain intensity and joint stiffness decreased in both groups at all follow-ups. Physical activity status was found to persist for 3 months after treatment only in mud pack group. Serum mean YKL-40 and hsCRP levels of the patients were higher compared to healthy control group. Serum YKL-40 level increased significantly only in hot pack group 3 months after the treatment (P < 0.017). No significant change was observed in hsCRP levels in both groups during the whole follow-up periods (P > 0.05). Mud pack and hot pack therapy were both demonstrated to be effective in symptomatic treatment of knee OA until the end of the 2-week treatment period, whereas only mud pack therapy was shown to be effective in functional status over time. In the hot pack group, increased serum YKL-40 level 3 months after the treatment might indicate persistence of cartilage degradation. Maintenance of YKL-40 level in mud pack therapy seems to slow down the progression of knee OA. PMID- 21258805 TI - Association of ADAM12-S protein with radiographic features of knee osteoarthritis and bone and cartilage markers. AB - ADAM12 (A disintegrin and metalloprotease) is one of the candidate genes demonstrating susceptibility to osteoarthritis. The purpose of this study was to investigate the relationship between ADAM12-S protein and radiographic knee osteoarthritis (KOA) and its correlation to several bone and cartilage biomarkers. The ADAM12-S protein was measured in 276 subjects (60% women, aged 32 60 years), including 181 individuals with and 95 without radiographic KOA features. The radiographs were obtained from both tibiofemoral (TF) and patellofemoral (PF) joints. The serum levels of ADAM12-S protein were measured by DELFIA1/AutoDELFIA research kit. The ADAM12-S protein was found in detectable ranges in 43 subjects (16 men), without statistical difference between the two genders. In the whole group, the ADAM12-S was related to radiographic KOA grades in TF (P = 0.004) as well in PF joint (P = 0.003). We also found a correlation between ADAM12-S protein and osteophytes in TF and/or PF joints (P = 0.003). No correlations were found between serum levels of S-CTx-I (C-terminal cross-linked telopeptides of type I collagen) or S-PINP (type I procollagen N-terminal propeptide) and ADAM12-S. Similarly, in the whole group, the ADAM12-S protein was not correlated with U-CTx-II (urinary C-telopeptide fragments of type II collagen); however, in the female group, trend to positive correlation between the investigated biomarkers (P = 0.019) was observed. The ADAM12-S protein could be elevated in some KOA cases, and this elevation correlates with the grades of the disease, mostly owning to development of osteophytes. This finding suggests the possible involvement of the ADAM12-S protein in the pathogenesis of KOA. PMID- 21258806 TI - Response of renal lesions during systemic treatment with sunitinib in patients with metastatic renal cell carcinoma: a single center experience with 14 patients. AB - PURPOSE: The tyrosine kinase inhibitor (TKI) sunitinib induces partial remissions (PR) in a substantial proportion of patients with metastatic renal cell carcinoma (mRCC). Only little is known about the activity of sunitinib in renal lesions in patients with metastatic disease, as most patients with synchronous metastases receive palliative nephrectomy. METHODS: Fourteen patients with clear cell mRCC with renal lesions and sunitinib therapy (50 mg OD, 4/2 scheme) were retrieved retrospectively from clinic records. Tumor assessment consisted of CT scans at least every two cycles, analyzed according to RECIST. In 5 of 14 patients, renal tumors were considered as the primary tumor, while the remaining patients had kidney metastases. In total, 65 target lesions were evaluated. RESULTS: The median progression-free survival (PFS) of sunitinib was 8.7 months (range: 2.7 40.2). Median overall survival (OS) from initiation of TKI therapy was 26 months (range: 3-55). Best response according to RECIST consisted of partial remission (PR) in 4 patients, stable disease (SD) in 7 patients, a complete remission (CR) in 1 patient, and 2 patients with progressive disease (PD). Analyzing the response of renal lesions only, 1 patient had PD, 8 patients had SD, 4 patients had PR, and 1 had a CR. Palliative nephrectomy was performed after two courses of sunitinib in 2 patients. CONCLUSIONS: In our cohort, similar responses of renal tumors and peripheral metastases were achieved with sunitinib treatment. Our results support the use of sunitinib to control renal tumor lesions in metastatic patients. PMID- 21258807 TI - beta-arrestin-2 is expressed in human prostate smooth muscle and a binding partner of alpha1A-adrenoceptors. AB - PURPOSE: Alpha1A-adrenoceptors are important regulators of prostatic smooth muscle tone and an important target for therapy of lower urinary tract symptoms. The function of heptahelical transmembrane receptors such as adrenoceptors can be regulated by beta-arrestin-2, which may bind to receptors besides G proteins. Here, we investigated the expression and alpha1A-adrenoceptor binding of beta arrestin-2 in the human prostate. METHODS: Human prostatic tissues were obtained from patients undergoing radical prostatectomies. The expression of beta-arrestin 2 and alpha1A-adrenoceptors was studied by RT-PCR, Western blot analysis, and immunohistochemistry. The protein-protein interaction between alpha1A adrenoceptors and beta-arrestin-2 was investigated by coimmunoprecipitation. RESULTS: RT-PCR and Western blot analysis demonstrated the expression of beta arrestin-2 mRNA and protein in the human prostate. Immunohistochemistry demonstrated beta-arrestin-2 expression in smooth muscle and stromal cells. Coimmunoprecipitation studies demonstrated that alpha1A-adrenoceptors in the human prostate may interact with beta-arrestin-2. Thus, specific binding of beta arrestin-2 to alpha1A-adrenoceptors was significantly higher than background during alpha1A-adrenoceptor detection in beta-arrestin-2 precipitates (P < 0.001) or during beta-arrestin-2 detection in alpha1A-adrenoceptor precipitates (P < 0.005). This interaction may be located to prostate smooth muscle cells, as expression of the alpha1A-adrenoceptor was exclusively found in smooth muscle cells after immunohistochemical staining. CONCLUSION: With beta-arrestin-2, we identified a new binding partner of the alpha1A-adrenoceptor in human prostate smooth muscle. Binding of beta-arrestin-2 may be involved in posttranslational regulation of prostate alpha1A-adrenoceptors. PMID- 21258809 TI - Degenerative osteoarthritis after Perthes' disease: a 36-year follow-up. AB - BACKGROUND: Although the prognosis of Perthes' disease at skeletal maturity is considered favorable, little is known about the long-term results after middle age. METHODS: We retrospectively analyzed the radiographic and functional outcomes of 67 patients (70 hips) who had been treated for Perthes' disease. Of these patients, 28 patients (29 hips) were evaluated using JOA (Japanese Orthopaedic Association) score and radiographs at follow-up (Group 1), 39 patients (41 hips) were evaluated by a postal questionnaire (Group 2). The mean follow-up period was 36.1 years. The mean age at follow-up was 43.1 years. RESULTS: Group 1, good radiographic results (Stulberg class I or II) were achieved in 59% of hips. No osteoarthritis (Tonnis Grade 0) was observed in only 48% of hips. The clinical results were good (JOA score >= 70) in 79% of hips. Disturbance of walking ability and activities of daily living was little. The Tonnis grade and JOA score declined after 40 years of age. All patients older than 50 years showed severe osteoarthritis. The severity of osteoarthritis correlated significantly with age at follow-up. Group 2, the clinical results were good (JOA score >= 56) in 76% of hips. In both groups, no patient had undergone total hip arthroplasty. Younger age at diagnosis (<8 years) correlated significantly with a better result. The JOA score correlated significantly with age at follow-up. CONCLUSION: Patients who were treated for Perthes' disease have a risk of osteoarthritis and a clinically poor outcome after the age of 40-50 years. PMID- 21258808 TI - Current concepts in the management of stroke in children with sickle cell disease. AB - Stroke is the most significant complication of sickle cell disease (SCD) in children with the potential for major morbidity and mortality. The recent two decades have witnessed tremendous advancements in understanding the pathophysiology of stroke, risk stratification of children and the role of timely preventative interventions. The aetiopathogenesis, types of stroke and specific risk factors are reviewed here with special emphasis on the role of transcranial Doppler ultrasonogram in the early identification of at-risk children. Published studies on primary and secondary prevention of stroke in children with SCD are analysed with respect to the levels of evidence, in favour of preventative and therapeutic strategies. The roles of the neurologist and the neurosurgeon are highlighted. PMID- 21258810 TI - Prevention of post-operative infections in spine surgery by wound irrigation with a solution of povidone-iodine and hydrogen peroxide. AB - INTRODUCTION: Starting from January 2009, we systematically irrigated the surgical wounds of patients undergoing spine surgery with a solution of povidone iodine (PVP-I) and hydrogen peroxide (H(2)O(2)). METHOD: We prospectively recorded the clinical data of patients who underwent spine surgery during 2009 and we compared the results with retrospectively reviewed clinical records of patients operated during 2008. Patients were analyzed for preoperative risk factors, type of surgical procedure, onset of the infection, clinical presentation, treatment, and outcome. We performed 460 spine surgeries during 2008 and 490 during 2009. RESULTS: We recorded seven post-operative infections in 2008 compared to none in 2009. CONCLUSION: We consider the solution of PVP-I plus H(2)O(2) effective in further reducing the rate of post-operative infection in spine surgery. PMID- 21258811 TI - Peripartum anesthetic management of a patient with brittle cornea syndrome. AB - Brittle cornea syndrome (BCS) is a rare autosomal recessive disease that affects the connective tissue. The syndrome is caused by genetic changes in the 4.7-Mb interval between the D16S3423 and D16S3425 markers on the 16q24 chromosome and mutations in the Zinc-Finger 469 gene (ZNF469). BCS is characterized by thin and fragile cornea that tends to perforate spontaneously or as a result of minor trauma to the eye. In addition, the patient usually suffers from hearing loss, mental retardation, hyperextensibility of skin and joints, as well as varying degrees of scoliosis. This phenotypical expression presents an interesting challenge to anesthetic care. We briefly present the perioperative management of a patient with BCS who underwent three cesarean sections. PMID- 21258812 TI - Functional organ preservation after chemoradiotherapy in elderly patients with loco-regionally advanced head and neck squamous cell carcinoma. AB - The aim of the present investigation is to evaluate the outcome after induction chemotherapy and concurrent multi-drug chemoradiotherapy (IC/CCRT) with or without post-chemoradiation neck dissection in medically fit elderly patients with loco-regionally advanced head and neck squamous cell carcinoma (HNSCC). Retrospective study including 44 elderly patients (median age 71 years; range 66 77 years) with previously untreated, inoperable, histologically proven non metastatic stage III or IV HNSCC. Following one cycle of IC, two cycles of cis platinum and 5-fluorouracil CCRT with conventional fractionated radiotherapy up to a dose of 66-70 Gy were administrated. A neck dissection was recommended for patients with node metastasis larger than 3 cm regardless of the response to therapy and for patients who had suspected persistent neck disease 8-12 weeks after completing treatment. Salvage surgery was considered for histologically proven persistent or recurrent tumor in the primary site. Time-to-event data were described using Kaplan-Meier actuarial curves. Overall, 37 patients (84.1%) completed the planned treatment. There were no cases of treatment-related deaths. Twenty-nine patients (65.9%) developed severe toxicities with grade 4 toxicity accounting for 22.7%. The median follow-up time in survivors was 41 months. Three year overall survival, progression-free survival, and functional progression-free survival estimates were 70.9, 67.0, and 57.3%, respectively. In selected medically fit elderly patients with loco-regionally advanced HNSCC, cis-platinum based chemoradiotherapy can be successfully applied, with moderate adverse events, in attempt to preserve a functional upper aerodigestive tract. PMID- 21258813 TI - The changes in submandibular gland size and function following chorda tympani section. AB - To investigate the effects of chorda tympani section on submandibular gland size and function in the early (postoperative day 7) and late (postoperative month 6) postoperative period by ultrasonography, scintigraphy, and biochemical analysis of the saliva patients with unilateral chronic otitis media. One-hundred and thirty patients (46 males and 84 females) who were >=16 years of age and diagnosed with unilateral chronic otitis media and for whom type 1 tympanoplasty was indicated in 1st Outpatient Clinic of Kartal Dr. Lutfi Kirdar Training and Research Hospital between August 2004 and February 2007 were enrolled in the study. Of 130 patients, 102 patients who were eligible and gave written approval were included in the study. However, of these patients 99 underwent type 1 tympanoplasty and 3 had a canal down mastoidectomy. In 99 patients, chorda tympani nerves of 16 were cut, but 3 patients had to be excluded due to allergic reactions. Before the operation, bilateral submandibular gland ultrasonography was performed on all patients and the anterior-posterior length, the frontal lateral-medial width (transverse), and the paramandibular depth of both submandibular glands were measured. In scintigraphic examinations, perfusion index (PI), uptake ratio and excretion fraction were measured. Then, in biochemical analysis of the saliva the levels of sodium, potassium, chloride, calcium, magnesium, amylase, and the values of pH and density were assessed by the saliva collection through Wharton duct. In the statistical comparison of operated and healthy side of the patients with respect to these parameters Mann Whitney U test, and in intragroup analysis Wilcoxon test was used. The volume of the submandibular gland of the operated side was significantly lower compared to the healthy side in postoperative month 6 (P < 0.05). According to the baseline volume of the submandibular gland of the healthy side, the increase in postoperative day 7 and month 6 were found to be statistically insignificant (P > 0.05). According to the baseline PI value, the decreases in the PI value in the postoperative day 7 and postoperative month 6 were statistically significant (P < 0.01). The uptake ratio of the patients was lower in the postoperative day 7 and month 6 than those at the baseline; however, the difference was statistically insignificant (P > 0.05). The excretion fraction values in the postoperative day 7 were significantly lower than the baseline values (P < 0.05), whereas the decrease in the EF values in the postoperative month 6 were statistically insignificant (P > 0.05). In conclusion, the present study was the first in the literature in which three parameters of assessment, such as ultrasonography, scintigraphy, and biochemical analysis, were used to determine the changes in submandibular gland size and function following the chorda tympani section. After chorda tympani section, the volume of submandibular gland decreased in the late postoperative period. Moreover, chorda tympani section led to decrease in the saliva secretion and the PI value of the patients in the early and late postoperative period. PMID- 21258814 TI - Mutation screening of mitofusin 2 in Charcot-Marie-Tooth disease type 2. AB - Charcot-Marie-Tooth (CMT) disease is among the most common inherited neurological disorders. Mutations in the gene mitofusin 2 (MFN2) cause the axonal subtype CMT2A, which has also been shown to be associated with optic atrophy, clinical signs of first motor neuron involvement, and early onset stroke. Mutations in MFN2 account for up to 20-30% of all axonal CMT type 2 cases. To further investigate the prevalence of MFN2 mutations and to add to the genotypic spectrum, we sequenced all exons of MFN2 in a cohort of 39 CMT2 patients. We identified seven variants, four of which are novel. One previously described change was co-inherited with a PMP22 duplication, which itself causes the demyelinating form CMT1A. Another mutation was a novel in frame deletion, which is a rare occurrence in the genotypic spectrum of MFN2 characterized mainly by missense mutations. Our results confirm a MFN2 mutation rate of ~15-20% in CMT2. PMID- 21258815 TI - Expression of the dnmt3 genes in zebrafish development: similarity to Dnmt3a and Dnmt3b. AB - The zebrafish differs from mammals in that they have six dnmt3 genes as opposed to the two that can produce a catalytically active protein in mammals. Zebrafish also do not show evidence of genomic imprinting and lack the Dnmt3l gene necessary to that process in mammals. As such, they offer a unique opportunity to compare the two genetic situations in order to define the roles of the multiple genes in developmental gene methylation. To this end, we have analyzed the developmental expression of the six dnmt3 genes in zebrafish and find that they fall into two distinct patterns. The expression patterns of the dnmt6 and dnmt8 genes, which more closely resemble the mammalian Dnmt3a gene in sequence, also show an expression pattern that is more similar to the expression of Dnmt3a rather than Dnmt3b. Conversely, the other four dnmt3 genes in zebrafish (dnmt3, dnmt4, dnmt5, and dnmt7) show an expression pattern that is more similar to Dnmt3b. The dnmt6 and dnmt8 genes are also expressed in the adult zebrafish and in the brain in particular. In situ expression analyses show that the dnmt6 and/or dnmt8 genes also show tissue-specific differences in expression with those two genes being more ubiquitously expressed in the developing zebrafish than the other dnmt3 genes. Although differences in dnmt3 function may exist between mammals and fish, our results showing similar expression patterns between the genes in fish and mammals suggest that the six dnmt3 genes in the zebrafish may be analogous to the two Dnmt3 genes in mammals. PMID- 21258816 TI - Effect of operational cycle time length on nitrogen removal in an alternating oxidation ditch system. AB - This paper refers to nitrogen removal optimization of an alternating oxidation ditch system through the use of a mathematical model and pilot testing. The pilot system where measurements have been made has a total volume of 120 m(3) and consists of two ditches operating in four phases during one cycle and performs carbon oxidation, nitrification, denitrification and settling. The mathematical model consists of one-dimensional mass balance (convection-dispersion) equations based on the IAWPRC ASM 1 model. After the calibration and verification of the model, simulation system performance was made. Optimization is achieved by testing operational cycles and phases with different time lengths. The limits of EU directive 91/271 for nitrogen removal have been used for comparison. The findings show that operational cycles with smaller time lengths can achieve higher nitrogen removals and that an "equilibrium" between phase time percentages in the whole cycle, for a given inflow, must be achieved. PMID- 21258817 TI - Pseudodominant inheritance of nephronophthisis caused by a homozygous NPHP1 deletion. AB - Nephronophthisis (NPHP) is an autosomal recessive kidney disease characterized by tubular basement membrane disruption, interstitial infiltration, and tubular cysts. NPHP leads to end-stage renal failure (ESRD) in the first three decades of life and is the most frequent genetic cause of chronic renal failure in children and young adults. Extrarenal manifestations are known, such as retinitis pigmentosa, brainstem and cerebellar anomalies, liver fibrosis, and ocular motor apraxia type Cogan. We report on a Turkish family with clinical signs of nephronophthisis. The phenotype occurred in two generations and therefore seemed to be inherited in an autosomal dominant pattern. Nevertheless, a deletion analysis of the NPHP1 gene on chromosome 2 was performed and showed a homozygous deletion. Analysis of the family pedigree indicated no obvious consanguinity in the last three generations. However, haplotype analysis demonstrated homozygosity on chromosome 2 indicating a common ancestor to the parents of all affected individuals. NPHP1 deletion analysis should always be considered in patients with apparently dominant nephronophthisis. Furthermore, three out of four patients developed ESRD between 27 and 43 years of age, which may be influenced by yet unknown modifier genes. PMID- 21258819 TI - Evaluation of the highly sensitized transplant recipient. AB - The immune response against alloantigens involves the production of antibodies and development of T-cell immunity. Recipients sensitized to HLA antigens may have antibodies to almost all donors and may not be able to find a suitable kidney transplant donor. Strategies available to enable these patients to obtain a transplant are to give priority to highly sensitized patients, to perform therapy for antibody reduction or to transplant with existing antibodies and to intervene as needed with post-transplant treatment. While sensitization against HLA antigens is the most important cause of immunological transplant failure, other types of alloantigens, many of them expressed selectively in endothelial cells, and autoantigens may also be involved. Molecular typing and solid-phase antibody testing have markedly changed this field in the last few years. Methods for the analysis of HLA antibodies and for the study of T-cell reactivity and sensitization will also be discussed. Virtual cross-matching can now be performed for many patients, resulting in considerable savings in time and effort. Successful application of this approach requires the intervention of highly trained personnel with a good understanding of the limitations of the procedure and with intimate knowledge of the antibody profiles of the patients on the waiting list. PMID- 21258818 TI - Hypertension in infancy: diagnosis, management and outcome. AB - Advances in the ability to identify, evaluate, and care for infants with hypertension, coupled with advances in the practice of Neonatology, have led to an increased awareness of hypertension in modern neonatal intensive care units. This review will present updated data on blood pressure values in neonates, with a focus on the changes that occur over the first days and weeks of life in both term and preterm infants. Optimal blood pressure measurement techniques as well as the differential diagnosis of hypertension in the neonate and older infants will be discussed. Recommendations for the optimal immediate and long-term evaluation and treatment, including potential treatment parameters, will be presented. We will also review additional information on outcome that has become available over the past decade. PMID- 21258820 TI - [Levobupivacaine vs. ropivacaine for continuous femoral analgesia after anterior cruciate ligament reconstruction]. AB - BACKGROUND: Levobupivacaine and ropivacaine are both used for continuous femoral analgesia after anterior cruciate ligament reconstruction; however it is unknown whether both drugs are equally effective regarding pain control, preservation of mobility and patient satisfaction. METHODS AND MATERIALS: In this randomized, placebo-controlled trial 84 patients undergoing anterior cruciate ligament (ACL) reconstruction with quadruple hamstring tendons were studied. For postoperative pain therapy levobupivacaine 0.125%, ropivacaine 0.2% or placebo control with NaCl 0.9% at a rate of 6 ml/h were used for 48 h using a femoral nerve catheter. All patients also received an i.v. patient-controlled analgesia (IVPCA) pump with piritramide. RESULTS: Patient satisfaction was significantly higher and night rest was better in both treatment groups compared to the placebo group but there appeared to be no major differences between the two local anesthetics. Opioid consumption was significantly higher in the placebo group compared to the levobupivacaine group but not the ropivacaine group. The pain scores showed a trend towards higher scores in the placebo group throughout but the difference only reached statistical significance on postoperative day 1. No statistical significant differences in motor block were found between the three groups. CONCLUSION: Postoperative analgesia for ACL reconstruction during the first 48 h using femoral block with a continuous infusion of levobupivacaine 0.125% or ropivacaine 0.2% in combination with an IVPCA is similarly effective and better than a placebo. Both studied drugs seem to be equally appropriate for this purpose. PMID- 21258821 TI - [Medical relevance of magnetic fields in pain therapy]. AB - BACKGROUND: Magnetic and electromagnetic fields have been accepted as real physical entities in medicine and are believed to achieve pain relief. Magnetic field therapy has been acknowledged as a non-invasive, safe and simple method for treatment of the site of injury, source of pain or inflammation, or other types of illnesses and pathologies. However, a consensus regarding the statistical relevance of the effects has not been established. MATERIALS AND METHODS: A detailed literature research was performed and the results were evaluated. Inclusion criteria were that the studies had to be randomized, double-blind and placebo-controlled, and no additional forms of treatment other than magnetic effects were allowed to be used. RESULTS: The evaluation of 17 studies with static magnetic fields showed on average no significant difference in pain relief between the group treated with magnetic fields and the placebo group. All studies using magnetic fields showed that forms of treatment conducted over a period of 30 min and at intervals of 1 week have no effects. In 10 studies with dynamic magnetic fields different effects were registered, which ranged from no effect to significant differences regarding pain relief between the treated and the control groups. CONCLUSIONS: Static magnetic fields are ineffective with respect to pain therapy. Dynamic magnetic fields show diverse effects. Hence, this therapy should be researched in depth. PMID- 21258822 TI - [Tapentadol: with two mechanisms of action in one molecule effective against nociceptive and neuropathic pain. Preclinical overview]. AB - Tapentadol (3-[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl] phenol) is a centrally acting analgesic of a new substance class for the treatment of severe nociceptive and neuropathic pain. Tapentadol combines MU-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in one molecule. Because of the combined mechanisms of action tapentadol offers a broad therapeutic spectrum for nociceptive as well as neuropathic pain. In different animal models its high efficacy was shown in acute nociceptive, acute and chronic inflammatory as well as in chronic neuropathic pain. Using several preclinical approaches it was shown that the noradrenergic component of tapentadol interacts with the opioid component and that both synergistically contribute to the analgesic effect of the substance. In comparison to known drugs with only one of the two modes of action, tapentadol, despite its high potency, has an improved tolerability profile in the relevant animal models, particularly with regard to gastrointestinal and central side effects. Tapentadol acts directly without metabolic activation and without formation of analgesically relevant metabolites. In different interaction studies a low potential for interactions was shown, thus clinically relevant drug-drug interactions are unlikely. Overall, tapentadol provides a safe pharmacodynamic pharmacokinetic profile. PMID- 21258823 TI - [Medium-term effects of a multimodal therapy on patients with fibromyalgia. Results of a controlled efficacy study]. AB - OBJECTIVE: Fibromyalgia shows a chronic course of the disease in most cases. Multimodal therapy has short-term effects but only intensive forms of therapy attain long-term effects. As part of an inpatient rehabilitation program a multimodal pain treatment including cognitive-behavioral therapy was conducted in order to evaluate medium-term effects. METHOD: The German pain questionnaire (DSF), the hospital anxiety and depression scale (HADS-D), the chronic pain questionnaire (FESV), the short form questionnaire on indicators of rehabilitation status (IRES-24) and the self-efficacy scale (ASES-D) were distributed to 166 fibromyalgia patients (intervention group n=116; control group n=50) before and after rehabilitation as well as 6 months after treatment. RESULTS: The intervention group showed better results regarding symptoms (pain intensity, anxiety, depression), state of health (somatic health, psychological well-being, functioning in everyday life) and self-efficacy. CONCLUSIONS: Based on the positive medium-term effects on functioning in everyday life and self efficacy there is evidence that patients benefit from multimodal rehabilitation programs including integrative patient education. PMID- 21258824 TI - Food intake and interdigestive gastrointestinal motility in ghrelin receptor mutant rats. AB - BACKGROUND: Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR). Ghrelin regulates feeding activity and interdigestive contractions of the stomach in rodents. To investigate the role of endogenous ghrelin in the digestive system, we have developed GHSR-mutant rats, named FHH Ghsr(m1Mcwi), using the Fawn-Hooded Hypertensive (FHH) parental strain. METHODS: N-ethyl-N-nitrosourea (ENU) was used as a mutagen. Genomic DNA prepared from a tail clip was analyzed using the targeting induced local lesions in genomes (TILLING) approach. The non-synonymous mutation in position 343 (NM_032075) led to the generation of a premature stop codon, causing deletion of the last 22 amino acids at the C-terminal of ghrelin receptor protein. Spontaneous and ghrelin-stimulated food intake was measured in wild-type (WT) FHH and FHH Ghsr(m1Mcwi) rats. For interdigestive motility recording, two strain gauge transducers were sutured on the antrum and duodenum. Spontaneous gastroduodenal contractions were recorded in freely moving conscious rats. RESULTS: Ghrelin (40 MUg/kg) failed to stimulate food intake in the mutant rats, while spontaneous food intake was not significantly different between the WT rats and FHH Ghsr(m1Mcwi) rats. Phase III-like contractions were observed in stomach and duodenum both in the WT and FHH-Ghsr(m1Mcwi) rats. In the WT rats, ghrelin (12 MUg/kg) administration enhanced spontaneous phase III-like contractions, and a GHSR antagonist, (D-lys3)GHRP-6 (0.28 mg/kg), abolished the spontaneous phase III like contractions. In FHH-Ghsr(m1Mcwi) rats, ghrelin and (D-lys3)GHRP-6 did not affect phase III-like contractions. CONCLUSIONS: It is suggested that the intact GHSR structure is essential for the ghrelin-dependent regulation of interdigestive motility and feeding behavior. Even in FHH-Ghsr(m1Mcwi) rats, spontaneous gastric phase III-like contractions were still observed, suggesting the development of a compensatory mechanism to maintain these contractions. PMID- 21258825 TI - Association between serum leptin and bone metabolic markers, and the development of heterotopic ossification of the spinal ligament in female patients with ossification of the posterior longitudinal ligament. AB - Obesity is a risk factor for ossification of the posterior longitudinal ligament (OPLL) of the spine, which is characterized by heterotopic bone formation in the posterior longitudinal spinal ligament. Hyperleptinemia is a common feature of obese people and leptin is believed to be an important factor in the pathogenesis of OPLL. However, the association between leptin and bone metabolism and the development of OPLL is not understood fully. The objective of the present study was to determine the association between serum leptin concentration and bone metabolic markers and the extent of heterotopic ossification of the spinal ligament in patients with OPLL. The serum concentrations of leptin, insulin, fructosamine, bone-specific alkaline phosphatase, and carboxyterminal propeptide of type I procollagen, urine deoxypyridinoline levels, and the number of vertebrae with OPLL involvement were measured in 125 (68 males and 57 females) patients with OPLL. The correlation between leptin and these other factors was then examined. Serum leptin and insulin concentrations were increased significantly in OPLL females compared to non-OPLL female controls. In the females with OPLL, serum leptin concentrations corrected for body mass index correlated positively with the number of vertebrae with OPLL involvement. In females, serum leptin levels were significantly higher in patients in whom OPLL extended to the thoracic and/or lumbar spine than in patients in whom OPLL was limited to the cervical spine. Our results suggest that hyperleptinemia, in combination with hyperinsulinemia, may contribute to the development of heterotopic ossification of the spinal ligament in female patients with OPLL. PMID- 21258826 TI - Screening for anorexia nervosa via measurement of serum leptin levels. AB - Due to their sub-normally low fat mass, leptin levels in patients with acute anorexia nervosa (AN) are well below reference levels for age and sex-matched controls. This hypoleptinemia entails endocrinological and behavioral characteristics observed in AN patients during starvation. We aimed to study the appropriateness of hypoleptinemia as a diagnostic marker for AN by assessing sensitivity, specificity and likelihood ratios for different referral serum leptin levels for predicting anorexia nervosa and healthy leanness. For prediction, we additionally generated a score based on a multivariate logistic model including body mass index (BMI; kg/m2) and leptin level. For this purpose, we measured leptin levels in 74 female patients with acute AN upon admission for inpatient or outpatient treatment. Adolescent and adult patients were recruited according to DSM-IV criteria from two multi-center studies. Additionally, leptin levels were measured in 65 female healthy, lean students. Mean serum leptin level was significantly decreased in patients with AN compared to underweight controls (0.87 +/- 0.90 vs. 6.43 +/- 3.55 MUg/L, p < 0.001). Leptin predicted AN independently of BMI; we confirmed a cutoff value in the range of 2 MUg/L as having both high specificity and sensitivity. Hypoleptinemia represents a state marker of acute AN and is useful for a laboratory-based diagnostic screening. PMID- 21258827 TI - Osteonecrosis in human immunodeficiency virus (HIV)-infected patients: a multicentric case-control study. AB - Osteonecrosis (ON) is a rare disabling complication occurring in patients with human immunodeficiency virus (HIV) infection at a higher frequency than in the general population despite effective combination antiretroviral therapy being made available, as recently documented by several retrospective studies. We designed a multicentric case-control study among HIV-infected patients cared for at institutions in the Italian CISAI group (Italian Study Group for Adverse Events in HIV Infection) to search for additional predictors of ON in this special population. All centers which observed at least one case of ON were requested to report data for central re-evaluation. Parallel HIV-positive, ON free controls were randomly selected and matched with confirmed cases of ON for sex, age and CD4 T-cell counts at the time of HIV diagnosis. Fifteen cases and controls were included in the final sample. Univariate statistical analyses revealed a significant association between ON and exposure to steroids (P = 0.001), exposure to one or more drugs in addition to HAART (Highly Active Anti Retroviral Therapy) (P = 0.03), high titers of total serum IgE (P = 0.02), loss of working ability (P = 0.03), triglycerides levels over 200 mg/dL before antiretrovirals (P = 0.03) and cholesterol levels over 200 mg/dL before and after antiretrovirals (P = 0.03 and 0.05, respectively). High serum IgE levels and loss of working ability in advance of ON appeared for the first time as possible predictors of ON in HIV patients, while long-term exposure to steroids, combined hyperlipemia and chronic treatment with other drugs in addition to antiretrovirals were confirmed. Predicting and preventing ON in the individual HIV-infected patient is therefore a clinically challenging opportunity. PMID- 21258828 TI - Oxygen cleavage with manganese and iron in ribonucleotide reductase from Chlamydia trachomatis. AB - The oxygen cleavage in Chlamydia trachomatis ribonucleotide reductase (RNR) has been studied using B3LYP* hybrid density functional theory. Class Ic C. trachomatis RNR lacks the radical-bearing tyrosine, crucial for activity in conventional class I (subclass a and b) RNR. Instead of the Fe(III)Fe(III) Tyr(rad) active state, C. trachomatis RNR has a mixed Mn(IV)Fe(III) metal center in subunit II (R2). A mixed MnFe metal center has never been observed as a radical cofactor before. The active state is generated by reductive oxygen cleavage at the metal site. On the basis of calculated barriers for oxygen cleavage in C. trachomatis R2 and R2 from Escherichia coli with a diiron, a mixed manganese-iron, and a dimanganese center, conclusions can be drawn about the effect of changing metals in R2. The oxygen cleavage is found to be governed by two factors: the redox potentials of the metals and the relative stability of the different peroxides. Mn(IV) has higher stability than Fe(IV), and the barrier is therefore lower with a mixed metal center than with a diiron center. With a dimanganese center, an asymmetric peroxide is more stable than the symmetric peroxide, and the barrier therefore becomes too high. Calculated proton-coupled redox potentials are compared to identify three possible R2 active states, the Fe(III)Fe(III)-Tyr(rad) state, the Mn(IV)Fe(III) state, and the Mn(IV)Mn(IV) state. A tentative energy profile of the thermodynamics of the radical transfer from R2 to subunit I is constructed to illustrate how the stability of the active states can be understood from a thermodynamical point of view. PMID- 21258829 TI - SWIFT MODELLER: a Java based GUI for molecular modeling. AB - MODELLER is command line argument based software which requires tedious formatting of inputs and writing of Python scripts which most people are not comfortable with. Also the visualization of output becomes cumbersome due to verbose files. This makes the whole software protocol very complex and requires extensive study of MODELLER manuals and tutorials. Here we describe SWIFT MODELLER, a GUI that automates formatting, scripting and data extraction processes and present it in an interactive way making MODELLER much easier to use than before. The screens in SWIFT MODELLER are designed keeping homology modeling in mind and their flow is a depiction of its steps. It eliminates the formatting of inputs, scripting processes and analysis of verbose output files through automation and makes pasting of the target sequence as the only prerequisite. Jmol (3D structure visualization tool) has been integrated into the GUI which opens and demonstrates the protein data bank files created by the MODELLER software. All files required and created by the software are saved in a folder named after the work instance's date and time of execution. SWIFT MODELLER lowers the skill level required for the software through automation of many of the steps in the original software protocol, thus saving an enormous amount of time per instance and making MODELLER very easy to work with. PMID- 21258830 TI - Hydrogen bonding interactions in noradrenaline-DMSO complexes: DFT and QTAIM studies of structure, properties and topology. AB - The hydrogen bonding interactions between noradrenaline (NA) and DMSO were studied with density functional theory (DFT) regarding their geometries, energies, vibrational frequencies, and topological features of the electron density. The quantum theory of atoms in molecules (QTAIM) and the natural bond orbital (NBO) analyses were employed to elucidate the hydrogen bonding interaction characteristics in noradrenaline-DMSO complexes. The H-bonds involving the hydroxyls hydrogen in NA and the O atom in DMSO are dominant intermolecular H-bonds and are stronger than other H-bonds involving the methyl hydrogen of DMSO as a H-donor. The weak H-bonds also include a pi H-bond which involves the benzene ring as a H-donor or H-acceptor. QTAIM identified the weak H bonds formed between the methyl hydrogen of DMSO and the N atom in NA in some complexes (AB5, AB6 and AB7), which cannot be further confirmed by NBO and other methods, so there are probably no interactions between hydrogen and nitrogen atoms among these complexes. A good linear relationship between logarithmic electron density (lnrho ( b )) at the bond critical point (BCP) and structural parameter (deltaR (H...Y)) was found. The formations of new H-bonds in some complexes are helpful to strengthen the original intramolecular H-bond, this is attributed to the cooperativity of H-bonds in complexes and can be learned from the structure results and the NBO and QTAIM analyses. Analysis of various physically meaningful contributions arising from the energy decomposition procedures show that the orbital interactions of H-bond is predominant during the formation of the complex, moreover, both the hydrogen bonding interaction and the structural deformation are responsible for the stability of the complexes. PMID- 21258831 TI - RNA and protein 3D structure modeling: similarities and differences. AB - In analogy to proteins, the function of RNA depends on its structure and dynamics, which are encoded in the linear sequence. While there are numerous methods for computational prediction of protein 3D structure from sequence, there have been very few such methods for RNA. This review discusses template-based and template-free approaches for macromolecular structure prediction, with special emphasis on comparison between the already tried-and-tested methods for protein structure modeling and the very recently developed "protein-like" modeling methods for RNA. We highlight analogies between many successful methods for modeling of these two types of biological macromolecules and argue that RNA 3D structure can be modeled using "protein-like" methodology. We also highlight the areas where the differences between RNA and proteins require the development of RNA-specific solutions. PMID- 21258832 TI - On possible existence of pseudobinary mixed valence fluorides of Ag(I)/Ag(II): a DFT study. AB - The DFT calculations performed within local density approximation disclose conceivable existence of two novel mixed-valence Ag(I)/Ag(II) fluorides, Ag(2)F(3), i.e., Ag(I)Ag(II)F(3) and Ag(3)F(4), i.e., Ag(I)(2)Ag(II)F(4). Ag(2)F(3) is predicted to crystallize in three equally stable NaCuF(3)-, KAgF(3) , or CuTeO(3)-type structures, while Ag(3)F(4) should be isostructural to Na(2)CuF(4). The calculated vibration-corrected energies of formation at 0 K of Ag(2)F(3) and Ag(3)F(4) (in their most stable polytypes) from binary fluorides are negative but small (respectively, -0.09 eV and -0.21 eV per formula unit). Formation of Ag(3)F(5) (which, in fact, is a mixed valence Ag(I)/Ag(III) salt) from binary fluorides is much less likely, since the energy of formation is quite positive of about a quarter eV. The predicted volumes per formula unit for all forms of Ag(2)F(3) are larger and that for K(2)CuF(4)-type Ag(3)F(4) is smaller than the sum of volumes of the corresponding binary fluorides; Ag(2)F(3) should not form at high pressure conditions due to a decomposition to the binary constituents. Ag(2)F(3) and Ag(3)F(4) should exhibit genuine mixed- and not intermediate-valence with quite different coordination spheres of Ag(I) and Ag(II). Nevertheless, they should not be electric insulators. Ag(2)F(3) is predicted to be a metallic ferrimagnet with a magnetic superexchange coupling constant, J, of -2 meV while Ag(3)F(4) should be a metallic ferromagnet with J of +52 meV. Since Ag(2)F(3) and Ag(3)F(4) are at the verge of thermodynamic stability, a handful of exothermic reactions have been proposed which could yield these as yet unknown compounds. PMID- 21258833 TI - Delayed presentation of a traumatic diaphragmatic rupture with intrapericardial herniation. AB - Thoracic and abdominal blunt traumas are the major causes of diaphragmatic rupture. These ruptures may be recognized at the time of the initial trauma, but are diagnosed months or even years later during the workup for related symptoms. We present herein a patient who suffered from abdominal pain and dyspnea years after a motor vehicle accident. A chest computed tomography (CT) demonstrated diaphragmatic rupture with intrapericardial herniation of intraabdominal organs. Exploratory laparotomy confirmed the diagnosis. In this report, we describe our management of this unusual diaphragmatic rupture. PMID- 21258834 TI - Clinical manifestation and prognostic factors of non-cholerae Vibrio infections. AB - Infections caused by non-cholerae Vibrio are uncommon. From July 2004 to June 2010, a total of 218 isolates of Vibrio species were identified from 171 patients treated at Chi Mei Medical Center, Taiwan. A total of 173 isolates of non cholerae Vibrio species were isolated from 127 patients. The most common type of infection was acute gastroenteritis (59.8%), followed by skin and soft tissue infection (SSTI) (26.0%) and primary bacteremia (11.0%). Other types of infection included biliary tract infection, peritonitis, and acute otitis media, each at a rate of less than 2%. For patients with acute gastroenteritis, V. parahaemolyticus comprised 92.1% of cases, but V. vulnificus was the most common pathogen causing SSTI. All episodes of bacteremia were caused by V. vulnificus. The all-cause mortality rate was 18.8% of 32 patients with SSTI and the fatality rate was significantly higher among patients with decreased albumin, elevated lactate, use of mechanical ventilation, intensive care unit (ICU) admission, and the presence of shock. In conclusion, non-cholerae Vibrio species caused protean manifestations that vary with the infecting Vibrio species. This epidemiological study helps physicians to better understand the clinical characteristics of infections caused by different non-cholerae Vibrio species. PMID- 21258835 TI - Morphological and crystallographic transformation from immature to mature coccoliths, Pleurochrysis carterae. AB - Morphology and crystallographic orientations of coccoliths, Pleurochrysis carterae, at the various growth stages were investigated using electron back scattered diffraction analyses and scanning electron microscope (SEM) stereo photogrammetry to understand the developments of two different coccolith units, namely V and R units. SEM observation indicates that the immature coccolith units at the earliest stage were not perfectly fixed on the organic base plates and several units were often lacked. The all units showed platy morphology and often lay parallel to the organic base plate. Their crystal orientations were close to that of the mature R units. With further growth, the platy morphology changes to a trapezoid to anvil-shape for both units, resulting in the interlocking structure of VR units. Morphological analyses present that the edges of the platy crystals parallel to the organic base plate were estimated as <48 1>, and their inner/upper surfaces were estimated as {10 14}. As they interlocked further, R units inclined more outward to develop the inner tube elements with {10 1 4} and then each unit develops differently distal and proximal shield elements, which are respectively estimated as {10 14} in the distal view and {2 1 10} planes in the proximal view. Based on the above results, the formation of different coccolith units and their growth were discussed. PMID- 21258836 TI - The Kampo medicine, Goshajinkigan, prevents neuropathy in patients treated by FOLFOX regimen. AB - BACKGROUND: Oxaliplatin is now considered a standard treatment for advanced or unresectable colorectal cancer, but its main dose-limiting toxicity is sensory neuropathy. The OPTIMOX (stop and go) approach offers a reasonable strategy, but the preventive agent is not established. It is reported that the Kampo medicine, Goshajinkigan (GJG), has recently been considered an effective agent for the neuropathy of taxanes and for vibration sensation in patients with diabetic neuropathy. The aim of this study was to clarify the efficacy of GJG for peripheral neuropathy associated with oxaliplatin therapy. PATIENTS AND METHOD: From 2007, 45 patients treated with modified FOLFOX6 for non-resectable or recurrent colorectal cancer participated in the study. Twenty-two patients (GJG group) received oral administration of 7.5 g/day of GJG every day during mFOLFOX6 therapy and 23 patients (control group) did not receive GJG. Neuropathy was evaluated during every course according to DEB-NTC (Neurotoxicity Criteria of Debiopharm). RESULTS: The median number of cycles per patient in the GJG group was 13 (range 4-32), and in the control group was 12 (range 4-28). The cumulative dose of oxaliplatin was 1105 mg/m(2) (GJG group) and 1120 mg/m(2) (control group). The incidence of grade 3 peripheral neuropathy in the GJG group was significantly lower than in the control group (p < 0.01, log-rank test). The incidence of grade 3 peripheral neuropathy after 10 courses was 0% in the GJG group and 12% in the control group, and after 20 courses was 33% in the GJG group and 75% in the control group. The percentage of grade 2 and 3 peripheral neuropathy in the GJG group was lower than that in the control group. There were no differences in adverse effects between the two groups except for peripheral neuropathy and influence on tumor response. CONCLUSION: The Kampo medicine, Goshajinkigan, is useful in preventing neuropathy in non-resectable or recurrent colorectal cancer patients treated with a FOLFOX regimen. PMID- 21258837 TI - Isolated splenic metastasis from colorectal cancer. AB - Splenic metastases are unusual, arising in less than 1% of all metastases. Isolated solitary splenic metastasis from colorectal carcinoma is considered exceptional. This rarity has been explained by several hypotheses relating to the anatomical, histological, and immunological features of the spleen. We review the reported cases of isolated solitary splenic metastasis from colorectal carcinoma and discuss the diagnostic and therapeutic options for this entity. We searched the English-language medical literature, using the Medline and Pubmed databases from January 1966 through July 2010, for articles reporting isolated splenic metastasis from colorectal carcinoma. Only 26 cases have been reported; four cases had synchronous splenic metastasis. Fifteen patients had regional lymph node involvement on diagnosis of primary carcinoma. The primary tumor was located in the left colon or in the rectum in 18 cases. Carcinoembryonic antigen (CEA) level was elevated in 73% of cases. All patients underwent curative splenectomy; only one patient had laparoscopic resection of the spleen. Mean reported survival interval was 19.5 months; only three patients were deceased at last follow-up. Solitary splenic metastasis from colorectal carcinoma is very rare; clinicians are advised to pay close attention when routinely evaluating patients with serial CEA levels and abdominal scans. Splenectomy seems to be the preferred treatment modality with improvement of long-term survival. However, definitive conclusions cannot be drawn from the small number of case reports available. PMID- 21258838 TI - Nephrotic syndrome developing during induction chemotherapy for childhood acute lymphoblastic leukemia. AB - This report is the first to document minimal change nephrotic syndrome occurring during induction chemotherapy for childhood acute lymphoblastic leukemia (ALL). This occurrence lends further support to the theory of immune cell dysregulation being central to the pathogenesis of nephrotic syndrome in ALL, rather than alternative postulations that this association is due to an increased risk of malignancy secondary to prior immunosuppressive treatment for nephrotic syndrome. PMID- 21258839 TI - Cardiac safety in cluster headache patients using the very high dose of verapamil (>=720 mg/day). AB - Use of high doses of verapamil in preventive treatment of cluster headache (CH) is limited by cardiac toxicity. We systematically assess the cardiac safety of the very high dose of verapamil (verapamil VHD) in CH patients. Our work was a study performed in two French headache centers (Marseilles-Nice) from 12/2005 to 12/2008. CH patients treated with verapamil VHD (>=720 mg) were considered with a systematic electrocardiogram (EKG) monitoring. Among 200 CH patients, 29 (14.8%) used verapamil VHD (877+/-227 mg/day). Incidence of EKG changes was 38% (11/29). Seven (24%) patients presented bradycardia considered as nonserious adverse event (NSAE) and four (14%) patients presented arrhythmia (heart block) considered as serious adverse event (SAE). Patients with EKG changes (1,003+/-295 mg/day) were taking higher doses than those without EKG changes (800+/-143 mg/day), but doses were similar in patients with SAE (990+/-316 mg/day) and those with NSAE (1,011+/ 309 mg/day). Around three-quarters (8/11) of patients presented a delayed-onset cardiac adverse event (delay >=2 years). Our work confirms the need for systematic EKG monitoring in CH patients treated with verapamil. Such cardiac safety assessment must be continued even for patients using VHD without any adverse event for a long time. PMID- 21258840 TI - Relative urban ecosystem health assessment: a method integrating comprehensive evaluation and detailed analysis. AB - Regarding the basic roles of urban ecosystem health assessment (i.e., discovering the comprehensive health status, and diagnosing the limiting factors of urban ecosystems), the general framework integrating comprehensive evaluation and detailed analysis is established, from both bottom-up and top-down directions. Emergy-based health indicators are established to reflect the urban ecosystem health status from a biophysical viewpoint. Considering the intrinsic uncertainty and relativity of urban ecosystem health, set pair analysis is combined with the emergy-based indicators to fill the general framework and evaluate the relative health level of urban ecosystems. These techniques are favorable for understanding the overall urban ecosystem health status and confirming the limiting factors of concerned urban ecosystems from biophysical perspective. Moreover, clustering analysis is applied by combining the health status with spatial geographical conditions. Choosing 26 typical Chinese cities in 2005, relative comprehensive urban ecosystem health levels were evaluated. The higher health levels of Xiamen, Qingdao, Shenzhen, and Zhuhai are in particular contrast to those of Wuhan, Beijing, Yinchuan, and Harbin, which are relatively poor. In addition, the conditions of each factor and related indicators are investigated through set pair analysis, from which the critical limiting factors of Beijing are confirmed. According to clustering analysis results, the urban ecosystems studied are divided into four groups. It is concluded that the proposed framework of urban ecosystem health assessment, which integrates comprehensive evaluation and detailed analysis and is fulfilled by emergy synthesis and set pair analysis, can serve as a useful tool to conduct diagnosis of urban ecosystem health. PMID- 21258842 TI - Profibrinolytic effect of Enzamin, an extract of metabolic products from Bacillus subtilis AK and Lactobacillus. AB - Fibrinolytic system impairment contributes to the development of thrombotic disease such as cardiovascular disease and stroke. Therefore, an agent that increases fibrinolytic activity may be useful for the prevention of these diseases. In this study, to explore novel profibrinolytic agents, we examined the profibrinolytic effect of Enzamin, an extract of metabolic products from Bacillus subtilis AK and Lactobacillus in vitro and in vivo. Enzamin directly enhanced plasmin activity generated by tissue-type plasminogen activator (t-PA) by twofold but not by urokinase-type plasminogen activator (u-PA) in vitro, which was measured employing both the chromogenic substrate H-D: -Val-Leu-Lys-pNA (S-2251) and fibrin plate. Enzamin also increased plasmin activity generated by t-PA in the cell lysate and culture medium of endothelial cells, measured by fibrin zymography. Furthermore, the oral administration of a 1% concentration of Enzamin increased plasmin activity generated by t-PA by 1.7-fold but not by u-PA in the euglobulin fraction of mouse plasma. In conclusion, Enzamin has a unique ability to enhance the fibrinolytic activity through an increase in endogenous plasmin activity generated by t-PA released from endothelial cells, and may be a beneficial supplement for the prevention of thrombotic episodes. PMID- 21258843 TI - Mechanisms of iron import in anthrax. AB - During an infection, bacterial pathogens must acquire iron from the host to survive. However, free iron is sequestered in host proteins, which presents a barrier to iron-dependent bacterial replication. In response, pathogens have developed mechanisms to acquire iron from the host during infection. Interestingly, a significant portion of the iron pool is sequestered within heme, which is further bound to host proteins such as hemoglobin. The copious amount of heme-iron makes hemoglobin an ideal molecule for targeted iron uptake during infection. While the study of heme acquisition is well represented in Gram negative bacteria, the systems and mechanism of heme uptake in Gram-positive bacteria has only recently been investigated. Bacillus anthracis, the causative agent of anthrax disease, represents an excellent model organism to study iron acquisition processes owing to a multifaceted lifecycle consisting of intra- and extracellular phases and a tremendous replicative potential upon infection. This review provides an in depth description of the current knowledge of B. anthracis iron acquisition and applies these findings to a general understanding of how pathogenic Gram-positive bacteria transport this critical nutrient during infection. PMID- 21258844 TI - In silico modeling of the Menkes copper-translocating P-type ATPase 3rd metal binding domain predicts that phosphorylation regulates copper-binding. AB - The Menkes (ATP7A) P(1B)-type ATPase is a transmembrane copper-translocating protein. It contains six similar high-affinity metal-binding domains (MBDs) in the N-terminal cytoplasmic tail that are important for sensing intracellular copper and regulating ATPase function through the transfer of copper between domains. Molecular characterization of copper-binding and transfer is predominantly dependent on NMR structures derived from E. coli expression systems. A limitation of these models is the exclusion of post-translational modifications. We have previously shown that the third copper-binding domain, MBD3, uniquely contains two phosphorylated residues: Thr-327, which is phosphorylated only in the presence of elevated copper; and Ser-339, which is constitutively phosphorylated independent of copper levels. Here, using molecular dynamic simulations, we have incorporated these phosphorylated residues into a model based on the NMR structures of MBD3. Our data suggests that constitutively phosphorylated Ser-339, which is in a loop facing the copper-binding site, may facilitate the copper transfer process by exposing the CxxC copper-binding region of MBD3. Copper-induced phosphorylation of Thr327 is predicted to stabilize this change in conformation. This offers new molecular insights into how cell signaling (phosphorylation) can affect MBD structure and dynamics and how this may in turn affect copper-binding and thus copper-translocation functions of ATP7A. PMID- 21258845 TI - Mammalian cell entry gene family of Mycobacterium tuberculosis. AB - Knowledge of virulence factors is important to understand the microbial pathogenesis and find better antibiotics. Mammalian cell entry (mce) is a crucial protein family for the virulence of Mycobacterium tuberculosis (M. tuberculosis). This review summarized the advances on mce genes. The genomic organization, characteristics of mce genes, phylogeny of this family, and their roles in M. tuberculosis virulence are emphasized in this review. PMID- 21258846 TI - Effect of blasting treatment and Fn coating on MG63 adhesion and differentiation on titanium: a gene expression study using real-time RT-PCR. AB - Biomaterial surface properties, via alterations in the adsorbed protein layer, and the presence of specific functional groups can influence integrin binding specificity, thereby modulating cell adhesion and differentiation processes. The adsorption of fibronectin, a protein directly involved in osteoblast adhesion to the extracellular matrix, has been related to different physical and chemical properties of biomaterial surfaces. This study used blasting particles of different sizes and chemical compositions to evaluate the response of MG63 osteoblast-like cells on smooth and blasted titanium surfaces, with and without fibronectin coatings, by means of real-time reverse transcription-polymerase chain reaction (qRT-PCR) assays. This response included (a) expression of the alpha(5), alpha(v) and alpha(3) integrin subunits, which can bind to fibronectin through the RGD binding site, and (b) expression of alkaline phosphatase (ALP) and osteocalcin (OC) as cell-differentiation markers. ALP activity and synthesis of OC were also tested. Cells on SiC-blasted Ti surfaces expressed higher amounts of the alpha(5) mRNA gene than cells on Al(2)O(3)-blasted Ti surfaces. This may be related to the fact that SiC-blasted surfaces adsorbed higher amounts of fibronectin due to their higher surface free energy and therefore provided a higher number of specific cell-binding sites. Fn-coated Ti surfaces decreased alpha(5) mRNA gene expression, by favoring the formation of other integrins involved in adhesion over alpha(5)beta(1). The changes in alpha(5) mRNA expression induced by the presence of fibronectin coatings may moreover influence the osteoblast differentiation pathway, as fibronectin coatings on Ti surfaces also decreased both ALP mRNA expression and ALP activity after 14 and 21 days of cell culture. PMID- 21258847 TI - Preparation and preliminary cytocompatibility of magnesium doped apatite cement with degradability for bone regeneration. AB - In the present study, we fabricated magnesium doped apatite cement (md-AC) with rapid self-setting characteristic by adding the mixed powders of magnesium oxide and calcium dihydrogen phosphate (MO-CDP) into hydroxyapatite cement (HAC). The results revealed that the md-AC with 50 wt% MO-CDP could set within 6 min and the compression strength could reach 51 MPa after setting for 1 h, indicating that the md-AC had highly initial mechanical strength. The degradability of the md-AC in Tris-HCl solution increased with the increase of MO-CDP amount, and the weight loss ratio of md-AC with 50 wt% MO-CDP was 57.5 wt% after soaked for 12 weeks. Newly flake-like apatite could be deposited on the md-AC surfaces after soaked in simulated body fluid (SBF) for 7 days. Cell proliferation ratio of MG(63) cells on md-AC was obviously higher than that of HAC on days 4 and 7. The cells with normal phenotype spread well on the md-AC surfaces and attached intimately with the substrate, and alkaline phosphatase (ALP) activity of the cells on md-AC significantly improved compared with HAC on day 7. The results demonstrate that the md-AC has a good ability to support cell proliferation and differentiation, and indicate a good cytocompatibility. PMID- 21258848 TI - Effectiveness of an interactive website aimed at empowerment of disability benefit claimants: results of a pragmatic randomized controlled trial. AB - INTRODUCTION: The aim of this study was to investigate the effectiveness of an interactive website aimed at empowerment of disability claimants, prior to the assessment of disability by an insurance physician. METHODS: A randomized controlled trial was conducted. Claimants applying for a work disability pension after being sick-listed for 104 weeks, were randomized into either an intervention group or control group. Participants who were randomized into the intervention group were able to logon to the website www.wiagesprek.nl , which mainly consisted of five interactive modules aimed at increasing knowledge, self awareness, expectations, self-efficacy, and active participation. Participants from the control group were directed to a 'sham' website with commonly available information only. The primary outcome was empowerment. Secondary outcomes included coping, knowledge, claimant satisfaction, perceived justice, and physician satisfaction. Outcomes were assessed at baseline, 2 days before the disability assessment, as well as 1 day after, 6 weeks, and 4 months after the disability assessment. RESULTS: Claimants were randomly assigned to the intervention group (n = 123) or a control group (n = 119). The intervention had no significant short- and long-term effects on empowerment, but the intervention increased claimants' knowledge significantly compared to the control group. Claimant satisfaction with the disability assessment interview and claimant perceived justice on the outcome of the assessment were lower in the intervention group (statistically not significant). Furthermore, the intervention had a significant negative effect on claimants perceived procedural justice. CONCLUSION: Although knowledge increased significantly, the intervention www.wiagesprek.nl was not successful in reaching its primary target, that is, to increase levels of empowerment among disability claimants, prior to the assessment of disability. PMID- 21258849 TI - An integrated review of the processes and factors relevant to vocational evaluation following traumatic brain injury. AB - INTRODUCTION: In order to develop the evidence base for a clinical practice guideline (CPG) for vocational evaluation following traumatic brain injury (TBI), we undertook a review to identify the key processes evaluators should follow and the key factors they should consider when completing a vocational evaluation. METHODS: Processes outlined in the Cochrane Handbook of Systematic Review guided our processes and included: development of review questions, search strategies and selection criteria; quality appraisal; extraction, analysis and data synthesis; drawing conclusions. Four data bases (i.e. Medline; PsychInfo; Embase; The Cochrane Library of Systematic Reviews) were searched for descriptive articles, quantitative and qualitative studies, and nine websites were searched for CPGs (e.g. Scottish Intercollegiate Guideline Network; US National Guideline Clearinghouse; New Zealand Guideline Group). Two reviewers independently appraised methodological quality. Data were extracted into evidence tables which included: study purpose; location; participants; design/method; themes; findings; relevant processes and factors. Directed content analysis was utilized to analyze and synthesize the descriptive process evidence. A constant comparative method was employed to compare study findings in relation to factors associated with successful employment. RESULTS: Results from process and factors syntheses are integrated into the Evidence-based Framework for Vocational Evaluation Following TBI. This framework identifies seven key processes in a vocational evaluation, including: (1) identification of the evaluation purpose and rationale; (2) intake process; (3) assessment of the person; (4) assessment of the environment; (5) assessment of the occupation/job requirements; (6) analysis and synthesis of assessment results; (7) development of evaluation recommendations. Relevant factors are integrated into each key process. CONCLUSIONS: This framework outlines the key information evaluators should gather, the domains of the person, environment and occupation they should assess, and elements of rigour they should consider when completing a vocational evaluation and making recommendations for work re-entry following a TBI. PMID- 21258850 TI - Vocational rehabilitation from the client's perspective using the International Classification of Functioning, Disability and Health (ICF) as a reference. AB - INTRODUCTION A mixed-methods (qualitative-quantitative), multicenter study was conducted using a focus group design to explore the lived experiences of persons in vocational rehabilitation (VR) with regard to functioning and contextual factors using six open-ended questions related to the ICF components. The results were classified by using the International Classification of Functioning, Disability and Health (ICF) as a frame of reference. METHODS The meaningful concepts within the transcribed data were identified and linked to ICF categories according to established linking rules. RESULTS The seven focus groups with 26 participants yielded a total of 4,813 relevant concepts which were linked to a total of 160 different second-level ICF categories. From the client perspective, the ICF components (a) body functions, (b) activities and participation and (c) environmental factors were equally represented, while (d) body structures appeared less frequently. Out of the total number of concepts, 864 concepts (18%) were assigned to the ICF component personal factors which is not yet classified but could indicate important aspects of resource management and strategy development of patients in VR. CONCLUSION Therefore, VR of patients must not be limited to anatomical and pathophysiologic changes, but should also consider a more comprehensive view which includes client's demands, strategies and resources in daily life and the context around the individual and social circumstances of their work situation. PMID- 21258851 TI - Validation of arsenic resistance in Bacillus cereus strain AG27 by comparative protein modeling of arsC gene product. AB - The ars gene system provides arsenic resistance to a variety of microorganisms and can be chromosomal or plasmid-borne. The arsC gene, which codes for an arsenate reductase is essential for arsenate resistance and transforms arsenate into arsenite, which is extruded from the cell. Therefore, arsC gene from Bacillus cereus strain AG27 isolated from soil was amplified, cloned and sequenced. The strain exhibited a minimum inhibitory concentration of 40 and 35 mM to sodium arsenate and sodium arsenite, respectively. Homology of the sequence, when compared with available database using BLASTn search showed that 300 bp amplicons obtained possess partial arsC gene sequence which codes for arsenate reductase, an enzyme involved in the reduction of arsenate to arsenite which is then effluxed out of the cell, thereby indicating the presence of efflux mechanism of resistance in strain. The efflux mechanism was further confirmed by atomic absorption spectroscopy and scanning electron microscopy studies. Moreover, three dimensional structure of modeled arsC from Bacillus cereus strain shares significant structural similarity with arsenate reductase protein of B.subtilis, consisting of, highly similar overall fold with single alpha/beta domain containing a central four stranded, parallel, open-twisted beta-sheet flanked by alpha-helices on both sides. The structure harbors the arsenic binding motif AB loop or P-loop that is highly conserved in arsenate reductase family. PMID- 21258852 TI - The complex interplay between mitochondrial dynamics and cardiac metabolism. AB - Mitochondria are highly dynamic organelles, capable of undergoing constant fission and fusion events, forming networks. These dynamic events allow the transmission of chemical and physical messengers and the exchange of metabolites within the cell. In this article we review the signaling mechanisms controlling mitochondrial fission and fusion, and its relationship with cell bioenergetics, especially in the heart. Furthermore we also discuss how defects in mitochondrial dynamics might be involved in the pathogenesis of metabolic cardiac diseases. PMID- 21258853 TI - Mitochondrial energy metabolism and redox responses to hypertriglyceridemia. AB - In this work we review recent findings that explain how mitochondrial bioenergetic functions and redox state respond to a hyperlipidemic in vivo environment and may contribute to the maintenance of a normal metabolic phenotype. The experimental model utilized to evidence these adaptive mechanisms is especially useful for these studies since it exhibits genetic hypertriglyceridemia and avoids complications introduced by high fat diets. Liver from hypertrigliceridemic (HTG) mice have a greater content of glycerolipids together with increased mitochondrial free fatty acid oxidation. HTG liver mitochondria have a higher resting respiration rate but normal oxidative phosphorylation efficiency. This is achieved by higher activity of the mitochondrial potassium channel sensitive to ATP (mitoK(ATP)). The mild uncoupling mediated by mitoK(ATP) accelerates respiration rates and reduces reactive oxygen species generation. Although this response is not sufficient to inhibit lipid induced extra-mitochondrial oxidative stress in whole liver cells it avoids amplification of this redox imbalance. Furthermore, higher mitoK(ATP) activity increases liver, brain and whole body metabolic rates. These mitochondrial adaptations may explain why these HTG mice do not develop insulin resistance and obesity even under a severe hyperlipidemic state. On the contrary, when long term high fat diets are employed, insulin resistance, fatty liver and obesity develop and mitochondrial adaptations are inefficient to counteract energy and redox imbalances. PMID- 21258855 TI - Inhibitory effects of prior low-dose X-irradiation on cold-induced brain injury in mouse. AB - We examined the inhibitory effects of low-dose X-irradiation on mouse brain tissue with cold-induced injury by comparing tissue samples from three groups of mice: control, sham-irradiated cold-exposed, and X-ray-irradiated (0.5 Gy) cold exposed mice. The water content in brain increased significantly in the sham irradiated group following the cold-induced injury relative to the control group. However, water content in brain tissue from the X-ray-irradiated group was significantly lower than that from the sham-irradiated group. Levels of antioxidants, such as superoxide dismutase and glutathione, in brain tissue from the X-ray-irradiated group were higher than those from the sham-irradiated group. Moreover, the cold injury-induced cell death, particularly apoptosis, while low dose irradiation inhibited cell death, especially among glial cells, but not numeral cells. These findings suggest that prior low-dose X-irradiation activated antioxidant function and inhibited cold-induced brain injury. PMID- 21258854 TI - A broad upregulation of cerebral chemokine genes by peripherally-generated inflammatory mediators. AB - Previously, we have shown that peripheral challenge of mice with double stranded RNA (dsRNA), a viral mimic, evokes global upregulation of cerebral inflammatory genes and, particularly, genes encoding chemokines. Because chemokine networks are potent modulators of brain function, the present study was undertaken to comprehensively characterize the cerebral response of chemokine ligand and receptor genes to peripheral immune system stimulation. Briefly, C57BL/6 mice were intraperitoneally injected with 12 mg/kg of polyinosinic-polycytidylic acid (PIC) and the expression of 39 mouse chemokine ligand and 20 receptor genes was monitored in the cerebellum by real time quantitative RT-PCR within 24 h. Almost half of the ligand genes featured either transient or sustained upregulation from several- to several thousand-fold. Five CXC type genes, i.e., Cxcl9, Cxcl11, Cxcl10, Cxcl2 and Cxcl1, were the most robustly upregulated, and were followed by six CC type genes, i.e., Ccl2, Ccl7, Ccl5, Ccl12, Ccl4 and Ccl11. Seven genes showed moderate upregulation, whereas the remaining genes were unresponsive. Six receptor genes, i.e., Cxcr2, Ccr7, Cxcr5, Ccr6, Ccr1 and Ccr5, featured a several fold upregulation. Similar chemokine gene response was observed in the forebrain and brainstem. This upregulation of chemokine genes could be induced in naive mice by transfer of blood plasma from PIC-challenged mice. Employing oligodeoxynucleotide-labeled PIC we further showed that intraperitoneally injected PIC was not transferred to the blood. In conclusion, peripheral PIC challenge elicits a broad upregulation of cerebral chemokine genes, and this upregulation is mediated by blood-borne agents. PMID- 21258856 TI - Cholesterol 27-hydroxylase but not apolipoprotein apoE contributes to A2A adenosine receptor stimulated reverse cholesterol transport. AB - Movement of free cholesterol between the cellular compartment and acceptor is governed by cholesterol gradients that are determined by several enzymes and reverse cholesterol transport proteins. We have previously demonstrated that adenosine A(2A) receptors inhibit foam cell formation and stimulate production of cholesterol 27-hydroxylase (CYP27A1), an enzyme involved in the conversion of cholesterol to oxysterols. We therefore asked whether the effect of adenosine A(2A) receptors on foam cell formation in vitro is mediated by CYP27A1 or apoE, a carrier for cholesterol in the serum. We found that specific lentiviral siRNA infection markedly reduced apoE or 27-hydroxylase mRNA in THP-1 cells. Despite diminished apoE expression (p < 0.0002, interferon-gamma (IFNgamma) CGS vs. IFNgamma alone, n=4), CGS-21680, an adenosine A(2A) receptor agonist, inhibits foam cell formation. In contrast, CGS-21680 had no effect on reducing foam cell formation in CYP27A1 KD cells (4 +/- 2%; p<0.5113, inhibition vs. IFNgamma alone, n=4). Previously, we reported the A(2A) agonist CGS-21680 increases apoAI mediated cholesterol efflux nearly twofold in wild-type macrophages. Adenosine receptor activation had no effect on cholesterol efflux in CYP27A1 KD cells but reduced efflux in apoE KD cells. These results demonstrate that adenosine A(2A) receptor occupancy diminishes foam cell formation by increasing expression and function of CYP27A1. PMID- 21258857 TI - Acceptance, appraisals, and coping in relation to migraine headache: an evaluation of interrelationships using daily diary methods. AB - Acceptance and chronic pain is an emerging topic both for research and intervention. Initial studies have demonstrated that acceptance is correlated with higher quality of daily emotional, social, and physical functioning in chronic pain populations. The purpose of the present study was to clarify the nature of the relationship between acceptance, appraisals that are relevant to chronic pain (i.e., control and catastrophizing), and coping among migraine headache sufferers. Seventy four participants with migraine headaches completed self report measures assessing appraisal, coping strategies, acceptance, and pain related disability. Sixty three participants also completed a 28-day daily dairy assessing headache activity, catastrophizing, control, acceptance, and coping strategies. Hierarchical regression and multilevel modeling were used to examine the relations between these variables. Results indicated that higher levels of pain-related acceptance were associated with lower levels of catastrophizing and pain-related interference, and increased perceived control. Participants who endorsed higher levels of pain-related acceptance also reported engaging in a higher level of activity and indicated they used fewer coping strategies on a daily basis. Acceptance continues to show promise as a way of viewing pain that lessens the detrimental impact of certain types of thoughts (i.e., catastrophizing), and leads to increased participation in daily life. PMID- 21258858 TI - Genetic associations between fibrinogen and cognitive performance in three Scottish cohorts. AB - There is increasing evidence to suggest that elevated plasma levels of fibrinogen are associated with late-life cognitive performance. This study tested the association of single nucleotide polymorphisms in the fibrinogen alpha (FGA) and beta (FGB) genes with cognitive performance. Data were analysed from three community-dwelling populations of older persons (>50 years) in central Scotland: the Aspirin for Asymptomatic Atherosclerosis (AAA) Trial (n = 2,091), the Edinburgh Type 2 Diabetes Study (ET2DS, n = 1,066), and the Lothian Birth Cohort 1936 (LBC1936, n = 1,091). Cognition was assessed using a battery of five, seven, and four psychometric tests, respectively. This information was used to derive a general cognitive factor. Weakly significant associations were found between the rs4220 (FGB), and rs2227412 (FGB) SNPs and a single test of cognitive performance in the AAA Trial (p < 0.05). These findings did not replicate in the LBC1936 or ET2DS cohorts, except for the rs2227412 SNP, which was significantly associated with the general cognitive factor in the ET2DS (p = 3.3 * 10(-4)). A summary term that combined results from all three studies suggested that the rs2227412 genotype associated with reduced cognitive ability also associated with higher plasma fibrinogen levels. These findings suggest a tentative role for fibrinogen as a determinant of late-life cognitive performance and justify further attempts at replication in older persons. PMID- 21258859 TI - Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study. AB - BACKGROUND: Coffee consumption has been associated with reduced markers of hepatic cell damage, reduced risk of chronic liver disease, and cirrhosis across a variety of populations. Data on the association between coffee consumption and risk of hepatocellular carcinoma (HCC), especially in high-risk populations, are sparse. METHODS: This study examines the relationship between coffee and caffeine consumption, and the risk of developing HCC within the Singapore Chinese Health Study, a prospective cohort of 63,257 middle-aged and older Chinese men and women, a relatively high-risk population for HCC. Baseline data on coffee consumption and other dietary and lifestyle factors were collected through in person interviews at enrollment between 1993 and 1998. RESULTS: As of 31 December 2006, 362 cohort participants had developed HCC. High levels of coffee or caffeine consumption were associated with reduced risk of HCC (p for trend < 0.05). Compared with non-drinkers of coffee, individuals who consumed three or more cups of coffee per day experienced a statistically significant 44% reduction in risk of HCC (hazard ratio 0.56, 95% confidence interval, 0.31-1.00, p = .049) after adjustment for potential confounders and tea consumption. CONCLUSION: These data suggest that coffee consumption may reduce the risk of developing HCC in Chinese in Singapore. PMID- 21258860 TI - Tailless-like (TLX) protein promotes neuronal differentiation of dermal multipotent stem cells and benefits spinal cord injury in rats. AB - Spinal cord injury (SCI) remains a formidable challenge in the clinic. In the current study, we examined the effects of the TLX gene on the proliferation and neuronal differentiation of dermal multipotent stem cells (DMSCs) in vitro and the potential of these cells to improve SCI in rats in vivo. DMSCs were stably transfected with TLX-expressing plasmid (TLX/DMSCs). Cell proliferation was examined using the MTT assay, and neuronal differentiation was characterized by morphological observation combined with immunocytochemical/immunofluorescent staining. The in vivo functions of these cells were evaluated by transplantation into rats with SCI, followed by analysis of hindlimb locomotion and post-mortem histology. Compared to parental DMSCs, TLX/DMSCs showed enhanced proliferation and preferential differentiation into NF200-positive neurons in contrast to GFAP positive astrocytes. When the undifferentiated cells were transplanted into rats with SCI injury, TLX/DMSCs led to significant improvement in locomotor recovery and healing of SCI, as evidenced by reduction in scar tissues and cavities, increase in continuous nerve fibers/axons and enrichment of NF200-positive neurons on the histological level. In conclusion, TLX promotes the proliferation and neuronal differentiation of DMSCs and thus, may serve as a promising therapy for SCI in the clinic. PMID- 21258862 TI - Image-guided sampling reveals increased stroma and lower glandular complexity in mammographically dense breast tissue. AB - Mammographic density (MD) adjusted for age and body mass index (BMI) is a strong heritable breast cancer risk factor; however, its biological basis remains elusive. Previous studies assessed MD-associated histology using random sampling approaches, despite evidence that high and low MD areas exist within a breast and are negatively correlated with respect to one another. We have used an image guided approach to sample high and low MD tissues from within individual breasts to examine the relationship between histology and degree of MD. Image-guided sampling was performed using two different methodologies on mastectomy tissues (n = 12): (1) sampling of high and low MD regions within a slice guided by bright (high MD) and dark (low MD) areas in a slice X-ray film; (2) sampling of high and low MD regions within a whole breast using a stereotactically guided vacuum assisted core biopsy technique. Pairwise analysis accounting for potential confounders (i.e. age, BMI, menopausal status, etc.) provides appropriate power for analysis despite the small sample size. High MD tissues had higher stromal (P = 0.002) and lower fat (P = 0.002) compositions, but no evidence of difference in glandular areas (P = 0.084) compared to low MD tissues from the same breast. High MD regions had higher relative gland counts (P = 0.023), and a preponderance of Type I lobules in high MD compared to low MD regions was observed in 58% of subjects (n = 7), but did not achieve significance. These findings clarify the histologic nature of high MD tissue and support hypotheses regarding the biophysical impact of dense connective tissue on mammary malignancy. They also provide important terms of reference for ongoing analyses of the underlying genetics of MD. PMID- 21258861 TI - Membrane localization of insulin receptor substrate-2 (IRS-2) is associated with decreased overall survival in breast cancer. AB - Recent studies have identified a role for insulin receptor substrate-2 (IRS-2) in promoting motility and metastasis in breast cancer. However, no published studies to date have examined IRS-2 expression in human breast tumors. We examined IRS-2 expression by immunohistochemistry (IHC) in normal breast tissue, benign breast lesions, and malignant breast tumors from the institutional pathology archives and a tumor microarray from a separate institution. Three distinct IRS-2 staining patterns were noted: diffusely cytoplasmic, punctate cytoplasmic, and localized to the cell membrane. The individual and pooled datasets were analyzed for associations of IRS-2 staining pattern with core clinical parameters and clinical outcomes. Univariate analysis revealed a trend toward decreased overall survival (OS) with IRS-2 membrane staining, and this association became significant upon multivariate analysis (P = 0.01). In progesterone receptor negative (PR-) tumors, in particular, IRS-2 staining at the membrane correlated with significantly worse OS than other IRS-2 staining patterns (P < 0.001). When PR status and IRS-2 staining pattern were evaluated in combination, PR- tumors with IRS-2 at the membrane were associated with a significantly decreased OS when compared with all other combinations (P = 0.002). Evaluation of IRS-2 staining patterns could potentially be used to identify patients with PR- tumors who would most benefit from aggressive treatment. PMID- 21258863 TI - Faith-based sex education programs: what they look like and who uses them. AB - The purpose of this study was to explore the kinds of sex education programs for youth available in mainline churches. This research project sought to identify the kinds of programs developed, the ages of the youth involved, the reasons for implementing the programs, the goals of the programs, the topics covered, and the perceived youth response to these programs as identified by youth ministers and leaders. The sample included 92 churches/synagogues with memberships over 300 that were within a 25-mile radius of our small, urban area in southeast Michigan. Findings from this study lay the groundwork for exploring whether these programs have an impact on adolescents' sexual behaviors. PMID- 21258864 TI - Developing and testing a spiritual care questionnaire in the Iranian context. AB - As most research exploring nurses' perceptions on the topic of spiritual care was conducted in Western countries, these findings may not be applicable in Iran because of cultural and health system differences. Therefore, a new survey instrument was developed for the Iranian context. The study was conducted in two steps: (1) development and validation of items for perception scale and (2) distribution of the questionnaire among nursing students to determine scale reliability and construct validity. The preliminary scale consisted of 50 items designed to measure the participants' perception of spiritual care. Construct validity of the scale was examined on the remaining 33 items. On interpretation of the items, the following four components were identified: (1) meeting patient as a being in meaning and hope, (2) meeting patient as a being in relationship, (3) meeting patient as a religious being, and (4) meeting patients as a being with autonomy. The results in this paper showed that preserving dignity in the nurses' practice meant getting involved in interpersonal caring relationships, with respect for the involved peoples' religious beliefs and their autonomy. Proper education and professionally led supervision with reflection on past and recent experiences may develop student nurses' and nurses' perceptions as well as their attitudes toward spiritual care and to achieve a realistic view of the profession. PMID- 21258865 TI - Antifungal properties of crude extracts of five Egyptian medicinal plants against dermatophytes and emerging fungi. AB - Antifungal properties of the crude extracts of five medicinal plants (Artemisia judaica, Ballota undulate, Cleome amblyocarpa, Peganum harmala, and Teucrium polium) were tested against dermatophytes and emerging fungi. Ethanol extract of Ballota undulate was the most effective against all tested fungi. Paecilomyces lilacinus, P. variotii, and Candida albicans were the most sensitive organisms. The minimum inhibitory concentration (MIC) of Ballota undulate ethanol extract against C. albicans, P. lilacinus, and P. variotii was 25 mg/ml. GC-MS analysis revealed that Ballota undulate ethanol extract contains 35 aliphatic and aromatic hydrocarbons, sesquiterpene hydrocarbon along with some other essential oils, which could be involved in antifungal activity. Light microscopy and scanning electron microscopy (SEM) have proved that Ballota undulate ethanol extract exhibits fungicidal effect on P. lilacinus through alterations in hyphal structures including budding of hyphal tip, anomalous structure, such as swelling, decrease in cytoplasmic content, with clear separation of cytoplasm from cell wall in hyphae. SEM clearly showed distorted mycelium, squashed and flattened conidiophores bearing damaged metullae. Eventually, the mycelia became papillated, flattened, and empty. Puncturing and squashing of hyphae as well as complete cell wall disruption were clear signs of complete death of hyphae. PMID- 21258866 TI - Class 1 integron in staphylococci. AB - As a major concern in public health, methicillin-resistant staphylococci (MRS) still remains one of the most prevalent pathogens that cause nosocomial infections throughout the world and has been recently labeled as a "super bug" in antibiotic resistance. Thus, surveillance and investigation on antibiotic resistance mechanisms involved in clinical MRS strains may raise urgent necessity and utmost significance. As a novel antibiotic resistance mechanism, class 1 integron has been identified as a primary source of antimicrobial resistance genes in Gram-negative organisms. However, most available studies on integrons had been limited within Gram-negative microbes, little is known for clinical Gram positive bacteria. Based on series studies of systematic integrons investigation in hundreds of staphylococci strains during 2001-2006, this review concentrated on the latest development of class 1 integron in MRS isolates, including summary of prevalence and occurrence of class 1 integron, analysis of correlation between integron and antibiotic resistance, further demonstration of the role integrons play as antibiotic determinants, as well as origin and evolution of integron associated gene cassettes during this study period. PMID- 21258867 TI - Phylogeny of kangaroo apples (Solanum subg. Archaesolanum, Solanaceae). AB - Kangaroo apples, subgenus Archaesolanum, are a unique and still poorly known group within the genus Solanum. Here we aimed to reveal phylogeny, historical biogeography and age of diversification of Archaesolanum. We sampled all recognized species of the group and sequenced three chloroplast regions, the trnT trnL spacer, trnL intron and trnL-trnF spacer to calibrate a molecular clock to estimate the age of the group. Distributional data were combined with the results of phylogenetic analysis to track the historical processes responsible for the current range of the group. Our analysis supported the monophyly of the kangaroo apples and the biogeographical disjunction between the two subclades within the group. Based on the divergence time estimates the most recent common ancestor of kangaroo apples is from the late Miocene age (~9 MYA). Based on the age estimate the common ancestors of the kangaroo apples are presumed to have arrived in Australia by long-distance dispersal. The two distinct lineages within the group have separated during the aridification of the continent and further speciated in the brief resurgence of rainforests during the Pliocene. PMID- 21258868 TI - Evaluation of anti-inflammatory and antinociceptive effects of D-002 (beeswax alcohols). AB - D-002, a mixture of six higher aliphatic alcohols purified from beeswax, displayed anti-inflammatory effects in carrageenan-induced pleurisy and cotton pellet granuloma in rats. The aim of the present study was to confirm the anti inflammatory properties of D-002 and to explore its potential analgesic effects. Xylene-induced mouse ear oedema was used to assess the anti-inflammatory effect, acetic acid-induced writhing and hot plate responses for the analgesic activity, and the open field and horizontal rotarod tests for motor performance. For anti inflammatory tests, mice were randomised into a negative vehicle control and five xylene-treated groups: the vehicle, D-002 (25, 50 and 200 mg/kg) and indomethacin 1 mg/kg (reference drug). Treatments were given for 15 days. Effects on oedema formation and myeloperoxidase (MPO) activity were tested. For analgesia and motor performance tests, mice were randomised into a vehicle control and D-002-treated groups (25, 50 and 200 mg/kg). Two sets of experiments were done, which included acute and repeat (15 days) dosing. D-002 (25, 50 and 200 mg/kg) significantly decreased xylene-induced ear oedema (44.7, 60.8 and 76.4%, respectively) and the increase of MPO activity induced by xylene (38.0, 47.0 and 57.0%, respectively), while indomethacin significantly inhibited xylene-induced oedema (59.9%) and MPO activity (57.5%). Single and repeat doses of D-002 (25, 50 and 200 mg/kg) decreased the acetic acid-induced writhing responses by 21.2, 28.2 and 40.1%, for the single doses; 25.2, 35.1 and 43.2%, respectively, for the repeat doses, but did not affect the hot plate, open field and rotarod behaviours. Aspirin 100 mg/kg significantly decreased acetic acid-induced abdominal constrictions and morphine (5 mg/kg) significantly increased the latency of the hot plate response. This study confirmed the anti-inflammatory effects of D-002 and demonstrated its analgesic effects on the acetic acid-induced writhing, but not on the hot plate response, which suggests that the antinociceptive effects of D-002 could be related to its anti-inflammatory activity. PMID- 21258869 TI - Serodiagnosis of borreliosis: indirect immunofluorescence assay, enzyme-linked immunosorbent assay and immunoblotting. AB - Lyme disease is an infectious, multi-system, tick-borne disease caused by genospecies of Borrelia burgdorferi bacteria sensu lato, characterized by remarkable heterogeneity. In this situation choosing an optimal antigen array for diagnostic tests seems problematic. The serological tests for borrelia routinely done in laboratories often produce ambiguous results, which makes a proper diagnosis rather complicated and thus delays the implementation of an appropriate treatment regimen. Thirty-seven outpatients and eight inpatients with suspected borreliosis diagnosis hospitalized at the Clinics of the Pomeranian Medical University (Szczecin, Poland), participated in the study. In order to detect the antibodies against Borrelia sensu lato three kinds of serological tests were used: indirect immunofluorescence assay (IIFA), enzyme-linked immunosorbent assay (ELISA), and immunoblot. The IIFA and immunoblot tests conducted on 45 patients (100%) produced positive results for both the IgM and IgG antibody types. In the case of ELISA, positive or borderline results were observed in only 24 patients (53.3%). The immunoblot test for IgM most frequently detected antibodies against the outer surface protein C (OspC) antigen (p25), and, in the case of IgG, against the recombinant variable surface antigen (VlsE). The IIFA screening test used for diagnosing Lyme borreliosis produced the highest percentage of positive results, which were then confirmed by immunoblot, but not by ELISA. Therefore using only ELISA as a screening test or for diagnosing Lyme borreliosis seems debatable. PMID- 21258870 TI - A conversation with memory. PMID- 21258872 TI - The effects of ozone therapy and coenzyme Q10 combination on oxidative stress markers in healthy subjects. AB - BACKGROUND: Ozone therapy is employed as a therapeutic agent in various diseases. Since ozone itself is a radical, using a small dosage of it is known to create an oxidative preconditioning in the body and trigger a strong antioxidant response against that. Coenzyme Q(10), as a strong antioxidant agent, is delivered as a supportive factor in many diseases involving oxidative stress. AIM: The aim of the study was to evaluate the effects of the combination treatment over oxidative stress in healthy individuals. METHODS: In the current study, 11 healthy volunteers were administered a combination of ozone therapy and Q(10) for 1 month. Blood samples were collected first right after the initial ozone therapy and then 1 month after the ozone therapy + coenzyme Q(10) treatment. We measured erythrocyte superoxide dismutase and catalase enzyme activities along with serum malondialdehyde levels. RESULTS: Compared with the pretreatment values, an increase was determined in the erythrocyte superoxide dismutase and catalase enzyme activities. However, malondialdehyde, an indicator of oxidative membrane damage, showed a reduction after the combination treatment. CONCLUSION: The results of this study reveal the beneficial effects of ozone therapy + coenzyme Q(10) combination in prevention of oxidative damage. PMID- 21258873 TI - Concentration, partial characterization, and immobilization of lipase extract from P. brevicompactum by solid-state fermentation of babassu cake and castor bean cake. AB - One relevant limitation hindering the industrial application of microbial lipases has been attributed to their production cost, which is determined by the production yield, enzyme stability among other. The objective of this work was to evaluate the concentration and immobilization of lipase extracts from Penicillium brevicompactum obtained by solid-state fermentation of babassu cake and castor bean cake. The precipitation with ammonium sulfate 60% of saturation of crude extract obtained with babassu cake as raw material showed an enhancement in hydrolytic and esterification activities from 31.82 to 227.57 U/g and from 170.92 to 207.40 U/g, respectively. Concentrated lipase extracts showed preference to medium-chain triglycerides and fatty acids. It is shown that the enzyme activity is maintained during storage at low temperatures (4 and -10 degrees C) for up to 30 days. Higher esterification activities were achieved when the lipase extract was immobilized in sodium alginate and activated coal. PMID- 21258874 TI - Multimodal neuromonitoring in a patient with aneurysmal subarachnoid hemorrhage associated with aortic coarctation. AB - BACKGROUND: Aortic coarctation (AC) rarely remains undiagnosed until adulthood. Intracranial aneurysms and spontaneous subarachnoid hemorrhage (SAH) are more frequent in patients with AC than in the general population. METHODS: The purpose of this report is to describe the management of a poor grade SAH patient with previously undiagnosed AC using advanced monitoring techniques of the brain and the cardiovascular system. RESULTS: A 28-year-old man with previously unknown AC was admitted with aneurysmal SAH WFNS grade 5. Head computed tomography demonstrated thick blood filling the basal cisterns, mild hydrocephalus, and global cerebral edema. The ruptured aneurysm of the anterior communicating artery was successfully coiled on the same day. Echocardiography revealed high grade isthmus stenosis with a pressure gradient of 60 mm Hg. Hospital course was complicated by prerenal failure and severe vasospasm. Neuromonitoring data (cerebral metabolism, brain tissue oxygenation, cerebral blood flow and intracranial pressure) were used as endpoint to define the optimal blood pressure to meet the cerebral metabolic and oxygen demand in each phase. CONCLUSIONS: Cerebral aneurysm rupture associated with coarctation of the aorta is rare. The aim of this report is to call attention to AC in, particularly, young patients presenting with SAH and to discuss advanced multimodal neuromonitoring techniques used to optimize intensive care management. PMID- 21258875 TI - The role of Th17 lymphocytes in the autoimmune and chronic inflammatory diseases. AB - The emerging role of interleukin-17 as a hallmark proinflammatory cytokine of the adaptive immune system produced by a new T helper cell subset termed "Th17" has received considerable attention. In this review we will focus on recent information regarding IL-17 and its relevance in autoimmune and chronic inflammatory diseases. PMID- 21258876 TI - Imatinib mesylate may induce long-term clinical response in FIP1L1-PDGFRalpha negative hypereosinophilic syndrome. AB - The idiopathic hypereosinophilic syndrome (HES) comprises a heterogenous group of disorders characterized by marked blood eosinophilia with eosinophilia-associated organ damage. Eight patients with a median age at diagnosis of 42 years (range 19 67) received imatinib mesylate (IM) for FIP1L1-PDGFRalpha-negative HES resistant to previous conventional treatment. Median number of prior therapies was 3 (range 2-4). Median time from diagnosis to IM initiation was 112 months (range 2-293). Four patients were treated daily with 100 mg IM, whereas the remaining four patients were treated daily with 400 mg IM. Four male patients (50%) achieved complete haematologic response (CHR) after median of 7 days (range 3-150) using 100 mg daily IM (n = 2) and 400 mg (n = 2). Median duration of IM treatment for IM responders was 18 months (range 2-88). No adverse events were reported throughout the treatment duration. Two patients maintained CHR while on 100 mg weekly IM. Four patients (2 men and 2 women) failed IM treatment. Median duration of IM for non-responding patients was 3 weeks (range 3-12). Non-responding HES patients were significantly older and had lower percentage of blood eosinophilia when compared with IM responders. Our results suggest that IM, even at lower than conventional doses, may induce and maintain long-term remission for FIP1L1 PDGFRalpha-negative HES. PMID- 21258877 TI - High-dose homoharringtonine versus standard-dose daunorubicin is effective and safe as induction and post-induction chemotherapy for elderly patients with acute myeloid leukemia: a multicenter experience from China. AB - The purpose of the study was to compare the antitumor efficacy and safety profile of high-dose homoharringtonine as induction and post-induction therapy compared to either standard-dose homoharringtonine or daunorubicin in elderly patients with newly diagnosed acute myeloid leukemia. A total of 254 patients, age range 60-77 years received induction and post-induction therapy containing daunorubicin, standard-dose homoharringtonine, or high-dose homoharringtonine. After one course of induction therapy, the overall complete remission rate was similar between treatment arms (58.7%, P = .92). Among 161 patients with acute myeloid leukemia (non-M5 subtype), estimated median overall survival was 39, 29, and 37 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .53). In the 93 patients with acute myeloid leukemia-M5 subtype, there was a significant difference in estimated median overall survival: 24, 24, and 52 months, respectively, in the daunorubicin, standard-dose homoharringtonine, and high-dose homoharringtonine treatment groups (P = .003). There was no significant difference in drug-related adverse events between treatment arms. High-dose homoharringtonine does not clearly increase the complete remission rate of elderly patients with acute myeloid leukemia. However, in the subset of elderly patients with acute monocytic leukemia, high-dose homoharringtonine as a first line regimen prolonged overall survival with minimal toxicity. PMID- 21258878 TI - Late recurrences of gastrointestinal stromal tumours (GISTs) after 5 years of follow-up. AB - In practice, relapses of gastrointestinal stromal tumours after long time of surgical resection occur. However, few published data are available for duration, intensity and imaging sources of follow-up in radically excised patients with localized disease. Therefore, every single institution chooses the surveillance schedule according to its experience. The aim of this study was to describe the late recurrences of disease 5 years after the primary tumour's excision in a series of patients with recurrent GIST from our institution. We retrospectively reviewed 42 patients with "recurrent" GIST, collected since 2001. Ten patients were always followed at our institution, and 32 patients came to our attention at the time of recurrence. The analysed series were divided into two groups: patients who developed recurrence before 5 years and patients who developed recurrence 5 years after the primary tumour's excision. Among 42 patients, 36 patients developed the recurrence within 5 years of the primary tumour excision, whereas 6 patients developed the recurrence 5 years after primary tumour excision diagnosed during follow-up or casually for other reasons. All patients had distant recurrence, involving liver and peritoneum, whereas no local relapse was observed. These patients were heterogeneous in primary tumour site, risk classification and molecular analysis. Duration of the follow-up for radically excised patients with GIST remains still unsettled; however, the integration of every clinical, pathological and molecular parameter is essential to optimize the duration and intensity of the follow-up for each single patient. PMID- 21258879 TI - Usefulness of the serum cross-linked N-telopeptide of type I collagen as a marker of bone metastasis from lung cancer. AB - Bone metastasis is an important factor for determining the appropriate treatment for patients with lung cancer. The cross-linked N-terminal telopeptide of type I collagen (NTx) is a metabolite of type I collagen, the main constituent of the bone matrix. Urinary NTx is recognized as a useful marker of bone metastasis, but the application of serum NTx and its cutoff value for determining bone metastasis from lung cancer have not been characterized. We measured serum NTx by enzyme linked immunosorbent assay of individuals who underwent staging during hospitalization for initial treatment of lung cancer in our department and compared the NTx levels with the presence of bone metastasis in staging. The study included 166 patients with lung cancer (128 men and 38 women), including 85 adenocarcinoma, 42 squamous cell carcinoma, 32 small-cell carcinoma, and 7 other cancer types. Bone metastasis was present in 73 cases. The average/median serum NTx of bone metastasis (+) and bone metastasis (-) was 27.8/23.8 and 17.1/16.5 nmol bone collagen equivalents/L, respectively. There was an intentional difference with P < 0.001. The cutoff value of the serum NTx level indicating bone metastasis from lung cancer was estimated using the receiver operating characteristics curve. The optimal cutoff value was found to be 22.0 (sensitivity: 61.6%, specificity: 89.2%). The results of univariate and multivariate analysis revealed that the serum NTx levels were significantly related to bone metastasis from lung cancer (P < 0.001). Measurement of serum NTx levels provides a simple diagnostic marker of bone metastasis from lung cancer. PMID- 21258880 TI - miR-497 modulates multidrug resistance of human cancer cell lines by targeting BCL2. AB - MicroRNAs (miRNAs) are short non-coding RNA molecules, which posttranscriptionally regulate genes expression and play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. Here, we investigated the possible role of miRNAs in the development of multidrug resistance (MDR) in human gastric and lung cancer cell lines. We found that miR-497 was downregulated in both multidrug-resistant human gastric cancer cell line SGC7901/vincristine (VCR) and multidrug-resistant human lung cancer cell line A549/cisplatin (CDDP) and the downregulation of miR-497 was concurrent with the upregulation of BCL2 protein, compared with the parental SGC7901 and A549 cell lines, respectively. In vitro drug sensitivity assay demonstrated that overexpression of miR-497 sensitized SGC7901/VCR and A549/CDDP cells to anticancer drugs, respectively. The luciferase activity of BCL2 3' untranslated region-based reporter constructed in SGC7901/VCR and A549/CDDP cells suggested that BCL2 was the direct target gene of miR-497. Enforced miR-497 expression reduced BCL2 protein level and sensitized SGC7901/VCR and A549/CDDP cells to VCR-induced and CDDP-induced apoptosis, respectively. Taken together, our findings first suggested that has-miR-497 could play a role in both gastric and lung cancer cell lines at least in part by modulation of apoptosis via targeting BCL2. PMID- 21258881 TI - Visual and spectrophotometric observations related to histology in a small sample of bruises from cadavers. AB - Spectrophotometry has been investigated as a means to estimate the age of bruises as experiments have indicated that it can be used to detect the presence of degradation products of hemoglobin (bilirubin and hemosiderin). However, there is no data relating spectrophotometric observations to histological findings in bruises of human skin. A small number of bruises in human cadavers were studied by spectrophotometry. The average first derivative value at 490 nm was more negative in bruises with stainable iron (hemosiderin) than in those without, confirming that spectrophotometry observations can indicate the presence of degradation products of hemoglobin in the skin. This confirms spectrophotometry may be a useful tool for estimating the age of bruises. PMID- 21258882 TI - Travel into a fairy land: a critique of modern qualitative and mixed methods psychologies. AB - In this article modern qualitative and mixed methods approaches are criticized from the standpoint of structural-systemic epistemology. It is suggested that modern qualitative methodologies suffer from several fallacies: some of them are grounded on inherently contradictory epistemology, the others ask scientific questions after the methods have been chosen, conduct studies inductively so that not only answers but even questions are often supposed to be discovered, do not create artificial situations and constraints on study-situations, are adevelopmental by nature, study not the external things and phenomena but symbols and representations--often the object of studies turns out to be the researcher rather than researched, rely on ambiguous data interpretation methods based to a large degree on feelings and opinions, aim to understand unique which is theoretically impossible, or have theoretical problems with sampling. Any one of these fallacies would be sufficient to exclude any possibility to achieve structural-systemic understanding of the studied things and phenomena. It also turns out that modern qualitative methodologies share several fallacies with the quantitative methodology. Therefore mixed methods approaches are not able to overcome the fundamental difficulties that characterize mixed methods taken separately. It is proposed that structural-systemic methodology that dominated psychological thought in the pre-WWII continental Europe is philosophically and theoretically better grounded than the other methodologies that can be distinguished in psychology today. Future psychology should be based on structural-systemic methodology. PMID- 21258883 TI - CD1a and CD1d genes polymorphisms in breast, colorectal and lung cancers. AB - CD1 molecules might contribute to anti-tumor immune response by presentation of tumor-derived lipid and glycolipid antigens to T cells and NKT cells. Polymorphisms in CD1 genes have been suggested to modify ligand binding of CD1 molecules and thereby change the antigen presenting ability of these molecules. The aim of this study was to investigate the exon 2 polymorphisms of CD1a and CD1d in several high incident cancers in Iran. For this purpose, 201 female breast cancer patients and 207 healthy women, 64 lung cancer patients and 95 healthy individuals and 109 patients with colorectal cancer and 109 healthy controls were recruited to this study. Using PCR-SSP method, no significant correlation was found in genotype and allele frequencies of CD1a between all three studied groups and their control counterparts. Moreover, a dominant frequency of CD1d 01 (A) allele was observed in the majority of studied individuals. No significant association between the CD1 polymorphisms and prognostic factors in breast, lung and colorectal cancers was detected. Our results highlight the conserved nature of CD1 genes and may point to the immuoregulatory functions of CD1 molecules in cancer that can be exerted through fine tuning of NK, T and NKT cells. PMID- 21258884 TI - Immunoexpression of SALL4 in Wilms tumors and developing kidney. AB - SALL4 is a zinc finger transcription factor that plays a role in the maintainance and pluripotency of embryonic stem cell and is important in renal development where SALL4 mutations give rise to renal malformations. Because Wilms tumor recapitulates renal embryogenesis, we hypothesized that Wilms tumor cells may also express SALL4. We performed immunohistochemistry for SALL4 on tissue microarray sections of Wilms tumors, nephrogenic rests, and fetal renal cortices. Half (26 out of 52) of the Wilms tumors showed SALL4 immunoreactivity, ranging from strong and diffuse to focal and weak. Blastemal, epithelial, and combined blastemal and epithelial patterns of immunoreactivity were identified. No cases showed stromal staining. In the fetal kidney, SALL4 expression was restricted to the blastema and primitive epithelium at 15 weeks' gestation. SALL4 staining was not seen at later gestational ages, in non-neoplastic postnatal kidneys, or in nephrogenic rests. Our study is the first to demonstrate SALL4 immunoreactivity in Wilms tumors and in developing fetal kidney. The absence of SALL4 staining in nephrogenic rests, the presumed precursors of Wilms tumors, is intriguing and suggests that Wilms tumors have a pluripotency quality that may be lacking in nephrogenic rests. PMID- 21258885 TI - Invasion of the hypoglossal nerve by adenoid cystic carcinoma of the tongue: case report and review of the literature. AB - Adenoid cystic carcinoma (ACC) is a rare but highly aggressive malignancy mainly originating from the salivary glands. ACC is well known for its propensity toward neural invasion (NI). NI is the process of neoplastic invasion in and along nerves. It is a distinct and well-documented phenomenon in ACC; however, it is an underestimated route of metastatic spread. Multiple distant metastases can be established through NI route, and NI is believed to portend a poor prognosis. Despite increasing recognition of NI in many malignancies, the molecular mechanism behind NI is not well established. We present a unique case of hypoglossal nerve invasion by ACC arising from the minor salivary glands in the tongue of a 34-year-old man. We also review and discuss current theories on the pathogenesis and mechanism of NI. PMID- 21258886 TI - Prognosis of patients with spontaneous rupture of hepatocellular carcinoma in cirrhosis. AB - The treatment of cirrhotic patients with spontaneous rupture of hepatocellular carcinoma (HCC) is controversial and largely dependent on general conditions of the patients and compensation of the underlying cirrhosis. We retrospectively reviewed clinical, imaging and surgical records of 24 consecutive cirrhotic patients (17 males, 7 females; age range 52-88 years) with hemoperitoneum from spontaneous rupture of HCC observed from June 2004 to January 2010 at our Institution. When indicated, patients were referred to surgery or trans-arterial embolization (TAE). Advanced decompensated patients were conservatively treated and clinically followed up. Spontaneous rupture of HCC was assessed by aspiration of bloody ascites at paracentesis in all cases. The presence of large blood-clots over HCC and liver surface at US and/or CT was considered a specific sign of ruptured HCC in 14 cases. In two out of four patients who underwent TAE active bleeding from tumor surface could be demonstrated. In 2 cases, the active hemorrhage from the HCC surface could be assessed by contrast-enhanced ultrasonography. Four out of 24 patients underwent surgery. Three out of four of these patients died within 2 weeks, 8 months, and 20 months after operation, respectively. The remaining patient is still alive at 52 months follow-up. Four patients underwent TAE and died at 1, 2, 6 and 10 months after treatment, because of recurrent peritoneal bleeding and/or liver failure. Sixteen patients with ruptured HCC in the advanced Child C cirrhosis were treated conservatively with blood derivative transfusion and with procoagulant drugs. All patients, but one died within 2-18 days. One patient survived the acute hemorrhage from ruptured HCC and died of liver failure after 3 months. We concluded that spontaneous rupture of HCC is usually a fatal event in patients with poor liver function, even after successful TAE. In compensated patients, timely surgical treatment can result in long term and even tumor-free survival of the patient. PMID- 21258887 TI - The effects of children's migration on elderly kin's health: a counterfactual approach. AB - Recent studies of migration and the left-behind have found that elders with migrant children actually experience better health outcomes than those with no migrant children, yet these studies raise many concerns about self-selection. Using three rounds of panel survey data from the Indonesian Family Life Survey, we employ the counterfactual framework developed by Rosenbaum and Rubin to examine the relationship between having a migrant child and the health of elders aged 50 and older, as measured by activities of daily living (ADL), self-rated health (SRH), and mortality. As in earlier studies, we find a positive association between old-age health and children's migration, an effect that is partly explained by an individual's propensity to have migrant children. Positive impacts of migration are much greater among elders with a high propensity to have migrant children than among those with low propensity. We note that migration is one of the single greatest sources of health disparity among the elders in our study population, and point to the need for research and policy aimed at broadening the benefits of migration to better improve health systems rather than individual health. PMID- 21258889 TI - Reflections on the past and future of integrative medicine from a lifelong student of the integration of Chinese and Western medicine. PMID- 21258890 TI - The state of the integrative medicine in the U.S. and Western World. PMID- 21258891 TI - The model of Western integrative medicine: the role of Chinese medicine. AB - The basic concept of integrative medicine (IM) is that by combining mainstream (biomedicine) with complementary and alternative medicine (CAM), synergistic therapeutic effects can be attained. When the methods of mind/body medicine (MBM) are added to this combination, as in Western countries, a new concept emerges that drastically changes the approach toward illness.It is interesting to note that the joining of traditional Chinese medicine and Western medicine in the early days of the Peoples' Republic of China preceded the Western model of IM by almost 50 years. Several elements that make up the key components of IM as practiced today in the West were already present in the Chinese version of IM, and Chinese medicine has played and continues to play an important role in advancing IM. However, one of the major differences between the Chinese and the Western models of IM today, besides MBM and some other treatment options, is that Western integrative medicine (WIM) strictly requires its CAM methods to be supported by scientific evidence.The therapeutic methods of IM and their applications are many and varied. However, they are most frequently employed to treat chronic medical conditions, e.g., bronchial asthma, rheumatic disease, chronic inflammatory bowel disorder and chronic pain. Other fields in which IM may be applied are internal medicine (inflammatory bowel diseases and cardiovascular diseases), musculoskeletal disorders, oncology (chemotherapy induced side effects), obstetrics and gynecology (dysmenorrhea, endometriosis, infertility and menopausal complaints), pediatrics, geriatrics, neurology (migraine and chronic headache), and psychiatry (anxiety and depression).The concept of WIM is discussed here in detail by reviewing its scope and implications for the practice of medicine and focusing on the role of Chinese medicine in WIM. PMID- 21258892 TI - Integrative medicine - traditional Chinese medicine, a model ? AB - The paper explores the concept of integrative medicine (IM) in relation to complementary and alternative medicine (CAM). It contrasts IM available in China to its availability in the West. The second part of the paper highlights tools which could facilitate opportunities for IM. The paper concludes with a plea to ensure and maintain the integrity of traditional Chinese medical practice, and to continue to increase developing the evidence base through a funded European Coordination Action between EU member states and China. PMID- 21258893 TI - Effect of Aike Mixture on the inflammatory infiltration in patients with chronic prostatitis type III A. AB - OBJECTIVE: To observe the effect of Aike Mixture (AKM) on prostatic inflammatory infiltration in patients with chronic prostatitis type III A (III A-CP/CPPS) and evaluate its anti-inflammatory action. METHODS METHODS: A total of 60 patients with III A-CP/CPPS suitable to operation and differentiated as Chinese medicine: Gan qi stagnancy syndrome type were selected. They were assigned with the random number table to two groups equally. Before operation, the patients in the treated group were administered with Proscar combined with AKM, but those in the control group treated with Proscar only. Suprapubic transvesical prostatectomy was performed two weeks later, and prostatic pathological examination was conducted. RESULTS: Grading of: inflammatory cell infiltration showed that the mean grade in the treated group was 0.78 +/- 0.90 grades, which was significantly lower than that in the control group 1.68 +/- 0.87 grades (P<0.05). However, the two groups were not different in the grades of fibroblast proliferation (1.50 +/- 0.70 grades vs 1.62 +/- 0.87 grades, P>0.05). CONCLUSION: AKM could suppress the inflammatory cell infiltration, be an effective and safe remedy for the treatment of IIIA-CP/CPPS of Gan-qi stagnancy syndrome type, and worthy for spreading in clinical use. PMID- 21258894 TI - Effect of Chinese drugs combining with chemotherapy on quality of life in 146 children with solid tumor. AB - OBJECTIVE: To explore the effect of Chinese drugs for supporting essence and strengthening Pi ( SESP) combining with chemotherapy on the quality of life (QOL) in the children with solid tumor. METHODS: Using a digital table, 146 children with solid tumor were randomized into two groups, 77 in the control group and 69 in the treated group. They received conventional chemotherapy, but to the patients in the treated group, SESP were administered additionally. The patients' scores of QOL and adverse reaction occurred were compared. RESULTS: The states in the treated group were superior to those in the control group. Statistical analysis showed that in the first year, the two groups were different in terms of somatic function, systemic symptoms, and general status (P<0.05) and also in the occurrence of adverse reaction (P<0.01). In the second year, the difference was shown in aspects of somatic function and adverse reaction occurrence (P<0.05). CONCLUSION: Chinese drugs for SESP combining with chemotherapy could raise tumor patients' QOL by improving their somatic function and clinical symptoms. PMID- 21258895 TI - MicroRNA expression patterns of the kidney in hyperuricemia mice treated with Xiezhuo Chubi Decoction. AB - OBJECTIVE: To investigate the effects of Xiezhuo Chubi Decoction (XZCBD) on the microRNA expression patterns of kidney in mice with hyperuricemia. METHODS: Sixty Kunming male mice were randomly divided into the high-, medium-, and low-dose XZCBD groups, benzbromarone group, model group, and control group. Except the control group, all mice were established with yeast method combined with uricase inhibition method to build hyperuricemia model, and the corresponding drugs (37.5 g/kg, 18.75 g/kg, 9.375 g/kg, and 0.02 g/kg per day) were administrated on the 7th day. On the 22nd day, the blood uric acid concentration was detected, and microRNA with obvious changes in kidney was screened with qRT-PCR. RESULTS: The uric acid in the model group was higher than that in the control group, and the levels of the uric acid were reduced after being treated with XZCBD; the differences among groups were significant (P<0.05). Compared with the control group, 32 kinds of microRNA expression changes were detected on the 15th day after being treated with high-dose XZCBD by microRNA expression profile screening. Among them, miR-34a could inhibit the expression of human urate anion exthanger 1, and miR-146a might have inhibited the inflammatory reaction. CONCLUSION: XZCBD could significantly reduce the serum uric acid level; its effect on hyperuricemia might be through affecting microRNA expressions. PMID- 21258896 TI - Effect of Bushen Huoxue Decoction on the orphan receptor and tyrosine hydroxylase in the brain of rats with Parkinson's disease. AB - OBJECTIVE: To explore the effect of Bushen Huoxue Decoction (BHD) on the orphan receptor (Nurr1) and tyrosine hydroxylase (TH) in the brain of rats with Parkinson's disease (PD). METHODS: One hundred and twenty SD rats were divided into 100 in the model group and 20 in the normal control group, fifty-eight SD rats from the model group, established into PD model successfully by injuring their substantia nigra (SSN) with 6-hydroxydopamine, were divided equally into the model group and the test group, and they were treated with saline and BHD, respectively, for eight successive weeks. The change in the rats' behavior before and after treatment was observed by counting the cycles of rotation induced by apomorphine injection; the pathology of neurons, level of Nurr1 mRNA expression, and amount of TH positive cells in SSN were observed after treatment. RESULTS: The rats' behavior was improved in the tested group significantly, the rotation cycle after treatment being 84.0 +/- 20.0 cycles/40 min, which was significantly lower than that in the model group (377.0 +/- 62.3 cycles/40 min, P<0.01). Besides, the Nurr1 mRNA expression and TH positive cell in the test group were 0.97 +/- 0.15 and 49.40 +/- 14.72, respectively, which were significantly higher than those in the model group, 0.22 +/- 0.03 and 5.45 +/- 2.58, respectively (all P<0.01). CONCLUSION: BHD could treat PD by enhancing the Nurr1 mRNA expression, increasing the TH content in brain, and promoting the repairing of injured neuron in cerebral SSN. PMID- 21258897 TI - Randomized clinical trials on Eastern-Western integrative medicine for health care in Korean literature: a systematic review. AB - OBJECTIVE: To summarize and critically evaluate the evidence for and against the effectiveness of Eastern-Western integrative medicine (EWIM) for health care compared to Eastern medicine (EM) or Western medicine (WM) alone. METHODS: Systematic searches were conducted on five Korean medical databases. Manual searches were also conducted through nine major Korean medical journals. Prospective randomized clinical trials (RCTs) were included if EWIM was tested for any type of conditions compared to EM or WM. RESULTS: There were one hundred forty-one possibly relevant studies were identified, and seven RCTs were included. The risk of bias was high in most studies. The EWIM methods were compared with EM or WM in patients with pain conditions in four studies. These studies showed favorable effects of EWIM on pain reduction in patients with shoulder pain and chronic headache compared with EM, while the other RCTs failed to do so in traffic injury patients. Two studies tested EWIM in patients with Bell's palsy compared with EM and found acute functional improvement. An RCT comparing EWIM with WM in patients with acne showed a significant difference. CONCLUSION: The results of our systematic review suggest that there is limited evidence for the superiority of EWIM over EM or WM in the treatment of pain and acute symptom improvement in patients with Bell's palsy. The evidence from our analysis was limited from the low number of RCTs included and the high risk of bias. Future RCTs appear to be warranted. PMID- 21258898 TI - Clinical practice guideline of traditional medicine for primary osteoporosis. PMID- 21258899 TI - Research on frequency of application with modern Chinese herbal medicine. AB - OBJECTIVE: To study the relationship between 500 kinds of commonly used Chinese herbal medicine and the classification of their efficacies in Chinese Materia Medica in relation to the common diseases listed in Internal Medicine. METHODS: Database retrieval frequency of the quantitative statistical method was adopted. First, the 8 980 kinds of Chinese herbal medicine recorded in Chinese Materia Medica were used as the original search objects, and 4 493 kinds which were cited in more than five articles were picked out and then rechecked for further title citations. Second, as judged based on the Criterion, the numbers of articles which included the medicines in the line of standards were examined. As a result, 500 species of Chinese herbal medicine were singled out based on their retrieval frequency and were then used for compilation of the classification statistics according to their efficacy and the common diseases in Internal Medicine. RESULTS: From the classification of Chinese medicines, herbs with wide efficiency and a meek nature had higher frequencies, but those which were not appropriate as decoctions had relatively lower frequencies. However, according to the average frequency, the Chinese herbal medicine for nourishing qi and tonifying blood, at 36,346 times and 34,544 times, respectively, were the most commonly used. Analyzed from the frequency of application of the Chinese medicine in the treatment of common diseases, most of the top 10 kinds of Chinese herbal medicine with the highest frequencies generally coincided with the 500 selected medicines. In addition, the Chinese medicines with clear pharmacological efficiency were easily isolated and purified to be made into injections, although other forms are more commonly used. CONCLUSION: The results of the research objectively reflected the current applications of Chinese herbal medicine, and could be used as references in teaching, research, clinical applications, and in compiling and increasing the drugs in textbooks and Pharmacopoeia. PMID- 21258901 TI - A new era at Attention, Perception, & Psychophysics. PMID- 21258900 TI - Evolution of the management of colorectal cancer using integrative medicine. AB - Colorectal cancer (CRC) remains one of the major causes of cancer death worldwide. In recent years, the development of new and effective management options, such as fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), total mesorectal excision (TME) and monoclonal antibody novel "targeted" therapies has led to a considerable improvement in the outcome of this disease. In China, studies on CRC using integrative medicine (IM) have made remarkable progress. We therefore review the recent developments in CRC treatment through IM and Western medicine, including research studies such as the exploitation of Chinese herbs for the disruption of the tumor cell cycle or inhibition of tumor cell proliferation, induction of tumor cell apoptosis, improvement of the immune system, and the curative effect of chemotherapy. We also examine clinical studies such as those on special prescriptions and medicines and IM in anti-cancer therapy. Particularly, we analyze the advantages and disadvantages of management with IM, and propose a suggestion for the management of colorectal cancer with IM, such as screening for effective prescriptions. We also analyze Chinese medicine, studying the pharmacologic mechanism of its anti-cancer effect, further strengthening the study of IM on CRC. PMID- 21258903 TI - Attention doesn't slide: spatiotopic updating after eye movements instantiates a new, discrete attentional locus. AB - During natural vision, eye movements can drastically alter the retinotopic (eye centered) coordinates of locations and objects, yet the spatiotopic (world centered) percept remains stable. Maintaining visuospatial attention in spatiotopic coordinates requires updating of attentional representations following each eye movement. However, this updating is not instantaneous; attentional facilitation temporarily lingers at the previous retinotopic location after a saccade, a phenomenon known as the retinotopic attentional trace. At various times after a saccade, we probed attention at an intermediate location between the retinotopic and spatiotopic locations to determine whether a single locus of attentional facilitation slides progressively from the previous retinotopic location to the appropriate spatiotopic location, or whether retinotopic facilitation decays while a new, independent spatiotopic locus concurrently becomes active. Facilitation at the intermediate location was not significant at any time, suggesting that top-down attention can result in enhancement of discrete retinotopic and spatiotopic locations without passing through intermediate locations. PMID- 21258904 TI - The time course of attentional capture under dual-task conditions. AB - Several recent studies have shown that attentional capture is not an automatic process. For example, abrupt peripheral onsets do not affect the processing of targets presented subsequently at that location when participants have to concurrently perform a perceptually demanding task elsewhere. This result leaves open the question of whether peripheral onsets lose their effectiveness in capturing attention or whether, instead, the performance of a perceptually demanding task entails a faster disengagement of attention from the cued location. Here, we measured exogenous spatial attentional-orienting effects either while participants performed a concurrent perceptually demanding central monitoring task (a rapid serial visual presentation of letters for a to-be detected digit target; Experiments 1 and 2) or in isolation (the baseline condition in Experiment 2). The results showed that peripheral onsets captured participants' attention at both the 80- and 190-ms stimulus onset asynchronies (SOAs) in the baseline condition. Crucially, however, during concurrent central monitoring, peripheral onsets were effective in capturing attention only at an 80 ms SOA, while the orienting effect disappeared as soon as a changing letter drew participants' attention back to the central stream (at an SOA of 190 ms). These findings demonstrate that task-irrelevant abrupt onsets cannot be entirely overridden by top-down attentional control, although attentional capture effects are dramatically reduced by an ongoing perceptually demanding task. PMID- 21258905 TI - The politics of attention: gaze-cuing effects are moderated by political temperament. AB - Gaze cues lead to reflexive shifts of attention even when those gaze cues do not predict target location. Although this general effect has been repeatedly demonstrated, not all individuals orient to gaze in an identical manner. For example, the magnitude of gaze-cuing effects have been reduced or eliminated in populations such as those scoring high on the Autism-Spectrum Quotient and in males relative to females (since males exhibit more autism-like traits). In the present study, we examined whether gaze cue effects would be moderated by political temperament, given that those on the political right tend to be more supportive of individualism--and less likely to be influenced by others--than those on the left. We found standard gaze-cuing effects across all subjects but systematic differences in these effects by political temperament. Liberals exhibited a very large gaze-cuing effect, whereas conservatives showed no such effect at various stimulus onset asynchronies. PMID- 21258906 TI - Does visual expertise improve visual recognition memory? AB - In general, humans have impressive recognition memory for previously viewed pictures. Many people spend years becoming experts in highly specialized image sets. For example, cytologists are experts at searching micrographs filled with potentially cancerous cells and radiologists are expert at searching mammograms for indications of cancer. Do these experts develop robust visual long-term memory for their domain of expertise? If so, is this expertise specific to the trained image class, or do such experts possess generally superior visual memory? We tested recognition memory of cytologists, radiologists, and controls with no medical experience for three visual stimulus classes: isolated objects, scenes, and mammograms or micrographs. Experts were better than control observers at recognizing images from their domain, but their memory for those images was not particularly good (D' ~ 1.0) and was much worse than memory for objects or scenes (D' > 2.0). Furthermore, experts were not better at recognizing scenes or isolated objects than control observers. PMID- 21258907 TI - The material-weight illusion induced by expectations alone. AB - In the material-weight illusion (MWI), equally weighted objects that appear to be made from different materials are incorrectly perceived as having different weights when they are lifted one after the other. Here, we show that continuous visual experience of the lift is not a prerequisite for this compelling misperception of weight; merely priming the lifters' expectations of heaviness is sufficient for them to experience a robust MWI. Furthermore, these expectations continued to influence the load force used to lift MWI-inducing stimuli trial after trial, supporting the notion that vision plays an important role in the skillful lifting of objects. PMID- 21258908 TI - On the role of intervening distractors in the attentional blink. AB - The attentional blink (AB) refers to the decline in accurate report for a second target (T2) when presented within about 500 ms of a first target (T1) embedded in a rapid serial visual presentation stream of distractors. It is debated whether the distractors presented shortly after T1 cause the AB directly, as is proposed by distractor-based models, or can modulate its amplitude only indirectly by increasing T1 difficulty, as is proposed by capacity-based models. To investigate this issue, an intervening distractor was presented at lag 1 (T1 + 1), at lag 2 (T1 + 2), or at neither of these two lags (no distractor). T2 was presented at either lag 3 or 9. An AB was observed even in the absence of intervening distractors, indicating that distractors are not necessary to produce an AB. Nonetheless, the T1 + 2 distractor did modulate the AB directly, without influencing T1 performance. Neither theory can fully account for the results but can do so given some modifications. PMID- 21258909 TI - Prior entry explains order reversals in the attentional blink. AB - When two targets are presented in rapid succession, the first target (T1) is usually identified, but the second target (T2) is often missed. A remarkable exception to this "attentional blink" occurs when T2 immediately follows the first T1, at lag 1. It is then often spared but reported in the wrong order--that is, before T1. These order reversals have led to the hypothesis that "lag 1 sparing" occurs because the two targets merge into a single episodic representation. Here, we report evidence consistent with an alternative theory: T2 receives more attention than T1, leading to prior entry into working memory. Two experiments showed that the more T2 performance exceeded that for T1, the more order reversals were made. Furthermore, precuing T1 led to a shift in performance benefits from T2 to T1 and to an equivalent reduction in order reversals. We conclude that it is not necessary to assume episodic integration to explain lag 1 sparing or the accompanying order reversals. PMID- 21258910 TI - Exogenous visual attention prolongs perceived duration. AB - Previous studies have shown that spatial attention prolongs the perceived duration of visual stimuli. Chen and O'Neill (Perception & Psychophysics, 63, 1229-1238, 2001) reported, however, the reversed result and thus challenged the generality of this attention effect. We therefore reinvestigated the influence of spatial attention on the perceived duration of visual stimuli in various experimental settings. In five experiments, perceived duration was longer for validly cued stimuli; thus, spatial attention was found to prolong perceived duration. In a further experiment, the specific conditions were such that neither the attention effect nor the reversed pattern, as found by Chen and O'Neill, emerged. Although we cannot provide a conclusive account of why Chen and O'Neill observed the reversed attention effect, the present results reinforce the generality of the spatial attention effect on perceived duration but also make advisable a systematic examination of the factors that might modulate this effect. PMID- 21258912 TI - Dividing attention between color and shape revisited: redundant targets coactivate only when parts of the same perceptual object. AB - When a single perceptual object provides two different reasons for a particular decision (by containing two qualitatively different targets), detailed analyses of the response-time distributions have shown that the two different reasons are jointly responsible for the final decision. The question is whether this coactivation occurs because the two targets contained by the object were from separate dimensions (e.g., color and shape) or were parts of the same perceptual object. Early work argued in favor of dimensions, implying that the types of information being processed is critical, as opposed to their sources; more recent work has argued in favor of objects. Experiment 1 in the present paper corrected for a potential bias in the design of some recent studies and found additional evidence in favor of objects. Two additional experiments directly manipulated whether redundant targets would be perceived as parts of one or two perceptual objects (while holding all else constant) and produced the strongest evidence to date that coactivation requires that the redundant targets be parts of one object. This reverses the original conclusion and suggests that the sources of information are critical, as opposed to the types. Two specific versions of the object-based model are discussed. PMID- 21258911 TI - Individual working memory capacity is uniquely correlated with feature-based attention when combined with spatial attention. AB - A growing literature suggests that working memory and attention are closely related constructs. Both involve the selection of task-relevant information, and both are characterized by capacity limits. Furthermore, studies using a variety of methodological approaches have demonstrated convergent working memory and attention-related processing at the individual, neural and behavioral level. Given the varieties of both constructs, the specific kinds of attention and WM must be considered. We find that individuals' working memory capacity (WMC) uniquely interacts with feature-based attention when combined with spatial attention in a cuing paradigm (Posner, 1980). Our findings suggest a positive correlation between WM and feature-based attention only within the spotlight of spatial attention. This finding lends support to the controlled attention view of working memory by demonstrating that integrated feature-based expectancies are uniquely correlated with individual performance on a working memory task. PMID- 21258913 TI - The initial stage of visual selection is controlled by top-down task set: new ERP evidence. AB - Salient visual singleton stimuli produce spatial cueing effects indicative of attentional capture only when they match current task sets, suggesting that capture is subject to top-down control. However, such task-set contingent capture effects could be associated with the top-down controlled disengagement of attention from non-matching stimuli that follows their initial bottom-up salience driven selection. Using the N2pc component as an event-related potential marker of attentional capture, we demonstrate that top-down task set already controls the initial rapid selection of salient visual singleton stimuli prior to any subsequent attentional disengagement. These findings provide new evidence for the primacy of top-down control over bottom-up salience in attentional capture. PMID- 21258914 TI - Orienting of attention, pupil size, and the norepinephrine system. AB - This research examined a novel suggestion regarding the involvement of the locus coeruleus-norepinephrine (LC-NE) system in orienting reflexive (exogenous) attention. A common procedure for studying exogenous orienting of attention is Posner's cuing task. Importantly, one can manipulate the required level of target processing by changing task requirements, which, in turn, can elicit a different time course of inhibition of return (IOR). An easy task (responding to target location) produces earlier onset IOR, whereas a demanding task (responding to target identity) produces later onset IOR. Aston-Jones and Cohen (Annual Review of Neuroscience, 28, 403-450, 2005) presented a theory suggesting two different modes of LC activity: tonic and phasic. Accordingly, we suggest that in the more demanding task, the LC-NE system is activated in phasic mode, and in the easier task, it is activated in tonic mode. This, in turn, influences the appearance of IOR. We examined this suggestion by measuring participants' pupil size, which has been demonstrated to correlate with the LC-NE system, while they performed cuing tasks. We found a response-locked phasic dilation of the pupil in the discrimination task, as compared with the localization task, which may reflect different firing modes of the LC-NE system during the two tasks. We also demonstrated a correlation between pupil size at the time of cue presentation and magnitude of IOR. PMID- 21258915 TI - The facing bias in biological motion perception: structure, kinematics, and body parts. AB - Depth-ambiguous point-light walkers (PLWs) elicit a facing bias: Observers perceive a PLW as facing toward them more often than as facing away (Vanrie,Dekeyser, & Verfaillie, Perception, 33, 547-560, 2004). While the facing bias correlates with the PLW's perceived gender (Brooks et al., Current Biology, 18, R728-R729, 2008; Schouten, Troje, Brooks, van der Zwan, & Verfaillie, Attention, Perception, & Psychophysics, 72,1256-1260, 2010), it remains unclear whether the change in perceived in-depth orientation is caused by a change in perceived gender. In Experiment 1, we show that structural and kinematic stimulus properties that lead to the same changes in perceived gender elicit opposite changes in perceived in-depth orientation, indicating that the relation between perceived gender and in-depth orientation is not causal. The results of Experiments 2 and 3 further suggest that the perceived in-depth orientation of PLWs is strongly affected by locally acting stimulus properties. The facing bias seems to be induced by stimulus properties in the lower part of the PLW. PMID- 21258916 TI - Brightness and image definition of pictures viewed from between the legs. AB - It has been documented that if we see a scene from between our own legs, it appears brighter and more distinct. We determined factors that are critical to these changes and elucidated how they are related to visual disorder that is contingent on bending the head. In Experiment 1, upright scene pictures were viewed with the head inverted. In Experiments 2 and 3, the 180 degrees rotated versions of the same pictures were seen with the head inverted and upright, respectively. In Experiment 4, geometric patterns were seen with the head inverted. In Experiment 5, apparent depth and organization of scene pictures were judged under combinations of retinal-image and head orientations. The first results demonstrated that the scene pictures, when seen with the head inverted, had a 9.8% increase in brightness and a 6.8% increase in image definition as compared to normal upright viewing, but these changes did not arise for geometric patterns. Second, these changes were mainly ascribed to a proprioceptive change of the head. Third, by inverting only the head or the retinal image, visual structure of pictures was disturbed but the visual disorder did not always change brightness and image definition. These findings are discussed. PMID- 21258917 TI - Information space is action space: perceiving the partial lengths of rods rotated on an axle. AB - In a single experiment, perceivers held unseen rods at some position along their lengths and reported the two partial lengths-to the left and to the right of the hand. Wielding was mechanically limited to a vertical plane. Previous research suggested that the information exploited for this task is captured in a space created from the moment of inertia and gravitational torque. The experiment reported here attempted to replicate the relevance of that space and to ask how exploration might access it. Perceivers were given feedback on accuracy on Blocks 2 and 3 of a four-block experiment, and their performance and position in information space were monitored. Exploratory movements were recorded. Judgments were shown to depend on inertial and gravitational torques, as expected. Analysis of exploratory movements suggested that occupying a locus in information space is equivalent to exploring at some angular acceleration. The apparent weighting of cues (gravitational and inertial torque), which might be interpreted as a cognitive process, was instead interpreted as a consequence of manner of exploration. PMID- 21258918 TI - Velocity perception for sounds moving in frequency space. AB - In three experiments, we considered the relative contribution of frequency change (Deltaf) and time change (Deltat) to perceived velocity (Deltaf/Deltat) for sounds that moved either continuously in frequency space (Experiment 1) or in discrete steps (Experiments 2 and 3). In all the experiments, participants estimated "how quickly stimuli changed in pitch" on a scale ranging from 0 (not changing at all) to 100 (changing very quickly). Objective frequency velocity was specified in terms of semitones per second (ST/s), with ascending and descending stimuli presented on each trial at one of seven velocities (2, 4, 6, 8, 10, 12, and 14 ST/s). Separate contributions of frequency change (Deltaf) and time change (Deltat) to perceived velocity were assessed by holding total Deltat constant and varying Deltaf or vice versa. For tone glides that moved continuously in frequency space, both Deltaf and Deltat cues contributed approximately equally to perceived velocity. For tone sequences, in contrast, perceived velocity was based almost entirely on Deltat, with surprisingly little contribution from Deltaf. Experiment 3 considered separate judgments about Deltaf and Deltat in order to rule out the possibility that the results of Experiment 2 were due to the inability to judge frequency change in tone sequences. PMID- 21258919 TI - The temporal weighting of loudness: effects of the level profile. AB - In four experiments, we studied the influence of the level profile of time varying sounds on temporal perceptual weights for loudness. The sounds consisted of contiguous wideband noise segments on which independent random-level perturbations were imposed. Experiment 1 showed that in sounds with a flat level profile, the first segment receives the highest weight (primacy effect). If, however, a gradual increase in level (fade-in) was imposed on the first few segments, the temporal weights showed a delayed primacy effect: The first unattenuated segment received the highest weight, while the fade-in segments were virtually ignored. This pattern argues against a capture of attention to the onset as the origin of the primacy effect. Experiment 2 demonstrated that listeners adjust their temporal weights to the level profile on a trial-by-trial basis. Experiment 3 ruled out potentially inferior intensity resolution at lower levels as the cause of the delayed primacy effect. Experiment 4 showed that the weighting patterns cannot be explained by perceptual segmentation of the sounds into a variable and a stable part. The results are interpreted in terms of memory and attention processes. We demonstrate that the prediction of loudness can be improved significantly by allowing for nonuniform temporal weights. PMID- 21258920 TI - No effect of synesthetic congruency on temporal ventriloquism. AB - A sound presented in temporal proximity to a light can alter the perceived temporal occurrence of that light (temporal ventriloquism). Recent studies have suggested that pitch-size synesthetic congruency (i.e., a natural association between the relative pitch of a sound and the relative size of a visual stimulus) might affect this phenomenon. To reexamine this, participants made temporal order judgements about small- and large-sized visual stimuli while high- or low-pitched tones were presented before the first and after the second light. We replicated a previous study showing that, at large sound-light intervals, sensitivity for visual temporal order was better for synesthetically congruent than for incongruent pairs. However, this congruency effect could not be attributed to temporal ventriloquism, since it disappeared at short sound-light intervals, if compared with a synchronous audiovisual baseline condition that excluded response biases. In addition, synesthetic congruency did not affect temporal ventriloquism even if participants were made explicitly aware of congruency before testing. Our results thus challenge the view that synesthetic congruency affects temporal ventriloquism. PMID- 21258921 TI - Crossmodal duration perception involves perceptual grouping, temporal ventriloquism, and variable internal clock rates. AB - Here, we investigate how audiovisual context affects perceived event duration with experiments in which observers reported which of two stimuli they perceived as longer. Target events were visual and/or auditory and could be accompanied by nontargets in the other modality. Our results demonstrate that the temporal information conveyed by irrelevant sounds is automatically used when the brain estimates visual durations but that irrelevant visual information does not affect perceived auditory duration (Experiment 1). We further show that auditory influences on subjective visual durations occur only when the temporal characteristics of the stimuli promote perceptual grouping (Experiments 1 and 2). Placed in the context of scalar expectancy theory of time perception, our third and fourth experiments have the implication that audiovisual context can lead both to changes in the rate of an internal clock and to temporal ventriloquism like effects on perceived on- and offsets. Finally, intramodal grouping of auditory stimuli diminished any crossmodal effects, suggesting a strong preference for intramodal over crossmodal perceptual grouping (Experiment 5). PMID- 21258922 TI - Cross-modal detection using various temporal and spatial configurations. AB - To better understand temporal and spatial cross-modal interactions, two signal detection experiments were conducted in which an auditory target was sometimes accompanied by an irrelevant flash of light. In the first, a psychometric function for detecting a unisensory auditory target in varying signal-to-noise ratios (SNRs) was derived. Then auditory target detection was measured while an irrelevant light was presented with light/sound stimulus onset asynchronies (SOAs) between 0 and +/-700 ms. When the light preceded the sound by 100 ms or was coincident, target detection (d') improved for low SNR conditions. In contrast, for larger SOAs (350 and 700 ms), the behavioral gain resulted from a change in both d' and response criterion (beta). However, when the light followed the sound, performance changed little. In the second experiment, observers detected multimodal target sounds at eccentricities of +/-8 degrees , and +/-24 degrees . Sensitivity benefits occurred at both locations, with a larger change at the more peripheral location. Thus, both temporal and spatial factors affect signal detection measures, effectively parsing sensory and decision-making processes. PMID- 21258923 TI - The role of attention in the localization of odors to the mouth. AB - Odors can be perceived as arising from the environment or as part of a flavor located in the mouth. One factor that may dictate where an odor is perceived to be is concurrent gustatory stimulation in the mouth. A taste may impair the ability to attend to an odor, especially if they are perceptually similar. Alternatively, salient mouth-based features of a flavor might command attention at the expense of smell. Experiment 1 and 2, using different stimulus sets, explored the impact of perceptually similar and dissimilar pairings of tastes in the mouth and odors at the nose. In each case, these were followed by judgments of the odor's location (mouth vs. nose). Perceptual similarity had no impact on localization judgments. Experiment 3 then manipulated the salience of the olfactory and gustatory cues and showed that each could independently shift the perceived location of an odorant-salient olfactory cues toward the nose and gustatory cues toward the mouth. These findings suggest that the salient features of a flavor may command attention at the expense of olfaction and, thereby, contribute to oral localization, with implications for flavor binding. PMID- 21258924 TI - Incongruence in number-luminance congruency effects. AB - Congruency tasks have provided support for an amodal magnitude system for magnitudes that have a "spatial" character, but conflicting results have been obtained for magnitudes that do not (e.g., luminance). In this study, we extricated the factors that underlie these number-luminance congruency effects and tested alternative explanations: (unsigned) luminance contrast and saliency. When luminance had to be compared under specific task conditions, we revealed, for the first time, a true influence of number on luminance judgments: Darker stimuli were consistently associated with numerically larger stimuli. However, when number had to be compared, luminance contrast, not luminance, influenced number judgments. Apparently, associations exist between number and luminance, as well as luminance contrast, of which the latter is probably stronger. Therefore, similar tasks, comprising exactly the same stimuli, can lead to distinct interference effects. PMID- 21258925 TI - Saccade control in natural images is shaped by the information visible at fixation: evidence from asymmetric gaze-contingent windows. AB - When people view images, their saccades are predominantly horizontal and show a positively skewed distribution of amplitudes. How are these patterns affected by the information close to fixation and the features in the periphery? We recorded saccades while observers encoded a set of scenes with a gaze-contingent window at fixation: Features inside a rectangular (Experiment 1) or elliptical (Experiment 2) window were intact; peripheral background was masked completely or blurred. When the window was asymmetric, with more information preserved either horizontally or vertically, saccades tended to follow the information within the window, rather than exploring unseen regions, which runs counter to the idea that saccades function to maximize information gain on each fixation. Window shape also affected fixation and amplitude distributions, but horizontal windows had less of an impact. The findings suggest that saccades follow the features currently being processed and that normal vision samples these features from a horizontally elongated region. PMID- 21258926 TI - [Muscle trauma in primary total hip arthroplasty depending on age, BMI, and surgical approach: minimally invasive anterolateral versus modified direct lateral approach]. AB - BACKGROUND: Maximum preservation of periarticular musculature is essential for the success of total hip arthroplasty. A poorer functional outcome often occurs following total hip arthroplasty, especially in older and overweight patients and is presumed to have a muscular basis. Minimally invasive hip endoprosthetics for muscle-preserving implantation have now become established in orthopedic surgery. METHODS: A primary hip endoprosthesis was implanted in a total of 39 patients using a transgluteal (modified direct-lateral, mDL, n=19) or anterolateral minimally invasive approach (ALMI, n=20). Magnetic resonance imaging was performed preoperatively as well as 3 and 12 months after the operation. Fatty atrophy (FA) of the gluteus medius muscle was evaluated as a function of body mass index (BMI), patient age and the influence of the access route. RESULTS: In the overweight group a significantly higher FA of the gluteus medius muscle was found 3 and 12 months after the operation and a significantly higher grade FA using the standard access in contrast to the normal weight group. A significantly higher FA of the gluteus medius muscle was found in the older patient group 3 and 12 months postoperation as well as a significantly higher atrophy using the mDL access. CONCLUSIONS: Muscle trauma is demonstrably reduced using a minimally invasive access, especially in older and overweight patients. In these patients there is also a substantially higher postoperative muscular atrophy after implantation of a prosthesis than in corresponding normal weight and younger patients. The higher vulnerability and poorer capacity for regeneration of periarticular musculature means that this patient group particularly profits from a minimally invasive access route. PMID- 21258927 TI - [Long-term results of thrust plate prostheses: comparison of patients younger than and older than 50 years]. AB - BACKGROUND: Hip replacement in patients younger than 50 years old is no longer an exception in view of the increasing necessity for care. The aim of the present study was to analyze whether the results after implantation of thrust plate prosthesis (TPP) with metaphyseal anchorage are equal for patients below 50 years compared to older patients. PATIENTS AND METHODS: The investigation comprised 465 TPP implantations. In 149 TPP the patient age was below 50 years (group A) und in 316 TPP cases above 50 years (group B). Clinical and radiological evaluation of the results for both groups was carried out as well as a differentiated survival analysis with defined endpoints. RESULTS: Survival analysis of group A (96%/13.2 years) showed a significantly improved survival rate compared to group B (86%/12.5 years). Additionally, the risk of prosthesis and/or radiological signs loosening of was significantly lower in group A than in group B (p <0.05). CONCLUSION: Comparison of long-term results of prostheses with intramedullary fixation shows that the anchorage principle of TPP with bone-saving implantation to the proximal femur is justified especially for patients below 50 years of age. PMID- 21258928 TI - Paratesticular rhabdomyosarcoma with metastatic encasement of the abdominal aorta. AB - Paratesticular rhabdomyosarcoma is a rare but aggressive malignancy in children and adolescents. Prognosis is related to initial tumor resectability as well as staging of the disease based on tumor invasiveness, tumor bulk, nodal disease and metastases. We report the unusual presentation of paratesticular rhabdomyosarcoma with metastatic extension through the inguinal canal and encasement of the abdominal aorta. These features portend a poor prognosis given their association with a greater stage of disease and unresectable nature at presentation. Delayed surgical resection follows a regimen of chemotherapy and radiation therapy in such cases of extensive disease. Encasement of the abdominal aorta has been shown to increase presurgical risk for intraoperative vascular injury when related to other malignancies, but its role in relation to metastatic paratesticular rhabdomyosarcoma has not been investigated. Also, rhabdomyosarcoma should be considered in the differential diagnoses of tumors that demonstrate encasement of the abdominal aorta. PMID- 21258929 TI - Impact of rigid and nonrigid registration on the determination of 18F-FDG PET based tumour volume and standardized uptake value in patients with lung cancer. AB - PURPOSE: Assessment of the metabolically active tumour tissue by FDG PET is evolving for use in the diagnosis of non-small-cell lung cancer (NSCLC), in the planning of radiotherapy, and in follow-up and response evaluation. For exact evaluation accurate registration of PET and CT data is required. The registration process is usually based on rigid algorithms; however, nonrigid algorithms are increasingly being used. The influence of the registration method on FDG PET based standardized uptake value (SUVmax) and metabolic tumour volume (MTV) definition has not yet been evaluated. We compared intra- and interindividual differences in SUV and MTV between rigid- and nonrigid-registered PET and CT acquired during different breathing manoeuvres. METHODS: The study group comprised 28 radiotherapy candidates with histologically proven NSCLC who underwent FDG PET acquisition and three CT acquisitions (expiration - EXP, inspiration - INS, mid-breath-hold - MID). All scans were registered with both a rigid (R) and a nonrigid (NR) procedure resulting in six fused datasets: R-INS, R EXP, R-MID, NR-INS, NR-EXP and NR-MID. For the delineation of MTVs a contrast oriented contouring algorithm developed in-house was used. To accelerate the delineation a semiautomatic software prototype was utilized. RESULTS: Tumour mean SUVmax did not differ for R and NR registration (R 17.5 +/- 7, NR 17.4 +/- 7; p=0.2). The mean MTV was higher by 3 +/- 12 ml (p=0.02) in the NR group than in the R group, as was the mean tumour diameter (by 0.1 +/- 0.2 cm; p<0.01). With respect to the three different breathing manoeuvres, there were no differences in MTV in the R group (p > 0.7). In intraindividual comparison there were no significant differences in MTVs concerning the registration pairs R-EXP (68 +/- 88 ml) vs. NR-EXP (69 +/- 85 ml) und R-MID (68 +/- 86 ml) vs. NR-MID (69 +/- 83 ml) (both p > 0.4). However, the MTVs were larger after NR registration during inspiration (R-INS 68 +/- 82 vs. NR-INS 78 +/- 93 ml; p=0.02). CONCLUSION: The use of nonrigid algorithms may lead to a change in MTV, whose extent is influenced by the breathing manoeuvre on CT. Nonrigid registration methods cannot be recommended for the definition of MTV if the CT scan is performed during inspiration. The choice of registration algorithm has no significant impact on SUVmax. PMID- 21258930 TI - Anatomic localization of motor entry points and accurate regions for botulinum toxin injection in the flexor digitorum superficialis. AB - PURPOSE: The aim of this study was to determine the motor entry points (MEPs) and the precise intramuscular nerve distribution of the flexor digitorum superficialis (FDS) and to provide accurate injection regions for botulinum toxin. METHODS: This study was performed on 46 fresh cadaveric arms with exposed intramuscular innervation of the FDS. For each main motor branch of the FDS, MEPs, where the nerve branch first pierced the muscle belly, and the proximal and distal limit points (PLPs and DLPs, respectively) of the terminal intramuscular nerve endings were located. These data were expressed as relative percentages and absolute distances in relation to the coordinate system, which defined the line between medial and lateral epicondyle of the humerus (ME and LE, respectively) as y-axis and the midpoint of ME and LE as origin. MEP distributions were analyzed using distances measured in tenths of the x and y axes. RESULTS: Two main branches innervated the FDS in 27 cases, the distal main branches of the FDS were classified into three types by origin. For proximal main branches, MEPs were located at x = 19.7% and y = 18.5%, whereas PLPs were located at x = 16.4%, and DLPs were located at x = 37.7%. For distal main branches, corresponding values were 31.6, 5.5, 50.9, and 73.1%. CONCLUSIONS: The parameters provided by this study should increase the efficacy and precision of neuromuscular botulinum toxin blockades administered to treat finger spasticity. PMID- 21258931 TI - Vascular characterisation of triple negative breast carcinomas using dynamic MRI. AB - OBJECTIVES: Triple-negative (ER-/PR-/HER2-) breast carcinomas (TNBC) are aggressive tumours with underexplored imaging features. This study investigates whether their vascular characteristics as assessed by dynamic contrast-enhanced (DCE) and dynamic susceptibility contrast-enhanced (DSC) MRI are distinct from the prognostically more favourable ER+/PR+/HER2- cancers. METHODS: Patients with primary breast cancer underwent MRI before neoadjuvant chemotherapy and were identified as ER-/PR-/HER2- or ER+/PR+/HER2- from core biopsy specimens. MRI parameters reflecting tissue perfusion, permeability, and extracellular leakage space were measured. Values for inflow transfer constant (K(trans)), outflow rate constant (k(ep)), leakage space (v(e)), area under the gadolinium curve (IAUGC(60) ), relative blood volume (rBV) and flow (rBF), and Mean Transit Time (MTT) were compared across receptor status and with known prognostic variables. RESULTS: Thirty seven patients were assessable in total (16 ER-/PR-/HER2-, 21 ER+/PR+/HER2-). Lower v(e) (p = 0.001), shorter MTT (p = 0.007) and higher k(ep) values (p = 0.044) were observed in TNBC. v(e) was lower across all T stages, node-negative (p = 0.004) and low-grade TNBC (p = 0.037). v(e) was the best predictor of triple negativity (ROC AUC 0.80). CONCLUSIONS: TNBC possess characteristic features on imaging, with lower extracellular space (higher cell density) and higher contrast agent wash-out rate (higher vascular permeability) suggesting a distinctive phenotype detectable by MRI. PMID- 21258932 TI - BMPR1A-mediated BMP1 signalling is disrupted in the cadmium-induced omphalocele in the chick model. AB - PURPOSE: In the chick embryo, administration of cadmium (Cd) induces omphalocele phenotype. The earliest histological changes in this model are observed commencing at 4-h post treatment (4H). The molecular mechanisms by which Cd acts during the critical period of embryogenesis remain unclear. Bone morphogenetic proteins (BMPs) and their receptors (BMPRs) regulate many fundamental biological processes and are involved in various embryonic morphogenesis, including ventral body wall (VBW) formation. Homozygous BMP1 mutant mice cause VBW defects. It has been reported that BMPR1A conditional knockouts also exhibit omphalocele phenotype. We designed this study to test the hypothesis that gene expression levels of BMP1 and BMPR1A are downregulated during the critical period of embryogenesis in the Cd chick model. METHODS: After 60-h incubation, chick embryos were exposed to either Cd or saline and then harvested 1H, 4H and 8H. Chicks were divided into control (n = 24) and Cd (n = 24). RT-PCR was performed and differences between the two groups were tested statistically (significance was accepted at p < 0.05). Immunohistochemical study was also performed to evaluate those proteins expression/distribution. RESULTS: The gene expression levels of BMP1 and BMPR1A at 4H were significantly downregulated in Cd group compared to controls. Immunoreactivity of BMP1 and BMPR1A was also markedly decreased in Cd-treated embryos compared to controls. CONCLUSION: Disruption of BMPR1A-mediated BMP1 signalling during the narrow window of early embryogenesis may interfere with normal VBW formation, causing omphalocele phenotype in the Cd chick model. PMID- 21258933 TI - Primary gastric pull-up in pure esophageal atresia: technique, feasibility and outcome. A prospective observational study. AB - AIM: To perform a definitive procedure in pure esophageal atresia by gastric pull up in the newborn. PATIENTS/METHODS: A primary gastric pull-up was performed in six newborns with pure esophageal atresia that presented between 1998 and 2009. The cervical esophagus was mobilized through the neck, the stomach was mobilized through laparotomy, the left gastric artery was ligated, and Pyloromyotomy was done. The stomach was brought into the neck via the trans hiatal route. A single layer esophageo-gastric anastomosis was done in the neck in all. RESULTS: The mean birth weight was 2.1 kg (range 1.9-2.7) and the age at surgery varied from 3 to 7 days (mean 4.5 days). The mean operative time was 146 min. All six neonates received postoperative elective ventilation for a period of 2-7 days (mean 5.3). Epidural morphine was given for postoperative pain relief. Four received TPN for 5-13 days. Three had minor leaks from the neck wound that healed spontaneously. Mean hospital stay was 14.6 with a range 13-20 days. There was no mortality. CONCLUSION: It is feasible to perform the gastric pull-up for long gap esophageal atresia in the newborn period, as a definitive procedure with no added risks to life in experienced hands. PMID- 21258934 TI - The role of primary myogenic regulatory factors in the developing diaphragmatic muscle in the nitrofen-induced diaphragmatic hernia. AB - PURPOSE: The nitrofen model of congenital diaphragmatic hernia (CDH) is widely used to investigate the pathogenesis of CDH. However, the exact pathomechanism of the diaphragmatic defect is still unclear. Diaphragmatic muscularization represents the last stage of diaphragmatic development. Myogenic differentiation 1 (MyoD) and myogenic factor 5 (Myf5) play a crucial role in muscularization. MyoD(-/-) : Myf5(+/-) mutant mice show reduced diaphragmatic size, whereas MyoD(+/-) : Myf5(-/-) mutants have normal diaphragms. We designed this study to investigate diaphragmatic gene expression of MyoD and Myf5 in the nitrofen CDH model. METHODS: Pregnant rats received nitrofen or vehicle on day 9 of gestation (D9), followed by cesarean section on D18 and D21. Fetal diaphragms (n = 40) were micro-dissected and divided into CDH group and controls. MyoD and Myf5 mRNA expression were determined using Real-time PCR. Immunohistochemistry was performed to evaluate protein expression of MyoD and Myf5. RESULTS: Relative diaphragmatic mRNA expression levels and immunoreactivity of MyoD were decreased in the CDH group on D18 and D21. Myf 5 mRNA and protein expression were not altered in the CDH group. CONCLUSION: This is the first study showing that MyoD expression is selectively decreased in the diaphragm muscle in the nitrofen model of CDH. PMID- 21258935 TI - Prenatal administration of retinoic acid upregulates connective tissue growth factor in the nitrofen CDH model. AB - PURPOSE: Recent studies have suggested that retinoids may be involved in the molecular mechanisms of pulmonary hypoplasia (PH) in congenital diaphragmatic hernia (CDH). Connective tissue growth factor (CTGF) plays a key role in foetal lung development and remodelling during later gestation. CTGF knockout mice exhibit PH with similar characteristics to the human and nitrofen-induced PH. Prenatal administration of retinoic acid (RA) has been shown to stimulate alveologenesis in nitrofen-induced PH. In vitro studies have revealed that RA can induce CTGF gene expression. We hypothesized that pulmonary gene expression of CTGF is downregulated during the later stages of lung development, and that prenatal administration of RA upregulates CTGF in the nitrofen CDH model. METHODS: Pregnant rats were exposed to either olive oil or nitrofen on day 9 (D9) of gestation. RA was given intraperitoneally on D18, D19 and D20. Foetuses were harvested on D21 and divided into control, CDH, control + RA and CDH + RA group. Pulmonary CTGF gene and protein expression levels were determined using RT-PCR and immunohistochemistry. RESULTS: On D21, CTGF relative mRNA expression levels were significantly downregulated in CDH group compared to controls. After RA treatment, expression levels of CTGF were significantly upregulated in CDH + RA and control + RA compared to the CDH group. Immunohistochemical studies confirmed these results. CONCLUSION: Downregulation of pulmonary CTGF gene and protein expression during later stages of lung development may interfere with normal alveologenesis in the nitrofen CDH model. Upregulation of CTGF pulmonary gene expression after prenatal RA treatment may promote lung growth by promoting alveologenesis in the nitrofen-induced CDH model. PMID- 21258936 TI - Usage of 64-detector-row spiral computed tomography volumetry in preoperative volume prediction in living donor liver transplantation in children. AB - PURPOSE: To investigate the correlation between the graft volume calculated by 64 detector-row spiral computed tomography (CT) and the graft weight measured during the living donor liver transplantation (LDLT) operation, and try to get an equation to help determine the possible weight of graft before operation. METHODS: 23 donors with left lateral lobe LDLT were enrolled to undergo 64 detector-row spiral CT and the imaging data at the hepatic venous phase was used for whole and partial liver volumetric measurement on a dedicated image postprocessing workstation. The resected part of donor liver was weighed during the operation. Statistical analysis with SPSS15.0 was used to analyze the correlation between the estimated liver volume by CT and the actual graft weight. RESULTS: The graft volume calculated preoperatively by CT (293.35 +/- 53.43 ml) was significantly larger than measured graft weight during the operation (252.82 +/- 50.96 g) (P < 0.05). All corresponding pre- and intraoperative data correlated significantly (R = 0.885) (P < 0.001). Intraoperatively expected weight (W (intraop)) in grams and volume calculated preoperatively by CT (V (preop)) in milliliters can be calculated with the equation W (intraop) (g) = 0.844 * V (preop) (ml) + 5.271. CONCLUSION: Liver volume calculated by 64 detector-row spiral CT preoperatively can predict the actual graft weight, which is very useful in donor selection in LDLT. PMID- 21258937 TI - A role for Pten in paediatric intestinal dysmotility disorders. AB - PURPOSE: The enteric nervous system (ENS) is a network of neurons and glia that lies within the gut wall. It is responsible for the normal regulation of gut motility and secretory activities. Hirschsprung's disease (HD) is a congenital defect of the ENS, characterised by an absence of ganglia in the distal colon. Intestinal neuronal dysplasia (IND) is a condition that clinically resembles HD, characterised by hyperganglionosis, giant and ectopic ganglia, resulting in intestinal dysmotility. Intestinal ganglioneuromatosis is characterised by hyperplasia and hypertrophy of enteric neuronal cells and causes chronic intestinal pseudo-obstruction (CIPO). Phosphatase and tensin homolog deleted on chromosome 10 (Pten) is a phosphatase that is critical for controlling cell growth, proliferation and cell death. A recent study of Pten knockout mice showed evidence of ganglioneuromatosis in the ENS suggesting a role for this protein in ENS development. Ganglioneuromatosis patients have also been shown to have a decreased level of Pten expression in the colon. The aim of our study was to investigate Pten expression in the ENS of HD and IND patients compared to normal controls. METHODS: Resected tissue from 10 HD and 10 IND type B patients was fixed and embedded in paraffin wax. Normal control colon tissue was obtained from ten patients who underwent a colostomy closure for imperforate anus. Sections were cut and immunohistochemistry was carried out using a Pten antibody. Results were analysed by light microscopy. RESULTS: Staining showed that Pten was strongly expressed in ganglia of both the submucosal and myenteric plexus of normal and HD specimens from the ganglionic colon. Pten expression was significantly reduced in the giant ganglia in IND patients in both the myenteric and submucosal plexuses compared to the normal controls. Specimens from the aganglionic region of HD did not show Pten expression. CONCLUSION: To the best of our knowledge, this is the first study demonstrating a marked reduction of Pten expression in the myenteric and submucous plexuses of IND patients. Neuronal Pten deficiency in IND may disrupt the chemical pathway associated with the proliferation and development of neuronal cells forming mature ganglia and thus cause motility dysfunction. PMID- 21258938 TI - Laparoscopic appendectomy is associated with lower morbidity in extremely obese children. AB - PURPOSE: In recent years there has been worldwide increase in childhood obesity. However, in the beginning laparoscopic appendectomy in obese children was contraindicated, now it is commonly used for the treatment of appendicitis. The purpose of this study was to compare open versus laparoscopic appendectomy in extremely obese children. METHODS: The hospital records of 1,383 consecutive patients, who underwent appendectomy for acute appendicitis between 2000 and 2009 were analyzed. 238 children (17.2%) were extremely obese. Extremely obese was defined, as greater than 2 standard deviations above the standardized mean weight for age. 61 of 238 (25.6%) patients had open appendectomy and 177 (74.3%) underwent laparoscopic appendectomy. The length of hospital stay, operation time, complication rate and frequency of taking postoperative pain relief were compared between open and laparoscopic appendectomy in extremely obese children. RESULTS: The incidence of complicated and non-complicated appendicitis was similar both in open and laparoscopic appendectomy group. Laparoscopic appendectomy for acute appendicitis in extremely obese children is associated with significantly shorter operating time (46.8 vs. 59.87 min, P < 0.05), lower overall complication rate (5 vs. 8.2%, P < 0.05) and lesser postoperative analgesia requirement (6.97* vs. 4.73*, P < 0.05). CONCLUSION: Laparoscopic appendectomy should be the procedure of choice for the treatment of acute appendicitis in extremely obese children. PMID- 21258939 TI - Urodynamics investigation on children with vesicoureteral reflux identifies overactive bladder and poor compliance in those with voiding dysfunction. AB - BACKGROUND: Up to 50% of children with vesicoureteral reflux (VUR) may have associated voiding dysfunction. It is thought to be an important determinate of the severity and resolution of VUR; however, to date there has been no objective measurement defining the impact of voiding dysfunction in children with VUR. The purpose of this study is to compare the urodynamic parameters of children with VUR who have and do not have symptomatic voiding dysfunction. METHODS: We performed a retrospective study of 138 children with a diagnosis of primary VUR who underwent urodynamic investigations. Information regarding patient demographics, grade and laterality of VUR and clinical history of bladder dysfunction were assessed. Urodynamic parameters recorded included detrusor overactivity, early and late compliance, voiding pressure, post-void residual volume and functional bladder capacity. Statistical analysis was performed using t Student analysis, Pearson's chi(2) test or Fischer's exact test, with a p < 0.05 as being significant. RESULTS: The mean age of the patients at the time of urodynamic evaluation was 5.8 years (SD 4.4). 30% had symptomatic voiding dysfunction based on the clinical history. Children without a history of voiding dysfunction had higher grades of VUR as compared to those with it (p = 0.002). Bladder hypertone, detrusor overactivity, detrusor hypereflexia and poor late bladder compliance presented a statistically significant higher incidence the incidence of bladder overactivity and poor late bladder compliance was higher in children with bladder dysfunction than those without it. CONCLUSION: Our findings suggest that voiding dysfunction does have objective and quantifiable effects on bladder dynamics. Urodynamic evaluation may play a role in the management of children with VUR by identifying those with bladder dysfunction secondary to abnormal voiding habits. PMID- 21258940 TI - Sibling vesicoureteral reflux in twins. AB - AIM OF STUDY: Few studies have evaluated the incidence of familial vesicoureteral reflux (VUR) among multiple gestation births. The purpose of this study was to determine the incidence and characteristics of VUR in twins in a large cohort of families with VUR. METHODS: Between 1998 and 2010, data were collected on 251 families (538 children) with at least 2 siblings who had VUR. The incidence of affected twins among the families was analysed. Data were assessed for age at presentation, gender, grading of VUR, laterality of affectation and renal scarring. VUR was diagnosed by voiding cystourethrography (VCUG) and dimercaptosuccinic acid (DMSA) scans were used to assess renal scarring. RESULTS: There were 12 families (4.8%) in which twins were affected with VUR. There were 12 index cases (7 males/5 females), and 12 siblings (1 male/11 females). All index cases presented with urinary tract infection (UTIs), whereas 2 siblings had UTIs and 10 were screened. All cases presented between 3 months and 2 years. Among the index cases, three had unilateral and nine had bilateral VUR. Among the siblings, four had unilateral and eight had bilateral VUR. Thirty-seven (90%) of the 41 affected renal refluxing units had high-grade VUR. Three index cases had renal scarring. No scarring was seen in the siblings. CONCLUSIONS: The vast majority of twins with VUR are females who have high grade VUR and a low incidence of renal scarring. Twins with VUR may represent a genetically different subgroup with female preponderance and severe reflux. PMID- 21258941 TI - Hot flakes in cold cases. AB - In the past, it was almost impossible for forensic scientists to separate DNA from an undefined number of different individuals in mixed stains where, for example, two or more suspects had handled the same weapon. Such samples often contain complex mixtures with the consequence of ambiguous or inconclusive mixed DNA profiles. Using the method described of comprehensive and/or targeted screening of shed cells adhering to tapings of garments or objects enables such stains to be individualized. To evaluate the method, 500 microscopically selected single skin flakes were analyzed using two different commercial STR kits to compare the success rates for each PCR typing system. The method has been validated for use in routine casework and has been shown to be rapid, sensitive, and reproducible. It can be predicted that many cases in the archives with body tapings, which have not yet been examined will benefit from this new or perhaps more appropriate, reanimated, technical development, and of particular importance are serious crimes, the so-called cold cases. The remarkable forensic value of this simple but time-consuming technique is exemplified by 2 out of approximately 100 cases already successfully solved using this approach. PMID- 21258942 TI - Development and validation of I-DNA1: a 15-Loci multiplex system for identity testing. AB - This paper presents a system for the multiplex amplification of 15 loci, known as I-DNA1, which combines mini and midiSTR technology, with amplicon sizes ranging from 49 to 297 bp. I-DNA1 analyses all the STR loci included in the CODIS and the Interpol Standard Set of loci, nine of the ten European core loci and seven of the eight German core loci, making it suitable for use in identifying humans. Moreover, its high sensitivity and the small size of its amplicons mean that I DNA1 is potentially highly useful for analysing highly degraded and/or very small DNA samples. PMID- 21258943 TI - Effect of dietary alginic acid on juvenile tilapia (Oreochromis niloticus) intestinal microbial balance, intestinal histology and growth performance. AB - The aim of the present study was to assess the effect of a commercial alginic acid source (Ergosan) on tilapia Oreochromis niloticus intestinal microbial balance, intestinal morphology, and growth parameters. Fish were fed a basal control diet or the basal diet plus a source of alginic acid (5 g kg(-1) Ergosan; Schering-Plough Aquaculture, UK) for 9 weeks. At the end of the trial, light and electron microscopy demonstrated that the morphology of the intestinal tract at the gross and ultra-structural level was not affected by dietary alginic acid inclusion. Both groups of fish displayed healthy, normal morphology with no signs of disease, cell or tissue damage. Intestinal epithelial leucocyte infiltration was not affected by dietary alginic acid. Molecular bacterial profiles derived from PCR-DGGE illustrated highly similar microbial communities (both within the lumen and associated with the intestinal mucosa) in the respective treatment groups. Microbial ecological parameters (e.g. species diversity and richness) also remained unaffected. Although not significant, trends towards elevated survival and body protein content were observed in the alginic acid-fed fish. These results are suggestive that alginic acid does not adversely impact the indigenous gastrointestinal microbial balance and subsequently does not impact upon the epithelial brush border integrity. Validation of non-detrimental impacts of immunostimulatory products on gastric microbiota and epithelial integrity should be pursued in future studies as maintaining microbial balance and epithelial integrity is essential for proper gut functionality. PMID- 21258944 TI - Dicyemid's dilemma: structure versus genes. The unorthodox structure of dicyemid reproduction. AB - The clear phylogenetic status of the enigmatic Phylum Dicyemida is still uncertain. Their primitive body plan lacks essential metazoan synapomorphies, while genetic data favor a kinship with higher lophotrochozoans. This ultrastructural study increases the confusion about this phylum by presenting an unusual gonad and sperm structure lacking all synapomorphies essential for the various phyla of the lophotrochozoans, either free-living ones or parasites. In Dicyema typus, gonadogenesis is reduced to a single somatic cell, i.e., the infusorigen's axial cell that functions as a somatic gonadal founder cell as soon as a spermatogonium takes residence in its cytoplasm. The spermiogenic cells resulting therefrom are not connected by intercellular bridges and permanently contain a bundle of microtubules in their cytoplasm, obviously a kind of "dormant" spindle having assembled without centrosomes. Primary spermatocytes develop so-called polycomplexes, multiple synaptinemal complexes. The structure of the sperm is based on a certain kind of somatic cell that has been minimally adapted to function as a sperm. The mature sperm consists in only three organelles: an ovoid nucleus with a somatic chromatin structure, numerous pore complexes and a centrally arranged cluster of coiled tubular structures; a bundle of microtubules embedded into a rim running along the nucleus longitudinal surface, projecting out of the cell like a spear; and a lipid vesicle tightly attached to one pole of the nucleus, touching there the adjacent bundle of microtubules. Immunelectron microscopy confirms the somatic condition of mature sperm, revealing somatic histone H1 immunoreactivity over the nucleus, which can be interpreted as synapomorphy shared with Protozoa, Porifera and Cnidaria. Fertilization occurs as selfing, where the sperm penetrates, "bundle of microtubules first", a primary oocyte attached vis-a-vis on the other side of the plasma membrane of the infusorigen's axial cell. This somatic situation points to an ancient evolutionary model rather than to a condition caused by retrogression due to their life as commensals. PMID- 21258945 TI - Isolation and characterization of neural stem cells from the neonatal rat cochlear nucleus. AB - Neural stem cells have been identified in multiple parts of the postnatal mammalian brain, as well as in the inner ear. No investigation of potential neural stem cells in the cochlear nucleus has yet been performed. The aim of this study was to investigate potential neural stem cells from the cochlear nucleus by neurosphere assay and in histological sections to prove their capacity for self renewal and for differentiation into progenitor cells and cells of the neuronal lineage. For this purpose, cells of the cochlear nucleus of postnatal day 6 rats were isolated and cultured for generation of primary neurospheres. Spheres were dissociated and cells analyzed for capacity for mitosis and differentiation. Cell division was detected by cell-counting assay and BrdU incorporation. Differentiated neural progenitor cells showed distinct labeling for Nestin and for Atoh1. Positive staining of beta-III Tubulin, glial fibrillary acid protein (GFAP) and myelin basic protein (MBP) showed differentiation into neurons, astrocytes and oligodendrocytes. Furthermore, Nestin- and BrdU-labeled cells could also be detected in histological sections. In conclusion, the isolated cells from the cochlear nucleus presented all the features of neural stem cells: cell division, presence of progenitor cells and differentiation into different cells of the neuronal lineage. The existence of neural stem cells may add to the understanding of developmental features in the cochlear nucleus. PMID- 21258946 TI - A mono-institutional prospective study on the effectiveness of a specialist psychotherapeutic intervention (POI) started at the diagnosis of cancer. AB - PURPOSE: We evaluated the effectiveness of an early POI in newly diagnosed cancer patients in reducing the occurrence of psychiatric disturbances. METHODS: We designed a mono-institutional prospective study involving all new patients admitted to the Oncology Department of Fatebenefratelli and Ophtalmic Hospital in Milan from January 2005 until September 2008. During the first visit, the oncologist could offer support with a psycho-oncologist. The patients who accepted had a first interview (T0), during which they took a self-evaluation test (HADS, Hospital Anxiety and Depression scale). On the basis of the score, the psycho-oncologist could offer psychotherapy and/or pharmacological intervention, if necessary. At the end of the eight sessions (T1), the patient repeated the self-evaluation test with the HADS, and we analysed both the difference in the HADS score between T0 and T1 and the clinical evaluation of the psycho-oncologist. RESULTS: Three hundred eighteen patients were evaluated with a psychoanalytical psychotherapy approach by two psycho-oncologists through a first interview and 90 of them were eligible for the present study also for the evaluation of HADS. The average HADS score in T0 was 15.26 for depression (sd=3.21) and 13.86 for anxiety (sd = 2.05). The reassessment at the end of the psychotherapy (T1) showed an average HADS score of 5.94 for depression (sd = 3.11) and 6.58 for anxiety (sd = 2.88). Only five patients were treated with a pharmacological approach alone. CONCLUSIONS: Considering all the limits of our study, we may conclude that an early POI significantly reduces patients' psychiatric symptoms and the risk of a negative evolution of pathological situations in those patients who are motivated and express a need for psychological help. PMID- 21258947 TI - Inequalities in access to cancer treatment: an analysis of cross-regional patient mobility in Greece. AB - PURPOSE: The quest of specialized oncology services represents an inelastic need for cancer patients that often leads to traveling in order to receive adequate care. The present survey assesses patient geographic mobility to access services for the prevention and treatment of neoplasmatic diseases in Greece, a country where the National Health System is characterized by severe misdistribution of oncology-specific resources. METHODS: Based on data from the National Statistical Service for 1999-2005 (last available), we estimated geographic mobility as the difference between oncology patients residing in a specific region and those receiving care in National Health System (NHS) facilities located in the region, for the ten administrative districts of Greece. Especially for Attica, we performed a sub-analysis according to cancer diagnosis. RESULTS: The most significant mobility is towards Attica, where patients receiving care within the region outnumber the patients actually residing by 48.9% annually, on average. Positive flows are also observed towards Macedonia (8.4%) and Epirus (7.8%). Negative flows are recorded in all remaining regions, the highest noticed in Sterea (-76.2%), Ionian Islands (-63.3%), Aegean Islands (-45.2%), and Thessaly ( 37.3%). The largest flow towards Attica is for cases of malignant neoplasms of the skin, uterus, male genital organs, and for Hodgkin's lymphomas. CONCLUSIONS: Misallocation of oncology-specific resources creates "two-tier" cancer patients based on ability to pay for traveling/accommodation. The severity and the consequences of the disease necessitate a bold approach to resource allocation and the establishment of integrated patient support networks that ensure all cancer patients are offered equal opportunities to effective treatment. PMID- 21258948 TI - Chemotherapy-induced nausea and vomiting in daily clinical practice: a community hospital-based study. AB - BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are major adverse effects of cancer chemotherapy. This study investigated: (1) the impact of CINV on patients' health-related quality of life (HRQL) in daily clinical practice; (2) the association between patient characteristics and type of antiemetics and CINV; and (3) the role of CINV in physicians' decisions to modify antiemetic treatment. PATIENTS AND METHODS: This prospective, multicenter study was conducted in nine general hospitals in the Netherlands. During three consecutive chemotherapy cycles, patients used a diary to record episodes of nausea, vomiting and antiemetic use. For each cycle, these ratings were made 1 day prior to and 7 days after having received chemotherapy. The influence of CINV on patients' HRQL was evaluated with the Functional Living Index-Emesis (FLIE) questionnaire at day 6 of each treatment cycle. (Changes in) antiemetic use were recorded by the treating nurse. Patient inclusion took place between May 2005 and May 2007. RESULTS: Two hundred seventy-seven patients were enrolled in the study. Acute and delayed nausea during the first treatment cycle was reported by 39% and 68% of the patients, respectively. The comparable figures for acute and delayed vomiting were 12% and 23%. During the first and subsequent treatment cycle, approximately one-third of the patients indicated that CINV had a substantial impact on their daily lives. Female patients and younger patients reported significantly more CINV than male and older patients. At all treatment cycles, patients receiving treatment with moderately emetogenic chemotherapy, containing anthracycline, reported more acute nausea than patients receiving highly emetogenic chemotherapy. Acute vomiting was associated significantly with change in (i.e., additional) antiemetic treatment. Delayed CINV did not influence antiemetic treatment. CONCLUSION: CINV continues to be a problem that adversely affects the daily lives of patients. CINV is worse in women and in younger patients. In daily clinical practice, acute CINV, but not delayed CINV, results in changes in antiemetic treatment. In view of the effects of not only acute, but also delayed CINV on daily life, more attention should be paid to adjustment of antiemetic treatment to cover CINV complaints, later during the chemotherapy cycle. PMID- 21258949 TI - Management of infratentorial subdural hygroma complicating foramen magnum decompression: a report of three cases. AB - Decompression of the foramen magnum for symptomatic Chiari malformation attends a small but significant risk of infratentorial subdural extra-arachnoid hygroma when an arachnoid-sparing procedure is attempted. We present three cases whereby an arachnoid-sparing procedure was carried out and resulted in infratentorial subdural hygroma and hydrocephalus. The complication was managed by re exploration of the posterior fossa and wide arachnoidotomy. In cases whereby the decision has been made to open the dura, we recommend routine arachnoidotomy in foramen magnum decompression, avoiding the risks of infratentorial subdural hygroma. In cases where arachnoid-sparing procedures have been attempted and subdural hygroma subsequently develops, we advocate re-exploration of the posterior fossa rather than cerebrospinal fluid diversion. PMID- 21258950 TI - A novel technique for impaction bone grafting in acetabular reconstruction of revision total hip arthroplasty using an ex vivo compaction device. AB - BACKGROUND: Impaction bone grafting allows restoration of the acetabular bone stock in revision hip arthroplasty. The success of this technique depends largely on achieving adequate initial stability of the component. To obtain well compacted, well-graded allograft aggregates, we developed an ex vivo compaction device to apply it in revision total hip arthroplasty on the acetabular side, and characterized mechanical properties and putative osteoconductivity of allograft aggregates. METHODS: Morselized allograft bone chips were compacted ex vivo using the creep technique and subsequent impaction technique to form the bone aggregates. Impaction allograft reconstruction of the acetabulum using an ex vivo compaction device was performed on eight hips. The mechanical properties and three-dimensional micro-CT-based structural characteristics of the bone aggregates were investigated. RESULTS: In clinical practice, this technique offered good reproducibility in reconstructing the cavity and the segmental defects of the acetabulum, with no migration and no loosening of the component. In vitro analysis showed that the aggregates generated from 25 g fresh-frozen bone chips gained compression stiffness of 13.5-15.4 MPa under uniaxial consolidation strain. The recoil of the aggregates after compaction was 2.6-3.9%. The compression stiffness and the recoil did not differ significantly from those measured using a variety of proportions of large- and small-sized bone chips. Micro-CT-based structural analysis revealed average pore sizes of 268-299 MUm and average throat diameter of pores in the bone aggregates of more than 100 MUm. These sizes are desirable for osteoconduction, although large interconnected pores of more than 500 MUm were detectable in association with the proportion of large-sized bone chips. Cement penetration into the aggregates was related to the proportion of large-sized bone chips. CONCLUSION: This study introduces the value of an ex vivo compaction device in bone graft compaction in clinical applications. In vitro analysis provided evidence that compaction of sequential layers of well-compacted, well-graded bone aggregates, i.e., the aggregates comprising smaller sized chips at the host bone side and larger sized chips at the component side, may have the advantages of initial stability of the acetabular component and biological response of the grafted aggregates. PMID- 21258951 TI - Modular neck prostheses in DDH patients: 11-year results. AB - BACKGROUND: Total hip replacement in developmental dysplasia of the hip is a demanding procedure and usually requires dedicated devices and special surgical techniques. Nevertheless, the described techniques have shown variable outcomes. The aim of this study was to assess the 11-year outcomes of an off-the-shelf modular neck prosthesis in dysplastic patients and to evaluate the ability of the modular neck system to adequately restore femoral offset, abductor muscles lever arm and leg length. METHODS: We retrospectively evaluated 61 modular neck prostheses implanted in 47 patients between June 1995 and March 2004. The preoperative diagnosis was developmental dysplasia of the hip in all cases. The clinical outcomes were assessed using the Harris hip score and the Western Ontario and McMaster Universities score. The femoral offset, abductor muscles lever arm, height and medialization of the hip center of rotation, and differences in leg length were evaluated on postoperative radiographs. Prosthesis survival was calculated according to the Kaplan-Meier method considering any reason for revision as failure. The average follow-up was 117.2 months (range 57 162 months). RESULTS: The cumulative survival at 11 years was 97.5%. One prosthesis failed 5 years after surgery because of a ceramic liner fracture due to an inappropriate obstetric maneuver during labour. At the latest follow-up the mean Harris hip score was 74.7 (range 23-91). Leg length discrepancy was avoided in the majority of cases; femoral offset was almost always restored. CONCLUSIONS: The results of this series support the use of modular neck prostheses as an effective alternative in the treatment of developmental dysplasia of the hip. The modularity was very efficient in restoring offset, leg length and maintaining stability with a good mid-long-term follow-up. Unlike other proposed surgical techniques, these good results are achievable by a standard surgical technique and with an off-the-shelf prosthesis. PMID- 21258952 TI - Focus on the essential: all great apes know when others are being attentive. AB - When begging for food, all great ape species are sensitive to a human's attention. However, studies investigating which cues are relevant for chimpanzees to assess the attentional state of others have produced highly inconsistent results. Some have suggested chimpanzees differentiate attention based on the status of the face or even the eyes, while others have indicated that body posture alone is the relevant cue. Kaminski et al. (Anim Cogn 7:216-223, 2004) compared the behaviour of chimpanzees, bonobos and orangutans while begging for food from a human experimenter who systematically varied his face and body orientation. Their results indicated that both factors, face and body orientation, affect apes' begging behaviour. The authors claimed that while body orientation provides information about the experimenter's general disposition to offer food, the visibility of the face provides information about the human's attentional state. In the current study, we tested this hypothesis with all four great apes species. However, unlike Kaminski et al. (Anim Cogn 7:216-223, 2004), the experimenter was able to hand over food regardless of body orientation. The results show that as soon as the offering of the food was no longer restricted, the orientation of the face became the key factor. Therefore, we present the first evidence that all great ape species are able to assess the attentional state of a recipient based on the orientation of the face. PMID- 21258953 TI - Recurrent brain abscess induced by pulmonary arteriovenous fistula. AB - Brain abscess associated with an arteriovenous fistula (AVF) is sometimes difficult to diagnose and tends to recur. We report a case of recurrent brain abscess due to a pulmonary AVF (PAVF). A 69-year-old woman with a mass in the left cerebral peduncle had taken a progressively worse and shown decorticate rigidity. After an intravenous antibiotic for fever of unknown origin was changed, her condition gradually improved. She was discharged with the help of a cane. Thirty-one months later, she suffered left hemiparesis. Magnetic resonance imaging revealed a cystic mass in the right lateral frontal lobe. At surgery, we confirmed pus in the cyst. A PAVF was detected and was treated with coil embolization. The left hemiparesis improved and the postoperative course was uneventful. Exhaustive study is absolutely necessary to detect the etiology of recurrent brain abscess and to achieve a cure. PMID- 21258954 TI - Anisakis simplex-induced anaphylaxis. AB - In recent years, Anisakis simplex has been shown to be an important etiologic agent responsible for food allergy and for gastrointestinal anisakiasis. We report a 61-year-old woman presenting with generalized urticaria and subsequent anaphylaxis after ingestion of raw mackerel. She rapidly recovered with administration of epinephrine and endoscopic extraction of an A. simplex larva. Serologic testing revealed specific IgE antibody to A. simplex was positive whereas that to mackerel was negative. She was diagnosed as IgE-mediated hypersensitivity to A. simplex. Patients diagnosed as fish-related or idiopathic allergy should be examined for evidence of Anisakis-induced allergy. PMID- 21258955 TI - Ampicillin/sulbactam for children hospitalized with community-acquired pneumonia. AB - Childhood community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide, but studies on the treatment of children hospitalized with CAP are limited. Although ampicillin/sulbactam is frequently used to treat the pediatric population there are very limited data about the effect of the parenteral form for childhood CAP. Hence, a retrospective study was conducted to assess clinical response to empirical parenteral ampicillin/sulbactam among children hospitalized with CAP. A total of 501 children with presumed bacterial etiology and treated with intravenous ampicillin/sulbactam were included in the study. Treatment was defined as failure if the initial ampicillin/sulbactam therapy was changed because of no clinical improvement 72 h or more after its use or clinical worsening at any time. Thirty-one (6.2%) children needed treatment change whereas 470 (93.8%) were treated successfully with ampicillin/sulbactam. In multivariate analysis, male gender [OR (95%CI): 3.32 (1.37-8.04), p = 0.008], CRP levels [OR (95%CI) 1.04 (1.01-1.08), p = 0.024], and existence of pleural effusion [OR (95%CI) 5.74 (2.17-15.15), p = 0.0001] were found to be significantly associated with treatment failure for the whole study group. For the subgroup of children between 3 and 60 months of age; respiratory rate [OR (95%CI) 1.06 (1.02-1.10), p = 0.0006] was also found to be an additional risk factor. In conclusion, this is the largest study showing that empiric parenteral ampicillin/sulbactam is effective, safe, and well tolerated for treatment of children hospitalized with CAP. However, pleural effusion was found to be the main factor associated with treatment failure. PMID- 21258956 TI - The genetic structure of Quercus crispula in northeastern Japan as revealed by nuclear simple sequence repeat loci. AB - Previous studies have reached different discussions about the genetic variation and genetic structure of Quercus crispula populations in northeastern Japan. This is a common oak species in Eastern Asia. Some studies have suggested that the populations in northeastern Japan were derived from those remaining in the southwest after the last glacial maximum (LGM), whilst other studies have found evidence that populations persisted in northeastern Japan during the LGM. Using seven highly polymorphic nuclear simple sequence repeat loci, we investigated the genetic structure of 16 Q. crispula populations along a latitudinal gradient in northeastern Japan (northern Honshu and Hokkaido), spanning about half of the species' biogeographic range in the country. Although the level of population differentiation was low (F (ST) = 0.021; [Formula: see text] = 0.090), two geographically differentiated clusters were detected by STRUCTURE analysis. The first cluster included most of the populations in Hokkaido, and may indicate continued survival throughout past glacial periods. We found a significant decrease in allelic richness with latitude, so the second cluster may represent an expansion of the lineage from Honshu during the post-glacial period. These results should enhance our understanding of historical north-south migrations of this species in northeastern Japan. PMID- 21258957 TI - Molecular technologies to improve the effectiveness of the sterile insect technique. AB - The application of the Sterile Insect Technique (SIT) in area-wide integrated pest management (AW-IPM) programmes continues to increase. However, programme efficiency can still be considerably enhanced when certain components of the technology are improved, such as the development of improved strains for mass rearing and release. These include strains that (1) produce only male insects for sterilization and release and (2) carry easily identifiable markers to identify released sterile insects in the field. Using both classical and modern biotechnology techniques, key insect pests are targeted, where SIT programmes are being implemented. The pests include mosquitoes, the Mexican fruit fly, the codling moth, the oriental fruit fly and the pink bollworm. This special issue summarizes the results of research efforts aimed at the development and evaluation of new strains to a level where a decision can be made as to their suitability for use in large scale SIT programmes. Major beneficiaries will be operational AW-IPM programmes that apply the SIT against major insect pests. PMID- 21258958 TI - Contribution of saccadic motion to intravitreal drug transport: theoretical analysis. AB - PURPOSE: The vitreous humor liquefies with age and readily sloshes during eye motion. The objective was to develop a computational model to determine the effect of sloshing on intravitreal drug transport for transscleral and intra vitreal drug sources at various locations METHODS: A finite element model based on a telescopic implicit envelope tracking scheme was developed to model drug dispersion. Flow velocities due to saccadic oscillations were solved for and were used to simulate drug dispersion. RESULTS: Saccades induced a three-dimensional flow field that indicates intense drug dispersion in the vitreous. Model results showed that the time scale for transport decreased for the sloshing vitreous when compared to static vitreous. Macular concentrations for the sloshing vitreous were found be much higher than that for the static vitreous. For low viscosities the position of the intravitreal source did not have a big impact on drug distribution. CONCLUSION: Model results show that care should be taken when extrapolating animal data, which are mostly done on intact vitreous, to old patients whose vitreous might be a liquid. The decrease in drug transport time scales and changes in localized concentrations should be considered when deciding on treatment modalities and dosing strategies. PMID- 21258959 TI - Alcohol consumption after the recognition of pregnancy and correlated factors among indigenous pregnant women in Taiwan. AB - To examine the rates and factors associated with alcohol consumption after the recognition of pregnancy among indigenous pregnant women, as well as the rates and factors associated with continuing alcohol consumption after the recognition of pregnancy among indigenous pregnant women who drank alcohol before the recognition of pregnancy in 10 hospitals in southern and eastern Taiwan. A total of 806 indigenous women who had just given birth in 10 hospitals in southern and eastern Taiwan were recruited. They were interviewed to collect their substance use information, demographic characteristics, psychological health status, history of physical abuse, and pregnancy history. The rates of alcohol consumption after the recognition of pregnancy in all indigenous pregnant women and the rates of continuing alcohol consumption after the recognition of pregnancy among those who drank alcohol before the recognition of pregnancy were calculated. The factors relating to alcohol consumption and continuing alcohol consumption after the recognition of pregnancy were examined using logistic regression analyses. The results of this study found that 26.6% of indigenous pregnant women drank alcohol at any stage after the recognition of pregnancy, and 52.5% of indigenous pregnant women who drank alcohol before the recognition of pregnancy persisted in drinking alcohol after the recognition of pregnancy. Multiple parities, smoking or chewing betel quid after the recognition of pregnancy, and a higher frequency of drinking alcohol before the recognition of pregnancy were significantly associated with alcohol consumption and continuing alcohol consumption after the recognition of pregnancy. Meanwhile, being single or divorced, and intimate partner violence after the recognition of pregnancy were significantly associated with alcohol consumption after the recognition of pregnancy. High prevalence rates of alcohol consumption and continuing alcohol consumption after the recognition of pregnancy were found among indigenous pregnant women in Taiwan. Early detection of alcohol consumption and effective intervention for alcohol consumption during pregnancy are needed. PMID- 21258960 TI - Content analysis of motivational counseling calls targeting obesity-related behaviors among postpartum women. AB - Our objective was to examine mothers' perspectives of obesity-related health behavior recommendations for themselves and their 0-6 month old infants. A health educator conducted 4 motivational counseling calls with 60 mothers of infants during the first 6 months postpartum. Calls addressed 5 behaviors for infants (breastfeeding, introduction of solid foods, sleep, TV, hunger cues), and 4 for mothers (eating, physical activity, sleep, TV). We recorded detailed notes from each call, capturing responsiveness to recommendations and barriers to change. Two independent coders analyzed the notes to identify themes. Mothers in our study were more interested in focusing on their infants' health behaviors than on their own. While most were receptive to eliminating their infants' TV exposure, they resisted limiting TV for themselves. There was some resistance to following infant feeding guidelines, and contrary to advice to avoid nursing or rocking babies to sleep, mothers commonly relied on these techniques. Return to work emerged as a barrier to breastfeeding, yet facilitated healthier eating, increased activity, and reduced TV time for mothers. The early postpartum period is a challenging time for mothers to focus on their own health behaviors, but returning to work appears to offer an opportunity for positive changes in this regard. To improve weight-related infant behaviors, interventions should consider mothers' perceptions of nutrition and physical activity recommendations and barriers to adherence. PMID- 21258961 TI - Providing general and preconception health care to low income women in family planning settings: perception of providers and clients. AB - This study examines both provider and client perceptions of the extent to which general health concerns are addressed in the context of publicly supported family planning care. A mail survey of family planning providers (n = 459) accepting Medicaid-covered clients in Arkansas and Alabama gathered data on reported actions and resource referral availability for ten categories of non contraceptive health concerns. A telephone survey of recent family planning clients of these providers (n = 1991) gathered data on the presence of 16 health concerns and whether and how they were addressed by the family planning provider. Data were collected in 2006-2007. More than half (56%) of clients reported having one or more general health concerns. While 43% of those concerns had been discussed with the family planning providers, only 8% had been originally identified by these providers. Women with higher trust in physicians and usual sources of general health care were more likely to discuss their concerns. Of those concerns discussed, 39% were reportedly treated by the family planning provider. Similarly, over half of responding providers reported providing treatment for acute and chronic health conditions and counseling on health behaviors during family planning visits. Lack of familiarity with referral resources for uninsured clients was identified as a significant concern in the provision of care to these clients. Greater engagement by providers in identifying client health concerns and better integration of publicly supported family planning with other sources of health care for low income women could expand the existing potential for delivering preconception or general health care in these settings. PMID- 21258962 TI - Pre-pregnancy body mass index and weight gain during pregnancy: relations with gestational diabetes and hypertension, and birth outcomes. AB - To study the relationship between pre-pregnancy body mass index (BMI) and weight gain during pregnancy with pregnancy and birth outcomes, with a focus on gestational diabetes and hypertension and their role in the association with fetal growth. We studied 1,884 mothers and offspring from the Eden mother-child cohort. Weight before pregnancy (W1) and weight after delivery (W2) were collected and we calculated BMI and net gestational weight gain (netGWG = (W2 - W1)/(weeks of gestation)). Gestational diabetes, hypertension gestational age and birth weight were collected. We used multivariate linear or logistic models to study the association between BMI, netGWG and pregnancy and birth outcomes, adjusting for center, maternal age and height, parity and average number of cigarettes smoked per day during pregnancy. High BMI was more strongly related to the risk of giving birth to a large-for-gestational-age (LGA) baby than high netGWG (odds ratio OR [95% CI] of 3.23 [1.86-5.60] and 1.61 [0.91-2.85], respectively). However, after excluding mothers with gestational diabetes or hypertension the ORs for LGA, respectively weakened (OR 2.57 [1.29-5.13]) for obese women and strengthened for high netGWG (OR 2.08 [1.14-3.80]). Low in comparison to normal netGWG had an OR of 2.18 [1.20-3.99] for pre-term birth, which became stronger after accounting for blood pressure and glucose disorders (OR 2.70 [1.37-5.34]). Higher net gestational weight gain was significantly associated with an increased risk of LGA only after accounting for blood pressure and glucose disorders. High gestational weight gain should not be neglected in regard to risk of LGA in women without apparent risk factors. PMID- 21258963 TI - Smoking in pregnancy in West Virginia: does cessation/reduction improve perinatal outcomes? AB - To determine if pregnant women decreasing/quitting tobacco use will have improved fetal outcomes. Retrospective analysis of pregnant smokers from 6/1/2006 12/31/2007 who received prenatal care and delivered at a tertiary medical care center in West Virginia. Variables analyzed included birth certificate data linked to intervention program survey data. Patients were divided into four study groups: <8 cigarettes/day-no reduction, <8 cigarettes/day-reduction, >=8 cigarettes/day-no reduction, and >=8 cigarettes/day-reduction. Analysis performed using ANOVA one-way test for continuous variables and Chi-square for categorical variables. Inclusion criteria met by 250 patients. Twelve women (4.8%) quit smoking; 150 (60%) reduced; 27 (10.8%) increased; and 61 (24.4%) had no change. Comparing the four study groups for pre-term births (<37 weeks), 25% percent occurred in >=8 no reduction group while 10% occurred in >=8 with reduction group (P = 0.026). The high rate of preterm birth (25%) in the non-reducing group depended on 2 factors: (1) >=8 cigarettes/day at beginning and (2) no reduction by the end of prenatal care. Finally, there was a statistically significant difference in birth weights between the two groups: >=8 cigarettes/day with no reduction (2,872.6 g) versus <8 cigarettes/day with reduction (3,212.4 g) (P = 0.028). Smoking reduction/cessation lowered risk of pre-term delivery (<37 weeks) twofold. Encouraging patients who smoke >=8 cigarettes/day during pregnancy to decrease/quit prior to delivery provides significant clinical benefit by decreasing the likelihood of preterm birth. These findings support tobacco cessation efforts as a means to improve birth outcome. PMID- 21258964 TI - AMP-activated protein kinase inhibits homocysteine-induced dysfunction and apoptosis in endothelial progenitor cells. AB - PURPOSE: Homocysteine (Hcy) has been shown to induce oxidative stress and apoptosis of endothelial progenitor cells (EPCs). AMP-activated protein kinase (AMPK) has been reported to have protective effects on endothelial function. However, effects of AMPK activation on Hcy-induced EPCs injury remain to be determined. In this study, we examined the effect of AMPK phosphorylation on Hcy induced NO bioavailability impairment and NADPH oxidase 4 (Nox4) derived reactive oxygen species (ROS) accumulation in EPCs. MATERIALS AND METHODS: EPCs were pre treated with various concentrations of 5-amino-4-imidazolecarboxamide riboside-l beta-D-ribofuranoside (AICAR), a pharmacological agonist of AMPK, and then incubated with Hcy for 24 h. Furthermore, we challenged EPCs with Hcy in the presence or absence of atorvastatin and AMPK-DN which expressed a dominant negative mutant of AMPK. Migration, proliferation and apoptosis were assayed to evaluate EPCs function. NO production, expression of endothelial nitric oxide synthase (eNOS), intracellular ROS levels and Nox4 activation were determined to explore the potential mechanisms of Hcy-induced EPCs dysfunction. RESULTS: We observed that AICAR attenuated the inhibition effects of Hcy on EPCs migration and proliferation. The apoptosis rates of EPCs were down-regulated by AICAR compared with the group treated with Hcy only [(0.25 mmol/L AICAR: 10.48 +/- 1.6%; 0.5 mmol/L AICAR: 8.70 +/- 1.0%; 1 mmol/L AICAR: 5.83 +/- 1.3%) vs. (500 MUmol/L Hcy only: 12.60 +/- 1.9%)]. We also found that NO production and eNOS expression were up-regulated by AICAR compared with the group treated with Hcy only, while ROS accumulation and Nox4 activation were inhibited. Furthermore, atorvastatin suppressed Hcy-induced dysfunction of EPCs, increased NO production and eNOS expression, and down-regulated ROS accumulation and Nox4 activation. And these effects of atorvastatin could be blunted by AMPK-DN. CONCLUSION: AMPK activation inhibits eNOS down-regulation and Nox4-derived ROS accumulation induced by Hcy in EPCs, and may contribute to the protective effects of atorvastatin on endothelial function. PMID- 21258965 TI - Biochemical, environmental, and genetic factors associated with paraoxonase (PON1) activity. PMID- 21258966 TI - Prebiotic potential and gastrointestinal effects of immature wheat grain (IWG) biscuits. AB - In this study the effects of immature wheat grains (IWG), a natural source of fructo-oligosaccharides (FOS), on intestinal microbiota and gastrointestinal function were evaluated. Ileal effluents from three ileostomates were collected for 8 h after IWG-enriched or Control biscuit administration, and then fermented in vitro with human faecal inoculum. On fermentation broths, microbial counts and SCFA were measured. Moreover, we investigated the effect of IWG biscuits on gastric emptying. Twelve healthy volunteers underwent ultrasound measurement of gastric emptying of a standard meal consumed 5 h after a breakfast composed by lactose-free milk and IWG or Control biscuits; hunger and satiety sensations were also evaluated in this period. Bifidobacteria and lactic acid bacteria counts were higher (P < 0.05) in IWG than in Control cultures, supporting the prebiotic effects of IWG, probably linked to its FOS content; moreover IWG fermentation produced more acetate. In vivo IWG biscuits delayed gastric emptying of the next meal (P < 0.05), decreased hunger (P < 0.001) and increased satiety (P < 0.005). Therefore in vitro results substantiate the potential of IWG as a prebiotic ingredient and in vivo data suggest an effect of IWG on gastric emptying and on persistent satiety. These preliminary data tend to support the use of IWG in formulating functional prebiotic products suitable to promote satiety. PMID- 21258967 TI - Interleukin-2 -330T>G genetic polymorphism associates with prognosis following surgery for thoracic esophageal squamous cell cancer. AB - BACKGROUND: Key molecules in the T helper (Th)1 and Th2 pathways underlie differential responses to the progression and surgical treatment of cancer. We investigated the relationship between Th1/Th2 cytokine polymorphism and prognosis in patients with thoracic esophageal squamous cell cancer. MATERIALS AND METHODS: The study participants were 159 Japanese patients treated for thoracic esophageal squamous cell cancer with curative esophagectomy at Akita University Hospital. We determined the associations between prognosis following esophagectomy and genetic polymorphisms in Th1 cytokines (interleukin [IL]-2, Interferon-gamma, IL-12beta), and Th2 cytokines (IL-4, IL-10). RESULTS: IL-2 -330T>G genetic polymorphism was significantly associated with prognosis after esophagectomy. Univariate and multivariate analyses using a Cox proportional hazards model revealed that patients carrying the IL-2 -330G/G genotype had a significantly poorer prognosis than those carrying the T/G or T/T genotype. However, IL-2 -330T>G polymorphism was not associated with preoperative serum IL-2 levels. Moreover, interferon gamma, IL-12beta, IL-4, and IL-10 genetic polymorphisms were not associated with prognosis after esophagectomy for thoracic esophageal squamous cell cancer. CONCLUSIONS: It is suggested that IL-2 -330T>G genetic polymorphism may be a predictive factor for prognosis in patients receiving esophagectomy for thoracic esophageal squamous cell cancer. PMID- 21258968 TI - A systematic review and meta-analysis of intralesional versus wide resection for intramedullary grade I chondrosarcoma of the extremities. AB - BACKGROUND: The surgical management of grade I intramedullary chondrosarcoma of bone remains controversial. The purpose of this study was to perform a systematic review and meta-analysis of published data to determine the oncologic outcomes of intralesional versus wide resection for grade I intramedullary chondrosarcoma. METHODS: Literature searches were performed through Medline, EMBASE, and the Cochrane Database. Cohort studies in which one patient group with grade I chondrosarcoma underwent wide resection and one underwent intralesional curettage were included. Two reviewers independently assessed all eligible papers with the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies. The outcome measures were the pooled odds ratio and 95% confidence intervals for the risk of local recurrence and metastasis calculated through the random-effects method. RESULTS: Five eligible studies were identified including a total of 190 patients, 78 of whom underwent intralesional resection and 112 of whom underwent wide resection. Only one pelvic lesion was identified, which underwent wide resection. There were a total of five local recurrences and three metastases. The risk for local recurrence and metastasis did not differ significantly between the two groups, with an odds ratio for intralesional resection of 2.26 (95% confidence interval, 0.41-12.62) and 0.44 (95% confidence interval, 0.04-5.21) respectively. CONCLUSIONS: Intralesional curettage as an alternative to wide resection for extrapelvic grade I chondrosarcoma of bone does not greatly increase the risk for local recurrence or metastasis. Overall effect estimates, however, should be interpreted with caution as a result of the relatively small number of events. PMID- 21258969 TI - Oscillations in biochemical reaction networks arising from pairs of subnetworks. AB - Biochemical reaction models show a variety of dynamical behaviors, such as stable steady states, multistability, and oscillations. Biochemical reaction networks with generalized mass action kinetics are represented as directed bipartite graphs with nodes for species and reactions. The bipartite graph of a biochemical reaction network usually contains at least one cycle, i.e., a sequence of nodes and directed edges which starts and ends at the same species node. Cycles can be positive or negative, and it has been shown that oscillations can arise as a result of either a positive cycle or a negative cycle. In earlier work it was shown that oscillations associated with a positive cycle can arise from subnetworks with an odd number of positive cycles. In this article we formulate a similar graph-theoretic condition, which generalizes the negative cycle condition for oscillations. This new graph-theoretic condition for oscillations involves pairs of subnetworks with an even number of positive cycles. An example of a calcium reaction network with generalized mass action kinetics is discussed in detail. PMID- 21258970 TI - Zinc and copper levels in severe heart failure and the effects of atrial fibrillation on the zinc and copper status. AB - Oxidative stress is involved in the pathogenesis of congestive heart failure (CHF). Some trace elements serve as antioxidant defenses. The purpose of this study was to analyze the effect of atrial fibrillation (AF) on zinc (Zn) and copper (Cu) levels in patients with advanced CHF. In this prospective study, serum Zn and Cu levels in 78 patients with clinically advanced CHF, i.e., New York Heart Association (NYHA) functional class III or IV (40 patients with AF and 38 in sinus rhythm) were measured using atomic absorption spectrophotometry. All patients also had a left ventricular ejection fraction (EF) of <35%. We recruited 40 volunteers with nearly the same age and weight as control. They had normal EF. There was no significant difference between patients with AF and those with sinus rhythm regarding serum Zn and Cu levels. However, both groups showed significant hypozincemia (p < 0.000) and a decreased Zn/Cu ratio (p < 0.03) compared with control group. Serum Cu levels were similar in the two groups and did not differ significantly from the control group. In patients with advanced CHF, irrespective of the rhythm, profound hypozincemia, and a decreased Zn/Cu ratio were present, which could be secondary to the activation of the renin-angiotensin-aldosterone system and CHF medications. The results suggest the need for more studies focusing on possible benefits with Zn nutriceutical replacement in patients with advanced CHF. PMID- 21258971 TI - Nucleophosmin delocalization in thyroid tumour cells. AB - Nucleophosmin (NPM) is a multifunctional nucleolar protein that, depending on the context, can act as oncogene or tumour suppressor. Mutations of the NPM1 gene induce delocalization of NPM in acute myeloid leukaemia. Differently, in solid tumours, only NPM overexpression, but not delocalization, has been so far reported. Here, NPM localization in thyroid tumours was investigated. By using immunohistochemistry, we show increase of NPM cytoplasmic localization in follicular adenomas and papillary carcinomas compared to normal thyroid tissue (p = 0.0125 and <0.0001, respectively). NPM1 mutations commonly found in human leukaemia are not present in thyroid tumours. Immunofluorescence in cultured cell lines was utilized to discriminate between nucleolar and nuclear localization. We show that in thyroid cancer cell lines NPM localizes both in the nucleolus and in nucleus, while in non-tumorigenic thyroid cell lines localizes only in nucleolus. Either presence of the histone deacetylase inhibitor trichostatin A or absence of thyroid-stimulating hormone induces NPM nuclear localization in non-tumorigenic thyroid cell lines. PMID- 21258972 TI - Complications of endoscopic and radiologic investigation of biliary tract disorders. AB - The investigation and treatment of disorders of the human biliary tree depend considerably on invasive endoscopic and radiologic procedures. These are associated with a significant risk of complications, some of which can be fatal. This review looks at these complications through the lens of 40 years of publications in the medical literature, and identifies the strengths and weaknesses of their current classification, diagnosis, and treatment. PMID- 21258974 TI - Combined use of an Airtraq(r) optical laryngoscope, Airtraq video camera, Airtraq wireless monitor, and a fibreoptic bronchoscope after failed tracheal intubation. PMID- 21258973 TI - New developments in pancreatic cancer. AB - Pancreatic adenocarcinoma presents in an advanced stage and has a dismal prognosis. Extensive recent research efforts have provided us with greater insight into the etiology of pancreatic cancer and have also improved our means of prognostication. Molecular analysis demonstrated that specific pathways involved in pancreatic carcinogenesis are perhaps more valuable to study than single genetic aberrations. Previous risk factors, including family history, body mass index, and current cigarette smoking, were validated and novel risks, such as ABO blood group alleles, were identified. Similar to other illnesses, combinations of healthful habits, such as not smoking, adhering to a Mediterranean dietary pattern, and engaging in physical activity, may decrease pancreatic cancer risk. Finally, CA 19-9 levels, the presence of diabetes mellitus, and a six-gene signature provided critical information regarding survival that could help guide treatment of individuals diagnosed with pancreatic adenocarcinoma. PMID- 21258975 TI - Dynamic hyperinflation and cardiac arrest during one-lung ventilation: a case report. AB - PURPOSE: Dynamic hyperinflation describes the phenomenon of progressive gas trapping that occurs in patients with severe airflow obstruction. It is associated with significant hemodynamic instability and may precipitate cardiac arrest. This report describes a case of hemodynamic collapse secondary to dynamic hyperinflation in a patient during one-lung ventilation. CLINICAL FEATURES: A 50 yr-old male with a pneumothorax secondary to a ruptured bulla was transferred to the operating room for a left bullectomy. Approximately 30 minutes after initiation of one-lung ventilation in the right lateral decubitus position, sudden ST segment elevation and hypotension occurred, which was refractory to large doses of vasopressor. This culminated in a pulseless electrical activity arrest. The patient was immediately placed supine, disconnected from the ventilator circuit, and resuscitated with chest compressions, fluids, and epinephrine. Auscultation of the right chest revealed no air entry, and needle decompression followed by chest tube insertion in the right chest did not demonstrate any evidence of a pneumothorax. Approximately three to five minutes after the onset of the arrest, the patient's hemodynamics stabilized and there was no evidence of ST elevation. The etiology of the arrest was likely due to dynamic hyperinflation. CONCLUSION: This report highlights the importance of having a high index of suspicion for dynamic hyperinflation and the key to its treatment: disconnection from the ventilator circuit and cessation of mechanical ventilation to allow the lungs to return to functional residual capacity. PMID- 21258976 TI - Perioperative glucose control: living in uncertain times--Continuing Professional Development. AB - PURPOSE: Hyperglycemia occurs frequently in surgical patients. The objective of this Continuing Professional Development (CPD) module is to review glucose physiology and pathophysiology and provide an update on the practical management of perioperative glucose based on recently published randomized controlled trials (RCTs). PRINCIPAL FINDINGS: In the mid 2000s, several professional medical organizations recommended the implementation of strict glucose control (glucose concentrations 4.4 to 6.1 mmol.L(-1)). However, the publication of new randomized controlled trials has dampened the initial enthusiasm. While the optimal glucose target range remains a matter of debate, hyperglycemia has been associated with increased morbidity and mortality in a variety of clinical settings. However, strict glucose control is associated with a sixfold increase in episodes of severe hypoglycemia (glucose levels < 2.2 mmol.L(-1)), which has also been linked with increased mortality. For critically ill patients, the American Diabetes Association and the American Association of Clinical Endocrinologists recommend aiming for a blood glucose level from 7.8 to 10.0 mmol.L(-1). While no specific target range can be recommended as yet during major surgery, glucose levels should be kept < 10.0 mmol.L(-1). In critically ill patients, glucose measured from capillary blood may give a falsely elevated value, so arterial blood sampling is preferred when measuring glucose. Frequent arterial blood glucose determination using an arterial blood gas analyzer or an International Organization for Standardization (ISO) 15197-compliant glucometer is crucial to avoid and detect deleterious hypoglycemic episodes. CONCLUSIONS: Although there is agreement that both hyperglycemia and hypoglycemia are deleterious, there is no consensus on the target glucose values to enhance clinical outcomes. PMID- 21258997 TI - Quantitative trait loci analysis for resistance to Cephalosporium stripe, a vascular wilt disease of wheat. AB - Cephalosporium stripe, caused by Cephalosporium gramineum, can cause severe loss of wheat (Triticum aestivum L.) yield and grain quality and can be an important factor limiting adoption of conservation tillage practices. Selecting for resistance to Cephalosporium stripe is problematic; however, as optimum conditions for disease do not occur annually under natural conditions, inoculum levels can be spatially heterogeneous, and little is known about the inheritance of resistance. A population of 268 recombinant inbred lines (RILs) derived from a cross between two wheat cultivars was characterized using field screening and molecular markers to investigate the inheritance of resistance to Cephalosporium stripe. Whiteheads (sterile heads caused by pathogen infection) were measured on each RIL in three field environments under artificially inoculated conditions. A linkage map for this population was created based on 204 SSR and DArT markers. A total of 36 linkage groups were resolved, representing portions of all chromosomes except for chromosome 1D, which lacked a sufficient number of polymorphic markers. Quantitative trait locus (QTL) analysis identified seven regions associated with resistance to Cephalosporium stripe, with approximately equal additive effects. Four QTL derived from the more susceptible parent (Brundage) and three came from the more resistant parent (Coda), but the cumulative, additive effect of QTL from Coda was greater than that of Brundage. Additivity of QTL effects was confirmed through regression analysis and demonstrates the advantage of accumulating multiple QTL alleles to achieve high levels of resistance. PMID- 21258998 TI - Identification of two blackleg resistance genes and fine mapping of one of these two genes in a Brassica napus canola cultivar 'Surpass 400'. AB - Blackleg resistant cultivars have been developed through conventional breeding methods and are successfully used globally to control this disease in canola production. To clone blackleg resistance genes and to understand the mechanism underlying the resistance, a blackleg resistant canola cultivar 'Surpass 400' was used to develop a gene mapping population. A previously reported high density genetic map was used to find a resistance gene region that corresponded to linkage group N10 in B. napus. Differential interactions between the resistant lines and a pathogen isolate were discovered with two resistance genes BLMR1 and BLMR2 identified through linkage analysis of five genome-specific molecular markers. BLMR1 provides resistance through the hypersensitive response that protects inoculated cotyledons from becoming infected, Unlike BLMR1, BLMR2 slows down the development of individual infection loci. BLMR1 and BLMR2 segregated independently in two large F(3)BC(2) populations. Fine mapping of BLMR1 was performed with 12 genome-specific molecular markers. The closest marker with a genetic distance of 0.13 cM to BLMR1 was identified, which lays a solid foundation for cloning BLMR1. PMID- 21258999 TI - Ten-year trends in benzodiazepine use in the Dutch population. AB - BACKGROUND: In the past decades knowledge on adequate treatment of affective disorders and awareness of the negative consequences of long-term benzodiazepine use increased. Therefore, a decrease in benzodiazepine use is expected, particularly in prolonged use. The aim of this study was to assess time trends in benzodiazepine use. METHODS AND MATERIAL: Data from the Longitudinal Aging Study Amsterdam (LASA) were used to investigate trends in benzodiazepine use between 1992 and 2002 in two population-based samples aged 55-64 years. Differences between the two samples with respect to benzodiazepine use and to sociodemographic, physical health and mental health characteristics were described and tested with chi-square tests and logistic regression analyses. RESULTS: Benzodiazepine use remained stable over 10 years, with 7.8% in LASA-1 (n = 874) and 7.9% in LASA-2 (n = 919) (p = 0.90) with a persisting preponderance in women and in people with low education, low income, chronic physical diseases, functional limitations, cognitive impairment, depression, anxiety complaints, sleep problems and when using antidepressants. Long-term use remained high with 70% in 1992 and 80% in 2002 of total benzodiazepine use. CONCLUSION: In the Dutch population aged 55-64, overall benzodiazepine use remained stable from 1992 to 2002, with a high proportion of long-term users, despite the effort to reduce benzodiazepine use and the renewal of the guidelines. More effort should be made to decrease prolonged benzodiazepine use in this middle-aged group, because of the increasing risks with ageing. PMID- 21259000 TI - Ethanol induces calcium influx via the Cch1-Mid1 transporter in Saccharomyces cerevisiae. AB - Yeast suffers from a variety of environmental stresses, such as osmotic pressure and ethanol produced during fermentation. Since calcium ions are protective for high concentrations of ethanol, we investigated whether Ca(2+) flux occurs in response to ethanol stress. We find that exposure of yeast to ethanol induces a rise in the cytoplasmic concentration of Ca(2+). The response is enhanced in cells shifted to high-osmotic media containing proline, galactose, sorbitol, or mannitol. Suspension of cells in proline and galactose-containing media increases the Ca(2+) levels in the cytoplasm independent of ethanol exposure. The enhanced ability for ethanol to induce Ca(2+) flux after the hypertonic shift is transient, decreasing rapidly over a period of seconds to minutes. There is partial recovery of the response after zymolyase treatment, suggesting that cell wall integrity affects the ethanol-induced Ca(2+) flux. Acetate inhibits the Ca(2+) accumulation elicited by the ethanol/osmotic stress. The Ca(2+) flux is primarily via the Cch1 Ca(2+) influx channel because strains carrying deletions of the cch1 and mid1 genes show greater than 90% reduction in Ca(2+) flux. Furthermore, a functional Cch1 channel reduced growth inhibition by ethanol. PMID- 21259001 TI - Oxidative stress-induced membrane shedding from RBCs is Ca flux-mediated and affects membrane lipid composition. AB - Phosphatidylserine (PS), which is normally localized in the cytoplasmic leaflet of the membrane, undergoes externalization during aging or trauma of red blood cells (RBCS: ). A fraction of this PS is shed into the extracellular milieu. Both PS externalization and shedding are modulated by the oxidative state of the cells. In the present study we investigated the effect of calcium (Ca) flux on oxidative stress-induced membrane distribution of PS and its shedding and on the membrane composition and functions. Normal human RBCs were treated with the oxidant t-butyl hydroperoxide, and thalassemic RBCs, which are under oxidative stress, were treated with the antioxidant vitamin C or N-acetylcystein. The intracellular Ca content was modulated by the Ca ionophore A23187 and by varying the Ca concentration in the medium. Ca flux was measured by Fluo-3, PS externalization and shedding were measured by quantitative flow cytometry and membrane composition was measured by (1)H-NMR analysis of the cholesterol and phospholipids. The results indicated that increasing the inward Ca flux induced PS externalization and shedding, which in turn increased the membrane cholesterol/phospholipid ratio and thereby increased the RBC osmotic resistance. In addition, these processes modulated the susceptibility of RBCs to undergo phagocytosis by macrophages; while PS externalization increased phagocytosis, the shed PS prevented it. These results indicate that PS redistribution and shedding from RBCs, which are mediated by increased calcium, have profound effects on the membrane composition and properties and, thus, may control the fate of RBCs under physiological and pathological conditions. PMID- 21259002 TI - The non-LTR retrotransposon R2 in termites (Insecta, Isoptera): characterization and dynamics. AB - The full-length element of the non-LTR retrotransposon R2 is here characterized in three European isopteran species: the more primitive Kalotermes flavicollis (Kalotermitidae), including two highly divergent mitochondrial lineages, and the more derived Reticulitermes lucifugus and R. urbis (Rhinotermitidae). Partial 3' sequences for R. grassei and R. balkanensis were also analyzed. The essential structural features of R2 elements are conserved in termites. Phylogenetic analysis revealed that termite elements belong to the same clade and that their phylogeny is fully compatible with the phylogeny of their host species. The study of the number and the frequency of R2 insertion variants in four R. urbis colonies suggests a greatly reduced, or completely absent, recent element activity. PMID- 21259003 TI - Early evolution of membrane lipids: how did the lipid divide occur? AB - The ubiquitous distribution, homology over three domains, and key role in the membrane formation of the enzymes of the CDP-alcohol phosphatidyltransferase family, as well as phylogenetic analyses of lipid synthesizing enzymes suggest that the membranes of Wachtershauser's hypothetical pre-cells (universal common ancestor) [Mol Microbiol 47:13-22 (2003)] comprised a lipid bilayer with four types of core lipids [G-1-P-isoprenoid ether (Ai), G-3-P-fatty acyl ester (Bf), G 1-P-fatty acyl ester (Af) and G-3-P-isoprenoid ether (Bi)]. Here, a complementary hypothesis is presented to explain the difference between archaeal and bacterial lipids (lipid divide). The main driving force of lipid segregation is assumed to be glycerophosphate (GP) enantiomers, as Wachtershauser proposed, but in the present study the hydrocarbon chains bound to each backbone are also hypothesized to affect lipid segregation. It is assumed that segregation was stimulated by different hydrocarbon chains bound to different GP backbones (Ai:Bf or Af:Bi). Because Ai and Bi are diastereomers and Af and Bf are enantiomers, Ai:Bf and Af:Bi are not equivalent. G-1-P-isoprenoid ether is provisionally assumed to segregate more easily from Bf than Bi does from Af. G-1-P-isoprenoid ether and Bf could more easily achieve the more stable homochiral membranes that are the ancestors of Archaea and Bacteria. This can explain why the extant archaeal and bacterial membrane lipids are mainly composed by Ai and Bf lipids, respectively. Because polar head groups were localized in the cytoplasmic compartment of pre cells, they were equally carried over to Archaea and Bacteria during differentiation. Consequently, the both descendants shared the main head groups of membrane phospholipids. PMID- 21259004 TI - An eight-week trial investigating the efficacy and tolerability of atorvastatin for children and adolescents with heterozygous familial hypercholesterolemia. AB - This study aimed to assess the efficacy and tolerability of atorvastatin in Tanner stage (TS) 1 patients ages 6 to 10 years and TS >= 2 patients ages 10 to <18 years with genetically confirmed heterozygous familial hypercholesterolemia (HeFH) and a low density lipoprotein cholesterol (LDL-C) level of 4 mmol/l (155 mg/dl) or higher. In this open-label, 8-week study, 15 TS 1 children were treated initially with atorvastatin 5 mg/day and 24 TS >= 2 children with 10 mg/day. Doses were doubled at week 4 if the LDL-C target (<3.35 mmol/l [130 mg/dl]) was not achieved. The efficacy variables were the percentage change from baseline in LDL-C, total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C), very low density lipoprotein cholesterol (VLDL-C), and apolipoprotein (Apo) A-I and Apo B. Safety evaluations included clinical monitoring, subject-reported adverse events (AEs), vital signs, and clinical laboratory tests. The mean values for LDL-C, TC, VLDL-C, and Apo B decreased by week 2 among all TS 1 and TS >= 2 patients, whereas TG, HDL-C, and Apo A-I varied considerably from week to week. After 8 weeks, the mean reduction in LDL-C was 40.7% +/- 8.4 for the TS 1 children and -39.7% +/- 10.3 for the TS >= 2 children. For the TS 1 patients, the mean reductions were -34.1% +/- 6.9 for TC and -6.0% +/- 32.1 for TG. The corresponding changes for the TS >= 2 patients were -35.6% +/- 9.5 for TC and -21.1% +/- 29.7 for TG. Four patients experienced mild to moderate treatment-related AEs. No serious AEs or discontinuations were reported. Overall, no difference in safety or tolerability was observed between the younger and older cohorts. Across the range of exposures after atorvastatin 5 to 10 mg (TS 1) or atorvastatin 10 to 20 mg (TS >= 2) doses for 8 weeks, clinically meaningful reductions in LDL-C, TC, VLDL-C, and Apo were observed with atorvastatin in pediatric patients who had HeFH. Atorvastatin also was well tolerated in this population. PMID- 21259005 TI - Phylogenetic analysis of methanogens in the pig feces. AB - In order to assess methanogen diversity in feces of pigs, archaeal 16S rRNA gene clone libraries were constructed from feces of the pig. After the amplification by PCR using primers Met86F and Met1340R, equal quantities of PCR products from each of the five pigs were mixed together and used to construct the library. Sequence analysis showed that the 74 clones were divided into ten phylotypes as defined by RFLP analysis. Phylogenetic analysis showed that three phylotypes were most closely affiliated with the genus Methanobrevibacter (46% of clones). The library comprised 55.4% unidentified euryarchaeal clones. Three phylotypes (LMG4, LMG6, LMG8) were not closely related to any known Euryarchaeota sequences. The phylogenetic analysis indicated that the archaea found in the libraries were all clustered into the Euryarchaeota. The data from the phylogenetic tree showed that those sequences belonged to three monophyletic groups. Phylotypes LGM2 and LGM7 grouped within the genus Methanobrevibacter. Phylotypes LGM4, LGM6, LGM8 and LGM9 grouped within the genus Methanosphaera. Other phylotypes grouped together, and formed a distantly related sister group to Aciduliprofundum boonei and species of the Thermoplasmatales including Thermoplasma volcanium and Thermoplasm acidophilum. Our results showed that methanogens belonging to the genus Methanobrevibacter were predominant in pig feces, and that many unique unknown archaea sequences were also found in the library. Nevertheless, whether these unique sequences represent new taxonomic groups and their role in the pig gut need further investigation. PMID- 21259006 TI - Dissipation of proton motive force is not sufficient to induce the phage shock protein response in Escherichia coli. AB - Phage shock proteins (Psp) and their homologues are found in species from the three domains of life: Bacteria, Archaea and Eukarya (e.g. higher plants). In enterobacteria, the Psp response helps to maintain the proton motive force (PMF) of the cell when the inner membrane integrity is impaired. The presumed ability of ArcB to sense redox changes in the cellular quinone pool and the strong decrease of psp induction in DeltaubiG or DeltaarcAB backgrounds suggest a link between the Psp response and the quinone pool. The authors now provide evidence indicating that the physiological signal for inducing psp by secretin-induced stress is neither the quinone redox state nor a drop in PMF. Neither the loss of the H(+)-gradient nor the dissipation of the electrical potential alone is sufficient to induce the Psp response. A set of electron transport mutants differing in their redox states due to the lack of a NADH dehydrogenase and a quinol oxidase, but retaining a normal PMF displayed low levels of psp induction inversely related to oxidised ubiquinone levels under microaerobic growth and independent of PMF. In contrast, cells displaying higher secretin induced psp expression showed increased levels of ubiquinone. Taken together, this study suggests that not a single but likely multiple signals are needed to be integrated to induce the Psp response. PMID- 21259007 TI - Polyarteritis nodosa and Henoch-Schonlein purpura nephritis in a child with familial Mediterranean fever: a case report. AB - Familial Mediterranean fever is an autosomal recessive disease characterized by recurrent self-limited attacks of fever accompanied by peritonitis, pleuritis, and arthritis. Approximately 5% of individuals with familial Mediterranean fever have been reported to have Henoch-Schonlein purpura and about 1% to have polyarteritis nodosa. A 7-year-old girl presenting with complaints of purpuric rash, abdominal pain, arthritis, hematuria, and proteinuria and having IgA depositions on renal biopsy was diagnosed as Henoch-Schonlein nephritis. She had a history of recurrent fever, abdominal and joint pain and M694 V compound homozygote mutation. Colchicine treatment was started for the diagnosis of FMF. When constitutional symptoms such as myalgia, weight loss, fatigue, fever, and hypertension were added to the clinical picture, the diagnosis of polyarteritis nodosa HSP was thought and confirmed by the demonstration of microaneurisms on renal arteries. There was no response to corticosteroid and cyclophosphamide treatments; however, the symptoms were rapidly and dramatically reduced after the administration of intravenous immunoglobulin. In conclusion, polyarteritis nodosa and Henoch-Schonlein purpura can be seen together with familial Mediterranean fever. It is also suggested that IVIG might be an important adjunct therapy in selected patients with polyarteritis nodosa, especially in the lack of response to steroids and immunsuppressive drugs. PMID- 21259008 TI - Imaging of Jaccoud's arthropathy in systemic lupus erythematosus: not only hands but also knees and feet. PMID- 21259009 TI - Clinical characteristics and electrodiagnostic features in patients with carpal tunnel syndrome, double crush syndrome, and cervical radiculopathy. AB - Similar unilateral neck and upper limb symptoms are often due to various entrapment neuropathies; carpal tunnel syndrome (CTS) and cervical radiculopathy (CR) are common causes among them. Therefore, we investigated the clinical characteristics and electrodiagnostic features of patients with carpal tunnel syndrome, cervical radiculopathy, and both conditions, called double crush syndrome (DCS). The medical records and electrodiagnostic reports of 866 patients with suspected CTS and CR visited a tertiary-care hospital were retrospectively analyzed. After excluding 101 patients with confounding conditions, 151 (20%) patients were diagnosed to have sole cases of CTS; 362 (47%) patients were diagnosed to have sole cases of CR; 198 (26%) patients were diagnosed to have DCS, while 54 (7%) patients had mere symptoms. Sole cases of CR had the highest incidences of neck pain, upper back pain, wrist and hand weakness. Female patients had the highest incidences of all the diseases in their sixth decade. Male patients had comparably distinguished high occurrence of all the diseases in their fifth to sixth decades. Although comparison of nerve conduction studies between patients with mere symptoms and patients with sole cases of CTS or DCS showed statistical differences, comparison between the latter two revealed no difference. We found most patients referred for electrodiagnostic studies had cervical radiculopathy. High concomitant occurrence of CTS and CR suggests cautious evaluation of patients with upper limb symptoms is important, because the management of these conditions is quite different. PMID- 21259010 TI - The expression of RANKL and OPG in the various grades of osteoarthritic cartilage. AB - The objective of the study was to determine whether cartilage expression of the bone regulating molecules receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) varies between the different grades of osteoarthritis (OA). Cartilage samples were obtained from 30 patients undergoing total hip/knee replacement surgery. Tissue sections were stained with Safranin O and graded. Immunohistochemical staining was then performed, and levels of RANKL and OPG expression were assessed using a semi-quantitative scoring system. In addition, levels of mRNA encoding for RANKL and OPG were determined by a relative real-time reverse transcription-polymerase chain reaction technique. We found that expression of RANKL protein, mRNA expression, and the ratio of RANKL: OPG mRNA was greater in grade 2 cartilage in comparison with grade 0 cartilage (P < 0.05). Increased RANKL staining in the grade 2 cartilage was predominantly in the peri-cellular region of the middle and deep zones as well as in the matrix of the superficial zone. OPG mRNA expression was greater in grade 3 cartilage in comparison with grade 0 cartilage (P < 0.05). Cartilage and subchondral bone are in close proximity and soluble proteins produced in the cartilage are likely to move from one compartment to the other. Our finding of increased expression of RANKL in grade 2 OA cartilage might explain the increase in bone turnover reported in the subchondral bone of OA patients. The changes seen in the different grades of tissue may also indicate that this effect occurs during the early stages of OA development. PMID- 21259011 TI - Neonatal functional intestinal obstruction and the presence of severely immature ganglion cells on rectal biopsy: 6 year experience. AB - PURPOSE: We report our experience of managing eight babies who presented with neonatal intestinal obstruction and whose rectal biopsies showed severely immature ganglion cells. METHODS: Neonatal unit records were reviewed to detect patients with suspected Hirschsprung's disease or functional intestinal obstruction. Those with intestinal atresia, anorectal malformation, malrotation, cystic fibrosis and prematurity were excluded. RESULTS: We identified 73 patients born at term. Twenty-seven did not need a rectal biopsy. Twenty-one had biopsy proven Hirschsprung's disease, while 17 had a normal rectal biopsy. Eight patients, all of whom presented with severe abdominal distension, showed immature ganglion cells. Seven had failed to pass meconium after birth. X-rays in all patients showed distended loops of bowel. Two neonates underwent an emergency laparotomy and a stoma. A repeat biopsy at 3 months showed maturation of ganglion cells and the stoma was reversed. Rectal biopsy was repeated in two other patients 2-9 months after the first biopsy and showed mature ganglion cells. At follow-up, one patient still suffers from severe constipation. Seven are asymptomatic now, including the two patients who needed a stoma. CONCLUSION: Immature ganglion cells on rectal biopsy may be an indicator of transient functional immaturity of the intestine. PMID- 21259012 TI - Does the length of the history influence the outcome of pneumatic reduction of intussusception in children? AB - PURPOSE: Intussusception is the most common cause of acute abdomen in infants and preschool children. Nonoperative reduction using air enema is an established treatment in children with intussusception. The aim of this study was to determine whether length of the history influences the outcome of pneumatic reduction of intussusception in children? METHODS: The medical records of 256 consecutive children with intussusception between July 1998 and June 2010, who underwent air enema reduction regardless of the length of the history were reviewed. In all 256 patients, intussusception was confirmed by ultrasound before proceeding to air enema. RESULTS: The length of history ranged from 2 to 240 h with median time of 18.5 h. The median age in 256 patients was 7 months (range 1 day to 12 years). The presenting clinical features included irritability/abdominal pain (77%), vomiting (80%), bleeding per rectum (36%) and palpable abdominal mass (50%). Air enema reduction was successful in 234 (91.5%) of the 256 patients. In 22 (8.5%) patients, air enema failed to reduce the intussusception and 3 (1.1%) of these patients had colonic perforation during the procedure. All 22 patients required surgery. The duration of symptoms did not influence the outcome of pneumatic reduction. 37 (14%) patients developed recurrence after successful pneumatic reduction of intussusception, with 58% presenting within 48 h of the initial procedure. CONCLUSION: Our data suggest that pneumatic reduction should be first-line treatment in all children with intussusception regardless of the length of the history. PMID- 21259013 TI - Fryns syndrome a presentation of two siblings with congenital diaphragmatic hernia. AB - INTRODUCTION: Congenital diaphragmatic hernia (CDH) is a congenital malformation that has a reported incidence ranging from 2.4 to 4.1 in 10,000 births. Despite advances in neonatal care, a mortality rate of 33% is still reported with isolated CDH, predominantly due to hypoxic respiratory failure secondary to pulmonary hypoplasia. Fryns syndrome is the most common autosomal recessive syndrome associated with CDH, reported in up to 10% of patients with CDH, comprising CDH, pulmonary hypoplasia, craniofacial abnormalities, distal limb hypoplasia and internal malformations. CASE PRESENTATION: We present two siblings with lethal CDH born within a 30 month period. The clinical course in these two infants is described and the possible mode of inheritance for CDH in this family is reviewed. CONCLUSION: In spite of lacking many advanced chromosomal evaluations in our institute we recommended for further investigation into isolated and particularly familial cases may lead to the identification of genetic abnormalities detectable with FISH assay, locus-specific DNA probes, or other new techniques. There remains an ongoing need for careful clinical review and blood banking of cases of CDH to allow better insight into the genetic causes of severe fetal anomalies such as CDH. PMID- 21259014 TI - Altered PITX2 and LEF1 gene expression in the cadmium-induced omphalocele in the chick model. AB - PURPOSE: Although, recent studies have suggested that disruption of somitogenesis may be involved in ventral body wall (VBW) defects; the molecular mechanisms of VBW defects remain unclear. In the chick embryo, the administration of cadmium (Cd) induces VBW defects similar to the human omphalocele. In this model, the earliest histological change in the somite occurs commencing at 4 h post-Cd treatment (4 h). PITX2 is expressed in somites, and PITX2 mutants have been shown to display VBW defects. PITX2 interacts with lymphoid enhancer factor-1 (LEF1) to regulate somite myogenesis. We designed this study to investigate the hypothesis that PITX2 and LEF1 genes are downregulated during the critical period of early embryogenesis in the Cd-induced omphalocele chick model. MATERIALS AND METHODS: Chick embryos were exposed to Cd or saline after 60 h incubation and harvested at 1, 4, and 8 h posttreatment. Chicks were then divided into two groups: control (n = 24), and Cd (n = 24). RT-PCR was performed and analyzed statistically (significant difference was accepted at p < 0.05). Immunohistochemistry was also performed to evaluate expression/distribution of those proteins. RESULTS: The mRNA expression levels of PITX2 and LEF1 at 4 h were significantly decreased in the Cd group compared with controls, whereas there were no differences at the other time points. Immunoreactivity of those proteins at 4 h was also markedly decreased in somites in the Cd-treated embryos compared with controls. CONCLUSIONS: Downregulation of PITX2 and LEF1 genes may interfere with ventral body wall formation in Cd chick model causing omphalocele by disrupting somite myogenesis. PMID- 21259015 TI - Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy. AB - The deposition of amyloid-beta (Abeta) peptides in the walls of leptomeningeal and cortical blood vessels as cerebral amyloid angiopathy (CAA) is present in normal ageing and the majority of Alzheimer's disease (AD) brains. The failure of clearance mechanisms to eliminate Abeta from the brain contributes to the development of sporadic CAA and AD. Here, we investigated the effects of CAA and ageing on the pattern of perivascular drainage of solutes in the brains of naive mice and in the Tg2576 mouse model of AD. We report that drainage of small molecular weight dextran along cerebrovascular basement membranes is impaired in the hippocampal capillaries and arteries of 22-month-old wild-type mice compared to 3- and 7-month-old animals, which was associated with age-dependent changes in capillary density. Age-related alterations in the levels of laminin, fibronectin and perlecan in vascular basement membranes were also noted in wild-type mice. Furthermore, dextran was observed in the walls of veins of Tg2576 mice in the presence of CAA, suggesting that deposition of Abeta in vessel walls disrupts the normal route of elimination of solutes from the brain parenchyma. These data support the hypothesis that perivascular solute drainage from the brain is altered both in the ageing brain and as a consequence of CAA. These findings have implications for the success of therapeutic strategies for the treatment of AD that rely upon the health of the ageing cerebral vasculature. PMID- 21259016 TI - Chorionic villus sampling and the risk of preeclampsia: a systematic review and meta-analysis. AB - OBJECTIVE: To perform systematic review and meta-analysis to evaluate the risk of preeclampsia after chorionic villus sampling (CVS). DATA SOURCES: A systematic search of PubMED and Web of Science from inception through August 2010, and bibliographies of review articles and eligible studies were performed. METHODS OF STUDY SELECTION: Six studies reported the risk of preeclampsia after CVS. All of the identified studies were retrospective and included in analysis. TABULATION, INTEGRATION, AND RESULTS: Reporting quality of the identified studies according to quality assessment scale for methodology in retrospective clinical reporting was moderate. Pooling was performed in two strata for control: (1) patients without any invasive prenatal diagnostic procedure served as control group: no significant difference was found in the odds ratio (OR) of preeclampsia (OR 0.79, 95% CI 0.38-1.64), severe preeclampsia (OR 0.49, 95% CI 0.04-5.78), gestational hypertension (OR 0.76, 95% CI 0.46-1.26), all pregnancy-induced hypertensive disorders (OR 0.80, 95% CI 0.46-1.41) between CVS and control groups. (2) Patients with amniocentesis combined with patients without any invasive prenatal diagnostic procedure served as control group: no significant difference was found in the OR of preeclampsia (OR 0.76, 95% CI 0.37-1.53), severe preeclampsia (OR 0.83, 95% CI 0.14-4.85), all pregnancy-induced hypertensive disorders (OR 0.92, 95% CI 0.55-1.53) between CVS and combined control groups. CONCLUSION: None of the included studies were randomized prospective trials designed to investigate the effect of CVS on preeclampsia. Accordingly, this review is limited by the heterogeneity, small number and retrospective nature of the available studies. CVS does not seem to increase the risk of preeclampsia or other pregnancy-induced hypertensive disorders. However, randomized prospective trials that are designed to investigate the risk of preeclampsia after CVS are needed to make a definite conclusion. PMID- 21259017 TI - Factor V Leiden and prothrombin G20210A in Portuguese women with recurrent miscarriage: is it worthwhile to investigate? AB - OBJECTIVE: To compare the prevalence of factor V Leiden (FVL) and prothrombin (PT) G20210A mutations in Portuguese women with unexplained recurrent miscarriage (RM) and a control group of parous women. MATERIALS AND METHODS: FVL and PT G20210A analysis were carried out in 100 women with three or more consecutive miscarriages and 100 controls with no history of pregnancy losses. Secondary analysis was made regarding gestational age at miscarriage (embryonic and fetal losses). RESULTS: Overall, the prevalence of FVL and PT G20210A was similar in women with RM (5 and 3%) compared with controls (5 and 1%) OR 1.36 (CI 95% 0.45 4.08). In RM embryonic subgroup, PT G20210A was observed in 1.3% of women and FVL prevalence (2.6%) was inclusively lesser than that of controls. Both polymorphisms were more prevalent in women with fetal losses than in controls, although statistical significance was not reached due to the small size of the >10 weeks' subgroup. CONCLUSION: These data indicate that neither FVL nor PT G20210A is associated with RM prior to 10 weeks of gestation. Therefore, its screening is not indicated as an initial approach in Portuguese women with embryonic RM and negative personal thromboembolic history. PMID- 21259018 TI - RETRACTED ARTICLE: reproductive toxicity and pathomorphological changes in rats after chronic oral exposure to low-dose depleted uranium. PMID- 21259019 TI - Radiation-induced cell cycle arrests in Ehrlich ascites carcinoma cells in vivo. AB - Radiation-induced progression delay in G(1)/S, S and G(2)/M phases of p53 wild type Ehrlich ascites carcinoma (EAC) cells growing in vivo was investigated by DNA flow cytometry. Different behavior patterns of EAC cells at the time after irradiation with low (2, 4, 6, 8 Gy) and high (10, 15, 20 Gy) doses were evaluated. While EAC cells showed a small progression delay in S phase and a dose dependent block in G(2)/M phase after the irradiation with low doses, a clear additional block in G(1)/S phase was observed after irradiation with high doses. An assessment of the damage response and repair networks at the time after irradiation might have important implication for the development of cancer management and treatment. PMID- 21259020 TI - Dose rate effect on micronuclei induction in human blood lymphocytes exposed to single pulse and multiple pulses of electrons. AB - The effects of single pulses and multiple pulses of 7 MV electrons on micronuclei (MN) induction in cytokinesis-blocked human peripheral blood lymphocytes (PBLs) were investigated over a wide range of dose rates per pulse (instantaneous dose rate). PBLs were exposed to graded doses of 2, 3, 4, 6, and 8 Gy of single electron pulses of varying pulse widths at different dose rates per pulse, ranging from 1 * 10(6) Gy s(-1) to 3.2 * 10(8) Gy s(-1). Different dose rates per pulse were achieved by changing the dose per electron pulse by adjusting the beam current and pulse width. MN yields per unit absorbed dose after irradiation with single electron pulses were compared with those of multiple pulses of electrons. A significant decrease in the MN yield with increasing dose rates per pulse was observed, when dose was delivered by a single electron pulse. However, no reduction in the MN yield was observed when dose was delivered by multiple pulses of electrons. The decrease in the yield at high dose rates per pulse suggests possible radical recombination, which leads to decreased biological damage. Cellular response to the presence of very large numbers of chromosomal breaks may also alter the damage. PMID- 21259022 TI - Modeling hematopoietic system response caused by chronic exposure to ionizing radiation. AB - A new model of the hematopoietic system response in humans chronically exposed to ionizing radiation describes the dynamics of the hematopoietic stem cell compartment as well as the dynamics of each of the four blood cell types (lymphocytes, neutrophiles, erythrocytes, and platelets). The required model parameters were estimated based on available results of human and experimental animal studies. They include the steady-state number of hematopoietic stem cells and peripheral blood cell lines in an unexposed organism, amplification parameters for each blood line, parameters describing proliferation and apoptosis, parameters of feedback functions regulating the steady-state numbers, and characteristics of radiosensitivity related to cell death and non-lethal cell damage. The model predictions were tested using data on hematological measurements (e.g., blood counts) performed in 1950-1956 in the Techa River residents chronically exposed to ionizing radiation since 1949. The suggested model of hematopoiesis is capable of describing experimental findings in the Techa River Cohort, including: (1) slopes of the dose-effect curves reflecting the inhibition of hematopoiesis due to chronic ionizing radiation, (2) delay in effect of chronic exposure and accumulated character of the effect, and (3) dose rate patterns for different cytopenic states (e.g., leukopenia, thrombocytopenia). PMID- 21259021 TI - Protective effects of selenocystine against gamma-radiation-induced genotoxicity in Swiss albino mice. AB - Selenocystine (CysSeSeCys), a diselenide aminoacid exhibiting glutathione peroxidase-like activity and selective antitumor effects, was examined for in vivo antigenotoxic and antioxidant activity in Swiss albino mice after exposure to a sublethal dose (5 Gy) of gamma-radiation. For this, CysSeSeCys was administered intraperitoneally (i.p.) to mice at a dosage of 0.5 mg/kg body weight for 5 consecutive days prior to whole-body gamma-irradiation. When examined in the hepatic tissue, CysSeSeCys administration reduced the DNA damage at 30 min after radiation exposure by increasing the rate of DNA repair. Since antigenotoxic agents could alter the expression of genes involved in cell cycle arrest and DNA repair, the transcriptional changes in p53, p21 and GADD45alpha were monitored in the hepatic tissue by real-time PCR. The results show that CysSeSeCys alone causes moderate induction of these three genes. However, CysSeSeCys pretreatment resulted in a suppression of radiation-induced enhancement of p21 and GADD45alpha expression, but did not affect p53 expression. Further analysis of radiation-induced oxidative stress markers in the same tissue indicated that CysSeSeCys significantly inhibits lipid peroxidation and prevents the depletion of antioxidant enzymes and glutathione (GSH) levels. Additionally, it also prevents radiation-induced DNA damage in other radiation sensitive cellular systems like peripheral leukocytes and bone marrow, which was evident by a decrease in comet parameters and micronucleated polychromatic erythrocytes (mn PCEs) frequency, respectively. Based on these observations, it is concluded that CysSeSeCys exhibits antigenotoxic effects, reduces radiation-induced oxidative stress, and is a promising candidate for future exploration as a radioprotector. PMID- 21259023 TI - The use of pupillometry in the assessment of cardiac autonomic function in elite different type trained athletes. AB - The aim of the present study was to evaluate cardiac autonomic function by pupillometry in male athletes. Fifteen elite endurance- (END) and eleven power trained (POWER) athletes and fifteen sedentary individuals (CONTROL) were studied. All subjects underwent three pupillometric measurements: at rest, peak exercise testing and recovery phase. The pupillometric indices studied were: baseline pupil radius (R1), minimum pupil radius (R2), maximum constriction velocity (VC(max)), maximum constriction acceleration (AC(max)), amplitude (AMP, R1-R2), constriction ratio (AMP%). During exercise, RR intervals were obtained for each subject with a Polar S810i for time and frequency domain heart rate variability (HRV) analysis. The following parameters of HRV were measured: standard deviation of all NN intervals (SDNN), the mean square successive differences (rMSSD), percent of NN intervals differing >50 ms from the preceding NN (pNN50), low (LF)- and high (HF)- frequency components of the autoregressive power spectrum of the NN intervals and their ratio (LF/HF). At rest and recovery, END showed significantly increased VC(max) and AC(max) compared to POWER and CONTROL. AMP% was significantly greater in END at rest, peak exercise and recovery compared to POWER and CONTROL. END and POWER had significantly greater AMP at rest and recovery compared to CONTROL. Moreover, all HRV indices were significantly increased in END compared to POWER and CONTROL. However, POWER showed significantly increased rMSSD and LF compared to CONTROL. HRV parameters were significantly correlated with pupillometric parameters during exercise. Our results indicated that any kind of exercise training and mainly endurance one affects autonomic regulation of pupillary light reflex. PMID- 21259024 TI - Combined carbohydrate-protein supplementation improves competitive endurance exercise performance in the heat. AB - Laboratory-based studies have demonstrated that adding protein (PRO) to a carbohydrate (CHO) supplement can improve thermoregulatory capacity, exercise performance and recovery. However, no study has investigated these effects in a competitive sporting context. This study assessed the effects of combined CHO-PRO supplementation on physiological responses and exercise performance during 8 days of strenuous competition in a hot environment. Twenty-eight cyclists participating in the TransAlp mountain bike race were randomly assigned to fitness-matched placebo (PLA 76 g L(-1) CHO) or CHO-PRO (18 g L(-1) PRO, 72 g L( 1) CHO) groups. Participants were given enough supplements to allow ad libitum consumption. Physiological and anthropometric variables were recorded pre- and post-exercise. Body mass decreased significantly from race stage 1 to 8 in the PLA group (-0.75 +/- 0.22 kg, P = 0.01) but did not change in the CHO-PRO group (0.42 +/- 0.42 kg, P = 0.35). Creatine kinase concentration and muscle soreness were substantially elevated during the race, but were not different between groups (P = 0.82, P = 0.44, respectively). Urine osmolality was significantly higher in the CHO-PRO versus the PLA group (P = 0.04) and the rise in tympanic temperature from pre- to post-exercise was significantly less in CHO-PRO versus PLA (P = 0.01). The CHO-PRO group also completed the 8 stages significantly quicker than the PLA group (2,277 +/- 127 vs. 2,592 +/- 68 min, respectively, P = 0.02). CHO-PRO supplementation therefore appears to prevent body mass loss, enhance thermoregulatory capacity and improve competitive exercise performance despite no effect on muscle damage. PMID- 21259025 TI - Oxygen uptake and ratings of perceived exertion at the lactate threshold and maximal fat oxidation rate in untrained adults. AB - The purpose of the study was to examine the relationship between VO(2) and RPE at the lactate threshold (LT) and maximal fat oxidation rate (FAT(MAX)) in untrained adults and determine the stability of the relationship across sex, age, and fitness status. A total of 148 untrained adults (mean age [year] = 30.5 +/- 13.9, height [m] = 1.72 +/- 0.08 m, body mass [kg] = 82.6 +/- 20.5, body fat [%] = 28.7 +/- 12.0) completed a continuous incremental VO(2) peak/LT protocol. Fat oxidation rates were determined using indirect calorimetry. The highest recorded fat oxidation rate was chosen as FAT(MAX). The breakpoint in the VO(2)-blood lactate relationship was chosen as LT. RPE was based on the Borg 6-20 scale. Bland-Altman plot analysis demonstrated that VO(2) FAT(MAX) systematically preceded VO(2) LT (mean bias = 1.3 ml kg(-1) min(-1)) with wide limits of agreement (+9.6 to -6.9 ml kg(-1) min(-1)). Multivariate ANOVA revealed a significant difference between VO(2) FAT(MAX) (12.7 +/- 7.5 ml kg(-1) min(-1)) and VO(2) LT (14.1 +/- 5.9 ml kg(-1) min(-1)) in the total sample (p = 0.04). There were no differences between the intensities when the sample was divided into sex, age, and fitness comparison groups (p values >0.05). RPE FAT(MAX) (9.4 +/- 2.5) preceded RPE LT (10.4 +/- 2.0) in the total sample (p = 0.008), but was not different across comparison groups (p > 0.05). The present data indicate that the highest rate of fat oxidation slightly precedes the LT in untrained adults. For exercise prescription, a Borg-RPE of 9-12 identifies both FAT(MAX) and LT. PMID- 21259026 TI - Post-concurrent exercise hemodynamics and cardiac autonomic modulation. AB - Concurrent training is recommended for health improvement, but its acute effects on cardiovascular function are not well established. This study analyzed hemodynamics and autonomic modulation after a single session of aerobic (A), resistance (R), and concurrent (A + R) exercises. Twenty healthy subjects randomly underwent four sessions: control (C:30 min of rest), aerobic (A:30 min, cycle ergometer, 75% of VO(2) peak), resistance (R:6 exercises, 3 sets, 20 repetitions, 50% of 1 RM), and concurrent (AR: A + R). Before and after the interventions, blood pressure (BP), heart rate (HR), cardiac output (CO), and HR variability were measured. Systolic BP decreased after all the exercises, and the greatest decreases were observed after the A and AR sessions (-13 +/- 1 and -11 +/- 1 mmHg, respectively, P < 0.05). Diastolic BP decreased similarly after all the exercises, and this decrease lasted longer after the A session. CO also decreased similarly after the exercises, while systemic vascular resistance increased after the R and AR sessions in the recovery period (+4.0 +/- 1.7 and +6.3 +/- 1.9 U, respectively, P < 0.05). Stroke volume decreased, while HR increased after the exercises, and the greatest responses were observed after the AR session (SV, A = -14.6 +/- 3.6, R = -22.4 +/- 3.5 and AR = -23.4 +/- 2.4 ml; HR, A =+13 +/- 2, R =+15 +/- 2 vs. AR =+20 +/- 2 bpm, P < 0.05). Cardiac sympathovagal balance increased after the exercises, and the greatest increase was observed after the AR session (A = +0.7 +/- 0.8, R = +1.0 +/- 0.8 vs. AR = +1.2 +/- 0.8, P < 0.05). In conclusion, the association of aerobic and resistance exercises in the same training session did not potentiate post-exercise hypotension, and increased cardiac sympathetic activation during the recovery period. PMID- 21259028 TI - First cases of giant pseudocyst complicating inguinal hernia repair. AB - INTRODUCTION: Giant pseudocyst is a rare type of complication following incisional hernia repair and its correct management is still unknown. MATERIALS AND METHODS: Herein, we describe two unreported cases of giant pseudocyst after inguinal hernia repair. Both patients underwent surgical treatment with partial excision of the pseudocapsule. The two patients were free from recurrence after 6 and 10 months of follow up, respectively. CONCLUSION: Subtotal surgical removal of the pseudocapsule is a definitive treatment. PMID- 21259027 TI - Trans-fascial laparoscopic mesh fixation: a procedural comparison using the standard suture passer versus iMESH stitcherTM device. AB - INTRODUCTION: Laparoscopic mesh repair has become an increasingly common method for repairing incisional hernias. The current method for fixating mesh to the abdominal wall includes tacking the mesh to the peritoneum and fascia and suturing the mesh to the fascia with trans-fascial sutures. The iMESH StitcherTM is a stitching device developed to both simplify and expedite this procedure by passing the suture from one arm of the iMESH stitcherTM to the other. The device enables a stitch to be created in three quick moves using only one hand. We compared both the efficacy and procedure time of trans-fascial mesh fixation when performed with the iMESH stitcherTM as compared to the standard suture passer method. METHODS: A mesh patch was installed on the internal abdominal wall of two pigs. Surgical residents and Medical students were participants in the study and were trained in both techniques. Each participant was asked to perform six fixations with each technique. The procedural time required for both fixation techniques was recorded. Participants were asked to assess subjectively the relative difficulty of each technique on a scale of 1-10 (10 = most difficult). RESULTS: Sixteen residents and students performed a total of 12 mesh fixations, each performing 6 fixations with each technique. Average mesh fixation suture time using the suture passer technique was 44 s for residents and 47 s for students. Average fixation suture time using the iMESH stitcherTM was 17 s for residents and 15 s for students. The average difficulty score for the suture passer technique was 6.1 as compared to 2.9 with iMESH stitcherTM. CONCLUSION: Trans-fascial fixation with the iMESH StitcherTM took significantly less time than the standard suture passer method. The iMESH StitcherTM significantly simplifies the procedure of transfascial fixation and potentially reduces technical difficulties. PMID- 21259029 TI - Management of congenital giant inguinal scrotal hernias in the newborn. AB - Giant inguinoscrotal hernias are a rare entity seen largely in the adult population. Presentation in the child is more unusual, with only one case previously documented. As there is scant literature regarding these hernias in children, their management may be challenging. Here, we present the case of a newborn born with giant bilateral inguinal hernias complicated by in utero perforation and meconium peritonitis managed by laparoscopy and then laparotomy for repair. The case illustrates several points that may be useful for pediatric surgeons who may encounter this condition. PMID- 21259030 TI - Contralateral metachronous inguinal hernias in adults: role for prophylaxis during the TEP repair. AB - PURPOSE: Contralateral exploration during laparoscopic totally extraperitoneal (TEP) inguinal herniorrhaphy allows for the repair of incidentally found hernias. Nonetheless, some patients with a negative contralateral exploration subsequently develop a symptomatic hernia on that side. We pondered the incidence of contralateral metachronous hernia development and whether prophylactic "repair" in these circumstances would be beneficial. METHODS: A retrospective analysis of patients who underwent laparoscopic TEP exploration at our institution was performed. Demographic, operative and follow-up information was obtained through medical record review, physical examination and telephone/mailed survey. RESULTS: From 1995 to 2009, a total of 1,479 inguinal herniorrhaphies on 976 patients were performed by a single staff surgeon. Bilateral exploration was completed in 923 (95%) of these patients, of whom bilateral repair was performed on 503 (55%). The study cohort comprises the 409 (42%) patients having a unilateral repair with a negative contralateral exploration and no previous contralateral hernia repair (n = 11). With a median follow-up of 5.9 years (range 0-14), 33 (8.1%) hernias developed on the previously "healthy" side, yielding incidence rates at 1, 5 and 10 years of 1.6, 5.9 and 11.8%, respectively. The median time to hernia development was 3.7 years (range 0.1-12.4). Of the 30 inguinal hernias that have been repaired, 25 (83%), 3 (10%) and 2 (7%) were of indirect, direct and pantaloon types, respectively. CONCLUSIONS: When considering prophylactic repair during TEP explorations, a yearly risk of 1.2% of developing a contralateral hernia after negative exploration needs to be balanced against the low but potential risk of groin pain following prophylactic repair. PMID- 21259031 TI - Prospective randomized evaluation of prophylactic antibiotic usage in patients undergoing tension free inguinal hernioplasty. AB - OBJECTIVES: Assessment of the usefulness of antibiotic prophylaxis in inguinal hernioplasty. MATERIALS AND METHODS: This prospective randomized double blind study was conducted on 98 patients. Group A (50 patients) received a single dose of intravenous amoxicillin and clavulanic acid, and Group P (48 patients) received an equal volume of normal saline placebo by intravenous bolus 30 min before the induction of anesthesia. Hernioplasty was performed with polypropylene mesh. Skin was closed using skin staples that were removed after complete wound healing. The surgical site infection was diagnosed according to APIC, CDC criteria ( http://www.apic.org ). RESULTS: The mean operative time was 38.8 +/- 10.8 min in group A versus 40.9 +/- 11.1 min in group P (P = 0.34). The mean hospitalization time was 1.3 +/- 0.463 days in group A versus 1.25 +/- 0.438 days in group P (P = 0.58). Four patients (2%) in group A and 6 patients (2.88%) in group P had wound infections (P = 0.47). Group A had 3 superficial infections and 1 deep infection while group P had 5 superficial infections and 1 deep infection. Antibiotic treatment of the wound infection was successful in all patients. Wound culture showed Staphylococcus aureus infection in 1 patient each group, Streptococcus pyogenes in 1 group A patient and Pseudomonas aeruginosa in 1 group P patient. Cultures in other patients in both groups were reported to be sterile. CONCLUSION: Prophylactic antibiotic usage in patients undergoing tension free inguinal hernioplasty did not show any statistically significant beneficial effects in reduction of surgical site infection. PMID- 21259032 TI - The use of mesh in acute hernia: frequency and outcome in 99 cases. AB - BACKGROUND: Incarceration of inguinal, umbilical and cicatricial hernias is a frequent problem. However, little is known about the relationship between the use of mesh and outcome after surgery. The goal of this study was to describe the relationship between the use of mesh in incarcerated hernia and the clinical outcome. PATIENTS AND METHODS: Correspondence, operation reports and patient files between January 1995 and December 2005 of patients presented at one academic and one teaching hospital in Rotterdam were searched for the following keywords: incarceration, strangulation and hernia. The patient characteristics, clinical presentation, pre-operative findings and clinical course were scored and analysed. RESULTS: A total of 203 patients could be identified: 76 inguinal, 52 umbilical, 39 incisional, 14 epigastric, 14 femoral, five trocar and three spigelian hernias. In the statistical analysis, epigastric, femoral, trocar and spigelian hernias were pooled, due to their small group sizes. One patient was excluded from the analysis because the hernia was not corrected during operation. In total, 99 hernias were repaired using mesh versus 103 primary suture repairs. Twenty-five wound infections were registered (12.3%). One mesh was removed during a reintervention for anastomotic leakage, although no signs of wound infection were present. Nine patients died, none of them due to wound-related problems [one cardiovascular, one ruptured aneurysm, two anastomotic leakage, two sepsis e causa incognita (e.c.i.), three pulmonary complications]. Univariate analysis showed that female patients (P = 0.007), adipose patients (P = 0.016), patients with an umbilical hernia (P = 0.01) and patients who underwent a bowel resection (P = 0.015) had a significantly higher rate of wound infections. The type of repair (e.g. primary suture or mesh), use of antibiotic prophylaxis, gender, ASA class and age showed no significant relation with post-operative wound infection. After logistic regression analysis, only bowel resection (P = 0.020) showed a significant relation with post-operative wound infection. CONCLUSIONS: Wound infection rates are high after the correction of acute hernia, but clinical consequences are relatively low. Mesh correction of an acute hernia seems to be safe and should be considered in every incarcerated hernia. PMID- 21259033 TI - Analysis and functional expression of NPP pathway-specific regulatory genes in Pseudonocardia autotrophica. AB - Using the genomics-guided polyene screening method, a rare actinomycetes called Pseudonocardia autotrophica was previously identified to contain functionally clustered nystatin-like biosynthetic genes and to produce a presumably novel polyene compound named nystatin-like Pseudonocardia polyene (NPP) (Kim et al., J Ind Microbiol Biotechnol 36:1425-1434, 2009). Since very low NPP productivity was observed in most P. autotrophica culture conditions, its biosynthetic pathway was proposed to be tightly regulated. Herein we report in silico analysis of six putative NPP pathway-specific regulatory genes present in its biosynthetic gene cluster, followed by functional overexpression of these regulatory genes in P. autotrophica. Three pathway-specific regulatory genes (nppRI, RIII, and RV) were predicted to belong to a typical LAL-type transcriptional family. Each regulatory gene was cloned under the strong constitutive ermE* promoter in a Streptomyces integrative pSET152 plasmid, followed by direct intergeneric conjugation from a plasmid-containing E. coli donor cell to P. autotrophica. While all the P. autotrophica exconjugants exhibited improved NPP productivity, the one containing nppRIII showed the highest NPP productivity improvement. In addition, culture time-dependent analysis revealed that the nppRIII-stimulated NPP biosynthesis was more significant in the late exponential growth stage than in the stationary stage. Moreover, the P. autotrophica nppRIII-disruption mutant failed to produce NPP, with significantly reduced transcription levels of most npp biosynthetic genes. The results described suggest that identification and overexpression of key pathway-specific regulatory gene, followed by optimum harvest timing, should be critical factors to maximize the productivity of an intrinsically low-level metabolite such as NPP produced by rare actinomycetes species. PMID- 21259034 TI - Selection of silk-binding peptides by phage display. AB - Peptides that bind to silkworm-derived silk fibroin fiber were selected from a phage-displayed random peptide library. The selected silk-binding peptides contained a consensus sequence QSWS which is important for silk-binding as confirmed by binding assays using phage and synthetic peptides. With further optimization, we anticipate that the silk-binding peptides will be useful for functionalization of silk for biomaterial applications. PMID- 21259035 TI - In vivo effects of isolated implantation of salmon-derived crosslinked atelocollagen sponge into an osteochondral defect. AB - We have developed crosslinked salmon-derived atelocollagen (SC) sponge, which has a denaturation temperature of 47 degrees C. Sixty-four knees of 32 mature rabbits were randomly divided into 4 groups after creating an osteochondral defect in the femoral trochlea. Defects in Groups I, II, and III were filled with the crosslinked SC sponge, the crosslinked porcine collagen (PC) sponge, and the non crosslinked PC sponge, respectively. In Group IV, defects were left untreated as the control. At 12 weeks after implantation, the histological score showed that Group I was significantly greater than Groups III (P = 0.0196) and IV (P = 0.0021). In addition, gene expression of type-2 collagen, aggrecan, and SOX9 was the greatest in Group I at 12 weeks. The fundamental in vivo properties of the crosslinked SC sponge showed that this is a promising biomaterial, specifically as a scaffold for cartilage tissue engineering. PMID- 21259036 TI - Existing roles of traditional healers (mor baan) in southern Thailand. AB - Traditional healers (mor baan) played an important role in Thai health long before the introduction of Western medicine. Although modern health professional play a key role of health care provider of Thai health care system, traditional healers and their practice still exist in most rural areas of Thailand. In this article, we address the roles and practices of traditional healers in southern Thailand. An ethnographic method was employed. This approach is the hallmark method used to describe the role and the practice of traditional healers and to grasp in-depth understanding of their everyday life. Participation observation and unstructured interview with 18 traditional healers were conducted. Thematic analysis method was used to analyse the data. Most of the traditional healers chose their role because they were influenced by their ancestors, although a few others chose it because of individual interests and a desire to help ill people. All are trained in multiple skills, using supernatural spirits, ceremonies and natural plant products as resources for counteracting various health problems. They refer patients to modern hospitals or other healers if they cannot adequately manage illness themselves. Their service provision is flexible and based on a holistic approach that suits people's lifestyles and needs. The role of traditional healer tends not to attract the interest of younger generations, although traditional healers have contributed greatly to people's health. Their presence improves people's access to healthcare and offers an alternative to modern medicine, which often has a limited role. We conclude that the services of traditional healers should be incorporated into contemporary healthcare provision of Thai health care system. PMID- 21259037 TI - The implementation of Good For The Neighborhood: a participatory community health program model in four minority underserved communities. AB - To describe the participatory approach used to develop "Good For The Neighborhood" (GFTN), a community program to improve the health of four underserved communities. A core program was developed involving a "park and stay" approach to impact four underserved predominately minority communities (two predominately African American, 1 predominately Latino, and the Seneca Nation of Indians). The core program includes health screenings, risk assessments, health education, and exposure to health services. An extensive tracking and evaluation system was developed to determine participation and impact on the community. Multi-methods (key informant interviews, focus groups, surveys) were implemented to gain feedback from community partners and participants as to how to adopt the program to meet the needs of the community. GFTN has been sustained for over 3 years and has reached over 3,500 predominately minority individuals in four communities with 1/3 of participants engaging regularly in the program. The program has evolved in the four communities to meet specific needs. A "park and stay" approach in partnership with the community has led to a strong program that community partners and residents embrace. Community ownership and social networking, including word-of-mouth from residents is essential to establishing a successful program. PMID- 21259038 TI - Exacerbation history is associated with medication and appointment adherence in MS. AB - Disease-modifying treatments are designed to prevent exacerbations in multiple sclerosis (MS). To date, few studies have examined the relationship between disease activity and treatment adherence in MS. The primary aim of this study was to examine the association between disease activity (e.g., annualized relapse rates), medication adherence, and appointment adherence in relapsing-remitting MS. Retrospective exacerbation and appointment data were collected and used to predict prospective medication adherence. Results indicated that patients with higher annualized relapse rates missed fewer doses of medication and were less likely to miss appointments. Conversely, patients with relatively stable disease were more likely to demonstrate poor medication adherence and poor appointment adherence. Patients who missed more appointments also missed more doses of their disease modifying medication. Future studies may wish to examine clinical methods designed to improve immunotherapy adherence among patients who are in relatively symptom-free stages of relapsing-remitting MS. PMID- 21259039 TI - Genotype-phenotype association studies of chromosome 8p inverted duplication deletion syndrome. AB - Individuals diagnosed with chromosome 8p inverted duplication deletion (invdupdel(8p)) manifest a wide range of clinical features and cognitive impairment. The purpose of this study is to employ array CGH technology to define more precisely the cytogenetic breakpoints and regions of copy number variation found in several individuals with invdupdel(8p), and compare these results with their neuropsychological characteristics. We examined the cognitive-behavioral features of two male and two female children, ages 3-15 years, with invdupdel(8p). We noted cognitive deficits that ranged from mild to severe, and adaptive behavior composites that ranged from significantly to substantially lower than adequate levels. CARS scores, a measure of autistic behavior, identified three children with autism or autistic-like features. Three of the four children exhibited attention deficits and hyperactivity consistent with a DSM-IV-TR diagnosis of ADHD. One child showed extreme emotional lability. Interestingly, intellectual disability was not correlated with deletion size, nor was the deletion location associated with the autistic phenotype. On the other hand, the duplication length in 8p21.1/8p22 was associated with cognitive deficit. In addition, a small locus of over-expression in 8p21.3 was common for all three participants diagnosed as autistic. A limitation of the study is its small sample size. Further analyses of the deleted and over-expressed regions are needed to ascertain the genes involved in cognitive function and, possibly, autism. PMID- 21259040 TI - DeFries-Fulker analysis of longitudinal reading performance data from twin pairs ascertained for reading difficulties and from their nontwin siblings. AB - Reading difficulties are both heritable and stable; however, little is known about the etiology of this stability. Results from a preliminary analysis of data from 56 twin pairs who participated in the Colorado Longitudinal Twin Study of Reading Disability (Astrom et al., Twin Res Hum Genet 10:434-439, 2007) suggested that about two-thirds of the proband deficit at follow-up was due to genetic factors that also influenced deficits at their initial assessment. Although our proband sample is now nearly twice as large, it is still relatively small; thus, to increase power, we subjected data from probands, co-twins and their nontwin siblings to a novel extension of DeFries-Fulker analysis (DeFries and Fulker, Behav Genet 15:467-473, 1985; DeFries and Fulker, Acta Genet Med Gemellol, 37, 205-216, 1988). In addition to providing estimates of univariate and bivariate heritability, this analysis facilitates a test of the difference between shared environmental influences for twins versus siblings. Longitudinal composite reading performance scores at 10.6 and 15.5 years of age, on average, were analyzed from 33 MZ and 64 DZ twin pairs in which at least one member of each pair had reading difficulties, and from 44 siblings of the probands. Scores were highly stable (.86 +/- .03, across probands, co-twins and siblings) and heritability of the group deficit at initial assessment was .67 +/- .22. Longitudinal bivariate heritability was .59 +/- .21, suggesting that nearly 60% of the proband reading deficit at follow-up is due to genetic factors that influenced reading difficulties at the initial assessment. However, tests for special twin environmental influences were nonsignificant. PMID- 21259041 TI - Caregiver role overload and network support in a sample of predominantly low income, African-American caregivers of persons living with HIV/AIDS: a structural equation modeling analysis. AB - While informal caregivers play an important role in improving the health of disadvantaged persons living with HIV/AIDS (PLHAs) in the United States, caregiver role overload has the potential for distress. We used latent profile analysis (LPA) to classify caregivers based on their perceived level of support and structural equation modeling (SEM) to examine the relationships among role overload, perceived support, caregiver demographic characteristics, and social network members' characteristics in a sample of 215 predominantly low-income, African-American informal caregivers. The LPA resulted in two classes of caregivers with higher and lower perceived support. The SEM results indicated that caregiver role overload was associated with being in the less supported class, younger age, and limited physical functioning, while social support class was associated with being female and being HIV seropositive in addition to support network characteristics. Interventions should address the support needs of HIV caregivers to reduce their potential for distress. PMID- 21259042 TI - Gender power control, sexual experiences, safer sex practices, and potential HIV risk behaviors among young Asian-American women. AB - We examined the prevalence of three domains of sexual behaviors among young Asian American women: sexual experiences, safer sex practices, and potential HIV risk behaviors. We also investigated the impact of gender power control on these domains. Among sexually experienced women, 51% reported using condoms during their most recent sex act, 63% reported inconsistent condom use, and 18% reported ever having forced sex. Multiple logistic regression analyses revealed that women's perceived lower relationship power control was not associated with vaginal sex or safer sex practices, but it was powerfully associated with forced sex and all three potential HIV risk behaviors. This study demonstrates that control within young Asian-American women's intimate relationships exerts different associations depending on the type of sexual behavior. The application of the Theory of Gender and Power should be employed with prudence when designing HIV interventions for this population. PMID- 21259043 TI - Social stability and HIV risk behavior: evaluating the role of accumulated vulnerability. AB - This study evaluated a cumulative and syndromic relationship among commonly co occurring vulnerabilites (homelessness, incarceration, low-income, residential transition) in association with HIV-related risk behaviors among 635 low-income women in Baltimore. Analysis included descriptive statistics, logistic regression, latent class analysis and latent class regression. Both methods of assessing multidimensional instability showed significant associations with risk indicators. Risk of multiple partners, sex exchange, and drug use decreased significantly with each additional domain. Higher stability class membership (77%) was associated with decreased likelihood of multiple partners, exchange partners, recent drug use, and recent STI. Multidimensional social vulnerabilities were cumulatively and synergistically linked to HIV risk behavior. Independent instability measures may miss important contextual determinants of risk. Social stability offers a useful framework to understand the synergy of social vulnerabilities that shape sexual risk behavior. Social policies and programs aiming to enhance housing and overall social stability are likely to be beneficial for HIV prevention. PMID- 21259044 TI - Reluctance to do blood testing limits HIV diagnosis and appropriate health care of sub-Saharan African migrants living in Spain. AB - This study investigates the reasons why sub-Saharan African migrants (SSAM) living in Spain may be unwilling to have their blood tested. A qualitative study was developed for 3 years (2006-2009) with the participation of 1338 SSAM. Cultural differences along with lack of information about Spanish health care system and health-related rights produced a feeling of mistrust towards medical staff. Reluctance to do blood testing may prevent SSAM from having a prompt HIV diagnosis and an appropriate health care. Linguistically and culturally adapted information is essential to overcome these barriers and achieve an equal access to health care services and HIV testing. PMID- 21259045 TI - A novel cationic ribonuclease with antimicrobial activity from Rana dybowskii. AB - A novel ribonuclease (RNase) A superfamily gene (Rdronc) has been cloned from the frog Rana dybowskii. The deduced amino acid sequence shows that it belongs to the ribonuclease A superfamily, with the highest identity, 73%, to Rana pipiens onconase. Adaptive evolution analysis based on maximum likelihood models of codon substitution has been conducted on 10 members of the Rana RNases of subcluster B. Rapid adaptive evolution and multiple positive selection sites have been detected, which indicates that these genes may be evolving under positive selection pressure. Functional assay demonstrates that the recombinant Rdronc protein possesses antimicrobial activity against Gram-negative Escherichia coli and Pseudomonas aeruginosa and weaker antimicrobial activity against Gram positive Staphylococcus aureus and yeast Candida albicans. Our findings support the hypothesis that ribonuclease A superfamily members may function in host defense of early-diversified vertebrates. PMID- 21259046 TI - Lercanidipine rescues hippocampus pyramidal neurons from mild ischemia-induced delayed neuronal death in SHRSP. AB - Stroke-prone spontaneously hypertensive rats (SHRSPs) are vulnerable to ischemia and delayed neuronal death (DND) of hippocampus pyramidal cells when bilateral carotid arteries are occluded for only 10 min. Since this occlusion induces just mild ischemia, the resulting DND may be an appropriate animal model for dementia in patient with essential hypertension exposed to small ischemic insults. This study was designed to compare the effects of the antihypertensive drugs lercanidipine, nicardipine, lisinopril, valsartan, and hydralazine on occlusion induced DND in SHRSPs. Drugs were administered for 2 weeks, from 15 to 17 weeks of age. 0.1% Nicardipine and 0.01 or 0.03% lercanidipine were administered in the SP diet (about 61.3, 5.7, and 18.8 mg/kg/day, respectively), and the remaining drugs were administered at 10 mg/kg/day using the mini-osmotic pump. The animals were operated on at 16 weeks of age, and DND was analyzed by histological examination 1 week later. Systolic blood pressure was measured at 15, 16, and 17 weeks of age. For chronic treatment, Calcium-channel blockers were administered from 8 to 17 weeks of age. All antihypertensive drugs significantly lowered systolic blood pressure at 16 weeks of age. Hydralazine and lisinopril were associated with the greatest reduction; however, lercanidipine, nicardipine, and valsartan effectively reduced systolic blood pressure to within a medium range. DND was significantly inhibited only by 0.03% lercanidipine. Chronic treatment with 0.03% lercanidipine also protected pyramidal neurons. The results of this study demonstrate that the long-acting, lipophilic Calcium-channel blocker lercanidipine inhibits occlusion-induced DND in SHRSPs and that lercanidipine may effectively reduce dementia induced by small ischemic insults in patients with essential hypertension. PMID- 21259047 TI - Expressions of forkhead class box O 3a on crushed rat sciatic nerves and differentiated primary Schwann cells. AB - Forkhead box-containing protein, class O 3 a (FOXO3a), an Akt downstream target, plays an important role in peripheral nervous system. FOXO3a shares the ability to be inhibited and translocated from the nucleus on phosphorylation by proteins such as Akt/PKB in the PI3K signaling pathway. To elucidate the expression and possible function of FOXO3a in lesion and repair, we performed an acute sciatic nerve crush model and studied differential expressions of FOXO3a. We observed that expressions of FOXO3a in Schwann cells (SCs) of the peripheral nervous system and cAMP-induced differentiation were dynamically regulated. Western blot analysis showed FOXO3a level significantly decreased post injury. Moreover, Immunofluorescence double labeling suggested the changes were striking especially in SCs. In vitro, Western blot analysis showed that the expression of FOXO3a was decreased in cAMP-induced differentiated primary SCs. The FOXO3a siRNA transfected SCs treated by cAMP promote differentiation of SCs through the PI3K/Akt pathway. The results indicate that FOXO3a plays an important role during differentiation of SCs. PMID- 21259048 TI - Electrical stimulation promotes BDNF expression in spinal cord neurons through Ca(2+)- and Erk-dependent signaling pathways. AB - Brief electrical stimulation has been shown to be effective in promoting neuronal regeneration following peripheral nerve injury. These effects are thought to be mediated largely by the upregulation of the expression of brain-derived neurotrophic factor (BDNF) in spinal cord neurons. However, the molecular mechanisms by which electrical stimulation can promote BDNF expression are not known. The mechanism involved in BDNF expression after electrical stimulation was explored in this study. Immunohistochemistry and Western blotting were used to test BDNF expression. Confocal microscopy was utilized to study intracellular Ca(2+) volume. Immunohistochemistry and Western blotting confirmed that brief electrical stimulation increased BDNF expression in spinal cord neurons both in vivo and in vitro. Treatment of cultured neurons with nifedipine, an inhibitor of voltage-gated calcium channels, significantly reduced the BDNF increase produced by electrical stimulation, and an inhibitor of Erk completely abolished the effect of electrical stimulation. Levels of BDNF expression in the presence of the Erk inhibitor were lower that in unstimulated and untreated controls, indicating that Erk activation is required to maintain baseline levels of BDNF. Confocal microscopy using a Ca(2+)-sensitive fluorochrome revealed that electrical stimulation is accompanied by an increase in intracellular Ca(2+) levels; the increase was partly blocked by nifedipine. These findings argue that electrical stimulation increases BDNF expression in spinal cord neurons by activating a Ca(2+)- and Erk-dependent signaling pathways. PMID- 21259049 TI - Neurodegenerative effects of recombinant HIV-1 Tat(1-86) are associated with inhibition of microtubule formation and oxidative stress-related reductions in microtubule-associated protein-2(a,b). AB - The human immunodeficiency virus 1 (HIV-1) protein Trans-activator of Transcription (Tat) is a nuclear regulatory protein that may contribute to the development of HIV-1 associated dementia by disrupting the neuronal cytoskeleton. The present studies examined effects of recombinant Tat(1-86; 1-100 nM) on microtubule-associated protein (MAP)-dependent and MAP-independent microtubule formation ex vivo and oxidative neuronal injury in rat organotypic hippocampal explants. Acute exposure to Tat(1-86) (>=1 nM) markedly reduced MAP-dependent and -independent microtubule formation ex vivo, as did vincristine sulfate (0.1-10 MUM). Cytotoxicity, as measured by propidium iodide uptake, was observed in granule cells of the DG with exposure to 100 nM Tat(1-86) for 24 or 72 h, while significant reductions in MAP-2 immunoreactivity were observed in granule cells and pyramidal cells of the CA1 and CA3 regions at each timepoint. These effects were prevented by co-exposure to the soluble vitamin E analog Trolox (500 MUM). Thus, effects of Tat(1-86) on the neuronal viability may be associated with direct interactions with microtubules and generation of oxidative stress. PMID- 21259050 TI - Results of secondary ureteral implantation after kidney transplantation. AB - BACKGROUND: We reviewed our experience with ureteral complications and secondary ureteral implantation after kidney transplantation. METHODS: Between 1997 and 2005, 636 patients underwent kidney transplantation at our transplant center. Ureteral implantation was performed in the Lich-Gregoire technique. Thirty-one patients with ureteral complications after kidney transplantation and subsequent secondary ureteral implantation were analyzed for operative parameters and long term transplant function. RESULTS: Twenty-seven patients had a ureteral stenosis and 4 patients a ureteral leakage. In 25 patients (81%), a resection of the distal transplant ureter followed by secondary ureteral implantation was performed. In 4 cases (13%), the native ureter was anastomosed to the transplant pelvis and in the remaining 2 cases (6%) to the transplant ureter. Three major complications occurred. At median follow-up of 5 years, 18/30 patients (60%) had a good transplant function and 12/30 patients (40%) had returned to dialysis. One patient with depression died from suicide. CONCLUSIONS: Secondary ureteral implantation can be performed with acceptable morbidity and good long-term transplant outcome. PMID- 21259051 TI - Leydig cell tumor in two brothers with congenital adrenal hyperplasia due to 11 beta hydroxylase deficiency: a case report. AB - Congenital adrenal 11-beta hydroxylase deficiency is a rare autosomal recessive syndrome characterized by deficient cortisol synthesis and testicular masses. It is extremely difficult to distinguish testicular tumors caused by this syndrome from Leydig cell tumors. As management for each differs, it is important to differentiate the syndromes from each other. Hereby, we present the case of two brothers affected by 11-beta hydroxylase deficiency and presenting with bilateral testicular masses. Two differential diagnoses were noticed for both patients: testicular adrenal rest tumors (TART) and Leydig cell tumor (LCT). In this study the tumors were yellow, firm, and non-tender with intra-testicular location. Histological studies showed cells in a cluster arrangement with low lipochrome pigment concentration. Tumors were unresponsive to ACTH suppression therapy, but a drop in levels of plasma testosterone and urinary 17-ketosteroids occurred after surgical treatment. Considering all above, they were finally diagnosed as having Leydig cell tumors. Both cases were managed by testis-sparing surgery. PMID- 21259052 TI - "Ego-dystonic" delusions as a predictor of dangerous behavior. AB - This paper aims to report a possible warning sign for dangerous behavior in delusional psychotic patients. We demonstrate an association between aggressive or auto-aggressive ideation and "ego-dystonic" grandiose delusions, where the patient believes to possess unique qualities but finds them unbearable. The study is based on the sample of seven interviews with five psychotic in-patients at the Kfar Shaul Mental Health Center, Jerusalem, Israel. All patients experienced an acute psychotic episode, and committed acts of aggression or suicidality. The research method is narrative analysis of semi-structured interviews. Patients report ideas of grandiose self-identification with deities, Biblical figures or celebrities, yet report their reluctance to be in these high positions due to feelings of unworthiness, withdrawal, and social isolation. Resulting frustration arguably leads to aggressive and suicidal ideation or actions. Contrary to the established view, grandiose delusions are not free of association with (auto )aggression. The patient's ego-dystonic attitude towards his/her delusional identity may serve as the warning sign for dangerous behavior and, as such, should be searched for and recognized by the mental health professionals. PMID- 21259053 TI - Bufadienolide compounds sensitize human breast cancer cells to TRAIL-induced apoptosis via inhibition of STAT3/Mcl-1 pathway. AB - The death receptor ligand TRAIL is considered a promising candidate for cancer therapy because of its preferential toxicity to malignant cells. However its efficacy has been challenged by a number of resistance mechanisms. Therefore, agents that can overcome the resistance to enhance therapeutic efficacy of TRAIL are needed. In the current study, we found that bufalin, bufotalin and gamabufotalin, key members of bufadienolides isolated from a traditional Chinese medicine ChanSu, significantly potentiated human breast cancer cells with different status of ER-alpha to apoptosis induction of TRAIL, as evidenced by enhanced Annexin V/FITC positive cells (apoptotic cells), cytoplasmic histone associated-DNA-fragments, membrane permeability transition (MPT), caspases activation and PARP cleavage. Further mechanistic investigation demonstrated that bufalin was able to significantly decrease Mcl-1 expression and modestly decrease Bcl-XL expression level. Down-regulations of these anti-apoptotic proteins were well correlated with inhibition of transcription factor STAT3 activation. The important consequence of down-regulation Mcl-1 in the enhancement action by combining bufalin with TRAIL was confirmed by either knockdown or overexpression of Mcl-1 approach. Our findings for the first time provided strong evidences that bufadienolide compounds have excellent potential to be developed as a novel class of sensitizers of TRAIL. PMID- 21259055 TI - Allergy and psychologic evaluations of patients with multiple drug intolerance syndrome. AB - The multiple drug intolerance syndrome is a clinical entity characterized by adverse drug reactions to at least three drugs, chemically, pharmacologically and immunogenically unrelated, manifested upon three different occasions, and with negative allergy testing. Symptoms referred by the patients are often subjective, of neurovegetative origin. The aim of the study is to characterize patients suffering from the multiple drug intolerance syndrome from a psychological point of view, and to compare them to healthy subjects. We studied 30 women suffering from the multiple drug intolerance syndrome. All subjects underwent the following psychodiagnostic tests: (1) the State Trait Anxiety Inventory-Form Y, (2) the Zung Self-rating Anxiety Scale, (3) the Zung Self-rating Depression Scale, (4) the Quality of life enjoyment and satisfaction questionnaire, (5) the Minnesota Multiphasic Inventory-2, (6) the Toronto Alexithymia Scale. The study group was compared to 30 healthy women. When compared with the control group, our patients showed: a higher anxiety, a higher grade of depression, this difference was statistically significant (p < 0.01); a high difference (p < 0.01) between the two groups as regards somatic symptoms; a higher grade of alexithymia (p < 0.01); and a worse quality of life, in all the analyzed ambits. These findings clearly demonstrate the importance of psychological symptoms in patients with the multiple drug intolerance syndrome, and show that a complex allergy and psychological work-up is mandatory in the management of these patients. PMID- 21259054 TI - Fungal proteases and their pathophysiological effects. AB - Proteolytic enzymes play an important role in fungal physiology and development. External digestion of protein substrates by secreted proteases is required for survival and growth of both saprophytic and pathogenic species. Extracellular serine, aspartic, and metalloproteases are considered virulence factors of many pathogenic species. New findings focus on novel membrane-associated proteases such as yapsins and ADAMs and their role in pathology. Proteases from fungi induce inflammatory responses by altering the permeability of epithelial barrier and by induction of proinflammatory cytokines through protease-activated receptors. Many fungal allergens possess proteolytic activity that appears to be essential in eliciting Th2 responses. Allergenic fungal proteases can act as adjuvants, potentiating responses to other allergens. Proteolytic enzymes from fungi contribute to inflammation through interactions with the kinin system as well as the coagulation and fibrinolytic cascades. Their effect on the host protease-antiprotease balance results from activation of endogenous proteases and degradation of protease inhibitors. Recent studies of the role of fungi in human health point to the growing importance of proteases not only as pathogenic agents in fungal infections but also in asthma, allergy, and damp building related illnesses. Proteolytic enzymes from fungi are widely used in biotechnology, mainly in food, leather, and detergent industries, in ecological bioremediation processes and to produce therapeutic peptides. The involvement of fungal proteases in diverse pathological mechanisms makes them potential targets of therapeutic intervention and candidates for biomarkers of disease and exposure. PMID- 21259056 TI - Radiation-induced sarcoma of head and neck: 50 years of experience at a single institution in an endemic area of nasopharyngeal carcinoma in China. AB - Radiation-induced sarcoma in the head and neck (RISHN) is a rare condition whose clinical presentation and management remain difficult because of its low incidence. In this retrospective study, we analyzed the symptoms, diagnosis, and the treatment of 16,634 patients with head and neck disease, who received radiotherapy between 1960 and 2010 at the Affiliated Tumor Hospital and its predecessor, Guangxi Medical University, China. Among these patients, 16 with a first tumor of nasopharyngeal carcinoma (NPC) and 1 with squamous carcinoma of the tongue met the criteria of RISHN in the head and neck. Our epidemiological data showed that the incidence of RISHN rose from 0.06 to 0.17% from 1960 to 2010; the 3-year overall survival rate was 19.1%, and 3-year disease-free survival rate was 11.1%. The mean latency (SD) period was 93.2 (33) months. Based on the experiences at our institution, we suggest that RISHN is a rare complication after radiotherapy for head and neck tumors, especially NPC. Owing to its low incidence, it should not be a major factor affecting decisions about radiotherapy. Nevertheless, there may be a possibility of increasing incidence of RISHN after radiotherapy of NPC, as shown in our epidemiological results. Given the poor prognosis of RISHN, this possibility should be taken into serious consideration before determination of high-dose radiotherapy for patients with NPC and other head and neck tumors. PMID- 21259057 TI - Association of beta-catenin, Wnt1, Smad4, Hoxa9, and Bmi-1 with the prognosis of esophageal squamous cell carcinoma. AB - In our previous study, Human Signal Transduction in Cancer Gene Array was used in 12 fresh tumor samples to detect the gene expression profiles in the esophageal squamous cell carcinoma (ESCC) tissues matched adjacent non-cancerous samples. Among genes up-regulated at least twofold, beta-catenin, Wnt1, Smad4, Hoxa9, and Bmi-1 were found. So subsequently, the aim of this study was to investigate the prognosis and clinicopathologic roles of beta-catenin, Wnt1, Smad4, Hoxa9, and Bmi-1 in ESCC tissue. The mRNA and protein expression levels of beta-catenin, Wnt1, Smad4, Hoxa9, and Bmi-1 genes in 70 ESCC and adjacent non-cancerous paraffin-embedded samples were determined by Real-Time Quantitative PCR (RT-PCR) and immunohistochemical staining. The mRNA expression level of beta-catenin, Wnt1, Smad4, Hoxa9, and Bmi-1 in ESCC was significantly higher than that in the adjacent non-cancerous tissues (0.0821 +/- 0.0416 vs. 0.0185 +/- 0.0201, P = 0.0000; 1.9934 +/- 1.9888 vs. 0.8863 +/- 0.665, P = 0.0184; 0.0298 +/- 0.0215 vs. 0.0189 +/- 0.0187, P = 0.0017; 2.098 +/- 0.091 vs. 1.016 +/- 0.078, P = 0.0000; 2.181 +/- 2.158 vs. 0.931 +/- 0.894, P = 0.0152; respectively), and the protein expression level of determined genes was also significantly higher than that in the adjacent non-cancerous tissues (0.2835 +/- 0.0844 vs. 0.2352 +/- 0.0670, P = 0.0003; 0.3830 +/- 0.0947 vs. 0.2721 +/- 0.1474, P = 0.0000; 0.2637 +/- 0.0348 vs. 0.2042 +/- 0.0180, P = 0.0000; 0.2058 +/- 0.0316 vs. 0.1218 +/- 0.0518, P = 0.0000; 0.2736 +/- 0.0834 vs. 0.2251 +/- 0.0571, P = 0.0001; respectively). Then, the overexpression of mRNA and protein levels of beta-catenin, Wnt1 and Bmi-1 was aggressively associated with lymph node metastasis, advanced pathological stage, and prognosis of the patients with ESCC (P < 0.05). The up-expression of Hoxa9 mRNA and protein was also aggressively associated with lymph node metastasis and advanced pathological stage (P < 0.05); however, the overexpression of Hoxa9 protein was not associated with the prognosis (P > 0.05). Meanwhile, the hypo expression of Smad4 mRNA was aggressively associated with advanced pathological stage and prognosis of the patients with ESCC (P < 0.05); however, the hypo expression of Smad4 protein was neutral to the prognosis and lymph node metastasis (P > 0.05). beta-catenin, Wnt1, Smad4, Hoxa9, and Bmi-1 protein expression analysis showed that the positive outcomes of the combined detection of Wnt1 and beta-catenin expression or Wnt1, beta-catenin and Bmi-1 expression were significantly worse than those of a single target protein expression (P < 0.05). Meantime, the prognosis of the combined positive expression of Wnt1, beta catenin, and Bmi-1 was poorer than that in the combined positive expression of Wnt1 and beta-catenin (P < 0.05). The prognosis of ESCC patients with the overexpression of Wnt1/beta-catenin and Bmi-1 was relatively poor, and the level of Wnt1/beta-catenin and Bmi-1 was conversely correlated with advanced pathological stage and lymph node metastasis. The expression level of Smad4 and Hoxa9 mRNA was also associated with the prognosis of the patients with ESCC, pathological stage, and lymph node metastasis; however, they might not be the independent prognostic factor. PMID- 21259059 TI - Ceramide induces apoptosis via caspase-dependent and caspase-independent pathways in mesenchymal stem cells derived from human adipose tissue. AB - Apoptosis of stem cells may be related to certain degenerative conditions such as progressive tissue damage and an inability to repair. Ceramide induces cell death in various cell types. However, the underlying mechanisms of ceramide-induced cell death in stem cells are not explored. This study was designed to investigate the cell death process caused by cell-permeable ceramide and to determine the underlying mechanisms in mesenchymal stem cells derived from human adipose tissue (hASCs). Ceramide caused a loss of cell viability in a concentration- and time dependent manner, which was largely attributable to apoptosis. Ceramide induced generation of reactive oxygen species (ROS) and disruption of the mitochondrial membrane potential. The ROS generation caused by ceramide was prevented by the antioxidant N-acetylcysteine (NAC). Although ceramide induced release of cytochrome c from mitochondria and activation of caspase-3, the ceramide-induced cell death was partially prevented by caspase inhibitors. Addition of ceramide caused apoptosis-inducing factor (AIF) nuclear translocation, which was prevented by antioxidant. Taken together, these data suggest that ceramide induces cell death through both caspase-dependent and caspase-independent mechanisms mediated by ROS generation in hASCs. PMID- 21259060 TI - Nanosized TiO2 caused minor airflow limitation in the murine airways. AB - The use of nanotechnology is increasing exponentially, whereas the possible adverse health effects of engineered nanoparticles (NPs) are so far less known. Standardized mouse bioassay was used to study sensory and pulmonary irritation, airflow limitation, and inflammation potency of nanosized TiO(2). Single exposure (0.5 h) to in situ generated TiO(2) (primary particle size 20 nm; geometric mean diameters of 91, 113, and 130 nm at mass concentrations of 8, 20, and 30 mg/m(3), respectively; crystal phase anatase + brookite (3:1)) caused airflow limitation in the conducting airways at each studied exposure concentration, which was shown as a reduction in expiratory flow, being at the lowest 73% of baseline. The response was not dose dependent. Repeated exposures (altogether 16 h, 1 h/day, 4 days/week for 4 weeks) to TiO(2) at mass concentration of 30 mg/m(3) caused as intense airflow limitation effect as the single exposures, and the extent of the responses stayed about the same along the exposure days. Sensory irritation was fairly minor. Pulmonary irritation was more pronounced during the latter part of the repeated exposures compared to the single exposures and the beginning of the repeated exposures. Sensory and pulmonary irritation were observed also in the control group, and, therefore, reaction by-products (NO(2) and C(3)H(6)) may have contributed to the irritation effects. TiO(2) NPs accumulated mainly in the pulmonary macrophages, and they did not cause nasal or pulmonary inflammation. In conclusion, the irritation and inflammation potencies of studied TiO(2) seemed to be low. PMID- 21259062 TI - Effects of experiment start time and duration on measurement of standard physiological variables. AB - Duration and start time of respirometry experiments have significant effects on the measurement of basal values for several commonly measured physiological variables (metabolic rate, evaporative water loss and body temperature). A longer measurement duration reduced values for all variables for all start times, and this was an effect of reduced animal activity rather than random sampling. However, there was also an effect of circadian rhythm on the timing of minimal physiological values. Experiment start time had a significant effect on time taken to reach minimal values for all variables, ranging from 0400 hours +/- 38 min (body temperature, start time 2300 hours) to 0854 hours +/- 52 min (evaporative water loss, start time 1700 hours). It also influenced the time of day that minimal values were obtained, ranging from 2224 hours +/- 40 min (carbon dioxide production, start time 1500 hours) to 0600 hours +/- 57 min (oxygen consumption, start time 2300 hours), and the minimum values measured. Consequently, both the measurement duration and the experiment start time should be considered in experimental design to account for both a handling and a circadian effect on the animal's physiology. We suggest that experiments to measure standard physiological variables for small diurnal birds should commence between 1700 and 2100 hours, and measurement duration should be at least 9 h. PMID- 21259061 TI - Approaches to evaluating climate change impacts on species: a guide to initiating the adaptation planning process. AB - Assessing the impact of climate change on species and associated management objectives is a critical initial step for engaging in the adaptation planning process. Multiple approaches are available. While all possess limitations to their application associated with the uncertainties inherent in the data and models that inform their results, conducting and incorporating impact assessments into the adaptation planning process at least provides some basis for making resource management decisions that are becoming inevitable in the face of rapidly changing climate. Here we provide a non-exhaustive review of long-standing (e.g., species distribution models) and newly developed (e.g., vulnerability indices) methods used to anticipate the response to climate change of individual species as a guide for managers grappling with how to begin the climate change adaptation process. We address the limitations (e.g., uncertainties in climate change projections) associated with these methods, and other considerations for matching appropriate assessment approaches with the management questions and goals. Thorough consideration of the objectives, scope, scale, time frame and available resources for a climate impact assessment allows for informed method selection. With many data sets and tools available on-line, the capacity to undertake and/or benefit from existing species impact assessments is accessible to those engaged in resource management. With some understanding of potential impacts, even if limited, adaptation planning begins to move toward the development of management strategies and targeted actions that may help to sustain functioning ecosystems and their associated services into the future. PMID- 21259063 TI - Expression of matrix metalloproteinases (MMP-2 and MMP-9) in recurrent respiratory papillomas and laryngeal carcinoma: clinical and morphological parallels. AB - The task of the present study was to investigate the expression of MMP-2 and MMP 9 in recurrent respiratory papillomas (RRP) and accomplish a comparative analysis with those in laryngeal squamous cell carcinoma (LSCC). The immunohistochemical expression of MMP-2 and MMP-9 was investigated in specimens taken from RRP (n = 38) and LSCC (n = 39) patient groups, and the normal tissue of vocal fold (n = 12, control group). The expression of MMP-2 and MMP-9, both in epithelium and stroma cells, was graded on a semiquantitative scale, ranging from 0 (no expression) to 18 points (high expression). Statistically significant differences in the expression of MMP-2 and MMP-9, both in epithelium and stroma among the RRP, LSCC patients and control group (epithelium) with the LSCC group having the highest MMPs expression scores were revealed. However, no statistically significant correlations among expression of MMPs and clinical and/or morphological features were found in the group of RRP patients. The MMP-2 stroma value of 10.4 points was determined as the optimum point (limiting value) for separating RRP and LSCC patient groups. Results of the present study indicate that the expression of both MMP-2 and MMP-9 are up-regulated early in development of laryngeal papillomas, when the benign neoplastic lesion begins and the next determinant step is concerned with the occurrence of malignization. These results seem promising, as they may improve our understanding of the molecular events leading to the papilloma formation and development, however, further research is needed. PMID- 21259064 TI - Efficacy of glial growth factor and nerve growth factor on the recovery of traumatic facial paralysis. AB - The aim of this study was to assess the effects of Glial growth factor (GGF) and nerve growth factor (NGF) on nerve regeneration in facial nerve anastomosis. In this study, approximately a 1-mm segment was resected from the facial nerve and the free ends were anastomosed. All animals underwent the same surgical procedure and 30 rabbits were grouped randomly in three groups. Control group, the group without any medications; NGF group, the group receiving 250 ng/0.1 ml NGF in the epineurium at the site of anastomosis; GBF group, the group receiving 500 ng/0.1 ml GGF in the epineurium at the site of anastomosis. Medications were given at the time of surgery, and at 24 and 48 h postoperatively. After 2 months, the sites of anastomosis were excised and examined using the electron microscope. It was found that the best regeneration was in the group receiving GGF as compared to the control group in terms of nerve regeneration. Schwann cell and glial cell proliferation were found to be significantly higher in the group receiving GGF as compared to the group receiving NGF. Besides, the number of myelin debris, an indicator of degeneration, was significantly lower in the group with GGF as compared to NGF and control groups (p < 0.005). Using GGF and NGF in order to increase regeneration after nerve anastomosis in experimental traumatic facial nerve paralysis may be a hopeful alternative treatment option in the future. However, further studies on human studies are required to support these results. PMID- 21259065 TI - Dynamic changes in the leaf proteome of a C3 xerophyte, Citrullus lanatus (wild watermelon), in response to water deficit. AB - Wild watermelon (Citrullus lanatus) is a xerophyte native to the Kalahari Desert, Africa. To better understand the molecular mechanisms of drought resistance in this plant, we examined changes in the proteome in response to water deficit. Wild watermelon leaves showed decreased transpiration and a concomitant increase in leaf temperature under water deficit conditions. Comparison of the proteome of stressed plants with that of unstressed plants by two-dimensional gel electrophoresis revealed that the intensity of 40 spots increased in response to the stress, and the intensity of 11 spots decreased. We positively identified 23 stress-induced and 6 stress-repressed proteins by mass spectrometry and database analyses. Interestingly, 15 out of the 23 up-regulated proteins (65% of annotated up-regulated proteins) were heat shock proteins (HSPs). Especially, 10 out of the 15 up-regulated HSPs belonged to the small heat shock protein (sHSP) family. Other stress-induced proteins included those related to antioxidative defense and carbohydrate metabolism. Fifteen distinct cDNA sequences encoding the sHSP were characterized from wild watermelon. Quantitative real-time PCR analysis of the representative sHSP genes revealed strong transcriptional up-regulation in the leaves under water deficit. Moreover, immunoblot analysis confirmed that protein abundance of sHSPs was massively increased under water deficit. Overall, these observations suggest that the defense response of wild watermelon may involve orchestrated regulation of a diverse array of functional proteins related to cellular defense and metabolism, of which HSPs may play a pivotal role on the protection of the plant under water deficit in the presence of strong light. PMID- 21259066 TI - Structure-activity relationships of diphenyl-ether as protoporphyrinogen oxidase inhibitors: insights from computational simulations. AB - Protoporphyrinogen oxidase (PPO, EC 1.3.3.4), which has been identified as a significant target for a great family of herbicides with diverse chemical structures, is the last common enzyme responsible for the seventh step in the biosynthetic pathway to heme and chlorophyll. Among the existing PPO inhibitors, diphenyl-ether is the first commercial family of PPO inhibitors and used as agriculture herbicides for decades. Most importantly, diphenyl-ether inhibitors have been found recently to possess the potential in Photodynamic therapy (PDT) to treat cancer. Herein, molecular dynamics simulations, approximate free energy calculations and hydrogen bond energy calculations were integrated together to uncover the structure-activity relationships of this type of PPO inhibitors. The calculated binding free energies are correlated very well with the values derived from the experimental k (i) data. According to the established computational models and the results of approximate free energy calculation, the substitution effects at different position were rationalized from the view of binding free energy. Some outlier (e.g. LS) in traditional QSAR study can also be explained reasonably. In addition, the hydrogen bond energy calculation and interaction analysis results indicated that the carbonyl oxygen on position-9 and the NO(2) group at position-8 are both vital for the electrostatic interaction with Arg98, which made a great contribution to the binding free energy. These insights from computational simulations are not only helpful for understanding the molecular mechanism of PPO-inhibitor interactions, but also beneficial to the future rational design of novel promising PPO inhibitors. PMID- 21259067 TI - Examining perceptions about mental health care and help-seeking among rural African American families of adolescents. AB - Rural African American children living in poverty have a higher prevalence rate of mental health disorders than their urban counterparts. While access to mental health services is lacking in resource scarce rural communities, African American rural residents may also be the most likely to confront significant barriers to care and help-seeking. Studies of mental health help-seeking behavior among rural families are rare, even rarer are studies of African Americans living in these areas. To address this gap, the current study examined perceptions about help seeking for adolescents with mental health problems among rural African American families. Data were obtained from African American mothers in rural Georgia to assess their perceptions of the mental health service system, help-seeking processes, and service experiences. A mixed-method approach was implemented, integrating a quantitative survey (n = 163) with qualitative interviews (subsample n = 21). Most of the mothers expressed confidence in mental health care providers' to help. Preferred sources of support, however, were family, church, and schools. Community stigma towards children with mental health problems and their families was a frequently endorsed perceived barrier to help seeking. Although cultural mistrust was one of the two most frequently endorsed barriers in the survey, it did not emerge as a universal barrier to help-seeking for the mothers in this sample. Implications for research, policy, and practice include addressing family concerns about stigma, preferences for informal support and non-specialty services in addressing adolescents' mental health problems, and building community resources to enable all youth to participate in community life. PMID- 21259068 TI - A comparison of treatment outcomes among chronically homelessness adults receiving comprehensive housing and health care services versus usual local care. AB - Service use and 2-year treatment outcomes were compared between chronically homelessness clients receiving comprehensive housing and healthcare services through the federal Collaborative Initiative on Chronic Homelessness (CICH) program (n = 281) a sample of similarly chronically homeless individuals receiving usual care (n = 104) in the same 5 communities. CICH clients were housed an average of 23 of 90 days (52%) more than comparison group subjects averaging over all assessments over a 2-year follow-up period. CICH clients were significantly more likely to report having a usual mental health/substance abuse treater (55% vs. 23%) or a primary case manager (26% vs. 9%) and to receive community case management visits (64% vs. 14%). They reported receiving more outpatient visits for medical (2.3 vs. 1.7), mental health (2.8 vs. 1.0), substance abuse treatment (6.4 vs. 3.6), and all healthcare services (11.6 vs. 6.1) than comparison subjects. Total quarterly healthcare costs were significantly higher for CICH clients than comparison subjects ($4,544 vs. $3,326) due to increased use of outpatient mental health and substance abuse services. Although CICH clients were also more likely to receive public assistance income (80% vs. 75%), and to have a mental health/substance provider at all, they expressed slightly less satisfaction with their primary mental health/substance abuse provider (satisfaction score of 5.0 vs. 5.4). No significant differences were found between the groups on measures of substance use, community adjustment, or health status. These findings suggest that access to a well funded, comprehensive array of permanent housing, intensive case management, and healthcare services is associated with improved housing outcomes, but not substance use, health status or community adjustment outcomes, among chronically homeless adults. PMID- 21259069 TI - Cardio-renal syndromes: from foggy bottoms to sunny hills. AB - "Cardio-renal syndromes" (CRS) are disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The current definition has been expanded into five subtypes whose etymology reflects the primary and secondary pathology, the time-frame and simultaneous cardiac and renal co-dysfunction secondary to systemic disease: CRS type I: acute worsening of heart function (AHF-ACS) leading to kidney injury and/or dysfunction. CRS type II: chronic abnormalities in heart function (CHF CHD) leading to kidney injury or dysfunction. CRS type III: acute worsening of kidney function (AKI) leading to heart injury and/or dysfunction. CRS type IV: chronic kidney disease (CKD) leading to heart injury, disease and/or dysfunction. CRS type V: systemic conditions leading to simultaneous injury and/or dysfunction of heart and kidney. These different subtypes may have a different pathophysiological mechanism and they may represent separate entities in terms of prevention and therapy. PMID- 21259070 TI - Advanced glycation end-products, a pathophysiological pathway in the cardiorenal syndrome. AB - The prevalence of heart failure (HF) is increasing. A distinction is made between diastolic HF (preserved left ventricular ejection fraction (LVEF)) and systolic HF (reduced LVEF). Advanced glycation end-products (AGEs) are crystallized proteins that accumulate during ageing, but are particularly increased in patients with diabetes mellitus and in patients with renal failure. Through the formation of collagen crosslinks, and by interaction with the AGE-receptor, which impairs calcium handling and increases fibrosis, AGE-accumulation has pathophysiologically been associated with the development of diastolic and renal dysfunction. Interestingly, diastolic dysfunction is a frequent finding in elderly patients, diabetic patients and in patients with renal failure. Taken together, this suggests that AGEs are related to the development and progression of diastolic HF and renal failure. In this review, the role of AGEs as a possible pathophysiological factor that link the development and progression of heart and renal failure, is discussed. Finally, the role of AGE intervention as a possible treatment in HF patients will be discussed. PMID- 21259071 TI - Meta-analysis of laparoscopic versus open resection for hepatocellular carcinoma. AB - BACKGROUND: Laparoscopic liver resection (LLR) remains to be established as a safe and effective alternative to open liver resection (OLR) for hepatocellular carcinoma (HCC). AIMS: The aim of this meta-analysis is to compare laparoscopic versus open resection for HCC with regard to perioperative and oncologic outcomes. METHODS: A literature search was performed to identify comparative studies reporting outcomes for both laparoscopic and open resection for HCC. Pooled odds ratios (OR) and weighted mean differences (WMD with 95% confidence intervals (95% CI) were calculated using either the fixed effects model or random effects model. RESULTS: Ten nonrandomized controlled studies matched the selection criteria and reported on 494 subjects, of whom 213 underwent LLR and 281 underwent OLR for HCC. Compared with the perioperative results of open surgery, reports on laparoscopic resection indicate potentially favourable outcomes in terms of operative blood loss (WMD: -160.57, 95% CI: -246.49 to 74.66), blood transfusion requirement (OR: 0.39, 95% CI: 0.18 to 0.86), postoperative morbidity (OR: 0.48, 95% CI: 0.29 to 0.78), and length of hospital stay (WMD: -5.53, 95% CI: -7.89 to -3.16). Concerning the oncologic outcomes, there was no difference between groups in surgical margin, overall survival and disease-free survival. CONCLUSIONS: LLR for HCC is superior to the OLR in terms of its perioperative results and does not compromise the oncological outcomes. Therefore, LLR may be an alternative choice for treatment of HCC. PMID- 21259072 TI - Successful control of peristomal infection by introducer-type percutaneous endoscopic gastrostomy: a retrospective historical control study. AB - BACKGROUND: The techniques of percutaneous endoscopic gastrostomy are classified as the pull and introducer methods. Peristomal infection is the most common procedure-related complication in the pull method. OBJECTIVES: The objective of this study was to compare procedure-related complications between the two methods and to assess the outcome of long-term use of the introducer method. METHODS: Between January 1999 and November 2009, 116 patients received percutaneous endoscopic gastrostomy at Seoul St. Mary's Hospital in Korea. Before June 2006, the pull method was used for all patients; since then, every patient had been treated using the introducer method. We compared outcomes and complications within 180 days of gastrostomy placement for the two methods. RESULTS: The pull method was performed on 63 patients and the introducer method on 53 patients. The occurrence of peristomal infection within 30 days was significantly lower in the introducer method group than in the pull method group (1.9% vs. 36.5%, P = 0.001). Methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Klebsiella pneumoniae were the major organisms isolated from the peristomal infection. The requirement for catheter reinsertion because of displacement, obstruction, or damage to the catheter between 30 and 180 days was significantly higher in the introducer method group than in the pull method group (40.5% vs. 0%, P = 0.001). CONCLUSIONS: Our results suggest the superiority of the introducer method in terms of infection control. However, the balloon-type catheter is associated with problems such as balloon insufficiency in long-term use. PMID- 21259073 TI - Consensus interferon: tailored therapy and the impact of adherence. PMID- 21259074 TI - Clinical significance of perihepatic lymphadenopathy in patients with chronic hepatitis C infection. AB - BACKGROUND: Patients with chronic hepatitis C (HCV) infection commonly have perihepatic lymph node enlargement (PLNE). We investigated the prognostic value of PLNE in the development of complicated cirrhosis and death, as well as the clinical and laboratory factors associated with the presence of PLNE in a cohort of HCV-infected veterans. METHODS: Using a retrospective cohort design, we compared the rate of development of decompensated cirrhosis and/or death in a group of HCV-infected patients who did not have evidence of decompensated cirrhosis stratified by the presence or absence of PLNE. We used Kaplan-Meier survival curves. We then evaluated which factors were predictive of detection of PLNE using logistic regression. RESULTS: A total of 131 patients were included in the study. Fifty-nine patients had PLNE and 72 patients did not. After a mean follow-up of 42 months, survival in the absence of progression to decompensated cirrhosis and/or death was not significantly different between the two groups (log-rank test, p = 0.27). The only factor predictive of progression to decompensated cirrhosis and/or death was the presence of cirrhosis at baseline (HR 13.13, 95% CI 2.21-79.41). In addition, cirrhosis was the only factor predictive of the detection of PLNE on CT scan (OR 3.09: CI 2.1-25.9). CONCLUSIONS: Presence of PLNE in patients with chronic HCV infection is strongly associated with subclinical cirrhosis. However, PLNE does not independently predict the progression of liver disease to decompensated cirrhosis and/or death in HCV-infected patients. PMID- 21259075 TI - A study of chronic pelvic pain after radiotherapy in survivors of locally advanced cervical cancer. AB - INTRODUCTION: Chronic pelvic pain (persisting pain in hips, groins or lower back) is poorly described in studies of cervical cancer survivors (CCSs). The aims of this study were to describe chronic pelvic pain and associated variables in CCSs surveyed >5 years post-radiotherapy, and to compare the presence of pain in hips and lower back in CCSs with findings in the general female population. METHODS: Ninety-one CCSs treated with radiotherapy between 1994 and 1999 were in 2005 included in a cross-sectional questionnaire-based study. They were asked about demographic variables, clinical symptoms, mental distress, and quality of life (QOL). Normative data (NORM) were collected from a population-study of Norwegian females. RESULTS: Pain in lower back and hips was significantly more prevalent (p < .001) in CCSs compared to NORMs. 35/92 (38%) of the CCSs had chronic pelvic pain. These women had significantly lower QOL, higher levels of anxiety and depression and more bladder and intestinal problems than those without chronic pelvic pain. In a multivariable regression model, use of analgesics and intestinal and bladder problems were significantly associated with chronic pelvic pain in the CCSs. CONCLUSIONS: CCSs have a higher prevalence of pain in lower back and hips than women in the general population, which might be due to late effects of radiation. 35/92 (38%) of the CCSs suffer from chronic pelvic pain, shown to be associated with high overall mental and somatic morbidity. IMPLICATIONS FOR CANCER SURVIVORS: Evaluation and management of pelvic pain is important in follow-up of CCSs treated with radiotherapy. PMID- 21259076 TI - Backbone assignment and secondary structure of the PsbQ protein from photosystem II. AB - PsbQ is one of the extrinsic proteins situated on the lumenal surface of photosystem II (PSII) in the higher plants and green algae. Its three-dimensional structure was determined by X-ray crystallography with exception of the residues 14-33. To obtain further details about its structure and potentially its dynamics, we approached the problem by NMR. In this paper we report (1)H, (15)N, and (13)C NMR assignments for the PsbQ protein. The very challenging oligo proline stretches could be assigned using (13)C-detected NMR experiments that enabled the assignments of twelve out of the thirteen proline residues of PsbQ. The identification of PsbQ secondary structure elements on the basis of our NMR data was accomplished with the programs TALOS+, web server CS23D and CS-Rosetta. To obtain additional secondary structure information, three-bond H(N)-H(alpha) J coupling constants and deviation of experimental (13)C(alpha) and (13)C(beta) chemical shifts from random coil values were determined. The resulting "consensus" secondary structure of PsbQ compares very well with the resolved regions of the published X-ray crystallographic structure and gives a first estimate of the structure of the "missing link" (i.e. residues 14-33), which will serve as the basis for the further investigation of the structure, dynamics and interactions. PMID- 21259120 TI - Extension of the HA-detection based approach: (HCA)CON(CA)H and (HCA)NCO(CA)H experiments for the main-chain assignment of intrinsically disordered proteins. AB - Extensive resonance overlap exacerbates assignment of intrinsically disordered proteins (IDPs). This issue can be circumvented by utilizing (15)N, (13)C' and (1)H(N) spins, where the chemical shift dispersion is mainly dictated by the characteristics of consecutive amino acid residues. Especially (15)N and (13)C' spins offer superior chemical shift dispersion in comparison to (13)C(alpha) and (13)C(beta) spins. However, HN-detected experiments suffer from exchange broadening of amide proton signals on IDPs especially under alkali conditions. To that end, we propose here two novel HA-detected experiments, (HCA)CON(CA)H and (HCA)NCO(CA)H and a new assignment protocol based on panoply of unidirectional HA detected experiments that enable robust backbone assignment of IDPs also at high pH. The new approach was tested at pH 6.5 and pH 8.5 on cancer/testis antigen CT16, a 110-residue IDP, and virtually complete backbone assignment of CT16 was obtained by employing the novel HA-detected experiments together with the previously introduced iH(CA)NCO scheme. Remarkably, also those 10 N-terminal residues that remained unassigned in our earlier HN-detection based assignment approach even at pH 6.5 were now readily assigned. Moreover, theoretical calculations and experimental results suggest that overall sensitivity of the new experiments is also applicable to small or medium sized globular proteins that require alkaline conditions. PMID- 21259121 TI - External validation of a model to predict the survival of patients presenting with a spinal epidural metastasis. AB - The surgical treatment of spinal metastases is evolving. The major problem is the selection of patients who may benefit from surgical treatment. One of the criteria is an expected survival of at least 3 months. A prediction model has been previously developed. The present study has been performed in order to validate externally the model and to demonstrate that this model can be generalized to other institutions and other countries than the Netherlands. Data of 356 patients from five centers in Germany, Spain, Sweden, and the Netherlands who were treated for metastatic epidural spinal cord compression were collected. Hazard ratios in the test population corresponded with those of the developmental population. However, the observed and the expected survival were different. Analysis revealed that the baseline hazard function was significantly different. This tempted us to combine the data and develop a new prediction model. Estimating iteratively, a baseline hazard was composed. An adapted prediction model is presented. External validation of a prediction model revealed a difference in expected survival, although the relative contribution of the specific hazard ratios was the same as in the developmental population. This study emphasized the need to check the baseline hazard function in external validation. A new model has been developed using an estimated baseline hazard. PMID- 21259122 TI - Sleep and the brain. AB - Sleep is a fundamental behavior ubiquitous in the animal kingdom, necessary for the support of physical health and in humans for the maintenance of cognitive function. While it influences all body systems, it is particularly important for the brain and is typically characterized using measures of brain electrical activity. Sleep undergoes predictable changes across the lifespan, with notably dramatic alterations occurring during adolescence and with old age. Over and above the normal development changes, however, upwards of a third of the adult population experience some form of insomnia on a regular basis. This issue's special section on "Sleep through the Ages" contains papers addressing the neurological and neuropsychological implications of sleep in adolescents, older adults and insomnia sufferers, highlighting relations of sleep with brain structure and function. PMID- 21259123 TI - What choline metabolism can tell us about the underlying mechanisms of fetal alcohol spectrum disorders. AB - The consequences of fetal exposure to alcohol are very diverse and the likely molecular mechanisms involved must be able to explain how so many developmental processes could go awry. If pregnant rat dams are fed alcohol, their pups develop abnormalities characteristic of fetal alcohol spectrum disorders (FASD), but if these rat dams were also treated with choline, the effects from ethanol were attenuated in their pups. Choline is an essential nutrient in humans, and is an important methyl group donor. Alcohol exposure disturbs the metabolism of choline and other methyl donors. Availability of choline during gestation directly influences epigenetic marks on DNA and histones, and alters gene expression needed for normal neural and endothelial progenitor cell proliferation. Maternal diets low in choline alter development of the mouse hippocampus, and decrement memory for life. Women eating low-choline diets have an increased risk of having an infant with a neural tube or orofacial cleft birth defect. Thus, the varied effects of choline could affect the expression of FASD, and studies on choline might shed some light on the underlying molecular mechanisms responsible for FASD. PMID- 21259125 TI - "It is not that I forget, it's just that I don't want other people to know": barriers to and strategies for adherence to antiretroviral therapy among HIV patients in Northern Vietnam. AB - Antiretroviral therapy (ART) started to become more widely available in Vietnam in 2005. However, up to now, very little is known about factors influencing ART adherence among people living with HIV (PLHIV) in Vietnam. This qualitative study aimed to describe factors influencing ART adherence among PLHIV in a northern province in Vietnam, and to explore possibilities of home delivery of ART. Forty eight participants (36 men and 12 women), including patients on ART and their relatives, were divided in seven focus group discussions. The topics discussed included: adherence obstacles encountered during ART, methods patients used to enhance adherence, treatment support structures, and attitudes toward home delivery of ART. All interviews were audio-recorded, then transcribed in Vietnamese. Manual manifest and latent content analysis was applied for data analysis in order to elucidate the presence of, meaning of, and relationships between concepts in the text. Stigma was identified as a strong barrier to ART adherence, as patients feared that taking medications in the presence of other persons would lead to suspicion or inadvertent disclosure of their HIV status. In addition to desires for non-disclosure influencing PLHIV's adherence, it also shaped their attitudes toward opting for more confidential ways of receiving ART support and care. Home delivery of ART medications was seen as undesirable by participants, who feared that it might increase social stigmatization. Participants wished for more community-based support, preferably from PLHIV who had received sufficient training. Based on the results of this study, an intervention strategy using PLHIV as community-based adherence supporters is currently being evaluated in a randomized controlled trial intervention, including 640 patients in Quang Ninh, Vietnam. PMID- 21259124 TI - Mini-review: synaptic integration in the cerebellar nuclei--perspectives from dynamic clamp and computer simulation studies. AB - The cerebellar nuclei (CN) process inhibition from Purkinje cells (PC) and excitation from mossy and climbing fiber collaterals. CN neurons in slices show intrinsic pacemaking activity, which is easily modulated by synaptic inputs. Our work using dynamic clamping and computer modeling shows that synchronicity between PC inputs is an important factor in determining spike rate and spike timing of CN neurons and that brief pauses in PC inputs provide a potent stimulus to trigger CN spikes. Excitatory input can equally control spike rate, but, due to a large slow, NMDA component also amplifies responses to inhibitory inputs. Intrinsic properties of CN neurons are well suited to provide prolonged responses to strong input transients and could be involved in motor pattern generation. One such specific mechanism is given by fast and slow rebound bursting. Nevertheless, we are just beginning to unravel synaptic integration in the CN, and the outcome of the work to date is best characterized by the generation of new specific questions that lend themselves to a combined experimental and computer modeling approach in future studies. PMID- 21259126 TI - Structural barriers to adherence to antiretroviral therapy in a resource constrained setting: the perspectives of health care providers. AB - The present study examined the chief structural barriers to antiretroviral treatment (ART) adherence from the perspective of health care workers who provide treatment to patients living with HIV and AIDS in South Africa. The main barrier to adherence as identified by participants in the study was the stigma associated with living with HIV, and thus with receiving AIDS treatment. A second barrier was the fact that some patients willfully decide to forgo treatment so that they could retain state disability benefits associated with a low CD4 count. Other barriers included the lack of finances for transport to clinics and food insecurity, especially when medication needed to be taken with food. These barriers to ART adherence are conceptualized in terms of Bronfenbrenner's Ecological Systems Theory. PMID- 21259127 TI - Highly stressed: stressful and traumatic experiences among individuals with HIV/AIDS in the Deep South. AB - A history of traumatic and/or stressful experiences is prevalent among HIV infected individuals and has been consistently associated with poorer health outcomes. However, little is known about incident stressful experiences and the factors that predict these experiences among HIV-infected individuals. Data from a longitudinal study of 611 HIV-infected individuals in the Southeastern USA were used to examine the frequency and types of incident stress reported in a 27-month period and to determine predictors associated with three incident stress measures (all stressful events, severe stressful events, and traumatic events such as physical assault). Incident stressful experiences frequently occurred among study participants, as 91% reported at least one stressful experience (median=3.5 experiences) and 10% of study participants reported traumatic stress in any given nine-month reporting period. Financial stressors were the most frequently reported by study participants. Greater emotional distress, substance use, and a higher number of baseline stressful experiences were significantly associated with reporting a greater number of incident stressful experiences and any traumatic experiences. Study results indicate that efforts are needed to identify individuals at risk for traumatic events and/or substantial stressors and to address the factors, including mental health and substance abuse, that contribute to these experiences. PMID- 21259128 TI - The interrelationship of men's self-reports of sexual risk behavior and symptoms and laboratory-confirmed STI-status in India. AB - This paper describes the interrelationship among men's self-reports of symptoms, unsafe sexual behavior, and biologically tested sexually transmitted infections (STIs). Data are drawn from the baseline survey of six-year (2001-2007) research and intervention project on men's sexual health and HIV/STI risk reduction conducted in three urban poor communities in Mumbai, India. The survey collected a wide range of demographic, attitudinal, knowledge, and behavioral data. In addition, men were tested for common STIs by selecting a systematic random sub sample of 816 men (assuming 20% non-response). Data in this paper are based on 641 men who had completed the survey interview and for whom the testing of blood and urine samples was conducted. Results suggest that the self-reported STI-like symptoms and unsafe sexual behavior taken together as a predictor of confirmed STIs improve the sensitivity to a significantly greater degree (chi2 = 2.83, p<0.05) as compared to the sensitivity of self-reported STI-like symptoms or unsafe sexual behavior alone as a predictor of confirmed STIs. In addition, the consistency of self-report was found to vary among socio-demographic and behaviorally defined sub-groups. These results provide preliminary support for the importance of population-based surveys, which collect all the three types of data such as reported behavior, symptoms and laboratory confirmed STIs for a full understanding of sexual risk and STIs and for identification of sub-groups within communities that vary in their ability to identify STI symptoms. PMID- 21259129 TI - HIV-1 seroprevalence and risk factors for HIV infection among first-time psychiatric admissions in Uganda. AB - This study investigated HIV seroprevalence and it's correlates among patients with first-time psychiatric admissions to two national referral hospitals in urban Kampala, Uganda. A structured standardised evaluation was used to assess patients for: Diagnostic and Statistical Manual IV psychiatric diagnosis, socio demographics, sexual behaviour and HIV status (for those HIV-positive, CDC classification and CD4 cell counts). The HIV-1 seroprevalence was 18.4% (95% CI, 13.8-23.0%). Factors that were independently associated with HIV-1 seropositivity were female gender and older age (41+years) and after adjusting for sex and age group, the nature of the current episode (highest among those with first episode of mental illness) and psychiatric diagnoses (highest in the organic affective disorders and delirium, lowest in those with bipolar affective disorder and psychotic syndromes). These results demonstrate that the prevalence of HIV is high among patients with severe mental illness in Africa and that HIV/AIDS adds to the burden of mental illness in high HIV prevalence countries in sub-Saharan Africa. Both HIV care programmes and psychiatric care clinics should be made aware of the frequent association of HIV infection and mental illness, and adopt important diagnostic and care elements of these complementary disciplines in the training and the day-to-day work of clinicians, nurses and counsellors. PMID- 21259130 TI - HIV-testing behavior among young migrant men who have sex with men (MSM) in Beijing, China. AB - Previous studies suggested a rapid increase of HIV prevalence among men who have sex with men (MSM) in China in recent years, from 0.4% in 2004 to 5.8% in 2006. However, some MSM had never been tested for HIV. In order to expand the accessibility to HIV testing, understanding HIV-testing behavior and barriers among MSM is important. Using data collected from 307 young migrant MSM (aged 18 29 years) in 2009 in Beijing, we aimed to identify psychological and structural barriers to HIV testing. MSM were recruited through peer outreach, informal social networks, Internet outreach, and venue-based outreach. Participants completed a confidential self-administered questionnaire. Results show that about 72% of MSM ever had an HIV test. Logistic regression analysis indicated that the HIV-testing behavior was associated with sexual risk behaviors (e.g., multiple sexual partners and inconsistent condom use for anal sex) and history of sexually transmitted diseases. Eighty four MSM (28%) who never had an HIV test reported that the psychological barriers mainly were perceived low risk of HIV infection and fears of being stigmatized. The structural barriers reported inconvenience of doing test and lack of confidentiality. Future HIV prevention programs should be strengthened among MSM to increase their awareness of HIV risk. Efforts are needed to increase access to quality and confidential HIV testing among MSM and reduce stigma against MSM. PMID- 21259131 TI - Quality of life assessment in HIV-infection: validation of the European Portuguese version of WHOQOL-HIV. AB - The assessment of quality of life (QOL) in HIV infection has emerged as being vital to research and clinical practice. This assessment is also a challenge due to the specific characteristics of the infection, the increased availability of therapeutics, as well as the epidemiological variability inherent to HIV infection. The purpose of this study was to investigate the psychometric properties of the European Portuguese version of the World Health Organization's QOL Instrument in HIV Infection (WHOQOL-HIV) and to test its performance in a sample of HIV-infected patients. The European Portuguese version of WHOQOL-HIV was administered in a sample of 200 HIV-positive patients. The patients also completed the Portuguese versions of Beck Depression Inventory (BDI) and Brief Symptom Inventory (BSI). The WHOQOL-HIV showed quite an acceptable internal consistency (Cronbach's alpha ranged from 0.86 to 0.95 across domains). Convergent validity with BDI and BSI was satisfactory for all domains (all r>0.50; p<0.001). Moreover, correlations between domains and between domains and overall QOL were all statistically significant (p<0.001). The reliability and validity studies of the European Portuguese version of the WHOQOL-HIV revealed good psychometric characteristics, which allows for the use of this version of WHOQOL in our country, and cross-cultural comparability. PMID- 21259132 TI - HIV status disclosure among HIV-positive African and Afro-Caribbean people in the Netherlands. AB - HIV status disclosure is often characterized as a dilemma. On the one hand, disclosure can promote health, social support, and psychological well-being. On the other, disclosure can lead to stigmatization, rejection, and other negative social interactions. Previous research has shown that HIV status disclosure is a reasoned process whereby the costs and benefits to oneself and to others are weighed. As such, understanding disclosure requires understanding the reasons for and against disclosure employed by people living with HIV (PLWH). In this study, disclosure among a population disproportionately affected by HIV in the Netherlands, namely African and Afro-Caribbean diaspora, was investigated. Reasons for nondisclosure were fear of stigmatization, previous negative experiences with disclosure, having observed the stigmatization of other PLWH, shame, the desire to protect others - particularly one's children and family - from stigmatization by association and/or worrying, and the belief that one's HIV status is a private matter. Participants reported disclosing because they were in a close and supportive relationship, disclosure led to emotional release, disclosure could lead to emotional or financial support, they felt a perceived duty to inform, and they had a desire to educate others about sexual risk-taking. The findings suggest that stigma plays an important role in disclosure decisions among these populations. They further point to a need for HIV-related stigma reduction interventions in African and Afro-Caribbean communities and culturally sensitive counseling for PLWH whereby caregivers do not automatically assume that disclosure is best but rather provide a safe environment in which the costs and benefits of disclosure can be weighed and strategies for disclosure can be developed, if perceived as beneficial by PLWH. PMID- 21259133 TI - Financial impact of California's new law to increase HIV screening by mandating insurance coverage. AB - To increase HIV testing, in 2008 California's governor signed the first piece of legislation in the USA to require private health plans to cover the cost of HIV testing regardless of whether testing is related to a primary diagnosis. This study assesses the impacts of the bill on coverage, testing rate, and cost for 22,190,000 Californians. All targeted individuals had some form of coverage for HIV testing before the mandate. If minimum expansion of coverage occurs, overall expenditures on HIV testing are projected to increase by US$554,000 in the year following the adoption of the law. If testing broadens to comply with the Centers for Disease Control and Prevention (CDC) testing guidelines, annual expenditures are projected to increase by US$10,151,000. This policy change could serve as a step toward making HIV testing a routine screening test. However, the impact of this mandate largely depends on people's awareness and willingness to adopt the CDC guidelines. PMID- 21259134 TI - Is 80% a passing grade? Meanings attached to condom use in an abstinence-plus HIV prevention programme in South Africa. AB - This study represents the first qualitative exploration of how condoms are perceived by at-risk youth, their parents, their teachers and HIV prevention programme staff in an abstinence-plus HIV prevention programme. Behavioural interventions for HIV prevention with youth may be divided into three categories, each with a different approach to condoms: abstinence-only, abstinence-plus and comprehensive approaches. Research has highlighted the limitations of abstinence only approaches and the emergence of early support for abstinence-plus interventions as HIV prevention strategies. Furthermore, research consistently demonstrates that condoms are socially mediated, reflecting diverse norms. However, there is a gap in the literature in terms of how condom use is framed, understood and represented by those delivering and receiving an abstinence-plus programme. This is critically important because advocates of a comprehensive approach to HIV prevention have flagged concern with the degree to which abstinence-plus programming may undermine confidence in condom use. Therefore, this study analyses meanings attached to condom use by stakeholders in an abstinence-plus HIV prevention programme in South Africa. Results demonstrate diverse meanings attached to condom use, including: condoms as second best to abstinence; condoms as a gendered response to HIV; condoms as a source of mockery; condoms as futile in a high-prevalence setting; condoms as part of conspiracy beliefs along racial and colonial lines; and, condoms as popular in HIV prevention because they can be counted. These findings have particular bearing for abstinence-plus HIV prevention programmes, which face the double challenge of (1) engaging with condom promotion in a way that takes into account their diverse social meanings, and (2) promoting condoms within their hierarchical framework of options in a way that does not inadvertently discourage their use. PMID- 21259135 TI - High prevalence of food insecurity among HIV-infected individuals receiving HAART in a resource-rich setting. AB - This study aimed to assess the prevalence and correlates of food insecurity in a cohort of HIV-infected individuals on highly active antiretroviral therapy (HAART) in British Columbia (BC), Canada. Adults receiving HAART voluntarily enrolled into the Longitudinal Investigations into Supportive and Ancillary Health Services (LISA) cohort. Individual food insecurity was measured using a modified version of the Radimer/Cornell Questionnaire. We performed bivariate analyses to determine differences between explanatory variables for individuals who were food secure and food insecure. We performed logistic regression to determine independent predictors of food insecurity. Of the 457 individuals enrolled in the LISA cohort, 324 (71.0%) were found to be food insecure. Multivariate analysis indicated that individuals who had an annual incomes less than $15,000 (odds ratio [OR] 3.15, 95% confidence interval [CI] 1.83, 5.44), used illicit drugs (OR 1.85, 95% CI 1.03, 3.33), smoked tobacco (OR 2.30, 95% CI 1.30, 4.07), had depressive symptoms (OR 2.34, 95% CI 1.38, 3.96), and were younger (OR 0.95, 95% CI, 0.92, 0.98) were more likely to be food insecure. Our results demonstrated a high (71%) prevalence of food insecurity among HIV infected individuals receiving HAART in this resource-rich setting, and that food insecurity is associated with a compendium of environmental and behavioral factors. More research is needed to understand the biological and social pathways linking food insecurity to these variables in order to identify program strategies that can effectively improve food security among HIV-infected populations. PMID- 21259136 TI - An evaluation of the impact of a community-based adherence support programme on ART outcomes in selected government HIV treatment sites in South Africa. AB - This study assessed the impact of a community-based adherence support service on the outcomes of patients on antiretroviral therapy (ART). The evaluation was a retrospective study based on patient clinical records. This study noted that a significantly higher proportion of patients with a community-based adherence supporter (also known as a patient advocate, PA) had viral load (VL) of less than 400 copies/ml at six months of treatment (70%, p=0.001); a significantly higher proportion of patients with PAs (89%) attained a treatment pickup rate of over 95% (67%; p=0.021). Patients at health facilities with PA services maintained a suppressed VL for a longer period as opposed to patients at health facilities without PA services (p=0.001), also patients at health facilities with PA services remained in care for longer periods (p=0.001). Therefore, the study concludes that integrated community-based adherence support is crucial in ensuring that patients remain in care, regularly pickup their treatment from ART clinics and are virologically suppressed. The study also underscores the importance of access to health services and the presence of an enabling environment in the treatment of AIDS. PMID- 21259137 TI - The attitudes of primary schoolchildren in Northern Thailand towards their peers who are affected by HIV and AIDS. AB - After more than a decade of the AIDS epidemic in Thailand, the number of children whose parents are living with HIV or have died from AIDS is increasing significantly and it has been reported that these children are often discriminated against by their peers. In order to better understand the current situation and to explore possible strategies to support HIV-affected children, this study examined children's attitudes towards HIV and AIDS using questionnaires and focus group discussions with children in Grades three-six in five primary schools in a northern province in Thailand. A total of 513 children (274 boys and 239 girls) answered the questionnaire and five focus groups were organised. The findings showed a strong positive correlation between children's belief that HIV could be transmitted through casual contact and their negative attitudes towards their HIV-affected peers. Most children overestimated the risk of HIV transmission through casual contact and this made their attitudes less tolerant and less supportive. After HIV prevention education (which included information on HIV transmission routes) was given in three of the study schools, the same questionnaire and focus groups were repeated and the findings showed that children's attitudes had become more supportive. These findings suggest that HIV prevention education delivered through primary schools in Thailand can be an effective way to help foster a more supportive and inclusive environment and reduce the stigma and discrimination that decrease educational access and attainment for HIV-affected schoolchildren. PMID- 21259138 TI - Home is where the HAART is: an examination of factors affecting neighbourhood perceptions among people with HIV/AIDS on antiretroviral therapy. AB - Understanding the neighbourhood perceptions of individuals living with HIV in urban and non-urban areas may help identify potential barriers to uptake and effectiveness of therapy. We evaluate how neighbourhood perceptions are influenced by socio-economic factors, such as food security and stable housing and other explanatory variables, among individuals receiving highly active antiretroviral therapy (HAART) in British Columbia. Neighbourhood perceptions, quality of life and socio-demographic information were collected in an interviewer-administered survey with study participants. Perception of neighbourhood problems, perception of neighbourhood cohesion and perception of relative standard of living were evaluated using previously defined scales. Bivariate and multivariate analyses were carried out to determine associations with neighbourhood perceptions, food security and stable housing. Our analyses were based on 457 participants, of whom 133 (29%) were food secure and 297 (65%) had stable housing. Mean scores for perceptions of neighbourhood problems and cohesion were 35 (IQR 15-58) and 57 (IQR 46-69), respectively. Being food secure and having stable housing was associated with a 9% and 11% decrease in perception of neighbourhood problems, respectively, and a 6% increase in the perception of neighbourhood cohesion in both cases. Food security and stable housing are related to neighbourhood perceptions among individuals on HAART. The results point to potential targets for intervention, involving improvements to living conditions such as housing and food security, which may promote treatment success for HAART, especially in marginalized communities. PMID- 21259139 TI - Sexual partner types and related sexual health risk among out-of-school adolescents in rural south-west Uganda. AB - This paper defines the range of sexual partners chosen by out-of-school adolescents from Masaka District in rural south-west Uganda, and implications for sexual and reproductive health discussed. Data are drawn from a sexual health needs assessment using applied anthropological techniques with 31 adolescents, their parents, guardians and community leaders. Data were analysed using inductive thematic methods. Out-of-school adolescents are exposed to risk both stable and casual sexual relationships. Young men and women want a stable relationship with one reliable partner. Young men seek a "steady" relationship with younger schoolgirls; some also seek multiple "casual" relationships with young women easily convinced with gifts. Young women accept "permanent" partnerships with traders or transport workers one-three years older than themselves; some accept "casual" relationship with age mates, others have "casual" relationships with older men. All relationships involve the exchange of gifts and money. Older partners, or "sugar daddies", are valued, despite the knowledge they are more likely to be HIV positive, because they offer greater financial rewards than age mates. Though far less common, some older women seek relationships with younger men, but are treated with suspicion by young men, who believe they are seeking to "infect" them "maliciously" with AIDS. The community sees these relationships as a source of AIDS in adolescents, and condemn older men, whom they believe to be "killing" the younger generation. Both young men and women are exposure to sexual health risk in their primary partnerships; young men in partnerships with schoolgirls who have concurrent partnerships with older men, unlikely to use condoms and young women with partners who work, and have casual relationships in urban trading centres. Health promotion encouraging partnership with age mates, discouraging sex with older partners and 100% condom use before marriage are most appropriate for out-of-school adolescents in this context. PMID- 21259140 TI - HIV-related stigma among South Asians in Toronto. AB - OBJECTIVES: This paper explores the nature of HIV-related stigma among South Asians in Toronto, its consequences for people living with it and its role in determining access to HIV services. DESIGN: The study is based on data from four focus group discussions with members of an HIV outreach organization, HIV positive men and women, and women of different ages from the mainstream South Asian community. The questions were adapted from the Explanatory Model Interview Catalog that has been widely used to assess health-related stigma. RESULTS: HIV related stigma was found to be high in Toronto's South Asian community. Respondents perceived it to be greater among South Asians than in other Canadian communities. South Asian families were said to harbor the most stigma, often rejecting HIV-positive members. Differences were noted between first- and second generation South Asian migrants in knowledge about, and stigma toward, HIV. Women living with HIV were found to be particularly disadvantaged and stigmatized. Because of stigma, many people living with HIV concealed their illness and avoided HIV-related services. CONCLUSION: Major gaps in knowledge about HIV among Canadian South Asians, and a considerable amount of stigma against people living with HIV, were found. The implications of stigma were highly problematic for people living with HIV, impeding access to services and social support. The paper concludes with recommendations to address stigma, based on suggestions from the study's participants. PMID- 21259141 TI - Comparison of major biocontrol strains of non-aflatoxigenic Aspergillus flavus for the reduction of aflatoxins and cyclopiazonic acid in maize. AB - Biological control of toxigenic Aspergillus flavus in maize through competitive displacement by non-aflatoxigenic strains was evaluated in a series of field studies. Four sets of experiments were conducted between 2007 and 2009 to assess the competitiveness of non-aflatoxigenic strains when challenged against toxigenic strains using a pin-bar inoculation technique. In three sets of experiments the non-aflatoxigenic strain K49 effectively displaced toxigenic strains at various concentrations or combinations. The fourth study compared the relative competitiveness of three non-aflatoxigenic strains (K49, NRRL 21882 from Afla-Guard(r), and AF36) when challenged on maize against two aflatoxin- and cyclopiazonic acid (CPA)-producing strains (K54 and F3W4). These studies indicate that K49 and NRRL 21882 are superior to AF36 in reducing total aflatoxin contamination. Neither K49 nor NRRL 21882 produce CPA and when challenged with K54 and F3W4, CPA and aflatoxins were reduced by 84-97% and 83-98%, respectively. In contrast, AF36 reduced aflatoxins by 20% with F3W4 and 93% with K54 and showed no reduction in CPA with F3W4 and only a 62% reduction in CPA with K54. Because AF36 produces CPA, high levels of CPA accumulate when maize is inoculated with AF36 alone or in combination with F3W4 or K54. These results indicate that K49 may be equally effective as NRRL 21882 in reducing both aflatoxins and CPA in maize. PMID- 21259142 TI - Co-contamination of aflatoxin B1 and fumonisin B1 in food and human dietary exposure in three areas of China. AB - Aflatoxins and fumonisins are ubiquitous foodborne toxicants and the co occurrence of these mycotoxins in human foods represents a significant public health concern, which has been strongly associated with human aflatoxicosis, neural tube defects, as well as many types of primary cancers. In this study the co-contamination of aflatoxin B(1) (AFB(1)) and fumonisin B(1) (FB(1)) in food and human dietary exposure was investigated in residents of three different areas of China. A total of 209 food samples were measured for AFB(1) and FB(1). The median AFB(1) levels were 13.5, 2.3 and 1.3 ug kg(-1) and the median FB(1) levels were 2.6, 0.4 and 0.3 mg kg(-1) in corn samples collected from Huaian (a high risk area for oesophageal cancer), Fusui (a high-risk area for liver cancer) and Huantai (a low-risk area for both oesophageal and liver cancers), respectively. The median level of AFB(1) in plant oil of Fusui was the highest (52.3 ug kg(-1)) among all food samples analysed. Co-contamination of these two mycotoxins was found in corn, rice and wheat flour. Based on measured food consumption data, the averaged daily dietary intake of AFB(1) was 0.397 ug (range = 0.269-1.218 ug) in residents of Huantai, 1.723 ug (0.224-49.772 ug) in Huaian, and 2.685 ug (1.006 14.534 ug) in Fusui. The averaged FB(1) daily dietary intake was 92.4 ug (range = 55.0-362.1 ug) for residents of Huantai, 460.0 ug (83.2-2894.5 ug) in Huaian, and 138.6 ug (30.0-10,541.6 ug) in Fusui. These data suggest that the co-exposure to AFB(1) and FB(1) in residents of rural China may contribute to the aetiology of human chronic diseases in high-risk areas. PMID- 21259143 TI - Educating leaders in hospital management: a pre-post study in Ethiopian hospitals. AB - Despite recent focus on health systems strengthening, few studies report large scale efforts to improve hospital management capacity in low-income countries, a central component of improving health care delivery. We sought to assess the contributions of a systems-based approach, the Ethiopian Hospital Management Initiative (EHMI), which established hospital chief executive officers (CEOs) trained through a Masters of Healthcare and Hospital Administration (MHA) degree programme in Ethiopia. We conducted a pre-post study of 24 hospitals that are managed by CEOs in the MHA programme. We measured changes in hospital functioning based on adherence to a set of 86 hospital performance standards across 12 management domains published in the Standards for Hospital Management in Ethiopia. We found that adherence to hospital performance standards increased significantly during the one-year follow-up (27% compared with 51% of standards met at baseline and follow-up, respectively; P-value < 0.001); overall improvement was driven by improvement in seven of the 12 management domains. The EHMI is an example of health systems strengthening with focus on building hospital management capacity. Early evidence suggests that the establishment of hospital CEOs and MHA training to equip them with management skills may promote scalable improvements in health facility functioning. PMID- 21259144 TI - A state survey of Child Advocacy Center therapists' attitudes toward treatment manuals and evidence-based practice. AB - The objective of this descriptive study was to examine Child Advocacy Center therapists' attitudes toward treatment manuals and evidence-based practices and to gather information about the treatments they use most frequently. An online survey was sent to 30 therapists employed by 15 Child Advocacy Centers in a southeastern state. The response rate was 70%. The respondents generally had positive attitudes toward the use of treatment manuals and the implementation of evidence-based practices. The treatment utilized most frequently was trauma focused cognitive-behavioral therapy. More outcome research of Child Advocacy Center services is needed, and information about how children and parents perceive the acceptability and outcomes of Child Advocacy Center services can be used to enhance services. PMID- 21259145 TI - Game-based cognitive-behavioral therapy (GB-CBT) group program for children who have experienced sexual abuse: a preliminary investigation. AB - This preliminary investigation examined the efficacy of a game-based cognitive behavioral therapy group program for elementary school-aged children who have experienced sexual abuse. Treatment aimed to improve: (a) internalizing symptoms, (b) externalizing behaviors, (c) sexually inappropriate behaviors, (d) social skills deficits, (e) self-esteem problems, and (f) knowledge of healthy sexuality and self-protection skills. Results indicate that game-based cognitive-behavioral therapy was effective for improving internalizing and externalizing symptoms, reducing sexually inappropriate behaviors, and improving children's knowledge of abuse and self-protection skills. Although results pointed in a positive direction for social skills and self-perception, these findings were not statistically significant. Clinical significance was also evaluated to assess the clinical utility of treatment effects. Treatment implications of the findings and future research directions are discussed. PMID- 21259146 TI - Practical ways psychotherapy can support physical healthcare experiences for male survivors of childhood sexual abuse. AB - Many survivors of child sexual abuse who engage in psychotherapy also experience physical health problems. This article summarizes the findings of a multiphased qualitative study about survivors' experiences in healthcare settings. The study informed the development of the Handbook on Sensitive Practice for Health Care Practitioners: Lessons from Adult Survivors of Childhood Sexual Abuse (Schachter, Stalker, Teram, Lasiuk, & Danilkewich, 2009), which is intended to help healthcare providers from all disciplines understand the effect of child sexual abuse on some survivors' abilities to access and benefit from health care. This paper discusses what psychotherapists can learn from the healthcare experiences of the male survivors who participated in this project. It also offers practical suggestions for supporting male clients who experience difficulty seeking treatment for physical health concerns. PMID- 21259147 TI - An exploratory qualitative study of the self-reported impact of female perpetrated childhood sexual abuse. AB - The limited findings on the impact of female-perpetrated sexual abuse of children are often contradictory, particularly in relation to males. In this exploratory qualitative study, a sample of nine men and five women who reported that they had been sexually abused by women in their childhood were recruited from the general community. They completed a questionnaire that asked them to describe various aspects of their abuse experiences and the perceived consequences. For both men and women, the abuse was associated with negative outcomes across a range of functional areas in both childhood and adulthood. Many impacts were similar to those reported by victims of male-perpetrated sexual abuse. It is argued that the consequences of female-perpetrated child sexual abuse are serious, and further research is required to bring these issues to the awareness of both the public and professionals working in the field of child protection and counseling. PMID- 21259148 TI - Differences between sexually victimized and nonsexually victimized male adolescent sexual abusers: developmental antecedents and behavioral comparisons. AB - This study compares sexually victimized and nonsexually victimized male adolescent sexual abusers on a number of variables. Self-report measures were administered to 325 male sexually abusive youth (average age 16) in six residential facilities in the Midwest, 55% of whom reported sexual victimization. The results indicate that the sexually victimized sexual abusers have more severe developmental antecedents (trauma, family characteristics, early exposure to pornography and personality) and recent behavioral difficulties (characteristics of sexual aggression, sexual arousal, use of pornography, and nonsexual criminal behavior) than the nonsexually victimized group. Results are contrasted with recent typological research, which found no relationship between sexual victimization and subtype membership. Treatment, research, and theoretical implications are discussed. PMID- 21259149 TI - Sentencing outcomes of convicted child sex offenders. AB - This research examines the sentencing outcomes of convicted child sexual offenders from data collected over an eight year period. Multiple regression and nominal log linear regression are used to examine length of prison sentence, length of probation sentence, and whether the convicted offender is actually sent to prison or to probation. While many independent variables appear to be related to sentence outcome, they fall into three categories: characteristics of the offender, characteristics of the victim, and characteristics of the crime. Additionally, while many variables appear related at the bivariate level, when multivariate analysis is applied, fewer variables remain significant, and these are mostly from the characteristics of the offense. PMID- 21259151 TI - Associations between young adults' use of sexually explicit materials and their sexual preferences, behaviors, and satisfaction. AB - This study examined how levels of sexually explicit material (SEM) use during adolescence and young adulthood were associated with sexual preferences, sexual behaviors, and sexual and relationship satisfaction. Participants included 782 heterosexual college students (326 men and 456 women; M(age) = 19.9) who completed a questionnaire online. Results revealed high frequencies and multiple types and contexts of SEM use, with men's usage rates systematically higher than women's. Regression analyses revealed that both the frequency of SEM use and number of SEM types viewed were uniquely associated with more sexual experience (a higher number of overall and casual sexual intercourse partners, as well as a lower age at first intercourse). Higher frequencies of SEM use were associated with less sexual and relationship satisfaction. The frequency of SEM use and number of SEM types viewed were both associated with higher sexual preferences for the types of sexual practices typically presented in SEM. These findings suggest that SEM use can play a significant role in a variety of aspects of young adults' sexual development processes. PMID- 21259152 TI - Young adults and casual sex: the relevance of college drinking settings. AB - This study investigated the relevance of college drinking settings on the likelihood of students having sexual intercourse with a stranger. A random sample of 7,414 undergraduates at 14 public California universities responded to questions regarding frequency of attendance at six different setting types since the beginning of the semester (e.g., Greek, residence-hall parties, and bars or restaurants), drinking behavior, and sexual activity. Multi-level modeling examined the association between each setting type and the occurrence of alcohol related sexual intercourse with a stranger. Findings indicated strong, positive associations between frequency of attendance at Greek parties, residence-hall parties, off-campus parties, and the occurrence of alcohol-related sex with a stranger. Frequency of attending the six settings and proportion of times drunk at the settings were also positively associated with alcohol-related sex with a stranger. Efforts aimed at preventing outcomes associated with casual sex (e.g., pregnancy, sexually transmitted infections, or mental health) should target specific drinking settings where students might be at high risk for risky alcohol use and unsafe sex behaviors. PMID- 21259153 TI - Challenges faced by editors. PMID- 21259154 TI - Differences between the sexes in technical mastery of rhythmic gymnastics. AB - The aims of this study were to determine possible differences between the sexes in specific rhythmic gymnastics techniques, and to examine the influence of various aspects of technique on rhythmic composition performance. Seventy-five students aged 21 +/- 2 years (45 males, 30 female) undertook four test sessions to determine: coefficients of asymmetry, stability, versatility, and the two rhythmic compositions (without apparatus and with rope). An independent-sample t test revealed sex-based differences in technique acquisition: stability for ball (P < 0.05; effect size = 0.65) and club (P < 0.05; effect size = 0.79) performance and rhythmic composition without apparatus (P < 0.05; effect size = 0.66). Multiple regression analysis revealed that the variables for assessing stability (beta = 0.44; P < 0.05) and versatility (beta = 0.61; P < 0.05) explained 61% of the variance in the rhythmic composition performance of females, and the variables for assessing asymmetry (beta = -0.38; P < 0.05), versatility (beta = 0.32; P < 0.05), and stability (beta = 0.29; P < 0.05) explained 52% of the variance in the rhythmic composition performance of males. The results suggest that female students dominate in body skill technique, while male students have the advantage with apparatus. There was a lack of an expressive aesthetic component in performance for males. The need for ambidexterity should be considered in the planning of training programmes. PMID- 21259155 TI - Optimizing kick rate and amplitude for Paralympic swimmers via net force measures. AB - Kicking is a key component of freestyle swimming yet the optimum combination of kick rate and kick amplitude remains unknown. For Paralympic swimmers, with upper and lower limb disabilities, the influence of the kick plays an important role in net force production. To determine optimum kick characteristics, 12 Paralympic swimmers aged 19.8 +/- 2.9 years (mean +/- s) were towed at their individual peak freestyle speed. The experimental conditions were (i) a prone streamline glide for passive trials and (ii) maximal freestyle kicking in a prone streamline for active trials at different speeds and kick amplitudes. Kick rate was quantified using inertial sensor technology. Towing speed was assessed using a novel and validated dynamometer, and net force was assessed using a Kistler force-platform system. When peak speed was increased by 5%, the active force increased 24.2 +/- 5.3% (90% confidence limits), while kick rate remained at approximately 150 kicks per minute. Larger amplitude kicking increased the net active force by 25.1 +/- 10.6%, although kick rate decreased substantially by 13.6 +/- 5.1%. Based on the current kick rate and amplitude profile adopted by Paralympic swimmers, these characteristics are appropriate for optimizing net force. PMID- 21259156 TI - The long-term athlete development model: physiological evidence and application. AB - Within the UK, the "Long Term Athlete Development" (LTAD) model has been proposed by a variety of national governing bodies to offer a first step to considering the approach to talent development. The model, which is primarily a physiological perspective, presents an advancement of understanding of developing athletic potential alongside biological growth. It focuses on training to optimize performance longitudinally, and considers sensitive developmental periods known as "windows of opportunity". However, it appears that there are a number of problems with this theoretical model that are not necessarily transparent to coaches. Principally, the model is only one-dimensional, there is a lack of empirical evidence upon which the model is based, and interpretations of the model are restricted because the data on which it is based rely on questionable assumptions and erroneous methodologies. Fundamentally, this is a generic model rather than an individualized plan for athletes. It is crucial that the LTAD model is seen as a "work in progress" and the challenge, particularly for paediatric exercise scientists, is to question, test, and revise the model. It is unlikely that this can be accomplished using classical experimental research methodology but this should not deter practitioners from acquiring valid and reliable evidence. PMID- 21259157 TI - Effect of hand paddles and parachute on the index of coordination of competitive crawl-strokers. AB - We investigated the effects of hand paddles and parachute on the relative duration of stroke phases and index of coordination of competitive crawl strokers. Eleven male-swimmers (age: 21.9 +/- 4.5 years; 50-m best time: 24.23 +/ 0.75 s) were evaluated in four maximal-intensity conditions: without equipment, with hand paddles, with parachute, and with both hand paddles and parachute. Relative stroke phase duration of each arm, swimming velocity, and stroke rate were analysed from video (60 Hz). The index of coordination was quantified based on the lag time between propulsive phases of each arm, which defined the coordination mode as catch-up, opposition or superposition. The stroke rate decreased in all conditions (P < 0.05) and swimming velocity decreased with parachute and with paddles + parachutes (P < 0.05). The coordination mode changed from catch-up in free swimming (-2.3 +/- 5.0%) to opposition with paddles (-0.2 +/- 3.8%), parachute (0.1 +/- 3.1%), and paddles + parachute (0.0 +/- 3.2%). Despite these variations, no significant differences were observed in relative duration of right and left arm-stroke phases, or in index of coordination. We conclude that the external resistances analysed do not significantly influence stroke phase organization, but, as a chronic effect, may lead to greater propulsive continuity. PMID- 21259158 TI - One face or two? Contrasting different versions of the chimeric faces test. AB - The chimeric faces test is a frequently used behavioural test of lateralisation; however the methodologies used vary considerably. In this experiment the one- and two-face versions of the test, using neutral/happy chimeras, were compared to see whether the laterality biases found are correlated. Both versions showed a significant left visual field (or half face) bias, indicating that both reflect the underlying right hemisphere superiority for processing positive facial emotion. Furthermore, the laterality bias was significantly correlated in both versions although reliability was higher for the two-face version. PMID- 21259159 TI - Oligonucleotide labeling using BODIPY phosphoramidite. AB - 4,4-Difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) derivatives were prepared and their photochemical properties were characterized. One such analogue, 4,4 difluoro-4-bora-1,3,5,7-tetramethyl-8-(5-hydroxypentyl)-3a,4a-diaza-s-indacene was transformed into the corresponding phosphoramidite and incorporated into oligodeoxyribonucleotides as a fluorescent reporter group. PMID- 21259160 TI - Further optimization of detritylation in solid-phase oligodeoxyribonucleotide synthesis. AB - Various conditions for optimum detritylation (i.e., the removal of 5'-O-trityl protecting groups) during solid-phase synthesis of oligodeoxyribonucleotides were investigated. Di- and tri-chloroacetic acids of variable concentrations were used to study the removal of the 4,4'-dimethoxytrityl (DMTr) group. It was found that the DMTr group could be completely removed under much milder acidic conditions than what are currently used for automated solid-phase synthesis. The 2,7 dimethylpixyl (DMPx) is proposed as an alternative and more readily removable group for the protection of the 5'-OH functions both in solid- and solution-phase synthesis. The improved detritylation conditions are expected to minimize the waste and offer a protocol for incorporation of acid sensitive building-blocks in oligonucleotides. PMID- 21259161 TI - An extracellullar nuclease from Bacillus firmus VKPACU-1: specificity and mode of action. AB - An extracellular nuclease from Bacillus firmus VKPACU-1 was multifunctional enzyme, this nuclease hydrolyzed poly U rapidly and more preferentially than the other homopolyribonucleotides. Hydrolysis of RNA this enzyme released mononucleotides in the order 5'UMP > 5'AMP > 5'GMP where as in hydrolysis of DNA the mononucleotides in the order of 5'dAMP > 5'dGMP > 5'dTMP and oligonucleotides. Uridylic linkages in RNA and adenylic linkages in DNA were preferentially cleaved by the nuclease. Nuclease produced oligonucleotides having only 3' hydroxyl and 5' phosphate termini. Present nuclease hydrolyzed RNA and DNA released oligonucleotides as major end products and mononucleotides, suggesting an endo mode of action. PMID- 21259162 TI - Oligonucleotide analogs with peptide internucleotide linkages. AB - Oligonucleotide analogs containing one or a few glycine, L-, and D-alanine or L and D-phenylalanine residues instead of phosphodiesterinternucleotide linkages were synthesized. The stability of the duplexes formed by modified oligonucleotides and their wildtype complements was studied. Oligonucleotides with D-alanine residues in internucleotide linkages form duplexes more stable than native ones (DeltaT(m) +0.2 degrees C per modification), whereas other modifications destabilize the duplexes. PMID- 21259163 TI - Synthesis and DNA binding studies of Mg(II) complex of Schiff base derived from vanillin and L-tryptophan. AB - The Mg(II) complex of Schiff base (K[HL]) derived from vanillin and L-tryptophan could bind with herring sperm DNA. The binding behaviors between them in physiological pH environment (pH 7.40) have been studied by spectroscopy, cyclic voltammetry and viscosity methods. Binding ratios of n(Mg(II)): n(K[HL]) = 1:1 and n(Mg(II)L): n(DNA) = 5:1 were confirmed. The obtained thermodynamic parameters suggest that the interaction between Mg(II)L and DNA is driven mainly by entropy. Combined with fluorimeteric studies, cyclic voltammetry, CD spectroscopy and viscosity methods, the results indicate the interaction modes between Mg(II)L and DNA are mainly with intercalation and involving some electrostatic interaction. PMID- 21259164 TI - Interrupted 2'-o,4'-C-aminomethylene bridged nucleic acid modification enhances pyrimidine motif triplex-forming ability and nuclease resistance under physiological condition. AB - Due to instability of pyrimidine motif triplex DNA at physiological pH, triplex stabilization at physiological pH is crucial in improving its potential in various triplex formation-based strategies in vivo, such as regulation of gene expression, mapping of genomic DNA, and gene-targeted mutagenesis. To this end, we investigated the effect of our previously reported chemical modification, 2' O,4'-C-aminomethylene bridged nucleic acid (2',4'- BNA(NC)) modification, introduced into interrupted and continuous positions of triplex-forming oligonucleotide (TFO) on pyrimidine motif triplex formation at physiological pH. The interrupted 2',4'-BNA(NC) modifications of TFO increased the binding constant of the triplex formation at physiological pH by more than 10-fold, and significantly increased the nuclease resistance of TFO. On the other hand, the continuous 2',4'-BNA(NC) modification of TFO showed lower ability to promote the triplex formation at physiological pH than the interrupted 2',4'-BNA(NC) modifications of TFO, and did not significantly change the nuclease resistance of TFO. Selection of the interruptedly 2',4'-BNA(NC)-modified positions in TFO was more favorable for achieving the higher binding affinity of the pyrimidine motif triplex formation at physiological pH and the higher nuclease resistance of TFO than that of the continuously 2',4'-BNA(NC)-modified positions in TFO. We conclude that the interrupted 2',4'-BNA(NC) modification of TFO could be a key chemical modification to enhance pyrimidine motif triplex-forming ability and nuclease resistance under physiological condition, and may eventually lead to progress in various triplex formation-based strategies in vivo. PMID- 21259166 TI - Abnormal temporal and parietal magnetic activations during the early stages of theory of mind in schizophrenic patients. AB - Schizophrenia is associated with abnormal cortical activation during theory of mind (ToM), as demonstrated by several fMRI or PET studies. Electrical and temporal characteristics of these abnormalities, especially in the early stages, remain unexplored. Nineteen medicated schizophrenic patients and 21 healthy controls underwent magnetoencephalography (MEG) recording to measure brain response evoked by nonverbal stimuli requiring mentalizing. Three conditions based on comic-strips were contrasted: attribution of intentions to others (AI), physical causality with human characters (PCCH), and physical causality with objects (PCOB). Minimum norm localization was performed in order to select regions of interest (ROIs) within bilateral temporal and parietal regions that showed significant ToM-related activations in the control group. Time-courses of each ROI were compared across group and condition. Reduced cortical activation within the 200 to 600 ms time-window was observed in the selected regions in patients. Significant group by condition interactions (i.e., reduced modulation in patients) were found in right posterior superior temporal sulcus, right temporoparietal junction, and right inferior parietal lobule during attribution of intentions. As in healthy controls, the presence of characters elicited activation in patients' left posterior temporal regions and temporoparietal junction. No group difference on evoked responses' latencies in AI was found. In conclusion, ToM processes in the early stages are functionally impaired in schizophrenia. MEG provides a promising means to refine our knowledge on schizophrenic social cognitive disorders. PMID- 21259167 TI - Views of parents of teenagers about licensing policies: a national survey. AB - OBJECTIVE: During the past two decades, many changes in licensing policies have been made in U.S. states, and more are being discussed. The views of parents of teenagers can inform debates about what licensing provisions should be considered and how well they will be received. The objective was to obtain the views of a nationally representative sample of parents of teenagers on a wide range of licensing practices. METHODS: Parents were interviewed via the internet in early 2010. Participants were 1226 parents of 15- to 18-year-olds drawn from a nationally representative panel of U.S. households recruited using probability based sampling. The panel included cell phone-only households, and Internet access was provided to those without it. Weighting procedures were applied to ensure that participants reflect the national population. RESULTS: Parents generally favored licensing policies that are as strong as or stronger than exist in any U.S. jurisdiction, including higher permit and licensing ages, long learner periods with high practice hour requirements, plus strong and long lasting night and passenger restrictions. The majority of parents approved of tougher driving tests, including a test to graduate to full license status (75%), enhanced penalties for traffic violations (94%) and violations of graduated licensing restrictions (78%), cell phone and texting bans (96-98%), and, to a somewhat lesser extent, license status identifiers (decals) on vehicles (65%) and the application of graduated licensing rules to novice drivers 18 and older (61%). Parents in the Northeast were significantly more supportive of older learner's permit and restricted driving ages than parents in other regions, and parents in the West were more supportive of strong passenger restrictions. CONCLUSIONS: Results suggest that many parents will support comprehensive licensing policies. Many of these policies are known to reduce teenage crash involvement. For others, research evidence of their effects is lacking and needs to be established. PMID- 21259168 TI - Cooperation between police and social treatment services offering treatment to drink and drug drivers--experience in Sweden. AB - OBJECTIVE: To describe and analyze a measure that has been introduced in Sweden with the objective of quickly offering treatment for the alcohol or drug problems suspected drink or drug drivers may have. The goal of the measure is that every suspected drink or drug driver shall, as soon as apprehended by the police, be offered contact with the social services or the dependency care and treatment service, which can offer a consultation and, if needed, suitable treatment. METHOD: Interviews and questionnaire surveys, as well as forms that describe the treatment received by each individual case. RESULTS: About 20 percent of all those who receive the offer from the police accept contact with the social services or the care and treatment service, and approximately 40 percent of these also attend the consultation. There is a favorable fundamental attitude to the method among the participating authorities. However, some shortcomings in application are revealed. One example concerns drug drivers who are offered contact with the social services or the care and treatment service to a considerably lesser extent than drink drivers. Another neglected group are the people who are at first suspected of drink driving but are later found to have an alcohol concentration below the legal limit. Compared with those who have an alcohol concentration above the legal limit, this group is offered contact to a lesser extent and also have a lower propensity to accept the offer. CONCLUSIONS: The results indicate a strong support for the method from involved authorities, but participation could be improved by giving more attention to neglected groups. PMID- 21259169 TI - Etiology of nonspecific cause of death coding in New York City motor vehicle crash-related fatalities. AB - OBJECTIVES: Nearly 20 percent of New York City's (NYC) accidental deaths are related to motor vehicles crashes (MVCs). Detailed International Classification of Disease (ICD-10; World Health Organization [WHO] 2007) cause-of-death coding of MVC-related fatalities improves surveillance and resulting identification of prevention strategies. We investigated ICD-10 codes in these fatalities and the potential to make them more specific. METHODS: We defined "nonspecific" MVC ICD 10 codes as all globally unspecific codes (V870-V878, V892) and any codes with nonspecific components regarding vehicle involved, decedent position in vehicle, or MVC setting. We calculated nonspecific-code frequency for 1999-2008 MVC deaths. We reviewed a random 10 percent sample of 2007-2008 MVC deaths (N=61) and medical examiner (ME) records of all nonspecific death certificates (N=52), including police accident reports ("full PAR") and summaries prepared by onsite police officers ("brief PAR") to determine whether MEs had sufficient information available but did not include that information at death certification. RESULTS: Among 1999-2008 NYC MVC deaths, 82.9 percent had nonspecific ICD-10 cause-of death codes. Similarly, of the 61 recent randomly sampled MVC deaths, 52 (85.2%) had nonspecific codes. Of 52 nonspecific death certificates from the random sample, 38 (73.1%) death certificates had adequate information available on full or brief PAR to be more specific at the time of death certification. Consistent with MEs' reports of high reliance on the brief PAR, most nonspecific death certificates (76.9%) lacked adequate information in the brief PAR to be more specific. CONCLUSION: Specific ICD-10 codes for MVC deaths depends on the level of detail provided by the ME in the "How Injury Occurred" and "If Transportation Injury Specify" death certificates sections. We have worked to ensure that key information is available to MEs in the brief PAR and educated MEs on the importance of this information to reduce the frequency of nonspecific codes and enhance injury prevention research. PMID- 21259170 TI - Are age-based licensing restrictions a meaningful way to enhance rural older driver safety? The need for exposure considerations in policy development. AB - The stated and revealed travel behavior of a sample of 60 rural drivers aged 54 92 years provided a basis to explore the potential effectiveness of two common driver's license restrictions aimed at older drivers: time of day and road class. The potential utility and impact of these restrictions have not been explored with revealed data for jurisdictions with a large population of rural older drivers where automobile dependence is high. Data were drawn from a multiday Global Positioning System-based travel diary survey of rural older drivers in New Brunswick, Canada. Revealed travel data showed that over 50 percent of the rural drivers in the sample did not drive after dark, and 40 percent drove less than 1 percent of their total surveyed kilometers on major highways, higher rates than from participant-stated responses. The proportion of participants taking night trips and traveling on major highways decreased with age. The majority of trips taken after dark by all participants had a rural destination. The average daily kilometers driven on major highways by men and women aged 75 years and older was nearly identical (1.79 km/day). These exposure considerations suggest that restricting night travel and major highway travel for the oldest rural drivers (75 years and older) may have limited utility given that the majority of participants did not drive in these situations, and for those who did, most of their trips were in rural areas where enforcement could be expected to be limited. A better approach may be to encourage increased self-regulation through training, age-friendly upgrades to transportation infrastructure to help rural older drivers stay driving safely as long as possible, and the development of appropriate rural alternatives to help a driver transition to nondriver. PMID- 21259171 TI - Factors influencing injury severity to highway workers in work zone intrusion accidents. AB - OBJECTIVE: Highway workers in work zones are in close proximity to traveling vehicles, exposing them to injury risks when vehicles intrude into the work zone. The purpose of this research was to perform an analysis of injuries endured by highway workers due to intrusion accidents and to identify factors that would have a significant effect on injury severity. METHODS: Ten years of California work zone injury data were collected and analyzed. The data were first used to determine trends in work zone injury. Statistical models were also created to evaluate variables influencing injury severity. Statistical models included multiple correspondence analysis, Cox proportional hazard regression, logistic regression, and Poisson regression. RESULTS: Statistical analysis of California injury data identified the 4 variables of accident/work zone location, work zone duration, time of day, and type of activity performed by the worker as having the most significant impact on injury severity. The results show that locations such as those on freeways/highways and stationary lane closures result in more severe injuries than work zones on city streets. Short-term stationary and short duration work zones had increased odds of nonminor injuries compared to mobile work zones. For the time of day, the results indicate that the odds of more serious injuries are higher during nonpeak hours than during peak rush hours. Finally, workers on foot have greater odds of experiencing a more severe injury versus workers inside vehicles. CONCLUSION: This research has shown that considering the effects of work zone location, duration, time of day, and worker activity can have the most significant impact on risk of injury to workers. Understanding these factors can provide a basis for planning and design of work zones to improve worker safety. PMID- 21259172 TI - Epidemiology of motor vehicle crashes in Utah. AB - OBJECTIVES: This study describes the frequency and pattern of vehicle crashes and safety belt use in Utah; the proportion of vehicle crashes involving safety belt use, alcohol, and fatigue; and the influence these factors and others have on emergency room visits or hospital admissions and on the severity of the outcome. METHODS: Data were obtained from the Utah Department of Transportation, Division of Traffic and Safety, from 1999 through 2005. Motor vehicle crash (MVC) data were linked to statewide hospital admission (inpatient) and emergency department (ED) records. RESULTS: The trend in rates of crashes significantly decreased for both males and females, with rates of crashes involving alcohol decreasing for males but increasing for females and rates of crashes involving fatigue remaining constant for males and females over the study period. Drivers not wearing a safety belt or intoxicated or fatigued were significantly more likely to have contributed to the crash, visit the emergency room, be admitted to the hospital, and experience severe injury or death. Drivers in crashes who were intoxicated or fatigued were significantly less likely to be wearing a safety belt. When a safety belt was worn at the time of the crash, sitting in the front seat was safer than in the second or third seats, and sitting on the left side of the vehicle was safer than on the right side or in the middle. However, when a safety belt was not worn at the time of the crash, sitting in the front seat was more likely associated with injury or death than in the second or third seats or sitting in the middle seat. CONCLUSION: Drivers in crashes who were intoxicated or fatigued were less likely to be wearing a safety belt and more likely to have contributed to the crash and experience serious injury or death. Severity of injury related to seat placement is moderated by safety belt use. PMID- 21259173 TI - Prediction of seat belt use among Iranian automobile drivers: application of the theory of planned behavior and the health belief model. AB - OBJECTIVE: Seat belt use plays an important role in traffic safety by reducing the severity of injuries and fatality rates during vehicle accidents. The aim of this study was to investigate predictors of self-reported seat belt use in a sample of automobile drivers in Bandar Abbas, Iran. The theory of planed behavior and the health belief model served as the conceptual framework for the study. METHODS: The convenience sample consisted of 284 eligible automobile drivers who frequented 8 petrol stations in different geographical areas of the city. Of the drivers approached to participate in the study, 21 declined to take part in the study and 12 other questionnaires were incomplete. Thus, a total of 251 questionnaires were analyzed (response rate=88.4%). A self-administered questionnaire including demographic characteristics and items arising from the theory of planed behavior and health belief model constructs were used to collect data. Data were analyzed using SPSS 16 (version 16, Chicago, IL, USA). RESULTS: The subjects' mean age was 31.6 years (SD=8.7), mostly male (72.9%), and 53.4 percent of them reported that they used their seat belt "often." Multiple regression analyses revealed that from the theory of planed behavior, attitude, subjective norms, and perceived behavioral control significantly predicted intention to use a seat belt (R2=0.38, F=51.1, p<.001); and subjective norms, perceived behavioral control, and behavioral intention significantly predicted seat belt use (R2=0.43, F=45.7, p<.001). Arising from the health belief model, perceived benefits and perceived barriers significantly predicted seat belt use (R2=0.39, F=26.2, p<.001). CONCLUSION: This study revealed that automobile drivers who perceived more subjective norms, more behavioral control, greater intention to use seat belts as well as more benefits and fewer barriers were more likely to use their seat belts. PMID- 21259174 TI - Variations in rear seat cushion properties and the effects on submarining. AB - OBJECTIVE: This study aims to investigate the effects of seating posture and seat cushion properties on submarining risk for rear seated children. METHODS: An instrumented 6-year-old Hybrid III dummy restrained by an inertial-reel 3-point seat belt was subjected to simulated frontal impacts (Deltav=28.8 km/h, peak acceleration=16 g). Dummy motion was captured using high-speed digital video. Head acceleration, neck loads, chest deflection, pelvic rotation, and femur displacement were used to assess submarining. Factors investigated included pre impact seating posture, seat cushion length, stiffness of the seat cushion foam, and the inclination of the seat cushion. RESULTS: The most severe submarining was observed when the dummy was seated in a slouched posture where pelvic rotation was over 3 times greater than in the upright seating posture. Though the standard seat cushion with the dummy seated in the upright posture recorded the lowest values of pelvic rotation and femur displacement, it is unlikely that a child will sit in such a posture. The shortened seat cushion increased femur displacement by 19 percent compared to the standard test seat, but it offers good pre-impact belt position. Submarining occurred in cases where the front edge of the seat collapsed during interactions with the dummy's buttocks. CONCLUSIONS: These data suggest that shortening the rear seat cushion alone will not necessarily prevent submarining, but this does allow improved seated posture of the occupant, thus reducing submarining risk. This study has also shown that the collapse of the front edge of the seat cushion is a critical factor in submarining risk. PMID- 21259175 TI - Head injury causation scenarios for belted, rear-seated children in frontal impacts. AB - OBJECTIVES: Head injuries are the most common serious injuries sustained by children in motor vehicle crashes and are of critical importance with regard to long-term disability. There is a lack of understanding of how seat belt restrained children sustain head injuries in frontal impacts. The aim of the study was to identify the AIS2+ head injury causation scenarios for rear-seated, belt-restrained children in frontal impacts, including the set of parameters contributing to the injury. METHOD: In-depth crash investigations from two National Highway Traffic Safety Administration (NHTSA) databases, the National Automotive Sampling System-Crashworthiness Data System (NASS-CDS; 1997-2008) and the Crash Injury Research and Engineering Network (CIREN; 1996-2009), were collected and analyzed in detail. Selection criteria were all frontal impacts with principal direction of force (PDOF) of 11, 12, and 1 o'clock involving rear seated, three-point belt-restrained, with or without booster cushion, children from 3 to 13 years with an AIS2+ head injury. Cases were analyzed using the BioTab method of injury causation assessment in order to systematically analyze the injury causation scenario for each case. RESULTS: There were 27 cases meeting the inclusion criteria, 19 cases with MAIS2 head injuries and 8 cases with MAIS3+ head injuries, including 2 fatalities. Three major injury causation scenarios were identified, including head contact with seatback (10 cases), head contact with side interior (7 cases,) and no evidence of head contact (9 cases). CONCLUSIONS: Head injuries with seatback or side interior contact typically included a PDOF greater than 10 degree (similar to the Insurance Institute for Highway Safety [IIHS] and EuroNCAP offset frontal testing) and vehicle maneuvers. For seatback contact, the vehicle's movements contributed to occupant kinematics inboard the vehicle, causing a less than optimal restraint of the torso and/or torso roll out of the shoulder belt. For side interior contact, the PDOF and/or maneuvers forced the occupant toward the side interior. The cases without evidence of head/face contact were characterized by high crash severity and accompanied by severe injuries to the thorax and spine. These data lead to increased understanding of the injury patterns and causation in this crash restraint scenario so that interventions to mitigate the burden of injury can be advanced. PMID- 21259176 TI - Helmet use and risk compensation in motorcycle accidents. AB - OBJECTIVE: The "risk compensation" hypothesis suggests that individuals offset perceived gains in safety by increasing their risk-taking behavior to maintain a stable or "homeostatic" level of risk. If this is true for motorcyclists, then helmet use, which reduces the risk of brain injury and death, may lead helmet users to take more risks when they ride. Thus, increased risk-taking by helmet users should show up as overrepresentation in crashes, and accident reconstruction should reveal risky behaviors in the seconds just before the crash. This article examines data from two separate studies involving the on scene, in-depth investigation and reconstruction of motorcycle crashes: 900 in Los Angeles (1976-1977) and another 1082 in Thailand (1999-2000). METHODS: Each crash was investigated on scene within minutes of its occurrence by teams of specially trained researchers and later reconstructed in order to identify precrash and crash events, verify helmet use/nonuse, etc. "Exposure" data on helmet use and other readily visible factors were also collected for the population-at-risk by observing riders who passed by each accident scene some time after a crash that had been investigated by the team. In this article, helmeted and unhelmeted accident-involved riders are compared to each other as well as to the population-at-risk. RESULTS: In Thailand, helmeted riders did not differ significantly from unhelmeted riders in alcohol use, precrash speed, being the primary or sole cause of the crash, or unsafe speed or lane positioning for the traffic conditions; they were no more likely to be in a single-vehicle accident, to crash by running off the road, or to lose control. In Los Angeles, drinking riders were half as likely to wear a helmet as nondrinkers. However, when drinkers and nondrinkers were segregated, helmeted riders were no more likely to cause their crash, run stop signs or red lights, commit other traffic code violations, or run off the road. They did not differ in speed or single vehicle crash rates. In both studies, helmeted riders were underrepresented in crashes compared to helmet use in the population-at-risk, and helmet use was associated with greater distances traveled. CONCLUSIONS: The data fail to support the hypothesis that the increased safety provided by motorcycle helmet use is offset by more risk-taking while riding. The only evidence of risk compensation was that helmet use increased with greater amounts of travel. PMID- 21259177 TI - Cervical spine rotation and range of motion: pilot measurements during driving. AB - OBJECTIVE: Previous studies have evaluated the cervical range of axial rotation during simulated driving conditions. The goals of this pilot study were to describe cervical spine rotation during in-car driving and determine the percentage of time outside neutral neck rotation and peak cervical axial rotation angles that the subjects adopted during various driving conditions. METHODS: Subjects drove around a specified route through the city of Guelph, Ontario, which included residential, thruway, and highway driving; additional minor driving tasks, such as lane changes, were also included. The cervical range of motion was measured continuously throughout the drive using an electromagnetic sensor; we also used videotape to document the specific driving tasks. RESULTS: The subjects spent 87.0 percent (SD=8.8) of time with their cervical spine in the neutral axial rotation position (+/-15 degrees). The percentage of time that the subjects spent outside of the neutral range of cervical axial rotation depended upon the driving section (including residential, thruway, and highway), and driving task being performed (starts, stops, and lane changes). The subjects spent a significantly greater proportion of time with their necks rotated beyond neutral during residential driving compared to thruway and highway driving (19.1% SD=8.3 vs. 10.7% SD=9.5 and 9.3% SD=8.7, respectively; p<.001). During driving, the peak angles of cervical axial rotation were an average of 35.7 degrees (SD=14.2) left and 42.5 degrees (SD=18.0) right. CONCLUSIONS: We observed a large degree of variability in cervical axial rotation during driving. We observed that most of the driving tasks related to stopping had increased proportion of time out of neutral rotation. Also, right-hand lane changes increased time out of neutral rotation more than left-hand lane changes. Drivers routinely adopt nonneutral head positions (on average 13% of the time); this is likely not enough to lead to injury. PMID- 21259178 TI - Sensitivity of THOR and Hybrid III dummy lower neck loads to belt systems in frontal impact. AB - OBJECTIVES: To determine head-neck biomechanics with a focus on lower neck injury metrics in frontal impact. The mid- and large-size Hybrid III dummies and the mid size Test device for Human Occupant Restraint (THOR) were positioned on a buck. Tests were conducted at low, medium, and high (3.3, 6.7, and 15.7 m/s) change in velocities using 3 restraint types: normal 3-point belt with no pretension (type A), 10-cm pretension (type B), and 200 N pretension (type C). Repeat tests were conducted. Measured vertical and shear forces and sagittal bending moments were evaluated at the upper and lower regions of the neck to different types of belt systems and at different change in velocities. Peak values normalized with respect to the belt type A were used in the comparative analysis. Metrics transformed to the occipital condyles and T1 were also evaluated. RESULTS: All dummies showed good repeatability. Peak measured and transformed upper and lower neck moments were greatest in the large-size dummy. The mid-size Hybrid III dummy responded with greater forces and moments than the THOR. Regardless of dummy type, anthropometry, and velocity, peak lower neck moments were more sensitive to belt types than peak lower neck forces. A similar pattern was apparent for upper neck data. Moments in the THOR were more sensitive than moments in the mid-size Hybrid III dummy. CONCLUSIONS: This study offers quantitative generic restraint based data and addresses response differences between dummies and dummies of the same family. Because of increased sensitivity to belt types at the upper and lower necks for both forces and moments, the THOR appears to be an improvement to better assess injury potential to rear seat occupants wherein frontal impact air bags do not exist. PMID- 21259179 TI - Modeling pedestrian violation behavior at signalized crosswalks in China: a hazards-based duration approach. AB - OBJECTIVE: Pedestrian violation is a major cause of traffic accidents involving pedestrians. The research objectives were to investigate the relationship between waiting duration and pedestrian violation and to provide a qualitative and quantitative analysis of the effects of human factors and external environmental factors on street-crossing behavior. METHODS: Pedestrians' street-crossing behavior was examined by modeling the waiting duration at signalized crosswalk. Pedestrian waiting duration was collected by video cameras and it was assigned as censored and uncensored data to distinguish between normal crossing and violating crossing. A nonparametric baseline duration model was introduced, and variables revealing personal characteristics, traffic conditions, and trip features were defined as covariates to describe the effects of internal and external factors. RESULTS: Pedestrians' crossing behaviors represented positive duration dependence that the longer the waiting time elapsed the more likely pedestrians would end the wait soon. The violation inclination of most pedestrians increased with the increasing waiting duration, but about 10 percent of pedestrians were at high risk of violation to cross the street. About half of pedestrians would still obey the traffic rules even after waiting for 50 s by the street. Human factors and the external environment played an important role in street-crossing behavior, especially for factors that involved pedestrians' subjective willingness. CONCLUSIONS: The street-crossing behavior of pedestrians was time dependent. Pedestrians behave differently under the effects of various factors. Pedestrian safety interventions that aim at reducing pedestrian injuries may need to consider these effects. The pedestrians' behavioral modifications, such as enhancing the safety awareness, might be the most efficient means to reducing the likelihood of pedestrian violation, though environmental modifications also worked well in improving pedestrian safety. PMID- 21259180 TI - Determinants of seat belt use among drivers in Sabzevar, Iran: a comparison of theory of planned behavior and health belief model. AB - OBJECTIVE: Although seat belt use can significantly decrease the risk of injury, few car drivers make use of seat belts in Iran. The aim of this study was to test the utility and efficiencyof the theory of planned behavior (TPB) and the health beliefmodel (HBM) in predicting intention to use a seat belt among car drivers in Sabzevar, Iran. METHODS: A cross-sectional, correlational design was employed. Cluster sampling was used to recruit 340 drivers to participate in the study. A self-administered questionnaire was applied to investigate variables of interest. Reliability and validity of the instruments were examined. The statistical analyses of the data included t test, one-way analysis of variance (ANOVA), bivariate correlation, and stepwise regression. RESULTS: All TPB and HBM variables were related to intention to use a seat belt in car drivers. All TPB (perceived behavioral control, subjective norms, and attitude) and HBM (perceived susceptibility and severity, benefits and barriers, and cues to action) variables were statistically significant predictors of seat belt use intention and accounted for 37.9 and 15.4 percent of the variation, respectively. CONCLUSIONS: Our results showed that the rate of seat belt use in Iran as a developing country is very low. Thus, developing and implementing effective interventional programs in order to promote seat belt use among car drivers is recommended. The findings of this study provide preliminary support for the TPB model as a more effective framework than HBM for examining seat belt use in car drivers. Our results demonstrated that TPB has greater predictive utility than HBM in seat belt use intention. PMID- 21259181 TI - [Extraosseous myeloma manifestation of the thyroid cartilage]. PMID- 21259182 TI - Interventional ultrasound-guided procedures in pancreatic pseudocysts, abscesses and infected necroses - treatment algorithm in a large single-center study. AB - Through a time period of 5 years, all consecutive patients were documented in this prospective single centre observational clinical study to investigate feasibility and outcome of ultrasound(US)- and EUS-guided drainage of symptomatic non-infected pancreatic pseudocysts and abscesses as well as the endoscopic debridement of infected necroses. RESULTS: From 03 / 23 / 2002 to 12 / 31 / 2008, 147 patients (females:males = 49:98 [1:2.0]) with pseudocysts (n = 32), abscesses (n = 81) and necroses (n = 34) were enrolled in the study. Technical success rate in US-guided external and in EUS-guided transmural drainage was 100 % and 97.0 %, respectively, whereas that of transpapillary (ERP-guided) drainage was 92.1 %. While the complication rate in external drainage was 3.7 %, this rate in transmural and transpapillary drainage was 9.6 % and 0, respectively. Late complications (> 24 h) were observed in 6.4 % of patients after transpapillary drainage (external drainage, 5.6 %; transmural drainage, 19.1 %). Complications in 5 cases (bleeding, n = 3; perforation, n = 1; dislocation of the prosthesis with perforation of the terminal ileum, n = 1) needed to be approached surgically. After a mean follow-up period of 20.7 months, 20.9 months, and 19.4 months, the definitive therapeutic success rate was 96.2 % in average for the three diagnoses such as pseudocyst (96.9 %), abscess (97.5 %), and necrosis (94.1 %), respectively (recurrency rate, 15.4 % in average; overall mortality, 0.7 % but no intervention-related death). CONCLUSION: US- and endoscopy-based management of pancreatic lesions as reported is suitable and favorable also in daily clinical routine since it is a safe and efficacious approach in experienced hands. PMID- 21259183 TI - Microwave ablation of liver metastases guided by contrast-enhanced ultrasound: experience with 125 metastases in 39 patients. AB - PURPOSE: The aim of our study was to evaluate the efficacy of microwave (MW) ablation of liver metastases guided by B-mode ultrasound (US) and contrast enhanced US (CEUS). MATERIALS AND METHODS: 39 patients (17 women and 22 men) with a total of 125 liver metastases were treated with percutaneous or intraoperative CEUS-guided MW ablation. The primary tumor was colorectal cancer (n = 31), breast cancer (n = 6), carcinoid tumor (n = 1), and gastrointestinal stromal tumor (GIST) (n = 1). The median number of metastases ablated in the 45 treatment sessions was 2 (range 1 - 11). The median size (maximum diameter) of the 125 metastases was 1.5 cm (range, 0.6 - 4.0 cm). Nineteen (15 %) of the 125 metastases were bigger than 2 cm. Metastases smaller than 2 cm were treated with a single needle, metastases bigger than 2 cm were treated with 2 or 3 parallel needles. RESULTS: The 45 MW ablation sessions were performed percutaneously (n = 30), during laparotomy (n = 3), or during laparotomy combined with liver resection (n = 12). The 39 patients were followed up for at least 4 months with a median duration of 11 months (range, 4 - 20 months). The technical success rate was 100 %. The clinical effectiveness was 100 % with complete coverage of the metastasis by the avascular coagulation zone evaluated on immediate post-ablation CEUS. Local tumor progression (local recurrence) was seen in 12 (9.6 %) of the 125 treated metastases, and affected 10 (26 %) of the 39 patients. One major complication was observed in the form of a liver abscess that easily resolved after percutaneous drainage. Four minor complications were observed: Three cases of pain located at the puncture site and one case of ascites. CEUS was valuable in all phases of ablation including pre-ablation staging and procedure planning, placement of MW needles in the tumor, immediate post-ablation control of coagulation size, and finally in the long term follow-up regime. CONCLUSION: CEUS guided MW ablation of liver metastases is an efficient and safe ablation technique with several advantages compared to other ablation modalities. PMID- 21259184 TI - Ultrasound Doppler score correlates with OMERACT RAMRIS bone marrow oedema and synovitis score in the wrist joint of patients with rheumatoid arthritis. AB - PURPOSE: MRI is considered the standard of reference for advanced imaging in rheumatoid arthritis (RA). However, in daily clinical practice ultrasound (US) imaging with Doppler information is more versatile and often used for fast and dynamic assessment of joint inflammation. The aim was to compare low-field MRI scores with the US Doppler measurements in the wrist joint of patients with RA. MATERIAL AND METHODS: Fifty consecutive patients with RA (46 women & 4 men) completed both low-field dedicated extremity MRI (E-scan(r), Esaote) and a high end US (Sequioa(r), Siemens) imaging of the wrist before initiating either biological treatment (n = 26) or intraarticular injection of Depomedrole(r) (n = 24). Mean age was 56 years (range 21 - 83 years); mean disease duration 87.2 months (range 4 - 349 months), mean DAS 28 4,8 (range 2 - 7). MRI was scored according to the OMERACT RAMRIS recommendations and US Doppler colour-fractions were determined. RESULTS: Using Spearman's rho, we found a relatively good to moderate correlation between the US colour-fraction and the total OMERACT bone marrow oedema and synovitis scores on MRI (r = 0.6; p < 0.001 and r = 0.4; p < 0.006 respectively). There was a trend but no significant correlation with the total OMERACT erosion score (r = 0.3; p = 0.06). CONCLUSION: Within limits, the OMERACT RAMRIS scores of inflammation in RA patients (bone marrow oedema and synovial enhancement) are comparable to the US colour-fraction measurements using a high-end US scanner. Both imaging modalities detect inflammation although showing different aspects of the inflammatory process in the wrist joint. The higher correlation between US colour-fractions and MRI bone marrow oedema indicates a potential importance of US Doppler in monitoring inflammatory disease changes in RA. PMID- 21259185 TI - Hoodia gordonii: an up-to-date review of a commercially important anti-obesity plant. AB - Hoodia gordonii is a spiny succulent plant popularly consumed for its purported anti-obesity effect. Traditionally used by the Khoi-San of South Africa and Namibia as a hunger and thirst suppressant while on long hunting trips, the commercialisation of this plant has been highly controversial due to intellectual property rights and benefit sharing issues, as well as the fact that several prominent pharmaceutical companies involved in its development have withdrawn their interest. Quality control has been the main focus of scientific studies as the supply of H. gordonii plant material is limited due to its sparse geographical distribution, slow maturation rate, need for a permit to cultivate or export material as well as high public demand, contributing to adulteration of a large amount of products. Despite the isolation of numerous steroidal glycosides from H. gordonii, the main focus has been on the pregnane glycoside P57, considered to be the active ingredient and marker molecule to determine quality of raw material and products. Publications based on scientific studies of key aspects such as in vivo biopharmaceutics, the biological activity of all chemical constituents, clinical efficacy, and especially safety are insufficient or completely absent causing great concern as H. gordonii is one of the most widely consumed anti-obesity products of natural origin. This review offers an up to-date overview of all the current available knowledge pertaining to H. gordonii achieved by systematic analysis of the available literature. PMID- 21259186 TI - Correlation between chromatographic fingerprint and antioxidant activity of Turnera diffusa (Damiana). AB - In the present contribution, the partial least squares (PLS) method was used to establish a correlation between the antioxidant activity (obtained by DPPH assay) and chromatographic profiles of TURNERA DIFFUSA extracts. Chromatograms were obtained using HPLC-DAD. A model was constructed using 40 samples with 2550 X variables corresponding to the responses obtained at different times; the Y variables consisted of experimental values of antioxidant activity of each extract (measured as EC50). Prior to this analysis, alignment of chromatograms was performed based on consideration of seven high-intensity signals present in all samples. The PLS1 model was validated by cross-validations; its capacity was evaluated using correlation parameters R2, root mean square error of calibration (RMSEC), and root mean square error of prediction (RMSEP). The best results were achieved with zero order chromatograms using five-point smoothing (R2 = 0.96, RMSEC = 3.31, and RMSEP = 7.86). Under these conditions, the optimal number of components was five. The model was applied to the prediction of antioxidant activity of commercial products; no significant differences were found between the experimental and predicted antioxidant activities for 83 % of them. PMID- 21259187 TI - Stage of action of naturally occurring andrographolides and their semisynthetic analogues against herpes simplex virus type 1 in vitro. AB - Andrographolide, an ENT-labdane diterpene, has been found to have activities against many viruses. Three free hydroxyls at C-3, C-14, and C-19 are involved in the activities. No stage of action has ever been explored. In this study, the naturally occurring compounds of andrographolide, 14-deoxy-11,12 didehydroandrographolide and 14-deoxyandrographolide, and eight semisynthetic analogues, modified at the three free OHs of andrographolide, were explored for their anti-HSV-1 activities. The concentrations that produced 80 % viable cells were used to test for both pre- and postinfections by using cytopathic effect reduction assays on Vero cell cultures. Three analogues, 14-acetyl-3,19 isopropylideneandrographolide, 14-acetylandrographolide, and 3,14,19 triacetylandrographolide, significantly exhibited preinfection step activity against the virus. For postinfection activity, only 3,19 isopropylideneandrographolide showed absolute inhibition of HSV-1 replication. Meanwhile, andrographolide exhibited slight inhibitory activities of 34.48 +/- 6.93 % and 56.90 +/- 2.65 % against HSV-1 for pre- and postinfection, respectively. The results confirm that the three hydroxyl moieties play a role in the anti-HSV-1 activity of andrographolide. From the study, it can be concluded that 14-acetyl analogues are good for blocking the viral entry, and 3,19 isopropylideneandrographolide, a cyclic dioxane analogue, is good for exerting postinfection anti-HSV-1 activity. PMID- 21259188 TI - Painting the pedicle: a twist-proof marking method. PMID- 21259189 TI - Use of microsurgical background as an anastomotic frame. PMID- 21259190 TI - [QALYs and fairness: health economic approaches to the fairness issue and their problems]. AB - Empirical studies have shown that QALY-maximization leads to results that are perceived as unfair. Health economists have attempted to integrate fairness aspects in Cost-Utility Analysis by means of equity weighting. A well-known example is Cost-Value Analysis (Nord et al.). Over and above the value of individual health related utilities, it tries to capture the value of distributing resources fairly. The debate has shown, however, that these approaches face several problems. The present contribution argues that the difficulties are of a more fundamental nature than most contributors to the debate have hitherto assumed. Cost-utility analysis, we believe, cannot consistently be adjusted to meet fairness objections by means of weighting schemes. PMID- 21259191 TI - [Mid-term clinical and MRI results after refixation of osteochondral fractures with resorbable implants]. AB - AIM: Refixation of osteochondral fractures with resorbable implants is a common surgical treatment. There are almost no studies that prove good clinical outcomes. Hence, the aim of the study was to evaluate the mid-term results after refixation of osteochondral fractures. METHODS: The results of 12 patients were recorded 6.5 (+/-1) years after refixation of osteochondral fractures measuring 3.4 cm (2) (+/-2.5) of the knee (8 *) or the ankle joint (4 *) with resorbable inplants. Clinical scores and a modified MRI score based on that of Henderson et al. were used. RESULTS: The clinical scores showed good to excellent results after 6.5 (+/-1) years (VAS pain: 1.9 [+/-2.4], Tegner: 5.0 [+/-1.7], Lysholm: 84.8 [+/-14.3], McDermott: 91.3 [+/-7.9], Knee Society: 189.4 [+/-12.1]). MRI showed with one exception good integration of the fractures. In 3 cases subchondral cysts could be found. In 7 cases changes in the chondral outline occurred. The effect of this was a modified Henderson score of 12.6 (+/-3.7). The MRI results did not correlate with the clinical outcome. CONCLUSION: Because of its good clinical results the refixation with resorbable implants can be recommended to treat osteochondral fractures. PMID- 21259192 TI - [Electromagnetic fields, electric current and bone healing - what is the evidence?]. AB - For more than 30 years the potential effects of electrical stimulation on bone healing have been investigated. Up to now this therapy is controversial and not established as a standardised treatment option. This systematic review and metaanalysis focuses on the potential effects of electromagnetic fields and high frequency electric fields on bony healing. In a systematic literature search randomised clinical trials were identified and analysed. Those studies with the primary endpoint "rate of bony healing" were combined in a metaanalysis which was performed with the "random effects" model. We found a total of 14 randomised clinical trials. These studies included a total of 915 patients. The majority of these studies used pulsed electromagnetic fields (PEMF). Out of the 14 studies nine were suitable for the metaanalysis which revealed a cumulative odds ratio of 3.5 and a 95 % confidence interval of 1.94-6.3. When performing a subgroup analysis a statistically significant result could not be confirmed by the studies with a higher methodological quality. In view of the heterogeneous physical parameters with different frequencies, time course, flux densities and in view of the methodological deficits, a general conclusion seems difficult. Recommendations or standards of therapy are so far not available. PMID- 21259232 TI - Effect of postconditioning on mitochondrial dysfunction in experimental aortic cross-clamping. AB - BACKGROUND: Cross-clamping of the aorta during abdominal aortic aneurysm surgery induces muscle ischaemia with resultant morbidity. This study tested whether ischaemic postconditioning would decrease mitochondrial dysfunction in skeletal muscle by reducing oxidative stress. METHODS: Three groups (9 rats each) underwent surgery, including a control group without ischaemia and an ischaemia reperfusion group that had 3 h ischaemia induced by aortic clamping and collateral vessel ligation, followed by 2 h of reperfusion. The third group had ischaemia for 3 h then underwent postconditioning comprising three short intervals of ischaemia-reperfusion at the onset of reperfusion. Activity of complexes I, II, III and IV of the mitochondrial respiratory chain was monitored in gastrocnemius muscle, along with oxidative stress measured by dihydroethidium (DHE) staining and antioxidant defence determined by measurement of glutathione levels. RESULTS: Ischaemia-reperfusion alone caused a significant reduction in maximal oxidative capacity (-31.8 per cent; P = 0.002), activity of complexes II, III and IV (-34.5 per cent; P = 0.007) and complex IV activity (-30.6 per cent; P = 0.039). It also increased reactive oxygen species (DHE staining increased to 223.1 per cent of control value; P = 0.027) and reduced antioxidant defence (glutathione level -28.6 per cent; P = 0.039). Postconditioning counteracted these deleterious effects by increasing mitochondrial complex I, II, III and IV activities, restoring muscle DHE staining and preserving glutathione content. CONCLUSION: Ischaemic postconditioning protects skeletal muscle mitochondria against ischaemia-reperfusion injury by reducing oxidative stress and preserving antioxidant defence in an experimental model. Mitochondrial protection to reduce reperfusion injury in clinical vascular surgery may be warranted. PMID- 21259233 TI - Negative appendicectomy and perforation rates in patients undergoing laparoscopic surgery for suspected appendicitis. AB - BACKGROUND: Despite widespread use of imaging technologies including ultrasonography and computed tomography, rates of negative appendicectomy and perforated appendicitis remain high. This trend analysis examined whether rates of negative appendicectomy and perforated appendicitis have decreased over time, and sought to evaluate clinical predictors associated with negative appendicectomy and perforated appendicitis. METHODS: This analysis was based on the prospective database of the Swiss Association of Laparoscopic and Thoracoscopic Surgery (SALTS). All patients aged 12 years and over undergoing emergency laparoscopic appendicectomy between 1995 and 2006 were included. Unadjusted and risk-adjusted logistic regression analyses were performed. RESULTS: A total of 7964 patients underwent laparoscopic appendicectomy, of whom 7452 (93.6 per cent) had acute appendicitis and 512 (6.4 per cent) had a macroscopically normal appendix. Perforation occurred in 1230 (16.5 per cent) of those with appendicitis. In multivariable analysis, younger age (12-18 years), female sex, absence of local or generalized peritonitis and an early point during the study period were significant predictors of negative appendicectomy. For perforated appendicitis, significant predictors included age over 36 years, presence of localized or generalized peritonitis, and high American Society of Anesthesiologists grade. The rate of negative appendicectomy decreased from 12.7 per cent in 1995 to 2.8 per cent in 2006, there being a significant reduction in both unadjusted and risk-adjusted analyses (P < 0.001 for trend). In adjusted analyses, the rate of perforated appendicitis did not increase significantly over time. CONCLUSION: The rate of negative appendicectomy decreased over time, without an accompanying increase in perforated appendicitis. The risk of having a negative appendicectomy was highest in girls aged 12-18 years without local or generalized peritonitis during the early study period, whereas perforation was associated with age over 36 years, presence of localized or generalized peritonitis, and greater co-morbidity. Copyright (c) 2011 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd. PMID- 21259234 TI - Transport behavior of hairless mouse skin during constant current DC iontophoresis I: baseline studies. AB - The fluxes of charged and nonionic molecules across hairless mouse skin (HMS) were induced by direct current iontophoresis and used to characterize the transport pathways of the epidermal membrane. Experimental data were used to determine permeability coefficients from which the effective pore radii (Rp) of the transport pathways were calculated. Permeants used in these experiments were nonionic permeants (urea, mannitol, and raffinose), monovalent cationic permeants (sodium, tetraethylammonium, and tetraphenylphosphonium ions), and monovalent anionic permeants (chloride, salicylate, and taurocholate ions). The Rp estimates obtained by the anionic permeant pairs were 49, 22, and 20 A for the chloride/salicylate (Cl:SA), chloride/taurocholate (Cl:TC), and salicylate/taurocholate (SA:TC) pairs, respectively; with the cationic permeant pairs, the Rp values obtained were 19, 30, and 24 A for the sodium/tetraethylammonium (Na:TEA), sodium/tetraphenylphosphonium (Na:TPP), and the tetraethylammonium/tetraphenylphosphonium (TEA:TPP) pairs, respectively. Rp estimates for HMS obtained from nonionic permeant experiments ranged from 6.7 to 13.4 A. When plotted versus their respective diffusion coefficients, all of the permeability coefficients for the cationic permeants were greater than those of the anionic permeants. Additionally, the magnitudes of permeability coefficients determined in the current study with HMS were of the same order of magnitude as those previously determined in our laboratory using human epidermal membrane under similar iontophoresis conditions. PMID- 21259235 TI - Preparation and transformation of true nifedipine polymorphs: investigated with differential scanning calorimetry and X-Ray diffraction pattern fitting methods. AB - The amorphous -> metastable and metastable -> stable crystalline phase transitions of nifedipine and their relationship with polymorph composition during storage at controlled temperature/humidity conditions were investigated. Metastable form C was produced from both differential scanning calorimetry (DSC) thermal treatment and storage [22 degrees C/0% and 75% relative humidity (RH)] of the amorphous form. Amorphous conversion rate accelerated with storage temperature up to 40 degrees C, but a further 8 degrees C increase to 48 degrees C (3 degrees C above the glass transition) resulted in a more than 12 fold decrease in amorphous conversion rate. DSC and X-Ray diffraction (XRD) analysis revealed a faster amorphous conversion rate relative to the metastable crystal transformation with 75% RH having a greater accelerative effect on the former. Relative phase quantification from XRD pattern fitting included the use of integrated peak intensities of the crystalline phases, Rietveld and the Rietveld-based partial or no known crystal structures method. Kinetic analysis with Johnson-Mehl-Avrami equation indicated that the accelerated amorphous conversion in 75% RH was associated with a 10-fold increase in rate constant with dimensional growth little affected. The smaller rate increase for metastable crystal conversion was associated with an increased dimensional growth while the rate constant was little affected. PMID- 21259236 TI - Preparation of poly(MePEGCA-co-HDCA) nanoparticles with confined impinging jets reactor: experimental and modeling study. AB - In this work, the biodegradable copolymer poly(methoxypolyethyleneglycolcyanoacrylate-co-hexadecylcyanoacrylate) is used to prepare nanoparticles via solvent displacement in a confined impinging jets reactor (CIJR). For comparison, nanoparticles constituted by the homopolymer counterpart are also investigated. The CIJR is a small passive mixer in which very fast turbulent mixing of the solvent (i.e., acetone and tetrahydrofuran) and of the antisolvent (i.e., water) solutions occurs under controlled conditions. The effect of the initial copolymer concentration, solvent type, antisolvent-to solvent ratio, and mixing rate inside the mixer on the final nanoparticle size distribution, surface properties, and morphology is investigated from the experimental point of view. The effect of some of these parameters is studied by means of a computational fluid dynamics (CFD) model, capable of quantifying the mixing conditions inside the CIJR. Results show that the CIJR can be profitably used for producing nanoparticles with controlled characteristics, that there is a clear correlation between the mixing rate calculated by CFD and the mean nanoparticle size, and therefore that CFD can be used to design, optimize, and scale-up these processes. PMID- 21259237 TI - Multivariate optimization of formulation variables influencing flurbiprofen proniosomes characteristics. AB - Flurbiprofen was formulated as a proniosomal transdermal gel with high drug loading (55.4%, w/w), using a series of nonionic surfactant and cholesterol. A two-factor, three-level randomized full factorial strategy was developed to optimize simultaneously the effect of surfactant fatty acid side chain length and the amount of cholesterol on the properties of the proniosomes, namely drug permeation characteristics such as steady-state transdermal flux (SSTF), permeability coefficient (PC), and drug entrapment efficiency. Graphical and mathematical analysis of the results allowed the identification and quantification of the formulation variables that showed significant effects on the selected responses. Polynomial equations fitted to the data were used to predict the responses in the optimal region. For maximizing the selected responses using a generalized desirability function, an optimum formulation was found to have a maximum side chain length and minimum cholesterol content. Optimized formulation showed highest entrapment of 39.45%, percentages drug permeated through cellulose ester membrane of 3.1 and 28.93 after 0.5 and 8 h, respectively, and SSTF and PC of 152 MUg/cm(2) h and 0.263 cm/h, respectively, through rabbit skin. These results demonstrated the efficacy of statistical experimental design to unveil the critical formulation interactions and variability affecting the performance of proniosomal formulations. PMID- 21259238 TI - Maintenance of supersaturation I: indomethacin crystal growth kinetic modeling using an online second-derivative ultraviolet spectroscopic method. AB - Formulations that produce supersaturated solutions after their oral administration have received increased attention as a means to improve bioavailability of poorly water-soluble drugs. Although it is widely recognized that excipients can prolong supersaturation, the mechanisms by which these beneficial effects are realized are generally unknown. Difficulties in separately measuring the kinetics of nucleation and crystal growth have limited progress in understanding the mechanisms by which excipients contribute to the supersaturation maintenance. This paper describes the crystal growth kinetic modeling of indomethacin, a poorly water-soluble drug, from supersaturated aqueous suspensions using a newly developed, online second-derivative ultraviolet spectroscopic method. The apparent indomethacin equilibrium solubility after crystal growth at a high degree of supersaturation (S=6) was approximately 55% higher than the indomethacin equilibrium solubility determined prior to growth, which was attributed to the deposition of a higher energy indomethacin form on the seed crystals. The indomethacin crystal growth kinetics (S=6) was of first order. By comparing the mass transfer coefficients from indomethacin dissolution and crystal growth, it was shown that the indomethacin crystal growth kinetics at S=6 was bulk diffusion controlled. The change in indomethacin seed crystal size distribution before and after crystal growth was determined and modeled using a mass-balance relationship. PMID- 21259239 TI - Silica-maltose composites: obtaining drug carrier systems through tailored ultrastructural nanoparticles. AB - The formation of tailored silica-maltose composites through a simple and direct sol-gel chemistry approach is demonstrated. The ultrastructural organization of the composite associated with their tailorability allows envisaging a future application in drug delivery field. Ultraviolet-visible spectroscopy is used to follow the maltose encapsulation yield, whereas a combination of characterization techniques is employed to reconstruct the multilevel hierarchical structure of composites. Scanning electron microscopy shows that the overall size of spherical composites can be tuned from 250 to 750 nm by changing the amount of maltose within the structure. Composite size distribution indicates that this synthesis approach produces structures with low polydispersity as required for drug delivery purposes. Small-angle X-ray scattering and nitrogen adsorption desorption techniques show evidence that the composite is elementarily formed by fundamental silica spheres with size ranging from approximately 4 to approximately 7 nm. Surface area of composites is reduced when maltose concentration is increased, which indicates that carbohydrate molecules are preferentially located into the interstitial space between fundamental silica spheres. Through an ultrastructural control over the synthesis process, it has been shown that sol-gel method employed here presents considerable potential for producing efficient drug carrier systems. PMID- 21259240 TI - Quantitative phase analyses through the Rietveld method with X-ray powder diffraction data of heat-treated carbamazepine form III. AB - The present work shows that the heated carbamazepine (CBZ) powder form III can be described as purely triclinic form I or a mixture of triclinic form I and monoclinic form III, depending on the resolution of the X-ray diffraction equipment used. Visual identification of the minor phase is possible when high resolution synchrotron light is used. Quantitative phase analyses of CBZ forms I and III, after thermal treatment, were performed by using both synchrotron and conventional copper rotating anode X-ray powder diffraction data and the Rietveld method. Also, the Rietveld method could be adequately applied to determine the phase percentage in the heated material, even when usual resolution data are acquired. PMID- 21259241 TI - Rapid solid-state analysis of freeze-dried protein formulations using NIR and Raman spectroscopies. AB - Noninvasive near-infrared (NIR) and Raman spectroscopies were applied to provide a fast and efficient insight into the formation of different mannitol solid forms occurring in freeze-dried formulations. Multivariate data analysis clearly showed the formation of delta-mannitol in the presence of protein, whereas beta-mannitol was observed in the absence of protein.The multivariate analysis of the NIR spectra also gave an indication for the formation of mannitol hemihydrate in the absence of protein. Spectroscopic techniques in combination with multivariate analysis can be applied for fast screening and identification of excipient solid state properties in pharmaceutical formulations. PMID- 21259242 TI - High sacrectomy for locally recurrent rectal cancer: Can long-term survival be achieved? AB - BACKGROUND: Locally recurrent rectal cancer involving the upper sacrum is generally considered a contra-indication to curative surgery. The aim of this study was to determine if a survival benefit was seen in patients undergoing high sacrectomy. METHODS: All patients with locally recurrent rectal cancer involving the sacrum above the 3rd sacral body between 1999 and 2007 were retrospectively reviewed. Kaplan-Meier survival analysis was performed. RESULTS: Nine patients were identified with a median age of 63 years. The proximal extent of sacral resection was through S2 (n = 6), S1 (n = 2), and L5-S1 (n = 1). All patients had R0 negative-margin resection. Median operative time was 13.7 hr, and median operative blood transfusion was 3.7 L. Thirty-day mortality was nil. Postoperative complications requiring surgical intervention occurred in three patients. Local re-recurrence in the pelvis occurred in one patient. The overall median survival was 31 months (range, 2-39 months). Three patients still alive are free of disease after 40, 76, and 101 months, respectively. Ultimately, all deaths were due to metastatic disease. CONCLUSIONS: High sacrectomy that achieves clear margins in patients with recurrent rectal cancer is safe and feasible. A majority will die of metastatic disease, but long-term survival may be possible in some patients. PMID- 21259243 TI - Using detection of survivin-expressing circulating tumor cells in peripheral blood to predict tumor recurrence following curative resection of gastric cancer. AB - BACKGROUND AND OBJECTIVES: The present study was designed to investigate the clinicopathological role of survivin-expressing circulating tumor cells (CTCs) and to determine whether the presence of survivin-expressing CTCs is an independent predictor of tumor recurrence following curative resection of gastric cancer. METHODS: This study included 98 patients who underwent potentially curative resection. Reverse transcription polymerase chain reaction enzyme linked immunosorbent assay (RT-PCR ELISA) was used to measure survivin mRNA in peripheral blood. RESULTS: Of the 98 patients studied, 45 (45.9%) were positive for survivin mRNA. Survivin mRNA expression correlated with Lauren classification (P < 0.001), pathological tumor (pT) stage (P < 0.001), pathological tumor node metastasis (pTNM) stage (P = 0.009), and degree of differentiation (P = 0.001). The pTNM stage and the status of survivin mRNA were independent prognostic factors of disease-free survival (P = 0.007 and <0.001, respectively). CONCLUSIONS: The detection of CTCs expressing survivin mRNA could be a good clinical biomarker used to predict the prognosis of patients with curatively resected gastric cancer. PMID- 21259244 TI - ADAM 10 is associated with gastric cancer progression and prognosis of patients. AB - BACKGROUND: The metalloproteinase domain-containing protein 10 (ADAM 10) has been implicated in the development and progression of gastric cancer. METHODS: Expression of ADAM 10 and C-erbB-2 were examined immunochemically in 436 clinicopathologically characterized gastric cancer cases. RESULTS: Protein levels of ADAM 10 and C-erbB-2 were up-regulated in gastric cancer lesions compared with adjacent non-cancerous tissues. Positive expression of ADAM 10 correlated with age, size of tumor, location of tumor, depth of invasion, vessel invasion, lymph node, and distant metastasis and TNM stage, and also with expression of C-erbB-2. In stages I, II, and III, the 5-year survival rate of patients with high ADAM 10 expression was significantly lower than in patients with low expression. However, in stage IV, ADAM 10 expression did not correlate with the 5-year survival rate. Further multivariate analysis suggests that up-regulation of ADAM 10 and C-erbB-2 were independent prognostic indicators for the disease, along with depth of invasion, lymph node and distant metastasis and TNM stage. CONCLUSION: Expression of ADAM 10 in gastric cancer is significantly associated with lymph node and distant metastasis, high C-erbB-2 expression, and poor prognosis. ADAM 10 and C erbB-2 proteins could be useful markers to predict tumor progression and prognosis. PMID- 21259245 TI - Analysis of DNA copy number aberrations by multiple ligation-dependent probe amplification on 50 intestinal type gastric cancers. AB - BACKGROUND AND OBJECTIVES: The molecular genetic alterations leading to gastric malignancy are largely unknown. This study aimed to unravel the genomic DNA copy number aberrations (CNAs) profile during gastric tumorigenesis. METHODS: In this study, we performed genomic profiling in a set of 50 intestinal type gastric carcinomas by a PCR-based relative quantification method, multiple ligation dependent probe amplification (MLPA) with 112 cancer-related gene loci selected throughout each human chromosome as probes of MLPA assay. RESULTS: Numerous chromosomal DNA CNAs, including gains of 3p22, 4q25, 8q24, 11p13, and 20q13, and losses of 1p36 and 9p21, were identified by MLPA assay as recurrent DNA CNAs in gastric cancer. Moreover, we found the median numbers of gains, losses, and total CNAs were significantly higher in lymph node metastasis positive patients than in cases without metastasis. And gain of 11p13 and losses of 9p21.3, 11q13.3, 17q25.3, and 22q11.23 were associated with lymph node metastasis (P < 0.05). Finally, two major groups, including G1 + 2 with a large number of CNAs and G3 + 4 with a small number of CNAs, can be successfully distinguished by hierarchical cluster analysis. CONCLUSIONS: Our results proved MLPA is a reliable and efficient method to evaluate DNA copy number changes in gastric cancers. PMID- 21259246 TI - Delay in treatment of early-stage hepatocellular carcinoma using radiofrequency ablation may impact survival of cirrhotic patients in a surveillance program. AB - BACKGROUND: The aim of this study was to evaluate the impact of the interval between diagnosis and treatment using radiofrequency (RF) ablation on the survival of patients with HCC detected through a surveillance program. METHODS: Between January 2004 and July 2007, 121 cirrhotic patients with 157 tumours detected through a surveillance program underwent RF ablation. A delay in treatment was defined as >5 weeks. The mean length of follow-up was 25 months (range 8-55 months). Cumulative survival of patients was analysed using the Kaplan-Meier method. Cox regression models were used to identify factors associated with patient survival. RESULTS: The 1-, 2- and 3-year survival rates were 92.5%, 78.5% and 67.2%. The independent predictors of poorer patient survival were time from diagnosis to treatment >5 weeks (pooled odds ratio [OR], 3.59; 95% confidence interval [CI], 1.58-8.18; P = 0.002), absence of complete ablation after the initial RF session (OR, 2.42; 95% CI 1.07-5.45; P = 0.033) and Child-Pugh B liver cirrhosis (OR, 2.46; 95% CI 1.06-5.70; P = 0.036). CONCLUSIONS: Delay in the start of effective treatment for HCC using RF ablation may be associated with poorer patient survival. PMID- 21259247 TI - Impact of blood transfusion on early outcome of liver resection for colorectal hepatic metastases. AB - BACKGROUND: The use of intra-operative blood transfusion has been associated with worse surgical outcome in patients undergoing liver resection for malignancy. METHODS: In a series of 127 consecutive patients who underwent partial liver resection for colorectal metastases, between July 1999 and March 2010, we studied, post-operative 90 days surgical outcome using Clavien multi-tier grading system, and the effect of a variety of related factors, including type of resection, surgical technique used, concomitant colo-rectal resection, non tumoral hepatic histological findings, site of primary tumor, and comorbidities, on the incidence of intra-operative blood transfusion. RESULTS: Patients who received blood transfusions during their liver resection were more likely to have a longer post-operative length of stay, to experience Clavien Grade IIIa or worse complication. Undergoing a major resection and the presence of portal fibrosis in the non-tumoral liver tissue were both correlated with an increase in intra operative blood transfusions. CONCLUSION: These clinical findings suggest that although several significant factors do not seem to influence the short-term outcome of surgery, it is important to be aware of the deleterious effects of the type of resection performed and the presence of portal fibrosis on blood loss during partial liver resection. PMID- 21259248 TI - Prognostic factors after early recurrence in patients who underwent curative resection for hepatocellular carcinoma. AB - BACKGROUND: The prognosis of the patients with early recurrence after curative hepatectomy for hepatocellular carcinoma (HCC) is usually dismal. METHODS: One hundred twenty-four patients underwent curative resection for HCC at Kyungpook National University Hospital from January 2002 to December 2006. An early recurrence was defined as a recurrence within 2 years after a curative resection. The risk factors associated with an early recurrence were analyzed as well as other risk factors correlated with survival after early recurrence. RESULTS: Early disease recurrence developed in 56 patients (45.2%). The risk factors associated with an early recurrence were a tumor size larger than 5 cm (P = 0.001) and the presence of tumor micrometastasis (P < 0.001). The 1 year/2 year overall survival, after early recurrence, was 57.0%/41.0% and the preoperative alpha-fetoprotein, C-reactive protein (CRP), tumor size, macroscopic vascular invasion, and number of tumors were associated with survival on the univariate analysis. The multivariate analysis showed that the independent risk factors for survival, after early disease recurrence, were a preoperative CRP >1.0 mg/dl and macroscopic vascular invasion. (P = 0.004, P < 0.001, respectively). CONCLUSION: The preoperative CRP and macroscopic vascular invasion were associated with the aggressiveness of early recurrent HCC. PMID- 21259249 TI - Usefulness of sonazoid-ultrasonography during hepatectomy in patients with liver tumors: A preliminary study. AB - BACKGROUND AND OBJECTIVES: To improve diagnostic accuracy of intraoperative ultrasonography (IOUS), we investigated the usefulness of new contrast medium of microbubble agent, Sonazoid as a preliminary study. METHOD: We examined IOUS in 50 patients with liver tumors who underwent hepatectomy. Sonazoid was administrated intravenously and Kupffer-phase images of the tumor were observed before hepatectomy. Sonazoid was reinjected to observe the tumor vasculature. RESULTS: The tumors included hepatocellular carcinoma (HCC) in 25 patients, intrahepatic cholangiocarcinoma in 3, colorectal liver metastasis in 14, gastrointestinal stromal tumor in 1, and benign hematoma in 1. Liver tumors were clearly detected as perfusion defect in most cases. Small lesions (<1 cm), extra capsular tumor growth, and portal vein tumor thrombus were also clearly detected on the Sonazoid-IOUS. Small occult tumors were detected in five cases. Differential diagnosis with suspicious non-tumorous lesions and benign mass was possible based on vascular findings at the early phase. In comparison with hepatectomy for HCC under conventional IOUS, the proportion of patients with positive surgical margin (0%) tended to be lower than that of the control group (P = 0.073). CONCLUSION: Sonazoid-IOUS is a promising useful tool to detect the precise tumor margin and small tumors, hence allowing curative hepatectomy or intraoperative ablation. PMID- 21259250 TI - Desmoplastic melanoma - the step-child in the melanoma family? AB - BACKGROUND AND OBJECTIVES: Desmoplastic melanoma (DM) is a rare variant of cutaneous melanoma. Our goal was to study the surgical management of DM, identify prognostic factors, and impact of treatment options. METHODS: Patients with DM (n = 1,735) were identified from the Surveillance, Epidemiology, and End Results database (1988-2006). RESULTS: The median age of the study population was 69 years and overall survival (OS) at 5 years 65%. DM was more common in males (65%), most commonly found on the head and neck (51%), and had a mean thickness of 2.97 mm. Patients undergoing a wide local excision (WLE; >=1 cm) had improved 5-year OS compared to a simple excision (<1 cm) or biopsy alone (67% vs. 60% vs. 45%, respectively, P < 0.001). Of 505 patients (29%) undergoing sentinel node biopsy (SLNB), only 14 (2.8%) were positive. Traditional prognostic factors such as Breslow thickness, nodal positivity, and ulceration did not predict survival. On multivariate analysis only adjuvant radiation therapy [HR 1.65 (95% CI 1.17 2.31)] and WLE correlated with survival [HR 0.47 (95% CI 0.32-0.69)]. CONCLUSIONS: Desmoplastic melanoma does not share traditional prognostic factors with the melanoma family. Surgical resection with wide margins is needed to optimize survival and routine SLNB may be unnecessary. PMID- 21259251 TI - Surgical outcome of modified versus conventional parotidectomy in treatment of benign parotid tumors. AB - BACKGROUND: Our proposed modified technique includes creating a posterior pedicle parotid gland fascia flap without separating the great auricular nerve branches through an aesthetic incision. This fascial flap is sutured back to the parotid bed creating a barrier of the aberrant regeneration of sympathetic fibers thus, theoretically, decreasing the incidence of Frey's syndrome. PATIENTS AND METHODS: Superficial parotidectomy for benign parotid neoplasms was carried out using either the conventional (Group 1) or modified (Group 2) technique. Outcomes of the two groups were reviewed. Both techniques were compared for the cosmetic outcome, great auricular nerve anesthesia, and the incidence of Frey's syndrome. RESULTS: The incision in the modified group was more cosmetic both subjectively and objectively. Postoperatively, transient numbness was reported by 21% of cases in the modified group. In the control group, transient sensory deficit was complained by all cases. Fourteen patients restored sensation completely within 2 years after surgery. The incidence of subjective Frey's syndrome was significantly lower in the modified group. Objectively, on starch iodine test, the incidence of Frey's syndrome was higher in both groups. CONCLUSION: In selected cases of benign parotid neoplasm, modified parotidectomy is an effective technique in improving the outcome of the procedure. PMID- 21259252 TI - Surgical management of patients with insulinomas: Result of 292 cases in a single institution. AB - BACKGROUND: Insulinoma is rare tumor with an incidence of approximately four cases per million per year. There are few large sample, single-center series that focus on the surgical management strategy of insulinomas. PATIENTS AND METHODS: Medical records of patients diagnosed as insulinoma from 1990 to 2010 in Peking Union Medical College Hospital were reviewed retrospectively. Clinical data were collected and statistically analyzed. RESULTS: A total of 328 patients were diagnosed with insulinomas; 292 of them underwent 320 operations, which included 46 laparoscopic surgeries. Tumor enucleation was the most common operative procedure. Multiple tumors were found in 30 cases; 17 cases were multiple endocrine neoplasia-1 syndrome. Thirteen patients with malignant insulinomas underwent tumor resection. Pancreatic fistula (PF) was the most frequent complication, and the incidence of clinical PFs (Grades B and C) was 14.4%. There was no significant statistical difference between open and laparoscopic surgery in blood loss, operative time, and complications. Metachronous tumors were noted in 11 patients. CONCLUSION: Surgery is the best treatment of choice for insulinoma patients. Surgical approach depends on tumor size, location, and its pathological characters. Laparoscopic management of insulinomas is feasible and safe for tumors located in the body or tail of the pancreas. Open surgery combined with intraoperative ultrasonography is recommended to avoid omission of lesions in patients with multiple insulinomas. An aggressive surgical approach is indicated for malignant insulinoma patients. PMID- 21259253 TI - Neoadjuvant radiotherapy and reconstruction using autologous vein graft for the treatment of inferior vena cava leiomyosarcoma. AB - BACKGROUND AND OBJECTIVES: Inferior vena cava (IVC) leiomyosarcomas are rare and are a relatively small subset of retroperitoneal sarcomas. The current approach is resection and ligation or reconstruction of the IVC. This study was undertaken to analyze the outcomes associated with the use of neoadjuvant radiotherapy and IVC reconstruction in the treatment of IVC leiomyosarcoma. METHODS: A retrospective clinicopathological review of patients treated during a 10-year period. RESULTS: Four patients were treated with neoadjuvant radiotherapy, median 47.5 Gy, all underwent margin negative resection with 75% of the tumors being high grade and all patients requiring resection of adjacent organs. Reconstruction of the IVC was performed with an autologous superficial femoral vein graft. There were no mortalities and the morbidity rate was 50%. At a median follow up of 37 months; two patients had a patent IVC, no patients had a local recurrence, and one patient developed a distant metastases treated successfully with metastectomy. CONCLUSIONS: Neoadjuvant radiotherapy and resection of the IVC leiomyosarcoma resulted in 100% local control, and all patients are alive at median follow up of 37 months. IVC reconstruction with the superficial femoral vein is safe and associated with acceptable short and long term morbidity. PMID- 21259254 TI - Esophageal cancer--the five year survivors. AB - BACKGROUND: Esophageal cancer in the United States carries a poor prognosis with overall 5 year survival rate of approximately 10%. Due to this dismal outcome, data analyzing factors predictive of survival for greater than 5 years are not available. METHODS: Single institution retrospective review of esophageal resection for curative intent from 1984 to 2004. We identified 50 actual 5 year survivors (long term survivors, LTS) out of 266 patients (19%) with invasive esophageal cancer and, using multivariate logistic regression, compared characteristics between the LTS, and short-term (<5 year) survivors (STS). RESULTS: There was no significant difference in clinical T stage or N stage by EUS (P = 0.81) or in the utilization of neoadjuvant therapy in the LTS versus STS (58% vs. 62%, respectively, P = 0.36). The LTS group was significantly more likely to have pathologic complete response (69% vs. 41%, P < 0.001), lower pathologic T stage, i.e., pT0, pTis, or pT1 (83% vs. 45%, P < 0.001), pN0 stage (97% vs. 68%, P < 0.001), favorable tumor differentiation (well or well to moderate, 39% vs. 13%, P < 0.001), and absence of angiolymphatic (88% vs. 69%, P < 0.01) or perineural invasion (95% vs. 83%, P = 0.04). In comparing the factors predictive of outcome in LTS versus the STS with increasing relative risk, absence of perineural invasion (RR 0.41 (0.27, 0.61)), negative margins (RR 0.41 (0.29, 0.57)), absence of angiolymphatic invasion (RR 0.39 (0.30, 0.51)), pN0 stage (RR 1.37 (1.23, 1.52)), pT0 or pT1 (RR 1.85 (1.64, 2.07)), pathologic complete response (RR 2.02 (1.76, 2.31)), and favorable tumor grade (RR 3.00 (2.49, 3.61)) were associated with improved survival. CONCLUSION: Tumor biological factors including favorable tumor grade may be the most important influence on 5 year actual survival in esophageal cancer. PMID- 21259255 TI - Significance of AEG-1 expression in correlation with VEGF, microvessel density and clinicopathological characteristics in triple-negative breast cancer. AB - PURPOSE: Our study is to examine astrocyte-elevated gene-1 (AEG-1) expression in triple-negative breast cancer and to determine whether it is associated with vascular endothelial growth factor (VEGF), microvessel density (MVD), clinicopathological parameters and poor survival. METHODS: Specimens from 125 patients with triple-negative breast cancers were investigated by immunohistochemistry for MVD, AEG-1 and VEGF expression. Correlations between the expression of AEG-1, VEGF, MVD, and various clinicopathological factors including survival status were studied. RESULTS: AEG-1 and VEGF were highly expressed in 56.8% and 52.8% of triple-negative breast cancer patients, respectively. The intensity of AEG-1 was gradually up-regulated from VEGF-MVD-low, VEGF-high, or MVD-high to VEGF-MVD-high tissues using Western blot analysis. Statistically significant correlation was found among AEG-1 and VEGF, and MVD. Moreover, AEG-1 expression was correlated with clinical stage, lymphatic venous invasion, lymph nodal metastasis, tumor size, Ki67, and recurrence. Patients with AEG-1 high expression showed far lower disease-free survival (DFS) and overall survival (OS) rates than those with AEG-1 low-expression. For VEGF and MVD, there were similar results in these patients. Only AEG-1 expression and tumor size were independent prognostic factors for both DFS and OS by multivariate analysis. However, the prognostic impact of tumor size was not as strong as that of AEG-1. CONCLUSIONS: AEG-1 expression may be related with tumor angiogenesis and progression and is a valuable prognostic factor in patients with triple-negative breast cancer. PMID- 21259256 TI - Marjolin's warty ulcer. AB - Marjolin's ulcer refers to malignant change within burn scar. The French surgeon Jean-Nicolas Marjolin is honored with the eponym. Marjolin described the "warty ulcer" in the first edition of Dictionnaire de Medecine. In his description, Marjolin did not actually state that this ulcer represented malignant transformation. Credit for noting the specific association involved in Marjolin's ulcer belongs to Caesar Hawkins, an English Surgeon, who described skin cancer arising in burn and flogging scars. PMID- 21259258 TI - Surgery-induced immunomodulation in breast cancer. PMID- 21259259 TI - Children's health and the environment: an overview. AB - Environmental pediatrics, the branch of pediatric medicine that studies the influence of the environment on children's health, has in the past decade grown exponentially. Rising rates of pediatric chronic disease and growing recognition of children's extensive exposures and great vulnerabilities to toxic hazards in the environment have catalyzed this expansion. New scientific initiatives have resulted. They include 14 Centers for Children's Environmental Health and Disease Prevention Research supported by the US National Institutes of Health and the US Environmental Protection Agency; a global network of Pediatric Environmental Health Specialty Units supported by the US Centers for Disease Control and Prevention/Agency for Toxic Substances and Disease Registry; new postdoctoral training programs in pediatric environmental medicine; and the National Children's Study, the largest prospective epidemiological study of children's health ever undertaken in the United States, which launched in 2009 and will follow 100,000 children from conception to age 21 to assess environmental influences on health and development. These research initiatives have delineated the exquisite vulnerability of fetuses, infants, and children to toxic hazards in the environment. They have led to discovery of new environmental causes of disease and disability in children. This issue of The Mount Sinai Journal of Medicine focuses on children's health and the environment. We have brought together thought leaders in children's environmental health to critically examine new research findings, to explore new opportunities for translating research to treatment and prevention, and to offer a vision for the future of this rapidly expanding field. PMID- 21259260 TI - Clinical services in environmental pediatrics. AB - Pediatric healthcare providers are confronted with environmental health problems frequently: the child with asthma exacerbated by the odor of paint in school or mouse antigen at home, the family who wants to know the risks and benefits of using different types of sunblock, or the community that asks the provider for advice on the potential health impacts of building the new elementary school next to the on-ramp to the interstate highway. Pediatric providers have not been well trained to deal with these questions in medical or nursing schools, residency training, or continuing-education settings. This article provides guidance on history taking, the physical examination, laboratory evaluations of patients and the environment, and making an assessment about and managing environmental health problems. Pediatric Environmental Health Specialty Units are discussed as a source of consultation and referral. The identification and utilization of evidence-based resources are stressed and clinicians are cautioned about non evidence-based assessments such as clinical ecology and hair analysis and non evidence-based management strategies such as chelation for autism. PMID- 21259262 TI - Contributions of built environment to childhood obesity. AB - As childhood obesity has reached epidemic proportions, it is critical to devise interventions that target the root causes of obesity and its risk factors. The two main components of childhood obesity are physical inactivity and improper nutrition, and it is becoming increasingly evident that the built environment can determine the level of exposure to these risk factors. Through a multidisciplinary literature review, we investigated the association between various built environment attributes and childhood obesity. We found that neighborhood features such as walkability/bikeability, mixed land use, accessible destinations, and transit increase resident physical activity; also that access to high-caloric foods and convenience stores increases risk of overweight and obesity, whereas the presence of neighborhood supermarkets and farmers' markets is associated with lower childhood body mass index and overweight status. It is evident that a child's built environment impacts his access to nutritious foods and physical activity. In order for children, as well as adults, to prevent onset of overweight or obesity, they need safe places to be active and local markets that offer affordable, healthy food options. Interventions that are designed to provide safe, walkable neighborhoods with access to necessary destinations will be effective in combating the epidemic of obesity. PMID- 21259263 TI - Environmental neurotoxicants and developing brain. AB - The brain of infants and children is uniquely sensitive to environmental neurotoxicants at levels far below those that are known to harm adults. There are multiple windows of vulnerability during which environmental exposures can interfere with normal development. The timing and duration of neurotoxicant exposures during development can give rise to a broad spectrum of structural and functional deficits. Only about 200 chemicals out of more than 80,000 registered with the United States Environmental Protection Agency have undergone extensive neurotoxicity testing, and many chemicals found in consumer goods are not required to undergo any neurodevelopmental testing. The cumulative effects of co contaminants and the difficulties in analyzing biomarkers of exposure in human tissues have complicated comprehensive risk assessment. Furthermore, population based studies that measure subtle effects on neurobehavioral outcomes are challenging to interpret and costly to conduct. Despite the fact that developmental neurotoxicity may be more severe and irreversible compared with adult toxicity, there is a relative paucity of toxicological data on developing systems for many high-production chemicals. This article provides an overview of the adverse neurological, cognitive, and behavioral outcomes associated with environmental exposures, with an emphasis on human studies. PMID- 21259261 TI - Childhood obesity and environmental chemicals. AB - Childhood and adolescent rates of obesity and overweight are continuing to increase in much of the world. Risk factors such as diet composition, excess caloric intake, decreased exercise, genetics, and the built environment are active areas of etiologic research. The obesogen hypothesis, which postulates that prenatal and perinatal chemical exposure can contribute to risk of childhood and adolescent obesity, remains relatively underexamined. This review surveys numerous classes of chemicals for which this hypothesis has been explored. We focus on human data where they exist and also discuss the findings of rodent and cell culture studies. Organochlorine chemicals as well as several classes of chemicals that are peroxisome proliferator-activated receptor agonists are identified as possible risk factors for obesity. Recommendations for future epidemiologic and experimental research on the chemical origins of obesity are also given. PMID- 21259264 TI - Climate change, aeroallergens, and pediatric allergic disease. AB - The degree to which aeroallergens are contributing to the global increase in pediatric allergic disease is incompletely understood. We review the evidence that links climate change to changes in aeroallergens such as pollen and outdoor mold concentrations and, subsequently, aeroallergen association with pediatric allergic disease. We specifically explore the evidence on both the exacerbation and the development of allergic disease in children related to outdoor pollen and mold concentrations. Pediatric allergic diseases include atopic dermatitis or eczema, allergic rhinitis or hay fever, and some types of asthma in children, typically defined as < 18 years of age. We discuss how the timing of aeroallergen exposure both in utero and in childhood could be associated with allergies. We conclude that the magnitude and type of health impacts due to climate change will depend on improved understanding of the relationship between climatic variables, multiple allergen factors, and allergic disease. Improved public-health strategies such as adequate humidity control, optimum air filtration and ventilation, and improved anticipatory public-health messaging will be critical to adaptation. PMID- 21259265 TI - Community engagement in children's environmental health research. AB - Community engagement strategies and skills can build trust and reduce historical mistrust between researchers, communities, and populations being studied, as well as contribute to the quality of study designs, methods, and dissemination of findings. This review paper discusses why community engagement is of increasing importance in children's environmental health research, describes models and the continuum of methods that are used, and discusses their challenges and benefits. Two case studies, representing different study designs and using different community engagement models and methods, and lessons learned from these cases, are described. Community engagement methods are best understood on a continuum based on the degree to which community members or representatives of community populations are involved in research planning, decision-making, and dissemination. Methods along this continuum include community consultation, community-based participatory research, and community consent to research. Community engagement knowledge and skills are especially important in the conduct of children's environmental health research, with its emphasis on reducing environmental risks at the community level, the increasing focus on genetics and gene-environment interactions, and the importance placed on translation of scientific results into behaviors and policies that protect the community. Across study designs, whether qualitative survey research, an observational epidemiology study, or a randomized intervention trial, understanding community interests, norms, and values is necessary to describe attitudes and behaviors of specific population groups, build evidence of cause and effect between environmental exposures and health, and demonstrate the effectiveness of interventions to reduce risks. PMID- 21259266 TI - Economics of children's environmental health. AB - Economic analyses are increasingly appearing in the children's environmental health literature. In this review, an illustrative selection of articles that represent cost analyses, cost-effectiveness analyses, and cost-benefit analyses is analyzed for the relative merits of each approach. Cost analyses remain the dominant approach due to lack of available data. Cost-effectiveness and cost benefit analyses in this area face challenges presented by estimation of costs of environmental interventions, whose costs are likely to decrease with further technological innovation. Benefits are also more difficult to quantify economically and can only be partially alleviated through willingness-to-pay approaches. Nevertheless, economic analyses in children's environmental health are highly informative and important informants to public-health and policy practice. Further attention and training in their appropriate use are needed. PMID- 21259268 TI - National Children's Study: update in 2010. AB - The National Children's Study will examine the effects of the environment and genetics on the growth, development, and health of children across the United States; it will follow participants from before birth until age 21 years. The goal of the study is to improve the health and well-being of children and contribute to understanding the roles various factors play in health and disease. Findings from the study will be made available as the research progresses, making potential benefits known to the public as soon as possible. A robust pilot study, or Vanguard Study, is underway to generate data for designing the subsequent Main Study. The goals of the Vanguard Study are feasibility, acceptability, and cost, and the goals of the Main Study will be exposure-response relationships and biological, environmental, and genetic interactions. The initial Vanguard Study experience among 7 study centers was successful in many ways, including delineating the topics to explore for the next phase of the Vanguard Study. Three different recruitment strategies are under evaluation to determine what approach to use for the Main Study. The organization of National Children's Study operations is currently based on a new decentralized business model. PMID- 21259267 TI - Methylmercury and brain development: imprecision and underestimation of developmental neurotoxicity in humans. AB - Methylmercury is now recognized as an important developmental neurotoxicant, though this insight developed slowly over many decades. Developmental neurotoxicity was first reported in a Swedish case report in 1952, and from a serious outbreak in Minamata, Japan, a few years later. Whereas the infant suffered congenital poisoning, the mother was barely harmed, thus reflecting a unique vulnerability of the developing nervous system. Nonetheless, exposure limits for this environmental chemical were based solely on adult toxicity until 50 years after the first report on developmental neurotoxicity. Even current evidence is affected by uncertainty, most importantly by imprecision of the exposure assessment in epidemiological studies. Detailed calculations suggest that the relative imprecision may be as much as 50%, or greater, thereby substantially biasing the results toward the null. In addition, as methylmercury exposure usually originates from fish and seafood that also contains essential nutrients, so-called negative confounding may occur. Thus, the beneficial effects of the nutrients may appear to dampen the toxicity, unless proper adjustment is included in the analysis to reveal the true extent of adverse effects. These problems delayed the recognition of low-level methylmercury neurotoxicity. However, such problems are not unique, and many other industrial compounds are thought to cause developmental neurotoxicity, mostly with less epidemiological support than methylmercury. The experience obtained with methylmercury should therefore be taken into account when evaluating the evidence for other substances suspected of being neurotoxic. PMID- 21259269 TI - Cell transplantation and gene therapy in Parkinson's disease. AB - Parkinson's disease is a progressive neurodegenerative disorder affecting, in part, dopaminergic motor neurons of the ventral midbrain and their terminal projections that course to the striatum. Symptomatic strategies focused on dopamine replacement have proven effective at remediating some motor symptoms during the course of disease but ultimately fail to deliver long-term disease modification and lose effectiveness due to the emergence of side effects. Several strategies have been experimentally tested as alternatives for Parkinson's disease, including direct cell replacement and gene transfer through viral vectors. Cellular transplantation of dopamine-secreting cells was hypothesized as a substitute for pharmacotherapy to directly provide dopamine, whereas gene therapy has primarily focused on restoration of dopamine synthesis or neuroprotection and restoration of spared host dopaminergic circuitry through trophic factors as a means to enhance sustained controlled dopamine transmission. This seems now to have been verified in numerous studies in rodents and nonhuman primates, which have shown that grafts of fetal dopamine neurons or gene transfer through viral vector delivery can lead to improvements in biochemical and behavioral indices of dopamine deficiency. However, in clinical studies, the improvements in parkinsonism have been rather modest and variable and have been plagued by graft-induced dyskinesias. New developments in stem-cell transplantation and induced patient-derived cells have opened the doors for the advancement of cell-based therapeutics. In addition, viral-vector-derived therapies have been developed preclinically with excellent safety and efficacy profiles, showing promise in clinical trials thus far. Further progress and optimization of these therapies will be necessary to ensure safety and efficacy before widespread clinical use is deemed appropriate. PMID- 21259270 TI - Do different facets of impulsivity predict different types of aggression? AB - This study examined the relations between impulsivity-related traits (as assessed by the UPPS-P Impulsive Behavior Scale) and aggressive behaviors. Results indicated that UPPS-P Lack of Premeditation and Sensation Seeking were important in predicting general violence. In contrast, UPPS-P Urgency was most useful in predicting intimate partner violence. To further explore relations between intimate partner violence and Urgency, a measure of autonomic response to pleasant and aversive stimuli and facets of Neuroticism from the NEO PI-R were used as control variables. Autonomic responsivity was correlated with intimate partner violence at the zero-order level, and predicted significant variance in intimate partner violence in regression equations. However, UPPS-P Urgency was able to account for unique variance in intimate partner violence, above and beyond measures of Neuroticism and arousal. Implications regarding the use of a multifaceted conceptualization of impulsivity in the prediction of different types of violent behavior are discussed. PMID- 21259271 TI - Myocardial ischemia is not always due to epicardial atheromatous disease. AB - Symptoms related to myocardial ischemia, for the most part, are due to high-grade epicardial coronary artery stenoses. However, in some instances at coronary angiography, no such lesions are seen to account for symptoms due to an imbalance between myocardial oxygen supply and myocardial oxygen demand. Thus, the finding of normal or nonobstructive epicardial coronary arteries at coronary angiography does not exclude the presence of myocardial ischemia in some patients. PMID- 21259272 TI - The slow cardiac myosin regulatory light chain in heart failure. PMID- 21259273 TI - Sinus rhythm restoration and treatment success: insight from recent clinical trials. AB - Atrial fibrillation (AF) is a common supraventricular tachyarrhythmia with substantial morbidity and mortality. This review briefly describes the mechanisms of AF development and progression, including electrical, structural, and contractile remodeling. In addition, the potential benefits of achieving and maintaining sinus rhythm are discussed. For example, rhythm control has been associated with improvements in left ventricular function, AF symptoms, exercise tolerance, the ability to perform activities of daily living, and quality of life. More recently, dronedarone, a noniodinated benzofuran derivative approved for use in the treatment of AF, was shown to significantly improve clinical outcomes including cardiovascular hospitalizations and death from any cause in A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death From Any Cause in Patients With Atrial Fibrillation/Atrial Flutter (ATHENA). The review concludes with an examination of AF treatment options and expectations. Evidence suggests that the complete absence of AF recurrence is not always achievable; however, complete restoration of sinus rhythm may not be necessary for patients to achieve clinically meaningful benefits. Copyright (c) 2011 Wiley Periodicals, Inc. The editorial assistance provided for this manuscript was funded by Sanofi-Aventis. The authors were fully responsible for all content and editorial decision, and received no financial support or other form of compensation related to the development of the paper. The authors have no other funding, financial relationships, or conflicts of interest to disclose. PMID- 21259274 TI - Rhythm control for management of patients with atrial fibrillation: balancing the use of antiarrhythmic drugs and catheter ablation. AB - Antiarrhythmic drug (AAD) therapy may be beneficial for patients with symptoms attributable to atrial fibrillation despite adequate rate control. The limited long-term efficacy of AAD and the relatively large proportion of patients discontinuing therapy because of side effects led to the development of nonpharmacological therapies to achieve rhythm control. Pressing questions remain about the effect of ablation therapy on long-term patient outcomes. Based on recent clinical trials and meta-analyses, ablation appears more effective and possibly safer than AAD for long-term maintenance of sinus rhythm in selected patients, but the evidence is insufficient to recommend ablation in preference to drug therapy as the first AAD therapy for the majority of patients in whom a rhythm control strategy is justified. Herein, we review the most current evidence supporting the use of AAD and catheter ablation in atrial fibrillation. PMID- 21259275 TI - Slow cardiac myosin regulatory light chain 2 (MYL2) was down-expressed in chronic heart failure patients. AB - BACKGROUND: Genetic studies have shown that many slow cardiac myosin regulatory light chain 2 (MYL2) gene mutations can cause hypertrophic cardiomyopathy, which is one of the most common causes of heart failure (HF). But until now there has been no pathological or histological evidence that MYL2 may be associated with HF development. Recent microarray studies indicated that myosin heavy chain expression changed in the pathological process of HF. Because MYL2 is a regulatory component of myosin heavy polypeptide, the role of MYL2 protein in HF needs to be studied. HYPOTHESIS: The level of expression of MYL2 may change in the heart tissue of patients with chronic HF. METHODS: We collected 28 human right auricle samples, 16 from chronic HF patients and 12 from healthy control subjects. Immunohistochemistry was carried out to observe the tissue-expression pattern of the MYL2 protein and Western blot methods were performed to quantify the relative MYL2 expression level. RESULTS: In chronic HF patients, the MYL2 protein level decreased significantly compared with normal controls (t test P < 0.05). Among the 16 HF patients, MYL2 expression in the severe HF group (New York Heart Association [NYHA] class III or IV) was even lower than that of the moderate HF group (NYHA class II) (t test P < 0.05). CONCLUSIONS: MYL2 was down expressed in HF tissues, and our findings suggested that MYL2 may play a role in the development and progression of chronic HF. PMID- 21259276 TI - Etiology of syncope in patients hospitalized with syncope and predictors of mortality and rehospitalization for syncope at 27-month follow-up. AB - The authors investigated the etiologies of syncope and risk factors for mortality and rehospitalization for syncope at 27-month follow-up in 325 consecutive patients, mean age 66 years, hospitalized for syncope. The causes of syncope were diagnosed in 241 patients (74%). Of 325 patients, 13 (4%) were rehospitalized for syncope and 38 (12%) died. Stepwise logistic regression analysis showed that significant independent prognostic factors for rehospitalization for syncope were diabetes (odds ratio [OR], 5.7; 95% confidence interval [CI], 1.6-20.4), atrial fibrillation (OR, 4.0; 95% CI, 1.0-15.6), and smoking (OR, 4.6; 95% CI, 1.3 16.8). Stepwise Cox regression analysis showed that significant independent prognostic factors for time to mortality were diabetes (hazard ratio [HR], 2.7; 95% CI, 1.4-5.2), coronary artery bypass graft surgery (HR, 2.9; 95% CI, 1.3 6.5), malignancy history (HR, 2.5; 95% CI, 1.2-5.2), narcotics use (HR, 4.0; 95% CI, 1.7-9.8), smoking (HR, 2.8; 95% CI, 1.4-5.5), atrial fibrillation (HR, 2.4; 95% CI, 1.0-5.4), and volume depletion (HR, 2.8; 95% CI, 1.4-5.8). Copyright (c) 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose. PMID- 21259277 TI - Effect of atenolol vs metoprolol succinate on vascular function in patients with hypertension. AB - BACKGROUND: We evaluated the effect of atenolol vs metoprolol succinate on vascular function in patients with essential hypertension. HYPOTHESIS: Given intrinsic differences between these agents, we hypothesized that atenolol and metoprolol succinate would have disparate effects on vascular function. METHODS: This study included 24 patients with hypertension (age 56 +/- 2 years, 8 female, body mass index 28 +/- 1) and featured a randomized, double-blind, crossover design. Each beta-blocker (atenolol or metoprolol succinate) was taken by patients once daily for a 4-week period. Measures of vascular function included peripheral augmentation index (AIx) and pulse wave amplitude reactive hyperemia index from peripheral arterial tonometry, and brachial artery flow-mediated dilation from ultrasound. RESULTS: There were similar reductions in mean arterial pressure following treatment with atenolol and metoprolol succinate. Compared with metoprolol succinate, there was a significant increase in peripheral AIx following atenolol therapy (P < 0.05). There were no changes in brachial artery flow-mediated dilation or pulse wave amplitude reactive hyperemia index following either drug treatment. CONCLUSIONS: Although atenolol and metoprolol succinate have similar effects on blood-pressure reduction, they have different effects on vascular function. Compared with metoprolol succinate, atenolol increases peripheral AIx. Neither drug has an effect on vascular endothelial function. These findings may have clinical implications, depending on the indication for treatment in an individual patient. PMID- 21259278 TI - Left ventricular contraction patterns in patients with suspected acute coronary syndrome and normal coronary angiograms: a new look at the takotsubo syndrome. AB - BACKGROUND: Original descriptions of the takotsubo syndrome (TS) included a characteristic left ventricular (LV) contraction pattern, "apical ballooning." Recently, several reports have associated contraction patterns not strictly conforming to the original description with TS. The specifics of the contraction pattern seem to set TS apart from the much larger population of patients with acute coronary syndrome (ACS) but no obstructive coronary artery disease (OCAD). This study was undertaken to compare patients with midventricular and apical dysfunction with those with other LV contraction patterns. HYPOTHESIS: If TS can present with a variety of patterns of LV dysfunction, then both those with and those without the pattern should have the clinical components previously assigned to the syndrome. METHODS: We studied LV contraction patterns in consecutive ACS patients referred for consideration of emergent or urgent percutaneous coronary intervention. RESULTS: Of the 893 patients evaluated in 2008, we excluded 862 on the basis of OCAD, preexisting LV dysfunction, or an obvious alternative cause of symptoms. The remaining 31 (3.5%) also had no OCAD but manifested an LV contraction abnormality. We compared the 15 patients (1.7%) whose ventriculograms met criteria for TS with the 16 patients (1.8%) whose did not. The most common alternative pattern was global hypokinesis, followed by a variety of segmental contraction abnormalities. Patients with the TS pattern were older and had evidence of greater myocardial injury. More than 85% were women. CONCLUSIONS: The TS pattern identifies a distinct subset of ACS patients with a remarkable predominance of postmenopausal women and is therefore fundamental to the definition of this entity. This distinctive facet of the syndrome is likely to be an important clue to its pathogenesis. We did not encounter patients with other patterns of LV dysfunction that could be thought to represent stress-induced cardiomyopathy. Copyright (c) 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose. PMID- 21259279 TI - Prevalence and impact of cardiovascular risk factors among patients presenting with acute coronary syndrome in the middle East. AB - The authors explored the prevalence and impact of the cardiovascular risk factors (CVRFs) in patients presenting with acute coronary syndrome (ACS). During a five month period in 2007, six adjacent Middle Eastern countries participated in the Gulf Registry of acute coronary events. CVRFs were identified on admission. Patients' characteristics and in-hospital outcomes were analyzed across the types of ACS. Among 6704 consecutive patients with ACS, 61% had non-ST elevation ACS (NSTEACS) and 39% had ST-elevation myocardial infarction (STEMI). Female sex, old age, diabetes mellitus, hypertension, dyslipidemia, and obesity were more prevalent in NSTEACS patients. STEMI patients were more likely to be smokers and less likely to be taking aspirin prior to the index admission. Chronic renal failure (CRF) and diabetes mellitus were independent predictors of in-hospital heart failure in NSTEACS, while CRF and hypertension were predictors of STEMI. Female sex and CRF were independent predictors of mortality in STEMI (odds ratio, 2.0; 95% confidence interval, 1.19-3.13 and odds ratio, 5.0; 95% confidence interval, 3.47-7.73, respectively). Assessment of the prevalence of CVRF in the acute coronary presentation is of important prognostic value for in-hospital morbidity and mortality. CVRF and its impact may differ according to ACS type, age, and sex. Coronary heart disease (CHD) is the leading cause of mortality and morbidity worldwide. To achieve a significant reduction in the prevalence of CHD, it is essential to adopt effective preventive strategies with adequate awareness of the epidemiology of cardiovascular risk factors (CVRFs).1 CVRFs include traditional and nontraditional factors. However, the US Preventive Services Task Force concluded that the evidence is insufficient to assess the balance of benefits and harms of using nontraditional risk factors.2,3 The World Health Organization has recognized obesity, hypertension, hypercholesterolemia, and smoking among the top10 traditional risk factors for premature death and morbidity.4 Since these risk factors are usually evident before developing CHD, knowledge of their prevalence in a given population allows the prediction of the likely burden of CHD.3 The American Heart Association has recognized many risk factors; some can be modified, treated, or controlled and some can not.5 The more risk factors present, the greater the likelihood of developing CHD. Currently, most reports for prevention of CHD are mainly derived from European centers and suggest that risk factors for CHD are varying from country to country.6 However, data from the Arab Middle East that evaluate the prevalence and impact of these risk factors in acute coronary events are scarce.4,7,8 We explore the prevalence of CVRFs in patients with acute coronary syndrome (ACS) who are living in the Arab Middle East and the impact of these factors on in-hospital heart failure (HF) and mortality. Copyright (c) 2011 Wiley Periodicals, Inc. The authors have no funding, financial relationships, or conflicts of interest to disclose. PMID- 21259280 TI - The effect of early and intensive statin therapy on ventricular premature beat or nonsustained ventricular tachycardia in patients with acute coronary syndrome. AB - BACKGROUND: To evaluate the prognostic value of early and intensive lipid lowering treatment on ventricular premature beat or nonsustained ventricular tachycardia (NSVT) after acute coronary syndrome (ACS) (ST-elevation myocardial infarction [STEMI], non-STEMI, and unstable angina pectoris). HYPOTHESIS: Provided that early and intensive lipid-lowering treatment can reduce ventricular premature beat or non-sustained ventricular tachycardia after ACS. METHODS: A total of 586 patients with ACS were randomly divided into 2 groups: group A (with conventional statin therapy, to receive 10 mg/day atorvastatin, n = 289) and group B (early and intensive statin therapy, 60 mg immediately and 40 mg/day atorvastatin, n = 297). The frequency of ventricular premature beat and NSVT was recorded with Holter monitoring after hospitalization (24 hours and 72 hours). RESULTS: Seventy-seven (11.8%) patients had NSVT. When compared to patients with no documented NSVT, patients with NSVT were older and more often had myocardial infarction, diabetes mellitus, atrial fibrillation, and an ejection fraction < 40% in their history. Ventricular premature beats decreased significantly in the early and aggressive treatment group (24 hours, P < 0.01; 72 hours, P < 0.001). A significant reduction in NSVT was seen in the early and aggressive (24 hours, P < 0.01; 72 hours, P < 0.001) group. No side effects were observed in either group. CONCLUSIONS: Early and intensive lipid-lowering treatment can obviously decrease ventricular premature beats and NSVT. PMID- 21259281 TI - Response to effectiveness and cost-effectiveness of public access automatic defibrillator (AED) programs. PMID- 21259283 TI - Numerical simulation of bubble dynamics in a micro-channel under a nonuniform electric field. AB - A numerical method is used to simulate the motion and coalescence of air bubbles in a micro-channel under a nonuniform electric field. The channel is equipped with arrays of electrodes embedded in its wall and voltages are applied on the electrodes to generate a specified electric field gradient in the longitudinal direction. In the study, the Navier-Stokes equations are solved by using the level set method handling the deformable/moving interfaces between the bubbles and the ambient liquid. Both the polarization Coulomb force and the dielectrophoresis force are considered as the force source of the Navier-Stokes equations by solving the Maxwell's equations. The flow field equations and the electric field equations are coupled and solved by using the finite element method. The electric field characteristics and the dynamic behavior of a bubble are analyzed by studying the distributions of the electric field and the force, the deformation and the moving velocity of the air bubble. The result suggests that the model of dispersed drops suspended in the immiscible dielectric liquid and driven by a nonuniform electric field is an effective method for the transportation and coalescence of micro-drops. PMID- 21259284 TI - Buffers to suppress sodium dodecyl sulfate adsorption to polyethylene oxide for protein separation on capillary polymer electrophoresis. AB - Although polyethylene oxide (PEO) offers several advantages as a sieving polymer in SDS capillary polymer electrophoresis (SDS-CPE), solution properties of PEO cause deterioration in the electrophoresis because PEO in solution aggregates itself, degrades into smaller pieces, and forms polymer-micelle complexes with SDS. We examined protein separation on SDS-CPE with PEO as a sieving matrix in four individual buffer solutions: Tris-CHES, Tris-Gly, Tris-Tricine, and Tris-HCl buffers. The solution properties of PEO as a sieving matrix in those buffers were examined by dynamic light scattering (DLS) and by surface tension. Preferential SDS adsorption onto PEO disturbed protein-SDS complexation and impaired the protein separation efficiency. Substantial adsorption of SDS to PEO was particularly observed in Tris-Gly buffer. The Tris-CHES buffer prevented SDS from adsorbing onto the PEO. Only Tris-CHES buffer achieved separation of six proteins. This study demonstrated efficient protein separation on SDS-CPE with PEO. PMID- 21259285 TI - Uncultured bacterial diversity in tropical maize (Zea mays L.) rhizosphere. AB - Structure of maize (Zea mays L.) rhizosphere bacteria was evaluated to explore the feasibility of identifying novel rhizosphere bacteria using culture independent method based on direct amplification and analysis of 16S rRNA gene (rRNA) sequences and especially to obtain a better understanding of bacterial community structure and diversity from maize. A total of 274 sequences were analyzed and assigned 48.00% Proteobacteria, 10.30% Actinobacteria, 9.90% Bacteroidetes, 6.60% Verrucomicrobia, 4.80% Acidobacteria, 1.80% Firmicutes, 1.50% Chloroflexi, 1.50% TM7, 1.10% Deinococcus-Thermus, 0.70% Planctomycetes, 0.70% Gemmatimonadetes and 0.40% Cyanobacteria. Economically important phyla Actinobacteria was second most dominant group after Proteobacteria, in our clone library. It would be interesting to hypothesize that root exudates from maize rhizosphere favors growth of Actinobacteria like microbes to eliminate pathogenic bacteria and decompose plant matter, for enhanced plant and soil health. An additional 12.8% of clone library (35 operational taxonomical units (OTUs) from 43 clones) with less than 94% similarity to any GenBank sequence could not be assigned to any known phylum and may represent unidentified bacterial lineages and suggests that a large amount of the rhizobacterial diversity remains to be characterized by culturing. PMID- 21259286 TI - Isolation and phosphate-solubilizing ability of a fungus, Penicillium sp. from soil of an alum mine. AB - The use of microorganisms to solubilize elemental phosphorus from insoluble rock phosphate is a promising method to greatly reduce not only environmental pollution but also production costs. Phosphate-solubilizing microorganisms were isolated from soils in China, and a fungus strain (PSM11-5) from a soil sample from an alum mine, with the highest phosphate solubilization potential, was selected and identified as a Penicillium sp. Strain PSM11-5 could grow in buffered medium with pH values between 3.0 and 8.0 and showed phosphate solubilizing activity at pH values from 5.0 to 8.0. It also exhibited a degree of tolerance to the heavy metal ions, Cd(2+), Co(2+), and Cr(6+). PSM11-5 could rapidly solubilize tricalcium phosphate, and a high phosphate-solubilizing efficiency of 98% was achieved in an optimized medium. The strain could solubilize rock phosphate and aluminum phosphate with a solubilizing efficiency of approximately 74.5%, but did not solubilize iron phosphate. Solubilization of phosphate depended on acidification. Analysis of PSM11-5 culture supernatants by capillary electrophoresis showed that tricalcium phosphate was solubilized to PO(4) (3-) and Ca(2+) , and that the organic acid produced by the fungus was mainly gluconic acid at approximately ca. 13 g l(-1). In addition, PSM11-5 produced ca. 830 mg l(-1) of citric acid when it was used to solubilize rock phosphate. These excellent properties of strain PSM11-5 suggest that the fungus has potential for agricultural and industrial utilization. PMID- 21259287 TI - Effects of Piriformospora indica and Sebacina vermifera on growth and yield of essential oil in fennel (Foeniculum vulgare) under greenhouse conditions. AB - Fennel (Foeniculum vulgare) is a very important plant in the family of Apiaceae. Effects of inoculation of two endophytic fungi (Piriformospora indica and Sebacina vermifera) in growth, yield and composition of the essential oil of fennel (F. vulgare) were evaluated in pot cultures. Dry fruits were ground with an electric grinder and oil was extracted by hydrodistillation, and their composition was determined by GC/MS. In pot experiment, the maximum dry weight of the green tissue and root and plant height were obtained with P. indica, and maximum number of umbels per plant and dry weight of 1000 fruits were produced with S. vermifera. The P. indica and S. vermifera inoculation significantly increased oil yield as compared to non-inoculated control plants. GC and GC/MS studies revealed that the level of anethole was increased with P. indica and S. vermifera. PMID- 21259288 TI - Screening of promoters from rhizosphere metagenomic DNA using a promoter-trap vector and flow cytometric cell sorting. AB - We constructed a facilitative and efficient promoter-trap vector, pCM-EGFP, for capturing and analyzing functional promoters from environmental DNA. The pCM-EGFP vector showed good chloramphenicol sensitivity and no enhanced green fluorescent protein (EGFP) gene expression. Promoter libraries were constructed for screening promoters responding to naringenin, a key molecule released from plant roots. After electroporation, E. coli transformants were incubated in LB broth containing chloramphenicol (10 MUg/ml) to select against transformants with no cloned promoter. E. coli cells were sorted using flow cytometry without naringenin, and then sorted again with high fluorescence after incubation in LB broth with naringenin (1 mM) at 28 degrees C for 12 h. The inducible properties of approximately 400 sorted cells were evaluated, with most cells showing only strong EGFP gene expression without inducible properties. Two clones (5-4E and 15 3D) displayed naringenin inducibility, and both contained a promoter bounded by a TetR-family regulator. The regulator knock-out mutant of the 5-4E clone lost its ability to be induced by naringenin. In conclusion, the pCM-EGFP vector may be used as an efficient promoter-trap vector and a combination of the vector with flow cytometric cell sorting was demonstrated to be an useful method for screening promoters responding to specific conditions or inducers. PMID- 21259289 TI - Isolation of nine Phytophthora capsici pectin methylesterase genes which are differentially expressed in various plant species. AB - Phytophthora capsici causes damage on many plants species, and secretes various pectin methylesterases during all stages of infection. We identified nine Pme genes (Pcpme 1-9) from a genomic library of highly virulent P. capsici strain SD33 and further analyzed the expression pattern of nine genes on three hosts: pepper, tomato, and cucumber using qRT-PCR during all stages of infection. All nine genes were found to be differentially expressed in three host species in the course of P. capsici interaction. The expression levels of the respective genes increased from 1 to 7 dpi in pepper, while most genes presented a decreasing trend of expression from 1 to 5 dpi in tomato fruits. However, in both fruits peaks were reached at 7 dpi. In cucumber fruits, each gene showed minor expression levels from 1 to 3 dpi, exhibited definite peaks at 5 dpi, and then decreased from 5 to 7 dpi. Thus, evidence from our studies of Pcpme gene expression in different plants at a rang of time points suggests that the late stages of infection may represent the most critical time for P. capsici to successfully express or/and secret PMEs. PMID- 21259290 TI - Antigenotoxicity of artepillin C in vivo evaluated by the micronucleus and comet assays. AB - Artepillin C (3,5-diprenyl-p-coumaric acid), a major compound found in Brazilian green propolis and Baccharis dracunculifolia, shows anti-inflammatory, antibacterial, antiviral, antioxidant and antitumoral activities, among others. The aim of this study was to evaluate the genotoxic potential of artepillin C and its ability to prevent the chemically induced chromosome breakage or loss and the primary DNA damage using the micronucleus and comet assays in male Swiss mice, respectively. The animals were treated by gavage with different doses of artepillin C (0.4, 0.8 and 1.6 mg kg(-1) b.w.). For the antigenotoxicity assays, the different doses of artepillin C were administered simultaneously to doxorubicin (DXR; micronucleus test; 15 mg kg(-1) b.w.) and to methyl methanesulfonate (MMS; comet assay; 40 mg kg(-1) b.w.). The results showed that artepillin C itself was not genotoxic in the mouse micronucleus and comet assays. In the animals treated with artepillin C and DXR, the number of micronucleated reticulocytes was significantly lower in comparison with the animals treated only with DXR. Regarding antigenotoxicity, artepillin C at the tested doses significantly reduced the extent of DNA damage in liver cells induced by MMS. PMID- 21259291 TI - Sequential measurements of glomerular filtration rate in conscious rats by a bolus injection of iodixanol and a single blood sample. AB - To estimate the glomerular filtration rate (GFR) sequentially in conscious rats, we validated a single-blood-sample method using a bolus injection of the nonionic contrast medium iodixanol as a tracer. First, to clarify basal age-related GFR profiles, iodixanol was intravenously administered once weekly at 1500 mg kg(-1) I to clinically healthy male F344 rats from 6 to 15 weeks of age. The blood sample was collected 120 min later, and serum iodixanol concentration was measured by HPLC. GFR values decreased gradually by 9 weeks, presumably due to rapidly increased body weights, and then remained constant from 10 weeks onward. When converting the GFR from body weight to body surface area, the reference range (40-60 ml min(-1) m(-2) ) in the latter was much more stable than that (6 11 ml min(-1) kg(-1) ) in the former. For nephropathy rats induced by cisplatin (3.75-7.5 mg kg(-1) , i.v., single dose), bromoethylamine hydrobromide (BEA, 250 500 mg kg(-1) , i.v., single dose) or puromycin aminonucleoside (PAN, 15 mg kg( 1) day(-1) , s.c., 10 days), GFR decreased or tended to decrease before increasing in serum urea nitrogen (UN) and creatinine concentrations. Accordingly, serum UN and creatinine concentrations became elevated when the GFR decreased to 50-60% of the basal value. This method without urine collection contributes to the reduction of animal numbers because of repeated application to the same animals. PMID- 21259292 TI - A novel method for measuring aromatase activity in tissue samples by determining estradiol concentrations. AB - Increasing scrutiny of endocrine disrupters has led to changes to European pesticide and biocide legislation and to the introduction of the Endocrine Disrupter Screening Program by the US EPA. One element of endocrine disrupter identification is to determine its effects on aromatase, but most available assays are limited as they depend on tritiated water production to indicate enzyme activity. Whilst acceptable for determining aromatase effects using a cell free approach, this method is unreliable for cell or tissue-based investigations as other cytochrome P-450 isoenzyme activities can similarly produce tritiated water and consequently confound interpretation of the aromatase data. To address this lack of specificity an assay directly measuring the final estrogen product by incubating rat tissue protein with testosterone and measuring the resultant estradiol concentration was developed. Using this approach we demonstrated marked increases in enzyme activity in pregnant rat ovary samples and dose-related inhibitions when incubating non-pregnant rat ovary samples with known aromatase inhibitors. Hepatic aromatase activity was investigated using our method and by tritiated water production with microsomes from rats dosed with the antiandrogen 1,1-dichloro-2,2-bis(4 chlorophenyl)ethane. Additional cytochrome P-450s were also measured. Treatment-related increased tritiated water production and general hepatic enzyme activity were recorded but estradiol was not increased, indicating that the increased tritiated water was due to general enzyme activity and not aromatase activity. A simple and specific method has been developed that can detect aromatase inhibition and induction, which when applied to tissue samples, provides a means of generating relevant animal data concerning chemical effects on the aromatase enzyme. PMID- 21259293 TI - Urinary biomarkers in hexachloro-1:3-butadiene-induced acute kidney injury in the female Hanover Wistar rat; correlation of alpha-glutathione S-transferase, albumin and kidney injury molecule-1 with histopathology and gene expression. AB - Hexachloro-1:3-butadiene (HCBD) causes kidney injury specific to the pars recta of the proximal tubule. In the present studies, injury to the nephron was characterized at 24 h following a single dose of HCBD, using a range of quantitative urinary measurements, renal histopathology and gene expression. Multiplexed renal biomarker measurements were performed using both the Meso Scale Discovery (MSD) and Rules Based Medicine platforms. In a second study, rats were treated with a single nephrotoxic dose of HCBD and the time course release of a range of traditional and newer urinary biomarkers was followed over a 25 day period. Urinary albumin (a marker of both proximal tubular function and glomerular integrity) and alpha-glutathione S-transferase (alpha-GST, a proximal tubular cell marker of cytoplasmic leakage) showed the largest fold change at 24 h (day 1) after dosing. Most other markers measured on either the MSD or RBM platforms peaked on day 1 or 2 post-dosing, whereas levels of kidney injury molecule-1 (KIM-1), a marker of tubular regeneration, peaked on day 3/4. Therefore, in rat proximal tubular nephrotoxicity, the measurement of urinary albumin, alpha-GST and KIM-1 is recommended as they potentially provide useful information about the function, degree of damage and repair of the proximal tubule. Gene expression data provided useful confirmatory information regarding exposure of the kidney and liver to HCBD, and the response of these tissues to HCBD in terms of metabolism, oxidative stress, inflammation, and regeneration and repair. PMID- 21259294 TI - Unique expression pattern of the three insulin receptor family members in the rat mammary gland: dominance of IGF-1R and IRR over the IR, and cyclical IGF-1R expression. AB - Supra-pharmacological doses of the insulin analog X10 (AspB10) increased the incidence of mammary tumors in female Sprague-Dawley rats in chronic toxicity studies, most likely via receptor-mediated mechanisms. However, little is known about the expression of the insulin receptor family in the rat mammary gland. Using laser micro-dissection, quantitative RT-PCR and immunohistochemistry, we examined the expression of IR (insulin receptor), IGF-1R (IGF-1 receptor), IRR (insulin receptor-related receptor), ERalpha (estrogen receptor alpha), ERbeta (estrogen receptor beta) and PR (progesteron receptor) in young, virgin, female Sprague-Dawley rats and compared to expression in reference organs. The mammary gland displayed the highest expression of IRR and IGF-1R. In contrast, low expression of IR transcripts was observed in the mammary gland tissue with expression of the IR-A isoform being 5-fold higher than the expression of the IR B. By immunohistochemistry, expression of IR and IGF-1R was detected in all mammary gland epithelial cells. Expression of ERalpha and PR was comparable between mammary gland and ovary, whereas expression of ERbeta was lower in mammary gland than in the ovary. Finally, expression of IGF-1R and PR in the mammary gland varied during the estrous cycle. These findings are important for the understanding of carcinogenic effects of insulin analogs in the rat mammary gland, and relevant for development of refined short-term models for preclinical safety assessment of insulin analogs. PMID- 21259296 TI - Occupational lung cancer in US women, 1984-1998. AB - BACKGROUND: Lung cancer is the leading cause of cancer death in US women, accounting for 72,130 deaths in 2006. In addition to smoking cessation, further reduction of the burden of lung cancer mortality can be made by preventing exposure to occupational lung carcinogens. Data for occupational exposures and health outcomes of US working women are limited. METHODS: Population-based mortality data for 4,570,711 women who died between 1984 and 1998 in 27 US States were used to evaluate lung cancer proportionate mortality over time by the usual occupation and industry reported on death certificates. Lung cancer proportionate mortality ratios were adjusted for smoking, using data from the National Health Interview Survey (NHIS) and the American Cancer Society's Cancer Prevention Study II. RESULTS: Analyses revealed that 194,382 white, 18,225 Black and 1,515 Hispanic women died 1984-1998 with lung cancer reported as the underlying cause of death. Following adjustment for smoking, significant excess proportionate lung cancer mortality was observed among US women working in the US manufacturing; transportation; retail trade; agriculture, forestry, and fishing; and nursing/personal care industries. Women employed in precision production, technical, managerial, professional specialty, and administrative occupations experienced some of the highest significantly excess proportionate lung cancer mortality during 1984-1998. CONCLUSIONS: The results of our study point to significantly elevated risks for lung cancer after adjustment for smoking among women in several occupations and industries. Because 6-17% of lung cancer in US males is attributable to known exposures to occupational carcinogens, and since synergistic interactions between cigarette smoke and other occupational lung carcinogens have been noted, it is important to continue research into the effects of occupational exposures on working men and women. PMID- 21259295 TI - Diphenyl diselenide potentiates nephrotoxicity induced by mercuric chloride in mice. AB - Following our long-standing interest in the mechanisms involved in selenium toxicity, the aim of this work was to extend our previous studies to gain a better understanding of mercuric chloride (HgCl2) + diphenyl diselenide (PhSe)2 toxicity. Mice received one daily dose of HgCl2 (4.6 mg kg(-1) , subcutaneously) for three consecutive days. Thirty minutes after the last injection of HgCl2, mice received a single dose of (PhSe)2 (31.2 mg kg(-1) , subcutaneously). Five hours after (PhSe)2 administration, mice were euthanized and delta aminolevulinate dehydratase, catalase (CAT), glutathione S-transferase (GST) and Na(+) , K(+) -ATPase activities as well as thiobarbituric acid-reactive substances (TBARS), ascorbic acid and mercury levels were determined in kidney and liver. Parameters in plasma (urea, creatinine, protein and erythropoietin), whole blood (hematocrit and hemoglobin) and urine (protein) were also investigated. HgCl2 + (PhSe)2 exposure caused a decrease in renal GST and Na(+) , K(+) -ATPase activities and an increase in renal ascorbic acid and TBARS concentrations when compared with the HgCl2 group. (PhSe)2 potentiated the increase in plasma urea caused by HgCl2. HgCl2 + (PhSe)2 exposure caused a reduction in plasma protein levels and an increase in hemoglobin and hematocrit contents when compared with the HgCl2 group. There was a significant reduction in hepatic CAT activity and an increase in TBARS levels in mice exposed to HgCl2 + (PhSe)2 when compared with the HgCl2 group. The results demonstrated that (PhSe)2 did not modify mercury levels in mice. In conclusion, (PhSe)2 potentiated damage caused by HgCl2 affecting mainly the renal tissue. PMID- 21259297 TI - Work-related fatalities among youth ages 11-17 in North Carolina, 1990-2008. AB - BACKGROUND: Local and national surveillance systems are in place that identify occupational deaths. However, due to certain restrictions, they are limited in their ability to accurately count these deaths among adolescent workers. METHODS: In this population-based study, we relied on primary data from the North Carolina medical examiner system to identify and describe all work-related fatalities among North Carolina youth under age 18 between 1990 and 2008. RESULTS: We identified 31 work-related deaths among youth ages 11-17. The majority occurred between 1990 and 1999. Most occurred in construction and agriculture. Vehicles and guns were responsible for the majority of deaths. CONCLUSIONS: Although the prevalence of adolescent work-related fatalities has seen a decline in North Carolina, the 31 deaths we detected signal a failure of the systems in place to prevent young worker fatalities. More remains to be done to protect the lives of adolescent workers. PMID- 21259298 TI - Incidence of work injuries amongst Danish adolescents and their association with work environment factors. AB - BACKGROUND: The objective was to examine the incidence of work accidents that required medical attention among Danish adolescents and to identify possible work environment factors associated with such accidents. METHODS: We collected information in two questionnaire rounds (2004 and 2007) from a birth cohort comprising all adolescents born in 1989 (n = 3,687) living in Ringkjobing County, Denmark. The questionnaire contained items on self-reported number of accidents and number of working hours in both rounds and on work environment factors in the second round. RESULTS: Approximately 5% of the adolescents who held a job, experienced a work injury at the age of 17. This equals an incidence of 65 accidents per million working hours. Most adolescents had decent working conditions, although nearly half reported that their work was heavy, monotonous or psychologically demanding. Heavy work, high psychological demands and low social support increased the risk of experiencing work injuries after adjustment for a number of factors. CONCLUSIONS: The incidence of work injuries among adolescents appears to be higher than the incidence among their older colleagues. Lack of social support from management significantly raised adolescents' risk of experiencing a work injury. This suggests that more direct supervision may be a good way of preventing accidents in this age group. PMID- 21259299 TI - The IARC october 2009 evaluation of benzene carcinogenicity was incomplete and needs to be reconsidered. AB - I have been familiar with the toxicological and epidemiological literature on benzene since I was a member of the NIOSH Benzene Task Force in 1975. I also am familiar with the procedures of IARC Monographs meetings from past participation, and as observer I applied this experience to the Monograph 100 F review. In October of 2009, a Working Group (WG) of the International Agency for Research on Cancer (IARC) met in Lyon, France to evaluate the available evidence for site specific cancer to humans for 33 chemical agents and related occupations previously categorized by IARC as human carcinogens. Generally, review and discussion of the epidemiological cancer literature related to benzene was limited due to the enormous amount of material needing to be covered since the last full monograph meeting on benzene in 1981, and because 32 other chemicals and occupations were also being evaluated. Moreover, among the 33 chemicals and occupations reviewed, there was some inconsistency in the use of studies for evaluating various cancers. In some situations, consideration could have been given to the inclusion of relevant unpublished, but readily available study results. Discussion and synthesis of the animal cancer studies and mechanistic data related to specific cancers also were limited. IARC's conclusion that there is sufficient evidence for benzene to cause acute non-lymphocytic leukemia only was based on an incomplete review. IARC should schedule another monographs meeting dedicated to a complete and full review and discussion of all potential cancers related to exposure to benzene and to benzene-containing mixtures. PMID- 21259300 TI - Updating IARC's carcinogenicity assessment of benzene. PMID- 21259301 TI - Chimpanzee oil-palm use in southern Cantanhez National Park, Guinea-Bissau. AB - Cantanhez National Park in southern Guinea-Bissau is a mosaic of forest, mangrove, savanna, and agricultural fields, with a high prevalence of oil-palm trees (Elaeis guineensis). It hosts many different animal species, including the chimpanzee (Pan troglodytes verus). Very little is known about the ecology of chimpanzees inhabiting this area. The main aims of this study were to evaluate chimpanzee nesting behavior, define trends of habitat use, and estimate chimpanzee density in four separate forests by applying the marked nest counts methodology. From the 287 new nests counted, 92% were built in oil-palm trees with a significantly higher frequency of nests in the forest edge than in forest cores. Differences in nest detection rates were observed in the four monitored forests, with two forests being more important for chimpanzee's nesting demands. The number of nests documented in the forests seemed to be correlated with the frequency of other signs of chimpanzee activity. Although chimpanzees selected nests on the forest edge, they were most frequently observed in forest core areas. Constraints associated with estimating chimpanzee density through oil-palm nest counting are discussed. PMID- 21259302 TI - Behavioral response of a chimpanzee mother toward her dead infant. AB - The mother-offspring bond is one of the strongest and most essential social bonds. Following is a detailed behavioral report of a female chimpanzee 2 days after her 16-month-old infant died, on the first day that the mother is observed to create distance between her and the corpse. A series of repeated approaches and retreats to and from the body are documented, along with detailed accounts of behaviors directed toward the dead infant by the mother and other group members. The behavior of the mother toward her dead infant not only highlights the maternal contribution to the mother-infant relationship but also elucidates the opportunities chimpanzees have to learn about the sensory cues associated with death, and the implications of death for the social environment. PMID- 21259303 TI - Information in the sample covariate distribution in prevalent cohorts. AB - Methods of estimation and inference about survival distributions based on length biased samples are well-established. Comparatively little attention has been given to the assessment of covariate effects in the context of length-biased samples, but prevalent cohort studies often have this objective. We show that, like the survival distribution, the covariate distribution from a prevalent cohort study is length-biased, and that this distribution may contain parametric information about covariate effects on the survival time. As a result, a likelihood based on the joint distribution of the survival time and the covariates yields estimates of covariate effects which are at least as efficient as estimates arising from a traditional likelihood which conditions on covariate values in the length-biased sample. We also investigate the empirical bias of estimators arising from a joint likelihood when the population covariate distribution is misspecified. The asymptotic relative efficiencies and empirical biases under model misspecification are assessed for both proportional hazards and accelerated failure time models. The various methods considered are applied in an illustrative analysis of risk factors for death following onset of dementia using data collected in the Canadian Study of Health and Aging. PMID- 21259305 TI - Optimal sampling in retrospective logistic regression via two-stage method. AB - Case-control sampling is popular in epidemiological research because of its cost and time saving. In a logistic regression model, with limited knowledge on the covariance matrix of the point estimator of the regression coefficients a priori, there exists no fixed sample size analysis. In this study, we propose a two-stage sequential analysis, in which the optimal sample fraction and the required sample size to achieve a predetermined volume of a joint confidence set are estimated in an interim analysis. Additionally required observations are collected in the second stage according to the estimated optimal sample fraction. At the end of the experiment, data from these two stages are combined and analyzed for statistical inference. Simulation studies are conducted to justify the proposed two-stage procedure and an example is presented for illustration. It is found that the proposed two-stage procedure performs adequately in the sense that the resultant joint confidence set has a well-controlled volume and achieves the required coverage probability. Furthermore, the optimal sample fractions among all the selected scenarios are close to one. Hence, the proposed procedure can be simplified by always considering a balance design. PMID- 21259306 TI - Augmented p-rep designs. AB - Early generation variety trials are very important in plant and tree breeding programs. Typically many entries are tested, often with very little resources available. Unreplicated trials using control plots are popular and it is common to repeat the trials at a number of locations. An alternative is to use p-rep designs, where a proportion of the test entries are replicated at each location; this can obviate the need for control plots. alpha-Designs are commonly used for replicated variety trials and we show how these can be adapted to produce efficient p-rep designs. PMID- 21259307 TI - When should one adjust for measurement error in baseline variables in observational studies? AB - Previously, we showed that in randomised experiments, correction for measurement error in a baseline variable induces bias in the estimated treatment effect, and conversely that ignoring measurement error avoids bias. In observational studies, non-zero baseline covariate differences between treatment groups may be anticipated. Using a graphical approach, we argue intuitively that if baseline differences are large, failing to correct for measurement error leads to a biased estimate of the treatment effect. In contrast, correction eliminates bias if the true and observed baseline differences are equal. If this equality is not satisfied, the corrected estimator is also biased, but typically less so than the uncorrected estimator. Contrasting these findings, we conclude that there must be a threshold for the true baseline difference, above which correction is worthwhile. We derive expressions for the bias of the corrected and uncorrected estimators, as functions of the correlation of the baseline variable with the study outcome, its reliability, the true baseline difference, and the sample sizes. Comparison of these expressions defines a theoretical decision threshold about whether to correct for measurement error. The results show that correction is usually preferred in large studies, and also in small studies with moderate baseline differences. If the group sample sizes are very disparate, correction is less advantageous. If the equivalent balanced sample size is less than about 25 per group, one should correct for measurement error if the true baseline difference is expected to exceed 0.2-0.3 standard deviation units. These results are illustrated with data from a cohort study of atherosclerosis. PMID- 21259308 TI - Bayesian inference for disease prevalence using negative binomial group testing. AB - Group testing, also known as pooled testing, and inverse sampling are both widely used methods of data collection when the goal is to estimate a small proportion. Taking a Bayesian approach, we consider the new problem of estimating disease prevalence from group testing when inverse (negative binomial) sampling is used. Using different distributions to incorporate prior knowledge of disease incidence and different loss functions, we derive closed form expressions for posterior distributions and resulting point and credible interval estimators. We then evaluate our new estimators, on Bayesian and classical grounds, and apply our methods to a West Nile Virus data set. PMID- 21259309 TI - Quantifying the impact of fixed effects modeling of clusters in multiple imputation for cluster randomized trials. AB - In cluster randomized trials (CRTs), identifiable clusters rather than individuals are randomized to study groups. Resulting data often consist of a small number of clusters with correlated observations within a treatment group. Missing data often present a problem in the analysis of such trials, and multiple imputation (MI) has been used to create complete data sets, enabling subsequent analysis with well-established analysis methods for CRTs. We discuss strategies for accounting for clustering when multiply imputing a missing continuous outcome, focusing on estimation of the variance of group means as used in an adjusted t-test or ANOVA. These analysis procedures are congenial to (can be derived from) a mixed effects imputation model; however, this imputation procedure is not yet available in commercial statistical software. An alternative approach that is readily available and has been used in recent studies is to include fixed effects for cluster, but the impact of using this convenient method has not been studied. We show that under this imputation model the MI variance estimator is positively biased and that smaller intraclass correlations (ICCs) lead to larger overestimation of the MI variance. Analytical expressions for the bias of the variance estimator are derived in the case of data missing completely at random, and cases in which data are missing at random are illustrated through simulation. Finally, various imputation methods are applied to data from the Detroit Middle School Asthma Project, a recent school-based CRT, and differences in inference are compared. PMID- 21259310 TI - Imputing unobserved values with the EM algorithm under left and right-truncation, and interval censoring for estimating the size of hidden populations. AB - Capture-recapture techniques have been used for considerable time to predict population size. Estimators usually rely on frequency counts for numbers of trappings; however, it may be the case that these are not available for a particular problem, for example if the original data set has been lost and only a summary table is available. Here, we investigate techniques for specific examples; the motivating example is an epidemiology study by Mosley et al., which focussed on a cholera outbreak in East Pakistan. To demonstrate the wider range of the technique, we also look at a study for predicting the long-term outlook of the AIDS epidemic using information on number of sexual partners. A new estimator is developed here which uses the EM algorithm to impute unobserved values and then uses these values in a similar way to the existing estimators. The results show that a truncated approach - mimicking the Chao lower bound approach - gives an improved estimate when population homogeneity is violated. PMID- 21259311 TI - Quantifying the predictive accuracy of time-to-event models in the presence of competing risks. AB - Prognostic models for time-to-event data play a prominent role in therapy assignment, risk stratification and inter-hospital quality assurance. The assessment of their prognostic value is vital not only for responsible resource allocation, but also for their widespread acceptance. The additional presence of competing risks to the event of interest requires proper handling not only on the model building side, but also during assessment. Research into methods for the evaluation of the prognostic potential of models accounting for competing risks is still needed, as most proposed methods measure either their discrimination or calibration, but do not examine both simultaneously. We adapt the prediction error proposal of Graf et al. (Statistics in Medicine 1999, 18, 2529-2545) and Gerds and Schumacher (Biometrical Journal 2006, 48, 1029-1040) to handle models with competing risks, i.e. more than one possible event type, and introduce a consistent estimator. A simulation study investigating the behaviour of the estimator in small sample size situations and for different levels of censoring together with a real data application follows. PMID- 21259312 TI - A semiparametric estimator of the bivariate distribution function for censored gap times. AB - Let (T(1), T(2)) be gap times corresponding to two consecutive events, which are observed subject to random right-censoring. In this paper, a semiparametric estimator of the bivariate distribution function of (T(1), T(2)) and, more generally, of a functional E [phi(T(1),T(2))] is proposed. We assume that the probability of censoring for T(2) given the (possibly censored) gap times belongs to a parametric family of binary regression curves. We investigate the conditions under which the introduced estimator is consistent. We explore the finite sample behavior of the estimator and of its bootstrap standard error through simulations. The main conclusion of this paper is that the semiparametric estimator may be much more efficient than purely nonparametric methods. Real data illustration is included. PMID- 21259313 TI - Higher order inference for the consensus mean in inter-laboratory studies. AB - In inter-laboratory studies, a fundamental problem of interest is inference concerning the consensus mean, when the measurements are made by several laboratories which may exhibit different within-laboratory variances, apart from the between laboratory variability. A heteroscedastic one-way random model is very often used to model this scenario. Under such a model, a modified signed log likelihood ratio procedure is developed for the interval estimation of the common mean. Furthermore, simulation results are presented to show the accuracy of the proposed confidence interval, especially for small samples. The results are illustrated using an example on the determination of selenium in non-fat milk powder by combining the results of four methods. Here, the sample size is small, and the confidence limits for the common mean obtained by different methods produce very different results. The confidence interval based on the modified signed log-likelihood ratio procedure appears to be quite satisfactory. PMID- 21259314 TI - On responder analyses when a continuous variable is dichotomized and measurement error is present. AB - In clinical studies results are often reported as proportions of responders, i.e. the proportion of subjects who fulfill a certain response criterion is reported, although the underlying variable of interest is continuous. In this paper, we consider the situation where a subject is defined as a responder if the (error free) continuous measurements post-treatment are below a certain fraction of (error-free) continuous measurements obtained pre-treatment. Focus is on the one sample case, but an extension to the two-sample case is also presented. The bias of different estimates for the proportion of responders is derived and compared. In addition, an asymptotically unbiased ML-type estimate for the proportion of responders is presented. The results are illustrated using data obtained in a clinical study investigating pre-menstrual dysphoric disorder (PMDD). PMID- 21259315 TI - Perspectives on gene therapy in myotonic dystrophy type 1. AB - Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder caused by a CTG expansion mutation located in the 3' untranslated region of the DMPK (DM1 protein kinase) gene. According to current evidence, mutant DMPK mRNAs containing the trinucleotide expansion are retained in the nucleus, entrapping Muscleblind (MBNL1) protein and several transcription factors in ribonuclear foci and stabilizing CUG binding protein, Elav-like family member 1 (CELF1), which ultimately causes aberrant pre-mRNA splicing and gene expression of particular genes and associated pathogenesis in patients with DM1. At present, treatment for DM1 is limited to symptomatic intervention, and there is no therapeutic approach to prevent or reverse disease progression. This Mini-Review is focused on the experimental advances obtained in cell-based and animal models toward the development of therapeutic treatments against DM1, providing a discussion of their potential application in clinical trials. Because the central core of DM1 pathogenesis is gain-of-function of mutant RNA, most studies target the mutant RNA by use of antisense oligonucleotides or small chemical compounds to eliminate or ameliorate its toxic effects. However, alternative strategies focused on reversing DM1 features without targeting of mutant DMPK RNA have recently emerged. PMID- 21259316 TI - Endogenous microglia regulate development of embryonic cortical precursor cells. AB - Microglia play important roles in the damaged or degenerating adult nervous system. However, the role of microglia in embryonic brain development is still largely uncharacterized. Here we show that microglia are present in regions of the developing brain that contain neural precursors from E11 onward. To determine whether these microglia are important for neural precursor maintenance or self renewal, we cultured embryonic neural precursors from the cortex of PU.1(-/-) mice, which we show lack resident microglia during embryogenesis. Cell survival and neurogenesis were similar in cultures from PU.1(-/-) vs. PU.1(+/+) mice, but precursor proliferation and astrogenesis were both reduced. Cortical precursors depleted of microglia also displayed decreased precursor proliferation and astrogenesis, and these deficits could be rescued when microglia were added back to the cultures. Moreover, when the number of microglia present in cortical precursor cultures was increased above normal levels, astrogenesis but not neurogenesis was increased. Together these results demonstrate that microglia present within the embryonic neural precursor niche can regulate neural precursor development and suggest that alterations in microglial number as a consequence of genetic or pathological events could perturb neural development by directly affecting embryonic neural precursors. PMID- 21259317 TI - HeyL promotes neuronal differentiation of neural progenitor cells. AB - Members of the Hes and Hey families of basic helix-loop-helix transcription factors are regarded as Notch target genes that generally inhibit neuronal differentiation of neural progenitor cells. We found that HeyL, contrary to the classic function of Hes and Hey factors, promotes neuronal differentiation of neural progenitor cells both in culture and in the embryonic brain in vivo. Furthermore, null mutation of HeyL decreased the rate of neuronal differentiation of cultured neural progenitor cells. HeyL binds to and activates the promoter of the proneural gene neurogenin2, which is inhibited by other Hes and Hey family members, and HeyL is a weak inhibitor of the Hes1 promoter. HeyL is able to bind other Hes and Hey family members, but it cannot bind the Groucho/Tle1 transcriptional corepressor, which mediates the inhibitory effects of the Hes family of factors. Furthermore, although HeyL expression is only weakly augmented by Notch signaling, we found that bone morphogenic protein signaling increases HeyL expression by neural progenitor cells. These observations suggest that HeyL promotes neuronal differentiation of neural progenitor cells by activating proneural genes and by inhibiting the actions of other Hes and Hey family members. PMID- 21259318 TI - Electron tomography of paranodal septate-like junctions and the associated axonal and glial cytoskeletons in the central nervous system. AB - The polarized domains of myelinated axons are specifically organized to maximize the efficiency of saltatory conduction. The paranodal region is directly adjacent to the node of Ranvier and contains specialized septate-like junctions that provide adhesion between axons and glial cells and that constitute a lateral diffusion barrier for nodal components. To complement and extend earlier studies on the peripheral nervous system, electron tomography was used to image paranodal regions from the central nervous system (CNS). Our three-dimensional reconstructions revealed short filamentous linkers running directly from the septate-like junctions to neurofilaments, microfilaments, and organelles within the axon. The intercellular spacing between axons and glia was measured to be 7.4 +/- 0.6 nm, over twice the value previously reported in the literature (2.5-3.0 nm). Averaging of individual junctions revealed a bifurcated structure in the intercellular space that is consistent with a dimeric complex of cell adhesion molecules composing the septate-like junction. Taken together, these findings provide new insight into the structural organization of CNS paranodes and suggest that, in addition to providing axo-glial adhesion, cytoskeletal linkage to the septate-like junctions may be required to maintain axonal domains and to regulate organelle transport in myelinated axons. PMID- 21259319 TI - Endothelins decrease the expression of aquaporins and plasma membrane water permeability in cultured rat astrocytes. AB - Some of the aquaporins (AQPs), a family of water channel proteins, are expressed in astrocytes. The expression of astrocytic AQPs is altered after brain insults, such as ischemia and head trauma. However, little is known about the regulation of AQP expressions. Endothelins (ETs), which are vasoconstrictor peptides, regulate several pathophysiological responses of astrocytes. In this study, the effects of ETs on AQP expressions and plasma membrane water permeability were examined in cultured rat astrocytes. Determination of AQP mRNA copy numbers revealed that AQP1 and AQP4 were expressed prominently in cultured astrocytes. ET 1 (100 nM) and Ala1,3,11,15-ET-1 (an ETB receptor agonist, 50 nM) decreased the AQP4 and AQP9 mRNA levels in cultured astrocytes, but the AQP1, -3, -5, and -8 mRNA levels remained unchanged. BQ788, an ETB receptor antagonist, reduced the effects of ET-1 on astrocytic AQP mRNAs, whereas FR139317, an ETA antagonist, had no effect. Immunoblot analyses revealed that treatment with ET-1 decreased the protein contents of AQP4 and AQP9 in both total cell lysates and plasma membrane fractions of cultured astrocytes. ET-1 and Ala1,3,11,15-ET-1 decreased hypoosmolarity-induced water influxes into cultured astrocytes. In the presence of 30 MUM Hg2+, which inhibits water movement through AQP1 and AQP9, the hypoosmolarity-induced water influxes were reduced. Phloretin, an inhibitor of AQP9, did not greatly affect the water influxes. The ET-induced decreases in water influxes were obtained in the presence of Hg2+ and phloretin. These results suggest that ET is a factor that regulates AQP expressions and water permeability in astrocytes. PMID- 21259320 TI - Maternal stress affects postnatal growth and the pituitary expression of prolactin in mouse offspring. AB - Maternal stress exerts long-lasting psychiatric and somatic on offspring, which persist into adulthood. However, the effect of maternal stress on the postnatal growth of pups has not been widely reported. In this study, we found that maternal immobilization stress (IS) during lactation resulted in low body weight of male mouse offspring, which persisted after weaning. Despite free access to chow, IS induced maternal malnutrition and decreased the serum insulin-like growth factor-1 (IGF-1) levels in the mothers and in the pups. mRNA expression analysis of anterior pituitary hormones in the pups revealed that growth hormone (GH) and prolactin (PRL), but no other hormones, were decreased by IS. Expression of the pituitary transcription factor PIT1 and isoforms of PITX2, which are essential for the development and function of GH-producing somatotropes and PRL producing lactotropes, was decreased, whereas that of PROP1, which is critical for the earlier stages of pituitary development, was unchanged. Immunohistochemistry also showed a decrease in pituitary PRL protein expression. These results suggest that stress in a postpartum mother has persistent effects on the body weight of the offspring. Reduced PRL expression in the offspring's pituitary gland may play a role in these effects. PMID- 21259321 TI - Dynamics of ultrastructural alterations in photosensitized crayfish glial and neuronal cells: Structures involved in transport processes and neuroglial interactions. AB - Photodynamic therapy (PDT) is used for cancer treatment, including brain tumors. To explore the dynamics of photodynamic injury of glial cells and neurons and corresponding neuroglial interactions, we studied ultrastructure of the PDT treated crayfish stretch receptor that consists of a single sensory neuron enwrapped by glial cells. Just after PDT, swelling of some mitochondria, dictyosomes, and endoplasmic reticulum cisterns occurred in neurons and glial cells. Tubular lattices involved in intraglial transport became swollen and disintegrated. At 1 hr postirradiation, these alterations were expanded to the whole cells. Segregation of the neuronal cytoplasm by Nissl bodies, which were involved in protein synthesis and transport along neurites, was lost. Swelling of submembrane cisterns prevented formation of glial protrusions and double-wall vesicles involved in the glia-to-neuron transport. Five hours later, glial layers lost organelles, stuck together, or dilated locally as a result of edema. In the neuronal cytoplasm, only demises of ER and swollen mitochondria were present, but few mitochondria retained normal structure. Thus, swelling of intracellular organelles, the first sign of photodynamic injury, occurred simultaneously in neurons and glia, but glial organelles were eliminated more quickly. Therefore, glial cells were less resistant to PDT than neurons. Adjacent glial layers were damaged less than remote ones, suggesting their protection by the neuron. The structures involved in glia-to-neuron (neuronal submembrane cisterns, glial protrusions, double-wall vesicles), intraglial (tubular lattices), and intraneuronal (Nissl bodies, Golgi apparatus, microtubular bundles) transport were impaired at the earlier stages of stretch receptor damage. PMID- 21259322 TI - Persistence of psychosine in brain lipid rafts is a limiting factor in the therapeutic recovery of a mouse model for Krabbe disease. AB - Sphingolipids are intrinsic components of membrane lipid rafts. The abnormal accumulation of these molecules may introduce architectural and functional changes in these domains, leading to cellular dysfunction. Galactosylsphingosine (psychosine) is a pathogenic lipid raft-associated molecule whose accumulation leads to brain deterioration and irreversible neurological handicap in the incurable leukodystrophy Krabbe disease (KD). The relevance of clearing excessive levels of pathogenic psychosine from lipid rafts in therapy for KD has not been investigated. The work presented here demonstrates that psychosine inhibits raft mediated endocytosis in neural cells. In addition, although in vitro enzyme reconstitution is sufficient for the reversal of related endocytic defects in affected neural cells, traditional in vivo enzyme therapies in the mouse model of KD appear to be insufficient for complete removal of pathogenic levels of raft associated psychosine. This work describes a mechanism that may contribute to limiting the in vivo efficacy of traditional therapies for KD. PMID- 21259324 TI - Delayed administration of dapsone protects from tissue damage and improves recovery after spinal cord injury. AB - After spinal cord injury (SCI), a complex cascade of pathophysiological processes increases the primary damage. The inflammatory response plays a key role in this pathology. Recent evidence suggests that myeloperoxidase (MPO), an enzyme produced and released by neutrophils, is of special importance in spreading tissue damage. Dapsone (4,4'-diaminodiphenylsulfone) is an irreversible inhibitor of MPO. Recently, we demonstrated, in a model of brain ischemia/reperfusion, that dapsone has antioxidant, antiinflammatory, and antiapoptotic effects. The effects of dapsone on MPO activity, lipid peroxidation (LP) processes, motor function recovery, and the amount of spared tissue were evaluated in a rat model of SCI. MPO activity had increased 24.5-fold 24 hr after SCI vs. the sham group, and it had diminished by 38% and 19% in the groups treated with dapsone at 3 and 5 hr after SCI, respectively. SCI increased LP by 45%, and this increase was blocked by dapsone. In rats treated with dapsone, a significant motor function recovery (Basso-Beattie-Bresnahan score, BBB) was observed beginning during the first week of evaluation and continuing until the end of the study. Spontaneous recovery 8 weeks after SCI was 9.2 +/- 1.12, whereas, in the dapsone-treated groups, it reached 13.6 +/- 1.04 and 12.9 +/- 1.17. Spared tissue increased by 42% and 33% in the dapsone-treated groups (3 and 5 hr after SCI, respectively) vs. SCI without treatment. Dapsone significantly prevented mortality. The results show that inhibition of MPO by dapsone significantly protected the spinal cord from tissue damage and enhanced motor recovery after SCI. PMID- 21259323 TI - Transgenic mice with enhanced neuronal major histocompatibility complex class I expression recover locomotor function better after spinal cord injury. AB - Mice that are deficient in classical major histocompatibility complex class I (MHCI) have abnormalities in synaptic plasticity and neurodevelopment and have more extensive loss of synapses and reduced axon regeneration after sciatic nerve transection, suggesting that MHCI participates in maintaining synapses and axon regeneration. Little is known about the biological consequences of up-regulating MHCI's expression on neurons. To understand MHCI's neurobiological activity better, and in particular its role in neurorepair after injury, we have studied neurorepair in a transgenic mouse model in which classical MHCI expression is up regulated only on neurons. Using a well-established spinal cord injury (SCI) model, we observed that transgenic mice with elevated neuronal MHCI expression had significantly better recovery of locomotor abilities after SCI than wild-type mice. Although previous studies have implicated inflammation as both deleterious and beneficial for recovery after SCI, our results point directly to enhanced neuronal MHCI expression as a beneficial factor for promoting recovery of locomotor function after SCI. PMID- 21259325 TI - Small molecule inhibitor of type I transforming growth factor-beta receptor kinase ameliorates the inhibitory milieu in injured brain and promotes regeneration of nigrostriatal dopaminergic axons. AB - Transforming growth factor-beta (TGF-beta), a multifunctional cytokine, plays a crucial role in wound healing in the damaged central nervous system. To examine effects of the TGF-beta signaling inhibition on formation of scar tissue and axonal regeneration, the small molecule inhibitor of type I TGF-beta receptor kinase LY-364947 was continuously infused in the lesion site of mouse brain after a unilateral transection of the nigrostriatal dopaminergic pathway. At 2 weeks after injury, the fibrotic scar comprising extracellular matrix molecules including fibronectin, type IV collagen, and chondroitin sulfate proteoglycans was formed in the lesion center, and reactive astrocytes were increased around the fibrotic scar. In the brain injured and infused with LY-364947, fibrotic scar formation was suppressed and decreased numbers of reactive astrocytes occupied the lesion site. Although leukocytes and serum IgG were observed within the fibrotic scar in the injured brain, they were almost absent in the injured and LY 364947-treated brain. At 2 weeks after injury, tyrosine hydroxylase (TH) immunoreactive fibers barely extended beyond the fibrotic scar in the injured brain, but numerous TH-immunoreactive fibers regenerated over the lesion site in the LY-364947-treated brain. These results indicate that inhibition of TGF-beta signaling suppresses formation of the fibrotic scar and creates a permissive environment for axonal regeneration. PMID- 21259326 TI - C-terminal mechano-growth factor induces heme oxygenase-1-mediated neuroprotection of SH-SY5Y cells via the protein kinase Cepsilon/Nrf2 pathway. AB - Recently, a variant of insulin-like growth factor-1, mechano-growth factor (MGF), has been discovered whose 24-amino-acid carboxy end is protective in models of stroke, nerve injury, and amyotrophic lateral sclerosis, suggesting broad spectrum neuroprotective properties. Moreover, we recently demonstrated in vitro and in vivo that a modified protease-resistant 24-amino-acid MGF derivative (MGF24) protects dopaminergic neurons from oxidative stress-induced apoptosis via induction of the stress response protein heme oxygenase-1. However, the underlying mechanism by which MGF24 up-regulates heme oxygenase-1 expression is unknown. In this study, we demonstrate that MGF24-induced heme oxygenase-1 up regulation is dependent on activation of protein kinase Cepsilon and NF-E2 related factor-2 (Nrf2). MGF24 induces nuclear translocation of Nrf2, and siRNA knockdown of Nrf2 or of heme oxygenase-1 prevents MGF24-induced heme oxygenase-1 up-regulation and neuroprotection of SH-SY5Y cells against 6-hydroxydopamine induced cell death. Pharmacological inhibition of ERK, p38 MAPK, PI3K/Akt, or PKC signaling revealed that only PKC inhibition by GF109203X prevents MGF24's ability to protect against 6-hydroxydopamine-induced cell death. GF109203X also prevented MGF24-induced Nrf2 nuclear translocation and heme oxygenase-1 up-regulation. siRNA knockdown of protein kinase Cepsilon blocks MGF24-induced Nfr2 nuclear translocation, heme oxygenase-1 expression, and neuroprotection. Taken together, these results demonstrate that PKC activity is needed for MGF24's activation of Nrf2, which in turn increases heme oxygenase-1 expression, a critical event in mediating MGF24's neuroprotection against 6-hydroxydopamine-induced apoptosis. PMID- 21259327 TI - Low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine causes inflammatory activation of astrocytes in nuclear factor-kappaB reporter mice prior to loss of dopaminergic neurons. AB - Neuroinflammation is implicated in the progression of numerous disease states of the CNS, but early inflammatory signaling events in glial cells that may predispose neurons to injury are not easily characterized in vivo. To address this question, we exposed transgenic mice expressing a nuclear factor-kappaB (NF kappaB)-driven enhanced green fluorescent protein (EGFP) reporter construct to low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and examined inflammatory activation of astrocytes in relation to neurobehavioral and neuropathological outcomes. The highest dose of MPTP (60 mg/kg total dose) caused a decrease in locomotor activity and a reduction in stride length. No significant loss of dopaminergic neurons in the substantia nigra was apparent at any dose. In contrast, expression of tyrosine hydroxylase in striatal fibers was reduced at 60 mg/kg MPTP, as were levels of dopamine and DOPAC. Colocalized expression of EGFP and inducible nitric oxide synthase (NOS2) occurred in astrocytes at 30 and 60 mg/kg MPTP and was associated with increased protein nitration in nigral dopaminergic neurons. Inhibition of NF-kappaB in primary astrocytes by expression of mutant IkappaBalpha suppressed expression of NOS2 and protected cocultured neurons from astrocyte-mediated apoptosis. These data indicate that inflammatory activation of astrocytes and enhanced nitrosative stress occurs at low doses of MPTP prior to loss of dopaminergic neurons. NF-kappaB-mediated expression of NOS2 appears to be a sensitive indicator of neuroinflammation that correlates with MPTP-induced neurochemical and neurobehavioral deficits prior to loss of dopaminergic neurons in the subtantia nigra. PMID- 21259328 TI - Lungfish aestivating activities are locked in distinct encephalic gamma aminobutyric acid type A receptor alpha subunits. AB - Ammonia in dipnoans plays a crucial role on neuronal homeostasis, especially for those brain areas that maintain torpor and awakening states in equilibrium. In the present study, specific alpha subunits of the major neuroreceptor inhibitory complex (GABA(A) R), which predominated during some phases of aestivation of the lungfish Protopterus annectens, turned out to be key adaptive factors of this species. From the isolation, for the first time, of the encoding sequence for GABA(A) R alpha1, alpha4 , and alpha5 subunits in Protopterus annectens, qPCR and in situ hybridization levels of alpha4 transcript in thalamic (P < 0.001) and mesencephalic (P < 0.01) areas proved to be significantly higher during long aestivating maintenance states. Very evident alpha5 mRNA levels were detected in diencephalon during short inductive aestivating states, whereas an alpha4 /alpha1 turnover characterized the arousal state. Contextually, the recovery of physiological activities appeared to be tightly related to an evident up regulation of alpha1 transcripts in telencephalic and cerebellar sites. Surprisingly, TUNEL and amino cupric silver methods corroborated apoptotic and neurodegenerative cellular events, respectively, above all in telencephalon and cerebellum of lungfish exposed to long maintenance aestivating conditions. Overall, these results tend to underlie a novel GABAergic-related ON/OFF molecular switch operating during aestivation of the lungfish, which might have a bearing on sleeping disorders. PMID- 21259329 TI - Projection neurons from the central nucleus of the amygdala to the nucleus pontis oralis. AB - The present retrograde labeling study was designed to determine the presence and pattern of projections from individual subdivisions of the central nucleus of the amygdala (CNA) to the nucleus pontis oralis (NPO), which is a critical brainstem site involved in the generation and maintenance of active (REM) sleep. Projections from the CNA were labeled with the retrograde tracer cholera toxin B subunit (CTB), which was injected, unilaterally, via microiontophoresis, into the NPO. Sections of the amygdala were immunostained in order to identify CTB-labeled CNA neurons and CNA neurons that contained CTB plus the vesicular glutamate transporter 2 (VGLUT2), which is a marker for glutamatergic neurons. Histological analyses revealed that retrogradely labeled neurons that project to the NPO were localized, ipsilaterally, within the medial, lateral, and capsular subdivisions of the CNA. In addition, a substantial proportion (24%) of all retrogradely labeled CNA neurons also exhibited VGLUT2 immunoreactivity. The present study demonstrates that glutamatergic neurons, which are present within various subdivisions of the CNA, project directly to the NPO. These data lend credence to the hypothesis that NPO neurons that are involved in the control of active sleep are activated by glutamatergic projections from the amygdala. PMID- 21259330 TI - Inhibition of glycogen synthase kinase-3beta by Angelica sinensis extract decreases beta-amyloid-induced neurotoxicity and tau phosphorylation in cultured cortical neurons. AB - Increasing evidence has shown that beta-amyloid (Abeta) induces hyperphosphorylation of tau and contributes to Abeta toxicity. Recently, tau hyperphosphorylation by glycogen synthase kinase-3beta (GSK-3beta) activation has been emphasized as one of the pathogenic mechanisms of Alzheimer's disease (AD). The phosphoinositide 3 kinase (PI3K)/Akt pathway is known as an upstream element of GSK-3beta. The inhibitory control of GSK-3beta, via the PI3K/Akt pathway, is an important mechanism of cell survival. In the present study, we investigated the neuroprotective effects of Angelica sinensis (AS), a traditional Chinese herbal medicine, against Abeta(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3beta signal pathway. We revealed that AS extract significantly attenuated Abeta(1-42) -induced neurotoxicity and tau hyperphosphorylation at multiple AD-related sites in a dose-dependent manner. Simultaneously, it increased the levels of phospho-Ser(473) -Akt and down regulated GSK-3beta activity by PI3K activation. The neuroprotective effects of AS extract against Abeta(1-42) -induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 MUM), a PI3K inhibitor. In addition, AS extract reversed the Abeta(1-42) -induced decrease in phosphorylation cyclic AMP response element binding protein (CREB), which could be blocked by the PI3K inhibitor. These results suggest that AS-mediated neuroprotection against Abeta toxicity is likely mediated by the PI3K/Akt/GSK 3beta signal pathway. PMID- 21259331 TI - Differential susceptibility to experimental autoimmune neuritis in Lewis rat strains is associated with T-cell immunity to myelin antigens. AB - Experimental autoimmune neuritis (EAN) is a CD4(+) T-cell-mediated inflammatory demyelinating disease of the peripheral nervous system (PNS) that serves as a model for Guillain-Barre syndrome (GBS) in humans. Various rat strains show different susceptibility to EAN. We examined PNS myelin-induced T- and B-cell responses and cytokine production in order to explore the mechanisms behind different EAN susceptibility in the three Lewis rat strains, Hannover, Charles River, and Taconic. Lewis rats of Hannover and Charles River strains exhibited a higher susceptibility to EAN than Lewis rats of the Taconic strain. The higher susceptibility was associated with increased inflammatory cell infiltrates and major histocompatibility class II expression as well as enhanced mitogenic (phytohemagglutinin-induced) and antigen-specific (P2 peptide 57-81-induced) lymphocyte proliferation compared with the Taconic strain. The Hannover strain also showed increased proinflammatory cytokine (interferon-gamma and tumor necrosis factor-alpha) production in the PNS. Cross-cultures of T cells and macrophages from Hannover and Taconic rats revealed that the Hannover rats exerted the strongest priming function of T cells. In contract, the P2 peptide induced antibody production was not different among the three Lewis rat strains. In conclusion, the differential susceptibility to EAN of Lewis rat strains is correlated primarily with T-cell immunity to myelin antigens. PMID- 21259332 TI - Minor neuronal damage and recovered cellular proliferation in the hippocampus after continuous unilateral forelimb restraint in normal rats. AB - Constraint-induced movement therapy (CIMT) involves the restraint of an intact limb to force the dominant use of an affected limb, in an attempt to enhance use dependent plasticity and reduce dysfunction. To investigate whether forced disuse of an intact forelimb with CIMT causes a loss of limb function and degenerative damage in the brain, a staircase test and a horizontal ladder test were carried out in control rats and forelimb-restrained rats, and then Argyrophil III silver staining, which is capable of detecting subtle neuronal damage, was used to examine histological alterations associated with restraint. No significant changes in forelimb function were observed in restrained rats. However, atypical weak argyrophilic neurons, an indicator of minor neural damage, were found in the bilateral hippocampus of restrained rats. This damage was not found in the cortex, striatum, or spinal cord. Investigation of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) revealed a clear reduction in the number of bromodeoxyuridine-positive cells in bilateral SGZ, but not in the SVZ, in restrained rats compared with controls. This reduction was accompanied by reduced mRNA expression of vascular endothelial growth factor and glial-derived neurotrophic factor. However, reduced cellular proliferation and decreased gene expression were recovered after the removal of the restraint. Our results suggest that forced disuse of the intact forelimb has no significant effect on skilled forelimb function but has a minor effect on neurogenesis in SGZ, suggesting that mild stress may be caused by the restraint. PMID- 21259333 TI - Role of the Nrf2-ARE pathway in early brain injury after experimental subarachnoid hemorrhage. AB - The nuclear factor erythroid 2-related factor 2 and antioxidant-response element (Nrf2-ARE) pathway is a key regulator for modulating inflammation and oxidative damage, which are involved in the pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Previous studies have demonstrated that Nrf2-ARE pathway play neural protective roles in traumatic brain injury, cerebral ischemia, and intracerebral hemorrhage models; however, it has not been investigated whether, and to what degree, the Nrf2-ARE pathway is induced by SAH, and the role of the Nrf2-ARE pathway in development of EBI following SAH remains unknown. Experiment 1 sought to investigate the time course of Nrf2-ARE activation in the cortex in the early stage of SAH. In experiment 2, we assessed the effect of sulforaphane (SUL; a specific Nrf2 activator) on regulation of the Nrf2-ARE pathway in the SAH model and evaluated the impact of SUL on EBI after SAH. The rat SAH model was used injection of 0.3 ml fresh arterial, nonheparinized blood into the prechiasmatic cistern over 20 sec. As a result, Nrf2 and its target gene product, heme oxygenase-1 (HO-1), were up-regulated in the cortex after SAH and peaked at 24 hr post-SAH. After intraperitoneal SUL administration, the elevated expression of Nrf2-ARE-related factors such as Nrf2, HO-1, NAD(P)H:quinone oxidoreductase 1 (NQO1), and glutathione S-transferase alpha1 (GST-alpha1) was detected in the cortex at 48 hr following blood injection. In the SUL-treated group, early brain damage such as brain edema, blood-brain barrier (BBB) impairment, cortical apoptosis, and motor deficits was significantly ameliorated compared with vehicle-treated SAH rats. Our results suggest that the Nrf2-ARE pathway is activated in the brain after SAH, playing a beneficial role in EBI development, possibly through inhibiting cerebral oxidative stress by inducing antioxidant and detoxifying enzymes. PMID- 21259335 TI - Morphology of hamstring torque-time curves following ACL injury and reconstruction: mechanisms and implications. AB - The purposes of this study were (i) to examine the effects of anterior cruciate ligament (ACL) status on hamstring force steadiness, peak hamstring strength, quadriceps (antagonist) activation, and physical performance, and (ii) to evaluate the associations of physical performance with hamstring steadiness and hamstring strength. Thirteen subjects with unilateral deficiency of the ACL (ACLD), 39 matched subjects with unilateral reconstructed ACL (ACLR; n = 25 with bone-patella tendon-bone (ACLR-PT) graft and n = 14 with combined semitendinosus and gracilis tendon (ACLR-STGT) graft) and 33 control subjects participated. Each subject performed maximal-effort isokinetic knee flexion repetitions at 180 degrees s(-1) with electromyography (EMG) electrodes attached to their medial and lateral quadriceps muscles. Physical performance was assessed using the single-limb long hop for distance. Wavelet-derived mean instantaneous frequency (Mif) of flexor torque-time curves was significantly (p < 0.05) higher (i.e., less smooth) in ACLR-STGT subjects compared to the ACLD, ACLR-PT and control subjects. No significant differences existed for peak hamstrings strength (i.e., peak torque produced) or quadriceps antagonist EMG activity. Positive correlations were identified between hamstrings force steadiness and quadriceps antagonist activity for ACLD (r = 0.797), ACLR-PT (r = 0.467), and ACLR-STGT (r = 0.628) subjects. For ACLR-STGT subjects, reduced hamstrings force steadiness associated with poorer long-hop performance (r = -0.695). Reduced steadiness amongst ACLR-STGT subjects may reflect motor output variability of the antagonist (i.e., quadriceps dyskinesia) and/or agonist musculature-a maladaptive feature which potentially contributes to poorer single-limb hop performance. Measures of hamstring force steadiness in combination with traditional measures of peak hamstring strength provide valuable clinical information regarding knee joint function following ACL injury/ACLR. PMID- 21259334 TI - Brain glycogen supercompensation in the mouse after recovery from insulin-induced hypoglycemia. AB - Brain glycogen is proposed to function under both physiological and pathological conditions. Pharmacological elevation of this glucose polymer in brain is hypothesized to protect neurons against hypoglycemia-induced cell death. Elevation of brain glycogen levels due to prior hypoglycemia is postulated to contribute to the development of hypoglycemia-associated autonomic failure (HAAF) in insulin-treated diabetic patients. This latter mode of elevating glycogen levels is termed "supercompensation." We tested whether brain glycogen supercompensation occurs in healthy, conscious mice after recovery from insulin induced acute or recurrent hypoglycemia. Blood glucose levels were lowered to less than 2.2 mmol/liter for 90 min by administration of insulin. Brain glucose levels decreased at least 80% and brain glycogen levels decreased approximately 50% after episodes of either acute or recurrent hypoglycemia. After these hypoglycemic episodes, mice were allowed access to food for 6 or 27 hr. After 6 hr, blood and brain glucose levels were restored but brain glycogen levels were elevated by 25% in mice that had been subjected to either acute or recurrent hypoglycemia compared with saline-treated controls. After a 27-hr recovery period, the concentration of brain glycogen had returned to baseline levels in mice previously subjected to either acute or recurrent hypoglycemia. We conclude that brain glycogen supercompensation occurs in healthy mice, but its functional significance remains to be established. PMID- 21259336 TI - Short or long fusion after thoracolumbar burst fractures does not alter selected gait parameters: a preliminary study. AB - We evaluated the gait characteristics of patients who had short or long-segment fusion after thoracolumbar burst fractures. The study included 12 patients (5 male, 7 female) who had vertebral fusion after traumatic thoracolumbar region (T12-L2) burst fractures. Patients were divided into two groups based on fixation type (short or long segment). Twelve healthy age and sex-matched subjects (seven male, five female) served as controls. Quantitative gait data, including all time distance (walking velocity, cadence, step time, step length, double support time), kinematic (joint rotation angles of pelvis, hip, knee, and ankle), and kinetic data (moments of hip in sagittal and coronal plane) were collected. Three patients had a T12, six patients an L1, and three patients had an L2 lesion. Patients in the two groups were similar in terms of age, sex, and time since operation. No significant differences were found in the time-distance, kinematic, and kinetic gait characteristics between the two groups. This preliminary study reveals that the gait characteristics of patients with short and long-segment fusion after thoracolumbar burst fractures were similar to those of healthy subjects and did not differ from each other. However, the present results should be interpreted with caution due to the small sample size. Future studies with larger groups are needed to provide additional data to validate these findings. PMID- 21259337 TI - Anterior border of the tibia as a landmark for extramedullary alignment guide in total knee arthroplasty for varus knees. AB - A disadvantage to using extramedullary alignment guides of the tibia for total knee arthroplasty (TKA) is difficulty in correctly identifying the ankle center. The anterior border of the tibia is easily palpable, as it is not covered by muscles and its shape is convex anteriorly. We hypothesized that appropriate points exist along the anterior border that can be used as landmarks for extramedullary guides. Prior to TKA, computed tomographic images of the entire tibia were obtained from 101 osteoarthritic knees with varus deformities. The relationship between the lines connecting two points on the anterior border and the mechanical axis was evaluated using 3D imaging software. The mean angles between each of 10 determined axes and the mechanical axis varied from 3.2 degrees varus to 2.1 degrees valgus in the coronal plane. In the sagittal plane, all axes referencing the anterior border of the tibia showed anterior inclination to the mechanical axis. The line connecting the medial one-third of the patellar tendon attachment and the distal one-fourth of the anterior border, however, was highly consistent and parallel to the mechanical axis in the coronal plane. This axis can be effectively used as a landmark for extramedullary guides during TKA. PMID- 21259338 TI - In situ deflection of tendon cell-cilia in response to tensile loading: an in vitro study. AB - To determine if a correlation exists between tensile loading and the deflection of tendon cell-cilia in situ, rat-tail tendon fascicles were stained for tubulin and mounted in a loading device attached to the stage of a confocal microscope. Individual tendon cells (n = 13) were identified and sequential images taken at 0%, 2%, 4%, 6%, and 8% grip to grip strain. The change in ciliary deflection angle was then measured at each strain level. To determine the ability of cilia to return to their original orientation, additional fascicles were loaded to 6% strain and then unloaded to 0% and tendon cell-ciliary (n = 10) deflection angle measured. There was a weak (r(2) = 0.40) but significant (p < 0.0001) correlation between the change in deflection angle and applied strain. Tensile loading produced a change in deflection angle from 0% to 3% (p = 0.039) and from 3% to 6% (p = 0.001) strain. There was no change (p = 1.000) in deflection angle from 6% to 8% strain. Reducing the strain from 6% to 0% resulted in a change (p = 0.048) in angle towards the pre-load position. However, the angle did not return to the pre-strain position (p = 0.025). These results demonstrate that tensile loading produces in situ deflection of tendon cell-cilia and supports the concept that cilia are involved in the mechanotransduction response of tendon cells. PMID- 21259339 TI - Cryoinsult parameter effects on the histologically apparent volume of experimentally induced osteonecrotic lesions. AB - Investigation of femoral head osteonecrosis would benefit from an animal model whose natural history includes progression to bony collapse of a segmental necrotic lesion. The bipedal emu holds attraction for systematic organ-level study of collapse mechanopathology. One established method of experimentally inducing segmental lesions is liquid nitrogen cryoinsult. Four cryoinsult parameters-hold temperature, freeze duration, freeze/thaw repetition, and thaw duration-were investigated to determine their individual and combined effects on resulting necrotic lesion morphology. 3D distributions of histologically apparent osteocyte necrosis from 24 emus receiving varying cryoinsults were used to develop univariate and multivariate linear regression models relating resulting necrotic lesion morphology to particular cryoinsult input parameters. These models were then applied to predict lesion size in four additional emus receiving differing input cryoinsults. The best multivariate regression model predicted lesion volumes that were accurate to better than 8% of overall emu femoral head volume. The hold temperature during cryoinsult was by far the most influential cryoinsult input parameter. The utility of this information is to enhance the consistency and predictability of cryoinsult-induced segmental lesion size for the purposes of systematic laboratory studies at the whole-organ level. PMID- 21259340 TI - Exercise enhances angiogenesis during bone defect healing in mice. AB - The aim of the present study was to investigate the effect of exercise on angiogenesis during bone defect healing in mice. We evaluated angiogenesis during cranial bone defect healing by intravital fluorescence microscopy (IVM) at days 0 21. To characterize the type of bone repair, we performed additional histomorphometric analyses at days 3-15. IVM was conducted in mice, which were housed in cages supplied with running wheels (exercise group; n=7) and compared to IVM results of mice, which were housed in cages without running wheels (controls; n=7). In the exercise group, we additionally performed correlation analyses between results of the IVM and the running distance. IVM showed an accelerated decrease of bone defect area in the exercise group compared to the control group. This was associated with a significantly higher blood vessel diameter in animals undergoing exercise at days 9 and 12 and a significant correlation between running distance and blood vessel density at day 9 (r = 0.74). Histomorphometry showed osseous bridging of the defect at day 9. The newly woven bone was covered by a neo-periosteum containing those blood vessels, which were visible by IVM. We conclude that exercise accelerates bone defect healing and stimulates angiogenesis during bore repair. PMID- 21259341 TI - Clinical correlates of similar pathologies in parkinsonian syndromes. AB - BACKGROUND: There have been no previous studies assessing the severity of regional atrophy, cell loss and lesion densities between the overlapping conditions of Parkinson's disease (PD), progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) and relating these pathologies to different clinical features. METHODS: Clinical indices and basal ganglia, brainstem, and cerebellar pathology from 43 longitudinally studied cases (PD = 8, PSP = 15, MSA = 12, controls = 8) were compared. A point-counting method was used to evaluate subregional volumes, and alpha-synuclein and phospho-tau immunohistochemistry was used to assess pathological inclusions and stage disease severity. Logistic regression analyses were used to identify pathological associations with clinical features. RESULTS: All PD, PSP, and MSA cases had severe degeneration of the substantia nigra. Clinical features correlated with tissue loss and the severity of inclusion pathologies. Levodopa responsiveness and a lack of resting tremor was associated with preservation of pallidal volume, the presence of gait ataxia was associated with atrophy of the putamen, and the parkinsonian-plus phenotype with early falls and supranuclear vertical gaze abnormalities had more substantial midbrain atrophy and greater inclusion pathology in the caudate nucleus. DISCUSSION: This is the first study to compare the severity of regional pathologies across parkinsonian conditions. The data show that tissue loss and inclusion densities in certain regions correlate with clinical indices, with regional volume changes likely to be the best indicator of clinical progression of disease. PMID- 21259342 TI - Validation of screening instruments for neuroepidemiological surveys of tic disorders. AB - BACKGROUND: The main purpose was to validate a multistage protocol to screen tic disorders in mainstream and special education centers and to investigate whether telephone-based interviews were accurate to diagnose tic disorders when compared with in-person neurological interviews. METHODS: A school-based survey of children and adolescents (6-16 years). A proxy report questionnaire for tic disorders was completed by teachers, observers, and parents. The diagnosis was confirmed by the neurologist based on the Diagnostic and Statistical Manual of Mental disorders (DSM-IV TR) criteria. The sensitivity, specificity, positive and negative predictive values, the likelihood ratio for a positive result (LR+), and the Kappa coefficients (k) for telephone-based interviews reliability were calculated. RESULTS: One hundred twenty subjects, 57 from special education center and 63 from a mainstream school were studied. The sensitivity of the proxy report questionnaire was 58% and 36% when completed by the observers (mainstream and special education center, respectively), 40 and 73% when completed by the teachers, and 58 and 36% when completed by the parents. Using any of these 3 screening sources, the sensitivity was 92%, the positive predictive value was 38%, and negative predictive value was 97% (mainstream schools), whereas the sensitivity was 82%, the positive predictive value was 20%, and negative predictive value was 82% (special education centers). Parents (mainstream schools) and teachers (special education center) produced the highest LR+ (7.25 and 1.26, respectively) and the intraobserver reliability of the telephone-based interviews versus in-person neurological interviews gave a k coefficient of 0.83. CONCLUSIONS: The efficiency of different screening instruments for tic disorders seems to vary in different settings. Telephone-based interviews may be a valid and convenient backup to ascertain the diagnosis of tic disorders when face-to face neurological examination is not possible. PMID- 21259343 TI - Botulinum toxin A versus B in sialorrhea: a prospective, randomized, double blind, crossover pilot study in patients with amyotrophic lateral sclerosis or Parkinson's disease. AB - BACKGROUND: Either botulinum toxins (BoNTs) A and B have been used for improving drooling in different neurological conditions. METHODS: Consecutive patients affected by Amyotrophic Lateral Sclerosis (ALS) or Parkinson's Disease (PD) accompanied by severe drooling were randomized to receive botulinum neurotoxin type A (BoNT-A) or B (BoNT-B) injections into the salivary glands. Following the first treatment, when sialorrhea returned to baseline (at least three months after the first injection), subjects were re-treated with the other serotype. Ultrasound-guided injections into parotid and submandibular glands were bilaterally performed: total doses were 250 U BoNT-A (Dysport) and 2500 U BoNT-B (Neurobloc). Objective (cotton roll weight) and subjective (ad hoc clinical scales) evaluations were performed at baseline, after 1 and 4 weeks, and every 4 weeks until drooling returned to baseline. RESULTS: Twenty-seven patients (15 ALS and 12 PD) were enrolled, fourteen completed the study. BoNT-A and BoNT-B treatments gave both subjective and objective improvements in all patients. The latency was significantly shorter after BoNT-B treatments (3.2 +/- 3.7 days) compared to BoNT-A (6.6 +/- 4.1 days; P = 0.002). The mean benefit duration was similar at 75 and 90 days for BoNT-A and BoNT-B, respectively (P = NS). The only toxin-related side effect was a change to saliva thickness. CONCLUSIONS: Either 250 U Dysport or 2500 U Neurobloc have similar effectiveness and safety in controlling sialorrhea. BoNT-B has a shorter latency and comparable duration. Cost analysis, considering the doses used in this study protocol favored BoNT-B treatment. PMID- 21259344 TI - Mitochondrial mimicry of multiple system atrophy of the cerebellar subtype. AB - BACKGROUND: We describe a patient with clinical and radiological findings suggestive of multiple system atrophy of the cerebellar subtype (MSA-C). METHODS/RESULTS: Sequencing of the polymerase-gamma 1 (POLG1) gene revealed the patient had compound heterozygous mutations of the POLG1 gene. Muscle biopsy revealed the presence of multiple mitochondrial DNA deletions and depletion, confirming the pathogenic nature of the POLG1 mutations. DISCUSSION: This case expands the spectrum of phenotypes associated with POLG1 mutations to include multiple system atrophy and prompts further consideration regarding whether routine screening for POLG1 mutations is indicated in this patient population. PMID- 21259346 TI - The structure of layered covalent-organic frameworks. AB - Covalent-Organic Frameworks (COFs) are a new family of 2D and 3D highly porous and crystalline materials built of light elements, such as boron, oxygen and carbon. For all 2D COFs, an AA stacking arrangement has been reported on the basis of experimental powder XRD patterns, with the exception of COF-1 (AB stacking). In this work, we show that the stacking of 2D COFs is different as originally suggested: COF-1, COF-5, COF-6 and COF-8 are considerably more stable if their stacking arrangement is either serrated or inclined, and layers are shifted with respect to each other by ~1.4 A compared with perfect AA stacking. These structures are in agreement with to date experimental data, including the XRD patterns, and lead to a larger surface area and stronger polarisation of the pore surface. PMID- 21259345 TI - Pulmonary response to surface-coated nanotitanium dioxide particles includes induction of acute phase response genes, inflammatory cascades, and changes in microRNAs: a toxicogenomic study. AB - Titanium dioxide nanoparticles (nanoTiO(2) ) are used in various applications including in paints. NanoTiO(2) inhalation may induce pulmonary toxicity and systemic effects. However, the underlying molecular mechanisms are poorly understood. In this study, the effects of inhaled surface-coated nanoTiO(2) on pulmonary global messenger RNA (mRNA) and microRNA (miRNA) expression in mouse were characterized to provide insight into the molecular response. Female C57BL/6BomTac mice were exposed for 1 hr daily to 42.4 +/- 2.9 (SEM) mg surface coated nanoTiO(2) /m(3) for 11 consecutive days by inhalation and were sacrificed 5 days following the last exposure. Physicochemical properties of the particles were determined. Pulmonary response to nanoTiO(2) was characterized using DNA microarrays and pathway-specific PCR arrays and related to data on pulmonary inflammation from bronchial lavages. NanoTiO(2) exposure resulted in increased levels of mRNA for acute phase markers serum amyloid A-1 (Saa1) and serum amyloid A-3 (Saa3), several C-X-C and C-C motif chemokines, and cytokine tumor necrosis factor genes. Protein analysis of Saa1 and 3 showed selective upregulation of Saa3 in lung tissues. Sixteen miRNAs were induced by more than 1.2-fold (adjusted P-value < 0.05) following exposure. Real time polymerase chain reaction confirmed the upregulation of miR-1, miR-449a and revealed dramatic induction of miR-135b (60-fold). Thus, inhalation of surface-coated nanoTiO(2) results in changes in the expression of genes associated with acute phase, inflammation and immune response 5 days post exposure with concomitant changes in several miRNAs. The role of these miRNAs in pulmonary response to inhaled particles is unknown and warrants further research. PMID- 21259347 TI - pH-switchable inversion of the metal-centered chirality of metallabenzenes: opposite stereodynamics in reactions of ruthenabenzene with L- and D-cysteine. AB - We report herein the first study on the chemical interaction between metallabenzenes and bioactive molecules. Due to its unique stereoelectronic activities, a phenanthroline-derived ruthenabenzene [Ru{CHC(PPh(3))CHC(PPh(3))CH}Cl(C(12)H(8)N(2))(PPh(3))]Cl(2) (1) selectively binds cysteine in aqueous solution at physiological pH and then undergoes a dynamic inversion of configuration at the Ru center. The structure of the L cysteine-binding product of 1 has been determined by means of X-ray diffraction. The replacement of the L-cysteine with the D form results in an inverted stereodynamic effect. Furthermore, the inversion process of the Ru-centered configuration could be conveniently controlled by a simple pH adjustment. This is attributed to the significant influence of a special intramolecular electrostatic interaction on the dynamic epimerization process of the cysteine-binding product. PMID- 21259348 TI - On the synergistic catalytic properties of bimetallic mesoporous materials containing aluminum and zirconium: the Prins cyclisation of citronellal. AB - Bimetallic three-dimensional amorphous mesoporous materials, Al-Zr-TUD-1 materials, were synthesised by using a surfactant-free, one-pot procedure employing triethanolamine (TEA) as a complexing reagent. The amount of aluminium and zirconium was varied in order to study the effect of these metals on the Bronsted and Lewis acidity, as well as on the resulting catalytic activity of the material. The materials were characterised by various techniques, including elemental analysis, X-ray diffraction, high-resolution TEM, N(2) physisorption, temperature-programmed desorption (TPD) of NH(3), and (27) Al MAS NMR, XPS and FT IR spectroscopy using pyridine and CO as probe molecules. Al-Zr-TUD-1 materials are mesoporous with surface areas ranging from 700-900 m(2) g(-1), an average pore size of around 4 nm and a pore volume of around 0.70 cm(3) g(-1). The synthesised Al-Zr-TUD-1 materials were tested as catalyst materials in the Lewis acid catalysed Meerwein-Ponndorf-Verley reduction of 4-tert-butylcyclohexanone, the intermolecular Prins synthesis of nopol and in the intramolecular Prins cyclisation of citronellal. Although Al-Zr-TUD-1 catalysts possess a lower amount of acid sites than their monometallic counterparts, according to TPD of NH(3), these materials outperformed those of the monometallic Al-TUD-1 as well as Zr-TUD 1 in the Prins cyclisation of citronellal. This proves the existence of synergistic properties of Al-Zr-TUD-1. Due to the intramolecular nature of the Prins cyclisation of citronellal, the hydrophilic surface of the catalyst as well as the presence of both Bronsted and Lewis acid sites synergy could be obtained with bimetallic Al-Zr-TUD-1. Besides spectroscopic investigation of the active sites of the catalyst material a thorough testing of the catalyst in different types of reactions is crucial in identifying its specific active sites. PMID- 21259349 TI - Synthesis of a [2]rotaxane incorporating a "magic sulfur ring" by the thiol-ene click reaction. AB - The mild and highly efficient thiol-ene click reaction has been used to construct a rotaxane incorporating dibenzo-24-crown-8 (DB24C8) and a dibenzylammonium derived thread in high yield under the irradiation of UV light. A rotaxane containing a disulfide linkage in the macrocycle was also synthesized by the thiol-ene click reaction. It has been demonstrated that the formation of the [2]rotaxane with the disulfide bond in the macrocycle occurs by a mechanism that is different to the threading-followed-by-stoppering process. The successful construction of a rotaxane directly from its constituent components, the macrocycle containing a disulfide linkage and the dibenzylammonium hexafluorophosphate salt, suggests that the space within the macrocycle incorporating the disulfide linkage is smaller than the phenyl unit and a plausible reaction mechanism has been proposed as follows: A small amount of the initiator forms two radicals upon the absorption of UV irradiation; the radicals act as a "key" to "unlock" the disulfide bond in the macrocycle. The resulting crown ether like moiety in the macrocycle is clipped around the ammonium ion center in the dumb-bell-shaped compound. The [2]rotaxane is generated upon recombination of the disulfide linkage. PMID- 21259350 TI - Carbohydrate recognition at the minor-groove of the self-complementary duplex d(CGCGAATTCGCG)2 by a synthetic glyco-oligoamide. AB - The structure of a neutral glyco-conjugate beta-Gal-Py-gamma-Py-Ind (1), designed as a probe for analyzing sugar-DNA interactions, when bound to a self complementary oligonucleotide duplex d(CGCG AATT CGCG)(2) has been deduced by employing (1)H NMR techniques. Analysis of the formed 1:1 complex demonstrated that the glycol ligand is bound in a hairpin-like conformation in which both pyrrole amino acid moieties are stacked, whereas the indole and the sugar residues are spatially close. The binding site is defined by the minor groove formed by the -AATT- stretch. In particular, the -Py-gamma-Py- region of the ligand is sited near the A5-A6 oligonucleotide residues, whereas the indole and the sugar rings are next to the T7-T8 base pairs. More relevant, the existence of a variety of intermolecular NOE correlations permitted the close proximity of the sugar to the minor groove to be assessed, thus showing that the binding of the glycoconjugate at the minor groove is the origin of the specificity of the glycoconjugate-DNA interaction. The experimental NMR data have been combined with restrained and unrestrained molecular dynamics calculations, to provide the 3D structure of the complex. PMID- 21259351 TI - The effect of Ginkgo biloba extract on mitochondrial oxidative phosphorylation in the normal and ischemic rat heart. AB - Free radical-induced myocardial damage and impairment of vascular endothelium dependent relaxation are amongst the most important mechanisms responsible for ischemic heart injury. Ginkgo biloba leaf extract (GE) has been reported to improve blood circulation in the brain and have a beneficial impact on the cardiovascular system but its cardioprotective effects have not been elucidated yet. Therefore, this study investigated the influence of GE in 70% ethanol (1:5) administered orally to rats on the functions of isolated heart mitochondria under normal and ischemic conditions. Wistar rats were given GE or ethanol (solvent control) at a dosage of 0.32 mL/kg in drinking water for 10 and 18 days, while the control animals received untreated drinking water. Mitochondrial respiration rates were determined oxygraphically. Pyruvate and malate, succinate or palmitoyl L-carnitine and malate were used as substrates. The GE treatment partially uncoupled mitochondrial oxidation from phosphorylation, reduced the generation of free radicals in the mitochondria, diminished the ischemia-induced V3 decrease and the degree of respiration stimulation by exogenous cytochrome c. Thus, these results indicate that GE exerts cardioprotective effects reducing ischemia-caused impairment of the functions of heart mitochondria. PMID- 21259352 TI - Antimicrobial evaluation of the polyisoprenylated benzophenones nemorosone and guttiferone A. AB - Polyisoprenylated benzophenones have been isolated from plants, particularly in the Clusiaceae family, and their biological properties recently have received considerable attention from a pharmacological point of view. The aim of the study was to investigate the polyisoprenylated benzophenones, nemorosone and guttiferone A, for their antimicrobial effect against a panel of bacteria, fungi and protozoan parasites. They showed a moderate activity against the Gram positive bacterium Staphylococcus aureus, while no activity was demonstrated against Escherichia coli and the fungi Trichophyton rubrum and Candida albicans. An interesting activity was found for Plasmodium falciparum with IC50 values lower than 1 MUm, while cytotoxicity on MRC-5 cells revealed CC50 values of 15.5 and 12.0 MUm, respectively, for nemorosone and guttiferone A. PMID- 21259353 TI - Quantification of 15-F2t-isoprostane in human plasma and urine: results from enzyme-linked immunoassay and liquid chromatography/tandem mass spectrometry cannot be compared. AB - Quantification of F(2)-isoprostanes is considered a reliable index of the oxidative stress status in vivo. Several immunoassays and chromatography/mass spectrometry-based assays are available for 15-F(2t)-isoprostane quantification. However, it remains unclear if results of immunoassays using different assays can be compared with those of liquid chromatography/mass spectrometry (LC/MS) assays. Previous studies comparing enzyme-linked immunosorbent assay (ELISA) and more specific gas chromatography/mass spectrometry assays have already indicated that ELISAs may overestimate 15-F(2t)-isoprostane concentrations in human plasma. Concentrations of 15-F(2t)-isoprostane in 25 human plasma and urine samples were measured by three commercially available ELISA assays (Assay Designs, Cayman Chemical and Oxford Biomedical Research) and compared with the concentrations measured with a validated, semi-automated high-throughput HPLC tandem mass spectrometry assay (LC/LC-MS/MS). All three ELISAs measured substantially higher 15-F(2t)-isoprostane concentrations (2.1-182.2-fold higher in plasma; 0.4-61.9 fold higher in urine) than LC/LC-MS/MS. Utilization of solid-phase extraction (SPE) columns, especially isoprostane affinity purification columns, brought ELISA isoprostane urine concentrations closer to the LC/LC-MS/MS results. However, SPE did not have much of an effect on ELISA plasma concentrations which remained significantly higher than corresponding LC/LC-MS/MS results. A poor correlation not only between LC/LC-MS/MS and immunoassay results, but also among the immunoassays was found. Especially in plasma, ELISAs grossly overestimate 15 F(2t)-isoprostane concentrations and are not comparable with each other or with LC/LC-MS/MS. It is most disturbing that a sample with relatively high concentrations measured with one ELISA may show low concentrations with another ELISA, and vice versa, potentially affecting the conclusions drawn from such data. The use of specific mass spectrometry-based assays seems advisable. PMID- 21259354 TI - Is wood pre-treatment essential for tree-ring nitrogen concentration and isotope analysis? AB - Tree-ring nitrogen concentrations and isotope ratios (delta(15)N) are gaining in popularity for environmental research although their use is still debated because of nitrogen mobility in tree stems. Modern studies generally present results on wood that is pre-treated to remove soluble nitrogen compounds and to minimize the impact of radial translocation on tree-ring nitrogen environmental records. However, the necessity to use such pre-treatment has never been fully assessed. Here we compare the nitrogen concentrations and delta(15)N values of two wood preparation protocols applied to beech and red spruce tree rings for the removal of soluble compounds from ring pairs with non pre-treated tree rings. For both tree species, pre-treatment did not minimize the radial patterns of tree-ring nitrogen concentrations and the increasing concentration trends that are coincident with the heartwood-sapwood boundary. Therefore, even if the tree-ring nitrogen concentrations are slightly modified by pre-treatment, these concentrations are considered to reflect internal stem processes rather than environmental conditions in both species. The delta(15)N values were similar for untreated and pre-treated ring pairs, suggesting that wood pre-treatment did not substantially change the delta(15)N values and temporal trends in ring series. In addition, tree-ring delta(15)N series of untreated and pre-treated wood did not show any sign of influence of the heartwood-sapwood boundary in either tree species, indicating that nitrogen translocation did not generate significant isotopic fractionation. We therefore suggest that untreated ring delta(15)N values of beech and red spruce trees can be used for environmental research. PMID- 21259355 TI - Charge inversion via concurrent cation and anion transfer: application to corticosteroids. AB - A novel charge inversion process that involves the removal of an excess cation from an analyte ion and the transfer of an anion to the neutral analyte in a single ion/ion encounter is described. Polyamidoamine (PAMAM) half-generation dendrimer anions that contain small anions, such as the chloride ion, were used as charge inversion reagents. Several competing processes can occur that include removal of the cation to neutralize the analyte, the removal of the excess cation and an additional proton to yield the deprotonated molecule, or removal of the excess cation and transfer of a small anion to the analyte. For the latter process to dominate, several requirements for both the reagent anion and the analyte cation must be met. The reagent anion must form multiply charged anions and must be able to incorporate one or more small anions for transfer. The analyte must have no strongly acidic sites as well as a relatively high affinity for small anion attachment. The PAMAM dendrimer anions must meet the conditions for the reagent anions and the cations of the corticosteroids meet the conditions for the analyte. The estrogenic steroid estrone, on the other hand, does not meet the requirements and, as a result, is largely neutralized when reacted with the reagent anions. This reaction, therefore, is highly selective and might serve as a useful reaction for the screening of appropriate analytes. PMID- 21259356 TI - Effective analysis of rotundone at below-threshold levels in red and white wines using solid-phase microextraction gas chromatography/tandem mass spectrometry. AB - Rotundone is an oxygenated sesquiterpene belonging to the family of guaianes, giving the 'peppery' aroma to white and black pepper and to red wines. Here we describe a novel, convenient protocol for the synthesis of rotundone, starting from a commercially available compound and requiring only two reaction steps, and an improved, faster method of GC separation (30 min) with selective quantisation of rotundone using tandem mass spectrometry in multiple reaction monitoring (MRM) mode with d(5)-rotundone as internal standard. With limits of detection (LODs) of 1.5 ng/L in white wine and 2.0 ng/L in red wine, intraday repeatability CV values of 6% and 5% at 50 ng/L and 500 ng/L and interday repeatability CV values of 13% and 6% at 50 ng/L and 500 ng/L, respectively, the improved protocol provides the desired sensitivity and selectivity for routine analysis of rotundone in both white and red wines. Initial application of this method highlighted the presence of unexpectedly high concentrations of rotundone, thus explaining the origin of the distinctive peppery aroma in Schioppettino and Vespolina red wines and in Gruener Veltliner white wines. PMID- 21259357 TI - First application of mass spectrometry and gas chromatography in investigation of alpha-cellulose hydrolysates: the influence of climate changes on glucose molecules in pine tree-rings. AB - We present the first results of the quantitative and qualitative gas chromatographic and isotope ratio mass spectrometric analysis of monosaccharides derived from acid hydrolysis of alpha-cellulose extracted from annual pine tree rings. The conifers investigated in this study grew in the Niepolomice Forest in Poland, and the annual rings covered the time span from 1940 to 2000 AD. The main components of the alpha-cellulose samples were two saccharides: glucose and mannose. The amount of glucose in the annual rings varied between 17 and 44%. The delta(13)C of glucose was found to be less negative than that of alpha-cellulose and the delta(18)O values in glucose were less positive than those in alpha cellulose. The content of monosaccharides in the alpha-cellulose samples has an influence on the isotope fractionation factors. The values of the carbon isotope fractionation factor increase with an increase in the monosaccharides concentration in alpha-cellulose, while the values of the oxygen isotope fractionation factor decrease with an increase in monosaccharides concentration in alpha-cellulose. The challenge is to establish, with respect to climate changes and environmental conditions, the significance of the interannual variations in the observed monosaccharide concentration. PMID- 21259358 TI - Identification and structural elucidation of new caprazamycins from Streptomyces sp. MK730-62F2 by liquid chromatography/electrospray ionization tandem mass spectrometry. AB - The development of reliable analytic methods, capable of separating mixtures of secondary metabolites as well as providing structural information, is essential for the investigation of secondary metabolites, e.g. from Streptomyces. Here we report a liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method using a triple quadrupole mass analyzer for the structural elucidation of caprazamycins and liposidomycins from culture extracts of the wild type producer strains. Comparison of the fragmentation patterns in positive as well as in negative ionization mode revealed several characteristic product ions used for identification of six new caprazamycins. Furthermore, a chromatographic method for the purification of nucleosides from cell cultures using a boronic acid gel was adapted for the partial purification of the culture extracts. PMID- 21259359 TI - A quantitation method for mass spectrometry imaging. AB - A new quantitation method for mass spectrometry imaging (MSI) with matrix assisted laser desorption/ionization (MALDI) has been developed. In this method, drug concentrations were determined by tissue homogenization of five 10 um tissue sections adjacent to those analyzed by MSI. Drug levels in tissue extracts were measured by liquid chromatography coupled to tandem mass spectrometry (LC/MS/MS). The integrated MSI response was correlated to the LC/MS/MS drug concentrations to determine the amount of drug detected per MSI ion count. The study reported here evaluates olanzapine in liver tissue. Tissue samples containing a range of concentrations were created from liver harvested from rats administered a single dose of olanzapine at 0, 1, 4, 8, 16, 30, or 100 mg/kg. The liver samples were then analyzed by MALDI-MSI and LC/MS/MS. The MALDI-MSI and LC/MS/MS correlation was determined for tissue concentrations of ~300 to 60,000 ng/g and yielded a linear relationship over two orders of magnitude (R(2) = 0.9792). From this correlation, a conversion factor of 6.3 +/- 0.23 fg/ion count was used to quantitate MSI responses at the pixel level (100 um). The details of the method, its importance in pharmaceutical analysis, and the considerations necessary when implementing it are presented. PMID- 21259360 TI - Characterisation of a modified oligonucleotide together with its synthetic impurities using accurate mass measurements. AB - Oligonucleotide-based drugs are beginning to establish themselves within the pharmaceutical industry as important agents in the treatment of various disease states with the potential of exhibiting high specificity with gene targeted therapies. Recent studies regarding RNA interference has stimulated interest in this field. There are now an increasing number of oligonucleotide-based pharmaceutical products in various stages of clinical development for the treatment of life-threatening diseases. As a result, the production of synthetic oligonucleotides has become increasingly important, with both antisense and RNAi related oligonucleotides under development as therapeutic agents. One potential drug candidate currently under development at GlaxoSmithKline, is a 2'-O-methyl phosphorothioate in which the non-bridging oxygens of the phosphate diester are replaced with sulphur. Oligonucleotides are polymeric sequences made from an array of nucleotides (RNA, DNA and their respective analogs) usually ranging from 20-100 nucleotides. The polar nature, low thermal stability, complexity and large molecular weights of oligonucleotides have posed a challenge for the analysis of oligonucleotides by mass spectrometry. This paper demonstrates the use of negative ion electrospray with a combination of high resolution and high mass accuracy for the characterisation of oligonucleotides with the intention of supporting an evidence of structure document for a regulatory submission. This is a new area within the mass spectrometry field and as such there is limited software amongst the instrument companies for the data processing for the analysis of these compounds. Therefore, many of the examples in the literature only use mass spectrometry to generate average molecular weights by deconvoluting the multiple charged states observed to give an average molecular weight; under utilizing the capability of high-resolution instruments. PMID- 21259361 TI - A study of resveratrol-copper complexes by electrospray ionization mass spectrometry and density functional theory calculations. AB - Resveratrol is a polyphenolic compound found in plants and human foods which has shown biological activities including chemoprevention, acting through a mechanism which involves the reduction of Cu(II) species. By electrospray ionization (ESI) mass spectrometry we have produced and detected the resveratrol-copper complexes [Resv+Cu](+), [Resv+Cu+H(2)O](+) and [2Resv+Cu](+) by using a resveratrol/CuSO(4) solution in CH(3)CN/H(2)O. The most stable structures of the detected complexes have been calculated at the B3LYP/6-311G(d) level of theory. Resveratrol interacts with the copper ion through nucleophilic carbon atoms on the aromatic ring and the alkenyl group. The fact that only singly charged ions were observed implies that Cu(II) is reduced to Cu(I) in the ESI process. For investigating the structure-reactivity correlation, we have carried out a similar study on the synthetic analogue dihydroresveratrol (DHResv). For the latter only the [DHResv+Cu](+) complex has been detected. PMID- 21259362 TI - Mass spectral analysis of N-oxides of Chemical Weapons Convention related aminoethanols under electrospray ionization conditions. AB - N,N'-Dialkylaminoethanols are the hydrolyzed products or precursors of chemical warfare agents such as V-agents and nitrogen mustards, and they are prone to undergo oxidation in environmental matrices or during decontamination processes. Consequently, screening of the oxidized products of aminoethanols in aqueous samples is an important task in the verification of chemical weapons convention related chemicals. Here we report the successful characterization of the N-oxides of N,N'-dialkylaminoethanols, alkyl diethanolamines, and triethanolamine using positive ion electrospray ionization mass spectrometry. The collision-induced dissociation (CID) spectra of the [M+H](+) and [M+Na](+) ions show diagnostic product ions that enable the unambiguous identification of the studied N-oxides, including those of isomeric compounds. The proposed fragmentation pathways are supported by high-resolution mass spectrometry data and product/precursor ion spectra. The CID spectra of [M+H](+) ions included [MH-CH(4)O(2)](+) as the key product ion, in addition to a distinctive alkene loss that allowed us to recognize the alkyl group attached to the nitrogen. The [M+Na](+) ions show characteristic product ions due to the loss of groups (R) attached to nitrogen either as a radical (R) or as a molecule [R+H or (R-H)] after hydrogen migration. PMID- 21259363 TI - Impact ionisation spectra from hypervelocity impacts using aliphatic poly(methyl methacrylate) microparticle projectiles. AB - We report impact ionisation spectra from spherical poly(methyl methacrylate) (PMMA) microparticles of 724 nm diameter impacting a rhodium target. These projectiles were coated with an ultrathin (~11 nm) overlayer of polypyrrole, an electrically conducting organic polymer; this enabled the accumulation of sufficient surface charge to allow electrostatic acceleration up to speeds of 4 to 8 km s(-1) using a high-voltage Van de Graaff instrument. A grid above the target (held at 3.33 kV cm(-1) with respect to the target) accelerated the cations that were generated during the hypervelocity impacts, and these ions then drifted to a charge detector. By measuring the collected charge vs. time and assuming only single ionisation events, time-of-flight mass spectra were obtained. Strong signals were observed for cationic species with ions of m/z 41, 65 and 115. There were also minor contributions from cations with masses ranging from m/z 29 to 142. The three major signals are assigned to fragment ions (C(3)H(5)(+), C(4)H(5)O(+)/C(5)H(9)(+) and C(6)H(11)O(2)(+)) which are known to be associated with the decomposition of PMMA. These impact ionisation spectra differ significantly from those reported earlier using polystyrene (PS) microparticles. The aliphatic PMMA microparticles generate small (m/z <100) fragment ions more readily at lower speeds than the predominantly aromatic PS microparticles, where speeds of at least 10 km s(-1) are typically required for substantial yields of low-mass fragment ions. This correlates well with the well known greater chemical and thermal fragility of PMMA compared to PS. The PMMA microparticles should prove useful synthetic mimics for aliphatic carbonaceous micrometeorites. PMID- 21259364 TI - Suppression correction and characteristic study in liquid chromatography/Fourier transform mass spectrometry measurements. AB - Analysis of peptide profiles from liquid chromatography/Fourier transform mass spectrometry (LC/FTMS) reveals a nonlinear distortion in intensity. Investigation of the measured C(13)/C(12) ratios comparing with theoretical ones shows that the nonlinearity can be attributed to signal suppression of low abundance peptide peaks. We find that the suppression is homogenous for different isotopes of identical peptides but non-homogenous for different peptides. We develop an iterative correction algorithm that corrects the intensity distortions for peptides with relatively high abundance. This algorithm can be applied in a wide range of applications using LC/FTMS. We also analyze the distortion characteristics of the instrument for lower abundance peptides, which should be considered when interpreting quantification results of LC/FTMS. PMID- 21259365 TI - Regioselective anion attachment leading to regiospecific decompositions of bifunctional steroids in negative ion electrospray tandem mass spectrometry. PMID- 21259366 TI - Imaging tumor hypoxia by magnetic resonance methods. AB - Tumor hypoxia results from the negative balance between the oxygen demands of the tissue and the capacity of the neovasculature to deliver sufficient oxygen. The resulting oxygen deficit has important consequences with regard to the aggressiveness and malignancy of tumors, as well as their resistance to therapy, endowing the imaging of hypoxia with vital repercussions in tumor prognosis and therapy design. The molecular and cellular events underlying hypoxia are mediated mainly through hypoxia-inducible factor, a transcription factor with pleiotropic effects over a variety of cellular processes, including oncologic transformation, invasion and metastasis. However, few methodologies have been able to monitor noninvasively the oxygen tensions in vivo. MRI and MRS are often used for this purpose. Most MRI approaches are based on the effects of the local oxygen tension on: (i) the relaxation times of (19)F or (1)H indicators, such as perfluorocarbons or their (1)H analogs; (ii) the hemodynamics and magnetic susceptibility effects of oxy- and deoxyhemoglobin; and (iii) the effects of paramagnetic oxygen on the relaxation times of tissue water. (19)F MRS approaches monitor tumor hypoxia through the selective accumulation of reduced nitroimidazole derivatives in hypoxic zones, whereas electron spin resonance methods determine the oxygen level through its influence on the linewidths of appropriate paramagnetic probes in vivo. Finally, Overhauser-enhanced MRI combines the sensitivity of EPR methodology with the resolution of MRI, providing a window into the future use of hyperpolarized oxygen probes. PMID- 21259367 TI - Blood oxygenation level-dependent (BOLD) total and extravascular signal changes and DeltaR2* in human visual cortex at 1.5, 3.0 and 7.0 T. AB - The characterisation of the extravascular (EV) contribution to the blood oxygenation level-dependent (BOLD) effect is important for understanding the spatial specificity of BOLD contrast and for modelling approaches that aim to extract quantitative metabolic parameters from the BOLD signal. Using bipolar crusher gradients, total (b = 0 s/mm(2) ) and predominantly EV (b = 100 s/mm(2) ) gradient echo BOLD DeltaR(2)* and signal changes (DeltaS/S) in response to visual stimulation (flashing checkerboard; f = 8 Hz) were investigated sequentially (within < 3 h) at 1.5, 3.0 and 7.0 T in the same subgroup of healthy volunteers (n = 7) and at identical spatial resolutions (3.5 * 3.5 * 3.5 mm(3)). Total DeltaR(2)* (z-score analysis) values were -0.61 +/- 0.10 s(-1) (1.5 T), -0.74 +/- 0.05 s(-1) (3.0 T) and -1.37 +/- 0.12 s(-1) (7.0 T), whereas EV DeltaR(2)* values were -0.28 +/- 0.07 s(-1) (1.5 T), -0.52 +/- 0.07 s(-1) (3.0 T) and -1.25 +/- 0.11 s(-1) (7.0 T). Although EV DeltaR(2)* increased linearly with field, as expected, it was found that EV DeltaS/S increased less than linearly with field in a manner that varied with TE choice. Furthermore, unlike DeltaR(2)*, total and EV DeltaS/S did not converge at 7.0 T. These trends were similar whether a z score analysis or occipital lobe-based region-of-interest approach was used for voxel selection. These findings suggest that calibrated BOLD approaches may benefit from an EV DeltaR(2)* measurement as opposed to a DeltaS/S measurement at a single TE. PMID- 21259368 TI - In vivo carotid plaque MRI using quantitative T2* measurements with ultrasmall superparamagnetic iron oxide particles: a dose-response study to statin therapy. AB - This study investigates T(2)* quantification in carotid plaques before and after the administration of ultrasmall superparamagnetic iron oxide particles (USPIOs) in a cohort of patients receiving statin therapy. Phantom studies were performed using gels with varying concentrations of USPIOs. In the phantom study, 12 gels were prepared with a range of freely distributed concentrations of USPIO nanoparticles (0-0.05 mg/mL). Relative signal intensity measurements were obtained from a T(2)*-weighted sequence as well as quantitative T(2)* (qT(2)*) measurements. In the patient study, 40 patients with >40% carotid stenosis were randomised to low- and high-dose statin therapy (10 and 80 mg of atorvastatin). Pre- and post- (36 h) USPIO-enhanced MRI were performed at baseline, and at 6 and 12 weeks. A linear mixed-effects model was applied to account for the inherent correlation of multiple-plaque measurements from the same patient and to assess dose-response differences to statin therapy. In the phantom study, the T(2)* weighted sequence demonstrated an initial increase (T(1) effect), followed by a decrease (T(2)* effect), in relative signal intensity with increasing concentrations of USPIO. The qT(2)* values decreased exponentially with increasing concentrations of USPIO. In the patient study, there was a highly significant difference in post-USPIO T(2)* measurements in plaques between the low- and high-dose statin groups. This was observed for both the difference in qT(2)* measurements (post-USPIO minus pre-USPIO) (p < 0.001) and for qT(2)* post USPIO only (p < 0.001). The post-USPIO qT(2)* values were as follows: baseline: low dose, 13.6 +/- 5.5 ms; high dose, 12.9 +/- 6.2 ms; 6 weeks: low dose, 13.3 +/ 6.7 ms; high dose, 14.3 +/- 7.7 ms; 12 weeks: low dose, 14.0 +/- 7.6 ms; high dose, 18.3 +/- 11.2 ms. It can be concluded that qT(2)* measurements provide an alternative method of quantifying USPIO uptake. These results also demonstrate that changes in USPIO uptake can be measured using post-USPIO imaging only. PMID- 21259369 TI - Risk-need assessment: bridging disciplinary and regional boundaries. PMID- 21259370 TI - Working with women prisoners who seriously harm themselves: ratings of staff expressed emotion (EE). AB - BACKGROUND: Prison staff are repeatedly exposed to prisoners' suicidal behaviours; this may impair their capacity to care. Expressed emotion (EE), as a descriptor of the 'emotional climate' between people, has been associated with challenging behaviour in closed environments, but not previously applied to working alliances in a prison. AIMS: To investigate the feasibility of rating EE between staff and suicidal women in prison; to test the hypothesis that most such staff-inmate alliances would be rated high EE. METHODS: All regular staff on two small UK prison units with high suicidal behaviour rates were invited to participate. An audiotaped five-minute speech sample (FMSS) about work with one nominated suicidal prisoner was embedded in a longer research interview, then rated by two trained raters, independent of the interview process and the prison. RESULTS: Seven prison officers and 8 clinically qualified staff completed interviews; 3 refused, but 17 others were not interviewed, reasons including not having worked long enough with any one such prisoner. Participants and non participants had similar relevant backgrounds. Contrary to our hypothesis, EE ratings were generally 'low'. As predicted, critical comments were directed at high frequency oppositional behaviour. CONCLUSIONS: EE assessments with prison staff are feasible, but our sample was small and turnover of prisoners high, so the study needs replication. Attributions about problem behaviour to illness, and/or traumatic life experience, tend to confirm generally supportive working relationships in this sample. PMID- 21259371 TI - Reducing antisocial behaviour among patients with severe mental illness living in the community: a feasibility study of the Reasoning and Rehabilitation Programme. PMID- 21259372 TI - Analysis of antioxidant metabolites by solvent extraction from sclerotia of Inonotus obliquus (Chaga). AB - INTRODUCTION: The sclerotia of Inonotus obliquus (Chaga) are effective therapeutic agents to treat several human malignant tumours and other diseases without unacceptable toxic side-effects. OBJECTIVE: To investigate solvent effects on metabolic profiles and antioxidant activities of extracts of Chaga. METHODOLOGY: Chaga was extracted by petroleum ether, chloroform, ethyl acetate, acetone, ethanol and water. Solvent effects on metabolites in the extracts were assayed by NMR-based metabolomic analysis. Antioxidant activities were indicated as capacities for scavenging superoxide anion, DPPH and hydroxyl radicals. RESULTS: Petroleum ether and chloroform extracts contained primarily lanostane type triterpenoids (LT), whereas the extracts of ethyl acetate, acetone and ethanol were characterised by the predominant presence of hispidin analogues and LT, and water extracts by polysaccharides and phenolic compounds. The ethyl acetate, acetone, ethanol and water extracts revealed remarkable potential for scavenging the tested radicals, while those of petroleum ether and chloroform did not. Polyphenols are the major contributors for quenching the tested free radicals, while in LT only compounds 16, 17 and 22 participated in scavenging hydroxyl radicals. CONCLUSION: Polyphenols in Chaga are the principles for quenching free radicals while polysaccharides and a few LT compounds contribute partially in scavenging DPPH and hydroxyl radicals, respectively. NMR-based metabolomic analysis is a useful method by which to correlate 1H-NMR spectra of Chaga extracts with their antioxidant activities, and this allows the prediction of potentials for scavenging free radicals by 1H-NMR spectroscopy. PMID- 21259373 TI - Identification of chemical constituents in extracts and rat plasma from Fructus Aurantii by UPLC-PDA-Q-TOF/MS. AB - INTRODUCTION: Fructus Aurantii, as a component of several compound formulae, shows many bioactivities. As is well known, the constituents of traditional Chinese medicines are very complex and multiple constituents are responsible for the therapeutic effect. However, the concrete compounds are difficult to confirm. Therefore, studies on the constituents absorbed into serum and their metabolites are necessary. OBJECTIVE: To search for the active constituents in Fructus Aurantii. METHODOLOGY: An ultra-performance liquid chromatography-photodiode array detector-quadrupole time-of-flight mass spectrometry (UPLC-PDA-Q-TOF/MS) method was established to analyse the aqueous extract in Fructus Aurantii and the constituents absorbed into blood. Compound identification was made by matching the empirical molecular formula with those of the reported compounds and UV spectra, and further elucidated by lower energy CID mass spectra. RESULTS: Twelve flavonoid O-glycosides were detected, and nine compounds were tentatively identified as polymethoxylated flavones. Six parent compounds were identified and four metabolites were observed in rat plasma, two of which were identified as naringenin glucuronide and hesperetin glucuronide, respectively. CONCLUSION: The approach developed has proved useful in the study of the active constituents in traditional Chinese medicines. PMID- 21259374 TI - Phytochemical fingerprinting of vegetable Brassica oleracea and Brassica napus by simultaneous identification of glucosinolates and phenolics. AB - INTRODUCTION: Brassica vegetables have been related to the prevention of cancer and degenerative diseases, owing to their glucosinolate and phenolic content. OBJECTIVE: Identification of glucosinolates, flavonoids and hydroxycinnamic acids in representative varieties of kale, cabbage and leaf rape. METHODOLOGY: One local variety of each crop was evaluated in this study using a multi-purpose chromatographic method that simultaneously separates glucosinolates and phenolics. Chromatograms were recorded at 330 nm for flavonoid glycosides and acylated derivatives and 227 nm for glucosinolates. RESULTS: Eight glucosinolates were identified in kale and cabbage, which exhibited the same glucosinolate profile, and 11 glucosinolates were identified in leaf rape. Furthermore, 20 flavonoids and 10 hydroxycinnamic acids were detected in kale and cabbage, while 17 flavonoids and eight hydroxycinnamic acids were found in leaf rape. CONCLUSIONS: This study has provided a deeper and comprehensive identification of health-promoting compounds in kale, cabbage and leaf rape, thus showing that they are a good source of glucosinolates and phenolic antioxidants. PMID- 21259375 TI - Isolation of four high-purity dammarane saponins from extract of Panax notoginseng by centrifugal partition chromatography coupled with evaporative light scattering detection in one operation. AB - INTRODUCTION: Centrifugal partition chromatography (CPC), as a continuous liquid liquid partition chromatography with no solid support matrix, combined with evaporative light scattering detection (ELSD) was employed for systematic separation and purification of weak-chromophoric saponins from a highly valued and important traditional Chinese herbal medicine, Panax notoginseng. OBJECTIVE: To separate and isolate high-purity saponins from extract of Panax notoginseng using CPC-ELSD with a simple and low toxicity solvent system. METHODOLOGY: Samples were preparaed by extracting the root material with acetone, treated with n-butanol and then freeze-dried. CPC-ELSD was applied in the separation and detection of notoginsenoside and ginsenosides from extract of Panax notoginseng using a solvent system composed of ethyl acetate-n-butanol-water (1:1:2, v/v/v). The saponins were analysed and identified by their retention time with high performance liquid chromatography (HPLC) coupled with ELSD, as well as electrospray ionisation tandem mass spectrometry (ESI-MS(n) ) in the negative and positive ion modes with the authentic standards. RESULTS: A total of 9.6 mg of notoginsenoside R1, 67.8 mg of ginsenoside Rg1, 2.3 mg of Re and 286.5 mg of Rb1 were purified from 487.2 mg of n-butanol extract of P. notoginseng. The purities of obtained saponins in a single run were assessed to be over 98% by HPLC-ELSD. CONCLUSION: CPC-ELSD was proved to be a very fast and efficient tool for separation of high-purity dammarane saponins. PMID- 21259376 TI - A systematic study of the polyphenolic composition of aqueous extracts deriving from several Cistus genus species: evolutionary relationship. AB - INTRODUCTION: Cistaceae is a large family of shrubs widely spread over the Mediterranean area. It includes Helianthemum, Halimium and Cistus genus. Cistus genus contains approximately 20 species distributed in three subgenus. The essential oil of Cistus species has been thoroughly studied, but the polyphenolic composition of the aerial parts of the different Cistus species needs further characterisation. OBJECTIVE: To perform a comparative analysis of the qualitative and quantitative polyphenolic composition of the aerial parts of the most commonly distributed Spanish Cistus species in order to find a relationship between chemotype and subgenus. METHODOLOGY: Thirteen aqueous extracts derived from 10 different Cistus species were analysed by using HPLC with diode array detection coupled to electrospray ion trap mass spectrometry technique (HPLC-DAD ESI-MS/MS). Their major compounds were identified and ellagitannins were quantified. Principal component analysis (PCA) was performed on the most relevant compounds to find out the statistical association between chemotype and variety. RESULTS: Three main groups of compounds were found, i.e. ellagitannins, flavonoids and phenolic acids derivatives. The polyphenolic profile was specific for each species, although the abundance of some compounds also varied depending on the soil type. Whereas C. ladanifer, C. salviifolius, C. populifolius and C. libanotis were specially rich in ellagitannins, C. clusii, C. laurifolius and C. monspeliensis contained significant amounts of flavonoids and much less ellagitannins. In contrast, C. crispus, C. incanus and C. albidus showed a polyphenolic profile mostly based on flavonoids. PCA analysis showed a strong relationship between Cistus subgenus and its chemotype based on the most relevant water-soluble polyphenolic compounds. CONCLUSIONS: Chemical composition of the leaves' aqueous extracts from plants belonging to the Cistus genus is strongly related to their subgenus, in agreement to previous taxonomical and phylogenetic divisions. In contrast, soil and climate are less influencing factors. Leucocistus and Halimioides subgenus showed a higher content in ellagitannins. However, Cistus subgenus had higher flavonoid content. PMID- 21259377 TI - Inverse association between toothbrushing and upper aerodigestive tract cancer risk in a Japanese population. AB - BACKGROUND: Oral hygiene is attracting increasing attention as a potential risk factor for cancers. To investigate the association between toothbrushing frequency and upper aerodigestive tract (UADT) cancer, the authors conducted a large-scale case-control study. METHODS: A total of 856 UADT cancer case participants and 2696 age- and sex-matched control subjects without cancer were included. Edentulous or participants with unknown frequency of toothbrushing or number of remaining teeth were excluded. Associations were assessed by odds ratios and 95% confidence intervals in logistic regression models with adjustment for potential confounders. RESULTS: Compared with toothbrushing once per day, the adjusted odds ratio for brushing twice or more was 0.82 (95% confidence interval: 0.68, 0.99) whereas that for not brushing was 1.79 (0.79, 4.05). This association was observed especially in subjects who had a history of heavy smoking or drinking. CONCLUSIONS: The authors suggest that toothbrushing could have a protective effect for UADT cancer. PMID- 21259378 TI - Long-term use of zopiclone, zolpidem and zaleplon among Danish elderly and the association with sociodemographic factors and use of other drugs. AB - PURPOSE: To estimate the degree of long-term use of zopiclone, zolpidem and zaleplon among Danes aged 65 and older and the association with sociodemographic factors and use of other drugs. METHODS: Danish register-based study of 5000 men and 5000 women aged 65 or older on 1 January 2004. Information on sociodemographic factors and drug redemptions were collected for 2003, with follow-up of zopiclone, zolpidem and zaleplon redemptions in 2004. Long-term use was defined as redemptions corresponding to a continuous daily use for more than 4 weeks (based on 1/2 DDD). The association between long-term use and sociodemographics and drug use was estimated by logistic regression. RESULTS: Ten per cent of all men and 16% of all women had a long-term use for minimum 4 weeks corresponding to 94% of the male and 93% of the female users. Four per cent of the men and 6% of the women had redeemed more than 1/2 DDD per day in 2004. Long term use was associated with: Being a woman, high age, widowed or divorced, high education and high gross income. Long-term use was also associated with use of other drugs, the association with ATC group N being the strongest. Restricting the analyses to individuals who had minimum one zopiclone, zolpidem or zaleplon redemption gave similar results. CONCLUSION: The results indicate that the guidance for length of use is not followed. Long-term use of zopiclone, zolpidem and zaleplon is associated with sociodemographic factors and use of other drugs, particularly from ATC group N. PMID- 21259379 TI - 'The greatest thing in the world is the family': the meaning of social support among black Caribbean and white British patients living with advanced cancer. AB - PURPOSE: Little is known about the perceptions and meanings of social support among black and minority ethnic groups living with advanced cancer in the UK. The aim of this study was to explore social support networks and their meaning among Black Caribbean and White British patients living with advanced cancer. METHOD: Semi-structured interviews were conducted with 26 Black Caribbean and 19 White British cancer patients and analysed using the framework approach. RESULTS: In all, 25 of 26 Black Caribbean and 18 of 19 White British participants volunteered views on the presence of social support in their lives. The presence of a spouse or partners was an indispensable feature within the social support networks in both ethnic groups. More Black Caribbean than White British participants referred to the presence of social networks made through their church communities as being a source of practical and emotional support. CONCLUSIONS: We recommend that when health and social-care professionals perform an assessment interview with patients from cultural backgrounds different to their own, opportunities should be made for patients to express information about their social support networks. This will help them to better understand their place alongside statutory services. Spouses and partners should be given greater recognition of their contribution in order to continue with their important role. PMID- 21259380 TI - Relationship of knowledge of psychosocial issues about cancer with psychic distress and adjustment among breast cancer clinic attendees in a Nigerian teaching hospital. AB - OBJECTIVES: The diagnosis of breast cancer prompts emotional reactions, which predispose to psychosocial problems and poor adjustment. Assessment of the psychosocial issues could help articulation of specific interventions. There is paucity of data on psychosocial issues in breast cancer from Nigeria. We assessed knowledge of psychosocial issues about breast cancer and its association with psychic distress and adjustment among women attending a Nigerian teaching hospital. METHODS: We used a descriptive survey design to assess 63 consecutive clinic attendees (mean age: 49.9, SD: 10.5) who met the eligibility criteria. Data were obtained using the following: a 15-item self-report validated psychosocial needs questionnaire, General Health Questionnaire (GHQ-12) and 10 item adjustment scale. RESULTS: Majority (63.4%) indicated they did not know much about the nature of breast cancer. The greatest area of worry was related to fear of death (81.0%). Knowledge about management of breast cancer was significantly inversely correlated with psychic distress (p<0.03). High psychic distress was significantly related to psychosocial concerns (p<0.01), and inversely correlated with adjustment (p<0.001).The most important predictor of psychic distress and adjustment was their fear about how people reacted to them. CONCLUSIONS: The findings support previous reports indicating that psychosocial concerns are associated with psychic distress and poor adjustment in breast cancer. Accordingly, a regular psycho-oncology service should include counseling on improved prognosis in cancer with early patronage of modern treatments, to allay fear of death; while public health education on social stigma should address fear of negative reactions from people. PMID- 21259381 TI - Functional connectivity in mild traumatic brain injury. AB - OBJECTIVES: Research suggests that the majority of mild traumatic brain injury (mTBI) patients exhibit both cognitive and emotional dysfunction within the first weeks of injury, followed by symptom resolution 3-6 months postinjury. The neuronal correlates of said dysfunction are difficult to detect with standard clinical neuroimaging, complicating differential diagnosis and early identification of patients who may not recover. This study examined whether resting state functional magnetic resonance imaging (fMRI) provides objective markers of injury and predicts cognitive, emotional, and somatic complaints in mTBI patients semiacutely (<3 weeks postinjury) and in late recovery (3-5 month) phases. METHODS: Twenty-seven semiacute mTBI patients and 26 gender, age, and education-matched controls were studied. Fifteen of 27 patients returned for a follow-up visit 3-5 months postinjury. The main dependent variables were spontaneous fluctuations (temporal correlation) in the default-mode (DMN) and fronto-parietal task-related networks as measured by fMRI. RESULTS: Significant differences in self-reported cognitive, emotional, and somatic complaints were observed (all P < 0.05), despite normal clinical (T1 and T2) imaging and neuropsychological testing results. Mild TBI patients demonstrated decreased functional connectivity within the DMN and hyper-connectivity between the DMN and lateral prefrontal cortex. Measures of functional connectivity exhibited high levels of sensitivity and specificity for patient classification and predicted cognitive complaints in the semi-acute injury stage. However, no changes in functional connectivity were observed across a 4-month recovery period. CONCLUSIONS: Abnormal connectivity between the DMN and frontal cortex may provide objective biomarkers of mTBI and underlie cognitive impairment. PMID- 21259383 TI - Predictability of saccadic behaviors is modified by transcranial magnetic stimulation over human posterior parietal cortex. AB - Predictability in the visual environment provides a powerful cue for efficient processing of scenes and objects. Recently, studies have suggested that the directionality and magnitude of saccade curvature can be informative as to how the visual system processes predictive information. The present study investigated the role of the right posterior parietal cortex (rPPC) in shaping saccade curvatures in the context of predictive and non-predictive visual cues. We used an orienting paradigm that incorporated manipulation of target location predictability and delivered transcranial magnetic stimulation (TMS) over rPPC. Participants were presented with either an informative or uninformative cue to upcoming target locations. Our results showed that rPPC TMS generally increased saccade latency and saccade error rates. Intriguingly, rPPC TMS increased curvatures away from the distractor only when the target location was unpredictable and decreased saccadic errors towards the distractor. These effects on curvature and accuracy were not present when the target location was predictable. These results dissociate the strong contingency between saccade latency and saccade curvature and also indicate that rPPC plays an important role in allocating and suppressing attention to distractors when the target demands visual disambiguation. Furthermore, the present study suggests that, like the frontal eye fields, rPPC is critically involved in determining saccade curvature and the generation of saccadic behaviors under conditions of differing target predictability. PMID- 21259382 TI - Altered default mode network connectivity in Alzheimer's disease--a resting functional MRI and Bayesian network study. AB - A number of functional magnetic resonance imaging (fMRI) studies reported the existence of default mode network (DMN) and its disruption due to the presence of a disease such as Alzheimer's disease (AD). In this investigation, first, we used the independent component analysis (ICA) technique to confirm the DMN difference between patients with AD and normal control (NC) reported in previous studies. Consistent with the previous studies, the decreased resting-state functional connectivity of DMN in AD was identified in posterior cingulated cortex (PCC), medial prefrontal cortex (MPFC), inferior parietal cortex (IPC), inferior temporal cortex (ITC), and hippocampus (HC). Moreover, we introduced Bayesian network (BN) to study the effective connectivity of DMN and the difference between AD and NC. When compared the DMN effective connectivity in AD with the one in NC using a nonparametric random permutation test, we found that connections from left HC to left IPC, left ITC to right HC, right HC to left IPC, to MPFC and to PCC were all lost. In addition, in AD group, the connection directions between right HC and left HC, between left HC and left ITC, and between right IPC and right ITC were opposite to those in NC group. The connections of right HC to other regions, except left HC, within the BN were all statistically in-distinguishable from 0, suggesting an increased right hippocampal pathological and functional burden in AD. The altered effective connectivity in patients with AD may reveal more characteristics of the disease and may serve as a potential biomarker. PMID- 21259384 TI - Correlation between gray matter density-adjusted brain perfusion and age using brain MR images of 202 healthy children. AB - We examined the correlation between brain perfusion and age using pulsed arterial spin-labeling (ASL) magnetic resonance images (MRI) in a large number of healthy children. We collected data on brain structural and ASL perfusion MRI in 202 healthy children aged 5-18 years. Structural MRI data were segmented and normalized, applying a voxel-based morphometric analysis. Perfusion MRI was normalized using the normalization parameter of the corresponding structural MRI. We calculated brain perfusion with an adjustment for gray matter density (BP-GMD) by dividing normalized ASL MRI by normalized gray matter segments in 22 regions. Next, we analyzed the correlation between BP-GMD and age in each region by estimating linear, quadratic, and cubic polynomial functions, using the Akaike information criterion. The correlation between BP-GMD and age showed an inverted U shape followed by a U-shaped trajectory in most regions. In addition, age at which BP-GMD was highest was different among the lobes and gray matter regions, and the BP-GMD association with age increased from the occipital to the frontal lobe via the temporal and parietal lobes. Our results indicate that higher order association cortices mature after the lower order cortices, and may help clarify the mechanisms of normal brain maturation from the viewpoint of brain perfusion. PMID- 21259386 TI - Lateralization of the arcuate fasciculus and its differential correlation with reading ability between young learners and experienced readers: a diffusion tensor tractography study in a Chinese cohort. AB - As Chinese reading engages a different neural network from alphabetic language reading, we investigate whether leftward lateralization of the arcuate fasciculus (AF), as observed in the Western population, is also present in the Chinese population and if it does, whether it is associated with better reading ability. Diffusion tensor tractography analysis on 75 Chinese subjects of three age groups (first graders, fourth graders, and college students) showed that 70-83% of them had leftward lateralization of the AF. The pattern of lateralization did not differ significantly among the three groups, suggesting that lateralization of the AF is formed at an early age and before one enters first grade. Among the first graders, who had just started to learn to read, subjects with strongly leftward lateralized AF scored significantly higher than those with other defined lateralization patterns in Chinese (P = 0.001) and English (P = 0.036) reading tasks. This association was not observed among the fourth graders and college students who were experienced Chinese readers. Among the fourth graders, females were found to obtain significantly higher Chinese (P = 0.033) and English reading scores than males (P = 0.002). Our study suggests a differential effect of leftward lateralization of the AF on reading ability at different stages of reading development in the Chinese population. PMID- 21259387 TI - Genetic variation of the alpha2b-adrenoceptor affects neural correlates of successful emotional memory formation. AB - OBJECTIVE: Enhanced memory for emotionally charged events helps us to remember potentially vital information. There are large interindividual differences in emotional-memory enhancement, but little is known about their neurobiological basis. Recently, a functional deletion variant of the gene that codes for the alpha2b-adrenoceptor (ADRA2B) has been shown to affect memory for emotional experiences. Initial neuroimaging evidence linked this behavioral effect to increased amygdala activity, but its influence on successful memory processing remains unknown. Therefore, the aim of this study was to investigate the effect of the common deletion in the ADRA2B gene on neural activity related to specific mnemonic processing, successful memory formation, and retrieval. METHODS: Twenty three noncarriers (10 males) and 28 deletion carriers (13 males) with a mean age of 24 years were investigated while performing an emotional-learning task with sad and happy scenes. Functional magnetic resonance imaging was acquired both during memory formation and retrieval. RESULTS: Although there were no differences in memory performance between groups, the common deletion variant of ADRA2B was related to enhanced activity in the amygdala and inferior frontal gyrus during successful emotional memory formation, but not retrieval. Deletion carriers showed a larger differential response in these brain regions between later-remembered and later-forgotten stimuli than nondeletion carriers did. CONCLUSION: Our results demonstrate that the ADRA2B polymorphism influences emotional memory formation but not memory retrieval in the amygdala and left inferior frontal gyrus. PMID- 21259385 TI - Reliability of functional magnetic resonance imaging associative encoding memory paradigms in non-demented elderly adults. AB - Functional magnetic resonance imaging (fMRI) holds significant potential to aid in the development of early interventions to improve memory function, and to assess longitudinal change in memory systems in aging and early Alzheimer's disease (AD). However, the test-retest reliability of hippocampal activation and of "beneficial" deactivation in the precuneus has yet to be fully established during memory encoding tasks in older subjects. Using a mixed block and event related face-name associative encoding paradigm, we assessed the reliability of hippocampal activation and default network deactivation over a 4- to 6-week interscan interval in 27 older individuals who were cognitively normal [Clinical Dementia Rating (CDR) Scale = 0; n = 18] or mildly impaired (CDR = 0.5; n = 9). Reliability was assessed in whole brain maps and regions of interest using both a full-task paradigm of six functional runs as well as an abbreviated paradigm of the first two functional runs, which would be advantageous for use in clinical trials. We found reliable hippocampal signal response across both block- and event-related designs in the right hippocampus. Comparable reliability in hippocampal activation was found in the full and the abbreviated paradigm. Similar reliability in hippocampal activation was observed across both CDR groups overall, but the CDR 0.5 group was more variable in left hippocampal activity. Task-related deactivation in the precuneus demonstrated much greater variability than hippocampal activation in all analyses. Overall, these results are encouraging for the utility of fMRI in "Proof of Concept" clinical trials investigating the efficacy of potentially therapeutic agents for treatment of age related memory changes, cognitive impairment, and early AD. PMID- 21259389 TI - Do we mind other minds when we mind other minds' actions? A functional magnetic resonance imaging study. AB - Action observation engages higher motor areas, possibly reflecting an internal simulation. However, actions considered odd or unusual were found to trigger additional activity in the so-called theory of mind (ToM) network, pointing to deliberations on the actor's mental states. In this functional magnetic resonance imaging study, the hypothesis was tested that an allocentric perspective on a normal action, and even more so the sight of the actor's face, suffices to evoke ToM activity. Subjects observed short videos of object manipulation filmed from either the egocentric or the allocentric perspective, the latter including the actor's face in half of the trials. On the basis of a regions of interest analysis using ToM coordinates, we found increased neural activity in several regions of the ToM network. First, perceiving actions from an allocentric compared with the egocentric perspective enhanced activity in the left temporoparietal junction (TPJ). Second, the presence of the actor's face enhanced activation in the TPJ bilaterally, the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC). Finally, the mPFC and PCC showed increased responses when the actor changed with respect to the preceding trial. These findings were further corroborated by zmap findings for the latter two contrasts. Together, findings indicate that observation of normal everyday actions can engage ToM areas and that an allocentric perspective, seeing the actor's face and seeing a face switch, are effective triggers. PMID- 21259388 TI - Altered motor network activation and functional connectivity in adult Tourette's syndrome. AB - Tourette's syndrome (TS) is a developmental neuropsychiatric disorder characterized by motor and vocal tics as well as psychiatric comorbidities. Disturbances of the fronto-striatal-thalamic pathways responsible for motor control and impulse inhibition have been previously described in other studies. Although differences in motor performance are well recognized, imaging data elucidating the neuronal correlates are scarce. Here, we examined 19 adult TS patients (13 men, aged 22-52 years, mean = 34.3 years) and 18 age- and sex matched controls (13 men, aged 24-57 years, mean = 37.6 years) in a functional magnetic resonance imaging study at 1.5 T. We corrected for possible confounds introduced by tics, motion, and brain-structural differences as well as age, sex, comorbidities, and medication. Patients and controls were asked to perform a sequential finger-tapping task using their right, left, and both hands, respectively. Task performance was monitored by simultaneous MR-compatible video recording. Although behavioral data obtained during scanning did not show significant differences across groups, we observed differential neuronal activation patterns depending on both handedness (dominant vs. nondominant) and tapping frequency in frontal, parietal, and subcortical areas. When controlling for open motor performance, a failure of deactivation in easier task conditions was found in the subgenual cingulate cortex in the TS patients. In addition, performance-related functional connectivity of lower- and higher-order motor networks differed between patients and controls. In summary, although open performance was comparable, patients showed different neuronal networks and connectivity patterns when performing increasingly demanding tasks, further illustrating the impact of the disease on the motor system. PMID- 21259390 TI - Studying disulfide bond rearrangement by MALDI-RTOF PSD and MALDI-TOF/RTOF high energy CID (20 keV) experiments of peptides derived from ammodytoxins. AB - Ammodytoxins (Atxs) are presynaptically neurotoxic phospholipases present in Vipera ammodytes ammodytes snake venom. Atxs show a high sequence homology and contain 14 cysteines which form seven biologically relevant disulfide bridges connecting non-neighboring cysteines. Formic acid cleavage was performed to confirm protein sequences by MALDI RTOF MS and resulted in 95.6% sequence coverage exhibiting only few formylations. Cysteine-containing peptides showed adjacent signals 2 and/or 4 Da lower (according to the number of cysteines present in the peptide) than the theoretical molecular weight indicating disulfide bridge rearrangement. Post-source decay (PSD) and high-energy collision induced dissociation (CID) at 20 keV experiments showed fragmentation pattern unique for the reduced, thiol group containing and the oxidized, disulfide bridge harboring peptides. Besides typical low-energy fragment ions observed during PSD experiments (a-, b-, y-type ions), additional high-energy fragment ions (c-, x-, w-, d-type and internal fragments) of significant intensity were generated during fragmentation at 20 keV. In the case of charge directing N- and C-termini, x- and w-type ions were also observed during PSD. Good and up to complete sequence coverage was achieved for all studied peptides from Atxs in the case of high energy CID, whereas PSD lacked information particularly for larger peptides. PMID- 21259391 TI - Effects of the net charge on abundance and stability of supramolecular surfactant aggregates in gas phase. AB - Self-assembling of amphiphilic molecules under electrospray ionization (ESI) conditions is characterized by quite unexpected phenomenology. The noticeable differences with respect to the condensed phase are attributable to the absence of the surfactant-solvent interactions, the presence of net charge in the aggregates, and the strong deviation from equilibrium conditions. Aiming to investigate the effects of the net charge on abundance and stability of supramolecular surfactant aggregates, positively and negatively charged aggregates of sodium bis(2-ethylhexyl)sulfosuccinate (AOT) and sodium methane sulfonate (MetS), butane sulfonate (ButS) and octane sulfonate (OctS) have been studied by ESI mass spectrometry, energy resolved mass spectrometry and density functional theory calculations. The negatively charged aggregates are found to be less stable than their positive counterparts. The results are consistent with a self-assembling pattern dominated by electrostatic interactions involving the counterions and head groups of the investigated amphiphilic compounds while the alkyl chains point outwards, protecting the aggregates from unlimited growth processes. PMID- 21259392 TI - Simultaneous determination of raltegravir and raltegravir glucuronide in human plasma by liquid chromatography-tandem mass spectrometric method. AB - Raltegravir is a highly efficacious inhibitor of HIV integrase. Large pharmacokinetic variability has been reported in clinical trials and this could be due to glucuronidation of raltegravir, the only reported metabolism pathway. In order to precisely evaluate and monitor the raltegravir and raltegravir glucuronide simultaneously, a novel, sensitive and robust liquid chromatography tandem mass spectrometric method was developed and validated for simultaneous determination of raltegravir and raltegravir glucuronide in human plasma. A simple protein precipitation with acetonitrile was utilized for plasma sample preparation prior to analysis. Baseline chromatographic separation was achieved on a ZORBAX Eclipse XDB-C8 using gradient elution mode. The run time was 9 min at a constant flow rate of 0.4 ml/min. The mass spectrometer was operated under a positive electrospray ionization condition. Excellent linearity (r(2) >= 0.9997) was achieved for raltegravir and raltegravir glucuronide in the range of 2-2000 nmol/l. The average recovery of raltegravir and raltegravir glucuronide was 105.8% and 102.2%, respectively. The precision (coefficient of variation) was 1.6 6.6% for raltegravir and 2.1-6.9 for raltegravir glucuronide, respectively. The accuracy was 98.6-106.1% for raltegravir and 96.3-100.3% for raltegravir glucuronide. The plasma samples were tested to be stable after nine freeze-thaw cycles and exposure to room temperature for 24 h. This well-validated assay was applied for the quantification of raltegravir and raltegravir glucuronide in plasma samples within 24 h after a single oral dose of 400 mg raltegravir in six healthy subjects. PMID- 21259393 TI - Alternative CHCA-based matrices for the analysis of low molecular weight compounds by UV-MALDI-tandem mass spectrometry. AB - Analysis of low molecular weight compounds (LMWC) in complex matrices by vacuum matrix-assisted laser desorption/ionization (MALDI) often suffers from matrix interferences, which can severely degrade limits of quantitation. It is, therefore, useful to have available a range of suitable matrices, which exhibit complementary regions of interference. Two newly synthesized alpha-cyanocinnamic acid derivatives are reported here; (E)-2-cyano-3-(naphthalen-2-yl)acrylic acid (NpCCA) and (2E)-3-(anthracen-9-yl)-2-cyanoprop-2enoic acid (AnCCA). Along with the commonly used alpha-cyano-4-hydroxycinnamic acid (CHCA), and the recently developed 4-chloro-alpha-cyanocinnamic acid (Cl-CCA) matrices, these constitute a chemically similar series of matrices covering a range of molecular weights, and with correspondingly differing ranges of spectral interference. Their performance was compared by measuring the signal-to-noise ratios (S/N) of 47 analytes, mostly pharmaceuticals, with the different matrices using the selected reaction monitoring (SRM) mode on a triple quadrupole instrument equipped with a vacuum MALDI source. AnCCA, NpCCA and Cl-CCA were found to offer better signal-to-noise ratios in SRM mode than CHCA, but Cl-CCA yielded the best results for 60% of the compounds tested. To better understand the relative performance of this matrix series, the proton affinities (PAs) were measured using the kinetic method. Their relative values were: AnCCA > CHCA > NpCCA > Cl-CCA. This ordering is consistent with the performance data. The synthesis of the new matrices is straightforward and they provide (1) tunability of matrix background interfering ions and (2) enhanced analyte response for certain classes of compounds. PMID- 21259394 TI - Development and validation of a liquid chromatography-tandem mass spectrometry method for the quantitation of synthetic cannabinoids of the aminoalkylindole type and methanandamide in serum and its application to forensic samples. AB - After the discovery of synthetic cannabimimetic substances in 'Spice'-like herbal mixtures marketed as 'incense' or 'plant fertilizer' the active compounds have been declared as controlled substances in several European countries. As expected, a monitoring of new herbal mixtures which continue to appear on the market revealed that shortly after control measures have been taken by legal authorities, other compounds were added to existing mixtures and to new products. Several compounds of the aminoalkylindole type have been detected so far in herbal mixtures but still their consumption cannot be detected by commonly used drug-screening procedures, encouraging drug users to substitute cannabis with those products. There is a increasing demand on the part of police authorities, hospitals and psychiatrists for detection and quantification of synthetic cannabinoids in biological samples originating from psychiatric inpatients, emergency units or assessment of fitness to drive. Therefore, a liquid chromatography-tandem mass spectrometry method after liquid-liquid extraction for the quantitation of JWH-015, JWH-018, JWH-073, JWH-081, JWH 200, JWH-250, WIN 55,212-2 and methanandamide and the detection of JWH-019 and JWH-020 in human serum has been developed and fully validated according to guidelines for forensic toxicological analyses. The method was successfully applied to 101 serum samples from 80 subjects provided by hospitals, detoxification and therapy centers, forensic psychiatric centers and police authorities. Fifty-seven samples or 56.4% were found positive for at least one aminoalkylindole. JWH-019, JWH-020, JWH-200, WIN 55,212-2 and methanandamide were not detected in any of the analyzed samples. PMID- 21259395 TI - Formation of dimethylnickelate(I) and dimethylsilverate(I) anions in the gas phase from nickel(II) acetate and silver(I) acetate by laser desorption/ionisation. PMID- 21259396 TI - Influence of methane addition on selenium isotope sensitivity and their spectral interferences. AB - The measurements of stable selenium (Se) isotopic signatures by multi-collector inductively coupled plasma mass spectrometry (MC-ICP-MS) are very challenging, due to the presence of spectral interferences and the low abundance of Se in environmental samples. We systematically investigated the effect of methane addition on the signal of Se isotopes and their interferences. It is the first time that the effect of methane addition has been assessed for all Se isotopes and its potential interferences using hydride generator multi-collector inductively coupled plasma mass spectrometry (HG-MC-ICP-MS). Our results show that a small methane addition increases the sensitivity. However, the response differs between a hydride generator and a standard introduction system, which might be related to differences in the ionization processes. Both argon and hydrogen-based interferences, the most common spectral interferences on selenium isotopes in HG-MC-ICP-MS, decrease with increasing methane addition. Therefore, analyte-interference ratios and precision are improved. Methane addition has thus a high potential for the application to stable Se isotopes ratios by HG-MC-ICP MS. PMID- 21259397 TI - Sensitivity and amplitude calibration of a Fourier transform 3D quadrupole ion trap mass spectrometer. AB - With a three-dimensional (3D) quadrupole ion trap running in a Fourier transform operating mode, the detected signal is an image of the collective motion of the confined ions. Consequently, it is assumed that the image signal is the sum of the axial trajectories of the simultaneously confined ions. The resulting frequency spectrum after Fourier transformation comprises frequency peaks at the axial secular frequencies of the confined species according to their mass/charge ratio. With a singly confined species, the maximal amplitude of the image signal is proportional to the amplitude of the secular axial frequency peak. The matrix method is employed to express the axial trajectory sampled at the confinement field period. In that case, the expression of the image signal, as well as its maximal amplitude, is calculated as a function of the trap operating conditions and initial axial positions and axial velocities of the ions. The initial position and velocity distributions are connected to the injection mode. With the steady ion flow injection mode (SIFIM) and an initial phase of the confinement field equal to kpi, the maximal amplitude of the image signal is proportional to either the sum of the initial axial positions or the number of confined ions and the mean value of the initial axial positions. By simulation, amplitude fluctuation of the frequency peak is then calculated for a number of ions ranging between some tens to some thousands of ions injected by SIFIM. The peak amplitude fluctuations induced by the fluctuations of the number of ions are seven times greater than those induced by the fluctuations of the distribution of the initial axial positions. PMID- 21259398 TI - Structure and dissociation characteristics of metal chloride anion clusters containing redox-active metal ions studied by laser desorption and electrospray ionization mass spectrometry and ab initio calculations. AB - Copper chloride anion clusters with both copper oxidation states can be made by laser desorption of CuCl(2) crystals. We have used this method to study the dissociation characteristics of such cluster ions. The stability and the structure of the observed complexes were probed by ab initio calculations. These calculations show that many of these complexes are bridged structures. Thus, for the Cu(2)Cl(4) dimer anion, formally [ClCu-Cl-CuCl(2)](-) , with putative mixed copper oxidation states, the two copper ions become equivalent through bridging. Such bridging does not occur when redox inactive metal ions are present as in [ClCu-Cl-CaCl(2)](-) . By observing the dissociation characteristics of a variety of metal chloride cluster anions produced from binary mixtures, the following Cl( ) affinity order is obtained: FeCl(3) > CuCl > CaCl(2) > FeCl(2) > AgCl ~ CuCl(2) ~ ZnCl(2) > LiCl. Ab initio calculations on the Cl(-) affinity of selected chlorides confirm this order as do Cl(-) affinity estimates from the experimentally known vertical electron detachment energies of the superhalogens CaCl(3)(-) and LiCl(2)(-) . An equimolar mixture of CuCl(2) and FeCl(3) produces an intense cluster ion, which, from (65)Cu labeling experiments, is best described as FeCl(4)(-)...Cu(+)...(-)Cl(4) Fe, a Cu(+) bound superhalogen FeCl(4)(-) dimer. The Cu(+) ion can be replaced by the redox inactive alkali cations and by Ag(+) but these metal ion bound FeCl(4)(-) dimers show an entirely different fragmentation behavior which is attributed to the absence of bridging. Electrospray ionization (ESI) of CuCl(2) produces an extended series of (CuCl(2))(n) Cl(-) anions (n = 1-11) and so in ESI very limited reduction of Cu(2+) takes place. The (CuCl(2))(n) Cl(-) anions show an abundant dissociation via loss of neutral Cu(2)Cl(4) which according to our ab initio calculations is 9 kcal/mol more stable than two CuCl(2). PMID- 21259399 TI - Development and validation of a liquid chromatography and ion spray tandem mass spectrometry method for the quantification of artesunate, artemether and their major metabolites dihydroartemisinin and dihydroartemisinin-glucuronide in sheep plasma. AB - Recently, promising fasciocidal activities of artesunate and artemether were described in rats and sheep. Therefore, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to quantify artesunate, artemether and their metabolites dihydroartemisinin and dihydroartemisinin-glucuronide in sheep plasma. Protein precipitation with methanol was used for sample workup. Reversed-phase high-performance liquid chromatography (HPLC) was performed using an Atlantis C18 analytical column with a mobile phase gradient system of ammonium formate and acetonitrile. The analytes were detected by MS/MS using selected reaction monitoring (SRM) with electrospray ionisation in the positive mode (transition m/z 267.4 -> 163.0). The analytical range for dihydroartemisinin, dihydroartemisinin-glucuronide and artesunate was 10-1000 ng/ml and for artemether 90-3000 ng/ml with a lower limit of quantification of 10 and 90 ng/ml, respectively. Inter- and intra-day accuracy and precision deviations were < 10%. Consistent relative recoveries (60-80%) were observed over the investigated calibration range for all analytes. All analytes were stable in the autosampler for at least 30 h (6 degrees C) and after three freeze and thaw cycles. The validation results demonstrated that the LC-MS/MS method is precise, accurate and selective and can be used for the determination of the artemisinins in sheep plasma. The method was applied successfully to determine the pharmacokinetic parameters of artesunate and its metabolites in plasma of intramuscularly treated sheep. PMID- 21259400 TI - Investigation of pituitary adenylate cyclase activating polypeptide in human gynecological and other biological fluids by using MALDI TOF mass spectrometry. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a multifunctional and pleiotropic neuropeptide. PACAP has diverse effects in the endocrine system, among others, it plays important roles in oogenesis, implantation and development of the nervous system. However, it is not known whether PACAP is present in the fluids of the human reproductive organs. The aim of the present study was to determine, by means of mass spectrometry and radioimmunoassay, whether PACAP is present in human amniotic fluid, ovarian follicular fluid and cervico-vaginal fluid. Samples were obtained from healthy adult volunteers. Our MALDI TOF and MALDI TOF/TOF spectrometry results show that PACAP38 is present in all of the follicular fluid samples, and PACAP-like immunoreactivity was also measured by radioimmunoassay. However, we did not find the characteristic peak representing the unmodified 38 amino acid form of the peptide in normal cervico-vaginal smear and amniotic fluid samples. Furthermore, we analyzed other body fluids for comparison, such as human nasal fluid, saliva and aqueous humor. PACAP was not found in these latter samples. In summary, the present study provides evidence for the presence of PACAP in human follicular fluid, suggesting a role in oocyte function, but determination of the exact physiological significance awaits further investigation. PMID- 21259401 TI - Sieve-based device for MALDI sample preparation. III. Its power for quantitative measurements. AB - The solid sample inhomogeneity is a weak point of traditional MALDI deposition techniques that reflects negatively on quantitative analysis. The recently developed sieve-based device (SBD) sample deposition method, based on the electrospraying of matrix/analyte solutions through a grounded sieve, allows the homogeneous deposition of microcrystals with dimensions smaller than that of the laser spot. In each microcrystal the matrix/analyte molar ratio can be considered constant. Then, by irradiating different portions of the microcrystal distribution an identical response is obtained. This result suggests the employment of SBD in the development of quantitative procedures. For this aim, mixtures of different proteins of known molarity were analyzed, showing a good relationship between molarity and intensity ratios. This behaviour was also observed in the case of proteins with quite different ionic yields. The power of the developed method for quantitative evaluation was also tested by the measurement of the abundance of IGPP[Oxi]GPP[Oxi]GLMGPP (m/z 1219) present in the collagen-alpha-5(IV) chain precursor, differently expressed in urines from healthy subjects and diabetic-nephropathic patients, confirming its overexpression in the presence of nephropathy. The data obtained indicate that SBD is a particularly effective method for quantitative analysis also in biological fluids of interest. PMID- 21259404 TI - Transplantation of CTLA4Ig gene-transduced adipose tissue-derived mesenchymal stem cells reduces inflammatory immune response and improves Th1/Th2 balance in experimental autoimmune thyroiditis. AB - BACKGROUND: Autoimmune thyroiditis is one of common organ-specific autoimmune disease. The aim of this study was to observe the effect of adipose tissue derived mesenchymal stem cells (ATMSC) and CTLA4Ig gene-transduced ATMSC on autoimmune thyroiditis. METHODS: Experimental autoimmune thyroiditis was induced by immunization with thyroglobulin. Animals were divided into three groups: (i) a half million of human ATMSC, (ii) a half million of murine CLTA4Ig gene transduced human ATMSC (CTLA4Ig-MSC), or (iii) normal saline (as control), which were administered intravenously four times within a 3-week period. Blood and tissue samples were collected 1 week after the last cell transplantation. RESULTS: The absorbance of serum thyroglobulin autoantibody (TgAA) in the CTLA4Ig MSC group was considerably lower than those in other groups. In culture supernatant of LPS-stimulated spleen cells, both of the MSC-treated groups showed significantly lower absorbances of TgAA than the control. Flow cytometric analysis of spleen cells revealed a significant decrease in the proportion of CD3+ and CD11b in the CTLA4Ig-MSC group compared to the other groups. Lymphocyte infiltration in the thyroid glands was also dramatically decreased in both of MSC treated groups. Cytokine analysis showed that ATMSC decreased the production of proinflammatory cytokines and improved the Th1/Th2 balance by down-regulating Th1 cytokines. CONCLUSION: Although CTLA4Ig-MSC transplantation had better result in reduction of serum TgAA, both of ATMSC and CTLA4Ig-MSC transplantations are promising treatments for autoimmune thyroiditis judging from the results of histopathology and cytokine analysis. They may be attractive candidates for treating organ-specific autoimmune disease. PMID- 21259405 TI - Creation of a panel of vectors based on ape adenovirus isolates. AB - BACKGROUND: We recently reported the isolation and sequencing of 30 novel adenoviruses from chimpanzees, bonobos and gorillas. These adenoviruses are promising candidates for the purpose of expanding the repertoire of adenoviral serotypes that can be used to create vectors for circumventing pre-existing neutralizing antibodies in human populations. We thus aimed to create vectors from 20 of the newly isolated adenoviruses. METHODS: Plasmid molecular clones were created that harbored the complete E1-deleted genomes from 20 of the newly isolated ape adenoviruses belonging to species B, C and E. The plasmids were transfected into human embryonic kidney (HEK) 293 cells to rescue vectors. We also tested normal human sera to determine the extent of pre-existing cross neutralizing anti-adenovirus neutralizing antibodies. RESULTS: Twelve vectors could be rescued and expanded following transfection into HEK 293 cells with yields (from fifty 150-mm culture dishes) that ranged from 3 * 10(11) to 7 * 10(13) viral particles. Sera from 50 normal human donors were tested for the presence of neutralizing activity against 21 of the newly isolated ape adenoviruses. Cross-neutralizing activity was generally low, although outliers with high neutralizing activity were frequently detected. Species B ape adenoviruses generally showed the least cross-neutralization with antibodies present in the human sera that were tested. CONCLUSIONS: E1-deleted adenovirus vectors can be created from a wide variety of ape adenoviruses that can be rescued and propagated in HEK 293 cells. The prevalence of pre-existing antibodies that can neutralize these adenoviruses in human populations is low. PMID- 21259406 TI - Antiglioma effects of combined use of a baculovirual vector expressing wild-type p53 and sodium butyrate. AB - BACKGROUND: Combination therapy is usually desirable for successful cancer treatment, especially in cancers that are resistant to single forms of therapy. METHODS: To achieve an optimal therapeutic effect against glioblastoma, we tested a strategy that combines baculovirus-mediated transfer of the p53 tumor suppressor gene with the use of sodium butyrate, a histone deacetylase inhibitor. This strategy was designed based on the findings that the transduction efficiency of baculovirus in mammalian cells can be markedly enhanced by the addition of histone deacetylase inhibitors and that these inhibitors are effective in inducing cell cycle arrest, differentiation, or apoptosis in tumor cells. RESULTS: We observed a synergistic effect of the combination of the two treatments in provoking apoptosis in glioblastoma cells with mutant p53. In a mouse glioma xenograft model, the tumor inhibitory effect of baculovirus expressed p53 was significantly enhanced by co-administration of sodium butyrate. CONCLUSIONS: These findings suggest a new approach to treat glioblastoma using baculovirus-mediated gene transfer in combination with administration of histone deacetylase inhibitor. PMID- 21259407 TI - Anti-DNA antibody modified coronary stent for plasmid gene delivery: results obtained from a porcine coronary stent model. AB - BACKGROUND: Previous work in our laboratory has demonstrated that the anti-DNA antibody-immobilized stent results in highly site-specific gene delivery in a rabbit carotid model. As a result of the similarity in the anatomy and physiology of the pig and human cardiovascular systems, the porcine coronary stent model was used in the present study to evaluate the site-specificity, efficiency and long term therapeutic effect of this gene delivery system in pig coronary arteries. METHODS: A reporter plasmid pEGFP (pEGFP-C1) was tethered on the antibody immobilized stents and assessed for site-specificity and efficiency in a pig coronary stent model. Inducible nitric oxide synthase (NOS) cDNA (pcDNA3.1-iNOS) was tethered on the stent as a therapeutic gene to evaluate the site-specificity and long-term therapeutic effect of this novel gene delivery system for the inhibition of restenosis after coronary stenting for 28 days. RESULTS: Both the pEGFP-C1 and pcDNA3.1-iNOS tethered stents achieved site-specific gene transfection without distal spreading in the porcine coronary model. The overall GFP transfection efficiency was 2.6 +/- 0.9% of the total cells, whereas the neointimal transfection was more than 6%. Histology and morphology studies showed no significant artery stenosis and intimal proliferation for 28 days after coronary stenting using pcDNA3.1-iNOS tethered stents. CONCLUSIONS: For the first time, we report the successful use of anti-DNA antibody-immobilized stent as plasmid gene delivery system that possess high efficiency and site-specificity in a porcine coronary stent model. The novel system showed long-term therapeutic effects on the inhibition of restenosis when pcDNA3.1-iNOS was tethered on the stent. PMID- 21259408 TI - Improved transfection efficiency of an aliphatic lipid substituted 2 kDa polyethylenimine is attributed to enhanced nuclear association and uptake in rat bone marrow stromal cell. AB - BACKGROUND: Lipid substitutions of cationic polymers are actively explored to enhance the efficiency of nonviral gene carriers. We recently took this approach to develop a novel gene carrier by grafting linoleic acid (LA) to relatively biocompatible 2 kDa polyethylenimine (PEI2). The resulting polymer (PEI2LA) displayed improved transfection efficiency over the unmodified PEI2. The intracellular kinetics and distribution of the respective polyplexes were investigated in the present study to gain a better understanding of the role of lipid modification in intracellular trafficking of gene carriers. METHODS: A Cy5 labeled plasmid DNA (pDNA) expressing the green fluorescent protein (GFP) was complexed with PEI2, PEI2LA, and 25 kDa polyethylenimine (PEI25) to transfect rat bone marrow stromal cells (BMSC). Subcellular fractionation was performed to measure the amount of nuclear associated pDNA. pDNA uptake, GFP-expression and nuclear-associated pDNA were measured by both flow cytometry and confocal laser scanning microscopy. RESULTS: PEI2LA mediated higher transgene expression and percentages of transfected cells than PEI25 and PEI2, respectively. There was a strong correlation between nuclear associated pDNA and transgene expression. PEI2LA polyplexes were significantly larger in size than PEI25. The amounts of pDNA associated with the nuclei were greater in PEI2LA than PEI25 polyplexes. The perinuclear pDNA distribution between GFP-expressing and nonGFP-expressing indicated that GFP-positive cells had a higher amount of pDNA associated with their nuclei. CONCLUSIONS: Improved transfection efficiency of PEI2LA was attributed to enhanced association with the nucleus, which may be a result of hydrophobic interaction between the lipid moieties on the modified lipopolymer and the nuclear membrane. PMID- 21259409 TI - Prophylactic, therapeutic and immune enhancement effect of liposome-encapsulated PolyICLC on highly pathogenic H5N1 influenza infection. AB - BACKGROUND: In view of the magnitude and severity of outbreaks of the highly pathogenic H5N1 influenza virus (H5N1-HPIV) and the threat to public health, there is an urgent need to develop broad-spectrum prophylactic and therapeutic agents against infection by H5N1-HPIV and other subtypes. METHODS AND RESULTS: In the present study, we explored the use of LE-PolyICLC, a liposome encapsulated double-stranded RNA, as a possible prophylactic, therapeutic and immune enhancement agent. In a mouse infection model, we showed that the administration of LE-PolyICLC intranasally before or shortly after infection could inhibit virus replication, leading to a significant reduction in pulmonary viral titres and a higher survival rate of infected mice. When used as a molecular adjuvant, LE PolyICLC significantly enhanced both the humoral and cellular responses elicited by inactivated H5N1 vaccine and augmented the protective efficacy provided by vaccination. Most importantly, the data also demonstrate that LE-PolyICLC could effectively attenuate the development of pulmonary fibrosis during the restoration period at day 14 after H5N1 infection. CONCLUSIONS: Taken together, the data obtained in the present study suggest that strong consideration should be given for the use of LE-PolyICLC as prophylactic and therapeutic agents and also as a vaccination adjuvant to combat highly pathogenic influenza infection and its associated complications such as pulmonary fibrosis. PMID- 21259410 TI - The Tn antigen-structural simplicity and biological complexity. AB - Glycoproteins in animal cells contain a variety of glycan structures that are added co- and/or posttranslationally to proteins. Of over 20 different types of sugar-amino acid linkages known, the two major types are N-glycans (Asn-linked) and O-glycans (Ser/Thr-linked). An abnormal mucin-type O-glycan whose expression is associated with cancer and several human disorders is the Tn antigen. It has a relatively simple structure composed of N-acetyl-D-galactosamine with a glycosidic alpha linkage to serine/threonine residues in glycoproteins (GalNAcalpha1-O-Ser/Thr), and was one of the first glycoconjugates to be chemically synthesized. The Tn antigen is normally modified by a specific galactosyltransferase (T-synthase) in the Golgi apparatus of cells. Expression of active T-synthase is uniquely dependent on the molecular chaperone Cosmc, which is encoded by a gene on the X chromosome. Expression of the Tn antigen can arise as a consequence of mutations in the genes for T-synthase or Cosmc, or genes affecting other steps of O-glycosylation pathways. Because of the association of the Tn antigen with disease, there is much interest in the development of Tn based vaccines and other therapeutic approaches based on Tn expression. PMID- 21259411 TI - Chromophore exchange in the blue light-sensitive photoreceptor YtvA from Bacillus subtilis. AB - YtvA from Bacillus subtilis was found as the first prokaryotic phototropin-like blue-light-responsive photoreceptor. It is composed of two domains, the photoactive LOV (light, oxygen, voltage) domain, which binds a flavin mononucleotide (FMN) as a chromophore and a STAS (sulfate transporter/anti-sigma factor antagonist) domain, which generates a physiological signal. Here we present a routine chromophore-exchange protocol that allows chemically synthesized, structurally modified chromophores instead of the naturally present flavin mononucleotide (FMN) chromophore to be introduced. FMN was exchanged for riboflavin (RF), flavin adenine dinucleotide (FAD), 7,8-didemethyl flavin mononucleotide (DMFMN), and 8-isopropyl flavin mononucleotide (iprFMN). LOV domains reconstituted with new flavins undergo the same photocycle as native YtvA LOV, consisting of triplet formation and covalent binding of the chromophore followed by a thermal recovery of the parent state, albeit with different kinetics and photophysical properties. Interestingly, the iprFMN chromophore, inducing steric hindrances to the protein, exhibits a very fast light-to-dark conversion and shows a high fluorescence quantum yield (0.4). Incorporation of FAD causes an increase of its fluorescence quantum yield from 0.04 (H(2)O) to 0.2. PMID- 21259412 TI - SSTR1- and SSTR3-selective somatostatin analogues. AB - We prepared the two enantiomers of 3-(3'-quinolyl)-alanine (Qla, 1) in multigram scale by asymmetric hydrogenation. These amino acids, protected as Fmoc derivatives, were then used in the solid-phase synthesis of two new somatostatin 14 (SRIF-14) analogues 8 a and 8 b, tetradecapeptides in which the tryptophan residue (Trp8) is replaced by one of the two enantiomers of 3-(3'-quinolyl) alanine (Qla8) and therefore lack the N--H bond in residue 8. The selectivity of these new analogues for the somatostatin receptors, SSTR1-5, was measured. Substitution with L-Qla8 yielded peptide 8 a, which was highly selective for SSTR1 and SSTR3, with an affinity similar to that of SRIF-14. Substitution by D Qla gave the relatively selective analogue 8 b, which showed high affinity for SSTR3 and significant affinity for SSTR1, SSTR2 and SSTR5. The biological results demonstrate that bulky and electronically poor aromatic amino acids at position 8 are compatible with strong activity with SSTR1 and SSTR3. Remarkably, these high affinity levels were achieved with peptides in which the conformational mobility was increased with respect to that of SRIF-14. This observation suggests that conformational rigidity is not required, and might be detrimental to the interaction with receptors SSTR1 and SSTR3. The absence of an indole N proton in Qla8 might also contribute to the increased flexibility observed in these analogues. PMID- 21259413 TI - Guidelines for the management of the foot health problems associated with rheumatoid arthritis. AB - BACKGROUND: Rheumatoid arthritis (RA) as a chronic systemic disease, commonly affects the feet, impacting negatively on patients' quality of life. Specialist podiatrists have a prime role to play in the assessment and management of foot and ankle problems within this patient group. However, it has been identified that in many areas there is no specialist podiatry service, with many patients being managed by non-specialist podiatrists. Therefore, the North West Clinical Effectiveness Group for the Foot in Rheumatic Diseases (NWCEG) identified the need to develop 'practitioner facing' guidelines for the management of specific foot health problems associated with RA. METHODS: Members of a guideline development group from the NWCEG each reviewed the evidence for specific aspects of the assessment and management of foot problems. Where evidence was lacking, 'expert opinion' was obtained from the members of the NWCEG and added as a consensus on current and best practice. An iterative approach was employed, with the results being reviewed and revised by all members of the group and external reviewers before the final guideline document was produced. RESULTS: The management of specific foot problems (callus, nail pathology, ulceration) and the use of specific interventions (foot orthoses, footwear, patient education, steroid injection therapy) are detailed and standards in relation to each are provided. A diagrammatic screening pathway is presented, with the aim of guiding non-specialist podiatrists through the complexity of assessing and managing those patients with problems requiring input from a specialist podiatrist and other members of the rheumatology multidisciplinary team. CONCLUSION: This pragmatic approach ensured that the guidelines were relevant and applicable to current practice as 'best practice', based on the available evidence from the literature and consensus expert opinion. These guidelines provide both specialist and non specialist podiatrists with the essential and 'gold standard' aspects of managing people with RA-related foot problems. PMID- 21259414 TI - Extended roles of non-physician health professionals and innovative models of care within Europe: results from a web-based survey. AB - BACKGROUND AND OBJECTIVE: Due to the increasing prevalence of rheumatic diseases, extended roles of non-physician health professionals and innovative models of care may be important options in rheumatology in the future. Extended roles have been pioneered in the UK, Canada, USA and Australia and been found to be effective and safe. However, few data are available about mainland Europe, so the aim of this study was to explore the current status of the extended roles undertaken by health professionals within Europe, and the corresponding models of care used. METHODS: Non-physician health professionals from various European countries were asked to complete a web-based survey using convenience and snowball sampling techniques. Data analysis involved calculating descriptive statistics and frequencies based on the countries where the participants currently worked. RESULTS: Of the 479 health professionals who filled in the survey, 430 (92%) indicated that they were performing extended roles. Considerable differences between the 27 participating countries existed, in terms of which extended roles and which innovative models of care were being used. Barriers to performing extended roles were cited as the attitude of rheumatologists in all but eight countries, while attitudes of patients were less common barriers. Lack of knowledge, education and educational opportunities were also experienced in several countries. CONCLUSION: The present study produced the first data on extended roles for non-physician health professionals and corresponding innovative models of care in rheumatology within Europe. We recommend increasing educational opportunities, as well as developing strategies to limit the barriers experienced. PMID- 21259415 TI - Robotic-assisted surgical removal of pelvic schwannoma: a novel approach to a rare variant. AB - BACKGROUND: Robotic-assisted excision of a pelvic schwannoma is presented. METHODS: A 27 year-old female presented with occasional numbness of the right thigh. Imaging studies revealed a large mass adjacent to the right ovary. Robotic surgery with adjunctive electrophysiological monitoring was performed. The mass was adhered to the L4, L5 roots and was displacing the iliac vessels and the ureter. The tumour bulk was decompressed and total excision was facilitated. RESULTS: Pathology revealed a neoplasm consisting of spindle cells. Immunochemistry revealed S-100(+) and a growth index Ki-67 < 1%. These findings were consistent with the diagnosis of ancient schwannoma. The intraoperative time was comparable to laparoscopy and the patient had an uneventful recovery. CONCLUSION: Ancient schwannoma is often diagnosed only when it is large enough to produce symptoms. Robotic surgery with adjunctive electrophysiological monitoring is a safe technique for the removal of large pelvic neurinomas. PMID- 21259416 TI - A laboratory training and evaluation technique for robot assisted ex vivo kidney transplantation. AB - The technique of kidney transplantation has been well established. The operation is typically performed through a lower quadrant muscle cutting incision. With advances in robotic technology, many procedures are now being performed using the robot. This article describes a simple model of ex-vivo kidney transplantation using the robotic technique. This is a good training model and could be applied in select group of patients in the clinical setting. PMID- 21259417 TI - Epidermal patterning in Arabidopsis: models make a difference. AB - The leaf and root epidermis in Arabidopsis provide ideal systems in which to explore the mechanisms that underlie the patterned assignment of cell fates during development. Extensive experimental studies have uncovered a complex interlocked feedback network that operates within the epidermis to coordinate the choice between hair and nonhair fates. A number of recent studies using mathematical models have begun to study this network, highlighting new mechanisms that have subsequently been confirmed in model-directed experiments. These studies illustrate the potential of integrated modeling and experimentation to shed new light on developmental processes. Moreover, these models enable systems level comparative analyses that may help understand the origin and role of properties, such as robustness and redundancy in developmental systems and, concomitantly, the evolution of development itself. PMID- 21259419 TI - On the mechanism of eukaryotic cell penetration by alpha- and beta-oligoarginines -targeting infected erythrocytes. AB - Fluorescein-labeled alpha- and beta-octaarginine amides were synthesized. The route, by which these oligoarginine (OA) derivatives enter cells (hepatocytes, fibroblasts, macrophages), was investigated by confocal fluorescence microscopy. Comparisons (by co-localization experiments) with compounds of known penetration modes revealed that the beta-octaarginine amide also uses multiple pathways to enter cells. There was no difference between the alpha- and the beta-OAs. Like other cell-penetrating peptides (CPPs), the beta-octaarginine eventually winds up in the nucleoli of the cell nuclei (cf. Chem. Biodiversity, 2004, 1, 65). Surprisingly, there was no entry of alpha- or beta-OA into intact and healthy human erythrocytes (which do not possess a nucleus). Blood cells infected by Plasmodium falciparum (malaria parasite) were, however, entered readily, and the OAs went all the way through a couple of membranes into the parasite. The potential of these results for delivering specific antimalarial drugs directly into the parasite is discussed. PMID- 21259420 TI - Chemical and pharmacological research on plants from the genus Senecio. PMID- 21259421 TI - Essential oils from neotropical Myrtaceae: chemical diversity and biological properties. AB - Myrtaceae family (121 genera, 3800-5800 spp.) is one of the most important families in tropical forests. They are aromatic trees or shrubs, which frequently produce edible fruits. In the neotropics, ca. 1000 species were found. Several members of this family are used in folk medicine, mainly as an antidiarrheal, antimicrobial, antioxidant, cleanser, antirheumatic, and anti-inflammatory agent and to decrease the blood cholesterol. In addition, some fruits are eaten fresh or used to make juices, liqueurs, and sweets very much appreciated by people. The flavor composition of some fruits belonging to the Myrtaceae family has been extensively studied due to their pleasant and intense aromas. Most of the essential oils of neotropical Myrtaceae analyzed so far are characterized by predominance of sesquiterpenes, some with important biological properties. In the present work, chemical and pharmacological studies carried out on neotropical Myrtaceae species are reviewed, based on original articles published since 1980. The uses in folk medicine and chemotaxonomic importance of secondary metabolites are also briefly discussed. PMID- 21259422 TI - Solid-phase microextraction (SPME) analysis of six Italian populations of Ephedra nebrodensis Tineo ex Guss. subsp. nebrodensis. AB - Headspace solid-phase microextraction (HS-SPME) coupled with GC/FID and GC/MS was applied for the first time in the analysis of the volatile fraction of an Ephedra species. Notably, six Italian populations (Marche, Abruzzo, and Sardinia) of Ephedra nebrodensis subsp. nebrodensis, covering almost the entire Italian area, were investigated to examine the chemical variability and to support the taxonomy of the species. A fiber screening with polymethylsiloxane (PDMS), Carboxen(TM) /polymethylsiloxane (CAR/PDMS), and polymethylsiloxane/divinylbenzene (PDMS/DVB) coatings, together with an optimization of the extraction conditions were carried out before analysis of the six populations. A total of 119 volatiles were identified in the headspace of different samples, accounting for 63.35-100.00% of the total volatiles. A great variability was found in the qualitative composition of different samples, since only 18 components were in common among all populations. The headspace composition was dominated by sesquiterpene hydrocarbons (52.30-88.32%), with beta-maaliene (traces-7.49%), beta-patchoulene (traces-1.29%), beta-panasinsene (traces-6.85%), alpha-isocomene (traces-31.25%), alpha-trans-bergamotene (traces-6.95%), alloaromadendrene (traces-33.20%), alpha acoradiene (traces-9.41%), and gamma-muurolene (0.61-16.33%) being the most abundant constituents. Noteworthy is the occurrence in a sample of two major unknown sesquiterpenes, one hydrocarbon (24.49%, RI: 1396) and one oxygenated compound (10.37%, RI: 1591), whose mass spectra were reported for the first time. Multivariate chemometric techniques, such as cluster analysis (CA) and principal component analysis (PCA), were used to characterize the samples according to the geographical origin. PMID- 21259423 TI - Alkaloid diversity in Galanthus elwesii and Galanthus nivalis. AB - Seventy alkaloids of galanthamine, lycorine, homolycorine, tazettine, haemanthamine, narciclasine, and tyramine types were detected by GC/MS in 25 Galanthus elwesii and seven Galanthus nivalis populations, collected from different locations in Bulgaria. Intraspecies diversity in the alkaloid profiles regarding the main alkaloid types (chemotypes) was observed. Tyramine-type protoalkaloids (namely, hordenine and its derivatives) were dominant in 19 populations of G. elwesii. In other populations of G. elwesii, the plants accumulated mainly homolycorine-, lycorine-, and galanthamine-type alkaloids. The alkaloid profiles of G. nivalis were dominated by narciclasine-, galanthamine-, lycorine-, haemanthamine-, or tazettine-type compounds. Geographical distribution of chemotypes indicated a relationship between populations, since adjacent populations often displayed similar alkaloid profiles. The results from year-to year sampling and transplantation experiments imply genetic determination of alkaloid synthesis in the two studied species of Galanthus. PMID- 21259424 TI - Synthesis, characterization, and DNA binding and cleavage properties of copper(II)-tryptophanphenyl-alanine-1,10-phenanthroline/2,2'-bipyridine complexes. AB - The mononuclear dipeptide-based Cu(II) complexes [Cu(II) (trp-phe)(phen)(H2O)] ? ClO4 (1) and [Cu(II) (trp-phe)(bpy)(H2O)] ? ClO4 (2) (trp phe=tryptophanphenylalanine, phen=1,10-phenanthroline, bpy=2,2'-bipyridine) were isolated, and their interaction with DNA was studied. They exhibit intercalative mode of interaction with DNA. The intercalative interaction was quantified by Stern-Volmer quenching constant (K(sq) =0.14 for 1 and 0.08 for 2). The Cu(II) complexes convert supercoiled plasmid DNA into its nicked circular form hydrolytically at physiological conditions at a concentration as low as 5 MUM (for 1) and 10 MUM (for 2). The DNA hydrolysis rates at a complex concentration of 50 MUM were determined as 1.74 h(-1) (R=0.985) for 1 and 0.65 h(-1) (R=0.965) for 2. The rate enhancement in the range of 2.40-4.10*107-fold compared to non catalyzed double-stranded DNA is significant. This was attributed to the presence of a H(2) O molecule in the axial position of the Cu complexes. PMID- 21259425 TI - Chemical composition and antimicrobial activity of the essential oils of Anthospermum emirnense and Anthospermum perrieri (Rubiaceae). AB - The essential oils of Anthospermum emirnense Baker and Anthospermum perrieri Homolle ex Puff, obtained by hydrodistillation in 0.03 and 0.02% yield, respectively, were analyzed by GC/MS. In both cases, the major constituents consisted of sesquiterpene hydrocarbons and oxygenated sesquiterpenes. The two species showed an important qualitative similarity, with 40 compounds common to A. emirnense and A. perrieri, including beta-elemene, trans-beta-caryophyllene, caryophyllene oxide, and tau-cadinol, which were major components in both cases. When tested for antimicrobial activity, both essential oils showed similar profiles and exhibited interesting minimal-inhibitory-concentration (MIC) values towards Bacillus subtilis, Chryseobacterium indologenes, Flavimonas oryzihabitans, and Yersinia enterocolitica. PMID- 21259426 TI - Tropane alkaloids from Erythroxylum caatingae Plowman. AB - Three tropane alkaloids, 1-3, were isolated from Erythroxylum caatingae, i.e., 6beta-benzoyloxy-3alpha-[(4-hydroxy-3,5-dimethoxybenzoyl)oxy]tropane (1), a new tropane alkaloid, along with the known alkaloids 3alpha,6beta-dibenzoyloxytropane (2) and 6beta-benzoyloxy-3alpha-[(3,4,5-trimethoxybenzoyl)oxy]tropane (catuabine B; 3). Their structures were determined by 2D- ((1) H and (13) C) NMR. By LC/ESI MS/MS analysis of the fractions of alkaloids 1-3, it was possible to detect five more alkaloids, 4-8, two of these, 4 and 8, possibly being new natural products. X-Ray crystallography of the chloride derivate of 1, i.e., 6beta-benzoyloxy 3alpha-(4-hydroxy-3,5-dimethoxybenzoyloxy)tropane hydrochloride (1a) confirmed the structure of 1. Cytotoxicity was tested against the cell lines HEp-2, NCI H292, and KB for the MeOH extract and alkaloid 3, and antitumor activity was tested against Sarcoma 180 only for the MeOH extract. PMID- 21259427 TI - Four new asterosaponins, hippasteriosides A - D, from the Far Eastern starfish Hippasteria kurilensis. AB - Four new sulfated steroidal glycosides (asterosaponins), hippasteriosides A-D (1 4, resp.), were isolated from the alcoholic extract of the Far Eastern starfish Hippasteria kurilensis, collected in the Sea of Okhotsk near Kuril Islands. Compounds 1-4 were determined to contain the same unprecedented hexasaccharide moiety, beta-D-xylopyranosyl-(1->3)-beta-D-fucopyranosyl-(1->2)-beta-D quinovopyranosyl-(1->4)-[beta-D-quinovopyranosyl-(1->2)]-beta-D-xylopyranosyl-(1 >3)-beta-D-quinovopyranosyl, linked to C(6) of 3-O-sulfonylated steroidal aglycons, which differ from each other in their side-chain structures. Structures 1-4 were elucidated by extensive NMR and MS techniques, and chemical transformations. Not all the asterosaponins show a prominent cytotoxic activity against human colon tumor HT-29 cells, but some of them, especially compound 4 demonstrate a remarkable inhibition of the HT-29 colony formation in soft-agar clonogenic assay, suggesting its anticancerogenic properties. PMID- 21259428 TI - Chemical and genetic diversity of Zataria multiflora Boiss. accessions growing wild in Iran. AB - Zataria multiflora Boiss. is an aromatic shrub belonging to the Lamiaceae family. Its aerial parts are used in the traditional medicine and in the pharmaceutical and food industries. The terpenoid and genetic profiles of 18 accessions of Z. multiflora, collected in different locations in Iran, have been analyzed by GC/FID and GC/MS or by AFLP (amplified fragment length polymorphism) analyses, respectively. Altogether, 56 compounds were identified in the essential oils, with the major constituents being thymol (6.0-54.9%), carvacrol (0.7-50.6%), linalool (1.2-46.8%), and p-cymene (1.6-14.8%). On the basis of the essential-oil composition, the 18 accessions were divided into four groups. The first group was characterized by a high content of carvacrol, thymol, and linalool, the second group was dominated by carvacrol, thymol, and p-cymene, the third group was characterized by a high concentration of thymol and a low content of carvacrol and p-cymene, and the forth group contained linalool and carvacrol as the main components. The AFLP results revealed that the average genetic similarity (GS) between the accessions was 0.61, ranging from 0.40 to 0.77. The UPGMA (unweighted pair-group method with arithmetic mean) cluster analysis divided all accessions into five groups at a similarity level of 0.60. The two clusters generated, the first based on the essential-oil compositions and the second on the AFLP data, showed a different pattern of relationships among the accessions. The knowledge of the Z. multiflora chemotype diversity, illustrated in this study, will allow an improvement of the homogeneity of the plant material for the production of different types of essential oils, depending on the demands of the pharmaceutical and food industries for specific uses. PMID- 21259429 TI - Comparison of the chemical composition and the organoleptic profile of virgin olive oil from two wild and two cultivated Tunisian Olea europaea. AB - With the aim to select new olive cultivars with superior physical and chemical properties than the cultivar Chemlali Sfax, the present study focused on the comparison of the chemical composition and the sensory profile of the virgin olive oils (VOOs) of two wild olive trees (Oleasters K and M) with those of VOOs obtained from Chemlali Sfax and Neb Jmel olive cultivars, all growing in the coastal region of Tunisia. Despite the variability in the chemical composition (fatty acids, pigments, and phenolic and volatile compounds) and the organoleptic profile of the VOOs of the oleasters and the cultivars, the quality indices (free fatty acids, peroxide value, and spectrophotometric indices K232 and K270) as well as the fatty acid composition of all VOOs studied met the commercial standards. Both the alpha-tocopherol and phenol contents varied between the genotypes. The Neb Jmel and Oleaster K VOOs had more than two times higher total phenol levels than the Chemlali Sfax and Oleaster M VOOs. Also the contents of volatile compounds differed between the olive oils studied. Chemlali Sfax and Oleaster K oils were more abundant in aldehydes, whereas Oleaster M VOO had higher contents of alcohols. These results were confirmed by a sensorial analysis showing that the later oil was deprived for consumption despite its abundance in alpha-tocopherol. In conclusion, the oleasters studied revealed to be interesting, since they produced oils with good quality characteristics in terms of minor compounds (phenols and volatiles) compared to the Chemlali Sfax cultivar. PMID- 21259430 TI - Individual and combined effects of subclinical doses of deoxynivalenol and fumonisins in piglets. AB - SCOPE: Deoxynivalenol (DON) and fumonisins (FB) are the most frequently encountered mycotoxins produced by Fusarium species and most commonly co-occur in animal diets. These mycotoxins were studied for their toxicity in piglets on several parameters including plasma biochemistry, organ histopathology and immune response. METHODS AND RESULTS: Twenty-four 5-wk-old animals were randomly assigned to four different groups, receiving separate diets for 5 wk, a control diet, a diet contaminated with either DON (3 mg/kg) or FB (6 mg/kg) or both toxins. At days 4 and 16 of the trial, the animals were subcutaneously immunized with ovalbumin to assess their specific immune response. The different diets did not affect animal performance and had minimal effect on hematological and biochemical blood parameters. By contrast, DON and FB induced histopathological lesions in the liver, the lungs and the kidneys of exposed animals. The liver was significantly more affected when the two mycotoxins were present simultaneously. The contaminated diets also altered the specific immune response upon vaccination as measured by reduced anti-ovalbumin IgG level in the plasma and reduced lymphocyte proliferation upon antigenic stimulation. Because cytokines play a key role in immunity, the expression levels of IL-8, IL-1beta, IL-6 and macrophage inflammatory protein-1beta were measured by RT-PCR at the end of the experiment. The expression of these four cytokines was significantly decreased in the spleen of piglets exposed to multi-contaminated diet. CONCLUSION: Taken together, our data indicate that ingestion of multi-contaminated diet induces greater histopathological lesions and higher immune suppression than ingestion of mono contaminated diets. PMID- 21259431 TI - Accurate analysis of trace pentachlorophenol in textiles by isotope dilution liquid chromatography-mass spectrometry. AB - A highly accurate method for measuring pentachlorophenol (PCP) concentrations in textile samples was developed. This highly accurate method for the analysis of textile samples is valuable, given the inherent challenges associated with the complexity of the sample matrix. This method can be applied to certify the concentration of pentachlorophenol in textile CRMs. A measurement procedure based on isotope dilution liquid chromatography-isotope dilution mass spectrometry (LC IDMS) was developed. Samples were pretreated with acid and then with n-hexane. Excellent precision was obtained. The validated concentration ranges for the method were 1.0-50 ng/g, the LOD was 1.0 ng/g, and the LOQ was 5.0 ng/g. The precision of this method is in the range of 0.80-1.40%. The method can trace to mass. PMID- 21259432 TI - Determination of polar impurities in biodiesels using solid-phase extraction and gas chromatography-mass spectrometry. AB - This paper reports on a method for development and validation for simultaneous characterization and determination of oxygenated polar impurities--free fatty carboxylic acids (FFAs), partial glycerides (monoacylglycerides, MGs), residual glycerol and free sterols--in various biodiesels based on the combination of solid-phase extraction (SPE), silylation and GC/MS technologies. The effects of various SPE and silylation conditions on the method recoveries were evaluated. Using this integrated SPE-GC/MS method, 38 target polar compounds (13 FFAs, 17 glycerides and 8 sterols) in 9 biodiesels derived from 4 different feedstocks were successfully separated and quantified. It was found that the carbon chain length of FFAs was ranged from C(6) to C(24), with C(16) and C(18) being the most abundant in all biodiesels. The total FFAs concentration was consistent with the acid values (AVs) measured by standard method ASTM D974-04. MG congeners with carbon number of 18 (mono-C18) were most abundant in the biodiesel samples, followed by mono-C(16) and free glycerol. beta-Sitosterol and campesterol were found to be the prevailing phytosterols in all pure vegetable oil-based biodiesels, while brassicasterol and stigmasterol was only significant in the biodiesel from canola oil and soybean oil, respectively, and abundant cholesterol was only detected in animal fat-based biodiesels. PMID- 21259433 TI - Separation and purification of ergosterol and stigmasterol in Anoectochilus roxburghii (wall) Lindl by high-speed counter-current chromatography. AB - Ergosterol and stigmasterol are the most common phytosterols in the traditional Chinese medicine. They are two major sterol compounds in Anoectochilus roxburghii (wall) Lindl (A. roxburghii) and have been proved to have many important biological activities. A method by using high-speed counter-current chromatography (HSCCC) has been successfully developed for separation and purification of ergosterol and stigmasterol in A. roxburghii simultaneously in this paper. The optimum conditions used in this method were as follows: The two phase solvent system consisted of n-hexane-ethylacetate-butanol-methanol-water (3.5:0.3:0.5:2.5:0.3, v/v); the rotation speed was 900 rpm; the flow rate of the lower phase was 1.5 mL/min. About 36.5 mg of ergosterol and 43.6 mg of stigmasterol were obtained from 100 g of A. roxburghii. The purity of ergosterol and stigmasterol was examined to be 92.0 and 95.5%, respectively, by using HPLC. The chemical structures of these components were identified by UV spectra, FT-IR, MS, (1) H-NMR and (13) C-NMR. The results demonstrated that high-speed counter current chromatography was a feasible method to separate and purify ergosterol and stigmasterol from the herb. This separation and purification method was more effective than many other conventional techniques. PMID- 21259434 TI - Establishment of A431 cell membrane chromatography-RPLC method for screening target components from Radix Caulophylli. AB - We describe here an analytical method of A431 cell membrane chromatography (A431/CMC) (CMC, cell membrane chromatography) combined with RPLC for recognition, separation, and identification of target components from traditional Chinese medicines (TCMs) Radix Caulophylli. The A431 cells with high expressed epidermal growth factor receptor (EGFR) were used to prepare the stationary phase in the CMC model. Retention fractions on the A431-CMC model were collected using an automated fraction collection and injection module (FC/I). Each fraction was analyzed by RPLC under the optimized conditions. Gefitinib and erlotinib were used as standard compounds to investigate the suitability and reliability of the A431 cell membrane chromatography-RPLC method prior to screening target component from Radix Caulophylli total alkaloids. The results indicated that caulophine and taspine were the target component acting on the epidermal growth factor receptor. This method could be an efficient way in drug discovery using natural medicinal herbs as a source of novel compounds. PMID- 21259435 TI - Exploring the elution mechanism of selenium species on liquid chromatography. AB - In the present work, the chromatographic behavior of eight selenium species, namely selenites (Se(IV)), selenates (Se(VI)), seleno-DL-methionine (Se-Met), selenocystine (Se-Cyst), selenocystamine (Se-CM), selenourea (Se-U), dimethylselenide ((CH(3))(2) Se) and dimethyldiselenide ((CH(3))(2) Se(2)), was investigated under different stationary and mobile phase conditions, in an effort to unravel secondary interferences in their underlying elution mechanism. For this purpose, two end-capped and a polar-embedded reversed-phase stationary phases were employed using different mobile phase conditions. Retention factors (log k(w)) were compared with octanol-water distribution coefficients (log D) as well as with log k(w) values on two immobilized artificial membrane (IAM) columns and two immobilized artificial plasma proteins stationary phases, obtained in our previous work. The role of electrostatic interactions was confirmed by introducing the net charge of the investigated Se species as an additional term in the log k(w)/log D interrelation, which in most cases proved to be statistically significant. Principal component analysis of retention factors on all stationary phases and octanol-water log D values, however, showed that the elution of the investigated selenium species is mainly governed by partitioning mechanism under all different chromatographic conditions, while the pH of the mobile phase and the special column characteristics have only a minor effect. PMID- 21259436 TI - Adhesion of preosteoblasts and fibroblasts onto poly(pentafluorostyrene)-based glycopolymeric films and their biocompatibility. AB - An efficient and metal-catalyst free method of glycopolymer synthesis via thiol/para-fluorine "click" reaction was used to graft acetylated 1-thio-beta-D glucopyranose and 1-thio-beta-D-galactopyranose onto a homopolymer of pentafluorostyrene (PFS) as well as onto a block copolymer of styrene and PFS. Subsequent deprotection of the carbohydrate moieties yielded well-defined, sugar modified polymers (PDI < 1.2). The prepared polymers were not cytotoxic against 3T3 fibroblasts and MC3T3-E1 preosteoblasts. Furthermore, the water-insoluble copolymers were drop-cast and examined as synthetic biocompatible coatings on poly(propylene) substrates for culturing the investigated cell types. Both fibro- and preosteoblasts showed stable adhesion and proliferation on the glycopolymer coated surfaces. PMID- 21259437 TI - Low thrombogenicity coating of nonwoven PET fiber structures for vascular grafts. AB - Vascular PET grafts (Dacron) have shown good performance in large vessels (>= 6 mm) applications. To address the urgent unmet need for small-diameter (2-6 mm) vascular grafts, proprietary high-compliance nonwoven PET fiber structures were modified with various PEG concentrations using PVA as a cross-linking agent, to fabricate non-thrombogenic mechanically compliant vascular grafts. The blood compatibility assays measured through platelet adhesion (SEM and mepacrine dye) and platelet activation (morphological changes, P-selectin secretion, and TXB2 production) demonstrate that functionalization using a 10% PEG solution was sufficient to significantly reduce platelet adhesion/activation close to optimal literature-reported levels observed on carbon-coated ePTFE. PMID- 21259438 TI - Polyaspartamide-graft-polymethacrylate nanoparticles for doxorubicin delivery. AB - A new PHEA-IB-PMANa(+) copolymer has been synthesized and its pH-induced self assembly has been investigated in an aqueous medium. PHEA-IB-PMANa+ formed nanoparticles with diameters from 25 to 50 nm upon protonation of the carboxylic acid moieties dislocated along the grafted polymethacrylate sodium salt side chains. The physico-chemical characterization of the nanoparticles was performed using light scattering, zeta-potential measurements, SEM, and AFM. Doxorubicin loaded nanoparticles were prepared and drug release profiles were evaluated under conditions mimicking physiological media. A biological characterization was carried out by testing the cytotoxicity on Caco-2 cells, and cellular uptake on mouse monocyte macrophage (J774 A.1) and Caco-2 cells. PMID- 21259439 TI - Single-chain antibody fragment production in Pichia pastoris: Benefits of prolonged pre-induction glycerol feeding. AB - Secretory production of a single-chain antibody fragment (scFv) by recombinant Pichia pastoris using the methanol inducible AOX1 promoter is limited biochemically by retarded secretion, and economically by the high demand for pure oxygen. To address the problem, the adaptation phase with growth-limiting feeding of glycerol before the production phase was optimized. In a standard procedure with a short glycerol-feeding phase before induction, scFv accumulated in the supernatant only after 15 h. Conversely, scFv started to appear immediately in the medium upon methanol induction when the glycerol-feeding phase was extended to 18 h. Interestingly, despite a significantly lower cell density in the cultivation with extended glycerol feeding, the same amount of functional product of 300 mg/L was obtained about 30 h after the start of glycerol feeding with both methods. mRNA analysis revealed that the higher and faster production of the product was related to longer lasting induction of the scFv mRNA. Additional effects of a better adaptation of the secretion machinery may be suggested by higher expression of unfolded protein response-related genes KAR2 and PDI. A clear benefit of the longer glycerol-feeding phase was a 75% reduction of the consumption of both pure oxygen and methanol, and a significantly lower cell density, which would be beneficial for down-stream purification of the product. PMID- 21259440 TI - Ultrasonication on a microfluidic chip to lyse single and multiple Pseudo nitzschia for marine biotoxin analysis. AB - We present a microfluidic platform, which provides a simple and efficient means for handling and processing Pseudo-nitzschia, a neurotoxin-producing marine algae. Currently, analyzing the production of such toxins is complicated by multiple environmental factors and high variability among individual Pseudo nitzschia species. To address this issue, we developed a device that can precisely trap single and multiple cells for subsequent lysis to extract relevant intracellular molecules. Our results show a cell trapping efficiency of up to 96%, which is achieved by hydrodynamic flow focusing. Additionally, complete cell lysis via ultrasonication can be accomplished within a few seconds. This platform can be applied to other algae and non-algae cell types with minimal modification, thus providing a valuable tool for studying biological intracellular mechanisms at the single and multi-cell level. PMID- 21259442 TI - Cellular uptake of Poly-(D,L-lactide-co-glycolide) (PLGA) nanoparticles synthesized through solvent emulsion evaporation and nanoprecipitation method. AB - Poly-(D,L-lactide-co-glycolide) (PLGA) nanoparticles have been widely studied for drug delivery. The aim of this study is to determine how cellular uptake of these nanoparticles is influenced by different surface properties, incubation time, particle concentration and cell types. Spherical coumarin-6 loaded PLGA nanoparticles with a size of about 100 nm were synthesized through solvent emulsion evaporation and nanoprecipitation methods. In vitro cellular uptake efficiency was determined using human bronchial epithelial cells (BEAS-2B) and murine monocyte-derived macrophage (RAW264.7) cells. PLGA nanoparticles were incubated with these cells in a concentration range of 10-300 MUg/ml for different time periods. The results show that cellular uptake decreased for nanoparticles surface coated with PVA surfactant and was especially limited for severely aggregated particles. At higher particle concentration, the total amount of particles taken up by cells increased while the uptake efficiency decreased. In addition, cells could take up more particles with longer incubation time, although the uptake rate decreased gradually with time. Finally, RAW264.7 cells show increased uptake compared to BEAS-2B cells. The information drawn from this study would provide important clues on how nanomaterials interact with cells and how these interactions can influence biocompatibility or toxicity. PMID- 21259441 TI - Modular bioreactor for primary human hepatocyte culture: medium flow stimulates expression and activity of detoxification genes. AB - Down-regulation of detoxification genes, notably cytochrome P450 (CYPs), in primary hepatocyte cultures is a long-standing and major concern. We evaluated the influence of medium flow in this model. Hepatocytes isolated from 12 different liver donors were cultured either in a multichamber modular bioreactor (MCmB, flow rate 250-500 MUL/min) or under standard/static conditions, and the expression of 32 genes, enzyme activities and biological parameters were measured 7-21 days later. mRNA expression of genes involved in xenobiotic/drug metabolism and transport, including CYP1A1, 1A2, 2B6, 2C9, 3A4 (and activities for some of them), UDP-glucuronosyltransferase (UGT) 1A1, UGT2B4, UGT2B7, glutathione S transferase (GSTalpha), and multidrug resistance protein 1 (MDR1) and MRP2, were specifically up-regulated by medium flow as compared with static controls in all cultures tested. In 2-week-old cultures, expression of detoxification genes reached levels close to or higher than those measured in freshly isolated hepatocytes. In contrast, CYP2D6 and most of other tested genes were not affected by medium flow. We conclude that medium flow specifically interferes with, and up regulates, the activity of xenosensors and/or the expression of detoxification genes in primary human hepatocytes. Down-regulation of detoxification genes in conventional (static) cultures is therefore partly a consequence of the absence of medium circulation. PMID- 21259443 TI - A magnetic adsorbent-based process for semi-continuous PEGylation of proteins. AB - A semi-continuous magnetic particle-based process for the controlled attachment of PEG (PEGylation) to proteins is described for the first time. Trypsin and 2 kDa mono-activated PEG were used to systematically develop the steps in the process. Proof of concept was shown in a microfluidics system to minimize reagent consumption. Two streams containing (i) 1.2 g/L trypsin and (ii) 4 g/L magnetic adsorbents derivatized with the reversible affinity ligand benzamidine were pumped into a pipe reactor. At the exit, a third solution of activated PEG (0-40 g/L) was introduced and the solutions immediately fed into a second reactor. Upon exiting, the mixture was combined in a third reactor with a fourth stream of free amine groups to stop the reaction (50 mM lysine). The mixture continued into a high-gradient magnetic separator where magnetic supports, with PEGylated trypsin still attached, were captured and washing and elution steps were subsequently carried out. Analysis of the conjugates (with SDS-PAGE & LC-MS) showed that the extent of PEGylation could be controlled by varying the reaction time or PEG concentration. Furthermore, the PEG-conjugates had higher enzyme activity compared to PEGylation of non-immobilized trypsin. PMID- 21259444 TI - 1-(3-biaryloxy-2-oxopropyl)indole-5-carboxylic acids and related compounds as dual inhibitors of human cytosolic phospholipase A2alpha and fatty acid amide hydrolase. AB - Cytosolic phospholipase A2alpha (cPLA2alpha) and fatty acid amide hydrolase (FAAH) are enzymes that have emerged as attractive targets for the development of analgesic and anti-inflammatory drugs. We recently reported that 1-[3-(4 octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (5) is a dual inhibitor of cPLA2alpha and FAAH. Structure-activity relationship studies revealed that substituents at the indole 3- and 5-positions and replacement of the indole scaffold of this compound by other heterocycles strongly influences the inhibitory potency against cPLA2alpha and FAAH, respectively. Herein we report the effect of variation of the 4-octyl residue of 5 and an exchange of its carboxylic acid moiety by some bioisosteric functional groups. Several of the compounds assayed were favorably active against both enzymes, and could therefore represent agents with improved analgesic and anti-inflammatory qualities in comparison with selective cPLA2 alpha and FAAH inhibitors. PMID- 21259446 TI - Enhanced bioanalyte detection in waveguide confined Raman spectroscopy using wavelength modulation. AB - Waveguide confined Raman spectroscopy (WCRS) incorporates a fibre based Raman detection system in a microfluidic platform enabling the spectroscopic detection of analyte. It offers the possibility to develop portable, alignment free devices for bio-analyte sensing with minimal sample preparation. Ultimate sensitivity is limited by the fibre auto-fluorescence background. Here we report enhanced bio analyte detection sensitivity by combining WCRS with continuous wavelength modulation technique. We used urea as a model analyte and the modulation parameters have been optimized to maximize the sensitivity of the device. PMID- 21259445 TI - Pyrido[1,2-a]benzimidazole-based agents active against tuberculosis (TB), multidrug-resistant (MDR) TB and extensively drug-resistant (XDR) TB. AB - The struggle against tuberculosis (TB) is still far from over. TB, caused by Mycobacterium tuberculosis, is one of the deadliest infections worldwide. Co infection with human immunodeficiency virus (HIV) and the emergence of multidrug resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR TB) strains have further increased the burden for this disease. Herein, we report the discovery of 2-(4-chlorobenzyl)-3-methyl-1-oxo-1H,5H-pyrido[1,2 a]benzimidazole-4-carbonitrile as an effective antitubercular agent and the structural modifications of this molecule that have led to analogues with improved potency and lower toxicity. A number of these derivatives were also active at sub-micromolar concentrations against resistant TB strains and devoid of apparent toxicity to Vero cells, thereby underscoring their value as novel scaffolds for the development of new anti-TB drugs. PMID- 21259447 TI - Soybean oil-isosorbide-based waterborne polyurethane-urea dispersions. AB - A series of soybean oil-based amide diol-isosorbide waterborne polyurethane-urea (PUU) dispersions have been successfully prepared, with amounts of isosorbide ranging from 0 to 20 wt % of the total diol content. The thermal and mechanical properties of the resulting PUU films have been characterized by dynamic mechanical analysis, differential scanning calorimetry, thermogravimetric analysis, and mechanical testing. The results reveal that the glass transition temperature is increased with increased amounts of isosorbide, and the mechanical properties are improved significantly with the incorporation of isosorbide. For example, the Young's modulus increases from 2.3 to 63 MPa and the ultimate tensile strength increases from 0.7 to 8.2 MPa when the isosorbide amount is increased from 0 to 20 wt %. The thermal stability decreases slightly with the incorporation of isosorbide. This work provides a new way of utilizing biorenewable materials, such as isosorbide and a soybean oil-based amide diol, for the preparation of high-performance polyurethane-urea coatings. PMID- 21259448 TI - My body belongs to me (not my family!). PMID- 21259450 TI - Aeration properties of a new sleeping surface for infants. AB - BACKGROUND: Prone sleeping position, use of soft mattresses and head covering by bedclothes are known risk factors for sudden infant death syndrome (SIDS). Rebreathing carbon dioxide (CO(2) ) may be a possible mechanism or a confounding factor of SIDS. OBJECTIVE: To compare the aeration properties of a new concept of infant sleeping surface (Net) to three commercial mattresses advertised to improve aeration and to two standard infant mattresses. DESIGN: Two experiments were performed: (I) A container (head box), filled with 7% CO(2) mixture, was opened to the mattress to allow gas mixture to passively diffuse outside and equilibrate with the surrounding room air. (II) Simulation of normal breathing of an infant, using a unidirectional reciprocal syringe, to determine CO(2) accumulation within the head box. METHODS: CO(2) concentrations in the head box were continuously measured until CO(2) levels fell below 1% or for 5 min (experiment I), or until CO(2) accumulation levels plateaued or for 6 min (experiment II). RESULTS: The Net had a significantly faster rate of CO(2) elimination (88.5 +/- 4.6 and 91.9 +/- 0.9 sec, Net alone and when covered with a sheet, respectively) compared to 238.3 +/- 14.2 sec to 387.8 +/- 7.9 sec for the other mattresses (P < 0.001). Only the Net was able to prevent CO(2) accumulation with maximal CO(2) levels (0.56 +/- 0.03% and 1.16 +/- 0.05%; Net alone and when covered with a sheet, respectively) significantly lower than the range of 4.6 6.3% for the other mattresses (P < 0.001). CONCLUSIONS: The new sleeping surface exhibited significantly better aeration properties in dispersing CO(2) and in preventing its accumulation. PMID- 21259449 TI - Screening for symptoms of depression and anxiety in adolescents and young adults with cystic fibrosis. AB - BACKGROUND: Although studies have assessed symptoms of depression and anxiety in individuals with cystic fibrosis (CF), few have been conducted since the advent of new medical treatments (e.g., nebulized antibiotics, ThAIRpy Vest). Study objectives were to: (1) document symptoms of depression and anxiety for adolescents and young adults with CF and compare with normative values, (2) examine the associations among depressive/anxiety symptoms and gender, age, lung function, and body mass index, and (3) determine the relations between adolescent and caregiver symptoms of depression and anxiety. METHODS: Patients and caregivers completed the Hospital Anxiety and Depression Scale (HADS) anytime (e.g., beginning or end) during routine CF clinic appointments. RESULTS: Participants included 59 adolescents/young adults with CF (M(age) = 15.8 years, 54% female, 98% Caucasian, M(FEV1% predicted) = 84.6) and caregivers of 40 adolescents. Although symptom scores were in the normative range for patients with CF (M(Depression) = 2.27 and M(Anxiety) = 5.59), 3% and 32% exhibited clinically elevated symptoms of depression and anxiety, respectively. Symptoms of depression and anxiety were significantly associated with age (r = 0.28, 0.36). Symptoms of depression and anxiety were also positively correlated (r = 0.48). Females endorsed higher anxiety symptoms than males. While adolescent and caregiver anxiety scores were not related, higher caregiver depressive symptoms were associated with older patient age and worse lung function. CONCLUSIONS: Data from the current study suggest low levels of depressive symptoms and substantial levels of anxiety symptoms in adolescents and young adults with CF. Consistent with prior literature, depressive symptoms appear higher in older patients and are significantly associated with anxiety symptoms. Caregiver symptomology appears to be more affected by an adolescent's health status, suggesting a need to screen caregivers when health begins to decline. PMID- 21259452 TI - Notes on the reports of the Royal commission on divorce and matrimonial causes. PMID- 21259451 TI - Notes eugeniques. PMID- 21259453 TI - Notes on the present working of the mental deficiency act. PMID- 21259454 TI - The eugenic field. PMID- 21259455 TI - Some moral aspects of eugenics. PMID- 21259457 TI - Psychology of parenthood. PMID- 21259456 TI - Editorial and other notes. PMID- 21259459 TI - Eugenics education society: its origin and work. PMID- 21259458 TI - Poor-law commission report. PMID- 21259460 TI - Eugenics and national efficiency. PMID- 21259462 TI - Editorial notes. PMID- 21259461 TI - Eugenics and crime. PMID- 21259463 TI - Eugenic qualities of primary importance. PMID- 21259464 TI - Can the school prepare for parenthood? PMID- 21259465 TI - I. The feeble-minded and voluntary effort. PMID- 21259467 TI - Editorial notes. PMID- 21259466 TI - II. The feeble-minded-a social danger. PMID- 21259468 TI - Note on the effects of small and persistent influences. PMID- 21259469 TI - Selection in marriage. PMID- 21259470 TI - Eugenics and the church. PMID- 21259471 TI - Adolescent girlhood under modern conditions, with special reference to motherhood. PMID- 21259472 TI - Eugenics and the superman: A racial science, and a racial religion. PMID- 21259473 TI - Race betterment: the nation's duty. PMID- 21259474 TI - The sterilisation of the unfit. PMID- 21259476 TI - Editorial notes. PMID- 21259475 TI - Discussion. PMID- 21259477 TI - Eugenics and pauperism. PMID- 21259478 TI - Education in sex hygiene. PMID- 21259479 TI - Racial poisons: 1. Venereal disease. PMID- 21259480 TI - Eugenic ideals for womanhood. PMID- 21259481 TI - Primitive eugenics. PMID- 21259482 TI - Editorial notes. PMID- 21259483 TI - The possible eugenic bearing of certain experiments with poultry. PMID- 21259484 TI - Racial poisons, II., alcohol. PMID- 21259485 TI - Eugenics and military service. PMID- 21259486 TI - Marriage laws and statutory experiments in eugenics in the United States. PMID- 21259487 TI - National self-selection. PMID- 21259488 TI - Walt Whitman as the poet of good breeding. PMID- 21259489 TI - Socialism. PMID- 21259491 TI - Editorial notes. PMID- 21259490 TI - The necessity for a national eugenic survey. PMID- 21259492 TI - War and manhood: Address given in Boston, July 4th, 1910. PMID- 21259493 TI - Editorial notes. PMID- 21259494 TI - Section I.-The eugenic principle in poor law administration. PMID- 21259495 TI - Section II.-The eugenic principle and the treatment of the feeble-minded. PMID- 21259496 TI - Section III.-Investigation into pauper family histories. PMID- 21259498 TI - Corrections for chart. PMID- 21259497 TI - Key to charts. PMID- 21259499 TI - Some examples of poor law eugenics. PMID- 21259500 TI - The majority report. PMID- 21259501 TI - The minority report. PMID- 21259502 TI - Editorial notes. PMID- 21259503 TI - Heredity and insanity. PMID- 21259504 TI - Woman's progress in relation to eugenics. PMID- 21259505 TI - Eugenics and deaf-mutism. PMID- 21259506 TI - The eugenics of migrants. PMID- 21259507 TI - Memoir. PMID- 21259508 TI - Methods and results of the Galton laboratory for national eugenics. PMID- 21259509 TI - The influence of a tropical climate on europeans. PMID- 21259510 TI - A study in degeneracy. PMID- 21259511 TI - Heredity of feeble-mindedness. PMID- 21259512 TI - Crime and eugenics in America. PMID- 21259513 TI - Heredity and destitution. PMID- 21259515 TI - Lead poisoning and the race. PMID- 21259514 TI - The aristocracy of infancy and the conditions of its birth. PMID- 21259516 TI - Eugenics and future human progress. PMID- 21259517 TI - Heredity and the jew. PMID- 21259518 TI - The influence of parental age on offspring. PMID- 21259519 TI - Thoughts on eugenics. PMID- 21259520 TI - Suggestions for the utilisation of bye-products by medical officers of health. PMID- 21259521 TI - Methods of research. PMID- 21259522 TI - The relation of eugenics to economics. PMID- 21259523 TI - Medical marriage certificates: A suggestion from New Zealand. PMID- 21259524 TI - Heredity and education : A plea for a national policy. PMID- 21259525 TI - Genetics and eugenics. PMID- 21259526 TI - Mendelian heredity in man. PMID- 21259527 TI - First steps towards eugenic reform. PMID- 21259528 TI - The hereditary tendency to twinning. With some observations concerning the theory of heredity generally: Part I. PMID- 21259529 TI - Nature and nurture.-A study in conditions. PMID- 21259531 TI - Marriage regulation and national family records. PMID- 21259532 TI - Immunity from disease considered in relation to eugenics. PMID- 21259533 TI - The eugenic appeal in moral education. PMID- 21259534 TI - American methods of introducing eugenic ideas into elementary schools. PMID- 21259535 TI - The inheritance of certain human abnormalities. PMID- 21259536 TI - The hereditary tendency to twinning. With some observations concerning the theory of heredity generally: Part II. PMID- 21259537 TI - The inheritance of mental characters. PMID- 21259538 TI - Hair and its heredity. PMID- 21259539 TI - Infant mortality and its administrative control. PMID- 21259540 TI - Women and eugenics. PMID- 21259541 TI - Insurance research and eugenics. PMID- 21259543 TI - Divorce and eugenics. PMID- 21259542 TI - Legal certificates of health before marriage: Personal health-declaration versus medical examination. PMID- 21259545 TI - The standardization of pedigrees: A recommendation. PMID- 21259544 TI - Human fertility. PMID- 21259546 TI - The eugenic ideal. PMID- 21259547 TI - How the difficulties in teaching eugenics may be overcome. PMID- 21259548 TI - How the difficulties of teaching eugenics in schools had been met. PMID- 21259549 TI - Discussion at morning session. PMID- 21259550 TI - Racial responsibility as a factor in the formation of character. PMID- 21259551 TI - The eugenic ideal as a factor in the formation of character. PMID- 21259552 TI - Method of introducing the eugenic ideal into schools. PMID- 21259553 TI - Afternoon discussion and passing of resolution. PMID- 21259554 TI - Difficulties in introducing the subject of eugenics into the elementary schools. PMID- 21259555 TI - The influence of disease upon racial efficiency and survival. PMID- 21259556 TI - The effect of economic conditions on the birth-rate. PMID- 21259557 TI - French commission on depopulation. PMID- 21259558 TI - Heredity and environment. PMID- 21259560 TI - Eugenics and public health. PMID- 21259559 TI - Inheritance of fecundity. PMID- 21259561 TI - The mental deficiency bill. PMID- 21259562 TI - The cost of degeneracy: Being part of the annual presidential address. PMID- 21259563 TI - The eugenics of war. PMID- 21259564 TI - A criticism of eugenics. PMID- 21259565 TI - Depopulation and eugenics-part I. PMID- 21259566 TI - The inferior quality of the first-born children. PMID- 21259567 TI - Heredity and environment. PMID- 21259568 TI - Heredity and environment. PMID- 21259569 TI - Depopulation. PMID- 21259570 TI - Eugenics and the Sunday school teacher. PMID- 21259571 TI - Medical marriage certificates. PMID- 21259572 TI - Eugenics and venereal disease. PMID- 21259573 TI - Eugenics as a branch of medical sociology. PMID- 21259574 TI - Psychology in the service of eugenics. PMID- 21259575 TI - Some hopes of a eugenist. PMID- 21259576 TI - Our critic criticised. PMID- 21259578 TI - Galton day. PMID- 21259577 TI - Depopulation and eugenics. Part II. PMID- 21259579 TI - Recent eugenic legislation in U.S.A. PMID- 21259580 TI - The alleged inferiority of the first-born. PMID- 21259581 TI - Francis Galton. PMID- 21259582 TI - A contribution to the biology of sex. PMID- 21259583 TI - The measurement of intelligence by the binet tests: Part I. PMID- 21259584 TI - Primogeniture and abnormality. PMID- 21259585 TI - Deafness and its prevention. PMID- 21259586 TI - Consanguineous marriages. PMID- 21259587 TI - The measurement of intelligence by the binet tests: Part II. PMID- 21259588 TI - The problem of the sex-ratio. PMID- 21259590 TI - Eugenics and the war. PMID- 21259589 TI - Education and eugenics. PMID- 21259591 TI - The habitual criminal. PMID- 21259592 TI - The heredity of abilities. PMID- 21259593 TI - Eugenic marriage bills in the Scandinavian countries. PMID- 21259594 TI - Alteration of autumn programme. PMID- 21259595 TI - Eugenics and the war. PMID- 21259596 TI - The measurement of intelligence. PMID- 21259597 TI - American eugenics. PMID- 21259598 TI - The measurement of intelligence. PMID- 21259599 TI - The employment of married women. PMID- 21259600 TI - Eugenics and war: The second Galton lecture. PMID- 21259601 TI - The causes of rise and fall in the population of the ancient world. PMID- 21259602 TI - Cuenot on preadaptation: A criticism. PMID- 21259603 TI - Eugenics and the poor law. PMID- 21259604 TI - The problem of our racial and national safety. PMID- 21259605 TI - Eugenics during and after the war. PMID- 21259606 TI - The influence of racial admixture in Egypt. PMID- 21259607 TI - The evolution of sexual preference. PMID- 21259608 TI - Mr. Luther Burbank-his methods and discoveries. PMID- 21259609 TI - Law and eugenics. PMID- 21259610 TI - Eugenics and the doctrine of the super-man. PMID- 21259611 TI - Some aspects of immigration to the United States in relation to the future American race. PMID- 21259612 TI - War and the breed. PMID- 21259613 TI - The study of heredity. PMID- 21259614 TI - Eugenic problems after the war: Galton lecture. PMID- 21259616 TI - "Biometrika.". PMID- 21259615 TI - The biological theory of nurture. PMID- 21259617 TI - An American experiment in prison reform. PMID- 21259619 TI - Ultimate victory. PMID- 21259618 TI - War and the breed. PMID- 21259620 TI - The study of heredity: Part II. PMID- 21259621 TI - War and the breed. PMID- 21259622 TI - Heredity and environment: A warning to eugenists. PMID- 21259623 TI - The theory of sex. PMID- 21259624 TI - The eugenics education society and venereal disease. PMID- 21259625 TI - The study of heredity: (Part III.). PMID- 21259626 TI - Eugenics and educational reform. PMID- 21259627 TI - Quality not quantity. PMID- 21259628 TI - The declining birth-rate: its causes and effects. PMID- 21259629 TI - The study of heredity: (Part IV.). PMID- 21259630 TI - Galton anniversary: The disabled sailor and soldier and the future of our race. PMID- 21259632 TI - Birth control and eugenics. PMID- 21259631 TI - A study in delinquency: A preliminary study of twelve families. PMID- 21259633 TI - Mental development of the South African native. PMID- 21259634 TI - A note on eugenics. PMID- 21259635 TI - Comments and criticisms. PMID- 21259636 TI - Save the children: Report on the physical welfare of mothers and children in England and Wales. PMID- 21259637 TI - The dysgenic effects of venereal diseases. PMID- 21259639 TI - Comments and criticisms. PMID- 21259638 TI - Teaching in schools, training colleges, and colleges. PMID- 21259640 TI - Disabled soldiers and school life. PMID- 21259641 TI - Eugenic aspects of national baby week. PMID- 21259642 TI - The eugenic principle in social reconstruction. PMID- 21259643 TI - Positive eugenics. PMID- 21259644 TI - Adaptation and adaptability. PMID- 21259645 TI - War and the stature of the population. PMID- 21259646 TI - Some recent documents on infant mortality and some reflections thereon. PMID- 21259647 TI - Comments and criticisms. PMID- 21259648 TI - Eugenics and national baby week. PMID- 21259649 TI - Eugenics and national baby week. PMID- 21259651 TI - Eugenics and national baby week. PMID- 21259650 TI - Eugenics and national baby week. PMID- 21259652 TI - Emigration. PMID- 21259654 TI - Reconstruction and public health. PMID- 21259653 TI - Divorce and illegitimacy. PMID- 21259655 TI - The eugenics education society and social reconstruction. PMID- 21259656 TI - Science teaching in secondary schools. PMID- 21259657 TI - Comments and criticisms. PMID- 21259659 TI - Divorce and the birth-rate. PMID- 21259658 TI - The eugenics of baby week. PMID- 21259660 TI - The mental deficiency act. PMID- 21259661 TI - The education bill and eugenics. PMID- 21259662 TI - Social legislation in America. PMID- 21259664 TI - Comments and criticisms. PMID- 21259663 TI - Niceforo on the highly superior German. PMID- 21259665 TI - The matrimonial causes bill. PMID- 21259666 TI - Correspondence. PMID- 21259667 TI - Environment as a factor in evolution. PMID- 21259668 TI - Save the children: Report on the physical welfare of mothers and children in Scotland. PMID- 21259669 TI - War and the balance of the sexes. PMID- 21259670 TI - Eugenic considerations in legislation. PMID- 21259671 TI - Emigration after the war. PMID- 21259672 TI - Salvation army emigration. PMID- 21259673 TI - On the question of careless marriages. PMID- 21259674 TI - Women citizens' association. PMID- 21259675 TI - The eugenic and social influence of the war. PMID- 21259677 TI - The sex ratio and emigration. PMID- 21259676 TI - The need for widespread eugenic reform during reconstruction. PMID- 21259678 TI - Some attempts towards race hygiene in France during the war. PMID- 21259679 TI - The causes of human variability. PMID- 21259680 TI - Comments and criticisms. PMID- 21259681 TI - Correspondence. PMID- 21259682 TI - Correspondence. PMID- 21259683 TI - Sterilization of degenerates and criminals considered from the standpoint of genetics. PMID- 21259684 TI - What nations and classes will prevail?: Galton lecture, February 17th, 1919. PMID- 21259685 TI - Correspondence. PMID- 21259686 TI - The sex ratio at birth. PMID- 21259687 TI - Correspondence. PMID- 21259688 TI - Correspondence. PMID- 21259689 TI - The relation of eugenics to other sciences. PMID- 21259690 TI - A school celebration for a "eugenics day.". PMID- 21259691 TI - Epilepsy: a review of "field work". PMID- 21259692 TI - The sex ratio at death. PMID- 21259694 TI - "Eugenics and imperial development.". PMID- 21259693 TI - A biologist in a new environment. PMID- 21259695 TI - Infant mortality during the war. PMID- 21259696 TI - Heredity and eugenics. PMID- 21259697 TI - The menace to the english race and to its traditions of present-day immigration and emigration. PMID- 21259699 TI - Correspondence. PMID- 21259698 TI - Memorandum on the evidence proposed to be given before the Royal commission on the income tax. PMID- 21259700 TI - Heredity and eugenics: Part II. Mental characters. PMID- 21259701 TI - Galton's place among anthropologists. PMID- 21259702 TI - Voluntary parenthood. PMID- 21259703 TI - Editorial comment on Mr. Mudge's article. PMID- 21259704 TI - Replies to Dr. Crew's arguments. PMID- 21259705 TI - Roman catholic criticism of eugenics, with reply from the president. PMID- 21259707 TI - An appeal. PMID- 21259706 TI - Cricitisms of the eugenics education society: and of Dr. Crew's article. PMID- 21259708 TI - Mental defect and prostitution. PMID- 21259709 TI - Memorandum on the consideration of heredity at the ministry of health. PMID- 21259710 TI - Criminality from the eugenic standpoint. PMID- 21259711 TI - Some aspects of eugenics and the income tax. PMID- 21259712 TI - Some birth rate problems. PMID- 21259713 TI - The fertility of the english middle classes. A statistical study. PMID- 21259715 TI - Correspondence. PMID- 21259714 TI - Fair and dark; is there a predominant type? PMID- 21259716 TI - Eugenics and religion. PMID- 21259717 TI - Evolution and the future of the human race. PMID- 21259718 TI - Some birth-rate problems. PMID- 21259720 TI - Correspondence. PMID- 21259719 TI - Birth control: a discussion. PMID- 21259722 TI - Inheritance and educability. PMID- 21259721 TI - Commonsense in racial problems. PMID- 21259723 TI - English and foreign marriage law in relation to mental disorder (Part I.). PMID- 21259725 TI - Birth control. PMID- 21259724 TI - Anglo-American university library for Central Europe (London school of economics). PMID- 21259726 TI - Eugenics versus civilization. PMID- 21259728 TI - English and foreign divorce law in relation to mental disorder. PMID- 21259727 TI - A comparative inquiry on the heredity and social conditions among certain insane, mentally defective, and normal persons. PMID- 21259730 TI - Army examinations and heredity. PMID- 21259729 TI - How should our society now strive to advance? PMID- 21259731 TI - Eugenics versus civilization. PMID- 21259732 TI - The field for eugenic reform. PMID- 21259733 TI - Army examinations and heredity. PMID- 21259735 TI - Galton centenary addresses. PMID- 21259734 TI - The danger of degeneracy. PMID- 21259736 TI - The neuroses and psychoses in relation to conscription and eugenics. PMID- 21259737 TI - Registration in relation to eugenics. PMID- 21259738 TI - Darwinian evolution of mutations. PMID- 21259739 TI - Harmonic and unharmonic crossings: Racetypes and racecrossings in Northern Norway. PMID- 21259740 TI - The danger of degeneracy: II. PMID- 21259741 TI - A guiding principle for eugenic reform. PMID- 21259742 TI - New data on the genesis of twins. PMID- 21259743 TI - The inheritance of acquired characters and its bearing on eugenic theory and practice. PMID- 21259744 TI - The reduction of the birth rate as a necessary instrument for the improvement of the race. PMID- 21259746 TI - Eugenics and the war. PMID- 21259745 TI - Some aspects of race study. PMID- 21259747 TI - Pauperism and heredity : A further report. PMID- 21259748 TI - Educability and inheritance. PMID- 21259749 TI - The true aristocracy: An address contributed to the international eugenics congress held in New York in September, 1921. PMID- 21259750 TI - Eugenics in international affairs. PMID- 21259751 TI - The evolution of the conscience in civilised communities: In special relation to sexual vices. PMID- 21259752 TI - Discussion on the inheritance of mental qualities, good and bad. PMID- 21259753 TI - Eugenic bearing of measurements of intelligence. PMID- 21259754 TI - The possible effects of germinal change upon the progress and decay of civilization. PMID- 21259755 TI - Mate selection. PMID- 21259756 TI - Observations on fecundity. PMID- 21259757 TI - The poor white in South Africa. PMID- 21259758 TI - Letter to the editor. PMID- 21259759 TI - The Galton lecture. PMID- 21259761 TI - The experimental analysis of sex. PMID- 21259760 TI - The work of the Eugenics Record Office. PMID- 21259762 TI - The new regional survey of Mexico : A study of a mixed and hybrid population. PMID- 21259763 TI - Sterilisation in America. PMID- 21259764 TI - Correspondence. PMID- 21259765 TI - Correspondence. PMID- 21259766 TI - The sub-man. PMID- 21259767 TI - The mental deficiency acts and their administration. PMID- 21259768 TI - The nucleus in relation to heredity. PMID- 21259769 TI - Correspondence. PMID- 21259770 TI - Mate selection. PMID- 21259771 TI - Birth control and eugenics in Holland. PMID- 21259772 TI - Observations on racial characteristics in England. PMID- 21259773 TI - The American eugenic society's programme. PMID- 21259774 TI - The work of tornier as affording a possible explanation of the causes of mutations. PMID- 21259775 TI - Observations on racial characteristics in England. PMID- 21259777 TI - Suggested programme of eugenic reform. PMID- 21259776 TI - Some aspects of reproduction considered in relation to eugenics. PMID- 21259778 TI - Eugenic aspects of the walworth women's welfare centre. PMID- 21259779 TI - Correspondence. PMID- 21259780 TI - Correspondence. PMID- 21259781 TI - Galton lecture. PMID- 21259782 TI - Studies in hereditary ability. PMID- 21259783 TI - The problem of eugenical sterilisation in Sweden. PMID- 21259784 TI - The racial effect of alcohol. PMID- 21259785 TI - The disappearance of culture. PMID- 21259787 TI - State certificate of marriage. PMID- 21259786 TI - The elimination of mental defect. PMID- 21259788 TI - Racial dangers of mental defect : The desirability of greatly increased institutional accommodation for mental defectives. PMID- 21259790 TI - The future of our race. PMID- 21259789 TI - Correspondence. PMID- 21259791 TI - Marriage. PMID- 21259792 TI - International biological registration. PMID- 21259793 TI - The biometrical study of heredity. PMID- 21259794 TI - Frequency of sex combinations in human families. PMID- 21259795 TI - The present position of mental deficiency under the act. PMID- 21259796 TI - The geographical aspect of eugenics. PMID- 21259797 TI - Family endowment in its bearing on the question of population. PMID- 21259798 TI - Family allowances. PMID- 21259799 TI - Correspondence. PMID- 21259801 TI - Correspondence. PMID- 21259803 TI - The influence of heredity in the etiology of tuberculosis. PMID- 21259802 TI - The ruin of Rome and its lessons for us. PMID- 21259804 TI - The work of the special school for mentally defective children. PMID- 21259806 TI - The present tendencies of population in Great Britain with respect to quantity and quality. PMID- 21259805 TI - Eugenics in America. PMID- 21259807 TI - The study of primitive races with special reference to forms of marriage. PMID- 21259808 TI - Modern marriage and monogamy. PMID- 21259809 TI - Further studies in hereditary ability. PMID- 21259811 TI - Position of eugenics in Germany. PMID- 21259810 TI - Race deterioration and practical politics. PMID- 21259812 TI - Fluctuations in natural increase in man. PMID- 21259814 TI - Report on mental deficiency in New Zealand. PMID- 21259813 TI - The relation of temperament to size of family. PMID- 21259815 TI - Correspondence. PMID- 21259816 TI - Correspondence. PMID- 21259817 TI - Expenditure on education and its effects on fertility. PMID- 21259818 TI - Genius as a biological problem. PMID- 21259819 TI - Decline in the birth-rate and "fecundability" of woman. PMID- 21259821 TI - Correspondence. PMID- 21259820 TI - The physiological factors governing the proportions of the sexes in man. PMID- 21259822 TI - Merx Plas Beggar colony: An experiment in applied eugenics. PMID- 21259823 TI - Evolution of the pre-historic races. PMID- 21259824 TI - Sterility and vitamin deficiency : Report of a lecture. PMID- 21259825 TI - Baye's theorem. PMID- 21259826 TI - Some reflections on eugenics and religion. PMID- 21259827 TI - The treatment of the congenitally unfit and of convicts by sterilization. PMID- 21259828 TI - Foundations of notable families. PMID- 21259829 TI - Social progress and racial decline. PMID- 21259830 TI - Eugenics: can it solve the problem of decay of civilizations? PMID- 21259831 TI - Correspondence. PMID- 21259832 TI - Correspondence. PMID- 21259833 TI - The eugenics policy of the society. PMID- 21259834 TI - An outline of a practical eugenic policy. PMID- 21259835 TI - Inbreeding in cattle and horses: With reference to certain effects therefrom in shorthorn cattle and clydesdale horses. PMID- 21259836 TI - Sterilization as a practical policy. PMID- 21259837 TI - The lake of haarlem as a settlement. PMID- 21259839 TI - Social selection of emigration. PMID- 21259838 TI - American emigration and eugenics. PMID- 21259840 TI - Population studies in Edinburgh. PMID- 21259841 TI - Modern eugenics. PMID- 21259842 TI - Natural selection. PMID- 21259843 TI - Anthropological studies of children. PMID- 21259844 TI - Migration in relation to racial problems. PMID- 21259845 TI - Insanity and detention. PMID- 21259846 TI - Correspondence. PMID- 21259847 TI - Mental disease in relation to eugenics: The Galton lecture. PMID- 21259848 TI - The legalization of voluntary eugenical sterilization. PMID- 21259849 TI - The mechanism of heredity and evolution. PMID- 21259850 TI - Berg's "nomogenesis." : A criticism of natural selection. PMID- 21259851 TI - Eugenic aspects of the Colwyn report. PMID- 21259852 TI - The actuarial treatment of official birth records. PMID- 21259853 TI - Habit and environment as makers of species. PMID- 21259854 TI - Darwinian interpretations. PMID- 21259855 TI - Survey of birth-rates of the world. PMID- 21259856 TI - Nature and nurture in Shakespeare's plays and elsewhere. PMID- 21259857 TI - Contribution to the fundamentals of a policy of population. PMID- 21259858 TI - The numerous families of former times. PMID- 21259860 TI - "Darwinian interpretations". PMID- 21259859 TI - Selection theory and its alternatives. PMID- 21259862 TI - The fundamental elements of the problems of population and migration. PMID- 21259861 TI - Correspondence. PMID- 21259863 TI - Race biological aspects of some problems of population. PMID- 21259864 TI - The Norwegian eugenic programme: Discussed at meetings of the eugenic society of Leningrad. PMID- 21259865 TI - Further contribution to selection theory and its alternatives. PMID- 21259866 TI - Correspondence. PMID- 21259867 TI - England to-day-and yesterday. PMID- 21259868 TI - Temperament and social class. PMID- 21259870 TI - The biology of superiority. PMID- 21259869 TI - The cost of a child. PMID- 21259871 TI - Causes of racial decay distribution of natural capacity: The need for a national stocktaking the Galton lecture, 1928. PMID- 21259872 TI - Correspondence. PMID- 21259873 TI - Natural selection-a correction. PMID- 21259875 TI - Correspondence. PMID- 21259874 TI - Correspondence. PMID- 21259876 TI - Income-tax rebates: The birth-rate and our future policy. PMID- 21259877 TI - The kin of genius: A study of the families of great men. PMID- 21259878 TI - Jews and gentiles: Their intellectual and temperamental differences. PMID- 21259879 TI - Infant welfare: And the health of schoolchildren. PMID- 21259880 TI - Natural and social selection: A 'blue-book' analysis. PMID- 21259881 TI - Work of birth control clinics. PMID- 21259882 TI - The sterilization bill: The eugenics society's first draft. PMID- 21259883 TI - Heredity and crime: Blood tests and inheritance in law. PMID- 21259884 TI - Scientific bases of birth control. PMID- 21259885 TI - The population union: Its formation, scheme, and future work. PMID- 21259886 TI - Differential birth rate analyzed: New light on causes from American figures. PMID- 21259887 TI - Correspondence. PMID- 21259888 TI - Eugenical reform of the House of Lords. PMID- 21259889 TI - The kin of genius-(II): A study of the families of great men. PMID- 21259890 TI - 'Rejuvenation' and Voronoff's racial claims. PMID- 21259891 TI - The differential birth rate changes: Stockholm 'upper' classes more fertile than the 'lower'. PMID- 21259892 TI - A Correction. PMID- 21259893 TI - Birth control-an alternative. PMID- 21259894 TI - And a criticism. PMID- 21259895 TI - Positive standards of fitness. PMID- 21259896 TI - Correspondence. PMID- 21259897 TI - Sex-ratios and marriage: Their relation to population growth and decline. PMID- 21259899 TI - Sterilization in practice: First-hand impressions of American methods and experience. PMID- 21259898 TI - The heredity of growth: Some biological aspects of school medical inspection. PMID- 21259900 TI - Major Darwin and his work. PMID- 21259901 TI - The society's coming of age: The growth of the eugenic movement. PMID- 21259902 TI - Hemilateral asymmetry in relation to cross-breeding. PMID- 21259903 TI - The physiology of inheritance: Recent work and its bearing on human problems. PMID- 21259904 TI - Our national burden of mental deficiency. PMID- 21259905 TI - Eugenics and Bernard Shaw. PMID- 21259906 TI - The reform of vital statistics: Outline of a system of national registration. PMID- 21259907 TI - Animal and human breeding: An attempt to study their common principles. PMID- 21259909 TI - The poor law and the control of mental disease. PMID- 21259908 TI - The herd instinct in animals: Its bearing on the bases of human society. PMID- 21259910 TI - The biology of growth: A review of its place in heredity and evolution. PMID- 21259911 TI - Health and prosperity in the nineteenth century. PMID- 21259912 TI - The human blood-groups: A survey of their nature and inheritance. PMID- 21259913 TI - Biological education. PMID- 21259914 TI - Balance of births and deaths. PMID- 21259915 TI - Havelock Ellis's studies. PMID- 21259916 TI - Birth control. PMID- 21259917 TI - Birth control. PMID- 21259918 TI - Birth control. PMID- 21259920 TI - The depopulation scare: A criticism of various statistical prophecies. PMID- 21259919 TI - Marriage and longevity. PMID- 21259921 TI - Human hybrids in various parts of the world. PMID- 21259922 TI - Some German population movements. PMID- 21259923 TI - Animal hybrids and progressive breeding. PMID- 21259925 TI - St. Thomas Aquinas and sterilization. PMID- 21259924 TI - Further pedigrees of ability: And an interesting link with Oliver Cromwell. PMID- 21259926 TI - Birth control questionnaire. PMID- 21259927 TI - A German point of view. PMID- 21259928 TI - Sterilization laws. PMID- 21259929 TI - The ethics of sterilization. PMID- 21259930 TI - The ethics of sterilization. PMID- 21259931 TI - The hormones controlling reproduction. PMID- 21259932 TI - "Mr. Punch" on eugenics. PMID- 21259933 TI - The 'silver ring' contraceptive. PMID- 21259935 TI - Pedigrees of disease and defect. PMID- 21259934 TI - Identical twins reared apart. PMID- 21259936 TI - Natural selection in man: And the evolution of human intelligence. PMID- 21259937 TI - A poetic apology. PMID- 21259938 TI - Eugenics as a moral ideal: The beginning of a progressive reform. PMID- 21259940 TI - The heredity of the tudors: And the common characteristics of the family. PMID- 21259939 TI - An oriental on vital statistics. PMID- 21259941 TI - The nordic myth: A critique of current racial theories. PMID- 21259942 TI - The lethal chamber proposal. PMID- 21259943 TI - A eugenic register. PMID- 21259944 TI - The individual eugenist's problem. PMID- 21259945 TI - Professor MacBride replies. PMID- 21259946 TI - Henry Twitchin, the society's benefactor. PMID- 21259947 TI - Race and cancer: An investigation of its incidence among Jews. PMID- 21259948 TI - The physical basis of mind: And the diagnosis of mental deficiency. PMID- 21259949 TI - Twins and orphans. PMID- 21259950 TI - Eugenics without mendelism: Some criticisms of current points of view. PMID- 21259951 TI - The heredity of the stewarts: A remarkably varied family. PMID- 21259952 TI - Negative eugenics. PMID- 21259953 TI - The heredity of the tudors. PMID- 21259954 TI - The heredity of the tudors. PMID- 21259956 TI - Social biology: The address at the inauguration of the new chair. PMID- 21259955 TI - The sterilization proposals: A history of their development. PMID- 21259958 TI - The general population. PMID- 21259957 TI - The size of their own and their parents' families. PMID- 21259959 TI - The present state of the nation: As deduced from recent vital statistics. PMID- 21259960 TI - Our special correspondence. PMID- 21259961 TI - Birth control information. PMID- 21259962 TI - Birth control investigation committee. PMID- 21259963 TI - Negative eugenics. PMID- 21259964 TI - Embryology and evolution. PMID- 21259965 TI - Positive eugenics in practice: An account of the first positive eugenic experiment. PMID- 21259966 TI - An Irish instance of positive eugenics. PMID- 21259968 TI - Mendelism and farm livestock: How improvement has and can be achieved. PMID- 21259967 TI - Biology and eugenics: Being a request to certain professional biologists. PMID- 21259969 TI - Race-crossing and glands: Some human hybrids and their parent stocks. PMID- 21259971 TI - Natural and social selection: 2.-In America as well as in England. PMID- 21259970 TI - On catholicism: As revealed in the latest encyclical of his holiness Pope Pius XI. PMID- 21259972 TI - Disease and defect: 2.-Amentia pedigrees from an English urban district. PMID- 21259973 TI - Warnings from nature: Or seven red flags from biology. PMID- 21259974 TI - Sir Josiah Stamp on eugenics. PMID- 21259975 TI - On in-relief for paupers. PMID- 21259976 TI - Embryology and evolution. PMID- 21259977 TI - The world population conference. PMID- 21259978 TI - Divorce and marriage reform: The address at the annual general meeting, 1931, of the eugenics society. PMID- 21259979 TI - Mathematical Darwinism: A discussion of the genetical theory of natural selection. PMID- 21259980 TI - Henry Twitchin's family history. PMID- 21259981 TI - Genetic problems in psychiatry: And their solution by the study of twins. PMID- 21259982 TI - Human sterility: A study of an unusual pedigree. PMID- 21259983 TI - Heredity and mortality: Family history in connection with life assurance. PMID- 21259984 TI - 1.-Population problems: An interim survey of the international population assembly. PMID- 21259985 TI - 2.-Some aspects of human biology: With especial reference to differential fertility. PMID- 21259987 TI - Eugenics abroad: 1. In America. PMID- 21259986 TI - 3.-Civilization and fertility: Has the reproductive power of western peoples declined? PMID- 21259988 TI - The sterilization bill. PMID- 21259989 TI - Positive eugenics in practice. PMID- 21259990 TI - Influence of pedigree cattle. PMID- 21259992 TI - Influence of pedigree cattle. PMID- 21259991 TI - The regulation of contraception. PMID- 21259993 TI - The law and sterilization. PMID- 21259994 TI - The social problem group: The president's account of the society's next task. PMID- 21259995 TI - Segregation of the fit: A plea for positive eugenics. PMID- 21259997 TI - Homogamy in fertility: An American study of the mating of like with like. PMID- 21259996 TI - Scapular types and human fitness : A study of an outward sign of biological efficiency. PMID- 21259998 TI - 2.-In Denmark. PMID- 21259999 TI - 3.-In Brazil. PMID- 21260000 TI - The regulation of contraception. PMID- 21260002 TI - AEsthetics and contraception. PMID- 21260001 TI - National economy and eugenics. PMID- 21260003 TI - War and the unfit. PMID- 21260005 TI - The genetic background of mental deficiency. PMID- 21260004 TI - On catholicism. PMID- 21260007 TI - Sterilization in Denmark: A eugenic as well as a therapeutic clause. PMID- 21260006 TI - Eugenics and education: The practices of ancient, primitive, and mediaeval societies. PMID- 21260008 TI - Eugenics abroad: 4.-In America. PMID- 21260009 TI - The insufficiency of education. PMID- 21260010 TI - The role of genetics in preventive medicine. PMID- 21260011 TI - The assessment of human temperament. PMID- 21260013 TI - "Stigmata of degeneracy". PMID- 21260012 TI - The social problem group. PMID- 21260015 TI - Eugenics and democracy. PMID- 21260014 TI - Eugenics and democracy. PMID- 21260016 TI - Eugenics and snobbery. PMID- 21260017 TI - Eugenics and snobbery. PMID- 21260018 TI - Eugenics negative and positive. PMID- 21260019 TI - Eugenics and socialism. PMID- 21260020 TI - On catholicism. PMID- 21260021 TI - On catholicism. PMID- 21260022 TI - The society's further projects. PMID- 21260023 TI - Neurology and eugenics: The role of experimental genetics in their development. PMID- 21260025 TI - Changes in family life: The questionnaire of the London school of economics. PMID- 21260024 TI - Eugenics and socialism: Their common ground and how it should be sought. PMID- 21260026 TI - The last ten years: Mrs. Hodson's record of work for eugenics. PMID- 21260027 TI - 5.-in Germany. PMID- 21260028 TI - Brain and mind. PMID- 21260029 TI - The social problem group: As illustrated by a series of East London pedigrees. PMID- 21260030 TI - Brain and mind. PMID- 21260031 TI - The social problem group. PMID- 21260033 TI - Legalizing sterilization. PMID- 21260032 TI - Eugenics and socialism. PMID- 21260034 TI - Eugenics and socialism. PMID- 21260035 TI - Practical family endowment: With especial consideration of the independent worker. PMID- 21260036 TI - The inheritance of blindness: The contribution of eugenics to the reduction of eye disease. PMID- 21260038 TI - 6.-In Holland. PMID- 21260037 TI - Sterilization in the empire: An account of the working of the Alberta act. PMID- 21260039 TI - Brain and mind. PMID- 21260040 TI - Brain and mind. PMID- 21260041 TI - Eugenics and socialism. PMID- 21260042 TI - "Preventive medicine". PMID- 21260043 TI - Eugenics and socialism. PMID- 21260044 TI - Eugenics and socialism. PMID- 21260045 TI - Family allowances: In the contemporary economic situation. PMID- 21260046 TI - Mental deficiency on merseyside : Its connection with the social problem group. PMID- 21260048 TI - 'Anticipation' in mental disease. PMID- 21260047 TI - Differential class fertility: A further report of the merseyside social survey. PMID- 21260049 TI - The inheritance of human fertility: A demonstration of its genetic basis. PMID- 21260050 TI - Sun bathing and amentia. PMID- 21260051 TI - "The inheritance of blindness"-corrigendum. PMID- 21260052 TI - Eugenic family endowment. PMID- 21260054 TI - Sir Bernard Mallet: Two appreciations. PMID- 21260053 TI - Vagrancy and amentia. PMID- 21260055 TI - Sinanthropus and other fossil men: Their relations to each other and to modern types. PMID- 21260056 TI - Mental deficiency-I: Some family histories. PMID- 21260057 TI - Mental deficiency-II: The sub-cultural group. PMID- 21260058 TI - Evolution by selection: The implications of Winter's selection experiment. PMID- 21260059 TI - Human fertility: II-a further study of German women. PMID- 21260061 TI - The physical mechanism of the human mind. PMID- 21260060 TI - Increase in mental deficiency. PMID- 21260062 TI - The english divorce law. PMID- 21260063 TI - The english divorce law. PMID- 21260064 TI - Differential fertility in Germany. PMID- 21260066 TI - The effects of controlling sex-determination. PMID- 21260065 TI - Differential fertility in Germany. PMID- 21260067 TI - A contraception museum. PMID- 21260068 TI - Sexual morality. PMID- 21260069 TI - Eugenics and capitalism. PMID- 21260071 TI - Divorce and eugenics: Some notes on their relationship. PMID- 21260070 TI - Eugenics and christianity. PMID- 21260072 TI - Abortion in Soviet Russia: Has the time come to legalize it elsewhere? PMID- 21260073 TI - Wealth and ability: Eugenics in the professions and crafts. PMID- 21260074 TI - Family endowment: I.-the development of the French and Belgian systems. PMID- 21260075 TI - Family endowment: II.-a proposal for constructive eugenics in England. PMID- 21260076 TI - Museum of contraception. PMID- 21260077 TI - The congress of genetics. PMID- 21260078 TI - Control of sex-determination. PMID- 21260079 TI - Eugenics and capitalism. PMID- 21260080 TI - Eugenics and capitalism. PMID- 21260082 TI - Eugenics and religion: Summary of a debate arranged by the eugenics society. PMID- 21260081 TI - My outlook on eugenics: The Galton lecture, Thursday, February 16th, 1933. PMID- 21260083 TI - Divorce for insanity. PMID- 21260084 TI - Eugenics and christianity. PMID- 21260085 TI - Family endowment. PMID- 21260086 TI - German eugenics propaganda. PMID- 21260087 TI - Genetics of grey hair. PMID- 21260088 TI - Protective adaptations. PMID- 21260089 TI - Protective adaptations. PMID- 21260090 TI - Mental disorders: An address to the society at the annual general meeting. PMID- 21260091 TI - Natural infertility: Factors influencing the results of contraceptive methods. PMID- 21260092 TI - A eugenic colony abroad: A proposal for South America. PMID- 21260093 TI - Eugenics & consanguineous marriages. PMID- 21260095 TI - Race mixture. PMID- 21260094 TI - Eugenics in Germany. PMID- 21260096 TI - Hereditary blindness: The report of the prevention of blindness committee. PMID- 21260097 TI - Acquired characters: Recent experimental evidence. PMID- 21260098 TI - Sterilization in Switzerland: Professor Hans Maier's address at the Royal college of surgeons. PMID- 21260100 TI - Eugenic legislation in Norway and Germany: Text of proposed laws. PMID- 21260099 TI - Eugenics abroad: VII.-In Holland. PMID- 21260101 TI - Eugenics and religion. PMID- 21260102 TI - Nazi anti-Jewish policy. PMID- 21260103 TI - Mendelian inheritance of mental deficiency. PMID- 21260104 TI - Eugenics and religion. PMID- 21260105 TI - Amentia in the East African. PMID- 21260106 TI - A subcultural family. PMID- 21260107 TI - Multiple intestinal tumours. PMID- 21260108 TI - Inheritance of acquired characters. PMID- 21260109 TI - Population control: Dr. Binnie Dunlop's address to the eugenics society. PMID- 21260110 TI - Professor McDougall's lamarckian experiment. PMID- 21260111 TI - Reception at headquarters of the society. PMID- 21260112 TI - The graz sterilization trial. PMID- 21260113 TI - Lucien March: An appreciation. PMID- 21260115 TI - Safeguards in eugenic sterilization. PMID- 21260114 TI - Sterilization: voluntary or compulsory? PMID- 21260116 TI - Sterilization in Switzerland. PMID- 21260117 TI - Legal aspects of sterilization. PMID- 21260118 TI - The treatment of ancestry in modern biographies. PMID- 21260119 TI - The genetics of intellect. PMID- 21260120 TI - Voluntary sterilization: Private member's resolution. PMID- 21260121 TI - The Kenya native. PMID- 21260122 TI - Sterilization: voluntary or compulsory? PMID- 21260123 TI - In- and out-breeding. PMID- 21260125 TI - Analysis of the Brock report. PMID- 21260124 TI - In- and out-breeding. PMID- 21260126 TI - In- and out-breeding. PMID- 21260127 TI - Eugenic influences in economics. PMID- 21260128 TI - The complex determinants of amentia. PMID- 21260129 TI - Some modern views of the human mind and its disorders. PMID- 21260130 TI - Aims and objects of the eugenics society. PMID- 21260132 TI - Genetics of intellect. PMID- 21260131 TI - The German sterilization law. PMID- 21260133 TI - German eugenics exhibition. PMID- 21260134 TI - Genetics of intellect. PMID- 21260135 TI - Sterilization a birth control method? PMID- 21260136 TI - Sterilization: voluntary or compulsory? PMID- 21260137 TI - Genetics of grey hair. PMID- 21260138 TI - Sterilization a birth control method? PMID- 21260139 TI - German eugenic legislation: An examination of fact and theory. PMID- 21260140 TI - The decline in the birth-rate: A study of the biological effects of emancipation of the peasants. PMID- 21260141 TI - The merseyside survey. PMID- 21260142 TI - The treatment of ancestry in earlier biographies. PMID- 21260143 TI - The press and eugenics: a review of reviews. PMID- 21260145 TI - Genetics of intellect. PMID- 21260144 TI - The graz sterilization trial: Judgment of the supreme court. PMID- 21260146 TI - The decline in population. PMID- 21260148 TI - Eugenics in Austria. PMID- 21260147 TI - The German sterilization law. PMID- 21260150 TI - The German sterilization law: Discussion on professor Muckermann's lecture. PMID- 21260149 TI - Parentage of defectives. PMID- 21260151 TI - The problem of maternal mortality. PMID- 21260152 TI - Eugenic legislation in Denmark. PMID- 21260153 TI - Population control in India. PMID- 21260155 TI - Decline in the birth-rate. PMID- 21260154 TI - Biometrika. PMID- 21260156 TI - Brain and mind. PMID- 21260157 TI - Eugenics in the light of population trends. PMID- 21260158 TI - Twins. PMID- 21260159 TI - Fitness for marriage. PMID- 21260160 TI - Eugenics in Norway. PMID- 21260161 TI - The problem of maternal mortality. PMID- 21260162 TI - The problem of maternal mortality. PMID- 21260163 TI - The problem of maternal mortality. PMID- 21260164 TI - Sterility and eugenics. PMID- 21260165 TI - Genetics of intellect. PMID- 21260166 TI - Prevention of hereditary blindness: A survey of professor Franceschetti's proposals. PMID- 21260167 TI - Eutelegenesis. PMID- 21260168 TI - Laboratory research in chemical contraception. PMID- 21260169 TI - Voluntary sterilization bill. PMID- 21260171 TI - Diminishing returns. PMID- 21260170 TI - Diminishing returns. PMID- 21260173 TI - The problem of maternal mortality. PMID- 21260172 TI - Diminishing returns. PMID- 21260174 TI - The Galton lecture. PMID- 21260175 TI - Cause and effect. PMID- 21260176 TI - Eugenics, academic and practical. PMID- 21260177 TI - Laws on health and marriage. PMID- 21260178 TI - The co-ordination of the records of births, marriages and deaths. PMID- 21260179 TI - Psychological syndromes in central nervous disease: A genetic interpretation. PMID- 21260180 TI - The genetics of amentia. PMID- 21260181 TI - Effects of contraception. PMID- 21260182 TI - The decline in population. PMID- 21260183 TI - Birth-rates and economics. PMID- 21260184 TI - Eugenics. PMID- 21260186 TI - Pre-marital health schedule: Memorandum issued by the schedule committee. PMID- 21260185 TI - German eugenics in practice. PMID- 21260187 TI - Race and politics. PMID- 21260189 TI - The decline in population. PMID- 21260188 TI - A eugenics programme for the United States: Memorandum by the American eugenics society. PMID- 21260190 TI - The decline in population. PMID- 21260191 TI - The decline in population. PMID- 21260192 TI - "Nordica". PMID- 21260193 TI - Miscegenation? PMID- 21260194 TI - Eugenics and society. PMID- 21260196 TI - The physiology of fertility in man and monkey. PMID- 21260195 TI - Speeches at the Galton dinner. PMID- 21260197 TI - Policy of the eugenics society. PMID- 21260198 TI - Policy of the eugenics society. PMID- 21260199 TI - Ancestry of Mr. Eden and his colleagues. PMID- 21260200 TI - Jews and Nordics. PMID- 21260201 TI - Jews and Nordics. PMID- 21260202 TI - The decline in population. PMID- 21260203 TI - The scope of eugenics. PMID- 21260204 TI - The scope of eugenics. PMID- 21260205 TI - Positive eugenics by restraint. PMID- 21260206 TI - This freedom. PMID- 21260207 TI - Berlin population congress. PMID- 21260208 TI - Assessment of feeble-mindedness in different countries. PMID- 21260209 TI - Assessment of feeble-mindedness in different countries. PMID- 21260210 TI - Eugenic aspects of the Merseyside survey. PMID- 21260212 TI - The pre-marital health schedule and the press. PMID- 21260211 TI - Eugenics in Czechoslovakia. PMID- 21260213 TI - Mr. Huxley's Galton lecture. PMID- 21260215 TI - Mr. Huxley's Galton lecture. PMID- 21260214 TI - A problem in ethics. PMID- 21260216 TI - Mr. Huxley's Galton lecture. PMID- 21260217 TI - Birth-control. PMID- 21260218 TI - Eugenics in U.S.A. PMID- 21260220 TI - The eugenics review. PMID- 21260219 TI - Nordics and Jews. PMID- 21260222 TI - The future of our population. PMID- 21260221 TI - Is national intelligence declining? PMID- 21260223 TI - Eugenics and the decline in population. PMID- 21260224 TI - Race crossing. PMID- 21260225 TI - Race crossing. PMID- 21260227 TI - Nordics and Jews. PMID- 21260226 TI - Policy of the society. PMID- 21260228 TI - Abortion and eugenics. PMID- 21260229 TI - Intelligence tests. PMID- 21260230 TI - Teeth of mental defectives. PMID- 21260232 TI - Eugenics as I see it. PMID- 21260231 TI - Positive eugenics by restraint. PMID- 21260233 TI - Falling population and positive eugenics. PMID- 21260234 TI - The inheritance of mental disorder. PMID- 21260235 TI - Population in Australia. PMID- 21260236 TI - The treasurer's page. PMID- 21260238 TI - The declining birth-rate. PMID- 21260237 TI - The declining birth-rate. PMID- 21260239 TI - View on race and eugenics: propaganda or science? PMID- 21260240 TI - View on race and eugenics: propaganda or science? PMID- 21260241 TI - View on race and eugenics: propaganda or science? PMID- 21260242 TI - View on race and eugenics: propaganda or science? PMID- 21260243 TI - Aerogenics-a new science. PMID- 21260244 TI - The prevalence of the mental defect. PMID- 21260245 TI - The prevalence of the mental defect. PMID- 21260246 TI - The prevalence of the mental defect. PMID- 21260247 TI - Protest (I). PMID- 21260248 TI - Protest (I). PMID- 21260249 TI - Protest (II). PMID- 21260250 TI - The female sex cycle. PMID- 21260251 TI - Protest (II). PMID- 21260252 TI - Positive eugenics by restraint. PMID- 21260253 TI - The female sex cycle. PMID- 21260254 TI - Positive eugenics by restraint. PMID- 21260256 TI - Visual discrimination tests. PMID- 21260255 TI - Eutelegenesis and sterility. PMID- 21260257 TI - Visual discrimination tests. PMID- 21260258 TI - Some economic consequences of a declining population. PMID- 21260259 TI - The heredity of the royal caste. PMID- 21260260 TI - Speeches at the Galton dinner. PMID- 21260261 TI - The population problem and the future. PMID- 21260262 TI - The treasurer's page. PMID- 21260263 TI - The "erbstock" hypothesis. PMID- 21260264 TI - The "erbstock" hypothesis. PMID- 21260265 TI - "We europeans". PMID- 21260266 TI - Policy of the society. PMID- 21260267 TI - Population. PMID- 21260268 TI - Professor J. B. S. Haldane's criticism. PMID- 21260269 TI - Positive eugenics by restraint. PMID- 21260270 TI - Professor J. B. S. Haldane's criticism. PMID- 21260271 TI - Positive eugenics by restraint. PMID- 21260272 TI - Further research on chemical contraception. PMID- 21260273 TI - Birth control wins. PMID- 21260274 TI - The development of eugenic policies: A memorandum by the American eugenics society. PMID- 21260275 TI - The treasurer's page. PMID- 21260276 TI - Robert Burton: eugenist. PMID- 21260277 TI - Australian population problems. PMID- 21260278 TI - Sex determination and the population problem. PMID- 21260279 TI - Promotion of middle-class fertility. PMID- 21260280 TI - Future trends in population. PMID- 21260281 TI - Some further relations between intelligence, fertility and socio-economic factors. PMID- 21260282 TI - Eugenic problems needing research. PMID- 21260283 TI - Veterinary eugenics. PMID- 21260284 TI - A practical method for the measurement of social competence. PMID- 21260285 TI - The treasurer's page. PMID- 21260286 TI - Sex ratio and population growth. PMID- 21260287 TI - Future trends in population. PMID- 21260289 TI - Population investigation committee: First annual report (January 1st, 1937 December 31st, 1937). PMID- 21260288 TI - Family allowances schemes. PMID- 21260290 TI - Haemophilia in the royal caste. PMID- 21260291 TI - The Andersons of peterhead. PMID- 21260292 TI - Problems of population from the conservative viewpoint. PMID- 21260293 TI - Sterilization in Sweden. PMID- 21260294 TI - Prenuptial medical examination in Turkey. PMID- 21260295 TI - Eugenics and the colonial question. PMID- 21260296 TI - Problems for research. PMID- 21260297 TI - Problems for research. PMID- 21260298 TI - Problems for research. PMID- 21260299 TI - Problems for research. PMID- 21260300 TI - Sex-ratio and the population. PMID- 21260301 TI - Some anthropological characteristics of hybrid populations. PMID- 21260302 TI - A declining birth-rate and the cost of education. PMID- 21260303 TI - Danish law on abortion. PMID- 21260304 TI - Population problems in the British Commonwealth. PMID- 21260305 TI - Eugenics Propaganda. PMID- 21260306 TI - Programme of the society. PMID- 21260307 TI - Eugenics and the colonial question. PMID- 21260308 TI - Medicine and eugenics. PMID- 21260309 TI - The measurement of differential reproduction by paternity rates. PMID- 21260310 TI - A study of the intelligence of Anglo-Chinese children. PMID- 21260311 TI - Fertility and economic status in London. PMID- 21260312 TI - Policy of the society. PMID- 21260313 TI - A scheme of practical eugenics. PMID- 21260314 TI - Anthropological characteristics of hybrid populations. PMID- 21260315 TI - Decline of British fertility. PMID- 21260316 TI - Population policies in Scandinavia. PMID- 21260317 TI - Eugenics and war. PMID- 21260318 TI - Modern developments in mental welfare work. PMID- 21260319 TI - The growth of education in England and its influence on the size of the family. PMID- 21260320 TI - Practical eugenics: Aims and methods of the American eugenics society. PMID- 21260321 TI - Gross reproduction rates for the departements of France, 1891 to 1931. PMID- 21260322 TI - A scheme of practical eugenics. PMID- 21260323 TI - Sex and culture. PMID- 21260324 TI - Sex and culture. PMID- 21260325 TI - Birth control laws in U.S.A. PMID- 21260326 TI - Intelligence and family size. PMID- 21260327 TI - "Intelligence" tests. PMID- 21260328 TI - The latest revision of the Binet intelligence tests. PMID- 21260330 TI - Population investigation committee: Second annual report January 1st, 1938 November 30th, 1938. PMID- 21260329 TI - The chemical composition of the Volpar contraceptive products, part I: Phenyl mercuric acetate as a spermicide. PMID- 21260331 TI - Unemployment and child-bearing. PMID- 21260332 TI - Sex and culture. PMID- 21260333 TI - Nature and nurture. PMID- 21260334 TI - Sex and culture. PMID- 21260335 TI - Positive eugenic policy. PMID- 21260336 TI - The chemical composition of the volpar contraceptive products, part 2. PMID- 21260337 TI - Friedrich Wilhelm Schallmeyer: 1857-1919: A pioneer in eugenics. PMID- 21260338 TI - Eugenic prognosis with respect to mental deficiency. PMID- 21260340 TI - The work of the population policies committee. PMID- 21260339 TI - External migration. PMID- 21260341 TI - Speeches at the Galton dinner. PMID- 21260342 TI - Athletics and other forms of ability. PMID- 21260343 TI - Population problems. PMID- 21260344 TI - Population problems. PMID- 21260345 TI - Britain and America. PMID- 21260346 TI - Eugenic garden city. PMID- 21260347 TI - Some problems of population. PMID- 21260348 TI - Eugenic measures in the third reich. PMID- 21260349 TI - Swedish law on abortion: Act relating to the termination of pregnancy, 17th June, 1938. PMID- 21260350 TI - Havelock Ellis, 1859-1939. PMID- 21260352 TI - Fertility, income and paternal age. PMID- 21260351 TI - A study in Indian fertility. PMID- 21260353 TI - Health of militiamen. PMID- 21260354 TI - Medical peace campaign. PMID- 21260355 TI - Diminishing returns. PMID- 21260356 TI - Eugenics propaganda. PMID- 21260357 TI - Diminishing returns. PMID- 21260358 TI - Abortion laws. PMID- 21260360 TI - A note on the length of life of "men of distinction". PMID- 21260359 TI - Maternity and child welfare work and the population problem. PMID- 21260361 TI - Obstacles to marriage. PMID- 21260362 TI - Housing asocial families in Holland. PMID- 21260363 TI - A note on the calculation of the net reproduction rate for married women. PMID- 21260364 TI - Correspondence. PMID- 21260365 TI - The geneticists' manifesto. PMID- 21260366 TI - Population and employment. PMID- 21260367 TI - The Malthusian doctrine. PMID- 21260368 TI - Obstacles to marriage. PMID- 21260369 TI - Military physique. PMID- 21260370 TI - Skilled and unskilled work. PMID- 21260371 TI - The struggle for life. PMID- 21260372 TI - Season of birth. PMID- 21260373 TI - Abortion-right or wrong? PMID- 21260375 TI - Psychological research in war time. PMID- 21260374 TI - Eugenics and mongrelization. PMID- 21260376 TI - The Galton Luncheon 1940: President's address on eugenic policy. PMID- 21260377 TI - Annual report 1939-40. PMID- 21260378 TI - Balance sheet. PMID- 21260379 TI - Investments. PMID- 21260380 TI - The health of working women. PMID- 21260381 TI - Nutrition in war time. PMID- 21260382 TI - Sexual misery as a population factor. PMID- 21260383 TI - Eugenics and the rights of man. PMID- 21260384 TI - Is war dysgenic? PMID- 21260385 TI - The family. PMID- 21260386 TI - Is war dysgenic? PMID- 21260387 TI - Is war dysgenic? PMID- 21260388 TI - The analysis of physique. PMID- 21260389 TI - The Galton Luncheon, 1941: Discussion on eugenics in war-time. PMID- 21260390 TI - The study of racial mixture in the British Commonwealth: Some anthropological preliminaries. PMID- 21260391 TI - The economic effects of a declining population. PMID- 21260392 TI - Correspondence. PMID- 21260393 TI - Correspondence. PMID- 21260394 TI - Family allowances in war time. PMID- 21260395 TI - Problems of penal reform. PMID- 21260397 TI - Annual report 1940-41. PMID- 21260396 TI - Health of militiamen. PMID- 21260398 TI - Balance sheet. PMID- 21260399 TI - Investments. PMID- 21260400 TI - Population trends and policies. PMID- 21260401 TI - A note on the intellectual differences of the sexes. PMID- 21260402 TI - War and the birth rate. PMID- 21260403 TI - Crime and punishment. PMID- 21260404 TI - Family allowances. PMID- 21260405 TI - Differential fertility. PMID- 21260407 TI - Family allowances and eugenics. PMID- 21260406 TI - Crime and punishment. PMID- 21260408 TI - A study of heredity in an isolated village community. PMID- 21260409 TI - The prevention of crippling. PMID- 21260410 TI - Family allowances. PMID- 21260411 TI - Family allowances. PMID- 21260412 TI - Family allowances. PMID- 21260413 TI - Eugenics and poverty. PMID- 21260414 TI - Racial mixture in Great Britain: some anthropological characteristics of the Anglo-negroid cross: A preliminary report. PMID- 21260415 TI - Nature and nurture in mental hygiene. PMID- 21260416 TI - Crime and punishment. PMID- 21260418 TI - Dysgenic effects of war. PMID- 21260417 TI - Crime and punishment. PMID- 21260419 TI - Population changes and economics. PMID- 21260421 TI - Annual report, 1941-2. PMID- 21260420 TI - An American eugenist speaks. PMID- 21260423 TI - The effect of the war on the birth rate. PMID- 21260422 TI - The eugenics society incorporated balance sheet, December 31st, 1941. PMID- 21260424 TI - Social and economic factors in psychiatry. PMID- 21260426 TI - Juvenile delinquency. PMID- 21260425 TI - Dogs and eugenics. PMID- 21260427 TI - Population changes and economics. PMID- 21260428 TI - The birth rate. PMID- 21260429 TI - Deterrents to parenthood. PMID- 21260430 TI - The eugenist. PMID- 21260431 TI - Infant and maternal mortality. PMID- 21260433 TI - Leonard Darwin, 1850-1943. PMID- 21260432 TI - German eugenic legislation in peace and war. PMID- 21260435 TI - The Galton lecture. PMID- 21260434 TI - Eugenic aspects of children's allowances. PMID- 21260436 TI - Deterrents to parenthood. PMID- 21260437 TI - Deterrents to parenthood. PMID- 21260438 TI - Deterrents to parenthood. PMID- 21260439 TI - Institute for the scientific treatment of delinquency. PMID- 21260440 TI - Annual report, 1942-3. PMID- 21260441 TI - Balance sheet. PMID- 21260442 TI - Investments. PMID- 21260443 TI - The span of life. PMID- 21260444 TI - The significance of recent brith-rate figures. PMID- 21260445 TI - Incentives to parenthood: Some data from the Pioneer health centre, Peckham. PMID- 21260447 TI - The span of life. PMID- 21260446 TI - Deterrents to parenthood. PMID- 21260448 TI - Family allowances. PMID- 21260450 TI - The size of family of the business, professional and titled classes. PMID- 21260449 TI - Deterrents to parenthood. PMID- 21260451 TI - Estimates of future populations of various countries. PMID- 21260452 TI - Estimates of future population. PMID- 21260453 TI - "Birth, poverty and wealth". PMID- 21260455 TI - Deterrents to parenthood. PMID- 21260454 TI - Deterrents to parenthood. PMID- 21260456 TI - Deterrents to parenthood. PMID- 21260458 TI - Eugenic aspects of social security. PMID- 21260457 TI - Deterrents to parenthood. PMID- 21260459 TI - Eugenics and contraception. PMID- 21260460 TI - Deterrents to parenthood. PMID- 21260461 TI - Deterrents to parenthood. PMID- 21260462 TI - Birth, poverty and wealth. PMID- 21260463 TI - The span of life. PMID- 21260464 TI - The birth-rate. PMID- 21260465 TI - Children's allowances. PMID- 21260466 TI - Estimates of future population. PMID- 21260467 TI - Population problems in the light of differential fertility. PMID- 21260468 TI - The social environment and eugenics. PMID- 21260469 TI - Eugenics and contraception. PMID- 21260470 TI - Eugenics and contraception. PMID- 21260471 TI - Eugenics and social security. PMID- 21260472 TI - Eugenics and social security. PMID- 21260473 TI - Contraception and eugenics. PMID- 21260474 TI - The order of merit: the holders and their kindred. PMID- 21260475 TI - Request for pedigrees. PMID- 21260476 TI - "Lebensraum". PMID- 21260477 TI - Demography-science and administration. PMID- 21260478 TI - Physical and psychological aspects of constitution. PMID- 21260479 TI - "Lebensraum". PMID- 21260480 TI - "The order of merit". PMID- 21260481 TI - Eugenics and family size. PMID- 21260482 TI - Early or late parenthood? PMID- 21260483 TI - The Peckham experiment. PMID- 21260484 TI - Population trends in Southern Rhodesia, 1941 to 1981. PMID- 21260485 TI - Reproduction rates of France and Spain: A survey of recent literature. PMID- 21260486 TI - Current notes on population trends in the British empire. PMID- 21260487 TI - War and the birth-rate. PMID- 21260488 TI - Eugenic aspects of the English criminal law. PMID- 21260489 TI - Current notes on demography. PMID- 21260490 TI - Lebensraum. PMID- 21260491 TI - An objective view? PMID- 21260492 TI - The population problem in a Crown colony (Kenya). PMID- 21260493 TI - Royal commission on population. PMID- 21260494 TI - Abortion. PMID- 21260495 TI - The Galton lecture, 1946: Presentation of the society's gold medal. PMID- 21260496 TI - Is Britain over-populated? PMID- 21260497 TI - Sex education. PMID- 21260498 TI - Positive eugenics: a proposal. PMID- 21260499 TI - Assortative mating. PMID- 21260501 TI - Reproductive physiology. PMID- 21260500 TI - Positive eugenics: a proposal. PMID- 21260502 TI - Trend of national intelligence. PMID- 21260503 TI - Is Britain over-populated? PMID- 21260504 TI - Sex education. PMID- 21260505 TI - Galton's outlook on religion. PMID- 21260506 TI - Myrdal's "nation and family". PMID- 21260507 TI - Positive eugenics: a proposal. PMID- 21260508 TI - Is Britain over-populated? PMID- 21260509 TI - Courtship and mating. PMID- 21260510 TI - Courtship and mating. PMID- 21260511 TI - Eugenic implications of the Rh factor. PMID- 21260512 TI - Eugenically desirable types. PMID- 21260514 TI - Assortative mating. PMID- 21260513 TI - Eugenically desirable types. PMID- 21260515 TI - Positive eugenics. PMID- 21260516 TI - The Galton lecture, 1947. PMID- 21260517 TI - Positive eugenics: a proposal. PMID- 21260519 TI - Eugenics and war criminality. PMID- 21260518 TI - Eutelegenesis and Rh incompatibility. PMID- 21260521 TI - Positive eugenics: a proposal. PMID- 21260520 TI - The descendants of sir George Villiers. PMID- 21260522 TI - "Modern marriage". PMID- 21260523 TI - The non-sane non-insane offender. PMID- 21260524 TI - The measurement of socially valuable qualities. PMID- 21260525 TI - Human genetics and the reviewers. PMID- 21260526 TI - The future of our population. PMID- 21260527 TI - The future of our population. PMID- 21260529 TI - Divorce and nullity. PMID- 21260528 TI - Parentage of mathematicians. PMID- 21260530 TI - Some reflections on genius. PMID- 21260531 TI - Some recent studies of intelligence: A survey of the society's "occasional papers". PMID- 21260532 TI - Our crowded Island. PMID- 21260533 TI - The Galton lecture, 1948. PMID- 21260534 TI - Marriage and the church. PMID- 21260535 TI - Human genetics. PMID- 21260536 TI - Marriage and the church. PMID- 21260537 TI - Marriage and the church. PMID- 21260538 TI - The birth-rate. PMID- 21260539 TI - Migration and the British Commonwealth. PMID- 21260540 TI - The philosophy of Wilfred Trotter: And its bearing on eugenics. PMID- 21260542 TI - Our crowded Island. PMID- 21260541 TI - Intelligence and size of family. PMID- 21260544 TI - Byrom Stanley Bramwell, 1877-1948. PMID- 21260545 TI - Reception for General Frederick Osborn. PMID- 21260543 TI - Illegitimacy. PMID- 21260547 TI - Divorce. PMID- 21260546 TI - Artificial insemination. PMID- 21260549 TI - The Galton lecture, 1949. PMID- 21260548 TI - Contraception and illegitimate births. PMID- 21260550 TI - A.I.H. and A.I.D. PMID- 21260552 TI - Pre-marital health examinations. PMID- 21260551 TI - The trend of intelligence. PMID- 21260554 TI - Mixing of races. PMID- 21260553 TI - A.I.H. and A.I.D. PMID- 21260555 TI - Maurice Newfield: It is with deep regret that we record the death of Dr. Maurice Newfield, editor of the eugenics review since 1933. PMID- 21260556 TI - The royal commission on population: The demographic position. PMID- 21260557 TI - The royal commission on population and the society's aims. PMID- 21260558 TI - The royal commission on population and P E P. PMID- 21260559 TI - The royal commission's report and the press. PMID- 21260560 TI - Some biological considerations in social evolution. PMID- 21260561 TI - Mixture of races. PMID- 21260562 TI - Mixture of races. PMID- 21260563 TI - Mixture of races. PMID- 21260564 TI - Mixture of races. PMID- 21260565 TI - Sierra popoluca speech. PMID- 21260566 TI - Intelligence and fertility: The Scottish 1947 survey. PMID- 21260567 TI - Family service units for problem families. PMID- 21260568 TI - Maurice Newfield. PMID- 21260570 TI - Fitness and survival. PMID- 21260569 TI - Mixture of races. PMID- 21260571 TI - A satisfactory population for Britain? PMID- 21260572 TI - War and eugenics. PMID- 21260573 TI - The primrose path : Some aspects of the population problem. PMID- 21260574 TI - The quality of the rural population. PMID- 21260575 TI - Welfare and population. PMID- 21260576 TI - The problems of quantity and quality in the british population. PMID- 21260578 TI - The control of population. PMID- 21260577 TI - The fate of national intelligence: test of a thirteen-year prediction. PMID- 21260580 TI - U.N.E.S.C.O. on race. PMID- 21260579 TI - Our average age. PMID- 21260581 TI - Colonial medical policy in relation to population growth. PMID- 21260582 TI - Constitution-mental disease and psychoanalysis. PMID- 21260583 TI - Intelligence and family size of college students. PMID- 21260584 TI - Galton's hereditary genius: Reprint of the second edition. PMID- 21260585 TI - Sterilization. PMID- 21260586 TI - Eugenics and human ecology. PMID- 21260588 TI - The ideal of an elite. PMID- 21260587 TI - Galton's views on race. PMID- 21260589 TI - Planned parenthood in India. PMID- 21260590 TI - Relationship between intelligence and size of family. PMID- 21260591 TI - Galton's hereditary genius: Reprint of the second edition. PMID- 21260592 TI - Biological aspects of totalitarianism. PMID- 21260593 TI - Hereditary genius. PMID- 21260594 TI - Neuroticism in twins. PMID- 21260596 TI - The population report: A statement from the hierarchy. PMID- 21260595 TI - Congenital malformations. PMID- 21260597 TI - Recent investigations of intelligence and its measurement. PMID- 21260598 TI - Mouths to feed. PMID- 21260599 TI - The population report. PMID- 21260600 TI - Heredity and environment in the determination of stature. PMID- 21260601 TI - Alexander Graham Bell. PMID- 21260602 TI - Prospects in the control of genetic disease. PMID- 21260603 TI - Birth control in Germany. PMID- 21260605 TI - Recording human constitution. PMID- 21260604 TI - Relationship between the intelligence of students and size of family. PMID- 21260607 TI - History in your blood. PMID- 21260608 TI - The eugenic hypothesis : (i) Positive eugenics. PMID- 21260609 TI - An international union of family organizations. PMID- 21260610 TI - Galton's hereditary genius. PMID- 21260611 TI - The Pope's discourse. PMID- 21260612 TI - Birth control and India. PMID- 21260613 TI - Birth control and India. PMID- 21260614 TI - "Eugenic" experiments conducted by the Nazis on human subjects. PMID- 21260616 TI - Do we want to end wars? PMID- 21260615 TI - Voluntary euthanasia legalisation society. PMID- 21260617 TI - Race and feminism. PMID- 21260618 TI - The genetics of mental deficiency. PMID- 21260619 TI - The stability of marriage. PMID- 21260620 TI - The eugenic hypothesis : (ii) Negative eugenics. PMID- 21260622 TI - Social statistics of Britain. PMID- 21260621 TI - The biochemistry of conception control. PMID- 21260623 TI - Race and athletics. PMID- 21260625 TI - Eugenics: Galton and after. PMID- 21260624 TI - J. B. S. haldane on eugenics. PMID- 21260626 TI - The biochemistry of conception control. PMID- 21260628 TI - The battle against hunger. PMID- 21260627 TI - The biochemistry of conception control. PMID- 21260629 TI - Road to happiness. PMID- 21260630 TI - Family planning: the past and the future. PMID- 21260631 TI - Family planning: the past and the future. PMID- 21260632 TI - Intelligence quotients and differential fertility: Some observations from Winchester college. PMID- 21260633 TI - Food, famine and the future. PMID- 21260634 TI - Oral contraceptives. PMID- 21260635 TI - Human nature: its development, variations and assessment. PMID- 21260636 TI - The biochemistry of conception control. PMID- 21260637 TI - The biochemistry of conception control. PMID- 21260638 TI - Human nature: its development, variations and assessment. PMID- 21260639 TI - Planned parenthood. PMID- 21260640 TI - Experimental studies of hereditary influences on behaviour. PMID- 21260641 TI - Family environment and intelligence. PMID- 21260642 TI - Food, famine and the future. PMID- 21260643 TI - Food, famine and the future. PMID- 21260644 TI - Food, famine and the future. PMID- 21260645 TI - Food, famine and the future. PMID- 21260646 TI - Differential fertility in 1951. PMID- 21260647 TI - Social selection in the welfare state. PMID- 21260648 TI - Population problems and family policy in France. PMID- 21260650 TI - The contribution of planned parenthood to the future of America. PMID- 21260649 TI - Intelligence and childbearing. PMID- 21260651 TI - Comments on general Osborn's address. PMID- 21260652 TI - Human sterilization and public understanding. PMID- 21260653 TI - Malthus in perspective. PMID- 21260654 TI - Personality differences and neurotic traits in normal twin schoolchildren: A study in psychiatric genetics. PMID- 21260655 TI - The united nations organizations and the world population problem. PMID- 21260656 TI - What is race? PMID- 21260657 TI - The eugenics society. PMID- 21260658 TI - Promising families: elite and moiety eugenics. PMID- 21260659 TI - Delinquent behaviour: some unanswered questions. PMID- 21260660 TI - Marriage (certificates of medical examination) bill: Explanatory memorandum. PMID- 21260661 TI - The value of medical examination before marriage. PMID- 21260662 TI - Professor Max Westenhofer on the problem of man's origin. PMID- 21260663 TI - The next million years. PMID- 21260664 TI - The next million years. PMID- 21260665 TI - The next million years. PMID- 21260666 TI - The next million years. PMID- 21260667 TI - Distribution of the sickle cell gene : A new light on the origin of the East Africans. PMID- 21260668 TI - The next million years. PMID- 21260669 TI - The next million years. PMID- 21260670 TI - The kinsey reports. PMID- 21260671 TI - The welfare state: a eugenic appraisal. PMID- 21260672 TI - Some aspects of world population and food resources. PMID- 21260673 TI - Physique and choice of career. PMID- 21260675 TI - Some observations on infant mortality in India: 1901-1951. PMID- 21260674 TI - Man's future challenged. PMID- 21260676 TI - The German sterilization act of 1933: "Gesetz zur verhutung erbkranken Nachwuchses". PMID- 21260678 TI - Energy in the future. PMID- 21260677 TI - Intelligence and family size in an adult sample. PMID- 21260679 TI - Post-war fertility trends in France and the United States. PMID- 21260680 TI - Genetic counselling. PMID- 21260681 TI - The ascertainment of promising families. PMID- 21260683 TI - Genetic and social aspects of the epilepsies of childhood. PMID- 21260682 TI - Demographic developments in great Britain since the royal commission on population. PMID- 21260684 TI - The eugenics society. PMID- 21260685 TI - The German sterilization act of 1933. PMID- 21260686 TI - The German sterilization act of 1933. PMID- 21260687 TI - The fertility of graduate women. PMID- 21260688 TI - The families of teachers. PMID- 21260689 TI - Billy graham. PMID- 21260691 TI - The rhythm method: two Indian experiments: Part I. PMID- 21260690 TI - The meaning and assessment of intelligence. PMID- 21260692 TI - Unsatisfactory parents and psychological disorder in their children. PMID- 21260694 TI - Natural regulation of numbers in human populations. PMID- 21260693 TI - The rhythm method: two Indian experiments: Part II. PMID- 21260695 TI - Immigration of coloured peoples. PMID- 21260696 TI - Electronic aids in demography-logister patent 731, 797. PMID- 21260697 TI - Promising families. PMID- 21260698 TI - Distribution of the sickle cell gene. PMID- 21260699 TI - Problem families in southampton. PMID- 21260700 TI - Family planning and eugenic movements in the mid-twentieth century. PMID- 21260701 TI - Unchecked populations: some comparisons of rapid growth. PMID- 21260702 TI - Relationship between the intelligence of technical college students and size of family. PMID- 21260703 TI - "Natural regulation of numbers in human populations". PMID- 21260704 TI - "Natural regulation of numbers in human populations". PMID- 21260705 TI - A register of intelligence. PMID- 21260707 TI - Galton and mid-century eugenics. PMID- 21260706 TI - An oral method of birth control. PMID- 21260708 TI - The inheritance and nature of extraversion. PMID- 21260709 TI - Japan's population problem. PMID- 21260711 TI - The designation of uncommon families. PMID- 21260710 TI - Immigration of coloured peoples. PMID- 21260712 TI - The personality characteristics of parents of promising children. PMID- 21260713 TI - Into the madding crowd: ceylon and its population problems. PMID- 21260714 TI - Problem families and their household budgets. PMID- 21260715 TI - Biological hazards of nuclear fission. PMID- 21260718 TI - Successful refertilization of a man who had been sterilized seven years previously. PMID- 21260717 TI - Linkage in human genetics. PMID- 21260719 TI - The hazards of nuclear radiation: Medical research council. The hazards to man of nuclear and allied radiations. PMID- 21260721 TI - Home background and selection for secondary education. PMID- 21260720 TI - Designation of uncommon families. PMID- 21260722 TI - Home background and selection for secondary education. PMID- 21260723 TI - The after-forty baby. PMID- 21260724 TI - Home background and selection for secondary education. PMID- 21260725 TI - Artificial insemination (donor). PMID- 21260726 TI - A new movement in France. PMID- 21260727 TI - The designation of uncommon families. PMID- 21260728 TI - The designation of uncommon families. PMID- 21260729 TI - Genetic-hygienic experiences in Denmark in recent years. PMID- 21260730 TI - Regional variations in intellectual ability in Britain. PMID- 21260731 TI - Twin research in tuberculosis. PMID- 21260732 TI - Maternal employment and the welfare of children: An account of a survey in progress. PMID- 21260733 TI - The measurement and inheritance of skin colour in man. PMID- 21260734 TI - The value of unhappiness. PMID- 21260736 TI - China's population policy. PMID- 21260735 TI - Family planning in China. PMID- 21260737 TI - Population problems in the British Caribbean. PMID- 21260738 TI - Biology and medicine. PMID- 21260740 TI - The eugenics society: Jubilee Dinner. PMID- 21260739 TI - Inheritance of mental ability. PMID- 21260741 TI - The development and use of artificial insemination. PMID- 21260743 TI - Intelligence and family size, 1949-56. PMID- 21260742 TI - Fertility and child mortality in cousin marriages : A study in a Moslem community in East Africa. PMID- 21260744 TI - The eugenics society: Statement of aims. PMID- 21260745 TI - Problem families. PMID- 21260746 TI - Eugenics in the age of crowding. PMID- 21260747 TI - Artificial insemination: the society's position. PMID- 21260748 TI - Ageing. PMID- 21260749 TI - The eugenics society-Jubilee Dinner. PMID- 21260750 TI - New human demands in industry. PMID- 21260752 TI - The family in contemporary society: a review. PMID- 21260751 TI - Twins brought up apart. PMID- 21260753 TI - The human sum. PMID- 21260754 TI - Human demands in industry. PMID- 21260755 TI - Fertility and mental illness. PMID- 21260756 TI - Three surveys of promising families. PMID- 21260757 TI - The control of evolution in man. PMID- 21260758 TI - Pre-marital instruction in Rhythm method. PMID- 21260759 TI - American research into population and resources. PMID- 21260760 TI - Differential fecundity and effectiveness of contraception. PMID- 21260762 TI - West Indian immigration: Some criticisms, comments and a rejoinder. PMID- 21260761 TI - On university entrance qualifications for students of biology. PMID- 21260763 TI - What are we doing about it? PMID- 21260765 TI - Eugenics in an atomic age. PMID- 21260764 TI - Reflections on a changing class structure. PMID- 21260766 TI - The control of evolution in man. PMID- 21260767 TI - Social and psychological factors affecting fertility: Summary of chief findings and implications for future studies. PMID- 21260768 TI - Marie Stopes. PMID- 21260769 TI - The population of Great Britain: some facts. PMID- 21260770 TI - Population and science. PMID- 21260771 TI - Physique and family structure. PMID- 21260773 TI - Migration and race mixture from the genetic angle. PMID- 21260772 TI - Eugenics and future society. PMID- 21260774 TI - Race and intelligence. PMID- 21260775 TI - Havelock Ellis. PMID- 21260776 TI - Population planning and quality of life. PMID- 21260777 TI - Growth, heredity and nutrition. PMID- 21260779 TI - Fertility differentials in England and Wales: Some facts. PMID- 21260778 TI - Maternal stature and reproductive efficiency. PMID- 21260781 TI - Morbidity and mortality in the first year of life. PMID- 21260780 TI - Intra-uterine devices. PMID- 21260782 TI - Mental health and the population. PMID- 21260784 TI - A.I.D. investigation council: Evidence submitted to the departmental committee. PMID- 21260783 TI - Cousin marriages. PMID- 21260785 TI - Trends in fertility in England and Wales: Some facts. PMID- 21260786 TI - Intra-uterine devices. PMID- 21260787 TI - Birth control in China-recent aspects. PMID- 21260788 TI - Evolutionary systems-animal and human. PMID- 21260789 TI - The Guinness family. PMID- 21260790 TI - The population of England and Wales in 1957: Some facts. PMID- 21260791 TI - Intra-uterine devices. PMID- 21260792 TI - Blood groups in the study of human populations. PMID- 21260794 TI - Migration to and from the United Kingdom: Some facts. PMID- 21260795 TI - "La limitation des naissances". PMID- 21260796 TI - Education in Russia. PMID- 21260797 TI - The output of scientists in Scotland. PMID- 21260798 TI - Biological fitness in man. PMID- 21260799 TI - A proposed standard system of nomenclature of human mitotic chromosomes. PMID- 21260800 TI - Galton's heritage. PMID- 21260802 TI - New life in old bodies. PMID- 21260803 TI - The Reith lectures 1959: The future of man. PMID- 21260804 TI - An estimate of the future population of England and Wales. PMID- 21260805 TI - Some studies of British heredity: Four recent books. PMID- 21260806 TI - Mortality trends: Some facts. PMID- 21260807 TI - Promising families: some conclusions. PMID- 21260808 TI - Public morality and the criminal law. PMID- 21260809 TI - Defective molecules as a cause of disease. PMID- 21260810 TI - On the nature of prejudice. PMID- 21260812 TI - China's population: Two recent books. PMID- 21260811 TI - Family follow-up studies into the eugenic aspects of morbidity: Interim progress report. PMID- 21260813 TI - Mortality in under-developed countries: Some facts. PMID- 21260814 TI - Human procreation in civilized society. PMID- 21260815 TI - Gifted children: The latest report of the terman studies. PMID- 21260816 TI - The cytogenetics of sex in man. PMID- 21260817 TI - 2000 A.D.-A biologist's thoughts on the next forty years. PMID- 21260818 TI - Legality of sterilization: a new outlook. PMID- 21260820 TI - Marriage in England and Wales: Some facts. PMID- 21260819 TI - The growth of scientific physiology. PMID- 21260821 TI - Public morality and the criminal law. PMID- 21260823 TI - European population contrasts: Some facts. PMID- 21260822 TI - Modern trends in the population genetics of man. PMID- 21260825 TI - On the nature of prejudice. PMID- 21260824 TI - On the nature of prejudice. PMID- 21260826 TI - Evolution. PMID- 21260827 TI - Inherited disease in man. PMID- 21260828 TI - A note on Malthus. PMID- 21260829 TI - Parson Malthus's great-grandfather: Daniel Malthus, Royal apothecary. PMID- 21260830 TI - Medical termination of pregnancy bill. PMID- 21260831 TI - The impending crisis. PMID- 21260832 TI - Cousin marriage and population structure. PMID- 21260833 TI - Voluntary sterilization: Introduction and summary. PMID- 21260834 TI - The international planned parenthood federation: part I: Its history and influence. PMID- 21260835 TI - The 1961 census of Great Britain: Some facts. PMID- 21260836 TI - Male sterilization and spermatogenesis. PMID- 21260837 TI - Cancer as a cause of death. PMID- 21260838 TI - Racial survival. PMID- 21260840 TI - Eugenics and the family: The national marriage guidance council's Herbert Gray lecture, October 18th, 1961. PMID- 21260839 TI - A survey of opinion. PMID- 21260842 TI - The eugenics society of Victoria (1936-1961). PMID- 21260841 TI - The international planned parenthood federation, part II: Its history and influence. PMID- 21260843 TI - Births in Great Britain: Some facts. PMID- 21260845 TI - Captain Barclay. PMID- 21260844 TI - Correspondence. PMID- 21260846 TI - America, Russia and Europe: Some demographic facts. PMID- 21260847 TI - Voluntary sterilization: the last sixty years. PMID- 21260848 TI - The English-speaking commonwealth: Some facts. PMID- 21260849 TI - Artificial insemination. PMID- 21260850 TI - The crowded world. PMID- 21260851 TI - Assortative mating in man. PMID- 21260853 TI - Statement of the eugenic position: By the special committee of the board of directors. PMID- 21260852 TI - Cross currents in the history of human genetics. PMID- 21260854 TI - A population picture of British Guiana. PMID- 21260856 TI - Voluntary sterilization: transitions throughout the world. PMID- 21260855 TI - Eugenics in evolutionary perspective. PMID- 21260857 TI - Demographic rivalry between U.S.A. and U.S.S.R: Some facts. PMID- 21260858 TI - The immigration bill. PMID- 21260859 TI - Causes and functions of genetic variety. PMID- 21260860 TI - Infectious diseases, the ABO blood groups and human evolution. PMID- 21260861 TI - Some fundamental considerations in human population cytogenetics. PMID- 21260862 TI - A further rise in births in Britain: Some facts. PMID- 21260864 TI - Three hundred years of demography. PMID- 21260863 TI - Change and control in human populations. PMID- 21260865 TI - Family diseases in N.H.S. general practice: A second report on the use of the morbidity indexing system. PMID- 21260866 TI - Distributions of uncommon disorders. PMID- 21260867 TI - Fertility in economically emergent countries: Some facts. PMID- 21260868 TI - Constructive fertility control through sterilization. PMID- 21260869 TI - Gonorrhoea and fertility in Uganda. PMID- 21260870 TI - Expanding frontiers of genetics: A review. PMID- 21260871 TI - Rapid falls in fertility in recent years: Some facts. PMID- 21260873 TI - Family planning: an assessment. PMID- 21260872 TI - Natural selection and fitness. PMID- 21260874 TI - Education and the humanist revolution. PMID- 21260875 TI - Natural selection and colour blindness. PMID- 21260876 TI - Genetics and race. PMID- 21260877 TI - Eugenics. PMID- 21260878 TI - Dr. Yoshio Koya: a memorable story. PMID- 21260880 TI - The ageing of the British population: Some facts. PMID- 21260879 TI - The making and the taking of life. PMID- 21260882 TI - Opinion surveys. PMID- 21260881 TI - Number fourteen. PMID- 21260884 TI - Younger marriages in England and Wales and the consequences for fertility: Some facts. PMID- 21260883 TI - Eugenics and over population. PMID- 21260885 TI - The legalization of medical abortion. PMID- 21260886 TI - The home and the school: A review. PMID- 21260887 TI - The diary of Richard Rumbold : A review. PMID- 21260888 TI - The which? Contraceptives supplement. PMID- 21260889 TI - The which? Contraceptives supplement. PMID- 21260890 TI - Contraception versus abortion. PMID- 21260891 TI - The distribution by age and marital status of the population of England and Wales in 1961: Some facts. PMID- 21260892 TI - "Canned philosophers". PMID- 21260893 TI - Abortion. PMID- 21260894 TI - Social factors affecting fertility in India. PMID- 21260895 TI - The study of mutation and selection in human populations. PMID- 21260896 TI - Congenital malformations in man and natural selection. PMID- 21260898 TI - The population of the United States of America: recent developments compared with trends in Britain: Some facts. PMID- 21260897 TI - The frequency of middle phalangeal hair in Britain: A pilot survey with comments on some methodological problems. PMID- 21260899 TI - The way ahead. PMID- 21260901 TI - Voluntary sterilization. PMID- 21260900 TI - Abortion and syphilis. PMID- 21260902 TI - One Galileo is enough: Some aspects of current population problems. PMID- 21260903 TI - Facial variation, with special reference to the people of Tristan Da Cunha. PMID- 21260904 TI - Biological aspects of social problems : A review. PMID- 21260905 TI - Estimates of the future growth of world population: Some alternatives. PMID- 21260906 TI - Anti-dysthanasia. PMID- 21260907 TI - Phases in a society's evolution. PMID- 21260908 TI - Internal factors in evolution. PMID- 21260910 TI - Differential marriage: Some facts. PMID- 21260909 TI - Population control in Japan: lessons for India. PMID- 21260911 TI - The population explosion. PMID- 21260913 TI - Abortion. PMID- 21260912 TI - Germinal choice. PMID- 21260914 TI - Commonwealth immigration: Some facts. PMID- 21260915 TI - Eugenics in the USSR? PMID- 21260917 TI - Falling birth-rates in the U.S.A: Some facts. PMID- 21260916 TI - Contraception and the Catholic theologians : A review. PMID- 21260918 TI - A fifth freedom? PMID- 21260919 TI - The numbers of the unmarried: Some facts. PMID- 21260920 TI - Abortion. PMID- 21260921 TI - Genetic and environmental factors in human ability: a review. PMID- 21260922 TI - Fertility differentials in England and Wales: Some facts. PMID- 21260923 TI - Your heredity and environment. PMID- 21260924 TI - Sociology, biology and population control. PMID- 21260925 TI - The role of genetic factors in the human face, jaws and teeth: a review. PMID- 21260926 TI - Genetic and environmental factors in human ability. PMID- 21260927 TI - Social and genetic influences on life and death : A review. PMID- 21260928 TI - [Pokrovskii's school]. PMID- 21260929 TI - [Current trends in diagnosis and treatment of arteriovenous angiodysplasia]. AB - A total of 240 patients with arteriovenous angiodysplasia (AVD) were examined and treated in A.V. Vishnevsky Institute of Surgery during 1997-2009. Embolization was performed in 196 (81.7%) patients. Staged embolization was the principal treatment modality in 84 (35%) patients presenting with inoperable lesions. The mean number of sessions was 3.6. Intraoperative embolization using hydrogel embols, Gianturco coils, and 96% alcohol was done in 17 (7.1%) patients. Radical surgery with the removal of angiomatous tissues was given to 33 (13.8%) patients. Palliative resections were made in patients with extensive lesions and impossibility of total removal of angiomatous tissues. Minor and major amputations were needed in 15 patients. It is concluded that intervention for microfistulous and confined macrofistulous lesions should be performed only in case of absolute indications for surgery. That in asymptomatic or subclinical cases is justified only for minor surface lesions fit for radical resection. Minor amputation is indicated in certain patients with arteriovenous fistulas on distal limb segments. Extensive delayed resections should be planned with the use of plastic surgical techniques (autodermoplasty using free flaps, mobilized flaps, and flaps with microvascular anastomosis). PMID- 21260930 TI - [Variants of reconstruction of carotid bifurcation in patients with atherosclerosis: history and current state of the art]. AB - A historical review of reconstructive surgery for atherosclerotic lesions of carotid bifurcation is presented along with indications for the use of various methods of vascularization of internal carotid artery based on the experience gained at the Department of Vascular Surgery, A.V. Vishnevsky Institute of Surgery. PMID- 21260931 TI - [Main aspects of ultrasound studies of carotid artery atherosclerotic lesions in clinical practice]. AB - The authors summarize results of the joint work of Departments of Vascular Surgery and Ultrasound Diagnosis, A.V. Vishnevsky Institute of Surgery. The main aspects of US study of patients with atherosclerotic carotid lesions are discussed necessary for comprehensive and high-quality examination taking into account severity of occlusion and anatomical features of carotid arteries. Structural characteristic of atherosclerotic plaques is presented based on the comparison of results of US and morphological studies. Analysis of plaque morphology and clinical features of the disease was used to develop classification distinguishing 6 main types of atherosclerotic plaques. Complicated diagnostic situations are considered that can be encountered during US diagnostics of atherosclerotic carotid lesions. PMID- 21260932 TI - [Dynamic assessment of corpus callosum and corticospinal tracts structure using diffusion-tensor MRI in diffuse axonal injury]. AB - BACKGROUND: Diffuse axonal injury (DAI) causes neurodegenerative processes in brain which can last weeks and months after traumatic brain injury. Aim of this study was to assess structural changes of corpus callosum and corticospinal tracts in dynamics using diffusion-tensor magnetic resonance imaging (DT-MRI) in severe DAI. MATERIALS AND METHODS: 14 patients with severe DAI (GCS < or = 8 in acute period) were examined using DT-MRI. In 12 cases 1.5 Tesla device was used, in 2-3 Tesla tomography was applied. Initial studies were performed on 3rd-17th days after injury and control studies were done between 3 weeks and 33 months after injury. Outcomes were assessed using GOS 6 months after injury and later. RESULTS: MR-tractography demonstrated almost absolutely absent visualization of ascending fibers of corpus callosum 3-20 weeks after brain injury in 5 patients with poor outcomes (severe disability and persistent vegetative state). Raized asymmetry of corticospinal tracts was associated with hemiparesis or quadriparesis in the same patients. In 6 patients with severe disability partial loss and thinning of corpus callosum fibers were observed. In 2 patients with good recovery and moderate disability repeated studies showed no severe changes in structure of corpus callosum. CONCLUSION: DT-MRI presents new data about structural changes of white matter tracts in traumatic brain injury. PMID- 21260933 TI - [Application of robotic assistance in surgical treatment of degenerative disease of lumbosacral spine]. AB - Robotic assistance has gained increasing popularity in spinal surgery recently. Robotic assistance provides higher effectiveness and safety especially in conditions of complicated anatomy. It also enables the novel, previously unavailable surgical techniques, such as GO-Lif for lumbar spine fusion. The aim of the study is to assess the applicability and effectiveness of the robotic assistance in surgical treatment of degenerative lesion of lumbar spine. 16 patients were operated with robotic assistance device (SpineAssist; MAZOR Surgical Technologies, Caesarea, Israel) between August 2009 and February 2010 in Spinal Department of Burdenko Neurosurgical Institute (Moscow, Russia) with degenerative disc disease. Preoperative assessment included MRI, X-rays and high resolution CT (slice < 1 mm). The CT is essential for preoperative planning using computed work station SpineAssist. The robot was utilized for automated intraoperative positioning of the instruments according to preoperatively planned trajectories. Basic parameters of surgeries were thoroughly recorded: overall surgery time, radiation dose (all manipulations were performed under fluoroscopic control), accuracy of screw placement relative to preoperative planning, which was assessed using postoperative high-resolution CT with 3D reconstruction. Particular interest of the study was focused on the novel fusion technique for lumbar spine: Go-Lif (Guided Oblique Lumbar Interbody Fusion). This fusion modality enables segment fixation with two screws only, it is comparable with pedicular screws in terms of stability, being far less invasive. It may be used standalone or together with TLIF techniques. Robotic assistance enabled optimal screw placement even in complex anatomical cases (thin pedicles and rotational deformity). No implant-related complications were recorded. Surgery time was much longer in first 2 cases, though in further it decreased nearly to conventional (without robot) surgery time. For radiation dose same tendency was observed--in first 2 cases all surgical steps were fluoroscopically controlled, in further cases--only for primary anatomy registration. Based on control CT, accuracy of implant placement with robotic assistance is 1 mm. PMID- 21260934 TI - [Age-related changes of topographic anatomy of trigeminal nerve root entry zone]. AB - Clinical anatomy of trigeminal nerve root was investigated on 51 cadaver human skull base specimen. 102 parameters of trigeminal nerve roots were analyzed. All specimens were divided into 3 groups for definition of age-related changes: < 40 years, between 41 and 50 years, > 50 years. We demonstrated that mean length and diameter of trigeminal nerve root did not change with age. Trigeminal nerve root entry zone is located inside pioarachnoidal infundibulum--subpial cavity. We found that pioarachnoidal infundibulum was prone to age-related involutive changes. PMID- 21260935 TI - [Long-term results of microvascular decompression in treatment of hemifacial spasm]. AB - BACKGROUND: Aim of the study was to assess results of treatment and quality of life of patients with hemifacial spasm (HFS) after microvascular decompression and to analyze intraoperative data in surgical revision of intracranial portion of facial nerve. MATERIALS AND METHODS: The study included 30 patients with HFS who underwent microvascular decompression. Duration of symptoms varied between 1 and 30 years (mean--6.7 years). Typical manifestation of spasm was observed in 28 cases, atypical--in 22. Severity of HS and its influence on everyday activity were assessed using 5-grade scale (by E. Tan), and surgical results--according to degree of clinical improvement combined with evaluation of quality of life using scale HFS-7. RESULTS. Most frequent type of conflict observed in the series was contact between facial nerve and AICA (64.4%). Compression of facial nerve root entry zone was revealed in vast majority of cases (93.3%), and in 2 patients (6.7%) site of compression was distal to the root entry zone. In a female patient with secondary HFS due to the tumor relations of neurovascular structures were altered and their displacement produced conflict between AICA loop and facial nerve. In our series hearing depression of different severity was observed in 16.7% of patients. This disorder is persistent and does not regress in the follow up period. All other symptoms of cranial nerve dysfunction are amenable to resolve within 1-2 months. CONCLUSION: Microvascular decompression of facial nerve is pathogenetically feasible and effective method of treatment of HFS. It allows achievement of consistent regression of symptoms and improvement of quality of life of patients with HFS. PMID- 21260936 TI - [Acute infectious diseases of the kidney and urinary bladder: effectiveness of management]. AB - Expert evaluation of quality of medical care for patients with acute urinary infections in outpatient departments of St-Petersburg stated that this care is inadequate in 90% cases. Risk of the condition aggravation was recognized by the experts in 32% cases. Medical errors in cystitis and pyelonephritis consisted of inadequate information collection (64 and 58%, respectively), misdiagnosis (20 and 12%, respectively), inadequate treatment (12 and 21%, respectively), succession errors (4 and 9%, respectively). Special programs of skill perfection should be introduced for urologists of outpatient departments. PMID- 21260937 TI - [Morphological changes in the ureteral wall in contact ureterolithotripsy]. AB - We studied a harmful action of laser, ultrasound and ballistic energies on intact wall of human ureter in 15 ureters of men and women with renal carcinoma aged 43 55 years (mean age 48 +/- 8 years) before nephrureterectomy in vivo. With growing time of exposure to laser radiation, ureteral mucosa undergoes destructive alterations up to muscular layer. Ureteral wall exposure to ultrasound do not change thickness of the wall considerably, cell elements remain viable. Histological examination of the ureteral wall after exposure to intraureteral ballistic impact suggests that 15 second and longer exposure to this impact may reduce probability of mucosal regeneration because of irreversible changes. The analysis of literature data and original findings shows that now there is no absolutely safe energy for contact ureterolithotripsy. PMID- 21260938 TI - [Radical retropubic prostatectomy accompanied with inguinal hernioplasty via preperitoneal approach]. AB - Radical prostatectomy is now widely practiced in the treatment of prostatic cancer (PC). If PC patients have inguinal hernia, hernioplasty can be made simultaneously with radical prostatectomy without one more surgical approach. The article presents pathogenetic rationale of hernioplasty from preperitoneal approach and an original technique of the simultaneous operation. Positive experience with 32 radical prostatectomies with hernioplasty is described. PMID- 21260939 TI - [Transvesical extraurethral adenomectomy and transurethral prostatic resection in adenoma: specific features]. AB - The procedure of transvesical extraurethral adenomectomy (EUA) and the results of its application were characterized in comparison with transurethral resection (TUR) of the prostate in adenoma. EUA is made via the approach through the extraperitoneal cut of the soft tissues of the anterior abdominal wall, anterior wall of the urinary bladder, semioval or sphenoid incision of the vesicourethral segment. Dissection is conducted of the affected posterior half-round of only proximal prostatic part of the urethra in unaffected anterior and lateral urethral surface. Adenomatous tissues are removed in fragments and radically. Enucleation of the adenomatous nodes is followed by correction of the vesicourethral segment and hemostasis. TUR of the prostate is made without incision of the soft tissues of the anterior abdominal wall, but with removal of the prostatic portion of the urethra, sphincter mechanism of the bladder. After TUR the prostate contains residual adenomatous tissue, inner wound cavity in adenoma bed. The wound of the anterior abdominal wall, anterior wall of the bladder and vesicourethral segment healed by primary intention for 10-14 days, while adenoma bed heals for 6-18 months. EUA does not cause such complication as "adenoma bed", urethral stricture, scar deformation of the bladder neck, urinary incontinence. Radical EUA produces complications 5 times less frequently than TUR of the prostate. PMID- 21260940 TI - [Intravesical electrostimulation and magnetophoresis in overactive bladder in females: efficacy of Amus-01-Intramag device with Intrastim attachment]. AB - High-frequency intravesical electroneurostimulation was made simultaneously with magnetophoresis of the mixture based on oxibutinin. Compared to effects of oral intake of oxibutinin, such method was two times more effective in relation to overactive bladder symptoms relief in shorter duration of the treatment and reduced side effects. Laser Doppler flowmetry discovered that the above combined treatment corrects microcirculation in bladder mucosa. PMID- 21260941 TI - [A method of urine derivation into the sygmorectal reservoir]. PMID- 21260942 TI - Entropy monitoring decreases isoflurane concentration and recovery time in pediatric day care surgery--a randomized controlled trial. AB - AIM: To assess if titrating anesthesia with entropy would result in faster awakening in children undergoing day care surgery. BACKGROUND: Entropy, an EEG based anesthesia depth monitor, has been used in children; however, only one other study has evaluated the effectiveness of entropy monitoring in decreasing awakening time and for titrating anesthetic agents in children undergoing short procedures under anesthesia. METHODS: In a randomized prospective single-blind parallel group trial, 50 ASA grade I-II children, aged 2-12 years, scheduled for lower abdominal or urological surgeries were studied after ethics committee approval and parental consent. The children were randomized to the entropy or control group. Following laryngeal mask airway insertion and caudal analgesia, anesthesia was maintained with nitrous oxide, oxygen, isoflurane. In the control group, anesthesia was titrated according to the hemodynamic parameters and the simultaneously monitored entropy values obscured from the anesthesiologist. In the entropy group, the entropy values (between 45 and 65) were used to titrate the anesthesia. RESULTS: Time to awakening from anesthesia was 7 (3-18) min in the entropy group when compared to 10 (5-21) min in the control group. (P < 0.05) The difference in the mean time to awakening was 2.72 min 95% CI (0.34, 5.1). The end tidal isoflurane concentrations were lower in the entropy group when compared to the control group 15 s following airway insertion (0.78 +/- 0.14 vs 1.24 +/- 0.19), 15 s post caudal and skin incision (0.68 +/- 0.40 vs 0.84 +/- 0.05, 0.68 +/- 0.03 vs 0.77 +/- 0.32, respectively) as well as 5 min after skin incision 0.67 +/- 0.04 vs 0.79 +/- 0.02), (P <= 0.05). CONCLUSION: In pediatric day care surgery, entropy monitoring resulted in statistically though not clinically significant faster awakening and significantly lower end - tidal isoflurane concentrations. PMID- 21260943 TI - Weighing in on the future of gene patenting. PMID- 21260945 TI - miR-31 in cancer: location matters. PMID- 21260944 TI - RB in breast cancer: differential effects in estrogen receptor-positive and estrogen receptor-negative disease. PMID- 21260946 TI - Nucleolar structure: it's all in a tangle. PMID- 21260947 TI - Old-fashioned genetic screens give new insights to DNA replication. PMID- 21260948 TI - The San Antonio Statement, with Ake Bergman. PMID- 21260949 TI - Toxicity and lifespan extension: complex outcomes of histone overexpression in budding yeast. PMID- 21260950 TI - A combination of 1alpha,25-dihydroxyvitamin D3, a plant-derived antioxidant and an inhibitor of the Cot1/Tlp2 oncogene as molecularly targeted weapons in the hematologist's battle against acute myeloid leukemias. PMID- 21260951 TI - Cdc25 phosphatases: differential regulation by ubiquitin-mediated proteolysis. PMID- 21260952 TI - Establishment of sister chromatid cohesion: the role of the clamp loaders. PMID- 21260953 TI - An unusual hurdle to renal transplantation: speckled abdominal opacities induced by lanthanum carbonate. PMID- 21260954 TI - Late diagnosis of human immunodeficiency virus (HIV) in two patients previously treated for pulmonary tuberculosis--a missed opportunity for an earlier HIV diagnosis? PMID- 21260955 TI - A case of haemoptysis, cutaneous leucocytoclastic vasculitis and positive ANCA- immunosuppression or not? PMID- 21260956 TI - Acetazolamide therapy in meningeal involvement of nephrogenic systemic fibrosis. PMID- 21260957 TI - Tamoxifen use in retroperitoneal fibrosis. PMID- 21260958 TI - Thrombotic thrombocytopenic purpura associated with disseminated varicella zoster in a multiple myeloma patient. PMID- 21260960 TI - What else life if not awkward? PMID- 21260959 TI - Intravitreal bevacizumab injection for central serous chorioretinopathy. PMID- 21260961 TI - Imagine: towards an integrated and applied social psychology. AB - This commentary does not aim to engage with the epistemological and ontological technicalities of the discursive psychology maintained by epistemological constructionism and discursive psychology reliant on ontological constructionism approaches that form the basis of the two papers under discussion; other commentators, both in this issue and in the future, are likely to do that. Instead, this commentary aims to situate both papers within a broader frame of contemporary, primarily British social psychology, to ponder the circumstances that gave rise to them and their implications for social psychologists, discursive and non-discursive, alike. We have organized this commentary into two parts. The first part considers two simple questions. First, why does Corcoran critique DPEC for failing to do things that other discursive approaches provide for? And, second, why does Corcoran take DPEC research to task for having too little potential for or made too little contribution to improving the lives and subjectivities of people in general? These two questions are not unrelated, but for clarity's sake we will try to answer them separately. The second part of this commentary will consider the influence of discursive psychology on social psychology more generally. PMID- 21260962 TI - Neuropsychiatric disorders: Neurons excited to death by SLE autoantibodies. PMID- 21260964 TI - Crystal arthritis: 'Treat-to-target' with allopurinol is feasible in patients with gout. PMID- 21260963 TI - Rheumatoid arthritis: Immunogenicity is predictive of future treatment success in RA. PMID- 21260965 TI - Osteoarthritis: Chondrocyte protection--SIRTified? PMID- 21260966 TI - Imaging: PET-CT promising in animal studies. PMID- 21260968 TI - Imaging: Optical molecular imaging to detect early endothelial activation: a promising novel modality for RA? PMID- 21260967 TI - Psoriasis: Could IL-23 go solo as a therapeutic target for psoriasis? PMID- 21260969 TI - Patient information page. Gynecomastia. PMID- 21260970 TI - [Medical, social and psychophysiologic aspects in formation of work potential concerning industrial workers in the region]. AB - The authors present results of long-standing research on medical, social and psychophysiologic characteristics of actual and potential workers as the most important components of work potential. The article covers importance of social and psychologic factors, functional state of cardiovascular system in formation of work potential. PMID- 21260971 TI - [Medical ecology: some results and research perspectives]. AB - The article summarizes materials of long-standing research evaluating influence of environmental (natural and anthropogenous) factors on health state of various population groups (exemplified by Siberia). The authors defined leading problems and ways of medical ecology development. PMID- 21260972 TI - [Public health problems in Siberian cities and regions]. AB - The article covers main results of long-standing studies of public health problems in Siberian cities and regions. The author evaluated role of social and ecologic, economic, psychosocial and other factors in formation of growth and losses in vital, work and reproductive potentials of population. PMID- 21260973 TI - [Main aspects of classification and course of occupational neurointoxication with toxic chemical complex in firemen]. AB - The article covers results of long-standing research of peculiarities of psychoneurologic syndromes formation in firemen during distant period after intoxication with toxic chemical complex. The authors studied course, peculiarities of early manifestations of neurointoxication. Analysis of the data obtained helped to classify occupational intoxication with toxic chemical complex, considering the clinical peculiarities. PMID- 21260974 TI - [Functional state of vision system under chronic mercury intoxication]. AB - Examination of chronic mercury intoxication patients in distant (post-contact) period revealed marked vision disorders and inhibited neuro-conductivity- inhibited neuronal structures of retina and optic nerve. PMID- 21260975 TI - [Serotonergic system of neurons in the CNS of terrestrial snail: morphology, ontogenesis, control of behavior]. AB - The morphology of the serotonergic neurons modulating withdrawal behavior in the CNS of terrestrial snail was studied. It was shown that only one Pd4 neuron projects to the pleural and parietal ganglia. Its intracellular stimulation caused the same effects as the stimulation of the whole group of modulatory neurons. In juvenile snails, the number of serotonergic neurons and their relative sizes are smaller than in adult animals, which can be the reason for the observed age-related differences in the withdrawal behavior. PMID- 21260976 TI - [Electrographic correlates of real and imaginary movements: spectral analysis]. AB - The research carried out with eight virtually healthy volunteers showed that movements were associated with the increased level of activation, primarily, in the central areas of the brain cortex, which was expressed in a reduction of the spectral power of alpha end beta frequencies and increase in the power of the gamma oscillations more expressed in the parietooccipital derivations of the left hemisphere. Mental reproduction of similar movements was accompanied by additional activation in the frontal, temporal, parietal, and occipitals regions and more pronounced increase in the power of the gamma oscillations. A number of electrographic phenomena associated with specific features of the movements were revealed. PMID- 21260977 TI - [EEG in mathematical logical problem solving]. AB - The model of mathematical logic tasks was developed at which decision there was a value coherence in delta-range raised. In low-frequency ranges (delta, theta, and alpha) a coherence of potentials of frontal cortex were increased. In high frequency ranges (beta1, beta2, gamma) in frontal cortex coherence was decreased, and its increasing in central, parietal, temporal, and occipital areas with prevalence in the left hemisphere. Most changes of quantity of positive connections observed in value diagonal coherence. Analysis of spectral power EEG has shown, that at the decision of tasks there is a generalised raising on a cortex in delta-range. Theta-activity increased in a frontal cortex, and gamma band was raised in occipital areas. A spectral power in an alpha range mainly decreased. PMID- 21260978 TI - [Corvidae are able to understand the logical structure in string-pulling tasks]. AB - The ability of the Corvidae to understand the logical structure in string-pulling tasks was studied in a set of experiments with varied position of strings. It was demonstrated that some hooded crows (Corvus cornix L.) and common ravens (Corvus corax L.) successfully completed the tasks where the strings were not intersected but placed so that the bait was positioned opposite the forepart of the empty string. Hooded crows also solved the task where the baits were attached to both strings, but one of the strings was disrupted. The task with two intersected strings where the bait was positioned opposite the forepart of the empty string was not solved by the crows. The results suggest the ability of both examined species to grasp the logical structure of such kind of tasks. PMID- 21260979 TI - [Age-related aspects of male rats sexual behavior with different senescence rates]. AB - Social and sexual behavior of males Wistar and senescence-accelerated OXYS rats was studied. The experimental model excluding direct interaction between partners showed that the exploratory activity decreased with aging in rats of both strains, but social motivation didn't change. No interstrain differences in intensity of sexual motivation in the presence of an inaccessible receptive female were observed in 4-month rats. The level of sexual motivation of 12-month Wistar rats didn't differ from that of 4-month animals. However, in 12-month OXYS males, sexual motivation was decreased as compared to both 4- and 12-month Wistar rats. The same regularities were found under conditions of direct interaction with a partner. Behavioral changes in 12-month OXYS rats were considered as genetically determinate abnormality at the initial stage of sexual behavior, i.e., sexual motivation. The results suggest the accelerated senescence of the reproductive system of OXYS rats. PMID- 21260980 TI - [The excitation wave returning to the hippocampus through the entorhinal cortex can reactivate the populations of "trained" CA1 neurons during deep sleep]. AB - It is suggested that the information about a new stimulus from the neocortex is transferred to the hippocampus and forms there a transient trace in the form of a distributed pattern of modified synapses. During sleep, the neuronal populations which store this trace are reactivated and return to the neocortex the information necessary for consolidation of the permanent memory trace. A possible mechanism of the reactivation of the "learned" hippocampal neurons during memory consolidation is the reverberation of excitation in the neuronal circuits connecting the hippocampus and the entorhinal cortex. In rats, we recorded responses in hippocampal field CA1 to stimulation of the Schaffer collaterals with potentiated synapses during wakefulness and sleep. We showed that in the periods of deep sleep, after the discharge of CA1 neurons, the wave of excitation passes through the entorhinal cortex and via the perforant path fibers enters the hippocampus and the dentate gyrus, causing in the latter the discharge of neurons. The repeated discharge of the CA1 neurons develops as the result of interaction of the early wave which is returned directly via the perforant path fibers and the late wave which is returned via the Schaffer collaterals, but not through the dentate gyrus and hippocampal field CA3 (trisynaptic pathway), but, probably, through the field CA2. PMID- 21260981 TI - [Food-procuring skill in rats: prolongations of the extension phase in final movements of right-handed rats]. AB - In Wistar rats with different forepaw preference trained to get food spheres from a narrow horizontal tube feeder, the duration of the paw extension phase was studied in both preliminary and final (successful) food-procuring movements. In left-handed rats, the paw extension was fastly in both preliminary and final movements than in right-handed animals. In right-handed animals, the extension phase of the final successful movements was much slower than that of preliminary movements, whereas in left-handed rats the slowing of the final extension was poorly expressed. The prolongation of the extension phase suggests a possibility of correction of the extension phase of the goal-directed movements PMID- 21260982 TI - [Effects of chronic imipramine treatment on behavior in mice of congenic strains AKR and AKR.CBA-D13Mit76 differing in the distal fragment of chromosome 13]. AB - Congenic mouse strain AKR.CBA-D13Mit76 carries the 59-70 cM fragment of chromosome 13 transferred from genome of cataleptic CBA/Lac strain to genome of AKR/J none-cataleptic strain. This fragment contains the major gene of predisposition to pinch-induced catalepsy. We investigated contribution of the fragment to regulation of sensitivity of catalepsy, sexual motivation and social investigation to classical tricyclic antidepressant imipramine. The sexual motivation was higher in AKR.CBA-D13Mit76 than in AKR mice. Chronic imipramine treatment (25 mg/kg) reduced it in AKR.CBA-D13Mit76 mice and had no effect on weakly expressed sexual motivation of AKR males. No significant effects of genotype or chronic imipramine treatment on characteristics of social interest were observed. Imipramine failed to alter catalepsy expression in AKR.CBA DI3Mit76 mice. Possible molecular genetic mechanisms underlying difference in behavioral responses to antidepressant administration are discussed. PMID- 21260983 TI - [Kinematic characteristics of the voluntary cyclic trunk movements in patients at the early stage of Parkinson's disease]. AB - Patients with the initial stage of Parkinson disease (PD) and matched controls performed repetitive bendings and turnings in standing position. Tasks included trunk movements in each of the anatomical planes: sagittal, frontal and axial. Electromagnetic system Flock of Birds was used for movement registration. Sensors were fixed at different segments of subject's body. Joint angles in the ankle, hip and torso as well as coordinates of the center of pressure served as output parameters. The amplitudes of joint angles were found to be lower in PD patients. Performance of the axial rotation revealed most pronounced differences. Thus, the amplitudes of joint angles of trunk movements in different anatomical planes reliably discriminate between PD patients and healthy subjects. PMID- 21260984 TI - [Decrease in sucrose solution consumption by CBA/Lac male mice under chronic social stress]. AB - The influence of repeated experience of social defeats in daily agonistic interactions on voluntary consumption of 1% sucrose solution supplemented with vanillin (0.2%) was studied in male mice of CBA/Lac strain with genetic predisposition to catalepsy as compared to depression-predisposed C57BL/6J mice. Intact mice of both strains prefered sucrose solution to water under conditions of two-bottle free choice. Sucrose solution intake was shown to decrease in losers of both strains exposed to social confrontations as compared to controls. It was suggested that the high level of anxiety revealed in mice of both strains can be the determining factor of the decrease in sucrose solution consumption under conditions of chronic social stress. PMID- 21260985 TI - [Detection of light intensity in the frog retina: evidence from dark and light adaptation]. AB - The frog retina was stimulated with light flashes homogeneous in space but not time. The time heterogeneity of stimulation was created by abrupt change of a referent stimulus for a stimulus with different luminance. Such changes form a time pattern, as well as sharp borders of luminance between the neighbor areas of the visual field form a spatial pattern. The electroretinogram recorded in response to presentation of a triad of stimuli: the onset of a short flash of homogeneous light after long dark (or light) adaptation of a retina, brief sequence of the referent and test light flashes varied in luminance, and the offset, with returning to the initial level of adaptation. It was shown that responses of the retina under conditions of time heterogeneity of stimulation could be divided in two types as well as under conditions of spatial heterogeneity. Such a dual change in amplitude confirms our earlier hypothesis on the existence of two mechanisms of luminance coding in the frog retina. The first mechanism encodes power characteristics of light, it forms the information on the absolute level of the environmental luminance. Its activity is connected basically with receptors and cells of the external plexiform layer of the frog's retina. It is responsible for the b-wave of the electroretinogram. The other mechanism associated with RERG is based on a vector code of stimuli. This mechanism forms the information on spatial and time differentiation of the light flow in the visual field and is connected basically with cells of the internal plexiform layer. The results suggest that the frog retina has the individual mechanism for time pattern detection, distinguishing it from the homogeneous light flow in a similar way as in case of spatial light pattern detection. It is possible that the first mechanism is responsible for the detection of any new stimulus in general, irrespective of its specificity, whereas the second mechanism serves for the measurement of suprathreshold differences between stimuli. PMID- 21260986 TI - [Effect of genotype and emotional stress on hygienic grooming in inbred mice]. AB - Body care behavior (grooming) is an adaptation aimed at removing litter particles, pathogenic microbes and parasites from animal fur and skin. Moreover, it serves as an indicator of animal health. It was observed that chronic stress suppressed fur cleaning. In this article, a technique of direct measurement of fur cleaning using the cleaning dynamics of a fluorescent spot applied on animal's back is described. Significant effects of genotype and emotional stress on the dynamics of fur cleaning are shown. Mice of C57BL/6, CBA and CC57BR strains clean green fluorescent spot rapidly (1-2 h) whereas animals of AKR strain clean it slowly (up to 24 h). Behavioral restriction for 30 min substantially reduced fur cleaning in AKR, CBA and CC57BR, but not in C57BL/6. The stress-induced attenuation of Hygienic grooming is a new index of sensitivity (resistance) to stress. PMID- 21260987 TI - [Methodology for pathogen collection]. AB - Provision of investigations with collection pathogen cultures must ensure the adequacy of the properties of museum cultures to the characteristics of their natural prototypes. The standard preparation of collection cultures by the protocols that is optimal to preserve the original properties of a natural pathogen population, all other things being equal, assures the compatibility of the results of studies irrespective of the place and time of their performance, i.e. their continuity. The original biological properties of microorganisms can be preserved under laboratory conditions when the minimum number of enrichment and restorative culture passages is made using the biological objects that have a minimum impact on the geno- and phenotype of specific culture strains. To unifying approaches to identifying stored and incoming pathogens, to standardize the principles of identification, passport issuing, long-term preservation of the original biological properties of the reference cultures of strains, and to set up a system for the interdepartmental information support of collection tasks are problem areas for the creation of a common federal collection of microorganisms. PMID- 21260988 TI - [Molecular genetic studies of the susceptibility of epidemic influenza A(H1N1) virus strains isolated in the 2006-2009 seasons in Russia to oseltamivir (Tamiflu)]. AB - Oseltamivir (Tamiflu) is recommended by WHO experts as a drug to treat and prevent of influenza and to create stocks if its new pandemic variant occurs. The susceptibility of influenza viruses to oseltamivir was studied by polymerase chain reaction-based techniques detecting specific mutations in the neuraminidase gene. The increase in the number of oseltamivir-resistant influenza viruses, isolated from the Russian Federation, with type 1 neuraminidase H274Y mutation from 49% (2007-20008) to 92% (2008-2009) did not depend on the frequency of oseltamivir use. Full correlation of the results obtained by various techniques allows them to be used to monitor the susceptibility of influenza viruses to oseltamivir. PMID- 21260989 TI - [Impact of mutations in the hemagglutinin gene of H5N1 influenza virus on antigenicity and virulence as revealed by site-specific mutagenesis]. AB - In our earlier studies, we have shown that amino acid changes in the hemagglutinin (HA) of influenza H5N1 virus escape mutants conferring resistance to monoclonal antibodies (MAbs) may correlate with a decrease of virus virulence for mice and that the virulence can be restored to the initial level by serial passages. In the present study, the mutations identical to those observed in the HA of a low-virulent escape mutant and its readapted variant were introduced into the HA gene by site-specific mutagenesis. The viruses produced by plasmid transfection and containing the HA gene either of A/Vietnam/1203/2004 (H5N1) virus with a deletion at the cleavage site, or of a low-virulent escape mutants, or of its readapted variant, in the presence of 6 genome segments of A/Puerto Rico/8/34 (H1N1) virus and the NA gene of A/Vietnam/1203/2004 (H5N1) virus, were assayed for virulence. Determination of virulence for mice indicated that amino acid substitution in the HA gene of a low-virulent escape mutant produced a decrease of virulence whereas the additional mutation identical to that acquired by the escape mutant in the course of readaptation restored the virulence to initial level. The findings are the first strong evidence for lower H5N1 virus virulence resulting from the amino acid substitution changing the antigenic specificity of HA and for restored virulence arising from compensating mutation in the HA gene. PMID- 21260990 TI - [Effect of the antiviral drug Ingaviruin on intracellular transformations and import into the nucleus of influenza A virus nucleocapsid protein]. AB - The paper presents the results of studying the effect of the antiviral drug Ingavirin on different stages of intracellular transformations of influenza A virus nucleocapsid protein (NP). Ingavirin 400-1000 microg/ml has been found to impair the biogenesis of influenza virus NP, to lower the efficiency of formation of conformationally mature compact NP oligomers, and to retard the migration of newly-synthesized NP from the cytoplasm to the nucleus. It is shown that there is an association of tritium-labeled Ingavirin with the nuclear membranes of MDCK cells. The investigations of the mechanisms of antiviral activity of Ingavirin are not only important for the characterization of this drug, but also promote the detection of potential targets to design novel antiviral agents. PMID- 21260991 TI - [Investigation of genetic polymorphism of the integrase gene in the HIV-1 subtype A populations circulating in the Russian Federation]. AB - The paper presents the data of an investigation of the genetic polymorphism of the pol gene encoding viral integrase (IN) in a HIV subtype A infected population in the Lipetsk Region. The investigators analyzed 32 virus subtype A samples obtained in 2002-2007. Polymorphism at the codons associated with IN resistance to chemicals was observed in 7 virus variants. The found substitutions had a pattern of genetic polymorphism and were unassociated with resistance in 6 patients with the test subtype A population. At the same time, minor RAL resistance mutation was revealed in 1 (3.1%) virus variant while the similar mutations in the subtype G population were about 10%. PMID- 21260992 TI - [Molecular epidemiology of HIV-1 strains in the Moscow Region]. AB - The Moscow Region is one of the HIV-1-affected subjects of the Russian Federation; there were 34613 HIV-1-infected subjects as of October 31, 2009. To characterize the molecular epidemiology of HIV-1 in the Moscow Region, the investigators obtained and studied HIV-1 variants from 61 infected subjects of the region, who were major risk groups: intravenous drug users (IDUs) and hetero- and homosexually infected persons. Genetic analysis of HIV-1 variants was carried out by sequencing the gag genes (729 nucleotides in length, including full-length protein p17 and partial p24) andlor env (270 nucleotides in length, V3 region) with further phylogenetic analysis. The findings demonstrated that HIV-1 subtype A variants are dominant in the Moscow Region and detectable in 93.5% of IDUs and 100% of heterosexually infected persons. Phylogenetically (and accordingly epidemiologically) unrelated HIV-1 subtype B strains were revealed in 4 patients, including 2 IDUs. PMID- 21260993 TI - [LMP1 gene polymorphism in patients with Epstein-Barr virus-negative gastric carcinomas in Russia]. AB - The investigation was undertaken to study the molecular characteristics of Epstein-Barr virus (EBV) LMP1 gene samples amplified from the tumor and intact tissues of patients with EBV-negative forms of gastric carcinoma (GC). The genetic structure of these samples determined by their sequencing was compared with that of the gene samples isolated from the cells of oropharyngeal washing specimens from the same patients with GC, as well as peripheral blood lymphocytes of patients with infectious mononucleosis (IM) and blood donors. The findings suggest that the samples of tumor tissue LMP1 from patients with GC have higher divergence than those from patients with IM and blood donors although no specific variants of the gene for GC were found. Comparison of LMP1 sequences from tumor tissue and cells of oropharyngeal washing specimens from the same patients with EBV-negative GC revealed the common LMP1 variant in 2 cases while they differed in 3 cases. The findings are an initial step in studying the role of EBV in the carcinogenesis of EBV-negative GC that is likely to be established by investigations on representative clinical material, by applying the up-to-date technologies. PMID- 21260994 TI - [Serological and molecular genetic markers of hepatitis C virus in infected donors]. AB - The frequency of hepatitis C virus (HCV) markers was determined in donors; the spectrum and activity of specific antibodies (anti-HCV), the distribution of virus genotypes, and HCV RNA concentrations were studied in virus carrier donors. The activity of antibodies in HCV RNA-negative donors was significantly lower than that in HCV RNA-positive donors (p < or = 0.001). There was a statistically significant difference in antibody activities in donors infected with genotype 1b as compared with those infected with genotype 3a (p < 0.001). However, no correlation was found between the concentration of a virus genome and the activity of specific antibodies. The risk for obtaining infected blood donations was determined during plasma screening by enzyme immunoassay (EIA). Our investigations have indicated that the frequency of serological window period donations is one case per 74750 test plasma units and that of HCV RNA-positive donations with low antibody positivity coefficients, which are frequently detectable as seronegative during screening for laboratory errors, is one case per 37375 test units. A combination of EIA and polymerase chain reaction has shown to minimize the risk of contamination of donor plasma with HCV markers. PMID- 21260995 TI - [RT-PCR detection of deformed wing virus in the honey bee Apis mellifera L. in the Moscow Region]. AB - Deformed wing virus (DWV) was first detected in the honey bee Apis mellifera by reverse transcriptase-polymerase chain reaction (RT-PCT) in the Moscow Region. Molecular phylogenetic analysis of the detected nucleotide sequence of the virus fragment VP2-VP1 of DWV demonstrated that the Russian virus sequence is united in the common cluster with all earlier revealed nucleotide sequences of DWV in the Genbank worldwide, which confirms the previous conclusions that this virus has recently distributed in the honey bee by Varroa destructor mite. It has been shown that the level of homology for all DWV nucleotide sequences is 98%, except for nucleoside sequence of 7D isolate from Turkey (96% homology), 96% homology with Kakugo virus and 84-86% homology with Varroa destructor virus 1; there is a preponderance of insignificant nucleotide substitutions, mainly transitions, which supports the evolutionary propinquity of 3 viruses. PMID- 21260996 TI - [Genotyping of varicella zoster virus strains isolated in Mongolia]. AB - This study analyzed 50 varicella zoster virus (VZV) samples collected during 2004 to 2007 from patients with VZV infection, who were treated at the National Center of Communicable Diseases, Ulan-Bator, Mongolia. The method based on amplification of specific DNA fragments of the ORF21, ORF22, and ORF50 genes was used, followed by the sequencing and detection of the status of characteristic point mutations in these fragments. The results indicated that the collected samples belonged to genotypes J (62%), M1 (18%), E1 (12%), E2 (4%), and M2 (4%). Moreover, restriction endonuclease polymorphism in ORF 62 for the cleavage site Smal and Mspl, in ORF 38 and ORF 54 for the cleavage site Pstl and Bgll were analyzed. All the samples were Sma- Msp-. All samples with genotype E were Pst+ Bgl-; all samples with genotype M1 and M2 were Pst+ Bgl+. Out of 31 samples with genotype J, 29 and 2 were Pst+ Bgl+ and Pst+ Bgl+, respectively. The study could identify the genotypes of VZV circulating in Mongolia and confirmed the absence of mutations characteristic for the vaccine strain. PMID- 21260997 TI - [Horizontal transmission routes of baculovirus infection in gypsy moth (Lymantria dispar L.)]. AB - The paper considers horizontal transmission routes of baculovirus infection in the gypsy moth (Lymantria dispar L.). The original method for modeling natural processes in controllable conditions allowed one to estimate the influence of factors on the occurrence of epizooties. The authors investigated 3 possible models of virus transmission from infected to uninfected gypsy moths: 1) infected and test caterpillars were kept and fed together (a complex route); 2) those which were in the immediate vicinity, but deprived of eating together (an aerial route); 3) test caterpillars were fed on the leaves on which infected caterpillars had eaten (an oral route). The investigations have shown that the complex and oral routes out of the considered models may be considered to be effective infection transmission routes for the horizontal spread of epizooties. Furthermore, the availability of sufficient amount of infected caterpillars in the population leads to a reduction in the resistance of healthy insects to other diseases. Thus, by taking into account the capacity of larvae for passive migration, the purpose of insecticidal treatment is to set up a few infection foci that will be a source for the spread of epizootias and contribute to an overall viability reduction of a pest population. PMID- 21260998 TI - [Influenza virus reproduction in the MDCK cells adapted to growth in serum-free Hybris-2 medium]. AB - Whether the MDCK cell line might adapt to grow in serum-free Hybris-2 medium and influenza viruses might be reproduced in the adapted cells was studied. Seventeen passages using the Hybris-2 medium yielded cells adapted to growth in this medium (MDCK-BS). The reproduction of influenza A (H1N1 and H3N2) and B viruses versus the cells cultured in Eagle's medium was studied. The laboratory strain of influenza A/Aichi/1/68 (H3N2) and the strain B/Ohio/01/05 of influenza B in equal titers were shown to be reproduced in both control cells on Eagle's medium and MDCK-BS cells adapted to growth in the Hybris-2 medium. The reproduction of the strains A/Brisbane/10/07 (H3N2) and A/Solomon Islands/3/06 (H1N1) was less active in the MDCK cells. Each strain of influenza viruses displayed varying infective activities. The developed serum-free Hybris-2 medium may be used for cultivation of monolayer continuous MDCK cells and for their reproduction of influenza A and B viruses. PMID- 21260999 TI - [The connection between molecular-cellular parameters and immune status of liquidators after Chernobyl accident]. AB - The genome damage (the frequencies of cells with micronuclei (MN), chromosome aberrations, the level of DNA double-strand breaks (DSB DNA), the concentration of reactive oxygen species (ROS) and 28 immunological parameters have been studied on the blood lymphocytes of Chernobyl accident liquidators. The purpose of this article was the investigation of cytogenetic, molecular changes of blood lymphocytes of irradiated individuals 24 years after accident, examination it there are correlation between genome damage and immunological parameters. It was shown that in lymphocytes of liquidators the frequencies of cells with MN and with all type of chromosome aberrations didn't differ from the lymphocytes of nonirradiated individuals, but the frequency of chromosome aberration type was increased, the level of DSB DNA was increased too. The concentration of ROS is decreased. The percent of cytotoxic CD8(+)-T-lymphocytes, natural killer cells (CD16(+)-lymphocytes), CD3+ CD16+ CD56+ (NK-T-cells), that posses antivirus and antitumor activity--HLA-DR+, regulatory T-lymphocytes (CD4+ CD25+high) in liquidators significantly increases. The level of serum immunoglobulin (Ig A) significantly increases too. The index of immune regulation, meaning of phagocyte neutrophil (FAN) and macrophage activity decreases. In liquidators there are significant correlation between the frequencies of cells with MN and the content of regulatory T-lymphocytes (p < 0.05), between the concentrations of ROS and activated T-lymphocytes. More connection is on the tendency level (p < 0.10): the frequency of chromosome aberrations, the DSB DNA level with natural killer cells and regulatory T-lymphocytes; the frequency of cells with MN and DSB DNA and FAM. We can suppose that genomic instability induced by the liquidators of Chernobyl accident consequences 24 years ago manifests now as increased genome damage and oxidative status decrease that can result in imbalance of cells and humoral immune status, disturbancies of health. PMID- 21261000 TI - [Molecular-cellular characteristic of blood lymphocytes in Hodgkin lymphoma]. AB - The molecular-cellular parameters complex has been studied on the blood lymphocytes of malignant Hodgkin's lymphoma (HL) patients: the frequency of cells with micronuclei (MN) and chromosome aberrations; the level of DNA single and double strand breaks - OR and DR DNA (DNA comet assay), oxidative status--the content of reactive oxygen species (ROS) by using nonfluorescent dye that is oxygenated in the cells to fluorescent reagent and detection of fluorescence intensity after there. It was shown that the patients with LH had the increased level of DR and OR DNA, the increased frequency of cells with chromosome aberrations and the number of aberrations per cell was increased too. The concentration of ROS is increased too for the most individuals with intoxication. In the process of the chemical and radiation therapy the increase of OR DNA level, the frequency of the cell with MN has been registered. The ROS concentration correlates with the level of DNA-strand breaks. So the blood lymphocytes of HL patients before treatment differ from the lymphocytes of healthy donors. The damage of genome and the change of oxidative status have been observed that can be additive markers for the HL diagnosis, their sensitivity to the treatment and the characteristic of lymphocytes changes by this disease. PMID- 21261001 TI - [Osmotic homeostasis as one of critical targets of cell damage by some environment factors]. AB - The analysis of ours and literary data confirmed author new conception of cell damage mechanism by some environment factors according which the system of osmotic homeostasis is one of the critical targets of such damage, is presented. PMID- 21261002 TI - [The radiationally induced change of level of double-stranded breaks DNA in neuroblasts of larvae and frequency of lethal mutations in sex cells of males Drosophila melanogaster]. AB - The level of damage DNA in neyroblastes of larvae and frequency of recessive sex linked lethal mutations of males from chronically irradiated populations Drosophila melanogaster, differing on mobile P-elements patterns, was estimated. Received results testify, that exposition in conditions a chronic gamma-radiation (absorbed radiation dose at one generation is compounds 10 mGy) result to increase of significance of parameters and change of sensitivity of cells to following of an acute irradiation in a dose of 3 Gy. PMID- 21261003 TI - [Inhibitors of the heat shock protein 90 activity: a novel class of tumor radiosensitizers]. AB - The 90 kDa heat shock protein (HSP90) is one of major chaperones of eukaryotes which catalyzes maturation and activation of its client proteins. Among the identified client proteins there are oncogene products, hormone or growth factor receptors and key components of signaling pathways responsible for the malignant growth of tumors or their resistance to chemotherapy and radiotherapy. In the case of inhibition of the HSP90 chaperone function, such proteins are inactivated and degraded soon that leads to simultaneous blocking several pathways essential for proliferation and survival of malignant cells; therefore, pharmacological inhibitors of the HSP90 chaperone activity could be used in anticancer therapy. At present, several HSP90 inhibitors are in preclinical testing or I-III Phase clinical trials as mono-agents or in combinations with other anticancer drugs or radiation. In the present review, all the data are summarized which characterize HSP90 inhibitors as effective radiosensitizers of tumor cells. Molecular mechanisms and selectivity of the radiosensitizing action of HSP90 inhibitors are here discussed as well as a possibility of their application to improve the outcome of radiotherapy. PMID- 21261004 TI - [Haemopoiesis-stimulating and radiomodifying effects of a preparation from a plant Chamaenerion angustifolium]. AB - The experiments as conducted in mice revealed radioprotective therapeutic effect of a preparation made from a plant Chamaenerion angustifolium. The preparation per oral administration in the course of 4 to 8 days post radiation at a dose range of 7.2 to 10.8 Gy promoted an increase in total amounts of blood leukocytes, marrow bone and spleen cells, and also some increase in survival rates among the animals. PMID- 21261005 TI - [Mathematical modeling of synergistic interaction of sequential thermoradiation action on mammalian cells]. AB - Data obtained by other authors for mammalian cells treated by sequential action of ionizing radiation and hyperthermia were used to estimate the dependence of synergistic enhancement ratio on the ratio of damages induced by these agents. Experimental results were described and interpreted by means of the mathematical model of synergism in accordance with which the synergism is expected to result from the additional lethal damage arising from the interaction of sublesions induced by both agents. PMID- 21261006 TI - [Quantitative dependence of sheep death on dose and dose rate of external gamma radiation]. AB - The results of experimental studies of sheep death at different dose rates of gamma-radiation have been analyzed. Parameters of a mathematical dependence of animal death on the exposure dose and dose rate have been identified. The evaluation of adequacy of the derived equation has demonstrated that the established relationship correctly describes the experimental data in studied dose rate range. PMID- 21261007 TI - [Non-thermal electromagnetic fields and estimation of the convulsive syndrome probable development]. AB - There are cases of development of a convulsive syndrome at influence of electromagnetic field (EMF) in physiotherapy practice, and in conditions of a professional work. There is a point of view that EMF can render medical effect at treatment of a epilepsy syndrome. Some publications specify on develop of epilepsy convulsions in experiment at EMF of various frequencies exposure. Four conditions which can promote development of convulsions at EMF exposure are considered. PMID- 21261009 TI - [Methodology for an assessment of derived radiation levels for agrocenoses]. AB - Radiation protection of agrarian ecosystems should be considered as an integral part of a system for radiation protection of environment, with a special concern to agroecosystems' features. A methodology is proposed for an assessment of maximum permissible doses of radiation impact for agrocenoses based on an unified analysis of available data about effects of radiation in cultivated plants. It is considered as a component of radiation protection system for agricultural ecosystems. Critical doses and dose rates are estimated for crops under different exposure situations. It is shown that doses that could result in decreasing indexes of productivity and survival for main crops below 50% are unlikely up to 170-200 Gy and 15-17 Gy at an acute exposure of dormant seeds and vegetative plants, correspondingly. At chronic exposure, above 10% loss of productivity in crops is not expected at dose rates below 3-10 mGy/h. PMID- 21261008 TI - [Ecological and genetic monitoring of muridae from populations undergone to the chronic irradiation]. AB - In work the data of long-term researches of consequences of chronic irradiation and radioactive pollution on a population of muridaea living in a zone of failure on the Chernobyl atomic power station and in territory of Northern radioecological station are resulted. It is shown, that chronic influence by investigated factors leads to authentically significant change of size of the genetic load determined on a level cytogenetic damages, intensity of reproduction, fertility. PMID- 21261010 TI - [Regulation of acidity of arable lands contaminated by Sr-90: analysis of cost of the averted doses of irradiation of population of Belarus]. AB - Results of researches on study of efficiency of soil acidity optimization on decrease of a collective doze from 90Sr to the population of Belarus are presented. On the basis of the "cost--benefit" analysis it is shown, that the savings for averted collective doze due to optimization of soil acidity of arable lands on cereals amount to 21-170 thousand US dollars per 1 man.-Sv depending on density of 90Sr soil contamination of districts of Belarus. It is established, that high effect on averting of collective doze 90Sr at cultivation of cereals can be expected at liming of sod-podsolic loamy sand soils with contamination density of 90Sr more than 12 kBq/m2, sand soils more than 16 kBq/m2, light loam soils more than 17 kBq/m2, at present time share of these lands in Belarus is about half from the area of the arable lands contaminated with radiostrontium - 86 thousand hectares. PMID- 21261011 TI - [Migration of Cs-137 in frozen soils of Yakutia]. AB - The present-day levels of 137Cs global fallout in frozen soils of the tundra and taiga zones of Yakutia are analyzed in the paper. Patterns of radionuclide migration in different types of zonal soils have been considered. Influence of the frozen forms of micro- and mesorelief over redistribution of 137Cs in soils is investigated. Mean velocities of vertical 137Cs migration in the main types of the frozen soils have been determined. We have found that mean velocity of 137Cs vertical migration in soil profiles depends on water condition and texture of soils. PMID- 21261012 TI - [Diagnosis and treatment of carotid body tumors]. AB - OBJECTIVE: To study the diagnosis and therapy of carotid body tumors. METHOD: A total of 44 patients with carotid body tumors were received and cured in people's hospital of Wuhan University from 1990 to 2010. Two of them were bilateral carotid body tumor patients. The operation were performed in all patients to remove the tumors. Among these patients, 39 of them were undertaken only tumor resecting, 6 were performed resecting of both tumors and external carotid artery and 1 were subjected to tumor resecting including internal carotid artery. RESULT: None of the patients died after operation. In addition, none were detected hemiplegia except that 2 had temporary hoarseness. No recurrence were observed during a follow-up of 2-24 months. CONCLUSION: The most effective way to cure carotid body tumor is surgical operation. A better result may attribute to some key factors included adequate preoperative preparation, making sure the anatomic relationship with vessels and bipolar coagulation under microscope. PMID- 21261013 TI - [Clinical value of ultrasonography in diagnosing recurrent nasopharyngeal carcinoma]. AB - OBJECTIVE: To study the clinical value of ultrasonography in diagnosing nasopharyngeal carcinoma. METHOD: Seventy-five patients with suspicious clinical symptoms of recurrent nasopharyngeal carcinoma were studied 0.5-3.0 years after radiotherapy. All received ultrasonography, computed tomography examination, nasendoscopy and nasopharyngeal biopsy. The diagnostic value of ultrasonography were then evaluated. RESULT: Of 75 cases, recurrent nasopharyngeal carcinomas were detected in 35 cases by ultrasonography. There were 26 cases confirmed pathologically, 9 cases false positive, 25 cases true negative and 15 cases false negative. Meanwhile, of 75 cases recurrent nasopharyngeal carcinomas were indicated in 35 cases by computed tomography. There were 27 cases confirmed pathologically, 8 cases false positive, 26 cases true negative and 14 cases false negative. There were no significant difference between the sensitivity, specificity and accuracy of ultrasonography and computed tomography in diagnosing recurrent nasopharyngeal carcinoma. CONCLUSION: Either ultrasonography or computed tomography has good diagnostic values in detecting recurrent nasopharyngeal carcinoma. Furthermore, both of them can complement each other. PMID- 21261014 TI - [Treatment of nasopharyngeal atresia with dual U-shaped mucosal flap repair and local dilatation]. AB - OBJECTIVE: The aim of current work was to investigate the methodology and effect of dual U-shaped mucosal flap repair plus local dilatation for the treatment of nasopharyngeal atresia. METHOD: Nine patients with nasopharyngeal stenosis were treated with dual U-shaped flap to repair the wound of retropharyngeal and soft palate mucosa. and then dilated by implanting a silicone tube. RESULT: The silicone tube was removed 6 months after the operation. The transverse diameter of nasopharynx maintained at about 2.0 - 2.5 cm, and anteroposterior diameter at about 1.0 cm. All cases had good nasal patency except velopharyngeal insufficiency and nasal regurgitation of food. After a 2 years follow-up, all cases had a good result except one still had the nasal regurgitation of food. CONCLUSION: U-shaped mucosal flap repair with local dilatation is an effective method for treatment of nasopharyngeal atresia. PMID- 21261015 TI - [Significance and relationship between apnea and subsequent hypoxemia of OSAHS patients in a waking state]. AB - OBJECTIVE: To explore the clinical significance and relationship between apnea and subsequent hypoxemia in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) in a waking state. METHOD: Fifty patients with snoring at night and suspected sleep breathing disorders were selected. Each patient was asked to stop breathing at the end of normal expiration level in a waking state and then hold their breath till the decline of the arterial oxygen saturation. The duration from the beginning of stopping breathing to the beginning of the following desaturation were recorded and defined as single delay period of desaturation. The subjects were asked to complete a Chinese version of Epworth Sleepiness Scale and tested by polysomnography all night long. Then the subjects were divided into four groups according to the apnea-hypopnea index (AHI): group 1, AHI < or = 5; group 2, AHI > 5-15; group 3, AHI > 15-30; group four AHI > 30. RESULT: The single delay period of desaturation in group 3 was shorter than that in group 1 (P < 0.05). And it in group 4 was shorter significantly than the other three groups (P < 0.01). AHI, the percentage of the total recorded time spent below 90% oxygen saturation level (TS90%), the time of sleep apnea-hypopnea per hour, heart rate and body mass index (BMI) had a negative relationship with the single delay period of desaturation (r = -0.709, -0.769, -0. 682, - 0.403, - 0.480, P < 0.01). Lowest arterial oxygen saturation (LSaO2 ) and mean arterial oxygen saturation (MSaO2) had a positive relationship with the single delay period of desaturation (r = 0.702, 0.610, P < 0.01). Age had no relationship with it. The single delay period of desaturation, AHI and LSaO2 had a linear relationship with ESS7 (r = -0.688, 0.568, -0.576, P < 0.01). CONCLUSION: The single delay period of desaturation in OSAHS patients get shorter with the degree of severity, especially in the severe ones. The shortening of the single delay period of desaturation maybe a protective mechanism for OSAHS patients so as to reduce the severity of apnea. AHI, LSaO2, TS90% and the sleep apnea-hypopnea time per hour have a close relationship with the single delay period of desaturation and it may provide valuable information for evaluating the severity of OSAHS patients, especially to the serious one. The single delay period of desaturation has a close relationship with ESS7 and may contribute to evaluate the severity of daytime sleepiness. PMID- 21261016 TI - [Surgical treatment for severe stenosis of esophageal access]. AB - OBJECTIVE: To evaluate the surgical management for the severe stenosis of peripheral esophageal access. METHOD: Twenty-three patients who underwent severe stenosis of peripheral esophageal access from 2000 to 2009, were retrospectively reviewed. The surgical plan was selected by considering the stage of stenosis, dilatation, reconstruction of hypopharynx, oesophagus or larynx. RESULT: Twenty two patients resumed a normal oral diet and 21 cases succeeded in decannulation, no stenosis recurred after a 1-9 years follow-up. CONCLUSION: The severe stenosis of peripheral esophageal access can get good results when the appropriate surgical plan were choice. PMID- 21261017 TI - [Expression of CCR6 and CCR7 in laryngeal squamous cell carcinoma]. AB - OBJECTIVE: To evaluate the expressions of chemokine receptor 6 (CCR6), chemokine receptor 7 (CCR7) and their ligands (CCL20, CCL19/CCL21) in laryngeal squamous cell carcinoma (LSCC), and then explore their correlation with the clinicopathological features of LSCC. METHOD: Blood samples, fresh specimens of LSCC and paired adjacent tissues were collected. The expressions of CCR6, CCR7 and their ligands CCL20, CCL19/ CCL21 mRNA as well as the protein CCR6, CCR7 were detected by real-time qRT-PCR and IHC respectively. Flow cytometry was also used to investigate CCR6, CCR7 expressed on PBMC. RESULT: The relative expression levels of CCR6, CCR7, CCL19 and CCL21 mRNA in tumor tissue was significantly higher than that of adjacent tissues (P < 0.05), while the relative expression level of CCL20 mRNA in tumor tissue were significantly lower than that of adjacent tissues (P < 0.05). IHC confirmed the expression of protein CCR6 and CCR7 in both tumor tissue and metastatic ILN and the expression levels of protein CCR6, CCR7 were higher in the cases with lymphatic metastasis than that of those without lymphatic metastasis (P < 0.05). FCM showed the percentage of CD4+ CCR6+ T cells of LSCC was significantly higher than that of normal control (P < 0.05), while that of CD4+ CCR7+ T cells was significantly lower (P < 0.05). CONCLUSION: CCR6 and CCR7 are expressed in tumor situ, metastatic LN and PBMC,and might exert a potential role in LSCC development. PMID- 21261018 TI - [Study on self-assessment, acoustic analysis, laryngoscopy for patients with voice surgery]. AB - OBJECTIVE: To study the self-assessment, acoustic analysis, laryngoscopy and its relationship for patients with voice disorders before and after surgery. METHODS: Fifty patients with voice disorders were undergone self-assessment, acoustic analysis, and laryngoscopy before and after voice surgery. Self-assessment were done by voice handicap index (VHI) Scale Chinese version, including functional (F), physiological (P), emotion (E) and its sum denoted as T. Acoustic analysis were made for patient samples by Dr. Speech voice analysis software and jitter (J), shimmer (S), normalized noise energy (NNE) were selected as three parameters. Laryngoscopic examination were used to record the closure of vocal cord morphologically (C). RESULT: In addition to E, F, P and T(VH) of VHI scale had a good correlation. In acoustic analysis J, S and NNE had a good correlation between them. F, P and T(VH) of VHI scale and acoustic analysis parameters J, S and NNE had a good correlation. Closed degree C and the VHI scale F, P and T(VH) as well as acoustic analysis parameters J, S, NNE had a good correlation. All the above data use were analyzed by Pearson correlation test. CONCLUSION: VHI scale Chinese version make the patient's subjective feelings as the center, thus it has some limitations for the impact of East-West cultural differences, age, educational level and other factors. Acoustic analysis can show a detailed objective aspect of the patient's voice quality and evaluate the result of surgical treatment. Laryngoscopy provide an excellent morphological evidence. Consistency of three methods can do a comprehensive assessment for the voice disease. PMID- 21261019 TI - [Imageology features and transoral approach of benign parapharyngeal space tumors]. AB - OBJECTIVE: To analyze the imageology features of benign parapharyngeal space (PPS) tumors, and also to summarize our experience in removing PPS benign tumors through transoral approach. METHOD: A retrospective review was conducted to 48 patients with benign tumors in PPS during a 10-year period. CT were performed in all patients, and only a few required MRI. Transoral approach (33.3%) and transcervical (39.6%) were the most commonly performed surgical procedures followed by the transcervical-transparotid approach (27.1%). RESULT: CT scan and MRI often provided complementary information to help the surgeons delineate the size, precise location and likely cause of these tumors. After a follow-up of three years, only 2 of 48 patients had disease recurrence. The transoral approach described herein safely allowed for en bloc resection of most benign neoplasms. No significant complications attributed to the approach itself. CONCLUSION: CT or MRI scan can distinguish prestyloid from poststyloid lesions, and to assess the extension of the tumor as well as its relationship with adjacent structures. The transoral approach safely provides access to some benign PPS tumors with a low rate of complications and recurrence as well as traditional transcervical approaches. PMID- 21261020 TI - [Study on inhibitory effects of allicin in mucoepidermoid carcinoma cells]. AB - OBJECTIVE: To observe the anticancer mechanism of allicin by observing the inhibitory effect of allicin on human salivary gland carcinoma cell line MEC-1. METHOD: Cell proliferation were measured by MTT assay at different doses and different hours. In the meantime, cell cycle was detected via flow cytometry after different dose incubation with different hours. RESULT: MTT results showed that the inhibitory rates of MEC-1 proliferations were increased in a concentration-and time-dependent manner. Flow cytometry analysis showed percent age of MEC-1 cells decreased in G0/G1 phase and increased in G2/M. But there was no evident change in S phase. The cells were mainly blocked in M phase, and the inhibitory effect of the allicin on MEC-1 cells increased with the increasing of concentration and time. CONCLUSION: Allicin can inhibit the growth of MEC-1 cells in vitro dramatically. PMID- 21261021 TI - [The experimental research for electrophysiology detection and electron microscopic observation on the ultrasonically activated shears injures recurrent laryngeal nerve at different time]. AB - OBJECTIVE: To determine the correlative factors on recurrent laryngeal nerve (RLN) injuries caused by ultrasonically activated shears (UAS). METHOD: Fifteen New Zealand rabbits (thirty recurrent laryngeal nerves) were randomly divided into 5 groups: group 1 and group 2 are those UAS works 1 mm away from RLN for 2 s and 4s separately, group 3 and group 4 are those UAS works 3 mm away from RLN for 2 s and 4 s separately, and the other one is control group. Electrophysiology was detected in each group. The RLN injuries of group 2, 3 and control group were observed with electron microscope. RESULT: Significant differences on amplitude and latency were found in all the experimental groups except group 3 when compared to the control group, and between every two experimental groups as well. Histological changes such as obviously swelling myelin lamellar, loosen and disordered structures, bubble-liked axon collapse and liquefaction of axoplasm were only observed in group 2. CONCLUSION: UAS is a new apparatus for cutting and coagulating in operations, which is safe and reliable to be applied for endoscopic surgery. It will be a new choice for treating thyroid neoplasm. PMID- 21261022 TI - [4th guidelines on diagnosis and treatment of obesity]. AB - Obesity is one of the leading public health problems in today's world. The situation is not significantly better in our country. The Republic of Croatia is among the countries with highest prevalence of obesity in the world. All attempts to stop the progression of obesity pandemic have not given satisfactory results up to date. On the other hand, the treatment of obesity is a long-term, exhausting and very complicated process with modest results. From 15th to 18th April 2010 the 4th Croatian Congress on Obesity with international participation was held in Umag with the aim of furthering knowledge about epidemiology, etiopathogenesis, complications and obesity treatment and to provide doctors who treat obesity with opportunity to share insights and experience. The Congress was attended by 200 doctors. At the Congress the Guidelines on Obesity Diagnostics and Treatment were adopted, which will provide practical help to doctors treating patients with obesity. PMID- 21261023 TI - [Results of treatment of displaced supracondylar fractures in children]. AB - Supracondylar fractures of humerus are the most common fractures in children. The management of severely displaced, unstable fractures of the humerus in children continues to be controversial. We undertook a retrospective study of 48 children with displaced supracondylar fractures (8 were treated with plaster and 40 with cross percutaneous Kirschner wire pinning). Only three children were treated with open reduction and percutaneous cross-pin fixation. Clinical outcome was evaluated by loss of elbow motion and change of carrying angle. According to Flynn s criteria, results were good or excellent in 93.7% patients. The cubitus varus is the most frequent long-term complication (16.7%). Closed reduction with percutaneous pin fixation is believed to represent a safe, reliable, and efficient method of managing displaced supracondylar fractures. PMID- 21261024 TI - [Adverse drug reactions of hydroxymethylglutaryl-CoA reductase inhibitors reported to agency for medicinal products and medical devices]. AB - Hydroxymethylglutaryl-CoA reductase inhibitors (statins) are drugs used in the treatment of chronic diseases and frequently in concomitant therapy with many other drugs. Therefore, the risk of adverse drug reactions (ADRs), especially those caused by interactions is high. Aim of the study was to describe and analyze ADRs caused by statins reported to Croatian Agency from March 2005 to December 2008, and to emphasize reasons of their occurrence. 136 of statin ADRs were reported. 12 % of all reported statins' ADRs were caused by interactions, which is higher than percent (5.6%) of interactions caused by all other drugs in 2005 and 2006. Proportion of serious ADRs related to administered dose and thus preventable was higher than proportion of all ADRs caused by statins (p = 0.003). Most serious ADRs could have been prevented with better understanding of interactions and by use of pharmacogenomics in identifying patients that are because of genetic predisposition more sensitive to standard doses. PMID- 21261025 TI - [Congenital hypoplasia of the lower portion of the left psoas muscle]. AB - We are presenting a case of a 58-year-old-male patient with a congenital hypoplasia of the lower portion of his left psoas muscle. This rare anomaly, which should be differentiated from other pathological conditions (destructive processes, tumors, metastases, inactivate atrophy), was discovered during the MRI examination of his lumbosacral (LS) spine which the patient underwent due to deterioration of chronic low back pain. His right psoas muscle was hypertrophic. CT examination of his abdomen has shown the identical finding. The MRI examination of his LS spine has shown the intensive and extensive degenerative changes. Besides the hypoplasia of the lower portion of his left psoas muscle, the radiological examinations of the LS spine (MRI) and abdomen (CT) have not shown any other congenital anomalies. Taking into consideration the patient history, the clinical finding, the results of the radiological and other examinations (EMNG) as well as the well known facts about psoas muscle anatomy and function (a stabilizer of the lumbar spine, pelvis and hip; the hip and trunk flexor; the lateral trunk flexor), in this case report, we analysed the clinical manifestations (lateral deviation of lumbar spine; pelvic asymmetry--elvic torsion; increased hip extension on the side of the hypoplastic psoas muscle) and also the late consequences of the unilateral hypoplasia of the psoas muscle (unilateral hypoplasia of the psoas muscle--the overloading of the LS spine and the other psoas muscle--the chronic low back pain--the compensatory hypertrophy of the other psoas muscle-->the intensive and extensive degenerative changes of the LS spine). PMID- 21261026 TI - [Acute lingual tonsillitis]. AB - Acute lingual tonsillitis is a rarely diagnosed cause of sore throat. The patient with acute lingual tonsillitis typically has severe sore throat, dysphagia and pain at the level of hyoid bone, and it is interesting that patients with previous palatine tonsillectomy can present with almost normal oral examination findings. The diagnosis of potentially fatal epiglottitis should be excluded. Because the base of the tongue can not be visualized by intraoral examination, diagnosis must be made by indirect or transnasal fiberoptic laryngoscopy. PMID- 21261027 TI - [Effects of pneumoperitoneumon liver function]. AB - Effects of pneumoperitoneum on liver function during laparoscopic procedures in most patients have no clinical relevance. However, with increasing number and types of surgical procedures the laparoscopic operation is now performed in high risk patients, including patients with pre-existing liver disease. In these patients laparoscopic procedures may lead to serious complication, including acute liver failure. Because postoperative liver damage induced by pneumoperitoneum has been underestimated, the aim of this article is to review the numerous factors influencing liver damage during laparoscopy and review of therapeutic options for their reduction. PMID- 21261028 TI - [The role of ultrasonography in evaluation of pathomorphological changes in humeroscapular periarthritis]. AB - The aim of this study was to present the distribution and representation of shoulder ultrasonographic (US) examination findings in patients with diagnosis of humeroscapular periarthritis. US examination findings in 141 patients, that is 147 symptomatic shoulders with diagnosis of humeroscapular periarthritis, were evaluated retrospectively. Outcomes of ultrasonography were distributed in groups by anatomical location, US examination finding and age. Descriptive statistics were used to analyze the data. Out of 147 analyzed shoulders, 87 (59.2%) were positive and 60 (40.8%) were negative upon US examination. The most frequent US abnormalities were detected in a supraspinatus tendon (55.3%), followed by long head of the biceps tendon (15.2%), bursitis (12.6%), subscapularis tendinitis (10.6%) and infraspinatus tendinitis (0.7%). The highest number of US abnormalities, as well as negative ultrasonographies, were detected at the age 40 to 65. The least negative US examination findings were at age over 65, where also the highest number of supraspinatus tears were detected. Due to high specificity and sensitivity in the evaluation of the rotator cuff, subacromial bursa and long head of the biceps tendon changes, ultrasound is a reliable method for evaluation of patients with painful shoulder. Its availability, noninvasivity and relatively low cost make it a method of choice for inital evaluation of such patients. Detailed history and clinical examination are going to lessen inadequate medical requests for ultrasonography. PMID- 21261029 TI - [Influence of obesity on fracture risk in osteoporosis]. AB - The skeleton is part of the locomotor system which has a static and a dynamic biomechanical function. Bone mass, bone shape and bone structure influence these skeleton functions and also determine bone strength, an important determinant of fracture risk. They are mostly genetically determined and linked with body shape, structure and weight. This relationship is also genetically determined. Changes in body weight, structure and shape through biomechanical and humoral mechanisms cause changes in the bone mass, shape and structure. These processes also lead to changes in neuromuscular system to occur which influence the risk of fall and bone strength. As long as the changes in body weight and body structure are within the physiological range, the fracture risk does not change significantly. Low body weight increases the risk of fracture. In obesity pathophysiological processes develop, some of which could negatively influence the fracture risk. The results of studying the influence of obesity on fracture risk have been contradictory. Based on the current knowledge, we may conclude that obesity probably does not protect from fracture. PMID- 21261030 TI - [Child in contemporary Croatian society]. AB - The symposium on the topic "Child in contemporary Croatian society", organized by Croatian Pediatric Society, Croatian Academy of Sciences and Arts, Ministry of health and social welfare and UNICEF Croatia Office, was held in Zagreb on December 12, 2009. The lecturers have shown important information on difficulties the children in Croatia are exposed to. Namely, diseases of the so called "new morbidity", which are becoming more and more frequent in the contemporary world, demand a new approach of work from all who participate in healthcare for children, including additional education. These diseases are not part of a practitioner's routine activity. Due to variety of problems children are exposed to, the approach can be only multidisciplinary. Basic national interest of every country (basic interest of every human society) should be to direct more attention and financial resources to the healthcare of children, which would ensure the existence and healthy future of the society. This approach requires a national consensus and clear political decision of all responsible official services. PMID- 21261031 TI - [Forerunners and development of medical licensure in Dalmatia: from individual initiatives to founding medical education in Split]. AB - Initiating licensure and medical education in Croatia was not only schooling itself, but struggle for national identity and institution of an academic setting, which, by itself, is paramount for cultural development anywhere. Throughout history, this struggle mostly ended with administrative discouragement and opposition to all such efforts of higher medical education by contemporary authorities. The paper elaborates on the first initiatives in this direction focused on the establishment of a degree of medical education in Dalmatia. Doctor Jakov Mirkovic (1748(?)-1824) was the first to become instrumental in the area. The aims, outlines and academic basis of those first initiatives were presented in a publication of his, leading eventually to the establishment of Split School of Medicine, University of Split, finally realized in 1997. PMID- 21261032 TI - [Screening for chronic kidney disease in patients with diabetes mellitus]. PMID- 21261034 TI - [Phytotherapy for benign prostatic hyperplasia]. PMID- 21261033 TI - [Pregnancy in rheumatic patients treated with biologic drugs]. PMID- 21261035 TI - [Prevention of cardiovascular diseases--problems of terminology]. PMID- 21261037 TI - [Invasive SEEG imaging in preoperative care of patients with drug resistant epilepsy]. PMID- 21261038 TI - [Evaluation of two hydroxyl-terminated monocationic ionic liquid stationary phases with high thermal stability for capillary gas chromatography]. AB - Novel hydroxyl-terminated ionic liquids of 1-(6-hydroxyhexyl)-3-butyl imidazolium bis(trifluoromethyl) sulfonylimide (HHBIM-NTf2) and 1-(8-hydroxyoctyl) -3-butyl imidazolium bis(trifluoromethyl) sulfonylimide (HOBIM-NTf2) were synthesized as stationary phases for capillary gas chromatography (GC). Besides, 1-octyl-3-butyl imidazolium bis(trifluoromethyl) sulfonylimide (OBIM-NTf2) was used as the reference. Selectivities and thermal stabilities of HHBIM-NTf2, HOBIM-NTf2 and OBIM-NTf2 were evaluated by means of the separation of Grob test mixture and positional isomers after the columns were conditioned up to 160 degrees C, 250 degrees C and 300 degrees C, respectively. As a result, baseline separations of Grob test mixture and alcohol mixture and better peak shapes were observed with HHBIM-NTf2 and HOBIM-NTf2. Importantly, baseline separation of dimethoxybenzene isomers was also achieved with HHBIM-NTf2 and HOBIM-NTf2. Satisfactory selectivity of HHBIM-NTf2 still remained even after conditioned at 300 degrees C for 8 h. The results for thermal stability showed that as GC stationary phases, HHBIM-NTf2 and HOBIM-NTf2 were stable at least up to 300 degrees C and 250 degrees C, respectively. The hydroxyl-terminated monocationic ionic liquids possess excellent selectivity and thermal stability and are alternative candidates for GC stationary phases. PMID- 21261039 TI - [Design of amplifier circuit for thermal conductivity detector in micro gas chromatography]. AB - Agilent 3000 + is a typical micro gas chromatograph (micro GC) which is widely used for its fast analysis, high resolution, wide dynamic range and energy efficient. However its amplifier circuit and analog-to-digital convertor (ADC) are of high power consumption and high working temperature. Based on the results of theoretical calculation, ADS1255, a 24-bit delta-sigma ADC from TI, was selected as the core component for its low noise and energy-efficient. Furthermore, a low noise, high common-mode voltage durable full differential amplifier circuit was designed to accomplish the functions of impedance matching, filtering, and level shifting in front of ADC. The full differential amplifier was optimized with the analysis of noise model and theoretical calculation. In addition, a testing platform was developed to test the full differential amplifier and ADC. The testing results showed that the American Society for Testing and Materials (ASTM) noise value of new full different amplifier and ADC was as low as 1.25 microV and the power dissipation was 3.7 W lower than that of the old circuit. The new circuit is low noise, energy-efficient, compact and cheap and can cater for the requirement of the micro GC of next generation. PMID- 21261040 TI - [Determination of glyphosate and aminomethylphosphonic acid in rice using liquid chromatography-tandem mass spectrometry]. AB - A method was developed for the determination of glyphosate (GLY) and aminomethylphosphonic acid (AMPA) in rice using liquid chromatography tandem mass spectrometry (LC-MS/MS). The sample was extracted with water followed by a simple cleanup with a C18 solid phase extraction (SPE) cartridge, and then GLY and AMPA were derivatized using 9-fluorenylmethoxycarbonyl (FMOC-Cl) in borate buffer. The derivatives of GLY and AMPA were separated on a C18 column with gradient elution with the mobile phase of acetonitrile and 5 mmol/L ammonium acetate (pH 9), and finally detected with negative ion electrospray ionization-mass spectrometry (ESI MS) in multiple reaction monitoring (MRM) mode. The results showed that the linearities of GLY and AMPA were in the concentration range of 0.000 50 to 1.0 mg/L with the correlation coefficients of 0.999 7 and 0.999 9, respectively. The mean spiked recoveries of GLY and AMPA at 3 spiked levels ranged from 72.5% to 113.6% with the relative standard deviations (RSD, n = 5) of 3.8% - 16.2%. The limits of detection were 2.0 and 3.0 microg/kg for GLY and AMPA, respectively. This method is rapid, sensitive, and suitable for simultaneous determination of GLY and AMPA in rice. PMID- 21261041 TI - [Determination of five synthetic sweeteners in wines using high performance liquid chromatography-tandem mass spectrometry]. AB - A high performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI MS/MS) method for the determination of five synthetic sweeteners (acesulfame, sodium saccharin, sodium cyclamate, aspartame and neotame) in wines has been developed. The HPLC separation was carried out on an Ultimate C18 column (100 mm x 2.1 mm, 3 microm). Several parameters, including the composition and pH of the mobile phase, column temperature and the monitor ions, were optimized for improving the chromatographic performance and the sensitivity of determination. The results demonstrated that the separation can be completed in less than 5 min by gradient elution with 20 mmol/L ammonium formate and 0.1% (v/v) formic acid (pH 3.8) and methanol as the mobile phase. The column temperature was kept at 45 degrees C. When the analytes were detected by ESI MS/MS under multiple reaction monitoring mode, the detection limits were 0.6, 5, 1, 0.8 and 0.2 microg/L for acesulfame, sodium saccharin, sodium cyclamate, aspartame and neotame, respectively. The average recoveries ranged from 87.2% to 103%. The relative standard deviations were not more than 1.2%. This method is rapid, accurate, highly sensitive and suitable for the quality control of low concentration of the synthetic sweeteners, which are illegally added to wines and other foods with complex matrices. PMID- 21261042 TI - [Determination of four carcinogens in mainstream cigarette smoke by liquid chromatography-tandem mass spectrometry]. AB - N-nitrosonornicotine (NNN), 4-( methylnitrosamino )-1-(3-pyridyl )-1-butanone (NNK), N-nitrosoanatabine (NAT) and N-nitrosoanabasine (NAB) are the most abundant carcinogens identified in tobacco and tobacco smoke. The accurate quantifications of NNN, NNK, NAT and NAB are necessary to evaluate its impact on the public health. A liquid chromatography-electrospray tandem mass spectrometry (LC-ESI MS/MS) method was developed to simultaneously determine NNN, NNK, NAT and NAB in mainstream cigarette smoke. Mainstream smoke was collected in a Cambridge filter pad and then was extracted by 10 mL 100 mmol/L ammonium acetate after 100 microL of mixed deuterated internal standards was added. Then the extract was detected by using positive electrospray ionization on a tandem mass spectrometer in multiple reaction monitoring (MRM) mode. NNN, NNK, NAT and NAB were separated on a Zorbax Eclipse XDB-C18 column with the gradient elution using mobile phase A (0.1% acetic acid in water) and mobile phase B (0.1% acetic acid in methanol). The detection limits for NNN, NNK, NAT and NAB were 0.019, 0.002, 0.008 and 0.007 microg/L, respectively. The recoveries were varied from 84.9% to 104.5% for Chinese Virginia cigarettes and the relative standard deviations (n = 8) ranged from 2.96% to 6.65%. This proposed approach, which provides a higher sensitivity and specificity, is suitable for the determination of NNN, NNK, NAT and NAB in mainstream cigarette smoke. PMID- 21261043 TI - [Determination of fifteen beta-agonists in animal urine by high performance liquid chromatography-tandem mass spectrometry]. AB - A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/ MS) method was established for the determination of fifteen beta-agonists (clenbuterol, ractopamine, salbutamol, cimaterol, mabuterol, tulobuterol, bambuterol, mapenterol, cimbuterol, zilpaterol, formoterol, clorprenaline, terbutaline, penbutolol and brombuterol) in animal urine. Perchloric acid solution was used to acidify the sample and precipitate protein in the sample. The sample was purified and concentrated by an HLB mini-column. The separation of the beta-agonist was performed on an Agilent 1100 HPLC system with a Eclipse XDB C18 column by using gradient elution with methanol and water (containing 0.1% (v/v) formic acid) as the mobile phases at a flow rate of 1 mL/min. Qualitative and quantitative analysis of the fifteen beta-agonists, which were ionized by electrospray ionization interface (ESI), were carried out in multiple reaction monitoring (MRM) mode with API 4000 tandem mass spectrometry. The calibration curves showed good linearity in the mass concentration range of 0.25 - 20 microg/L with the correlation coefficients r > or = 0.999 5. The recoveries of the fifteen beta-agonists ranged from 62.1% to 107% at the spiked levels of 0.25, 1.0 and 10 microg/L. The relative standard deviations (n = 10) were between 3.5% and 9.9%. The limits of quantification (S/N > 10) were 0.25 microg/L for all the analytes. This method is simple, rapid, sensitive and accurate. PMID- 21261044 TI - [Effect of menthol cigarette on rats for metabonomics by liquid chromatography mass spectrometry]. AB - A liquid chromatography-mass spectrometry (LC-MS) method was developed for the metabonomics study of menthol cigarette effect on rats. Urines from three groups of rats were analyzed, including control rats, rats treated with menthol cigarette and rats treated with normal cigarette, and the data were processed by the method of principal component analysis (PCA). The PCA score plot showed that the metabolic difference between the rats treated with menthol cigarette and the control rats was smaller than that between the rats treated with normal cigarette and the control rats. Based on the PCA score plot, eight important metabolites, for example, kynurenic acid, were found and identified. Their relative concentration changes among the three groups further indicated that menthol cigarette maybe decrease the metabolic effect on rats. PMID- 21261045 TI - [Determination of 11 carbamate pesticide residues in Glycyrrhizae radix et rhizoma and its extracts using ultra performance liquid chromatography-tandem mass spectrometry with gel permeation chromatographic clean-up]. AB - An ultra performance liquid chromatography-electrospray ionization tandem mass spectrometric method (UPLC-ESI MS/MS) has been developed for the determination of 11 carbamate pesticide residues in Glycyrrhizae radix et rhizoma and its extracts. After extracted by acetonitrile and cleaned up by gel permeation chromatography (GPC), the samples were determined by UPLC-ESI MS/MS. Glycyrrhizae radix et rhizoma and its extracts were analyzed as model examples. When the spiked levels were 0.02, 0.04, and 0.1 mg/kg in the samples, the average recoveries of 11 carbamate pesticides from Glycyrrhizae radix et rhizoma were obtained from 72.2% to 94.0%, the relative standard deviations (RSDs) ranged from 0.7% to 7.8%. The average recoveries of 11 carbamate pesticides in Glycyrrhizae radix et rhizoma extract ranged from 73.8% to 94.7% and the RSDs ranged from 1.5% to 12.7%. The sensitivity, accuracy, and precision of this method can meet the requirements of the pesticide residue analysis, and the method can be applied to determine carbamate pesticide residues in Glycyrrhizae radix et rhizoma, Astragali radix and their extracts. PMID- 21261046 TI - [High performance liquid chromatography/electrospray ionization ion-trap mass spectrometry analysis of chitooligosaccharides by pre-column derivatization with 3-amino-9-ethylcarbazole]. AB - A pre-column derivatization method was established for chitooligosaccharides (COS) analysis, employing 3-amino-9-ethylcarbazole (AEC) as a derivatization reagent. The enamine was generated by the reaction of the reducing end of COS and the primary amine of AEC, and then reduced to secondary amines by NaBH3 CN. Under the optimized high performance liquid chromatography (HPLC) and electrospray ionization ion-trap mass spectrometry (ESI-MS) conditions, the HPLC separation was carried out on an RP C18 column (250 mm x 4.6 mm, 5 microm) with a gradient elution using acetonitrile and ammonium acetate as mobile phase. The derivative was successfully analyzed by HPLC, ESI-MS and on line HPLC-ESI-MS in positive-ion mode. The established method is simple, high sensitive and reproducible, which has great potential application to component analysis, quality control and structure activity relationship analysis of COS. PMID- 21261047 TI - [Determination of 2-acetyl-1-pyrroline in aroma rice using gas chromatography mass spectrometry]. AB - A gas chromatography-mass spectrometry method was developed for the determination of 2-acetyl-1-pyrroline in aroma rice. 2,4,6-Trimethylpyridine (TMP) was added into the sample of aroma rice as internal standard, and the compound was extracted by the mixture of anhydrous ethyl alcohol and methylene chloride (1: 1, v/v) at 80 degrees C for 3 h under sealed condition in water bath. The effects of the temperature and time on the extraction were investigated. The analyte was separated and determined using gas chromatography-mass spectrometry on an HP-5MS capillary column (30 m x 0.25 mm x 0.25 microm) in scan monitoring mode. Calculated as 2,4, 6-trimethylpyridine, the average recovery of the method was 82.57% with the relative standard deviation of 5.09%, and the detection limit of method was 0.01 mg/kg. The method was employed for the determination of 2-acetyl 1-pyrroline in 11 aroma rice breeding varieties. The results showed that 2-acetyl 1-pyrroline was detected in 5 aroma rice varieties, including Qingxiangmi, Taixiang R207, Texmati, Guixiangsinuo and Zhongjian 2, with the contents of 0.097, 0.098, 0.699, 0.045 and 0.047 mg/kg, respectively. The method is simple, rapid and sensitive with low sample and reagent consumption. It is suitable for screening a lot of aroma rice varieties in breeding through the determination of 2-acetyl-1-pyrroline content. PMID- 21261048 TI - [Refolding of reduced/denatured RNase A the hydrophobic liquid-solid interface]. AB - The renaturation of the reduced/denatured RNase A on the hydrophobic liquid-solid interface was investigated using hydrophobic interaction chromatography (HIC). The effects of urea concentrations, the ratios of reduced and oxidized glutathiones (GSH and GSSG), the pH of mobile phase and protein concentrations on the refolding efficiency and mass recovery of the reduced/denatured RNase A were investigated in detail. The results indicated that the reduced/ denatured RNase A can be refolded completely under the optimized conditions of pH 8.0, 2.0 mol/L urea and the concentration ratio of GSH/GSSG of 8: 1 in mobile phase. When the denatured protein was at the concentration of 5.0 mg/mL, the bioactivity efficiency and mass recoveries were 98.0% and 61.9% for 8.0 mol/L urea-denatured RNase A, respectively; and 100.1% and 66.8% for 7.0 mol/L guanidine hydrochloride (GuaHCl)-denatured RNase A, respectively. It proves that HIC is a powerful tool and new approach for protein refolding. PMID- 21261049 TI - [Analysis of seven compounds in mainstream cigarette smoke by ultra performance liquid chromatography using a beta-cyclodextrin mobile phase additive]. AB - A rapid method for the analysis of hydroquinone, resorcinol, catechol, phenol, p cresol, m-cresol, and o-cresol in mainstream cigarette smoke by ultra performance liquid chromatography (UPLC) using a beta-cyclodextrin (beta-CD) mobile phase additive was developed. The seven major phenolic compounds in mainstream smoke were collected with YC/T 255-2008 standard method. The extract was filtrated with 0.22 microm filtration film and then subjected to UPLC analysis. The separation was performed on an ACQUITY UPLC BEH Shield RP18 column, and the mobile phase with 4 g/L beta-CD additive was used. The fluorescence detection condition was optimized. The analysis time was 10 mm for one sample. Comparing with the high performance liquid chromatography (HPLC) methods published, the p-cresol and m cresol were completely separated. In addition, the effect of beta-CD on fluorescence enhancement for seven major phenolic compounds was significant. The linearity were good between the peak area and the concentration in the linear ranges of seven phenolic compounds, and the correlation coefficients were greater than 0.999 9. The limits of detection of the method were 4 - 14 ng/cig, and the recoveries were 95.5% - 103.5% with relative standard deviations (RSDs) less than 4%. PMID- 21261050 TI - [Simultaneous determination of 7 nucleosides in Asterias rollestoni using reversed-phase high performance liquid chromatography]. AB - A method for the simultaneous determination of 7 nucleosides in Asterias rollestoni was developed using reversed-phase high performance liquid chromatography (RP-HPLC). Analytes were extracted by ultrasonic-assisted extraction and separated on two different C18 columns, which were connected in series, under the gradient elution with the mobile phases of methanol and 0.2% (v/v) acetic acid/water at room temperature. The chromatographic conditions were as follows: flow rate, 0.8 mL/min; detection wavelength, 260 nm; injection volume, 20 microL. Under the optimized conditions, good linear relationships between the values of mass concentrations and the peak areas of hypoxanthine, uridine, xanthine, thymine, inosine, guanosine and thymidine were observed in the ranges of 0.65 -40, 0.80 -40, 0.80 -40, 1.15 - 40, 0.80 - 40, 0.50 - 40, and 0.65 - 40 mg/L, respectively. The relative standard deviations were around 0.72% - 3.23% and the recoveries were around 90.00% - 105.00%. The results showed that the developed method is sensitive, accurate and reproducible. It is suitable for the analysis of nucleosides in Asterias rollestoni with high recoveries and it is expected to be used for the quality control and evaluation of Asterias rollestoni. PMID- 21261051 TI - [Determination of 10 volatile organic compounds in toys by headspace gas chromatography-mass spectrometry]. AB - A headspace gas chromatography-mass spectrometry (HS-GC-MS) method was developed for the determination of 10 residual volatile organic compounds (VOCs) in toys. The experimental conditions such as headspace temperature, headspace time and the analytical conditions of GC-MS were optimized. Toy samples were treated at 140 degrees C for 45 min, and then the evolved products were separated on a DB-624 column, determined by MS and quantified by external standard method. The recoveries were from 79% to 106% and the relative standard deviations (RSDs) were from 0.4% to 5.6%. The linear range was 0.001 - 2.0 microg with a good linear correlation coefficient (r > 0.994 0) and the limits of quantification (LOQ) were less than 0 66 mg/kg. The method is accurate, simple, rapid, and is suitable for the analysis of residual VOCs in various toys. PMID- 21261052 TI - [Determination of pinoresinol diglucoside in Qing' e Pills by ultra performance liquid chromatography]. AB - A new ultra performance liquid chromatographic (UPLC) method was established for the determination of pinoresinol diglucoside (PDG) in Qing' e Pills. After extracted by the Soxhlet's method, the methanol extracts of the samples were passed through a Waters Oasis HLB SPE column to achieve good chromatographic performance. The separation was performed on a Waters Acquity C18 BEH column (100 mm x 1.0 mm, 1.7 microm) with acetonitrile-water (the pH adjusted to 4.0 with phosphoric acid) (9: 91, v/v) as the mobile phase at a flow rate of 0.1 mL/min. The detection wavelength was set at 227 nm, the column temperature was 25 degrees C and the injection volume was 0.5 microL. Under the optimized conditions, there was good linear relationship between the mass concentration and the peak area of PDG in the range of 1.40 - 506.00 mg/L with the correlation coefficient of 1. The average recoveries of PDG at three levels ranged from 100.10% to 102.37%. The method is accurate, sensitive, highly reproducible and suitable for the quality control of Qing' e Pills. PMID- 21261053 TI - [Isolation and purification of esculetin from the seeds of Euphorbia lathyris L. using high-speed counter-current chromatography]. AB - A method for the isolation and purification of esculetin from the seeds of Euphorbia lathyris L. was developed using high-speed counter-current chromatography (HSCCC). The ethyl acetate extract of the seeds of Euphorbia lathyris L. was separated by the HSCCC directly. Different solvent systems were investigated, and the results showed that the best solvent system was the two phase solvent system composed of chloroform-methanol-water (4: 3: 2, v/ v/v). The lower phase was used as the mobile phase and the upper phase was used as the stationary phase. A total of 80 mg esculetin with the purity of 99.04% was successfully obtained from 200 mg crude extract of the seeds of Euphorbia lathyris L. The results indicate that optimized HSCCC offers a preferred method for the preparation of esculetin from the seeds of Euphorbia lathyris L. PMID- 21261054 TI - [Separation and preparation of two rotenoids from the roots of Derris by high speed counter-current chromatography]. AB - Two rotenoids (rotenone and deguelin) were successfully isolated and purified from the roots of Derris by high-speed counter-current chromatography (HSCCC) with a two-phase solvent system composed of n-hexane-ethylacetate-methanol-water (7: 0. 25:5:3, v/v/v/v) on a preparative scale. The lower phase was used as the mobile phase and the upper phase was used as the stationary phase. The revolution speed was 850 r/min, the detection wavelength was set at 254 nm and the flow rate was 2.0 mL/min. Under the optimized conditions, within 2.5 h, 6.4 mg of rotenone with the purity of 96.60% and 23.4 mg of deguelin with the purity of 97.87% were obtained from 50 mg of the crude extract of the roots of Derris in a one-step elution. The results indicate that the rotenone and deguelin with high purities can be obtained by HSCCC, and the established method can provide the basic experimental material for the intensive study of rotenoids. PMID- 21261055 TI - [Determination of lambda-cyhalothrin residue tea and soil using gas chromatography]. AB - A gas chromatographic (GC) method was established for the determination of lambda cyhalothrin residue in tea and soil. Tea and soil samples were extracted with hexane, separated by capillary column and determined by gas chromatography electron capture detector (GC-ECD). The average recoveries of lambda-cyhalothrin in tea and soil were 89.0% - 94.1% and 89.8% - 94.7%, respectively at the spiking levels of 0.02 to 2.00 mg/kg. The corresponding relative standard deviations (RSDs, n = 5) were 3.0% -4.9% and 2.5% -4.2%, respectively. The limit of detection (S/N = 3) was 0.002 mg/kg for lambda-cyhalothrin. The degradations of 2.5% lambda-cyhalothrin microemulsion in tea and soil in Changsha, Hunan were investigated and the degradation equations were Y = 3.199 6e(-0.339 4x) and Y = 0.122 4e(-0.103 6x) with the correlation coefficients of 0.995 6 and 0.924 7, respectively. The half-lives of lambda-cyhalothrin in tea and soil were 2.04 days and 6.69 days, respectively. PMID- 21261056 TI - [Mobile genetic elements in plant sex evolution]. AB - The most significant theories of the appearance and maintenance of sex are presented. However, in the overwhelming majority of existing theories, the problem of sex, which is the central problem of evolutionary biology, is considered primarily through the prism of reproductive features of living organisms, whereas the issue of molecular driving forces of sexual reproduction id restricted to the possible role of mobile genetic elements (MGEs) in the appearance of sexual reproduction. The structural and functional significance of MGEs in the genomic organization of plants is illustrated. It is shown that MGEs could act as important molecular drivers of sex evolution in plants. The involvement of MGEs in the formation of sex chromosomes and possible participation in seeds-without-sex reproduction (apomixis) is discussed. Thus, the hypothesis on the active MGE participation in sex evolution is in good agreement with the modern views on pathways and directions of sex evolution in plants. PMID- 21261057 TI - [Cotransformation of aspen and birch with three T-DNA regions from two different replicons in one Agrobacterium tumefaciens strain]. AB - The cointegration rate into the aspen and birch genomes of foreign genes from a binary vector and a disarmed Ti plasmid pCBE21 carried by the same Agrobacterium tumefaciens strain was studied. The cotransformation rate for the genes within the Ti plasmid varied from 30 to 100%; while the transformation rate for the gene from T(L) region was twofold higher as compared with the T(R) region. On the average, the gene transfer from all three T-DNAs was recorded in 10.9% of the transgenic lines. For the vector pBI121, the cotransformation rates for the genes from both regions of pCBE21 T-DNA were higher as compared with the vector pGS. In addition, a concurrent transfer of the genes from the Ti plasmid T(L) and T(R) regions was recorded only after the transformation with the vector pBI121. These results can be used for constructing woody plants containing several genes. PMID- 21261058 TI - [Analysis of the inheritance patterns of 5'-truncated copies of the German cockroach R2 retroposons in individual crosses]. AB - The inheritance patterns of the 5'-truncated copies of R2 retroposons were analyzed in individual crosses of the German cockroach. The recombination level within the cluster of ribosomal RNA genes was determined. It was demonstrated that only the frequencies of individual variants of 5'-truncated retroposon copies are appropriate for population analysis rather than the patterns characterizing individual X chromosomes. The methodical approach used in the work is convenient for studying the genetic variation in ribosomal DNA multigene families. PMID- 21261059 TI - [A new yeast strain for brewery: properties and advantages]. AB - Beer is a natural product and is a multicomponent system that has both positive and negative consumer properties. Organoleptical off-flavors of beer are difficult to eliminate. Yeasts are the main active component of the system. The relationship between beer quality and yeast usage is well known. New industrial strains for brewery are continuously developed. An industrial yeast Saccharomyces cerevisiae strain was obtained and showed high technological properties, including efficient fermentation, a reduced production of sulfur hydrate, and a high diacetyl reduction rate. The advantages made it possible to develop new brands of beer and nonalcoholic products. The commercial use of the strain was patented. The strain was deposited in the Russian Collection of Industrial Microorganisms. PMID- 21261060 TI - [Revised classification of native probiotic strains of Lactobacillus used in Russian Federation]. AB - Thirteen strains of industrial bacterial cultures of the genus Lactobacillus (from a collection of Gabrichevsky Research Institute of Epidemiology and Microbiology) were studied. These strains were used for decades in Russian Federation for food and drug production, as ferments for lactic acid products, for production of probiotics, biologically active and veterinary preparations. Complex analysis of data on cultures obtained using microbiological and molecular genetic methods was conducted for the first time. Biochemical characteristics of these cultures were studied and the sequence of the proximal region of 16S ribosomal RNA gene was determined. The employment of the test system API-50CHL was shown to broaden the opportunities of a more accurate biochemical identification of bacteria belonging to the genus Lactobacillus, in comparison with the set ANAEROTEST-23. According to the results obtained in a comparative analysis of nucleotide sequences of 16S rRNA gene, all strains examined show 97 99% homology of the proximal region of this gene with that of the type representatives of studied species. These data allowed taxonomic reclassification of the species position of cultures with consideration of the more advanced level of systematics. Nucleotide sequences of gene fragments of examined lactobacilli strains were recorded in NCBI database (accession numbers of deposits GU560031, GU560032, GU560033, GU560034, GU560035, GU560036, GU560037, GU560038, GU560039, GU560040, GU560041, GU560042, GU560043). PMID- 21261061 TI - [Polymorphism of hordein-coding loci in cultivated barley (Hordeum vulgare L.) in Afghanistan]. AB - Polymorphism of hordeins encoded by the HrdA, Hrd B, and Hrd Floci was analyzed in 84 accessions of local barley (Hordeum vulgare L.) varieties from major agricultural regions of Afghanistan using starch gel electrophoresis. Forty alleles of the Hrd A locus with the frequencies from 0.12 to 32.73%, 62 alleles of the Hrd B locus with the frequencies from 0.12 to 14.29%, and five alleles of the Hrd Flocus with the frequencies from 0.59 to 32.15% have been identified. The conclusion about genetic similarity of barley populations from different regions of Afghanistan is made on the basis of cluster analysis of the matrix of allele frequencies in barley populations from 31 localities. The local barley populations form four unequal clusters. The largest cluster I includes populations from 14 localities of Afghanistan. The second largest cluster IV consists of populations from ten localities, and clusters II and III comprise populations from four and three localities, respectively. Each of the four clusters includes populations from different regions of northern and southern Afghanistan. Based on our results, we conclude that the diversity of hordein coding loci and the distribution of their alleles among different regions of Afghanistan are the consequences of introduction of barley landraces and their distribution over trade routes. PMID- 21261062 TI - [Dynamics of hybrid necrosis genes in Russian cultivars of common wheat (Triticum aestivum L.)]. AB - Study of necrosis genotypes of 72 Russian cultivars of winter common wheat has confirmed a tendency towards "washing off" of genotypes with the Ne1 gene. Fifty six percent of cultivars have the genotype ne1ne1Ne2Ne2, and 44% have the genotype ne1ne1ne2ne2; i.e., they are free of hybrid necrosis genes. The results of the study indicate that the diversity of the original ancestors in the groups of cultivars with the ne1ne 1Ne2Ne2 and ne1ne1ne2ne2 genotypes is almost the same. This determines the instability of the tendency towards a higher prevalence of the nel ne 1Ne2Ne2 genotype in recent years. The changes in the diversity of the original ancestors with time have shown an increase in the diversity index. These processes may somewhat decrease the rate of genetic erosion caused by the fact that the Ne1Ne1ne2ne2 falls out of breeding. The routes of transmission of necrosis gene alleles from ancestors to descendants have been traced using extended pedigrees, and this information has been used to identify the probable donors and sources of hybrid necrosis gene alleles. In most cases, the cultivars Mironovskaya 808 and Krasnodarskaya 39 are the putative sources of the Ne2allele (60.6 and 27.3% of all cases, respectively). The old cultivar Gostianum 237 from Saratov oblast is the putative source of the Ne2 allele in the cultivar Krasnodarskaya 39. The cultivars Bezostaya 1 and Odesskaya 51 (whose pedigree also includes Bezostaya 1) are the donors of the recessive genotype ne1nelne2ne2 in 93.5% of cases. The old Ukrainian cultivar Ukrainka is the most frequent source of recessive alleles. The strength of the Ne2 allele has been estimated in 36 cultivars. The results indicate that modifier genes affect the expression of tumor necrosis genes. PMID- 21261063 TI - [Relationships of eelpouts of genus Zoarces (Zoarcidae, Pisces) inferred from molecular genetic and morphological data]. AB - Molecular genetic and morphological analysis of eelpouts of the genus Zoarces was carried out. Based on the mitochondrial DNA sequence variation, haplotypes of notched-fin eelpout, Z. elogatus, more closely related Fedorov eelpout, Z. fedorovi, and common eelpout, Z. viviparus, as well as of Andriyashev eelpout, Z. andriashevi, were grouped in one macrocluster. Haplotypes of American eelpout, Z. americanus, and blotched eelpout, Z. gillii, clustered separately from other species. The genetic differences between Z. gillii and the other eelpout species were very high for within-genus comparisons, constituting 7.62%. Species divergence in terms of morphological characters was generally consistent with molecular genetic data and confirmed distinct isolation of American eelpout, and especially of blotched eelpout. PMID- 21261064 TI - [Incomplete congruence between morphobiological characters and sex-specific molecular markers in Pacific salmons: II. Population and temporal variability of the phenomenon]. AB - The congruence between secondary sexual characters and molecular markers, linked to the Y chromosome was examined in Asian populations of five Pacific salmon species of the genus Oncorhynchus. Our results support the existence of discrepancy between secondary sexual characters and sex-linked molecular markers in all species examined, which suggests the existence of similar or identical mechanism responsible for this phenomenon in Pacific salmons. Clinal latitudinal directional variation of the character confirmed the possibility that this phenomenon could be adaptively important, including its importance for regulation of the population number. In addition to natural factors affecting the degree of discrepancy between morphobiological characters and molecular markers in the Pacific salmon populations, anthropogenic factors, in particular intense fishery of certain population or population group, is also important. PMID- 21261065 TI - [Comparative analysis of STR and SNP polymorphism in the populations of sockeye salmon (Oncorhynchus nerka) from Eastern and Western Kamchatka]. AB - Sockeye salmon samples from five largest lacustrine-riverine systems of Kamchatka Peninsula were tested for polymorphism at six microsatellite (STR) and five single nucleotide polymorphism (SNP) loci. Statistically significant genetic differentiation among local populations from this part of the species range examined was demonstrated. The data presented point to pronounced genetic divergence of the populations from two geographical regions, Eastern and Western Kamchatka. For sockeye salmon, the individual identification test accuracy was higher for microsatellites compared to similar number of SNP markers. Pooling of the STR and SNP allele frequency data sets provided the highest accuracy of the individual fish population assignment. PMID- 21261066 TI - [Molecular-phylogenetic analysis of cyclopoids (Copepoda: Cyclopoida) from Lake Baikal and its water catchment basin]. AB - Baikalian cyclopoids represent one of the richest endemic faunas of freshwater cyclopoid copepods. The genus Diacyclops Kiefer, 1927 is the most numerous by species number in the lake. In this work, molecular-phylogenetic analysis of 14 species and 1 sub-species from Lake Baikal and its water catchment basin is performed. The regions of mitochondrial cytochrom-oxydase I (COI) and of nuclear small-subunit 18S rRNA were used as evolution markers. In the obtained set of nucleotide sequences of COT gene, an effect of synonymous substitution saturation is revealed. Baikalian representatives of the genus Diacyclops form at phylogenetic schemes by two markers a monophyletic griup, it suggest their origin from a common ancestral form. Preliminary estimate of the age of this group is 20 25 My. PMID- 21261067 TI - [Cytogenetic mechanisms of aneuploidy in somatic cells of chemonuclear industry professionals with incorporated plutonium-239]. AB - Risks related to occupational exposure of humans to ionizing radiation remains a focus of attention. Of special importance is the poorly understood effect of ionizing radiation on the rate of numerical chromosome aberrations in human somatic cells. The purpose of this study was characterization of a radiation induced increase in the rate of aneuploidy induced by incorporated plutonium-239 (239Pu) in somatic cells of chemonuclear industry workers. Significant differences in the chromosome 2, 7, 8, 12, and Y aneuploidy rate have been found between subjects with incorporated 239Pu and control subjects have been demonstrated. Chromosome nondisjunction has been found to be the main mechanism of aneuploidy induced by incorporated 239Pu. PMID- 21261068 TI - [The genetic history of long-term Russian resident populations of polar northeastern Siberia based on mitochondrial DNA variability]. AB - The mtDNA variation has been studied in representatives of the Russkoe Ust'e (n = 30), Kolyma (n = 31), and Markovo (n = 26) ethnic subgroups originating from Russian military men, hunters, and fishers who married local Yukaghir women and settled at the Arctic Ocean coast and on the Anadyr' River more than 350 years ago. The mtDNA haplotypes characteristic of indigenous Siberian peoples have been demonstrated to form the basis of the mitochondrial gene pool of long-term Russian resident populations of the region. Only one of 30 identified haplotypes belonging to 11 haplogroups (H2a) is characteristic of European populations. The C and D haplogroups are the most diverse. The analysis has revealed the characteristics of the population structure of the long-term Russian resident populations and allowed them to be interpreted in terms of recent historical and environmental processes. PMID- 21261069 TI - [Genetic polymorphism of Microbotryum violaceum s. I. isolates collected from different plant species on the territory of Russia]. AB - The present-day studies in the field of systematics and phylogeny of microorganisms, fungi, in particular, are characterized by a wide use of new approaches and methods of molecular biology. The use of a diversity of genetic markers permits a distinct differentiation of closely related species into individual evolutionary independent lines. It is shown in this work that all Microbotryum violaceum s. l. isolates studied by us are divided into five evolutionary groups according to the host plant. PMID- 21261070 TI - [Protective action of reactivating factor of Luteococcus japonicus subsp. casei toward cells of Escherichia coli reparation mutants inactivated with UV-light]. AB - Reactivating factor (RF) from Luteococcus japonicus subsp. casei had a protective action on UV-irradiated cells of Escherichia coli AB1157 with a native reparation system and on cells of isogenic reparation mutants of E. coli UvrA-, RecA-, and PolA-: the effect resulted in multifold increase of survivability. Defense action of L. casei exometabolite is not connected with stimulating reparation systems in E. coli, and, probably, it is mediated by involvement of the exometabolite in the mechanism of cell division. RF did not provoke the reactivation of E. coli cells inactivated by UV-light. PMID- 21261071 TI - [Characteristics of proteins synthesized by hydrogen-oxidizing microorganisms]. AB - The study was conducted to determine the biological value of proteins synthesized by hydrogen-oxidizing microorganisms--the hydrogen bacteria Alcaligenes eutrophus Z1 and Ralstonia eutropha B5786 and the CO-resistant strain of carboxydobacterium Seliberia carboxydohydrogena Z1062. Based on a number of significant parameters characterizing the biological value of a product, the proteins of hydrogen oxidizing microorganisms have been found to occupy an intermediate position between traditional animal and plant proteins. The high total protein in biomass of these microorganisms, their complete amino acid content, and availability to proteolytic enzymes allow for us to consider these microorganisms as potential protein producers. PMID- 21261072 TI - [Extracellular proteolytic activity of bacteria from soda-salt lakes of Transbaikalia]. AB - Influence of nitrogen source on proteinases synthesis in aerobic alkalotolerant and halotolerant bacteria from soda-salt lakes of Transbaikalia was studied. Maximal accumulation of proteinases was revealed on medium with peptones. Introduction of various sources of nitrogen in the medium did not result in increase of enzyme activity in cultural liquid. It was indicated that secreting proteinases of the studied bacteria strains possess narrow substrate specificity, hydrolyze proteins and n-nitroanilide substrates have maximal activity during GlpAALpNA hydrolysis. Data of inhibitory analysis and substrate specificity of studied extracellular enzymes indicate that they belong to a class of serine proteinases of subtilisin-like type. PMID- 21261073 TI - [Oxidative biotransformation of thioanisole by Rhodococcus rhodochrous IEGM 66 cells]. AB - Comparative study of sulfoxidation activity of free and immobilized Rhodococcus rhodochrous IEGM 66 cells was performed. Free Rhodococcus cells (in the presence of 0.1 vol % n-hexadecane) displayed maximal oxidative activity towards thioanisole (0.5 g/l), a prochiral organic sulfide, added after 48-h cultivation of bacterial cells. Higher sulfide concentrations inhibited sulfoxidation activity of Rhodococcus. Use of immobilized cells allowed the 2-day preparatory stage to be omitted and a complete thioanisole bioconversion to be achieved in 24 h in the case that biocatalyst and 0.5 g/l thioanisole were added simultaneously. The biocatalyst immobilized on gel provides for complete thioanisole transformation into (S)-thioanisole sulfoxide (optical purity of 82.1%) at high (1.0-1.5 g/l) concentrations of sulfide substrate. PMID- 21261074 TI - [Degradation of chlorinated biphenyls and products of their bioconversion by Rhodococcus sp. B7a strain]. AB - Strain Rhodococcus sp. B7a isolated from artificially polluted soil destructs mono- and di-substituted ortho- and/or para-chlorinated biphenyls with utilization of chlorinated benzoic acids and shows high degradation activity as regards trichlorinated biphenyls. It is shown that p-hydroxybenzoic and protocatehoic acids are the products of p-chlorobenzoic acid catabolism. PMID- 21261076 TI - [Composite biodegradable materials based on polyhydroxyalkanoate]. AB - Conditions for the processing and mixing of biodegradable polymers at temperatures less than their thermal destruction (130-150 degrees C) using standard equipment have been identified. The structure of the polyhydroxybutyrate/valerate (PHB/V) copolymer has been revealed and peculiarities of the crystal phase formation at different monomer ratios have been investigated. It was shown that pure PHB with molecular mass 180-270 kDa has elastic module approximately 1.2 GPa, strength approximately 25 MPa, and elongation at break approximately 10%. The most active biodestructors of PHB, PHB/V, and their composites have been selected (Aspergillus caespitosus), and the ability of basidiomycete Panus tigrinus to biodegrade polyalkanoates was demonstrated for the first time. It was shown that A. caespitosus degraded PHB/V and Biopol films along with the PHB with the destruction rate depending on the technology of the film production, on the molecular mass, and on the extend of the polymer crystallinity. PMID- 21261075 TI - [Intensification of surfactant synthesis in Rhodococcus erythropolis EK-1 cultivated on hexadecane]. AB - Activity of key enzymes of n-alkane metabolism was determined in cells of Rhodococcus erythropolis EK-1, a surfactant producer grown on n-hexadecane. Potassium cations were found to inhibit alkane hydroxylase and NADP(+)-dependent aldehyde dehydrogenase, while sodium cations were found to activate these enzymes. Decreased potassium concentration (to 1 mM), increased sodium concentration (to 35 mM), and addition of 36 micromol/l Fe(II), required for alkane hydroxylase activity, resulted in increased activity of the enzymes of n hexadecane metabolism and in a fourfold increase of surfactant synthesis. A 1.5 1.7-fold increase in surfactant concentration after addition of 0.2% fumarate (gluconeogenesis precursor) and 0.1% citrate (lipid synthesis regulator) to the medium with n-hexadecane results from enhanced synthesis of trehalose mycolates, as evidenced by a 3-5-fold increase in phosphoenolpyruvate synthetase and trehalose phosphate synthase, respectively. PMID- 21261077 TI - [Structure peculiarities of cell walls of Acremonium chrysogenum--an autotroph of cephalosporin C]. AB - Alterations of cell walls of Acremonium chrysogenum occurring at intensive synthesis of cephalosporin C has been studied. It is shown, using electron microscopy, that the cell wall of the cells ofATCC 11550 strain ("wild" type) became looser and thicker during growth. The cell wall of the cells of strain 26/8 (hyperautotroph of cephalosporin C) considerably degraded by the end of the stationary phase. Biochemical analysis has shown that these alterations entailed decrease of the proteins' content covalently or noncovalently linked with the polysaccharides of cell walls of both strains. An increase of sensitivity of cell walls of the strain-superproducer to an activity of lytic enzymes of chitinase, laminarinase, proteinase K, and lyticase preparation has been observed during the growth, but this increase has not been found in the case of "wild" type strain. The obtained results evidence to the structure failure of the cell wall of A. chrysogenum entailing the intensive creation of antibiotic. PMID- 21261078 TI - [Regulatory role of monoamine neurotransmitters in Saccharomyces cerevisiae cells]. AB - Proliferation of Saccharomyces cerevisiae EPF cells on solid maltose-peptone yeast extract (MPY) medium was stimulated by the addition of monoamine neurotransmitters. Dopamine turned out to be the most efficient among them: it caused approximately 8-fold growth stimulation at 1 microM concentration. The dopamine effect was partly mimicked by apomorphine, a dopamine receptor agonist. Serotonin and histamine produced less significant (1.5-2-fold) effects, and norepinephrine virtually failed to stimulate yeast culture growth. These data point to a specific, apparently receptor-dependent mode of action of the tested neurotransmitters on S. cerevisiae cells. Using high efficiency liquid chromatography, serotonin, catecholamines (dopamine and norepinephrine), catecholamines precursor dioxyphenylamine, and oxidized amine products (homovanilic acid, dihydrophenylacetic acid, and 5-hydroxyindolacetic acid) were established to be accumulated in yeast cells up to (sub)micromolar concentrations without their release into the culture fluid supernatant (CSF). The results obtained suggest that the tested amine neurotransmitters and related compounds do not serve as autoregulators in the yeast population. Nevertheless, they may be involved in the regulation of yeast population development by other ecosystem components. PMID- 21261079 TI - [Increase in glucoamylase productivity of Aspergillus awamori strain by combination of radiating mutagenesis and plasmid transformation methods]. AB - Increase in the level of amylolytic genes activator protein encoded by amyR gene was shown to result in enhancement of glucoamylase productivity of A. awamori strain by 30%. However, the same effect equal to 30% increase can be achieved by introduction of extra copies of gla gene encoding glucoamylase. These two effects were not additive, which gave the possibility to suggest an additional limitation in the egulation mechanism of glucoamylase gene expression in Aspergillus family strains while introducing an additional copies of amyR and gla genes. PMID- 21261080 TI - [Xylanase of the micromycete Rhizopus var. microsporus 595: preparation, structural and functional characteristics, and application]. AB - Procedures for the production of endo-1,4-beta-xylanase have been developed. An active producer-Rhizopus var. microsporus BKMF-595-has been chosen, and the conditions of surface and submerged cultivation, as well as the composition of the culture medium for this strain, have been optimized to ensure maximum yield of the target enzyme. Activity of xylomicrosporin Px equaled 123 U/g, while the activity of xylomicrosporin Gx equaled 25 U/cm3. Homogeneous enzyme preparations, purified 59.44-fold and 72.6-fold, have been obtained. The dependence of endo-1,4 beta-xylanase catalytic activity on temperature and pH of the reaction medium has been studied. The enzyme has been shown to be most stable in the pH range 5.0-6.0 and to be thermostable. Amino acid composition and subunit structure of the enzyme were determined; the molecular masses of the subunits equaled 50 and 56 kDa. Carboxyl groups of glutamic and aspartic acid residues of the active center were experimentally shown to play an important role in catalysis. The potential of this enzyme for beer production has been demonstrated. PMID- 21261082 TI - [Effectiveness of AO anatomical locking compression plate in treating type C distal humeral fracture]. AB - OBJECTIVE: To evaluate the effectiveness of the AO anatomical locking compression plate in treating type C distal humeral fracture. METHODS: Between July 2008 and April 2009, 13 cases of type C distal humeral fracture were treated with the AO anatomical locking compression plates. There were 5 males and 8 females with an average age of 52.1 years (range, 24-80 years). Fractures were caused by tumbling in 7 cases, by traffic accident in 4 cases, and by falling from height in 2 cases. According to Association for Osteosynthesis/Orthopaedic Trauma Association (AO/OTA) classification, there were 3 cases of type C1, 6 cases of type C2, and 4 cases of type C3. Two cases complicated by ulnar nerve injuries, 1 by radial nerve injury, 2 by fractures of ulnar olecranon, 3 by fractures of other parts of extremities, and 6 by osteoporosis. The time from injury to hospitalization ranged from 3 hours to 4 days (0.9 day on average). RESULTS: All the incisions achieved healing by first intention. Thirteen cases were followed up 12 to 21 months with an average of 15.9 months. According to the X-ray films, unions were achieved both at fracture site and the olecranon osteotomy site with a healing time of 8 to 13 weeks (10 weeks on average). The function of elbows recovered from 3 to 32 weeks (10 weeks on average). No fixation failure, myositis ossificans, delayed union, or malunion occurred during the follow-up. The Mayo Elbow Performance score ranged from 75 to 100 with an average score of 95.8; the results were excellent in 9 cases, good in 3 cases, and fair in 1 case with an excellent and good rate of 92.3%. CONCLUSION: The AO anatomical locking compression plate has a good fixation in treating type C distal humeral fracture. Through the approach of olecranon osteotomy, it is easy to get anatomical reduction, stable fixation, and early exercise. PMID- 21261081 TI - [Distribution of O-glycosylases in marine fungi of the Sea of Japan and the Sea of Okhotsk: characterization of exocellular N-acetyl-beta-D-glucosaminidase of the marine fungus Penicillium canescens]. AB - The capacity to produce exocellular enmzymes was studied for 92 samples of fungi from various marine habitats in the Sea of Okhotsk (78 strains) and the Sea of Japan (14 strains). Strains producing highly active glycanases and glycosidases were found. Synthesis of O-glycosylhydrolases was stimulated by addition of laminaran to the nutrient medium. Highly purified N-acetyl-beta-D-glucosaminidase was isolated from the marine fungus Penicillium canescens. The molecular weight of the enzyme determined by SDS-Na-electrophoresis was 68 kDa. The enzyme displayed maximum activity at pH 4.5 and temperature 45 degrees C. Inactivation half-time of the enzyme at 50 degrees C was 25 min. N-acetyl-beta-D glucosaminidase hydrolyzed both beta-glucosaminide and beta-galactosaminide bonds and possessed a high transglycosylazing activity. PMID- 21261083 TI - [Comparison of effectiveness between minimally invasive plating osteosynthesis and expandable intramedullary nailing technique in treatment of middle third humeral shaft fractures]. AB - OBJECTIVE: To compare the effectiveness of two minimally invasive methods: minimally invasive plating osteosynthesis (MIPO) and expandable intramedullary nailing technique in treatment of middle third humeral shaft fractures. METHODS: The clinical data were retrospectively analyzed and compared from 33 cases with middle third humeral shaft fractures between May 2004 and December 2008. All the patients were divided into 2 groups: 14 patients were treated with MIPO technique (group A) and 19 with expandable intramedullary nailing technique (group B). In group A, there were 10 males and 4 females with an average age of 35 years (range, 21-51 years). The disease cause was traffic accident in 5 cases, tumbling in 6 cases, machine related trauma in 2 cases, crushed by a heavy object in 1 case. Six fractures were classified as AO type A, 6 as type B, and 2 as type C. The time from injury to operation was 3 to 11 days with an average of 5.9 days. In group B, there were 12 males and 7 females with an average age of 40 years (range, 19-68 years). The disease cause was traffic accident in 7 cases, tumbling in 8 cases, falling from height in 3 cases, crush injury in 1 case. Ten fractures were classified as AO type A, 8 as type B, and 1 as type C. The time from injury to operation was 2 to 6 days with an average of 4.2 days. There was no significant difference in general data between 2 groups (P > 0.05). RESULTS: The operation time was (104.6 +/- 25.8) minutes in group A and (85.0 +/- 35.7) minutes in group B, showing no significant difference (P > 0.05). Incision healed by first intention without iatrogenic radial nerve palsy in 2 groups. The patients were followed up 21.4 months on average (range, 12-37 months) in group A and 20.5 months on average (range, 22-35 months) in group B. The X-ray films showed bony healing in all patients. The fracture union time was (16.4 +/- 6.1) weeks in group A and (15.0 +/- 2.5) weeks in group B, showing no significant difference (P > 0.05). The University of California Los Angeles (UCLA) End-Result scores were 34.1 +/- 1.1 in group A and 31.8 +/- 2.6 in group B and the Mayo Elbow Performance scores were 100 in group A and 97.6 +/- 3.9 in group B; all showing significant differences (P < 0.05). CONCLUSION: Good clinical outcomes could be obtained when middle third humeral shaft fractures are treated by either MIPO or expandable intramedullary nailing techniques. However, MIPO technique could offer better shoulder and elbow functional results. PMID- 21261084 TI - [Wrist joint reconstruction with vascularized fibular head graft after resection of distal radius giant cell tumor]. AB - OBJECTIVE: To observe the effectiveness of wrist joint reconstruction with vascularized fibular head graft after resection of distal radius giant cell tumor. METHODS: Between March 2000 and March 2009, 31 cases of distal radius giant cell tumor were treated with extended resection and vascularized fibular head graft for repairing defects of the distal radius, and reconstructing wrist joint. There were 14 males and 17 females with an average age of 37.2 years (range, 15-42 years). The disease duration ranged from 1 month to 2 years and 3 months with an average of 8 months. The size of tumor was 6.5 cm x 3.5 cm-8.0 cm x 4.5 cm. The range of motion (ROM) of wrist joint was as follows: extension 5-15 degrees (mean, 10.7 degrees), flexion 9-21 degrees (mean, 14.2 degrees), radial inclination 0-10 degrees (mean, 8.6 degrees), and ulnar inclination 0-15 degrees (mean, 7.9 degrees). The ROM of forearm was as follows: pronation 15-50 degrees (mean, 28.7 degrees) and supination 10-25 degrees (mean, 16.5 degrees). The histopathological examination revealed that there were 5 cases of stage I, 17 of stage II, and 9 of stage III. RESULTS: All patients achieved primary healing of incision and were followed up 1-9 years with an average of 4.5 years. The X-ray films showed that bone healing time was 12-16 weeks with an average of 13 weeks. No tumors recurrence was observed. The ROM of wrist joint was as follows at 1 year after operation: extension 20-50 degrees (mean, 29.0 degrees), flexion 30-50 degrees (mean, 35.0 degrees), radial inclination 10-20 degrees (mean, 16.5 degrees), and ulnar inclination 20-25 degrees (mean, 23.5 degrees). The ROM of forearm was as follows: pronation 40-90 degrees (mean, 68.3 degrees) and supination 30-80 degrees (mean, 59.6 degrees). There were significant differences in the ROM between before operation and after operation (P < 0.05). According to the Krimmer et al wrist score, the results were excellent in 17 cases, good in 12, and fair in 2. CONCLUSION: Wrist joint reconstruction with vascularized fibular head graft can restore function of wrist joint. The operation is proved to be safe and effective in treating distal radius giant cell tumor. PMID- 21261085 TI - [Comparison of effectiveness of three operations in treatment of displaced femoral neck fractures in the elderly patients]. AB - OBJECTIVE: To compare the effectiveness of internal fixation, hemiarthroplasty, and total hip arthroplasty in the treatment of displaced femoral neck fractures in elderly patients so as to provide the evidence for the selection of therapeutic methods. METHODS: Between May 2005 and April 2008, 108 elderly patients with displaced femoral neck fractures were treated by internal fixation with compression screw (IF group, n = 31), hemiarthroplasty (HA group, n = 37), and total hip arthroplasty (THA group, n = 40). In IF group, there were 8 males and 23 females with an average age of 73 years (range, 65-80 years); fractures were caused by tumbling (25 cases) and traffic accident (6 cases), including 17 cases of Garden type III and 14 cases of Garden type IV; and the time from injury to operation ranged from 8 hours to 13 days with an average of 4.2 days. In HA group, there were 10 males and 27 females with an average age of 74 years (range, 65-80 years); fractures were caused by tumbling (29 cases) and traffic accident (8 cases), including 21 cases of Garden type III and 16 cases of Garden type IV; and the time from injury to operation ranged from 1 to 14 days with an average of 4.4 days. In THA group, there were 11 males and 29 females with an average age of 73 years (range, 66-80 years); fractures were caused by tumbling (32 cases) and traffic accident (8 cases), including 23 cases of Garden type III and 17 cases of Garden type IV; and the time from injury to operation ranged from 2 to 14 days with an average of 5.6 days. There was no significant difference in general data among 3 groups (P > 0.05). RESULTS: There were significant differences in operation time and blood loss among 3 groups (P < 0.05), and IF group was less than other 2 groups. All patients were followed up 1 year and 4 months to 2 years and 3 months with an average of 1 year and 8 months. In IF group, HA group, and THA group, the rates of early postoperative complications were 19.4% (6/31), 8.1% (3/37), and 7.5% (3/40), respectively; the rates of late postoperative complications were 29.0% (9/31), 13.5% (5/37), and 7.5% (3/40), respectively; and the reoperation rates were 29.0% (9/31), 10.8% (4/37), and 5.0% (2/40), respectively. The rates of the early postoperative complication, late postoperative complication, and reoperation rate were significantly higher in IF group than in HA group and THA group (P < 0.05), but there was no significant difference between HA group and THA group (P > 0.05). The mortality rates were 16.1% (5/31), 13.5% (5/37), and 15.0% (6/40) in IF group, HA group, and THA group, respectively; showing no significant difference (P > 0.05). According to Harris hip score, the excellent and good rates were 65.4% (17/26), 81.3% (26/32), and 85.3% (29/34) in IF group, HA group, and THA group, respectively; showing significant differences among 3 groups (P < 0.05). CONCLUSION: According to patient's age, life expectancy, and general conditions, THA is a reasonable choice for the patients aged 65-80 years with displaced femoral neck fracture. PMID- 21261086 TI - [Therapeutic evaluation of femoral intertrochanteric fractures by InterTan]. AB - OBJECTIVE: To evaluate the effectiveness of InterTan in the treatment of femoral intertrochanteric fractures. METHODS: Between April 2009 and July 2009, 57 patients with femoral intertrochanteric fracture were treated with InterTan. There were 33 males and 24 females with an average age of 68 years (range, 45-88 years). The locations were left side in 31 cases and right side in 26 cases and all fractures were closed fractures. According to Association for Osteosynthesis/Orthopaedic Trauma Association (AO/OTA) classification, there were 23 cases of type 31-A1, 27 of type 31-A2, and 7 of type 31-A3. The disease duration was 2 to 8 days with an average of 3.3 days. The data of operative time, blood loss, perioperative blood transfusion, hospitalization day, fracture healing time, and Harris hip score were recorded. RESULTS: The operative time and the blood loss were (74.5 +/- 19.7) minutes and (148.8 +/- 79.6) mL, respectively. There were significant differences in the operative time and the blood loss among the AO/OTA subgroups (P < 0.05). Twenty-five patients required a blood transfusion and the transfusion volume was (264.0 +/- 90.7) mL. The average hospitalization days were 7 days (range, 6-9 days). Thirty-five patients were followed up 12 to 15 months (13.3 months on average). X-ray films showed that all fractures healed within (2.8 +/- 0.8) months. The healing time of fracture was (2.4 +/- 0.6), (2.9 +/- 0.9), and (3.8 +/- 0.5) months in 31-A1 subgroup, 31-A2 subgroup, and 31-A3 subgroup, respectively. There was no significant difference in healing time of fracture between 31-A1 subgroup and 31-A2 subgroup (P > 0.05), and there were significant differences between 31-A3 group and 31-A1 subgroup, 31 A2 subgroup (P < 0.05). No shortening, cut-out, varus malposition, femoral shaft fracture, or implant failures was found. The Harris score at the final follow-up was 84.5 +/- 8.2 with an excellent and good rate of 80% (15 cases of excellent, 13 of good, 6 of fair, and 1 of poor). Twenty patients (57%) recovered the walking ability. CONCLUSION: The new intertrochanteric antegrade nail of InterTan can be used to treat femoral intertrochanteric fractures with good clinical outcomes, high union rate, and less complications. PMID- 21261087 TI - [Effectiveness of acetabular transverse and posterior wall fractures by Kocher Langenbeck approach]. AB - OBJECTIVE: To investigate the surgical treatment effectiveness of acetabular transverse and posterior wall fractures by Kocher-Langenbeck approach. METHODS: Between January 2002 and February 2009, 17 patients with acetabular transverse and posterior wall fractures were treated with Kocher-Langenbeck approach and fracture reduction and fixation. There were 12 males and 5 females with an average age of 33.4 years (range, 20-65 years). The disease causes were traffic accident in 16 cases and falling from height in 1 case. The disease duration was 6 hours to 11 days. According to Letournel classification, all fractures were rated as acetabular transverse and posterior wall fractures. Concomitant injuries included posterior hip dislocation in 3 cases, fracture of extremities in 8 cases, injury of sciatic nerve in 3 cases, craniocerebral injury in 1 case, and lienal rupture in 1 case. RESULTS: The incisions healed primarily and no complication of infection and deep venous thrombosis occurred after operation. All patients were followed up 12 to 36 months with an average of 19 months. The X ray films showed that fracture healed 3 to 5 months after operation. After operation, anatomic reduction was found in 9 cases, satisfactory reduction in 5 cases, and unsatisfactory reduction in 3 cases according to Matta et al criterion. According to modified grading system of Merle D'Aubigne and Postel, the results were excellent in 4 cases, good in 9, fair in 3, and poor in 1 at last follow-up with an excellent and good rate of 76.5%. The nerve function was recovered in patients with sciatic nerve injury at 12 months after symptomatic treatment. Traumatic arthritis occurred in 5 cases, avascular necrosis of the femoral head in 1, and heterotopic ossification in 5 between 9 weeks and 12 months after operation. CONCLUSION: For acetabular transverse and posterior wall fractures, it is important to make adequate preoperative preparation, to get the imaging data, and to perform open reduction and internal fixation with Kocher Langenbeck approach as early as possible. PMID- 21261088 TI - [Effectiveness of posterior malleolus fixation in treating ankle fracture]. AB - OBJECTIVE: To evaluate the effectiveness of posterior malleolus fixation on the function of ankle in patients with ankle fracture. METHODS: Between June 2007 and June 2009, 110 patients with ankle fracture were treated with posterior malleolus fixation in 59 patients (fixation group) or without fixation in 51 patients (non fixation group). In fixation group, there were 31 males and 28 females with an average age of 62.6 years (range, 19-75 years); the causes of injury included traffic accident (20 cases), falling (18 cases), and sprain (21 cases) with a disease duration of 1-3 days (2.2 days on average); and the locations were left ankle in 32 cases and right ankle in 27 cases, including 6 cases of type I, 23 of type II, 19 of type III, and 11 of type IV according to the ankle fracture classification. In non-fixation group, there were 38 males and 13 females with an average age of 64.5 years (range, 16-70 years); the causes of injury included traffic accident (15 cases), falling (12 cases), and sprain (24 cases) with a disease duration of 1-3 days (2.5 days on average); and the locations were left ankle in 22 cases and right ankle in 29 cases, including 8 cases of type I, 16 of type II, 19 of type III, and 8 of type IV according to the ankle fracture classification. There was no significant difference in general data between 2 groups (P > 0.05). RESULTS: All patients of 2 groups achieved wound healing by first intention. The patients were followed up 12-18 months (16 months on average). X-ray films showed that fractures healed at 8-12 weeks (10 weeks on average) in fixation group and at 10-14 weeks (12 weeks on average) in non fixation group. There were significant differences in the clinical score (89.28 +/- 8.62 vs. 86.88 +/- 9.47, P < 0.05), postoperative reposition score (33.34 +/- 2.15 vs. 31.24 +/- 2.89, P < 0.05), and osteoarthritis score (13.22 +/- 1.66 vs. 12.46 +/- 2.03, P < 0.05) according to Phillips ankle scoring system between 2 groups at last follow-up. There was no significant difference in clinical score of type I and II patients between 2 groups (P > 0.05), but significant differences were found in clinical score and osteoarthritis score of type III and IV patients between 2 groups (P < 0.05). There were significant differences in the postoperative reposition score between 2 groups in all types of fractures (P < 0.05). CONCLUSION: The posterior malleolus fixation may provide satisfactory clinical functional outcomes for ankle fracture. Proper fracture classification and correct method of internal fixation are important for achieving good reduction and improving the long-term results. PMID- 21261089 TI - [Diagnosis and surgical treatment of tarsometatarsal joint complex injuries]. AB - OBJECTIVE: To explore the diagnosis and surgical treatment of tarsometatarsal joint complex injuries. METHODS: Between January 2000 and October 2009, 24 cases of tarsometatarsal joint complex injuries were treated. There were 14 males and 10 females with an average age of 38 years (range, 21-65 years). Injury was caused by a machine in 8 cases, by traffic accident in 12 cases, and by falling from height in 4 cases. All fractures were closed. The time from injury to hospitalization was 2-17 hours (5 hours on average). Open reduction and internal fixation with screw were performed. RESULTS: Incision healed by first intention in other patients except 1 patient who had effusion at incision. Twenty-three cases were followed up 12-47 months with an average of 23 months. X-ray films showed that all fractures healed after 9-15 weeks of operation (13 weeks on average). No complication was found, such as osteofascial compartment syndrome, nonunion infection, loosening or breakage of the internal fixator. According to Maryland scoring, the results were excellent in 7 cases, good in 8 cases, fair in 5 cases, and poor in 3 cases with an excellent and good rate of 65.2%. CONCLUSION: Anatomical reduction and stable fixation are important for satisfying results in treating tarsometatarsal joint complex injuries. PMID- 21261090 TI - [Comparative effectiveness of surgical and non-surgical treatment for pediatric mandibular condylar fractures]. AB - OBJECTIVE: To compare the effectiveness of open reduction and conservative treatment for pediatric mandibular condylar fractures and to provide the evidence for the selection of clinical therapy. METHODS: The clinical data were retrospectively analyzed from 25 patients with the mandibular condylar fractures between January 1988 and December 2006. Of them, 8 patients (11 fractures) were treated with surgical treatment (surgical group) and 17 patients (22 fractures) with non-surgical treatment (non-surgical group). In surgical group, there were 6 males (9 fractures) and 2 females (2 fractures) with an age range of 8-13 years; fracture was caused by tumbling in 7 cases and by traffic accident in 1 with an interval of 1-6 days between injury and hospitalization; and 5 cases were identified as unilateral condylar fractures (3 complicated by mental fractures) and 3 cases as bilateral condylar fractures complicated by mental fractures. In non-surgical group, there were 12 males (15 fractures) and 5 females (7 fractures) with an age range of 3-12 years; fracture was caused by falling from height in 4 cases, by tumbling in 10, and by traffic accident in 3 with an interval of 1-25 days between injury and hospitalization; and 12 cases were identified as unilateral condylar fractures (3 complicated by mental fractures) and 5 cases as bilateral condylar fractures (1 complicated by mental fracture). RESULTS: Incision healed by first intention in surgical group, and 25 cases were followed up 1-6 years with an average of 3.5 years. At 12 months after treatment, no temporomandibular joint pain, eating disorder, or limited mandibular movement occurred in 2 groups. No significant difference was observed in opening mouth extent, protrusive and lateral movements between 2 groups at 6 and 12 months (P > 0.05). During centric occlusion, mental point located at the midline with symmetric face figure. Two patients in surgical group and 3 in non-surgical group had slight snap when opening their mouths. Mandible deviation was observed in 3 patients of 2 groups, respectively when gaping. The X-ray films showed healing of fracture and condylar remodeling at 3-6 months. Mandibular ramus were symmetric in cephalometry. CONCLUSION: Good effectiveness can be obtained by surgical or non-surgical treatment in pediatric mandibular condylar fractures. Considering the pediatric mandibular condyle having powerful healing and reconstructing potency and avoiding secondary injury on the temporomandibular joint from surgery, non-surgical treatment should be first selected for the pediatric mandibular condylar fractures in patients under 7 years. PMID- 21261091 TI - [Study on correlation between single nucleotide polymorphism in promotor of hepatic lipase gene and nontraumatic avascular necrosis of femoral head]. AB - OBJECTIVE: To explore the correlation between the single nucleotide polymorphism (SNP) in the promotor of hepatic lipase (HL) gene and nontraumatic avascular necrosis of the femoral head (ANFH). METHODS: Between January 2007 and June 2009, 243 patients with ANFH were treated (case group), including 143 cases of steroid induced, 79 cases of alchol-induced, and 21 cases of idiopathic. There were 156 males and 87 females with an age ranged from 16 to 64 years. A total of 96 normal individuals (matched for age, sex, and nation) served as control group. The blood sample of all subjects were collected to extract DNA. The promotor of HL was sequenced to find the SNP. A statistic on the frequencies of the genotype and the allele of the SNP was made. The frequencies of the genotype and the allele were analyzed with chi2 test according to case-control principle. RESULTS: The rs59644784 and rs1800588 were found in the sequenced region. It was accorded with Hardy-Weinbery genetic equilibrium law in rs59644784 and rs1800588 of the control group and case group. There was no significant difference in the allele and genotype of rs59644784 and rs1800588 between the control group and case group (P > 0.05). The two SNPs existed complete linkage disequilibrium according to the linkage disequilibrium analysis. CONCLUSION: The heterozygosity of the SNP is not consistency, and heterozygosity may be associated with the diversity of the race. ANFH is not associated with rs59644784 and rs1800588 SNPs. PMID- 21261092 TI - [Study on effect of recombinant adeno-associated virus vector co-expressing human vascular endothelial growth factor 165 and human bone morphogenetic protein 7 genes on bone regeneration and angiopoiesis in vivo]. AB - OBJECTIVE: To study the effect of recombinant adeno-associated virus (rAAV) vector co-expressing human vascular endothelial growth factor 165 (hVEGF165) and human bone morphogenetic protein 7 (hBMP-7) genes on bone regeneration and angiopoiesis in vivo so as to provide a theoretical basis for the gene therapy of avascular necrosis of the femoral head (ANFH). METHODS: Twenty-four male adult New Zealand rabbits were made the ischemic hind limb model and divided into 4 groups (n = 6). The 3rd generation rabbit bone marrow mesenchymal stem cells (BMSCs) were transfected with the following 4 virus and were administered intramuscularly into the ischemic thigh muscle of 4 groups, respectively: rAAV hVEGF165-internal ribosome entry site (IRES)-hBMP-7 (group A), rAAV-hVEGF165 green fluorescent protein (GFP) (group B), rAAV-hBMP-7-GFP (group C), and rAAV IRES-GFP (group D). At 8 weeks after injection, the blood flow of anterior tibial artery in the rabbit hind limb was detected by ultrasonographic image. Immunohistochemical staining for CD34 was performed to identify the proliferation of capillary. Another 24 male adult New Zealand rabbits were made the femur muscle pouch model and divided into 4 groups (n = 6). The above 4 BMSCs transfected with rAAV were administered intramuscularly into the muscle pouch. At 8 weeks after injection, X-ray radiography was used to assess orthotopic bone formation, and von Kossa staining to show mineralization. RESULTS: No symptoms of local or systemic toxicity were observed after rAAV injection. At 8 weeks after injection, the ratio of ischemic to normal blood flow and the number of capillaries in group A were the highest among 4 groups (P < 0.05). The ratio of ischemic to normal blood flow and the number of capillaries in group B were significantly higher than those in group C and group D (P < 0.05). However, there was no significant difference between group C and group D (P > 0.05). At 8 weeks after injection, orthotopic ossification and mineralization were evidently detected in group A and group C, and group A was stronger than group C. No obvious evidence of orthotopic ossification and mineralization were observed in group B and group D. CONCLUSION: rAAV-hVEGF165-IRES-hBMP-7 vector has the biological activities of inductive bone regeneration and angiopoiesis in vivo. PMID- 21261093 TI - [Biomechanical effects of insertion location and bone cement augmentation on fixation strength of iliac screw]. AB - OBJECTIVE: To compare the maximum pull-out strength of the upper iliac screw and lower iliac screw with and without polymethylmethacrylate (PMMA) augmentation, and to provide the experimental evidences for the rational use of iliac screws. METHODS: Ten intact human ilium from 5 donated cadavers with formalin embalmed were selected. The bone mineral density (BMD) of L1-4 of each cadaver was measured with a dual energy X-ray absorptiometry. The screws placed in the upper and lower iliac column were named as the upper and lower iliac screw, respectively. Using 70 mm length and 7.5 mm diameter screws with and without PMMA augmentation, 4 iliac screw technique models were sequentially established and tested as follows: upper iliac screw (group A), upper iliac screw with PMMA augmentation (group B), lower iliac screw (group C), and lower iliac screw with PMMA augmentation (group D). Each ilium was mounted on a material testing machine with its position similar to standing. Under 2 000 cyclic compressive loadings of 100-300 N to the screw, the maximum pull-out strength of iliac screw was measured. RESULTS: The BMD value of the 5 human cadavers was (0.88 +/- 0.06) g/cm2. All the iliac screws were inserted into the screw tracts accurately as expected. No screw penetrations of acetabulum or cortex was not observed through visual inspection. There was no "halo" ring sign surrounding any screw after the 2 000 cycle loading. The maximum pull-out strengths of groups A, B, C, and D were (964 +/- 250), (1462 +/- 266), (1537 +/- 279), and (1964 +/- 422) N, respectively. Group D exhibited the highest maximum pull-out strength among the 4 groups (P < 0.05). No significant difference was detected between groups B and C (P > 0.05); however, groups B, C showed higher maximum pull-out strength than group A (P < 0.05). CONCLUSION: The lower iliac screw offers significantly higher fixation strength than the upper iliac screw; PMMA augmentation could effectively increase the fixation strength of iliac screws and therefore could be applied in the salvage of iliac screw loosening. PMID- 21261094 TI - [Biomechanical analysis of stability of internal fixator for proximal humeral fractures]. AB - OBJECTIVE: To review the biomechanics of internal fixators for proximal humeral fractures, and to compare the mechanical stability of various internal fixators. METHODS: The literature concerning the biomechanics of internal fixators for proximal humeral fractures was extensively analyzed. RESULTS: The most important things for best shoulder functional results are optimal anatomical reduction and stable fixation. At present, there are a lot of methods to treat proximal humeral fractures. Locking-plate exhibits significant mechanical stability and has many advantages over other internal fixators by biomechanical comparison. CONCLUSION: Locking-plate has better fixation stability than other internal fixators and is the first choice to treat proximal humeral fractures. PMID- 21261095 TI - [Progress of relationship between biofilm and prosthetic joint infection]. AB - OBJECTIVE: To summarize the effect of biofilm (BF) on the occurrence of prosthetic joint infection (PJI). METHODS: The domestic and abroad original literature in recent years about the relationship between BF and PJI was reviewed. RESULTS: Infection is a critical complication for prosthetic joint replacement. Basic research shows one of the reasons for PJI is BF. After adherence of the bacteria to the surface of prosthetic joint, BF forms through a series of regulation and control system. And it lead to the occurrence of PJI. Recently a lot of progress have been made in the research fields of BF related PJI, which have covered aetiology, diagnosis, treatment, and prevention. Different studies show that BF has close relationship with PJI. CONCLUSION: BF is proved to have close relationship with PJI. It is important on clinical significances to diagnose, treat, and prevent PJI. PMID- 21261096 TI - [Progress of osteosarcoma therapy]. AB - OBJECTIVE: To review the research progress of the treatment of osteosarcoma, and to thoroughly understand its current state of research and prospect so as to lay a solid foundation for the clinical treatment. METHODS: The clinical and experimental research literatures about treatment of osteosarcoma were extensively reviewed and analyzed. RESULTS: The present treatment of osteosarcoma is still need to comprehensive therapy which combine chemotherapy and surgical treatment. There are some progresses in gene therapy and molecular targeting therapy which can improve survival rate. Furthermore, well-designed studies and clinical trials are needed to evaluate the potential therapeutic impact before they are used in clinical. CONCLUSION: Advancement in chemotherapeutic regimens has improved survival and limb-sparing surgery in the treatment of osteosarcoma, but the progress of gene therapy and molecular targeting therapy gives new hope for osteosarcoma patients. PMID- 21261097 TI - [Treatment of multi-level cervical spondylotic myelopathy by anterior segmental decompression and autograft fusion]. AB - OBJECTIVE: To evaluate the clinical effects of anterior segmental decompression and autograft fusion in treating multi-level cervical spondylotic myelopathy (CSM). METHODS: Between January 2007 and May 2009, 23 patients with multi-level CSM were treated with anterior segmental decompression, autograft fusion, and internal fixation. There were 16 males and 7 females with an average age of 58 years (range, 49-70 years). Consecutive 3 segments of C3, 4, C4, 5, and C5, 6 involved in 15 cases and C4, 5, C5, 6, and C6, 7 in 8 cases. All patients suffered sensory dysfunction in limbs and trunk, hyperactivity of tendon reflexes of both lower extremities, walking with limp, and weakening of hand grip. Cervical MRI showed degeneration and protrusion of intervertebral disc and compression of cervical cord. The disease duration was 6 to 28 months (12.5 months on average). Japanese Orthopaedic Association (JOA) score system was adopted for therapeutic efficacy evaluation. JOA scores were recorded preoperatively, 1 week, 3 months, and 12 months postoperatively. RESULTS: Dura tear occurred in 1 case and was treated by filling with gelatin sponge during operation; no cerebrospinal fluid leakage was observed after operation. All the incisions healed by first intention. All cases were followed up 12 to 24 months (15.1 months on average), and no vertebral artery injury or recurrent laryngeal nerve injury occurred. The nervous symptoms in all cases were improved significantly within 1 week after operation. Lower limb muscle strength increased, upper limb abnormal sensation disappeared, and limb moved more agile. A 2-mm collapses of titanium mesh into upper terminal plate were found in 1 case and did not aggravated during follow-up. The other internal fixator was in appropriate situation, and the fusion rate was 100%. The JOA score increased from 9.1 +/- 0.3 preoperatively to 14.3 +/- 0.4 at 12 months postoperatively with an improvement rate of 65.8% +/- 0.2%, showing significant difference (P < 0.01). According to Odom evaluation scale, the results were excellent in 10 cases, good in 8 cases, fair in 4 cases, and poor in 1 case. CONCLUSION: Anterior segmental decompression and autograft fusion is a recommendable technique for multi-level CSM, which can make full decompression, conserve the stability of cervical cord, and has high fusion rate. PMID- 21261098 TI - [Anterior segmental decompression and double-plate fixation for treatment of skip cervical spondylotic myelopathy]. AB - OBJECTIVE: To evaluate the clinical outcomes and values of anterior segmental decompression and double-plate fixation (ASDDF) for treatment of skip cervical spondylotic myelopathy (SCSM). METHODS: Between June 2005 and June 2008, 17 patients with SCSM were treated with ASDDF. There were 10 males and 7 females with an average age of 58.8 years (range, 41-74 years) and an average disease duration of 9.7 months (range, 6-39 months). According to Japanese Orthopaedic Association (JOA) score system, 2 patients were rated as extreme severe condition, 7 as severe, 7 as moderate, and 1 as mild. MRI images showed 42 affected cervical disc levels, including 26 disc levels with high-intensity intramedullary lesions on T2, 4 with low-intensity intramedullary lesions on T1, and 12 with significant cord compression but no signal change; according to Nagata classification scale, there were 5 abnormal segments at class I, 21 at class II, and 16 at class III. The rate of fusion, the Cobb angle, and the range of motion (ROM) of the cervical spine were measured preoperatively and postoperatively by the X-ray examinations. The improvement of the neurological function was evaluated by the JOA score. RESULTS: The average time of follow-up was 28.6 months (range, 24-58 months). After operation, dysphagia occurred in 2 cases (symptom relief after 1 month), hoarseness in 1 case (symptom relief after 3 months of methylcobalamin treatment), and degeneration of adjacent segments without symptom in 3 cases. The X-ray films showed the fusion rate of 100% at 12 months after operation without displacement, resorption or collapse of bone graft, and without breakage or loosening of plate and screw. The Cobb angles were (13.3 +/- 10.4) degrees preoperatively, (15.8 +/- 10.8) degrees immediately postoperatively, and (15.4 +/- 11.4) degrees at last follow-up; the ROM of the cervical spine were (41.3 +/- 17.4) degrees preoperatively and (23.8 +/- 18.8) degrees at last follow-up; and the JOA scores were 8.2 +/- 2.9 preoperatively, 13.7 +/- 3.0 at 12 months postoperatively, and 13.9 +/- 2.8 at last follow-up. All indexes showed significant differences between before operation and after operation (P < 0.05). The results of JOA scores were excellent in 8 cases, good in 6, fair in 2, and poor in 1 with an average improvement rate of 66.8% (range, 14%-88%) for the neurological function. CONCLUSION: Adequate decompression, high rate of fusion, solid mechanical stability, improvement of total cervical lordosis, and the neurological function can be achieved through ASDDF for treatment of SCSM. PMID- 21261099 TI - [Long-term effectiveness of percutaneous laser disc decompression in treatment of cervical spondylosis]. AB - OBJECTIVE: To retrospectively analyze the long-term effectiveness of percutaneous laser disc decompression (PLDD) in treatment of cervical spondylosis. METHODS: Between March 2003 and June 2005, 156 patients with cervical spondylosis were treated with PLDD. There were 74 males and 82 females with an average age of 55.4 years (range, 31-74 years). The disease duration varied from 2 months to 15 years. Fifty-nine patients were classified as cervical spondylotic radiculopathy, 48 as vertebral-artery-type cervical spondylosis, 19 as cervical spondylotic myelopathy, and 30 as mixed type spondylosis. The lesions were located at the levels of C3, 4 in 32 discs, C4, 5 in 66 discs, C5, 6 in 89 discs, and C6, 7 in 69 discs, and including 71 one-level lesion and 85 multi-level lesions. All cases were followed up to study the long-term effectiveness and correlative factors. RESULTS: A total of 117 (75%) patients' symptoms were lightened or eased up immediately after operation. Discitis occurred in 1 case at 3 days after operation and was cured after 3 weeks of antibiotic use. All patients were followed up 5 years to 7 years and 3 months (5 years and 6 months on average). According to Macnab criteria, the long-term effectiveness was excellent in 60 cases (38.46%), good in 65 cases (41.67%), fair in 19 cases (12.18%), and poor in 12 cases (7.69%); the excellent and good rate was 80.13%. No significant difference was observed in the wedge angels and displacements of the intervertebral discs between before and after operations (P > 0.05). Multiple factors logistic regression showed that the disease duration and patient's age had obvious relationship with the effectiveness of treatment (P < 0.05), while the type of cervical spondylosis, disc protrusion degree, mild cervical instability, and lesion scope had no correlation with the effectiveness of treatment (P > 0.05). CONCLUSION: PLDD is safe and effective in treatment of cervical spondylosis with less complication. There is no impact on the stability in cervical spinal constructs. The disease duration and patient's age have obvious impact on the long-term effectiveness of treatment. The type of cervical spondylosis, disc protrusion degree, cervical instability, and lesion scope are not the correlative factors. PMID- 21261100 TI - [One-stage posterior approach and pedicle instrumentation for correction of scoliosis associated with Chiari I malformation in adolescent]. AB - OBJECTIVE: To analyze the clinical features of scoliosis associated with Chiari I malformation in adolescent patients, and to explore the validity and safety of one-stage posterior approach and vertebral column resection for the correction of severe scoliosis. METHODS: Between October 2004 and August 2008, 17 adolescent patients with scoliosis associated with Chiari I malformation were treated with surgical correction through posterior approach and pedicle instrumentation. There were 9 males and 8 females with an average age of 15.1 years (range, 12-19 years). The MRI scanning showed that 16 of 17 patients had syringomyelia in cervical or thoracic spinal cord. Apex vertebra of scoliosis were located at T7 12. One-stage posterior vertebral column resection and instrumental correction were performed on 9 patients whose Cobb angle of scoliosis or kyphosis was more than 90 degrees, or who was associated with apparent neurological deficits (total spondylectomy group). Other 8 patients underwent posterior instrumental correction alone (simple correction group). All patients' fixation and fusion segment ranged from upper thoracic spine to lumbar spine. RESULTS: The operative time and the blood loss were (384 +/- 65) minutes and (4 160 +/- 336) mL in total spondylectomy group, and were (246 +/- 47) minutes and (1 450 +/- 213) mL in simple correction group; showing significant differences (P < 0.05). In total spondylectomy group, coagulation disorder occurred in 1 case, pleural perforation in 4 cases, and lung infection in 1 case. In simple correction group, pleural perforation occurred in 1 case. These patients were improved after symptomatic treatment. All patients were followed up 24-36 months (32.5 months on average). Bony healing was achieved at 6-12 months in total spondylectomy group. No breakage or pulling-out of internal fixator occurred. The angles of kyphosis and scoliosis were significantly improved at 1 week after operation (P < 0.01) when compared with those before operation. The correction rates of scoliosis and kyphosis (63.4% +/- 4.6% and 72.1% +/- 5.8%) in total spondylectomy group were better than those (69.4% +/- 17.6% and 48.8% +/- 19.3%) in simple correction group. CONCLUSION: Suboccipital decompression before spine deformity correction may not always be necessary in adolescent scoliosis patients associated with Chiari I malformation. In patients with severe and rigid curve or apparente neurological deficits, posterior vertebral column resection would provide the opportunity of satisfied deformity correction and decrease the risk of neurological injury connected with surgical correction. PMID- 21261101 TI - [Three-dimensional finite element investigation of lateral mass screw fixation and transarticular screw fixation in lower cervical spine]. AB - OBJECTIVE: To establish sophisticated three-dimensional finite element model of the lower cervical spine and reconstruct lower cervical model by different fixation systems after three-column injury, and to research the stress distribution of the internal fixation reconstructed by different techniques. METHODS: The CT scan deta were obtained from a 27-year-old normal male volunteer. Mimics 10.01, Geomagic Studio10.0, HyperMesh10.0, and Abaqus 6.9.1 softwares were used to obtain the intact model (C3-7), the model after three-column injury, and the models of reconstructing the lower cervical spine after three-column injury through different fixation systems, namely lateral mass screw fixation (LSF) and transarticular screw fixation (TSF). The skull load of 75 N and torsion preload of 1.0 N*m were simulated on the surface of C3. Under conditions of flexion, extension, lateral bending, and rotation, the Von Mises stress distribution regularity of internal fixation system was evaluated. RESULTS: The intact model of C3-7 was successfully established, which consisted of 177 944 elements and 35 668 nodes. The results of the biomechanic study agreed well with the available cadaveric experimental data, suggesting that they were accord with normal human body parameters and could be used in the experimental research. The finite element models of the lower cervical spine reconstruction after three-column injury were established. The stress concentrated on the connection between rod and screw in LSF and on the middle part of screw in TSF. The peak values of Von Mises stress in TSF were higher than those in LSF under all conditions. CONCLUSION: For the reconstruction of lower cervical spine, TSF has higher risk of screw breakage than LSF. PMID- 21261102 TI - [Current development of research of biodegradable interbody fusion Cage]. AB - OBJECTIVE: To summarize the basic research and the clinical application of biodegradable interbody fusion Cage. METHODS: Recent literature concerning biodegradable interbody fusion Cage at home and abroad was extensively reviewed, and current developments of the basic research and the clinical application of biodegradable interbody fusion Cage were investigated. RESULTS: Basic research shows that the stiffness of biodegradable interbody fusion Cage is lower than that of metallic Cage, so it can enhance interbody fusion. As interbody fusion proceeded, biodegradable interbody fusion Cage degrades constantly, but the speed of degradation can not keep in parallel with that of fusion. In addition, the tissue response to degradation products is controversy. Clinical application shows that the biodegradable interbody fusion Cage can enhance interbody fusion and maintain disc space height. The short-term results are good, however, the long-term results need further observation. CONCLUSION: Biodegradable interbody fusion Cage can effectively enhance interbody fusion. PMID- 21261103 TI - [Comparison of two repairing procedures for abdominal wall reconstruction in patients with flank hernia]. AB - OBJECTIVE: To analyze the clinical therapeutic effect of extended Sublay technique via previous incision for repairing flank hernias in comparison with routine Sublay technique. METHODS: Between May 2004 and May 2009, 41 patients with flank hernia were treated by extended Sublay repair via previous incision (extended Sublay repair group, n = 18) and by routine Sublay repair (routine Sublay repair group, n = 23). In extended Sublay repair group, there were 11 males and 7 females with an average age of 45.2 years (range, 32-61 years); flank hernia was caused by flank incision operation (12 patients with surgery history of nephrectomy, adrenalectomy, and vascular procedure) and traffic accident (6 patients) with an average disease duration of 14.5 months (range, 8-23 months); and the locations were the left flank region in 11 patients (7 affected superior lumbar triangles and 4 affected inferior lumbar triangles) and the right flank region in 7 patients (5 affected superior lumbar triangles and 2 affected inferior lumbar triangles). In routine Sublay repair group, there were 14 males and 9 females with an average age of 48.7 years (range, 33-64 years); flank hernia was caused by flank incision operation (15 patients with surgery history of nephrectomy, adrenalectomy, and vascular procedure), traffic accident (6 patients), and falling (2 patients) with an average disease duration of 18.2 months (range, 11-27 months); and the locations were the left flank region in 10 patients (5 affected superior lumbar triangles and 5 affected inferior lumbar triangles) and the right flank region in 13 patients (9 affected superior lumbar triangles and 4 affected inferior lumbar triangles). There was no significant difference in general data between 2 groups (P > 0.05). RESULTS: The mesh size in extended Sublay repair group was significantly larger than that in routine Sublay repair group [(618.2 +/- 40.6) cm2 vs. (512.2 +/- 36.5) cm2, P < 0.05]. There was no significant difference in hernia ring size, operation time, and hospitalization day between 2 groups (P > 0.05). In extended Sublay repair group, the patients were followed up 17 to 35 months (26.2 months on average) with an early complication incidence of 27.8% (hematomas in 2 cases, seroma in 1 case, and chronic pain in 2 cases within 1 month) and a late complication incidence of 0 (no hernia recurrence and abdominal wall bulge during follow-up). In routine Sublay repair group, the patients were followed up 14-35 months (24.5 months on average) within early complication incidence of 13.0% (seroma in 1 case and chronic pains in 2 cases within 1 month) and a late complication incidence of 30.4% (hernia recurrence in 3 cases and abdominal wall bulge in 4 cases at 1-3 months). There was significant difference in the late complication incidence between 2 groups (P < 0.05). CONCLUSION: Extended Sublay technique is a safe and effective approach for flank hernia repair. Making clear the anatomy of lumbar region, harvesting adequate space for mesh overlap, and effectively-fixing are critical to ideal clinical outcomes. PMID- 21261104 TI - [Effect of continuous elastic outside distraction on change of collagen content in female minipig's nipples and their supporting tissues]. AB - OBJECTIVE: To observe the effect of continuous elastic outside distraction on the change of collagen content in female minipig's nipples and their supporting tissues, and to investigate the mechanism of continuous elastic outside distraction correcting inverted nipples. METHODS: Three 3-month-old female minipigs (weighing 18.5-22.0 kg), which had 12 nipples, were employed. Four nipples of each minipig were not treated as control group (n = 12), and the other nipples were continuously distracted with inverted nipple correction instruments as experimental group (n = 24). The nipple specimens were harvested at 2, 4, 8, and 12 weeks after distraction and HE staining was performed to observe the change of their tissue structure. And saturated picric acid sirius red staining was used to observe the distribution and content of collagen types I and III, image analysis software for quantitative analysis. RESULTS: The control group had normal structure of epidermis at all time points. In experimental group, the epidermis thickened; basal cells, fibroblasts, and capillary significantly proliferated along with the times; and the content and the density of collagen types I and III increased gradually. There were significant differences in collagen type I at 4, 8, and 12 weeks, and in collagen type III at 2, 4, 8, and 12 weeks between 2 groups (P < 0.01). There were significant differences in the ratio of collagen type I to III at 2 and 4 weeks between 2 groups (P < 0.05). CONCLUSION: Continuous elastic outside distraction can increase the quantity of collagen types I and III in the tissue, the thickness of the dermis, and the height of the nipple, which may be one of key mechanisms of correction the inverted nipple by continuous elastic outside distraction. PMID- 21261105 TI - [Ectopic osteogenesis of immortalized human bone marrow mesenchymal stem cells and heterogeneous bone]. AB - OBJECTIVE: To provide the seed cells for bone tissue engineering, to establish immortalized human bone marrow mesenchymal stem cells (MSCxj) and to investigate the ectopic osteogenesis of MSCxj. METHODS: MSCxjs of the 35th and 128th generations were maintained and harvested when the cell density reached 2 x 10(9). Then, these cells were co-cultured with heterogeneous bone scaffold in groups A (the 35th generation, n = 12) and group B (the 128th generation, n = 12); heterogeneous bone alone was used in group C (n = 12). The cell proliferation was observed by scanning electron microscopy (SEM) after 48 hours and 18 days of osteogenic induction culture. The complex was implanted subcutaneously through a 3-mm-incision at both sides of the back in 18 nude mice. Tetracycline labeling was performed before the animals were sacrificed. Tetracycline fluorescence staining, HE staining, ponceau staining, and immunohistochemistry staining for osteocalcin were performed at 4, 8, and 12 weeks after transplantation; the morphologic quantitative analysis was made. RESULTS: After 48 hours, SEM showed that MSCxjs adhered to heterogeneous bone and grew well; after 18 days, a large number of new filamentous extracellular matrix and small granules were found to cover the cells. The results of tetracycline fluorescence staining, HE staining, and ponceau staining in groups A and B showed that the osteogenesis was not obvious at 4 weeks after transplantation; osteoid matrix deposition was noted around and in the heterogeneous bone at 8 weeks; and osteogenesis was increased at 12 weeks. There was no significant difference in bone formation between groups A and B. Osteogenesis was not observed in group C. The osteocalcin expressions were positive in groups A and B. The bone ingrown percentages of groups A and B were 5.64% +/- 2.68% and 4.92% +/- 2.95% at 8 weeks, and 13.94% +/- 2.21% and 14.34% +/- 3.46% at 12 weeks, showing significant differences between 8 weeks and 12 weeks at the same group (P < 0.05) and no significant difference between groups A and B at the same time (P > 0.05). CONCLUSION: MSCxj has favorable abilities of ectopic osteogenesis and can be applied as seeded cells in bone tissue engineering. PMID- 21261106 TI - [Study on bone marrow mesenchymal stem cells transfected with adenovirus hepatocyte growth factor gene promoting wounds repair in diabetic rats]. AB - OBJECTIVE: To explore the effects of bone marrow mesenchymal stem cells (BMSCs) transfected with adenovirus hepatocyte growth factor (Ad-HGF) on wound repair in diabetic rats. MRTHODS: BMSCs from male Wistar rats were isolated by density gradient centrifugation, cultured, and transfected with Ad-HGF. The multiplicity of infection was 100. Diabetic models were established in 20 female Wistar rats by diets in high fat and sugar plus intraperitoneal injection of streptozotocin (30 mg/kg). Then 2 full-thickness skin wounds (approximately 1.5 cm in diameter) were made on the dorsum. The rats were randomly divided into 4 groups (n = 5 rats). After wounding, the 0.3 mL suspensions of BMSCs (group A), Ad-HGF (group B), BMSCs transfected with Ad-HGF (group C), and PBS (group D) were injected directly into the dermal of wounds. The transverse diameter and longitudinal diameter of wound were measured at 21 days after treatment. At 7 days and 28 days after treatment, HE staining was performed to evaluate wound healing. The contents of hydroxyproline and advanced glycosylation end products (AGEs) in the wounds were measured by enzyme linked immunosorbent assay and fluorospectrophotometer, respectively, at 3, 7, 14, and 28 days after treatment. RESULTS: At 21 days after treatment, the wounds almost healed in group C, and the transverse diameter and longitudinal diameter were 0 and (0.110 +/- 0.024) cm, respectively. But the wounds healed partially in groups A, B, and D, and the transverse diameter and longitudinal diameter were (0.470 +/- 0.051) cm and (0.590 +/- 0.041) cm, (0.390 +/- 0.042) cm and (0.480 +/- 0.032) cm, and (0.700 +/- 0.068) cm and (0.820 +/- 0.068) cm, respectively. There were significant differences in wound healing between group C and groups A, B, and D (P < 0.05). The wound healing time of group C [(20.5 +/- 1.9) days] was significantly shorter (P < 0.05) than those of groups A, B, and D [(28.3 +/- 1.9), (25.9 +/- 2.3), and (36.6 +/- 5.1) days]. At 7 days, the HE staining showed that evident epidermis transportation, collagen formation, and leukocytes infiltration were observed in group C. At 28 days, the HE staining showed that the epidermis in group C was significantly thinner and more regular than those in other groups, and the decreased collagen and many small vessels were observed in group C. The content of hydroxyproline in group C was higher than those in groups A, B, and D at 7 days and 14 days (P < 0.05). The contents of AGEs in group C was lower than those in groups A, B, and D at 14 days and 28 days (P < 0.05). CONCLUSION Transplantation of BMSCs transfected with Ad-HGF can accelerate the wounds repair in diabetic rats. PMID- 21261107 TI - [Markers of endothelial function in the early stages of essential hypertension and the effect of antihypertensive therapy]. AB - OBJECTIVE: Endothelial abnormalities appear to play a role in the pathogenesis of atherosclerotic/atherothrombotic complications of hypertension. They may contribute to the increased risk and severity of target organ damage. The aim of the study was to investigate the endothelial markers in patients at the early stages of mild-to-moderate untreated hypertension with low-to-moderate added risk, and the effect of antihypertensive therapy by perindopril, telmisartan or rilmenidine on endothelial function. SUBJECTS AND METHODS: The measurements were carried out in 54 previously untreated hypertensive patients before and after one month of antihypertensive therapy by perindopril-arginine (5 mg once daily, n = 20), telmisartan (40 mg once daily, n = 16), rilmenidine (1 mg once daily, n = 18) or after placebo administration (n = 23). A population of 50 healthy normotensive subjects of similar sex, age and ethnic origin was also examined. Plasma thrombomodulin (TM) and von Willebrand factor (vWF) measurements were used as indicators of endothelial dysfunction. RESULTS: In untreated hypertensive patients compared with a control group of healthy subjects a significant increase of plasma vWF (86.26 +/- 26.18 IU/dl against 69.14 +/- 18.74 IU/dl, P < 0.001) and TM (35.98 +/- 12.98 ng/ml against 29.34 +/- 9.18 ng/ml, P < 0.01) was found. BP was reduced (P < 0.001) or normalized due to each therapy. No significant changes of endothelial markers after placebo administration were found. A decrease of plasma vWF antigen level after 1 month of therapy by perindopril (from 81.93 +/- 22.07 to 72.88 +/- 23.26 IU/dl, P < 0.05) or rilmenidine (from 100.6 +/- 26.09 to 86.07 +/- 27.66 IU/dl, P < 0.05) was observed. No significant changes of vWF antigen levels were found after telmisartan therapy. We failed to find any changes of plasma TM due to any therapy. CONCLUSION: Our results demonstrate that antihypertensive treatment by perindopril or rilmenidine has a favourable affect on some endothelial markers. PMID- 21261108 TI - [HIV lipodystrophy]. AB - Combined antiretroviral therapy results in extraordinary decrease of morbidity and mortality of HIV-infected patients and in an essential change of the HIV/AIDS disease prognosis. However, long-term intake of antiretroviral medicaments is related to occurrence of metabolic and morphological abnormalities, of which some have been combined into a new syndrome--the so called HIV lipodystrophy. The HIV lipodystrophy syndrome covers metabolic and morphological changes. Metabolic changes include dyslipidaemia with hypercholesterolaemia and/or hypertriglyceridaemia, insulin resistance with hyperinsulinaemia and hyperlaktataemia. Morphological changes have the nature of lipoatrophia (loss of subcutaneous fat--on the cheeks, on extremities, on buttocks and marked prominence of surface veins) or lipohypertrophia (growth of fat tissue--on the chest, in the dorsocervical area, lipomatosis of visceral tissues and organs, fat accumulation in the abdominal area). Several HIV lipodystrophy features are very similar to the metabolic syndrome of the general population. That is why this new syndrome represents a prospective risk of premature atherosclerosis and increase of the cardiovascular risk in young HIV positive individuals. The article mentions major presented studies dealing with the relation of antiretroviral treatment and the cardiovascular risk. The conclusions of the studies are not unequivocal--this is, among others, given by the reason that their length is short from the viewpoint of atherogenesis. The major risk of subclinical atherosclerosis acceleration seems to be related to the deep immunodeficiency and low number of CD4+ lymphocytes and florid, uncontrolled HIV infection with a high number of HIV-1 RNA copies actually circulating in the plasma. The question, whether metabolic and morphological changes related to HIV and cART carry a similar atherogenic potential as in the general population, remains open for future. PMID- 21261109 TI - [Metformin as the first line antidiabetic agent]. AB - Metformin is considered to be the only drug suitable in patients with prediabetes and is the drug of choice in patients with type 2 diabetes. Apart from important antidiabetic effect, it also has some important additional effects: reduced incidence of tumours, positive effects on cardiovascular system, stimulation of immunity, positive effects on the bone, effect on ovulation, influence over body weight reduction, pancreas-protective effects (reduced incidence of carcinoma and possible effect on reduction in incidence of pancreatitis during incretin treatment), positive effects on liver steatosis. Since diabetes patients live with increased cardiovascular risk, it is important to continuously remind ourselves of the positive cardiovascular effects of metformin. PMID- 21261110 TI - [Pulmonary Langerhans cell histiocytosis--evaluation of the disease activity and treatment response using PET-CT (SUV(max) Pulmo/SUV(max) Hepar index). Description of own experience and literature review]. AB - Pulmonary Langerhans cell histiocytosis (LCH) manifests with dyspnoea and a cough with no significant expectoration, with spontaneous pneumothorax being the first symptom in some patients. The disease is caused by multiple granulomas in terminal bronchioles, visible on high resolution CT (HRCT) as nodules. During the further course of the disease, these nodules progress through cavitating nodules into thick-walled and, subsequently, thin-walled cysts. LCH may affect the lungs only or multiple organs simultaneously. Pulmonary LCH may continually progress or remit spontaneously. Treatment is indicated in patients in whom pulmonary involvement is associated with multi-system involvement or when a progression of the pulmonary lesions has been confirmed. To document the disease progression, examination of the lungs using HRCT is routinely applied. Increasing number of nodules suggests disease progression. However, determining the number of nodules is extremely difficult. Measuring radioactivity of the individual small pulmonary loci (nodules) using PET is not possible due to the high number and small size of the nodules. Our centre has a register of 23 patients with LCH; the pulmonary form had been diagnosed in 7 patients. A total of 19 PET and PET-CT examinations were performed in 6 of these patients. PET-CT was performed using the technique of maximum fluorodeoxyglucose accumulation in a defined volume of the right lung- SUV(max) Pulmo. In order to compare the results of examinations performed using the same and different machines over time as well as in order to evaluate pulmonary activity, the maximum fluorodeoxyglucose accumulation in a defined volume of the right lung (SUV(max) Pulmo) to maximum fluorodeoxyglucose accumulation in a defined volume of the liver tissue (SUV(max) Hepar) ratio (index) was used. The disease progression was evaluated using the SUV(max) Pulmo/SUV(max) Hepar index in the six patients with pulmonary LCH. The index value was compared to other parameters characterising the disease activity (HRCT of the lungs, examination of pulmonary function and clinical picture). The SUV(max) Pulmo/SUV(max) Hepar index correlated closely with other disease activity parameters. The traditional PET-CT examination is useful in detecting the LCH loci in the bone, nodes and other tissue but not in the presence of diffuse involvement of pulmonary parenchyma. Measuring the maximum fluorodeoxyglucose accumulation in a defined volume of the right lung and expressing this activity as the SUV(max) Pulmo/SUV(max) Hepar index appears to be a promising approach. Our initial experience suggests that the results obtained using this method correlate well with other parameters that characterise activity of pulmonary LCH. However, this is a pilot study and further verification is required. PMID- 21261111 TI - [Recommended approach in indications for genetic examination in the diagnosis of thrombophilic states in the vascular system]. PMID- 21261112 TI - [Clinical expert forum: diagnosis and therapy of acute porphyria. 11-12 June 2010, Paris (France)]. PMID- 21261113 TI - [Influence of iodine saturation on thyreopathy incidence in selected regions of the Czech Republic]. AB - Thyreopathy--a disorder of thyroid gland--is, together with diabetes, one of the most common endocrine diseases and, similarly to other endocrinopathies, higher prevalence is seen in women than in men. When eliminating iodine deficiency, it should to be taken into account that the mean ioduria in the general population reaches 100-200 microg/l, just 1.3% of the population does not reach ioduria of 50 microg/l and the prevalence of goitre in school children declines below 5%. The 1991 and 1997 period was a period of slight iodine deficiency (ioduria < 100 microg/I) and was followed, between 1998 and 2006, by a period of optimum iodine saturation (ioduria > 100 microg/l). Median ioduria observed over one year follow up differed in different age groups, highest values were seen in the 18-35 age group and declined with age. Median iodinuria depended on the year of follow up, age and gender (p < 0.0000). Thyroid gland hypofunction was more frequent in women and ioduria levels > 100 microg/I, thyroid gland hyperfunction was also more frequent in women but with ioduria levels < 100 microg/l. Hypofunction, subclinical hypofunction, hyperfunction and subclinical hyperfunction were more frequent in women. Of unexplained laboratory findings, isolated hypothyroxinemia was more frequent in women and isolated hyperthyroxinemia was more frequent in men. Euthyreosis was more frequent in men than women. PMID- 21261114 TI - [Activity of the hypothalamic-pituitary-adrenal axis in patients with rheumatoid arthritis]. AB - The controlled data accumulated so far support only subtle alterations in hypothalamic-pituitary-adrenal (HPA) axis function in rheumatoid arthritis (RA), mainly at the adrenal level, and particularly in a subset of premenopausal onset women. Consequences of the subtle HPA alterations in RA for the disease development remain unclear. From a broader perspective, the unresponsiveness of the HPA axis to chronic inflammation in RA can be simply considered an ongoing adaptation to chronic disease. PMID- 21261115 TI - [Evaluation of 11beta-hydroxysteroid dehydrogenase type 1 activity in female patients with rheumatoid arthritis]. AB - INTRODUCTION: Cortisol levels in patients with rheumatoid arthritis (RA) are considered inadequate to ongoing inflammation. One possible mechanism ofthe relative cortisol deficit can be decreased 11beta-hydroxysteroid dehydrogenase type 1 (11BHSD1) activity, an enzyme that converts inactive cortisone to active cortisol. The aim of the study was to determine systemic and local activity of 11 BHSD1 in female patients with RA. METHODS: Six female RA patients without glucocorticoid therapy (age 29 +/- 2 years, BMI 21 +/- 1 kg/m2) and six healthy women (age 30 +/- 2 years, BMI 21 +/- 1 kg/m2) were studied. Endogenous cortisol production was suppressed by dexamethasone. 11BHSD1 activity was evaluated by changes in concentrations of total plasma, free plasma, salivary and cortisol in subcutaneous adipose tissue after cortisone acetate administration (25 mg per os). RESULTS: Concentrations of total plasma, free plasma, salivary, and tissue cortisol increased significantly, however there was no significant difference between RA patients and controls. CONCLUSION: The result suggests comparable systemic and adipose tissue conversion of cortisone to cortisol. Despite chronic inflammation, systemic activity of 11BHSD1 is not responsible for relative adrenal deficiency in RA. Changes in local activity of the enzyme in tissues affected by inflammatory process cannot be excluded. PMID- 21261116 TI - [Genetic background of adrenal cortex tumours--news]. AB - This review has summarized the current knowledge of the genetic background of tumors originating from adrenocortical tissue, manifested as a part of inherited or familial syndromes, as well as specific forms of sporadic tumors caused by aberrant expression of G-protein coupled receptors. PMID- 21261117 TI - [Immunoendocrine associations in adrenal glands]. AB - Immune and endocrine systems are basic regulatory mechanisms of organism and, including the nervous system, maintain the organism's homeostasis. The main immune system representatives are mononuclear cells, T- and B-cells and their products, in the endocrine system the main representatives are cells of the glands with inner secretion and their products. One of the most important glands for maintaining homeostasis are adrenal glands. It has been proven that either cells of the immune system, either endocrine cells can, although in trace amounts, produce mutually mediators of both systems (hormones, cytokines). Disorders in one system can lead to pathological symptoms in the other system. Also here represent adrenals an important model. PMID- 21261118 TI - [Extremely low SHBG level in consequence of Pro156Leu SHBG polymorphism--case reports of two women with polycystic ovary syndrome]. AB - Presented case reports illustrate clinical manifestations of two women with polycystic ovary syndrome who had extremely low serum SHBG levels (Sex Hormone Binding Globulin) due to homozygote carriership of the rare Pro156Leu SHBG polymorphism. PMID- 21261119 TI - [Genetic background of tumors originating from adrenomedullar and extraadrenal chromaffin tissue--update]. AB - It is anticipated that an inherited/familial forms of pheochromocytomas cause approximately 20% of all pheochromocytomas. Therefore, the classic "rule of 10" axioma used to remember the key features of disorder is invalid. Various mutations in several genes have been identified, which underly syndromes with paragangliomas and/or pheochromocytomas. The more candidate genes, the less numbers of patients with apparently sporadic forms of the disorder. This review has summarized the current knowledge of the genetic background of tumors orginating from adrenomedullar and extra-adrenal chromaffin tissue. PMID- 21261120 TI - [Birth weight and genetic risk of type 2 diabetes in Czech population]. AB - INTRODUCTION: Birth weight is associated with type 2 diabetes mellitus and other late-onset metabolic diseases. Reduced birth weight is associated with an increased risk of insulin resistance, type 2 diabetes, and atherosclerosis. Also high birth weight represents risk factor for development of type 2 diabetes later in life. In this study, we investigate whether type 2 diabetes risk-confering alleles and biochemical as well as anthropometrical type 2 diabetes risk markers associate with birth weight in our Czech cohort. RESULTS: Association between high birth weight and higher BMI in adulthood was found. Low birth weight was associated with higher glycaemia and insulinaemia as well as lower peripheral insulin sensitivity during oGTT. The examination of candidate genes provides evidence that Ngn3 and PPARalpha are involved in final birth weight regulation. CONCLUSION: According to our results, we suggest that birth weight should be an integral part of medical history record. PMID- 21261121 TI - [Iodine deficiency in the world and in the Czech Republic--current status and perspectives]. AB - Iodopenia is importance world-wide problem--the cause of spectrum of iodine deficiency disorders (IDD). The "simple" way for its compensation is iodine supplementation--preferably by iodinization of salt: in the Czech Republic prevalence of IDD was very high in the past. The complex program for compensation of iodine deficiency realized in the CR includes improvement of salt iodization, supplementation of pregnant and lactating women, fortification of products for babies' nutrition and increasing use of iodinized salt in general population incl. food industry. Thus CR is country with compensated iodine deficiency according to criteria WHO, UNICEF, ICCIDD. In future, however, systematic interest should be focused on optimalization of iodine saturation, esp. in pregnant women and evaluation of possible risk of supranormal iodine intake (impairment of thyroid function, activation of thyroid autoimmunity). Taking in account, the changes of nutrition and life style systematic monitoring of quality of iodine supplementation seems to be essential. PMID- 21261122 TI - Challenges and opportunities in environmental biosafety research. PMID- 21261123 TI - [Dentistry in Wikipedia: A quantitative and qualitative analysis]. AB - The aim of this study was to assess the scientific quality of the 265 dental articles that were present in January 2008 in the German-language version of Wikipedia. For this purpose, the Wikipedia entries were examined for their correctness by comparing them with the current dental literature. Every article was classified as having "textbook quality", "partial textbook quality" or "missing textbook quality". Of the 261 usable articles, 28% were qualitatively comparable to a textbook, while 56% had partial textbook quality. About 16% of the articles fell into the third group. Almost half of the Wikipedia entries fulfilled the qualitative standards, whereas the remaining articles were characterized by omissions. Hence, individuals interested in dental topics should not exclusively rely on Wikipedia. For a cursory overview, however, a search in Wikipedia appears to be in order. PMID- 21261124 TI - How the Affordable Care Act will strengthen primary care and benefit patients, providers, and payers. AB - Although primary care is fundamental to health system performance, the United States has undervalued and underinvested in primary care for decades. This brief describes how the Affordable Care Act will begin to address the neglect of America's primary care system and, wherever possible, estimates the potential impact these efforts will have on patients, providers, and payers. The health reform law includes numerous provisions for improving primary care: temporary increases in Medicare and Medicaid payments to primary care providers; support for innovation in the delivery of care, with an emphasis on achieving better health outcomes and patient care experiences; enhanced support of primary care providers; and investment in the continued development of the primary care workforce. PMID- 21261125 TI - Amendments to regulations regarding eligibility for a Medicare prescription drug subsidy. Interim final rule with request for comments. AB - We are revising our regulations to incorporate changes to the Medicare prescription drug coverage low-income subsidy (Extra Help) program made by the Affordable Care Act which was enacted on March 23, 2010. Under our interpretation of section 3304 of the Affordable Care Act and this interim final rule, if the death of a beneficiary's spouse would decrease or eliminate the subsidy provided by the Extra Help program, we will, based on a determination, or redetermination, extend the effective period of eligibility for the most recent determination or redetermination until 1 year after the month following the month we are notified of the death of the spouse. These regulatory changes will allow us to implement this provision of the Affordable Care Act when it goes into effect on January 1, 2011. We are also revising our regulations to incorporate changes made by the Medicare Improvements for Patients and Providers Act of 2008 (MIPPA), which affect the way we account for income and resources when determining eligibility for the Extra Help program. The statute provides that we no longer count as a resource the value of any life insurance policy for Extra Help applications filed, or redeterminations that are effective, on or after January 1, 2010. In addition, we will no longer count as income the help a beneficiary receives when someone else provides food and shelter, or pays household bills for food, mortgage, rent, electricity, water, property taxes, or heating fuel or gas. These revisions will update our rules to reflect these statutory changes. PMID- 21261126 TI - Informed consent elements. Final rule. AB - The Food and Drug Administration (FDA) is amending the current informed consent regulations to require that informed consent documents and processes for applicable drug (including biological products) and device clinical trials include a specific statement that clinical trial information will be entered into a databank. The databank referred to in this final rule is the clinical trial registry databank maintained by the National Institutes of Health/National Library of Medicine (NIH/NLM) which was created by statute. The submission of clinical trial information to this data bank also is required by statute. This amendment to the informed consent regulations is required by the Food and Drug Administration Amendments Act of 2007 (FDAAA) and is designed to promote transparency of clinical research to participants and patients. PMID- 21261127 TI - Medicare program; end-stage renal disease quality incentive program. Final rule. AB - This final rule will implement a quality incentive program (QIP) for Medicare outpatient end-stage renal disease (ESRD) dialysis providers and facilities with payment consequences beginning January 1, 2012, in accordance with section 1881(h) of the Act (added on July 15, 2008 by section 153(c) of the Medicare Improvements for Patients and Providers Act (MIPPA)). Under the ESRD QIP, ESRD payments made to dialysis providers and facilities under section 1881(b)(14) of the Social Security Act will be reduced by up to two percent if the providers/facilities fail to meet or exceed a total performance score with respect to performance standards established with respect to certain specified measures. PMID- 21261128 TI - Establishment of the permanent certification program for health information technology. Final rule. AB - This final rule establishes a permanent certification program for the purpose of certifying health information technology (HIT). This final rule is issued pursuant to the authority granted to the National Coordinator for Health Information Technology (the National Coordinator) by section 3001(c)(5) of the Public Health Service Act (PHSA), as added by the Health Information Technology for Economic and Clinical Health (HITECH) Act. The permanent certification program will eventually replace the temporary certification program that was previously established by a final rule. The National Coordinator will use the permanent certification program to authorize organizations to certify electronic health record (EHR) technology, such as Complete EHRs and/or EHR Modules. The permanent certification program could also be expanded to include the certification of other types of HIT. PMID- 21261129 TI - TRICARE; coverage of National Cancer Institute (NCI) sponsored Phase I studies. Final rule. AB - This final rule adds coverage of National Cancer Institute (NCI) sponsored Phase I studies for certain beneficiaries. The NCI sponsored clinical treatment trials are conducted in a series of steps called phases. Phase I trials are the first studies conducted in people. They evaluate how a new drug should be given (by mouth, injected into the blood, or injected into the muscle), how often, and what dose is safe. PMID- 21261130 TI - Mesoscale in neuroimaging: creating bridges between the microscopic and system levels. PMID- 21261131 TI - A chance to shape community services. PMID- 21261132 TI - Electrically silent neurons in the substantia gelatinosa of the rat spinal cord. AB - Substantia gelatinosa (SG) neurons are usually categorized on three main types: tonic, adapting and delayed firing (DFNs), based on characteristic firing response evoked by sustained stimulation. Here, the existence of electrically silent neurons (ESNs, 9.3%) is reported by using patch-clamp recording and confocal microscopy in spinal cord slices from 3-5 weeks-old rats. Those neurons does not generate spikes at their resting membrane potential (approximately -69 mV) but only at preliminary depolarization to > -60 mV In the latter case, spikes appeared starting from the end of stimulation, which is characteristic feature of DFNs. With the exception of APs block, all other passive and active electrophysiological properties of ESNs and DFNs were similar. Their main morphological properties (vertical orientation of dendritic tree and axonal trajectory) were close too. A distinctive feature of ESNs was larger amplitude of outward A-type K+ current (K(A)). The results suggest that the latter might cause a block of APs in ESNs, while these cells likely are a functional (i.e., non firing) subtype of DFNs. The role of DFNs in descending control of pain transmission via modulation of its K(A) is hypothesized. PMID- 21261133 TI - Neutrophil apoptosis and hypoxia. AB - Neutrophils are the most abundant population of leukocytes, which constitute the defense against pathogens. Released by neutrophils the proteolytic enzymes and reactive oxygen species help in eliminating infections, but also cause extensive tissue damage. Neutrophil apoptosis plays an essential role in cell homeostasis and resolution of inflammation. It is mediated by a complex network of intracellular apoptotic/survival signaling pathways and can be modulated by a variety of extracellular stimuli such as hypoxia. Here, we review recent studies on the mechanisms of neutrophil death and survival accentuating on neutrophil apoptosis under hypoxic conditions. Neutrophils possess components of both extrinsic and intrinsic apoptotic routes. However in neutrophils this mechanism has special features. The involvement of death receptors, caspases, mitochondria, and Bcl-2 proteins are discussed. Both the transcription factor NF-kappaB and p38MAPK regulate the neutrophil apoptotic program. Despite that reactive oxygen species (ROS) can directly promote and/or adjust apoptosis, there is no consensus about the role of ROS on neutrophil lifespan. Thus both the type of ROS involved and the site of their generation may be important for neutrophil apoptosis. Finally, hypoxia can activate several signaling pathways. The possible differences between the effects of sustained and intermittent hypoxia are also addressed. PMID- 21261134 TI - Clinical importance of determination of cytokines in patients with ovary tumours. AB - Benign ovary tumours share about 75-87% of true ovary tumours. Authentically high indicator of IL-6 and the TNF-alpha have all types of ovary tumours. Benign ovary formations are accompanied by lower maintenance of IL-6 and the TNF-alpha in blood serum, than at malignant tumours. PMID- 21261135 TI - Injunctive social norms primacy over descriptive social norms in retirement savings decisions. AB - Consistent with the global trend to shift responsibility for retirement income provision from the public purse to individuals has been encouragement to save more and to manage investment strategy. Analyzing data from 2,300 respondents to a randomly distributed questionnaire, this article focuses on the motivational importance of social norms. The study finds injunctive social norms (what is commonly approved or disapproved of) exert greater influence than descriptive social norms (what is commonly done) in predicting retirement savings intentions. Modeling employs the theory of planned behavior, and also finds injunctive social norm has predictive primacy over attitude and perceived behavioral control. Discussion advocates a balanced approach to intervention design, and identifies opportunities for the further study of normative message framing. PMID- 21261136 TI - Motivation to provide help to older parents in Norway, Spain, and Israel. AB - We explore from a cross-national perspective three motivations in adult children to provide help to older parents: affectual solidarity, parental need for care, and filial norms. The sample is 1,055 adult children from Norway, Spain, and Israel, countries selected because they represent different family cultures and welfare regimes. Affectual solidarity and parental need for care was found to influence amount of help in all three countries, whereas filial norms was found to have no effect. Country context had a differential impact. In Israel, affectual solidarity was more strongly associated with amount of help. In Israel and Norway, parents' need for care was related to amount of help; in Spain help provided was high, regardless of parents' need for care. We demonstrate the universality of motivations to provide help to older parents and the influence of cultural context on these motivations, taking into account within-country differences. PMID- 21261137 TI - Attitudes toward older people and coworkers' intention to work with older employees: a Taiwanese study. AB - The aim of this research was to examine attitudinal barriers to the employment of Taiwanese older workers (aged 60 and above). Face-to-face interviews were conducted to collect data using structured questionnaires from a sample of full time employees (N= 258). We found that: (1) positive attitudes toward older people in general, perceived subjective norm, and traditional Chinese cultural values were all related to stronger intentions to work with older employees; (2) the model derived from the theory of reasoned action emerged the best model accounting for behavioral intention among competing structural models. The associations of positive attitudes and subjective norm with intention were found after controlling for demographics, cultural values, and personal contact experiences with older people. Our results highlight the importance and urgency of more concerted research to inform public and organizational policies to better promote and manage the careers of older employees in an aging, economically developing society. PMID- 21261138 TI - Mental health literacy in Hmong and Cambodian elderly refugees: a barrier to understanding, recognizing, and responding to depression. AB - This study aims to explore mental health literacy, specifically focusing on depression, among Southeast Asian (SEA) elderly refugees residing in the Twin Cities of St. Paul and Minneapolis, Minnesota. Three focus groups were held with nine mental health professionals who work with SEA elders. Jorm's mental health literacy framework guided the study theoretically. For data analysis, grounded theory was employed by utilizing MAX QDA2. Four themes emerged from the analysis: 1) lack of knowledge about specific mental disorders, 2) culture-specific knowledge and beliefs on the causes of depression, 3) lack of awareness about professional help, and 4) cultural attitudes toward seeking mental health services. The findings indicated that cultural beliefs of SEA elders impact their ability to understand, recognize, and respond to depression. Barriers to treatment were identified and recommendations were made to reduce mental health disparity in this elderly population. PMID- 21261139 TI - Hospice and palliative care: the time to get involved is now. PMID- 21261140 TI - The difference between Tdap and DTaP; dabigatran versus warfarin. PMID- 21261141 TI - Just how dangerous is this forearm lesion? PMID- 21261142 TI - Genomics: Present-day practices and future trends. PMID- 21261143 TI - Juvenile idiopathic arthritis: can you recognize this complex diagnosis? PMID- 21261144 TI - Esophageal carcinoma: matching patients with treatment methods. PMID- 21261145 TI - A misleading resting ECG in a patient with left bundle branch block. PMID- 21261146 TI - MICU care delivered by PAs versus residents: do PAs measure up? AB - BACKGROUND: Data on the perfomance of physician assistants in a medical intensive care unit are scarce. OBJECTIVE: To compare clinical outcomes between patients admitted to a resident-run MICU and a PA-run MICU. METHODS: Retrospective analysis of prospectively collected MICU data was performed for 5,346 patients admitted to an MICU from January 2004 through January 2007; 3,971 patients were admitted to a resident-run MICU (resident group) and 1,375 to a PA-run MICU (PA group). RESULTS: The groups were relatively similar, though the resident group had a higher rate of renal insufficiency (25% vs. 22%, P = .05) and the PA group had a higher rate of cerebrovascular accidents (5.6% vs. 4%, P = .02). Hospital length of stay (LOS) was similar, with a median of 9 days in the PA group and 8 days in the resident group (P = .59). MICU LOS was slightly longer for the PA group: a median of 2.58 days (1.55-4.86) vs. 2.33 days (1.39-4.16) in the resident group. After matching by propensity score, we could not confirm this increased LOS. There was no difference in hospital mortality or in ICU mortality between the two groups either in uncontrolled or controlled analyses. Survival analyses showed no difference in 28-day survival between the two groups. CONCLUSION: A PA-run MICU has similar outcomes when compared to a resident-run MICU. PMID- 21261147 TI - Testosterone replacement therapy: take an informed, individualized approach. PMID- 21261148 TI - Quick recertification series: Carpal tunnel syndrome. PMID- 21261149 TI - Substitution of PAs and NPs for doctors in ED settings. PMID- 21261151 TI - Patient information. What is HPV? PMID- 21261150 TI - Should my son get an HPV vaccine? PMID- 21261152 TI - Pain in a 2-year-old girl who refuses to bear weight. PMID- 21261153 TI - Mystery solved: The evolution of diagnostic abilities in genetic testing. PMID- 21261154 TI - Case of the month. Right ventricular failure from pulmonary arterial hypertension. PMID- 21261155 TI - We will help you to overcome next year's challenges. PMID- 21261156 TI - Consortia want nurses on board. PMID- 21261157 TI - Expert eyes see a difficult year ahead as NHS overhaul begins to bite. PMID- 21261158 TI - Amid the tinsel and the trees, 'tis also the season to be tactful. PMID- 21261159 TI - Identifying people at risk of fuel poverty to prevent excess winter deaths. AB - An analysis of excess winter deaths across the West Midlands found higher levels in the NHS Birmingham East and North area than in the rest of the region. The trust created an algorithm to identify those at risk of excess winter death and fuel poverty. PMID- 21261160 TI - Community acquired pneumonia in a three year old child: dealing with a difficult case. PMID- 21261161 TI - Early diagnosis of lymphoedema helps to reduce its psychological and social impact. AB - Lymphoedema is often unrecognised by both health professionals and patients. In addition, its impact is often underestimated. This article discusses how to recognise the condition, the consequences of misdiagnosis, reducing or preventing complications and various treatment options. PMID- 21261162 TI - Going for Gold: how a training programme is supporting nurses to improve end of life care. PMID- 21261163 TI - Introducing a programme for post-registration induction and essential skills development. AB - Post-registration nursing induction can be a neglected area. This article describes the rationale, processes and methods used to establish a model for post registration nursing induction and knowledge and skills development. This model integrates the personal development review and planning process in the context of the Knowledge and Skills Framework, and provides a format for ongoing career development. PMID- 21261164 TI - Get vaccinated to reduce the impact of flu this winter. PMID- 21261166 TI - What's on your Christmas list--a higher salary? PMID- 21261165 TI - Going the extra mile to meet dying patients' festive wishes. PMID- 21261167 TI - The role of behavioral economics and behavioral decision making in Americans' retirement savings decisions. AB - Traditional economic theory posits that people make decisions by maximizing a utility function in which all of the relevant constraints and preferences are included and weighed appropriately. Behavioral economists and decision-making researchers, however, are interested in how people make decisions in the face of incomplete information, limited cognitive resources, and decision biases. Empirical findings in the areas of behavioral economics and judgment and decision making (JDM) demonstrate departures from the notion that man is economically rational, illustrating instead that people often act in ways that are economically suboptimal. This article outlines findings from the JDM and behavioral-economics literatures that highlight the many behavioral impediments to saving that individuals may encounter on their way to financial security. I discuss how behavioral and psychological issues, such as self-control, emotions, and choice architecture can help policymakers understand what factors, aside from purely economic ones, may affect individuals' savings behavior. PMID- 21261168 TI - Expanding access to health care for Social Security Disability Insurance beneficiaries: early findings from the accelerated benefits demonstration. AB - Most Social Security Disability Insurance (DI) beneficiaries must complete a 5 month waiting period before they become entitled to DI cash benefits and an additional 24-month waiting period before Medicare benefits begin. The Accelerated Benefits (AB) demonstration is a randomized experiment designed to test the effects of providing newly entitled DI beneficiaries who do not have health insurance with a generous health benefits package during the Medicare waiting period. This article presents early findings on the prevalence of health insurance coverage among newly entitled beneficiaries and the characteristics of those without health insurance. It also examines the effects of AB on health care utilization, the extent to which AB reduces unmet medical needs, and the costs of providing the AB health benefits package. PMID- 21261169 TI - The decision to exclude agricultural and domestic workers from the 1935 Social Security Act. AB - The Social Security Act of 1935 excluded from coverage about half the workers in the American economy. Among the excluded groups were agricultural and domestic workers-a large percentage of whom were African Americans. This has led some scholars to conclude that policymakers in 1935 deliberately excluded African Americans from the Social Security system because of prevailing racial biases during that period. This article examines both the logic of this thesis and the available empirical evidence on the origins of the coverage exclusions. The author concludes that the racial-bias thesis is both conceptually flawed and unsupported by the existing empirical evidence. The exclusion of agricultural and domestic workers from the early program was due to considerations of administrative feasibility involving tax-collection procedures. The author finds no evidence of any other policy motive involving racial bias. PMID- 21261170 TI - Retiring in debt? An update on the 2007 near-retiree cohort. AB - This research note uses 2007 Survey of Consumer Finances (SCF) data to update the authors' work reported in a prior article, which used earlier data to assess debt levels among households approaching retirement in 1995 and 2004. The authors assess whether there have been changes in the debt holdings of near-retirees in 2007, a point in time reflecting the start of the recent financial and economic crisis. Results show that debt levels of near-retirees were modestly higher in 2007 than in 2004, overall and across several subgroups. The results reinforce a general finding of the original article that current near-retirees, primarily baby boomers, are approaching retirement with more debt compared with their counterparts in the mid-1990s. Because the 2007 SCF data captures only the beginning of the current recession, the authors expect future trends to differ from the results presented here. PMID- 21261171 TI - Introduction and overview of the 2010 annual report of the board of trustees of the federal old-age and survivors insurance and federal disability insurance trust funds. PMID- 21261172 TI - Extracorporeal photopheresis: a review on the immunological aspects and clinical applications. AB - Extracorporeal photopheresis (ECP) was hailed as a new therapeutic concept for the treatment of diseases caused by aberrant T lymphocytes since it was first described more than twenty years ago. Advances in molecular biology and immunology have allowed a greater understanding of the mechanisms involved in ECP. As a result, ECP is being increasingly considered as a safe and promising immunomodulatory therapy with diverse clinical applications. At present ECP is approved by the FDA for the treatment of cutaneous T-cell lymphoma (CTCL). ECP is considered a relatively safe and promising immunomodulatory therapy with diverse clinical applications reported in the literature. ECP has been used in the treatment of patients following acute allograft rejection in cardiac, lung, renal or liver transplantation, graft-versus-host disease, systemic lupus erythematosus, systemic scleroderma, rheumatoid arthritis and pemphigus vulgaris. The use of ECP as a novel form of therapy is in constant evolution with newer studies focusing on the treatment of patients with Crohn's disease and the immunological effects of ECP in children with type 1 diabetes mellitus. However, because the exact mechanism by which ECP exerts its effects remains to be described in detail and because important questions regarding the use of ECP in the clinical setting, such as length of therapy or design of specific protocols, concomitant use of immunosupressive therapy, patient characteristics, long term side effects, assessment of therapy efficacy and cost effectiveness continue to remain unanswered, the exact role of ECP cannot be fully established except in the case of patients with CTCL and GvHD. Nevertheless, future clinical studies with ECP can be done with the objective of designing more appropriate treatment protocols based on expected patient response and with a side effect profile that is fairly tolerable. PMID- 21261173 TI - Novel inhibitors of Rac1 in metastatic breast cancer. AB - OBJECTIVE: Rho family GTPases are molecular switches that control signaling pathways regulating a myriad of cellular functions. Rac1, a Rho family member, plays a critical role in several aspects of tumorigenesis, cancer progression, invasion, and metastasis. Rac proteins are not mutated in most invasive human cancers but are found to be overactive or over-expressed. Since Rho GTPases are activated by guanine nucleotide exchange factors (GEFs), inhibition of the interaction of Rac with its GEFs is a targeted strategy for blocking Rac activation. METHODS: The IC50 of NSC23766, an inhibitor of the interaction of Rac1 with a subset of GEFs, is too high for therapeutic use and more efficacious inhibitors are desired. Therefore, we initiated the synthesis of new derivatives of NSC23766 with modifications of the substituents connected to the central pyrimidine ring, and tested their Rac1 inhibitory activity. RESULTS: Several of the NSC23766 derivatives were shown to inhibit Rac1 activity of cancer cells with higher efficiency (20-50% more) than NSC23766. The new compounds are not toxic to normal mammary epithelial cells and are more efficient (60-70%) than NSC23766 in inhibiting cell migration and reducing cell spreading and extension of lamellipodia, cell functions regulated by Rac that contribute to cancer invasion. CONCLUSION: Based on the results, we conclude that the novel compounds show promise of further development as small molecule inhibitors of invasive breast cancer progression. PMID- 21261174 TI - Prevalence of childhood obesity in a representative sample of elementary school children in Puerto Rico by socio-demographic characteristics, 2008. AB - OBJECTIVE: Childhood obesity is a worldwide epidemic; its prevalence has quadrupled in the US among children from 6-11 y/o. In the US, Hispanic children have a higher prevalence of obesity compared to non-Hispanic whites. No representative data was available for Puerto Rican children from first to sixth grades in Puerto Rico or the US. The aim of this study was to measure the prevalence of childhood obesity among Puerto Rican children from first to sixth grade by different socio-demographic characteristics in a sub-urban municipality in Puerto Rico. METHODS: A two-stage stratified cluster sampling design was used (n = 250). Weights and heights were measured twice to the nearest 0.1 kg and 0.1 cm, respectively. Weight status of children was determined based on the CDC criteria. Chi-square and Fisher tests were used to compare proportions. Simple logistic regressions were used to assess associations with socio-demographic variables. RESULTS: Nearly half of the students (51.0%) were boys; mean age was 9.5 + 1.9 years. Almost 40% of the children had family monthly incomes under $1,000. Overall childhood obesity prevalence (BMI > 95th percentile) was 26.8%. Prevalence of having some type of overweight (BMI for age > 85%) was statistically similar by gender and school grade. Low family-income children had 76% higher odds of having some type of overweight compared with those with higher income. CONCLUSION: This study documents a high prevalence of Puerto Rican childhood obesity among first to sixth grade regardless of grade level and gender, which is higher than the prevalence among Hispanics in the US. A higher probability of overweight was seen among the poorer children. This is the first study conducted among first to sixth graders. Thus, it calls for attention towards Puerto Rican children in the island and the US. PMID- 21261175 TI - Incidence trends of cervical cancer in Puerto Rico, 1987-2004. AB - OBJECTIVE: Cervical cancer was the leading malignancy among women in Puerto Rico when the Central Cancer Registry was first established by law in 1950. The screening program for cervical cancer in PR was initiated in 1961 when cytological laboratories were established in regional hospitals throughout the island, reaching its peak in 1973. In 2004, invasive cervical cancer ranked fifth among the top cancers in women in PR, representing 4% of all newly diagnosed cancers and 2% of all cancer-related deaths among women. The purpose of this study was to evaluate the incidence trends of cervical cancer by histology type in PR. METHODS: Cervical cancer cases (n = 3,516) diagnosed from 1987-2004 were obtained from the Puerto Rico Central Cancer Registry. Age-adjusted and age specific incidence rates by histological type were calculated. Annual percent changes were estimated to evaluate the incidence trends from 1987 to 2004. RESULTS: From 1987 to 2004, the incidence of cervical cancer showed a downward trend (APC = -2.1%). Seventy-six percent (76.3%) of invasive cervical cancer cases were squamous cell carcinoma (SCC), 15.4% were adenocarcinoma (ADC), and 8.3% had other histologies. When histology was considered, a decreasing trend was observed for the incidence rates of SCC (APC = -3.2%, p < 0.05), with the greatest decrease being seen in women aged 60-74 (APC = -6.6%, p < 0.05). While the overall incidence rate of ADC remained stable (APC = 0.8%, p > 0.05), it increased in women aged 30-44 (APC = 3.8%, p < 0.05). CONCLUSION: Overall, the incidence rates for cervical cancer (SCC in particular), have decreased in PR. However, ADC does not present a similar decreasing trend. This trend, which is similar with other populations, could be explained, in part, by a decreasing prevalence of risk factors. Nevertheless, analysis by specific age group shows variations in the risk, which need careful consideration since they could imply changes in factors associated with each of the histological types. PMID- 21261176 TI - Relationship between sporadic hyperplastic polyps and colorectal neoplasia in Hispanic veterans. AB - OBJECTIVE: Hyperplastic polyps (HP) traditionally have been regarded as having no malignant potential. Some studies have suggested that HP in the distal colon may predict presence of adenomatous polyps in the proximal colon. Other studies have failed to show this relationship. The purpose of this study was to evaluate for the first time in our Hispanic veterans population if there was a relationship between the presence of sporadic HP and colorectal neoplasia (CRN) and to evaluate if proposed risk factors for CRN are also risk factors for sporadic HP. METHODS: The study consisted of a retrospective review of all the medical records of patients who underwent a colonoscopy for the first time during the calendar year 2005 and had a pathologic diagnosis of HP, tubular adenoma (TA), tubulovillous adenoma (TVA), villous adenoma (VA) and/or colon adenocarcinoma at the VA Caribbean Healthcare System. Patient's age, BMI, smoking and alcohol use history, presence of DM, cholesterol and triglyceride levels, use of aspirin and the size and location of the lesions were recorded. Records with incomplete data and patients with a prior colonoscopy were excluded. RESULTS: 861 patient records were reviewed of which 405 met the inclusion criteria. Most patients (99%) of the patients were males, mean age 67.5 (range 36-87). The total number of colonic lesions was 1,065 (240 hyperplastic, 825 CRN). Histologic evaluation of lesions revealed: 121 patients who had HP, 331 with TA, 33 with TVA, 12 with VA, 13 with serrated adenomas and 61 patients had adenocarcinoma. Univariate analysis revealed that patients with HP appeared to have a lower likelihood of having TA (p < 0.001), adenocarcinoma (p = 0.002), and CRN in general (P < 0.001) as compared to patients without HP. Multivariate analysis with logistic regression revealed that patients with HP had a significantly lower likelihood of having TA (adjusted OR = 0.21; 95% CI 0.12-0.37), and adenocarcinoma (adjusted OR = 0.33; 95% CI 0.15-0.73) compared to patients without HP. No correlation was found between DM, use of alcohol, smoking, or aspirin use and the presence of sporadic HP. CONCLUSION: The present study suggests that the presence of HP is not associated with CRN in our veteran population. None of the risk factors proposed for CRN appear to be also risk factors for developing HP. The results of this study support current colon cancer guidelines in which surveillance for HP is not recommended. PMID- 21261177 TI - The prevalence of vertebral fractures in San Juan, Puerto Rico: a population based study among females aged 50 years and over. AB - OBJECTIVE: The participation of Puerto Rico in the Latin American Vertebral Osteoporosis Study (LAVOS) has allowed us to study the magnitude of the problem of osteoporosis in the female population residing in San Juan. The objective of LAVOS was to estimate the prevalence of vertebral fractures in Latin American women using a random sample of females selected from cities across five Latin American countries. METHODS: A probability cluster design was employed to select a random sample of households in San Juan, Puerto Rico, in order to interview 400 females aged 50 years and over. A 30-minute face-to-face interview gathered data on demographics, risk factors, and life styles. Data regarding bone mineral densities of the spine and hip by DXA and lateral dorsolumbar X-rays were obtained using international protocols; digital morphometry was used to determine vertebral deformities, with the results being classified according to Eastell criteria. This article summarizes the main findings observed in San Juan, Puerto Rico. RESULTS: Overall weighted prevalence of vertebral fractures was 11.2% (95% CI: 8.5%, 14.7%). Age-specific prevalence of vertebral fractures was as follows: 5.4% (95% CI: 2.7%, 10.7%) in the 50-59 years age group, 8.3% (95% CI: 4.4%, 15.1%) in the 60-69 years group, 16.2% (95% CI: 10.5%, 25.0%) in the 70-79 years group, and 22.4% (95% CI: 13.3%, 35.1%) in participants > or = 80 years. Factors significantly associated with vertebral fractures were being 70-79 years old (adjusted POR70-79 vs. 50-59 = 2.9; 95% CI: 1.1, 7.4), being > or = 80 years old (adjusted POR > or = 80 vs .50-59 = 3.3; 95% CI: 1.2, 9.4), and a T-score < or = 2.5 in the lumbar spine (adjusted POR = 2.5; 95% CI: 1.5, 5.7) and in the femoral neck (adjusted POR = 3.5; 95% CI: 1.5, 8.0). Personal history of fractures was marginally associated with vertebral fractures after adjusting for the remaining risk factors (adjusted POR = 2.0; 95% CI: 1.0, 4.0). Nearly 94% of the women with vertebral fractures were not aware of their bone status. Using the WHO classification, we determined that 71% had osteoporosis, 21%, osteopenia, and 8%, normal bone mineral densities. Bone mineral densities in the lumbar spine and femoral neck were significantly lower in women with vertebral fractures. Non vertebral fractures were more common in women with a personal history of prior vertebral fractures. The prevalence of the most common non-vertebral fractures were hip, 1% (95% CI: 0.4%, 2.7%), and wrist, 5.9% (95% CI: 4.0%, 8.7%), respectively. CONCLUSION: This is the first population-based study of osteoporotic fractures in Puerto Rico and should serve as a guide to health providers and policy makers in the prevention and treatment of this disease. PMID- 21261178 TI - Development and psychometric properties of the evidence-based professional practice scale (EBPP-S). AB - OBJECTIVE: Evidence based-practice (EBP) is now being integrated into many systems of health care. To date, little research has been conducted in Puerto Rico regarding EBP. A brief measure of health provider for Evidence Based Professional Practice-Scale (EBPP-S) was developed to measure attitudes, behaviors and knowledge. METHODS: The study consisted in two phases. In the first phase the scale was developed and exploratory factor analyses (EFA) were conducted (n = 65). In the second phase, the EFA model was tested in another sample (n = 86) using confirmatory factor analysis (CFA). Both samples were drawn from mental health service providers. RESULTS: Three factors of the EBPP-S were identified in the first phase (1) attitudes, (2) behaviors, and (3) knowledge. The internal reliability for the 43-item scale using the Cronbach's a was .93. The principal dimensions of the scale were analyzed using a CFA. A three-factor model with 17 items was supported by the data. The results showed an internal consistency of .88 for the 17-item version of the scale. CONCLUSION: The preliminary results for the EBPP-S are promising and the use of this scale to measure evidence based-practice is discussed. PMID- 21261179 TI - Visual acuity and nystagmus following strabismus surgery in patients with oculocutaneous albinism. AB - OBJECTIVE: To evaluate the effect of strabismus surgery on nystagmus and visual acuity in patients with oculocutaneous albinism. METHODS: We conducted a non concurrent retrospective study of 13 Puerto Rican patients with all types of oculocutaneous albinism who underwent strabismus surgery. Patients underwent genetic linkage analysis to reach a final oculocutaneous albinism classification prior to surgery. Strabismus surgery was modified by under-correction of 0.5 mm in each muscle from the standard Marshall Parks' measurements in all patients. RESULTS: Six of the 13 patients with oculocutaneous reported an improved best corrected visual acuity after surgery. Two of the 13 patients with oculocutaneous had no nystagmus following strabismus surgery. All patients were orthotropic following surgery. CONCLUSION: Strabismus surgical undercorrection may be of benefit in patients with oculocutaneous albinism. PMID- 21261180 TI - A preliminary report on pelvic floor reconstruction through colpocleisis from 2001 to 2007 at the University Hospital of the Puerto Rico Medical Center. AB - OBJECTIVE: Describe the pre-, intra-, and postoperative experience of colpocleisis in a group of patients at the University Hospital of the Puerto Rico Medical Center. METHODS: A chart review was done on a subgroup of patients, 70 years or older, on which colpocleisis was performed between January 2001 and December 2007. The evaluation included demographics, comorbidities, and previous pelvic surgeries. The Pelvic Organ Prolapse Quantification (POP-Q) System was used to evaluate pelvic organ prolapse. Surgical procedures, outcomes, and related data were tabulated. RESULTS: Nineteen patients with a mean age of 77 years underwent the procedure, 57.8% presenting more than one comorbidity. Seventy-three percent of the patients had a BMI over 25. Sixty-three percent reported prior pelvic surgeries, 94.7% had stage IV pelvic prolapse, and 73.6% underwent concomitant procedures. Spinal anesthesia was most often used (68%), and the mean hospital stay was 2.1 days. Thirty-one percent of interviewed patients reported preoperative impairment in their daily activities that resolved completely after surgery. Incontinence symptoms resolved in 69% of patients. Ninety-two percent of the patients reported full satisfaction with the surgery. CONCLUSION: Colpocleisis is a safe pelvic reconstructive procedure for high-risk patients with multiple comorbidities. Regional anesthesia can be offered with minimal blood loss, short operative time, and early ambulation. PMID- 21261181 TI - Sustained virologic response among Latino veterans; does it represent the cure of chronic hepatitis C infection? AB - OBJECTIVE: Short-term benefits of achieving sustained virologic response (SVR) to treatment for hepatitis C virus infection (HCV) have been well established. However long-term data on benefits of achieving SVR has just begun to emerge. The purpose of this study was to determine whether SVR truly represents long- term viral eradication in a Latino veteran population and document clinical and biochemical outcomes in this group. METHODS: This was a two-phase study, which consisted of a single center retrospective study followed by a cross-sectional analysis which includes a single clinic visit. The first phase of the study consisted of a retrospective record review of all HCV patients treated at the VA Caribbean Healthcare System from 1990 to 2006. Records were reviewed to identify patients who had completed therapy, had documented SVR and at least 12 months of time elapsed since end of therapy. The second phase of the study entailed a single appointment to the gastroenterology research clinics, for blood testing and a short risk factor questionnaire. RESULTS: Sixty four patients were enrolled; mostly males with a mean age at time of enrollment of 54.3 years (range 37-72). One hundred percent of subjects self reported their ethnicity as Hispanic, born in Puerto Rico. Most of our population had HCV genotype 1. Forty seven of 64 (73.4%) patients were naive to therapy while 4 (6.3%) were previously treated. In 13 (20.3%) patients, the prior treatment status could not be clearly established. Regarding therapy used to achieve SVR, 32 (50.0%) patients received interferon (IFN) and ribavarin, 28 (43.8%) peginterferon (PEG) and ribavarin and 4 (6.3%) IFN monotherapy. There was no statistical difference in long-term SVR among these 3 three treatment alternatives. A pre-treatment biopsy specimen was available on 37/64 (57.8%) of our subjects. Marked fibrosis and/or cirrhosis was present in 14/37 (37.8%) subjects who had a pre-treatment biopsy. At the time of the study visit mild elevation of aspartate aminotransferase (AST) was identified only in 5 (7.8%) patients. Alanine aminotransferase (ALT) and bilirubin were normal. Only 3/64 (4.7%) had elevations in alkaline phosphatase. None (0/58) of the patients who presented with normal enzymes had detectable viral load, whereas 20% (1/5) of those with elevated liver function tests had evidence of viremia (p < 0.001). Overall, only 1 (1.6%) patient of our study group had evidence of virological relapse after having achieved SVR, which was documented 30 months after the end of therapy. No identifiable risk factors for re-infection were identified. CONCLUSION: In conclusion, in this Latino veteran population, achievement of (SVR) is a good predictor of clinical outcomes and long-term (HCV) eradication. Altered liver function tests seems to be the best predictor of relapse and should prompt the clinician to investigate for recurrence. For those that after achieving SVR maintain normal liver enzymes, routine follow up viral load demonstrates to have a very low yield and may not be required. PMID- 21261182 TI - Exposure to non-therapeutic INR in a high risk cardiovascular patient: potential hazard reduction with genotype-guided warfarin (Coumadin) dosing. AB - A case to illustrate the utility of genetic screening in warfarin (Coumadin) management is reported. A 45 year-old woman of Puerto Rican ancestry was admitted to the emergency room twice within one month with chest pain. She was diagnosed with congestive heart failure, which was stabilized both times. At her second release, warfarin therapy was initiated at 5 mg/ day to prevent thrombus formation and was lowered to 3.75 mg/day at day 7 by her primary physician. International Normalized Ratio (INR) test results in the follow-up period at days 1, 7, and 10 of warfarin therapy were 4.5, 6.5, and 7.3, respectively-far in excess of the therapeutic range, despite the lower dosage in effect from day 7 onward. The patient achieved target INR over the next 43 days after downward adjustment of the dose to a dose of 1.5 mg/day by trial and error. DNA-typing specific for the CYP2C9*2,*3,*4,*5,*6 alleles and seven variants in the VKORC1 gene, including the VKORC1-1639 G > A polymorphism, revealed the presence of combinatorial CYP2C9*2/*3 and VKORC1-1639 G/A genotypes in this patient. Entering the patient's demographic and genotype status data into independent algorithms available in the public domain to predict effective warfarin dose yielded predicted doses which ranged from 1.5 to 1.8 mg/day. Notably, the prediction of 1.5 mg/day, which was generated by the online resource www.warfarindosing.org, coincided with the patient's actual effective warfarin dose. We conclude that the rapid rise in INR observed upon the initiation of warfarin therapy and the final effective warfarin dose of 1.5 mg/day, are attributable in some part to the presence of two minor alleles in CYP2C9, which together significantly reduce warfarin metabolism. Warfarin genotyping can therefore inform the clinician of the predicted effective warfarin dose. The results highlight the potential for warfarin genetic testing to improve patient care. PMID- 21261183 TI - Vitamin C and cancer: what can we conclude--1,609 patients and 33 years later: comment on the article by Cabanillas. PMID- 21261184 TI - Vitamin C and cancer: what can we conclude--1,609 patients and 33 years later: comment on the article by Cabanillas. PMID- 21261185 TI - Duties with dividends. PMID- 21261186 TI - John Greenwood, dentist to President Washington. AB - In the practice of dentistry in colonial times, no name shines more brightly than that of John Greenwood, the favorite dentist of President George Washington. But it is more than this alone that brings luster to his name and renown. A study of the advertisements he placed in newspapers in Massachusetts and New York gives us an insight into his treatments and his mode of practice. A newly discovered advertisement adds to our knowledge of this remarkable practitioner. PMID- 21261187 TI - Effect of dentin treatment time with tetraclean on its residual antibacterial activity. AB - The goal of this study was to evaluate the effect of dentin treatment duration (10 minutes, 24 hours, and seven days) with Tetraclean on its residual antibacterial activity in bovine root dentin. Results showed that the number of colony-forming units in all three experimental groups was zero at the first culture. Furthermore, the 10-minute group and seven-day group demonstrated the highest and the lowest number of colony-forming units, respectively. PMID- 21261188 TI - Good, clinical pain practice for pediatric procedure pain: metric considerations. AB - This paper is a brief primer in pediatric pain measurement.Two measurement instruments--the Faces, Legs, Activity, Cry and Consolability Scale and the Faces of Pain Scale-Revised--are presented along with their limitations. PMID- 21261189 TI - Teeth whitening secrets uncovered!!! Well not so much. PMID- 21261190 TI - The effect of culture on urinary incontinence: do we really understand? PMID- 21261191 TI - Traces: making sense of urodynamics testing--Part 2: uroflowmetry. AB - Uroflowmetry is an electronic recording of urinary flow. It is typically measured by one of two types of transducers. One type measures the weight of urine as it falls into a beaker or container placed on the transducer, and the other uses a spinning disc to measure urinary flow. Uroflowmetry is a non-invasive, comparatively inexpensive study often used to identify voiding abnormalities. Experienced clinicians can use uroflow tracings to differentiate a continuous (normal) flow pattern from abnormal patterns. While uroflowmetry has been found to reliably distinguish normal from abnormal flow patterns, uroflowmetry does not reliably distinguish the underlying cause of voiding abnormalities. Differential diagnosis of poor detrusor contraction strength from bladder outlet obstruction relies on a voiding pressure flow study that combines uroflowmetry with the various pressure studies used to generate a cystometrogram and pelvic floor muscle electromyography. PMID- 21261192 TI - Overview of the social impact of urinary incontinence with a focus on Turkish women. AB - Although urinary incontinence is a common problem among women and can seriously affect their quality of life, more than half of women report no discomfort with the disorder, and most do not seek medical help. In Turkey, women traditionally prefer not to seek medical advice for a urinary incontinence problem. Except for treatment-seeking behaviors, women practice coping methods for the management of urinary incontinence. The problem of urinary incontinence has been gaining more importance in recent years, and nurses' roles and responsibilities have been increased in this area. Consequently, there have been developments in Turkey related to the education of nurses. PMID- 21261193 TI - Promotion of urinary continence worldwide. AB - Millions of individuals around the world suffer from urinary incontinence. This article discusses worldwide urinary incontinence, and the use of information and communication technology to facilitate global nursing collaboration. PMID- 21261194 TI - The fistula crisis in sub-Saharan Africa: an ongoing struggle in education and awareness. AB - This article examines the social and physical causes of obstetric fistulas, as well as resulting social and psychological consequences. Preventative strategies are addressed using Niger as a microcosm for this devastating condition that affects two million women worldwide. PMID- 21261195 TI - Radical nephrectomy with inferior vena cava (IVC) thrombectomy: implications for post-operative nursing care. AB - The surgery required to remove a renal cell carcinoma with inferior vena cava (IVC) tumor thrombus is complex. IVC tumor thrombus is a complicating factor that occurs in 4% to 10% of patients with renal cell carcinoma. Nurses need to understand this surgical procedure and its inherent risks to proactively and successfully manage the patient's post-operative care and discharge plan. PMID- 21261196 TI - Getting ready for certification: renal cell carcinoma. PMID- 21261197 TI - Global health education: international collaboration at ICDDR,B. AB - The purpose of this commentary is to provide an overview of the growing interest in global health education at ICDDR,B and to review examples of how this has grown from public-health research and education to include clinical education (medical and nursing) as well. This parallels the growth of the institution, with an increased focus on educational linkages within and beyond Bangladesh and the rise in interest in global health at western medical schools. Specific collaborations, their setup and structure are described. This is presented as a model for other centres of excellence in developing countries to engage their partners in the South and North on matters of education and research for mutual cooperation and benefit. PMID- 21261198 TI - Serological analysis of human pandemic influenza (H1N1) in Thailand. AB - The study was aimed at determining the prevalence of pandemic influenza (H1N1) 2009 among patients with respiratory tract diseases during July-December 2009 using real-time reverse transcription polymerase chain reaction. Haemagglutination inhibition (HI) assay was performed to detect antibody titres against pandemic influenza in 255 medical personnel, 307 members of the general population during the second week of December 2009 in Khon Kaen province, Thailand, and in 100 stored sera collected from people of different age-groups during 2008. The results showed that the pandemic (H1N1) 2009 had occurred during July-December 2009. The results of the HI test after the wave of this outbreak showed that 123 (48%) of the 255 sera collected from the medical personnel, 109 (36%) of the 307 sera obtained from the general population, and only two of the 100 stored sera from 2008 contained antibodies (HI titres > or = 40) against pandemic influenza. Antibody against the pandemic (H1N1) 2009 was found in at least one-third of the population. In conclusion, the prevalence of virus and serological data obtained from the study can be used as the serological background level of the Thai population after the July-December pandemic. Finally, the serological data might be useful for outbreak-prevention and control strategies and for the management of vaccination for the pandemic (H1N1) 2009 in Thailand. PMID- 21261199 TI - Quantifying the association between Campylobacter infection and Guillain-Barre syndrome: a systematic review. AB - Guillain-Barre Syndrome (GBS) is a neurologic disease that causes ascending paralysis and is triggered by a preceding bacterial or viral infection. Several studies have shown that patients with GBS have a recent history of infection due to Campylobacter jejuni. A literature review of published studies that reported rates of Campylobacter infection before or in conjunction with GBS was done. These reported data were used for calculating the proportion of GBS cases who tested positive for Campylobacter compared to the control population and the incidence of GBS among patients infected with Campylobacter. Results of the analysis suggest that 31% of 2,502 GBS cases included in these papers are attributable to Campylobacter infection. PMID- 21261200 TI - Performance of a community-based health and nutrition-education intervention in the management of diarrhoea in a slum of Delhi, India. AB - Diarrhoeal infections are the fifth leading cause of death worldwide and continue to take a high toll on child health. Mushrooming of slums due to continuous urbanization has made diarrhoea one of the biggest public-health challenges in metropolitan cities in India. The objective of the study was to carry out a community-based health and nutrition-education intervention, focusing on several factors influencing child health with special emphasis on diarrhoea, in a slum of Delhi, India. Mothers (n=370) of children, aged >12-71 months, identified by a door-to-door survey from a large urban slum, were enrolled in the study in two groups, i.e. control and intervention. To ensure minimal group interaction, enrollment for the control and intervention groups was done purposively from two extreme ends of the slum cluster. Baseline assessment of knowledge, attitudes, and practices on diarrhoea-related issues, such as oral rehydration therapy (ORT), oral rehydration salt (ORS), and continuation of breastfeeding during diarrhoea, was carried out using a pretested questionnaire. Thereafter, mothers (n=195) from the intervention area were provided health and nutrition education through fortnightly contacts achieved by two approaches developed for the study- 'personal discussion sessions' and 'lane approach'. The mothers (n=175) from the control area were not contacted. After the intervention, there was a significant (p=0.000) improvement in acquaintance to the term 'ORS' (65-98%), along with its method of reconstitution from packets (13-69%); preparation of home-made sugar salt solution (10-74%); role of both in the prevention of dehydration (30-74%) and importance of their daily preparation (74-96%); and continuation of breastfeeding during diarrhoea (47-90%) in the intervention area. Sensitivity about age-specific feeding of ORS also improved significantly (p=0.000) from 13% to 88%. The reported usage of ORS packets and sugar-salt solution improved significantly from 12% to 65% (p=0.000) and 12% to 75% (p=0.005) respectively. The results showed that health and nutrition-education intervention improved the knowledge and attitudes of mothers. The results indicate a need for intensive programmes, especially directed towards urban slums to further improve the usage of oral rehydration therapy. PMID- 21261201 TI - Self-reported body changes and associated factors in persons living with HIV. AB - The study aimed at verifying the associated factors of self-perceived body changes in adults living with HIV in highly-active antiretroviral therapy (HAART) in the city of Sao Paulo, Brazil. This cross-sectional study was conducted among people living with HIV on HAART for at least three months. A standardized questionnaire was used for assessing self-perceived body changes. Associated factors relating to self-reported body changes in people living with HIV (PLHIV) were assessed with Student's t-test and chi-square test. In total, 507 patients were evaluated. The mean time since diagnosis was 6.6 years [standard deviation (SD) +/- 4.1], and the mean duration of HAART was 5.1 years (SD +/- 3.3). Self perceived body changes were reported by 79.5% of the participants and were associated with viral load and duration of HAART. Fibre intake was lower among males who gained in abdominal fat (p=0.035). HAART-related body changes were reported by the large majority of the population and were associated with demographic and clinical variables. PMID- 21261202 TI - Is there a role for patent medicine vendors in tuberculosis control in southern Nigeria? AB - Patent medicine vendors (PMVs) are a ubiquitous feature of the informal health sector in Nigeria. A previous study on healthcare-seeking behaviour of persons with chronic cough in southern Nigeria found that over 60% of respondents chose the PMV as a healthcare provider of first instance. This study sought to determine the willingness and capability of PMVs to play a role in the national tuberculosis (TB)-control effort. Study sites were selected through a multi-stage sampling process. In total, 388 PMVs, 17 principal officers of PMV associations, and 17 community leaders were purposively selected. Sets of structured questionnaire were administered to the PMVs while information from the principal officers of PMV associations and community leaders was elicited through in-depth interviews and focus-group discussions (FGDs). Quantitative data were collated using the Epi Info software (version 6.04) and analyzed using the SPSS software (version 15). Most (90%) PMVs indicated that they would be ready to cooperate with the national TB-control programme, if trained. Seventy-three percent attended persons with prolonged cough in the course of their career. However, 48% did not know the cause of TB. Only 3% ever-attended a training session on TB control. Sixty-six percent completed at least 12 years of schooling with secondary school certificate. Eighty percent of the community leaders were happy with the work of PMVs. About two-thirds (65.6%) of the PMVs were male. The PMVs are positively disposed to playing roles in TB control. Given this positive disposition and their widespread acceptance in healthcare-delivery in the communities, they have potentials for playing a role in TB control in southern Nigeria. PMID- 21261203 TI - Arsenic and cadmium in food-chain in Bangladesh--an exploratory study. AB - Arsenic contamination of tubewell water is a major public-health problem in Bangladesh. In the recent years, the use of shallow and deep tubewell water for irrigation and the use of excess amount of cheap fertilizers and pesticides containing cadmium pose a serious threat of contamination of arsenic and cadmium in food. In an exploratory study, arsenic and cadmium were measured in foods from Matlab, a rural area in Bangladesh, that is extensively affected by arsenic and the economy is agriculture-based. Raw and cooked food samples were collected from village homes (households, n=13) and analyzed to quantify concentrations of arsenic and cadmium using atomic absorption spectrophotometry. Washing rice with water before cooking reduced the concentration of arsenic in raw rice by 13-15%. Rice, when cooked with excess water discarded, showed a significant decrease in arsenic concentration compared to that cooked without discarding the water (p<0.001). In contrast, concentration of cadmium did not decrease in cooked rice after discarding water. Cooked rice with discarded water had significantly lower concentration of arsenic compared to raw rice (p=0.002). Raw rice had higher concentration of arsenic compared to raw vegetables (p<0.001); however, no such difference was found for cadmium. Compared to raw vegetables (e.g. arum), concentration of arsenic increased significantly (p=0.024) when cooked with arsenic-contaminated water. Thus, the practice of discarding excess water while cooking rice reduces the concentration of arsenic but not of cadmium in cooked rice. However, water generally not discarded when cooking vegetables to avoid loss of micronutrients consequently retains arsenic. The results suggest that arsenic and cadmium have entered the food-chain of Bangladesh, and the cooking practices influence the concentration of arsenic but not of cadmium in cooked food. PMID- 21261204 TI - Association between nutritional status and positive childhood disability screening using the ten questions plus tool in Sarlahi, Nepal. AB - The study was conducted to examine the association between the indicators of malnutrition and disability of children as reported by caregivers. The Ten Questions Plus questionnaire was administered to caregivers of 1,902 children aged 1-9 years, during August 2007-March 2008, in rural Nepal. Height and weight of children were also measured. The main outcome was a positive response to one or more questions. In total, 514 (27%) children had a positive response to at least one question. Moderate stunting [odds ratio (OR)=1.47, 95% confidence interval (CI) 1.02-2.12) and severe (OR=2.39, 95% CI 1.60-3.57) stunting were independently associated with reported delay in sitting, standing, or walking. Severe stunting was also associated with report of delayed learning compared to other children of similar age (OR=2.01, 95% CI 1.27-3.20). Parental report of disability was quite prevalent in this setting, with over a quarter of the sample screening positive. Chronic malnutrition may be associated with delayed motor and mental development. PMID- 21261205 TI - Duration of breastfeeding and its correlates in Bangladesh. AB - The purpose of this study was to assess the duration of breastfeeding and the sociodemographic factors affecting it. Data for the study were drawn from the Bangladesh Demographic and Health Survey 2004. In total 5,364 mothers were included in the study. The life table and Cox's proportional hazards model were employed for the analysis of breastfeeding-related data, which showed that the average duration of breastfeeding was 31.9 months. Cox regression analysis revealed that the duration of breastfeeding was positively associated with maternal age, contraceptive-use, work status, and religion and was negatively associated with age at marriage, parity, delivery status, region, and maternal education. Younger mothers, having higher education, higher maternal parity, caesarean-section birth, being a Muslim, and mothers who have not used any contraceptive were associated with lower duration of breastfeeding. The findings suggest that health institutions can play a significant role in promoting breastfeeding in Bangladesh. Educational campaigns that stress the benefits of lactation are important strategies for encouraging mothers to breastfeed longer. PMID- 21261206 TI - Gender differences in obesogenic behaviour, socioeconomic and metabolic factors in a population-based sample of Iranians: the IHHP study. AB - This study investigated the gender differences in association of some behavioural and socioeconomic factors with obesity indices in a population-based sample of 12,514 Iranian adults. The mean body mass index (BMI), waist circumference (WC), and the waist-to-hip ratio (WHR) were significantly higher in women than in men. Current and passive smoking had an inverse association with BMI among males whereas current smoking, transportation by a private car, and longer duration of watching television (TV) had a positive association with BMI among females. Current and passive smoking, cycling, and Global Dietary Index (GDI) had an inverse association with WC among males. Higher consumption of fruits and vegetables, current and passive smoking, duration of daily sleep, and GDI had an inverse association with WC among females. Using a private car for transportation had a significant positive association with WHR among both males and females. Living in an urban area, being married, and having a higher education level increased the odds ratio of obesity among both the genders. Non-manual work also increased this risk among males whereas watching TV and current smoking increased this risk among females. Such gender differences should be considered for culturally-appropriate interventional strategies to be implemented at the population level for tackling obesity and associated cardiometabolic risk factors. PMID- 21261207 TI - Community-based health workers achieve high coverage in neonatal intervention trials: a case study from Sylhet, Bangladesh. AB - A large proportion of four million neonatal deaths occur each year during the first 24 hours of life. Research is particularly needed to determine the efficacy of interventions during the first 24 hours. Large cadres of community-based workers are required in newborn-care research both to deliver these interventions in a standardized manner in the home and to measure the outcomes of the study. In a large-scale community-based efficacy trial of chlorhexidine for cleansing the cord in north-eastern rural Bangladesh, a two-tiered system of community-based workers was established to deliver a package of essential maternal and newborn care interventions and one of three umbilical cord-care regimens. At any given time, the trial employed approximately 133 community health workers--each responsible for 4-5 village health workers and a population of approximately 4,000. Over the entire trial period, 29,760 neonates were enrolled, and 87% of them received the intervention (their assigned cord-care regimen) within 24 hours of birth. Approaches to recruitment, training, and supervision in the study are described. Key lessons included the importance of supportive processes for community-based workers, including a strong training and field supervisory system, community acceptance of the study, consideration of the setting, study objectives, and human resources available. PMID- 21261208 TI - Barriers to sexual health services for young people in Nepal. AB - Although sexual and reproductive health education and services are provided to young people, current rates of HIV infection and pregnancy are increasing in Nepal, indicating that young people do not always use sexual health services. Health facilities have apparently failed to provide young people with specialized sexual health education and services. This study explored the barriers to using sexual health services, including condom-use among young people in Nepal. Participants from 10 focus groups and 31 in-depth interviews, carried out by a same-sex researcher, reported many socioeconomic, cultural and physical norms that impose barriers to accessing information on sexual health and relevant services. It is concluded that the establishment of youth-friendly service centres in convenient places might help encourage young people to use sexual health services. PMID- 21261209 TI - Abdominal tuberculosis in a child presenting with radiological evidence of pneumatosis intestinalis and portal venous gas. AB - Pneumatosis intestinalis, in association with portal venous gas, is a rare finding in children and young adults. In radiological studies, it is characterized by gas-filled cysts within the bowel-wall. It is often a sign of the serious significant underlying illness and is associated with a poor prognosis. A case of pneumatosis intestinalis and portal venous gas associated with abdominal tuberculosis in a child is presented here. Despite responding well to anti-tubercular treatment, he died suddenly at home, two months after discharge. It is recommended that cases with pneumatosis intestinalis should be carefully observed, although symptoms appear to be improving. PMID- 21261210 TI - How editors of psychiatric journals perceive their role? A follow-up appraisal seven years after. PMID- 21261211 TI - Authors are not criminals and editors should not be policemen. AB - Authors are a necessary and most appreciated basis for the publishing of any scientific journal. They should be welcomed for their creativity, originality and productivity, not stigmatized in general as cheaters and criminals because a very few were tempted beyond their control to cut the slices a bit too thin, overdo the utilization of leftover data, listed too many authors to a paper, forgot to report a harmless study to an ethical committee, or in very few cases commit severe actions of fraud. The managerial way of thinking, meeting every author with systems of control and limitations is like poison to creative minds. Instead of appointing editors as policemen, we may preferably meet the vast majority of classical scholarly working scientists with trust, confidence and support, facilitating the process of disseminating the results from their creative minds- and of course consequently show the deliberately cheating researchers the door when they act unfaithfully to the scientific society. PMID- 21261212 TI - The place of the British Journal of Psychiatry in the mental health league. AB - The British Journal of Psychiatry is an independent mainstream general psychiatric journal that competes reasonably well with others in the field. It does so by keeping a healthy balance between the demands of its readers, its contributors and the need for good science. It publishes an eclectic mix of original articles, reviews, editorials, reappraisals, comment, opinion and extras, the latter including poetry, short summaries, literature and psychiatry, and a touch of humour. These contributions are not always in keeping with the harsh requirements of the impact factor, but we judge that this makes for a better all-round journal that advances psychiatry in all its manifold aspects and is anything but dull. PMID- 21261213 TI - The many lives of an (associate) editor. AB - The role of editor of a journal attracts the vision of a scholar isolated in an ivory tower selecting "la creme" of the submitted papers, with no other preoccupations that the scientific rigour. This, is of course, only one of the many roles - or, as this editorial calls them, lives--of an editor. The essential skills are many and more complex, and an editor will encounter many problems that are related to such diverse issues as anticipating scientific trends, investigating misbehaviours, settling ethical disputes, and interfacing with the lay press. It is exciting and rewarding, and never predictable. PMID- 21261214 TI - World Psychiatry and the WPA task force to promote dissemination of psychiatric research conducted in low and middle income countries. AB - World Psychiatry, the official journal of the World Psychiatric Association (WPA), is now published in five languages (English, Spanish, Chinese, Russian and French) and reaches more than 33,000 psychiatrists in 121 countries. It received recently its first impact factor, 3.896. The publication of the journal has two objectives. The first is to reach as many psychiatrists of the various countries of the world as possible, disseminating information on recent significant clinical, service and research developments in a language that can be assimilated by the vast majority of them. The second is to give voice to psychiatrists of all regions of the world, encouraging submission of research papers, commentaries and reports on innovative service modalities. Related to this second objective has been the establishment by the WPA of a task force aiming to promote dissemination of psychiatric research conducted in low and middle income countries. Among the objectives of this task force is to advise and support the editors of high quality journals produced in those countries in their efforts to achieve indexation. PMID- 21261215 TI - Longitudinal imaging studies in schizophrenia: the relationship between brain morphology and outcome measures. AB - Imaging studies have tried to identify morphological outcome measures of schizophrenia in the last two decades. In particular, longitudinal studies have reported a correlation between larger ventricles, decreased prefrontal volumes and worse outcome. This would potentially allow to isolate subtypes of schizophrenia patients with a worse prognosis and more evident biological impairments, ultimately helping in designing specific rehabilitation interventions. PMID- 21261216 TI - The process of producing a "NICE" guideline. AB - This paper describes the process of preparing a Clinical Guideline for "NICE", the National Institute for Health and Clinical Excellence in the United Kingdom. The procedure involves the group appointed to prepare the guideline relating to the various "stakeholders" who have an interest on the one hand, and satisfying the fairly demanding standards set by NICE on the other. The strengths and limitations of the approach based on evidence based medicine are discussed. PMID- 21261217 TI - Parental bonding and eating psychopathology in bulimia nervosa: personality traits as possible mediators. AB - AIMS: The relationship between eating disorders, attachment, personality traits and eating psychopathology remains unexplored. This study tested the mediating role of temperament and character between parental bonding and psychopathology in bulimic women. METHODS: 154 bulimic subjects and 154 healthy controls were compared using Parental Bonding Instrument (PBI), Temperament and Character Inventory (TCI), Eating Disorder Inventory-2 (EDI-2), and Beck Depression Inventory (BDI). Multiple regression analysis tested the mediation of personality traits between parenting and eating psychopathology. RESULTS: Bulimic subjects displayed low maternal and paternal care and low self-directedness, and high novelty seeking and eating psychopathology. Maternal care was negatively related to social insecurity, inadequacy and impulsiveness. Paternal care predicted novelty seeking, self-directedness, interoceptive awareness, impulsiveness, and asceticism. The mediation effect of self-directedness between paternal care and psychopathology was significant, not the one of novelty seeking. CONCLUSIONS: Parental care is lower in bulimic than in control women even when controlled for possible confounding variables. Some eating psychopathology traits are related to maternal and paternal care, but not the bulimia subscale. Paternal care is also related to temperament and character traits which are related to eating psychopathology. Self-directedness mediates with different degrees between parenting and eating psychopathology. Clinical implications are discussed. PMID- 21261219 TI - Do financial incentives increase treatment adherence in people with severe mental illness? A systematic review. AB - AIM: To identify whether financial or material incentives improve treatment adherence in people with severe mental illness. METHOD: A systematic review of studies published between 1950 and 2008 was conducted. EMBASE, MEDLINE, EBM, AMED and PsycINFO were searched. Studies were included if a financial or material incentive was offered and if the sample had a severe mental illness. RESULTS: Fourteen articles were identified; three studies on adherence to psychiatric treatment and one on physical exercise. Ten articles used incentives for adherence to substance misuse treatment programmes. In all studies, financial incentives were associated with an increase in adherence; however the effect was not always maintained once the incentive was withdrawn. CONCLUSION: While existing research suggests that financial incentives may improve treatment adherence in severely mentally ill populations, very few studies focus on psychiatric treatment. Further research may address the long term effectiveness of incentives on adherence in this population. PMID- 21261218 TI - The economic impact of mental health stigma and discrimination: a systematic review. AB - People with mental illness face stigma and discrimination in a variety of settings which can have an economic impact. AIM: The aim of this paper was to identify literature on the economic impact of mental illness stigma. METHODS: A systematic review of the literature identified 30 papers from 27 studies by searching electronic databases and hand searching reference lists. RESULTS: Mental illness stigma/discrimination was found to impact negatively on employment, income, public views about resource allocation and healthcare costs. CONCLUSIONS: Stigma and discrimination regarding mental health problems lead to adverse economic effects for people with these conditions. Interventions that reduce stigma may therefore also be economically beneficial. PMID- 21261220 TI - Primary care and the early phases of schizophrenia in the Czech Republic. AB - AIM: To explore knowledge, treatment setting, attitudes and needs associated with patients in early phases of psychosis among general practitioners (GPs) in Prague, and to compare results with GPs from 6 countries participating in the International GP Study (IGPS) on Early Psychosis (Canada, Australia, New Zealand, England, Norway, Austria). METHODS: Survey questionnaires were mailed to 648 GPs in the city of Prague. RESULTS: The response rate was 19.9%. Prague GPs showed significantly lower diagnostic knowledge of early phases of psychosis compared to their international colleagues. They frequently indicated depression/anxiety and somatic complaints as early warnings of psychosis. They more often considered their behaviour to be problematic and more commonly handed them over to specialists. The majority of Prague GPs wished specialized outpatient services for low-threshold referrals of such patients. CONCLUSIONS: Along the mental health reforms in the Czech Republic which emphasis the role of primary care, GPs' knowledge of the early warning signs of psychosis needs to be improved. PMID- 21261221 TI - Effect of medication-related factors on adherence in people with schizophrenia: a European multi-centre study. AB - AIM: To investigate the relation between medication-related factors and adherence in people with schizophrenia in outpatient treatment. METHODS: The sample comprised 409 outpatients (ICD-10 diagnosis of schizophrenia) with clinician rated instability in four European cities (Amsterdam, The Netherlands; Verona, Italy; Leipzig, Germany; London, Great Britain). Adherence was assessed using the Medication Adherence Questionnaire (patient perspective), and the Clinician Rating Scale (clinician perspective). Examined medication-related factors were type (atypical vs. typical), application (oral vs. depot), daily dose frequency of antipsychotic medication (Medication History Scale), number of side effects (Liverpool University Neuroleptic Side Effect Rating Scale), and patient attitudes toward medication (Drug Attitude Inventory). Multiple regression analysis was used to identify predictors of adherence by medication-related factors. RESULTS: Adherence, as rated by patient and clinician, was predicted by patient attitude towards medication, but was unrelated to type of drug, formulation or side effects of antipsychotic medication. A high daily dose frequency was associated with better adherence, but only when rated by the patient. CONCLUSIONS: In order to improve adherence there is a need to seriously consider and attempt to improve patient attitude toward medication. However, type of antipsychotic and other medication-related factors may not be as closely related to adherence as it has often been suggested. PMID- 21261222 TI - Screening of binge eating in a community mental health service. PMID- 21261223 TI - Inadvertent intraocular injection of botulinum toxin A. AB - This report describes an inadvertent perforation of the globe while injecting botulinum toxin A into the medial rectus muscle without electromyography guidance. Botulinum toxin A does not appear to have toxic effects on the human retina. Close observation and necessary measures to treat any retinal breaks and control increased intraocular pressure should be undertaken. PMID- 21261224 TI - Telepsychiatry for children and adolescents. AB - The shortage and inadequate distribution of psychiatric care providers decreases access to mental health care for children and adolescents. One solution to the shortage is telepsychiatry. Studies of telepsychiatry show that it is effective and well received by both clinicians and patients. Despite its obvious benefits, challenges to the use of telepsychiatry remain. PMID- 21261225 TI - Vitamin D and depression. AB - Vitamin D is an essential nutrient proven to be important for bone health. It has other physiological functions, and there are plausible reasons for investigating vitamin D in depressive disorders. Some cross-sectional clinical and epidemiologic studies, but not all studies, have found that low levels of vitamin D are significantly associated with higher levels of depressive symptoms or with a depression diagnosis. However, cross-sectional studies cannot establish causality, and the methodology of these studies has been criticized. Due to the poor quality of the treatment studies, the effectiveness of vitamin D for depression cannot be adequately assessed. Current evidence does not definitively demonstrate that vitamin D deficiency is a cause of or risk for developing depression or that vitamin D is an effective therapy for depression. PMID- 21261226 TI - Improving the quality of care of veterans with diabetes. A simulation intervention for psychiatric nurses. AB - The primary objective of this study was to provide and evaluate strategies beneficial in preparing psychiatric nurses to exercise clinical judgment needed for adequate assessment and care of veterans with diabetes. Psychiatric nurses completed a pretest evaluation of their knowledge of care for veterans with diabetes. During the intervention stage, a human patient simulator was used to create an interactive scenario for participants to propose a diagnosis and administer treatment. Clinical judgment attributes were evaluated during the simulation by instructors using a rubric. Participants then completed a posttest evaluation. In addition, data about medical transfer rates for veterans with diabetes were provided 1 month before and 1 month after project implementation. All participants (N=20) demonstrated an increase on posttest scores. Medical emergencies decreased from 55% to 20% after project implementation, indicating improvement in the quality of care of veterans with diabetes. PMID- 21261227 TI - Mental illness and problematic sexual behaviors. A review of the recent literature. AB - Advanced practice nurses and other health care professionals have increasingly been working with individuals with mental illnesses who also have a history of sexual misconduct. Unfortunately, due partly to minimal research on the subject- especially in the nursing field--these professionals are addressing the needs of this population without adequate preparation. This article provides an overview of mental illness and problematic sexual behaviors (MI/PSB) and highlights the importance of additional research for the MI/PSB population as a subgroup of sex offenders. PMID- 21261228 TI - The development and testing of an instrument to measure successful aging. AB - This article reports the development and testing of the Successful Aging Inventory (SAI). Two hundred participants completed two versions of the SAI, a Likert format and dichotomous format. To test the validity of the SAI, participants also completed the Life Satisfaction Inventory-A, Purpose in Life Test, Mastery Scale, and the Center for Epidemiologic Studies Depression Scale. Both versions of the SAI had acceptable psychometric properties. Principal components analysis resulted in five factors for the Likert version, accounting for 62.19% of the variance. The SAI shows promise as a measure of successful aging and also has the potential to be a useful method of tracking older adults' overall progress and improvements in response to health promotion strategies. The next step is to evaluate its sensitivity and appropriateness for use with ethnic and racial minority older adults, and those with more varied health status. PMID- 21261229 TI - Family and friends to the rescue: experiences of rural older adults with heart failure. AB - The purpose of this study was to describe the experiences of rural community dwelling older adults with heart failure who required assistance with activities of daily living (ADLs) and instrumental ADLs (IADLs). The context of the study was a rural area in a southern U.S. state. Twenty older adults with ADL/IADL needs living in the rural area were recruited during hospitalization and interviewed in their homes after discharge. The semi-structured interview focused on ADLs/IADLs and community resources. This qualitative descriptive study used hermeneutic methods for analysis. Four themes were identified: Accepting Limitations, Disappointments and Unmet Expectations, Figure It Out, and Complex Connections. The findings indicate that despite the older adults' medical conditions, they were able to set up complex arrangements, which allowed them to remain in their homes. Understanding the help older adults require after discharge will assist nurses in developing programs that are available, accessible, and acceptable to older adults who live in rural areas. PMID- 21261230 TI - Integrating results from smoking cessation drug research and development into clinical occupational health practice. AB - This article documents evidence-based pharmacologic interventions to promote successful smoking cessation among employees who smoke. The article also highlights supporting evidence for the use of pharmacologic agents to treat tobacco dependence and can guide successful, personalized, pharmacologic smoking cessation interventions in occupational clinical practice. Prescribing clinicians will also find information about the latest research and development of medications to promote smoking cessation, including recently implemented black box warnings by the U.S. Food and Drug Administration. PMID- 21261231 TI - Facilitating repositioning in bed. AB - Repositioning patients in bed presents an occupational hazard to direct care nursing staff. Much research has been conducted in the area of safe patient handling and movement. However, little progress has been made in reducing risks associated with patient repositioning, especially pulling patients toward the head of the bed. This laboratory study investigated risk reduction achieved by introducing the gravity assist feature into bed system design for post-acute health care. Through the application of gravity assist, the amount of work required to reposition a simulated 200-pound patient was reduced by 67%. This reduction in work should reduce some of the occupational risk for nurses. PMID- 21261232 TI - I need you to finish Evan's quilt. PMID- 21261233 TI - Promoting continence in individuals with dementia. AB - Urinary incontinence (UI) is common in individuals with dementia as the disease progresses. The primary reasons for incontinence are often not related to pathology in the urinary system but are frequently attributed to losses associated with dementia. This article discusses the scope of the problem of UI in individuals with dementia, possible causes, and assessment methods, as well as interventions that can achieve improved outcomes. PMID- 21261235 TI - Functional transitions of nursing home residents with middle-stage dementia. AB - Nurses and family members are key players responding to changes in the functional abilities of nursing home residents. This study compares families' and nurses' attributions and actions in the period immediately following the functional transitions of nursing home residents with middle-stage dementia. The walking and eating abilities of 120 residents were monitored every 2 weeks for a year. Observed functional losses triggered a total of 72 interviews with family members and nurses. Data were analyzed using quantitative description. Although both groups were more likely to attribute eating disability to dementia and walking disability to something other than dementia, there was less agreement in attributions for individual residents. Differences in attributions for functional losses can lead to disagreements about the appropriate course of action. Nurses working with family members toward a common understanding of the cause of functional decline will help inform a coordinated therapeutic response. PMID- 21261236 TI - Examining nursing practice with older adults through a historical lens. AB - Scholars have suggested that negative views toward older individuals are prevalent in Western society and that health care practices with older adults are influenced by these beliefs. In this article, a historical lens is used to examine health practices and social ideas about aging to provide a clearer understanding of the current challenges to nursing practice with an aging population. Parallels between nursing practices of the past and present are discussed. It is suggested that negative beliefs about older adults are related to social ideas that originated in antiquity and yet continue to influence social institutions and practices with an older population. PMID- 21261237 TI - Evidence-based practices for the prevention of weight loss in nursing home residents. AB - Weight loss is common among nursing home residents. Food intake is often inadequate for elderly residents but is only one of several factors contributing to potential weight loss. Three common issues resulting in weight loss include starvation (or wasting), cachexia, and sarcopenia. Significant weight loss leads to increased mortality, increased morbidity, and decreased quality of life. The purpose of this article is to discuss the geriatric syndrome of weight loss in elderly nursing home residents and provide recommendations to decrease and prevent weight loss. A list of available evidence-based protocols related to weight loss issues is provided. PMID- 21261238 TI - Taking on the challenge of clinical teaching in nursing homes. AB - While the goal of professional nursing programs is to ensure that students have a basic level of competency to care for older adults in a variety of care settings, the greatest challenge is to garner students' enthusiasm about caring for older adults in nursing homes. To increase and strengthen the professional nursing workforce in nursing homes, schools of nursing must ensure that students have appropriately placed, well-designed, and innovative clinical experiences in nursing homes with faculty who are knowledgeable about the nursing home environment and the professional nursing care needs of its residents. Four factors identified as keys to success in developing exemplary clinical experiences for students in nursing homes include: (a) nursing homes with positive reputations and providing quality care, (b) faculty knowledgeable and enthused about nursing homes, (c) committed partnerships between schools of nursing and nursing homes, and (d) creative and innovative clinical teaching strategies. PMID- 21261239 TI - Work organization and health issues in long-term care centers. AB - This qualitative study explored common and divergent perceptions of caregivers and managers regarding occupational health and safety, work organization, and psychosocial concerns in long-term care centers. Both common and differing issues were identified. Both groups agreed on the importance of ergonomic concerns, the high prevalence of stress, and receptiveness to participatory health promotion programs. However, numerous work organization issues and physical and psychosocial workplace hazards were identified by certified nursing assistants but were not mentioned by managers. The results suggest that different perceptions naturally arise from people's varying positions in the occupational hierarchy and their consequent exposures to health and safety hazards. Improved systems of communication that allow frontline workers to express their concerns would make it possible to create solutions to these problems. PMID- 21261240 TI - Pediatric ocular injuries from airsoft toy guns. AB - PURPOSE: To report ocular injuries caused by airsoft guns in children. METHODS: A retrospective chart review of pediatric patients who sustained ocular injuries related to airsoft guns between November 2005 and December 2007. Place of trauma, presenting symptoms and signs, surgical interventions performed, and final visual outcome were reviewed. RESULTS: Thirty-two patients with a mean age of 8.8 +/- 4.0 years (range: 1.5 to 18 years) were examined; 28 were boys (87.5%). Presenting visual acuity ranged from hand motions to 20/20 and could not be assessed in 2 patients. Hyphema was a common finding that was present in 24 cases, corneal abrasions were present in 10 cases, and raised intraocular pressure was present in 7 cases. Seven patients presented with traumatic cataract, and two had iridodialysis. Immediate surgical intervention was performed in 7 patients and 7 patients were scheduled for elective surgery. The patients presented after an average of 1.9 +/- 1.9 days (range: 4 hours to 6 days) after the injury. Average follow-up was 18 days (range: 7 days to 5 months). Final visual acuity was 20/200 or worse in 5 patients, 20/40 or better in 23 patients, and could not be assessed in 2 cases. CONCLUSION: Airsoft guns can cause a variety of serious injuries, sometimes necessitating operative intervention. The long-term morbidity from some of these injuries is significant. Airsoft guns are capable of inflicting serious and permanent ocular damage. PMID- 21261241 TI - A randomized clinical trial comparing myectomy and recession in the management of inferior oblique muscle overaction. AB - PURPOSE: It is still not clear whether inferior oblique recession or inferior oblique myectomy is a better option for weakening inferior oblique overaction (IOOA). The aim of this study was to compare the effect of these two methods on IOOA. METHODS: Patients who were candidates for surgical management of IOOA were randomly assigned to either IO myectomy or recession. Complete ophthalmic examinations were performed before surgery. In the myectomy group, 5 mm was excised from the inferior temporal region of IO muscle(s). In the recession group, the IO muscle was disinserted and subsequently sutured to a point 2 mm lateral and 4 mm posterior to the insertion of the inferior rectus muscle on the temporal side. Satisfactory results were defined as an IO function of grade 0 or 1+ at 3 months postoperatively. RESULTS: The study included 50 patients (82 eyes) with a mean age of 12.3 +/- 5.9 years (range: 3 to 32 years). Both methods were effective on the weakening of IOOA (P < .001). The rate of satisfactory results was similar in both groups (P = .686). The rate of residual IOOA and IO underaction did not differ between the two groups. Regarding the changes of horizontal or vertical deviations, V pattern, and dissociated vertical deviation, there was no statistically significant difference between the two groups. CONCLUSION: For treatment of IOOA, both IO myectomy and recession can be used with similar success rate. PMID- 21261242 TI - Neural circuit involved in idiopathic infantile nystagmus syndrome based on FMRI. AB - PURPOSE: To identify the neural circuitry of idiopathic infantile nystagmus syndrome (INS), characterized by an early onset alternating series of slow and rapid eye movements that can manifest in different waveforms and genetic lines. The neural circuitry of INS is currently unknown. METHODS: A novel functional magnetic resonance imaging (fMRI) method, referred to as the null zone fMRI technique, was used to identify the neural circuitry for INS. In the null zone fMRI technique, a gaze position with minimal nystagmus within the null zone was linked to the fMRI "off" condition and a gaze position with robust nystagmus outside of the null zone was linked to the fMRI "on" condition. Eye movements were monitored with an fMRI compatible eye tracker and observed in real time to ensure subject compliance in "on" and "off" states. Subjects with INS (n = 4) included three family members (a mother and two daughters) with presumed autosomal dominant INS, as well as age- and gender-matched normal controls (n = 3). RESULTS: Three of four subjects with INS demonstrated significant increased activation of the declive of the cerebellum, whereas no normal subjects under identical conditions showed activation of the declive of the cerebellum. Both groups showed significant activation in the occipital lobe (Brodmann areas 17, 18, 19, and cuneus). CONCLUSION: A novel fMRI method demonstrated that the declive of the cerebellum is actively involved in INS. These are the first results to identify the cerebellum, and specifically the declive, as a possible site involved in the ocular motor dysfunction known as INS. PMID- 21261243 TI - Improvement in visual acuity following surgery for correction of head posture in infantile nystagmus syndrome. AB - PURPOSE: To report the effect of the abnormal head posture (AHP) correcting procedures on the visual acuity improvement in patients with infantile nystagmus syndrome (INS) and the visual acuity improvement outcomes in different AHP correcting surgeries in INS. METHODS: This was a prospective, non-randomized, interventional study. Twenty-eight patients underwent the Anderson-Kestenbaum procedure or the modified Anderson procedure with or without tenotomy of at least one horizontal recti for correction of AHP. Best-corrected binocular null zone acuity and degree of AHP was recorded preoperatively and compared with those done 1 month postoperatively. RESULTS: The average null zone logarithm of the minimum angle of resolution acuity was 0.42 preoperatively, which improved significantly to 0.33 postoperatively (P = .002). The AHP ranged from 10 degrees to 40 degrees (mean: 20.89 degrees ), which improved significantly to a mean of 3.21 degrees (P = .000). No significant difference (P = .65) was found in the visual acuity improvement among patients who underwent the Anderson-Kestenbaum procedure or the modified Anderson procedure with or without tenotomy. No significant difference in the visual acuity improvement was seen in patients who underwent tenotomy of at least one horizontal rectus muscle along with the modified Anderson procedure compared to those who underwent the modified Anderson procedure alone (P = .28). CONCLUSION: The procedures used mainly for correction of AHP in INS do yield significant improvement in the visual acuity. This improvement is seen in patients undergoing surgery for both horizontal and vertical AHP. PMID- 21261244 TI - Electrophysiological evaluation of retinal function in children receiving vigabatrin medication. AB - PURPOSE: To evaluate retinal function in children taking vigabatrin and to explore the influence of age and dose parameters on the results of full-field electroretinography (ff-ERG). METHODS: The ff-ERGs from 14 children receiving vigabatrin were compared with ff-ERGs from healthy controls. Treated children were further grouped according to age (pre-school = 12-71 months; older = 72-228 months). Parameters of drug dosage were compared. RESULTS: Treated children showed rod and cone dysfunction reflected by reduced b-wave amplitudes for the isolated rod response, the combined rod-cone response, and the 30-Hz flicker response. The a-wave amplitude and implicit time for the combined rod-cone response, reflecting photoreceptor function, were also altered. Further evaluation of age groups revealed similar findings in the pre-school group but not in the older group. Alterations in ff-ERG were seen in 57% of the treated children. Pre-school children had received significantly higher daily drug doses with start of medication at younger age. No differences were found concerning cumulative doses or duration of medication. CONCLUSION: Alterations in ff-ERG are as frequent in children as in adults and the results indicate that exposure to high daily doses of vigabatrin may be associated with increased risk of retinal dysfunction, including photoreceptor damage, not previously shown in children. Thus, recommendations of careful follow-up for children receiving vigabatrin are supported. PMID- 21261245 TI - Toward evidence-based nursing education: deliberate practice and motor skill learning. PMID- 21261246 TI - Using simulation innovation to facilitate learning nursing concepts: medical and mental health. PMID- 21261247 TI - Thermal induction of an alternatively folded state in human IgG-Fc. AB - We report the formation of a non-native, folded state of human IgG4-Fc induced by a high temperature at neutral pH and at a physiological salt concentration. This structure is similar to the molten globule state in that it displays a high degree of secondary structure content and surface-exposed hydrophobic residues. However, it is highly resistant to chemical denaturation. The thermally induced state of human IgG4-Fc is thus associated with typical properties of the so called alternatively folded state previously described for murine IgG, IgG-Fab, and individual antibody domains (V(L), V(H), C(H)1, and C(H)3) under acidic conditions in the presence of anions. Like some of these molecules, human IgG4-Fc in its alternative fold exists as a mixture of different oligomeric structures, dominated by an equilibrium between monomeric and heptameric species. Heating further induces the formation of fibrous structures in the micrometer range. PMID- 21261248 TI - How mobile are sorbed cations in clays and clay rocks? AB - Diffusion of cations and other contaminants through clays is of central interest, because clays and clay rocks are widely considered as barrier materials for waste disposal sites. An intriguing experimental observation has been made in this context: Often, the diffusive flux of cations at trace concentrations is much larger and the retardation smaller than expected based on their sorption coefficients. So-called surface diffusion of sorbed cations has been invoked to explain the observations but remains a controversial issue. Moreover, the corresponding surface diffusion coefficients are largely unknown. Here we show that, by an appropriate scaling, published diffusion data covering a broad range of cations, clays, and chemical conditions can all be modeled satisfactorily by a surface diffusion model. The average mobility of sorbed cations seems to be primarily an intrinsic property of each cation that follows inversely its sorption affinity. With these surface mobilities, cation diffusion coefficients can now be estimated from those of water tracers. In pure clays at low salinities, surface diffusion can reduce the cation retardation by a factor of more than 1000. PMID- 21261249 TI - Reproducible (1)H NMR-based metabolomic responses in fish exposed to different sewage effluents in two separate studies. AB - Treated sewage effluents contain complex mixtures of micropollutants, raising concerns about effects on aquatic organisms. The addition of advanced treatment steps has therefore been suggested. However, some of these could potentially produce effluents affecting exposed organisms by unknown modes of action. Here, (1)H NMR (proton nuclear magnetic resonance spectroscopy) metabolomics of fish blood plasma was used to explore potential responses not identified by more targeted (chemical or biological) assays. Rainbow trout was exposed in parallel to six differently treated effluents (e.g., conventional activated sludge, addition of sand filter, further addition of ozonation and/or a moving bed biofilm reactor or a separate membrane bioreactor line). Multivariate data analysis showed changes in the metabolome (HDL, LDL, VLDL and glycerol-containing lipids, cholesterol, glucose, phosphatidylcholine, glutamine, and alanine) between treatment groups. This formed the basis for postulating a hypothesis on how exposure to effluent treated by certain processes, including ozonation, would affect the metabolic profiles of exposed fish. The hypothesis withstood testing in an independent study the following year. To conclude, (1)H NMR metabolomics proved suitable for identifying physiological responses not identified by more targeted assays used in parallel studies. Whether these changes are linked to adverse effects remains to be tested. PMID- 21261251 TI - Identification of proanthocyanidin dimers and trimers, flavone C-Glycosides, and antioxidants in Ficus deltoidea , a malaysian herbal tea. AB - Phenolic compounds in an aqueous infusion of leaves of Ficus deltoidea (Moraceae), a well-known herbal tea in Malaysia, were analyzed by HPLC coupled to photodiode array and fluorescence detectors and an electrospray ionization tandem mass spectrometer. Following chromatography of extracts on a reversed phase C(12) column, 25 flavonoids were characterized and/or tentatively identified with the main constituents being flavan-3-ol monomers, proanthocyanidins, and C-linked flavone glycosides. The proanthocyanidins were dimers and trimers comprising (epi)catechin and (epi)afzelechin units. No higher molecular weight proanthocyanidin polymers were detected. The antioxidant activity of F. deltoidea extract was analyzed using HPLC with online antioxidant detection. This revealed that 85% of the total antioxidant activity of the aqueous F. deltoidea infusion was attributable to the flavan-3-ol monomers and the proanthocyanidins. PMID- 21261252 TI - Foaming properties of wheat gliadin. AB - We studied gliadin solubility, surface tension and foam behavior, and the presence of different gliadin types in gliadin aqueous solutions and foams as a function of pH. Gliadin has excellent foaming properties only at neutral and alkaline pH. Its solubility is minimal near neutral pH, while almost complete at acidic and alkaline pH. Surface tensions of gliadin solutions are minimal around neutral pH, higher at alkaline pH, and highest at acidic pH, which corresponds well with their respective foaming properties. Foams at acidic and alkaline pH values are enriched in gamma-gliadin, while foams at pH 8.0 have a similar distribution of alpha- and gamma-gliadins. Thus, gamma-gliadin predominantly contributes to the foaming properties of gliadin. The poor foaming properties of gliadin at pH 2.0 improve in the presence of 0.25 and 1.0% NaCl. It follows that the presence of positively charged amino acid residues hinders the formation of stable foam at acidic pH. PMID- 21261253 TI - Ultralow secondary electron emission of graphene. AB - In order to ensure that vacuum electronic devices work with high overall efficiency, it is required to use materials with low secondary electron emission to fabricate or coat collectors, grids, and envelope walls of the devices. We report that the secondary electron yields of monolayer graphenes are ultralow, comparable with the lowest yields of the materials currently used in this practical application. This offers a pathway for the application of light graphene with only one-atom thickness and good electronic and thermal conductivities in vacuum electronic devices. PMID- 21261254 TI - Spectroscopic and electronic structure studies of copper(II) binding to His111 in the human prion protein fragment 106-115: evaluating the role of protons and methionine residues. AB - The prion protein (PrP(C)) is implicated in the spongiform encephalopathies in mammals, and it is known to bind Cu(II) at the N-terminal region. The region around His111 has been proposed to be key for the conversion of normal PrP(C) to its infectious isoform PrP(Sc). The principal aim of this study is to understand the role of protons and methionine residues 109 and 112 in the coordination of Cu(II) to the peptide fragment 106-115 of human PrP, using different spectroscopic techniques (UV-vis absorption, circular dichroism, and electron paramagnetic resonance) in combination with detailed electronic structure calculations. Our study has identified a proton equilibrium with a pK(a) of 7.5 associated with the Cu(II)-PrP(106-115) complex, which is ascribed to the deprotonation of the Met109 amide group, and it converts the site from a 3NO to a 4N equatorial coordination mode. These findings have important implications as they imply that the coordination environment of this Cu binding site at physiological pH is a mixture of two species. This study also establishes that Met109 and Met112 do not participate as equatorial ligands for Cu, and that Met112 is not an essential ligand, while Met109 plays a more important role as a weak axial ligand, particularly for the 3NO coordination mode. A role for Met109 as a highly conserved residue that is important to regulate the protonation state and redox activity of this Cu binding site, which in turn would be important for the aggregation and amyloidogenic properties of the protein, is proposed. PMID- 21261255 TI - Anti-tumor and anti-inflammatory properties of ankaflavin and monaphilone A from monascus purpureus NTU 568. AB - An azaphilonidal derivative monaphilone A (MA) was recently isolated from the fermented products of Monascus purpureus NTU 568 by our laboratory. We report here the exploration of apoptosis-related and anti-inflammatory properties of MA and ankaflavin (AK) by some experiments about inducing death of human laryngeal carcinoma cell line HEp-2 and reducing inflammatory responses on murine macrophage RAW 264.7 cells. We employed a ssDNA enzyme-linked immunosorbent assay (ELISA) kit to investigate the nuclear changes of early apoptosis induced by AK and MA on HEp-2 cells and used a western blot and an enzyme activity assay to demonstrate the activation of caspase-3, caspase-8, and caspase-9 by MA and AK. Our studies revealed that AK and MA may decrease lipopolysaccharide (LPS)-induced inflammatory responses, including nitrite productions and expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in RAW 264.7 cells. All evidence support that azaphilonidal derivatives from M. purpureus NTU 568, such as AK and MA, are suitable for the development of chemotherapy or chemopreventive agents. PMID- 21261256 TI - Effects of processing steps on the phenolic content and antioxidant activity of beer. AB - A new analytical method (liquid chromatography-antioxidant, LC-AOx) was used that is intended to separate beer polyphenols and to determine the potential antioxidant activity of these constituents after they were allowed to react online with a buffered solution of the radical cation 2,2'-azinobis(3 ethylbenzothiazoline-6-sulfonic acid) (ABTS(*+)). Using the LC-AOx method, it was possible to demonstrate that the extent of the antioxidant activity was very much dependent on the phenolic compound considered. The method was also applied to the analysis of beer extracts and allowed the evaluation of their antioxidant activity at different steps of beer processing: brewing, boiling, and fermentation. This study showed that the total antioxidant activity remained unchanged throughout beer processing, as opposed to the polyphenolic content, which showed a 3-fold increase. Hopping and fermentation steps were the main causes of this increase. However, the increase measured after fermentation was attributed to a better extraction of polyphenols due to the presence of ethanol, rather than to a real increase in their content. Moreover, this method allowed the detection of three unknown antioxidant compounds, which accounted for 64 +/- 4% of the total antioxidant activity of beer and were individually more efficient than caffeic acid and epicatechin. PMID- 21261257 TI - Multiwavelength Raman microspectroscopy for rapid prediction of soot oxidation reactivity. AB - Multiwavelength Raman microspectroscopy (MWRM) analysis for characterization of soot structure and reactivity was developed. This new method is based on the dispersive character of carbon D mode in Raman spectra (i.e., red shift and increase in intensity at higher excitation wavelength, lambda(0)). The approach was proven by investigating various diesel soot samples and related carbonaceous materials at different lambda(0) (785, 633, 532, and 514 nm). In order to compare the behavior of the D mode for various samples and to derive a single parameter characterizing the soot structure, the difference of integrals for pairs of spectra collected at different lambda(0) was calculated. MWRM analysis revealed substantial differences in the structural ordering which decreases from graphite, over Printex XE2 and various diesel soot samples, to spark discharge soot. To obtain the relation between structure and reactivity of soot, MWRM analysis was combined with temperature-programmed oxidation (TPO). TPO allowed us to characterize the oxidation behavior of soot in terms of the maximum emission (CO + CO(2)) temperature and reactivity index. The latter was calculated by introducing the reactivity limits: spark discharge soot containing a large amount of disorder represents the upper limit, whereas the lower limit is given by graphite powder with high structural order. The comparison of MWRM (viz., the observed Raman difference integrals) and TPO data revealed a linear correlation between soot structure and oxidation reactivity. Thus, we demonstrated for the first time the potential of MWRM for a robust and rapid prediction of diesel soot reactivity based on the structure-reactivity correlation. PMID- 21261258 TI - Hyperspectral nanoscale imaging on dielectric substrates with coaxial optical antenna scan probes. AB - We have demonstrated hyperspectral tip-enhanced Raman imaging on dielectric substrates using linearly polarized light and nanofabricated coaxial antenna tips. A full Raman spectrum was acquired at each pixel of a 256 by 256 pixel contact-mode atomic force microscope image of carbon nanotubes grown on a fused silica microscope coverslip, allowing D and G mode intensity and D-mode peak shifts to be measured with ~20 nm spatial resolution. Tip enhancement was sufficient to acquire useful Raman spectra in 50-100 ms. Coaxial scan probes combine the efficiency and enhanced, ultralocalized optical fields of plasmonically coupled antennae with the superior topographical imaging properties of sharp metal tips. The yield of the coaxial tip fabrication process is close to 100%, and the tips are sufficiently durable to support hours of contact-mode force microscope imaging. Our coaxial probes avoid the limitations associated with the "gap-mode" imaging geometry used in most tip-enhanced Raman studies to date, where a sharp metal tip is held ~1 nm above a metallic substrate with the sample located in the gap. PMID- 21261259 TI - Nanotrap and mass analysis of aromatic molecules by phenyl group-modified nanoparticle. AB - To functionalize the surface of nanoparticles with phenyl groups for subsequent cross-linking with aromatic molecules by mutual interactions, we prepared functional nanoparticles (d = 3 nm) by silanization with phenyl-triethoxysilane. The nanoparticles had Fe(2)O(3) cores conjugated to phenyl groups; this was confirmed by Fourier transform infrared (FT-IR) spectroscopy and absorption spectrophotometry. The typical C-H and C-C peaks and the absorption at 240 nm, which corresponds to aromatic rings, were detected in the spectroscopic results for the phenyl group-modified nanoparticles. The nanoparticles could ionize aromatic (colchicine, reserpine, and bradykinin peptide) and nonaromatic (L-alpha phosphatidylethanolamine,dioleoyl, and polyethylene glycol) molecules by nanoparticle-assisted laser desorption/ionization mass spectrometry. The nanoparticles worked as a selective trap and an ionization-assisting reagent in mass spectrometry for the aromatic molecular targets. PMID- 21261260 TI - Integrated microdynamics mechanism of the thermal-induced phase separation behavior of poly(vinyl methyl ether) aqueous solution. AB - The thermal behavior of a poly(vinyl methyl ether) (PVME) aqueous solution (30 wt %) during a heating-and-cooling cycle is studied using FTIR spectroscopy in combination with 2D correlation analysis. The FTIR spectral data of O-H, CH(3)-O, and C-H stretching vibration regions provide detailed changes of hydrophilic and hydrophobic groups of PVME. Hydrogen bonds between hydrophilic groups and water and hydration interactions between hydrophobic groups and water are confirmed to be completely reversible in the heating-and-cooling cycle. Two-dimensional correlation method helps us to understand the microdynamics mechanism of phase separation behavior of PVME 30 wt % aqueous solution. During the heating process, the initially hydrated CH(3) groups start to dehydrate as the first action of phase separation, and the initially hydrated CH(2) groups follow to start their dehydration; interestingly, water molecules leave CH(2) groups very fast, and the whole dehydration process of CH(2) groups finishes even earlier than that of CH(3). After hydrophobic groups finish their dehydrations, hydrogen bonds between hydrophilic group and water start to dissociate. 1:2 adducts formed between PVME and water dissociate first and transfer to the 1:1 adducts, whereas with further heating, 1:1 adducts eventually dissociate and release free water and free CH(3) O. PCMW method is used as supplement to determine changing conditions of various chemical structures. During the phase separation, O-H hydrogen bond in 1:2 adduct is found to dissociate between 35.5 and 39 degrees C in a [Formula: see text] style, whereas the 1:1 adduct (also considered as free water) increases between 35.5 and 39 degrees C in a [Formula: see text] style. Moreover, dehydration conditions of hydrophobic groups are also found. Both of the dehydrated states CH(3) and CH(2) increase like [Formula: see text]. PMID- 21261261 TI - Dynamic moisture sorption characteristics of enzyme-resistant recrystallized cassava starch. AB - The interaction of moisture with enzyme-resistant recrystallized starch, prepared by heat-moisture treatment of debranched acid-modified or debranched non-acid modified cassava starch, was investigated in comparison with the native granules. Crystallinities of the powdered products were estimated by X-ray diffraction. Moisture sorption was determined using dynamic vapor sorption analyzer and data fitted to various models. Percent crystallinities of native starch (NS), non-acid modified recrystallized starch (NAMRS), and acid-modified recrystallized starch (AMRS) were 39.7, 51.9, and 56.1%, respectively. In a(w) below 0.8, sorption decreased in the order NS > NAMRS > AMRS in line with increasing sample crystallinities but did not follow this crystallinity dependence at higher a(w) because of condensation and polymer dissolution effects. Adsorbed moisture became internally absorbed in NS but not in NAMRS and AMRS, which might explain the high resistance of the recrystallized starches to digestion because enzyme and starch cannot approach each other over fairly sufficient surface at the molecular level. PMID- 21261262 TI - Cellular responses associated with dibucaine-induced phospholipidosis. AB - A wide range of cationic amphiphilic drugs (CADs) from different therapeutic areas are known to cause phospholipidosis both in vivo and in vitro. Although the relevance of this storage disorder for human health remains uncertain, CADs have been repeatedly associated with clinical side effects, and as a result, phospholipidosis is of major concern for drug development in the pharmaceutical industry. An important unresolved question in this field is whether phospholipidosis is really linked to cellular toxicity. This work was focused on studying cellular responses associated with CAD-induced phospholipidosis in cultured mammalian kidney cells. Dibucaine (2-butoxy-N-[2 diethylaminoethyl]quinoline-4-carboxamide), an amide-type anesthetic with poorly defined cytotoxic effects, was used to induce phospholipidosis in Vero cells. The results from several assays that measure cell viability, proliferation, and morphological changes indicated that dibucaine-induced lysosomal phospholipidosis was accompanied by cellular defense responses such as transient growth arrest and autophagy, under mild stress conditions. Conversely, when tolerance limits were exceeded treated Vero cells underwent extensive and irreparable injury, leading ultimately to cell death. Our data provide additional information that may be of considerable interest for drug safety assessment. PMID- 21261263 TI - A facile and practical copper powder-catalyzed, organic solvent- and ligand-free Ullmann amination of aryl halides. AB - A facile and practical method that the copper powder-catalyzed Ullmann amination of aryl halides with aqueous methylamine under organic solvent- and ligand-free condition at 100 degrees C and in air gave N-arylamines as sole products in good to excellent yields. The presence of a small amount of air is essential. Other aliphatic primary amines show good to very high reactivity. Secondary amines and aniline are not reactive. Sensitive substituents (i.e., CHO, MeCO, CN and Cl) are tolerable in the reaction. PMID- 21261264 TI - Studies of intracorneal distribution and cytotoxicity of quantum dots: risk assessment of eye exposure. AB - The cornea is a potential route of exposure and drug administration for nanoparticles. In this work, we use noninvasive two-photon microscopic imaging to study the distribution and permeability pathway of CdSe/ZnS core/shell quantum dots (QDs) capped with three different functional groups through the cornea. With no additional staining, the two-photon image clearly discloses that fluorescent QDs penetrate and reside within the interlamellar space of second harmonic generating collagenous stroma when the corneal epithelium barrier is injured. An in vitro cytotoxicity test using bovine corneal stromal cells incubated individually with all three kinds of QDs indicates that the cell viability decreases significantly as the QD concentration and incubation period increased. The results also show that the specific QDs influence corneal stromal cell viability up to a significant magnitude of 50% under a relatively low concentration (5-20 nM) and short exposure period (24-48 h). Furthermore, two photon imaging shows that QDs can be retained within the cornea up to 26 days in an in vivo mouse model. On the basis of our in vivo and in vitro data, we conclude that QDs can penetrate and be retained within cornea long enough to cause consequential cytotoxicity, under the circumstance in which the corneal epithelium barrier is injured. Since corneal abrasion is quite a common situation in daily life, our work raises public attention to the potential risk of eye exposure to nanoparticles. PMID- 21261265 TI - Slow-equilibration approximation in macroscopic approach to studying kinetics at equilibrium. AB - Macroscopic approach to studying kinetics at equilibrium (MASKE) facilitates measurements of rate constants of formation (k(+)) and dissociation (k(-)) of affinity complexes in the state of chemical equilibrium. MASKE relies on "informational nonequilibrium" created by a nonuniform initial spatial distribution of a label on one of the reactants. In general, finding k(+) and k( ) by MASKE requires fitting experimental label-propagation patterns-dependencies of label concentrations on a coordinate or time-with the simulated label propagation patterns. Here we introduce a simple fitting-free approach for finding the rate constants in the case of slow equilibration. Slow equilibration means that the characteristic equilibration time of the labeled reactant and labeled complex, t(eq), is much greater than the characteristic separation time of the labeled reactant and labeled complex, t(sep). We developed the mathematics for this approach by solving the differential equations of mass transfer using the assumption of slow equilibration. The approach was then tested and its accuracy was studied by applying it to label-propagation patterns created with the earlier-developed exact solution of the mass-transfer equations. The results proved that the approximate solution was correct. They also showed that k(+) and k(-) can be found with this fitting-free approach with a relative error less than 20% if t(sep) < 0.6t(eq). The practical limitations of our slow-equilibration approximation are discussed. PMID- 21261266 TI - Gradient tandem mass spectrometry interfaced with ion mobility separation for the characterization of supramolecular architectures. AB - Traveling wave ion mobility mass spectrometry (TWIM MS) was combined with gradient tandem mass spectrometry (gMS(2)) to deconvolute and characterize superimposed ions with different charges and shapes formed by electrospray ionization (ESI) of self-assembled, hexameric metallomacrocycles composed of terpyridine-based ligands and Cd(II) ions. ESI conditions were optimized to obtain intact hexameric cation assemblies in a low charge state (2+), in order to minimize overlapping fragments of the same mass-to-charge ratio. With TWIM MS, intact hexameric ions could be separated from remaining fragments and aggregates. Collisional activation of these hexameric ions at varying collision energies (gMS(2)), followed by TWIM separation, was then performed to resolve macrocyclic from linear hexameric species. Because of the different stabilities of these architectures, gMS(2) changes their relative amounts, which can be monitored individually after subsequent ion mobility separation. On the basis of this unique strategy, hexameric cyclic and linear isomers have been successfully resolved and identified. Complementary structural information was gained by the gMS(2) fragmentation pattern of the metallosupramolecules, acquired by collisionally activated dissociation after TWIM dispersion. TWIM MS interfaced with gMS(2) should be particularly valuable for the characterization of a variety of supramolecular polymers, which often contain isomeric architectures that yield overlapping fragments and aggregates upon ESI MS analysis. PMID- 21261267 TI - Determination of phospholipid regiochemistry by Ag(I) adduction and tandem mass spectrometry. AB - Collision-activated dissociation (CAD) and infrared multiphoton dissociation (IRMPD) of Ag-adducted phospholipids were investigated as structural tools. Previously, determination of the acyl chains at the two phospholipid esterification sites has been performed based on the R(1)COO(-)/R(2)COO(-) ratio in negative ion mode CAD tandem mass spectrometry. However, the observed product ion ratio is dependent on the extent of unsaturation of the fatty acyl group at sn-2 as well as on the total chain length. Similarly, in positive ion mode CAD with/without alkaline or alkaline earth metal adduction, the ratio of product ions resulting from either R(1)COOH or R(2)COOH neutral losses is dependent on the nature of the phospholipid polar headgroup. Ag(+) ion chromatography, in which silver ions are part of the stationary phase, can provide information on double bond number/distribution as well as double bond configuration (cis/trans) because of interaction between Ag(+) ions and olefinic pi electrons of fatty acids and lipids. We hypothesized that interactions between double bonds and Ag(+) may be utilized to also reveal phospholipid esterification site information in tandem mass spectrometry. CAD and IRMPD of Ag-adducted phospholipids with unsaturated fatty acids (R(x)COOH, x = 1 or 2) provided characteristic product ions, [R(x)COOH + Ag](+), and their neutral losses. The characteristic product ions and their abundances do not depend on the type of polar headgroup or the number of double bonds of unsaturated acyl chains. Tandem mass spectrometry of Cu adducted phospholipids was also performed for comparison based on the Lewis acid and base properties of Cu(+) and phospholipid double bonds, respectively. PMID- 21261268 TI - Understanding the effect of surface chemistry on charge generation and transport in poly (3-hexylthiophene)/CdSe hybrid solar cells. AB - For hybrid solar cells, interfacial chemistry is one of the most critical factors for good device performance. We have demonstrated that the size of the surface ligands and the dispersion of nanoparticles in the solvent and in the polymer are important criteria in obtaining optimized device performance. The size of the ligands will affect the charge transport at the particle/particle and particle/polymer interfaces and the chemical structures of the ligands will determine their compatibility with the solvent and polymer. Hence other than pyridine, 2-thiophenemethylamine also showed good potential as ligand replacement for poly(3-hexylthiophene)/CdSe hybrid solar cells. With the right ligand combination, we have shown that the power conversion efficiency improved by a factor of 6 after ligand exchange. PMID- 21261270 TI - Thermal and electron-induced decomposition of 2-butanol on Pt(111). AB - The adsorption, thermal evolution, and electron irradiation of 2-butanol on Pt(111) were investigated with reflection absorption infrared spectroscopy (RAIRS). A simulated vibrational spectrum of a single 2-butanol molecule was calculated using density functional theory to facilitate vibrational assignments. Exposures of 0.2 Langmuir (L) and lower result in both isolated 2-butanol molecules with minimal lateral interactions and hydrogen-bonded clusters. The thermal evolution following a 4.0 L exposure shows that the hydrogen-bonded multilayer desorbs around 170 K, leaving a 2-butanol monolayer where hydrogen bonding still exists. At 190 K, a new feature at 1699 cm(-1) is attributed to the formation of butanone. Irradiation with 750 or 100 eV electrons leads to 2 butanol desorption and partial conversion to butanone, as indicated by the appearance of a peak at 1709 cm(-1). PMID- 21261269 TI - Dendrimer display of tumor-homing peptides. AB - In vivo selection of phage libraries that display random peptide sequences on their surface has yielded a number of peptides that specifically home to tumor tissue. In this study, two different peptides are introduced to synthetic dendritic scaffolds via oxime chemistry and the resulting compounds are analyzed for tumor homing. Modification of the dendritic wedge with a short, linear peptide that homes to clotted plasma proteins showed that a specific receptor in tumor tissue is recognized, but that the extravasation is likely affected by the size of the construct. In contrast, a positively charged cyclic peptide with cell penetrating properties was capable of directing the entire dendritic architecture toward a specific receptor in tumor lymphatics. These observations are in agreement with results previously reported for micelles and nanoparticles and emphasize the influence of peptide properties and overall size on the biodistribution of multivalent macromolecules. PMID- 21261271 TI - 2-azapinanes: aza analogues of the enantiomeric pinyl carbocation intermediates in pinene biosynthesis. AB - The enantiomeric 2-azapinanes, aza analogues of the pinyl carbocation intermediates in pinene biosynthesis, were synthesized from (-)- and (+)-cis pinonic acids. The individual reactions in the 5-step sequence were Beckmann rearrangement of the pinonic acid oximes, cyclization to the N-acetyl lactams, hydrolysis to the NH-lactams, N-methylations, and LiAlH(4) reductions. The anti stereochemistry of the N-methyl groups in the salts with respect to the gem dimethyl bridge was established by NOE measurements and by X-ray diffraction analysis. PMID- 21261272 TI - Multinuclear Pd/Zn complex-catalyzed asymmetric alkylative ring-opening reaction of oxabicyclic alkenes. AB - A multinuclear palladium catalyst can be used to realize the efficient catalytic asymmetric alkylative ring-opening reaction of oxabicyclic alkenes using dimethylzinc. The use of (R)-BINOL-PHOS bearing bisphosphine and diol moieties is essential for achieving excellent catalytic performance; the corresponding monophosphine and hydroxy-protected derivatives showed lower catalytic activities and/or enantioselectivities. The generation of Pd/Zn-multinuclear complexes is a key feature of the present catalysis. PMID- 21261273 TI - Fluorescence near gold nanoparticles for DNA sensing. AB - We investigated fluorescence quenching and enhancement near gold nanoparticles (GNP) of various sizes using fluorescently labeled hairpin DNA probes of different lengths. A closed hairpin caused intimate contact between the fluorophore and the gold, resulting in an efficient energy transfer (quenching). Upon hybridization with complementary DNA, the DNA probes were stretched yielding a strong increase in fluorescence signal. By carefully quantifying the amount of bound fluorescent probes and the GNP concentrations, we were able to determine the quenching and enhancement efficiencies. We also studied the size and distance dependence theoretically, using both FDTD simulations and the Gersten-Nitzan model and obtained a good agreement between experiments and theory. On the basis of experimental and theoretical studies, we report over 96.8% quenching efficiency for all particle sizes tested and a maximal signal increase of 1.23 after DNA hybridization. The described results also demonstrate the potential of gold nanoparticles for label free DNA sensing. PMID- 21261274 TI - Laser-induced forward transfer of polymer light-emitting diode pixels with increased charge injection. AB - Laser-induced forward transfer (LIFT) has been used to print 0.6 mm * 0.5 mm polymer light-emitting diode (PLED) pixels with poly[2-methoxy, 5-(2 ethylhexyloxy)-1,4-phenylene vinylene] (MEH-PPV) as the light-emitting polymer. The donor substrate used in the LIFT process is covered by a sacrificial triazene polymer (TP) release layer on top of which the aluminium cathode and functional MEH-PPV layers are deposited. To enhance electron injection into the MEH-PPV layer, a thin poly(ethylene oxide) (PEO) layer on the Al cathode or a blend of MEH-PPV and PEO was used. These donor substrates have been transferred onto both plain indium tin oxide (ITO) and bilayer ITO/PEDOT:PSS (poly(3,4 ethylenedioxythiophene) poly(styrenesulfonate) blend) receiver substrates to create the PLED pixels. For comparison, devices were fabricated in a conventional manner on ITO substrates coated with a PEDOT:PSS hole-transporting layer. Compared to multilayer devices without PEO, devices with ITO/PEDOT:PSS/MEH PPV:PEO blend/Al architecture show a 100 fold increase of luminous efficiency (LE) reaching a maximum of 0.45 cd/A for the blend at a brightness of 400 cd/m(2). A similar increase is obtained for the polymer light-emitting diode (PLED) pixels deposited by the LIFT process, although the maximum luminous efficiency only reaches 0.05 cd/A for MEH-PPV:PEO blend, which we have attributed to the fact that LIFT transfer was carried out in an ambient atmosphere. For all devices, we confirm a strong increase in device performance and stability when using a PEDOT:PSS film on the ITO anode. For PLEDs produced by LIFT, we show that a 25 nm thick PEDOT:PSS layer on the ITO receiver substrate considerably reduces the laser fluence required for pixel transfer from 250 mJ/cm(2) without the layer to only 80 mJ/cm(2) with the layer. PMID- 21261275 TI - Horseradish peroxidase functionalized fluorescent gold nanoclusters for hydrogen peroxide sensing. AB - The fluorescence of metal nanoclusters provides an amusing optic feature to be applied in various fields. However, rational design of dual functional fluorescent metal nanoclusters directed by active enzyme with targeted application remains little explored. In this work, we report a new strategy to construct enzyme functionalized fluorescent gold nanoclusters via a biomineralization process for the detection of hydrogen peroxide. Horseradish peroxidase (HRP) was used as a model functional template to direct the synthesis of fluorescent gold nanoclusters (Au NCs) at physiological conditions to form HRP Au NCs bioconjugates. We found that the fluorescence of HRP-Au NCs can be quenched quantitatively by adding H(2)O(2), indicating that HRP enzyme remains active and enables catalytic reaction of HRP-Au NCs and H(2)O(2). Upon the addition of H(2)O(2) under optimal conditions, the fluorescence intensity quenched linearly over the range of 100 nM to 100 MUM with high sensitivity (LOD = 30 nM, S/N = 3). This study would be potentially extended to other functional proteins to generate dual functional nanoclusters and applied to real time monitoring of biologically important targets in living cells. PMID- 21261276 TI - Antibacterial activity of electrospun polymer mats with incorporated narrow diameter single-walled carbon nanotubes. AB - Polymer coatings featuring nonleaching antibacterial agents are needed to significantly reduce bacterial colonization and subsequent biofilm formation. Previously, single-walled carbon nanotubes (SWNTs) have been reported to be strong antimicrobial agents that kill microbes on contact. However, the antibacterial activity of freestanding polymer mats with a low weight percent of incorporated SWNTs has not been demonstrated. In this study, four different weight percents of well characterized, small diameter (0.8 nm) SWNTs were incorporated into electrospun polysulfone (PSf) mats. Electrospun PSf-SWNT mats were observed to be flexible and composed of continuous, cylindrical, and randomly oriented fibers. SEM micrographs revealed that SWNT ends were distributed along the longitudinal fiber axis. Loss of bacteria (Escherichia coli) viability was observed to directly correlate to increased SWNT incorporation within the mat, ranging from 18% for 0.1 wt % SWNTs to 76% for 1.0 wt % SWNTs. Time-dependent bacterial cytotoxicity studies indicated that the antimicrobial action of the PSf-SWNT mats occurs after a short contact time of 15 min or less. This study demonstrates the potential applicability of electrospun PSf-SWNT mats as antibacterial coatings. PMID- 21261277 TI - Highly enantioselective Pd-catalyzed allylic alkylation of indoles using Sulfur MOP ligand. AB - The preparation of various (R)-Sulfur-MOP ligands with aryl and alkyl substituents on sulfur, and the application of these ligands to Pd-catalyzed asymmetric allylic alkylation of indoles is reported. The sulfur substituent served as an effective stereocontrol element, and in the case of the 2-i-PrPh substituent on sulfur, the allylation products from an array of simple and substituted indoles were obtained with high enantioselectivity (up to 95% ee). PMID- 21261278 TI - Novel bolaamphiphilic pyrimidinophane as building block for design of nanosized supramolecular systems with concentration-dependent structural behavior. AB - A new macrocyclic bolaamphiphile with thiocytosine fragments in the molecule (B1) has been synthesized and advanced as perspective platform for the design of soft supramolecular systems. Strong concentration-dependent structural behavior is observed in the water-DMF (20% vol) solution of B1 as revealed by methods of tensiometry, conductometry, dynamic light scattering, and atomic force microscopy. Two breakpoints are observed in the surface tension isotherms. The first one, around 0.002 M, is identified as a critical micelle concentration (cmc), whereas the second critical concentration of 0.01 M is a turning point between the two models of the association involved. Large aggregates of ca. 200 nm are mostly formed beyond the cmc, whereas small micelle-like aggregates exist above 0.01 M. The growth of aggregates between these critical points occurs, resulting in a gel-like behavior. An unusual decrease in the solution pH with concentration takes place, which is assumed to originate from the steric hindrance around the B1 head groups. Because of controllable structural behavior, B1 is assumed to be a candidate for the development of biomimetic catalysts, nanocontainers, drug and gene carriers, etc. PMID- 21261279 TI - Oxorhenium(V) complexes with pyrazole based aryloxide ligands and application in olefin epoxidation. AB - We synthesized and characterized a set of new oxorhenium(V) complexes coordinated by various pyrazole containing phenol (L1-L3) and naphthol ligands (L4-L7). Depending on the starting material, we were able to selectively synthesize monosubstituded or disubstituted complexes of the type [ReOBr(2)L(PPh(3))] (1-7; L = L1-L7) and [ReOClL(2)] (L = L1 8; L2 9; L4 10; L6 11), respectively. All complexes are stable to air and moisture, both in solid state as well as in solution. Furthermore, the cationic oxorhenium(V) complex [ReO(L1)(2)(NCMe)](OTf) (8a) was obtained upon chloride abstraction with silver triflate from 8. All new complexes were able to catalyze the epoxidation of cis-cyclooctene in yields up to 64%. The ease of preparation and their tolerance to air and moisture, as well as the simple ligand modifications, make them an interesting class of novel catalysts. An attempted reduction of perchlorate ClO(4)(-) with complex 8 was unsuccessful. Molecular structures of complexes 1, 4, 6, 7, 8, 8a, 10, and 11 were determined by single crystal X-ray diffraction analyses. PMID- 21261280 TI - Rapid prototyping of arrayed microfluidic systems in polystyrene for cell-based assays. AB - Microfluidic cell-based systems have enabled the study of cellular phenomena with improved spatiotemporal control of the microenvironment and at increased throughput. While poly(dimethylsiloxane) (PDMS) has emerged as the most popular material in microfluidics research, it has specific limitations that prevent microfluidic platforms from achieving their full potential. We present here a complete process, ranging from mold design to embossing and bonding, that describes the fabrication of polystyrene (PS) microfluidic devices with similar cost and time expenditures as PDMS-based devices. Emphasis was placed on creating methods that can compete with PDMS fabrication methods in terms of robustness, complexity, and time requirements. To achieve this goal, several improvements were made to remove critical bottlenecks in existing PS embossing methods. First, traditional lithographic techniques were adapted to fabricate bulk epoxy molds capable of resisting high temperatures and pressures. Second, a method was developed to emboss through-holes in a PS layer, enabling creation of large arrays of independent microfluidic systems on a single device without need to manually create access ports. Third, thermal bonding of PS layers was optimized in order to achieve quality bonding over large arrays of microsystems. The choice of materials and methods was validated for biological function in two different cell-based applications to demonstrate the versatility of our streamlined fabrication process. PMID- 21261282 TI - Turn-on and near-infrared fluorescent sensing for 2,4,6-trinitrotoluene based on hybrid (gold nanorod)-(quantum dots) assembly. AB - In this study, we design a FRET system consisting of gold nanorod (AuNR) and quantum dots (QDs) for turn-on fluorescent sensing of 2,4,6-trinitrotoluene (TNT) in near-infrared region. The amine-terminated AuNR and carboxyl-terminated QDs first form a compact hybrid assembly through amine-carboxyl attractive interaction, which leads to a high-efficiency (>92%) FRET from QDs to AuNRs and an almost complete emission quenching. Next, added TNT molecules break the preformed assembly because they can replace the QDs around AuNRs, based on the specific reaction of forming Meisenheimer complexes between TNT and primary amines. Thus, the FRET is switched off, and a more than 10 times fluorescent enhancement is obtained. The fluorescence turn-on is immediate, and the limit of detection for TNT is as low as 0.1 nM. Importantly, TNT can be well distinguished from its analogues due to their electron deficiency difference. The developed method is successfully applied to TNT sensing in real environmental samples. PMID- 21261281 TI - Intermonomer electron transfer between the low-potential b hemes of cytochrome bc1. AB - Cytochrome (cyt) bc(1) is a structural dimer with its monomers consisting of the Fe-S protein, cyt b, and cyt c(1) subunits. Its three-dimensional architecture depicts it as a symmetrical homodimer, but the mobility of the head domain of the Fe-S protein indicates that the functional enzyme exists in asymmetrical heterodimeric conformations. Here, we report a new genetic system for studying intra- and intermonomer interactions within the cyt bc(1) using the facultative phototrophic bacterium Rhodobacter capsulatus. The system involves two different sets of independently expressed cyt bc(1) structural genes carried by two plasmids that are coharbored by a cell without its endogenous enzyme. Our results indicate that coexpressed cyt bc(1) subunits were matured, assorted, and assembled in vivo into homo- and heterodimeric enzymes that can bear different mutations in each monomer. Using the system, the occurrence of intermonomer electron transfer between the low-potential b hemes of cyt bc(1) was probed by choosing mutations that perturb electron transfer at the hydroquinone oxidation (Q(o)) and quinone reduction (Q(i)) sites of the enzyme. The data demonstrate that active heterodimeric variants, formed of monomers carrying mutations that abolish only one of the two (Q(o) or Q(i)) active sites of each monomer, are produced, and they support photosynthetic growth of R. capsulatus. Detailed analyses of the physicochemical properties of membranes of these mutants, as well as purified homo- and heterodimeric cyt bc(1) preparations, demonstrated that efficient and productive electron transfer occurs between the low-potential b(L) hemes of the monomers in a heterodimeric enzyme. Overall findings are discussed with respect to intra- and intermonomer interactions that take place during the catalytic turnover of cyt bc(1). PMID- 21261283 TI - Osazone anion radical complex of rhodium(III). AB - One electron paramagnetic parent osazone complex of rhodium of type trans Rh(L(NHPh)H(2))(PPh(3))(2)Cl(2) (1), defined as an osazone anion radical complex of rhodium(III), trans-Rh(III)(L(NHPh)H(2)(*-))(PPh(3))(2)Cl(2), 1((t-RhL*)), with a minor contribution (~2%) of rhodium(II) electromer, trans Rh(II)(L(NHPh)H(2))(PPh(3))(2)Cl(2), 1((t-Rh*L)), and their nonradical congener, trans-[Rh(III)(L(NHPh)H(2))(PPh(3))(2)Cl(2)]I(3) ([t-1](+)I(3)(-)), have been isolated and are substantiated by spectra, bond parameters, and DFT calculations on equivalent soft complexes [Rh(L(NHPh)H(2))(PMe(3))(2)Cl(2)] (3) and [Rh(L(NHPh)H(2))(PMe(3))(2)Cl(2)](+) (3(+)). 1 is not stable in solution and decomposes to [t-1](+) and a new rhodium(I) osazone complex, [Rh(I)(L(NHPh)H(2))(PPh(3))Cl] (2). 1 absorbs strongly at 351 nm due to MLCT and LLCT, while [t-1](+) and 2 absorb moderately in the range of 300-450 nm, respectively, due to LMCT and MLCT elucidated by TD-DFT calculations on 3((t RhL*)), [t-3](+), and Rh(I)(L(NHPh)H(2))(PMe(3))Cl (4). EPR spectra of solids at 295 and 77 K, and dichloromethane-toluene frozen glass at 77 K of 1 are similar with g = 1.991, while g = 2.002 for the solid at 25 K. The EPR signal of 1 in dichloromethane solution is weaker (g = 1.992). In cyclic voltammetry, 1 displays two irreversible one electron transfer waves at +0.13 and -1.22 V, with respect to Fc(+)/Fc coupling, due to oxidation of 1((t-RhL*)) to [t-1](+) at the anode and reduction of rhodium(III) to rhodium(II), i.e., [t-1](+) to electromeric 1((t Rh*L)) at the cathode. PMID- 21261284 TI - Effector analogues detect varied allosteric roles for conserved protein-effector interactions in pyruvate kinase isozymes. AB - The binding site for allosteric inhibitor (amino acid) is highly conserved between human liver pyruvate kinase (hL-PYK) and the rabbit muscle isozyme (rM(1) PYK). To detail similarities/differences in the allosteric function of these two homologues, we quantified the binding of 45 amino acid analogues to hL-PYK and their allosteric impact on affinity for the substrate, phosphoenolpyruvate (PEP). This complements a similar study previously completed for rM(1)-PYK. In hL-PYK, the minimum chemical requirements for effector binding are the same as those identified for rM(1)-PYK (i.e., the l-2-aminopropanaldehyde substructure of the effector is primarily responsible for binding). However, different regions of the effector determine the magnitude of the allosteric response in hL-PYK vs rM(1) PYK. This finding is inconsistent with the idea that allosteric pathways are conserved between homologues of a protein family. PMID- 21261285 TI - Large favorable enthalpy changes drive specific RNA recognition by RNA recognition motif proteins. AB - The RNA recognition motif (RRM) is a prevalent class of RNA binding domains. Although a number of RRM/RNA structures have been determined, thermodynamic analyses are relatively uncommon. Here, we use isothermal titration calorimetry to characterize single-stranded (ss)RNA binding by four representative RRM containing proteins: (i) U2AF(65), (ii) SXL, (iii) TIA-1, and (iv) PAB. In all cases, ssRNA binding is accompanied by remarkably large favorable enthalpy changes (-30 to -60 kcal mol(-1)) and unfavorable entropy changes. Alterations of key RRM residues and binding sites indicate that under the nearly physiological conditions of these studies, large thermodynamic changes represent a signature of specific ssRNA recognition by RRMs. PMID- 21261286 TI - Uptake, distribution, and speciation of selenoamino acids by human cancer cells: X-ray absorption and fluorescence methods. AB - Selenium compounds exhibit chemopreventative properties at supranutritional doses, but the efficacy of selenium supplementation in cancer prevention is dependent on the chemical speciation of the selenium supplement and its metabolites. The uptake, speciation, and distribution of the common selenoamino acid supplements, selenomethionine (SeMet) and Se-methylselenocysteine (MeSeCys), in A549 human lung cancer cells were investigated using X-ray absorption and fluorescence spectroscopies. X-ray absorption spectroscopy of bulk cell pellets treated with the selenoamino acids for 24 h showed that while selenium was found exclusively in carbon-bound forms in SeMet-treated cells, a diselenide component was identified in MeSeCys-treated cells in addition to the carbon-bound selenium species. X-ray fluorescence microscopy of single cells showed that selenium accumulated with sulfur in the perinuclear region of SeMet-treated cells after 24 h, but microprobe selenium X-ray absorption near-edge spectroscopy in this region indicated that selenium was carbon-bound rather than sulfur-bound. X-ray absorption and X-ray fluorescence studies both showed that the selenium content of MeSeCys-treated cells was much lower than that of SeMet-treated cells. Selenium was distributed homogeneously throughout the MeSeCys-treated cells. PMID- 21261287 TI - Assembly of the base excision repair complex on abasic DNA and role of adenomatous polyposis coli on its functional activity. AB - The assembly and stability of base excision repair (BER) proteins in vivo with abasic DNA and the role of adenomatous polyposis coli (APC) protein in this process are currently unclear. We have studied the assembly of a multiprotein BER complex onto abasic DNA (F-DNA) and characterized the physical and functional activity of the associated proteins. We found that the BER complex contained all the essential components of the long-patch BER system, such as APE1, Pol-beta, Fen1, and DNA ligase I. Interestingly, wild-type APC was also present in the BER complex. Kinetics of the assembly of BER proteins onto the F-DNA were rapid and appeared in sequential order depending upon their requirement in the repair process. The presence of wild-type APC in the BER complex caused a decrease in the level of assembly of BER proteins and negatively affected long-patch BER. These results suggest that major BER proteins in the complex are assembled onto F DNA and are competent in performing DNA repair. Wild-type APC in the BER complex reduces the repair activity, probably because of interaction with multiple components of the system. PMID- 21261289 TI - Segregation behaviors and radial distribution of dopant atoms in silicon nanowires. AB - Gaining an understanding the dynamic behaviors of dopant atoms in silicon nanowires (SiNWs) is the key to achieving low-power and high-speed transistor devices using SiNWs. The segregation behavior of boron (B) and phosphorus (P) atoms in B- and P-doped SiNWs during thermal oxidation was closely observed using B local vibrational peaks and Fano broadening in optical phonon peaks of B-doped SiNWs by micro-Raman scattering. Electron spin resonance (ESR) signals from conduction electrons were used for P-doped SiNWs. Our results showed that B atoms preferentially segregate in the surface oxide layer, whereas P atoms tend to accumulate in the Si region around the interface of SiNWs. The radial distribution of P atoms in SiNWs was also investigated to prove the difference segregation behaviors between of P and B atoms. PMID- 21261288 TI - Evidence for a high-spin Fe(IV) species in the catalytic cycle of a bacterial phenylalanine hydroxylase. AB - Phenylalanine hydroxylase is a mononuclear non-heme iron protein that uses tetrahydropterin as the source of the two electrons needed to activate dioxygen for the hydroxylation of phenylalanine to tyrosine. Rapid-quench methods have been used to analyze the mechanism of a bacterial phenylalanine hydroxylase from Chromobacterium violaceum. Mossbauer spectra of samples prepared by freeze quenching the reaction of the enzyme-(57)Fe(II)-phenylalanine-6 methyltetrahydropterin complex with O(2) reveal the accumulation of an intermediate at short reaction times (20-100 ms). The Mossbauer parameters of the intermediate (delta = 0.28 mm/s, and |DeltaE(Q)| = 1.26 mm/s) suggest that it is a high-spin Fe(IV) complex similar to those that have previously been detected in the reactions of other mononuclear Fe(II) hydroxylases, including a tetrahydropterin-dependent tyrosine hydroxylase. Analysis of the tyrosine content of acid-quenched samples from similar reactions establishes that the Fe(IV) intermediate is kinetically competent to be the hydroxylating intermediate. Similar chemical-quench analysis of a reaction allowed to proceed for several turnovers shows a burst of tyrosine formation, consistent with rate-limiting product release. All three data sets can be modeled with a mechanism in which the enzyme-substrate complex reacts with oxygen to form an Fe(IV)?O intermediate with a rate constant of 19 mM(-1) s(-1), the Fe(IV)?O intermediate hydroxylates phenylalanine with a rate constant of 42 s(-1), and rate-limiting product release occurs with a rate constant of 6 s(-1) at 5 degrees C. PMID- 21261290 TI - Growth of titanium dioxide nanorods in 3D-confined spaces. AB - Three-dimensional (3D) nanowire (NW) networks are promising architectures for effectively translating the extraordinary properties of one-dimensional objects into a 3D space. However, to uniformly grow NWs in a 3D confined space is a serious challenge due to the coupling between crystal growth and precursor concentration that is often dictated by the mass flow characteristic of vapor or liquid phase reactants within the high-aspect ratio submicrometer channels in current strategies. We report a pulsed chemical vapor deposition (CVD) process that successfully addressed this issue and grew TiO(2) nanorods uniformly covering the entire inner surface of highly confined nanochannels. We propose a mechanism for the anisotropic growth of anatase TiO(2) based on the surface reaction-limited CVD process. This strategy would lead to the realization of NW based 3D nanoarchitectures from various functional materials for the applications of sensors, solar cells, catalysts, energy storage systems, and so forth. PMID- 21261291 TI - G protein- and agonist-bound serotonin 5-HT2A receptor model activated by steered molecular dynamics simulations. AB - A 5-HT(2A) receptor model was constructed by homology modeling based on the beta(2)-adrenergic receptor and the G protein-bound opsin crystal structures. The 5-HT(2A) receptor model was transferred into an active conformation by an agonist ligand and a G(alphaq) peptide in four subsequent steered molecular dynamics (MD) simulations. The driving force for the transformation was the addition of several known intermolecular and receptor interhelical hydrogen bonds enforcing the necessary helical and rotameric movements. Subsquent MD simulations without constraints confirmed the stability of the activated receptor model as well as revealed new information about stabilizing residues and bonds. The active 5 HT(2A) receptor model was further validated by retrospective ligand screening of more than 9400 compounds, whereof 182 were known ligands. The results show that the model can be used in drug discovery for virtual screening and structure-based ligand design as well as in GPCR activation studies. PMID- 21261292 TI - High-performance transparent conductive films using rheologically derived reduced graphene oxide. AB - In this work, we produced large-area graphene oxide (GO) sheets with fewer defects on the basal plane by application of shear stress in solution to obtain high-quality reduced graphene oxide (RGO) sheets without the need for post annealing processes. This is described as rheologically derived RGO. The large area GO sheets were generated using a homogenizer in aqueous solution, which induced slippage of the GO in the in-plane direction during the exfoliation process, in contrast with the conventional sonication method. The effects of chemical reduction under mild conditions demonstrated that the formation of structural defects during the exfoliation process affected the RGO properties. In the Raman spectra, the I(D)/I(G) ratio of the homogenized RGO (HRGO) increased more than that of the sonicated RGO (SRGO) due to the large number of ordered six fold rings on the basal plane. The enhanced sheet resistance of the HRGO thin film was found to be 2.2 kOmega/sq at 80% transmittance. The effective exfoliation method has great potential for application to high-performance RGO transparent conducting films. PMID- 21261293 TI - Morphology-controlled flame synthesis of single, branched, and flower-like alpha MoO3 nanobelt arrays. AB - We report an atmospheric, catalyst-free, rapid flame synthesis technique for growing single, branched, and flower-like alpha-MoO(3) nanobelt arrays on diverse substrates. The growth rate, morphology, and surface coverage density of the alpha-MoO(3) nanobelts were controlled by varying the flame equivalence ratio, the source temperature, the growth substrate temperature, and the material and morphology of the growth substrate. This flame synthesis technique is a promising, alternative way to synthesize one-dimensional metal oxide nanostructures in general. PMID- 21261295 TI - Thermal conversion of electronic and electrical properties of AuCl3-doped single walled carbon nanotubes. AB - By using carbon-free inorganic atomic layer involving heat treatment from 150 to 300 degrees C, environmentally stable and permanent modulation of the electronic and electrical properties of single-walled carbon nanotubes (SWCNTs) from p-type to ambi-polar and possibly to n-type has been demonstrated. At low heat treatment temperature, a strong p-doping effect from Au(3+) ions to CNTs due to a large difference in reduction potential between them is dominant. However at higher temperature, the gold species are thermally reduced, and thermally induced CNT-Cl finally occurs by the decomposition reaction of AuCl(3). Thus, in the AuCl(3) doped SWCNTs treated at higher temperature, the p-type doping effect is suppressed and an n-type property from CNT-Cl is thermally induced. Thermal conversion of the majority carrier type of AuCl(3)-doped SWNTs is systematically investigated by combining various optical and electrical tools. PMID- 21261294 TI - Rational methods for the selection of diverse screening compounds. AB - Traditionally a pursuit of large pharmaceutical companies, high-throughput screening assays are becoming increasingly common within academic and government laboratories. This shift has been instrumental in enabling projects that have not been commercially viable, such as chemical probe discovery and screening against high-risk targets. Once an assay has been prepared and validated, it must be fed with screening compounds. Crafting a successful collection of small molecules for screening poses a significant challenge. An optimized collection will minimize false positives while maximizing hit rates of compounds that are amenable to lead generation and optimization. Without due consideration of the relevant protein targets and the downstream screening assays, compound filtering and selection can fail to explore the great extent of chemical diversity and eschew valuable novelty. Herein, we discuss the different factors to be considered and methods that may be employed when assembling a structurally diverse compound collection for screening. Rational methods for selecting diverse chemical libraries are essential for their effective use in high-throughput screens. PMID- 21261296 TI - Bioactive compounds from the fern Lepisorus contortus. AB - Phytochemical investigation of the whole plant of Lepisorus contortus (Christ) Ching led to the isolation of five new phenylethanoid glycosides (1-5), each containing a caffeoyl group, a new flavonoid glycoside (10), and 14 known compounds (6-9 and 11-15, syringic acid, vanillic acid, phloretic acid, diplopterol, and beta-sitosterol). This is the first report of phenylethanoid glycosides from the family Polypodiaceae. Compounds 1-15 were evaluated for their cancer chemopreventive potential based on their ability to inhibit tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB activity, nitric oxide (NO) production, and aromatase, quinone reductase 2 (QR-2), and COX-1/-2 activities. Quercetin-3-O-beta-d-glucoside (15) demonstrated inhibition against QR2 with an IC(50) value of 3.84 MUM, which confirmed kaempferol/quercetin glycosides as the active compounds to inhibit QR2. The compound also demonstrated NF-kappaB activity with an IC(50) value of 33.6 MUM. In addition, compounds 1, 2, 4, and 6 showed aromatase activity with IC(50) values of 30.7, 32.3, 26.8, and 35.3 MUM, respectively. PMID- 21261297 TI - Configurational assignment of cyclic peroxy metabolites provides an insight into their biosynthesis: isolation of plakortolides, seco-plakortolides, and plakortones from the Australian marine sponge Plakinastrella clathrata. AB - Sixteen new compounds, comprising nine new plakortolides K-S (1-9), four seco plakortolides (10-13), and three plakortones (14-16), were isolated from the Australian sponge Plakinastrella clathrata. Structural elucidation, including relative configurational assignment, was based on extensive spectroscopic analysis, while the absolute configurations of 1-4 were deduced from (1)H NMR analyses on MPA esters derived from Zn/AcOH reduction products. Diastereomeric sets of plakortolides, e.g., K and L, or M and N, differed in configuration at C 3/C-4 rather than at C-6, a stereochemical result that compromises a biosynthetic pathway involving Diels-Alder cycloaddition of molecular oxygen to a Delta(3,5) diunsaturated fatty acid precursor. The biosynthesis may plausibly involve cyclization of a 6-hydroperoxydienoic acid intermediate following stereospecific introduction of the hydroperoxy group into a polyketide-derived precursor. Isolated seco-plakortolides converted under mild conditions into plakortones with full retention of configuration, suggesting C-6 hydroxy attack on an alpha,beta unsaturated lactone intermediate. The NMR data reported for the compound named plakortolide E are inconsistent with the current literature structure and are those of the corresponding seco-plakortolide (19). The reported conversion of the metabolite into a plakortone ether on storage is consistent with this structural revision. PMID- 21261299 TI - Viscoelastic evaluation of average length of cellulose nanofibers prepared by TEMPO-mediated oxidation. AB - Dynamic viscoelasticity measurements were performed for aqueous dispersions of cellulose nanofibers prepared by TEMPO (2,2,6,6-tetramethylpiperidine-1-oxyl radical)-mediated oxidation and subsequent mechanical disintegration in water. The frequency dependence of the storage and loss moduli of 0.02% (w/v) dispersions of TEMPO-oxidized cellulose nanofibers in water showed terminal relaxation behavior at relatively lower angular frequencies. This strongly suggests that each cellulose nanofiber in the dispersion behaves as a semiflexible rod-like macromolecular chain or colloidal particle. Furthermore, a clear boundary was observed between the terminal relaxation and rubbery plateau regions. The longest viscoelastic relaxation time, tau, was estimated from the angular frequency, corresponding to the boundary point, and the average length of the cellulose nanofibers, L, was estimated using the equation tau = pieta(s)L(3)/[18k(B)T ln(L/d)]. The equation gave a value of L = 2.2 MUm, which was in good agreement with TEM observations. PMID- 21261298 TI - Making structural sense of dimerization interfaces of delta opioid receptor homodimers. AB - Opioid receptors, like other members of the G protein-coupled receptor (GPCR) family, have been shown to associate to form dimers and/or oligomers at the plasma membrane. Whether this association is stable or transient is not known. Recent compelling evidence suggests that at least some GPCRs rapidly associate and dissociate. We have recently calculated binding affinities from free energy estimates to predict transient association between mouse delta opioid receptor (DOR) protomers at a symmetric interface involving the fourth transmembrane (TM4) helix (herein termed "4" dimer). Here we present disulfide cross-linking experiments with DOR constructs with cysteines substituted at the extracellular ends of TM4 or TM5 that confirm the formation of DOR complexes involving these helices. Our results are consistent with the involvement of TM4 and/or TM5 at the DOR homodimer interface, but possibly with differing association propensities. Coarse-grained (CG) well-tempered metadynamics simulations of two different dimeric arrangements of DOR involving TM4 alone or with TM5 (herein termed "4/5" dimer) in an explicit lipid-water environment confirmed the presence of two structurally and energetically similar configurations of the 4 dimer, as previously assessed by umbrella sampling calculations, and revealed a single energetic minimum of the 4/5 dimer. Additional CG umbrella sampling simulations of the 4/5 dimer indicated that the strength of association between DOR protomers varies depending on the protein region at the interface, with the 4 dimer being more stable than the 4/5 dimer. PMID- 21261300 TI - Endotoxin removing method based on lipopolysaccharide binding protein and polyhydroxyalkanoate binding protein PhaP. AB - Polyhydroxyalkanoates (PHAs) granule associated protein PhaP has a strong affinity to PHA and other hydrophobic polymers. Human lipopolysaccharide binding protein (hLBP) is a natural endotoxin receptor in plasma. In this study, genes encoding hLBP fused with PhaP were expressed in Pichia pastoris GS115 for production of the fusion protein. The purified rhLBP-PhaP fusion protein was immobilized on particles of polyhydroxybutyrate (PHB), which is a member of microbial polyhydroxyalkanoates (PHA). The rhLBP-PhaP-coated PHB particles were added to endotoxin containing water and protein solutions to study their endotoxin removal and protein recovery efficiencies. The influences of ionic strengths and pH on endotoxin removal and protein recovery in different protein solutions were also studied using acidic proteins including bovine serum albumin (BSA), ovalbumin, and basic protein alpha-chymotrypsinogen as model proteins. The results showed that rhLBP-PhaP particles could remove endotoxin with an efficiency of over 90%. All endotoxin removal and protein recovery efficiencies were only slightly affected by ionic strengths but were drastically affected by pH changes. Our results demonstrated that rhLBP-PhaP particles with their high efficiency, ease of preparation, and nontoxicity will be a suitable system for endotoxin removal in the protein purification industry. PMID- 21261301 TI - Enzymatic polymerization catalyzed by immobilized endoglucanase on gold. AB - Enzymatic polymerization was carried out on gold by immobilized genetically engineered endoglucanase II (EGII) from Trichoderma viride , and the polymerization behavior and the produced cellulose were analyzed in comparison with those by free enzymes. Mutant EGIIs were EGII(core2) and EGII(core2H), which consist of two sequential catalytic core domains with one His-tag (His6) on N terminal and with totally two His-tags on both terminals, respectively. His tagged EGIIs were immobilized via Ni chelators of nitrilotriacetic acid (NTA) introduced on gold surface. From SPR measurements, the affinity of EGII(core2H) to the surface was higher than that of EGII(core2), and the molecular occupation area of EGII(core2H) was larger than that of EGII(core2), indicating that EGII(core2H) was immobilized with utilizing two His-tags introduced on both terminals. The hydrolytic activity of the immobilized EGII(core2H) using cellohexaose as substrate was slightly lower than that of free EGII(core2H) when they were compared at the same amount in the hydrolytic system. Enzymatic polymerization catalyzed by both immobilized EGII(core2) and EGII(core2H) proceeded with producing highly crystalline cellulose in comparison with free enzyme. Immobilization of the endoglucanase is thus effective to obtain crystalline cellulose due to the high density of the catalytic domain on gold. PMID- 21261303 TI - Nanoscience and nanotechnology in the posthype era. PMID- 21261305 TI - Nanotechnology regulation: a study in claims making. AB - There appears to be consensus on the notion that the hazards of nanotechnology are a social problem in need of resolution, but much dispute remains over what that resolution should be. There are a variety of potential policy tools for tackling this challenge, including conventional direct regulation, self regulation, tort liability, financial guarantees, and more. The literature in this area is replete with proposals embracing one or more of these tools, typically using conventional regulation as a foil in which its inadequacy is presented as justification for a new proposed approach. At its core, the existing literature raises a critical question: What is the most effective role of government as regulator in these circumstances? This article explores that question by focusing upon two policy approaches in particular: conventional regulation and self-regulation, often described as hard law and soft law, respectively. Drawing from the sociology of social problems, the article examines the soft law construction of the nanotechnology problem and the associated solutions, with emphasis on the claims-making strategies used. In particular, it critically examines the rhetoric and underlying grounds for the soft law approach. It also sets out the grounds and framework for an alternative construction and solution-the concept of iterative regulation. PMID- 21261306 TI - Nanomaterials in the environment: from materials to high-throughput screening to organisms. AB - One of the challenges in the field of nanotechnology is environmental health and safety (EHS), including consideration of the properties of engineered nanomaterials (ENMs) that could pose dangers to the environment. Progress in the field of nanomaterial development and nanotoxicology was presented at the International Conference on the Environmental Implications of Nanotechnology at the California NanoSystems Institute (CNSI) on the UCLA campus on May 11-14, 2010. This event was cohosted by the University of California Center for the Environmental Implications of Nanotechnology (UC CEIN) and the Center for the Environmental Implications of NanoTechnology (CEINT) based at Duke University. Participants included scientists and scholars from various backgrounds, including chemistry, biology, engineering, nanomaterial science, toxicology, ecology, mathematics, sociology, and policy makers. The topics of discussion included safety evaluation of ENMs from an environmental perspective, nanotoxicology, ecotoxicology, safe design of ENMs, environmental risk assessment, public perception of nanotechnology, application of ENMs in consumer products, and many more. The UC CEIN presented data on their predictive toxicological approach to the assessment of ENM libraries, which were designed and synthesized to develop an understanding of the material properties that could lead to hazard generation at the cellular and organismal levels in the environment. This article will focus on the first metal oxide ENM library that was introduced to harmonize research activities in the UC CEIN, with particular emphasis on the safety assessment of ZnO on cells and organisms. Methods of decreasing the observed toxic effects will also be discussed as an integral component of the UC CEIN's activity in developing safer nanomaterials to lessen their environmental impacts. PMID- 21261302 TI - Proteome of human subcutaneous adipose tissue stromal vascular fraction cells versus mature adipocytes based on DIGE. AB - Adipose tissue contains a heterogeneous population of mature adipocytes, endothelial cells, immune cells, pericytes, and preadipocytic stromal/stem cells. To date, a majority of proteomic analyses have focused on intact adipose tissue or isolated adipose stromal/stem cells in vitro. In this study, human subcutaneous adipose tissue from multiple depots (arm and abdomen) obtained from female donors was separated into populations of stromal vascular fraction cells and mature adipocytes. Out of 960 features detected by 2-D gel electrophoresis, a total of 200 features displayed a 2-fold up- or down-regulation relative to each cell population. The protein identity of 136 features was determined. Immunoblot analyses comparing SVF relative to adipocytes confirmed that carbonic anhydrase II was up-regulated in both adipose depots while catalase was up-regulated in the arm only. Bioinformatic analyses of the data set determined that cytoskeletal, glycogenic, glycolytic, lipid metabolic, and oxidative stress related pathways were highly represented as differentially regulated between the mature adipocytes and stromal vascular fraction cells. These findings extend previous reports in the literature with respect to the adipose tissue proteome and the consequences of adipogenesis. The proteins identified may have value as biomarkers for monitoring the physiology and pathology of cell populations within subcutaneous adipose depots. PMID- 21261307 TI - How colloidal nanoparticles could facilitate multiplexed measurements of different analytes with analyte-sensitive organic fluorophores. AB - Multiplexed measurements of several analytes in parallel using analyte-sensitive organic fluorophores can be hampered by spectral overlap of the different fluorophores. The authors discuss how nanoparticles can help to overcome this problem. First, different organic fluorophores can be separated spatially by confining them to separate containers, each bearing a nanoparticle-based barcode. Second, by coupling different fluorophores to nanoparticles with different fluorescence lifetimes that serve as donors for excitation transfer, the effective fluorescence lifetime of the organic fluorophores as acceptors can be tuned by fluorescence resonance energy transfer (FRET). Thus, the fluorophores can be distinguished by their effective lifetimes. This is an example of how the modification of classical functional materials has already yielded improved and even new functionalities by the integration of nanoparticles with hybrid materials. We outline future opportunities in this area. PMID- 21261308 TI - The phases in a non-ionic surfactant (C12E6)-water ternary system: a coarse grained computer simulation. AB - A dissipative particle dynamics computer simulation is used to investigate the ability of small oil molecules (hexane, dodecane, and octadecane) to control phase structures in nonionic surfactant-water systems. The model is successfully tested against the experimental results for binary and ternary systems where the third components are "swelling" and "penetrating" oils. The experimentally observed phases present in such systems were successfully modeled. In addition, the simulations show the locations of the oil molecules within the bilayer and the surfactant chain conformation. While the simulations confirm much of what is expected from experiment and theoretical models, evidence is found for the terminal methyl end of the surfactant molecules being located slightly closer to the interfacial region than other groups in the same chain. PMID- 21261309 TI - Electronic quantum fluxes during pericyclic reactions exemplified for the Cope rearrangement of semibullvalene. AB - The outcome of a pericyclic reaction is typically represented by arrows in the Lewis structure of the reactant, symbolizing the net electron transfer. Quantum simulations can be used to interpret these arrows in terms of electronic fluxes between neighboring bonds. The fluxes are decomposed into contributions from electrons in so-called pericyclic orbitals, which account for the mutation of the Lewis structure for the reactant into that for the product, in other valence and in core orbitals. Series of time-integrated fluxes of pericyclic electrons can be assigned to the arrows, for example 0.09-0.23 electrons for Cope rearrangement of semibullvalene, with hysteresis-type time evolutions for 27.3 fs. This means asynchronous electronic fluxes during synchronous rearrangement of all the nuclei. These predictions should become observable by emerging techniques of femto- to attosecond time-resolved spectroscopy. PMID- 21261311 TI - Aggregation of capped hexaglycine strands into hydrogen-bonding motifs representative of pleated and rippled beta-sheets, collagen, and polyglycine I and II crystal structures. A density functional theory study. AB - We compare the energies and enthalpies of inter-action of three- and seven stranded capped polyglycine aggregates in both the pleated and rippled antiparallel and parallel beta-sheet structures as well as the collagenic (three strand) or polyglycine II-like (seven-strand) forms using density functional theory at the B3LYP/D95(d,p) level. We present the overall interaction energies as broken down into pure H-bonding between the strands at the geometries they assume in the aggregates and the distortion energies required to achieve those geometries starting from the fully relaxed single strands. While the antiparallel sheets represent the most stable structures for both the three- and seven-strand structures, the pure H-bonding interactions are the smallest for these structures. The overall interaction energies are dominated by the energy required to distort the relaxed polyglycine strands rather than the H-bonding energies. The antiparallel beta-sheet constrained to C(s) symmetry has a lower enthalpy, but higher energy, of interaction than the fully optimized structure. PMID- 21261312 TI - Spectroscopic study of maghemite nanoparticles surface-grafted with DMSA. AB - Nanosized maghemite (below 10 nm average diameter), surface-functionalized with meso-2,3-dimercaptosuccinic acid (DMSA), was investigated with respect to the content of DMSA molecules attached onto its surface and the onset of S-S bridges due to oxidation of neighboring S-H groups. To support our investigation, we introduced the use of photoacoustic spectroscopy to monitor thiol groups (S-H) conjugated with Raman spectroscopy to monitor the disulfide bridges (S-S). The normalized intensity (N(R)) of the Raman feature peaking at 500 cm(-1) was used to probe the S-S bridge whereas the normalized intensity (N(P)) of the photoacoustic band-S (0.42-0.65 MUm) was used to probe the S-H moiety. The perfect linearity observed in the N(R) versus (1 - N(P)) plot strongly supports the oxidation process involving neighboring S-H groups as the DMSA surface grafting coefficient increases whereas the approach used in this report allows the evaluation of the [S-H]/[S-S] ratio. The observation of the reduction of the hydrodynamic diameter as the nominal DMSA-grafting increases supports the proposed model picture, in which the intraparticle (interparticle) S-S bridging takes place at higher (lower) DMSA-grafting values. PMID- 21261310 TI - Understanding the specificity of a docking interaction between JNK1 and the scaffolding protein JIP1. AB - The up-regulation of JNK activity is associated with a number of disease states. The JNK-JIP1 interaction represents an attractive target for the inhibition of JNK-mediated signaling. In this study, molecular dynamics simulations have been performed on the apo-JNK1 and the JNK1*L-pepJIP1 and JNK1*D-pepJIP1 complexes to investigate the interaction between the JIP1 peptides and JNK1. Dynamic domain studies based on essential dynamics (ED) analysis of apo-JNK1 and the JNK1*L pepJIP1 complex have been performed to analyze and compare details of conformational changes, hinge axes, and hinge bending regions in both structures. The activation loop, the alphaC helix, and the G loop are found to be highly flexible and to exhibit significant changes in dynamics upon L-pepJIP1 binding. The conformation of the activation loop for the apo state is similar to that of inactive apo-ERK2, while the activation loop in JNK1*L-pepJIP1 complex resembles that of the inactive ERK2 bound with pepHePTP. ED analysis shows that, after the binding of l-pepJIP1, the N- and C-terminal domains of JNK1 display both a closure and a twisting motion centered around the activation loop, which functions as a hinge. In contrast, no domain motion is detected for the apo state for which an open conformation is favored. The present study suggests that L pepJIP1 regulates the interdomain motions of JNK1 and potentially the active site via an allosteric mechanism. The binding free energies of L-pepJIP1 and D-pepJIP1 to JNK1 are estimated using the molecular mechanics Poisson-Boltzmann and generalized-Born surface area (MM-PB/GBSA) methods. The contribution of each residue at the interaction interface to the binding affinity of L-pepJIP1 with JNK1 has been analyzed by means of computational alanine-scanning mutagenesis and free energy decomposition. Several critical interactions for binding (e.g., Arg156/L-pepJIP1 and Glu329/JNK1) have been identified. The binding free energy calculation indicates that the electrostatic interaction contributes critically to specificity, rather than to binding affinity between the peptide and JNK1. Notably, the binding free energy calculations predict that D-pepJIP1 binding to JNK1 is significantly weaker than the L form, contradicting the previous suggestion that D-pepJIP1 acts as an inhibitor toward JNK1. We have performed experiments using purified JNK1 to confirm that, indeed, D-pepJIP1 does not inhibit the ability of JNK1 to phosphorylate c-Jun in vitro. PMID- 21261313 TI - Effect of shear rates on the MLV formation and MLV stability region in the C12E5/D2O system: rheology and rheo-NMR and rheo-SANS experiments. AB - At high temperatures, pentaethylene glycol monododecyl ether (C12E5) in D2O forms a swollen lamellar phase. This letter reports the shear-induced multilamellar vesicle (MLV) formation in a sample that contains 40 wt % C12E5 dissolved in D2O at 55 degrees C. This transition has been investigated by time-resolved rheo nuclear magnetic resonance, rheo small-angle neutron scattering, and rheometry. The typical transient viscosity behavior of MLV formation has been discovered at 1 s(-1). For the first time, it has been found that MLVs are not stable over time when subjected to high shear rates. Our results show that the MLV stability is confined in a narrow region in the range 1-10 s(-1) shear rates. This is not observed for other CnEm surfactants. PMID- 21261315 TI - Ab initio and RRKM study of the HCN/HNC elimination channels from vinyl cyanide. AB - Ab initio CCSD and CCSD(T) calculations with the 6-311+G(2d,2p) and the 6 311++G(3df,3pd) basis sets were carried out to characterize the vinyl cyanide (C(3)H(3)N) dissociation channels leading to hydrogen cyanide (HCN) and its isomer hydrogen isocyanide (HNC). Our computations predict three elimination channels giving rise to HCN and another four channels leading to HNC formation. The relative HCN/HNC branching ratios as a function of internal energy of vinyl cyanide were computed using RRKM theory and the kinetic Monte Carlo method. At low internal energies (120 kcal/mol), the total HCN/HNC ratio is about 14, but at 148 kcal/mol (193 nm) this ratio becomes 1.9, in contrast with the value 124 obtained in a previous ab initio/RRKM study at 193 nm (Derecskei-Kovacs, A.; North, S. W. J. Chem. Phys.1999, 110, 2862). Moreover, our theoretical results predict a ratio of rovibrationally excited acetylene over total acetylene of 3.3, in perfect agreement with very recent experimental measurements (Wilhelm, M. J.; Nikow, M.; Letendre, L.; Dai, H.-L. J. Chem. Phys.2009, 130, 044307). PMID- 21261314 TI - Hydrostatic pressure reveals bilayer phase behavior of dioctadecyldimethylammonium bromide and chloride. AB - Bilayer phase transitions of dioctadecyldimethylammonium bromide (2C(18)Br) and chloride (2C(18)Cl) were observed by differential scanning calorimetry and high pressure light-transmittance measurements. The 2C(18)Br bilayer membrane showed different kinds of transitions depending on preparation methods of samples under atmospheric pressure. Under certain conditions, the 2C(18)Br bilayer underwent three kinds of transitions, the metastable transition from the metastable lamellar crystal (L(c(2))) phase to the metastable lamellar gel (L(beta)) phase at 35.4 degrees C, the metastable main transition from the metastable L(beta) phase to the metastable liquid crystalline (L(alpha)) phase at 44.5 degrees C, and the stable transition from the stable lamellar crystal (L(c(1))) phase to the stable L(alpha) phase at 52.8 degrees C. On the contrary, the 2C(18)Cl bilayer underwent two kinds of transitions, the stable transition from the stable L(c) phase to the stable L(beta) phase at 19.7 degrees C and the stable main transition from the stable L(beta) phase to the stable L(alpha) phase at 39.9 degrees C. The temperatures of the phase transitions of the 2C(18)Br and 2C(18)Cl bilayers were almost linearly elevated by applying pressure. It was found from the temperature (T)-pressure (p) phase diagram of the 2C(18)Br bilayer that the T p curves for the main transition and the L(c(1))/L(alpha) transition intersect at ca. 130 MPa because of the larger slope of the former transition curve. On the other hand, the T-p phase diagram of the 2C(18)Cl bilayer took a simple shape. The thermodynamic properties for the main transition of the 2C(18)Br and 2C(18)Cl bilayers were comparable to each other, whereas those for the L(c(1))/L(alpha) transition of the 2C(18)Br bilayer showed considerably high values, signifying that the L(c(1)) phase of the 2C(18)Br bilayer is extremely stable. These differences observed in both bilayers are attributable to the difference in interaction between a surfactant and its counterion. PMID- 21261316 TI - Intermolecular potential energy surface of the N2-CO dimer: ab initio investigation and analytical representation. AB - In this work, for the first time, an analytical four-dimensional representation for the intermolecular potential of the N(2)-CO dimer is constructed from ab initio calculations. The most stable structure of dimer is found to be a distorted T-shape conformation with CO forming the top and N(2) the leg of T. Important structures of the dimer are characterized, and surprisingly, it is found that in contrast with general assumptions, the potential energy surface of the N(2)-CO dimer has a single symmetry unique minimum. The energy profile of a minimum energy path that connects two T-shaped saddle points to the minimum structure is derived. Important structures are characterized along this path to represent the concerted internal rotation of monomers within the complex. The second virial coefficient is calculated from the fitted PES, and reasonable agreement is found with recent experimental results. PMID- 21261317 TI - Reaction of the i-C4H5 (CH2CCHCH2) radical with O2. AB - The resonantly stabilized radical i-C(4)H(5) (CH(2)CCHCH(2)) is an important intermediate in the combustion of unsaturated hydrocarbons and is thought to be involved in the formation of polycyclic aromatic hydrocarbons through its reaction with acetylene (C(2)H(2)) to form benzene + H. This study uses quantum chemistry and statistical reaction rate theory to investigate the mechanism and kinetics of the i-C(4)H(5) + O(2) reaction as a function of temperature and pressure, and unlike most resonantly stabilized radicals we show that i-C(4)H(5) is consumed relatively rapidly by its reaction with molecular oxygen. O(2) addition occurs at the vinylic and allenic radical sites in i-C(4)H(5), with respective barriers of 0.9 and 4.9 kcal mol(-1). Addition to the allenic radical form produces an allenemethylperoxy radical adduct with only around 20 kcal mol( 1) excess vibrational energy. This adduct can isomerize to the ca. 14 kcal mol( 1) more stable 1,3-divinyl-2-peroxy radical via concerted and stepwise processes, both steps with barriers around 10 kcal mol(-1) below the entrance channel energy. Addition of O(2) to the vinylic radical site in i-C(4)H(5) directly forms the 1,3-divinyl-2-peroxy radical with a small barrier and around 36.8 kcal mol( 1) of excess energy. The 1,3-divinyl-2-peroxy radical isomerizes via ipso addition of the O(2) moiety followed by O atom insertion into the adjacent C-C bond. This process forms an unstable intermediate that ultimately dissociates to give the vinyl radical, formaldehyde, and CO. At higher temperatures formation of vinylacetylene + HO(2), the vinoxyl radical + ketene, and the 1,3-divinyl-2-oxyl radical + O paths have some importance. Because of the adiabatic transition states for O(2) addition, and significant reverse dissociation channels in the peroxy radical adducts, the i-C(4)H(5) + O(2) reaction proceeds to new products with rate constant of around 10(11) cm(3) mol(-1) s(-1) at typical combustion temperatures (1000-2000 K). For fuel-rich flames we show that the reaction of i C(4)H(5) with O(2) is likely to be faster than that with C(2)H(2), bringing into question the importance of the i-C(4)H(5) + C(2)H(2) reaction in initiating ring formation in sooting flames. PMID- 21261318 TI - Barrierless proton transfer within short protonated peptides in the presence of water bridges. A density functional theory study. AB - We have used density functional theory at the B3LYP/6-31++G(d,p) level of theory to investigate proton transfer in protonated N(2)-acetyl-N(1)-methylglycinamide and N-acetylglycyl-N(1)-methylglycinamide with multiwater assistance and to determine the structures and energies of the most important minima and transition states corresponding to the proton-transfer pathways. We propose mechanisms for proton transfer between adjacent and nonadjacent carbonyl oxygen atoms with water bridge assistance. The presence of a two-water bridge connected to the two carbonyl oxygen atoms provides a proton-transfer mechanism having such a low barrier that the excess proton is almost freely mobile. PMID- 21261320 TI - Development and application of a ReaxFF reactive force field for hydrogen combustion. AB - To investigate the reaction kinetics of hydrogen combustion at high-pressure and high-temperature conditions, we constructed a ReaxFF training set to include reaction energies and transition states relevant to hydrogen combustion and optimized the ReaxFF force field parameters against training data obtained from quantum mechanical calculations and experimental values. The optimized ReaxFF potential functions were used to run NVT MD (i.e., molecular dynamics simulation with fixed number of atoms, volume, and temperature) simulations for various H(2)/O(2) mixtures. We observed that the hydroperoxyl (HO(2)) radical plays a key role in the reaction kinetics at our input conditions (T >= 3000 K, P > 400 atm). The reaction mechanism observed is in good agreement with predictions of existing continuum-scale kinetic models for hydrogen combustion, and a transition of reaction mechanism is observed as we move from high pressure, low temperature to low pressure, high temperature. Since ReaxFF derives its parameters from quantum mechanical data and can simulate reaction pathways without any preconditioning, we believe that atomistic simulations through ReaxFF could be a useful tool in enhancing existing continuum-scale kinetic models for prediction of hydrogen combustion kinetics at high-pressure and high-temperature conditions, which otherwise is difficult to attain through experiments. PMID- 21261321 TI - Communication: A concerted mechanism between proton transfer of Zundel anion and displacement of counter cation. AB - Ab initio path integral molecular dynamics simulation of M(+)(H(3)O(2)(-)) (M = Li, Na, and K) has been carried out to analyze how the structure and dynamics of a low-barrier hydrogen-bonded Zundel anion, H(3)O(2)(-), can be affected by the counter alkali metal cation, M(+). Our simulation predicts that the quantum proton transfer in Zundel anion can be strongly coupled to the motion of counter cation located nearby. A smaller cation can induce larger structural distortion of the Zundel anion fragment making the proton transfer barrier higher, and hence, lower the vibrational excitation energy. It is also argued that a large H/D isotope effect is present. PMID- 21261322 TI - Communication: The permanent electric dipole moment of thorium monoxide, ThO. AB - The optical Stark spectrum of the E(0(+)) - X(1)Sigma(+) (1,0) band of thorium monoxide, ThO, was recorded and analyzed to determine the permanent electric dipole moments, MU, for the E(0(+)) (v = 1) and X(1)Sigma(+) (v = 0) states. Values of 2.782 +/- 0.012 D (X) and 3.534 +/- 0.010 D (E) were obtained. The uncertainties are 2sigma statistical error. The systematic errors are estimated to be less than 1%. The experimental results are used to access the quality of electronic structure calculations of the properties of the X(1)Sigma(+) (v = 0) state. PMID- 21261323 TI - Communication: Delayed asymmetric Coulomb fission of molecular clusters: application of a dielectric liquid-drop model. AB - Delayed asymmetric Coulomb fission in size-selected molecular dication clusters has been recorded for the first time. Observations on (NH(3))(n)(2+) clusters show that fragmentation accompanied by charge separation can occur on a microsecond time scale, exhibits considerable asymmetry, and involves a kinetic energy release of ~0.9 eV. The fission process has been modeled by representing the fragments as charged dielectric spheres and the calculated maximum in the electrostatic interaction energy between the fragments gives a good account of the measured kinetic energy release. A simple kinetic model shows that instrumental factors may contribute to the observation of asymmetric fragmentation. PMID- 21261324 TI - Multireference composite approaches for the accurate study of ground and excited electronic states: C2, N2, and O2. AB - A multireference analog of the correlation consistent composite approach (MR ccCA) based on complete active space with second-order perturbation theory (CASPT2) has been utilized in an investigation of the ground and valence excited states of C(2), N(2), and O(2). The performance of different second-order multireference perturbation theory methods including second-order n-electron valence state perturbation theory, second-order multireference Moller-Plesset, and second-order generalized van Vleck perturbation theory has been analyzed as potential alternatives to CASPT2 within MR-ccCA. The MR-ccCA-P predicts spectroscopic constants with overall mean absolute deviations from experimental values of 0.0006 A, 7.0 cm(-1), and 143 cm(-1) for equilibrium bond length (r(e)), harmonic frequency (omega(e)), and term values (T(e)), respectively, which are comparable to the predictions by more computationally costly multireference configuration interaction-based methods. PMID- 21261325 TI - Numerical analysis of relaxation times of multiple quantum coherences in the system with a large number of spins. AB - We study the decay of multiple quantum (MQ) NMR coherences in systems with the large number of equivalent spins. As being created on the preparation period of the MQ NMR experiment, they decay due to the dipole-dipole interactions (DDI) on the evolution period of this experiment. It is shown that the relaxation time decreases with the increase in MQ coherence order (according to the known results) and in the number of spins. We also consider the modified preparation period of the MQ NMR experiment [G. A. Alvarez and D. Suter, Phys. Rev. Lett. 104, 230403 (2010)] concatenating the short evolution periods under the secular DDI Hamiltonian (the perturbation) with the evolution period under the nonsecular averaged two-spin/two-quantum Hamiltonian. The influence of the perturbation on the decoherence rate is investigated for the systems consisting of 200-600 equivalent spins. PMID- 21261326 TI - Free energy gap laws for the pulse-induced and stationary fluorescence quenching by reversible charge transfer in polar solutions. AB - The Stern-Volmer constants for either pulse-induced or stationary fluorescence being quenched by a contact charge transfer are calculated and their free energy dependencies (the free energy gap laws) are specified. The reversibility of charge transfer is taken into account as well as spin conversion in radical ion pairs, followed by their recombination in either singlet or triplet neutral products. The natural decay of triplets as well as their impurity quenching by ionization are accounted for when estimating the fluorescence quantum yield and its free energy dependence. PMID- 21261327 TI - Towards an understanding of many-particle effects in hydrophobic association in methane solutions. AB - This paper applies the multiscale coarse-graining method [S. Izvekov and G. A. Voth, J. Phys. Chem. B 109, 2469 (2005); J. Chem. Phys. 123, 134105 (2005)] to analyze many-body effects in concentrated methane solutions. Pairwise decompositions of N-particle solute-solute potentials of mean force (PMFs), and the respective solvent cavity potentials, enthalpic, entropic, and heat capacity of hydrophobic association, are calculated directly from unconstrained molecular dynamics simulations of methane solutions at different molar fractions, with the highest being 0.055. The many-body effects in hydrophobic hydration are further studied using N-methane PMFs, which are explicitly dependent on solvent coordinates. PMID- 21261328 TI - Reconsidering an analytical gradient expression within a divide-and-conquer self consistent field approach: exact formula and its approximate treatment. AB - An analytical energy gradient formula for the density-matrix-based linear-scaling divide-and-conquer (DC) self-consistent field (SCF) method was proposed in a previous paper by Yang and Lee (YL) [J. Chem. Phys. 103, 5674 (1995)]. Since the formula by YL does not correspond to the exact gradient of the DC-SCF energy, we derive the exact formula by direct differentiation, which requires solving the coupled-perturbed equations while including the inter-subsystem coupling terms. Next, we present an alternative formula for approximately evaluating the DC-SCF energy gradient, assuming the variational condition for the subsystem density matrices. Numerical assessments confirmed that the DC-SCF energy gradient values obtained by the present formula are in reasonable agreement with the conventional SCF values when adopting a reliable buffer region. Furthermore, the performance of the present method was found to be better than that of the YL method. PMID- 21261329 TI - Charge-transfer separability and size-extensivity in the equation-of-motion coupled cluster method: EOM-CCx. AB - We study the charge-transfer separability (CTS) property of the Fock space (FS) and equation-of-motion (EOM) coupled cluster (CC) methods by analysing the charge transfer (CT) excitation energy versus the donor-acceptor (D-A) distance. All FS CC approaches fulfill the CT separability condition which is not the case for the standard EOM-CC approaches. This defect of the EOM-CC scheme can be fixed by slight modification of the H matrix's diagrammatic structure, namely by adding some "dressing" composed of disconnected terms. The latter guarantee CTS of the respective EOM-CC scheme and marginally improve local excitations. The newly proposed variant of the EOM-CCSD approach is termed EOM-CCSDx (size-extensive EOM CCSD). PMID- 21261330 TI - Strong spin-orbit effects in small Pt clusters: geometric structure, magnetic isomers and anisotropy. AB - Ab initio density functional calculations including spin-orbit coupling (SOC) have been performed for Pt(n), n = 2-6 clusters. The strong SOC tends to stabilize planar structures for n = 2-5, whereas for clusters consisting of six atoms, three-dimensional structures remain preferred. SOC leads to the formation of large orbital magnetic moments and to a mixing of different spin states. Due to the spin-mixing the total magnetic moment may be larger or smaller than the spin moment in the absence of SOC. Both spin and orbital moments are found to be anisotropic. Because of the strong SOC the energy differences between coexisting magnetic isomers can be comparable to or even smaller than their magnetic anisotropy energies. In this case the lowest barrier for magnetization reversal can be determined by a magnetic isomer which is different from the ground state configuration. PMID- 21261331 TI - The role of range-separated Hartree-Fock exchange in the calculation of magnetic exchange couplings in transition metal complexes. AB - We assess the dependence of magnetic exchange couplings on the variation of Hartree-Fock exchange (HFX) admixture in global hybrid functionals and the range separation parameter omega in range-separated hybrid functionals in a set of 12 spin-1/2 binuclear transition metal complexes. The global hybrid PBEh (hybrid Perdew-Burke-Ernzerhof) and range-separated hybrids HSE (Heyd-Scuseria-Ernzerhof) and LC-omegaPBE (long-range corrected hybrid PBE) are employed for this assessment, and exchange couplings are calculated from energy differences within the framework of the spin-projected approach. It is found that these functionals perform optimally for magnetic exchange couplings with 35% HFX admixture for PBEh, omega = 0.50 a.u.(-1) for LC-omegaPBE, and omega at or near 0.0 a.u.(-1) for HSE (which corresponds to PBEh). We find that in their standard respective forms, LC-omegaPBE slightly outperforms PBEh, while PBEh with 35% HFX yields exchange couplings closer to experiment than those of LC-omegaPBE with omega = 0.50 a.u.(-1). Additionally, we show that the profile of exchange couplings with respect to omega in HSE is appreciably flat from 0 to 0.2 a.u.(-1). This combined with the fact that HSE is computationally more tractable than global hybrids makes HSE an attractive alternative for the evaluation of exchange couplings in extended systems. These results are rationalized with respect to how varying the parameters within these functionals affects the delocalization of the magnetic orbitals, and conclusions are made regarding the relative importance of range separation versus global mixing of HFX for the calculation of exchange couplings. PMID- 21261332 TI - Finite temperature application of the corrected propagator method to reactive dynamics in a condensed-phase environment. AB - The recently proposed mixed quantum-classical method is extended to applications at finite temperatures. The method is designed to treat complex systems consisting of a low-dimensional quantum part (the primary system) coupled to a dissipative bath described classically. The method is based on a formalism showing how to systematically correct the approximate zeroth-order evolution rule. The corrections are defined in terms of the total quantum Hamiltonian and are taken to the classical limit by introducing the frozen Gaussian approximation for the bath degrees of freedom. The evolution of the primary system is governed by the corrected propagator yielding the exact quantum dynamics. The method has been tested on a standard model system describing proton transfer in a condensed phase environment: a symmetric double-well potential bilinearly coupled to a bath of harmonic oscillators. Flux correlation functions and thermal rate constants have been calculated at two different temperatures for a range of coupling strengths. The results have been compared to the fully quantum simulations of Topaler and Makri [J. Chem. Phys. 101, 7500 (1994)] with the real path integral method. PMID- 21261333 TI - A combined effective fragment potential-fragment molecular orbital method. II. Analytic gradient and application to the geometry optimization of solvated tetraglycine and chignolin. AB - The gradient for the fragment molecular orbital (FMO) method interfaced with effective fragment potentials (EFP), denoted by FMO/EFP, was developed and applied to polypeptides solvated in water. The structures of neutral and zwitterionic tetraglycine immersed in water layers of 2.0, 2.5, 3.0, 3.5, 4.0, and 4.5 A are investigated by performing FMO/EFP geometry optimizations at the RHF/cc-pVDZ level of theory for the solutes. The geometries optimized with FMO RHF/EFP are compared to those from the conventional RHF/EFP and are found to be in very close agreement. Using the optimized geometries, the stability of the hydrated zwitterionic and neutral structures is discussed structurally and in terms of energetics at the second-order Moller-Plesset theory (MP2)/cc-pVDZ level. To demonstrate the potential of the method for proteins, the geometry of hydrated chignolin (protein data bank ID: 1UAO) was optimized, and the importance of the inclusion of water was examined by comparing the solvated and gas phase structures of chignolin with the experimental NMR structure. PMID- 21261334 TI - Strongly correlated mechanisms of a photoexcited radical reaction from the anti Hermitian contracted Schrodinger equation. AB - Photoexcited radical reactions are critical to processes in both nature and materials, and yet they can be challenging for electronic structure methods due to the presence of strong electron correlation. Reduced-density-matrix (RDM) methods, based on solving the anti-Hermitian contracted Schrodinger equation (ACSE) for the two-electron RDM (2-RDM), are examined for studying the strongly correlated mechanisms of these reactions with application to the electrocyclic interconversion of allyl and cyclopropyl radicals. We combine recent extensions of the ACSE to excited states [G. Gidofalvi and D. A. Mazziotti, Phys. Rev. A 80, 022507 (2009)] and arbitrary spin states [A. E. Rothman, J. J. Foley IV, and D. A. Mazziotti, Phys. Rev. A 80, 052508 (2009)]. The ACSE predicts that the ground state ring closure of the allyl radical has a high 52.5 kcal/mol activation energy that is consistent with experimental data, while the closure of an excited allyl radical can occur by disrotatory and conrotatory pathways whose transition states are essentially barrierless. Comparisons are made with multireference second- and third-order perturbation theories and multireference configuration interaction. While predicted energy differences do not vary greatly between methods, the ACSE appears to improve these differences when they involve a strongly and a weakly correlated radical by capturing a greater share of single reference correlation that increases the stability of the weakly correlated radicals. For example, the ACSE predicts a -39.6 kcal/mol conversion of the excited allyl radical to the ground-state cyclopropyl radical in comparison to the -32.6 to -37.3 kcal/mol conversions predicted by multireference methods. In addition, the ACSE reduces the computational scaling with the number of strongly correlated orbitals from exponential (traditional multireference methods) to quadratic. Computed ground- and excited-state 2-RDMs are nearly N-representable. PMID- 21261335 TI - A new Lanczos-based algorithm for simulating high-frequency two-dimensional electron spin resonance spectra. AB - The Lanczos algorithm (LA) is a useful iterative method for the reduction of a large matrix to tridiagonal form. It is a storage efficient procedure requiring only the preceding two Lanczos vectors to compute the next. The quasi-minimal residual (QMR) method is a powerful method for the solution of linear equation systems, Ax = b. In this report we provide another application of the QMR method: we incorporate QMR into the LA to monitor the convergence of the Lanczos projections in the reduction of large sparse matrices. We demonstrate that the combined approach of the LA and QMR can be utilized efficiently for the orthogonal transformation of large, but sparse, complex, symmetric matrices, such as are encountered in the simulation of slow-motional 1D- and 2D-electron spin resonance (ESR) spectra. Especially in the 2D-ESR simulations, it is essential that we store all of the Lanczos vectors obtained in the course of the LA recursions and maintain their orthogonality. In the LA-QMR application, the QMR weight matrix mitigates the problem that the Lanczos vectors lose orthogonality after many LA projections. This enables substantially more Lanczos projections, as required to achieve convergence for the more challenging ESR simulations. It, therefore, provides better accuracy for the eigenvectors and the eigenvalues of the large sparse matrices originating in 2D-ESR simulations than does the previously employed method, which is a combined approach of the LA and the conjugate-gradient (CG) methods, as evidenced by the quality and convergence of the 2D-ESR simulations. Our results show that very slow-motional 2D-ESR spectra at W-band (95 GHz) can be reliably simulated using the LA-QMR method, whereas the LA-CG consistently fails. The improvements due to the LA-QMR are of critical importance in enabling the simulation of high-frequency 2D-ESR spectra, which are characterized by their very high resolution to molecular orientation. PMID- 21261336 TI - Explicitly correlated multireference configuration interaction: MRCI-F12. AB - An internally contracted multireference configuration interaction is developed which employs wave functions that explicitly depend on the electron-electron distance (MRCI-F12). This MRCI-F12 method has the same applicability as the MRCI method, while having much improved basis-set convergence with little extra computational cost. The F12b approximation is used to arrive at a computationally efficient implementation. The MRCI-F12 method is applied to the singlet-triplet separation of methylene, the dissociation energy of ozone, properties of diatomic molecules, and the reaction barrier and exothermicity of the F + H(2) reaction. These examples demonstrate that already with basis sets of moderate size the method provides near complete basis set MRCI accuracy, and hence quantitative agreement with the experimental data. As a side product, we have also implemented the explicitly correlated multireference averaged coupled pair functional method (MRACPF-F12). PMID- 21261337 TI - Strong correlation treated via effective hamiltonians and perturbation theory. AB - We propose a new approach to determine a suitable zeroth-order wavefunction for multiconfigurational perturbation theory. The same ansatz as in complete active space (CAS) wavefunction optimization is used but it is split in two parts, a principal space (A) and a much larger extended space (B). Lowdin's partitioning technique is employed to map the initial eigenvalue problem to a dimensionality equal to that of (A) only. Combined with a simplified expression for the (B) portion of the wavefunction, we are able to drastically reduce the storage and computational demands of the wavefunction optimization. This scheme is used to produce reference wavefunctions and energies for subsequent second-order perturbation theory (PT2) corrections. Releasing the constraint of computing the exact CAS energy and wavefunction prior to the PT2 treatment introduces a nonstandard paradigm for multiconfigurational methods. Based on the results of test calculations, we argue that principal parts with only few percents of the total number of CAS configurations could provide final multiconfigurational PT2 energies of the same accuracy as in the standard paradigm. In the future, algorithmic improvements for this scheme will bring into reach active spaces much beyond the present limit of CAS-based methods, therefore allowing for accurate studies of systems featuring strong correlation. PMID- 21261338 TI - Double excitations in correlated systems: a many-body approach. AB - A coherent approach to the description of double excitations in correlated materials is presented: We derive stringent mathematical conditions on the algebraical structure of the Bethe-Salpeter and time-dependent density functional theory kernels that avoid the occurrence of spurious and nonphysical excitations. We discuss how these conditions need to be respected at any level of approximation, including the commonly used local density and static screening approximations. We propose a correlated kernel for the Bethe-Salpeter equation, and we illustrate several aspects of our approach with numerical calculations for model molecular systems. PMID- 21261339 TI - Configurational temperature and local properties of the anisotropic Gay-Berne liquid crystal model: applications to the isotropic liquid/vapor interface and isotropic/nematic transition. AB - Molecular simulations in the isothermal statistical ensembles require that the macroscopic thermal and mechanical equilibriums are respected and that the local values of these properties are constant at every point in the system. The thermal equilibrium in Monte Carlo simulations can be checked through the calculation of the configurational temperature, k(B)T(conf)=<|?(r)U(r(N))|(2)>/, where ?(r) is the nabla operator of position vector r. As far as we know, T(conf) was never calculated with the anisotropic Gay-Berne potential, whereas the calculation of T(conf) is much more widespread with more common potentials (Lennard Jones, electrostatic, ...). We establish here an operational expression of the macroscopic and local configurational temperatures, and we investigate locally the isotropic liquid phase, the liquid / vapor interface, and the isotropic-nematic transition by Monte Carlo simulations. PMID- 21261340 TI - Density-dependent analysis of nonequilibrium paths improves free energy estimates II. A Feynman-Kac formalism. AB - The nonequilibrium fluctuation theorems have paved the way for estimating equilibrium thermodynamic properties, such as free energy differences, using trajectories from driven nonequilibrium processes. While many statistical estimators may be derived from these identities, some are more efficient than others. It has recently been suggested that trajectories sampled using a particular time-dependent protocol for perturbing the Hamiltonian may be analyzed with another one. Choosing an analysis protocol based on the nonequilibrium density was empirically demonstrated to reduce the variance and bias of free energy estimates. Here, we present an alternate mathematical formalism for protocol postprocessing based on the Feynmac-Kac theorem. The estimator that results from this formalism is demonstrated on a few low-dimensional model systems. It is found to have reduced bias compared to both the standard form of Jarzynski's equality and the previous protocol postprocessing formalism. PMID- 21261341 TI - A variational principle in Wigner phase-space with applications to statistical mechanics. AB - We consider the Dirac-Frenkel variational principle in Wigner phase-space and apply it to the Wigner-Liouville equation for both imaginary and real time dynamical problems. The variational principle allows us to deduce the optimal time-evolution of the parameter-dependent Wigner distribution. It is shown that the variational principle can be formulated alternatively as a "principle of least action." Several low-dimensional problems are considered. In imaginary time, high-temperature classical distributions are "cooled" to arrive at low temperature quantum Wigner distributions whereas in real time, the coherent dynamics of a particle in a double well is considered. Especially appealing is the relative ease at which Feynman's path integral centroid variable can be incorporated as a variational parameter. This is done by splitting the high temperature Boltzmann distribution into exact local centroid constrained distributions, which are thereafter cooled using the variational principle. The local distributions are sampled by Metropolis Monte Carlo by performing a random walk in the centroid variable. The combination of a Monte Carlo and a variational procedure enables the study of quantum effects in low-temperature many-body systems, via a method that can be systematically improved. PMID- 21261342 TI - Quasiclassical trajectory calculations for Li(2(2)P(J)) + H2 -> LiH(X(1)Sigma+) + H: influence by vibrational excitation and translational energy. AB - Ab initio potential energy surfaces and the corresponding analytical energy functions of the ground 1A' and excited 2A' states for the Li(2(2)P) plus H(2) reaction are constructed. Quasiclassical trajectory calculations on the fitted energy functions are performed to characterize the reactions of Li(2(2)P) with H(2)(v = 0, j = 1) and H(2)(v = 1, j = 1) as well as the reaction when the vibrational energy is replaced by collision energy. For simplicity, the transition probability is assumed to be unity when the trajectories go through the crossing seam region and change to the lower surface. The calculated rotational distributions of LiH(v = 0) for both H(2)(v = 0, j = 1) and H(2)(v = 1, j = 1) reactions are single-peaked with the maximum population at j' = 7, consistent with the previous observation. The vibrational excitation of H(2)(v = 1) may enhance the reaction cross section of LiH(v' = 0) by about 200 times, as compared to a result of 93-107 reported in the experimental measurements. In contrast, the enhancement is 3.1, if the same amount of energy is deposited in the translational states. This endothermic reaction can be considered as an analog of late barrier. According to the trajectory analysis, the vibrational excitation enlarges the H-H distance in the entrance channel to facilitate the reaction, but the excess energy may not open up additional reaction configuration. PMID- 21261343 TI - Efficient exact-exchange time-dependent density-functional theory methods and their relation to time-dependent Hartree-Fock. AB - A recently introduced time-dependent exact-exchange (TDEXX) method, i.e., a response method based on time-dependent density-functional theory that treats the frequency-dependent exchange kernel exactly, is reformulated. In the reformulated version of the TDEXX method electronic excitation energies can be calculated by solving a linear generalized eigenvalue problem while in the original version of the TDEXX method a laborious frequency iteration is required in the calculation of each excitation energy. The lowest eigenvalues of the new TDEXX eigenvalue equation corresponding to the lowest excitation energies can be efficiently obtained by, e.g., a version of the Davidson algorithm appropriate for generalized eigenvalue problems. Alternatively, with the help of a series expansion of the new TDEXX eigenvalue equation, standard eigensolvers for large regular eigenvalue problems, e.g., the standard Davidson algorithm, can be used to efficiently calculate the lowest excitation energies. With the help of the series expansion as well, the relation between the TDEXX method and time dependent Hartree-Fock is analyzed. Several ways to take into account correlation in addition to the exact treatment of exchange in the TDEXX method are discussed, e.g., a scaling of the Kohn-Sham eigenvalues, the inclusion of (semi)local approximate correlation potentials, or hybrids of the exact-exchange kernel with kernels within the adiabatic local density approximation. The lowest lying excitations of the molecules ethylene, acetaldehyde, and pyridine are considered as examples. PMID- 21261344 TI - Microscopic simulations of supersonic and subsonic exothermic chemical wave fronts and transition to detonation. AB - We perform microscopic simulations using the direct simulation Monte Carlo approach to an exothermic chemical wave front of Fisher-Kolmogorov, Petrovsky, Piskunov-type in a one-dimensional gaseous medium. The results confirm the existence of a transition from a weak detonation or deflagration to a Chapman Jouguet detonation wave, that we already investigated at the macroscopic scale [G. Dumazer et al., Phys. Rev. E 78, 016309 (2008)]. In the domain of weak detonation or deflagration, the discrepancy between the propagation speeds deduced from the simulations and the macroscopic balance equations of hydrodynamics is explained by two microscopic effects, the discretization of the variables, known as cutoff effect, and the departure from local equilibrium. Remarkably, the propagation speed of a Chapman-Jouguet detonation wave is not sensitive to these perturbations of microscopic origin. PMID- 21261345 TI - An incremental correlation approach to excited state energies based on natural transition/localized orbitals. AB - A new incremental approach to the computation of vertical excitation energies is presented. The method works based on the definition of a dominant occupied orbital where the excitation takes place (natural transition orbital) and by localizing the remaining occupied space. The use of a reduced two-body expansion leads to a linear number of terms to be computed. A series of benchmark calculations have been carried out on small to medium sized photoactive systems. The results compare well to the full calculations, with maximum deviations of 0.3 eV, and an average absolute deviation of about 0.08 eV. In addition, a energy decomposition analysis is made on the basis of orbital distances to the chromophore region. First results indicate that orbitals beyond a relatively small radius can be safely neglected, leading to further drastic savings in the calculations. PMID- 21261346 TI - NMR nuclear magnetic shielding anisotropy of linear molecules within the linear response within the elimination of the small component approach. AB - The influence of the spin-Zeeman (SZ) operator in the evaluation of the spin orbit effect on the nuclear magnetic shielding tensor in the context of the linear response within the elimination of the small component approach is critically discussed. It is shown that such term yields no contribution to the isotropic nuclear magnetic shielding constant, but it may be of great importance in the determination of individual tensor components, and particularly of the tensor anisotropy. In particular, an interesting relation between the SZ and orbital Zeeman contributions to the spin-orbit effect for the case of linear molecules is shown to hold. Numerical examples for the BrH, IH, and XeF(2) molecules are presented which show that, provided the SZ term is taken into account, results of the individual shielding tensor components and the tensor anisotropy are in good agreement with those obtained by other theoretical methods, and particularly by the Dirac-Hartree-Fock approach. PMID- 21261347 TI - Explicit correlation and intermolecular interactions: investigating carbon dioxide complexes with the CCSD(T)-F12 method. AB - We have optimized the lowest energy structures and calculated interaction energies for the CO(2)-Ar, CO(2)-N(2), CO(2)-CO, CO(2)-H(2)O, and CO(2)-NH(3) dimers with the recently developed explicitly correlated coupled cluster singles doubles and perturbative triples [CCSD(T)]-F12 methods and the associated VXZ-F12 (where X = D,T,Q) basis sets. For a given cardinal number, we find that results obtained with the CCSD(T)-F12 methods are much closer to the CCSD(T) complete basis set limit than the conventional CCSD(T) results. The relatively modest increase in the computational cost between explicit and conventional CCSD(T) is more than compensated for by the impressive accuracy of the CCSD(T)-F12 method. We recommend use of the CCSD(T)-F12 methods in combination with the VXZ-F12 basis sets for the accurate determination of equilibrium geometries and interaction energies of weakly bound electron donor acceptor complexes. PMID- 21261348 TI - A first principles molecular dynamics study of excess electron and lithium atom solvation in water-ammonia mixed clusters: structural, spectral, and dynamical behaviors of [(H2O)5NH3]- and Li(H2O)5NH3 at finite temperature. AB - First principles molecular dynamics simulations are carried out to investigate the solvation of an excess electron and a lithium atom in mixed water-ammonia cluster (H(2)O)(5)NH(3) at a finite temperature of 150 K. Both [(H(2)O)(5)NH(3)]( ) and Li(H(2)O)(5)NH(3) clusters are seen to display substantial hydrogen bond dynamics due to thermal motion leading to many different isomeric structures. Also, the structures of these two clusters are found to be very different from each other and also very different from the corresponding neutral cluster without any excess electron or the metal atom. Spontaneous ionization of Li atom occurs in the case of Li(H(2)O)(5)NH(3). The spatial distribution of the singly occupied molecular orbital shows where and how the excess (or free) electron is primarily localized in these clusters. The populations of single acceptor (A), double acceptor (AA), and free (NIL) type water and ammonia molecules are found to be significantly high. The dangling hydrogens of these type of water or ammonia molecules are found to primarily capture the free electron. It is also found that the free electron binding motifs evolve with time due to thermal fluctuations and the vertical detachment energy of [(H(2)O)(5)NH(3)](-) and vertical ionization energy of Li(H(2)O)(5)NH(3) also change with time along the simulation trajectories. Assignments of the observed peaks in the vibrational power spectra are done and we found a one to one correlation between the time-averaged populations of water and ammonia molecules at different H-bonding sites with the various peaks of power spectra. The frequency-time correlation functions of OH stretch vibrational frequencies of these clusters are also calculated and their decay profiles are analyzed in terms of the dynamics of hydrogen bonded and dangling OH modes. It is found that the hydrogen bond lifetimes in these clusters are almost five to six times longer than that of pure liquid water at room temperature. PMID- 21261349 TI - Rotational spectroscopy and molecular structure of the 1-chloro-1-fluoroethylene acetylene complex. AB - Guided by ab initio calculations, Fourier transform microwave spectra in the 6-21 GHz region are obtained for seven isotopomers of the complex formed between 1 chloro-1-fluoroethylene and acetylene. These include the four possible combinations of (35)Cl- and (37)Cl-containing CH(2)CClF with the most abundant acetylene isotopic modification, HCCH, and its H(13)C(13)CH analogue, as well as three singly substituted deuterated isotopomers. Analysis of the spectra determines the rotational constants and additionally, the complete chlorine quadrupole hyperfine coupling tensors in both the inertial and principal electric field gradient axis systems, and where appropriate, the diagonal components of the deuterium quadrupole coupling tensors. The inertial information contained in the rotational constants provides the structure for CH(2)CClF-HCCH: a primary, hydrogen bonding interaction existing between the HCCH donor and the F atom acceptor on the 1-chloro-1-fluoroethylene moiety, while a secondary interaction occurs between the acetylenic bond on the HCCH molecule and the H atom cis to the hydrogen-bonded F atom on the substituted ethylene, which causes the hydrogen bond to deviate from linearity. This is similar to the structure obtained for 1,1 difluoroethylene-HCCH [H. O. Leung and M. D. Marshall, J. Chem. Phys. 126, 154301 (2006)], and indeed, to within experimental uncertainty, the intermolecular interactions in CH(2)CClF-HCCH and its 1,1-difluoroethylene counterpart are practically indistinguishable, even though ab initio calculations at the MP2/6 311G++(2d, 2p) level suggest that the former complex is more strongly bound. PMID- 21261350 TI - Excitation and dissociation of tungsten hexacarbonyl W(CO)6: statistical and nonstatistical dissociation processes. AB - We have studied the excitation and dissociation processes of the molecule W(CO)(6) in collisions with low kinetic energy (3 keV) protons, monocharged fluorine, and chlorine ions using double charge transfer spectroscopy. By analyzing the kinetic energy loss of the projectile anions, we measured the excitation energy distribution of the produced transient dications W(CO)(6)(2+). By coincidence measurements between the anions and the stable or fragments of W(CO)(6)(2+), we determined the energy distribution for each dissociation channel. Based on the experimental data, the emission of the first CO was tentatively attributed to a nonstatistical direct dissociation process and the emission of the second or more CO ligands was attributed to the statistical dissociation processes. The dissociation energies for the successive breaking of the W-CO bond were estimated using a cascade model. The ratio between charge separation and evaporation (by the loss of CO(+) and CO, respectively) channels was estimated to be 6% in the case of Cl(+) impact. PMID- 21261351 TI - Intermediates of CO oxidation on iron oxides: an experimental and theoretical study. AB - Reactions of laser-ablated iron oxides with CO in excess argon are investigated by infrared adsorption spectroscopy and density functional theoretical calculations. The carbonyl iron oxides OFe(CO)(n) (n = 1-3) and O(2)Fe(CO)(m) (m = 1, 2) are generated during sample deposition or annealing, whereas CO(2) is greatly produced at the expense of these carbonyl iron oxides upon UV irradiation, showing the formation of intermediate carbonyl iron oxides in the oxidation of carbon monoxide to carbon dioxide. These intermediate carbonyl iron oxides are characterized on the basis of isotopic substitution, stepwise annealing, change of CO concentration and laser energy, and comparison with theoretical calculations. The overall agreement between the experimental and calculated vibrational frequencies, relative absorption intensities, and isotopic shifts supports the identification of these complexes from the matrix infrared spectra. The reaction pathways for the formation of the products are proposed based on the experimental and theoretical results presented. PMID- 21261352 TI - Rotational spectra and equilibrium structures of H2SiS and Si2S. AB - The rotational spectra of two small silicon sulfides, silanethione H(2)SiS and the disilicon sulfide ring Si(2)S, have been detected in the centimeter band by Fourier transform microwave spectroscopy of a molecular beam; lines of H(2)SiS were also observed in the millimeter band up to 377 GHz in a glow discharge. Precise rotational and centrifugal distortionconstants have been determined for the normal and a number of the more abundant rare isotopic species of both closed shell molecules. Theoretical equilibrium (r(e)) structures of H(2)SiS and Si(2)S were derived from coupled-cluster calculations that included triple and quadruple excitations, core correlation, and extrapolation to the basis-set limit. The r(e) structures agree to within 5*10(-4) A and 0.1(?) with empirical equilibrium (r(e)(emp)) structures derived from the experimental rotational constants, combined with theoretical vibrational and electronic corrections. Both H(2)SiS and Si(2)S are good candidates for radioastronomical detection in the circumstellar shells of evolved carbon-rich stars such as IRC+10216, because they are fairly polar and are similar in composition to the abundant astronomical molecule SiS. PMID- 21261353 TI - Density functional study of the magnetic properties of Bi4Mn clusters: discrepancy between theory and experiment. AB - We have performed collinear and noncollinear calculations on neutral Bi(4)Mn and collinear ones on ionized Bi(4)Mn with charges +1 and -1 to find out why theoretical calculations will not predict the magnetic state found in the experiment. We have used the density functional theory to find a fit between the theoretical prediction of the magnetic moment and the experimental value. Our calculations have consisted in a structural search of local energy minima, and the lowest energy magnetic state for each resulting isomer. The geometry optimization found three local minima whose fundamental state is the doublet spin state. These isomers could not be found in previous theoretical works, but they are higher in energy than the lowest-lying isomer by ~1.75 eV. This magnetic state could help understand the experiment. Calculations of noncollinear magnetic states for the Bi(4)Mn do not lower the total magnetic moment. We conclude arguing how the three isomers with doublet state could actually be the ones measured in the experiment. PMID- 21261354 TI - Direct observation of the substitution effects on the hydrogen bridge dynamics in selected Schiff bases--a comparative molecular dynamics study. AB - We have studied substituent effects on the properties of the intramolecular hydrogen bond of some ortho-hydroxy Schiff bases using density functional theory (DFT) based first-principle molecular dynamics (FPMD) and path integral molecular dynamics. The studied compounds possess a strong intramolecular hydrogen bond (r((O???N)) <= 2.6 A), which can be tuned by substitution to either (i) enhance the basicity of the acceptor moiety by induction effects or (ii) decrease the hydrogen bond length through steric repulsion. DFT calculations and FPMD were employed to investigate structural and dynamical properties of the selected molecules, while quantum effects on the structural properties were assessed using path integral FPMD. The simulations were performed in vacuo and in the solid state to study the influence of the environment on the hydrogen bond and spectroscopic properties. We give computational support to the suggestion that induction effects are less effective to tune the intramolecular hydrogen bond properties of the discussed ortho-hydroxy Schiff bases than the steric or the environmental effects. PMID- 21261355 TI - Semiclassical dynamics simulations of charge transport in stacked pi-systems. AB - Charge transfer processes within stacked pi-systems were examined for the stacked ethylene dimer radical cation with inclusion of a bridge containing up to three formaldehyde molecules. The electronic structure was treated at the complete active space self-consistent field and multireference configuration interaction levels. Nonadiabatic interactions between electronic and nuclear degrees of freedom were included through semiclassical surface hopping dynamics. The processes were analyzed according to fragment charge differences. Static calculations explored the dependence of the electronic coupling and on-site energies on varying geometric parameters and on the inclusion of a bridge. The dynamics simulations gave the possibility for directly observing complex charge transfer and diabatic trapping events. PMID- 21261356 TI - Electronic structure of the two isomers of the anionic form of p-coumaric acid chromophore. AB - A theoretical study of the electronic structure of the photoactive yellow protein (PYP) model chromophore, para-coumaric acid (p-CA), is presented. Electronically excited states of the phenolate and carboxylate isomers of the deprotonated p-CA are characterized by high-level ab initio methods including state-specific and multistate multireference pertrubation theory (SS-CASPT2, and MS-CASPT2), equation-of-motion coupled-cluster methods with single and double substitutions (EOM-CCSD) and with an approximate account of triple excitations (CC3). We found that the two isomers have distinctly different patterns of ionization and excitation energies. Their excitation energies differ by more than 1 eV, in contradiction to the experimental report [Rocha-Rinza et al., J. Phys. Chem. A 113, 9442 (2009)]. The calculations confirm metastable (autoionizing) character of the valence excited states of both phenolate and carboxylate isomers of p-CA( ) in the gas phase. The type of resonance is different in the two forms. In the phenolate, the excited state lies above the detachment continuum (a shape resonance), whereas in the carboxylate the excited pi->pi(*) state lies below the pi-orbital ionization continuum, but is above the states derived from ionization from three other orbitals (Feshbach resonance). The computed oscillator strength of the bright electronic state in the phenolate is higher than in the carboxylate, in agreement with Huckel's model predictions. The analysis of photofragmentation channels shows that the most probable products for the methylated derivatives of the phenolate and carboxylate forms of p-CA(-) are CH(3), CH(2)O and CH(3), CH(2)O, CO(2), respectively, thus suggesting an experimental probe that may discriminate between the two isomers. PMID- 21261357 TI - Slice imaging of nitric acid photodissociation: The O(1D) + HONO channel. AB - We report an imaging study of nitric acid (HNO(3)) photodissociation near 204 nm with detection of O((1)D), one of the major decomposition products in this region. The images show structure reflecting the vibrational distribution of the HONO coproduct and significant angular anisotropy that varies with recoil speed. The images also show substantial alignment of the O((1)D) orbital, which is analyzed using an approximate treatment that reveals that the polarization is dominated by incoherent, high order contributions. The results offer additional insight into the dynamics of the dissociation of nitric acid through the S(3) (2 (1)A(')) excited state, resolving an inconsistency in previously reported angular distributions, and pointing the way to future studies of the angular momentum polarization. PMID- 21261358 TI - Gaussian charge polarizable interaction potential for carbon dioxide. AB - A number of simple pair interaction potentials of the carbon dioxide molecule are investigated and found to underestimate the magnitude of the second virial coefficient in the temperature interval 220-448 K by up to 20%. Also the third virial coefficient is underestimated by these models. A rigid, polarizable, three site interaction potential reproduces the experimental second and third virial coefficients to within a few percent. It is based on the modified Buckingham exp 6 potential, an anisotropic Axilrod-Teller correction, and Gaussian charge densities on the atomic sites with an inducible dipole at the center of mass. The electric quadrupole moment, polarizability, and bond distances are set to equal experiment. Density of the fluid at 200 and 800 bars pressure is reproduced to within some percent of observation over the temperature range 250-310 K. The dimer structure is in passable agreement with electronically resolved quantum mechanical calculations in the literature, as are those of the monohydrated monomer and dimer complexes using the Gaussian charge polarizable model water potential. Qualitative agreement with experiment is also obtained, when quantum corrections are included, for the relative stability of the trimer conformations, which is not the case for the pair potentials. PMID- 21261359 TI - Reaction of C2H2(+) (n . nu2, m . nu5) with NO2: reaction on the singlet and triplet surfaces. AB - Integral cross sections and product recoil velocity distributions were measured for reaction of C(2)H(2)(+) with NO(2), in which the C(2)H(2)(+) reactant was prepared in its ground state, and with mode-selective excitation in the cis-bend (2nu(5)) and CC stretch (n . nu(2), n = 1, 2). Because both reactants have one unpaired electron, collisions can occur with either singlet or triplet coupling of these unpaired electrons, and the contributions are separated based on distinct recoil dynamics. For singlet coupling, reaction efficiency is near unity, with significant branching to charge transfer (NO(2)(+)), O(-) transfer (NO(+)), and O transfer (C(2)H(2)O(+)) products. For triplet coupling, reaction efficiency varies between 13% and 19%, depending on collision energy. The only significant triplet channel is NO(+) + triplet ketene, generated predominantly by O(-) transfer, with a possible contribution from dissociative charge transfer at high collision energies. NO(2)(+) formation (charge transfer) can only occur on the singlet surface, and appears to be mediated by a weakly bound complex at low energies. O transfer (C(2)H(2)O(+)) also appears to be dominated by reaction on the singlet surface, but is quite inefficient, suggesting a bottleneck limiting coupling to this product from the singlet reaction coordinate. The dominant channel is O(-) transfer, producing NO(+), with roughly equal contributions from reaction on singlet and triplet surfaces. The effects of C(2)H(2)(+) vibration are modest, but mode specific. For all three product channels (i.e., charge, O( ), and O transfer), excitation of the CC stretch fundamental (nu(2)) has little effect, 2 . nu(2) excitation results in ~50% reduction in reactivity, and excitation of the cis-bend overtone (2 . nu(5)) results in ~50% enhancement. The fact that all channels have similar mode dependence suggests that the rate limiting step, where vibrational excitation has its effect, is early on the reaction coordinate, and branching to the individual product channels occurs later. PMID- 21261360 TI - Photodissociation dynamics of hydroxybenzoic acids. AB - Aromatic amino acids have large UV absorption cross-sections and low fluorescence quantum yields. Ultrafast internal conversion, which transforms electronic excitation energy to vibrational energy, was assumed to account for the photostability of amino acids. Recent theoretical and experimental investigations suggested that low fluorescence quantum yields of phenol (chromophore of tyrosine) are due to the dissociation from a repulsive excited state. Radicals generated from dissociation may undergo undesired reactions. It contradicts the observed photostability of amino acids. In this work, we explored the photodissociation dynamics of the tyrosine chromophores, 2-, 3- and 4 hydroxybenzoic acid in a molecular beam at 193 nm using multimass ion imaging techniques. We demonstrated that dissociation from the excited state is effectively quenched for the conformers of hydroxybenzoic acids with intramolecular hydrogen bonding. Ab initio calculations show that the excited state and the ground state potential energy surfaces change significantly for the conformers with intramolecular hydrogen bonding. It shows the importance of intramolecular hydrogen bond in the excited state dynamics and provides an alternative molecular mechanism for the photostability of aromatic amino acids upon irradiation of ultraviolet photons. PMID- 21261361 TI - I2 molecular elimination in single-photon dissociation of CH2I2 at 248 nm by using cavity ring-down absorption spectroscopy. AB - Following single-photon dissociation of CH(2)I(2) at 248 nm, I(2) molecular elimination is detected by using cavity ring-down absorption spectroscopy. The technique comprises two laser beams propagating in a perpendicular configuration, in which a tunable laser beam along the axis of the ring-down cell probes the I(2) fragment in the B (3)Pi(ou)(+) - X (1)Sigma(g)(+) transition. The nascent vibrational populations for v = 0, 1, and 2 levels are obtained with a population ratio of 1:(0.65 +/- 0.10):(0.30 +/- 0.05), corresponding to a Boltzmann-like vibrational temperature of 544 +/- 73 K. The quantum yield of the ground state I(2) elimination reaction is determined to be 0.0040 +/- 0.0025. With the aid of ab initio potential energy calculations, the pathway of molecular elimination is proposed on the energetic ground state CH(2)I(2) via internal conversion, followed by asynchronous three-center dissociation. A positive temperature effect supports the proposed mechanism. PMID- 21261362 TI - Crystal nucleation of colloidal hard dumbbells. AB - Using computer simulations, we investigate the homogeneous crystal nucleation in suspensions of colloidal hard dumbbells. The free energy barriers are determined by Monte Carlo simulations using the umbrella sampling technique. We calculate the nucleation rates for the plastic crystal and the aperiodic crystal phase using the kinetic prefactor as determined from event driven molecular dynamics simulations. We find good agreement with the nucleation rates determined from spontaneous nucleation events observed in event driven molecular dynamics simulations within error bars of one order of magnitude. We study the effect of aspect ratio of the dumbbells on the nucleation of plastic and aperiodic crystal phases, and we also determine the structure of the critical nuclei. Moreover, we find that the nucleation of the aligned close-packed crystal structure is strongly suppressed by a high free energy barrier at low supersaturations and slow dynamics at high supersaturations. PMID- 21261363 TI - Observation of ultrafast Q-band fluorescence in horse heart cytochrome c in reduced and oxidized forms. AB - The dynamics of fluorescence from horse heart cytochrome c is investigated in reduced (ferrous) and oxidized (ferric) forms by a streak camera and an up conversion technique under B-band excitation at 415 nm. In the reduced form, we found the Q-band emission at 550 and 600 nm originated from the S(1) state in a short time range. A very broad continuum observed from 440 to 660 nm had only shown a slow component and was assigned to impurity. In the reduced form, the lifetime of S(1) was determined to be 120 fs by using the up-conversion technique. In the oxidized form, the S(1) lifetime was estimated to be 21 fs. These values are consistent with the values estimated from the quantum yield in order of their magnitude. PMID- 21261364 TI - A study of the relation between translational and rotational diffusion through measurement of molecular recollision. AB - Translational and rotational diffusion rates of perdeuterated tempone (PDT) in ethanol are determined using electron paramagnetic resonance spectroscopy. The translational motion is measured on two scales: the macroscopic, as represented by the Heisenberg spin-exchange rate, and the microscopic, which entails recollisions between the same spin-exchange particle pair. The spin-exchange and recollision rates are used together to calculate the overall translational diffusion coefficient without recourse to assumptions concerning the value of the Stokes radius or collision distance. When observed as a function of solvent isothermal compressibility, the recollision time in ethanol is displaced from the common alkane curve at low temperatures but joins that curve at higher temperatures. Rotational correlation times in ethanol are obtained and show a decreasing rotation-translation coupling with increasing temperature, revealing a pattern that is qualitatively identical with respect to both collision and recollision. In comparison, an examination of PDT diffusion in toluene reveals an increasing rotation-translation coupling with increasing temperature. The contrasting behavior of the coupling in the two solvents is attributable to the degree of anisotropy in PDT rotation. PMID- 21261365 TI - Pure optical dephasing dynamics in semiconducting single-walled carbon nanotubes. AB - We report a detailed study of ultrafast exciton dephasing processes in semiconducting single-walled carbon nanotubes employing a sample highly enriched in a single tube species, the (6,5) tube. Systematic measurements of femtosecond pump-probe, two-pulse photon echo, and three-pulse photon echo peak shift over a broad range of excitation intensities and lattice temperature (from 4.4 to 292 K) enable us to quantify the timescales of pure optical dephasing (T(2)(*)), along with exciton-exciton and exciton-phonon scattering, environmental effects as well as spectral diffusion. While the exciton dephasing time (T(2)) increases from 205 fs at room temperature to 320 fs at 70 K, we found that further decrease of the lattice temperature leads to a shortening of the T(2) times. This complex temperature dependence was found to arise from an enhanced relaxation of exciton population at lattice temperatures below 80 K. By quantitatively accounting the contribution from the population relaxation, the corresponding pure optical dephasing times increase monotonically from 225 fs at room temperature to 508 fs at 4.4 K. We further found that below 180 K, the pure dephasing rate (1/T(2)(*)) scales linearly with temperature with a slope of 6.7 +/- 0.6 MUeV/K, which suggests dephasing arising from one-phonon scattering (i.e., acoustic phonons). In view of the large dynamic disorder of the surrounding environment, the origin of the long room temperature pure dephasing time is proposed to result from reduced strength of exciton-phonon coupling by motional narrowing over nuclear fluctuations. This consideration further suggests the occurrence of remarkable initial exciton delocalization and makes nanotubes ideal to study many-body effects in spatially confined systems. PMID- 21261366 TI - Does transparent nematic phase exist in 5CB/DDAB/water microemulsions? From the viewpoint of temperature dependent dielectric spectroscopy. AB - Liquid crystal colloids have received tremendous attention because of its great potential both in the understanding of the liquid crystalline phase and in searching for new application of liquid crystals. Inverse microemulsion composed of 4-cyano-4-n-pentylbiphenyl (5CB), didodecyl dimethyl ammonium bromide, and water was investigated by means of broadband dielectric spectroscopy in this study. Based on the understanding of previous investigations on the same system, the isotropic phase was taken into account to quantitatively characterize the bulklike relaxations after the isotropic-to-nematic phase transition. Analogous results concerning the phase transition and phase composition to other investigations were obtained. In addition to bulklike relaxations, a new relaxation was observed at the frequency range about two orders lower than bulklike relaxations. This new relaxation shows abnormal temperature dependence, suggesting that superstructures composed of water droplets and confined 5CB molecules exist. This superstructure possibly possesses a confined nanoscaled liquid crystal ordering and may correspond to the notion of the transparent nematic phase. PMID- 21261367 TI - Two features at the two-dimensional freezing transitions. AB - We studied the two-dimensional freezing transitions in monolayers of microgel colloidal spheres with short-ranged repulsions in video-microscopy experiments, and monolayers of hard disks, and Yukawa particles in simulations. These systems share two common features at the freezing points: (1) the bimodal distribution profile of the local orientational order parameter; (2) the two-body excess entropy, s(2), reaches -4.5+/-0.5 k(B). Both features are robust and sensitive to the freezing points, so that they can potentially serve as empirical freezing criteria in two dimensions. Compared with the conventional freezing criteria, the first feature has no finite-size ambiguities and can be resolved adequately with much less statistics; and the second feature can be directly measured in macroscopic experiments without the need for microscopic information. PMID- 21261368 TI - Plasmonic field enhancement of individual nanoparticles by correlated scanning and photoemission electron microscopy. AB - We present results of a combined two-photon photoemission and scanning electron microscopy investigation to determine the electromagnetic enhancement factors of silver-coated spherical nanoparticles deposited on an atomically flat mica substrate. Femtosecond laser excitation of the nanoparticles produces intense photoemission, attributed to near-resonant excitation of localized surface plasmons. Enhancement factors are determined by comparing the respective two photon photoemission yields measured for single nanoparticles and the surrounding flat surface. For p-polarized, 400 nm (~3.1 eV) femtosecond radiation, a distribution of enhancement factors is found with a large percentage (67%) of the nanoparticles falling within a median range. A correlated scanning electron microscopy analysis demonstrated that the nanoparticles typifying the median of the distribution are characterized by spherical shapes and relatively smooth silver film morphologies. In contrast, the largest enhancement factors were produced by a small percentage (7%) of particles that displayed silver coating defects that altered the overall particle structure. Comparisons are made between the experimentally measured enhancement factors and previously reported calculations of the localized near-field enhancement for isolated silver nanoparticles. PMID- 21261369 TI - Structural, electronic, and optical properties of crystalline iodoform under high pressure: a first-principles study. AB - The high pressure phases, electronic structure, and optical properties of iodoform at zero temperature have been investigated by first-principles pseudopotential plane-wave calculations based on the density-functional theory. A new high pressure polar monoclinic structure with space group Cc, denoted as beta phase, has been observed after a series of simulated annealing and geometry optimizations. Our calculated enthalpies showed that the transition from alpha to beta phase occurs at 40.1 GPa. Electronic structure calculated results showed that the insulator-metal transition in alpha phase due to band overlap is found at about 32 GPa. In addition, the calculated absorption spectra of iodoform are consistent with the experimental results. PMID- 21261370 TI - Effect of hydration on the dielectric properties of C-S-H gel. AB - The behavior of water dynamics confined in hydrated calcium silicate hydrate (C-S H) gel has been investigated using broadband dielectric spectroscopy (BDS; 10(-2) 10(6) Hz) in the low-temperature range (110-250 K). Different water contents in C S-H gel were explored (from 6 to 15 wt%) where water remains amorphous for all the studied temperatures. Three relaxation processes were found by BDS (labeled 1 to 3 from the fastest to the slowest), two of them reported here for the first time. We show that a strong change in the dielectric relaxation of C-S-H gel occurs with increasing hydration, especially at a hydration level in which a monolayer of water around the basic units of cement materials is predicted by different structural models. Below this hydration level both processes 2 and 3 have an Arrhenius temperature dependence. However, at higher hydration level, a non-Arrhenius behavior temperature dependence for process 3 over the whole accessible temperature range and, a crossover from low-temperature Arrhenius to high-temperature non-Arrhenius behavior for process 2 are observed. Characteristics of these processes will be discussed in this work. PMID- 21261371 TI - Sedimentation of aggregating colloids. AB - We investigate the combined effects of gravity, attractive interactions, and brownian motion in suspensions of colloidal particles and nonadsorbing polymer. Depending on the effective strength of gravitational forces, resulting from a density mismatch between the colloids and the solvent, and the magnitude and range of the depletion interactions induced by the polymer, sedimentation in these suspensions can result in an equilibrium structure or a kinetically arrested state. We employ large-scale molecular dynamics simulations to systematically classify the different regimes that arise as a function of attraction strength and gravitational stress. Whereas strong attractions lead to cluster aggregation and low-density arrested states, moderate attractions can enhance crystallization of the colloidal particles in the sediment. We make direct comparisons to experimental results to infer general conclusions about the mechanisms leading to mechanically stable sediments. PMID- 21261372 TI - Resolution of strongly competitive product channels with optimal dynamic discrimination: application to flavins. AB - Fundamental molecular selectivity limits are probed by exploiting laser controlled quantum interferences for the creation of distinct spectral signatures in two flavin molecules, erstwhile nearly indistinguishable via steady-state methods. Optimal dynamic discrimination (ODD) uses optimally shaped laser fields to transiently amplify minute molecular variations that would otherwise go unnoticed with linear absorption and fluorescence techniques. ODD is experimentally demonstrated by combining an optimally shaped UV pump pulse with a time-delayed, fluorescence-depleting IR pulse for discrimination amongst riboflavin and flavin mononucleotide in aqueous solution, which are structurally and spectroscopically very similar. Closed-loop, adaptive pulse shaping discovers a set of UV pulses that induce disparate responses from the two flavins and allows for concomitant flavin discrimination of ~16sigma. Additionally, attainment of ODD permits quantitative, analytical detection of the individual constituents in a flavin mixture. The successful implementation of ODD on quantum systems of such high complexity bodes well for the future development of the field and the use of ODD techniques in a variety of demanding practical applications. PMID- 21261373 TI - On melting dynamics and the glass transition. I. Glassy aspects of melting dynamics. AB - The following properties are in the present literature associated with the behavior of supercooled glass-forming liquids: faster than exponential growth of the relaxation time, dynamical heterogeneities, growing point-to-set correlation length, crossover from mean-field behavior to activated dynamics. In this paper we argue that these properties are also present in a much simpler situation, namely the melting of the bulk of an ordered phase beyond a first order phase transition point. This is a promising path toward a better theoretical, numerical and experimental understanding of the above phenomena and of the physics of supercooled liquids. We discuss in detail the analogies and the differences between the glass and the bulk melting transitions. PMID- 21261374 TI - On melting dynamics and the glass transition. II. Glassy dynamics as a melting process. AB - There are deep analogies between the melting dynamics in systems with a first order phase transition and the dynamics from equilibrium in super-cooled liquids. For a class of Ising spin models undergoing a first-order transition--namely p spin models on the so-called Nishimori line--it can be shown that the melting dynamics can be exactly mapped to the equilibrium dynamics. In this mapping the dynamical--or mode-coupling--glass transition corresponds to the spinodal point, while the Kauzmann transition corresponds to the first-order phase transition itself. Both in mean field and finite dimensional models this mapping provides an exact realization of the random first-order theory scenario for the glass transition. The corresponding glassy phenomenology can then be understood in the framework of a standard first-order phase transition. PMID- 21261375 TI - The low frequency dynamics of supercooled LiBr, 6H2O. AB - We present results of a series of experiments performed on LiBr, 6H(2)0 from room temperature down to 172 K ~ 1.2T(g). These ultrasound, Brillouin and depolarized light scattering, and transient grating experiments show that, above 215 K, this solution behaves like supercooled water: its zero frequency sound velocity C(0) continuously decreases with decreasing temperature, and the reorientational dynamics of the water molecules can be directly detected at some temperatures of this domain. Conversely, below 215 K, a new regime sets in, where the apparent C(0) is practically temperature independent and where a beta, Arrenhius like, relaxation process coexists with the usual, Vogel-Fulcher like, alpha relaxation process of the supercooled liquid. These results are similar to those recently obtained in LiCl, 6H(2)O. The onset of the new regime is possibly due to an increase of the interaction of the water molecules with a neighboring Li(+) ion when lowering the temperature. We also compare our results with published dielectric data on water solutions of glass forming polyalcohols. Some of them present a low temperature splitting of their relaxation time similar to what is found in LiBr, 6H(2)O. PMID- 21261376 TI - Entropy change on the cooling and heating paths between liquid and glass and the residual entropy. AB - We analyze the C(p)-T data for the glassy state of eight materials of varied molecular interactions and structures to investigate how the use of the C(p)d ln T integral in the time-dependent (nonreversible) thermodynamic path between a liquid and glass affects our estimates of the entropy. Since the change in entropy on such a path cannot be determined, we estimate the upper and lower values of the change, Deltasigma, from the C(p)d ln T integral. For the same rates of cooling and heating and without annealing, Deltasigma on the cooling path is negligibly different from that on the heating path. The difference is ~1/60th-1/25th of the lowest known value of the residual entropy and even less than the configurational entropy of the supercooled liquid at its kinetic freezing temperature. Thus use of the C(p)d ln T integral in the nonreversible path does not introduce significant errors in estimating the residual entropy. Dynamic C(p) data cannot be used to infer that configurational entropy decreases on glass formation. Time dependence of the C(p)-T path has little consequence for reality of the residual entropy. PMID- 21261377 TI - Solute-solvent intermolecular vibronic coupling as manifested by the molecular near-field effect in resonance hyper-Raman scattering. AB - Vibronic coupling within the excited electronic manifold of the solute all-trans beta-carotene through the vibrational motions of the solvent cyclohexane is shown to manifest as the "molecular near-field effect," in which the solvent hyper Raman bands are subject to marked intensity enhancements under the presence of all-trans-beta-carotene. The resonance hyper-Raman excitation profiles of the enhanced solvent bands exhibit similar peaks to those of the solute bands in the wavenumber region of 21,700-25,000 cm(-1) (10,850-12,500 cm(-1) in the hyper Raman exciting wavenumber), where the solute all-trans-beta-carotene shows a strong absorption assigned to the 1A(g) -> 1B(u) transition. This fact indicates that the solvent hyper-Raman bands gain their intensities through resonances with the electronic states of the solute. The observed excitation profiles are quantitatively analyzed and are successfully accounted for by an extended vibronic theory of resonance hyper-Raman scattering that incorporates the vibronic coupling within the excited electronic manifold of all-trans-beta carotene through the vibrational motions of cyclohexane. It is shown that the major resonance arises from the B-term (vibronic) coupling between the first excited vibrational level (v = 1) of the 1B(u) state and the ground vibrational level (v = 0) of a nearby A(g) state through ungerade vibrational modes of both the solute and the solvent molecules. The inversion symmetry of the solute all trans-beta-carotene is preserved, suggesting the weak perturbative nature of the solute-solvent interaction in the molecular near-field effect. The present study introduces a new concept, "intermolecular vibronic coupling," which may provide an experimentally accessible/theoretically tractable model for understanding weak solute-solvent interactions in liquid. PMID- 21261378 TI - Density matrix based microscopic theory of molecule metal-nanoparticle interactions: linear absorbance and plasmon enhancement of intermolecular excitation energy transfer. AB - A microscopic theory of interacting molecule metal-nanoparticle (MNP) systems is presented and used to compute absorption spectra and the plasmon enhancement of intermolecular excitation energy transfer (EET). The approach is based on a nonperturbative consideration of the Coulomb coupling matrix elements responsible for EET between the molecules and the MNP. In this way, the need to determine the local fields induced by surface plasmon excitations of the MNP is removed, but the whole description is restricted to distances among the interacting species less than the wavelength of absorbed photons. Based on a density matrix theory, the approach accounts for the vibrational level structure of the molecules, intramolecular vibrational energy redistribution (IVR), and plasmon damping. Numerical results for linear absorbance spectra and EET dynamics are offered. In this respect the importance of energy dissipation in the MNP due to rapid surface plasmon decay is emphasized. PMID- 21261379 TI - Dynamic disorder in molecular semiconductors: charge transport in two dimensions. AB - A semiclassical model to study charge transport in molecular semiconductors is extended from one to an arbitrary number of dimensions. The model is applied to the calculation of the charge mobility of the holes in the two dimensional plane of rubrene with the largest charge mobility. The absolute values of the computed mobility tensor, evaluated without adjustable parameters, are in excellent agreement with the experimental results of Podzorov et al. [Phys. Rev. Lett. 95, 226601 (2005)] and have the correct temperature dependence. The localization length and density of states determined by dynamic disorder are analyzed in detail and provide a global description of the charge transport process in agreement with the spectroscopic experiments. The effect of correlation in the modeling of dynamic disorder is also investigated. PMID- 21261380 TI - Determination of the sticking coefficient and scattering dynamics of water on ice using molecular beam techniques. AB - The sticking coefficient for D(2)O impinging on crystalline D(2)O ice was determined for incident translational energies between 0.3 and 0.7 eV and for H(2)O on crystalline H(2)O ice at 0.3 eV. These experiments were done using directed molecular beams, allowing for precise control of the incident angle and energy. Experiments were also performed to measure the intensity and energy of the scattered molecules as a function of scattering angle. These results show that the sticking coefficient was near unity, slightly increasing with decreasing incident energy. However, even at the lowest incident energy, some D(2)O did not stick and was scattered from the ice surface. We observe under these conditions that the sticking probability asymptotically approaches but does not reach unity for water sticking on water ice. We also present evidence that the scattered fraction is consistent with a binary collision; the molecules are scattered promptly. These results are especially relevant for condensation processes occurring under nonequilibrium conditions, such as those found in astrophysical systems. PMID- 21261381 TI - Scattering of hyperthermal argon atoms from clean and D-covered Ru(0001) surfaces. AB - Hyperthermal Ar atoms were scattered from a Ru(0001) surface held at temperatures of 180, 400 and 600 K, and from a Ru(0001)-(1*1)D surface held at 114 and 180 K. The resultant angular intensity and energy distributions are complex. The in plane angular distributions have narrow (FWHM <= 10 degrees ) near-specular peaks and additional off-specular features. The energy distributions show an oscillatory behavior as a function of outgoing angle. In comparison, scattered Ar atoms from a Ag(111) surface exhibit a broad angular intensity distribution and an energy distribution that qualitatively tracks the binary collision model. The features observed for Ru, which are most evident when scattering from the clean surface at 180 K and from the Ru(0001)-(1*1)D surface, are consistent with rainbow scattering. The measured TOF profiles cannot be adequately described with a single shifted Maxwell-Boltzmann distribution. They can be fitted by two components that exhibit complex variations as a function of outgoing angle. This suggests at least two significantly different site and/or trajectory dependent energy loss processes at the surface. The results are interpreted in terms of the stiffness of the surface and highlight the anomalous nature of the apparently simple hcp(0001) ruthenium surface. PMID- 21261382 TI - Electronic excitations induced by hydrogen surface chemical reactions on gold. AB - Associated with chemical reactions at surfaces energy may be dissipated exciting surface electronic degrees of freedom. These excitations are detected using metal insulator-metal (MIM) heterostructures (Ta-TaOx-Au) and the reactions of H with and on a Au surface are probed. A current corresponding to 5*10(-5) electrons per adsorbing H atom and a marked isotope effect are observed under steady-state conditions. Analysis of the current trace when the H atom flux is intermitted suggests that predominantly the recombination reaction creates electronic excitations. Biasing the front versus the back electrode of the MIM structure provides insights into the spectrum of electronic excitations. The observed spectra differ for the two isotopes H and D and are asymmetric when comparing negative and positive bias voltages. Modeling indicates that the excited electrons and the concurrently created holes differ in their energy distributions. PMID- 21261383 TI - A synchrotron-based photoemission study of the MoO3/Co interface. AB - The electronic structures at the MoO(3)/Co interface were investigated using synchrotron-based ultraviolet and x-ray photoelectron spectroscopy. It was found that interfacial chemical reactions lead to the reduction of Mo oxidation states and the formation of Co-O bonds. These interfacial chemical reactions also induce a large interface dipole, which significantly increases the work function of the cobalt substrate. In addition, two interface states located at 1.0 and 2.0 eV below the Fermi level are identified. These two states overlap at film thickness of between 2-4 nm, which suggests the MoO(3) intermediate layer may facilitate ohmic charge transport. PMID- 21261384 TI - Anisotropic optical functions of alpha-1,4,4-tetraphenyl-1,3-butadiene. AB - One of the known monoclinic polymorphs of 1,1,4,4-tetraphenyl-1,3-butadiene was grown by the floating-drop technique. This material is of interest for blue emitting devices and for fundamental studies on intermolecular interactions, excited states and vibronic coupling in the fields of chemical physics and materials science. Polarized UV-visible spectra are reported. The origin of the optical bands is resolved. The results give information on the intermolecular interactions and are compared with theoretical predictions and modeling. The full material dielectric tensor is provided, as deduced from generalized spectroscopic ellipsometry. Details on the use of this technique on strongly anisotropic and absorbing molecular materials are given. Some typical features of the optical spectra are also demonstrated to be very sensitive to the presence of misaligned domains, which, in our samples, are found to be rotated around the normal to the surface and whose amount is determined. The method allows discriminating among monocrystals, in-plane polycrystalline samples, layered samples formed by misaligned successive layers, or samples with both types of disorder. Two independent parameters giving the fraction of misaligned domains or layers are suggested for the characterization and optimization of the growth and deposition of molecular organic materials. PMID- 21261385 TI - Anomalous strong exchange narrowing in excitonic systems. AB - We investigate theoretically the phenomenon of exchange narrowing in the absorption spectrum of a chain of monomers, which are coupled via resonant dipole dipole interaction. The individual (uncoupled) monomers exhibit a broad absorption line shape due to the coupling to an environment consisting of a continuum of vibrational modes. Upon increasing the interaction between the monomers, the absorption spectrum of the chain narrows. For a non-Markovian environment with a Lorentzian spectral density, we find a narrowing of the peak width [full width at half maximum (FWHM)] by a factor 1/N, where N is the number of monomers. This is much stronger than the usual 1/?N narrowing. Furthermore, it turns out that for a Markovian environment no exchange narrowing at all occurs. The relation of different measures of the width (FWHM, standard deviation) is discussed. PMID- 21261386 TI - Non-markovian quantum state diffusion for absorption spectra of molecular aggregates. AB - In many molecular systems one encounters the situation where electronic excitations couple to a quasi-continuum of phonon modes. The interaction to that often structured continuum may be highly frequency dependent, e.g. due to some weakly damped high frequency modes. To handle such a situation, an approach combining the non-markovian quantum state diffusion description of open quantum systems with an efficient but abstract approximation was recently applied to calculate energy transfer and absorption spectra of molecular aggregates [J. Roden, A. Eisfeld, W. Wolff, W. T. Strunz, Phys. Rev. Lett. 103, 058301 (2009)]. To explore the validity of the used approximation for such complicated systems, in the present work we compare the calculated (approximative) absorption spectra with exact results. These are obtained from the method of pseudomodes, which we show to be capable of determining the exact spectra for small aggregates and a few pseudomodes. It turns out that in the cases considered, the results of the two approaches mostly agree quite well. The advantages and disadvantages of the two approaches are discussed. PMID- 21261387 TI - Effect of the concentration on sol-gel transition of telechelic polyelectrolytes. AB - Telechelic polyelectrolytes, bearing short hydrophobic blocks at both ends, will ionize into polyions and their counterions when dissolved in water. With the variation of concentration, the interplay between short range attraction and the long range electrostatic interaction as well as the counterion distribution exerts a major influence on the chain conformations (two basic conformations: loop and nonloop, the latter can be subdivided into three association types: free, dangling, and bridge), the cluster structure and the forming of a physical gel. For weak hydrophobic interaction, the relative strong electrostatic interaction dominates the gelation progress; sol-gel transition occurs at higher concentrations due to electrostatic screening and mainly involves the forming of stretched nonloop conformations such as dangling and bridge. While for strong hydrophobic interaction, the hydrophobic interaction dominates and the electrostatic interaction provides a contribution to the formation of gels by maintaining a spatial swelling structure, resulting in a much lower concentration region of sol-gel transition; besides, the sol-gel transition is characterized by the competition of the forming of loop and bridge chains. PMID- 21261388 TI - Structural aggregates of rod-coil copolymer solutions. AB - The optoelectronic properties of rod-coil diblock copolymers with pi-conjugation are greatly affected by molecular packing, which is closely related to their micellar morphology. Self-assembly of rod-coil block copolymer B(y)A(x) in a selective solvent for its coil block is studied by using dissipative particle dynamics, where B(y)A(x) denotes the polymer comprising of y rodlike B beads and x coil-like A beads. The influences of polymer concentration, component compatibility, solvent quality for coil block, rod-block length, and pi-pi interaction on the resulting aggregate conformations are examined. It was found that distinctly different from coil-coil copolymers, the aggregates of rod-coil copolymers exhibit morphological and structural diversity induced by the intrinsically rigid nature of the rod blocks. In general, the aggregate adopts the overall shape of sphere, cylinder, perforated sheet, or network. The morphology of the rod-block domain within aggregate is even richer and the interesting structures such as porous sphere, spherical spiral, helical bundles, discrete chunks, and nematic cylinder are observed. The short-range order parameter indicates that as rod length is long enough, neighboring rods begin to orient parallel to one another and nematic domains appear. Moreover, in the presence of pi-pi interactions, the neighboring rods within the B domains become more coherently oriented and smectic domains can thus be formed. PMID- 21261389 TI - Simulation of aggregating particles in complex flows by the lattice kinetic Monte Carlo method. AB - We develop and validate an efficient lattice kinetic Monte Carlo (LKMC) method for simulating particle aggregation in laminar flows with spatially varying shear rate, such as parabolic flow or flows with standing vortices. A contact time model was developed to describe the particle-particle collision efficiency as a function of the local shear rate, G, and approach angle, theta. This model effectively accounts for the hydrodynamic interactions between approaching particles, which is not explicitly considered in the LKMC framework. For imperfect collisions, the derived collision efficiency [E=1 - ?(0)(pi/2) sintheta exp(-2cotthetaGamma(agg)/G)dtheta] was found to depend only on Gamma(agg)/G, where Gamma(agg) is the specified aggregation rate. For aggregating platelets in tube flow, Gamma(agg)=0.683 s(-1) predicts the experimentally measured epsilon across a physiological range (G = 40-1000 s(-1)) and is consistent with alpha(2b)beta(3)-fibrinogen bond dynamics. Aggregation in parabolic flow resulted in the largest aggregates forming near the wall where shear rate and residence time were maximal, however intermediate regions between the wall and the center exhibited the highest aggregation rate due to depletion of reactants nearest the wall. Then, motivated by stenotic or valvular flows, we employed the LKMC simulation developed here for baffled geometries that exhibit regions of squeezing flow and standing recirculation zones. In these calculations, the largest aggregates were formed within the vortices (maximal residence time), while squeezing flow regions corresponded to zones of highest aggregation rate. PMID- 21261390 TI - Dynamic coupling between the LID and NMP domain motions in the catalytic conversion of ATP and AMP to ADP by adenylate kinase. AB - The catalytic conversion of adenosine triphosphate (ATP) and adenosine monophosphate (AMP) to adenosine diphosphate (ADP) by adenylate kinase (ADK) involves large amplitude, ligand induced domain motions, involving the opening and the closing of ATP binding domain (LID) and AMP binding domain (NMP) domains, during the repeated catalytic cycle. We discover and analyze an interesting dynamical coupling between the motion of the two domains during the opening, using large scale atomistic molecular dynamics trajectory analysis, covariance analysis, and multidimensional free energy calculations with explicit water. Initially, the LID domain must open by a certain amount before the NMP domain can begin to open. Dynamical correlation map shows interesting cross-peak between LID and NMP domain which suggests the presence of correlated motion between them. This is also reflected in our calculated two-dimensional free energy surface contour diagram which has an interesting elliptic shape, revealing a strong correlation between the opening of the LID domain and that of the NMP domain. Our free energy surface of the LID domain motion is rugged due to interaction with water and the signature of ruggedness is evident in the observed root mean square deviation variation and its fluctuation time correlation functions. We develop a correlated dynamical disorder-type theoretical model to explain the observed dynamic coupling between the motion of the two domains in ADK. Our model correctly reproduces several features of the cross-correlation observed in simulations. PMID- 21261391 TI - Electron capture induced dissociation of doubly protonated pentapeptides: dependence on molecular structure and charge separation. AB - We have studied electron capture induced dissociation of a set of doubly protonated pentapeptides, all composed of one lysine (K) and either four glycine (G) or four alanine (A) residues, as a function of the sequence of these building blocks. Thereby the separation of the two charges, sequestered on the N-terminal amino group and the lysine side chain, is varied. The characteristic cleavage of N-C(alpha) bonds is observed for all peptides over the whole backbone length, with the charge carrying fragments always containing K. The resulting fragmentation patterns are very similar if G is replaced by A. In the case of [XKXXX+2H](2+) (X=A or G), a distinct feature is observed in the distribution of backbone cleavage fragments and the probability for ammonia loss is drastically reduced. This may be due to an isomer with an amide oxygen as protonation site giving rise to the observed increase in breakage at a specific site in the molecule. For the other peptides, a correlation with the distance between amide oxygen and the charge at the lysine side chain has been found. This may be an indication that it is only the contribution from this site to the charge stabilization of the amide pi(*) orbitals which determines relative fragment intensities. For comparison, complexes with two crown ether molecules have been studied as well. The crown ether provides a shielding of the charge and prevents the peptide from folding and internal hydrogen bonding, which leads to a more uniform fragmentation behavior. PMID- 21261392 TI - Evaluating force field accuracy with long-time simulations of a beta-hairpin tryptophan zipper peptide. AB - We have combined graphics processing unit-accelerated all-atom molecular dynamics with parallel tempering to explore the folding properties of small peptides in implicit solvent on the time scale of microseconds. We applied this methodology to the synthetic beta-hairpin, trpzip2, and one of its sequence variants, W2W9. Each simulation consisted of over 8 MUs of aggregated virtual time. Several measures of folding behavior showed good convergence, allowing comparison with experimental equilibrium properties. Our simulations suggest that the intramolecular interactions of tryptophan side chains are responsible for much of the stability of the native fold. We conclude that the ff99 force field combined with ff96 phi and psi dihedral energies and an implicit solvent can reproduce plausible folding behavior in both trpzip2 and W2W9. PMID- 21261393 TI - Effects of osmolytes on the helical conformation of model peptide: molecular dynamics simulation. AB - Co-solvents such as glycerol and sorbitol are small organic molecules solvated in the cellular solutions that can have profound effects on the protein structures. Here, the molecular dynamics simulations and comparative structural analysis of magainin, as a peptide model, in pure water, 2,2,2-trifluoroethanol/water, glycerol/water, and sorbitol/water are reported. Our results show that the peptide NMR structure is largely maintained its native structure in osmolytes water mixtures. The simulation data indicates that the stabilizing effect of glycerol and sorbitol is induced by preferential accumulation of glycerol and sorbitol molecules around the nonpolar and aromatic residues. Thus, the presence of glycerol and sorbitol molecules decreases the interactions of water molecules with the hydrophobic residues of the peptide, and the alpha helical structure is stabilized. PMID- 21261394 TI - Comment on "Slow Debye-type peak observed in the dielectric response of polyalcohols" [J. Chem. Phys. 132, 044504 (2010)]. PMID- 21261396 TI - Editorial: Selected papers from the Third International Conference on Foundations of Systems Biology in Engineering (FOSBE 2009). PMID- 21261397 TI - Modelling and analysis of an ensemble of eukaryotic translation initiation models. AB - Programmed protein synthesis plays an important role in the cell cycle. Deregulated translation has been observed in several cancers. In this study, the authors constructed an ensemble of mathematical models describing the integration of growth factor signals with translation initiation. Using these models, the authors estimated critical structural features of the translation architecture. Sensitivity and robustness analysis with and without growth factors suggested that a balance between competing regulatory programmes governed translation initiation. Proteins such as Akt and mTor promoted initiation by integrating growth factor signals with the assembly of the 80S initiation complex. However, negative regulators such as PTEN and 4EBP1 restrained initiation in the absence of stimulation. Other proteins such as eIF4E were also found to be structurally critical as deletion of amplification of these components resulted in a network incapable of nominal operation. These findings could help understand the molecular basis of translation deregulation observed in cancer and perhaps lead to new anti-cancer therapeutic strategies. [Includes supplementary material]. PMID- 21261398 TI - Investigation of IL-6 and IL-10 signalling via mathematical modelling. AB - Steatosis, i.e., the accumulation of fat in hepatocytes, plays an important role in the progression of non-alcoholic fatty liver disease (NAFLD). It has been shown that STAT3 activation is involved in a decrease of lipid accumulation while C/EBP is correlated with an increase of fat content and steatosis. It is known that STAT3 and C/EBP are activated by IL-6 and that IL-6 signalling is also affected by IL-10, even though the exact mechanism is unclear. This paper develops a model for IL-6 and IL-10 signal transduction and then investigates the effect that stimulation with these cytokines has on the transcription factor dynamics. In an initial step, some parameters of a previously developed IL-6 signalling model are re-estimated based upon newly developed experimental data for the Jak-STAT pathway. Furthermore, the Erk-C/EBP pathway model is extended to also include the activated transcription factor C/EBP in the nucleus. Since IL-10 signals through the Jak-STAT but not the Erk-C/EBP pathway, a model was developed which includes interaction between IL-6 and IL-10 signalling as both mechanisms share signal transduction through the Jak-STAT pathway. Based upon the model, the activity ratio of Jak-STAT and Erk-C/EBP was investigated for different stimulation levels of IL-6 and IL-10. PMID- 21261399 TI - Minimum protein oscillator based on multisite phosphorylation/dephosphorylation. AB - The authors propose a novel minimum oscillator whereby a protein with multiple phosphorylation sites directly embedded in a negative feedback loop can exhibit oscillation. They demonstrate that if the fully phosphorylated substrate inhibits the first phosphorylation step in a cooperative manner, multisite substrates can exhibit oscillatory behaviour at the presence of a kinase and phosphatase. With a fixed number of sites, the non-linearity of the negative feedback and the substrate/enzyme ratio must be above certain threshold values to generate undamped oscillation. There is an inverse relationship between the number of phosphorylation sites and the minimum non-linearity of the negative feedback required for oscillation; that is, the ultrasensitivity and time delay rooted in multisite phosphorylation compensate for the explicit non-linearity in the negative feedback. The period and amplitude of oscillation are mainly determined by the number of phosphorylation sites and the substrate/enzyme ratio. The authors' results suggest that a multisite protein can be exploited for the construction of a synthetic protein oscillator featuring simplicity, robustness and tunability. PMID- 21261400 TI - Pharmacokinetic/pharmacodynamic modelling of intracellular gemcitabine triphosphate accumulation: translating in vitro to in vivo. AB - A detailed intracellular (IC) model describing the pharmacokinetics (PK) of gemcitabine (2',2'-difluoro-2'-deoxycytidine, dFdC) was developed and linked to a systemic plasma dFdC PK model. Based on in vivo PK, pharmacodynamic (PD) effect predictions were made using a simplified cell-cycle model (CCM). A reduced-order compartmental model describing the IC metabolism of dFdC was fit to in vitro data taken from the literature to estimate the kinetic parameters of gemcitabine triphosphate (dFdCTP) generation and elimination in leukaemia cells. For comparison with in vivo patient data, the proposed detailed IC model, coupled with the systemic PK model and the CCM PD model, was simulated; Monte Carlo randomisation of the parameter vector was used to simulate interpatient variability. This comparison of model-generated IC dFdCTP concentrations with literature values in peripheral blood mononuclear cells (PBMCs) revealed qualitative and quantitative agreement. A tumour interstitial compartment connecting the plasma and IC models allowed prediction of solid tumour dFdCTP concentration. PMID- 21261401 TI - Modelling the dual role of Per phosphorylation and its effect on the period and phase of the mammalian circadian clock. AB - Circadian clocks are regulated at the post-translational level by a variety of processes among which protein phosphorylation plays a prominent, although complex, role. Thus, the phosphorylation of different sites on the clock protein PER by casein kinase I (CKI) can lead to opposite effects on the stability of the protein and on the period of circadian oscillations. Here the authors extend a computational model previously proposed for the mammalian circadian clock by incorporating two distinct phosphorylations of PER by CKI. On the basis of experimental observations the authors consider that phosphorylation at one site (denoted here PER-P1) enhances the rate of degradation of the protein and decreases the period, while phosphorylation at another site (PER-P2) stabilises the protein, enhances the transcription of the Per gene, and increases the period. The model also incorporates an additional phosphorylation of PER by the Glycogen Synthase Kinase 3 (GSK3). The authors show that the extended model incorporating the antagonistic effects of PER phosphorylations by CKI can account for observations pertaining to (i) the decrease in period in the Tau mutant, because of an increase in phosphorylation by CKI leading to PER-P1, and (ii) the familial advanced sleep phase syndrome (FASPS) in which the period is shortened and the phase of the oscillations is advanced when the rate of phosphorylation leading to PER-P2 is decreased. The model further accounts for the increase in period observed in the presence of CKI inhibitors that decrease the rate of phosphorylation leading to both PER-P1 and PER-P2. A similar increase in period results from inhibition of GSK3. [Includes supplementary material]. PMID- 21261402 TI - Distribution-based sensitivity metric for highly variable biochemical systems. AB - Classical sensitivity analysis is routinely used to identify points of fragility or robustness in biochemical networks. However, intracellular systems often contain components that number in the thousands to tens or less and consequently motivate a stochastic treatment. Although methodologies exist to quantify sensitivities in stochastic models, they differ substantially from those used in deterministic regimes. Therefore it is not possible to tell whether observed differences in sensitivity measured in deterministic and stochastic elaborations of the same network are the result of methodology or model form. The authors introduce here a distribution-based methodology to measure sensitivity that is equally applicable in both regimes, and demonstrate its use and applicability on a sophisticated mathematical model of the mouse circadian clock that is available in both deterministic and stochastic variants. The authors use the method to produce sensitivity measurements on both variants. They note that the rank-order sensitivity of the clock to parametric perturbations is extremely well conserved across several orders of magnitude. The data show that the clock is fragile to perturbations in parameters common to the cellular machinery ('global' parameters) and robust to perturbations in parameters that are clock-specific ('local' parameters). The sensitivity measure can be used to reduce the model from its original 73 ordinary differential equations (ODEs) to 18 ODEs and to predict the degree to which parametric perturbation can distort the phase response curve of the clock. Finally, the method is employed to evaluate the effect of transcriptional and translational noise on clock function. [Includes supplementary material]. PMID- 21261403 TI - Legitimacy of the stochastic Michaelis-Menten approximation. AB - Michaelis-Menten kinetics are commonly used to represent enzyme-catalysed reactions in biochemical models. The Michaelis-Menten approximation has been thoroughly studied in the context of traditional differential equation models. The presence of small concentrations in biochemical systems, however, encourages the conversion to a discrete stochastic representation. It is shown that the Michaelis-Menten approximation is applicable in discrete stochastic models and that the validity conditions are the same as in the deterministic regime. The authors then compare the Michaelis-Menten approximation to a procedure called the slow-scale stochastic simulation algorithm (ssSSA). The theory underlying the ssSSA implies a formula that seems in some cases to be different from the well known Michaelis-Menten formula. Here those differences are examined, and some special cases of the stochastic formulas are confirmed using a first-passage time analysis. This exercise serves to place the conventional Michaelis-Menten formula in a broader rigorous theoretical framework. PMID- 21261404 TI - So, you want to be a systems biologist? Determinants for creating graduate curricula in systems biology. AB - Systems biology is uniquely situated at the interface of computing, mathematics, engineering and the biological sciences. This positioning creates unique challenges and opportunities over other interdisciplinary studies when developing academic curricula. Integrative systems biology attempts to span the field from observation to innovation, and thus requires successful students to gain skills from mining to manipulation. The authors outline examples of graduate program structures, as well as curricular aspects and assessment metrics that can be customised around the environmental niche of the academic institution towards the formalisation of effective educational opportunities in systems biology. Some of this material was presented at the 2009 Foundations of Systems Biology in Engineering (FOSBE 2009) Conference in Denver, August 2009. PMID- 21261405 TI - Development of a decisional balance scale for young adult marijuana use. AB - This study describes the development and validation of a decisional balance scale for marijuana use in young adults. Scale development was accomplished in four phases. First, 53 participants (70% female, 68% freshman) provided qualitative data that yielded content for an initial set of 47 items. In the second phase, an exploratory factor analysis on the responses of 260 participants (52% female, 68% freshman) revealed two factors, corresponding to pros and cons. Items that did not load well on the factors were omitted, resulting in a reduced set of 36 items. In the third phase, 182 participants (49% female, 37% freshmen) completed the revised scale and an evaluation of factor structure led to scale revisions and model respecification to create a good-fitting model. The final scales consisted of 8 pros (alpha = 0.91) and 16 cons (alpha = 0.93), and showed evidence of validity. In the fourth phase (N = 248, 66% female, 70% freshman), we confirmed the factor structure, and provided further evidence for reliability and validity. The Marijuana Decisional Balance Scale enhances our ability to study motivational factors associated with marijuana use among young adults. PMID- 21261406 TI - Community reinforcement approach plus vouchers among cocaine-dependent outpatients: twelve-month outcomes. AB - The aims of this study were to assess the effectiveness of the Community Reinforcement Approach (CRA) plus vouchers treatment in a cohort of Spanish cocaine-dependent outpatients, and to examine the maintenance of treatment effects after the voucher intervention was discontinued. Sixty-four adult outpatients were randomly assigned to one of two treatment conditions, CRA plus vouchers or standard care. The vouchers program was implemented from weeks 1 to 24. Among patients assigned to the CRA plus vouchers condition, 65.5% completed 12 months of treatment versus 28.6% of those assigned to the standard care condition (p = .003). At the 12-month assessment, 58.6% of patients assigned to the CRA plus vouchers condition were abstinent, compared with 25.7% in the standard care condition (p = .008); furthermore, 34.5% of patients assigned to the CRA plus vouchers condition achieved twelve months of continuous cocaine abstinence, versus 17.1% in the standard care condition. Those treated in the CRA plus vouchers condition also achieved greater improvements in psychosocial functioning than those treated in the standard care condition. Overall, these results reveal an extension of the effectiveness of the CRA plus vouchers treatment to a community sample of cocaine-dependent outpatients, while also supporting the maintenance of treatment effects for 6 months after completion of the voucher program. PMID- 21261407 TI - Cannabis use among military veterans after residential treatment for posttraumatic stress disorder. AB - The present investigation prospectively evaluated whether treatment changes in PTSD symptom severity, among military Veterans in residential PTSD treatment, were related to cannabis use 4 months after discharge from residential rehabilitation. The sample was comprised of 432 male military Veteran patients (Mage = 51.06 years, SD = 4.17), who had a primary diagnosis of PTSD and were admitted to a VA residential rehabilitation program for PTSD. Results demonstrated that lower levels of change in PCL-M scores between treatment intake and discharge were significantly predictive of greater frequency of cannabis use at 4-month follow-up (p < .05), even after accounting for the effects of length of treatment stay and frequency of cannabis use during the 2 months before treatment intake. Furthermore, post hoc analyses revealed that less change in PTSD avoidance/numbing and hyperarousal symptom severity during treatment was significantly predictive of a greater frequency of cannabis use at 4-month follow up, after controlling for relevant covariates. Notably, these effects were specific to cannabis and were not found for the other substances examined among this sample, including alcohol and opiates. Implications of the findings are discussed with regard to the extant literature and future directions. PMID- 21261408 TI - Toward a new approach to the study of personality in culture. AB - We review recent developments in the study of culture and personality measurement. Three approaches are described: an etic approach that focuses on establishing measurement equivalence in imported measures of personality, an emic (indigenous) approach that studies personality in specific cultures, and a combined emic-etic approach to personality. We propose the latter approach as a way of combining the methodological rigor of the etic approach and the cultural sensitivity of the emic approach. The combined approach is illustrated by two examples: the first with origins in Chinese culture and the second in South Africa. The article ends with a discussion of the theoretical and practical implications of the combined emic-etic approach for the study of culture and personality and for psychology as a science. PMID- 21261409 TI - Toward an understanding of situational judgment item validity and group differences. AB - This paper evaluates 2 adjustments to common scoring approaches for situational judgment tests (SJTs). These adjustments can result in substantial improvements to item validity, reductions in mean racial differences, and resistance to coaching designed to improve scores. The first adjustment, applicable to SJTs that use Likert scales, controls for elevation and scatter (Cronbach & Gleser, 1953). This adjustment improves item validity. Also, because there is a White Black mean difference in the preference for extreme responses on Likert scales (Bachman & O'Malley, 1984), these adjustments substantially reduce White-Black mean score differences. Furthermore, this adjustment often eliminates the score elevation associated with the coaching strategy of avoiding extreme responses (Cullen, Sackett, & Lievens, 2006). Item validity is shown to have a U-shaped relationship with item means. This holds both for SJTs with Likert score response formats and for SJTs where respondents identify the best and worst response option. Given the U-shaped relationship, the second adjustment is to drop items with midrange item means. This permits the SJT to be shortened, sometimes dramatically, without necessarily harming validity. PMID- 21261410 TI - Neural activity during health messaging predicts reductions in smoking above and beyond self-report. AB - OBJECTIVE: The current study tested whether neural activity in response to messages designed to help smokers quit could predict smoking reduction, above and beyond self-report. DESIGN: Using neural activity in an a priori region of interest (a subregion of medial prefrontal cortex [MPFC]), in response to ads designed to help smokers quit smoking, we prospectively predicted reductions in smoking in a community sample of smokers (N = 28) who were attempting to quit smoking. Smoking was assessed via expired carbon monoxide (CO; a biological measure of recent smoking) at baseline and 1 month following exposure to professionally developed quitting ads. RESULTS: A positive relationship was observed between activity in the MPFC region of interest and successful quitting (increased activity in MPFC was associated with a greater decrease in expired CO). The addition of neural activity to a model predicting changes in CO from self-reported intentions, self-efficacy, and ability to relate to the messages significantly improved model fit, doubling the variance explained (R2self-report = .15, R2self-report + neural activity = .35, R2change = .20). CONCLUSION: Neural activity is a useful complement to existing self-report measures. In this investigation, we extend prior work predicting behavior change based on neural activity in response to persuasive media to an important health domain and discuss potential psychological interpretations of the brain-behavior link. Our results support a novel use of neuroimaging technology for understanding the psychology of behavior change and facilitating health promotion. PMID- 21261411 TI - Aging and task switching: a meta-analysis. AB - A meta-analysis of 26 published articles (with 36 independent participant groups) was conducted to analyze the relationship between task-switching effects and aging. Latency served as the dependent measure. Multilevel modeling was used to test for additive and multiplicative complexity effects in local and global switch costs. Global task switching was found to add 1 or more stages to processing and resulted in a marked age deficit. Local task-switching costs, on the other hand, showed a multiplicative complexity effect but no specific attention-related age deficits. Cueing or switch predictability did not affect age differences. PMID- 21261412 TI - Aging increases inattentional blindness to the gorilla in our midst. AB - When engaged in an attention-demanding task, people are surprisingly vulnerable to inattentional blindness--the failure to notice an unexpected event. Two theories of cognitive aging, attentional capacity models and inhibitory deficit models, make opposite predictions about age differences in susceptibility to inattentional blindness. We tested these predictions using an inattentional blindness paradigm developed by Simons and Chabris (1999) and found that older adults were more likely to experience inattentional blindness than young adults. These results are compatible with attentional capacity models of cognitive aging but not with current inhibitory deficit models. PMID- 21261414 TI - Cue interactions in flavor preference learning: a configural analysis. AB - Four experiments showed that the preference normally established to a neutral flavor cue that was paired with maltodextrin was attenuated when that cue was conditioned in compound with another flavor--overshadowing. Furthermore, two experiments showed that the preference for a neutral flavor conditioned as part of a compound was further attenuated if the other element in that compound was separately paired with the reinforcer--blocking. These results stand in contrast to a number of previous compound flavor preference conditioning experiments, which have not revealed reliable cue competition effects. These discrepant findings are discussed in terms of the effects of within-compound associations and a configural perspective on potentiation. Modeling of this configural perspective predicts that a compound of two separately trained cues will elicit a similar response to the individual cues themselves--absence of summation. Two experiments confirmed this prediction. PMID- 21261415 TI - Intertrial interval as a contextual stimulus: further analysis of a novel asymmetry in temporal discrimination learning. AB - Four experiments investigated discrimination learning when the duration of the intertrial interval (ITI) signaled whether or not the next conditional stimulus (CS) would be paired with food pellets. Rats received presentations of a 10-s CS separated half the time by long ITIs and half the time by short ITIs. When the long ITI signaled that the CS would be reinforced and the short interval signaled that it would not be (Long+/Short-), rats learned the discrimination readily. However, when the short ITI signaled that the CS would be reinforced and the long interval signaled that it would not (Short+/Long-), discrimination learning was much slower. Experiment 1 compared Long+/Short- and Short+/Long- discrimination learning with 16-min/4-min or 4-min/1-min ITI combinations. Experiment 2 found no evidence that Short+/Long- learning is inferior because the temporal cue corresponding to the short interval is ambiguous. Experiment 3 found no evidence that Short+/Long- learning is poor because the end of a long ITI signals a substantial reduction in delay to the next reinforcer. Long+/Short- learning may be faster than Short+/Long-because elapsing time involves exposure to a sequence of hypothetical stimulus elements (e.g., A then B), and feature-positive discriminations (AB+/A-) are learned quicker than feature-negative discriminations (A+/AB-). Consistent with this view, Experiment 4 found a robust feature-positive effect when sequentially presented CSs played the role of elements A and B. PMID- 21261416 TI - Varying temporal contiguity and interference in a human avoidance task. AB - Temporal contiguity and number of interfering events were manipulated in a human avoidance (Martians) task, which required participants to prevent an "invasion" when a particular visual stimulus ("shield") appeared by releasing the space bar before the shield was activated. A particular symbol, 1 of up to 6, functioned as a brief warning signal. The signal-offset to shield-onset (S-S) interval varied between groups, as did the number of additional symbols acting as distractors. In Experiments 1 and 2, speed of learning declined as a linear function of both trace interval and number of distractors. Path analysis showed that the effects of the S-S interval depended primarily on the number of distractors during this interval. Experiment 2 further demonstrated that participants who failed to suppress responding were generally unable to identify which symbol was the signal, suggesting that the presence of distractors disrupted detection of the contingency rather than performance. Overall, the results indicated that learning to associate 2 temporally separated events depends mainly on the amount of interference and little on the time interval between them. PMID- 21261417 TI - Unpacking unpacking: greater detail can reduce perceived likelihood. AB - Past research suggests that a categorical event is perceived to be more likely if its subcases are explicitly delineated or "unpacked." In 6 studies, we find that unpacking can often make an event seem less likely, especially when the details being unpacked are already highly accessible. Process evidence shows that the provision of greater detail accompanying unpacking reduces the simplicity of an event and that this dysfluency is used as a negative cue for likelihood. This work establishes processing fluency as a mechanism that opposes the other effects of unpacking, such as enhanced accessibility. PMID- 21261418 TI - Perception of emotional expression in musical performance. AB - Expression in musical performance is largely communicated by the manner in which a piece is played; interpretive aspects that supplement the written score. In piano performance, timing and amplitude are the principal parameters the performer can vary. We examined the way in which such variation serves to communicate emotion by manipulating timing and amplitude in performances of classical piano pieces. Over three experiments, listeners rated the emotional expressivity of performances and their manipulated versions. In Experiments 1 and 2, timing and amplitude information were covaried; judgments were monotonically decreasing with performance variability, demonstrating that the rank ordering of acoustical manipulations was captured by participants' responses. Further, participants' judgments formed an S-shaped (sigmoidal) function in which greater sensitivity was seen for musical manipulations in the middle of the range than at the extremes. In Experiment 3, timing and amplitude were manipulated independently; timing variation was found to provide more expressive information than did amplitude. Across all three experiments, listeners demonstrated sensitivity to the expressive cues we manipulated, with sensitivity increasing as a function of musical experience. PMID- 21261419 TI - The colors of the alphabet: naturally-biased associations between shape and color. AB - Many letters of the alphabet are consistently mapped to specific colors in English-speaking adults, both in the general population and in individuals with grapheme-color synaesthesia who perceive letters in color. Here, across six experiments, we tested the ubiquity of the color/letter associations with typically developing toddlers, literate children, and adults. We found that pre literate children associate O with white and X with black and discovered that they also associate I and ameboid nonsense shapes with white; Z and jagged nonsense shapes with black; and C with yellow; but do not make a number of other associations (B blue; Y yellow; A red; G green) seen in literate children and adults. The toddlers' mappings were based on the shape and not the sound of the letter. The results suggest that sensory cortical organization initially binds specific colors to some specific shapes and that learning to read can induce additional associations, likely through the influence of higher order networks as letters take on meaning. PMID- 21261420 TI - Transactional problem content in cost discounting: parallel effects for probability and delay. AB - Four experiments investigated the effects of transactional content on temporal and probabilistic discounting of costs. Kusev, van Schaik, Ayton, Dent, and Chater (2009) have shown that content other than gambles can alter decision making behavior even when associated value and probabilities are held constant. Transactions were hypothesized to lead to similar effects because the cost to a purchaser always has a linked gain, the purchased commodity. Gain amount has opposite effects on delay and probabilistic discounting (e.g., Benzion, Rapoport, & Yagil, 1989; Green, Myerson, & Ostaszewski, 1999), a finding that is not consistent with descriptive decision theory (Kahneman & Tversky, 1979; Loewenstein & Prelec, 1992). However, little or no effect on discounting has been observed for losses or costs. Experiment 1, using transactions, showed parallel effects for temporal and probabilistic discounting: Smaller amounts were discounted more than large amounts. As the cost rises, people value the commodity more, and they consequently discount less. Experiment 2 ruled out a possible methodological cause for this effect. Experiment 3 replicated Experiment 1. Experiment 4, using gambles, showed no effect for temporal discounting, because of the absence of the linked gain, but the same effect for probabilistic discounting, because prospects implicitly introduce a linked gain (Green et al., 1999; Prelec & Loewenstein, 1991). As found by Kusev et al. (2009), these findings are not consistent with decision theory and suggest closer attention should be paid to the effects of content on decision making. PMID- 21261421 TI - Adults' strategies for simple addition and multiplication: verbal self-reports and the operand recognition paradigm. AB - Accurate measurement of cognitive strategies is important in diverse areas of psychological research. Strategy self-reports are a common measure, but C. Thevenot, M. Fanget, and M. Fayol (2007) proposed a more objective method to distinguish different strategies in the context of mental arithmetic. In their operand recognition paradigm, speed of recognition memory for problem operands after solving a problem indexes strategy (e.g., direct memory retrieval vs. a procedural strategy). Here, in 2 experiments, operand recognition time was the same following simple addition or multiplication, but, consistent with a wide variety of previous research, strategy reports indicated much greater use of procedures (e.g., counting) for addition than multiplication. Operation, problem size (e.g., 2 + 3 vs. 8 + 9), and operand format (digits vs. words) had interactive effects on reported procedure use that were not reflected in recognition performance. Regression analyses suggested that recognition time was influenced at least as much by the relative difficulty of the preceding problem as by the strategy used. The findings indicate that the operand recognition paradigm is not a reliable substitute for strategy reports and highlight the potential impact of difficulty-related carryover effects in sequential cognitive tasks. PMID- 21261422 TI - Congruity effects in the survival processing paradigm. AB - Five experiments were conducted to investigate a proposal by Butler, Kang, and Roediger (2009) that congruity (or fit) between target items and processing tasks might contribute, at least partly, to the mnemonic advantages typically produced by survival processing. In their research, no significant survival advantages were found when words were preselected to be highly congruent or incongruent with a survival and control (robbery) scenario. Experiments 1a and 1b of the present report show that survival advantages, in fact, generalize across a wide set of selected target words; each participant received a unique set of words, sampled without replacement from a large pool, yet significant survival advantages remained. In Experiment 2, we found a significant survival advantage using words that had been preselected by Butler et al. to be highly unrelated (or irrelevant) to both the survival and control scenarios. Experiment 3 showed a significant survival advantage using word sets that had been preselected to be highly congruent with both scenarios. Finally, Experiment 4 mixed congruent and incongruent words in the same list, more closely replicating the design used by Butler et al., and a highly reliable main effect of survival processing was still obtained (although the survival advantage for the congruent words did not reach conventional levels of statistical significance). Our results suggest that the null effects of survival processing obtained by Butler et al. may not generalize beyond their particular experimental design. PMID- 21261423 TI - Semantic integration as a boundary condition on inhibitory processes in episodic retrieval. AB - Recalling an experience often impairs the later retention of related traces, a phenomenon known as retrieval-induced forgetting (RIF). Research has shown that episodic associations protect competing memories from RIF (Anderson & McCulloch, 1999). We report 4 experiments that examined whether semantic associations also protect against RIF. In all experiments, robust RIF occurred when there were few associations between practiced and nonpracticed sets, but RIF was abolished when there were many. The benefits of semantic integration were independent of episodic integration strategies and were not mediated by intentional use of the associations. Rather, these results establish a new boundary condition on RIF- semantic integration--that has a potent impact on the magnitude of RIF and may explain variability in the RIF phenomenon. PMID- 21261424 TI - Bogus concerns about the false prototype enhancement effect. AB - Two experiments addressed the mechanism responsible for the false prototype effect, the phenomenon in which a prototype gradient can be obtained in the absence of learning. Previous demonstrations of this effect have occurred solely in a single-category paradigm in which transfer patterns are assigned or not to the learning category. We tested the hypothesis that any extraneous variable potentially responsible for this effect, such as compactness varying with pattern distortion (Zaki & Nosofsky, 2004), may be functional in the single-category paradigm but not when multiple categories are available at the time of transfer. In the present study, subjects received a bogus or a real category learning phase, followed by a transfer test that required assignment into 1 or 3 prototype categories. The results showed that a minimal prototype gradient was obtained in the bogus conditions, with performance approaching chance levels when classification into 3 categories was required. In contrast, a substantial prototype gradient effect was found following learning. We conclude that the prototype gradient typically obtained following multiple-category learning is primarily driven by real learning and that the false prototype effect is itself an artifact of the single-category paradigm. PMID- 21261425 TI - Encoding modality can affect memory accuracy via retrieval orientation. AB - Research indicates that false memory is lower following visual than auditory study, potentially because visual information is more distinctive. In the present study we tested the extent to which retrieval orientation can cause a modality effect on memory accuracy. Participants studied unrelated words in different modalities, followed by criterial recollection tests that selectively oriented retrieval toward one study modality at a time. Memory errors were lower when oriented toward visual than toward auditory information, thereby generalizing the modality effect to an explicit source memory task. Moreover, these effects persisted independent of the test presentation modality, indicating that retrieval orientation overrode the potential cuing properties of the test stimulus. An independent manipulation check confirmed that visual recollections were subjectively experienced as more distinctive than auditory recollections. These results suggest that retrieval orientation is sufficient to cause a modality effect on memory accuracy by focusing monitoring processes on the recollection of studied features that are diagnostic of prior presentation. PMID- 21261426 TI - Generalizing linguistic structures under high attention demands. AB - We explored whether the generalization of rules based on simple structures depends on attention. Participants were exposed to a stream of artificial words that followed a simple syllabic structure (ABA or AAB), overlaid on a sequence of familiar noises. After passively listening, participants successfully recognized the individual words present in the stream among foils, and they were able to generalize the underlying word structure to new exemplars. Yet, when attention was diverted from the speech stream (by requiring participants to monitor the sequence of noises), recognition of the individual words fell dramatically irrespective of word structure, whereas generalization depended on stimulus structure. For structures based on vowel repetitions across nonadjacent syllables (ABA; Experiment 1), generalization was affected by attention. In contrast, for structures based on adjacent repetitions (AAB; Experiment 2), generalization capacity was unaffected by attention. This pattern of results was replicated under favorable conditions for generalization, such as increased token variability and the implementation of the rule over whole syllables (Experiments 3 and 4). These results suggest a differential effect of attention on rule learning and generalization depending on stimulus structure. PMID- 21261427 TI - The effect of grammatical gender on object categorization. AB - In 3 experiments, we investigated the effect of grammatical gender on object categorization. Participants were asked to judge whether 2 objects, whose names did or did not share grammatical gender, belonged to the same semantic category by pressing a key. Monolingual speakers of English (Experiment 1), Italian (Experiments 1 and 2), and Spanish (Experiments 2 and 3) were tested in their native language. Italian and Spanish participants responded faster to pairs of stimuli sharing the same gender, whereas no difference was observed for English participants. In Experiment 2, the pictures were chosen in such a way that the grammatical gender of the names was opposite in Italian and Spanish. Therefore, the same pair of stimuli gave rise to different patterns depending on the gender congruency of the names in the languages. In Experiment 3, Spanish speakers performed the same task under an articulatory suppression condition, showing no grammatical gender effect. The locus where meaning and gender interact can be located at the level of the lexical representation that specifies syntactic information: Nouns sharing the same grammatical gender activate each other, thus facilitating their processing and speeding up responses, either to semantically related pairs or to semantically unrelated pairs. PMID- 21261428 TI - Unskilled but aware: reinterpreting overconfidence in low-performing students. AB - People are generally overconfident in their self-assessments and this overconfidence effect is greatest for people of poorer abilities. For example, poor students predict that they will perform much better on exams than they do. One explanation for this result is that poor performers in general are doubly cursed: They lack knowledge of the material, and they lack awareness of the knowledge that they do and do not possess. The current studies examined whether poor performers in the classroom are truly unaware of their deficits by examining the relationship between students' exam predictions and their confidence in these predictions. Relative to high-performing students, the poorer students showed a greater overconfidence effect (i.e., their predictions were greater than their performance), but they also reported lower confidence in these predictions. Together, these results suggest that poor students are indeed unskilled but that they may have some awareness of their lack of metacognitive knowledge. PMID- 21261429 TI - Ideas for the future of JCCP in terms of content, structure, and format. AB - Once again, a change has occurred. As you probably noticed, the color of the cover for this issue of the Journal of Consulting and Clinical Psychology (JCCP) is different, signaling the "changing of the guard" of the editorial team. JCCP has a long-standing legacy of excellence in publishing high-quality, cutting edge, and innovative research and scholarship in clinical psychology. Its increasing Institute for Scientific Information (ISI) impact factor rating continues to attest to its influence on the field overall. As the new editor, I intend to do my utmost to preserve this reputation. Moreover, I am humbled upon reflecting on those before me in this position, as well as excited about shepherding such a premier journal over the course of the next 6 years. I am cognizant not only of the impact that this journal has on the science of clinical psychology but also of its influence on clinical practice and service delivery via the dissemination and adoption of evidenced-based interventions. In this context, I am grateful for having been able to assemble such a high-caliber team of associate and consulting editors. This editorial presents some ideas for the future of JCCP in terms of content, structure, and format. PMID- 21261430 TI - A meta-analysis of predictors of offender treatment attrition and its relationship to recidivism. AB - OBJECTIVE: The failure of offenders to complete psychological treatment can pose significant concerns, including increased risk for recidivism. Although a large literature identifying predictors of offender treatment attrition has accumulated, there has yet to be a comprehensive quantitative review. METHOD: A meta-analysis of the offender treatment literature was conducted to identify predictors of offender treatment attrition and examine its relationship to recidivism. The review covered 114 studies representing 41,438 offenders. Sex offender and domestic violence programs were also examined separately given their large independent literatures. RESULTS: The overall attrition rate was 27.1% across all programs (k = 96), 27.6% from sex offender programs (k = 34), and 37.8% from domestic violence programs (k = 35). Rates increased when preprogram attrition was considered. Significant predictors included demographic characteristics (e.g., age, rw = -.10), criminal history and personality variables (e.g., prior offenses, rw = .14; antisocial personality, rw = .14), psychological concerns (e.g., intelligence, rw = -.14), risk assessment measures (e.g., Statistical Information on Recidivism scale, rw =.18), and treatment related attitudes and behaviors (e.g., motivation, rw = -.13). Results indicated that treatment noncompleters were higher risk offenders and attrition from all programs significantly predicted several recidivism outcomes ranging from rw = .08 to .23. CONCLUSIONS: The clients who stand to benefit the most from treatment (i.e., high-risk, high-needs) are the least likely to complete it. Offender treatment attrition can be managed and clients can be retained through an awareness of, and attention to, key predictors of attrition and adherence to responsivity considerations. PMID- 21261431 TI - Posttraumatic stress disorder and intimate relationship problems: a meta analysis. AB - OBJECTIVE: The authors conducted a meta-analysis of empirical studies investigating associations between indices of posttraumatic stress disorder (PTSD) and intimate relationship problems to empirically synthesize this literature. METHOD: A literature search using PsycINFO, Medline, Published International Literature on Traumatic Stress (PILOTS), and Dissertation Abstracts was performed. The authors identified 31 studies meeting inclusion criteria. RESULTS: True score correlations (rho) revealed medium-sized associations between PTSD and intimate relationship discord (rho = .38, N = 7,973, K = 21), intimate relationship physical aggression perpetration (rho = .42, N = 4,630, K = 19), and intimate relationship psychological aggression perpetration (rho = .36, N = 1,501, K = 10). The strength of the association between PTSD and relationship discord was higher in military (vs. civilian) samples, and when the study was conducted in the United States (vs. other country), and the study represented a doctoral dissertation (vs. published article). The strength of the association between PTSD and physical aggression was higher in military (vs. civilian) samples, males (vs. females), community (vs. clinical) samples, studies examining PTSD symptom severity (vs. diagnosis), when the physical aggression measure focused exclusively on severe violence (vs. a more inclusive measure), and the study was published (vs. dissertation). For the PTSD-psychological aggression association, 98% of the variance was accounted for by methodological artifacts such as sampling and measurement error; consequently, no moderators were examined in this relationship. CONCLUSIONS: Findings highlight a need for the examination of models explaining the relationship difficulties associated with PTSD symptomatology and interventions designed to treat problems in both areas. PMID- 21261432 TI - The effect of five smoking cessation pharmacotherapies on smoking cessation milestones. AB - OBJECTIVE: Most smoking cessation studies have used long-term abstinence as their primary outcome measure. Recent research has suggested that long-term abstinence may be an insensitive index of important smoking cessation mechanisms. The goal of the current study was to examine the effects of 5 smoking cessation pharmacotherapies using Shiffman et al.'s (2006) approach of examining the effect of smoking cessation medications on 3 process markers of cessation or smoking cessation milestones: initial abstinence, lapse, and the lapse-relapse transition. METHOD: The current study (N = 1,504; 58.2% female and 41.8% male; 83.9% Caucasian, 13.6% African American, 2.5% other races) examined the effect of 5 smoking cessation pharmacotherapy treatments versus placebo (bupropion, nicotine lozenge, nicotine patch, bupropion + lozenge, patch + lozenge) on Shiffman et al.'s smoking cessation milestones over 8 weeks following a quit attempt. RESULTS: Results show that all 5 medication conditions decreased rates of failure to achieve initial abstinence and most (with the exception of the nicotine lozenge) decreased lapse risk; however, only the nicotine patch and bupropion + lozenge conditions affected the lapse-relapse transition. CONCLUSIONS: These findings demonstrate that medications are effective at aiding initial abstinence and decreasing lapse risk but that they generally do not decrease relapse risk following a lapse. The analysis of cessation milestones sheds light on important impediments to long-term smoking abstinence, suggests potential mechanisms of action of smoking cessation pharmacotherapies, and identifies targets for future treatment development. PMID- 21261433 TI - Therapist adherence in brief strategic family therapy for adolescent drug abusers. AB - OBJECTIVE: Therapist adherence has been shown to predict clinical outcomes in family therapy. In prior studies, adherence has been represented broadly by core principles and a consistent family (vs. individual) focus. To date, these studies have not captured the range of clinical skills that are represented in complex family-based approaches or examined how variations in these skills predict different clinically relevant outcomes over the course of treatment. In this study, the authors examined the reliability and validity of an observational adherence measure and the relationship between adherence and outcome in a sample of drug-using adolescents who received brief strategic family therapy within a multisite effectiveness study. METHOD: Participants were 480 adolescents (age 12 17) and their family members, who were randomized to the Brief Strategic Family Therapist treatment condition (J. Szapocznik, U. Hervis, & S. Schwartz, 2003) or treatment as usual. The adolescents were mostly male (377 vs. 103 female) and Hispanic (213), whereas 148 were White, and 110 were Black. Therapists were also randomly assigned to treatment condition within agencies. RESULTS: Results supported the proposed factor structure of the adherence measure, providing evidence that it is possible to capture and discriminate between distinct dimensions of family therapy. Analyses demonstrated that the mean levels of the factors varied over time in theoretically and clinically relevant ways and that therapist adherence was associated with engagement and retention in treatment, improvements in family functioning, and reductions in adolescent drug use. CONCLUSIONS: Clinical implications and future research directions are discussed, including the relevance of these findings on training therapists and studies focusing on mechanisms of action in family therapy. PMID- 21261434 TI - Moderating effects of a craving intervention on the relation between negative mood and heavy drinking following treatment for alcohol dependence. AB - OBJECTIVE: Negative affect is a significant predictor of alcohol relapse, and the relation between negative affect and drinking has been shown to be strongly mediated by alcohol craving. Thus, targeting craving during treatment could potentially attenuate the relation between negative affect and drinking. METHOD: The current study is a secondary analysis of data from the COMBINE study, a randomized clinical trial that combined pharmacotherapy with behavioral intervention in the treatment of alcohol dependence. Our goal in the current study was to examine whether a treatment module that targeted craving would predict changes in negative mood during the 16-week combined behavioral intervention (n = 776) and the relation among changes in mood, craving, and changes in heavy drinking during treatment and 1 year posttreatment. RESULTS: Changes in negative mood were significantly associated with changes in heavy drinking during treatment (f2 = 0.78). Participants (n = 432) who received the craving module had significantly fewer heavy drinking days during treatment (d = 0.31), and receiving the module moderated the relation between negative mood and heavy drinking during treatment (f2 = 0.92) and 1 year posttreatment (f2 = 0.03). Moderating effects of the craving module were mediated by changes in craving during treatment. Within-subject analyses indicated significant pre- to postmodule reductions in negative mood. Additionally, postmodule craving significantly mediated the association between negative mood and heavy drinking during treatment and at posttreatment. CONCLUSIONS: The craving module of the combined behavioral intervention may weaken the relation between negative affect and heavy drinking by fostering greater decreases in craving during treatment. PMID- 21261435 TI - Effectiveness of partner social support predicts enduring psychological distress after hematopoietic stem cell transplantation. AB - OBJECTIVE: Hematopoietic stem cell transplant (HSCT) survivors who are 1 to 3 years posttransplant are challenged by the need to resume valued social roles and activities--a task that may be complicated by enduring transplant-related psychological distress common in this patient population. The present study investigated whether transplant survivors who receive adequate social support from their spouse or intimate partner experience lower distress. METHOD: Effects of receiving a greater quantity of partner support (a common approach to studying enacted support) were compared with effects of receiving more effective partner support (i.e., support that more closely matches their needs in terms of its quantity and quality). Men and women (N = 230) who were 1 to 3 years posttransplant completed measures of partner support quantity (Manne & Schnoll, 2001), partner social support effectiveness (Rini & Dunkel Schetter, 2010), and psychological distress (Brief Symptom Inventory; Derogatis & Spencer, 1982). Potential medical and sociodemographic confounds were controlled in analyses. RESULTS: As hypothesized, survivors reported less distress when they received more effective partner support (p < .001). Quantity of partner support was not associated with distress (p = .23). An interaction revealed that when partner support was effective, the quantity of support survivors received was not associated with their distress (p = .90); however, when partner support was ineffective, receiving a greater quantity of partner support was associated with substantially elevated distress (p = .002). CONCLUSIONS: Findings suggest that clinical approaches to addressing or preventing enduring distress after HSCT should target features of partner support related to its appraised effectiveness. PMID- 21261436 TI - Diagnostic efficiency of DSM-IV indicators for binge eating episodes. AB - OBJECTIVE: Research has examined various aspects of the validity of the research criteria for binge eating disorder (BED) but has yet to evaluate the utility of the 5 Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) "indicators for impaired control" specified to help determine loss of control while overeating (i.e., binge eating). We examined the diagnostic efficiency of these indicators proposed as part of the research criteria for BED (eating until uncomfortably full; eating when not hungry; eating more rapidly than usual; eating in secret; and feeling disgust, shame, or depression after the episode). METHOD: A total of 916 community volunteers completed a battery of measures including questions about each of the indicators. Participants were categorized into 3 groups: BED (N = 164), bulimia nervosa (BN; N = 83), and non-binge-eating controls (N = 669). Four conditional probabilities (sensitivity, specificity, positive predictive power [PPP], and negative predictive power [NPP]) as well as total predictive value (TPV) and kappa coefficients were calculated for each indicator criterion in separate analyses comparing BED, BN, and combined BED + BN groups relative to controls. RESULTS: PPPs and NPPs suggest all of the indicators have predictive value, with eating alone because embarrassed (PPP = .80) and feeling disgusted (NPP = .93) performing as the best inclusion and exclusion criteria, respectively. The best overall indicators for correctly identifying binge eating (based on TPV and kappa) were eating when not hungry and eating alone because embarrassed. CONCLUSIONS: All 5 proposed indicators for impaired control for determining binge eating have utility, and the diagnostic efficiency statistics provide guidance for clinicians and the DSM-5 regarding their usefulness for inclusion or exclusion. PMID- 21261437 TI - Gender differences in emotional risk for self- and other-directed violence among externalizing adults. AB - OBJECTIVE: Women and men generally differ in how frequently they engage in other- and self-directed physical violence and may show distinct emotional risk factors for engagement in these high-impact behaviors. To inform this area, we investigated gender differences in the relationship of emotional tendencies (i.e., anger, hostility, and anhedonic depression) that may represent risk for other-directed violence (i.e., physical fighting, attacking others unprovoked) and self-directed violence (i.e., self-injury, suicide attempts). METHOD: The ethnically diverse sample consisted of 372 adults (252 men and 120 women age 18 55) with a history of criminal convictions. Facets of emotional risk assessed with the Aggression Questionnaire (Buss & Warren, 2000) and Mood and Anxiety Symptom Questionnaire (Watson et al., 1995) were entered simultaneously as explanatory variables in regression analyses to investigate their unique contributions to other- and self-directed physical violence in men and women. RESULTS: Analyses revealed that anhedonic depressive tendencies negatively predicted other-directed violence and positively predicted self-directed violence in men and women, consistent with a model of depression in which aggression is turned inward (Henriksson et al., 1993). Gender differences, however, emerged for the differential contributions of anger and hostility to other- and self-directed violence. Trait anger (i.e., difficulty controlling one's temper) was associated with other-directed violence selectively in men, whereas trait hostility (i.e., suspiciousness and alienation) was associated with self- and other-directed violence among women. CONCLUSIONS: The divergent findings for trait anger and hostility underscore the need to examine gender-specific risk factors for physical violence to avoid excluding potentially useful clinical features of these mental health outcomes. PMID- 21261438 TI - High- and low-level dissonance-based eating disorder prevention programs with young women with body image concerns: an experimental trial. AB - OBJECTIVE: As cognitive dissonance is theorized to contribute to the effects of dissonance-based eating disorder prevention programs, we evaluated a high dissonance version of this program against a low-dissonance version and a wait list control condition to provide an experimental test of the mechanism of intervention effects. METHOD: Female college students (N = 124, mean age = 20.9 years, SD = 3.9) with body image concerns were randomized to the 3 conditions. The high-dissonance program was designed to maximize dissonance induction, and the low-dissonance program was designed to minimize it; the substantive content of the 2 programs was matched. RESULTS: Relative to controls, those in the high dissonance condition showed significantly greater reductions in thin-ideal internalization, body dissatisfaction, dieting, and eating disorder symptoms by posttest, and those in the low-dissonance condition showed significantly greater reductions in the first 3 outcomes by posttest, with most of these effects persisting to 3-month follow-up. High-dissonance participants showed significantly greater reductions in eating disorder symptoms than low-dissonance participants did by posttest, but this effect was nonsignificant by 3-month follow-up. CONCLUSIONS: Results suggest that dissonance induction contributes to intervention effects but imply that the intervention content, nonspecific factors, and demand characteristics play a much more potent role in producing effects. PMID- 21261440 TI - Hydrogen peroxide enhances phagocytosis of Pseudomonas aeruginosa in hyperoxia. AB - Mechanical ventilation with hyperoxia is a necessary treatment for patients with respiratory distress. However, patients on mechanical ventilation have increased susceptibility to infection. Studies including ours have shown that reactive oxygen species (ROS), generated by exposure to prolonged hyperoxia, can cause a decrease in the phagocytic activity of alveolar macrophages. Hydrogen peroxide (H2O2) is a form of ROS generated under hyperoxic conditions. In this study, we examined whether treatment with H2O2 directly affects macrophage phagocytic ability in RAW 264.7 cells that were exposed to either 21% O2 (room air) or 95% O2 (hyperoxia). Moderate concentrations (ranging from 10 to 250 MUM) of H2O2 significantly enhanced macrophage phagocytic activity and restored hyperoxia suppressed phagocytosis through attenuation of hyperoxia-induced disorganization of actin cytoskeleton and actin oxidation. These results indicate that H2O2 at low-moderate concentrations can be beneficial to host immune responses by improving macrophage phagocytic activity. PMID- 21261441 TI - The leaf extract of Spondias mombin L. displays an anti-inflammatory effect and suppresses inducible formation of tumor necrosis factor-alpha and nitric oxide (NO). AB - Extracts of Spondias mombin L. (Anacardiacea) is used in the traditional medicine of Africa and Latin America to treat many inflammatory conditions, with repeated claims of efficacy. However, there are no scientific data yet to support these claims and the mechanism through which the extract may be acting is still unknown. This study was undertaken to investigate the effects of the methanolic extract of the leaf of S. mombin (SM) on inflammation and to uncover some of the possible mechanisms that could explain any observed changes. The anti inflammatory activity of the extract was investigated in Wistar rats using intraplantar injection of carrageenan as an in vivo model of inflammation. The effect of oral supplementation of the SM extract on tumor necrosis factor (TNF) alpha levels after an intraperitoneal lipopolysaccharide (LPS; 1 mg/kg) challenge was investigated in mice. The effect of SM on TNF-alpha and inducible nitric oxide (iNO) production by LPS-stimulated bone marrow-derived macrophages (BM-MO) was also investigated in vitro. BM-MO were preincubated for 2 h with SM (0-100 MUg/ml), activated with LPS, and then TNF-alpha and NO production measured in the cell-free conditioned culture supernatant after 24 h of incubation. The study showed that pre-treatment of rats with the SM extract (at 100, 200, and 400 mg/kg, per os) caused a significant dose-related inhibition of carrageenan induced paw edema over a 4-h period. In treated mice, LPS-inducible (systemic) TNF-alpha levels were found to be significantly lower as a result of their receiving the SM extract. In vitro, SM treatment caused a dose-dependent decrease in LPS-inducible TNF-alpha and NO production by BM-MO compared to the effects of treatment of the cells with LPS alone. Taken together, the results of these studies suggest that supplementation with SM extract can alleviate inflammatory responses and that this could possibly be via a suppression of the production of pro-inflammatory mediators and cytokines such as TNF-alpha and iNO. PMID- 21261439 TI - Effects of environmentally-relevant levels of perfluorooctane sulfonate on clinical parameters and immunological functions in B6C3F1 mice. AB - In the first part of a series of studies to account for perfluorooctane sulfonate (PFOS)-induced sheep red blood cell (SRBC)-specific immunoglobulin M (IgM) antibody suppression in mice, a survey of clinical and immunotoxicological endpoints was examined. Adult female B6C3F1 mice were exposed orally for 28 days to a total administered dose (TAD) of 0, 0.1, 0.5, 1, or 5 mg PFOS/kg. Uterus wet weight was significantly decreased compared with control at the 5 mg/kg dose. No indications of wasting syndrome, malnutrition, alteration of thyroid homeostasis, or signs of overt toxicity were observed. Numbers of splenic CD19+/CD21-, CD19+/CD21+, B220+/CD40+, CD4+/CD154-, CD4+/CD154+, and MHC-II+ cells were not altered. Additionally, ex vivo interleukin-4 (IL-4), IL-5, and IL-6 production by in vitro anti-CD3- or phorbol myristate acetate-stimulated CD4+ T-cells was not affected. Ex vivo IL-6 production by B-cells was significantly increased by in vitro stimulation with either anti-CD40 or lipopolysaccharide. Increased IL-6 production by B-cells was the most sensitive endpoint assessed resulting in alterations at the lowest dose tested (0.1 mg/kg TAD) following anti-CD40 stimulation. Further studies are required to characterize effects on inflammatory markers such as IL-6 at environmentally relevant concentrations of PFOS and to determine the key events associated with PFOS-induced IgM suppression to address potential human health risks. PMID- 21261442 TI - Comparative pulmonary toxicity of inhaled nickel nanoparticles; role of deposited dose and solubility. AB - In this pilot study, we investigated which physicochemical properties of nickel hydroxide nanoparticles (nano-NH) were mainly responsible in inducing pulmonary toxicity. First, we studied the role of nickel ions solubilized from nano-NH by comparing the toxic effects of nano-NH to those of readily soluble nickel sulfate nanoparticles (nano-NS). Additionally, to test whether there was a non-specific stress response due to particle morphology, we compared the toxicity of nano-NH with that of carbon nanoparticles (nano-C) and titanium dioxide nanoparticles (nano-Ti), both of which had similar physical properties such as particle size and shape, to nano-NH. We exposed mice to each type of nanoparticles for 4?h via a whole-body inhalation system and examined oxidative stress and inflammatory responses in the lung. We also determined the lung burden and clearance of Ni following nano-NH and nano-NS exposures. The results showed that lung deposition of nano-NH was significantly greater than that of nano-NS and nano-NH appeared to have stronger inflammogenic potential than nano-NS even when lung Ni burden taken into consideration. This suggests that the toxicity of nano-NH is not driven solely by released Ni ions from deposited nano-NH particles. However, it is unlikely that the greater toxic potential of nano-NH is attributable to a generic stress response from any nanoparticle exposure, since nano-C and nano-Ti did not elicit toxic responses similar to those of nano-NH. These results indicate that the observed pulmonary toxicity by inhaled nano-NH were chemical-specific and deposited dose and solubility are key factors to understand toxicity induced by nano-NH. PMID- 21261443 TI - Role of the infections in recurrent spontaneous abortion. AB - Embryo-fetal infections have been reported to cause recurrent spontaneous abortions (RSAs) at a rate lower than 4%. The possible mechanisms include production of toxic metabolic byproducts, fetal or placental infection, chronic endometrial infection, and chorio-amnionitis. Viruses appear to be the most frequently involved pathogens, since some of them can produce chronic or recurrent maternal infection. In particular, cytomegalovirus during pregnancy can reach the placenta by viremia, following both primary and recurrent infection, or by ascending route from the cervix, mostly following reactivation. Another herpesvirus, herpes simplex virus type 2, less frequently type 1, causes recurrent infections of the genital tract, which can involve the feto-placental unit. Parvoviruses have also been implicated in the development of repeated fetal loss. Among bacterial infections, Chlamydia trachomatis, Ureaplasma urealyticum,and Mycoplasma hominis have been mostly associated with occurrence of RSA. An increased risk of abortion among women with bacterial vaginosis (BV) during early pregnancy was also shown, but questions arise about the role of chronic BV in its occurrence. Although a definitive relationship between recurrently active infections and RSA is still lacking, mostly due to difficulties in demonstrating the pathogenic role of each individual isolated pathogen, diagnosis and therapy of RSA-related infections should be attempted. The diagnosis of infectious agents as a possible cause of RSA might lead to a therapeutic approach with antiviral drugs and antibiotics or using immunoglobulins, which can display both anti-infective neutralizing and immunomodulating properties. PMID- 21261444 TI - Depression in pregnancy: time of screening and access to psychiatric care. AB - OBJECTIVE: To determine the timing of screening for postpartum depression that optimizes access to psychiatric care. METHODS: Cross-sectional evaluation of women receiving obstetric care in a community-based medical center clinic from March to July 2006, who were screened for depression at 36 weeks gestation, delivery, and 6 weeks postpartum using the Edinburgh Postnatal Depression Scale. Positive screens generated referrals for psychiatric evaluation. The rate of positive screens for depression and psychiatric follow-up at each time point was evaluated. RESULTS: Of the 293 patients evaluated, the distribution of the first screen which occurred during the study period was 21% at 36 weeks, 31% at delivery, and 48% at 6 weeks postpartum. The incidence of a positive screen was 5% at 36 weeks, 16% at delivery and 14% at 6 weeks postpartum. Access to psychiatric care occurred in 33% at 36 weeks, 15% at 6 weeks postpartum and 100% at delivery (p = 0.001). CONCLUSION: Screening for depression in the hospital after delivery improves access to psychiatric care. PMID- 21261445 TI - Periodontal disease and bacterial vaginosis as genetic and environmental markers for the risk of spontaneous preterm labor and preterm birth. AB - OBJECTIVE: The aim of this study was to review the evidence associating periodontal disease, and bacterial vaginosis with preterm birth, and the link with gene polymorphism, as well as the preventions and interventions which might reduce the risk of spontaneous preterm labor and preterm births in women with periodontal disease and/or bacterial vaginosis. BACKGROUND: Preterm birth accounts for 70% of perinatal mortality, nearly 50% of long term neurological morbidity, and a significant impact on health care costs. There is evidence that spontaneous preterm labor and preterm birth are associated with intrauterine infection due to abnormal genital and/or oral colonization. Periodontal disease and bacterial vaginosis share microbiological similarities, and both conditions are associated with spontaneous preterm labor and preterm birth. In addition, periodontal disease and bacterial vaginosis have been linked through gene polymorphism. METHODS: A review of the literature using widely accepted scientific search engines in English language. RESULTS: Studies evaluating antibiotic administration to eradicate periodontal disease and/or bacterial vaginosis responsible organisms, and minimize the risk of preterm births have yielded conflicting results. With respect to bacterial vaginosis, the timing and the choice of antibiotic administration might partly explain the conflicting results. The use of scaling and/or root planning for women with periodontal disease appears to reduce the risk of preterm birth, but routine administration of antibiotics has not demonstrated any impact on preterm birth. CONCLUSION: Prospective studies evaluating the association of gene polymorphism with preterm birth, and the contribution of periodontal disease and bacterial vaginosis are needed. PMID- 21261446 TI - Pregnancy planning in women with pregestational diabetes. AB - OBJECTIVES: Women with pregestational diabetes are advised to plan their pregnancies to optimize glycemia and reduce fetal complications. We evaluated the adequacy of pregnancy planning effort and medical planning in pregnant women with type 1 and type 2 diabetes. METHODS: This retrospective cohort study surveyed pregnant women with pregestational diabetes mellitus between 2006 and 2008 in Ontario, Canada. We evaluated three measures of pregnancy planning: pregnancy planning effort, medical planning based on prepregnancy glycemic control, and folic acid use. We compared women with type 1 and type 2 diabetes and explored predictors of pregnancy planning. RESULTS: Of the 163 women studied (89 type 1, 74 type 2 diabetes), 47% reported high pregnancy planning effort, 58% reported attempts to optimize glycemic control, and 56% took folic acid before pregnancy. Of those who reported high pregnancy planning, 20% did not medically plan their pregnancies. Rates were similar between women with type 1 and type 2 diabetes. The most important predictor of pregnancy planning was having discussed plans with their physician. CONCLUSIONS: Our findings suggest that pregnancy planning is suboptimal in women with both type 1 and type 2 diabetes, highlighting a need to improve preconception counseling for all women with pregestational diabetes. PMID- 21261447 TI - The effects of sivelestat sodium hydrate on uterine contraction and the concentration of maternal and fetal blood cytokines in a sheep model of intra amniotic infection induced by lipopolysaccharide. AB - OBJECTIVE: To evaluate the effects of a neutrophil elastase inhibitor, sivelestat sodium hydrate, in a sheep model of intra-amniotic infection(IAI) induced by lipopolysaccharide (LPS) injected into the intra-amniotic compartment. METHODS: We examined 15 chronically instrumented ewes, the ewes were assigned randomly as group A (five ewes) administered an antibiotic after LPS administration, group B (five ewes) administered a neutrophil elastase inhibitor (0.2 mg/kg/h) with an antibiotic after LPS administration, and group C (five ewes) a sham operation group. Uterine contraction was evaluated by fetal tracheal pressure and concentrations of PGE2, IL-6, IL-8, TNF-alpha in maternal and fetal blood before and after LPS administration were measured chronologically. RESULTS: (1) All ewes of group A delivered within 72 h, but only one ewe of group B delivered. Uterine contraction of group B was suppressed about 60% in comparison with group A. (2) Maternal blood concentrations of PGE2, IL-6, IL-8, and TNF-alpha level of group A increased chronologically and when compared with groups B and C the increase was significantly higher. (3) There were no significant changes in the fetal blood cytokines in any of the three groups. CONCLUSION: Administration of neutrophil elastase inhibitor might suggest a useful strategy to prevent premature delivery resulting from intrauterine infection. PMID- 21261448 TI - Improving maternal and neonatal departments in high and low resource settings: the opinion of local health providers. AB - AIM: We compared local health caregivers' opinions regarding the priority areas for improving the maternal and neonatal departments in low and high resource countries. METHODS: Personnel involved in maternal and neonatal care operating in level III, teaching hospitals in four countries (Sri Lanka, Mongolia, USA, and Italy) were asked to fill out an anonymous, written questionnaire. RESULTS: The questionnaire was completed by 1112 out of 1265 (87.9%) participants. "Personnel's education" was classified as the first most important intervention by health providers working in high (49.0%) as well as in low (29.9%) resource countries, respectively. Improvement in salary, equipment, internet access, and organizational protocols were considered as the most important interventions by a significantly larger percentage of personnel from low resource countries in comparison with those from high resource countries. Health providers from high resource countries considered organizational aspects (to define specific roles and responsibilities) as a priority more frequently than their colleagues from low resource countries. CONCLUSIONS: Although education of personnel was valued as the highest priority for improving maternal and neonatal departments there are substantial differences in priorities associated with the working setting. Local caregivers' opinion may contribute to better design interventions in settings with high or limited resources. PMID- 21261449 TI - 50-Gram glucose challenge test: is it indicative of outcomes in women without gestational diabetes mellitus? AB - OBJECTIVE: To examine whether the 50-gram glucose challenge test (GCT) is associated with perinatal outcomes in women without gestational diabetes mellitus (GDM). METHODS: This is a retrospective cohort study of 13,789 women who received the GCT and did not have a diagnosis of GDM at the University of California, San Francisco UCSF. GCT values were categorized and examined as predictors of perinatal morbidity using chi-square test and multivariable logistic regression analyses adjusting for maternal characteristics. RESULTS: In women with an elevated GCT but without GDM, the odds of preeclampsia, cesarean delivery, and elevated birth weight were increased. The odds of large-for-gestational age status were increased with aOR 2.0 (95% CI 1.38-2.90) in the 160-179 mg/dl group. The odds of shoulder dystocia was increased with aOR 3.35 (CI 1.03-10.88) in the >=180 mg/dl group. CONCLUSION: In women without GDM, elevated 50-gram GCT values were associated with higher odds of perinatal morbidity. These findings further support evidence that impaired glucose tolerance is a continuum with possible associated adverse outcomes even at mild ranges; additional research is required to investigate appropriate interventions for women with abnormal screens for GDM. PMID- 21261450 TI - Sublexical properties of spoken words modulate activity in Broca's area but not superior temporal cortex: implications for models of speech recognition. AB - Many models of spoken word recognition posit that the acoustic stream is parsed into phoneme level units, which in turn activate larger representations [McClelland, J. L., & Elman, J. L. The TRACE model of speech perception. Cognitive Psychology, 18, 1-86, 1986], whereas others suggest that larger units of analysis are activated without the need for segmental mediation [Greenberg, S. A multitier theoretical framework for understanding spoken language. In S. Greenberg & W. A. Ainsworth (Eds.), Listening to speech: An auditory perspective (pp. 411-433). Mahwah, NJ: Erlbaum, 2005; Klatt, D. H. Speech perception: A model of acoustic-phonetic analysis and lexical access. Journal of Phonetics, 7, 279 312, 1979; Massaro, D. W. Preperceptual images, processing time, and perceptual units in auditory perception. Psychological Review, 79, 124-145, 1972]. Identifying segmental effects in the brain's response to speech may speak to this question. For example, if such effects were localized to relatively early processing stages in auditory cortex, this would support a model of speech recognition in which segmental units are explicitly parsed out. In contrast, segmental processes that occur outside auditory cortex may indicate that alternative models should be considered. The current fMRI experiment manipulated the phonotactic frequency (PF) of words that were auditorily presented in short lists while participants performed a pseudoword detection task. PF is thought to modulate networks in which phoneme level units are represented. The present experiment identified activity in the left inferior frontal gyrus that was positively correlated with PF. No effects of PF were found in temporal lobe regions. We propose that the observed phonotactic effects during speech listening reflect the strength of the association between acoustic speech patterns and articulatory speech codes involving phoneme level units. On the basis of existing lesion evidence, we interpret the function of this auditory-motor association as playing a role primarily in production. These findings are consistent with the view that phoneme level units are not necessarily accessed during speech recognition. PMID- 21261451 TI - The development of cortical sensitivity to visual word forms. AB - The ability to extract visual word forms quickly and efficiently is essential for using reading as a tool for learning. We describe the first longitudinal fMRI study to chart individual changes in cortical sensitivity to written words as reading develops. We conducted four annual measurements of brain function and reading skills in a heterogeneous group of children, initially 7-12 years old. The results show age-related increase in children's cortical sensitivity to word visibility in posterior left occipito-temporal sulcus (LOTS), nearby the anatomical location of the visual word form area. Moreover, the rate of increase in LOTS word sensitivity specifically correlates with the rate of improvement in sight word efficiency, a measure of speeded overt word reading. Other cortical regions, including V1, posterior parietal cortex, and the right homologue of LOTS, did not demonstrate such developmental changes. These results provide developmental support for the hypothesis that LOTS is part of the cortical circuitry that extracts visual word forms quickly and efficiently and highlight the importance of developing cortical sensitivity to word visibility in reading acquisition. PMID- 21261452 TI - The memory function of noradrenergic activity in non-REM sleep. AB - There is a long-standing assumption that low noradrenergic activity during sleep reflects mainly the low arousal during this brain state. Nevertheless, recent research has demonstrated that the locus coeruleus, which is the main source of cortical noradrenaline, displays discrete periods of intense firing during non REM sleep, without any signs of awakening. This transient locus coeruleus activation during sleep seems to occur in response to preceding learning-related episodes. In the present study, we manipulate noradrenergic activity during sleep in humans with either the alpha2-autoreceptor agonist clonidine or the noradrenaline reuptake inhibitor reboxetine. We show that reducing noradrenergic activity during sleep, but not during wakefulness, impairs subsequent memory performance in an odor recognition task. Increasing noradrenergic availability during sleep, in contrast, enhances memory retention. We conclude that noradrenergic activity during non-REM sleep interacts with other sleep-related mechanisms to functionally contribute to off-line memory consolidation. PMID- 21261454 TI - Double dissociation of dopamine genes and timing in humans. AB - A number of lines of evidence implicate dopamine in timing [Rammsayer, T. H. Neuropharmacological approaches to human timing. In S. Grondin (Ed.), Psychology of time (pp. 295-320). Bingley, UK: Emerald, 2008; Meck, W. H. Neuropharmacology of timing and time perception. Brain Research, Cognitive Brain Research, 3, 227 242, 1996]. Two human genetic polymorphisms are known to modulate dopaminergic activity. DRD2/ANKK1-Taq1a is a D(2) receptor polymorphism associated with decreased D(2) density in the striatum [Jonsson, E. G., Nothen, M. M., Grunhage, F., Farde, L., Nakashima, Y., Propping, P., et al. Polymorphisms in the dopamine D(2) receptor gene and their relationships to striatal dopamine receptor density of healthy volunteers. Molecular Psychiatry, 4, 290-296, 1999]; COMT Val158Met is a functional polymorphism associated with increased activity of the COMT enzyme such that catabolism of synaptic dopamine is greater in pFC [Meyer-Lindenberg, A., Kohn, P. D., Kolachana, B., Kippenhan, S., McInerney-Leo, A., Nussbaum, R., et al. Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genotype. Nature Neuroscience, 8, 594-596, 2005]. To investigate the role of dopamine in timing, we genotyped 65 individuals for DRD2/ANKK1-Taq1a, COMT Val158Met, and a third polymorphism, BDNF Val66Met, a functional polymorphism affecting the expression of brain-derived neurotrophic factor [Egan, M. F., Kojima, M., Callicott, J. H., Goldberg, T. E., Kolachana, B. S., Bertolino, A., et al. The BDNF val66met polymorphism affects activity dependent secretion of BDNF and human memory and hippocampal function. Cell, 112, 257-269, 2003]. Subjects were tested on a temporal discrimination task with sub- and supra-second intervals (500- and 2000-msec standards) as well as a spontaneous motor tempo task. We found a double dissociation for temporal discrimination: the DRD2/ANKK1-Taq1a polymorphism (A1+ allele) was associated with significantly greater variability for the 500-msec duration only, whereas the COMT Val158Met polymorphism (Val/Val homozygotes) was associated with significantly greater variability for the 2000-msec duration only. No differences were detected for the BDNF Vall66Met variant. Additionally, the DRD2/ANKK1-Taq1a polymorphism was associated with a significantly slower preferred motor tempo. These data provide a potential biological basis for the distinctions between sub- and supra-second timing and suggest that BG are integral for the former whereas pFC is implicated in the latter. PMID- 21261453 TI - A neural region of abstract working memory. AB - Over 350 years ago, Descartes proposed that the neural basis of consciousness must be a brain region in which sensory inputs are combined. Using fMRI, we identified at least one such area for working memory, the limited information held in mind, described by William James as the trailing edge of consciousness. Specifically, a region in the left intraparietal sulcus was found to demonstrate load-dependent activity for either visual stimuli (colored squares) or a combination of visual and auditory stimuli (spoken letters). This result was replicated across two experiments with different participants and methods. The results suggest that this brain region, previously well known for working memory of visually presented materials, actually holds or refers to information from more than one modality. PMID- 21261455 TI - Phytotoxicity and biotransformation of La2O3 nanoparticles in a terrestrial plant cucumber (Cucumis sativus). AB - With the increasing applications of metal-based nanoparticles in various commercial products, it is necessary to address their environmental fate and potential toxicity. In this work, we assessed the phytotoxicity of lanthanum oxide (La2O3) NPs to cucumber plants and determined its distribution and biotransformation in roots by TEM and EDS, as well as STXM and NEXAFS. LaCl3 was also studied as a reference toxicant. La2O3 NPs and LaCl3 were both transformed to needle-like LaPO4 nanoclusters in the intercellular regions of the cucumber roots. In vitro experiments demonstrated that the dissolution of La2O3 NPs was significantly enhanced by acetic acid. Accordingly, we proposed that the dissolution of NPs at the root surface induced by the organic acids extruded from root cells played an important role in the phytotoxicity of La2O3 NPs. The reactions of active NPs at the nano-bio interface should be taken into account when studying the toxicity of dissolvable metal-based nanoparticles. PMID- 21261456 TI - Liposomal architecture boosts biocompatibility of nanohybrid cerasomes. AB - Biomimetic cerasome has drawn much attention as a novel drug delivery system because its atomic layer of polyorganosiloxane surface imparts higher morphological stability than conventional liposomes and its liposomal bilayer structure reduces the overall rigidity and density greatly compared to silica nanoparticles. But, the issues about the interactions between cerasomes and biological systems have not been addressed as far as we could find. Herein, we reported cellular uptake of cerasomes and their biological effects toward human umbilical vein endothelial cells (HUVECs) compared with silica nanoparticles. The results indicated that the uptake of cerasomes by HUVECs was a concentration-, time-, and energy-dependent process and occurred probably through a process of clathrin-mediated endocytosis, which resulted in rearrangement of the cell cytoskeleton. Cerasomes affected different aspects of cell function to a smaller extent than silica nanoparticles, including cell proliferation, cell cycle, cell apoptosis, endogenous ROS level and pro-inflammatory molecular expression. In a word, cerasomes are more biocompatible than silica nanoparticles due to the incorporation of the liposomal architecture into cerasomes. The preliminary data will assist in the further development of new cerasome-based delivery systems. PMID- 21261457 TI - Measurement of airborne nanoparticle surface area using a filter-based gas adsorption method for inhalation toxicology experiments. AB - Measurement of the surface area of airborne nanoparticles as administered to an experimental subject is critical for characterizing exposures during inhalation experiments. A filter-based surface area measurement methodology is described herein that allows for such determinations. Krypton gas adsorption was used to determine total particle surface area. Track-etched polycarbonate 0.4 MUm pore filters were chosen as the collection substrate for metal oxide particles due to their highly reproducible surface areas and low background weights. The subject nanomaterials included two different batches of ultrafine TiO2, TiO2 nanorods, and SiO2. The instrument detection limit for surface area was 200 cm2 (0.02 m2). Ninety percent confidence interval estimates of method accuracy were 17.7-23.5% with a point estimate of 20.8%. The filter-based surface area measurement strategy is demonstrated to be a viable sampling and analysis methodology that provides much needed physical characterization information of particles as administered in an animal inhalation chamber. PMID- 21261458 TI - The effect of PEGylation on the stability of small therapeutic proteins. AB - The influence of PEGylation on the thermal stability of small therapeutic proteins was evaluated using two model proteins. Changes in the midpoint of thermal unfolding and the ability to properly refold after thermal denaturation were monitored by differential scanning calorimetry (DSC) as a function of PEGylation and pH. The results showed that PEGylation increased the thermal stability of both model proteins as well as their ability to refold properly after thermal denaturation. The DSC results were compared to traditional accelerated stability data that were collected using size exclusion high performance liquid chromatography (SE-HPLC). The DSC data agreed reasonably well with those from SE-HPLC indicating that microcalorimetry can be an efficient screening tool for PEGylated proteins. PMID- 21261460 TI - Gene therapy of intracranial glioma using interleukin 12-secreting human umbilical cord blood-derived mesenchymal stem cells. AB - Clinical trials of gene therapy using a viral delivery system for glioma have been limited. Recently, gene therapy using stem cells as the vehicles for delivery of therapeutic agents has emerged as a new treatment strategy for malignant brain tumors. In this study, we used human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) as delivery vehicles with glioma-targeting capabilities, and modified interleukin-12 (IL-12p40N220Q; IL-12M) as a novel therapeutic gene. We also engineered UCB-MSCs to secret IL-12M (UCB-MSC-IL12M) via tetrameric cell-permeable peptide (4HP4)-mediated adenoviral transduction. We confirmed the migratory capacity of UCB-MSC-IL12M toward GL26 mouse glioma cells by an in vitro migration assay and in vivo injection of UCB-MSC-IL12M into the ipsilateral hemisphere of implanted gliomas in C57BL/6 mice. In vivo efficacy experiments showed that intratumoral injection of UCB-MSC-IL12M significantly inhibited tumor growth and prolonged the survival of glioma-bearing mice compared with control mice. Antitumor effects were associated with increased local IL-12M levels, followed by interferon-gamma secretion and T-cell infiltration in intracranial gliomas, as well as antiangiogenesis. Interestingly, tumor-free mice after UCB-MSC-IL12M treatment were resistant to ipsilateral and contralateral tumor rechallenge, which was closely associated with tumor-specific long-term T cell immunity. Thus, our results provide the rationale for designing novel experimental protocols to induce long-term antitumor immunity against intracranial gliomas using UCB-MSCs as an effective delivery vehicle for therapeutic cytokines including IL-12M. PMID- 21261462 TI - 454 Genome sequencing of Pseudoperonospora cubensis reveals effector proteins with a QXLR translocation motif. AB - Pseudoperonospora cubensis is a biotrophic oomycete pathogen that causes downy mildew of cucurbits, a devastating foliar disease threatening cucurbit production worldwide. We sequenced P. cubensis genomic DNA using 454 pyrosequencing and obtained random genomic sequences covering approximately 14% of the genome, thus providing the first set of useful genomic sequence information for P. cubensis. Using bioinformatics approaches, we identified 32 putative RXLR effector proteins. Interestingly, we also identified 29 secreted peptides with high similarity to RXLR effectors at the N-terminal translocation domain, yet containing an R-to-Q substitution in the first residue of the translocation motif. Among these, a family of QXLR-containing proteins, designated as PcQNE, was confirmed to have a functional signal peptide and was further characterized as being localized in the plant nucleus. Internalization of secreted PcQNE into plant cells requires the QXLR-EER motif. This family has a large number of near identical copies within the P. cubensis genome, is under diversifying selection at the C-terminal domain, and is upregulated during infection of plants, all of which are common characteristics of characterized oomycete effectors. Taken together, the data suggest that PcQNE are bona fide effector proteins with a QXLR translocation motif, and QXLR effectors are prevalent in P. cubensis. Furthermore, the massive duplication of PcQNE suggests that they might play pivotal roles in pathogen fitness and pathogenicity. PMID- 21261461 TI - Contributions of gene marking to cell and gene therapies. AB - The first human genetic modification studies used replication-incompetent integrating vector vectors to introduce marker genes into T lymphocytes and subsequently into hematopoietic stem cells. Such studies have provided numerous insights into the biology of hematopoiesis and immune reconstitution and contributed to clinical development of gene and cell therapies. Tracking of hematopoietic reconstitution and analysis of the origin of residual malignant disease after hematopoietic transplantation has been possible via gene marking. Introduction of selectable marker genes has enabled preselection of specific T cell populations for tumor and viral immunotherapy and reduced the threat of graft-versus-host disease, improving the survival of patients after allogeneic marrow transplantation. Marking studies in humans, murine xenografts, and large animals have helped optimize conditions for gene transfer into CD34(+) hematopoietic progenitors, contributing to the achievement of gene transfer efficiencies sufficient for clinical benefit in several serious genetic diseases such as X-linked severe combined immunodeficiency and adrenoleukodystrophy. When adverse events linked to insertional mutagenesis arose in clinical gene therapy trials for inherited immunodeficiencies, additional animal studies using gene marking vectors have greatly increased our understanding of genotoxicity. The knowledge gained from these studies is being translated into new vector designs and clinical protocols, which we hope will continue to improve the efficiency, effectiveness and safety of these promising therapeutic approaches. PMID- 21261463 TI - Activation of a Lotus japonicus subtilase gene during arbuscular mycorrhiza is dependent on the common symbiosis genes and two cis-active promoter regions. AB - The subtilisin-like serine protease SbtM1 is strongly and specifically induced during arbuscular mycorrhiza (AM) symbiosis in Lotus japonicus. Another subtilase gene, SbtS, is induced during early stages of nodulation and AM. Transcript profiling in plant symbiosis mutants revealed that the AM-induced expression of SbtM1 and the gene family members SbtM3 and SbtM4 is dependent on the common symbiosis pathway, whereas an independent pathway contributes to the activation of SbtS. We used the specific spatial expression patterns of SbtM1 promoter beta d-glucuronidase (GUS) fusions to isolate cis elements that confer AM responsiveness. A promoter deletion and substitution analysis defined two cis regions (region I and II) in the SbtM1 promoter necessary for AM-induced GUS activity. 35S minimal promoter fusions revealed that either of the two regions is sufficient for AM responsiveness when tested in tandem repeat arrangement. Sequence-related regions were found in the promoters of AM-induced subtilase genes in Medicago truncatula and rice, consistent with an ancient origin of these elements predating the divergence of the angiosperms. PMID- 21261459 TI - State of the APC/C: organization, function, and structure. AB - The ubiquitin-proteasome protein degradation system is involved in many essential cellular processes including cell cycle regulation, cell differentiation, and the unfolded protein response. The anaphase-promoting complex/cyclosome (APC/C), an evolutionarily conserved E3 ubiquitin ligase, was discovered 15 years ago because of its pivotal role in cyclin degradation and mitotic progression. Since then, we have learned that the APC/C is a very large, complex E3 ligase composed of 13 subunits, yielding a molecular machine of approximately 1 MDa. The intricate regulation of the APC/C is mediated by the Cdc20 family of activators, pseudosubstrate inhibitors, protein kinases and phosphatases and the spindle assembly checkpoint. The large size, complexity, and dynamic nature of the APC/C represent significant obstacles toward high-resolution structural techniques; however, over the last decade, there have been a number of lower resolution APC/C structures determined using single particle electron microscopy. These structures, when combined with data generated from numerous genetic and biochemical studies, have begun to shed light on how APC/C activity is regulated. Here, we discuss the most recent developments in the APC/C field concerning structure, substrate recognition, and catalysis. PMID- 21261464 TI - Loss of cAMP-dependent protein kinase A affects multiple traits important for root pathogenesis by Fusarium oxysporum. AB - The soilborne fungal pathogen Fusarium oxysporum causes vascular wilt and root rot diseases in many plant species. We investigated the role of cyclic AMP dependent protein kinase A of F. oxysporum (FoCPKA) in growth, morphology, and root attachment, penetration, and pathogenesis in Arabidopsis thaliana. Affinity of spore attachment to root surfaces of A. thaliana, observed microscopically and measured by atomic force microscopy, was reduced by a loss-of-function mutation in the gene encoding the catalytic subunit of FoCPKA. The resulting mutants also failed to penetrate into the vascular system of A. thaliana roots and lost virulence. Even when the mutants managed to enter the vascular system via physically wounded roots, the degree of vascular colonization was significantly lower than that of the corresponding wild-type strain O-685 and no noticeable disease symptoms were observed. The mutants also had reduced vegetative growth and spore production, and their hyphal growth patterns were distinct from those of O-685. Coinoculation of O-685 with an focpkA mutant or a strain nonpathogenic to A. thaliana significantly reduced disease severity and the degree of root colonization by O-685. Several experimental tools useful for studying mechanisms of fungal root pathogenesis are also introduced. PMID- 21261465 TI - HrpG and HrpX play global roles in coordinating different virulence traits of Xanthomonas axonopodis pv. citri. AB - Xanthomonas axonopodis pv. citri is the causal agent of citrus canker, which is one of the most serious diseases of citrus. To understand the virulence mechanisms of X. axonopodis pv. citri, we designed and conducted genome-wide microarray analyses to characterize the HrpG and HrpX regulons, which are critical for the pathogenicity of X. axonopodis pv. citri. Our analyses revealed that 232 and 181 genes belonged to the HrpG and HrpX regulons, respectively. In total, 123 genes were overlapped in the two regulons at any of the three selected timepoints representing three growth stages of X. axonopodis pv. citri in XVM2 medium. Our results showed that HrpG and HrpX regulated all 24 type III secretion system genes, 23 type III secretion system effector genes, and 29 type II secretion system substrate genes. Our data revealed that X. axonopodis pv. citri regulates multiple cellular activities responding to the host environment, such as amino acid biosynthesis; oxidative phosphorylation; pentose-phosphate pathway; transport of sugar, iron, and potassium; and phenolic catabolism, through HrpX and HrpG. We found that 124 and 90 unknown genes were controlled by HrpG and HrpX, respectively. Our results suggest that HrpG and HrpX interplay with a global signaling network and co-ordinate the expression of multiple virulence factors for modification and adaption of host environment during X. axonopodis pv. citri infection. PMID- 21261466 TI - Molecular, ultrastructural, and biological characterization of Pennsylvania isolates of Plum pox virus. AB - Plum pox virus (PPV) was identified in Pennsylvania in 1999. The outbreak was limited to a four-county region in southern Pennsylvania. Initial serological and molecular characterization indicated that the isolates in Pennsylvania belong to the D strain of PPV. The Pennsylvania isolates were characterized by sequence analysis, electron microscopy, host range, and vector transmission to determine how these isolates related to their previously studied European counterparts. Genetically, Pennsylvania (PPV-Penn) isolates were more closely related to each other than to any other PPV-D strains, and isolates from the United States, Canada, and Chile were more closely related to each other than to European isolates. The PPV-Penn isolates exist as two clades, suggesting the possibility of multiple introductions. Electron microscopy analysis of PPV-Penn isolates, including cytopathological studies, indicated that the virions were similar to other Potyvirus spp. PPV-Penn isolates had a herbaceous host range similar to that of European D isolates. There were distinct differences in the transmission efficiencies of the two PPV-Penn isolates using Myzus persicae and Aphis spiraecola as vectors; however, both PPV-Penn isolates were transmitted by M. persicae more efficiently than a European D isolate but less efficiently than a European M isolate. PMID- 21261467 TI - Risk factors for crop health under global change and agricultural shifts: a framework of analyses using rice in tropical and subtropical Asia as a model. AB - Plant disease epidemiology requires expansion of its current methodological and theoretical underpinnings in order to produce full contributions to global food security and global changes. Here, we outline a framework which we applied to farmers' field survey data set on rice diseases in the tropical and subtropical lowlands of Asia. Crop health risks arise from individual diseases, as well as their combinations in syndromes. Four key drivers of agricultural change were examined: labor, water, fertilizer, and land availability that translate into crop establishment method, water shortage, fertilizer input, and fallow period duration, respectively, as well as their combinations in production situations. Various statistical approaches, within a hierarchical structure, proceeding from higher levels of hierarchy (production situations and disease syndromes) to lower ones (individual components of production situations and individual diseases) were used. These analyses showed that (i) production situations, as wholes, represent very large risk factors (positive or negative) for occurrence of disease syndromes; (ii) production situations are strong risk factors for individual diseases; (iii) drivers of agricultural change represent strong risk factors of disease syndromes; and (iv) drivers of change, taken individually, represent small but significant risk factors for individual diseases. The latter analysis indicates that different diseases are positively or negatively associated with shifts in these drivers. We also report scenario analyses, in which drivers of agricultural change are varied in response to possible climate and global changes, generating predictions of shifts in rice health risks. The overall set of analyses emphasizes the need for large-scale ground data to define research priorities for plant protection in rapidly evolving contexts. They illustrate how a structured theoretical framework can be used to analyze emergent features of agronomic and socioecological systems. We suggest that the concept of "disease syndrome" can be borrowed in botanical epidemiology from public health to emphasize a holistic view of disease in shifting production situations in combination with the conventional, individual disease-centered perspective. PMID- 21261468 TI - Characterization of the RcsC sensor kinase from Erwinia amylovora and other Enterobacteria. AB - RcsC is a hybrid sensor kinase which contains a sensor domain, a histidine kinase domain, and a receiver domain. We have previously demonstrated that, although the Erwinia amylovora rcsC mutant produces more amylovoran than the wild-type (WT) strain in vitro, the mutant remains nonpathogenic on both immature pear fruit and apple plants. In this study, we have comparatively characterized the Erwinia RcsC and its homologs from various enterobacteria. Results demonstrate that expression of the Erwinia rcsC gene suppresses amylovoran production in various amylovoran overproducing WT and mutant strains, thus suggesting the presence of a net phosphatase activity of Erwinia RcsC. Findings have also demonstrated that rcsC homologs from other enterobacteria could not rescue amylovoran production of the Erwinia rcsC mutant in vitro. However, virulence of the Erwinia rcsC mutant is partially restored by rcsC homologs from Pantoea stewartii, Yersinia pestis, and Salmonella enterica but not from Escherichia coli on apple shoots. Domain swapping experiments have indicated that replacement of the E. coli RcsC sensor domain by those of Erwinia and Yersinia spp. partially restores virulence of the Erwinia rcsC mutant, whereas chimeric constructs containing the sensor domain of E. coli RcsC could not rescue virulence of the Erwinia rcsC mutant on apple. Interestingly, only chimeric constructs containing the histidine kinase and receiver domains of Erwinia RcsC are fully capable of rescuing amylovoran production. These results suggest that the sensor domain of RcsC may be important in regulating bacterial virulence, whereas the activity of the histidine kinase and receiver domains of Erwinia RcsC may be essential for amylovoran production in vitro. PMID- 21261469 TI - C-terminal region of plant ferredoxin-like protein is required to enhance resistance to bacterial disease in Arabidopsis thaliana. AB - Protein phosphorylation is an important biological process associated with elicitor-induced defense responses in plants. In a previous report, we described how plant ferredoxin-like protein (PFLP) in transgenic plants enhances resistance to bacterial pathogens associated with the hypersensitive response (HR). PFLP possesses a putative casein kinase II phosphorylation (CK2P) site at the C terminal in which phosphorylation occurs rapidly during defense response. However, the contribution of this site to the enhancement of disease resistance and the intensity of HR has not been clearly demonstrated. In this study, we generated two versions of truncated PFLP, PEC (extant CK2P site) and PDC (deleted CK2P site), and assessed their ability to trigger HR through harpin (HrpZ) derived from Pseudomonas syringae as well as their resistance to Ralstonia solanacearum. In an infiltration assay of HrpZ, PEC intensified harpin-mediated HR; however, PDC negated this effect. Transgenic plants expressing these versions indicate that nonphosphorylated PFLP loses its ability to induce HR or enhance disease resistance against R. solanacearum. Interestingly, the CK2P site of PFLP is required to induce the expression of the NADPH oxidase gene, AtrbohD, which is a reactive oxygen species producing enzyme. This was further confirmed by evaluating the HR on NADPH oxidase in mutants of Arabidopsis. As a result, we have concluded that the CK2P site is required for the phosphorylation of PFLP to enhance disease resistance. PMID- 21261470 TI - Morphological and molecular analysis of Fusarium lateritium, the cause of gray necrosis of hazelnut fruit in Italy. AB - Fusarium lateritium is a globally distributed plant pathogen. It was recently reported as the causal agent of nut gray necrosis (NGN) on hazelnut. Isolate characterization within F. lateritium was undertaken to investigate how morphological and molecular diversity was associated with host and geographic origin. Morphological studies combined with inter-simple-sequence repeat (ISSR) analysis, and phylogenetic analyses using translation elongation factor 1alpha (TEF-1alpha), beta-tubulin genes, and nuclear ribosomal DNA internal transcribed spacer (ITS) sequences were conducted to resolve relationships among 32 F. lateritium isolates from NGN-affected hazelnut fruit, and 14 from other substrates or 8 from other hosts than hazelnut. Colonies of F. lateritium from hazelnut showed dark grayish-olive differing from the orange-yellow color of all other isolates from other hosts. Generally, isolates from NGN-affected fruit failed to produce sporodochia on carnation leaf agar. The influence of host and substrate on the genetic structure of F. lateritium was supported by ISSR and analyzed with principal coordinates analysis. A relationship between hazelnut and genetic variation was inferred. Phylogenetic analysis of ITS provided limited resolution while TEF-1alpha and beta-tubulin analyses allowed a clear separation between the European and non-European F. lateritium isolates retrieved from GenBank, regardless of host. Though morphological traits of F. lateritium isolates from hazelnut were generally uniform in defining a typical morphogroup, they were not yet phylogenetically defined. In contrast, the typology related to slimy deep orange cultures, due to spore mass, grouped clearly separated from the other F. lateritium isolates and revealed a congruence between morphology and phylogeny. PMID- 21261471 TI - S-glutathionylation reshapes our understanding of endothelial nitric oxide synthase uncoupling and nitric oxide/reactive oxygen species-mediated signaling. AB - Oxidative stress has been shown to convert endothelial nitric oxide synthase (eNOS) from an NO-producing enzyme to an enzyme that generates superoxide, a process termed NOS uncoupling. This uncoupling of eNOS converts it to function as an NADPH oxidase with superoxide and hydrogen peroxide generation. eNOS uncoupling has been associated with many pathophysiologic conditions, such as heart failure, ischemia/reperfusion injury, hypertension, atherosclerosis, and diabetes. The mechanisms implicated in the uncoupling of eNOS include oxidation of the critical NOS cofactor tetrahydrobiopterin, depletion of L-arginine, and accumulation of methylarginines. All of these prior mechanisms of eNOS-derived reactive oxygen species formation occur primarily at the heme of the oxygenase domain and are blocked by heme blockers or the NOS inhibitor N-nitro-L-arginine methylester. Recently, we have identified another unique mechanism of redox regulation of eNOS through S-glutathionylation that was shown to be important in cell signaling and vascular disease. Herein, we briefly review the mechanisms of eNOS uncoupling as well as their interrelationships and the evidence for their importance in disease. PMID- 21261472 TI - Proteomic studies coupled with RNAi methodologies can shed further light on the downstream effects of telomerase in glioma. AB - A comprehensive proteomic study utilizing 2D-DIGE and MALDI-TOF was used to assess the effect of inhibiting two different regulatory mechanisms of telomerase in glioma. RNAi was used to target hTERT and hsp90alpha. Inhibition of telomerase activity resulted in downregulation of various cytoskeletal proteins with correlative evidence of the involvement of telomerase in regulating the expression of vimentin. Inhibition of telomerase via sihTERT resulted in the downregulation of vimentin expression in glioma cell lines in a grade-specific manner. This study identified novel downstream role of telomerase in regulating the expression of vimentin, thereby affecting tumor progression and metastasis. PMID- 21261473 TI - Dysregulation of betaglycan expression in primary human endometrial carcinomas. AB - TGFbeta signaling cascade plays a vital role in neoplastic transformation, but the function of betaglycan, which is a TGFbeta accessory receptor, is still unknown in particular cancer. Evaluation of betaglycan expression both at mRNA (real-time PCR) and protein (ELISA) level in the context of TGFbeta canonical signaling components, i.e., TGFbeta1, TGFbeta2, and TGFbetaRII, in endometrial carcinomas was performed. Betaglycan mRNA expression level was significantly (p < .001) downregulated with simultaneous betaglycan protein level upregulation in cancer samples. Obtained results suggest that endometrial cancer is associated with disruption of accessory receptor betaglycan expression, what may alter TGFbeta2-induced signaling. PMID- 21261474 TI - Patient's perception of care quality during radiotherapy sessions using respiratory gating techniques: validation of a specific questionnaire. AB - This prospective study was designed to validate a questionnaire on patients' perception of care quality during respiratory-gated radiotherapy for breast or lung cancer. Psychometric tests were performed on selected patients. Confirmatory factorial analyses and capacity to discriminate the responses were achieved to validate the best model on 297 patients. Factorial analyses identified the following three scales: (a) perception of quality, (b) global satisfaction, and (c) physical or emotional experience. The scales were able to differentiate patients' responses according to radiotherapy modalities. The questionnaire presented adequate psychometric properties. This tool could be used for the assessment from the patient's point of view. PMID- 21261475 TI - LMWH bemiparin and ULMWH RO-14 reduce the endothelial angiogenic features elicited by leukemia, lung cancer, or breast cancer cells. AB - Low-molecular-weight heparins (LMWH) are anticoagulant drugs that also possess antitumor properties. We evaluated whether "second generation" LMWH bemiparin and the Ultra-Low-MWH (ULMWH) RO-14 are able to inhibit in vitro the angiogenic response of microvascular endothelium stimulated by tumor-cell-conditioned media (TCM) from human leukemia, lung cancer, and breast cancer cells. Bemiparin and RO 14 dose dependently inhibited the increase of capillary-like tube formation (Matrigel-based assay) and endothelial migration (wound-healing assay) induced by TCM. Both drugs also inhibited angiogenic response elicited by purified VEGF and FGF-2. These findings support a possible role of these molecules as adjuvant drugs in cancer treatment. PMID- 21261476 TI - SMARCA5 methylation and expression in gastric cancer. AB - Here, we first evaluated SMARCA5 expression and promoter DNA methylation in gastric carcinogenesis. Immunohistochemistry and methylation-specific PCR were analyzed in 19 and 48 normal mucosa and in 52 and 92 gastric cancer samples, respectively. We observed higher immunoreactivity of SMARCA5 in gastric cancer samples than in normal mucosa. Moreover, SMARCA5 promoter methylation was associated with the absence of protein expression. Our findings suggest that SMARCA5 has a potential role in proliferation and malignancy in gastric carcinogenesis. PMID- 21261477 TI - A new endoscopic classification system of early-stage esophageal carcinoma and its usefulness in assessing the infiltration depth of esophageal carcinoma. AB - The growth pattern, height, and depth of early esophageal carcinoma were observed under gastroscopy and endoscopic ultrasonography. The infiltration depth of carcinomas was determined pathologically. Early esophageal carcinomas were classified into five types by endoscopy: surface propagating growth, intraluminal growth, intramural growth, bilateral growth, and mixed growth. Intramucosal and submucosal carcinomas were differentiated on the basis of the different types, height of intraluminal growth and bilateral growth, and depth of intramural growth type. The accuracy of differentiate diagnosis was 87.2%. Our results indicate that this new endoscopic classification system can accurately differentiate intramucosal and submucosal infiltration of early-stage esophageal carcinomas. PMID- 21261478 TI - Distinguishing early-stage pancreatic cancer patients from disease-free individuals using serum profiling. AB - This study evaluated the usefulness of electrospray mass spectrometry to distinguish sera of early-stage pancreatic cancer patients from disease-free individuals. Sera peak data were generated from 33 pancreatic cancer patients and 30 disease-free individuals. A "leave one out" cross-validation procedure discriminated stage I/II pancreatic cancer versus disease-free sera with a p value <.001 and a receiver-operator characteristic curve area value of 0.85. Predictive values for cancer stage I/II test efficiency, specificity, and sensitivity were 78%, 77%, and 79%, respectively. These studies indicate that electrospray mass spectrometry is useful for distinguishing sera of early-stage pancreatic cancer patients from disease-free individuals. PMID- 21261479 TI - Prognostic assessment and adjuvant treatment strategies within early-stage, sporadic triple negative breast cancer patients. AB - An adjuvant chemotherapeutic standard has not been identified in triple negative breast cancer (TNBC) yet. One hundred and forty-one adjuvant treated TNBC patients had a median follow-up of 71 months. Larger tumor size (p = .005) and positive lymph-node status (p = .033) were associated with a significant shorter overall survival. Sixty-one percent of patients received anthracycline-containing chemotherapy, 28.4% a non-anthracycline-containing regimen, and 10.6% an anthracycline/taxane-containing regimen. Overall survival, disease-free survival, local recurrence-free survival and distant disease-free survival did not differ between the chemotherapeutic groups. Non-anthracycline-containing regimen appeared to be an effective treatment in TNBC. PMID- 21261480 TI - Radiographic evaluations of molar intrusion and changes with or without retention in rats. AB - OBJECTIVE: To describe radiographic changes caused by molar intrusion with or without retention methods in rats. MATERIALS AND METHODS: Thirty 12-week-old male rats were assigned to six groups (n = 5 each). Molar intrusion was achieved with an intrusion spring to two maxillary molars for 2 weeks. The control group underwent the same experimental conditions, but without the intrusion spring. The intrusion and control groups were then euthanized. In four groups, the intrusion spring was disengaged after intrusion and the new molar positions were either retained or not with an occlusal bite-block for 1 or 2 weeks. Radiographic changes were measured in the cusp tip, root apices, and alveolar crests. RESULTS: After 2 weeks of intrusion, the cusp tip and root apices had moved apically compared with the control group. However, the alveolar crests were similar in the intrusion and control groups. With retention bite-block, the new position of the intruded cusp tip was maintained, but the root apices had moved occlusally, and the alveolar crest between the two intruded molars had moved apically. Without retention, the cusp tip and root apices had moved occlusally, and the alveolar crest between the intruded molar and unintruded molars had moved occlusally compared with the intrusion group. CONCLUSION: Rat molars were successfully intruded and maintained at the altered position with retention bite-block. However, the apical root resorption was observed as an instant response. The alveolar crest adjacent to the intruded molars was repositioned apically, but that was a delayed response compared to root resorption. PMID- 21261481 TI - Changes in the cervical spine of children with juvenile idiopathic arthritis evaluated with lateral cephalometric radiographs: a case control study. AB - OBJECTIVE: To evaluate whether plain lateral cephalometric radiographs in the neutral position could be used as a diagnostic tool to investigate changes in the cervical spine related to juvenile idiopathic arthritis (JIA). MATERIALS AND METHODS: Lateral cephalometric radiographs of 82 subjects, 21 males and 61 females (8-25 years old), affected with JIA were revised and compared with 82 healthy control subjects matched in age and gender. Changes inspected in the cervical spine were erosions of the dens and fusion of the apophyseal joints. Anterior atlantoaxial subluxation of the first vertebra in relation to the second was examined by measuring the anterior atlanto-dens interval (aADI). Atlantoaxial impaction (AAI) was studied by using the Sakaguchi-Kauppi method. RESULTS: In the JIA sample, erosion was seen in 14.7%, (12 patients), of the patients and apophyseal joint ankylosis (fusion) in 18.3%, (15 patients). Three children and one adult had aADI more than 4.5 or 3 mm, respectively, which is considered to be abnormally increased, and AAI was noted in 13.0% of the subjects. In total, 35%, (29 children), of the children with JIA showed one or several radiographically visible changes as described earlier. Two of the control subjects showed ankylosis of the apophyseal joints, and one had aADI of 4 mm. Compared with the controls, significantly more changes were found in the JIA group. CONCLUSION: It can be concluded that arthritic changes in the cervical spine can be detected at a young age on plain lateral cephalometric radiographs and should be evaluated when available. PMID- 21261482 TI - A retrospective randomized double-blind comparison study of the effectiveness of Hawley vs vacuum-formed retainers. AB - OBJECTIVE: To compare Hawley with vacuum-formed retainers. MATERIALS AND METHODS: Eighty-two patients who had received treatment with upper and lower fixed appliances were randomly assigned either a Hawley or a vacuum-formed retainer. Study models were fabricated for each patient on day of debond and 2 months, 6 months, and 12 months after debond. Using a specially constructed pantograph, four variables were measured for each set of models at each of these time periods. These were upper and lower intermolar widths, intercanine widths, arch length, and a modified Little's index of irregularity. Method error was determined by repeating the measurements on 10 sets of models. RESULTS: For each of the variables under test and at each of the four time periods, there were no statistically significant differences (alpha = .05) between each of the two retainers, vacuum-formed and Hawley. CONCLUSION: The degree of relapse that is likely to occur following a course of fixed appliance therapy is unlikely to be affected by the choice of retainer, vacuum-formed or Hawley. Therefore, when deciding on the type of retainer to be fitted following fixed appliance therapy, other factors such as cost may play a more significant role. PMID- 21261483 TI - Changes in upper airway width associated with Class II treatments (headgear vs activator) and different growth patterns. AB - OBJECTIVE: To investigate the upper airways for anteroposterior width against different growth patterns and for alterations during various Class II treatments. MATERIALS AND METHODS: Cephalograms from three treatment groups (headgear, activator, and bite-jumping appliance) were evaluated by a single investigator at baseline and at the end of orthodontic treatment. Cephalograms were used to determine upper airway width at different levels in the anteroposterior plane. Patients in the headgear group were additionally divided into six subsets on the basis of y-axis values to assess the influence of different growth patterns. RESULTS: Small increases in pharyngeal width were noted at all vertical level segments, both at baseline and during orthodontic treatments. No significant differences in these small increases were noted across various treatment modalities and growth patterns. CONCLUSION: Upper airway changes did not significantly vary with the different treatment modalities investigated in the present study. Nevertheless, reductions in pharyngeal width potentially triggering or exacerbating obstructive sleep apnea syndrome (OSAS) are always possible in the headgear phase. PMID- 21261484 TI - Do fluoride and casein phosphopeptide-amorphous calcium phosphate affect shear bond strength of orthodontic brackets bonded to a demineralized enamel surface? AB - OBJECTIVE: To compare the effects of fluoride and casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) containing topical agents on shear bond strength (SBS) and fracture mode of orthodontic brackets bonded to demineralized enamel. MATERIALS AND METHODS: Eighty freshly extracted human premolar teeth were randomly divided into four equal groups. The first group was the control, and no pretreatment was performed on this group. In the remaining three groups, demineralization process was performed and teeth were stored in artificial saliva. In group II, bonding was performed after demineralization. Pretreatment with fluoride and CPP-ACP gels was performed in groups III and IV, respectively. Brackets were bonded using a conventional system. The SBS of these brackets was measured and recorded in MPa. Adhesive remnant index (ARI) scores were determined after the brackets failed. Data were analyzed with analysis of variance (ANOVA), Tukey, and G-tests at the P < .05 level. RESULTS: ANOVA comparison of four groups revealed statistically significant differences. No significant differences were found between control and CPP-ACP-treated groups. However, lower SBS values were recorded for group II (6.6 +/- 3.9 MPa) and group III (17.1 +/- 2.9 MPa). ARI scores were significantly different among the four groups (P < .001). No enamel detachment was found in the control group, and enamel detachment measured 75% for group II. CONCLUSIONS: Fluoride and CPP-ACP gel applications showed higher debonding forces compared to bonding in untreated demineralized samples. CPP-ACP pretreatment resulted in comparable SBS values compared with the control group. PMID- 21261485 TI - Measurement accuracy of a computer-assisted three-dimensional analysis and a conventional two-dimensional method. AB - OBJECTIVE: To determine the differences between manual and cephalometric measurements on different sections of the human skull, which were obtained using computer-assisted three-dimensional (3D) analysis and conventional two dimensional (2D) techniques. MATERIALS AND METHODS: Measurements were carried out on 13 dry human skulls, then 2D cephalograms and 3D computed tomographic (CT) images were obtained. Anatomic landmarks were determined and marked with clay before CT images were taken, and the same landmarks were marked with the help of metallic balls and pins for lateral and frontal cephalograms. Manual, lateral/frontal cephalometric, and computer-assisted 3D cephalometric measurements were compared statistically. One-way analysis of variance and Tukey Honestly Significant Difference tests were used to compare the results among the groups. RESULTS: All measurements were statistically insignificant between the computer-assisted 3D and manual measurements. On the other hand, the differences between the conventional 2D and the manual measurements were statistically significant. The greatest amount of magnification was found at the Nasion-Menton distance (14.6%), which was located at the farthest distance from the central x ray beam in the lateral cephalogram (P < .01). For the same reason, the greatest enlargement (16.2%) was observed in the distance between the zygomaticomaxillary sutures on the conventional frontal cephalogram (P < .01). CONCLUSIONS: The computer-aided 3D cephalometric measurements were found to be more accurate than the conventional cephalometric measurements. The results revealed that 3D cephalometric measurements were consistent with the manual measurements. In addition, the magnification and distortion might limit the results of conventional cephalometric measurements. PMID- 21261486 TI - Validity of upper airway assessment in children: a clinical, cephalometric, and MRI study. AB - OBJECTIVE: To test the hypothesis that the capability of two-dimensional lateral cephalogram in recognizing pharyngeal obstruction is poor compared with the capability of three-dimensional magnetic resonance imaging (MRI) and clinical observation of tonsillar size. MATERIALS AND METHODS: The study participants were 36 prepubertal children (19 male, 17 female; mean age 7.3 +/- 1.43 years, range 4.8-9.8 years) with sleep-disordered breathing diagnosed by nocturnal polygraphy. Pharyngeal airway was imaged with a low-field open-configuration MRI scanner. Tonsillar size was clinically determined and lateral skull radiographs were taken and measured. Pearson correlation coefficients were calculated between the clinical, cephalometric, and MRI variables. RESULTS: Nasopharyngeal and retropalatal cephalometric variables had a significant positive correlation with the MRI findings. Both techniques showed the narrowest measurement to be located in the retropalatal region. Clinical assessment of tonsillar size correlated inversely with MRI findings such as minimal retropalatal cross-sectional airway area (P = .000), minimal retroglossal cross-sectional airway area (P = .015), and intertonsillar airway width (P = .000). Cephalometric soft palate and tonsillar area correlated with clinical tonsillar size (P = .001). CONCLUSIONS: The hypothesis is rejected. The findings confirm that the lateral cephalogram is a valid method for measuring dimensions of the nasopharyngeal and retropalatal region. When evaluating oropharyngeal size, clinical assessment of tonsillar size is a relatively reliable method. PMID- 21261487 TI - Effect of anterior teeth display during smiling on the self-perceived impacts of malocclusion in adolescents. AB - OBJECTIVE: To investigate the impact of the anterior teeth display during smiling (ATDDS) on the self-perceived psychosocial impacts of malocclusion in adolescents. MATERIALS AND METHODS: This cross-sectional study included a convenience sample of 301 adolescents (mean age 16.1 years, SD 1.8 years; 58.1% female). Two instruments were used for data collection: (1) the Dental Aesthetic Index (DAI) and (2) the Psychosocial Impact of Dental Aesthetics Questionnaire (PIDAQ). In addition, ATDDS was assessed in posing smiling, and adolescents' satisfaction with their dental appearance was investigated. Data analysis included descriptive statistics, Kruskal-Wallis test and Mann-Whitney U-test, Spearman correlation, and multiple linear regression analysis. RESULTS: Significant associations were observed between independent variables (ATDDS, DAI scores, and satisfaction with dental appearance) and total PIDAQ score (R(2) = 0.37) and dental self-confidence (R(2) = 0.37), psychological impact (R(2) = 0.30), esthetic concern (R(2) = 0.20), and social impact (R(2) = 0.15). CONCLUSION: The excessive anterior teeth display during smiling may potentially influence the self-perceived psychosocial impacts of malocclusion in adolescents depending on the severity level of malocclusion and the self-reported satisfaction with dental appearance. PMID- 21261488 TI - Clinical outcomes for patients finished with the SureSmileTM method compared with conventional fixed orthodontic therapy. AB - OBJECTIVE: Utilize American Board of Orthodontics (ABO) cast/radiographic evaluation (CRE) to compare a series of 63 consecutive patients, finished with manual wire bending (conventional) treatment, vs a subsequent series of 69 consecutive patients, finished by the same orthodontist using the SureSmileTM (SS) method. MATERIALS AND METHODS: Records of 132 nonextraction patients were scored by a calibrated examiner blinded to treatment mode. Age and discrepancy index (DI) between groups were compared by t-tests. A chi-square test was used to compare for differences in sex and whether the patient was treated using braces only (no orthopedic correction). Analysis of covariance tested for differences in CRE outcomes and treatment times, with sex and DI included as covariates. A logarithmic transformation of CRE outcomes and treatment times was used because their distributions were skewed. Significance was defined as P < .05. RESULTS: Compared with conventional finishing, SS patients had significantly lower DI scores, less treatment time (~7 months), and better CRE scores for first-order alignment-rotation and interproximal space closure; however, second-order root angulation (RA) was inferior. CONCLUSION: SS patients were treated in less time to better CRE scores for first-order rotation (AR) and interproximal space closure (IC) but on the average, malocclusions were less complex and second order root alignment was inferior, compared with patients finished with manual wire bending. PMID- 21261489 TI - Effect of zoledronic acid on bone healing subsequent to mini-implant insertion. AB - OBJECTIVE: To examine remodeling in bone supporting mini-implants by comparing a no drug (ND) group with a group that received a potent intravenous bisphosphonate in a canine model. MATERIALS AND METHODS: Twelve skeletally mature (2- to 3-year old) male dogs were divided into two groups. Seven dogs were administered 0.1 mg/kg/mo of zoledronic acid (ZA) for 16 weeks, while five age-matched dogs received no drug. Two mini-implants (Tomas, Dentaurum, Newton, Pa) were placed unilaterally in the maxilla and mandible (4 mini-implants per animal * 12 = 48). Serial fluorescent bone labels were administered in vivo. Postmortem, the bone blocks containing the mini-implants were harvested and used for histomorphometric analyses at two regions of interest (adjacent: within 1 mm of interface; distant: 1-4 mm from the interface) supporting the mini-implant. Data were analyzed using mixed models. RESULTS: In general, the ZA group had a significantly lower bone formation rate than the ND group (P < .05) for all jaws/regions except for the adjacent region in the maxilla, P = .12. Despite the reduction, mean intracortical remodeling in the ZA group ranged from 35%-42% per year in the implant adjacent bone. This rate is substantially higher than that reported for noninjured sites in the jaw. CONCLUSIONS: Bone remodeling is typically elevated in implant supporting bone. After ZA administration, the healing response represented by elevated turnover in implant supporting bone was diminished but was not abolished. PMID- 21261490 TI - Effect of short curing times with a high-intensity light-emitting diode or high power halogen on shear bond strength of metal brackets before and after thermocycling. AB - OBJECTIVE: To test the hypothesis that short curing times using a high-intensity light-emitting diode (LED) or high-power halogen are not associated with compromised shear bond strength (SBS) of metal brackets before and after thermocycling. MATERIALS AND METHODS: Two hundred forty extracted human premolar teeth were divided into six groups of 40 each. Metal brackets were bonded using a light-cured composite (Transbond XT). In group 1 a conventional halogen light (Hilux) was used for 40 seconds. In groups 2, 3, and 4 a high-power halogen light (Swiss Master) was used for 2, 3, and 6 seconds, respectively. In groups 5 and 6 a high-intensity LED (Bluephase) was used for 10 and 20 seconds, respectively. After bonding, half of the specimens in each group were thermocycled, and all specimens were tested for SBS. After debonding, the bracket bases and the enamel surfaces were scored according to the Adhesive Remnant Index. RESULTS: Two-way analysis of variance detected significant differences in SBS values with respect to curing method (type of light-curing unit and curing time) (P = .0001) and thermocycling (P = .01). Tukey post hoc analysis showed that with or without thermocycling the mean SBS values of groups 1, 4, 5, and 6 were not significantly different, whereas group 2 showed the lowest SBS values. The predominant failure site for groups 2 and 3 was between the bracket and the adhesive and for groups 4, 5, 6 it was at the tooth/adhesive interface. CONCLUSION: Curing time can be reduced to 6 seconds with high-power halogen light and to 10 seconds with high intensity LED without compromising in vitro SBS of metal brackets. PMID- 21261491 TI - "Safe zones" for miniscrew implant placement in different dentoskeletal patterns. AB - OBJECTIVE: To assess the influence of different dentoskeletal patterns on the availability of interradicular spaces and to determine the safe zones for miniscrew implant placement. MATERIALS AND METHODS: Periapical radiographs of 60 subjects with skeletal Class I, II, or III patterns were examined. For each interradicular site, the areas and distances at 3, 5, 7, 9, and 11 mm from the alveolar crest were measured. RESULTS: In the maxilla, the greatest interradicular space was between the second premolar and the first molar. In the mandible, the greatest interradicular space was between the first and second molars, followed by the first and second premolars. Significant differences in interradicular spaces among the skeletal patterns were observed. Maxillary interradicular spaces, particularly between the first and second molars, in the subjects with skeletal Class II patterns, were greater than those in the subjects with skeletal Class III patterns. In contrast, in the mandible, interradicular spaces in the subjects with skeletal Class III patterns were greater than those in the subjects with skeletal Class II patterns. CONCLUSIONS: For all skeletal patterns, the safest zones were the spaces between the second premolar and the first molar in the maxilla, and between the first and second premolars and between the first and second molars in the mandible. PMID- 21261492 TI - Informational value and bias of videos related to orthodontics screened on a video-sharing Web site. AB - OBJECTIVE: To assess the informational value, intention, source, and bias of videos related to orthodontics screened by the video-sharing Internet platform YouTube. METHODS: YouTube (www.youtube.com) was scanned in July 2010 for orthodontics-related videos using an adequately defined search term. Each of the first 30 search results of the scan was categorized with the system-generated sorts "by relevance" and "most viewed" (total: 60). These were rated independently by three assessors, who completed a questionnaire for each video. The data were analyzed statistically using Friedman's test for dependent samples, Kendall's tau, and Fleiss's kappa. RESULTS: The YouTube scan produced 5140 results. There was a wide variety of information about orthodontics available on YouTube, and the highest proportion of videos was found to originate from orthodontic patients. These videos were also the most viewed ones. The informational content of most of the videos was generally judged to be low, with a rather poor to inadequate representation of the orthodontic profession, although a moderately pro-orthodontics stance prevailed. It was noticeable that the majority of contributions of orthodontists to YouTube constituted advertising. This tendency was not viewed positively by the majority of YouTube users, as was evident in the divergence in the proportions when sorting by "relevance" and "most viewed." CONCLUSION: In the light of the very large number of people using the Internet as their primary source of information, orthodontists should recognize the importance of YouTube and similar social media Web sites in the opinion-forming process, especially in the case of adolescents. PMID- 21261493 TI - Functional adaptability of temporomandibular joint mechanoreceptors after an increase in the occlusal vertical dimension in rats. AB - OBJECTIVE: To investigate the effects of an experimentally-induced increase in the occlusal vertical dimension (iOVD) on the functional characteristics of temporomandibular joint (TMJ) mechanoreceptors in rats. MATERIALS AND METHODS: Sixty 13-week-old male albino Wistar rats were divided into control and iOVD groups (30 animals each). The vertical dimension between the maxillary and mandibular molars in the iOVD group was increased by 2.0 mm with a build-up of resin on the maxillary molars. Single-unit activities of TMJ mechanoreceptors were evoked by passive jaw movement. Recording was performed from the gasserian ganglion 1 day and 1, 3, 5, 7, and 9 weeks after the establishment of iOVD. RESULTS: Compared with the control group, the firing threshold was significantly lower at 1, 3, and 5 weeks after iOVD in the iOVD group. There were no significant differences in the firing threshold at 1 day, or 7 or 9 weeks. The maximum instantaneous firing frequency was significantly higher at 1, 3, and 5 weeks after iOVD in the iOVD group, but there were no significant differences at 1 day, or 7 or 9 weeks. There were no significant differences in the average firing frequency during the experimental period. CONCLUSIONS: The present study findings suggest that TMJ mechanoreceptors in adult rats may ultimately adapt to iOVD. PMID- 21261494 TI - Maxillary ulceration resulting from using a rapid maxillary expander in a diabetic patient. AB - One of the characteristics of diabetes mellitus is the exaggerated inflammatory response. The present report shows the reaction from the use of a rapid maxillary expander in a diabetic patient. A 9-year-old child presented an uncommon reaction to the treatment with a rapid maxillary expander, and on follow-up examination, it was discovered that the patient had diabetes mellitus. After controlling the disease, the proposed treatment was used without further incidents. The case calls attention to the presence of uncommon responses to treatment and the need for the orthodontist to suspect a patient's systemic compromise. PMID- 21261495 TI - The FISH-BOL collaborators' protocol. AB - The Fish barcode of life (FISH-BOL) initiative seeks to establish a reference sequence library of short, standardized mitochondrial gene sequences derived from the 5' end of the cytochrome c oxidase subunit I gene (DNA barcodes) to facilitate the rapid, accurate, and cost-effective DNA-based identification of all fishes, regardless of life-stage, sex, or specimen condition. This task requires the participation of scientists from around the world and its success is predicated on the development and acceptance of standard protocols for the collection of specimens associated provenance data. Here, we provide guidelines for specimen collection, imaging, preservation, and archival, as well as meta data collection and submission protocols developed for the FISH-BOL campaign in order to promote efficient participation in FISH-BOL by a broadening array of international participants. PMID- 21261496 TI - DNA barcoding analysis of fish species diversity in four north Greek lakes. AB - MATERIALS AND METHODS: The present study is the first to apply DNA barcoding on identifying 37 freshwater fish species from the rich Balkan ichthyofauna. RESULTS: The results are highly successful since in most cases barcodes cluster according to species, in agreement with morphological taxonomic studies. This is also evident based on mean conspecific and congeneric Kimura two-parameter distance values. The 5.6-fold difference between these values is lower than previous barcoding studies, possibly due to the restricted samplings and the recent taxonomy reevaluation for several species. A number of species were identified, where future work is needed: For the species Scardinius erythrophthalmus, Perca fluviatilis, and Rutilus rutilus, the divergence values found among conspecific populations could warrant their placement into different species; for Barbus and Rhodeus populations, the reported interspecific distances found were lower than expected; and for Cobitis species, the application of barcoding seems problematic, due to their complicated reproduction. CONCLUSION: The extension of this work to other Greek or even Balkan freshwater systems should clarify the situation. PMID- 21261497 TI - Results of the Japan Association of Childhood Leukemia Study (JACLS) NHL-98 protocol for the treatment of B-cell non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia in childhood. AB - The Japan Association of Childhood Leukemia Study (JACLS) NHL-98 is a multicenter study designed to evaluate treatment outcomes in Japanese children with B-cell non-Hodgkin lymphoma (B-NHL) and mature B-cell acute lymphoblastic leukemia (B ALL). The study was supported by a central pathology review system and used a new, standardized protocol with short, intensive treatment regimens. From April 1998 to May 2002, 69 patients with B-NHL and B-ALL up to 16 years of age were enrolled in the NHL-98 study. Treatment was stratified by risk group; patients with limited disease were in groups A and B, and those with extensive disease were in groups C and D. Patients in groups B, C, and D received consolidation phases with high-dose methotrexate (HDMTX) followed by other multi-agent chemotherapy. Patients in group A did not receive either MTX or etoposide. Only patients in group D received etoposide. The event-free survival rates were 100% in groups A and B, 75.1% in group C, and 66.2% in group D. Overall, patients with limited disease had favorable results. For patients with extensive disease, additional treatment options such as increased doses of anticancer drugs warrant further investigation. PMID- 21261498 TI - Clinical and biological features of t(4;14) multiple myeloma: a prospective study. AB - The t(4;14) translocation, found in 15% of multiple myeloma (MM), indicates a poor prognosis. Clinico-biological features associated with this severe outcome and the impact of novel agents are unknown. We report a series of 102 consecutive patients with t(4;14) MM. The median age was 56 years. The isotype was IgA in 42%, and the median serum beta(2)-microglobulin was 2.3 mg/L. FGFR3 expression was lacking in 20 (19%) cases. Monoclonal gammopathy of undetermined significance (MGUS) or smoldering MM (sMM) was found in 26 patients (25%). Seven (27%) became symptomatic in a median time of 9 months. Fifty-six of 76 patients with symptomatic MM received high-dose therapy (HDT). The overall response rate (ORR) was 93% (22% CR, 44% VGPR), and the median progression-free survival (PFS) was 12 months. Twenty-four (37%) patients experienced aggressive relapse. Post-second line ORR was 51% and the median PFS was 7 months, with a trend for longer PFS in patients treated with a bortezomib-based regimen. Median overall survival after HDT was 31 months. t(4;14) is detected in patients with MGUS/sMM and this does not require immediate chemotherapy. Patients with t(4;14) MM have a high ORR after HDT, contrasting with a short PFS and aggressive relapses, and, despite novel agents, still have a poor prognosis. PMID- 21261499 TI - Real time tissue elastography for diagnosis of cutaneous T-cell lymphoma. PMID- 21261500 TI - Transcriptional deregulation of oncogenic myocyte enhancer factor 2C in T-cell acute lymphoblastic leukemia. AB - Myocyte enhancer factor 2C (MEF2C) encodes a transcription factor which is ectopically expressed in T-cell acute lymphoblastic leukemia (T-ALL) cell lines, deregulated directly by ectopically expressed homeodomain protein NKX2-5 or by loss of promoter regions via del(5)(q14). Here, we analyzed the MEF2C 5'-region, thus identifying potential regulatory binding sites for GFI1B, basic helix-loop helix proteins, STAT5, and HOXA9/HOXA10. Chromatin immunoprecipitation and overexpression analyses demonstrated direct activation by GFI1B and LYL1 and inhibition by STAT5. HOXA9/HOXA10 activated expression of NMYC which in turn mediated MEF2C repression, indicating an indirect mode of regulation via NMYC interactor (NMI) and STAT5. Lacking comma: Chromosomal deletion of the STAT5 binding site in LOUCY cells reduced protein levels of STAT5 in some MEF2C-positve T-ALL cell lines, and the presence of inhibitory IL7-JAK-STAT5 signaling highlighted the repressive impact of this factor in MEF2C regulation. Taken together, our results indicate that the expression of MEF2C in T-ALL cells is principally deregulated via activating leukemic transcription factors GFI1B or NKX2-5 and by escaping inhibitory developmental STAT5 signaling. PMID- 21261502 TI - Associations between multiple myeloma and other malignancies. PMID- 21261501 TI - Deciding on the therapy of multiple myeloma using genetic risk stratification. PMID- 21261503 TI - Aberrant expression of CD30 in aggressive systemic mastocytosis and mast cell leukemia: a differential diagnosis to consider in aggressive hematopoietic CD30 positive neoplasms. AB - During the past two decades the immunophenotype of normal, reactive, and neoplastic mast cells (MCs) has been established. These studies have convincingly demonstrated that MCs form a separate lineage within the myeloid cell family. A most intriguing finding was that in contrast to normal MCs, neoplastic MCs in systemic mastocytosis (SM) aberrantly express several lymphoid marker antigens such as CD2 and CD25. This phenomenon has now been topped by the unexpected observation that neoplastic MCs in aggressive variants of SM and MC leukemia (leukemic variant of SM) aberrantly express CD30, whereas this antigen, Ki-1, is not detectable or is expressed only weakly in MCs in most patients with indolent SM. These observations may have implications for the evolution of SM as well as for diagnostic evaluation and grading in these patients. Moreover, these observations suggest that advanced SM has to be considered as a differential diagnosis of CD30-positive lymphoid neoplasms. Finally, CD30 may be considered as a potential target of antibody-based therapeutic intervention in advanced mast cell disorders. PMID- 21261504 TI - Primary mediastinal large B-cell lymphoma: optimal therapy and prognostic factors in 41 consecutive Asian patients. AB - This retrospective study aimed to evaluate the clinical characteristics and prognostic factors of Asian patients with primary mediastinal large B-cell lymphoma (PMBCL) and to determine the role of rituximab in this entity. Forty-one consecutive patients from 1997 to 2009 were included: 14 received CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone), while 27 more recently treated patients received CHOP with rituximab (R-CHOP). All patients with a complete or partial response received consolidation involved field radiotherapy (RT). After a median follow-up of 31.2 months (104.4 months for CHOP and 28.8 months for R-CHOP), the overall survival (OS) and progression free survival (PFS) for R-CHOP- and CHOP-treated patients were 87% vs. 57% and 88% vs. 36%, respectively. R-CHOP resulted in an improvement of PFS (hazard ratio [HR] 8.27, 95% confidence interval [CI] 2.23-30.74, p = 0.002) and OS (HR 4.20, 95% CI 1.05-16.8, p = 0.04). Nineteen patients had positron emission tomography/computed tomography (PET/CT) evaluation after six cycles of R-CHOP (metabolic complete response 13, partial metabolic response five, and metabolic progression one). All five patients with a metabolic partial response received RT instead of intensive salvage chemotherapy; four remained progression-free. In patients with PMBCL, R-CHOP in combination with involved field radiotherapy portended a 3-year OS rate of 87%, which is comparable to historical survival rates with more intensive chemotherapy regimens. PMID- 21261505 TI - Neferine increases STI571 chemosensitivity via inhibition of P-gp expression in STI571-resistant K562 cells. AB - We investigated the effects of neferine (Nef) on STI571 sensitivity and the possible mechanism in STI571-resistant K562/G01 cells. We observed cell proliferation by the modified MTT (methyl thiazolyl tetrazolium) assay. We determined the intracellular concentration of STI571 in K562/G01 cells by high performance liquid chromatography (HPLC), the expression of P-glycoprotein (P-gp) by Western blotting, and the expression of MDR-1 mRNA by reverse transcriptase polymerase chain reaction (RT-PCR). We observed that drug resistance to STI571 for K562/G01 cells was 43.99-fold higher than that for K562 cells. We also observed that a low concentration of Nef (<8 MUM) and verapamil hydrochloride (VRP) (<10 MUM) showed no direct cytotoxicity but significantly reduced the 50% cell growth inhibitory concentration (IC(50)) values of STI571 in K562/G01 cells. The reverse multiples for 8 MUM Nef and 10 MUM VRP were approximately two-fold. Both Nef (8 MUM) and VRP (10 MUM) decreased MDR-1 mRNA and P-gp protein expression and increased intracellular STI57I concentrations significantly in K562/G01 cells. Nef is a candidate chemical that can increase STI571 chemosensitivity in STI571-resistant K562 cells by inhibition of P-gp expression and increasing intracellular STI571 accumulation. PMID- 21261506 TI - Reduction in waiting time for diagnosis and treatment of head and neck cancer - a fast track study. AB - Acceleration of diagnosis and initiation of treatment for head and neck cancer requires optimal organization and multidisciplinary collaboration. A project at the Head and Neck Oncology Centre, Aarhus University Hospital aimed at accelerating patient flow. MATERIAL AND METHODS: Initiatives were implemented throughout the year 2007. Focus was on optimizing logistics for all patients referred to the center with suspected head and neck cancer. Initiatives included a full-time case manager, pre-booked slots for clinical work-up and weekly tumor boards. Key-dates were registered and relevant intervals were quantitatively evaluated and compared to a reference-group from 2006. RESULTS: We registered 446 patients. Waiting times for first clinical examination on ENT department were reduced from median eight to median two days through 2007 (p < 0.0001). Time from first clinical examination and until referral for treatment was reduced from median 21 to median nine days (p < 0.0001). Time from referral to treatment and until initiation of treatment was reduced from median 26 to median 15 days (p < 0.001). The net result of these reductions was a reduced overall time from median 57 days ultimo 2006 to median 29 days ultimo 2007 (p < 0.0001). CONCLUSION: The current project has shown that it is possible to reduce waiting times in head and neck cancer. Through logistic changes, employment of a full-time case manager, strengthening the multidisciplinary tumor board and giving higher priority for head and neck cancer patients, the overall time from first suspicion of cancer until treatment start was reduced from 57 calendar days to 29 calendar days. PMID- 21261507 TI - Adult survivors of childhood malignant lymphoma are not aware of their risk of late effects. AB - PURPOSE: Survivors after malignant lymphoma are at high risk of late effects. In order to take full responsibility for their own health they need knowledge about their diagnosis, treatment and risk of late effects. We assessed such knowledge in adult survivors of childhood malignant lymphoma. MATERIAL AND METHODS: In 2007 2009 128 five-year survivors after childhood malignant lymphoma participated in a national cross-sectional questionnaire-based survey combined with clinical examination. [Males: 69, females: 59, treatment period 1970-2000, median age (range) at diagnosis: 14 years (0-18), at survey: 32 years (19-55), Hodgkin lymphoma (HL): 84, Non-Hodgkin lymphoma (NHL): 44]. Prior to the clinical examination a semi-structured interview on the survivors' knowledge was conducted by a study nurse. The individual survivors' responses were compared with his/her medical record. RESULTS: One hundred and twenty one reported their diagnosis correctly, seven reported that they had cancer, but could not specify malignant lymphoma. Thirty-three could not differentiate between HL and NHL. One hundred and twenty three reported their treatment modalities correctly (radiotherapy vs. chemotherapy vs. combined). Eighty-five (66%) were not aware of any risks for late effects. The remaining 43 listed at least one of the following late effects; infertility, heart-problems, impaired dental status, hypothyroidism, breast cancer, reduced muscle growth, fatigue and reduced memory or concentration. Thirty-seven survivors who provided additional comments reported that they had received some information about risk of late effects from their therapists. Age at diagnosis or educational level were not associated with knowledge about possible late effects while treatment period was. CONCLUSIONS: Norwegian long term survivors of childhood malignant lymphomas are showing improved level of knowledge of their diagnosis and treatment modalities during the last decade. Still, independent of age at diagnosis and level of education, they are insufficiently aware of their risk of late effects. PMID- 21261508 TI - Detection of EpCAM positive and negative circulating tumor cells in metastatic breast cancer patients. AB - BACKGROUND: Immunomagnetic EpCAM based methods are used to enrich circulating tumor cells (CTCs) in metastatic breast cancer (mBC) patients. EpCAM negative CTCs may be missed. We addressed the question of the reliability of an EpCAM dependent assay to enrich CTCs. METHODS: To elucidate this issue, our study has been designed to assess two different CTC enrichment technologies (i) in EpCAM positive (+) and EpCAM negative cell lines and (ii) in mBC patients in dependency on their respective EpCAM expression. These two technologies encompass one anti EpCAM immunomagnetic enrichment technology, MACS HEA MicroBeads((r)) (MACS), and one EpCAM independent density centrifugation method, OncoQuick((r)) plus (OQ+). Furthermore, the coherence between EpCAM expression in the primary tumor tissue of mBC patients and the CTC detection rates in the corresponding patients is analyzed. RESULTS: (i) MACS recovered significantly more EpCAM (+) than EpCAM (-) tumor cells (p < 0.001) in spiked blood samples. With OQ+ no significantly different recovery rates between EpCAM (+) and EpCAM (-) tumor cells (p = 0.796) were detected. (ii) In mBC patients MACS yielded a significantly higher (p = 0.024) detection rate of EpCAM (+) CTCs. No statistically significant difference (p = 0.070) was found concerning the EpCAM status-based detection rate of CTCs by OQ+. (iii) CTC detection rates are independent of the primary tumors' EpCAM expression. CONCLUSIONS: EpCAM (-) CTCs can not be detected by immunomagnetic EpCAM dependent enrichment methods. EpCAM independent enrichment technologies seem to be superior to detect the entire CTC population. Evaluation of CTCs as prognostic marker should compromise EpCAM (+) and (-) subpopulations. PMID- 21261509 TI - The atherogenic index of plasma is increased by hormonal contraception. AB - BACKGROUND/AIMS: Oral contraceptives are known to induce secondary dyslipidemia. The aim of this study was to determine if hormonal contraceptives affect the new atherogenic index of plasma (AIP) = log[triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C)] together with the total cholesterol/HDL-C (TC/HDL-C) and the apolipoprotein B/apolipoprotein A1 (apoB/apoA1) ratios. DESIGN AND METHODS: This study included 43 healthy women. Blood lipids, apoA1, apoB and the high-sensitivity C-reactive protein (hsCRP) concentration were examined before the start of hormonal contraception and after 3, 6 and 9 months of its regular use. AIP, the apoB/apoA1 ratio and the TC/HDL-C ratio were calculated. RESULTS: After 9 months of continued hormonal contraception, we found significantly increased levels of TC, HDL-C, low-density lipoprotein cholesterol (LDL-C), TG, apoA1 and apoB (p < 0.05 for all analytes). The TC/HDL-C and apoB/apoA1 ratios remained unchanged; however, the AIP and the hsCRP concentration increased significantly (p < 0.005 and p < 0.006). LDL-C increased slightly over the first three examinations (0, 3, 6 months), and the rest of the indices increased over the first two examinations (0, 3 months) and maintained stable values through the fourth examination (9 months). CONCLUSIONS: The increased AIP and hs-CRP concentration after 9 months of hormonal contraception demonstrate that contraceptive-induced dyslipidemia has a proatherogenic nature, even when the TC/HDL-C and the apoB/apoA1 ratios are unchanged. PMID- 21261510 TI - Relationship of increased circulating adrenomedullin with cardiac dysfunction, inflammation, oxidative stress and volume overload in hemodialysis patients. AB - Adrenomedullin (AM) is a peptide involved in cardiovascular homeostasis. The aim of our study was to investigate whether circulating AM might be related to cardiac function, volume overload, oxidative stress and inflammation in hemodialysis patients. Plasma adrenomedullin, C-reactive protein (CRP), oxidized LDL (ox-LDL), lipoprotein (a), systolic and diastolic cardiac functions were assessed before hemodialysis in 80 patients as well as in 40 healthy control subjects. Plasma adrenomedullin levels were significantly higher in the hemodialysis group compared to the control group. Plasma adrenomedullin levels were negatively correlated with systolic and diastolic blood pressure, S/D ratio, deceleration time, left ventricular ejection fraction, ox-LDL and lipoprotein (a). However, it was positively correlated with CRP, delta body weight, mitral E/A wave, and inferior vena cava diameter. Higher plasma adrenomedullin levels may provide a possible index of cardiac dysfunction, systemic inflammation, and volume overload conditions in haemodialysis patients with concomitant cardiovascular disease. In addition, the negative correlation between ox-LDL, lipoprotein (a) and adrenomedullin may suggest that endogenous AM is an important protective factor in anti-atherosclerosis and might be useful as a new target for prevention and therapy for the disease. PMID- 21261511 TI - Vector-borne and zoonotic diseases continues its growth. PMID- 21261512 TI - Interview with Pedro Fernando da Costa Vasconcelos, MD, PhD. Interview by Vicki Glaser. PMID- 21261515 TI - Identification of novel FUS mutations in sporadic cases of amyotrophic lateral sclerosis. AB - Mutations in the FUS gene have been recently associated with amyotrophic lateral sclerosis (ALS). While most of the variants have been identified in patients with a family history of the disease, a few mutations were also found in sporadic patients. Considering this, we wanted to evaluate the frequency of mutations in the coding region of the FUS gene in a sporadic ALS (SALS) cohort compared to a control population. We tested 475 SALS cases of European origin and 475 matched controls for coding variations in the 15 exons of the FUS gene. Rare novel variants were identified in a total of five SALS patients: one missense, one deletion, one frameshift, and one nonsense substitution. Two of the four variants are located in the carboxy terminal of the protein where the previously reported variants were mostly clustered. In conclusion, FUS gene mutations are rare in SALS, with four new FUS variants identified in five different SALS cases. These findings will help evaluate the proportion of FUS variations in the SALS population, and to better understand its contributing role to ALS pathology. PMID- 21261516 TI - The effect of galactagogue herbal tea on breast milk production and short-term catch-up of birth weight in the first week of life. AB - OBJECTIVES: The aim of this study was to evaluate whether consumption of maternal herbal tea containing fenugreek had any effects on breast milk production and infants' weight gain pattern in the early postnatal period. DESIGN AND SUBJECTS: Sixty-six (66) mother-infant pairs were randomly assigned to 3 groups. Group 1 (n = 22) consisted of mothers who were receiving herbal tea containing fenugreek every day. Group 2 (n = 22) and group 3 (n = 22) were assigned as placebo and controls, respectively. OUTCOME MEASURES: Birth weight, loss of birth weight, time of regain of birth weight, amount of breast milk assessed on the third day after delivery were determined. RESULTS: Maximum weight loss was significantly lower in infants in group 1 compared to both the placebo and control groups (p < 0.05). Infants in group 1 regained their birth weight earlier than those in control and placebo groups (p < 0.05). The mean measured breast milk volume of the mothers who received galactagogue tea was significantly higher than the placebo and control groups (p < 0.05). CONCLUSIONS: Maternal galactagogue herbal tea supplementation seems to be useful for enhancing breast milk production and facilitating infant birth weight regain in early postnatal days. PMID- 21261517 TI - Starting in immunology by way of immunopathology. AB - This article comments on my trajectory first from Havana as a medical student, to Pittsburgh as a pathology intern, then to La Jolla. It reviews my initial experience in immunology research at the Scripps Research Institute in the early 1960s. Under Frank Dixon, my work examined how antibodies to the glomerular basement membrane (GBM) cause disease. I present these studies in the broader context of immunological renal injury. The early studies by Dixon and his group examining the models of acute or chronic serum sickness were major for our understanding of renal and vascular pathology. I review them because of their historical importance in immunopathology and also cover facets of Dixon's overall contributions to immunology. The studies in serum sickness and anti-GBM nephritis led to an understanding of autoimmune glomerulonephritides, the first proven autoantibody-induced diseases. PMID- 21261518 TI - Zebrafish models for cancer. AB - First established as a valuable vertebrate model system for studying development, zebrafish have emerged as an attractive animal system for modeling human cancers. Major technical advances have been essential for the generation of zebrafish cancer models relevant to human diseases. These models develop tumors in various organ sites that bear striking resemblance to human malignances, both histologically and genetically. Thus, the focus of cancer research in zebrafish has transcended the need to validate zebrafish as a viable model organism to study cancer biology. With the significant advantages of in vivo imaging, the power of forward genetics, well-established high efficiency for transgenesis, and ease of transplantation, further exploration of the zebrafish cancer models not only will generate unique insights into underlying mechanisms of cancer but will also provide platforms useful for drug discovery. PMID- 21261519 TI - Pathogenesis of myeloma. AB - Multiple myeloma (MM) is a neoplasm of post-germinal center, terminally differentiated B cells. It is characterized by a multifocal proliferation of clonal, long-lived plasma cells within the bone marrow (BM) and associated skeletal destruction, serum monoclonal gammopathy, immune suppression, and end organ sequelae. MM is preceded by an age-progressive premalignant condition termed monoclonal gammopathy of undetermined significance. Unlike the genomes of most hematological malignancies, and similar to those of solid-tissue neoplasms, MM genomes are typified by numerous structural and numerical chromosomal aberrations as well as mutations in a number of oncogenes and tumor-suppressor genes, some of which have been linked to disease pathogenesis and clinical behavior. Recent studies have also defined the importance of interactions between the MM cells and their BM microenvironment, dysregulation in signaling pathways and in a specialized subpopulation of cells within the tumor (termed myeloma cancer stem cells) for tumor cell growth and survival, and the development of resistance to therapy. PMID- 21261521 TI - Revised STRICTA as an extension of the CONSORT statement: more items should be involved in the checklist. PMID- 21261541 TI - DiagnoCure acquires new high-value diagnostic tests. PMID- 21261526 TI - New genes behind Crohn's disease. PMID- 21261520 TI - A glimpse of various pathogenetic mechanisms of diabetic nephropathy. AB - Diabetic nephropathy is a well-known complication of diabetes and is a leading cause of chronic renal failure in the Western world. It is characterized by the accumulation of extracellular matrix in the glomerular and tubulointerstitial compartments and by the thickening and hyalinization of intrarenal vasculature. The various cellular events and signaling pathways activated during diabetic nephropathy may be similar in different cell types. Such cellular events include excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products, activation of protein kinase C, increased expression of transforming growth factor beta and GTP-binding proteins, and generation of reactive oxygen species. In addition to these metabolic and biochemical derangements, changes in the intraglomerular hemodynamics, modulated in part by local activation of the renin-angiotensin system, compound the hyperglycemia-induced injury. Events involving various intersecting pathways occur in most cell types of the kidney. PMID- 21261550 TI - Prevalence of hemolytic specimens referred for arterial blood gas analysis. PMID- 21261551 TI - Evidence-based tailored conservative treatment of knee and hip osteoarthritis: between knowing and doing. AB - OBJECTIVE: Insufficient data are available on the efficacy of combined conservative interventions recommended by treatment guidelines for knee/hip osteoarthritis (OA). The aims of this observational cohort study were (i) to estimate the results of an evidence-based 12-week tailored multimodal conservative treatment protocol for patients with knee/hip OA and (ii) to identify predictors for response. METHODS: After obtaining data on previous OA related interventions, multimodal treatment was offered to patients with knee and/or hip OA at a specialized outpatient clinic. Treatment with analgesics was tailored using a numeric rating scale (NRS) for pain, aiming for NRS <= 4. The following outcome measures were assessed: (i) the proportion of patients fulfilling OMERACT-OARSI (Outcome Measures in Rheumatoid Arthritis Clinical Trials/Osteoarthritis Research Society International) responder criteria and (ii) the proportion of patients with NRS pain <= 4 after 12 weeks. RESULTS: A total of 183 out of 299 patients was included. OMERACT-OARSI responder criteria were fulfilled at 12 weeks in 47% of patients; 39% reached NRS pain <= 4. The only independent predictor for response was the number of previously used non steroidal anti-inflammatory drugs (NSAIDs). The majority of patients had not been exposed adequately to conservative treatment modalities for knee and/or hip OA in the past (81%). CONCLUSION: Evidence-based multimodal conservative treatment using a standardized protocol for knee and/or hip OA is feasible and successful in 47% of patients. In general, response could not be predicted. Basic first-line recommended conservative treatment options have not been used adequately prior to referral to secondary care in the vast majority of patients. PMID- 21261552 TI - Gender differences in patients presenting with first-episode psychosis in Hong Kong: a three-year follow up study. AB - OBJECTIVE: The aim of the current study was to investigate gender differences with respect to pre-treatment characteristics, clinical presentation, service utilization and functional outcome in patients presenting with first-episode psychosis. METHODS: A total of 700 participants (men, n = 360; women, n = 340) aged 15 to 25 years consecutively enrolled in a territory-wide first-episode psychosis treatment programme in Hong Kong from July 2001 to August 2003 were studied. Baseline and three-year follow up variables were collected via systematic medical file review. RESULTS: At service entry, men had significantly lower educational attainment (p < 0.01), longer median duration of untreated psychosis (p < 0.001), fewer past suicidal attempts (p < 0.01), more severe negative symptoms (p < 0.05) and fewer affective symptoms (p < 0.01) than women. There was no significant gender difference in age of onset. In three-year follow up, men had more prominent negative symptoms (p < 0.001), fewer affective symptoms (p < 0.01), more violent behaviour and forensic records (p < 0.01), and higher rate of substance abuse (p < 0.01). Women achieved higher levels of functioning than men (Social Occupational Functioning Assessment Scale (SOFAS), p < 0.001) and a significantly higher proportion of women than men engaged in full time employment or study for at least 12 consecutive months (p < 0.001) in the initial three years after psychiatric treatment. CONCLUSION: Notable gender differences in clinical profiles, illness trajectory and functional outcome were demonstrated in Chinese young people suffering from first-episode psychosis. Differential needs between men and women and hence gender-specific therapeutic strategies should be considered in early intervention service. PMID- 21261553 TI - A qualitative assessment of the acceptability and potential demand for medical abortion among university students in Durban, South Africa. AB - OBJECTIVES: To assess the acceptability of medical abortion as a method for pregnancy termination among young South African women, and further investigate the potential demand for medical abortion. METHODS: Qualitative study based on in depth interviews. The interviews were conducted with 20 sexually active, female university students in Durban, South Africa. RESULTS: The findings suggest that there is a demand for medical abortion among this sample of young women. Most of them find medical abortion an acceptable method, and would choose it if they were faced with an unwanted pregnancy. Some of the positive aspects of medical abortion raised were: increased privacy; avoidance of surgery; and sense of greater control. Some of the negative aspects of medical abortion were: fear of adverse side effects; high cost; follow-up visits; and potential psychological stress. While the majority of women find this method acceptable, there were reservations and concerns about introducing it into the public sector such as misuse and abuse of the medication by clients and providers. CONCLUSION: Medical abortion should be introduced into the public sector in South Africa, and this method be made affordable, accessible, and available for women. PMID- 21261554 TI - Using participatory action research in community-based rehabilitation for people with acquired brain injury: from service provision to partnership with Aboriginal communities. AB - PURPOSE: Community-based rehabilitation (CBR) developed in response to delivery of rehabilitation services to people with disability in developing countries, and appears appropriate to address rehabilitation needs of rural and remote populations, including Australian Aboriginal People with acquired brain injury (ABI). This article will describe participatory action research (PAR) as a vehicle for exploring and translating the CBR model within a mainstream brain injury rehabilitation service in Queensland, Australia. METHOD: PAR was conducted with two self-selected remote Aboriginal communities in Far North Queensland. Key components to this project were the employment of a local Aboriginal worker, facilitating community engagement and consultation. PAR elements of planning, action and review were conducted through individual and group meetings and activities within the communities across a 3-year period. RESULTS: The project has facilitated expansion and change within the current brain injury rehabilitation service model in line with CBR philosophical foundations, including community development and partnership as a desirable way of engaging with key stakeholders. CONCLUSIONS: The focus on community consultation through PAR and the development of community partnerships has increased the cultural competency of the rehabilitation service, the capacity of participating communities and of the sector to respond in ways that are valued and owned by Aboriginal People with brain injury, their families and communities. PMID- 21261555 TI - In vivo and in vitro distribution of type 5 and fiber-modified oncolytic adenoviruses in human blood compartments. AB - BACKGROUND: Successful tumor targeting of systemically administered oncolytic adenoviruses may be hindered by interactions with blood components. MATERIALS AND METHODS: Blood distribution of oncolytic adenoviruses featuring type 5 adenovirus fiber, 5/3 capsid chimerism, or RGD-4C in the fiber knob was investigated in vitro and in patients with refractory solid tumors. RESULTS: Virus titers and prevalence in serum of patients increased over the first post-treatment week, suggesting replication. Detection of low virus loads was more sensitive in blood clots than in serum, although viral levels > 500 viral particles/mL did not differ significantly between both sample types. While adenovirus bound to erythrocytes, platelets, granulocytes, and peripheral blood mononuclear cells in vitro, the virus was mainly detectable in erythrocytes and granulocytes in cancer patients. Taken together with a temporary post-treatment decrease in thrombocyte counts, platelet activation by adenovirus and subsequent clearance seem likely to occur in humans. Fiber modifications had limited observed effect on virus distribution in blood cell compartments. Neutrophils, monocytes and cytotoxic T lymphocytes were the major leukocyte subpopulations interacting with adenoviruses. CONCLUSION: Serum and blood clots are relevant to estimate oncolytic adenovirus replication. Insight into viral interactions with blood cells may contribute to the development of new strategies for tumor delivery. PMID- 21261556 TI - Matrix metalloproteinase-beta19 expressed in cerebral amyloid angiopathy. AB - BACKGROUND: Cerebral amyloid angiopathy (CAA) is a frequent finding in the brains of patients with Alzheimer's disease (AD). CAA may be complicated with CAA associated intracerebral haemorrhage (CAAH). Previous studies have revealed matrix metalloproteinase (MMP) expression in a mouse model of CAA and in human intracerebral haemorrhage. Here we studied the involvement of MMPs in human CAA and CAAH. MATERIAL AND METHODS: To investigate the putative expression of MMPs in human CAA and CAAH (Step 1), immunohistochemistry (IHC) against MMPs-1, -2, -7, 9, -19 and -26 was applied on tissue microarray (TMA) constructed of cerebral samples from 29 individuals with AD, 15 with CAAH and 2 controls. The findings in TMA were confirmed (Step 2) in tissue samples from 64 individuals, 45 presenting with CAA (including 36 with CAAH) and 19 without CAA (including 11 with hypertensive cerebral haemorrhage). RESULTS: In Step 1, immunoreactivity against MMPs-19 and -26 was detected in cerebral blood vessels in CAA. The results were confirmed in Step 2, where CAA (p<0.001) and intracerebral haemorrhage (p=0.045) were associated with vascular immunoreactivity against MMP-19. Multivariate analysis showed that the association between vascular MMP-19 and intracerebral haemorrhage was dependent from CAA. MMP-26 associated with CAA (p=0.021) but not with intracerebral haemorrhage. CONCLUSION: This is the first human study showing local MMP-19 immunoreactivity in the Abeta-amyloid-laden blood vessels in CAA, suggesting that MMPs may be involved in CAA. PMID- 21261557 TI - Electrophysiological features of familial amyloid polyneuropathy in endemic area. AB - The process of deterioration of peripheral nerve function in familial amyloid polyneuropathy (FAP) with amyloidogenic transthyretin (ATTR) Val30Met has not been systematically evaluated hitherto. We performed nerve conduction studies in 69 patients with FAP with ATTR Val30Met from one of the endemic areas in Japan. Sensory conduction velocity (SCV), motor conduction velocity (MCV), the size of the compound muscle action potential (CMAP) and distal latency (DL) were measured in the ulnar and tibial nerves. SCV was evaluated using the orthodromic method with needle recording electrodes. These electrophysiological parameters were compared with clinical stage of FAP and duration of neuropathy. When subjects noted minimal neuropathic symptoms only in the feet, motor and sensory nerve function in both the hands and feet had already been disturbed. Sensory nerve action potential on the foot disappeared more rapidly than CMAP. CMAP on foot muscle rapidly decreased during the initial 2 years and completely disappeared within 10 years. The duration of illness and deterioration parameters (CMAP of the abductor digiti minimi muscle, MCV and SCV of the ulnar nerve and DL of both ulnar and tibial nerves) were linearly correlated. CMAP was the most sensitive and reliable parameter to evaluate motor nerve degeneration in FAP. PMID- 21261558 TI - Pemetrexed in advanced non-small cell lung cancer. AB - INTRODUCTION: For patients with advanced NSCLC, treatment outcomes are still disappointing and the search for new active and safe drugs is warranted. The chemotherapeutic agent pemetrexed has produced, in the last years, an innovation of therapeutic algorithms of this disease, and this review is aimed at describing the role of pemetrexed in the treatment of NSCLC. AREAS COVERED: In the present review, we discuss the mechanism of action of pemetrexed, its safety profile and the main clinical data on pemetrexed in NSCLC treatment. The reader will gain information on pemetrexed efficacy in the first-line, second-line and maintenance treatment of advanced NSCLC. Moreover, the histotype-based approach to NSCLC treatment, which is important for the selection of patients to be treated with pemetrexed, is clarified. EXPERT OPINION: The recent introduction of pemetrexed in the first-line and maintenance treatment of advanced non-squamous NSCLC represents, in our opinion, a significant step forward in the treatment of this disease in the last 3 years. Furthermore, cisplatin plus pemetrexed has a more favorable safety profile as compared with those of pre-existing cisplatin-based regimens. PMID- 21261559 TI - Physical and sexual lifetime violence: prevalence and influence on fear of childbirth before, during and after delivery. AB - OBJECTIVES: To estimate the prevalence of self-reported lifetime violence and to assess whether women exposed to any physical violence or sexual violence (SEV) had a higher risk of having fear of childbirth (FOC) before, during or after delivery compared with women without such history. METHODS: FOC was measured at three time points in this Danish multicentre cohort study. Data were based on two self-administered questionnaires filled in by 2638 obstetrically low-risk nulliparous women together with data collected during labour. The women were grouped according to severity: never experienced violence (NEV), moderate physical violence (MPV), severe physical violence (SPV) and SEV. RESULTS: In total, 426 women (16.1%) reported experience of MPV as the most vehement type of violence, another 262 women (9.9%) had experienced SPV and further 244 women (9.2%) had experienced SEV. Experience of SEV was associated with an increased risk of severe FOC after delivery compared with women from NEV, odds ratio 1.5 (95% confidence intervals: 1.02-2.27). CONCLUSIONS: Women with a lifetime experience of SEV appeared with severe FOC only after delivery. Hence, healthcare personnel may need to consider women without obvious FOC during pregnancy but at increased risk, as seen in women exposed to SEV. PMID- 21261560 TI - New times for the International Society of Psychosomatic Obstetrics and Gynaecology (ISPOG). PMID- 21261561 TI - Postpartum mental health screening and diagnosis by obstetrician-gynecologists. AB - Postpartum depression (PPD) and postpartum psychosis (PPP) can impact mother, infant, and family. Obstetrician-gynecologists (ob-gyns) are often the most frequent medical contact for postpartum women, and so are in a position to identify women needing psychological care. This study assessed ob-gyns' knowledge, attitudes, and practices regarding diagnosing PPD/PPP. A survey was sent to 400 members of the American College of Obstetricians and Gynecologists who have volunteered to participate in research. Response rate was 56%. Routine screening for PPD and PPP is conducted by 72% and 30% of respondents, respectively. Personal experience (through friend, family, or self) was associated with increased screening. Perceived PPP screening barriers are similar to those found in the PPD literature: time constraints, lack of training, and lack of knowledge of diagnostic criteria. In responding to standardised vignettes, physicians were more likely to over-diagnose, than under diagnose PPD/PPP. This study is the first to provide exploratory data of ob-gyns' knowledge, attitudes, and practice regarding PPD and PPP. Ob-gyns are screening for PPD/PPP, though not universally so. Future research should identify ways to mitigate screening barriers. PMID- 21261564 TI - Hedgehog-mediated regulation of thyroid hormone action through iodothyronine deiodinases. AB - INTRODUCTION: The three iodothyronine deiodinases catalyze the metabolic pathway that removes one iodine residue from the T4 molecule, thus producing either the active T3 or the inactive metabolite rT3. Hence, deiodination is a potent mechanism by which to modulate thyroid hormone (TH) action at cellular level, thereby allowing cells to customize their own T3 availability, both spatially and temporally, irrespective of TH serum concentrations. Sonic hedgehog (Hh) regulates patterning and growth of a remarkable variety of tissues throughout embryogenesis. Its constitutive activation is associated with cancer development. AREAS COVERED: Recent evidences from two independent systems implicate the Hh signaling pathway in regulation of TH action via modulation of deiodinase expression. Interestingly, many critical developmental events, for example, amphibian metamorphosis, are tightly regulated by the TH and Hh signaling pathways. This review provides an overview of recent data referring to the intricate regulation of deiodinase activity and intracellular TH action by the Hh pathway. EXPERT OPINION: This functional cross-talk provides a paradigm for interaction between two key signaling pathways critical during development and neoplastic transformation. This interaction may be relevant in other tissues and situations in which the two signaling pathways participate. Deciphering these mechanisms constitutes an exciting field for future research. PMID- 21261565 TI - Effect of various treatments on leptin, adiponectin, ghrelin and neuropeptide Y in patients with type 2 diabetes mellitus. AB - INTRODUCTION: Several peptides are involved in the regulation of food intake and energy expenditure, among which are leptin, adiponectin, ghrelin and neuropeptide Y (NPY). These peptides may be implicated in the obesity seen in the majority of patients with type 2 diabetes mellitus (T2DM). AREAS COVERED: The present review considers: i) the role of leptin, adiponectin, ghrelin and NPY in patients with T2DM, and, ii) the effect of insulin as well as oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet agents on these peptides in patients with T2DM. EXPERT OPINION: Patients with T2DM have either lower or similar leptin levels, decreased adiponectin and ghrelin levels, and increased NPY circulating levels compared with nondiabetic controls. Treatment with insulin, oral hypoglycemic, antihypertensive, hypolipidemic, antiobesity and antiplatelet drugs may influence the levels of these peptides. It is not widely appreciated that several drugs commonly administered to patients with T2DM can influence adipokine levels. The clinical relevance of these effects needs to be evaluated. PMID- 21261563 TI - Nuclear factor-erythroid 2-related factor 2 as a chemopreventive target in colorectal cancer. AB - INTRODUCTION: Numerous epidemiological studies have linked consumption of cruciferous vegetables to a reduced risk of colorectal cancer (CRC) in individuals. It is currently well accepted that chronic inflammation is a contributing factor in 15 - 20% malignancies including CRC. Many chemopreventive compounds are effective in preclinical systems and many ongoing clinical trials are showing promising findings. Many of these compounds could activate the antioxidant responsive element (ARE), a critical regulatory element for Phase II protective/detoxification and antioxidative stress enzymes mediated by nuclear factor-erythroid 2-related factor 2 (Nrf2). Recently, Nrf2 has emerged as a novel target for the prevention of CRC. AREAS COVERED: A full literature search was performed using PubMed with the key words 'ARE, Nrf2, colon, colorectal cancer, chemoprevention, cancer prevention', and all relevant publications are included. EXPERT OPINION: The use of Nrf2 knockout mice has provided key insights into the toxicological and chemopreventive importance of this pathway. Mounting evidence has revealed that Nrf2 is a critical regulator of inflammation as well, a major driving force for CRC progression and formation. Targeting the Nrf2/ARE pathway may present a novel therapeutic approach for the treatment of not only colorectal inflammatory diseases but the frequent subsequent development of CRC as well. PMID- 21261566 TI - Effect of perfluorohexane on the expression of cellular adhesion molecules and surfactant protein A in human mesothelial cells in vitro. AB - The intraperitoneal instillation of perfluorocarbons augmented systemic oxygenation and was protective in mesenteric ischemia-reperfusion and experimental lung injury. To study biocompatibility and potential anti inflammatory effects of intraperitoneal perfluorocarbons, we evaluated the influence of perfluorohexane and/or inflammatory stimuli on human mesothelial cells in vitro. Perfluorohexane exposure neither impaired cell viability nor induced cellular activation. TNFalpha enhanced ICAM-1 expression, which was not attenuated by simultaneous perfluorohexane treatment. Concentration of intracellular surfactant protein A tended to be higher in perfluorohexane treated cells compared to controls. Our in vitro data add further evidence that intraperitoneal perfluorocarbon application is feasible without adverse local effects. PMID- 21261567 TI - Antibody-based therapy in Alzheimer's disease. AB - INTRODUCTION: Alzheimer's disease (AD) is a progressive, age-dependent, neurodegenerative disorder being the most common cause of dementia. The pathological hallmarks are extracellular amyloid-beta (Abeta) deposition and intracellular neurofibrillary tangles containing hyperphosphorylated tau. Stunning results in vaccination trials in transgenic animals led to an antibody based approach to develop immunotherapeutics for AD. Thus, several monoclonal antibodies raised against Abeta as well as polyclonal antibodies are currently in clinical testing and some of them already entered Phase III clinical trials. New upcoming experimental approaches like antibodies recognizing specific conformational epitopes, single-chain variable fragment antibodies, or intrabodies give hope of further drug development for this incurable disease. AREAS COVERED: The rationale and putative mode of action of antibody-based immunotherapy in AD and delineates correlations for other neurodegenerative diseases. Current clinical trials and recent results of therapeutic antibodies in AD are presented. EXPERT OPINION: Antibodies against Abeta will not only broaden the therapeutic repertoire but also our knowledge about the pathology in AD. Further results of the clinical trials and new antibody-based approaches will shed light on the importance of Abeta and its removal in AD. PMID- 21261569 TI - Lung recruitment: who, when and how? PMID- 21261568 TI - Diurnal variation of connective tissue metabolites in early and long-standing rheumatoid arthritis and in healthy individuals. AB - OBJECTIVE: To study the circadian variability of circulating connective tissue metabolites in patients with very early (VERA) and long-standing rheumatoid arthritis (LRA) and in healthy control individuals. METHODS: Eleven patients with newly diagnosed, untreated RA, disease duration < 6 months, and 10 patients with LRA were included, together with 16 healthy control subjects. Seven blood samples were drawn serially from each participant at 3-hourly intervals from 10.00-22.00 h, fasting at 07.00 h the following day and finally at 10.00 h. Cartilage oligomeric matrix protein (COMP) and hyaluronan (HYA) were quantified by enzyme linked immunosorbent assay (ELISA) and the N-terminal propeptide of collagen type III (PIIINP) was determined by radioimmunoassay (RIA). RESULTS: The two RA subsets did not differ with respect to age, gender distribution, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), immunoglobulin M rheumatoid factor (IgM-RF) status, global health status and pain. Healthy controls were younger than both VERA and LRA patients. At baseline, PIIINP, HYA, and COMP were increased significantly in both RA cohorts compared with controls. No circadian rhythmicity was recorded with respect to HYA and PIIINP. By contrast, COMP was decreased at 07.00 h in all three study groups; this decline was particularly prominent in LRA. CONCLUSION: Within-day changes of PIIINP, HYA, and COMP are qualitatively similar in RA at different stages and in healthy individuals, indicating that the connective tissue responses to rhythmic physiological signals are not abolished by disease-modifying anti-rheumatic drug (DMARD) therapy. Serum for measurement of HYA and COMP should be collected between 10.00 and 20.00 h. PMID- 21261570 TI - Effects of recruitment manoeuvres on haemodynamics, oxygen exchange and oxygen delivery in patients with acute lung injury and acute respiratory distress syndrome. AB - OBJECTIVE: To evaluate the impact of a recruitment manoeuvre (RM) on haemodynamics, gas exchange, and oxygen transport in patients with acute lung injury (ALI) an acute respiratory distress syndrome (ARDS) under mechanical ventilation. DESIGN, SETTING AND PARTICIPANTS: Prospective interventional study in the intensive care unit of a teaching hospital in Buenos Aires, Argentina. The study was carried out between June 2002 and March 2003. Eleven consecutive patients with ALI and ARDS who required an RM were included. Haemodynamic measurements and blood samples were taken before and during the RM, and at 2 and 30 minutes after the RM. INTERVENTION: After baseline measurements, positive end expiratory pressure (PEEP) was set at 40cmH(2)O for 45 seconds. MAIN OUTCOME MEASURES: Systemic haemodynamics, oxygen exchange and oxygen delivery. RESULTS: Mean PEEP before the RM was 14 (SD, 3) cmH(2)O, and was maintained after the RM. The RM did not modify the arterial partial pressure of oxygen (PaO(2)) but did induce small but significant changes in the mean arterial partial pressure of carbon dioxide (Pa-ETCO(2)) and arterial minus end-tidal PCO(2) gradient (PaCO(2)) at 2 minutes and 30 minutes after the RM (P<0.05). The mean cardiac index dropped from 3.08 (SD, 0.84) to 2.37 (SD, 0.75) L/min/m(2) (P<0.001) during the RM and then returned to baseline values. Mean systolic blood pressure also fell transitorily during the RM, from 131 (SD, 15) to 104 (SD, 25) mmHg, but diastolic and mean arterial pressures remained unchanged. Oxygen consumption and the arterial mixed venous oxygen content gradient increased after the RM (P<0.05). CONCLUSION: In our small series of patients with ALI/ARDS ventilated with high levels of PEEP, the RM failed to improve oxygen exchange and induced deleterious effects on haemodynamics. PMID- 21261571 TI - A detailed feeding algorithm improves delivery of nutrition support in an intensive care unit. AB - OBJECTIVE: To determine whether a detailed feeding algorithm improved nutrition support of critically ill patients compared with a standard feeding protocol. DESIGN, SETTING AND PARTICIPANTS: Pre- and post-intervention comparison of nutrition commencement and nutritional adequacy in intensive care unit patients receiving enteral or parenteral nutrition until length of stay (LOS) exceeded 30 days, oral intake resumed, the patient was discharged from the ICU or the patient died. The study was conducted at the Royal Brisbane & Women's Hospital, a tertiary hospital with 27 ICU beds, in 2005 (pre-intervention) and 2007 (post intervention). INTERVENTION: A detailed feeding algorithm that included commencement of nutrition support, progression to goal nutrition rates and management of gastric residual volumes. MAIN OUTCOME MEASURES: Time to commencement of nutrition support; time to reach goal nutrition rate; nutritional adequacy over ICU stay. RESULTS: No demographic differences between pre- (n=42) and post-implementation (n=41) patient groups were observed. Implementation of the detailed feeding algorithm reduced the mean time to commence nutrition support from 28 hours to 16 hours (P=0.035). Time to reach goal nutrition rate fell from 22 hours to 13 hours, although the difference was not statistically significant. There was no significant difference between pre- and post implementation groups in the number of patients reaching goal volume during ICU admission. Interruptions were a major obstacle to goal volumes of enteral feeds being reached. CONCLUSIONS: Introduction of a detailed feeding algorithm resulted in earlier commencement of nutrition support and increased numbers of patients reaching goal rates in less time. To improve nutritional adequacy, the algorithm needs to be modified to account for unavoidable interruptions during ICU stay. PMID- 21261572 TI - Does after-hours discharge of ICU patients influence outcome? AB - OBJECTIVE: To assess the frequency of after-hours discharges of patients from the intensive care unit and its effect on in-hospital mortality. DESIGN, SETTING AND PARTICIPANTS: Observational cohort study conducted in the ICU of Westmead Hospital, a tertiary care teaching hospital in Sydney. All adult patients admitted to the ICU between 1 January 2004 and 31 December 2006 were included in the study cohort. Patients were grouped into two categories based on the time of discharge from the ICU: during work hours (08:00-17:59 hours) or after-hours (18:00-07:59 hours). MAIN OUTCOME MEASURE: Mortality after discharge from the ICU according to time of discharge. MEASUREMENTS AND MAIN RESULTS: 2300 patients accounted for 2451 admission episodes during the study period. There were 151 readmissions, involving 133 patients (5.8%). Excluded from the study cohort were 36 patients (1.6%) who were discharged home, 39 (1.7%) who were transferred to other hospitals, and 354 (15.4%) who died during their first stay in the ICU. Data on the remaining 1871 patients who were discharged alive at the end of their first ICU admission were included in our analysis. Of these patients, 1221 (65.3%) were discharged from the ICU during work-hours and 650 (34.7%) after hours. Crude mortality for patients discharged after-hours was 13.7%, compared with 10.1% for those discharged during work hours. After adjustment for age, APACHE II score and discharge destination, the risk of mortality among patients discharged after-hours was statistically significant (adjusted odds ratio, 1.38 [95% CI, 1.01-1.88]; P < 0.05). CONCLUSIONS: A high proportion of patients (34.7%) were discharged from the ICU after-hours. Discharge after-hours was associated with a higher risk of in-hospital mortality than discharge during work hours. PMID- 21261573 TI - A survey of antibiotic prescribing practices in Australian and New Zealand intensive care units. AB - OBJECTIVE: To evaluate antibiotic prescribing practices in empirical and directed treatment of severe sepsis and septic shock in Australian and New Zealand intensive care units. DESIGN, SETTING AND PARTICIPANTS: Case vignette survey of intended antibiotic prescribing for ICU patients with sepsis associated with community-acquired pneumonia (CAP), intra-abdominal infection (IAI), hospital acquired pneumonia (HAP) or an unidentified infectious cause (UIC). Eighty-four specialists and advanced trainees working in an ICU setting in Australia and New Zealand responded to a questionnaire survey conducted between February and May 2009. MAIN OUTCOME MEASURES: Empirical and directed antibiotic therapy, including mode of administration, frequency of administration, dose and duration of therapy. RESULTS: A total of 656 antibiotics were empirically "prescribed", including 25 unique antibiotics. Combination therapy was prescribed in 82% of cases, with dual cover for CAP and triple therapy for IAI most common. Directed single-agent cover for Pseudomonas aeruginosa in HAP and flucloxacillin monotherapy for methicillin-sensitive Staphylococcus aureus bacteraemia were prescribed in 65% and 51% of cases, respectively. Supportive gentamicin therapy was commonly recommended (32% of all cases), predominantly in the form of once daily dosing. Daily gentamicin dosage varied from 3 to 7mg/kg (excluding one outlier), and was largely compliant with recommendations (76% of doses being >=5 mg/kg). Main areas of noncompliance with guidelines were provision of broader cover for resistant organisms and Beta-lactam underdosing. Continuous and extended infusions were uncommon (5%). CONCLUSIONS: Antibiotic prescribing was largely appropriate, but consideration of site-specific resistance profiles and avoidance of low dosing is advocated to provide appropriate upfront cover, prevent underdosing and reduce the risk of developing resistant organisms. PMID- 21261574 TI - Unplanned admission to the intensive care unit in the very elderly and risk of in hospital mortality. AB - BACKGROUND: Unplanned admission to the intensive care unit has been shown to significantly increase the risk of inhospital mortality. Medical advances and increased expectations have resulted in a greater number of very elderly patients (80 years and over) being admitted to the ICU. The risk of in-hospital death associated with unplanned admission to the ICU in very elderly patients has not been clearly defined. OBJECTIVE: To estimate the risk of in-hospital mortality associated with unplanned admission to the ICU in patients aged 80 years and over. DESIGN, SETTING AND PARTICIPANTS: Retrospective review of an adult intensive care database. The setting was Liverpool Hospital, a large teaching hospital in Sydney, Australia, with a 28-bed ICU that has about 2000 admissions per year. We analysed data on very elderly patients (n = 1680), aged 80 years or more, admitted to the ICU between 1 January 1997 and 31 December 2007. MAIN OUTCOME MEASURES: Baseline risk factors for inhospital mortality. RESULTS: Mortality among patients with unplanned ICU admissions was 47%, compared with 25% in patients with planned admissions (adjusted rate ratio [RR], 1.92 [95% CI, 1.59 2.32]). An estimated 50% of the overall risk of inhospital death among very elderly patients was attributable to a combination of unplanned admission to the ICU, the presence of at least one comorbid condition, acute renal failure and respiratory failure requiring intubation. CONCLUSION: Unplanned admission to the ICU increases the risk of in-hospital mortality in very elderly patients. At least 50% of the risk of in-hospital death in this age group is attributable to a combination of unplanned ICU admission, comorbidity (>=1 comorbid condition), acute renal failure and respiratory failure. PMID- 21261575 TI - Enteral nutrition for patients in septic shock: a retrospective cohort study. AB - BACKGROUND: Haemodynamic instability is frequently considered a contraindication to enteral feeding. However, gastrointestinal function and the success of enteral feeding have never been formally examined in patients with shock. OBJECTIVE: To assess the adequacy of enteral nutrition in mechanically ventilated septic patients with and without shock. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study of septic patients receiving enteral nutrition in the intensive care unit of the Royal Adelaide Hospital in 2006. Patient data were obtained from case notes, nursing charts and dietitian notes. Enteral feeding was reviewed over a 7 day period in septic patients who were ventilated on more than 3 days. Adequacy of nutrition was defined as net calories delivered (including propofol) as a percentage of goal calories prescribed. MEAN OUTCOME MEASURES: Mean time to initiation of feeds; percentage of nutritional goals reached. RESULTS: 43 patients (mean age, 54 [SD, 20] years; mean APACHE II score, 20 [SD, 8]) were identified, of whom 33 had shock. The median length of ICU stay was 13 days (range, 3-55 days), and 32 patients (74%) survived hospital. Seventeen patients (40%) received <60% of goal nutrition over the 7 days. Overall calorie delivery improved over time and peaked at 86% of goal calories by Day 6. The mean time from ICU admission to start of feeding was 1.4 (range, 0-8) days. The mean time to initiation of feeding was not different in patients with or without shock: 1.3 (SD, 1.7) days v 1.7 (SD, 1.3) days (P=0.16). Patients with shock had higher mean daily gastric aspirate volumes than those without (113 [SD, 153] mL v 39 [SD, 47] mL; P=0.02), but no difference was found in the percentage of their nutritional goals reached (69% [SD, 23%] v 77% [SD, 16%]; P=0.2). CONCLUSION: Despite delayed gastric emptying, protocoldirected enteral feeding can be considered in patients with septic shock. PMID- 21261576 TI - Bowel motions in critically ill patients: a pilot observational study. AB - BACKGROUND: Limited information exists on the factors affecting bowel motions and the physical characteristics of stools in mechanically ventilated patients in the intensive care environment. We hypothesised that most stools in critically ill patients are not formed and that both diarrhoea and non-defecation are common. DESIGN, SETTING AND PATIENTS: Pilot prospective observational study of 44 patients in a tertiary intensive care unit who were mechanically ventilated for more than 24 hours. METHODS: We collected data on the frequency and appearance (Bristol stool chart) of bowel motions, and administration of nutrition, narcotics, anti-emetics, prokinetics and laxatives. RESULTS: Forty-four patients (31 male) with a mean age of 60.3 years were monitored for 274 ventilation days. There were 168 days (61.3%) with no defecation. During the 106 days (38.8%) with bowel motions, there were 101 days (36.9%) with loose stools and 33 days (12.0%) with at least one episode of diarrhoea. Formed stools were present on only 5 days (1.8%). No patients developed clinical or radiological evidence of constipation or pseudoobstruction. Treatment with lactulose (P = 0.009) and ondansetron (P = 0.02) was associated with a day with bowel motions, while use of morphine (P = 0.025) was associated with non-defecation. Lactulose treatment was the only factor associated with stool volume (P < 0.001). A higher rate of enteral nutrition was associated with looser stools (P < 0.001), while morphine was negatively associated with looser stools (P < 0.001). CONCLUSIONS: Among patients receiving mechanical ventilation for more than 24 hours, lack of bowel motions (non-defecation) was the most common physiological state. However, diarrhoea was also relatively common, and formed stools were rare. PMID- 21261577 TI - Inhibition of ATP-sensitive potassium channels attenuates propofol-induced vasorelaxation. AB - BACKGROUND: Infusion of propofol often causes significant vasodilation, which is followed by a profound drop in blood pressure. However, the exact underlying molecular mechanisms of this clinically important phenomenon remain unclear. OBJECTIVE: To determine the biological role of endothelium in propofol-induced vasorelaxation and the underlying molecular mechanisms of this response in the rat aorta. DESIGN, SETTING AND SUBJECTS: Ex vivo assessment of vasomotor function in rat aortic rings, with or without endothelium, after addition of propofol or etomidate. In vivo randomised study of haemodynamic changes in Sprague Dawley rats after administration of propofol, with or without prior infusion of a K(ATP) antagonist. In vitro measurement of intracellular calcium in cultured vascular smooth muscle cells (VSMC) treated with propofol. The experiments were conducted in a research laboratory at the National Cheng Kung University, Taiwan, from August 2008 to July 2009. INTERVENTIONS: Changes in isometric tension of precontracted rat aortic rings were recorded after cumulative addition of propofol (3-300uM). An ATP-sensitive potassium (K(ATP)) channel blocker, glibenclamide (10uM), was incubated in the organ bath before the addition of propofol. Haemodynamic changes after intravenous administration of propofol in the presence or absence of PNU-37883A (a vascular-specific K(ATP) channel blocker) were recorded in anaesthetised rats. Alterations in intracellular calcium and ATP levels in cultured VSMC treated with propofol were measured. RESULTS: Compared with etomidate, propofol induced a significant concentration dependent vascular relaxation response that was independent of the presence of endothelium. The relaxation response was almost completely abolished by K(ATP) channel antagonism. Levels of intracellular calcium were significantly attenuated in cultured VSMC treated with propofol (10mM). Pre-treatment with PNU- 37883A significantly attenuated propofol-induced hypotension in anaesthetised rats. CONCLUSIONS: Development of hypotension after systemic administration of propofol is mainly caused by its direct relaxation effect on vascular smooth muscle. This response is mainly mediated by activation of K(ATP) channels. PMID- 21261578 TI - Metformin-associated lactic acidosis (MALA): clinical profile and outcomes in patients admitted to the intensive care unit. AB - BACKGROUND: Metformin, a widely used hypoglycaemic agent in type 2 diabetes mellitus, is uncommonly associated with lactic acidosis, a serious condition with high mortality. OBJECTIVE: To evaluate the incidence of metforminassociated lactic acidosis (MALA) in an Australian intensive care unit, and the clinical profile and outcomes of patients admitted to the ICU with this diagnosis. DESIGN, SETTING AND PARTICIPANTS: We analysed data on patients admitted to a 14-bed tertiary care adult ICU over a 5-year period (January 2003 to December 2007). We did manual searches of ICU discharge summaries, reviewing case notes and cross referencing with the ICU electronic database to identify and characterise patients with an ICU discharge diagnosis of MALA. MALA was defined as a syndrome of elevated blood lactate level with acidaemia in patients taking metformin (after other causes of lactic acidosis had been excluded). RESULTS: There were 17 patients in our study cohort, with a mean age of 65 (SD, 9.9) years. MALA was diagnosed in 6 per 1000 ICU admissions. All patients with MALA presented with gastrointestinal symptoms of nausea, vomiting and/or diarrhoea, and 11 had clinical signs of dehydration. Patients had evidence of severe acidosis (mean pH 6.92 [SD, 0.26]; anion gap, 34 [SD, 10]); high lactate levels (mean 9.6 [SD, 4.1] mmol/L); and acute renal dysfunction (mean creatinine level 585 [SD, 305] umol/L). The mean APACHE (Acute Physiology and Chronic Health Evaluation) III score was 106.4 (SD, 42.9). The mean invasive mechanical ventilation time (for 13 patients who required ventilation) was 23.4 (SD, 32.3) hours, and mean ICU length of stay was 62.8 (SD, 53.5) hours. Thirteen patients required dialysis and vasopressor support and two had a negative laparotomy; 5/17 patients (29%) died. APACHE III score, arterial pH on admission and male sex were associated with an increased risk of death in hospital (P < 0.05). CONCLUSION: MALA is a not uncommon cause of ICU admission. Gastrointestinal symptoms predominate in MALA, and the condition is associated with significant morbidity and mortality. PMID- 21261579 TI - Mortality prediction and outcomes among burns patients from Australian and New Zealand intensive care units. AB - BACKGROUND: Acute Physiology and Chronic Health Evaluation (APACHE) III scores have been shown to correlate with outcomes for patients with burn injuries. It is unknown whether they can be used to compare outcomes between intensive care units that admit patients with burns in Australia and New Zealand. OBJECTIVE: To assess the APACHE III-j score as a predictor of mortality for burns patients and use it to compare riskadjusted outcomes between different ICUs. DESIGN, SETTING AND PARTICIPANTS: Retrospective cohort study of all patients listed in the Australian and New Zealand Intensive Care Society Adult Patient Database with a diagnosis of burns between 1 January 2001 and 30 June 2008. Logistic regression analysis was used to assess the relationship between APACHE III-j score and mortality, and to derive a predicted risk of death for each patient. Standardized mortality ratios for individual ICUs were calculated and outcome variation assessed. RESULTS: Data on 1618 patients were included in the analysis (mean age, 40.6 years; mortality, 13.2%). Increasing APACHE III-j scores were significantly associated with increasing likelihood of death (odds ratio, 1.05 [95%CI, 1.04-1.06]). The largest ICU and two small ICUs had risk-adjusted outcomes that were significantly better than the rest. Over the study period there was a decline in observed mortality accompanied by a parallel reduction in predicted risk of death. CONCLUSION: The APACHE III-j score is a good predictor of death among burns patients admitted to ICUs in Australia and New Zealand. It can be used to compare risk-adjusted outcomes between individual ICUs and over time. PMID- 21261580 TI - Haemodynamic stability is maintained during extended daily diafiltration in critically ill septic patients. AB - BACKGROUND: Extended daily diafiltration (EDDf) is a prolonged intermittent dialysis technique introduced as an alternative to continuous renal replacement therapy in critically ill patients. Although EDDf has the advantages of ease of use, low cost and patient tolerability, there is concern that the high blood and dialysate flow rates used with EDDf may precipitate haemodynamic instability. OBJECTIVE: To identify whether haemodynamic changes occur during the course of EDDf therapy in adult patients who are admitted to the intensive care unit with sepsis and require dialysis. DESIGN, SETTING AND PARTICIPANTS: A prospective observational study of patients fitting the inclusion criteria who were admitted to the ICU of the Gold Coast Hospital, Queensland, during the period 1 January 2002 to 31 December 2005. MAIN OUTCOME MEASURES: Mean arterial pressure (MAP) and heart rate (HR) before, during and after EDDf treatment. RESULTS: 178 EDDf treatments were administered to 44 patients. Haemodynamic parameters remained stable during EDDf, despite median blood flow rates of 265 mL/min and dialysate flow rates of 300 mL/min: MAP was 81.2 mmHg before EDDf v 82.7 mmHg after EDDf (P = 0.13); HR was 100.4 beats/min before EDDf v 98.9 beats/ min after EDDf (P = 0.23). For treatments in which vasopressive support was required (n = 75), no increase in dose requirement was observed. Patient mortality at the time of hospital discharge (41%) was less than the rate predicted by APACHE III scores (52%). CONCLUSION: EDDf did not significantly worsen haemodynamic stability in patients with sepsis during their treatment. PMID- 21261581 TI - Assessment of the clinical utility of an ultrasonic monitor of cardiac output (the USCOM) and agreement with thermodilution measurement. PMID- 21261582 TI - ECMO: expertise and equipoise. PMID- 21261583 TI - Protein & Peptide Letters. Editorial. PMID- 21261584 TI - Protein dynamics in solution. PMID- 21261585 TI - Targeting the orexin system: a new approach for treating insomnia. PMID- 21261586 TI - Parkinson's disease: kinase busters to the rescue? Commentary. PMID- 21261587 TI - Power troubles in Parkinson's disease. Commentary. PMID- 21261588 TI - Putting a finger on neurotrophic protein therapy in Parkinson's disease. Commentary. PMID- 21261589 TI - The role of corticotropin-releasing hormone in the pathophysiology of depression: therapeutic implications. AB - Stress responses have been posited to be a key component of mental health and disease by playing essential roles both in normal adaptive processes and maladaptive physiological responses that in part underlie the pathogenesis of certain subtypes of mood and anxiety disorders. Early research focused on delineating the function of the hypothalamic-pituitary-adrenal (HPA) axis and subsequently examined its role in mediating the mammalian stress responses and its hyperactivity in depression. Much evidence now supports an important function of the biological mediators of this system in relation to not only depression, but also anxiety, substance abuse, and psychotic disorders, and implicates several components of this system as areas of intervention for novel pharmacotherapy. Perhaps the best studied central nervous system (CNS) component of this system is corticotropin-releasing factor (CRF), and considerable research has focused on its role in the HPA axis, as well in extrahypothalamic brain regions. PMID- 21261590 TI - Synthetic sphingosine 1-phosphate receptor modulators--opportunities and potential pitfalls. AB - Sphingosine 1-phosphate (S1P) evokes a plethora of physiological responses by stimulating members of a G protein-coupled receptor family, known as S1P receptors. Currently five different mammalian S1P receptor subtypes, S1P1-5, each with a different cellular expression pattern, were identified. The S1P1 receptor in particular has attracted major interest throughout the pharmaceutical industry following the breakthrough discovery that this S1P receptor subtype is critically involved in the regulation of lymphocyte trafficking through secondary lymphoid organs. Since then, examples of synthetic S1P1 agonists with lymphocyte reducing and immunomodulating activity demonstrated efficacy in numerous preclinical models of autoimmune disease and transplantation. Notably FTY720 (fingolimod), a pro-drug that is phosphorylated in vivo and converted into a non-selective S1P1,3,4,5 receptor agonist, has been widely used to increase the understanding of S1P1 receptor biology. Results from recently completed phase III clinical trials using FTY720 paved the way for this non-selective S1P1 receptor agonist to become the first oral therapy in multiple sclerosis, with potential expansion into many other autoimmune diseases. This review briefly outlines the field of S1P1 receptor biology and summarizes recent approaches in medicinal chemistry to discover potent and selective S1P1 receptor agonists. In particular, the complexity of discovering a molecule akin to FTY720 but with an improved side effect profile will be discussed. PMID- 21261591 TI - Discovery of dual orexin receptor antagonists (DORAs) for the treatment of insomnia. AB - Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness. Orexin receptor antagonists promote sleep in animals and humans. Indeed, small molecule orexin receptor antagonists have demonstrated clinical proof-of-concept in the treatment of primary insomnia. This review describes optimization of orexin receptor antagonists across diverse structural classes with a focus on how molecules were designed to optimize potency, physicochemical properties, pharmacokinetics, brain penetration, and in vivo activity. PMID- 21261592 TI - mGluR5 negative allosteric modulators overview: a medicinal chemistry approach towards a series of novel therapeutic agents. AB - Allosteric modulators of metabotropic glutamate receptors (mGluR) subtypes 1-8 have been shown to offer a valid way to develop small molecule non aminoacid-like therapeutics that can be administered orally and that readily cross the blood brain barrier. Allosteric modulators of glutamatergic receptors and in particular mGluR5 have emerged as a novel and highly desirable class of compounds for the treatment of central nervous system (CNS) disorders and peripheral disorders. This article provides medicinal chemistry highlights around the chemical classes of potent and highly selective mGluR5 negative allosteric modulators (NAMs) and their therapeutic potential. In addition, it describes the medicinal chemistry approach from the discovery to the clinical candidate selection of a new series of heteroaryl-butynylpyridines targeting mGluR5. The multiparametric optimization of the initial starting point which ended in the selection of potential clinical candidates combining the best pharmacophoric features is presented. The pharmacological properties are reported and support the interest of these agents for new therapeutic approaches. Furthermore, a summary of the diverse mGluR5 Positron Emission Tomography (PET) radioligands is reported. PMID- 21261593 TI - Molecular determinants of selective agonist and antagonist binding to the histamine H4 receptor. AB - The deorphanization of the histamine H4 receptor (H4R) has led to a significant number of scientific publications and patent applications. Whereas some histamine H1, H2 and H3 receptor ligands were found to have significant affinity for H4R, several agonists and antagonists with high affinity for H4R and selectivity over the other histamine receptors were successfully designed and synthesized. Moreover, site-directed mutation studies on H4R have been performed and reveal detailed information on receptor-ligand interactions. This review will focus on the most important H4R ligand scaffolds and their structure-activity relationships and selectivity over other histamine receptors and specific H4R functional activity. Experimental data are used to construct and validate high resolution three-dimensional receptor-ligand models and, vice versa, in silico models are used to design and rationalize experimental studies to probe receptor ligand interactions. PMID- 21261594 TI - The evolution of histamine H3 antagonists/inverse agonists. AB - This article describes our efforts along with recent advances in the development, biological evaluation and clinical proof of concept of small molecule histamine H3 antagonists/inverse agonists. The H3 receptor is a presynaptic autoreceptor within the Class A GPCR family, but also functions as a heteroreceptor modulating levels of neurotransmitters such as dopamine, acetylcholine, norepinephrine, serotonin, GABA and glutamate. Thus, H3R has garnered a great deal of interest from the pharmaceutical industry for the possible treatment of obesity, epilepsy, sleep/wake, schizophrenia, Alzheimer's disease, neuropathic pain and ADHD. Within the two main classes of H3 ligands, both imidazole and non-imidazole derived, have shown sufficient potency and specificity which culminated with efficacy in preclinical models for various CNS disorders. Importantly, conserved elements have been identified within the small molecule H3 ligand scaffolds that resulted in a highly predictive pharmacophore model. Understanding of the pharmacophore model has allowed several groups to dial H3R activity into scaffolds designed for other CNS targets, and engender directed polypharmacology. Moreover, Abbott, GSK, Pfizer and several others have reported positive Phase I and/or Phase II data with structurally diverse H3R antagonists/inverse agonists. PMID- 21261596 TI - EBI2, GPR18 and GPR17--three structurally related, but biologically distinct 7TM receptors. AB - 7TM receptors constitute one of the largest superfamilies of proteins in the human genome. They are involved in a large number of physiological and pathological processes in the human body and thus represent major and important drug targets for the pharmaceutical industry. Although the majority have been deorphanized, many remain orphan, and these orphan receptors constitute a large pool of potential drug targets. This review focuses on one of these orphan targets, the Epstein-Barr Virus-induced receptor 2, EBI2 (or GPR183), together with two structurally related receptors, GPR17 and GPR18. The pharmacology and "druggability" of these three receptors is reviewed through a thorough description of their structural and functional properties and in vivo biology together with a status of currently available ligands for these receptors. PMID- 21261595 TI - Novel anti-inflammatory--pro-resolving mediators and their receptors. AB - Resolution of inflammation, an actively coordinated program, is essential to maintain host health. It involves effective removal of inflammatory stimuli and the spatio-temporal control of leukocyte trafficking as well as chemical mediator generation. During the active resolution process, new classes of small, local acting endogenous autacoids, namely the lipoxins, D and E series resolvins, (neuro)protectins, and maresins have been identified. These specialized pro resolving lipid mediators (SPM) prevent excessive inflammation and promote removal of microbes and apoptotic cells, thereby expediting resolution and return to tissue homeostasis. As part of their molecular mechanism, SPM exert their potent actions via activating specific pro-resolving G-protein coupled receptors. Together these SPM and their receptors provide new concepts and opportunities for therapeutics, namely promoting active resolution as opposed to the conventionally used enzyme inhibitors and receptor antagonists. This approach may offer new targets suitable for drug design for treating inflammation related diseases, for the new terrain of resolution pharmacology. PMID- 21261598 TI - Flow cytometry-based characterization of label-retaining stem cells following transplacental BrdU labelling. AB - A method to characterize and culture stem cells from neonate mouse epidermis after transplacental BrdU (bromo-deoxyuridine) administration is described. We have characterized stem cells by their properties viz. to retain BrdU label, adhere rapidly onto collagen-fibronectin substratum and express a specific biomarker beta-1-integrin. BrdU-labelled cells (detected using monoclonal antibody) constituted a sum of 18% of the total number of cells. The ability of freshly isolated keratinocytes [LRCs (label-retaining cells)] to bind to primary BrdU antibody or to pick up PI (propidium iodide) stain was distinguishable. Viable LRCs did not retain PI. Such cells, termed EpSC (epidermis stem cell), were PI negative and BrdU positive. EpSC constituted 6% of the total cell yield. Culture in low Ca2+ medium and susceptibility to differentiation in the presence of high Ca2+ levels further characterized the stem cells. This protocol is useful for studying transplacental carcinogenesis. PMID- 21261597 TI - Malignant potential of H22 hepatocarcinoma cells increases after recovery from IFN-gamma-mediated inhibition. AB - IFN-gamma (interferon gamma) can effectively suppress tumours, but it has also been found to promote tumour progression. However, the underlying mechanisms by which it enhances malignancy have not been fully elucidated. By using a mouse model that expresses IFN-gamma locally in muscle, we found that the growth potential of tumours was increased after a quick decrease of IFN-gamma. Furthermore, the up-regulation of IRF-2 (IFN regulatory factor 2) and down regulation of IRF-1 were also found in the tumour cells. Along these lines, IFN gamma led to down-regulated expression of cyclin-D1, Bcl-2 and Bcl-xL and up regulated expression of p21WAF1 and Bax in tumour cells. Yet, the expression of these genes, as well as activation of ERK (extracellular signal-regulated kinase) and NF-kappaB (nuclear factor-kappaB), was also reversed shortly after a decrease in IFN-gamma, all of which resulted in increase tumour cell proliferation and apoptosis resistance. These findings indicate that the malignant potential of tumour cells may be suppressed by interfering with IRF-2 signalling pathways during and after decreased IFN-gamma in tumour microenvironments. PMID- 21261599 TI - Systematic review and meta-analysis of the clinical factors associated with the suicide of psychiatric in-patients. AB - OBJECTIVE: To estimate the strength of the associations between the suicide of psychiatric in-patients and demographic, historical, symptomatic, diagnostic and treatment factors. METHOD: A systematic review and meta-analysis of controlled studies of the suicide of psychiatric in-patients including suicides while on approved or unapproved leave. RESULTS: Factors that were significantly associated with in-patient suicide included a history of deliberate self-harm, hopelessness, feelings of guilt or inadequacy, depressed mood, suicidal ideas and a family history of suicide. Patients suffering from both schizophrenia and depressed mood appeared to be at particular risk. The association between suicidal ideas and in patient suicide was weak and did not reach statistical significance after a quantitative correction for publication bias. A high-risk categorization as defined by a combination of retrospectively determined individual risk factors was strongly statistically associated with in-patient suicide (OR=10.9), with a sensitivity of 64% and a specificity of 85%. CONCLUSION: Despite the apparently strong association between high-risk categorization and subsequent suicide, the low base rate of in-patient suicide means that predictive value of a high-risk categorization is below 2%. The development of safer hospital environments and improved systems of care are more likely to reduce the suicide of psychiatric in patients than risk assessment. PMID- 21261600 TI - Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of birth defects. AB - OBJECTIVE: To assess the methodological value of studies that signaled one or more selective serotonin reuptake inhibitors (SSRIs) as teratogenic agents. METHOD: Medical literature, published in English (1980-November 2010), was searched using MEDLINE/PubMed, TOXNET, EMBASE, and The Cochrane Library to identify all articles, reporting primary data that suggested any increased rate of congenital malformations following prenatal exposure to SSRIs as a group or single SSRI agents. RESULTS: Reviewed studies showed some severe methodological limitations, such as data coming from retrospective studies and incomplete information available with reference to timing of exposure and dosages. Further, data continue to be extrapolated from automated databases that do not declare whether the women reported actually used the prescribed medication. Further, it should be noted the distinct lack of research analysis available with reference to the potential impact of non-iatrogenic confounders on pregnancy. CONCLUSION: In light of such considerations, the hypothesized teratogenicity of SSRIs remains undemonstrated. Hence, further, well-designed research is needed to differentiate definitively the detrimental impact of depression on pregnancy outcomes from potential iatrogenic events. PMID- 21261601 TI - Unraveling the genetic and molecular basis of posterior column ataxia and retinitis pigmentosa. PMID- 21261602 TI - Exploring the genetic origins of Treacher Collins syndrome. PMID- 21261603 TI - A specific subtype of infantile Parkinsonism-dystonia identified. PMID- 21261604 TI - Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations. AB - Childhood brain tumours may be due to germline bi-allelic mismatch repair (MMR) gene mutations in MLH1, MSH2, MSH6 or PMS2. These mutations can also lead to colorectal neoplasia and haematological malignancies. Here, we review this syndrome and present siblings with early-onset rectal adenoma and papillary glioneural brain tumour, respectively, due to novel germline bi-allelic PMS2 mutations. Identification of MMR protein defects can lead to early diagnosis of this condition. In addition, assays for these defects may help to classify brain tumours for research protocols aimed at targeted therapies. PMID- 21261605 TI - Physical forces may cause Hox gene collinearity in the primary and secondary axes of the developing vertebrates. AB - The features of spatial and temporal Hox gene collinearity along the anteroposterior and secondary axes of vertebrate development have been extensively studied. However, the understanding of these features remains problematic. Some genetic engineering experiments were performed and the consequent modifications of the Hoxd gene expressions in the vertebrate limb and trunk were presented. A two-phases model was proposed to describe the above results but still many data cannot be explained. In the present work a different mechanism is put forward in order to deal with the above experiments. This alternative mechanism (coined biophysical model), is based on the hypothesis that physical forces decondense and 'loop out' the chromatin fiber causing the observed Hox gene collinearity phenomena at the early stages of axonal development. The two models are compared in detail. The biophysical model adequately explains the data even in cases where the results are characterized as unexpected. Furthermore, the biophysical model predicts that the Hox gene expressions are entangled in space and time and this coupling is compatible with the data of the early developmental stages. Additional experiments are proposed for a direct test of this model. PMID- 21261606 TI - Sperm motility-initiating substance in newt egg-jelly induces differential initiation of sperm motility based on sperm intracellular calcium levels. AB - Sperm motility-initiating substance (SMIS), a novel motility inducer from newt egg-jelly, is activated by the release from associated jelly substances at the beginning of internal fertilization and affects female-stored sperm. We examined motility initiation kinetics of newt sperm in response to SMIS by monitoring the changes of sperm intracellular calcium ([Ca2(+)](i)). In quiescent non-motile sperm loaded with the Ca2(+) indicator Fluo-4, intracellular free Ca2(+) was observed around mitochondria using confocal scanning laser microscopy. A slight increase in [Ca2(+)](i) occurred simultaneously and transiently at motility initiation in sperm treated with either heated jelly extract (hJE) containing activated SMIS, or a low osmotic solution, which naturally initiates motility in externally-fertilizing amphibians and can initiate motility in urodele sperm. When the increase of [Ca2(+)](i) at motility-initiation was monitored using spectrofluorometry, large increases in [Ca2(+)](i) occurred immediately in the low osmotic solution and within 1.5 min in the hJE. In the intact jelly extract (no heating), small increases of [Ca2(+)](i) irregularly occurred from around 1 min and for about 4 min, during which motility was differentially initiated among sperm. These results indicate that the SMIS induces differential initiation of sperm motility depending on the activational states of the SMIS and its overall activity. The motility initiation in the jelly extract was delayed in sperm whose intracellular Ca2(+) had been chelated with BAPTA-AM. The relative levels of [Ca2(+)](i) were variable with a mean of 414 +/- 256 nmol/L among resting sperm, suggesting that the level of [Ca2(+)](i) in the resting sperm modulates the responsiveness to the SMIS. PMID- 21261607 TI - Cytoplast containing reprogramming-related factors from human embryonic stem cells arrested at metaphase. AB - Generating pluripotent stem cells directly from a patient's somatic cells is one of the major methods to avoid rejection in future regenerative medicine. It is reported that human embryonic stem cells (hESCs) are able to reprogram the nuclei of fully differentiated human somatic cells, apparently conferring on them a pluripotent state. However, the ability of the cytoplasts from enucleated hESCs to reprogram somatic cells causes much controversy. Here we detect the location of pluripotency-related factors such as Oct4/Nanog/Sox2 in the hESCs at division and non-division stage and obtain the cytoplasts of hESCs by centrifugation. We demonstrate for the first time that the cytoplast from hESCs arrested at the division phase of cell the cycle contains the reprogramming factors and this kind of cytoplast can be obtained through gradient centrifugation. These give us direct proof of the possibility of reprogramming somatic cell using cytoplast of hESCs and make this a possible method for getting patient-specific pluripotent cells without extrinsic DNA introduction. PMID- 21261608 TI - Embryonic ionocytes in the European sea bass (Dicentrarchus labrax): Structure and functionality. AB - Early ionocytes have been studied in the European sea bass (Dicentrarchus labrax) embryos. Structural and functional aspects were analyzed and compared with those observed in the same conditions (38 ppt) in post hatching stages. Immunolocalization of Na(+) /K(+) -ATPase (NKA) in embryos revealed the presence of ionocytes on the yolk sac membrane from a stage 12 pair of somites (S), and an original cluster around the first gill slits from stage 14S. Histological investigations suggested that from these cells, close to the future gill chambers, originate the ionocytes observed on gill arches and gill filaments after hatching. Triple immunocytochemical staining, including NKA, various Na(+) /K(+) /2Cl- cotransporters (NKCCs) and the chloride channel "cystic fibrosis transmembrane regulator" (CFTR), point to the occurrence of immature and mature ionocytes in early and late embryonic stages at different sites. These observations were completed with transmission electronic microscopy. The degree of functionality of ionocytes is discussed according to these results. Yolk sac membrane ionocytes and enteric ionocytes seem to have an early role in embryonic osmoregulation, whereas gill slits tegumentary ionocytes are presumed to be fully efficient after hatching. PMID- 21261609 TI - Development of Ca2(+) signaling mechanisms and cell motility in presumptive ectodermal cells during amphibian gastrulation. AB - This study investigated the development of Ca2(+) signaling mechanisms and their role in initiating morphogenetic cell movement in the presumptive ectoderm of Japanese newt (Cynops pyrrhogaster) during gastrulation. Histochemical staining using fluorescently labeled ryanodine and dihydropyridine probes revealed that dihydropyridine receptor (L-type Ca2(+) channels) appeared in stage 12b embryos, while ryanodine receptors were expressed in both stage 11 and 12b embryos. Transmission electron microscopy of stage 12b embryos showed abundant peripheral couplings, which are couplings of the endoplasmic reticulum and cell membrane with an approximate 12 nm gap. Caffeine increased the intracellular free Ca2(+) concentration ([Ca2(+)](i)) in presumptive ectodermal cells isolated from both stage 11 and 12b embryos, while (+/-)-Bay K 8644 ((+/-)-BayK) increased [Ca2(+)](i) in cells isolated from stage 12b embryos, but not in cells isolated from stage 11 embryos. Dantrolene and nifedipine completely inhibited increases in [Ca2(+)](i) after treatment with caffeine and (+/-)-BayK, respectively. Caffeine activated the motility of cells isolated from both stage 11 and 12b embryos, but (+/-)-BayK only activated the motility of cells isolated from stage 12b embryos. These findings suggested that formation of the Ca2(+) -induced Ca2(+) release system in presumptive ectodermal cells during gastrulation plays an important role in the initiation and execution of epibolic extension. PMID- 21261610 TI - Atelocollagen-mediated systemic administration of myostatin-targeting siRNA improves muscular atrophy in caveolin-3-deficient mice. AB - Small interfering RNA (siRNA)-mediated silencing of gene expression is rapidly becoming a powerful tool for molecular therapy. However, the rapid degradation of siRNAs and their limited duration of activity require efficient delivery methods. Atelocollagen (ATCOL)-mediated administration of siRNAs is a promising approach to disease treatment, including muscular atrophy. Herein, we report that ATCOL mediated systemic administration of a myostatin-targeting siRNA into a caveolin-3 deficient mouse model of limb-girdle muscular dystrophy 1C (LGMD1C) induced a marked increase in muscle mass and a significant recovery of contractile force. These results provide evidence that ATCOL-mediated systemic administration of siRNAs may be a powerful therapeutic tool for disease treatment, including muscular atrophy. PMID- 21261611 TI - Peptidyl-prolyl cis-trans isomerase xFKBP1B induces ectopic secondary axis and is involved in eye formation during Xenopus embryogenesis. AB - Although Xenopus FKBP1A (xFKBP1A) induces an ectopic dorsal axis in Xenopus embryos, involvement of xFKBP1B, a vertebrate paralogue of FKBP1A, in embryogenesis remains undetermined. Here, we demonstrate that xFKBP1B induces ectopic dorsal axis and involves in eye formation of Xenopus embryos. Injection of the xFKBP1B mRNA in ventral blastomeres of 4-cell stage Xenopus embryos induced a secondary axis and showed multiplier effect to that of xFKBP1A on this when xFKBP1A was co-injected. In addition, BMP4 and Smad1 mRNAs did not affect the ability of xFKBP1B to induce the ectopic secondary axis when either was co injected with xFKBP1B in ventral blastomeres, whereas they downed out that of xFKBP1A, suggesting that xFKBP1A and xFKBP1B induce the ectopic secondary axis through affecting different pathways from each other. On the other hand, the injection of the FKBP1B mRNA in dorsal blastomeres showed eye malformation, and suppressed almost completely the expression of Rx1, Mitf, and Vax2 mRNAs. xFKBP1B was expressed in the dorsal side of the embryo including the eye during embryogenesis at least until stage 46. Injection of morpholino of the xFKBP1B mRNA in dorsal blastomeres induced additional retina or failed to close tapetum nigrum in the ventral side within the optic cap, whereas it did not affect the dorsal organ development. The injection of the morpholino reduced the expression of Xotx2 and Rx1 mRNAs in the eye. These observations suggest that xFKBP1B is a key factor that regulates the expression levels of the genes involved in eye formation during Xenopus embryogenesis. PMID- 21261612 TI - Conditional knockdown of target gene expression by tetracycline regulated transcription of double strand RNA. AB - In vivo electroporation has served as an effective tool for the study of developmental biology. Here we report tetracycline inducible gene knockdown by electroporation. Our system consists of genome integration of a cassette encoding long double strand RNA (dsRNA) of a gene of interest by electroporation, transcription of which is assured by RNA polymerase II, and induction of transcription of dsRNA by tetracyclin. Long dsRNA decapped by ribozyme in the cassette and without poly A tail is processed into siRNA within nuclei. We could successfully induce knockdown of En2 and Coactosin by Dox administration. PMID- 21261613 TI - Polo-like kinase 1 is required for localization of Posterior End Mark protein to the centrosome-attracting body and unequal cleavages in ascidian embryos. AB - In ascidian embryos, the posterior-localized maternal factor Posterior End Mark (PEM) is responsible for patterning embryos along the anterior-posterior axis with regard to both cleavage pattern involving unequal cell divisions and gene expression. Although PEM plays important roles in embryogenesis, its mechanism of action is still unclear because PEM has no known functional domain. In the present study, we explored the candidate of PEM partner proteins in Halocynthia roretzi using yeast two-hybrid screening. We isolated a homologue of Polo-like kinase 1 (Plk1), a key regulator of cell division and highly conserved in eukaryotes, as the first potential binding partner of PEM. We biochemically confirmed that interaction occurred between the Plk1 and PEM proteins. Immunostaining showed that Plk1 protein concentrates in the centrosome-attracting body (CAB) at the posterior pole, where PEM protein is also localized. The CAB is a subcellular structure that plays an important role in generating the posterior cleavage pattern. Plk1 localization to the CAB was dependent on the cell cycle phases during unequal cleavage. Inhibition of Plk1 with specific drugs resulted in failure of the nucleus to migrate towards the posterior pole and formation of a microtubule bundle between the CAB and a centrosome, similarly to inhibition of PEM function, suggesting that both proteins are involved in the same process of unequal cleavages. This interrupted nuclear migration was rescued by overexpression of PEM. In Plk1-inhibited embryos, the localization of PEM protein to the CAB was impaired, indicating that Plk1 is required for appropriate localization of PEM. PMID- 21261614 TI - Antioxidant defense and apoptotic effectors in ascorbic acid and beta glycerophosphate-induced osteoblastic differentiation. AB - MC3T3-E1 cells grown in the presence of ascorbic acid and beta-glycerophosphate (AA/beta-GP) express alkaline phosphatase and produce an extensive collagenous extracellular matrix. Differentiated MC3T3-E1 cells are more sensitive to hydrogen peroxide-induced oxidative stress than undifferentiated cells. In this study, we compared the profile of antioxidant enzymes and molecular markers of apoptosis in undifferentiated and differentiated MC3T3-E1 cells (cell differentiation was induced by treatment with AA/beta-GP). Differentiated osteoblasts showed lower expression and activity of catalase, glutathione S transferase and glutathione peroxidase. The total superoxide dismutase activity and the expression of Cu/Zn superoxide dismutase were also lower, while the expression of Mn superoxide dismutase was higher in differentiated osteoblasts. The level of malondialdehyde, a widely used marker for oxidative stress, was lower in the AA/beta-GP group compared with control cells, but this difference was not significant. Western blotting showed that treatment with AA/beta-GP increased the Bax/Bcl-2 ratio used as an index of cellular vulnerability to apoptosis. In addition, the activities of caspases 3, 8 and 9 and cleaved poly (ADP) ribose polymerase were significantly higher in differentiated cells. These findings provide new insights into how changes in the activities of major antioxidant enzymes and in the signaling pathways associated with apoptosis may influence the susceptibility of bone cells to oxidative stress. PMID- 21261615 TI - Role of syndecan-4 side chains in turkey satellite cell growth and development. AB - Syndecan-4 is a cell membrane heparan sulfate proteoglycan that is composed of a core protein and covalently attached glycosaminoglycans (GAG) and N-linked glycosylated (N-glycosylated) chains. Syndecan-4 has been shown to function independent of its GAG chains. Syndecan-4 may derive its biological function from the N-glycosylated chains due to the biological role of N-glycosylated chains in protein folding and cell membrane localization. The objective of the current study was to investigate the role of syndecan-4 N-glycosylated chains and the interaction between GAG and N-glycosylated chains in turkey myogenic satellite cell proliferation, differentiation, and fibroblast growth factor 2 (FGF2) responsiveness. The wild type turkey syndecan-4 and the syndecan-4 without GAG chains were cloned into the expression vector pCMS-EGFP and used as templates to generate syndecan-4 N-glycosylated one-chain and no-chain mutants with or without GAG chains. The wild type syndecan-4, all of the syndecan-4 N-glycosylated chain mutants were transfected into turkey myogenic satellite cells. Cell proliferation, differentiation, and responsiveness to FGF2 were measured. The overexpression of syndecan-4 N-glycosylated mutants with or without GAG chains did not change cell proliferation, differentiation, and responsiveness to FGF2 compared to the wild type syndecan-4 except that the overexpression of syndecan-4 N-glycosylated mutants without GAG chains increased cell proliferation at 48 and 72 h post-transfection. These data suggest that syndecan-4 functions in an FGF2 independent manner, and the N-glycosylated and GAG chains are required for syndecan-4 to regulate turkey myogenic satellite cell proliferation, but not differentiation. PMID- 21261616 TI - Involvement of Delta and Nodal signals in the specification process of five types of secondary mesenchyme cells in embryo of the sea urchin, Hemicentrotus pulcherrimus. AB - Secondary mesenchyme cells (SMCs) of the sea urchin embryo are composed of pigment cells, blastocoelar cells, spicule tip cells, coelomic pouch cells and muscle cells. To learn how and when these five types of SMCs are specified in the veg2 descendants, Notch or Nodal signaling was blocked with gamma-secretase inhibitor or Nodal receptor inhibitor, respectively. All types of SMCs were decreased with DAPT, while sensitivity to this inhibitor varied among them. Pulse treatment revealed that five types of SMCs are divided into "early" (pigment cells and blastocoelar cells) and "late" (spicule tip cells, coelomic pouch cells and muscle cells) groups; the "early" group was sensitive to DAPT up to the hatching, and the "late" group was sensitive until the mesenchyme blastula stage. Judging from timing of the shift of Delta-expressing regions, it was suggested that the "early" group and "late" groups are derived from the lower and the middle tier of veg2 descendants, respectively. Interestingly, numbers of SMCs were also altered with SB431542; blastocoelar cells, coelomic pouch cells and circum-esophageal muscles decreased, whereas pigment cells and spicule tip cells increased in number. Pulse-treatment showed that the "early" group was sensitive up to the mesenchyme blastula stage, while the "late" group up to the onset of gastrulation. Thus, it became clear that precursor cells of the "early" and "late" groups, which are located in different regions in the vegetal plate, receive Delta and Nodal signals at different timings, resulting in the diversification of SMCs. Based on the obtained results, the specification processes of five types of SMCs are diagrammatically presented. PMID- 21261617 TI - 8-Hydroxy-2'-deoxyguanosine is a prognostic mediator for cardiac event. AB - BACKGROUND: DNA in the nucleus is one of the major targets of reactive oxygen species (ROS), and oxidative DNA damage has been implicated in the pathogenesis of chronic heart failure. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) is produced from deoxyguanosine in DNA by ROS. The purpose of this present study was to examine the clinical significance of serum 8-OHdG levels in patients with heart failure. METHODS: We measured serum 8-OHdG levels in 230 patients with chronic heart failure and 42 control subjects without heart failure by sandwich enzyme-linked immunosorbent assay. Patients were prospectively followed during a median follow up period of 472 days with the end points of cardiac death or progressive heart failure requiring re-hospitalization. RESULTS: Serum 8-OHdG concentrations were higher in patients with heart failure than in control subjects (P < 0.001) and increased with advancing New York Heart Association (NYHA) functional class (P < 0.001). Normal upper limit of 8-OHdG level was determined as mean +/- 2SD value from 42 control subjects (0.40 ng mL(-1)). Abnormally high serum 8-OHdG levels (> 0.40 ng mL(-1)) were observed in 21.2%, 43.1%, 42.6% and 69.4% through NYHA I to IV (P < 0.001). A total of 66 cardiac events occurred during a follow-up period, and Kaplan-Meier survival curves demonstrated that cardiac event rate was markedly higher in patients with high 8-OHdG levels than in those with normal 8 OHdG levels (62.4% vs. 29.6%, P = 0.0007). CONCLUSIONS: Serum 8-OHdG levels provide important prognostic information for the risk stratification of patients with heart failure. PMID- 21261618 TI - Age and gender differences in urea breath test results. AB - BACKGROUND: (13) C urea breath test (UBT) results, used for the diagnosis of Helicobacter pylori infection, fluctuate in different age groups. We characterized both the age- and gender-based trends of UBT results, from early childhood through late adulthood. METHODS: A national H. pylori referral laboratory was screened for all positive UBTs during 2007-2008, determined as a delta over baseline (DOB) >= 3.5. Data were analysed with respect to both age and gender. RESULTS: In the studied period, 61,060 UBTs were performed and 24,237 were positive. After excluding multiple testing for an individual, a total of 21,767 positive results were analysed. The male/female ratio for positive UBTs was 1 : 1.77. DOB results decreased as age increased from a maximum of 38.6 +/- 21 at age 3-5 years to 21.1 +/- 12 at age 19-30 in females (P < 0.001) and from 30.0 +/- 16 at age 6-10 years to 14.7 +/- 8 at age 19-30 years in males (P < 0.0001). At this point, the values reached a nadir for both genders. In patients older than 60 years, old test results increased moderately (P < 0.003). In all age groups, except 6-10 years old, females had significantly higher UBT results than males. CONCLUSIONS: The decrease in mean UBT values already occurs during the first decade of life, and results increase following the sixth decade. Females have significantly higher results than males even in early childhood and throughout old age. PMID- 21261619 TI - Genetic variation in renin predicts the effects of thiazide diuretics. AB - BACKGROUND: While genetic variants of renin-angiotensin-aldosterone system (RAAS) may modify the blood pressure (BP) response to thiazide diuretics, there was no evidence of genetic variations in renin (REN) playing a role. This study aimed to address the potential effects of genetic variations of RAAS on the response to initial treatment of hydrochlorothiazide (HCTZ). MATERIALS AND METHODS: We enrolled nondiabetic hypertensive patients with a systolic blood pressure (SBP) >=140 or a diastolic blood pressure (DBP) >=90mmHg, who were either previously untreated or unsatisfactorily treated. After lifestyle modification and diet instruction for 2weeks, 90 patients with persistently elevated BP were given HCTZ 50 mg every morning for 2 weeks. Single nucleotide polymorphism markers were selected from genes involving in RAAS, including rs7079 and rs699 of angiotensinogen, rs4293 and rs4353 of angiotensin-converting enzyme and rs1464816 and rs11240688 of REN. RESULTS: The patients were divided into three groups according to the SBP response after HCTZ. The upper 1/3 responders had older age (P=0.035), higher SBP (P=0.039), higher pulse pressure (P=0.006) and lower plasma REN activity (PRA) (P=0.020) when compared with the lower 1/3 responders. Renin rs11240688 CC polymorphism (beta=9.931, corrected P=0.012), Log PRA (beta=7.451, P=0.004) and baseline SBP (beta=0.299, P=0.006) were the independent predictors for the BP lowering response. CONCLUSIONS: In addition to PRA, renin rs11240688 CC polymorphism may also independently predict the effect of HCTZ. PMID- 21261620 TI - Salivary infectious agents and periodontal disease status. AB - BACKGROUND AND OBJECTIVES: The potential of salivary microorganisms to diagnose periodontal disease and to guide periodontal treatment is a research topic of current interest. This study aimed to determine whether the salivary counts of periodontopathic microbes correlated with the periodontal pocket counts of the same infectious agents, and whether the salivary counts of the test infectious agents could distinguish among individuals with periodontal health and various types of periodontal disease. MATERIAL AND METHODS: The study included 150 systemically healthy adults, of whom 37 were periodontally healthy, 31 had gingivitis, 46 had chronic periodontitis and 36 had aggressive periodontitis. Each study subject contributed microbial samples from the two deepest periodontal pockets of the dentition and from whole saliva. Aggregatibacter actinomycetemcomitans, Campylobacter rectus, Fusobacterium nucleatum, Porphyromonas gingivalis, Prevotella intermedia, Tannerella forsythia and Epstein Barr virus were identified using the TaqMan real-time PCR methodology. Statistical analysis was performed using the Mann-Whitney U-test and the receiver operating characteristic statistics. RESULTS: C. rectus, F. nucleatum, P. gingivalis, P. intermedia and T. forsythia occurred with significantly higher copy-counts in salivary samples from patients with gingivitis, chronic periodontitis and aggressive periodontitis than from periodontally healthy individuals. A. actinomycetemcomitans only showed higher salivary copy-counts in subjects with aggressive periodontitis compared with subjects with healthy periodontium, and the salivary copy-counts of Epstein-Barr virus did not reveal any significant difference among the four subject groups studied. The diagnostic sensitivity for periodontitis was 89.19 for P. gingivalis and for T. forsythia and 86.49 for P. intermedia, with specificities ranging from 83.78 to 94.59. The optimal copy-counts per mL saliva for identifying periodontitis were 40,000 for P. gingivalis, 700,000 for T. forsythia and 910,000 for P. intermedia. CONCLUSION: Salivary copy-counts of P. gingivalis, T. forsythia and P. intermedia appear to have the potential to identify the presence of periodontitis, whereas the salivary level of the other test infectious agents may possess little or no diagnostic utility. Longitudinal studies are warranted to determine the ability of salivary copy-counts of major periodontopathic bacteria to predict future periodontal breakdown. PMID- 21261621 TI - The efficacy of host response modulation therapy (omega-3 plus low-dose aspirin) as an adjunctive treatment of chronic periodontitis (clinical and biochemical study). AB - BACKGROUND AND OBJECTIVE: Regeneration of lost periodontal tissues is considered to be one of the most challenging aspects of periodontal therapy. Our current understanding of the role of the host immuno-inflammatory response in periodontal diseases forms the basis of new therapeutic approaches. The aim of this study was to evaluate the efficacy of systemic administration of omega-3 polyunsaturated fatty acids plus low-dose aspirin as an adjunctive treatment to regenerative therapy of furcation defects. MATERIAL AND METHODS: Forty patients displaying at least a single grade II furcation defect were enrolled in the study. They were randomly allocated into two groups: an experimental group receiving decalcified freeze-dried bone allograft (DFDBA) + omega-3 polyunsaturated fatty acids combined with low-dose aspirin; and a control group receiving DFDBA + placebo. Clinical parameters were monitored at baseline, and at 3 and 6 mo following therapy, and included plaque index, gingival index, gingival bleeding index, probing pocket depth and clinical attachment level. The biochemical markers assessed in gingival crevicular fluid samples were interleukin-1beta and interleukin-10. RESULTS: The experimental intervention resulted in a greater mean probing pocket depth reduction (P < 0.001) and gain in clinical attachment (P < 0.05) compared with the control at 6 mo. Furthermore, the experimental protocol was able to achieve a significant modulatory effect on the levels of interleukin 1beta and interleukin-10 compared with control therapy. CONCLUSION: The findings suggest that the combination therapy demonstrated successful reduction of gingival inflammation, reduction of pocket depth and attachment level gain, accompanied by a trend for modulation of the cytokines profile in gingival crevicular fluid. PMID- 21261622 TI - Structure, viability and bacterial kinetics of an in vitro biofilm model using six bacteria from the subgingival microbiota. AB - BACKGROUND AND OBJECTIVE: There are few in vitro models available in the scientific literature for study of the structure, formation and development of the subgingival biofilm. The purpose of this study was to develop and validate an in vitro biofilm model, using representative selected bacteria from the subgingival microbiota. MATERIAL AND METHODS: Six standard reference strains were used to develop biofilms over sterile ceramic calcium hydroxyapatite discs coated with saliva within the wells of presterilized polystyrene tissue culture plates. The selected species represent initial (Streptococcus oralis and Actinomyces naeslundii), early (Veillonella parvula), secondary (Fusobacterium nucleatum) and late colonizers (Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans). The structure of the biofilm obtained was studied using a vital fluorescence technique in conjunction with confocal laser scanning microscopy. The biofilm bacterial kinetics were studied by terminal restriction fragment length polymorphism analysis. RESULTS: After 12 h, initial and early colonizers were the first microorganisms detected adhering to the calcium hydroxyapatite discs. The intermediate colonizer F. nucleatum was not detected in the model until 24 h of incubation. Late colonizers A. actinomycetemcomitans and P. gingivalis could be measured inside the biofilm after 48 h. The biofilm reached its steady state between 72 and 96 h after inoculation, with bacterial vitality increasing from the hydroxyapatite surface to the central part of the biofilm. CONCLUSION: An in vitro biofilm model was developed and validated, demonstrating a pattern of bacterial colonization and maturation similar to the in vivo development of the subgingival biofilm. PMID- 21261623 TI - Molecular survey of atheromatous plaques for the presence of DNA from periodontal bacterial pathogens, archaea and fungi. AB - BACKGROUND AND OBJECTIVE: Chronic infections, such as periodontitis, have been associated with the development and progression of atherosclerosis. The mechanisms through which this occurs have yet to be elucidated. This study was carried out to detect periodontopathic bacteria as well as archaea and fungi in atheromatous plaques and search for factors associated with their occurrence in atheromas. MATERIAL AND METHODS: A cross-sectional study was carried out including 30 patients diagnosed with atherosclerosis in the carotid, coronary or femoral arteries. Plaques were collected during surgery and analysed using PCR to detect Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola and members of the Synergistetes group. Samples were also surveyed with universal primers for bacterial, archaeal and fungal DNA. Patients responded to a questionnaire to determine factors associated with PCR results. RESULTS: All dentate individuals (66.7%) had periodontal disease, 95% of which was severe and 65% extensive. None of the targeted periodontopathic bacteria was found in the atheromas. No sample yielded positive results for fungal and archaeal DNA. Four samples (13%) were positive for the presence of bacterial DNA. Of these, three participants were dentate (two with severely chronic generalized periodontitis and one with severely chronic localized periodontitis). CONCLUSION: This study did not confirm previous findings of periodontal pathogens in atheromas, making it impossible to establish factors associated with their presence in plaques. Presence of bacterial DNA in some samples indicates that periodontal or nonoral bacterial species other than the ones targeted in this study may be involved with some cases of atherosclerosis. PMID- 21261624 TI - Magnesium transporters, MGT2/MRS2-1 and MGT3/MRS2-5, are important for magnesium partitioning within Arabidopsis thaliana mesophyll vacuoles. AB - * Magnesium accumulates at high concentrations in dicotyledonous leaves but it is not known in which leaf cell types it accumulates, by what mechanism this occurs and the role it plays when stored in the vacuoles of these cell types. * Cell specific vacuolar elemental profiles from Arabidopsis thaliana (Arabidopsis) leaves were analysed by X-ray microanalysis under standard and serpentine hydroponic growth conditions and correlated with the cell-specific complement of magnesium transporters identified through microarray analysis and quantitative polymerase chain reaction (qPCR). * Mesophyll cells accumulate the highest vacuolar concentration of magnesium in Arabidopsis leaves and are enriched for members of the MGT/MRS2 family of magnesium transporters. Specifically, AtMGT2/AtMRS2-1 and AtMGT3/AtMRS2-5 were shown to be targeted to the tonoplast and corresponding T-DNA insertion lines had perturbed mesophyll-specific vacuolar magnesium accumulation under serpentine conditions. Furthermore, transcript abundance of these genes was correlated with the accumulation of magnesium under serpentine conditions, in a low calcium-accumulating mutant and across 23 Arabidopsis ecotypes varying in their leaf magnesium concentrations. * We implicate magnesium as a key osmoticum required to maintain growth in low calcium concentrations in Arabidopsis. Furthermore, two tonoplast-targeted members of the MGT/MRS2 family are shown to contribute to this mechanism under serpentine conditions. PMID- 21261625 TI - Carbon reserves and canopy defoliation determine the recovery of Scots pine 4 yr after a drought episode. AB - * Severe drought may increase physiological stress on long-lived woody vegetation, occasionally leading to mortality of overstory trees. Little is known about the factors determining tree survival and subsequent recovery after drought. * We used structural equation modeling to analyse the recovery of Scots pine (Pinus sylvestris) trees 4 yr after an extreme drought episode occurred in 2004-2005 in north-east Spain. Measured variables included the amount of green foliage, carbon reserves in the stem, mistletoe (Viscum album) infection, needle physiological performance and stem radial growth before, during and after the drought event. * The amount of green leaves and the levels of carbon reserves were related to the impact of drought on radial growth, and mutually correlated. However, our most likely path model indicated that current depletion of carbon reserves was a result of reduced photosynthetic tissue. This relationship potentially constitutes a feedback limiting tree recovery. In addition, mistletoe infection reduced leaf nitrogen content, negatively affecting growth. Finally, successive surveys in 2009-2010 showed a direct association between carbon reserves depletion and drought-induced mortality. * Severe drought events may induce long-term physiological disorders associated with canopy defoliation and depletion of carbon reserves, leading to prolonged recovery of surviving individuals and, eventually, to delayed tree death. PMID- 21261626 TI - Three metallothionein isoforms and sequestration of intracellular silver in the hyperaccumulator Amanita strobiliformis. AB - Metallothioneins (MTs) are cysteine-rich peptides involved in heavy metal tolerance of many eukaryotes. Here, we examined their involvement in intracellular binding of silver (Ag) in the ectomycorrhizal fungus Amanita strobiliformis. The Ag complexes and their peptide ligands were characterized using chromatography and mass spectrometry. The full-length coding sequences obtained from a cDNA library were used for complementation assays in yeast mutant strains. Abundance of respective transcripts in A. strobiliformis was measured by quantitative real-time reverse-transcribed polymerase chain reaction (qRT-PCR). Ag-speciation analyses showed that intracellular Ag was in wild-grown fruit bodies and cultured extraradical mycelia of A. strobiliformis sequestered by metallothioneins. The determined sequence of the peptide facilitated isolation of three cDNA clones, AsMT1a, AsMT1b and AsMT1c. These encode isomorphic MTs consisting of 34 amino acid residues and sharing 82% identity. In mycelia the expression of AsMT1s is induced by Ag. All AsMT1s expressed in yeasts complemented hypersensitivity of mutants to cadmium (Cd) and copper (Cu) and formed Ag complexes. Only the Ag-AsMT1a complex was detected in the A. strobiliformis fruit body in which AsMT1a was the prevailing transcript. The present study identified the existence of metallothionein isoforms in ectomycorrhizal fungi. We demonstrated that intracellular sequestration of Ag in fruit bodies and mycelia of hyperaccumulating A. strobiliformis is dominated by metallothioneins. PMID- 21261627 TI - Fitness consequences of natural variation in flooding-induced shoot elongation in Rumex palustris. AB - * Plants can respond to their environment by morphological plasticity. Generally, the potential benefits of adaptive plastic responses are beyond doubt under predictable environmental changes. However, the net benefits may be less straightforward when plants encounter temporal stresses, such as flooding in river flood plains. * Here, we tested whether the balance of costs and benefits associated with flooding-induced shoot elongation depends on the flooding regime, by subjecting Rumex palustris plants with different elongation capacity to submergence of different frequency and duration. * Our results showed that reaching the surface by shoot elongation is associated with fitness benefits, as under less frequent, but longer, flooding episodes plants emerging above the floodwater had greater biomass production than plants that were kept below the surface. As we predicted, slow-elongating plants had clear advantages over fast elongating ones if submergence was frequent but of short duration, indicating that elongation also incurs costs. * Our data suggest that high costs select for weak plasticity under frequent environmental change. In contrast to our predictions, however, fast-elongating plants did not have an overall advantage over slow-elongating plants when floods lasted longer. This indicates that the delicate balance between benefits and costs of flooding-induced elongation depends on the specific characteristics of the flooding regime. PMID- 21261628 TI - Analysis of the bacterial heat shock response to photodynamic therapy-mediated oxidative stress. AB - Antimicrobial photodynamic therapy (PDT) has recently emerged as an effective modality for the selective destruction of bacteria and other pathogenic microorganisms. We investigated whether PDT induced protective responses such as heat shock proteins (HSPs) in bacteria. Using the photosensitizer Toluidine Blue O (TBO) at sublethal PDT conditions, a seven-fold increase in bacterial HSP GroEL and a three-fold increase in HSP DnaK were observed in Escherichia coli post PDT. Pretreatment with 50 degrees C heat for 30 min reduced PDT killing in both E. coli and in Enterococcus faecalis, with the most pronounced inhibition occurring at 50 MUm TBO with 5 J cm(-2) 635 nm light, where E. coli killing was reduced by 2 log(10) and E. faecalis killing was reduced by 4 log(10). Finally, inhibition of the highly conserved chaperone DnaK using a small molecule benzylidene lactam HSP inhibitor potentiated (but not significantly) the effect of PDT at a TBO concentration of 2.5 MUm in E. faecalis; however, this effect was not observed in E. coli presumably because inhibitor could not gain access due to Gram-negative permeability barrier. Induction of HSPs may be a mechanism whereby bacteria could become resistant to PDT and warrants the need for further study in the application of dual PDT-HSP-inhibition therapies. PMID- 21261629 TI - The primary photophysics of the Avena sativa phototropin 1 LOV2 domain observed with time-resolved emission spectroscopy. AB - The phototropins are blue-light receptors that base their light-dependent action on the reversible formation of a covalent bond between a flavin mononucleotide (FMN) cofactor and a conserved cysteine in light, oxygen or voltage (LOV) domains. The primary reactions of the Avena sativa phototropin 1 LOV2 domain were investigated by means of time-resolved and low-temperature fluorescence spectroscopy. Synchroscan streak camera experiments revealed a fluorescence lifetime of 2.2 ns in LOV2. A weak long-lived component with emission intensity from 600 to 650 nm was assigned to phosphorescence from the reactive FMN triplet state. This observation allowed determination of the LOV2 triplet state energy level at physiological temperature at 16600 cm(-1). FMN dissolved in aqueous solution showed pH-dependent fluorescence lifetimes of 2.7 ns at pH 2 and 3.9-4.1 ns at pH 3-8. Here, too, a weak phosphorescence band was observed. The fluorescence quantum yield of LOV2 increased from 0.13 to 0.41 upon cooling the sample from 293 to 77 K. A pronounced phosphorescence emission around 600 nm was observed in the LOV2 domain between 77 and 120 K in the steady-state emission. PMID- 21261630 TI - Cloning and functional characterization of a GNA-like lectin from Chinese Narcissus (Narcissus tazetta var. Chinensis Roem). AB - A full-length cDNA encoding Narcissus tazetta lectin (NTL) was isolated from Chinese narcissus (N. tazetta var. Chinensis Roem). The open reading frame (ORF) was 519 bp long and encoded 172 amino acids with a theoretical isoelectric point of 5.27 and a calculated molecular mass of 18.6 kDa. Conserved domain analysis indicated that it possessed three D-(+)-mannose-binding sites, presumed to be similar to those of Galanthus nivalis agglutinin (GNA)-like lectins. A recombinant (glutathione S-transferase) GST-NTL fusion protein of around 40 kDa was successfully synthesized in vitro. Lysates of cells expressing this recombinant protein exhibited significant hemagglutinating activity [418 hemagglutinating units (HU)], as did the purified protein (265 HU). Sugar specificity assays suggested that mannose is the only sugar that significantly inhibits this hemagglutinating activity, confirming that NTL is a member of the GNA-like lectin family. NTL is highly transcribed in flowers, leaves and roots, but less so in scales. However, similar levels of the NTL protein were observed in all four of these organs by western blotting. A fluorescent NTL-GFP (green fluorescent protein) fusion protein was found to be primarily localized in the vacuole of transformed onion epidermal cells, indicating that NTL may be a vacuolar storage protein. This is the first study in which the function of NTL has been examined and provides a considerable body of data concerning its physiological role in Chinese narcissus. The results obtained may be useful in the molecular engineering of plants with enhanced tolerance of biotic and abiotic stresses. Moreover, they may be relevant to medical applications of lectins. PMID- 21261631 TI - Testing an assumption of the E-Z Reader model of eye-movement control during reading: using event-related potentials to examine the familiarity check. AB - According to the E-Z Reader model of eye-movement control, the completion of an early stage of lexical processing, the familiarity check, causes the eyes to move forward during reading (Reichle, Pollatsek, Fisher, & Rayner, 1998). Here, we report an event-related potential (ERP) experiment designed to examine the hypothesized familiarity check at the electrophysiological level. The results indicate ERP components modulated by word frequency at the time of the predicted familiarity check. These findings are consistent with the hypothesis that an early stage of lexical processing is linked to the "decisions" about when to move the eyes during reading. PMID- 21261632 TI - An affective computing approach to physiological emotion specificity: toward subject-independent and stimulus-independent classification of film-induced emotions. AB - The hypothesis of physiological emotion specificity has been tested using pattern classification analysis (PCA). To address limitations of prior research using PCA, we studied effects of feature selection (sequential forward selection, sequential backward selection), classifier type (linear and quadratic discriminant analysis, neural networks, k-nearest neighbors method), and cross validation method (subject- and stimulus-(in)dependence). Analyses were run on a data set of 34 participants watching two sets of three 10-min film clips (fearful, sad, neutral) while autonomic, respiratory, and facial muscle activity were assessed. Results demonstrate that the three states can be classified with high accuracy by most classifiers, with the sparsest model having only five features, even for the most difficult task of identifying the emotion of an unknown subject in an unknown situation (77.5%). Implications for choosing PCA parameters are discussed. PMID- 21261633 TI - N2ac: an ERP component associated with the focusing of attention within an auditory scene. AB - Humans must often focus attention onto relevant sensory signals in the presence of simultaneous irrelevant signals. This type of attention has been explored in vision with the N2pc component, and the present study sought to find an analogous auditory effect. In Experiment 1, two 750-ms sounds were presented simultaneously, one from each of two lateral speakers. On each trial, participants indicated whether one of the two sounds was a pre-defined target. We found that targets elicited an N2ac component: a negativity in the N2 latency range at anterior contralateral electrodes. We also observed a later and more posterior contralateral positivity. Experiment 2 replicated these effects and demonstrated that they arose from competition between attended and unattended tones rather than reflecting lateralized effects of attention for individual tones. The N2ac component may provide a useful tool for studying selective attention within auditory scenes. PMID- 21261634 TI - The reduced N1 to self-generated tones: an effect of temporal predictability? AB - Tones that are self-generated elicit a smaller N1 than externally triggered tones. Typically, however, self-generated tones are also more predictable in time than externally triggered ones. The present study investigated whether the attenuated N1 can be explained by predictability based on the temporal relationship between action and effect. Participants listened to tones that were self-generated by a key-press or preceded by a visual cue. The tones followed the key-presses or cues after a fixed (predictable context) or variable delay (unpredictable context). Tones triggered by a key-press elicited a smaller N1 than tones following a visual cue. This finding suggests that the reduced N1 to self-generated tones is not merely due to the fact that the tone's timing can be predicted based on its temporal relationship to the key-press. Whether a tone was presented in a predictable or an unpredictable context did not affect the N1. PMID- 21261635 TI - Resveratrol and cellular mechanisms of cancer prevention. AB - The use of novel and improved chemopreventive and chemotherapeutic agents for the prevention and treatment of cancer is on the rise. Natural products have always afforded a rich source of such agents. Epidemiological evidence suggests that a higher flavonoid intake is associated with low cancer risk. Accumulating data clearly indicate that the induction of apoptosis is an important component in the chemoprevention of cancer by naturally occurring dietary agents. Resveratrol, a naturally occurring polyphenol, demonstrates pleiotropic health benefits, including antioxidant, anti-inflammatory, antiaging, cardioprotective, and neuroprotective activities. Because of these properties and their wide distribution throughout the plant kingdom, resveratrol is envisioned as a potential chemopreventive/curative agent. Currently, a number of preclinical findings from our lab and elsewhere suggest resveratrol to be a promising natural weapon in the war against cancer. Remarkable progress in elucidating the molecular mechanisms underlying the anticancer properties of resveratrol has been achieved. Here, we focus on some of the myriad pathways that resveratrol targets to exert its chemopreventive role and advocate that resveratrol holds tremendous potential as an efficient anticancer drug of the future. PMID- 21261636 TI - Bioavailability of resveratrol. AB - This paper reviews our current understanding of the absorption, bioavailability, and metabolism of resveratrol, with an emphasis on humans. The oral absorption of resveratrol in humans is about 75% and is thought to occur mainly by transepithelial diffusion. Extensive metabolism in the intestine and liver results in an oral bioavailability considerably less than 1%. Dose escalation and repeated dose administration of resveratrol does not appear to alter this significantly. Metabolic studies, both in plasma and in urine, have revealed major metabolites to be glucuronides and sulfates of resveratrol. However, reduced dihydroresveratrol conjugates, in addition to highly polar unknown products, may account for as much as 50% of an oral resveratrol dose. Although major sites of metabolism include the intestine and liver (as expected), colonic bacterial metabolism may be more important than previously thought. Deconjugation enzymes such as beta-glucuronidase and sulfatase, as well as specific tissue accumulation of resveratrol, may enhance resveratrol efficacy at target sites. Resveratrol analogs, such as methylated derivatives with improved bioavailability, may be important in future research. PMID- 21261637 TI - Resveratrol: a cardioprotective substance. AB - Coronary heart disease (CHD) is a major and preventable cause of morbidity and death in the United States. Recently, significant research efforts have been directed at an epidemiological phenomenon known as the "French paradox." This observation refers to the coexistence of high risk factors with unanticipated low incidence of CHD, and is postulated to be associated with low-to-moderate consumption of red wine. In vivo studies have shown that red wine intake is more CHD-preventative in comparison to other alcoholic drinks; enhanced cardioprotection may be attributed to grape-derived polyphenols, e.g., resveratrol, in red wine. This review summarizes results of in vitro and animal studies showing that resveratrol exerts multifaceted cardioprotective activities, as well as evidence demonstrating the presence of proteins specifically targeted by resveratrol, as exemplified by N-ribosyldihydronicotinamide:quinone oxidoreductase, NQO2. A mechanism encompassing nongenomic and genomic effects and a research roadmap is proposed as a framework for uncovering further insights on cardioprotection by resveratrol. PMID- 21261638 TI - Resveratrol in cardiovascular health and disease. AB - Resveratrol, initially used for cancer therapy, has shown beneficial effects against most degenerative and cardiovascular diseases from atherosclerosis, hypertension, ischemia/reperfusion, and heart failure to diabetes, obesity, and aging. The cardioprotective effects of resveratrol are associated with its preconditioning-like action potentiated by its adaptive response. During preconditioning, small doses of resveratrol can exert an adaptive stress response, forcing the expression of cardioprotective genes and proteins such as heat shock and antioxidant proteins. Similarly, resveratrol can induce autophagy, another form of stress adaptation for degrading damaged or long-lived proteins, as a first line of protection against oxidative stress. Resveratrol's interaction with multiple molecular targets of diverse intracellular pathways (e.g., action on sirtuins and FoxOs through multiple transcription factors and protein targets) intertwines with those of the autophagic pathway to give support in the modified redox environment after stem cell therapy, which leads to prolonged survival of cells. The successful application of resveratrol in therapy is based upon its hormetic action similar to any toxin: exerting beneficial effects at lower doses and cytotoxic effects at higher doses. PMID- 21261639 TI - Anti-diabetic effects of resveratrol. AB - Diabetes mellitus is a complex metabolic disease affecting about 5% of people all over the world. Data from the literature indicate that resveratrol is a compound exerting numerous beneficial effects in organisms. Rodent studies, for example, have demonstrated that resveratrol decreases blood glucose in animals with hyperglycemia. This effect seems to predominantly result from increased intracellular transport of glucose. Resveratrol was also demonstrated to induce effects that may contribute to the protection of beta cells in diabetes. In experiments on pancreatic islets, the ability of resveratrol to reduce insulin secretion was demonstrated; this effect was confirmed in animals with hyperinsulinemia, in which resveratrol decreased blood insulin levels. Moreover, inhibition of cytokine action and attenuation of the oxidative damage of the pancreatic tissue by resveratrol were recently shown. Studies of animals with insulin resistance indicate that resveratrol may also improve insulin action. The mechanism through which resveratrol improves insulin action is complex and involves reduced adiposity, changes in gene expression, and changes in the activities of some enzymes. These data indicate that resveratrol may be useful in preventing and treating diabetes. PMID- 21261640 TI - Effect of resveratrol on fat mobilization. AB - Higher levels of body fat are associated with increased risk for development of numerous adverse health conditions. Phytochemicals are potential agents to inhibit differentiation of preadipocytes, stimulate lipolysis, and induce apoptosis of existing adipocytes, thereby reducing adipose tissue mass. Resveratrol decreased adipogenesis and viability in maturing preadipocytes; these effects were mediated not only through down-regulating adipocyte specific transcription factors and enzymes but also by genes that modulate mitochondrial function. Additionally, resveratrol increased lipolysis and reduced lipogenesis in mature adipocytes. In addition, combining resveratrol with other natural products produced synergistic activities from actions on multiple molecular targets in the adipocyte life cycle. Treatment of mice with resveratrol alone was shown to improve resistance to weight gain caused by a high-fat diet. Moreover, dietary supplementation of aged ovariectomized rats with a combination of resveratrol and vitamin D, quercetin, and genistein not only decreased weight gain but also inhibited bone loss. Combining several phytochemicals, including resveratrol, or using them as templates for synthesizing new drugs, provides a large potential for using phytochemicals to target adipocyte adipogenesis, apoptosis, and lipolysis. PMID- 21261641 TI - Transport, stability, and biological activity of resveratrol. AB - Numerous studies have reported interesting properties of trans-resveratrol, a phytoalexin, as a preventive agent of several important pathologies: vascular diseases, cancers, viral infections, and neurodegenerative processes. These beneficial effects of resveratrol have been supported by observations at the cellular and molecular levels in both cellular and in vivo models, but the cellular fate of resveratrol remains unclear. We suggest here that resveratrol uptake, metabolism, and stability of the parent molecule could influence the biological effects of resveratrol. It appears that resveratrol stability involves redox reactions and biotransformation that influence its antioxidant properties. Resveratrol's pharmacokinetics and metabolism represent other important issues, notably, the putative effects of its metabolites on pathology models. For example, some metabolites, mainly sulfate-conjugated resveratrol, show biological effects in cellular models. The modifications of resveratrol stability, chemical structure, and metabolism could change its cellular and molecular targets and could be crucial for improving or decreasing its chemopreventive properties. PMID- 21261642 TI - Chemoprevention in experimental animals. AB - The potential cancer-preventive effects of resveratrol, evident from the data obtained by various studies, are summarized in this review. Resveratrol (trans 3,5,4'-trihydroxystilbene), a naturally occurring polyphenolic compound, was first isolated in 1940 as a constituent of the roots of white Hellebore (Veratrum grandiflorum O. Loes), and is now found to be present in various plants including grapes, berries, peanuts, and red wine. This review first briefly describes the current evidence on the link between resveratrol and cancer occurrence, based on epidemiological studies. Subsequently, investigations with resveratrol in animal models of colon carcinogenesis are presented, followed by a comprehensive compilation of resveratrol on cancer. In the second part, the article focuses on results from investigations on cancer-preventive mechanisms of resveratrol. Biological activities including antioxidant effects, modulation of carcinogen metabolism, anti-inflammatory potential, antioxidant properties, antiproliferative mechanisms by induction of apoptosis, and cell differentiation are discussed. Some novel information on its modulating effects on cell signaling pathway, metabolism studies, bioavailability, and cancer-preventive efficacy is also provided. Based on these findings, resveratrol may be used as a promising candidate for cancer chemoprevention. PMID- 21261643 TI - Resveratrol modulates astroglial functions: neuroprotective hypothesis. AB - Resveratrol, a redox active compound present in grapes and wine, has a wide range of biological effects, including cardioprotective, chemopreventive, and anti inflammatory activities. The central nervous system is a target of resveratrol, which can pass the blood-brain barrier and induce neuroprotective effects. Astrocytes are one of the most functionally diverse groups of cells in the nervous system, intimately associated with glutamatergic metabolism, transmission, synaptic plasticity, and neuroprotection. In this review, we focus on the resveratrol properties and response to oxidative insult on important astroglial parameters involved in brain plasticity, such as glutamate uptake, glutamine synthetase activity, glutathione content, and secretion of the trophic factor S100B. PMID- 21261644 TI - Resveratrol and apoptosis. AB - Resveratrol is a naturally occurring stilbene with desirable cardioprotective and anti-cancer properties. We have demonstrated the existence of a plasma membrane receptor for resveratrol near the arginine-glycine-aspartate (RGD) recognition site on integrin alpha(v)beta3 that is involved in stilbene-induced apoptosis of cancer cells. Resveratrol treatment in vitro causes activation and nuclear translocation of mitogen-activated protein kinase (ERK1/2), consequent phosphorylation of Ser-15 of p53, and apoptosis. An RGD peptide blocks these actions of resveratrol. By a PD98059-inhibitable process, resveratrol causes inducible COX-2 to accumulate in the nucleus where it complexes with pERK1/2 and p53. Chromatin immunoprecipitation reveals binding of nuclear COX-2 to promoters of certain p53-responsive genes, including PIG3 and Bax. NS-398, a specific pharmacologic inhibitor of COX-2, prevents resveratrol-induced complexing of nuclear ERK1/2 with COX-2 and with pSer-15-p53 and subsequent apoptosis; cyclooxygenase enzyme activity is not involved. Molecular steps in the pro apoptotic action of resveratrol in cancer cells include induction of intranuclear COX-2 accumulation relevant to activation of p53. Epidermal growth factor, estrogen, and thyroid hormone act downstream of ERK1/2 to prevent resveratrol induced apoptosis. PMID- 21261645 TI - Chemopreventive effects of resveratrol and resveratrol derivatives. AB - Resveratrol is considered to have a number of beneficial effects. Recently, our group modified the molecule and synthesized a number of compounds with different biochemical effects. Polymethoxy and polyhydroxy derivatives of resveratrol were shown to inhibit tumor cell growth in various cell lines and inflammation pathways (cyclooxygenases activity), in part more effectively than resveratrol itself. One lead compound (hexahydroxystilbene, M8) turned out to be the most effective inhibitor of tumor cell growth and of cyclooxygenase 2 activity. M8 was then studied in two different human melanoma mouse models. This novel resveratrol analog was able to inhibit melanoma tumors in a primary tumor model alone and in combination with dacarbacine, an anticancer compound that is used for melanoma treatment. We also tested the development of lymph node metastasis in a second melanoma model and again M8 successfully inhibited the tumor as well as the size and weight of lymph node metastasis. Hydroxylated resveratrol analogs therefore represent a novel class of anticancer compounds and promising candidates for in vivo studies. PMID- 21261646 TI - The beneficial effect of resveratrol on severe acute pancreatitis. AB - Acute pancreatitis is a common kind of acute abdominal disease. The management of severe acute pancreatitis (SAP) is a challenge because of its high morbidity, which is due to systemic inflammatory response syndrome and multiorgan dysfunction syndrome. Therefore, it is important to explore therapies to control the disease's progression. A series of in vivo and in vitro experiments has demonstrated that resveratrol-an extract from Chinese herbs, grapes, and many plants-exhibits a wide range of biological and pharmacological activities, including anti-inflammatory, antioxidation, and chemopreventive effects, as well as the inhibition of platelet aggregation, which could benefit the treatment of SAP. Here, we examine the possible mechanism of resveratrol in treating the progression of SAP. Resveratrol could inhibit the production and progression of SAP through down-regulating pro-inflammatory cytokines, improving microcirculation, modulating cell apoptosis, and blocking calcium overload. We propose that resveratrol has a potentially therapeutic effect on the progression of SAP. PMID- 21261647 TI - Neuroprotective properties of resveratrol and derivatives. AB - Stilbenoid compounds consist of a family of resveratrol derivatives. They have demonstrated promising activities in vitro and in vivo that indicate they may be useful in the prevention of a wide range of pathologies, such as cardiovascular diseases and cancers, as well have anti-aging effects. More recently stilbenoid compounds have shown promise in the treatment and prevention of neurodegenerative disorders, such as Huntington's, Parkinson's, and Alzheimer's diseases. This paper primarily focuses on the impact of stilbenoids in Alzheimer's disease and more specifically on the inhibition of beta-amyloid peptide aggregation. PMID- 21261648 TI - MicroRNA signatures of resveratrol in the ischemic heart. AB - Until the middle of the last decade, few people had heard of microRNAs (miRNAs), 21- to 23-nucleotide conserved RNAs. MicroRNAs represent a new paradigm because they regulate most physiological processes and thus have immense potential for medical advancement. Resveratrol, a red wine-derived polyphenolic compound, has been shown to have significant effects in various disease models, such as cardioprotection in ischemic heart, diabetes, and chemoprevention of cancers. The targets of resveratrol include various pathways and molecules, such as sirtuins, FOXOs, and autophagy. The successful application of resveratrol lies in understanding its mechanisms of action through direct and indirect interactions with pathways, including miRNAs. For example, a unique miRNA footprint is present in the heart treated with resveratrol. Targets of those miRNAs have potential implications for physiological and pathophysiological processes in health and disease. PMID- 21261650 TI - The phenomenon of resveratrol: redefining the virtues of promiscuity. AB - Cancer chemoprevention entails the ingestion of dietary or pharmaceutical agents that can prevent, delay, or reverse the process of carcinogenesis. With support provided by the National Cancer Institute, we have been actively engaged in the systematic discovery and characterization of natural chemopreventive agents. The typical approach involves identifying active crude substances such as extracts derived from terrestrial plants or marine organisms, utilizing in vitro bioassay systems, followed by the isolation of pure active components. As part of this project, an extract obtained from a nonedible Peruvian legume, Cassia quinquangulata Rich. (Leguminosae), was evaluated and found to be active as an inhibitor of cyclooxygenase. The active component was identified as resveratrol. Surprisingly broad spectrum activity was observed, indicative of potential to inhibit carcinogenesis at the stages of initiation, promotion, and progression. This discovery has led to many additional research efforts. There are now around 3,500 papers concerning some aspect of resveratrol action, yet the molecule is unusually promiscuous and specific mechanisms remain elusive. Considering the structural simplicity of this stilbene, the intensity of interest is phenomenal. PMID- 21261649 TI - Anti-inflammatory effects of resveratrol: possible role in prevention of age related cardiovascular disease. AB - Cardiovascular diseases are the most common cause of death among the elderly in the Western world. Resveratrol (3,5,4'-trihydroxystilbene) is a plant-derived polyphenol that was shown to exert diverse anti-aging activity mimicking some of the molecular and functional effects of caloric restriction. This mini-review focuses on the molecular and cellular mechanisms activated by resveratrol in the vascular system, and explores the links between its anti-oxidative and anti inflammatory effects, which could be exploited for the prevention or amelioration of vascular aging in the elderly. PMID- 21261651 TI - Safety of resveratrol with examples for high purity, trans-resveratrol, resVida((r)). AB - Studies with resVida((r)) (a high purity trans-resveratrol) show that trans resveratrol is a substance of low oral toxicity. An acceptable daily intake (ADI) in food of 450 mg/day has been defined, a level well beyond natural dietary intake of trans-resveratrol. The ADI was based on no-observed-adverse-effect levels (NOAELs) of 750 mg/kg bw/day in 13-week developmental toxicity studies by the dietary route and a standard safety margin of 100. In studies by gavage, the kidney and bladder are target organs at very high dosages (2,000-3,000 mg/kg bw/day). Six-month studies in rat and rabbit models show no significant increase in toxicity in comparison to 4-week studies. Lower quoted NOAELs in gavage studies (ca. 300 mg/kg bw/day) potentially reflect more rapid bioavailability, but different dosage regimes complicate comparisons. Short-term studies show no genotoxicity in vivo. A 6-month mouse carcinogenicity model showed no increase in tumors. Clinical data support an ADI of at least 450 mg/day, and kinetic data from the DSM 13-week toxicity study also support the expectation of no increase in toxicity with longer term intake. PMID- 21261652 TI - Resveratrol and life extension. AB - Age is the most important risk factor for diseases affecting the Western world, and slowing age-related degeneration would greatly improve the quality of human life. In rodents, caloric restriction (CR) extends lifespan by up to 50%. However, attempts to mimic the effects of CR pharmacologically have been limited by our poor understanding of the mechanisms involved. SIRT1 is proposed to mediate key aspects of CR, and small molecule activators may therefore act as CR mimetics. The polyphenol resveratrol activates SIRT1 in an in vitro assay, and produces changes that resemble CR in vivo, including improvements in insulin sensitivity, endurance, and overall survival in obese mice. However, resveratrol has numerous other targets that could contribute to its health benefits. Moreover, unlike bona fide CR, resveratrol has not been shown to extend lifespan in lean mice. Overexpression of SIRT1 or treatment with a novel activator is sufficient to improve metabolism, supporting the idea that resveratrol could act through this pathway. However, the poor phenotype of SIRT1 null mice has thus far precluded a more definitive test. PMID- 21261653 TI - Resveratrol in cancer management: where are we and where we go from here? AB - Resveratrol has been shown to afford protection against several diseases. A plethora of studies have suggested that resveratrol imparts cancer chemopreventive and therapeutic responses. However, an important issue with the future development of resveratrol for disease management is its low bioavailability due to its rapid metabolism in mammals. Therefore, efforts are needed to enhance its bioavailability in humans. In this direction, some possible scenarios include enhancing the bioavailability of resveratrol by novel mechanism based combinations with agents that can inhibit the in vivo metabolism of resveratrol, nanoparticle-mediated delivery, use of naturally occurring or synthetic analogues of resveratrol, and use of conjugated metabolites of resveratrol, though these need to be carefully evaluated as they may need to be deconjugated from resveratrol at the target organ to elicit a biological response. Thus, concerted and multidisciplinary efforts are needed to take resveratrol to the next level, that is, from the "bench-to-bedside." PMID- 21261655 TI - Clinical trials of resveratrol. AB - An expanding body of preclinical evidence suggests resveratrol has the potential to impact a variety of human diseases. To translate encouraging experimental findings into human benefits, information is first needed on the safety, pharmacokinetics, pharmacodynamics, and, ultimately, clinical efficacy of resveratrol. Published clinical trials have largely focused on characterizing the pharmacokinetics and metabolism of resveratrol. Recent studies have also evaluated safety and potential mechanisms of activity following multiple dosing, and have found resveratrol to be safe and reasonably well-tolerated at doses of up to 5 g/day. However, the occurrence of mild to moderate side effects is likely to limit the doses employed in future trials to significantly less than this amount. This review describes the available clinical data, outlines how it supports the continuing development of resveratrol, and suggests what additional information is needed to increase the chances of success in future clinical trials. PMID- 21261654 TI - Chemosensitization of tumors by resveratrol. AB - Because tumors develop resistance to chemotherapeutic agents, the cancer research community continues to search for effective chemosensitizers. One promising possibility is to use dietary agents that sensitize tumors to the chemotherapeutics. In this review, we discuss that the use of resveratrol can sensitize tumor cells to chemotherapeutic agents. The tumors shown to be sensitized by resveratrol include lung carcinoma, acute myeloid leukemia, promyelocytic leukemia, multiple myeloma, prostate cancer, oral epidermoid carcinoma, and pancreatic cancer. The chemotherapeutic agents include vincristine, adriamycin, paclitaxel, doxorubicin, cisplatin, gefitinib, 5 fluorouracil, velcade, and gemcitabine. The chemosensitization of tumor cells by resveratrol appears to be mediated through its ability to modulate multiple cell signaling molecules, including drug transporters, cell survival proteins, cell proliferative proteins, and members of the NF-kappaB and STAT3 signaling pathways. Interestingly, this nutraceutical has also been reported to suppress apoptosis induced by paclitaxel, vincristine, and daunorubicin in some tumor cells. The potential mechanisms underlying this dual effect are discussed. Overall, studies suggest that resveratrol can be used to sensitize tumors to standard cancer chemotherapeutics. PMID- 21261656 TI - Prospective validation of 'Allergy-Control-SCORE(TM)': a novel symptom-medication score for clinical trials. AB - BACKGROUND: Combined symptom and medication scores (SMS) are recommended as primary endpoints in clinical trials. Several SMS have been created, but none has been formally validated. OBJECTIVE: To evaluate the validity of the 'Allergy Control-SCORE(c) (ACS)', a novel instrument to assess patient's allergy severity by recording symptoms and rescue medication. METHODS: One hundred and twenty-one consenting subjects (age 18-65 year), including 81 patients with allergic rhino conjunctivitis and/or asthma and 40 healthy controls, participated in the study. They recorded daily nasal, eye, and lung symptoms using a 4-point scale (none, mild, moderate, and severe) and use of anti-symptomatic medication. Pollen counts were monitored during the study period. Symptom and medication scores values were compared to global allergy severity, quality of life, and allergy-related medical consultations. Feasibility was tested through a questionnaire on comprehensibility, easiness of use, and completeness. Retest reliability was assessed by testing consistency, in relation to pollen exposure, and for values recorded during each of 2 consecutive weeks. RESULTS: Convergent reliability analysis indicated a highly significant correlation between ACS(c) and global allergy severity (P < 0.0001), quality of life (P < 0.0001), and allergy-related medical consultations (P < 0.0001). Scores were highly related to pollen counts. Allergy-Control-SCORE(c) showed a good retest reliability (r = 0.81; P < 0.0001) and discriminated extremely well between patients with allergy and healthy controls (6.1 +/- 4.8 vs 0.2 +/- 0.5; t = 10.82; P < 0.0001) with a sensitivity of 97% and a specificity of 87%. Study participants evaluated the feasibility of the SMS as excellent. CONCLUSIONS: Allergy-Control-SCORE(c) is a valid and reliable instrument to assess allergy severity in clinical trials and observational studies of respiratory allergic diseases. PMID- 21261657 TI - MeDALL (Mechanisms of the Development of ALLergy): an integrated approach from phenotypes to systems medicine. AB - The origin of the epidemic of IgE-associated (allergic) diseases is unclear. MeDALL (Mechanisms of the Development of ALLergy), an FP7 European Union project (No. 264357), aims to generate novel knowledge on the mechanisms of initiation of allergy and to propose early diagnosis, prevention, and targets for therapy. A novel phenotype definition and an integrative translational approach are needed to understand how a network of molecular and environmental factors can lead to complex allergic diseases. A novel, stepwise, large-scale, and integrative approach will be led by a network of complementary experts in allergy, epidemiology, allergen biochemistry, immunology, molecular biology, epigenetics, functional genomics, bioinformatics, computational and systems biology. The following steps are proposed: (i) Identification of 'classical' and 'novel' phenotypes in existing birth cohorts; (ii) Building discovery of the relevant mechanisms in IgE-associated allergic diseases in existing longitudinal birth cohorts and Karelian children; (iii) Validation and redefinition of classical and novel phenotypes of IgE-associated allergic diseases; and (iv) Translational integration of systems biology outcomes into health care, including societal aspects. MeDALL will lead to: (i) A better understanding of allergic phenotypes, thus expanding current knowledge of the genomic and environmental determinants of allergic diseases in an integrative way; (ii) Novel diagnostic tools for the early diagnosis of allergy, targets for the development of novel treatment modalities, and prevention of allergic diseases; (iii) Improving the health of European citizens as well as increasing the competitiveness and boosting the innovative capacity of Europe, while addressing global health issues and ethical issues. PMID- 21261658 TI - Clinical trials in allergic conjunctivits: a systematic review. AB - BACKGROUND: Ocular allergy represents one of the most common conditions encountered by allergists and ophthalmologists. However, there is wide variability of study designs in clinical trials of allergic conjunctivitis, which results in conflicting evidence on their optimal management. We conducted a systematic review of clinical trials to critically evaluate their quality and to highlight biases to be avoided in future clinical research in ocular allergy. METHODS: Clinical trials in allergic conjunctivitis performed since 1965 were retrieved, and data on patients, interventions, comparison of interventions, and outcomes were extracted. Four authors independently assessed articles for inclusion in the systematic review and assessed trials' quality using the Jadad scale. RESULTS: Three hundred and sixty-two trials were included in the study. Only a minority of trials fulfilled all the criteria of proper clinical trial design. In most of the studies, there was a very limited use of objective (quantifiable) parameters for both patients' selection and evaluation of drug efficacy and safety. Several outcomes of primary importance, such as disease relapses and recurrence rate, were omitted in clinical trials of allergic conjunctivitis. CONCLUSIONS: Evidence coming out of clinical trials in ocular allergy is limited, and this affects the strength of recommendations to health care providers and policy makers for optimal management. Standardized diagnostic criteria for patient selection and quantifiable primary outcomes are recommended to improve the design of future clinical trials in allergic conjunctivitis. PMID- 21261659 TI - Levels of filaggrin degradation products are influenced by both filaggrin genotype and atopic dermatitis severity. AB - BACKGROUND: Filaggrin, coded by FLG, is the main source of several major components of natural moisturizing factor (NMF) in the stratum corneum (SC), including pyrrolidone carboxylic acid (PCA) and urocanic acid (UCA). Loss offunction mutations in FLG lead to reduced levels of filaggrin degradation products in the SC. It has recently been suggested that expression of filaggrin may additionally be influenced by the atopic inflammatory response. In this study, we investigated the levels of several breakdown products of filaggrin in the SC in healthy controls (CTRL) and patients with atopic dermatitis (AD) in relation to FLG null allele status. We examined the relationship between NMF (defined here as the sum of PCA and UCA) and AD severity. METHODS: The SC levels of filaggrin degradation products including PCA, UCA, histidine (HIS) and tyrosine were determined in 24 CTRL and 96 patients with moderate-to-severe AD. All subjects were screened for 11 FLG mutations relevant for the study population. RESULTS: The levels of PCA, UCA and HIS correlated with FLG genotype. Furthermore, these levels were higher in the CTRL when compared to AD patients with no FLG mutations. Multiple regression analysis showed that NMF levels were independently associated with FLG genotype and severity of disease. CONCLUSION: Decreased NMF is a global feature of moderate-to-severe AD; within AD, FLG genotype is the major determinant of NMF, with disease severity as a secondary modifier. NMF components are reliably determined by a noninvasive and relatively inexpensive tape stripping technique. PMID- 21261660 TI - Aspergillus sensitization is associated with airflow limitation and bronchiectasis in severe asthma. AB - BACKGROUND: Abnormalities, including bronchiectasis, that are detectable on high resolution computed tomography (HRCT) have been associated with severe asthma. Bronchiectasis is associated with the diagnosis of allergic bronchopulmonary aspergillosis (ABPA), which also occurs in patients with severe asthma. We sought to determine the frequency and pattern of HRCT abnormality and the relationship with Aspergillus fumigatus sensitization in one severe asthma population. METHODS: We examined our database of patients attending a supraregional severe asthma service (Manchester, UK). Clinical, physiological and immunological characteristics were compared between those with HRCT evidence of airway disease (specifically bronchiectasis) and those with no radiological abnormality. RESULTS: Of 133 patients analysed, 111 (83.4%) had an abnormal HRCT with bronchial wall thickening (41.3%), bronchiectasis (35.3%), air trapping (20.3%) and bronchial dilatation (16.5%) occurring most frequently. Radiological evidence of airway disease was associated with more obstructive spirometry (postbronchodilator FEV1/FVC ratio 73.2%vs 64.8% [difference -8.5%, 95% CI -16.9 to -0.1, P = 0.048]). A. fumigatus sensitization was associated with a 2.01 increased hazard ratio of bronchiectasis (95% CI 1.26 to 3.22, P = 0.005), and more obstructive spirometry (postbronchodilator FEV1/FVC ratio 57.6 vs 70.3 [difference -12.8, 95% CI -19.8 to -5.7, P = 0.001]). Patients with A. fumigatus sensitization had variable clinical and radiological characteristics that frequently did not conform to the conventional diagnostic criteria for ABPA. CONCLUSION: Patients with severe asthma frequently have radiological abnormalities on HRCT. Sensitization to A. fumigatus is associated with bronchiectasis and greater airflow obstruction, even when diagnostic criteria for ABPA are not met. PMID- 21261661 TI - Impact of mometasone furoate nasal spray on individual ocular symptoms of allergic rhinitis: a meta-analysis. AB - BACKGROUND: Intranasal corticosteroids (INSs) are a mainstay of treatment of allergic rhinitis (AR) nasal symptoms. The INS mometasone furoate nasal spray (MFNS) has well-documented efficacy and safety for the treatment and prophylaxis of nasal symptoms of seasonal AR (SAR) and for the treatment of nasal symptoms of perennial AR (PAR). Increasing interest has focused on whether INSs, including MFNS, may have beneficial effects on the ocular symptoms frequently associated with AR. METHODS: We performed a meta-analysis of 10 randomized, placebo controlled trials of the efficacy of MFNS 200 mcg daily in relieving ocular allergy symptoms, including itching/burning, redness, and tearing/watering in both SAR and PAR. Four PAR studies and six SAR studies are included in the analysis. A fixed-effect inverse variance model was used to calculate weighted mean differences, 95% confidence intervals (CIs) for each comparison, and a combined overall treatment effect (Z) with P-value. RESULTS: In both analyses of SAR and PAR studies, including 3132 patients, all individual ocular symptoms were reduced in patients treated with MFNS. Overall treatment effect was significant for all three individual ocular symptoms in the SAR studies (Z = 9.18 for tearing, Z = 10.15 for itching, and Z = 8.88 for redness; P < 0.00001 for all) and in the PAR studies (Z = 5.94, P < 0.00001 for tearing; Z = 2.43, P = 0.02 for itching; and Z = 2.42, P = 0.02 for redness). CONCLUSIONS: Our findings add to the growing body of literature supporting the positive class effect of INSs, including MFNS, on ocular symptoms associated with SAR and PAR. PMID- 21261662 TI - Bronchodilation test in patients with allergic rhinitis. AB - BACKGROUND: Allergic rhinitis (AR) may be considered a risk factor for the onset of asthma. Recently, it has been reported that forced expiratory flow between 25% and 75% of vital capacity (FEF25-75) may predict a positive response to bronchodilation test in asthmatic children. The aim of this study was to evaluate a large group of adult AR patients to investigate the frequency of response to bronchodilation test and FEF25-75 values. METHODS: One thousand four hundred and sixty-nine consecutive patients suffering from persistent AR were evaluated. Clinical examination, spirometry, and bronchodilation test were performed in all patients. RESULTS: In this study, 62.9% of patients had reversibility to bronchodilation test and 17.8% had impaired FEF25-75 values (<= 65% of predicted). Impaired FEF25-75 values associated with longer rhinitis duration may predict reversibility to bronchodilation test (OR = 11.3; P < 0.001). In addition, a FEF25-75 cutoff value <= 71% of predicted may already discriminate patients with reversibility. CONCLUSIONS: This study highlights that about two thirds of patients with persistent AR may be considered at risk of becoming asthmatic. This finding should be adequately considered as a precocious spirometry may allow the early detection of patients prone to develop asthma and consequently to treat them. PMID- 21261663 TI - Functional effects of interleukin 31 in human primary keratinocytes. AB - BACKGROUND: Interleukin (IL)-31 is a T-cell cytokine acting through a heterodimeric receptor composed of IL-31RA and OSMR which is expressed on epithelial cells including keratinocytes. A major function of IL-31 in atopic dermatitis (AD) is the induction of pruritus in the skin. Inflammatory effects of IL-31 in human primary keratinocytes (HPKs) still remain unclear. We investigated expression, regulation of the IL-31 receptor as well as functions of IL-31 in HPKs. METHODS: Human primary keratinocytes were stimulated with TLR-2 ligands (Pam3Cys, lipoteichoic acid and peptidoglycan), or Th1 and Th2 associated cytokines (IFN-gamma and IL-4), respectively. IL-31R expression and regulation as well as functional effects of IL-31 stimulation were then investigated at both the mRNA and protein level and compared with HPKs from patients with AD. The STAT signalling pathway and TLR-2 expression were investigated using Western blot and Immunohistochemical stainings, respectively. RESULTS: Pam3Cys or IFN-gamma significantly up-regulated IL-31RA and OSMR expression. IL-31 activated STAT-3 phosphorylation in HPKs which was augmented after preactivation with Pam3Cys or IFN-gamma. IL-31 enhanced the secretion of CCL2 after up-regulation of the receptor with Pam3Cys or IFN-gamma. However, this was not observed in keratinocytes from AD patients where an impaired TLR-2 expression was found. CONCLUSIONS: Together, our findings show a functional role of IL-31 in HPKs and provide a new link between TLR-2 ligands and IL-31 which might be dysregulated in AD. Altered function of IL-31 may have implications for cutaneous inflammation in eczema where skin colonization with Staphylococcus aureus and dysregulation of TLR-2 have been described. PMID- 21261665 TI - Commentary on Falk. PMID- 21261664 TI - How the African trypanosomes evade host immune killing. AB - Unlike other protozoan parasites, African trypanosomes never enter the host cell at any stage of their development. Instead, these parasites swim freely in the immunologically hostile host tissue fluids. During the course of infection, a complex interaction between the host immune responses and trypanosome survival strategies occurs. Continued contacts with the host's immune system occurring during the course of infection could have provided strong selection pressure for African trypanosomes to evolve very sophisticated mechanisms to evade immune killing to survive the hostile immunological environment in the infected host. This review discusses some of the documented immunological evasion mechanisms African trypanosomes employ for their survival and perpetuity. PMID- 21261666 TI - Prolonged ventricular pauses in an asymptomatic athlete with "apparent Mobitz type II second-degree atrioventricular block". AB - We report the case of a 30-year-old basketball player with asymptomatic, nocturnal ventricular pauses of >3,000 ms, the longest being ~12,000 ms, who was misdiagnosed with Mobitz type II second-degree atrioventricular (AV) block. Conversely, the tracings were characteristic of a vagally mediated AV block, a phenomenon first described by Massie and called "apparent Mobitz type II AV block." Although the patient was asymptomatic with ventricular pauses occurring only at night, it was decided to implant a permanent pacemaker to prevent neurological damage or life-threatening ventricular arrhythmias resulting from repeated, abnormally prolonged ventricular pauses. The persistence of AV block after a 3-month detraining period led us to believe that our decision was reasonable. PMID- 21261667 TI - Preventing shoulder pain after cardiac rhythm management device implantation: a randomized, controlled study. AB - INTRODUCTION: Shoulder pain and disability ipsilateral to the implant site is a common complication of cardiac rhythm device implantation, yet very little has been published about this morbidity. We designed a study to assess the potential benefit of a simple exercise protocol in preventing shoulder pain postoperatively. METHODS AND RESULTS: Patients undergoing subcutaneous device implantation were randomized to one of two groups. The control group received standard instructions, whereas the exercise group was instructed on specific exercises aimed at strengthening or stretching the shoulder girdle, to be completed 3 days per week. Groups were postoperatively monitored for the development of shoulder discomfort and shoulder impingement by using physical examination and disability questionnaires. At 1 month, seven of 21 control patients reported developing shoulder pain or discomfort compared to one of 23 in the exercise group (P = 0.02). At 6 months, four of 23 control patients still reported worsening shoulder symptoms, compared to none in the exercise group (P = 0.11). In the control group, five of 19 patients developed a positive impingement test at 1 month, versus none in the exercise group (P = 0.01). Scores for the questionnaires designed to assess shoulder pain and dysfunction were worse in the control group. There were no activity-related complications in either group. CONCLUSION: Shoulder pain and disability occurs often following cardiac rhythm management device implantation. A simple exercise program aimed at strengthening the shoulder girdle is effective at preventing this complication. PMID- 21261668 TI - Massive parallel 16S rRNA gene pyrosequencing reveals highly diverse fecal bacterial and fungal communities in healthy dogs and cats. AB - This study evaluated the fecal microbiota of 12 healthy pet dogs and 12 pet cats using bacterial and fungal tag-encoded FLX-Titanium amplicon pyrosequencing. A total of 120,406 pyrosequencing reads for bacteria (mean 5017) and 5359 sequences (one pool each for dogs and cats) for fungi were analyzed. Additionally, group specific 16S rRNA gene clone libraries for Bifidobacterium spp. and lactic acid producing bacteria (LAB) were constructed. The most abundant bacterial phylum was Firmicutes, followed by Bacteroidetes in dogs and Actinobacteria in cats. The most prevalent bacterial class in dogs and cats was Clostridia, dominated by the genera Clostridium (clusters XIVa and XI) and Ruminococcus. At the genus level, 85 operational taxonomic units (OTUs) were identified in dogs and 113 OTUs in cats. Seventeen LAB and eight Bifidobacterium spp. were detected in canine feces. Ascomycota was the only fungal phylum detected in cats, while Ascomycota, Basidiomycota, Glomeromycota, and Zygomycota were identified in dogs. Nacaseomyces was the most abundant fungal genus in dogs; Saccharomyces and Aspergillus were predominant in cats. At the genus level, 33 different fungal OTUs were observed in dogs and 17 OTUs in cats. In conclusion, this study revealed a highly diverse bacterial and fungal microbiota in canine and feline feces. PMID- 21261669 TI - Review article: methods of measuring gastric acid secretion. AB - BACKGROUND: Gastric acid has an important pathophysiological role in human beings. Numerous methods have been evaluated over the years in an attempt to measure gastric acid and stomach acidity, to study the role of gastric acid in gastrointestinal diseases in humans and to evaluate the effects of acid suppressing drugs. AIM: To review methods that have been used to measure gastric acid and gastric acidity. METHODS: Searches of the electronic databases PUBMED, MEDLINE and EMBASE, were performed with articles restricted to English language and human subjects. References were also identified from the bibliographies of selected articles. RESULTS: Methods for measuring gastric acid include both invasive and non-invasive techniques. Invasive tests include the conventional gastric acid aspiration tests, gastric pH measurement techniques and endoscopic methods. Non-invasive methods use urinary analysis, breath analysis, serum pepsinogens assay, scintigraphic techniques, impedence tomography and alkaline tide for measurement of gastric acid. CONCLUSIONS: Several methods of measuring gastric acid exist. Invasive tube tests are uncomfortable and time consuming, whereas most of the non-invasive methods are at best semiquantitative and useful in detecting low or absent acid secretion. Further attempts to explore new methods for measuring gastric acid are therefore warranted. PMID- 21261670 TI - Night-time intra-oesophageal bile and acid: a comparison between gastro oesophageal reflux disease patients who failed and those who were treated successfully with a proton pump inhibitor. AB - BACKGROUND: Little is known about the contribution of bile and acid reflux to night-time symptoms generation in patients who failed PPI treatment. AIM: To compare the degree of night-time oesophageal acid and bile [by the surrogate duodenogastroesophageal reflux (DGER)] exposure between gastro-oesophageal reflux disease (GERD) patients who failed and those who fully responded to PPI once a day while on treatment. METHODS: Gastro-oesophageal reflux disease patients were assigned to the PPI failure group if they continued to report symptoms >=3/week and to the PPI success group if they were asymptomatic for the last 3 months while on PPI once a day. All patients underwent upper endoscopy and subsequently simultaneous 24-h oesophageal Bilitec and pH testing while on PPI treatment. RESULTS: Twenty-three patients were enrolled into the PPI failure group and 24 patients into the PPI success group. The percentage of night-time pH<4 and the number of night-time acid reflux episodes were significantly higher in the PPI failure group as compared with the PPI success group. All night-time DGER parameters were similar between the PPI failure and PPI success groups. CONCLUSIONS: Night-time oesophageal acid exposure is significantly higher in the PPI failure group vs. PPI success group. The degree of night-time bile reflux is similar in the two groups of patients with GERD. PMID- 21261671 TI - Embedded spirituality: gardening in daily life and stressful life experiences. AB - BACKGROUND: There is a limited body of research examining the relationship between spirituality and leisure, or the impact of leisure in the context of daily life, and life with stressful events. AIM: To examine the meaning of gardens and gardening across different life experiences using hermeneutic phenomenology to focus on the lived experience of leisure gardening. METHODS: Most participants were interviewed once in each season over a 1 year period usually in their home. There were 42 participants (27 women and 15 men) in this study. Fifteen individuals had been diagnosed with cancer and were in varying stages of diagnosis and treatment. Three people had a chronic and progressive disease. Four women were grieving the death of their spouse. Participants ranged in age from 32 to 80 years. RESULTS: In this paper, we focus on the spirituality related themes in this study: spirituality as connectedness; spirituality as an expression of inner being; the garden as a spiritual place and gardening as spiritual activity; gardening as a spiritual journey; and, stewardship. Participants with religious views saw their garden as an extension of their spirituality and a confirmation of their beliefs. Participants with secular or sacred views of spirituality that was not related to any religious beliefs were more likely to embed their spirituality in their relationship with nature as manifested in their garden. CONCLUSION: This study extends current theory regarding leisure and its contribution to meaning focused coping, and spirituality as a significant component of leisure in living with stressful health and life events. PMID- 21261672 TI - A targeted fimA DNA vaccine prevents alveolar bone loss in mice after intra-nasal administration. AB - AIM: To construct a dendritic cell (DC)-targeted DNA vaccine against FimA of Porphyromonas gingivalis and evaluate the immunogenicity and protection in mice. MATERIALS AND METHODS: A targeted DNA plasmid pCTLA4-FimA, which encodes the signal peptide and extracellular regions of mouse cytotoxic T lymphocyte associated antigen 4 (CTLA4), the hinge and Fc regions of human Iggamma1 and FimA of P. gingivalis, was constructed. Mice were immunized with pCTLA4-FimA, the non targeted DNA plasmid pFimA, which contains only fimA gene, or pCI vector intra nasally. Serum and saliva antibody responses were detected by enzyme-linked immunosorbent assay. The protection against P. gingivalis-induced periodontitis was evaluated by measuring alveolar bone loss in mice. RESULTS: Mice immunized with pCTLA4-FimA showed elevated levels of specific serum IgG and salivary IgA antibody responses compared with mice immunized with pFimA (p<0.01). Both pFimA and pCTLA4-FimA immunized groups showed significantly lower alveolar bone loss, with the magnitude protection greater in the latter (p<0.01), compared with the pCI immunized group. CONCLUSIONS: The DC-targeted DNA construct pCTLA4-FimA enhanced both systemic and mucosal immunity following intra-nasal immunization. A DNA-based immunization strategy may be an effective way to attenuate periodontitis induced by P. gingivalis. PMID- 21261674 TI - Cutaneous Hodgkin-type lymphoproliferative lesion associated with immunomodulatory therapy for ulcerative colitis. AB - Immunomodulatory drugs have demonstrated efficacy in the therapy against autoimmune diseases such as rheumatoid arthritis, Crohn's disease or ulcerative colitis. Tumor necrosis factor-alpha (TNF-alpha) represents a target molecule for the treatment of these entities. Use of monoclonal antibodies can block the proinflammatory function of TNF-alpha. It has been shown that this action can reactivate quiescent chronic diseases as well as modify the immune response or potentiate carcinogens, thereby increasing the risk of secondary tumor development. In this context, different types of solid or hematological tumors have been documented. We present the case of a male with chronic ulcerative colitis who secondarily developed a cutaneous Hodgkin-type lymphoproliferative lesion associated with immunodeficiency. This secondary tumor developed after 6 months of treatment with anti-TNF-alpha. PMID- 21261673 TI - Effect of periodontal treatment on receptor activator of NF-kappaB ligand and osteoprotegerin levels and relative ratio in gingival crevicular fluid. AB - AIM: Receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG) have an established role in the pathogenesis of periodontitis, which is characterized by an increased RANKL/OPG ratio. The present study aims to investigate changes of RANKL, OPG and their relative ratio in gingival crevicular fluid (GCF) of periodontitis patients after non-surgical periodontal treatment. MATERIALS AND METHODS: GCF was obtained from chronic periodontitis (n=14), generalized aggressive periodontitis (G-AgP; n=13) patients at baseline. The patients received scaling and root planing and were recalled after 2, 3 and 4 months for follow-up clinical examination and sampling. The total amounts and concentrations of RANKL and OPG in GCF were measured by enzyme-linked immunosorbent assay, and their relative ratio was calculated. RESULTS: The RANKL/OPG ratio remained unchanged and did not correlate with clinical parameters throughout the monitoring period, despite the improved clinical outcome. This trend was similar in both chronic and G-AgP. CONCLUSIONS: Although the RANKL/OPG ratio has a potential diagnostic value for untreated periodontitis, it may not be a suitable predictor of clinically successful treatment outcome. As conventional therapy does not negatively modulate this ratio, the host could still be susceptible to further periodontal tissue destruction, warranting the consideration of adjunctive treatments. PMID- 21261675 TI - Formaldehyde induces neurotoxicity to PC12 cells involving inhibition of paraoxonase-1 expression and activity. AB - 1. Formaldehyde (FA) has been found to cause toxicity to neurons. However, its neurotoxic mechanisms have not yet been clarified. Increasing evidence has shown that oxidative damage is one of the most critical effects of formaldehyde exposure. Paraoxonase-1 (PON-1) is a pivotal endogenous anti-oxidant. Thus, we hypothesized that FA-mediated downregulation of PON1 is associated with its neurotoxicity. 2. In the present work, we used PC12 cells to study the neurotoxicity of FA and explore whether PON-1 is implicated in FA-induced neurotoxicity. 3. We found that FA has potent cytotoxic and apoptotic effects on PC12 cells. FA induces an accumulation of intracellular reactive oxygen species along with downregulation of Bcl-2 expression, as well as increased cytochrome c release. FA significantly suppressed the expression and activity of PON-1 in PC12 cells. Furthermore, H(2)S, an endogenous anti-oxidant gas, antagonizes FA-induced cytotoxicity as well as 2-hydroxyquinoline, a specific inhibitor of PON-1, which also induces cytotoxicity to PC12 cells. 4. The results of the present study provide, for the first time, evidence that the inhibitory effect on PON-1 expression and activity is involved in the neurotoxicity of FA, and suggest a promising role of PON-1 as a novel therapeutic strategy for FA-mediated toxicity. PMID- 21261677 TI - Prediction and evaluation of fetal toxicity induced by NSAIDs using transplacental kinetic parameters obtained from human placental perfusion studies. AB - AIM: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) in full-term pregnant women leads to fetal or neonatal toxicity, such as constriction of the ductus arteriosus (DA) and persistent pulmonary hypertension in the newborn. The aim of this study was to predict quantitatively the fetal toxicity of three NSAIDs (antipyrine, salicylic acid and diclofenac) using the transplacental pharmacokinetic parameters obtained from our previous placental perfusion studies. METHODS: Human fetal plasma concentration profile after oral administration of each NSAID to the mother was estimated using the transplacental pharmacokinetic parameters and pharmacokinetic parameters in adult women. The fetal plasma concentration-response relationship for the three NSAIDs was estimated by pharmacokinetic/pharmacodynamic analysis of the results of previous studies investigating the effects of NSAIDs on the ratio of inner diameter of the DA to that of the pulmonary artery (DA/PA) in rats and the plasma concentration profiles of NSAIDs in pregnant rats. RESULTS: The risk of constriction of the DA was well predicted by the model. Mean DA/PA ratio after oral administration of diclofenac to the mother was estimated to be 39.0%, whereas both of the corresponding values after oral administration of antipyrine and salicylic acid were estimated to be 5.9%. These results suggest that the fetal risk of diclofenac is higher than those of salicylic acid and antipyrine. CONCLUSIONS: This study presents a novel approach to predict quantitatively the fetal risk of NSAIDs administered to the mother. Human placental perfusion study and pharmacokinetic/pharmacodynamic analysis may provide basic data for predicting human fetal toxicity of drugs. PMID- 21261678 TI - Changing practice in haematopathology: the impact of new technologies and better understanding of pathogenesis. PMID- 21261679 TI - Epidemiology of lymphomas. AB - Epidemiological reports on lymphomas often begin, and sometimes end, by stating that little is known about the causes of the condition(s) under study. This is slowly changing as information on the pathological diversity of subtypes accumulates. This review examines the epidemiology of lymphomas, focusing on the impact of the latest World Health Organization (WHO) classification. Use of appropriate disease classifications is critical to the research process, but many studies conducted in previous decades have been hampered by the need to aggregate data into the broad lymphoma groupings of Hodgkin and non-Hodgkin, either because primary source information was recorded in that way, or because diagnostic standards were inconsistently applied. Population-based data on age and gender are presented using the latest WHO classification, revealing considerable subtype heterogeneity. Aetiological factors highlighted include the unexplained male bias that is strikingly evident for many subtypes across all ages, and the relationship with autoimmune disease, which, although often associated with increased lymphoma risk, is generally more common in females. This is an exciting time for epidemiological research into haematological malignancies, where the application of modern disease classifications is beginning to discriminate between subtypes revealing features that future aetiological hypotheses should seek to address. PMID- 21261680 TI - The molecular pathogenesis of Hodgkin lymphoma. AB - Hodgkin lymphoma (HL) is an unusual malignancy in that the tumour cells, the Hodgkin and Reed-Sternberg (HRS) cells, are a minor component of the tumour mass, the bulk of which is a mixed cellular infiltrate. There is compelling evidence that HRS cells are clonal B cells that have lost their B cell phenotype. Mature B cells lacking B cell receptors would normally die by apoptosis, and therefore HRS cells must have developed mechanisms to facilitate survival. The escape from apoptosis and transcriptional reprogramming of HRS cells are interlinked and appear central to disease pathogenesis. Epstein-Barr virus (EBV) is present in the HRS cells of a proportion of cases and expresses genes with a plausible oncogenic function. It is likely that EBV plays a role in reprogramming and survival through dysregulation of several signalling networks and transcription factors, including nuclear factor (NF)-kappaB. Activation of NF-kappaB is a feature of all HRS cells and gene mutations affecting this pathway appear common in EBV-negative HL. The HRS cell furthers its own survival by attracting a supportive microenvironment of immune and stromal cells, and suppressing local immune responsiveness. Although many questions remain unanswered, the last two decades have witnessed a considerable increase in our knowledge of this complex disease. PMID- 21261681 TI - MALT lymphoma: many roads lead to nuclear factor-kappab activation. AB - Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma is characterized genetically by several recurrent, but mutually exclusive, chromosome translocations. To date, it has been shown that at least the oncogenic products of t(1;14)(p22;q32)/BCL10-IGH, t(14;18)(q32;21)/IGH-MALT1 and t(11;18)(q21;q21)/API2-MALT1 activate the nuclear factor (NF)-kappaB activation pathway. Recently, A20, an essential global NF-kappaB inhibitor, was found to be inactivated by somatic deletion and/or mutation in translocation negative MALT lymphomas. However, these genetic abnormalities alone are not sufficient for malignant transformation and thus need to cooperate with other factors in MALT lymphomagenesis. Recent studies have shown steady, exciting progresses in our understanding of the biological functions of BCL10, MALT1 and A20 in the regulation of the NF-kappaB activation pathways and the biology of lymphocytes. This review discusses the implication of these recent advances in the molecular pathogenesis of MALT lymphoma, and explores how the above genetic abnormalities cooperate with immunological stimulation in the development of lymphoma. PMID- 21261682 TI - The coming of age of microRNA for B cell lymphomas. AB - The human genome is made up of only approximately one-third of gene coding sequences. The remainder of non-coding sequences, the majority of the DNA code, are poorly understood, but it is now recognized that short portions are transcribed into RNA sequences with common structures sharing length and shape. They have the ability to regulate the expression of genes by binding and inhibiting the RNA coding for genes. These were named microRNA (miRNA). Over the last decade much has been learnt about miRNAs. They are fewer than 1000 in number for the human genome, but each influences a large number of genes and functional pathways, being important controlling influences in both normal function and disease. In the field of lymphoid malignancies we are entering a new era with greater understanding of the role miRNAs in normal B cell development and their disruption in B cell malignancies. This opens the door for both prognostic and diagnostic markers, as well as potential for novel therapies related to identification of the deranged pathways they control. This review outlines the current state of our knowledge of miRNA for B cell malignancies and while already of some clinical utility, there is still much to learn. PMID- 21261683 TI - Pathology and biology of peripheral T-cell lymphomas. AB - Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous group of more than 20 neoplastic entities derived from mature T cells and natural killer (NK) cells involved in innate and adaptive immunity. With few exceptions these malignancies, which may present as disseminated, predominantly extranodal or cutaneous, or predominantly nodal diseases, are clinically aggressive and have a dismal prognosis. Their diagnosis and classification is hampered by several difficulties, including a significant morphological and immunophenotypic overlap across different entities, and the lack of characteristic genetic alterations for most of them. Although there is increasing evidence that the cell of origin is a major determinant for the delineation of several PTCL entities, however, the cellular derivation of most entities remains poorly characterized and/or may be heterogeneous. The complexity of the biology and pathophysiology of PTCLs has been only partly deciphered. In recent years, novel insights have been gained from genome-wide profiling analyses. In this review, we will summarize the current knowledge on the pathobiological features of peripheral NK/T-cell neoplasms, with a focus on selected disease entities manifesting as tissue infiltrates primarily in extranodal sites and lymph nodes. PMID- 21261684 TI - The challenge of the microenvironment in B-cell lymphomas. AB - B-cell non-Hodgkin lymphomas (B-NHL) represent the most common malignant lymphoid neoplasms, with the majority of these arising from germinal centre or post germinal centre B cells, due to (at least) a disruption of the different phases of normal B-cell development. The most common B-cell lymphoma subtypes include follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma and mantle cell lymphoma. As with other malignancies, it has been demonstrated that the development and progression of B-cell lymphomas involves complex interactions between the neoplastic B-cells and the surrounding microenvironment, including stromal cells, the intratumoral vasculature, the various types of macrophages, as well as T-cells, including regulatory T-cells (also termed T-regs). The complex communications between the cell populations involves interplay between chemokines, chemokine receptors and adhesion molecules, and the balance between these determines whether there is a tumour cell growth promotion or inhibition. The demonstration of the importance of the microenvironment in B-NHL has been shown recently using methodologies such as gene expression profiling, and has been validated in some B-NHL lymphoma subtypes using other techniques, such as immunohistochemistry. This is particularly in the case of follicular lymphomas, in which both T-regs and macrophages have been demonstrated to have prognostic value. As such, the microenvironment of B-cell lymphomas represents a challenge to the development of therapeutic agents, requiring re-direction and inclusion of these non-neoplastic supportive cells into future treatment strategies. PMID- 21261685 TI - Occult B-cell lymphoproliferative disorders. AB - The term monoclonal B-cell lymphocytosis (MBL) was recently introduced to identify individuals with a population of monoclonal B cells in the absence of other features that are diagnostic of a B-cell lymphoproliferative disorder. MBL is often identified through hospital investigation of a mild lymphocytosis, and approximately 1% of such individuals develop progressive disease requiring treatment per year. However, in population studies using high-sensitivity flow cytometry, MBL may be detectable in more than 10% of adults aged over 60 years, and clinical progression is rare. The majority of MBL cases have features that are characteristic of chronic lymphocytic leukaemia, but an increasing amount of information is becoming available about MBL with the features of other B-cell lymphoproliferative disorders. In addition to flow cytometry findings, the incidental detection of an occult B-cell lymphoproliferative disorder is also occurring in a significant proportion of tissue biopsy samples. In this review, the clinical and biological relationship between MBL and B-cell lymphoproliferative disorders will be discussed, with a focus on identifying the differences between low levels of peripheral blood or bone marrow involvement with lymphoma and the monoclonal B-cell populations that commonly occur in elderly adults. PMID- 21261686 TI - Flow cytometry and its use in the diagnosis and management of mature lymphoid malignancies. AB - The last decade has seen major advances in flow cytometric immunophenotyping and this has expanded the utility of flow cytometry to investigate the antigens present on normal and neoplastic haematopoietic cells. This review summarizes how flow cytometry is used currently in the diagnosis and management of mature lymphoid malignancies. The establishment of disease-specific phenotypes allows the creation of assays which can detect neoplastic cells with high specificity and sensitivity. Certain lymphoid neoplasms are well defined immunophenotypically, while others are more heterogeneous. The availability of more sophisticated cytometers and a wider selection of antibodies in routine diagnostic laboratories will lead to the resolution of these more complex disease entities. PMID- 21261687 TI - Impact of gene expression profiling in lymphoma diagnosis and prognosis. AB - Lymphoma classification has changed several times over time as our understanding of normal and malignant lymphocyte biology has advanced. This has improved prognostication, but there remain large diagnostic groups with diverse outcomes. In an attempt to refine diagnosis and prognostic power in these, global gene expression profiling (GEP) has been used to further improve our understanding of lymphoma. This review will cover the impact of GEP on the diagnosis, prognosis, biological understanding and identification of novel treatments for the main types of lymphoma, as well its translation to clinical practice. Specifically, it will cover the use of GEP to identify prognostic subgroups within existing diagnostic categories, in an attempt to improve prognostication in those subgroups with wide variation in outcome. Many of these studies have given additional novel insights into the biology of lymphoma, including the role of the immune system and the stromal environment. The improved understanding that these studies have given have suggested possible new treatments, linking diagnosis, prognosis, biological understanding and improved treatment. PMID- 21261688 TI - Molecular cytogenetics of lymphoma: where do we stand in 2010? AB - For the past 20 years most malignant lymphomas have been classified as clinicopathological entities, each with its own combination of clinical, morphological, immunophenotypic and molecular genetic characteristics. Molecular and cytogenetic abnormalities can be detected by a wide range of techniques, ranging from conventional karyotyping to single nucleotide polymorphism analysis. In this review, we consider the common genetic abnormalities found in lymphoma and discuss the advantages and disadvantages of individual techniques used in their detection. Finally, we discuss briefly possible novel developments in the field of lymphoma diagnostics. PMID- 21261689 TI - Haematological malignancies: the rationale for integrated haematopathology services, key elements of organization and wider contribution to patient care. AB - The National Institute for Clinical Excellence (NICE) defined the process of care for haematological malignancies in Improving outcomes in haematological cancers. The manual in 2003. The most challenging recommendation has been the requirement to develop integrated laboratory services for accurate diagnosis. This is an aim that has not been fully achieved. The unified concept of haematological malignancy is recent and based on an understanding of the cellular pathology of the bone marrow and immune systems. Historical UK pathology practice has previously resulted in the separation of laboratory haematology from histopathology and of liquid and tissue specimens. Proposals for reintegration and centralization with specialist-led, centralized diagnostic and reporting services challenge the fragmented historical model. Accuracy and certainty of diagnosis remains problematic, particularly for lymphomas, with evidence that the accuracy of diagnosis is slowly improving but still only approaches 85%. There is a potentially significant human and financial cost of diagnostic errors. No nationwide, validated and comparable epidemiology/population-based data exist for accurate and complete ascertainment of new cases of haematological cancer, service planning or clinical outcomes monitoring. This article examines the original rationale behind the NICE guidance and outlines the key components and processes of an integrated diagnostic service. PMID- 21261690 TI - The histopathology of drugs of abuse. AB - The use of drugs for recreational purposes is widespread. The drugs used can be divided into groups including stimulants (cocaine, amphetamines, etc.), opiates and opioids (heroin, oxycodone, methadone, fentanyl, etc.), sedatives (benzodiazepines and related substances) and miscellaneous drugs, including ketamine and cannabis (marijuana). These drugs can have profound effects on all organ systems in the body. The method of administration, whether by injection or inhalation, can cause localized and systemic effects, including the transmission of infection and granulomata at the site of injection and in the lungs. Suppurative abscesses from injection can result in systemic amyloidosis. Stimulants have profound effects on the cardiovascular and cerebrovascular systems, with enlarged hearts with fibrosis seen microscopically and cerebral infarction and haemorrhage. Crack cocaine use is also associated with changes in the pulmonary system, including carbon pigmented intra-alveolar macrophages, emphysema and pulmonary arterial changes. Cannabis use is associated with brown pigmented macrophages in the lung as well as changes in the respiratory tract epithelium. Opiates/opioids are associated with inhalational pneumonitis and hypoxic brain damage due to their respiratory depressant effects. Heroin use has been associated with focal segmental glomerulonephritis (heroin-associated nephropathy: HAN). 3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) use is associated with changes in the cardiovascular system. Its use can lead to hyperpyrexia, which results in systemic changes. Ketamine abuse has been associated with cystitis. Drugs of abuse may affect testicular function. In analysing the effects of drugs at autopsy a systematic approach to sampling of histology is required. PMID- 21261692 TI - Analysis of international content of ranked nursing journals in 2005 using ex post facto design. AB - AIM: The purpose of this study was to examine articles in ISI-ranked nursing journals and to analyse the articles and journals, using definitions of international and article content. BACKGROUND: Growing emphasis on global health includes attention on international nursing literature. Contributions from Latin America and Africa have been reported. Attention to ranked nursing journals to support scholarship in global health is needed. METHOD: Using an ex post facto design, characteristics of 2827 articles, authors and journals of 32 ranked nursing journals for the year 2005 were analysed between June 2006 and June 2007. Using definitions of international and of article content, research questions were analysed statistically. FINDINGS: (a) 928 (32.8%) articles were international; (b) 2016 (71.3%) articles were empirical or scholarly; (c) 826 (89.3%) articles reflecting international content were scholarly or empirical; (d) among international articles more were empirical (66.3 % vs. 32.8 %; chi(2) ((1)) = 283.6, P < 0.001); (e) among non-international articles more were scholarly (29.2 % vs. 22.7 %; chi(2) ((1)) = 15.85, P < 0.001; 22.7 %); (f) 1004 (78.0 %) articles were international, based on author characteristics; (f) 20 (62.5 %) journals were led by an international editorial team; and (g) international journals had more international articles (3.6 % vs. 29.2 %; chi(2) ((1)) = 175.75, P < 0.001) and higher impact factors than non-international journals (t = -14.43, P < 0.001). CONCLUSION: Articles with empirical content appear more frequently in international journals. Results indicate the need to examine the international relevance of the nursing literature. PMID- 21261691 TI - Relationships and betrayal among young women: theoretical perspectives on adolescent dating abuse. AB - AIMS: Adolescent dating abuse is not specifically described by any current nursing theory, and this article presents discussion of some existing theories that could inform a nursing theory of adolescent dating abuse. To account for the effects of gender, this discussion is limited to young women. BACKGROUND: Adolescent dating abuse is an important and understudied international issue for nursing. Theoretical frameworks can support development of nursing scholarship for such issues. No single theory yet exists in nursing to explain the experiences and health ramifications of dating abuse among young women. DATA SOURCES: A summary table of theories is provided. Literature was gathered via database search and bibliographic snowballing from reference lists of relevant articles. Included literature dates from 1982 through 2010. DISCUSSION: Theories of relationship formation and function are discussed, including attachment, investment, feminist and gender role conflict theories. Betrayal trauma theory is considered as a mechanism of injury following an abusive dating experience. IMPLICATIONS FOR NURSING: Gender, relationship and adolescence combine in a complex developmental moment for young women. To improve nursing care for those at risk for or in the throes of abusive relationships, it is critical to develop specific nursing approaches to understanding these relationships. CONCLUSION: Existing theories related to relationship and traumatic experiences can be combined in the development of a nursing theory of adolescent dating abuse among young women. PMID- 21261693 TI - Development and validation of the paediatric cancer coping scale. AB - AIM: The purpose of this study was to develop and test the psychometric properties of the paediatric cancer coping scale in children with cancer. BACKGROUND: Coping is a mediator between stressful events and adaptation. However, existing tools cannot be used to assess and understand coping strategies in children with cancer in Taiwan. METHODS: A total of 229 children with cancer were recruited from three medical centres in Taiwan in 2008-2009. Internal consistency and test-retest reliability were estimated by Cronbach's alpha and intra-class correlation coefficient respectively. The factor structure was determined by exploratory factor analysis and confirmatory factor analysis. Pearson's correlation coefficient was employed to test the convergent and discriminate validity. RESULTS: The paediatric cancer coping scale demonstrated internal consistency (alpha = 0.91) and a 2-week test-retest reliability (intra class correlation coefficient = 0.86). Its construct validity was confirmed by factor analysis, which extracted and defined three categories of coping strategies: cognitive coping, problem-oriented coping and defensive coping; these three factors explained 40% of the total variance with factor loadings ranging from 0.31 to 0.71. Convergent and discriminate validities were demonstrated by significant correlations among the coping, resilience and anxiety subscales. CONCLUSIONS: The paediatric cancer coping scale is a reliable and valid scale to measure and examine coping strategies in children with cancer. PMID- 21261695 TI - Seclusion as a necessary intervention: the relationship between burnout, job satisfaction and therapeutic optimism and justification for the use of seclusion. AB - AIMS: This paper is a report of the study of nurses' attitudes to the use of seclusion. More specifically, the aim was to address the relationship between burnout, job satisfaction and therapeutic optimism and justification of the use of seclusion. BACKGROUND: Research findings demonstrate that nurses continue to view seclusion as a necessary intervention. Factors that might be associated with attitudes have not been examined. METHODS: Questionnaires were distributed to nurses employed in inpatient units across eight mental health services in Queensland in 2008. Heyman Attitudes to Seclusion Survey, Elsom Therapeutic Optimism Scale, Maslach's Burnout Inventory and Minnesota Satisfaction Questionnaires were completed (N = 123). Data analysis involved descriptive statistics and Pearson product-moment correlation coefficients. RESULTS: Most participants considered certain behaviours particularly those involving harm to self, others or to property as appropriate reasons for the use of seclusion and were consistent with their perceptions of the likely practice on their unit. An association was found between therapeutic optimism and emotional exhaustion (burnout) and justifications for the use of seclusion. Participants with higher optimism scores and lower scores for emotional exhaustion were significantly less likely to support the use of seclusion in specific situations. CONCLUSIONS: The relationship between therapeutic optimism and emotional exhaustion gives new information that might influence strategies and approaches taken with the aim of reducing seclusion use. Further research is warranted to explore these relationships and their implications. PMID- 21261694 TI - A pilot study of a systematic method for translating patient satisfaction questionnaires. AB - AIMS: This paper is a report of a descriptive comparative pilot study of use of a method that simultaneously tests the content validity and quality of translation of English-to-Chinese translations of two patient satisfaction questionnaires: the La Monica-Oberst Patient Satisfaction Scale and Hospital Consumer Assessment of Healthcare Providers and Systems. BACKGROUND: Patient satisfaction is an important indicator of the quality of healthcare services. In China, however, few good translations of patient satisfaction instruments sensitive to nursing services exist. METHODS: The descriptive pilot study took place in 2009 and used content validity indexing techniques to evaluate the content, context and criterion relevance of a survey question. The expert raters were 10 nursing faculty and 10 patients who evaluated the two patient satisfaction questionnaires. The experts evaluated the relevance of each item on a scale of 1 4 and the research team compared their responses to choose the most appropriate. Only the nurse faculty experts, who were bilingual, evaluated the quality of the translation using a binary rating. RESULTS: The 'Nurse Rater' relevance scores of the LaMonica-Oberst Patient Satisfaction Scale and the Hospital Consumer Assessment of Healthcare Providers and Systems were 0.96 and 0.95 respectively, whereas the patient's overall relevance scores were 0.89 and 0.95. A Mann-Whitney U-test demonstrated that results between the two groups were statistically significantly different (P = 0.0135). CONCLUSIONS: Using content validity indexing simultaneously with translation processes was valuable for selecting and evaluating survey instruments in different contexts. PMID- 21261696 TI - Factors affecting nurse practitioner role implementation in Canadian practice settings: an integrative review. AB - AIM: To review the literature about the Canadian experience with nurse practitioner role implementation and identify influencing factors. BACKGROUND: Although nurse practitioners have been in existence for more than 40 years, their integration into healthcare systems has been challenging. While frameworks exist to guide implementation of these roles, clear identification of factors influencing role implementation may inform best practices. Given that Canada has witnessed considerable growth in nurse practitioner positions in the past decade, an exploration of its experience with role implementation is timely. DATA SOURCES: A review of Canadian literature from 1997 to 2010 was conducted. Electronic databases including CINAHL, Cochrane Database of Systematic Reviews, Health Source: Nursing Academic Edition, Medline, Social Science Index, PubMed, Web of Science and PsychINFO and government and professional organization websites were searched. METHODS: An integrative review was performed guided by Whittemore and Knafl's method. RESULTS: Ten published studies and two provincial reports were included. Numerous facilitators and barriers to implementation were identified and analysed for themes. Three concepts influencing implementation emerged: involvement, acceptance and intention. Involvement is defined as stakeholders actively participating in the early stages of implementation. Acceptance is recognition and willingness to work with nurse practitioner. Intention relates to how the role is defined. CONCLUSION: This integrative review revealed three factors that influence nurse practitioner role implementation in Canada: involvement, acceptance and intention. Strategies to enhance these factors may inform best practice role implementation processes. PMID- 21261697 TI - A qualitative analysis of stress, uplifts and coping in the personal and professional lives of Singaporean nurses. AB - AIM: This paper is a report of a descriptive study of nurses' experiences of daily stress and coping. BACKGROUND: Much of the research on stress in nursing is quantitative and has focused on only work stressors. Moreover, few studies have examined the uplifting side of living and the role it may play in moderating stress. A theoretical framework on stress and coping, 'hassles' and 'uplifts' was used to examine nurses' experiences across their personal and professional lives from a qualitative perspective. METHODS: A purposive sample of Singaporean hospital nurses (n = 23) identified using a snowball sampling technique, participated in two sets of email interviews in 2009. The qualitative data were analysed using thematic analysis. RESULTS: Three themes were identified as constituting daily hassles: (i) time pressures, (ii) nature of nursing work and (iii) multiple roles. Uplifts were expressed in relation to one main theme of feeling good extending across nurses' personal and professional lives. Three themes were identified as ways of coping: (i) taking time out, (ii) seeking emotional support and (iii) belief systems. CONCLUSION: The interaction between personal and professional life plays a major role in Singaporean nurses' experiences of stress and coping. However, stress may be ameliorated through effective management and strong familial support. Nurses and employers are recommended to use uplifts and identify ways of coping to minimize attrition and contribute to the development of a healthy workforce. PMID- 21261698 TI - Nurse burnout and its association with occupational stress in a cross-sectional study in Shanghai. AB - AIM: This paper is a report of a study investigating nurse burnout and its association with occupational stressors in Shanghai, China. BACKGROUND: Burnout is described as feelings of emotional exhaustion, depersonalization and reduced personal accomplishment. Measuring burnout among nurses and its association with occupational stressors are important in providing appropriate intervention to reduce stress and burnout. METHOD: In total, 527 nurses from 41 hospitals in Shanghai returned self-reported questionnaires in June 2008. Their burden of burnout was measured by the Chinese version of 'Maslach Burnout Inventory', and their stress by the Chinese version of 'job content questionnaire' and 'effort reward imbalance questionnaire'. RESULTS: Most nurses (74.76%) had a Demand/Control ratio higher than 1 and 27.13% had an Effort/Reward ratio higher than 1. The nurses showed a high level of emotional exhaustion, moderate level of depersonalization, and low level of reduced personal accomplishment. Linear regression analyses showed higher burden of stress and burnout among nurses at younger age, or on shift duty or from higher grade hospitals. Both the job content questionnaire and effort-reward imbalance questionnaire models had good predictive powers of the nurses' burnout, especially the effort-reward imbalance questionnaire model is more powerful than the other in predicting two Maslach Burnout Inventory subscales of emotional exhaustion and depersonalization. CONCLUSION: Nurses in Shanghai were suffering from high levels of burnout, which was strongly associated with work-related stress. Interventions in reducing occupational stress are needed to reduce the burden of burnout in Chinese nurses. PMID- 21261699 TI - Psychometric validity of the Problem-Focused Style of Coping scale: in relation to self-efficacy and life satisfaction among nursing staff in Taiwan. AB - AIMS: This paper is a report of a study of psychometric properties of the Problem Focused Style of Coping-Chinese version questionnaire. BACKGROUND: Coping with stress is an important topic in the 21th century, which deserves further attention. Although a variety of instruments have emerged to assess an individual's coping responses to stress, research suggests that numerous problems are associated with the current measurements. Since most coping scales are criticized as lacking valid estimates across occupational samples and cultures, there is an immediate need to develop a reliable and valid coping-style scale. METHOD: The study used a convenience sample and a sampling frame consisting of 307 nurses from different medical units in two regional hospitals in Taiwan. The data collection period was from May 2009 to June 2009. Exploratory factor analyses and reliability estimates were calculated. RESULTS: The factor analysis revealed three coping factors: reflective, suppressive and reactive. All reliability and validity estimates were satisfactory. CONCLUSION: The Problem Focused Style of Coping-Chinese version questionnaire is a valid and reliable measure of nurses' dispositional coping style and can be used for educational training programmes to enhance nurses' stress management skills. PMID- 21261700 TI - Characterization of swarming motility in Citrobacter freundii. AB - Bacterial swarming motility is a flagella-dependent translocation on the surface environment. It has received extensive attention as a population behavior involving numerous genes. Here, we report that Citrobacter freundii, an opportunistic pathogen, exhibits swarming movement on a solid medium surface with appropriate agar concentration. The swarming behavior of C. freundii was described in detail. Insertional mutagenesis with transposon Mini-Tn5 was carried out to discover genetic determinants related to the swarming of C. freundii. A number of swarming genes were identified, among which flhD, motA, motB, wzx, rfaL, rfaJ, rfbX, rfaG, rcsD, rcsC, gshB, fabF, dam, pgi, and rssB have been characterized previously in other species. In mutants related to lipopolysaccharide synthesis and RcsCDB signal system, a propensity to form poorly motile bacterial aggregates on the agar surface was observed. The aggregates hampered bacterial surface migration. In several mutants, the insertion sites were identified to be in the ORF of yqhC, yeeZ, CKO_03941, glgC, and ttrA, which have never been shown to be involved in swarming. Our results revealed several novel characteristics of swarming motility in C. freundii which are worthy of further study. PMID- 21261701 TI - Disseminated cutaneous phaeohyphomycosis in immunocompetent child. AB - We present a 6-year-old immunocompetent child with disseminated cutaneous phaeohyphomycosis, affecting his face, arms, thighs, and chest. He was treated with oral itraconazole 100 mg once a day for 5 months and surgical excision of the residual lesions. Disseminated phaeohyphomycosis is very infrequent in immunocompetent children. PMID- 21261702 TI - Hepatic infantile hemangiomas treated with oral propranolol--a case series. AB - Hepatic infantile hemangiomas may be associated with morbidity and mortality, and traditional therapies may be associated with significant side effects. Since propranolol has been recently used successfully to treat cutaneous infantile hemangiomas, we decided to use it in three patients who presented with hepatic and skin hemangiomatosis. Three patients with skin and hepatic infantile hemangiomas, two of whom had evidence of cardiovascular compromise and one of whom had extensive liver involvement and hypothyroidism, were treated with oral propranolol. Regression of both skin and hepatic hemangiomas was noted in all patients, as was resolution of the cardiac symptoms and decreased thyroid requirement in two patients each. Propranolol was well tolerated without any adverse effects. Propranolol should be considered as a potential first-line therapy in patients with symptomatic hepatic hemangiomatosis. PMID- 21261703 TI - The clinical spectrum and therapeutic challenge of eczema herpeticum. AB - We present 5 cases of eczema herpeticum in patients with severe recalcitrant atopic dermatitis to illustrate the range of possible clinical findings and supporting laboratory data that can obscure the diagnosis and complicate treatment. Major issues include: the need for aggressive laboratory evaluation (molecular diagnostics, viral cultures, skin biopsy, serology); the possibility of recurrent or chronic infection; the value of empiric antiviral therapy; the possibility of infection with thymidine-kinase resistant strains; and the importance of achieving control over the dermatitis with nonmyelosuppressive immunomodulating agents such as intravenous immunoglobulin or interferon gamma for dermatitis that requires systemic treatment. PMID- 21261704 TI - Plexiform fibrohistiocytic tumor with molecular and cytogenetic analysis. AB - A child with plexiform fibrohistiocytic tumor is presented, in whom a superficial biopsy was misdiagnosed as an inflammatory granuloma. Cytogenetic analysis revealed a 46,X,del(X)(q13)[3]/46,XX[23] karyotype. However, fluorescence in situ hybridization (FISH) and array-comparative genomic hybridization (CGH) analysis failed to detect any numerical or quantitative genomic anomaly. Because of lack of specific chromosomal hallmarks, a molecular diagnosis of plexiform fibrohistiocytic tumor with the currently available tools is not reliable. PMID- 21261705 TI - The influence of music on aEEG activity in neurologically healthy newborns >=32 weeks' gestational age. AB - AIM: Music is increasingly being used in neonatal intensive care units to aid neurodevelopmental care. The aim of this pilot study was to examine the possible effects of music on quiet sleep (QS) in neurologically healthy newborns. METHODS: Twenty newborns >=32 weeks' gestational age admitted to the neonatal intensive care unit at The Royal Children's Hospital in Melbourne for specialist consultation were randomly assigned to experimental or control groups. Ten subjects were exposed to music (Music for Dreaming, (Sound Impressions, Pty. Ltd.) using a CD player (50-55 decibel A). Amplitude-integrated EEG was recorded on the BrainZ Monitor (BRM2, Version 8.0, Natus). Background pattern, presence and quality of sleep-wake cycles (SWC) were assessed before and after exposure to music. RESULTS: All 20 subjects showed continuous background patterns with developing SWC. Whereas no subject in the control group showed differences in their QS and eight patients in the intervention group showed lower minimum amplitudes of their QS after music exposure. Also, the length of QS and interval between QS epochs became progressively longer in all ten subjects of the intervention group. CONCLUSION: We report a trend to more mature SWC in subjects who were exposed to music when compared to controls suggesting that there might be a small effect of music on quiet sleep in newborns. PMID- 21261708 TI - Much ado about Nutlin. PMID- 21261709 TI - Solid pseudopapillary tumor and wnt signaling pathway ... Way to go!? PMID- 21261710 TI - "Normal" range of alanine aminotransferase levels for Asian population. PMID- 21261711 TI - Treatment of hepatitis C virus infection in patients with end-stage renal disease. AB - Hepatitis C virus (HCV) infection is a major health problem in patients with end stage renal disease (ESRD). The incidence of acute HCV infection during maintenance dialysis is much higher than that in the general population because of the risk of nosocomial transmission. Following acute HCV infection, most patients develop chronic HCV infection, and a significant proportion develop chronic hepatitis, cirrhosis, and even hepatocellular carcinoma. Overall, chronic hepatitis C patients on hemodialysis bear an increased risk of liver-related morbidity and mortality, either during dialysis or after renal transplantation. Interferon (IFN) therapy is modestly effective for the treatment of HCV infection in ESRD patients. Conventional or pegylated IFN monotherapy has been used to treat acute hepatitis C in ESRD patients with excellent safety and efficacy. Regarding chronic hepatitis C, approximately one-third of patients can achieve a sustained virological response (SVR) after conventional or pegylated IFN monotherapy. The combination of low-dose ribavirin and conventional or pegylated IFN has further improved the SVR rate in treatment-naive or retreated ESRD patients in clinical trials. Similar to the treatment of patients with normal renal function, baseline and on-treatment HCV virokinetics are useful to guide optimized therapy in ESRD patients. Of particular note, IFN-based therapy is not recommended at the post-renal transplantation stage because of the low SVR rate and risk of acute graft rejection. In conclusion, ESRD patients with HCV infection should be encouraged to receive antiviral therapy, and those who achieve an SVR usually have long-term, durable, virological, biochemical, and histological responses. PMID- 21261712 TI - Is endoscopic surveillance for non-dysplastic Barrett's esophagus cost-effective? Review of economic evaluations. AB - BACKGROUND AND AIM: Several health economic evaluations have explored the cost effectiveness of endoscopic surveillance for patients with non-dysplastic Barrett's esophagus, with conflicting results. By comparing results across studies and highlighting key methodological and data limitations a platform for future, more rigorous analyses, can be developed. METHODS: A systematic literature review was undertaken of studies evaluating cost-effectiveness of surveillance for non-dysplastic Barrett's esophagus. Articles were included if they assessed both cost and health outcomes for surveillance versus no surveillance. A descriptive review was undertaken and the quality of the studies appraised against best-practice recommendations for economic evaluations and modeling studies. RESULTS: Seven publications met the inclusion criteria. All used decision-analytic Markov models. Half of the evaluations found surveillance was not cost-effective. At best, surveillance produced improved outcomes at a cost of US$16 640 per quality-adjusted life-year, and at worst it did more harm than good and at a greater cost. The quality of the evaluations and generalizability to the Asia-Pacific region was diminished as a result of inadequate or inconsistent evidence supporting parameter estimates, such as quality of life, endoscopic sensitivity and specificity and cancer recurrence rates. CONCLUSIONS: Unless newly emerging technologies improve the quality adjusted survival benefit conferred by endoscopic surveillance, this strategy is unlikely to be cost-effective. Obsolete assumptions and incomplete analyses reduce the quality of published evaluations. For these reasons new evaluations are required that encompass the growing evidence base for new technologies, such as new endoscopic therapies for high-grade dysplasia and intramucosal cancer. PMID- 21261713 TI - Endoscopic band ligation followed by sclerotherapy: Is it superior to sclerotherapy in children with extrahepatic portal venous obstruction? AB - BACKGROUND AND AIM: There is scarcity of data about children on a combination of endoscopic variceal ligation (EVL) and endoscopic sclerotherapy (EST). We assessed the efficacy of EVL followed by EST and EST alone in children with extrahepatic portal venous obstruction (EHPVO). METHODS: From January 2000 to March 2007, 186 consecutive children (mean age 6.3 +/- 4.2 years, 82% boys) with EHPVO with variceal bleeding were included. EVL followed by EST (Group I, n = 101) or EST alone (Group II, n = 60) was carried out at 3-weekly intervals until eradication. Surveillance endoscopy was done at 3 to 6-monthly intervals. In all cases, the number of sessions required to eradicate the esophageal varices, the volume of sclerosant, the complications and the endoscopic outcome on follow up were recorded. RESULTS: Eradication was achieved in 158 of 161 (98%) children and 25 were lost to follow up. Group I required significantly fewer sessions (5.2 +/- 1.8 vs 6.8 +/- 2.8, P < 0.005), less sclerosant (13 +/- 8.2 mL vs 30 +/- 20 mL, P < 0.001) and had fewer complications (7% vs 28%, P < 0.001) as compared with Group II. On follow up (33 +/- 17.6 months in Group I and 43 +/- 16.7 months in Group II), there was a significant increase in the prevalence of portal hypertensive gastropathy as well as isolated gastric varices in both the groups. However, the prevalence of gastroesophageal varices decreased. CONCLUSIONS: EVL followed by EST is better than EST alone in children with EHPVO as it requires fewer sessions and has fewer complications. However, following eradication, evolution of gastric varices and portal hypertensive gastropathy was similar in the two groups. PMID- 21261714 TI - Helicobacter pylori and pathogenesis of gallbladder cancer. AB - BACKGROUND AND AIM: Gallbladder cancer (GBC) is a rare but leading cause of cancer-related deaths worldwide. The incidence of GBC is increasing at an alarming rate in the Varanasi region, and its etiology remains obscure. METHODS: A total of 108 patients, 54 with GBC and 54 with gallstone diseases (GSD), were examined for Helicobacter pylori (H. pylori) in gallbladder specimens by rapid urease test, biochemical test, histology, culture, serology, polymerase chain reaction (PCR), and partial DNA sequencing. PCR was done using heat shock protein 60 (Hsp60) gene-nested primers. RESULT: Forty (74%) patients with GBC had gallstones. Upon culture, H. pylori colonies were identified in 24 (44%) GBC and 18 (33%) GSD specimens. H. pylori was detected in 20 (37%) GBC and 15 (28%) GSD samples upon histology. Serology was positive in 17 (32%) GBC and 15 (28%) GSD patients. The DNA isolated from GBC and GSD specimens was amplified by PCR with Hsp60-nested primers in 18 (33%) patients with GBC and 15 (28%) with GSD (P > 0.05). These sequences had 98% similarity with the presubmitted Hsp60 sequences of H. pylori in the National Centre for Biotechnology Information's GenBank. CONCLUSION: The results revealed that H. pylori was present in a large population, including both GBC and GSD patients, which indicates its endemic presence in the Varanasi region. Thus, it appears H. pylori might not have a significant role in the etiopathogenesis of GBC in our region. PMID- 21261716 TI - Advantages of endoscopic submucosal dissection versus endoscopic oblique aspiration mucosectomy for superficial esophageal tumors. AB - BACKGROUND AND AIM: In the treatment of superficial esophageal tumors (SET), en bloc histologically-complete resection reduces the risk of local recurrence. Endoscopic oblique aspiration mucosectomy (EOAM) and endoscopic submucosal dissection (ESD) have been applied to resect SET. The aim of this study was to retrospectively determine whether ESD is more advantageous than EOAM for SET. METHODS: In the present study, there was a total of 122 patients in whom 162 SET were resected endoscopically at Hiroshima University Hospital. EOAM (83 lesions/63 patients) or ESD (79 lesions/59 patients) was performed. En bloc histologically-complete resection rates, operation time, complications, and the local recurrence rate were studied. RESULTS: In SET > 20 mm, the en bloc histologically-complete resection rate was significantly higher with ESD than with EOAM (94% vs 42%, P < 0.001). In SET of 16-20 mm, the rate tended to be higher with ESD than with EOAM (100% vs 81%, P = 0.08). In SET < 15 mm, the rates did not differ significantly between groups. The average operation time was significantly longer for ESD than for EOAM, regardless of tumor size (49.7 +/- 33.0 min vs 19.1 +/- 6.1 min, P < 0.001). Complication rates did not differ significantly between groups. The local recurrence rate was significantly lower with ESD than with EOAM (0%, mean observation period: 18.9 months vs 9%, mean observation period: 30.7 months, P = 0.03). CONCLUSION: Although increased operation time with ESD remains problematic, SET > 15 mm should be treated with ESD to reduce local recurrence. In lesions <= 15 mm, EOAM might be preferable, especially in high-risk patients. PMID- 21261715 TI - Clinical and immunohistochemical features of 34 solid pseudopapillary tumors of the pancreas. AB - BACKGROUND AND AIM: Clinicopathological data regarding pancreatic solid pseudopapillary tumors (SPT) in a multiethnic country are limited. The aim of the present study was to characterize pancreatic SPT in Australia. METHODS: Clinicopathological features, treatment, immunohistochemical findings and outcome data of 34 patients (79% Caucasian, 12% Asian, 6% South Pacific Islander and 3% African) with pancreatic SPT were reviewed. RESULTS: The most presenting complaint was abdominal pain. Median diameter of tumors was 60 mm (range: 20 220); predominantly located in the pancreatic tail (tail : body : head = 23:3:8). All tumors were resected and patients underwent surgery, including a liver resection for metastasis, all patients were alive after a median follow up of 70 months (IQR: 48-178). Two patients underwent repeated surgery for local recurrences with liver metastases after 8 and 18 months, which were successfully managed by surgical resection. Completeness of excision, perineural spread, vascular space invasion, mitotic rate and cellular atypia did not predict recurrence. In all cases, there was aberrant nuclear staining of beta-catenin and a loss of membranous expression of E-cadherin with aberrant nuclear localization of the cytoplasmic domain. Most pancreatic SPT were also strongly positive for CD10 (96%), progesterone receptor (79%), cytokeratin (28%), synapthophysin (26%) and chromogranin (15%). CONCLUSIONS: Pancreatic SPT occur in all races and are uniformly indolent. Given complete resection of a pancreatic SPT is usually curative and recurrences can be treated with re-operation, correct diagnosis is important. PMID- 21261717 TI - The severity of endoscopic gastric atrophy could help to predict Operative Link on Gastritis Assessment gastritis stage. AB - BACKGROUND AND AIMS: The aims of the present study were to evaluate the role of moderate-to-severe endoscopic gastric atrophy (EGA) on predicting Operative Link on Gastritis Assessment (OLGA) gastritis stage, and to assess the association of high-stage OLGA gastritis with gastric neoplasia in patients with non-ulcer dyspepsia. METHODS: A cross-sectional study was carried out on 280 dyspeptic outpatients. EGA was assessed according to the Kimura-Takemoto classification. Gastritis stage was established according to the OLGA staging system and gastric neoplasia was assessed according to the Vienna classification. The pathologists who read the specimens were kept blind to the endoscopic results. RESULTS: The mean age of patients was 46.1 years (range 20-78 years) with a male-to-female ratio of 1:1. High-stage gastritis (e.g. stage III or IV) was confirmed in 13 (4.6%) patients. All of these patients were more than 40 years-of-age (P = 0.01), had Helicobacter pylori infection (P = 0.0006) and moderate-to-severe EGA (P < 0.001). Low-grade dysplasia was found in seven patients: 4/13 (30.7%) with high stage gastritis versus 3/267 (1.1%) with low-stage gastritis (P < 0.001). Six of these patients had moderate-to-severe EGA (P = 0.048). The sensitivity, specificity, positive predictive value and negative predictive value of this endoscopic finding in high-stage gastritis diagnosis were 100%, 57.7%, 10.3% and 100%, respectively. CONCLUSIONS: OLGA high-stage gastritis was associated with gastric dysplasia and was mostly diagnosed in patients with moderate-to-severe EGA. The absence of this endoscopic finding could effectively rule out the possibility of having high-stage gastritis. PMID- 21261718 TI - Efficacy of hyaluronic acid in endoscopic mucosal resection of colorectal tumors. AB - BACKGROUND AND AIM: Endoscopic mucosal resection (EMR) is the standard procedure for colorectal tumors. High mucosal elevation by submucosal injection is important for definite en bloc resection and the prevention of perforation. Hyaluronic acid (HA) is a reportedly useful injection solution for high and long lasting mucosal elevation, but the ideal HA concentration for optimization of mucosal elevation maintenance, injection pressure, and cost is unknown. In the present study, we assessed the appropriate concentration of HA for EMR. METHODS: A resected porcine colon and esophagus were used. The injection solutions examined were 0.9% normal saline (NS) and four concentrations of an 800-KDa HA preparation (0.4%, 0.2%, 0.13%, and 0.1%). Each solution (2 mL) was injected into the submucosa; injection pressure was calculated, and elevation was measured. The durations of mucosal elevation and EMR were additionally assessed in the living minipig colon. RESULTS: In the resected porcine colon, the mucosal elevation was measured 0, 2, 4, and 6 min after the submucosal injection. All concentrations of HA solution maintained greater mucosal elevation at all times than NS (P < 0.05). An almost similar result was obtained in the resected porcine esophagus. The injection pressure correlated with the HA concentration. In the living minipig colon, mucosal elevation diminished 2 min after the submucosal injection with NS, but was maintained 2 min after injection with 0.4%, 0.2%, and 0.13% HA. The average duration of EMR was 139 s. CONCLUSIONS: Mucosal elevation by HA was greater than that by NS in resected and living animal models. We recommend 0.13% HA for maintaining mucosal elevation, injection pressure, and cost. PMID- 21261719 TI - Healthy range for serum ALT and the clinical significance of "unhealthy" normal ALT levels in the Korean population. AB - BACKGROUND AND AIMS: It remains unclear whether the currently-used normal range for serum alanine aminotransferase (ALT) levels really reflects a healthy liver. The present study was conducted to evaluate the healthy range of serum ALT in the Korean adult population and to determine the clinical significance of unhealthy levels. METHODS: We reviewed the medical records, including questionnaires and the results of laboratory and radiological tests conducted at the Health Promotion Center at Korea University Anam Hospital between March 2005 and February 2007. The records, written in questionnaire form, included baseline data, such as physical status, social behaviors, medication history, and past and present disease histories. RESULTS: The mean age of the 7403 enrolled patients was 48 years, and 49.9% of these patients were male. A healthy cohort was selected after excluding patients who showed any abnormalities of the factors that were significantly associated with the serum ALT level upon multivariate regression analysis. The upper limit of the healthy range of the serum ALT level (i.e. 95th percentile) in the healthy population was 31 IU/L for males and 23 IU/L for females. The prevalence of metabolic syndrome and insulin resistance (IR) were significantly higher in patients with an 'unhealthy' normal ALT level than in those with a healthy ALT level. CONCLUSION: In our study, the upper limit of the healthy range of the serum ALT level was 31 IU/L for males and 23 IU/L for females. An unhealthy normal ALT level was associated with a higher prevalence of metabolic syndrome and IR. PMID- 21261720 TI - Factors associated with unreliable liver stiffness measurement and its failure with transient elastography in the Chinese population. AB - BACKGROUND AND AIM: Liver stiffness measurement (LSM) with transient elastography is a non-invasive and reliable test for liver fibrosis. However a small proportion of patients may have unreliable LSM or LSM failure. The aim of the present study was to investigate the factors associated with unreliable LSM or LSM failure in Chinese patients. METHODS: We prospectively recruited liver patients for LSM. Unreliable LSM was defined as < 10 valid shots, an interquartile range (IQR)/LSM > 30%, or a success rate < 60%. LSM failure was defined as zero valid shots. RESULTS: Among 3205 patients with LSM, 371 (11.6%) and 88 (2.7%) had unreliable LSM and LSM failure, respectively. The rates started to increase when body mass index (BMI) >= 28.0 kg/m(2) . Comparing patients with BMI >= 28.0-29.9 kg/m(2) versus those with BMI >= 30.0 kg/m2, the rates of unreliable LSM (16.4% vs 18.9%; P = 0.62) and LSM failure (11.8% vs 17.8%; P = 0.16) were similar. BMI >= 28.0 kg/m2 was the most important factor associated with unreliable LSM (odds ratio [OR] = 2.9, 95% confidence interval [CI] = 2.1 3.9, P < 0.0001) and LSM failure (OR = 10.1, 95% CI = 6.4-14.2, P < 0.0001). Central obesity, defined as waist circumference > 80 cm in women and > 90 cm in men, was another independent risk factor of unreliable LSM (OR = 1.3, 95% CI = 1.0-1.6, P = 0.04) and LSM failure (OR = 5.8, 95% CI = 2.9-11.5, P < 0.0001). CONCLUSION: BMI >= 28.0 kg/m2 and central obesity were the independent risk factors of unreliable LSM and LSM failure in Chinese, and these rates were significantly higher in patients with extreme BMI. PMID- 21261721 TI - Role of polymorphic N-acetyl transferase2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis. AB - BACKGROUND AND AIM: Antituberculosis drugs, isoniazid and rifampicin, in combination, are known to develop drug-induced hepatotoxicity (DIH). A higher risk of DIH during antituberculosis treatment (ATT) has been reported in the Indian subcontinent compared to its Western counterparts. The role of genetic factors in a higher incidence of ATT hepatotoxicity in the Indian population is still unclear. The present study was aimed at investigating the role of the N acetyltransferase2 (NAT2) and cytochrome P4502E1 (CYP2E1) gene polymorphisms in ATT hepatotoxicity. METHODS: The study population included 218 pulmonary tuberculosis patients who were started on ATT and followed up for the occurrence of ATT-induced hepatitis. The genetic polymorphisms of the NAT2 and CYP2E1 genes were studied by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The occurrence of DIH was 18.8% (41/218). There was a higher prevalence of NAT2 slow-acetylator genotypes in DIH (70.73%) compared to non-DIH (44.63%; P < 0.05). The frequency of the NAT2*5/*7 and NAT2*6/*7 genotypes was significantly higher in DIH than non-DIH (19.51% vs 6.78%, and 19.51% vs 5.08%). No association of the CYP2E1 RsaI polymorphism could be demonstrated with DIH. However, the DraI C/D genotype of the CYP2E1 gene was mostly prevalent in DIH (85.37%), compared to non-DIH (64.41%) (P < 0.05). Slow acetylator status and the CYP2E1 C/D or C/C genotype together showed a higher frequency in DIH (65.85%) compared to non-DIH (28.81%) (P < 0.0001). CONCLUSION: The study demonstrates for the first time a possible association between the DraI polymorphism of the CYP2E1 gene and the risk of ATT hepatotoxicity. The genotyping of the NAT2 and CYP2E1 genes could possibly identify the groups at highest risk of developing ATT-induced hepatitis prior to medication. PMID- 21261722 TI - No evidence of the unfolded protein response in patients with chronic hepatitis C virus infection. AB - BACKGROUND AND AIM: Hepatitis C virus (HCV) proteins activate the unfolded protein response (UPR) in experimental models. The role of the UPR in the pathogenesis of HCV-induced liver injury has not been determined. Our aim was to investigate the role of the UPR in the pathogenesis of chronic HCV. METHODS: Liver biopsy samples from 124 patients with chronic HCV and 24 HCV/HBV-negative subjects with histologically normal liver (NDL) were assessed. The hepatic mRNA expression of components of the UPR was measured by semi-quantitative real-time polymerase chain reaction. Glucose regulated protein (GRP) 78 protein expression was assessed by immunohistochemistry. RESULTS: The expression of GRP78 mRNA and growth arrest and damage inducible protein 34 (GADD34) mRNA was significantly lower in subjects with HCV than NDL (P = 0.007 and P < 0.001, respectively). There was no significant difference in the expression of GRP94 mRNA, spliced X box binding protein 1 (sXBP1) mRNA, C/EBP homologous protein mRNA (CHOP) and ER degradation enhancing alpha-mannosidase-like protein (EDEM) mRNA and GRP78 protein between patients with HCV and NDL. There were no relationships between elements of the UPR and inflammation or fibrosis in patients with HCV. CONCLUSION: Downstream components of UPR were not activated in patients with chronic HCV. Therefore, the UPR may not play a prominent role in liver injury in patients with chronic HCV infection. PMID- 21261723 TI - Apolipoprotein E genotypes modulate fibrosis progression in patients with chronic hepatitis C and persistently normal transaminases. AB - BACKGROUND AND AIM: Carriage of the apolipoprotein E (Apo E) variants, E2, E3 and E4, affects cholesterol metabolism and may be involved in the persistence of hepatitis C virus (HCV) infection. Our aim was to verify whether carriage of specific Apo E variants modulates the course of hepatitis C. METHODS: We studied a cohort of 116 HCV-positive patients (49 male subjects) with persistently normal transaminases and an Ishak staging score <= 2 at an initial biopsy. These untreated patients underwent regular clinical monitoring (median histological follow up: 10 years). Apo E variants were genotyped and results were related to the histological outcome. RESULTS: The mean +/- standard deviation staging scores were 0.9 +/- 0.7 at entry versus 1.9 +/- 1.2 at the end of follow up, P < 0.0001. Initial and final staging scores in the E3/E3 homozygotes (n = 74) were 1.0 +/- 0.7 versus 2.1 +/- 1.3, P < 0.0001, while in the remaining patients (n = 42) they were 0.9 +/- 0.6 versus 1.5 +/- 1.0, P < 0.002. A synergistic effect was observed between Apo E polymorphisms and baseline serum cholesterol values: patients not carrying any E3 allele, as well as carriers of a single E3 allele with serum cholesterol concentration > 190 mg/dL were more likely to have a favorable outcome (final vs initial staging score increased in 7/66, did not change in 10/46, and decreased in 3/4, P <0.005). CONCLUSIONS: Some of the variability in the natural history of patients with persistently normal transaminases with initially mild hepatitis C can be related to their Apo E genetic background. PMID- 21261724 TI - Parity, age at first birth, and risk of death from liver cancer: Evidence from a cohort in Taiwan. AB - BACKGROUND AND AIM: The present study was undertaken to examine whether there is an association between parity and age at first birth and risk of liver cancer. METHODS: The study cohort consisted of 1,292,462 women who had a first and singleton childbirth between 1 January 1978 and 31 December 1987. We tracked each woman from the time of their first childbirth to 31 December 2007, and their vital status was ascertained by linking records with the computerized mortality database. Cox proportional hazard regression models were used to estimate the relative risks (RR) of death from liver cancer associated with parity and age at first birth. RESULTS: There were 826 liver cancer deaths during 32,464,186.58 person-years of follow-up. The mortality rate of liver cancer was 2.54 cases per 100,000 person-years. The adjusted RR was 1.59 (95% confidence interval [CI] = 1.36-1.86) for women who gave birth between 26 and 30, 2.41 (95% CI = 1.81-3.20) for women who gave birth between 31 and 35, and 6.26 (95% CI = 4.27-9.19) for women who gave birth after 35 years of age, respectively, when compared with women who gave birth at less than 25 years of age. The adjusted RR was 0.72 (95% CI = 0.59-0.87) for women who had two to three children, and 0.63 (95% CI = 0.47 0.84) for women with four or more births, respectively, when compared with women who had given birth to only one child. CONCLUSIONS: The present study suggests that reproductive factors (parity and early age at first birth) may confer a protective effect on the risk of liver cancer. PMID- 21261725 TI - Prospective validation of the Chinese University Prognostic Index and comparison with other staging systems for hepatocellular carcinoma in an Asian population. AB - BACKGROUND AND AIM: Hepatitis B viral (HBV) infection is the predominant etiology of hepatocellular carcinoma (HCC) in Asia. Our group previously reported a staging system known as the Chinese University Prognostic Index (CUPI) for HCC populations of which HBV infection is the predominant etiology. This study aims to validate CUPI and compare with other published staging systems. METHODS: We analyzed a prospective cohort of patients with newly diagnosed HCC from 2003 to 2005. All patients were staged with CUPI, Barcelona Clinic Liver Cancer Classification (BCLC), Cancer of the Liver Italian Program score (CLIP), tumor node-metastasis (TNM) and Okuda systems at diagnosis. They were followed with survival data and the performance of each staging system (in terms of homogeneity, discriminatory ability and monotonicity of gradient) were analyzed and compared. RESULTS: A total of 595 patients (80.2% with chronic HBV infection) were analyzed. The median follow-up was 41.4 months and the median survival was 6.6 months. Multivariate analyses identified symptomatic disease, ascites, vascular involvement, Child-Pugh-stage, alpha-fetoprotein and treatment to be the independent prognostic factors. CUPI could identify three groups with statistically significant survival difference (P < 0.0001). Both CUPI and CLIP had the most favorable performance in terms of discriminatory ability, homogeneity and monotonicity. CUPI performed the best in predicting 3-month survival while CLIP performed better in predicting the outcome of 6- and 12-month survival rate. BCLC was inferior to CLIP and CUPI in the overall performance. CONCLUSION: We have validated CUPI in a population composed of predominant HBV related HCC. CUPI is an appropriate staging system for HBV-related HCC. In patients with advanced HCC, both CUPI and CLIP offer good risk stratification. PMID- 21261726 TI - Platelets prevent acute hepatitis induced by anti-fas antibody. AB - BACKGROUND AND AIM: Platelets provide many functions in the body, especially to the liver. The purpose of this study is to investigate the effect of thrombocytosis with acute hepatitis induced by anti-Fas antibody and its mechanism. METHODS: Acute hepatitis was induced by administration of anti-Fas antibody in normal and thrombocytotic C57BL6J mice. For thrombocytosis, thrombopoietin; PEG-rHuMGDF was injected 5 days before and just prior to administration of anti-Fas antibody. To investigate the mechanisms, hepatocyte cell line (AML12) and sinusoidal endothelial cell line (M1) were induced apoptosis by staurosporine. They were cultured with platelets or thrombopoietin. Examination items were as follows: platelet number, alanine aminotransferase (ALT), histological findings, TUNEL (TdT-mediated dUTP-biotin Nick End Labeling) staining, and the expression of proteins associated with apoptosis in vivo and in vitro. RESULTS: Platelets were significantly increased in the thrombocytotic group (P < 0.01). Serum ALT levels were significantly reduced by thrombocytosis at 6, 24 and 72 h after the administration (P < 0.05). In histological findings, hemorrhagic necrosis was observed in the normal group, but not observed in the thrombocytotic group. TUNEL-positive hepatocytes were reduced and the expression of cleaved caspase-3 was significantly decreased in the thrombocytotic group. The phosphorylation of Akt, the increment of Bcl-xL and the decrease of cleaved caspase-3 were observed in AML12 cells cultured with platelets, but were not observed cultured with thrombopoietin. Platelets and thrombopoietin had no anti apoptotic effect on M1 cells. CONCLUSION: Increase of platelets has a preventative effect against acute hepatitis induced by the anti-Fas antibody. It is suggested that platelets have a direct protective effect against apoptosis of hepatocytes. PMID- 21261727 TI - Reversal of hepatic steatosis by omega-3 fatty acids measured non-invasively by (1) H-magnetic resonance spectroscopy in a rat model. AB - BACKGROUND AND AIM: Living donors with marked (> 33%) macrovesicular steatosis (MaS) are excluded from living donor liver transplantation procedures. Experimental studies have shown that the development of steatosis can be prevented by supplementation with omega-3 fatty acids (FA), but no studies have investigated the reduction of steatosis using omega-3 FA. The aim of the present study was to investigate whether administration of omega-3 FA is effective in reducing steatosis. METHODS: After fatty liver (FL) induction by a 3-week methionine/choline-deficient (MCD) diet, male Wistar rats were daily administered per gavage omega-3 FA (FL+Omega-3), omega-3-poor lipid solution (FL+Lipid), or NaCl (FL+NaCl) during 2 weeks. Control animals received standard chow without treatment. Determination of steatosis degree was performed before, during, and after treatment by clinical 3.0 T 1H-magnetic resonance spectroscopy (1H-MRS) and by histology and gas chromatography at the end of the 2-week treatment period. RESULTS: Hepatic fat content (1H-MRS) was significantly reduced after 1 and 2 weeks of omega-3 FA treatment. Histological analysis revealed a mild (5-33%) MaS degree in omega-3-treated animals vs severe (> 66%) MaS in the FL+Lipid and FL+NaCl groups. Hepatic omega-6 : 3 FA ratio and total FA content were reduced in the FL+Omega-3 group. Furthermore, de novo lipogenesis (C16, C16 : 1omega7, C18 : 1omega9) was also lowered. The reduction in hepatic fat content was associated with decreased lobular inflammation and hepatic tumor necrosis factor- alpha and interleukin levels as well as an increased antioxidative capacity. CONCLUSION: Omega-3 FA are capable of reversing severe hepatic MaS and ameliorating pathophysiological features of non-alcoholic steatohepatitis such as hepatocellular damage, lobular inflammation, and a reduced antioxidative capacity. PMID- 21261728 TI - Expression and modulation of Na(+) /H(+) exchanger 1 gene in hepatocellular carcinoma: A potential therapeutic target. AB - BACKGROUND AND AIM: Na(+) /H(+) exchanger 1 (NHE1), a regulator of intracellular pH (pHi), plays a significant role in regulating tumor cell growth and apoptosis. In the present study, we determined its role in hepatocellular carcinoma (HCC). METHODS: Immunohistochemistry was carried out to detect NHE1 expression in HCC tissue for the correlation of NHE1 with clinicopathological data from patients. NHE1-siRNA and 5- (N-ethyl-N-isopropyl) amiloride (EIPA, highly specific inhibitor of NHE1) were used to assess the function of NHE1 in HCC cells by using gene transfection, methyl thiazolyl tetrazolium (MTT), flow cytometry, and nude mouse xenograft assays as well as fluorescence spectroscopy. RESULTS: We found that NHE1 expression was increased in HCC tissues and cells in which its expression was associated with the increased tumor size, venous invasion and advanced tumor stages. However, suppression of NHE1 expression by using NHE1 siRNA and EIPA reduced growth, but induced apoptosis of HCC cells. EIPA also inhibited tumor growth in nude mouse xenografts of HCC cells. CONCLUSIONS: The data from our current study demonstrates that NHE1 was overexpressed in HCC and that inhibition of NHE1 could be a potential therapeutic target for HCC. PMID- 21261729 TI - MDM2 antagonist can inhibit tumor growth in hepatocellular carcinoma with different types of p53 in vitro. AB - BACKGROUND AND AIMS: Nutlin-3, a selective small-molecule inhibitor of the p53 MDM2 interaction, has been shown to have antitumor activities in various tumors with wild-type p53. However, its effect on hepatocellular carcinoma (HCC) with different types of p53 remains unclear. This study is designed to determine nutlin-3's antitumor efficacy and underlying mechanisms of action in human HCC cells. METHODS: Cell viability assay, cell cycle analysis, apoptosis assay, western blot, co- immunoprecipitation and siRNA experiments were analyzed in three human HCC cells. Anti-tumoral effects of nutlin-3 targeting the p53 and p73 pathways were evaluated in HCC cell lines. RESULTS: Nutlin-3 exerted the greatest anti-tumoral effect to three human HCC cells with wild-type p53, mutant p53 and p53-null. Nutlin-3 not only upregulated p53 in HepG2 cells, but also p73 in Huh7 and Hep3B cells, and disrupted p53-MDM2 and p73-MDM2 complexes in HCC cells. The compound inhibited cell proliferation, induced G0/G1 phase arrest, decreased the levels of CyclinD1, CyclinE, CDK2, CDK4, PCNA and E2F-1, and increased the levels of p21 and p27. It also induced apoptosis, increased the Bax/Bcl-2 ratio, then activated caspase-9 and caspase-3. CONCLUSIONS: Nutlin-3 has significant anticancer effects against human HCC cells, regardless of p53 status, indicating that it is a promising therapy for human hepatocellular carcinoma. PMID- 21261730 TI - Prevalence and clinical profile of celiac disease in type 1 diabetes mellitus in north India. AB - BACKGROUND AND AIM: There is scanty data on the occurrence of celiac disease in patients with type 1 diabetes mellitus in South Asia. Our aim was to study the prevalence and clinical profile of celiac disease in patients with type 1 diabetes mellitus in a tertiary care referral centre in north India. METHODS: Consecutive patients of type 1 diabetes mellitus attending the Endocrine clinic of our institute between January 2002 and December 2008 were screened using anti tissue transglutaminase antibodies (tTGAb), and those positive were subjected to duodenal biopsy. Clinical profile of these patients was recorded. RESULTS: Out of 189 patients of type 1 diabetes mellitus, 21 (11.1%) were diagnosed to have celiac disease on the basis of positive serology (tTGAb) and duodenal histology. The mean age at diagnosis of diabetes was 10.81 +/- 7.3 years and that of celiac disease was 13.74 +/- 5.71 years, with a difference of 5.18 +/- 4.75 years between the two. Only 2/21 patients with celiac disease had been diagnosed before detection of diabetes mellitus. Short stature was the commonest (52.3%) manifestation of celiac disease, followed by anemia (47.3), weight loss (42.8%), diarrhea (28.6%) and abdominal pain (14.2%). After initiating gluten free diet, 14/16 symptomatic patients had reversal of anemia, weight loss and diarrhea. Growth rate velocity improved from 2.3 +/- 1.0 cm/year to 5.5 +/- 2.4 cm/year in those with short stature. CONCLUSION: Celiac disease is highly prevalent in patients with type 1 diabetes mellitus (11.1%) and majority of them (90.5%) were diagnosed on screening. Routine screening is required for early diagnosis and combat associated co-morbidities. PMID- 21261731 TI - Clinical characteristics of TIMP2, MMP2, and MMP9 gene polymorphisms in colorectal cancer. AB - BACKGROUND AND AIM: Genetic variations and the expression profile of matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) are involved in the invasion and metastasis of colorectal cancer. METHODS: The gene profiles of TIMP2 and MMP were assayed from 333 colorectal cancer using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: TIMP2-418*G/*G, TIMP2 303*G/*G and MMP9-1562*C/*C were more frequent in patients than in controls (P = 0.020, P < 0.0001 and P < 0.044, respectively). Frequency of TIMP2-418*G/*G was higher in patients with metastasis than in those without metastasis, and that of TIMP2 303*G/*G was higher in patients with rectal cancer than in those with colon cancer (P = 0.008 and P =0.022, respectively). TIMP2 303*A/*A and MMP2-1575*G/*G were less frequent in patients than in controls (P = 0.001 and P = 0.005, respectively). The TIMP2-418*G303*G haplotype was more frequent (P < 0.0001) and MMP2-1575*G-735*C haplotype was less frequent in patients than in controls (P= 0.005). CONCLUSION: Specific single-nucleotide polymorphism in TIMP2 and MMP appeared to be associated with tumorigenesis and biological behavior in colorectal cancer, which is expected be further verified in a larger cohort in the future. PMID- 21261732 TI - Reduced small-intestinal injury induced by indomethacin in interleukin-17A deficient mice. AB - BACKGROUND AND AIMS: The pathogenesis of enteropathy induced by non-steroidal anti-inflammatory drugs (NSAIDs) is still unclear, and there are no established treatments. Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has been associated with the development of chronic inflammatory diseases, including autoimmune diseases. To define the role of IL-17A in small intestinal injury and inflammation, we studied the effects of indomethacin administration in mice with targeted deletions of the IL-17A gene. METHODS: Male C57BL/6 (wild-type) and homozygous IL-17A(-/-) C57BL/6 mice were subjected to this study. Indomethacin (10 mg/kg) was subcutaneously administered to induce small-intestinal damage. Indomethacin-induced lesions in the small intestine were evaluated by measuring the injured area and by histopathology. Also assessed were myeloperoxidase (MPO) activity, as an index of neutrophil accumulation, and intestinal mRNA expression for inflammatory cytokines. RESULTS: The area of macroscopic ulcerative lesions, the MPO activity and the mRNA expression of inflammatory-associated chemokines, such as keratinocyte chemoattractant (KC), monocyte chemotactic protein-1 (MCP 1), and granulocyte-colony stimulating factor (G-CSF), were significantly increased in indomethacin-treated groups compared with the sham groups. The development of intestinal lesions by indomethacin was inhibited in IL-17A(-/-) mice compared with wild-type mice, together with significant suppression of the increased levels of MPO activities and KC, MCP-1, and G-CSF levels. CONCLUSION: These findings demonstrate that IL-17A contributes to the development of indomethacin-induced small intestinal injury through upregulation of G-CSF, KC, and MCP-1. IL-17A might be a promising new therapeutic target to treat NSAID induced enteritis. PMID- 21261733 TI - Effect of Lactobacillus plantarum LP-Onlly on gut flora and colitis in interleukin-10 knockout mice. AB - BACKGROUND AND AIM: Probiotics are used in the therapy of inflammatory bowel disease. This study aimed to determine the effects of probiotic Lactobacillus plantarum LP-Onlly (LP) on gut flora and colitis in interleukin-10 knockout (IL 10(-/-) ) mice, a model of spontaneous colitis. METHODS: IL-10(-/-) and wild-type mice were used at 8 weeks of age and LP by gavage was administered at a dose of 10(9) cells/day per mice for 4 weeks. Mice were maintained for another one week without LP treatment. The colonic tissues were collected for histological and ultrastructural analysis at death after 4 weeks treatment of LP, and the feces were collected at 1-week intervals throughout the experiment for the analysis of gut flora and LP using selective culture-based techniques. RESULTS: Compared with control mice, IL-10(-/-) mice developed a severe intestinal inflammation and tissue damage, and had an abnormal composition of gut microflora. LP administration attenuated colitis with the decreased inflammatory scoring and histological injury in the colon of IL-10(-/-) mice. In addition, LP administration increased the numbers of beneficial total bifidobacteria and lactobacilli, and decreased the numbers of potential pathogenic enterococci and Clostridium perfringens, although the decrease of coliforms was not significant after LP treatment in IL-10(-/-) mice. CONCLUSIONS: Oral administration of LP was effective in the treatment of colitis, with the direct modification of gut microflora in IL-10(-/-) mice. This probiotic strain could be used as a potential adjuvant in the therapy of inflammatory bowel disease, although further studies are required in human. PMID- 21261734 TI - Education and imaging: gastrointestinal: palmar metastasis in undifferentiated colonic carcinoma. PMID- 21261735 TI - Education and imaging: gastrointestinal: Inferior vena cava filter migration causing hematemesis. PMID- 21261736 TI - Education and imaging: gastrointestinal: colonic intusscusception to the rectum with a sigmoid colon cancer as a lead point. PMID- 21261737 TI - Education and imaging: hepatobiliary and pancreatic: focal steatohepatitis mimicking a metastasis. PMID- 21261738 TI - Education and imaging: hepatobiliary and pancreatic: focal nodular hyperplasia. PMID- 21261739 TI - Pediatric Allergy and Immunology--our journal is moving forward. PMID- 21261741 TI - Chronic spontaneous urticaria in children: itching for insight. AB - While there is increasing information about the pathogenesis and treatment of chronic spontaneous urticaria (csU) in adults, there is little published information about csU in children. Consequently, most of the recommendations contained in current guidelines for the prevention and treatment of csU in infants and children is based on extrapolation of data obtained in adults. To rectify this, this review points out critical gaps in our knowledge and suggests strategies which may help us to improve our understanding of this condition. How common is csU in children? What do we know about its clinical presentation and the presence of useful biomarkers? What are its common underlying causes? What is the course of csU in children? How does csU affect the everyday life of children? What treatment options are available for children? To answer these questions, two separate types of information are required. The first is information about the prevalence of the condition in the community at large and how csU affects the everyday life of both the child-patient and the parent or carer. Because most csU cases in infants and children do not come to specialists but are treated by general practitioners or by parents using over-the-counter medications, these questions may be answered only by general population surveys or schools programmes. The second is clinical information including family history and disease presentation, the presence of biomarkers and comorbidities, objective measures of severity, frequency and duration of exacerbations, the response to therapy and the time to remission. Targeted questionnaires need to be developed and validated for these investigations. This has already begun in Germany with the establishment of the CU-KID Netzwerk (Email address: cu-kid@charite.de), the aim of which is to identify clinical centres and colleagues who treat children with urticaria and to initiate the information gathering described above. PMID- 21261742 TI - Is Johnny wheezing? Parent-child agreement in the Childhood Asthma in America survey. AB - We compared responses of children and parents to determine their level of agreement in a national, population-based survey regarding asthma-related health of US children. A telephone-based survey was conducted in 2004 among a national probability sample of children with current asthma in the United States. To compare responses between parent-child pairs, a subset of 284 children aged 10-15 were interviewed in addition to the parents. This survey collected data on asthma symptom prevalence, physical activity limitations and impact of exercise on asthma, and asthma management including medication use. Paired responses were compared using the kappa (kappa) statistic. Overall, parents of 10-15-yr-olds underestimated the burden of asthma experienced by their children, especially the effects on physical activity. More than half (58%) of children replied that exercise was a trigger for their asthma compared to only 35% of parents (kappa 0.23). Children were more likely than parents to mention activity limitations, specifically avoiding physical exertion (63% vs. 49%-kappa 0.004). Prevalence of symptoms was also underreported by parents relative to children, particularly breathing problems (41% vs. 67%-kappa 0.16) and cough (45% vs. 64%-kappa 0.14). Maintenance therapy use in the past 4 weeks was reported by 35% of children, whereas 44% of parents believed their children had used maintenance therapy (kappa 0.47). Relative to children's self-report, parents underestimated avoidance tactics used by their children with asthma, including exercise and physical activity self-limitation to prevent the onset or worsening of asthma symptoms. Parents also underreported asthma symptoms of their children aged 10-15 years old and were discordant with their children regarding medication use. Increasing regular communication about asthma between child, parent, and physician is warranted to improve asthma control and overall health. PMID- 21261743 TI - Childhood acute urticaria in northern and southern Europe shows a similar epidemiological pattern and significant meteorological influences. AB - Acute urticaria (AU) is a common condition that often presents in childhood. Although there is a general perception of cyclic annual trends in AU, no one has tried to identify any seasonal variation on its prevalence and incidence, associate environmental influences and impute geographic, ethnic, or even genetic features that may contribute to its onset. We aimed to analyze the influence of climate and geographic parameters on annual fluctuation of AU cases referred to the Emergency Departments (EDs) of Norwich (UK) and Heraklion (Crete, Greece), compare all identifiable potential triggers and severity, and calculate the prevalence and incidence of AU. Record-based data of all children up to 14 yr of age referred to both EDs between June 2005 and May 2007 were examined retrospectively. Demographic characteristics and any potential identifiable triggers of AU were recorded and compared. Poisson's regression was utilized to examine any influence of meteorological parameters on AU incidence. Edwards' test for seasonality was applied to identify any significant seasonal trend of the AU incidence within each city. Seven hundred and twenty-nine AU cases were identified (324 in Norwich and 405 in Heraklion), among 56,624 total referrals (28,931 and 27,693 cases, respectively). Respiratory infections were found to be the most commonly associated potential triggers of AU and food allergens the least. AU cases and incidence rates in both cities were equally distributed during the study period. A non-significant seasonal trend in AU incidence (October, April-May) was observed in Norwich, in contrast to a significant seasonal pattern (December, February-May) of AU in Heraklion. Temperature was inversely associated with AU incidence, while the statistically significant effect of relative humidity varied. Acute childhood urticaria shows a similar epidemiological pattern in northern and southern Europe regardless of the expected differences in genetic, geographic, and environmental background. Temperature and humidity are correlated with AU incidence. Seasonality of several acute respiratory viral infections, the most prominent associated trigger of AU, coincides with the observed AU seasonality, suggesting a potential linkage. However, this needs to be elucidated from larger epidemiological studies. PMID- 21261744 TI - Traffic-related air pollution and dry night cough during the first 8 years of life. PMID- 21261745 TI - Validation of ARIA (Allergic Rhinitis and its Impact on Asthma) classification in a pediatric population: the PEDRIAL study. AB - Allergic rhinitis (AR) is the commonest chronic disease in children. Allergic Rhinitis and its Impact on Asthma (ARIA) classification based on symptom duration (intermittent vs. persistent) and severity (mild vs. moderate/severe) has not been yet validated in children. Thus our objective was to validate ARIA classification in children, after determining the severity and duration of AR in a pediatric population, using ARIA definitions. Children aged 6-12 with a diagnosis of AR were included in an observational, cross-sectional, multicenter study. Patients were classified according to ARIA guidelines. AR symptoms were assessed using the Total Four Symptoms Score (T4SS). Severity was also evaluated by the patient using a visual analogue scale (VAS). Comparisons were made by means of a statistical analysis. One thousand two hundred and seventy-five children from 271 centers were included. Among them, 59.5% had intermittent and 40.5% persistent AR, while 60.7% seasonal and 39.3% perennial according to dated classification, with significant differences existing between one classification and another; 89.7% had moderate/severe rhinitis. Significantly higher T4SS and VAS scores were obtained in moderate/severe compared to mild AR. In our experience, the current ARIA classification can be considered a valid tool also in children from 6- to 12-yr old. PMID- 21261746 TI - Association of Blattella germanica sensitization with atopic diseases in pediatric allergic patients. AB - BACKGROUND: The extent to which the sensitization to the German cockroach Blattella germanica (BG) affects onset/presence of rhinoconjunctivitis (RC) in children is unknown. OBJECTIVES: The present work was aimed to assess the prevalence of BG sensitization in an outpatient pediatric population from an allergy clinic, the association with allergic diseases, and the effect of age in children with allergic sensitization. METHODS: Five hundred and four consecutive children with at least one positive skin test to a panel of 17 food and inhalant allergens, including BG, and with personal history of atopic diseases, were enrolled in an Allergy Unit of Palermo, Mediterranean area of Southern Italy. A questionnaire was administered to obtain data on epidemiologic and clinical characteristics. Atopy index was computed as the number of the individual positive skin prick tests. Logistic regression was used to estimate the associations between age classes and BG sensitization and RC, as well as the population-attributable risk (PAR) for RC. RESULTS: Prevalence of BG sensitization was 10.5% (5.2% and 15.8% in lower and upper age classes respectively, p=0.0001). Atopy index significantly increased from the lower to the higher age class (p<0.0001). The older age class (OR 3.12; 95% CI 1.57-6.19) and a higher atopy index (OR 37.16; 95% CI 5.04-274.13) were recognized as main risks factors for BG sensitization. CONCLUSION: In the upper age class, the PAR of BG sensitization for RC was 20.6%. BG sensitization increases in the higher ages, along with atopic index, and BG sensitization is associated with rhinoconjunctivis in older allergic children. PMID- 21261747 TI - Instrumental analysis of the pattern of improvement and that of recurrence of melasma in Thai females treated with Kligman-Willis triple combination therapy: confirmation by using its two different formulae. AB - BACKGROUND: Melasma is common among females. At present, its most reliable topical treatment is the Kligman-Willis formula. OBJECTIVES: To evaluate objectively the pattern of pigmentation improvement and recurrence. METHODS: Thirty-four Thai females with melasma showing similar lesions on both cheeks were randomly assigned to 8-week daily treatment with either one of two different versions of the formula together with strict sun protection. They were objectively evaluated instrumentally with a Mexameter(r) every 2 weeks, and were followed up for the subsequent 40 weeks. RESULTS: Thirty of 34 subjects who completed their 8-week treatment displayed a similar improvement pattern with either formulae. All expressed satisfaction with the results of the treatment. Instrumental evaluation detected that the pigmentation reached a nadir after 6 weeks, regardless of the formulae. Twenty-one subjects, who were further followed up, exhibited mild relapse within 2 months after finishing the treatment. Yet, their pigmentation levels remained significantly lower than those before treatment. Both formulae increased transepidermal water loss and skin surface hydration during the treatment period. CONCLUSION: Melasma in Thai females responded well to the Kligman-Willis formula. A relapse that was detected with the instrumental measurement after treatment discontinuation suggests the necessity to continue even intermittent treatment after attaining therapeutic success. PMID- 21261748 TI - Innate immunity: a crucial target for zinc in the treatment of inflammatory dermatosis. AB - BACKGROUND: Zinc is a cofactor of many metalloenzymes explaining that it plays a crucial role in cell proliferation and also in the regulation of immune system. It has been shown by different data that it could play a crucial role not only in the regulation of adaptative immunity but also in innate immunity which plays a crucial role in skin. OBJECTIVES: In this article, we proposed an overview of published information in the literature, on zinc and cutaneous innate immunity. METHODS: At the basic level, we gave a synthesis of data related to zinc's cutaneous targets in innate immunity, and then at clinical level selected studies on cutaneous disorders where zinc could be a therapeutic approach and discussed the targets of zinc in these pathologies. RESULTS/CONCLUSION: The specific activity of zinc salts on the innate immunity of the skin with different targets can explain why zinc is more specifically involved in cutaneous affection in which inflammation plays a particular important role, such as inflammatory acne, acrodermatitis enteropathica, hidradenitis suppurativa, folliculitis decalvans. PMID- 21261749 TI - Topical cidofovir for viral warts in children. PMID- 21261750 TI - Non-attendance rate in a Danish University Clinic of Dermatology. AB - AIM: To clarify the rate of non-attendance (NA) in an out-patient clinic. METHODS: Attendance lists of 3592 patients were collected daily from 21 July-21 August and 21 October-21 November, 2009. NA patients were contacted to determine extenuations. To study NA in relation to diagnosis and age, a control group of patients who attended before or after a NA was established. Furthermore, two time periods from 8:00-11:30 AM and 11:30 AM-3:00 pm were compared. RESULTS: In total, 13% NA gave no cancellation (54.2% females and 45.8% males). Divided into age groups, 496 patients 0-25 years old had appointments, but 87 (18.6%) showed NA. In the 26-65 years old, 2188 patients were planned, but 313 (14.1%) showed NA. Over 65 years old, 878 patients were planned, but 69 patients (7.9%) showed NA. NA was higher (P < 0.05) in patients 0-25 years old in comparison with the other age groups. Diagnoses had no influence on the rate of NA (P > 0.05), neither had seasons nor time of the day. The main explanations reported by the NA were: forgetfulness (34.3%), erroneous scheduling (27.7%) and various reasons (38.0%). However, 18.5% had shown NA before while 17.1% were NA first timers. CONCLUSION: The NA rate 13% of 3592 patients was mostly patient-related. Erroneous scheduling was estimated to be 3.6%. NA was more frequent among young patients. NA rate is small in comparison with non-adherence to medicines, however, of major practical and economic consequence for the health system. SMS or e-mail notification and improved scheduling are potential actions to improve NA in the routine. PMID- 21261751 TI - Skin ageing. AB - Similar to the entire organism, skin is subject to an unpreventable intrinsic ageing process. Additionally, skin ageing is also influenced by exogenous factors. Ultraviolet radiation in particular results in premature skin ageing, also referred to as extrinsic skin ageing or photoageing, which is the main cause of the changes associated with the ageing process in sun-exposed areas. Despite their morphological and pathophysiological differences, intrinsic and extrinsic ageing share several molecular similarities. The formation of reactive oxygen species and the induction of matrix metalloproteinases reflect the central aspects of skin ageing. Accumulation of fragmented collagen fibrils prevents neocollagenesis and accounts for the further degradation of the extracellular matrix by means of positive feedback regulation. The importance of extrinsic factors in skin ageing and the detection of its mechanisms have furthered the development of various therapeutic and preventive strategies. PMID- 21261752 TI - Effect of gossypol on blood serum parameters and small intestinal morphology of male broilers. AB - Summary In the present study, the effect of varied gossypol (GOSS) amounts was investigated on blood parameters, the digesta pH, villus height, villus width, and crypta depth, width of duodenum, jejunum and ileum. A total of one hundred eight Ross 308 male broilers were fed with four diet groups as follows: no gossypol (control), gossypol rate 62 mg/kg (GOSS 62), gossypol rate 124 mg/kg (GOSS 124) and gossypol rate 186 mg/kg (GOSS 186). The effect of used gossypol amounts on blood parameters was not found to be statistically significant. Increases in digesta pH values of jejunum and ileum with GOSS 186 diet group were found to be statistically significant. The results also indicated that, except duodenum villus height, there was no statistical difference effect of GOSS on epithelial cell thickness, villus height, villus width, crypta depth and crypta width of the duodenum, jejunum and ileum. There have been no clearly negative effects of higher gossypol amounts up to 186 mg/kg diets on these parameters. PMID- 21261753 TI - Piroxicam and meloxicam ameliorate hepatic oxidative stress and protein carbonylation in Kupffer and sinusoidal endothelial cells promoted by ischemia reperfusion injury. AB - The present study was aimed to assess the effect of protein carbonylation (PC) in hepatic cells and effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on indicators of tissue damage induced by liver ischemia-reperfusion injury (LIRI). Warm ischemia was performed by partial vascular occlusion during 90 min in Wistar rats. In serum, we determined the catalytic activity of Alanine Aminotransferase, Aspartate Aminotransferase, Lacticate Dehydrogenase, and Ornithine Carbamoyltransferase. In liver samples, we studied cellular alterations by means of histologic studies, lipid peroxidation, PC by immunohistochemistry, apoptosis and reactive oxygen species in bile by electron paramagnetic resonance. Based on PC data, sinusoidal endothelial cells (SEC) and Kupffer cells (KC) were the first to exhibit LIRI-associated oxidative damage and prior to parenchymal cells. Administration of piroxicam or meloxicam during the pre-ischemic period produced a highly significant decrease in all studied injury indicators. No significant differences were revealed between the protective action of the two drugs. The data shown here suggest the potential use of NSAIDs such as piroxicam or meloxicam in minimizing ischemic event-caused damage in liver. We also propose that PC may be employed as an adequate tool to assess tissue damage after oxidative stress. PMID- 21261754 TI - Abstracts of the 44th Annual Conference of Physiology and Pathology of Reproduction and 36th Mutual Conference on Veterinary and Human Reproductive Medicine. February 16-19, 2011. Hannover, Germany. PMID- 21261755 TI - Proneurotrophin-3 may induce Sortilin-dependent death in inner ear neurons. AB - The precursor of the neurotrophin (NT) nerve growth factor (NGF) (proNGF) serves physiological functions distinct from its mature counterpart as it induces neuronal apoptosis through activation of a p75 NT receptor (p75(NTR) ) and Sortilin death-signalling complex. The NTs brain-derived nerve growth factor (BDNF) and NT3 provide essential trophic support to auditory neurons. Injury to the NT-secreting cells in the inner ear is followed by irreversible degeneration of spiral ganglion neurons with consequences such as impaired hearing or deafness. Lack of mature NTs may explain the degeneration of spiral ganglion neurons, but another mechanism is possible as unprocessed proNTs released from the injured cells may contribute to the degeneration by induction of apoptosis. Recent studies demonstrate that proBDNF, like proNGF, is a potent inducer of Sortilin:p75(NTR) -mediated apoptosis. In addition, a coincident upregulation of proBDNF and p75(NTR) has been observed in degenerating spiral ganglion neurons, but the Sortilin expression in the inner ear is unresolved. Here we demonstrate that Sortilin and p75(NTR) are coexpressed in neurons of the neonatal inner ear. Furthermore, we establish that proNT3 exhibits high-affinity binding to Sortilin and has the capacity to enhance cell surface Sortilin:p75(NTR) complex formation as well as to mediate apoptosis in neurons coexpressing p75(NTR) and Sortilin. Based on the examination of wildtype and Sortilin-deficient mouse embryos, Sortilin does not significantly influence the developmental selection of spiral ganglion neurons. However, our results suggest that proNT3 and proBDNF may play important roles in the response to noise-induced injuries or ototoxic damage via the Sortilin:p75(NTR) death-signalling complex. PMID- 21261756 TI - Intrinsic phototransduction persists in melanopsin-expressing ganglion cells lacking diacylglycerol-sensitive TRPC subunits. AB - In mammals, intrinsically photosensitive retinal ganglion cells (ipRGCs) mediate various non-image-forming photic responses, such as circadian photoentrainment, pupillary light reflex and pineal melatonin suppression. ipRGCs directly respond to environmental light by activation of the photopigment melanopsin followed by the opening of an unidentified cation-selective channel. Studies in heterologous expression systems and in the native retina have strongly implicated diacylglycerol-sensitive transient receptor potential channels containing TRPC3, TRPC6 and TRPC7 subunits in melanopsin-evoked depolarization. Here we show that melanopsin-evoked electrical responses largely persist in ipRGCs recorded from early postnatal (P6-P8) and adult (P22-P50) mice lacking expression of functional TRPC3, TRPC6 or TRPC7 subunits. Multielectrode array (MEA) recordings performed at P6-P8 stages under conditions that prevent influences from rod/cone photoreceptors show comparable light sensitivity for the melanopsin-evoked responses in these mutant mouse lines in comparison to wild-type (WT) mice. Patch clamp recordings from adult mouse ipRGCs lacking TRPC3 or TRPC7 subunits show intrinsic light-evoked responses equivalent to those recorded in WT mice. Persistence of intrinsic light-evoked responses was also noted in ipRGCs lacking TRPC6 subunits, although with significantly smaller magnitudes. These results demonstrate that the melanopsin-evoked depolarization in ipRGCs is not mediated by either TRPC3, TRPC6 or TRPC7 channel subunits alone. They also suggest that the melanopsin signaling pathway includes TRPC6-containing heteromeric channels in mature retinas. PMID- 21261757 TI - Modulation of sensory and motor cortex activity during speech preparation. AB - Previous studies have shown that speaking affects auditory and motor cortex responsiveness, which may reflect the influence of motor efference copy. If motor efference copy is involved, it would also likely influence auditory and motor cortical activity when preparing to speak. We tested this hypothesis by using auditory event-related potentials and transcranial magnetic stimulation (TMS) of the motor cortex. In the speech condition subjects were visually cued to prepare a vocal response to a subsequent target, which was compared to a control condition without speech preparation. Auditory and motor cortex responsiveness at variable times between the cue and target were probed with an acoustic stimulus (Experiment 1, tone or consonant-vowels) or motor cortical TMS (Experiment 2). Acoustic probes delivered shortly before targets elicited a fronto-central negative potential in the speech condition. Current density analysis showed that auditory cortical activity was attenuated at the beginning of the slow potential in the speech condition. Sensory potentials in response to probes had shorter latencies (N100) and larger amplitudes (P200) when consonant-vowels matched the sound of cue words. Motor cortex excitability was greater in the speech than in the control condition at all time points before picture onset. The results suggest that speech preparation induces top-down regulation of sensory and motor cortex responsiveness, with different time courses for auditory and motor systems. PMID- 21261758 TI - Common biology of craving across legal and illegal drugs - a quantitative meta analysis of cue-reactivity brain response. AB - The present quantitative meta-analysis set out to test whether cue-reactivity responses in humans differ across drugs of abuse and whether these responses constitute the biological basis of drug craving as a core psychopathology of addiction. By means of activation likelihood estimation, we investigated the concurrence of brain regions activated by cue-induced craving paradigms across studies on nicotine, alcohol and cocaine addicts. Furthermore, we analysed the concurrence of brain regions positively correlated with self-reported craving in nicotine and alcohol studies. We found direct overlap between nicotine, alcohol and cocaine cue reactivity in the ventral striatum. In addition, regions of close proximity were observed in the anterior cingulate cortex (ACC; nicotine and cocaine) and amygdala (alcohol, nicotine and cocaine). Brain regions of concurrence in drug cue-reactivity paradigms that overlapped with brain regions of concurrence in self-reported craving correlations were found in the ACC, ventral striatum and right pallidum (for alcohol). This first quantitative meta analysis on drug cue reactivity identifies brain regions underlying nicotine, alcohol and cocaine dependency, i.e. the ventral striatum. The ACC, right pallidum and ventral striatum were related to drug cue reactivity as well as self reported craving, suggesting that this set of brain regions constitutes the core circuit of drug craving in nicotine and alcohol addiction. PMID- 21261760 TI - When to initiate and discontinue biologic treatments for rheumatoid arthritis? AB - The introduction of biologic therapies heralded a new era in the treatment for chronic inflammatory autoimmune diseases of which rheumatoid arthritis is one of the most prevalent. From a scientific point of view, these therapies demonstrated that the targeting of individual cytokines or cell-surface markers is a very effective approach. For the physician, the appropriate selection of patients in whom these therapies should be initiated is critical, as is the even more contentious issue of whether these therapies can or should be discontinued in selected patients with excellent clinical responses. Whereas the former issue has been addressed in a large number of clinical trials and observational studies, the latter remains poorly investigated and is currently the subject of further study. PMID- 21261761 TI - The sucrose transporter family in Populus: the importance of a tonoplast PtaSUT4 to biomass and carbon partitioning. AB - Plasma membrane, proton-coupled Group II sucrose symporters (SUT) mediate apoplastic phloem loading and sucrose efflux from source leaves in Arabidopsis and agricultural crop species that have been studied to date. We now report that the most abundantly expressed SUT isoform in Populus tremula*alba, PtaSUT4, is a tonoplast (Group IV) symporter. PtaSUT4 transcripts were readily detected in conducting as well as mesophyll cells in stems and source leaves. In comparison, Group II orthologs PtaSUT1 and PtaSUT3 were very weakly expressed in leaves. Both Group II and Group IV SUT genes were expressed in secondary stem xylem of Populus. Transgenic poplars with RNAi-suppressed PtaSUT4 exhibited increased leaf to-stem biomass ratios, elevated sucrose content in source leaves and stems, and altered phenylpropanoid metabolism. Transcript abundance of several carbohydrate active enzymes and phenylalanine ammonia-lyases was also altered in transgenic source leaves. Nitrogen-limitation led to a down-regulation of vacuolar invertases in all plants, which resulted in an augmentation of sucrose pooling and hexose depletion in source leaves and secondary xylem of the transgenic plants. These results are consistent with a major role for PtaSUT4 in orchestrating the intracellular partitioning, and consequently, the efflux of sucrose from source leaves and the utilization of sucrose by lateral and terminal sinks. Our findings also support the idea that PtaSUT4 modulates sucrose efflux and utilization in concert with plant N-status. PMID- 21261759 TI - Activation of D2-like receptors in rat ventral tegmental area inhibits cocaine reinstated drug-seeking behavior. AB - Relapse is a hallmark of cocaine addiction. Cocaine-induced neuroplastic changes in the mesocorticolimbic circuits critically contribute to this phenomenon. Pre clinical evidence indicates that relapse to cocaine-seeking behavior depends on activation of dopamine neurons in the ventral tegmental area. Thus, blocking such activation may inhibit relapse. Because the activity of dopamine neurons is regulated by D2-like autoreceptors expressed on somatodendritic sites, this study, using the reinstatement model, aimed to determine whether activation of D2 like receptors in the ventral tegmental area can inhibit cocaine-induced reinstatement of extinguished cocaine-seeking behavior. Rats were trained to self administer i.v. cocaine (0.25 mg/infusion) under a modified fixed-ratio 5 schedule. After such behavior was well learned, rats went through extinction training to extinguish cocaine-seeking behavior. The effect of quinpirole, a selective D2-like receptor agonist microinjected into the ventral tegmental area, on cocaine-induced reinstatement was then assessed. Quinpirole (0-3.2 MUg/side) dose-dependently decreased cocaine-induced reinstatement and such effects were reversed by the selective D2-like receptor antagonist eticlopride when co microinjected with quinpirole into the ventral tegmental area. The effect appeared to be specific to the ventral tegmental area because quinpirole microinjected into the substantia nigra had no effect. Because D2-like receptors are expressed on rat ventral tegmental area dopamine neurons projecting to the pre-frontal cortex and nucleus accumbens, our data suggest that these dopamine circuits may play a critical role in cocaine-induced reinstatement. The role of potential changes in D2-like receptors and related signaling molecules of dopamine neurons in the vulnerability to relapse was discussed. PMID- 21261762 TI - AtNUFIP, an essential protein for plant development, reveals the impact of snoRNA gene organisation on the assembly of snoRNPs and rRNA methylation in Arabidopsis thaliana. AB - In all eukaryotes, C/D small nucleolar ribonucleoproteins (C/D snoRNPs) are essential for methylation and processing of ribosomal RNAs. They consist of a box C/D small nucleolar RNA (C/D snoRNA) associated with four highly conserved nucleolar proteins. Recent data in HeLa cells and yeast have revealed that assembly of these snoRNPs is directed by NUFIP protein and other auxiliary factors. Nevertheless, the precise function and biological importance of NUFIP and the other assembly factors remains unknown. In plants, few studies have focused on RNA methylation and snoRNP biogenesis. Here, we identify and characterise the AtNUFIP gene that directs assembly of C/D snoRNP. To elucidate the function of AtNUFIP in planta, we characterized atnufip mutants. These mutants are viable but have severe developmental phenotypes. Northern blot analysis of snoRNA accumulation in atnufip mutants revealed a specific degradation of C/D snoRNAs and this situation is correlated with a reduction in rRNA methylation. Remarkably, the impact of AtNUFIP depends on the structure of snoRNA genes: it is essential for the accumulation of those C/D snoRNAs encoded by polycistronic genes, but not by monocistronic or tsnoRNA genes. We propose that AtNUFIP controls the kinetics of C/D snoRNP assembly on nascent precursors to overcome snoRNA degradation of aberrant RNPs. Finally, we show that AtNUFIP has broader RNP targets, controlling the accumulation of scaRNAs that direct methylation of spliceosomal snRNA in Cajal bodies. PMID- 21261763 TI - A soybean beta-expansin gene GmEXPB2 intrinsically involved in root system architecture responses to abiotic stresses. AB - Root system architecture responds plastically to some abiotic stresses, including phosphorus (P), iron (Fe) and water deficiency, but its response mechanism is still unclear. We cloned and characterized a vegetative beta-expansin gene, GmEXPB2, from a Pi starvation-induced soybean cDNA library. Transient expression of 35S::GmEXPB2-GFP in onion epidermal cells verified that GmEXPB2 is a secretory protein located on the cell wall. GmEXPB2 was found to be primarily expressed in roots, and was highly induced by Pi starvation, and the induction pattern was confirmed by GUS staining in transgenic soybean hairy roots. Results from intact soybean composite plants either over-expressing GmEXPB2 or containing knockdown constructs, showed that GmEXPB2 is involved in hairy root elongation, and subsequently affects plant growth and P uptake, especially at low P levels. The results from a heterogeneous transformation system indicated that over-expressing GmEXPB2 in Arabidopsis increased root cell division and elongation, and enhanced plant growth and P uptake at both low and high P levels. Furthermore, we found that, in addition to Pi starvation, GmEXPB2 was also induced by Fe and mild water deficiencies. Taken together, our results suggest that GmEXPB2 is a critical root beta-expansin gene that is intrinsically involved in root system architecture responses to some abiotic stresses, including P, Fe and water deficiency. In the case of Pi starvation responses, GmEXPB2 may enhance both P efficiency and P responsiveness by regulating adaptive changes of the root system architecture. This finding has great agricultural potential for improving crop P uptake on both low-P and P-fertilized soils. PMID- 21261764 TI - Why replication is important in landscape genetics: American black bear in the Rocky Mountains. AB - We investigated how landscape features influence gene flow of black bears by testing the relative support for 36 alternative landscape resistance hypotheses, including isolation by distance (IBD) in each of 12 study areas in the north central U.S. Rocky Mountains. The study areas all contained the same basic elements, but differed in extent of forest fragmentation, altitude, variation in elevation and road coverage. In all but one of the study areas, isolation by landscape resistance was more supported than IBD suggesting gene flow is likely influenced by elevation, forest cover, and roads. However, the landscape features influencing gene flow varied among study areas. Using subsets of loci usually gave models with the very similar landscape features influencing gene flow as with all loci, suggesting the landscape features influencing gene flow were correctly identified. To test if the cause of the variability of supported landscape features in study areas resulted from landscape differences among study areas, we conducted a limiting factor analysis. We found that features were supported in landscape models only when the features were highly variable. This is perhaps not surprising but suggests an important cautionary note - that if landscape features are not found to influence gene flow, researchers should not automatically conclude that the features are unimportant to the species' movement and gene flow. Failure to investigate multiple study areas that have a range of variability in landscape features could cause misleading inferences about which landscape features generally limit gene flow. This could lead to potentially erroneous identification of corridors and barriers if models are transferred between areas with different landscape characteristics. PMID- 21261765 TI - Assessing the complex architecture of polygenic traits in diverged yeast populations. AB - Phenotypic variation arising from populations adapting to different niches has a complex underlying genetic architecture. A major challenge in modern biology is to identify the causative variants driving phenotypic variation. Recently, the baker's yeast, Saccharomyces cerevisiae has emerged as a powerful model for dissecting complex traits. However, past studies using a laboratory strain were unable to reveal the complete architecture of polygenic traits. Here, we present a linkage study using 576 recombinant strains obtained from crosses of isolates representative of the major lineages. The meiotic recombinational landscape appears largely conserved between populations; however, strain-specific hotspots were also detected. Quantitative measurements of growth in 23 distinct ecologically relevant environments show that our recombinant population recapitulates most of the standing phenotypic variation described in the species. Linkage analysis detected an average of 6.3 distinct QTLs for each condition tested in all crosses, explaining on average 39% of the phenotypic variation. The QTLs detected are not constrained to a small number of loci, and the majority are specific to a single cross-combination and to a specific environment. Moreover, crosses between strains of similar phenotypes generate greater variation in the offspring, suggesting the presence of many antagonistic alleles and epistatic interactions. We found that subtelomeric regions play a key role in defining individual quantitative variation, emphasizing the importance of the adaptive nature of these regions in natural populations. This set of recombinant strains is a powerful tool for investigating the complex architecture of polygenic traits. PMID- 21261766 TI - Temporal isolation explains host-related genetic differentiation in a group of widespread mycoparasitic fungi. AB - Understanding the mechanisms responsible for divergence and specialization of pathogens on different hosts is of fundamental importance, especially in the context of the emergence of new diseases via host shifts. Temporal isolation has been reported in a few plants and parasites, but is probably one of the least studied speciation processes. We studied whether temporal isolation could be responsible for the maintenance of genetic differentiation among sympatric populations of Ampelomyces, widespread intracellular mycoparasites of powdery mildew fungi, themselves plant pathogens. The timing of transmission of Ampelomyces depends on the life cycles of the powdery mildew species they parasitize. Internal transcribed spacer sequences and microsatellite markers showed that Ampelomyces populations found in apple powdery mildew (Podosphaera leucotricha) were genetically highly differentiated from other Ampelomyces populations sampled from several other powdery mildew species across Europe, infecting plant hosts other than apple. While P. leucotricha starts its life cycle early in spring, and the main apple powdery mildew epidemics occur before summer, the fungal hosts of the other Ampelomyces cause epidemics mainly in summer and autumn. When two powdery mildew species were experimentally exposed to Ampelomyces strains naturally occurring in P. leucotricha in spring, and to strains naturally present in other mycohost species in autumn, cross-infections always occurred. Thus, the host-related genetic differentiation in Ampelomyces cannot be explained by narrow physiological specialization, because Ampelomyces were able to infect powdery mildew species they were unlikely to have encountered in nature, but instead appears to result from temporal isolation. PMID- 21261767 TI - Motor disturbances during non-REM and REM sleep in narcolepsy-cataplexy: a video polysomnographic analysis. AB - Motor events during sleep can be frequently observed in patients with narcolepsy cataplexy. We hypothesized that increased motor events and related arousals contribute to sleep fragmentation in this disease. We aimed to perform a detailed whole-night video-polysomnographic analysis of all motor events during non-rapid eye movement and rapid eye movement sleep in a group of narcolepsy-cataplexy patients and matched controls, and to assess the association with arousals. Video polysomnographic registrations of six narcolepsy-cataplexy patients and six sex- and age-matched controls were analysed. Each motor event in the video was classified according to topography, number of involved body parts, duration and its association with arousals. The mean motor activity index was 59.9 +/- 23.0 h( 1) in patients with narcolepsy-cataplexy compared with 15.4 +/- 9.2 h(-1) in controls (P = 0.004). Distribution of motor events was similar in non-rapid eye movement and rapid eye movement sleep in the patient group (P = 0.219). In narcolepsy-cataplexy, motor events involved significantly more body parts (>= 2 body regions: 38.2 +/- 15.6 versus 14.9 +/- 10.0; P = 0.011). In addition, the proportion of motor events lasting longer than 1 s was higher in patients than controls (88% versus 44.4%; P < 0.001). Both total and motor activity-related arousal indices were increased in narcolepsy-cataplexy (total arousal index: 21.6 +/- 9.0 versus 8.7 +/- 3.5; P = 0.004; motor activity-related arousal index: 17.6 +/- 9.8 versus 5.9 +/- 2.3; P = 0.002). Motor activity and motor activity-related arousal indices are increased in both non-rapid eye movement and rapid eye movement sleep in narcolepsy-cataplexy compared with controls. This supports the concept of a general sleep motor dysregulation in narcolepsy-cataplexy, which potentially contributes to or even underlies sleep fragmentation in this disease. PMID- 21261768 TI - Sexual selection is positively associated with ecological generalism among agamid lizards. AB - Natural and sexual selection shape the evolution of species but the interplay between them is poorly understood. Two phylogenetic studies on birds have suggested that species with greater sexual dichromatism have a broader habitat use. We show that in agamid lizards, species with more elaborate secondary sexual traits are also ecologically more opportunistic. Species with greater dimorphism in head size and ornamentation have greater altitudinal range and broader habitat use, respectively, and species with greater sexual dichromatism have wider microhabitat use. Body size was positively associated with sexual and ecological generalism, but associations between ecological and sexual traits remained after accounting for body size. We suggest that sexual and natural selection may be linked either because sexual selection can promote generalism at the population level by favouring 'good genes', or because higher population densities may be associated with both stronger sexual selection and broader resource use. PMID- 21261769 TI - The evolution of parental care in stochastic environments. AB - Parental care is of fundamental importance to understanding reproductive strategies and allocation decisions. Here, we explore how parental care strategies evolve in variable environments. Using a set of life-history trait trade-offs, we explore the relative costs and benefits of parental care in stochastic environments. Specifically, we consider the cases in which environmental variability results in varying adult death rates, egg death rates, reproductive rate and carrying capacity. Using a measure of fitness appropriate for stochastic environments, we find that parental care has the potential to evolve over a wide range of life-history characteristics when the environment is variable. A variable environment that affects adult or egg death rates can either increase or decrease the fitness of care relative to that in a constant environment, depending on the specific costs of care. Variability that affects carrying capacity or adult reproductive rate has negligible effects on the fitness associated with care. Increasing parental care across different life history stages can increase fitness gains in variable environments. Costly investment in care is expected to affect the overall fitness benefits, the fitness optimum and rate of evolution of parental care. In general, we find that environmental variability, the life-history traits affected by such variability and the specific costs of care interact to determine whether care will be favoured in a variable environment and what levels of care will be selected. PMID- 21261770 TI - Rapid evolution of parasitoids when faced with the symbiont-mediated resistance of their hosts. AB - Insects harbour a wild diversity of symbionts that can spread and persist within populations by providing benefits to their host. The pea aphid Acyrthosiphon pisum maintains a facultative symbiosis with the bacterium Hamiltonella defensa, which provides enhanced resistance against the aphid parasitoid Aphidius ervi. Although the mechanisms associated with this symbiotic-mediated protection have been investigated thoroughly, little is known about its evolutionary effects on parasitoid populations. We used an experimental evolution procedure in which parasitoids were exposed either to highly resistant aphids harbouring the symbiont or to low innate resistant hosts free of H. defensa. Parasitoids exposed to H. defensa gained virulence over time, reaching the same parasitism rate as those exposed to low aphid innate resistance only. A fitness reduction was associated with this adaptation as the size of parasitoids exposed to H. defensa decreased through generations. This study highlighted the considerable role of symbionts in host-parasite co-evolutionary dynamics. PMID- 21261771 TI - Effective heritability of targets of sex-ratio selection under environmental sex determination. AB - Selection is expected to maintain primary sex ratios at an evolutionary equilibrium. In organisms with temperature-dependent sex determination (TSD), targets of sex-ratio selection include the thermal sensitivity of the sex determining pathway (hereafter, sex determination threshold) and nest-site choice. However, offspring sex may be canalized for nests located in thermally extreme environments; thus, genetic variance for the sex determination threshold is not expressed and is invisible to direct selection. The concept of 'effective heritability' accounts for this dependence and provides a more realistic prediction of the expected evolutionary response to selection in the wild. Past estimates of effective heritability of the sex determination threshold, which were derived from laboratory data, suggested that the potential for the sex determination threshold to evolve in the wild was extremely low. We re-evaluated original estimates of this parameter by analysing field-collected measures of nest temperatures, vegetation cover and clutch sex ratios from nests in a population of painted turtles (Chrysemys picta). We coupled these data with measurements of broad-sense heritability of the sex determination threshold in C. picta, using an experiment that splits clutches of eggs between a constant temperature (i.e. typical laboratory incubation) and a daily fluctuating temperature (i.e. similar to natural nests) with the same mean. We found that (i) the effective heritability of the sex determination threshold appears to have been historically underestimated and the effective heritability of nest-site choice has been overestimated and (ii) significant family-by-incubation treatment interaction exists for sex for C. picta between constant- and fluctuating temperature regimes. Our results suggest that the thermal sensitivity of the sex determining pathway may play a larger, more complex role in the microevolution of TSD than traditionally thought. PMID- 21261772 TI - Virulence evolution in response to anti-infection resistance: toxic food plants can select for virulent parasites of monarch butterflies. AB - Host resistance to parasites can come in two main forms: hosts may either reduce the probability of parasite infection (anti-infection resistance) or reduce parasite growth after infection has occurred (anti-growth resistance). Both resistance mechanisms are often imperfect, meaning that they do not fully prevent or clear infections. Theoretical work has suggested that imperfect anti-growth resistance can select for higher parasite virulence by favouring faster-growing and more virulent parasites that overcome this resistance. In contrast, imperfect anti-infection resistance is thought not to select for increased parasite virulence, because it is assumed that it reduces the number of hosts that become infected, but not the fitness of parasites in successfully infected hosts. Here, we develop a theoretical model to show that anti-infection resistance can in fact select for higher virulence when such resistance reduces the effective parasite dose that enters a host. Our model is based on a monarch butterfly-parasite system in which larval food plants confer resistance to the monarch host. We carried out an experiment and showed that this environmental resistance is most likely a form of anti-infection resistance, through which toxic food plants reduce the effective dose of parasites that initiates an infection. We used these results to build a mathematical model to investigate the evolutionary consequences of food plant-induced resistance. Our model shows that when the effective infectious dose is reduced, parasites can compensate by evolving a higher per-parasite growth rate, and consequently a higher intrinsic virulence. Our results are relevant to many insect host-parasite systems, in which larval food plants often confer imperfect anti-infection resistance. Our results also suggest that - for parasites where the infectious dose affects the within-host dynamics - vaccines that reduce the effective infectious dose can select for increased parasite virulence. PMID- 21261773 TI - Population divergence in chemical signals and the potential for premating isolation between islet- and mainland populations of the Skyros wall lizard (Podarcis gaigeae). AB - When sexually selected traits diverge because of different local selective environments, premating isolation might arise as a correlated response. However, sexually selected traits might also diverge by stochastic forces. Here, we show that odour-based mate preferences and scent composition have diverged between islet- and mainland populations of Skyros wall lizard, Podarcis gaigeae. We quantified the degree of scent-mediated premating isolation between populations. Islet lizards preferred scent from islet lizards, whereas the mainland populations were less discriminatory. The pheromone compositions differed more between islets than between islet- and mainland populations and did not differ significantly between mainland populations. There was a tendency for population divergence in pheromones to be positively correlated with neutral genetic divergence. This might indicate a role for genetic drift in evolutionary change in these signals and partial decoupling between signals and preferences. Our results suggest that chemical signals and associated mate preferences can diverge through stochastic and selective forces and influence premating isolation. PMID- 21261774 TI - Differences in bacterial diversity of host-associated populations of Phylloxera notabilis Pergande (Hemiptera: Phylloxeridae) in pecan and water hickory. AB - Host-associated differentiation (HAD) is the presence of genetically divergent, host-associated populations. It has been suggested that microbial symbionts of insect herbivores may play a role in HAD by allowing their insect hosts to use different plant species. The objective of this study was to document if host associated populations of Phylloxera notabilis Pergande (Hemiptera: Phylloxeridae) in pecan and water hickory corresponded with differences in the composition of their associated bacteria. To test this hypothesis, we characterized the symbionts present in P. notabilis associated with these two tree species through metagenomic analyses using 454 sequencing. Differences in bacterial diversity were found between P. notabilis populations associated with pecan and water hickory. The bacteria, Pantoea agglomerans and Serratia marcescens, were absent in the P. notabilis water hickory population, whereas both species accounted for more than 69.72% of bacterial abundance in the pecan population. PMID- 21261775 TI - Claudin-6 is of limited sensitivity and specificity for the diagnosis of atypical teratoid/rhabdoid tumors. AB - Recent gene expression microarray analyses have indicated that claudin-6 is specifically expressed in atypical teratoid rhabdoid tumors (AT/RTs), suggesting a role as a positive diagnostic marker in addition to SMARCB1 (INI1) loss, which is encountered in the majority of AT/RTs. In order to investigate the potential of claudin-6 as a diagnostic marker, expression was investigated in 59 AT/RTs and 60 other primary central nervous system (CNS) tumors, including primitive neuroectodermal tumors, medulloblastomas, choroid plexus tumors, and both pediatric and adult low- and high-grade gliomas using immunohistochemistry. Claudin-6 was expressed in 17/59 AT/RTs (29%), but also in a variety of other primary CNS tumors, including 60% of medulloblastomas and 21% of malignant gliomas. Even though high staining scores (2+ or 3+) were more often encountered in AT/RTs (Chi-square 4.177; P=0.041), the overall frequency of claudin-6 staining was not significantly higher in AT/RTs as compared with the other tumors (17/59 vs. 16/60; Chi-square=0.328; P=0.567). In a subgroup of 43 AT/RT patients, of which follow-up data were available, claudin-6 expression did not show any correlation with survival. In conclusion, claudin-6 immunohistochemistry is of limited sensitivity and specificity for the diagnosis of AT/RT and does not correlate with clinical behavior. PMID- 21261776 TI - Effect of porcelain-firing cycles and surface finishing on the marginal discrepancy of titanium copings. AB - PURPOSE: The aim of the study was to evaluate the effect of simulated porcelain firing cycles and surface finishing on the marginal fit of commercially pure titanium (Cp Ti) copings. MATERIALS AND METHODS: A machined stainless steel die system with standard 0.5-mm copings was fabricated. Wax patterns were prepared by pouring the molten wax on a two-part stainless steel die. Thirty specimens were cast in Cp Ti. These were divided into three groups with ten specimens in each group. Group 1 was treated with conventional cold working and later oxidized. Group 2 specimens were oxidized initially and then cold worked. Group 3 was heat treated in its original investment and later treated as in group 1. All specimens were later subjected to sequential simulated porcelain firing cycles, that is, oxidation, bonder, opaque, body, and glaze firing. Following the completion of each firing cycle, marginal discrepancy was measured in MUm using a traveling microscope. The obtained data were subjected to one-way analysis of variance (ANOVA) and Student's t-test. The statistical level of significance was set at 1%. RESULTS: The results showed that the mean and SD values (in MUm) were 55 +/- 2.6, 43 +/- 3.0, and 68 +/- 4.0 after oxidation for groups 1, 2, and 3, respectively. Mean and SD values (in MUm) after glaze firing were 76 +/- 3.9, 64 +/- 4.1, and 89 +/- 4.3 for groups 1, 2, and 3, respectively. The mean marginal opening was largest for group 3 specimens. One-way ANOVA showed the difference within the three groups was highly significant after oxidation (F-value 149.37 at p-value 0.0000) and glaze firing (F-value 82.43 at p-value 0.0000). CONCLUSIONS: (1) The Student's t-test values demonstrated that increased marginal openings of the specimens resulted after the sequential simulated porcelain firing cycles. (2) Marginal discrepancy values improved when the specimens were thermocycled prior to cold working. PMID- 21261777 TI - Effect of resin coating and chlorhexidine on the microleakage of two resin cements after storage. AB - PURPOSE: This study evaluated the effect of resin coating and chlorhexidine (CH) on microleakage of two resin cements (Panavia F2.0, Nexus 2) after water storage. MATERIALS AND METHODS: Class V cavities were prepared on the facial and lingual surfaces of 120 intact human molars with gingival margins placed 1 mm below the cementoenamel junction. Indirect composite inlays were fabricated. The specimens were randomly assigned into six groups (n = 40). Indirect composite inlays (Gradia) were cemented as follows: Group 1 (control): inlays were cemented with Panavia F2.0 according to the manufacturer's instructions. Group 2: the ED-primed (ED Primer, Kuraray Dental, Tokyo, Japan) dentin was coated with a resin layer before cementation of the inlays with Panavia F2.0. Group 3: a 2% CH solution was applied before bonding with Panavia F2.0. Group 4: after CH application, the primed dentin was coated with a resin layer before cementation with Panavia F2.0. Group 5: (control) after applying Optibond Solo Plus, the inlays were cemented with Nexus 2. Group 6: after etching, CH was applied, and cementation was performed similarly to group 5. Half the specimens in each group were stored in distilled water for 24 hours, while the other half were stored in distilled water for 6 months. After storage, the teeth were placed in 1% methylene blue dye for 24 hours, sectioned, and evaluated under a 20* stereomicroscope. Dye penetration was scored using 0 to 3 criteria. Data were analyzed using nonparametric tests. RESULTS: Resin coating of ED primer for Panavia F2.0 significantly reduced microleakage at the gingival margins after 6 months (p < 0.05). CH application in Panavia F2.0 did not lead to a significant difference in the microleakage at both margins, after 24 hours and 6 months (p > 0.05). The application of CH showed significantly less microleakage than that of the control group at the gingival margins of Nexus 2 after 6 months. In general, gingival margins showed more microleakage than occlusal margins. CONCLUSION: An additional resin layer applied to a self-etch cement can improve long-term dentinal sealing for indirect restorations, while CH cannot; however, CH reduces gingival microleakage in an etch-and-rinse cement after aging. PMID- 21261778 TI - Alveolar distraction osteogenesis of the severely atrophic anterior maxilla: surgical and prosthetic challenges. AB - Significant maxillary anterior osseous defects are considered contraindications for fixed partial dentures. This clinical report discusses the surgical and restorative treatment protocol of a patient who sustained trauma to the premaxilla and was treated by distraction osteogenesis to provide an adequate restorative platform for an implant-retained fixed prosthesis. PMID- 21261779 TI - Usage of spacers in respiratory laboratories and the delivered salbutamol dose of spacers available in Australia and New Zealand. AB - BACKGROUND AND OBJECTIVE: Purchase and disinfection costs together with medication delivery factors may influence the choice of drug delivery options. This study assessed salbutamol delivery habits used in respiratory laboratories and quantified the delivered salbutamol dose of locally available spacers. METHODS: An online survey was used to obtain data on disinfection processes, costs and delivery device choices. The delivered dose of six commercial spacers was assessed. Particle size distribution of salbutamol (Ventolin, GSK, 100ug/actuation) from six spacers of each type was measured by quantifying the amount of drug (ug) deposited on each stage of an Anderson Cascade Impactor (ACI) using UV spectrophotometry. Clinical conditions were simulated using a flow volume simulator (FVS) and delivery of salbutamol via a pressurized metered dose inhaler and spacer to a low-resistance filter was measured. RESULTS: Fifty survey responses were obtained, with 37 (74%) using >=1 type of spacer of which 92% processed single use spacers. The most commonly used spacers were Volumatic (n=24), Breath-a-tech (n=8) and Space Chamber (n=7). The median disinfection cost was $2.45. Delivered salbutamol dose varied significantly and ranged from 16.98 to 38.28 ug with the ACI and 22.56 to 58.82 ug with the FVS. Using the FVS, small volume spacers delivered similar doses (22.56 to 28.46 ug), while large-volume spacers delivery was more varied (24.31 to 58.82 ug). CONCLUSIONS: The majority of respiratory laboratories had not updated re-processing policies to comply with new regulations. The delivered salbutamol dose varied significantly and this might effect the choice of preferred spacer type. PMID- 21261780 TI - Regional ventilation distribution determined by electrical impedance tomography: reproducibility and effects of posture and chest plane. AB - BACKGROUND AND OBJECTIVE: Reliable assessment of regional lung ventilation and good reproducibility of electrical impedance tomography (EIT) data are the prerequisites for the future application of EIT in a clinical setting. The aims of our study were to determine (i) the reproducibility of repeated EIT measurements and (ii) the effect of the studied transverse chest plane on ventilation distribution in different postures. METHODS: Ten healthy adult subjects were studied in three postures on two separate days. EIT and spirometric data were obtained during tidal breathing and slow vital capacity (VC) manoeuvres. EIT data were acquired in two chest planes at 13 scans/s. Reproducibility of EIT findings was assessed by Bland-Altman analysis and Pearson correlation in 16 regions of interest in each plane. Regional ventilation distribution during tidal breathing and deep expiration was determined as fractional ventilation in four quadrants of the studied chest cross-sections. RESULTS: Our study showed a good reproducibility of EIT measurements repeated after an average time interval of 8 days. Global tidal volumes and VCs determined by spirometry on separate days were not significantly different. Regional ventilation in chest quadrants assessed by EIT was also unaffected. Posture exerted a significant effect on ventilation distribution among the chest quadrants during spontaneous breathing and deep expiration in both planes. The spatial distribution patterns in the two planes were not identical. CONCLUSIONS: We conclude that regional EIT ventilation findings are reproducible and recommend that the EIT examination location on the chest is carefully chosen especially during repeated measurements and follow-up. PMID- 21261781 TI - Clinical usefulness of B-type natriuretic peptide in the diagnosis of pleural effusions due to heart failure. AB - BACKGROUND AND OBJECTIVE: Light's criteria are frequently used to evaluate the exudative or transudative nature of pleural effusions. However, misclassification resulting from the use of Light's criteria has been reported, especially in the setting of diuretic use in patients with heart failure (HF). The objective of this study was to evaluate the utility of B-type natriuretic peptide (BNP) measurements as a diagnostic tool for determining the cardiac aetiology of pleural effusions. METHODS: Patients with pleural effusions attributable to HF (n = 34), hepatic hydrothorax (n = 10), pleural effusions due to cancer (n = 21) and pleural effusions due to tuberculosis (n = 12) were studied. Diagnostic thoracentesis was performed for all 77 patients. Receiver operating characteristic (ROC) curves were constructed to determine the diagnostic accuracy of plasma BNP and pleural fluid BNP for the prediction of HF. RESULTS: The areas under the ROC curves were 0.987 (95% CI 0.93-0.998) for plasma BNP and 0.949 (95% CI 0.874-0.986) for pleural fluid BNP, for distinguishing between patients with pleural effusions caused by HF (n = 34) and those with pleural effusions attributable to other causes (n = 43). The cut-off concentrations with the highest diagnostic accuracy for the diagnosis of HF as the cause of pleural effusion were 132 pg/mL for plasma BNP (sensitivity 97.1%, specificity 97.4%) and 127 pg/mL for pleural fluid BNP (sensitivity 97.1%, specificity 87.8%). CONCLUSIONS: In patients with pleural effusions of suspected cardiac origin, measurements of BNP in plasma and pleural fluid may be useful for the diagnosis of HF as the underlying cause. PMID- 21261782 TI - Chronic bronchitis is not necessary to define COPD. PMID- 21261783 TI - Sputum zinc concentration and clinical outcome in older asthmatics. AB - BACKGROUND AND OBJECTIVE: Mouse models of asthma show that zinc deficiency is associated with airway inflammation (AI), which is attenuated by zinc supplements. Whether zinc has a similar role in the human airway remains controversial, with studies demonstrating both high and low plasma zinc concentrations [Zn] in asthmatic patients compared with control subjects. This variability may reflect the inability of plasma measurements to accurately assess airway zinc levels. Examination of induced sputum is an established technique for measuring AI and mediators of inflammation. Recent advances allow measurement of the rapidly exchangeable (labile) and total zinc pools in sputum. The aims of this study were to measure labile and total [Zn] in sputum and plasma of subjects with or without asthma, and second to correlate [Zn] with symptoms, asthma severity, lung function (FEV(1)) and airway hyper-responsiveness. METHODS: A total of 163 subjects (114 with asthma) completed a single visit for sputum induction and a blood test. Labile and total [Zn] were measured by Zinquin fluorescence and atomic absorption spectrophotometry. RESULTS: The mean (SD) age of subjects with and without asthma was 55 (14) and 57 (14) years, respectively. Baseline FEV(1) was significantly lower in subjects with asthma (94.2 (16)%) than in those without asthma (103 (16.6)%). Sputum total and labile [Zn] were lower in subjects with asthma compared with control subjects, with median (interquartile range) values of 31.8 (117) versus 50 (188.5), P = 0.02 and 0 (48) versus 26 (84.5) ug/L, P = 0.05, respectively. Increased frequency of wheeze, as well as asthma severity and reduced FEV(1), was associated with significantly lower labile sputum [Zn]. CONCLUSIONS: These findings suggest that sputum [Zn] reflect clinical outcomes and underlying AI, suggesting a potential role for zinc as a biomarker in asthma. PMID- 21261784 TI - Combination of endobronchial ultrasound-guided transbronchial needle aspiration with standard bronchoscopic techniques for the diagnosis of stage I and stage II pulmonary sarcoidosis. AB - BACKGROUND AND OBJECTIVE: Standard bronchoscopic techniques (transbronchial lung biopsy and endobronchial biopsy) provide a diagnosis in 70% of patients with pulmonary sarcoidosis. Previous data suggest that endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a high sensitivity in patients with sarcoidosis. The feasibility and utility of combining EBUS-TBNA with standard bronchoscopic techniques is unknown. The aim of this study was to evaluate the feasibility, safety and efficacy of combined EBUS-TBNA and standard bronchoscopic techniques in patients with suspected sarcoidosis and enlarged mediastinal or hilar lymphadenopathy. METHODS: Forty consecutive patients with suspected pulmonary sarcoidosis and enlarged mediastinal or hilar lymph nodes (radiographical stage I and stage II) underwent EBUS-TBNA followed by transbronchial biopsies and endobronchial biopsies under conscious sedation. RESULTS: Thirty-nine out of 40 patients successfully underwent combined EBUS-TBNA and standard bronchoscopy. Twenty-seven patients were diagnosed with sarcoidosis, eight had tuberculosis, two had reactive lymphadenopathy, two had lymphoma and one had metastatic adenocarcinoma. In patients with sarcoidosis, the sensitivity of EBUS-TBNA for detection of non-caseating granulomas was 85%, compared with a sensitivity of 35% for standard bronchoscopic techniques (P < 0.001). The diagnostic yield of combined EBUS-TBNA and bronchoscopy was 93% (P < 0.0001). CONCLUSIONS: Combination of EBUS-TBNA with standard bronchoscopic techniques is safe and feasible, and optimizes the diagnostic yield in patients with pulmonary sarcoidosis and enlarged intrathoracic lymphadenopathy. PMID- 21261785 TI - Critical findings of severe influenza A (H1N1) pneumonia in children. AB - BACKGROUND: Pandemic influenza A (H1N1) causes severe pneumonia in children. The mechanism of development of respiratory failure in pneumonia patients remains unknown. This report describes clinical features of childhood influenza A pneumonia. METHODS: The clinical and laboratory findings of 31 H1N1 pneumonia patients hospitalized in Iwata City Hospital from 1 October 2009 to 31 January 2010 were reviewed. Intubation and mechanical ventilation were required due to respiratory failure in eight patients, who were classified as the intubation group. Other patients without mechanical ventilation were classified as the non intubation group. Clinical features and laboratory findings were compared between the two groups. RESULTS: The median age was 6.3 years (range, 3-10 years). The male to female ratio was 22:9. Clinical manifestations of tachycardia, tachypnea and cyanosis were significant findings in the intubation group at admission. Lymphocytopenia was observed in both groups. Leukocytosis with neutrophilia was the risk factor for intubation. CONCLUSIONS: Tachycardia, tachypnea, cyanosis and leukocytosis with neutrophilia, could be useful predictors at admission to identify high-risk influenza A (H1N1) pneumonia in children. PMID- 21261786 TI - Probiotic, zinc and lactose-free formula in children with rotavirus diarrhea: are they effective? AB - BACKGROUND: The aim of the present study was to evaluate the effectiveness of zinc, probiotic bacteria, and lactose-free formula and their different combinations in the treatment of rotavirus diarrhea in young children. METHODS: Eight different treatment groups were formed: group 1, 60 patients receiving Saccharomyces boulardii; group 2, 60 patients receiving zinc; group 3, 60 patients receiving lactose-free formula; group 4, 60 patients receiving S. boulardii plus zinc; group 5, 60 patients receiving S. boulardii plus lactose free formula; group 6, 60 patients receiving zinc plus lactose-free formula; group 7, 60 patients receiving S. boulardii plus zinc plus lactose-free formula; group 8, 60 patients receiving only oral and/or parenteral rehydration solutions. RESULTS: No statistically significant differences were found in the time to resolution of fever after intervention between the treatment groups and the control group. The time to resolution of vomiting was significantly lower in group 4 compared with groups 1 and 5. The duration of diarrhea was significantly reduced in groups 2 and 4 compared to control. A statistically significant difference in the duration of hospitalization was observed for the groups 2 and 4 in comparison to the control group. CONCLUSIONS: A different combination of adjunct therapies did not seem to bring additional value to rehydration therapy in children with rotavirus diarrhea except for in those receiving only zinc and zinc plus S. boulardii. Further studies are required to determine the optimal protocol of adjunct therapy use in children with rotavirus diarrhea. PMID- 21261787 TI - Ablation of supraventricular tachycardia allows more liberal therapy in some children with attention-deficit-hyperactivity disorder. AB - BACKGROUND: First-line therapy for children with attention-deficit-hyperactivity disorder (ADHD) is stimulant medication, which may have potential cardiovascular side-effects. In patients with supraventricular tachycardia or Wolf-Parkinson White syndrome (WPW), therapy for ADHD could become challenging. The purpose of the present study was to review the authors' experience of performing electrophysiologic study (EPS) with or without ablation to determine how it affected ADHD therapy. METHODS: Retrospective chart review of patients who underwent EPS between 2002 and 2009 was carried out. All patients under 21 years of age who had prior diagnosis of ADHD were included. RESULTS: Twenty patients met the inclusion criteria. The mean age was 12.1 +/- 2.7 years (range: 5.6-16.8 years). The patients were diagnosed with ADHD on average 3.9 +/- 2.7 years (range: 6 months-9 years) prior to the EPS. All patients had a structurally normal heart. Sixteen patients had cardiac symptoms. Seventeen patients underwent ablation of the arrhythmia substrate (16/17, 94% successful). Three patients with asymptomatic WPW were at low risk for life-threatening arrhythmias and did not have ablation. After the EPS, two patients had increased doses of their ADHD medications, and two patients whose health-care providers stopped the stimulant medication prior to EPS because of recurrent tachycardia were restarted on medications. All other patients on ADHD medications continued therapy. CONCLUSIONS: EPS for risk stratification and ablation of arrhythmia substrate is safe and effective, allowing more liberal therapy in patients with ADHD and supraventricular tachycardia or WPW. PMID- 21261788 TI - Evaluation of Japanese practice guidelines for newly diagnosed childhood idiopathic thrombocytopenic purpura. AB - BACKGROUND: Practice guidelines for childhood idiopathic thrombocytopenic purpura (ITP) were proposed in 1998 and 2004 in Japan. It is important to evaluate the feasibility and validity of the guidelines because the guidelines are based not on evidence but on opinion. METHODS: Records of 30 consecutive hospitalized patients aged 0-15 years (median, 3 years; 17 boys, 13 girls) were retrospectively reviewed. The feasibility and validity of the 2004 guidelines were evaluated by calculating an implementation rate, a response rate to first treatments, and a final clinical outcome. RESULTS: Deviation from the guidelines was found in two patients. Management of the other 28 patients followed the guidelines. The implementation rate was 93.3%. Twenty-one of the 28 eligible patients (75%) responded to the first treatment, whereas seven patients (25%) required additional treatment. In 23 patients (76.7%) platelet counts returned to normal within 6 months. Seven patients (23.3%) developed chronic conditions. All patients had no complications and achieved a platelet count >150 000/uL within 6 years. CONCLUSION: The 2004 Japanese guidelines are feasible and valid for the management of newly diagnosed childhood ITP patients. PMID- 21261789 TI - Seizure-modifying potential of histamine H1 antagonists: a clinical observation. AB - BACKGROUND: The widely used histamine H(1) antagonists have a potential to induce seizures, although clinical evaluation is scarce except for a few case reports. METHODS: The medical records of all pediatric consultations at Enshu General Hospital due to seizures during two successive winter seasons were collected. Cases involving known convulsive background were excluded. Seizures were categorized into two types: generalized seizures ceasing within 5 min ("typical"); and others ("atypical"). Eligible subjects were classified based on type of seizure and whether they were receiving histamine H(1) antagonists or not; the association between these classifications was examined using Fisher's exact test. RESULTS: There were 66 eligible consultations among 95 consultations due to seizures. A significantly increased incidence of atypical seizures among patients receiving histamine H(1) antagonists was found (P= 0.041; 95% confidence interval: 1.028-16.40; Fisher's exact test). CONCLUSION: Clinical doses of histamine H(1) antagonists have the potential to adversely modify seizures in children. PMID- 21261790 TI - Oral ingestion of Lentinula edodes mycelia extract inhibits B16 melanoma growth via mitigation of regulatory T cell-mediated immunosuppression. AB - Mitigation of regulatory T cell-mediated immunosuppression is crucial for optimal in vivo anti-tumor immune responses. In this study, we examined the anti-tumor effect induced by oral ingestion of an immunomodulating diet comprised of Lentinula edodes mycelia (L.E.M.) extract. C57BL/6 mice were inoculated subcutaneously in the footpad with B16 melanoma and fed L.E.M. extract. Ingestion of L.E.M. extract significantly inhibited tumor growth, and this in vivo anti tumor effect was not observed in nude mice, suggesting a T cell-dependent mechanism. In addition, ingestion of L.E.M. extract led to significant restoration of H-2K(b) -restricted and melanoma-reactive T cells in the spleen and draining lymph nodes of melanoma-bearing mice. Flow cytometry analysis revealed that the percentage of Foxp3(+) CD4(+) T cells increased in spleen and draining lymph nodes in melanoma-bearing mice, but decreased significantly with ingestion of L.E.M. extract. Importantly, selective depletion of CD8(+) T cells abolished the L.E.M.-induced anti-tumor effect, whereas that of CD4(+) T cells or CD25(+) cells showed no additive influence on the effect. Real-time PCR analysis revealed that ingestion of L.E.M. extract by melanoma-bearing mice decreased the level of Foxp3 mRNA within the tumor tissues, and lowered plasma transforming growth factor (TGF)-beta. Furthermore, an in vitro assay revealed that an immunosuppressive activity of CD4(+) T cells from melanoma-bearing mice was canceled by ingestion of L.E.M. extract. Our results indicate that oral ingestion of L.E.M. extract restores immune responses of class I-restricted and melanoma reactive CD8(+) T cells in melanoma-bearing mice, presumably by a mitigation of regulatory T cells-mediated immunosuppression. PMID- 21261791 TI - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone promoted gastric cancer growth through prostaglandin E receptor (EP2 and EP4) in vivo and in vitro. AB - Prostaglandin E (EP) receptor is positively related with COX-2, which is involved in cancer biology. A mechanistic study on how 4-(methylnitrosamino)-1-(3-pyridyl) 1-butanone (NNK) promotes gastric carcinogenesis is lacking. Recently, we found that nicotine promoted tumor growth through upregulation of the COX 2/prostaglandin E(2) pathway. This extended our study on the involvement of EP receptors in gastric carcinogenesis. Both in vitro and in vivo studies showed that NNK promoted cancer cell growth with concomitant EP2 and EP4 upregulation. We found that NNK stimulated vascular endothelial growth factor (VEGF) and angiogenesis, but suppressed apoptosis by increasing Bcl2 and decreasing caspase 3 expressions. Both EP2 and EP4 siRNA significantly impaired these tumorigenic actions of NNK in xenograft tumor. Cell cycle analysis showed that NNK increased S phase entry with increased cyclin D1 and the associated cyclin-dependent kinase 4/6, and downregulation of p21 and p27. The p38 phosphorylation was EP2/4 dependent, and SB203580 (p38 inhibitor) suppressed NNK-induced prostaglandin E(2) , VEGF, and cell proliferation. Antagonists of EP2 or EP4 abolished the elevated VEGF and VEGF receptor-2. These data strongly indicate that EP2/4 are important for NNK-promoted gastric carcinogenesis, thus providing a framework for future evaluation of EP antagonist(s) as anticancer drugs for smokers. PMID- 21261792 TI - Seizure-induced Takotsubo cardiomyopathy and thrombocytopenia. PMID- 21261793 TI - Childhood refractory focal epilepsy following acute febrile encephalopathy with anti-amphiphysin antibody. PMID- 21261794 TI - IgM monoclonal gammopathy-associated neuropathies with different IgM specificity. AB - BACKGROUND AND PURPOSE: Antibodies directed against myelin-associated glycoprotein (MAG) are believed to be the most frequent biologic marker of the neuropathies associated with IgM monoclonal gammopathy of undetermined significance (MGUS). The objective of this study was to examine the prevalence of antiganglioside and/or sulfatide-positive patients and their clinical findings, including therapeutic response, compared to anti-MAG-positive or seronegative patients. METHODS: We prospectively followed 46 patients with MGUS who were diagnosed in our tertiary referral centers for polyneuropathy since 1997. All patients underwent nerve conduction studies and were tested for anti-MAG, gangliosides, and sulfatide antibodies. All the anagraphic and clinical data (including symptoms, disability scale, therapy, secondary malignancy development) were recorded in a database and compared between three patients' groups (anti-MAG positive; antiganglioside/sulfatide-positive; no reactivity). RESULTS: Anti-MAG reactivity was present in 17 (37%) patients; other 17 patients (37%) had antiganglioside/sulfatide reactivity and 12 (26%) had no reactivity. Patients with antiganglioside/sulfatide positivity, although heterogeneous by a clinical and neurophysiological point of view, had the most severe neuropathic manifestations and a higher disability score at nadir (P < 0.001). These patients had a better response to both intravenous immunoglobulin therapy and rituximab. CONCLUSIONS: Our results suggest that antiganglioside/sulfatide-positive patients form a relevant portion of patients with MGUS-associated polyneuropathy seen in tertiary care centers and should be considered in future studies on treatment response. PMID- 21261795 TI - Histidine acts as a co-germinant with glycine and taurocholate for Clostridium difficile spores. AB - AIMS: It is well established that the bile salt sodium taurocholate acts as a germinant for Clostridium difficile spores and the amino acid glycine acts as a co-germinant. The aim of this study was to determine whether any other amino acids act as co-germinants. METHODS AND RESULTS: Clostridium difficile spore suspensions were exposed to different germinant solutions comprising taurocholate, glycine and an additional amino acid for 1 h before heating shocking (to kill germinating cells) or chilling on ice. Samples were then re germinated and cultured to recover remaining viable cells. Only five amino acids out of the 19 common amino acids tested (valine, aspartic acid, arginine, histidine and serine) demonstrated co-germination activity with taurocholate and glycine. Of these, only histidine produced high levels of germination (97.9 99.9%) consistently in four strains of Cl. difficile spores. Some variation in the level of germination produced was observed between different PCR ribotypes, and the optimum concentration of amino acids with taurocholate for the germination of Cl. difficile NCTC 11204 spores was 10-100 mmol l-1. CONCLUSIONS: Histidine was found to be a co-germinant for Cl. difficile spores when combined with glycine and taurocholate. PMID- 21261797 TI - Microbial communities in bulk fluids and biofilms of an oil facility have similar composition but different structure. AB - The oil-water-gas environments of oil production facilities harbour abundant and diverse microbial communities that can participate in deleterious processes such as biocorrosion. Several molecular methods, including pyrosequencing of 16S rRNA libraries, were used to characterize the microbial communities from an oil production facility on the Alaskan North Slope. The communities in produced water and a sample from a 'pig envelope' were compared in order to identify specific populations or communities associated with biocorrosion. The 'pigs' are used for physical mitigation of pipeline corrosion and fouling and the samples are enriched in surface-associated solids (i.e. paraffins, minerals and biofilm) and coincidentally, microorganisms (over 10(5) -fold). Throughout the oil production facility, bacteria were more abundant (10- to 150-fold) than archaea, with thermophilic members of the phyla Firmicutes (Thermoanaerobacter and Thermacetogenium) and Synergistes (Thermovirga) dominating the community. However, the structure (relative abundances of taxa) of the microbial community in the pig envelope was distinct due to the increased relative abundances of the genera Thermacetogenium and Thermovirga. The data presented here suggest that bulk fluid is representative of the biofilm communities associated with biocorrosion but that certain populations are more abundant in biofilms, which should be the focus of monitoring and mitigation strategies. PMID- 21261798 TI - DNA-, rRNA- and mRNA-based stable isotope probing of aerobic methanotrophs in lake sediment. AB - A stable isotope probing (SIP) approach was used to study aerobic methane oxidizing bacteria (methanotrophs) in lake sediment. Oligotrophic Lake Stechlin was chosen because it has a permanently oxic sediment surface. 16S rRNA and the pmoA gene, which encodes a subunit of the methane monooxygenase enzyme, were analysed following the incubation of sediment with (13) CH(4) and the separation of (13) C-labelled DNA and RNA from unlabelled nucleic acids. The incubation with (13) CH(4) was performed over a 4-day time-course and the pmoA genes and transcripts became progressively labelled such that approximately 70% of the pmoA genes and 80% of the transcripts were labelled at 96 h. The labelling of pmoA mRNA was quicker than pmoA genes, demonstrating that mRNA-SIP is more sensitive than DNA-SIP; however, the general rate of pmoA transcript labelling was comparable to that of the pmoA genes, indicating that the incorporation of (13) C into ribonucleic acids of methanotrophs was a gradual process. Labelling of Betaproteobacteria was clearly seen in analyses of 16S rRNA by DNA-SIP and not by RNA-SIP, suggesting that cross-feeding of the (13) C was primarily detected by DNA-SIP. In general, we show that the combination of SIP approaches provided valuable information about the activity and growth of the methanotrophic populations and the cross-feeding of methanotroph metabolites by other microorganisms. PMID- 21261799 TI - Multiple alkane hydroxylase systems in a marine alkane degrader, Alcanivorax dieselolei B-5. AB - Alcanivorax dieselolei strain B-5 is a marine bacterium that can utilize a broad range of n-alkanes (C(5) -C(36) ) as sole carbon source. However, the mechanisms responsible for this trait remain to be established. Here we report on the characterization of four alkane hydroxylases from A. dieselolei, including two homologues of AlkB (AlkB1 and AlkB2), a CYP153 homologue (P450), as well as an AlmA-like (AlmA) alkane hydroxylase. Heterologous expression of alkB1, alkB2, p450 and almA in Pseudomonas putida GPo12 (pGEc47DeltaB) or P. fluorescens KOB2Delta1 verified their functions in alkane oxidation. Quantitative real-time RT-PCR analysis showed that these genes could be induced by alkanes ranging from C(8) to C(36) . Notably, the expression of the p450 and almA genes was only upregulated in the presence of medium-chain (C(8) -C(16) ) or long-chain (C(22) C(36) ) n-alkanes, respectively; while alkB1 and alkB2 responded to both medium- and long-chain n-alkanes (C(12) -C(26) ). Moreover, branched alkanes (pristane and phytane) significantly elevated alkB1 and almA expression levels. Our findings demonstrate that the multiple alkane hydroxylase systems ensure the utilization of substrates of a broad chain length range. PMID- 21261800 TI - Multidimensional NMR analysis reveals truncated lignin structures in wood decayed by the brown rot basidiomycete Postia placenta. AB - Lignocellulose biodegradation, an essential step in terrestrial carbon cycling, generally involves removal of the recalcitrant lignin barrier that otherwise prevents infiltration by microbial polysaccharide hydrolases. However, fungi that cause brown rot of wood, a major route for biomass recycling in coniferous forests, utilize wood polysaccharides efficiently while removing little of the lignin. The mechanism by which these basidiomycetes breach the lignin remains unclear. We used recently developed methods for solubilization and multidimensional (1) H-(13) C solution-state NMR spectroscopy of ball-milled lignocellulose to analyse aspen wood degraded by Postia placenta. The results showed that decay decreased the content of the principal arylglycerol-beta-aryl ether interunit linkage in the lignin by more than half, while increasing the frequency of several truncated lignin structures roughly fourfold over the level found in sound aspen. These new end-groups, consisting of benzaldehydes, benzoic acids and phenylglycerols, accounted for 6-7% of all original lignin subunits. Our results provide evidence that brown rot by P. placenta results in significant ligninolysis, which might enable infiltration of the wood by polysaccharide hydrolases even though the partially degraded lignin remains in situ. Recent work has revealed that the P. placenta genome encodes no ligninolytic peroxidases, but has also shown that this fungus produces an extracellular Fenton system. It is accordingly likely that P. placenta employs electrophilic reactive oxygen species such as hydroxyl radicals to disrupt lignin in wood. PMID- 21261804 TI - Could increased time spent in a thermal comfort zone contribute to population increases in obesity? AB - Domestic winter indoor temperatures in the USA, UK and other developed countries appear to be following an upwards trend. This review examines evidence of a causal link between thermal exposures and increases in obesity prevalence, focusing on acute and longer-term biological effects of time spent in thermal comfort compared with mild cold. Reduced exposure to seasonal cold may have a dual effect on energy expenditure, both minimizing the need for physiological thermogenesis and reducing thermogenic capacity. Experimental studies show a graded association between acute mild cold and human energy expenditure over the range of temperatures relevant to indoor heating trends. Meanwhile, recent studies of the role of brown adipose tissue (BAT) in human thermogenesis suggest that increased time spent in conditions of thermal comfort can lead to a loss of BAT and reduced thermogenic capacity. Pathways linking cold exposure and adiposity have not been directly tested in humans. Research in naturalistic and experimental settings is needed to establish effects of changes in thermal exposures on weight, which may raise possibilities for novel public health strategies to address obesity. PMID- 21261805 TI - Contribution of the P2Y12 receptor-mediated pathway to platelet hyperreactivity in hypercholesterolemia. AB - BACKGROUND: In hypercholesterolemia, platelets demonstrate increased reactivity and promote the development of cardiovascular disease. OBJECTIVE: This study was carried out to investigate the contribution of the ADP receptor P2Y12-mediated pathway to platelet hyperreactivity due to hypercholesterolemia. METHODS: Low density lipoprotein receptor-deficient mice and C57Bl/6 wild-type mice were fed on normal chow and high-fat (Western or Paigen) diets for 8 weeks to generate differently elevated cholesterol levels. P2Y12 receptor-induced functional responses via G(i) signaling were studied ex vivo when washed murine platelets were activated by 2MeSADP and PAR4 agonist AYPGKF in the presence and absence of indomethacin. Platelet aggregation and secretion, alpha(IIb)beta(3) receptor activation and the phosphorylation of extracellular signal-regulated protein kinase (ERK) and Akt were analyzed. RESULTS: Plasma cholesterol levels ranged from 69 +/- 10 to 1011 +/- 185 mg dL(-1) depending on diet in mice with different genotypes. Agonist-dependent aggregation, dense and alpha-granule secretion and JON/A binding were gradually and significantly (P < 0.05) augmented at low agonist concentration in correlation with the increasing plasma cholesterol levels, even if elevated thromboxane generation was blocked. These functional responses were induced via increased levels of G(i) -mediated ERK and Akt phosphorylation in hypercholesterolemic mice vs. normocholesterolemic animals. In addition, blocking of the P2Y12 receptor by AR-C69931MX (Cangrelor) resulted in strongly reduced platelet aggregation in mice with elevated cholesterol levels compared with normocholesterolemic controls. CONCLUSIONS: These data revealed that the P2Y12 receptor pathway was substantially involved in platelet hyperreactivity associated with mild and severe hypercholesterolemia. PMID- 21261806 TI - Mechanisms underlying FeCl3-induced arterial thrombosis. AB - BACKGROUND: The FeCl(3)-induced vascular injury model is widely used to study thrombogenesis in vivo, but the processes leading to vascular injury and thrombosis are poorly defined. OBJECTIVES: The aim of our study was to better characterize the mechanisms of FeCl(3)-induced vascular injury and thrombus formation, in order to evaluate the pathophysiological relevance of this model. METHODS: FeCl(3) was applied at different concentrations (from 7.5% to 20%) and for different time periods (up to 5 min) to mouse carotid or mesenteric arteries. RESULTS: Under all the conditions tested, ultrastructural analysis revealed that FeCl(3) diffused through the vessel wall, resulting in endothelial cell denudation without exposure of the inner layers. Hence, only the basement membrane components were exposed to circulating blood cells and might have contributed to thrombus formation. Shortly after FeCl(3) application, numerous ferric ion-filled spherical bodies appeared on the endothelial cells. Interestingly, platelets could adhere to these spheres and form aggregates. Immunogold labeling revealed important amounts of tissue factor at their surface, suggesting that these spheres may play a role in thrombin generation. In vitro experiments indicated that FeCl(3) altered the ability of adhesive proteins, including collagen, fibrinogen and von Willebrand factor, to support platelet adhesion. Finally, real-time intravital microscopy showed no protection against thrombosis in GPVI-immunodepleted and beta(1)(-/-) mice, suggesting that GPVI and beta(1) integrins, known to be involved in initial platelet adhesion and activation, do not play a critical role in FeCl(3)-induced thrombus formation. CONCLUSION: This model should be used cautiously, in particular to study the earliest stage of thrombus formation. PMID- 21261807 TI - Calibration of combined thromboplastins with the International Standard for Thromboplastin, rabbit, plain. PMID- 21261808 TI - Identification of the genes affecting the regulation of riboflavin synthesis in the flavinogenic yeast Pichia guilliermondii using insertion mutagenesis. AB - Pichia guilliermondii is a representative of a group of so-called flavinogenic yeast species that overproduce riboflavin (vitamin B(2)) in response to iron limitation. Using insertion mutagenesis, we isolated P. guilliermondii mutants overproducing riboflavin. Analysis of nucleotide sequence of recombination sites revealed that insertion cassettes integrated into the genome disrupting P. guilliermondii genes similar to the VMA1 gene of Ashbya gossypii and Saccharomyces cerevisiae and FES1 and FRA1 genes of S. cerevisiae. The constructed P. guilliermondiiDeltavma1-17 mutant possessed five- to sevenfold elevated riboflavin production and twofold decreased iron cell content as compared with the parental strain. Pichia guilliermondiiDeltafra1-45 mutant accumulated 1.8-2.2-fold more iron in the cells and produced five- to sevenfold more riboflavin as compared with the parental strain. Both Deltavma1-17 and Deltafes1-77 knockout strains could not grow at 37 degrees C in contrast to the wild-type strain and the Deltafra1-45 mutant. Increased riboflavin production by the wild-type strain was observed at 37 degrees C. Although the Deltafes1-77 mutant did not overproduce riboflavin, it showed partial complementation when crossed with previously isolated P. guilliermondii riboflavin-overproducing mutant rib80-22. Complementation analysis revealed that Deltavma1-17 and Deltafra1-45 mutants are distinct from previously reported riboflavin-producing mutants hit1-1, rib80-22 and rib81-31 of this yeast. PMID- 21261810 TI - The impact of telomeres and telomerase in cellular biology and medicine: it's not the end of the story. PMID- 21261811 TI - Re: Moving towards in situ tracheal regeneration: the bionic tissue engineered transplantation approach. J. Cell. Mol. Med. Vol. 14, No. 7, 2010, pp. 1877-1889. PMID- 21261812 TI - Toward the domestication of lignocellulosic energy crops: learning from food crop domestication. AB - Domestication of cereal crops has provided a stable source of food for thousands of years. The extent to which lignocellulosic crops will contribute to the world's renewable energy depends largely on how the new crops will be domesticated. Growing miscanthus as biofuel feedstocks on marginal and degraded land in northern and northwestern China offers an example for developing theoretical framework and practical strategies for energy crop domestication. The domestication should incorporate the highest possible genetic diversity from wild species, focus on the improvement of drought and cold tolerance especially in the stage of crop establishment, increase the efficiencies of water and nutrient uses and photosynthesis, adjust vegetative growing season according to local temperature and precipitation, and reduce or prevent seed production. Positive ecological effects on soil conservation, landscape restoration, carbon sequestration, and hydrological cycles should be maximized, while negative impact on biodiversity needs to be minimized. With the development of other sources of renewable energy, the role of lignocellulosic crops may evolve from primarily energy production to increasingly ecological restoration and biomaterial development. The integration of this new cropping system into the existing agriculture may open a new avenue to the long-term sustainability of our society. PMID- 21261813 TI - Rapid characterization of woody biomass digestibility and chemical composition using near-infrared spectroscopy. AB - Rapid determination of the properties of lignocellulosic material is highly desirable for biomass production and utilization. In the present study, measurements of woody biomass digestibility and chemical composition using near infrared reflectance (NIR) spectroscopy were calibrated. Poplar and eucalyptus materials were recorded in NIR spectrum as well as determined for their chemical compositions of Klason lignin, alpha-cellulose, holocellulose, lignin syringyl/guaiacyl (S/G) ratio and enzymatic digestibility. Fitting of the NIR information with chemical properties and digestibility by partial least-squares (PLS) regression generated a group of trained NIR models that were able to be used for rapid biomass measurement. Applying the models for woody biomass measurements led to a reliable evaluation of the chemical composition and digestibility, suggesting the feasibility of using NIR spectroscopy in the rapid characterization of biomass properties. PMID- 21261814 TI - Secondary substrate binding strongly affects activity and binding affinity of Bacillus subtilis and Aspergillus niger GH11 xylanases. AB - The secondary substrate binding site (SBS) of Bacillus subtilis and Aspergillus niger glycoside hydrolase family 11 xylanases was studied by site-directed mutagenesis and evaluation of activity and binding properties of mutant enzymes on different substrates. Modification of the SBS resulted in an up to three-fold decrease in the relative activity of the enzymes on polymeric versus oligomeric substrates and highlighted the importance of several amino acids in the SBS forming hydrogen bonds or hydrophobic stacking interactions with substrates. Weakening of the SBS increased K(d) values by up to 70-fold in binding affinity tests using natural substrates. The impact that modifications in the SBS have both on activity and on binding affinity towards polymeric substrates clearly shows that such structural elements can increase the efficiency of these single domain enzymes on their natural substrates. PMID- 21261815 TI - alpha-Enolase: a promising therapeutic and diagnostic tumor target. AB - alpha-enolase (ENOA) is a metabolic enzyme involved in the synthesis of pyruvate. It also acts as a plasminogen receptor and thus mediates activation of plasmin and extracellular matrix degradation. In tumor cells, EpsilonNuOmicronAlpha is upregulated and supports anaerobic proliferation (Warburg effect), it is expressed at the cell surface, where it promotes cancer invasion, and is subjected to a specific array of post-translational modifications, namely acetylation, methylation and phosphorylation. Both ENOA overexpression and its post-translational modifications could be of diagnostic and prognostic value in cancer. This review will discuss recent information on the biochemical, proteomics and immunological characterization of ENOA, particularly its ability to trigger a specific humoral and cellular immune response. In our opinion, this information can pave the way for effective new therapeutic and diagnostic strategies to counteract the growth of the most aggressive human disease. PMID- 21261817 TI - The application of Tet repressor in prokaryotic gene regulation and expression. AB - Inducible gene expression based upon Tet repressor (tet regulation) is a broadly applied tool in molecular genetics. In its original environment, Tet repressor (TetR) negatively controls tetracycline (tc) resistance in bacteria. In the presence of tc, TetR is induced and detaches from its cognate DNA sequence tetO, so that a tc antiporter protein is expressed. In this article, we provide a comprehensive overview about tet regulation in bacteria and illustrate the parameters of different regulatory architectures. While some of these set-ups rely on natural tet-control regions like those found on transposon Tn10, highly efficient variations of this system have recently been adapted to different Gram negative and Gram-positive bacteria. Novel tet-controllable artificial or hybrid promoters were employed for target gene expression. They are controlled by regulators expressed at different levels either in a constitutive or in an autoregulated manner. The resulting tet systems have been used for various purposes. We discuss integrative elements vested with tc-sensitive promoters, as well as tet regulation in Gram-negative and Gram-positive bacteria for analytical purposes and for protein overproduction. Also the use of TetR as an in vivo biosensor for tetracyclines or as a regulatory device in synthetic biology constructs is outlined. Technical specifications underlying different regulatory set-ups are highlighted, and finally recent developments concerning variations of TetR are presented, which may expand the use of prokaryotic tet systems in the future. PMID- 21261818 TI - Pseudomonas aeruginosa PAO1 virulence factors and poplar tree response in the rhizosphere. AB - Whole-transcriptome analysis was used here for the first time in the rhizosphere to discern the genes involved in the pathogenic response of Pseudomonas aeruginosa PAO1 as well as to discern the response of the poplar tree. Differential gene expression shows that 185 genes of the bacterium and 753 genes of the poplar tree were induced in the rhizosphere. Using the P. aeruginosa transcriptome analysis, isogenic knockout mutants, and two novel plant assays (poplar and barley), seven novel PAO1 virulence genes were identified (PA1385, PA2146, PA2462, PA2463, PA2663, PA4150 and PA4295). The uncharacterized putative haemolysin repressor, PA2463, upon inactivation, resulted in greater poplar virulence and elevated haemolysis while this mutant remained competitive in the rhizosphere. In addition, disruption of the haemolysin gene itself (PA2462) reduced the haemolytic activity of P. aeruginosa, caused less cytotoxicity and reduced barley virulence, as expected. Inactivating PA1385, a putative glycosyl transferase, reduced both poplar and barley virulence. Furthermore, disrupting PA2663, a putative membrane protein, reduced biofilm formation by 20-fold. Inactivation of PA3476 (rhlI) increased virulence with barley as well as haemolytic activity and cytotoxicity, so quorum sensing is important in plant pathogenesis. Hence, this strategy is capable of elucidating virulence genes for an important pathogen. PMID- 21261819 TI - Metabolic engineering to enhance bacterial hydrogen production. AB - Hydrogen fuel is renewable, efficient and clean, and fermentative bacteria hold great promise for its generation. Here we use the isogenic Escherichia coli K-12 KEIO library to rapidly construct multiple, precise deletions in the E. coli genome to direct the metabolic flux towards hydrogen production. Escherichia coli has three active hydrogenases, and the genes involved in the regulation of the formate hydrogen lyase (FHL) system for synthesizing hydrogen from formate via hydrogenase 3 were also manipulated to enhance hydrogen production. Specifically, we altered regulation of FHL by controlling the regulators HycA and FhlA, removed hydrogen consumption by hydrogenases 1 and 2 via the hyaB and hybC mutations, and re-directed formate metabolism using the fdnG, fdoG, narG, focA, fnr and focB mutations. The result was a 141-fold increase in hydrogen production from formate to create a bacterium (BW25113 hyaB hybC hycA fdoG/pCA24N-FhlA) that produces the largest amount of hydrogen to date and one that achieves the theoretical yield for hydrogen from formate. In addition, the hydrogen yield from glucose was increased by 50%, and there was threefold higher hydrogen production from glucose with this strain. PMID- 21261820 TI - Bacterial decolorization of textile dyes is an extracellular process requiring a multicomponent electron transfer pathway. AB - Many studies have reported microorganisms as efficient biocatalysts for colour removal of dye-containing industrial wastewaters. We present the first comprehensive study to identify all molecular components involved in decolorization by bacterial cells. Mutants from the model organism Shewanella oneidensis MR-1, generated by random transposon and targeted insertional mutagenesis, were screened for defects in decolorization of an oxazine and diazo dye. We demonstrate that decolorization is an extracellular reduction process requiring a multicomponent electron transfer pathway that consists of cytoplasmic membrane, periplasmic and outer membrane components. The presence of melanin, a redox-active molecule excreted by S. oneidensis, was shown to enhance the dye reduction rates. Menaquinones and the cytochrome CymA are the crucial cytoplasmic membrane components of the pathway, which then branches off via a network of periplasmic cytochromes to three outer membrane cytochromes. The key proteins of this network are MtrA and OmcB in the periplasm and outer membrane respectively. A model of the complete dye reduction pathway is proposed in which the dye molecules are reduced by the outer membrane cytochromes either directly or indirectly via melanin. PMID- 21261821 TI - Activity and viability of polycyclic aromatic hydrocarbon-degrading Sphingomonas sp. LB126 in a DC-electrical field typical for electrobioremediation measures. AB - There has been growing interest in employing electro-bioremediation, a hybrid technology of bioremediation and electrokinetics for the treatment of contaminated soil. Knowledge however on the effect of weak electrokinetic conditions on the activity and viability of pollutant-degrading microorganisms is scarce. Here we present data about the influence of direct current (DC) on the membrane integrity, adenosine triphosphate (ATP) pools, physico-chemical cell surface properties, degradation kinetics and culturability of fluorene-degrading Sphingomonas sp. LB126. Flow cytometry was applied to quantify the uptake of propidium iodide (PI) and the membrane potential-related fluorescence intensities (MPRFI) of individual cells within a population. Adenosine tri-phosphate contents and fluorene biodegradation rates of bulk cultures were determined and expressed on a per cell basis. The cells' surface hydrophobicity and electric charge were assessed by contact angle and zeta potential measurements respectively. Relative to the control, DC-exposed cells exhibited up to 60% elevated intracellular ATP levels and yet remained unaffected on all other levels of cellular integrity and functionality tested. Our data suggest that direct current (X=1 V cm(-1); J=10.2 mA cm(-2)) as typically used for electrobioremediation measures has no negative effect on the activity of the polycyclic aromatic hydrocarbon (PAH)-degrading soil microorganism, thereby filling a serious gap of the current knowledge of the electrobioremediation methodology. PMID- 21261822 TI - Development and validation of an approach to produce large-scale quantities of CpG-methylated plasmid DNA. AB - The prokaryotic CpG-specific DNA methylase from Spiroplasma, SssI methylase, has been extensively used to methylate plasmid DNA in vitro to investigate the effects of methylation in vertebrate systems. Currently available methods to produce CpG-methylated plasmid DNA have certain limitations and cannot generate large quantities of methylated DNA without cost or problems of purity. Here we describe an approach in which the SssI methylase gene has been introduced into the Escherichia coli bacterial genome under the control of an inducible promoter. Plasmid DNA propagated in this bacterium under conditions which induce the methylase gene result in significant (>90%) CpG methylation. Methylated DNA produced by this approach behaves similarly to methylated DNA produced in vitro using the purified methylase. The approach is scalable allowing for the production of milligram quantities of methylated plasmid DNA. PMID- 21261823 TI - Mutant HbpR transcription activator isolation for 2-chlorobiphenyl via green fluorescent protein-based flow cytometry and cell sorting. AB - Mutants were produced in the A-domain of HbpR, a protein belonging to the XylR family of sigma(54)-dependent transcription activators, with the purpose of changing its effector recognition specificity from 2-hydroxybiphenyl (2-HBP, the cognate effector) to 2-chlorobiphenyl (2-CBP). Mutations were introduced in the hbpR gene part for the A-domain via error-prone polymerase chain reaction, and assembled on a gene circuitry plasmid in Escherichia coli, permitting HbpR dependent induction of the enhanced green fluorescent protein (egfp). Cells with mutant HbpR proteins responsive to 2-CBP were enriched and separated in a flow cytometry-assisted cell-sorting procedure. Some 70 mutants were isolated and the A-domain mutations mapped. One of these had acquired true 2-CBP recognition but reacted hypersensitively to 2-HBP (20-fold more than the wild type), whereas others had reduced sensitivity to 2-HBP but a gain of 2-CBP recognition. Sequencing showed that most mutants carried double or triple mutations in the A domain gene part, and were not located in previously recognized conserved residues within the XylR family members. Further selection from a new mutant pool prepared of the hypersensitive mutant did not result in increased 2-CBP or reduced 2-HBP recognition. Our data thus demonstrate that a one-step in vitro 'evolutionary' adaptation of the HbpR protein can result in both enhancement and reduction of the native effector recognition. PMID- 21261824 TI - Massively parallel pathogen identification using high-density microarrays. AB - Identification of microbial pathogens in clinical specimens is still performed by phenotypic methods that are often slow and cumbersome, despite the availability of more comprehensive genotyping technologies. We present an approach based on whole-genome amplification and resequencing microarrays for unbiased pathogen detection. This 10 h process identifies a broad spectrum of bacterial and viral species and predicts antibiotic resistance and pathogenicity and virulence profiles. We successfully identify a variety of bacteria and viruses, both in isolation and in complex mixtures, and the high specificity of the microarray distinguishes between different pathogens that cause diseases with overlapping symptoms. The resequencing approach also allows identification of organisms whose sequences are not tiled on the array, greatly expanding the repertoire of identifiable organisms and their variants. We identify organisms by hybridization of their DNA in as little as 1-4 h. Using this method, we identified Monkeypox virus and drug-resistant Staphylococcus aureus in a skin lesion taken from a child suspected of an orthopoxvirus infection, despite poor transport conditions of the sample, and a vast excess of human DNA. Our results suggest this technology could be applied in a clinical setting to test for numerous pathogens in a rapid, sensitive and unbiased manner. PMID- 21261825 TI - Rhizoremediation of lindane by root-colonizing Sphingomonas. AB - We used a two-step enrichment approach to isolate root-colonizing hexachlorocyclohexane (HCH)-degrading microorganisms. The first step consists of the use of classical liquid enrichment to isolate gamma-HCH degraders. The gamma HCH-degrading microbes were attached in mass to corn seeds sown in soil with gamma-HCH, and after plant development we rescued bacteria growing on root tips. Bacteria were then subjected to a second enrichment round in which growth on liquid medium with gamma-HCH and inoculation of corn seeds were repeated. We then isolated bacteria on M9 minimal medium with gamma-HCH from root tips. We were able to isolate four Sphingomonas strains, all of which degraded alpha-, beta-, gamma- and delta-HCH. Two of the strains were particularly good colonizers of corn roots, reaching high cell density in vegetated soil and partly removing gamma-HCH. In contrast, these bacteria performed poorly in unplanted soils. This study supports the hypothesis that the removal of persistent toxic chemicals can be accelerated by combinations of plants and bacteria, a process generally known as rhizoremediation. PMID- 21261827 TI - Wine genomics. PMID- 21261828 TI - New avenues for Microbial Biotechnology: the beginning of a golden era. PMID- 21261829 TI - Metabolically engineered bacteria for producing hydrogen via fermentation. AB - Hydrogen, the most abundant and lightest element in the universe, has much potential as a future energy source. Hydrogenases catalyse one of the simplest chemical reactions, 2H(+) + 2e(-) <-> H(2), yet their structure is very complex. Biologically, hydrogen can be produced via photosynthetic or fermentative routes. This review provides an overview of microbial production of hydrogen by fermentation (currently the more favourable route) and focuses on biochemical pathways, theoretical hydrogen yields and hydrogenase structure. In addition, several examples of metabolic engineering to enhance fermentative hydrogen production are presented along with some examples of expression of heterologous hydrogenases for enhanced hydrogen production. PMID- 21261830 TI - Microcalorimetry: a response to challenges in modern biotechnology. AB - Almost any process in life is accompanied by heat changes which can be monitored by isothermal titration calorimetry (ITC) and differential scanning calorimetry (DSC). Both techniques are now established tools in fundamental research but over the last decade a clear tendency towards more problem-driven applications is noted. This review aims at summarizing these problem-oriented applications of microcalorimetry and the solutions both techniques can provide to problems in biotechnology. The biotechnological issues to which microcalorimetry has been successfully applied are as diverse as rational drug design, overcoming drug resistance, optimization of long-term stability of proteins, estimation of the bioavailability of drugs, control of complex pharmaceutical products or the optimization of gene delivery efficiency. The main limitation of microcalorimetry, which is the relatively large amounts of sample necessary for analysis, is less important in the biotechnology sector which frequently uses large-scale produced bulk products for analysis. The recently developed high throughput DSC and ITC microcalorimeters will additionally reduce the labour intensity of these techniques. Due to the precision of microcalorimetric analyses and the versatility of processes which can be studied, it is expected that ITC and DSC will soon be key technologies in biotechnological research. PMID- 21261831 TI - Microbial whole-cell arrays. AB - The coming of age of whole-cell biosensors, combined with the continuing advances in array technologies, has prepared the ground for the next step in the evolution of both disciplines - the whole-cell array. In the present review, we highlight the state-of-the-art in the different disciplines essential for a functional bacterial array. These include the genetic engineering of the biological components, their immobilization in different polymers, technologies for live cell deposition and patterning on different types of solid surfaces, and cellular viability maintenance. Also reviewed are the types of signals emitted by the reporter cell arrays, some of the transduction methodologies for reading these signals and the mathematical approaches proposed for their analysis. Finally, we review some of the potential applications for bacterial cell arrays, and list the future needs for their maturation: a richer arsenal of high-performance reporter strains, better methodologies for their incorporation into hardware platforms, design of appropriate detection circuits, the continuing development of dedicated algorithms for multiplex signal analysis and - most importantly - enhanced long term maintenance of viability and activity on the fabricated biochips. PMID- 21261832 TI - Internal arsenite bioassay calibration using multiple bioreporter cell lines. AB - Bioassays with bioreporter bacteria are usually calibrated with analyte solutions of known concentrations that are analysed along with the samples of interest. This is done as bioreporter output (the intensity of light, fluorescence or colour) does not only depend on the target concentration, but also on the incubation time and physiological activity of the cells in the assay. Comparing the bioreporter output with standardized colour tables in the field seems rather difficult and error-prone. A new approach to control assay variations and improve application ease could be an internal calibration based on the use of multiple bioreporter cell lines with drastically different reporter protein outputs at a given analyte concentration. To test this concept, different Escherichia coli based bioreporter strains expressing either cytochrome c peroxidase (CCP, or CCP mutants) or beta-galactosidase upon induction with arsenite were constructed. The reporter strains differed either in the catalytic activity of the reporter protein (for CCP) or in the rates of reporter protein synthesis (for beta galactosidase), which, indeed, resulted in output signals with different intensities at the same arsenite concentration. Hence, it was possible to use combinations of these cell lines to define arsenite concentration ranges at which none, one or more cell lines gave qualitative (yes/no) visible signals that were relatively independent of incubation time or bioreporter activity. The discriminated concentration ranges would fit very well with the current permissive (e.g. World Health Organization) levels of arsenite in drinking water (10 ug l(-1)). PMID- 21261833 TI - Physiological responses of Pseudomonas putida to formaldehyde during detoxification. AB - Pseudomonas putida KT2440 exhibits two formaldehyde dehydrogenases and two formate dehydrogenase complexes that allow the strain to stoichiometrically convert formaldehyde into CO(2). The strain tolerated up to 1.5 mM formaldehyde and died in the presence of 10 mM. In the presence of 0.5 mM formaldehyde, a sublethal concentration of this chemical, the growth rate decreased by about 40% with respect to growth in the absence of the toxicant. Transcriptomic analysis revealed that in response to low formaldehyde concentrations, a limited number of genes (52) were upregulated. Based on the function of these genes it seems that sublethal concentrations of HCOH trigger responses to overcome DNA and protein damage, extrude this toxic compound, and detoxify it by converting the chemical to CO(2). In strains bearing mutations of the upregulated genes we analysed growth inhibition by 1.5 mM HCOH and killing rates by 10 mM HCOH. Mutants in the MexEF/OprN efflux pump and in the DNA repair genes recA and uvrB were hypersensitive to 10 mM HCOH, the killing rate being three to four orders of magnitude higher than those in the wild-type strain. Mutants in other upregulated genes died at slightly higher or at similar rates to the parental strain. Regarding growth inhibition, we found that mutants in glutathione biosynthesis, stress response mediated by 2-hydroxy acid dehydrogenases and two efflux pumps of the MSF family were unable to grow in the presence of 1.5 mM HCOH. In an independent screening test we searched for mutants which were hypersensitive to formaldehyde, but whose expression did not change in response to this chemical. Two mutants with insertions in recD and fhdA were found which were unable to grow in the presence of 1.5 mM HCOH. The recD mutant was hypersensitive to 10 mM HCOH and died at a higher rate than the parental strain. PMID- 21261834 TI - Poly-3-hydroxyalkanoate synthases from Pseudomonas putida U: substrate specificity and ultrastructural studies. AB - The substrate specificity of the two polymerases (PhaC1 and PhaC2) involved in the biosynthesis of medium-chain-length poly-hydroxyalkanoates (mcl PHAs) in Pseudomonas putida U has been studied in vivo. For these kind of experiments, two recombinant strains derived from a genetically engineered mutant in which the whole pha locus had been deleted (P. putida U Deltapha) were employed. These bacteria, which expresses only phaC1 (P. putida U Deltapha pMC-phaC1) or only phaC2 (P. putida U Deltapha pMC-phaC2), accumulated different PHAs in function of the precursor supplemented to the culture broth. Thus, the P. putida U Deltapha pMC-phaC1 strain was able to synthesize several aliphatic and aromatic PHAs when hexanoic, heptanoic, octanoic decanoic, 5-phenylvaleric, 6-phenylhexanoic, 7 phenylheptanoic, 8-phenyloctanoic or 9-phenylnonanoic acid were used as precursors; the highest accumulation of polymers was observed when the precursor used were decanoic acid (aliphatic PHAs) or 6-phenylhexanoic acid (aromatic PHAs). However, although it synthesizes similar aliphatic PHAs (the highest accumulation was observed when hexanoic acid was the precursor) the other recombinant strain (P. putida U Deltapha pMC-phaC2) only accumulated aromatic PHAs when the monomer to be polymerized was 3-hydroxy-5-phenylvaleryl-CoA. The possible influence of the putative three-dimensional structures on the different catalytic behaviour of PhaC1 and PhaC2 is discussed. PMID- 21261835 TI - Development of a LytE-based high-density surface display system in Bacillus subtilis. AB - The three N-terminal, tandemly arranged LysM motifs from a Bacillus subtilis cell wall hydrolase, LytE, formed a cell wall-binding module. This module, designated CWBM(LytE), was demonstrated to have tight cell wall-binding capability and could recognize two classes of cell wall binding sites with fivefold difference in affinity. The lower-affinity sites were approximately three times more abundant. Fusion proteins with beta-lactamase attached to either the N- or C-terminal end of CWBM(LytE) showed lower cell wall-binding affinity. The number of the wall bound fusion proteins was less than that of CWBM(LytE). These effects were less dramatic with CWBM(LytE) at the N-terminal end of the fusion. Both CWBM(LytE) and beta-lactamase were essentially functional whether they were at the N- or C terminal end of the fusion. In the optimal case, 1.2 * 10(7) molecules could be displayed per cell. As cells overproducing CWBM(LytE) and its fusions formed filamentous cells (with an average of nine individual cells per filamentous cell), 1.1 * 10(8)beta-lactamase molecules could be displayed per filamentous cell. Overproduced CWBM(LytE) and its fusions were distributed on the entire cell surface. Surface exposure and accessibility of these proteins were confirmed by immunofluorescence microscopy. PMID- 21261836 TI - An Arabidopsis thaliana ABC transporter that confers kanamycin resistance in transgenic plants does not endow resistance to Escherichia coli. AB - Concerns have been raised about potential horizontal gene transfer (HGT) of antibiotic resistance markers (ARMs) from transgenic plants to bacteria of medical and environmental importance. All ARMs used in transgenic plants have been bacterial in origin, but it has been recently shown that an Arabidopsis thaliana ABC transporter, Atwbc19, confers kanamycin resistance when overexpressed in transgenic plants. Atwbc19 was evaluated for its ability to transfer kanamycin resistance to Escherichia coli, a kanamycin-sensitive model bacterium, under simulated HGT, staged by subcloning Atwbc19 under the control of a bacterial promoter, genetically transforming to kanamycin-sensitive bacteria, and assessing if resistance was conferred as compared with bacteria harbouring nptII, the standard kanamycin resistance gene used to produce transgenic plants. NptII provided much greater resistance than Atwbc19 and was significantly different from the no-plasmid control at low concentrations. Atwbc19 was not significantly different from the no-plasmid control at higher concentrations. Even though HGT risks are considered low with nptII, Atwbc19 should have even lower risks, as its encoded protein is possibly mistargeted in bacteria. PMID- 21261838 TI - Energy, heat, flavours and aromas of Microbial Biotechnology. PMID- 21261839 TI - Unpublished but public microbial genomes with biotechnological relevance. PMID- 21261840 TI - Biofuels from microbes: a comprehensive view. PMID- 21261841 TI - Microbial-based motor fuels: science and technology. AB - The production of biofuels via microbial biotechnology is a very active field of research. A range of fuel molecule types are currently under consideration: alcohols, ethers, esters, isoprenes, alkenes and alkanes. At the present, the major alcohol biofuel is ethanol. The ethanol fermentation is an old technology. Ongoing efforts aim to increase yield and energy efficiency of ethanol production from biomass. n-Butanol, another microbial fermentation product, is potentially superior to ethanol as a fuel but suffers from low yield and unwanted side products currently. In general, biodiesel fuels consist of fatty acid methyl esters in which the carbon derives from plants, not microbes. A new biodiesel product, called microdiesel, can be generated in engineered bacterial cells that condense ethanol with fatty acids. Perhaps the best fuel type to generate from biomass would be biohydrocarbons. Microbes are known to produce hydrocarbons such as isoprenes, long-chain alkenes and alkanes. The biochemical mechanisms of microbial hydrocarbon biosynthesis are currently under study. Hydrocarbons and minimally oxygenated molecules may also be produced by hybrid chemical and biological processes. A broad interest in novel fuel molecules is also driving the development of new bioinformatics tools to facilitate biofuels research. PMID- 21261842 TI - Induction of natural competence in Bacillus cereus ATCC14579. AB - Natural competence is the ability of certain microbes to take up exogenous DNA from the environment and integrate it in their genome. Competence development has been described for a variety of bacteria, but has so far not been shown to occur in Bacillus cereus. However, orthologues of most proteins involved in natural DNA uptake in Bacillus subtilis could be identified in B. cereus. Here, we report that B. cereus ATCC14579 can become naturally competent. When expressing the B. subtilis ComK protein using an IPTG-inducible system in B. cereus ATCC14579, cells grown in minimal medium displayed natural competence, as either genomic DNA or plasmid DNA was shown to be taken up by the cells and integrated into the genome or stably maintained respectively. This work proves that a sufficient structural system for DNA uptake exists in B. cereus. Bacillus cereus can be employed as a model system to investigate the mechanism of DNA uptake in related bacteria such as Bacillus anthracis and Bacillus thuringiensis. Moreover, natural competence provides an important tool for biotechnology, as it will allow more efficient transformation of B. cereus and related organisms, e.g. to knockout genes in a high-throughput way. PMID- 21261843 TI - Tracing explosives in soil with transcriptional regulators of Pseudomonas putida evolved for responding to nitrotoluenes. AB - Although different biological approaches for detection of anti-personnel mines and other unexploded ordnance (UXO) have been entertained, none of them has been rigorously documented thus far in the scientific literature. The industrial 2,4,6 trinitrotoluene (TNT) habitually employed in the manufacturing of mines is at all times tainted with a small but significant proportion of the more volatile 2,4 dinitrotoluene (2,4 DNT) and other nitroaromatic compounds. By using mutation prone PCR and DNA sequence shuffling we have evolved in vitro and selected in vivo variants of the effector recognition domain of the toluene-responsive XylR regulator of the soil bacterium Pseudomonas putida that responds to mono-, bi- and trinitro substituted toluenes. Re-introduction of such variants in P. putida settled the transcriptional activity of the cognate promoters (Po and Pu) as a function of the presence of nitrotoluenes in the medium. When strains bearing transcriptional fusions to reporters with an optical output (luxAB, GFP) were spread on soil spotted with nitrotoluenes, the signal triggered by promoter activation allowed localization of the target compounds on the soil surface. Our data provide a proof of concept that non-natural transcription factors evolved to respond to nitroaromatics can be engineered in soil bacteria and inoculated on a target site to pinpoint the presence of explosives. This approach thus opens new ways to tackle this gigantic humanitarian problem. PMID- 21261844 TI - PEGylation of bacteriophages increases blood circulation time and reduces T helper type 1 immune response. AB - The increasing occurrence of antibiotic-resistant pathogens is of growing concern, and must be counteracted by alternative antimicrobial treatments. Bacteriophages represent the natural enemies of bacteria. However, the strong immune response following application of phages and rapid clearance from the blood stream are hurdles which need to be overcome. Towards our goal to render phages less immunogenic and prolong blood circulation time, we have chemically modified intact bacteriophages by conjugation of the non-immunogenic polymer monomethoxy-polyethylene glycol (mPEG) to virus proteins. As a proof of concept, we have used two different polyvalent and strictly virulent phages of the Myoviridae, representing typical candidates for therapeutical approaches: Felix O1 (infects Salmonella) and A511 (infects Listeria). Loss of phage infectivity after PEGylation was found to be proportional to the degree of modification, and could be conveniently controlled by adjusting the PEG concentration. When injected into naive mice, PEGylated phages showed a strong increase in circulation half-life, whereas challenge of immunized mice did not reveal a significant difference. Our results suggest that the prolonged half-life is due to decreased susceptibility to innate immunity as well as avoidance of cellular defence mechanisms. PEGylated viruses elicited significantly reduced levels of T helper type 1-associated cytokine release (IFN-gamma and IL-6), in both naive and immunized mice. This is the first study demonstrating that PEGylation can increases survival of infective phage by delaying immune responses, and indicates that this approach can increase efficacy of bacteriophage therapy. PMID- 21261845 TI - T-DNA insertion, plasmid rescue and integration analysis in the model mycorrhizal fungus Laccaria bicolor. AB - Ectomycorrhiza is a mutualistic symbiosis formed between fine roots of trees and the mycelium of soil fungi. This symbiosis plays a key role in forest ecosystems for the mineral nutrition of trees and the biology of the fungal communities associated. The characterization of genes involved in developmental and metabolic processes is important to understand the complex interactions that control the ectomycorrhizal symbiosis. Agrobacterium-mediated gene transfer (AMT) in fungi is currently opening a new era for fungal research. As whole genome sequences of several fungi are being released studies about T-DNA integration patterns are needed in order to understand the integration mechanisms involved and to evaluate the AMT as an insertional mutagenesis tool for different fungal species. The first genome sequence of a mycorrhizal fungus, the basidiomycete Laccaria bicolor, became public in July 2006. Release of Laccaria genome sequence and the availability of AMT makes this fungus an excellent model for functional genomic studies in ectomycorrhizal research. No data on the integration pattern in Laccaria genome were available, thus we optimized a plasmid rescue approach for this fungus. To this end the transformation vector (pHg/pBSk) was constructed allowing the rescue of the T-DNA right border (RB)-genomic DNA junctions in Escherichia coli. Fifty-one Agrobacterium-transformed fungal strains, picked up at random from a larger collection of T-DNA tagged strains (about 500), were analysed. Sixty-nine per cent were successfully rescued for the RB of which 87% were resolved for genomic integration sequences. Our results demonstrate that the plasmid rescue approach can be used for resolving T-DNA integration sites in Laccaria. The RB was well conserved during transformation of this fungus and the integration analysis showed no clear sequence homology between different genomic sites. Neither obvious sequence similarities were found between these sites and the T-DNA borders indicating non-homologous integration of the transgenes. Majority (75%) of the integrations were located in predicted genes. Agrobacterium mediated gene transfer is a powerful tool that can be used for functional gene studies in Laccaria and will be helpful along with plasmid rescue in searching for relevant fungal genes involved in the symbiotic process. PMID- 21261847 TI - Mining GOLD and new model organisms in biotechnology. PMID- 21261848 TI - Natural products genomics. PMID- 21261853 TI - What gets turned on in the rhizosphere? PMID- 21261852 TI - Genomics of biological wastewater treatment. PMID- 21261850 TI - Microbial reporters of metal bioavailability. AB - When attempting to assess the extent and the implications of environmental pollution, it is often essential to quantify not only the total concentration of the studied contaminant but also its bioavailable fraction: higher bioavailability, often correlated with increased mobility, signifies enhanced risk but may also facilitate bioremediation. Genetically engineered microorganisms, tailored to respond by a quantifiable signal to the presence of the target chemical(s), may serve as powerful tools for bioavailability assessment. This review summarizes the current knowledge on such microbial bioreporters designed to assay metal bioavailability. Numerous bacterial metal sensor strains have been developed over the past 15 years, displaying very high detection sensitivities for a broad spectrum of environmentally significant metal targets. These constructs are based on the use of a relatively small number of gene promoters as the sensing elements, and an even smaller selection of molecular reporter systems; they comprise a potentially useful panel of tools for simple and cost-effective determination of the bioavailability of heavy metals in the environment, and for the quantification of the non-bioavailable fraction of the pollutant. In spite of their inherent advantages, however, these tools have not yet been put to actual use in the evaluation of metal bioavailability in a real environmental remediation scheme. For this to happen, acceptance by regulatory authorities is essential, as is a standardization of assay conditions. PMID- 21261854 TI - Limits in energy generation and biotechnology of primary and secondary products. PMID- 21261849 TI - Metabolic regulation and overproduction of primary metabolites. AB - Overproduction of microbial metabolites is related to developmental phases of microorganisms. Inducers, effectors, inhibitors and various signal molecules play a role in different types of overproduction. Biosynthesis of enzymes catalysing metabolic reactions in microbial cells is controlled by well-known positive and negative mechanisms, e.g. induction, nutritional regulation (carbon or nitrogen source regulation), feedback regulation, etc. The microbial production of primary metabolites contributes significantly to the quality of life. Fermentative production of these compounds is still an important goal of modern biotechnology. Through fermentation, microorganisms growing on inexpensive carbon and nitrogen sources produce valuable products such as amino acids, nucleotides, organic acids and vitamins which can be added to food to enhance its flavour, or increase its nutritive values. The contribution of microorganisms goes well beyond the food and health industries with the renewed interest in solvent fermentations. Microorganisms have the potential to provide many petroleum-derived products as well as the ethanol necessary for liquid fuel. Additional applications of primary metabolites lie in their impact as precursors of many pharmaceutical compounds. The roles of primary metabolites and the microbes which produce them will certainly increase in importance as time goes on. In the early years of fermentation processes, development of producing strains initially depended on classical strain breeding involving repeated random mutations, each followed by screening or selection. More recently, methods of molecular genetics have been used for the overproduction of primary metabolic products. The development of modern tools of molecular biology enabled more rational approaches for strain improvement. Techniques of transcriptome, proteome and metabolome analysis, as well as metabolic flux analysis. have recently been introduced in order to identify new and important target genes and to quantify metabolic activities necessary for further strain improvement. PMID- 21261855 TI - Glutamate racemase as a target for drug discovery. AB - The bacterial cell wall is a highly cross-linked polymeric structure consisting of repeating peptidoglycan units, each of which contains a novel pentapeptide substitution which is cross-linked through transpeptidation. The incorporation of D-glutamate as the second residue is strictly conserved across the bacterial kingdom. Glutamate racemase, a member of the cofactor-independent, two-thiol based family of amino acid racemases, has been implicated in the production and maintenance of sufficient d-glutamate pool levels required for growth. The subject of over four decades of research, it is now evident that the enzyme is conserved and essential for growth across the bacterial kingdom and has a conserved overall topology and active site architecture; however, several different mechanisms of regulation have been observed. These traits have recently been targeted in the discovery of both narrow and broad spectrum inhibitors. This review outlines the biological history of this enzyme, the recent biochemical and structural characterization of isozymes from a wide range of species and developments in the identification of inhibitors that target the enzyme as possible therapeutic agents. PMID- 21261856 TI - Biotechnological applications of Listeria's sophisticated infection strategies. AB - Listeria monocytogenes is a Gram-positive bacterium that is able to survive both in the environment and to invade and multiply within eukaryotic cells. Currently L. monocytogenes represents one of the most well-studied and characterized microorganisms in bacterial pathogenesis. A hallmark of L. monocytogenes virulence is its ability to breach bodily barriers such as the intestinal epithelium, the blood-brain barrier as well as the placental barrier to cause severe systemic disease. Curiously, this theme is repeated at the level of the interaction between the individual cell and the bacterium where its virulence factors contribute to the ability of the bacteria to breach cellular barriers. L. monocytogenes is a model to study metabolic requirements of bacteria growing in an intracellular environment, modulation of signalling pathways in the infected cell and interactions with cellular defences involving innate and adaptive immunity. Technical advances such as the creation of LISTERIA-susceptible mouse strains, had added interest in the study of the natural pathogenesis of the disease via oral infection. The use of attenuated strains of L. monocytogenes as vaccines has gained considerable interest because they can be used to express heterologous antigens as well as to somatically deliver recombinant DNA to eukaryotic cells. A novel vaccine concept, the use of non-viable but metabolically active bacteria to induced immunoprotective responses, has been developed with L. monocytogenes. In this mini-review, we review the strategies used by L. monocytogenes to subvert the cellular functions at different stages of the infection cycle in the host and examine how these properties are being exploited in biotechnological and clinical applications. PMID- 21261857 TI - Community structure and antibiotic production of Streptomyces nodosus bioreactors cultured in liquid environments. AB - Immobilized bacteria are being assessed by industry for drug delivery, novel fermentation systems and the protection of organisms in harsh environments. Alginate bioreactors containing Streptomyces nodosus were examined for community structure, cell viability and amphotericin production under different growth conditions. When cell proliferation was encouraged, substrate hyphae were found inside the alginate matrix and within multicellular projections on the surface of the capsule. The periphery of these projections had erect and branched hyphae, morphologically identical to aerial hyphae. Antibiotic production from immobilized organisms was assessed using conditioned culture medium to eliminate the emergence of a free-dwelling population. These organisms sporulated with reduced antibiotic production compared with free-dwelling cultures. The commitment to sporulate was independent of a surface but dependent on community size and nutritional status. This is the first report of the sporulation of S. nodosus in liquid cultures and description of the multicellular community the organism adopts at a solid-liquid interface. PMID- 21261858 TI - Constructing and testing the thermodynamic limits of synthetic NAD(P)H:H2 pathways. AB - NAD(P)H:H(2) pathways are theoretically predicted to reach equilibrium at very low partial headspace H(2) pressure. An evaluation of the directionality of such near-equilibrium pathways in vivo, using a defined experimental system, is therefore important in order to determine its potential for application. Many anaerobic microorganisms have evolved NAD(P)H:H(2) pathways; however, they are either not genetically tractable, and/or contain multiple H(2) synthesis/consumption pathways linked with other more thermodynamically favourable substrates, such as pyruvate. We therefore constructed a synthetic ferredoxin-dependent NAD(P)H:H(2) pathway model system in Escherichia coli BL21(DE3) and experimentally evaluated the thermodynamic limitations of nucleotide pyridine-dependent H(2) synthesis under closed batch conditions. NADPH dependent H(2) accumulation was observed with a maximum partial H(2) pressure equivalent to a biochemically effective intracellular NADPH/NADP(+) ratio of 13:1. The molar yield of the NADPH:H(2) pathway was restricted by thermodynamic limitations as it was strongly dependent on the headspace:liquid ratio of the culture vessels. When the substrate specificity was extended to NADH, only the reverse pathway directionality, H(2) consumption, was observed above a partial H(2) pressure of 40 Pa. Substitution of NADH with NADPH or other intermediates, as the main electron acceptor/donor of glucose catabolism and precursor of H(2), is more likely to be applicable for H(2) production. PMID- 21261859 TI - Aldehyde oxidase carrying an unusual subunit structure from Pseudomonas sp. MX 058. AB - Pseudomonas sp. MX-058 produces aldehyde oxidase catalysing glyoxal to glyoxylic acid. Two aldehyde oxidases (F10 and F13) were purified to homogeneity from Pseudomonas sp. MX-058. F10 and F13 had subunit structures, a heterotetramer and heteropentamer respectively. The N-terminal amino acid sequences of all subunits were highly homologous to amino acid sequences of the putative oxidoreductases of Pseudomonas strains. All of these homologous oxidoreductases have a heterotrimer structure consisting of 85-88 (alpha), 37-39 (beta) and 18-23 (gamma) kDa subunits. However, the alpha-subunits of F10 and F13 might have decomposed into two [80 (alpha(1)) and 9 kDa (alpha(2))] and three [58 (alpha(1')), 22 (alpha(1")) and 9 (alpha(2)) kDa] subunits, respectively, while the beta- and gamma-subunits remained intact. Both F10 and F13 show high activity toward several aliphatic and aromatic aldehydes. The aldehyde oxidases of Pseudomonas sp. MX-058 has unique protein structures, alpha(1)alpha(2)betagamma for F10 and alpha(1')alpha(1")alpha(2)betagamma for F13, a heterotetramer and heteropentamer respectively. The enzymes exhibit significantly low activity toward glyoxylic acid compared with glyoxal, which is an advantageous property for glyoxylic acid production from glyoxal. PMID- 21261860 TI - Exploration of twin-arginine translocation for expression and purification of correctly folded proteins in Escherichia coli. AB - Historically, the general secretory (Sec) pathway of Gram-negative bacteria has served as the primary route by which heterologous proteins are delivered to the periplasm in numerous expression and engineering applications. Here we have systematically examined the twin-arginine translocation (Tat) pathway as an alternative, and possibly advantageous, secretion pathway for heterologous proteins. Overall, we found that: (i) export efficiency and periplasmic yield of a model substrate were affected by the composition of the Tat signal peptide, (ii) Tat substrates were correctly processed at their N-termini upon reaching the periplasm and (iii) proteins fused to maltose-binding protein (MBP) were reliably exported by the Tat system, but only when correctly folded; aberrantly folded MBP fusions were excluded by the Tat pathway's folding quality control feature. We also observed that Tat export yield was comparable to Sec for relatively small, well-folded proteins, higher relative to Sec for proteins that required cytoplasmic folding, and lower relative to Sec for larger, soluble fusion proteins. Interestingly, the specific activity of material purified from the periplasm was higher for certain Tat substrates relative to their Sec counterparts, suggesting that Tat expression can give rise to relatively pure and highly active proteins in one step. PMID- 21261861 TI - Hypersensitive response and acyl-homoserine lactone production of the fire blight antagonists Erwinia tasmaniensis and Erwinia billingiae. AB - Fire blight caused by the Gram-negative bacterium Erwinia amylovora can be controlled by antagonistic microorganisms. We characterized epiphytic bacteria isolated from healthy apple and pear trees in Australia, named Erwinia tasmaniensis, and the epiphytic bacterium Erwinia billingiae from England for physiological properties, interaction with plants and interference with growth of E. amylovora. They reduced symptom formation by the fire blight pathogen on immature pears and the colonization of apple flowers. In contrast to E. billingiae, E. tasmaniensis strains induced a hypersensitive response in tobacco leaves and synthesized levan in the presence of sucrose. With consensus primers deduced from lsc as well as hrpL, hrcC and hrcR of the hrp region of E. amylovora and of related bacteria, these genes were successfully amplified from E. tasmaniensis DNA and alignment of the encoded proteins to other Erwinia species supported a role for environmental fitness of the epiphytic bacterium. Unlike E. tasmaniensis, the epiphytic bacterium E. billingiae produced an acyl-homoserine lactone for bacterial cell-to-cell communication. Their competition with the growth of E. amylovora may be involved in controlling fire blight. PMID- 21261862 TI - Erythrophore cell response to food-associated pathogenic bacteria: implications for detection. AB - Cell-based biosensors have been proposed for use as function-based detectors of toxic agents. We report the use of Betta splendens chromatophore cells, specifically erythrophore cells, for detection of food-associated pathogenic bacteria. Evaluation of erythrophore cell response, using Bacillus spp., has revealed that this response can distinguish pathogenic Bacillus cereus from a non pathogenic B. cereus DeltaplcR deletion mutant and a non-pathogenic Bacillus subtilis. Erythrophore cells were exposed to Salmonella enteritidis, Clostridium perfringens and Clostridium botulinum. Each bacterial pathogen elicited a response from erythrophore cells that was distinguished from the corresponding bacterial growth medium, and this observed response was unique for each bacterial pathogen. These findings suggest that erythrophore cell response has potential for use as a biosensor in the detection and toxicity assessment for food associated pathogenic bacteria. PMID- 21261864 TI - Genomics of dairy fermentations. PMID- 21261865 TI - Environmental Microbiology meets Microbial Biotechnology. PMID- 21261866 TI - Outlook for benefits of sediment microbial fuel cells with two bio-electrodes. AB - The benefits of sediment microbial fuel cells (SMFCs) go beyond energy generation for low-power applications. Aside from producing electrical energy, SMFCs can enhance the oxidation of reduced compounds at the anode, thus bringing about the removal of excessive or unwanted reducing equivalents from submerged soils. Moreover, an SMFC could be applied to control redox-dependent processes in sediment layers. Several cathodic reactions that may drive these sediment oxidation reactions are examined. Special attention is given to two biologically mediated cathodic reactions, respectively employing an oxygen reduction and a manganese cycle. Both reactions imply a low cost and a high electrode potential and are of interest for reactor-type MFCs as well as for SMFCs. PMID- 21261867 TI - Do transgenic plants affect rhizobacteria populations? AB - Plant genetic manipulation has led to the development of genetically modified plants (GMPs) expressing various traits. Since their first commercial use in 1996, GMPs have been increasingly used, reaching a global cultivating production area of 114.3 million hectares in 2007. The rapid development of agricultural biotechnology and release of GMPs have provided many agronomic and economic benefits, but has also raised concerns over the potential impact these plants might have on the environment. Among these environmental concerns, the unintentional impact that GMPs might have on soil-associated microbes, especially rhizosphere-inhabiting bacteria or rhizobacteria, represents one of the least studied and understood areas. As rhizobacteria are responsible for numerous key functions including nutrient cycling and decomposition, they have been defined as good indicator organisms to assess the general impact that GMPs might have on the soil environment. This minireview summarizes the results of various experiments that have been conducted to date on the impact of GMPs on rhizobacteria. Both biological and technical parameters are discussed and an attempt is made to determine if specific rhizobacterial responses exist for the different categories of GMPs developed to date. PMID- 21261868 TI - Metabolically engineered Escherichia coli for efficient production of glycosylated natural products. AB - Significant achievements in polyketide gene expression have made Escherichia coli one of the most promising hosts for the heterologous production of pharmacologically important polyketides. However, attempts to produce glycosylated polyketides, by the expression of heterologous sugar pathways, have been hampered until now by the low levels of glycosylated compounds produced by the recombinant hosts. By carrying out metabolic engineering of three endogenous pathways that lead to the synthesis of TDP sugars in E. coli, we have greatly improved the intracellular levels of the common deoxysugar intermediate TDP-4 keto-6-deoxyglucose resulting in increased production of the heterologous sugars TDP-L-mycarose and TDP-D-desosamine, both components of medically important polyketides. Bioconversion experiments carried out by feeding 6 deoxyerythronolide B (6-dEB) or 3-alpha-mycarosylerythronolide B (MEB) demonstrated that the genetically modified E. coli B strain was able to produce 60- and 25-fold more erythromycin D (EryD) than the original strain K207-3, respectively. Moreover, the additional knockout of the multidrug efflux pump AcrAB further improved the ability of the engineered strain to produce these glycosylated compounds. These results open the possibility of using E. coli as a generic host for the industrial scale production of glycosylated polyketides, and to combine the polyketide and deoxysugar combinatorial approaches with suitable glycosyltransferases to yield massive libraries of novel compounds with variations in both the aglycone and the tailoring sugars. PMID- 21261869 TI - High shear enrichment improves the performance of the anodophilic microbial consortium in a microbial fuel cell. AB - In many microbial bioreactors, high shear rates result in strong attachment of microbes and dense biofilms. In this study, high shear rates were applied to enrich an anodophilic microbial consortium in a microbial fuel cell (MFC). Enrichment at a shear rate of about 120 s(-1) resulted in the production of a current and power output two to three times higher than those in the case of low shear rates (around 0.3 s(-1)). Biomass and biofilm analyses showed that the anodic biofilm from the MFC enriched under high shear rate conditions, in comparison with that under low shear rate conditions, had a doubled average thickness and the biomass density increased with a factor 5. The microbial community of the former, as analysed by DGGE, was significantly different from that of the latter. The results showed that enrichment by applying high shear rates in an MFC can result in a specific electrochemically active biofilm that is thicker and denser and attaches better, and hence has a better performance. PMID- 21261871 TI - Manganese-oxidizing bacteria mediate the degradation of 17alpha-ethinylestradiol. AB - Manganese (II) and manganese-oxidizing bacteria were used as an efficient biological system for the degradation of the xenoestrogen 17alpha ethinylestradiol (EE2) at trace concentrations. Mn(2+)-derived higher oxidation states of Mn (Mn(3+), Mn(4+)) by Mn(2+)-oxidizing bacteria mediate the oxidative cleavage of the polycyclic target compound EE2. The presence of manganese (II) was found to be essential for the degradation of EE2 by Leptothrix discophora, Pseudomonas putida MB1, P. putida MB6 and P. putida MB29. Mn(2+)-dependent degradation of EE2 was found to be a slow process, which requires multi-fold excess of Mn(2+) and occurs in the late stationary phase of growth, implying a chemical process taking place. EE2-derived degradation products were shown to no longer exhibit undesirable estrogenic activity. PMID- 21261870 TI - Identification of furfural as a key toxin in lignocellulosic hydrolysates and evolution of a tolerant yeast strain. AB - The production of fuel ethanol from low-cost lignocellulosic biomass currently suffers from several limitations. One of them is the presence of inhibitors in lignocellulosic hydrolysates that are released during pre-treatment. These compounds inhibit growth and hamper the production of ethanol, thereby affecting process economics. To delineate the effects of such complex mixtures, we conducted a chemical analysis of four different real-world lignocellulosic hydrolysates and determined their toxicological effect on yeast. By correlating the potential inhibitor abundance to the growth-inhibiting properties of the corresponding hydrolysates, we identified furfural as an important contributor to hydrolysate toxicity for yeast. Subsequently, we conducted a targeted evolution experiment to improve growth behaviour of the half industrial Saccharomyces cerevisiae strain TMB3400 in the hydrolysates. After about 300 generations, representative clones from these evolved populations exhibited significantly reduced lag phases in medium containing the single inhibitor furfural, but also in hydrolysate-supplemented medium. Furthermore, these strains were able to grow at concentrations of hydrolysates that effectively killed the parental strain and exhibited significantly improved bioconversion characteristics under industrially relevant conditions. The improved resistance of our evolved strains was based on their capacity to remain viable in a toxic environment during the prolonged, furfural induced lag phase. PMID- 21261873 TI - Directed evolution of Aspergillus niger glucoamylase to increase thermostability. AB - Using directed evolution and site-directed mutagenesis, we have isolated a highly thermostable variant of Aspergillus niger glucoamylase (GA), designated CR2-1. CR2-1 includes the previously described mutations Asn20Cys and Ala27Cys (forming a new disulfide bond), Ser30Pro, Thr62Ala, Ser119Pro, Gly137Ala, Thr290Ala, His391Tyr and Ser436Pro. In addition, CR2-1 includes several new putative thermostable mutations, Val59Ala, Val88Ile, Ser211Pro, Asp293Ala, Thr390Ser, Tyr402Phe and Glu408Lys, identified by directed evolution. CR2-1 GA has a catalytic efficiency (k(cat)/K(m)) at 35 degrees C and a specific activity at 50 degrees C similar to that of wild-type GA. Irreversible inactivation tests indicated that CR2-1 increases the free energy of thermoinactivation at 80 degrees C by 10 kJ mol(-1) compared with that of wild-type GA. Thus, CR2-1 is more thermostable (by 5 kJ mol(-1) at 80 degrees C) than the most thermostable A. niger GA variant previously described, THS8. In addition, Val59Ala and Glu408Lys were shown to individually increase the thermostability in GA variants by 1 and 2 kJ mol(-1), respectively, at 80 degrees C. PMID- 21261876 TI - Microbial Biotechnology. Editorial. PMID- 21261874 TI - Decreasing Enterobacter sakazakii (Cronobacter spp.) food contamination level with bacteriophages: prospects and problems. AB - Enterobacter sakazakii (Cronobacter spp.) is an opportunistic pathogen, which can cause rare, but life-threatening infections in neonates and infants through feeding of a contaminated milk formula. We isolated 67 phages from environmental samples and tested their lytic host range on a representative collection of 40 E. sakazakii strains. A cocktail of five phages prevented the outgrowth of 35 out of 40 test strains in artificially contaminated infant formula. Two E. sakazakii phages represented prolate head Myoviridae. Molecular tests identified them as close relatives of Escherichia coli phage T4. The remaining three phages represented isometric head Myoviridae with large genome size of 140 and 200 kb, respectively, which belonged to two different DNA hybridization groups. A high dose of 10(8) pfu ml(-1) of phage could effectively sterilize a broth contaminated with both high and low pathogen counts (10(6) and 10(2) cfu ml(-1)). In contrast, broth inoculated with 10(4) phage and 10(2) bacteria per ml first showed normal bacterial growth until reaching a cell titre of 10(5) cfu ml(-1). Only when crossing this threshold, phage replication started, but it could not reduce the contamination level below 100 cfu ml(-1). Phages could be produced with titres of 10(10) pfu ml(-1) in broth culture, but they were not stable upon freeze-drying. Addition of trehalose or milk formula stabilized the phage preparation, which then showed excellent storage stability even at elevated temperature. PMID- 21261877 TI - A broad range of themes in Microbial Biotechnology. PMID- 21261872 TI - Development of an oligonucleotide microarray method for Salmonella serotyping. AB - Adequate identification of Salmonella enterica serovars is a prerequisite for any epidemiological investigation. This is traditionally obtained via a combination of biochemical and serological typing. However, primary strain isolation and traditional serotyping is time-consuming and faster methods would be desirable. A microarray, based on two housekeeping and two virulence marker genes (atpD, gyrB, fliC and fljB), has been developed for the detection and identification of the two species of Salmonella (S. enterica and S. bongori), the five subspecies of S. enterica (II, IIIa, IIIb, IV, VI) and 43 S. enterica ssp. enterica serovars (covering the most prevalent ones in Austria and the UK). A comprehensive set of probes (n = 240), forming 119 probe units, was developed based on the corresponding sequences of 148 Salmonella strains, successfully validated with 57 Salmonella strains and subsequently evaluated with 35 blind samples including isolated serotypes and mixtures of different serotypes. Results demonstrated a strong discriminatory ability of the microarray among Salmonella serovars. Threshold for detection was 1 colony forming unit per 25 g of food sample following overnight (14 h) enrichment. PMID- 21261878 TI - Human flora-associated rodents--does the data support the assumptions? AB - There is little direct literature detailing exhaustive bacteriological studies comparing human donor faecal flora, human flora-associated (HFA) mouse models and conventional rodent faecal flora. While there is a premise that the implanted donor faecal flora from humans is established in the rodent model the evidence is incomplete and indeed for groups such as Bifidobacterium spp. it is lacking. The reviewed bacteriology studies are generally lacking in detail with the exception of one study from which the data have mostly been overlooked when cited by other workers. While there are studies that suggest that the HFA rodent model is more relevant to man than studies with conventional rodents, the hypothesis remains to be proven. This review concludes that the established microbial flora in the HFA rodent model is different to that of donor human faecal flora, and this clearly raises the question as to whether this matters, after all a model is a model and as such models can be useful even should they fail to be a true representation of, in this case, the gastrointestinal tract. What matters is that there is a proper understanding of the limitations of the model as we attempt to unravel the significance of the components of the gastrointestinal flora in health and disease; examples of why such an analysis is important are provided with regard to obesity and nutritional studies. The data do unsurprisingly suggest that diet is an extremely influential variable when interpreting HFA and conventional rodent data. The microbiology data from direct bacteriology and indirect enzyme studies show that the established microbial flora in the HFA rodent model is different to that of donor human faecal flora. The significance of this conclusion remains to be established. PMID- 21261879 TI - Positively regulated bacterial expression systems. AB - Regulated promoters are useful tools for many aspects related to recombinant gene expression in bacteria, including for high-level expression of heterologous proteins and for expression at physiological levels in metabolic engineering applications. In general, it is common to express the genes of interest from an inducible promoter controlled either by a positive regulator or by a repressor protein. In this review, we discuss established and potentially useful positively regulated bacterial promoter systems, with a particular emphasis on those that are controlled by the AraC-XylS family of transcriptional activators. The systems function in a wide range of microorganisms, including enterobacteria, soil bacteria, lactic bacteria and streptomycetes. The available systems that have been applied to express heterologous genes are regulated either by sugars (L arabinose, L-rhamnose, xylose and sucrose), substituted benzenes, cyclohexanone related compounds, epsilon-caprolactam, propionate, thiostrepton, alkanes or peptides. It is of applied interest that some of the inducers require the presence of transport systems, some are more prone than others to become metabolized by the host and some have been applied mainly in one or a limited number of species. Based on bioinformatics analyses, the AraC-XylS family of regulators contains a large number of different members (currently over 300), but only a small fraction of these, the XylS/Pm, AraC/P(BAD), RhaR-RhaS/rhaBAD, NitR/PnitA and ChnR/Pb regulator/promoter systems, have so far been explored for biotechnological applications. PMID- 21261880 TI - Interplay of metagenomics and in vitro compartmentalization. AB - In recent years, the application of approaches for harvesting DNA from the environment, the so-called, 'metagenomic approaches' has proven to be highly successful for the identification, isolation and generation of novel enzymes. Functional screening for the desired catalytic activity is one of the key steps in mining metagenomic libraries, as it does not rely on sequence homology. In this mini-review, we survey high-throughput screening tools, originally developed for directed evolution experiments, which can be readily adapted for the screening of large libraries. In particular, we focus on the use of in vitro compartmentalization (IVC) approaches to address potential advantages and problems the merger of culture-independent and IVC techniques might bring on the mining of enzyme activities in microbial communities. PMID- 21261882 TI - Uracil influences quorum sensing and biofilm formation in Pseudomonas aeruginosa and fluorouracil is an antagonist. AB - Pseudomonas aeruginosa is an ubiquitous, opportunistic pathogen whose biofilms are notoriously difficult to control. Here we discover uracil influences all three known quorum-sensing (QS) pathways of P. aeruginosa. By screening 5850 transposon mutants for altered biofilm formation, we identified seven uracil related mutations that abolished biofilm formation. Whole-transcriptome studies showed the uracil mutations (e.g. pyrF that catalyses the last step in uridine monophosphate synthesis) alter the regulation of all three QS pathways [LasR-, RhlR- and 2-heptyl-3-hydroxy-4-quinolone (PQS)-related regulons]; addition of extracellular uracil restored global wild-type regulation. Phenotypic studies confirmed uracil influences the LasR (elastase), RhlR (pyocyanin, rhamnolipids), PQS and swarming regulons. Our results also demonstrate uracil influences virulence (the pyrF mutant was less virulent to barley). Additionally, we found an anticancer uracil analogue, 5-fluorouracil, that repressed biofilm formation, abolished QS phenotypes and reduced virulence. Hence, we have identified a central regulator of an important pathogen and a potential novel class of efficacious drugs for controlling cellular behaviour (e.g. biofilm formation and virulence). PMID- 21261881 TI - Mechanism of action of and resistance to quinolones. AB - Fluoroquinolones are an important class of wide-spectrum antibacterial agents. The first quinolone described was nalidixic acid, which showed a narrow spectrum of activity. The evolution of quinolones to more potent molecules was based on changes at positions 1, 6, 7 and 8 of the chemical structure of nalidixic acid. Quinolones inhibit DNA gyrase and topoisomerase IV activities, two enzymes essential for bacteria viability. The acquisition of quinolone resistance is frequently related to (i) chromosomal mutations such as those in the genes encoding the A and B subunits of the protein targets (gyrA, gyrB, parC and parE), or mutations causing reduced drug accumulation, either by a decreased uptake or by an increased efflux, and (ii) quinolone resistance genes associated with plasmids have been also described, i.e. the qnr gene that encodes a pentapeptide, which blocks the action of quinolones on the DNA gyrase and topoisomerase IV; the aac(6')-Ib-cr gene that encodes an acetylase that modifies the amino group of the piperazin ring of the fluoroquinolones and efflux pump encoded by the qepA gene that decreases intracellular drug levels. These plasmid-mediated mechanisms of resistance confer low levels of resistance but provide a favourable background in which selection of additional chromosomally encoded quinolone resistance mechanisms can occur. PMID- 21261883 TI - Indole and 7-hydroxyindole diminish Pseudomonas aeruginosa virulence. AB - Indole is an extracellular biofilm signal for Escherichia coli, and many bacterial oxygenases readily convert indole to various oxidized compounds including 7-hydroxyindole (7HI). Here we investigate the impact of indole and 7HI on Pseudomonas aeruginosa PAO1 virulence and quorum sensing (QS)-regulated phenotypes; this strain does not synthesize these compounds but degrades them rapidly. Indole and 7HI both altered extensively gene expression in a manner opposite that of acylhomoserine lactones; the most repressed genes encode the mexGHI-opmD multidrug efflux pump and genes involved in the synthesis of QS regulated virulence factors including pyocyanin (phz operon), 2-heptyl-3-hydroxy 4(1H)-quinolone (PQS) signal (pqs operon), pyochelin (pch operon) and pyoverdine (pvd operon). Corroborating these microarray results, indole and 7HI decreased production of pyocyanin, rhamnolipid, PQS and pyoverdine and enhanced antibiotic resistance. In addition, indole affected the utilization of carbon, nitrogen and phosphorus, and 7HI abolished swarming motility. Furthermore, 7HI reduced pulmonary colonization of P. aeruginosa in guinea pigs and increased clearance in lungs. Hence, indole-related compounds have potential as a novel antivirulence approach for the recalcitrant pathogen P. aeruginosa. PMID- 21261884 TI - Functional analysis of aromatic biosynthetic pathways in Pseudomonas putida KT2440. AB - Pseudomonas putida KT2440 is a non-pathogenic prototrophic bacterium with high potential for biotechnological applications. Despite all that is known about this strain, the biosynthesis of essential chemicals has not been fully analysed and auxotroph mutants are scarce. We carried out massive mini-Tn5 random mutagenesis and screened for auxotrophs that require aromatic amino acids. The biosynthesis of aromatic amino acids was analysed in detail including physical and transcriptional organization of genes, complementation assays and feeding experiments to establish pathway intermediates. There is a single pathway from chorismate leading to the biosynthesis of tryptophan, whereas the biosynthesis of phenylalanine and tyrosine is achieved through multiple convergent pathways. Genes for tryptophan biosynthesis are grouped in unlinked regions with the trpBA and trpGDE genes organized as operons and the trpI, trpE and trpF genes organized as single transcriptional units. The pheA and tyrA gene-encoding multifunctional enzymes for phenylalanine and tyrosine biosynthesis are linked in the chromosome and form an operon with the serC gene involved in serine biosynthesis. The last step in the biosynthesis of these two amino acids requires an amino transferase activity for which multiple tyrB-like genes are present in the host chromosome. PMID- 21261885 TI - Arabinoxylan-oligosaccharides (AXOS) affect the protein/carbohydrate fermentation balance and microbial population dynamics of the Simulator of Human Intestinal Microbial Ecosystem. AB - Arabinoxylan-oligosaccharides (AXOS) are a recently newly discovered class of candidate prebiotics as - depending on their structure - they are fermented in different regions of gastrointestinal tract. This can have an impact on the protein/carbohydrate fermentation balance in the large intestine and, thus, affect the generation of potentially toxic metabolites in the colon originating from proteolytic activity. In this study, we screened different AXOS preparations for their impact on the in vitro intestinal fermentation activity and microbial community structure. Short-term fermentation experiments with AXOS with an average degree of polymerization (avDP) of 29 allowed part of the oligosaccharides to reach the distal colon, and decreased the concentration of proteolytic markers, whereas AXOS with lower avDP were primarily fermented in the proximal colon. Additionally, prolonged supplementation of AXOS with avDP 29 to the Simulator of Human Intestinal Microbial Ecosystem (SHIME) reactor decreased levels of the toxic proteolytic markers phenol and p-cresol in the two distal colon compartments and increased concentrations of beneficial short-chain fatty acids (SCFA) in all colon vessels (25-48%). Denaturant gradient gel electrophoresis (DGGE) analysis indicated that AXOS supplementation only slightly modified the total microbial community, implying that the observed effects on fermentation markers are mainly caused by changes in fermentation activity. Finally, specific quantitative PCR (qPCR) analysis showed that AXOS supplementation significantly increased the amount of health-promoting lactobacilli as well as of Bacteroides-Prevotella and Clostridium coccoides Eubacterium rectale groups. These data allow concluding that AXOS are promising candidates to modulate the microbial metabolism in the distal colon. PMID- 21261888 TI - Bioremediation, a broad perspective. PMID- 21261886 TI - tmRNA of Streptomyces collinus and Streptomyces griseus during the growth and in the presence of antibiotics. AB - Streptomycetes are soil microorganisms with the potential to produce a broad spectrum of secondary metabolities. The production of antibiotics is accompanied by a decrease in protein synthesis, which raises the question of how these bacteria survived the transition from the primary to the secondary metabolism. Translating ribosomes incapable to properly elongate or terminate polypeptide chain activate bacterial trans-translation system. Abundance and stability of the tmRNA during growth of Streptomyces collinus and Streptomyces griseus producing kirromycin and streptomycin, respectively, was analysed. The level of tmRNA is mostly proportional to the activity of the translational system. We demonstrate that the addition of sub-inhibitory concentrations of produced antibiotics to the cultures from the beginning of the exponential phase of growth leads to an increase in tmRNA levels and to an incorporation of amino acids into the tag peptides at trans-translation of stalled ribosomes. These findings suggest that produced antibiotics induce tmRNA that facilitate reactivation of stalled complex of ribosomes and maintain viability. The effect of antibiotics that inhibit the cell-wall turnover, DNA, RNA or protein synthesis on the level of tmRNA was examined. Antibiotics interfering with ribosomal target sites are more effective at stimulation of the tmRNA level in streptomycetes examined than those affecting the synthesis of DNA, RNA or the cell wall. PMID- 21261889 TI - Mining for new enzymes. PMID- 21261890 TI - Food and gut microbes for thoughts. PMID- 21261891 TI - Predictions: evolutionary trajectories and planet medicine. PMID- 21261892 TI - Back to the roots. PMID- 21261893 TI - The microbial reactome. PMID- 21261894 TI - Microbial genomics as pursuit of happiness. PMID- 21261896 TI - Metagenetics: spending our inheritance on the future. PMID- 21261895 TI - Optimizing rational vaccine design. PMID- 21261897 TI - Future shock from the microbe electric. PMID- 21261898 TI - Listening to microbial conversations. PMID- 21261899 TI - Microbial biotechnology meets environmental microbiology. PMID- 21261900 TI - Building bugs. PMID- 21261901 TI - Removal of organic toxic chemicals in the rhizosphere and phyllosphere of plants. PMID- 21261902 TI - Visualizing bacterial surfaces in real time. PMID- 21261903 TI - Coral microbiology. PMID- 21261904 TI - Measurements versus understanding: the (metabol)omics dilemma. PMID- 21261905 TI - Engineered exploitation of microbial potential. PMID- 21261906 TI - Human biome biotechnology and the personalization of odour profiles. PMID- 21261907 TI - The future is artificial. PMID- 21261908 TI - Mining the microbes--the human microbiome as model. PMID- 21261909 TI - Predictive microbial ecology. PMID- 21261910 TI - Genomics of deep-sea and sub-seafloor microbes. PMID- 21261911 TI - Microbial degradation of lignin: how a bulky recalcitrant polymer is efficiently recycled in nature and how we can take advantage of this. AB - Lignin is the second most abundant constituent of the cell wall of vascular plants, where it protects cellulose towards hydrolytic attack by saprophytic and pathogenic microbes. Its removal represents a key step for carbon recycling in land ecosystems, as well as a central issue for industrial utilization of plant biomass. The lignin polymer is highly recalcitrant towards chemical and biological degradation due to its molecular architecture, where different non phenolic phenylpropanoid units form a complex three-dimensional network linked by a variety of ether and carbon-carbon bonds. Ligninolytic microbes have developed a unique strategy to handle lignin degradation based on unspecific one-electron oxidation of the benzenic rings in the different lignin substructures by extracellular haemperoxidases acting synergistically with peroxide-generating oxidases. These peroxidases poses two outstanding characteristics: (i) they have unusually high redox potential due to haem pocket architecture that enables oxidation of non-phenolic aromatic rings, and (ii) they are able to generate a protein oxidizer by electron transfer to the haem cofactor forming a catalytic tryptophanyl-free radical at the protein surface, where it can interact with the bulky lignin polymer. The structure-function information currently available is being used to build tailor-made peroxidases and other oxidoreductases as industrial biocatalysts. PMID- 21261912 TI - Atrazine biodegradation in the lab and in the field: enzymatic activities and gene regulation. AB - Atrazine is an herbicide of the s-triazine family that is used primarily as a nitrogen source by degrading microorganisms. While many catabolic pathways for xenobiotics are subjected to catabolic repression by preferential carbon sources, atrazine utilization is repressed in the presence of preferential nitrogen sources. This phenomenon appears to restrict atrazine elimination in nitrogen fertilized soils by indigenous organisms or in bioaugmentation approaches. The mechanisms of nitrogen control have been investigated in the model strain Pseudomonas sp. ADP. Expression of atzA, atzB ad atzC, involved in the conversion of atrazine in cyanuric acid, is constitutive. The atzDEF operon, encoding the enzymes responsible for cyanuric acid mineralization, is a target for general nitrogen control. Regulation of atzDEF involves a complex interplay between the global regulatory elements of general nitrogen control and the pathway-specific LysR-type regulator AtzR. In addition, indirect evidence suggests that atrazine transport may also be a target for nitrogen regulation in this strain. The knowledge about regulatory mechanisms may allow the design of rational bioremediation strategies such as biostimulation using carbon sources or the use of mutant strains impaired in the assimilation of nitrogen sources for bioaugmentation. PMID- 21261914 TI - Field metabolomics and laboratory assessments of anaerobic intrinsic bioremediation of hydrocarbons at a petroleum-contaminated site. AB - Field metabolomics and laboratory assays were used to assess the in situ anaerobic attenuation of hydrocarbons in a contaminated aquifer underlying a former refinery. Benzene, ethylbenzene, 2-methylnaphthalene, 1,2,4- and 1,3,5 trimethylbenzene were targeted as contaminants of greatest regulatory concern (COC) whose intrinsic remediation has been previously reported. Metabolite profiles associated with anaerobic hydrocarbon decay revealed the microbial utilization of alkylbenzenes, including the trimethylbenzene COC, PAHs and several n-alkanes in the contaminated portions of the aquifer. Anaerobic biodegradation experiments designed to mimic in situ conditions showed no loss of exogenously amended COC; however, a substantive rate of endogenous electron acceptor reduction was measured (55 +/- 8 uM SO(4) day(-1)). An assessment of hydrocarbon loss in laboratory experiments relative to a conserved internal marker revealed that non-COC hydrocarbons were being metabolized. Purge and trap analysis of laboratory assays showed a substantial loss of toluene, m- and o xylene, as well as several alkanes (C(6)-C(12)). Multiple lines of evidence suggest that benzene is persistent under the prevailing site anaerobic conditions. We could find no in situ benzene intermediates (phenol or benzoate), the parent molecule proved recalcitrant in laboratory assays and low copy numbers of Desulfobacterium were found, a genus previously implicated in anaerobic benzene biodegradation. This study also showed that there was a reasonable correlation between field and laboratory findings, although with notable exception. Thus, while the intrinsic anaerobic bioremediation was clearly evident at the site, non-COC hydrocarbons were preferentially metabolized, even though there was ample literature precedence for the biodegradation of the target molecules. PMID- 21261913 TI - Chitosan and its antimicrobial potential--a critical literature survey. AB - Chitosan, an aminopolysaccharide biopolymer, has a unique chemical structure as a linear polycation with a high charge density, reactive hydroxyl and amino groups as well as extensive hydrogen bonding. It displays excellent biocompatibility, physical stability and processability. The term 'chitosan' describes a heterogeneous group of polymers combining a group of physicochemical and biological characteristics, which allow for a wide scope of applications that are both fascinating and as yet uncharted. The increased awareness of the potentials and industrial value of this biopolymer lead to its utilization in many applications of technical interest, and increasingly in the biomedical arena. Although not primarily used as an antimicrobial agent, its utility as an ingredient in both food and pharmaceutical formulations lately gained more interest, when a scientific understanding of at least some of the pharmacological activities of this versatile carbohydrate began to evolve. However, understanding the various factors that affect its antimicrobial activity has become a key issue for a better usage and a more efficient optimization of chitosan formulations. Moreover, the use of chitosan in antimicrobial systems should be based on sufficient knowledge of the complex mechanisms of its antimicrobial mode of action, which in turn would help to arrive at an appreciation of its entire antimicrobial potential. PMID- 21261915 TI - Bioremediation of marine oil spills: when and when not--the Exxon Valdez experience. AB - In this article we consider what we have learned from the Exxon Valdez oil spill (EVOS) in terms of when bioremediation should be considered and what it can accomplish. We present data on the state of oiling of Prince William Sound shorelines 18 years after the spill, including the concentration and composition of subsurface oil residues (SSOR) sampled by systematic shoreline surveys conducted between 2002 and 2007. Over this period, 346 sediment samples were analysed by GC-MS and extents of hydrocarbon depletion were quantified. In 2007 alone, 744 sediment samples were collected and extracted, and 222 were analysed. Most sediment samples from sites that were heavily oiled by the spill and physically cleaned and bioremediated between 1989 and 1991 show no remaining SSOR. Where SSOR does remain, it is for the most part highly weathered, with 82% of 2007 samples indicating depletion of total polycyclic aromatic hydrocarbon (Total PAH) of >70% relative to EVOS oil. This SSOR is sequestered in patchy deposits under boulder/cobble armour, generally in the mid-to-upper intertidal zone. The relatively high nutrient concentrations measured at these sites, the patchy distribution and the weathering state of the SSOR suggest that it is in a form and location where bioremediation likely would be ineffective at increasing the rate of hydrocarbon removal. PMID- 21261916 TI - Assessing in situ rates of anaerobic hydrocarbon bioremediation. AB - Identifying metabolites associated with anaerobic hydrocarbon biodegradation is a reliable way to garner evidence for the intrinsic bioremediation of problem contaminants. While such metabolites have been detected at numerous sites, the in situ rates of anaerobic hydrocarbon decay remain largely unknown. Yet, realistic rate information is critical for predicting how long individual contaminants will persist and remain environmental threats. Here, single-well push-pull tests were conducted at two fuel-contaminated aquifers to determine the in situ biotransformation rates of a suite of hydrocarbons added as deuterated surrogates, including toluene-d(8), o-xylene-d(10), m-xylene-d(10), ethylbenzene d(5) (or -d(10)), 1, 2, 4-trimethylbenzene-d(12), 1, 3, 5-trimethylbenzene-d(12), methylcyclohexane-d(14) and n-hexane-d(14). The formation of deuterated fumarate addition and downstream metabolites was quantified and found to be somewhat variable among wells in each aquifer, but generally within an order of magnitude. Deuterated metabolites formed in one aquifer at rates that ranged from 3 to 50 ug l(-1) day(-1), while the comparable rates at another aquifer were slower and ranged from 0.03 to 15 ug l(-1) day(-1). An important observation was that the deuterated hydrocarbon surrogates were metabolized in situ within hours or days at both sites, in contrast to many laboratory findings suggesting that long lag periods of weeks to months before the onset of anaerobic biodegradation are typical. It seems clear that highly reduced conditions are not detrimental to the intrinsic bioremediation of fuel-contaminated aquifers. PMID- 21261917 TI - The construction of a whole-cell biosensor for phosphonoacetate, based on the LysR-like transcriptional regulator PhnR from Pseudomonas fluorescens 23F. AB - The phnA gene that encodes the carbon-phosphorus bond cleavage enzyme phosphonoacetate hydrolase is widely distributed in the environment, suggesting that its phosphonate substrate may play a significant role in biogeochemical phosphorus cycling. Surprisingly, however, no biogenic origin for phosphonoacetate has yet been established. To facilitate the search for its natural source we have constructed a whole-cell phosphonoacetate biosensor. The gene encoding the LysR-type transcriptional activator PhnR, which controls expression of the phosphonoacetate degradative operon in Pseudomonas fluorescens 23F, was inserted in the broad-host-range promoter probe vector pPROBE-NT, together with the promoter region of the structural genes. Cells of Escherichia coli DH5alpha that contained the resultant construct, pPANT3, exhibited phosphonoacetate-dependent green fluorescent protein fluorescence in response to threshold concentrations of as little as 0.5 uM phosphonoacetate, some 100 times lower than the detection limit of currently available non-biological analytical methods; the pPANT3 biosensor construct in Pseudomonas putida KT2440 was less sensitive, although with shorter response times. From a range of other phosphonates and phosphonoacetate analogues tested, only phosphonoacetaldehyde and arsonoacetate induced green fluorescent protein fluorescence in the E. coli DH5alpha (pPANT3) biosensor, although at much-reduced sensitivities (50 uM phosphonoacetaldehyde and 500 uM arsonoacetate). PMID- 21261918 TI - Application of nitroarene dioxygenases in the design of novel strains that degrade chloronitrobenzenes. AB - Widespread application of chloronitrobenzenes as feedstocks for the production of industrial chemicals and pharmaceuticals has resulted in extensive environmental contamination with these toxic compounds, where they pose significant risks to the health of humans and wildlife. While biotreatment in general is an attractive solution for remediation, its effectiveness is limited with chloronitrobenzenes due to the small number of strains that can effectively mineralize these compounds and their ability to degrade only select isomers. To address this need, we created engineered strains with a novel degradation pathway that reduces the total number of steps required to convert chloronitrobenzenes into compounds of central metabolism. We examined the ability of 2-nitrotoluene 2,3-dioxygenase from Acidovorax sp. strain JS42, nitrobenzene 1,2-dioxygenase (NBDO) from Comamonas sp. strain JS765, as well as active-site mutants of NBDO to generate chlorocatechols from chloronitrobenzenes, and identified the most efficient enzymes. Introduction of the wild-type NBDO and the F293Q variant into Ralstonia sp. strain JS705, a strain carrying the modified ortho pathway for chlorocatechol metabolism, resulted in bacterial strains that were able to sustainably grow on all three chloronitrobenzene isomers without addition of co-substrates or co inducers. These first-generation engineered strains demonstrate the utility of nitroarene dioxygenases in expanding the metabolic capabilities of bacteria and provide new options for improved biotreatment of chloronitrobenzene-contaminated sites. PMID- 21261919 TI - Cyclopropane fatty acids are involved in organic solvent tolerance but not in acid stress resistance in Pseudomonas putida DOT-T1E. AB - Bacterial membranes constitute the first physical barrier against different environmental stresses. Pseudomonas putida DOT-T1E accumulates cyclopropane fatty acids (CFAs) in the stationary phase of growth. In this strain the cfaB gene encodes the main cyclopropane synthase responsible of the synthesis of CFAs, and its expression is mediated by RNA polymerase with sigma factor sigma(38). We generated a cfaB mutant of P. putida DOT-T1E and studied its response to solvents, acid pH and other stress conditions such as temperature changes, high osmolarity and the presence of antibiotics or heavy metals in the culture medium. A CfaB knockout mutant was more sensitive to solvent stress than the wild-type strain, but in contrast to Escherichia coli and Salmonella enterica, the P. putida cfaB mutant was as tolerant to acid shock as the wild-type strain. The cfaB mutant was also as tolerant as the parental strain to a number of drugs, antibiotics and other damaging agents. PMID- 21261920 TI - Molecular and biochemical characterization of the tetralin degradation pathway in Rhodococcus sp. strain TFB. AB - The tetralin biodegradation pathway in Rhodococcus sp. strain TFB, a Gram positive bacterium resistant to genetic manipulation, was characterized using a proteomic approach. Relative protein expression in cell free extracts from tetralin- and glucose-grown cells was compared using the 2D-DIGE technique. Identification of proteins specifically expressed in tetralin-grown cells was used to characterize a complete set of genes involved in tetralin degradation by reverse genetics. We propose a tetralin degradation pathway analogous to that described for Sphingomonas macrogolitabida strain TFA. TFB thn genes are organized into three operons; two contain all of the structural genes and are transcribed in the same direction, while the third operon, thnST, is transcribed in the opposite direction and encodes a two-component regulatory system, whose transcription is higher in tetralin-grown cells. In addition to tetralin induction, TFB thn structural genes are subject to glucose repression. Primer extension assays and translational thnA1::gfp and thnS::gfp fusions were used to characterize putative promoter regions. A mutational analysis of the thnA1 promoter region allowed us to define nucleotides within the cis regulatory elements that are important for the control of thn gene expression. PMID- 21261921 TI - Coupling a genome-scale metabolic model with a reactive transport model to describe in situ uranium bioremediation. AB - The increasing availability of the genome sequences of microorganisms involved in important bioremediation processes makes it feasible to consider developing genome-scale models that can aid in predicting the likely outcome of potential subsurface bioremediation strategies. Previous studies of the in situ bioremediation of uranium-contaminated groundwater have demonstrated that Geobacter species are often the dominant members of the groundwater community during active bioremediation and the primary organisms catalysing U(VI) reduction. Therefore, a genome-scale, constraint-based model of the metabolism of Geobacter sulfurreducens was coupled with the reactive transport model HYDROGEOCHEM in an attempt to model in situ uranium bioremediation. In order to simplify the modelling, the influence of only three growth factors was considered: acetate, the electron donor added to stimulate U(VI) reduction; Fe(III), the electron acceptor primarily supporting growth of Geobacter; and ammonium, a key nutrient. The constraint-based model predicted that growth yields of Geobacter varied significantly based on the availability of these three growth factors and that there are minimum thresholds of acetate and Fe(III) below which growth and activity are not possible. This contrasts with typical, empirical microbial models that assume fixed growth yields and the possibility for complete metabolism of the substrates. The coupled genome-scale and reactive transport model predicted acetate concentrations and U(VI) reduction rates in a field trial of in situ uranium bioremediation that were comparable to the predictions of a calibrated conventional model, but without the need for empirical calibration, other than specifying the initial biomass of Geobacter. These results suggest that coupling genome-scale metabolic models with reactive transport models may be a good approach to developing models that can be truly predictive, without empirical calibration, for evaluating the probable response of subsurface microorganisms to possible bioremediation approaches prior to implementation. PMID- 21261922 TI - Microbial responses to xenobiotic compounds. Identification of genes that allow Pseudomonas putida KT2440 to cope with 2,4,6-trinitrotoluene. AB - Pseudomonas putida KT2440 grows in M9 minimal medium with glucose in the presence of 2,4,6-trinitrotoluene (TNT) at a similar rate than in the absence of TNT, although global transcriptional analysis using DNA microarrays revealed that TNT exerts some stress. Response to TNT stress is regulated at the transcriptional level, as significant changes in the level of expression of 65 genes were observed. Of these genes, 39 appeared upregulated, and 26 were downregulated. The identity of upregulated genes suggests that P. putida uses two kinds of strategies to overcome TNT toxicity: (i) induction of genes encoding nitroreductases and detoxification-related enzymes (pnrA, xenD, acpD) and (ii) induction of multidrug efflux pump genes (mexEF/oprN) to reduce intracellular TNT concentrations. Mutants of 13 up- and 7 downregulated genes were analysed with regards to TNT toxicity revealing the role of the MexE/MexF/OprN pump and a putative isoquinoline 1-oxidoreductase in tolerance to TNT. The ORF PP1232 whose transcriptional level did not change in response to TNT affected growth in the presence of nitroaromatic compounds and it was found in a screening of 4000 randomly generated mutants. PMID- 21261924 TI - Bioleaching genomics. PMID- 21261925 TI - Microbial Biotechnology from medicine to bacterial population dynamics. PMID- 21261927 TI - Overcoming the restriction barrier to plasmid transformation and targeted mutagenesis in Bifidobacterium breve UCC2003. AB - In silico analysis of the Bifidobacterium breve UCC2003 genome predicted two distinct loci, which encode three different restriction/modification systems, each comprising a modification methylase and a restriction endonuclease. Based on sequence homology and observed protection against restriction we conclude that the first restriction endonuclease, designated BbrI, is an isoschizomer of BbeI, the second, BbrII, is a neoschizomer of SalI, while the third, BbrIII, is an isoschizomer of PstI. Expression of each of the B. breve UCC2003 methylase encoding genes in B. breve JCM 7017 established that BbrII and BbrIII are active and restrict incoming DNA. By exploiting knowledge on restriction/modification in B. breve UCC2003 we successfully increased the transformation efficiency to a level that allows the reliable generation of mutants by homologous recombination using a non-replicative plasmid. PMID- 21261926 TI - The role of the cell wall in fungal pathogenesis. AB - Fungal infections are a serious health problem. In recent years, basic research is focusing on the identification of fungal virulence factors as promising targets for the development of novel antifungals. The wall, as the most external cellular component, plays a crucial role in the interaction with host cells mediating processes such as adhesion or phagocytosis that are essential during infection. Specific components of the cell wall (called PAMPs) interact with specific receptors in the immune cell (called PRRs), triggering responses whose molecular mechanisms are being elucidated. We review here the main structural carbohydrate components of the fungal wall (glucan, mannan and chitin), how their biogenesis takes place in fungi and the specific receptors that they interact with. Different model fungal pathogens are chosen to illustrate the functional consequences of this interaction. Finally, the identification of the key components will have important consequences in the future and will allow better approaches to treat fungal infections. PMID- 21261928 TI - A versatile and scalable strategy for glycoprofiling bifidobacterial consumption of human milk oligosaccharides. AB - Human milk contains approximately 200 complex oligosaccharides believed to stimulate the growth and establishment of a protective microbiota in the infant gut. The lack of scalable analytical techniques has hindered the measurement of bacterial metabolism of these and other complex prebiotic oligosaccharides. An in vitro, multi-strain, assay capable of measuring kinetics of bacterial growth and detailed oligosaccharide consumption analysis by FTICR-MS was developed and tested simultaneously on 12 bifidobacterial strains. For quantitative consumption, deuterated and reduced human milk oligosaccharide (HMO) standards were used. A custom software suite developed in house called Glycolyzer was used to process the large amounts of oligosaccharide mass spectra automatically with (13)C corrections based on de-isotoping protocols. High growth on HMOs was characteristic of Bifidobacterium longum biovar infantis strains, which consumed nearly all available substrates, while other bifidobacterial strains tested, B. longum bv. longum, B. adolescentis, B. breve and B. bifidum, showed low or only moderate growth ability. Total oligosaccharide consumption ranged from a high of 87% for B. infantis JCM 7009 to only 12% for B. adolescentis ATCC 15703. A detailed analysis of consumption glycoprofiles indicated strain-specific capabilities towards differential metabolism of milk oligosaccharides. This method overcomes previous limitations in the quantitative, multi-strain analysis of bacterial metabolism of HMOs and represents a novel approach towards understanding bacterial consumption of complex prebiotic oligosaccharides. PMID- 21261929 TI - A molecular key for building hyphae aggregates: the role of the newly identified Streptomyces protein HyaS. AB - Streptomycetes produce many metabolites with medical and biotechnological applications. During fermentations, their hyphae build aggregates, a process in which the newly identified protein HyaS plays an important role. The corresponding hyaS gene is present within all investigated Streptomyces species. Reporter fusions indicate that transcription of hyaS occurs within substrate hyphae of the Streptomyces lividans wild type (WT). The HyaS protein is dominantly associated with the substrate hyphae. The WT strain forms cylindrically shaped clumps of densely packed substrate hyphae, often fusing to higher aggregates (pellets), which remain stably associated during shaking. Investigations by electron microscopy suggest that HyaS induces tight fusion-like contacts among substrate hyphae. In contrast, the pellets of the designed hyaS disruption mutant DeltaH are irregular in shape, contain frequently outgrowing bunches of hyphae, and fuse less frequently. DeltaH complemented with a plasmid carrying hyaS resembles the WT phenotype. Biochemical studies indicate that the C terminal region of HyaS has amine oxidase activity. Investigations of DeltaH transformants, each carrying a specifically mutated gene, lead to the conclusion that the in situ oxidase activity correlates with the pellet-inducing role of HyaS, and depends on the presence of certain histidine residues. Furthermore, the level of undecylprodigiosin, a red pigment with antibiotic activity, is influenced by the engineered hyaS subtype within a strain. These data present the first molecular basis for future manipulation of pellets, and concomitant production of secondary metabolites during biotechnological processes. PMID- 21261930 TI - Biofilm formation and proteolytic activities of Pseudoalteromonas bacteria that were isolated from fish farm sediments. AB - In order to save natural resources and supply good fishes, it is important to improve fish-farming techniques. The survival rate of fish fry appears to become higher when powders of foraminifer limestone are submerged at the bottom of fish farming fields, where bacterial biofilms often grow. The observations suggest that forming biofilms can benefit to keep health status of breeding fishes. We employed culture-based methods for the identification and characterization of biofilm-forming bacteria and assessed the application of their properties for fish farming. Fifteen bacterial strains were isolated from the biofilm samples collected from fish farm sediments. The 16S rRNA gene sequences indicated that these bacteria belonged to the genera, Pseudoalteromonas (seven strains), Vibrio (seven strains) and Halomonas (one strain). It was found that Pseudoalteromonas strains generally formed robust biofilms in a laboratory condition and produced extracellular proteases in a biofilm-dependent manner. The results suggest that Pseudoalteromonas bacteria, living in the biofilm community, contribute in part to remove excess proteineous matters from the sediment sludge of fish farms. PMID- 21261931 TI - Nitric oxide-mediated dispersal in single- and multi-species biofilms of clinically and industrially relevant microorganisms. AB - Strategies to induce biofilm dispersal are of interest due to their potential to prevent biofilm formation and biofilm-related infections. Nitric oxide (NO), an important messenger molecule in biological systems, was previously identified as a signal for dispersal in biofilms of the model organism Pseudomonas aeruginosa. In the present study, the use of NO as an anti-biofilm agent more broadly was assessed. Various NO donors, at concentrations estimated to generate NO levels in the picomolar and low nanomolar range, were tested on single-species biofilms of relevant microorganisms and on multi-species biofilms from water distribution and treatment systems. Nitric oxide-induced dispersal was observed in all biofilms assessed, and the average reduction of total biofilm surface was 63%. Moreover, biofilms exposed to low doses of NO were more susceptible to antimicrobial treatments than untreated biofilms. For example, the efficacy of conventional chlorine treatments at removing multi-species biofilms from water systems was increased by 20-fold in biofilms treated with NO compared with untreated biofilms. These data suggest that combined treatments with NO may allow for novel and improved strategies to control biofilms and have widespread applications in many environmental, industrial and clinical settings. PMID- 21261932 TI - The expression of recombinant genes in Escherichia coli can be strongly stimulated at the transcript production level by mutating the DNA-region corresponding to the 5'-untranslated part of mRNA. AB - Secondary structures and the short Shine-Dalgarno sequence in the 5'-untranslated region of bacterial mRNAs (UTR) are known to affect gene expression at the level of translation. Here we report the use of random combinatorial DNA sequence libraries to study UTR function, applying the strong, sigma(32)/sigma(38) dependent, and positively regulated Pm promoter as a model. All mutations in the libraries are located at least 8 bp downstream of the transcriptional start site. The libraries were screened using the ampicillin-resistance gene (bla) as reporter, allowing easy identification of UTR mutants that display high levels of expression (up to 20-fold increase relative to the wild-type at the protein level). Studies of the two UTR mutants identified by a modified screening procedure showed that their expression is stimulated to a similar extent at both the transcript and protein product levels. For one such mutant a model analysis of the transcription kinetics showed significant evidence of a difference in the transcription rate (about 18-fold higher than the wild type), while there was no evidence of a difference in transcript stability. The two UTR sequences also stimulated expression from a constitutive sigma(70)-dependent promoter (P1/P(anti tet)), demonstrating that the UTR at the DNA or RNA level has a hitherto unrecognized role in transcription. PMID- 21261933 TI - Probing the heterologous metabolism supporting 6-deoxyerythronolide B biosynthesis in Escherichia coli. AB - Heterologous biosynthesis offers a new way to capture the medicinal properties presented by complex natural products. In this study, production of 6 deoxyerythronolide B (6dEB), the polyketide precursor to the antibiotic erythromycin, was used to probe the heterologous pathways needed for Escherichia coli-derived biosynthesis. More specifically, the heterologous proteins responsible for 6dEB production were varied by adjusting their respective gene dosage levels. In this way, heterologous components required for posttranslational modification, 6dEB biosynthesis, and substrate provision were adjusted in expression levels to observe the relative effect each has on final heterologous biosynthesis. The results indicate that both the biosynthetic and substrate provision heterologous proteins impact 6dEB formation to a greater extent when compared with posttranslational modification and suggest these components for future protein and metabolic engineering. PMID- 21261935 TI - Comparative effectiveness of lifestyle interventions on cardiovascular risk factors among a Dutch overweight working population: a randomized controlled trial. AB - BACKGROUND: Overweight (Body Mass Index [BMI] >= 25 kg/m2) and obesity (BMI >= 30 kg/m2) are associated with increased cardiovascular risk, posing a considerable burden to public health. The main aim of this study was to investigate lifestyle intervention effects on cardiovascular risk factors in healthy overweight employees. METHODS: Participants were 276 healthy overweight employees (69.2% male; mean age 44.0 years [SD 9.2]; mean BMI 29.7 kg/m2 [SD 3.1]). They were randomized to one of two intervention groups receiving a six month lifestyle intervention with behavior counseling by phone (phone group) or e-mail (Internet group), or to a control group receiving usual care. Body weight, height, waist circumference, sum of skinfolds, blood pressure, total cholesterol level and predicted aerobic fitness were measured at baseline, at 6 and at 24 months. Regression analyses included the 141 participants with complete data. RESULTS: At 6 months a significant favorable effect on total cholesterol level (-0.2 mmol/l, 95%CI -0.5 to -0.0) was observed in the phone group and a trend for improved aerobic fitness (1.9 ml/kg/min, 95%CI -0.2 to 3.9) in the Internet group. At two years, favorable trends for body weight (-2.1 kg, 95%CI -4.4 to 0.2) and aerobic fitness (2.3 ml/kg/min, 95%CI -0.2 to 4.8) were observed in the Internet group. CONCLUSIONS: The intervention effects were independent of the used communication mode. However short-term results were in favor of the phone group and long-term results in favor of the internet group. Thus, we found limited evidence for our lifestyle intervention to be effective in reducing cardiovascular risk in a group of apparently healthy overweight workers. TRIAL REGISTRATION: ISRCTN04265725. PMID- 21261936 TI - Predialysis therapeutic care and health-related quality of life at dialysis onset (The pharmacoepidemiologic AVENIR study). AB - BACKGROUND: To determine the impact of the quality of pre-dialysis nephrological care on health-related quality of life (HRQoL) at dialysis onset, which has not been well evaluated. METHODS: All adults who began a dialysis treatment in the administrative region of Lorraine (France) in 2005 or 2006, were enrolled in this prospective observational study. HRQoL was measured using the Kidney Disease Quality of Life V36 questionnaire, which enables calculation of two generic (physical and mental) and three specific dimensions (Symptoms/problems, Effects and Burden of kidney disease). The specific dimensions were scored from 0 to 100 (worst to best possible functioning). Pre-dialysis nephrological care was measured using three indicators: quality of therapeutic practices (evaluated across five main aspects: hypertension/proteinuria, anemia, bone disease, metabolic acidosis and dyslipidemia), time since referral to a nephrologist and number of nephrology consultations in the year preceding dialysis treatment. RESULTS: Two thousand and eighty-three (67.4%) patients were referred to a nephrologist more than 1 month before dialysis initiation and completed the HRQoL questionnaire. Quality of therapeutic practices was significantly associated with the Mental component. Time since referral to a nephrologist was associated with Symptoms/problems and the Effects of kidney disease dimensions, but no relationship was found between the number of nephrology consultations and HRQoL. CONCLUSIONS: HRQoL at dialysis onset is significantly influenced by the quality of pre-dialysis nephrological care. Therefore, disease management should be emphasized. PMID- 21261937 TI - Identification of rhizome-specific genes by genome-wide differential expression analysis in Oryza longistaminata. AB - BACKGROUND: Rhizomatousness is a key component of perenniality of many grasses that contribute to competitiveness and invasiveness of many noxious grass weeds, but can potentially be used to develop perennial cereal crops for sustainable farmers in hilly areas of tropical Asia. Oryza longistaminata, a perennial wild rice with strong rhizomes, has been used as the model species for genetic and molecular dissection of rhizome development and in breeding efforts to transfer rhizome-related traits into annual rice species. In this study, an effort was taken to get insights into the genes and molecular mechanisms underlying the rhizomatous trait in O. longistaminata by comparative analysis of the genome-wide tissue-specific gene expression patterns of five different tissues of O. longistaminata using the Affymetrix GeneChip Rice Genome Array. RESULTS: A total of 2,566 tissue-specific genes were identified in five different tissues of O. longistaminata, including 58 and 61 unique genes that were specifically expressed in the rhizome tips (RT) and internodes (RI), respectively. In addition, 162 genes were up-regulated and 261 genes were down-regulated in RT compared to the shoot tips. Six distinct cis-regulatory elements (CGACG, GCCGCC, GAGAC, AACGG, CATGCA, and TAAAG) were found to be significantly more abundant in the promoter regions of genes differentially expressed in RT than in the promoter regions of genes uniformly expressed in all other tissues. Many of the RT and/or RI specifically or differentially expressed genes were located in the QTL regions associated with rhizome expression, rhizome abundance and rhizome growth-related traits in O. longistaminata and thus are good candidate genes for these QTLs. CONCLUSION: The initiation and development of the rhizomatous trait in O. longistaminata are controlled by very complex gene networks involving several plant hormones and regulatory genes, different members of gene families showing tissue specificity and their regulated pathways. Auxin/IAA appears to act as a negative regulator in rhizome development, while GA acts as the activator in rhizome development. Co-localization of the genes specifically expressed in rhizome tips and rhizome internodes with the QTLs for rhizome traits identified a large set of candidate genes for rhizome initiation and development in rice for further confirmation. PMID- 21261938 TI - Comparison of membrane proteins of Mycobacterium tuberculosis H37Rv and H37Ra strains. AB - BACKGROUND: The potential causes for variation in virulence between distinct M. tuberculosis strains are still not fully known. However, differences in protein expression are probably an important factor. In this study we used a label-free quantitative proteomic approach to estimate differences in protein abundance between two closely related M. tuberculosis strains; the virulent H37Rv strain and its attenuated counterpart H37Ra. RESULTS: We were able to identify more than 1700 proteins from both strains. As expected, the majority of the identified proteins had similar relative abundance in the two strains. However, 29 membrane associated proteins were observed with a 5 or more fold difference in their relative abundance in one strain compared to the other. Of note, 19 membrane- and lipo-proteins had higher abundance in H37Rv, while another 10 proteins had a higher abundance in H37Ra. Interestingly, the possible protein-export membrane protein SecF (Rv2586c), and three ABC-transporter proteins (Rv0933, Rv1273c and Rv1819c) were among the more abundant proteins in M. tuberculosis H37Rv. CONCLUSION: Our data suggests that the bacterial secretion system and the transmembrane transport system may be important determinants of the ability of distinct M. tuberculosis strains to cause disease. PMID- 21261940 TI - An ultrasonographic evaluation of skin thickness in breast cancer patients after postmastectomy radiation therapy. AB - BACKGROUND: To determine the usefulness of ultrasonography in the assessment of post radiotherapy skin changes in postmastectomy breast cancer patients. METHODS: Patients treated for postmastectomy radiotherapy in National University Hospital (NUH) and Tan Tock Seng Hospital (TTSH), Singapore between January 2004- December 2005 was recruited retrospectively. Ultrasound scan was performed on these Asian patients who had been treated to a total dose of 46-50 Gy with 1 cm bolus placed on the skin. The ultrasound scans were performed blinded to the RTOG scores, and the skin thickness of the individually marked points on the irradiated chest wall was compared to the corresponding points on the non-irradiated breast. RESULTS: The mean total skin thickness inclusive of the epidermis and the dermis of the right irradiated chest wall was 0.1712 mm (+/- 0.03392 mm) compared with the contra-lateral non-irradiated breast which was 0.1845 mm (+/- 0.04089 mm; p = 0.007). The left irradiated chest wall had a mean skin thickness of 0.1764 mm (+/ 0.03184 mm) compared with the right non-irradiated breast which was 0.1835 mm (+/- 0.02584 mm; p = 0.025). These independent t-tests produced a significant difference of reduced skin thickness on the right irradiated chest wall, p = 0.007 (p < 0.05) and left irradiated chest wall p = 0.025 (p < 0.025) in comparison to the non-irradiated skin thickness investigating chronic skin reactions. Patients with grade 2 acute skin toxicity presented with thinner skin as compared to patients with grade 1 (p = 0.006). CONCLUSIONS: This study has shown that there is a statistically significant difference between the skin thicknesses of the irradiated chest wall and the contra-lateral non-irradiated breast and a predisposition to chronic reactions was found in patients with acute RTOG scoring of grade1 and grade 2. PMID- 21261939 TI - Weight science: evaluating the evidence for a paradigm shift. AB - Current guidelines recommend that "overweight" and "obese" individuals lose weight through engaging in lifestyle modification involving diet, exercise and other behavior change. This approach reliably induces short term weight loss, but the majority of individuals are unable to maintain weight loss over the long term and do not achieve the putative benefits of improved morbidity and mortality. Concern has arisen that this weight focus is not only ineffective at producing thinner, healthier bodies, but may also have unintended consequences, contributing to food and body preoccupation, repeated cycles of weight loss and regain, distraction from other personal health goals and wider health determinants, reduced self-esteem, eating disorders, other health decrement, and weight stigmatization and discrimination. This concern has drawn increased attention to the ethical implications of recommending treatment that may be ineffective or damaging. A growing trans-disciplinary movement called Health at Every Size (HAES) challenges the value of promoting weight loss and dieting behavior and argues for a shift in focus to weight-neutral outcomes. Randomized controlled clinical trials indicate that a HAES approach is associated with statistically and clinically relevant improvements in physiological measures (e.g., blood pressure, blood lipids), health behaviors (e.g., eating and activity habits, dietary quality), and psychosocial outcomes (such as self-esteem and body image), and that HAES achieves these health outcomes more successfully than weight loss treatment and without the contraindications associated with a weight focus. This paper evaluates the evidence and rationale that justifies shifting the health care paradigm from a conventional weight focus to HAES. PMID- 21261941 TI - IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different anti-thromboembolic prophylaxis therapeutics. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a thromboembolic complication that can occur with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Our objective was to determine and compare the incidence of IgG-class HIT antibodies in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) with different antithrombotic prophylaxis therapies and their contributions to the occurrence of venous thromboembolism (VTE). METHODS: A prospective observational study was performed for 374 Japanese patients undergoing THA or TKA to determine the incidence of VTE. IgG-class anti PF4/heparin antibodies were measured using IgG-specific EIA before and after the operation. RESULTS: In the clinical outcome, the incidence of symptomatic deep vein thrombosis (DVT) was 15.0% (56/374, TKA; 35, THA; 21) and pulmonary emboli (PE) were not observed. The total seroconversion incidence of IgG-class PF4/heparin antibodies was 19.8% (74/374). The seroconversion incidence of IgG class PF4/heparin antibodies was higher in patients receiving UFH (32.7%) compared to those receiving LMWH (9.5%) or fondaparinux (14.8%). Furthermore, the seroconversion incidence was significantly higher in patients undergoing TKA compared to those undergoing THA. Based on multivariate analysis, seroconversion of the IgG-class PF4/heparin antibodies was independent a risk factor for symptomatic DVT. CONCLUSION: Our findings show that the seroconversion of IgG class anti-PF4/heparin antibodies differed with various anti-thrombotic prophylaxis therapeutics and was associated with the risk of DVT in a subset of patients undergoing total joint arthroplasty (TKA and THA). PMID- 21261942 TI - Age related incidence and early outcomes of hip fractures: a prospective cohort study of 1177 patients. AB - INTRODUCTION: Associated with the increase in the aging population, there is an increase in the incidence of hip fractures worldwide. Outcome following such fractures is affected by age of the patient. This study aims to assess the incidence and early outcome of hip fractures, comparing between different age groups. METHODS: Data of hip fractures collected over a period of five years was analysed. Patients were divided into three groups, group A (patients under the age of 64), group B (patients between 65 and 84 years of age), and group C (patients over the age of 85). RESULTS: Of the 1177 patients included in the study, there were 90 patients in group A, 702 patients in group B and 385 patients in group C. There was a female preponderance across all age groups, and this increased as age advanced (p < 0.0001). A significantly larger number of older patients lived alone and needed aids to walk before the injury (p < 0.0001). There was no significant difference in the type of fracture across the three groups (p = 0.13). A higher proportion of the elderly with intracapsular fractures were treated by replacement arthroplasty. Older patients who had internal fixation of intracapsular fractures had a better walking ability at 4 months. The overall deterioration in mobility was greater in older patients (p < 0.0001). Mortality was higher in older patients. CONCLUSIONS: Hip fractures are more common among females irrespective of age group. Older patients have a higher mortality and a greater deterioration of walking ability after such injuries. Internal fixation of intracapsular fractures have demonstrated satisfactory early outcome in the immediate period. This could be attributed to retention of native bone, better propioception and shorter operation time. PMID- 21261943 TI - Recent human evolution has shaped geographical differences in susceptibility to disease. AB - BACKGROUND: Searching for associations between genetic variants and complex diseases has been a very active area of research for over two decades. More than 51,000 potential associations have been studied and published, a figure that keeps increasing, especially with the recent explosion of array-based Genome-Wide Association Studies. Even if the number of true associations described so far is high, many of the putative risk variants detected so far have failed to be consistently replicated and are widely considered false positives. Here, we focus on the world-wide patterns of replicability of published association studies. RESULTS: We report three main findings. First, contrary to previous results, genes associated to complex diseases present lower degrees of genetic differentiation among human populations than average genome-wide levels. Second, also contrary to previous results, the differences in replicability of disease associated-loci between Europeans and East Asians are highly correlated with genetic differentiation between these populations. Finally, highly replicated genes present increased levels of high-frequency derived alleles in European and Asian populations when compared to African populations. CONCLUSIONS: Our findings highlight the heterogeneous nature of the genetic etiology of complex disease, confirm the importance of the recent evolutionary history of our species in current patterns of disease susceptibility and could cast doubts on the status as false positives of some associations that have failed to replicate across populations. PMID- 21261944 TI - Caries induced cytokine network in the odontoblast layer of human teeth. AB - BACKGROUND: Immunologic responses of the tooth to caries begin with odontoblasts recognizing carious bacteria. Inflammatory propagation eventually leads to tooth pulp necrosis and danger to health. The present study aims to determine cytokine gene expression profiles generated within human teeth in response to dental caries in vivo and to build a mechanistic model of these responses and the downstream signaling network. RESULTS: We demonstrate profound differential up regulation of inflammatory genes in the odontoblast layer (ODL) in human teeth with caries in vivo, while the pulp remains largely unchanged. Interleukins, chemokines, and all tested receptors thereof were differentially up-regulated in ODL of carious teeth, well over one hundred-fold for 35 of 84 genes. By interrogating reconstructed protein interaction networks corresponding to the differentially up-regulated genes, we develop the hypothesis that pro inflammatory cytokines highly expressed in ODL of carious teeth, IL-1beta, IL 1alpha, and TNF-alpha, carry the converged inflammatory signal. We show that IL1beta amplifies antimicrobial peptide production in odontoblasts in vitro 100 fold more than lipopolysaccharide, in a manner matching subsequent in vivo measurements. CONCLUSIONS: Our data suggest that ODL amplifies bacterial signals dramatically by self-feedback cytokine-chemokine signal-receptor cycling, and signal convergence through IL1R1 and possibly others, to increase defensive capacity including antimicrobial peptide production to protect the tooth and contain the battle against carious bacteria within the dentin. PMID- 21261945 TI - Evolution of the nuclear ribosomal DNA intergenic spacer in four species of the Daphnia pulex complex. AB - BACKGROUND: Concerted evolution refers to the pattern in which copies of multigene families show high intraspecific sequence homogeneity but high interspecific sequence diversity. Sequence homogeneity of these copies depends on relative rates of mutation and recombination, including gene conversion and unequal crossing over, between misaligned copies. The internally repetitive intergenic spacer (IGS) is located between the genes for the 28S and 18S ribosomal RNAs. To identify patterns of recombination and/or homogenization within IGS repeat arrays, and to identify regions of the IGS that are under functional constraint, we analyzed 13 complete IGS sequences from 10 individuals representing four species in the Daphnia pulex complex. RESULTS: Gene conversion and unequal crossing over between misaligned IGS repeats generates variation in copy number between arrays, as has been observed in previous studies. Moreover, terminal repeats are rarely involved in these events. Despite the occurrence of recombination, orthologous repeats in different species are more similar to one another than are paralogous repeats within species that diverged less than 4 million years ago. Patterns consistent with concerted evolution of these repeats were observed between species that diverged 8-10 million years ago. Sequence homogeneity varies along the IGS; the most homogeneous regions are downstream of the 28S rRNA gene and in the region containing the core promoter. The inadvertent inclusion of interspecific hybrids in our analysis uncovered evidence of both inter- and intrachromosomal recombination in the nonrepetitive regions of the IGS. CONCLUSIONS: Our analysis of variation in ribosomal IGS from Daphnia shows that levels of homogeneity within and between species result from the interaction between rates of recombination and selective constraint. Consequently, different regions of the IGS are on substantially different evolutionary trajectories. PMID- 21261947 TI - Computed tomography and magnetic resonance imaging of desmoplastic fibroma with simultaneous manifestation in two unusual locations: a case report. AB - INTRODUCTION: Desmoplastic fibroma is an extremely rare primary benign bone tumor. It occurs most often in the mandible, followed by the femur and pelvis. To the best of our knowledge, fewer than 200 cases have been described in the published literature. Furthermore, this case is the first report of desmoplastic fibroma with simultaneous presentation in two different locations. CASE PRESENTATION: We present an unusual case of desmoplastic fibroma in a 56-year-old Caucasian man, who presented to our hospital with lumbar pain. Computed tomography and magnetic resonance imaging were performed, demonstrating two lytic expansile lesions affecting both his left iliac bone and his left sacral wing. Curettage and cortical-cancellous grafting was performed, followed by postoperative computed tomography and magnetic resonance imaging. CONCLUSION: Desmoplastic fibroma with unusual and simultaneous manifestations in two different locations has never been reported previously to the best of our knowledge. The purpose of this case report is to present the computed tomography and magnetic resonance imaging features of this rare tumor before and after the surgical treatment. Furthermore, the radiological findings with the description of the characteristics and the clinical presentation of this rare tumor, contribute to the wide spectrum of manifestations of this tumor, in order to recognize it and to have the appropriate management. PMID- 21261946 TI - Investigating the effect of paralogs on microarray gene-set analysis. AB - BACKGROUND: In order to interpret the results obtained from a microarray experiment, researchers often shift focus from analysis of individual differentially expressed genes to analyses of sets of genes. These gene-set analysis (GSA) methods use previously accumulated biological knowledge to group genes into sets and then aim to rank these gene sets in a way that reflects their relative importance in the experimental situation in question. We suspect that the presence of paralogs affects the ability of GSA methods to accurately identify the most important sets of genes for subsequent research. RESULTS: We show that paralogs, which typically have high sequence identity and similar molecular functions, also exhibit high correlation in their expression patterns. We investigate this correlation as a potential confounding factor common to current GSA methods using Indygene http://www.cbio.uct.ac.za/indygene, a web tool that reduces a supplied list of genes so that it includes no pairwise paralogy relationships above a specified sequence similarity threshold. We use the tool to reanalyse previously published microarray datasets and determine the potential utility of accounting for the presence of paralogs. CONCLUSIONS: The Indygene tool efficiently removes paralogy relationships from a given dataset and we found that such a reduction, performed prior to GSA, has the ability to generate significantly different results that often represent novel and plausible biological hypotheses. This was demonstrated for three different GSA approaches when applied to the reanalysis of previously published microarray datasets and suggests that the redundancy and non-independence of paralogs is an important consideration when dealing with GSA methodologies. PMID- 21261948 TI - Acquired A amyloidosis from injection drug use presenting with atraumatic splenic rupture in a hospitalized patient: a case report. AB - INTRODUCTION: Little is known about splenic rupture in patients who develop systemic acquired A amyloidosis. This is the first report of a case of atraumatic splenic rupture in a patient with acquired A amyloidosis from chronic injection drug use. CASE PRESENTATION: A 58-year-old Caucasian man with a long history of injection drug use, hospitalized for infective endocarditis, experienced atraumatic splenic rupture and underwent splenectomy. Histopathological and microbiological analyses of the splenic tissue were consistent with systemic acquired A amyloidosis, most likely from injection drug use, that led to splenic rupture without any recognized trauma or evidence of bacterial embolization to the spleen. CONCLUSION: In patients with chronic inflammatory conditions, including the use of injection drugs, who experience acute onset of left upper quadrant pain, the diagnosis of atraumatic splenic rupture must be considered. PMID- 21261949 TI - The effectiveness of the Liverpool care pathway in improving end of life care for dying cancer patients in hospital. A cluster randomised trial. AB - BACKGROUND: Most cancer patients still die in hospital, mainly in medical wards. Many studies in different countries have shown the poor quality of end-of-life care delivery in hospitals. The Program "Liverpool Care Pathway for the dying patient" (LCP), developed in the UK to transfer the hospice model of care into hospitals and other care settings, is a complex intervention to improve the quality of end-of-life care. The results from qualitative and quantitative studies suggest that the LCP Program can improve significantly the quality of end of-life care delivery in hospitals, but no randomised trial has been conducted till now. METHODS AND DESIGN: This is a randomized cluster trial, stratified by regions and matched for assessment period. Pairs of eligible medical wards from different hospitals will be randomized to receive the LCP-I Program or no intervention until the end of the trial. The LCP-I Program will be implemented by a Palliative Care Unit.The assessment of the end-points will be performed for all cancer deaths occurred in the six months after the end of the LCP-I implementation in the experimental wards and, in the same period of time, in the matched control wards. The primary end-point is the overall quality of end-of life care provided on the ward to dying cancer patients and their families, assessed using the Global Scale of the Italian version of the Toolkit "After death Bereaved Family Member Interview". DISCUSSION: This study can be interpreted as a Phase III trial according to the Medical Research Council Framework. In this study, the effectiveness of a fully defined intervention is assessed by comparing the distribution of the endpoints in the experimental and in the control arm. RESEARCH ID: RFPS-2006-6-341619 TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01081899. PMID- 21261950 TI - Lingual juvenile xanthogranuloma in a woman: a case report. AB - INTRODUCTION: Juvenile xanthogranuloma is a rare non-Langerhans cell histiocytosis that usually occurs during infancy and early childhood. The presence of single or multiple raised cutaneous lesions characterize this self healing disorder. Extracutaneous sites are rare. CASE PRESENTATION: We present a rare case of oral juvenile xanthogranuloma in a 49-year-old Caucasian woman. The histopathologic diagnosis of the lingual neoformation was histiocitary proliferation with the presence of giant cells, Touton type, compatible with juvenile xanthogranuloma. CONCLUSION: To establish an accurate diagnosis, microscopic evaluation and immunohistochemical staining are necessary. Dentists, dermatologists and general practitioners may be the first to recognize this rare condition during the inspection of the oral cavity. PMID- 21261951 TI - Is it possible to diagnose the therapeutic adherence of patients with COPD in clinical practice? A cohort study. AB - BACKGROUND: Therapeutic adherence of patients with chronic obstructive pulmonary disease (COPD) is poor. It is therefore necessary to determine the magnitude of non-adherence to develop strategies to correct this behaviour. The purpose of this study was to analyse the diagnostic validity of indirect adherence methods. METHODS: SAMPLE: 195 COPD patients undergoing scheduled inhaled treatment attending 5 Primary Care Centres of Malaga, Spain. VARIABLES: Sociodemographic profile, illness data, spirometry, quality of life (St. George Respiratory Questionnaire: SGRQ), and inhaled medication counting (count of dose/pill or electronic monitoring) were collected. The patient's knowledge of COPD (Batalla test:BT),their attitude towards treatment (Morisky-Green test: MGT) and their self-reported therapeutic adherence (Haynes-Sackett test: HST) were used as methods of evaluating adherence. The follow-up consisted four visits over one year (the recruitment visit: V0; and after 1 month:V1; 6 months:V2; and 1 year:V3). RESULTS: The mean age was 69.59 (95% CI, 68.29-70.89) years old and 93.8% were male. Other findings included: 85.4% had a low educational level, 23.6% were smokers, 71.5% mild-moderate COPD stage with a FEV1 = 56.86 (SD = 18.85); exacerbations per year = 1.41(95% CI, 1-1.8). The total SGRQ score was 44.96 (95% CI, 42.46-47.46), showing a mild self-perceived impairment in health. The prevalence of adherence (dose/pill count) was 68.1% (95% CI, 60.9-75.3) at V1, 80% (95% CI, 73-87) at V2 and 84% (95% CI, 77.9) at V3. The MGT showed a specificity of 67.34% at V1, 76.19% at V2 and 69.62% at V3. The sensitivity was 53.33% at V1, 66.66% at V2 and 33.33% at V3.The BT showed a specificity of 55.1% at V1, 70.23% at V2 and 67.09% at V3. The sensitivity was 68.88% at V1, 71.43% at V2 and 46.66% at V3. Considering both tests together, the specificity was 86.73% at V1, 94.04% at V2 and 92.49% at V3 and the sensitivity was 37.77% at V1, 47.62% at V2 and 13.3% at V3. CONCLUSIONS: The prevalence of treatment adherence changes over time. Indirect methods (dose/pill count and self-reported) can be useful to detect non-adherence in COPD patients. The combination of MGT and BT is the best approach to test self-reported adherence. PMID- 21261952 TI - A complex regional intervention to implement advance care planning in one town's nursing homes: Protocol of a controlled inter-regional study. AB - BACKGROUND: Advance Care Planning (ACP) is an emerging strategy to ensure that well-reflected, meaningful and clearly documented treatment preferences are available and respected when critical decisions about life-sustaining treatment need to be made for patients unable to consent. In Germany, recent legislation confirms that advance directives (AD) have to be followed if they apply to the medical situation, but implementation of ACP has not yet been described. METHODS/DESIGN: In a longitudinal controlled study, we compare 1 intervention region (4 nursing homes [n/hs], altogether 421 residents) with 2 control regions (10 n/hs, altogether 985 residents). Inclusion went from 01.02.09 to 30.06.09, observation lasted until 30.06.10. Primary endpoint is the prevalence of ADs at follow-up, 17 (12) months after the first (last) possible inclusion. Secondary endpoints compare relevance and validity of ADs, process quality, the rate of life-sustaining interventions and, in deceased residents, location of death and intensity of treatment before death. The regional multifaceted intervention on the basis of the US program Respecting Choices(r) comprises training of n/h staff as facilitators, training of General Practitioners, education of hospital and ambulance staff, and development of eligible tools, including Physician Orders for Life-Sustaining Treatment in case of Emergency (POLST-E). Participation data: Of 1406 residents reported to live in the 14 n/hs plus an estimated turnover of 176 residents until the last possible inclusion date, 645 (41%) were willing to participate. Response rates were 38% in the intervention region and 42% in the control region. Non-responder analysis shows an equal distribution of sex and age but a bias towards dependency on nursing care in the responder group. Outcome analysis of this study will become available in the course of 2011. DISCUSSION: Implementing an ACP program for the n/hs and related health care providers of a region requires a complex community intervention with the effect of nothing less than a cultural shift in this health care sector. This study is to our knowledge the first to develop a strategy for regional implementation of ACP, and to evaluate its feasibility in a controlled design. PMID- 21261953 TI - The transcription factor PHR1 plays a key role in the regulation of sulfate shoot to-root flux upon phosphate starvation in Arabidopsis. AB - BACKGROUND: Sulfate and phosphate are both vital macronutrients required for plant growth and development. Despite evidence for interaction between sulfate and phosphate homeostasis, no transcriptional factor has yet been identified in higher plants that affects, at the gene expression and physiological levels, the response to both elements. This work was aimed at examining whether PHR1, a transcription factor previously shown to participate in the regulation of genes involved in phosphate homeostasis, also contributed to the regulation and activity of genes involved in sulfate inter-organ transport. RESULTS: Among the genes implicated in sulfate transport in Arabidopsis thaliana, SULTR1;3 and SULTR3;4 showed up-regulation of transcripts in plants grown under phosphate deficient conditions. The promoter of SULTR1;3 contains a motif that is potentially recognizable by PHR1. Using the phr1 mutant, we showed that SULTR1;3 up-regulation following phosphate deficiency was dependent on PHR1. Furthermore, transcript up-regulation was found in phosphate-deficient shoots of the phr1 mutant for SULTR2;1 and SULTR3;4, indicating that PHR1 played both a positive and negative role on the expression of genes encoding sulfate transporters. Importantly, both phr1 and sultr1;3 mutants displayed a reduction in their sulfate shoot-to-root transfer capacity compared to wild-type plants under phosphate-deficient conditions. CONCLUSIONS: This study reveals that PHR1 plays an important role in sulfate inter-organ transport, in particular on the regulation of the SULTR1;3 gene and its impact on shoot-to-root sulfate transport in phosphate-deficient plants. PHR1 thus contributes to the homeostasis of both sulfate and phosphate in plants under phosphate deficiency. Such a function is also conserved in Chlamydomonas reinhardtii via the PHR1 ortholog PSR1. PMID- 21261954 TI - PRE-1, a cis element sufficient to enhance cone- and rod- specific expression in differentiating zebrafish photoreceptors. AB - BACKGROUND: Appropriate transcriptional regulation is required for cone photoreceptor development and integrity. To date, only a few cis-regulatory elements that control cone photoreceptor-specific expression have been characterised. The alpha-subunit of cone transducin (TalphaC) is specifically expressed in cone photoreceptors and is required for colour vision. In order to better understand the molecular genetics controlling the initiation of cone photoreceptor-specific expression in vivo, we have utilised zebrafish to identify cis-regulatory elements in the upstream promoter region of the TalphaC gene. RESULTS: A 0.5 kb TalphaC promoter fragment is sufficient to direct cone-specific expression in transgenic larvae. Within this minimal promoter, we identify photoreceptor regulatory element-1 (PRE-1), a unique 41 bp sequence. PRE-1 specifically binds nuclear factors expressed in ocular tissue. PRE-1 is not required for cone-specific expression directed from a 2.5 kb TalphaC promoter. However, PRE-1-like sequences, with potential functional redundancy, are located in this 2.5 kb promoter. PRE-1-rho which has the highest sequence and structural homology to PRE-1 is located in the rhodopsin promoter. Surprisingly, PRE-1 and PRE-1-rho are functionally distinct. We demonstrate that PRE-1, but not PRE-1 rho, is sufficient to enhance expression from a heterologous UV cone promoter. PRE-1 is also sufficient to enhance expression from a heterologous rhodopsin promoter without altering its rod photoreceptor specificity. Finally, mutations in consensus E-box and Otx sites prevent PRE-1 from forming complexes with eye nuclear protein and enhancing photoreceptor expression. CONCLUSIONS: PRE-1 is a novel cis-regulatory module that is sufficient to enhance the initiation of photoreceptor-specific gene expression in differentiating rod and cone photoreceptors. PMID- 21261955 TI - Multiple-locus, variable number of tandem repeat analysis (MLVA) of the fish pathogen Francisella noatunensis. AB - BACKGROUND: Since Francisella noatunensis was first isolated from cultured Atlantic cod in 2004, it has emerged as a global fish pathogen causing disease in both warm and cold water species. Outbreaks of francisellosis occur in several important cultured fish species making a correct management of this disease a matter of major importance. Currently there are no vaccines or treatments available. A strain typing system for use in studies of F. noatunensis epizootics would be an important tool for disease management. However, the high genetic similarity within the Francisella spp. makes strain typing difficult, but such typing of the related human pathogen Francisella tullarensis has been performed successfully by targeting loci with higher genetic variation than the traditional signature sequences. These loci are known as Variable Numbers of Tandem Repeat (VNTR). The aim of this study is to identify possible useful VNTRs in the genome of F. noatunensis. RESULTS: Seven polymorphic VNTR loci were identified in the preliminary genome sequence of F. noatunensis ssp. noatunensis GM2212 isolate. These VNTR-loci were sequenced in F. noatunensis isolates collected from Atlantic cod (Gadus morhua) from Norway (n = 21), Three-line grunt (Parapristipoma trilineatum) from Japan (n = 1), Tilapia (Oreochromis spp.) from Indonesia (n = 3) and Atlantic salmon (Salmo salar) from Chile (n = 1). The Norwegian isolates presented in this study show both nine allelic profiles and clades, and that the majority of the farmed isolates belong in two clades only, while the allelic profiles from wild cod are unique. CONCLUSIONS: VNTRs can be used to separate isolates belonging to both subspecies of F. noatunensis. Low allelic diversity in F. noatunensis isolates from outbreaks in cod culture compared to isolates wild cod, indicate that transmission of these isolates may be a result of human activity. The sequence based MLVA system presented in this study should provide a good starting point for further development of a genotyping system that can be used in studies of epizootics and disease management of francisellosis. PMID- 21261956 TI - Phenotypic characteristics of human type II alveolar epithelial cells suitable for antigen presentation to T lymphocytes. AB - BACKGROUND: Type II alveolar epithelial cells (AECII) are well known for their role in the innate immune system. More recently, it was proposed that they could play a role in the antigen presentation to T lymphocytes but contradictory results have been published both concerning their surface expressed molecules and the T lymphocyte responses in mixed lymphocyte cultures. The use of either AECII cell line or fresh cells could explain the observed discrepancies. Thus, this study aimed at defining the most relevant model of accessory antigen presenting cells by carefully comparing the two models for their expression of surface molecules necessary for efficient antigen presentation. METHODS: We have compared by flow cytometry the surface expression of the major markers involved in the immunological synapse on the A549 cell line, the most popular model of type II alveolar epithelial cells, and freshly isolated cells. HLA-DR, CD80, CD86, ICOS L, CD54, CD58 surface expression were studied in resting conditions as well as after IFN-gamma/TNF-alpha treatment, two inflammatory cytokines, known to modulate some of these markers. RESULTS: The major difference found between the two cells types was the very low surface expression of HLA-DR on the A549 cell line compared to its constitutive expression on freshly isolated AECII. The surface expression of co-stimulatory molecules from the B7 family was very low for the CD86 (B7-2) and ICOS-L (B7-H2) and absent for CD80 (B7-1) on both freshly isolated cells and A549 cell line. Neither IFN-gamma nor TNF-alpha could increase the expression of these classical co-stimulatory molecules. However CD54 (ICAM-1) and CD58 (LFA-3) adhesion molecules, known to be implicated in B7 independent co stimulatory signals, were well expressed on the two cell types. CONCLUSIONS: Constitutive expression of MHC class I and II molecules as well as alternative co stimulatory molecules by freshly isolated AECII render these cells a good model to study antigen presentation. PMID- 21261957 TI - Socio-demographic factors and processes associated with stages of change for smoking cessation in pregnant versus non-pregnant women. AB - BACKGROUND: The tobacco control community assumes that the most effective interventions are personalized. Nevertheless, little attention is paid to understanding differences between pregnant and non-pregnant European women in terms of the social factors that influence tobacco use and the processes of change used to quit smoking. METHODS: The study consecutively enrolled 177 pregnant women who acknowledged smoking the year before pregnancy and 177 non pregnant women who acknowledged smoking the year before their clinic visit for a Pap test. RESULTS: With respect to socio-demographic factors, the stages of change in pregnant women were associated with level of education, marital status, and the presence of roommates, partners and friends who smoke. In pregnant women, there was no statistically significant difference in the processes used to stop smoking among the stages of change. Furthermore, behavioral processes were higher in non-pregnant women than in pregnant women, and the difference was statistically significant in the advanced stages of behavioral change. Both pregnant and non-pregnant women showed higher levels of acceptance towards smoking in the earlier stages of change, but the acceptability of smoking in the pre-contemplative stage was higher in non-pregnant women. Greater craving was detected in non-pregnant vs. pregnant women at all stages and reached a statistically significant level at the pre-contemplative stage. CONCLUSION: Pregnancy is a favorable time to stop smoking since pregnant women are more likely to be in an advanced stage of behavioral change. Pregnant and non-pregnant women are distinct populations in the types and processes of change involved in smoking cessation. The intervention programs to promote smoking cessation and prevent relapses will need to take these differences into account. PMID- 21261958 TI - Role of innate signalling pathways in the immunogenicity of alphaviral replicon based vaccines. AB - BACKGROUND: Alphaviral replicon-based vectors induce potent immune responses both when given as viral particles (VREP) or as DNA (DREP). It has been suggested that the strong immune stimulatory effect induced by these types of vectors is mediated by induction of danger signals and activation of innate signalling pathways due to the replicase activity. To investigate the innate signalling pathways involved, mice deficient in either toll-like receptors or downstream innate signalling molecules were immunized with DREP or VREP. RESULTS: We show that the induction of a CD8+ T cell response did not require functional TLR3 or MyD88 signalling. However, IRF3, converging several innate signalling pathways and important for generation of pro-inflammatory cytokines and type I IFNs, was needed for obtaining a robust primary immune response. Interestingly, type I interferon (IFN), induced by most innate signalling pathways, had a suppressing effect on both the primary and memory T cell responses after DREP and VREP immunization. CONCLUSIONS: We show that alphaviral replicon-based vectors activate multiple innate signalling pathways, which both activate and restrict the induced immune response. These results further show that there is a delicate balance in the strength of innate signalling and induction of adaptive immune responses that should be taken into consideration when innate signalling molecules, such as type I IFNs, are used as vaccine adjuvant. PMID- 21261959 TI - Reduced spiral ganglion neuronal loss by adjunctive neurotrophin-3 in experimental pneumococcal meningitis. AB - BACKGROUND: Hearing loss is a frequent long-term complication of pneumococcal meningitis (PM). Its main pathological correlate is damage to the organ of Corti and loss of spiral ganglion neurons. The only current treatment option is cochlear implants which require surviving neurons. Here, we investigated the impact of systemically applied neurotrophin-3 (NT-3) on long-term hearing loss and the survival of neurons. METHODS: Eighteen hours after infection with S. pneumoniae, C57BL/6 mice were treated with a combination of ceftriaxone with NT-3 or dexamethasone or placebo. Hearing, cochlear damage, and brain damage were assessed by audiometry and histology. RESULTS: The main findings from immunohistochemical visualization of neurotrophins (NT-3, BDNF) and their receptors (TrkB, TrkC, and p75) in the cochlea were (i) enhanced staining for the cell survival-promoting receptor TrkB and (ii) increased NT-3 staining in NT-3 treated mice, showing that systemically applied NT-3 reaches the cochlea. The major effects of adjunctive NT-3 treatment were (i) a reduction of meningitis induced hearing impairment and (ii) a reduction of spiral ganglion neuronal loss. The efficacy of NT-3 therapy was comparable to that of dexamethasone. CONCLUSION: Systemically applied NT-3 might be an interesting candidate to improve hearing outcome after pneumococcal meningitis. PMID- 21261960 TI - Greater severity of new onset asthma in allergic subjects who smoke: a 10-year longitudinal study. AB - BACKGROUND: Little is known about the association between cigarette smoking and asthma severity. We assessed smoking as a determinant of disease severity and control in a cohort of clinic-referred allergic subjects who developed new onset asthma. METHODS: Allergic rhinitis subjects with no asthma (n = 371) were followed-up for 10 years and routinely examined for asthma diagnosis. In those who developed asthma (n = 152), clinical severity and levels of asthma control were determined. Among these subjects, 74 (48.7%) were current smokers, 17 (11.2%) former smokers, and 61 (40.1%) never smokers. RESULTS: When comparing current or past smokers to never smokers they had a higher risk of severe asthma in the univariate analysis, which became non-significant in the multivariate analysis. On the other hand, the categories of pack-years were significantly related to severe asthma in a dose response relationship in both the univariate and multivariate analysis: compared to 0 pack years, those who smoked 1-10 pack years had an OR(95% CI) of 1.47(0.46-4.68), those who smoked 11-20 pack-years had an OR of 2.85(1.09-7.46) and those who smoked more than 20 pack-years had an OR of 5.59(1.44-21.67) to develop more severe asthma. Smokers with asthma were also more likely to have uncontrolled disease. A significant dose-response relationship was observed for pack-years and uncontrolled asthma. Compared to 0 pack years, those who smoked 1-10 pack-years had an OR of 5.51(1.73-17.54) and those who smoked more than 10 pack-years had an OR of 13.38(4.57-39.19) to have uncontrolled asthma. CONCLUSIONS: The current findings support the hypothesis that cigarette smoking is an important predictor of asthma severity and poor asthma control. PMID- 21261961 TI - Development of an in situ assay for simultaneous detection of the genomic and replicative form of PCV2 using padlock probes and rolling circle amplification. AB - BACKGROUND: In this study we utilized padlock probes and rolling circle amplification as a mean to detect and study the replication of porcine circovirus type 2 (PCV2) in cultured cells and in infected tissue. Porcine circovirus type 2 is a single-stranded circular DNA virus associated with several severe diseases, porcine circovirus diseases (PCVD) in pigs, such as postweaning multisystemic wasting syndrome. The exact reason and mechanisms behind the trigger of PCV2 replication that is associated with these diseases is not well-known. The virus replicates with rolling circle replication and thus also exists as a double stranded replicative form. RESULTS: By applying padlock probes and rolling circle amplification we could not only visualise the viral genome but also discriminate between the genomic and the replicative strand in situ. The genomic strand existed in higher numbers than the replicative strand. The virus accumulated in certain nuclei but also spread into the cytoplasm of cells in the surrounding tissue. In cultured cells the average number of signals increased with time after infection. CONCLUSIONS: We have developed a method for detection of both strands of PCV2 in situ that can be useful for studies of replication and in situ detection of PCV2 as well as of DNA viruses in general. PMID- 21261962 TI - Pyrosequencing the transcriptome of the greenhouse whitefly, Trialeurodes vaporariorum reveals multiple transcripts encoding insecticide targets and detoxifying enzymes. AB - BACKGROUND: The whitefly Trialeurodes vaporariorum is an economically important crop pest in temperate regions that has developed resistance to most classes of insecticides. However, the molecular mechanisms underlying resistance have not been characterised and, to date, progress has been hampered by a lack of nucleotide sequence data for this species. Here, we use pyrosequencing on the Roche 454-FLX platform to produce a substantial and annotated EST dataset. This 'unigene set' will form a critical reference point for quantitation of over expressed messages via digital transcriptomics. RESULTS: Pyrosequencing produced around a million sequencing reads that assembled into 54,748 contigs, with an average length of 965 bp, representing a dramatic expansion of existing cDNA sequences available for T. vaporariorum (only 43 entries in GenBank at the time of this publication). BLAST searching of non-redundant databases returned 20,333 significant matches and those gene families potentially encoding gene products involved in insecticide resistance were manually curated and annotated. These include, enzymes potentially involved in the detoxification of xenobiotics and those encoding the targets of the major chemical classes of insecticides. A total of 57 P450s, 17 GSTs and 27 CCEs were identified along with 30 contigs encoding the target proteins of six different insecticide classes. CONCLUSION: Here, we have developed new transcriptomic resources for T. vaporariorum. These include a substantial and annotated EST dataset that will serve the community studying this important crop pest and will elucidate further the molecular mechanisms underlying insecticide resistance. PMID- 21261963 TI - Differential effects of frozen storage on the molecular detection of bacterial taxa that inhabit the nasopharynx. AB - BACKGROUND: Frozen storage often precedes metagenomic analysis of biological samples; however, the freezing process can have adverse effects on microbial composition. The effect of freezing on the detection of bacteria inhabiting the infant nasopharynx, a major reservoir of bacterial pathogens, was investigated. METHODS: 16S ribosomal RNA (rRNA) gene-based terminal restriction fragment length polymorphism (T-RFLP) analysis of nasopharyngeal (NP) swabs from twelve Gambian infants was employed. NP swabs were analysed within hours of collection and then after 30 days of storage at -70 degrees C. RESULTS: There was substantial heterogeneity among subjects with respect to the effect of freezing on the number of operational taxonomic units (OTUs) detected. Nevertheless, the mean number of OTUs decreased after frozen storage and the relative abundance for 72% of the OTUs changed by less than 0.5% after deep frozen storage. There were differences in the odds of detection and relative abundance of OTUs matched with Moraxella sp., Haemophilus sp./Burkholderia sp., and Pseudomonas sp. A strong interaction between sex and the effect of freezing was found, whereby there was no significant change observed for males while the mean number of OTUs significantly declined among female infants following frozen storage. CONCLUSIONS: Although frozen storage of biological samples is often necessary for archiving and logistic purposes, the potential effects on the number of taxa (composition) detected in microbial community studies are significant and should not be overlooked. Moreover, genetic factors such as sex may influence the integrity of nucleic acids during the freezing process. PMID- 21261964 TI - Transcriptome dynamics and molecular cross-talk between bovine oocyte and its companion cumulus cells. AB - BACKGROUND: The bi-directional communication between the oocyte and its companion cumulus cells (CCs) is crucial for development and functions of both cell types. Transcripts that are exclusively expressed either in oocytes or CCs and molecular mechanisms affected due to removal of the communication axis between the two cell types is not investigated at a larger scale. The main objectives of this study were: 1. To identify transcripts exclusively expressed either in oocyte or CCs and 2. To identify those which are differentially expressed when the oocyte is cultured with or without its companion CCs and vice versa. RESULTS: We analyzed transcriptome profile of different oocyte and CC samples using Affymetrix GeneChip Bovine Genome array containing 23000 transcripts. Out of 13162 genes detected in germinal vesicle (GV) oocytes and their companion CCs, 1516 and 2727 are exclusively expressed in oocytes and CCs, respectively, while 8919 are expressed in both. Similarly, of 13602 genes detected in metaphase II (MII) oocytes and CCs, 1423 and 3100 are exclusively expressed in oocytes and CCs, respectively, while 9079 are expressed in both. A total of 265 transcripts are differentially expressed between oocytes cultured with (OO+CCs) and without (OO CCs) CCs, of which 217 and 48 are over expressed in the former and the later groups, respectively. Similarly, 566 transcripts are differentially expressed when CCs mature with (CCs+OO) or without (CCs-OO) their enclosed oocytes. Of these, 320 and 246 are over expressed in CCs+OO and CCs-OO, respectively.While oocyte specific transcripts include those involved in transcription (IRF6, POU5F1, MYF5, MED18), translation (EIF2AK1, EIF4ENIF1) and CCs specific ones include those involved in carbohydrate metabolism (HYAL1, PFKL, PYGL, MPI), protein metabolic processes (IHH, APOA1, PLOD1), steroid biosynthetic process (APOA1, CYP11A1, HSD3B1, HSD3B7). Similarly, while transcripts over expressed in OO+CCs are involved in carbohydrate metabolism (ACO1, 2), molecular transport (GAPDH, GFPT1) and nucleic acid metabolism (CBS, NOS2), those over expressed in CCs+ OO are involved in cellular growth and proliferation (FOS, GADD45A), cell cycle (HAS2, VEGFA), cellular development (AMD1, AURKA, DPP4) and gene expression (FOSB, TGFB2). CONCLUSION: In conclusion, this study has generated large scale gene expression data from different oocyte and CCs samples that would provide insights into gene functions and interactions within and across different pathways that are involved in the maturation of bovine oocytes. Moreover, the presence or absence of oocyte and CC factors during bovine oocyte maturation can have a profound effect on transcript abundance of each cell types, thereby showing the prevailing molecular cross-talk between oocytes and their corresponding CCs. PMID- 21261965 TI - The Armeo Spring as training tool to improve upper limb functionality in multiple sclerosis: a pilot study. AB - BACKGROUND: Few research in multiple sclerosis (MS) has focused on physical rehabilitation of upper limb dysfunction, though the latter strongly influences independent performance of activities of daily living. Upper limb rehabilitation technology could hold promise for complementing traditional MS therapy. Consequently, this pilot study aimed to examine the feasibility of an 8-week mechanical-assisted training program for improving upper limb muscle strength and functional capacity in MS patients with evident paresis. METHODS: A case series was applied, with provision of a training program (3*/week, 30 minutes/session), supplementary on the customary maintaining care, by employing a gravity supporting exoskeleton apparatus (Armeo Spring). Ten high-level disability MS patients (Expanded Disability Status Scale 7.0-8.5) actively performed task oriented movements in a virtual real-life-like learning environment with the affected upper limb. Tests were administered before and after training, and at 2 month follow-up. Muscle strength was determined through the Motricity Index and Jamar hand-held dynamometer. Functional capacity was assessed using the TEMPA, Action Research Arm Test (ARAT) and 9-Hole Peg Test (9HPT). RESULTS: Muscle strength did not change significantly. Significant gains were particularly found in functional capacity tests. After training completion, TEMPA scores improved (p = 0.02), while a trend towards significance was found for the 9HPT (p = 0.05). At follow-up, the TEMPA as well as ARAT showed greater improvement relative to baseline than after the 8-week intervention period (p = 0.01, p = 0.02 respectively). CONCLUSIONS: The results of present pilot study suggest that upper limb functionality of high-level disability MS patients can be positively influenced by means of a technology-enhanced physical rehabilitation program. PMID- 21261966 TI - A multidisciplinary primary care team consultation in a socio-economically deprived community: an exploratory randomised controlled trial. AB - BACKGROUND: Psychosocial problems in socioeconomically deprived communities are not always amenable to traditional medical approaches. Mothers living in these areas are a particularly vulnerable group. The objective of this study was to evaluate the effectiveness of a lengthened multi-disciplinary team consultation in primary care in reducing anxiety and depression in mothers. METHODS: This was a prospective randomised controlled trial of a multidisciplinary team consultation against normal care. 94 mothers were recruited from three general practices from an area of extreme socio-economic deprivation. Mothers randomised into the intervention group attended a multidisciplinary consultation with up to four case-specific health care professionals. Consultations addressed medical, psychological and social problems and lasted up to one hour. Conventional primary care continued to be available to the intervention families. Control group families received normal primary care services. The outcomes measured were anxiety and depression as using the Hospital Anxiety and Depression Scale (HADS), health status using SF36v2, and quality of life using the abbreviated Schedule for the Evaluation of Individual Quality of Life (SEIQoL-DW) at baseline, 6 months and 12 months. RESULTS: Ordered logistic regression was used to analyse the data. There was no significant difference found between intervention and control groups after 6 months and 12 months in all of the measured outcomes. CONCLUSIONS: The new lengthened multi-disciplinary team consultation did not have any impact on the mental health, general health, and quality of life of mothers after 6 and 12 months. Other methods of primary health care delivery in socio economically deprived communities need to be evaluated. PMID- 21261967 TI - Can vagus nerve stimulation halt or ameliorate rheumatoid arthritis and lupus? AB - Acetylcholine, the principal vagus neurotransmitter, inhibits inflammation by suppressing the production of pro-inflammatory cytokines through a mechanism dependent on the alpha7 nicotinic acetylcholine receptor subunit (alpha7nAChR) that explains why vagus nerve stimulation is anti-inflammatory in nature. Strong expression of alpha7nAChR in the synovium of rheumatoid arthritis and psoriatic arthritis patients was detected. Peripheral macrophages and synovial fibroblasts respond in vitro to specific alpha7nAChR cholinergic stimulation with potent inhibition of proinflammatory cytokines. Fibroblasts balance inflammatory mechanisms and arthritis development through feedback cholinergic stimulation by nearby immune cells. Collagen induced arthritis in alpha7nAChR(-/-) mice was significantly severe and showed increased synovial inflammation and joint destruction compared to the wild-type mice. Similar to vagal nerve stimulation and alpha7nAChR agonists, polyunsaturated fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also suppress inflammation. In view of their similar anti-inflammatory actions, it is proposed that vagal nerve stimulation, alpha7nAChR agonists and EPA and DHA may augment the formation of anti inflammatory lipid molecules: lipoxins, resolvins, protectins and maresins. This implies that therapies directed at regulation of the cholinergic and alpha7nAChR mediated mechanisms and enhancing the formation of lipoxins, resolvins, protectins and maresins may halt and/or ameliorate rheumatoid arthritis, lupus and other rheumatological conditions. PMID- 21261968 TI - Evaluation of a pilot cooperative medical scheme in rural China: impact on gender patterns of health care utilization and prescription practices. AB - BACKGROUND: In 2003 the Chinese government introduced voluntary cooperative medical schemes (CMS), soon to be in place throughout rural China. Families who chose to enroll do so as a single unit and nothing is known about any differential effect of these new schemes on family members. This study evaluates the impact of one pilot CMS in Anhui Province on health care use by girls aged less than 5 years and women 65 years or older, and on the pattern and cost of prescriptions. METHODS: Health care records were extracted covering a 10 year period, before, during and after the pilot CMS in 4 townships, one with the intervention and 3 comparison townships without. The impact of the intervention on the age and gender distribution of patients presenting for health care and on the prescription of certain drugs was assessed by logistic regression. The cost of prescriptions before, during and after the intervention period was also assessed. RESULTS: 203,058 registration and 643,588 prescription records were identified. During the intervention there was a reduced likelihood overall that a patient was female (OR = 0.92: 95%CI 0.87-0.97) at the intervention site. Girls aged < 5 years had an increased likelihood of health care (OR = 1.41: 95%CI 1.23 1.59) during the CMS, but women >= 65 years were relatively disadvantaged (OR = 0.84: 95%CI 0.75-0.95). The use of antibiotics and systemic steroids increased disproportionately at the intervention site for patients >= 5 years. Prescription costs at the township hospital also increased at the intervention site, particularly for older men. CONCLUSIONS: This evaluation suggests that all family members did not benefit equally from the pilot CMS and that women >= 65 years may be disadvantaged by the newly available reimbursements of health care costs through the CMS. It points to the need, in future evaluations, to use individuals rather than families as the unit of analysis, in order to determine whether such health care inequalities are wide-spread and persistent or are reduced in the longer term. The results also support earlier concerns about the influence of new funding resources on prescription practices and the need for regulation of for profit prescribing. PMID- 21261969 TI - iPhy: an integrated phylogenetic workbench for supermatrix analyses. AB - BACKGROUND: The increasing availability of molecular sequence data means that the accuracy of future phylogenetic studies is likely to by limited by systematic bias and taxon choice rather than by data. In order to take advantage of increasing datasets, user-friendly tools are required to facilitate phylogenetic analyses and to reduce duplication of dataset assembly efforts. Current phylogenetic pipelines are dependency-heavy and have significant technical barriers to use. RESULTS: Here we present iPhy, a web application that lets non technical users assemble, share and analyse DNA sequence datasets for multigene phylogenetic investigations. Built on a simple client-server architecture, iPhy eases the collection of gene sets for analysis, facilitates alignment and reliably generates phylogenetic analysis-ready data files. Phylogenetic trees generated in external programs can be imported and stored, and iPhy integrates with iTol to allow trees to be displayed with rich data annotation. The datasets collated in iPhy can be shared through the client interface. We show how systematic biases can be addressed by using explicit criteria when selecting sequences for analysis from a large dataset. A representative instance of iPhy can be accessed at iphy.bio.ed.ac.uk, but the toolkit can also be deployed on a local server for advanced users. CONCLUSIONS: iPhy provides an easy-to-use environment for the assembly, analysis and sharing of large phylogenetic datasets, while encouraging best practices in terms of phylogenetic analysis and taxon selection. PMID- 21261970 TI - Fructose impairs glucose-induced hepatic triglyceride synthesis. AB - Obesity, type 2 diabetes and hyperlipidemia frequently coexist and are associated with significantly increased morbidity and mortality. Consumption of refined carbohydrate and particularly fructose has increased significantly in recent years and has paralled the increased incidence of obesity and diabetes. Human and animal studies have demonstrated that high dietary fructose intake positively correlates with increased dyslipidemia, insulin resistance, and hypertension. Metabolism of fructose occurs primarily in the liver and high fructose flux leads to enhanced hepatic triglyceride accumulation (hepatic steatosis). This results in impaired glucose and lipid metabolism and increased proinflammatory cytokine expression. Here we demonstrate that fructose alters glucose-stimulated expression of activated acetyl CoA carboxylase (ACC), pSer hormone sensitive lipase (pSerHSL) and adipose triglyceride lipase (ATGL) in hepatic HepG2 or primary hepatic cell cultures in vitro. This was associated with increased de novo triglyceride synthesis in vitro and hepatic steatosis in vivo in fructose- versus glucose-fed and standard-diet fed mice. These studies provide novel insight into the mechanisms involved in fructose-mediated hepatic hypertriglyceridemia and identify fructose-uptake as a new potential therapeutic target for lipid-associated diseases. PMID- 21261972 TI - Confident predictability: identifying reliable gene expression patterns for individualized tumor classification using a local minimax kernel algorithm. AB - BACKGROUND: Molecular classification of tumors can be achieved by global gene expression profiling. Most machine learning classification algorithms furnish global error rates for the entire population. A few algorithms provide an estimate of probability of malignancy for each queried patient but the degree of accuracy of these estimates is unknown. On the other hand local minimax learning provides such probability estimates with best finite sample bounds on expected mean squared error on an individual basis for each queried patient. This allows a significant percentage of the patients to be identified as confidently predictable, a condition that ensures that the machine learning algorithm possesses an error rate below the tolerable level when applied to the confidently predictable patients. RESULTS: We devise a new learning method that implements: (i) feature selection using the k-TSP algorithm and (ii) classifier construction by local minimax kernel learning. We test our method on three publicly available gene expression datasets and achieve significantly lower error rate for a substantial identifiable subset of patients. Our final classifiers are simple to interpret and they can make prediction on an individual basis with an individualized confidence level. CONCLUSIONS: Patients that were predicted confidently by the classifiers as cancer can receive immediate and appropriate treatment whilst patients that were predicted confidently as healthy will be spared from unnecessary treatment. We believe that our method can be a useful tool to translate the gene expression signatures into clinical practice for personalized medicine. PMID- 21261971 TI - Treatment of myofascial trigger points in patients with chronic shoulder pain: a randomized, controlled trial. AB - BACKGROUND: Shoulder pain is a common musculoskeletal problem that is often chronic or recurrent. Myofascial trigger points (MTrPs) cause shoulder pain and are prevalent in patients with shoulder pain. However, few studies have focused on MTrP therapy. The aim of this study was to assess the effectiveness of multimodal treatment of MTrPs in patients with chronic shoulder pain. METHODS: A single-assessor, blinded, randomized, controlled trial was conducted. The intervention group received comprehensive treatment once weekly consisting of manual compression of the MTrPs, manual stretching of the muscles and intermittent cold application with stretching. Patients were instructed to perform muscle-stretching and relaxation exercises at home and received ergonomic recommendations and advice to assume and maintain good posture. The control group remained on the waiting list for 3 months. The Disabilities of Arm, Shoulder and Hand (DASH) questionnaire score (primary outcome), Visual Analogue Scale for Pain (VAS-P), Global Perceived Effect (GPE) scale and the number of muscles with MTrPs were assessed at 6 and 12 weeks in the intervention group and compared with those of a control group. RESULTS: Compared with the control group, the intervention group showed significant improvement (P < 0.05) on the DASH after 12 weeks (mean difference, 7.7; 95% confidence interval (95% CI), 1.2 to 14.2), on the VAS-P1 for current pain (mean difference, 13.8; 95% CI, 2.6 to 25.0), on the VAS-P2 for pain in the past 7 days (mean difference, 10.2; 95% CI, 0.7 to 19.7) and VAS-P3 most severe pain in the past 7 days (mean difference, 13.8; 95% CI, 0.8 to 28.4). After 12 weeks, 55% of the patients in the intervention group reported improvement (from slightly improved to completely recovered) versus 14% in the control group. The mean number of muscles with active MTrPs decreased in the intervention group compared with the control group (mean difference, 2.7; 95% CI, 1.2 to 4.2). CONCLUSIONS: The results of this study show that 12-week comprehensive treatment of MTrPs in shoulder muscles reduces the number of muscles with active MTrPs and is effective in reducing symptoms and improving shoulder function in patients with chronic shoulder pain. TRIAL REGISTRATION NUMBER: ISRCTN: ISRCTN75722066. PMID- 21261973 TI - Antinociception produced by Thalassia testudinum extract BM-21 is mediated by the inhibition of acid sensing ionic channels by the phenolic compound thalassiolin B. AB - BACKGROUND: Acid-sensing ion channels (ASICs) have a significant role in the sensation of pain and constitute an important target for the search of new antinociceptive drugs. In this work we studied the antinociceptive properties of the BM-21 extract, obtained from the sea grass Thalassia testudinum, in chemical and thermal models of nociception in mice. The action of the BM-21 extract and the major phenolic component isolated from this extract, a sulphated flavone glycoside named thalassiolin B, was studied in the chemical nociception test and in the ASIC currents of the dorsal root ganglion (DRG) neurons obtained from Wistar rats. RESULTS: Behavioral antinociceptive experiments were made on male OF 1 mice. Single oral administration of BM-21 produced a significant inhibition of chemical nociception caused by acetic acid and formalin (specifically during its second phase), and increased the reaction time in the hot plate test. Thalassiolin B reduced the licking behavior during both the phasic and tonic phases in the formalin test. It was also found that BM-21 and thalassiolin B selectively inhibited the fast desensitizing (tau < 400 ms) ASIC currents in DRG neurons obtained from Wistar rats, with a nonsignificant action on ASIC currents with a slow desensitizing time-course. The action of thalassiolin B shows no pH or voltage dependence nor is it modified by steady-state ASIC desensitization or voltage. The high concentration of thalassiolin B in the extract may account for the antinociceptive action of BM-21. CONCLUSIONS: To our knowledge, this is the first report of an ASIC-current inhibitor derived of a marine-plant extract, and in a phenolic compound. The antinociceptive effects of BM-21 and thalassiolin B may be partially because of this action on the ASICs. That the active components of the extract are able to cross the blood-brain barrier gives them an additional advantage for future uses as tools to study pain mechanisms with a potential therapeutic application. PMID- 21261974 TI - PileLine: a toolbox to handle genome position information in next-generation sequencing studies. AB - BACKGROUND: Genomic position (GP) files currently used in next-generation sequencing (NGS) studies are always difficult to manipulate due to their huge size and the lack of appropriate tools to properly manage them. The structure of these flat files is based on representing one line per position that has been covered by at least one aligned read, imposing significant restrictions from a computational performance perspective. RESULTS: PileLine implements a flexible command-line toolkit providing specific support to the management, filtering, comparison and annotation of GP files produced by NGS experiments. PileLine tools are coded in Java and run on both UNIX (Linux, Mac OS) and Windows platforms. The set of tools comprising PileLine are designed to be memory efficient by performing fast seek on-disk operations over sorted GP files. CONCLUSIONS: Our novel toolbox has been extensively tested taking into consideration performance issues. It is publicly available at http://sourceforge.net/projects/pilelinetools under the GNU LGPL license. Full documentation including common use cases and guided analysis workflows is available at http://sing.ei.uvigo.es/pileline. PMID- 21261975 TI - Impact of early parenteral nutrition completing enteral nutrition in adult critically ill patients (EPaNIC trial): a study protocol and statistical analysis plan for a randomized controlled trial. AB - BACKGROUND: For critically ill patients treated in intensive care units (ICU), two feeding strategies are currently being advocated, one by American/Canadian and the other by European expert guidelines. These guidelines differ particularly in the timing of initiating parenteral nutrition (PN) in patients for whom enteral nutrition (EN) does not reach caloric targets. METHODS/DESIGN: The EPaNIC trial is an investigator-initiated, non-commercial, multi-center, randomized, controlled, clinical trial with a parallel group design. This study compares early (European guideline) versus late (American/Canadian guideline) initiation of PN when EN fails to reach a caloric target. In the early PN group, PN is initiated within 24-48 hours after ICU admission to complete early enteral nutrition (EN) up to a calculated nutritional target. In the late PN group, PN completing EN is initiated when the target is not reached on day 8. In both groups, the same early EN protocol is applied. The study is designed to compare clinical outcome (morbidity and mortality) in the 2 study arms as well as to address several mechanistical questions. We here describe the EPaNIC study protocol and the statistical analysis plan for the primary report of the clinical results. DISCUSSION: The study has been initiated as planned on august 01 2007. One interim analysis advised continuation of the trial. The study will be completed in February 2011. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT00512122. PMID- 21261976 TI - Long-term outcome in medical patients aged 80 or over following admission to an intensive care unit. AB - INTRODUCTION: The aim of this study was to evaluate factors influencing short- and long-term survival in medical patients aged 80 and over following admission to an intensive care unit. METHODS: All patients aged 80 years or over and admitted between 2001 and 2006 were included in this study. Survival was evaluated between the time of admission and June 2009; factors associated with mortality were determined. Health-related quality of life was evaluated using Short Form (SF)-36 in long-term survivors. RESULTS: For the 299 patients included (mean age, 84 +/- 4 y), hospital mortality was 55%. Factors independently associated with hospital mortality were a higher SAPS II score at ICU admission; the existence of a fatal disease as reflected by the McCabe score and a cardiac diagnosis at admission. In the 133 hospital survivors, median survival time was 710 days (95% CI, 499-921). Two-year mortality rates were 79% of the initial cohort and 53% of hospital survivors. The standardized ratio of mortality at 2 years after hospital discharge was 2.56 (95% CI, 2.08-3.12) when compared with age- and gender-adjusted mortality of the general population. Factors independently associated with mortality at 2 years after hospital discharge were SAPS II score at ICU admission and the McCabe score. Conversely, functional status prior to admission as assessed by Knaus or Karnofsky scores was not associated with long-term mortality. In long-term survivors, SF-36 physical function scores were poor but scores for pain, emotional well-being and social function were not much affected. CONCLUSIONS: The severity of acute disease at admission influences mortality at the hospital and following discharge in patients aged 80 or over. Although up to 50% of patients discharged from the hospital were still alive at 2 years, mortality was increased when compared with the general population. Physical function of long-term hospital survivors was greatly altered. PMID- 21261977 TI - Variants in KCNQ1 increase type II diabetes susceptibility in South Asians: a study of 3,310 subjects from India and the US. AB - BACKGROUND: Polymorphisms in intron 15 of potassium voltage-gated channel, KQT like subfamily member 1 (KCNQ1) gene have been associated with type II diabetes (T2D) in Japanese genome-wide association studies (GWAS). More recently a meta analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the KCNQ1 gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US. METHODS: We examined the association between four variants in the KCNQ1 gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US. RESULTS: Our data confirmed the association of a new signal at the KCNQ1 locus (rs231362) with T2D showing an allelic odds ratio (OR) of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036) and combined cohorts (meta-analysis OR 1.14; p = 0.018). Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 * 10-4 in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009). CONCLUSIONS: Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through beta cell function. PMID- 21261978 TI - Amyloid beta dimers/trimers potently induce cofilin-actin rods that are inhibited by maintaining cofilin-phosphorylation. AB - BACKGROUND: Previously we reported 1 MUM synthetic human amyloid beta1-42 oligomers induced cofilin dephosphorylation (activation) and formation of cofilin actin rods within rat hippocampal neurons primarily localized to the dentate gyrus. RESULTS: Here we demonstrate that a gel filtration fraction of 7PA2 cell secreted SDS-stable human Abeta dimers and trimers (Abetad/t) induces maximal neuronal rod response at ~250 pM. This is 4,000-fold more active than traditionally prepared human Abeta oligomers, which contain SDS-stable trimers and tetramers, but are devoid of dimers. When incubated under tyrosine oxidizing conditions, synthetic human but not rodent Abeta1-42, the latter lacking tyrosine, acquires a marked increase (620 fold for EC50) in rod-inducing activity. Gel filtration of this preparation yielded two fractions containing SDS stable dimers, trimers and tetramers. One, eluting at a similar volume to 7PA2 Abetad/t, had maximum activity at ~5 nM, whereas the other, eluting at the void volume (high-n state), lacked rod inducing activity at the same concentration. Fractions from 7PA2 medium containing Abeta monomers are not active, suggesting oxidized SDS-stable Abeta1-42 dimers in a low-n state are the most active rod inducing species. Abetad/t-induced rods are predominantly localized to the dentate gyrus and mossy fiber tract, reach significance over controls within 2 h of treatment, and are reversible, disappearing by 24 h after Abetad/t washout. Overexpression of cofilin phosphatases increase rod formation when expressed alone and exacerbate rod formation when coupled with Abetad/t, whereas overexpression of a cofilin kinase inhibits Abetad/t-induced rod formation. CONCLUSIONS: Together these data support a mechanism by which Abetad/t alters the actin cytoskeleton via effects on cofilin in neurons critical to learning and memory. PMID- 21261979 TI - Lineage-specific evolution of the vertebrate Otopetrin gene family revealed by comparative genomic analyses. AB - BACKGROUND: Mutations in the Otopetrin 1 gene (Otop1) in mice and fish produce an unusual bilateral vestibular pathology that involves the absence of otoconia without hearing impairment. The encoded protein, Otop1, is the only functionally characterized member of the Otopetrin Domain Protein (ODP) family; the extended sequence and structural preservation of ODP proteins in metazoans suggest a conserved functional role. Here, we use the tools of sequence- and cytogenetic based comparative genomics to study the Otop1 and the Otop2-Otop3 genes and to establish their genomic context in 25 vertebrates. We extend our evolutionary study to include the gene mutated in Usher syndrome (USH) subtype 1G (Ush1g), both because of the head-to-tail clustering of Ush1g with Otop2 and because Otop1 and Ush1g mutations result in inner ear phenotypes. RESULTS: We established that OTOP1 is the boundary gene of an inversion polymorphism on human chromosome 4p16 that originated in the common human-chimpanzee lineage more than 6 million years ago. Other lineage-specific evolutionary events included a three-fold expansion of the Otop genes in Xenopus tropicalis and of Ush1g in teleostei fish. The tight physical linkage between Otop2 and Ush1g is conserved in all vertebrates. To further understand the functional organization of the Ushg1-Otop2 locus, we deduced a putative map of binding sites for CCCTC-binding factor (CTCF), a mammalian insulator transcription factor, from genome-wide chromatin immunoprecipitation-sequencing (ChIP-seq) data in mouse and human embryonic stem (ES) cells combined with detection of CTCF-binding motifs. CONCLUSIONS: The results presented here clarify the evolutionary history of the vertebrate Otop and Ush1g families, and establish a framework for studying the possible interaction(s) of Ush1g and Otop in developmental pathways. PMID- 21261980 TI - Cooperative contributions of interferon regulatory factor 1 (IRF1) and IRF8 to interferon-gamma-mediated cytotoxic effects on oligodendroglial progenitor cells. AB - BACKGROUND: Administration of exogenous interferon-gamma (IFNgamma) aggravates the symptoms of multiple sclerosis (MS), whereas interferon-beta (IFNbeta) is used for treatment of MS patients. We previously demonstrated that IFNgamma induces apoptosis of oligodendroglial progenitor cells (OPCs), suggesting that IFNgamma is more toxic to OPCs than IFNbeta. Thus we hypothesized that a difference in expression profiles between IFNgamma-inducible and IFNbeta inducible genes in OPCs would predict the genes responsible for IFNgamma-mediated cytotoxic effects on OPCs. We have tested this hypothesis particularly focusing on the interferon regulatory factors (IRFs) well-known transcription factors up regulated by IFNs. METHODS: Highly pure primary rat OPC cultures were treated with IFNgamma and IFNbeta. Cell death and proliferation were assessed by MTT reduction, caspase-3-like proteinase activity, Annexin-V binding, mitochondrial membrane potential, and BrdU-incorporation. Induction of all nine IRFs was comprehensively compared by quantitative PCR between IFNgamma-treated and IFNbeta treated OPCs. IRFs more strongly induced by IFNgamma than by IFNbeta were selected, and tested for their ability to induce OPC apoptosis by overexpression and by inhibition by dominant-negative proteins or small interference RNA either in the presence or absence of IFNgamma. RESULTS: Unlike IFNgamma, IFNbeta did not induce apoptosis of OPCs. Among nine IRFs, IRF1 and IRF8 were preferentially up regulated by IFNgamma. In contrast, IRF7 was more robustly induced by IFNbeta than by IFNgamma. Overexpressed IRF1 elicited apoptosis of OPCs, and a dominant negative IRF1 protein partially protected OPCs from IFNgamma-induced apoptosis, indicating a substantial contribution of IRF1 to IFNgamma-induced OPC apoptosis. On the other hand, overexpression of IRF8 itself had only marginal proapoptotic effects. However, overexpressed IRF8 enhanced the IFNgamma-induced cytotoxicity and the proapoptotic effect of overexpressed IRF1, and down-regulation of IRF8 by siRNA partially but significantly reduced preapoptotic cells after treatment with IFNgamma, suggesting that IRF8 cooperatively enhances IFNgamma-induced OPC apoptosis. CONCLUSIONS: This study has identified that IRF1 and IRF8 mediate IFNgamma-signaling leading to OPC apoptosis. Therapies targeting at these transcription factors and their target genes could reduce IFNgamma-induced OPC loss and thereby enhance remyelination in MS patients. PMID- 21261981 TI - WordCluster: detecting clusters of DNA words and genomic elements. AB - BACKGROUND: Many k-mers (or DNA words) and genomic elements are known to be spatially clustered in the genome. Well established examples are the genes, TFBSs, CpG dinucleotides, microRNA genes and ultra-conserved non-coding regions. Currently, no algorithm exists to find these clusters in a statistically comprehensible way. The detection of clustering often relies on densities and sliding-window approaches or arbitrarily chosen distance thresholds. RESULTS: We introduce here an algorithm to detect clusters of DNA words (k-mers), or any other genomic element, based on the distance between consecutive copies and an assigned statistical significance. We implemented the method into a web server connected to a MySQL backend, which also determines the co-localization with gene annotations. We demonstrate the usefulness of this approach by detecting the clusters of CAG/CTG (cytosine contexts that can be methylated in undifferentiated cells), showing that the degree of methylation vary drastically between inside and outside of the clusters. As another example, we used WordCluster to search for statistically significant clusters of olfactory receptor (OR) genes in the human genome. CONCLUSIONS: WordCluster seems to predict biological meaningful clusters of DNA words (k-mers) and genomic entities. The implementation of the method into a web server is available at http://bioinfo2.ugr.es/wordCluster/wordCluster.php including additional features like the detection of co-localization with gene regions or the annotation enrichment tool for functional analysis of overlapped genes. PMID- 21261983 TI - Arsenic species in weathering mine tailings and biogenic solids at the Lava Cap Mine Superfund Site, Nevada City, CA. AB - BACKGROUND: A realistic estimation of the health risk of human exposure to solid phase arsenic (As) derived from historic mining operations is a major challenge to redevelopment of California's famed "Mother Lode" region. Arsenic, a known carcinogen, occurs in multiple solid forms that vary in bioaccessibility. X-ray absorption fine-structure spectroscopy (XAFS) was used to identify and quantify the forms of As in mine wastes and biogenic solids at the Lava Cap Mine Superfund (LCMS) site, a historic "Mother Lode" gold mine. Principal component analysis (PCA) was used to assess variance within water chemistry, solids chemistry, and XAFS spectral datasets. Linear combination, least-squares fits constrained in part by PCA results were then used to quantify arsenic speciation in XAFS spectra of tailings and biogenic solids. RESULTS: The highest dissolved arsenic concentrations were found in Lost Lake porewater and in a groundwater-fed pond in the tailings deposition area. Iron, dissolved oxygen, alkalinity, specific conductivity, and As were the major variables in the water chemistry PCA. Arsenic was, on average, 14 times more concentrated in biologically-produced iron (hydr)oxide than in mine tailings. Phosphorous, manganese, calcium, aluminum, and As were the major variables in the solids chemistry PCA. Linear combination fits to XAFS spectra indicate that arsenopyrite (FeAsS), the dominant form of As in ore material, remains abundant (average: 65%) in minimally-weathered ore samples and water-saturated tailings at the bottom of Lost Lake. However, tailings that underwent drying and wetting cycles contain an average of only 30% arsenopyrite. The predominant products of arsenopyrite weathering were identified by XAFS to be As-bearing Fe (hydr)oxide and arseniosiderite (Ca2Fe(AsO4)3O3*3H2O). Existence of the former species is not in question, but the presence of the latter species was not confirmed by additional measurements, so its identification is less certain. The linear combination, least-squares fits totals of several samples deviate by more than +/- 20% from 100%, suggesting that additional phases may be present that were not identified or evaluated in this study. CONCLUSIONS: Sub- to anoxic conditions minimize dissolution of arsenopyrite at the LCMS site, but may accelerate the dissolution of As-bearing secondary iron phases such as Fe3+ oxyhydroxides and arseniosiderite, if sufficient organic matter is present to spur anaerobic microbial activity. Oxidizing, dry conditions favor the stabilization of secondary phases, while promoting oxidative breakdown of the primary sulfides. The stability of both primary and secondary As phases is likely to be at a minimum under cyclic wet-dry conditions. Biogenic iron (hydr)oxide flocs can sequester significant amounts of arsenic; this property may be useful for treatment of perpetual sources of As such as mine adit water, but the fate of As associated with natural accumulations of floc material needs to be assessed. PMID- 21261982 TI - New insights into HIV-1-primary skin disorders. AB - Since the first reports of AIDS, skin involvement has become a burdensome stigma for seropositive patients and a challenging task for dermatologist and infectious disease specialists due to the severe and recalcitrant nature of the conditions. Dermatologic manifestations in AIDS patients act as markers of disease progression, a fact that enhances the importance of understanding their pathogenesis.Broadly, cutaneous disorders associated with HIV type-1 infection can be classified as primary and secondary. While the pathogenesis of secondary complications, such as opportunistic infections and skin tumours, is directly correlated with a decline in the CD4+ T cell count, the origin of the certain manifestations primarily associated with the retroviral infection itself still remains under investigation.The focus of this review is to highlight the immunological phenomena that occur in the skin of HIV-1-seropositive patients, which ultimately lead to skin disorders, such as seborrhoeic dermatitis, atopic dermatitis, psoriasis and eosinophilic folliculitis. Furthermore, we compile the latest data on how shifts in the cytokines milieu, impairments of the innate immune compartment, reactions to xenobiotics and autoimmunity are causative agents in HIV-1-driven skin diseases. Additionally, we provide a thorough analysis of the small animal models currently used to study HIV-1-associated skin complications, centering on transgenic rodent models, which unfortunately, have not been able to fully unveil the role of HIV-1 genes in the pathogenesis of their primarily associated dermatological manifestations. PMID- 21261984 TI - Deep RNA sequencing analysis of readthrough gene fusions in human prostate adenocarcinoma and reference samples. AB - BACKGROUND: Readthrough fusions across adjacent genes in the genome, or transcription-induced chimeras (TICs), have been estimated using expressed sequence tag (EST) libraries to involve 4-6% of all genes. Deep transcriptional sequencing (RNA-Seq) now makes it possible to study the occurrence and expression levels of TICs in individual samples across the genome. METHODS: We performed single-end RNA-Seq on three human prostate adenocarcinoma samples and their corresponding normal tissues, as well as brain and universal reference samples. We developed two bioinformatics methods to specifically identify TIC events: a targeted alignment method using artificial exon-exon junctions within 200,000 bp from adjacent genes, and genomic alignment allowing splicing within individual reads. We performed further experimental verification and characterization of selected TIC and fusion events using quantitative RT-PCR and comparative genomic hybridization microarrays. RESULTS: Targeted alignment against artificial exon exon junctions yielded 339 distinct TIC events, including 32 gene pairs with multiple isoforms. The false discovery rate was estimated to be 1.5%. Spliced alignment to the genome was less sensitive, finding only 18% of those found by targeted alignment in 33-nt reads and 59% of those in 50-nt reads. However, spliced alignment revealed 30 cases of TICs with intervening exons, in addition to distant inversions, scrambled genes, and translocations. Our findings increase the catalog of observed TIC gene pairs by 66%.We verified 6 of 6 predicted TICs in all prostate samples, and 2 of 5 predicted novel distant gene fusions, both private events among 54 prostate tumor samples tested. Expression of TICs correlates with that of the upstream gene, which can explain the prostate specific pattern of some TIC events and the restriction of the SLC45A3-ELK4 e4-e2 TIC to ERG-negative prostate samples, as confirmed in 20 matched prostate tumor and normal samples and 9 lung cancer cell lines. CONCLUSIONS: Deep transcriptional sequencing and analysis with targeted and spliced alignment methods can effectively identify TIC events across the genome in individual tissues. Prostate and reference samples exhibit a wide range of TIC events, involving more genes than estimated previously using ESTs. Tissue specificity of TIC events is correlated with expression patterns of the upstream gene. Some TIC events, such as MSMB-NCOA4, may play functional roles in cancer. PMID- 21261985 TI - Longitudinal characterization of antimicrobial resistance genes in feces shed from cattle fed different subtherapeutic antibiotics. AB - BACKGROUND: Environmental transmission of antimicrobial-resistant bacteria and resistance gene determinants originating from livestock is affected by their persistence in agricultural-related matrices. This study investigated the effects of administering subtherapeutic concentrations of antimicrobials to beef cattle on the abundance and persistence of resistance genes within the microbial community of fecal deposits. Cattle (three pens per treatment, 10 steers per pen) were administered chlortetracycline, chlortetracycline plus sulfamethazine, tylosin, or no antimicrobials (control). Model fecal deposits (n = 3) were prepared by mixing fresh feces from each pen into a single composite sample. Real time PCR was used to measure concentrations of tet, sul and erm resistance genes in DNA extracted from composites over 175 days of environmental exposure in the field. The microbial communities were analyzed by quantification and denaturing gradient gel electrophoresis (DGGE) of PCR-amplified 16S-rRNA. RESULTS: The concentrations of 16S-rRNA in feces were similar across treatments and increased by day 56, declining thereafter. DGGE profiles of 16S-rRNA differed amongst treatments and with time, illustrating temporal shifts in microbial communities. All measured resistance gene determinants were quantifiable in feces after 175 days. Antimicrobial treatment differentially affected the abundance of certain resistance genes but generally not their persistence. In the first 56 days, concentrations of tet(B), tet(C), sul1, sul2, erm(A) tended to increase, and decline thereafter, whereas tet(M) and tet(W) gradually declined over 175 days. At day 7, the concentration of erm(X) was greatest in feces from cattle fed tylosin, compared to all other treatments. CONCLUSION: The abundance of genes coding for antimicrobial resistance in bovine feces can be affected by inclusion of antibiotics in the feed. Resistance genes can persist in feces from cattle beyond 175 days with concentrations of some genes increasing with time. Management practices that accelerate DNA degradation such as frequent land application or composting of manure may reduce the extent to which bovine feces serves as a reservoir of antimicrobial resistance. PMID- 21261986 TI - Biclustering of gene expression data by correlation-based scatter search. AB - BACKGROUND: The analysis of data generated by microarray technology is very useful to understand how the genetic information becomes functional gene products. Biclustering algorithms can determine a group of genes which are co expressed under a set of experimental conditions. Recently, new biclustering methods based on metaheuristics have been proposed. Most of them use the Mean Squared Residue as merit function but interesting and relevant patterns from a biological point of view such as shifting and scaling patterns may not be detected using this measure. However, it is important to discover this type of patterns since commonly the genes can present a similar behavior although their expression levels vary in different ranges or magnitudes. METHODS: Scatter Search is an evolutionary technique that is based on the evolution of a small set of solutions which are chosen according to quality and diversity criteria. This paper presents a Scatter Search with the aim of finding biclusters from gene expression data. In this algorithm the proposed fitness function is based on the linear correlation among genes to detect shifting and scaling patterns from genes and an improvement method is included in order to select just positively correlated genes. RESULTS: The proposed algorithm has been tested with three real data sets such as Yeast Cell Cycle dataset, human B-cells lymphoma dataset and Yeast Stress dataset, finding a remarkable number of biclusters with shifting and scaling patterns. In addition, the performance of the proposed method and fitness function are compared to that of CC, OPSM, ISA, BiMax, xMotifs and Samba using Gene the Ontology Database. PMID- 21261987 TI - Incidence of bone metastases and skeletal-related events in breast cancer patients: a population-based cohort study in Denmark. AB - BACKGROUND: Breast cancer (BrCa) is the most commonly diagnosed cancer among women in the industrialized world. More than half of women presenting with metastatic BrCa develop bone metastases. Bone metastases increase the risk of skeletal-related events (SREs), defined as pathological fractures, spinal cord compression, bone pain requiring palliative radiotherapy, and orthopaedic surgery. Both bone metastases and SREs are associated with unfavorable prognosis and greatly affect quality of life. Few epidemiological data exist on SREs after primary diagnosis of BrCa and subsequent bone metastasis. We therefore estimated the incidence of bone metastases and SREs in newly-diagnosed BrCa patients in Denmark from 1999 through 2007. METHODS: We estimated the overall and annual incidence of bone metastases and SREs in newly-diagnosed breast cancer patients in Denmark from January 1, 1999 to December 31, 2007 using the Danish National Patient Registry (DNPR), which covers all Danish hospitals. We estimated the cumulative incidence of bone metastases and SREs and associated 95% confidence intervals (CI) using the Kaplan-Meier method. RESULTS: Of the 35,912 BrCa patients, 178 (0.5%) presented with bone metastases at the time of primary breast cancer diagnosis, and of these, 77 (43.2%) developed an SRE during follow up. A total of 1,272 of 35,690 (3.6%) BrCa patients without bone metastases at diagnosis developed bone metastases during a median follow-up time of 3.4 years. Among these patients, 590 (46.4%) subsequently developed an SRE during a median follow-up time of 0.7 years. Incidence rates of bone metastases were highest the first year after the primary BrCa diagnosis, particularly among patients with advanced BrCa at diagnosis. Similarly, incidence rates of a first SRE was highest the first year after first diagnosis of a bone metastasis. CONCLUSIONS: The high incidence of SREs following the first year after first diagnosis of a bone metastasis underscores the need for early BrCa detection and research on effective treatments to delay the onset of SREs. PMID- 21261988 TI - Health education for microcredit clients in Peru: a randomized controlled trial. AB - BACKGROUND: Poverty, lack of female empowerment, and lack of education are major risk factors for childhood illness worldwide. Microcredit programs, by offering small loans to poor individuals, attempt to address the first two of these risk factors, poverty and gender disparity. They provide clients, usually women, with a means to invest in their businesses and support their families. This study investigates the health effects of also addressing the remaining risk factor, lack of knowledge about important health issues, through randomization of members of a microcredit organization to receive a health education module based on the World Health Organization's Integrated Management of Childhood Illness (IMCI) community intervention. METHODS: Baseline data were collected in February 2007 from clients of a microcredit organization in Pucallpa, Peru (n = 1,855) and their children (n = 598). Loan groups, consisting of 15 to 20 clients, were then randomly assigned to receive a health education intervention involving eight monthly 30-minute sessions given by the organization's loan officers at monthly loan group meetings. In February 2008, follow-up data were collected, and included assessments of sociodemographic information, knowledge of child health issues, and child health status (including child height, weight, and blood hemoglobin levels). To explore the effects of treatment (i.e., participation in the health education sessions) on the key outcome variables, multivariate regressions were implemented using ordinary least squares. RESULTS: Individuals in the IMCI treatment arm demonstrated more knowledge about a variety of issues related to child health, but there were no changes in anthropometric measures or reported child health status. CONCLUSIONS: Microcredit clients randomized to an IMCI educational intervention showed greater knowledge about child health, but no differences in child health outcomes compared to controls. These results imply that the intervention did not have sufficient intensity to change behavior, or that microcredit organizations may not be an appropriate setting for the administration of child health educational interventions of this type. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, NCT01047033. PMID- 21261989 TI - Dietary cholesterol, female gender and n-3 fatty acid deficiency are more important factors in the development of non-alcoholic fatty liver disease than the saturation index of the fat. AB - BACKGROUND: The central feature of NAFLD is a disturbed fatty-acid metabolism with hepatic lipid accumulation. However, the factors that determine the severity of NAFLD, including the role of nutrition, gender, and plasma lipid levels, remain to be determined. METHODS: High-fat diets (42 en% fat), containing 0.2% cholesterol, were fed to male and female wild-type and hyperlipidemic APOE2ki C57BL/6J mice for three weeks. The fats were, in order of decreasing saturation, fractionated palm fat (fPF; ~95%), cocoa butter (CB; ~60%), olive oil (OO; ~15%), sunflower oil (SO; ~12%), and high-oleic-acid sunflower oil (hoSO; ~7%). Plasma and liver triglycerides (concentration and composition), liver inflammation (Ccl2, Cd68, Tnf-alpha mRNA), and infiltration of macrophages (Cd68, Cd11b immunohistochemistry) and neutrophils (Mpo) were quantified. RESULTS: Addition of cholesterol to a low-fat diet decreased plasma HDL and increased (V)LDL levels in APOE2ki mice. Plasma cholesterol levels in female, but not male APOE2ki mice correlated significantly with inflammation. Kupffer cells of inflamed livers were swollen. Wild-type mice refused the highly saturated fPF diet. The high-fat CB, OO, and SO diets induced hyperglycemia and a 2-fold increase in hepatic fat content in male, but not female wild-type mice (in females, hepatic fat content was similar to that in males fed a high-fat diet). All high-fat diets induced macrovesicular setatosis. APOE2ki mice were protected against high-fat diet induced steatosis and hyperglycemia, except when fed a hoSO diet. This diet caused a 5-fold increase in liver triglyceride and mead-acid content, and an increased expression of lipogenic genes, suggesting a deficiency in poly unsaturated fatty acids. Irrespective of the composition of the high-fat diet, oleic acid was the main triglyceride component of liver fat in wild-type and APOE2ki mouse livers. Liver inflammation was dependent on genotype (APOE2ki > wild type), gender (female > male), and cholesterol content (high > low) of the diet, but not on dietary fat composition. CONCLUSIONS: Dietary cholesterol plays a determining, independent role in inflammation, especially in female mice. The fatty-acid saturation of the diet hardly affected hepatic steatosis or inflammation. PMID- 21261991 TI - Conveying misinformation: Top-ranked Japanese books on tobacco. AB - BACKGROUND: Tobacco control efforts in Japan have lagged other high income countries, possibly because the Japanese government partially owns Japan Tobacco, Inc. In Japan, tobacco use is still often regarded as an issue of manners rather than an issue of health. Information about tobacco is available, but may not always be accurate. We explored what information Japanese consumers might access by reading popular Japanese books about tobacco. METHODS: We searched Amazon.com Japan using the term "Tobacco", identifying the top 12 books by "relevance" and "bestselling." We eliminated duplicates and books not concerned with tobacco use and classified the remaining books as pro-smoking, anti-smoking, or neutral. We reviewed the pro-smoking books, published 2004-2009, and analyzed examples of misinformation by theme. RESULTS: Pro-smoking popular books conveyed five types of misinformation: doubt about science; suggestions that smoking increased health, longevity, virility, etc.; trivializing tobacco's effects; attacking public health advocates/authorities; and linking tobacco use with authenticity, history, or civil rights. At least one book was authored by a former Japan Tobacco employee; another used a popular Japan Tobacco advertising phrase. CONCLUSIONS: Creating doubt and confusion about tobacco serves tobacco industry interests and re-creates a strategy developed by US tobacco interests more than 40 years ago. Japanese readers may be misled by texts such as those reviewed. Tobacco control and public health advocates in Japan and globally should expose and counter such misinformation. "Naming and shaming" may be effective. PMID- 21261990 TI - Issues associated with the use of phosphospecific antibodies to localise active and inactive pools of GSK-3 in cells. AB - BACKGROUND: Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine (Ser/Thr) kinase comprising two isoforms, GSK-3alpha and GSK 3beta. Both enzymes are similarly inactivated by serine phosphorylation (GSK 3alpha at Ser21 and GSK-3beta at Ser9) and activated by tyrosine phosphorylation (GSK-3alpha at Tyr279 and GSK-3beta at Tyr216). Antibodies raised to phosphopeptides containing the sequences around these phosphorylation sites are frequently used to provide an indication of the activation state of GSK-3 in cell and tissue extracts. These antibodies have further been used to determine the subcellular localisation of active and inactive forms of GSK-3, and the results of those studies support roles for GSK-3 phosphorylation in diverse cellular processes. However, the specificity of these antibodies in immunocytochemistry has not been addressed in any detail. RESULTS: Taking advantage of gene silencing technology, we examined the specificity of several commercially available anti phosphorylated GSK-3 antibodies. We show that antibodies raised to peptides containing the phosphorylated Ser21/9 epitope crossreact with unidentified antigens that are highly expressed by mitotic cells and that mainly localise to spindle poles. In addition, two antibodies raised to peptides containing the phosphorylated Tyr279/216 epitope recognise an unidentified protein at focal contacts, and a third antibody recognises a protein found in Ki-67-positive cell nuclei. While the phosphorylated Ser9/21 GSK-3 antibodies also recognise other proteins whose levels increase in mitotic cells in western blots, the phosphorylated Tyr279/216 antibodies appear to be specific in western blotting. However, we cannot rule out the posssibility that they recognise very large or very small proteins that might not be detected using a standard western blotting approach. CONCLUSIONS: Our findings indicate that care should be taken when examining the subcellular localisation of active or inactive GSK-3 and, furthermore, suggest that the role of GSK-3 phosphorylation in some cellular processes be reassessed. PMID- 21261993 TI - Trends in all cause and viral liver disease-related hospitalizations in people with hepatitis B or C: a population-based linkage study. AB - BACKGROUND: Previous studies have reported an excess burden of cancer and mortality in populations with chronic hepatitis B (HBV) or C (HCV), but there are limited data comparing hospitalization rates. In this study, we compared hospitalization rates for all causes and viral liver disease in people notified with HBV or HCV in New South Wales (NSW), Australia. METHODS: HBV and HCV notifications were linked to their hospital (July 2000-June 2006), HIV and death records. Standardized hospitalization ratios (SHRs) were calculated using rates for the NSW population. Random effects Poisson regression was used to examine temporal trends. RESULTS: The SHR for all causes and non alcoholic liver disease was two-fold higher in the HCV cohort compared with the HBV cohort (SHRs 1.4 (95%CI: 1.4-1.4) v 0.6 (95%CI: 0.6-0.6) and 14.0 (95%CI: 12.7-15.4) v 5.4 (95%CI: 4.5-6.4), respectively), whilst the opposite was seen for primary liver cancer (SHRs 16.2 (95%CI: 13.8-19.1) v 29.1 (95%CI: 24.7-34.2)). HIV co-infection doubled the SHR except for primary liver cancer in the HCV/HIV cohort. In HBV and HCV mono-infected cohorts, all cause hospitalization rates declined and primary liver cancer rates increased, whilst rates for non alcoholic liver disease increased by 9% in the HCV cohort but decreased by 14% in the HBV cohort (P < 0.001). CONCLUSION: Hospital-related morbidity overall and for non alcoholic liver disease was considerably higher for HCV than HBV. Improved treatment of advanced HBV-related liver disease may explain why HBV liver-related morbidity declined. In contrast, HCV liver-related morbidity increased and improved treatments, especially for advanced liver disease, and higher levels of treatment uptake are required to reverse this trend. PMID- 21261992 TI - Developing the atlas of cancer in Queensland: methodological issues. AB - BACKGROUND: Achieving health equity has been identified as a major challenge, both internationally and within Australia. Inequalities in cancer outcomes are well documented, and must be quantified before they can be addressed. One method of portraying geographical variation in data uses maps. Recently we have produced thematic maps showing the geographical variation in cancer incidence and survival across Queensland, Australia. This article documents the decisions and rationale used in producing these maps, with the aim to assist others in producing chronic disease atlases. METHODS: Bayesian hierarchical models were used to produce the estimates. Justification for the cancers chosen, geographical areas used, modelling method, outcome measures mapped, production of the adjacency matrix, assessment of convergence, sensitivity analyses performed and determination of significant geographical variation is provided. CONCLUSIONS: Although careful consideration of many issues is required, chronic disease atlases are a useful tool for assessing and quantifying geographical inequalities. In addition they help focus research efforts to investigate why the observed inequalities exist, which in turn inform advocacy, policy, support and education programs designed to reduce these inequalities. PMID- 21261994 TI - The Trypanosoma cruzi Sylvio X10 strain maxicircle sequence: the third musketeer. AB - BACKGROUND: Chagas disease has a diverse pathology caused by the parasite Trypanosoma cruzi, and is indigenous to Central and South America. A pronounced feature of the trypanosomes is the kinetoplast, which is comprised of catenated maxicircles and minicircles that provide the transcripts involved in uridine insertion/deletion RNA editing. T. cruzi exchange genetic material through a hybridization event. Extant strains are grouped into six discrete typing units by nuclear markers, and three clades, A, B, and C, based on maxicircle gene analysis. Clades A and B are the more closely related. Representative clade B and C maxicircles are known in their entirety, and portions of A, B, and C clades from multiple strains show intra-strain heterogeneity with the potential for maxicircle taxonomic markers that may correlate with clinical presentation. RESULTS: To perform a genome-wide analysis of the three maxicircle clades, the coding region of clade A representative strain Sylvio X10 (a.k.a. Silvio X10) was sequenced by PCR amplification of specific fragments followed by assembly and comparison with the known CL Brener and Esmeraldo maxicircle sequences. The clade A rRNA and protein coding region maintained synteny with clades B and C. Amino acid analysis of non-edited and 5'-edited genes for Sylvio X10 showed the anticipated gene sequences, with notable frameshifts in the non-edited regions of Cyb and ND4. Comparisons of genes that undergo extensive uridine insertion and deletion display a high number of insertion/deletion mutations that are likely permissible due to the post-transcriptional activity of RNA editing. CONCLUSION: Phylogenetic analysis of the entire maxicircle coding region supports the closer evolutionary relationship of clade B to A, consistent with uniparental mitochondrial inheritance from a discrete typing unit TcI parental strain and studies on smaller fragments of the mitochondrial genome. Gene variance that can be corrected by RNA editing hints at an unusual depth for maxicircle taxonomic markers, which will aid in the ability to distinguish strains, their corresponding symptoms, and further our understanding of the T. cruzi population structure. The prevalence of apparently compromised coding regions outside of normally edited regions hints at undescribed but active mechanisms of genetic exchange. PMID- 21261995 TI - Worm Phenotype Ontology: integrating phenotype data within and beyond the C. elegans community. AB - BACKGROUND: Caenorhabditis elegans gene-based phenotype information dates back to the 1970's, beginning with Sydney Brenner and the characterization of behavioral and morphological mutant alleles via classical genetics in order to understand nervous system function. Since then C. elegans has become an important genetic model system for the study of basic biological and biomedical principles, largely through the use of phenotype analysis. Because of the growth of C. elegans as a genetically tractable model organism and the development of large-scale analyses, there has been a significant increase of phenotype data that needs to be managed and made accessible to the research community. To do so, a standardized vocabulary is necessary to integrate phenotype data from diverse sources, permit integration with other data types and render the data in a computable form. RESULTS: We describe a hierarchically structured, controlled vocabulary of terms that can be used to standardize phenotype descriptions in C. elegans, namely the Worm Phenotype Ontology (WPO). The WPO is currently comprised of 1,880 phenotype terms, 74% of which have been used in the annotation of phenotypes associated with greater than 18,000 C. elegans genes. The scope of the WPO is not exclusively limited to C. elegans biology, rather it is devised to also incorporate phenotypes observed in related nematode species. We have enriched the value of the WPO by integrating it with other ontologies, thereby increasing the accessibility of worm phenotypes to non-nematode biologists. We are actively developing the WPO to continue to fulfill the evolving needs of the scientific community and hope to engage researchers in this crucial endeavor. CONCLUSIONS: We provide a phenotype ontology (WPO) that will help to facilitate data retrieval, and cross-species comparisons within the nematode community. In the larger scientific community, the WPO will permit data integration, and interoperability across the different Model Organism Databases (MODs) and other biological databases. This standardized phenotype ontology will therefore allow for more complex data queries and enhance bioinformatic analyses. PMID- 21261996 TI - Identification and regulation of c-Myb target genes in MCF-7 cells. AB - BACKGROUND: The c-Myb transcription factor regulates differentiation and proliferation in hematopoietic cells, stem cells and epithelial cells. Although oncogenic versions of c-Myb were first associated with leukemias, over expression or rearrangement of the c-myb gene is common in several types of solid tumors, including breast cancers. Expression of the c-myb gene in human breast cancer cells is dependent on estrogen stimulation, but little is known about the activities of the c-Myb protein or what genes it regulates in estrogen-stimulated cells. METHODS: We used chromatin immunoprecipitation coupled with whole genome promoter tiling microarrays to identify endogenous c-Myb target genes in human MCF-7 breast cancer cells and characterized the activity of c-Myb at a panel of target genes during different stages of estrogen deprivation and stimulation. RESULTS: By using different antibodies and different growth conditions, the c-Myb protein was found associated with over 10,000 promoters in MCF-7 cells, including many genes that encode cell cycle regulators or transcription factors and more than 60 genes that encode microRNAs. Several previously identified c-Myb target genes were identified, including CCNB1, MYC and CXCR4 and novel targets such as JUN, KLF4, NANOG and SND1. By studying a panel of these targets to validate the results, we found that estradiol stimulation triggered the association of c-Myb with promoters and that association correlated with increased target gene expression. We studied one target gene, CXCR4, in detail, showing that c-Myb associated with the CXCR4 gene promoter and activated a CXCR4 reporter gene in transfection assays. CONCLUSIONS: Our results show that c-Myb associates with a surprisingly large number of promoters in human cells. The results also suggest that estradiol stimulation leads to large-scale, genome-wide changes in c-Myb activity and subsequent changes in gene expression in human breast cancer cells. PMID- 21261997 TI - Development of a risk score for low back pain in office workers--a cross sectional study. AB - BACKGROUND: Low back pain (LBP) is common among office workers and is the most common cause of work-related disability in people under 45 years of age. The aetiology of LBP is widely accepted to be multi-factorial. Prognostic research into office workers at risk of developing LBP has received limited attention. The aims of this study were to develop a risk score to identify office workers likely to have LBP and to evaluate its predictive power. METHODS: 397 office workers filled out a self-administered questionnaire and underwent physical examination. The questionnaire gathered data on individual, work-related physical and psychosocial data as well as the presence of low back pain in the previous 4 weeks. The physical examination included measurement of body weight, height, waist circumference, hamstrings length, spinal scoliosis, spinal curve, Backache Index and lumbar stability. Logistic regression was used to select significant factors associated with LBP to build a risk score. The coefficients from the logistic regression model were transformed into the components of a risk score. RESULTS: The model included six items: previous history of working as an office worker, years of work experience, continuous standing for >2 hrs/d, frequency of forward bending during work day, chair having lumbar support and Backache Index outcome. The risk score for LBP in office workers (The Back pain Risk score for Office Workers: The BROW) was built with a risk score ranging from 0 to 9. A cut off score of >= 4 had a sensitivity of 80% and a specificity of 58%. The positive predictive value and negative predictive values were 70% each. CONCLUSIONS: The BROW is easy and quick to administer. It appears to have reasonable sensitivity, specificity, positive predictive value and negative predictive values for the cut off point of >= 4. The BROW is a promising tool for use to identify office workers in need of early interventions. Further prospective study is needed to validate the predictive performance of the BROW. PMID- 21261998 TI - A role for pharmacists in community-based post-discharge warfarin management: protocol for the 'the role of community pharmacy in post hospital management of patients initiated on warfarin' study. AB - BACKGROUND: Shorter periods of hospitalisation and increasing warfarin use have placed stress on community-based healthcare services to care for patients taking warfarin after hospital discharge, a high-risk period for these patients. A previous randomised controlled trial demonstrated that a post-discharge service of 4 home visits and point-of-care (POC) International Normalised Ratio (INR) testing by a trained pharmacist improved patients' outcomes. The current study aims to modify this previously trialled service model to implement and then evaluate a sustainable program to enable the smooth transition of patients taking warfarin from the hospital to community setting. METHODS/DESIGN: The service will be trialled in 8 sites across 3 Australian states using a prospective, controlled cohort study design. Patients discharged from hospital taking warfarin will receive 2 or 3 home visits by a trained 'home medicines review (HMR)-accredited' pharmacist in their 8 to 10 days after hospital discharge. Visits will involve a HMR, comprehensive warfarin education, and POC INR monitoring in collaboration with patients' general practitioners (GPs) and community pharmacists. Patient outcomes will be compared to those in a control, or 'usual care', group. The primary outcome measure will be the proportion of patients experiencing a major bleeding event in the 90 days after discharge. Secondary outcome measures will include combined major bleeding and thromboembolic events, death, cessation of warfarin therapy, INR control at 8 days post-discharge and unplanned hospital readmissions from any cause. Stakeholder satisfaction will be assessed using structured postal questionnaire mailed to patients, GPs, community pharmacists and accredited pharmacists at the completion of their study involvement. DISCUSSION: This study design incorporates several aspects of prior interventions that have been demonstrated to improve warfarin management, including POC INR testing, warfarin education and home visits by trained pharmacists. It faces several potential challenges, including the tight timeframe for patient follow-up in the post-discharge period. Its strengths lie in a strong multidisciplinary team and the utilisation of existing healthcare frameworks. It is hoped that this study will provide the evidence to support the national roll-out of the program as a new Australian professional community pharmacy service. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Number 12608000334303. PMID- 21262000 TI - Differential molecular information of maurotoxin peptide recognizing IK(Ca) and Kv1.2 channels explored by computational simulation. AB - BACKGROUND: Scorpion toxins are invaluable tools for ion channel research and are potential drugs for human channelopathies. However, it is still an open task to determine the molecular basis underlying the diverse interactions between toxin peptides and ion channels. The inhibitory peptide Maurotoxin (MTX) recognized the distantly related IK(Ca) and Kv1.2 channel with approximately the same potency and using the same functional residues, their differential binding mechanism remain elusive. In this study, we applied computational methods to explore the differential binding modes of MTX to Kv1.2 and IK(Ca) channels, which would help to understand the diversity of channel-toxin interactions and accelerate the toxin-based drug design. RESULTS: A reasonably stable MTX-IK(Ca) complex was obtained by combining various computational methods and by in-depth comparison with the previous model of the MTX-Kv1.2 complex. Similarly, MTX adopted the beta sheet structure as the interacting surface for binding both channels, with Lys23 occluding the pore. In contrast, the other critical residues Lys27, Lys30, and Tyr32 of MTX adopted distinct interactions when associating with the IK(Ca) channel. In addition, the residues Gln229, Ala230, Ala233, and Thr234 on the IK(Ca) channel turret formed polar and non-polar interactions with MTX, whereas the turret of Kv1.2 was almost not involved in recognizing MTX. In all, the pairs of interacting residues on MTX and the IK(Ca) channel of the bound complex indicated that electrostatic and Van der Waal interactions contributed equally to the formation of a stable MTX-IK(Ca) complex, in contrast to the MTX-Kv1.2 binding that is dominantly mediated by electrostatic forces. CONCLUSIONS: Despite sharing similar pharmacological profiles toward both IK(Ca) and Kv1.2 channels, MTX adopted totally diverging modes in the two association processes. All the molecular information unveiled here could not only offer a better understanding about the structural differences between the IK(Ca) and Kv1.2 channels, but also provide novel structural clues that will help in the designing of more selective molecular probes to discriminate between these two channels. PMID- 21262001 TI - Rapid isolation of mycoviral double-stranded RNA from Botrytis cinerea and Saccharomyces cerevisiae. AB - BACKGROUND: In most of the infected fungi, the mycoviruses are latent or cryptic, the infected fungus does not show disease symptoms, and it is phenotypically identical to a non-infected strain of the same species. Because of these properties, the initial stage in the search for fungi infected with mycoviruses is the detection of their viral genome, which in most of the described cases corresponds to double-stranded RNA (dsRNA). So to analyze a large number of fungal isolates it is necessary to have a simple and rapid method to detect dsRNA. RESULTS: A rapid method to isolate dsRNA from a virus-infected filamentous fungus, Botrytis cinerea, and from a killer strain of Saccharomyces cerevisiae using commercial minicolumns packed with CF11 cellulose was developed. In addition to being a rapid method, it allows to use small quantities of yeasts or mycelium as starting material, being obtained sufficient dsRNA quantity that can later be analyzed by agarose gel electrophoresis, treated with enzymes for its partial characterization, amplified by RT-PCR and cloned in appropriate vectors for further sequencing. CONCLUSIONS: The method yields high quality dsRNA, free from DNA and ssRNA. The use of nucleases to degrade the DNA or the ssRNA is not required, and it can be used to isolate dsRNA from any type of fungi or any biological sample that contains dsRNA. PMID- 21261999 TI - Evaluation of the efficacy of radiation-modifying compounds using gammaH2AX as a molecular marker of DNA double-strand breaks. AB - Radiation therapy is a widely used therapeutic approach for cancer. To improve the efficacy of radiotherapy there is an intense interest in combining this modality with two broad classes of compounds, radiosensitizers and radioprotectors. These either enhance tumour-killing efficacy or mitigate damage to surrounding non-malignant tissue, respectively. Radiation exposure often results in the formation of DNA double-strand breaks, which are marked by the induction of H2AX phosphorylation to generate gammaH2AX. In addition to its essential role in DDR signalling and coordination of double-strand break repair, the ability to visualize and quantitate gammaH2AX foci using immunofluorescence microscopy techniques enables it to be exploited as an indicator of therapeutic efficacy in a range of cell types and tissues. This review will explore the emerging applicability of gammaH2AX as a marker for monitoring the effectiveness of radiation-modifying compounds. PMID- 21262002 TI - Research into the (Cost-) effectiveness of the ketogenic diet among children and adolescents with intractable epilepsy: design of a randomized controlled trial. AB - BACKGROUND: Epilepsy is a neurological disorder, characterized by recurrent unprovoked seizures which have a high impact on the individual as well as on society as a whole. In addition to the economic burden, epilepsy imposes a substantial burden on the patients and their surroundings. Patients with uncontrolled epilepsy depend heavily on informal care and on health care professionals. About 30% of patients suffer from drug-resistant epilepsy. The ketogenic diet can be a treatment of last resort, especially for children. The beneficial effect of the ketogenic diet has been proven, but information is lacking about its cost-effectiveness. In the current study we will evaluate the (cost-) effectiveness of the ketogenic diet in children and adolescents with intractable epilepsy. METHODS/DESIGN: In a RCT we will compare the ketogenic diet with usual care. Embedded in this RCT will be a trial-based and model-based economic evaluation, looking from a societal perspective at the cost effectiveness and cost-utility of the ketogenic diet versus usual care. Fifty children and adolescents (aged 1-18) with intractable epilepsy will be screened for eligibility before randomization into the intervention or the usual care group. The primary outcome measure is the proportion of children with a 50% or more reduction in seizure frequency. Secondary outcomes include seizure severity, side effects/complaints, neurocognitive, socio-emotional functioning, and quality of life. Costs and productivity losses will be assessed continuously by a prospective diary and a retrospective questionnaire. Measurements will take place during consults at baseline, at 6 weeks and at 4 months after the baseline period, and 3, 6, 9 and 12 months follow-up after the 4 months consult. DISCUSSION: The proposed research project will be the first study to provide data about the cost-effectiveness of the ketogenic diet for children and adolescents with intractable epilepsy, in comparison with usual care. It is anticipated that positive results in (cost-) effectiveness of the proposed intervention will contribute to the improvement of treatment for epilepsy in children and adolescents and will lead to a smaller burden to society. PMID- 21262003 TI - A graphical simulation software for instruction in cardiovascular mechanics physiology. AB - BACKGROUND: Computer supported, interactive e-learning systems are widely used in the teaching of physiology. However, the currently available complimentary software tools in the field of the physiology of cardiovascular mechanics have not yet been adapted to the latest systems software. Therefore, a simple-to-use replacement for undergraduate and graduate students' education was needed, including an up-to-date graphical software that is validated and field-tested. METHODS: Software compatible to Windows, based on modified versions of existing mathematical algorithms, has been newly developed. Testing was performed during a full term of physiological lecturing to medical and biology students. RESULTS: The newly developed CLabUZH software models a reduced human cardiovascular loop containing all basic compartments: an isolated heart including an artificial electrical stimulator, main vessels and the peripheral resistive components. Students can alter several physiological parameters interactively. The resulting output variables are printed in x-y diagrams and in addition shown in an animated, graphical model. CLabUZH offers insight into the relations of volume, pressure and time dependency in the circulation and their correlation to the electrocardiogram (ECG). Established mechanisms such as the Frank-Starling Law or the Windkessel Effect are considered in this model. The CLabUZH software is self contained with no extra installation required and runs on most of today's personal computer systems. CONCLUSIONS: CLabUZH is a user-friendly interactive computer programme that has proved to be useful in teaching the basic physiological principles of heart mechanics. PMID- 21262004 TI - Development and evaluation of a virtual microscopy application for automated assessment of Ki-67 expression in breast cancer. AB - BACKGROUND: The aim of the study was to develop a virtual microscopy enabled method for assessment of Ki-67 expression and to study the prognostic value of the automated analysis in a comprehensive series of patients with breast cancer. METHODS: Using a previously reported virtual microscopy platform and an open source image processing tool, ImageJ, a method for assessment of immunohistochemically (IHC) stained area and intensity was created. A tissue microarray (TMA) series of breast cancer specimens from 1931 patients was immunostained for Ki-67, digitized with a whole slide scanner and uploaded to an image web server. The extent of Ki-67 staining in the tumour specimens was assessed both visually and with the image analysis algorithm. The prognostic value of the computer vision assessment of Ki-67 was evaluated by comparison of distant disease-free survival in patients with low, moderate or high expression of the protein. RESULTS: 1648 evaluable image files from 1334 patients were analysed in less than two hours. Visual and automated Ki-67 extent of staining assessments showed a percentage agreement of 87% and weighted kappa value of 0.57. The hazard ratio for distant recurrence for patients with a computer determined moderate Ki-67 extent of staining was 1.77 (95% CI 1.31-2.37) and for high extent 2.34 (95% CI 1.76-3.10), compared to patients with a low extent. In multivariate survival analyses, automated assessment of Ki-67 extent of staining was retained as a significant prognostic factor. CONCLUSIONS: Running high throughput automated IHC algorithms on a virtual microscopy platform is feasible. Comparison of visual and automated assessments of Ki-67 expression shows moderate agreement. In multivariate survival analysis, the automated assessment of Ki-67 extent of staining is a significant and independent predictor of outcome in breast cancer. PMID- 21262006 TI - [A man with a painful leg]. AB - A 72-year-old man with a history of prostate cancer was seen with pain in the right leg and the left arm. He suffered from a clostridial myonecrosis. Physical examination showed typical findings of purple discoloration of the skin and hemorrhagic bullae. The patient eventually died because of septic shock. PMID- 21262005 TI - Small dense LDL particles--a predictor of coronary artery disease evaluated by invasive and CT-based techniques: a case-control study. AB - BACKGROUND: Coronary angiography is the current standard method to evaluate coronary atherosclerosis in patients with suspected angina pectoris, but non invasive CT scanning of the coronaries are increasingly used for the same purpose. Low-density lipoprotein (LDL) cholesterol and other lipid and lipoprotein variables are major risk factors for coronary artery disease. Small dense LDL particles may be of particular importance, but clinical studies evaluating their predictive value for coronary atherosclerosis are few. METHODS: We performed a study of 194 consecutive patients with chest pain, a priori considered of low to intermediate risk for significant coronary stenosis (>50% lumen obstruction) who were referred for elective coronary angiography. Plasma lipids and lipoproteins were measured including the subtype pattern of LDL particles, and all patients were examined by coronary CT scanning before coronary angiography. RESULTS: The proportion of small dense LDL was a strong univariate predictor of significant coronary artery stenosis evaluated by both methods. After adjustment for age, gender, smoking, and waist circumference only results obtained by traditional coronary angiography remained statistically significant. CONCLUSION: Small dense LDL particles may add to risk stratification of patients with suspected angina pectoris. PMID- 21262007 TI - [Acute pain at the emergency department: better treatment required]. AB - Acute pain is common among patients at the emergency department and is still not being treated adequately. Repeated measurement and documentation of pain is essential for adequate pain treatment. The patient determines how much analgesia is needed. Pharmacological pain relief should not be delayed during the diagnostic process, not even in cases of abdominal pain. Opioids play a central role in the treatment of acute pain. Opiophobia is not justified. Adequate pain relief started at the emergency department must be continued throughout both hospital admission and discharge to home. PMID- 21262008 TI - [Agranulocytosis/granulocytopenia after long-term use of thiamazole]. AB - Agranulocytosis/granulocytopenia is a rare side effect of thyreostatics. Earlier publications state that for thiamazole this side effect occurs during the first few months of treatment. In two patients this thiamazole-induced agranulocytosis/granulocytopenia only occurred after years of treatment. A 53 year-old man presented with fever after a visit to Suriname. He had used thiamazole for 12 years for Graves' hyperthyroidism. The second patient, a 31 year-old woman, presented at the emergency department with fever and sore throat after 13 years of intermittent treatment with thiamazole. Both patients had an agranulocytosis/granulocytopenia and leukopenia. This was thought to be a side effect of thiamazole and blood values normalised after cessation of therapy. Both patients were treated empirically with broad-spectrum antibiotics during the agranylocytic period. They then received radioactive sodium iodide. To our knowledge this case report is the first to describe agranulocytosis/granulocytopenia following long-term treatment with thiamazole. PMID- 21262009 TI - [Acute perceptive hearing loss. Importance of tuning fork test in primary care]. AB - A 56-year-old woman presented with acute right-sided hearing loss. At first presentation she was diagnosed as having otitis media with effusion. No tuning fork test was performed. After four weeks she was finally correctly diagnosed as having a right-sided sensorineural hearing loss of 90 dB. As a result of the delay no treatment was started. Her hearing loss did not show any improvement after three months. Sensorineural hearing loss is a rare, potentially invalidating condition with a considerable psychological impact. The treatment consists of systemic steroids, which may only be useful if started within 14 days after symptoms start. Some patients are initially treated for conductive hearing loss. Routine performance of the tuning fork test helps in differentiating between conductive and perceptive hearing loss. In cases of acute perceptive hearing loss, patients should be referred to the otorhinolaryngologist to exclude possible causes and start treatment and guidance. PMID- 21262010 TI - [Cholesterol homeostasis and enterohepatic connection: new insights in cholesterol absorption]. AB - The intestines have been proposed as the 'new player' in the field of atherosclerosis as a result of recent discoveries on intestinal cholesterol absorption and excretion. 'Niemann-Pick C1-like 1' is one of the most important transport proteins in the process of intestinal and biliary cholesterol absorption. Cholesterol is not only excreted via the hepato-biliary route but is also excreted directly into the intestinal lumen; this transintestinal cholesterol excretion is particularly important in mice. Other cholesterol transporters have also been identified, including the ABC transporters, which have been linked to rare disorders such as sitosterolemia. Inhibition of intestinal cholesterol absorption increases the hepatic synthesis of cholesterol and vis versa; several different genes and hormones play an important role in this process. When the effect of statins is insufficient or they cause too many side-effects, additional inhibition of intestinal cholesterol absorption is indicated. PMID- 21262012 TI - [Clinical use of the analysis of the entire genome]. AB - Ten years ago the human genome sequence was published. Subsequently, large investments were made in genomics research, also in the Netherlands, which promised major changes in diagnostics, therapy and prevention. So far however, the consequences in health care are few. The results of genome-wide association studies are so far of hardly any clinical use. The cost of genome information is dropping quickly. Earlier this year, the Lancet published an analysis of the genome sequence of a single research worker (2010;375:1525-3). Mutations were found in genes associated with sudden cardiac death, risk factors for common disorders and pharmacogenetic variations. The paper is a milestone. Similar analyses will show many unknown variants. In clinical genetics, whole-genome techniques are increasingly used. Apart from clinically useful information, many unexpected findings are revealed. The question of who may store genome information needs to be answered. It is questionable whether true informed consent is possible; further discussion is needed. PMID- 21262013 TI - [A man with pleural lesions]. AB - A 65-year-old male was diagnosed with colorectal cancer metastasized to the liver. CT imaging showed benign calcified pleural plaques. During liver resection white plaques on the diaphragm and inside of the thorax were observed. In the past the patient had worked with asbestos for 25 years. PMID- 21262014 TI - [Desmoid tumours in the abdominal wall]. AB - Desmoid tumours are benign tumours originating from musculoaponeurotic structures and the fascia. They usually are slow-growing, without metastatic potential. However, their local behaviour can be infiltrative and aggressive, leading to damage of adjacent structures causing organ dysfunction. They carry a high risk of relapse. In this paper, three case studies of women aged 33, 35 and 42 years, respectively, illustrate the presentation, diagnostics and therapy of abdominal desmoid tumours. All three were surgically treated and recovered. Desmoid tumours occur most commonly in fertile women. Although the etiology is unknown, there is a correlation with scar tissue, pregnancy and radiotherapy. Abdominal desmoid tumours have the lowest relapse rate of all desmoid tumours. In toto resection is the treatment of choice. Radiotherapy in addition to surgery may be considered when risk of relapse is high. PMID- 21262015 TI - [New drugs: money-back guarantee?]. AB - When a new medical technology, for example a new drug, is introduced onto the market there should be a discussion of the balance between "uncertainty versus value to society and demand". The new technology is sometimes given the benefit of the doubt due to a lack of information. Follow-up investigation is actually essential but is seldom mandatory and hardly ever spontaneously initiated. Specific measures, based on stimulation or penalization, could reduce the degree of uncertainty concerning the efficacy, safety and efficiency of a new technology. A serious option when a new drug produces disappointing results is to pay the manufacturer less. PMID- 21262016 TI - [Intentional paracetamol intoxication in children]. AB - As paracetamol is widely used and easily available acetaminophen auto intoxication is frequently seen. In the majority of patients no complications will occur, but in a small group it may lead to liver damage and death. Children are less susceptible to complications than adults. Cornerstone of treatment is the antidote acetylcysteine, administration of which can be based on the Rumack Matthew nomogram. This nomogram has only been validated in adults, but nevertheless is also used in children. Gastric lavage should not be implemented, active charcoal can be given to a conscious cooperative patient within 1 hour of ingestion of acetaminophen. A multidisciplinary approach to treatment is needed with the collaboration of an emergency physician, paediatrician or internist, pharmacist and also a child psychiatrist. PMID- 21262017 TI - [Masson tumour: a benign vascular lesion]. AB - A 39-year-old woman presented with a swelling on the left inner thigh. Physical examination was suggestive of a lipoma. However, peri-operatively the lump appeared to be a vascular tumour arising from the great saphenous vein. Histological examination revealed a benign Masson tumour, a rare vascular tumour that is characterized by endothelial hyperplasia and the presence of papillary structures. It is of clinical importance to distinguish the benign Masson tumour from a malignant angiosarcoma. PMID- 21262018 TI - [Intestinal duplication cyst in children: laparoscopically assisted resection is preferred]. AB - A 5-year-old boy was seen for a second opinion as he had episodes of severe abdominal pain and a variably distended abdomen. Ultrasonography showed a suspected duplication cyst of the terminal ileum. A laparoscopically assisted resection was performed. Histology confirmed the diagnosis of a duplication cyst. A few months later a 10-year-old boy presented with a history of abdominal pain, diarrhoea and vomiting. Abdominal ultrasonography showed an intussusception halfway up the transverse colon where a cyst was seen with a fluid level. The intussusception was reduced during laparoscopy and resection of the duplication cyst of the ileum was performed. Although intestinal duplication cysts are rare (prevalence 1:4500), it is important to know they exist. Laparoscopically assisted resection is an elegant way of treating duplication cysts in children. PMID- 21262020 TI - [Treatment of chronic anal fissures: diltiazem or isosorbide dinitrate as first choice?]. AB - Chronic anal fissures are a painful condition frequently seen in general practice, with an incidence of 2,5/1000 per year. According to the practice guidelines of the Dutch College of General Practitioners, isosorbide dinitrate 1% ointment (ISDN) is the treatment of first choice for chronic anal fissures. Systemic side-effects such as headache are reported in 27% of all cases. This side effect in combination with the frequent application of ISDN (4-6 times daily) leads to a low compliance for this therapy. A meta-analysis of the Cochrane Collaboration showed similar efficacy of diltiazem compared to ISDN. Diltiazem has several advantages: the application frequency is only twice daily, no systemic side-effects have been reported, the total costs of treatment are lower than the costs of ISDN and a standard preparation of diltiazem ointment is available. Therefore, diltiazem 2% ointment should be the first line treatment for chronic anal fissures. PMID- 21262021 TI - [Organ-sparing treatment for rectal cancer]. AB - Current treatment for rectal cancer including TME surgery and pre-operative (chemo)radiotherapy is associated with functional problems. Permanent stomas, faecal incontinence and sexual dysfunction have a great impact on quality of life. Therefore, organ-preserving treatment of rectal cancer has been introduced. Transanal excision without further treatment is only indicated in pT1 tumours with good prognostic characteristics. In more advanced tumours, pre-operative chemoradiotherapy can be used for down-staging. In patients with almost complete clinical response, transanal excision of the remaining lesion or a 'wait-and-see' policy with intensive follow-up can be implemented. Although initial cohort studies are promising, well designed prospective studies still have to prove the safety of this organ-preserving approach. PMID- 21262022 TI - [Physical examination of the heart]. AB - Although almost every doctor daily carries out physical examination of the heart, there is little reliable research into the value of the conclusions. Inspection and palpation of the apex beat and percussion of the left heart border are important in diagnosing enlargement of the heart. If the dullness falls within the mid-clavicular line, cardiac enlargement is almost certainly excluded. The presence of an abnormal heart murmur indicates a high probability of a haemodynamically significant ventricular septal defect or valve deficiency. The absence of a murmur definitely does not exclude a serious valve deficiency. In case of abnormal heart sounds, such as irregular rhythms, splitting of heart sounds or extra sounds, further investigations are always necessary to determine the clinical importance. PMID- 21262023 TI - [Dermatitis or arthritis as a sign of gonorrhoea]. AB - Disseminated gonococcal infection occurs in less than 5% of patients infected with Neisseria gonorrhoeae. The majority of these patients present with arthritis, tenosynovitis, polyarthralgia or dermatitis. In this article we present two patients with disseminated gonococcal infection, each with different symptoms. The first patient, a 23-year-old woman, was suffering from erythema nodosum, chronic polyarthralgia and weight loss. The second patient, a 32-year old woman, was suffering from arthritis and tenosynovitis. Both patients were admitted for parenteral treatment with ceftriaxone. Disseminated gonococcal infection can be treated with a short course of broad spectrum parenteral antibiotics. Therapy can be switched to oral therapy in accordance with the susceptibility pattern of the N. gonorrhoea strain and when an improvement in the patient is noted. PMID- 21262024 TI - [Low back pain and MRI-abnormalities: atypical polymyalgia rheumatica]. AB - A 64-year-old man was admitted to hospital with increasing low back pain, radiating to his upper legs. MRI of the lumbar spine showed inflammatory lesions of vertebrae L3-L5, after which the patient was treated with flucloxacilline for 6 weeks. However, he did not improve and the pain became more extensive. Finally, PET-CT study showed abnormalities in shoulders, back and hips, indicating a probable diagnosis of polymyalgia rheumatica. Upon treatment with prednisone, the pain quickly decreased and 3 months later the inflammatory changes visible on MRI were clearly reduced. Polymyalgia rheumatica (PMR) is often recognized by its typical clinical presentation, but in atypical cases, investigation using imaging may be helpful. Abnormalities in shoulder and hip joints are most common, but signs of cervical and lumbar interspinous bursitis might also be found in patients with PMR. PMID- 21262025 TI - [Zoonotic bacterium: duty to notify advisable]. AB - Vibrio vulnificus is a zoonotic bacterium that can be found in raw fish (mainly eel and oysters) and seawater. Human infections may extend from wound infections to fasciitis necroticans or primary sepsis with a mortality rate of more than 50%. Although V. vulnificus is mainly found in the USA, its worldwide spread is also likely to involve the Netherlands, as demonstrated by an increasing number of infected fish farms. Since 2007, V. vulnificus infections have become a notifiable infectious disease in the USA. Due to the high mortality rate and an increase in the number of elderly people with known risk factors for infection, we argue that human V. vulnificus infections should become a notifiable infectious disease in the Netherlands as well. This would provide reliable information on the epidemiology and facilitate correct risk assessment for public health. PMID- 21262026 TI - [Appropriate care for anxiety and depression]. AB - OBJECTIVE: To evaluate care received for anxiety and depression, to identify which patient-, GP- and practice factors obstruct delivery of care in accordance with Dutch College of General Practitioners' (NHG) practice guidelines, and to evaluate the costs and effects of guideline-concordant care. DESIGN: Descriptive study. METHODS: During the baseline assessment of the Netherlands study of depression and anxiety--which has followed a large number of adults with and without psychiatric complaints since 2004--various questionnaires and diagnostic interviews were completed. At one year follow-up, the severity of symptoms of anxiety and depression, overall functioning or dysfunction, healthcare use and absenteeism from employment over the past year were assessed. Data from electronic medical patient records were studied to determine whether NHG practice guidelines had been followed. RESULTS: Of the 721 patients with an anxiety or depressive disorder, 57% (n = 413) indicated receiving some form of care; two thirds of this group received appropriate care according to NHG practice guidelines (n = 281). At patient level the severity of depressive symptoms, the self-evaluated need for care, a high level of education and accessibility of care were most strongly associated with guideline adherence; at general practitioner level, collaboration with other mental health professionals was most strongly associated with guideline adherence. On average, all patients had symptoms that were less serious than a year previously, irrespective of which care they had received. Guideline-concordant care was significantly more expensive. CONCLUSION: Half of the patients who had not received care did not think that they needed it. Of those who had received care, those with more severe symptoms and greatest need for care were most likely to have received guideline-concordant care. Both patients and general practitioners seemed well able to assess whether care was needed or not. PMID- 21262027 TI - [Familial history of ovarian carcinoma: policy]. AB - Women who carry a BRCA mutation have a greatly increased risk for serous ovarian carcinoma and tubal carcinoma. Since preventative ovarian screening is not effective, these women are advised to undergo prophylactic bilateral salpingo oophorectomy (pBSO) around the age of 40 years. Following pBSO, hormone replacement therapy is advisable up to the age of 45-50 years, with the exception of those women with a history of breast cancer. The advice for women with a familial history of ovarian carcinoma but without the BRCA mutation is less clear. Based on data from the literature, we suggest considering pBSO only in women with at least two first or second degree family members with epithelial ovarian carcinoma. pBSO is not indicated in women from families without a BRCA mutation who have no family members, or just one family member, with epithelial ovarian carcinoma. In these families the lifetime risk for ovarian cancer is considered to be well below 10%. PMID- 21262028 TI - [Examining the lymph nodes]. AB - Enlarged lymph nodes occur frequently and imply a benign or systematic disorder. In primary care, only 1% of patients with an unexplained lymphadenopathy have a malignancy. In the case of unexplained lymphadenopathy the most important diagnostic dilemma is whether biopsy should be applied. In young patients the necessity of lymph node biopsy can be accurately predicted using the following parameters: abnormal chest X-ray; lymph node > 2 cm and ear, nose and throat symptoms. In adults the necessity of biopsy may be reliably predicted using the following parameters: age; lymph node tenderness; lymph node size; consistency, presence of supraclavicular lymph nodes and generalised pruritus. PMID- 21262029 TI - [Accurate predictors for acute diverticulitis]. AB - In a relatively high percentage of patients with a clinically suspected diverticulitis a different diagnosis is established after imaging tests, such as 'appendicitis' or 'intestinal obstruction'. The clinical diagnosis 'acute diverticulitis' is correct for between 43% and 68% of suspected patients. Strongly predictive variables for the diagnosis are tenderness in the left lower abdomen only, CRP > 50 mg/l and absence of vomiting. This triad has a positive predictive value of 97% (95% CI: 83-99) for the final diagnosis 'diverticulitis'. The negative predictive value is much lower, namely 47%: the absence of 1 of the 3 factors does not (sufficiently) exclude 'diverticulitis'. This triad can be an easy-to-use decision rule to rule in diverticulitis. PMID- 21262030 TI - [Dutch College of General Practitioners' practice guideline on symptoms of the hand and wrist: a summary]. AB - The first edition of the practice guideline for general practitioners (GPs) on hand and wrist symptoms was published in January 2010 by the Dutch College of General Practitioners. This practice guideline provides GPs with pointers for the diagnosis and treatment of hand and wrist symptoms. Carpal tunnel syndrome (CTS) can be diagnosed on its typical clinical presentation alone. The treatment of mild symptoms of CTS, trigger finger and De Quervain's tenosynovitis is conservative, or sometimes a corticosteroid injection: more severe or persistent symptoms require referral to hospital. Mallet finger is treated with a splint for 6 weeks, surgical intervention is necessary for large avulsion fractures or persisting symptoms after treatment with a splint. PMID- 21262031 TI - [Dutch College of General Practitioner's practice guideline on polymyalgia rheumatica and temporal arteritis]. AB - The practice guideline for general practitioners (GPs) on polymyalgia rheumatica and temporal arteritis was published in February 2010 by the Dutch College of General Practitioners. This guideline provides GPs with recommendations for the diagnosis and treatment of polymyalgia rheumatica. After other disorders have been excluded, the diagnosis of 'polymyalgia rheumatica' is made in patients over the age of 50 who have bilateral pain in the neck and shoulder girdle and/or hip girdle that has lasted for longer than 4 weeks, morning stiffness that lasts longer than 60 minutes and an ESR > 40 mm in the first hour. After the diagnosis is made treatment with prednisone or prednisolone 15 mg per day is started. This dosage is diminished very gradually according to a uniform treatment schedule during a period of 3 months, thereafter depending on the clinical course. The practice guideline pays attention to the diagnosis and management of temporal arteritis only when it occurs concurrently with polymyalgia rheumatica. PMID- 21262032 TI - [Guideline on diagnosis and treatment of acute appendicitis: imaging prior to appendectomy is recommended]. AB - Every year, over 2500 unnecessary appendectomies are carried out in the Netherlands. At the initiative of the Dutch College of Surgeons, the evidence based guideline on the diagnosis and treatment of acute appendicitis was developed. This guideline recommends that appendectomy should not be carried out without prior imaging. Ultrasonography is the recommended imaging technique in patients with suspected appendicitis. After negative or inconclusive ultrasonography, a CT scan can be carried out. Appendectomy is the standard treatment for acute appendicitis; this can be done either by open or laparoscopic surgery. The first choice treatment of appendicular infiltrate is conservative treatment. PMID- 21262033 TI - [Practice guideline prevention, diagnosis and treatment of tuberculosis in patients with an HIV infection]. AB - An interdisciplinary workgroup from the National Committee for Practical Tuberculosis Control in the Netherlands has written an evidence-based practice guideline on the prevention, diagnosis, and treatment of HIV-infected patients with active tuberculosis or latent tuberculosis infection. The diagnosis and treatment of tuberculosis are effectively the same in patients with or without an HIV infection. The diagnosis is more complex in a patient with an HIV infection due to the effect of the immunodeficiency on diagnostic parameters. Concomitant treatment of tuberculosis and HIV is complicated by drug interactions and overlapping adverse effects. In patients with tuberculosis and an HIV infection, the tuberculosis is preferably treated before antiretroviral therapy is started. The nurse or nurse practitioner in the organisation where the tuberculosis is diagnosed is responsible for supporting the HIV patient with tuberculosis. PMID- 21262034 TI - Impaired decision making and feedback evaluation in borderline personality disorder. AB - BACKGROUND: Increased impulsivity is considered to be a core characteristic of borderline personality disorder (BPD) and has been shown to play a significant role in decision making and planning. Neuropsychological studies in BPD revealed impairments of executive functions, and it is assumed that these deficits are related to altered feedback processing. However, research on executive functions in BPD is still limited and the underlying deficits remain an open question. The present study, therefore, explored whether decision-making deficits are related to altered feedback evaluation in BPD. METHOD: A total of 18 BPD patients and 18 matched healthy controls underwent a modified version of the Iowa Gambling Task while an electroencephalogram was recorded. Feedback processing was examined by measuring the feedback-related negativity (FRN) and the P300 as electrophysiological correlates of feedback evaluation. RESULTS: Behavioural results revealed that BPD patients, relative to controls, made more risky choices and did not improve their performance. With regard to the FRN, amplitudes in BPD patients did not discriminate between positive and negative feedback information. Further, BPD patients showed reduced FRN amplitudes, which were associated with enhanced impulsivity and enhanced risk taking. In contrast, the P300 amplitudes following negative feedback were increased in BPD patients, relative to controls. CONCLUSIONS: This study indicates that BPD patients are impaired in decision making, which might be related to a dysfunctional use of feedback information. Specifically, BPD patients did not learn to avoid disadvantageous selections, even though they attended to negative consequences. PMID- 21262035 TI - Differential susceptibility to the environment: toward an understanding of sensitivity to developmental experiences and context. PMID- 21262036 TI - Differential susceptibility to the environment: an evolutionary- neurodevelopmental theory. AB - Two extant evolutionary models, biological sensitivity to context theory (BSCT) and differential susceptibility theory (DST), converge on the hypothesis that some individuals are more susceptible than others to both negative (risk promoting) and positive (development-enhancing) environmental conditions. These models contrast with the currently dominant perspective on personal vulnerability and environmental risk: diathesis stress/dual risk. We review challenges to this perspective based on emerging theory and data from the evolutionary, developmental, and health sciences. These challenges signify the need for a paradigm shift in conceptualizing Person x Environment interactions in development. In this context we advance an evolutionary--neurodevelopmental theory, based on DST and BSCT, of the role of neurobiological susceptibility to the environment in regulating environmental effects on adaptation, development, and health. We then outline current thinking about neurogenomic and endophenotypic mechanisms that may underpin neurobiological susceptibility, summarize extant empirical research on differential susceptibility, and evaluate the evolutionary bases and implications of BSCT and DST. Finally, we discuss applied issues including methodological and statistical considerations in conducting differential susceptibility research; issues of ecological, cultural, and racial--ethnic variation in neurobiological susceptibility; and implications of differential susceptibility for designing social programs. We conclude that the differential susceptibility paradigm has far-reaching implications for understanding whether and how much child and adult development responds, for better and for worse, to the gamut of species-typical environmental conditions. PMID- 21262037 TI - Prenatal programming of postnatal plasticity? AB - Evidence indicates that maternal prenatal distress predicts problematic health and behavioral outcomes in children as well as infant/child cortisol levels and negative emotionality as reviewed here. Evidence that these physiological and behavioral characteristics themselves moderate environmental effects on development in a "for better and for worse" manner consistent with Belsky's differential susceptibility hypothesis and Boyce and Ellis' notions of biological sensitivity to context raises the prospect that susceptibility to rearing is a function of nurture (i.e., fetal environment), consistent with Boyce and Ellis' proposal that plasticity can be shaped by developmental experience. This hypothesis is supported by new findings from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development showing that low birth weight, a marker for an adverse prenatal environment, predicts infant difficult temperament, which is a susceptibility factor that we previously showed as moderating, in a for better and for worse manner, the effects of parenting and child care quality on socioemotional functioning. Moreover, recent Gene * Environment interaction research raises the prospect that some fetuses may be more susceptible to such "prenatal programming of postnatal plasticity" as a result of their genetic makeup. If this proves true, it will be consistent with the conclusion that early developmental plasticity is a function of both nature and nurture and may be evolutionarily adaptive, a further possibility considered in the discussion. PMID- 21262038 TI - Differential susceptibility to rearing environment depending on dopamine-related genes: new evidence and a meta-analysis. AB - In the current paper we present new empirical data and meta-analytic evidence for the role of dopamine-related genes as a susceptibility factor interacting with the rearing environment for better and for worse, that is, increasing children's susceptibility to both the adverse effects of unsupportive environments and the beneficial effects of supportive rearing. In Study 1 we examined the readiness of 91 7-year-old children to donate their money to a charity (UNICEF). We tested whether the association between attachment and donating behavior was moderated by the presence of the dopamine receptor D4 (DRD4) 7-repeat allele. The attachment story completion task was used to assess attachment as an index of the quality of the rearing environment. Children with secure attachment representations donated more but only if they had the DRD4 7-repeat allele. In Study 2 we present the results of a meta-analysis of gene-environment studies on children up to 10 years of age involving dopamine-related genes (dopamine receptor D2, DRD4, dopamine transporter). The cumulative negative effects of these "risk genes" and adverse rearing environments have been stressed, but potentially cumulative positive effects of these same genes interacting with positive rearing environments remained largely unnoticed. We examined the associations between negative and positive rearing environments and developmental outcomes as moderated by dopamine related gene polymorphisms. Children with the less efficient dopamine-related genes did worse in negative environments than the comparisons without the "genetic risk," but they also profited most from positive environments. Findings are discussed in light of evolutionary theory, and illustrated with some practical implications of differential susceptibility. PMID- 21262039 TI - Heritability of children's prosocial behavior and differential susceptibility to parenting by variation in the dopamine receptor D4 gene. AB - Theoretical considerations and new empirical evidence suggest that children's development cannot simply be explained by either genes or environment but that their interaction is important to understanding child behavior. In particular, a genetic polymorphism, the exon III repeat region of the dopamine receptor D4, has been the focus of interest regarding differential susceptibility to parental influence. To study environmental and genetic influences on children's prosocial behavior, 168 twin pairs (mean age = 44 months) participated in an experiment that assessed prosocial behavior via three measures: compliant prosocial behavior elicited in response to social requests, self-initiated prosocial behavior enacted voluntarily, and mothers' rating of children's behavior. Genetic effects accounted for 34% to 53% of the variance in prosocial behavior. The rest of the variance was accounted for by nonshared environment and error. Parenting measures of maternal positivity, negativity, and unexplained punishment did not correlate significantly with children's prosocial behavior. However, when parenting was stratified by presence or absence of the child's dopamine receptor D4 7-repeat allele in an overlapping sample of 167 children to model differential susceptibility to parental influence, a richer picture emerged. Positive parenting related meaningfully to mother-rated prosocial behavior, and unexplained punishment related positively to self-initiated prosocial behavior, but only among children carrying the 7-repeat allele. The findings demonstrate that a molecular genetic strategy, based on genotyping of common polymorphisms and combined with a classic twin approach, provides a richer description of how genes and environment interact to shape children's behavior, and allows for the identification of differential sensitivity to parental influence. PMID- 21262042 TI - The interactive effect of marital conflict and stress reactivity on externalizing and internalizing symptoms: the role of laboratory stressors. AB - Growing evidence supports the biological sensitivity to context theory, which posits that physiologically reactive children, as indexed by autonomic nervous system (ANS) reactivity to laboratory stressors, are more susceptible to both negative and positive environmental influences than their low reactive peers. High biological sensitivity is a risk factor for behavioral and health problems in the context of high adversity, whereas in contexts of low adversity it has been found to promote positive adaptation. However, several studies have shown the opposite effect, finding that children who exhibited high ANS reactivity in response to interpersonal stressors were buffered from the deleterious effects of marital conflict, whereas children who showed low ANS reactivity were more vulnerable to high levels of marital conflict. Using an ethnically diverse sample of 260 kindergartners (130 girls, 130 boys), the current study investigated whether the interaction effect of marital conflict and the two branches of ANS reactivity on children's externalizing and internalizing symptoms differs with the nature of the laboratory challenge task used to measure children's stress response. As hypothesized, results indicate that the interaction between ANS reactivity and marital conflict significantly predicted children's behavior problems, but the direction of the effect varied with the nature of the challenge task (i.e., interpersonal or cognitive). This study illustrates the importance of considering the effect of laboratory stimuli when assessing whether children's ANS reactivity moderates the effects of adversity exposure on adaptation. PMID- 21262040 TI - Reported early family environment covaries with menarcheal age as a function of polymorphic variation in estrogen receptor-alpha. AB - Age at menarche, a sentinel index of pubertal maturation, was examined in relation to early family relationships (conflict, cohesion) and polymorphic variation in the gene encoding estrogen receptor-alpha (ESR1) in a midlife sample of 455 European American women. Consistent with prior literature, women who reported being raised in families characterized by close interpersonal relationships and little conflict tended to reach menarche at a later age than participants reared in families lacking cohesion and prone to discord. Moreover, this association was moderated by ESR1 variation, such that quality of the family environment covaried positively with menarcheal age among participants homozygous for minor alleles of the two ESR1 polymorphisms studied here (rs9304799, rs2234693), but not among women of other ESR1 genotypes. In addition, (a) family relationship variables were unrelated to ESR1 variation, and (b) genotype dependent effects of childhood environment on age at menarche could not be accounted for by personality traits elsewhere shown to explain heritable variation in reported family conflict and cohesion. These findings are consistent with theories of differential susceptibility to environmental influence, as well as the more specific hypothesis (by Belsky) that girls differ genetically in their sensitivity to rearing effects on pubertal maturation. PMID- 21262041 TI - Quality of early family relationships and the timing and tempo of puberty: effects depend on biological sensitivity to context. AB - Guided by evolutionary-developmental theories of biological sensitivity to context and reproductive development, the current research examined the interactive effects of early family environments and psychobiologic reactivity to stress on the subsequent timing and tempo of puberty. As predicted by the theory, among children displaying heightened biological sensitivity to context (i.e., higher stress reactivity), higher quality parent-child relationships forecast slower initial pubertal tempo and later pubertal timing, whereas lower quality parent-child relationships forecast the opposite pattern. No such effects emerged among less context-sensitive children. Whereas sympathetic nervous system reactivity moderated the effects of parent-child relationships on both breast/genital and pubic hair development, adrenocortical activation only moderated the effect on pubic hair development. The current results build on previous research documenting what family contexts predict variation in pubertal timing by demonstrating for whom those contexts matter. In addition, the authors advance a new methodological approach for assessing pubertal tempo using piecewise growth curve analysis. PMID- 21262043 TI - Hippocampal volume and sensitivity to maternal aggressive behavior: a prospective study of adolescent depressive symptoms. AB - It has been suggested that biological factors confer increased sensitivity to environmental influences on depressive symptoms during adolescence, a crucial time for the onset of depressive disorders. Given the critical role of the hippocampus in sensitivity to stress and processing of contextual aspects of the environment, investigation of its role in determining sensitivity to environmental context seems warranted. This study prospectively examined hippocampal volume as a measure of sensitivity to the influence of aggressive maternal behavior on change in depressive symptoms from early to midadolescence. The interaction between aggressive maternal behavior and hippocampal volume was found to predict change in depressive symptoms. Significant sex differences also emerged, whereby only for girls were larger bilateral hippocampal volumes more sensitive to the effects of maternal aggressive behavior, particularly with respect to experiencing the protective effects of low levels of maternal aggressiveness. These findings help elucidate the complex relationships between brain structure, environmental factors such as maternal parenting style, and sensitivity to (i.e., risk for, and protection from) the emergence of depression during this life stage. Given that family context risk factors are modifiable, our findings suggest the potential utility of targeted parenting interventions for the prevention and treatment of adolescent depressive disorder. PMID- 21262044 TI - Enhancing infant attachment security: an examination of treatment efficacy and differential susceptibility. AB - This randomized controlled trial examined (a) the efficacy of a brief intervention designed to increase the rate of secure infant attachment, (b) the differential susceptibility hypothesis, and (c) whether maternal attachment styles moderated the expected Treatment x Irritability interaction in predicting infant attachment outcomes. Although there was no main effect of treatment, a significant Treatment x Irritability interaction revealed intervention effects for the highly irritable infants only, thus supporting one of two predictions of the differential susceptibility hypothesis: highly irritable infants would have disproportionately better outcomes than moderately irritable infants in better conditions (i.e., with intervention). When separate analyses were conducted with maternal attachment styles, we found significant three-way interactions among treatment, irritability, and each of the examined maternal attachment style dimensions (i.e., secure-fearful and dismissing-preoccupied). Specifically, with more secure mothers, beneficial effects of intervention emerged for highly irritable infants. For more dismissing mothers, the results revealed support for both predictions of the differential susceptibility hypothesis: highly irritable infants, compared to moderately irritable infants, were both more likely to be secure with intervention and less likely to be secure when in the control group. It is interesting that, for more preoccupied mothers, a treatment effect emerged only for moderately irritable infants. We discuss the implications of these findings for the differential susceptibility hypothesis as well as for early intervention. PMID- 21262045 TI - Biological sensitivity to context moderates the effects of the early teacher child relationship on the development of mental health by adolescence. AB - The moderating effects of biological sensitivity to context (physiological and behavioral stress reactivity) on the association between the early teacher-child relationship and the development of adolescent mental health problems were examined in a community sample of 96 children. Grade 1 measures of biological sensitivity to context included physiological (i.e., slope of mean arterial pressure across a 20- to 30-min stress protocol) and behavioral (i.e., temperamental inhibition/disinhibition) markers. Grade 1 measures of the teacher child relationship included positive (i.e., closeness) and negative (i.e., conflict) qualities. Mental health symptoms were assessed at Grades 1 and 7. Results of a multiple regression analysis indicated substantial association of the teacher-child relationship with the development of adolescent mental health symptoms, especially for more reactive children. In addition to teacher-child relationship main effects, all four Reactivity x Teacher-Child Relationship interaction terms were statistically significant when controlling for Grade 1 symptom severity, suggesting that both physiological and behavioral reactivity moderate the association of both adverse and supportive aspects of the teacher child relationship with Grade 7 symptom severity over and above Grade 1 severity. There were important differences, depending on which stress reactivity measure was considered. The importance of these findings for recent theoretical arguments regarding biological sensitivity to context and differential susceptibility is discussed. PMID- 21262046 TI - Brain and personality bases of insensitivity to infant cues in neglectful mothers: an event-related potential study. AB - This investigation examined the neural and personality correlates of processing infant facial expressions in mothers with substantiated neglect of a child under 5 years old. Event-related potentials (ERPs) were recorded from 14 neglectful and 14 control mothers as they viewed and categorized pictures of infant cries, laughs, and neutral faces. Maternal self-reports of anhedonia and empathy were also completed. Early (negative occipitotemporal component peaking at around 170 ms on the scalp [N170] and positive electrical potential peaking at about 200 ms [P200]) and late positive potential (LPP) components were selected. Both groups of mothers showed behavioral discrimination between the different facial expressions via reaction time and accuracy measures. Neglectful mothers did not exhibit increased N170 amplitude at temporal leads in response to viewing crying versus laughing and neutral expressions compared to control mothers. Both groups had greater P200 and LPP amplitudes at centroparietal leads in response to viewing crying versus neutral facial expressions. However, neglectful mothers displayed an overall attenuated brain response in LPP that was related to their higher scores in social anhedonia but not to their empathy scores. The ERP data suggest that the brain's failures in the early differentiation of cry stimuli and in the sustained processing of infant expressions related to social anhedonia may underlie the insensitive responding in neglectful mothers. The implications of these results for the design and evaluation of preventive interventions are discussed. PMID- 21262047 TI - Emerging self-regulation in toddlers born preterm or low birth weight: differential susceptibility to parenting? AB - The differential susceptibility to parenting model was examined in relation to toddler self-regulation in a prospective longitudinal study of infants born preterm or low birth weight. We followed 153 mother-infant dyads across five time points between the infant's Neonatal Intensive Care Unit stay and 24 months postterm. Assessments of infant temperament, quality of early parenting interactions, contextual variables, and toddler effortful control and behavior problems were conducted. Results supported differential susceptibility and dual risk models in addition to documenting main effects of early parenting on children's emerging self-regulation. Our data suggested that preterm or low birth weight infants who were prone to distress or rated by mothers as more difficult were particularly susceptible to the effects of early negative parenting. PMID- 21262048 TI - Efficacy of a home-visiting intervention aimed at improving maternal sensitivity, child attachment, and behavioral outcomes for maltreated children: a randomized control trial. AB - The efficacy of a short-term attachment-based intervention for changing risk outcomes for children of maltreating families was examined using a randomized control trial. Sixty-seven primary caregivers reported for maltreatment and their children (1-5 years) were randomly assigned to an intervention or control group. The intervention group received 8 weekly home visits directed at the caregiver child dyad and focused on improving caregiver sensitivity. Intervention sessions included brief discussions of attachment-emotion regulation-related themes and video feedback of parent-child interaction. Comparison of pre- and posttest scores revealed significant improvements for the intervention group in parental sensitivity and child attachment security, and a reduction in child disorganization. Older children in the intervention group also showed lower levels of internalizing and externalizing problems following intervention. This is the first study to demonstrate the efficacy of short-term attachment-based intervention in enhancing parental sensitivity, improving child security, and reducing disorganization for children in the early childhood period. PMID- 21262049 TI - Relationship of maternal negative moods to child emotion regulation during family interaction. AB - The relationship of maternal hostile and depressive moods to children's downregulation of unprovoked anger and sadness/fear was assessed in a community sample of 267 5-year-old boys and girls. The speed of children's downregulation of unprovoked anger and sadness/fear was based on real-time observations during mother-child interaction. The association of downregulation with maternal mood was estimated using Bayesian event history analysis. As mothers reported higher depressive mood, both boys and girls were faster to downregulate anger displays as those displays accumulated during mother child interaction. The speed of boys' downregulation of anger and of sadness/fear was not associated with maternal hostile mood. As mothers reported more hostile mood, girls were faster to downregulate displays of sadness/fear, but the speed of this downregulation slowed as those displays accumulated during ongoing mother-child interaction. These associations of child downregulation and maternal mood were observed after controlling for child adjustment. The data suggest frequent exposure to different negative maternal moods affect children's expression and regulation of emotions in relatively specific ways, conditional on the type of maternal mood, the type of child emotion, and child gender. PMID- 21262051 TI - Child and context characteristics in trajectories of physical and relational victimization among early elementary school children. AB - Transactional models suggest that peer victimization results from both individual and context differences, and understanding these differences may point to important targets for prevention and interventions that reduce victimization. Multilevel modeling was used to examine within-person (aggression and emotional dysregulation), between-person (sex and age), and between-school (participation in a victimization prevention program) factors that influence changes in physical and relational victimization over the first three years of elementary school. Children (n = 423) reported their experiences of peer victimization at entry into Grade 1 and at the end of Grade 1, Grade 2, and Grade 3. On average, trajectories of both physical and relational victimization declined. However, for individual children, teacher-rated aggression was associated with increases in physical and relational victimization, while emotional dysregulation was associated with attenuation of longitudinal declines in physical victimization and increases in relational victimization. Individual differences in sex and age at entry into Grade 1 did not significantly influence victimization trajectories over Grades 1 to 3. Children who participated in the WITS(r) victimization prevention program showed significant declines in physical and relational victimization. Levels of victimization among nonparticipants remained stable. Implications of child and context characteristics for preventing peer victimization in elementary school are discussed. PMID- 21262050 TI - Reciprocal relations between parents' physical discipline and children's externalizing behavior during middle childhood and adolescence. AB - Using data from two long-term longitudinal projects, we investigated reciprocal relations between maternal reports of physical discipline and teacher and self ratings of child externalizing behavior, accounting for continuity in both discipline and externalizing over time. In Study 1, which followed a community sample of 562 boys and girls from age 6 to 9, high levels of physical discipline in a given year predicted high levels of externalizing behavior in the next year, and externalizing behavior in a given year predicted high levels of physical discipline in the next year. In Study 2, which followed an independent sample of 290 lower income, higher risk boys from age 10 to 15, mother-reported physical discipline in a given year predicted child ratings of antisocial behavior in the next year, but child antisocial behavior in a given year did not predict parents' use of physical discipline in the next year. In neither sample was there evidence that associations between physical discipline and child externalizing changed as the child aged, and findings were not moderated by gender, race, socioeconomic status, or the severity of the physical discipline. Implications for the reciprocal nature of the socialization process and the risks associated with physical discipline are discussed. PMID- 21262052 TI - Individual differences in the development of early peer aggression: integrating contributions of self-regulation, theory of mind, and parenting. AB - This prospective longitudinal study focused on self-regulatory, social-cognitive, and parenting precursors of individual differences in children's peer-directed aggression at early school age. Participants were 199 3-year-old boys and girls who were reassessed following the transition to kindergarten (5.5-6 years). Peer aggression was assessed in preschool and school settings using naturalistic observations and teacher reports. Children's self-regulation abilities and theory of mind understanding were assessed during a laboratory visit, and parenting risk (corporal punishment and low warmth/responsiveness) was assessed using interview based and questionnaire measures. Individual differences in children's peer aggression were moderately stable across the preschool to school transition. Preschool-age children who manifested high levels of aggressive peer interactions also showed lower levels of self-regulation and theory of mind understanding, and experienced higher levels of adverse parenting than others. Our main finding was that early corporal punishment was associated with increased levels of peer aggression across the transition from preschool to school, as was the interaction between low maternal emotional support and children's early delays in theory of mind understanding. These data highlight the need for family-directed preventive efforts during the early preschool years. PMID- 21262053 TI - Early adolescents' temperament, emotion regulation during mother-child interactions, and depressive symptomatology. AB - This study examined the relations among temperament, emotion regulation, and depressive symptoms in early adolescents. Early adolescents provided self-reports of temperament on two occasions, as well as reports on emotion regulation and depressive symptomatology. Furthermore, 163 of these adolescents participated in event-planning and problem-solving interactions with their mothers. Adolescents with temperaments that were high in negative emotionality or low in effortful control displayed more emotionally dysregulated behaviors during the interaction tasks, reported having maladaptive responses to negative affect more often and adaptive responses less often, and had more depressive symptoms. In particular, adolescents with the high negative emotionality and low effortful control temperament combination reported the highest levels of depressive symptomatology. Sequential analyses of family interactions indicated that adolescents with more depressive symptoms were more likely to reciprocate their mothers' negative affective behaviors. Adolescents' adaptive and maladaptive responses to negative affect mediated the associations between their temperament and concurrent depressive symptoms. PMID- 21262054 TI - Subgenual anterior cingulate responses to peer rejection: a marker of adolescents' risk for depression. AB - Extensive developmental research has linked peer rejection during adolescence with a host of psychopathological outcomes, including depression. Moreover, recent neuroimaging research has suggested that increased activity in the subgenual region of the anterior cingulate cortex (subACC), which has been consistently linked with depression, is related to heightened sensitivity to peer rejection among adolescents. The goal of the current study was to directly test the hypothesis that adolescents' subACC responses are predictive of their risk for future depression, by examining the relationship between subACC activity during peer rejection and increases in depressive symptoms during the following year. During a functional magnetic resonance imaging scan, 20 13-year-olds were ostensibly excluded by peers during an online social interaction. Participants' depressive symptoms were assessed via parental reports at the time of the scan and 1 year later. Region of interest and whole-brain analyses indicated that greater subACC activity during exclusion was associated with increases in parent reported depressive symptoms during the following year. These findings suggest that subACC responsivity to social exclusion may serve as a neural marker of adolescents' risk for future depression and have implications for understanding the relationship between sensitivity to peer rejection and the increased risk of depression that occurs during adolescence. PMID- 21262055 TI - Exposure to peer delinquency as a mediator between self-report pubertal timing and delinquency: a longitudinal study of mediation. AB - This study examined exposure to peer delinquency as a mediator between pubertal timing and self-reported delinquency longitudinally and whether this mediational model was moderated by either gender or maltreatment experience. Data were obtained from Time 1, 2, and 3 of a longitudinal study of maltreatment and development. At Time 1 the sample comprised 454 children aged 9-13 years. Analyses via structural equation modeling supported full mediation. Gender did not moderate this mediational relationship, but maltreatment experience did. The results show that early maturing males and females are both at risk for being exposed to peers that may draw them into delinquent behavior. In addition, the mechanism linking early pubertal timing to delinquency differs depending on maltreatment experience. PMID- 21262056 TI - Identity disturbance in adolescence: associations with borderline personality disorder. AB - Although establishing a coherent identity is often viewed as a normative developmental task of adolescence, an important question is whether forms of identity disturbance seen in adult personality disorders can also be distinguished in adolescents. If so, such disturbances would constitute an essential target for research and clinical interventions. The goal of this study is to investigate the nature of identity disturbance in an adolescent clinical sample and to explore its links with personality pathology, particularly borderline personality disorder. A national random sample of 139 psychiatrists and clinical psychologists completed a battery of instruments on a randomly selected adolescent patient in their care, including measures of Axis II symptoms and the Identity Disturbance Questionnaire-Adolescent Version, an instrument designed for clinically experienced observers that assesses a wide range of manifestations of potential identity disturbance among adolescents. Factor analysis of the Identity Disturbance Questionnaire--Adolescent Version yielded four clinically and conceptually coherent factors that resembled dimensions previously identified in adults: lack of normative commitment, role absorption, painful incoherence, and lack of consistency. As in adults, identity disturbance in adolescents is a clinically meaningful, multidimensional construct exhibiting significant relationships with different forms of severe personality pathology, most notably borderline personality disorder. As such, identity disturbance can be a manifestation of psychopathology above and beyond the typical Sturm und Drang (storm and stress) of adolescence. PMID- 21262057 TI - Longitudinal predictors of adult socioeconomic attainment: the roles of socioeconomic status, academic competence, and mental health. AB - Educational attainment and occupational status are key markers of success in adulthood. We expand upon previous research that focused primarily on the contributions of academic competence and family socioeconomic status (SES) by investigating the role of mental health in predicting adult SES. In a longitudinal study spanning 30 years, we used structural equation modeling to examine how parental mental health in early childhood and family SES, offspring academic competence, and offspring mental health in adolescence relate to occupational and educational attainment at age 30. Results were that adolescent academic competence predicted adult educational attainment, and that educational attainment then predicted occupational attainment. The pathways between academic competence and occupational attainment, family SES and educational attainment, and family SES and occupational attainment were not significant. In contrast, adolescent mental health not only predicted educational attainment, but was also directly related to adult occupational attainment. Finally, early maternal mental health was associated with offspring's adult socioeconomic attainment through its relations with adolescent academic competence and mental health. These results highlight the importance of mental health to adult socioeconomic attainment. PMID- 21262058 TI - Changes in women's alcoholic, antisocial, and depressive symptomatology over 12 years: a multilevel network of individual, familial, and neighborhood influences. AB - In a sample of 273 adult women and their families, we examined the effects of women's psychopathology history, their social support, their husbands' and children's symptomatology, family stress, and neighborhood environment on their alcohol problems, antisocial behavior, and depression over a 12-year period during their 30s and early 40s. Women's alcohol problems and antisocial behavior decreased but their depression symptoms increased over time. Women's disorder history and their partners' parallel symptomatology were associated with their symptoms. For women's antisocial behavior, their own history of alcoholism and their partners' alcohol problems were also significant risk factors. Higher levels of social support were associated with lower levels of depression in women. Children's externalizing behavior was positively correlated with their mothers' alcohol problems and antisocial behavior, whereas children's internalizing behavior was positively correlated with their mothers' depression. Neighborhood residential instability was associated with higher levels of alcoholic and depressive symptomatology in women. Intervention efforts might target women with young children by improving social support, educational or professional training opportunity, access to family counseling, and neighborhood environment. PMID- 21262059 TI - Gyrification and neural connectivity in schizophrenia. AB - There is emerging evidence for a connection between the surface morphology of the brain and its underlying connectivity. The foundation for this relationship is thought to be established during brain development through the shaping influences of tension exerted by viscoelastic nerve fibers. The tension-based morphogenesis results in compact wiring that enhances efficient neural processing. Individuals with schizophrenia present with multiple symptoms that can include impaired thought, action, perception, and cognition. The global nature of these symptoms has led researchers to explore a more global disruption of neuronal connectivity as a theory to explain the vast array of clinical and cognitive symptoms in schizophrenia. If cerebral function and form are linked through the organization of neural connectivity, then a disruption in neural connectivity may also alter the surface morphology of the brain. This paper reviews developmental theories of gyrification and the potential interaction between gyrification and neuronal connectivity. Studies of gyrification abnormalities in children, adolescents, and adults with schizophrenia demonstrate a relationship between disrupted function and altered morphology in the surface patterns of the cerebral cortex. This altered form may provide helpful clues in understanding the neurobiological abnormalities associated with schizophrenia. PMID- 21262060 TI - Molecular mechanisms of genomic imprinting and clinical implications for cancer. AB - Genomic imprinting is an epigenetic marking of genes in the parental germline that ensures the stable transmission of monoallelic gene expression patterns in a parent-of-origin-specific manner. Epigenetic marking systems are thus able to regulate gene activity independently of the underlying DNA sequence. Several imprinted gene products regulate cell proliferation and fetal growth; loss of their imprinted state, which effectively alters their dosage, might promote or suppress tumourigenic processes. Conversely, global epigenetic changes that underlie tumourigenesis might affect imprinted gene expression. Here, we review imprinted genes with regard to their roles in epigenetic predisposition to cancer, and discuss acquired epigenetic changes (DNA methylation, histone modifications and chromatin conformation) either as a result of cancer or as an early event in neoplasia. We also address recent work showing the potential role of noncoding RNA in modifying chromatin and affecting imprinted gene expression, and summarise the effects of loss of imprinting in cancer with regard to the roles that imprinted genes play in regulating growth signalling cascades. Finally, we speculate on the clinical applications of epigenetic drugs in cancer. PMID- 21262061 TI - Real-time estimation of daily physical activity intensity by a triaxial accelerometer and a gravity-removal classification algorithm. AB - We have recently developed a simple algorithm for the classification of household and locomotive activities using the ratio of unfiltered to filtered synthetic acceleration (gravity-removal physical activity classification algorithm, GRPACA) measured by a triaxial accelerometer. The purpose of the present study was to develop a new model for the immediate estimation of daily physical activity intensities using a triaxial accelerometer. A total of sixty-six subjects were randomly assigned into validation (n 44) and cross-validation (n 22) groups. All subjects performed fourteen activities while wearing a triaxial accelerometer in a controlled laboratory setting. During each activity, energy expenditure was measured by indirect calorimetry, and physical activity intensities were expressed as metabolic equivalents (MET). The validation group displayed strong relationships between measured MET and filtered synthetic accelerations for household (r 0.907, P < 0.001) and locomotive (r 0.961, P < 0.001) activities. In the cross-validation group, two GRPACA-based linear regression models provided highly accurate MET estimation for household and locomotive activities. Results were similar when equations were developed by non-linear regression or sex specific linear or non-linear regressions. Sedentary activities were also accurately estimated by the specific linear regression classified from other activity counts. Therefore, the use of a triaxial accelerometer in combination with a GRPACA permits more accurate and immediate estimation of daily physical activity intensities, compared with previously reported cut-off classification models. This method may be useful for field investigations as well as for self monitoring by general users. PMID- 21262062 TI - Characteristics of energy under-reporting in children and adolescents. AB - Under-reporting (UR) of food intake is an issue of concern, as it may distort the relationships studied between diet and health. This topic has been scarcely addressed in children. The objective of the study was to assess the extent of UR in French children and investigate associated covariates. A total of 1455 children aged 3-17 years were taken from the nationally representative cross sectional French etude Individuelle Nationale des Consommations Alimentaires (INCA2) dietary survey (2006-7). Food intake was reported in a 7 d diet record. Socio-economic status, sedentary behaviour, weight perception variables and food habits were collected by questionnaires. Weight and height were measured. Under reporters were identified according to the Goldberg criterion adapted to children. Multivariate logistic regressions investigated the associations between UR and covariates. Rates of under-reporters were 4.9 and 26.0 % in children aged 3-10 and 11-17 years, respectively (P < 0.0001), without significant differences between boys and girls. Overall, UR was positively associated with a lower socio economic status, overweight, skipping breakfast and dinner, a higher contribution of proteins to energy intake (EI), and a lower contribution of simple carbohydrates to EI. Under-reporters aged 3-10 years also had a higher sedentary behaviour and a lower snack-eating frequency. In adolescents, UR was also associated with a less-frequent school canteen attendance, a perception of being overweight, a wish to weigh less, and current and past restrictive diets. In conclusion, under-reporters differ from plausible reporters in several characteristics related to diet, lifestyle, weight status and socio-economic status. Therefore, it is important to consider this differential UR bias when investigating diet-disease associations in children. PMID- 21262063 TI - Impact of overweight and glucose tolerance on postprandial responses to high- and low-glycaemic index meals. AB - The beneficial effects of a low-glycaemic index (GI) meal on postprandial glucose and insulin levels have been demonstrated. However, limited data are available on the impact of overweight and glucose tolerance on postprandial responses to different GI meals. Our aim was to study the effects of physiological characteristics on postprandial glucose, insulin and lipid responses and the relative glycaemic response (RGR) of a low-GI (LGI) and a high-GI (HGI) meal. We recruited twenty-four normal-weight and twenty-four overweight subjects, twelve with normal glucose tolerance (NGT) and twelve with impaired glucose tolerance (IGT) in each group. Both test meals were consumed once and the glucose reference twice. Blood glucose and insulin were measured in the fasting state and over a 2 h period after each study meal, and TAG and NEFA were measured in the fasting state and over a 5 h period. The glucose responses of subjects with IGT differed significantly from those of subjects with NGT. The highest insulin responses to both meals were observed in overweight subjects with IGT. Physiological characteristics did not influence TAG or NEFA responses or the RGR of the meals. The LGI meal resulted in lower glucose (P < 0.001) and insulin (P < 0.001) responses, but higher TAG responses (P < 0.001), compared with the HGI meal. The GI of the meals did not affect the NEFA responses. In conclusion, the LGI meal causes lower glucose and insulin responses, but higher TAG responses, than the HGI meal. The RGR of the meals does not differ between normal-weight and overweight subjects with NGT or IGT. PMID- 21262064 TI - Dietary nicotinic acid supplementation improves hepatic zinc uptake and offers hepatoprotection against oxidative damage. AB - We examined the effect of dietary nicotinic acid (NA) variations before and after oxidative stress (OS) treatment on the antioxidant defence system, function and morphology of the liver along with Zn status in rats. OS was generated by three intraperitoneal injections of tert-butyl hydroperoxide in the first week for the pre-exposure group and in the third week for the post-exposure group, respectively. These groups were further divided into subgroups and fed on a diet with marginally deficient Zn (10 mg Zn/kg diet) and NA variations as NA deficient, normal and excess with 10, 30 and 1000 mg NA/kg diet, respectively. Aspartate aminotransferase and alanine aminotransferase levels were elevated in rats with OS coupled with the Zn- and NA-deficient diet, which decreased towards normal with excess dietary NA. Excess NA supplementation in the OS pre-exposure group resulted in nearly preserved hepatic architecture with normal hepatocytes, whereas maximum tissue destruction was evident in the post-exposure group with NA deficiency. Dose-dependent improvement in the antioxidant defence system, enhanced reduced glutathione levels, lowered lipid peroxidation and higher hepatic Zn levels were observed with NA supplementation. The effect was more prominent in the pre-exposure group. In conclusion, dietary NA supplementation improves hepatic Zn uptake and results in hepatoprotection against OS-induced damage in rats. PMID- 21262065 TI - How much is too much? A case report of nutritional supplement use of a high performance athlete. AB - Although dietary nutrient intake is often adequate, nutritional supplement use is common among elite athletes. However, high-dose supplements or the use of multiple supplements may exceed the recommended daily allowance (RDA) of particular nutrients or even result in a daily intake above tolerable upper limits (UL). The present case report presents nutritional intake data and supplement use of a highly trained male swimmer competing at international level. Habitual energy and micronutrient intake were analysed by 3 d dietary reports. Supplement use and dosage were assessed, and total amount of nutrient supply was calculated. Micronutrient intake was evaluated based on RDA and UL as presented by the European Scientific Committee on Food, and maximum permitted levels in supplements (MPL) are given. The athlete's diet provided adequate micronutrient content well above RDA except for vitamin D. Simultaneous use of ten different supplements was reported, resulting in excess intake above tolerable UL for folate, vitamin E and Zn. Additionally, daily supplement dosage was considerably above MPL for nine micronutrients consumed as artificial products. Risks and possible side effects of exceeding UL by the athlete are discussed. Athletes with high energy intake may be at risk of exceeding UL of particular nutrients if multiple supplements are added. Therefore, dietary counselling of athletes should include assessment of habitual diet and nutritional supplement intake. Educating athletes to balance their diets instead of taking supplements might be prudent to prevent health risks that may occur with long-term excess nutrient intake. PMID- 21262066 TI - Iodine intakes of 100-300 MUg/d do not modify thyroid function and have modest anti-inflammatory effects. AB - Little information is available as to whether doses of iodide similar to those recommended in clinical practice for the prevention of iodine deficiency in pregnant women affect thyroid function. The aim of the present study was to analyse whether doses of iodide can affect thyroid function in adults, and evaluate its effect on plasma markers of oxidative stress, inflammation and acute phase proteins. A total of thirty healthy volunteers (ten men and twenty women) with normal thyroid function were randomly assigned to three groups (n 10). Each group received a daily dose of 100, 200 or 300 MUg of iodide in the form of KI for 6 months. Free tetraiodothyronine (FT4) levels at day 60 of the study were higher in the groups treated with 200 and 300 MUg (P = 0.01), and correlated with the increase in urinary iodine (r 0.50, P = 0.007). This correlation lost its significance after adjustment for the baseline FT4. The baseline urinary iodine and FT4 correlated positively with the baseline glutathione peroxidase. On day 60, urinary iodine correlated with C-reactive protein (r 0.461, P = 0.018), and free triiodothyronine correlated with IL-6 (r - 0.429, P = 0.025). On day 60, the changes produced in urinary iodine correlated significantly with the changes produced in alpha1-antitrypsin (r 0.475, P = 0.014) and ceruloplasmin (r 0.599, P = 0.001). The changes in thyroid-stimulating hormone correlated significantly with the changes in alpha1-antitrypsin (r - 0.521, P = 0.005) and ceruloplasmin (r - 0.459, P = 0.016). In conclusion, the administration of an iodide supplement between 100 and 300 MUg/d did not modify thyroid function in a population with adequate iodine intake. The results also showed a slight anti-inflammatory and antioxidative action of iodide. PMID- 21262067 TI - International survey on attitudes toward ethics in health technology assessment: An exploratory study. AB - OBJECTIVES: The objective of this exploratory study was to survey international health technology assessment (HTA) professionals to determine attitudes toward ethics in HTA. METHODS: An exploratory, quantitative, cross-sectional study design was developed. The sample population (n = 636) was selected from authors of the 206 articles published in the International Journal of Technology Assessment in Health Care between 2005 and 2007. A survey instrument was piloted and e-mailed. RESULTS: The response rate was low (n = 104; 16.4 percent). Respondents were primarily middle-aged (46 +/- 11 years) male (62 percent) health professionals from Western countries (n = 92; 88.5 percent), with a mean of 10 (+/- 6 years) years of HTA experience. Although at least 90 percent of respondents agreed that healthcare decisions involved value judgments and that ethical analysis was important to HTA, respondents were divided as to whether normative (n = 45; 44.6 percent) or descriptive (n = 38; 37.6 percent) ethical recommendations were necessary. Most respondents (n = 83; 81.4 percent) believed that HTA should include citizen participation, but two thirds (n = 67; 67.0 percent) agreed that the final decision should be restricted to decision makers. A majority of respondents thought that ethical analysis could be discussed anywhere within the HTA process, either by an expert trained in ethics (n = 62; 60.8 percent) or by an external consultant (n = 80; 78.4 percent). CONCLUSIONS: This study showed that ethical discourse in HTA is constrained by practical considerations, which serves to limit moral inquiry. To increase ethical analysis, a positive attitude toward ethics needs to be fostered within the HTA community. PMID- 21262068 TI - Atrioventricular septal defect with coexisting tricuspid atresia. AB - We describe two infants having an atrioventricular septal defect in the setting of a double inlet atrioventricular connection, but with patency of the left-sided valvar orifice and an imperforate right-sided valvar component, and a further case with atrioventricular septal defect and an imperforate Ebstein's malformation, all producing the haemodynamic effect of tricuspid atresia. We make comparisons with the arrangement in trisomy 16 mice, in whom deficient atrioventricular septation is seen at times with the common atrioventricular junction exclusively connected to the left ventricle, a situation similar to that seen in two of our infants. We also review previous reports emphasising the important theoretical implication of the findings despite their rarity. PMID- 21262069 TI - Using threshold values for cost per quality-adjusted life-year gained in healthcare decisions. AB - BACKGROUND: In many countries, the incremental cost-effectiveness ratio (ICER) is used to assess whether an intervention is worth its costs. At the same time, policy makers often feel uncomfortable with refusing reimbursement of any intervention purely on the basis of the fact that the ICER exceeds a specific threshold value. Reluctance to define a single threshold value for the ICER seems to have been stronger in social security systems than in national healthcare services systems. This study explores how basic differences between healthcare systems impact upon the potential usefulness of an ICER threshold value. METHODS: This study is a narrative review of literature about the theoretical foundations of the ICER threshold value approach and its practical relevance in different types of healthcare systems. RESULTS: A single ICER threshold value cannot be maintained, defined, or measured and should not be used as a policy-making tool. None of the solutions presented up until now to make the ICER threshold approach a valuable policy-making tool overcome the important weaknesses of the approach. CONCLUSIONS: ICERs and ICER threshold values are insufficient for assessing interventions' value for money. Rather, they should be considered as one element in the decision-making process. Complete rationalization of the decision-making process by means of quantitative decision criteria is undesirable and not feasible. Increasing transparency in the criteria used for a decision and explicitness about the relative importance of each criterion should, therefore, be the major goal. PMID- 21262070 TI - Pericardial patch valve in the tricuspid position in an infant. AB - A 10-month-old infant with severe tricuspid valve disease due to staphylococcal bacterial endocarditis, underwent surgical replacement of the valve. The new valve was fashioned using an autologous pericardial patch. Over 3 years of follow up, the new valve has functioned satisfactorily, with moderately elevated right atrial pressure. PMID- 21262071 TI - Moving cautiously: Public involvement and the health technology assessment community. AB - OBJECTIVES: This study explores the factors that enhance or reduce the prospects for public involvement in the activities of health technology assessment (HTA) agencies. METHODS: The analytical framework for this study is based on the work of John W. Kingdon, which provides a comprehensive synthesis of the factors influencing governments and public organizations' agenda. The study draws insights from forty-two semistructured telephone interviews with informants involved in international HTA networks and/or in HTA agencies in Canada, Denmark, and the United Kingdom. RESULTS: This exploratory study suggests that the HTA community is moving toward greater public involvement. However, the HTA community remains cautious and ambivalent about the technical feasibility of public involvement, its acceptability to policy makers and practitioners, and its impacts on HTA agencies' resources and procedures. CONCLUSIONS: The study stresses the importance of conducting rigorous and compelling evaluations to inform HTA agencies' decision to adopt, or reject, public involvement practices. PMID- 21262073 TI - Aortic stenosis in a patient with Hurler's syndrome after bone marrow transplantation. AB - We describe a case of severe aortic stenosis in a 16-year-old male with Hurler's syndrome who had prior bone marrow transplantation. The excised aortic valve leaflets showed characteristic pathologic findings of Hurler's syndrome. This is the first case report of aortic valve replacement in a patient with Hurler's syndrome treated with bone marrow transplantation that demonstrates progression of the aortic valve disease despite treatment. PMID- 21262072 TI - What principles should govern the use of managed entry agreements? AB - BACKGROUND: To ensure rapid access to new potentially beneficial health technologies, obtain best value for money, and ensure affordability, healthcare payers are adopting a range of innovative reimbursement approaches that may be called Managed Entry Agreements (MEAs). METHODS: The Health Technology Assessment International (HTAi) Policy Forum sought to identify why MEAs might be used, issues associated with implementation and develop principles for their use. A 2 day deliberative workshop discussed key papers, members' experiences, and collectively addressed four policy questions that resulted in this study. RESULTS: MEAs are used to give access to new technologies where traditional reimbursement is deemed inappropriate. Three different forms of MEAs have been identified: management of budget impact, management of uncertainty relating to clinical and/or cost-effectiveness, and management of utilization to optimize performance. The rationale for using these approaches and their advantages and disadvantages differ. However, all forms of MEA should take the form of a formal written agreement among stakeholders, clearly identifying the rationale for the agreement, aspects to be assessed, methods of data collection and review, and the criteria for ending the agreement. CONCLUSIONS: MEAs should only be used when HTA identifies issues or concerns about key outcomes and/or costs and/or organizational/budget impacts that are material to a reimbursement decision. They provide patient access and can be useful to manage technology diffusion and optimize use. However, they are administratively complex and may be difficult to negotiate and their effectiveness has yet to be evaluated. PMID- 21262074 TI - Novel frameshift mutation in Troponin C ( TNNC1) associated with hypertrophic cardiomyopathy and sudden death. AB - PurposeHypertrophic cardiomyopathy is the most common cause of sudden death in young people, including trained athletes, and is caused by mutations in genes encoding proteins of the cardiac sarcomere. Mutations in the Troponin C gene (TNNC1) are a rare genetic cause of hypertrophic cardiomyopathy. We describe a novel type of mutation (c.363dupG) in Troponin C, a rare form of hypertrophic cardiomyopathy. METHODS: A family in which a 19-year-old asymptomatic male died of sudden cardiac death due to hypertrophic cardiomyopathy was genetically studied by sequencing 17 genes associated with hypertrophic cardiomyopathy or its phenocopies. RESULTS: A c.363dupG mutation in Troponin C was identified, and tested across the family. CONCLUSIONS: We report the first frameshift mutation (c.363dupG or p.Gln122AlafsX30) in Troponin C causing hypertrophic cardiomyopathy (and sudden cardiac death) in a 19-year-old male, and have demonstrated that the mutation segregates with hypertrophic cardiomyopathy within the family. PMID- 21262075 TI - Improving ethics analysis in health technology assessment. AB - OBJECTIVES: The aim of this study was to critically examine the current guidance for conducting ethics analysis in health technology assessment (HTA) and to offer recommendations for how to improve this practice. METHODS: MEDLINE, Philosopher's Index, and Google Scholar were searched for articles and reports using the keywords "ethics" and "health technology assessment" and related terms. Bibliographies of all relevant articles were also examined for additional references. A philosophical analysis of the existing guidance was conducted. RESULTS: We offer three recommendations for improving ethics analysis in HTA. First, ethical and legal issues must be clearly separated so that all policy relevant questions that the technology raises can be considered clearly and systematically. Second, analysts must make better use of ethics theory and discuss better how particular theoretical approaches and associated analytic tools are selected to make transparent which alternative approaches were considered and why they were rejected. Third, the necessity for philosophical expertise to adequately conduct ethics analysis needs to be acknowledged. CONCLUSIONS: To act on these recommendations for ethics analysis, we offer these three steps forward: acknowledge and use relevant expertise, further develop models for conducting and reporting ethics analyses, and make use of untapped resources in the literature. PMID- 21262077 TI - Factors affecting success of blood pressure measurements during ambulatory blood pressure monitoring in children with renal disease. AB - AIM: To analyse blood pressure characteristics during 24-hour ambulatory blood pressure monitoring in children and to assess factors that influence its success over 24 hours and during patient-recorded awake (DAY) and sleep (NIGHT) periods. METHODS: A total of 169 consecutive ambulatory blood pressure monitoring studies were conducted in 154 patients over 30 months. For each ambulatory study, we measured the percentage of successful measurements both at the first attempt (S initial%) and following any automated repeat attempt if initial attempts had failed (S-final%). These were measured over 24-hour, DAY, and NIGHT periods. RESULTS: We found that blood pressure measurements at NIGHT were more successful than measurements attempted during the DAY (p<0.05). There was no influence of age, gender, height, weight, body mass index and estimated glomerular filtration rate with the proportion of successful measurements during the 24-hour, DAY, and NIGHT periods. On stepwise multiple regression analysis, the indexed mean systolic blood pressure over 24 hours was the only factor having a significant influence on the proportion of successful measurements over the 24-hour and DAY periods, although it only accounted for three-tenths of the variance; it had no influence on the overall success of measurements at NIGHT. CONCLUSION: Ambulatory blood pressure monitoring in children provides reliable data both during the patient's awake and sleep periods with higher success of measurements at NIGHT as opposed to DAY periods. PMID- 21262078 TI - Photodynamic diagnosis of bladder cancer compared with white light cystoscopy: Systematic review and meta-analysis. AB - OBJECTIVES: The aim of this study was to assess the test performance and clinical effectiveness of photodynamic diagnosis (PDD) compared with white light cystoscopy (WLC) in people suspected of new or recurrent bladder cancer. METHODS: A systematic review was conducted of randomized controlled trials (RCTs), nonrandomized comparative studies, or diagnostic cross-sectional studies comparing PDD with WLC. Fifteen electronic databases and Web sites were searched (last searches April 2008). For clinical effectiveness, only RCTs were considered. RESULTS: Twenty-seven studies (2,949 participants) assessed test performance. PDD had higher sensitivity than WLC (92 percent, 95 percent confidence interval [CI], 80-100 percent versus 71 percent, 95 percent CI, 49-93 percent) but lower specificity (57 percent, 95 percent CI, 36-79 percent versus 72 percent, 95 percent CI, 47-96 percent). For detecting higher risk tumors, median range sensitivity of PDD (89 percent [6-100 percent]) was higher than WLC (56 percent [0-100 percent]) whereas for lower risk tumors it was broadly similar (92 percent [20-95 percent] versus 95 percent [8-100 percent]). Four RCTs (709 participants) using 5-aminolaevulinic acid (5-ALA) as the photosensitising agent reported clinical effectiveness. Using PDD at transurethral resection of bladder tumor (TURBT) resulted in fewer residual tumors at check cystoscopy (relative risk [RR], 0.37, 95 percent CI, 0.20-0.69) and longer recurrence-free survival (RR, 1.37, 95 percent CI, 1.18-1.59), compared with WLC. CONCLUSIONS: PDD detects more bladder tumors than WLC, including more high-risk tumors. Based on four RCTs reporting clinical effectiveness, 5-aminolaevulinic acid-mediated PDD at TURBT facilitates a more complete resection and prolongs recurrence-free survival. PMID- 21262079 TI - A comparison of cardiac post-conditioning and remote pre-conditioning in paediatric cardiac surgery. AB - BACKGROUND: Remote ischaemic pre-conditioning and cardiac ischaemic post conditioning provide myocardial protection in cardiac surgery. However, these two endogenous strategies have not been directly compared in a clinical setting. The purpose of this study was to compare the efficacy of remote ischaemic pre conditioning and post-conditioning in providing myocardial protection to children undergoing cardiopulmonary bypass for surgical repair of ventricular septal defect. METHODS: We randomly assigned 60 paediatric patients scheduled for surgical correction of congenital ventricular septal defect to the post conditioning group (n = 20), remote pre-conditioning group (n = 20), or control group (n = 20). Post-conditioning consisted of 30 seconds of ischaemia and 30 seconds of reperfusion achieved by clamping and unclamping the aorta, repeated three times over 3 minutes immediately after cardioplegic arrest. Remote ischaemic pre-conditioning consisted of 5 minutes of lower limb ischaemia followed by 5 minutes of reperfusion using a blood-pressure cuff inflated to a pressure of 200 millimetres of mercury, also repeated three times over 30 minutes. We assayed creatine kinase-MB, troponin I. RESULTS: Mean age, cardiopulmonary bypass times, and aortic cross-clamp times were matched across groups. Both post-conditioning and remote ischaemic pre-conditioning reduced the peak release of creatine kinase-MB (86.1 plus or minus 24.1 units per litre and 92.8 plus or minus 20.6 units per litre, respectively, versus 111.0 plus or minus 44.6 units per litre in the control, p less than 0.05) and troponin I (0.28 plus or minus 0.10 nanogram per millilitre and 0.26 plus or minus 0.09 nanogram per millilitre, respectively, versus 0.49 plus or minus 0.19 nanogram per millilitre in the control group, p less than 0.05). CONCLUSIONS: Our study demonstrates that ischaemic post-conditioning and remote ischaemic pre-conditioning provide comparable myocardial benefit in children undergoing cold blood cardioplegic arrest. PMID- 21262080 TI - Dietary supplementation with selenium and vitamin E improves milk yield, composition and rheological properties of dairy Jonica goats. AB - The objective of this study was to evaluate the effect of dietary supplementation with selenium (Se) and vitamin E (VitE) on milk yield, composition and renneting parameters in dairy Jonica breed goats. Forty multiparous lactating goats fed the same basal diet were randomly allocated to 1 of 2 dietary treatments: for 135 days, the experimental period. Basal diet was composed by ad libitum mixed vetch oat hay and a definite amount of a pelleted concentrate. Dietary treatments included: (1) the control diet containing background Se and VitE only, and (2) the experimental diet containing sodium selenite as the Se supplement in concentrate (0.20 mg/head per day of Na-selenite and 20 mg/day per head of VitE). During the trial, no significant differences (P>0.05) were registered in dry matter intake and body weight gain among groups. Goats fed Se-VitE diet showed the highest milk production (P<0.05), and fat (P<0.01) and protein (P<0.05) yields and percentages. Somatic cell count were significantly lower in Se-VitE diet compared with control group (P<0.05). Significant differences (P<0.05) were observed in milk renneting properties. Based on our results, it was concluded that dietary supplementation with SE and VitE led to an increase of milk production and quality in Jonica goat, with positively improvement in milk coagulation aptitude. PMID- 21262081 TI - Sex differences in life expectancy in Canada: immigrant and native-born populations. AB - A growing body of research often indicates that immigrant populations in Western countries enjoy a lower level of mortality in relation to their native-born host populations. In this literature, sex differences in mortality are often reported but substantive analyses of the differences are generally lacking. The present investigation looks at sex differences in life expectancy with specific reference to immigrant and Canadian-born populations in Canada during 1971 and 2001. For these two populations, sex differences in expectation of life at birth are decomposed into cause-of-death components. Immigrants in Canada have a higher life expectancy than their Canadian-born counterparts. In absolute terms, immigrant females enjoy the highest life expectancy. In relative terms, however, immigrant men show a larger longevity advantage, as their expectation of life at birth exceeds that of Canadian-born men by a wider margin than do foreign-born females in relation to Canadian-born females. It is also found that immigrants have a smaller sex differential in life expectancy as compared with the Canadian born. Decomposition analysis shows this is a function of immigrants having smaller sex differences in death rates from heart disease and cancer. Factors thought to underlie these differentials between immigrants and the Canadian born are discussed and suggestions for further research are given. PMID- 21262082 TI - Genetic and morphological variation in Echinorhynchus gadi Zoega in Muller, 1776 (Acanthocephala: Echinorhynchidae) from Atlantic cod Gadus morhua L. AB - Previous studies have shown considerable variability in morphological features and the existence of genetically distinct sibling species in the acanthocephalan Echinorhynchus gadi Zoega in Muller, 1776. The aim of the present study was to follow up and extend those earlier studies by using a combination of DNA analysis and morphometrics to investigate differences between samples of E. gadi from Atlantic cod Gadus morhua L. caught at five fishing grounds in the Baltic Sea and three in different parts of the North Atlantic. Twelve morphological features were measured in 431 specimens of E. gadi, 99 individuals were studied by polymerase chain reaction-restriction fragment length polymorphosm (PCR-RFLP), and selected PCR products were sequenced. The molecular analyses showed the nucleotide sequences of E. gadi rDNA from cod caught at all the sampling sites to be identical. The comparative morphological study, in contrast, revealed significant differences between samples of E. gadi from different sampling sites and showed the separation of E. gadi into two groups corresponding approximately to the systematic classification of cod into the two subspecies, Atlantic G. morhua morhua and Baltic G. morhua callarias. The E. gadi infrapopulation size had a significant effect on some of the morphological features. The results are discussed in relation to cod population biology, the hydrography of the study area and the history of the Baltic Sea formation. PMID- 21262083 TI - Drug-eluting stents versus bare-metal stents in acute myocardial infarction: A systematic review and meta-analysis. AB - OBJECTIVES: Recent concerns have been raised for the safety after drug-eluting stents (DES) implantation compared with the use of bare-metal stents (BMS) in patients with ST-elevation acute myocardial infarction (STEMI). The objective of this study was to estimate the relative impact of DES versus BMS on mortality, myocardial infarction (MI), target vessel revascularization (TVR), and stent thrombosis (ST) in STEMI patients by performing comprehensive meta-analyses of randomized controlled trials (RCTs) and observational studies. METHODS: We performed an electronic search and manual search of studies presented through September 2009, without language restrictions. An approach of "using systematic reviews" was used. Two independent reviewers extracted prespecified data from each study. A random-effects model was used to combine trials and to perform stratified analyses based on study designs and the duration of follow-up. RESULTS: Fourteen RCTs were identified (N = 7,654). Compared with BMS, DES significantly reduced TVR (risk ratio [RR], 0.48; 95 percent confidence interval [CI], 0.41-0.56) and MI (RR, 0.77; 95 percent CI, 0.61-0.97), without increasing mortality (RR, 0.88; 95 percent CI, 0.70-1.10) and ST (RR, 0.93; 95 percent CI, 0.72-1.21). Among 35 observational studies (N = 44,849), the use of DES was associated with a significant reduction in mortality (RR, 0.85; 95 percent CI, 0.79-0.91) and TVR (RR, 0.61; 95 percent CI, 0.48-0.77). MI and ST were significantly lower in the DES group within 1-year follow-up, but there were no differences within 2 years of follow-up. There was no evidence of statistical heterogeneity and publication bias. CONCLUSIONS: These data in aggregate suggest that using DES in STEMI patients is safe and efficacious, but there are differences between RCT and observational data comparing DES and BMS. PMID- 21262084 TI - Improving patient access to cancer drugs in India: Using economic modeling to estimate a more affordable drug cost based on measures of societal value. AB - BACKGROUND: Using multiples of India's per capita gross domestic product (GDP) as the threshold for economic value as suggested by the World Health Organization (WHO), decision analysis modeling was used to estimate a more affordable monthly cost in India for a hypothetical new cancer drug that provides a 3-month survival benefit to Indian patients with metastatic colorectal cancer (mCRC). METHODS: A decision model was developed to simulate progression-free and overall survival in mCRC patients receiving chemotherapy with and without the new drug. Costs for chemotherapy and side-effects management were obtained from both public and private hospitals in India. Utility estimates measured as quality-adjusted life years (QALY) were determined by interviewing twenty-four oncology nurses using the Time Trade-Off technique. The monthly cost of the new drug was then estimated using a target threshold of US$9,300 per QALY gained, which is three times the Indian per capita GDP. RESULTS: The base-case analysis suggested that a price of US$98.00 per dose would be considered cost-effective from the Indian public healthcare perspective. If the drug were able to improve patient quality of life above the standard of care or survival from 3 to 6 months, the price per dose could increase to US$170 and US$253 and offer the same value. CONCLUSIONS: The use of the WHO criteria for estimating the cost of a new drug based on economic value for a developing country like India is feasible and can be used to estimate a more affordable cost based on societal value thresholds. PMID- 21262085 TI - Introducing patients' and the public's perspectives to health technology assessment: A systematic review of international experiences. AB - OBJECTIVES: The aim of this study was to review international experiences of patient or public involvement in the field of health technology assessment (HTA). METHODS: A systematic review of the scientific literature was conducted. A literature search was performed across nine databases. Other literature was identified through citation tracking, government websites (HTA agencies), and Internet search engines. Characteristics of the studies, description of the activities related to patient or public involvement, impact of these activities on the HTA process, and factors facilitating or limiting involvement were abstracted independently by two reviewers. RESULTS: A total of 1,441 potentially relevant papers were identified by the main search strategy. Among these, seventeen papers met the inclusion criteria; other search strategies identified seven additional documents. The findings reveal that patient or public involvement in HTA activities was reported in two domains, research and HTA process. In the research domain, patients are consulted to gather evidence about their perspectives, experiences, or preferences about a health technology. These perspectives could add key dimensions to the evaluation of health technologies that might otherwise be overlooked. In the domain of the HTA process, patients or public representatives participate in different stages of this process: prioritization, evidence assessment, or dissemination of findings. CONCLUSIONS: There are few published examples of experiences involving patients and the public in HTA. These examples show that patients' or the public's perspectives could add important dimensions to the evaluation of health technologies. However, there is a need to develop more systematic approaches to considering patients' and the public's perspectives in HTA. PMID- 21262086 TI - Addressing issues in health technology assessment promotion: Motives, enablers, and barriers. AB - OBJECTIVES: The aim of this study was to analyze the motives, enablers, and barriers to promote or initiate health technology assessment (HTA) in different contexts. METHODS: An observational study design was used to address the above question that included a survey questionnaire and a two-phase study. The respondents for the questionnaire and first round of the study were from HTA agencies of high income countries and those low and middle income countries that have managed to establish HTA agencies (n = 50), that are members of International Network of Agencies for Health Technology Assessment (INAHTA), EuroScan, or European network for Health Technology Assessment (EUnetHTA). The second round of the study was exclusively with respondents from low and middle income countries that were manly affiliated to Health Technology Assessment International (HTAi) interest subgroup for low and middle income countries and aimed to initiate HTA activities (n = 34). RESULTS: Forty-one of fifty HTA agencies answered the survey questionnaire. Thirty-three of fifty individuals belonging to HTA agencies from high income countries and sixteen of thirty-four individuals from low and middle income countries answered in the first and second phases of the study, respectively. In the promotion and/or initiation of HTA, the top three motives were the same for both high income and low and middle income countries. The top three enablers were also similar but the prioritization varies. The top three barriers were more context specific. CONCLUSIONS: HTA promotion or initiation is influenced by the following: (i) key players that affect the time taken to establish HTA agencies; (ii) three models for HTA promotion and initiation: top-down (political interest), bottom-up (academic/research interest), and converging (political and academic/research interests); and (iii) motives, enablers, and barriers at the local context. PMID- 21262087 TI - What aspects of the health technology assessment process recommended by international health technology assessment agencies received the most attention in Poland in 2008? AB - OBJECTIVES: The primary objective of this study was to determine the extent to which international standards on transparency and quality are met by the health technology assessment (HTA) process in Poland. A secondary objective is to describe the outcomes of the HTA process and their associated factors. METHODS: All published online HTA appraisal and meeting proceedings on pharmaceutical products in 2008 were reviewed using a score card developed from international checklists recommended by INAHTA and ECHTA. RESULTS: The sixty-nine reports reviewed showed that five of nine transparency standards and six of eight quality standards were usually met by the HTA reports. Areas for improvement for transparency include inputs from external stakeholders, availability of English summaries, conclusions, implications of results, and suggested program of action. Areas of improvement for quality include appropriateness of target population and comparator/s, sufficiency of evidence on efficacy and safety, methodological rigor, economic model assumptions, and adaptation to the Polish setting. A consideration of the ethical and social consequences to the healthcare system must also be strengthened. CONCLUSIONS: The study demonstrates that the incorporation and implementation of the HTA appraisal process in Poland has been successful. HTA appraisal reports in Poland have considered most of the international standards of transparency and quality. Recommendations for both HTA users and doers are forwarded for the improvement of the HTA process in the Polish setting. PMID- 21262088 TI - The true role of horizon scanning in Australia: Who it informs and why. PMID- 21262090 TI - ICER is good for us--Possibly not for you, he or she. PMID- 21262091 TI - A sixty-five-year-old man with rash, fever, and generalized weakness. AB - Diffuse erythematous rash accompanied by high-grade fever, eosinophilia, and facial edema can be caused by a variety of infective, allergic, or systemic etiologies. We present a case of 65-year-old man with septic arthritis, who had a vancomycin antibiotic spacer placed in his infected knee and was also started on intravenous (i.v.) vancomycin. After 2 weeks he presented with sudden onset of fever and generalized weakness. Physical examination was significant for tachycardia and hypotension, facial edema, diffuse erythematous rash, and bilateral wheezing. Laboratory values indicated acute renal insufficiency associated with eosinophiluria and significant peripheral eosinophilia. Septic shock was highly suspected and he was treated with i.v. fluids and broad-spectrum antibiotics. Despite aggressive management his condition rapidly deteriorated with persistent of shock state, increase in facial edema, and rash. Other suspected etiologies included hypersensitivity reactions to i.v. antibiotics (piperacillin/tazobactam) or vancomycin, systemic vasculitis, or idiosyncratic reactions to medications such as Stevens-Johnson syndrome. The patient was started on high-dose i.v. steroids, which led to improvement of his clinical condition. Clinical presentation of adverse drug reactions is highly variable and may present as potentially life-threatening multiorgan failure. Early recognition of the etiology and removing the offending agent is important to improve the outcome. PMID- 21262092 TI - Hereditary angioedema: Historical aspects, classification, pathophysiology, clinical presentation, and laboratory diagnosis. AB - Hereditary angioedema (HAE) is a rare disorder first described in 1888 by Sir William Osler. Since then, our understanding of this condition has increased tremendously. This article reviews the historical aspects, classification, pathophysiology, clinical presentation, and laboratory diagnosis of HAE. A review was performed of historical and current literature of HAE. HAE I and II are related to insufficient production of C1-esterase inhibitor (C1-INH) or production of a dysfunctional C1-INH protein, respectively. HAE III is not related to C1-INH deficiency and the pathogenesis is unknown. Bradykinin appears to be the main mediator responsible for angioedema in patients with C1-INH deficiencies. Angioedema of the extremities, face, and upper airway along with gastrointestinal angioedema are the most common clinical features in HAE. The laboratory tests that are most commonly used in the diagnosis of HAE include C4, C1-INH concentration, and C1-INH function. Advances in our understanding of the pathogenesis of HAE have led to several advances in the therapy of this disease. Despite our more thorough understanding of the genetics and pathophysiology of HAE, many questions remain unanswered. PMID- 21262093 TI - Update on the acute treatment of hereditary angioedema. AB - Hereditary angioedema (HAE) is a genetic autosomal dominant condition caused by C1-esterase inhibitor protein (C1INH) deficiency that results in episodic tissue angioedema. Recently, new therapies have been developed to more effectively manage this rare but serious condition. This review will provide a concise summary of HAE acute treatment options for the practicing allergist/immunologist. Clinical study data for emerging HAE therapies were reviewed and summarized. Based on efficacy and safety data from completed clinical studies, three new HAE treatments have recently been approved by the Food and Drug Administration: nanofiltered plasma-derived C1INH for prophylactic therapy, pasteurized plasma derived C1INH for acute therapy, and ecallantide for acute therapy. Two other promising therapies, recombinant C1INH and icatibant, are in various stages of the U.S. regulatory process. The medical management of HAE is entering a new era with the availability of safe, effective condition-specific treatments. Clinicians should consider a number of patient- and medication-specific factors when designing individualized treatment plans for HAE patients. PMID- 21262094 TI - Update on preventive therapy (prophylaxis) of hereditary angioedema. AB - The prophylaxis of patients with hereditary angioedema to prevent attacks has gone through major revision as new agents for prophylaxis have come on the market. Earlier treatments, developed empirically, included the fibinolysis inhibitors epsilon aminocaproic acid and tranexamic acid and attenuated androgens such as danazol. With the development of these agents, many patients had relief of severe symptoms, and drugs in these classes have been the only treatments available in America. Their major disadvantage has been their side effects, which range from minor to severe. In Europe various products containing C1 inhibitor, the serum protein deficient in this disease, were prepared from pooled donor plasma. They were reported to be effective in ending attacks and in prophylaxis, but these products in general were not used in prophylaxis, in part because of the short half life of the plasma protein. One such product, C1 esterase inhibitor, has now been shown in a rigorous double-blind study to be effective in prevention of hereditary angioedema attacks and has been approved by the US Federal Drug Administration for prophylaxis of the disease. Its use has been attended by few side-effects, reflecting the fact that it is the purified naturally circulating product. PMID- 21262095 TI - Efficacy of intranasal corticosteroids for the ocular symptoms of allergic rhinitis: A systematic review. AB - Current treatment options for allergic rhinoconjunctivitis include topical antihistamines, vasoconstrictors, mast cell stabilizers, intranasal corticosteroids (INCS), and nonsteroidal anti-inflammatory drugs that are generally used as a supplement to oral or intranasal therapies, necessitating the use of multiple treatments for the different symptoms of allergic rhinitis (AR). To assess the efficacy of INCS for ocular symptoms (OS) of AR. A search was performed of clinical trials (n = 32) from 1973 to 2009 of English articles (Medline, Embase, and PubMed) using "intranasal corticosteroid," "allergic rhinitis," "ocular symptoms," "allergic conjunctivitis," and "rhinoconjunctivitis" as key words. Quality assessment for the 32 eligible studies was performed using the Jadad score. Statistical analysis for continuous data was done by weighted mean difference or standardized mean difference. Thirty two trials were included and separated into three different groups. The overall weighted mean was obtained from the Jadad score and came out to 9.29 (95% CI, 8.7 9.88). For meta-analysis for total OS scores and individual symptoms (10 parallel studies) the weighted mean was 10.17 (95% CI, 9.34-11). In the parallel studies, meta-analysis of individual symptoms (nine studies) gave a weighted mean of 10.09 (95% CI, 9.55-10.63). For eye symptoms but no individual symptoms (13 studies), the weighted mean was 8.56 (95% CI, 7.66-9.46). To date, clinical studies conducted statistically showed the efficacy of INCS on the OS of AR as evidenced by the meta-analysis results for the studies reporting total OSs. PMID- 21262097 TI - Mast cell and eosinophil activation during early phase of grass pollen-induced ocular allergic reaction. AB - Both mast cells and eosinophils were implicated in the pathophysiology of allergic conjunctivitis; however, the potential role of eosinophils in an early phase of allergic reaction has not been elucidated. The aim of this study was to assess the relation between clinical symptoms and sequence of mast cells and eosinophils specific mediators release into tear fluid during conjunctival allergen provocation. Patients with grass pollen rhinoconjunctivitis (n = 38) and healthy volunteers (n = 10) were challenged with increasing doses of allergen applied on the conjunctiva. The clinical symptoms were assessed by clinical score. Tear fluid was collected from 12 patients before provocation, at 20 and 40 minutes after positive response. Tryptase and eosinophil cationic protein (ECP) were measured using UniCap and 15-hydroxyeicosanoid acid (15-HETE) with a specific immunoassay. All allergic patients (but no control subjects) had a positive clinical response to the challenge. In 1 patient symptoms appeared after 50 BU/mL of grass allergen administration, in 3 patients symptoms appeared after 500 BU/mL (7.9% of patients), in 14 patients symptoms appeared after 1600 BU/mL (36.8%), and in 20 patients symptoms appeared after 5000 BU/mL (52.6%). The allergen dose was not correlated with the skin-prick test diameter. The mean tryptase concentration increased at 20 minutes from "nondetectable" to 5.89 +/- 1.97 micrograms/L and then decreased to 1.77 +/- 1.07 micrograms/L (n = 12; p < 0.05) at 40 minutes. ECP concentration was not changed at 20 minutes but increased at 40 minutes from 1.38 +/- 0.98 micrograms/L before provocation to 10.61 +/- 7.78 micrograms/L (n = 7; p < 0.05). There was no change in 15-HETE release. Both mast cells and eosinophils are activated during allergic reaction in conjunctiva and activation of eosinophils is preceded by activation of mast cells. PMID- 21262096 TI - Hereditary angioedema: Validation of the end point time to onset of relief by correlation with symptom intensity. AB - Time to onset of symptom relief in hereditary angioedema (HAE) is a common primary end point in clinical studies but it has never been validated by correlation with the course of HAE symptoms. This study was designed as a retrospective validation of the primary end point for a placebo-controlled phase II/III study in patients with HAE. Ninety-eight abdominal attacks were treated with 10 or 20 U/kg of a highly purified C1 esterase inhibitor (C1-INH) concentrate or placebo. The primary end point was the time to onset of symptom relief, as determined by the patients. Patients assessed the intensity of the symptoms of pain, nausea, vomiting, cramps, and diarrhea over time. By Spearman rank correlation, the primary end point was compared with the time to first reduction of (1) any symptom intensity, (2) the sum of symptom intensity scores, and (3) the intensity of the last symptom present at baseline. The C1-INH, 20 U/kg, and placebo groups were compared by one-sided two-sample Wilcoxon tests. The time to first reduction in intensity of the last symptom present at baseline had the highest correlation with the primary end point (r = 0.77). The time to onset of symptom relief and the time to the first reduction in intensity of the last symptom were significantly shorter for the C1-INH, 20 U/kg, group compared with placebo (p = 0.009 and p = 0.0036, respectively). The association with the intensity of single symptoms confirmed that the time to onset of symptom relief is an appropriate end point for assessing the efficacy of C1-INH therapy. PMID- 21262098 TI - Is response to allergen immunotherapy a good phenotypic marker for differentiating between allergic rhinitis and mixed rhinitis? AB - This study was designed to determine if patients with allergic rhinitis (AR) and mixed rhinitis (MR) subtypes have similar treatment outcomes after a full course of allergen immunotherapy (AIT). A historical pre- and posttreatment study design was used to identify all AR patients in a large allergy practice who started AIT in 2001 and completed at least a 3-year course. One reviewer compiled data through chart review using a standardized form that recorded allergic and nonallergic irritant triggers, symptoms, and medication requirements before and after completion of >=3 years of AIT. Other than age, there were no significant differences in baseline demographic characteristics, allergic triggers, or rhinitis symptoms between the AR and MR groups. Both groups experienced reduced episodes of sinusitis after AIT. Although both groups also had a significant decrease in the mean number of rhinitis medications after AIT (p < 0.001), the reduction in number of medications was significantly greater for the AR versus the MR group (1.24 +/- 1.09 versus 2.09 +/- 1.55; p = 0.0023). AIT is a very effective treatment for AR and MR patients. However, these data support the classification of MR as a distinct rhinitis phenotype because MR patients required significantly more medications after a full course of AIT to control their nonallergic-induced symptoms. PMID- 21262099 TI - Recruitment factors which affect the outcome of a seasonal allergic rhinitis trial. AB - Although intranasal corticosteroids (INSs) are the first-line treatment for seasonal allergic rhinitis (SAR), some patients do not respond adequately, reflecting biological heterogeneity or confounding conditions. The objective of this study was to determine what recruitment factors identify SAR subjects who will be unresponsive to mometasone furoate (MF). We performed a 2-week, double blind, placebo-controlled, parallel study on 40 subjects with SAR. Each subject underwent a decongestant test using oxymetazoline. Baseline nasal symptoms, nasal peak inspiratory flow (NPIF) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores were recorded. Next, subjects were randomized to either 200 MUg of MF or placebo. Symptom diaries and NPIF measurements were completed twice daily. After 2 weeks, subjects repeated the RQLQ and the global assessment of symptoms. There was a significant reduction in symptoms in the MF group compared with placebo (p <= 0.05) in patients with baseline total symptom scores of >=6. Multivariate analysis showed that treatment (MF versus placebo; p = 0.049) and amount of decongestion (percent change in NPIF after oxymetazoline; p = 0.008) predicted the improvement in total nasal symptoms. In clinical trials, SAR subjects must report multiple symptoms to be responsive to treatment with INSs. Our results also support the use of the decongestant test for choice of appropriate study volunteers, both to ensure participation of potentially responsive subjects and to eliminate those with confounding issues. PMID- 21262100 TI - The nature of melon allergy in ragweed-allergic subjects: A study of 1000 patients. AB - Previous studies suggest cross-reactivity between specific ragweed pollen and melon allergens. This study was designed to clarify the origin of the cross reactivity between ragweed pollen and the gourd family. One thousand ragweed allergic subjects were interviewed about the presence of oral allergy syndrome (OAS) induced by melon or watermelon and were divided into reactive to <=3 seasonal allergen sources or >3 seasonal allergen sources. Patients reporting melon and/or watermelon allergy underwent a skin-prick test (SPT) with fresh melon and, after 2006, also with profilin-enriched date palm pollen extract. Because no IgE reactivity to melon extract was detected in vitro, ELISA was performed using date palm pollen extract, and inhibition experiments were performed using grass pollen, date palm profilin, and bovine serum albumin (BSA) as inhibitors. Six hundred forty-six and 354 subjects reacted to <=3 seasonal allergens or >3 seasonal allergens, respectively; 4/646 (1%) and 81/354 (23%) reported a history of melon/watermelon-induced OAS (p < 0.0001). Forty-three of 46 (93%) melon reactors scored positive on SPT with the profilin-enriched extract, which was positive in 0/2 (0%) versus 43/44 (98%) reactive to <=3 or >3 seasonal allergen sources, respectively (p < 0.0001). in vitro, serum from melon allergic subjects showed a strong IgE reactivity to the profilin-enriched date palm pollen extract, which was abolished by preabsorption with both grass pollen extract and date palm pollen extract, but not by BSA. In ragweed pollen-allergic subjects, melon allergy is most likely associated with cross-sensitization to the plant pan-allergen profilin and not to specific ragweed pollen allergens. This study confirms the association between profilin sensitization and melon allergy. PMID- 21262101 TI - Association between subcutaneous abdominal fat and airway hyperresponsiveness. AB - Epidemiological studies have shown that obesity is significantly associated with airway hyperresponsiveness (AHR). The aim of this study was to determine the effect of abdominal fat distribution on the prevalence of AHR. This study was conducted on subjects who visited the Seoul National University Hospital Gangnam Center from October 2003 to January 2009. Medical records of 3205 subjects who had both a methacholine bronchial provocation test and an abdominal CT scan were retrospectively reviewed. One hundred sixty-one subjects with AHR and their 161 controls were selected for the analysis. Total, subcutaneous, and visceral abdominal fat were objectively measured by an abdominal CT scan. Both body mass index (BMI) and waist circumference were significantly associated with AHR after adjustment for smoking (BMI: OR, 1.20; 95% confidence interval [CI], 1.07-1.35; waist circumference: OR, 1.07; 95% CI, 1.02-1.11). Total and subcutaneous abdominal fat increased the risk of AHR with an OR of 1.47 (95% CI, 1.08-2.02) in the case of total abdominal fat, and an OR of 1.99 (95% CI, 1.19-3.31) in the case of subcutaneous abdominal fat. However, visceral abdominal fat was not associated with AHR. The association between subcutaneous abdominal fat and AHR was consistent, especially in men. Subcutaneous abdominal fat was significantly associated with AHR, but visceral abdominal fat was not. These results suggest a possible role for subcutaneous fat on the later development of asthma. PMID- 21262102 TI - Cardiopulmonary arrest in a patient with delayed diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. AB - We present the case of a 21-year-old male patient with a history of autoimmune nephritis, peripheral eosinophilia, eosinophilic esophagitis, and enteropathy who developed subacute worsening cardiomyopathy with systolic dysfunction. Diagnostic studies revealed a one-codon deletion in the FoxP3 gene, which led to the diagnosis of immune dysregulation polyendocrinopathy, enteropathy X-linked syndrome. Unfortunately, this patient suffered from cardiopulmonary arrest with resulting anoxic encephalopathy before diagnosis confirmation. Here, we discuss the key issues surrounding the diagnostic and therapeutic approaches to this patient's condition. PMID- 21262103 TI - A fatal anaphylactic reaction to paclitaxel is described, which was preceded by a possible delayed reaction to the initial infusion. PMID- 21262104 TI - Deafness: malaria as a forgotten cause. AB - BACKGROUND: Ototoxicity from antimalarials is a well publicised cause of deafness and a great deal of time and resources are spent assessing it in relation to new drugs. The effect of the malaria parasite itself on hearing is, however, poorly documented and most evidence is anecdotal. This paper aims to collate existing evidence of this association. METHODS: Two systematic literature searches were performed on Ovid Medline, first for 'malaria' and 'hearing loss' or 'hearing impairment' or 'deafness', and secondly for 'cerebral malaria' and 'neurologic' or 'neurological' or 'neurocognitive sequelae'. The articles were then individually studied for relevance. RESULTS: Malaria has been implicated as a rare cause of hearing loss in various studies, but recommendations and hypotheses have not been taken seriously or investigated. Searches also returned numerous studies of neurological sequelae after cerebral malaria, a small proportion of which observed hearing impairments on follow-up. However, no attempt was made to distinguish between treatment and disease as the cause. A few antimalarial drug trials which assessed hearing before treatment found unexplained hearing loss which improved with elimination of the parasite. CONCLUSION: Evidence from this review suggests that the falciparum parasite is a potential cause of hearing loss. Malaria is a disease of such high prevalence that even if only a small proportion of survivors develop this impairment the effects on children's education could be detrimental. More attention should be focussed on investigating this association as the clinical and pathophysiological implications are potentially considerable. PMID- 21262105 TI - Perinatal tuberculosis. PMID- 21262106 TI - Clinical manifestations and outcome in HIV-infected young infants presenting with acute illness in Durban, South Africa. AB - OBJECTIVES: In young infants, early development of symptomatic HIV infection increases the risk of morbidity and mortality. A prospective study was conducted over a 1-year period in a region with a high burden of HIV in order to describe the clinical presentation of HIV infection in infants aged between 0 and 59 days on attendance at hospital and the factors associated with the need for urgent hospital management. METHODS: Sick young infants presenting to the King Edward VIII Hospital, Durban between February 2003 and January 2004 were enrolled. After systematic evaluation by a primary health worker, an experienced paediatrician determined the primary diagnosis and need for urgent hospital management. Comparisons of these assessments were stratified by HIV status. Children were classified as HIV-uninfected (HIV ELISA-negative), HIV-exposed-but-uninfected (HIV ELISA-positive and HIV RNA PCR-negative), HIV-infected (HIV ELISA-positive and HIV viral load >400 copies/ml). RESULTS: Of 925 infants enrolled, 652 (70.5%) had their HIV status determined: 70 (10.7%) were HIV-infected, 271 (41.6%) HIV exposed-but-uninfected, and 311 (47.7%) HIV-uninfected. Factors associated with an increased probability of being HIV-infected included if the mother had children from more than one sexual partner, if the infant had had contact with a tuberculosis-infected person or if the HIV-infected mother and/or her exposed infant failed to receive nevirapine prophylaxis. Signs of severe illness were more frequently encountered in HIV-infected than in HIV-exposed-but-uninfected infants, including the prevalence of chest in-drawing (20.3% vs 8.8%, p = 0.004) and severe skin pustules (18.6% vs 8.6%, p = 0.01). Among infants requiring urgent hospital management, observed or reported feeding difficulties and severe skin pustules were more common in HIV-infected than uninfected infants. More HIV infected infants (12.9%) required hospitalisation than those who were HIV-exposed but-uninfected (7.7%) or uninfected (7.4%). Primary diagnoses of pneumonia, sepsis or oral thrush were more frequently seen in HIV-infected than exposed-but uninfected or HIV-uninfected children. CONCLUSION: Early recognition and triaging of infants suspected of having HIV infection provides an opportunity for early diagnosis and treatment which could prevent the adverse impact of rapidly progressive HIV disease. PMID- 21262107 TI - A preliminary examination of the effects of genetic variants of redox enzymes on susceptibility to oedematous malnutrition and on percentage cytotoxicity in response to oxidative stress in vitro. AB - BACKGROUND: The causes of oedematous vs non-oedematous childhood malnutrition (OM vs NOM) remain elusive. It is possible that inherited differences in handling oxidant stressors are a contributing factor. AIMS: To test for associations between polymorphisms in five genes and (i) risk of OM, a case-control study, and (ii) percentage cytotoxicity in peripheral blood mononuclear cells (PBMCs) exposed to hydrogen peroxide (H(2)O(2)), an in vitro cell challenge study. METHODS: Participants had been admitted previously for treatment of OM (cases, n = 74) or NOM (controls, n = 50), or were an independent set of healthy pregnant women (n = 47) who donated peripheral blood mononuclear cells. We tested for associations between genetic variation and outcome using single markers or a bivariate score constructed by counting numbers of deleterious alleles for each of 15 possible pairs of markers. RESULTS: In the case-control study there were no significant single-marker associations with OM. We did find that higher bivariate scores were associated with OM for the pair of NAD(P)H:quinone oxidoreductase 1 and catalase (odds ratio 2.00, 95% CI 1.05-3.82). In the cell challenge experiments, there were no significant associations with percentage cytotoxicity. CONCLUSIONS: Variation in this small set of genes seems unlikely to have a large impact on either risk of OM or cytotoxicity after H(2)O(2) exposure. The use of larger sample sizes to test the effects of a much larger set of genetic variants will be required in order to determine whether genetic variation contributes to the risk of OM. Such studies have potential for improving our understanding of causal pathways in OM. PMID- 21262108 TI - Prevalence of rheumatic heart disease among school-children in Aden, Yemen. AB - BACKGROUND: Rheumatic heart disease (RHD) is an important contributor to cardiovascular disease in children and adults in Yemen. This is the first report to determine the prevalence of RHD among school-children in the city of Aden. METHODS: A cross-sectional case-finding survey of RHD was conducted in 6000 school-children aged 5-16 years. Echocardiography was undertaken in those with clinical signs of organic heart disease. RESULTS: The prevalence of RHD was 36.5/1000 school-children, which is one of the highest reported among school echocardiography surveys in the world. RHD was more common in 10-16-year-old students. RHD was diagnosed in more than one member of the families of 53 (24.2%) of the children. Mitral regurgitation (MR) was detected in 49.8%, 26.6% had MR with mitral valve prolapse and 17.8% had combined MR and aortic regurgitation. Fifty-eight children were diagnosed with congenital heart disease (CHD), representing a prevalence of 9.7/1000. The main types of CHD were mitral valve prolapse, patent ductus arteriosus, atrial septal defect, pulmonary stenosis and aortic stenosis. Congenital mitral valve prolapse found in 36 children was three times more common in males than females. Children with RHD were more likely to be from low-income families with poor housing and greater overcrowding (49.3%, 39.3% and 64.8%) than children with CHD (44.8%, 32.8% and 48.3%, respectively). CONCLUSIONS: The high prevalence of RHD is a major public health problem in Yemen. Urgent screening surveys and an RHD prophylactic programme of appropriate management of group A beta-haemolytic streptococcal pharyngotonsilitis are required. PMID- 21262109 TI - Safety and efficacy of deferasirox in multitransfused Indian children with beta thalassaemia major. AB - BACKGROUND: Iron chelation is an important component of management of transfusion dependent patients with thalassaemia major. Deferasirox is a relatively new oral iron chelator and experience of its use in children is limited. AIM: To report experience with deferasirox in north Indian children with beta-thalassaemia major. METHODS: This prospective study included 40 patients with transfusion dependent beta-thalassaemia major. The patients were receiving deferiprone alone (37 patients) or deferiprone and desferrioxamine combination (three patients) before commencing deferasirox. Patients were clinically monitored every month. Information on side-effects including gastro-intestinal symptoms, skin rash or discoloration, jaundice and complaints regarding vision and hearing were obtained from patient records. Laboratory investigations included complete blood count and renal and liver function tests estimated at baseline and then every month. Serum ferritin level was estimated at baseline and then every 3 months. The initial dose of deferasirox was 20 mg/kg/body weight and was increased to 25 mg/kg if serum ferritin remained unchanged or increased 3 months after deferasirox therapy. RESULTS: Therapy with deferasirox in 40 children was well tolerated. Gastro-intestinal symptoms were the most common side-effects. Nausea, vomiting and abdominal pain were observed in 25%, 20% and 15% patients, respectively. Skin rashes were seen in 5% cases. We observed greyish-brown pigmentation of the skin in four (10%) children which has not been described before. A non-progressive rise in serum creatinine was observed in 16 (40%) patients. In the majority, however, serum creatinine remained within the normal range. Leucopenia, neutropenia and thrombocytopenia were not observed. None of the side-effects necessitated cessation of the drug therapy. Serum ferritin levels fell in 24 of 32 patients (75%) who received deferasirox for over 1 year from a mean (SD) 6323.37 (2756.5) MUg/L to 5458.91 (2301.2) MUg/L (p<0.05). CONCLUSIONS: Therapy with deferasirox is safe in paediatric patients with thalassaemia major. However, they should be carefully monitored for side-effects. PMID- 21262110 TI - The role of Helicobacter pylori infection in gastro-oesophageal reflux in Iranian children. AB - BACKGROUND: The relationship between Helicobacter pylori and gastro-oesophageal reflux disease (GORD) in children is controversial. AIM: To determine the role of H. pylori infection and GORD in children living in a region which is endemic for H. pylori infection. METHODS: A cross-sectional study was undertaken in 263 children aged 3-18 years, all of whom had symptoms of GORD and underwent upper gastro-intestinal endoscopy. H. pylori status was determined by conventional rapid urease test and Giemsa staining of antral and cardiac biopsies. Biopsies of the oesophagus and gastric mucosa were obtained from the lower oesophagus, the antrum and cardia according to standard protocol. RESULTS: Of the 263 patients, 81 (31.5%) had GORD and 162 (61.5%) had gastritis. There were 59 H. pylori infected patients (22.4%) and 204 were uninfected. H. pylori infection was detected in 52 (88.1%) of the antral and 10 (1.9%) of the cardiac biopsies. Three (5.1%) of the biopsies revealed infection of both antrum and cardia and in seven (11.8%) only the cardia was infected. The prevalence of H. pylori infection among patients with GORD (13/83, 15%) was significantly lower than in those without GORD (46/180, 26%) (OR 0.54, CI 0.27-0.93, p<0.05). The prevalence of H. pylori infection among those with gastritis (48/162, 30%) was significantly higher than in those without gastritis (11/101, 10.8%) (OR 3.44, CI 1.69-7.015, p<0.001). CONCLUSION: H. pylori infection might protect against GORD. PMID- 21262111 TI - Introduction of bubble CPAP in a teaching hospital in Malawi. AB - BACKGROUND: Continuous positive airway pressure (CPAP) is relatively inexpensive and can be easily taught; it therefore has the potential to be the optimal respiratory support device for neonates in developing countries. OBJECTIVE: The possibility of implementing bubble CPAP in a teaching hospital with a large neonatology unit but very limited resources was investigated. METHODS: A CPAP system was developed consisting of a compressor, oxygen concentrator, water bottle to control the pressure and binasal prongs. Neonates with birthweights between 1 and 2.5 kg with persistent respiratory distress 4 hours after birth were eligible for bubble CPAP. RESULTS: In the 7-week introduction period from 11 March until 27 April 2008, 11 neonates were treated with CPAP. Five of these neonates met the inclusion criteria and six neonates did not meet these criteria. Of the five neonates who received CPAP and met the inclusion criteria, three survived. The six infants who did not meet the inclusion criteria included three preterm infants with apnoea (all died), two with birthweights <1 kg (both died) and a firstborn twin (1.2 kg) who survived. No major complications of CPAP occurred. Bubble CPAP could be used independently by nurses after a short training period. CONCLUSION: Successful long-term implementation of CPAP depends on the availability of sufficient trained nursing staff. PMID- 21262112 TI - Myocardial ischaemia in sickle cell anaemia: evaluation using a new scoring system. AB - BACKGROUND: Sickle cell anaemia (SCA) is associated with recurrent multi-organ ischaemia and infarction. Myocardial ischaemia (MI) and infarction are increasingly recognised as features of SCA. The prevalence and severity of MI in children with SCA is not known. AIM: To evaluate the usefulness of a new scoring system based on the standard surface electrocardiogram (ECG) in determining the prevalence and severity of MI in children with SCA. METHOD: MI prevalence and scores derived from standard surface ECGs of 35 children with SCA aged 3-18 years who presented consecutively during 38 episodes of vaso-occlusive crisis (VOC) were compared with those of 40 age- and sex-matched SCA patients in the steady state and 40 anaemic non-SCA patients. In SCA subjects with VOC, ECG was repeated approximately 1 week and 4-8 weeks post crisis and the respective MI scores were compared with their intra-crisis ECG and those of the two other groups. RESULTS: Mean (SD) MI scores were significantly higher during vaso-occlusive crises [1.82 (0.20)] compared with the steady state [1.15 (0.15)] and non-SCA anaemic controls [1.13 (0.21)], p = 0.017. SCA patients in crisis were 5.5 (1.20-13.99) times more likely to have MI compared with non-SCA anaemic controls (p = 0.025). They were also 3.66 (1.05-12.74, p = 0.042) and 7.58 (1.31-43.92, p = 0.024) times more likely to have mild and significant MI, respectively. MI scores derived from the post-crisis ECGs were similar to those of steady-state SCA patients. CONCLUSION: ECG changes consistent with MI are common in children with SCA, especially during vaso-occlusive crises. Our proposed MI scoring system could be a useful screening tool for early detection of significant MI during crises, facilitating early institution of intervention. Further studies are needed to determine the specificity of the observed changes and to validate the proposed screening tool. PMID- 21262113 TI - Perinatal tuberculosis: four cases and use of broncho-alveolar lavage. AB - Despite the high prevalence of tuberculosis in adults and children, congenital and perinatal forms of tuberculosis are rare. Four patients with perinatal tuberculosis are described. Diagnosis was made by demonstration of acid-fast bacilli (AFB) on broncho-alveolar lavage (BAL) specimens (two cases), gastric aspirate smear (one case) and lymph node fine-needle aspirate (one case). All of the above specimens were subsequently positive on culture. Two infants died of progressive pulmonary failure, and one of the mothers died, despite the institution of anti-tuberculous therapy. BAL specimen examination for AFB is useful in the diagnosis of perinatal tuberculosis, especially in infants with smear-negative gastric aspirate. PMID- 21262114 TI - Perinatal tuberculosis: two unusual cases. AB - Two immunocompromised infants with perinatal tuberculosis are reported. Both presented with bilateral miliary mottling of the lungs. The first was a 4-month old boy with a history of prolonged administration of prednisolone. He had tuberculous meningitis. Diagnosis was confirmed by PCR in serum and CSF. His mother had tuberculous endometritis. The second was a 1-month-old boy with perinatal HIV infection. Diagnosis was made by PCR in serum. Both parents were HIV-infected and had open pulmonary tuberculosis. PMID- 21262115 TI - Auto-immune haemolytic anaemia concurrent with Plasmodium vivax infection: a case report. AB - A 7-month-old Myanmar boy was admitted with a 3-day history of fever. He was markedly pale and his temperature was 38.2 degrees C. Peripheral blood smear demonstrated Plasmodium vivax infection with spherocytosis and auto-agglutination of red blood cells. Haematocrit was 16% and reticulocyte count 14.9%. Direct and indirect antiglobulin tests were positive. Antibody analysis was positive for auto-antigen I. P. vivax malaria with auto-immune haemolytic anaemia (AIHA) was diagnosed. He was treated with chloroquine and primaquine for the P. vivax infection, and oral prednisolone for the AIHA. Because of the clinical symptoms of anaemia and mild dyspnoea, blood with the least incompatible red blood cells was transfused. The clinical symptoms and signs improved. At follow-up 3 and 7 weeks after treatment, his haematocrit, reticulocyte count and peripheral blood smear results were within normal limits. Prednisolone was then tapered and stopped. The patient has since been well with no detectable recurrence of AIHA. PMID- 21262116 TI - Exertional rhabdomyolysis after influenza A (H3N2) infection in a basketball player boy. AB - A 14-year-old professional basketball player developed symptoms of influenza which was subsequently confirmed to be caused by influenza A (H3N2). He was given a 5-day course of oseltamivir. Two days after completing the course, he resumed basketball and developed rhabdomyolysis associated with acute renal failure and disseminated intravascular coagulation. This appears to be the first report of exercise-induced rhabdomyolysis associated with influenza A (H3N2). PMID- 21262117 TI - Variation in the gut microbiota of laboratory mice is related to both genetic and environmental factors. AB - During recent years, the composition of the gut microbiota (GM) has received increasing attention as a factor in the development of experimental inflammatory disease in animal models. Because increased variation in the GM might lead to increased variation in disease parameters, determining and reducing GM variation between laboratory animals may provide more consistent models. Both genetic and environmental aspects influence the composition of the GM and may vary between laboratory animal breeding centers and within an individual breeding center. This study investigated the variation in cecal microbiota in 8-wk-old NMRI and C57BL/6 mice by using denaturing gradient gel electrophoresis to profile PCR-derived amplicons from bacterial 16S rRNA genes. Comparison of the cecal microbiotas revealed that the similarity index of the inbred C57BL/6Sca strain was 10% higher than that of the outbred Sca:NMRI stock. Comparing C57BL/6 mice from 2 vendors revealed significant differences in the microbial profile, whereas the profiles of C57BL/6Sca mice raised in separate rooms within the same breeding center were not significantly different. Furthermore, housing in individually ventilated cages did not lead to intercage variation. These results show that denaturing gradient gel electrophoresis is a simple tool that can be used to characterize the gut microbiota of mice. Including such characterizations in future quality control programs may increase the reproducibility of mouse studies. PMID- 21262118 TI - Endpoints in myelin-deficient (MD) rats. AB - Health problems in some animal models remain unexplained, rendering in vivo studies ethically challenging, especially when experimental animals are prone to sudden death. Over the last 3 decades, the myelin-deficient (md) rat, a strain with severe dysmyelination due to mutant proteolipid protein, has been key to important discoveries in mechanisms of myelination and glial cell biology. The usefulness of this mutant rat, however, has been limited by sudden death during the fourth week of life. Timely euthanasia has been difficult because the cause of these mortalities remains unexplained and the endpoint not determined. In this clinicopathologic study, we determined that sudden onset of hindlimb paralysis inevitably leads to paralysis of the urinary bladder and then breathing difficulties because of severe injury to the spinal cord in the midthoracic region with concurrent narrowing of the vertebral canal due to fracture of a vertebral body. Sudden onset of hindlimb paralysis likely is related to seizures and severe muscle spasms that begin to occur at the end of the third week of life. Once seizure activity begins, we recommend frequent monitoring of md rats for hindlimb paralysis and distention of the urinary bladder as indication of endpoints mandating prompt euthanasia. PMID- 21262119 TI - Dark-phase light contamination disrupts circadian rhythms in plasma measures of endocrine physiology and metabolism in rats. AB - Dark-phase light contamination can significantly disrupt chronobiologic rhythms, thereby potentially altering the endocrine physiology and metabolism of experimental animals and influencing the outcome of scientific investigations. We sought to determine whether exposure to low-level light contamination during the dark phase influenced the normally entrained circadian rhythms of various substances in plasma. Male Sprague-Dawley rats (n = 6 per group) were housed in photobiologic light-exposure chambers configured to create 1) a 12:12-h light:dark cycle without dark-phase light contamination (control condition; 123 MUW/cm(2), lights on at 0600), 2) experimental exposure to a low level of light during the 12-h dark phase (with 0.02, 0.05, 0.06, or 0.08 MUW/cm(2) light at night), or 3) constant bright light (123 MUW/cm(2)). Dietary and water intakes were recorded daily. After 2 wk, rats underwent 6 low-volume blood draws at 4-h intervals (beginning at 0400) during both the light and dark phases. Circadian rhythms in dietary and water intake and levels of plasma total fatty acids and lipid fractions remained entrained during exposure to either control conditions or low-intensity light during the dark phase. However, these patterns were disrupted in rats exposed to constant bright light. Circadian patterns of plasma melatonin, glucose, lactic acid, and corticosterone were maintained in all rats except those exposed to constant bright light or the highest level of light during the dark phase. Therefore even minimal light contamination during the dark phase can disrupt normal circadian rhythms of endocrine metabolism and physiology and may alter the outcome of scientific investigations. PMID- 21262120 TI - Left ventricular hypertrophy is prevalent in Sprague-Dawley rats. AB - Unrecognized cardiovascular abnormalities may confound the interpretation of research data collected using rats. However, although SPF rat colonies are screened for microbes and kept under standardized environmental conditions, their cardiovascular status is largely unknown. We recently performed surgery on anesthetized 80-d-old Sprague-Dawley rats and observed a high mortality that could not be attributed to the procedures or preceding treatments. Upon necropsy, cardiomyopathy was readily apparent in a substantial proportion of these rats. To further evaluate the nature of this condition, we evaluated the histology and morphology of hearts from both Sprague-Dawley and Lewis rats. Compared with Lewis rats, Sprague-Dawley rats had greater left ventricular wall thickness and larger cardiomyocyte cell size. Severe left ventricle hypertrophy was present in 38% of young adult Sprague-Dawley rats. These findings may have implications for research models that use Sprague-Dawley rats. PMID- 21262121 TI - A nonlethal young domesticated ferret (Mustela putorius furo) model for studying pandemic influenza virus A/California/04/2009 (H1N1). AB - Recent events have heightened the need for the rapid development of vaccines directed against pandemic influenza H1N1 viruses circulating during 2009 to 2010. The current study was conducted to establish a virus challenge dose for a subsequent CA/04 vaccine efficacy study in 3-mo-old domesticated ferrets. An additional consideration in using CA/04 in ferrets is the selection of endpoints on which to base the challenge dose, given the potential nonlethality of this particular model. Four doses ranging from 10(4) to 10(7) TCID(50) units of CA/04 per animal were administered by intranasal instillation to groups of male and female ferrets, and virus titers in nasal washes obtained 1, 3, and 5 d thereafter were determined in MDCK cells. Dosed ferrets developed clinically mild infections. Peak virus titers occurred on day 3 after instillation regardless of dose. Virus-treated ferrets had less weight gain than did untreated ferrets. In conclusion, 3-mo-old ferrets can be infected with doses as low as 10(4) TCID(50) units of CA/04, and virus titers in nasal washes and decreased body weight gain can be used to assess the course of nonlethal infection of 3-mo-old ferrets by CA/04. PMID- 21262122 TI - Small intestinal permeability and serum folate and cobalamin absorption after surgical construction of permanent jejunal fistulas in laboratory beagle dogs. AB - Permanent jejunal fistulas enable easy, noninjurious, repeated and direct administration to and collection from the small intestines of conscious laboratory dogs. This study aimed at identifying potential alterations in the small intestinal morphology and function of this canine model after the surgery required to establish the fistulas. Assays of serum folate and cobalamin and (51)Cr-EDTA permeability tests were performed before and 4 wk after experimental jejunoplasties in 14 laboratory beagle dogs. Serum folate concentrations (mean +/ SD) before (12.22 +/- 1.80 MUg/L) and after (14.14 +/- 1.70 MUg/L) jejunal surgery were within reference ranges for healthy dogs, although folate concentrations were higher after surgery. The cobalamin concentrations and the 6 h urinary excretion of (51)Cr-EDTA before (573.50 +/- 150.04 ng/L and 6.75 +/- 1.56%, respectively) and after (496.71 +/- 164.22 ng/L and 6.41 +/- 1.10%) were normal for healthy dogs, and no significant differences between pre- and postsurgical values were detected. The findings of the present study indicate that the small intestinal vitamin absorption and permeability of laboratory beagle dogs with jejunal fistulas remains unimpaired. PMID- 21262123 TI - Morphometric comparison of the lumbar cancellous bone of sheep, deer, and humans. AB - To investigate the feasibility of using deer and sheep as animal models for the human spine, we compared the microarchitectural dimensions of the deer and sheep spines and with human data. To this end, we adopted the traditional bone tissue morphometric method, using figure analysis software for quantitative analysis of 2D images of bone tissue. Compared with those of humans, the lumbar cancellous bone of deer and sheep has higher microarchitectural indices, more densely packed bone trabeculae, lower porosity, and higher bone mass. Despite specific differences in various morphologic indices, the anisotropy of lumbar cancellous bone in deer and sheep shows the same trend as that in humans. PMID- 21262125 TI - Thoracic radiography as a refinement methodology for the study of H1N1 influenza in cynomologus macaques (Macaca fascicularis). AB - Recent advances in the technology associated with digital radiography have created new opportunities for biomedical research applications. Here we evaluated the use of thoracic radiography as a noninvasive refinement methodology for the cynomologus macaque (Macaca fascicularis) model of H1N1 infection. Thoracic radiographic evaluations of macaques infected with any of 3 strains of emerging H1N1 swine-associated influenza virus isolated during the recent pandemic were compared with those of macaques infected with the currently circulating Kawasaki strain of H1N1 influenza. Ventrodorsal, right, and left lateral thoracic radiographs were obtained at days 0, 1, 6, 8, 11, and 14 after infection. A board certified veterinary radiologist who was blinded to the study design evaluated the images. Numeric scores of extent and severity of lung involvement assigned to each radiograph were compared and demonstrated a significant and substantial difference among groups. The radiographic evaluation allowed for noninvasive assessment of lung involvement, disease onset, progression, and resolution of radiographic changes associated with H1N1 influenza infection. PMID- 21262124 TI - Experimental induction of reduced ovarian reserve in a nonhuman primate model (Macaca fascicularis). AB - Chronic diseases including coronary heart disease and osteoporosis represent a substantial health burden to postmenopausal women, yet the initiation of these conditions and their relationships with reproductive aging remain poorly understood. This situation is due, in part, to the lack of animal models reflecting ovarian and hormonal characteristics of peri- and postmenopausal women. Ovaries of women approaching menopause are nearly depleted of primordial follicles but retain a pool of larger developing follicles and androgen-producing stroma, a condition known as reduced ovarian reserve (ROR). The long-term goal of the research presented here was to create a monkey model of reproductive aging, beginning with ROR and progressing to perimenopause and finally postmenopause. Here we sought to develop a method to reduce primordial follicles in cynomolgus monkeys (Macaca fascicularis) and document hormonal changes associated with follicle reduction or ROR. At 30 d after surgical placement of a biodegradable fiber containing approximately 200 mg of 4-vinlycyclohexene diepoxide (VCD) next to one ovary in each of 8 monkeys, primordial follicles were reduced by approximately 70%, with a corresponding decrease (83%) in antimullerian hormone (AMH, a serum marker of ovarian follicle numbers). At 4 mo after VCD-treatment of both ovaries in 29 monkeys (approximately 200 mg VCD per ovary), AMH was reduced 56% from baseline, testosterone was unchanged, and follicular phase estradiol was slightly increased. These data indicate that VCD treatment markedly reduced primordial follicles while preserving larger estradiol- and testosterone producing follicles and ovarian stroma, a condition that mimics ROR in women. PMID- 21262126 TI - Radiographic incidence of spinal osteopathologies in captive rhesus monkeys (Macaca mulatta). AB - Degenerative spinal disease is a leading cause of chronic disability both in humans and animals. Although widely seen as a normal occurrence of aging, degenerative spinal disease can be caused by various genetic, iatrogenic, inflammatory, and congenital factors. The objective of this study was to characterize the degenerative spine-related diseases and the age at onset in a random subpopulation of 20 captive rhesus monkeys (Macaca mulatta; male, 13; female, 7; age: range, 4 to 27 y; median, 18.5 y). Spinal radiographic evaluation (left lateral, right lateral, and ventrodorsal views) of the spinal column (C1 to S1) was performed, and spinal degenerative disease was scored. The incidence of osteopathology was higher in the 14- to 18-y-old group, but incidence did not differ according to sex. In the studied population, degenerative changes were present in monkeys as young as 9 y of age. PMID- 21262127 TI - Inbred and outbred mice have equivalent variability in a cockroach allergen induced model of asthma. AB - Outbred mice traditionally are considered to display high variability, thereby limiting their use in some studies. Researchers frequently are encouraged to use inbred strains of mice because of the greater homogeneity of these experimental animals. We compared the pulmonary inflammatory response of inbred BALB/cJ mice to that of outbred HSD-ICR mice by measuring multiple variables, including cytokines, chemokines, number of pulmonary inflammatory cells, and respiratory parameters. Cockroach allergens induced significant pulmonary inflammation in both BALB and ICR mice. Our comparisons of the coefficients of variance for 148 discrete data sets for each strain or stock indicated that BALB and ICR mice have roughly equivalent intrastrain or -stock variability in our model of asthma-like pulmonary inflammation. The average coefficient of variance, calculated as the ratio of the SD to the mean of a data set, was 0.35 +/- 0.34 for BALB mice compared with 0.31 +/- 0.32 for ICR mice. In conclusion, inbred BALB and outbred ICR mice have roughly equivalent intrastrain or -stock variability in a murine model of asthma-like pulmonary inflammation. PMID- 21262128 TI - Assessment of rpoB and 16S rRNA genes as targets for PCR-based identification of Pasteurella pneumotropica. AB - Diagnosis of Pasteurella pneumotropica in laboratory animals relies on isolation of the organism, biochemical characterization, and, more recently, DNA-based diagnostic methods. 16S rRNA and rpoB gene sequences were examined for development of a real-time PCR assay. Partial sequencing of rpoB (456 bp) and 16S rRNA (1368 bp) of Pasteurella pneumotropica isolates identified by microbiologic and biochemical assays indicated that either gene sequence can be used to distinguish P. pneumotropica from other members of the Pasteurellaceae family. However, alignment of rpoB sequences from the Pasteurella pneumotropica Heyl (15 sequences) and Jawetz (16 sequences) biotypes with other Pasteurellaceae sequences from GenBank indicated that although rpoB DNA sequencing could be used for diagnosis, development of diagnostic primers and probes would be difficult, because the sequence variability between Heyl and Jawetz biotypes is not clustered in any particular region of the rpoB sequence. In contrast, alignment of 16S rRNA sequences revealed a region with unique and stable nucleotide motifs sufficient to permit development of a specific fluorogenic real-time PCR assay to confirm P. pneumotropica isolated by culture and to differentiate Heyl and Jawetz biotypes. PMID- 21262129 TI - Pharmacologic characteristics of bladder micturition function in anesthetized mice. AB - In the present study, we observed the effects of an alpha(1)-adrenoceptor agonist (phenylephrine), beta-adrenoceptor agonist (isoprenaline), muscarinic cholinoceptor agonist (carbachol), and alpha(1)-adrenoceptor antagonist (doxazosin) on the bladder micturition function in anesthetized mice. Changes in bladder pressure in response to filling and blood pressure were recorded by using a data acquisition system. Phenylephrine (50 to 800 MUg/kg) increased vesical micturition pressure in a dose-dependent manner but increased micturition basal pressure only at 800 MUg/kg. Carbachol (3 to 7 MUg/kg) increased the intercontraction interval and micturition time in a dose-dependent manner but increased micturition basal pressure only at 7 MUg/kg. Isoprenaline (10 to 1000 MUg/kg) increased micturition time and decreased vesical micturition pressure in a dose-dependent manner. Doxazosin (10 to 1000 MUg/kg) did not affect bladder micturition function but dose-dependently inhibited phenylephrine-induced increases in vesical micturition pressure. Carbachol (7 MUg/kg) and isoprenaline (1 mg/kg) caused a transient fall in blood pressure, whereas doxazosin (1 mg/kg) had a long-lasting hypotensive effect. The maximal decrease in systolic and mean blood pressure by carbachol did not differ from that by doxazosin and isoprenaline, respectively. Phenylephrine (800 MUg/kg) transiently increased the blood pressure of anesthetized mice. These results indicate that activation of muscarinic cholinoceptors decreases voiding frequency and increases bladder capacity in anesthetized mice. Activation of alpha(1)-adrenoceptors mainly increases vesical micturition pressure, whereas activation of beta-adrenoceptors decreases vesical micturition pressure and prolongs micturition time in anesthetized mice. PMID- 21262130 TI - Electrocardiography as a tool for validating myocardial ischemia-reperfusion procedures in mice. AB - This paper evaluates the modifications induced by ischemia and ischemia reperfusion in mice after permanent or transient, respectively, ligation of the left coronary artery and establishes a correlation among the extent of ischemia, electrocardiograph features, and infarct size. The left coronary artery was ligated 1 mm distal from the tip of the left auricle. Histologic analysis revealed that 30-min ischemia (n = 9) led to infarction involving 9.7% +/- 0.5% of the left ventricle, whereas 1-h ischemia (n = 9) resulted in transmural infarction of 16.1% +/- 4.6% of the left ventricle. In contrast, 24-h ischemia (n = 8) and permanent ischemia (n = 8) induced similarly sized infarcts (33% +/- 2% and 31.8% +/- 0.7%, respectively), suggesting ineffective reperfusion after 24-h ischemia. Electrocardiography revealed that ligation of the left coronary artery led to ST height elevation (204 compared with 14 MUV) and QTc prolongation (136 compared with 76 ms). Both parameters rapidly normalized on reperfusion, demonstrating that electrocardiography was important for validating correct ligation and reperfusion. In addition, electrocardiography predicted the severity of the myocardial damage induced by ischemia. Our results show that electrocardiographic changes present after 30-min ischemia were reversed on reperfusion; however, prolonged ischemia induced pathologic electrocardiographic patterns that remained even after reperfusion. The mouse model of myocardial ischemia-reperfusion can be improved by using electrocardiography to validate ligation and reperfusion during surgery and to predict the severity of infarction. PMID- 21262131 TI - Urinary biomarkers for monitoring disease progression in the Han:SPRD-cy rat model of autosomal-dominant polycystic kidney disease. AB - The Han:SRPD-cy rat is a well-recognized model of human autosomal-dominant polycystic kidney disease. The disease is characterized by the development of progressive renal cysts, leading to declining renal function. Disease progression typically is monitored by measurement of plasma urea concentration. Although plasma urea may be an adequate measure of overall renal function, urinary biomarkers capable of accurately monitoring disease progression may be equally useful. The goal of this study was to assess several urinary biomarkers as potential markers of disease progression in male and female Han:SPRD-cy rats. These biomarkers were compared with changes in plasma urea concentration and morphometric changes as the disease progressed. Urinary activity of N-acetyl-beta D-glucosaminidase and concentration of alpha-glutathione S-transferase were measured as markers of proximal tubular dysfunction, glutathione S-transferase Yb1 as a distal tubular marker, and collagen IV as a biomarker for glomerular lesions. Urinary albumin was used as biomarker of glomerular or proximal tubular lesions. Albuminuria increased in male rats as the disease progressed, correlating with increasing plasma urea and morphologic changes. Urine concentrations of alpha-glutathione S-transferase decreased significantly in the male heterozygotic compared with wildtype rats in the later stages of the disease. Urinary concentrations of glutathione S-transferase Yb1 and collagen IV and activity of N-acetyl-beta-D-glucosaminidase did not change during disease progression. Measurement of urinary albumin and concentrations of alpha glutathione S-transferase may be useful for monitoring disease progression in the male Han:SPRD-cy rat model in future experiments. PMID- 21262132 TI - Fecal dehydroepiandrosterone (DHEA) immunoreactivity as a noninvasive index of circulating DHEA activity in young male laboratory rats. AB - Evidence suggests that dehydroepiandrosterone (DHEA) plays a key role in stress and coping responses. Fecal sampling permits assessment of hormone-behavior interactions reliably and effectively, but no previous study has compared circadian- or stress-dependent alterations between serum DHEA and its fecal metabolites. In the current study, young (28 d of age) male rats were assigned to either an experimental (n = 6) or control (n = 6) group. Rats in the experimental group were exposed to a forced swim test to assess their behavioral and physiologic response to an environmental stressor; blood samples were drawn before the test (baseline), immediately after the test, and at 2 later time points. Only fecal samples were collected from control animals. Fecal DHEA and corticosterone metabolites were monitored in all animals for 24 h. DHEA metabolites in control rats exhibited significant diurnal variation, showing a similar temporal pattern as that of corticosterone metabolites. In addition, fecal and serum DHEA levels were highly correlated. Significant peaks in both DHEA and corticosterone metabolite levels were detected. These data suggest that measures of fecal DHEA can provide a complementary, noninvasive method of assessing adrenal gland function in rats. PMID- 21262133 TI - Aerosolized Bacillus anthracis infection in New Zealand white rabbits: natural history and intravenous levofloxacin treatment. AB - The natural history for inhalational Bacillus anthracis (Ames strain) exposure in New Zealand white rabbits was investigated to better identify potential, early biomarkers of anthrax. Twelve SPF Bordetella-free rabbits were exposed to 150 LD(50) aerosolized B. anthracis spores, and clinical signs, body temperature, complete blood count, bacteremia, and presence of protective antigen in the blood (that is, antigenemia) were examined. The development of antigenemia and bacteremia coincided and preceded both pyrexia and inversion of the heterophil:lymphocyte ratio, an indicator of infection. Antigenemia was determined within 1 h by electrochemiluminescence immunoassay, compared with the 24-h traditional culture needed for bacteremia determination. Rabbits appeared clinically normal until shortly before succumbing to anthrax approximately 47 h after challenge or approximately 22 h after antigenemia, which suggests a relatively narrow therapeutic window of opportunity. To evaluate the therapeutic rabbit model, B. anthracis-exposed rabbits were treated (after determination of antigenemia and later confirmed to be bacteremic) intravenously with the fluoroquinolone antibiotic levofloxacin for 5 d at a total daily dose of 25 or 12.5 mg/kg, resulting in nearly 90% and 70% survival, respectively, to the study end (28 d after challenge). The peak level for 12.5 mg/kg was equivalent to that observed for a 500-mg daily levofloxacin dose in humans. These results suggest that intravenous levofloxacin is an effective therapeutic against inhalational anthrax. Taken together, our findings indicate that antigenemia is a viable and early biomarker for B. anthracis infection that can be used as a treatment trigger to allow for timely intervention against this highly pathogenic disease. PMID- 21262134 TI - Catheterization of intestinal loops in ruminants does not adversely affect loop function. AB - Catheterized intestinal loops may be a valuable model to elucidate key components of the host response to various treatments within the small intestine of ruminants. We examined whether catheterizing ileal loops in sheep affected the overall health of animals and intestinal function, whether a bacterial treatment could be introduced into the loops through the catheters, and whether broad spectrum antibiotics could sterilize the loops. Escherichia coli cells transformed to express the GFP gene were introduced readily into the loops through the catheters, and GFP E. coli cells were localized within the injected loops. Catheterized loops, interspaces, and intact ileum exhibited no abnormalities in tissue appearance or electrical resistance. Expression of the IFNgamma, IL1alpha, IL4, IL6, IL12p40, IL18, TGFbeta1, and TNFalpha cytokine genes did not differ significantly among the intact ileum, catheterized loops, and interspaces, nor did the expression of the gene for inducible nitric oxide synthase. Broad-spectrum antibiotics administered during surgery did not sterilize the loops or interspaces and did not substantively change the composition of the microbiota. However, antibiotics reduced the overall number of bacterial cells within the loop and the relative abundance of community constituents. We concluded that catheterization of intestinal loops did not adversely affect health or loop function in sheep. Furthermore, allowing animals to recover fully from surgery and to clear pharmaceuticals will remove any confounding effects due to these factors, making catheterized intestinal loops a feasible model for studying host responses in ruminants. PMID- 21262135 TI - Refinement of vascular access port placement in nonhuman primates: complication rates and outcomes. AB - Chronic vascular access is often needed in experimental animal studies, and vascular access ports (VAP) have been proposed as an alternative to conventional venipuncture. We previously reported on VAP implantation by using femoral venous cutdown (FVC) and tunneling. In an attempt to decrease the moderate complications associated with the FVC method, we developed the single-incision, peripheral insertion (SIPI) method. In a retrospective evaluation, 92 FVC procedures were compared with 113 SIPI procedures in cynomolgus and rhesus macaques and baboons with as much as 2.5 y of follow-up. The rate of complications was significantly lower for the SIPI method than for the FVC method (19.4% versus 33.7%), particularly in regard to infectious complications (8.0% versus 27.3%, respectively). In addition, VAP patency for blood sampling and fluid infusion was significantly better for the SIPI method than for the FVC method, with 1-y patency rate of 83% and 46%, respectively, and 2-y patency rate of 74% and 36%, respectively. Additional advantages of the SIPI method include the simplified implantation of the VAP and access in the homecage without any sedation or restraint after appropriate training of animals to cooperate. We conclude that the SIPI method presents an opportunity for refinement and is superior to the FVC method for chronic vascular access. PMID- 21262137 TI - [Angiogenesis imaging: the forward position of lung cancer image in the 21 century]. PMID- 21262136 TI - Blood D-(-)-3-hydroxybutyrate concentrations after oral administration of trioctanoin, trinonanoin, or tridecanoin to newborn rhesus monkeys (Macaca mulatta). AB - Premature newborn infants are born with limited stores of glycogen and fat. Energy, such as medium-chain triglycerides (MCT), which can spare the use of body protein as metabolic energy, may be beneficial. This study compares MCT containing C8, C9, or C10 fatty acids as oral sources of energy for newborn rhesus monkeys (Macaca mulatta). On day 1 of life, 4 groups of 5 monkeys were given a single dose of water or MCT by nasogastric tube. The dose provided approximately 80% of the expected energy requirement. Plasma C8:0, C9:0, and C10:0 fatty acids and whole-blood D-(-)-3-hydroxybutyrate (3HB) concentrations were measured at 0, 1, and 3 h after dosing. Concentrations of free fatty acids (C8, C9, or C10) and ketone (3HB) increased with time after the dose. At 1 and 3 h, concentrations of C8 and C9 did not differ, but C9 was greater than C10. At 1 h, blood 3HB concentrations due to C8 triglyceride were higher than C9 or C10 (503 versus 174 and 225 MUmol/L respectively). As MCT chain length increased from C8 to C10, blood concentration of 3HB decreased. Odd-chain MCT (C9 versus C8) resulted in lower whole-blood ketone (3HB), perhaps due to C9 metabolism or the rate of release or uptake of fatty acids. These results have implications for the use of MCT in nutritional supplements for preterm infants. PMID- 21262138 TI - [CT and MRI findings of cancerous invasion of the main pulmonary artery in lung cancer: the correlation with pathologic features and the value in making surgical plan]. AB - BACKGROUND: To study the correlation between CT/MRI features and surgical and pathological findings of cancerous invasion of the main pulmonary artery (CIMPA) in lung cancer and to evaluate the role of CT and MRI in making surgical plan. METHODS: CT findings in 15 cases and MRI findings in 13 cases were observed and blindly compared with surgical and pathological findings in this prospective study of 23 cases of central type lung cancer. RESULTS: The CT and MRI features showed as follows: the wall thickening sign in 73.7% of CT and 84.6% of MRI; lumen narrowing sign in 55.3% of CT and 69.2% of MRI; peri-vascular fat sign in 100.0% of both CT and MRI. Two types of CIMPA were visualized: contacted type (10 cases in CT and 7 cases in MRI) and encased type (5 cases in CT and 6 cases in MRI). Surgically, contacted type was found in 10 cases who all underwent lobectomy with sleeve-angioplasty. Encased type was found in 13 cases, among whom unresectable in 2, pneumonectomy in 7, and lobectomy with angioplasty in 4. Of the 21 resected specimen, the cancerous infiltration was demonstrated 100.0% (21/21) in adventitia, 66.7% (14/21) in media and 4.8% (1/21) in intima. There was no significant difference in the deepness of the cancer infiltration between the two types (P>0.05). Acute or chronic inflammatory infiltration which enhanced the thickening of the wall were shown on all specimens. CT and MRI findings were well corresponding to surgical and pathological appearance (Kappa value = 0.61 in CT and 0.84 in MRI). CONCLUSIONS: In our study of CIMPA, CT and MRI features characterized by wall thickening and lumen narrowing without occlusion are closely correlated with pathological findings that cancerous invasion prominently limited adventitia and media with remarkable proliferation of connective tissue, and classifying two types is valuable in making surgical plan. PMID- 21262139 TI - [Difference of microvessel structure between benign and malignant solitary pulmonary nodules and its relationship with CT enhancement level]. AB - BACKGROUND: To improve the differential diagnosis accuracy for solitary pulmonary nodules (SPNs), and to study the basis and mechanisms of enhancement by comparing with the microvessel constructions (microvessel density and basement membrane of microvessels) in SPNs. METHODS: Dynamic contrast enhancement CT scanning were performed in 38 peripheral lung cancer, 5 hamartoma and 10 inflammatory lesions which were less than 3 cm in diameter with Siemens Plus S or Marconi MX 8000 spiral CT scanner. The CT time-attenuation curves were interpreted. The microvessel density (MVD) and the basement membrane of microvessels of the resected specimens were observed with the ABC immuno-histochemical method in all patients. RESULTS: The CT contrasted value of lung cancer [(49.05+/-16.08) HU] and inflammatory lesions [(49.59+/-21.30) HU] were significantly higher than that of hamartoma [(8.98+/-4.56) HU] (t=7.48, P < 0.05; t=8.35, P < 0.05), but the enhancement of lung cancer was similar to that of inflammatory lesions (t=0.76, P > 0.05). The time-attenuation curve of inflammatory lesions tended to increase faster and reach a higher peak value than that of lung cancer, and both of them maintained a high plateau after crossing. The hamartoma showed a slight increase and demonstrated a low plateau curve. The MVD of SPNs was positively related to CT enhancement (r=0.805 1). The microvessel counts of peripheral lung cancer (48.45+/-10.09) and inflammatory lesions (49.60+/-19.94) were significantly higher than that of hamartoma (8.70+/-7.30) (t=11.64, P < 0.001; t=6.09, P < 0.001), but no significant difference was found between lung cancer and inflammatory lesions (t=-0.26, P=0.799). There was no any difference in continuity of basement membrane between nodules with enhanced CT less than 30 HU and higher than 30 U (Chi-square=3.13, P > 0.05). CONCLUSIONS: The microvessel counts mainly contribute to the enhancement of SPNs. The basement membrane is not related to nodule enhancement, but it might influence the pattern of time attenuation curve. PMID- 21262140 TI - [The value of MR dynamic time-resolved subtracted imaging in evaluating the blood supply by systemic artery in patients with lung cancer]. AB - BACKGROUND: To explore the application value of MR dynamic time-resolved subtracted imaging in qualitative and quantitative assessment of blood supply by systemic artery in patients with lung cancer. METHODS: A prospective study using MR FSPGR pulse sequence dynamic scan after contrast enhancement was undertaken in fifty-one patients with lung cancer which were proved by cytology or/and histology. The time-resolved subtracted imaging were acquired using the pre- and post-enhanced images in different phases of pulmonary circulation during the first-pass period (FPP) of contrast agent. The time-signal curves of FPP at four ROI placed on pulmonary artery (PA), descending aorta (DA), mass (M) and contralateral pulmonary parenchyma (PP), and the ST (start-time) and PT (peak time) of those four ROI were measured. The enhancement ratio of the signals of M/PP at PA/DA peak time (E MP , E MA , E PP , E PA ) were calculated. RESULTS: According to the time-resolved subtracted imaging during PA phase, intensity of the signal was low in 7 cases, medium in 2, but not enhanced in other 42 cases. All the 51 cancer masses were remarkably enhanced during DA phase. During FPP, the ST [(5.90+/-0.51)s] and PT [(12.75+/-0.67)s] of PP were slightly later than the ST [(4.19+/-0.43)s] and PT [(10.59+/-0.66)s] of PA, while the ST [(11.03+/ 0.80)s] and PT [(33.62+/-3.06)s] of cancer masses were later than ST [(9.43+/ 0.59)s] and PT [(19.81+/-4.14)s] of DA. E MA was significantly higher than E MP (91.47%+/-18.83% vs 15.38%+/-11.03%, P < 0.001), while E PP were remarkably higher than E PA (273.83%+/-48.60% vs 140.65%+/-24.40%, P < 0.001). CONCLUSIONS: MR dynamic time-resolved subtracted imaging is feasible to be a non-invasive technique in qualitative and relatively quantitative assessment of blood supply by systemic artery in patients with lung cancer. PMID- 21262141 TI - [Preliminary study on the dynamic enhanced multi-slice spiral CT in the evaluation of blood flow patterns of malignant solitary pulmonary nodules]. AB - BACKGROUND: To investigate the methods of dynamic enhanced multi-slice spiral CT in the evaluation of blood flow patterns of malignant solitary pulmonary nodules (SPNs). METHODS: Fifty-seven patients with malignant SPNs (<=4 cm) underwent dynamic multi-slice spiral CT (Marconi Mx8000) scan before and after contrast enhancement by injecting 90 ml contrast material with a rate of 4 ml/s. Twenty nine patients in protocol one were scanned every 2 seconds during 15-45 seconds and 75-105 seconds after injection, while 28 patients in protocol two were scanned every 2 seconds during 11-41 seconds and 71-101 seconds. All patients were then scanned every 30 seconds during 2-9 minutes. The collimation was 2.5 mm for lesions of <=3 cm and 5 mm for lesions of 3-4 cm. Standard algorithm was used in the image reconstruction. The perfusion, peak height, ratio of peak height of the SPN to that of the aorta and mean transit time were calculated. RESULTS: The enhancement value, perfusion, ratio of peak height of the SPN to that of the aorta and mean transit time were (34.61+/-11.37) HU, (31.17+/-11.18) ml/(min*100 g), 13.90%+/-4.15%, (13.96+/-5.86) s separately in protocol one, and (36.54+/ 10.89) HU, (29.80+/-8.80) ml/(min*100 g), 15.01%+/-4.83%, (13.34+/-5.12) s respectively in protocol two. No statistically significant difference was found between the two groups. In addition, mean transit time from all 28 patients in protocol two were obtained, but only part of them were measured in protocol one (22/29). CONCLUSIONS: Dynamic enhanced multi-slice spiral CT is a kind of non invasive method for quantitative evaluation of blood flow patterns of malignant solitary pulmonary nodules. It might have potential significance in angiogenesis research for lung cancer. PMID- 21262142 TI - [A preliminary application of MR dynamic time-resolved subtracted perfusion imaging to qualitative and partial quantitative evaluation of the blood supply by pulmonary artery in peripheral type lung cancer]. AB - BACKGROUND: To explore the application of MR time-resolved subtracted perfusion imaging to qualitatively and partially quantitatively evaluate blood supply by pulmonary artery in patients with peripheral type lung cancer. METHODS: Twenty three patients with peripheral type lung cancer proved cytologically or/and histologically underwent MR perfusion study. The time-resolved subtracted imaging which provided the perfusion images in different phases were performed. First pass time-signal intensity curves of pulmonary artery, descending aorta, lung mass were obtained respectively, and start-time and peak-time of them were compared. The signal enhanced ratio of the masses in pulmonary artery and aorta perfusion phases were calculated respectively. RESULTS: Fourteen masses began to enhance during pulmonary circulation phase and reached peak value during systematic-circulation phase, and the average signal change ratio during pulmonary circulation phase was much smaller than that during systematic circulation phase, indicating their blood supply came both from pulmonary and systematic blood circulation, but mainly from the latter. Seven masses began to enhance and reached peak value during systematic-circulation phase, indicating their blood supply came mainly from systematic blood circulation. Two masses began to enhance and reached peak value during pulmonary-circulation phase, indicating their blood supply came mainly from pulmonary blood circulation. CONCLUSIONS: MR dynamic time-resolved subtracted perfusion imaging is feasible to qualitatively and relatively quantitatively evaluate blood supply of pulmonary artery for peripheral type lung cancer. PMID- 21262143 TI - [CT features and anatomic distribution of pleural dissemination in lung cancer]. AB - BACKGROUND: To study the CT appearance of lung cancer combined with pleural dissemination and its anatomic characteristics. METHODS: CT findings of 32 cases of lung cancer with pleural dissemination proved by surgery and pathology were analyzed. RESULTS: The main CT manifestations were pleural effusion (24 cases), visceral pleural dissemination with nodules (10 cases), parietal pleural dissemination with nodules (16 cases), and pleural thickening (31 cases). Out of the cases with visceral pleural disseminations, nodules distributed on the lung surface in 9 sites, while on the interlobular pleura in 10 sites. Parietal pleural dissemination with nodules were found in 45 sites which located on the diaphragmatic pleura, the costal pleura, the mediastinal pleura, and the pulmonary ligament. The diameters of the small nodules ranged from 2 to 5 mm, and the large nodules from 5 to 10 mm. There were direct invasion with tumor induced pleural thickening in 10 cases, while indirect invasion in 21 cases. In the later cases, 9 cases had parietal pleural thickening less than 10 mm, 4 circumferential pleural thickening, 5 mediastinal pleural involvement thickening, and 3 pulmonary ligament thickening. CONCLUSIONS: Pleural effusion is the main manifestation of lung cancer combined with pleural dissemination. The CT features of lung cancer with pleural dissemination are the parietal and visceral pleural nodules, as well as the pleural thickening. The nodules are likely to distribute on parietal pleura of the diaphragmatic and the costal pleura, and they may transfer to the pulmonary ligament.The early small disseminating nodules are miliary in size, and only can be detected on the pulmonary window of chest CT scan. PMID- 21262144 TI - [The relationship among CT appearances and dynamic enhancement and microvessel density of peripheral lung cancer]. AB - BACKGROUND: To investigate the relationship among the CT appearances, the dynamic CT enhancement and the microvessel density (MVD) of peripheral lung cancer. METHODS: Thirty-three patients with peripheral lung cancer proved by surgery and pathology underwent enhancement dynamic CT scan before operation, including 14 squamous cell carcinoma and 19 adenocarcinoma. The MVD was measured in resected tumor specimens with immunohistochemical method of LSAB. RESULTS: The MVD value of adenocarcinoma was significantly higher than that of squamous cell carcinoma (63.4+/-11.9 versus 50.2+/-16.3, P < 0.05). The MVD values were higher in junction zone and interstitial areas than those in parenchymal areas, necrotic zones and scar areas of tumors. There were significant relationships among the MVD value and diameter of tumor, lobulation sign, vessel convergence sign, pleural retraction sign and lymph node metastasis (P < 0.05 ). The mean enhanced CT values was (43.4+/-11.8) HU in adenocarcinomas, and (34.6+/-10.7) HU in squamous cell carcinomas (P < 0.05). The CT values of both adenocarcinoma and squamous cell carcinoma had positive correlations to their corresponding MVD values (r=0.719, P < 0.01;r=0.819, P < 0.01). CONCLUSIONS: The CT appearances and the enhanced CT values of peripheral lung carcinomas are closely related to their MVD values, which might be an indicator to identify the histological classification and to predict the malignant degree of tumor. PMID- 21262145 TI - [A study on the pericancerous tissue and vascular changes in non-small cell lung cancer with high-resolution CT]. AB - BACKGROUND: To investigate the CT changes of pericancerous tissues with high resolution CT (HRCT) and to explore the specific signs of CT in non-small cell lung cancer. METHODS: Thirty-one patients with non-small cell lung cancer and 12 patients with benign pulmonary nodules were analysed. An attention was paid on bronchovascular bundles, vessels and interlobular septa. HRCT films were read independently by two radiologists and results were statistically Chi-square tested. RESULTS: In the cancer group, 20 cases (64.5%) had thickening of bronchovascular bundles, 15 cases (48.4%) angiectasis of superior lobular arteries, 13 cases (41.9%) angiectasis of superior lobular veins, 16 cases (51.6%) thickening of interlobular septa, and 5 cases (16.1%) ground-glass opacity. In benign pulmonary lesion group, the values were 2 (16.7%) , 1 (8.3%), 2 (16.7%), 6 (50.0%) and 5 (41.7%) cases respectively. Significant differences were found between the two groups in the thickening of bronchovascular bundles and the angiectasis of superior lobular arteries. CONCLUSIONS: Thickening of bronchovascular bundles and angiectasis of superior lobular arteries are the specific signs of non-small cell lung cancer. PMID- 21262146 TI - [The staging of pulmonary angiography with the multi-slice spiral CT: to evaluate its significance in cancerous invasion of central pulmonary artery in lung cancer]. AB - BACKGROUND: To explore the possibility of the staging of pulmonary angiography with multi slice spiral CT (MSCT) and to evaluate its value in making surgical plan for patients with lung cancer. METHODS: MSCT with two-segment injection and three-protocol scan was performed in 73 patients with central type lung cancer. According to the site and degree, the involvement of pulmonary artery was divided into three grades and blindly compared with the surgery and pathology. RESULTS: MSCT in 68 cases (93.15%, 68/73) was successfully performed. The involvement of central pulmonary artery was grade I in 4 cases (5.88%, 4/68), grade II in 9 (13.23%, 9/68), and grade III in 55 (80.88%, 55/68). All patients with grade I underwent lobectomy. There was remarkable difference of lobectomy ratio between grade II and III (Chi-square=64.03, P < 0.005) and also between IIIa and IIIb (Chi-square=68.69, P < 0.005). All patients with grade IIIc were ruled out from surgery. CONCLUSIONS: The staging of pulmonary angiography by MSCT is useful to demonstrate the site and degree of involvement of central pulmonary artery and provides more precise evidence of images for making surgical plan. PMID- 21262147 TI - [A multicenter randomized phase II trial of domestic product of nrhTNF in the treatment of non-small cell lung cancer]. AB - BACKGROUND: To evaluate and compare the effects and toxicity of the domestic product of nrhTNF combined with chemotherapy in the trial group and chemotherapy alone in the control group in the treatment of patients with non-small cell lung cancer (NSCLC). METHODS: Ninety patients with NSCLC in multicenter were randomly devided into trial group and control group. Each group had 45 patients. Chemotherapy with CAP regimen was given for the patients in the trial group. Meanwhile, nrhTNF injection of 4*106U/m 2 was also given from the 1st to 7th days, the 11th to 17th days on the chemotherapy course. Twenty-one days were as a cycle, 2 cycles were given each patients. Chemotherapy alone with CAP regimen was given in the control group. The chemothepeutic effects and toxicity were observed and compared between the two groups after the therapy. RESULTS: Of the 90 patients, 3 cases in each group were out of the trial because of economy. The other 84 cases (each group had 42 patients) could be used to analyze and evaluate the clinical effects and toxicity. The response rate of chemotherapy was 47.62% (20/42) in the trial group and 19.05% (8/42) in the control group (P=0.002) respectively. The KPS was 85.02+/-10.74 in the trial group, and 81.35+/-9.63 in the control group (P=0.038). No significant difference of degree III+IV toxicity was observed between the trial group and control group (P > 0.05). The side effects related to nrhTNF included slight fever, cold like symptoms, pain, and red and swelling in injection site. All of them were mild and didn't need any treatment and disappeared after the therapy. CONCLUSIONS: The results demonstrate that the effects of domestic nrhTNF combined with chemotherapy can remarkably higher than that of chemotherapy alone in the treatment of NSCLC. It is able to increase the sensitivity to chemotherapy and improve the quality of life of the patients. The toxicity is also slight and is worth to expand clinical use, so as to further evaluate its effect and toxicity. PMID- 21262148 TI - [Expressions of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 and their correlation with metastasis and prognosis in lung cancer]. AB - BACKGROUND: To investigate the expressions of matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinase 1 (TIMP-1) and their correlation with metastasis and prognosis in human lung cancer. METHODS: Immunohistochemical S-P method was used to detect the expression of MMP-9 and TIMP-1 in 65 lung cancer tissues, 35 hyperplastic and dysplastic epithelium from patients with non cancerous pulmonary diseases, and 30 normal epithelial tissues of the lung. RESULTS: The positive expression rates of MMP-9 in normal tissue, hyperplastic or dysplastic epithelium, and lung cancer tissue were 16.7%(5/30), 42.9%(15/35) and 72.3%(47/65) respectively, whereas the positive rates of TIMP-1 expression in normal tissue, hyperplastic or dysplastic epithelium, and lung cancer tissue were 6.7%(2/30), 28.6%(10/35) and 50.8%(33/65) respectively. Significant differences of the expression rates of MMP-9 and TIMP-1 were found between lung cancer and normal groups, between lung cancer and hyperplasia groups, and between hyperplasia and normal groups (P < 0.05). Small cell carcinoma and adenocarcinoma had higher MMP-9 expression than squamous cell carcinoma (P < 0.025). Expression rate of MMP-9 had negative relation with cell differentiation of lung cancer (P < 0.05), and positive relation with TNM stage (P < 0.025). Between the survival time < 2 years group and >=2 years groups, both the expressions of MMP-9 and TIMP 1 had significant difference (P < 0.05 ). The expression of MMP-9 was closely related to metastasis of lung cancer (P < 0.005), but the expression of TIMP-1 was not related to metastasis. CONCLUSIONS: Overexpression of MMP-9 may appear in precancerous lesion and at the early stage of lung cancer. Activation of MMP-9 gene may be an important factor for oncogenesis of the lung. MMP-9 and TIMP-1 may play important roles in lung cancer invasion and metastasis, their overexpression could act as a reference to evaluate metastasis and unfavourable prognosis of lung cancer. PMID- 21262149 TI - [Expression of FLIP and its correlation with apoptosis in non-small cell lung cancer]. AB - BACKGROUND: To investigate the relation between FLIP expression and apoptosis in non-small cell lung cancer (NSCLC). METHODS: FLIP expression was examined in forty-eight paraffin-embeded NSCLC samples and 16 benign pulmonary disease tissues by immunohistochemistry method. Apoptosis of NSCLC cells was detected by TUNEL technique. RESULTS: The positive rate of FLIP expression in NSCLC was 83.33%(40/48), which was significantly higher than that in benign pulmonary disease tissues (P < 0.01). The expression level of FLIP was closely related to TNM stages and lymph node involvement, but not to histological classification and cell differentiation. No correlation was observed between the expression of FLIP and apoptosis index of tumor cells (r=-0.211,P > 0.05 ). CONCLUSIONS: Overexpression of FLIP may be involved in the progression of NSCLC, but its expression may not be related to cell apoptosis in NSCLC. PMID- 21262150 TI - [Analysis of the causes of misdiagnosis on CT films of 45 patients with lung cancer]. AB - BACKGROUND: To analyze the causes of computed tomographic misdiagnosis of pulmonary carcinoma. METHODS: From September 1991 to January 2002, 45 cases of pulmonary carcinoma misdiagnosed by CT were analyzed retrospectively. Twenty-six cases of pulmonary tuberculosis and 15 cases of pulmonary pneumonia misdiagnosed as pulmonary carcinoma by CT were studied as control subjects. All of these cases were confirmed by surgery and clinical course. The CT appearances of these cases were independently reviewed in a double blind method by three experienced radiologists. Then they discussed together in order to search for the factors of CT misdiagnosis and formed a consensus interpretation. RESULTS: Forty-five cases of pulmonary carcinoma were misdiagnosed as pulmonary tuberculosis in 19 cases, pneumonia in 14 cases, abscess in 4 cases, pleural mesothelioma in 2 cases, normal in 2 cases, and others in 4 cases. The fundamental manifestations of misdiagnosed cases were lobar or segmental shadows (26 cases), solitary mass or nodule (19 cases).The reasons of CT misdiagnosis were very confusing. The main factors were:(i) Missed diagnosis (2 cases, 4.5%). One case had an endobronchial mass and another had the erosion of rib. (ii) Twenty-four cases (53.3%) due to mis interpretation and lack of experience. (iii) The manifestations in CT were atypical (19 cases,42.2%). CONCLUSIONS: Not identifying accurately the CT appearances and excessively emphasizing the specificity of some signs are the main causes of the misdiagnosis. A reasonable and careful CT examination, summarizing analysis combined with clinical findings, and the accumulation of diagnostic experience will help to reduce the CT misdiagnostic rate of pulmonary carcinomas. PMID- 21262151 TI - [The metastatic pattern of thoracic lymph nodes in 306 patients with lung cancer]. AB - BACKGROUND: To study the metastatic pattern of thoracic lymph nodes in patients with resectable lung cancer. METHODS: From January 1992 to December 2000, radical lobectomy or pneumonectomy and systemic lymphadenectomy were performed in 306 patients with lung cancer. Number, size, colour and hardness of lymph nodes in each region were recorded and neoplastic metastasis was examined by pathology. RESULTS: Out of 4 614 resected lymph nodes from 2 456 regions, 954 lymph nodes from 521 regions were confirmed to have metastasis. The metastatic rates of thoracic lymph nodes and mediastinal lymph nodes were 61.8% and 43.5% , respectively. The metastatic frequencies in regions around the hilar or root of lung (11,10,7,5,4) were higher than those of regions far from the root of lung (9,6,3,2,1). There was a remarkably higher metastatic rate of lymph nodes in small cell lung cancer than that in non small cell lung cancer (P < 0.01 ). The metastatic rate was closely related to size, colour and hardness of lymph nodes (P < 0.001, P < 0.001 , P < 0.001 ). CONCLUSIONS: Most of neoplastic metastasis of lymph nodes spreads from proximal to distal areas, lower to upper regions, and from the hilar to the mediastinal. A few mediastinal lymph nodes show a skipping pattern. It is necessary to perform systemic lymphadenectomy during pulmonary resection. PMID- 21262152 TI - [MGMT expression and its relationship with efficacy of chemotherapy and prognosis in patients with non-small cell lung cancer]. AB - BACKGROUND: To study the expression of MGMT and its relationship with efficacy of chemotherapy and prognosis in patients with non-small cell lung cancer (NSCLC). METHODS: MGMT was detected in 128 NSCLC tissues and 10 normal pulmonary tissues by immunohistochemistry. According to the level of MGMT , 128 patients with NSCLC were divided into the group Mer- with negative MGMT expression and the group Mer+ with positive MGMT expression. RESULTS: MGMT positively expressed in 61 of 128 patients with NSCLC (47.66%), but none of normal group. No significant relationship was found among MGMT expression and TNM stages, lymph node metastasis and histological classification of the cancer. However, the mean survival periods and survival rates in group Mer- were significantly higher than those of group Mer+ (P < 0.01 , P < 0.05). In 45 evaluable patients, total response rates were 42.86% and 4.17% in Mer- and Mer+ patients respectively (P < 0.001); and there were remarkably longer mean survival periods and higher survival rates in Mer- patients than those in Mer+ patients (P < 0.01, P < 0.05). CONCLUSIONS: Expression of MGMT may be helpful to predict efficacy of chemotherapy and prognosis in patients with NSCLC. PMID- 21262153 TI - [Application of transbronchial needle aspiration in the bronchial submucosa]. AB - BACKGROUND: To explore the applicable value of transbronchial needle aspiration (TBNA) in the bronchial submucosa. METHODS: TBNA biopsy was performed in 76 cases of pulmonary diseases, which had no endoscopically visible pathologic change. The results of TBNA were compared with that of brushing for cytological examination. RESULTS: The correct diagnosis of the pulmonary diseases was 85.5% (65/76) for TBNA and 55.3%(42/76) for brushing cytology, and the correct diagnosis of lung cancer was 78.0%(39/50) for TBNA, 38.0% (19/50) for brushing cytology. Slight bleeding at the penestrated site was observed in 52 patients and there were no other severe complications. CONCLUSIONS: TBNA is a safe, simple and effective method in clinical application and could be used widely. PMID- 21262154 TI - [The role of surgery and multimodality therapy in the treatment of early-stage lung cancer]. PMID- 21262155 TI - [Immunohistochemical and ultrastructual study of so-called sclerosing hemangioma of the lung suggests different origins of cells]. AB - BACKGROUND: To study the morphological characteristics, immunohistochemical stain and histological origin of so-called sclerosing hemangioma of the lung (S-SH), and to investigate the significance and diagnostic value of expressions of surfactant protein B (SP-B), thyroid transcription factor-1 (TTF-1) and other markers in S-SH. METHODS: Using transmission electron microscope and immunohistochemistry methods, the expressions of SP-B, TTF-1, mast cell trypsin (MCT), epithelial antigen markers (CK-H, CK-L, EMA, CEA), mesothelial antigen (MC), neuroendocrine markers (NSE, Ch-A, synaptophysin, calcitonin, ACTH, GH), vimentin and CD34 were observed in 30 cases of S-SH. RESULTS: S-SH demonstrated a mixture of four histological patterns: solid, papillary, hemorrhagic and sclerotic pattern, which often showed transitional phenomena. Cuboidal cells on the surface, which contained short microvilli and lamellar bodies in cytoplasm, arranged in one row and sometimes interfused into multinuclear giant cells. Immunohistochemical results showed that these cells demonstrated strongly positive staining to SP-B, TTF-1, CK-L, EMA and CEA. The other major cell component-polygonal stromal cells were strongly positive to vimentin and TTF-1, and positive or weakly positive to 2 or 3 neuroendocrine markers in each case. Sparse neuroendocrine granulae and abundant microtubules were observed in cytoplasm of the cells. Both cuboidal and polygonal cells displayed negative immunohistochemical results to CD34 and MC. Some cell clusters in solid region were positive for SP-B and EMA. Mast cells which were positive for MCT existed sparsely in almost full vision field. CONCLUSIONS: Cuboidal cells of S-SH originate from reactive proliferating type II pneumocytes and sometimes interfuse into multinuclear giant cells. The polygonal cells in stroma probably originate from multipotential primitive respiratory epithelium and have multiple differentiating ability. The presence of mast cells is also one of histological characteristics of S-SH. PMID- 21262156 TI - [Combining SSH and cDNA microarray for identification of lung cancer related genes]. AB - BACKGROUND: To screen and identify differentially expressed genes among lung cancer tissues, paracancerous pulmonary tissues and some other kinds of tumor tissues using suppression subtractive hybridization (SSH) and cDNA Microarray. METHODS: One cDNA chip was made by gathering clones of three differentially expressed cDNA libraries which came from BEP2D cell lines during three different malignant transformed phases. Then the clones were hybridizated with cDNA probes which extracted from 15 cases of lung cancer tissues, 5 cases of paracancerous pulmonary tissues and 24 cases of other 8 kinds of tumor tissues respectively. RESULTS: Twenty-six cDNAs were obtained which expressed higher in lung cancer tissues than that in paracancerous pulmonary tissues. Thirty-one cDNAs expressed remarkably higher in paracancerous tissues than those in cancer tissues. Compared with other 8 kinds of tumors, paracancerous tissues had 63 overexpressed cDNAs and lung cancer tissues had 87 overexpressed cDNAs. CONCLUSIONS: The combination of SSH and cDNA microarray is rapid and effective for screening and identification of differentially expressed genes in different samples. It may be potentially useful for diagnosis of lung cancer to further study the differentially expressed genes among lung cancer tissues, paracancerous pulmonary tissues and other tumor tissues. PMID- 21262157 TI - [Cyclooxygenase-2, inducible nitric oxide synthase protein expression and vasculature during experimental rat lung carcinogenesis]. AB - BACKGROUND: To investigate the expression of cyclooxygenase-2 (COX-2) protein and inducible nitric oxide synthase (iNOS) protein during the experimental lung carcinogenesis in rats, as well as their association with microvessel density (MVD). METHODS: Diethylinitrosamine and 3-methylcholanthrene were instilled into the left lobar bronchus to induce lung squamous cell carcinoma in 88 Wistar rats, and 10 nomal rats as controls. COX-2, iNOS expression and MVD count of the specimens obtained from the rats were examined by immunohistochemistry. RESULTS: A total of 155 specimens of various pathological phase during the carcinogenesis were obtained: 14 hyperplasia, 25 squamous metaplasia, 33 dysplasia, 12 carcinoma in situ, 54 infiltration carcinoma, and 17 metastasis. The immunohistochemical score (IHS) of COX-2 significantly increased in dysplasia, carcinoma in situ and metastasis (P < 0.01,P < 0.05,P < 0.01). IHS of iNOS significantly increased in hyperplasia and metastasis (P < 0.05,P < 0.01 ). Remarkably increased MVD was found in carcinoma in situ, infiltration carcinoma and metastasis (P < 0.01, P < 0.01, P < 0.01). There was a positive correlation between COX-2 and iNOS (r=0.601 6,P < 0.001) expression. Expression of COX-2 or iNOS were remarkably related to MVD count (P < 0.01,P < 0.01) CONCLUSIONS: COX-2 and iNOS may play important roles in the carcinogenesis of experimental rat lung squamous cell carcinoma as well as its progress, and it may be associated with stimulating angiogenesis. PMID- 21262158 TI - [Study on clonal expression of T cells bearing dominant TCR Vbeta in non-small cell lung cancers]. AB - BACKGROUND: To investigate the distribution of TCR Vbeta subfamily T clonal cells in peripheral blood lymphocytes (PBL), tumor infiltrating lymphocytes (TIL) and lymphocytes in non-cancerous lung tissues of patients with non-small-cell lung cancer (NSCLC) and to see the inclination of the T cell antigen receptor (TCR) Vbeta subfamilies' expression. METHODS: Complimentarily determining region 3 (CDR3) of TCR 24 variable region genes was analyzed in PBL, TIL and lymphocytes in non cancerous lung tissues from 24 NSCLC cases with reverse transcriptase polymerase chain reaction (RT-PCR) and gene scan techniques to identify the distribution and clonality of TCR Vbeta subfamily T cells. RESULTS: Only a portion of Vbeta T cells were found in patients with NSCLC, whereas 24 TCR Vbeta subfamily T cells were detected in 10 healthy controls. Vbeta5 subfamily was expressed mostly in TIL and the frequency of Vbeta5 in TIL (6/18, 33.3%) was much higher than that of PBL (1/24, 4.2%) and T cells infiltrating non-cancerous lung tissues (0/12) (P < 0.05). Oligoc lonal T cells were found in 2 cases with Vbeta5 subfamily and polyclonal T cells in 4 cases. CONCLUSIONS: There are dominant and clonal TCR Vbeta subfamilies expressed in TIL of NSCLC patients, which may be the tumor associated antigens (TAA) specific. PMID- 21262159 TI - [The relationship between glycoconjugate expression on cell surface and histological classification of pulmonary tumors]. AB - BACKGROUND: To investigate the relationship between progressive development of mouse pulmonary tumors and expression of cell surface saccharide and to provide a theoretical basis for diagnosis of pulmonary benign and malignant lesions.. METHODS: A/J strain mice at 5 weeks of age were treated intraperitoneally with 20 methylcholanthrene, and 292 pulmonary lesions including 237 benign lesions (hyperplasia, alveolar adenoma, and papillary adenoma) and 55 malignant tumors (papillary adenocarcinoma) were obtained. The binding affinities of cells in normal respiratory epithelia and various proliferative lesions to four peroxidase conjugated lectins, Maclura pomifera agglutinin (MPA), Arachis hypogea agglutinin (PNA), Ricinus communis agglutinin (RCA), and wheat germ agglutinin (WGA) were examined. RESULTS: Cells of hyperplasias and alveolar adenomas showed fairly strong affinities to all the lectins. However, most of papillary adenoma cells and papillary adenocarcinoma cells lost their binding affinities to MPA, PNA, and RCA, but not to WGA. Between the benign and malignant lesions, there were significant differences in binding affinities of cells to MPA (Chi-square =46.89,P < 0.01), PNA (Chi-square =36.77,P < 0.01) and RCA (Chi-square=52.87,P < 0.01), but not to WGA (Chi-square=0.09,P > 0.05). CONCLUSIONS: According to the different complex glycoconjugates on cell surface of various pulmonary lesions, the binding affinities to MPA, PNA and RCA are quite different between the benign and malignant lesions. The detection of bindings is helpful to the differential diagnosis of the pulmonary benign and malignant lesions. PMID- 21262160 TI - [Detection of micrometastasis in lymph nodes of patients with non-small-cell lung cancer: its biological significance]. AB - BACKGROUND: To evaluate the biological significance of the lymphnode micrometastasis in non-small-cell lung cancer (NSCLC). METHODS: Ninety regional lymph nodes indicated to be tumor free by conventional histopathologic methods were taken from 39 patients who underwent pulmonary resection for NSCLC. CK immunohistochemical staining was used to detect the micrometastatic tumor cells in lymph nodes. Expressions of p53, p21(ras) and Ki67 in primary pulmonary lesions were also detected by immunochemical methods. RESULTS: Micrometastasis were found in 26 lymph nodes (28.89%) of 22 patients (56.4%). The proportion of patients with micrometastasis whose primary lesions had the expressions of p53, p21(ras) and Ki67 was higher than those without micrometastasis whose primary lesions had no expressions of p53, p21(ras) and Ki67. The proportion of patients with micrometastasis whose tumor size was more than and less than 3 cm was 55.6% and 58.3% respectively (P=1.000). CONCLUSIONS: Expressions of p53, p21(ras) and Ki67 in primary pulmonary lesions has certain relations with micrometastasis in lymph nodes. PMID- 21262161 TI - [Proliferation and identification of the dendritic cells from the peripheral blood of patients with lung cancer]. AB - BACKGROUND: To culture and proliferate dendritic cells from the peripheral blood of patients with lung cancer, to observe the morphologic and phenotypic characteristics of these cells and to lay a foundation for applying dendritic cells in the biotherapy of lung cancer. METHODS: The mononuclear cells isolated from peripheral blood of patients with lung cancer were cultured with the supplement of DCGF to generate dendritic cells. Tumor associated antigens were added into dendritic cell culture on the eighth day. The morphologic characteristics of those cells were observed with inverted or electron microscopes and the phenotypic figures were analyzed with FCM. RESULTS: A large number of mature dendritic cells were obtained from the peripheral blood of patients with lung cancer and showed specific morphologic and phenotypic characteristics. The specific antigen expressed as follows: CD80: 81.8%, HLA DR: 98.3%, CD86: 69.8%, CD1a: 19.7%, CD14: 83.1%. CONCLUSIONS: The mature dendritic cells can be obtained by culturing the peripheral blood of lung cancer patients, which lays the further foundation for clinical biotherapy of tumor. PMID- 21262162 TI - [A clinicopathologic study on neoadjuvant chemotherapy in the treatment of non small-cell lung cancer]. AB - BACKGROUND: To explore the clinicopathological changes of non-small cell lung cancer tissues after neoadjuvant chemotherapy with MVP (MMC+VDS+DDP) regimen and its concordance with clinical evaluation, and to study the clinical value of neoadjuvant chemotherapy. METHODS: A total of 84 patients with NSCLC were randomized into combinated therapy group (42 cases) and surgical group (42 cases). The combinated therapy group were given MVP regimen for 2 cycles before operation and 2-4 cycles after operation, however, the surgical group only received surgical treatment. The efficacy of preoperative chemotherapy were determined by pathologic examination under light microscope and electron microscope and clinical evaluation. RESULTS: Combinated therapy group showed various degrees of degeneration and necrosis of tumor cells, which was not found in surgical group. The overall response rate of neoadjuvant chemotherapy was 59.5% (25/42) by both pathological and clinical evaluation. The coincidence ratio of the two evaluation methods was 71.4% (Kappa value=0.407,P < 0.01). Between the two groups, there was a significant difference in total survival rate (P=0.047). And further analysis showed that survival rate was remarkably different in patients with stage III between the two groups (P=0.037), but not in those with stage I and II (P > 0.05). CONCLUSIONS: Degeneration and necrosis with fibrosis are the main pathological phenotypes of the primary lesion after induction chemotherapy, which can be showed by clinical evaluation to chemotherapy efficacy. The preoperative and postoperative adjuvant chemotherapy may be benefical to patients with stage-III NSCLC. PMID- 21262163 TI - [Trends in the epidemiology of lung cancer in Henan, China]. AB - BACKGROUND: To evaluate the epidemiological trends of lung cancer in Henan, China. METHODS: Cancer mortality data were collected from 1974 to 1999. The mortality trends of lung cancer were studied. Secular trend on lung cancer form 1974 to 2010 with regression used for spatial analysis. RESULTS: The data showed that lung cancer was the dominating cause of all cancer-related deaths in Henan. During the period of 1974 to 1999, marked changes took place in Henan in the mortality rate of lung cancer. Lung cancer mortality rates increased from 4.15 per 100 000 in the early seventies to 12.13 per 100 000 in the late nineties, lung cancer accounted for 5.09% of all cancer related deaths in the early seventies and 14.09% in the late nineties. In general, men had higher mortality rate than women, and urban area had higher mortality rates than rural area. The mortality rate for male and female would be about 25 per 100 000 and 15 per 100 000 respectively in 2010 if no intervention strategy was taken CONCLUSIONS: The overall age-adjusted mortality rate of lung cancer in Henan has increased during the past two decades, strengthening education for health is very important in cancer control. PMID- 21262164 TI - [Analysis of lung cancer incidence in Wuzhou city from 1981 to 2000]. AB - BACKGROUND: To investigate the incidence of lung cancer and the trend of the incidence in Wuzhou. METHODS: Based on the lung cancer patients' data collected in Wuzhou from 1981 to 2000, statistical analysis of the lung cancer incidence rates was performed, the lung cancer incidence rates for age-groups and for periods of time were calculated, and the incidence rates for different periods were compared. Using standard world populations the standardized incidence rates of lung cancer and the intercept standardized rate were also calculated. RESULTS: The lung cancer incidence rate was high in Wuzhou. The lung cancer accounted for 21.65% (1 264/5 838) of all cancers. From 1981 to 2000, the incidence rate of lung cancer in Wuzhou increased markedly (P < 0.001); the incidence rate for males increased by 88.43% from 25.33*10-5 to 47.37*10-5 ; the rate for females rose by 121.22% from 10.12*10-5 to 24.66*10-5 . So was the standardized incidence rate. The median age for the male was 64.5 years old, while the median age for the female was 65.6. 88.8% of the patients were in the age of 55-year-old or more CONCLUSIONS: The lung cancer incidence rate in Wuzhou is high, and the incidence is significantly increased. Therefore, preventing lung cancer is one of the main cancer prevention tasks in Wuzhou. PMID- 21262165 TI - [A clinical study on efficacy of gemcitabine and carboplatin versus paclitaxel and carboplatin in the treatment of advanced non-small cell lung cancer]. AB - BACKGROUND: To evaluate the efficacy and toxicity of gemcitabine and carboplatin (GC) versus paclitaxel and carboplatin (TC) in the treatment of non-small cell lung cancer (NSCLC). METHODS: A total of 64 patients with advanced NSCLC diagnosed by pathology were randomly divided into two groups. Gemcitabine and carboplatin were administrated to the patients in GC group (n=30), and paclitaxel and carboplatin in the TC group (n=34), 28 days as a cycle. All patients received at least two cycles. RESULTS: The overall response rate was 53.3% in the GC group and 58.8% in the TC group (P > 0.05). The main toxicities were well tolerated and consisted of leukopenia, nausea, vomiting and peripheral neuritis, which occurred more frequently in the TC group than in the GC group (P < 0.05). CONCLUSIONS: Both of the two regimens of gemcitabine plus carboplatin and paclitaxel plus carboplatin are feasible, well tolerated and effective in the treatment of NSCLC, and the former may be safer than the latter. PMID- 21262166 TI - [Comparison of navelbine plus ifosfamide and cisplatin versus ifosfamide plus cisplatin in the treatment of advanced non small cell lung cancer]. AB - BACKGROUND: To observe the efficacy and safety of navelbine (NVB) combined with ifosfamide (IFO) and cisplatin (DDP) (NIP regimen) and IFO plus DDP (IP regimen) for advanced non-small cell lung cancer (NSCLC). METHODS: One hundred and twenty patients with advanced NSCLC pathologically proved were randomly divided into group A (NIP regimen, n=60) and group B (IP regimen, n=60). RESULTS: In group A, 58 patients were evaluable. The response rates were 58.62%(34/58), 65.58%(17/26) and 53.12% (17/32) in whole group, untreated patients, and retreated patients, respectively. The median duration of survival was 11.3 months. One-year survival rate was 40.0%. In group B, 59 patients could be evaluated. The response rates were 40.68%(24/59), 63.33%(19/30) and 17.24%(5/29) in whole group, untreated patients, and retreated patients, respectively. The median duration of survival was 9 months and 1-year survival rate was 36.7%. There was no significant difference in objective response rate among all the patients and the patients with no prior treatment between the two groups ( P > 0.05, P > 0.05). However, among retreated patients, the response rate in group A was remarkably higher than that in group B ( P < 0.05). The main dose limiting toxicity was myelosuppression. Leukopenia at grade III+IV was significantly higher in the NIP arm than in the IP arm ( P < 0.05). CONCLUSIONS: NIP yields a higher response rate than IP does in retreated patients, with acceptable toxicity, which can be the first line regimen in the retreatment of advanced NSCLC. IP regimen showes a similar response rate and less toxicity in initial patients, compared with NIP regimen, so it might be considered a relevant regimen in initial patients with advanced NSCLC. PMID- 21262167 TI - [Vaccination of boys against HPV--yes/no?]. PMID- 21262168 TI - [Need of better preoperative staging of endometrial cancer]. AB - Endometrial cancer is one of the most frequent gynaecological cancers in Danish women. The staging of the cancer is done surgically in accordance with guidelines from the International Federation of Gynaecology and Obstetrics. The method has proven insufficient and unsuitable because treatment is frequently decided during surgery and the final staging is done by the pathologist when examining the specimen. Too many patients are over- or under-treated and there is a high demand for new diagnostic tools for preoperative staging of endometrial cancer. We have reviewed recent literature on the subject. PMID- 21262169 TI - [Clinically significant improvements in clinical microbiology]. AB - Technical developments have made several clinically significant improvements in clinical microbiology possible during the latest decade. DNA sequencing and mass spectrometry have dramatically changed accuracy and speed of the identification of bacteria. Polymerase chain reaction amplification of bacterial DNA and DNA sequencing have provided hitherto unseen opportunities for identification of non cultivable bacteria in clinical samples. Routine functional characterization of bacteria isolated from patients is constantly expanding. The changes benefit both individual patients and the understanding of bacterial pathology. PMID- 21262170 TI - [Aldosterone exacerbates chronic renal insufficiency]. AB - It is now clear that the synthesis of aldosterone (A) and the expression of the mineralocorticoid receptor also appear in the extra-adrenal tissues. Experimental studies have succeeded in showing the connection between A and the pathological mechanisms that appear in the development of chronic kidney diseases (CKD). Unfortunately, it is not currently possible to decide whether the effects of A are clinically relevant or not due to the lack of controlled trials. CONCLUSION: A very likely has a role in the development of CKD, although considerably more clinical investigation is needed. PMID- 21262171 TI - [New treatment options for primary immune thrombocytopenia]. AB - Primary immune thrombocytopenia (ITP)--formerly known as idiopathic thrombocytopenic purpura--is an autoimmune disorder characterized by immune mediated thrombocytopenia. The aetiology of ITP remains unknown, but studies have shown that multiple immunological mechanisms are involved in the pathogenesis of ITP. This article aims to provide an overview of current treatment options, with particular emphasis on new biological therapies: rituximab, a monoclonal anti CD20 antibody, and the thrombopoietin receptor agonists romiplostim and eltrombopag. PMID- 21262172 TI - [The pathogenesis of primary immune thrombocytopenia]. AB - Primary immune thrombocytopenia (ITP)--formerly known as idiopathic thrombocytopenic purpura--is an autoimmune disorder characterized by immune mediated thrombocytopenia. The aetiology of ITP remains unknown, but studies have shown that multiple immunological mechanisms are involved in the pathogenesis of ITP.This article aims to provide an overview of our knowledge of the pathogenesis of ITP. PMID- 21262173 TI - [Mobile CT at neurointensive sections--it is possible]. AB - Intrahospital transportation can be complicated and hazardous. Mobile computerized tomography (CT) of the head performed at the neurointensive care unit is a new technique that minimizes the need for transportation of unstable patients. Even small changes in physiological parameters can be detrimental for these patients and cause secondary injury and thus affect their prognoses. The portable CT scanner in the neurointensive care unit holds great potential, but the high price level may limit its use. PMID- 21262174 TI - [Good's syndrome with lymphopenia and neutropenia]. AB - Good's syndrome (GS) is a rare immunodeficiency complicating thymoma and characterized by absence of B-cells, hypogammaglobulinaemia and a reduced CD4 T cell level. Autoimmune neutropenia coexisting with GS is very unusual and carries a poor prognosis due to severe immunodeficiency. We report a case of a thymoma patient with GS and autoimmune neutropenia. Neutropenia disappeared on filgrastrim, prednisone and azathioprine treatment. However, the patient still suffers from GS and requires regular prophylactic immunoglobulin injections. On this treatment, the patient has survived for nine years. PMID- 21262175 TI - [Moyamoya]. AB - The disease moyamoya is rare in Europe, but it is seen more frequently in Japan and other Asian countries. Moyamoya is characterized by progressing occlusion of the cerebral arteries and secondary development of pathological collateral vessels induced by ischaemia. This case report describes a newly diagnosed patient with moyamoya, who was referred to a paediatric clinic because of headache and involuntary movements and sounds. Due to the rare occurrence of moyamoya, the purpose of this case report is to draw attention to its diagnosis with a view to achieving an early diagnosis of the disease. PMID- 21262176 TI - [Maternal post partum arteriovenous fistula with objective tinnitus]. AB - This case-report describes an otherwise healthy younger woman with post partum onset of objective pulsatile tinnitus. Neuroradiological examination revealed a dural fistula that was later closed using endovascular coiling technique, after which the patient's tinnitus disappeared. At 6-month follow-up the patient was symptom-free. This case report emphasises the importance of examining for objective tinnitus in patients complaining of tinnitus, as the causes of objective pulsatile tinnitus can frequently be treated successfully. PMID- 21262177 TI - [Metastasizing esthesioneuroblastoma]. AB - Esthesioneuroblastoma is a rare malignant tumour that originates from the olfactory region. Its incidence is about 0.4 per million per year. The most common symptoms include epistaxis, headache, nasal obstruction, hyposmia and eye symptoms. Diagnosis of this rare tumour is often delayed. We present a case in which a 61-year-old male was referred due to proptosis and loss of vision. Magnetic resonance imaging showed a tumour in the nasal cavity involving the orbit, the frontal lope of the brain and lymph nodes in the neck. The case was staged according to Kadish as a stage C. Surgery was performed and postoperative radiotherapy planned. PMID- 21262178 TI - [Adenocarcinoma in the terminal ileum in a patient with no previous history of Crohn's disease]. AB - We present a case of a 60-year-old man with no previous history of Crohn's disease who presented with abdominal pain and vomiting. X-ray examination of the abdomen showed obstructive ileus and the patient underwent emergency surgery. The resected terminal ileum was stenosed with characteristic changes of Crohn's disease. In the area of stenosis, dysplastic changes of the mucosa were present. In continuation of the dysplastic areas, a well-differentiated adenocarcinoma T3N0M0V0 was present. PMID- 21262181 TI - WHO publishes report on health and health inequalities based on data from the Eurostat Labour Force Survey. PMID- 21262182 TI - Secondary attack rate of pandemic influenza A(H1N1) 2009 in Western Australian households, 29 May-7 August 2009. AB - Understanding household transmission of the pandemic influenza A(H1N1)2009 virus, including risk factors for transmission, is important for refining public health strategies to reduce the burden of the disease. During the influenza season of 2009 we investigated transmission of the emerging virus in 595 households in which the index case was the first symptomatic case of influenza A(H1N1)2009. Secondary cases were defined as household contacts with influenza-like illness (ILI) or laboratory-confirmed influenza A(H1N1)2009, occurring at least one day after but within seven days following symptom onset in the index case. ILI developed in 231 of the 1,589 household contacts, a secondary attack rate of 14.5% (95% confidence interval (CI): 12.9-16.4). At least one secondary case occurred in 166 of the 595 households (a household transmission rate of 27.9%; 95% CI: 24.5-31.6).Of these, 127 (76.5%) households reported one secondary case and 39 (23.5%) households reported two or more secondary cases. Secondary attack rates were highest in children younger than five years (p=0.001), and young children were also more efficient transmitters (p=0.01). Individual risk was not associated with household size. Prophylactic antiviral therapy was associated with reduced transmission (p=0.03). The secondary attack rate of ILI in households with a confirmed pandemic influenza A(H1N1)2009 index case was comparable to that described previously for seasonal influenza. PMID- 21262184 TI - Two waves of pandemic influenza A(H1N1) 2009 in Wales--the possible impact of media coverage on consultation rates, April-December 2009. AB - In the United Kingdom, the influenza A(H1N1) 2009 pandemic had a distinct two wave pattern of general practice consultations for influenza-like illness (ILI). We describe the epidemiology of the influenza pandemic in Wales between April and December 2009 using integrated data from a number of independent sources: GP surveillance, community virology surveillance, hospital admissions and deaths, and media enquiries monitoring. The first wave peaked in late July at 100 consultations per 100,000 general practice population and attracted intensive media coverage. The positivity rate for the A(H1N1)2009 influenza did not exceed 25% and only 44 hospitalisations and one death were recorded. By contrast, the second wave peaked in late October and although characterised by lower ILI consultation rates (65 consultations per 100,000 general practice population) and low profile media activity, was associated with much higher positivity rates for pandemic influenza A(H1N1)2009 (60%) and substantially more hospital admissions (n=379) and deaths (n=26). The large number of ILI-related consultations during the first wave in Wales probably reflected the intensive media activity rather than influenza virus circulating in the community. Data from community surveillance schemes may therefore have considerably overestimated the true incidence of influenza. This has implications for the future interpretation of ILI surveillance data and their use in policy making, and underlines the importance of using integrated epidemiological, virological and hospital surveillance data to monitor influenza activity. PMID- 21262183 TI - Oseltamivir-resistant influenza viruses circulating during the first year of the influenza A(H1N1) 2009 pandemic in the Asia-Pacific region, March 2009 to March 2010. AB - During the first year of the influenza A(H1N1) 2009 pandemic, unprecedented amounts of the neuraminidase inhibitors, predominantly oseltamivir, were used in economically developed countries for the treatment and prophylaxis of patients prior to the availability of a pandemic vaccine. Due to concerns about the development of resistance, over 1,400 influenza A(H1N1) 2009 viruses isolated from the Asia-Pacific region during the first year of the pandemic (March 2009 to March 2010) were analysed by phenotypic and genotypic assays to determine their susceptibility to the neuraminidase inhibitors. Amongst viruses submitted to the World Health Organization Collaborating Centre for Reference and Research in Melbourne, Australia,oseltamivir resistance was detected in 1.3% of influenza A(H1N1) 2009 strains from Australia and 3.1% of strains from Singapore, but none was detected in specimens received from other countries in Oceania or south-east Asia, or in east Asia. The overall frequency of oseltamivir resistance in the Asia-Pacific region was 16 of 1,488 (1.1%). No zanamivir-resistant viruses were detected. Of the 16 oseltamivir-resistant isolates detected, nine were from immunocompromised individuals undergoing oseltamivir treatment and three were from immunocompetent individuals undergoing oseltamivir treatment. Importantly, four oseltamivir-resistant strains were from immunocompetent individuals who had not been treated with oseltamivir, demonstrating limited low-level community transmission of oseltamivir-resistant strains. Even with increased use of oseltamivir during the pandemic, the frequency of resistance has been low, with little evidence of community-wide spread of the resistant strains. Nevertheless, prudent use of the neuraminidase inhibitors remains necessary, as does continued monitoring for drug-resistant influenza viruses. PMID- 21262185 TI - Early spread of the 2009 influenza A(H1N1) pandemic in the United Kingdom--use of local syndromic data, May-August 2009. AB - Following the confirmation of the first two cases of pandemic influenza on 27 April 2009 in the United Kingdom (UK), syndromic surveillance data from the Health Protection Agency (HPA)/QSurveillance and HPA/NHS Direct systems were used to monitor the possible spread of pandemic influenza at local level during the first phase of the outbreak. During the early weeks, syndromic indicators sensitive to influenza activity monitored through the two schemes remained low and the majority of cases were travel-related. The first evidence of community spread was seen in the West Midlands region following a school-based outbreak in central Birmingham. During the first phase several Primary Care Trusts had periods of exceptional influenza activity two to three weeks ahead of the rest of the region. Community transmission in London began slightly later than in the West Midlands but the rates of influenza-like illness recorded by general practitioners (GPs) were ultimately higher. Influenza activity in the West Midlands and London regions peaked a week before the remainder of the UK. Data from the HPA/NHS Direct and HPA/QSurveillance systems were mapped at local level and used alongside laboratory data and local intelligence to assist in the identification of hotspots, to direct limited public health resources and to monitor the progression of the outbreak. This work has demonstrated the utility of local syndromic surveillance data in the detection of increased transmission and in the epidemiological investigation of the pandemic and has prompted future spatio-temporal work. PMID- 21262186 TI - Electronic real-time surveillance for influenza-like illness: experience from the 2009 influenza A(H1N1) pandemic in Denmark. AB - To enhance surveillance for influenza-like illness (ILI)in Denmark, a year-round electronic reporting system was established in collaboration with the Danish medical on-call service (DMOS). In order to achieve real-time surveillance of ILI, a checkbox for ILI was inserted in the electronic health record and a system for daily transfer of data to the national surveillance centre was implemented. The weekly number of all consultations in DMOS was around 60,000, and activity of ILI peaked in week 46 of 2009 when 9.5% of 73,723 consultations were classified as ILI. The incidence of ILI reached a maximum on 16 November 2009 for individuals between five and 24 years of age, followed by peaks in children under five years, adults aged between 25 and 64 years and on 27 November in senior citizens(65 years old or older). In addition to the established influenza surveillance system, this novel system was useful because it was timelier than the sentinel surveillance system and allowed for a detailed situational analysis including subgroup analysis on a daily basis. PMID- 21262187 TI - Hormones: a potential explanation for differences in response rates to therapy for chronic hepatitis C infection. PMID- 21262188 TI - Intranasal co-administration with the mouse zona pellucida 3 expressing construct and its coding protein induces contraception in mice. AB - The zona pellucida 3 (ZP3), an autoantigen, once used to develop contraceptive vaccine has been faced a safety issue. Avoiding its pathogenic T cell activation, we intranasally co-delivered the mZP3 DNA- and protein-based vaccines in mice and observed that a higher level of sIgA and IgG antibodies in vaginal washes, bronchoalveolar lavages and serum and yielded a lower level of fertility and mean litter size. Importantly, histological analysis showed that normal follicular developments of the infertile mice were not disrupted in the co-delivered group. Thus, the intranasal co-delivery may present a safe strategy for the development of contraceptive vaccine. PMID- 21262190 TI - Estradiol pretreatment attenuated nicotine-induced endothelial cell apoptosis via estradiol functional membrane receptor. AB - Cigarette smoking is highly associated with increased cardiovascular disease complications. The female population, however, manifests reduced cardiovascular morbidity. We define nicotine's effect upon human umbilical vein endothelial cells (HUVECs), determine whether estradiol might ameliorate endothelial dysfunction via its membrane estrogen receptor (mER), and attempt to elucidate the underlying mechanisms. Endothelial cells were pretreated with estradiol-BSA and measured resultant ion flux across the cells via the patch clamp technique to assess mER is functionality. Estradiol-BSA administration was associated with 30% decreased nicotine-induced apoptosis and also attenuated nicotine-activated phosphorylation of p38 and ERK. Pretreatment of estradiol-BSA triggered a low calcium influx, suggesting ahead low influx calcium played a critical role in the underlying protective mechanisms of estradiol. Furthermore, this estradiol-BSA protection against apoptosis remained effective in the presence of tamoxifen, an intracellular estrogen receptor (iER) inhibitor. Additionally, tamoxifen did not abolish estradiol-BSA's inhibitory effect upon p38 and ERK's activation, giving evidence to the obligatory role of p38 and ERK signaling in the estradiol-BSA's anti-apoptotic action via mER. Our study provides evidence that nicotine enhances endothelial cell apoptosis, but estrogen exerts anti-apoptotic effect through its functional membrane estrogen receptor. Clinically, the nicotine in cigarettes might contribute to endothelial dysfunction, whereas ambient estradiol may provide cellular protection against nicotine-induced injury through its functional membrane receptor via MAPK pathway downregulation. PMID- 21262191 TI - An enzymatic photometric assay for 2-deoxyglucose uptake in insulin-responsive tissues and 3T3-L1 adipocytes. AB - An enzymatic assay adapted to photometric analysis with 96-well microplates was evaluated for the measurement of 2-deoxyglucose (2DG) uptake in insulin responsive tissues and differentiated 3T3-L1 adipocytes. For in vivo measurements, a small amount of nonradiolabeled 2DG was injected into mice without affecting glucose metabolism. For photometric quantification of the small amount of 2-deoxyglucose 6-phosphate (2DG6P) that accumulates in cells, we introduced glucose-6-phosphate dehydrogenase, glutathione reductase, and 5,5' dithiobis(2-nitrobenzoic acid) to the recycling amplification reaction of NADPH. We optimized the enzyme reaction for complete oxidation of endogenous glucose 6 phosphate (G6P) and glucose in mouse tissues in vivo and serum as well as in 3T3 L1 adipocytes in vitro. All reactions are performed in one 96-well microplate by consecutive addition of reagents, and the assay is able to quantify 2DG and 2DG6P in the range of 5-80 pmol. The results obtained with the assay for 2DG uptake in vitro and in vivo in the absence or presence of insulin stimulation was similar to those obtained with the standard radioisotopic method. Thus, the enzymatic assay should prove to be useful for measurement of 2DG uptake in insulin responsive tissues in vivo as well as in cultured cells. PMID- 21262192 TI - Analysis of TPOX short tandem repeat locus with matrix-associated laser desorption/ionization time-of-flight-based restriction fragment mass polymorphism assay. AB - Short tandem repeat (STR) loci are routinely analyzed by capillary electrophoresis. However, this method has several disadvantages, including long operational time, low throughput, and inaccuracy. As a result of the introduction of matrix-associated laser desorption/ionization time-of-flight (MALDI-TOF) and electrospray ionization (ESI), mass spectrometry has become an alternative method for genotyping polymorphic STR loci. Here we established a restriction fragment mass polymorphism (RFMP) assay for genotyping STR locus, TPOX, by typeIIS restriction endonuclease cleavage of polymerase chain reaction (PCR) amplicon followed by MALDI-TOF mass spectrometry. The resulting TPOX genotypes from this assay were in good agreement with the results from direct DNA sequencing and GeneScan assays. Our results showed that the RFMP assay is an accurate and high throughput method for analyzing long DNA fragments such as STR markers. Further research with multiple STR loci may allow this assay to be used for diverse applications such as forensics, paternity tests, and detection of genetic disorders. PMID- 21262193 TI - Purification and characterization of cystathionine beta-synthase bearing a cobalt protoporphyrin. AB - Human cystathionine beta-synthase (CBS), a pivotal enzyme in the metabolism of homocysteine, is a pyridoxal-5'-phosphate-dependent enzyme that also contains heme, a second cofactor whose function is still unclear. One strategy for elucidation of heme function is its replacement with different metalloporphyrins or with porphyrins containing different substituent groups. This paper describes a novel expression approach and purification of cobalt CBS (CoCBS), which results in a high yield of fully active, high purity enzyme, in which heme is substituted by Co-protoporphyrin IX (CoPPIX). Metal content analysis showed that the enzyme contained 92% cobalt and 8% iron. CoCBS was indistinguishable from wild-type FeCBS in its activity, tetrameric oligomerization, PLP saturation and responsiveness to the allosteric activator, S-adenosyl-l-methionine. The observed biochemical and spectral characteristics of CoCBS provide further support for the suggestion that heme is involved in structural integrity and folding of this unusual enzyme. PMID- 21262194 TI - Temperature-pressure phase diagram of a heterogeneous anionic model biomembrane system: results from a combined calorimetry, spectroscopy and microscopy study. AB - By using Fourier transform infrared (FT-IR) spectroscopy in combination with differential scanning calorimetry (DSC) coupled with pressure perturbation calorimetry (PPC), ultrasound velocimetry, Laurdan fluorescence spectroscopy, fluorescence microscopy and atomic force microscopy (AFM), the temperature and pressure dependent phase behavior of the five-component anionic model raft lipid mixture DOPC/DOPG/DPPC/DPPG/cholesterol (20:5:45:5:25 mol%) was investigated. A temperature range from 5 to 65 degrees C and a pressure range up to 16 kbar were covered to establish the temperature-pressure phase diagram of this heterogeneous model biomembrane system. Incorporation of 10-20 mol% PG still leads to liquid ordered (l(o))-liquid-disordered (l(d)) phase coexistence regions over a wide range of temperatures and pressures. Compared to the corresponding neutral model raft mixture (DOPC/DPPC/Chol 25:50:25 mol%), the p,T-phase diagram is - as expected and in accordance with the Gibbs phase rule - more complex, the phase sequence as a function of temperature and pressure is largely similar, however. This anionic heterogeneous model membrane system will serve as a more realistic model biomembrane system to study protein interactions with anionic lipid bilayers displaying liquid-disordered/liquid-ordered domain coexistence over a wide range of the temperature-pressure plane, thus allowing also studies of biologically relevant systems encountered under extreme environmental conditions. PMID- 21262195 TI - The amyloidogenic SEVI precursor, PAP248-286, is highly unfolded in solution despite an underlying helical tendency. AB - Amyloid fibers in human semen known as SEVI (semen-derived enhancer of viral infection) dramatically increase the infectivity of HIV and other enveloped viruses, which appears to be linked to the promotion of bridging interactions and the neutralization of electrostatic repulsion between the host and the viral cell membranes. The SEVI precursor PAP(248-286) is mostly disordered when bound to detergent micelles, in contrast to the highly alpha-helical structures found for most amyloid proteins. To determine the origin of this difference, the structures of PAP(248-286) were solved in aqueous solution and with 30% and 50% trifluoroethanol. In solution, pulsed field gradient (PFG)-NMR and (1)H-(1)H NOESY experiments indicate that PAP(248-286) is unfolded to an unusual degree for an amyloidogenic peptide but adopts significantly helical structures in TFE solutions. The clear differences between the structures of PAP(248-286) in TFE and SDS indicate electrostatic interactions play a large role in the folding of the peptide, consistent with the slight degree of penetration of PAP(248-286) into the hydrophobic core of the micelle. This is another noticeable difference between PAP(248-286) and other amyloid peptides, which generally show penetration into at least the headgroup region of the bilayer, and may explain some of the unusual properties of SEVI. PMID- 21262197 TI - N- and O-methylation of sphingomyelin markedly affects its membrane properties and interactions with cholesterol. AB - We have prepared palmitoyl sphingomyelin (PSM) analogs in which either the 2-NH was methylated to NMe, the 3-OH was methylated to OMe, or both were methylated simultaneously. The aim of the study was to determine how such modifications in the membrane interfacial region of the molecules affected interlipid interactions in bilayer membranes. Measuring DPH anisotropy in vesicle membranes prepared from the SM analogs, we observed that methylation decreased gel-phase stability and increased fluid phase disorder, when compared to PSM. Methylation of the 2-NH had the largest effect on gel-phase instability (T(m) was lowered by ~7 degrees C). Atomistic molecular dynamics simulations showed that fluid phase bilayers with methylated SM analogs were more expanded but thinner compared to PSM bilayers. It was further revealed that 3-OH methylation dramatically attenuated hydrogen bonding also via the amide nitrogen, whereas 2-NH methylation did not similarly affect hydrogen bonding via the 3-OH. The interactions of sterols with the methylated SM analogs were markedly affected. 3-OH methylation almost completely eliminated the capacity of the SM analog to form sterol-enriched ordered domains, whereas the 2-NH methylated SM analog formed sterol-enriched domains but these were less thermostable (and thus less ordered) than the domains formed by PSM. Cholestatrienol affinity to bilayers containing methylated SM analogs was also markedly reduced as compared to its affinity for bilayers containing PSM. Molecular dynamics simulations revealed further that cholesterol's bilayer location was deeper in PSM bilayers as compared to the location in bilayers made from methylated SM analogs. This study shows that the interfacial properties of SMs are very important for interlipid interactions and the formation of laterally ordered domains in complex bilayers. PMID- 21262196 TI - Structural and functional roles of small group-conserved amino acids present on helix-H7 in the beta(2)-adrenergic receptor. AB - Sequence analysis of the class A G protein-coupled receptors (GPCRs) reveals that most of the highly conserved sites are located in the transmembrane helices. A second level of conservation exists involving those residues that are conserved as a group characterized by small and/or weakly polar side chains (Ala, Gly, Ser, Cys, Thr). These positions can have group conservation levels of up to 99% across the class A GPCRs and have been implicated in mediating helix-helix interactions in membrane proteins. We have previously shown that mutation of group-conserved residues present on transmembrane helices H2-H4 in the beta(2)-adrenergic receptor (beta(2)-AR) can influence both receptor expression and function. We now target the group-conserved sites, Gly315(7.42) and Ser319(7.46), on H7 for structure-function analysis. Replacing Ser319(7.46) with smaller amino acids (Ala or Gly) did not influence the ability of the mutant receptors to bind to the antagonist dihydroalprenolol (DHA) but resulted in ~15-20% agonist-independent activity. Replacement of Ser319(7.46) with the larger amino acid leucine lowered the expression of the S319L mutant and its ability to bind DHA. Both the G315A and G315S mutants also exhibited agonist-independent signaling, while the G315L mutant did not show specific binding to DHA. These data indicate that Gly315(7.42) and Ser319(7.46) are stabilizing beta(2)-AR in an inactive conformation. We discuss our results in the context of van der Waals interactions of Gly315(7.42) with Trp286(6.48) and hydrogen bonding interactions of Ser319(7.46) with amino acids on H1-H2-H7 and with structural water. PMID- 21262198 TI - Ethanol impairs the assembly and disassembly of actin cytoskeleton and cell adhesion via the RhoA signaling pathway, catenin p120 and E-cadherin in CCK stimulated pancreatic acini. AB - The purpose of the present study was to evaluate the effects of EtOH on RhoA, actin cytoskeleton, catenin p120 and E-cadherin and their interactions in CCK stimulated rat pancreatic acini. In isolated rat pancreatic acinar cells, CCK stimulation enhanced protein expression and association of RhoA, G(alpha13), Vav 2, catenin p120 and E-cadherin. CCK induced translocation and activation of RhoA and actin-filamentous assembly and disassembly. RhoA was diffusely localized throughout the acinar cell in the resting state and redistributed to the apical site in response to submaximal CCK stimulation and to a lesser extent in response to supramaximal CCK stimulation. Ethanol and subsequent submaximal CCK stimulation mimicked the effect of supramaximal CCK stimulation in terms of amylase secretion and morphologic effects. However, inhibition of RhoA translocation and activation were observed only with ethanol pretreatment. Ethanol followed by supramaximal CCK stimulation disrupted the well-defined localization of catenin p120 and E-cadherin around the lateral plasma membrane. These data suggest that ethanol impaired the assembly and disassembly of actin cytoskeleton and impaired cell-cell adhesion via the RhoA signaling pathways, catenin p120 and E-cadherin in CCK-stimulated pancreatic acini. PMID- 21262199 TI - Activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) is needed for the TGFbeta-induced chondrogenic and osteogenic differentiation of mesenchymal stem cells. AB - The role of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway on the osteogenesis of progenitor and stem cells has received a lot of attention due to conflicting results in the literature. ERK1/2 has been reported to be both activating and inhibitory to the osteogenesis of different cell types under varying culture conditions. This study focused specifically on the role of ERK1/2 on the chondrogenesis and osteogenesis of mesenchymal stem cells (MSC) induced by cytokine exposure. Bone marrow-derived MSC were cultured in three-dimensional fibrin gel scaffolds and stimulated down the chondrogenic and osteogenic programs by addition of TGF-beta3 to and osteogenic buffer media. Cells were cultured under control conditions (no cytokine supplementation), treated with TGF-beta3 or treated with PD98059+TGF-beta3 for 7 days. RT-PCR results show that addition of TGF-beta3 significantly upregulates the phosphorylation of ERK1/2 and induces the cells down the chondrogenic and osteogenic pathways (as demonstrated by the significant upregulation of aggrecan, sox9, collagen types 1 & 2 gene expressions). Inhibition of ERK1/2 phosphorylation with PD98059 led to the abolishment of the upregulation of chondrogenic and osteogenic-specific gene expressions. These results demonstrate that ERK1/2 is needed for the chondrogenic and osteogenic differentiation of MSC as induced by TGF-beta3 supplementation. PMID- 21262200 TI - Inhibitory effect of memantine, an NMDA-receptor antagonist, on electroporation induced inward currents in pituitary GH3 cells. AB - The membrane electroporation-induced inward current (IMEP) in pituitary tumor (GH3) cells was characterized. This current emerges irregularly when membrane hyperpolarizations to -200 mV with a holding potential of -80 mV were elicited. Neither E-4031 (10 MUM), glibenclamide (30 MUM), nor ZD7288 (30 MUM) caused any effects on IMEP. The single-channel conductance and pore radius were estimated to be around 1.12 nS and 1.7 nm, respectively. LaCl3- and memantidine (MEM)-induced block of this current was also examined. The IC50 value for LaCl3- and MEM induced inhibition of IMEP was 35 and 75 MUM, respectively. However, unlike LaCl3, MEM (300 MUM) did not exert any effect on voltage-gated Ca2+ current. In inside-out configuration, MEM applied to either external or internal surface of the excised patch did not suppress the activity of ATP-sensitive K+ channels expressed in GH3 cells, although glibenclamide significantly suppressed channel activity. This study provides the first evidence to show that MEM, a non competitive antagonist of N-methyl D-aspartate receptors, directly inhibits the amplitude of IMEP in pituitary GH3 cells. MEM-mediated block of IMEP in these cells is unlinked to its inhibition of glutamate-induced currents or ATP sensitive K+ currents. The channel-suppressing properties of MEM might contribute to the underlying mechanisms by which it and its structurally related compounds affect neuronal or neuroendocrine function. PMID- 21262201 TI - Dihydroavenanthramide D inhibits human breast cancer cell invasion through suppression of MMP-9 expression. AB - Dihydroavenanthramide D (DHAvD) is a synthetic analog to naturally occurring avenanthramide, which is the active component of oat. Previous study demonstrates that DHAvD strongly inhibits activation of nuclear factor-kappa B (NF-kappaB), which is a major component in cancer cell invasion. The present study investigated whether DHAvD can modulate MMP-9 expression and cell invasion in MCF 7 human breast cancer cells. MMP-9 expression and cell invasion in response to 12 O-tetradecanoylphorbol-13-acetate (TPA) was increased, whereas these inductions were muted by DHAvD. DHAvD also suppressed activation of mitogen-activated protein kinase (MAPK), and MAPK-mediated nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) activations in TPA-treated MCF-7 cells. The results indicate that DHAvD-mediated inhibition of TPA-induced MMP-9 expression and cell invasion involves the suppression of the MAPK/NF-kappaB and MAPK/AP-1 pathways in MCF-7 cells. DHAvD may have potential value in breast cancer metastasis. PMID- 21262202 TI - Cortical GABAergic neurons and cerebellar Purkinje cells respond to ischemia pathogenic factors differently. AB - GABAergic neurons in the central nervous system are vulnerable to hazard situations, such as ischemia and toxic substances, under which their dysfunction results in neuronal excitotoxicity and subsequently cell death. How ischemia related pathogenic factors influence the functions of different GABAergic neurons remains to be documented. We investigated this issue at cortical GABAergic neurons and cerebellar Purkinje cells in brain slices by whole-cell recordings. Our results demonstrate that ischemia, cellular Ca(2+)-overload and acidosis lower the spike capacity of cortical GABAergic neurons, but elevate that of cerebellar Purkinje cells. These changes of spike encoding at two types of GABAergic cells are associated with the different effects of three factors on spike refractory periods and threshold potentials, which are mediated by voltage gated sodium channels. Mechanisms underlying such differences are discussed. PMID- 21262204 TI - Methylprednisolone exacerbates acute critical illness-related corticosteroid insufficiency associated with traumatic brain injury in rats. AB - Emerging evidence demonstrates that severe illness could induce critical illness related corticosteroid insufficiency (CIRCI) and cause poor prognosis. The purpose of this study was to test the hypothesis that methylprednisolone (MP), a synthetic glucocorticoid, promotes post-traumatic apoptosis in both the hypothalamus and pituitary, resulting in acute CIRCI and increased mortality in the acute phase of traumatic brain injury (TBI). We tested this hypothesis by measuring acute CIRCI in rats subjected to fluid percussion injury (FPI) and treated with MP (5-30mg/kg). The corticosteroid response to TBI was evaluated using the corticosterone increase index (CII), where values less than 2.5 were considered indicative of acute CIRCI. The CII of MP treated rats was comparable to that of saline treated control rats before injury but was significantly decreased in injured rats receiving high-dose MP on post-injury day 7. Similarly, the incidence of acute CIRCI was significantly higher in the high-dose MP group on post-injury day 7. Furthermore, the CII of rats that did not survive post injury was significantly lower compared to that of survival and was indicative of acute CIRCI. We also examined apoptosis in the paraventricular nucleus (PVN) of the hypothalamus and the adenohypophysis of the pituitary, using a TUNEL assay and transmission electron microscopy (TEM). The number of TUNEL-positive cells was significantly higher in injured rats treated with high-dose MP. No TUNEL positive cells were detected in the adenohypophysis across experimental groups at either 7 or 14days after TBI. However, autopsies performed on rats that did not survive post-injury revealed obvious apoptotic cells in the adenohypophysis. Moreover, TEM revealed morphological changes characteristic of apoptosis in both the PVN and adenohypophysis of high-dose MP treated rats. These data suggest that MP therapy for TBI could increase neuronal apoptosis in both the hypothalamus and pituitary and consequently exacerbate acute CIRCI and mortality induced by TBI. PMID- 21262203 TI - Estrogen-induced signaling attenuates soluble Abeta peptide-mediated dysfunction of pathways in synaptic plasticity. AB - Neuromodulation of synaptic plasticity by 17beta-estradiol (E2) is thought to influence information processing and storage in the cortex and hippocampus. Because E2 rapidly affects cortical memory and synaptic plasticity, we examined its effects on phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase (ERK), and alpha-amino-3-hydroxy 5-methyl-4-isoxazolepropionic acid receptor (AMPAR) [AMPA-type glutamate receptor subunit 1 (GluR1 subunit)], all of which are important for the induction and maintenance of synaptic plasticity and memory. Acute E2 treatment resulted in an increased temporal and spatial phosphorylation pattern of CaMKII, ERK, and AMPAR (GluR1 subunit). By using inhibitors, we were able to attribute GluR1 phosphorylation to CaMKII at serine 831, and we also found that E2 treatment increased GluR1 insertion into the surface membrane. Because soluble amyloid-beta (Abeta) oligomers inhibit CaMKII and ERK activation, which is necessary for synaptic plasticity, we also tested E2's ability to ameliorate Abeta-induced dysfunction of synaptic plasticity. We found that estrogen treatment in neuronal culture, slice culture, and in vivo, ameliorated Abeta oligomer-induced inhibition of CaMKII, ERK, and AMPAR phosphorylation, and also ameliorated the Abeta oligomer-induced reduction of dendritic spine density in a CaMKII-dependent manner. These phosphorylation events are correlated with the early stage of inhibitory avoidance learning, and our data show that E2 improved inhibitory avoidance memory deficits in animals treated with soluble Abeta oligomers. This study identifies E2-induced signaling that attenuates soluble Abeta peptide mediated dysfunction of pathways in synaptic plasticity. PMID- 21262205 TI - Galectin-3 expression in delayed neuronal death of hippocampal CA1 following transient forebrain ischemia, and its inhibition by hypothermia. AB - The ischemic damage in the hippocampal CA1 sector following transient ischemia, delayed neuronal death, is a typical apoptosis, but the mechanism underlying the delayed neuronal death is still far from fully understood. Galectin-3 is a beta galactosidase-binding lectin which is important in cell proliferation and apoptotic regulation. Galectin-3 is expressed by microglial cells in experimental models of adult stroke. It has been reported that activated microglial cells are widely observed in the brain, including in the hippocampal CA1 region after transient ischemic insult. In the present study, time course expression of galectin-3 following transient forebrain ischemia in gerbils was examined by immunohistochemistry, combined with Iba-1 immunostaining (a specific microglial cell marker), hematoxylin and eosin staining (for morphological observation), and in situ terminal dUTP-biotin nick end labeling of DNA fragments method (for determination of cell death). Following transient ischemia, we observed a transient increase of galectin-3 expression in CA1 region, which was maximal 96h after reperfusion. Galectin-3 expression was predominately localized within CA1 region and observed only in cells which expressed Iba-1. The galectin-3-positive microglial cells emerge after the onset of neuronal cell damage. Expressions of galectin-3 and Iba-1 were strongly reduced by hypothermia during ischemic insult. Prevention of galectin-3 and Iba-1 expression in microglia by hypothermia has led us to propose that hypothermia either inhibits microglial activation or prevents delayed neuronal death itself. Our results indicate that galectin-3 might exert its effect by modulating the neuronal damage in delayed neuronal death. PMID- 21262206 TI - Prolactin is a peripheral marker of manganese neurotoxicity. AB - Excessive exposure to Mn induces neurotoxicity, referred to as manganism. Exposure assessment relies on Mn blood and urine analyses, both of which show poor correlation to exposure. Accordingly, there is a critical need for better surrogate biomarkers of Mn exposure. The aim of this study was to examine the relationship between Mn exposure and early indicators of neurotoxicity, with particular emphasis on peripheral biomarkers. Male Wistar rats (180-200g) were injected intraperitoneally with 4 or 8 doses of Mn (10mg/kg). Mn exposure was evaluated by analysis of Mn levels in brain and blood along with biochemical end points (see below). RESULTS: Brain Mn levels were significantly increased both after 4 and 8 doses of Mn compared with controls (p<0.001). Blood levels failed to reflect a dose-dependent increase in brain Mn, with only the 8-dose-treated group showing significant differences (p<0.001). Brain glutathione (GSH) levels were significantly decreased in the 8-dose-treated animals (p<0.001). A significant and dose-dependent increase in prolactin levels was found for both treated groups (p<0.001) compared to controls. In addition, a decrease in motor activity was observed in the 8-dose-treated group compared to controls. CONCLUSIONS: (1) The present study demonstrates that peripheral blood level is a poor indicator of Mn brain accumulation and exposure; (2) Mn reduces GSH brain levels, likely reflecting oxidative stress; (3) Mn increases blood prolactin levels, indicating changes in the integrity of the dopaminergic system. Taken together these results suggest that peripheral prolactin levels may serve as reliable predictive biomarkers of Mn neurotoxicity. PMID- 21262208 TI - Categorical scaling of duration as a function of temporal context in aged rats. AB - Aged male rats at 10, 20, and 30 mo of age were trained on a 2.0 vs. 8.0-s duration bisection procedure using both auditory and visual signals and were then tested with visual signal durations in which the spacing of the intermediate signal durations was held constant as the short (S) and long (L) anchor durations were moved progressively closer to each other across blocks of sessions. Auditory clicks also preceded some trials in order to determine the potential effects of arousal and/or distraction on the timing of visual signals. The consequences of aging, reducing the S:L ratio, and auditory clicks were to increase the likelihood of observing reversals in response classifications around the geometric mean of the anchor durations. Taken together, these results suggest that the bisection "reversal effect" is dependent upon the calculation of the subjective mid-point between the two anchor durations and the differential setting of response thresholds around this category boundary as a function of temporal context. PMID- 21262207 TI - Hydrocephalus and abnormal subcommissural organ in mice lacking presenilin-1 in Wnt1 cell lineages. AB - Presenilin-1 (PS1) is a transmembrane protein that is in many cases responsible for the development of familial Alzheimer's disease. PS1 is widely expressed in embryogenesis and is essential for neurogenesis, somitogenesis, angiogenesis, and cardiac morphogenesis. To further investigate the role of PS1 in the brain, we inactivated the PS1 gene in Wnt1 cell lineages using the Cre-loxP recombination system. Here we show that conditional inactivation of PS1 in Wnt1 cell lineages results in congenital hydrocephalus and subcommissural organ abnormalities, suggesting a possible role of PS1 in the regulation of cerebrospinal fluid homeostasis. PMID- 21262209 TI - Silencing of PINK1 induces mitophagy via mitochondrial permeability transition in dopaminergic MN9D cells. AB - Accumulation of dysfunctional Mitochondria has been implicated in the pathogenesis of Parkinson's disease (PD). Mutations in PTEN-induced kinase 1 (PINK1), which encodes a putative mitochondrial serine/threonine kinase, have been identified in early-onset forms of PD. Recent data showed that the loss of PINK1 function led to oxidative stress, mitochondrial damage and autophagic elimination of damaged mitochondria. But the precise mechanism of autophagy induced by loss of PINK1 is unclear. In this study, we found that in mouse dopaminergic MN9D cells, down-regulation of PINK1 by RNA interference resulted in induction of mitochondrial autophagy (mitophagy), abnormal mitochondrial morphology, partial loss of mitochondrial membrane potential and increased production of reactive oxygen species (ROS). Mitophagy in these cells was associated with the up-regulation of autophagy activator Beclin 1 and opening of mitochondrial permeability transition (MPT) pore. These findings suggest that PINK1 may regulate mitophagy through controlling MPT pore opening and general autophagy regulators. PMID- 21262210 TI - Electrostatics of carboxylated anionic vesicles for improving entrapment capacity. AB - Electrostatic interaction is an important secondary force affecting the structure, stability, and function of lipid vesicles (liposomes). For this study, a negatively charged lipid with carboxylic acid was mixed with phospholipid to produce anionic vesicles. The electrostatics of the carboxylated anionic vesicle (ca. 200 nm diameter) was determined and correlated with entrapment capacity of the vesicles. Correlative analysis revealed the zeta potential of the vesicles as a factor quantitatively affecting the entrapment capacity for a water-soluble marker, in which the entrapment capacity reached its maximum level in less than 30 mV of zeta potential. Transmission electron microscopy (TEM) revealed that the vesicles with high entrapment capacity are composed of a unilamellar membrane. This finding is expected to be useful for efficient encapsulation of water soluble pharmaceuticals within vesicles. PMID- 21262211 TI - BRAFV600E detection in melanoma is highly improved by COLD-PCR. AB - BACKGROUND: The BRAF gene has been identified as an oncogene in human cancer and the V600E mutation has been shown to be associated with clinico pathological features of primary invasive melanomas. As BRAF may be an attractive therapeutic target, it is crucial to have a sensitive method for detecting mutated DNA in biological samples. Our aim was to investigate COLD-PCR (co-amplification at lower denaturation temperature-PCR) as a new approach for the pre-analytical enrichment of the BRAFV600E variant in formalin fixed paraffin embedded (FFPE) melanoma tissues. METHODS: COLD-PCR was used to selectively amplify BRAFV600E minority alleles from mixtures of wild-type and mutated sequences, and from biological samples. The method shows higher specificity than other conventional PCR-based methods in detecting somatic mutations. RESULTS: We used COLD-PCR to increase the theoretical sensitivity of three different post-PCR methods: sequencing, pyrosequencing and HRMA. The gain in sensitivity seems to be more evident for HRMA, which allows the detection of 3.1% mutated alleles. More than 20% of patients initially classified negative for BRAFV600E were found positive after COLD-PCR. CONCLUSIONS: COLD-PCR was confirmed as a suitable method for the enrichment of mutated alleles, particularly for samples in which the percentage of tumor cells is very low. PMID- 21262213 TI - Development of a cryopreservation protocol for testicular interstitial cells with the account of temperature intervals for controlled cooling below -60 degrees S. AB - A long course of anticancer therapy may lead to testicular steroidogenesis destruction. Cryopreservation of testicular interstitial cells (TIC) would be a strategy to protect hormonal and fertile potential of pre-pubertal boys treated with chemo - or radiotherapy. The aim of this research was to optimize protocols for freezing of TIC. Essential physical processes associated with the presence of dimethyl sulphoxide (Me(2)SO) in the cryoprotectant solution take place at the temperatures below -60 degrees S. These processes are the eutectic crystallization at the stage of freezing and the recrystallization before the melting of the eutectic mixture at the stage of heating. Both of the processes affect the viability of the cells subjected to cryopreservation. Temperature intervals when these processes take place were determined by the method of thermoplastic deformation for 10% Me(2)SO selected for cryopreservation of TIC. Rat TIC were cryopreserved using five different protocols which varied in cooling rates within the chosen temperature intervals. Post-thaw cell viability and metabolic activity were evaluated by Trypan Blue and 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide (MTT) staining assays. Leydig cell recovery after cryopreservation was measured by 3-beta-hydroxysteroid dehydrogenase reaction. Based on the obtained results, the authors developed a cryopreservation protocol for TIC which makes it possible to achieve great cell viability due to using controlled cooling rates within the temperature intervals below -60 degrees S. PMID- 21262212 TI - Cytotoxicity effects of cryoprotectants as single-component and cocktail vitrification solutions. AB - Cryoprotectant (CPA) cytotoxicity constitutes a challenge in developing cryopreservation protocols, specifically in vitrification where high CPA concentrations are necessary to achieve the ice-free, vitreous state. Few cytotoxicity studies have investigated vitrification-relevant concentrations of CPAs, and the benefits and disadvantages of cocktail solutions and of incorporating non-permeating solutes have not been fully evaluated. In this study, we address these issues by determining the cytotoxicity kinetics for dimethylsulfoxide (Me(2)SO) and 1,2-propanediol (PD) on alginate-encapsulated betaTC-tet mouse insulinomas for a range of concentrations and temperatures. Cytotoxicity kinetics were also determined for two cocktails, DPS (3M Me(2)SO+3M PD+0.5M sucrose) and PEG400 (1M Me(2)SO+5M PD+0.34M poly(ethylene)glycol with M.W. of 400). PD was found to be more cytotoxic than Me(2)SO at higher concentrations and temperatures. This was reflected in PEG400 being more cytotoxic at room temperature than PEG400 at 4 degrees C or DPS at either temperature. Addition of non-permeating solutes increased the cytotoxicity of cocktails. Furthermore, results indicate that CPA cytotoxicity may not be additive and that combining CPAs may increase cytotoxicity synergistically. Finally, when comparing cytotoxic effects towards encapsulated HepG2 and betaTC tet cells, and towards betaTC-tet cells in capsules and in monolayers, CPAs appear more cytotoxic towards cells with higher metabolic activity. The incorporation of these results in the rational design of CPA addition/removal processes in vitrification is discussed. PMID- 21262214 TI - The Bin3 RNA methyltransferase is required for repression of caudal translation in the Drosophila embryo. AB - Bin3 was first identified as a Bicoid-interacting protein in a yeast two-hybrid screen. In human cells, a Bin3 ortholog (BCDIN3) methylates the 5' end of 7SK RNA, but its role in vivo is unknown. Here, we show that in Drosophila, Bin3 is important for dorso-ventral patterning in oogenesis and for anterior-posterior pattern formation during embryogenesis. Embryos that lack Bin3 fail to repress the translation of caudal mRNA and exhibit head involution defects. bin3 mutants also show (1) a severe reduction in the level of 7SK RNA, (2) reduced binding of Bicoid to the caudal 3' UTR, and (3) genetic interactions with bicoid, and with genes encoding eIF4E, Larp1, polyA binding protein (PABP), and Ago2. 7SK RNA coimmunoprecipitated with Bin3 and is present in Bicoid complexes. These data suggest a model in which Bicoid recruits Bin3 to the caudal 3' UTR. Bin3's role is to bind and stabilize 7SK RNA, thereby promoting formation of a repressive RNA protein complex that includes the RNA-binding proteins Larp1, PABP, and Ago2. This complex would prevent translation by blocking eIF4E interactions required for initiation. Our results, together with prior network analysis in human cells, suggest that Bin3 interacts with multiple partner proteins, methylates small non coding RNAs, and plays diverse roles in development. PMID- 21262215 TI - The bHLH factor deadpan is a direct target of Notch signaling and regulates neuroblast self-renewal in Drosophila. AB - A defining feature of stem cells is their capacity to renew themselves at each division while producing differentiated progeny. How these cells balance self renewal versus differentiation is a fundamental issue in developmental and cancer biology. The Notch signaling pathway has long been known to influence cell fate decisions during development. Indeed, there is a great deal of evidence correlating its function with the regulation of neuroblast (NB) self-renewal during larval brain development in Drosophila. However, little is known about the transcription factors regulated by this pathway during this process. Here we show that deadpan (dpn), a gene encoding a bHLH transcription factor, is a direct target of the Notch signaling pathway during type II NB development. Type II NBs undergo repeated asymmetric divisions to self-renew and to produce immature intermediate neural progenitors. These cells mature into intermediate neural progenitors (INPs) that have the capacity to undergo multiple rounds of asymmetric division to self-renew and to generate GMCs and neurons. Our results indicate that the expression of dpn at least in INPs cells depends on Notch signaling. The ectopic expression of dpn in immature INP cells can transform these cells into NBs-like cells that divide uncontrollably causing tumor over growth. We show that in addition to dpn, Notch signaling must be regulating other genes during this process that act redundantly with dpn. PMID- 21262216 TI - The zinc finger transcription factors Osr1 and Osr2 control synovial joint formation. AB - Synovial joints enable smooth articulations between different skeletal elements and are essential for the motility of vertebrates. Despite decades of extensive studies of the molecular and cellular mechanisms of limb and skeletal development, the molecular mechanisms governing synovial joint formation are still poorly understood. In particular, whereas several signaling pathways have been shown to play critical roles in joint maintenance, the mechanism controlling joint initiation is unknown. Here we report that Osr1 and Osr2, the mammalian homologs of the odd-skipped family of zinc finger transcription factors that are required for leg joint formation in Drosophila, are both strongly expressed in the developing synovial joint cells in mice. Whereas Osr1(-/-) mutant mice died at midgestation and Osr2(-/-) mutant mice had only subtle defects in synovial joint development, tissue-specific inactivation of Osr1 in the developing limb mesenchyme in Osr2(-/-) mutant mice caused fusion of multiple joints. We found that Osr1 and Osr2 function is required for maintenance of expression of signaling molecules critical for joint formation, including Gdf5, Wnt4 and Wnt9b. In addition, joint cells in the double mutants failed to upregulate expression of the articular cartilage marker gene Prg4. These data indicate that Osr1 and Osr2 function redundantly to control synovial joint formation. PMID- 21262217 TI - Birthdating studies reshape models for pituitary gland cell specification. AB - The intermediate and anterior lobes of the pituitary gland are derived from an invagination of oral ectoderm that forms Rathke's pouch. During gestation proliferating cells are enriched around the pouch lumen, and they appear to delaminate as they exit the cell cycle and differentiate. During late mouse gestation and the postnatal period, anterior lobe progenitors re-enter the cell cycle and expand the populations of specialized, hormone-producing cells. At birth, all cell types are present, and their localization appears stratified based on cell type. We conducted a birth dating study of Rathke's pouch derivatives to determine whether the location of specialized cells at birth is correlated with the timing of cell cycle exit. We find that all of the anterior lobe cell types initiate differentiation concurrently with a peak between e11.5 and e13.5. Differentiation of intermediate lobe melanotropes is delayed relative to anterior lobe cell types. We discovered that specialized cell types are not grouped together based on birth date and are dispersed throughout the anterior lobe. Thus, the apparent stratification of specialized cells at birth is not correlated with cell cycle exit. Thus, the currently popular model of cell specification, dependent upon timing of extrinsic, directional gradients of signaling molecules, needs revision. We propose that signals intrinsic to Rathke's pouch are necessary for cell specification between e11.5 and e13.5 and that cell-cell communication likely plays an important role in regulating this process. PMID- 21262218 TI - 5-Hydroxytryptamine induces cyclooxygenase-2 in rat vascular smooth muscle cells: Mechanisms involving Src, PKC and MAPK activation [corrected]. AB - Considering the importance of 5-hydroxytryptamine (5-HT) and cyclooxygenase (COX) products in vascular pathology, we investigated the effects of 5-HT on COX expression in rat vascular smooth muscle cells (VSMCs), and to provide mechanistic insights into these effects. VSMCs were enzymatically isolated from aortic media of Wistar rats. Incubation of VSMCs with 5-HT for 24h stimulated prostaglandin I(2) production, but this stimulation was completely suppressed by NS-398, a selective COX-2 inhibitor. 5-HT induced transient COX-2, but not COX-1, protein and mRNA expression in concentration- and time-dependent manners. This effect of 5-HT was completely inhibited by sarpogrelate, a 5-HT(2A) receptor antagonist. 5-HT-induced COX-2 expression was markedly blunted by Ca(2+) depletion; GF 109203X, a protein kinase C (PKC) inhibitor; PP2, an inhibitor of Src-family tyrosine kinase (Src); PD 98059, an inhibitor of extracellular signal regulated kinase (ERK) activation; SB 203580, an inhibitor of p38 mitogen activated protein kinase (MAPK); and SP 600125, an inhibitor of c-Jun N-terminal kinase (JNK). 5-HT activated ERK and p38 MAPK, followed by JNK activation. PP2 inhibited these activations, while GF 109203X inhibited only JNK activation. Furthermore, PD 98059 inhibited JNK activation. These results suggest that 5-HT induces COX-2 expression in rat VSMCs, and that PKC, Src, and MAPK activation are each essential for the full expression of COX-2 pathways. PMID- 21262219 TI - (2S,4S)-4-Fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}-pyrrolidine-2 carbonitrile monobenzenesulfonate (TS-021) is a selective and reversible dipeptidyl peptidase IV inhibitor. AB - The incretin hormone glucagon-like peptide-1 (GLP-1) has significant roles in the regulation of postprandial glucose metabolism, and the active form of GLP-1 is rapidly degraded by dipeptidyl peptidase (DPP)-IV. Therefore, DPP-IV inhibition is a promising approach for the treatment of type 2 diabetes. In the present study, we investigated the character of a DPP-IV inhibitor, TS-021, (2S, 4S)-4 fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}-pyrrolidine-2-carbonitrile monobenzenesulfonate both in vitro and in vivo. TS-021 inhibits DPP-IV activity in human plasma with an IC(50) value of 5.34nM. In kinetics experiments, TS-021 had a relatively higher dissociation rate constant, with a k(off) value of 1.09*10(-3)s, despite exhibiting a potent human plasma DPP-IV inhibition activity with a K(i) value of 4.96nM. TS-021 exhibited significant inhibition selectivity against DPP-8 (>600 fold), DPP-9 (>1200 fold) and other peptidases examined (>15,000 fold). In normal rats, dogs and monkeys, a single oral dose of TS-021 exhibited favorable pharmacokinetic profiles. In Zucker fatty (fa/fa) rats, a rat model of obesity and impaired glucose tolerance, the oral administration of TS 021 resulted in the suppression of plasma DPP-IV activity and an increase in the active form of GLP-1. Furthermore, TS-021 exhibited a significant improvement in glucose tolerance by increasing the plasma insulin level during oral glucose tolerance tests at doses of 0.02-0.5mg/kg. These results suggest that TS-021 is a selective and reversible dipeptidyl peptidase IV inhibitor and has excellent characteristics as an oral anti-diabetic agent for postprandial hyperglycemia in patients with impaired glucose tolerance or type 2 diabetes. PMID- 21262220 TI - Coenzyme Q10 counteracts testicular injury induced by sodium arsenite in rats. AB - The protective effect of coenzyme Q10 against testicular toxicity induced by sodium arsenite (10mg/kg/day, orally for two consecutive days) was investigated in rats. Coenzyme Q10 treatment (10mg/kg/day, i.p.) was applied for five consecutive days, starting three days before arsenite administration. Coenzyme Q10 significantly increased serum testosterone level which was reduced by sodium arsenite. Coenzyme Q10 significantly suppressed lipid peroxidation, restored the depleted antioxidant defenses, and attenuated the increases of tumor necrosis factor-alpha and nitric oxide resulted from arsenic administration. Also, the elevation of arsenic ion, and the reductions of selenium and zinc ions in testicular tissue were mitigated by coenzyme Q10. Histopathological examination showed that testicular injury mediated by arsenic was ameliorated by coenzyme Q10 treatment. Immunohistochemical analysis revealed that coenzyme Q10 significantly decreased the arsenic-induced expression of inducible nitric oxide synthase, nuclear factor-kappaB, Fas ligand and caspase-3 in testicular tissue. It was concluded that coenzyme Q10 represents a potential therapeutic option to protect the testicular tissue from the detrimental effects of arsenic intoxication. PMID- 21262221 TI - Mechanism of autophagy induction and role of autophagy in antagonizing mitomycin C-induced cell apoptosis in silibinin treated human melanoma A375-S2 cells. AB - The aim of this study was to elucidate the molecular mechanisms mediating silibinin-induced autophagy in A375-S2 cells. In the present study it was found that silibinin-induced autophagy through increasing the conversion of LC3 I to LC3 II and up-regulating Beclin-1 expression, which was concomitant with p53 suppression and NF-kappaB activation. P53 inhibitor, pifithrin-alpha (PFT-alpha), increased autophagy and enhanced the expression of NF-kappaB. Moreover, inducing p53 accumulation with MG132 reduced autophagic ratio, and repressed the expression and activation of NF-kappaB expression. NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC) suppressed autophagy. Autophagic specific inhibitor 3-methyladenine (3-MA) treatment reversed silibinin-induced p53 suppression as well as NF-kappaB activation, suggesting that there was a positive feedback loop between p53 inhibition-mediated NF-kappaB activation and autophagy. In addition, we also found that 3-MA efficiently abrogated silibinin's cyto protective effect against mitomycin C-induced cell death, and reversed the suppressive efficacy of silibinin on p53 expression, suggesting that autophagy contributed to silibinin's cyto-protective effect against mitomycin C-induced cell death in A375-S2 cells. PMID- 21262223 TI - Increased in vivo [11C]raclopride binding to brain dopamine receptors in amphetamine-treated rats. AB - The hypothesis that repeated daily doses of amphetamine increases the number of available dopamine D(2) receptors in vivo in rat striatum, and may enhance the response to subsequent amphetamine challenge doses, was examined. The in vivo binding potentials of [(11)C]raclopride, a D(2) receptor antagonist, were determined in male CD-1 rats under five conditions: (1) drug-naive with saline challenge, (2) drug naive with 5mg/kg amphetamine challenge, (3) amphetamine dosed (five daily repeated s.c. doses of 5mg/kg amphetamine) and saline challenge, (4) amphetamine-dosed and amphetamine challenge, and (5) saline treated (five daily repeated s.c. doses) and saline challenged. Radiotracer studies in amphetamine-dosed animals were done after a 10-day drug free interval. In the amphetamine-dosed group the baseline [(11)C]raclopride binding was increased by 63% compared to saline-treated controls. The response to an amphetamine challenge, evidenced by a reduction of [(11)C]raclopride binding, was doubled in amphetamine-dosed animals (40%) compared to drug-naive controls (20%). These results support increased baseline in vivo dopamine D(2) receptor antagonist radioligand binding after repeated amphetamine administration in rats. PMID- 21262222 TI - Both GABA(B) receptor activation and blockade exacerbated anhedonic aspects of nicotine withdrawal in rats. AB - Nicotine dependence is maintained by the aversive, depression-like effects of nicotine withdrawal and the rewarding effects of acute nicotine. GABA(B) receptor antagonists exhibit antidepressant-like effects in rodents, whereas GABA(B) receptor agonists attenuate the rewarding effects of nicotine. Recent studies with GABA(B) receptor positive modulators showed that these compounds represent potentially improved medications for the treatment of nicotine dependence because of fewer side-effects than GABA(B) receptor agonists. Thus, GABA(B) receptor agonists and antagonists, and GABA(B) receptor positive modulators may have efficacy as smoking cessation aids by targeting different aspects of nicotine dependence and withdrawal. The present study assessed the effects of the GABA(B) receptor agonist CGP44532, the GABA(B) receptor antagonist CGP56433A, and the GABA(B) receptor positive modulator BHF177 on the anhedonic aspects of nicotine withdrawal. Rats were prepared with stimulating electrodes in the posterior lateral hypothalamus. After establishing stable intracranial self-stimulation (ICSS) thresholds, rats were prepared with subcutaneous osmotic minipumps delivering either nicotine or saline for 7 or 14days. ICSS thresholds were assessed 6h post-pump removal. Thirty hours after pump removal, CGP44532, CGP56433A, and BHF177 were administered 30min prior to ICSS testing. Both GABA(B) receptor activation (CGP44532 and BHF177) and blockade (CGP56433A) elevated ICSS thresholds in all groups, resulting in exacerbated effects of nicotine withdrawal in the nicotine-treated groups. These similar effects of GABA(B) receptor activation and blockade on the anhedonic depression-like aspects of nicotine withdrawal were surprising and perhaps reflect differential efficacy of these compounds at presynaptic hetero- and autoreceptors, as well as postsynaptic, GABA(B) receptors. PMID- 21262224 TI - Aldosterone alters the participation of endothelial factors in noradrenaline vasoconstriction differently in resistance arteries from normotensive and hypertensive rats. AB - This study analyzed the effect of aldosterone (0.05mg/kg per day, 3 weeks) on vasoconstriction induced by noradrenaline in mesenteric resistance arteries from WKY rats and SHR. Contraction to noradrenaline was measured in mesenteric resistance arteries from untreated and aldosterone-treatedrats from both strains. Participation of nitric oxide (NO), superoxide anions, thromboxane A(2) (TxA(2)) and prostacyclin in this response was determined. 6-keto-prostaglandin (PG)F1alpha and thromboxane B(2) (TxB(2)) releases were determined by enzyme immunoassay. NO and superoxide anion release were also determined by fluorescence and chemiluminiscence, respectively. Aldosterone did not modify noradrenaline induced contraction in either strain. In mesenteric resistance arteries from both aldosterone-treated groups, endothelium removal or preincubation with NO synthesis inhibitor L-NAME increased the noradrenaline-induced contraction, while incubation with the superoxide anion scavenger tempol decreased it. Preincubation with either the COX-1/2 or COX-2 inhibitor (indomethacin and NS-398, respectively) decreased the noradrenaline contraction in aldosterone-treated animals, while this response was not modified by COX-1 inhibitor SC-560. TxA(2) synthesis inhibitor (furegrelate), or TxA2 receptor antagonist (SQ 29 548) also decreased the noradrenaline contraction in aldosterone-treated animals. In untreated SHR, but not WKY rats, this response was increased by L-NAME, and reduced by tempol, indomethacin, NS-398 or SQ 29 548. Aldosterone treatment did not modify NO or TxB(2) release, but it did increase superoxide anion and 6-keto PGF(1alpha) release in mesenteric resistance arteries from both strains. In conclusion, chronic aldosterone treatment reduces smooth muscle contraction to alpha-adrenergic stimuli, producing a new balance in the release of endothelium derived prostanoids and NO. PMID- 21262225 TI - Pharmacological characterization of zinc and copper interaction with the human alpha(1A)-adrenoceptor. AB - Metal ions have a major role in human health, and interact with many classes of receptors including the G-protein coupled receptors. In the peripheral system, zinc mainly accumulates in the soft prostate organ and, with copper, influences prostate disease progression, from normal to hypertrophic or cancerous states. The development of these pathologies may be influenced by the alpha(1A) adrenoceptor, the principal regulator of prostate tonicity. There is currently no information on possible interactions between metals and the alpha(1A) adrenoceptor. We therefore studied the effects of several mono- and divalent ions on this receptor subtype using binding and functional experiments performed on expressed cloned human alpha(1A)-adrenoceptor. Regardless of the counter anion used, Zn(2+) and Cu(2+) interact with alpha(1A)-adrenoceptor with apparent affinities in the low micromolar range. In addition, using specific binding experiments, we established that these ions acted as negative allosteric ligands on prazosin/alpha(1A)-adrenoceptor interaction, but in a different manner from the allosteric modulator 5-(N-ethyl-N-isopropyl)-amiloride, suggesting distinct mode of interaction. In addition, the presence of Cu(2+) weakly decreased epinephrine affinity, whereas the addition of Zn(2+) shifted to the left the epinephrine binding curve, revealing a positive allosteric effect but only on half of the binding site. Finally, cell-based functional experiments demonstrated that Zn(2+) and Cu(2+) antagonized epinephrine activation in an insurmountable manner, by reducing agonist efficacy without any shift in the epinephrine activation curves. This study shows the interactions between metal ions and the alpha(1A)-adrenoceptor with affinities compatible with physiological concentrations and suggests that zinc and copper may have a biological role in prostate function. PMID- 21262226 TI - Desmin mutations in the terminal consensus motif prevent synemin-desmin heteropolymer filament assembly. AB - Disorganization of the desmin network is associated with cardiac and skeletal myopathies characterized by accumulation of desmin-containing aggregates in the cells. Multiple associations of intermediate filament proteins form a network to increase mechanical and functional stability. Synemin is a desmin-associated type VI intermediate filament protein. Neither its impact on desmin network nor how it integrates into desmin filament is yet elucidated. To gain more insight into the molecular basis of these processes, we coexpressed synemin with different desmin mutants in ex vivo models. The screening of fourteen desmin mutants showed that synemin with desmin mutants revealed two behaviors. Firstly, synemin was co localized in desmin aggregates and its coexpression decreased the number of cells containing aggregates. Secondly, synemin was excluded from the aggregates, then synemin had no effect on desmin network organization. Among fourteen desmin mutants, there were only three mutants, p.E401K, p.R406W and p.E413K, in which synemin was not found in aggregates. This behavior was correlated to the abnormal salt-bridges of desmin-dimer as seen in silico constructs. Moreover, desmin constructs in silico and published results in literature have predicted that the salt-bridges absence in the desmin filament building prevent longitudinal annealing and/or radial compaction. These results suggest that the state of desmin-filament assembly is crucial for synemin anchorage and consequently might involve mechanical and functional stability of the cytoskeletal network. PMID- 21262228 TI - Neuroendocrine-immune interaction in fish: differential regulation of phagocyte activity by neuroendocrine factors. AB - Coping with physical, chemical and biological disturbances depends on an extensive repertoire of physiological, endocrinological and immunological responses. Fish provide intriguing models to study bi-directional interaction between the neuroendocrine and the immune systems. Macrophages and granulocytes are the main actors in the first and rapid innate immune response. They are resident in different organs and are moreover rapidly recruited and activated upon infection. They act in response to recognition of pathogen-associated molecular patterns (PAMPs) via a repertoire of surface and intracellular receptors by inducing a plethora of defense reactions aiming to eradicate the pathogen. Subsequent production of inflammatory mediators stimulates other leukocytes required to develop an adaptive and specific antibody response. The type of phagocyte reaction will therefore depend on their differentiation state, specific receptor repertoire and their specific location. Apart from these pathogen induced responses, immune reactivity may be modulated by neuroendocrine factors. Over the last years we extensively studied changes in carp stress axis activity and the effect of its end-products on the immune system in an acute stress paradigm. We focus on specific neuroendocrine receptors on leukocytes and their effect on crucial phagocyte activities. We performed identification and functional analyses of different glucocorticoid, opioid and adrenergic receptors on carp phagocytes. Results show that their ligands of neuroendocrine origin may have substantial impact on specific phagocyte functions in a differential way. Inflammatory and microbicidal responses fight pathogens but may be detrimental to the host tissue. Neuroendocrine modulation may regulate inflammation to reach an optimum defense while preventing excessive host cell damage. PMID- 21262227 TI - GATA factors regulate proliferation, differentiation, and gene expression in small intestine of mature mice. AB - BACKGROUND & AIMS: GATA transcription factors regulate proliferation, differentiation, and gene expression in multiple organs. GATA4 is expressed in the proximal 85% of the small intestine and regulates the jejunal-ileal gradient in absorptive enterocyte gene expression. GATA6 is co-expressed with GATA4 but also is expressed in the ileum; its function in the mature small intestine is unknown. METHODS: We investigated the function of GATA6 in small intestine using adult mice with conditional, inducible deletion of Gata6, or Gata6 and Gata4, specifically in the intestine. RESULTS: In ileum, deletion of Gata6 caused a decrease in crypt cell proliferation and numbers of enteroendocrine and Paneth cells, an increase in numbers of goblet-like cells in crypts, and altered expression of genes specific to absorptive enterocytes. In contrast to ileum, deletion of Gata6 caused an increase in numbers of Paneth cells in jejunum and ileum. Deletion of Gata6 and Gata4 resulted in a jejunal and duodenal phenotype that was nearly identical to that in the ileum after deletion of Gata6 alone, revealing common functions for GATA6 and GATA4. CONCLUSIONS: GATA transcription factors are required for crypt cell proliferation, secretory cell differentiation, and absorptive enterocyte gene expression in the small intestinal epithelium. PMID- 21262229 TI - Peptide mimics of hapten DNP: the effect of affinity of anti-DNP monoclonal antibodies for the selection of phage-displayed mimotopes. AB - Biopanning of two linear (6- and 15-mer) and two constrained (10- and 17-mer) phage-displayed peptide libraries with two anti-DNP monoclonal antibodies (mAbs) selected seven unique peptide sequences using only the low affinity anti-DNP monoclonal antibody. The selected peptides contained two of 6, one of 10, two of 15 and two of 17 amino acids in length. They were all rich in hydrophobic residues. Both 15-mer peptides had antigenic regions of eight amino acids as revealed by a spot scan assay. Two of the 17-mer and one of the 10-mer peptides displayed on phage competed with free DNP for the low affinity anti-DNP mAb. These findings highlight (i) the selective power of phage displayed peptide libraries to identify peptides that mimic the shape of a small hapten molecule such as DNP, (ii) the possible preferential bias of phage libraries towards low affinity antibodies, (iii) the importance of using a panel of phage libraries for selecting peptide mimics. PMID- 21262230 TI - Metabolism, hypoxia and the diabetic heart. AB - The diabetic heart becomes metabolically remodelled as a consequence of exposure to abnormal circulating substrates and hormones. Fatty acid uptake and metabolism are increased in the type 2 diabetic heart, resulting in accumulation of intracellular lipid intermediates and an increased contribution of fatty acids towards energy generation. Cardiac glucose uptake and oxidation are decreased, predominantly due to increased fatty acid metabolism, which suppresses glucose utilisation via the Randle cycle. These metabolic changes decrease cardiac efficiency and energetics in both humans and animal models of diabetes. Diabetic hearts have decreased recovery following ischemia, indicating a reduced tolerance to oxygen-limited conditions. There is evidence that diabetic hearts have a compromised hypoxia signalling pathway, as hypoxia-inducible factor (HIF) and downstream signalling from HIF are reduced following ischemia. Failure to activate HIF under oxygen-limited conditions results in less angiogenesis, and an inability to upregulate glycolytic ATP generation. Given that glycolysis is already suppressed in the diabetic heart under normoxic conditions, the inability to upregulate glycolysis in response to hypoxia may have deleterious effects on ATP production. Thus, impaired HIF signalling may contribute to metabolic and energetic abnormalities, and impaired collateral vessel development following myocardial infarction in the type 2 diabetic heart. PMID- 21262231 TI - Heterosubunit composition and crystal structures of a novel bacterial M16B metallopeptidase. AB - Three subfamilies of metallopeptidase family M16 enzymes--M16A, M16B, and M16C- are widely distributed among eukaryotes and prokaryotes. SPH2681, a periplasmic M16B protein found in Sphingomonas sp. strain A1, contains an HXXEH motif essential for Zn(2+) binding and catalytic activity. SPH2682 is another member of M16B, which lacks the metal-binding motif but conserves an active-site R/Y pair commonly found in the C-terminal half of M16 enzymes. Two genes coding for SPH2681 and SPH2682 assemble into a single operon in the bacterial genome. This study determined SPH2681 to be constitutively expressed in strain A1 cells grown on different carbon sources, suggesting a more general cellular function. SPH2681 and SPH2681/SPH2682 were overexpressed in Escherichia coli, purified, and characterized. SPH2681 was found to associate with SPH2682, forming a heterosubunit enzyme with peptidase activity, while SPH2681 alone exhibited no enzymatic activity. X-ray crystallography of the SPH2681/SPH2682 complex revealed two conformations (open and closed heterodimeric forms) within the same crystal. Compared with the closed form, the open form contains two subunits rotated away from each other by approximately 8 degrees , increasing the distance between the zinc ion and active-site residues by up to 8 A. In addition, many hydrogen bonds are formed or broken on change between the conformations of the heterodimers, suggesting that subunit dynamics is a prerequisite for catalysis. To our knowledge, this is the first report on both conformational forms of the same M16 peptidase, providing a unique insight into the general proteolytic mechanism of M16 proteases. PMID- 21262232 TI - Structural analysis of protein folding by the long-chain archaeal chaperone FKBP26. AB - In the cell, protein folding is mediated by folding catalysts and chaperones. The two functions are often linked, especially when the catalytic module forms part of a multidomain protein, as in Methanococcus jannaschii peptidyl-prolyl cis/trans isomerase FKBP26. Here, we show that FKBP26 chaperone activity requires both a 50-residue insertion in the catalytic FKBP domain, also called 'Insert-in Flap' or IF domain, and an 80-residue C-terminal domain. We determined FKBP26 structures from four crystal forms and analyzed chaperone domains in light of their ability to mediate protein-protein interactions. FKBP26 is a crescent shaped homodimer. We reason that folding proteins are bound inside the large crescent cleft, thus enabling their access to inward-facing peptidyl-prolyl cis/trans isomerase catalytic sites and ipsilateral chaperone domain surfaces. As these chaperone surfaces participate extensively in crystal lattice contacts, we speculate that the observed lattice contacts reflect a proclivity for protein associations and represent substrate interactions by FKBP26 chaperone domains. Finally, we find that FKBP26 is an exceptionally flexible molecule, suggesting a mechanism for nonspecific substrate recognition. PMID- 21262233 TI - Converting a marginally hydrophobic soluble protein into a membrane protein. AB - delta-Helices are marginally hydrophobic alpha-helical segments in soluble proteins that exhibit certain sequence characteristics of transmembrane (TM) helices [Cunningham, F., Rath, A., Johnson, R. M. & Deber, C. M. (2009). Distinctions between hydrophobic helices in globular proteins and TM segments as factors in protein sorting. J. Biol. Chem., 284, 5395-402]. In order to better understand the difference between delta-helices and TM helices, we have studied the insertion of five TM-like delta-helices into dog pancreas microsomal membranes. Using model constructs in which an isolated delta-helix is engineered into a bona fide membrane protein, we find that, for two delta-helices originating from secreted proteins, at least three single-nucleotide mutations are necessary to obtain efficient membrane insertion, whereas one mutation is sufficient in a delta-helix from the cytosolic protein P450BM-3. We further find that only when the entire upstream region of the mutated delta-helix in the intact cytochrome P450BM-3 is deleted does a small fraction of the truncated protein insert into microsomes. Our results suggest that upstream portions of the polypeptide, as well as embedded charged residues, protect delta-helices in globular proteins from being recognized by the signal recognition particle-Sec61 endoplasmic-reticulum-targeting machinery and that delta-helices in secreted proteins are mutationally more distant from TM helices than delta-helices in cytosolic proteins. PMID- 21262235 TI - Structure basis of bigelovin as a selective RXR agonist with a distinct binding mode. AB - The nuclear receptor retinoid X receptor (RXR) functions potently in the regulation of homeostasis and cell development, while rexinoids as RXR agonists have proved their therapeutic potential in the treatment of metabolic diseases and cancer. Here, the natural product bigelovin was identified as a selective RXRalpha agonist. Interestingly, this compound could not transactivate RXRalpha:RXRalpha homodimer but could enhance the transactivation of RXRalpha:peroxisome proliferator-activated receptor gamma heterodimer and repress that of RXRalpha:liver X receptor (LXR) alpha heterodimer, while it had no effects on RXRalpha:farnesoid X receptor heterodimer. Considering that the effective role of LXR response element involved transactivation of sterol regulatory element-binding protein-1c mediated by RXRalpha:LXRalpha in triglyceride elevation, such LXR response element repressing by bigelovin has obviously addressed its potency for further research. Moreover, our determined crystal structure of the bigelovin-activated RXRalpha ligand-binding domain with the coactivator human steroid receptor coactivator-1 peptide revealed that bigelovin adopted a distinct binding mode. Compared with the known RXR ligands, bigelovin lacks the acidic moiety in structure, which indicated that the acidic moiety rendered little effects on RXR activation. Our results have thereby provided new insights into the structure-based selective rexinoids design with bigelovin as a potential lead compound. PMID- 21262234 TI - The DNA-binding domain of human PARP-1 interacts with DNA single-strand breaks as a monomer through its second zinc finger. AB - Poly(ADP-ribose)polymerase-1 (PARP-1) is a highly abundant chromatin-associated enzyme present in all higher eukaryotic cell nuclei, where it plays key roles in the maintenance of genomic integrity, chromatin remodeling and transcriptional control. It binds to DNA single- and double-strand breaks through an N-terminal region containing two zinc fingers, F1 and F2, following which its C-terminal catalytic domain becomes activated via an unknown mechanism, causing formation and addition of polyadenosine-ribose (PAR) to acceptor proteins including PARP-1 itself. Here, we report a biophysical and structural characterization of the F1 and F2 fingers of human PARP-1, both as independent fragments and in the context of the 24-kDa DNA-binding domain (F1+F2). We show that the fingers are structurally independent in the absence of DNA and share a highly similar structural fold and dynamics. The F1+F2 fragment recognizes DNA single-strand breaks as a monomer and in a single orientation. Using a combination of NMR spectroscopy and other biophysical techniques, we show that recognition is primarily achieved by F2, which binds the DNA in an essentially identical manner whether present in isolation or in the two-finger fragment. F2 interacts much more strongly with nicked or gapped DNA ligands than does F1, and we present a mutational study that suggests origins of this difference. Our data suggest that different DNA lesions are recognized by the DNA-binding domain of PARP-1 in a highly similar conformation, helping to rationalize how the full-length protein participates in multiple steps of DNA single-strand breakage and base excision repair. PMID- 21262236 TI - Effects on sleep and dopamine levels of microdialysis perfusion of cannabidiol into the lateral hypothalamus of rats. AB - AIMS: The major non-psychoactive component of Cannabis sativa, cannabidiol (CBD), displays a plethora of actions including wakefulness. In the present study, we addressed whether perfusing CBD via microdialysis into lateral hypothalamus (LH) during the lights-on period would modify the sleep-wake cycle of rats as well as the contents of dopamine (DA) collected from nucleus accumbens (AcbC). Additionally, we tested whether perfusion of CBD into LH would block the sleep rebound after a sleep deprivation period. MAIN METHODS: Electroencephalogram and electromyogram electrodes were implanted in rats as well as a guide-cannula aimed to LH or AcbC. CBD perfusion was carried out via cannulae placed into LH whereas contents of DA were collected from AcbC and analyzed using HPLC means. KEY FINDINGS: We found that microdialysis perfusion of CBD (30, 60, or 90 nM) into LH of rat enhances alertness and suppresses sleep. This effect was accompanied with an increase in DA extracellular levels collected from the AcbC. Furthermore, perfusion of CBD into LH after total sleep deprivation prevented the sleep rebound. SIGNIFICANCE: These findings enhance the investigation about the neurobiological properties of CBD on sleep modulation. PMID- 21262237 TI - Partial hepatectomy aggravates cyclosporin A-induced neurotoxicity by lowering the function of the blood-brain barrier in mice. AB - AIMS: Cyclosporin A, a calcineurin inhibitor, produces neurotoxicity with relatively high frequency in organ-transplanted patients. The aim of the present study was to clarify whether acute liver failure (ALF) simulated to the transient liver dysfunction at an early phase after liver transplantation increases the susceptibility to cyclosporin A-induced neurotoxicity through the blood-brain barrier (BBB) dysfunction. MAIN METHODS: The right internal, left lateral and left internal lobes in male ddy mice were surgically excised under sodium pentobarbital anesthesia. Effect of cyclosporin A on harmine-induced tremors was examined and BBB permeability to (3)[H]cyclosporin A was assessed in partially (70%) hepatectomized mice at postoperative days 1, 3 and 7. KEY FINDINGS: Patrial hepatectomy aggravated harmine-induced tremors. Cyclosporin A (50mg/kg, i.p.) markedly augmented harmine-induced tremors in partially hepatectomized mice at postoperative day 1. Consistent with these behavioral findings, the brain uptake of (3)[H]cyclosporin A in mice injected with (3)[H]cyclosporin A into the jugular vein at postoperative day 1 was significantly increased by partial hepatectomy compared with sham operation. SIGNIFICANCE: Our results indicate that ALF increases BBB permeability to cyclosporin A by lowering the function of P glycoprotein and tight junctions, consequently leading to augmentation of cyclosporin A-induced neurotoxicity. The possibility that cyclosporin A increases the risk of neurotoxicity including tremors at an early phase of liver transplantation must be considered. PMID- 21262238 TI - The characteristics of therapeutic effect of pinocembrin in transient global brain ischemia/reperfusion rats. AB - AIMS: The therapeutic effect of pinocembrin, together with the therapeutic time window, in the transient global cerebral ischemia/reperfusion (I/R) rats was investigated. MAIN METHODS: Adult male Sprague-Dawley rats were subjected to global cerebral ischemia for 20 min by four-vessel occlusion. Pinocembrin (1 and 5mg/kg) was administrated intravenously 30 min before ischemia and 30 min, 2h, 6h after reperfusion, respectively. Neurological scores, brain edema and histological examination by Nissl staining were employed to assess the neuronal injury after ischemia and the neuroprotection by pinocembrin. The activities of superoxide dismutase (SOD), myeloperoxidase (MPO) and the content of malondialdehyde (MDA) in brain tissue were tested by colorimetric assays. Alterations of neurotransmitters were determined by a high performance liquid chromatography-electrochemical method. KEY FINDINGS: Pinocembrin significantly ameliorated neurological deficits and brain edema, and alleviated the degree of hippocampal neuronal loss at 24h after global cerebral I/R with a broad therapeutic time window. It was found that treatment with pinocembrin reduced the compensatory increase of SOD activity and decreased the MDA level and MPO activity in a dose-dependent manner. The metabolic balance between excitatory and inhibitory amino acids was modulated by pinocembrin treatment. SIGNIFICANCE: These findings suggest that pinocembrin provides neuroprotection against global cerebral ischemic injury with a wide therapeutic time window, which may be attributed to its antioxidative, antiinflammatory and antiexcitotoxic effects. PMID- 21262239 TI - Basal sympathetic activity to the microcirculation in tetraplegic man revealed by wavelet transform of laser Doppler flowmetry. AB - BACKGROUND: The 1984/86 published neurogram results showing only rare sympathetic nerve activity (SNA) to the muscles and skin in tetraplegia are still accepted. The present study by a different method attempted to confirm or deny those findings. METHODS AND RESULTS: The effect of basal SNA to the microcirculation of the feet and calf in 10 complete (AIS A) traumatic tetraplegic and 10 healthy age matched subjects were evaluated by wavelet transform of laser Doppler flowmetry (LDF) recordings. The results clearly indicated there is significant basal SNA from the decentralized spinal cord in tetraplegia. In addition, wavelet analysis allowed a study of other influences on the microcirculation besides SNA. Collectively, in tetraplegia compared with controls, the powers of the low frequency oscillations in blood flow were reduced; in that the endothelium caused less vasodilatation while the SNA and intrinsic vascular smooth muscles induced smaller degrees of vasoconstriction. However, the high frequency and especially the cardiac powers were greater. The latter presenting an obvious important factor for the preservation of blood flow in the microcirculation. CONCLUSIONS: It is suggested that basal SNA to the cutaneous microcirculation occurs in complete tetraplegia, and the significant levels of circulating noradrenaline reported by others indicate this is also true in other parts of the body. This may explain the usual absence of severe, incapacitating, autonomic deficiency in this condition. PMID- 21262240 TI - Spike-timing dependent plasticity in striatal interneurons. AB - Basal ganglia, an ensemble of interconnected subcortical nuclei, are involved in adaptive motor planning and procedural learning. Striatum, the primary input nucleus of basal ganglia, extracts the pertinent cortical and thalamic information from background noise in relation with the environmental stimuli and motivation. The striatum comprises different neuronal populations: the GABAergic striatal output neurons, three classes of GABAergic interneurons and the cholinergic cells. Striatal interneurons exert a powerful control of striatal output neuron excitability and therefore shape the cortico-basal ganglia information processing. Besides output neurons, striatal interneurons also receive directly cortical information and are able to adapt their behavior depending on the level of cortical and striatal activation. In this review, we focus on the corticostriatal long-term synaptic efficacy changes occurring in interneurons, and especially the spike-timing dependent plasticity (STDP), as a Hebbian synaptic learning rule. Combined with the striatal local interactions between interneurons and output neurons, we will consider the functional consequences of the interneuron plasticity on the striatal output. This article is part of a Special Issue entitled 'Synaptic Plasticity & Interneurons'. PMID- 21262241 TI - The role of neurexins in schizophrenia and autistic spectrum disorder. AB - Schizophrenia and autistic spectrum disorder (ASD) are common, chronic mental conditions with both genetic and environmental components to their aetiology. The identification of genes influencing susceptibility to these disorders offers a rational route towards a clearer understanding of the neurobiology, and with this the prospect of treatment and prevention strategies tailored towards the remediation of the altered pathways. Copy number variants (CNVs) underlie many serious illnesses, including neurological and neurodevelopmental syndromes. Recent studies assessing copy number variation in ASD and schizophrenia have repeatedly observed heterozygous deletions eliminating exons of the neurexin 1alpha gene (but not the neurexin-1beta gene) in patients with ASD and schizophrenia. The neurexins are synaptic adhesion proteins that are known to play a key role in synaptic formation and maintenance. The functional significance of the recurrent deletion is poorly understood, but the availability of mice with deletion of the promoter and first exon of neurexin-1alpha provides direct access to the biological effects of neurexin-1alpha disruption on phenotypes relevant to ASD and schizophrenia. We review the evidence for the role of neurexin-1alpha in schizophrenia and ASD, and consider how genetic disruption of neurexin-1alpha may underpin the neuropathology contributing to these distinct neurodevelopmental disorders. PMID- 21262242 TI - The orbitofrontal cortex and its role in the assignment of behavioural significance. AB - Converging evidence suggests a specific role for the orbitofrontal cortex (OFC) in processing of reinforcer value and stimulus hedonicity. However, in a recent study posterior parts of the OFC were also activated in the absence of physical reward or positive reinforcement, namely when affectively neutral stimuli were perceived as salient and required an immediate adjustment of behaviour. This suggests that the OFC may be similarly responsive to different types of behaviourally significant events irrespective of their affective valence or the associated response demands. The present functional neuroimaging study aimed at testing this hypothesis. By systematically varying the exact nature of the behavioural significance of experimental stimuli we were able to directly compare neural responses to significant events that signalled the chance to gain a monetary reward for correct performance with brain activation related to salient, but affectively neutral events that occurred unexpectedly and required a rapid adjustment of behaviour towards these events. The observed commonalities in orbitofrontal activation for different types of significant events, which occurred independent of the hedonic value or the actual response requirements, confirmed the hypothesis that the OFC may be more generally involved in evaluating the behavioural relevance of salient environmental stimuli and is not restricted to the processing of reward and positive incentive value. Our findings thus further underscore the putative role of the OFC in the prioritisation of attentional selection and behavioural control. PMID- 21262243 TI - Top-down control of visual cortex in migraine populations. AB - The pathophysiology of migraine includes a heightened excitability of visual cortex that persists between headache events and that has been linked to impaired inhibitory intracortical processes. Here we examined the hypothesis that this cortical pathophysiology would affect the top-down attentional control of visual cortex. We asked two groups of participants-migraineurs (N=29) and non-migraine controls (N=29)-to perform a probabilistic spatial orienting task as we measured visual sensory cortical responses via event-related potentials (ERPs). Data were then analyzed as a function of whether the ERP-eliciting stimulus was in the fovea vs. parafovea, and whether the stimulus' location was attended or unattended. In this regard, we found two key between-groups differences in the effect of attention on sensory-evoked visual-cortical activity. First, relative to controls, migraineurs showed a larger attention effect in the visual N1 ERP component for events at the fovea. Second, unlike controls, migraineurs showed no early-phase attention effect in the P1 ERP component for events in the parafovea. Despite these altered ERP responses in migraineurs, however, corresponding behavioral data indicated that they also had heightened response performance. Taken together, our results support the hypothesis that migraineurs have an altered top-down attentional control of visual cortex, with the data suggesting that the effect may be tied to a reduced ability to suppress sensory-evoked activity for unattended events in the visual periphery. PMID- 21262245 TI - The role of episodic memory in controlled evaluative judgments about attitudes: an event-related potential study. AB - Event-related potentials (ERPs) are unique in their ability to provide information about the timing of activity in the neural networks that perform complex cognitive processes. Given the dearth of extant data from normal controls on the question of whether attitude representations are stored in episodic or semantic memory, the goal here was to study the nature of the memory representations used during conscious attitude evaluations. Thus, we recorded ERPs while participants performed three tasks: attitude evaluations (i.e., agree/disagree), autobiographical cued recall (i.e., You/Not You) and semantic evaluations (i.e., active/inactive). The key finding was that the parietal episodic memory (EM) effect, a well-established correlate of episodic recollection, was elicited by both attitude evaluations and autobiographical retrievals. By contrast, semantic evaluations of the same attitude items elicited less parietal activity, like that elicited by Not You cues, which only access semantic memory. In accord with hemodynamic results, attitude evaluations and autobiographical retrievals also produced overlapping patterns of slow potential (SP) activity from 500 to 900ms preceding the response over left and right inferior frontal, anterior medial frontal and occipital brain areas. Significantly different patterns of SP activity were elicited in these locations for semantic evaluations and Not You cues. Taken together, the results indicate that attitude representations are stored in episodic memory. Retrieval timing varied as a function of task, with earlier retrievals in both evaluation conditions relative to those in the autobiographical condition. The differential roles and timing of memory retrieval in evaluative judgment and memory retrieval tasks are discussed. PMID- 21262244 TI - Amygdala activity at encoding corresponds with memory vividness and with memory for select episodic details. AB - It is well known that amygdala activity during encoding corresponds with subsequent memory for emotional information. It is less clear how amygdala activity relates to the subjective and objective qualities of a memory. In the present study, participants viewed emotional and neutral objects while undergoing a functional magnetic resonance imaging scan. Participants then took a memory test, identifying which verbal labels named a studied object and indicating the vividness of their memory for that object. They then retrieved episodic details associated with each object's presentation, selecting which object exemplar had been studied and indicating in which screen quadrant, study list, and with which encoding question the exemplar had been studied. Parametric analysis of the encoding data allowed examination of the processes that tracked with increasing memory vividness or with an increase in the diversity of episodic details remembered. Dissociable networks tracked these two increases, and amygdala activity corresponded with the former but not the latter. Subsequent-memory analyses revealed that amygdala activity corresponded with memory for exemplar type but not for other episodic features. These results emphasize that amygdala activity does not ensure accurate encoding of all types of episodic detail, yet it does support encoding of some item-specific details and leads to the retention of a memory that will feel subjectively vivid. The types of episodic details tied to amygdala engagement may be those that are most important for creating a subjectively vivid memory. PMID- 21262246 TI - Regulation by chronic-mild stress of glucocorticoids, monocyte chemoattractant protein-1 and adiposity in rats fed on a high-fat diet. AB - Stress has been reported as a widespread problem and several studies have linked obesity and inflammation-related diseases. Moreover, the combination of suffering from chronic stress and high energy intake might be related to the onset of some metabolic diseases. To study the possible relationships between stress, inflammatory status and obesity, a chronic-mild stress (CMS) paradigm with a high fat dietary intake model (Cafeteria diet) was implemented on male Wistar rats for 11 weeks. Stress and dietary intake effects on animal adiposity, serum biochemical as well as glucocorticoids and inflammation markers were all analyzed. As expected, consuming a high-fat diet increased body weight, adiposity and insulin resistance in non-stressed animals. A decrease of total white adipose tissue (WAT) and an increase of fecal glucocorticoids, as well as angiotensinogen, and monocyte chemoattractant protein-1 (MCP-1) expression level in retroperitoneal WAT were found only on control-stressed rats. Regarding the serum MCP-1, a decrease was observed on animals under CMS while being fed Cafeteria diet. Furthermore, 11beta-hydroxysteroid dehydrogenase activity, a glucocorticoid and obesity biomarker in the liver, was influenced by high-fat diet intake but not by stress. Finally, statistical analysis showed a strong relation between MCP-1 expression levels in retroperitoneal WAT, fecal corticosterone and total WAT. This trial proved that CMS induced a glucocorticoid mediated response, which was reduced by the intake of a Cafeteria diet. These findings suggest that a high-fat diet could protect against a stress condition and revealed a different behavior to a stressful environment depending on the nutritional status. PMID- 21262247 TI - "Snacking" causes long term attenuation of HPA axis stress responses and enhancement of brain FosB/deltaFosB expression in rats. AB - A history of limited, intermittent intake of palatable food (sucrose drink) attenuates hypothalamic-pituitary-adrenal (HPA) axis stress responses and induces markers of neuronal plasticity in stress- and reward-regulatory brain regions. Synaptic plasticity could provide a mechanism for long-term changes in neuronal function, implying that sucrose stress-dampening may endure over long periods of time. The present study tests the persistence of HPA axis dampening and plasticity after cessation of palatable drinking. Adult, male Long-Evans rats (n=10-13) with free access to water and chow were given additional twice-daily access to 4ml sucrose (30%) or water for 14days. Rats were subsequently tested for HPA responsiveness to an acute (20min) restraint stress at 1, 6 and 21days after the cessation of sucrose. Brains were collected for immunohistochemical analysis of FosB/deltaFosB, a marker of long-term neuronal plasticity, in the basolateral amygdala (BLA) and nucleus accumbens (NuAc). Prior sucrose consumption significantly decreased the plasma corticosterone response to restraint at 1day after the last palatable drink presentation, and also increased FosB/deltaFosB-positive cells in the BLA and in the NuAc core. This HPA-dampening persisted through 21days after the termination of the palatable drink, as did the increased FosB/deltaFosB immunoreactivity in both the BLA and the NuAc core. These data suggest that chronic palatable food intake causes lasting changes in stress/reward-modulatory circuitry and that the suppressed hormonal response to stress that can persist well beyond periods of palatable drink exposure. PMID- 21262248 TI - Pre-learning stress differentially affects long-term memory for emotional words, depending on temporal proximity to the learning experience. AB - Stress exerts a profound, yet complex, influence on learning and memory and can enhance, impair or have no effect on these processes. Here, we have examined how the administration of stress at different times before learning affects long-term (24-hr) memory for neutral and emotional information. Participants submerged their dominant hand into a bath of ice cold water (Stress) or into a bath of warm water (No stress) for 3 min. Either immediately (Exp. 1) or 30 min (Exp. 2) after the water bath manipulation, participants were presented with a list of 30 words varying in emotional valence. The next day, participants' memory for the word list was assessed via free recall and recognition tests. In both experiments, stressed participants exhibited greater blood pressure, salivary cortisol levels, and subjective pain and stress ratings than non-stressed participants in response to the water bath manipulation. Stress applied immediately prior to learning (Exp. 1) enhanced the recognition of positive words, while stress applied 30 min prior to learning (Exp. 2) impaired free recall of negative words. Participants' recognition of positive words in Experiment 1 was positively associated with their heart rate responses to the water bath manipulation, while participants' free recall of negative words in Experiment 2 was negatively associated with their blood pressure and cortisol responses to the water bath manipulation. These findings indicate that the differential effects of pre-learning stress on long term memory may depend on the temporal proximity of the stressor to the learning experience and the emotional nature of the to-be-learned information. PMID- 21262249 TI - Novel and efficient synthesis of 22-alkynyl-13,24(23)-cyclo-18,21-dinorchol-22-en 20(23)-one analogues. AB - The efficient synthesis of some 22-alkynyl-13,24(23)-cyclo-18,21-dinorchol-22-en 20(23)-ones was investigated. 22-Iodocyclo-18,21-dinorcholenones were prepared from cyclo-18,21-dinorcholenones using I(2)/DMAP/pyridine system firstly. The cross coupling reaction of 22-iodocyclo-18,21-dinorcholenones and 1-alkynes was carried out efficiently catalyzed by tetrakis(triphenylphosphine) palladium/cuprous iodide in the presence of base diisopropylethylamine. This strategy offered a very straightforward and efficient method for access to conjugated alkynyl cyclo-18,21-dinorcholenones from the cyclo-18,21 dinorcholenones and 1-alkynes in excellent overall yields. Evaluation of the synthesized compounds for cytotoxicity against KB, HeLa, MKN-28 and MCF-7 cell lines showed that the 22-alkynylcyclodinorchoenones possessing hydroxylethyl and hydroxylmethyl mono-substituted side chain at the end of alkynyl group have significantly inhibition activity. PMID- 21262250 TI - Induction of Fas receptor and Fas ligand by nodularin is mediated by NF-kappaB in HepG2 cells. AB - Nodularin is a natural toxin with multiple features, including inhibitor of protein phosphatases 1 and 2A as well as tumor initiator and promoter. One unique feature of nodularin is that this chemical is a hepatotoxin. It can accumulate into the liver after contact and lead to severe damage to hepatocyte, such as apoptosis. Fas receptor (Fas) and Fas ligand (FasL) system is a critical signaling network triggering apoptosis. In current study, we investigated whether nodularin can induce Fas and FasL expression in HepG2 cell, a well used in vitro model for the study of human hepatocytes. Our data showed nodularin induced Fas and FasL expression, at both mRNA and protein level, in a time- and dose dependent manner. We also found nodularin induced apoptosis at the concentration and incubation time that Fas and FasL were significantly induced. Neutralizing antibody to FasL reduced nodularin-induced apoptosis. Further studies demonstrated that nodularin promoted nuclear translocation and activation of p65 subunit of NF-kappaB. By applying siRNA targeting p65, which knocked down p65 in HepG2 cells, we successfully impaired the activation of NF-kappaB by nodularin. In these p65 knockdown cells, we observed that Fas and FasL expression and apoptosis induced by nodularin were significantly reduced. These findings suggest the induction of Fas and FasL expression and thus cell apoptosis in HepG2 cells by nodularin is mediated through NF-kappaB pathway. PMID- 21262251 TI - Hexavalent chromium-induced apoptosis of granulosa cells involves selective sub cellular translocation of Bcl-2 members, ERK1/2 and p53. AB - Hexavalent chromium (CrVI) has been widely used in industries throughout the world. Increased usage of CrVI and atmospheric emission of CrVI from catalytic converters of automobiles, and its improper disposal causes various health hazards including female infertility. Recently we have reported that lactational exposure to CrVI induced a delay/arrest in follicular development at the secondary follicular stage. In order to investigate the underlying mechanism, primary cultures of rat granulosa cells were treated with 10 MUM potassium dichromate (CrVI) for 12 and 24h, with or without vitamin C pre-treatment for 24h. The effects of CrVI on intrinsic apoptotic pathway(s) were investigated. Our data indicated that CrVI: (i) induced DNA fragmentation and increased apoptosis, (ii) increased cytochrome c release from the mitochondria to cytosol, (iii) downregulated anti-apoptotic Bcl-2, Bcl-XL, HSP70 and HSP90; upregulated pro apoptotic BAX and BAD, (iv) altered translocation of Bcl-2, Bcl-XL, BAX, BAD, HSP70 and HSP90 to the mitochondria, (v) upregulated p-ERK and p-JNK, and selectively translocated p-ERK to the mitochondria and nucleus, (vi) activated caspase-3 and PARP, and (vii) increased phosphorylation of p53 at ser-6, ser-9, ser-15, ser-20, ser-37, ser-46 and ser-392, increased p53 transcriptional activation, and downregulated MDM-2. Vitamin C pre-treatment mitigated CrVI effects on apoptosis and related pathways. Our study, for the first time provides a clear insight into the effect of CrVI on multiple pathways that lead to apoptosis of granulosa cells which could be mitigated by vitamin C. PMID- 21262252 TI - Daily treatment with alpha-naphthoflavone enhances follicular growth and ovulation rate in the rat. AB - The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and the first protein involved in a variety of physiological and toxicological processes, including those of xenobiotic metabolizing enzymes. AhR has been found in the ovary of many species and seems to mediate the ovarian toxicity of many environmental contaminants, which are AhR ligands. However, the role of AhR in the ovarian function is unknown. Therefore, the aim of this work was to study the action of alpha-naphthoflavone (alphaNF), known to be an AhR antagonist, on both follicular growth and ovulation. Immature Sprague-Dawley rats were daily injected intraperitoneally with alphaNF (0.1-80 mg/kg) or vehicle for 12 days, and primed with gonadotrophins (eCG/hCG) to induce follicular growth and ovulation. Ovaries were obtained 20 h after hCG administration. By means of immunohistochemistry, we found that the numbers of primordial, primary and antral follicles were increased in rats treated with 80 mg/kg alphaNF and that there were no differences with other doses. Likewise, the ovarian weight and the ovulation rate, measured by both number of oocytes within oviducts and corpora lutea in ovarian sections, were increased when the rats received either 1 or 10mg/kg daily. Although further studies are necessary to know the mechanism of action of alphaNF, it is possible that the different ovarian processes can be differentially responsive to the presence of different levels of alphaNF, and that the same or different endogenous AhR ligands can be involved in these ovarian processes in a cell type dependent manner. PMID- 21262253 TI - Induction of cytochromes P450 1A1 and 1A2 by tanshinones in human HepG2 hepatoma cell line. AB - Diterpenoid tanshinones including tanshinone IIA (TIIA), cryptotanshinone (CTS), tanshinone I (TI) and dihydrotanshinone I (DHTI) are the major bioactive components from Danshen. The major aim of our present study was to investigate the induction potential of these four main components of tanshinones (TIIA, CTS, TI, and DHTI) on the expression of CYP1A1 and CYP1A2 in HepG2 cells. Our results showed that all of these four tanshinones caused a significant time- and concentration-dependent increase in the amount of CYP1A1/2 expression in HepG2 cells. These induction effects were further characterized through transcriptional regulation: the induction of CYP1A1/2 mRNA level by tanshinones was completely blocked by the transcription inhibitor actinomycin D; the expression of CYP1A1/2 heterogeneous nuclear RNA was induced by tanshinone treatment; and CYP1A1 mRNA stability was not influenced by these tanshinones. Interestingly, tanshinones plus B[a]P produced additive/synergistic effect on CYP1A1/2 induction. In addition, the tanshinone-induced CYP1A1/2 expression was abolished by the aryl hydrocarbon receptor (AhR) antagonist resveratrol, suggesting an AhR dependent transcription mechanism. In the reporter gene assay, while TI and DHTI significantly induced AhR-dependent luciferase activity, TIIA and CTS failed to induce this activity. Collectively, the tanshinones could induce CYP1A1 and CYP1A2 expression through transcriptional activation mechanism and exert differential effects on activating AhR in HepG2 cells. Our findings suggest that rational administration of tanshinones should be considered with respect to their effect on AhR and CYP1A1/2 expression. PMID- 21262254 TI - New challenges from an "old" toxin. PMID- 21262255 TI - Age trajectories of physiological indices in relation to healthy life course. AB - We analysed relationship between the risk of onset of "unhealthy life" (defined as the onset of cancer, cardiovascular diseases, or diabetes) and longitudinal changes in body mass index, diastolic blood pressure, hematocrit, pulse pressure, pulse rate, and serum cholesterol in the Framingham Heart Study (Original Cohort) using the stochastic process model of human mortality and aging. The analyses demonstrate how decline in resistance to stresses and adaptive capacity accompanying human aging can be evaluated from longitudinal data. We showed how these components of the aging process, as well as deviation of the trajectories of physiological indices from those minimising the risk at respective ages, can lead to an increase in the risk of onset of unhealthy life with age. The results indicate the presence of substantial gender difference in aging related decline in stress resistance and adaptive capacity, which can contribute to differences in the shape of the sex-specific patterns of incidence rates of aging related diseases. PMID- 21262256 TI - The effect of pictorial warnings on cigarette packages on attentional bias of smokers. AB - Given that previous studies demonstrated that smoking-related cues (like cigarette packages) grab the attention of smokers and thereby contribute to craving and tobacco seeking we investigated how pictorial health warnings presented on cigarette packages affect attention allocation towards cigarette packages. The WHO advises the use of pictorial health warnings on cigarette packages. However, at present no experimental studies are available investigating if pictorial warnings modulate incentive properties of cigarette packages. Fifty nine tobacco smokers and 55 non-smokers performed a visual dot probe task to assess attention allocation towards cigarette packages with and without health warnings. Smokers were divided a priori in a group of light smokers (<20 cigarettes/day; n=39) and heavy smokers (>=20 cigarettes/day; n=20). Psychometric measures on anxiety and nicotine craving were administered. Light smokers showed an attentional bias towards packages without pictorial warnings while no effects were observed in the other groups. In heavy smokers attention allocation towards pictorial health warnings was associated with an increase of craving and anxiety. The results have a potential public health perspective as pictorial health warnings might be an effective strategy to reduce attentional bias towards cigarette packages of light smokers, while counterproductive effects in heavy smokers warrant further investigation. PMID- 21262257 TI - Baicalein protects the brain against neuron impairments induced by MPTP in C57BL/6 mice. AB - Many studies of Parkinson's disease suggest that oxidative stress is involved in the neurodegenerative process. Baicalein has been shown to have antioxidant effects. The present study examines the effect of baicalein on 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in C57BL/6 mice. MPTP treatment impaired spontaneous motor activity and rotarod performance, but baicalein improved this deficit. Moreover, baicalein at 280 and 560 mg/kg exhibited a protective effect against the MPTP-induced decrease in tyrosine hydroxylase (TH)-positive fibers in the substantia nigra, demonstrated by the immunohistological, morphological and behavioral outcomes. MPTP treatment also decreased dopamine levels in the striatum. However, treatment with baicalein attenuated these decreases in dopamine levels by changing dopamine catabolism and inhibiting dopamine turnover. The neuroprotective effect of baicalein on dopaminergic neurons may partly be due to its antioxidant properties. Therefore, we speculate that baicalein might be a promising candidate for prevention or treatment of oxidative stress-related neurodegenerative disorders such as Parkinson's disease. PMID- 21262258 TI - Rheological properties of ovalbumin hydrogels as affected by surfactants addition. AB - The gel properties of ovalbumin mixtures with three different surfactants (sodium perfluorooctanoate, sodium octanoate and sodium dodecanoate) have been studied by rheological techniques. The gel elasticities were determined as a function of surfactant concentration and surfactant type. The fractal dimension of the formed structures was evaluated from plots of storage modulus against surfactant concentration. The role of electrostatic, hydrophobic and disulfide SS interactions in these systems has been demonstrated to be the predominant. The viscosity of these structures tends to increase with surfactant concentration, except for the fluorinated one. Unfolded ovalbumin molecules tend to form fibrillar structures that tend to increase with surfactant concentration, except for the fluorinated one. This fact has been related to the particular nature of this molecule. PMID- 21262259 TI - Radiation crosslinking polymerization of sterculia polysaccharide-PVA-PVP for making hydrogel wound dressings. AB - The present study deals with the modification of sterculia gum by PVA-PVP through radiation crosslinking, to develop the hydrogels meant for the delivery of antimicrobial agent to the wounds. The hydrogels were characterized by SEM, FTIR, TGA and swelling studies. For the evaluation of swelling and drug release mechanism, the swelling kinetics and in vitro release dynamics of model drug from this matrix have been studied respectively in the solution of different pHs and simulated wound fluid. After 24h swelling per gram of the hydrogel has taken (17.03+/-0.19)g of simulated wound fluid and has released (0.230+/-0.01)mg of drug in the simulated fluid. The release of drug in simulated fluids occurred through non-Fickian diffusion mechanism. PMID- 21262260 TI - Anti-tumor effects of proteoglycan from Phellinus linteus by immunomodulating and inhibiting Reg IV/EGFR/Akt signaling pathway in colorectal carcinoma. AB - Proteoglycan (P1) purified from Phellinus linteus has been reported to have anti disease activities. The objectives of our research were to determine the anti tumor effect and possible mechanisms of P1 on human cancer cells. Cell inhibition assay showed that P1 has an antiproliferative effect on HepG2, HT-29, NCI-H 460 and MCF-7 human colon cancer cells, especially it was very effective in inhibiting HT-29 cells. When HT-29-bearing mice were treated with P1(100mg/kg), there was relative increase in spleen and thymus weights, the plasmatic pIgR and IgA levels were significantly increased, also there was a notable decrease in plasmatic PGE2, Reg IV, EGFR and Akt concentrations measured by ELISA. RT-PCR analysis suggested that P1-induced HT-29 apoptosis appeared to be associated with a decrease in the levels of expression of Reg IV and EGFR. These results suggest that P1 might have two potential roles in treating cancer; it acts as an immunopotentiator partly through protecting T cells from escaping PGE2 attack and enhancing the mucosal IgA response, and as a direct inhibitor by disrupting the Reg IV/EGFR/Akt signaling pathway. PMID- 21262261 TI - A new automated method for rat sleep deprivation with minimal confounding effects on corticosterone and locomotor activity. AB - The function of sleep in physiology, behaviour and cognition has become a primary focus of neuroscience. Its study inevitably includes experimental sleep deprivation designs. However, concerns exist regarding confounds like stress, increased locomotor activity levels, and decreased motivation to perform operant tasks induced by the methods employed. We here propose a novel procedure for sleep deprivation in rats and evaluate how it affects sleep, corticosterone concentration profiles, locomotor activity levels, and motivation to perform an operant task. Before, during and after 12h of total sleep deprivation by means of gradually increasing the rotation variability and the speed of a novel automated, two-compartment sleep deprivation device, sleep-wake states were assessed by electroencephalography (n=21), brain extracellular corticosterone concentrations using microdialysis (n=11), locomotor activity by infrared measurements (n=8), and operant performance using a fixed-interval-fixed-ratio task (n=16). Sleep was effectively prevented during the procedure; rats on average slept less than 1% of the time (0.8+/-0.2%, mean+/-standard error). Brain corticosterone concentrations were mildly increased during the procedure, but did not exceed normal peak concentrations. Locomotor activity was not only increased during the procedure, but also did not exceed the peak levels found during undisturbed wakefulness. Food restriction to 12 g/rat/day prevented sleep deprivation from reducing the motivation to perform an operant task. This novel procedure can be applied to sleep deprive rats in a highly effective way, while keeping corticosterone and locomotor activity within the normal range. PMID- 21262262 TI - Spike removal through multiscale wavelet and entropy analysis of ocular motor noise: a case study in patients with cerebellar disease. AB - Wavelet decomposition of ocular motor signals was investigated with a view to its use for noise analysis and filtering. Ocular motor noise may be physiological, depending on brain activities, or experimental, depending on the eye recording machine, head movements and blinks. Experimental noise, such as spikes, must be removed, preserving noise due to neuro-physiological activities. The proposed method uses wavelet multiscale decomposition to remove spikes and optimizes the procedure by means of the covariance of the eye signals. To measure the noise on eye motor control, we used the wavelet entropy. The method was tested on patients with cerebellar disorders and healthy subjects. A significant difference in wavelet entropy was observed, indicating this quantity as a valuable measure of physiological motor noise. PMID- 21262263 TI - The MHC, disease and selection. AB - Given large sample sizes, whole genome screens are now able to identify even quite modest contributions of common human genetic variation to disease. These approaches, made possible by the development of high-throughput, dense SNP genotyping, find few associations stronger than those for the human MHC, in multigenic autoimmune conditions. They confirm earlier findings that the major variants affecting susceptibility and resistance to autoimmunity relate to MHC class I and class II genes. It is generally assumed, although there are few good examples, that selection for resistance to infection drives evolution of MHC variation. Many MHC-associated diseases may be the price paid for an effective immune response. Interestingly, the MHC appears to influence susceptibility to conditions unrelated to immunity, including some neuropathologies. The infectious history of the individual, conditioned by their MHC, may exert an indirect effect on these diseases, although there are hints of more direct involvement of MHC molecules in neuronal systems. Here I survey the variety of conditions associated with the MHC in relation to ideas that selection through disease resistance is dependent upon MHC variation, not only at the level of the individual, but also at the level of the population. PMID- 21262265 TI - Functional interaction between morphine and central amygdala cannabinoid CB1 receptors in the acquisition and expression of conditioned place preference. AB - The present study was done to determine whether cannabinoid CB1 receptors of the central amygdala (CeA) are implicated in morphine-induced place preference. Using a 3-day schedule of conditioning, it was found that subcutaneous (s.c.) administration of morphine (2, 4 and 6 mg/kg) caused a significant dose-dependent conditioned place preference (CPP) in male Wistar rats. Intra-CeA microinjection of the cannabinoid CB1 receptor agonist arachidonylcyclopropylamide (ACPA; 0.5, 2.5 and 5 ng/rat) dose-dependently potentiated the morphine (2mg/kg)-induced CPP. Furthermore, the administration of ACPA (5 ng/rat, intra-CeA) alone induced a significant CPP. It should be considered that the higher dose of ACPA (5 ng/rat, intra-CeA) in combination with morphine decreased locomotor activity on the testing phase. On the other hand, intra-CeA microinjection of the cannabinoid CB1 receptor antagonist AM251 (120 ng/rat) alone induced a significant conditioned place aversion (CPA). Moreover, intra-CeA microinjection of AM251 (90 and 120 ng/rat) inhibited the morphine-induced place preference with a significant interaction. Intra-CeA microinjection of AM251 reversed the effect of ACPA on morphine response. Interestingly, microinjection of ACPA (2.5 and 5 ng/rat) or AM251 (60-120 ng/rat) into the CeA increased or decreased the expression of morphine (6 mg/kg)-induced place preference respectively. These observations provide evidence that cannabinoid CB1 receptors of the CeA are involved in mediating reward and these receptors are also implicated in the acquisition and expression of morphine-induced CPP. PMID- 21262264 TI - Protection of cholinergic and antioxidant system contributes to the effect of berberine ameliorating memory dysfunction in rat model of streptozotocin-induced diabetes. AB - Memory impairment induced by streptozotocin in rats is a consequence of changes in CNS that are secondary to chronic hyperglycemia, impaired oxidative stress, cholinergic dysfunction, and changes in glucagon-like peptide (GLP). Treatment with antihyperglycemics, antioxidants, and cholinergic agonists are reported to produce beneficial effect in this model. Berberine, an isoquinoline alkaloid is reported to exhibit anti-diabetic and antioxidant effect, acetylcholinesterase (AChE) inhibitor, and increases GLP release. However, no report is available on influence of berberine on streptozotocin-induced memory impairment. Therefore, we tested its influence against cognitive dysfunction in streptozotocin-induced diabetic rats using Morris water maze paradigm. Lipid peroxidation and glutathione levels as parameters of oxidative stress and choline esterase (ChE) activity as marker of cholinergic function were assessed in the cerebral cortex and hippocampus. Thirty days after diabetes induction rats showed a severe deficit in learning and memory associated with increased lipid peroxidation, decreased reduced glutathione, and elevated ChE activity. In contrast, chronic treatment with berberine (25-100mg/kg, p.o., twice daily, 30 days) improved cognitive performance, lowered hyperglycemia, oxidative stress, and ChE activity in diabetic rats. In another set of experiment, berberine (100mg/kg) treatment during training trials also improved learning and memory, lowered hyperglycemia, oxidative stress, and ChE activity. Chronic treatment (30 days) with vitamin C or metformin, and donepezil during training trials also improved diabetes-induced memory impairment and reduced oxidative stress and/or choline esterase activity. In conclusion, the present study demonstrates treatment with berberine prevents the changes in oxidative stress and ChE activity, and consequently memory impairment in diabetic rats. PMID- 21262266 TI - Effects of 5-HT(2A) and 5-HT(2C) receptor antagonists on acute and chronic dyskinetic effects induced by haloperidol in rats. AB - An important limitation of classical antipsychotic drugs such as haloperidol (HAL) is their liability to induce extrapyramidal motor symptoms acutely and tardive dyskinetic syndromes when given chronically. These effects are less likely to occur with newer antipsychotic drugs, an attribute that is often thought to result from their serotonin-2 (5-HT(2)) receptor antagonistic properties. In the present study, we used selected doses of the 5-HT(2A) antagonist M100,907, the 5-HT(2C) antagonist SB242,084 and the mixed 5-HT(2A/C) antagonist ketanserin to re-examine the respective roles of 2A vs. 2C 5-HT(2) receptor subtypes in both acute and chronic motor effects induced by HAL. Acutely, SB242,084 (0.5 mg/kg) reduced HAL-induced catalepsy, while M100,907 (0.5 mg/kg) and ketanserin (1 mg/kg) were without effect. None of the drugs reduced HAL-induced Fos expression in the striatum or frontal cortex, and M100,907 actually potentiated HAL-induced Fos expression in the n. accumbens. In rats chronically treated with HAL, both ketanserin and SB242,084 attenuated vacuous chewing movements, while M100,907 had no effect. In addition, 5-HT(2C) but not 5 HT(2A) mRNA levels were altered in several brain regions after chronic HAL. These results highlight the importance of 5-HT2(2C) receptors in both acute and chronic motoric side effects of HAL, and suggest that 5-HT(2C) antagonism could be targeted as a key property in the development of new antipsychotic medications. PMID- 21262267 TI - Voluntary wheel running produces resistance to inescapable stress-induced potentiation of morphine conditioned place preference. AB - In rodents, exposure to acute inescapable, but not escapable, stress potentiates morphine conditioned place preference (CPP), an effect that is dependent upon hyperactivation of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). Six weeks of voluntary wheel running constrains activation of DRN 5-HT neurons during exposure to inescapable stress. Six weeks of voluntary wheel running before inescapable stress blocked stress-induced potentiation of morphine CPP. PMID- 21262269 TI - Learning deferred imitation of long spatial sequences. AB - Sequence learning has been the subject of research in various paradigms but has not been investigated for learning deferred imitation of long spatial sequences. In this task no guiding stimuli support the sequence reproduction and all sequence information has to be recalled from memory. We investigate this kind of imitation learning with a task in which a long sequence of spatial positions has to be reproduced without guiding stimuli, either by manual pointing or by ocular fixations. Sequences consisting of 20 positions were acquired after only 25 training trials. The persistence of learned sequences over several days showed that the sequence was retained in long-term memory. A transfer test revealed that the learned sequence was independent of the effector. A detailed analysis of the error distributions of pointing and ocular fixations was performed to characterize the guiding control signal. The independence of the variable position errors from the movement directions as well as the lack of error propagation between successive targets suggest that the reproduction in this learning task was guided by sequential positions rather than sequential displacements. PMID- 21262268 TI - Nucleus accumbens dopamine and mu-opioid receptors modulate the reinstatement of food-seeking behavior by food-associated cues. AB - The high attrition rates for dietary interventions aimed at promoting a healthier body mass may be caused, at least in part, by constant exposure to environmental stimuli that are associated with palatable foods. In both humans and animals, conditioned stimuli (CSs) that signal reward availability reliably reinstate food and drug-seeking behaviors. The nucleus accumbens (NAcc) is critically involved in the cue-evoked reinstatement of food-seeking, but the role of individual neurotransmitter systems within the NAcc remains to be determined. These experiments tested the effects of intra-accumbal pharmacological manipulations of dopamine (DA) D(1) and D(2) receptors, mu-opioid receptors, or serotonin (5-HT) receptors on cue-evoked relapse to food-seeking. Rats were trained to lever press for sucrose pellets and the concurrent presentation of a light-tone CS. Once training was complete, lever-pressing was extinguished in the absence of either sucrose or CS presentation. Once each rat had reached extinction criterion, they received two reinstatement sessions in which lever pressing was renewed by response-contingent presentation of the CS. Prior to each reinstatement test, rats received NAcc microinfusions of saline or the selective D(1) receptor antagonist SCH 23390, the D(2) receptor antagonist raclopride, the mu-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO), or 5-HT hydrogen maleate. Compared to saline test days, intra-accumbens infusions of SCH 23390 (1 MUg/0.5 MUL), raclopride (1 MUg/0.5 MUL), or DAMGO (0.25 MUg/0.5 MUL) effectively blocked the cue-evoked reinstatement of food-seeking. In contrast, stimulation of serotonin (5-HT) receptors by 5-HT hydrogen maleate (5 MUg/0.5 MUL) had no effect on cue-induced reinstatement. These novel data support roles for NAcc DA D(1), D(2), and mu-opioid receptors in the cue-evoked reinstatement of food seeking. PMID- 21262270 TI - Away game or home match: the influence of venue and serotonin transporter genotype on the display of offensive aggression. AB - Aggression can be modulated by both genetic and environmental factors. Here, we analyse how the serotonin transporter (5-HTT) genotype and the environmental situation in which a contest takes place shape the display of offensive aggression. Therefore, male wildtype, heterozygous, and homozygous 5-HTT knockout mice, which are known to differ in inborn levels of anxiety, were confronted three times with a docile opponent in one of three environmental situations: own territory, opponent's territory or neutral area. The main findings were: The frequency of approaching the contestant in order to gather information about him depended significantly on the venue but not on the genotype with lowest frequencies in the opponent's territory. The decision how quickly to attack the opponent was significantly influenced by the 5-HTT genotype but not by the venue: Homozygous 5-HTT knockout mice showed longest latencies. The sum of offensive aggression was significantly influenced by the 5-HTT genotype, the environmental situation, and a genotype by environment interaction. It is likely that, due to their varying genetic predisposition for anxiety, mice of the three genotypes were differentially affected by the aversiveness of the respective venue and the opponent's behaviour, which influenced their decision to display offensive aggression. As a consequence, the amount of aggression shown by homozygous 5-HTT knockout mice was influenced by the venue and the opponent's behaviour, whereas heterozygotes reacted only to the venue. Strikingly, wildtypes behaved always the same way, irrespective of venue and opponent. PMID- 21262271 TI - Effects of D-cycloserine on MPTP-induced behavioral and neurological changes: potential for treatment of Parkinson's disease dementia. AB - Glutamatergic dysfunction has been implicated in the neurodegeneration seen in Parkinson's disease (PD). Sub-chronic intraperitoneal injection with D cycloserine (DCS), a partial agonist at the glycine binding site of the N-methyl D-aspartate (NMDA) receptor, at dosages of 30, 100, or 200 mg/kg/day, was used to evaluate the role of NMDA receptors in neuronal and behavioral changes in a 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Starting one day after intra-nigral infusion of MPTP, transient disturbance of motor function in the rotarod test was observed. This impairment spontaneously recovered to control levels 6 days after MPTP lesioning and DCS treatment facilitated recovery. MPTP lesioning also caused deficits in working memory and anxiety-like behavior in the T-maze and elevated plus-maze tests, respectively. Further, object recognition was disrupted in MPTP-lesioned rats, and interleukin 2 levels in the striatum, amygdala, and non-prefrontal cortex were increased, both changes being restored by DCS treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration, microglial activation, and cell loss in the hippocampal CA1 area were all improved by DCS treatment. These results suggest that NMDA receptors are involved in PD-related neuronal and behavioral dysfunctions and that DCS may have clinical potential in the treatment of dementia associated with PD. PMID- 21262272 TI - Serotonergic involvement in methamphetamine-induced locomotor activity: a detailed pharmacological study. AB - The mechanism by which the psychostimulant methamphetamine (METH) increases locomotor activity may be attributable to indirect activation of serotonin (5-HT) and dopamine (DA) receptors. In the present study, the ability of the serotonin reuptake inhibitor fluvoxamine, 5-HT(1A), 5-HT(1B), 5-HT(2A) and 5-HT(2C) receptor antagonists WAY100635, GR127935, M100907 and SB242084, and the 5-HT(2C) receptor agonists WAY163909 and Ro 60-0175 or the 5-HT synthesis inhibitor para chlorophenylalanine (pCPA) to alter METH-induced hyperactivity was analysed. Further, for comparative purposes, the involvement of the DA D(1) and D(2) receptor antagonists SCH23390 and haloperidol, D(2) partial agonists terguride, ( )3PPP and aripiprazole and finally clozapine were assessed. Doses of pCPA that attenuated 5-HT levels reduced METH activity. The 5-HT(1B) antagonist GR127935 had no effect on METH-induced locomotor activity but blocked that induced by MDMA. The 5-HT(1A) antagonist WAY100635 reduced activity but this did not reach significance. In contrast, M100907 (minimal effective dose; MED=0.125 mg/kg), WAY163909 (MED=3mg/kg), Ro 60-0175 (MED=3mg/kg), haloperidol (MED=0.1mg/kg), clozapine (MED=5mg/kg), aripiprazole (MED=1mg/kg), (-)3PPP (MED=3mg/kg), terguride (MED=0.2mg/kg) and SCH23390 (MED=0.001325 mg/kg) attenuated METH induced locomotor activity. Administration of 20mg/kg fluvoxamine attenuated, while SB242084 (MED=0.25mg/kg) potentiated METH-induced activity. These results contribute significantly to the understanding of the mechanism of action of this psychostimulant and suggest for the first time, that METH-induced locomotor stimulation is modulated by 5-HT(2A) and 5-HT(2C) receptors, but demonstrate that 5-HT(1B) receptors are not directly involved. The involvement of the dopaminergic system was also demonstrated. PMID- 21262273 TI - Leptin differentially regulates NPY secretion in hypothalamic cell lines through distinct intracellular signal transduction pathways. AB - Leptin acts as a key peripheral hormone in distinct neurons in the hypothalamus to modulate both reproductive function and energy homeostasis. The control of neuropeptide Y (NPY) secretion is an example of a process that can be differentially regulated by leptin. In order to further understand these distinct modulatory effects, we have used immortalized, neuronal hypothalamic cell lines expressing NPY, mHypoE-38 and mHypoE-46. We found that these cell lines express the endogenous leptin receptor, ObRb, and secrete detectable levels of NPY. We exposed the neurons to 100nM leptin for 1h and determined that the basal levels of NPY in the cell lines were differentially regulated: NPY secretion was inhibited in mHypoE-46 neurons, whereas NPY secretion was induced in the mHypoE 38 neurons. In order to determine the mechanisms involved in the divergent regulation of NPY release, we analyzed the activity of a number of signaling components using phospho-specific antibodies directed towards specific proteins in the MAP kinase, PI3K, and AMPK pathways, among others. We found that leptin activated a different combination of second messengers in each cell line. Importantly, we could link the regulation of NPY secretion to different signaling pathways, AMPK in the mHypoE-46 and both MAPK and PI3K in the mHypoE-38 neurons. This is the first demonstration that leptin can specifically regulate individual NPY neuron secretory responses through distinct signaling pathways. PMID- 21262275 TI - Real-time cellular impedance measurements detect Ca(2+) channel-dependent oscillations of morphology in human H295R adrenoma cells. AB - Endocrine cells, such as H295R have been widely used to study secretion of steroid and other hormones. Exocytosis-dependent hormone release is accompanied by an increase in plasma membrane surface area and a decrease in vesicle content. Recovery of vesicles and decrease in plasma membrane area is achieved by endocytotic processes. These changes in the extent of the surface area lead to morphological changes which can be determined by label-free real-time impedance measurements. Exo- and endocytosis have been described to be triggered by activation of L-type Ca(2+) channels. The present study demonstrates that activation of L-type calcium channels induces prolonged oscillating changes in cellular impedance. The data support the hypothesis that a tight regulation of the intracellular Ca(2+) concentration is a prerequisite for the observed cellular impedance oscillations. Furthermore evidence is presented for a mechanism in which the oscillations depend on a Ca(2+)-triggered calmodulin dependent cascade involving myosin light chain kinase, nonmuscle myosin II and ultimately actin polymerization, a known determinant for cell shape changes and exocytosis in secretory cells. The described assay provides a method to determine continuously prolonged changes in cellular morphology such as exo/endocytosis cycles. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21262274 TI - Insights into modulation of calcium signaling by magnesium in calmodulin, troponin C and related EF-hand proteins. AB - The Ca(2+)-binding helix-loop-helix structural motif called "EF-hand" is a common building block of a large family of proteins that function as intracellular Ca(2+)-receptors. These proteins respond specifically to micromolar concentrations of Ca(2+) in the presence of ~1000-fold excess of the chemically similar divalent cation Mg(2+). The intracellular free Mg(2+) concentration is tightly controlled in a narrow range of 0.5-1.0mM, which at the resting Ca(2+) levels is sufficient to fully or partially saturate the Ca(2+)-binding sites of many EF-hand proteins. Thus, to convey Ca(2+) signals, EF-hand proteins must respond differently to Ca(2+) than to Mg(2+). In this review the structural aspects of Mg(2+) binding to EF-hand proteins are considered and interpreted in light of the recently proposed two-step Ca(2+)-binding mechanism (Grabarek, Z., J. Mol. Biol., 2005, 346, 1351). It is proposed that, due to stereochemical constraints imposed by the two-EF-hand domain structure, the smaller Mg(2+) ion cannot engage the ligands of an EF-hand in the same way as Ca(2+) and defaults to stabilizing the apo-like conformation of the EF-hand. It is proposed that Mg(2+) plays an active role in the Ca(2+)-dependent regulation of cellular processes by stabilizing the "off state" of some EF-hand proteins, thereby facilitating switching off their respective target enzymes at the resting Ca(2+) levels. Therefore, some pathological conditions attributed to Mg(2+) deficiency might be related to excessive activation of underlying Ca(2+)-regulated cellular processes. This article is part of a Special Issue entitled: 11th European Symposium on Calcium. PMID- 21262276 TI - An image-based assay for high throughput screening of Giardia lamblia. AB - Giardia lamblia is a protozoan parasite that causes widespread gastrointestinal illness. Drugs to treat giardiasis are limited, but efforts to discover new anti giardial compounds are constrained by the lack of a facile system for cell culture and inhibitor testing. We achieved robust and reproducible growth of G. lamblia in 384-well tissue culture plates in a modified TYI-S-33 medium. A high throughput assay for the screening of potential anti-giardial compounds was developed utilizing the WB strain of G. lamblia and automated optical detection of parasites after growth with tested inhibitors. We screened a library of 1600 known bioactive molecules and identified 12 compounds that inhibited growth of G. lamblia at low- or sub-micromolar concentrations. Our high throughput assay should facilitate evaluation of available chemical libraries for novel drugs to treat giardiasis. PMID- 21262277 TI - Identification of bacteria in culture negative and polymerase chain reaction (PCR) positive intraocular specimen from patients with infectious endopthalmitis. AB - A novel Denaturing High-Performance Liquid Chromatography (dHPLC)-based technique allows rapid high-resolution analysis of PCR products. We show the application of this PCR/dHPLC approach for direct detection and identification of bacterium from the Eubacterial PCR amplified products of aqueous and vitreous aspirates from patients with endopthalmitis and to differentially identify the culture negative cases and initiate appropriate therapy. The aim of this study is to identify culture negative PCR positive cases by the application of PCR based DNA sequencing. A total of 116 intraocular specimens were subjected for the study. Sixty-nine different bacteria were identified using dHPLC based DNA sequencing of which predominant ones were Gram-positive bacteria and cannot be cultured by conventional methods. Forty eight different bacteria detected in this study is being reported for the first time in infectious endopthalmitis. PMID- 21262279 TI - Efficient chimeric promoters derived from full-length and sub-genomic transcript promoters of Figwort mosaic virus (FMV). AB - Addition of multiple repeats of the FS3 upstream activation sequence (FS3-UAS, 270 to -60) intra-molecularly to the TATA containing core-domain of the FS3 (-151 to +31) promoter resulted in 2-3-folds enhanced promoter activity. The chimeric promoter, FS3-UAS-3X with maximum activity, showed 3.31 times stronger activity in root vascular tissue compared to FS3 promoter and could be used efficiently in translational research. PMID- 21262278 TI - Heart rate stress response dampening: the impact of alcohol, family history, and gender on at risk children and siblings. AB - OBJECTIVE: In the following study we tested the stress response dampening (SRD) model which postulates that stress responses are more likely to be attenuated by alcohol in individuals at risk for alcohol dependence than in persons without that risk. In a laboratory experiment we examined a) if SRD effects exist for both sons and healthy daughters of alcohol dependent fathers, and b) if SRD effects exist for siblings of alcohol dependent males. METHODS: We recruited 104 subjects at risk and 51 matched control subjects. In a laboratory experiment, study subjects received alcohol in one of two laboratory sessions and a stress paradigm served to elicit heart rate stress responses. RESULTS: Heart rate stress responses were attenuated by alcohol in female family history positive (FHP) and female family history negative (FHN) subjects, however not in males. A multiple regression analysis revealed "Heart Rate Stress Response in the Non-Alcohol Condition" and "Blood Alcohol Level" as significant predictors of SRD. CONCLUSIONS: According to our findings, females carry a distinct risk for developing alcohol dependence, regardless of their family history and regardless of their degree of familial relationship. This is an important issue for devising models concerning the development and maintenance of alcohol dependence in females. The study extends the current research literature, which mainly focuses on male subjects at risk, by including female subjects at risk, as well as siblings at risk of both genders. PMID- 21262280 TI - Site-specific tetrameric streptavidin-protein conjugation using sortase A. AB - Streptavidin is tetrameric protein which has tight and specific biotin binding affinity, and streptavidin modification of proteins or small molecules is widely used for biotechnology tool. Here, we demonstrate site-specific streptavidin protein conjugation using enzymes. We focused on sortase A, a transpeptidase from Staphylococcus aureus. A streptavidin-tagged LPETG motif (Stav-LPETG) was expressed in Escherichia coli. We achieved soluble streptavidin expression in E. coli without refolding using a cold shock expression system. Then we successfully conjugated Stav-LPETG with pentaglycine-appended green fluorescence protein (Gly5 GFP) or triglycine-appended glucose oxidase (Gly3-GOD) using sortase A. SDS-PAGE analysis showed site-specific tetrameric streptavidin-protein conjugation with the tagged proteins. In addition, the functions of a Stav-GOD conjugate, i.e., biotin-binding and glucose oxidase activity, were significantly higher compared to those of streptavidin-GOD conjugates prepared by chemical modification. PMID- 21262281 TI - Significant enhancement of (R)-mandelic acid production by relieving substrate inhibition of recombinant nitrilase in toluene-water biphasic system. AB - The enantioselective hydrolysis of mandelonitrile with whole cells of a recombinant Escherichia coli expressing nitrilase activity was severely inhibited by the substrate at high concentrations (>300mM), which resulted in a low yield of the target product (R)-(-)-mandelic acid. To relieve the substrate inhibition and to enhance the (R)-(-)-mandelic acid productivity, eight water-organic solvent biphasic systems were attempted in this work. Toluene was found to be the most suitable solvent as the organic phase among the solvents tested. Various parameters were systematically examined and optimized in shake flasks. The phase volume ratio, buffer pH and reaction temperature were shown to be sensitive parameters affecting both the yield and the enantiopurity of product in the biphasic system. Under the optimized conditions, significant enhancement of substrate tolerance from 200mM to 500mM and average productivity from 179.6gl( 1)d(-1) to 352.6gl(-1)d(-1) were achieved. Subsequently, the biocatalytic hydrolysis of mandelonitrile was successfully carried out in a stirred reactor (2 l scale) by repeated use of the calcium alginate entrapped cells for 5 batches, affording 110.7g (R)-(-)-mandelic acid in 98.0% ee (enantiomeric excess) and a specific production of 13.8g (mandelic acid) g(-1) (cell), respectively. PMID- 21262282 TI - Genome sequence of B. amyloliquefaciens type strain DSM7(T) reveals differences to plant-associated B. amyloliquefaciens FZB42. AB - The complete genome sequence of Bacillus amyloliquefaciens type strain DSM7(T) is presented. A comparative analysis between the genome sequences of the plant associated strain FZB42 (Chen et al., 2007) with the genome of B. amyloliquefaciens DSM7(T) revealed obvious differences in the variable part of the genomes, whilst the core genomes were found to be very similar. The strains FZB42 and DSM7(T) have in common 3345 genes (CDS) in their core genomes; whilst 547 and 344 CDS were found to be unique in DSM7(T) and FZB42, respectively. The core genome shared by both strains exhibited 97.89% identity on amino acid level. The number of genes representing the core genome of the strains FZB42, DSM7(T), and Bacillus subtilis DSM10(T) was calculated as being 3098 and their identity was 92.25%. The 3,980,199 bp genome of DSM7(T) contains numerous genomic islands (GI) detected by different methods. Many of them were located in vicinity of tRNA, glnA, and glmS gene copies. In contrast to FZB42, but similar to B. subtilis DSM10(T), the GI were enriched in prophage sequences and often harbored transposases, integrases and recombinases. Compared to FZB42, B. amyloliquefaciens DSM7(T) possessed a reduced potential to non-ribosomally synthesize secondary metabolites with antibacterial and/or antifungal action. B. amyloliquefaciens DSM7(T) did not produce the polyketides difficidin and macrolactin and was impaired in its ability to produce lipopeptides other than surfactin. Differences established within the variable part of the genomes, justify our proposal to discriminate the plant-associated ecotype represented by FZB42 from the group of type strain related B. amyloliquefaciens soil bacteria. PMID- 21262283 TI - Myeloid-derived suppressor cells exhibit two bioenergetic steady-states in vitro. AB - Growing tumours have acquired several mechanisms to resist to immune recognition. Among these strategies, myeloid-derived suppressor cells (MDSCs) contribute to tumour escape by suppressing T-cell specific anti-tumoural functions. The development of therapies that could specifically inhibit MDSC maturation, recruitment, accumulation and immunosuppressive functions is thus of great interest. This requires the identification of valuable biomarkers of MDSC behaviour in vitro. As for immune cells, whose energetic state is known as a biomarker of their functionality, we have characterized in vitro the metabolic and energetic behaviour of MSC-1 cells, an immortalized cell line derived from mouse MDSCs and used as model cell line. Combined results from in vitro(31)P-NMR with living cells and HPLC-MS analyses from cell extracts allowed to identify two distinct bioenergetic steady-states that coincided with exponential and stationary growth phases. While the adenylate energy charge remained constant throughout the culture duration, both the percentage of total pyrimidines, the UTP-to-ATP and PME (phosphomonoesters)-to-NTP ratios were higher at the exponential growth phase compared to the plateau phase, suggesting metabolically active cells and the production of growth-related molecules. Conversely, the NTP ratio increased at the entry of the stationary phase revealing the deterioration of the global bioenergetic status and the arrest of anabolic processes. PMID- 21262284 TI - Activity and stability of cross-linked tyrosinase aggregates in aqueous and nonaqueous media. AB - Cross-linked tyrosinase aggregates were prepared by precipitating the enzyme with ammonium sulfate and subsequent cross-linking with glutaraldehyde. Both activity and stability of these cross-linked enzyme aggregates (CLEAs) in aqueous solution, organic solvents, and ionic liquids have been investigated. Immobilization effectively improved the stability of the enzyme in aqueous solution against various deactivating conditions such as pH, temperature, denaturants, inhibitors, and organic solvents. The stability of the CLEAs in various organic solvents such as tert-butanol (t(1/2)=326.7h at 40 degrees C) was significantly enhanced relative to that in aqueous solution (t(1/2)=5.5h). The effect of thermodynamic water activity (a(w)) on the CLEA activity in organic media was examined, demonstrating that the enzyme incorporated into CLEAs required an extensive hydration (with an a(w) approaching 1.0) for optimizing its activity. The impact of ionic liquids on the CLEA activity in aqueous solution was also assessed. PMID- 21262285 TI - Chemostat study of citric acid production from glycerol by Yarrowia lipolytica. AB - The aim of the study was to examine how the dilution rate and the chemical composition of the production medium impacts on the synthesis of citric acid by the Yarrowia lipolytica strain Wratislavia AWG7 from glycerol in a chemostat culture. The yeast Y. lipolytica Wratislavia AWG7, an acetate (acet(-)) and morphological (fil(-)) mutant, was cultured in a nitrogen- and phosphorus-limited medium at the dilution rate of 0.009-0.031h(-1) in the chemostat. Under steady state conditions, the increase in the dilution rate was paralleled by the decrease in citric acid concentration (from 86.5 to 51.2gL(-1)), as well as by the increase in the volumetric rate (from 0.78 to 1.59gL(-1)h(-1)) and specific rate (from 0.05 to 0.18gg(-1)h(-1)) of citric acid production. The yield of the production process varied from 0.59 to 0.67gg(-1). In a 550-h continuous culture of the yeast test, at a dilution rate of 0.01h(-1), in a medium with enhanced concentrations of carbon, nitrogen and phosphorus sources, the concentration of citric acid, the concentration of biomass and the volumetric rate of citric acid production were 97.8gL(-1), 22.2gL(-1) and 0.98gL(-1)h(-1), respectively. The yield of the process decreased to 0.49gg(-1). The number of dead cells did not exceed 1% while that of the budding cells accounted for about 20%. Owing to the low content of isocitric acid and polyols, the fermentation process was characterized by a high purity. This study has produced the following finding: the double mutant Y. lipolytica AWG7 is an effective citric acid producer, with the ability to preserve its properties unchanged during the long run of the continuous chemostat process. This is a valued technological feature of such mutants. PMID- 21262286 TI - Expression and purification of bioactive soluble murine stem cell factor from recombinant Escherichia coli using thioredoxin as fusion partner. AB - Stem cell factor (SCF) known as the c-kit ligand, plays important roles in spermatogenesis, melanogenesis and early stages of hematopoiesis. As for the latter, SCF is essential for growth and expansion of hematopoietic stem and progenitor cells. We herein describe the production of recombinant murine SCF from Escherichia coli as soluble thioredoxin-fusion protein. The formation of insoluble and inactive inclusion bodies, usually observed when SCF is expressed in E. coli, was almost entirely prevented. After purification based on membrane adsorber technology, the fusion protein was subsequently cleaved by TEV protease in order to release mature mSCF. Following dialysis and a final purification step, the target protein was isolated in high purity. Bioactivity of mSCF was proven by different tests (MTT analogous assay, long-term proliferation assay) applying a human megakaryocytic cell line. Furthermore, the biological activity of the uncleaved fusion protein was tested as well. We observed a significant activity, even though it was less than the activity displayed by the purified mSCF. In summary, avoiding inclusion body formation we present an efficient production procedure for mSCF, one of the most important stem cell cytokines. PMID- 21262287 TI - Identification of a novel Soybean mosaic virus isolate in China that contains a unique 5' terminus sharing high sequence homology with Bean common mosaic virus. AB - Two soybean viral isolates 4469-4 and Sc6 from plants in China were characterized by serological assays, pathogenicity tests, full-genome sequencing and sequence analyses. Both isolates are determined to be Soybean mosaic virus (SMV) isolates but 4469-4 is different from other known SMVs by inducing symptoms on common bean. 4469-4 has an RNA genome of 9994 nucleic acids (nt) encoding 3202 amino acids (aa), which is approximately 400 nt longer than that of Sc6 and other SMV strains. Comparison with SMV and SMV-related potyviruses suggests that 4469-4 shares high nt and aa sequence identify (>92%) with other SMV strains. However, significant diversity between 4469-4 and other SMV strains was observed in the 5' genomic region. In contrast, this region is highly similar to the corresponding region of Bean common mosaic virus (BCMV). Recombination analyses conclude that there is a recombination site near the nt 900 of 4469-4. Taken together these data suggest that 4469-4 may result from recombination between SMV and BCMV or a BCMV-like virus in the N-terminus of the genome. PMID- 21262288 TI - Sequence characterization of a Peruvian isolate of Sweet potato chlorotic stunt virus: further variability and a model for p22 acquisition. AB - Sweet potato chlorotic stunt virus (SPCSV) is probably the most important virus infecting sweetpotato worldwide, causing severe synergistic disease complexes with several co-infecting viruses. To date only one isolate (Ug), corresponding to the EA strain has been completely sequenced. It was later shown to be unusual in that, in contrast to most isolates, it encoded an additional p22 protein at the 3' end of RNA1. We report the complete sequence and genome organization of a Peruvian isolate of SPCSV (m2-47) as determined by siRNA deep sequencing. We confirm that the ORF encoding p22 is lacking from m2-47 and all tested Peruvian and South American isolates, whereas additional isolates containing p22 were identified from Uganda. Other potentially important genomic differences such as two small ORFs encoding putative small hydrophobic proteins instead of one, upstream the hsp70h gene and a more divergent sequence at its RNA1 3'-UTR in contrast to SPCSV isolates that contain p22 are discussed and a model for recent acquisition of p22 in Uganda is proposed. A role for p22 as a pathogenicity enhancer of SPCSV is also provided by complementary expression of p22 in transgenic sweetpotato plants. PMID- 21262289 TI - Nanobody-shell functionalized thermosensitive core-crosslinked polymeric micelles for active drug targeting. AB - The aim of this study was to develop poly(ethylene glycol)-b-poly[N-(2 hydroxypropyl) methacrylamide-lactate] (mPEG-b-p(HPMAm-Lac(n))) core-crosslinked thermosensitive biodegradable polymeric micelles suitable for active tumor targeting, by coupling the anti-EGFR (epidermal growth factor receptor) EGa1 nanobody to their surface. To this end, PEG was functionalized with N succinimidyl 3-(2-pyridyldithio)-propionate (SPDP) to yield a PDP-PEG-b-p(HPMAm Lac(n)) block copolymer. Micelles composed of 80% mPEG-b-p(HPMAm-Lac(n)) and 20% PDP-PEG-b-p(HPMAm-Lac(n)) were prepared and lysozyme (as a model protein) was modified with N-succinimidyl-S-acetylthioacetate, deprotected with hydroxylamine hydrochloride and subsequently coupled to the micellar surface. The micellar conjugates were characterized using SDS-PAGE and gel permeation chromatography (GPC). Using the knowledge obtained with lysozyme conjugation, the EGa1 nanobody was coupled to mPEG/PDP-PEG micelles and the conjugation was successful as demonstrated by western blot and dot blot analysis. Rhodamine labeled EGa1 micelles showed substantially higher binding as well as uptake by EGFR over expressing cancer cells (A431 and UM-SCC-14C) than untargeted rhodamine labeled micelles. Interestingly, no binding of the nanobody micelles was observed to EGFR negative cells (3T3) as well as to14C cells in the presence of an excess of free nanobody. This demonstrates that the binding of the nanobody micelles is indeed by interaction with the EGF receptor. In conclusion, EGa1 decorated (mPEG/PDP PEG)-b-(pHPMAm-Lac(n)) polymeric micelles are highly promising systems for active drug targeting. PMID- 21262291 TI - Validation of the parent mealtime action scale (PMAS) when applied to children referred to a hospital-based feeding clinic. AB - The purpose of this study was to validate the Parent Mealtime Action Scale (PMAS) when applied to a clinical sample of 231 children with feeding problems and then to examine its association with demographic variables, diet, and weight. Parents completed questionnaires that included the PMAS, the Child Eating Behavior Questionnaire, and measure of diet variety. Confirmatory factor analysis revealed good fit for the nine dimensions of parent mealtime action found in the original PMAS study. Results from the present study suggest that the PMAS provides a valid tool for measuring parent mealtime actions of hospital samples of children with feeding problems. PMID- 21262290 TI - Electro-gene transfer to skin using a noninvasive multielectrode array. AB - Because of its large surface area and easy access for both delivery and monitoring, the skin is an attractive target for gene therapy for cutaneous diseases, vaccinations and several metabolic disorders. The critical factors for DNA delivery to the skin by electroporation (EP) are effective expression levels and minimal or no tissue damage. Here, we evaluated the non-invasive multielectrode array (MEA) for gene electrotransfer. For these studies we utilized a guinea pig model, which has been shown to have a similar thickness and structure to human skin. Our results demonstrate significantly increased gene expression 2 to 3 logs above injection of plasmid DNA alone over 15 days. Furthermore, gene expression could be enhanced by increasing the size of the treatment area. Transgene-expressing cells were observed exclusively in the epidermal layer of the skin. In contrast to caliper or plate electrodes, skin EP with the MEA greatly reduced muscle twitching and resulted in minimal and completely recoverable skin damage. These results suggest that EP with MEA can be an efficient and non-invasive skin delivery method with less adverse side effects than other EP delivery systems and promising clinical applications. PMID- 21262292 TI - Registered dietitian's personal beliefs and characteristics predict their teaching or intention to teach fresh vegetable food safety. AB - The Theory of Planned Behavior was used to determine if dietitians personal characteristics and beliefs about fresh vegetable food safety predict whether they currently teach, intend to teach, or neither currently teach nor intend to teach food safety information to their clients. Dietitians who participated in direct client education responded to this web-based survey (n=327). The survey evaluated three independent belief variables: Subjective Norm, Attitudes, and Perceived Behavioral Control. Spearman rho correlations were completed to determine variables that correlated best with current teaching behavior. Multinomial logistical regression was conducted to determine if the belief variables significantly predicted dietitians teaching behavior. Binary logistic regression was used to determine which independent variable was the better predictor of whether dietitians currently taught. Controlling for age, income, education, and gender, the multinomial logistical regression was significant. Perceived behavioral control was the best predictor of whether a dietitian currently taught fresh vegetable food safety. Factors affecting whether dietitians currently taught were confidence in fresh vegetable food safety knowledge, being socially influenced, and a positive attitude toward the teaching behavior. These results validate the importance of teaching food safety effectively and may be used to create more informed food safety curriculum for dietitians. PMID- 21262293 TI - JmjC-domain-containing histone demethylases of the JMJD1B type as putative precursors of endogenous DSIP. AB - Delta sleep inducing peptide (WAGGDASGE, DSIP) is a well known multifunctional regulatory peptide. Numerous studies have confirmed its stress-protective and adaptive activity which is independent of the origin or nature of the stress or other harmful factors. However, the biosynthetic origin of DSIP remains obscure, since nothing is known of its protein precursor(s) and their encoding gene(s). We have performed a comprehensive analysis of available gene and protein databases for homologous peptide sites within mammalian resources including man. A family of Jumonji C (JmjC)-domain-containing histone demethylases was shown to contain a sequence fragment closely homologous to DSIP. One type of these ubiquitous and phylogenetically ancient proteins encoded by JMJD1B gene includes the WKGGNASGE sequence that differs from DSIP by only 2 amino acid residues in positions 2 and 5. The respective peptide was synthesized and its biological effects were evaluated in a preliminary way in the forced swimming and antitoxic tests. We suggest that the histone demethylases of the JmjC-group containing DSIP-related region can be considered as possible protein precursors of endogenous peptides with DSIP-like activity. PMID- 21262294 TI - Leishmanicidal activity of synthetic antimicrobial peptides in an infection model with human dendritic cells. AB - Different species of Leishmania are responsible for cutaneous, mucocutaneous or visceral leishmaniasis infections in millions of people around the world [14]. The adverse reactions caused by antileishmanial drugs, emergence of resistance and lack of a vaccine have motivated the search for new therapeutic options to control this disease. Different sources of antimicrobial molecules are under study as antileishmanial agents, including peptides with antimicrobial and/or immunomodulatory activity, which have been considered to be potentially active against diverse species of Leishmania[7,39]. This study evaluated the cytotoxicity on dendritic cells, hemolytic activity, leishmanicidal properties on Leishmania panamensis and Leishmania major promastigotes and effectiveness on parasite intracellular forms (dendritic cells infected with L. panamensis and L. major promastigotes), when each parasite in culture was exposed to different concentrations of a group of synthetic peptides with previously reported antimicrobial properties, which were synthesized based on their naturally occurring reported sequences. Dermaseptin, Pr-2 and Pr-3 showed inhibitory activity on the growth of L. panamensis promastigotes, while Andropin and Cecropin A (with a selectivity index of 4 and 40, respectively) showed specific activity against intracellular forms of this species. The activities of Andropin and Cecropin A were exclusively against the intracellular forms of the parasite, therefore indicating the relevance of these two peptides as potential antileishmanial agents. In the case of L. major promastigotes, Melittin and Dermaseptin showed inhibitory activity, the latter also showed a selectivity index of 8 against intracellular forms. These findings suggest Andropin, Cecropin A and Dermaseptin as potential therapeutic tools to treat New and Old World cutaneous leishmaniasis. PMID- 21262295 TI - Pharmacology of a new tritiated endomorphin-2 analog containing the proline mimetic cis-2-aminocyclohexanecarboxylic acid. AB - As part of ongoing work aimed at generating proteolytically stable, readily applicable, radiolabeled endomorphin-2 (EM-2) analogs for elucidation of the topological requirements of peptide binding to MU-opioid receptors, we report here on the synthesis, radiolabeling, binding kinetics and binding site distribution of an EM-2 analog in which Pro(2) is replaced by 2 aminocyclohexanecarboxylic acid, ACHC. [(3)H][(1S,2R)ACHC](2)EM-2 (specific activity 63.49Ci * mmol(-1)) bound specifically to its binding sites with high affinity (K(D) = 0.55 +/- 0.06 nM) and saturably, yielding a receptor density, B(max) of 151 +/- 4 fmol * mg protein(-1) in rat brain membranes. A similar affinity value was obtained in kinetic assays. Both Na(+) and Gpp(NH)p decreased the affinity, proving the agonist character of the radioligand. Specific MU opioid ligands displaced the radioligand with much higher affinities than did delta- and kappa-ligands. The autoradiographic distribution of the binding sites of [(3)H][(1S,2R)ACHC](2)EM-2 agreed well with the known locations of the MU opioid receptors in the rat brain. In consequence of its high affinity, selectivity and enzymatic resistance [19], the new radioligand will be a good tool in studies of the topographical requirements of MU-opioid-specific peptide binding. PMID- 21262296 TI - Central and peripheral forms of C-type natriuretic peptide (CNP): evidence for differential regulation in plasma and cerebrospinal fluid. AB - Aminoterminal proCNP (NTproCNP), a stable product of CNP gene expression and readily measured in human plasma, provides a new approach to studies of CNP which is rapidly degraded at source. CNP is detectable in human CSF but the presence and proportions of NTproCNP in CSF are unknown. Since CNP is widely expressed throughout the CNS, we hypothesized that the ratio of NTproCNP to CNP in CSF is greatly increased when compared to plasma and that CSF CNP peptides may contribute to their concentrations in the systemic circulation. Concurrent plasma and CSF concentrations of CNP forms were measured in 51 subjects undergoing spinal anesthesia for arranged orthopedic procedures. Elevated concentrations of NTproCNP (1045 +/- 359 pmol/L), characterized by HPLC-RIA, were found in CSF and greatly exceeded those of CNP (7.9 +/- 3.2 pmol/L). The ratio of NTproCNP to CNP in CSF (145 +/- 55) was much higher than in plasma (31 +/- 27). A significant inverse relation was found between plasma and CSF CNP concentrations (r = -0.29, p < 0.05). cGMP and neprilysin were unrelated to CNP levels in CSF. We conclude that CNP is differentially regulated across the brain in normal health. Despite markedly elevated levels of NTproCNP in CSF, it is unlikely that these contribute to systemic levels in healthy adults. Identifying NTproCNP as the dominant CNP form in CSF opens up the possibility of its use in future studies exploring CNP regulation within the CNS and possible applications in the diagnosis and monitoring of subjects with central neural disorders. PMID- 21262297 TI - Purification and structural characterization of a novel antibacterial peptide from Bellamya bengalensis: activity against ampicillin and chloramphenicol resistant Staphylococcus epidermidis. AB - Increasing tendency of clinical bacterial strains resistant to conventional antibiotics has being a great challenge to the public's health. Antimicrobial peptides, a new class of antibiotics is known to have the activity against a wide range of bacteria resistant to conventional antibiotics. An antimicrobial peptide of 1676 Da was purified from Bellamya bengalensis, a fresh water snail, using ultrafiltration and reversed phase liquid chromatography. The effect of this peptide on Staphylococcus epidermidis resistant to ampicillin and chloramphenicol was investigated; the MIC and MBC values were 8 MUg/ml and 16 MUg/ml, respectively. Complete sequence of the peptide was determined by tandem mass spectrometry (MS/MS). Further, peptide net charge, hydrophobicity and molecular modeling were evaluated in silico for better understanding the probable mechanisms of action. The peptide showed the specificity to bacterial membranes. Hence, this reported peptide revealed a promising candidate to contribute in the development of therapeutic agent for Staphylococcal infections. PMID- 21262299 TI - Purification, synthesis and characterization of AaCtx, the first chlorotoxin-like peptide from Androctonus australis scorpion venom. AB - AaCtx is the first chlorotoxin-like peptide isolated from Androctonus australis scorpion venom. Its amino acid sequence shares 70% similarity with chlorotoxin from Leiurus quinquestriatus scorpion venom, from which it differs by twelve amino acids. Due to its very low concentration in venom (0.05%), AaCtx was chemically synthesized. Both native and synthetic AaCtx were active on invasion and migration of human glioma cells. However, their activity was found to be lower than that of chlorotoxin. The molecular model of AaCtx shows that most of amino acids differing between AaCtx and chlorotoxin are localized on the N terminal loop and the alpha-helix. Based on known compounds that block chloride channels, we suggest that the absence of negative charged amino acids on AaCtx structure may be responsible for its weak activity on glioma cells migration and invasion. This finding serves as a starting point for structure-function relationship studies leading to design high specific anti-glioma drugs. PMID- 21262298 TI - S-thanatin in vitro prevents colistin resistance and improves its efficacy in an animal model of Pseudomonas aeruginosa sepsis. AB - An experimental study was performed to evaluate the interaction between s thanatin and colistin both in vitro and in vivo, using two Pseudomonas aeruginosa strains with different patterns of susceptibilities. We evaluated whether selecting for colistin-resistant P. aeruginosa could be prevented in vitro by combining colistin with s-thanatin. The strains were serially exposed in broth to twofold stepwise increasing concentrations of colistin alone or in combination with a fixed concentration [0.25* minimum inhibitory concentration (MIC)] of s thanatin. We also performed an in vitro synergy study. For in vivo studies, a mouse model of Pseudomonas sepsis has been used. Main outcome measures were lethality and quantitative blood cultures. Exposure to colistin alone gradually selected for Pseudomonas strains with an increased MIC. In vitro studies, s thanatin showed a positive interaction with colistin, and was able to prevent its resistance. In vivo studies, s-thanatin combined with colistin exhibited the highest efficacy on all main outcome measurements. These results highlight the potential usefulness of this combination and provide a future therapeutic alternative in severe Pseudomonas infections. PMID- 21262300 TI - Purification and identification of a novel primitive secretory enzyme catalyzing the hydrolysis of imidazole-related dipeptides in the jawless vertebrate Lethenteron reissneri. AB - Imidazole-related dipeptides, such as carnosine and anserine, occur widely in skeletal muscles of jawed vertebrates. All of the known enzymes that catalyze the hydrolysis of these dipeptides belong to the M20A metallopeptidase subfamily; two secretory enzymes, serum carnosinase (EC 3.4.13.20) and anserinase (EC 3.4.13.5), and one non-secretory enzyme, cytosolic nonspecific dipeptidase (EC 3.4.13.18). Here we report the enzymatic characterization and molecular identification of an unidentified enzyme, which catalyzes the hydrolysis of these dipeptides, from the skeletal muscle of Far Eastern brook lamprey (Lethenteron reissneri). A 60-kDa subunit protein of the enzyme was purified to near homogeneity. We cloned two M20A genes from the skeletal muscle of Far Eastern brook lamprey; one was a secretory-type gene encoding for the 60-kD protein, and another was a non secretory-type gene presumably encoding for cytosolic nonspecific dipeptidase. Our findings indicate that the purified enzyme is a N-glycosylated secretory M20A dipeptidase distributed specifically in the jawless vertebrate group, and may be derived from a common ancestor gene between serum carnosinase and anserinase. We propose that this dipeptidase is a novel secretory M20A enzyme and is classified as neither serum carnosinase nor anserinase. PMID- 21262302 TI - Uptake, transport and regulation of JBP485 by PEPT1 in vitro and in vivo. AB - Cyclo-trans-4-L-hydroxyprolyl-L-serine (JBP485) is a dipeptide with anti hepatitis activity that has been chemically synthesized. Previous experiments in rats showed that JBP485 was well absorbed by the intestine after oral administration. The human peptide transporter (PEPT1) is expressed in the intestine and recognizes compounds such as dipeptides and tripeptides. The purposes of this study were to determine if JBP485 acted as a substrate for intestinal PEPT1, and to investigate the characteristics of JBP485 uptake and transepithelial transport by PEPT1. The uptake of JBP485 was pH dependent in human intestinal epithelial cells Caco-2. And JBP485 uptake was also significantly inhibited by glycylsarcosine (Gly-Sar, a typical substrate for PEPT1 transporters), JBP923 (a derivative of JBP485), and cephalexin (CEX, a beta lactam antibiotic and a known substrate of PEPT1) in Caco-2 cells. The rate of apical-to-basolateral transepithelial transport of JBP485 was 1.84 times higher than that for basolateral-to-apical transport. JBP485 transport was obviously inhibited by Gly-Sar, JBP923 and CEX in Caco-2 cells. The uptake of JBP485 was increased by verapamil but not by cyclosporin A (CsA) and inhibited by the presence of Zn(2+) or the toxic metabolite of ethanol, acetaldehyde (AcH) in Caco 2 cells. The in vivo uptake of JBP485 was increased by verapamil and decreased by ethanol in vivo, which was consisted with the in vitro study. PEPT1 mRNA levels were enhanced after exposure of the cells to JBP485 for 24h, compared to control. In conclusion, JBP485 was actively transported by the intestinal oligopeptide transporter PEPT1. This mechanism is likely to contribute to the rapid absorption of JBP485 by the gastrointestinal tract after oral administration. PMID- 21262303 TI - Long-term peripheral infusion of nociceptin/orphanin FQ promotes hyperplasia, activation and migration of mucosal mast cells in the rat gastric fundus. AB - The endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ) modulates behavioral and gastrointestinal responses to stress. Mucosal mast cells (MMCs) are primary mediators of stress-related responses in the gastrointestinal tract. We investigated the influence of N/OFQ and of the N/OFQ peptide (NOP) receptor antagonist, UFP-101, on MMCs in the rat gastric fundus. N/OFQ was infused subcutaneously for 52 h at 0.1, 1 and 10 MUg/kg/h and at 1 MUg/kg/h for 4h, 52 h, 7 days and 14 days via Alzet osmotic minipumps. Density of MMCs and connective tissue mast cells (CTMCs) was assessed histochemically and immunohistochemically. Activation and location of MMCs were assessed by transmission electron microscopy. Contacts between MMCs and nerve elements were assessed by double immunofluorescence. N/OFQ (1 MUg/kg/h) and UFP-101 (10 and 30 MUg/kg/h) were infused subcutaneously in the absence and presence of acute cold-restraint stress and density of MMCs was assessed. Peripheral N/OFQ dose-dependently increased the density of MMCs, while not influencing CTMCs. The increasing effect was maintained up to 14 days following continuous infusion, while after termination of the 4-h infusion, the effect declined rapidly. The peptide promoted the activation of MMCs and their migration from the lamina propria toward the epithelial layer. The association between MMCs and nerve fibers was time dependently down-regulated following N/OFQ infusion. The stress-induced hyperplasia of MMCs was not influenced by N/OFQ and abolished by UFP-101. UFP-101 alone was ineffective. The present results suggest that endogenous N/OFQ could be considered a potential component of the circuit neuropeptides-mast cells-stress. PMID- 21262301 TI - Effects of glycine-extended and serine13-phosphorylated forms of peptide YY on food intake in rats. AB - The gut hormone peptide YY(3-36)-amide [PYY(3-36)-NH(2)] is significantly more potent than PYY(1-36)-NH(2) in reducing food intake in rats and humans. Other Gly extended and Ser(13)-phosphorylated PYY forms have been detected or predicted based upon known cellular processes of PYY synthesis and modification. Here we compared the effects of 3-h IV infusion of PYY(1-36)-NH(2), PYY(3-36)-NH(2), PYY(1-36)-Gly-OH, PYY(3-36)-Gly-OH, Ser(13)(PO(3))-PYY(1-36)-NH(2), Ser(13)(PO(3))-PYY(3-36)-NH(2), Ser(13)(PO(3))-PYY(1-36)-Gly-OH, and Ser(13)(PO(3))-PYY(3-36)-Gly-OH during the early dark period on food intake in freely feeding rats. PYY(3-36)-NH(2) and Ser(13)(PO(3))-PYY(3-36)-NH(2) reduced food intake similarly at 50 pmol/kg/min, while only PYY(3-36)-NH(2) reduced food intake at 15 pmol/kg/min. PYY(1-36)-NH(2) and Ser(13)(PO(3))-PYY(1-36)-NH(2) reduced food intake similarly at 50 and 150 pmol/kg/min. In contrast, PYY(1-36) Gly-OH, PYY(3-36)-Gly-OH, Ser(13)(PO(3))-PYY(3-36)-Gly-OH, and Ser(13)(PO(3)) PYY(1-36)-Gly-OH had no effect on food intake at doses of 50 or 150 pmol/kg/min. Taken together, these results indicate that (i) PYY(3-36)-NH(2) is significantly more potent than PYY(1-36)-NH(2) in reducing food intake, (ii) Gly-extended forms of PYY are significantly less potent than non-extended forms, and (iii) Ser(13) phosphorylation of PYY(3-36)-NH(2) decreases the anorexigenic potency PYY(3-36) NH(2), but not PYY(1-36)-NH(2). Thus, PYY(3-36)-NH(2) appears to be the most potent PYY form for reducing food intake in rats. PMID- 21262304 TI - Characterization of antimicrobial peptides in skin secretions from discrete populations of Lithobates chiricahuensis (Ranidae) from central and southern Arizona. AB - Populations of the Chiricahua leopard frog Lithobates chiricahuensis (Ranidae) occupying regions in southern Arizona (southern range) are morphologically distinct from those from the Mogollon Rim of central Arizona (northern range) and a comparison of DNA sequences of mitochondrial genes has suggested that they may represent separate species. Peptidomic analysis of norepinephrine-stimulated skin secretions has led to the identification of six peptides with antimicrobial activity in samples from specimens from both groups. The primary structure of the peptides (esculentin-2 CHa, ranatuerin-2 CHa, -CHb, and -CHc, and brevinin-1 CHa and -CHb) isolated from both southern and northern range frogs are identical consistent with the proposal that the two populations are conspecific. However, palustrin-2CHa and the atypical brevinin-1 CHc (FFPTIAG*****LTKLFCA ITKKC), containing a five amino acid residue deletion, were identified only in secretions from southern range specimens. Consequently, there is some support for the proposal that the two populations are closely related but separate species but this support is relatively weak. Esculentin-2 CHa (GFSSIFRGVAKFASKGLG KDLAKLGVDLVACKISKQC) displayed the highest antimicrobial potency (MIC <= 10MUM) against a variety of microorganisms and was only moderately hemolytic (LC(50) = 150 MUM). Cladistic analysis based upon the primary structures of brevinin-1 peptides indicates a close phylogenetic relationship between L. chiricahuensis, L. onca, and L. yavapaiensis. PMID- 21262305 TI - Nitric oxide is a central component in neuropeptide regulation of appetite. AB - In recent years, there have been a large number of neuropeptides discovered that regulate food intake. Many of these peptides regulate food intake by increasing or decreasing nitric oxide (NO). In the current study, we compared the effect of the food modulators ghrelin, NPY and CCK in NOS KO mice. Satiated homozygous and heterozygous NOS KO mice and their wild type controls were administered ghrelin ICV. Food intake was measured for 2h post injection. Ghrelin did not increase food intake in the homozygous NOS KO mice compared to vehicle treated NOS KO mice, whereas food intake was increased in the wild type controls compared to vehicle treated wild type controls. NPY was administered ICV and food intake measured for 2h. Homozygous NOS KO mice showed no increase in food intake after NPY administration, whereas the wild type controls did. In our final study, we administered CCK intraperitoneally to homozygous and heterozygous NOS KO mice and their wild type controls after overnight food deprivation. Food intake was measured for 1h after injection. CCK inhibited food intake in wild type mice after overnight food deprivation, however, CCK failed to inhibit food intake in the NOS KO mice. The heterozygous mice showed partial food inhibition after the CCK. The current results add further support to the theory that NO is a central mediator in food intake. PMID- 21262306 TI - Minimal antimicrobial peptidic sequence from hemoglobin alpha-chain: KYR. AB - Hemoglobin is an animal protein described as a source of biologically active peptides. Peptic digestion of bovine hemoglobin alpha-chain allowed obtaining peptide fractions with antimicrobial activity. These peptides were purified by reverse-phase High-Performance Liquid Chromatography (HPLC) and characterized by mass spectrometry. The minimal inhibitory concentration and mode of action of these peptides were studied against five bacterial strains including Escherichia coli and Salmonella enteritidis as Gram-negative bacteria and Listeria innocua, Micrococcus luteus and Staphylococcus aureus as Gram-positive bacteria. The action aforementioned peptides were studied on artificial membranes as well. The most active peptides resulted to be the short ones. Consequently, the minimal peptidic sequence necessary for the antibacterial activity was clearly determined: KYR. PMID- 21262307 TI - Prevention of hydrogen peroxide-induced oxidative stress in HDF cells by peptides derived from seaweed pipefish, Syngnathus schlegeli. AB - Two new peptides derived from seaweed pipefish Syngnathus schlegeli, SPP 1(QLGNLGV) and SPP-2 (SVMPVVA) were assessed for their ability to prevent hydrogen peroxide induced oxidative stress in human dermal fibroblasts (HDFs). Both peptides showed a significant hydroxyl radical scavenging activity when tested by ESR technique. And also the peptides effectively suppressed the hydrogen peroxide induced ROS production and DNA damage in HDF cells. Furthermore the two peptides increase the protein expression levels of intracellular antioxidant enzymes SOD1, GSH and catalase in hydrogen peroxide stressed HDF cells. At the cellular signaling level, SPPs block the NF-kappaB activation which may lead to the reduction of oxidative stress mediated damage of HDF cells. These finding indicate the potential antioxidant effects of SPPs as response to H(2)O(2) stimulation. PMID- 21262308 TI - Modulation of gastric motility by brain-gut peptides using a novel non-invasive miniaturized pressure transducer method in anesthetized rodents. AB - Acute in vivo measurements are often the initial, most practicable approach used to investigate the effects of novel compounds or genetic manipulations on the regulation of gastric motility. Such acute methods typically involve either surgical implantation of devices or require intragastric perfusion of solutions, which can substantially alter gastric activity and may require extended periods of time to allow stabilization or recovery of the preparation. We validated a simple, non-invasive novel method to measure acutely gastric contractility, using a solid-state catheter pressure transducer inserted orally into the gastric corpus, in fasted, anesthetized rats or mice. The area under the curve of the phasic component (pAUC) of intragastric pressure (IGP) was obtained from continuous manometric recordings of basal activity and in responses to central or peripheral activation of cholinergic pathways, or to abdominal surgery. In rats, intravenous ghrelin or intracisternal injection of the thyrotropin-releasing hormone agonist, RX-77368, significantly increased pAUC while coeliotomy and cacal palpation induced a rapid onset inhibition of phasic activity lasting for the 1-h recording period. In mice, RX-77368 injected into the lateral brain ventricle induced high-amplitude contractions, and carbachol injected intraperitoneally increased pAUC significantly, while coeliotomy and cecal palpation inhibited baseline contractile activity. In wild-type mice, cold exposure (15 min) increased gastric phasic activity and tone, while there was no gastric response in corticotropin releasing factor (CRF)-overexpressing mice, a model of chronic stress. Thus, the novel solid-state manometric approach provides a simple, reliable means for acute pharmacological studies of gastric motility effects in rodents. Using this method we established in mice that the gastric motility response to central vagal activation is impaired under chronic expression of CRF. PMID- 21262309 TI - A recombinant vesicular stomatitis virus encoding HIV-1 receptors and human OX40 ligand efficiently eliminates HIV-1-infected CD4-positive T cells expressing OX40. AB - OX40 protein is highly expressed on activated CD4-positive T cells that are susceptible for human immunodeficiency virus type 1 (HIV-1) infection. To target and kill HIV-1-infected OX40(+) T cells, we used a recombinant vesicular stomatitis virus (rVSV) lacking its envelope glycoprotein (DeltaG) and instead expressing HIV-1 receptors CD4/CXCR4 and OX40 ligand (OX40L). Expression of OX40L as well as HIV-1 receptors on the VSV particles led to specific infection of OX40(+) T cells, including primary cells, either acutely or chronically infected with X4 HIV-1. Consequently, the rVSV rapidly eliminated these infected cells and caused a marked reduction of HIV-1 viral load in culture. Inclusion of the OX40L gene in the VSV recombinant led to significantly better infection and HIV-1 elimination compared with an rVSVDeltaG expressing only HIV-1 receptors. A novel rVSVDeltaG encoding both HIV-1 receptors and OX40L has a potentially greater therapeutic value than an rVSVDeltaG expressing only HIV-1 receptors. PMID- 21262310 TI - Impact of pronase on flow cytometric crossmatch outcome. AB - Pronase treatment of lymphocytes is used to reduce nonspecific binding of immunoglobulins in flow cytometric crossmatch (FCXM) tests and at higher concentrations to remove CD20 from the cell surface. We examined the effect of pronase treatment on human leukocyte antigen (HLA) expression and on FCXM results. Lymphocytes were tested untreated and after treatment with either 2 mg/mL (10 cell donors) or 1 mg/mL (6 cell donors) of pronase. The 2 mg/mL concentration reduced HLA expression in 28 of 30 (93%) cases. The reduction was statistically significant for HLA class I antigens on T cells (33 +/- 10%, p = 0.0006), class I on B cells (23 +/- 13%, p = 0.012), and class II on B cells (45 +/- 37%, p = 0.005). FCXMs were performed using pronase-treated and untreated cells. The 2 mg/mL concentration of pronase reduced reactivity in 5 of 16 (31%) tests of T cells and 15 of 16 (94%) tests of B cells. Of the remaining 11 T-cell tests, the reactivity was unchanged (<= 10% difference) in 5 and increased by 18 73% in 6. Treatment with 1 mg/mL of pronase significantly increased reactivity in 20 of 23 tests of T cells (87%, p = 6.0 * 10(-5)). These data indicate that pronase treatment may result in erroneous FCXM results. PMID- 21262312 TI - Age-related changes in natural killer cell receptors from childhood through old age. AB - Most studies on natural killer (NK) cells and aging have focused on overall cell numbers and global cytotoxic activity. NK cell functions are controlled by surface receptors belonging to three major families: killer cell immunoglobulin like receptors (KIRs), natural cytotoxicity receptors (NCRs), and C-type lectins. The expression of these receptors was investigated from childhood through old age in T, NKT- and NK cells and also in the CD56(dim) (cytotoxic) and CD56(bright) (responsible for cytokine production) NK cell subsets. A decrease in the expression of activating receptors (NKp30 and NKp46) was observed in NK cells in elderly individuals. KIR expression was increased only in the CD56(bright) subset. Children presented similar results regarding expression of NKp30 and KIR, but not NKp46. NKG2D expression was decreased in T cells of elderly subjects. Analysis of KIR genotype revealed that KIR2DL5 and KIR2DS3 were significantly associated with old age. Cytotoxic activity was preserved from childhood through old age, suggesting that the increase of the absolute number of CD56(dim), observed in elderly, may represent a compensatory mechanism for the receptor expression alterations. This initial study provides the framework for more focused studies of this subject, which are necessary to determine whether the changing balance of NK receptor expression may influence susceptibility to infectious, inflammatory, and neoplastic diseases. PMID- 21262313 TI - Phenotypic polymorphism of haptoglobin: a novel risk factor for the development of infection in liver cirrhosis. AB - The alpha-chain alleles 1 and 2 of haptoglobin (Hp) molecule account for three phenotypes, which have biologically important differences in their antioxidant, scavenging, and immunomodulatory properties and may thereby influence the course of inflammatory diseases. A follow-up observational study was conducted to assess the association between haptoglobin phenotype and the development of clinically significant bacterial infections in patients with liver cirrhosis. Sera of 336 patients with liver cirrhosis of various etiologies and 384 healthy subjects were investigated. Haptoglobin phenotypes were determined by gel electrophoresis and assigned corresponding genotype. Haptoglobin phenotype distributions of patients and controls was similar (Hp1-1: 10.7% vs 11.5%, Hp2-1: 47.9% vs 46.1% and Hp2-2: 41.4% vs 42.4%). The probability of clinically significant bacterial infections was calculated for each haptoglobin phenotype (Hp1-1: 50.0%, Hp2-1: 36.0% and Hp2 2: 26.6%, p = 0.039). In a logistic regression analysis, Hp1-1 phenotype (p = 0.015, OR: 2.74, 95% CI: 1.22-6.13), Child-Pugh stage (p = 0.038, OR: 1.40, 95% CI: 1.02-1.91) and presence of co-morbidities (p < 0.001, OR: 2.64, 95% CI: 1.63 4.27) were independently associated with infections. In a Cox regression analysis, Hp1-1 phenotype (p = 0.014), Child-Pugh stage C (p < 0.001), and presence of co-morbidities (p = 0.004) were associated with time to first infectious episode. Phenotypic haptoglobin polymorphism was independent predictor for risk and time to first clinically significant bacterial infectious episode. PMID- 21262311 TI - The influence of human leukocyte antigen class I alleles and their population frequencies on human immunodeficiency virus type 1 control among African Americans. AB - Populations of African ancestry continue to account for a disproportionate burden of the human immunodeficiency virus type 1 (HIV-1) epidemic in the United States. We investigated the effects of human leukocyte antigen (HLA) class I markers in association with virologic and immunologic control of HIV-1 infection among 338 HIV-1 subtype B-infected African Americans in 2 cohorts: Reaching for Excellence in Adolescent Care and Health (REACH) and HIV Epidemiology Research Study (HERS). One-year treatment-free interval measurements of HIV-1 RNA viral loads and CD4(+) T cells were examined both separately and combined to represent 3 categories of HIV-1 disease control (76 controllers, 169 intermediates, and 93 noncontrollers). Certain previously or newly implicated HLA class I alleles (A*32, A*36, A*74, B*14, B*1510, B*3501, B*45, B*53, B*57, Cw*04, Cw*08, Cw*12, and Cw*18) were associated with 1 or more of the endpoints in univariate analyses. After multivariable adjustments for other genetic and nongenetic risk factors of HIV-1 progression, the subset of alleles more strongly or consistently associated with HIV-1 disease control included A*32, A*74, B*14, B*45, B*53, B*57, and Cw*08. Carriage of infrequent HLA-B but not HLA-A alleles was associated with more favorable disease outcomes. Certain HLA class I associations with control of HIV 1 infection cross the boundaries of race and viral subtype, whereas others appear confined within one or the other of those boundaries. PMID- 21262314 TI - Body signals, cardiac awareness, and the perception of time. AB - Recent research suggests that our sense of time intervals in the range of seconds is directly related to activity in the insular cortex, which contains the primary sensory area for interoception. We therefore investigated whether performance in a duration reproduction task might correlate with individual interoceptive awareness and with measurable changes in autonomic activity during the task. Thirty-one healthy volunteers participated in an interoceptive (heartbeat) perception task and in repeated temporal reproduction trials using intervals of 8, 14, and 20s duration while skin conductance levels and cardiac and respiratory periods were recorded. We observed progressive increases in cardiac periods and decreases in skin conductance level during the encoding and (less reliably) the reproduction of these intervals. Notably, individuals' duration reproduction accuracy correlated positively both with the slope of cardiac slowing during the encoding intervals and with individual heartbeat perception scores. These results support the view that autonomic function and interoceptive awareness underpin our perception of time intervals in the range of seconds. PMID- 21262315 TI - Solitude and cortisol: associations with state and trait affect in daily life. AB - The social context can impact psychological and physiological functioning. Being alone, in particular, is experienced as more negative on average than being with others, in both normative and pathological populations. This study investigates whether daily solitude is associated with changes in cortisol and, if so, whether momentary and trait affect can explain this relationship. Forty-four female college students used the Experience Sampling Method during a week, completing questionnaires and collecting saliva 8 times daily. Effects of current solitude, affect, and trait affectivity on cortisol were tested with multilevel regression. Cortisol levels were significantly higher when individuals were alone. Although momentary affective states changed during solitude and were also associated with cortisol, they did not fully explain the effects of solitude on cortisol. Trait affectivity moderated the association between solitude and cortisol. Findings may help clarify how daily experience may heighten risk of depression or other negative health outcomes in vulnerable individuals. PMID- 21262316 TI - Love withdrawal is related to heightened processing of faces with emotional expressions and incongruent emotional feedback: evidence from ERPs. AB - Parental use of love withdrawal is thought to affect children's later psychological functioning because it creates a link between children's performance and relational consequences. To investigate whether love withdrawal is also associated with the underlying level of basic information processing in the brain, we studied event-related potentials to feedback stimuli that combined performance feedback with emotional facial expressions. We focused on the VPP (face processing) and N400 (incongruence processing). More maternal use of love withdrawal was related to more positive VPP amplitudes, larger effects of the emotional facial expression on VPP amplitude, and more negative N400 responses to incongruent combinations of feedback and facial expressions. Our findings suggest a heightened processing of faces with emotional expressions and greater sensitivity to incongruence between feedback and facial expression in individuals who experienced more love withdrawal. PMID- 21262317 TI - Cerebral blood flow and behavioural effects of caffeine in habitual and non habitual consumers of caffeine: a near infrared spectroscopy study. AB - Caffeine has been shown to modulate cerebral blood flow, with little evidence of tolerance to these effects following habitual use. However, previous studies have focused on caffeine levels much higher than those found in dietary servings and have compared high caffeine consumers with low consumers rather than 'non consumers'. The current placebo-controlled double-blind, balanced-crossover study employed near infrared spectroscopy to monitor pre-frontal cerebral-haemodynamics at rest and during completion of tasks that activate the pre-frontal cortex. Twenty healthy young habitual and non-habitual consumers of caffeine received 75 mg caffeine or placebo. Caffeine significantly decreased cerebral blood flow but this was subject to a significant interaction with consumption status, with no significant effect being shown in habitual consumers and an exaggerated effect in non-habitual consumers. These findings suggest that caffeine, at levels typically found in a single dietary serving, is able to modulate cerebral blood flow but these effects are subject to tolerance. PMID- 21262319 TI - Familiarity of objects affects susceptibility to the sound-induced flash illusion. AB - Audition is accepted as more reliable (thus dominant) than vision when temporal discrimination is required by the task. However, it is not known whether the characteristics of the visual stimulus, for example its familiarity to the perceiver, affect auditory dominance. In this study we manipulated familiarity of the visual stimulus in a well-established multisensory phenomenon, i.e., the sound-induced flash illusion. This illusion occurs when, for example, one brief visual stimulus (e.g., a flash) is presented in close temporal proximity with two brief sounds; participants perceive two flashes instead of one. We found that when the visual stimuli (faces or buildings) were familiar, participants were less susceptible to the illusion than when they were unfamiliar. As the illusion has been ascribed to early cross-sensory interactions between vision and audition, the present work offers behavioural evidence that high level processing of objects' characteristics such as familiarity, affects early temporal multisensory integration. Possible mechanisms underlying the effect of familiarity are discussed. PMID- 21262318 TI - Clarifying relations between dispositional aggression and brain potential response: overlapping and distinct contributions of impulsivity and stress reactivity. AB - Impulsive-aggressive individuals exhibit deficits in amplitude of the P3 brain potential response, however, it remains unclear how separable dispositional traits account for this association. The current study sought to clarify the basis of this association by examining contributions of trait impulsiveness and stress reactivity to the observed relationship between dispositional aggression and amplitude of the P3 brain potential response in a visual novelty-oddball procedure. A significant negative association was found between aggressiveness and amplitude of P3 response to both target and novel stimuli over frontal central scalp sites. Impulsivity showed a parallel inverse relationship with P3 amplitude, attributable to its overlap with dispositional aggression. In contrast, stress reactivity did not exhibit a zero-order association with P3 amplitude, but modestly predicted P3 in a positive direction after accounting for its overlap with aggression. Results are discussed in terms of their implications for individual difference variables and brain processes underlying impulsive aggressive behavior. PMID- 21262320 TI - Guided motor training induces dendritic spine plastic changes in adult rat cerebellar purkinje cells. AB - The simple cerebellar lobule is involved in several neuromotor processes and it is activated during guided exercise. Although guided exercises are essential for motor rehabilitation, the plastic events that occur in the simple cerebellar lobule during motor training remain unknown. In this study, normal adult rats were intensely trained on a motorized treadmill during a period of four weeks (IT group) varying both the velocity and the slope of the moving belt, and they were compared to a mildly trained (MC) group and an intact control group (IC). Dendritic spine density and proportions of the different spine types on Purkinje cells was assessed in the cerebellar simple lobule, as was drebrin A expression. Both dendritic spine density and drebrin expression increased in the MC and IT groups. Stubby spines were more abundant in the MC animals, while there was an increase in both stubby and wide spines in IT rats. In addition, mushroom spines were more numerous in the IT group. Increases in stubby and wide spines could be related to regulation of the excitability in Purkinje cells due to the motor training regime experienced by the MC and IT rats. Moreover, the observed increase in mushroom spines in the IT group could be related with the motor adjustments imposed by training. PMID- 21262321 TI - Autonomic activity and baroreflex sensitivity in patients submitted to carotid stenting. AB - Arterial baroreflex and cardiac autonomic control play important roles in hemodynamic instability after carotid artery stenting (CAS). Spontaneous baroreflex sensitivity (BRS), heart rate variability (HRV) and blood pressure variability (BPV) are established tools for the assessment of arterial baroreflex and cardiac autonomic activity. Aim of the study was to evaluate cardiac autonomic activity (by means of HRV, BPV and BRS) after CAS and to explore the impact of internal carotid artery stenosis on BRS changes after CAS. 37 patients (68+/-10.45 years) with internal carotid stenosis underwent CAS. HRV, BPV and BRS were measured in all subjects before and at 1 and 72h after CAS. ANOVA was performed to compare BRS, HRV and BPV parameters before and after CAS. Spearman analysis was performed to determine a possible correlation between carotid stenosis degree (or carotid plaque diameter) and BRS changes (DeltaBRS). LF/HF (index of sympatho-vagal balance) decreased during postoperative period, in comparison with baseline (2.32+/-1.70 vs 1.65+/-1.40, p<0.05). There was a significant negative correlation between carotid stenosis degree and DeltaBRS (r= 0.35, p=0.03) and between carotid plaques thickness and DeltaBRS (r=-0.36, p=0.02). CAS procedure may cause an alteration of carotid wall mechanical properties, increasing baroreflex sensitivity. BRS does not increase in all the patients, because arterial wall damage and nerve destruction determined by atherosclerotic plaque may reduce DeltaBRS. PMID- 21262322 TI - Dopamine depresses melanin concentrating hormone neuronal activity through multiple effects on alpha2-noradrenergic, D1 and D2-like dopaminergic receptors. AB - Two neuronal populations of the lateral hypothalamus that, respectively, produce melanin-concentrating hormone (MCH) and orexin peptides are crucially involved in control of metabolism, feeding and related goal-oriented behaviors. In contrast to orexin neurons, mainly involved in short-term regulation of feeding, MCH neurons participate in long-term control of energy storage and body weight. Beyond its effect on feeding, MCH has also been shown to be involved in regulation of seeking behavior and addiction through modulation of dopamine (DA) metabolism. This regulation is essential for reinforcement-associated behaviors. Moreover, drugs of abuse, which increase extracellular DA levels, are known to decrease food intake. Consistent with this observation, DA has been shown to modulate orexin neurons of the lateral hypothalamus. However, no study is available concerning the effects of DA on MCH neurons. Whole-cell patch-clamp recordings were done in hypothalamic mouse brain slices. MCH neurons were identified by Tau-Cyan-GFP labeling using a transgenic mouse model (MCH-GFP). First, we show that DA (10-200 MUM) induces an outward current in MCH neurons. However, this current is not due to activation of DA receptors, but mediated through activation of alpha2-noradrenergic receptors and subsequent opening of G protein activated inward rectifier K+ (GIRK) channels. Current-clamp experiments revealed that this GIRK-activation leads to hyperpolarization, thus decreasing excitability of MCH neurons. Furthermore, we confirm that MCH neurons receive mainly GABAergic inputs rather than glutamatergic ones. We show that DA modulates these inputs in a complex manner: at low concentrations, DA activates D1-like receptors, promoting presynaptic activity, whereas, at higher concentrations (100 MUM), D2-like receptor activation inhibits presynaptic activity. Overall, DA should lead to a decrease in MCH neuron excitability, likely resulting in down regulation of MCH release and feeding behavior. PMID- 21262324 TI - Inhibition of beta-amyloid1-42 internalization attenuates neuronal death by stabilizing the endosomal-lysosomal system in rat cortical cultured neurons. AB - A number of recent studies have indicated that accumulation of beta amyloid (Abeta) peptides within neurons is an early event which may trigger degeneration of neurons and subsequent development of Alzheimer's disease (AD) pathology. However, very little is known about the internalization and/or subcellular sites involved in trafficking of Abeta peptides into the neurons that are vulnerable in AD pathology. To address this issue we evaluated internalization of fluoroscein conjugated Abeta1-42 (FAbeta1-42) and subsequent alteration of endosomal lysosomal (EL) markers such as cathepsin D, Rab5 and Rab7 in rat cortical cultured neurons. It is evident from our results that internalization of FAbeta1 42, which occurred in a dose- and time-dependent manner, triggered degeneration of neurons along with increased levels and/or altered distribution of cathepsin D, Rab5 and Rab7. Our results further revealed that FAbeta1-42 internalization was attenuated by phenylarsine oxide (a general inhibitor of endocytosis) and sucrose (an inhibitor of clathrin-mediated endocytosis) but not by antagonists of N-methyl-d-aspartate (NMDA) glutamate receptors. Additionally, inhibition of FAbeta1-42 endocytosis not only protected neurons against toxicity but also reversed the altered levels/distributions of EL markers. These results, taken together, suggest that internalization of exogenous Abeta1-42, which is partly mediated via a clathrin-dependent process, can lead to degeneration of neurons, possibly by activating the EL system. Inhibition of FAbeta endocytosis attenuated toxicity, thus suggesting a potential strategy for preventing loss of neurons in AD pathology. PMID- 21262323 TI - Age-related loss of orexin/hypocretin neurons. AB - Aging is associated with many physiological alterations-such as changes in sleep patterns, metabolism and food intake-suggestive of hypothalamic dysfunction, but the effects of senescence on specific hypothalamic nuclei and neuronal groups that mediate these alterations is unclear. The lateral hypothalamus and contiguous perifornical area (LH/PFA) contains several populations of neurons, including those that express the neuropeptides orexin (hypocretin) or melanin concentrating hormone (MCH). Collectively, orexin and MCH neurons influence many integrative homeostatic processes related to wakefulness and energy balance. Here, we determined the effect of aging on numbers of orexin and MCH neurons in young adult (3-4 months) and old (26-28 months) Fisher 344/Brown Norway F1 hybrid rats. Aged rats exhibited a loss of greater than 40% of orexin-immunoreactive neurons in both the medial and lateral (relative to the fornix) sectors of the LH/PFA. MCH-immunoreactive neurons were also lost in aged rats, primarily in the medial LH/PFA. Neuronal loss in this area was not global as no change in cells immunoreactive for the pan-neuronal marker, NeuN, was observed in aged rats. Combined with other reports of altered receptor expression or behavioral responses to exogenously-administered neuropeptide, these data suggest that compromised orexin (and, perhaps, MCH) function is an important mediator of age related homeostatic disturbances of hypothalamic origin. The orexin system may represent a crucial substrate linking homeostatic and cognitive dysfunction in aging, as well as a novel therapeutic target for pharmacological or genetic restoration approaches to preventing or ameliorating these disturbances. PMID- 21262325 TI - The neural correlates of insight in Chinese verbal problems: an event related potential study. AB - The electrophysiological correlates of "Chinese anagrams" solving were studied using high-density event-related potentials (ERPs). Results showed that Insight solutions elicited a more positive ERP deflection (P400-600) than did Search solutions in the time window of 400-600 ms. Dipole source analysis showed that the generator of P400-600 was localized in the fusiform gyrus, which might be involved in breaking mental sets during reconstruction of the Chinese anagrams. Then, Insight solutions elicited a more positive ERP deflection (LPC) than did Search solutions between 640 and 780 ms. Dipole source analysis showed that the generator of LPC was localized in the right superior temporal gyrus, which might reflect forming novel associations when subjects regrouped the decompositions of the characters. PMID- 21262326 TI - Inhibitory effect of tanshinones on rat CYP3A2 and CYP2C11 activity and its structure-activity relationship. AB - This study investigated the effect of tanshinones on rat liver microsomal CYP3A2 and 2C11 activity and explored the structure-activity relationship of tanshinones with CYP3A activity. Cryptotanshinone, tanshinone I and tanshinone IIA were competitive CYP3A2 inhibitors (K(i) = 199-243 MUM) and CYP2C11 inhibitors (K(i) = 91-118 MUM). Dihydrotanshinone was not only a noncompetitive inhibitor of CYP3A2 (K(i) = 110 MUM), but also a competitive CYP2C11 inhibitor (K(i) = 55 MUM). The structural difference between dihydrotanshinone and tanshinone I at C-15 position of furan ring resulted in the different modes of inhibition on CYP3A activity. PMID- 21262327 TI - New spirobenzofuranoid dibenzocyclooctadiene lignans from Kadsura oblongifolia. AB - Two new spirobenzofuranoid dibenzocyclooctadiene lignans, kadsulignans O (1) and P (2) were isolated from the stems of Kadsura oblongifolia, together with five known same type lignans, kadsulignans C (3), E (4), F (5), G (6), and heteroclitin J (7). Their structures were elucidated on the basis of spectral evidences and comparisons with literatures. Compounds 3-7 were isolated from this plant for the first time. PMID- 21262328 TI - Flavonol-rich fractions of yaupon holly leaves (Ilex vomitoria, Aquifoliaceae) induce microRNA-146a and have anti-inflammatory and chemopreventive effects in intestinal myofibroblast CCD-18Co cells. AB - Polyphenolics extracted from yaupon holly (Ilex vomitoria, Aquifoliaceae) (YH) leaves were investigated in human colon cells for their chemopreventive and anti inflammatory activities. An activity-guided fractionation allowed the selection of YH flavonol-rich fraction due to its preferential inhibition of HT-29 colon cancer viability over the normal CCD-18Co colon cells. Quercetin and kaempferol 3 rutinosides, main components identified in this fraction, protected CCD-18Co cells against reactive oxidative species (ROS) in part due to increased activity of antioxidant enzymes. In addition, up-regulation of microRNA-146a (miR-146a) known as a negative regulator of pro-inflammatory NF-kappaB activation was the underlying molecular mechanism that protected CCD-18Co from inflammation. PMID- 21262329 TI - A new hepoprotective saponin from Semen Celosia cristatae. AB - A new triterpenoid saponin, named semenoside A (1), was isolated from Semen Celosia cristatae. Its structure was elucidated on the basis of 1D, 2D NMR, HR FAB-MS and ESI-MS techniques, and physicochemical properties. The hepatoprotective activity of semenoside A with an oral dose of 1.0, 2.0 and 4.0mg/kg, respectively, were investigated by carbon tetrachloride (CCl(4)) induced hepatotoxicity in mice. The results indicated that it had significant hepatoprotective effects (p < 0.01). PMID- 21262330 TI - Alkaloids derived from genus Veratrum and Peganum of Mongolian origin as multidrug resistance inhibitors of cancer cells. AB - Alkaloids comprise one of the largest groups of plant secondary metabolites including vinca alkaloids. The ability of six alkaloids from Veratrum lobelianum, one from Veratrum nigrum and three from Peganum nigellastrum to modify transport activity of MDR1 was studied. Flow-cytometry in a multidrug-resistant human MDR1 gene-transfected mouse lymphoma cells (L5178Y) was applied. The inhibition of multidrug resistance was investigated by measuring the accumulation of rhodamine 123 in cancer cells. Veralosinine and veranigrine were the most effective resistance modifiers. In a checkerboard method veralosinine and veranigrine enhanced the antiproliferative effects of doxorubicin on MDR cells in combination. The structure-activity relationships were discussed. PMID- 21262331 TI - Effects of treatment with St. John's Wort on blood glucose levels and pain perceptions of streptozotocin-diabetic rats. AB - This present study was undertaken to examine treating effects of St. John's Wort (SJW) extract on nociceptive perception of STZ-diabetic animals based on its potential antidiabetic and antinociceptive activities. One week administrations of SJW extract (125 and 250 mg/kg) induced significant decrease in high blood glucose levels of three weeks STZ-diabetic rats and improved their dysregulated metabolic parameters. In addition, SJW extract treatment caused restoration in the mechanical hyperalgesia of diabetic animals. These findings provide a rationale for the traditional use of SJW against diabetes and display the potential of this plant as a new drug candidate/source for the treatment of diabetic pain. PMID- 21262332 TI - Assessment of in vitro dermal absorption of the kaurenic acid from Coespeletia moriziana extracts. AB - Espeletiinae are plants which grow above 3000 m of altitude in the Northern Andes and kaurenic acid was extracted from the leaves of Coespeletia moritziana. This compound has shown a wide range of biological activities, including cytotoxicity which is efficient in cancer therapy. The percutaneous penetration of this compound was measured in vitro using Franz cells. At appropriate intervals for up to 24h, diffusion samples were analyzed using HPLC. At the end of the test period, the amount of kaurenic acid was determined in each compartment and approximately 10% of kaurenic acid had been absorbed and was found in the skin layers. PMID- 21262333 TI - Construction of a novel bioluminescent reporter system for investigating Shiga toxin expression of enterohemorrhagic Escherichia coli. AB - A novel chromosome-plasmid hybrid bioluminescent reporter system (C-P reporter system) utilizing Photorhabdus luminescens luxCDABE genes has been constructed to monitor the expression of Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2) in enterohemorrhagic Escherichia coli (EHEC) in real time. The luxCDABE genes of P. luminescens have been cloned and divided into a luxCDAB cassette and a luxE gene. A promoter-less luxE gene introduced downstream from stx1 and from stx2 on EHEC chromosomes in single copies, and other luxCDAB genes were expressed on a multicopy number expression plasmid into the same cells. These Stx1- and Stx2 bioluminescent reporter strains expressed bioluminescence into bacteria cells when the expression of the promoter-less luxE gene was expressed in response to the promoter activity of stx1 and stx2, respectively. The expression levels of bioluminescence were identical to the production levels of Stx1 and Stx2 in the Stx1- and Stx2-bioluminescent reporter strains, and these strains produced both Stxs at the same respective levels as those of the parent EHEC strains. Using these reporter strains, we examined the profiles of Stx1 and Stx2 expression in EHEC. We found that production of both Stx1 and Stx2 in EHEC was enhanced upon contact with intestinal epithelial cells and within macrophages. However, the expression profiles between Stx1 and Stx2 in EHEC were different from each other under these conditions. Thus, these results suggested that this C-P reporter system is useful for determining the gene expression profile of bacteria. PMID- 21262334 TI - Lack of PPARalpha exacerbates lipopolysaccharide-induced liver toxicity through STAT1 inflammatory signaling and increased oxidative/nitrosative stress. AB - Peroxisome proliferator-activated receptor-alpha (PPARalpha) has been implicated in a potent anti-inflammatory activity. However, no information is available on whether PPARalpha can affect signal transducers and activator of transcription proteins (STATs) in acute liver damage. Thus, this study was aimed to investigate the in vivo role of PPARalpha in elevating STATs as well as oxidative/nitrosative stress in a model of lipopolysaccharide (LPS)-induced acute hepatic inflammatory injury. Using age-matched Ppara-null and wild-type (WT) mice, we demonstrate that the deletion of PPARalpha aggravates LPS-mediated liver injury through activating STAT1 and NF-kappaB-p65 accompanied by increased levels of pro-inflammatory cytokines. Furthermore, the activities of key anti-oxidant enzymes and mitochondrial complexes were significantly decreased while lipid peroxidation and protein nitration were elevated in LPS-exposed Ppara-null mice compared to WT. These results indicate that PPARalpha is important in preventing LPS-induced acute liver damage by regulating STAT1 inflammatory signaling pathways and oxidative/nitrosative stress. PMID- 21262335 TI - Absence of association between mitochondrial DNA C150T polymorphism and longevity in a Han Chinese population. AB - Human longevity has been associated with mitochondrial DNA (mtDNA) coding region polymorphisms, as well as the C150T polymorphism in the non-coding region in previous studies especially in Europeans. This study investigated the potential association between the mtDNA C150T polymorphism and longevity in a Han Chinese population. Leukocyte mtDNAs from two groups of a Han Chinese population living in Dujiangyan city of Sichuan province, including 556 longevous individuals (90 108 years-old) and 403 unrelated controls, were analyzed and mtDNA haplogroups were determined by sequencing control regions and restriction fragment length polymorphisms (RFLPs) in coding regions. Our results did not show a universal association between the mitochondrial C150T polymorphism and longevity in this population. Even when mtDNA haplogroups defined by C150T and gender were taken into account, there was no significant association with longevity. In conclusion, the mtDNA C150T polymorphism could not present an accumulation in an elderly Han Chinese population. Previous association studies might have been influenced by nuclear DNA and/or environment factors. PMID- 21262336 TI - Biomaterials based on chitin and chitosan in wound dressing applications. AB - Wound dressing is one of the most promising medical applications for chitin and chitosan. The adhesive nature of chitin and chitosan, together with their antifungal and bactericidal character, and their permeability to oxygen, is a very important property associated with the treatment of wounds and burns. Different derivatives of chitin and chitosan have been prepared for this purpose in the form of hydrogels, fibers, membranes, scaffolds and sponges. The purpose of this review is to take a closer look on the wound dressing applications of biomaterials based on chitin, chitosan and their derivatives in various forms in detail. PMID- 21262337 TI - Atypical (RIO) protein kinases from Haemonchus contortus--promise as new targets for nematocidal drugs. AB - Almost nothing is known about atypical kinases in multicellular organisms, including parasites. Supported by information and data available for the free living nematode, Caenorhabditis elegans, and other eukaryotes, the present article describes three RIO kinase genes, riok-1, riok-2 and riok-3, from Haemonchus contortus, one of the most important parasitic nematodes of small ruminants. Analyses of these genes and their products predict that they each play critical roles in the developmental pathways of parasitic nematodes. The findings of this review indicate prospects for functional studies of these genes in C. elegans (as a surrogate) and opportunities for the design of a novel class of nematode-specific inhibitors of RIO kinases. The latter aspect is of paramount importance, given the serious problems linked to anthelmintic resistance in parasitic nematode populations of livestock. PMID- 21262338 TI - Role of dihydrotestosterone in post-stroke peripheral immunosuppression after cerebral ischemia. AB - Stroke is a sexually dimorphic disease with male gender considered a disadvantage in terms of risk and disease outcome. In intact males, stroke induces peripheral immunosuppression, characterized by decreased splenocyte numbers and proliferation and altered percentages of viable T, B, and CD11b+ cells. To investigate whether the potent androgen and known immunomodulator, dihydrotestosterone (DHT), exacerbates post-stroke immunosuppression in castrated male mice after focal stroke, we evaluated the effect of middle cerebral artery occlusion (MCAO) on peripheral and central nervous system (CNS) immune responses in castrated mice with or without controlled levels of DHT. MCAO reduced spleen cell numbers in both groups, but altered T cell and B cell percentages in remaining splenocytes and concomitantly increased the percentage of CD11b+ blood cells solely in DHT-replaced animals at 24 h. Furthermore, DHT-replacement reduced splenocyte proliferation which was accompanied by an increased percentage of immunosuppressive regulatory T cells relative to castrates 96 h post-MCAO. In brain, the percentages of immune cell populations in the ischemic hemisphere relative to the non-ischemic hemisphere were similar between castrated and DHT replaced mice after MCAO. These data suggest DHT modulates peripheral immunosuppression after MCAO but with relatively little effect on early immune response of the recovering CNS. PMID- 21262339 TI - Adolescent binge alcohol exposure induces long-lasting partial activation of microglia. AB - Accumulating evidence indicates that the adolescent hippocampus is highly susceptible to alcohol-induced structural damage and behavioral deficits. Microglia are vitally important brain constituents needed to support and maintain proper neural function; however, alcohol's effects on microglia have only recently gained attention. The microglial response to alcohol during adolescence has yet to be studied; therefore, we examined hippocampal microglial activation in an adolescence binge alcohol exposure model. Adolescent male Sprague-Dawley rats were administered ethanol 3 times/day for 4 days and were sacrificed 2, 7, and 30 days later. Bromo-deoxy-Uridine was injected 2 days after ethanol exposure to label dividing cells. Microglia morphology was scored using the microglia marker Iba-1, while the extent of microglial activation was examined with ED-1, major histocompatibility complex-II (MHC-II), and tumor necrosis factor (TNF) alpha expression. Ethanol induced significant morphological change in hippocampal microglia, consistent with activation. In addition, ethanol increased the number of BrdU+ cells throughout all regions of the hippocampus 2 days after the last dose. Confocal microscopy showed that the proliferating BrdU+ cells in each region were Iba-1+ microglia. Importantly, newly born microglia survived and retained their morphological characteristics 30 days after ethanol exposure. Ethanol did not alter hippocampal ED-1, MHC-II, or TNF-alpha expression, suggesting that a single period of binge ethanol exposure does not induce a full microglial-driven neuroinflammatory response. These results establish that ethanol triggers partial microglial activation in the adolescent hippocampus that persists through early adulthood, suggesting that alcohol exposure during this unique developmental time period has long-lasting consequences. PMID- 21262340 TI - The inflammatory footprints of alcohol-induced oxidative damage in neurovascular components. AB - Microvessels, the main components of the blood-brain barrier (BBB) are vulnerable to oxidative damage during alcohol-induced stress. Alcohol produces oxidative damage within the vessels and in the brain. Using our animal model of catheter implant into the common carotid artery (CCA), we trace the footprints of alcohol induced oxidative damage and inflammatory process at the BBB and into the brain. The uniqueness of the finding is that ethanol causes oxidative damage in all neurovascular components by activating NADPH oxidase and inducible nitric oxide synthase in the brain. It is not the oxidants but the ethanol that traverses through the BBB because we found that the highly reactive peroxynitrite does not cross the BBB. Thus, oxidative damage is caused at the site of oxidant production in the microvessels and in the brain. Our data indicate that acetaldehyde (the primary metabolite of ethanol) is the inducer/activator of these enzymes that generate oxidants in brain neurovascular cells. Evidence for alcohol-induced BBB damage is indicated by the alterations of the tight junction protein occludin in intact microvessels. Importantly, we demonstrate that the site of BBB oxidative damage is also the site of immune cells aggregation in the microvessels, which paves the path for inflammatory footprints. These findings reveal the underlying mechanisms that ethanol-elicited BBB oxidative damage initiates the brain vascular inflammatory process, which ultimately leads to neuroinflammation. PMID- 21262341 TI - Absence of neurotoxicity with medicinal grade terbutaline in the rat model. AB - To evaluate neurological effects of terbutaline, rats were injected with saline, terbutaline (Sigma or American Pharmaceutical Partners (APPTM)) at 0.5 mg/kg-d or 10 mg/kg-d between postnatal days (PND) 2-5 or 11-14. Brains collected 24 h after last injection were used to determine corpus-callosum thickness, Purkinje cell and neuronal number in the cerebellum. Ambulation, distance traveled, resting time and time on rotarod were analyzed. Terbutaline (both doses/grades at PND 11 14) decreased corpus-callosum thickness. Ambulation time was significantly decreased in the 10 mg/kg-d (Sigma) and 0.5 mg/kg-d of terbutaline (APPTM) (PND 2 5) juvenile-rats and 10 mg/kg-d-Sigma adult-rats, 0.5 mg/kg-d APPTM (PND 11-14) adult-rats. Resting time was increased in both doses of APPTM (PND 2-5) in juvenile-rats, 10 mg/kg-d Sigma adult-rats. 10 mg/kg-d-Sigma (PND 2-5) decreased distance traveled in adult-rats. 0.5 mg/kg-d-Sigma (PND 2-5 and PND 11-14) decreased the time spent on rotarod (30 RPM) in adult-rats. Sigma terbutaline Sigma had 2* as much free base compared to APPTM. In conclusion, APPTM terbutaline did not have a deleterious effect on the developing rat brain. PMID- 21262342 TI - Quercetin attenuates cadmium-induced oxidative damage and apoptosis in granulosa cells from chicken ovarian follicles. AB - The attenuating effect of quercetin on cadmium-induced oxidative damage and apoptosis was investigated in cultured granulosa cells from chicken ovarian follicles. Results showed that exposure to 5 MUM CdCl(2) induced a decrease in granulosa cell number and viability, caused chromatin condensation and DNA fragmentation. Moreover, cadmium treatment markedly increased malondialdehyde level and decreased glutathione peroxidase and superoxide dismutase activities. Furthermore, cadmium provoked higher BAX expression, inhibited expression of BCL2 and X-linked inhibitor of apoptosis protein (XIAP) and activated caspase-3. However, simultaneous supplementation with 1 MUg/ml quercetin protected granulosa cells against cadmium-induced cytotoxicity through attenuating lipid peroxidation, renewing antioxidant enzymes activities and alleviating apoptosis by modulating XIAP, BAX and BCL2 expression, and inhibiting caspase-3 activity. Therefore, these results suggested that quercetin, as a widely distributed dietary antioxidant, contributes potentially to prevent cadmium-induced cytotoxicity in granulosa cells through attenuating lipid peroxidation, elevating intracellular antioxidant status and inhibiting apoptosis to ensure reproductive health. PMID- 21262343 TI - Effects of methylmercury on male reproductive functions in Wistar rats. AB - In this study we investigated the effects of subacute exposure to methylmercury (MeHg) on male reproductive functions in rats by means of determination of alterations in structural and functional parameters. Adult male Wistar rats received 0, 0.5, 1.0 or 3.0 mg/kg/body weight/day orally, daily MeHg for 14 days. Sperm motility, the relative sperm count and transit time in the caput/corpus epididymis, were all reduced at all doses. The lowest dose increased the number of sperm head abnormalities; daily sperm production was elevated at the intermediate dose; while at the highest dose there was a decrease in serum testosterone levels and a rise in mercury (Hg) content in reproductive organs, liver and kidneys. In conclusion, MeHg exposure produced damages on male reproductive functions which may be attributed, at least in part, to the reduction in serum testosterone levels. These consequences could potentially result in infertility in rats. PMID- 21262344 TI - In vitro effects of Uranium on human fetal germ cells. AB - Uranium (U) is found in the environment and its use in industrial or military activities has led to concerns about its potential toxicity. The reprotoxicity of this heavy metal has been established in adult animals; however, no studies have examined its effect on human fetal gonads. Using an organ culture system, we investigated the effects of uranyl acetate on human gonads during the first trimester of gestation (7-12 weeks), which is a critical step in the development of a functional reproductive system. In human fetal ovaries, 0.05 mM U significantly decreased germ cell density by increasing their apoptosis rate. In human fetal testes, 0.1mM U similarly reduced the number of germ cells. The human fetal germ cells are more sensitive to U than mouse germ cells in the same experimental conditions. This is the first evidence that U may impair the development of the human gonads. PMID- 21262345 TI - Effects of spinal or general anesthesia on F2-isoprostanes and isofurans during ischemia/reperfusion of the leg in patients undergoing knee replacement surgery. AB - General and spinal anesthesia are used extensively in orthopedic surgery. However, these methods of anesthesia may result in different amounts of oxygen being delivered to the patient. Ischemia/reperfusion injury after release of the tourniquet initiates free radical-mediated oxidative stress. F2-isoprostanes are reliable markers of in vivo lipid peroxidation. However, under conditions of high oxygen tension, isofurans are formed. We aimed to compare plasma isofurans and F2 isoprostanes in spinal versus general anesthesia in patients undergoing knee replacement surgery in a randomized, blinded study. Thirty-nine patients were randomized to spinal (SA; n = 19) or general anesthesia (GA; n = 20). Blood was collected before anesthesia, and a tourniquet was then applied to the limb during surgery. After release of the tourniquet, blood samples were collected at 30 min, 2 h, and 24 h for measurement of plasma F2-isoprostanes and isofurans by gas chromatography-mass spectrometry. The two groups were comparable in age and body mass index. Plasma F2-isoprostanes were significantly lower in the GA patients compared with the SA patients (p = 0.045). In contrast, the GA patients had significantly elevated plasma isofurans (p = 0.032). Increased isofurans during GA compared with SA are likely to reflect increased oxidative stress due to elevated oxygen concentrations during GA. Further studies are required to assess the implications of these findings on perioperative outcomes. PMID- 21262346 TI - Mitochondrial complex I impairment in leukocytes from type 2 diabetic patients. AB - Diabetes is associated with oxidative stress. This study evaluated the rates of oxidative stress and mitochondrial impairment in type 2 diabetes patients. The study population consisted of 182 diabetic patients and 50 body-composition- and age-matched controls. We assessed anthropometric and metabolic parameters and mitochondrial function by evaluating mitochondrial oxygen (O2) consumption, reactive oxygen species (ROS) production, glutathione (GSH) levels, GSH/GSSG ratio, mitochondrial membrane potential, and mitochondrial complex I activity in polymorphonuclear cells from diabetes type 2 patients. We found an increase in waist circumference and augmented serum levels of triglycerides, proinflammatory cytokines (IL-6 and TNF-alpha), homocysteine, glycated hemoglobin, ultrasensitive C-reactive protein, glucose, insulin, and homeostasis model assessment of insulin resistance score in diabetic patients versus controls. There was an impairment of mitochondrial function in diabetic patients, evidenced by a decrease in mitochondrial O2 consumption, an increase in ROS production, decreased GSH/GSSG ratio, a drop in GSH levels, and an undermining of the mitochondrial membrane potential. Furthermore, an impairment of mitochondrial complex I was detected. This study supports the hypothesis of an association of type 2 diabetes and the rate of impaired mitochondrial function. We also propose that one of the targets of oxidative stress responsible for diabetes is mitochondrial complex I. PMID- 21262347 TI - Inhibition of thioredoxin reductase 1 by porphyrins and other small molecules identified by a high-throughput screening assay. AB - The selenoprotein thioredoxin reductase 1 (TrxR1) has in recent years been identified as a promising anticancer drug target. A high-throughput assay for discovery of novel compounds targeting the enzyme is therefore warranted. Herein, we describe a single-enzyme, dual-purpose assay for simultaneous identification of inhibitors and substrates of TrxR1. Using this assay to screen the LOPAC1280 compound collection we identified several known inhibitors of TrxR1, thus validating the assay, as well as several compounds hitherto unknown to target the enzyme. These included rottlerin (previously reported as a PKCdelta inhibitor and mitochondrial uncoupler) and the heme precursor protoporphyrin IX (PpIX). We found that PpIX was a potent competitive inhibitor of TrxR1, with a K(i)=2.7 MUM with regard to Trx1, and in the absence of Trx1 displayed time-dependent irreversible inhibition with an apparent second-order rate constant (k(inact)) of (0.73 +/- 0.07) * 10-3 MUM-1 min-1. Exogenously delivered PpIX was cytotoxic, inhibited A549 cell proliferation, and was found to also inhibit cellular TrxR activity. Hemin and the ferrochelatase inhibitor NMPP also inhibited TrxR1 and showed cytotoxicity, but less potently compared to PpIX. We conclude that rottlerin-induced cellular effects may involve targeting of TrxR1. The unexpected finding of PpIX as a TrxR1 inhibitor suggests that such inhibition may contribute to symptoms associated with conditions of abnormally high PpIX levels, such as reduced ferrochelatase activity seen in erythropoietic protoporphyria. Finally, additional inhibitors of TrxR1 may be discovered and further characterized based upon the new high-throughput TrxR1 assay presented here. PMID- 21262348 TI - Activation of the PI3K pathway increases TLR-induced TNF-alpha and IL-6 but reduces IL-1beta production in mast cells. AB - Recognition of bacterial constituents by mast cells (MCs) is dependent on the presence of pattern recognition receptors, such as Toll-like receptors (TLRs). The final cellular response, however, depends on the influence of multiple environmental factors. In the current study we tested the hypothesis that the PI3K-activating ligands insulin-like growth factor-1 (IGF-1), insulin, antigen, and Steel Factor (SF) are able to modulate the TLR4-mediated production of proinflammatory cytokines in murine MCs. Costimulation with any of these ligands caused increased LPS-triggered secretion of IL-6 and TNF-alpha, but attenuated the production of IL-1beta, though all three cytokines were produced in an NFkappaB-dependent manner. The pan-specific PI3K-inhibitor Wortmannin reverted the altered production of these cytokines. In agreement, MCs deficient for SHIP1, a negative regulator of the PI3K pathway, showed augmented secretion of IL-6/TNF alpha and reduced production of IL-1beta in response to LPS alone. The differential effects of IGF-1 on TLR4-mediated cytokine production were also observed in the context of TLR2 and IL-33 receptor-mediated MC activation. Importantly, these effects were seen in both bone marrow-derived and peritoneal MCs, suggesting general relevance for MCs. Using pharmacological and genetic tools, we could show that the p110delta isoform of PI3K is strongly implicated in SF-triggered suppression of LPS-induced IL-1beta production. Costimulation with antigen was affected to a lesser extent. In conclusion, NFkappaB-dependent production of proinflammatory cytokines in MCs is differentially controlled by PI3K-activating ligand/receptor systems. PMID- 21262349 TI - Fc gamma receptor IIb modulates the molecular Grb2 interaction network in activated B cells. AB - B cells require signals transduced by the B cell antigen receptor (BCR) to provide humoral adaptive immunity. These signals are modulated by co-receptors like the Fcgamma receptor IIb (FcgammaRIIb) that prevents activation of B cells after co-ligation with the BCR. Positive and negative effectors need to be precisely organized into signaling complexes, which requires adapter proteins like the growth factor receptor-bound protein 2 (Grb2). Here, we address the question how Grb2-mediated signal integration is affected by FcgammaRIIb. Our data reveal that concomitant engagement of BCR and FcgammaRIIb leads to markedly increased Grb2-mediated formation of ternary protein complexes comprising downstream of kinase-3 (Dok-3), Grb2, and the SH2 domain-containing inositol phosphatase (SHIP). Consistently, we found Grb2 to be required for full FcgammaRIIb-mediated negative regulation. To investigate how FcgammaRIIb influences the entire Grb2 interactions, we utilized quantitative mass spectrometry to make a differential interactome analysis. This approach revealed a shift of Grb2 interactions towards negative regulators like Dok-3, SHIP and SHP 2 and reduced binding to other proteins like CD19. Hence, we provide evidence that Grb2-mediated signal integration is a dynamic process that is important for the crosstalk between the BCR and its co-receptor FcgammaRIIb. PMID- 21262350 TI - Protein kinase CK2 links polyamine metabolism to MAPK signalling in Drosophila. AB - MAPK signalling is a complex process not only requiring the core components Raf, MEK and Erk, but also many proteins like the scaffold protein KSR and several kinases to specifically localize, modulate and fine-tune the outcome of the pathway in a cell context specific manner. In mammals, protein kinase CK2 was shown to bind to the scaffold protein KSR and to phosphorylate Raf proteins at a conserved serine residue in the negative-charge regulatory (N-) region, thereby facilitating maximal activity of the MAPK signalling pathway. In this work we show that in Drosophila CK2 is also bound to KSR. However, despite the presence of a corresponding serine residue in the N-region of DRaf, CK2-mediated phosphorylation of DRaf takes place on a serine residue at the N-terminus and is required for Erk activation. Previous work identified polyamines as regulators of CK2 kinase activity. The main cellular source of polyamines is the catabolism of amino acids. Evidence is provided that phosphorylation of DRaf by CK2 is modulated by polyamines, with spermine being the most potent inhibitor of the reaction. We suggest that CK2 is able to monitor intracellular polyamine levels and translates this information to modulate MAPK signalling. PMID- 21262351 TI - Nuclear factor p65 interacts with Keap1 to repress the Nrf2-ARE pathway. AB - Keap1 is an inhibitor of Nrf2 involved in Nrf2-dependent antioxidant response. However, the mechanisms on how Keap1 regulates Nrf2-ARE signaling pathway remains to be determined. Here, by using a yeast two-hybrid technology, p65 subunit of NF kappaB transcription factor was identified as a partner of Keap1. We show that Keap1 physically associated with p65 in vivo and in vitro. Overexpression of p65 inhibited Nrf2-dependent transcription induced by diethylmaleate (DEM) or tert butyl hydroxyquinone (tBHQ). Knock down of Keap1 by RNA interference partially blocked the repression of Nrf2-mediated activation by p65. It was demonstrated that p65 decreased Nrf2 binding to its cognate DNA sequences and enhanced Nrf2 ubiquitination. The N-terminal region of p65 is necessary for both the interaction with Keap1 and its transcriptional suppression activity. Moreover, nuclear translocation of Keap1 was augmented by p65. Taken together, our findings suggest that NF-kappaB signaling inhibits Nrf2-ARE pathway through the interaction of p65 and Keap1. PMID- 21262353 TI - Compartmentalized CDK2 is connected with SHP-1 and beta-catenin and regulates insulin internalization. AB - The cyclin-dependant kinase Cdk2 is compartmentalized in endosomes but its role is poorly understood. Here we show that Cdk2 present in hepatic endosome fractions is strictly located in a Triton X-100-resistant environment. The endosomal Cdk2 was found to be associated with the protein tyrosine phosphatase SHP-1, a regulator of insulin clearance, and the actin anchor beta-catenin, a known substrate for both Cdk2 and SHP-1. In the plasma membranes and endosome fractions, beta-catenin is associated with CEACAM1, also known as regulator of insulin clearance. We show that beta-catenin, not CEACAM1, is a substrate for Cdk2. Partial down-modulation of Cdk2 in HEK293 cells increased the rate of insulin internalization. These findings reveal that Cdk2 functions, at least in part, via a Cdk2/SHP-1/beta-catenin/CEACAM1 axis, and show for the first time that Cdk2 has the capacity to regulate insulin internalization. PMID- 21262352 TI - BCAR3/AND-34 can signal independent of complex formation with CAS family members or the presence of p130Cas. AB - BCAR3 binds to the carboxy-terminus of p130Cas, a focal adhesion adapter protein. Both BCAR3 and p130Cas have been linked to resistance to anti-estrogens in breast cancer, Rac activation and cell motility. Using R743A BCAR3, a point mutant that has lost the ability to bind p130Cas, we find that BCAR3-p130Cas complex formation is not required for BCAR3-mediated anti-estrogen resistance, Rac activation or discohesion of epithelial breast cancer cells. Complex formation was also not required for BCAR3-induced lamellipodia formation in BALB/c-3T3 fibroblasts but was required for optimal BCAR3-induced motility. Although both wildtype and R743A BCAR3 induced phosphorylation of p130Cas and the related adapter protein HEF1/NEDD9, chimeric NSP3:BCAR3 experiments demonstrate that such phosphorylation does not correlate with BCAR3-induced anti-estrogen resistance or lamellipodia formation. Wildtype but not R743A BCAR3 induced lamellipodia formation and augmented cell motility in p130Cas(-/-) murine embryonic fibroblasts (MEFs), suggesting that while p130Cas itself is not strictly required for these endpoints, complex formation with other CAS family members is, at least in cells lacking p130Cas. Overall, our work suggests that many, but not all, BCAR3-mediated signaling events in epithelial and mesenchymal cells are independent of p130Cas association. These studies also indicate that disruption of the BCAR3-p130Cas complex is unlikely to reverse BCAR3-mediated anti-estrogen resistance. PMID- 21262354 TI - Differential activities of the Drosophila JAK/STAT pathway ligands Upd, Upd2 and Upd3. AB - JAK/STAT signalling in vertebrates is activated by multiple cytokines and growth factors. By contrast, the Drosophila genome encodes for only three related JAK/STAT ligands, Upd, Upd2 and Upd3. Identifying the differences between these three ligands will ultimately lead to a greater understanding of this disease related signalling pathway and its roles in development. Here, we describe the analysis of the least well characterised of the Upd-like ligands, Upd3. We show that in tissue culture-based assays Upd3-GFP is secreted from cells and appears to interact with the extracellular matrix (ECM) in a similar manner to Upd, while still non-autonomously activating JAK/STAT signalling. Quantification of each of the Upd-like ligands in conditioned media has allowed us to determine the activity of equal amounts of each ligand on JAK/STAT ex vivo and reveals that Upd is the most potent ligand in this system. Finally, investigations into the effects of ectopic expression of Upd3 in vivo have confirmed its ability to activate pathway signalling at long-distance. PMID- 21262355 TI - Phospholipase C-eta1 is activated by intracellular Ca(2+) mobilization and enhances GPCRs/PLC/Ca(2+) signaling. AB - Phospholipase C-eta1 (PLC-eta1) is the most recently identified PLC isotype and is primarily expressed in nerve tissue. However, its functional role is unclear. In the present study, we report for the first time that PLC-eta1 acts as a signal amplifier in G protein-coupled receptor (GPCR)-mediated PLC and Ca(2+) signaling. Short-hairpin RNA (shRNA)-mediated knockdown of endogenous PLC-eta1 reduced lysophosphatidic acid (LPA)-, bradykinin (BK)-, and PACAP-induced PLC activity in mouse neuroblastoma Neuro2A (N2A) cells, indicating that PLC-eta1 participates in GPCR-mediated PLC activation. Interestingly, ionomycin-induced PLC activity was significantly decreased by PLC-eta1, but not PLC-eta2, knockdown. In addition, we found that intracellular Ca(2+) source is enough for PLC-eta1 activation. Furthermore, the IP(3) receptor inhibitor, 2-APB, inhibited LPA-induced PLC activity in control N2A cells, whereas this effect was not observed in PLC-eta1 knockdown N2A cells, suggesting a pivotal role of intracellular Ca(2+) mobilization in PLC-eta1 activation. Finally, we found that LPA-induced ERK1/2 phosphorylation and expression of the downstream target gene, krox-24, were significantly decreased by PLC-eta1 knockdown, and these knockdown effects were abolished by 2-APB. Taken together, our results strongly suggest that PLC-eta1 is activated via intracellular Ca(2+) mobilization from the ER, and therefore amplifies GPCR-mediated signaling. PMID- 21262356 TI - A novel cross-talk between endothelin-1 and cyclic AMP signaling pathways in the regulation of GLUT1 transcription in 3T3-L1 adipocytes. AB - We showed previously that chronic exposure to both endothelin-1 (ET-1) and cAMP resulted in a synergistic increase in Glut1 transcription in 3T3-L1 adipocytes via a protein kinase C (PKC)-dependent mechanism. In the present study, we further examined the molecular mechanism involved. Employing transient transfections with Glut1 promoter/enhancer -luciferase reporter and several dominant negative or constitutively active PKC mutants, we identified PKCepsilon as the responsible PKC. Investigation with deletion and mutation mutants of the promoter/enhancer reporter suggested that Sp1, CREB and AP-1 responsive elements on enhancer 2 were involved. Furthermore, chromatin immunoprecipitation and co immunoprecipitation analysis were applied to characterize the interactions between these transcription factors and their bindings to enhancer 2 in vivo. The results indicate that there are both negative and positive interactions between ET-1 and cAMP signaling pathways. On the one hand, cAMP inhibits ET-1 induced NF kappaB activation required for ET-1-stimulated Glut1 transcription; on the other hand, cAMP, via sustained CREB phosphorylation, may activate AP-1 and cooperate with ET-1-activated PKCepsilon to enhance Sp1 expression and consequently to generate a stable enhancer 2-bound Sp1/pCREB/AP-1 complex, which can strongly facilitate Glut1 transcription more than the additive effect of ET-1 and cAMP alone. PMID- 21262357 TI - Tn5045, a novel integron-containing antibiotic and chromate resistance transposon isolated from a permafrost bacterium. AB - A novel antibiotic and chromate resistance transposon, Tn5045, was isolated from a permafrost strain of Pseudomonas sp. Tn5045 is a compound transposon composed of three distinct genetic elements. The backbone element is a Tn1013-like Tn3 family transposon, termed Tn1013*, that contains the tnpA and the tnpR genes, encoding the transposase and resolvase, respectively, the res-site and four genes (orfA, B, C, D) related to different house-keeping genes. The second element is class 1 integron, termed InC*, which is inserted into the Tn1013* res-region and contains 5'-CS-located integrase, 3'-CS-located qacE?1 and sulfonamide resistance sulI genes, and a single cassette encoding the streptomycin resistance aadA2 gene. The third element is a TnOtChr-like Tn3 family transposon termed TnOtChr*, which is inserted into the transposition module of the integron and contains genes of chromate resistance (chrB, A, C, F). Tn5045 is the first example of an ancient integron-containing mobile element and also the first characterized compound transposon coding for both antibiotic and chromate, resistance. Our data demonstrate that antibiotic and chromate resistance genes were distributed in environmental bacteria independently of human activities and provide important insights into the origin and evolution of antibiotic resistance integrons. PMID- 21262358 TI - Isolation and purification of a modified phenazine, griseoluteic acid, produced by Streptomyces griseoluteus P510. AB - Antibiotic phenazine derivatives and their formation pathways were studied in a new Streptomyces strain P510. Culture characteristics and 16S rRNA nucleotide analysis confirmed strain P510 as Streptomyces griseoluteus. The culture medium of this strain showed strong antimicrobial and antifungal activities. Using organic solvent extraction, silica gel column chromatography and HPLC, a modified phenazine, griseoluteic acid, and a shikimic acid-derived metabolite, p hydroxybenzaldehyde, were separated and purified. In addition, the biological activity of griseoluteic acid (GA), an important intermediate for biosynthesis of phenazine derivatives, was also investigated in this research. It significantly inhibited growth of Bacillus subtilis. The presence of GA and p hydroxybenzaldehyde implied that the phenazine biosynthesis pathway in S. griseoluteus P510 might be initiated with shikimic acid, using phenazine-1, 6 dicarboxylic acid as the precursor. The discovery of a partial analogical sequence of phenazine biosynthetic genes, sgpC, sgpD and sgpE, in S. griseoluteus P510 further supported this hypothesis. PMID- 21262359 TI - Comparison of culture-dependent and -independent methods for bacterial community monitoring during Montasio cheese manufacturing. AB - The microbial community in milk is of great importance in the manufacture of traditional cheeses produced using raw milk and natural cultures. During milk curdling and cheese ripening, complex interactions occur in the microbial community, and accurate identification of the microorganisms involved provides essential information for understanding their role in these processes and in flavor production. Recent improvements in molecular biological methods have led to their application to food matrices, and thereby opened new perspectives for the study of microbial communities in fermented foods. In this study, a description of microbial community composition during the manufacture and ripening of Montasio cheese was provided. A combined approach using culture dependent and -independent methods was applied. Culture-dependent identification was compared with 16S clone libraries sequencing data obtained from both DNA and reverse-transcribed RNA (cDNA) amplification and real-time quantitative PCR (qPCR) assays developed to detect and quantify specific bacterial species/genera (Streptococcus thermophilus, Lactobacillus casei, Pediococcus pentosaceus, Enterococcus spp., Pseudomonas spp.). S. thermophilus was the predominant LAB species throughout the entire ripening period of Montasio cheese. The culture independent method demonstrates the relevant presence of Pseudomonas spp. and Lactococcus piscium at the beginning of ripening. The culture-dependent approach and the two culture-independent approaches produced complementary information, together generating a general view of cheese microbial ecology. PMID- 21262360 TI - Estrogen receptor beta signaling regulates the progression of Chinese non-small cell lung cancer. AB - Prospective studies have found that the risk of non-small cell lung cancer (NSCLC) has close relationship with estrogen. The effects of estrogens are mediated via two estrogen receptor (ER) isoforms, that is, ER alpha (ERalpha) and ER beta (ERbeta). ERalpha in NSCLC has been evaluated mostly by immunohistochemistry. However, our previous study showed that ERbeta was also highly expressed in Chinese NSCLC. But the roles of ERbeta in Chinese NSCLC have not been clarified as yet. So in the present study, two Chinese lung adenocarcinoma cell lines, SPC-A1 and LTEP-a2, were used and the role of ERbeta in lung tumorigenesis was focused to be investigated by in vitro and in vivo experiments. The results showed that over-expressed ERbeta can promote the development of NSCLC, while siRNAs targeting ERbeta gene can inhibit growth of NSCLC cells and induce apoptosis of these cells via mitochondrial depolarization and caspase-3 activation. These results indicated that ERbeta plays an important role in development of Chinese NSCLC. This suggests that ERbeta deactivation or down-regulation may possess potential therapeutic utility for the treatment of lung cancer. PMID- 21262361 TI - Alterations of folliculogenesis in women with polycystic ovary syndrome. AB - The objective of the present study was to examine some factors involved in follicular development of women with polycystic ovary syndrome (PCOS). Women with PCOS showed increased levels of serum luteinizing hormone (LH) but decreased follicular production of progesterone and estradiol by pre-ovulatory follicles. The mRNA expression corresponding to steroidogenic acute regulatory protein (StAR), and 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) was increased, while that corresponding to cytochrome P450 aromatase (P450arom) was decreased in PCOS follicles as compared to controls. No changes in the mRNA expression for 3beta-hydroxysteroid dehydrogenase 2 (3beta-HSD2), cytochrome P450 side-chain cleavage (P450scc), cytochrome P450 17 alpha hydroxylase/lyase (P450c17), cyclooxygenase 2 (COX2), and transcription factors (GATA-4 and GATA-6) were found. We conclude that despite the hyper-luteinized environment of PCOS follicles, these follicles produce lower levels of progesterone and estradiol, and that this is characterized by increased degradation of progesterone and decreased estradiol synthesis. Our data demonstrate that the synthesis of prostaglandin F2alpha (PGF2alpha) may be affected in PCOS-follicles and that the transcription factors GATA-4 and GATA-6 are present in PCOS-follicles but they are not involved in the abnormal transcription observed in the steroidogenic enzymes. PMID- 21262362 TI - NADPH oxidase-mediated oxidative damage to proteins in the postsynaptic density after transient cerebral ischemia and reperfusion. AB - NADPH oxidase is an important source of superoxide in the central nervous system. Although NADPH oxidase is localized near the postsynaptic site in neurons, little is known about the pathophysiological role of NADPH oxidase in synapses after cerebral ischemia and reperfusion. In the present study, we sought to determine the role of NADPH oxidase in oxidative damage to postsynaptic density (PSD) proteins, which were isolated from rats subjected to transient focal cerebral ischemia and reperfusion. The amounts of carbonylated PSD proteins were increased after transient focal cerebral ischemia and reperfusion. This change was accompanied by an increase in the level of NADPH oxidase subunits in the PSD. The administration of apocynin, an NADPH oxidase inhibitor, attenuated both the protein carbonylation in the PSD and cerebral infarct volume. We further demonstrated that the decreases seen in the amounts of PSD-associated proteins, such as neuroligin, N-cadherin, and SAP102, in the PSD were prevented by treatment with apocynin. These results suggest that pronounced activation of NADPH oxidase in the PSD after cerebral ischemia and reperfusion may be related to the focal oxidative damage to synaptic functions and subsequent development of ischemia and reperfusion-induced cerebral injury. PMID- 21262363 TI - Production and characterization of Acidothermus cellulolyticus endoglucanase in Pichia pastoris. AB - The endoglucanase (E1) from Acidothermus cellulolyticus has been used extensively in cellulase research. The goal of this work was to produce high levels of this enzyme in a system that facilitates purification. A codon-optimized synthetic gene for A. cellulolyticus E1 with a C-terminal histidine tag was cloned into the genome of Pichia pastoris. Strain KM71H expressed the most enzyme, with a yield of 550mg/L culture supernatant. The temperature optimum (80 degrees C) and pH optimum (5.1) of the purified enzyme agree with previously determined values for the enzyme produced in other systems. Michaelis-Menten kinetic parameters were determined, using a fluorescent substrate (methylumbelliferyl-beta-d cellobioside) at various temperatures. This thermostable enzyme can be used in future cellulosic biofuels-related research. PMID- 21262365 TI - Co-expression of the Plasmodium falciparum molecular chaperone, PfHsp70, improves the heterologous production of the antimalarial drug target GTP cyclohydrolase I, PfGCHI. AB - Molecular chaperones have been used for the improved expression of target proteins within heterologous systems; however, the chaperone and target protein have seldom been matched in terms of origin. We have developed a heterologous co expression system that allows independent expression of the plasmodial chaperone, PfHsp70, and a plasmodial target protein. In this study, the target was Plasmodium falciparum GTP cyclohydrolase I (PfGCHI), the first enzyme in the plasmodial folate pathway. The sequential expression of the molecular chaperone followed by the target protein increased the expression of soluble functional PfGCHI. His-tagged PfGCHI was successfully purified using nickel affinity chromatography, and the specific activity was determined by high performance liquid chromatography with spectrofluorometeric detection to be 5.93nmol/h/mg. This is the first report of a heterologous co-expression system in which a plasmodial chaperone is harnessed for the improved production and purification of a plasmodial target protein. PMID- 21262364 TI - New ligation-independent cloning vectors compatible with a high-throughput platform for parallel construct expression evaluation using baculovirus-infected insect cells. AB - Biomedical research has undergone a major shift in emphasis over the past decade from characterizing the genomes of organisms to characterizing their proteomes. The high-throughput approaches that were successfully applied to sequencing of genomes, such as miniaturization and automation, have been adapted for high throughput cloning and protein production. High-throughput platforms allow for a multi-construct, multi-parallel approach to expression optimization and construct evaluation. We describe here a series of baculovirus transfer and expression vectors that contain ligation-independent cloning regions originally designed for use in high-throughput Escherichia coli expression evaluation. These new vectors allow for parallel cloning of the same gene construct into a variety of baculovirus or E. coli expression vectors. A high-throughput platform for construct expression evaluation in baculovirus-infected insect cells was developed to utilize these vectors. Data from baculovirus infection expression trials for multiple constructs of two target protein systems relevant to the study of human diseases are presented. The target proteins exhibit a wide variation in behavior and illustrate the benefit of investigating multiple cell types, fusion partners and secretion signals in optimization of constructs and conditions for eukaryotic protein production. PMID- 21262366 TI - Partial volume effect as a hidden covariate in DTI analyses. AB - During the last decade, diffusion tensor imaging (DTI) has been used extensively to investigate microstructural properties of white matter fiber pathways. In many of these DTI-based studies, fiber tractography has been used to infer relationships between bundle-specific mean DTI metrics and measures-of-interest (e.g., when studying diffusion changes related to age, cognitive performance, etc.) or to assess potential differences between populations (e.g., comparing males vs. females, healthy vs. diseased subjects, etc.). As partial volume effects (PVEs) are known to affect tractography and, subsequently, the estimated DTI measures sampled along these reconstructed tracts in an adverse way, it is important to gain insight into potential confounding factors that may modulate this PVE. For instance, for thicker fiber bundles, the contribution of PVE contaminated voxels to the mean metric for the entire fiber bundle will be smaller, and vice-versa - which means that the extent of PVE-contamination will vary from bundle to bundle. With the growing popularity of tractography-based methods in both fundamental research and clinical applications, it is of paramount importance to examine the presence of PVE-related covariates, such as thickness, orientation, curvature, and shape of a fiber bundle, and to investigate the extent to which these hidden confounds affect diffusion measures. To test the hypothesis that these PVE-related covariates modulate DTI metrics depending on the shape of a bundle, we performed simulations with synthetic diffusion phantoms and analyzed bundle-specific DTI measures of the cingulum and the corpus callosum in 55 healthy subjects. Our results indicate that the estimated bundle-specific mean values of diffusion metrics, including the frequently used fractional anisotropy and mean diffusivity, were indeed modulated by fiber bundle thickness, orientation, and curvature. Correlation analyses between gender and diffusion measures yield different results when volume is included as a covariate. This indicates that incorporating these PVE-related factors in DTI analyses is imperative to disentangle changes in "true microstructural" tissue properties from these hidden covariates. PMID- 21262367 TI - Reconciling phylogeography and ecological niche models for New Zealand beetles: Looking beyond glacial refugia. AB - Mitochondrial DNA (cox1) sequence data and recently developed coalescent phylogeography models were used to construct geo-spatial histories for the New Zealand fungus beetles Epistranus lawsoni and Pristoderus bakewelli (Zopheridae). These methods utilize continuous-time Markov chains and Bayesian stochastic search variable selection incorporated in BEAST to identify historical dispersal patterns via ancestral state reconstruction. Ecological niche models (ENMs) were incorporated to reconstruct the potential geographic distribution of each species during the Last Glacial Maximum (LGM). Coalescent analyses suggest a North Island origin for E. lawsoni, with gene flow predominately north-south between adjacent regions. ENMs for E. lawsoni indicated glacial refugia in coastal regions of both main islands, consistent with phylogenetic patterns but at odds with the coalescent dates, which implicate much older topographic events. Dispersal matrices revealed patterns of gene flow consistent with projected refugia, suggesting long-term South Island survival with population vicariance around the Southern Alps. Phylogeographic relationships are more ambiguous for P. bakewelli, although long-term survival on both main islands is evident. Divergence dates for both species are consistent with the topographic evolution of New Zealand over the last 10Ma, whereas the signature of the LGM is less apparent in the time scaled phylogeny. PMID- 21262369 TI - Brother of CDO (BOC) expression in equine articular cartilage. AB - Brother of CDO (BOC) is a cell surface receptor that derives its name from the structurally related protein, cell adhesion molecule-related/down-regulated by oncogenes (CDO, sometimes CDON). High levels of BOC mRNA and protein expression have been described in embryonic tissues with active cell proliferation and ongoing cellular differentiation(1,2). A microarray-based screen of RNA isolated from 11 different adult equine tissues unexpectedly identified BOC as having an expression pattern restricted to articular cartilage. The objective of this study was to further investigate BOC expression in adult articular cartilage relative to other tissues. Both RT-qPCR and mRNA sequencing confirmed the microarray data. Steady state BOC mRNA levels in articular cartilage were substantially higher than in the other adult tissues tested, neonatal tendon, placenta, and whole embryo. The expression of BOC displayed a pattern of tissue specificity comparable to well established cartilage matrix protein biomarkers. BOC mRNA levels in articular cartilage increased with age, but were rapidly down-regulated when chondrocytes were enzymatically isolated from the cartilage matrix and expanded in monolayer culture. Relative expression patterns of CDO were broadly similar, but displayed lower fold change differences. A functional role in articular cartilage that involves Hedgehog signaling is suggested by the known binding affinity of BOC for all three Hedgehog ligands. These data also extend BOC and CDO biology to a post-mitotic and highly differentiated cell type within a mature tissue. PMID- 21262368 TI - Osteoarthritis-like damage of cartilage in the temporomandibular joints in mice with autoimmune inflammatory arthritis. AB - OBJECTIVE: To study temporomandibular joint (TMJ) involvement in an autoimmune murine model of rheumatoid arthritis (RA), a disease characterized by inflammatory destruction of the synovial joints. Although TMJ dysfunction is frequently found in RA, TMJ involvement in RA remains unclear, and TMJ pathology has not been studied in systemic autoimmune animal models of RA. METHODS: Proteoglycan (PG) aggrecan-induced arthritis (PGIA) was generated in genetically susceptible BALB/c mice. TMJs and joint tissues/cartilage were harvested for histological and immunohistochemical analyses and RNA isolation for quantitative polymerase chain-reaction. Serum cytokine levels were measured in mice with acute or chronic arthritis, and in non-arthritic control animals. RESULTS: Despite the development of destructive synovitis in the limbs, little or no synovial inflammation was found in the TMJs of mice with PGIA. However, the TMJs of arthritic mice showed evidence of aggrecanase- and matrix metalloproteinase mediated loss of glycosaminoglycan-containing aggrecan, and in the most severe cases, structural damage of cartilage. Serum levels of pro-inflammatory cytokines, including interleukin (IL)-1beta, were elevated in arthritic animals. Expression of the IL-1beta gene was also high in the inflamed limbs, but essentially normal in the TMJs. Local expression of genes encoding matrix degrading enzymes (aggrecanases and stromelysin) was upregulated to a similar degree in both the limbs and the TMJs. CONCLUSION: We propose that constantly elevated levels of catabolic cytokines, such as IL-1beta, in the circulation (released from inflamed joints) create a pro-inflammatory milieu within the TMJ, causing local upregulation of proteolytic enzymes and subsequent loss of aggrecan from cartilage. PMID- 21262370 TI - Intracellular delivery of serum-derived hepatitis C virus. AB - A robust and reliable cell culture system for serum-derived HCV (HCVser) has not been established yet because of the presence of neutralizing antibody and tropism for infection. To overcome this obstacle, we employed a lipid-mediated protein intracellular delivery reagent (PIDR) that permits internalization of proteins into cells. Although entry of HCVcc was not enhanced by the treatment with PIDR, entry of HCVser into hepatoma cell lines (Huh7 and HepG2) and immortalized primary hepatocytes (Hc and HuS/E2) was significantly enhanced by the PIDR treatment. The entry of HCVser into Huh7 cells in the presence of PIDR was resistant to the neutralization by an anti-hCD81 antibody, suggesting that PIDR is capable of internalizing HCVser in a receptor-independent manner. Interestingly, the PIDR-mediated entry of HCVser and HCVcc was enhanced by the addition of sera from chronic hepatitis C patients but not from healthy donors. In addition, neutralization of HCVcc infection by anti-E2 antibody was canceled by the treatment with PIDR. In conclusion, the PIDR is a valuable tool to get over the obstacle of neutralizing antibodies to internalize HCV into cells and might be useful for the establishment of in vitro propagation HCVser. PMID- 21262371 TI - Partial depletion of CD4(+)CD25(+)Foxp3(+) T regulatory cells significantly increases morbidity during acute phase Toxoplasma gondii infection in resistant BALB/c mice. AB - CD4(+)CD25(+)Foxp3(+) T regulatory (Treg) cells, are known to regulate responses to infectious agents. Here we compared disease progression in BALB/c and C57BL/6(B6) mice infected perorally with Toxoplasma gondii for 7 days and examined the affect of partial depletion of Treg cells in these mice. BALB/c mice were seen to be resistant to peroral infection whereas B6 mice were susceptible in terms of mortality. Although the depletion of Treg cells before infection had no effect on the survival of B6 or BALB/c mice, it resulted in increased parasite burdens in BALB/c mice, especially in the lamina propria, but not in B6 mice. Pro inflammatory cytokines were also increased in Treg cells depleted BALB/c mice as compared to B6 mice. In addition Treg cell depleted BALB/c mice displayed increased ileal histopathology compared to their non-treated counterparts. These findings provide evidence for the contribution of Treg cells, in the resistance of BALB/c mice against peroral T. gondii infection. PMID- 21262372 TI - Rhodococcus equi human clinical isolates enter and survive within human alveolar epithelial cells. AB - Rhodococcus equi is an emerging opportunistic human pathogen associated with immunosuppressed people, especially those infected with the human immunodeficiency virus (HIV). This pathogen resides primarily within lung macrophages of infected patients, which may explain in part its ability to escape normal pulmonary defense mechanisms. Despite numerous studies as a pulmonary pathogen in foals, where a plasmid seems to play an important role in virulence, information on the pathogenesis of this pathogen in humans is still scarce. In this study, fluorescence microscopy and vancomycin protection assays were used to investigate the ability of R. equi human isolates to adhere to and to invade the human alveolar epithelial cell line A549. Our findings indicate that some R. equi clinical strains are capable of adhering, entering and surviving within the alveolar cell line, which may contribute to the pathogen persistence in lung tissues. PMID- 21262373 TI - HIV-associated dementia in the era of highly active antiretroviral therapy (HAART). AB - Neurological complications associated with HIV-1 are being recognized as a common disorder in AIDS patients, especially patients with HIV-associated dementia (HAD). However, our knowledge of the complicated pathogenesis and clinical symptoms of HAD is limited by an incomplete understanding of the biology of HIV-1 in the nervous system. Therefore, this review focuses on the pathogenesis of HAD in the context of novel highly active antiretroviral therapy (HARRT) regimens. PMID- 21262374 TI - Dysfunctional mitochondria contain endogenous high-affinity human Toll-like receptor 4 (TLR4) ligands and induce TLR4-mediated inflammatory reactions. AB - Mitochondria, known to share many common features with prokaryotic cells, accumulate several endogenous ligands of the pattern-recognition Toll-like receptor 4 (TLR4), such as the heat shock proteins (Hsp) 70 and 60. TLR4 specifically recognises and responds to LPS of Gram-negative bacteria and participates in both autoimmune reactions and tissue regeneration due to its ability to recognise endogenous ligands. In the present study we show that mitochondria extracts obtained from hydrogen peroxide-dysfunctionalised cells induce a pro-inflammatory response in human THP-1 myeloid leukaemia cells. This inflammatory response was similar to that caused by LPS and much stronger than that induced by the extracts of normal mitochondria. Such reactions include activation of stress-adaptation hypoxia-inducible factor 1 alpha (HIF-1alpha) and expression/release of the pro-inflammatory cytokines IL-6 and TNF-alpha. Pre treatment of THP-1 myeloid macrophages with TLR4-neutralising antibody before exposure to mitochondria extracts or LPS attenuated the inflammatory responses. Signalling pathways recruited by TLR4 in response to LPS and mitochondria-derived ligands were found to be the same. An in vitro ELISA-based TLR4-ligand binding assay, in which the ligand-binding domain of human TLR4 was immobilised, showed that mitochondria extracts contain endogenous TLR4 ligands. These results were verified in surface plasmon resonance experiments in which the affinity of the ligands derived from dysfunctional mitochondria was comparable with that of LPS and was much higher than that observed for normal mitochondria. PMID- 21262375 TI - Biofunctionalization of a generic collagenous triple helix with the alpha2beta1 integrin binding site allows molecular force measurements. AB - The integrin alpha2beta1 plays an important role in force-transmitting cell matrix interactions. It recognizes the peptide sequence GFOGER (O=4-hydroxy proline) presented as trimer within a collagenous triple-helical framework. We produced the recombinant non-hydroxylated mini-collagen, termed FC3, which harbors the alpha2beta1 integrin recognition site. FC3 consists of a foldon stabilized host triple helix of three chains with 10 GPP-repeats, into which the integrin binding motif was inserted. The triple-helical structure could further be stabilized by covalently cross-linking the three chains. Unlike collagen-I, FC3 lacks binding sites for matrix proteins and cellular receptors other than the collagen-binding integrins. It showed a preference for alpha2beta1 over alpha1beta1 integrin, especially when the chains were neither cross-linked nor prolyl-hydroxylated. Using FC3 as substratum for primary skin fibroblasts, we showed that the loss of alpha2beta1 integrin could not be compensated by other collagen-binding integrins, suggesting a major role of alpha2beta1 integrin in exerting sufficient mechanical force to induce or sustain cell spreading. Atomic force microscopy revealed that a single alpha2beta1 integrin can withstand tensile forces of up to approximately 160pN before it releases FC3. Moreover, FC3 is fully competent to agonistically elicit alpha2beta1 integrin-induced cell reactions, such as recruitment of alpha2beta1 integrin into focal adhesions and lamellipodia formation. The biofunctionalized mini-collagen sheds light on the molecular forces of the alpha2beta1 integrin-collagen interaction, which affects tissue homeostasis by contracting the connective tissue and by contributing to interstitial tissue pressure regulation. Additionally, biofunctionalized mini collagens can be useful in force-resistant cell attachment to biomedical materials. PMID- 21262376 TI - Caveolin-3 is a direct molecular partner of the Cav1.1 subunit of the skeletal muscle L-type calcium channel. AB - Caveolin-3 is the striated muscle specific isoform of the scaffolding protein family of caveolins and has been shown to interact with a variety of proteins, including ion channels. Mutations in the human CAV3 gene have been associated with several muscle disorders called caveolinopathies and among these, the P104L mutation (Cav-3(P104L)) leads to limb girdle muscular dystrophy of type 1C characterized by the loss of sarcolemmal caveolin. There is still no clear-cut explanation as to specifically how caveolin-3 mutations lead to skeletal muscle wasting. Previous results argued in favor of a role for caveolin-3 in dihydropyridine receptor (DHPR) functional regulation and/or T-tubular membrane localization. It appeared worth closely examining such a functional link and investigating if it could result from the direct physical interaction of the two proteins. Transient expression of Cav-3(P104L) or caveolin-3 specific siRNAs in C2C12 myotubes both led to a significant decrease of the L-type Ca(2+) channel maximal conductance. Immunolabeling analysis of adult skeletal muscle fibers revealed the colocalization of a pool of caveolin-3 with the DHPR within the T tubular membrane. Caveolin-3 was also shown to be present in DHPR-containing triadic membrane preparations from which both proteins co-immunoprecipitated. Using GST-fusion proteins, the I-II loop of Ca(v)1.1 was identified as the domain interacting with caveolin-3, with an apparent affinity of 60nM. The present study thus revealed a direct molecular interaction between caveolin-3 and the DHPR which is likely to underlie their functional link and whose loss might therefore be involved in pathophysiological mechanisms associated to muscle caveolinopathies. PMID- 21262377 TI - Klf10 induces cell apoptosis through modulation of BI-1 expression and Ca2+ homeostasis in estrogen-responding adenocarcinoma cells. AB - Estrogen stimulates cell growth and inhibits apoptosis through estrogen receptor mediated mechanisms in many cell types. Remarkably, there is another dimension to estrogen action by which apoptosis is induced in breast cancer cells. While these mechanisms are not yet completely understood, finding the molecules involved has paved the way for the development of a new drug group. Using ChIP-chip, we have demonstrated that Klf10, a Kruppel-like zinc finger transcription factor, which was induced in response to estrogen, directly modulates the transcription of BI-1 (Bax inhibitor-1; also called the testis-enhanced gene transcript, TEGT). Eventually, the estrogen induced Klf10 and then suppresses BI-1 transcription. The estrogen/Klf10/BI-1 interrelationship was further confirmed using BI-1 promoter and EMSA assays. The estrogen-elicited reduction of BI-1 promoter activity was significantly reversed when the Klf10 binding element was mutated to abolish Klf10 binding. A si-Klf10 antisense-oligo nucleotide was also able to restore BI-1 promoter activity to its pre-estrogen-treatment level. BI-1 is known to regulate stress via the endoplasmic reticulum; in this context down-regulation of BI-1 is able to cause Ca(2+) release and trigger an apoptosis pathway in breast cancer. In our study, Klf10 not only suppressed cellular BI-1 expression but also increased the cytosolic Ca(2+) concentration, eventually causing apoptotic cell death. Based on these results, we suggest the pathway by which estrogen induces apoptosis is possibly through an up-regulation of Klf10 that decreases BI-1 and finally increases the concentration of cytoplasmic calcium. PMID- 21262378 TI - Outsourcing chemical synthesis in the drug discovery process. AB - The positive effects of outsourcing chemical synthesis are enhanced if the provider offers, as the strategic partner, unique expertise and complements the existing internal competencies of pharmaceutical companies. The emerging cooperation model of leased competence offers additional access to high-level specialist knowledge: external service providers are temporarily integrated into internal R&D teams and can support R&D projects flexibly and quickly. Practice examples show that this cooperation model supports the efficient realization of milestones and, in the long-term, helps to build up a high internal competence level, especially in small pharmaceutical companies. PMID- 21262379 TI - Intestinal delivery of non-viral gene therapeutics: physiological barriers and preclinical models. AB - The future of nucleic acid-based therapeutics is dependent on achieving successful delivery. Recently, there has been an increasing interest in delivery via the gastrointestinal tract. Gene therapy via this route has many advantages, including non-invasive access and the versatility to treat local diseases, such as inflammatory bowel disease, as well as systemic diseases, such as haemophilia. However, the intestine presents several distinct barriers and, therefore, the design of robust non-viral delivery systems is key to future success. Several non viral delivery strategies have provided evidence of activity in vivo. To facilitate the design of more efficient and safe gene medicines, more physiologically relevant models, at both the in vitro and in vivo levels, are essential. PMID- 21262380 TI - Recent progress toward biomarker identification in osteoarthritis. AB - Osteoarthritis (OA), the most common and disabling form of arthritic disease, is characterized by a slow and progressive degeneration of articular cartilage. Its etiology is multifactorial and includes genetic predisposition, obesity and aging. In addition to the cartilage itself, OA also involves the surrounding tissues, including the synovium and the subchondral bone. This clinical heterogeneity complicates the identification of biomarkers that are crucial for prompt pharmacological intervention at the early stages of the disease and for monitoring treatment efficacy with higher sensitivity than existing imaging methods. In this review, we highlight the difficulties associated with OA diagnosis and discuss the most recent research efforts and successes for the identification of reliable OA biomarkers. PMID- 21262381 TI - The VEGF/Rho GTPase signalling pathway: a promising target for anti angiogenic/anti-invasion therapy. AB - It has become increasingly apparent that current antiangiogenic therapy elicits modest effects in clinical settings. In addition, it remains challenging to treat cancer metastasis through antiangiogenic regimes. Rho GTPases are essential for vascular endothelial growth factor (VEGF)-mediated angiogenesis and are involved in tumour cell invasion. This review discusses novel therapeutic strategies that interfere with Rho GTPase signalling and further explores this network as a target for anticancer therapy through interference with tumour angiogenesis and invasion. Recent findings describe the development of innovative Rho GTPase inhibitors. Positive clinical effects of Rho GTPase targeting in combination with conventional anticancer therapy is of increasing interest. PMID- 21262382 TI - Exploiting personalized information for reagent selection in drug design. AB - Drug discovery is currently being industrialized. This fact is confusing, given that it is happening in times when the rest of the world has entered the subsequent information age. Here, we introduce a concept and an infrastructure for the now popular and well-known recommender systems in the context of exploiting one of the cornerstones of drug design: chemical reagent selection. The goal is to create and transfer information openly to facilitate intuition and serendipity in drug design. The system is tailored to highlight reagents from our corporate reagent database; reagents that a chemist might not have considered based purely on their own experience. PMID- 21262383 TI - Antiangiogenic therapy using nanotechnological-based delivery system. AB - Of the many approaches for the treatment of cancer, angiogenesis and the additional promotion of apoptosis in cancer stem cells by using combinatorial therapy is usually the most recommended. There has been increased interest in the use of antiapoptotic and antiangiogenic biomolecules, such as antiangiogenic microRNA, small interfering RNA, inhibitor of apoptosis protein-binding peptides and Von Hippel-Lindau tumor suppressors, as well as targeting ligands, such as aptamers. Therefore, it is tempting to suggest that such molecules could be used for anticancer therapy. As we review here, such exploitation can be achieved by using nanotechnology and RNA-carrying cationic cell-penetrating peptides, for better protection from the enzymatic digestion and enhanced cellular internalization of these biomolecules. PMID- 21262384 TI - A modified protocol for the comet assay allowing the processing of multiple samples. AB - In the present study, we developed a modified protocol for the basic comet assay that increased efficiency without sacrificing assay reliability. A spreader was used to spread agarose-embedded cells on a slide, making the manipulation and processing of multiple samples easier. Using this technique, we are able to rapidly prepare five or more comet assay samples on one slide. To demonstrate the effect of the protocol modifications on assay reliability, we present an example of how the comet assay was used in our laboratory to analyze the effect of melatonin (N-acetyl-5-methoxitryptamine; MEL) on the DNA repair ability of Gentiana macrophylla Pall. protoplasts after irradiation with different doses of ultraviolet-B radiation. A slight, but statistically significant (P<0.01), dose related protective effect of MEL was observed in our experiments. The first use of the comet assay was to confirm the antioxidant and DNA repair functions of MEL in plants. The modified protocol is cost-effective and provides substantial advantages over the conventional comet assay. PMID- 21262385 TI - Antiproliferative and anticytotoxic effects of cell fractions and exopolysaccharides from Lactobacillus casei 01. AB - Cell fractions including heat-treated cells, crude cell walls, intracellular extracts and exopolysaccharides (EPSs) obtained from Lactobacillus casei 01 were first studied for their effects on the proliferation of human intestinal epithelial cells, intestine 407 and the human colon cancer cell, HT-29. Their effects on the cytotoxicity of 4-nitroquinoline 1-oxide (4-NQO) against intestine 407 were further investigated. The results revealed that EPS exhibited the highest antiproliferation activity on HT-29 cells while the viability of intestine 407 cells was not affected by EPS at a concentration of 5-50MUg/mL. It was also noted that all the cell fractions and EPS from L. casei 01 reduced the cytotoxicity of 4-NQO against intestine 407 with EPS showing the highest anticytotoxic activity. Additionally, it was found that EPS might exert blocking and bioanticytotoxic effects by both adjusting the function of intestine 407 and repairing the 4-NQO-damaged cells, thus reducing cytotoxicity of 4-NQO. PMID- 21262386 TI - Identification of novel three allergens from Anisakis simplex by chemiluminescent immunoscreening of an expression cDNA library. AB - Anisakis simplex is a representative nematode parasitizing marine organisms, such as fish and squids, and causes not only anisakiasis but also IgE-mediated allergy. Although 10 kinds of proteins have so far been identified as A. simplex allergens, many unknown allergens are considered to still exist. In this study, a chemiluminescent immunoscreening method with higher sensitivity than the conventional method was developed and used to isolate IgE-positive clones from an expression cDNA library of A. simplex. As a result, three kinds of proteins, Ani s 11 (307 amino acid residues), Ani s 11-like protein (160 residues) and Ani s 12 (295 residues), together with three known allergens (Ani s 5, 6 and 9), were found to be IgE reactive. Furthermore, ELISA data showed that both recombinant Ani s 11 and 12 expressed in Escherichia coli are recognized by about half of Anisakis-allergic patients. Ani s 11 and Ani s 11-like protein are characterized by having six and five types of short repetitive sequences (5-16 amino acid residues), respectively. Both proteins share as high as 78% sequence identity with each other and also about 45% identity with Ani s 10, which includes two types of short repetitive sequences. On the other hand, Ani s 12 is also structurally unique in that it has five tandem repeats of a CX(13 25)CX(9)CX(7,8)CX(6) sequence, similar to Ani s 7 having 19 repeats of a CX(17 25)CX(9-22)CX(8)CX(6) sequence. The repetitive structures are assumed to be involved in the IgE-binding of the three new allergens. PMID- 21262387 TI - 1alpha,25-Dihydroxyvitamin D3 exerts tissue-specific effects on estrogen and androgen metabolism. AB - It is well-known that 1alpha,25-dihydroxyvitamin D(3) and analogs exert anti proliferative and pro-differentiating effects and these compounds have therefore been proposed to be of potential use as anti-cancer agents. Due to its effects on aromatase gene expression and enzyme activity, 1alpha,25-dihydroxyvitamin D(3) has been proposed as an interesting substance in breast cancer treatment and prevention. In the present study, we have examined the effects of 1alpha,25 dihydroxyvitamin D(3) on estrogen and androgen metabolism in adrenocortical NCI H295R cells, breast cancer MCF-7 cells and prostate cancer LNCaP cells. The NCI H295R cell line has been proposed as a screening tool to study endocrine disruptors. We therefore studied whether this cell line reacted to 1alpha,25 dihydroxyvitamin D(3) treatment in the same way as cells from important endocrine target tissues. 1alpha,25-Dihydroxyvitamin D(3) exerted cell line-specific effects on estrogen and androgen metabolism. In breast cancer MCF-7 cells, aromatase gene expression and estradiol production were decreased, while production of androgens was markedly increased. In NCI-H295R cells, 1alpha,25 dihydroxyvitamin D(3) stimulated aromatase expression and decreased dihydrotestosterone production. In prostate cancer LNCaP cells, aromatase expression increased after the same treatment, as did production of testosterone and dihydrotestosterone. In summary, our data show that 1alpha,25 dihydroxyvitamin D(3) exerts tissue-specific effects on estrogen and androgen production and metabolism. This is important knowledge about 1alpha,25 dihydroxyvitamin D(3) as an interesting substance for further research in the field of breast cancer prevention and treatment. Furthermore, the observed cell line-specific effects are of importance in the discussion about NCI-H295R cells as a model for effects on estrogen and androgen metabolism. PMID- 21262388 TI - Muscarinic regulation of Kenyon cell dendritic arborizations in adult worker honey bees. AB - The experience of foraging under natural conditions increases the volume of mushroom body neuropil in worker honey bees. A comparable increase in neuropil volume results from treatment of worker honey bees with pilocarpine, an agonist for muscarinic-type cholinergic receptors. A component of the neuropil growth induced by foraging experience is growth of dendrites in the collar region of the calyces. We show here, via analysis of Golgi-impregnated collar Kenyon cells with wedge arborizations, that significant increases in standard measures of dendritic complexity were also found in worker honey bees treated with pilocarpine. This result suggests that signaling via muscarinic-type receptors promotes the increase in Kenyon cell dendritic complexity associated with foraging. Treatment of worker honey bees with scopolamine, a muscarinic inhibitor, inhibited some aspects of dendritic growth. Spine density on the Kenyon cell dendrites varied with sampling location, with the distal portion of the dendritic field having greater total spine density than either the proximal or medial section. This observation may be functionally significant because of the stratified organization of projections from visual centers to the dendritic arborizations of the collar Kenyon cells. Pilocarpine treatment had no effect on the distribution of spines on dendrites of the collar Kenyon cells. PMID- 21262389 TI - Endosulfan affects health variables in adult zebrafish (Danio rerio) and induces alterations in larvae development. AB - Adult zebrafish (Danio rerio) were exposed to 0 (control), 0.16 or 0.48MUg/L of the insecticide, endosulfan, for 28days. Haematology, whole body ions, thiobarbituric acid reactive substances (TBARS), Na(+)K(+)-ATPase, organ histology and reproduction were assessed in adults. The resulting offspring were examined for latent effects on development (heart rate and morphometrics). On day 14, adult fish exposed to 0.16MUg/L endosulfan showed significantly lower red blood cell counts than those exposed to 0.48MUg/L endosulfan; adult fish exposed to 0.16 ug/L also showed elevated TBARS compared to controls. Both concentrations of endosulfan caused a 4.0 fold increase in Na(+)K(+)-ATPase activity compared to controls (ANOVA, p<0.05). On day 14, the livers of fish exposed to endosulfan had fewer, enlarged hepatocytes, with cell diameters greater than the controls (ANOVA, p<0.05). Morphological alterations in the progeny of fish exposed to endosulfan were observed. Heart beat frequency was significantly lower in larvae from exposed adults to 0.16 MUg/L compared to the control (ANOVA, p<0.05). These findings show that sublethal exposure to endosulfan causes adverse sublethal effects in adult D. rerio, and effects on the development of their offspring. PMID- 21262390 TI - A comparison of two methods for retrieving ICD-9-CM data: the effect of using an ontology-based method for handling terminology changes. AB - OBJECTIVE: Most existing controlled terminologies can be characterized as collections of terms, wherein the terms are arranged in a simple list or organized in a hierarchy. These kinds of terminologies are considered useful for standardizing terms and encoding data and are currently used in many existing information systems. However, they suffer from a number of limitations that make data reuse difficult. Relatively recently, it has been proposed that formal ontological methods can be applied to some of the problems of terminological design. Biomedical ontologies organize concepts (embodiments of knowledge about biomedical reality) whereas terminologies organize terms (what is used to code patient data at a certain point in time, based on the particular terminology version). However, the application of these methods to existing terminologies is not straightforward. The use of these terminologies is firmly entrenched in many systems, and what might seem to be a simple option of replacing these terminologies is not possible. Moreover, these terminologies evolve over time in order to suit the needs of users. Any methodology must therefore take these constraints into consideration, hence the need for formal methods of managing changes. Along these lines, we have developed a formal representation of the concept-term relation, around which we have also developed a methodology for management of terminology changes. The objective of this study was to determine whether our methodology would result in improved retrieval of data. DESIGN: Comparison of two methods for retrieving data encoded with terms from the International Classification of Diseases (ICD-9-CM), based on their recall when retrieving data for ICD-9-CM terms whose codes had changed but which had retained their original meaning (code change). MEASUREMENTS: Recall and interclass correlation coefficient. RESULTS: Statistically significant differences were detected (p<0.05) with the McNemar test for two terms whose codes had changed. Furthermore, when all the cases are combined in an overall category, our method also performs statistically significantly better (p<0.05). CONCLUSION: Our study shows that an ontology-based ICD-9-CM data retrieval method that takes into account the effects of terminology changes performs better on recall than one that does not in the retrieval of data for terms whose codes had changed but which retained their original meaning. PMID- 21262391 TI - The roles of the sympathetic nervous system in osteoporotic diseases: A review of experimental and clinical studies. AB - With the rapid aging of the world population, the issue of skeletal health is becoming more prominent and urgent. The bone remodeling mechanism has sparked great interest among bone research societies. At the same time, increasing clinical and experimental evidence has driven attention towards the pivotal role of the sympathetic nervous system (SNS) in bone remodeling. Bone remodeling is thought to be partially controlled by the hypothalamus, a process which is mediated by the adrenergic nerves and neurotransmitters. Currently, new knowledge about the role of the SNS in the development and pathophysiology of osteoporosis is being generated. The aim of this review is to summarize the evidence that proves the involvement of the SNS in bone metabolism and to outline some common osteoporotic diseases that occur under different circumstances. The adrenergic signaling pathway and its neurotransmitters are involved to various degrees of importance in the development of osteoporosis in postmenopause, as well as in spinal cord injury, depression, unloading and the complex regional pain syndrome. In addition, clinical and pharmacological studies have helped to increase the comprehension of the adrenergic signaling pathway. We try to individually examine the contributions of the SNS in osteoporotic diseases from a different perspective. It is our hope that a further understanding of the adrenergic signaling by the SNS will pave the way for conceptualizing optimal treatment regimens for osteoporosis in the near future. PMID- 21262393 TI - Switching rheumatoid arthritis treatments: an update. AB - The first approved biological agents for the treatment of rheumatoid arthritis (RA) were tumour necrosis factor (TNF) antagonists, all of which improve disease signs and symptoms, and slow or prevent structural damage; however, they are not equally effective in all patients. About 30% of patients treated with a TNF agent fail to achieve an improvement of 20% in the American College of Rheumatology (ACR) criteria, and even more patients lose efficacy during therapy or experience adverse events. Switching to a second TNF inhibitor has become an established approach to patients who fail or are intolerant of treatment with the first. However, there is only one published large randomised clinical trial evaluating the benefits of switching TNF antagonists, and data from observational studies and clinical practice are conflicting. Many parameters influence switching TNF agents, including the type of failure or TNF antagonist. However, many RA patients can be successfully treated with a second TNF antagonist, especially those discontinuing the first because of secondary failure or adverse events. PMID- 21262394 TI - Too rapid increase and too much breathlessness are distinct indices of exertional dyspnea in COPD. AB - To assess whether different indices of dyspnea can be obtained from cardiopulmonary exercise test and whether these indices correlate with distinct physiological parameters in COPD. Forty-two COPD patients (12 females, median [IQ] age 66 [56-70] years; FEV(1)% predicted: 51 [38-65]) underwent pulmonary function and incremental exercise tests. A power law function described the oxygen consumption (V(O2)-Dyspnea relationship from which two indices correlated with MRC score: dyspnea score measured at 50% of predicted V(O2) (too much breathless for that effort) and tangent measured at 50% of peak dyspnea (too rapid increase in dyspnea at this time point). The former independently correlated with ventilation on exercise, while the latter independently correlated with baseline hyperinflation. An upward shift of both (iso)-V(O2) and ventilation was evidenced in patients with higher levels of dyspnea (MRC score >= 3) and their tangents were significantly different. In conclusion, baseline hyperinflation is associated with the perception of a too rapid increase in dyspnea on exercise in COPD. PMID- 21262395 TI - The effects of fixed electrical charge on chondrocyte behavior. AB - In this study we have compared the effects of negative and positive fixed charges on chondrocyte behavior in vitro. Electrical charges have been incorporated into oligo(poly(ethylene glycol) fumarate) (OPF) using small charged monomers such as sodium methacrylate (SMA) and (2-(methacryloyloxy) ethyl)-trimethyl ammonium chloride (MAETAC) to produce negatively and positively charged hydrogels, respectively. The physical and electrical properties of the hydrogels were characterized by measuring and calculating the swelling ratio and zeta potential, respectively. Our results revealed that the properties of these OPF modified hydrogels varied according to the concentration of charged monomers. Zeta potential measurements demonstrated that the electrical properties of the OPF hydrogel surfaces changed on incorporation of SMA and MAETAC and that these changes in electrical properties were dose-dependent. Attenuated total reflectance Fourier transform infrared spectroscopy was used to determine the hydrogel surface composition. To assess the effects of surface properties on chondrocyte behavior primary chondrocytes isolated from rabbit ears were seeded as a monolayer on top of the hydrogels. We demonstrated that the cells remained viable over 7 days and began to proliferate while seeded on top of the hydrogels. Collagen type II staining was positive in all samples, however, the staining intensity was higher on negatively charged hydrogels. Similarly, glycosaminoglycan production was significantly higher on negatively charged hydrogels compared with a neutral hydrogel. Reverse transcriptase polymerase chain reaction showed up-regulation of collagen type II and down-regulation of collagen type I on the negatively charged hydrogels. These findings indicate that charge plays an important role in establishing an appropriate environment for chondrocytes and, hence, in the engineering of cartilage. Thus, further investigations into charged hydrogels for cartilage tissue engineering is merited. PMID- 21262396 TI - Adult intussusception in Northern India. AB - BACKGROUND: Adult intussusception is infrequently encountered in Asians. The diagnosis is often late because of the variable presentation. The optimal treatment is not universally agreed upon. PURPOSE: To determine the causes and management of this uncommon entity in India. METHODS: A retrospective review of patients with postoperative diagnosis of intussusception between March 2003 and March 2008 was conducted in a tertiary care centre in North India. Data relating to diagnosis, treatment and histopathology was analyzed. RESULTS: Twenty-seven patients, aged 15-72 years with 28 intussusceptions were studied. Four patients (14.29%) had acute presentation, 16 (57.14%) subacute and 7 (25%) had chronic symptoms. The most common type of intussusception was enteroenteric. A diagnosis of intussusception on contrast enhanced computed tomogram was made in 84% and a lead point was identified in 89%. A causative factor could be identified in 89% (25 out of 28 intussusceptions) which was malignant in 37% and benign in 48%. The most common underlying malignant lesions were adenocarcinoma (50%), and lymphoma (25%). Among benign lesions, small bowel polyps were the most common (57%). All cases underwent surgical intervention. Bowel resection was performed in 89%. There was no mortality. CONCLUSION: Our series highlights a high frequency of a demonstrable cause of intussusception in a tropical country. Overall our results are similar to those reported from other countries. Resection of the involved bowel is recommended because of high incidence of underlying pathology. PMID- 21262392 TI - Insulin-resistant brain state: the culprit in sporadic Alzheimer's disease? AB - Severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to take a pivotal role in early sporadic Alzheimer's disease (sAD) pathology. Indeed, the "insulin-resistant brain state" has been hypothesized to form the core of the neurodegenerative events that occur in sAD. In this vein, intracerebroventricular administration of subdiabetogenic doses of streptozotocin (STZ) in rats can induce an insulin-resistant brain state, which is proposed as a suitable experimental model of sAD. This review highlights the involvement of disturbed brain insulin metabolism in sAD etiopathogenesis. Furthermore, current knowledge demonstrates that central STZ administration produces brain pathology and behavioral changes that resemble changes found in sAD patients. The STZ-intracerebroventricularly treated rat represents a promising experimental tool in this field by providing new insights concerning early brain alterations in sAD, which can be translated in novel etiopathogenic and therapeutic approaches in this disease. PMID- 21262397 TI - Circumferential skin creases, cleft palate, typical face, intellectual disability and growth delay: "circumferential skin creases Kunze type". AB - Congenital symmetrical circumferential skin creases are a rare feature, often described as the "Michelin Tire Baby" syndrome and in general having a good prognosis. In some patients however, the circumferential skin creases are associated with other congenital malformations. We describe 2 unrelated patients presenting with multiple circumferential skin creases, growth retardation, developmental delay, a typical facial appearance and cleft palate. In literature, 6 patients with an almost identical clinical phenotype have been described. This well recognizable syndrome should be distinguished from the "Michelin Tire Baby" syndrome and we therefore propose the term "circumferential skin creases Kunze type". PMID- 21262398 TI - A high-quality secretome of A549 cells aided the discovery of C4b-binding protein as a novel serum biomarker for non-small cell lung cancer. AB - Cancer secretomes are a promising source for biomarker discovery. The analysis of cancer secretomes still faces some difficulties mainly related to the intracellular contamination, which hinders the qualification and follow-up validations. This study aimed to establish a high-quality secretome of A549 cells by using the cellular proteome as a reference and to test the merits of this refined secretome for biomarker discovery for non-small cell lung cancer (NSCLC). Using one-dimensional gel electrophoresis followed by liquid-chromatography tandem mass spectrometry, we comprehensively investigated the secretome and the concurrent cellular proteome of A549 cells. A high-quality secretome consisting of 382 proteins was refined from 889 initial secretory proteins. More than 85.3% of proteins were annotated as secreted and 76.8% as extracellular or membrane bound. The discriminative power of the lung-cancer associated secretome was confirmed by gene expression and serum proteomic data. The elevated level of C4b binding Protein (C4BP) in NSCLC blood was verified by enzyme-linked immunosorbent assays (ELISA, p = 6.07e-6). Moreover, the serum C4BP level in 89 patients showed a strong association with the clinical staging of NSCLC. Our reference-experiment driven strategy is simple and widely applicable, and may facilitate the identification of novel promising biomarkers of lung cancer. PMID- 21262399 TI - The accessible cerebral vascular proteome in a mouse model of cerebral beta amyloidosis. AB - Assessing protein changes in the cerebral vasculature of brain disorders may increase our understanding of disease pathogenesis and facilitate diagnostic and therapeutic intervention. By combining perfusion of mice with a charged reactive biotin derivative and subsequent quantification of the biotinylated proteins, the proteome accessible from the vasculature in an APPPS1 transgenic mouse model of cerebral beta-amyloidosis was identified and compared to that in non-transgenic control mice. Our results provide proof-of-concept of this technology for the identification of new targets for antibody-based therapy or pharmacodelivery, and for neuroimaging in neurodegenerative diseases. PMID- 21262400 TI - A gel-based proteomic method reveals several protein pathway abnormalities in fetal Down syndrome brain. AB - A large series of protein pathway components have been shown to be dysregulated in Down syndrome (DS) brain. No information about pathomechanisms linked to the trisomic state can be obtained from adult DS brain, however, as neurodegeneration occurs from the fourth decade. The aim of the study was to search for protein dysregulation in fetal DS brain before neurodegenerative changes are observed. Proteins were extracted from fetal DS and control frontal cortex, run on 2-DE, followed by quantification of protein spots with subsequent nano-ESI-LC-MS/MS analysis using an ion trap. Aberrant expression of proteins tropomodulin-2, tubulin alpha 1A chain, and alpha-internexin may indicate disturbed synaptic plasticity; fatty acid binding protein 7 suggests impaired maintenance of neuroepithelial cells; and creatine kinase B may reflect defective energy metabolism. RNA binding protein 4B derangement may represent impaired splicing, altered retrotransposon gag domain-containing protein 1 levels may be pointing to altered retrotransposition, and level changes of the potassium-chloride transporter solute carrier family 12 member 7 may lead to impaired ion fluxes with electrophysiological consequences. Taken together, aberrant protein levels from several pathways in fetal DS are challenging as well as fertilizing the area of research and providing the basis for additional neurochemical and functional studies. PMID- 21262401 TI - Protein signatures associated with tumor cell dissemination in head and neck cancer. AB - Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide. Strong prognostic indicators that predict development of distant metastases are the presence and number of lymph node metastases in the neck, and extranodal spread. Recently, it was shown in several studies that also the presence of disseminated tumor cells (DTC) in the bone marrow predicts development of distant metastases. We have investigated whether protein signatures could be detected in primary HNSCC that distinguish tumors that disseminate into the bone marrow from those that do not. Therefore, DTC-positive and -negative primary HNSCC tumors were analyzed by 2D-DIGE. A signature consisting of 51 differential protein spots was identified upon stratification for bone marrow status, which allowed a correct classification of DTC-positive and DTC-negative HNSCC tumors in 95% of cases, using hierarchical clustering. The most prominent feature within this signature was the down-regulation of CK19 in DTC-positive tumors. Our data show that tumor cell dissemination to the bone marrow, the onset of hematogenic metastasis, can be deduced from the protein profile in the primary tumor. The highly significant down-regulation of CK19 supports a model of epithelial-mesenchymal transition for tumors that show a high proclivity for hematogenic dissemination. PMID- 21262402 TI - Comparative effects of teriparatide and strontium ranelate in the periosteum of iliac crest biopsies in postmenopausal women with osteoporosis. AB - The periosteum contains osteogenic cells that regulate the outer shape of bone and contribute to determine its cortical thickness, size and position. We assessed the effects of subcutaneous injections of teriparatide (TPTD, 20MUg/day) or oral strontium ranelate (SrR, 2g/day) in postmenopausal women with osteoporosis on new bone formation activity at the periosteal and endosteal bone surfaces using dynamic histomorphometric measurements. Evaluable tetracycline labeled transiliac crest bone biopsies were analyzed from 27 patients in the TPTD group, and 22 in the SrR group after six months of treatment. Measurements were conducted on the thicker and thinner cortices separately, and comparisons between the thicker, thinner and combined cortices were carried out. At the combined periosteal cortex, the mineralization surface as a percent of bone surface (MS/BS%) was greater for TPTD (mean+/-SE: 8.08+/-1.22%) than SrR (3.22+/-1.05%) (p<0.005). The difference in mineral apposition rate (MAR) between TPTD (0.35+/ 0.06MUm/day) and SrR (0.14+/-0.06MUm/day) was also significant (p<0.05), while that of bone formation rate per bone surface (BFR/BS) between TPTD (0.014+/-0.004 mm(3)/mm(2)/year) and SrR (0.004+/-0.003 mm(3)/mm(2)/year) was not (p=0.057). Statistically significant differences between the two treatments were also observed for MS/BS%, BFR/BS, MAR and the double-labeled perimeter in the periosteum of the thicker, but not thinner, iliac crest cortices. The comparison between the thicker and thinner cortices of both periosteal and endosteal surfaces showed statistically significant differences for MAR and the double labeled perimeter for TPTD treated women. There were no statistically significant differences in any bone formation dynamic measurements between the two cortices in the SrR group. In conclusion, most of the bone formation and mineralization variables were significantly higher for TPTD- than SrR-treated women at both the periosteal and endosteal combined cortices. The response to TPTD for dynamic bone formation measurements in the periosteal surface was greater for the thicker than thinner cortex, but this difference was not significant in SrR treated patients. This may reflect a greater ability of TPTD to enhance responsiveness of bone to the mechanical loading environment. These effects on bone formation may underlie the improvement in bone quality in patients with osteoporosis treated with TPTD. PMID- 21262403 TI - Orthodontic extrusion and implant site development using an interocclusal appliance for a severe mucogingival deformity: a clinical report. AB - A multidisciplinary therapy used to treat a patient with a severe mucogingival deformity in the area of maxillary anterior teeth is presented. The simple technique uses an interocclusal appliance and elastic band for orthodontic extrusion to correct the mucogingival deformity and develop an implant site. This approach is designed to increase the amount of keratinized tissue and new alveolar bone, which are necessary for the development of an implant site. Clinical and radiographic examinations at the 5-year follow-up revealed a successful tooth replacement and improved esthetic appearance that was achieved with multidisciplinary treatment. The advantages and disadvantages of this technique are discussed. PMID- 21262404 TI - Designing and manufacturing an auricular prosthesis using computed tomography, 3 dimensional photographic imaging, and additive manufacturing: a clinical report. AB - The method of fabricating an auricular prosthesis by digitally positioning a mirror image of the soft tissue, then designing and using rapid prototyping to produce the mold, can reduce the steps and time needed to create a prosthesis by the traditional approach of sculpting either wax or clay. The purpose of this clinical report is to illustrate how the use of 3-dimensional (3-D) photography, computer technology, and additive manufacturing can extensively reduce many of the preliminary procedures currently used to create an auricular prosthesis. PMID- 21262405 TI - Effect of abutment tooth color, cement color, and ceramic thickness on the resulting optical color of a CAD/CAM glass-ceramic lithium disilicate-reinforced crown. AB - STATEMENT OF PROBLEM: A dark-colored prepared abutment tooth may negatively affect the esthetic outcome of a ceramic restoration if the tooth is restored using translucent enamel-like ceramic materials. PURPOSE: The purpose of this study was to evaluate the cumulative effect that the tooth abutment color, cement color, and ceramic thickness have on the resulting optical color of a CAD/CAM glass-ceramic lithium disilicate-reinforced crown. MATERIAL AND METHODS: A CAD/CAM glass-ceramic lithium disilicate-reinforced monolithic crown (IPS e.max CAD LT) was fabricated. Three possible crown restoration variables were tested in vitro. The procedure examined 4 prepared abutment tooth colors (light, medium light, medium dark, and dark), 2 cement (Variolink II) colors (translucent and opaque), and 4 ceramic thickness values (1.0 mm, 1.5 mm, 2.0 mm, and 2.5 mm). The color of each combination was measured using a spectrophotometer, and the average values of the color difference (DeltaE) were calculated. The data were analyzed with a 3-way ANOVA (tooth abutment color, ceramic thickness, and luting agent) and Tukey's HSD test (alpha=.05), which evaluated within-group effects of the tooth abutment color to the DeltaE at each ceramic thickness. RESULTS: The DeltaE values of a CAD/CAM glass-ceramic lithium disilicate-reinforced crown were significantly influenced by the tooth abutment color (P<.001), cement color (P<.001), and ceramic thickness (P<.001). Significant interactions were present among these 3 variables (P<.001). A dark-colored abutment tooth demonstrated the greatest DeltaE values relative to other variables tested. An increase in ceramic thickness resulted in a significant decrease in DeltaE values (P<.01). The DeltaE values were slightly decreased when the crowns were cemented using the opaque cement. CONCLUSIONS: This study demonstrated that underlying tooth abutment color, cement color, and ceramic thickness all influence the resulting optical color of CAD/CAM glass-ceramic lithium disilicate-reinforced restorations. PMID- 21262406 TI - Perceived color shift of a shade guide according to the change of illuminant. AB - STATEMENT OF PROBLEM: The perceived color of shade guide tabs is influenced by different spectral compositions of different light sources, and this can influence color matching. PURPOSE: The purpose of this study was to determine the amount of perceived shift in color and color coordinates of a shade guide using 3 different light sources: CIE standard illuminant D65 (daylight), A (incandescent lamp), and F9 (fluorescent lamp). MATERIAL AND METHODS: CIE color coordinates L*, a*, b*, chroma, and the spectral reflectance of shade tabs in a shade guide (Vitapan 3D-Master) were measured by a spectroradiometer under D65, A, and F9 simulators. Perceived color and color coordinate shifts due to the change of illuminant were determined. The influence of the type of light and shade designation of the 26 tabs on the color coordinates was analyzed by a 2-way ANOVA; correlations in the color coordinates between each corresponding pair under the 3 illuminants were determined (alpha=.05). RESULTS: All of the color coordinates were influenced by the type of illuminant and shade designation of the shade tabs (P<.001); however, each corresponding coordinate pair showed significant correlations under different illuminants (r=0.930 to 0.997, P<.01). Color differences under different illuminants were in the range of 3.1 to 9.1 DeltaE units; all of these differences were perceptible (DeltaE>2.6). Lightness decreased and chroma increased when the illuminant was changed from the D65 simulator to the A or F9 simulators. CONCLUSIONS: Perceptible shifts in the color of shade guide tabs under different ambient lighting conditions were confirmed by a spectroradiometer; these color shifts were influenced by the type of illuminant used. PMID- 21262407 TI - The effects of temperature and bleaching gels on the properties of tooth-colored restorative materials. AB - STATEMENT OF PROBLEM: The effects of bleaching on tooth-colored restorative materials remains controversial. Since previous in vitro research has been performed at different environmental temperatures, it is hypothesized that the temperature differences may be the reason for the conflicting reported results. PURPOSE: The purpose of this study was to examine the effect of a simulated at home bleaching regimen on surface and subsurface microhardness of restorative materials at 2 different environmental temperatures. MATERIAL AND METHODS: Seven restorative materials were tested: 4 composite resins, a polyacid-modified composite (compomer), a conventional glass-ionomer cement (CGIC), and a ceramic. For each material, 48 specimens were prepared and divided into 4 groups (n=12): bleaching group at a temperature of 25 degrees C, control group at 25 degrees C, bleaching group at 37 degrees C, and control group at 37 degrees C. The specimens from the bleaching groups were treated with 10% carbamide peroxide for an 8-hour daily test period for 14 days, while the control specimens were stored in artificial saliva for 14 days. The surface and subsurface (0.1-1.0 mm) microhardness values were determined by a Vickers microhardness tester. The surface microhardness data were analyzed with 3-way ANOVA for the effect of different materials, bleaching, and environmental temperature. The subsurface microhardness data were analyzed with repeated measures 4-way ANOVA for the effect of different materials, bleaching, environmental temperature, and subsurface depth as a repeated measure. A post hoc Tukey's Honestly Significant Difference test was used for comparisons among different groups (alpha=.05). RESULTS: All of the materials showed a loss of surface microhardness, except for the ceramic after bleaching at 37 degrees C. However, only the compomer and CGIC were found to have surface softening after bleaching at 25 degrees C. For compomer and CGIC specimens, bleaching affected microhardness at different subsurface levels ranging from 0.1 mm to 0.5 mm. Bleaching at a higher temperature decreased the subsurface microhardness at deeper levels. CONCLUSIONS: The effects of bleaching on restorative materials were material dependent. Environmental temperature influenced the effects of bleaching on surface and subsurface microhardness of restorative materials. Bleaching at increased temperatures showed greater softening effects on the surface and subsurface layers of dental materials. PMID- 21262408 TI - Evaluation of the absolute marginal discrepancy of zirconia-based ceramic copings. AB - STATEMENT OF PROBLEM: Marginal fit is an important factor for the long-term success of ceramic restorations; however, it is difficult to compare results from studies on marginal accuracy of zirconium oxide-based restorations that used various computer-assisted systems, because different methods were used to obtain the data. PURPOSE: The purpose of this study was to analyze the effect of different manufacturing techniques on the marginal adaptation of zirconia ceramic copings. MATERIAL AND METHODS: An extracted mandibular first premolar was prepared for a complete coverage restoration and subsequently duplicated 40 times in a liquid crystal polymer (LCP). Ceramic copings (n=10) were fabricated on the LCP models using the following systems: glass-infiltrated zirconia-toughened alumina (In-Ceram Zirconia) and yttrium cation-doped tetragonal zirconia polycrystals (In-Ceram YZ, Cercon, and Procera Zirconia). The absolute marginal discrepancy of the cores was assessed by using an image analysis system. The data were analyzed using 1-way ANOVA and Scheffe's test (alpha=.05). RESULTS: The mean marginal openings were 29.98 +/- 3.97 MUm for the In-Ceram Zirconia group, 12.24 +/- 3.08 MUm for the In-Ceram YZ group, 13.15 +/- 3.01 MUm for the Cercon group, and 8.67 +/- 3.96 MUm for the Procera group. Significant differences were found among the 4 systems (P<.05). CONCLUSIONS: The marginal accuracy achieved for the 4 zirconia-based ceramic crown systems analyzed was within the range of clinical acceptance (120 MUm). PMID- 21262409 TI - Finite element analysis of strength and adhesion of cast posts compared to glass fiber-reinforced composite resin posts in anterior teeth. AB - STATEMENT OF PROBLEM: Previous studies on the strength of teeth restored with posts have not resolved the controversy as to which post systems provide the greatest strength and longevity. PURPOSE: The purpose of this study was to compare the strength of teeth restored using cast posts with those restored using glass fiber-reinforced composite resin posts and to evaluate the bond strength of the posts to dentin. MATERIAL AND METHODS: The investigation was conducted by using finite element analysis, combined with the application of contact elements. Three-dimensional (3-D) models of the maxillary central incisors were generated: IT, an intact tooth; CC, a tooth with a ceramic crown; FP, a tooth restored with an FRC (glass fiber-reinforced composite resin) post; CPAu, a tooth restored with a gold alloy cast post; and CPNi, a tooth restored with an NiCr (nickel chromium alloy) cast post. Each model was subjected to vertical and oblique loads with a force of 100 N. To evaluate the strength of the restored tooth, ceramics, and composite resin, the modified von Mises failure criterion was used, the Tsai-Wu criterion for FRC, and the von Mises criterion for gold and NiCr alloy. The equivalent stresses found in the tested models were compared with the tensile strength of the respective materials. Contact stresses in the luting cement dentin interface were calculated. RESULTS: The maximum mvM (modified von Mises failure criterion) stresses in the dentin of the teeth restored with FRC posts were reduced by 21%, and in those restored with cast NiCr posts, stresses were reduced by 25% when compared to the stresses in the intact tooth. The equivalent stresses in metal posts were several times higher than in FRC posts, but did not exceed the tensile strength of the materials. The highest mvM stress in the luting resin cement around the FRC post was 55% higher than in the luting resin cement around the metal post, under an oblique load. In the ceramic crown, which covered the composite resin post and core, the highest mvM stress was 30.7 MPa, whereas with the metal post and core, it was 23 MPa. CONCLUSIONS: Cast metal posts resulted in lower stresses in the dentin of the restored teeth than did FRC posts. Irrespective of the material, the equivalent stresses in the posts did not exceed their tensile strength. Lower stresses were present in the luting cement and the cement-dentin interface around cast posts than around FRC posts. In the ceramic crown supported by a metal post and core, the stresses were lower than those observed in the crown supported by a composite resin core foundation. PMID- 21262410 TI - Pressure transmission and distribution under denture bases using denture teeth with different materials and cuspal angulations. AB - STATEMENT OF PROBLEM: Pressure transmission and distribution under denture bases may be variable depending on the different materials and cuspal angulations of denture teeth. PURPOSE: The purpose of this study was to evaluate pressure transmission and distribution under impact load using denture teeth made with different materials and cuspal angulations. MATERIAL AND METHODS: Three types (acrylic resin, microfilled composite resin, and ceramic) and 4 different cuspal angulations (0 degree, 20 degree, 33 degree, and 35 degree) of denture teeth were evaluated. Pressure transmission, distribution, and maximum pressure (n=10) were observed with pressure-sensitive sheets under an impact load. Data were statistically analyzed with 2-way ANOVA (alpha=.05) to determine significant interactions between denture tooth materials and cuspal angulations with respect to pressure transmission, followed by 1-way ANOVA (alpha=.05) to examine how materials and angulations jointly affected the pressure. Two 1-way ANOVAs were performed on the acrylic resin and ceramic denture teeth with the inclusion of 20 degree denture teeth groups. Tukey HSD and Tamhane's post hoc tests were used to evaluate data differences among groups. RESULTS: Denture tooth materials and cuspal angulations had significant interactions with respect to average pressure (P<.001) and maximum pressure transmission (P=.007). Zero-degree denture teeth showed significantly lower average and maximum pressures than 33- and 35-degree denture teeth for all 3 denture tooth materials (P<.001). Denture teeth with greater cuspal angulations demonstrated significantly higher average pressure transmission for all ceramic denture teeth groups (P<.05). CONCLUSIONS: Pressure transmission and distribution varied among denture teeth made of different materials and with different cuspal angulations. Cusped denture teeth presented significantly higher average pressure and maximum pressure transmission compared to 0-degree denture teeth. PMID- 21262411 TI - A technique to retrieve fractured implant screws. PMID- 21262412 TI - Steps towards integrated psychosomatic medicine--the example of psychocardiology. PMID- 21262413 TI - Short-term cognitive behavioral therapy for non-cardiac chest pain and benign palpitations: a randomized controlled trial. AB - OBJECTIVES: Many patients with noncardiac chest pain or benign palpitations have poor prognosis in terms of symptom persistence, limitations in everyday activities, and reduced health-related quality of life (HRQOL). The aim of the study was to compare a three-session manualized cognitive behavioral therapy (CBT) intervention with normal care for patients with noncardiac chest pain or benign palpitations in a randomized controlled trial. METHODS: Patients with persistent complaints six months after a negative evaluation at a cardiological outpatient clinic were invited to participate. Of the 94 eligible patients, 40 agreed to participate and were randomly assigned to either an intervention or control group. Patients in the intervention group received three manualized sessions with CBT, including one physical activity exposure session. The control group received usual care from their general practitioner. RESULTS: There were significantly larger improvements in the treatment group regarding fear of bodily sensations, avoidance of physical activity, depression and some domains of HRQOL at the end of treatment, and at three- and 12-month follow-up. A substantial proportion (about three-quarters) of the intervention effects on depression and avoidance of physical activity could be attributed to (was mediated by) the large reduction in catastrophic interpretations of bodily sensations. CONCLUSION: A three-session program of manualized CBT, including exposure to physical activity, was effective treatment for patients with noncardiac chest pain and benign palpitations up to the 12-month follow-up. PMID- 21262414 TI - Autonomic cardiovascular control and responses to experimental pain stimulation in fibromyalgia syndrome. AB - OBJECTIVE: This study involves a comprehensive investigation of autonomic cardiovascular regulation in fibromyalgia syndrome (FMS) at rest and during painful stimulation and its association with pain indices. METHODS: In 35 patients and 29 healthy controls, electrocardiography, impedance cardiography, and finger continuous blood pressure measurements were conducted. For the purpose of experimental pain induction, a cold pressor test was applied. RESULTS: FMS patients showed lower pain threshold and tolerance, as well as higher ratings of pain intensity and unpleasantness on visual analogue scales. Resting stroke volume, myocardial contractility, R-R interval, heart rate variability, and sensitivity of the cardiac baroreflex were reduced in the patients, and increases in stroke volume and myocardial contractility during cold pressor stimulation were less pronounced. In the whole sample as well as in the FMS group, baroreflex sensitivity was inversely associated with subjective pain intensity, and a higher number of baroreflex operations per unit of time predicted higher pain tolerance. CONCLUSIONS: The data suggest impaired autonomic cardiovascular regulation in FMS in terms of reduced sympathetic and parasympathetic influences, as well as blunted sympathetic reactivity to acute stress. The association between baroreflex function and pain experience reflects the pain inhibition mediated by the baroreceptor system. Given the reduced baroreflex sensitivity in FMS, one may assume deficient ascending pain inhibition arising from the cardiovascular system, which may contribute to the exaggerated pain sensitivity of FMS. PMID- 21262415 TI - Psychiatric comorbidity in cardiovascular inpatients: costs, net gain, and length of hospitalization. AB - OBJECTIVE: Although psychiatric comorbidity often goes undetected and untreated in cardiovascular patients, it is not clear whether the costs for a special treatment of psychiatric comorbidity are appropriately reflected in the reimbursement system. To investigate the economic impact of psychiatric comorbidity, we compared costs, returns, net gain, and duration of hospitalization in cardiovascular inpatients with and without psychiatric comorbidity. METHODS: For a period of 2 years, we analyzed costs, net gain, and other outcome variables according to the diagnosis-related group (DRG) system for cardiovascular inpatients of a German university department (n = 940). Psychiatric disorders were diagnosed by the treating physicians based on clinical criteria and results from the Patient Health Questionnaire (PHQ). With respect to the outcome variables, we compared patients with and without a psychiatric disorder, controlling for sociodemographic characteristics. RESULTS: The average total costs of hospitalization (mean +/- S.E.) for cardiovascular patients without psychiatric comorbidity and for patients with psychiatric comorbidity differed significantly (?5142 +/- 210 vs. ?7663 +/- 571; d = 0.39). The increased costs for patients with psychiatric comorbidity were related to elevated returns, but the net gain for patients without psychiatric comorbidity was ?277 +/- 119. In contrast, the treatment of internal medicine patients with psychiatric disorders resulted in a net loss of -?624 +/- 324 (overall group difference, d = 0.25). CONCLUSION: Psychiatric comorbidity in cardiovascular inpatients leads to higher costs that are not reflected in the current reimbursement system in Germany. The inappropriate reimbursement of psychiatric comorbidity in cardiovascular inpatients may result in a serious undertreatment of these patients. PMID- 21262416 TI - Type D personality and illness perceptions in myocardial infarction patients. AB - OBJECTIVES: To determine the relationship between Type D personality (the tendency to experience negative emotions and to be socially inhibited) and illness beliefs in postmyocardial infarction (MI) patients. METHODS: One hundred and ninety-two MI patients participated. Patients were assessed on demographic variables and completed the Type D Scale (DS14) and Brief Illness Perceptions Questionnaire one week post-MI. RESULTS: Multivariate analysis of variance revealed that Type D patients were significantly different from non-Type D patients on every illness perception dimension. Type D patients believe that their illness has significantly more serious consequences (P<.001), will last significantly longer (P<.001), will be significantly less controllable by them (P<.05) or through treatment (P<.001) compared to non-Type D patients, and experience significantly more symptoms that they attribute to their illness (P<.001). In addition, they are significantly more concerned about their illness (P<.05), experience significantly more emotions as a result (P<.001), and find their illness to be significantly less comprehensible compared to non-Type D individuals (P<.001). CONCLUSION: Type D individuals possess a distinct profile of illness beliefs, which may help explain the adverse effect of Type D on health outcomes following MI. Future research should evaluate intervention strategies to tackle illness perceptions in these high-risk patients. PMID- 21262418 TI - Disease-specific quality-of-life measures as predictors of mortality in individuals living with type 2 diabetes. AB - OBJECTIVE: The aim of this study was to examine whether disease-specific quality of-life measures are independent predictors of mortality in patients with type 2 diabetes. METHODS: A cohort of 420 patients with type 2 diabetes was recruited from the outpatient clinic of a medical center. At baseline, the disease-specific measure of the Diabetes Impact Measurement Scales (DIMS) and clinical and biological marker variables were measured. The DIMS domains included symptoms, diabetes-related morale, social role fulfillment, and well-being. Complications consisted of stroke, heart disease, visual impairment, amputations, kidney disease, cognitive impairment, and incontinence. Mortality data were collected from the national mortality register using personal identification numbers. Multivariate Cox proportional hazards models were used. RESULTS: The overall mortality rate was 10.9%. The DIMS scales of symptoms and well-being and the total score were significantly associated with mortality, independent of age, gender, glucose control, and complications. When the scales of the DIMS were simultaneously considered, only symptom and social role fulfillment of the DIMS exerted a significant effect on mortality. Patients in the categories of the second and third quartiles (worse status) had significantly increased risk compared with those in the category of the fourth quartile (best status) [for the symptom scale: RR = 13.10, 95% confidence interval (CI) = 2.75-62.50 and RR = 5.49, 95% CI = 1.50-20.09, respectively; for the social role fulfillment scale: RR = 6.18, 95% CI = 1.10-34.87 and RR = 6.53, 95% CI = 1.40-30.57, respectively]. CONCLUSION: Our data suggest that the unique contribution of health-related quality of life to mortality was independent of objective health measures, such as glucose control and complications. PMID- 21262417 TI - The association between mood and anxiety disorders with vascular diseases and risk factors in a nationally representative sample. AB - OBJECTIVE: To investigate the association between mood and anxiety disorders and vascular diseases after controlling for vascular disease risk factors. METHODS: Using a nationally representative sample of adults (N=5692) from the National Comorbidity Survey-Replication (NCS-R), participants with mood disorders were hierarchically classified as having any lifetime history of mania, hypomania, or major depression. Anxiety disorders were also assessed. The reference group consisted of those without mental disorders. Vascular disease was determined by self-reported history of heart disease, heart attack, or stroke on the NCS-R survey. Vascular risk factors included diabetes, high blood pressure, and obesity. RESULTS: In multivariate logistic regression models that controlled for obesity, high blood pressure, smoking and diabetes, vascular disease was associated with bipolar disorder in women [odds ratio (OR) 2.80, 95% confidence interval (CI) 1.63-4.80], and major depressive disorder in men (OR 1.85, 95% CI 1.17-2.92). Controlling for anxiety disorders reduced the associations in both men and women, and in fact, anxiety disorders were more strongly associated with vascular diseases in men, whereas bipolar disorder continued to be an important correlate of vascular disease in women. CONCLUSION: These findings demonstrate the importance of evaluation of sex differences, mood disorder subtype and co occurring anxiety disorders in assessing the association between mood disorders and vascular diseases. Future research should investigate potential biologic mechanisms for these associations in order to define potential targets for intervention. PMID- 21262419 TI - Associations between illness perceptions and health-related quality of life in adults with cystic fibrosis. AB - OBJECTIVE: The objective of this work was to examine the relationship between illness perception, health status, and health-related quality of life (HRQOL) in a cohort of adults with cystic fibrosis (CF). METHODS: In the Project on Adult Care in Cystic Fibrosis, we administered five subscales (Illness Consequences, Illness Coherence, Illness Timeline--Cyclical, Personal Control, and Treatment Control) of the Illness Perception Questionnaire--Revised (IPQ-R). Multivariable linear regression analyses explored the associations between illness perception, health status, symptom burden, and physical and psychosocial HRQOL, as measured by various domains of the Cystic Fibrosis Questionnaire--Revised (CFQ-R). RESULTS: Among the 199 respondents (63% female; mean age, 36.8 +/- 10.2 years), IPQ-R scores did not differ on age, gender, or lung function. In multivariable regression models, neither clinical characteristics nor physical or psychological symptom burden scores were associated with CFQ-R physical domains. In contrast, higher scores on Illness Consequences were associated with lower psychosocial CFQ R scores. Higher scores on the Illness Coherence and Personal Control scales were associated with higher psychosocial CFQ-R scores. CONCLUSION: Adults with CF report a high understanding of their disease, feel that CF has significant consequences, and endorse both personal and treatment control over their outcomes. Illness perceptions did not vary with increased age or worsening disease severity, suggesting that illness perceptions may develop during adolescence. Illness perceptions were associated with psychosocial, but not physical, aspects of HRQOL. Efforts to modify illness perceptions as part of routine clinical care and counseling may lead to improved quality of life for adults with CF. PMID- 21262420 TI - Reliable integrative assessment of health care needs in elderly persons: the INTERMED for the Elderly (IM-E). AB - OBJECTIVE: With the increasing prevalence of multiple conditions in older age, the high prevalence of mental disorders, and the many social challenges facing elderly people, a high-risk patient group in need of interdisciplinary (biological, psychological, and social) care is emerging. The INTERMED interview is an integrative assessment method that identifies patients with complex health care needs. The aim of this study was to develop and evaluate the INTERMED for the Elderly (IM-E), specifically for use in populations of elderly persons. METHODS: In focus groups conducted with the authors of the original INTERMED, the variables and anchor points that had to be adjusted to the needs and situation of the elderly and to the demands of a population-based study were discussed and altered. The final version of the IM-E was conducted with 42 elderly persons. Participants were doubly scored by two trained raters; the interrater reliability [intraclass correlation coefficient (ICC) (2,1)] was calculated. RESULTS: The IM E was well accepted by the elderly persons interviewed. ICCs for the various domains of the IM-E ranged between .87 and .95, while the ICC for the sum score was .95. Regarding the cutoff point of 20/21 for patients with complex health care needs, a kappa of .75 was achieved. CONCLUSIONS: The IM-E is a reliable integrative assessment instrument. It is well suited for epidemiological settings to adequately describe the percentage of elderly patients with complex health care needs. In clinical settings, it can be used to identify elderly patients in need of interdisciplinary care. PMID- 21262421 TI - Medication beliefs predict medication adherence in older adults with multiple illnesses. AB - OBJECTIVE: To examine factors preventing medication nonadherence in community dwelling older adults with multiple illnesses (multimorbidity). Nonadherence threatens successful treatment of multimorbidity. Adherence problems can be intentional (e.g., deliberately choosing not to take medicines or to change medication dosage) or unintentional (e.g., forgetting to take medication) and might depend on a range of factors. This study focused in particular on the role of changes in beliefs about medication to explain changes in adherence. METHODS: Longitudinal study with N = 309 individuals aged 65-85 years with two or more diseases at three measurement points over six months. Medication adherence and beliefs about medicines were assessed by questionnaire. Hierarchical weighted least squares regression analyses were used to predict individual intentional and unintentional nonadherence. RESULTS: Changes in intentional nonadherence were predicted by changes in specific necessity beliefs (B = -.19, P<.01), after controlling for sociodemographic factors, health status and number of prescribed medicines. Changes in unintentional nonadherence were predicted by changes in general overuse beliefs (B = .26, P<.01), controlling for the same covariates. CONCLUSION: Beliefs about medication affect both intentional and unintentional adherence to medication in multimorbid older adults. This points to the importance of addressing medication beliefs in patient education to improve adherence. PMID- 21262422 TI - Impaired decision making among morbidly obese adults. AB - OBJECTIVE: The Iowa Gambling Task (IGT) measures affective decision making and has revealed decision making impairments across a wide range of eating disorders. This study aimed to investigate affective decision making in severely obese individuals. METHODS: Forty-two (12 male, 30 female) morbidly obese participants (mean BMI = 41.45) and 50 comparison participants (17 male, 33 female) matched for age, gender and education, completed the IGT. RESULTS: Obese participants performed significantly worse on the IGT compared to the comparison group, with 69% of the obese group demonstrating clinically impaired decision making. There was no evidence of learning across the five trial blocks in obese participants, with significant differences between the groups emerging in blocks 3, 4, and 5. IGT impairment was unrelated to BMI or eating pathology. CONCLUSION: Obese participants were significantly impaired on the IGT. The pattern of performance suggested a potential inability to maximise an immediate reward or program a delayed reward. The findings support the view that common decision making impairments exist across disordered eating populations. Future research is required to specify the source and mechanisms of these decision making deficits. The logical progression of this research is the development of interventions which improve decision making capacity and measure subsequent impact on psychological and physical outcomes. PMID- 21262423 TI - NICE guideline: evidence for pharmacological treatment of delirium. PMID- 21262425 TI - Overview on guidelines and recommendations for generic low-molecular-weight heparins. AB - The first generic low-molecular-weight heparin (LMWH) was approved by the Food and Drug Administration (FDA) end of July 2010 for clinical use in all medical indications where the branded product enoxaparin has reached approval. Many LMWHs have been approved for prophylaxis and the treatment of venous and arterial thromboembolism based on the results of large clinical trials. Generic LMWHs are now marketed in various countries. The European Medicines Agency (EMA) has set up guidelines for the production of generic LMWHs. The International Society of Thrombosis, the North American Thrombosis Forum and other scientific organisations raised concerns regarding the safety of generic LMWHs due to the possibility of a reduced quality of the anticoagulants to ensure a lower price compared to the branded LMWHs. They have published statements for the production of generic LMWHs to ensure the quality of the products and the safety for patients. The present review describes the differences between the actual guidelines and recommendations for the production of generic version of LMWHs. PMID- 21262426 TI - Low-molecular-weight heparins have no place in recurrent miscarriage: debate--for the motion. PMID- 21262424 TI - Thirty-day mortality rate in women with cancer and venous thromboembolism. Findings from the RIETE Registry. AB - The influence of the site of cancer on outcome in cancer women with venous thromboembolism (VTE) is poorly understood. Reliable information on its influence might facilitate better use of prevention strategies. We assessed the 30-day outcome in all women with active cancer in the RIETE Registry, trying to identify if differences exist according to the tumor site. Up to May 2010, 2474 women with cancer and acute VTE had been enrolled. The most common sites were the breast (26%), colon (13%), uterus (9.3%), and haematologic (8.6%) cancers. During the 30 day study period, 329 (13%) patients died. Of them, 71 (2.9%) died of pulmonary embolism (PE), 22 (0.9%) died of bleeding. Fatal PE was more common in women with breast, colorectal, lung or pancreatic cancer (59% of the fatal PEs). Fatal bleeding was more frequent in women with colorectal, haematologic, ovarian cancer or carcinoma of unknown origin (55% of fatal bleedings). PMID- 21262427 TI - LMWH have no place in recurrent pregnancy loss: debate-against the motion. AB - The SPIN and ALIFE intervention trials apparently support that LMWHs should not be advocated in patients with idiopathic RPL. There are however some concerns. Epidemiology implies that most of the included patients shared recurrent regulatory embryonic losses associated with isolated cytogenetics defects, a dominant good prognosis entity which doesn't have to be treated. The real PL illness, idiopathic foetal loss with normal karyotypes, was a minority. Primary and secondary RPL cases were included, whose prognostic, applied to non-sporadic PLs, cannot be similar. Thrombophilic patients were a minority, despite existing data suggesting a LMWH beneficial effect. LMWHs were associated with LDA, previously suspected to be deleterious in PL patients with thrombophilia. The two indubitably planned-to-be negative trials will positively contribute to limit aberrant LMWH treatments in non-selected RPL women cared without comprehensive clinical categorisation. This is not the real clinical target for LMWHs, which still has to be fully investigated. PMID- 21262428 TI - Antifibrinolytics in women with menorrhagia. AB - Heavy menstrual bleeding is associated with increased local fibrinolysis. Antifibrinolytic agents have been used in women with menorrhagia with and without bleeding disorders, and have been demonstrated to decrease menstrual blood flow approximately 50% and improve quality of life. Most studies have been done with the antifibrinolytic agent tranexamic acid, a synthetic lysine derivative. Studies have been performed comparing tranexamic acid with placebo, non-steroidal anti-inflammatory agents, and progesterone in women with menorrhagia and have predominantly demonstrated a greater reduction in menstrual blood flow with tranexamic acid. In women with menorrhagia and an underlying bleeding disorder, tranexamic acid was compared to intranasal desmopressin and also demonstrated a greater reduction in menstrual blood flow. In aggregate the studies demonstrate that antifibrinolytic agents are effective medical management for women with menorrhagia with or without bleeding disorders, reducing menstrual blood flow and improving quality of life. PMID- 21262429 TI - Post-partum hemorrhage in women with rare bleeding disorders. AB - Post-partum hemorrhage (PPH) accounts for a substantial fraction of maternal deaths in the general population. Among all women, however, those affected with rare bleeding disorders (RBDs) represent a particular group since to usual bleeding symptoms, they are likely to experience bleedings associated to obstetrical and gynaecological problems. Pregnancy and childbirth, two important stages in the life of a woman, pose a special clinical challenge in women with RBDs, since information about these issues are really scarce and limited to few case reports. These data show that all women with RBDs, except for FXI deficiency, have to be considered potentially at risk for developing PPH, therefore they should be monitored carefully during and immediately after pregnancy. The implication is that women with bleeding disorders may require prophylaxis and/or close observation for several weeks and should be followed by a multidisciplinary team including expertises such as laboratory haematologist, obstetrician-gynaecologist, anaesthesiologist, family physician, and laboratory technician. PMID- 21262430 TI - Neonatal IVH--mechanisms and management. AB - Intra-ventricular hemorrhage (IVH) occurs predominantly in very low birth weight premature infants. Survivors of severe IVH frequently experience long-term consequences including major neurological deficits. Advances in neonatal and obstetric care in the last decades, have led to a steady decline in mortality and in the incidence of IVH. However, significant improvements in the survival rates small premature infants have led to an increase in the population of newborns prone to IVH. The pathogenesis of IVH is multifactorial. Prematurity of the germinal matrix, fluctuations in cerebral blood flow, hypoxic ischemic cerebral injury and developmental hemostatic abnormalities of newborns are important risk factors. The following manuscript will address the epidemiology and pathogenesis of IVH and review studies regarding potential pro-coagulant therapy. PMID- 21262431 TI - The diagnostic management of acute venous thromboembolism during pregnancy: recent advancements and unresolved issues. AB - Adequate diagnostic management of suspected venous thromboembolism (VTE) in pregnant women is of great importance. The diagnostic performance of clinical decision rules and D-dimer testing is influenced by physiological changes during pregnancy and is understudied. Recent studies have addressed these issues by developing a new clinical decision rule and raising the D-dimer level cut-off points. With imaging of suspected pulmonary embolism (PE) the radiation exposure remains a concern. Recent studies have adjusted CT settings and scan length to minimize this exposure without loss of image quality. Furthermore the first choice imaging modality of suspected PE in pregnant women remains a matter of debate in view of studies showing high inadequacy rates for both CT scanning and VQ scanning. Issues concerning the diagnostic management of VTE in pregnant women and advancements made in recent years will be discussed. PMID- 21262432 TI - Murine models of obesity and hormonal therapy. AB - Obesity is a common disorder, and related diseases such as diabetes, atherosclerosis, hypertension, cardiovascular disease and cancer are a major cause of mortality and morbidity in Westerntype societies. Development of obesity is associated with extensive modifications in adipose tissue involving adipogenesis, angiogenesis and extracellular matrix proteolysis. The fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems cooperate in these processes. Adipogenesis is tightly associated with angiogenesis, as shown by the findings that adipose tissue expiants trigger blood vessel formation, whereas in turn adipose tissue endothelial cells promote preadipocyte differentiation. A nutritionally induced obesity model in transgenic mice has been used extensively to study the role of the fibrinolytic and MMP systems and of angiogenesis in the development of obesity. Most studies support a role of these systems in adipogenesis and obesity, and suggest that their modulation may affect development of adipose tissue. Such models have also shown that treatment of obese female mice with estrogens has the potential to improve obesity, insulin resistance and glucose intolerance, via decreased expression of lipogenic genes. Thus, murine models of obesity have been very useful tools to study mechanisms of adipose tissue development, as well as effects of hormonal therapy. PMID- 21262433 TI - Thrombin generation tests. AB - The recent development of semi-automated methods has revived interest in the thrombin generation test, a global assay that measures the overall tendency of a plasma sample to form thrombin after initiation of coagulation. The thrombin generation curve, which is characterised by a lag phase followed by the formation and subsequent inhibition of thrombin, reflects all three phases of coagulation (initiation, propagation and termination). However, the specific contribution of each coagulation factor or inhibitor to the assay outcome depends on the reaction conditions used (e.g. tissue factor concentration used to trigger coagulation, addition of thrombomodulin or activated protein C). Although several studies have shown a correlation between thrombin generation and the risk of bleeding or venous thrombosis, the application of thrombin generation assays to clinical decision-making is still hampered by standardisation problems. The present paper discusses these issues with particular reference to Calibrated Automated Thrombography. PMID- 21262434 TI - Postmenopausal hormone therapy and venous thromboembolism. AB - INTRODUCTION: Hormone therapy (HT) is the most effective treatment to counteract menopauserelated symptoms. Because venous thromboembolism (VTE) is the main harmful effect of HT among young postmenopausal women, reducing VTE risk appears to be a relevant strategy to improve the benefit/risk profile of HT among postmenopausal women. METHODS: This article is a review of recent findings regarding the VTE risk among women using HT. RESULTS: Recent data confirmed the safety of the transdermal route of estrogens administration in postmenopausal women requiring treatment. In addition, epidemiological data showed that use of concomitant progestins could increase VTE risk compared with progesterone use. Finally, results of a meta-analysis showed that the VTE risk increased with doses of oral estrogens. CONCLUSION: The route of estrogen administration, the type of concomitant progestogens and the dose of estrogens are three important determinants of the thrombotic risk among postmenopausal women using HT. PMID- 21262435 TI - Epidemiology of the contraceptive pill and venous thromboembolism. AB - Current users of combined oral contraceptives have an increased risk of venous thromboembolism. The risk appears to be higher during the first year of use and disappears rapidly once oral contraception is stopped. There is a strong interaction between hereditary defects of coagulation, combined oral contraceptive use and venous thromboembolism. Nevertheless, the routine screening of women before they use combined oral contraception is not recommended. Venous thromboembolism seems to be higher in overweight users, and after air, and possibly other forms of, travel. Both the oestrogen and progestogen content of combined oral contraceptives have been implicated in differences in venous thrombotic risk between products. Even if real, the absolute difference in risk between products is small, because the background incidence of venous thromboembolism in young women is low. All currently available combined oral contraceptives are safe. Progestogen-only oral contraceptives are not associated with an increased risk of venous thromboembolism. PMID- 21262436 TI - Controversies in postpartum contraception: when is it safe to start oral contraceptives after childbirth? AB - The timely initiation of contraception postpartum is an important consideration for breastfeeding and non-breastfeeding women; many women prefer oral contraceptive pills to other methods. In breastfeeding women, combined hormonal pills are not recommended prior to 6 weeks postpartum, due to effects on milk production. Although progestogen-only pills do not adversely affect milk, lack of data regarding possible effects on infants exposed to progestogens in breastmilk renders timing of initiation of this method controversial. In non-breastfeeding women, elevated risk of venous thromboembolism restricts use of combined hormonal pills prior to 21 days postpartum. From 21 to 42 days, use of combined hormonal pills should be assessed based on a woman's personal venous thromboembolism risk profile; after 42 days postpartum there is no restriction in the use of combined hormonal pills for otherwise healthy women. Non-breastfeeding women may safely use progestogen-only pills at any time during the postpartum. PMID- 21262437 TI - Mechanisms of anti-phospholipid antibody formation and action. AB - The antiphospholipid syndrome is an autoimmune disease characterised by the clinical features of recurrent thrombosis in the venous or arterial circulation and foetal losses in combination with circulating anti-phospholipid antibodies in the blood of the afflicted patients. Over the last 25 years numerous studies have established the correlation between the presence of antibodies against anionic phospholipids and thrombo-embolic manifestations but how these antibodies cause thrombosis is still unclear. Most scientists now accept the fact that only a subset of the antiphospholipid antibodies has clinical relevance. Not antibodies to anionic phospholipids but rather antibodies to beta2-glycoprotein I are thought to be the major cause for the pathological manifestations. beta2 Glycoprotein I is a plasma protein without a known function and persons lacking beta2-Glycoprotein I are completely healthy. Our challenge is to understand why auto-antibodies against such a dispensable protein are so common and how antibodies directed against a protein without obvious function can induce the severe clinical manifestations observed in this syndrome. PMID- 21262438 TI - Role of tissue factor in pregnancy complications: crosstalk between coagulation and inflammation. AB - Bad pregnancy outcomes have been associated with increased activation of the coagulation cascade and inflammation, in particular the activation of the complement cascade. Recent studies have suggested that inflammatory processes modulate thrombogenic pathways and vice versa. We studied the cross-talk between the coagulation and the complement cascade in the pathogenesis of recurrent miscarriages and preeclampsia in mice. We identified tissue factor (TF) as a crucial mediator of fetal and placental damage in mouse models of recurrent miscarriages and preeclampsia. Increased TF expression increases the release of reactive oxygen species and antiangiogenic molecules from inflammatory cells inducing trophoblast damage and bad pregnancy outcomes. We also demonstrated that pravastatin, by downregulating TF expression, prevents miscarriages and the onset of preeclampsia in mice. PMID- 21262439 TI - Antiphospholipid syndrome: unusual clinical presentations. AB - Although the typical thrombotic manifestations of antiphospholipid syndrome, and pregnancy complications, are well recognised, the literature is awash with reports of more obscure associations and apparent complications. Some occur sufficiently frequently to be regarded as occasional features of the syndrome, whereas in other instances there remains doubt about any pathogenic role for antiphospholipid antibodies. The distinction is important as wrong assumptions may lead to failure to seek alternative diagnoses and the implementation of inappropriate treatments. PMID- 21262440 TI - Prevention of VTE in women with cancer. AB - The prevention of venous thromboembolism (VTE) in women with cancer requires special consideration. The presence of cancer results in both non-surgical and surgical patients having increased risk of VTE. This usually leads to a modification of the recommended preventive therapy, affecting the type, dose and length of therapy. Cancer patients have other factors which may predispose them to bleeding. Prevention of VTE in cancer patients is important in a number of settings and has been investigated in many of these. These can be broadly classified into three areas: (1) Non-surgical patients in hospital and outpatient care: (1.1) Acutely ill medical patients with incidental cancer or with complications related to cancer; (1.2) Cancer patients receiving therapy- chemotherapy, hormonal therapy, radiotherapy. (2) Surgical care: (2.1) Surgical procedures for cancer therapy; (2.2) Surgical procedures for non-cancer indications in cancer patients. (3) Long-term prevention of VTE in otherwise well outpatients with cancer and its effect on mortality. PMID- 21262441 TI - APS--controversies in diagnosis and management, critical overview of current guidelines. AB - Because the diagnosis of antiphospholipid syndrome is based on laboratory data, performance and interpretation of such tests is essential. Positivity in a single test among Lupus Anticoagulant (LA), anti cardiolipin (aCL) and anti beta2 glycoprotein I (abeta2GPI) antibodies calls APS diagnosis into question. Conversely, triple positivity is strongly associated to thrombosis and pregnancy morbidity. A new era in studying APS should take into account different antiphospholipid antibodies profiles. Clinical studies on groups of patients that are homogeneous in terms of laboratory tests will provide information on the real risk of patients and on the real effect of therapeutic interventions. PMID- 21262442 TI - Vascular complications in diabetic pregnancy. AB - Until now, vascular complications in diabetic pregnancy are mainly related to hyperglycemia caused by type 1 diabetes (Type 1 DM). Progression of diabetic retinopathy (DR) occurs at least temporarily during pregnancy and postpartum. There is a short-term increase in the level of retinopathy during pregnancy that persisted into the first year postpartum. Nephropathy is associated with increased risk of preeclampsia, nephrotic syndrome, preterm delivery, fetal growth restriction, and perinatal mortality. Presence of retinopathy increases also risk of preeclampsia and also poor glycemic control. The pregnancy itself (first or subsequent) is not a long-term risk factor for developing microalbuminuria, any retinopathy, proliferative retinopathy, or neuropathy. The prevalence of type 2 diabetes (Type 2 DM) is rising leading to similar or even worse pregnancy outcome than in T1 DM. Micro- and macroangiopathic complications still rather rare in the mother will also become more prevalent with increasing age, obesity and more severe forms of Type 2 DM. Good glycemic control, normotension, lack of nephropathy as well as lack of pre proliferative/proliferative changes of diabetic retinopathy and lack of signs of macroangiopathies are good prognostic factors as regards the progression of vascular complications during pregnancy. Women with diabetes should be evaluated before pregnancy for microangiopathies, treated and followed closely during pregnancy by obstetrician, internist/diabetologue, cardiologist and ophthalmologist and nephrologist. PMID- 21262443 TI - Anticoagulant therapy in pregnant women with mechanical prosthetic heart valves: no easy option. AB - The choice of anticoagulant agent for pregnant women with mechanical prosthetic heart valves introduces a clinical dilemma for women and the clinicians caring for them. Options include continuing oral anticoagulants (OAC) such as warfarin throughout pregnancy, switching from warfarin to unfractionated heparin or low molecular weight heparin (LMWH) in the first trimester then back to warfarin until close to delivery or taking unfractionated heparin or LMWH throughout pregnancy. The dilemma is that warfarin is the most effective a preventing maternal thromboembolic complications but causes significant fetal morbidity and mortality; unfractionated heparin and in particular LMWH have good fetal outcomes but the risk of thromboembolic complications is high. What is considered to be an "acceptable level" of risk to mother and infant may differ from one clinician to another and of equal importance, it may also differ from one woman to the next. An unbiased discussion of the pros and cons of each option is required to allow women to make and informed and confident choice in this very difficult clinical situation. PMID- 21262444 TI - Resistance to anti-platelet agents. AB - In the last few years, the concept of resistance to antiplatelet agents has been largely emphasized in the medical literature, although its definition is still uncertain. The real prevalence of resistance to aspirin appears to be rather low. In contrast, resistance to clopidogrel (a P2Y12 inhibitor), which is mostly due to inefficient metabolism of the pro-drug clopidogrel to its active metabolite, is a rather frequent condition, which is associated with lower clinical efficacy of the drug. The proposed solution to the problem of clopidogrel resistance, based on monitoring the pharmacological response with platelet function tests, is cumbersome, not effective in all treated patients and not practicable yet, because the most appropriate laboratory test has not yet been identified. The use of new P2Y12 inhibitors, such as prasugrel and ticagrelor, which adequately inhibit P2Y12-dependent platelet function in the vast majority of treated subjects, appears the best solution to the problem of clopidogrel resistance. PMID- 21262445 TI - Angiogenesis in gestational vascular complications. AB - Vascular endothelial growth factor (VEGF) is a key player in vasculogenesis and angiogenesis in the embryo, and essential in neovascularization in adults. Natural VEGF inhibitors such as soluble VEGF receptors, among them the soluble VEGF-trapping receptor Flt1 (sFlt1), participate in VEGF regulation. Decreased levels of VEGF and increased levels of sFlt1 have been implicated in the pathophysiology of preeclampsia. We discovered a soluble receptor, sFlt1-14, qualitatively different from sFlt1 and a potent VEGF inhibitor. It is generated in a cell type specific fashion, primarily in nonendothelial cells, most notably in vascular smooth muscle cells. We showed that increased production of soluble VEGF receptors in pregnancy is owing to expression of sFlt1-14, from the end of the first trimester to term. This expression is markedly elevated in preeclampsia, and is expressed chiefly by syncitial knots. In subsequent studies we found that sFlt1 is a strong heparin binder: this capability enables it to stay attached to blood vessels and to the placenta. Ex vivo, sFlt1 can be heparin displaced to medium from aortic segments and placental villi. In vivo, pregnant women treated with the low molecular weight heparin (LMWH) have elevated sFlt1 levels in their circulations. Interestingly, LMWH raised VEGF levels over and above the increase in sFlt1 levels in these patients. Heparanaseoverexpressing non-pregnant as well as pregnant transgenic mice present elevated levels of sFlt1 in their circulations. Ex vivo prevention of heparanase maturation through cathepsin L inhibition, or targeting heparanase directly with a neutralizing antibody, both resulted in a marked reduction in sFlt1 secretion to medium of normal and preeclamptic placental expiants. These findings uncover a new level of regulation that controls sFlt1 bio-distribution, and directs it to function in the vicinity of its producing cell. Heparanase or LMWH has the ability to liberate sFlt1 from its retention, so this process may be a potential target for preeclampsia treatment. PMID- 21262446 TI - Microparticles and pregnancy complications. AB - Microparticles (MPs) are shed from cell membranes of a variety of cells, promote thrombus formation, mediate pro-inflammatory effects and may cause endothelial dysfunction. Normal pregnancy is characterized by increased levels of MPs compared to non-pregnant healthy women but the prevalence, cell origin and the role of MPs in pregnancy-related complications remain controversial. Normal pregnancy is an acquired hyper-coagulable state due to an increase in procoagulants and decrease in natural anticoagulants. Pregnancy-related complications such as preeclampsia, intrauterine fetal growth restriction (IUGR) and fetal loss are associated with placental dysfunction and may cause significant maternal and fetal morbidity and mortality. This article highlights the role of microparticles in maternal placental crosstalk and the interplay between microparticles, thrombosis and pregnancy complications. PMID- 21262447 TI - New insights into the etiology of preeclampsia: identification of key elusive factors for the vascular complications. AB - The incidence of preeclampsia is reduced by a third in smokers, but not in snuff users. Soluble Flt-1 (sFlt-1) and soluble endoglin (sEng) are increased prior to the clinical onset of preeclampsia. Animals exposed to high circulating levels of sFlt-1 and sEng elicit severe preeclampsia-like symptoms. Smokers have reduced circulating sFlt-1 and cigarette smoke extract decreases sFlt-1 release from placental villous explants. An anti-inflammatory enzyme, heme oxygenase-1 (HO-1) and its metabolite carbon monoxide (CO), inhibit sFlt-1 and sEng release. Women with preeclampsia exhale less CO than women with normal pregnancies and HO expression decreases as the severity of preeclampsia increases. In contrast, sFlt 1 levels increase with increasing severity. More importantly, chorionic villous sampling from women at eleven weeks gestation shows that HO-1 mRNA expression is decreased in women who go on to develop preeclampsia. Collectively, these facts provide compelling evidence to support the proposition that the pathogenesis of preeclampsia is largely due to loss of HO activity. This results in an increase in inflammation and excessive elevation of the two key anti-angiogenic factors responsible for the clinical signs of preeclampsia. These findings provide strong evidence for a protective role of HO-1 in pregnancy and identify HO as a target for the treatment of preeclampsia. The cardiovascular drugs, statins, stimulate HO-1 expression and inhibit sFlt-1 release in vivo and in vitro, thus, they have the potential to ameliorate early onset preeclampsia. The StAmP trial is underway to address this and if positive, its outcome will lead to the very first therapeutic intervention to prolong affected pregnancies. PMID- 21262448 TI - Anticoagulant prophylaxis for placenta mediated pregnancy complications. AB - Thrombophilias are not yet established as a cause of the placenta-mediated pregnancy complications (pregnancy loss, pre-eclampsia, small for gestational age and placental abruption). A thrombophilia may be only one of many factors that lead to development of these complications. Our recent large systematic review of prospective cohort studies highlight that the association between thrombophilia and placenta mediated pregnancy complications is far from proven. The small step of previously describing an association in case control studies has led a large number of clinicians and opinion leaders to take the large leap of accepting this relationship as being causal and potentially treatable with anticoagulant interventions. Furthermore, while data in women with prior severe pre-eclpamsia, abruption and small for gestational age births without thrombophilia suggests some promise for anticoagulant prophylaxis to prevent complications in subsequent pregnancies in these women, in the absence of large well done and generalisable "no intervention" controlled studies adopting anticoagulant prophylaxis to prevent these complications is premature. The absence of strong evidence, coupled with the small potential for harm from anticoagulant prophylaxis suggests that these drugs should be considered experimental in thrombophilic and non thrombophilic women with prior placenta mediated pregnancy complications. PMID- 21262449 TI - Recent findings in the epidemiology, diagnosis and treatment of superficial-vein thrombosis. AB - Recent data on lower-limb superficial-vein thrombosis (SVT) may substantially impact its clinical management. Thus, the clear confirmation that SVT is closely linked to deep-vein thrombosis (DVT) or pulmonary embolism (PE) highlights the potential severity of the disease. DVT or PE are diagnosed in 20-30% of SVT patients. Moreover, clinically relevant symptomatic thromboembolic events complicate isolated SVT (without concomitant DVT or PE at diagnosis) in 4-8% of patients. For the first time, an anticoagulant treatment, once-daily 2.5 mg fondaparinux for 45 days, was demonstrated to be effective and safe for preventing these symptomatic thromboembolic events in patients with lower-limb isolated SVT in the randomized placebo-controlled CALISTO study. Based on these recent findings, new recommendations on the management of SVT patients, including complete ultrasonography examination of the legs, and in patients with isolated SVT, prescription of once-daily 2.5 mg fondaparinux subcutaneously for 45 days on top of symptomatic treatments, may be proposed. PMID- 21262450 TI - Venous thrombosis at unusual site in women. AB - Several sex-related differences in the incidence rate, clinical presentation and outcomes of VTE were recently investigated. Gender-related risk factors, such as the use of oral contraceptives (OC) and pregnancy, in particular in women with a thrombophilic state, are associated with an increased risk of venous thromboembolism (VTE). In the middle age population, many studies report a higher incidence of VTE in men than in women, but the incidence rate of pulmonary embolism (PE) secondary to deep vein thrombosis (DVT) seems to be higher in women than in men, especially when older than 50 years. Finally, a recent meta-analysis showed that men have about a 50% higher risk than women of recurrent VTE, regardless of the site of the first DVT or the risk factors associated with the index event. The most common manifestations of VTE are represented by DVT of the lower limbs and PE, but VTE can potentially involve any section of the venous system, including cerebral veins, abdominal and pelvic veins, and the veins of the upper limbs. The scope of this article is to provide an overview of VTE in unusual sites, with particular focus on the epidemiology, on gender specific risk factors, and on clinical outcome in women. PMID- 21262451 TI - The post thrombotic syndrome. AB - More than one-third of women with deep venous thrombosis (DVT) will develop the postthrombotic syndrome (PTS), and 5-10% develop severe PTS, which can manifest as venous ulcers. Typical features of PTS include chronic pain, swelling, heaviness, edema and skin changes in the affected limb. The main risk factors for PTS are persistent leg symptoms one month after acute DVT, anatomically extensive DVT, recurrent ipsilateral DVT, obesity and older age. Use of compression stockings for two years after DVT appears to reduce the incidence and severity of PTS but issues remain regarding their use and effectiveness. The cornerstone of managing PTS is compression therapy, primarily using ECS. Venoactive medications such as aescin and rutosides may provide short term relief of PTS symptoms. Further studies to elucidate the pathophysiology of PTS, to identify clinical and biological risk factors and to test new preventive and therapeutic approaches to PTS are needed. PMID- 21262452 TI - Thromboprophylaxis after cesarean section: decision analysis. AB - Although venous thromboembolism (VTE) is the leading cause of maternal mortality in developed countries, the usefulness of preventive low-molecular weight heparin (LMWH) after cesarean section remains a matter of controversy. This article will review a recent decision analysis addressing this question, comparing a 7-day LMWH with none in this setting. Prophylaxis with LMWH yielded the highest quality adjusted life expectancy, with a net gain of 1.5 days per treated patient. Sensitivity analyses showed the incidence of VTE after cesarean section and the haemorrhagic risk related to LMWH to be critical, at threshold values of 0.22% and 0.24% respectively. In the hypothetical cases created by the authors, LMWH was safe but only marginally more effective in women with no risk factors. With the addition of other risk factors, reductions in VTE greatly outnumbered the increase in major hemorrhages. This study highlights the need to assess the individual thrombotic risk in women after a cesarean section. PMID- 21262453 TI - Is placental haemostasis relevant to recurrent implantation failure? PMID- 21262454 TI - Placental pathology in pregnancy complications. AB - Among pregnancy pathologies preeclampsia and fetal growth restriction are among the leading causes of maternal and perinatal mortality and morbidity. For both syndromes, the etiologies are still unclear in many facets. For the development of preeclampsia the presence of the placenta is a prerequisite, while for FGR a variety of other factors may be decisive. Cases with a combination of FGR and preeclampsia are the most severe cases and need clinical intervention. Studies on such cases have misled scientists and clinicians to hypothesize that a failure of trophoblast invasion is a specific feature of the early onset type of preeclampsia. Recent development in preeclampsia specific biomarkers and the intense use of Doppler ultrasound measurements already in the first trimester of pregnancy has resulted in a new understanding of the pathways leading to preeclampsia or FGR. PMID- 21262455 TI - The dark side of TV screens. PMID- 21262456 TI - Controlled demolition: Smurf1 regulates neuronal polarity by substrate switching. AB - During axon specification, growth promoting proteins localize selectively to the growing axon. In this issue of Neuron, Cheng et al. report how selective protein degradation, controlled by a substrate switch of the ubiquitin ligase Smurf1, specifies Par6 and RhoA localization and thereby regulates neuronal polarity. PMID- 21262457 TI - The multiple faces of RIM. AB - Rab3 interacting molecules (RIMs) are highly enriched in the active zones of presynaptic terminals. It is generally thought that they operate as effectors of the small G protein Rab3. Three recent papers, by Han et al. (this issue of Neuron), Deng et al. (this issue of Neuron), and Kaeser et al. (a recent issue of Cell), shed new light on the functional role of RIM in presynaptic terminals. First, RIM tethers Ca2+ channels to active zones. Second, RIM contributes to priming of synaptic vesicles by interacting with another presynaptic protein, Munc13. PMID- 21262458 TI - Stressed and depressed? Check your GDNF for epigenetic repression. AB - Some adults fail to adapt to chronic stress, developing symptoms of depression and anxiety. In this issue of Neuron, Uchida and colleagues link maladaptive stress responses to GDNF through a comprehensive investigation of the neurotrophic factor's regulation. Further, this study is an excellent example for investigators interested in neuroepigenetics research. PMID- 21262459 TI - Dynamic formation of functional networks by synchronization. AB - The cerebral cortex consists of numerous, densely interconnected, functionally specialized areas that need to cooperate in ever-changing constellations depending on the actual cognitive or executive task. One way to achieve this dynamic coordination could be phase-locking of synchronized oscillatory activity. In this issue of Neuron, Hipp et al. provide supportive evidence by analyzing EEG signals associated with an ambiguous audiovisual discrimination task. PMID- 21262460 TI - Out of thin air: sensory detection of oxygen and carbon dioxide. AB - Oxygen (O2) and carbon dioxide (CO2) levels vary in different environments and locally fluctuate during respiration and photosynthesis. Recent studies in diverse animals have identified sensory neurons that detect these external variations and direct a variety of behaviors. Detection allows animals to stay within a preferred environment as well as identify potential food or dangers. The complexity of sensation is reflected in the fact that neurons compartmentalize detection into increases, decreases, and short-range and long-range cues. Animals also adjust their responses to these prevalent signals in the context of other cues, allowing for flexible behaviors. In general, the molecular mechanisms for detection suggest that sensory neurons adopted ancient strategies for cellular detection and coupled them to brain activity and behavior. This review highlights the multiple strategies that animals use to extract information about their environment from variations in O2 and CO2. PMID- 21262461 TI - Anti-abeta therapeutics in Alzheimer's disease: the need for a paradigm shift. AB - Most current Alzheimer's disease (AD) therapies in advanced phases of development target amyloid beta-peptide (Abeta) production, aggregation, or accumulation. Translational models suggest that anti-Abeta therapies may be highly effective if tested as agents to prevent or delay development of the disease or as therapies for asymptomatic patients with very early signs of AD pathology. However, anti Abeta therapeutics are currently being tested in symptomatic patients where they are likely to be much less effective or ineffective. The lack of alignment between human clinical studies and preclinical studies, together with predictions about optimal trial design based on our understanding of the initiating role of Abeta aggregates in AD, has created a treatment versus prevention dilemma. In this perspective, we discuss why it is imperative to resolve this dilemma and suggest ways for moving forward in the hopes of enhancing the development of truly effective AD therapeutics. PMID- 21262462 TI - Dual roles of Notch in regulation of apically restricted mitosis and apicobasal polarity of neuroepithelial cells. AB - How the mitosis of neuroepithelial stem cells is restricted to the apical ventricular area remains unclear. In zebrafish, the mosaic eyes(rw306) (moe/epb41l5(rw306)) mutation disrupts the interaction between the putative adaptor protein Moe and the apicobasal polarity regulator Crumbs (Crb), and impairs the maintenance of neuroepithelial apicobasal polarity. While Crb interacts directly with Notch and inhibits its activity, Moe reverses this inhibition. In the moe(rw306) hindbrain, Notch activity is significantly reduced, and the number of cells that proliferate basally away from the apical area is increased. Surprisingly, activation of Notch in the moe(rw306) mutant rescues not only the basally localized proliferation but also the aberrant neuroepithelial apicobasal polarity. We present evidence that the Crb?Moe complex and Notch play key roles in a positive feedback loop to maintain the apicobasal polarity and the apical-high basal-low gradient of Notch activity in neuroepithelial cells, both of which are essential for their apically restricted mitosis. PMID- 21262463 TI - Phosphorylation of E3 ligase Smurf1 switches its substrate preference in support of axon development. AB - Ubiquitin E3 ligases serve for ubiquitination of specific substrates, and its ligase efficacy is regulated by interacting proteins or substrate modifications. Whether and how the ligases themselves are modified by cellular signaling is unclear. Here we report that protein kinase A (PKA)-dependent phosphorylation of Smad Ubiquitin Regulatory Factor 1 (Smurf1) can switch its substrate preference between two proteins of opposing actions on axon development. Extracellular factors that promote axon formation elevated Smurf1 phosphorylation at a PKA site Thr306, and preventing this phosphorylation reduced axon formation in cultured hippocampal neurons and impaired polarization of cortical neurons in vivo. Thr306 phosphorylation changed the relative affinities of Smurf1 for its substrates, leading to reduced degradation of polarity protein Par6 and increased degradation of growth-inhibiting RhoA. Thus, PKA-dependent phosphorylation of the E3 ligase could switch its substrate preference, contributing to selective protein degradation required for localized cellular function. PMID- 21262464 TI - Nodes of Ranvier act as barriers to restrict invasion of flanking paranodal domains in myelinated axons. AB - Accumulation of voltage-gated sodium (Na(v)) channels at nodes of Ranvier is paramount for action potential propagation along myelinated fibers, yet the mechanisms governing nodal development, organization, and stabilization remain unresolved. Here, we report that genetic ablation of the neuron-specific isoform of Neurofascin (Nfasc(NF186)) in vivo results in nodal disorganization, including loss of Na(v) channel and ankyrin-G (AnkG) enrichment at nodes in the peripheral nervous system (PNS) and central nervous system (CNS). Interestingly, the presence of paranodal domains failed to rescue nodal organization in the PNS and the CNS. Most importantly, using ultrastructural analysis, we demonstrate that the paranodal domains invade the nodal space in Nfasc(NF186) mutant axons and occlude node formation. Our results suggest that Nfasc(NF186)-dependent assembly of the nodal complex acts as a molecular boundary to restrict the movement of flanking paranodal domains into the nodal area, thereby facilitating the stereotypic axonal domain organization and saltatory conduction along myelinated axons. PMID- 21262465 TI - The molecular and cellular basis of bitter taste in Drosophila. AB - The extent of diversity among bitter-sensing neurons is a fundamental issue in the field of taste. Data are limited and conflicting as to whether bitter neurons are broadly tuned and uniform, resulting in indiscriminate avoidance of bitter stimuli, or diverse, allowing a more discerning evaluation of food sources. We provide a systematic analysis of how bitter taste is encoded by the major taste organ of the Drosophila head, the labellum. Each of 16 bitter compounds is tested physiologically against all 31 taste hairs, revealing responses that are diverse in magnitude and dynamics. Four functional classes of bitter neurons are defined. Four corresponding classes are defined through expression analysis of all 68 gustatory taste receptors. A receptor-to-neuron-to-tastant map is constructed. Misexpression of one receptor confers bitter responses as predicted by the map. These results reveal a degree of complexity that greatly expands the capacity of the system to encode bitter taste. PMID- 21262466 TI - In vivo time-lapse imaging and serial section electron microscopy reveal developmental synaptic rearrangements. AB - Dendrites, axons, and synapses are dynamic during circuit development; however, changes in microcircuit connections as branches stabilize have not been directly demonstrated. By combining in vivo time-lapse imaging of Xenopus tectal neurons with electron microscope reconstructions of imaged neurons, we report the distribution and ultrastructure of synapses on individual vertebrate neurons and relate these synaptic properties to dynamics in dendritic and axonal arbor structure over hours or days of imaging. Dynamic dendrites have a high density of immature synapses, whereas stable dendrites have sparser, mature synapses. Axons initiate contacts from multisynapse boutons on stable branches. Connections are refined by decreasing convergence from multiple inputs to postsynaptic dendrites and by decreasing divergence from multisynapse boutons to postsynaptic sites. Visual deprivation or NMDAR antagonists decreased synapse maturation and elimination, suggesting that coactive input activity promotes microcircuit development by concurrently regulating synapse elimination and maturation of remaining contacts. PMID- 21262467 TI - Postsynaptic TrkC and presynaptic PTPsigma function as a bidirectional excitatory synaptic organizing complex. AB - Neurotrophin receptor tyrosine kinases (Trks) have well-defined trophic roles in nervous system development through kinase activation by neurotrophins. Yet Trks have typical cell-adhesion domains and express noncatalytic isoforms, suggesting additional functions. Here we discovered noncatalytic TrkC in an unbiased hippocampal neuron-fibroblast coculture screen for proteins that trigger differentiation of neurotransmitter release sites in axons. All TrkC isoforms, but not TrkA or TrkB, function directly in excitatory glutamatergic synaptic adhesion by neurotrophin-independent high-affinity trans binding to axonal protein tyrosine phosphatase receptor PTPsigma. PTPsigma triggers and TrkC mediates clustering of postsynaptic molecules in dendrites, indicating bidirectional synaptic organizing functions. Effects of a TrkC-neutralizing antibody that blocks TrkC-PTPsigma interaction and TrkC knockdown in culture and in vivo reveal essential roles of TrkC-PTPsigma in glutamatergic synapse formation. Thus, postsynaptic TrkC trans interaction with presynaptic PTPsigma generates bidirectional adhesion and recruitment essential for excitatory synapse development and positions these signaling molecules at the center of synaptic pathways. PMID- 21262468 TI - RIM determines Ca2+ channel density and vesicle docking at the presynaptic active zone. AB - At presynaptic active zones, neurotransmitter release is initiated by the opening of voltage-gated Ca2+ channels close to docked vesicles. The mechanisms that enrich Ca2+ channels at active zones are, however, largely unknown, possibly because of the limited presynaptic accessibility of most synapses. Here, we have established a Cre-lox based conditional knockout approach at a presynaptically accessible central nervous system synapse, the calyx of Held, to directly study the functions of RIM proteins. Removal of all RIM1/2 isoforms strongly reduced the presynaptic Ca2+ channel density, revealing a role of RIM proteins in Ca2+ channel targeting. Removal of RIMs also reduced the readily releasable pool, paralleled by a similar reduction of the number of docked vesicles, and the Ca2+ channel-vesicle coupling was decreased. Thus, RIM proteins co-ordinately regulate key functions for fast transmitter release, enabling a high presynaptic Ca2+ channel density and vesicle docking at the active zone. PMID- 21262470 TI - The molecular and cellular identity of peripheral osmoreceptors. AB - In mammals, the osmolality of the extracellular fluid (ECF) is highly stable despite radical changes in salt/water intake and excretion. Afferent systems are required to detect hypo- or hyperosmotic shifts in the ECF to trigger homeostatic control of osmolality. In humans, a pressor reflex is triggered by simply drinking water which may be mediated by peripheral osmoreceptors. Here, we identified afferent neurons in the thoracic dorsal root ganglia (DRG) of mice that innervate hepatic blood vessels and detect physiological hypo-osmotic shifts in blood osmolality. Hepatic sensory neurons are equipped with an inward current that faithfully transduces graded changes in osmolality within the physiological range (~15 mOsm). In mice lacking the osmotically activated ion channel, TRPV4, hepatic sensory neurons no longer exhibit osmosensitive inward currents and activation of peripheral osmoreceptors in vivo is abolished. We have thus identified a new population of sensory neurons that transduce ongoing changes in hepatic osmolality. PMID- 21262469 TI - RIM proteins activate vesicle priming by reversing autoinhibitory homodimerization of Munc13. AB - At a synapse, the presynaptic active zone mediates synaptic vesicle exocytosis. RIM proteins are active zone scaffolding molecules that--among others--mediate vesicle priming and directly or indirectly interact with most other essential presynaptic proteins. In particular, the Zn2+ finger domain of RIMs binds to the C2A domain of the priming factor Munc13, which forms a homodimer in the absence of RIM but a heterodimer with it. Here, we show that RIMs mediate vesicle priming not by coupling Munc13 to other active zone proteins as thought but by directly activating Munc13. Specifically, we found that the isolated Zn2+ finger domain of RIMs autonomously promoted vesicle priming by binding to Munc13, thereby relieving Munc13 homodimerization. Strikingly, constitutively monomeric mutants of Munc13 rescued priming in RIM-deficient synapses, whereas wild-type Munc13 did not. Both mutant and wild-type Munc13, however, rescued priming in Munc13 deficient synapses. Thus, homodimerization of Munc13 inhibits its priming function, and RIMs activate priming by disrupting Munc13 homodimerization. PMID- 21262471 TI - Sun compass integration of skylight cues in migratory monarch butterflies. AB - Migrating monarch butterflies (Danaus plexippus) use a time-compensated sun compass to navigate from eastern North America to their overwintering grounds in central Mexico. Here we describe the neuronal layout of those aspects of the butterfly's central complex likely to establish part of the internal sun compass and find them highly homologous to those of the desert locust. Intracellular recordings from neurons in the monarch sun compass network reveal responses tuned to specific E-vector angles of polarized light, as well as azimuth-dependent responses to unpolarized light, independent of spectral composition. The neural responses to these two stimuli in individual neurons are mediated through different regions of the compound eye. Moreover, these dual responses are integrated to create a consistent representation of skylight cues in the sun compass throughout the day. The results advance our understanding of how ambiguous sensory signals are processed by the brain to elicit a robust behavioral response. PMID- 21262472 TI - Epigenetic status of Gdnf in the ventral striatum determines susceptibility and adaptation to daily stressful events. AB - Stressful events during adulthood are potent adverse environmental factors that can predispose individuals to psychiatric disorders, including depression; however, many individuals exposed to stressful events can adapt and function normally. While stress vulnerability may influence depression, the molecular mechanisms underlying the susceptibility and adaptation to chronic stress within the brain are poorly understood. In this study, two genetically distinct mouse strains that exhibit different behavioral responses to chronic stress were used to demonstrate how the differential epigenetic status of the glial cell-derived neurotrophic factor (Gdnf) gene in the ventral striatum modulates susceptibility and adaptation to chronic stress. Our results suggest that the histone modifications and DNA methylation of the Gdnf promoter have crucial roles in the control of behavioral responses to chronic stress. Our data provide insights into these mechanisms, suggesting that epigenetic modifications of Gdnf, along with genetic and environmental factors, contribute to behavioral responses to stress. PMID- 21262474 TI - Oscillatory synchronization in large-scale cortical networks predicts perception. AB - Normal brain function requires the dynamic interaction of functionally specialized but widely distributed cortical regions. Long-range synchronization of oscillatory signals has been suggested to mediate these interactions within large-scale cortical networks, but direct evidence is sparse. Here we show that oscillatory synchronization is organized in such large-scale networks. We implemented an analysis approach that allows for imaging synchronized cortical networks and applied this technique to EEG recordings in humans. We identified two networks: beta-band synchronization (~20 Hz) in a fronto-parieto-occipital network and gamma-band synchronization (~80 Hz) in a centro-temporal network. Strong perceptual correlates support their functional relevance: the strength of synchronization within these networks predicted the subjects' perception of an ambiguous audiovisual stimulus as well as the integration of auditory and visual information. Our results provide evidence that oscillatory neuronal synchronization mediates neuronal communication within frequency-specific, large scale cortical networks. PMID- 21262473 TI - Using the structure of inhibitory networks to unravel mechanisms of spatiotemporal patterning. AB - Neuronal networks exhibit a rich dynamical repertoire, a consequence of both the intrinsic properties of neurons and the structure of the network. It has been hypothesized that inhibitory interneurons corral principal neurons into transiently synchronous ensembles that encode sensory information and subserve behavior. How does the structure of the inhibitory network facilitate such spatiotemporal patterning? We established a relationship between an important structural property of a network, its colorings, and the dynamics it constrains. Using a model of the insect antennal lobe, we show that our description allows the explicit identification of the groups of inhibitory interneurons that switch, during odor stimulation, between activity and quiescence in a coordinated manner determined by features of the network structure. This description optimally matches the perspective of the downstream neurons looking for synchrony in ensembles of presynaptic cells and allows a low-dimensional description of seemingly complex high-dimensional network activity. PMID- 21262476 TI - Emergency contraception, the bottom line. PMID- 21262477 TI - Age of onset of polycystic ovarian syndrome in girls may be earlier than previously thought. AB - OBJECTIVES: To study the age at diagnosis of polycystic ovarian syndrome (PCOS) in a pediatric population. To compare risk factors involved in causing PCOS in preadolescent and adolescent girls. To review the current literature on the reported age of PCOS in girls. DESIGN: A retrospective chart review and systematic review of the literature. PARTICIPANTS: Patients included 58 girls (age <= 18 yrs) with a diagnosis of PCOS based on the Rotterdam criteria. Girls were grouped as preadolescents (<13 yrs) or adolescents (13-18 yrs). Clinical and biochemical data were reviewed from the time of diagnosis. MAIN OUTCOME MEASURES: Age at diagnosis. Differences in risk factors for PCOS (Ethnicity, obesity, family history of PCOS, birth weight, age at pubarche, thelarche and menarche, evidence of hyperandrogenism and/or insulin resistance) were compared between the two groups. RESULTS: There were 26% (15/58) preadolescent girls (9-12 yrs) vs 74% (43/58) adolescents (13-18 yrs). There was no significant difference between the two groups in ethnicity, BMI z-score, family history of maternal PCOS, birth weight, hyperandrogenism, or insulin resistance. Preadolescents with PCOS had significantly earlier onset of pubarche and thelarche than adolescents with PCOS, by 1.9 and 1.5 yrs, respectively (P = 0.018, 0.030). In addition to earlier puberty, PCOS developed 2.1 years sooner after thelarche in preadolescents than in adolescents. (P = 0.008) Preadolescents were significantly taller for age than adolescents (72nd % vs 43rd %) (P = 0.005). A review of the 28 studies published in the last 3 years that included PCOS patients with age <=18 yrs described only 6.4% (27/425) of pediatric subjects with age <13 yrs. Four were primarily pediatric studies that included patients under the age of 13 yrs, with 9.4% (12/127) of the patients <13 yrs. CONCLUSION: Increased awareness of PCOS in young females is needed. PCOS may occur at a younger age in girls who develop early pubarche and thelarche. Therefore, the diagnosis and workup should be considered in young girls with risk factors suggestive of PCOS. PMID- 21262478 TI - Intrauterine contraception in adolescents and young women: a descriptive study of use, side effects, and compliance. AB - OBJECTIVE: Describe characteristics, compliance, efficacy, and side effect profile of adolescents and young women who use intrauterine contraception (IC). STUDY DESIGN: Retrospective chart review of adolescent and young women who had IC devices placed over a 3-year period. Comparative statistics between devices and population characteristics were performed using the Fisher exact and the t test. RESULTS: Eighty-nine patients were included in the study. The mean age at insertion was 19.5 years (range 16-22 years). Copper was used in 13% of patients; levonorgestrel (LNG) was used in 87%. The mean duration of use was 331.3 days (copper vs LNG; P = .2254). Side effects included infection (9%, but no pelvic inflammatory disease), pain (28%), partner felt strings (9%), and bleeding (32%). Reasons for removal included side effects (25%), desired fertility (5%), expulsion (3%), and pregnancy (2%). There were no pregnancies associated with the LNG IC, and there were fewer removals because of side effects than with the copper IUD (P = .0180). CONCLUSION: IC is a reliable method of contraception in teens and young adults. There were fewer removals because of side effects in the LNG group, although overall other variables are similar between methods. PMID- 21262479 TI - Meeting the gastrointestinal needs of a culturally and linguistically diverse patient population. PMID- 21262480 TI - Thermodynamic perspectives on genetic instructions, the laws of biology and diseased states. AB - This article examines in a broad perspective entropy and some examples of its relationship to evolution, genetic instructions and how we view diseases. Living organisms are programmed by functional genetic instructions (FGI), through cellular communication pathways, to grow and reproduce by maintaining a variety of hemistable, ordered structures (low entropy). Living organisms are far from equilibrium with their surrounding environmental systems, which tends towards increasing disorder (increasing entropy). Organisms free themselves from high entropy (high disorder) to maintain their cellular structures for a period of time sufficient to allow reproduction and the resultant offspring to reach reproductive ages. This time interval varies for different species. Bacteria, for example need no sexual parents; dividing cells are nearly identical to the previous generation of cells, and can begin a new cell cycle without delay under appropriate conditions. By contrast, human infants require years of care before they can reproduce. Living organisms maintain order in spite of their changing surrounding environment that decreases order according to the second law of thermodynamics. These events actually work together since living organisms create ordered biological structures by increasing local entropy. From a disease perspective, viruses and other disease agents interrupt the normal functioning of cells. The pressure for survival may result in mechanisms that allow organisms to resist attacks by viruses, other pathogens, destructive chemicals and physical agents such as radiation. However, when the attack is successful, the organism can be damaged until the cell, tissue, organ or entire organism is no longer functional and entropy increases. PMID- 21262481 TI - Two polymorphic linker histone loci in Guinea fowl erythrocytes. AB - A variable migration of linker histone H1.b and H1.c spots in two-dimensional polyacrylamide gel patterns of total erythrocyte histone H1 has been detected during population screening in two differently plumaged Guinea fowl strains. Alloforms, H1.b1 and H1.b2 as well as H1.c1 and H1.c2, differing in apparent molecular weights tended to form only phenotypes b1 and b2 or c1 and c2 in a white-feathered strain while all phenotypes (b1, b2 and b1b2 or c1, c2 and c1c2, respectively) were present in a black-feathered population. Accordingly, the white-feathered population significantly deviated from the Hardy-Weinberg principle (chi-square test, d.f=1, p<<0.001) due to a lack of heterozygotes while the black-feathered population conformed to the Hardy-Weinberg equilibrium (p>0.05) at both H1.b and H1.c loci. Differential electrophoretic mobilities of the C-peptides from a partial chemical cleavage (N-bromosuccinimide) or limited enzymatic digestion (alpha-chymotrypsin and protease V8) of the histone H1.b and H1.c alloforms seem to indicate that altered amino acid sequence segments might be located either at the C-terminal end of globular domain or in the C-terminal domain itself. PMID- 21262482 TI - Differential reproductive timing in Echinocardium spp.: the first Mediterranean survey allows interoceanic and interspecific comparisons. AB - Echinocardium cordatum had long been considered as cosmopolitan, but molecular data revealed it is a complex of cryptic species, with two non-hybridizing species (B1 & B2) in the Mediterranean Sea living in syntopy with Echinocardium mediterraneum. Histological analyses of the gonads from a 17-month sampling period revealed a statistically significant time lag between the Maturity Indices of E. cordatum and E. mediterraneum. The main environmental stimulus may be different for the two nominal species, possibly seawater temperature for E. cordatum and chlorophyll a concentration for E. mediterraneum. Within the E. cordatum complex, spawning timing and synchrony are different according to major geographic areas (Atlantic/Pacific/Mediterranean) and/or the corresponding genetic subdivision [A/P/(B1 & B2)]. In contrast, the effects of temperature on the reproductive cycle seem rather to mirror the genetic lineages than environmental similarities of the different localities. Between the sister species (B1 & B2) no differences could be detected, maybe due to small sample sizes. PMID- 21262483 TI - Induced mutagenesis in Jatropha curcas L. using gamma rays and detection of DNA polymorphism through RAPD marker. AB - The aim of this study is to examine the effect of different doses (control, 5, 10, 15, 20 and 25 Kr) of gamma irradiation on seed germination, flowering, fruit and seed traits of Jatropha curcas and to identify DNA polymorphism among the mutants through a Randomly Amplified Polymorphic DNA (RAPD) marker analysis. The improved agronomic traits such as flowering, fruits and seeds were recorded in 5 Kr dose and seed germination percentage in 10 Kr dose treated plants, while corresponding parameters were reduced significantly (P>0.05) in 25 Kr dose gamma rays treated plants when compared to that of control. All the twenty-three random primers used except six primers, namely OPAW16, OPAK07, OPAK15, OPS01, OPAK20 and OPAL09 were showed polymorphic bands. The primers: OPAW16, OPAK07, OPAK15, OPS01, OPAK20 and OPAL09 produced only one band each across the six mutants, while the primers: OPU13, OPAB 15, OPF01 and OPAB11 were produced with maximum number of bands (8). The number of amplicons varied from 1 to 8 with an average of 3.9 bands, of which 2.3 were polymorphic. The percentage of polymorphism per primer ranged from 0 to 100 with an average of 55.16%. The Jaccard's coefficients of dissimilarity varied from 0.324 to 0.397, indicative of the level of genetic variation among the mutants studied. The maximum dissimilarity value (0.397) was observed in 5 Kr mutant while the minimum value (0.250) was observed in 20 Kr mutant when compared to that of control. In a dendrogram constructed based on genetic similarity coefficients, the mutants were grouped into three main clusters; (a) control, 10, 15 and 20 Kr dose mutants clustered together, (b) 25 Kr dose grouped alone, (c) 5 Kr dose also grouped alone. The mutants showing the differences in morphological traits showed DNA polymorphism in PCR profile amplified by RAPD marker. It is concluded that DNA polymorphism detected by RAPD analysis offered a useful molecular marker for the identification of mutants in gamma radiation treated plants. PMID- 21262484 TI - Mathematical modeling of energy metabolism and hemodynamics of WHO grade II gliomas using in vivo MR data. AB - Therapeutic management of low-grade gliomas (LGG) is a challenge because they have undergone anaplastic transformation with variable delay. Today, only progressive volume growth on successive MRI allows an in vivo monitoring of this evolution. On the other hand, multinuclear spectroscopy and perfusion available during MRI may also provide assessment of metabolic changes underlying morphological modifications. To overcome this drawback, we developed a mathematical model of the metabolism and the hemodynamic of gliomas, based on a physiological model previously published, and including the MR parameters. This allows us to suggest that some specific profiles of metabolic and hemodynamic changes would be good indicators of potential anaplastic transformation. PMID- 21262485 TI - Pomology observations, morphometric analysis, ultrastructural study and allelic profiles of "olivastra Seggianese" endocarps from ancient olive trees (Olea europaea L.). AB - Preliminary studies of historical sources and remote sensing were used to identify ancient olive trees near archaeological sites and heritage buildings in the Orcia Valley (Siena, Italy). Distinctive characters were assessed by traditional pomological observation. Trees with similar characters were selected on the basis of the features of endocarps, the only structure that survives aerobic deterioration and conserves useful botanical information for centuries. Non-invasive morphometric analysis of endocarp size and shape established morphological variations in individuals of different populations. Plastid organization in the endocarp and location of DNA in the endocarp tegument were detected by morphological and ultrastructural observations using light and electron microscopy. Cytoplasmic markers with high polymorphism were used to test similarity of endocarp and leaf DNA within individuals and to confirm low variability and minimal divergence between individuals. The ancient trees studied showed the same allelic profiles and therefore belonged to a distinct cultivar. The traditional pomological descriptions of the trees, leaves and fruits, morphometric analysis of size, and shape elliptic Fourier analysis of endocarp outline, ultrastructural observations and allelic profiles of endocarp tegument delineated the general species-specific qualities of the cultivar "olivastra Seggianese" of the Orcia Valley. PMID- 21262486 TI - Few, small, and male: multiple effects of reduced nest space on the offspring of the solitary wasp, Euodynerus (Pareuodynerus) posticus (Hymenoptera: Vespidae). AB - The size of the preexisting wood cavities used as nests by aculeate Hymenoptera is expected to have consequences on fitness parameters such as offspring number and size. We evaluated the consequences of using small and large (three-times more voluminous) trap-nests by the solitary wasp, Euodynerus (Pareuodynerus) posticus (Herrich-Schaeffer). Following life-history and sex allocation theories, a number of non-mutually exclusive hypotheses were formulated: i.e. small nests either produce smaller or fewer offspring and/or more males, the cheaper sex. Wasps built about 28% more, but shorter brood cells in large nests, although their volume was still much higher in large nests. Adult males had smaller body size in small nests, but female size did not differ between large and small nests, possibly as an adaptive response against the future higher foraging costs of size-reduced females. Sex-ratio was often biased towards males in small nests. Mortality did not differ between large and small nests. We conclude that E. (P.) posticus females would benefit from using larger nests, but that the sex-ratio would be probably overall unbalanced if females would not use also smaller, male oriented tunnels. PMID- 21262487 TI - [Alder forests of Numidia (N.E. Algeria): floristic biodiversity, vulnerability and conservation]. AB - The phytoecological study of the alder forests of north-east Algeria shows that these habitats with boreal affinities harbour very high species richness (> 400 species) and complex structures, which suggest their ancient origin. They correspond phytosociologically to two syntaxa, the Campanulo alatae-Alnenion glutinosae (riparian alder forests) and the Rusco hypophylli-Alnetum glutinosae (peat-forming alder carrs), respectively. Their degraded state and their regressive dynamics, observed during the 14 years of the study, reveal their precarious situation and their rapid ongoing decline under the influence of human induced uncontroled disturbances (cutting, burning, draining, dumping...). With regard to their ecological, historical and patrimonial importance, the alder forests of Algerian Numidia should be urgently protected, with the aim of assuring the perennity of their exceptional floristic corteges. PMID- 21262488 TI - Relative importance of habitat and landscape scales on butterfly communities of urbanizing areas. AB - Agricultural decline and urbanization entail rapid alterations of the patterns of organization of rural landscapes in Europe. The spread of the urban footprint to the adjacent countryside contributes to the development of new anthropogenic ecosystems in formerly rural hinterlands. In this study, butterflies are considered as biological indicators of these rapid environmental changes. Our purpose is to better understand changes in biodiversity related to the evolution of available habitats in a mutating landscape. In this study, we investigate butterfly communities of four land-use types (fallow lands, gardens, vineyards, woodlands) within different landscape contexts. Our results reveal that variations in structure and functional composition of these communities are related to different levels of human disturbance at both landscape scale and habitat scale. PMID- 21262489 TI - Multiscale aspects of mechanical properties of biological materials. AB - Multiscale aspects of mechanical properties of biological materials have developed into an emerging area of research with impact in a broad range of disciplines ranging from medicine to materials science, defining a biomateriomics approach that facilitates a new paradigm in understanding the interplay of structure and function. Mechanical properties of biological materials are critical for virtually all physiological processes and cover all the scales, from the molecular to the macroscale, and provide access to mechanistic understanding and engineering design of novel tools for disease diagnosis, disease treatment and biomaterials development or for the transfer of biologically inspired materials and structures. The integrated use of simulation and experiment can address key challenges in this field and will result in new tools for the analysis and synthesis of complex materials. PMID- 21262490 TI - Introducing our new associate editor: Pekka Vallittu. PMID- 21262491 TI - Robustness and optimal use of design principles of arthropod exoskeletons studied by ab initio-based multiscale simulations. AB - Recently, we proposed a hierarchical model for the elastic properties of mineralized lobster cuticle using (i) ab initio calculations for the chitin properties and (ii) hierarchical homogenization performed in a bottom-up order through all length scales. It has been found that the cuticle possesses nearly extremal, excellent mechanical properties in terms of stiffness that strongly depend on the overall mineral content and the specific microstructure of the mineral-protein matrix. In this study, we investigated how the overall cuticle properties changed when there are significant variations in the properties of the constituents (chitin, amorphous calcium carbonate (ACC), proteins), and the volume fractions of key structural elements such as chitin-protein fibers. It was found that the cuticle performance is very robust with respect to variations in the elastic properties of chitin and fiber proteins at a lower hierarchy level. At higher structural levels, variations of design parameters such as the volume fraction of the chitin-protein fibers have a significant influence on the cuticle performance. Furthermore, we observed that among the possible variations in the cuticle ingredients and volume fractions, the experimental data reflect an optimal use of the structural variations regarding the best possible performance for a given composition due to the smart hierarchical organization of the cuticle design. PMID- 21262493 TI - Molecular structure, mechanical behavior and failure mechanism of the C-terminal cross-link domain in type I collagen. AB - Collagen is a key constituent in structural materials found in biology, including bone, tendon, skin and blood vessels. Here we report a first molecular level model of an entire overlap region of a C-terminal cross-linked type I collagen assembly and carry out a nanomechanical characterization based on large-scale molecular dynamics simulation in explicit water solvent. Our results show that the deformation mechanism and strength of the structure are greatly affected by the presence of the cross-link, and by the specific loading condition of how the stretching is applied. We find that the presence of a cross-link results in greater strength during deformation as complete intermolecular slip is prevented, and thereby particularly affects larger deformation levels. Conversely, the lack of a cross-link results in the onset of intermolecular sliding during deformation and as a result an overall weaker structure is obtained. Through a detailed analysis of the distribution of deformation by calculating the molecular strain we show that the location of largest strains does not occur around the covalent bonding region, but is found in regions further away from this location. The insight developed from understanding collagenous materials from a fundamental molecular level upwards could play a role in advancing our understanding of physiological and disease states of connective tissues, and also enable the development of new scaffolding material for applications in regenerative medicine and biologically inspired materials. PMID- 21262492 TI - Mechanical properties of hydroxyapatite single crystals from nanoindentation data. AB - In this paper we compute elastoplastic properties of hydroxyapatite single crystals from nanoindentation data using a two-step algorithm. In the first step the yield stress is obtained using hardness and Young's modulus data, followed by the computation of the flow parameters. The computational approach is first validated with data from the existing literature. It is observed that hydroxyapatite single crystals exhibit anisotropic mechanical response with a lower yield stress along the [1010] crystallographic direction compared to the [0001] direction. Both work hardening rate and work hardening exponent are found to be higher for indentation along the [0001] crystallographic direction. The stress-strain curves extracted here could be used for developing constitutive models for hydroxyapatite single crystals. PMID- 21262494 TI - A coarse-grain molecular dynamics model for sickle hemoglobin fibers. AB - The intracellular polymerization of deoxy-sickle cell hemoglobin (HbS) has been identified as the main cause of sickle cell disease. Therefore, the material properties and biomechanical behavior of polymerized HbS fibers is a topic of intense research interest. A solvent-free coarse-grain molecular dynamics (CGMD) model is developed to represent a single hemoglobin fiber as four tightly bonded chains. A finitely extensible nonlinear elastic (FENE) potential, a bending potential, a torsional potential, a truncated Lennard-Jones potential and a Lennard-Jones potential are implemented along with the Langevin thermostat to simulate the behavior of a polymerized HbS fiber in the cytoplasm. The parameters of the potentials are identified via comparison of the simulation results to the experimentally measured values of bending and torsional rigidity of single HbS fibers. After it is shown that the proposed model is able to very efficiently simulate the mechanical behavior of single HbS fibers, it is employed in the study of the interaction between HbS fibers. It is illustrated that frustrated fibers and fibers under compression require a much larger interaction force to zipper than free fibers resulting in partial unzippering of these fibers. Continuous polymerization of the unzippered fibers via heterogeneous nucleation and additional unzippering under compression can explain the formation of HbS fiber networks and consequently the wide variety of shapes of deoxygenated sickle cells. PMID- 21262495 TI - Brownian dynamics simulations of charged semiflexible polymers confined to curved surfaces. AB - As an extension of the generalized bead-rod model developed earlier by the authors, this paper proposes a method for Brownian dynamics simulations of charged semiflexible polymers confined to various curved surfaces such as spherical, cylindrical, ellipsoidal and toroidal. We model charged semiflexible polymers as discrete wormlike chains consisting of virtual beads connected by inextensible rods with length varying according to the characteristic radius of curvature of the confining surface. The long-range electrostatic interactions are incorporated via the Debye-Hueckel potential. The geometrical constraints associated with the inextensible rods are realized by the so-called linear constraint solver. For a semiflexible polymer chain confined to a spherical surface, an analytical expression for the winding number is obtained by using an existing exact closed-form solution of the mean-square end-to-end distance. The proposed simulation method is then validated against theoretical predictions for both charged and uncharged polymer chains under surface confinements. PMID- 21262496 TI - Multiscale modeling and simulation of soft adhesion and contact of stem cells. AB - Recently, we have developed a multiscale soft matter model for stem cells or primitive cells in general, aiming at improving the understanding of mechanotransduction mechanism of cells that is responsible for information exchange between cells and their extracellular environment. In this paper, we report the preliminary results of our research on multiscale modeling and simulation of soft contact and adhesion of cells. The proposed multiscale soft matter cell model may be used to model soft contact and adhesion between cells and their extracellular substrates. This model is a generalization of the Fluid Mosaic Model (Singer and Nicolson, 1972), or an extension of Helfrich's liquid crystal membrane model (Helfrich, 1973). To the best of the authors' knowledge, this may be the first time that a soft matter model is developed for cell contact and adhesion. Moreover we have developed and implemented a Lagrange type meshfree Galerkin formulation and the computational algorithm for the proposed cell model. Comparison study with experimental data has been conducted to validate the parameters of the model. By using the soft matter cell model, we have simulated the soft adhesive contact process between cells and their extracellular substrates. The simulation shows that the cell can sense substrate elasticity by responding in different manners from cell spreading motion to cell contact configurations. PMID- 21262497 TI - Dimensional analysis and parametric studies for designing artificial nacre. AB - Nacre, the iridescent material found in Abalone shells, exhibits remarkable strength and toughness despite its composition of over 95% brittle ceramic. Its hierarchical structure over multiple length scales gives rise to its increase in toughness despite its material composition. In this work we develop a computational model of composites incorporating key morphological features of nacre's microstructure. By conducting a parametric analysis we are able to determine an optimal geometry that increases energy dissipation over 70 times. We discuss the contribution of varying ceramic strengths and size effect to see how this affects the overall performance of the composite. We then compare our simulations to experiments performed on a material possessing the same microstructure investigated computationally. For both simulations and experiments we show that our optimal geometry corresponds to that of natural nacre indicating the importance of specifically incorporating nacre's key morphological and constituent features. This combination of simulations and experiments gives great insight to the delicate interplay between material parameters and microstructure showing that if we optimally combine all aspects, we can develop novel synthetic materials with superior performance. PMID- 21262498 TI - The role of mechanical stress on the formation of a curly pattern of human hair. AB - Understanding the factors that contribute to the curly morphology of human hair is important for anthropological and physiological studies. In the present study, the possible role of mechanical stress on the formation and selection of such a curly pattern of hair is explored. Based on the model of hair curling upon being squeezed through pinched nails, it is found that different levels and configurations of external forces could lead to the variation of residual strains, which in turn, is related to the two-dimensional (2D) and three dimensional (3D) spatial hair curvatures. The mechanical principles are readily applicable to hair curling geometry due to the growth force exerted by hair follicles. The key mechanical parameters controlling the formation of a curly pattern of hair, as well as the key geometrical shape factors characterizing the hair morphology, are identified and correlated. The results obtained from the mechanical model are qualitatively consistent with those of previous experiments and observations. PMID- 21262501 TI - Reducing vascular disease risk in the type 2 diabetic patient. PMID- 21262502 TI - In search of self-awareness: results of the National Lipid Association 2010 Lipid Pulse membership survey. AB - BACKGROUND: In 2010 a survey of the National Lipid Association (NLA) membership was developed and launched with the objective of exploring the demographics, practice patterns, and educational needs of the health professionals in our organization involved in the practice of clinical lipidology. OBJECTIVES: To report the results of this survey and use this information to enable the organization to better serve the needs of our membership. METHODS: A 30-question survey was administered to the NLA membership before and shortly after the Annual Scientific Sessions in May, 2010. Demographic information, test ordering patterns, educational needs and resources, and technology awareness of 640 valid respondents was assessed. RESULTS: The respondents represent a balanced mix of practitioners in rural and metropolitan population centers throughout the United States. Physicians represent 67%, nurse practitioners and physician assistants 16%, and pharmacists 8% of the respondents. Among physicians, 50% are internal medicine or family medicine specialists, 32% cardiologists, and 11% endocrinologists. Most working in lipid clinics reported that their clinic was financially solvent. The respondents believed that adjunctive lipoprotein testing was clinically useful in risk prediction. The greatest educational needs included statin intolerance; strategies for improving compliance; metabolic syndrome; and lipoprotein particle and apolipoprotein B concentration. The most important sources of lipid information were the Journal of Clinical Lipidology and the NLA Annual Scientific Sessions. CONCLUSIONS: The survey provided valuable information that may be used to better serve the practice and educational needs of the membership of the NLA. PMID- 21262503 TI - Statin therapy in the prevention and treatment of atrial fibrillation. AB - Atrial fibrillation (AF) is the most common adult rhythm disorder, and it is associated with a substantial rate of morbidity and economic burden. There is an increasing body of literature in which the authors investigated the pleiotropic effects of statin therapy in relation to AF. In this comprehensive review, we examine the mechanism of AF as well as potential mechanisms supporting statin use in both the prevention and treatment of AF. In clinical studies, statin therapy appears to be useful in the prevention of AF in patients with coronary artery disease and possibly congestive heart failure and in the prevention of perioperative AF in cardiac surgery. Its utility in patients with paroxysmal AF may be limited to the prevention of incident AF, but it does not appear to inhibit the progression of paroxysmal AF to chronic AF. Further large scale, randomized, placebo-controlled studies are needed in perioperative use in noncardiac surgery and in patients undergoing ablation or cardioversion of AF. PMID- 21262504 TI - Differences in lipoprotein particle subclass distribution for Japanese Americans in Hawaii and Japanese in Japan: the INTERLIPID study. AB - BACKGROUND: Current data suggest that low density lipoprotein (LDL) and high density lipoprotein (HDL) subclass concentrations relate directly to the risk of coronary heart disease (CHD). Earlier Studies indicated that Japanese in Japan had lower rates of CHD than Japanese Americans in Hawaii. Rates of CHD appear to continue to be lower in Japan despite increasing cholesterol levels in Japan and decreasing CHD rates in the United States. OBJECTIVE: To provide insight into CHD rate differences. METHODS: Nuclear Magnetic Resonance (NMR) measurements of lipoprotein subclasses were used to assess lipoprotein particle concentration and size in samples from these two genetically similar populations in Japan and Hawaii. RESULTS: Japanese Americans had significantly higher age- and risk factor adjusted concentrations of lipoprotein particles implicated in atherogenesis, including large very low density lipoprotein (VLDL; P < 0.001), small LDL (P < 0.001), and small HDL (women, P < 0.001; men, P < 0.01), and significantly lower concentrations of large LDL (P < 0.001) and the putative cardio-protective large HDL (P < 0.05) than Japanese in Japan. Average age- and risk factor- adjusted LDL and HDL particle sizes were also significantly (P < 0.001) smaller in Japanese Americans. Adjustment for body mass index markedly reduced the differences in some lipoprotein measures, including total LDL and large HDL particle concentrations for both genders, total VLDL particle concentration for women, and large VLDL concentration and average HDL particle size for men. CONCLUSIONS: Differences in lipoprotein subclass distributions and lifestyle factors such as body weight may contribute to differences in CHD incidence for Japanese in Japan and Japanese Americans. PMID- 21262505 TI - Etiology and risk of lactescent plasma and severe hypertriglyceridemia. AB - BACKGROUND: Plasma lactescence is a clinical sign of severe hypertriglyceridemia (hyperTG; TG >10 mmol/L), which is likely to be observed more frequently in the next decades because of the growing prevalence of obesity and diabetes worldwide. OBJECTIVE: The objective of this study was to describe the clinical expression of plasma lactescence. METHODS: A total of 354 subjects with lactescent plasma hyperTG (mean TG +/- SD: 17.1 +/- 1.8 mmol/L) were classified according to blood appearance, etiology, and biochemical characteristics. The resulting phenotypes were compared with those of 364 normolipidemic controls (TG <=2 mmol/L) and 487 clear plasma hyperTG subjects (5 < TG <=9 mmol/L). The association of lactescent plasma with clinical covariates (obesity, coronary artery disease, peripheral artery disease, hypertension, diabetes, glucose intolerance, pancreatitis, and response to TG-lowering drugs) was performed by the use of multiple regression models. RESULTS: The risk of pancreatitis increased as a function of the plasma creamy white collar and was the greatest among nonobese individuals with early onset lactescence not responding to current TG-lowering drugs (familial hyperchylomicronemia). Patients with lactescent plasma and yellowish palmar xanthomas (dysbetalipoproteinemia) responded significantly better to fibrates than the other severe hyperTG phenotypes but were at greater risk of peripheral atherosclerosis. Overweight and obese patients with a creamy supernatant and a cloudy, cream of tomato, infranatant caused by hyper apolipoprotein B showed the most deleterious cardiometabolic risk profile, followed by the severe hyperTG normal apolipoprotein B phenotype, the most frequent cause of lactescent plasma. CONCLUSION: Lactescent plasma hyperTG represents a clinically heterogeneous group of high-risk patients. PMID- 21262506 TI - Patient tolerance regarding different low-density lipoprotein apheresis columns: frequent minor side effects and high patient satisfaction. AB - BACKGROUND: Side effects and patient satisfaction in low-density lipoprotein (LDL) apheresis treatment has been less vigorously studied than hemodialysis treatment in end-stage renal failure. OBJECTIVE: In the present study we systematically compared three different LDL apheresis columns with respect to side effects and patient satisfaction. METHODS: Three patients with heterozygous familial hypercholesterolemia went through six treatments with each of the LDL apheresis columns DL-75, LA-15, and EC-50W. Possible side effects were recorded during and after apheresis treatment, and patient satisfaction was assessed by means of a visual analogue scale ranging from 1 to 10. RESULTS: One or several side effects during apheresis were noted in 40%, 29%, and 30% of the treatments for the columns DL-75, LA-15, and EC-50W, respectively. There were no statistically significant differences between the columns. Side effects after apheresis were noted in 33%, 33%, and 18% of the treatments for the columns DL 75, LA-15, and EC-50W, respectively. The latter column was statistically different from the two others. However, general patient satisfaction was high, with visual analogue scale scores of 8.8, 8.7, and 8.9 for DL-75, LA-15, and EC 50W, respectively. CONCLUSIONS: Side effects were noted quite frequently during and after LDL apheresis, although significantly there were fewer when the EC-50W column was used after apheresis treatment. Patient satisfaction with the LDL apheresis treatment was high with all columns. PMID- 21262507 TI - Lipoprotein-associated phospholipase A2 mass and activity in children with heterozygous familial hypercholesterolemia and unaffected siblings: effect of pravastatin. AB - BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is an independent risk factor of cardiovascular disease and a target of treatment. Lp PLA(2) levels in children have not been previously reported. The effect of statin therapy on Lp-PLA(2) mass and activity in children with familial hypercholesterolemia (FH) is also not known. METHODS: Lp-PLA(2) mass and activity levels were measured at baseline and after 2 years in 178 children with FH randomized to pravastatin or placebo and in 78 unaffected and untreated siblings. At the end of the randomized period, all FH children were then placed on pravastatin for an additional 2 years, and Lp-PLA(2) mass and activity levels were correlated with changes in carotid intima-media thickness during 4 years of follow-up. RESULTS: Baseline levels of Lp-PLA(2) mass and activity were significantly greater in children with FH compared with unaffected siblings (mass: 240.3 +/- 41.6 vs 222.1 +/- 36.5 ng/mL, P = .002; activity: 205.7 +/- 41.6 vs 124.3+/-23.0 nmol/min/mL, P < .0001). In the randomized FH cohort, after 2 years treatment, Lp-PLA(2) mass (217.8 +/- 35.0 vs 231.5 +/- 34.8 ng/mL, P = .001) and activity (178.8 +/- 37.3 vs 206.2 +/- 33.5 nmol/min/mL, P < .0001) were significantly reduced by pravastatin compared with placebo. Change in Lp-PLA(2) activity was related to change in low-density lipoprotein cholesterol (pravastatin: r = 0.53, P < .0001, placebo: r = 0.23, P < .001) but change in Lp PLA(2) mass was not related to change in low-density lipoprotein cholesterol. Baseline levels of Lp-PLA(2) mass and activity were not significantly associated with carotid intima-media thickness at baseline or at 4 years. CONCLUSION: Lp PLA(2) mass and activity are significantly elevated in children with heterozygous FH compared with unaffected siblings and are significantly reduced by pravastatin therapy. PMID- 21262508 TI - The combined effect of hypothyroidism and hyperlipoproteinemia. PMID- 21262509 TI - A working memory account for spatial-numerical associations. AB - Several psychophysical and neuropsychological investigations have suggested that the mental representation of numbers takes the form of a number line along which magnitude is positioned in ascending order according to our reading habits. A longstanding debate is whether this spatial frame is triggered automatically as intrinsic part of the number semantics or whether it constitutes a short-term representation constructed during task execution. Although several observations clearly favor the working memory account, its causal involvement has not yet been demonstrated. In two experiments we show that information stored in working memory get spatially coded in function of its ordinal position in the sequence and that the spatial-numerical associations typically observed in number categorization tasks draw upon this mechanism. PMID- 21262510 TI - Reliability of TMS-related measures of tibialis anterior muscle in patients with chronic stroke and healthy subjects. AB - A lack of normative data for transcranial magnetic stimulation (TMS)-related measures of the lower limb muscles in patients with stroke prevents us from understanding whether changes in TMS-related measures are induced by treatment or are due to their variability and/or the natural evolution of the disease. The purpose of this study was to determine the reliability of three TMS-related measures: motor threshold (MT), motor evoked potential latency (MEP Lat) and MEP amplitude (MEP Amp), linked to the corticospinal control of the tibialis anterior (TA) muscle in sixteen patients with chronic stroke and in sixteen aged-matched healthy subjects. Test-retest reliability was estimated using the intraclass correlation coefficient (ICC) with its 95% confidence interval (95% CI) and standard error of measurement (SEM). In healthy subjects the reliability of all the TMS-related measures yielded an ICC>=0.75. Similar reproducibility levels were found in patients with chronic stroke, with the exception of MEP Amp on the paretic side (ICC=0.38). These results suggest that the TMS-related measures investigated are reliable both in healthy subjects and, with the exception of MEP Amp on the paretic side, in patients with chronic stroke. PMID- 21262511 TI - Editorial comment. PMID- 21262512 TI - Preliminary experience with external ureteropelvic stent: alternative to double-j stent in laparoscopic pyeloplasty in children. AB - PURPOSE: We assessed whether an external ureteropelvic stent was a feasible and safe alternative to Double-J(r) stent after laparoscopic pyeloplasty in children, thus avoiding a second general anesthesia. MATERIALS AND METHODS: Our study included 22 concurrent age matched children who underwent retroperitoneal laparoscopic pyeloplasty between 2000 and 2008. In group 1 an external ureteropelvic stent was inserted through the renal pelvis, then clamped on postoperative day 2. In group 2 a Double-J stent was antegradely inserted. The ureteropelvic stent was removed at the outpatient clinic on day 10, while the Double-J stent was removed under general anesthesia at 1 month. We retrospectively compared operative time, hospital stay, intraoperative and postoperative complications, and followup. RESULTS: Mean+/-SD age at surgery was 31+/-9 months in group 1 and 37+/-12 months in group 2. Mean+/-SD operative time was slightly shorter in group 1 (190+/-40 minutes) than in group 2 (205+/-23 minutes). No intraoperative complications were encountered during placement of stent. Mean+/-SD hospital stay was 2.18+/-1.20 days in group 1 and 2.45+/-0.54 days in group 2. No postoperative complications were reported in group 1. The Double-J stent was noted in the posterior urethra in 1 patient in group 2, requiring cystoscopic repositioning. No patient had urinary tract infection. Median followup was 34 months (range 22 to 56) in group 1 and 35 months (16 to 72) in group 2. CONCLUSIONS: The feasibility of external ureteropelvic stenting after laparoscopic pyeloplasty will pave the way to minimizing the use of Double J stenting and eliminating a second general anesthesia for catheter removal. PMID- 21262513 TI - Interaction of Lamb mode (A(o)) with structural discontinuity and generation of "Turning modes" in a T-joint. AB - In the present work, the interaction of the fundamental anti-symmetric guided Lamb mode (A(o)) with a structural discontinuity in a composite structure was studied through Finite Element numerical simulations and experiments. The structural component selected for this study was a T-joint section made from glass/epoxy material. This co-cured composite structure is made-up of an upper shell (skin) and a spar as the sub-components. It was observed that when A(o) mode interacts with the junction (structural discontinuity) of these sub components, a mode-converted S(o) mode is generated. Experiments were conducted using air-coupled ultrasound to validate the numerical simulations. The back propagating "Turning modes", which propagate from the thin region to the spar web and vice versa, were also numerically simulated and experimentally verified. PMID- 21262514 TI - Dengue virus PrM/M proteins fail to show pH-dependent ion channel activity in Xenopus oocytes. AB - The transmembrane domains (TMDs) of dengue virus type-1 M protein (DENV-1M) were reported to form cation-selective channels in artificial lipid bilayers. We further explored this observation using the two-electrode voltage clamp (TEVC) method on the Xenopus laevis oocytes expressing DENV PrM and M proteins. Using myc epitope tagged M proteins, M was first shown to adopt its predicted native topology in mammalian cells when expressed on its own. The recombinant proteins were then successfully expressed on the surface of Xenopus oocytes. Using influenza A M2 (Inf A/M2) protein as a control, we measured the conductance of oocytes expressing DENV proteins under hyperpolarized or low-pH conditions. Inf A/M2 showed pH-dependent, amantadine-sensitive channel activity that was consistent with previously published reports. However, no activity was detected for DENV proteins. We conclude that DENV PrM and M proteins do not show pH activated ion channel activity. PMID- 21262515 TI - Neonatal rhesus monkey is a potential animal model for studying pathogenesis of EV71 infection. AB - Data from limited autopsies of human patients demonstrate that pathological changes in EV71-infected fatal cases are principally characterized by clear inflammatory lesions in different parts of the CNS; nearly identical changes were found in murine, cynomolgus and rhesus monkey studies which provide evidence of using animal models to investigate the mechanisms of EV71 pathogenesis. Our work uses neonatal rhesus monkeys to investigate a possible model of EV71 pathogenesis and concludes that this model could be applied to provide objective indicators which include clinical manifestations, virus dynamic distribution and pathological changes for observation and evaluation in interpreting the complete process of EV71 infection. This induced systemic infection and other collected indicators in neonatal monkeys could be repeated; the transmission appears to involve infecting new monkeys by contact with feces of infected animals. All data presented suggest that the neonatal rhesus monkey model could shed light on EV71 infection process and pathogenesis. PMID- 21262516 TI - Deletion analysis of the 3' long terminal repeat sequence of plant retrotransposon Tto1 identifies 125 base pairs redundancy as sufficient for first strand transfer. AB - Retroviruses and many retrotransposons are flanked by sequence repeats called long terminal repeats (LTRs). These sequences contain a promoter region, which is active in the 5' LTR, and transcription termination signals, which are active in the LTR copy present at the 3' end. A section in the middle of the LTR, called Redundancy region, occurs at both ends of the mRNA. Here we show that in the copia type retrotransposon Tto1, the promoter and terminator functions of the LTR can be supplied by heterologous sequences, thereby converting the LTR into a significantly shorter sub-terminal repeat. An engineered Tto1 element with 125 instead of the usual 574 base pairs repeated in the 5' and 3' region can still promote strand transfer during cDNA synthesis, defining a minimal Redundancy region for this element. Based on this finding, we propose a model for first strand transfer of Tto1. PMID- 21262517 TI - Interaction between Core protein of classical swine fever virus with cellular IQGAP1 protein appears essential for virulence in swine. AB - Here we show that IQGAP1, a cellular protein that plays a pivotal role as a regulator of the cytoskeleton interacts with Classical Swine Fever Virus (CSFV) Core protein. Sequence analyses identified residues within CSFV Core protein (designated as areas I, II, III and IV) that maintain homology to regions within the matrix protein of Moloney Murine Leukemia Virus (MMLV) that mediate binding to IQGAP1 [EMBO J, 2006 25:2155]. Alanine-substitution within Core regions I, II, III and IV identified residues that specifically mediate the Core-IQGAP1 interaction. Recombinant CSFV viruses harboring alanine substitutions at residues (207)ATI(209) (I), (210)VVE(212) (II), (213)GVK(215) (III), or (232)GLYHN(236) (IV) have defective growth in primary swine macrophage cultures. In vivo, substitutions of residues in areas I and III yielded viruses that were completely attenuated in swine. These data shows that the interaction of Core with an integral component of cytoskeletal regulation plays a role in the CSFV cycle. PMID- 21262518 TI - Entry of a heparan sulphate-binding HRV8 variant strictly depends on dynamin but not on clathrin, caveolin, and flotillin. AB - The major group human rhinovirus type 8 can enter cells via heparan sulphate. When internalized into ICAM-1 negative rhabdomyosarcoma (RD) cells, HRV8 accumulated in the cells but caused CPE only after 3 days when used at high MOI. Adaptation by three blind passages alternating between RD and HeLa cells resulted in variant HRV8v with decreased stability at acidic pH allowing for productive infection in the absence of ICAM-1. HRV8v produced CPE at 10 times lower MOI within 1 day. Confocal fluorescence microscopy colocalization and the use of pharmacological and dominant negative inhibitors revealed that viral uptake is clathrin, caveolin, and flotillin independent. However, it is blocked by dynasore, amiloride, and EIPA. Furthermore, HRV8v induced FITC-dextran uptake and colocalized with this fluid phase marker. Except for the complete inhibition by dynasore, the entry pathway of HRV8v via HS is similar to that of HRV14 in RD cells that overexpress ICAM-1. PMID- 21262519 TI - Enter the kill zone: initiation of death signaling during virus entry. AB - Infection of host cells by a variety of viruses results in programmed cell death or apoptosis. In many cases, early events in virus replication that occur prior to synthesis of viral proteins and replication of viral genomes directly or indirectly activate signaling pathways that culminate in cell death. Using examples of viruses for which prodeath signaling is better defined, this review will describe how cell entry steps including virus attachment to receptors, virus uncoating in endosomes, and events that occur following membrane penetration lead to apoptosis. The relevance and physiologic consequences of early induction of prodeath signaling to viral pathogenesis also will be discussed. PMID- 21262520 TI - Energy minimization strategies and renewable energy utilization for desalination: a review. AB - Energy is a significant cost in the economics of desalinating waters, but water scarcity is driving the rapid expansion in global installed capacity of desalination facilities. Conventional fossil fuels have been utilized as their main energy source, but recent concerns over greenhouse gas (GHG) emissions have promoted global development and implementation of energy minimization strategies and cleaner energy supplies. In this paper, a comprehensive review of energy minimization strategies for membrane-based desalination processes and utilization of lower GHG emission renewable energy resources is presented. The review covers the utilization of energy efficient design, high efficiency pumping, energy recovery devices, advanced membrane materials (nanocomposite, nanotube, and biomimetic), innovative technologies (forward osmosis, ion concentration polarization, and capacitive deionization), and renewable energy resources (solar, wind, and geothermal). Utilization of energy efficient design combined with high efficiency pumping and energy recovery devices have proven effective in full-scale applications. Integration of advanced membrane materials and innovative technologies for desalination show promise but lack long-term operational data. Implementation of renewable energy resources depends upon geography-specific abundance, a feasible means of handling renewable energy power intermittency, and solving technological and economic scale-up and permitting issues. PMID- 21262521 TI - Removal of petroleum pollutants and monitoring of bacterial community structure in a membrane bioreactor. AB - The long-term operational stability (159 d) in removal of organics and ammonia from synthetic wastewater was investigated. The experiment was carried out in two identical plug flow membrane bioreactors (MBR) (each with a submerged A4 Kubota membrane) operated under aerobic conditions. The vacuum distillate of a crude oil fraction in the emulsified state, which was used to model the petroleum pollutants, was added into the feed medium. The performance of biological treatment was evaluated by physicochemical analyses such as nitrogen forms, COD, and BOD. Additionally, monitoring of PAHs in the wastewaters was performed using HPLC-diode array detector. Moreover, the community structure of bacteria was analyzed by polymerase chain reaction-denaturing gradient gel electrophoresis. The MBR treatment was very effective with reduction by more than 90% of COD and Total Organic Carbon. Nearly complete removal of petroleum originated non-polar micropollutants was observed. The influence of the highest dosage of petroleum pollutants (1000 MULL(-1)) on the bacterial community was noted. PMID- 21262522 TI - Increased genetic diversity of Viola tricolor L. (Violaceae) in metal-polluted environments. AB - Changes in DNA sequences affecting cryptic intraspecific variability are very important mechanisms of plant microevolutionary processes, initiating species diversification. In polluted environments, intra- and interpopulation changes at the molecular level proceed rapidly and lead to the formation of new ecotypes in a relatively short time. We used ISSR PCR fingerprinting data to analyze the genetic diversity and genetic structure of seven populations of Viola tricolor: four growing on soil contaminated with heavy metals (Zn, Pb, Cd; waste heaps) and three from control soil. The populations from the polluted sites showed higher genetic polymorphism (%(poly)=84%) and gene diversity (H(T)=0.1709) than the control populations (%(poly)=75% and H(T)=0.1448). The number of private markers we detected within metallicolous (MET) populations was more than double that found within non-metallicolous (NON) populations (15 vs. 7). The STRUCTURE and UPGMA analyses showed clear genetic differences between the NON and MET populations. Based on broad analyses of the genetic parameters, we conclude that the effect of these polluted environments on the genetic diversity of the MET populations, separating them from the NON populations, is evidence of microevolutionary processes at species level, leading to species divergence and the emergence of local ecotypes better adapted to their different environments. PMID- 21262523 TI - Comparative effectiveness of mixed organic substrates to mushroom compost for treatment of mine drainage in passive bioreactors. AB - Bioreactors are one possible best sustainable technology to address the mine impacted water problems. Several prospective substrates (mushroom compost, cow manure, sawdust, wood chips, and cut rice straw) were characterized for their ability to serve as a source of food and energy for sulfate-reducing bacteria. Twenty bench-scale batch bioreactors were then designed and set up to investigate relative effectiveness of various mixtures of substrates to that of mushroom compost, the most commonly used substrate in field bioreactors, for treating mine drainage with acidic (pH 3) and moderate pH (pH 6). Overall, reactive mixtures showed satisfactory performances in generating alkalinity, reducing sulfate and removing metals (Al>Fe>Mn) (up to 100%) at both pH conditions, for all substrates. The mixture of sawdust and cow manure was found as the most effective whereas the mixture containing 40% cut rice straw gave limited efficiency, suggesting organic carbon released from this substrate is not readily available for biodegradation under anaerobic conditions. The mushroom compost-based bioreactors released significant amount of sulfate, which may raise a more concern upon the start-up of field-scale bioreactors. The correlation between the extent of sulfate reduction and dissolved organic carbon/SO(4)(2-) ratio was weak and this indicates that the type of dissolved organic carbon plays a more important role in sulfate reduction than the absolute concentration and that the ratio is not sensitive enough to properly describe the relative effectiveness of substrate mixtures. PMID- 21262524 TI - Ungulate biogeography, statistical methods, and the proficiency of Middle Stone Age hunters. PMID- 21262525 TI - Successful treatment of refractory acute GVHD complicated by severe intestinal transplant-associated thrombotic microangiopathy using recombinant thrombomodulin. PMID- 21262526 TI - In vivo clearance and metabolism of recombinant activated factor VII (rFVIIa) and its complexes with plasma protease inhibitors in the liver. AB - INTRODUCTION: Recombinant activated factor VII (rFVIIa, NovoSeven(r)) is injected intravenously for the treatment of haemophilia patients with inhibitory antibodies. In plasma, rFVIIa forms complexes with protease inhibitors, primarily antithrombin III (ATIII). The liver is believed to be involved in clearance of rFVIIa, however, it is not known whether the liver is also involved for the clearance of the rFVIIa-ATIII complex. In this study, we explored the fate of intravenously injected rFVIIa from plasma to the hepatic lysosomes. MATERIALS AND METHODS: A novel method using magnetic chromatography was used to isolate catabolic organelle (CO) fractions from mouse liver following injection of superparamagnetic dextran (SPD)-coated iron oxide particles and rFVIIa. The effect of co-circulating SPD particles on rFVIIa pharmacokinetic (PK) parameters was evaluated by ELISA. Cryo-immuno transmission electron microscopy (TEM) was used to study hepatic distribution of SPD particles and rFVIIa. The isolated hepatic CO fractions were characterized using Western Blotting (WB). RESULTS: Cryo-immuno TEM of the liver confirmed hepatic co-localisation of SPD particles and rFVIIa in identical endosomes and lysosomes of both hepatocytes and Kupffer cells. SPD particles did not affect the PK parameters of rFVIIa. WB analysis of plasma and CO fractions detected rFVIIa as the full-length protein and also in high molecular weight (HMW) complexes with ATIII and alpha-2 macroglobulin (alpha 2M). CONCLUSIONS: Following injection, both hepatocytes and Kupffer cells appeared to be involved in the hepatic clearance and metabolism of both full length rFVIIa and rFVIIa in complex with at least two plasma protease inhibitors; ATIII and alpha-2M. PMID- 21262527 TI - Acetylthiocholine (ATC)--cleaving cholinesterase (ChE) activity as a potential biomarker of pesticide exposure in the Manila clam, Ruditapes philippinarum, of Korea. AB - The acetylthiocholine (ATC) - cleaving cholinesterase (ChE) activity in Manila clam, which is widely distributed throughout the coastal environment of Korea, was assayed as a potentially useful biomarker of organophosphorous pesticides (OPs). A clear dose-response relationship was determined between inhibited ChE in adductor muscle of clams and four OPs (methidathion, chlorpyrifos, diazinon, IBP) which are heavily used OPs in Korea. The measured EC(50)-24 h values of methidathion, chlorpyrifos, diazinon, and IBP for Ruditapes philippinarum were 7.16 MUg l(-1), 0.34 mg l(-1), 3.01 mg l(-1), and 3.41 mg l(-1), respectively. In field studies, ChE activity in Manila clams collected from 23 stations in the mid western coastal region demonstrated spatial variation with statistical differences. These results suggest that ChE activity in R. philippinarum is a potential biomarker for assessing organophosphorous pesticide contamination in coastal environments. PMID- 21262528 TI - Angiogenesis in ischemic tissue produced by spheroid grafting of human adipose derived stromal cells. AB - Stem cells offer significant therapeutic promise for the treatment of ischemic disease. However, stem cells transplanted into ischemic tissue exhibit limited therapeutic efficacy due to poor engraftment in vivo. Several strategies for improving the survival and engraftment of stem cells in ischemic tissue have been developed including transplantation in combination with growth factor delivery, genetic modification of stem cells, and the use of cell-transplantation scaffolds. Here, we demonstrate that human adipose-derived stromal cells (hADSCs) cultured and grafted as spheroids exhibit improved therapeutic efficacy for ischemia treatment. hADSCs were cultured in monolayer or spheroids. Spheroid cultures were more effective in preconditioning hADSCs to a hypoxic environment, upregulating hypoxia-adaptive signals (i.e., stromal cell-derived factor-1alpha and hypoxia-inducible factor-1alpha), inhibiting apoptosis, and enhancing secretion of both angiogenic and anti-apoptotic factors (i.e., hepatocyte growth factor, vascular endothelial growth factor, and fibroblast growth factor 2) compared to monolayer cultures. Moreover, cell harvesting following spheroid cultures avoided damage to extracellular matrices due to harsh proteolytic enzyme treatment, thereby preventing anoikis (apoptosis induced by a lack of cell-matrix interaction). Following intramuscular transplantation to ischemic hindlimbs of athymic mice, hADSC spheroids showed improved cell survival, angiogenic factor secretion, neovascularization, and limb survival as compared to hADSCs grafted as dissociated cells. Taken together, spheroid cultures precondition hADSCs to a hypoxic environment, and grafting hADSCs as spheroids to ischemic limbs improves therapeutic efficacy for ischemia treatment due to enhanced cell survival and paracrine effects. Spheroid-based cell delivery could be a simple and effective strategy for improving stem cell therapy for ischemic diseases, eliminating the need for growth factor delivery, biomaterial scaffolds or genetic modification. PMID- 21262529 TI - Flotillin-dependent endocytosis and a phagocytosis-like mechanism for cellular internalization of disulfide-based poly(amido amine)/DNA polyplexes. AB - Extensive research is currently performed on designing safe and efficient non viral carriers for gene delivery. To increase their efficiency, it is essential to have a thorough understanding of the mechanisms involved in cellular attachment, internalization and intracellular processing in target cells. In this work, we studied in vitro the cellular dynamics of polyplexes, composed of a newly developed bioreducible poly(amido amine) carrier, formed by polyaddition of N,N-cystamine bisacrylamide and 1-amino-4-butanol (p(CBA-ABOL)) on retinal pigment epithelium (RPE) cells, which are attractive targets for ocular gene therapy. We show that these net cationic p(CBA-ABOL)/DNA polyplexes require a charge-mediated attachment to the sulfate groups of cell surface heparan sulfate proteoglycans in order to be efficiently internalized. Secondly, we assessed the involvement of defined endocytic pathways in the internalization of the polyplexes in ARPE-19 cells by using a combination of endocytic inhibitors, RNAi depletion of endocytic proteins and live cell fluorescence colocalization microscopy. We found that the p(CBA-ABOL) polyplexes enter RPE cells both via flotillin-dependent endocytosis and a PAK1 dependent phagocytosis-like mechanism. The capacity of polyplexes to transfect cells was, however, primarily dependent on a flotillin-1-dependent endocytosis pathway. PMID- 21262530 TI - Multifunctional silica nanotubes for dual-modality gene delivery and MR imaging. AB - This work demonstrated the development of multifunctional silica nanotubes (SNT) by functionalization of their inner void and outer surface with magnetic fluorescence nanocomposites and cationic polymers, respectively. The successful construction of BPEI-SNT was established by electron energy loss spectroscopy in conjugation with standard analytical tools. The mean fluorescence intensity in a FACS assay, a luciferase gene expression assay and a confocal fluorescence study demonstrated the efficacy of BPEI-SNT as a gene delivery vector. Endocytotic uptake was also demonstrated by the colocalization of LysoTracker Red((r)) and green fluorescent quantum dots. Moreover, enhanced magnetic resonance imaging revealed the potential of the BPEI-SNT nanocomposite to act as a dual-modality nano-device. PMID- 21262531 TI - High-quality water-soluble and surface-functionalized upconversion nanocrystals as luminescent probes for bioimaging. AB - Rare-earth upconversion nanophosphors (UCNPs) have great potential to become excellent biological luminescent labels for fluorescence bioimaging. However, it is still difficult to directly synthesize high-quality water-soluble UCNPs bearing appropriate functional groups using a one-step synthetic strategy. Herein, we report a one-step synthetic strategy for high-quality water-soluble and surface-functionalized UCNPs using a hydrothermal reaction assisted by binary cooperative ligands (HR-BCL). In this system, 6-aminohexanoic acid and oleate were introduced to control nuclear generation and crystal growth of small nanoparticles. The UCNPs synthesized here showed high crystalline and intense upconversion luminescence emission. Fourier-transform infrared and nuclear magnetic resonance spectroscopy indicated that 6-aminohexanoic acid and oleate cooperate as surface ligands to co-control the surface of UCNPs. Thus, the water solubility of the as-prepared UCNPs can be tuned by changing the molar ratio of 6 aminohexanoic acid to oleate. The AA-modified UCNPs provided a free amine content of (6.0 +/- 0.2) * 10(-5) mol/g, which renders them dispersible in aqueous solution and allows further conjugation with folic acid (FA) for targeted bioimaging. Furthermore, the amine-functionalized UCNPs show intense near infrared upconversion luminescence and were successfully applied in the lymphatic capillary bioimaging of small animals with a high signal-to-noise ratio, suggesting that these surface-functionalized UCNPs are promising candidates for luminescent biolabels. PMID- 21262532 TI - Integrative design of a poly(ethylene glycol)-poly(propylene glycol)-alginate hydrogel to control three dimensional biomineralization. AB - A mineralized polymeric matrix has been extensively studied to understand biomineralization processes and to further regulate phenotypic functions of various cells involved in osteogenesis and physiological homeostasis. It has been often proposed that several matrix variables including charge density, hydrophobicity, and pore size play vital roles in modulating composition and morphology of minerals formed within a three dimensional (3D) matrix. However, the aspects have not yet been systematically examined because a tool enabling the independent control of the matrix variables is lacking. This study presents an advanced integrative strategy to control morphology and composition of biominerals with matrix properties, by using a hydrogel formulated to independently control charge density, hydrophobicity, and porosity. The hydrogel consists of poly(ethylene glycol) monomethacrylate (PEGmM), poly(propylene glycol) monomethacrylate (PPGmM), and methacrylic alginate (MA), so the charge density and hydrophobicity of the hydrogel can be separately controlled with mass fractions of MA and PPGmM. Also, hydrogels which present only nano-sized pores, termed nanoporous hydrogels, are lyophilized and rehydrated to prepare the hydrogels containing micro-sized pores, termed microporous hydrogels. We find that increasing the mass fractions of MA and PPGmM of the microporous hydrogel promotes the growth of apatite layers because of the increases in the charge density, hydrophobicity and pore size. In contrast, increasing mass fractions of MA and PPGmM of the nanoporous hydrogel enhances the formation of calcium carbonate minerals. The dependency of the mineralization on hydrogel variables is related to the change in supersaturation of mineral ions. Overall, the results of this study will be highly useful to better understand the interplay of matrix variables in biomineralization and to design a wide array of mineralized matrix potentially used in cell therapies and tissue engineering. PMID- 21262533 TI - Systemic distribution, nuclear entry and cytotoxicity of amorphous nanosilica following topical application. AB - Currently, nanomaterials (NMs) with particle sizes below 100 nm have been successfully employed in various industrial applications in medicine, cosmetics and foods. On the other hand, NMs can also be problematic in terms of eliciting a toxicological effect by their small size. However, biological and/or cellular responses to NMs are often inconsistent and even contradictory. In addition, relationships among NMs physicochemical properties, absorbency, localization and biological responses are not yet well understood. In order to open new frontiers in medical, cosmetics and foods fields by the safer NMs, it is necessary to collect the information of the detailed properties of NMs and then, build the prediction system of NMs safety. The present study was designed to examine the skin penetration, cellular localization, and cytotoxic effects of the well dispersed amorphous silica particles of diameters ranging from 70 nm to 1000 nm. Our results suggested that the well-dispersed amorphous nanosilica of particle size 70 nm (nSP70) penetrated the skin barrier and caused systemic exposure in mouse, and induced mutagenic activity in vitro. Our information indicated that further studies of relation between physicochemical properties and biological responses are needed for the development and the safer form of NMs. PMID- 21262534 TI - The impact of nanoparticle ligand density on dendritic-cell targeted vaccines. AB - Dendritic-cell (DC) targeted antigen delivery systems hold promise for enhancing vaccine efficacy and delivery of therapeutics. However, it is not known how the number and density of targeting ligands on such systems may affect DC function and subsequent T cell response. We modified the surface of biodegradable nanoparticles loaded with antigen with different densities of the mAb to the DC lectin DEC-205 receptor and assessed changes in the cytokine response of DCs and T cells. DEC-205 targeted nanoparticles unexpectedly induced a differential cytokine response that depended on the density of ligands on the surface. Strikingly, nanoparticle surface density of DEC-205 mAb increased the amount of anti-inflammatory, IL-10, produced by DCs and T cells. Boosting mice with DEC-205 targeted OVA-nanoparticles after immunization with an antigen in CFA induced a similar pattern of IL-10 response. The correlation between DC production of IL-10 as a function of the density of anti-DEC-205 is shown to be due to cross-linking of the DEC-205 receptor. Cross-linking also increased DC expression of the scavenger receptor CD36, and blockade of CD36 largely abrogated the IL-10 response. Our studies highlight the importance of target ligand density in the design of vaccine delivery systems. PMID- 21262536 TI - Patterns of cancer invasion revealed by QDs-based quantitative multiplexed imaging of tumor microenvironment. AB - Tumor growth and progression depends on their microenvironment, which undergoes constant co-evolution because of the dynamic tumor-stormal interactions. Such co evolution has long been under appreciated due to the lack of appropriate technology platforms to simultaneously reveal these complex interactions. Here we report on a quantum dots based multiplexed imaging and spectrum analysis technology to simultaneously study major components of tumor stroma, including type IV collagen, tumor angiogenesis, macrophages infiltration and tissue destructive proteolytic enzyme matrix metalloproteinase 9. The new technology revealed a panoramic picture of the tempo-spatial co-evolution of tumor cells and their stroma at the architecture level. Four patterns of tumor invasion with distinctive co-evolution features were identified as Washing pattern, Ameba-like pattern, Polarity pattern and Linear pattern. This quantum dots based multiplexed technology could help gain new insight into the complex process of tumor invasion, and formulate new anti-cancer strategies. PMID- 21262535 TI - Nucleation and growth of mineralized bone matrix on silk-hydroxyapatite composite scaffolds. AB - We describe a composite hydroxyapatite (HA)-silk fibroin scaffold designed to induce and support the formation of mineralized bone matrix by human mesenchymal stem cells (hMSCs) in the absence of osteogenic growth factors. Porous three dimensional silk scaffolds were extensively used in our previous work for bone tissue engineering and showed excellent biodegradability and biocompatibility. However, silk is not an osteogenic material and has a compressive stiffness significantly lower than that of native bone. In the present study, we explored the incorporation of silk sponge matrices with HA (bone mineral) micro-particles to generate highly osteogenic composite scaffolds capable of inducing the in vitro formation of tissue-engineered bone. Different amounts of HA were embedded in silk sponges at volume fractions of 0%, 1.6%, 3.1% and 4.6% to enhance the osteoconductive activity and mechanical properties of the scaffolds. The cultivation of hMSCs in the silk/HA composite scaffolds under perfusion conditions resulted in the formation of bone-like structures and an increase in the equilibrium Young's modulus (up to 4-fold or 8-fold over 5 or 10 weeks of cultivation, respectively) in a manner that correlated with the initial HA content. The enhancement in mechanical properties was associated with the development of the structural connectivity of engineered bone matrix. Collectively, the data suggest two mechanisms by which the incorporated HA enhanced the formation of tissue engineered bone: through osteoconductivity of the material leading to increased bone matrix production, and by providing nucleation sites for new mineral resulting in the connectivity of trabecular-like architecture. PMID- 21262538 TI - Can onset and recovery in depression be predicted by temperament? A systematic review and meta-analysis. AB - BACKGROUND: Behavioural inhibition and more specifically harm avoidance temperament dimension (HA) has been found to be associated with depression. Temperament and Character Inventory (TCI) by Cloninger et al. is the most widely used instrument in the assessment of temperament. The aims of the present study were to explore 1) if current or future depressive symptoms in non-clinical adult sample can be explained by TCI temperament dimensions, and 2) if recovery from major depression (MDD) during the acute phase of treatment is predictable by TCI temperament dimensions. METHOD: Literature search from eight databases. Systematic review and meta-analysis. RESULTS: High HA was associated with current depressive symptoms in 11/12 studies and with depressive trait in 3/4 studies. In MDD studies, a consistent negative change in HA was found during treatment and this change was even more clearly associated with treatment response. LIMITATIONS: The studies with general population samples were heterogeneous in methodology. Most of the intervention studies were of case-control design. CONCLUSIONS: HA is indisputably associated with the risk and treatment response in depression. PMID- 21262537 TI - Cellular and extracellular programming of cell fate through engineered intracrine , paracrine-, and endocrine-like mechanisms. AB - A cell's fate is tightly controlled by its microenvironment. Key factors contributing to this microenvironment include physical contacts with the extracellular matrix and neighboring cells, in addition to soluble factors produced locally or distally. Alterations to these cues can drive homeostatic processes, such as tissue regeneration/wound healing, or may lead to pathologic tissue dysfunction. In vitro models of cell and tissue microenvironments are desirable for enhanced understanding of the biology and ultimately for improved treatment. However, mechanisms to exert specific control over cellular microenvironments remains a significant challenge. Genetic modification has been used but is limited to products that can be manufactured by cells and release kinetics of therapeutics cannot easily be controlled. Herein we describe a non genetic approach to engineer cells with an intracellular depot of phenotype altering agent/s that can be used for altering cell fate via intracrine-, paracrine-, and endocrine-like mechanisms. Specifically, we show that human mesenchymal stem cells (MSCs) can be engineered with poly lactide-co-glycolic acid (PLGA) particles containing dexamethasone, which acts on cytoplasmic receptors. The controlled release properties of these particles allowed for sustained intracellular and extracellular delivery of agent to promote differentiation of particle-carrying cells, as well as neighboring cells and distant cells that do not contain particles. PMID- 21262539 TI - Stability of prospective memory deficits in individuals with schizotypal personality traits. PMID- 21262540 TI - Differential associations between schizotypy facets and emotion traits. AB - Although emotional deficits in schizotypy have been reported, the exact nature of these deficits is not well understood. The goal of the current research was to further differentiate possible emotion deficits in schizotypy. In the current study, individuals with elevated social anhedonia (SocAnh; n=54) and elevated perceptual aberration/magical ideation (PerMag; n=27) were compared to control participants (n=304) on measures of attention to either positive or negative affect, level of anticipatory versus consummatory pleasure, and on the influence of negative mood on judgment of future risk. SocAnh was associated with decreased attention to positive emotions. At the same time, SocAnh was associated with both decreased anticipatory and decreased consummatory pleasure. In addition, in contrast to the other groups, there was no association in the SocAnh group between current negative mood and performance on a judgment task. In contrast to SocAnh, PerMag was associated with increased attention to negative emotions. Overall, these results suggest that SocAnh is associated with decreased attention to and experience of positive emotions and that PerMag is associated with increased attention to negative emotions. PMID- 21262542 TI - Protein kinases JAK and ERK mediate protective effect of interleukin-2 upon ganglion cells of the developing rat retina. AB - Interleukin-2 (IL-2), a prototypical pro-inflammatory cytokine firstly related to T cells differentiation, exerts pleiotrophic functions in several areas of the central nervous system. Previously we had described the neurotrophic roles of this interleukin upon retinal neurons. Therefore, the aim of this work was to investigate the signaling pathways involved in the neuroprotective effect of IL-2 on axotomized RGC. Herein we demonstrated that at postnatal day 2 IL-2 receptor alpha subunit (IL-2Ralpha) is expressed in inner plexiform layer, retinal ganglion cells layer and retinal nerve fibers layer. Moreover, using a model of organotypic retinal explants and rhodamine dextran retrograde labeling for specifically quantify RGC, we showed that IL-2 increased the survival of axotomized RGC after 2 (85.43+/-5.43%) and 5 (50.23%+/-5.32) days in vitro. Western blot analysis demonstrated that IL-2 treatment increased the phosphorilation of both extracellular signal-regulated kinases (ERK)1/2 and AKT (~two fold). However, its neuroprotective effect upon RGC was dependent of Janus kinase (JAK) and ERK1/2 activity but not of AKT activity. Taken together our results showed that the IL-2 neuroprotective action upon RGC in vitro is mediated by JAK and ERK1/2 activation. PMID- 21262541 TI - Coping styles predict responsiveness to cognitive behaviour therapy in psychosis. AB - The study aimed to determine the clinical and neuropsychological predictors of responsiveness to cognitive behavioural therapy for psychosis (CBTp). Sixty patients with schizophrenia or schizoaffective disorder and 25 healthy individuals took part in the study. Thirty patients (25 protocol completers) received CBTp in addition to standard care (SC); 30 patients (18 protocol completers) received SC only. All patients were assessed on symptoms using the Positive and Negative Syndrome Scale (PANSS) and clinical and neuropsychological function before and after CBTp. Symptoms and self-esteem improved to a greater extent in the CBTp+SC than SC control group. Greater pre-therapy coping ability and the self-reflectiveness dimension of cognitive insight at baseline predicted improvement in symptoms in the CBTp+SC group, but not the SC control group, explaining up to 21% of the variance in symptom improvement. Pre-therapy neuropsychological function, duration of illness, clinical insight and gender did not predict CBTp responsiveness. Being able to have a range of coping strategies and reflect on one's experiences while refraining from overconfidence in one's interpretations before therapy is conducive to better CBTp responsiveness. PMID- 21262543 TI - The endocannabinoid arachidonylethanolamide attenuates aspects of lipopolysaccharide-induced changes in energy intake, energy expenditure and hypothalamic Fos expression. AB - Arachidonylethanolamide (AEA), an endocannabinoid, regulates both appetite and the immune system. The present study investigated in the rat the ability of AEA (1mg/kg, s.c.) to attenuate the lipopolysaccharide (LPS)-induced (100MUg/kg, i.p.) changes in metabolic indices and Fos expression within hypothalamic and mesolimbic systems. AEA attenuated LPS-induced fever and hypophagia, abolished LPS-induced decreases in Fos expression within the arcuate and ventromedial nucleus of the hypothalamus, while both AEA and LPS independently increased Fos expression within the nucleus accumbens. These results highlight the importance of hypothalamic and mesolimbic systems in the regulation of appetite and energy partitioning. PMID- 21262544 TI - Systemic amyloidosis presenting as constrictive pericarditis in a young adult. PMID- 21262545 TI - Comparison of CRT and CRT-D in heart failure: systematic review of controlled trials. AB - BACKGROUND: Few studies have directly compared cardiac resynchronisation therapy (CRT) with combined CRT-cardioverter defibrillator therapy (CRT-D) in patients with left ventricular (LV) impairment. We performed a systematic analysis to assess the therapeutic effects of CRT and CRT-D in patients with LV impairment and heart failure. METHODS: The Medline database from 1970 to September 2010 was searched. The major outcome examined was the all-cause death rate. RESULTS: A total of 3404 patients were retrieved from seven studies. Overall, CRT-D reduced all-cause death by 8.42% compared with CRT [odds ratio (OR) 0.52, 95% confidence interval (CI) 0.43-0.81, P=0.001, I(2)=63.9%]. An increased benefit was seen after extended follow-up (after 1 year, OR 0.56, CI 0.41-0.77, P=0.0004, I(2)=64.9%), but not after relatively short follow-up (within 1 year, P=0.11). Results from other endpoints examined, such as death from sudden cardiac death and heart failure, also supported CRT-D treatment. CONCLUSIONS: Evidence from current randomised and non-randomised trials demonstrates some superiorities of CRT-D over CRT, such as all-cause death rate after one-year follow-up and cardiac death, in patients with LV impairment. However, these findings must be verified in larger, randomised, prospective trials, including with extended patient follow up. PMID- 21262546 TI - Identifying novel mutations of NKX2-5 congenital heart disease patients of Chinese minority groups. PMID- 21262547 TI - Brachytherapy with permanent gold grain seeds for squamous cell carcinoma of the lip. AB - PURPOSE: To describe the use of radioactive gold grain implantation for squamous cell carcinoma of the lip. METHODS: Retrospective review of 51 patients treated with permanent gold ((198)Au) grain implant brachytherapy. The seed arrangement delivered a dose of 5500 cGy at 0.5 cm from a single plane. Primary endpoints were local recurrence and cosmetic outcome. RESULTS: Median follow-up was 27 months. Median age was 69 years. The majority (90%) were T1 lesions. None of the patients had evidence of regional lymph node or distant metastasis. Twelve patients had recurrent disease with prior surgery and five patients had previous head and neck radiation. Local control was achieved in 49 patients. Good cosmesis was achieved in 48 patients. Two-year actuarial estimates for local failure-free survival, disease-free survival and overall survival were 97.9%, 94.1% and 87.9%, respectively; no deaths were attributable to lip cancer. CONCLUSIONS: Gold grain interstitial low-dose rate brachytherapy provides excellent local control and cosmesis in patients with squamous cell carcinoma of the lip. This technique provides an excellent option for patients that are elder or live remotely. It is particularly useful for lesions that are small, in previously radiated areas, or treated with prior surgery. PMID- 21262548 TI - Differentiation between hypoxic and non-hypoxic experimental tumors by dynamic contrast-enhanced magnetic resonance imaging. AB - BACKGROUND AND PURPOSE: Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) has been suggested to be a useful method for detecting tumor hypoxia. In this study, we investigated whether DCE-MRI can differentiate between hypoxic and non-hypoxic experimental tumors. MATERIALS AND METHODS: Three tumor models with hypoxic tissue and three tumor models without hypoxic tissue were subjected to DCE-MRI. Parametric images of K(trans) (the volume transfer constant of Gd-DTPA) and v(e) (the fractional distribution volume of Gd-DTPA) were produced by pharmacokinetic analysis of the DCE-MRI series. Tumor oxygenation status was assessed by using a radiobiological assay and a pimonidazole-based immunohistochemical assay. Tumor response to fractionated irradiation (six fractions of 2Gy in 60h) was measured in vitro by using a clonogenic assay. RESULTS: Tumors with hypoxic regions were more resistant to radiation treatment than were tumors without hypoxia. K(trans) was significantly higher for radiation sensitive tumors without hypoxia than for radiation resistant tumors with hypoxic regions, whereas v(e) did not differ significantly between non-hypoxic and hypoxic tumors. CONCLUSION: This study supports the clinical attempts to establish DCE-MRI as a noninvasive method for providing useful biomarkers for personalized radiation therapy. PMID- 21262549 TI - Genetic characterization of the CcpA-dependent, cellobiose-specific PTS system comprising CelB, PtcB and PtcA that transports lactose in Lactococcus lactis IL1403. AB - Lactose metabolism is one of the most important areas of research on Lactic Acid Bacteria (LAB). In rapidly acidifying industrial Lactococcus lactis strains, lactose is transported by a lactose-specific phosphotransferase system (PTS) encoded by a plasmid. However, an alternative lactose catabolic pathway was evidenced in the plasmid-cured, and thus initially lactose-negative L. lactis IL1403. We showed that in this strain the chromosomally-encoded cellobiose specific PTS system comprising the celB, ptcB and ptcA genes is also able to transport lactose. By expression studies in the wild type IL1403 strain and IBB550, its ccpA-deficient derivative, we demonstrated that celB, ptcB and ptcA are tightly regulated by the general catabolite repression system, whereas celB additionally requires the presence of cellobiose to be fully induced. The comparison of expression levels of sugar catabolic genes indicated that the efficiency of CcpA-mediated catabolic repression depends on conservation of the cre sequence, and that in the case of perfect matching with the cre consensus, CcpA still drives a strong repression even under non-repressing conditions. PMID- 21262550 TI - Salmonella Typhimurium internalization is variable in leafy vegetables and fresh herbs. AB - Despite washing and decontamination, outbreaks linked to consumption of fresh or minimally-processed leafy greens have been increasingly reported in recent years. In order to assure the safety of produce it is necessary to gain knowledge regarding the exact routes of contamination. Leaf internalization through stomata was previously reported as a potential route of contamination, which renders food borne pathogens protected from washing and disinfection by sanitizers. In the present study we have examined the incidence (percentage of microscopic fields harboring >= 1 GFP-tagged bacteria) of Salmonella Typhimurium on the surface and underneath the epidermis in detached leaves of seven vegetables and fresh herbs. The incidence of internalized Salmonella varied considerably among the different plants. The highest incidence was observed in iceberg lettuce (81 +/- 16%) and arugula leaves (88 +/- 16%), while romaine (16 +/- 16%) and red-lettuce (20 +/- 15%), showed significantly lower incidence (P < 0.05). Internalization incidence in fresh basil was 46 +/- 12%, while parsley and tomato leaves demonstrated only marginal internalization (1.9 +/- 3.3% and 0.56 +/- 1.36%, respectively). Internalization of Salmonella in iceberg lettuce largely varied (0-100%) through a 2 year survey, with a higher incidence occurring mainly in the summer. These results imply that Salmonella internalization occurs in several leafy vegetables and fresh herbs, other than iceberg lettuce, yet the level of internalization largely varies among plants and within the same crop. Since internalized bacteria may evade disinfection, it is of great interest to identify plants which are more susceptible to bacterial internalization, as well as plant and environmental factors that affect internalization. PMID- 21262551 TI - SigB plays a major role in Listeria monocytogenes tolerance to bile stress. AB - The ability of Listeria monocytogenes to tolerate high levels of bile stress is critical to its successful infection and colonization in the human gastrointestinal tract. L. monocytogenes encodes bile salt hydrolase by a bsh gene which plays a significant role in hydrolyzing high concentrations of bile salt when L. monocytogenes grows under hypoxemic condition. As the bsh promoter contains consensus SigB and PrfA binding sites, we investigated the role of SigB (sigma(B)) and PrfA in L. monocytogenes tolerance against bile stress by comparing the survival of isogenic deletion mutants of L. monocytogenes EGD(DeltasigB), EGD(DeltaprfA) and EGD(DeltaprfADeltasigB) with their parent strain EGD at high levels of bile salt. Our results show that the sigB deletion significantly reduced the MICs of bile salt for EGD(DeltasigB) and EGD(DeltaprfADeltasigB) (2.6% and 2.2% vs 3.5% in wild type strain EGD), while the growth rates of these two sigB deletion mutants (EGD(DeltasigB) and EGD(DeltaprfADeltasigB)) were affected the most in the presence of 3% bile salt. Pre-exposure to alkali (pH 9.0) and osmotic (0.3M NaCl) stresses for a short period of time (30 min) resulted in improved growth of L. monocytogenes as well as its prfA-sigB isogenic mutants even under sublethal concentrations of bile salt, while pre-exposure to acid pH (pH 4.5) failed to provide cross-protection against subsequent bile stress. Furthermore, the sigB gene had more remarkable influence than that of prfA on bsh expression, as much lower levels of bsh transcription were observed in EGD(DeltasigB) and EGD(DeltaprfADeltasigB). Meanwhile, bsh expression in the deletion mutants did not respond to elevated levels of bile salt. These data indicate that sigma(B) might play a crucial role in Listeria survival under bile salt environment in the gastrointestinal tract before its successful colonization, invasion and intracellular propagation. PMID- 21262552 TI - Assessment of a simple function to evaluate the relationship between mass flux reduction and mass removal for organic-liquid contaminated source zones. AB - The efficacy of a simple mass-removal function for characterizing mass-flux reduction/mass-removal behavior for organic-liquid contaminated source zones was evaluated using the data obtained from a series of flow-cell experiments. The standard function, which employs a constant exponent, could not adequately reproduce the non-singular (multi-step) behavior exhibited by the measured data. Allowing the exponent to change as a function of mass removal (as the organic liquid distribution and relative permeability change) produced non-singular relationships similar to those exhibited by the measured data. Four methods were developed to dynamically inform the exponent through use of measurable system indicator parameters. Key factors that mediate the magnitude of mass flux (dilution and source accessibility) were accounted for using measures of source zone cross-sectional area, ganglia-to-pool (GTP) ratio, and relative permeability. The two methods that incorporated only the ganglia-to-pool ratio produced adequate simulations of the observed behavior for early stages of mass removal, but not for later stages. The method that incorporated parameters accounting for the source zone cross-sectional area (i.e., measure of system dilution) and source accessibility (GTP ratio and relative permeability) provided the most representative simulations of the observed data. PMID- 21262553 TI - Helping understand nutritional gaps in the elderly (HUNGER): a prospective study of patient factors associated with inadequate nutritional intake in older medical inpatients. AB - BACKGROUND & AIMS: Malnutrition and poor intake during hospitalisation are common in older medical patients. Better understanding of patient-specific factors associated with poor intake may inform nutritional interventions. The aim of this study was to measure the proportion of older medical patients with inadequate nutritional intake, and identify patient-related factors associated with this outcome. METHODS: Prospective cohort study enrolling consecutive consenting medical inpatients aged 65 years or older. Primary outcome was energy intake less than resting energy expenditure estimated using weight-based equations. Energy intake was calculated for a single day using direct observation of plate waste. Explanatory variables included age, gender, number of co-morbidities, number of medications, diagnosis, usual residence, nutritional status, functional and cognitive impairment, depressive symptoms, poor appetite, poor dentition, and dysphagia. RESULTS: Of 134 participants (mean age 80 years, 51% female), only 41% met estimated resting energy requirements. Mean energy intake was 1220 kcal/day (SD 440), or 18.1 kcal/kg/day. Factors associated with inadequate energy intake in multivariate analysis were poor appetite, higher BMI, diagnosis of infection or cancer, delirium and need for assistance with feeding. CONCLUSIONS: Inadequate nutritional intake is common, and patient factors contributing to poor intake should be considered in designing nutritional interventions. PMID- 21262554 TI - A 700-year record of mercury in avian eggshells of Guangjin Island, South China Sea. AB - Ancient eggshells over the past 700 years were extracted from an ornithogenic sediment profile on Guangjin Island, South China Sea. Based on SEM and nitrogen isotope analyses, we determined that neither post-depositional processes nor seabirds' dietary changes had a large influence on eggshell Hg levels. The historical change of Hg in these eggshells was reconstructed. Eggshell Hg was a marker for past Hg deposition in marine environment. The eggshell Hg showed three small peaks at around 1300AD, 1600 AD and 1700-1750AD and rapid increase since 1800 AD. Before 1970 AD the Hg deposition in the Xisha area had global distribution characteristics, with increased Hg emissions due to global anthropogenic activities in industrial times. However, after 1970 AD, a further sharp increase up to present day occurred, implying that the Hg production center had gradually shifted from Europe and America to Asia. PMID- 21262555 TI - Antiviral therapy for hepatitis B virus-associated hepatocellular carcinoma: potential to reduce the tumor recurrence rates and/or improve overall survival. PMID- 21262556 TI - Unexplained stillbirth versus SIDS: common congenital diseases of the autonomic nervous system--pathology and nosology. AB - OBJECTIVE: To contribute to a more balanced assessment of the morphological substrates underlying unexplained perinatal death and SIDS. METHODS: In-depth histological, immunohistochemical and genetic examinations were performed on the autonomic nervous and cardiac conduction systems in 95 unexpected perinatal deaths, 140 SIDS and 78 controls (44 infants and 34 perinatal death victims). RESULTS: The study revealed the localization and the nature of a variety of specific congenital abnormalities of the autonomic nervous system, central and peripheral, and of the cardiac conduction system that represent the morphological substrates of the pathophysiological mechanism of sudden fetal death and SIDS. CONCLUSIONS: The observation of similar anomalies of the autonomic nervous and the cardiac conduction systems in both unexplained perinatal deaths and SIDS indicates their common congenital nature. Therefore, the definitions of these deaths, currently nosographically distinct, should be unified. PMID- 21262557 TI - Neonatal transport: a review of the current evidence. PMID- 21262558 TI - Adult intussusception secondary to colorectal cancer in a young man: a case report. AB - BACKGROUND: The occurrence of adult intussusception from colorectal cancer in a 27-year-old man is quite uncommon. OBJECTIVES: To raise awareness of the incidence of intussusception in adults, to educate others about the protean manifestations and high association with malignancy of the disease, and to provide treatment recommendations. CASE REPORT: We present a case of a 27-year old man with a non-contributory family history who presented to the Emergency Department multiple times over a 10-month period with vague abdominal complaints. Clinical symptoms ultimately included a 75-lb weight loss, fatigue, mild right sided abdominal pain, and anemia. Computed tomography scan of the abdomen revealed right-sided colocolic intussusception with a lead point. The patient underwent a right hemicolectomy with ileocolic anastomosis. Pathologic evaluation and staging revealed a stage IIIB poorly differentiated adenocarcinoma. Molecular analysis was negative for genetic causes. CONCLUSION: This case demonstrates how intussusception and possible colorectal cancer must be included in the differential diagnosis even in young adults who have persistent abdominal complaints. PMID- 21262559 TI - Reading performance after implantation of a small-aperture corneal inlay for the surgical correction of presbyopia: Two-year follow-up. AB - PURPOSE: To evaluate the change in reading-performance parameters after implantation of the Kamra small-aperture intracorneal inlay over a 2-year follow up. SETTING: University Eye Clinic, Paracelsus Medical University, Salzburg, Austria. DESIGN: Cohort study. METHODS: This study comprised naturally emmetropic presbyopic patients. Bilateral reading acuity, reading distance, reading speed, and the smallest log-scaled sentence were evaluated in a standardized testing procedure using the Salzburg Reading Desk. The minimum postoperative follow-up was 24 months. RESULTS: The study enrolled 32 patients. The reading desk results showed a significant improvement in each parameter tested. After a mean follow-up of 24.2 months +/- 0.8 (SD), the mean reading distance changed from the preoperative value of 48.1 +/- 5.5 cm to 38.9 +/- 6.3 cm (P < .0001), the mean reading acuity at best distance improved from 0.3 +/- 0.14 logRAD to 0.24 +/- 0.11 logRAD (P < .000001), and the mean reading speed increased from 142 +/- 13 words per minute (wpm) to 149 +/- 17 wpm (P=.029). One patient lost 1 line, and 1 patient had no change. The improvement was up to 6 log-scaled lines (mean improvement 2.7 +/- 1.6 lines) in the other 30 patients. CONCLUSIONS: After implantation of the small-aperture intracorneal inlay, there was an improvement in all tested reading performance parameters in emmetropic presbyopic patients; the improvement was the result of an increased depth of field. These 2-year results indicate that the inlay is an effective treatment for presbyopia. PMID- 21262560 TI - Model of anesthesia care that combines anesthesiologists and registered nurses during cataract surgery. AB - PURPOSE: To determine the safety and practicality of a combined anesthesiologist and registered nurse model of anesthesia care in cataract surgery. SETTING: Mayo Clinic, Rochester, Minnesota, USA. DESIGN: Case series. METHODS: This retrospective review comprised consecutive patients having phacoemulsification cataract surgery and peribulbar injection anesthesia combined with propofol intravenous sedation between August 1, 2004, and July 31, 2006. In all cases, anesthesiologist-supervised intravenous propofol sedation during injection anesthesia was followed by registered nurse observation for the remainder of the surgery. Outcome measures were the rate of subsequent anesthesiologist intervention, intraoperative complications, and associated risk factors. Logistic regression models were used to estimate risk for anesthesiologist intervention. RESULTS: The study reviewed 3656 cases. There were no serious medical complications leading to postoperative hospitalization. Fifty-four cases (1.5%) required subsequent intraoperative anesthesiologist intervention. Evaluation of systolic hypertension (40 of 54 cases, 74%) was the most common reason for anesthesiologist intervention. There was no correlation between anesthesiologist intervention and patient age or sex (P=.77 and P=.41, respectively). The risk for anesthesiologist intervention increased 2.2-fold for every 1 unit increase in the American Society of Anesthesiologists Physical Status score (P=.007). CONCLUSION: The monitoring of cataract surgery patients by registered nurses after anesthesiologist-supervised intravenous propofol sedation during injection anesthesia was associated with very low complication and anesthesiologist intervention rates. PMID- 21262561 TI - Photorefractive keratectomy using a 213 nm wavelength solid-state laser in eyes with previous conductive keratoplasty to treat presbyopia: Early results. AB - PURPOSE: To evaluate the efficacy and safety of photorefractive keratectomy (PRK) using a 213 nm wavelength solid-state laser to treat regression in eyes that had previous conductive keratoplasty (CK) for presbyopia. SETTING: Outpatient refractive surgery center, Manila, Philippines. DESIGN: Prospective consecutive case series. METHODS: Consecutive eyes that had previous CK for presbyopia were treated with PRK using a 213 nm wavelength solid-state laser (Pulzar Z1). Uncorrected near (UNVA) and distance (UDVA) visual acuities (monocular and binocular), corrected distance visual acuity (CDVA), refraction, keratometry, and slitlamp evidence of corneal haze and other complications were evaluated for up to 6 months after surgery. RESULTS: The study evaluated 20 eyes (20 patients). Six months after PRK, 47% of eyes had monocular UNVA of Jaeger (J) 3 or better and 27% had a binocular UDVA of 0.10 logMAR (20/25 Snellen equivalent) or better with a concurrent UNVA of J3 or better. Seventy-three percent of eyes were within +/-1.00 diopter of the attempted refraction. No eye lost 2 or more lines of CDVA or developed significant corneal haze. CONCLUSION: Photorefractive keratectomy after CK using a 213 nm wavelength solid-state laser produced functional visual acuity in presbyopic patients in the short term (6 months). PMID- 21262562 TI - Management of pain with diclofenac after femtosecond-assisted laser in situ keratomileusis. AB - PURPOSE: To evaluate the safety and efficacy of topical diclofenac sodium 0.1% after femtosecond laser-assisted laser in situ keratomileusis (LASIK). SETTING: W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA. DESIGN: Clinical trial. METHODS: Pain was assessed in patients treated with topical diclofenac sodium 0.1% or artificial tears immediately after LASIK using a numeric pain scale and a combined picture-numeric pain scale 0, 2, 4, 12, and 24 hours postoperatively. Visual outcomes and complications were noted up to 24 hours. RESULTS: The study enrolled 100 eyes of 50 patients. Patients treated with diclofenac 0.1% reported less pain than the control group on both pain scales 2, 4, 12, and 24 hours after surgery, with the maximum benefit at 4 hours (P=.02). Fewer patients in the diclofenac group (76.0%) than in the control group (91.3%) used oral pain and/or anxiolytic medications during the first 24 hours after surgery (P=.25). Ninety-eight eyes had an uncorrected distance visual acuity of 20/40 or better. Mild peripheral diffuse lamellar keratitis accounted for the majority of perioperative complications (n = 15). CONCLUSION: Pain after femtosecond laser-assisted LASIK was mild and was reduced with a single dose of topical diclofenac sodium 0.1% given immediately after surgery. PMID- 21262563 TI - Real-time three-dimensional transesophageal echocardiography in patients with secundum atrial septal defects: outcomes following transcatheter closure. AB - BACKGROUND: Successful transcatheter closure of atrial septal defects (ASDs) requires the accurate assessment of defect size and morphology. Assessment of ASD anatomy may be difficult by two-dimensional (2D) echocardiography. The aim of this study was to test the hypothesis that real-time three-dimensional (3D) transesophageal echocardiography (TEE) may provide more accurate morphologic assessment of ASDs than multiplane 2D TEE. METHODS: Twenty-four patients with ASDs were imaged using 2D and real-time 3D TEE. ASD shape and size were assessed using 3D TEE retrospectively. Maximal ASD dimensions obtained by 3D TEE were compared with unstretched and balloon-stretched dimensions on 2D TEE. Planimetered defect area by 3D TEE was compared with area calculated using the ellipse formula from 2D imaging. Twenty of the 24 patients underwent transcatheter ASD closure. Closure device size was based on findings on 2D TEE. Follow-up was conducted by 2D transthoracic echocardiography. RESULTS: Of the 24 ASDs, 6 (25%) were circular, 10 (42%) were oval, and 8 (33%) were complex in shape. The mean maximal dimension was larger by 3D TEE compared with 2D TEE (1.8 +/- 0.8 vs 1.5 +/- 0.6 cm; P < .05). There was no difference in the mean area measured by either modality, but for complex-shaped defects, area measured by 3D TEE was larger than that by 2D TEE (2.8 +/- 1.3 vs 1.7 +/- 1.4 cm(2); P < .05). Follow-up transthoracic echocardiography was available for 19 of the 20 patients undergoing transcatheter closure. Nine patients had residual right-to-left shunting 1 to 6 months after ASD closure, and the majority of these were complex in shape. In patients with residual shunting, ASD area by 3D TEE was 27% larger than by 2D TEE, whereas in patients without residual shunting, there was significantly less discrepancy between 3D and 2D areas (19%; P = .0027). CONCLUSIONS: Three-dimensional TEE can identify ASD shape. Maximal dimensions on 3D TEE were well correlated with balloon-stretched 2D dimensions. Two-dimensional TEE can underestimate the area of complex-shaped ASDs, which may result in residual right-to-left shunting. PMID- 21262564 TI - Ameliorated course of glucose-6-phosphate isomerase (G6PI)-induced arthritis in IFN-gamma receptor knockout mice exposes an arthritis-promoting role of IFN gamma. AB - The absence of IFN-gamma signaling leads to an increased inflammatory response in many murine models of autoimmune diseases induced by a CFA-assisted immunization schedule. We investigated the role of endogenous IFN-gamma in arthritis induced by immunization with glucose-6-phosphate isomerase (G6PI) in CFA in DBA/1 mice. Surprisingly, and in contrast to our previous findings in collagen-induced arthritis (CIA), G6PI-induced arthritis was found to be reduced in IFN-gamma receptor-deficient (IFN-gammaR KO) mice, demonstrating a proinflammatory role for IFN-gamma in this model. Milder disease in IFN-gammaR KO mice was associated with less vigorous innate and adaptive immune responses early (day 9) after immunization: less proliferation of myeloid cells in the spleen, less osteoclast formation, less G6PI-reactive Th cells (as measured by ex vivo stimulation and flow cytometry and by in vivo skin reactivity to G6PI) and lower G6PI-specific immunoglobulin serum levels. Surprisingly, on day 21, despite continued milder disease in IFN-gammaR KO mice, their Th cell responses were no longer diminished but augmented as compared to wild-type mice, and their numbers of immature myeloid splenocytes were also more increased. These data reveal that IFN-gamma signaling is critical for the induction of the early immune responses which trigger G6PI-induced arthritis. The strikingly different clinical consequences of absent IFN-gamma signaling in G6PI-induced arthritis compared with the very similarly induced CIA emphasize that the role of a single cytokine in experimentally induced arthritis depends critically on the very nature of the inciting (auto)antigen and in particular on the kinetics of the disease manifestation elicited by the antigen. PMID- 21262565 TI - Effect of aripiprazole augmentation of clozapine in schizophrenia: a double blind, placebo-controlled study. AB - The simultaneous prescription of two or more antipsychotic drugs in combination is a common treatment strategy for those patients who have demonstrated a suboptimal response to clozapine; nevertheless, evidence suggesting potential advantages of combination treatment with clozapine plus one antipsychotic in terms of efficacy and tolerability are still sparse. The present 24-week double blind, randomized, placebo-controlled trial of adjunctive aripiprazole to clozapine therapy in schizophrenia was aimed to explore the efficacy of aripiprazole add-on pharmacotherapy on clinical symptomatology and cognitive functioning in a sample of patients with treatment-resistant schizophrenia receiving clozapine. After clinical and neurocognitive assessments patients were randomly allocated to receive, in a double-blind design, either up to 15 mg/day of aripiprazole or a placebo. A final sample of thirty-one patients completed the study. The results obtained indicate that aripiprazole added to stable clozapine treatment showed a beneficial effect on the positive and general psychopathological symptomatology in a sample of treatment-resistant schizophrenia patients. Regarding executive cognitive functions, aripiprazole augmentation of clozapine had no significant effects. The findings provide evidence that aripiprazole augmentation of clozapine treatment is well-tolerated and may be of benefit for patients who are partially responsive to clozapine monotherapy; further double-blind, placebo-controlled trials in a larger number of patients are required to evaluate the therapeutic potential of aripiprazole augmentation of clozapine. PMID- 21262566 TI - Autotrophic nitrite removal in the cathode of microbial fuel cells. AB - Nitrification to nitrite (nitritation process) followed by reduction to dinitrogen gas decreases the energy demand and the carbon requirements of the overall process of nitrogen removal. This work studies autotrophic nitrite removal in the cathode of microbial fuel cells (MFCs). Special attention was paid to determining whether nitrite is used as the electron acceptor by exoelectrogenic bacteria (biologic reaction) or by graphite electrodes (abiotic reaction). The results demonstrated that, after a nitrate pulse at the cathode, nitrite was initially accumulated; subsequently, nitrite was removed. Nitrite and nitrate can be used interchangeably as an electron acceptor by exoelectrogenic bacteria for nitrogen reduction from wastewater while producing bioelectricity. However, if oxygen is present in the cathode chamber, nitrite is oxidised via biological or electrochemical processes. The identification of a dominant bacterial member similar to Oligotropha carboxidovorans confirms that autotrophic denitrification is the main metabolism mechanism in the cathode of an MFC. PMID- 21262567 TI - Effect of endoxylanase and alpha-L-arabinofuranosidase supplementation on the enzymatic hydrolysis of steam exploded wheat straw. AB - The cost and hydrolytic efficiency of enzymes are major factors that restrict the commercialization of the bioethanol production process from lignocellulosic biomass. Hemicellulases and other accessory enzymes are becoming crucial to increase enzymatic hydrolysis (EH) yields at low cellulase dosages. The aim of this work was to evaluate the effect of two recombinant hemicellulolytic enzymes on the EH of steam pretreated wheat straw. Pretreatments at two severity conditions were performed and the whole slurry obtained after steam explosion pretreatment was employed as substrate. An endoxylanase (Xln C) from Aspergillus nidulans and an alpha-L-arabinofuranosidase (AF) from Aspergillus niger, have been applied in combination with cellulase enzymes. A degree of synergism of 29.5% and increases up to 10% in the EH yields were obtained, showing the potential of accessory activities to improve the EH step and make the whole process more effective. PMID- 21262568 TI - Bio-oil from hydro-liquefaction of Dunaliella salina over Ni/REHY catalyst. AB - The hydro-liquefaction of Dunaliella salina over solid acid catalyst was examined under moderate conditions (200 degrees C, 2.0 MPa, 60 min). The significant increment of bio-oil yield was obtained over Ni/REHY catalyst, increasing about 20% compared without modified REHY. H(2)-temperature-programmed desorption (H(2) TPD) and X-ray powder diffraction (XRD) demonstrated that Ni/REHY as bifunctional catalyst played roles in hydrogenation and cracking, and further achieved the deoxygenation and desulfurization of D. salina under hydrogen gas. The oxygen and sulfur contents of bio-oils decreased relative to D. salina, and the higher heating value (HHV) significantly increased to 30.11 MJ/kg. From gas chromatography/mass spectrometry (GC/MS), the dominant compounds of the bio-oils were found to be esters, glycerins. The qualities of bio-oils were greatly improved. Hydro-liquefaction was beneficial to the exploration of bio-oils from microalgae. PMID- 21262569 TI - Monitoring the biochemical hydrogen and methane potential of the two-stage dark fermentative process. AB - A two-step process has been recently proposed whereby the products of biological hydrogen production processes are used as substrates for biological methane production. The aim of the present study is to evaluate a simple bench-scale batch procedure for measuring the biochemical hydrogen and methane potential of organic substances as a two-step simulated process. Glucose fermentation showed an hydrogen and methane recovery (measured as the ratio of electron equivalents recovered as hydrogen and methane and electron equivalents of the initial substrate added) from the initial substrate of 13.3% and 75.5%, respectively, that approximates mass balance closure. On the contrary, gas recoveries ranging from 61% to 75% were measured from wastes originating from the food-industry. Moreover, the results demonstrate that the substrate origins significantly influence the ratio of H(2) and CH(4) recovery. PMID- 21262570 TI - A comparative study of the effect of refining on charge of various pulps. AB - This work studied the influence of refining on various pulp properties such as freeness, specific surface area, specific volume, water retention value, surface charge, total charge and tensile index of five different pulps. At a freeness level the wheat straw pulp exhibited higher surface charge and total charge compared to other pulps. The specific surface area, specific volume and water retention value of the pulps increased with increased refining. The total fibre charge as determined by conductometric titrations was not affected by refining. However, the surface charge as determined by titrations with poly-DADMAC increased with refining. The increases in specific surface area of pulps by refining resulted in a higher fibre surface charge and also better fibre-fibre bonding. The linear regression models developed using experimental data were found to be accurate. The comparison of model predicted data and the experimental data showed an excellent agreement between them. PMID- 21262571 TI - Synthesis, structure-activity relationships and preliminary antitumor evaluation of benzothiazole-2-thiol derivatives as novel apoptosis inducers. AB - A series of novel benzothiazole-2-thiol derivatives were synthesized, and their anti-proliferative activities on HepG2 and MCF-7 cells were investigated. Most compounds had inhibitory effects on cell growth, and some of them were more effective than cisplatin. Compounds 6m and 6t displayed good inhibitory activities against a panel of different types of human cancer cell lines, with IC(50) values in the low micromolar range. Further biological evaluation indicated that 6m induced apoptosis in HepG2 cancer cells. Structure-activity relationships were also proposed. PMID- 21262572 TI - Risk factors for gastrointestinal complications in patients undergoing coronary artery bypass graft surgery. AB - OBJECTIVE: To determine the risk factors for the development of gastrointestinal complications (GICs) after coronary artery bypass graft (CABG) surgery. DESIGN: A single-center, retrospective study. SETTING: A tertiary care hospital. PARTICIPANTS: Six thousand seven hundred ninety-four patients undergoing isolated CABG surgery between 2002 and 2006. INTERVENTIONS: Clinical characteristics of the patients with GICs and control group patients were analyzed by stepwise logistic regression analysis. The control group consisted of a total of 95 patients randomly selected among the ones who had no gastrointestinal finding or symptoms (cohort: control, 1:5 ratio). MEASUREMENTS AND MAIN RESULTS: Nineteen patients (0.3%) developed major surgical GICs after CABG surgery. Overall, the 30 day mortality was 42.1% among patients with GICs and 2.6% without GICs. Multivariate analysis identified 4 independent predictors for GICs: age greater than 70 years (p = 0.001; odds ratio [OR] = 5.6; 95% confidence interval [CI], 2.1-25.9), reoperation for bleeding (p = 0.005; OR = 7.7; 95% CI, 2.8-56.2), a prolonged cardiopulmonary bypass time (p = 0.007; OR = 3.7; 95% CI, 1.3-15.6), and an increased postoperative creatinine level (p = 0.036; OR = 2.3; 95% CI, 1.1 13.4). CONCLUSION: A delayed diagnosis of complications is an important problem in the management of major surgical GICs. The present results suggest that surgeons and intensivists must be alert to patients older than 70 years, a cardiopulmonary bypass time longer than 60 minutes, reoperation for bleeding after CABG surgery, and postoperative creatinine level higher than 1.7 mg/dL. PMID- 21262573 TI - Factors influencing prognosis in patients with marfan syndrome after aortic surgery. AB - OBJECTIVE: Aortic aneurysm formation leading eventually to aortic rupture or dissection in early adult life is a fatal outcome of Marfan syndrome (MFS). Advances in the treatment of the syndrome have improved prognosis, but the long term reoperation rate is still high. It remains unknown which factors influence the long-term prognosis, including the reoperation and mortality rates, in surgically treated Chinese patients with MFS. The authors studied 125 such patients to investigate factors influencing prognosis after aortic surgery. DESIGN: A retrospective clinical investigation. SETTING: An academic medical center. SUBJECTS: One hundred twenty-five Marfan patients who had undergone aortic surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The indications for aortic surgery were aortic aneurysm and/or dissection in the 125 Marfan patients. The most commonly performed procedure was the Bentall in 92 patients. Sixteen patients underwent total arch replacement combined with stented elephant trunk implantation. Ten patients underwent the David procedure. Overall in-hospital and 30-day mortality rate was 1.6%. The survival rate was 97.5%, 91.4%, and 74.2% at 1, 5, and 10 years after surgery, respectively. The reoperation rate was 2.5%, 12.9%, and 32.9% at 1, 5, and 10 years after surgery, respectively. Multivariate analysis revealed that increased systolic blood pressure (Sys BP) was the predictor of death (p < 0.05), and body mass index and smoking were significant predictors of reoperation (p < 0.05). CONCLUSIONS: The present findings report the factors influencing the prognosis of Chinese patients with MFS after aortic surgical procedures. Managing these risk factors may enable health care professionals to improve the prognosis of MFS patients after aortic surgical procedures. PMID- 21262574 TI - Estimating the volume of chronic pleural effusions using transesophageal echocardiography. AB - OBJECTIVE: To develop a simple method of quantifying the volume of chronic pleural effusions caused by heart failure using transesophageal echocardiography measurement of the maximum cross-sectional area of the pleural effusion. DESIGN: A prospective observational case series. SETTING: An operating room. PARTICIPANTS: Twenty-eight patients undergoing cardiac surgery known to have chronic pleural effusions caused by heart failure diagnosed preoperatively in whom surgical management included draining the effusion. INTERVENTIONS: Transesophageal echocardiography was in situ for clinical reasons. The drainage of all pleural effusions was performed according to clinical judgement. MEASUREMENT AND MAIN RESULT: The maximum cross-sectional area (CSA(max)) in centimeters squared of the pleural effusion on transesophageal echocardiography was recorded. The chest and pleural cavity were opened, the pleural effusion was drained, and total amount of fluid drained was recorded. The data were analyzed on a log-log plot with the conclusion that volume (V) in milliliters could be estimated from the following formula: V = 4.5 . CSA(max)(3/2). CONCLUSION: This study showed a simple way of quantifying the volume of chronic pleural effusions from heart failure in patients undergoing cardiac surgery, with potential for clinical applications. PMID- 21262575 TI - Intraoperative assessment of mitral valve area after mitral valve repair: comparison of different methods. AB - OBJECTIVE: In the present study, 3 different methods to measure the mitral valve area (MVA) after mitral valve repair (MVRep) were studied. Data obtained immediately after repair were compared with postoperative data. The objective was to determine the feasibility and correlation between intraoperative and postoperative MVA data. DESIGN: A prospective study. SETTING: A tertiary care medical center. PARTICIPANTS: Twenty-five elective adult surgical patients scheduled for MVRep. METHODS: Echocardiographic data included MVAs obtained using the pressure half-time (PHT), 2-dimensional planimetry (2D-PLAN), and the continuity equation (CE). These data were obtained immediately after cardiopulmonary bypass and were compared with data obtained before hospital discharge (transthoracic echocardiogram 1) and 6 to 12 months after surgery (transthoracic echocardiogram 2). Intraoperative care was guided by hemodynamic goals designed to optimize cardiac function. RESULTS: The data show good agreement and correlation between MVA obtained with PHT and 2D-PLAN within and between each time period. MVA data obtained with the CE in the postoperative period were lower than and did not correlate or agree as well with other MVA data. CONCLUSION: The MVA recorded immediately after valve repair, using PHT, correlated and agreed with MVA data obtained in the postoperative period. These results contrast with previously published data and could highlight the impact of hemodynamic function during the assessment of MVA. PMID- 21262576 TI - An unusual foreign body in the foot: traumatic implantation of a human tooth. AB - We report the case of a 29-year-old man who presented to the emergency department with persistent swelling and pain in his right foot, initially reported to be related to stepping on something while walking on the beach. When radiographs showed what appeared to be a human tooth embedded in the foot, the patient admitted to having been in a fight, during which he kicked his opponent in the jaw with his foot. The tooth was surgically removed and oral antibiotic therapy was administered for 1 week. The wound eventually healed by secondary intention without complications, and the patient returned to his regular activities 15 days after the operation. PMID- 21262577 TI - Beaming the columns for Charcot diabetic foot reconstruction: a retrospective analysis. AB - This study explored the concept of "beaming" the medial and lateral longitudinal columns as a variation of the current technique for hindfoot and Lisfranc Charcot reconstruction. We reviewed radiographic changes and outcomes for patients who underwent Charcot foot reconstruction at our facility over the 14-year period from January 1994 to January 2008. Beaming was performed on 71 Charcot foot deformities in 70 patients, 22 (31%) of which displayed an isolated hindfoot deformity, 20 (28%) an isolated Lisfranc deformity, and 29 (41%) with a combination of hindfoot and Lisfranc deformities. The average radiographic follow up was 31.00 +/- 22.97 months. Group 1 consisted of reconstructions that involved only medial and lateral column beams and showed significant improvements in radiographic alignment between the preoperative and postoperative measurements, including Meary's angle (P < .001), calcaneal inclination angle (P = .004), tarsometatarsal angle (P = .002), talonavicular angle (P = .035), and the calcaneocuboid angle (P = .006). Group 2, which consisted of reconstructions that involved medial and lateral column beams and either a subtalar arthroereisis (n = 18) or a subtalar joint fusion (n = 10), also showed significant improvements, including Meary's angle (P < .001), tarsometatarsal angle (P < .001), talonavicular angle (P = .002), and the calcaneocuboid angle (P < .001), although calcaneal inclination did not statistically significantly change (P = .054). In both groups, the surgical intervention maintained the correction and was useful for Charcot reconstruction. Complications included pin tract infections, broken pin, osteomyelitis, transfer lesions, and ulcerations. PMID- 21262578 TI - Use of the Mini TightRope(r) for correction of hallux varus deformity. AB - The flexible form of acquired hallux varus has historically been treated with a number of applicable soft tissue procedures, most of which combine medial capsular release with adjunct procedures aimed at restoring the transverse plane balance of the digit. In this report, a surgical technique for correction of hallux varus that employs the use of an implanted button and suture device, namely the Mini TightRope((r)), is described. Rather than relying on the patient's own soft tissues, this device applies tension to anchor the hallux in the proper alignment. The device is easily adjusted during the course of the surgery and readily enables accurate correction of the hallux in the transverse plane. The indications, technical execution, postoperative care, and potential complications related to our use of the Mini TightRope((r)) for correction of hallux varus are described, and the case of an adult woman who underwent the procedure for correction of acquired hallux varus is presented. In the authors' experience, the Mini TightRope((r)) is a viable option that mimics restoration of the lateral collateral ligaments of the first metatarsophalangeal joint, and we believe this technique to be superior to other soft tissue surgical procedures used to repair flexible hallux varus. PMID- 21262579 TI - Deactivation of sodium tetradecyl sulphate injection by blood proteins. AB - OBJECTIVES: The aim of this work was to quantify the volume of blood required to deactivate 1 ml of 3% sodium tetradecyl sulphate (STS). DESIGN: A series of experiments were performed where the concentration of STS remaining in a stock solution was measured after adding increasing volumes of blood protein solutions. MATERIALS AND METHODS: Increasing volumes of bovine serum albumin, bovine erythrocytes and a mixture of both was added to a stock solution of STS. The BP manual titration method was used to measure the assay of the remaining STS. RESULTS: The method was reproducible and increasing volumes of blood protein lowered the STS concentration in a linear fashion. Approximately 2 ml of a 4% blood protein solution deactivates 1 ml of 3% STS, which means approximately 0.5 ml of whole blood will deactivate 1 ml of 3% STS. CONCLUSIONS: Sodium tetradecyl sulphate injection is deactivated by a relatively small volume of blood. The practical implication is that changes in technique to reduce the blood volume in larger veins and to introduce fresh aliquots of sclerosant along the length of the vein could improve the efficacy of sclerotherapy. PMID- 21262580 TI - Increased vein wall apoptosis in varicose vein disease is related to venous hypertension. AB - OBJECTIVES: The study aimed to evaluate a wide range of apoptotic markers in the vein wall of patients with superficial chronic venous disease (SCVD) compared with normal veins. DESIGN: This was an observational study. METHODS: Vein specimens were obtained from 19 patients suffering from SCVD. From each patient, a specimen of the proximal part of the great saphenous vein (GSV), a specimen of the distal part of the vein and a specimen of a varicose tributary were obtained. Immunohistochemical analysis was used to localise the expression of BAX, p53, Caspase 3, BCL-2, BCL-6, BCL-xs, BCL-xl and Ki-67. Vein specimens from 10 healthy GSVs were used as controls. RESULTS: Saphenous vein specimens from patients with SCVD showed increased BAX, Caspase 3, BCL-xl and BCL-xs (p < 0.01 for all) and Ki 67 (p = 0.02) compared with healthy GSVs. In the venous disease group, GSV specimens from the distal ankle area showed increased BAX (p < 0.01) and BCL-xs (p = 0.031) compared with varicose tributaries specimens, which subsequently showed increased BAX (p = 0.044), Caspase 3 (p = 0.028) and BCL-xs (p = 0.037) compared with specimens from the proximal GSV. In addition, in the venous disease group, specimens from distal GSV showed increased BAX (p < 0.01), Caspase 3 (p = 0.019) and BCL-xs (p = 0.014) compared with the proximal GSV. CONCLUSION: Varicose veins exhibit increased apoptotic activity, by means of increased BAX, Caspase 3, BCL-xl and BCL-xs, compared with normal veins. Patients with varicose vein disease show increased apoptosis in the distal saphenous trunk compared with the proximal saphenous trunk, suggesting an association between chronic venous hypertension and apoptosis. PMID- 21262581 TI - Feline chronic kidney disease: can we move from treatment to prevention? AB - Chronic kidney disease (CKD) is arguably the most common disease of older domestic cats. Recent research has focused on treatment options and prognostic variables. Specifically, the roles of dietary protein, hypertension and proteinuria as potential causes of a progressive decline in kidney function have been evaluated. The value of prescription kidney diets and the prognostic value of proteinuria have been confirmed. However, in contrast to dogs, rodents and people, significant proteinuria is uncommon in the cat and hypertension is not a prognostic indicator. Despite significant progress, the cause of CKD in the overwhelming majority of cats remains unknown and fundamental questions remain unanswered. Treatment of feline CKD is limited to non-specific options until some of the causes and pathophysiological mechanisms that result in chronic tubulointerstitial nephritis are identified. PMID- 21262582 TI - Diagnostic value of the neutrophil myeloperoxidase index in horses with systemic inflammation. AB - The myeloperoxidase index (MPXI) was investigated as a diagnostic indicator of systemic inflammation in a retrospective study using data from 859 hospitalised horses. A reference interval of 8.5-10.4 for the MPXI was established. In horses with systemic inflammatory response syndrome (SIRS), the MPXI was significantly lower than in healthy horses, those with localised inflammation and those with sepsis. The MPXI in horses with sepsis was also significantly lower than in healthy animals and those with localised inflammation. Horses in the SIRS group with leucopenia, white blood cell (WBC) count within the reference interval (WRI) or leucocytosis had significantly lower MPXIs than healthy horses, those with localised inflammation and those with sepsis in the same WBC count subgroups. In horses with sepsis and WBC count WRI, the MPXI was significantly lower than in healthy horses or those with localised inflammation. MPXI is a useful complementary tool to identify horses with systemic inflammation, especially if they have WBC counts WRI. PMID- 21262583 TI - Mitochondrial dysfunction in muscle tissue of complex regional pain syndrome type I patients. AB - Reactive oxygen species (ROS) are known to be involved in the pathophysiology of complex regional pain syndrome type I (CRPS I). Since the mitochondrial respiratory chain is a major source of ROS, we hypothesized that mitochondria play a role in the pathophysiology of CRPS I. The hypothesis was tested by studying mitochondrial energy metabolism in muscle tissue from amputated limbs of CRPS I patients. We observed that mitochondria obtained from CRPS I muscle tissue displayed reduced mitochondrial ATP production and substrate oxidation rates in comparison to control muscle tissue. Moreover, we observed reactive oxygen species evoked damage to mitochondrial proteins and reduced MnSOD levels. It remains to be established if the mitochondrial dysfunction that is apparent at the end-stage of CRPS I is also present in earlier stages of the disease, or are secondary to CRPS I. The observation of a reduced mitochondrial energy production combined with reactive oxygen species induced damage in muscle tissue from CRPS I patients warrants further studies into the involvement of mitochondrial dysfunctioning in the pathophysiology of CRPS I. PMID- 21262584 TI - The macrophage Ox-LDL receptor, CD36 and its association with type II diabetes mellitus. AB - Type II diabetes mellitus (T2DM) is a common and serious metabolic disorder worldwide. It is the third leading cause of death after cancer and cardiovascular disease (CVD). Over time, diabetes mellitus can lead to different complications like atherosclerosis, coronary heart disease and many micro- and macrovascular diseases. CD36 is a class B scavenger receptor whose expression is prevalent in vascular lesions. It has been shown that high plasma low density lipoprotein (LDL) levels become atherogenic when oxidized to modified LDL (Ox-LDL) by inducing foam cell formation via enhanced CD36 expression on macrophages. In addition to Ox-LDL, raised levels of glucose, insulin resistance, low HDL cholesterol, increased levels of free fatty acid (FFA) all result in increased expression of CD36, thereby contributing to T2DM and related atherosclerosis. Adipocytokines such as tumor necrosis factor-alpha (TNF-alpha), C-reactive protein (CRP), adiponectin, leptin, resistin along with peroxisome proliferator activated receptor-gamma (PPAR-gamma) are important mediators in glucose homeostasis in association with CD36 and can be used as markers for T2DM and atherosclerosis. Several of these gene variants have shown association with lipid metabolism, T2DM and related complications. An attempt has been made to review the CD36 macrophage receptor and related molecules in association with T2DM. PMID- 21262585 TI - Effects of ultrasound on the thermal and structural characteristics of proteins in reconstituted whey protein concentrate. AB - The sonication-induced changes in the structural and thermal properties of proteins in reconstituted whey protein concentrate (WPC) solutions were examined. Differential scanning calorimetry, UV-vis, fluorescence and circular dichroism spectroscopic techniques were used to determine the thermal properties of proteins, measure thiol groups and monitor changes to protein hydrophobicity and secondary structure, respectively. The enthalpy of denaturation decreased when WPC solutions were sonicated for up to 5 min. Prolonged sonication increased the enthalpy of denaturation due to protein aggregation. Sonication did not alter the thiol content but resulted in minor changes to the secondary structure and hydrophobicity of the protein. Overall, the sonication process had little effect on the structure of proteins in WPC solutions which is critical to preserving functional properties during the ultrasonic processing of whey protein based dairy products. PMID- 21262586 TI - Growth and poliovirus production of Vero cells on a novel microcarrier with artificial cell adhesive protein under serum-free conditions. AB - A microcarrier is used for the three-dimensional (3D) culture of adhesion dependent mammalian cells. We developed a novel microcarrier by binding ProNectin F, an artificial cell adhesive protein synthesized by genetically engineered Escherichia coli to a polyacrylic superabsorbent polymer. The microcarrier is characterized by containing no animal-derived components. The serum-free culture of Vero cells for vaccine production using the microcarrier increased the number of Vero cells by approximately 30% compared with the existing dextran beads coated with porcine Type I collagen, which resulted in approximately a 30% to 40% increase in the infectivity titer of the Sabin 2 strain of poliovirus. These results suggested that the developed microcarrier should be unprecedented in permitting high-yield vaccine production by means of a serum-free culture. PMID- 21262588 TI - Special section: from the American Epilepsy Society 2009 Annual Course. Introduction. PMID- 21262587 TI - Dormant ovoid cells of Mycobacterium tuberculosis are formed in response to gradual external acidification. AB - It is believed that latent tuberculosis is associated with the persistence of Mycobacterium tuberculosis (MTB) in a dormant-like state. Dormant cells of MTB with coccoid morphology were produced in some in vivo studies, but similar forms were not produced in the known in vitro models in sufficient amounts to permit their characterization. This work demonstrates the efficient formation of phase dark ovoid cells in MTB cultures within 150 days after the onset of stationary phase. During this time the medium underwent gradual acidification (pH 8.5 -> 4.7) as a result of cellular metabolism. A rapid change in the external pH resulted in cell degradation and death. In common with the dormant forms found in other organisms, the ovoid cells had thickened cell walls, a low metabolic activity and elevated resistance to antibiotics and heating. The ovoid cells had lost the ability to form colonies on solid medium and were thus regarded as operationally "non-culturable". At an early stage in the acidification process (about 40 days post inoculation), the ovoid cells self-resuscitated when placed in fresh liquid medium. However, ovoid cells, stored for a prolonged time, required supernatant from active MTB cells, or externally added recombinant form of resuscitation promoting factor (Rpf) for successful resuscitation. It is suggested that the adaptation of cellular metabolism leading to gradual acidification of the external medium results in the formation of morphologically distinct dormant MTB cells in vitro. The model of MTB dormancy developed here could be a useful tool for the development of new drugs against latent TB. PMID- 21262589 TI - Complex transient epileptic amnesia. AB - Transient epileptic amnesia is a rare but probably underrecognized form of temporal lobe epilepsy, which typically manifests as episodic isolated memory loss. Consequently, transient epileptic amnesia may be readily misdiagnosed as a nonepileptic memory dysfunction in older individuals. When appropriately recognized, it has been described as a treatment-responsive syndrome amenable to antiepileptic drugs. We describe a patient with drug-resistant transient epileptic amnesia treated with unilateral temporal lobectomy. Prolonged postictal slowing in the mesial temporal structures was evident on invasive electroencephalography 5 hours after the occurrence of a brief focal seizure. These findings support the theory of a Todd phenomenon as the underlying pathophysiological mechanism in transient epileptic amnesia. PMID- 21262590 TI - Oral estroprogestins after laparoscopic surgery to excise endometriomas: continuous or cyclic administration? Results of a multicenter randomized study. AB - STUDY OBJECTIVE: To evaluate continuous (CON) compared with cyclic (CYC) administration of combined oral estroprogestins for 6 months after laparoscopic excision of ovarian endometriomas associated with pain. DESIGN: Multicenter, prospective, randomized trial (Canadian Task Force classification I). SETTING: Tertiary care university hospitals. PATIENTS: Fifty-seven women aged 18 to 40 years with ovarian endometriomas associated with moderate to severe pelvic pain who underwent laparoscopic excision of the disease. INTERVENTIONS: Patients were randomized to receive postoperative estroprogestins for 6 months, administered as either a CON or CYC regimen. MEASUREMENTS AND MAIN RESULTS: At 3, 6, 12, and 24 months postoperatively, patients were evaluated for recurrence of endometriomas (defined as cysts >3 cm in greatest diameter) using ultrasonography, for recurrence of pain using a visual analog scale, and for patient satisfaction. After a minimum follow-up of 12 months (mean, 22 months), at intent-to-treat analysis, no endometrioma recurrence was observed in the CON group, whereas there was recurrence in 1 patient (4%) in the CYC group. Pain recurred in 5 and 9 patients, respectively (17% vs 32%; p = .23). Compared with pretreatment values, pain scores improved in both groups, with no significant difference between the 2 groups. Most patients in both groups were either satisfied or very satisfied, with no significant difference between treatment groups. However, compared with the CYC group, significantly more patients in the CON group experienced moderate to severe adverse effects, and therapy was discontinued (41% vs 14%; p = .03). CONCLUSIONS: Although both regimens were equally effective insofar as postoperative pain and recurrence of endometrioma, when compared with the CYC regimen, the CON regimen seems to be associated with significantly more adverse effects and discontinuation rates. PMID- 21262591 TI - Robotic surgical training program in gynecology: how to train residents and fellows. AB - A protocol was established to standardize surgical training using the da Vinci Surgical System. Third- and fourth-year residents and first-year fellows in obstetrics and gynecology participated. The protocol includes online instruction and 2 hands-on modules: platform set-up and surgical skills. Platform set-up provides orientation to the console, visual platform, surgical cart ("robot"), camera set-up, port placement, and instrument insertion and removal. Surgical skills includes specific drills using rubber models that simulate human tissue: manipulation, dissection, and simple and advanced suturing. Performance times were recorded for each trainee, as well as previous robotic experience. Times were compared with goals established by Intuitive Surgical, Inc., to assess feasibility of this protocol and baseline robotic surgical aptitude. All trainees (n = 17) completed the training protocol. Performance times met goals for docking and dissection. These times also varied according to level of training. Performance times for manipulation and simple and advanced suturing were prolonged across all groups. Overall pass rates were 100% for docking, 90% for dissection, 11.8% for manipulation, and 0% for simple and advanced suturing. Dissection pass rates varied according to level of training. Performance times and pass rates were not improved with higher level of training or previous robotic experience. Resident and fellow instruction in new surgical technology is an important part of training in obstetrics and gynecology. Herein is reported a method to accomplish robotic training that standardizes instruction and assessment of skills. PMID- 21262593 TI - Differential expression of immune and stress genes in the skin of Atlantic cod (Gadus morhua). AB - The present study describes the transcriptional profiles of selected immune and stress genes with putative important roles in the cutaneous immune defense of Atlantic cod (Gadus morhua). In addition it shows differential expression of many genes at the dorsal and ventral sides of fish, in general having the highest expression at the latter side. Genes related to antibacterial activity, antiviral response, cytokine production, glucose transport, stress response and anti apoptotic activity were monitored and bactericidal/permeability-increasing protein/lipopolysaccharide-binding protein (BPI-LBP), g-type lysozyme, transferrin, metallothionein, fortilin, interferon regulatory factor-1 (IRF-1), a CC chemokine isoform, interleukin-8 (IL-8), glucose transport (GLUT)-1, -3 and 4, Cu,Zn-superoxide dismutase (Cu,Zn-SOD), catalase and hsp 70 showed significantly higher expression at the ventral side. Further g-type lysozyme, metallothionein, fortilin, IRF-1, interferon gamma, interleukin-1beta (IL-1beta), GLUT-3 and -4, catalase and anti apoptotic gene Bcl-X1 were highly expressed in adult cod skin. Therefore fish skin can be considered an immunological active site, especially at the ventral side of Atlantic cod. PMID- 21262594 TI - EST analysis on the gonad development related organs and microarray screen for differentially expressed genes in mature ovary and testis of Scylla paramamosain. AB - A total of 5160 high quality ESTs (expressed sequence tags) averaging 357 bp were collected from normalized cDNA libraries created from testis, ovary and mixed organs of mud crab Scylla paramamosain. Clustering and assembly of these ESTs resulted in a total of 3837 unique sequences with 576 overlapping contigs and 3261 singletons. Comparisons with the GenBank non-redundant (Nr) protein database (BLASTx, e-values <10(-5)) revealed putative functions or matched homologs from other organisms for 847 (22%) of the ESTs. Several gonad development related genes such as cathepsin C, thioredoxin peroxidase, vitellogenin receptor precursor, 50S ribosomal protein L24 and ubiquitin-conjugating enzyme E2 isoform 2 were identified from this EST project and demonstrated as gonad differential expression genes by rqRT-PCR. Sixty five different types of SSRs (simple sequence repeats) were identified from the total 411 EST-SSR motifs. A home-made cDNA microarray containing 5664 spots was developed and the hybridization results indicated that 39 unique transcripts were differentially expressed in testis and ovaries (P<0.05). The expression levels of eleven unique transcripts examined by rqRT-PCR were matched with microarray fairly. These results will provide a useful resource for functional genomic studies on the biology of reproduction of mud crab. PMID- 21262595 TI - Ambient carbon monoxide and fine particulate matter in relation to preeclampsia and preterm delivery in western Washington State. AB - BACKGROUND: Preterm delivery and preeclampsia are common adverse pregnancy outcomes that have been inconsistently associated with ambient air pollutant exposures. OBJECTIVES: We aimed to prospectively examine relations between exposures to ambient carbon monoxide (CO) and fine particulate matter [<= 2.5 MUm in aerodynamic diameter (PM2.5)] and risks of preeclampsia and preterm delivery. METHODS: We used data from 3,509 western Washington women who delivered infants between 1996 and 2006. We predicted ambient CO and PM2.5 exposures using regression models based on regional air pollutant monitoring data. Models contained predictor terms for year, month, weather, and land use characteristics. We evaluated several exposure windows, including prepregnancy, early pregnancy, the first two trimesters, the last month, and the last 3 months of pregnancy. Outcomes were identified using abstracted maternal medical record data. Covariate information was obtained from maternal interviews. RESULTS: Predicted periconceptional CO exposure was significantly associated with preeclampsia after adjustment for maternal characteristics and season of conception [adjusted odds ratio (OR) per 0.1 ppm=1.07; 95% confidence interval (CI), 1.02-1.13]. However, further adjustment for year of conception essentially nullified the association (adjusted OR=0.98; 95% CI, 0.91-1.06). Associations between PM2.5 and preeclampsia were nonsignificant and weaker than associations estimated for CO, and neither air pollutant was strongly associated with preterm delivery. Patterns were similar across all exposure windows. CONCLUSIONS: Because both CO concentrations and preeclampsia incidence declined during the study period, secular changes in another preeclampsia risk factor may explain the association observed here. We saw little evidence of other associations with preeclampsia or preterm delivery in this setting. PMID- 21262596 TI - Modeling spatial patterns of traffic-related air pollutants in complex urban terrain. AB - BACKGROUND: The relationship between traffic emissions and mobile-source air pollutant concentrations is highly variable over space and time and therefore difficult to model accurately, especially in urban settings with complex terrain. Regression-based approaches using continuous real-time mobile measurements may be able to characterize spatiotemporal variability in traffic-related pollutant concentrations but require methods to incorporate temporally varying meteorology and source strength in a physically interpretable fashion. OBJECTIVE: We developed a statistical model to assess the joint impact of both meteorology and traffic on measured concentrations of mobile-source air pollutants over space and time. METHODS: In this study, traffic-related air pollutants were continuously measured in the Williamsburg neighborhood of Brooklyn, New York (USA), which is affected by traffic on a large bridge and major highway. One-minute average concentrations of ultrafine particulate matter (UFP), fine particulate matter [<= 2.5 MUm in aerodynamic diameter (PM2.5)], and particle-bound polycyclic aromatic hydrocarbons were measured using a mobile-monitoring protocol. Regression modeling approaches to quantify the influence of meteorology, traffic volume, and proximity to major roadways on pollutant concentrations were used. These models incorporated techniques to capture spatial variability, long- and short-term temporal trends, and multiple sources. RESULTS: We observed spatial heterogeneity of both UFP and PM2.5 concentrations. A variety of statistical methods consistently found a 15-20% decrease in UFP concentrations within the first 100 m from each of the two major roadways. For PM2.5, temporal variability dominated spatial variability, but we observed a consistent linear decrease in concentrations from the roadways. CONCLUSIONS: The combination of mobile monitoring and regression analysis was able to quantify local source contributions relative to background while accounting for physically interpretable parameters. Our results provide insight into urban exposure gradients. PMID- 21262598 TI - A novel mutation (p.Arg94Gly) of keratin 17 in a Chinese family with steatocystoma multiplex. PMID- 21262597 TI - Perinatal exposure to low doses of dioxin can permanently impair human semen quality. AB - BACKGROUND: In recent decades, young men in some industrialized areas have reportedly experienced a decrease in semen quality. OBJECTIVE: We examined effects of perinatal dioxin exposure on sperm quality and reproductive hormones. METHODS: We investigated sperm quality and hormone concentrations in 39 sons (mean age, 22.5 years) born between 1977 and 1984 to mothers exposed to dioxin after the accident in Seveso, Italy (1976), and 58 comparisons (mean age, 24.6 years) born to mothers exposed only to background dioxin. Maternal dioxin levels at conception were extrapolated from the concentrations measured in 1976 serum samples. RESULTS: The 21 breast-fed sons whose exposed mothers had a median serum dioxin concentration as low as 19 ppt at conception had lower sperm concentration (36.3 vs. 86.3 million/mL; p = 0.002), total count (116.9 vs. 231.1; p = 0.02), progressive motility (35.8 vs. 44.2%; p = 0.03), and total motile count (38.7 vs. 98 million; p = 0.01) than did the 36 breast-fed comparisons. The 18 formula-fed exposed and the 22 formula-fed and 36 breast-fed comparisons (maternal dioxin background 10 ppt at conception) had no sperm-related differences. Follicle stimulating hormone was higher in the breast-fed exposed group than in the breast fed comparisons (4.1 vs. 2.63 IU/L; p = 0.03) or the formula-fed exposed (4.1 vs. 2.6 IU/L; p = 0.04), and inhibin B was lower (breast-fed exposed group, 70.2; breast-fed comparisons, 101.8 pg/mL, p = 0.01; formula-fed exposed, 99.9 pg/mL, p = 0.02). CONCLUSIONS: In utero and lactational exposure of children to relatively low dioxin doses can permanently reduce sperm quality. PMID- 21262600 TI - BVA highlights potential impact of increased tuition fees. PMID- 21262599 TI - Immunohistochemical expression patterns of the microRNA-processing enzyme Dicer in cutaneous malignant melanomas, benign melanocytic nevi and dysplastic melanocytic nevi. AB - Dicer is an essential cytosolic enzyme necessary for processing pre-microRNAs into mature microRNAs (miRNAs). Although a variety of malignancies have been attributed to perturbations in the miRNA machinery, there has been little research conducted on the role of miRNAs in cutaneous malignant melanoma and its premalignant lesions. In this small pilot study, we therefore investigated the distribution of Dicer by immunohistochemistry in cutaneous malignant melanomas, as well as in benign and dysplastic melanocytic nevi. Dicer was assessed in ten cutaneous malignant melanomas (CMM), benign melanocytic nevi (BMN), and dysplastic melanocytic nevi (DMN), by standard immunohistochemical staining. Semiquantitative analyses determined expression indices (EIs), which associate the conventional area fraction of labeled cells with immunostaining intensity scores, based on visual qualitative examination by two independent observers. Mean EI scores were significantly higher in the CMM group compared to those in the BMN group (p < 0.05). However, EI differences between BMN and DMN as well as between CMM and DMN were not significant (p > 0.05). For CMM we observed a significant correlation of Breslow tumor thickness and Dicer EI (r = 0.84, p = 0.022). For all three groups investigated, Dicer-positive staining was primarily located in the epidermis, specifically in melanocytes. By immunohistochemistry, Dicer staining was significantly higher in melanoma cells than in benign melanocytes. This preliminary study indicates that alterations in the miRNA machinery could exist and should be subject of further investigation. PMID- 21262602 TI - Badger vaccine research data made public. PMID- 21262604 TI - Global clampdown on illegal wildlife trade. PMID- 21262605 TI - Proceedings adjourned in disciplinary case. PMID- 21262606 TI - BEVA calls for better enforcement of horse transport rules. PMID- 21262608 TI - Histophilus somni infection in cows with fertility problems and vaginitis. AB - Histophilus somni associated with vaginitis in cattle; fasciolosis still prevalent in cattle; clostridial metritis in a large goat herd; detachment of the ischial tuberosity in pigs; fowl cholera in commercial and backyard flocks. These are among matters discussed in the Veterinary Laboratories Agency's (VLA's) disease surveillance report for September. PMID- 21262609 TI - Assessment of welfare on 24 commercial UK dairy goat farms based on direct observations. AB - The preliminary findings from an investigation into the health and welfare of goats on commercial dairy goat farms in the UK are described. An assessment protocol involving direct observations of the goats was developed in order to assess their welfare. Twenty-four dairy goat farms in England and Wales were visited and assessed during the period autumn 2004 to summer 2005. The main welfare issues identified were lameness and claw overgrowth, udder and teat lesions, skin lesions and pruritus. PMID- 21262610 TI - Presence of the glycogen synthase 1 (GYS1) mutation causing type 1 polysaccharide storage myopathy in continental European draught horse breeds. AB - The purpose of this study was to determine which continental European draught horse breeds harbour a mutation in the glycogen synthase 1 gene (GYS1) that is known to be responsible for type 1 polysaccharide storage myopathy in quarter horses and North American draught horses. Of a non-random selection of continental European draught horses belonging to 13 breeds, 62 per cent (250 of 403) tested were found to carry the mutant allele. The horses were located in Belgium, France, Germany, The Netherlands, Spain and Sweden. The mutation was identified in animals from each of the breeds examined. In the breeds in which more than 15 animals were available for testing, the highest percentages of GYS1 positive horses were found in the Belgian trekpaard (92 per cent; 35 of 38 horses tested), Comtois (80 per cent; 70 of 88), Netherlands trekpaard (74 per cent; 17 of 23), Rheinisch-Deutsches kaltblut (68 per cent; 30 of 44) and Breton (64 per cent; 32 of 51). PMID- 21262611 TI - Survey of the current use of pharmacokinetic model-driven drug delivery in small animal anaesthesia and analgesia in Italy. AB - Veterinary surgeons in Italy were surveyed about their current practice with regard to the use of propofol and intravenous opioids during anaesthesia and for treatment of acute pain in small animals. Questionnaires were e-mailed to all 171 members of the Italian Society of Veterinary Regional Anaesthesia and Pain Medicine. Information was requested on the type of practice the veterinarians worked in, the administration techniques used and the perceived benefit of pumps with target-controlled infusion (TCI) capability implementing small animal pharmacokinetic models. A total of 168 responses were received (response rate 98.2 per cent). Of the respondents, 121 (72.0 per cent) worked in a first-opinion private practice, 25 (14.9 per cent) worked in a 24/7 private practice, 11 (6.5 per cent) worked in a referral private practice, eight (4.8 per cent) worked in a university hospital, two (1.2 per cent) were not currently practising with small animals and one (0.6 per cent) had retired. Of the 130 (78.8 per cent) practising respondents who reported using a syringe pump, eight (4.8 per cent) used a TCI system, 31 (18.8 per cent) used manual TCI, 40 (24.2 per cent) used a bolus elimination-transfer scheme and 51 (31 per cent) used a constant-rate infusion. As a result, 79 of 165 (47.9 per cent) practising respondents used a pharmacokinetic model-driven method of drug delivery. The majority of respondents (81.2 per cent) believed that the use of pumps with TCI capability would improve practice and patient care. PMID- 21262612 TI - Milk production in early lactation in a dairy herd following supplementation with iodine, selenium and cobalt. PMID- 21262613 TI - Use of desmopressin eye drops in the treatment of equine congenital central diabetes insipidus. PMID- 21262614 TI - Lead poisoning in calves associated with eosinophilic meningitis. PMID- 21262615 TI - Risks to cattle transported long distances in late pregnancy. PMID- 21262616 TI - Eimeria ivitaensis in British alpacas. PMID- 21262617 TI - Dairy production and a life worth living. PMID- 21262620 TI - Poultry welfare: new regulations introduced. PMID- 21262622 TI - Support for TB-affected farmers. PMID- 21262621 TI - New venture promotes excellence in veterinary research and education. PMID- 21262623 TI - Antimicrobial sales rise in 2009. PMID- 21262624 TI - RVC appoints its next principal. PMID- 21262625 TI - Concerns grow about PPR in Tanzania. PMID- 21262626 TI - Production animal centre opens at Glasgow. PMID- 21262627 TI - Diverging destinies? Comparing the profession in the USA and UK. PMID- 21262628 TI - Advice on antibiotic-resistant infections. PMID- 21262629 TI - First-choice therapy for dogs presenting with diarrhoea in clinical practice. AB - Computerised referral histories were reviewed for dogs admitted to the University of Liverpool Small Animal Teaching Hospital between January 2000 and December 2008 with diarrhoea among the clinical signs. A total of 371 cases presenting to the referring veterinary surgeon were included in the study, and information was compiled regarding signalment, clinical signs and treatment given at the initial consultation. Various breeds, ages and sexes were represented. Antibacterials were used in 263 (71 per cent) cases, steroids in 71 (19 per cent) cases and miscellaneous antidiarrhoeal products (including probiotics, prebiotics, adsorbents and antimotility drugs) in 98 (26 per cent) cases. Other drugs used included antiemetics (48 of 371 [13 per cent] cases), gastric protectants (37 of 371 [10 per cent] cases) and sulfasalazine (26 of 371 [7 per cent] cases). Antibacterial administration was positively associated with hyperthermia (odds ratio [OR]=2.97, P=0.012) and anorexia (OR=2.17, P=0.0075), but negatively associated with both weight loss (OR=0.55, P=0.036) and tenesmus (OR=0.43, P=0.035). In contrast, use of antidiarrhoeal products was positively associated with the presence of faecal mucus (OR=1.77, P=0.043), and negatively associated with vomiting (OR=0.57, P=0.025) and weight loss (OR=0.52, P=0.033). PMID- 21262630 TI - Factors affecting the mortality of weaned piglets during commercial transport between farms. AB - Factors affecting the number of weaned piglets found dead after commercial transport between farms were studied by means of multilevel Poisson regression. Information relating to 58,682 piglets during 109 journeys in different EU countries was collected at the end of each journey by means of questionnaires. Overall, 0.07 per cent of all the transported piglets were found dead on arrival, and deaths of piglets were recorded in 13.8 per cent of journeys. The final regression model, which was calculated using the complete records from 105 journeys, included the total duration of the journey, the mean outside temperature during the journey, whether the piglets were fasted before transport, whether drinking water was provided, the type of ventilation in the vehicle and the interaction between journey duration and the mean outside temperature. The duration of the journey and the mean outside temperature showed a significant interaction effect, with a gradual increase in the predicted number of dead piglets with increasing journey duration as the outside temperature increased. Providing the piglets with drinking water and having mechanically assisted ventilation (fans) in the vehicle during the journey significantly reduced the number of deaths, as did fasting the piglets before transport. PMID- 21262631 TI - Clinicopathological and ultrasonographic findings in 40 water buffaloes (Bubalus bubalis) with traumatic pericarditis. AB - Forty buffaloes with traumatic pericarditis were examined to characterise the ultrasonographic findings in buffaloes with traumatic pericarditis, determine the extent of the lesions and assess the prognosis. The most noticeable clinical presentations were presternal oedema (73 per cent) and jugular and mammary vein distension (88 per cent). Laboratory findings included neutrophilic leucocytosis, elevated total protein concentration, hypoalbuminaemia, hypergammaglobulinaemia and increased concentration of free fatty acids. Ultrasonographically, fluid in the pericardium appeared as either mild or massive anechoic accumulations containing fibrin threads or were imaged as homogenous, echogenic pericardial effusions. Moderate to severe corrugation of the reticular wall was observed. Deposits of fibrinous tissue interspersed with fluid pockets were seen between the reticulum, dorsal ruminal sac and diaphragm. Perireticular and mediastinal abscesses were imaged and appeared as echogenic lines with anechoic, echogenic, homogenous or heterogeneous contents. Additional ultrasonographic findings included hepatomegaly, dilation of the caudal vena cava, hepatic and portal veins, ascites, echogenic pleural effusions and vegetations of the tricuspid, mitral and pulmonary valves. The ultrasonographic findings were confirmed at postmortem examination. PMID- 21262632 TI - Local interleukin-2 therapy of bovine vulval papilloma and carcinoma complex. PMID- 21262633 TI - Brucella species antibodies and isolation in wild boar in north-east Spain. PMID- 21262634 TI - Comparison of canine distemper viruses in domestic dogs and wild raccoon dogs in South Korea. PMID- 21262635 TI - Cattle Health Certification Standards and BVDV control. PMID- 21262636 TI - Strategy for eradicating BVD from Scotland. PMID- 21262639 TI - Treatment of psoroptic mange in cattle. PMID- 21262640 TI - Infectious bursal disease-like virus in cases of transmissible viral proventriculitis. PMID- 21262641 TI - Snapshot of the veterinary professions in 2010. PMID- 21262644 TI - Proposal to change bluetongue vaccination rules. PMID- 21262647 TI - Reminder on illegal mutilations of horses. PMID- 21262649 TI - One Health: the small animal dimension. AB - Earlier this year, the World Small Animal Veterinary Association (WSAVA) established a One Health committee with the remit of positioning small companion animals in the global One Health framework. Here, Michael Day, the chairman of that committee, explains how companion animals fit within the One Health concept. PMID- 21262650 TI - Brain and skull lesions resulting from use of percussive bolt, cervical dislocation by stretching, cervical dislocation by crushing and blunt trauma in turkeys. AB - Three experiments were conducted to assess brain damage resulting from percussive bolt shooting and cervical dislocation by crushing (neck crushing) in turkey hens (mean [se] bodyweight 11.4 [0.1] kg); percussive bolt shooting and blunt trauma in turkey toms (13.1 [0.2] kg); and percussive bolt shooting, blunt trauma and cervical dislocation by stretching (neck stretching) in broiler turkeys (3.9 [0.3] kg). Brain and skull damage were assessed using macroscopic and microscopic evaluations and CT. Macroscopic subcutaneous haemorrhage was significantly greater with the percussive bolt in all three experiments (hens P=0.01, toms P=0.02, broilers P=0.0003), and skull fractures were more severe for toms (P<0.0001) and broilers (P=0.03) killed with the percussive bolt versus blunt trauma. In a subsample of turkeys, microscopic brain damage was present in all turkeys killed by percussive bolt shooting (five hens, 10 toms and four broilers) and blunt trauma (nine toms and three broilers), but only in one of four turkeys killed by neck crushing and one of four turkeys killed by neck stretching. Percussive bolt shooting and blunt trauma most likely caused death by directly disrupting brain function, whereas neck stretching and neck crushing probably resulted in death from cerebral hypoxia and ischaemia. PMID- 21262651 TI - Virulence gene profiles and intimin subtypes of Shiga toxin-producing Escherichia coli isolated from healthy and diarrhoeic calves. AB - The virulence properties of Shiga toxin-producing Escherichia coli (STEC) strains isolated from diarrhoeic and non-diarrhoeic calves were compared. The strains were also tested for O157:H7, O111 and O26 serotypes, using PCR and conventional serotyping methods. E coli strains isolated from 297 faecal samples, from 200 diarrhoeic and 97 non-diarrhoeic calves, were screened by multiplex PCR assay for the stx1, stx2, eae and Ehly virulence genes. STECs were recovered from 8 per cent of diarrhoeic calves and 10.3 per cent of non-diarrhoeic calves. The predominant virulence gene profile was stx1/eae/Ehly (47.3 per cent) among isolates from diarrhoeic calves and eae/Ehly (36.8 per cent) among isolates from non-diarrhoeic calves. Among three tested serogroups, the predominant serogroup was O26 (18.4 per cent), and O157:H7 was not detected. Intimin subtyping by restriction fragment length polymorphism analysis revealed only three intimin subtypes (beta, gamma and ). A significant difference was observed in the distribution of Int- between two groups. Int- was present in 50 per cent of the isolates from diarrhoeic calves and in 11.1 per cent of the isolates from non diarrhoeic calves; this difference was statistically significant (P=0.01). PMID- 21262652 TI - Medical management of Trichophyton dermatophytosis using a novel treatment regimen in L'Hoest's monkeys (Cercopithecus lhoesti). AB - An outbreak of Trichophyton dermatophytosis was diagnosed in a group of four L'Hoest's monkeys (Cercopithecus lhoesti) housed in the primate section at a zoological collection. The affected animals presented with areas of non-pruritic alopecia, scaling and crusting. The diagnosis was based on culture and direct microscopy of hair plucks. Treatment was commenced with oral terbinafine at a dose of 8.25 mg/kg bodyweight, topical enilconazole washes and disinfectant fogging of the enclosure. Control measures were designed to limit the spread of infection and reduce the zoonotic risk. Treatment was successful, with no further clinical cases being diagnosed and with resolution of the clinical signs after four weeks and mycological cure after eight weeks. PMID- 21262653 TI - QX-type infectious bronchitis virus in commercial flocks in the UK. PMID- 21262654 TI - Pain after injection of a new formulation of propofol in six dogs. PMID- 21262655 TI - Staphylococcus aureus mastitis in Texel sheep associated with suckling twins. PMID- 21262658 TI - Detection of IBV QX in commercial broiler flocks in the UK. PMID- 21262659 TI - Digit amputation by lay foot trimmers. PMID- 21262660 TI - Reducing the suicide rate in the profession. PMID- 21262662 TI - Multiresistant Escherichia coli in racing pigeons. PMID- 21262663 TI - Concern about spending cuts aired at Northern Ireland dinner. PMID- 21262664 TI - Strong support for reform of the Dangerous Dogs Act. PMID- 21262666 TI - Vets urged to report caesareans to the Kennel Club. PMID- 21262667 TI - Meat and milk from cloned animals 'unlikely to present any food safety risk'. PMID- 21262668 TI - Safeguarding animal health and welfare in challenging times. PMID- 21262670 TI - Veterinary medicines: product update. PMID- 21262671 TI - Twice as many outbreaks of lungworm disease in Scottish cattle as in 2009. AB - Parasitic bronchitis in cattle; sudden deaths due to hypomagnesaemia in adult cattle; louping ill confirmed in adult cattle and young sheep; copper poisoning in Lleyn ewes associated with access to clover herbage with high copper and low molybdenum; polyarthritis due to Mycoplasma hyorhinis in growing pigs. These are among matters discussed in the disease surveillance report for September from SAC Consulting: Veterinary Services (SAC C VS). PMID- 21262672 TI - Acute phase protein concentrations in dogs with nasal disease. AB - The concentrations of C-reactive protein (CRP), serum amyloid A, haptoglobin (Hp) and alpha(1)-acid glycoprotein were measured in dogs with clinical signs of nasal disease and compared with those of healthy dogs in order to determine the expression of these proteins in cases of canine nasal disease. A significant difference (P<0.001) between the symptomatic group and the control group was found for both CRP and Hp. Among the animals with nasal disease, a significant intergroup difference (P<0.05) was found in the expression of Hp between dogs with aspergillosis and those with chronic rhinitis. PMID- 21262673 TI - Safety of a non-adjuvanted therapeutic vaccine for the treatment of feline dermatophytosis. AB - The safety of a non-adjuvanted inactivated fungal vaccine for the treatment of dermatophytosis in cats was investigated in two studies: a controlled laboratory study, and a placebo-controlled double-blind field study with a cross-over design in Europe. In the laboratory study, two groups of 10 cats each were administered an intramuscular twofold overdose, followed by five single 1 ml doses, of either vaccine or control product at 14-day intervals. In the field study, cats were treated with three intramuscular injections of 1 ml vaccine administered at 14 day intervals, as recommended by the manufacturer. A total of 89 cats were enrolled in the field study and divided into two groups to receive either vaccine or placebo for the first three treatments, followed by the opposite product for the final three treatments. The cats enrolled in the two studies were 12 weeks of age or older, as recommended by the manufacturer. All the cats were monitored closely for possible injection site reactions, systemic reactions (including changes in rectal body temperature) and adverse events. The results from both studies showed no significant differences between the vaccinated cats and the control or placebo-treated cats with regard to local or systemic reactions. A few mild to moderate local reactions were noted, but these were evenly distributed between the vaccinated and placebo-treated cats and resolved within a few days. No severe or serious adverse events related to the vaccinations were observed. PMID- 21262674 TI - Fracture of the extensor process of the distal phalanx in a bull and a cow. AB - Two cases of extensor process fracture of the distal phalanx in the forelimb in a Holstein bull and a lactating Holstein cow are described. Each animal showed acute onset of severe lameness with a gait characterised by lengthening of the cranial phase of the step in order to place more weight on the heel. Mild swelling and a localised pain response upon application of deep pressure above the coronet were also observed. A definitive diagnosis was made by radiography with complementary ultrasonography, which provided the best definition of the fracture fragment over the dorsal aspect of the distal interphalangeal joint. Applying a wooden block to a sound claw for three weeks was curative and provided a good prognosis in both cases. PMID- 21262675 TI - Rabies in two vaccinated dogs in Israel. PMID- 21262676 TI - Total oxidant and antioxidant capacities and nitric oxide levels in cattle with traumatic reticuloperitonitis. PMID- 21262677 TI - Infectious coryza in chickens in Great Britain. PMID- 21262678 TI - Possible resistance in equine pinworms. PMID- 21262679 TI - Requirement for extramural studies. PMID- 21262680 TI - Composition of RCVS Council. PMID- 21262691 TI - Northern Ireland disease surveillance, July to September 2010. PMID- 21262692 TI - Short-lived carriage of foot-and-mouth disease virus in human nasal cavities after exposure to infected animals. AB - A quarantine period for potentially contaminated personnel can be used to reduce the risk of transfer of foot-and-mouth disease virus (FMDV) from infected to susceptible premises. This is set at 72 hours in the UK, on the basis of results from laboratory studies and field observations. Previous analysis of FMDV carriage within human nasal cavities has relied upon virus isolation by culture in susceptible cells. This study, involving 51 people, evaluated a PCR method, which detected viral genomic material within 35 nasal swabs taken from personnel after up to eight hours exposure to infected animals. Only one of 23 people who was PCR-positive immediately after exposure to FMDV-infected animals remained positive the following day, indicating a low risk of prolonged carriage of virus in the nasal cavities. PMID- 21262693 TI - Antibodies to parvovirus, distemper virus and adenovirus conferred to household dogs using commercial combination vaccines containing Leptospira bacterin. AB - To examine how the inclusion (+) or exclusion (-) of inactivated Leptospira antigens in a vaccine for canine parvovirus type 2 (CPV-2), canine distemper virus (CDV) and canine adenovirus type 2 (CAdV-2) affects antibody titres to CPV 2, CDV and CAdV-1 antigens, household dogs were vaccinated with commercially available vaccines from one of three manufacturers. CPV-2, CDV and CAdV-1 antibody titres were measured 11 to 13 months later and compared within three different age groups and three different bodyweight groups. There were significant differences between CPV-2 antibody titres in dogs vaccinated with (+) vaccine and those vaccinated with (-) vaccine for two products in the two-year old group and for one product in the greater than seven-year-old group; no significant differences were seen that could be attributed to bodyweight. No differences in CDV antibody titres were observed within age groups, but a significant difference was seen in the 11 to 20 kg weight group for one product. Significant differences in CAdV-1 antibody titres were seen for one product in both the two-year-old group and the <=10 kg weight group. PMID- 21262694 TI - Survey of prevalence and control of ectoparasites in caged poultry in China. AB - To investigate the prevalence and control of ectoparasites in China, 1200 questionnaires were delivered to caged commercial layer or parent hen keepers. Of the 860 respondents, 785 (91.3 per cent) claimed they found suspected ectoparasites in their birds and 833 samples were received. Ectoparasites of the species Dermanyssus gallinae, Ornithonyssus sylviarum or Menacanthuss stramineus were found in 736 (88.4 per cent) samples. For caged commercial layers, D gallinae was the most common ectoparasite (64.1 per cent). For caged parent hens, O sylviarum was the most common ectoparasite (46.9 per cent). Most bird keepers (95.0 per cent of commercial layer keepers and 74.9 per cent of parent hen keepers) used pyrethroids, organophosphates or other insecticides or acaricides to control ectoparasites. However, 34.6 per cent of layer keepers and 25.7 per cent of parent hen keepers did not re-treat their birds with insecticides or acaricides within two weeks after the first treatment. Sanitation procedures, including cleaning, washing and disinfection, were conducted in empty houses between flocks and on most commercial layer farms and parent hen farms. However, insecticides or acaricides were used in empty houses between flocks only in 24.8 per cent of commercial layer farms and in 36.1 per cent of parent hen farms. PMID- 21262695 TI - Idiopathic bovine neonatal pancytopenia in a Scottish beef herd. PMID- 21262696 TI - Changes in age at diagnosis of PMWS in pigs in Spain, 1998 to 2008. PMID- 21262697 TI - Ensuring a future for clinical research. PMID- 21262699 TI - Sarcoptic mange in alpacas. PMID- 21262700 TI - TB Health Check Wales. PMID- 21262701 TI - Use of acupuncture in veterinary medicine. PMID- 21262702 TI - Composition of RCVS Council. PMID- 21262703 TI - Responsible use of anthelmintics in sheep. PMID- 21262704 TI - Decide on responsibilities before costs, says RCS advisory group. PMID- 21262705 TI - Health check gives a clearer picture of bovine TB in Wales. PMID- 21262706 TI - 'Think life' at Christmas, urges canine charity. PMID- 21262707 TI - Higher tuition fees to be linked to wider access. PMID- 21262708 TI - Finding out about veterinary medicines authorised in the UK. PMID- 21262710 TI - Parasitic bronchitis causes problems in cattle. AB - Parasitic bronchitis (lungworm, husk) in cattle Lead poisoning in cattle associated with bonfire ash Deaths of ewes associated with faulty administration of boluses Streptococcus suis associated with respiratory and nervous disease in pigs Blackhead and mycoplasmosis causing losses in turkeys These are among matters discussed in the Veterinary Laboratories Agency's (VLA's) disease surveillance report for October. PMID- 21262711 TI - Electrocardiography of the normal domestic pet rabbit. AB - To establish a well-tolerated technique for recording electrocardiograms (ECGs) and a reference range for the normal pet rabbit ECG, 46 healthy pet rabbits were studied. The following reference ranges were calculated. Heart rate was 198 to 330 bpm. P waves had a duration of 0.01 to 0.05 seconds and an amplitude of 0.04 to 0.12 mV. The P-R interval was 0.04 to 0.08 seconds and the duration of the QRS complex was 0.02 to 0.06 seconds. The amplitude of the R wave was 0.03 to 0.39 mV. The Q-T interval was 0.08 to 0.16 seconds. The amplitude of the T wave was 0.05 to 0.17 mV. Mean electrical axis was found to be -43 degrees to +80 degrees . Evidence of variation due to breed or bodyweight was not found to be significant, except for a quadratic relationship between R wave amplitude and bodyweight. The ECG recording technique used in this study for pet rabbits was well tolerated and shown to be both reliable and repeatable. PMID- 21262712 TI - Detection of Coxiella burnetii in placenta and abortion samples from British ruminants using real-time PCR. AB - A real-time PCR was developed to detect Coxiella burnetii (the cause of Q fever) in ruminant placentas and aborted fetuses. Primer and probe sets previously developed for human tissue studies were used to target the insertion sequence IS1111 gene for C burnetii. The assay was highly sensitive, with a limit of detection of 10 copies of template, theoretically equating to a single bacterium, and did not cross-react with a panel of other bacteria. To determine sensitivity on field samples submitted for the diagnosis of abortion, results using the IS1111 PCR assay were compared with a com1 PCR assay. When applied to ruminant abortion material, including placental cotyledons and fetal samples, the IS1111 and com1 assays yielded positive results in 23 (25 per cent) of 93 and 19 (20 per cent) of 93 samples, respectively. One infected goat herd was monitored for 31 months: 57 (92 per cent) of 62 placental cotyledon samples from aborting and non aborting goats, and 10 (30 per cent) of 33 fetal samples were positive by the IS1111 PCR assay. PMID- 21262713 TI - Observational study of 14 cases of chronic pancreatitis in dogs. AB - This study reports the clinical, clinicopathological and ultrasonographic findings from dogs with chronic pancreatitis (CP). Fourteen dogs with clinical signs consistent with CP and histological confirmation of the disease were evaluated. Abdominal ultrasound and clinical pathology results were recorded. Sensitivities of pancreatic enzymes for diagnosis of CP were calculated with two different cut-off values. The mean age of affected dogs was 9.1 years. Spaniels were the most common breed with CP, representing seven of the 14 dogs in this study. CP was histologically severe in nine cases. Most dogs showed chronic low grade gastrointestinal signs and abdominal pain. Five dogs had exocrine pancreatic insufficiency and five dogs had diabetes mellitus. The sensitivity of elevated trypsin-like immunoreactivity for CP was 17 per cent. The sensitivities of canine pancreatic lipase immunoreactivity, lipase and amylase for CP were 44 to 67 per cent or 14 to 28 per cent depending on the cut-off value used. Cholesterol was elevated in 58 per cent of samples. Liver enzymes were often elevated. The pancreas appeared abnormal on 56 per cent of ultrasound examinations. Ten dogs had died by the end of the study period; only one case was due to CP. PMID- 21262714 TI - Further assessment of air filtration for preventing PRRSV infection in large breeding pig herds. PMID- 21262715 TI - Morphometric assessment of cranial volumes in age-matched Cavalier King Charles spaniels with and without syringomyelia. PMID- 21262716 TI - Cryptosporidium species in calves submitted for postmortem examination in England and Wales. PMID- 21262717 TI - Need for a new kind of partnership on animal health. AB - The report from the England Advisory Group on Responsibility and Cost Sharing recommends a new approach built around the idea of an England Partnership Board. Rosemary Radcliffe, the group's chair, gives her perspective. PMID- 21262718 TI - Supplementation of dairy cows with iodine. PMID- 21262719 TI - Climate change and economic priorities. PMID- 21262720 TI - Digit amputation by lay foot trimmers. PMID- 21262722 TI - Sheep scab reinstated as a notifiable disease in Scotland. PMID- 21262723 TI - Government to clamp down on unauthorised pet remedies. PMID- 21262728 TI - Scanning for microchips--what should the BVA's position be? PMID- 21262729 TI - Tailored reference limits for urine corticoid:creatinine ratio in dogs to answer distinct clinical questions. AB - To establish reference intervals for the urinary corticoid:creatinine ratio (UCCR) determined by chemiluminometric immunoassay, UCCR was measured by this method in 50 healthy dogs. To assess the diagnostic performance of different cut off levels, the UCCR of 66 dogs with hyperadrenocorticism and 87 dogs with diseases mimicking hyperadrenocorticism were used to construct a receiver operating characteristic (ROC) curve. The upper reference limit derived from morning samples in healthy dogs was 30.81 * 10(-6). The area under the ROC curve was 0.94. The diagnostic cut-off with the highest negative likelihood ratio was 26.5 * 10(-6) (sensitivity 1, specificity 0.54), whereas the cut-off with the highest positive likelihood ratio was 161.2 * 10(-6) (specificity 0.988, sensitivity 0.515). The application of these two different diagnostic cut-offs eliminated the necessity to perform additional tests in 53 per cent of the patient population. PMID- 21262730 TI - Influence of modified open lung concept ventilation on the cardiovascular and pulmonary function of horses during total intravenous anaesthesia. AB - The influence of a modified open lung concept (mOLC) on pulmonary and cardiovascular function during total intravenous anaesthesia (TIVA) in horses was evaluated. Forty-two warmblood horses (American Society of Anesthesiologists class 1 to 2), scheduled for elective surgery (mean [sd] weight 526 [65] kg, age 6.4 [5.4] years) were randomly divided into three groups: ventilation with mOLC, intermittent positive-pressure ventilation (IPPV), and spontaneous breathing. Premedication (0.8 mg/kg xylazine), induction (2.2 mg/kg ketamine and 0.05 mg/kg diazepam) and maintenance of anaesthesia with TIVA (1.4 mg/kg/hour xylazine, 5.6 mg/kg/hour ketamine and 131.1 mg/kg/hour guaifenesin), with inhalation of 35 per cent oxygen in air, were identical in all horses. Heart rate, respiratory rate, mean arterial blood pressure (MAP), pH, and arterial partial pressure of oxygen (p(a)O(2)) and carbon dioxide (p(a)CO(2)) were evaluated. Data were collected every 10 minutes from 20 to 90 minutes anaesthesia time. Factorial analysis of variance and Tukey's post hoc test were used for statistical analysis (a=5 per cent). Horses in the mOLC-ventilated group had an overall significantly higher p(a)O(2) (16.9 [1.0] v 11.7 [1.34] v 10.5 [0.57] kPa) and lower MAP (93.1 [5.47] v 107.1 [6.99] v 101.2 [5.45] mmHg) than the IPPV and spontaneously breathing groups, respectively. PMID- 21262731 TI - Retrospective detection by negative contrast electron microscopy of faecal viral particles in free-living wild red squirrels (Sciurus vulgaris) with suspected enteropathy in Great Britain. AB - Transmission electron microscopy identified adenovirus particles in 10 of 70 (14.3 per cent) samples of large intestinal content collected at postmortem examination from free-living wild red squirrels (Sciurus vulgaris) across Great Britain between 2000 and 2009. Examination was limited to cases in which an enteropathy was suspected on the basis of predetermined macroscopic criteria such as semi-solid or diarrhoeic faeces, suspected enteritis or the presence of intussusception. In most cases, meaningful histological examination of enteric tissue was not possible due to pronounced autolysis. Two (2.9 per cent) of the samples were negative for adenovirus but were found to contain rotavirus particles, a novel finding in this species. PMID- 21262732 TI - Treatment of Malassezia overgrowth with itraconazole in 15 cats. PMID- 21262733 TI - Prevalence of Borrelia infection in ticks from wildlife in south-west England. PMID- 21262734 TI - Use of acupuncture in veterinary medicine. PMID- 21262735 TI - Giardiosis in Eurasian badgers (Meles meles). PMID- 21262736 TI - Reducing the suicide rate in the profession. PMID- 21262737 TI - Use of acupuncture in veterinary medicine. PMID- 21262738 TI - Inequities in advice on vitamin D? PMID- 21262739 TI - Early vs. delayed invasive strategy in patients with acute coronary syndromes without ST-segment elevation: a meta-analysis of randomized studies. AB - Although early percutaneous coronary intervention has been demonstrated to reduce the risk of mortality in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), there are emerging conflicting data as to whether the catheterization needs to be done very early or whether it could be delayed while the patient receives medical therapy. The aim of the current study was to perform a meta-analysis of randomized controlled trials (RCTs) comparing early vs. delayed invasive strategies for NSTE-ACS patients. Medline/CENTRAL and the Web were searched for RCTs comparing early vs. delayed invasive strategies for NSTE ACS patients. The primary endpoint was all cause mortality, whereas myocardial infarction (MI), coronary revascularizations and 30-day major bleeding complications were secondary end points. Fixed or random effects models were used based on statistical heterogeneity. As a sensitivity analysis, Bayesian random effects meta-analysis was performed in addition to the classical random effects meta-analysis. A total of 5 RCTs were finally included, enrolling 4155 patients. As compared with a delayed strategy, an early invasive approach did not significantly reduce the rates of death [odds ratio (OR) 95% confidence interval (95% CI) = 0.81 (95% CI 0.60-1.09), P = 0.17], MI [OR = 1.18 (95% CI 0.68-2.05), P = 0.55] or revascularizations [OR = 0.97 (0.77-1.24), P = 0.82]. There was a not significant trend toward fewer major bleeding complications for the early invasive approach [OR (95% CI) = 0.76 (0.55-1.04), P = 0.08]. The present meta analysis shows that for NSTE-ACS patients a routine early invasive strategy does not significantly improve survival nor reduce MI and revascularization rates as compared with a delayed approach. PMID- 21262740 TI - A hybrid ICD extraction approach using laser and transfemoral extraction technique. PMID- 21262741 TI - Symmetrical peripheral gangrene, an uncommon complication of tuberculosis. PMID- 21262742 TI - Toward microRNA-mediated gene regulatory networks in plants. AB - Current achievements in plant microRNA (miRNA) research area are inspiring. Molecular cloning and functional elucidation have greatly advanced our understanding of this small RNA species. As one of the ultimate goals, many research efforts devoted to draw a comprehensive view of miRNA-mediated gene regulatory networks in plants. Numerous bioinformatics tools competent for network analysis have been available. However, the most important point for network construction is to obtain reliable analytical results based on sufficient experimental data. Here, we introduced a general workflow to retrieve and analyze the desired data sets that serve as the cornerstones for network construction. For the upstream analyses of miRNA genes, the sequence feature of miRNA promoters should be characterized. And, regulatory relationships between transcription factors (TFs) and miRNA genes need to be investigated. For the downstream part, we emphasized that the high-throughput degradome sequencing data were especially useful for genuine miRNA-target pair identification. Functional characterization of the miRNA targets is essential to provide deep biological insights into certain miRNA-mediated pathways. For miRNAs themselves, studies on their organ- or tissue-specific expression patterns and the mechanism of self-regulation were discussed. Besides, exhaustive literature mining is required to further support or improve the established networks. It is desired that the introduced framework for miRNA-mediated network construction is timely and useful and could inspire more research efforts in the miRNA research area. PMID- 21262743 TI - Predicting posttraumatic stress following pediatric injury: a systematic review. AB - OBJECTIVE: To review the recent empirical literature concerning development of posttraumatic stress symptoms following pediatric injury and summarize risk and predictive factors that will inform clinical practice and research. METHODS: A systematic search of online databases such as PsycInfo, PILOTS, MedLine, and PubMed was performed. Further studies were identified through the reference lists of selected articles. RESULTS: Pre-injury psychological problems, the child's subjective experience of trauma severity/life threat, elevated heart rate immediately following the trauma, beliefs regarding initial symptoms, active thought suppression, and parental posttraumatic stress appear to be consistent predictors of persisting posttraumatic stress in children following injury. CONCLUSIONS: Specific variables may be useful in predicting posttraumatic stress following injury, which are discussed in terms of existing models of pediatric traumatic stress. Methodologies of included studies are also discussed. PMID- 21262744 TI - The impact of caregiver distress on the longitudinal development of child acute post-traumatic stress disorder symptoms in pediatric injury victims. AB - OBJECTIVE: The present study prospectively examined the development of child PTSD symptoms (PTSS) and the impact of caregiver PTSS on child PTSS following injury. METHODS: One hundred and eighteen ED patients and their caregivers were interviewed in-hospital and 2- and 6-weeks posttrauma. Structural equation modeling and hierarchical linear regressions examined the development of PTSS. RESULTS: A model combining child and caregiver 2-week PTSS into one latent family PTSS variable provided the best fit to the data. Child in-hospital avoidance symptoms predicted higher levels of 2-week family PTSS. Two-week family PTSS predicted child 6-week PTSS. Post hoc analyses revealed an interaction between in hospital caregiver avoidance symptoms and child reexperiencing symptoms in predicting 6-week child PTSS. CONCLUSIONS: Results highlight the dynamic development of child PTSS. Different symptom clusters may be related to higher PTSS at differing times posttrauma and may inform the development of time sensitive methods of assessment and intervention for injury victims. PMID- 21262745 TI - Paracetamol and antibiotics in childhood and subsequent development of wheezing/asthma: association or causation? AB - BACKGROUND: Several studies found an association between early administration of paracetamol and antibiotics and development of wheezing. This could be due to confounding: wheeze and asthmatic symptoms in early childhood are difficult to distinguish from respiratory tract infections that are widely treated with these drugs; in case of persistence of symptoms up to school age, this could explain the observed relationship. METHODS: We investigated the association between paracetamol and antibiotics use in the first year of life and wheezing phenotypes, i.e. wheezing starting in different time periods (early, persistent and late-onset) in the SIDRIA-2 study, a cross-sectional survey of 16,933 children aged 6-7 years. Directed acyclic graph (DAG) was used to depict the causal structure. RESULTS: Paracetamol and antibiotics administration in the first year were associated with early wheezing (first 2 years of life only) [odds ratio (OR): 2.27; 95% confidence interval (95% CI): 1.98-2.62 and OR = 3.76, 95% CI: 3.31-4.27] and with persistent wheezing (first 2 years + last 12 months) (OR = 1.77, 95% CI: 1.49-2.10 and OR = 3.06, 95% CI: 2.60-3.60), whereas the association with late-onset wheezing (in the last 12 months only) was weak (OR = 1.12, 95% CI: 0.97-1.31 and OR = 1.18, 95% CI: 1.02-1.38 for paracetamol and antibiotics, respectively). DAG shows that even in the absence of a direct (causal) arrow from early drugs use to wheezing at school age, the two are associated due to confounding (through the 'infection' node). CONCLUSIONS: It is important to take into account different phenotypes in order to disentangle the association of paracetamol and antibiotics with wheezing. PMID- 21262746 TI - Review: increasing fluoride concentrations in toothpastes improved prevention of dental caries. PMID- 21262747 TI - Avoiding clinical trials in children. PMID- 21262748 TI - Understanding cloacal anomalies. AB - Persistent cloaco is the most severe type of anorectal malformation encountered in children. Patients with cloacal anomalies have a high incidence of associated anomalies most commonly: urinary tract and spinal. Persistent cloaca remains a difficult reconstructive challenge but it is now possible to anatomically correct the defect with surgery in the majority of patients. This review discusses embryology, prenatal diagnosis, neonatal physical and radiological findings. A summary of early management and investigation is provided and the commonest surgical reconstruction techniques are discussed. The main goals of surgical reconstruction are the achievement of bowel and bladder control for the child and normal sexual function in adult life. Although the majority of cloaca patients can achieve faecal and urinary continence with the surgical reconstructive procedures performed today, many require additional/multiple urological procedures to achieve continence, treat bladder dysfunction and to protect renal function. One half of patients will develop renal failure, so regular and life long surveillance is mandatory. Due to the high number of associated gynaecological problems all patients should be assessed by a paediatric gynaecologist at puberty. PMID- 21262750 TI - A review of the fundamental principles and evidence base in the use of extracorporeal membrane oxygenation (ECMO) in critically ill adult patients. AB - Extracorporeal membrane oxygenation (ECMO) comprises a commonly used method of extracorporeal life support. It has proven efficacy and is an accepted modality of care for isolated respiratory or cardiopulmonary failure in neonatal and pediatric populations. In adults, there are conflicting studies regarding its benefit, but it is possible that ECMO may be beneficial in certain adult populations beyond postcardiotomy heart failure. As such, all intensivists should be familiar with the evidence-base and principles of ECMO in adult population. The purpose of this article is to review the evidence and to describe the fundamental steps in initiating, adjusting, troubleshooting, and terminating ECMO so as to familiarize the intensivist with this modality. PMID- 21262749 TI - Analytic review: Interleukin-6 in surgery, trauma, and critical care: part I: basic science. AB - A variety of cytokines play a role in the response to an inflammatory stimulus. The interleukin-6 (IL-6)-type cytokines are released in response to tissue injury or an inflammatory stimulus. They act locally and systemically to generate a variety of physiologic responses, principal among them is the acute phase response. The IL-6 type cytokines demonstrate pleiotropy and redundancy of actions. This is made possible by the distinctive characteristics of the IL-6 receptor complex, which contains an ubiquitous subunit that is shared by most IL 6-type cytokines, as well as a cytokine-specific subunit. PMID- 21262751 TI - Review of a large clinical series: Predicting death for patients with abdominal septic shock. AB - This paper reports the result of the MEDAN project that analyzes a multicenter septic shock patient data collection. The mortality prognosis based on 4 scores that are often used is compared with the prognosis of a trained neural network. We built an alarm system using the network classification results. Method. We analyzed the data of 382 patients with abdominal septic shock who were admitted to the intensive care unit (ICU) from 1998 to 2002. The analysis includes the calculation of daily sepsis-related organ failure assessment (SOFA), Acute Physiological and Chronic Health Evaluation (APACHE) II, simplified acute physiology score (SAPS) II, multiple-organ dysfunction score (MODS) scores for each patient and the training and testing of an appropriate neural network. Results. For our patients with abdominal septic shock, the analysis shows that it is not possible to predict their individual fate correctly on the day of admission to the ICU on the basis of any current score. However, when the trained network computes a score value below the threshold during the ICU stay, there is a high probability that the patient will die within 3 days. The trained neural network obtains the same outcome prediction performance as the best score, the SOFA score, using narrower confidence intervals and considering three variables only: systolic blood pressure, diastolic blood pressure and the number of thrombocytes. We conclude that the currently best available score for abdominal septic shock may be replaced by the output of a trained neural network with only 3 input variables. PMID- 21262752 TI - A positive response to a recruitment maneuver with PEEP titration in patients with ARDS, regardless of transient oxygen desaturation during the maneuver. AB - Recruitment maneuvers (RMs) can expand collapsed alveoli in ventilated patients. The optimal method for delivering RMs is unknown. PURPOSE: To evaluate the safety and the respiratory and hemodynamic effects of a staircase recruitment maneuver (SRM) with decremental positive end expiratory pressure (PEEP) titration and the consequences of desaturation during the SRM in patients with early acute lung injury (ALI). METHODS: In total, 20 consecutive patients with early ALI were enrolled and received an SRM. Patients were given 15 +/- 3 cm H(2)O pressure controlled ventilation. Positive end expiratory pressure was increased from baseline (range 10-18) to 20, 30, and 40 cm H(2)O every 2 minutes to achieve maximum alveolar pressure of 55 +/- 3 cm H(2)O, then decreased at 3-minute intervals to 25, 22.5, 20, 17.5, and 15 cm H(2)O until a decrease of 1% to 2% oxygen saturation from maximum was detected. Positive end expiratory pressure was left at the level where the fall in oxygen saturation occurred. Standard respiratory and circulatory variables, arterial and central venous gases were measured before, during, and after the SRM. RESULTS: There were significant improvements in shunt fraction (36.3% +/- 10% to 26.4% +/- 14%, P < .001), oxygen saturation (93.4% +/- 2% to 96.8% +/- 3%, P = .007), partial pressure of oxygen, arterial (PaO(2))/fraction of inspired oxygen ([FIO(2)]; 150 +/- 42 to 227 +/- 100, P = .004), lung compliance (33.9 +/- 9.1 to 40.1 +/- 11.4 mL/cm H(2)O, P < .01), and chest x-ray (CXR) after the SRM. Briefly, 80% of the patients responded and the response was maintained at 1 hour. In total, 8 patients desaturated 6.1% +/- 2.8% in SaO(2) during the SRM but 5 of those improved SaO(2) relative to baseline by the end of the SRM. CONCLUSIONS: In all, 80% of the patients with early ALI responded to the SRM with decremental PEEP titration. Desaturation during the SRM did not indicate a failed response 1 hour later. PMID- 21262753 TI - A program to improve the quality of emergency endotracheal intubation. AB - OBJECTIVE: To assess the results of a quality improvement (QI) project designed to improve safety of emergency endotracheal intubation (EEI). DESIGN: Single center prospective observational. SETTING: 16-bed intensive care unit. PARTICIPANTS: Nine pulmonary/critical care fellows. INTERVENTIONS: For 3 years, EEI performed by the medical intensive care unit team were analyzed to identify interventions that would improve quality of the procedure. By segmental process analysis, the procedure of EEI was subjected to iterative change. Major components of process improvement were development of a combined team approach, a mandatory checklist, use of crew resource management (CRM) tactics, and postevent debriefing. Quality analysis and improvement included training of fellows using scenario-based training (SBT) with computerized patient simulator (CPS) to improve mechanical skills of intubation and team leadership. Fellows received 15 sessions of SBT with CPS using a combined checklist and team approach before assuming team leadership position during real-life EEI. MEASUREMENTS: For a 10 month period, fellows carried digital voice recorders to EEI; which, when combined with recording of continuous oximetry and BP monitoring were used to assess the quality of EEI. MAIN RESULTS: 128 EEI were performed of which 101 had full data recorded. Complications were 14% severe hypoxemia (<80% saturation), 6% severe hypotension (SBP<70 mm Hg), 1% death, 20% difficult EEI (>= 3 attempts), 11% esophageal intubations, 2% aspiration, and 1% dental injury; 62% EEI were successfully achieved on first attempt, 11% required >3 attempts. CONCLUSIONS: EEI may be performed by pulmonary/critical medicine (PCCM) fellows with safety comparable to that described in other studies on EEI. Important parts of the program included the use of formal iterative QI approach, the use of intensive SBT with CPS, basic CRM, a comprehensive checklist, and a combined team approach. A key benefit of the program was to make the process of EEI fully transparent for ongoing quality and safety improvement. PMID- 21262754 TI - Persistent left superior vena cava in a child presenting with mild hypoxemia. PMID- 21262755 TI - Management of skin abscesses by primary care pediatricians. AB - BACKGROUND: Staphylococcus aureus is a common cause of skin abscesses. OBJECTIVE: To evaluate primary care pediatricians' management of skin abscesses. METHODS: A national mail survey of a random sample of 385 general pediatricians conducted from April to June 2010. RESULTS: The response rate was 49%. Most respondents (72%) were aware that the Centers for Disease Control and Prevention has recommendations for the management of soft tissue infections. Only 10% reported that no one in their practice could perform incision and drainage an uncomplicated abscess. Approximately one third (34%) reported that it is too time consuming to do so. About half (55%) were interested in further training in abscess management. CONCLUSION: Although most primary care pediatric practices are prepared to manage uncomplicated abscesses, more than half were interested in further training in the management of this condition. A comprehensive training program of skin infections could not only improve abscess management but also decrease barriers related to such care. PMID- 21262756 TI - Attention-deficit/hyperactivity disorder: a shift toward resilience? AB - Children with attention-deficit/hyperactivity disorder (ADHD) present a concern across clinical, academic, and social domains. However, a subset of these children does fairly well symptomatically and functionally. This article employs a resilience framework to organize the research on factors that promote favorable outcomes in ADHD. A PubMed search was conducted using key words: resilience and ADHD. Of particular interest were articles focusing on modifiable protective factors, such as parenting and pharmacotherapy. There is consensus that genetics strongly contributes to the etiology of ADHD. Parental, peer, and environmental factors may interact with genes to moderate the developmental expression of ADHD. Pharmacotherapy research reveals that medications exert positive effects of modest magnitude in academic achievement, social functioning and quality of life. However, there is insufficient evidence to determine whether treatment can modify developmental outcomes. Efforts to strengthen family support along with access to health and educational resources may also optimize outcomes. PMID- 21262757 TI - Focused assessment of patients with asthma in the emergency department. AB - Asthma remains a common cause for presentation to the emergency department. Multiple clinical asthma scores (CAS) have been developed to assess the severity of an asthma exacerbation. The objective of this retrospective study was to determine if adoption of a CAS and asthma guidelines identifies patients with more severe asthma and to identify factors that predict the need for hospital admission. The results identified the admission rates in the pre- and post-CAS groups to be similar. Within the post-CAS group, patients requiring admission received more aggressive therapy and were frequently hypoxic on initial presentation. In conclusion, CAS aids in identifying severe asthma exacerbations. Lack of response to aggressive therapy or hypoxia on initial presentation should prompt the emergency department physician to arrange for admission. PMID- 21262759 TI - Needle aspiration for the etiologic diagnosis of children with cellulitis in the era of community-acquired methicillin-resistant Staphylococcus aureus. AB - OBJECTIVE: Cellulitis is a common problem in children but determining the causative agent is difficult. One tool used to identify the etiology is needle aspiration. The purpose of this study was to determine the utility of needle aspiration in pediatric patients with cellulitis in the era of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). METHODS: This was a prospective descriptive study conducted in the emergency department of a tertiary care children's hospital. A convenience sample of healthy children, 0 to 18 years old, with cellulitis were enrolled. A standard cellulitis aspiration technique was performed. RESULTS: Twenty patients were enrolled and had cultures obtained. The etiologic agent was determined in 15% (3/20) of patients. The positive cultures were all MRSA. CONCLUSIONS: Although needle aspiration of cellulitis was of low yield, the only pathogens isolated in this study were CA-MRSA. Empiric antibiotics for cellulitis should include coverage for MRSA. In circumstances in which bacterial etiology and antibiotic susceptibility knowledge would be critical, needle aspiration should be considered. PMID- 21262760 TI - How they cope: a qualitative study of the coping skills of hospice volunteers. AB - The purpose of this phenomenological study was to examine the coping techniques utilized by hospice volunteers. Individual semi-structured interviews were conducted with 15 hospice volunteers who had at least 1 year of experience, working as a hospice volunteer with direct patient care. The interviews were digitally recorded, transcribed, and analyzed utilizing qualitative research methods. The results indicated the volunteers used problem-focused coping (seeking advice from members of the hospice interdisciplinary team), emotion focused coping (talking with others, going to funerals), meaning making through appraisal (religious beliefs, downward comparison), and physical techniques (walking, deep breathing). The most significant coping mechanism utilized for the volunteer was talking with the volunteer coordinator. Implications for hospice volunteer coordinators are also discussed. PMID- 21262758 TI - Viral etiology of acute febrile respiratory illnesses in hospitalized children younger than 24 months. AB - BACKGROUND: Respiratory infections are a leading cause of pediatric hospitalizations. This study investigated whether virus-virus or virus-Bordetella co-infections are more frequent or more severe than previously recognized. METHODS: This is a 3-year prospective study of children younger than 24 months hospitalized with a febrile respiratory illness. Viral pathogens were detected using multiplex polymerase chain reaction (PCR), enzyme-linked immunoassays, and/or viral cultures from nasopharyngeal samples. Bordetella infections were detected by PCR. RESULTS: A total of 201 patients were enrolled. Respiratory viruses were detected in 187 (93%) patients, with 52 (28%) multipathogen infections. The most common viruses detected were respiratory syncytial virus and rhinovirus/enterovirus. There were no differences in illness severity when comparing patients infected with one pathogen and those with multipathogen infection. CONCLUSION: Virus co-infection in young children hospitalized with an acute febrile respiratory infection is common but does not appear to be associated with illness severity. PMID- 21262761 TI - Overestimation of drinking norms and its association with alcohol consumption in apprentices. AB - AIMS: To investigate associations of normative misperceptions and drinking behaviors in apprentices, complementing the previous literature on university students. METHODS: A survey in a defined region of northern Germany was carried out among 1124 apprentices attending vocational schools. Using items from the short form of the Alcohol Use Disorders Identification Test (AUDIT-C), drinking behaviors and normative perceptions of drinking in the reference group of same gender apprentices were assessed. Demographic, smoking- and drinking-related predictors for normative misperceptions were explored. RESULTS: Personal drinking behavior was positively correlated with perceived norms, both for drinking frequency (males: Kendall's tau = 0.33, P < 0.01; females: tau = 0.22, P < 0.01) and drinking quantity (males: Kendall's tau = 0.39, P < 0.01; females: tau = 0.25, P < 0.01). Alcohol use disorders according to AUDIT-C cut-offs were more prevalent in subjects who overestimated drinking quantity in their reference group than in those who correctly estimated or underestimated drinking quantity (male: P < 0.01; relative risk (RR) 1.78; female: P < 0.01; RR 1.65). Concerning drinking frequency, this difference was only found in males (P < 0.01; RR 1.49). Male gender and higher alcohol use were positively associated with normative misperceptions of both drinking quantity and frequency. CONCLUSION: Interventions correcting alcohol use misperceptions might be effective in reducing problem drinking in adolescents with heterogeneous educational levels. PMID- 21262762 TI - Paradoxical changes in alcohol consumption and CAGE ratings between 1996 and 2006 in the general population of Geneva. AB - AIMS: To assess changes between 1996 and 2006 in alcohol use and dependence in the general population of Geneva, Switzerland. METHODS: Postal surveys of alcohol consumption patterns in representative samples of the general population were compared. The four-item CAGE (Cut down, Annoyed, Guilty, Eye-opener) screener was used to estimate alcohol dependence. RESULTS: There were 742 participants in 1996 (response rate 75%) and 1487 in 2006 (76%). The proportions of daily drinkers (1996: 18%; 2006: 10%; P < 0.001), and of heavy drinkers (>14 drinks/week) decreased between 1996 (13%) and 2006 (7%; P < 0.001). However, decreases in heavy drinking were limited to men aged 30+ and women aged 30-49. The average number of drinks/week decreased from 6.4 in 1996 to 5.0 in 2006 (P < 0.001). Perception of safe drinking levels decreased between 1996 (4 drinks/day) and 2006 (3 drinks/day, P < 0.001). The prevalence of alcohol dependence, defined as a CAGE score >= 2, increased among women (1996: 6%; 2006: 14%; P = 0.001), but not among men (1996: 18%, 2006: 19%). Two of the CAGE items were endorsed more frequently by women in 2006 than in 1996: 'guilty' (1996: 9%; 2006: 15%; P = 0.018) and 'should cut down' (1996: 12%; 2006: 18%; P = 0.04). Drinking and driving did not change significantly over time (2006: 21% of men, 9% of women). CONCLUSION: Alcohol consumption, heavy drinking and perceived levels of safe drinking decreased over these 10 years, but not drunk driving or alcohol dependence. Paradoxically, alcohol dependence even increased among women, driven by CAGE items 'guilty' and 'should cut down', suggesting that changes in CAGE scores reflected changes in the social acceptability of drinking rather than changes in dependence. PMID- 21262764 TI - Inhibitory phosphorylation of cyclin-dependent kinase 1 as a compensatory mechanism for mitosis exit. AB - The current paradigm states that exit from mitosis is triggered by the ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) acting in concert with an activator called CDC20. While this has been well established for a number of systems, the evidence of a critical role of CDC20 in somatic cells is not unequivocal. In this study, we reexamined whether mitotic exit can occur properly after CDC20 is depleted. Using single-cell analysis, we found that CDC20 depletion with small interfering RNAs (siRNAs) significantly impaired the degradation of APC/C substrates and delayed mitotic exit in various cancer cell lines. The recruitment of cyclin B1 to the core APC/C was defective after CDC20 downregulation. Nevertheless, CDC20-depleted cells were still able to complete mitosis, albeit requiring twice the normal time. Intriguingly, a high level of cyclin-dependent kinase 1 (CDK1)-inhibitory phosphorylation was induced during mitotic exit in CDC20-depleted cells. The expression of an siRNA-resistant CDC20 rescued both the mitotic exit delay and the CDK1-inhibitory phosphorylation. Moreover, the expression of a nonphosphorylatable CDK1 mutant or the downregulation of WEE1 and MYT1 abolished mitotic exit in CDC20-depleted cells. These findings indicate that, in the absence of sufficient APC/C activity, an alternative mechanism that utilized the classic inhibitory phosphorylation of CDK1 could mediate mitotic exit. PMID- 21262766 TI - Dnmt3a1 upregulates transcription of distinct genes and targets chromosomal gene clusters for epigenetic silencing in mouse embryonic stem cells. AB - Dnmt3a1 and Dnmt3a2 are two de novo DNA methyltransferases expressed in mouse embryonic stem cells (mESCs). They differ in that a 219-amino-acid (aa) amino (N) terminal noncatalytic domain is present only in Dnmt3a1. Here, we examined the unique functions of Dnmt3a1 in mESCs by targeting the coding sequence of the Dnmt3a1 N-terminal domain tagged with enhanced green fluorescent protein (GFP) for insertion into the mouse Rosa26 locus. Using these targeted cells (GFP 3a1Nter), we showed that Dnmt3a1 was efficiently recruited to the silenced Oct3/4 and activated Vtn (vitronectin) gene promoters via its unique N-terminal domain. This recruitment affected the two genes in contrasting ways, compromising Oct3/4 gene promoter DNA methylation to prevent consolidation of the silent state while significantly reducing Vtn transcription. We used this negative effect of the Dnmt3a1 N-terminal domain to investigate the extent of transcriptional regulation by Dnmt3a1 in mESCs by using microarrays. A small group of all-trans retinoic acid (tRA)-inducible genes had lower transcript levels in GFP-3a1Nter cells than in wild-type mESCs. Intriguingly, this group included genes that are important for fetal nutrition, placenta development, and metabolic functions and is enriched for a distinct set of imprinted genes. We also identified a larger group of genes that showed higher transcript levels in the GFP-3a1Nter-expressing cells than in wild-type mESCs, including pluripotency factors and key regulators of primordial germ cell differentiation. Thus, Dnmt3a1 in mESCs functions primarily as a negative and to a lesser extent as a positive regulator of transcription. Our findings suggest that Dnmt3a1 positively affects transcription of specific genes at the promoter level and targets chromosomal domains to epigenetically silence gene clusters in mESCs. PMID- 21262768 TI - Early-onset aging and defective DNA damage response in Cdc14b-deficient mice. AB - The Cdc14 dual-specificity phosphatase plays a key role in the mitotic exit of budding yeast cells. Mammals have two homologues, Cdc14a and Cdc14b. Unlike the yeast counterpart, neither Cdc14a nor Cdc14b seems to be essential for mitotic exit. To determine the physiological function of Cdc14b, we generated mice deficient in the phosphatase. The mutant mice were viable and did not display overt abnormalities. However, these mice developed signs of aging at much younger ages than the wild-type mice. At the cellular level, the Cdc14b-deficient mouse embryonic fibroblasts (MEFs) grew more slowly than the controls at later passages as a result of increased rates of senescence. Consistent with these premature aging phenotypes, Cdc14b-deficient cells accumulated more endogenous DNA damage than the wild-type cells, and more Cdc14b-deficient MEFs entered senescence than control MEFs in response to exogenous DNA damage. However, no deficiencies in DNA damage checkpoint response were detected in Cdc14b mutant cells, suggesting that the function of Cdc14b is required for efficient DNA damage repair. PMID- 21262765 TI - Dynamic BRG1 recruitment during T helper differentiation and activation reveals distal regulatory elements. AB - T helper cell differentiation and activation require specific transcriptional programs accompanied by changes in chromatin structure. However, little is known about the chromatin remodeling enzymes responsible. We performed genome-wide analysis to determine the general principles of BRG1 binding, followed by analysis of specific genes to determine whether these general rules were typical of key T cell genes. We found that binding of the remodeling protein BRG1 was programmed by both lineage and activation signals. BRG1 binding positively correlated with gene activity at protein-coding and microRNA (miRNA) genes. BRG1 binding was found at promoters and distal regions, including both novel and previously validated distal regulatory elements. Distal BRG1 binding correlated with expression, and novel distal sites in the Gata3 locus possessed enhancer like activity, suggesting a general role for BRG1 in long-distance gene regulation. BRG1 recruitment to distal sites in Gata3 was impaired in cells lacking STAT6, a transcription factor that regulates lineage-specific genes. Together, these findings suggest that BRG1 interprets both differentiation and activation signals and plays a causal role in gene regulation, chromatin structure, and cell fate. Our findings suggest that BRG1 binding is a useful marker for identifying active cis-regulatory regions in protein-coding and miRNA genes. PMID- 21262767 TI - Tctex-1, a novel interaction partner of Rab3D, is required for osteoclastic bone resorption. AB - Vesicular transport along microtubules must be strictly regulated to sustain the unique structural and functional polarization of bone-resorbing osteoclasts. However, the molecular mechanisms bridging these vesicle-microtubule interactions remain largely obscure. Rab3D, a member of the Rab3 subfamily (Rab3A/B/C/D) of small exocytotic GTPases, represents a core component of the osteoclastic vesicle transport machinery. Here, we identify a new Rab3D-interacting partner, Tctex-1, a light chain of the cytoplasmic dynein microtubule motor complex, by a yeast two hybrid screen. We demonstrate that Tctex-1 binds specifically to Rab3D in a GTP dependent manner and co-occupies Rab3D-bearing vesicles in bone-resorbing osteoclasts. Furthermore, we provide evidence that Tctex-1 and Rab3D intimately associate with the dynein motor complex and microtubules in osteoclasts. Finally, targeted disruption of Tctex-1 by RNA interference significantly impairs bone resorption capacity and mislocalizes Rab3D vesicles in osteoclasts, attesting to the notion that components of the Rab3D-trafficking pathway contribute to the maintenance of osteoclastic resorptive function. PMID- 21262769 TI - CCN5, a novel transcriptional repressor of the transforming growth factor beta signaling pathway. AB - CCN5 is a member of the CCN (connective tissue growth factor/cysteine-rich 61/nephroblastoma overexpressed) family and was identified as an estrogen inducible gene in estrogen receptor-positive cell lines. However, the role of CCN5 in breast carcinogenesis remains unclear. We report here that the CCN5 protein is localized mostly in the cytoplasm and in part in the nucleus of human tumor breast tissue. Using a heterologous transcription assay, we demonstrate that CCN5 can act as a transcriptional repressor presumably through association with histone deacetylase 1 (HDAC1). Microarray gene expression analysis showed that CCN5 represses expression of genes associated with epithelial-mesenchymal transition (EMT) as well as expression of key components of the transforming growth factor beta (TGF-beta) signaling pathway, prominent among them TGF-betaRII receptor. We show that CCN5 is recruited to the TGF-betaRII promoter, thereby providing a mechanism by which CCN5 restricts transcription of the TGF-betaRII gene. Consistent with this finding, CCN5, we found, functions to suppress TGF beta-induced transcriptional responses and invasion that is concomitant with EMT. Thus, our data uncovered CCN5 as a novel transcriptional repressor that plays an important role in regulating tumor progression functioning, at least in part, by inhibiting the expression of genes involved in the TGF-beta signaling cascade that is known to promote EMT. PMID- 21262763 TI - A novel Gli3 enhancer controls the Gli3 spatiotemporal expression pattern through a TALE homeodomain protein binding site. AB - The zinc finger transcription factor Gli3 is an essential mediator of hedgehog signaling. Gli3 has a dynamic expression pattern during embryonic development. In the neural tube, Gli3 transcripts are patterned along the anteroposterior and dorsoventral axes such that the initial broad expression in the posterior neural tube becomes dorsally restricted as neurogenesis takes place. Little is known about the molecular mechanisms that regulate this dynamic expression. Here, we report on a phylogenetic analysis of the Gli3 locus that uncovered a novel regulatory element, HCNE1. HCNE1 contains a compound Pbx/Meis binding site that binds Pbx and Meis/Prep proteins in vitro and in vivo. We show that HCNE1 recapitulates Gli3 expression in the developing neural tube and that mutations in the Pbx/Meis binding site affect the spatiotemporal control of HCNE1 transcriptional activity. Ectopic expression or loss of function of Pbx and Meis/Prep proteins in the chick and mouse embryo results in aberrant expression of endogenous Gli3 transcripts. We propose a novel role for TALE proteins in establishing the correct spatiotemporal expression pattern of Gli3 in the vertebrate spinal cord, thus implicating TALE transcription factors in early embryonic patterning events controlled by Sonic hedgehog signaling. PMID- 21262771 TI - MK-STYX, a catalytically inactive phosphatase regulating mitochondrially dependent apoptosis. AB - Evasion of apoptosis is a significant problem affecting an array of cancers. In order to identify novel regulators of apoptosis, we performed an RNA interference (RNAi) screen against all kinases and phosphatases in the human genome. We identified MK-STYX (STYXL1), a catalytically inactive phosphatase with homology to the mitogen-activated protein kinase (MAPK) phosphatases. Despite this homology, MK-STYX knockdown does not significantly regulate MAPK signaling in response to growth factors or apoptotic stimuli. Rather, RNAi-mediated knockdown of MK-STYX inhibits cells from undergoing apoptosis induced by cellular stressors activating mitochondrion-dependent apoptosis. This MK-STYX phenotype mimics the loss of Bax and Bak, two potent guardians of mitochondrial apoptotic potential. Similar to loss of both Bax and Bak, cells without MK-STYX expression are unable to release cytochrome c. Proapoptotic members of the BCL-2 family (Bax, Bid, and Bim) are unable to trigger cytochrome c release in MK-STYX-depleted cells, placing the apoptotic deficiency at the level of mitochondrial outer membrane permeabilization (MOMP). MK-STYX was found to localize to the mitochondria but is neither released from the mitochondria upon apoptotic stress nor proximal to the machinery currently known to control MOMP, indicating that MK-STYX regulates MOMP using a distinct mechanism. PMID- 21262770 TI - New role for granulocyte colony-stimulating factor-induced extracellular signal regulated kinase 1/2 in histone modification and retinoic acid receptor alpha recruitment to gene promoters: relevance to acute promyelocytic leukemia cell differentiation. AB - The induction of the granulocytic differentiation of leukemic cells by all-trans retinoic acid (RA) has been a major breakthrough in terms of survival for acute promyelocytic leukemia (APL) patients. Here we highlight the synergism and the underlying novel mechanism between RA and the granulocyte colony-stimulating factor (G-CSF) to restore differentiation of RA-refractory APL blasts. First, we show that in RA-refractory APL cells (UF-1 cell line), PML-RA receptor alpha (RARalpha) is not released from target promoters in response to RA, resulting in the maintenance of chromatin repression. Consequently, RARalpha cannot be recruited, and the RA target genes are not activated. We then deciphered how the combination of G-CSF and RA successfully restored the activation of RA target genes to levels achieved in RA-sensitive APL cells. We demonstrate that G-CSF restores RARalpha recruitment to target gene promoters through the activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway and the subsequent derepression of chromatin. Thus, combinatorial activation of cytokines and RARs potentiates transcriptional activity through epigenetic modifications induced by specific signaling pathways. PMID- 21262772 TI - Human NDR kinases control G(1)/S cell cycle transition by directly regulating p21 stability. AB - The G(1) phase of the cell cycle is an important integrator of internal and external cues, allowing a cell to decide whether to proliferate, differentiate, or die. Multiple protein kinases, among them the cyclin-dependent kinases (Cdks), control G(1)-phase progression and S-phase entry. With the regulation of apoptosis, centrosome duplication, and mitotic chromosome alignment downstream of the HIPPO pathway components MST1 and MST2, mammalian NDR kinases have been implicated to function in cell cycle-dependent processes. Although they are well characterized in terms of biochemical regulation and upstream signaling pathways, signaling mechanisms downstream of mammalian NDR kinases remain largely unknown. We identify here a role for human NDR in regulating the G(1)/S transition. In G(1) phase, NDR kinases are activated by a third MST kinase (MST3). Significantly, interfering with NDR and MST3 kinase expression results in G(1) arrest and subsequent proliferation defects. Furthermore, we describe the first downstream signaling mechanisms by which NDR kinases regulate cell cycle progression. Our findings suggest that NDR kinases control protein stability of the cyclin-Cdk inhibitor protein p21 by direct phosphorylation. These findings establish a novel MST3-NDR-p21 axis as an important regulator of G(1)/S progression of mammalian cells. PMID- 21262774 TI - Using guided reflection to reduce test anxiety in nursing students. AB - Test anxiety is a phenomenon that can affect as many as 40% of students. Many nursing students are under great stress from long hours of study, a rigorous curriculum, and balancing work and family life. These stressors can lead to anxiety in many areas of the student's life, most notably in situations where he or she is being evaluated. This article will aim to discuss how the use of guided reflection can help the student actualize his or her feelings about test anxiety by using Johns's Model for Structured Reflection. By using cues from the model and structure provided by a guide, the student will partake in a journey to gain insight about oneself and discover ways to decrease test anxiety that can be incorporated into the student's holistic self-care plan. PMID- 21262775 TI - Exploring the concept of manliness in relation to the phenomenon of crying: a Bourdieusian approach. AB - The concept of manliness related to the phenomenon of crying can be better understood by tracing the roots of the language of manliness through history. A Bourdieusian theoretical approach is used, incorporating the analytics of habitus, bodily hexis, and symbolic violence. This less-studied phenomenon of crying is investigated from a holistic, biopsychosocial framework. Manliness is a social construct that has remained surprisingly consistent throughout history. The importance of this concept to physical, psychological, and social health and well-being is addressed from a holistic nursing perspective. This is a timely issue for men's mental health, for example, that of returning combat veterans experiencing loss, grief, and posttraumatic stress. This exploration provides insight for nursing by analyzing the concept of manliness, which stems largely from militaristic roots, and might present obstacles to emotional release. PMID- 21262776 TI - Fertility determinants after conservative surgery for mucinous borderline tumours of the ovary (excluding peritoneal pseudomyxoma). AB - BACKGROUND The aim of this study was to define determinants of fertility in patients treated conservatively for mucinous borderline ovarian tumours (MBOTs), and to compare outcomes after salpingo-oophorectomy or cystectomy. METHODS This was a retrospective cohort study of fertility results in a series of patients treated conservatively for MBOTs and desiring pregnancy. Conservative surgery was defined as preservation of the uterus and ovarian tissue in one or both adnexa(e). Fertility results were compared with patients who had undergone a cystectomy or a (salpingo-)oophorectomy. Only patients with a minimum of 1 year of follow-up were included. Epidemiological, surgical, histological parameters and other prognostic factors for fertility results were investigated. RESULTS A group of 31 patients who had been treated conservatively between 1997 and 2004 and who desired pregnancy were investigated. Patients were treated by unilateral salpingo-oophorectomy (USO) (n = 19) or cystectomy (n = 12). The 5-year recurrence-free survival rate was higher in the USO group compared with the cystectomy group (94.7 versus 49.1%, P = 0.041). Among the 31 women, 12 had become pregnant. The 5-year probabilities of pregnancy were comparable between the cystectomy and salpingo-oophorectomy groups (41.8 and 45.9%, respectively, P= 0.66). None of the other factors studied (epidemiological, surgical and histological parameters) were associated with fertility results. CONCLUSIONS The use of salpingo-oophorectomy rather than cystectomy should be preferred during conservative surgery for patients with MBOTs because it decreases the risk of recurrence and does not impair fertility. PMID- 21262778 TI - Reticulocyte population data in different erythropoietic states. AB - AIMS: To assess changes in reticulocyte impedance volume, conductivity and light scatter (reticulocyte population data or RPD) obtained with the volume, conductivity and laser light scatter (VCS) technology in healthy subjects and in different erythropoietic states. METHODS: Blood samples were analysed with the Beckman-Coulter LH750 system, using the VCS method, from a group of 40 healthy subjects and three groups of patients with different types of untreated or treated anaemia: 24 cases of iron deficiency at the time of diagnosis, 16 patients with iron deficiency anaemia during intravenous iron administration, and 57 patients with chronic kidney disease undergoing dialysis and administration of rHu-erythropoietin and intravenous iron. RESULTS: RPD data were reproducible. Average mean channels for volume were 50.9 for controls and 49.2, 55.7 and 64.0 for the three patient groups, respectively. Average mean channels for conductivity were 52.0 for controls and 59.8, 55.7 and 56.1 for the three patient groups. Average mean channels for light scatter were 108.4 for controls and 113.3, 117.3 and 128.2 for the three patient groups. SD data indicated increased dispersion in the patient groups. CONCLUSION: When values in the patient groups are compared with reference values obtained in healthy controls, the main differences are found in impedance volume and light scatter, which were both increased in patients with stimulated erythropoiesis. These data indicate the opportunity to further evaluate the clinical usefulness of RPD in haematological diseases. PMID- 21262777 TI - Protein expression analysis of ALCAM and CEACAM6 in breast cancer metastases reveals significantly increased ALCAM expression in metastases of the skin. AB - AIMS: For prediction and understanding of underlying mechanisms of organ-specific metastases, various gene and protein expression signatures have been identified in primary breast carcinomas. These expression signatures often include several genes coding for adhesion molecules, such as activated leucocyte cell adhesion molecule (ALCAM/CD166) and carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), both of which may play an important role in the development of distant metastases because of their adherent properties. Owing to their predominantly membranous localisation, they are also considered to have certain therapeutic potential. Apart from expression data obtained in the primary tumour, data for gene and protein expression patterns in distant breast cancer metastases are rare. Therefore this study focuses on analysing the distribution of ALCAM and CEACAM6 protein expression in breast cancer metastases from different sites. METHODS: Immunohistochemical staining for ALCAM and CEACAM6 in 117 breast cancer metastases derived from liver (n=24), lung (n=19), brain (n=21), bone (n=36) and skin (n=17) was performed. RESULTS: Immunoreactive scores (IRS) for ALCAM in all metastases except skin metastases ranged from 2.63 to 5.10 (membranous) and 2.79 to 3.67 (cytoplasmic), showing a positive correlation with each other (r=0.690, p<0.001). In skin metastases, ALCAM expression was significantly stronger (membranous IRS, 8.76; cytoplasmic IRS, 7.12; p<0.001). Mean staining intensity for CEACAM6 was IRS 3.88. No or weak CEACAM6 and ALCAM staining (IRS 0-3) was seen in 53% vs 27% of all metastases. CONCLUSIONS: Compared with CEACAM6, ALCAM showed significantly stronger protein expression in breast cancer skin metastases compared with metastases in all other sites. PMID- 21262780 TI - Propensity scores: from naive enthusiasm to intuitive understanding. AB - Estimation of the effect of a binary exposure on an outcome in the presence of confounding is often carried out via outcome regression modelling. An alternative approach is to use propensity score methodology. The propensity score is the conditional probability of receiving the exposure given the observed covariates and can be used, under the assumption of no unmeasured confounders, to estimate the causal effect of the exposure. In this article, we provide a non-technical and intuitive discussion of propensity score methodology, motivating the use of the propensity score approach by analogy with randomised studies, and describe the four main ways in which this methodology can be implemented. We carefully describe the population parameters being estimated - an issue that is frequently overlooked in the medical literature. We illustrate these four methods using data from a study investigating the association between maternal choice to provide breast milk and the infant's subsequent neurodevelopment. We outline useful extensions of propensity score methodology and discuss directions for future research. Propensity score methods remain controversial and there is no consensus as to when, if ever, they should be used in place of traditional outcome regression models. We therefore end with a discussion of the relative advantages and disadvantages of each. PMID- 21262781 TI - Geomed. PMID- 21262782 TI - Interventions to optimise prescribing in care homes: systematic review. AB - BACKGROUND: prescribing for older people is a complex process and can elevate the risk of inappropriate prescribing, with potentially severe consequences. With a growing ageing population, strategies to improve prescribing in care homes are essential. Our aim was to review systematically the effects of interventions to optimise prescribing in care homes. METHOD: databases searched were MEDLINE, EMBASE, International Pharmaceutical Abstracts and the Cochrane Library from 1990. Search terms included were 'nursing home', 'residential home', 'inappropriate prescribing', 'education' and 'intervention'. Two independent reviewers undertook screening and methodological quality assessment, using the Downs and Black rating scale. RESULTS: the search strategy retrieved 16 studies that met the inclusion criteria. Four intervention strategies were identified: staff education, multi-disciplinary team (MDT) meetings, pharmacist medication reviews and computerised clinical decision support systems (CDSSs). Complex educational programmes that focused on improving patients' behavioural management and drug prescribing were the most studied area, with six of eight studies highlighting an improvement in prescribing. Mixed results were found for pharmacist interventions. CDSSs were evaluated in two studies, with one showing a significant improvement in appropriate drug orders. Two of three studies examining MDT meetings found an overall improvement in appropriate prescribing. A meta-analysis could not be performed due to heterogeneity in the outcome measures. CONCLUSION: results are mixed and there is no one interventional strategy that has proved to be effective. Nevertheless, education including academic detailing seems to show most promise. A multi-faceted approach and clearer policy guidelines are likely to be required to improve prescribing for these vulnerable patients. PMID- 21262784 TI - HIV priorities and health distributions in a rural region in Tanzania: a qualitative study. AB - BACKGROUND: International and national agencies play a major role in setting HIV care-and-treatment priorities in low-income-countries. Little is known about priority setting at lower health-system levels. The objective of this article is to explore experiences of HIV priority decisions, at what levels these decisions are made and how they might influence the distribution of health benefits in a high-endemic region in Tanzania. METHODS: This is a qualitative study using observations, key documents and semistructured focus-group and individual interviews (43) with health workers, patients and administrators at one regional and one district hospital. The analysis was based on an editing analysis style. RESULTS: Health workers did not perceive themselves as bedside rationing agents and they reported following national recommendations and felt they have little impact on important priority decisions. Health benefit distributions were largely determined by priority decisions made at a national level. External factors, such as eligibility criteria, inadequate funding and barriers to access seemed to play a major role in the actual distribution of health services and benefits in the region. Patient groups who were actually given high priority were the sickest patients, those living near a facility and those who could afford long journeys and frequent visits. Low-priority groups were those experiencing other co morbidities or treatment failure, children, asymptomatic patients and the poorest. CONCLUSIONS/SIGNIFICANCE: The interaction of priority setting across health-system levels and their impact on distribution of health outcomes in the population has been underestimated. The distributional pattern of health outcomes calls for further normative assessment. PMID- 21262785 TI - The incidence of syphilis, HIV and HCV and associated factors in a cohort of men who have sex with men in Nanjing, China. AB - OBJECTIVE: This study investigated the incidence of syphilis, HIV and hepatitis C virus (HCV), as well as factors associated with syphilis seroconversion among men who have sex with men (MSM) in Nanjing, China. METHODS: A cohort of MSM was recruited by respondent-driven sampling methods. Those who were syphilis-, HIV- and HCV-seronegative at the baseline were invited to be retested at month 6. A Poisson regression analysis was performed. RESULTS: Of the 416 participants in the study, 348 participants were HIV-, syphilis- and HCV-negative at the baseline, 250 (71.84%) of whom returned for retesting at month 6. Nine of these 250 participants had seroconverted to syphilis-positive (incidence=7.58 per 100 person-years (PY); 95% CI 2.63 to 12.53 per 100 PY), and five had seroconverted to HIV-positive (incidence=4.17 per 100 PY; 95% CI=0.52 to 7.83 per 100 PY). No HIV and syphilis coinfection and no HCV seroconversion were found. Multivariate analysis identified four statistically significant factors predicting syphilis seroconversion, including currently single marital status (RR=0.32, 95% CI 0.16 to 0.65, p<0.01), monthly income >US$300 (RR=2.68, 95% CI 1.28 to 5.61, p<0.01), self-reported homosexual orientation (RR=0.48, 95% CI 0.24 to 0.96, p<0.05) and recruitment of male sex partners mostly from gay saunas (RR=6.72, 95% CI 2.88 to 15.68, p<0.01). CONCLUSIONS: The high incidence of syphilis and HIV reflects the seriousness and urgency of the HIV and sexually transmitted diseases (STD) epidemics among MSM in China. Effective interventions of syphilis treatment and prevention should target MSM with characteristics reflecting the aforementioned risk factors. PMID- 21262786 TI - Variations in the epidemiology of primary, secondary and early latent syphilis, England and Wales: 1999 to 2008. AB - OBJECTIVE: To investigate factors associated with variations in diagnoses of primary, secondary and early latent syphilis in England and Wales. METHODS: Data were derived from two sources: diagnoses made in genitourinary medicine clinics reported on form KC60, and information collected through National Enhanced Syphilis Surveillance (NESS). Multinomial regression modelling was used for data analysis. RESULTS: Between 1999 and 2008, 12,021 NESS reports were received, 54% of KC60 reports. The dominant profile of the epidemic was one of white men who have sex with men aged 35-44, often co-infected with HIV, centred in larger cities. During this period, the proportion of primary cases increased over time, while the proportion of secondary cases fell. Primary cases exceeded secondary cases by 2004. The proportion of early latent cases remained relatively stable over time and tended to be lower than that of primary and secondary infection. Patients who attended because they had symptoms of infection, had been identified through partner notification, were HIV positive, and were UK born were more likely to present with primary or secondary infection than with early latent infection. A higher proportion of early latent cases were seen among patients who were Asian, had contacted sexual partners through saunas, bars and the internet, had untraceable partners, and had acquired infection in Manchester. CONCLUSIONS: The continuing syphilis epidemic indicates that control has only been partially effective, with ongoing transmission being sustained. Intensive and targeted efforts delivered locally are required to interrupt further transmission. PMID- 21262773 TI - Arginine methylation by PRMT5 at a naturally occurring mutation site is critical for liver metabolic regulation by small heterodimer partner. AB - Small Heterodimer Partner (SHP) inhibits numerous transcription factors that are involved in diverse biological processes, including lipid and glucose metabolism. In response to increased hepatic bile acids, SHP gene expression is induced and the SHP protein is stabilized. We now show that the activity of SHP is also increased by posttranslational methylation at Arg-57 by protein arginine methyltransferase 5 (PRMT5). Adenovirus-mediated hepatic depletion of PRMT5 decreased SHP methylation and reversed the suppression of metabolic genes by SHP. Mutation of Arg-57 decreased SHP interaction with its known cofactors, Brm, mSin3A, and histone deacetylase 1 (HDAC1), but not with G9a, and decreased their recruitment to SHP target genes in mice. Hepatic overexpression of SHP inhibited metabolic target genes, decreased bile acid and hepatic triglyceride levels, and increased glucose tolerance. In contrast, mutation of Arg-57 selectively reversed the inhibition of SHP target genes and metabolic outcomes. The importance of Arg 57 methylation for the repression activity of SHP provides a molecular basis for the observation that a natural mutation of Arg-57 in humans is associated with the metabolic syndrome. Targeting posttranslational modifications of SHP may be an effective therapeutic strategy by controlling selected groups of genes to treat SHP-related human diseases, such as metabolic syndrome, cancer, and infertility. PMID- 21262788 TI - Rhabdomyosarcoma in 8 horses. AB - This multi-institutional report describes 8 cases of rhabdomyosarcoma in horses. Four neoplasms were in the tongue and other areas of the mouth or head, 2 were in the abdominal wall, and 1 each was in right shoulder muscles and heart. Four rhabdomyosarcomas that were less than 10 cm in diameter were treated by surgical excision or radiation with no recurrence. Two neoplasms greater than 10 cm in diameter in the abdominal wall and the right shoulder were considered inoperable and led to decisions to euthanize the horses. Two neoplasms were incidental findings at necropsy. All the neoplasms were classified as embryonal except for 1 pleomorphic rhabdomyosarcoma. These 8 cases were evaluated with 9 published case reports of equine rhabdomyosarcoma. For all cases, the most common sites were limb muscles (5/17) and tongue (4/17). Metastasis was reported in 4 of the previously published cases; none was found in this study. PMID- 21262789 TI - Antibiotics in urinary-tract infections. Sustained change in prescribing habits by practice test and self-reflection: a mixed methods before-after study. AB - BACKGROUND The German guideline recommends trimethoprim (TMP) for the treatment of uncomplicated lower-urinary-tract infections (uLUTI) in primary care. In the authors' research network, the participating general practitioners (GPs) were asked why they prescribe mostly quinolones instead. The GPs stated the perception of a high rate of therapy failure of TMP and strongly rejected the guideline. OBJECTIVE To examine prescribing behaviour for uLUTI and whether a practice test of TMP might effect a change in prescribing habits. METHODS The study was conducted using observational and qualitative elements. A first focus-group (n=6) assessed reasons for current prescribing behaviour. In a 3-month practice test, patients with uLUTI were prescribed TMP (150 mg twice for 3 days). In a second focus group, the GPs (n=12) were presented with the results of the practice test. RESULTS The first focus group revealed that prescribing was mainly driven by former hospital training and what was perceived as common therapy. GPs felt no need to change a successful regimen. In the practice test, TMP had a success rate of 94% (84 episodes of uLUTI). The second focus group revealed that the practice test had strongly changed opinions in favour of TMP. Self-reflection and ownership of data acquisition were seen as major contributions for change in prescribing. After the test period, TMP remained the antibiotic most often prescribed. CONCLUSION Internal evidence and peer-group opinion are strong determinants for clinical decisions. A self-conducted practice test, together with self-reflection in a peer group, strongly supports the process of change. PMID- 21262790 TI - Is the job satisfaction of primary care team members associated with patient satisfaction? AB - BACKGROUND Previous research has shown a correlation between physician job satisfaction and patient satisfaction with quality of care, but the connection between job satisfaction of other primary care team members and patient satisfaction is yet unclear. OBJECTIVE To evaluate whether there is an association between patient satisfaction and job satisfaction of the members of patient care teams. DESIGN The study was based on data from the European Practice Assessment and used an observational design. SETTING 676 primary care practices in Germany. PARTICIPANTS 47 168 patients, 676 general practitioners (practice principals), 305 physician colleagues (trainees and permanently employed physicians) and 3011 non-physician practice members (nurses, secretaries). MAIN OUTCOME MEASURES Patient evaluation was measured using the 23-item EUROPEP questionnaire. Job satisfaction was measured using the 10-item Warr-Cook-Wall job satisfaction scale and further items relating to practice structure. Bivariate correlations were applied in which factors of patient satisfaction and practice structure were compared with physicians and non-physicians satisfaction. RESULTS Patient satisfaction correlates positively with the general job satisfaction of the non-physician (r=0.25, p<0.01) and no significant correlation was found for the general job satisfaction of practice principals and physician colleagues. Patients' satisfaction with the practice organisation correlates positively with the general job satisfaction of the non-physicians (r=0.30, p<0.01) and their view of practice structure (r=0.29, p<0.01). CONCLUSIONS The correlation between non-physician team member satisfaction and patient satisfaction was higher than the correlation between satisfaction of physicians and patients. Patients seem to be sensitive to aspects of practice structure. PMID- 21262791 TI - Pressure ulcers: effectiveness of risk-assessment tools. A randomised controlled trial (the ULCER trial). AB - OBJECTIVE: To evaluate the effectiveness of two pressure-ulcer screening tools against clinical judgement in preventing pressure ulcers. DESIGN: A single blind randomised controlled trial. SETTING: A large metropolitan tertiary hospital. PARTICIPANTS: 1231 patients admitted to internal medicine or oncology wards. Patients were excluded if their hospital stay was expected to be 2 days or less. INTERVENTIONS: Participants allocated to either a Waterlow (n=410) or Ramstadius (n=411) screening tool group or to a clinical judgement group (n=410) where no formal risk screening instrument was used. MAIN OUTCOME MEASURE: Incidence of hospital acquired pressure ulcers ascertained by regular direct observation. Use of any devices for the prevention of pressure ulcers, documentation of a pressure plan and any dietetic or specialist skin integrity review were recorded. RESULTS: On admission, 71 (5.8%) patients had an existing pressure ulcer. The incidence of hospital-acquired pressure ulcers was similar between groups (clinical judgement 28/410 (6.8%); Waterlow 31/411 (7.5%); Ramstadius 22/410 (5.4%), p=0.44). Significant associations with pressure injury in regression modelling included requiring a dietetic referral, being admitted from a location other than home and age over 65 years. CONCLUSION: The authors found no evidence to show that two common pressure-ulcer risk-assessment tools are superior to clinical judgement to prevent pressure injury. Resources associated with use of these tools might be better spent on careful daily skin inspection and improving management targetted at specific risks. STUDY REGISTRATION: The trial was registered with the Australian and New Zealand Clinicat Trials Registry (ACTRN 12608000541303). PMID- 21262787 TI - Improved efficacy for ezetimibe and rosuvastatin by attenuating the induction of PCSK9. AB - Reducing circulating LDL-cholesterol (LDL-c) reduces the risk of cardiovascular disease in people with hypercholesterolemia. Current approaches to reduce circulating LDL-c include statins, which inhibit cholesterol synthesis, and ezetimibe, which blocks cholesterol absorption. Both elevate serum PCSK9 protein levels in patients, which could attenuate their efficacy by reducing the amount of cholesterol cleared from circulation. To determine whether PCSK9 inhibition could enhance LDL-c lowering of both statins and ezetimibe, we utilized small interfering RNAs (siRNAs) to knock down Pcsk9, together with ezetimibe, rosuvastatin, and an ezetimibe/rosuvastatin combination in a mouse model with a human-like lipid profile. We found that ezetimibe, rosuvastatin, and ezetimibe/rosuvastatin combined lower serum cholesterol but induce the expression of Pcsk9 as well as the Srebp-2 hepatic cholesterol biosynthesis pathway. Pcsk9 knockdown in combination with either treatment led to greater reductions in serum non-HDL with a near-uniform reduction of all LDL-c subfractions. In addition to reducing serum cholesterol, the combined rosuvastatin/ezetimibe/Pcsk9 siRNA treatment exhibited a significant reduction in serum APOB protein and triglyceride levels. Taken together, these data provide evidence that PCSK9 inhibitors, in combination with current therapies, have the potential to achieve greater reductions in both serum cholesterol and triglycerides. PMID- 21262792 TI - Telephone triage by nurses in primary care out-of-hours services in Norway: an evaluation study based on written case scenarios. AB - BACKGROUND: The use of nurses for telephone-based triage in out-of-hours services is increasing in several countries. No investigations have been carried out in Norway into the quality of decisions made by nurses regarding our priority degree system. There are three levels: acute, urgent and non-urgent. METHODS: Nurses working in seven casualty clinics in out-of-hours districts in Norway (The Watchtowers) were all invited to participate in a study to assess priority grade on 20 written medical scenarios validated by an expert group. 83 nurses (response rate 76%) participated in the study. A one-out-of-five sample of the nurses assessed the same written cases after 3 months (n = 18, response rate 90%) as a test-retest assessment. RESULTS: Among the acute, urgent and non-urgent scenarios, 82%, 74% and 81% were correctly classified according to national guidelines. There were significant differences in the proportion of correct classifications among the casualty clinics, but neither employment percentage nor profession or work experience affected the triage decision. The mean intraobserver variability measured by the Cohen kappa was 0.61 (CI 0.52 to 0.70), and there were significant differences in kappa with employment percentage. Casualty clinics and work experience did not affect intrarater agreement. CONCLUSION: Correct classification of acute and non-urgent cases among nurses was quite high. Work experience and employment percentage did not affect triage decision. The intrarater agreement was good and about the same as in previous studies performed in other countries. Kappa increased significantly with increasing employment percentage. PMID- 21262793 TI - The efficacy of computer-enabled discharge communication interventions: a systematic review. AB - CONTEXT: Traditional manual/dictated discharge summaries are inaccurate, inconsistent and untimely. Computer-enabled discharge communications may improve information transfer by providing a standardised document that immediately links acute and community healthcare providers. OBJECTIVE: To conduct a systematic review evaluating the efficacy of computer-enabled discharge communication compared with traditional communication for patients discharged from acute care hospitals. DATA SOURCES: MEDLINE, EMBASE, Cochrane CENTRAL Register of Controlled Trials and MEDLINE In-Process. Keywords from three themes were combined: discharge communication, electronic/online/web-based and controlled interventional studies. STUDY SELECTION: Study types included: clinical trials, quasiexperimental studies with concurrent controls and controlled before--after studies. Interventions included: (1) automatic population of a discharge document by computer database(s); (2) transmission of discharge information via computer technology; or (3) computer technology providing a 'platform' for dynamic discharge communication. Controls included: no intervention or traditional manual/dictated discharge summaries. Primary outcomes included: mortality, readmission and adverse events/near misses. Secondary outcomes included: timeliness, accuracy, quality/completeness and physician/patient satisfaction. DATA EXTRACTION: Description of interventions and study outcomes were extracted by two independent reviewers. RESULTS: 12 unique studies were identified: eight randomised controlled trials and four quasi-experimental studies. Pooling/meta analysis was not possible, given the heterogeneity of measures and outcomes reported. The primary outcomes of mortality and readmission were inconsistently reported. There was no significant difference in mortality, and one study reported reduced long-term readmission. Intervention groups experienced reductions in perceived medical errors/adverse events, and improvements in timeliness and physician/patient satisfaction. CONCLUSIONS: Computer-enabled discharge communications appear beneficial with respect to a number of important secondary outcomes. Primary outcomes of mortality and readmission are less commonly reported in this literature and require further study. PMID- 21262794 TI - Determination of symbiotic nodule occupancy in the model Vicia tetrasperma using a fluorescence scanner. AB - BACKGROUND: Fluorescent tagging of nodule bacteria forming symbioses with legume host plants represents a tool for vital tracking of bacteria inside the symbiotic root nodules and monitoring changes in gene activity. The constitutive expression of heterologous fluorescent proteins, such as green fluorescent protein (GFP), also allows screening for nodule occupancy by a particular strain. Imaging of the fluorescence signal on a macro-scale is associated with technical problems due to the robustness of nodule tissues and a high level of autofluorescence. SCOPE: These limitations can be reduced by the use of a model species with a fine root system, such as Vicia tetrasperma. Further increases in the sensitivity and specificity of the detection and in image resolution can be attained by the use of a fluorescence scanner. Compared with the standard CCD-type cameras, the availability of a laser source of a specified excitation wavelength decreases non specific autofluorescence while the photomultiplier tubes in emission detection significantly increase sensitivity. The large scanning area combined with a high resolution allow us to visualize individual nodules during the scan of whole root systems. Using a fluorescence scanner with excitation wavelength of 488 nm, a band-pass specific emission channel of 532 nm and a long-pass background channel of 555 nm, it was possible to distinguish nodules occupied by a rhizobial strain marked with one copy of cycle3 GFP from nodules colonized by the wild-type strain. CONCLUSIONS: The main limitation of the current plant model and GFP with the wild-type emission peak at 409 nm is a sharp increase in root autofluorescence below 550 nm. The selectivity of the technique can be enhanced by the use of red-shifted fluorophores and the contrasting labelling of the variants, provided that the excitation (482 nm) and emission (737 nm) maxima corresponding to root chlorophyll are respected. PMID- 21262795 TI - Applying a regional community concept to forest birds of eastern North America. AB - The regional community concept embraces the idea that species interactions across large areas shape both the geographic/ecological distributions and the local abundances of populations. Within this framework, I analyzed the distribution and abundance of 79 species of land birds across 142 ca. 10-ha census plots from standardized breeding bird censuses in deciduous and mixed forests of eastern North America. To characterize the regional ecological space, plots were ordinated on the basis of species abundances. Within the regional community defined by these synthetic axes, the distribution and abundance of individual species did not appear to be shaped by competition or to reflect the adaptations of individuals: (i) local abundance and population extent across the ordination axes were unrelated, (ii) pairwise correlation coefficients of species abundances were centered on 0, (iii) average species distribution and abundance were independent of the number of close relatives, and (iv) distribution and abundance exhibited no evolutionary (phylogenetic) conservatism. To explain these seemingly random patterns, I speculate that species are approximately evenly matched competitors over much of the region and that their distributions and relative abundances are determined by the labile coevolutionary outcomes of interactions with specialized pathogens. Thus, despite the appearance that random processes determine patterns in the distribution and abundance of populations in the regional community, it is plausible that species-specific deterministic interactions are responsible. Although competition is a dominant force in ecological communities, variation in the distribution and abundance of individual species might instead reflect the outcome of interactions with specialized antagonists, including pathogens. PMID- 21262797 TI - Neutral theory as a predictor of avifaunal extinctions after habitat loss. AB - The worldwide loss of natural habitats leads not only to the loss of habitat endemic species but also to further and protracted extinctions in the reduced areas that remain. How rapid is this process? We use the neutral theory of biodiversity to answer this question, and we compare the results taken with observed rates of avifaunal extinctions. In the neutral model, we derive an exact solution for the rate of species loss in a closed community. The simple, closed form solution exhibits hyperbolic decay of species richness with time, which implies a potentially rapid initial decline followed by much slower rates long term. Our empirical estimates of extinction times are based on published studies for avifaunal extinctions either on oceanic islands or in forest fragments, which span a total of six orders of magnitude in area. These estimates show that the time to extinction strongly depends on the area. The neutral-theory predictions agree well with observed rates over three orders of magnitude of area (between 100 and 100,000 ha) both for islands and forest fragments. Regarding the species abundance distribution, extinction times based on a broken-stick model led to better agreement with observation than if a log-series model was used. The predictions break down for very small or very large areas. Thus, neutrality may be an affordable assumption for some applications in ecology and conservation, particularly for areas of intermediate size. PMID- 21262798 TI - Activation of the plasma membrane Na/H antiporter Salt-Overly-Sensitive 1 (SOS1) by phosphorylation of an auto-inhibitory C-terminal domain. AB - The plasma membrane sodium/proton exchanger Salt-Overly-Sensitive 1 (SOS1) is a critical salt tolerance determinant in plants. The SOS2-SOS3 calcium-dependent protein kinase complex up-regulates SOS1 activity, but the mechanistic details of this crucial event remain unresolved. Here we show that SOS1 is maintained in a resting state by a C-terminal auto-inhibitory domain that is the target of SOS2 SOS3. The auto-inhibitory domain interacts intramolecularly with an adjacent domain of SOS1 that is essential for activity. SOS1 is relieved from auto inhibition upon phosphorylation of the auto-inhibitory domain by SOS2-SOS3. Mutation of the SOS2 phosphorylation and recognition site impeded the activation of SOS1 in vivo and in vitro. Additional amino acid residues critically important for SOS1 activity and regulation were identified in a genetic screen for hypermorphic alleles. PMID- 21262799 TI - VGJphi integration and excision mechanisms contribute to the genetic diversity of Vibrio cholerae epidemic strains. AB - Most strains of Vibrio cholerae are not pathogenic or cause only local outbreaks of gastroenteritis. Acquisition of the capacity to produce the cholera toxin results from a lysogenic conversion event due to a filamentous bacteriophage, CTX. Two V. cholerae tyrosine recombinases that normally serve to resolve chromosome dimers, XerC and XerD, promote CTX integration by directly recombining the ssDNA genome of the phage with the dimer resolution site of either or both V. cholerae chromosomes. This smart mechanism renders the process irreversible. Many other filamentous vibriophages seem to attach to chromosome dimer resolution sites and participate in the rapid and continuous evolution of toxigenic V. cholerae strains. We analyzed the molecular mechanism of integration of VGJ, a representative of the largest family of these phages. We found that XerC and XerD promote the integration of VGJ into a specific chromosome dimer resolution site, and that the dsDNA replicative form of the phage is recombined. We show that XerC and XerD can promote excision of the integrated prophage, and that this participates in the production of new extrachromosomal copies of the phage genome. We further show how hybrid molecules harboring the concatenated genomes of CTX and VGJ can be produced efficiently. Finally, we discuss how the integration and excision mechanisms of VGJ can explain the origin of recent epidemic V. cholerae strains. PMID- 21262800 TI - Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1). AB - Inducible cAMP early repressor (ICER) is a transcriptional repressor, which, because of alternate promoter use, is generated from the 3' region of the cAMP response modulator (Crem) gene. Its expression and nuclear occurrence are elevated by high cAMP levels in naturally occurring regulatory T cells (nTregs). Using two mouse models, we demonstrate that nTregs control the cellular localization of ICER/CREM, and thereby inhibit IL-2 synthesis in conventional CD4(+) T cells. Ablation of nTregs in depletion of regulatory T-cell (DEREG) mice resulted in cytosolic localization of ICER/CREM and increased IL-2 synthesis upon stimulation. Direct contacts between nTregs and conventional CD4(+) T cells led to nuclear accumulation of ICER/CREM and suppression of IL-2 synthesis on administration of CD28 superagonistic (CD28SA) Ab. In a similar way, nTregs communicated with B cells and induced the cAMP-driven nuclear localization of ICER/CREM. High levels of ICER suppressed the induction of nuclear factor of activated T cell c1 (Nfatc1) gene in T cells whose inducible Nfatc1 P1 promoter bears two highly conserved cAMP-responsive elements to which ICER/CREM can bind. These findings suggest that nTregs suppress T-cell responses by the cAMP dependent nuclear accumulation of ICER/CREM and inhibition of NFATc1 and IL-2 induction. PMID- 21262802 TI - Fast and accurate decisions through collective vigilance in fish shoals. AB - Although it has been suggested that large animal groups should make better decisions than smaller groups, there are few empirical demonstrations of this phenomenon and still fewer explanations of the how these improvements may be made. Here we show that both speed and accuracy of decision making increase with group size in fish shoals under predation threat. We examined two plausible mechanisms for this improvement: first, that groups are guided by a small proportion of high-quality decision makers and, second, that group members use self-organized division of vigilance. Repeated testing of individuals showed no evidence of different decision-making abilities between individual fish. Instead, we suggest that shoals achieve greater decision-making efficiencies through division of labor combined with social information transfer. Our results should prompt reconsideration of how we view cooperation in animal groups with fluid membership. PMID- 21262801 TI - Different nuclease requirements for exosome-mediated degradation of normal and nonstop mRNAs. AB - Two general pathways of mRNA decay have been characterized in yeast. In one pathway, the mRNA is degraded by the cytoplasmic form of the exosome. The exosome has both 3' to 5' exoribonuclease and endoribonuclease activity, and the available evidence suggests that the exonuclease activity is required for the degradation of mRNAs. We confirm here that this is true for normal mRNAs, but that aberrant mRNAs that lack a stop codon can be efficiently degraded in the absence of the exonuclease activity of the exosome. Specifically, we show that the endo- and exonuclease activities of the exosome are both capable of rapidly degrading nonstop mRNAs and ribozyme-cleaved mRNAs. Additionally, the endonuclease activity of the exosome is not required for endonucleolytic cleavage in no-go decay. In vitro, the endonuclease domain of the exosome is active only under nonphysiological conditions, but our findings show that the in vivo activity is sufficient for the rapid degradation of nonstop mRNAs. Thus, whereas normal mRNAs are degraded by two exonucleases (Xrn1p and Rrp44p), several endonucleases contribute to the decay of many aberrant mRNAs, including transcripts subject to nonstop and no-go decay. Our findings suggest that the nuclease requirements for general and nonstop mRNA decay are different, and describe a molecular function of the core exosome that is not disrupted by inactivating its exonuclease activity. PMID- 21262806 TI - A monodactyl nonavian dinosaur and the complex evolution of the alvarezsauroid hand. AB - Digital reduction is a striking evolutionary phenomenon that is clearly exemplified in theropod dinosaurs by the functionally didactyl manus of tyrannosaurids, the flight-adapted manus of birds (Aves), and the tridactyl but digit II-dominated manus of alvarezsauroids. The enlargement of manual digit II in alvarezsauroids and the concurrent reduction of the lateral digits have been interpreted as adaptations for digging, although no detailed biomechanical analysis of hand function has so far been carried out for this group. In the derived alvarezsauroid clade Parvicursorinae, the lateral digits are so small as to be presumably vestigial. Here we report a new alvarezsauroid, Linhenykus monodactylus gen. et sp. nov., based on a specimen from the Upper Cretaceous Wulansuhai Formation of Inner Mongolia, China. Cladistic analysis identifies Linhenykus as the most basal parvicursorine, and digit II of the manus retains a slender morphology and other primitive features. However, Linhenykus is also highly apomorphic in exhibiting the most extreme reduction of the lateral manual digits seen in any alvarezsauroid. Phalanges are retained only on the most medial digit (digit II), making Linhenykus the only known functionally monodactyl nonavian dinosaur. Other parvicursorines are more primitive in retaining a tridactyl manus but more derived in that digit II is highly robust and shows other apomorphic features in both of its phalanges. The unexpected combination of features seen in the hand of Linhenykus points to a complex mosaic pattern of manual evolution in alvarezsauroids, with loss of the presumably vestigial outer digits being decoupled from change in the form of digit II. PMID- 21262803 TI - Human IL-3/GM-CSF knock-in mice support human alveolar macrophage development and human immune responses in the lung. AB - Mice with a functional human immune system have the potential to allow in vivo studies of human infectious diseases and to enable vaccine testing. To this end, mice need to fully support the development of human immune cells, allow infection with human pathogens, and be capable of mounting effective human immune responses. A major limitation of humanized mice is the poor development and function of human myeloid cells and the absence of human immune responses at mucosal surfaces, such as the lung. To overcome this, we generated human IL-3/GM CSF knock-in (hIL-3/GM-CSF KI) mice. These mice faithfully expressed human GM-CSF and IL-3 and developed pulmonary alveolar proteinosis because of elimination of mouse GM-CSF. We demonstrate that hIL-3/GM-CSF KI mice engrafted with human CD34(+) hematopoietic cells had improved human myeloid cell reconstitution in the lung. In particular, hIL-3/GM-CSF KI mice supported the development of human alveolar macrophages that partially rescued the pulmonary alveolar proteinosis syndrome. Moreover, human alveolar macrophages mounted correlates of a human innate immune response against influenza virus. The hIL-3/GM-CSF KI mice represent a unique mouse model that permits the study of human mucosal immune responses to lung pathogens. PMID- 21262805 TI - NogoA restricts synaptic plasticity in the adult hippocampus on a fast time scale. AB - Whereas the role of NogoA in limiting axonal fiber growth and regeneration following an injury of the mammalian central nervous system (CNS) is well known, its physiological functions in the mature uninjured CNS are less well characterized. NogoA is mainly expressed by oligodendrocytes, but also by subpopulations of neurons, in particular in plastic regions of the CNS, e.g., in the hippocampus where it is found at synaptic sites. We analyzed synaptic transmission as well as long-term synaptic plasticity (long-term potentiation, LTP) in the presence of function blocking anti-NogoA or anti-Nogo receptor (NgR) antibodies and in NogoA KO mice. Whereas baseline synaptic transmission, short term plasticity and long-term depression were not affected by either approach, long-term potentiation was significantly increased following NogoA or NgR1 neutralization. Synaptic potentiation thus seems to be restricted by NogoA. Surprisingly, synaptic weakening was not affected by interfering with NogoA signaling. Mechanistically of interest is the observation that by blockade of the GABA(A) receptors normal synaptic strengthening reoccurred in the absence of NogoA signaling. The present results show a unique role of NogoA expressed in the adult hippocampus in restricting physiological synaptic plasticity on a very fast time scale. NogoA could thus serve as an important negative regulator of functional and structural plasticity in mature neuronal networks. PMID- 21262804 TI - Transdifferentiation of glioblastoma cells into vascular endothelial cells. AB - Glioblastoma (GBM) is the most malignant brain tumor and is highly resistant to intensive combination therapies and anti-VEGF therapies. To assess the resistance mechanism to anti-VEGF therapy, we examined the vessels of GBMs in tumors that were induced by the transduction of p53(+/-) heterozygous mice with lentiviral vectors containing oncogenes and the marker GFP in the hippocampus of GFAP-Cre recombinase (Cre) mice. We were surprised to observe GFP(+) vascular endothelial cells (ECs). Transplantation of mouse GBM cells revealed that the tumor-derived endothelial cells (TDECs) originated from tumor-initiating cells and did not result from cell fusion of ECs and tumor cells. An in vitro differentiation assay suggested that hypoxia is an important factor in the differentiation of tumor cells to ECs and is independent of VEGF. TDEC formation was not only resistant to an anti-VEGF receptor inhibitor in mouse GBMs but it led to an increase in their frequency. A xenograft model of human GBM spheres from clinical specimens and direct clinical samples from patients with GBM also showed the presence of TDECs. We suggest that the TDEC is an important player in the resistance to anti-VEGF therapy, and hence a potential target for GBM therapy. PMID- 21262808 TI - Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome. AB - Among the hallmark phenotypes reported in individuals with fragile X syndrome (FXS) are deficits in attentional function, inhibitory control, and cognitive flexibility, a set of cognitive skills thought to be associated with the prefrontal cortex (PFC). However, despite substantial clinical research into these core deficits, the PFC has received surprisingly little attention in preclinical research, particularly in animal models of FXS. In this study, we sought to investigate the molecular, cellular, and behavioral consequences of the loss of the fragile X mental retardation protein in the PFC of Fmr1 KO mice, a mouse model of FXS. We identify a robust cognitive impairment in these mice that may be related to the deficits in cognitive flexibility observed in individuals with FXS. In addition, we report that levels of proteins involved in synaptic function, including the NMDA receptor subunits NR1, NR2A, and NR2B; the scaffolding proteins PSD-95 and SAPAP3; and the plasticity-related gene Arc, are decreased in the prefrontal cortex of Fmr1 KO mice and are partly correlated with behavioral performance. Finally, we report that expression of c-Fos, a marker of neuronal activity, is decreased in the PFC of Fmr1 KO mice. Together, these data suggest that Fmr1 KO mice may represent a valuable animal model for the PFC associated molecular, cellular, and behavioral abnormalities in FXS and that this model may be useful for testing the efficacy of therapeutic strategies aimed at treating the cognitive impairments in FXS. PMID- 21262807 TI - Activity levels in the left hemisphere caudate-fusiform circuit predict how well a second language will be learned. AB - How second language (L2) learning is achieved in the human brain remains one of the fundamental questions of neuroscience and linguistics. Previous neuroimaging studies with bilinguals have consistently shown overlapping cortical organization of the native language (L1) and L2, leading to a prediction that a common neurobiological marker may be responsible for the development of the two languages. Here, by using functional MRI, we show that later skills to read in L2 are predicted by the activity level of the fusiform-caudate circuit in the left hemisphere, which nonetheless is not predictive of the ability to read in the native language. We scanned 10-y-old children while they performed a lexical decision task on L2 (and L1) stimuli. The subjects' written language (reading) skills were behaviorally assessed twice, the first time just before we performed the fMRI scan (time 1 reading) and the second time 1 y later (time 2 reading). A whole-brain based analysis revealed that activity levels in left caudate and left fusiform gyrus correlated with L2 literacy skills at time 1. After controlling for the effects of time 1 reading and nonverbal IQ, or the effect of in-scanner lexical performance, the development in L2 literacy skills (time 2 reading) was also predicted by activity in left caudate and fusiform regions that are thought to mediate language control functions and resolve competition arising from L1 during L2 learning. Our findings suggest that the activity level of left caudate and fusiform regions serves as an important neurobiological marker for predicting accomplishment in reading skills in a new language. PMID- 21262809 TI - Barhl2 limits growth of the diencephalic primordium through Caspase3 inhibition of beta-catenin activation. AB - Little is known about the respective contributions of cell proliferation and cell death to the control of vertebrate forebrain growth. The homeodomain protein barhl2 is expressed in the diencephalons of Xenopus, zebrafish, and mouse embryos, and we previously showed that Barhl2 overexpression in Xenopus neuroepithelial cells induces Caspase3-dependent apoptosis. Here, barhl2 is shown to act as a brake on diencephalic proliferation through an unconventional function of Caspase3. Depletion of Barhl2 or Caspase3 causes an increase in diencephalic cell number, a disruption of the neuroepithelium architecture, and an increase in Wnt activity. Surprisingly, these changes are not caused by decreased apoptosis but instead, are because of an increase in the amount and activation of beta-catenin, which stimulates excessive neuroepithelial cell proliferation and induces defects in beta-catenin intracellular localization and an up-regulation of axin2 and cyclinD1, two downstream targets of beta-catenin/T cell factor/lymphoid enhancer factor signaling. Using two different sets of complementation experiments, we showed that, in the developing diencephalon, Caspase3 acts downstream of Barhl2 in limiting neuroepithelial cell proliferation by inhibiting beta-catenin activation. Our data argue that Bar homeodomain proteins share a conserved function as cell type-specific regulators of Caspase3 activities. PMID- 21262812 TI - Yes-associated protein (YAP) transcriptional coactivator functions in balancing growth and differentiation in skin. AB - In mammals, skin begins as a single-layered epithelium, which, through a series of signals, either stratifies and differentiates to become epidermis or invaginates downward to make hair follicles (HFs). To achieve and maintain proper tissue architecture, keratinocytes must intricately balance growth and differentiation. Here, we uncover a critical and hitherto unappreciated role for Yes-associated protein (YAP), an evolutionarily conserved transcriptional coactivator with potent oncogenic potential. We show that YAP is highly expressed and nuclear in single-layered basal epidermal progenitors. Notably, nuclear YAP progressively declines with age and correlates with proliferative potential of epidermal progenitors. Shortly after initiation of HF morphogenesis, YAP translocates to the cytoplasm of differentiating cells. Through genetic analysis, we demonstrate a role for YAP in maintaining basal epidermal progenitors and regulating HF morphogenesis. YAP overexpression causes hair placodes to evaginate into epidermis rather than invaginate into dermis. YAP also expands basal epidermal progenitors, promotes proliferation, and inhibits terminal differentiation. In vitro gain-and-loss of function studies show that primary mouse keratinocytes (MKs) accelerate proliferation, suppress differentiation, and inhibit apoptosis when YAP is activated and reverse these features when YAP is inhibited. Finally, we identify Cyr61 as a target of YAP in MKs and demonstrate a requirement for TEA domain (TEAD) transcriptional factors to comediate YAP functions in MKs. PMID- 21262811 TI - Lack of the endosomal SNAREs vti1a and vti1b led to significant impairments in neuronal development. AB - Fusion between membranes is mediated by specific SNARE complexes. Here we report that fibroblasts survive the absence of the trans-Golgi network/early endosomal SNARE vti1a and the late endosomal SNARE vti1b with intact organelle morphology and minor trafficking defects. Because vti1a and vti1b are the only members of their SNARE subclass and the yeast homolog Vti1p is essential for cell survival, these data suggest that more distantly related SNAREs acquired the ability to function in endosomal traffic during evolution. However, absence of vti1a and vti1b resulted in perinatal lethality. Major axon tracts were missing, reduced in size, or misrouted in Vti1a(-/-) Vti1b(-/-) embryos. Progressive neurodegeneration was observed in most Vti1a(-/-) Vti1b(-/-) peripheral ganglia. Neurons were reduced by more than 95% in Vti1a(-/-) Vti1b(-/-) dorsal root and geniculate ganglia at embryonic day 18.5. These data suggest that special demands for endosomal membrane traffic could not be met in Vti1a(-/-) Vti1b(-/-) neurons. Vti1a(-/-) and Vti1b(-/-) single deficient mice were viable without these neuronal defects, indicating that they can substitute for each other in these processes. PMID- 21262810 TI - Selection of distinct Hox-Extradenticle interaction modes fine-tunes Hox protein activity. AB - Hox genes encode transcription factors widely used for diversifying animal body plans in development and evolution. To achieve functional specificity, Hox proteins associate with PBC class proteins, Pre-B cell leukemia homeobox (Pbx) in vertebrates, and Extradenticle (Exd) in Drosophila, and were thought to use a unique hexapeptide-dependent generic mode of interaction. Recent findings, however, revealed the existence of an alternative, UbdA-dependent paralog specific interaction mode providing diversity in Hox-PBC interactions. In this study, we investigated the basis for the selection of one of these two Hox-PBC interaction modes. Using naturally occurring variations and mutations in the Drosophila Ultrabithorax protein, we found that the linker region, a short domain separating the hexapeptide from the homeodomain, promotes an interaction mediated by the UbdA domain in a context-dependent manner. While using a UbdA-dependent interaction for the repression of the limb-promoting gene Distalless, interaction with Exd during segment-identity specification still relies on the hexapeptide motif. We further show that distinctly assembled Hox-PBC complexes display subtle but distinct repressive activities. These findings identify Hox-PBC interaction as a template for subtle regulation of Hox protein activity that may have played a major role in the diversification of Hox protein function in development and evolution. PMID- 21262814 TI - Major global radiation of corvoid birds originated in the proto-Papuan archipelago. AB - A central paradigm in island biogeography has been the unidirectional "downstream" colonization of islands from continents (source to sink) based on the idea that less-diverse island communities are easier to invade than biologically more-diverse continental communities. Recently, several cases of "upstream" colonization (from islands to continents) have been documented, challenging the traditional view. However, all these cases have involved individual island species that have colonized mainland regions. Here, using molecular phylogenetic data, divergence time estimates, lineage diversity distributions, and ancestral area analyses, we reconstruct the spread of a species-rich (>700 species) passerine bird radiation (core Corvoidea) from its late Eocene/Oligocene origin in the emerging proto-Papuan archipelago north of Australia, including multiple colonizations from the archipelago to Southeast Asia. Thus, islands apparently provided the setting for the initiation of a major songbird radiation that subsequently invaded all other continents. Morphological and behavioral adaptations of the core Corvoidea as generalist feeders in open habitats, which facilitated dispersal and colonization, apparently evolved in the descendants of sedentary forest birds that invaded the proto-Papuan archipelago. The archipelago evidently provided islands of the right size, number, and proximity to continental areas to support the adaptation and diversification of vagile colonizers that went on to increase avian diversity on a global scale. PMID- 21262813 TI - Comparable T helper 1 (Th1) and CD8 T-cell immunity by targeting HIV gag p24 to CD8 dendritic cells within antibodies to Langerin, DEC205, and Clec9A. AB - Improved protein-based vaccines should facilitate the goal of effective vaccines against HIV and other pathogens. With respect to T cells, the efficiency of immunization, or "immunogenicity," is improved by targeting vaccine proteins to maturing dendritic cells (DCs) within mAbs to DC receptors. Here, we compared the capacity of Langerin/CD207, DEC205/CD205, and Clec9A receptors, each expressed on the CD8(+) DC subset in mice, to bring about immunization of microbial-specific T cells from the polyclonal repertoire, using HIV gag-p24 protein as an antigen. alpha-Langerin mAb targeted splenic CD8(+) DCs selectively in vivo, whereas alpha DEC205 and alpha-Clec9A mAbs targeted additional cell types. When the mAb heavy chains were engineered to express gag-p24, the alpha-Langerin, alpha-DEC205, and alpha-Clec9A fusion mAbs given along with a maturation stimulus induced comparable levels of gag-specific T helper 1 (Th1) and CD8(+) T cells in BALB/c * C57BL/6 F1 mice. These immune T cells were more numerous than targeting the CD8( ) DC subset with alpha-DCIR2-gag-p24. In an in vivo assay in which gag-primed T cells were used to report the early stages of T-cell responses, alpha-Langerin, alpha-DEC205, and alpha-Clec9A also mediated cross-presentation to primed CD8(+) T cells if, in parallel to antigen uptake, the DCs were stimulated with alpha CD40. alpha-Langerin, alpha-DEC205, and alpha-Clec9A targeting greatly enhanced T cell immunization relative to nonbinding control mAb or nontargeted HIV gag-p24 protein. Therefore, when the appropriate subset of DCs is targeted with a vaccine protein, several different receptors expressed by that subset are able to initiate combined Th1 and CD8(+) immunity. PMID- 21262815 TI - Interspecies pheromone signaling promotes biofilm formation and same-sex mating in Candida albicans. AB - The opportunistic pathogen Candida albicans undergoes a parasexual mating cycle in which cells must switch from the conventional "white" form to the alternative "opaque" form to become mating competent. Pheromones secreted by opaque cells induce the formation of polarized mating projections and result in cell-cell conjugation. In contrast, white cells are unable to undergo mating, but can still respond to pheromone by expression of adhesion genes that promote biofilm formation. In this study, we have analyzed the dual ability of pheromones to activate mating by opaque cells and biofilm formation by white cells. We first show that there is considerable plasticity in interactions between the alpha pheromone and its receptor, Ste2, by analysis of analogs of the alpha pheromone. Significantly, substituted forms of alpha pheromone can induce a response in opaque cells and this is sufficient to drive same-sex a-a cell fusion and homothallic mating. In addition, pheromone analogs were able to induce adhesion and biofilm formation in white cells of C. albicans. Because of the observed plasticity in pheromone signaling, we subsequently tested putative pheromones from multiple Candida species and identified nonnative ligands that can induce self-mating and biofilm responses in C. albicans. Our findings demonstrate that environmental signals can initiate C. albicans parasexual reproduction and biofilm formation, and highlight the role of the pheromone-signaling apparatus in mediating these functions. PMID- 21262817 TI - Identification of a brain center whose activity discriminates a choice behavior in zebrafish. AB - The ability to make choices and carry out appropriate actions is critical for individual survival and well-being. Choice behaviors, from hard-wired to experience-dependent, have been observed across the animal kingdom. Although differential engagement of sensory neuronal pathways is a known mechanism, neurobiological substrates in the brain that underlie choice making downstream of sensory perception are not well understood. Here, we report a behavioral paradigm in zebrafish in which a half-light/half-dark visual image evokes an innate choice behavior, light avoidance. Neuronal activity mapping using the immediate early gene c-fos reveals the engagement of distinct brain regions, including the medial zone of the dorsal telencephalic region (Dm) and the dorsal nucleus of the ventral telencephalic area (Vd), the teleost anatomical homologs of the mammalian amygdala and striatum, respectively. In animals that were subjected to the identical sensory stimulus but displayed little or no avoidance, strikingly, the Dm and Vd were not engaged, despite similar levels of activation in the brain nuclei involved in visual processing. Based on these findings and previous connectivity data, we propose a neural circuitry model in which the Dm serves as a brain center, the activity of which predicates this choice behavior in zebrafish. PMID- 21262818 TI - De novo-engineered transcription activator-like effector (TALE) hybrid nuclease with novel DNA binding specificity creates double-strand breaks. AB - Site-specific and rare cutting nucleases are valuable tools for genome engineering. The generation of double-strand DNA breaks (DSBs) promotes homologous recombination in eukaryotes and can facilitate gene targeting, additions, deletions, and inactivation. Zinc finger nucleases have been used to generate DSBs and subsequently, for genome editing but with low efficiency and reproducibility. The transcription activator-like family of type III effectors (TALEs) contains a central domain of tandem repeats that could be engineered to bind specific DNA targets. Here, we report the generation of a Hax3-based hybrid TALE nuclease with a user-selected DNA binding specificity. We show that the engineered TALE nuclease can bind to its target sequence in vitro and that the homodimeric TALE nuclease can cleave double-stranded DNA in vitro if the DNA binding sites have the proper spacing and orientation. Transient expression assays in tobacco leaves suggest that the hybrid nuclease creates DSB in its target sequence, which is subsequently repaired by nonhomologous end-joining repair. Taken together, our data show the feasibility of engineering TALE-based hybrid nucleases capable of generating site-specific DSBs and the great potential for site-specific genome modification in plants and eukaryotes in general. PMID- 21262816 TI - Rack1 is required for Vangl2 membrane localization and planar cell polarity signaling while attenuating canonical Wnt activity. AB - The vertebrate planar cell polarity (PCP) pathway shares molecular components with the beta-catenin-mediated canonical Wnt pathway but acts through membrane complexes containing Vang or Frizzled to orient neighboring cells coordinately. The molecular interactions underlying the action of Vang in PCP signaling and specification, however, are yet to be delineated. Here, we report the identification of Rack1 as an interacting protein of a vertebrate Vang protein, Vangl2. We demonstrate that Rack1 is required in zebrafish for PCP-regulated processes, including oriented cell division, cellular polarization, and convergent extension during gastrulation. We further show that the knockdown of Rack1 affects membrane localization of Vangl2 and that the Vangl2-interacting domain of Rack1 has a dominant-negative effect on Vangl2 localization and gastrulation. Moreover, Rack1 antagonizes canonical Wnt signaling. Together, our data suggest that Rack1 regulates the localization of an essential PCP protein and acts as a molecular switch to promote PCP signaling. PMID- 21262819 TI - A chromatin insulator driving three-dimensional Polycomb response element (PRE) contacts and Polycomb association with the chromatin fiber. AB - Regulation of gene expression involves long-distance communication between regulatory elements and target promoters, but how this is achieved remains unknown. Insulator elements have been proposed to modulate the communication between regulatory elements and promoters due to their ability to insulate genes from regulatory elements or to take part in long-distance interactions. Using a high-resolution chromatin conformation capture (H3C) method, we show that the Drosophila gypsy insulator behaves as a conformational chromatin border that is able to prohibit contacts between a Polycomb response element (PRE) and a distal promoter. On the other hand, two spaced gypsy elements form a chromatin loop that is able to bring an upstream PRE in contact with a downstream gene to mediate its repression. Chromatin immunoprecipitation (ChIP) profiles of the Polycomb protein and its associated H3K27me3 histone mark reflect this insulator-dependent chromatin conformation, suggesting that Polycomb action at a distance can be organized by local chromatin topology. PMID- 21262825 TI - Impacts of climate change on the world's most exceptional ecoregions. AB - The current rate of warming due to increases in greenhouse gas (GHG) emissions is very likely unprecedented over the last 10,000 y. Although the majority of countries have adopted the view that global warming must be limited to <2 degrees C, current GHG emission rates and nonagreement at Copenhagen in December 2009 increase the likelihood of this limit being exceeded by 2100. Extensive evidence has linked major changes in biological systems to 20th century warming. The "Global 200" comprises 238 ecoregions of exceptional biodiversity [Olson DM, Dinerstein E (2002) Ann Mo Bot Gard 89:199-224]. We assess the likelihood that, by 2070, these iconic ecoregions will regularly experience monthly climatic conditions that were extreme in 1961-1990. Using >600 realizations from climate model ensembles, we show that up to 86% of terrestrial and 83% of freshwater ecoregions will be exposed to average monthly temperature patterns >2 SDs (2sigma) of the 1961-1990 baseline, including 82% of critically endangered ecoregions. The entire range of 89 ecoregions will experience extreme monthly temperatures with a local warming of <2 degrees C. Tropical and subtropical ecoregions, and mangroves, face extreme conditions earliest, some with <1 degrees C warming. In contrast, few ecoregions within Boreal Forests and Tundra biomes will experience such extremes this century. On average, precipitation regimes do not exceed 2sigma of the baseline period, although considerable variability exists across the climate realizations. Further, the strength of the correlation between seasonal temperature and precipitation changes over numerous ecoregions. These results suggest many Global 200 ecoregions may be under substantial climatic stress by 2100. PMID- 21262821 TI - Transient depletion of regulatory T cells in transgenic mice reactivates virus specific CD8+ T cells and reduces chronic retroviral set points. AB - Although chronic infections with viruses such as HIV and hepatitis C virus have been associated with regulatory T cell (Treg)-mediated suppression of virus specific CD8(+) T-cell activity, no causal relationship between Tregs and chronic viral set points has been established. Using transgenic mice in which Tregs can be selectively ablated, we now show that transient depletion of Tregs during a chronic retroviral infection allows exhausted CD8(+) T cells to regain antiviral functions, including secretion of cytokines, production of cytotoxic molecules, and virus-specific cytolytic activity. Furthermore, short-term Treg ablation resulted in long-term reductions in chronic virus loads. These results demonstrate that Treg-mediated immunosuppression can be a significant factor in the maintenance of chronic viral infections and that Treg-targeted immunotherapy could be a valuable component in therapeutic strategies to treat chronic infectious diseases. PMID- 21262820 TI - Optical probing of a dynamic membrane interaction that regulates the TREK1 channel. AB - TREK channels produce background currents that regulate cell excitability. These channels are sensitive to a wide variety of stimuli including polyunsaturated fatty acids (PUFAs), phospholipids, mechanical stretch, and intracellular acidification. They are inhibited by neurotransmitters, hormones, and pharmacological agents such as the antidepressant fluoxetine. TREK1 knockout mice have impaired PUFA-mediated neuroprotection to ischemia, reduced sensitivity to volatile anesthetics, altered perception of pain, and a depression-resistant phenotype. Here, we investigate TREK1 regulation by Gq-coupled receptors (GqPCR) and phospholipids. Several reports indicate that the C-terminal domain of TREK1 is a key regulatory domain. We developed a fluorescent-based technique that monitors the plasma membrane association of the C terminus of TREK1 in real time. Our fluorescence and functional experiments link the modulation of TREK1 channel function by internal pH, phospholipid, and GqPCRs to TREK1-C-terminal domain association to the plasma membrane, where increased association results in greater activity. In keeping with this relation, inhibition of TREK1 current by fluoxetine is found to be accompanied by dissociation of the C-terminal domain from the membrane. PMID- 21262826 TI - Land inheritance establishes sibling competition for marriage and reproduction in rural Ethiopia. AB - Intergenerational transfer of wealth has been proposed as playing a pivotal role in the evolution of human sibling relationships. Sibling rivalry is assumed to be more marked when offspring compete for limited heritable resources, which are crucial for reproductive success (e.g., land and livestock); whereas in the absence of heritable wealth, related siblings may cooperate. To date, comparative studies undertaken to support this evolutionary assumption have been confounded by other socioecological factors, which vary across populations, e.g., food sharing and intergroup conflict. In this article we explore effects of sibling competition and cooperation for agricultural resources, marriage, and reproduction in one contemporary Ethiopian agropastoralist society. Here recent changes in land tenure policy, altering transfers of land from parents to offspring, present a unique framework to test the importance of intergenerational transfers of wealth in driving sibling competition, while controlling for socioeconomic biases. In households where land is inherited, the number of elder brothers reduces a man's agricultural productivity, marriage, and reproductive success, as resources diminish and competition increases with each additional sibling. Where land is not inherited (for males receiving land directly from the government and all females) older siblings do not have a competitive effect and in some instances may be beneficial. This study has wider implications for the evolution of human family sizes. Recent changes in wealth transfers, which have driven sibling competition, may be contributing to an increased desire for smaller family sizes. PMID- 21262828 TI - A mechanism for graded motor control encoded in the channel properties of the muscle ACh receptor. AB - The larva of the invertebrate chordate Ciona intestinalis possesses only 36 striated muscle cells and lacks body segmentation. It can swim, however, like a vertebrate tadpole, and how its simple body achieves such sophisticated motor control remains puzzling. We found that muscle contractions in Ciona larvae are variable and can be changed by sensory stimuli, so that neuromuscular transmission can convert the variable neural inputs into graded muscle activity. We characterized the molecular nature of the nicotinic acetylcholine receptor (nAChR) at neuromuscular synapses. When heterologously expressed in Xenopus oocytes, this nAChR channel exhibited two biophysical features resembling vertebrate neuronal nAChRs rather than the muscle type: inward rectification and high Ca(2+) permeability. Both of these properties were abolished by a simple mutation at the channel pore in one of the non-alpha subunits, called BGDE3, so as to adopt the sequence of related subunits in vertebrates, gamma and epsilon. In vivo exchange of native BGDE3 with this mutant severely disrupted graded motor control, producing instead sporadic all-or-none-like flexions. The graded nature of excitation-contraction (E-C) coupling in this organism is based on the traits of the nAChR channel pore, which confer fine controllability on such a coarse motor architecture. PMID- 21262824 TI - Crystal structure of a gammadelta T-cell receptor specific for the human MHC class I homolog MICA. AB - gammadelta T cells play important roles in bridging innate and adaptive immunity, but their recognition mechanisms remain poorly understood. Human gammadelta T cells of the V(delta)1 subset predominate in intestinal epithelia and respond to MICA and MICB (MHC class I chain-related, A and B; MIC) self-antigens, mediating responses to tumorigenesis or viral infection. The crystal structure of an MIC reactive V(delta)1 gammadelta T-cell receptor (TCR) showed expected overall structural homology to antibodies, alphabeta, and other gammadelta TCRs, but complementary determining region conformations and conservation of V(delta)1 use revealed an uncharacteristically flat potential binding surface. MIC, likewise, serves as a ligand for the activating immunoreceptor natural killer group 2, D (NKG2D), also expressed on gammadelta T cells. Although MIC recognition drives both the TCR-dependent stimulatory and NKG2D-dependent costimulatory signals necessary for activation, interaction analyses showed that MIC binding by the two receptors was mutually exclusive. Analysis of relative binding kinetics suggested sequential recognition, defining constraints for the temporal organization of gammadelta T-cell/target cell interfaces. PMID- 21262829 TI - Coupling of ferredoxin and heterodisulfide reduction via electron bifurcation in hydrogenotrophic methanogenic archaea. AB - In methanogenic archaea growing on H(2) and CO(2) the first step in methanogenesis is the ferredoxin-dependent endergonic reduction of CO(2) with H(2) to formylmethanofuran and the last step is the exergonic reduction of the heterodisulfide CoM-S-S-CoB with H(2) to coenzyme M (CoM-SH) and coenzyme B (CoB SH). We recently proposed that in hydrogenotrophic methanogens the two reactions are energetically coupled via the cytoplasmic MvhADG/HdrABC complex. It is reported here that the purified complex from Methanothermobacter marburgensis catalyzes the CoM-S-S-CoB-dependent reduction of ferredoxin with H(2). Per mole CoM-S-S-CoB added, 1 mol of ferredoxin (Fd) was reduced, indicating an electron bifurcation coupling mechanism: 2H(2) + Fd(OX) + CoM-S-S-CoB-->Fd(red)(2-) + CoM SH + CoB-SH + 2H(+). This stoichiometry of coupling is consistent with an ATP gain per mole methane from 4 H(2) and CO(2) of near 0.5 deduced from an H(2) threshold concentration of 8 Pa and a growth yield of up to 3 g/mol methane. PMID- 21262823 TI - Activating AMP-activated protein kinase (AMPK) slows renal cystogenesis. AB - Renal cyst development and expansion in autosomal dominant polycystic kidney disease (ADPKD) involves both fluid secretion and abnormal proliferation of cyst lining epithelial cells. The chloride channel of the cystic fibrosis transmembrane conductance regulator (CFTR) participates in secretion of cyst fluid, and the mammalian target of rapamycin (mTOR) pathway may drive proliferation of cyst epithelial cells. CFTR and mTOR are both negatively regulated by AMP-activated protein kinase (AMPK). Metformin, a drug in wide clinical use, is a pharmacological activator of AMPK. We find that metformin stimulates AMPK, resulting in inhibition of both CFTR and the mTOR pathways. Metformin induces significant arrest of cystic growth in both in vitro and ex vivo models of renal cystogenesis. In addition, metformin administration produces a significant decrease in the cystic index in two mouse models of ADPKD. Our results suggest a possible role for AMPK activation in slowing renal cystogenesis as well as the potential for therapeutic application of metformin in the context of ADPKD. PMID- 21262822 TI - A gradient of childhood self-control predicts health, wealth, and public safety. AB - Policy-makers are considering large-scale programs aimed at self-control to improve citizens' health and wealth and reduce crime. Experimental and economic studies suggest such programs could reap benefits. Yet, is self-control important for the health, wealth, and public safety of the population? Following a cohort of 1,000 children from birth to the age of 32 y, we show that childhood self control predicts physical health, substance dependence, personal finances, and criminal offending outcomes, following a gradient of self-control. Effects of children's self-control could be disentangled from their intelligence and social class as well as from mistakes they made as adolescents. In another cohort of 500 sibling-pairs, the sibling with lower self-control had poorer outcomes, despite shared family background. Interventions addressing self-control might reduce a panoply of societal costs, save taxpayers money, and promote prosperity. PMID- 21262830 TI - Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus-host recombinant. AB - The RNA virus, hepatitis E virus (HEV) is the most or second-most important cause of acute clinical hepatitis in adults throughout much of Asia, the Middle East, and Africa. In these regions it is an important cause of acute liver failure, especially in pregnant women who have a mortality rate of 20-30%. Until recently, hepatitis E was rarely identified in industrialized countries, but Hepatitis E now is reported increasingly throughout Western Europe, some Eastern European countries, and Japan. Most of these cases are caused by genotype 3, which is endemic in swine, and these cases are thought to be zoonotically acquired. However, transmission routes are not well understood. HEV that infect humans are divided into nonzoonotic (types 1, 2) and zoonotic (types 3, 4) genotypes. HEV cell culture is inefficient and limited, and thus far HEV has been cultured only in human cell lines. The HEV strain Kernow-C1 (genotype 3) isolated from a chronically infected patient was used to identify human, pig, and deer cell lines permissive for infection. Cross-species infections by genotypes 1 and 3 were studied with this set of cultures. Adaptation of the Kernow-C1 strain to growth in human hepatoma cells selected for a rare virus recombinant that contained an insertion of 174 ribonucleotides (58 amino acids) of a human ribosomal protein gene. PMID- 21262827 TI - Human thrombopoietin knockin mice efficiently support human hematopoiesis in vivo. AB - Hematopoietic stem cells (HSCs) both self-renew and give rise to all blood cells for the lifetime of an individual. Xenogeneic mouse models are broadly used to study human hematopoietic stem and progenitor cell biology in vivo. However, maintenance, differentiation, and function of human hematopoietic cells are suboptimal in these hosts. Thrombopoietin (TPO) has been demonstrated as a crucial cytokine supporting maintenance and self-renewal of HSCs. We generated RAG2(-/-)gamma(c)(-/-) mice in which we replaced the gene encoding mouse TPO by its human homolog. Homozygous humanization of TPO led to increased levels of human engraftment in the bone marrow of the hosts, and multilineage differentiation of hematopoietic cells was improved, with an increased ratio of myelomonocytic verus lymphoid lineages. Moreover, maintenance of human stem and progenitor cells was improved, as demonstrated by serial transplantation. Therefore, RAG2(-/-)gamma(c)(-/-) TPO-humanized mice represent a useful model to study human hematopoiesis in vivo. PMID- 21262832 TI - C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice. AB - The full-length AML1-ETO (AE) fusion gene resulting from t(8;21)(q22;q22) in human acute myeloid leukemia (AML) is not sufficient to induce leukemia in animals, suggesting that additional mutations are required for leukemogenesis. We and others have identified activating mutations of C-KIT in nearly half of patients with t(8;21) AML. To test the hypothesis that activating C-KIT mutations cooperate with AE to cause overt AML, we generated a murine transduction and transplantation model with both mutated C-KIT and AE. To overcome the intracellular transport block of human C-KIT in murine cells, we engineered hybrid C-KIT (HyC-KIT) by fusing the extracellular and transmembrane domains of the murine c-Kit in-frame to the intracellular signaling domain of human C-KIT. We showed that tyrosine kinase domain mutants HyC-KIT N822K and D816V, as well as juxtamembrane mutants HyC-KIT 571+14 and 557-558Del, could transform murine 32D cells to cytokine-independent growth. The protein tyrosine kinase inhibitor dasatinib inhibited the proliferation of 32D cells expressing these C-KIT mutants, with potency in the low nanomolar range. In mice, HyC-KIT N822K induced a myeloproliferative disease, whereas HyC-KIT 571+14 induces both myeloproliferative disease and lymphocytic leukemia. Interestingly, coexpression of AE and HyC-KIT N822K led to fatal AML. Our data have further enriched the two hit model that abnormalities of both transcription factor and membrane/cytosolic signaling molecule are required in AML pathogenesis. Furthermore, dasatinib prolonged lifespan of mice bearing AE and HyC-KIT N822K-coexpressing leukemic cells and exerted synergic effects while combined with cytarabine, thus providing a potential therapeutic for t(8;21) leukemia. PMID- 21262833 TI - Symmetry, asymmetry, and kinetics of silencing establishment in Saccharomyces cerevisiae revealed by single-cell optical assays. AB - In Saccharomyces cerevisiae, silent chromatin inhibits the expression of genes at the HML, HMR, and telomeric loci. When silent chromatin forms de novo, the rate of its establishment is influenced by different chromatin states. In particular, loss of the enzyme Dot1, an H3 K79 methyltransferase, leads to rapid silencing establishment. We tested whether silencing establishment was antagonized by H3 K79 methylation or by the Dot1 protein itself competing with Sir3 for binding sites on nucleosomes. To do so, we monitored fluorescence activity in cells containing a GFP gene within the HML locus during silencing establishment in a series of dot1 and histone mutant backgrounds. Silencing establishment rate was correlated with Dot1's enzymatic function rather than with the Dot1 protein itself. In addition, histone mutants that mimicked the conformation of unmethylated H3 K79 increased the rate of silencing establishment, indicating that the H3 K79 residue affected silencing independently of Dot1 abundance. Using fluorophore-based reporters, we confirmed that mother and daughter cells often silence in concert, but in instances where asymmetric silencing occurs, daughter cells established silencing earlier than their mothers. This noninvasive technique enabled us to demonstrate an asymmetry in silencing establishment of a key regulatory locus controlling cell fate. PMID- 21262831 TI - Bioluminescence imaging of Abeta deposition in bigenic mouse models of Alzheimer's disease. AB - Transgenic (Tg) mouse models of Alzheimer's disease have served as valuable tools for investigating pathogenic mechanisms related to Abeta accumulation. However, assessing disease status in these animals has required time-consuming behavioral assessments or postmortem neuropathological analysis. Here, we report a method for tracking the progression of Abeta accumulation in vivo using bioluminescence imaging (BLI) on two lines of Tg mice, which express luciferase (luc) under control of the Gfap promoter as well as mutant human amyloid precursor protein. Bigenic mice exhibited an age-dependent increase in BLI signals that correlated with the deposition of Abeta in the brain. Bioluminescence signals began to increase in 7-mo-old Tg(CRND8:Gfap-luc) mice and 14-mo-old Tg(APP23:Gfap-luc) mice. When Tg(APP23:Gfap-luc) mice were inoculated with brain homogenates from aged Tg(APP23) mice, BLI detected the accelerated disease onset and induced Abeta deposition at 11 mo of age. Because of its rapid, noninvasive, and quantitative format, BLI permits the objective repeated analysis of individual mice at multiple time points, which is likely to facilitate the testing of Abeta-directed therapeutics. PMID- 21262834 TI - Experimental selection of hypoxia-tolerant Drosophila melanogaster. AB - Through long-term laboratory selection (over 200 generations), we have generated Drosophila melanogaster populations that tolerate severe, normally lethal, levels of hypoxia. Because of initial experiments suspecting genetic mechanisms underlying this adaptation, we compared the genomes of the hypoxia-selected flies with those of controls using deep resequencing. By applying unique computing and analytical methods we identified a number of DNA regions under selection, mostly on the X chromosome. Several of the hypoxia-selected regions contained genes encoding or regulating the Notch pathway. In addition, previous expression profiling revealed an activation of the Notch pathway in the hypoxia-selected flies. We confirmed the contribution of Notch activation to hypoxia tolerance using a specific gamma-secretase inhibitor, N-[N-(3,5-Difluorophenacetyl)-L alanyl]-S-phenylglycine t-butyl ester (DAPT), which significantly reduced adult survival and life span in the hypoxia-selected flies. We also demonstrated that flies with loss-of-function Notch mutations or RNAi-mediated Notch knockdown had a significant reduction in hypoxia tolerance, but those with a gain-of-function had a dramatic opposite effect. Using the UAS-Gal4 system, we also showed that specific overexpression of the Notch intracellular domain in glial cells was critical for conferring hypoxia tolerance. Unique analytical tools and genetic and bioinformatic strategies allowed us to discover that Notch activation plays a major role in this hypoxia tolerance in Drosophila melanogaster. PMID- 21262836 TI - Interleukin-2 inhibits FMS-like tyrosine kinase 3 receptor ligand (flt3L) dependent development and function of conventional and plasmacytoid dendritic cells. AB - Steady-state development of plasmacytoid dendritic cells (pDCs) and conventional dendritic cells (cDCs) requires the ligand for FMS-like tyrosine kinase 3 receptor (flt3L), but little is known about how other cytokines may also control this process. In this study, we show that IL-2 inhibits the development of both pDCs and cDCs from bone marrow cells under flt3L stimulation, by acting on lineage(-) flt3(+) precursors. This inhibition of DC development by IL-2 requires IL-2Ralpha and IL2Rbeta. IL-2Ralpha is specifically expressed in one stage of the DC precursor: the monocyte and DC progenitors (MDPs). Furthermore, more MDPs are found in flt3L-stimulated bone marrow cultures when IL-2 is present, suggesting that IL-2 may be inhibiting DC development at the MDP stage. Consistent with our in vitro findings, we observe that nonobese diabetic (NOD) mice, which express less IL-2 compared with diabetes-resistant NOD.Idd3/5 mice, have more splenic pDCs. Additionally, DCs developed in vitro in the presence of flt3L and IL-2 display reduced ability to stimulate T-cell proliferation compared with DCs developed in the presence of flt3L alone. Although the addition of IL-2 does not increase the apoptosis of DCs during their development, DCs developed in the presence of IL-2 are more prone to apoptosis upon interaction with T cells. Together our data show that IL-2 can inhibit both the development and the function of DCs. This pathway may have implications for the loss of immune tolerance: Reduced IL-2 signaling may lead to increased DC number and T-cell stimulatory capacity. PMID- 21262835 TI - Structure of the Lassa virus nucleoprotein reveals a dsRNA-specific 3' to 5' exonuclease activity essential for immune suppression. AB - Lassa fever virus, a member of the family Arenaviridae, is a highly endemic category A pathogen that causes 300,000-500,000 infections per year in Western Africa. The arenaviral nucleoprotein NP has been implicated in suppression of the host innate immune system, but the mechanism by which this occurs has remained elusive. Here we present the crystal structure at 1.5 A of the immunosuppressive C-terminal portion of Lassa virus NP and illustrate that, unexpectedly, its 3D fold closely mimics that of the DEDDh family of exonucleases. Accompanying biochemical experiments illustrate that NP indeed has a previously unknown, bona fide exonuclease activity, with strict specificity for double-stranded RNA substrates. We further demonstrate that this exonuclease activity is essential for the ability of NP to suppress translocation of IFN regulatory factor 3 and block activation of the innate immune system. Thus, the nucleoprotein is a viral exonuclease with anti-immune activity, and this work provides a unique opportunity to combat arenaviral infections. PMID- 21262837 TI - Requirement for ribosomal protein S6 kinase 1 to mediate glycolysis and apoptosis resistance induced by Pten deficiency. AB - Pten inactivation promotes cell survival in leukemia cells by activating glycolytic metabolism. We found that targeting ribosomal protein S6 kinase 1 (S6K1) in Pten-deficient cells suppressed glycolysis and induced apoptosis. S6K1 knockdown decreased expression of HIF-1alpha, and HIF-1alpha was sufficient to restore glycolysis and survival of cells lacking S6K1. In the Pten(fl/fl) Mx1 Cre(+) mouse model of leukemia, S6K1 deletion delayed the development of leukemia. Thus, S6K1 is a critical mediator of glycolytic metabolism, cell survival, and leukemogenesis in Pten-deficient cells. PMID- 21262838 TI - The chromatin-remodeling enzyme BRG1 modulates vascular Wnt signaling at two levels. AB - The ATP-dependent chromatin-remodeling enzyme brahma-related gene 1 (BRG1) regulates transcription of specific target genes during embryonic and postnatal development. Deletion of Brg1 from embryonic blood vessels results in yolk sac vascular remodeling defects. We now report that misregulation of the canonical Wnt signaling pathway underlies many Brg1 mutant vascular phenotypes. Brg1 deletion resulted in down-regulation of several Wnt receptors of the frizzled family, degradation of the intracellular Wnt signaling molecule beta-catenin, and an overall decrease in Wnt signaling in endothelial cells. Pharmacological stabilization of beta-catenin significantly rescued Brg1 mutant vessel morphology and transcription of Wnt target genes. Our data demonstrate that BRG1 impacts the canonical Wnt pathway at two different levels in vascular endothelium: through transcriptional regulation of both Wnt receptor genes and Wnt target genes. These findings establish an epigenetic mechanism for the modulation of Wnt signaling during embryonic vascular development. PMID- 21262839 TI - An aquaporin-4/transient receptor potential vanilloid 4 (AQP4/TRPV4) complex is essential for cell-volume control in astrocytes. AB - Regulatory volume decrease (RVD) is a key mechanism for volume control that serves to prevent detrimental swelling in response to hypo-osmotic stress. The molecular basis of RVD is not understood. Here we show that a complex containing aquaporin-4 (AQP4) and transient receptor potential vanilloid 4 (TRPV4) is essential for RVD in astrocytes. Astrocytes from AQP4-KO mice and astrocytes treated with TRPV4 siRNA fail to respond to hypotonic stress by increased intracellular Ca(2+) and RVD. Coimmunoprecipitation and immunohistochemistry analyses show that AQP4 and TRPV4 interact and colocalize. Functional analysis of an astrocyte-derived cell line expressing TRPV4 but not AQP4 shows that RVD and intracellular Ca(2+) response can be reconstituted by transfection with AQP4 but not with aquaporin-1. Our data indicate that astrocytes contain a TRPV4/AQP4 complex that constitutes a key element in the brain's volume homeostasis by acting as an osmosensor that couples osmotic stress to downstream signaling cascades. PMID- 21262840 TI - The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins. AB - C1q-like genes (C1ql1-C1ql4) encode small, secreted proteins that are expressed in differential patterns in the brain but whose receptors and functions remain unknown. BAI3 protein, in contrast, is a member of the cell-adhesion class of G protein-coupled receptors that are expressed at high levels in the brain but whose ligands have thus far escaped identification. Using a biochemical approach, we show that all four C1ql proteins bind to the extracellular thrombospondin repeat domain of BAI3 with high affinity, and that this binding is mediated by the globular C1q domains of the C1ql proteins. Moreover, we demonstrate that addition of submicromolar concentrations of C1ql proteins to cultured neurons causes a significant decrease in synapse density, and that this decrease was prevented by simultaneous addition of the thrombospondin-repeat fragment of BAI3, which binds to C1ql proteins. Our data suggest that C1ql proteins are secreted signaling molecules that bind to BAI3 and act, at least in part, to regulate synapse formation and/or maintenance. PMID- 21262841 TI - Genome and transcriptome analyses of the mountain pine beetle-fungal symbiont Grosmannia clavigera, a lodgepole pine pathogen. AB - In western North America, the current outbreak of the mountain pine beetle (MPB) and its microbial associates has destroyed wide areas of lodgepole pine forest, including more than 16 million hectares in British Columbia. Grosmannia clavigera (Gc), a critical component of the outbreak, is a symbiont of the MPB and a pathogen of pine trees. To better understand the interactions between Gc, MPB, and lodgepole pine hosts, we sequenced the ~30-Mb Gc genome and assembled it into 18 supercontigs. We predict 8,314 protein-coding genes, and support the gene models with proteome, expressed sequence tag, and RNA-seq data. We establish that Gc is heterothallic, and report evidence for repeat-induced point mutation. We report insights, from genome and transcriptome analyses, into how Gc tolerates conifer-defense chemicals, including oleoresin terpenoids, as they colonize a host tree. RNA-seq data indicate that terpenoids induce a substantial antimicrobial stress in Gc, and suggest that the fungus may detoxify these chemicals by using them as a carbon source. Terpenoid treatment strongly activated a ~100-kb region of the Gc genome that contains a set of genes that may be important for detoxification of these host-defense chemicals. This work is a major step toward understanding the biological interactions between the tripartite MPB/fungus/forest system. PMID- 21262842 TI - 2D luminescence imaging of pH in vivo. AB - Luminescence imaging of biological parameters is an emerging field in biomedical sciences. Tools to study 2D pH distribution are needed to gain new insights into complex disease processes, such as wound healing and tumor metabolism. In recent years, luminescence-based methods for pH measurement have been developed. However, for in vivo applications, especially for studies on humans, biocompatibility and reliability under varying conditions have to be ensured. Here, we present a referenced luminescent sensor for 2D high-resolution imaging of pH in vivo. The ratiometric sensing scheme is based on time-domain luminescence imaging of FITC and ruthenium(II)tris-(4,7-diphenyl-1,10 phenanthroline). To create a biocompatible 2D sensor, these dyes were bound to or incorporated into microparticles (aminocellulose and polyacrylonitrile), and particles were immobilized in polyurethane hydrogel on transparent foils. We show sensor precision and validity by conducting in vitro and in vivo experiments, and we show the versatility in imaging pH during physiological and chronic cutaneous wound healing in humans. Implementation of this technique may open vistas in wound healing, tumor biology, and other biomedical fields. PMID- 21262843 TI - Lysosomal trapping of a radiolabeled substrate of P-glycoprotein as a mechanism for signal amplification in PET. AB - The radiotracer [(11)C]N-desmethyl-loperamide (dLop) images the in vivo function of P-glycoprotein (P-gp), a transporter that blocks the entry of drugs that are substrates into brain. When P-gp is inhibited, [(11)C]dLop, a potent opiate agonist, enters and becomes trapped in the brain. This trapping is beneficial from an imaging perspective, because it amplifies the PET signal, essentially by accumulating radioactivity over time. As we previously demonstrated that this trapping was not caused by binding to opiate receptors, we examined whether [(11)C]dLop, a weak base, is ionically trapped in acidic lysosomes. To test this hypothesis, we measured [(3)H]dLop accumulation in human cells by using lysosomotropics. Because the in vivo trapping of dLop was seen after P-gp inhibition, we also measured [(3)H]dLop uptake in P-gp-expressing cells treated with the P-gp inhibitor tariquidar. All lysosomotropics decreased [(3)H]dLop accumulation by at least 50%. In P-gp-expressing cells, tariquidar (and another P gp inhibitor) surprisingly decreased [(3)H]dLop uptake. Consequently, we measured [(11)C]dLop uptake before and after tariquidar preadministration in lysosome-rich organs of P-gp KO mice and humans. After tariquidar pretreatment in both species, radioactivity uptake in these organs decreased by 35% to 40%. Our results indicate that dLop is trapped in lysosomes and that tariquidar competes with dLop for lysosomal accumulation in vitro and in vivo. Although tariquidar and dLop compete for lysosomal trapping in the periphery, such competition does not occur in brain because tariquidar has negligible entry into brain. In summary, tariquidar and [(11)C]dLop can be used in combination to selectively measure the function of P-gp at the blood-brain barrier. PMID- 21262844 TI - Predicting and optimizing asymmetric catalyst performance using the principles of experimental design and steric parameters. AB - Using a modular amino acid based chiral ligand motif, a library of ligands was synthesized systematically varying the substituents at two positions. The effects of these changes on ligand structure were probed in the enantioselective allylation of benzaldehyde, acetophenone, and methylethyl ketone under Nozaki Hiyama-Kishi conditions. The resulting three-dimensional datasets allowed for the construction of mathematical surface models which describe the interplay of substituent effects on enantioselectivity for a given reaction. The surface models were both extrapolated and manipulated to predict the enantioselective outcomes of several previously untested ligands. Analyses were also used to predict optimal ligand structure of a minimal dataset. Within the dataset, a linear free energy relationship was also discovered and a direct comparison of both the linear prediction as well as the three-dimensional prediction illustrates the potential predictive power of using a three-dimensional model approach to asymmetric catalyst development. PMID- 21262846 TI - Casein kinase-2 mediates cell survival through phosphorylation and degradation of inositol hexakisphosphate kinase-2. AB - The inositol pyrophosphate, diphosphoinositol pentakisphosphate, regulates p53 and protein kinase Akt signaling, and its aberrant increase in cells has been implicated in apoptosis and insulin resistance. Inositol hexakisphosphate kinase 2 (IP6K2), one of the major inositol pyrophosphate synthesizing enzymes, mediates p53-linked apoptotic cell death. Casein kinase-2 (CK2) promotes cell survival and is upregulated in tumors. We show that CK2 mediated cell survival involves IP6K2 destabilization. CK2 physiologically phosphorylates IP6K2 at amino acid residues S347 and S356 contained within a PEST sequence, a consensus site for ubiquitination. HCT116 cells depleted of IP6K2 are resistant to cell death elicited by CK2 inhibitors. CK2 phosphorylation at the degradation motif of IP6K2 enhances its ubiquitination and subsequent degradation. IP6K2 mutants at the CK2 sites that are resistant to CK2 phosphorylation are metabolically stable. PMID- 21262847 TI - Interactions of anthrax lethal factor with protective antigen defined by site directed spin labeling. AB - The protective antigen (PA) moiety of anthrax toxin forms oligomeric pores that translocate the enzymatic moieties of the toxin--lethal factor (LF) and edema factor (EF)--across the endosomal membrane of mammalian cells. Here we describe site-directed spin-labeling studies that identify interactions of LF with the prepore and pore conformations of PA. Our results reveal a direct interaction between the extreme N terminus of LF (residues 2-5) and the Phi-clamp, a structure within the lumen of the pore that catalyzes translocation. Also, consistent with a recent crystallographic model, we find that, upon binding of the translocation substrate to PA, LF helix alpha1 separates from helices alpha2 and alpha3 and binds in the alpha-clamp of PA. These interactions, together with the binding of the globular part of the N-terminal domain of LF to domain 1' of PA, indicate that LF interacts with the PA pore at three distinct sites. Our findings elucidate the state from which translocation of LF and EF proceeds through the PA pore. PMID- 21262848 TI - Evaporation kinetics and phase of laboratory and ambient secondary organic aerosol. AB - Field measurements of secondary organic aerosol (SOA) find significantly higher mass loads than predicted by models, sparking intense effort focused on finding additional SOA sources but leaving the fundamental assumptions used by models unchallenged. Current air-quality models use absorptive partitioning theory assuming SOA particles are liquid droplets, forming instantaneous reversible equilibrium with gas phase. Further, they ignore the effects of adsorption of spectator organic species during SOA formation on SOA properties and fate. Using accurate and highly sensitive experimental approach for studying evaporation kinetics of size-selected single SOA particles, we characterized room-temperature evaporation kinetics of laboratory-generated alpha-pinene SOA and ambient atmospheric SOA. We found that even when gas phase organics are removed, it takes ~24 h for pure alpha-pinene SOA particles to evaporate 75% of their mass, which is in sharp contrast to the ~10 min time scale predicted by current kinetic models. Adsorption of "spectator" organic vapors during SOA formation, and aging of these coated SOA particles, dramatically reduced the evaporation rate, and in some cases nearly stopped it. Ambient SOA was found to exhibit evaporation behavior very similar to that of laboratory-generated coated and aged SOA. For all cases studied in this work, SOA evaporation behavior is nearly size independent and does not follow the evaporation kinetics of liquid droplets, in sharp contrast with model assumptions. The findings about SOA phase, evaporation rates, and the importance of spectator gases and aging all indicate that there is need to reformulate the way SOA formation and evaporation are treated by models. PMID- 21262849 TI - Ixabepilone, a novel microtubule-targeting agent for breast cancer, is a substrate for P-glycoprotein (P-gp/MDR1/ABCB1) but not breast cancer resistance protein (BCRP/ABCG2). AB - Ixabepilone is the first epothilone to be approved for clinical use. Current data suggest the epothilones have a role in treating taxane-resistant cancers and ixabepilone is unaffected by at least some of the mechanisms underlying chemoresistance. Here, we report a series of cytotoxicity and transport studies to assess the potential role of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in ixabepilone resistance. A significant decrease in ixabepilone-mediated cytotoxicity was observed in Madin-Darby canine kidney cells transfected with human multidrug resistance 1 (MDR1) comparative with the parental cells (IC(50) > 2000 nM versus 90 nM). Overexpression of P-gp also resulted in significantly decreased cell susceptibility to docetaxel, paclitaxel, and vinblastine. Bidirectional transport of ixabepilone across monolayers of porcine kidney-derived cells expressing human MDR1 showed a significantly increased efflux ratio relative to the parental cells. A BCRP-overexpressing cell line was developed by transfecting human embryonic kidney (HEK)-293 cells with BCRP cDNA and confirmed by immunoblotting and bodipy prazosin and mitoxantrone uptake. Neither P-gp nor multidrug resistance protein 2 was detected in the cells by corresponding polyclonal antibodies. This HEK-BCRP cell line demonstrated resistance to docetaxel, paclitaxel, vinblastine, and mitoxantrone, in comparison with the parental cell line (7.3, 4.3, 2.9, and 11.9 resistance factor, respectively). Transport inhibition by BCRP inhibitor fumitremorgin C and broad efflux inhibitor N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl] phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918) restored drug sensitivity. In contrast, ixabepilone was far less susceptible to BCRP mediated resistance, resulting in a resistance factor of only 1.2-fold. In summary, these results suggest that P-gp could cause resistance to ixabepilone in tumors and affect the disposition of the drug, but it is unlikely that BCRP mediates any drug resistance to ixabepilone. PMID- 21262851 TI - Inhibition of recombinant L-type voltage-gated calcium channels by positive allosteric modulators of GABAA receptors. AB - Benzodiazepines (BDZs) depress neuronal excitability via positive allosteric modulation of inhibitory GABA(A) receptors (GABA(A)R). BDZs and other positive GABA(A)R modulators, including barbiturates, ethanol, and neurosteroids, can also inhibit L-type voltage-gated calcium channels (L-VGCCs), which could contribute to reduced neuronal excitability. Because neuronal L-VGCC function is up regulated after long-term GABA(A)R modulator exposure, an interaction with L VGCCs may also play a role in physical dependence. The current studies assessed the effects of BDZs (diazepam, flurazepam, and desalkylflurazepam), allopregnanolone, pentobarbital, and ethanol on whole-cell Ba(2+) currents through recombinant neuronal Ca(v)1.2 and Ca(v)1.3 L-VGCCs expressed with beta(3) and alpha(2)delta-1 in HEK293T cells. Allopregnanolone was the most potent inhibitor (IC(50), ~10 MUM), followed by BDZs (IC(50), ~50 MUM), pentobarbital (IC(50), 0.3-1 mM), and ethanol (IC(50), ~300 mM). Ca(v)1.3 channels were less sensitive to pentobarbital inhibition than Ca(v)1.2 channels, similar to dihydropyridine (DHP) L-VGCC antagonists. All GABA(A)R modulators induced a negative shift in the steady-state inactivation curve of Ca(v)1.3 channels, but only BDZs and pentobarbital induced a negative shift in Ca(v)1.2 channel inactivation. Mutation of the high-affinity DHP binding site (T1039Y and Q1043M) in Ca(v)1.2 channels reduced pentobarbital potency. Despite the structural similarity between benzothiazepines and BDZs, mutation of an amino acid important for diltiazem potency (I1150A) did not affect diazepam potency. Although L-VGCC inhibition by BDZs occurred at concentrations that are possibly too high to be clinically relevant and is not likely to play a role in the up-regulation of L VGCCs during long-term treatment, pentobarbital and ethanol inhibited L-VGCCs at clinically relevant concentrations. PMID- 21262852 TI - How physicians have learned to handle sickness-certification cases. AB - BACKGROUND: Sickness absence is a common ''prescription'' in health care in many Western countries. Despite the significance of sick-listing for the life situation of patients, physicians have limited training in how to handle sickness certification cases and the research about sickness-certification practices is scarce. AIM: Gain knowledge on physicians' learning regarding management of sickness certification of patients in formal, informal, and non-formal learning situations, respectively, and possible changes in this from 2004 to 2008. METHODS: Data from two comprehensive questionnaires to physicians in Sweden about their sickness-certification practice in 2004 (n = 7665) and 2008 (n = 36,898); response rates: 71% and 61%, respectively. Answers from all the physicians <=64 years old and who had sickness certification tasks (n = 4019 and n = 14,210) were analysed. OUTCOME MEASURES: ratings of importance of different types of learning situations for their sickness-certification competence. RESULTS: Few physicians stated that formal learning situations had contributed to a large or fairly large extent to their competence in sickness certification, e.g. undergraduate studies had done that for 17%, internship for 37%, and resident training for 46%, respectively. Contacts with colleagues had been helpful for 65%. One-third was helped by training arranged by social insurance offices. There was a significant increase between 2004 and 2008 in all items related to formal and non-formal learning situations, while there were no changes regarding informal learning situations. CONCLUSIONS: This study of all physicians in Sweden shows that physicians primarily attain competence in sickness certification in their daily clinical practice; through contacts with colleagues and patients. PMID- 21262850 TI - Synergistic interaction between the two mechanisms of action of tapentadol in analgesia. AB - The novel centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1 ethyl-2-methyl-propyl)-phenol hydrochloride] combines two mechanisms of action, MU-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI), in a single molecule. Pharmacological antagonism studies have demonstrated that both mechanisms of action contribute to the analgesic effects of tapentadol. This study was designed to investigate the nature of the interaction of the two mechanisms. Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid antagonist naloxone or the alpha(2)-adrenoceptor antagonist yohimbine. Two different pain models were used: 1) low-intensity tail flick and 2) spinal nerve ligation. In each model, we obtained dose-effect relations to reveal the effect of tapentadol based on MOR agonism, NRI, and unblocked tapentadol. Receptor fractional occupation was determined from tapentadol's brain concentration and its dissociation constant for each binding site. Tapentadol produced dose-dependent analgesic effects in both pain models, and its dose-effect curves were shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Both isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated very pronounced synergistic interaction between the two mechanisms of action of tapentadol. This may explain why tapentadol is only 2- to 3-fold less potent than morphine across a variety of preclinical pain models despite its 50-fold lower affinity for the MOR. This is probably the first demonstration of a synergistic interaction between the occupied receptors for a single compound with two mechanisms of action. PMID- 21262853 TI - Gender differences in factors associated with sexual intercourse among Estonian adolescents. AB - AIMS: To examine factors associated with early sexual intercourse among 15 to 16 year-old adolescents by gender. METHODS: The data were collected from a random sample of Estonian basic schools' ninth grade pupils in 1999 using self-completed questionnaires. A multivariate logistic regression analysis for boys and girls was used to test for associations between sexual intercourse, and personal gender role-related attitudes, attitudes towards sexual intercourse, pubertal timing, smoking status and experience of drunkenness. RESULTS: Of the respondents, 14.6% of boys and 13.1% of girls had experienced sexual intercourse. Traditional gender role-related attitudes were associated with sexual intercourse among girls, but not among boys. Smoking and experience of drunkenness was strongly associated with sexual intercourse for both genders. CONCLUSIONS: Gender differences in the association between gender role-related attitudes and early sexual intercourse were observed among 15 to 16-year-olds in Estonia. Smoking and experience of drunkenness were strongly related to sexual intercourse for both genders. PMID- 21262854 TI - Intravenous flumazenil infusion to treat benzodiazepine dependence should be performed in the inpatient clinical setting for high risk of seizure. PMID- 21262855 TI - Dopamine in nucleus accumbens: salience modulation in latent inhibition and overshadowing. AB - Latent inhibition (LI) is demonstrated when non-reinforced pre-exposure to a to be-conditioned stimulus retards later learning. Learning is similarly retarded in overshadowing, in this case using the relative intensity of competing cues to manipulate associability. Electrolytic/excitotoxic lesions to shell accumbens (NAc) and systemic amphetamine both reliably abolish LI. Here a conditioned emotional response procedure was used to demonstrate LI and overshadowing and to examine the role of dopamine (DA) within NAc. Experiment 1 showed that LI but not overshadowing was abolished by systemic amphetamine (1.0 mg/kg i.p.). In Experiment 2, 6-hydroxydopamine (6-OHDA) was used to lesion DA terminals within NAc: both shell- and core- (plus shell-)lesioned rats showed normal LI and overshadowing. Experiment 3 compared the effects of amphetamine microinjected at shell and core coordinates prior to conditioning: LI, but not overshadowing, was abolished by 10.0 but not 5.0 ug/side amphetamine injected in core but not shell NAc. These results suggest that the abolition of LI produced by NAc shell lesions is not readily reproduced by regionally restricted DA depletion within NAc; core rather than shell NAc mediates amphetamine-induced abolition of LI; overshadowing is modulated by different neural substrates. PMID- 21262857 TI - The effects of acute tryptophan depletion on neuropsychological function, mood and movement in the healthy elderly. AB - Few studies have investigated the function of the serotonin (5-HT) system in the elderly. Previous studies have shown effects of reducing serotonin function, by acute tryptophan depletion (ATD), on neuropsychological function in healthy subjects but this technique has not previously been employed over a wide age range in the elderly. This study compared the effects of ATD on mood, cognitive function and motor function in two groups of healthy volunteers, one group aged 50-69 and the other aged 70-89. The effects of ATD were investigated in a double blind, placebo-controlled, counterbalanced, crossover, randomized design. The effects of ATD were not significantly different between age groups, suggesting that there is relatively little functional change across these age ranges. Compared with studies in much younger age groups there was, however, more evidence of an adverse effect of ATD on psychomotor function and working memory. There was no effect of ATD on mood despite inclusion of subjects with a family history of depression. PMID- 21262856 TI - Dissociation of antidepressant-like activity of escitalopram and nortriptyline on behaviour and hippocampal BDNF expression in female rats. AB - A major hypothesis of depression postulates that a dysregulation of the neurotrophin systems is directly involved in the pathophysiology of depression, and that restoration of such deficits may underlie the therapeutic efficacy of antidepressant treatment. One key finding supporting this hypothesis is upregulation of brain derived neurotrophic factor (BDNF) in the hippocampus after antidepressant treatment. Here, we further test the hypothesis of BDNF involvement in antidepressant action in a genetic rat model of depression after chronic oral treatment with escitalopram, nortriptyline or placebo. Active treatments had significant behavioural antidepressant-like actions in female rats of the Flinders Sensitive Line (FSL) and non-selected Sprague Dawley (SD) rats, while Flinders Resistant Line (FRL) rats were unaffected. Escitalopram, but not nortriptyline, markedly reduced BDNF mRNA levels in the dentate gyrus of FSL rats. The BDNF downregulation was common to the four major promoters of the gene. Treatments did not affect BDNF expression in FRL or SD strains. We conclude that the antidepressant effects of escitalopram and nortriptyline, two common drugs with different pharmacological profiles, appear to be unrelated to the regulation of hippocampal BDNF expression in female rats. These results indicate that the tropic hypothesis of depression has limitations and emphasize the need for validated disease models of depression to assess potential treatment targets. PMID- 21262858 TI - Acute effects of donepezil in healthy young adults underline the fractionation of executive functioning. AB - The cholinergic system is involved in the modulation of both bottom-up and top down attentional control. Top-down attention engages multiple executive control processes, but few studies have investigated whether all or selective elements of executive functions are modulated by the cholinergic system. To investigate the acute effects of the pro-cholinergic donepezil in young, healthy volunteers on distinct components of executive functions we conducted a double-blind, placebo controlled, independent-groups design study including 42 young healthy male participants who were randomly assigned to one of three oral treatments: glucose (placebo), donepezil 5 mg or donepezil 7.5 mg. The test battery included measures of different executive components (shifting, updating, inhibition, dual-task performance, planning, access to long-term memory), tasks that evaluated arousal/vigilance/visuomotor performance, as well as functioning of working memory subsidiary systems. Donepezil improved sustained attention, reaction times, dual-task performance and the executive component of digit span. The positive effects in these executive tasks did not correlate with arousal/visuomotor/vigilance measures. Among the various executive domains investigated donepezil selectively increased dual-task performance in a manner that could not be ascribed to improvement in arousal/vigilance/visuomotor performance nor working memory slave systems. Other executive tasks that rely heavily on visuospatial processing may also be modulated by the cholinergic system. PMID- 21262859 TI - Alcohol Use Disorders Identification Test (AUDIT) scores are elevated in antipsychotic-induced hyperprolactinaemia. AB - Hyperprolactinaemia in antipsychotic treated patients with schizophrenia is a consequence of D2 receptor (DRD2) blockade. Alcohol use disorder is commonly comorbid with schizophrenia and low availability of striatal DRD2 may predispose individuals to alcohol use. In this pilot study we investigated whether hyperprolactinaemia secondary to pharmacological DRD2 blockade was associated with alcohol use disorder in 219 (178 males and 41 females) patients with schizophrenia. Serum prolactin determinations were made in patients diagnosed with schizophrenia and maintained on antipsychotic agents. Clinical assessment included demographics, family history and administration of the AUDIT (Alcohol Use Disorders Identification Test). Higher AUDIT scores were associated with prolactin-raising antipsychotic medication (n=106) compared with prolactin sparing medication (n=113). Risperidone (n=63) treated patients had higher AUDIT scores and prolactin levels than those on other atypical antipsychotics (n = 113). Across the entire sample, patients with a prolactin greater than 800 mIU/L had higher AUDIT scores and were more likely to exceed the cut-off score for harmful and hazardous alcohol use. These differences were not explained by potential confounds related to clinical features and demographics, comorbidity or medication side-effects. These data suggest that by lowering dosage, or switching to another antipsychotic agent, the risk for alcohol use disorder in those with schizophrenia may be reduced. This hypothesis requires testing using a prospective methodology. PMID- 21262860 TI - The A2a adenosine receptor modulates the reinforcement efficacy and neurotoxicity of MDMA. AB - Adenosine is an endogenous purine nucleoside that plays a neuromodulatory role in the central nervous system. A2a adenosine receptors have been involved in reward related processes, inflammatory phenomena and neurotoxicity reactions. In the present study, we investigated the role of A2a adenosine receptors on the acute pharmacological effects, reinforcement and neuroinflammation induced by MDMA administration. First, the acute effects of MDMA on body temperature, locomotor activity and anxiety-like responses were measured in A2a knockout mice and wild type littermates. Second, MDMA reinforcing properties were evaluated using the intravenous self-administration paradigm. Finally, we assessed striatal astrogliosis and microgliosis as markers of MDMA neurotoxicity. Our results showed that acute MDMA produced a biphasic effect on body temperature and increased locomotor activity and anxiogenic-like responses in both genotypes. However, MDMA reinforcing properties were dramatically affected by the lack of A2a adenosine receptors. Thus, wild-type mice maintained MDMA self-administration under a fixed ratio 1 reinforcement schedule, whereas the operant response appeared completely abolished in A2a knockout mice. In addition, the MDMA neurotoxic regime produced an enhanced inflammatory response in striatum of wild type mice, revealed by a significant increase in glial expression, whereas such activation was attenuated in mutant mice. This is the first report indicating that A2a adenosine receptors play a key role in reinforcement and neuroinflammation induced by the widely used psychostimulant. PMID- 21262861 TI - SHOX interacts with the chondrogenic transcription factors SOX5 and SOX6 to activate the aggrecan enhancer. AB - SHOX (short stature homeobox-containing gene) encodes a transcription factor implicated in skeletal development. SHOX haploinsufficiency has been demonstrated in Leri-Weill dyschondrosteosis (LWD), a skeletal dysplasia associated with disproportionate short stature, as well as in a variable proportion of cases with idiopathic short stature (ISS). In order to gain insight into the SHOX signalling pathways, we performed a yeast two-hybrid screen to identify SHOX-interacting proteins. Two transcription factors, SOX5 and SOX6, were identified. Co immunoprecipitation assays confirmed the existence of the SHOX-SOX5 and SHOX-SOX6 interactions in human cells, whereas immunohistochemical studies demonstrated the coexpression of these proteins in 18- and 32-week human fetal growth plates. The SHOX homeodomain and the SOX6 HMG domain were shown to be implicated in the SHOX SOX6 interaction. Moreover, different SHOX missense mutations, identified in LWD and ISS patients, disrupted this interaction. The physiological importance of these interactions was investigated by studying the effect of SHOX on a transcriptional target of the SOX trio, Agc1, which encodes one of the main components of cartilage, aggrecan. Our results show that SHOX cooperates with SOX5/SOX6 and SOX9 in the activation of the upstream Agc1 enhancer and that SHOX mutations affect this activation. In conclusion, we have identified SOX5 and SOX6 as the first two SHOX-interacting proteins and have shown that this interaction regulates aggrecan expression, an essential factor in chondrogenesis and skeletal development. PMID- 21262862 TI - Over-expression of Grhl2 causes spina bifida in the Axial defects mutant mouse. AB - Cranial neural tube defects (NTDs) occur in mice carrying mutant alleles of many different genes, whereas isolated spinal NTDs (spina bifida) occur in fewer models, despite being common human birth defects. Spina bifida occurs at high frequency in the Axial defects (Axd) mouse mutant but the causative gene is not known. In the current study, the Axd mutation was mapped by linkage analysis. Within the critical genomic region, sequencing did not reveal a coding mutation whereas expression analysis demonstrated significant up-regulation of grainyhead like 2 (Grhl2) in Axd mutant embryos. Expression of other candidate genes did not differ between genotypes. In order to test the hypothesis that over-expression of Grhl2 causes Axd NTDs, we performed a genetic cross to reduce Grhl2 function in Axd heterozygotes. Grhl2 loss of function mutant mice were generated and displayed both cranial and spinal NTDs. Compound heterozygotes carrying both loss (Grhl2 null) and putative gain of function (Axd) alleles exhibited normalization of spinal neural tube closure compared with Axd/+ littermates, which exhibit delayed closure. Grhl2 is expressed in the surface ectoderm and hindgut endoderm in the spinal region, overlapping with grainyhead-like 3 (Grhl3). Axd mutants display delayed eyelid closure, as reported in Grhl3 null embryos. Moreover, Axd mutant embryos exhibited increased ventral curvature of the spinal region and reduced proliferation in the hindgut, reminiscent of curly tail embryos, which carry a hypomorphic allele of Grhl3. Overall, our data suggest that defects in Axd mutant embryos result from over-expression of Grhl2. PMID- 21262863 TI - Effects of nortriptyline on QT prolongation: a safety pharmacology study. AB - Nortriptyline, a second-generation tricyclic antidepressant, is an active metabolite of amitriptyline. Amitriptyline induces QT prolongation and torsades de pointes (TdP), which causes sudden death. We studied the cardiovascular safety of nortriptyline, including QT prolongation risk. We examined the effects of nortriptyline on the cardiovascular system in vivo and in vitro in accordance with the ICH-S7B guideline. We tested its effect on QT interval in conscious telemetered dogs. We also performed in vitro electrophysiological studies on hERG tail currents using stably transfected human embryonic kidney 293 (HEK293) cells. Action potential parameters were studied in isolated rabbit purkinje fibers. Nortriptyline dose-dependently blocked hERG current, with a tail IC(50) value of 2.20 +/- 0.09 MUM (n = 4). In the APD assay, total amplitude, Vmax, and resting membrane potential were not significantly changed by 1 MUM nortriptyline, but nortriptyline at 0.3 and 1 MUM shortened APD(50) and APD(90). Nortriptyline did not affect QTcV at 2 or 6 mg/kg, but slightly increased QTcV at 20 mg/kg. In conclusion, it is unlikely that nortriptyline affects the ventricular repolarization process at therapeutic dosages. PMID- 21262864 TI - Increased erythrocyte antioxidant status protects against smoking induced hemolysis in moderate smokers. AB - Cigarette smoking is common in societies worldwide and has been identified as injurious to human health. Human red blood cells are important targets for electrophilic and oxidant foreign compounds. In the present study, the possible role of antioxidant status on smoking-induced erythrocyte hemolysis of smokers was studied. Erythrocyte superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activities, reduced glutathione (GSH) level, erythrocyte membrane lipid peroxidation, total cholesterol and phospholipids were determined. Further, nitrite/nitrate levels (NO(2)/NO(3)) in both plasma and erythrocyte lysate were measured. Results showed increased plasma and erythrocyte membrane lipid peroxidation and nitrite/nitrate levels in smokers. The activities of SOD, CAT and GPx were also increased with reduced glutathione (GSH) level in smokers. No significant change was observed in smokers red cell hemolysis and cholesterol/phospholipid (C/P) ratio compared to controls. Erythrocyte membrane lipid peroxidation was positively correlated with SOD (r = 0.482, p < 0.01) and GPx (r = 0.368, p < 0.018) in smokers. Increased levels of nitrite/nitrate and antioxidant status of erythrocytes might be playing a crucial role in protecting red cell from free radical damage induced by cigarette smoke. PMID- 21262865 TI - Modulation of lead biohazards using a combination of epicatechin and lycopene in rats. AB - The toxicity of many heavy metals is due to their ability to cause oxidative damage to tissues. Lead is one of the most important metals that pollute the natural environment due to man's impact The aim of this study is to investigate the potential protective effect of epicatechin alone or combined with lycopene against toxicity of lead in male rats. Five groups of rats were involved in this study; the first was control while the other four injected with lead acetate (100 mg/kg BW) subcutaneous for 2 weeks. On the other hand, the third, fourth and fifth groups were injected with epicatechin, lycopene or epicatechin + lycopene, respectively. Results obtained showed that, the combined treatment (epicatechin + lycopene) exert its effects (100%) against toxic effects against lead by lowering the liver enzymes alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and gamma glutamyle transferase (GGT) activities and decrease lipid peroixdation (MDA) and enhances the superoxide dismutase (SOD) activity. The high-density lipoprotein cholesterol (HDL-c) level was significantly decreased and low-density lipoprotein cholesterol (LDL-c) level was statistically significantly increased in lead-injected rats as compared with control group. The combined treatment with epicatechin and lycopene justify these levels to nearly normal values. The erythrocyte level of total glutathione was decreased in lead-injected rats as compared with control group (p < 0.001). The combined effect is significantly higher than individual treatment lycopene alone or epicatechin. A negative correlation was found between the blood lead and SOD (r = -0.6) and glutathione (r = -0.81) while a positive correlation with MDA level (r = 0.7). PMID- 21262866 TI - Effect of type 2 diabetes on the dynamic response characteristics of leg vascular conductance during exercise. AB - In this study we tested the hypothesis that type 2 diabetes impairs the dynamic response of leg vascular conductance (LVC) during exercise. LVC (leg blood flow/mean arterial pressure) responses were studied during intermittent contractions of the calf muscle in subjects with type 2 diabetes (n = 9), heavy controls (n = 10) and lean controls (n = 8) using a biexponential function and an estimate of the mean response time (MRT). The time constant of the second phase of LVC was significantly greater in type 2 diabetes (66.4 +/- 29.2 s) than the heavy (22.2 +/- 13.4 s) and lean (21.8 +/- 9.3 s) controls, resulting in a significantly greater MRT in the diabetic group (median [IQR] = 30.7 [24.6-46.5] s versus 16.3 [4.3-23.2] s and 18.4 [13.7-19.3] s). These data support the hypothesis and suggest that a slowed hyperaemic response in the exercising limb might contribute to exercise intolerance in diabetic subjects. PMID- 21262867 TI - Oxidative stress, antioxidant status and lipid profile in the saliva of type 2 diabetics. AB - BACKGROUND: The aim of this study was to assess the salivary content of lipid peroxidation and antioxidants in patients with type 2 diabetes. METHOD: We studied 25 patients with type 2 diabetes and other 25 age- and sex-matched health control. To evaluate the oxidative status we measured the levels of malondialdehyde (MDA) in the saliva and serum of all participants. Lipid profile was also estimated through measuring total cholesterol, triglycerides, low density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and very low-density lipoprotein cholesterol (VLDL-C) levels. Antioxidant levels were also assessed through measuring the salivary and serum concentration of uric acid, superoxide dismutase and reduced glutathione (GSH). RESULTS: The high concentration of lipid fractions in saliva usually follows that recorded in serum. Salivary MDA levels, a product of lipid peroxidation, were significantly increased among diabetics together with uric acid. However, GSH levels were similar to those of the control group. CONCLUSION: Lipid peroxidation and antioxidant parameters assessed in saliva of diabetic patients may be of great importance in evaluating the disease activity and severity. The increase in lipid peroxidation and the tendency of antioxidants to rise in diabetes is probably due to an adaptive response to the pro-oxidant status of diabetes. PMID- 21262868 TI - Validation of the Chinese version of the Walking Impairment Questionnaire in patients with both peripheral arterial disease and type 2 diabetes mellitus. AB - The aim of present study is to translate and validate a Chinese version of the WIQ in patients with PAD and T2DM. A cross-sectional survey was conducted. After translation, a convenience sample of 59 patients with PAD and T2DM completed the Chinese WIQ, the Chinese SF-36 and the 6MWT. The ICC and Cronbach's alpha were calculated to determine the reliability and internal consistency, respectively.Validity was evaluated by correlation coefficients between WIQ, SF 36 and 6MWD. The internal consistency determined by Cronbach's alpha was 0.93. Test-retest reliability expressed by ICC was 0.93. Significant correlations were observed between WIQ, SF-36 and 6MWD (rho (s) =0.27 ~0.88, p < 0.01).The Chinese version of the WIQ has satisfactory reliability and validity and can be used to assess walking ability in type 2 diabetic PAD patients. PMID- 21262869 TI - Correlates of acute insulin resistance in the early phase of non-diabetic ST elevation myocardial infarction. AB - The relationship between insulin secretion and acute insulin resistance (as assessed by Homeostatic Model Assessment [HOMA] index) and clinical and biochemical parameters in the early phase of non-diabetic ST-elevation myocardial infarction (STEMI) is so far unexplored. We aimed at assessing this relation in 286 consecutive STEMI patients without previously known diabetes submitted to primary percutaneous coronary intervention (PCI). Insulin resistance (as indicated by HOMA) was detectable in 67.1%. Non-parametric correlation showed that HOMA index was significantly correlated with BMI (r = 0.242; p < 0.0001) and HbA(1c) (r = 0.189; p < 0.001). At multivariable backward linear regression analysis, glycaemia was directly related to leukocyte count (p = 0.0003), age (p = 0.0001), creatine kinase isoform MB (CK-MB) (p = 0.00278) and lactate (p < 0.0001). Insulin was directly and significantly related to glycaemia (p = 0.0006), body mass index (BMI) (p = 0.00028) and lactate (p = 0.0096) In the early phase of STEMI without previously known diabetes the acute glucose dysmetabolism is quite complex, comprising increased glucose values and the development of acute insulin resistance. While insulin secretion is strictly related to BMI, apart from glucose levels, increased glucose values can be mainly related to the acute inflammatory response (as indicated to leukocyte count and C RP), to age and to the degree of myocardial damage (as inferred by CK-MB). PMID- 21262870 TI - Insulin resistance and cardiovascular disease risk factors in subjects with prehypertension. AB - Prehypertension is considered to be associated with increased cardiovascular disease (CVD), and some data suggest that insulin resistance is common in this group. The goal of this study was to quantify insulin action by determining the steady-state plasma glucose (SSPG) concentration during the insulin suppression test in apparently healthy individuals with prehypertension (n=126) and to elucidate the relationship between insulin action and CVD risk.We found a marked heterogeneity in insulin sensitivity in the prehypertension group, and when we divided the population into insulin-sensitive, insulin-resistant and intermediate groups, there were significant (p<0.01) increases in plasma glucose and triglyceride concentrations and decreases in high-density lipoprotein cholesterol concentrations with progressive degrees of insulin resistance. These data show that at least one-third of patients with prehypertension are insulin resistant, display the accompanying metabolic abnormalities, and merit enhanced surveillance and intensive efforts at therapeutic intervention to prevent CVD. PMID- 21262871 TI - Metformin decreases thyrotropin in overweight women with polycystic ovarian syndrome and hypothyroidism. AB - OBJECTIVE: To assess the effect of metformin administration on thyroid function in overweight women with polycystic ovarian syndrome (PCOS). METHODS: Twenty seven overweight women with PCOS and hypothyroidism were selected. Fifteen patients (group I) were treated with metformin 1500 mg/day for 6 months and 12 patients (group II) with placebo. Serum thyrotropin (TSH), free T3 and free T4 were measured at baseline and 6 months after the beginning of the study. RESULTS: A significant decrease (p<0.001) in TSH levels was observed in group I but not in group II subjects after 6 months of metformin treatment. No significant change in free T3 and free T4 was observed throughout the study in any group. CONCLUSION: In obese PCOS patients with primary hypothyroidism, metformin results in a significant fall and sometimes normalisation of TSH, without causing any reciprocal changes in other thyroid function parameters. PMID- 21262873 TI - Projected cancer mortality among Japanese males under different smoking prevalence scenarios: evidence for tobacco control goal setting. AB - OBJECTIVE: Male smoking prevalence is still high in Japan, and quantitative information for tobacco control is scarce. The aim of the present study was to project cancer mortality among Japanese males under different future scenarios of smoking prevalence. METHODS: The target population comprised Japanese males aged 40-79 years in 2007, whose smoking prevalence was 35%. On the basis of the pooled data from three large-scale cohort studies in Japan, the effects of age, years of smoking and years after smoking cessation on the time to all-cancer or lung cancer death were estimated by an accelerated failure time model. The parameter estimates were used to project the annual number of deaths from all cancers and lung cancer by running simulations for different future scenarios of smoking prevalence. Each scenario was evaluated by the cumulative number of avoided deaths when compared with the status quo and by the percent change (from the baseline year) in age-standardized rate of mortality. RESULTS: Reducing the smoking prevalence from 35% in 2007 to 0% in 2017 was estimated to avoid 333 900 all-cancer deaths and 171 100 lung cancer deaths in 20 years. Even when we shortened the projection period to 10 years, these numbers of avoided deaths would be 81 100 and 38 800, respectively. The age-standardized rate of all-cancer mortality was estimated to decrease by 9.6% in 10 years and 18.1% in 20 years. CONCLUSIONS: Reducing the prevalence of smoking among males would be effective in reducing the cancer burden even within 10 years in countries with a high male smoking prevalence. PMID- 21262874 TI - Relationship between pretreatment FDG uptake and local control after stereotactic body radiotherapy in stage I non-small-cell lung cancer: the preliminary results. AB - OBJECTIVE: Relationship between pretreatment uptake of (18)F-fluoro-2-deoxy-d glucose and local control after stereotactic body radiotherapy in stage I non small-cell lung cancer was examined. METHODS: Between June 2006 and June 2009, 90 clinically diagnosed stage I primary lung cancer in 86 patients were treated with stereotactic body radiotherapy in Shikoku Cancer Center. Among these, 51 tumors in 51 patients were evaluated by positron emission tomography using (18)F-fluoro 2-deoxy-d-glucose before treatment. Twenty-six tumors of histopathologically confirmed non-small-cell lung cancer were reviewed in this study. Tumors were divided into two groups by the threshold maximum standardized uptake value of 5.0 (high-uptake tumors, 9; low-uptake tumors, 17). One tumor with low uptake was pure ground-glass opacity. Typically, 48 Gy in four fractions was given at the isocenter. RESULTS: Follow-up time was 4-44 months (median, 21 months). Local failure-free rates at 15 months of the high-uptake group and the low-uptake group were 40% and 93% for all tumors (P= 0.0001), 0% and 91% for tumors 3 cm or less (P= 0.0004), 50% and 100% for tumors larger than 3 cm, and 40% and 89% for the mainly solid tumors (P= 0.0010). There were no statistically significant differences of local failure-free rates according to age, sex and tumor size (P= 0.4804, P= 0.4170 and P= 0.3638, respectively). CONCLUSIONS: High uptake of (18)F fluoro-2-deoxy-d-glucose in a primary tumor was the significant unfavorable factor for local control after stereotactic body radiotherapy in stage I non small-cell lung cancer. PMID- 21262875 TI - Low-dose-rate definitive brachytherapy for high-grade vaginal intraepithelial neoplasia. AB - BACKGROUND: Treatment of high-grade vaginal intraepithelial neoplasia (VAIN) is controversial and could include surgical excision, topical medication, brachytherapy, or other treatments. We report the results of low-dose-rate (LDR) vaginal brachytherapy for grade 3 VAIN (VAIN-3) over a 25-year period at Gustave Roussy Institute. PATIENTS AND METHODS: We retrospectively reviewed the files of all patients treated at Gustave Roussy Institute for VAIN-3 since 1985. The treatment consisted of LDR brachytherapy using a personalized vaginal mold and delivered 60 Gy to 5 mm below the vaginal mucosa. All patients had at least an annual gynecological examination, including a vaginal smear. RESULTS: Twenty eight patients were eligible. The median follow-up was 41 months. Seven patients had a follow-up <2 years, and the median follow-up for the remaining 21 patients was 79 months. The median age at brachytherapy was 63 years (range, 38-80 years). Twenty-six patients had a history of VAIN recurring after cervical intraepithelial neoplasia and 24 had a previous hysterectomy. The median brachytherapy duration was 4.5 days. Median doses to the International Commission of Radiation Units and Measurements rectum and bladder points were 68 Gy and 45 Gy, respectively. The median prescription volume (60 Gy) was 74 cm(3). Only one "in field" recurrence occurred, corresponding to a 5- and 10-year local control rate of 93% (95% confidence interval, 70%-99%). The treatment was well tolerated, with no grade 3 or 4 late toxicity and only one grade 2 digestive toxicity. No second cancers were reported. CONCLUSION: LDR brachytherapy is an effective and safe treatment for vaginal intraepithelial neoplasia. PMID- 21262876 TI - Functional expression of transgenic 1sDHPR channels in adult mammalian skeletal muscle fibres. AB - We investigated the effects of the overexpression of two enhanced green fluorescent protein (EGFP)-tagged alpha1sDHPR variants on Ca2+ currents (ICa), charge movements (Q) and SR Ca2+ release of muscle fibres isolated from adult mice. Flexor digitorum brevis (FDB)muscles were transfected by in vivo electroporation with plasmids encoding for EGFP-alpha1sDHPR-wt and EGFP alpha1sDHPR-T935Y (an isradipine-insensitive mutant). Two-photon laser scanning microscopy (TPLSM) was used to study the subcellular localization of transgenic proteins, while ICa, Q and Ca2+ release were studied electrophysiologically and optically under voltage-clamp conditions. TPLSM images demonstrated that most of the transgenic alpha1sDHPR was correctly targeted to the transverse tubular system (TTS). Immunoblotting analysis of crude extracts of transfected fibres demonstrated the synthesis of bona fide transgenic EGFP-alpha1sDHPR-wt in quantities comparable to that of native alpha1sDHPR. Though expression of both transgenic variants of the alpha subunit of the dihydropyridine receptor (alpha1sDHPR) resulted in ~50% increase in Q, they surprisingly had no effect on the maximal Ca2+ conductance (gCa) nor the SR Ca2+ release. Nonetheless, fibres expressing EGFP-alpha1sDHPR-T935Y exhibited up to 70% isradipine-insensitive ICa (ICa-ins) with a right-shifted voltage dependence compared to that in control fibres. Interestingly, Qand SRCa2+ release also displayed right-shifted voltage dependence in fibres expressing EGFP-alpha1sDHPR-T935Y. In contrast, the midpoints of the voltage dependence of gCa, Q and Ca2+ release were not different from those in control fibres and in fibres expressing EGFP-alpha1sDHPR-wt. Overall, our results suggest that transgenic alpha1sDHPRs are correctly trafficked and inserted in the TTS membrane, and that a substantial fraction of the mworks as conductive Ca2+ channels capable of physiologically controlling the release of Ca2+ from the SR. A plausible corollary of this work is that the expression of transgenic variants of the alpha1sDHPR leads to the replacement of native channels interacting with the ryanodine receptor 1 (RyR1), thus demonstrating the feasibility of molecular remodelling of the triads in adult skeletal muscle fibres. PMID- 21262877 TI - Hypoxia inducible factor 1 links fast-patterned muscle activity and fast muscle phenotype in rats. AB - Exercise influences muscle phenotype by the specific pattern of action potentials delivered to the muscle, triggering intracellular signalling pathways. PO2 can be reduced by an order of magnitude in working muscle. In humans, carriers of a hyperactive polymorphism of the transcription factor hypoxia inducible factor 1alpha (HIF-1alpha) have 50% more fast fibres, and this polymorphism is prevalent among strength athletes. We have investigated the putative role of HIF-1alpha in mediating activity changes in muscle.When rat muscles were stimulated with short high frequency bursts of action potentials known to induce a fast muscle phenotype, HIF-1alpha increased by about 80%. In contrast, a pattern consisting of long low frequency trains known to make fast muscles slow reduced the HIF 1alpha level of the fast extensor digitorum longus (EDL) muscle by 44%. Nuclear protein extracts from normal EDL contained 2.3-fold more HIF-1alpha and 4-fold more HIF-1beta than the slow soleus muscle, while von-Hippel-Lindau protein was 4.8-fold higher in slow muscles. mRNA displayed a reciprocal pattern; thus FIH-1 mRNA was almost 2-fold higher in fast muscle, while the HIF-1alpha level was half, and consequently protein/mRNA ratio for HIF-1alpha was more than 4-fold higher in the fast muscle, suggesting that HIF-1alpha is strongly suppressed post transcriptionally in slow muscles.When HIF-1alpha was overexpressed for 14 days after somatic gene transfer in adult rats, a slow-to-fast transformation was observed, encompassing an increase in fibre cross sectional area, oxidative enzyme activity and myosin heavy chain. The latter was shown to be regulated at the mRNA level in C2C12 myotubes. PMID- 21262878 TI - Maternal obesity eliminates the neonatal lamb plasma leptin peak. AB - A neonatal peak in rodent plasma leptin plays a central role in regulating development of the hypothalamic appetite control centres. Maternal obesity lengthens and amplifies the peak in altricial rodent species. The precise timing and characteristics of the neonatal leptin peak have not been established in offspring of either normal or obese mothers in any precocial species. We induced obesity by feeding female sheep for 60 days before conception, and throughout pregnancy and parturition with 150% of the diet consumed by control ewes fed to National Research Council recommendations.We have reported that mature offspring of obese sheep fed similarly exhibited increased appetite, weight gain and obesity in response to ad libitum feeding at 19 months of age. We observed a leptin peak in lambs of control ewes between days 6 and 9 of postnatal life, earlier than reported in rodents. This peak was not present in lambs born to obese ewes. The leptin peak in lambs born to control ewes was not clearly related to any changes in plasma cortisol, insulin, triiodothyronine, IGF-1 or glucose. However, there was a significant increase in cortisol at birth in lambs born to obese ewes related to an increase in leptin in the first day of life. We conclude that the increased cortisol seen in lambs of obese sheep plays a role in disrupting the normal peak of leptin in lambs born to obese ewes thereby predisposing them to increased appetite and weight gain in later life. PMID- 21262879 TI - Functional and developmental expression of a zebrafish Kir1.1 (ROMK) potassium channel homologue Kcnj1. AB - The zebrafish, Danio rerio, is emerging as an important model organism for the pathophysiological study of some human kidney diseases, but the sites of expression and physiological roles of a number of protein orthologues in the zebrafish nephron remain mostly undefined. Here we show that a zebrafish potassium channel is orthologous to the mammalian kidney potassium channel, ROMK. The cDNA (kcnj1) encodes a protein (Kcnj1) that when expressed in Xenopus laevis oocytes displayed pH- and Ba2+-sensitive K+-selective currents, but unlike the mammalian channel, was completely insensitive to the peptide inhibitor tertiapin Q. In the pronephros, kcnj1 transcript expression was restricted to a distal region and overlapped with that of sodium-chloride cotransporter Nkcc, chloride channel ClC-Ka, and ClC-Ka/b accessory subunit Barttin, indicating the location of the diluting segment. In a subpopulation of surface cells, kcnj1 was coexpressed with the a1a.4 isoform of the Na+/K+-ATPase, identifying these cells as potential K+ secretory cells in this epithelium. At later stages of development, kcnj1 appeared in cells of the developing gill that also expressed the a1a.4 subunit.Morpholino antisense-mediated knockdown of kcnj1 was accompanied by transient tachycardia followed by bradycardia, effects consistent with alterations in extracellular K+ concentration in the embryo.Our findings indicate that Kcnj1 is expressed in cells associated with osmoregulation and acts as a K+ efflux pathway that is important in maintaining extracellular levels of K+ in the developing embryo. PMID- 21262880 TI - Intima-media thickness and flow-mediated dilatation in the Helsinki study of very low birth weight adults. AB - BACKGROUND: Adults born at a very low birth weight (VLBW) (< 1500 g), compared with those born at term, bear risk factors for cardiovascular disease, including higher blood pressure and insulin resistance. OBJECTIVE: We studied, in young adults born at a VLBW, early signs of an accelerated atherosclerotic process and the relationship of these signs with postnatal growth. METHODS: We compared 92 with a VLBW with 68 who were born at term. At age 18 to 27, we measured stiffness and intima-media thickness (IMT) of the right carotid artery and flow-mediated dilatation (FMD) of the right brachial artery. RESULTS: Those with a VLBW had 1.1% units higher FMD (95% confidence interval [CI]: 0.0-2.2) (P = .06) and 0.5% units higher IMT relative to lumen size (95% CI: 0.1-0.9). IMT or FMD, when analyzed as the absolute change in millimeters, and carotid stiffness in the groups were similar. Among those with a VLBW, each 100-g-greater weight gain during the first 2 postnatal weeks predicted 1.1% units higher FMD (95% CI: 0.2 2.0) in adulthood. CONCLUSIONS: Although young adults born at VLBWs, compared with those born at term, have higher levels of risk factors for cardiovascular disease, we found no clear evidence for elevated early markers of atherosclerosis. However, in relation to artery lumen diameter, IMT in the participants who had a VLBW was higher than in those who were born at term. In our study, weight gain during the first postnatal weeks had no harmful effect on the arteries in young adulthood. PMID- 21262881 TI - Prospective assessment of practice pattern variations in the treatment of pediatric gastroenteritis. AB - OBJECTIVES: We aimed to determine whether significant variations in the use of intravenous rehydration existed among institutions, controlling for clinical variables, and to assess variations in the use of ancillary therapeutic and diagnostic modalities. METHODS: We conducted a prospective cohort study of children 3 to 48 months of age who presented to 11 emergency departments with acute gastroenteritis, using surveys, medical record reviews, and telephone follow-up evaluations. RESULTS: A total of 647 eligible children were enrolled and underwent chart review; 69% (446 of 647 children) participated in the survey, and 89% of survey participants (398 of 446 children) had complete follow-up data. Twenty-three percent (149 of 647 children) received intravenous rehydration (range: 6%-66%; P < .001) and 13% (81 of 647 children) received ondansetron (range: 0%-38%; P < .001). Children who received intravenous rehydration had lower Canadian Triage Acuity Scale scores at presentation (3.1 +/- 0.5 vs 3.5 +/- 0.5; P < .0001). Regression analysis revealed that the greatest predictor of intravenous rehydration was institution location (odds ratio: 3.0 [95% confidence interval: 1.8-5.0]). Children who received intravenous rehydration at the index visit were more likely to have an unscheduled follow-up health care provider visit (29% vs 19%; P = .05) and to revisit an emergency department (20% vs 9%; P = .002). CONCLUSIONS: In this cohort, intravenous rehydration and ondansetron use varied dramatically. Use of intravenous rehydration at the index visit was significantly associated with the institution providing care and was not associated with a reduction in the need for follow-up care. PMID- 21262882 TI - Does fellowship pay: what is the long-term financial impact of subspecialty training in pediatrics? AB - OBJECTIVES: To (1) analyze the financial returns of fellowship training in pediatrics and to compare them with those generated from a career in general pediatrics and (2) evaluate the effects of including the newly enacted federal loan-repayment program and of changing the length of fellowship training. BACKGROUND: Although the choice to enter fellowship is based on many factors, economic considerations are important. We are not aware of any study that has focused on the financial impact of fellowship training in pediatrics. METHODS: Using standard financial techniques, we estimated the financial returns that a graduating pediatric resident might anticipate from additional fellowship training followed by a career as a pediatric subspecialist and compared them with the returns that might be expected from starting a career as a general pediatrician immediately after residency. RESULTS: The financial returns of pediatric fellowship training varied greatly depending on which subspecialty fellowship was chosen. Pursuing a fellowship in most pediatric subspecialties was a negative financial decision when compared with pursuing no fellowship at all and practicing as a general pediatrician. Incorporating the federal loan repayment program targeted toward pediatric subspecialists and decreasing the length of fellowship training from 3 to 2 years would substantially increase the financial returns of the pediatric subspecialties. CONCLUSIONS: Pediatric subspecialization yielded variable financial returns. The results from this study can be helpful to current pediatric residents as they contemplate their career options. In addition, our study may be valuable to policy makers evaluating health care reform and pediatric workforce-allocation issues. PMID- 21262883 TI - Noninvasive ventilation for respiratory distress syndrome: a randomized controlled trial. AB - CONTEXT: Strategies for reducing exposure to endotracheal ventilation through the use of early noninvasive ventilation has proven to be safe and effective, but the option with the greatest benefits needs to be determined. OBJECTIVE: To determine, in infants with respiratory distress syndrome, if early nasal intermittent positive-pressure ventilation (NIPPV) compared with nasal continuous positive airway pressure (NCPAP) decreases the need for mechanical ventilation. PATIENTS AND METHODS: In this single-center, randomized controlled trial, infants (gestational ages 26 to 33/7 weeks) with respiratory distress syndrome were randomly assigned to receive early NIPPV or NCPAP. Surfactant was administered as rescue therapy. The primary outcome was the need for mechanical ventilation within the first 72 hours of life. RESULTS: A total of 200 infants, 100 in each arm, were randomly assigned. Rates of the primary outcome did not differ significantly between the NIPPV (25%) and NCPAP (34%) groups (relative risk [RR]: 0.71 [95% confidence interval (CI): 0.48-1.14]). In posthoc analysis, from 24 to 72 hours of life, significantly more infants in the NIPPV group remained extubated compared with those in the NCPAP groups (10 vs 22%; RR: 0.45 [95% CI: 0.22-0.91]). This difference was also noted in the group of infants who received surfactant therapy, NIPPV (10.9%), and NCPAP (27.1%) (RR: 0.40 [95% CI: 0.18 0.86]). CONCLUSIONS: Early NIPPV did not decrease the need for mechanical ventilation compared with NCPAP, overall, in the first 72 hours of life. However, further studies to assess the potential benefits of noninvasive ventilation are warranted, especially for the most vulnerable or preterm infants. PMID- 21262886 TI - Hearing screening in a well-infant nursery: profile of automated ABR-fail/OAE pass. AB - OBJECTIVES: The goals were to examine the prevalence of a screening outcome pattern of auditory brainstem response fail/otoacoustic emission pass (ABR-F/OAE P) in a cohort of infants in well-infant nurseries (WINs), to profile children at risk for auditory neuropathy spectrum disorder, and to compare inpatient costs for 2 screening protocols using automated auditory brainstem response (ABR) and otoacoustic emission (OAE) screening. METHODS: A total of 10.6% (n = 2167) of 20 529 infants admitted to WINs in 2006-2009 were screened for auditory neuropathy spectrum disorder risk by using an experimental protocol (automated ABR testing first, followed by OAE testing if the automated ABR test was not passed). A second WIN cohort (n = 281) was screened by using the standard WIN protocol for the facility (OAE testing first, followed by automated ABR testing if the OAE test was not passed). Comparisons were made regarding preparation and testing times and personnel costs. RESULTS: The ABR-F/OAE-P outcome was found for 0.92% of infants in WINs in inpatient testing and none in outpatient rescreening. The time for test preparation was 4 times longer and that for test administration was 2.6 times longer for the experimental protocol, compared with the standard protocol. Inpatient costs for the experimental protocol included 3 times greater personnel time costs. CONCLUSIONS: Less than 1% of infants in WINs had ABR-F/OAE P screening outcomes as inpatients and none as outpatients. These results suggest that prevalence is low for infants cared for in WINs and use of OAE testing as a screening tool in WINs is not unreasonable. PMID- 21262884 TI - Effects of recombinant human prolactin on breast milk composition. AB - OBJECTIVE: The objective of this study was to determine the impact of recombinant human prolactin (r-hPRL) on the nutritional and immunologic composition of breast milk. METHODS: We conducted 2 trials of r-hPRL treatment. In the first study, mothers with documented prolactin deficiency were given r-hPRL every 12 hours in a 28-day, open-label trial. In the second study, mothers with lactation insufficiency that developed while they were pumping breast milk for their preterm infants were given r-hPRL daily in a 7-day, double-blind, placebo controlled trial. Breast milk characteristics were compared before and during 7 days of treatment. RESULTS: Among subjects treated with r-hPRL (N = 11), milk volumes (73 +/- 36 to 146 +/- 54 mL/day; P < .001) and milk lactose levels (155 +/- 15 to 184 +/- 8 mmol/L; P = .01) increased, whereas milk sodium levels decreased (12.1 +/- 2.0 to 8.3 +/- 0.5 mmol/L; P = .02). Milk calcium levels increased in subjects treated with r-hPRL twice daily (2.8 +/- 0.6 to 5.0 +/- 0.9 mmol/L; P = .03). Total neutral (1.5 +/- 0.3 to 2.5 +/- 0.4 g/L; P = .04) and acidic (33 +/- 4 to 60 +/- 6 mg/L; P = .02) oligosaccharide levels increased in r hPRL-treated subjects, whereas total daily milk immunoglobulin A secretion was unchanged. CONCLUSIONS: r-hPRL treatment increased milk volume and induced changes in milk composition similar to those that occur during normal lactogenesis. r-hPRL also increased antimicrobially active oligosaccharide concentrations. These effects were achieved for women with both prolactin deficiency and lactation insufficiency. PMID- 21262885 TI - Occurrence of aortic aneurysms in 5 cases of Wiskott-Aldrich syndrome. AB - Aortic aneurysms are a rare condition in children. Here we report the occurrence of aortic aneurysms in 5 children with Wiskott-Aldrich syndrome (WAS). Three patients had a WAS score of 4, and 2 patients had a WAS score of 5, but autoimmunity was only present in 1 patient. Discovery was fortuitous in 4 cases after chest radiography or thoracic or abdominal computed tomography, which was performed to investigate unrelated symptoms; in 1 patient, thoracic pain was an alerting sign. Age at diagnosis was 10 to 16 years. Aneurysms were confined to the thoracic aorta in 4 cases and to the abdominal aorta in 1 case and were from 2 to 6 cm in size. Aortic surgery was successfully performed on the single symptomatic patient. Two other patients are alive: there has been a low progression of the aneurysm 15 years after hematopoietic stem cell transplantation in 1 patient and no evidence of progression after 12 years of follow-up without hematopoietic stem cell transplantation in the second patient. Two patients died 2 and 4 years after diagnosis from unrelated complications. A systematic retrospective search of 33 other patients with WAS for whom imaging material was available did not reveal the presence of aortic aneurysms. This unusual frequency of aortic aneurysm found in patients with WAS (5 of 38) indicates that aneurysm can be an underdiagnosed complication of WAS. It is presently unclear whether it is caused by an infectious and/or autoimmune/inflammatory process. Therefore, we suggest that aneurysms of large vessels should be systematically searched for in patients with WAS. PMID- 21262887 TI - Impact of rotavirus vaccination on hospital-acquired rotavirus gastroenteritis in children. AB - OBJECTIVE: Data show that after the implementation of routine rotavirus vaccination for infants in the United States, community-acquired (CA) rotavirus cases declined substantially in the 2007-2008 season. The impact of community based rotavirus vaccination on the substantial burden of hospital-acquired (HA) rotavirus has not been documented. PATIENTS AND METHODS: We assessed CA and HA rotavirus, respiratory syncytial virus, and influenza infections at Children's Memorial Hospital for 5 winter seasons (defined as occurring from September through May) from 2003 to 2008. We also report rotavirus data from the 2008-2009 season. RESULTS: A similar dramatic decline (>60% compared with the median of previous seasons) occurred in the rates of cases of both CA (P < .0001) rotavirus hospitalizations and HA (P < .01) rotavirus infections in the 2007-2008 season compared with previous seasons, whereas the rates of CA and HA influenza and respiratory syncytial virus, respectively, remained stable. Improvements in hand hygiene compliance did not correlate with a reduction in the transmission rate of rotavirus in the hospital. Both CA and HA rotavirus rates remained much lower in the 2008-2009 than in the 2003-2007 seasons. CONCLUSIONS: Community-based rotavirus vaccination is associated with a substantial reduction in the number of children who are admitted with rotavirus. These data also indicate that routine community-based rotavirus infant vaccination protects hospitalized children from acquiring rotavirus. Vaccination efforts should be encouraged as a strategy to affect the substantial burden of HA rotavirus. PMID- 21262888 TI - Sleep duration, sleep regularity, body weight, and metabolic homeostasis in school-aged children. AB - OBJECTIVE: The goal was to explore the effects of duration and regularity of sleep schedules on BMI and the impact on metabolic regulation in children. METHODS: Sleep patterns of 308 community-recruited children 4 to 10 years of age were assessed with wrist actigraphs for 1 week in a cross-sectional study, along with BMI assessment. Fasting morning plasma levels of glucose, insulin, lipids, and high-sensitivity C-reactive protein also were measured for a subsample. RESULTS: Children slept 8 hours per night, on average, regardless of their weight categorization. A nonlinear trend between sleep and weight emerged. For obese children, sleep duration was shorter and showed more variability on weekends, compared with school days. For overweight children, a mixed sleep pattern emerged. The presence of high variance in sleep duration or short sleep duration was more likely associated with altered insulin, low-density lipoprotein, and high-sensitivity C-reactive protein plasma levels. Children whose sleep patterns were at the lower end of sleep duration, particularly in the presence of irregular sleep schedules, exhibited the greatest health risk. CONCLUSIONS: Obese children were less likely to experience "catch-up" sleep on weekends, and the combination of shorter sleep duration and more-variable sleep patterns was associated with adverse metabolic outcomes. Educational campaigns, aimed at families, regarding longer and more-regular sleep may promote decreases in obesity rates and may improve metabolic dysfunction trends in school-aged children. PMID- 21262889 TI - Chlamydia screening among young women: individual- and provider-level differences in testing. AB - OBJECTIVE: We assessed differences in chlamydia screening rates according to race/ethnicity, insurance status, age, and previous sexually transmitted infection (STI) or pregnancy. METHODS: A retrospective cohort study was performed using electronic medical record and billing data for women 14 to 25 years of age in 2002-2007, assessing differences in the odds of a chlamydia test being performed at that visit. RESULTS: Adjusted odds of a chlamydia test being performed were lower among women 14 to 15 years of age (odds ratio: 0.83 [95% confidence interval: 0.70-1.00]) and 20 to 25 years of age (20-21 years, odds ratio: 0.78 [95% confidence interval: 0.70-0.89]; 22-23 years, odds ratio: 0.76 [95% confidence interval: 0.67-0.87]; 24-25 years, odds ratio: 0.64 [95% confidence interval: 0.57-0.73]), compared with women 18 to 19 years of age. Black women had 3 times increased odds (odds ratio: 2.96 [95% confidence interval: 2.66-3.28]) and Hispanic women nearly 13 times increased odds (odds ratio: 12.89 [95% confidence interval: 10.85-15.30]) of testing, compared with white women. Women with public (odds ratio: 1.74 [95% confidence interval: 1.58 1.91]) and public pending (odds ratio: 6.85 [95% confidence interval: 5.13-9.15]) insurance had increased odds of testing, compared with women with private insurance. After first STI diagnosis, differences according to race/ethnicity persisted but were smaller; after first pregnancy, differences persisted. CONCLUSIONS: Despite recommendations to screen all sexually active young women for chlamydia, providers screened women differently according to age, race/ethnicity, and insurance status, although differences were reduced after first STI or pregnancy. PMID- 21262890 TI - A parent-led family-focused treatment program for overweight children aged 5 to 9 years: the PEACH RCT. AB - OBJECTIVE: To evaluate a healthy lifestyle intervention to reduce adiposity in children aged 5 to 9 years and assess whether adding parenting skills training would enhance this effect. PARTICIPANTS AND METHODS: We conducted a single blinded randomized controlled trial of prepubertal moderately obese (International Obesity Task Force cut points) children, aged 5 to 9 years. The 6 month program targeted parents as the agents of change for implementing family lifestyle changes. Only parents attended group sessions. We measured BMI and waist z scores and parenting constructs at baseline, 6, 12, 18, 24 months. RESULTS: Participants (n = 169; 56% girls) were randomized to a parenting skills plus healthy lifestyle group (n = 85) or a healthy lifestyle-only group (n = 84). At final 24-month assessment 52 and 54 children remained in the parenting skills plus healthy lifestyle and the healthy lifestyle-only groups respectively. There were reductions (P < .001) in BMI z score (0.26 [95% confidence interval: 0.22 0.30]) and waist z score (0.33 [95% confidence interval: 0.26-0.40]). There was a 10% reduction in z scores from baseline to 6 months that was maintained to 24 months with no additional intervention. Overall, there was no significant group effect. A similar pattern of initial improvement followed by stability was observed for parenting outcomes and no group effect. CONCLUSIONS: Using approaches that specifically target parent behavior, relative weight loss of ~10% is achievable in moderately obese prepubertal children and can be maintained for 2 years from baseline. These results justify an investment in treatment as an effective secondary obesity-prevention strategy. PMID- 21262892 TI - Current referral patterns and means to improve accuracy in diagnosis of undescended testis. AB - OBJECTIVES: The goals were to determine current referral patterns for boys suspected of having undescended testis (UDT) and to identify factors to assist primary care providers in distinguishing retractile testes from UDTs on the basis of history, physical examination, or imaging findings. METHODS: By using a standardized history assessment, visual inspection of the scrotum for symmetry, physical examination, and review of previously obtained imaging findings, we performed a prospective observational study with consecutive patients referred to a pediatric urologist for evaluation of UDT. RESULTS: Of 118 boys, 51 (43%) had descended testes, 60 (51%) had UDTs, and 7 (6%) had initially indeterminate findings. Boys with UDT were referred at a median age of 43.3 months. Patients referred at <1 year or >10 years of age were significantly more likely to have UDT than were those referred at 1 to 10 years of age. History of UDT at birth, prematurity, and scrotal asymmetry strongly increased the risk of UDT. Genital ultrasonography had been performed for 25% of patients, incorrectly indicating UDT for 48%. CONCLUSIONS: Most boys were referred well beyond the recommended age of <12 months for orchiopexy. Only one-half of the patients had UDT, with most errors in diagnosis being made for boys 1 to 10 years of age, which suggests difficulty distinguishing UDT from retractile testis. Positive birth history findings, prematurity, and scrotal asymmetry predicted UDT and can be used by primary care physicians in their assessment before referral. Genital ultrasonography did not distinguish UDTs from retractile testes. PMID- 21262893 TI - Early experiences and predictors of recruitment success for the National Children's Study. AB - OBJECTIVES: We aimed to describe 17 months of experience with household recruitment of live births for the National Children's Study in Queens, a highly urban, diverse borough of New York City (NYC), and to assess predictors of recruitment success. METHODS: Recruitment data (enumeration, pregnancy screening of age-eligible women, identification of pregnancies, and consent) for the period of January 2009 through May 2010 were calculated. Geographic information systems were used to create 11 community-level variables for each of the 18 study segments where recruitment occurred, using US Census, NYC Office of Vital Statistics, NYC Department of City Planning, and NYC Police Department data. Recruitment yields were analyzed with respect to these variables at the segment level. RESULTS: Enumeration identified 4889 eligible women, of whom 4333 (88.6%) completed the pregnancy screener. At least 115 births were lost because of an inability of the pregnancy screener to identify pregnant women, whereas another 115 could be expected to be lost because of missed enumerations and pregnancy screeners. The consent rate was 60.3%. Segments with higher percentages of low birth weight had higher enumeration, pregnancy screening, and consent rates. CONCLUSIONS: In a highly immigrant, urban setting, households could be approached for recruitment of women to participate in the National Children's Study with consent rates equal to those experienced in clinical settings. Refinement of the pregnancy screener and other recruitment materials presents an opportunity to optimize recruitment, improve the representativeness of study participants, and improve the cost-effectiveness of study execution. PMID- 21262891 TI - Post-HAART outcomes in pediatric populations: comparison of resource-limited and developed countries. AB - CONTEXT: No formal comparison has been made between the pediatric post-highly active antiretroviral therapy (HAART) outcomes of resource-limited and developed countries. OBJECTIVE: To systematically quantify and compare major baseline characteristics and clinical end points after HAART between resource-limited and developed settings. METHODS: Published articles and abstracts (International AIDS Society 2009, Conference on Retroviruses and Opportunistic Infections 2010) were examined from inception (first available publication for each search engine) to March 2010. Publications that contained data on post-HAART mortality, weight-for age z score (WAZ), CD4 count, or viral load (VL) changes in pediatric populations were reviewed. Selected studies met the following criteria: (1) patients were younger than 21 years; (2) HAART was given (>= 3 antiretroviral medications); and (3) there were >20 patients. Data were extracted for baseline age, CD4 count, VL, WAZ, and mortality, CD4 and virologic suppression over time. Studies were categorized as having been performed in a resource-limited country (RLC) or developed country (DC) on the basis of the United Nations designation. Mean percentage of deaths per cohort and deaths per 100 child-years, baseline CD4 count, VL, WAZ, and age were calculated for RLCs and DCs and compared by using independent samples t tests. RESULTS: Forty RLC and 28 DC publications were selected (N = 17 875 RLCs; N = 1835 DC). Mean percentage of deaths per cohort and mean deaths per 100 child-years after HAART were significantly higher in RLCs than DCs (7.6 vs 1.6, P < .001, and 8.0 vs 0.9, P < .001, respectively). Mean baseline CD4% was 12% in RLCs and 23% in DCs (P = .01). Mean baseline VLs were 5.5 vs 4.7 log(10) copies per mL in RLCs versus DCs (P < .001). CONCLUSIONS: Baseline CD4% and VL differ markedly between DCs and RLCs, as does mortality after pediatric HAART. Earlier diagnosis and treatment of pediatric HIV in RLCs would be expected to result in better HAART outcomes. PMID- 21262894 TI - Going local: devolving national pay for performance programmes. PMID- 21262896 TI - Palliative care in people with chronic obstructive pulmonary disease. PMID- 21262900 TI - Guidance on assisted suicide is confusing and risky, Warnock tells commission. PMID- 21262897 TI - Living and dying with severe chronic obstructive pulmonary disease: multi perspective longitudinal qualitative study. AB - OBJECTIVES: To understand the perspectives of people with severe chronic obstructive pulmonary disease (COPD) as their illness progresses, and of their informal and professional carers, to inform provision of care for people living and dying with COPD. DESIGN: Up to four serial qualitative interviews were conducted with each patient and nominated carer over 18 months. Interviews were transcribed and analysed both thematically and as narratives. PARTICIPANTS: 21 patients, and 13 informal carers (a family member, friend, or neighbour) and 18 professional carers (a key health or social care professional) nominated by the patients. SETTING: Primary and secondary care in Lothian, Tayside, and Forth Valley, Scotland, during 2007-9. RESULTS: Eleven patients died during the study period. Our final dataset comprised 92 interviews (23 conducted with patient and informal carer together). Severe symptoms that caused major disruption to normal life were described, often in terms implying acceptance of the situation as a "way of life" rather than an "illness." Patients and their informal carers adapted to and accepted the debilitating symptoms of a lifelong condition. Professional carers' familiarity with the patients' condition, typically over many years, and prognostic uncertainty contributed to the difficulty of recognising and actively managing end stage disease. Overall, patients told a "chaos narrative" of their illness that was indistinguishable from their life story, with no clear beginning and an unanticipated end described in terms comparable with attitudes to death in a normal elderly population. CONCLUSIONS: Our findings challenge current assumptions underpinning provision of end of life care for people with COPD. The policy focus on identifying a time point for transition to palliative care has little resonance for people with COPD or their clinicians and is counter productive if it distracts from early phased introduction of supportive care. Careful assessment of possible supportive and palliative care needs should be triggered at key disease milestones along a lifetime journey with COPD, in particular after hospital admission for an exacerbation. PMID- 21262902 TI - Cochrane review questions evidence for statins for primary prevention in low risk groups. PMID- 21262905 TI - European parliament agrees rules on cross border healthcare. PMID- 21262907 TI - Are ACEI/ARBs associated with the decreased peritoneal protein clearance in long term PD patients? AB - Objective. Peritoneal protein clearance (PrC) is recognized as a new marker of systemic endothelial dysfunction and predictor of mortality in patients on peritoneal dialysis (PD). Given that angiotensin-converting enzyme inhibitors (ACEI)/angiotensin II receptor blockers (ARBs) could improve endothelial dysfunction in the general population, we aim to explore whether this benefit is present in the PD population. METHODS: We analysed data from a PD cohort with data prospectively collected. The PrC, defined daily doses (DDDs) of ACEI/ARBs, as well as other clinical variables were recorded at baseline and then repeatedly measured at 3- to 6-month intervals till to death or censoring. A total of 156 patients were treated with ACEI/ARBs with 0.60 of median time-averaged DDDs, the untreated group consisted of 149 patients who received none of the above drugs during the follow-up. RESULTS: The baseline and time-averaged PrC were 69.9 +/- 34.7 mL/day and 75.2 +/- 28.3 mL/day, respectively. Time-averaged PrC was an independent predictor of mortality adjusted for recognized confounders in a multivariate Cox regression model (P = 0.037). There were no significant differences in the time course of PrC (P = 0.82) and peritoneal protein loss (P = 0.83) between the ACEI/ARBs group and the untreated group after adjustment for age, gender, diabetes, baseline C-reactive protein, mean blood pressure and baseline PrC or baseline peritoneal protein loss in the generalized linear mixed model. CONCLUSIONS: We conclude that ACEI/ARBs did not correlate with a decreased PrC in this observational study. The effect of higher doses of ACEI/ARBs needs to be determined in future interventional studys. PMID- 21262908 TI - Heterotrimeric G-protein regulation of ROS signalling and calcium currents in Arabidopsis guard cells. AB - Heterotrimeric G proteins composed of Galpha, Gbeta, and Ggamma subunits are important signalling agents in both animals and plants. In plants, G proteins modulate numerous responses, including abscisic acid (ABA) and pathogen associated molecular pattern (PAMP) regulation of guard cell ion channels and stomatal apertures. Previous analyses of mutants deficient in the sole canonical Arabidopsis Galpha subunit, GPA1, have shown that Galpha-deficient guard cells are impaired in ABA inhibition of K(+) influx channels, and in pH-independent activation of anion efflux channels. ABA-induced Ca(2+) uptake through ROS activated Ca(2+)-permeable channels in the plasma membrane is another key component of ABA signal transduction in guard cells, but the question of whether these channels are also dependent on Galpha for their ABA response has not been evaluated previously. We used two independent Arabidopsis T-DNA null mutant lines, gpa1-3 and gpa1-4, to investigate this issue. We observed that gpa1 mutants are disrupted both in ABA-induced Ca(2+)-channel activation, and in production of reactive oxygen species (ROS) in response to ABA. However, in response to exogenous H(2)O(2) application, I(Ca) channels are activated normally in gpa1 guard cells. In addition, H(2)O(2) inhibition of stomatal opening and promotion of stomatal closure are not disrupted in gpa1 mutant guard cells. These data indicate that absence of GPA1 interrupts ABA signalling between ABA reception and ROS production, with a consequent impairment in Ca(2+)-channel activation. PMID- 21262909 TI - Human essential myosin light chain isoforms revealed distinct myosin binding, sarcomeric sorting, and inotropic activity. AB - AIMS: In this paper, we tested the hypothesis that different binding affinities of the C-terminus of human cardiac alkali (essential) myosin light chain (A1) isoforms to the IQ1 motif of the myosin lever arm provide a molecular basis for distinct sarcomeric sorting and inotropic activity. METHODS AND RESULTS: We employed circular dichroism and surface plasmon resonance spectroscopy to investigate structural properties, secondary structures, and protein-protein interactions of a recombinant head-rod fragments of rat cardiac beta-myosin heavy chain aa664-915 with alanine-mutated IQ2 domain (rbeta-MYH(664-915)IQ(ala4)) and A1 isoforms [human atrial (hALC1) and human ventricular (hVLC-1) light chains]. Double epitope-tagging competition was used to monitor the intracellular localization of exogenously introduced hALC-1 and hVLC-1 constructs in neonatal rat cardiomyocytes. Contractile functions of A1 isoforms were investigated by monitoring shortening and intracellular-free Ca(2+) (Fura-2) of adult rat cardiomyocytes infected with adenoviral (Ad) vectors using hALC-1 or beta galactosidase as expression cassettes. hALC-1 bound more strongly (greater than three-fold lower K(D)) to rbeta-MYH(664-915) than did hVLC-1. Sorting specificity of A1 isoforms to sarcomeres of cardiomyocytes rose in the order hVLC-1 to hALC 1. Replacement of endogenous VLC-1 by hALC-1 in adult rat cardiomyocytes increased contractility while the systolic Ca(2+) signal remained unchanged. CONCLUSION: Intense myosin binding of hALC-1 provides a mechanism for preferential sarcomeric sorting and Ca(2+)-independent positive inotropic activity. PMID- 21262911 TI - The effect of distance to health-care facilities on childhood mortality in rural Burkina Faso. AB - This study aims to investigate the relation between distance to health facilities, measured as continuous travel time, and mortality among infants and children younger than 5 years of age in rural Burkina Faso, an area with low health facility density. The study included 24,555 children born between 1993 and 2005 in the Nouna Health and Demographic Surveillance System. The average walking time from each village to the closest health facility was obtained for both the dry and the rainy season, and its effect on infant (<1 year), child (1-4 years), and under-5 mortality overall was analyzed by Cox regression. The authors observed 3,426 childhood deaths, corresponding to a 5-year survival of 85%. Walking distance was significantly related to both infant and child mortality, although the shape of this effect varied distinctly between the 2 age groups. Overall, under-5 mortality, adjusted for confounding, was more than 50% higher at a distance of 4 hours compared with having a health facility in the village (P < 0.0001, 2 sided). The region of residence was an additional determinant for under 5 mortality. The findings of this study emphasize the importance of geographic accessibility of health care for child survival in sub-Saharan Africa and demonstrate the need to improve health-care access to achieve the Millennium Development Goals. PMID- 21262910 TI - Validation of a small set of ancestral informative markers for control of population admixture in African Americans. AB - Confounding due to population stratification is a potential source of concern in population-based genetic association studies, particularly in recently admixed populations such as African Americans. Several methods have been developed to control for population stratification in the context of genome-wide association studies. Because these approaches require thousands of genotypes from genetic markers, they are not well suited to be used in genetic association analyses without genome-wide data. An alternative approach to control for population stratification is to estimate admixture proportions by using ancestral informative markers (AIMs). The authors evaluated whether a relatively small number of AIMs would be sufficient to estimate ancestral proportions in African Americans. They first estimated European admixture proportions in 1,757 subjects from the Black Women's Health Study (1995-2009) by genotyping an admixture panel of 1,373 AIMs; they then compared these results with those obtained using smaller sets of AIMs. The authors found that just 30 AIMs are needed to obtain very high correlation of estimates with the entire set (r = 0.89; P < 0.0001). A set of 200 AIMs gave an almost perfect correlation with the entire set (r = 0.98; P < 0.0001). These results show that a small number of AIMs are sufficiently precise to estimate European admixture in African Americans. PMID- 21262912 TI - Lipid accumulation product: a powerful marker of metabolic syndrome in healthy population. AB - OBJECTIVE: The metabolic syndrome (MS) is a cluster of cardiometabolic factors, which predisposes to diabetes and cardiovascular disease (CVD). Early detection of high-risk individuals for MS using accurate measures of insulin resistance (IR) could improve detection and prevention of CVD and diabetes. The aim of this study was to explore the ability of lipid accumulation product (LAP), compared with traditional measures of IR, to identify MS. DESIGN: In total, 768 Spanish adults were recruited. MS was assessed using the revised criteria of National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) and International Diabetes Federation (IDF). Measures of IR such as homeostasis model assessment of IR and LAP, an index of lipid accumulation based on a combination of waist circumference and serum triglycerides, were calculated. Receiver operating characteristic analysis was performed in order to detect the parameter with the best predictive capability for MS. RESULTS: The prevalence of MS NCEP/ATP III and MS-IDF was 15.1 and 20.5% for men respectively, and 15.4 and 17.5% for women. LAP showed the highest diagnostic accuracy for MS-NCEP/ATP III (area under the curve 0.91 and 0.90 among males and females) and MS-IDF (0.88 for both males and females). This was confirmed by internal validation using 20 000 bootstrap samples. Among males and females, different LAP cut-off values exhibited high sensitivity (78-85%) and specificity (78-85%) for MS-NCEP/ATP III and MS-IDF identification with elevated efficiency (proportion of positives and negatives classified correctly by the test=78-85%). When the sample was stratified according to decades of life, LAP exhibited a slightly lower performance among women than men, especially for MS-IDF detection. CONCLUSIONS: In non-diabetic adults LAP has a strong and reliable diagnostic accuracy for MS IDF and, especially, MS-NCEP/ATP III among females and, in particular, among males from Spain. PMID- 21262913 TI - Absence of an integrated Stiles-Crawford function for coherent light. AB - The Stiles-Crawford effect that relates visibility to pupil point is typically expressed by a Gaussian function at any given wavelength of illumination. The pupil location of the maximum and the width of this function refer, respectively, to the pointing and waveguide properties of individual cone photoreceptors. In vision simulations, the function is integrated across the pupil when estimating effective retinal images, but the validity of this approach has still not been unequivocally confirmed. Indeed, aberrations and coherence properties may significantly alter not only the amplitude but also the phase distribution of the light at the retina in a way that differs fundamentally from that of the Maxwellian illumination configuration used when characterizing the effect. Here, we report on an experimental comparison of the traditionally determined Stiles Crawford function and the equivalent for annular and half-annular apertures using extended highly coherent and incoherent sources. We show that an integrated Stiles-Crawford function is absent for coherent light but remains valid for highly incoherent light at the pupil. The results are supported by numerical evidence for coherent light propagation and are in agreement with a light coupling understanding of retina photoreceptor waveguides. PMID- 21262914 TI - MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase. AB - MYC is a potential target for many cancers but is not amenable to existing pharmacologic approaches. Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) by statins has shown potential efficacy against a number of cancers. Here, we show that inhibition of HMG-CoA reductase by atorvastatin (AT) blocks both MYC phosphorylation and activation, suppressing tumor initiation and growth in vivo in a transgenic model of MYC-induced hepatocellular carcinoma (HCC) as well as in human HCC-derived cell lines. To confirm specificity, we show that the antitumor effects of AT are blocked by cotreatment with the HMG-CoA reductase product mevalonate. Moreover, by using a novel molecular imaging sensor, we confirm that inhibition of HMG-CoA reductase blocks MYC phosphorylation in vivo. Importantly, the introduction of phosphorylation mutants of MYC at Ser62 or Thr58 into tumors blocks their sensitivity to inhibition of HMG-CoA reductase. Finally, we show that inhibition of HMG-CoA reductase suppresses MYC phosphorylation through Rac GTPase. Therefore, HMG-CoA reductase is a critical regulator of MYC phosphorylation, activation, and tumorigenic properties. The inhibition of HMG-CoA reductase may be a useful target for the treatment of MYC-associated HCC as well as other tumors. PMID- 21262915 TI - Activation of the aryl hydrocarbon receptor AhR Promotes retinoic acid-induced differentiation of myeloblastic leukemia cells by restricting expression of the stem cell transcription factor Oct4. AB - Retinoic acid (RA) is used to treat leukemia and other cancers through its ability to promote cancer cell differentiation. Strategies to enhance the anticancer effects of RA could deepen and broaden its beneficial therapeutic applications. In this study, we describe a receptor cross-talk system that addresses this issue. RA effects are mediated by RAR/RXR receptors that we show are modified by interactions with the aryl hydrocarbon receptor (AhR), a protein functioning both as a transcription factor and a ligand-dependent adaptor in an ubiquitin ligase complex. RAR/RXR and AhR pathways cross-talk at the levels of ligand-receptor and also receptor-promoter interactions. Here, we assessed the role of AhR during RA-induced differentiation and a hypothesized convergence at Oct4, a transcription factor believed to maintain stem cell characteristics. RA upregulated AhR and downregulated Oct4 during differentiation of HL-60 promyelocytic leukemia cells. AhR overexpression in stable transfectants downregulated Oct4 and also decreased ALDH1 activity, another stem cell associated factor, enhancing RA-induced differentiation as indicated by cell differentiation markers associated with early (CD38 and CD11b) and late (neutrophilic respiratory burst) responses. AhR overexpression also increased levels of activated Raf1, which is known to help propel RA-induced differentiation. RNA interference-mediated knockdown of Oct4 enhanced RA-induced differentiation and G(0) cell-cycle arrest relative to parental cells. Consistent with the hypothesized importance of Oct4 downregulation for differentiation, parental cells rendered resistant to RA by biweekly high RA exposure displayed elevated Oct4 levels that failed to be downregulated. Together, our results suggested that therapeutic effects of RA-induced leukemia differentiation depend on AhR and its ability to downregulate the stem cell factor Oct4. PMID- 21262916 TI - Thymidylate synthase and excision repair cross-complementing group-1 as predictors of responsiveness in mesothelioma patients treated with pemetrexed/carboplatin. AB - PURPOSE: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. EXPERIMENTAL DESIGN: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients. RESULTS: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome. CONCLUSIONS: In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted. PMID- 21262917 TI - Prognostic significance of p14ARF, p15INK4b, and p16INK4a inactivation in malignant peripheral nerve sheath tumors. AB - PURPOSE: p14(ARF), p15(INK4b), and p16(INK4a) are tumor suppressor genes that are located closely at 9p21 and are often coinactivated by genetic or epigenetic alterations. Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma with poor prognosis. However, the prognostic implications of inactivation of p14(ARF), p15(INK4b), and p16(INK4a) in MPNSTs have not been adequately investigated. Here we carried out a genetic, epigenetic, and expression analysis of p14(ARF), p15(INK4b), and p16(INK4a), and clarified the prognostic significance of their inactivation in MPNSTs. EXPERIMENTAL DESIGN: p14(ARF), p15(INK4b), and p16(INK4a) protein expressions were assessed by immunohistochemistry in 129 formalin-fixed samples of MPNST including 85 primary tumors. Thirty-nine samples, for which frozen material was available, were also investigated by Western blotting and quantitative reverse transcription PCR (RT PCR) to detect p14(ARF), p15(INK4b), and p16(INK4a) protein and mRNA expression, and by multiplex real-time PCR, PCR single strand conformation polymorphism and methylation-specific PCR to detect p14(ARF), p15(INK4b), and p16(INK4a) gene alterations. RESULTS: Immunohistochemically decreased expressions of p14(ARF), p15(INK4b), and p16(INK4a) were observed in 48%, 54%, and 49% of primary MPNSTs, respectively, and were significantly correlated with their concordant mRNA levels. As for gene alterations, homozygous deletion of CDKN2A was detected in one third of the cases. Inactivation of p14(ARF) and p16(INK4a) was associated with poor prognosis by both univariate and multivariate analyses. Furthermore, cases with inactivation of all p14(ARF), p15(INK4b), and p16(INK4a) genes showed the worst prognosis in a combined prognostic assessment. CONCLUSION: A comprehensive analysis of p14(ARF), p15(INK4b), and p16(INK4a) inactivation status provides useful prognostic information in MPNSTs. PMID- 21262918 TI - Randomised, double-blind, placebo-controlled trial of fructo-oligosaccharides in active Crohn's disease. AB - INTRODUCTION: The commensal intestinal microbiota drive the inflammation associated with Crohn's disease. However, bacteria such as bifidobacteria and Faecalibacterium prausnitzii appear to be immunoregulatory. In healthy subjects the intestinal microbiota are influenced by prebiotic carbohydrates such as fructo-oligosaccharides (FOS). Preliminary data suggest that FOS increase faecal bifidobacteria, induce immunoregulatory dendritic cell (DC) responses and reduce disease activity in patients with Crohn's disease. AIMS AND METHODS: To assess the impact of FOS in patients with active Crohn's disease using an adequately powered randomised double-blind placebo-controlled trial with predefined clinical, microbiological and immunological end points. Patients with active Crohn's disease were randomised to 15 g/day FOS or non-prebiotic placebo for 4 weeks. The primary end point was clinical response at week 4 (fall in Crohn's Disease Activity Index of >= 70 points) in the intention-to-treat (ITT) population. RESULTS: 103 patients were randomised to receive FOS (n = 54) or placebo (n = 49). More patients receiving FOS (14 (26%) vs 4 (8%); p = 0.018) withdrew before the 4-week end point. There was no significant difference in the number of patients achieving a clinical response between the FOS and placebo groups in the ITT analysis (12 (22%) vs 19 (39%), p = 0.067). Patients receiving FOS had reduced proportions of interleukin (IL)-6-positive lamina propria DC and increased DC staining of IL-10 (p < 0.05) but no change in IL-12p40 production. There were no significant differences in the faecal concentration of bifidobacteria and F prausnitzii between the groups at baseline or after the 4 week intervention. CONCLUSION: An adequately powered placebo-controlled trial of FOS showed no clinical benefit in patients with active Crohn's disease, despite impacting on DC function. ISRCTN50422530. PMID- 21262919 TI - Factors motivating and affecting health information exchange usage. AB - OBJECTIVE: Health information exchange (HIE) is the process of electronically sharing patient-level information between providers. However, where implemented, reports indicate HIE system usage is low. The aim of this study was to determine the factors associated with different types of HIE usage. DESIGN: Cross-sectional analysis of clinical data from emergency room encounters included in an operational HIE effort linked to system user logs using crossed random-intercept logistic regression. MEASUREMENTS: Independent variables included factors indicative of information needs. System usage was measured as none, basic usage, or a novel pattern of usage. RESULTS: The system was accessed for 2.3% of all encounters (6142 out of 271,305). Novel usage patterns were more likely for more complex patients. The odds of HIE usage were lower in the face of time constraints. In contrast to expectations, system usage was lower when the patient was unfamiliar to the facility. LIMITATIONS: Because of differences between HIE efforts and the fact that not all types of HIE usage (ie, public health) could be included in the analysis, results are limited in terms of generalizablity. CONCLUSIONS: This study of actual HIE system usage identifies patients and circumstances in which HIE is more likely to be used and factors that are likely to discourage usage. The paper explores the implications of the findings for system redesign, information integration across exchange partners, and for meaningful usage criteria emerging from provisions of the Health Information Technology for Economic & Clinical Health Act. PMID- 21262920 TI - Social but safe? Quality and safety of diabetes-related online social networks. AB - OBJECTIVE: To foster informed decision-making about health social networking (SN) by patients and clinicians, the authors evaluated the quality/safety of SN sites' policies and practices. DESIGN: Multisite structured observation of diabetes focused SN sites. Measurements 28 indicators of quality and safety covering: (1) alignment of content with diabetes science and clinical practice recommendations; (2) safety practices for auditing content, supporting transparency and moderation; (3) accessibility of privacy policies and the communication and control of privacy risks; and (4) centralized sharing of member data and member control over sharing. RESULTS: Quality was variable across n=10 sites: 50% were aligned with diabetes science/clinical practice recommendations with gaps in medical disclaimer use (30% have) and specification of relevant glycosylated hemoglobin levels (0% have). Safety was mixed with gaps in external review approaches (20% used audits and association links) and internal review approaches (70% use moderation). Internal safety review offers limited protection: misinformation about a diabetes 'cure' was found on four moderated sites. Of nine sites with advertising, transparency was missing on five; ads for unfounded 'cures' were present on three. Technological safety was poor with almost no use of procedures for secure data storage and transmission; only three sites support member controls over personal information. Privacy policies' poor readability impedes risk communication. Only three sites (30%) demonstrated better practice. Limitations English-language diabetes sites only. CONCLUSION: The quality/safety of diabetes SN is variable. Observed better practice suggests improvement is feasible. Mechanisms for improvement are recommended that engage key stakeholders to balance autonomy, community ownership, conditions for innovation, and consumer protection. PMID- 21262921 TI - Social disparities in internet patient portal use in diabetes: evidence that the digital divide extends beyond access. AB - The authors investigated use of the internet-based patient portal, kp.org, among a well-characterized population of adults with diabetes in Northern California. Among 14,102 diverse patients, 5671 (40%) requested a password for the patient portal. Of these, 4311 (76%) activated their accounts, and 3922 (69%), logged on to the patient portal one or more times; 2990 (53%) participants viewed laboratory results, 2132 (38%) requested medication refills, 2093 (37%) sent email messages, and 835 (15%) made medical appointments. After adjustment for age, gender, race/ethnicity, immigration status, educational attainment, and employment status, compared to non-Hispanic Caucasians, African-Americans and Latinos had higher odds of never logging on (OR 2.6 (2.3 to 2.9); OR 2.3 (1.9 to 2.6)), as did those without an educational degree (OR compared to college graduates, 2.3 (1.9 to 2.7)). Those most at risk for poor diabetes outcomes may fall further behind as health systems increasingly rely on the internet and limit current modes of access and communication. PMID- 21262922 TI - Effectiveness of an information technology intervention to improve prophylactic antibacterial use in the postoperative period. AB - BACKGROUND: A 2005 report from the Centers for Medicare and Medicaid Services and the Centers for Disease Control Surgical Infection Prevention program indicated that only 41% of prophylactic antibacterials were correctly stopped within 24 h of the end of surgery. Electronic order sets have shown promise as a means of integrating guideline information with electronic order entry systems and facilitating safer, more effective care. OBJECTIVE: The aim was to study the effectiveness of a computer-based antibacterial order set on increasing the proportion of patients who have antibacterial wound prophylaxis discontinued in the appropriate time frame. DESIGN: The authors conducted a quasi-experimental interrupted time-series analysis over an 8-month study period with the implementation of a computer-based order system designed to prevent excessive duration of surgical prophylaxis antibacterials. MEASUREMENT: The primary outcome was the proportion of surgeries with antibacterials discontinued in the appropriate time frame. Additionally, we evaluated the percent of surgeries after implementation of the electronic intervention with chart documentation of infection among surgeries where the prescriber indicated the reason for antibacterial therapy was treatment. RESULTS: The computer-based order intervention significantly improved the proportion of surgeries with timely discontinuation of antibacterials from 38.8% to 55.7% (p < 0.001) in the intervention hospital, while the control hospital remained at 56-57% (p = 0.006 for the difference between treated and control hospitals). In surgeries after intervention implementation where a prescriber indicated the reason for antibacterial therapy was treatment, the prevalence of chart documented infection was only 14%. CONCLUSIONS: A computer-based electronic order set intervention increased timely discontinuation of postoperative antibacterials. PMID- 21262923 TI - The patient and the computer in the primary care consultation. AB - OBJECTIVE: Studies of the doctor-patient relationship have focused on the elaboration of power and/or authority using a range of techniques to study the encounter between doctor and patient. The widespread adoption of computers by doctors brings a third party into the consultation. While there has been some research into the way doctors view and manage this new relationship, the behavior of patients in response to the computer is rarely studied. In this paper, the authors use Goffman's dramaturgy to explore patients' approaches to the doctor's computer in the consultation, and its influence on the patient-doctor relationship. DESIGN: Observational study of Australian general practice. 141 consultations from 20 general practitioners were videotaped and analyzed using a hermeneutic framework. RESULTS: Patients negotiated the relationship between themselves, the doctor, and the computer demonstrating two themes: dyadic (dealing primarily with the doctor) or triadic (dealing with both computer and doctor). Patients used three signaling behaviors in relation to the computer on the doctor's desk (screen watching, screen ignoring, and screen excluding) to influence the behavior of the doctor. Patients were able to draw the doctor to the computer, and used the computer to challenge doctor's statements. CONCLUSION: This study demonstrates that in consultations where doctors use computers, the computer can legitimately be regarded as part of a triadic relationship. Routine use of computers in the consultation changes the doctor-patient relationship, and is altering the distribution of power and authority between doctor and patient. PMID- 21262924 TI - R engine cell: integrating R into the i2b2 software infrastructure. AB - Informatics for Integrating Biology and the Bedside (i2b2) is an initiative funded by the NIH that aims at building an informatics infrastructure to support biomedical research. The University of Pavia has recently integrated i2b2 infrastructure with a registry of inherited arrhythmogenic diseases. Within this project, the authors created a novel i2b2 cell, named R Engine Cell, which allows the communication between i2b2 and the R statistical software. As survival analyses are routinely performed by cardiology researchers, the authors have first concentrated on making Kaplan-Meier analyses available within the i2b2 web interface. To this aim, the authors developed a web-client plug-in to select the patient set on which to perform the analysis and to display the results in a graphical, intuitive way. R Engine Cell has been designed to easily support the integration of other R-based statistical analyses into i2b2. PMID- 21262925 TI - Differential disposition of chenodeoxycholic acid versus taurocholic acid in response to acute troglitazone exposure in rat hepatocytes. AB - Inhibition of bile acid (BA) transport may contribute to the hepatotoxicity of troglitazone (TRO), a peroxisome proliferator-activated receptor gamma agonist. Typically, studies use taurocholic acid (TCA) as a model substrate to investigate effects of xenobiotics on BA disposition. However, TRO may differentially affect the transport of individual BAs, potentially causing hepatocyte accumulation of more cytotoxic BAs. The effects of TRO on the disposition of [(14)C]-labeled chenodeoxycholic acid ([(14)C]CDCA), an unconjugated cytotoxic BA, were determined in suspended hepatocytes and sandwich-cultured hepatocytes (SCH) from rats. (E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl][[3-(dimethylamino)-3 oxopropyl]thio]methyl]thio]-propanoic acid (MK571), a multidrug resistance associated protein (MRP) inhibitor, was included to evaluate involvement of MRPs in CDCA disposition. Accumulation in cells + bile of total [(14)C]CDCA species in SCH was sixfold greater than [(3)H]TCA and unaffected by 1 and 10MUM TRO; 100MUM TRO and 50MUM MK571 ablated biliary excretion and significantly increased intracellular accumulation of total [(14)C]CDCA species. Results were similar in Mrp2-deficient TR(-) rat hepatocytes. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed that taurine- and glycine-conjugated CDCA, in addition to unconjugated CDCA, accumulated in hepatocytes during the 10 min incubation. In suspended rat hepatocytes, initial [(14)C]CDCA uptake was primarily Na(+)-independent, whereas initial [(3)H]TCA uptake was primarily Na(+) dependent; TRO and MK571 decreased [(14)C]CDCA uptake to a lesser extent than [(3)H]TCA. Unexpectedly, MK571 inhibited Na(+)-taurocholate cotransporting polypeptide and bile salt export pump. Differential effects on uptake and efflux of individual BAs may contribute to TRO hepatotoxicity. Although TCA is the prototypic BA used to investigate the effects of xenobiotics on BA transport, it may not be reflective of other BAs. PMID- 21262926 TI - The oncogenic kinase Pim-1 is modulated by K-Ras signaling and mediates transformed growth and radioresistance in human pancreatic ductal adenocarcinoma cells. AB - Oncogenic Pim-1 kinase is upregulated in multiple solid cancers, including human pancreatic ductal adenocarcinoma (PDAC), a highly lethal disease with few useful treatment options. Pim-1 is also transcriptionally induced upon oncogenic K-Ras mediated transformation of the human pancreatic ductal epithelial (HPDE) cell model of PDAC. Given the near ubiquitous presence of mutant K-Ras in PDAC and its critical role in this disease, we wished to study the effects of oncogenic K-Ras signaling on Pim-1 expression, as well as the role of Pim-1 in growth transformation of PDAC cells. Pim-1 protein levels were upregulated in both PDAC cell lines and patient tumor tissues. Furthermore, ectopic oncogenic K-Ras increased Pim-1 expression in human pancreatic nestin-expressing (HPNE) cells, a distinct immortalized cell model of PDAC. Conversely, shRNA-mediated suppression of oncogenic K-Ras decreased Pim-1 protein in PDAC cell lines. These results indicate that oncogenic K-Ras regulates Pim-1 expression. The kinase activity of Pim-1 is constitutively active. Accordingly, shRNA-mediated suppression of Pim-1 in K-Ras-dependent PDAC cell lines decreased Pim-1 activity, as measured by decreased phosphorylation of the pro-apoptotic protein Bad and increased expression of the cyclin-dependent kinase inhibitor p27Kip1. Biological consequences of inhibiting Pim-1 expression included decreases in both anchorage dependent and -independent cell growth, invasion through Matrigel and radioresistance as measured by standard clonogenic assays. These results indicate that Pim-1 is required for PDAC cell growth, invasion and radioresistance downstream of oncogenic K-Ras. Overall, our studies help to elucidate the role of Pim-1 in PDAC growth transformation and validate Pim-1 kinase as a potential molecular marker for mutated K-Ras activity. PMID- 21262927 TI - A few more pieces in the puzzle of non-compaction cardiomyopathy. PMID- 21262928 TI - Revisiting the obesity paradox in heart failure: new insights? PMID- 21262929 TI - Treating diabetes by improving cardiac output. PMID- 21262930 TI - A shared parameter model for the estimation of longitudinal concomitant intervention effects. AB - We investigate a change-point approach for modeling and estimating the regression effects caused by a concomitant intervention in a longitudinal study. Since a concomitant intervention is often introduced when a patient's health status exhibits undesirable trends, statistical models without properly incorporating the intervention and its starting time may lead to biased estimates of the intervention effects. We propose a shared parameter change-point model to evaluate the pre- and postintervention time trends of the response and develop a likelihood-based method for estimating the intervention effects and other parameters. Application and statistical properties of our method are demonstrated through a longitudinal clinical trial in depression and heart disease and a simulation study. PMID- 21262931 TI - The effect of enamel bleaching on the shear bond strengths of metal and ceramic brackets. AB - The aim of this study was to evaluate the effects of bleaching and delayed bonding on the shear bond strengths of metal and ceramic brackets bonded with light and chemically cure composite resin to human enamel. One hundred and twenty extracted human premolar teeth were randomly divided into three groups of 40 each. The first two groups were bleached with 20 per cent carbamide peroxide (CP) at-home bleaching agent. No bleaching procedures were applied to the third group and served as control. The first two and control groups were divided into equal subgroups according to different adhesive-bracket combinations. Specimens in group 1 (n = 40) were bonded 24 hours after bleaching process was completed while the specimens in group 2 (n = 40) were bonded 14 days after. The specimens in all groups were debonded with a Universal testing machine while the modified adhesive remnant index was used to evaluate fracture properties. No statistically significant differences were found between the shear bond strengths of metal and ceramic brackets bonded to bleached enamel after 24 hours, 14 days, and unbleached enamel with light or chemical cure adhesives (P > 0.05). The mode of failure was mostly at the bracket/adhesive interface and cohesive failures within the resin were also observed. Our findings indicated that at-home bleaching agents that contain 20 per cent CP did not significantly affect the shear bond strength of metal and ceramic orthodontic brackets to enamel when bonding is performed 24 hours or 14 days after bleaching. PMID- 21262932 TI - A comparative study of qualitative and quantitative methods for the assessment of adhesive remnant after bracket debonding. AB - The amount of the residual adhesive after bracket debonding is frequently assessed in a qualitative manner, utilizing the adhesive remnant index (ARI). This study aimed to investigate whether quantitative assessment of the adhesive remnant yields more precise results compared to qualitative methods utilizing the 4- and 5-point ARI scales. Twenty debonded brackets were selected. Evaluation and scoring of the adhesive remnant on bracket bases were made consecutively using: 1. qualitative assessment (visual scoring) and 2. quantitative measurement (image analysis) on digital photographs. Image analysis was made on scanning electron micrographs (SEM) and high-precision elemental maps of the adhesive remnant as determined by energy dispersed X-ray spectrometry. Evaluations were made in accordance with the original 4-point and the modified 5-point ARI scales. Intra class correlation coefficients (ICCs) were calculated, and the data were evaluated using Friedman test followed by Wilcoxon signed ranks test with Bonferroni correction. ICC statistics indicated high levels of agreement for qualitative visual scoring among examiners. The 4-point ARI scale was compliant with the SEM assessments but indicated significantly less adhesive remnant compared to the results of quantitative elemental mapping. When the 5-point scale was used, both quantitative techniques yielded similar results with those obtained qualitatively. These results indicate that qualitative visual scoring using the ARI is capable of generating similar results with those assessed by quantitative image analysis techniques. In particular, visual scoring with the 5 point ARI scale can yield similar results with both the SEM analysis and elemental mapping. PMID- 21262933 TI - Dental age in patients with impacted maxillary canines related to the position of the impacted teeth. AB - The aim of the study was to determine whether there are differences in dental age (DA) using the method of Demirjian, in patients with impacted buccal or palatal maxillary canines in relation to unaffected controls. DA was estimated using Demirjian's method on panoramic radiographs of two groups of Caucasian patients. The study group consisted of 116 patients aged from 12 to 16 years (80 females and 36 males) that was further divided into 54 patients with unilateral or bilateral palatally impacted maxillary canines and 62 patients with buccally positioned canines. The control group of 116 subjects without canine impaction was matched to the study group by age and gender. Calculated DAs and differences between dental and chronological age (CA) were compared between the groups. Statistical analysis was performed using Shapiro-Wilk, Mann-Whitney U, and Student's t-test. DA was significantly lower in patients with impacted maxillary canines than in healthy controls and also when palatal or buccal ectopia was considered. The rate of dental development in patients with palatally impacted canines did not differ from that of subjects with buccal canine displacement. The differences between DA and CA were higher in healthy controls (increase in DA) than in patients with impacted maxillary canines. DA estimation using Demirjian's method may be lower than expected in subjects with maxillary canine impaction. PMID- 21262934 TI - Variations in cyclic mandibular movements during treatment of Class II malocclusions with removable functional appliances. AB - The aim of the study was to establish whether juveniles with a Class II malocclusion change the neuromuscular control of mandibular movements during the course of orthodontic treatment with removable functional appliances (RFAs). Neuromuscular control can be indirectly evaluated by recording cyclic planar mandibular movements which were freely carried out by the patients (28 girls, 14 boys, aged 11.1 +/- 1.1 years at the start of treatment) and measured with an ultrasonic device before, during, and after Class II functional appliance therapy, with either an activator or a bite jumping plate. The cyclic movements represented simultaneous rotations of the mandible around a maxillary and mandibular fixed axis (MFHA) and could be characterized by MU(alpha)-diagrams (MU = swing angle of MFHA, alpha = mouth opening angle) and path length (L) of the MFHA. The MU(alpha)-diagrams clearly divided into four parts: movement representing protrusion, mouth opening, and two parts of backward closing as known from Posselt diagrams. Parameters from the Posselt and MU(alpha)-diagrams were checked by one-factor analysis of variance on a 5 per cent significance level for group dependency. For one-third of the patients investigated, no significant changes were seen in any parameter pre- or post-therapy. However, patients showing an initially large mouth opening capacity or a very short condylar path changed their neuromuscular control to that of Class I subjects. Analysis of MU(alpha)-diagrams provides the possibility of assessing changes in the neuromuscular control of the mandible during Class II treatment. PMID- 21262935 TI - Effects of a torsion load on the shear bond strength with different bonding techniques. AB - The purpose of this study was to test the hypothesis that a torsional load applied after bracket bonding does not affect the shear bond strength (SBS) with different bonding techniques. Sixty human premolars were divided into two groups (experimental and control) to investigate the effects of a torsion load, and the two groups were further subdivided into three groups of 10 for the evaluation of different adhesive systems (one etch-and-rinse adhesive, Transbond XT; two self etching primer adhesives, Transbond Plus and Beauty Ortho Bond). A torsion load (1.45 N/cm) was applied by beta-titanium wire at 15 minutes after bracket bonding in the experimental groups. All specimens were then thermocycled between 5 and 55 degrees C for approximately 1 week (6000 cycles). The SBS for each sample was examined with a universal testing machine and the adhesive remnant index (ARI) score was calculated. Data were compared by two-way analysis of variance, Student's t-test, and a chi-square test. The SBS for Transbond XT after thermocycling with a torsion load was significantly lower than that without a torsion load. For Transbond Plus and Beauty Ortho Bond, there was no significant difference in the mean SBS between specimens thermocycled with and without a torsion load. No significant difference in the distribution of frequencies among the ARI categories was observed among the six groups, although the ARI scores for specimens with a torsion load tended to be higher than those without a torsion load. In conclusion, the SBS of the conventional etch-and-rinse adhesive system significantly decreased under a torsion load with thermocycling. PMID- 21262936 TI - Relationship between masseter muscle size and maxillary morphology. AB - The aim of this study was to investigate the relationship between masseter muscle size and craniofacial morphology, focusing on the maxilla. Twenty-four patients (11 males and 13 females; mean age 27.6 +/- 5.6 years) underwent cephalometric analyses. Ultrasonography was used to measure the cross-sectional area (CSA) of the masseter muscle and bite force was measured using pressure sensitive film. The results showed that CSA-relaxed was positively correlated with upper anterior face height (UAFH)/total anterior face height (TAFH) and negatively with lower anterior face height (LAFH)/TAFH and LAFH (P < 0.05). CSA-clenched was correlated positively with SN-palatal, FH-palatal, UAFH/TAFH, and lower posterior face height (LPFH)/total posterior face height (TPFH) and negatively with LAFH/TAFH, LAFH, upper posterior face height (UPFH)/TPFH, and UPFH (P < 0.05). Bite force was positively correlated with LPFH/TPFH and negatively with UPFH/TPFH (P < 0.05). As the masseter became larger, the anterior maxillary region tended to shift downwards relative to the cranial base, whereas the posterior region tended to shift upwards. The decrease in LAFH/TAFH and increase in LPFH/TPFH as the size of the masseter muscle increases may be influenced not only by the inclination of the mandibular plane but also by the clockwise rotation of the maxilla. PMID- 21262937 TI - Congenital varicella syndrome: the evidence for secondary prevention with varicella-zoster immune globulin. PMID- 21262938 TI - Rescuing doctors in distress. PMID- 21262940 TI - Preventing congenital varicella syndrome with immunization. PMID- 21262939 TI - The potential economic impact of restricted access to angiotensin-receptor blockers. AB - BACKGROUND: The use of angiotensin-receptor blockers increased by more than 4000% in Canada from 1996 to 2006. The benefit of these medications over angiotensin converting-enzyme (ACE) inhibitors has not been proven aside from a reduction in dry cough. We estimated the potential cost savings that might have been achieved had access to angiotensin-receptor blockers been restricted. METHODS: We performed a cost-minimization analysis with a decision-tree model using a societal perspective over a one-year period. Sources of data for model parameters included IMS Health Canada data collected from one-third of all retail pharmacies for the cost and use of angiotensin-receptor blockers and ACE inhibitors in each province, as well as published studies for administrative costs and incidence of dry cough. We used Monte Carlo simulations with 10 000 iterations to test the impact of several model parameters (e.g., drug prices, administrative costs and the incidence of dry cough). All data are in 2006 Canadian dollars. RESULTS: A policy that would have restricted access to angiotensin-receptor blockers might have saved more than $77 million in Canada in 2006. The simulations yielded similar savings for the year (mean $58.3 million, 95% confidence interval $29.3 million to $90.8 million). Every simulation showed a cost savings. INTERPRETATION: Had access to angiotensin-receptor blockers been restricted, the potential cost savings to the Canadian health care system might have been more than $77 million in 2006, likely without any adverse effect on cardiovascular health. PMID- 21262941 TI - Pocket-sized help for people with dementia. PMID- 21262942 TI - Donor conception and children's rights: a parent's decision. PMID- 21262943 TI - The centralized approach to guidelines development. PMID- 21262944 TI - Leptospirosis: pulmonary hemorrhage in a returned traveller. PMID- 21262945 TI - Swiss medical technology industry gobbling up market share. PMID- 21262946 TI - Empathic responses in clinical practice: intuition or tuition? PMID- 21262947 TI - The therapeutic value of hyper-suggestibility. PMID- 21262948 TI - Bilateral carotid body paragangliomas. PMID- 21262949 TI - Experts call for health infoway "watchdog". PMID- 21262950 TI - Drug formulations that require less than 0.1 mL of stock solution to prepare doses for infants and children. AB - Intravenous doses of medications require formulations that permit accurate preparation and administration. Current equipment does not permit accurate measurement of volumes less than 0.1 mL. In a study of four hypothetical standard pediatric patients, we found that 28 common medications required less than 0.1 mL of available formulation to prepare the dose. In a clinical study of actual use in a pediatric intensive care unit (ICU), 5245 (7.4%) of 71 218 intravenous doses required preparation from less than 0.1 mL of stock solution. For 28.5% of the 1531 ICU admissions, at least one dose was prepared from a volume of less than 0.1 mL. Our findings identify a substantial source of dosing error. Correction will require revision of preparation methods, regulatory requirements and manufacturing practices. PMID- 21262951 TI - Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. AB - BACKGROUND: Pheochromocytomas are rare catecholamine-producing tumors derived in more than 30% of cases from mutations in 9 tumor-susceptibility genes identified to date, including von Hippel-Lindau tumor suppressor (VHL); succinate dehydrogenase complex, subunit B, iron sulfur (Ip) (SDHB); and succinate dehydrogenase complex, subunit D, integral membrane protein (SDHD). Testing of multiple genes is often undertaken at considerable expense before a mutation is detected. This study assessed whether measurements of plasma metanephrine, normetanephrine, and methoxytyramine, the O-methylated metabolites of catecholamines, might help to distinguish different hereditary forms of the tumor. METHODS: Plasma concentrations of O-methylated metabolites were measured by liquid chromatography with electrochemical detection in 173 patients with pheochromocytoma, including 38 with multiple endocrine neoplasia type 2 (MEN 2), 10 with neurofibromatosis type 1 (NF1), 66 with von Hippel-Lindau (VHL) syndrome, and 59 with mutations of SDHB or SDHD. RESULTS: In contrast to patients with VHL, SDHB, and SDHD mutations, all patients with MEN 2 and NF1 presented with tumors characterized by increased plasma concentrations of metanephrine (indicating epinephrine production). VHL patients usually showed solitary increases in normetanephrine (indicating norepinephrine production), whereas additional or solitary increases in methoxytyramine (indicating dopamine production) characterized 70% of patients with SDHB and SDHD mutations. Patients with NF1 and MEN 2 could be discriminated from those with VHL, SDHB, and SDHD gene mutations in 99% of cases by the combination of normetanephrine and metanephrine. Measurements of plasma methoxytyramine discriminated patients with SDHB and SDHD mutations from those with VHL mutations in an additional 78% of cases. CONCLUSIONS: The distinct patterns of plasma catecholamine O-methylated metabolites in patients with hereditary pheochromocytoma provide an easily used tool to guide cost-effective genotyping of underlying disease-causing mutations. PMID- 21262952 TI - Myeloperoxidase improves risk stratification in patients with ischemia and normal cardiac troponin I concentrations. AB - BACKGROUND: We assessed the ability of myeloperoxidase (MPO) to identify the risk for major adverse cardiac events (MACE) in patients who present with ischemic symptoms suggestive of acute coronary syndrome and have a normal cardiac troponin I (cTnI) value. METHODS: We used Siemens (n = 400) and Abbott (n = 350) assays to measure MPO and cTnI in plasma samples from 400 patients. Event rates (myocardial infarction, cardiac death, percutaneous coronary intervention, coronary artery bypass grafting) were estimated by the Kaplan-Meier method and compared with the log-rank statistic. RESULTS: At the 30-day follow-up, the adjusted hazard ratios for MACE were 3.9 (P < 0.001) for increased cTnI and 2.7 (P = 0.006) for increased MPO for the Siemens assays and were 5.5 (P < 0.001) for increased cTnI and 2.9 (P = 0.001) for increased MPO for the Abbott assays. Similar findings were observed with 6 months of follow-up. Patients who initially had a normal cTnI value and an increased Siemens MPO value demonstrated a higher rate of MACE at 30 days than those in whom both values were normal (16.1% vs 3.6%, P = 0.002) and 6 months (18.1% vs 5.0%, P = 0.002). Similarly, patients who had an increased Abbott MPO result demonstrated a higher MACE rate at 30 days (12.3% vs 3.9%, P = 0.03) and at 6 months (16.2% vs 5.1%, P = 0.01) than those with normal values. CONCLUSIONS: A combination of MPO and cTnI allowed the identification of a greater proportion of patients at risk for MACE than the use of cTnI alone. Increased MPO values remained predictive of future cardiac events even when the cTnI value was normal. PMID- 21262953 TI - Clinical features and successful management of suicidal digoxin toxicity without use of digoxin-specific antibody (Fab) fragments--is it possible? AB - A retrospective study of 147 consecutive cases of suicidal digoxin poisoning was undertaken in order to determine the severity and outcome of toxicity without use of digoxin-specific Fab fragments. This study showed that suicidal digoxin poisoning in young patients is usually mild to moderate; even underlying cardiac disease and chronic use of digoxin has no effect on the severity of toxicity and incidence of lethal dysrhythmia in these cases. This type of toxicity responds appropriately to conventional treatment. PMID- 21262954 TI - An urgent necessity under general anaesthesia--surgical gloves made into re breathing bag. AB - Anaesthetic practice in resource-poor countries often requires a lot of improvisation on the part of practitioners in order to meet the needs of patients. Disposables in a low-resource environment are usually stretched beyond the manufacturer's recommended life span. While anaesthetizing a six-month-old baby with cleft lip, the reservoir bag was accidentally torn and was replaced with latex surgical gloves. In the absence of a spare bag this replacement served the patient throughout the period of surgery. PMID- 21262955 TI - Clubfoot in Malawi: local theories of causation. AB - This paper examines local theories of the causation of clubfoot expressed by the guardians of children undergoing treatment at clinics run by the Malawi National Clubfoot Programme (MNCP). Core data was collected and analysed using qualitative methodologies of critical medical anthropology. Sixty detailed case studies were completed, each based on an extended open-ended interview with patient guardians. Five main theories of causation were put forward: God; the devil; witchcraft or curses; biological reasons; and inherited condition. Each was elaborated in a variety of ways. There is growing international recognition of the importance of examining the relationship between culture and disability. This study is the first attempt to do so for clubfoot in Malawi. It provides a platform on which to build future qualitative research that can be harnessed by the MNCP and similar initiatives to develop their knowledge base and service provision, both in Malawi and the wider African context. PMID- 21262956 TI - Cardiotoxicity from 'safe' herbomineral formulations. AB - Many herbomineral preparations are currently being used as therapeutic remedies for common ailments. Commonly known cardiotoxic herbs are Aconitum ferox (aconite), Areca catechu (betel nut), Thevetia peruviana (yellow oleander) and Cleistanus collinus (oduvan). Herbs mixed with lead, copper and/or mercury are known to be highly toxic. They produce cardiac arrhythmias, mainly ventricular ectopics, ventricular tachycardia and various degrees of arterioventricular (AV) blocks. We report 12 such successive cases where the patients developed vague feelings of discomfort, dizziness, chest discomfort and ventricular arrhythmias following herbal drug ingestion which warranted the immediate discontinuation of the drug. Three of the patients died. This paper emphasizes the risk of unsupervised use of herbomineral preparations by patients who believe that the remedies are always 'safe' and the urgent necessity for the pharmacognostic identification of the constituent herbs, their toxicological studies, uniform nomenclature, authenticity and standardization of plants and their parts before advocating them for therapeutic use. PMID- 21262957 TI - AMPK and Akt determine apoptotic cell death following perturbations of one-carbon metabolism by regulating ER stress in acute lymphoblastic leukemia. AB - AICAr is a cell-permeable nucleotide that has been used in vivo and in vitro to activate AMPK. Our previous findings have shown that AICAr as a single agent induces dose- and time-dependent growth inhibition in acute lymphoblastic leukemia (ALL) cell lines. In addition, the combination of AICAr with antifolates [methotrexate (MTX) or pemetrexed] has been shown to further potentiate AMPK activation and to lead to greater cytotoxicity and growth inhibition in leukemia and other malignant cell types. Our data presented herein show that sustained endoplasmic reticulum (ER) stress is the predominant mechanism behind the synergistic induction of cell death by the combination of AICAr plus the inhibitor of one-carbon metabolism, MTX, in Bp- and T-ALL, as evidenced by induction of several unfolded protein response markers leading to apoptosis. We also show for the first time that AICAr in combination with MTX significantly induces Akt phosphorylation in ALL. Under these conditions, the concomitant inhibition of Akt, a cellular antagonist of AMPK, leads to further upregulation of AMPK activity and alleviates AICAr plus MTX-induced ER stress and apoptosis. Therefore, we also show that the concomitant activation of AMPK actually rescues the cells from AICAr plus MTX-induced ER stress and apoptosis. Our data suggest that the effects of AMPK activation on cell death or survival differ contextually depending on its signaling alterations with related oncogenic pathways and provide insight into the reported paradoxical proapoptotic versus prosurvival effects of AMPK activation. PMID- 21262958 TI - The role of utility value in achievement behavior: the importance of culture. AB - Two studies tested how participants' responses to utility value interventions and subsequent interest in a math technique vary by culture (Westerners vs. East Asians) and levels of initial math interest. Participants in Study 1 were provided with information about the utility value of the technique or not. The manipulation was particularly effective for East Asian learners with initially lower math interest, who showed more interest in the technique relative to low interest Westerners. Study 2 compared the effects of two types of utility value (proximal or distal) and examined the effects on interest, effort, performance, and process variables. Whereas East Asian participants reaped the most motivational benefits from a distal value manipulation, Westerners benefited the most from a proximal value manipulation. These findings have implications for how to promote motivation for learners with different cultural backgrounds and interests. PMID- 21262959 TI - Homeostatic proliferation generates long-lived natural killer cells that respond against viral infection. AB - Cells of the immune system undergo homeostatic proliferation during times of lymphopenia induced by certain viral infections or caused by chemotherapy and radiation treatment. Natural killer (NK) cells are no exception and can rapidly expand in number when placed into an environment devoid of these cells. We explored the lifespan and function of mouse NK cells that have undergone homeostatic proliferation in various settings of immunodeficiency. Adoptive transfer of mature NK cells into lymphopenic mice resulted in the generation of a long-lived population of NK cells. These homeostasis-driven NK cells reside in both lymphoid and nonlymphoid organs for >6 mo and, similar to memory T cells, self-renew and slowly turn over at steady state. Furthermore, homeostatically expanded NK cells retained their functionality many months after initial transfer and responded robustly to viral infection. These findings highlight the ability of mature NK cells to self-renew and possibly persist in the host for months or years and might be of clinical importance during NK cell adoptive immunotherapy for the treatment of certain cancers. PMID- 21262960 TI - The malaria circumsporozoite protein has two functional domains, each with distinct roles as sporozoites journey from mosquito to mammalian host. AB - Plasmodium sporozoites make a remarkable journey from the mosquito midgut to the mammalian liver. The sporozoite's major surface protein, circumsporozoite protein (CSP), is a multifunctional protein required for sporozoite development and likely mediates several steps of this journey. In this study, we show that CSP has two conformational states, an adhesive conformation in which the C-terminal cell-adhesive domain is exposed and a nonadhesive conformation in which the N terminus masks this domain. We demonstrate that the cell-adhesive domain functions in sporozoite development and hepatocyte invasion. Between these two events, the sporozoite must travel from the mosquito midgut to the mammalian liver, and N-terminal masking of the cell-adhesive domain maintains the sporozoite in a migratory state. In the mammalian host, proteolytic cleavage of CSP regulates the switch to an adhesive conformation, and the highly conserved region I plays a critical role in this process. If the CSP domain architecture is altered such that the cell-adhesive domain is constitutively exposed, the majority of sporozoites do not reach their target organs, and in the mammalian host, they initiate a blood stage infection directly from the inoculation site. These data provide structure-function information relevant to malaria vaccine development. PMID- 21262961 TI - Localization of the dantrolene-binding sequence near the FK506-binding protein binding site in the three-dimensional structure of the ryanodine receptor. AB - Dantrolene is believed to stabilize interdomain interactions between the NH2 terminal and central regions of ryanodine receptors by binding to the NH2 terminal residues 590-609 in skeletal ryanodine receptor (RyR1) and residues 601 620 in cardiac ryanodine receptor (RyR2). To gain further insight into the structural basis of dantrolene action, we have attempted to localize the dantrolene-binding sequence in RyR1/RyR2 by using GFP as a structural marker and three-dimensional cryo-EM. We inserted GFP into RyR2 after residues Arg-626 and Tyr-846 to generate GFP-RyR2 fusion proteins, RyR2Arg-626-GFP and RyR2Tyr-846 GFP. Insertion of GFP after residue Arg-626 abolished the binding of a bulky GST- or cyan fluorescent protein-tagged FKBP12.6 but not the binding of a smaller, nontagged FKBP12.6, suggesting that residue Arg-626 and the dantrolene-binding sequence are located near the FKBP12.6-binding site. Using cryo-EM, we have mapped the three-dimensional location of Tyr-846-GFP to domain 9, which is also adjacent to the FKBP12.6-binding site. To further map the three-dimensional location of the dantrolene-binding sequence, we generated 10 FRET pairs based on four known three-dimensional locations (FKBP12.6, Ser-437-GFP, Tyr-846-GFP, and Ser-2367-GFP). Based on the FRET efficiencies of these FRET pairs and the corresponding distance relationships, we mapped the three-dimensional location of Arg-626-GFP or -cyan fluorescent protein, hence the dantrolene-binding sequence, to domain 9 near the FKBP12.6-binding site but distant to the central region around residue Ser-2367. An allosteric mechanism by which dantrolene stabilizes interdomain interactions between the NH2-terminal and central regions is proposed. PMID- 21262962 TI - Halotolerant cyanobacterium Aphanothece halophytica contains an Na+-dependent F1F0-ATP synthase with a potential role in salt-stress tolerance. AB - Aphanothece halophytica is a halotolerant alkaliphilic cyanobacterium that can grow in media of up to 3.0 m NaCl and pH 11. Here, we show that in addition to a typical H(+)-ATP synthase, Aphanothece halophytica contains a putative F(1)F(0) type Na(+)-ATP synthase (ApNa(+)-ATPase) operon (ApNa(+)-atp). The operon consists of nine genes organized in the order of putative subunits beta, epsilon, I, hypothetical protein, a, c, b, alpha, and gamma. Homologous operons could also be found in some cyanobacteria such as Synechococcus sp. PCC 7002 and Acaryochloris marina MBIC11017. The ApNa(+)-atp operon was isolated from the A. halophytica genome and transferred into an Escherichia coli mutant DK8 (Deltaatp) deficient in ATP synthase. The inverted membrane vesicles of E. coli DK8 expressing ApNa(+)-ATPase exhibited Na(+)-dependent ATP hydrolysis activity, which was inhibited by monensin and tributyltin chloride, but not by the protonophore, carbonyl cyanide m-chlorophenyl hydrazone (CCCP). The Na(+) ion protected the inhibition of ApNa(+)-ATPase by N,N'-dicyclohexylcarbodiimide. The ATP synthesis activity was also observed using the Na(+)-loaded inverted membrane vesicles. Expression of the ApNa(+)-atp operon in the heterologous cyanobacterium Synechococcus sp. PCC 7942 showed its localization in the cytoplasmic membrane fractions and increased tolerance to salt stress. These results indicate that A. halophytica has additional Na(+)-dependent F(1)F(0)-ATPase in the cytoplasmic membrane playing a potential role in salt-stress tolerance. PMID- 21262963 TI - AaCAT1 of the yellow fever mosquito, Aedes aegypti: a novel histidine-specific amino acid transporter from the SLC7 family. AB - Insect yolk protein precursor gene expression is regulated by nutritional and endocrine signals. A surge of amino acids in the hemolymph of blood-fed female mosquitoes activates a nutrient signaling system in the fat bodies, which subsequently derepresses yolk protein precursor genes and makes them responsive to activation by steroid hormones. Orphan transporters of the SLC7 family were identified as essential upstream components of the nutrient signaling system in the fat body of fruit flies and the yellow fever mosquito, Aedes aegypti. However, the transport function of these proteins was unknown. We report expression and functional characterization of AaCAT1, cloned from the fat body of A. aegypti. Expression of AaCAT1 transcript and protein undergoes dynamic changes during postembryonic development of the mosquito. Transcript expression was especially high in the third and fourth larval stages; however, the AaCAT1 protein was detected only in pupa and adult stages. Functional expression and analysis of AaCAT1 in Xenopus oocytes revealed that it acts as a sodium independent cationic amino acid transporter, with unique selectivity to L histidine at neutral pH (K(0.5)(L-His) = 0.34 +/- 0.07 mM, pH 7.2). Acidification to pH 6.2 dramatically increases AaCAT1-specific His(+)-induced current. RNAi mediated silencing of AaCAT1 reduces egg yield of subsequent ovipositions. Our data show that AaCAT1 has notable differences in its transport mechanism when compared with related mammalian cationic amino acid transporters. It may execute histidine-specific transport and signaling in mosquito tissues. PMID- 21262964 TI - Microtubule-associated protein 1S (MAP1S) bridges autophagic components with microtubules and mitochondria to affect autophagosomal biogenesis and degradation. AB - The ubiquitously distributed MAP1S is a homologue of the exclusively neuronal distributed microtubule-associated protein 1A and 1B (MAP1A/B). They give rise to multiple isoforms through similar post-translational modification. Isoforms of MAP1S have been implicated in microtubule dynamics and mitotic abnormalities and mitotic cell death. Here we show that ablation of the Map1s gene in mice caused reduction in the B-cell CLL/lymphoma 2 or xL (Bcl-2/xL) and cyclin-dependent kinase inhibitor 1B (P27) protein levels, accumulation of defective mitochondria, and severe defects in response to nutritive stress, suggesting defects in autophagosomal biogenesis and clearance. Furthermore, MAP1S isoforms interacted with the autophagosome-associated light chain 3 of MAP1A/B (LC3), a homologue of yeast autophagy-related gene 8 (ATG8), and recruited it to stable microtubules in a MAP1S and LC3 isoform-dependent mode. In addition, MAP1S interacted with mitochondrion-associated leucine-rich PPR-motif containing protein (LRPPRC) that interacts with the mitophagy initiator and Parkinson disease-related protein Parkin. The three-way interactions of MAP1S isoforms with LC3 and microtubules as well as the interaction of MAP1S with LRPPRC suggest that MAP1S isoforms may play positive roles in integration of autophagic components with microtubules and mitochondria in both autophagosomal biogenesis and degradation. For the first time, our results clarify roles of MAP1S in bridging microtubules and mitochondria with autophagic and mitophagic initiation, maturation, trafficking, and lysosomal clearance. Defects in the MAP1S-regulated autophagy may impact heart disease, cancers, neurodegenerative diseases, and a wide range of other diseases. PMID- 21262965 TI - The transmembrane domain of the molecular chaperone Cosmc directs its localization to the endoplasmic reticulum. AB - The molecular basis for retention of integral membrane proteins in the endoplasmic reticulum (ER) is not well understood. We recently discovered a novel ER molecular chaperone termed Cosmc, which is essential for folding and normal activity of the Golgi enzyme T-synthase. Cosmc, a type II single-pass transmembrane protein, lacks any known ER retrieval/retention motifs. To explore specific ER localization determinants in Cosmc we generated a series of Cosmc mutants along with chimeras of Cosmc with a non-ER resident type II protein, the human transferrin receptor. Here we show that the 18 amino acid transmembrane domain (TMD) of Cosmc is essential for ER localization and confers ER retention to select chimeras. Moreover, mutations of a single Cys residue within the TMD of Cosmc prevent formation of disulfide-bonded dimers of Cosmc and eliminate ER retention. These studies reveal that Cosmc has a unique ER-retention motif within its TMD and provide new insights into the molecular mechanisms by which TMDs of resident ER proteins contribute to ER localization. PMID- 21262966 TI - Tubulin tyrosine ligase-like genes ttll3 and ttll6 maintain zebrafish cilia structure and motility. AB - Tubulin post-translational modifications generate microtubule heterogeneity and modulate microtubule function, and are catalyzed by tubulin tyrosine ligase-like (TTLL) proteins. Using antibodies specific to monoglycylated, polyglycylated, and glutamylated tubulin in whole mount immunostaining of zebrafish embryos, we observed distinct, tissue-specific patterns of tubulin modifications. Tubulin modification patterns in cilia correlated with the expression of ttll3 and ttll6 in ciliated cells. Expression screening of all zebrafish tubulin tyrosine ligase like genes revealed additional tissue-specific expression of ttll1 in brain neurons, ttll4 in muscle, and ttll7 in otic placodes. Knockdown of ttll3 eliminated cilia tubulin glycylation but had surprisingly mild effects on cilia structure and motility. Similarly, knockdown of ttll6 strongly reduced cilia tubulin glutamylation but only partially affected cilia structure and motility. Combined loss of function of ttll3 and ttll6 caused near complete loss of cilia motility and induced a variety of axonemal ultrastructural defects similar to defects previously observed in zebrafish fleer mutants, which were shown to lack tubulin glutamylation. Consistently, we find that fleer mutants also lack tubulin glycylation. These results indicate that tubulin glycylation and glutamylation have overlapping functions in maintaining cilia structure and motility and that the fleer/dyf-1 TPR protein is required for both types of tubulin post translational modification. PMID- 21262967 TI - Peroxiredoxin 6 phosphorylation and subsequent phospholipase A2 activity are required for agonist-mediated activation of NADPH oxidase in mouse pulmonary microvascular endothelium and alveolar macrophages. AB - Peroxiredoxin 6 (Prdx6), a bifunctional enzyme with glutathione peroxidase and phospholipase A2 (PLA(2)) activities, participates in the activation of NADPH oxidase 2 (NOX2) in neutrophils, but the mechanism for this effect is not known. We now demonstrate that Prdx6 is required for agonist-induced NOX2 activation in pulmonary microvascular endothelial cells (PMVEC) and that the effect requires the PLA(2) activity of Prdx6. Generation of reactive oxygen species (ROS) in response to angiotensin II (Ang II) or phorbol 12-myristate 13-acetate was markedly reduced in perfused lungs and isolated PMVEC from Prdx6 null mice. Rac1 and p47(phox), cytosolic components of NOX2, translocated to the endothelial cell membrane after Ang II treatment in wild-type but not Prdx6 null PMVEC. MJ33, an inhibitor of Prdx6 PLA(2) activity, blocked agonist-induced PLA(2) activity and ROS generation in PMVEC by >80%, whereas inhibitors of other PLA(2)s were ineffective. Transfection of Prx6 null cells with wild-type and C47S mutant Prdx6, but not with mutants of the PLA(2) active site (S32A, H26A, and D140A), "rescued" Ang II-induced PLA(2) activity and ROS generation. Ang II treatment of wild-type cells resulted in phosphorylation of Prdx6 and its subsequent translocation from the cytosol to the cell membrane. Phosphorylation as well as PLA(2) activity and ROS generation were markedly reduced by the MAPK inhibitor, U0126. Thus, agonist-induced MAPK activation leads to Prdx6 phosphorylation and translocation to the cell membrane, where its PLA(2) activity facilitates assembly of the NOX2 complex and activation of the oxidase. PMID- 21262969 TI - Chemical control of FGF-2 release for promoting calvarial healing with adipose stem cells. AB - Chemical control of protein secretion using a small molecule approach provides a powerful tool to optimize tissue engineering strategies by regulating the spatial and temporal dimensions that are exposed to a specific protein. We placed fibroblast growth factor 2 (FGF-2) under conditional control of a small molecule and demonstrated greater than 50-fold regulation of FGF-2 release as well as tunability, reversibility, and functionality in vitro. We then applied conditional control of FGF-2 secretion to a cell-based, skeletal tissue engineering construct consisting of adipose stem cells (ASCs) on a biomimetic scaffold to promote bone formation in a murine critical-sized calvarial defect model. ASCs are an easily harvested and abundant source of postnatal multipotent cells and have previously been demonstrated to regenerate bone in critical-sized defects. These results suggest that chemically controlled FGF-2 secretion can significantly increase bone formation by ASCs in vivo. This study represents a novel approach toward refining protein delivery for tissue engineering applications. PMID- 21262968 TI - Molecular mechanisms of TNFR-associated factor 6 (TRAF6) utilization by the oncogenic viral mimic of CD40, latent membrane protein 1 (LMP1). AB - Latent membrane protein 1 (LMP1), encoded by Epstein-Barr virus, is required for EBV-mediated B cell transformation and plays a significant role in the development of posttransplant B cell lymphomas. LMP1 has also been implicated in exacerbation of autoimmune diseases such as systemic lupus erythematosus. LMP1 is a constitutively active functional mimic of the tumor necrosis factor receptor superfamily member CD40, utilizing tumor necrosis factor receptor-associated factor (TRAF) adaptor proteins to induce signaling. However, LMP1-mediated B cell activation is amplified and sustained compared with CD40. We have previously shown that LMP1 and CD40 use TRAFs 1, 2, 3, and 5 differently. TRAF6 is important for CD40 signaling, but the role of TRAF6 in LMP1 signaling in B cells is not clear. Although TRAF6 binds directly to CD40, TRAF6 interaction with LMP1 in B cells has not been characterized. Here we tested the hypothesis that TRAF6 is a critical regulator of LMP1 signaling in B cells, either as part of a receptor associated complex and/or as a cytoplasmic adaptor protein. Using TRAF6-deficient B cells, we determined that TRAF6 was critical for LMP1-mediated B cell activation. Although CD40-mediated TRAF6-dependent signaling does not require the TRAF6 receptor-binding domain, we found that LMP1 signaling required the presence of this domain. Furthermore, TRAF6 was recruited to the LMP1 signaling complex via the TRAF1/2/3/5 binding site within the cytoplasmic domain of LMP1. PMID- 21262970 TI - Clemastine potentiates the human P2X7 receptor by sensitizing it to lower ATP concentrations. AB - P2X7 receptors have emerged as potential drug targets for the treatment of medical conditions such as e.g. rheumatoid arthritis and neuropathic pain. To assess the impact of pharmaceuticals on P2X7, we screened a compound library comprising approved or clinically tested drugs and identified several compounds that augment the ATP-triggered P2X7 activity in a stably transfected HEK293 cell line. Of these, clemastine markedly sensitized Ca(2+) entry through P2X7 to lower ATP concentrations. Extracellularly but not intracellularly applied clemastine rapidly and reversibly augmented P2X7-mediated whole-cell currents evoked by non saturating ATP concentrations. Clemastine also accelerated the ATP-induced pore formation and Yo-Pro-1 uptake, increased the fractional NMDG(+) permeability, and stabilized the open channel conformation of P2X7. Thus, clemastine is an extracellularly binding allosteric modulator of P2X7 that sensitizes P2X7 to lower ATP concentrations and facilitates its pore dilation. The activity of clemastine on native P2X7 receptors, Ca(2+) entry, and whole-cell currents was confirmed in human monocyte-derived macrophages. Similar effects were observed in murine bone marrow-derived macrophages. Consistent with the data on recombinant P2X7, clemastine augmented the ATP-induced cation entry and Yo-Pro-1 uptake. In accordance with the observation that P2X7 controls the cytokine release from LPS primed macrophages, we found that clemastine augmented the IL-1beta release from LPS-primed human macrophages. Collectively, these data point to a sensitization of the recombinantly or natively expressed human P2X7 receptor toward its physiological activator, ATP, possibly leading to a modulation of macrophage dependent immune responses. PMID- 21262971 TI - Protein-tyrosine phosphatase DEP-1 controls receptor tyrosine kinase FLT3 signaling. AB - Fms-like tyrosine kinase 3 (FLT3) plays an important role in hematopoietic differentiation, and constitutively active FLT3 mutant proteins contribute to the development of acute myeloid leukemia. Little is known about the protein-tyrosine phosphatases (PTP) affecting the signaling activity of FLT3. To identify such PTP, myeloid cells expressing wild type FLT3 were infected with a panel of lentiviral pseudotypes carrying shRNA expression cassettes targeting different PTP. Out of 20 PTP tested, expressed in hematopoietic cells, or presumed to be involved in oncogenesis or tumor suppression, DEP-1 (PTPRJ) was identified as a PTP negatively regulating FLT3 phosphorylation and signaling. Stable 32D myeloid cell lines with strongly reduced DEP-1 levels showed site-selective hyperphosphorylation of FLT3. In particular, the sites pTyr-589, pTyr-591, and pTyr-842 involved in the FLT3 ligand (FL)-mediated activation of FLT3 were hyperphosphorylated the most. Similarly, acute depletion of DEP-1 in the human AML cell line THP-1 caused elevated FLT3 phosphorylation. Direct interaction of DEP-1 and FLT3 was demonstrated by "substrate trapping" experiments showing association of DEP-1 D1205A or C1239S mutant proteins with FLT3 by co immunoprecipitation. Moreover, activated FLT3 could be dephosphorylated by recombinant DEP-1 in vitro. Enhanced FLT3 phosphorylation in DEP-1-depleted cells was accompanied by enhanced FLT3-dependent activation of ERK and cell proliferation. Stable overexpression of DEP-1 in 32D cells and transient overexpression with FLT3 in HEK293 cells resulted in reduction of FL-mediated FLT3 signaling activity. Furthermore, FL-stimulated colony formation of 32D cells expressing FLT3 in methylcellulose was induced in response to shRNA-mediated DEP 1 knockdown. This transforming effect of DEP-1 knockdown was consistent with a moderately increased activation of STAT5 upon FL stimulation but did not translate into myeloproliferative disease formation in the 32D-C3H/HeJ mouse model. The data indicate that DEP-1 is negatively regulating FLT3 signaling activity and that its loss may contribute to but is not sufficient for leukemogenic cell transformation. PMID- 21262972 TI - Protein kinase A-mediated 14-3-3 association impedes human Dapper1 to promote dishevelled degradation. AB - Wnt signaling regulates embryo development and tissue homeostasis, and its deregulation leads to an array of diseases, including cancer. Dapper1 has been shown to be a key negative regulator of Wnt signaling. However, its function and regulation remain poorly understood. In this study, we report that 14-3-3beta interacts with human Dapper1 (hDpr1). The interaction is dependent on protein kinase A (PKA)-mediated phosphorylation of hDpr1 at Ser-237 and Ser-827. 14-3 3beta binding attenuates the ability of hDpr1 to promote Dishevelled (Dvl) degradation, thus enhancing Wnt signaling. We further provide evidence that PKA mediated Dpr1 phosphorylation may contribute to growth and tumor formation of colon cancer Caco2 cells. Finally, we show that cyclooxygenase-2 expression and PKA activation are positively correlated with Dvl protein levels in colon cancer samples. Together, our findings establish a novel layer of regulation of Wnt signaling by PKA via the 14-3-3-Dpr1-Dvl axis. PMID- 21262973 TI - Erythropoietin protects intestinal epithelial barrier function and lowers the incidence of experimental neonatal necrotizing enterocolitis. AB - The impermeant nature of the intestinal barrier is maintained by tight junctions (TJs) formed between adjacent intestinal epithelial cells. Disruption of TJs and loss of barrier function are associated with a number of gastrointestinal diseases, including neonatal necrotizing enterocolitis (NEC), the leading cause of death from gastrointestinal diseases in preterm infants. Human milk is protective against NEC, and the human milk factor erythropoietin (Epo) has been shown to protect endothelial cell-cell and blood-brain barriers. We hypothesized that Epo may also protect intestinal epithelial barriers, thereby lowering the incidence of NEC. Our data demonstrate that Epo protects enterocyte barrier function by supporting expression of the TJ protein ZO-1. As immaturity is a key factor in NEC, Epo regulation of ZO-1 in the human fetal immature H4 intestinal epithelial cell line was examined and demonstrated Epo-stimulated ZO-1 expression in a dose-dependent manner through the PI3K/Akt pathway. In a rat NEC model, oral administration of Epo lowered the incidence of NEC from 45 to 23% with statistical significance. In addition, Epo treatment protected intestinal barrier function and prevented loss of ZO-1 at the TJs in vivo. These effects were associated with elevated Akt phosphorylation in the intestine. This study reveals a novel role of Epo in the regulation of intestinal epithelial TJs and barrier function and suggests the possible use of enteral Epo as a therapeutic agent for gut diseases. PMID- 21262974 TI - Vaccinia H1-related phosphatase is a phosphatase of ErbB receptors and is down regulated in non-small cell lung cancer. AB - Vaccinia H1-related phosphatase (VHR) is classified as a dual specificity phosphatase. Unlike typical dual specificity phosphatases, VHR lacks the MAPK binding domain and shows poor activity against MAPKs. We found that EGF receptor (EGFR) was a direct substrate of VHR and that overexpression of VHR down regulated EGFR phosphorylation, particularly at Tyr-992 residue. Expression of VHR inhibited the activation of phospholipase Cgamma and protein kinase C, both downstream effectors of Tyr-992 phosphorylation of EGFR. Decreasing VHR expression by RNA interference caused higher EGFR phosphorylation at Tyr-992. In addition to EGFR, VHR also directly dephosphorylated ErbB2. Consistent with these results, suppression of VHR augmented the foci formation ability of H1299 non small cell lung cancer (NSCLC) cells, whereas overexpression of VHR suppressed cell growth in both two- and three-dimensional cultures. Expression of VHR also suppressed tumor formation in a mouse xenograft model. Furthermore, VHR expression was significantly lower in NSCLC tissues in comparison to that in normal lung tissues. Collectively, this study shows that down-regulation of VHR expression enhances the signaling of ErbB receptors and may be involved in NSCLC pathogenesis. PMID- 21262976 TI - Effects of choice white grease and soybean oil on growth performance, carcass characteristics, and carcass fat quality of growing-finishing pigs. AB - A total of 144 barrows and gilts (initial BW = 44 kg) were used in an 82-d experiment to evaluate the effects of dietary fat source and duration of feeding fat on growth performance, carcass characteristics, and carcass fat quality. Dietary treatments were a corn-soybean meal control diet with no added fat and a 2 * 4 factorial arrangement of treatments with 5% choice white grease (CWG) or soybean oil (SBO) fed from d 0 to 26, 54, 68, or 82. At the conclusion of the study (d 82), pigs were slaughtered, carcass characteristics were measured, and backfat and jowl fat samples were collected. Fatty acid analysis was performed, and iodine value (IV) was calculated for all backfat and jowl fat samples. Pigs fed SBO tended to have increased (P = 0.07) ADG compared with pigs fed CWG. For pigs fed SBO, increasing feeding duration increased (quadratic, P < 0.01) ADG and G:F. For pigs fed CWG, increasing feeding duration improved (quadratic, P < 0.01) G:F. For pigs fed SBO or CWG, increasing feeding duration increased carcass yield (quadratic, P < 0.04) and HCW (quadratic, P < 0.02). Dietary fat source and feeding duration did not affect backfat depth, loin depth, or lean percentage. As expected, barrows had greater ADG and ADFI (P < 0.01) and poorer G:F (P = 0.03) than gilts. Barrows also had greater last-rib (P = 0.04) and 10th-rib backfat (P < 0.01) and reduced loin depth and lean percentage (P < 0.01) compared with gilts. Increasing feeding duration of CWG or SBO increased (P < 0.10) C18:2n-6, PUFA, PUFA:SFA ratio, and IV in jowl fat and backfat. Pigs fed SBO had greater (P < 0.01) C18:2n-6, PUFA, PUFA:SFA ratio, and IV but decreased (P < 0.01) C18:1 cis 9, C16:0, SFA, and MUFA concentrations compared with pigs fed CWG in jowl fat and backfat. Barrows had decreased (P = 0.03) IV in jowl fat and backfat compared with gilts. In summary, adding SBO or CWG increased the amount of unsaturated fat deposited. Increasing feeding duration of dietary fat increases the amount of unsaturated fatty acids, which leads to softer carcass fat. PMID- 21262975 TI - The value of using DNA markers for beef bull selection in the seedstock sector. AB - The objective of this study was to estimate the value derived from using DNA information to increase the accuracy of beef sire selection in a closed seedstock herd. Breeding objectives for commercial production systems targeting 2 diverse markets were examined using multiple-trait selection indexes developed for the Australian cattle industry. Indexes included those for both maternal (self replacing) and terminal herds targeting either a domestic market, where steers are finished on pasture, or the export market, where steers are finished on concentrate rations in feedlots and marbling has a large value. Selection index theory was used to predict the response to conventional selection based on phenotypic performance records, and this was compared with including information from 2 hypothetical marker panels. In 1 case the marker panel explained a percentage of additive genetic variance equal to the heritability for all traits in the breeding objective and selection criteria, and in the other case to one half of this amount. Discounted gene flow methodology was used to calculate the value derived from the use of superior bulls selected using DNA test information and performance recording over that derived from conventional selection using performance recording alone. Results were ultimately calculated as discounted returns per DNA test purchased by the seedstock operator. The DNA testing using these hypothetical marker panels increased the selection response between 29 to 158%. The value of this improvement above that obtained using traditional performance recording ranged from $89 to 565 per commercial bull, and $5,332 to 27,910 per stud bull. Assuming that the entire bull calf crop was tested to achieve these gains, the value of the genetic gain derived from DNA testing ranged from $204 to 1,119 per test. All values assumed that the benefits derived from using superior bulls were efficiently transferred along the production chain to the seedstock producer incurring the costs of genotyping. These results suggest that the development of greater-accuracy DNA tests for beef cattle selection could be beneficial from an industry-wide perspective, but the commercial viability will strongly depend on price signaling throughout the production chain. PMID- 21262977 TI - Winter-feeding systems for gestating sheep I. Effects on pre- and postpartum ewe performance and lamb progeny preweaning performance. AB - Mature pregnant crossbred ewes (n = 90) were used in a randomized complete block design and assigned to 1 of 3 winter-feeding systems differing in primary feed source: haylage (HL), limit-fed corn (CN), or limit-fed dried distillers grains (DDGS). Effects of these winter-feeding strategies on ewe and lamb performance were determined. Diets were formulated to meet or exceed NRC (1985) nutrient requirements during gestation and were fed from about d 60 of gestation until parturition. All ewes were fed a common diet postpartum. Every 2 wk during gestation, BW and BCS were collected and diets were adjusted to maintain similar BW gain for ewes fed CN and DDGS vs. HL. At 80 and 122 d of gestation, jugular blood samples were collected at 0, 3, 6, and 9 h postfeeding to measure plasma glucose, insulin, NEFA, and blood urea nitrogen concentrations. At birth, 6 lambs per treatment were killed to measure body composition. At 28 +/- 2 d postpartum, milk yield was measured. Lambs were weaned at 61 +/- 4 d of age. During mid gestation (d 60 to 115), BW gain of ewes was similar among treatments; however, at d 115 of gestation ewes fed HL had a smaller (P = 0.04) BCS than ewes fed DDGS or CN. Plasma glucose concentrations were greater (P <= 0.004) in ewes fed CN than in those fed HL or DDGS just before feeding on d 80 and 122 of gestation, whereas ewes fed DDGS vs. CN or HL had greater (P <= 0.04) plasma insulin concentrations at 3 h postfeeding. At parturition, ewe BW was greatest for DDGS, least for HL, and intermediate for CN (P <= 0.003). Ewes fed CN and DDGS had greater BCS at parturition than those fed HL, but by weaning, ewes fed DDGS had greater BCS (P <= 0.05) than those fed CN or HL. Birth BW tended (P = 0.09) to be heavier for lambs from ewes fed CN and DDGS than from those fed HL prepartum, but there was no difference (P = 0.19) due to ewe gestation diet on lamb BW at weaning. At birth, lamb muscle, bone, organ, and fat measures were not affected (P > 0.13) by treatment. Ewe milk production and lamb preweaning ADG were also similar (P > 0.44) among treatments. Prepartum dam winter feed source did not have detrimental effects on pre- or postpartum ewe performance, but altered prepartum maternal nutrient supply during gestation, which affected birth weight but not preweaning growth or mortality. PMID- 21262978 TI - Winter-feeding systems for gestating sheep II. Effects on feedlot performance, glucose tolerance, and carcass composition of lamb progeny. AB - Mature pregnant crossbred ewes (n = 90) were used in a randomized complete block design experiment and were assigned to 1 of 3 winter-feeding systems differing in primary feed source: haylage (HL), limit-fed corn (CN), or limit-fed dried distillers grains (DDGS). Effects of these winter-feeding strategies on postweaning progeny performance were determined. Lamb progeny (n = 96) were weaned at 61 +/- 4 d of age and fed a common high-concentrate diet. Lambs were assigned to feedlot pen (n = 18) based on dam mid-gestation pen. Growth rate, DMI, and ADG were determined for the first 40 d of the finishing period. At 96 +/ 4 d of age, 1 wether lamb was randomly selected from each pen (n = 18) for a glucose tolerance test. The experiment was terminated, and lambs were slaughtered individually when they were determined to have achieved 0.6-cm 12th-rib fat thickness. After a 24-h chill, carcass data were collected and a 2.54-cm chop was removed from each lamb from the LM posterior to the 12th rib for ether extract analysis. Additional carcass measurements of bone, muscle, and fat from the shoulder, rack, loin, and leg were collected on 35 carcasses. At weaning, lamb BW was not different among treatments, whereas final BW tended to be greater (P = 0.09) for lambs from ewes fed DDGS and CN during gestation than from those fed HL. Overall lamb growth rate from birth to slaughter was not different among treatments. Lambs from ewes fed DDGS vs. CN or HL tended to have a greater initial insulin response (P = 0.09). Dressing percent was less (P = 0.04) in lambs from ewes fed DDGS, but no difference (P = 0.16) was detected in HCW among treatments. As expected, 12th rib fat thickness was similar among treatments, whereas LM area was largest to smallest (P = 0.05) in lambs from ewes fed CN, HL, and DDGS, respectively. Proportion of internal fat tended to be greatest to smallest (P = 0.06) in lambs from ewes fed DDGS, CN, and HL, respectively. Calculated boneless trimmed retail cuts percentage was less (P = 0.04) in lambs from ewes fed DDGS than CN or HL. Loin muscle weight as a percentage of wholesale cut tended (P = 0.10) to be greater in lambs from ewes fed CN and HL than DDGS, whereas other muscle, bone, and fat weights and proportions were similar (P > 0.24) among treatments. Prepartum diet during mid to late gestation of ewes altered postnatal fat and muscle deposition and may be associated with alterations in insulin sensitivity of progeny. PMID- 21262979 TI - Effect of dietary cation-anion difference on urinary pH, feedlot performance, nitrogen mass balance, and manure pH in open feedlot pens. AB - Six experiments were conducted to evaluate dietary cation-anion difference (DCAD) in concentrate diets on urinary pH, feedlot performance, and N mass balance. In Exp. 1, 15 wether lambs (33.5 +/- 3.0 kg) in five 3 * 3 Latin squares were fed a basal diet of 82.5% dry-rolled corn (DRC), 7.5% alfalfa hay, 5% molasses, and 5% supplement with different proportions of anionic and cationic salts. The DCAD was -45, -24, -16, -8, 0, +8, +16, +24, +32, and +40 mEq per 100 g of DM with the control basal diet (DCAD = +8) included in each square. Urinary pH increased (cubic, P < 0.01) as DCAD increased and DMI increased linearly (P < 0.01) with increasing DCAD. In Exp. 2 and 3, 8 Holstein steers (312 +/- 24 kg) were used in 2 consecutive 4 * 4 Latin squares. Steers were fed either the same basal diet as Exp. 1 or a basal diet with 20% wet distillers grains (WDGS) replacing DRC. In Exp. 2, DCAD was adjusted to -2, -12, and -22 mEq per 100 g of DM from the basal diet (DCAD = +8) and DCAD was adjusted in Exp. 3 to -12, -22, and -32 mEq per 100 g of DM from the basal WDGS diet (DCAD = -2). Urinary pH decreased linearly as DCAD decreased (P < 0.01) in both experiments, whereas DMI decreased linearly in Exp. 2 (P = 0.02) but not Exp. 3 (P = 0.96). In Exp. 4, 6 crossbred steers (373 +/- 37 kg) were used in a 2-period crossover design. Steers were fed the same basal diet as Exp. 3 with DCAD of -16 (NEG) and +20 (POS) mEq per 100 g of DM. Urinary pH and DMI (P < 0.05) were less for cattle fed the NEG diet compared with POS. In 2 experiments, steers (n = 96 each) were fed NEG or POS as calves (260 +/ 22 kg of BW) for 196 d from November to May (Exp. 5) or as yearlings (339 +/- 32 kg of BW) for 145 d from June to October (Exp. 6). Final BW, DMI, ADG, and HCW were not different (P > 0.11) among treatments in either experiment. Efficiency of BW gain was increased (P = 0.05) for steers fed NEG compared with POS in Exp. 5 but was not different (P = 0.11) in Exp. 6. Amount of N intake, retention, excretion, and manure N (kg/steer) were not different (P > 0.11) among treatments in either experiment. Manure pH (soil, feces, and urine) was decreased (P < 0.01) in pens fed NEG compared with POS in both experiments. Amount of N lost (kg/steer) was not different (P = 0.44) in Exp. 5, but tended (P = 0.09) to be 10.6% greater for POS compared with NEG in Exp. 6. Urinary pH was decreased by reducing DCAD, but this had minimal effect on N losses in open feedlot pens in these experiments. PMID- 21262980 TI - Left ventricular filling pressure assessment using left atrial transit time by cardiac magnetic resonance imaging. AB - BACKGROUND: Left atrial (LA) size and function reflect left ventricular (LV) hemodynamics. In the present study, we developed a novel method to determine LA circulation transit time (LATT) by MRI and demonstrated its close association with LV filling pressure. METHODS AND RESULTS: All subjects were prospectively recruited and underwent contrast-enhanced MR dynamic imaging. Mean LATT was determined as the time for contrast to transit through the LA during the first pass. In an invasive study group undergoing clinically indicated cardiac catheterization (n=25), LATT normalized by R-R interval (nLATT) was closely associated with LV early diastolic pressure (r=0.850, P=0.001), LV end-diastolic pressure (r=0.910, P<0.001), and mean diastolic pressure (r=0.912, P<0.001). In a larger noninvasive group (n=56), nLATT was prolonged in patients with LV systolic dysfunction (n=47) (10.1+/-3.0 versus 6.6+/-0.7 cardiac cycles in normal control subjects, n=9; P<0.001). Using a linear regression equation derived from the invasive group, noninvasive subjects were divided into 3 subgroups by estimated LV end-diastolic pressure: <=10 mm Hg, 11 to 14 mm Hg, and >=15 mm Hg. There were graded increases from low to high LV end-diastolic pressure subgroups in echocardiographic mitral medial E/e' ratio: 9+/-5, 11+/-4, and 13+/-3 (P=0.023); in B-type natriuretic peptide (interquartile range): 44 (60) pg/mL, 87 (359) pg/mL, and 371 (926) pg/mL (P=0.002); and in N-terminal pro-B-type natriuretic peptide: 57 (163) pg/mL, 208 (990) pg/mL, and 931 (1726) pg/mL (P=0.002), demonstrating the ability of nLATT to assess hemodynamic status. CONCLUSIONS: nLATT by cardiac MR is a promising new parameter of LV filling pressure that may provide graded noninvasive hemodynamic assessment. PMID- 21262981 TI - Features of disrupted plaques by coronary computed tomographic angiography: correlates with invasively proven complex lesions. AB - BACKGROUND: This study was designed as a "proof-of-concept" to establish whether coronary computed tomographic angiography (CTA) has the capability to identify morphological features of plaque disruption. METHODS AND RESULTS: In patients with unstable angina undergoing CTA and invasive coronary angiography within 30 days, quantitative CTA analysis was performed on all plaques for percent stenosis, volume, remodeling index, and volume of low-attenuation plaque (<50 Hounsfield units). Plaques with >25% stenosis were evaluated for CTA features of disruption, including ulceration and intraplaque dye penetration. Using invasive coronary angiography complex plaque as the reference standard for disruption, the sensitivity and specificity of ulceration and intraplaque dye penetration by CTA were determined. In 60 patients, 294 plaques were identified by CTA, of which 109 (37%) had features of disruption, including ulceration in 53 (18%) lesions and intraplaque dye penetration in 80 (27%). Compared with nondisrupted lesions, plaques with ulceration or intraplaque dye penetration by CTA were more voluminous (313+/-356 mm(3) versus 118+/-93 mm(3) P<0.0001), more often positively remodeled (94.5% versus 44.3%, P<0.0001), contained more low attenuation plaque (99+/-161 mm(3) versus 19+/-18 mm(3), P<0.0001), and were more often complex by ICA (57.8% versus 8.1%, P<0.0001). CTA features of disruption demonstrated modest to good sensitivity (53% to 81%) and good specificity (82% to 95%) for complex plaque by invasive coronary angiography. CONCLUSIONS: In this highly selected group of patients with unstable angina, CTA can delineate features of plaque disruption, including ulceration and intraplaque dye penetration, which are specific markers of invasively identified complex plaque. Further studies are needed to confirm the generalizability of the results and to explore the clinical and prognostic implications of these findings. PMID- 21262982 TI - New species and distribution records of Clavulina (Cantharellales, Basidiomycota) from the Guiana Shield. AB - Two new species of Clavulina Schroet. (Clavulinaceae, Cantharellales, Basidiomycota) and new distribution records for Clavulina amazonensis Corner and Clavulina sprucei (Berk.) Corner are described from the Pakaraima Mountains of Guyana, in the central Guiana Shield region. These fungi occur in rainforests dominated by ectomycorrhizal (ECM) trees of the leguminous genus Dicymbe (Fabaceae subfam. Caesalpinioideae). Macromorphological, micromorphological and habitat data are provided for each species. Nuclear ribosomal DNA sequences of the internal transcribed spacer region and 28S subunit were obtained for new species and from representative collections of C. amazonensis and C. sprucei. The two new species, Clavulina kunmudlutsa sp. nov. and Clavulina tepurumenga sp. nov., constitute important edible fungi for the Patamona Amerindians. Our specimens of C. sprucei represent the first reports of the species since 1853 as well as a range extension of nearly 1500 km, while sequence data from basidiomata as well as ECM roots suggest that this taxon consists of a cryptic species complex. PMID- 21262983 TI - Operculomyces is a new genus in the order Rhizophydiales. AB - In recent years molecular phylogenies based on analyses of rDNA sequences have advanced knowledge of the Chytridiomycota, but much alpha taxonomic work remains. We have discovered an operculate chytrid that molecular phylogenies placed in the Rhizophydiales, an order that currently contains a single operculate species, the rest having inoperculate zoospore release. Because descriptions of genera in the Chytridiomycota now rely on transmission electron microscopic features of the zoospore as well as molecular evidence we studied the zoospore ultrastructure of the isolate to confirm its placement in the Rhizophydiales and to evaluate it as a new genus. Its suite of ultrastructural characters confirmed its placement within the Rhizophydiales, and its J-shaped, multilayered spur and the position of the nonflagellate centriole at a slight angle to the kinetosome make it unique within the Rhizophydiales, thus supporting molecular evidence indicating that the isolate represents a new genus. Herein we describe zoospore ultrastructure and scanning electron and light microscopic level morphology of this monocentric, endogenous, operculate chytrid and describe it as a new genus and species, Operculomyces laminatus. PMID- 21262984 TI - Spore to spore culture of Didymium operculatum, a new Myxomycete from the Atacama Desert of Chile. AB - A new species of Didymium (Myxomycetes), D. operculatum, is described in this paper, and details of its life cycle are provided. The new species was recorded during studies of the Atacama Desert in Chile. It has been collected directly in the field and isolated in moist chamber cultures prepared with material from an endemic cactus. The distinguishing characters of this species are its dehiscence by means of an apical operculum combined with a whitish calcareous stalk and the banded reticulate ornamentation of the spores. The morphology of this new myxomycete was examined with scanning electron microscopy and light microscopy, and micrographs of relevant details are included in this paper. Some comments are made on the patterns of distribution of Didymium species in arid lands and adaptive characters enabling this genus to colonize such extreme environments. It is proposed that a longer cycle and the ability to resort to resistant forms many times during their development reflect the response of these myxomycetes to the largely unfavorable conditions of their environment. PMID- 21262985 TI - Ethanolic and aqueous extracts derived from Australian fungi inhibit cancer cell growth in vitro. AB - Fifteen Australian macrofungi were investigated for cytotoxic activity. Ethanol, cold and hot water extracts of each species were screened for cytotoxic activity against normal mouse fibroblast cells (NIH/3T3), healthy human epithelial kidney cells (HEK-293), four cancer cell lines, gastric adenocarcinoma cells (AGS), two mammary gland adenocarcinoma cells (MDA-MB-231, MCF7) and colorectal adenocarcinoma cells (HT-29) with a validated MTT assay. Most extracts derived from Omphalotus nidiformis, Cordyceps cranstounii and Cordyceps gunnii demonstrated significant cytotoxic activity toward a variety of cancer cell lines. In contrast only some extracts from Coprinus comatus, Cordyceps hawkesii, Hypholoma fasciculare, Lepista nuda, Leratiomyces ceres and Ophiocordyceps robertsii displayed significant cytotoxic activity, which was usually selective for only one or two cancer cell lines tested. The least cytotoxic species evaluated in this study were Agaricus bitorquis, Coprinopsis atrametaria, Psathyrella asperospora, Russula clelandii, Tricholoma sp. AU2 and Xerula mundroola. PMID- 21262986 TI - Hypocrea peltata: a mycological Dr Jekyll and Mr Hyde? AB - Hypocrea peltata (Pezizomycotina, Hypocreales, Hypocreaceae) is a common, widespread essentially subtropical species, with an uncharacteristically large stroma and asci containing four large and four small bicellular ascospores. Its only anamorph consists of indehiscent aleuriospores; it does not form a Trichoderma anamorph, which is typical of most Trichoderma/Hypocrea species. Hypocrea peltata grows very well at 37 C. The large stromata and failure to form a Trichoderma anamorph could lead one to doubt its generic placement. However sequences of the internal transcribed spacer region (ITS), 28S nuclear large subunit (LSU) of rDNA and RNA polymerase subunit II (rpb2) regions indicate that it represents a unique lineage within Trichoderma/Hypocrea. ITS and rbp2 sequences derived from cultures of H. peltata are identical to the "unidentified Hypocreaceae" reported in the literature as being isolated from lung of a patient with non-fatal pulmonary fibrosis. PMID- 21262987 TI - Terfezia disappears from the American truffle mycota as two new genera and Mattirolomyces species emerge. AB - Reexamination and molecular phylogenetic analyses of American Terfezia species and Mattirolomyces tiffanyae revealed that their generic assignments were wrong. Therefore we here propose these combinations: Mattirolomyces spinosus comb. nov. (= Terfezia spinosa), Stouffera longii gen. & comb. nov. (= Terfezia longii) and Temperantia tiffanyae gen. & comb. nov. (= Mattirolomyces tiffanyae). In addition we describe a new species, Mattirolomyces mexicanus spec. nov. All species belong to the Pezizaceae. Based on these results Terfezia is not known from North America, Mattirolomyces is represented by two species and two new monotypic genera are present. PMID- 21262988 TI - New records of the Cryphonectriaceae from southern Africa including Latruncellus aurorae gen. sp. nov. AB - The Cryphonectriaceae accommodates some of the world's most important tree pathogens, including four genera known from native and introduced Myrtales in Africa. Surveys in the past 3 y in southern Africa have led to the discovery of cankers with fruiting structures resembling those of the Cryphonectriaceae on trees in the Myrtales in Namibia, South Africa, Swaziland and Zambia. These fungi were identified with morphological characteristics and DNA sequence data. For the first time we report Chrysoporthe austroafricana from Namibia and on Syzygium guineense and Holocryphia eucalypti in Swaziland on a Eucalyptus grandis clone. The host and geographic ranges of Celoporthe dispersa are expanded to include S. legatti in South Africa and S. guineense in Zambia. In addition a monotypic genus, Latruncellus aurorae gen. sp. nov., is described from Galpinia transvaalica (Lythraceae, Myrtales) in Swaziland. The present and other recent studies clearly emphasize the limited understanding of the diversity and distribution of fungi in the Cryphonectriaceae in Africa. PMID- 21262989 TI - Wood decomposing abilities of diverse lignicolous fungi on nondecayed and decayed beech wood. AB - We tested the decay abilities of 28 isolates from 28 lignicolous fungal species (Basidiomycota, Ascomycota and Zygomycota) with the pure culture test. We used beech wood powder in varying moisture conditions and decay stages (nondecayed, intermediately decayed and well decayed) as substrates. The weight loss in wood powder was -0.2-17.8%. Five isolates of Basidiomycota (Bjerkandera adusta, Mycena haematopus, Omphalotus guepiniformis, Trametes hirsuta, Trametes versicolor) caused high weight losses in nondecayed wood. We detected significant effects of decay stage on weight loss in wood in most isolates tested, whereas moisture content rarely had an effect on weight loss. Among Basidiomycota and Xylariaceae in Ascomycota weight loss was greater for nondecayed wood than for intermediately and well decayed wood. In contrast four isolates in Ascomycota (Scytalidium lignicola, Trichoderma hamatum, T. harzianum, T. koningii) caused substantial weight loss in intermediately and well decayed wood, although they rarely caused weight loss in nondecayed wood. Zygomycota caused low weight loss in wood. Wood decay stages also affected decomposition of wood chemical components. Acid unhydrolyzable residue (AUR) decomposition was reduced, whereas holocellulose decomposition was stimulated by some strains of Basidiomycota and Ascomycota in well decayed wood. T. harzianum in particular caused significant weight loss of holocellulose in well decayed wood, although this fungus caused negligible weight loss of both AUR and holocellulose in nondecayed wood. We discuss these changes in the decay patterns of AUR and holocellulose with varying wood decay stages in relation to the role of fungal decomposition of woody debris in forests. PMID- 21262990 TI - Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. AB - BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in the United States and is responsible for 17% of national health expenditures. As the population ages, these costs are expected to increase substantially. METHODS AND RESULTS: To prepare for future cardiovascular care needs, the American Heart Association developed methodology to project future costs of care for hypertension, coronary heart disease, heart failure, stroke, and all other CVD from 2010 to 2030. This methodology avoided double counting of costs for patients with multiple cardiovascular conditions. By 2030, 40.5% of the US population is projected to have some form of CVD. Between 2010 and 2030, real (2008$) total direct medical costs of CVD are projected to triple, from $273 billion to $818 billion. Real indirect costs (due to lost productivity) for all CVD are estimated to increase from $172 billion in 2010 to $276 billion in 2030, an increase of 61%. CONCLUSIONS: These findings indicate CVD prevalence and costs are projected to increase substantially. Effective prevention strategies are needed if we are to limit the growing burden of CVD. PMID- 21262991 TI - CYP2C19 genotype and proton pump inhibitors in clopidogrel-treated patients: does it take two to tango? PMID- 21262992 TI - Clinical events as a function of proton pump inhibitor use, clopidogrel use, and cytochrome P450 2C19 genotype in a large nationwide cohort of acute myocardial infarction: results from the French Registry of Acute ST-Elevation and Non-ST Elevation Myocardial Infarction (FAST-MI) registry. AB - BACKGROUND: Clopidogrel requires metabolic activation by cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs. METHODS AND RESULTS: The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naive patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P=0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively. CONCLUSION: PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles. PMID- 21262993 TI - Conditional transgenic expression of fibroblast growth factor 9 in the adult mouse heart reduces heart failure mortality after myocardial infarction. AB - BACKGROUND: Fibroblast growth factor 9 (FGF9) is secreted from bone marrow cells, which have been shown to improve systolic function after myocardial infarction (MI) in a clinical trial. FGF9 promotes cardiac vascularization during embryonic development but is only weakly expressed in the adult heart. METHODS AND RESULTS: We used a tetracycline-responsive binary transgene system based on the alpha myosin heavy chain promoter to test whether conditional expression of FGF9 in the adult myocardium supports adaptation after MI. In sham-operated mice, transgenic FGF9 stimulated left ventricular hypertrophy with microvessel expansion and preserved systolic and diastolic function. After coronary artery ligation, transgenic FGF9 enhanced hypertrophy of the noninfarcted left ventricular myocardium with increased microvessel density, reduced interstitial fibrosis, attenuated fetal gene expression, and improved systolic function. Heart failure mortality after MI was markedly reduced by transgenic FGF9, whereas rupture rates were not affected. Adenoviral FGF9 gene transfer after MI similarly promoted left ventricular hypertrophy with improved systolic function and reduced heart failure mortality. Mechanistically, FGF9 stimulated proliferation and network formation of endothelial cells but induced no direct hypertrophic effects in neonatal or adult rat cardiomyocytes in vitro. FGF9-stimulated endothelial cell supernatants, however, induced cardiomyocyte hypertrophy via paracrine release of bone morphogenetic protein 6. In accord with this observation, expression of bone morphogenetic protein 6 and phosphorylation of its downstream targets SMAD1/5 were increased in the myocardium of FGF9 transgenic mice. CONCLUSIONS: Conditional expression of FGF9 promotes myocardial vascularization and hypertrophy with enhanced systolic function and reduced heart failure mortality after MI. These observations suggest a previously unrecognized therapeutic potential for FGF9 after MI. PMID- 21262994 TI - Educational initiatives for quality improvement projects: can you teach an old dog new tricks? PMID- 21262995 TI - Appropriate use criteria for stress single-photon emission computed tomography sestamibi studies: a quality improvement project. AB - BACKGROUND: We previously reported the application of the 2005 American College of Cardiology Foundation appropriate use criteria for stress single-photon emission computed tomography (SPECT) imaging to patients at Mayo Clinic (Rochester, MN) in 2005 and 2006. A subsequent internal quality improvement project focused on physician education in an attempt to reduce the rate of inappropriate SPECT studies. METHODS AND RESULTS: Our 2008 physician education effort, focused on 4 specific indications that accounted for 88% of the inappropriate SPECT studies, included a presentation at medical grand rounds, a publication in the staff newsletter, meetings with physician administrators, and focused presentations to departments/divisions with many ordering physicians. We then remeasured the appropriateness of SPECT studies using previously published methods. The general categories of study indications, eg, after revascularization, were similar in 273 SPECT patients in 2008 and in our 2005 (n=284) and 2006 (n=284) cohorts. There was a trend suggesting a change in the overall classification of appropriateness over time (P=0.08) and a significant change in the rate of inappropriate studies over time (P=0.018). Inappropriate studies decreased from 14.4% in 2005 to 7.0% in 2006 before initiation of the quality improvement project. After completion of the quality improvement project, inappropriate studies increased to 11.7% (P=0.06). The 95% confidence limits for the 4.7% increase in inappropriate studies after the quality improvement project included a decrease of 0.2% and an increase of 9.6%. CONCLUSIONS: This quality improvement project, focused on feedback, physician education, and remeasurement, did not reduce the rate of inappropriate stress SPECT studies in a single academic medical center. Similar limited interventions focused on physician education alone may have limited benefit. More extensive intervention may be necessary to improve the quality of care with appropriateness criteria. PMID- 21262996 TI - Nationwide cohort study of risk of ischemic heart disease in patients with celiac disease. AB - BACKGROUND: Studies on ischemic heart disease (IHD) incidence in individuals with celiac disease (CD) are contradictory and do not take small intestinal pathology into account. METHODS AND RESULTS: In this Swedish population-based cohort study, we examined the risk of IHD in patients with CD based on small intestinal histopathology. We defined IHD as death or incident disease in myocardial infarction or angina pectoris in Swedish national registers. In 2006 to 2008, we collected duodenal/jejunal biopsy data on CD (equal to villous atrophy; Marsh 3; n=28 190 unique individuals) and inflammation without villous atrophy (Marsh 1 to 2; n=12 598) from all 28 pathology departments in Sweden. A third cohort consisted of 3658 individuals with normal mucosa but positive CD serology (Marsh 0, latent CD). We found an increased risk of incident IHD in patients undergoing small intestinal biopsy that was independent of small intestinal histopathology (CD: hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.11 to 1.28; 991 events; inflammation: HR, 1.28; 95% CI, 1.19 to 1.39; 809 events; and latent CD: HR, 1.14; 95% CI, 0.87 to 1.50; 62 events). Celiac disease (HR, 1.22; 95% CI, 1.06 to 1.40) and inflammation (HR, 1.32; 95% CI, 1.14 to 1.52) were both associated with death resulting from IHD, whereas latent CD was not (HR, 0.71; 95% CI, 0.34 to 1.50). CONCLUSIONS: Individuals with CD or small intestinal inflammation are at increased risk of incident IHD. We were unable to show a positive association between latent CD and incident IHD. PMID- 21262997 TI - Efficacy of quantified home-based exercise and supervised exercise in patients with intermittent claudication: a randomized controlled trial. AB - BACKGROUND: This prospective, randomized, controlled clinical trial compared changes in exercise performance and daily ambulatory activity in peripheral artery disease patients with intermittent claudication after a home-based exercise program, a supervised exercise program, and usual-care control. METHODS AND RESULTS: Of the 119 patients randomized, 29 completed home-based exercise, 33 completed supervised exercise, and 30 completed usual-care control. Both exercise programs consisted of intermittent walking to nearly maximal claudication pain for 12 weeks. Patients wore a step activity monitor during each exercise session. Primary outcome measures included claudication onset time and peak walking time obtained from a treadmill exercise test; secondary outcome measures included daily ambulatory cadences measured during a 7-day monitoring period. Adherence to home-based and supervised exercise was similar (P=0.712) and exceeded 80%. Both exercise programs increased claudication onset time (P<0.001) and peak walking time (P<0.01), whereas only home-based exercise increased daily average cadence (P<0.01). No changes were seen in the control group (P>0.05). The changes in claudication onset time and peak walking time were similar between the 2 exercise groups (P>0.05), whereas the change in daily average cadence was greater with home-based exercise (P<0.05). CONCLUSIONS: A home-based exercise program, quantified with a step activity monitor, has high adherence and is efficacious in improving claudication measures similar to a standard supervised exercise program. Furthermore, home-based exercise appears more efficacious in increasing daily ambulatory activity in the community setting than supervised exercise. PMID- 21262998 TI - Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia. AB - BACKGROUND: Oxidized low-density lipoprotein reduces endothelial nitric oxide production (an important mediator of vasoregulation) and activates p38 mitogen activated protein kinase (MAPK), a mediator of vascular inflammation. Animal models of vascular stress have previously predicted improvements in vascular function after p38 MAPK inhibition. We hypothesized that a selective p38alpha/beta MAPK inhibitor (losmapimod; GW856553) would improve compromised nitric oxide-mediated vasoregulation in patients with hypercholesterolemia. METHODS AND RESULTS: Untreated hypercholesterolemic patients (low-density lipoprotein cholesterol >4.1 mmol/L) were randomized to receive losmapimod 7.5 mg (n=27) or placebo (n=29) twice daily for 28 days. Patients with known vascular disorders (eg, diabetes mellitus, coronary heart disease) were excluded. Forearm blood flow was measured by venous occlusion plethysmography in response to serial intra-arterial infusion of acetylcholine, sodium nitroprusside, and N(G) monomethyl-L-arginine (L-NMMA). Acetylcholine and L-NMMA responses were significantly impaired (P=0.01 and P=0.03) compared with responses in control subjects (n=12). In hypercholesterolemic patients treated with losmapimod, responses to acetylcholine were improved by 25% (95% confidence interval, 5 to 48; P=0.01), to sodium nitroprusside by 20% (95% confidence interval, 3 to 40; P=0.02), and to L-NMMA by 10% (95% confidence interval, -1 to 23; P=0.07) compared with placebo. C-reactive protein was reduced by 57% (95% confidence interval, -81 to -6%; P<0.05) in patients treated with losmapimod compared with placebo. CONCLUSIONS: Losmapimod improves nitric oxide-mediated vasodilatation in hypercholesterolemic patients, which is consistent with findings in previous translational animal models. These data support the hypothesis that attenuating the inflammatory milieu by inhibiting p38 MAPK activity improves NO activity. This suggests p38 MAPK as a novel target for patients with cardiovascular disease. PMID- 21262999 TI - Dexamethasone arterializes venous endothelial cells by inducing mitogen-activated protein kinase phosphatase-1: a novel antiinflammatory treatment for vein grafts? AB - BACKGROUND: Vein grafting in coronary artery surgery is complicated by a high restenosis rate resulting from the development of vascular inflammation, intimal hyperplasia, and accelerated atherosclerosis. In contrast, arterial grafts are relatively resistant to these processes. Vascular inflammation is regulated by signaling intermediaries, including p38 mitogen-activated protein (MAP) kinase, that trigger endothelial cell (EC) expression of chemokines (eg, interleukin-8, monocyte chemotactic protein-1) and other proinflammatory molecules. Here, we have tested the hypothesis that p38 MAP kinase activation in response to arterial shear stress (flow) may occur more readily in venous ECs, leading to greater proinflammatory activation. METHODS AND RESULTS: Comparative reverse transcriptase polymerase chain reaction and Western blotting revealed that arterial shear stress induced p38-dependent expression of monocyte chemotactic protein-1 and interleukin-8 in porcine jugular vein ECs. In contrast, porcine aortic ECs were protected from shear stress-induced expression of p38-dependent chemokines as a result of rapid induction of MAP kinase phosphatase-1. However, we observed with both cultured porcine jugular vein ECs and perfused veins that venous ECs can be protected by brief treatment with dexamethasone, which induced MAP kinase phosphatase-1 to suppress proinflammatory activation. CONCLUSIONS: Arterial but not venous ECs are protected from proinflammatory activation in response to short-term exposure to high shear stress by the induction of MAP kinase phosphatase-1. Dexamethasone pretreatment arterializes venous ECs by inducing MAP kinase phosphatase-1 and may protect veins from inflammation. PMID- 21263001 TI - Left atrial undifferentiated pleomorphic sarcoma causing mitral valve obstruction. PMID- 21263000 TI - Noonan syndrome gain-of-function mutations in NRAS cause zebrafish gastrulation defects. AB - Noonan syndrome is a relatively common developmental disorder that is characterized by reduced growth, wide-set eyes and congenital heart defects. Noonan syndrome is associated with dysregulation of the Ras-mitogen-activated protein-kinase (MAPK) signaling pathway. Recently, two mutations in NRAS were reported to be associated with Noonan syndrome, T50I and G60E. Here, we report a mutation in NRAS, resulting in an I24N amino acid substitution, that we identified in an individual bearing typical Noonan syndrome features. The I24N mutation activates N-Ras, resulting in enhanced downstream signaling. Expression of N-Ras-I24N, N-Ras-G60E or the strongly activating mutant N-Ras-G12V, which we included as a positive control, results in developmental defects in zebrafish embryos, demonstrating that these activating N-Ras mutants are sufficient to induce developmental disorders. The defects in zebrafish embryos are reminiscent of symptoms in individuals with Noonan syndrome and phenocopy the defects that other Noonan-syndrome-associated genes induce in zebrafish embryos. MEK inhibition completely rescued the activated N-Ras-induced phenotypes, demonstrating that these defects are mediated exclusively by Ras-MAPK signaling. In conclusion, mutations in NRAS from individuals with Noonan syndrome activated N-Ras signaling and induced developmental defects in zebrafish embryos, indicating that activating mutations in NRAS cause Noonan syndrome. PMID- 21263002 TI - Letter by Lozano et al regarding articles, "transcatheter valve-in-valve implantation for failed bioprosthetic heart valves" and "percutaneous therapy for valvular heart disease: a huge advance and a huge challenge to do it right". PMID- 21263003 TI - Letter by Bryan regarding article, "red and processed meat consumption and risk of incident coronary heart disease, stroke, and diabetes mellitus: a systematic review and meta-analysis". PMID- 21263004 TI - The perils of combination antithrombotic therapy and potential resolutions. PMID- 21263005 TI - The progression of hypertensive heart disease. PMID- 21263007 TI - Serious cardiovascular outcomes in diabetes: the role of hypoglycemia. PMID- 21263006 TI - When stable becomes unstable: the perils of impersonal medicine. PMID- 21263008 TI - Pulmonary vein stenosis due to a compressive malignant tumor detected by transesophageal echocardiography. PMID- 21263009 TI - A screen for novel phosphoinositide 3-kinase effector proteins. AB - Class I phosphoinositide 3-kinases exert important cellular effects through their two primary lipid products, phosphatidylinositol 3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P(2)). As few molecular targets for PtdIns(3,4)P(2) have yet been identified, a screen for PI 3-kinase-responsive proteins that is selective for these is described. This features a tertiary approach incorporating a unique, primary recruitment of target proteins in intact cells to membranes selectively enriched in PtdIns(3,4)P(2). A secondary purification of these proteins, optimized using tandem pleckstrin homology domain containing protein-1 (TAPP-1), an established PtdIns(3,4)P(2) selective ligand, yields a fraction enriched in proteins of potentially similar lipid binding character that are identified by liquid chromatography-tandem MS. Thirdly, this approach is coupled to stable isotope labeling with amino acids in cell culture using differential isotope labeling of cells stimulated in the absence and presence of the PI 3-kinase inhibitor wortmannin. This provides a ratio-metric readout that distinguishes authentically responsive components from copurifying background proteins. Enriched fractions thus obtained from astrocytoma cells revealed a subset of proteins that exhibited ratios indicative of their initial, cellular responsiveness to PI 3-kinase activation. The inclusion among these of tandem pleckstrin homology domain containing protein-1, three isoforms of Akt, switch associated protein-70, early endosome antigen-1 and of additional proteins expressing recognized lipid binding domains demonstrates the utility of this strategy and lends credibility to the novel candidate proteins identified. The latter encompass a broad set of proteins that include the gene product of TBC1D2A, a putative Rab guanine nucleotide triphosphatase activating protein (GAP) and IQ motif containing GAP1, a potential tumor promoter. A sequence comparison of the former protein indicates the presence of a pleckstrin homology domain whose lipid binding character remains to be established. IQ motif containing GAP1 lacks known lipid interacting components and a preliminary analysis here indicates that this may exemplify a novel class of atypical phosphoinositide (aPI) binding domain. PMID- 21263010 TI - Polymorphism of the 5-HT transporter and response to antidepressants: randomised controlled trial. AB - BACKGROUND: Antidepressants exhibit a variety of pharmacological actions including inhibition of the serotonin and noradrenaline transporters. We wished to investigate whether genetic variation could be used to target or personalise treatment, in a comparison of selective serotonin reuptake inhibitors (SSRIs) with noradrenaline reuptake inhibitors (NARIs). AIMS: To test the hypothesis that patients homozygous for the long (insertion) polymorphism of the serotonin transporter (5-HTTLPR) have an increased response to SSRI antidepressants but not to NARI antidepressants. METHOD: In an individually randomised, parallel-group controlled trial, people meeting criteria for a depressive episode who were referred by their general practitioner were randomised to receive either citalopram (an SSRI) or reboxetine (an NARI). Randomisation was by means of a remote automated system accessed by telephone. The main outcome was depressive symptoms, measured by Beck Depression Inventory (BDI) total score 6 weeks after randomisation. The trial was registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN31345163). RESULTS: Altogether 298 participants were randomised to receive citalopram and 303 were randomised to reboxetine. At 6 weeks follow-up, complete data were available for 258 participants taking citalopram and 262 taking reboxetine. We found no evidence to support an influence of 5-HTTLPR on outcome following antidepressant treatment. The interaction term for BDI score at 6 weeks was 0.50 (95% CI -2.04 to 3.03, P = 0.70), which indicated that responses to the SSRI and NARI were similar irrespective of 5-HTTLPR genotype. CONCLUSIONS: It is unlikely that the 5 HTTLPR polymorphism alone will be clinically useful in predicting response to antidepressants in people with depression. PMID- 21263011 TI - State-dependent alteration in face emotion recognition in depression. AB - BACKGROUND: Negative biases in emotional processing are well recognised in people who are currently depressed but are less well described in those with a history of depression, where such biases may contribute to vulnerability to relapse. AIMS: To compare accuracy, discrimination and bias in face emotion recognition in those with current and remitted depression. METHOD: The sample comprised a control group (n = 101), a currently depressed group (n = 30) and a remitted depression group (n = 99). Participants provided valid data after receiving a computerised face emotion recognition task following standardised assessment of diagnosis and mood symptoms. RESULTS: In the control group women were more accurate in recognising emotions than men owing to greater discrimination. Among participants with depression, those in remission correctly identified more emotions than controls owing to increased response bias, whereas those currently depressed recognised fewer emotions owing to decreased discrimination. These effects were most marked for anger, fear and sadness but there was no significant emotion * group interaction, and a similar pattern tended to be seen for happiness although not for surprise or disgust. These differences were confined to participants who were antidepressant-free, with those taking antidepressants having similar results to the control group. CONCLUSIONS: Abnormalities in face emotion recognition differ between people with current depression and those in remission. Reduced discrimination in depressed participants may reflect withdrawal from the emotions of others, whereas the increased bias in those with a history of depression could contribute to vulnerability to relapse. The normal face emotion recognition seen in those taking medication may relate to the known effects of antidepressants on emotional processing and could contribute to their ability to protect against depressive relapse. PMID- 21263013 TI - Sleep-wake cycles and cognitive functioning in schizophrenia. AB - BACKGROUND: Irregular sleep-wake cycles and cognitive impairment are frequently observed in schizophrenia, however, how they interact remains unclear. AIMS: To investigate the repercussions of circadian rhythm characteristics on cognitive performance and psychopathology in individuals with schizophrenia. METHOD: Fourteen middle-aged individuals diagnosed with schizophrenia underwent continuous wrist actimetry monitoring in real-life settings for 3 weeks, and collected saliva samples to determine the onset of endogenous melatonin secretion as a circadian phase marker. Moreover, participants underwent multiple neuropsychological testing and clinical assessments throughout the study period. RESULTS: Sleep-wake cycles in individuals with schizophrenia ranged from well entrained to highly disturbed rhythms with fragmented sleep epochs, together with delayed melatonin onsets and higher levels of daytime sleepiness. Participants with a normal rest-activity cycle (objectively determined by high relative amplitude of day/night activity) performed significantly better in frontal lobe function tasks. Stepwise regression analysis revealed that relative amplitude and age represented the best predictors for cognitive performance (Stroop colour-word interference task, Trail Making Test A and B, semantic verbal fluency task), whereas psychopathology (Positive and Negative Syndrome Scale) did not significantly correlate with either cognitive performance levels or the quality of sleep-wake cycles. CONCLUSIONS: Consolidated circadian rhythms and sleep may be a prerequisite for adequate cognitive functioning in individuals with schizophrenia. PMID- 21263012 TI - Treatment of suicidal people around the world. AB - BACKGROUND: Suicide is a leading cause of death worldwide; however, little information is available about the treatment of suicidal people, or about barriers to treatment. AIMS: To examine the receipt of mental health treatment and barriers to care among suicidal people around the world. METHOD: Twenty-one nationally representative samples worldwide (n=55 302; age 18 years and over) from the World Health Organization's World Mental Health Surveys were interviewed regarding past-year suicidal behaviour and past-year healthcare use. Suicidal respondents who had not used services in the past year were asked why they had not sought care. RESULTS: Two-fifths of the suicidal respondents had received treatment (from 17% in low-income countries to 56% in high-income countries), mostly from a general medical practitioner (22%), psychiatrist (15%) or non psychiatrist (15%). Those who had actually attempted suicide were more likely to receive care. Low perceived need was the most important reason for not seeking help (58%), followed by attitudinal barriers such as the wish to handle the problem alone (40%) and structural barriers such as financial concerns (15%). Only 7% of respondents endorsed stigma as a reason for not seeking treatment. CONCLUSIONS: Most people with suicide ideation, plans and attempts receive no treatment. This is a consistent and pervasive finding, especially in low-income countries. Improving the receipt of treatment worldwide will have to take into account culture-specific factors that may influence the process of help-seeking. PMID- 21263014 TI - Model-based evaluation of similarity in pharmacokinetics of two formulations of the blood-derived plasma product c1 esterase inhibitor. AB - A novel formulation of C1 esterase inhibitor concentrate, a plasma product used in the treatment of hereditary angioedema (HAE), was studied in a clinical trial for similarity in pharmacokinetics (PK) compared with the reference product. Direct trial data were limited given the availability of patients, and therefore a modeling approach was used to study similarity. Type I error of the study was evaluated using simulations based on retrospective data. A population PK modeling analysis was performed on data from the trial. Analysis of variance was carried out on results of a noncompartmental PK analysis (NCA) of the clinical data. Simulations showed that type I error was inflated to 62% (P < .05) when bioequivalence criteria (confidence intervals within 80%-125%) were adhered to strictly. In the clinical trial, 13 HAE patients were evaluable. The population PK analysis showed no significant differences in PK parameters, whereas confidence intervals for all parameters were within 80% to 125%. The relative differences in area under the curve, incremental recovery, and mean residence time estimated using NCA were all close to 1. The novel formulation showed similar PK characteristics to the original formulation. The model-based approach showed that strict criteria for PK comparison could not be applied in this analysis. PMID- 21263015 TI - N-acetylcysteine as a novel prophylactic treatment for ifosfamide-induced nephrotoxicity in children: translational pharmacokinetics. AB - Ifosfamide (IFO), which is used in the treatment of pediatric solid tumors, causes high rates of nephrotoxicity. N-acetylcysteine (NAC), an antidote for acetaminophen overdose, has been shown to prevent IFO-induced renal cell death and nephrotoxicity in both LLCPK-1 cells and a rat model. To facilitate the use of NAC in preventing IFO-induced nephrotoxicity in children, the authors compared the systemic exposure to NAC in children treated for acetaminophen overdose to the systemic exposure of the therapeutically effective rat model. The mean systemic exposure in the rat model was 18.72 mM.h (range, 9.92-30.02 mM.h), compared to the mean systemic exposure found in treated children (14.48 mM.h; range, 6.22-32.96 mM.h). They also report 2 pediatric cases in which NAC attenuated acute renal failure associated with IFO when given concurrently with their chemotherapy treatment. Systemic exposure to NAC measured in 1 of these cases was comparable to that in the children treated for acetaminophen overdose. These results corroborate NAC's potential to protect against IFO-induced nephrotoxicity in children when used in its clinically approved dose schedule and supports a clinical trial in children. PMID- 21263016 TI - Actin polymerization drives septation of Listeria monocytogenes namA hydrolase mutants, demonstrating host correction of a bacterial defect. AB - The Gram-positive bacterial cell wall presents a structural barrier that requires modification for protein secretion and large-molecule transport as well as for bacterial growth and cell division. The Gram-positive bacterium Listeria monocytogenes adjusts cell wall architecture to promote its survival in diverse environments that include soil and the cytosol of mammalian cells. Here we provide evidence for the enzymatic flexibility of the murein hydrolase NamA and demonstrate that bacterial septation defects associated with a loss of NamA are functionally complemented by physical forces associated with actin polymerization within the host cell cytosol. L. monocytogenes DeltanamA mutants formed long bacterial chains during exponential growth in broth culture; however, normal septation could be restored if mutant cells were cocultured with wild-type L. monocytogenes bacteria or by the addition of exogenous NamA. Surprisingly, DeltanamA mutants were not significantly attenuated for virulence in mice despite the pronounced exponential growth septation defect. The physical force of L. monocytogenes-mediated actin polymerization within the cytosol was sufficient to sever DeltanamA mutant intracellular chains and thereby enable the process of bacterial cell-to-cell spread so critical for L. monocytogenes virulence. The inhibition of actin polymerization by cytochalasin D resulted in extended intracellular bacterial chains for which septation was restored following drug removal. Thus, despite the requirement for NamA for the normal septation of exponentially growing L. monocytogenes cells, the hydrolase is essentially dispensable once L. monocytogenes gains access to the host cell cytosol. This phenomenon represents a notable example of eukaryotic host cell complementation of a bacterial defect. PMID- 21263017 TI - Lipoxin A4 inhibits porphyromonas gingivalis-induced aggregation and reactive oxygen species production by modulating neutrophil-platelet interaction and CD11b expression. AB - Porphyromonas gingivalis is an etiological agent that is strongly associated with periodontal disease, and it correlates with numerous inflammatory disorders, such as cardiovascular disease. Circulating bacteria may contribute to atherogenesis by promoting CD11b/CD18-mediated interactions between neutrophils and platelets, causing reactive oxygen species (ROS) production and aggregation. Lipoxin A4 (LXA4) is an endogenous anti-inflammatory and proresolving mediator that is protective of inflammatory disorders. The aim of this study was to investigate the effect of LXA4 on the P. gingivalis-induced activation of neutrophils and platelets and the possible involvement of Rho GTPases and CD11b/CD18 integrins. Platelet/leukocyte aggregation and ROS production was examined by lumiaggregometry and fluorescence microscopy. Integrin activity was studied by flow cytometry, detecting the surface expression of CD11b/CD18 as well as the exposure of the high-affinity integrin epitope, whereas the activation of Rac2/Cdc42 was examined using a glutathione S-transferase pulldown assay. The study shows that P. gingivalis activates Rac2 and Cdc42 and upregulates CD11b/CD18 and its high-affinity epitope on neutrophils, and that these effects are diminished by LXA4. Furthermore, we found that LXA4 significantly inhibits P. gingivalis-induced aggregation and ROS generation in whole blood. However, in platelet-depleted blood and in isolated neutrophils and platelets, LXA4 was unable to inhibit either aggregation or ROS production, respectively. In conclusion, this study suggests that LXA4 antagonizes P. gingivalis-induced cell activation in a manner that is dependent on leukocyte-platelet interaction, likely via the inhibition of Rho GTPase signaling and the downregulation of CD11b/CD18. These findings may contribute to new strategies in the prevention and treatment of periodontitis-induced inflammatory disorders, such as atherosclerosis. PMID- 21263018 TI - Dissemination of persistent intestinal bacteria via the mesenteric lymph nodes causes typhoid relapse. AB - Enteric pathogens can cause relapsing infections in a proportion of treated patients, but greater understanding of this phenomenon is hindered by the lack of appropriate animal models. We report here a robust animal model of relapsing primary typhoid that initiates after apparently successful antibiotic treatment of susceptible mice. Four days of enrofloxacin treatment were sufficient to reduce bacterial loads below detectable levels in all major organs, and mice appeared otherwise healthy. However, any interruption of further antibiotic therapy allowed renewed fecal shedding and renewed bacterial growth in systemic tissues to occur, and mice eventually succumbed to relapsing infection. In vivo imaging of luminescent Salmonella identified the mesenteric lymph nodes (MLNs) as a major reservoir of relapsing infection. A magnetic-bead enrichment strategy isolated MLN-resident CD11b(+) Gr-1(-) monocytes associated with low numbers of persistent Salmonella. However, the removal of MLNs increased the severity of typhoid relapse, demonstrating that this organ serves as a protective filter to restrain the dissemination of bacteria during antibiotic therapy. Together, these data describe a robust animal model of typhoid relapse and identify an important intestinal phagocyte subset involved in protection against the systemic spread of enteric infection. PMID- 21263019 TI - Polymicrobial infection with periodontal pathogens specifically enhances microRNA miR-146a in ApoE-/- mice during experimental periodontal disease. AB - Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia are periodontal pathogens associated with the etiology of adult periodontitis as polymicrobial infections. Recent studies demonstrated that oral infection with P. gingivalis induces both periodontal disease and atherosclerosis in hyperlipidemic and proatherogenic ApoE(-/-) mice. In this study, we explored the expression of microRNAs (miRNAs) in maxillas (periodontium) and spleens isolated from ApoE(-/-) mice infected with P. gingivalis, T. denticola, and T. forsythia as a polymicrobial infection. miRNA expression levels, including miRNA miR-146a, and associated mRNA expression levels of the inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were measured in the maxillas and spleens from mice infected with periodontal pathogens and compared to those in the maxillas and spleens from sham-infected controls. Furthermore, in response to these periodontal pathogens (as mono- and polymicrobial heat-killed and live bacteria), human THP-1 monocytes demonstrated similar miRNA expression patterns, including that of miR-146a, in vitro. Strikingly, miR-146a had a negative correlation with TNF-alpha secretion in vitro, reducing levels of the adaptor kinases IL-1 receptor-associated kinase 1 (IRAK-1) and TNF receptor associated factor 6 (TRAF6). Thus, our studies revealed a persistent association of miR-146a expression with these periodontal pathogens, suggesting that miR-146a may directly or indirectly modulate or alter the chronic periodontal pathology induced by these microorganisms. PMID- 21263020 TI - Experimental infection with Schistosoma mansoni in CCR5-deficient mice is associated with increased disease severity, as CCR5 plays a role in controlling granulomatous inflammation. AB - The plasma level of the chemokine CCL3 is elevated in patients with chronic severe schistosomiasis mansoni. We have previously shown that CCL3(-/-) mice with experimental infection showed diminished pathology and worm burden compared to those of wild-type (WT) mice. To elucidate further the role of CC chemokines during schistosomiasis mansoni infection, we evaluated the course of infection in C57BL/6J mice deficient in CCR5, one of the receptors for CCL3. The CCR5 deficiency proved to be remarkably deleterious to the host, since mortality rates reached 70% at 14 weeks postinfection in CCR5(-/-) mice and 19% in WT mice. The increased lethality was not associated with an increased parasite burden, since similar numbers of eggs and adult worms were found in mice from both groups. Liver granulomas of chronically infected CCR5(-/-) mice were larger and showed greater numbers of cells and collagen deposition than liver granulomas from WT mice. This was associated with higher levels of production of intereleukin-5 (IL 5), IL-13, CCL3, and CCL5 in infected CCR5(-/-) mice than in infected WT mice. Moreover, at 8 weeks after infection, just before changes in pathology and mortality, the numbers of FoxP3-positive cells were lower in liver granulomas of CCR5(-/-) mice than in WT mice. In conclusion, the CCR5 deletion is deleterious to mice infected with Schistosoma mansoni, and this is associated with enhanced fibrosis and granulomatous inflammation. PMID- 21263021 TI - Role of Salmonella Pathogenicity Island 1 protein IacP in Salmonella enterica serovar typhimurium pathogenesis. AB - Gram-negative bacteria, including Salmonella enterica serovar Typhimurium, exploit type III secretion systems (T3SSs) through which virulence proteins are delivered into the host cytosol to reinforce invasive and replicative niches in their host. Although many secreted effector proteins and membrane-bound structural proteins in the T3SS have been characterized, the functions of many cytoplasmic proteins still remain unknown. In this study, we found that IacP, encoded by Salmonella pathogenicity island 1, was important for nonphagocytic cell invasion and bacterial virulence. When the iacP gene was deleted from several Salmonella serovar Typhimurium strains, the invasion into INT-407 epithelial cells was significantly decreased compared to that of their parental strains, and retarded rearrangements of actin fibers were observed for the iacP mutant-infected cells. Although IacP had no effect on the secretion of type III translocon proteins, the levels of secretion of the effector proteins SopB, SopA, and SopD into the culture medium were decreased in the iacP mutant. In a mouse infection model, mice infected with the iacP mutant exhibited alleviated pathological signs in the intestine and survived longer than did wild-type infected mice. Taken together, IacP plays a key role in Salmonella virulence by regulating the translocation of T3SS effector proteins. PMID- 21263022 TI - Listeria monocytogenes infection induces prosurvival metabolic signaling in macrophages. AB - Host cells use metabolic signaling through the LXRalpha nuclear receptor to defend against Listeria monocytogenes infection. 25-Hydroxycholesterol is a natural ligand of LXRs that is produced by the enzyme cholesterol 25-hydroxylase (CH25H). We found that expression of Ch25h is upregulated following L. monocytogenes infection in a beta interferon (IFN-beta)-dependent fashion. Moreover, increased Ch25h expression promotes survival of L. monocytogenes infected cells and increases sensitivity of the host to infection. We determined that expression of Cd5l, a prosurvival gene, is controlled by CH25H. In addition, we found that CD5L inhibits activation of caspase-1, promoting survival of infected macrophages. Our results reveal a mechanism by which an intracellular pathogen can prolong survival of infected cells, thus providing itself with a protected environment in which to replicate. PMID- 21263023 TI - NOD-like receptor activation by outer membrane vesicles from Vibrio cholerae non O1 non-O139 strains is modulated by the quorum-sensing regulator HapR. AB - Vibrio cholerae is an inhabitant of aquatic systems and one of the causative agents of severe dehydrating diarrhea in humans. It has also emerged as an important cause of different kinds of inflammatory responses, and in particular, V. cholerae strains of the non-O1 non-O139 serogroups (NOVC) have been associated with such infections in human. We analyzed the potential of outer membrane vesicles (OMVs) derived from the NOVC strain V:5/04 to induce inflammatory responses in human host cells. V:5/04 OMVs were taken up by human epithelial cells and induced inflammatory responses. Small interfering RNA (siRNA)-mediated gene knockdown revealed that the inflammatory potential of NOVC OMVs was partially mediated by the nucleotide-binding domain-, leucine-rich repeat containing family member NOD1. Physiochemical analysis of the content of these OMVs, in conjunction with NOD1 and NOD2 reporter assays in HEK293T cells, confirmed the presence of both NOD1 and NOD2 active peptidoglycan in the OMVs. Furthermore, we show that deletion of the quorum-sensing regulator HapR, which mimics an infective life style, specifically reduced the inflammatory potential of the V:5/04 OMVs and their ability to activate NOD1 and NOD2. In conclusion, our study shows that NOVC OMVs elicit immune responses mediated by NOD1 and NOD2 in mammalian host cells. Moreover, we provide evidence that the quorum-sensing machinery plays an important regulatory role in this process by attenuating the inflammatory potential of OMVs under infective conditions. This work thus identifies a new facet of how Vibrio affects host immune responses and defines a role for the quorum-sensing machinery in this process. PMID- 21263024 TI - Matthew Welch: The many branches of actin regulation. Interview by Ben Short. PMID- 21263025 TI - p53 and its mutants in tumor cell migration and invasion. AB - In about half of all human cancers, the tumor suppressor p53 protein is either lost or mutated, frequently resulting in the expression of a transcriptionally inactive mutant p53 protein. Loss of p53 function is well known to influence cell cycle checkpoint controls and apoptosis. But it is now clear that p53 regulates other key stages of metastatic progression, such as cell migration and invasion. Moreover, recent data suggests that expression of mutant p53 is not the equivalent of p53 loss, and that mutant p53s can acquire new functions to drive cell migration, invasion, and metastasis, in part by interfering with p63 function. PMID- 21263026 TI - N-WASP is required for membrane wrapping and myelination by Schwann cells. AB - During peripheral nerve myelination, Schwann cells sort larger axons, ensheath them, and eventually wrap their membrane to form the myelin sheath. These processes involve extensive changes in cell shape, but the exact mechanisms involved are still unknown. Neural Wiskott-Aldrich syndrome protein (N-WASP) integrates various extracellular signals to control actin dynamics and cytoskeletal reorganization through activation of the Arp2/3 complex. By generating mice lacking N-WASP in myelinating Schwann cells, we show that N-WASP is crucial for myelination. In N-WASP-deficient nerves, Schwann cells sort and ensheath axons, but most of them fail to myelinate and arrest at the promyelinating stage. Yet, a limited number of Schwann cells form unusually short internodes, containing thin myelin sheaths, with the occasional appearance of myelin misfoldings. These data suggest that regulation of actin filament nucleation in Schwann cells by N-WASP is crucial for membrane wrapping, longitudinal extension, and myelination. PMID- 21263027 TI - Replication protein A promotes 5'-->3' end processing during homology-dependent DNA double-strand break repair. AB - Replication protein A (RPA), the eukaryotic single-strand deoxyribonucleic acid (DNA [ss-DNA])-binding protein, is involved in DNA replication, nucleotide damage repair, mismatch repair, and DNA damage checkpoint response, but its function in DNA double-strand break (DSB) repair is poorly understood. We investigated the function of RPA in homology-dependent DSB repair using Xenopus laevis nucleoplasmic extracts as a model system. We found that RPA is required for single-strand annealing, one of the homology-dependent DSB repair pathways. Furthermore, RPA promotes the generation of 3' single-strand tails (ss-tails) by stimulating both the Xenopus Werner syndrome protein (xWRN)-mediated unwinding of DNA ends and the subsequent Xenopus DNA2 (xDNA2)-mediated degradation of the 5' ss-tail. Purified xWRN, xDNA2, and RPA are sufficient to carry out the 5'-strand resection of DNA that carries a 3' ss-tail. These results provide strong biochemical evidence to link RPA to a specific DSB repair pathway and reveal a novel function of RPA in the generation of 3' ss-DNA for homology-dependent DSB repair. PMID- 21263028 TI - RNA polymerase I-specific subunits promote polymerase clustering to enhance the rRNA gene transcription cycle. AB - RNA polymerase I (Pol I) produces large ribosomal RNAs (rRNAs). In this study, we show that the Rpa49 and Rpa34 Pol I subunits, which do not have counterparts in Pol II and Pol III complexes, are functionally conserved using heterospecific complementation of the human and Schizosaccharomyces pombe orthologues in Saccharomyces cerevisiae. Deletion of RPA49 leads to the disappearance of nucleolar structure, but nucleolar assembly can be restored by decreasing ribosomal gene copy number from 190 to 25. Statistical analysis of Miller spreads in the absence of Rpa49 demonstrates a fourfold decrease in Pol I loading rate per gene and decreased contact between adjacent Pol I complexes. Therefore, the Rpa34 and Rpa49 Pol I-specific subunits are essential for nucleolar assembly and for the high polymerase loading rate associated with frequent contact between adjacent enzymes. Together our data suggest that localized rRNA production results in spatially constrained rRNA production, which is instrumental for nucleolar assembly. PMID- 21263029 TI - Bro1 binding to Snf7 regulates ESCRT-III membrane scission activity in yeast. AB - Endosomal sorting complexes required for transport (ESCRTs) promote the invagination of vesicles into the lumen of endosomes, the budding of enveloped viruses, and the separation of cells during cytokinesis. These processes share a topologically similar membrane scission event facilitated by ESCRT-III assembly at the cytosolic surface of the membrane. The Snf7 subunit of ESCRT-III in yeast binds directly to an auxiliary protein, Bro1. Like ESCRT-III, Bro1 is required for the formation of intralumenal vesicles at endosomes, but its role in membrane scission is unknown. We show that overexpression of Bro1 or its N-terminal Bro1 domain that binds Snf7 enhances the stability of ESCRT-III by inhibiting Vps4 mediated disassembly in vivo and in vitro. This stabilization effect correlates with a reduced frequency in the detachment of intralumenal vesicles as observed by electron tomography, implicating Bro1 as a regulator of ESCRT-III disassembly and membrane scission activity. PMID- 21263030 TI - Distinct ECM mechanosensing pathways regulate microtubule dynamics to control endothelial cell branching morphogenesis. AB - During angiogenesis, cytoskeletal dynamics that mediate endothelial cell branching morphogenesis during vascular guidance are thought to be regulated by physical attributes of the extracellular matrix (ECM) in a process termed mechanosensing. Here, we tested the involvement of microtubules in linking mechanosensing to endothelial cell branching morphogenesis. We used a recently developed microtubule plus end-tracking program to show that specific parameters of microtubule assembly dynamics, growth speed and growth persistence, are globally and regionally modified by, and contribute to, ECM mechanosensing. We demonstrated that engagement of compliant two-dimensional or three-dimensional ECMs induces local differences in microtubule growth speed that require myosin II contractility. Finally, we found that microtubule growth persistence is modulated by myosin II-mediated compliance mechanosensing when cells are cultured on two dimensional ECMs, whereas three-dimensional ECM engagement makes microtubule growth persistence insensitive to changes in ECM compliance. Thus, compliance and dimensionality ECM mechanosensing pathways independently regulate specific and distinct microtubule dynamics parameters in endothelial cells to guide branching morphogenesis in physically complex ECMs. PMID- 21263031 TI - Asymmetric distribution of Echinoid defines the epidermal leading edge during Drosophila dorsal closure. AB - During Drosophila melanogaster dorsal closure, lateral sheets of embryonic epidermis assemble an actomyosin cable at their leading edge and migrate dorsally over the amnioserosa, converging at the dorsal midline. We show that disappearance of the homophilic cell adhesion molecule Echinoid (Ed) from the amnioserosa just before dorsal closure eliminates homophilic interactions with the adjacent dorsal-most epidermal (DME) cells, which comprise the leading edge. The resulting planar polarized distribution of Ed in the DME cells is essential for the localized accumulation of actin regulators and for actomyosin cable formation at the leading edge and for the polarized localization of the scaffolding protein Bazooka/PAR-3. DME cells with uniform Ed fail to assemble a cable and protrude dorsally, suggesting that the cable restricts dorsal migration. The planar polarized distribution of Ed in the DME cells thus provides a spatial cue that polarizes the DME cell actin cytoskeleton, defining the epidermal leading edge and establishing its contractile properties. PMID- 21263032 TI - MGMT is a molecular determinant for potency of the DNA-EGFR-combi-molecule ZRS1. AB - To enhance the potency of current EGFR inhibitors, we developed a novel strategy that seeks to confer them an additional DNA damaging function, leading to the design of drugs termed combi-molecules. ZRS1 is a novel combi-molecule that contains an EGFR tyrosine kinase targeting quinazoline arm and a methyltriazene based DNA damaging one. We examined its effect on human tumor cell lines with varied levels of EGFR and O6-methylguanine DNA methyltransferase (MGMT). ZRS1 was more potent than the clinical methylating agent temozolomide in all cell lines, regardless of their MGMT status. However, its potency was in the same range as or less than that of Iressa, an EGFR inhibitor, against MGMT-proficient cells. In the MGMT-deficient or in MGMT-proficient cells exposed to the MGMT inhibitor O6 benzylguanine, its potency was superior to that of Iressa and temozolomide or a temozolomide+Iressa combination. Cell signaling analysis in A549 (MGMT(+)) and A427 (MGMT(-)) showed that ZRS1 strongly inhibited EGFR phosphorylation and related signaling pathways. In addition, the p53 pathway was activated by DNA damage in both cell lines, but apoptosis was significantly more pronounced in A427 cells. Using MGMT shRNA to block endogenous MGMT protein expression in A549 resulted in significant sensitization to ZRS1. Furthermore, transfection of MGMT into A427 greatly decreased the potency of ZRS1. These results conclusively show that MGMT is a critical molecular determinant for the full-blown potency of the dual EGFR-DNA targeting combi-molecule. PMID- 21263033 TI - Osteopontin-c splicing isoform contributes to ovarian cancer progression. AB - Ovarian carcinoma is one of the most aggressive gynecological diseases and generally diagnosed at advanced stages. Osteopontin (OPN) is one of the proteins overexpressed in ovarian cancer and is involved in tumorigenesis and metastasis. Alternative splicing of OPN leads to 3 isoforms, OPNa, OPNb, and OPNc. However, the expression pattern and the roles of each of these isoforms have not been previously characterized in ovarian cancer. Herein, we have evaluated the expression profiling of OPN isoforms in ovarian tumor and nontumor samples and their putative roles in ovarian cancer biology using in vitro and in vivo functional assays. OPNa and OPNb were expressed both in tumor and nontumor ovarian samples, whereas OPNc was specifically expressed in ovarian tumor samples. The isoform OPNc significantly activated OvCar-3 cell proliferation, migration, invasion, anchorage-independent growth and tumor formation in vivo. Additionally, we have also shown that some of the OPNc-dependent protumorigenic roles are mediated by PI3K/Akt signaling pathway. OPNc stimulated immortalized ovarian epithelial IOSE cell proliferation, indicating a role for this isoform in ovarian cancer tumorigenesis. Functional assays using OPNc conditioned medium and an anti-OPNc antibody have shown that most cellular effects observed herein were promoted by the secreted OPNc. According to our data, OPNc-specific expression in ovarian tumor samples and its role on favoring different aspects of ovarian cancer progression suggest that secreted OPNc contributes to the physiopathology of ovarian cancer progression and tumorigenesis. Altogether, the data open possibilities of new therapeutic approaches for ovarian cancer that selectively down regulate OPNc, altering its properties favoring ovarian tumor progression. PMID- 21263034 TI - Cortical connections of functional zones in posterior parietal cortex and frontal cortex motor regions in new world monkeys. AB - We examined the connections of posterior parietal cortex (PPC) with motor/premotor cortex (M1/PM) and other cortical areas. Electrical stimulation (500 ms trains) delivered to microelectrode sites evoked movements of reach, defense, and grasp, from distinct zones in M1/PM and PPC, in squirrel and owl monkeys. Tracer injections into M1/PM reach, defense, and grasp zones showed dense connections with M1/PM hand/forelimb representations. The densest inputs outside of frontal cortex were from PPC zones. M1 zones were additionally connected with somatosensory hand/forelimb representations in areas 3a, 3b, and 1 and the somatosensory areas of the upper bank of the lateral sulcus (S2/PV). Injections into PPC zones showed primarily local connections and the densest inputs outside of PPC originated from M1/PM zones. The PPC reach zone also received dense inputs from cortex caudal to PPC, which likely relayed visual information. In contrast, the PPC grasp zone was densely connected with the hand/forelimb representations of areas 3a, 3b, 1, and S2/PV. Thus, the dorsal parietal-frontal network involved in reaching was preferentially connected to visual cortex, whereas the more ventral network involved in grasping received somatosensory inputs. Additional weak interlinks between dissimilar zones (e.g., PPC reach and PPC grasp) were apparent and may coordinate actions. PMID- 21263035 TI - Alterations in corticolimbic dendritic morphology and emotional behavior in cannabinoid CB1 receptor-deficient mice parallel the effects of chronic stress. AB - Many changes produced by chronic stress are similar to those seen in cannabinoid CB(1) receptor-deficient mice. In the current study, we examined both anxiety like behavior and dendritic complexity within the prefrontal cortex and basolateral amygdala (BLA) in wild-type and CB(1) receptor-deficient mice, under basal conditions and following exposure to 21 days of protracted restraint stress. CB(1) receptor-deficient mice exhibited increased indices of anxiety in the elevated plus maze under basal conditions that were similar in magnitude to changes seen in wild-type mice exposed to chronic stress. Chronic stress or deletion of the CB(1) receptor also produced a reduction in both apical dendritic length and branch points of neurons within layer II/III of the prelimbic region of the prefrontal cortex. Pyramidal neurons in the (BLA) of CB(1) receptor deficient mice were found to have increased dendritic length compared with wild type. Chronic stress increased dendritic length of these amygdalar neurons in both wild-type and CB(1) receptor-deficient mice. Collectively, these data demonstrate that loss of cannabinoid CB(1) receptor signaling produces a chronic stress-like phenotype under basal conditions and provide a putative neural substrate that may subserve the changes in emotional behavior seen following disruption of CB(1) receptor signaling. PMID- 21263036 TI - Neuronal responses in visual area V2 (V2) of macaque monkeys with strabismic amblyopia. AB - Amblyopia, a developmental disorder of spatial vision, is thought to result from a cascade of cortical deficits over several processing stages beginning at the primary visual cortex (V1). However, beyond V1, little is known about how cortical development limits the visual performance of amblyopic primates. We quantitatively analyzed the monocular and binocular responses of V1 and V2 neurons in a group of strabismic monkeys exhibiting varying depths of amblyopia. Unlike in V1, the relative effectiveness of the affected eye to drive V2 neurons was drastically reduced in the amblyopic monkeys. The spatial resolution and the orientation bias of V2, but not V1, neurons were subnormal for the affected eyes. Binocular suppression was robust in both cortical areas, and the magnitude of suppression in individual monkeys was correlated with the depth of their amblyopia. These results suggest that the reduced functional connections beyond V1 and the subnormal spatial filter properties of V2 neurons might have substantially limited the sensitivity of the amblyopic eyes and that interocular suppression was likely to have played a key role in the observed alterations of V2 responses and the emergence of amblyopia. PMID- 21263037 TI - Brain structure correlates of individual differences in the acquisition and inhibition of conditioned fear. AB - Research employing aversive conditioning paradigms has elucidated the neurocircuitry involved in acquiring and diminishing fear responses. However, the factors underlying individual differences in fear acquisition and inhibition are not presently well understood. In this study, we explored whether the magnitude of individuals' acquired fear responses and the modulation of these responses via 2 fear reduction methods were correlated with structural differences in brain regions involved in affective processing. Physiological and structural magnetic resonance imaging data were obtained from experiments exploring extinction retention and intentional cognitive regulation. Our results identified 2 regions in which individual variation in brain structure correlated with subjects' fear related arousal. Confirming previous results, increased thickness in ventromedial prefrontal cortex was correlated with the degree of extinction retention. Additionally, subjects with greater thickness in the posterior insula exhibited larger conditioned responses during acquisition. The data suggest a trend toward a negative correlation between amygdala volume and fear acquisition magnitude. There was no significant correlation between fear reduction via cognitive regulation and thickness in our prefrontal regions of interest. Acquisition and regulation measures were uncorrelated, suggesting that while certain individuals may have a propensity toward increased expression of conditioned fear, these responses can be diminished via both extinction and cognitive regulation. PMID- 21263039 TI - Resolving the compartmentation and function of C4 photosynthesis in the single cell C4 species Bienertia sinuspersici. AB - Bienertia sinuspersici is a land plant known to perform C(4) photosynthesis through the location of dimorphic chloroplasts in separate cytoplasmic domains within a single photosynthetic cell. A protocol was developed with isolated protoplasts to obtain peripheral chloroplasts (P-CP), a central compartment (CC), and chloroplasts from the CC (C-CP) to study the subcellular localization of photosynthetic functions. Analyses of these preparations established intracellular compartmentation of processes to support a NAD-malic enzyme (ME) type C(4) cycle. Western-blot analyses indicated that the CC has Rubisco from the C(3) cycle, the C(4) decarboxylase NAD-ME, a mitochondrial isoform of aspartate aminotransferase, and photorespiratory markers, while the C-CP and P-CP have high levels of Rubisco and pyruvate, Pidikinase, respectively. Other enzymes for supporting a NAD-ME cycle via an aspartate-alanine shuttle, carbonic anhydrase, phosophoenolpyruvate carboxylase, alanine, and an isoform of aspartate aminotransferase are localized in the cytosol. Functional characterization by photosynthetic oxygen evolution revealed that only the C-CP have a fully operational C(3) cycle, while both chloroplast types have the capacity to photoreduce 3-phosphoglycerate. The P-CP were enriched in a putative pyruvate transporter and showed light-dependent conversion of pyruvate to phosphoenolpyruvate. There is a larger investment in chloroplasts in the central domain than in the peripheral domain (6-fold more chloroplasts and 4-fold more chlorophyll). The implications of this uneven distribution for the energetics of the C(4) and C(3) cycles are discussed. The results indicate that peripheral and central compartment chloroplasts in the single-cell C(4) species B. sinuspersici function analogous to mesophyll and bundle sheath chloroplasts of Kranz-type C(4) species. PMID- 21263038 TI - Genetic control of a transition from black to straw-white seed hull in rice domestication. AB - The genetic mechanism involved in a transition from the black-colored seed hull of the ancestral wild rice (Oryza rufipogon and Oryza nivara) to the straw-white seed hull of cultivated rice (Oryza sativa) during grain ripening remains unknown. We report that the black hull of O. rufipogon was controlled by the Black hull4 (Bh4) gene, which was fine-mapped to an 8.8-kb region on rice chromosome 4 using a cross between O. rufipogon W1943 (black hull) and O. sativa indica cv Guangluai 4 (straw-white hull). Bh4 encodes an amino acid transporter. A 22-bp deletion within exon 3 of the bh4 variant disrupted the Bh4 function, leading to the straw-white hull in cultivated rice. Transgenic study indicated that Bh4 could restore the black pigment on hulls in cv Guangluai 4 and Kasalath. Bh4 sequence alignment of all taxa with the outgroup Oryza barthii showed that the wild rice maintained comparable levels of nucleotide diversity that were about 70 times higher than those in the cultivated rice. The results from the maximum likelihood Hudson-Kreitman-Aguade test suggested that the significant reduction in nucleotide diversity in rice cultivars could be caused by artificial selection. We propose that the straw-white hull was selected as an important visual phenotype of nonshattered grains during rice domestication. PMID- 21263040 TI - The import and export business in plastids: transport processes across the inner envelope membrane. PMID- 21263041 TI - The Deaf Acculturation Scale (DAS): development and validation of a 58-item measure. AB - This study involved the development and validation of the Deaf Acculturation Scale (DAS), a new measure of cultural identity for Deaf and hard-of-hearing (hh) populations. Data for this study were collected online and involved a nation-wide sample of 3,070 deaf/hh individuals. Results indicated strong internal reliabilities for all the subscales, and construct validity was established by demonstrating that the DAS could discriminate groups based on parental hearing status, school background, and use of self-labels. Construct validity was further demonstrated through factorial analyses, and findings resulted in a final 58-item measure. Directions for future research are discussed. PMID- 21263042 TI - Pentatricopeptide repeat proteins constrain genome evolution in chloroplasts. AB - Higher plants encode hundreds of pentatricopeptide repeat proteins (PPRs) that are involved in several types of RNA processing reactions. Most PPR genes are predicted to be targeted to chloroplasts or mitochondria, and many are known to affect organellar gene expression. In some cases, RNA binding has been directly demonstrated, and the sequences of the cis-elements are known. In this work, we demonstrate that RNA cis-elements recognized by PPRs are constrained in chloroplast genome evolution. Cis-elements for two PPR genes and several RNA editing sites were analyzed for sequence changes by pairwise nucleotide substitution frequency, pairwise indel frequency, and maximum likelihood (ML) phylogenetic distances. All three of these analyses demonstrated that sequences within the cis-element are highly conserved compared with surrounding sequences. In addition, we have compared sequences around chloroplast editing sites and homologous sequences in species that lack an editing site due to the presence of a genomic T. Cis-elements for RNA editing sites are highly conserved in angiosperms; by contrast, comparable sequences around a genomically encoded T exhibit higher rates of nucleotide substitution, higher frequencies of indels, and greater ML distances. The loss in requirement for editing to create the ndhD start codon has resulted in the conversion of the PPR gene responsible for editing that site to a pseudogene. We show that organellar dependence on nuclear encoded PPR proteins for gene expression has constrained the evolution of cis elements that are required at the level of RNA processing. Thus, the expansion of the PPR gene family in plants has had a dramatic effect on the evolution of plant organelle genomes. PMID- 21263043 TI - Decreased progesterone receptor isoform expression in luteal phase fallopian tube epithelium and high-grade serous carcinoma. AB - We previously reported that BRCA1/2-mutated fallopian tube epithelium (FTE) collected during the luteal phase exhibits gene expression profiles more closely resembling that of high-grade serous carcinoma (HGSC) specimens than FTE collected during the follicular phase or from control patients. Since the luteal phase is characterised by high levels of progesterone, we determined whether the expression of progesterone receptor (PR) and PR-responsive genes was altered in FTE obtained from BRCA mutation carriers during the luteal phase of the menstrual cycle. RT-qPCR confirmed a decreased expression of PR mRNA in FTE during the luteal phase relative to follicular phase, in both BRCA1/2 mutation carriers and control patients. Immunohistochemistry using isoform-specific antibodies confirmed a low level of both PR-A and PR-B in HGSC and a lower level of staining in FTE samples obtained during the luteal phase compared with the follicular phase. No significant difference in PR-A or PR-B staining was found based on patient BRCA mutation status. Analysis of our previously reported gene expression profiles based upon known PR-A- and PR-B-specific target genes did not partition samples by BRCA mutation status, indicating that overall FTE PR response is not altered in BRCA mutation carriers. HGSC samples grouped separately from other samples, consistent with the observed loss of PR expression. These findings indicate no overall difference in PR signalling in FTE as a function of BRCA mutation status. Thus, the molecular similarity of BRCA1/2-mutated luteal phase FTE and HGSC likely results from an altered response to luteal phase factors other than progesterone. PMID- 21263044 TI - IGF1 and risk of additional breast cancer in the WHEL study. AB - IGF1, IGF-binding protein-3 (IGFBP-3), IGFBP-1, insulin, leptin, and adiponectin have been inconsistently associated with breast cancer incidence. We explore how these factors are related to breast cancer recurrence and how tamoxifen treatment is related to IGF1 levels among breast cancer survivors in the Women's Healthy Eating and Living (WHEL) study. A nested case-control design was used to match breast cancer cases (who had an additional breast cancer event) to controls. Baseline blood samples from 510 matched cases and controls were analyzed for IGF1 levels; a subset of 188 pairs were analyzed for five other hormones and binding proteins. Median follow-up was 7.3 years. Matching was on recruitment site, cancer stage, age at cancer diagnosis, dates of cancer diagnosis, and randomization. Cox proportional hazards regression models, stratified on case control pair, were used to assess the associations. Insulin, IGFBP-1, IGFBP-3, leptin, and adiponectin did not significantly predict recurrence of breast cancer. IGF1 was positively, but not significantly, associated with recurrence (hazard ratio (HR): 1.33 (95% confidence interval (CI) 0.98-1.81)) in the unadjusted analyses. Adjusting for menopausal status and tamoxifen use attenuated the HR to 1.07 (95% CI 0.76-1.40). Analyses of case-control pairs with discordant tamoxifen use show opposing HR: IGF1 predicts higher risk of recurrence if cases did not receive tamoxifen treatment. In conclusion, no significant association was found between IGF1 levels, or other related factors, and risk of additional breast cancer among breast cancer survivors. Tamoxifen can confound analysis of IGF1 and recurrence. This supports re-evaluating significance of IGF1 to breast cancer recurrence. PMID- 21263045 TI - Effect of half-life on the pharmacodynamic index of zanamivir against influenza virus delineated by a mathematical model. AB - Intravenous zanamivir is recommended for the treatment of hospitalized patients with complicated oseltamivir-resistant influenza virus infections. In a companion paper, we show that the time above the 50% effective concentration (time>EC(50)) is the pharmacodynamic (PD) index predicting the inhibition of viral replication by intravenous zanamivir. However, for other neuraminidase inhibitors, the ratio of the area under the concentration-time curve to the EC(50) (AUC/EC(50)) is the most predictive index. Our objectives are (i) to explain the dynamically linked variable of intravenous zanamivir by using different half-lives and (ii) to develop a new, mechanism-based population pharmacokinetic (PK)/PD model for the time course of viral load. We conducted dose fractionation studies in the hollow fiber infection model (HFIM) system with zanamivir against an oseltamivir resistant influenza virus. A clinical 2.5-h half-life and an artificially prolonged 8-h half-life were simulated for zanamivir. The values for the AUC from 0 to 24 h (AUC(0-24)) of zanamivir were equivalent for the two half-lives. Viral loads and zanamivir pharmacokinetics were comodeled using data from the present study and a previous dose range experiment via population PK/PD modeling in S ADAPT. Dosing every 8 h (Q8h) suppressed the viral load better than dosing Q12h or Q24h at the 2.5-h half-life, whereas all regimens suppressed viral growth similarly at the 8-h half-life. The model provided unbiased and precise individual (Bayesian) (r(2), >0.96) and population (pre-Bayesian) (r(2), >0.87) fits for log(10) viral load. Zanamivir inhibited viral release (50% inhibitory concentration [IC(50)], 0.0168 mg/liter; maximum extent of inhibition, 0.990). We identified AUC/EC(50) as the pharmacodynamic index for zanamivir at the 8-h half life, whereas time>EC(50) best predicted viral suppression at the 2.5-h half life, since the trough concentrations approached the IC(50) for the 2.5-h but not for the 8-h half-life. The model explained data at both half-lives and holds promise for optimizing clinical zanamivir dosage regimens. PMID- 21263046 TI - Zanamivir, at 600 milligrams twice daily, inhibits oseltamivir-resistant 2009 pandemic H1N1 influenza virus in an in vitro hollow-fiber infection model system. AB - In 2009, a novel H1N1 influenza A virus emerged and spread worldwide, initiating a pandemic. Various isolates obtained from disparate parts of the world were shown to be uniformly resistant to the adamantanes but sensitive to the neuraminidase inhibitors oseltamivir and zanamivir. Over time, resistance to oseltamivir became more prevalent among pandemic H1N1 virus isolates, while most remained susceptible to zanamivir. The government has proposed the use of intravenous (i.v.) zanamivir to treat serious influenza virus infections among hospitalized patients. To use zanamivir effectively for patients with severe influenza, it is necessary to know the optimal dose and schedule of administration of zanamivir that will inhibit the replication of oseltamivir sensitive and -resistant influenza viruses. Therefore, we performed studies using the in vitro hollow-fiber infection model system to predict optimal dosing regimens for zanamivir against an oseltamivir-sensitive and an oseltamivir resistant virus. Our results demonstrated that zanamivir, at a dose of 600 mg given twice a day (Q12h), inhibited the replication of oseltamivir-sensitive and oseltamivir-resistant influenza viruses throughout the course of the experiment. Thus, our findings suggest that intravenous zanamivir, at a dose of 600 mg Q12h, could be used to treat hospitalized patients suffering from serious infections with oseltamivir-sensitive or -resistant influenza viruses. PMID- 21263047 TI - Resistance and tolerance to tropodithietic acid, an antimicrobial in aquaculture, is hard to select. AB - The antibacterial compound tropodithietic acid (TDA) is produced by bacteria of the marine Roseobacter clade and is thought to explain the fish probiotic properties of some roseobacters. The aim of the present study was to determine the antibacterial spectrum of TDA and the likelihood of development of TDA resistance. A bacterial extract containing 95% TDA was effective against a range of human-pathogenic bacteria, including both Gram-negative and Gram-positive bacteria. TDA was bactericidal against Salmonella enterica serovar Typhimurium SL1344 and Staphylococcus aureus NCTC 12493 and killed both growing and nongrowing cells. Several experimental approaches were used to select mutants resistant to TDA or subpopulations of strains with enhanced tolerance to TDA. No approach (single exposures to TDA extract administered via different methods, screening of a transposon library for resistant mutants, or prolonged exposure to incremental concentrations of TDA) resulted in resistant or tolerant strains. After more than 300 generations exposed to sub-MIC and MIC concentrations of a TDA-containing extract, strains tolerant to 2* the MIC of TDA for wild-type strains were selected, but the tolerance disappeared after one passage in medium without TDA extract. S. Typhimurium mutants with nonfunctional efflux pump and porin genes had the same TDA susceptibility as wild-type strains, suggesting that efflux pumps and porins are not involved in innate tolerance to TDA. TDA is a promising broad-spectrum antimicrobial in part due to the fact that enhanced tolerance is difficult to gain and that the TDA-tolerant phenotype appears to confer only low-level resistance and is very unstable. PMID- 21263048 TI - Emergence of linezolid-resistant Staphylococcus aureus after prolonged treatment of cystic fibrosis patients in Cleveland, Ohio. AB - Linezolid (LZD)-resistant Staphylococcus aureus (LRSA) isolates were monitored from 2000 to 2009 in Cleveland, OH. LRSA first emerged in 2004 only in cystic fibrosis (CF) patients, with 11 LRSA-infected CF patients being identified by 2009. LRSA was isolated from 8 of 77 CF patients with S. aureus respiratory tract infection treated with LZD from 2000 to 2006. Analysis of clinical data showed that the 8 CF patients with LRSA received more LZD courses (18.8 versus 5.9; P = 0.001) for a longer duration (546.5 versus 211.9 days; P < 0.001) and had extended periods of exposure to LZD (83.1 versus 30.1 days/year; P < 0.001) than the 69 with LZD-susceptible isolates. Five LRSA isolates included in the clinical analysis (2000 to 2006) and three collected in 2009 were available for molecular studies. Genotyping by repetitive extrapalindromic PCR and pulsed-field gel electrophoresis revealed that seven of these eight LRSA strains from unique patients were genetically similar. By multilocus sequence typing, all LRSA isolates were included in clonal complex 5 (seven of sequence type 5 [ST5] and one of ST1788, a new single-locus variant of ST5). However, seven different variants were identified by spa typing. According to the Escherichia coli numbering system, seven LRSA isolates contained a G2576T mutation (G2603T, S. aureus numbering) in one to four of the five copies of domain V of the 23S rRNA genes. One strain also contained a mutation (C2461T, E. coli numbering) not previously reported. Two strains, including one without domain V mutations, possessed single amino acid substitutions (Gly152Asp or Gly139Arg) in the ribosomal protein L3 of the peptidyltransferase center, substitutions not previously reported in clinical isolates. Emergence of LRSA is a serious concern for CF patients who undergo prolonged courses of LZD therapy. PMID- 21263049 TI - Mutational analysis of the thienamycin biosynthetic gene cluster from Streptomyces cattleya. AB - The generation of non-thienamycin-producing mutants with mutations in the thnL, thnN, thnO, and thnI genes within the thn gene cluster from Streptomyces cattleya and their involvement in thienamycin biosynthesis and regulation were previously reported. Four additional mutations were independently generated in the thnP, thnG, thnR, and thnT genes by insertional inactivation. Only the first two genes were found to play a role in thienamycin biosynthesis, since these mutations negatively or positively affect antibiotic production. A mutation of thnP results in the absence of thienamycin production, whereas a 2- to 3-fold increase in thienamycin production was observed for the thnG mutant. On the other hand, mutations in thnR and thnT showed that although these genes were previously reported to participate in this pathway, they seem to be nonessential for thienamycin biosynthesis, as thienamycin production was not affected in these mutants. High-performance liquid chromatography (HPLC)-mass spectrometry (MS) analysis of all available mutants revealed some putative intermediates in the thienamycin biosynthetic pathway. A compound with a mass corresponding to carbapenam-3-carboxylic acid was detected in some of the mutants, suggesting that the assembly of the bicyclic nucleus of thienamycin might proceed in a way analogous to that of the simplest natural carbapenem, 1-carbapen-2-em-3 carboxylic acid biosynthesis. The accumulation of a compound with a mass corresponding to 2,3-dihydrothienamycin in the thnG mutant suggests that it might be the last intermediate in the biosynthetic pathway. These data, together with the establishment of cross-feeding relationships by the cosynthesis analysis of the non-thienamycin-producing mutants, lead to a proposal for some enzymatic steps during thienamycin assembly. PMID- 21263050 TI - In vitro susceptibility of Madurella mycetomatis to posaconazole and terbinafine. AB - Presently, therapy of eumycetoma in Sudan is still based on surgery combined with prolonged ketoconazole therapy. This usually results in a poor clinical outcome. To determine if posaconazole and terbinafine could offer better therapeutic alternatives, the in vitro susceptibilities of 34 Madurella mycetomatis strains were determined. It appeared that posaconazole was highly active against M. mycetomatis but terbinafine was only moderately active. Since posaconazole has an excellent safety profile, it might provide an important alternative in mycetoma therapy. PMID- 21263051 TI - Comparison of the antibacterial properties of phage endolysins SAL-1 and LysK. AB - In spite of the high degree of amino acid sequence similarity between the newly discovered phage endolysin SAL-1 and the phage endolysin LysK, SAL-1 has an approximately 2-fold-lower MIC against several Staphylococcus aureus strains and higher bacterial cell-wall-hydrolyzing activity than LysK. The amino acid residue change contributing the most to this enhanced enzymatic activity is a change from glutamic acid to glutamine at the 114th residue. PMID- 21263052 TI - Penetration of topically administered 0.5-percent caspofungin eye drops into human aqueous humor. AB - Ten participants attending elective anterior segment eye surgery received 0.5% caspofungin eye drops either 1 drop hourly for 4 h or 1 drop an hour before surgery. The eye drops were generally well tolerated. In the absence of inflammation or corneal abrasion, topical caspofungin does not achieve clinically relevant concentrations. PMID- 21263053 TI - Antimicrobial susceptibilities and molecular epidemiology of clinical isolates of Clostridium difficile in taiwan. AB - The antimicrobial susceptibility and virulence factors of Clostridium difficile clinical isolates in Taiwan have not previously been reported. One hundred and thirteen isolates were collected from two major teaching hospitals in Taiwan from 2001 to 2009. Molecular typing was performed by an automated repetitive extragenic palindromic sequence-based PCR (rep-PCR) method (DiversiLab; Bacterial Barcodes, Inc., Athens, GA) and PCR ribotyping. Detection of tcdA, tcdB, cdtA, and cdtB genes was performed using a multiplex PCR assay, and gyrA and gyrB genes of moxifloxacin-nonsusceptible isolates were sequenced. All isolates were susceptible to vancomycin and metronidazole. Ninety-five (84%) isolates were susceptible to moxifloxacin, and the MIC(90) for nemonoxacin was 4 MUg/ml. Tigecycline showed favorable antibacterial activity (MIC(90) of 0.06 MUg/ml). Thirteen rep-PCR types were identified as a predominant rep-PCR type (type A; non North American pulsed-field gel electrophoresis type 1 [NAP1], -NAP7, or -NAP8) accounting for 52.2% (59 isolates). Nine of 18 moxifloxacin-nonsusceptible isolates belonged to the rep-PCR type A. The rep-PCR type A and C isolates were distinct from NAP1 (ribotype 027) and NAP8 (ribotype 078) as determined by PCR ribotyping. Seventy-four (65%) isolates harbored tcdA and tcdB, and 15 (13%) harbored cdtAB encoding binary toxin. Eleven isolates had a gene deletion in tcdC, including a 39-bp deletion (9 isolates) and an 18-bp deletion (2). In conclusion, dissemination of a predominant C. difficile clone in southern and northern Taiwan was noted. However, no NAP1 (ribotype 027) isolate could be discovered in this study. PMID- 21263054 TI - Pharmacodynamics of razupenem (PZ601) studied in an in vitro pharmacokinetic model of infection. AB - Simulations of administration of razupenem at 1 g every 12 h by 1-h intravenous (i.v.) infusion were performed in an in vitro pharmacokinetic model of infection. The antibacterial effect of this razupenem dosing regimen against six strains of Staphylococcus aureus (one methicillin-sensitive S. aureus [MSSA] strain [MIC, 0.015 MUg/ml] and five methicillin-resistant S. aureus [MRSA] strains [MIC range, 0.09 to 3 MUg/ml]) and five strains of Enterobacteriaceae (three Escherichia coli strains [two containing extended-spectrum beta-lactamases {ESBLs}] and two Enterobacter sp. strains [one with an AmpC enzyme and the other with a raised razupenem MIC; MIC range, 0.09 to 6 MUg/ml]) was assessed. Against the MSSA and MRSA strains, razupenem produced a >3.5-log-unit reduction in viable count after 24 h. There were no changes in population profiles. In a second series of experiments, over 5 days there was rapid initial clearance of MRSA from the model followed by regrowth after 48 h. MRSA colonies appeared on 2* MIC recovery medium after 72 h with strain 33820 (MIC, 3.0 MUg/ml) and at 120 h with strain 27706 (MIC, 1.5 MUg/ml). Against E. coli and Enterobacter spp., razupenem produced a >3.5-log-unit reduction in bacterial counts for all strains except that with an MIC of 6 MUg/ml, where razupenem had a notably poorer antibacterial effect. Population profiles were unchanged after 48 h of exposure to razupenem except for Enterobacter strain 34425 (MIC, 6.0 MUg/ml), where colonies were recovered from media containing 2*, 4*, and 8* MIC. In dose-ranging studies with MRSA strains, the percentage of the dosing interval that the free drug concentration remained higher than the pathogen MIC (fT>MIC) for a 24-h bacteriostatic effect was 5.0% +/- 1.4%, and that for a 1-log-unit reduction in count was 12.5% +/- 5.8%. Population profiles indicated growth on 2* MIC recovery medium at fT>MIC values of 1 to 35% but not at a value of >35%. In a similar set of experiments with Enterobacteriaceae, the fT>MIC for a 24-h bacteriostatic effect was 34.2% +/- 7.6% and that for a 1-log-unit reduction in count was 42.5% +/- 7.8%. Population analysis profiles indicated growth on recovery media with 2*, 4*, and 8* MIC at fT>MICs in the range of 1 to 69% but rarely at values of >= 70%. In conclusion, razupenem at simulated human doses of 1 g i.v. every 12 h has a marked antibacterial effect on MSSA and MRSA strains with MICs of <= 3.0 MUg/ml and Enterobacteriaceae with MICs of <= 0.4 MUg/ml. fT>MIC targets of >= 35% for MRSA and >= 70% for Enterobacteriaceae should provide significant antibacterial effects combined with low risks of changing pathogen antibiotic population profiles. PMID- 21263055 TI - Heterogeneity of Tn5253-like composite elements in clinical Streptococcus pneumoniae isolates. AB - Several drug resistances in Streptococcus pneumoniae are associated with mobile genetic elements, which are loosely subdivided into a group of smaller (18- to 27 kb) and a group of larger (>50-kb) elements. While the elements of the former group, which typically carry the tetracycline resistance determinant tet(M) and whose prototype is Tn916 (18 kb), have been studied extensively, the larger elements, whose prototype is Tn5253 (~65.5 kb), are not as well explored. Tn5253 is a composite structure consisting of two independent conjugative transposons, Tn5251 (which is virtually identical to Tn916) and Tn5252 (~47.5 kb), with the former inserted into the latter. Tn5252, which so far has only partially been sequenced, carries an integrase gene, driving its site-specific insertion into the host cell genome, and the chloramphenicol resistance cat(pC194) determinant. This study investigated 20 clinical isolates of S. pneumoniae, which were selected on the basis of cat(pC194)-mediated chloramphenicol resistance. All 20 isolates harbored a Tn5253-like element. The composite elements (some of which have been completely sequenced) demonstrated considerable heterogeneity that stemmed from a dual variability: in the Tn5252-like element, due primarily to differences in the integrase gene but also to differences in cargo genes and in the overall genetic organization, and in the Tn916-like element, with the possible involvement, besides Tn916, of a number of Tn916 family pneumococcal elements carrying different erythromycin resistance genes. In mating experiments, only one composite element, containing a less typical Tn916 family element, appeared to be nonmobile. Being part of a Tn5253-like composite element may confer on some Tn916-like transposons, which are apparently nontransferable as independent genetic elements, the ability to be mobilized. PMID- 21263056 TI - Antibiotics cure anthrax in animal models. AB - Respiratory anthrax, in the absence of early antibiotic treatment, is a fatal disease. This study aimed to test the efficiency of antibiotic therapy in curing infected animals and those sick with anthrax. Postexposure prophylaxis (24 h postinfection [p.i.]) of guinea pigs infected intranasally with Bacillus anthracis Vollum spores with doxycycline, ofloxacin, imipenem, and gentamicin conferred protection. However, upon termination of treatment, the animals died from respiratory anthrax. Combined treatment with antibiotics and active vaccination with a protective antigen-based vaccine leads to full protection even after cessation of treatment. Delaying the initiation of antibiotic administration to over 24 h p.i. resulted in treatment of animals with anthrax exhibiting various degrees of bacteremia and toxemia. Treatment with doxycycline or ciprofloxacin cured sick guinea pigs and rabbits exhibiting bacteremia levels up to 10(5) CFU/ml. Addition of anti-protective antigen (PA) antibodies augmented the efficiency of protection, allowing the cure of guinea pigs and rabbits with 10- to 20-fold-higher bacteremia levels, up to 7 * 10(5) CFU/ml and 2 * 10(6) CFU/ml, respectively. Treatment with ciprofloxacin and a monoclonal anti-PA antibody rescued rabbits with bacteremia levels up to 4 * 10(6) CFU/ml. During antibiotic administration, all surviving animals developed a protective immune response against development of a fatal disease and subcutaneous challenge with Vollum spores. In conclusion, these results demonstrate that antibiotic treatment can prevent the development of fatal disease in respiratory-anthrax-infected animals and can cure animals after disease establishment. A therapeutic time window of 40 h to 48 h from infection to initiation of efficient antibiotic mediated cure was observed. PMID- 21263057 TI - Combination therapy of murine mucormycosis or aspergillosis with iron chelation, polyenes, and echinocandins. AB - Liposomal amphotericin B (LAmB) combined wither either micafungin or deferasirox was synergistic in previous murine studies with mucormycosis or aspergillosis. We hypothesized that triple therapy using LAmB, micafungin, and deferasirox could further improve outcomes of mucormycosis or aspergillosis. Triple therapy improved survival and reduced tissue fungal burden of mice with mucormycosis and to a lesser extent with aspergillosis. Continued investigation into the use of triple therapy against mucormycosis and aspergillosis is warranted. PMID- 21263058 TI - Efficacy of fentanyl and/or lidocaine on total antioxidants and total oxidants during craniotomy. AB - OBJECTIVE: The aim of this study was to investigate the oxidative, hemodynamic, and analgesic effects of local lidocaine infiltration, or intravenous (IV) fentanyl injection, or a combination of lidocaine and IV fentanyl during head fixation in a 3-pin headrest in patients undergoing elective craniotomy. DESIGN: Double-blind, randomized, placebo-controlled study. SETTING: Gaziantep University Medical Faculty, Department of Anesthesiology and Reanimation. METHODS: Eighty patients were randomly assigned to one of four groups. Five minutes before pin fixation, patients in group L received 1 mg/kg of lidocaine 2% for scalp infiltration (n=20), group F received 1 MUg/kg of IV fentanyl (n=20), group FL received 1 mg/kg of lidocaine 2% and 1 MUg/kg of fentanyl (n=20), and group P received a placebo (n=20). Following standard anesthesia, basal, pre- and post fixational hemodynamic data were recorded. Blood samples were taken for evaluation of oxidant and antioxidant levels before and after pin fixation. RESULTS: The total antioxidant levels after pin fixation were highest in group FL followed by group F, then group L and finally group P (ie, FL>F>L>P) (P<0.05). The mean arterial blood pressure (MAP) after pin fixation was higher than the MAP before pin fixation in groups L and P (P<0.05), but was lower in groups F and FL (P<0.05). CONCLUSION: The combination of fentanyl and lidocaine before pin fixation is useful in preventing severe hemodynamic response to pain stimuli, such as pin fixation, and in increasing total antioxidant levels in the post fixational period during craniotomy in adults. PMID- 21263059 TI - Blood type, hormone receptor status, HER2/neu status, and survival in breast cancer: a retrospective study exploring relationships in a phenotypically well defined cohort. AB - PURPOSE: Altered glycosylation has been associated with oncogenic potential. Relationships of blood types (where expression is due to glycosylation pattern) and HER2/neu (where expression arises due to altered glycosylation) and breast cancer-associated markers like estrogen receptor/progesterone receptor (ER/PR) were examined and related to outcomes in patients with breast cancer. METHODS: A population-based retrospective study of 426 surgical breast cancer patients examined relationships between (1) patient characteristics, (2) breast tumor characteristics, and (3) outcomes of women diagnosed at the same medical center over a 10-year period relative to specific molecules defined by glycosylation patterns (eg. blood group, HER2/neu) and (4) ER/PR status. RESULTS: Following stratification by blood group, subjects exhibited significant differences in tumor size with persons in blood groups A and B having greater numbers of tumors <= 2 cm and those with blood types AB and O having tumors >2 cm. After adjusting for age, disease stage, and treatment with trastuzumab, tamoxifen, or aromatase inhibitors, no significant differences were observed in 5-year overall and disease-free survival based on blood type grouping. Blood group B was over represented among the breast cancer cohort compared to the reference population, while blood group AB was under-represented. CONCLUSION: No significant differences were observed in overall and disease-free survival based on blood group. No correlation was noted between HER2/neu, ER or PR status, and blood group type. Among this cohort, HER2/neu positivity was less than 20% and correlated with a 5-year disease-free survival rate >= 75% and overall survival of >80% across all blood groups. PMID- 21263060 TI - Swallow syncope: a case report and review of the literature. AB - Swallow or deglutition syncope is a relatively rare syndrome. It is a vagally mediated syncope induced by swallowing. Swallow syncope may occur in all age groups and, when diagnosed, is treatable. A woman, aged 60 years, presented with an episode of a syncopal attack associated with swallowing a sandwich. She had a 6-month history of recurrent episodes of lightheadedness while eating solid foods. Telemetry monitoring demonstrated several episodes of severe bradycardia and complete atrioventricular block with up to a 7.0 second pause associated with meals. Computed tomography of the head and neck revealed no significant findings, and barium esophagram was normal. Echocardiogram was within normal limits. Her symptoms resolved after permanent pacemaker placement. Herein, we review the diagnosis, mechanism, and management of swallow syncope. PMID- 21263061 TI - Reduced maladaptive behavior and improved social function in a child with PDD-NOS treated with progesterone. AB - This case report presents the use of progesterone for the regulation of an atypical menstrual cycle in a girl, aged 11 years, who is also diagnosed with Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS). The progesterone injections alleviated the prolonged, heavy monthly blood flow, but also caused significant improvements in the patient's mood, behavior, and cognition within four weeks following the initial injections. The use of hormonal treatments, such as progesterone, to effect mood, behavior, and cognition should be further researched to determine other potential therapeutic uses. PMID- 21263062 TI - Does the portrayal of tanning in Australian women's magazines relate to real women's tanning beliefs and behavior? AB - Content analysis data on the tans of 4,422 female Caucasian models sampled from spring and summer magazine issues were combined with readership data to generate indices of potential exposure to social modeling of tanning via popular women's magazines over a 15-year period (1987 to 2002). Associations between these indices and cross-sectional telephone survey data from the same period on 5,675 female teenagers' and adults' tanning attitudes, beliefs, and behavior were examined using logistic regression models. Among young women, greater exposure to tanning in young women's magazines was associated with increased likelihood of endorsing pro-tan attitudes and beliefs. Among women of all ages, greater exposure to tanned models via the most popular women's magazines was associated with increased likelihood of attempting to get a tan but lower likelihood of endorsing pro-tan attitudes. Popular women's magazines may promote and reflect real women's tanning beliefs and behavior. PMID- 21263064 TI - Expression of patients' and providers' identities during the medical interview. AB - We apply the Communication Theory of Identity to investigate how patients display their ethnic identities during intercultural patient-provider interactions. Ethnic identity displays play a large part in reflecting patients' and providers' assumptions about the other, as well as their communicative needs. We collected paper-and-pencil responses from a convenience sample of providers and their patients, and conducted a constant comparative analysis of their open-ended reports of a recent intercultural medical interview. The results revealed how both parties viewed their roles in intercultural medical encounters and how they looked for accommodative behaviors from the other party. We draw implications for new applications and future developments of the Communication Theory of Identity and Communication Accommodation Theory. PMID- 21263063 TI - Appalachian residents' experiences with and management of multiple morbidity. AB - Approximately three fourths of middle-aged and older adults have at least two simultaneously occurring chronic conditions ("multiple morbidity," or MM), a trend expected to increase dramatically throughout the world. Rural residents, who tend to have fewer personal and health resources, are more likely to experience MM. To improve our understanding of the ways in which vulnerable, rural residents in the United States experience and manage MM, we interviewed 20 rural Appalachian residents with MM. We identified the following themes: (a) MM has multifaceted challenges and is viewed as more than the sum of its parts; (b) numerous challenges exist to optimal MM self-management, particularly in a rural, underresourced context; however, (c) participants described strategic methods of managing MM, including prioritizing certain conditions and management strategies and drawing heavily on assistance from informal and formal sources. PMID- 21263065 TI - Being me and being us in a family living close to death at home. AB - We used interpretive description to describe how everyday life close to death was experienced and dealt with in families with one member who had a life-threatening illness. We performed 28 individual, couple, and group interviews with five families. We found two patterns, namely, "being me in a family living close to death" and "being us in a family living close to death." "Being me" meant that every individual in the family had to deal with the impending death, regardless of whether or not he or she was the person with the life-threatening illness. This was linked to ways of promoting the individual's self-image, or "me-ness." This pattern was present at the same time as the pattern of "being us," or in other words, being a family, and dealing with impending death and a new "we-ness" as a group. "Striving for the optimal way of living close to death" was the core theme. PMID- 21263066 TI - 'Who is Helsinki?' Sex workers advise improving communication for good participatory practice in clinical trials. AB - After premature closures in 2004 of biomedical human immunodeficiency virus (HIV) prevention trials involving sex workers in Africa and Asia, the Joint United Nations Programme on HIV/AIDS (UNAIDS) and Global Advocacy for HIV Prevention (AVAC) undertook consultations to establish better participatory guidelines for such trials in order to address ethical concerns. This study investigated sex workers' knowledge and beliefs about research ethics and good participatory practices (GPP) and the perspectives of sex workers on research participation. A 33-question survey based on criteria identified by UNAIDS and AVAC was translated into three other languages. Participants were recruited through mailing lists and contacts with existing sex work networks. In total, 74 responses from Europe, the Americas and Asia were received. Thirty percent of respondents reported first hand involvement in biomedical HIV prevention trials. Seventy percent indicated a lack of familiarity with codes of ethics for research. This paper focuses exclusively on communication issues described in survey responses. Communication was an important theme: the absence of clear communication between trial participants and investigators contributed to premature trial closures in at least two sites. Sex workers had recommendations for how researchers might implement GPP through improved communication, including consultation at the outset of planning, explaining procedures in non-technical terms and establishing clear channels for feedback from participants. PMID- 21263067 TI - Host APCs augment in vivo expansion of donor natural regulatory T cells via B7H1/B7.1 in allogeneic recipients. AB - Foxp3(+) regulatory T (Treg) cells include thymic-derived natural Treg and conventional T-derived adaptive Treg cells. Both are proposed to play important roles in downregulating inflammatory immune responses. However, the mechanisms of Treg expansion in inflammatory environments remain unclear. In this study, we report that, in an autoimmune-like graft-versus-host disease model of DBA/2 (H 2(d)) donor to BALB/c (H-2(d)) recipients, donor Treg cells in the recipients predominantly originated from expansion of natural Treg cells and few originated from adaptive Treg cells. In vivo neutralization of IFN-gamma resulted in a marked reduction of donor natural Treg expansion and exacerbation of graft-versus host disease, which was associated with downregulation of host APC expression of B7H1. Furthermore, host APC expression of B7H1 was shown to augment donor Treg survival and expansion. Finally, donor Treg interactions with host APCs via B7.1/B7H1 but not PD-1/B7H1 were demonstrated to be critical in augmenting donor Treg survival and expansion. These studies have revealed a new immune regulation loop consisting of T cell-derived IFN-gamma, B7H1 expression by APCs, and B7.1 expression by Treg cells. PMID- 21263068 TI - Fascin1 promotes cell migration of mature dendritic cells. AB - Dendritic cells (DCs) play central roles in innate and adaptive immunity. Upon maturation, DCs assemble numerous veil-like membrane protrusions, disassemble podosomes, and travel from the peripheral tissues to lymph nodes to present Ags to T cells. These alterations in morphology and motility are closely linked to the primary function of DCs, Ag presentation. However, it is unclear how and what cytoskeletal proteins control maturation-associated alterations, in particular, the change in cell migration. Fascin1, an actin-bundling protein, is specifically and greatly induced upon maturation, suggesting a unique role for fascin1 in mature DCs. To determine the physiological roles of fascin1, we characterized bone marrow-derived, mature DCs from fascin1 knockout mice. We found that fascin1 is critical for cell migration: fascin1-null DCs exhibit severely decreased membrane protrusive activity. Importantly, fascin1-null DCs have lower chemotactic activity toward CCL19 (a chemokine for mature DCs) in vitro, and in vivo, Langerhans cells show reduced emigration into draining lymph nodes. Morphologically, fascin1-null mature DCs are flatter and fail to disassemble podosomes, a specialized structure for cell-matrix adhesion. Expression of exogenous fascin1 in fascin1-null DCs rescues the defects in membrane protrusive activity, as well as in podosome disassembly. These results indicate that fascin1 positively regulates migration of mature DCs into lymph nodes, most likely by increasing dynamics of membrane protrusions, as well as by disassembling podosomes. PMID- 21263069 TI - Activation receptor-induced tolerance of mature NK cells in vivo requires signaling through the receptor and is reversible. AB - NK cell responses are determined by signals received through activating and inhibitory cell surface receptors. Ly49H is an NK cell-specific activating receptor that accounts for the genetic resistance to murine CMV (MCMV). The Ly49H receptor has been shown to interact with two adaptor proteins (DAP12 and DAP10). In the context of MCMV infection, interaction of m157 (the MCMV-encoded ligand for Ly49H) with Ly49H results in activation of Ly49H-expressing NK cells. Chronic exposure of Ly49H with m157, however, induces tolerance in these same cells. The mechanism of this tolerance remains poorly understood. Using a transgenic mouse model, we demonstrate that induction of tolerance in Ly49H(+) NK cells by chronic exposure to m157, in vivo, requires signaling through the Ly49H adaptor protein DAP12, but not the DAP10 adaptor protein. Furthermore, mature Ly49H-expressing NK cells from wild-type mice can acquire a tolerant phenotype by 24 h posttransfer into a transgenic C57BL/6 mouse that expresses m157. The tolerant phenotype can be reversed, in vivo, if tolerant NK cells are transferred to mice that do not express the m157 protein. Thus, continuous activating receptor engagement can induce a transient tolerance in mature NK cells in vivo. These observations provide new insight into how activating receptor engagement shapes NK cell function and has important implications in how NK cells respond to tumors and during chronic viral infection. PMID- 21263070 TI - Cross-talk between programmed death-1 and suppressor of cytokine signaling-1 in inhibition of IL-12 production by monocytes/macrophages in hepatitis C virus infection. AB - Hepatitis C virus (HCV) dysregulates innate immune responses and induces persistent viral infection. We previously demonstrated that HCV core protein impairs IL-12 expression by monocytes/macrophages (M/M(Phi)s) through interaction with a complement receptor gC1qR. Because HCV core-mediated lymphocyte dysregulation occurs through the negative immunomodulators programmed death-1 (PD 1) and suppressor of cytokine signaling-1 (SOCS-1), the aim of this study was to examine their role in HCV core-mediated IL-12 suppression in M/M(Phi)s. We analyzed TLR-stimulated, primary CD14(+) M/M(Phi)s from chronically HCV-infected and healthy subjects or the THP-1 cell line for PD-1, SOCS-1, and IL-12 expression following HCV core treatment. M/M(Phi)s from HCV-infected subjects at baseline exhibited comparatively increased PD-1 expression that significantly correlated with the degree of IL-12 inhibition. M/M(Phi)s isolated from healthy and HCV-infected individuals and treated with HCV core protein displayed increased PD-1 and SOCS-1 expression and decreased IL-12 expression, an effect that was also observed in cells treated with gC1qR's ligand, C1q. Blocking gC1qR rescued HCV core-induced PD-1 upregulation and IL-12 suppression, whereas blocking PD-1 signaling enhanced IL-12 production and decreased the expression of SOCS-1 induced by HCV core. Conversely, silencing SOCS-1 expression using small interfering RNAs increased IL-12 expression and inhibited PD-1 upregulation. PD-1 and SOCS-1 were found to associate by coimmunoprecipitation studies, and blocking PD-1 or silencing SOCS-1 in M/M(Phi) led to activation of STAT-1 during TLR stimulated IL-12 production. These data suggested that HCV core/gC1qR engagement on M/M(Phi)s triggers the expression of PD-1 and SOCS-1, which can associate to deliver negative signaling to TLR-mediated pathways controlling expression of IL 12, a key cytokine linking innate and adaptive immunity. PMID- 21263071 TI - Dysregulation of TIM-3-galectin-9 pathway in the cystic fibrosis airways. AB - The T-cell Ig and mucin domain-containing molecules (TIMs) have emerged as promising therapeutic targets to correct abnormal immune function in several autoimmune and chronic inflammatory conditions. It has been reported that proinflammatory cytokine dysregulation and neutrophil-dominated inflammation are the main causes of morbidity in cystic fibrosis (CF). However, the role of TIM receptors in CF has not been investigated. In this study, we demonstrated that TIM-3 is constitutively overexpressed in the human CF airway, suggesting a link between CF transmembrane conductance regulator (CFTR) function and TIM-3 expression. Blockade of CFTR function with the CFTR inhibitor-172 induced an upregulation of TIM-3 and its ligand galectin-9 in normal bronchial epithelial cells. We also established that TIM-3 serves as a functional receptor in bronchial epithelial cells, and physiologically relevant concentrations of galectin-9 induced TIM-3 phosphorylation, resulting in increased IL-8 production. In addition, we have demonstrated that both TIM-3 and galectin-9 undergo rapid proteolytic degradation in the CF lung, primarily because of neutrophil elastase and proteinase-3 activity. Our results suggest a novel intrinsic defect that may contribute to the neutrophil-dominated immune response in the CF airways. PMID- 21263073 TI - IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. AB - Programmed cell death-1 (PD-1) is an inhibitory coreceptor for T lymphocytes that provides feedback inhibition of T cell activation. Although PD-1's expression on T cells is known to be activation dependent, the factors that determine the timing, intensity, and duration of PD-1 expression in immune reactions are not fully understood. To address this question, we performed a fine mapping analysis of a conserved 5'-flanking region of the PD-1 gene and identified a putative IFN stimulation response element, which was responsible for PD-1 transcription in the 2B4.11 T cell line. Consistent with this finding, activation by IFN-alpha enhanced both the induction and maintenance of PD-1 expression on TCR-engaged primary mouse T cells through an association IFN-responsive factor 9 (IRF9) to the IFN stimulation response element. Furthermore, PD-1 expression on Ag-specific CD8(+) T cells was augmented by IFN-alpha in vivo. We propose that strong innate inflammatory responses promote primary T cell activation and their differentiation into effector cells, but also cause an attenuated T cell response in sustained immune reactions, at least partially through type I IFN-mediated PD 1 transcription. Based on this idea, we demonstrate that IFN-alpha administration in combination with PD-1 blockade in tumor-bearing mice effectively augments the antitumor immunity, and we propose this as a novel and rational approach for cancer immunotherapy. PMID- 21263072 TI - Distinct functions for the glycans of tapasin and heavy chains in the assembly of MHC class I molecules. AB - Complexes of specific assembly factors and generic endoplasmic reticulum (ER) chaperones, collectively called the MHC class I peptide-loading complex (PLC), function in the folding and assembly of MHC class I molecules. The glycan-binding chaperone calreticulin (CRT) and partner oxidoreductase ERp57 are important in MHC class I assembly, but the sequence of assembly events and specific interactions involved remain incompletely understood. We show that the recruitments of CRT and ERp57 to the PLC are codependent and also dependent upon the ERp57 binding site and the glycan of the assembly factor tapasin. Furthermore, the ERp57 binding site and the glycan of tapasin enhance beta(2)m and MHC class I heavy (H) chain recruitment to the PLC, with the ERp57 binding site having the dominant effect. In contrast, the conserved MHC class I H chain glycan played a minor role in CRT recruitment into the PLC, but impacted the recruitment of H chains into the PLC, and glycan-deficient H chains were impaired for tapasin-independent and tapasin-assisted assembly. The conserved MHC class I glycan and tapasin facilitated an early step in the assembly of H chain-beta(2)m heterodimers, for which tapasin-ERp57 or tapasin-CRT complexes were not required. Together, these studies provide insights into how PLCs are constructed, demonstrate two distinct mechanisms by which PLCs can be stabilized, and suggest the presence of intermediate H chain-deficient PLCs. PMID- 21263074 TI - HIV replication in CD4+ T lymphocytes in the presence and absence of follicular dendritic cells: inhibition of replication mediated by alpha-1-antitrypsin through altered IkappaBalpha ubiquitination. AB - Follicular dendritic cells (FDCs) increase HIV replication and virus production in lymphocytes by increasing the activation of NF-kappaB in infected cells. Because alpha-1-antitrypsin (AAT) decreases HIV replication in PBMCs and monocytic cells and decreases NF-kappaB activity, we postulated that AAT might also block FDC-mediated HIV replication. Primary CD4(+) T cells were infected with HIV and cultured with FDCs or their supernatant with or without AAT, and ensuing viral RNA and p24 production were monitored. NF-kappaB activation in the infected cells was also assessed. Virus production was increased in the presence of FDC supernatant, but the addition of AAT at concentrations >0.5 mg/ml inhibited virus replication. AAT blocked the nuclear translocation of NF-kappaB p50/p65 despite an unexpected elevation in associated phosphorylated and ubiquitinated IkappaBalpha (Ub-IkappaBalpha). In the presence of AAT, degradation of cytoplasmic IkappaBalpha was dramatically inhibited compared with control cultures. AAT did not inhibit the proteasome; however, it altered the pattern of ubiquitination of IkappaBalpha. AAT decreased IkappaBalpha polyubiquitination linked through ubiquitin lysine residue 48 and increased ubiquitination linked through lysine residue 63. Moreover, lysine reside 63-linked Ub-IkappaBalpha degradation was substantially slower than lysine residue 48-linked Ub IkappaBalpha in the presence of AAT, correlating altered ubiquitination with a prolonged IkappaBalpha t(1/2). Because AAT is naturally occurring and available clinically, examination of its use as an inhibitory agent in HIV-infected subjects may be informative and lead to the development of similar agents that inhibit HIV replication using a novel mechanism. PMID- 21263075 TI - Distinct different contributions of the alternative and classical complement activation pathway for the innate host response during sepsis. AB - Complement activation represents a crucial innate defense mechanism to invading microorganisms, but there is an eminent lack of understanding of the separate contribution of the different complement activation pathways to the host response during sepsis. We therefore investigated different innate host immune responses during cecal ligation and puncture (CLP)-induced sepsis in mice lacking either the alternative (fD(-/-)) or classical (C1q(-/-)) complement activation pathway. Both knockout mice strains showed a significantly reduced survival and increased organ dysfunction when compared with control mice. Surprisingly, fD(-/-) mice demonstrated a compensated bacterial clearance capacity as control mice at 6 h post CLP, whereas C1q(-/-) mice were already overwhelmed by bacterial growth at this time point. Interestingly, at 24 h after CLP, fD(-/-) mice failed to clear bacteria in a way comparable to control mice. However, both knockout mice strains showed compromised C3 cleavage during sepsis. Investigating potential causes for this discrepancy, we were able to demonstrate that despite normal bacterial clearance capacity early during the onset of sepsis, fD(-/-) mice displayed increased inflammatory cytokine generation and neutrophil recruitment into lungs and blood when compared with both control- and C1q(-/-) mice, indicating a potential loss of control over these immune responses. Further in vitro experiments revealed a strongly increased Nf-kappaB activation capacity in isolated neutrophils from fD(-/-) mice, supporting this hypothesis. Our results provide evidence for the new concept that the alternative complement activation pathway exerts a distinctly different contribution to the innate host response during sepsis when compared with the classical pathway. PMID- 21263076 TI - Time to disseminate cognitive behavioral treatment of insomnia: comment on "Efficacy of brief behavioral treatment for chronic insomnia in older adults". PMID- 21263077 TI - Electronic health records and clinical decision support systems: impact on national ambulatory care quality. AB - BACKGROUND: Electronic health records (EHRs) are increasingly used by US outpatient physicians. They could improve clinical care via clinical decision support (CDS) and electronic guideline-based reminders and alerts. Using nationally representative data, we tested the hypothesis that a higher quality of care would be associated with EHRs and CDS. METHODS: We analyzed physician survey data on 255,402 ambulatory patient visits in nonfederal offices and hospitals from the 2005-2007 National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey. Based on 20 previously developed quality indicators, we assessed the relationship of EHRs and CDS to the provision of guideline-concordant care using multivariable logistic regression. RESULTS: Electronic health records were used in 30% of an estimated 1.1 billion annual US patient visits. Clinical decision support was present in 57% of these EHR visits (17% of all visits). The use of EHRs and CDS was more likely in the West and in multiphysician settings than in solo practices. In only 1 of 20 indicators was quality greater in EHR visits than in non-EHR visits (diet counseling in high risk adults, adjusted odds ratio, 1.65; 95% confidence interval, 1.21-2.26). Among the EHR visits, only 1 of 20 quality indicators showed significantly better performance in visits with CDS compared with EHR visits without CDS (lack of routine electrocardiographic ordering in low-risk patients, adjusted odds ratio, 2.88; 95% confidence interval, 1.69-4.90). There were no other significant quality differences. CONCLUSIONS: Our findings indicate no consistent association between EHRs and CDS and better quality. These results raise concerns about the ability of health information technology to fundamentally alter outpatient care quality. PMID- 21263079 TI - Clinical decision support and rich clinical repositories: a symbiotic relationship: comment on "Electronic health records and clinical decision support systems". PMID- 21263078 TI - Efficacy of brief behavioral treatment for chronic insomnia in older adults. AB - BACKGROUND: Chronic insomnia is a common health problem with substantial consequences in older adults. Cognitive behavioral treatments are efficacious but not widely available. The aim of this study was to test the efficacy of brief behavioral treatment for insomnia (BBTI) vs an information control (IC) condition. METHODS: A total of 79 older adults (mean age, 71.7 years; 54 women [70%]) with chronic insomnia and common comorbidities were recruited from the community and 1 primary care clinic. Participants were randomly assigned to either BBTI, consisting of individualized behavioral instructions delivered in 2 intervention sessions and 2 telephone calls, or IC, consisting of printed educational material. Both interventions were delivered by a nurse clinician. The primary outcome was categorically defined treatment response at 4 weeks, based on sleep questionnaires and diaries. Secondary outcomes included self-report symptom and health measures, sleep diaries, actigraphy, and polysomnography. RESULTS: Categorically defined response (67% [n = 26] vs 25% [n = 10]; chi(2) = 13.8) (P < .001) and the proportion of participants without insomnia (55% [n = 21] vs 13% [n = 5]; chi(2) = 15.5) (P < .001) were significantly higher for BBTI than for IC. The number needed to treat was 2.4 for each outcome. No differential effects were found for subgroups according to hypnotic or antidepressant use, sleep apnea, or recruitment source. The BBTI produced significantly better outcomes in self reported sleep and health (group * time interaction, F(5,73) = 5.99, P < .001), sleep diary (F(8,70) = 4.32, P < .001), and actigraphy (F(4,74) = 17.72, P < .001), but not polysomnography. Improvements were maintained at 6 months. CONCLUSION: We found that BBTI is a simple, efficacious, and durable intervention for chronic insomnia in older adults that has potential for dissemination across medical settings. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00177203. PMID- 21263080 TI - Translating weight loss and physical activity programs into the community to preserve mobility in older, obese adults in poor cardiovascular health. AB - BACKGROUND: Limitations in mobility are common among older adults with cardiovascular and cardiometabolic disorders and have profound effects on health and well-being. With the growing population of older adults in the United States, effective and scalable public health approaches are needed to address this problem. Our goal was to determine the effects of a physical activity and weight loss intervention on 18-month change in mobility among overweight or obese older adults in poor cardiovascular health. METHODS: The study design was a translational, randomized controlled trial of physical activity (PA) and weight loss (WL) on mobility in overweight or obese older adults with cardiovascular disease (CVD) or at risk for CVD. The study was conducted within the community infrastructure of Cooperative Extension Centers. Participants were randomized to 1 of 3 interventions: PA, WL + PA, or a successful aging (SA) education control arm. The primary outcome was time to complete a 400-m walk in seconds (400MWT). RESULTS: A significant treatment effect (P = .002) and follow-up testing revealed that the WL + PA group improved their 400MWT (adjusted mean [SE], 323.3 [3.7] seconds) compared with both PA (336.3 [3.9] seconds; P = .02) and SA (341.3 [3.9] seconds; P < .001). Participants with poorer mobility at baseline benefited the most (P < .001). CONCLUSION: Existing community infrastructures can be effective in delivering lifestyle interventions to enhance mobility in older adults in poor cardiovascular health with deficits in mobility; attention should be given to intervening on both weight and sedentary behavior since weight loss is critical to long-term improvement in mobility. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00119795. PMID- 21263081 TI - Pre- and post-transplantation risk factors for delirium onset and severity in patients undergoing hematopoietic stem-cell transplantation. AB - PURPOSE: To determine pre- and post-transplantation risk factors for delirium onset and severity during the acute phase of myeloablative hematopoietic stem cell transplantation (HSCT). PATIENTS AND METHODS: Ninety adult patients with malignancies admitted to the Fred Hutchinson Cancer Research Center for their first HSCT were assessed prospectively from 1 week before transplantation to 30 days after transplantation. Delirium was assessed three times per week using the Delirium Rating Scale and the Memorial Delirium Assessment Scale. Potential risk factors were assessed by patient self-report, charts, and computerized records. Multivariable analysis of time to onset of a delirium episode was undertaken using Cox proportional hazards regression with time-varying covariates. Analysis for delirium severity was carried out using a linear mixed effects model. Validation and sensitivity analyses were performed on the final models. RESULTS: Forty-five patients (50%) experienced a delirium episode. Pretransplantation risk factors for onset and higher severity of delirium were higher mean alkaline phosphatase and blood urea nitrogen (BUN) levels. Poorer pretransplantation executive functioning was also associated with higher delirium severity. Higher doses of opioid medications were the only post-transplantation risk factor for delirium onset (hazard ratio, 1.05; 95% CI, 1.02 to 1.08). Higher opioid doses, current and prior pain, and higher BUN levels were post-transplantation risk factors for greater delirium severity (all P < .01). CONCLUSION: Pre- and post transplantation factors can assist in identifying patients who are at risk for delirium during myeloablative HSCT and may enable clinical interventions to prevent delirium onset or decrease delirium symptoms. PMID- 21263082 TI - Influence of gynecologic oncologists on the survival of patients with endometrial cancer. AB - PURPOSE: Despite a lack of evidence for survival benefit, the American College of Obstetrics and Gynecology has recommendations for referral to gynecologic oncologists for the treatment of endometrial cancer. Therefore, we propose to determine the influence of gynecologic oncologists on the treatment and survival of patients with endometrial cancer. PATIENTS AND METHODS: Data were obtained from Medicare and Surveillance, Epidemiology, and End Results (SEER) databases from 1988 to 2005. Kaplan-Meier and Cox proportional hazard methods were used for analyses. RESULTS: Of 18,338 women, 21.4% received care from gynecologic oncologists (group A) while 78.6% were treated by others (group B). Women in group A were older (age > 71 years: 49.6% v 44%; P < .001), had more lymph nodes (> 16) removed (22% v 17%; P < .001), presented with more advanced (stages III to IV) cancers (21.9% v 14.6%; P < .001), had higher-grade tumors (P < .001), and were more likely to receive chemotherapy for advanced disease (22.6% v 12.4%; P < .001). In those with stages II to IV disease, the 5-year disease-specific survival (DSS) of group A was 79% versus 73% in group B (P = .001). Moreover, in advanced-stage (III to IV) disease, group A had 5-year DSS of 72% versus 64% in group B (P < .001). However, no association with DSS was identified in stage I cancers. On multivariable analysis, younger age, early stage, lower grade, and treatment by gynecologic oncologists were independent prognostic factors for improved survival. CONCLUSION: Patients with endometrial cancer treated by gynecologic oncologists were more likely to undergo staging surgery and receive adjuvant chemotherapy for advanced disease. Care provided by gynecologic oncologists improved the survival of those with high-risk cancers. PMID- 21263083 TI - Should oncologists be aware in their clinical practice of KRAS molecular analysis? PMID- 21263084 TI - NUT midline carcinoma in a young woman. PMID- 21263085 TI - More questions about the European Organisation for Research and Treatment of Cancer 22881-10882 boost trial. PMID- 21263086 TI - American society of clinical oncology statement: toward individualized care for patients with advanced cancer. AB - Patients with advanced incurable cancer face complex physical, psychological, social, and spiritual consequences of disease and its treatment. Care for these patients should include an individualized assessment of the patient's needs, goals, and preferences throughout the course of illness. Consideration of disease directed therapy, symptom management, and attention to quality of life are important aspects of quality cancer care. However, emerging evidence suggests that, too often, realistic conversations about prognosis, the potential benefits and limitations of disease-directed therapy, and the potential role of palliative care, either in conjunction with or as an alternative to disease-directed therapy, occur late in the course of illness or not at all. This article addresses the American Society of Clinical Oncology's (ASCO's) vision for improved communication with and decision making for patients with advanced cancer. This statement advocates an individualized approach to discussing and providing disease-directed and supportive care options for patients with advanced cancer throughout the continuum of care. Building on ASCO's prior statements on end-of-life care (1998) and palliative care (2009), this article reviews the evidence for improved patient care in advanced cancer when patients' individual goals and preferences for care are discussed. It outlines the goals for individualized care, barriers that currently limit realization of this vision, and possible strategies to overcome these barriers that can improve care consistent with the goals of our patients and evidence-based medical practice. PMID- 21263087 TI - High survival rate after two-stage resection of advanced colorectal liver metastases: response-based selection and complete resection define outcome. AB - PURPOSE: Prolonged survival after two-stage resection (TSR) of advanced colorectal liver metastases (CLM) may be the result of selection of best responders to chemotherapy. The impact of complete resection in this well selected group is controversial. PATIENTS AND METHODS: Data on 890 patients undergoing resection and 879 patients who received only chemotherapy for CLM were collected prospectively. We used intent-to-treat analysis to evaluate the survival of patients who underwent TSR. Additionally, we evaluated a cohort of nonsurgically treated patients selected to mirror the TSR population: colorectal metastases with liver-only disease, objective response to chemotherapy, and alive 1 year after chemotherapy initiation. RESULTS: Sixty-five patients underwent the first stage of TSR; 62 patients fulfilled the inclusion criteria for the medical group. TSR patients had a mean of 6.7 +/- 3.4 CLM with mean size of 4.5 +/- 3.1 cm. Nonsurgical patients had a mean of 5.9 +/- 2.9 CLM with mean size of 5.4 +/- 3.4 cm (not significant). Forty-seven TSR patients (72%) completed the second stage. Progression between stages was the main cause of noncompletion of the second stage (61%). After 50 months median follow-up, the 5-year survival rate was 51% in the TSR group and 15% in the medical group (P = .005). In patients who underwent TSR, noncompletion of TSR and major postoperative complications were independently associated with worse survival. CONCLUSION: TSR is associated with excellent outcome in patients with advanced CLM as a result of both selection by chemotherapy and complete resection of metastatic disease. PMID- 21263088 TI - Fulminant acneiform eruptions after administration of dovitinib in a patient with renal cell carcinoma. PMID- 21263089 TI - Future directions in the treatment of neuroendocrine tumors: consensus report of the National Cancer Institute Neuroendocrine Tumor clinical trials planning meeting. AB - Neuroendocrine tumors (NETs) arise from a variety of anatomic sites and share the capacity for production of hormones and vasoactive peptides. Because of their perceived rarity, NETs have not historically been a focus of rigorous clinical research. However, the diagnosed incidence of NETs has been increasing, and the estimated prevalence in the United States exceeds 100,000 individuals. The recent completion of several phase III studies, including those evaluating octreotide, sunitinib, and everolimus, has demonstrated that rigorous evaluation of novel agents in this disease is both feasible and can lead to practice-changing outcomes. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trials planning meeting to identify key unmet needs, develop appropriate study end points, standardize clinical trial inclusion criteria, and formulate priorities for future NET studies for the US cooperative group program. Emphasis was placed on the development of well-designed clinical trials with clearly defined efficacy criteria. Key recommendations include the evaluation of pancreatic NET separately from NETs of other sites and the exclusion of patients with poorly differentiated histologies from trials focused on low-grade histologies. Studies evaluating novel agents for the control of hormonal syndromes should avoid somatostatin analog washout periods when possible and should include quality-of-life end points. Because of the observed long survival after progression of many patients, progression-free survival is recommended as a feasible and relevant primary end point for both phase III studies and phase II studies where a delay in progression is expected in the absence of radiologic responses. PMID- 21263090 TI - Response of lymphangioleiomyomatosis to a mammalian target of rapamycin inhibitor (temsirolimus) -based treatment. PMID- 21263091 TI - Complete histologic response induced by sorafenib in advanced hepatocellular carcinoma: a case report. PMID- 21263092 TI - Treatment of low-risk gestational trophoblastic neoplasia. PMID- 21263093 TI - Successful radical treatment of midline carcinoma with t(15;19) diagnosed by endobronchial ultrasound-derived transbronchial needle aspiration. PMID- 21263094 TI - Palliative cancer care: an epidemiologic study. AB - PURPOSE: To analyze the need for palliative care in hospital patients who have cancer. Palliative care is an essential component of comprehensive cancer care and identification of palliative care needs (PCNs) of patients with cancer is a topic that has not been thoroughly studied. PATIENTS AND METHODS: Data were collected prospectively from inpatients of University Medical Center Freiburg in Freiburg, Germany, with 982 hospital beds included in the study. During the observation period of 17 months, each patient discharged from a hospital ward was screened by surveying the treating physician who was responsible for dismissal about patients' PCNs based on the WHO 1990 definition of palliative care. To complete obligatory electronic discharge management, a modified dismissal form asking to classify the patient as having PCN "yes/no" had to be filled out for each patient discharged. RESULTS: The response rate was 96% with data for 39,849 patients that could be analyzed. A total of 6.9% of all hospital patients and 9.1% of patients older than age 65 years were considered to have PCNs. Of the 2,757 patients with PCNs, 67% (n = 1,836) had cancer. Among the 11,584 patients with cancer, 15.8% were classified as having PCNs. PCNs were particularly high in patients with head and neck cancer (28.3%), malignant melanoma (26.0%), and brain tumors (18.2%). Suffering from cancer increases the probability of developing PCNs by a factor of 3.63 (95% CI, 3.27 to 4.04). For patients with metastatic cancer, the risk of developing PCNs is increased 12-fold (odds ratio, 12.27; 95% CI, 11.07 to 13.60). CONCLUSION: Structures to provide palliative care for patients with cancer are needed. PMID- 21263095 TI - Preoperative chemoradiotherapy using concurrent capecitabine and irinotecan in magnetic resonance imaging-defined locally advanced rectal cancer: impact on long term clinical outcomes. AB - PURPOSE: To assess long-term clinical outcomes of preoperative chemoradiotherapy of magnetic resonance imaging (MRI)-defined locally advanced rectal adenocarcinoma using concurrent irinotecan and capecitabine. PATIENTS AND METHODS: One hundred ten patients without distant metastases entered this phase II trial North West/North Wales Clinical Oncology Group (NWCOG) -2 after MRI demonstration of tumor threatening (<= 2 mm) or involving mesorectal fascia. Pelvic radiotherapy was given to 45 Gy in 25 fractions over 5 weeks with concurrent oral capecitabine at 650 mg/m(2) twice per day continuously days 1 through 35 and intravenous irinotecan at 60 mg/m(2) once weekly weeks 1 to 4. One hundred seven patients subsequently underwent surgical resection. RESULTS: Comparing prechemoradiotherapy MRI scans with histology of the resected specimen, 72 patients (67%) had their initial MRI T stage downstaged and 64 patients (80%) had their N stage downstaged. Twenty-four patients (22%) demonstrated a pathologic complete response (ypCR) and 98 patients (92%) demonstrated a negative circumferential resection margin (> 1 mm). Three-year local recurrence-free survival was 96.9%, metastasis-free survival (MFS) was 71.1%, disease-free survival was (DFS) 63.5%, and overall survival (OS) was 88.2%. By univariate analysis, lower histologic stage was significantly associated with superior MFS, DFS, and OS, whether expressed as ypT0-2 versus ypT3-4, ypN0 versus ypN1-2, or ypCR/microfoci (near-ypCR) versus other patients. By multivariate analysis both ypN stage (P = .048) and ypCR/microfoci/others (P = .013) remained significant predictors of DFS but only ypCR/microfoci/others for OS (P = .005) with no difference in outcome between ypCR compared to microfoci. CONCLUSION: This regimen demonstrates high response rates and promising long-term survival. Downstaging to ypCR/microfoci may be a useful short-term surrogate for long-term survival but needs validation in large phase III trials powered for survival outcomes. PMID- 21263097 TI - Seizures and radionecrosis from non-small-cell lung cancer presenting as increased fluorodeoxyglucose uptake on positron emission tomography. PMID- 21263096 TI - How genetically engineered mouse tumor models provide insights into human cancers. AB - Genetically engineered mouse models (GEMMs) of human cancer were first created nearly 30 years ago. These early transgenic models demonstrated that mouse cells could be transformed in vivo by expression of an oncogene. A new field emerged, dedicated to generating and using mouse models of human cancer to address a wide variety of questions in cancer biology. The aim of this review is to highlight the contributions of mouse models to the diagnosis and treatment of human cancers. Because of the breadth of the topic, we have selected representative examples of how GEMMs are clinically relevant rather than provided an exhaustive list of experiments. Today, as detailed here, sophisticated mouse models are being created to study many aspects of cancer biology, including but not limited to mechanisms of sensitivity and resistance to drug treatment, oncogene cooperation, early detection, and metastasis. Alternatives to GEMMs, such as chemically induced or spontaneous tumor models, are not discussed in this review. PMID- 21263098 TI - Reorganization of functional areas of the brain after brain irradiation. PMID- 21263099 TI - Pediatric phase I trial and pharmacokinetic study of dasatinib: a report from the children's oncology group phase I consortium. AB - PURPOSE Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-beta receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program. PATIENTS AND METHODS A phase I study of dasatinib in pediatric patients with refractory solid tumors or imatinib-refractory, Philadelphia chromosome-positive leukemia was performed. Dose levels of 50, 65, 85, and 110 mg/m2/dose, administered orally twice daily for 28 days, with courses repeated without interruption, were studied. Pharmacokinetic studies were performed with the initial dose. RESULTS: A total of 39 patients (solid tumors, n = 28; chronic myeloid leukemia [CML], n = 9; acute lymphoblastic leukemia, n = 2) were enrolled. No dose-limiting toxicities (DLTs) were observed at the 50, 65, and 85 mg/m2 dose levels. At 110 mg/m2, two of six patients experienced DLT including grade 2 diarrhea and headache. In children with leukemia, grade 4 hypokalemia (50 mg/m2), grade 3 diarrhea (85 mg/m2), and grade 2 creatinine elevation (50 mg/m2) were observed. DLT in later courses included pleural effusions, hemangiomatosis, and GI hemorrhage. There were three complete cytogenetic responses, three partial cytogenetic responses, and two partial/minimal cytogenetic responses observed in evaluable patients with CML. CONCLUSION Overall, drug disposition and tolerability of dasatinib were similar to those observed in adult patients. PMID- 21263100 TI - Phase III trial of weekly methotrexate or pulsed dactinomycin for low-risk gestational trophoblastic neoplasia: a gynecologic oncology group study. AB - PURPOSE: There is no consensus on the best regimen for the primary treatment of low-risk gestational trophoblastic neoplasia (GTN). PATIENTS AND METHODS: Two commonly used single-drug regimens were compared with respect to the proportion of patients meeting the criteria for a complete response (CR) in a randomized phase III trial conducted by the Gynecologic Oncology Group. Eligibility was purposefully broad to maximize the generalizability of the results and included patients with a WHO risk score of 0 to 6 and patients with metastatic disease (limited to lung lesions < 2 cm, adnexa, or vagina) or choriocarcinoma. RESULTS: Two hundred forty women were enrolled, and 216 were deemed eligible. Biweekly intravenous dactinomycin 1.25 mg/m2 was statistically superior to weekly intramuscular (IM) methotrexate 30 mg/m2 (CR: 70% v 53%; P = .01). Similarly, in patients with low-risk GTN as defined before the 2002 WHO risk score revisions (risk score of 0 to 4 and excluding choriocarcinoma), response was 58% and 73% in the methotrexate and dactinomycin arms, respectively (P = .03). Both regimens were less effective if the WHO risk score was 5 or 6 or if the diagnosis was choriocarcinoma (CR: 9% and 42%, respectively). There were two potential recurrences; one at 4 months (dactinomycin) and one at 22 months (methotrexate). Not all patients completed follow-up. Both regimens were well tolerated. CONCLUSION: The biweekly dactinomycin regimen has a higher CR rate than the weekly IM methotrexate regimen in low-risk GTN, a generally curable disease. PMID- 21263101 TI - Early evaluation of tumoral response to antiangiogenic therapy by arterial spin labeling perfusion magnetic resonance imaging and susceptibility weighted imaging in a patient with recurrent glioblastoma receiving bevacizumab. PMID- 21263102 TI - Cigarette smoking and the incidence of breast cancer. AB - BACKGROUND: Tobacco smoke contains carcinogens, which may increase the risk of breast cancer (BC). Conversely, cigarette smoking also has antiestrogenic effects, which may reduce the risk of BC. The association between smoking and BC remains controversial. METHODS: Prospective cohort study of 111 140 participants of the Nurses' Health Study from 1976 to 2006 for active smoking and 36 017 women from 1982 to 2006 for passive smoking. RESULTS: During 3 005 863 person-years of follow-up, 8772 incident cases of invasive BC were reported. After adjustment for potential confounders, the hazard ratio (HR) of BC was 1.06% (95% confidence interval [CI], 1.01%-1.10%) for ever smokers relative to never smokers. Breast cancer incidence was associated with a higher quantity of current (P for trend = .02) and past (P for trend = .003) smoking, younger age at smoking initiation (P for trend = .01), longer duration of smoking (P for trend = .01), and more pack years of smoking (P for trend = .005). Premenopausal smoking was associated with a slightly higher incidence of BC (HR, 1.11; 95% CI, 1.07-1.15 for every increase of 20 pack-years), especially smoking before first birth (1.18; 1.10-1.27 for every increase of 20 pack-years). Conversely, the direction of the association between postmenopausal smoking and BC was inverse (0.93; 0.85-1.02 for every increase of 20 pack-years). Passive smoking in childhood or adulthood was not associated with BC risk. CONCLUSION: Active smoking, especially smoking before the first birth, may be associated with a modest increase in the risk of BC. PMID- 21263103 TI - Randomized controlled trial of cognitive behavioral therapy vs standard treatment to prevent recurrent cardiovascular events in patients with coronary heart disease: Secondary Prevention in Uppsala Primary Health Care project (SUPRIM). AB - BACKGROUND: Psychosocial factors are independently associated with increased risk of cardiovascular disease (CVD) morbidity and mortality, but the effects of psychosocial factor intervention on CVD are uncertain. We performed a randomized controlled clinical trial of cognitive behavioral therapy (CBT) to measure its effects on CVD recurrence. METHODS: The study included 362 women and men 75 years or younger who were discharged from the hospital after a coronary heart disease event within the past 12 months. Patients were randomized to receive traditional care (reference group, 170 patients) or traditional care plus a CBT program (intervention group, 192 patients), focused on stress management, with 20 two hour sessions during 1 year. Median attendance at each CBT session was 85%. Outcome variables were all-cause mortality, hospital admission for recurrent CVD, and recurrent acute myocardial infarction. RESULTS: During a mean 94 months of follow-up, the intervention group had a 41% lower rate of fatal and nonfatal first recurrent CVD events (hazard ratio [95% confidence interval], 0.59 [0.42 0.83]; P = .002), 45% fewer recurrent acute myocardial infarctions (0.55 [0.36 0.85]; P = .007), and a nonsignificant 28% lower all-cause mortality (0.72 [0.40 1.30]; P = .28) than the reference group after adjustment for other outcome affecting variables. In the CBT group there was a strong dose-response effect between intervention group attendance and outcome. During the first 2 years of follow-up, there were no significant group differences in traditional risk factors. CONCLUSIONS: A CBT intervention program decreases the risk of recurrent CVD and recurrent acute myocardial infarction. This may have implications for secondary preventive programs in patients with coronary heart disease. Trial Registration clinicaltrials.gov Identifier: NCT00888485. PMID- 21263104 TI - Albuminuria and decline in cognitive function: The ONTARGET/TRANSCEND studies. AB - BACKGROUND: Microvascular disease of the kidney (manifesting as albuminuria) and of the brain (manifesting as cognitive decline) may share a common pathogenesis. Gaining an understanding of the concomitant history of these 2 conditions may inform clinical practice and lead to novel prevention and treatment approaches. METHODS: A total of 28 384 participants with vascular disease or diabetes mellitus were examined. At baseline and year 5, participants underwent a Mini Mental State Examination (MMSE) and urine testing for albumin excretion. Multivariable logistic regression was used to determine the association between albumin excretion and MMSE score, cross-sectionally and prospectively, and whether angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker use modified the association. RESULTS: Compared with participants with normoalbuminuria, those with microalbuminuria (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.11-1.44]) and macroalbuminuria (1.49; 1.20-1.85) were more likely to have a reduced MMSE score (<24). On follow-up, participants with baseline albuminuria had increased odds of cognitive decline (decrease in MMSE score >=3 points) compared with those with normoalbuminuria (microalbuminuria: OR, 1.22; 95% CI, 1.07-1.38; macroalbuminuria: 1.21; 0.94-1.55). Participants who developed new albuminuria had increased odds of cognitive decline during follow up compared with those who remained normoalbuminuric (new microalbuminuria: OR, 1.30; 95% CI, 1.12-1.52; new macroalbuminuria: 1.77; 1.24-2.54). Participants with baseline macroalbuminuria treated with an angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker had lower odds of MMSE decline than participants treated with placebo. CONCLUSION: Factors that contribute to albuminuria may contribute to cognitive decline, supporting the notion that both conditions share a common microvascular pathogenesis. Trial Registration clinicaltrials.gov Identifier: NCT00153101. PMID- 21263105 TI - Risk of influenza-like illness in an acute health care setting during community influenza epidemics in 2004-2005, 2005-2006, and 2006-2007: a prospective study. AB - BACKGROUND: The person-to-person transmission of influenza-like illness (ILI) and influenza has been described mostly in long-term care units. Studies in acute hospital settings are rare and mostly retrospective. METHODS: We prospectively estimated the relative risk (RR) of hospital-acquired (HA) ILI during hospitalization according to in-hospital exposures to contagious individuals. Surveillance of ILI and laboratory-confirmed influenza was undertaken at Edouard Herriot Hospital (1100 beds) during 3 influenza seasons. A total of 21 519 patients and 2153 health care workers (HCWs) from 2004 to 2007 were included. The RR of HA-ILI in patients was calculated according to exposure to other contagious patients and HCWs. RESULTS: For patients exposed to at least 1 contagious HCW compared with those with no documented exposure in the hospital, the RR of HA-ILI was 5.48 (95% confidence interval [CI], 2.09-14.37); for patients exposed to at least 1 contagious patient, the RR was 17.96 (95% CI, 10.07-32.03); and for patients exposed to at least 1 contagious patient and 1 contagious HCW, the RR was 34.75 (95% CI, 17.70-68.25). CONCLUSIONS: Hospitalized patients exposed to potentially infectious patients and HCWs with ILI inside the hospital are at greater risk for HA-ILI. Such results identify priorities regarding preventive measures for seasonal or pandemic influenza. PMID- 21263106 TI - Immunization disparities by Hispanic ethnicity and language preference. AB - BACKGROUND: Seasonal influenza and pneumococcal immunization rates are substantially lower for older Hispanics than for non-Hispanic whites. METHODS: Beneficiary-reported past-year influenza and lifetime pneumococcal immunization for English- and Spanish-preferring Hispanic beneficiaries were compared with those for non-Hispanic whites in cross-sectional bilingual survey data using data from 244 618 randomly sampled community-dwelling respondents (age >=65 years) with the 2008 Medicare Consumer Assessment of Healthcare Providers and Systems survey (a 62% response rate). Weighted logistic regression estimated immunization disparities with and without adjustment for health status, sociodemographic variables related to access, and location. Hierarchical models examined the role of specific geographic factors in immunization disparities. RESULTS: Pneumococcal immunization rates for Spanish- and English-speaking Hispanics were substantially lower than those for non-Hispanic whites (40% and 56% vs 74%; P < .001 for both comparisons). Influenza immunization rates for Spanish- and English-speaking Hispanics were also lower than for non-Hispanic whites (64% and 68% vs 76%; P < .001 for both comparisons). Health status-adjusted differences were similar; additional adjustment for sociodemographics reduced pneumococcal disparities by approximately one-third and influenza disparities by approximately half, but all disparities remained significant. Pneumococcal disparities were consistently smaller for patients in managed care plans. Influenza disparities were greater both in linguistically isolated areas and in "new destination" areas without long standing Hispanic populations. CONCLUSIONS: Hispanic seniors, especially when Spanish-preferring and in linguistically isolated "new destinations," such as the Southeast, continue to be immunized at markedly lower rates than non-Hispanic whites, even after adjustment for health and sociodemographics. Individual physicians and policymakers may be able to assist this vulnerable group by addressing cultural and linguistic barriers to immunization. PMID- 21263107 TI - A clinical solution to antimicrobial resistance in community-acquired pneumonia: narrowing the spectrum of antimicrobial therapy: comment on "Current and potential usefulness of pneumococcal urinary antigen detection in hospitalized patients with community-acquired pneumonia to guide antimicrobial therapy". PMID- 21263108 TI - Maintenance of certification in internal medicine: facts and misconceptions. PMID- 21263109 TI - Maintenance of certification: moving forward: comment on "Maintenance of certification in internal medicine". PMID- 21263110 TI - Surrogate consent for percutaneous endoscopic gastrostomy. PMID- 21263111 TI - Analytical issues regarding rosiglitazone meta-analysis. PMID- 21263112 TI - Where do diagnostic adverse events come from? PMID- 21263113 TI - Lack of evaluation of the effects of single preventive measures for falling. PMID- 21263114 TI - A critical role of interleukin-10 in modulating hypoxia-induced preeclampsia-like disease in mice. AB - Hypoxia has been implicated in the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy. However, in vivo evidence and mechanistic understanding remain elusive. Preeclampsia is associated with impaired placental angiogenesis. We have recently shown that interleukin (IL)-10 can support trophoblast-driven endovascular crosstalk. Accordingly, we hypothesize that pathological levels of oxygen coupled with IL-10 deficiency induce severe preeclampsia-like features coupled with elevated production of antiangiogenic factors, apoptotic pathways, and placental injury. Exposure of pregnant wild-type and IL-10(-/-) mice to 9.5% oxygen resulted in graded placental injury and systemic symptoms of renal pathology, proteinuria (wild-type 645.15 +/- 115.73 versus 198.09 +/- 93.45; IL 10(-/-) 819.31 +/- 127.85 versus 221.45 +/- 82.73 MUg/mg/24 hours) and hypertension (wild-type 118.37 +/- 14.45 versus 78.67 +/- 14.07; IL-10(-/-) 136.03 +/- 22.59 versus 83.97 +/- 18.25 mm Hg). Recombinant IL-10 reversed hypoxia-induced features in pregnant IL-10(-/-) mice confirming the protective role of IL-10 in preeclampsia. Hypoxic exposure caused marked elevation of soluble fms-like tyrosine kinase 1 (110.8 +/- 20.1 versus 44.7 +/- 11.9 ng/mL) in IL-10(-/-) mice compared with their wild-type counterparts (81.6 +/- 13.1 versus 41.2 +/- 8.9 ng/mL), whereas soluble endoglin was induced to similar levels in both strains (approximately 380 +/- 50 versus 180 +/- 31 ng/mL). Hypoxia-induced elevation of p53 was associated with marked induction of proapoptotic protein Bax, downregulation of Bcl-2, and trophoblast-specific apoptosis in utero placental tissue. Collectively, we conclude that severe preeclampsia pathology could be triggered under certain threshold oxygen levels coupled with intrinsic IL-10 deficiency, which lead to excessive activation of antiangiogenic and apoptotic pathways. PMID- 21263115 TI - Persistent macrovascular and microvascular dysfunction in patients with malignant hypertension. AB - Endothelial dysfunction is characteristic of patients with essential hypertension, but only limited data are available on different aspects of endothelial function in patients with malignant-phase hypertension. We investigated myocardial perfusion using real-time quantitative myocardial contrast echocardiography with concurrent assessment of macrovascular and microvascular endothelial damage/dysfunction in patients with previous malignant hypertension (but now in stable phase), who were compared with patients with treated "high-risk" hypertension (hypertension) and healthy controls. We measured flow (hyperemia)-mediated dilation and response to glyceryl trinitrate of brachial artery (ultrasound), microvascular (forearm) response to acetylcholine and sodium nitroprusside (laser Doppler), pulse wave velocity, circulating endothelial and endothelial progenitor cells in 15 patients with malignant hypertension, 40 matched patients with hypertension, and 40 healthy controls. Patients with malignant hypertension had impaired endothelial-dependant response to acetylcholine (P<0.001, but not to sodium nitroprusside) compared with hypertension and impaired reaction to both stimuli compared with healthy subjects (P<0.001). Patients with malignant hypertension had increased circulating endothelial cells (P=0.001), endothelial progenitors (P=0.008), and stiffness (P=0.003). Both hypertensive groups had impaired response to hyperemia and glyceryl trinitrate when compared with healthy controls (P<0.05). Both hypertensive groups had similar myocardial perfusion, which was significantly lower than in healthy controls. There were no significant differences in hyperemia and endothelium-independent stimuli between the 2 hypertensive groups. In conclusion, despite fairly well-controlled blood pressure, malignant hypertension patients had more pronounced abnormalities of macrovascular and microvascular function (which seem to be both endothelium dependent and endothelium independent) compared with patients with hypertension and healthy controls. PMID- 21263117 TI - Mechanisms underlying hypertension and obesity: a melanocortin linkage in the brain. PMID- 21263116 TI - Sympathetic response to insulin is mediated by melanocortin 3/4 receptors in the hypothalamic paraventricular nucleus. AB - Hyperinsulinemia increases sympathetic nerve activity and contributes to cardiovascular dysfunction in obesity and diabetes. Neurons of the hypothalamic paraventricular nucleus (PVN) regulate sympathetic nerve activity through mono- and poly-synaptic connections to preganglionic neurons in the spinal cord. The purpose of the present study was to determine whether PVN neurons mediate the sympathetic response to insulin. Hyperinsulinemic-euglycemic clamps were performed in alpha-chloralose-anesthetized, male Sprague-Dawley rats (280-420 g) by an infusion of insulin (3.75 mU/kg per min) and 50% dextrose (0.75-2.0 mL/h) for 120 minutes. At 90 minutes, insulin significantly increased lumbar sympathetic nerve activity without any change in renal sympathetic nerve activity, heart rate, or blood glucose levels. Inhibition of the PVN with bilateral injection of the GABA(A) receptor agonist muscimol completely reversed the sympathoexcitatory response. However, direct injection of insulin into the PVN did not alter lumbar sympathetic nerve activity, and thereby suggests that insulin activates neurons upstream of the PVN. Interestingly, the sympathetic response to insulin was eliminated by PVN injection of the melanocortin 3/4 receptor antagonist SHU9119, but was unaffected by the angiotensin II type 1 receptor antagonist losartan. A final set of experiments suggests activation of PVN neurons during hyperinsulinemia increases glutamatergic drive to the rostral ventrolateral medulla. Collectively, these findings indicate that insulin activates a melanocortin-dependent pathway to the PVN that increases glutamatergic drive to the rostral ventrolateral medulla and alters cardiovascular function. PMID- 21263118 TI - Impact of aging on conduit artery retrograde and oscillatory shear at rest and during exercise: role of nitric oxide. AB - Aging has been recently associated with increased retrograde and oscillatory shear in peripheral conduit arteries, a hemodynamic environment that favors a proatherogenic endothelial cell phenotype. We evaluated whether nitric oxide (NO) bioavailability in resistance vessels contributes to age-related differences in shear rate patterns in upstream conduit arteries at rest and during rhythmic muscle contraction. Younger (n=11, age 26 +/- 2 years) and older (n=11, age 61 +/ 2 years) healthy subjects received intra-arterial saline (control) and the NO synthase inhibitor N(G)-Monomethyl-L-arginine. Brachial artery diameter and velocities were measured via Doppler ultrasound at rest and during a 5-minute bout of rhythmic forearm exercise. At rest, older subjects exhibited greater brachial artery retrograde and oscillatory shear (-13.2 +/- 3.0 s(-1) and 0.11 +/ .0.02 arbitrary units, respectively) compared with young subjects (-4.8 +/- 2.3 s(-1) and 0.04 +/- 0.02 arbitrary units, respectively; both P<0.05). NO synthase inhibition in the forearm circulation of young, but not of older, subjects increased retrograde and oscillatory shear (both P<0.05), such that differences between young and old at rest were abolished (both P>0.05). From rest to steady state exercise, older subjects decreased retrograde and oscillatory shear (both P<0.05) to the extent that no exercise-related differences were found between groups (both P>0.05). Inhibition of NO synthase in the forearm circulation did not affect retrograde and oscillatory shear during exercise in either group (all P>0.05). These data demonstrate for the first time that reduced NO bioavailability in the resistance vessels contributes, in part, to age-related discrepancies in resting shear patterns, thus identifying a potential mechanism for increased risk of atherosclerotic disease in conduit arteries. PMID- 21263119 TI - Ambulatory blood pressure monitoring in 9357 subjects from 11 populations highlights missed opportunities for cardiovascular prevention in women. AB - To analyze sex-specific relative and absolute risks associated with blood pressure (BP), we performed conventional and 24-hour ambulatory BP measurements in 9357 subjects (mean age, 52.8 years; 47% women) recruited from 11 populations. We computed standardized multivariable-adjusted hazard ratios for associations between outcome and systolic BP. During a course of 11.2 years (median), 1245 participants died, 472 of cardiovascular causes. The number of fatal combined with nonfatal events was 1080, 525, and 458 for cardiovascular and cardiac events and for stroke, respectively. In women and men alike, systolic BP predicted outcome, irrespective of the type of BP measurement. Women compared with men were at lower risk (hazard ratios for death and all cardiovascular events=0.66 and 0.62, respectively; P<0.001). However, the relation of all cardiovascular events with 24-hour BP (P=0.020) and the relations of total mortality (P=0.023) and all cardiovascular (P=0.0013), cerebrovascular (P=0.045), and cardiac (P=0.034) events with nighttime BP were steeper in women than in men. Consequently, per a 1 SD decrease, the proportion of potentially preventable events was higher in women than in men for all cardiovascular events (35.9% vs 24.2%) in relation to 24-hour systolic BP (1-SD, 13.4 mm Hg) and for all-cause mortality (23.1% vs 12.3%) and cardiovascular (35.1% vs 19.4%), cerebrovascular (38.3% vs 25.9%), and cardiac (31.0% vs 16.0%) events in relation to systolic nighttime BP (1-SD, 14.1 mm Hg). In conclusion, although absolute risks associated with systolic BP were lower in women than men, our results reveal a vast and largely unused potential for cardiovascular prevention by BP-lowering treatment in women. PMID- 21263120 TI - Relation of brachial and digital measures of vascular function in the community: the Framingham heart study. AB - Impaired vascular function contributes to the development of clinical cardiovascular disease. The relation between vasodilator function assessed noninvasively in the brachial and digital arteries remains incompletely defined. In the Framingham Offspring, Third Generation and Omni Cohorts, we measured flow mediated dilation (FMD; n = 7031; age 48 +/- 13 years; age range, 19 to 88 years; 54% women) and peripheral arterial tonometry (PAT) ratio (n = 4352; 55 +/- 16 years; age range, 19 to 90 years; 51% women). Abnormal vascular function for each measure was defined by the sex-specific fifth percentile in a reference group free of conventional cardiovascular risk factors. The prevalence of abnormal FMD but not abnormal PAT ratio was higher with advancing age. In multivariable models, higher body mass index was associated with a higher prevalence of both abnormal FMD and PAT ratio. Additional correlates of abnormal FMD included increasing age and higher systolic blood pressure. In contrast, correlates of abnormal PAT ratio included lower systolic blood pressure, increasing total/high density lipoprotein cholesterol ratio, diabetes, smoking, and lipid-lowering medication. Whereas women had higher FMD and PAT ratios compared with men, using sex-specific reference values, women had a higher prevalence of abnormal brachial and digital vascular function. In participants who had concurrent testing (n = 1843), PAT ratio was not significantly associated with FMD in multivariable models. In this large, community-based cohort, brachial and digital measures of vascular function had differing relations with cardiovascular risk factors and were nearly uncorrelated with each other. These results suggest that FMD and PAT provide distinct information regarding vascular function in conduit versus smaller digital vessels. PMID- 21263122 TI - Ambulatory blood pressure monitoring to assess cardiovascular risk in women. PMID- 21263121 TI - Cardiovascular and sympathetic effects of disrupting tyrosine 985 of the leptin receptor. AB - Leptin acts in the brain to regulate food intake and energy expenditure. Leptin also increases renal sympathetic nerve activity and arterial pressure. The divergent signaling capacities of the leptin receptor (ObRb) mediate the stimulation of various intracellular pathways that are important for leptin control of physiological processes. We evaluated the cardiovascular and sympathetic consequences of disrupting the signal emanating from tyrosine985 of ObRb. For this, we used Lepr(L985) (l/l) mice, which carry a loss of function mutation replacing tyrosine985 of ObRb with leucine. Body weight of l/l mice was not significantly different from wild-type controls. In contrast, radiotelemetry measurements revealed that the l/l mice had higher arterial pressure and heart rate as compared with controls. Ganglionic blockade caused a greater arterial pressure fall in the l/l mice relative to controls. In addition, leptin treatment induced a larger increase in arterial pressure and heart rate in the l/l versus wild-type mice. Finally, we compared the response of renal and brown adipose tissue sympathetic nerve activity to intracerebroventricular injection of leptin (2 MUg) between l/l and control mice. Leptin-induced increase in renal sympathetic nerve activity was greater in l/l mice relative to controls. In contrast, the brown adipose tissue sympathetic nerve activity response to leptin was attenuated in the l/l mice relative to controls. These data indicate that selective loss of leptin receptor signaling emanating from tyrosine985 enhances the cardiovascular and renal sympathetic effects of leptin. These findings provide important insight into the molecular mechanisms underlying leptin's effects on the sympathetic cardiovascular function and arterial pressure. PMID- 21263123 TI - Angiotensinergic signaling in the brain mediates metabolic effects of deoxycorticosterone (DOCA)-salt in C57 mice. AB - Low-renin hypertension accounts for ~ 25% of essential hypertensive patients. It is modeled in animals by chronic delivery of deoxycorticosterone acetate and excess dietary sodium (the DOCA-salt model). Previous studies have demonstrated that DOCA-salt hypertension is mediated through activation of the brain renin angiotensin system. Here, we demonstrate robust metabolic phenotypes of DOCA-salt treatment. Male C57BL/6J mice (6 to 8 weeks old) received a subcutaneous pellet of DOCA (50 mg for 21 days) and were offered a 0.15 mol/L NaCl drink solution in addition to regular chow and tap water. Treatment resulted in mild hypertension, a blunting of weight gain, gross polydipsia, polyuria, and sodium intake, alterations in urinary sodium and potassium turnover, and serum sodium retention. Most strikingly, DOCA-salt mice exhibited no difference in food intake but did exhibited a large elevation in basal metabolic rate. Normalization of blood pressure by hydralazine (500 mg/L in drink solutions) attenuated the hydromineral phenotypes and renal renin suppression effects of DOCA-salt but had no effect on the elevated metabolic rate. In contrast, intracerebroventricular infusion of the angiotensin II type 1 receptor antagonist losartan (5 MUg/h) attenuated the elevation in metabolic rate with DOCA-salt treatment. Together, these data illustrate the necessity of angiotensinergic signaling within the brain, independent of blood pressure alterations, in the metabolic consequences of DOCA salt treatment. PMID- 21263124 TI - Dietary iron restriction prevents hypertensive cardiovascular remodeling in Dahl salt-sensitive rats. AB - Iron accumulation is associated with the pathogenesis of several cardiovascular diseases. However, the preventive effects of iron restriction (IR) against cardiovascular disease remain obscure. We investigated the effects of dietary IR on cardiovascular pathophysiology and the involved mechanism in Dahl salt sensitive rats. Dahl salt-sensitive rats were provided either a normal or high salt (HS) diet. Another subset of Dahl salt-sensitive rats were fed an HS with iron-restricted (HS+IR) diet for 11 weeks. Dahl salt-sensitive rats given an HS diet developed hypertension, heart failure, and decreased a survival rate after 11 weeks on the diet. In contrast, IR attenuated the development of hypertension and heart failure, thereby improving survival rate. Dietary IR suppressed cardiovascular hypertrophy, fibrosis, and inflammation in HS rats. The phosphorylation of Akt, AMP-activated protein kinase, and endothelial nitric oxide synthase was decreased in the aorta of HS rats, whereas they were ameliorated by the IR diet. Aortic expression of the cellular iron import protein transferrin receptor 1, and the iron storage protein ferritin H-subunit, was upregulated in HS rats. IR also attenuated proteinuria and increased oxidative stress in the HS group. N(G)-nitro-L-arginine methyl ester abolished the beneficial effects of IR and decreased survival rate in HS+IR rats. Dietary IR had protective effects on salt-induced hypertension, cardiovascular remodeling, and proteinuria through the inhibition of oxidative stress, and maintenance of Akt, AMP-activated protein kinase, and endothelial nitric oxide synthase in the aorta. IR could be an effective strategy for prevention of HS-induced organ damage in salt-sensitive hypertensive patients. PMID- 21263125 TI - T regulatory lymphocytes prevent angiotensin II-induced hypertension and vascular injury. AB - Angiotensin (Ang) II induces hypertension by mechanisms mediated in part by adaptive immunity and T effector lymphocytes. T regulatory lymphocytes (Tregs) suppress T effector lymphocytes. We questioned whether Treg adoptive transfer would blunt Ang II-induced hypertension and vascular injury. Ten- to 12-week-old male C57BL/6 mice were injected IV with 3 *10(5) Treg (CD4(+)CD25(+)) or T effector (CD4(+)CD25(-)) cells, 3 times at 2-week intervals, and then infused or not with Ang II (1 MUg/kg per minute, SC) for 14 days. Ang II increased systolic blood pressure by 43 mm Hg (P<0.05), NADPH oxidase activity 1.5-fold in aorta and 1.8-fold in the heart (P<0.05), impaired acetylcholine vasodilatory responses by 70% compared with control (P<0.05), and increased vascular stiffness (P<0.001), mesenteric artery vascular cell adhesion molecule expression (2-fold; P<0.05), and aortic macrophage and T-cell infiltration (P<0.001). All of the above were prevented by Treg but not T effector adoptive transfer. Ang II caused a 43% decrease in Foxp3(+) cells in the renal cortex, whereas Treg adoptive transfer increased Foxp3(+) cells 2-fold compared with control. Thus, Tregs suppress Ang II-mediated vascular injury in part through anti-inflammatory actions. Immune mechanisms modulate Ang II-induced blood pressure elevation, vascular oxidative stress, inflammation, and endothelial dysfunction. PMID- 21263126 TI - Systemic but not central nervous system nitric oxide synthase inhibition exacerbates the hypertensive effects of chronic melanocortin-3/4 receptor activation. AB - We examined whether systemic or central nervous system (CNS) inhibition of nitric oxide synthase exacerbates the cardiovascular responses of chronic CNS melanocortin 3/4 receptor activation. Sprague-Dawley rats implanted with telemetry probes, venous catheters, and intracerebroventricular (ICV) cannulae were divided in 3 groups. After control measurements, the NO synthase inhibitor L NAME was infused (10 MUg/kg/min intravenous) for 17 days and, starting on day 7 of L-NAME infusion, the melanocortin 3/4 receptor agonist melanotan II (MTII; 10 ng/hr; group 1) or saline vehicle (group 2) was infused ICV for 10 days. A third group not treated with L-NAME also received MTII ICV. Melanocortin 3/4 receptor activation caused a greater increase in mean arterial pressure (MAP) and heart rate in rats treated with intravenous L-NAME (35 +/- 6 mm Hg and 56 +/- 8 bpm) than L-NAME plus vehicle or MTII alone (22 +/- 5 and 9 +/- 2 mm Hg, and 26 +/- 14 and 27 +/- 5 bpm), despite a 58% and 50% reduction in food intake during the first 6 days of MTII infusion. To test if the amplified pressor response to MTII after L-NAME was attributable to a reduction in nitric oxide availability in the brain, we also infused L-NAME directly into the CNS alone or in combination with MTII. ICV infusion of L-NAME plus MTII caused only ~ 10 mm Hg increase in MAP with no change in heart rate, similar to the effects of ICV infusion of MTII alone, whereas ICV infusion of L-NAME alone had no effect on MAP. These results suggest that reduction in peripheral, but not CNS, nitric oxide production augments MAP sensitivity to CNS melanocortin 3/4 receptor activation. PMID- 21263127 TI - Impaired interaction between efferent and afferent renal nerve activity in SHR involves increased activation of alpha2-adrenoceptors. AB - Activation of efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), leading to decreases in ERSNA by activation of the renorenal reflexes in the overall goal of maintaining low ERSNA. The renorenal reflex responses to various stimuli are impaired in spontaneously hypertensive rats (SHR). Because renal tissue density of alpha(2)-adrenoceptors (ARs) is increased in SHR, we examined whether the ERSNA-induced increases in ARNA are impaired in SHR and, if so, the role of alpha(2)-ARs. The ARNA responses to increases in ERSNA were impaired in SHR, 2390 +/- 460%.seconds, versus in Wistar-Kyoto rats, 6620 +/- 1690%.seconds. Renal pelvic release of substance P was not altered by 6250 pmol/L norepinephrine (NE) in SHR but was increased by 250 pmol/L NE in Wistar-Kyoto rats, from 5.7 +/- 0.7 to 12.5+/-1.3 pg/min. Renal pelvic administration of the alpha(2)-AR antagonist rauwolscine enhanced the ERSNA-induced increases in ARNA, 4170 +/- 900%.seconds, in SHR but not in Wistar Kyoto rats. In the presence of rauwolscine, 250 pmol/L NE increased substance P release, from 5.2 +/- 0.3 to 11.2 +/- 0.8 pg/min, in pelvises from SHR. Because angiotensin II suppresses the activation of renal mechanosensory nerves in SHR, we examined whether losartan improved the ERSNA-induced ARNA responses. Losartan had no effect on the ARNA responses or the NE-induced increases in substance P in SHR. However, losartan+rauwolscine resulted in further enhancement of the responsiveness of the renal sensory nerves to increases in ERSNA and NE in SHR but not in WKY. We conclude that increased activation of renal alpha(2)-ARs and angiotensin II type 1 receptors contributes to the impaired interaction between ERSNA and ARNA in SHR. PMID- 21263128 TI - Flow-mediated dilation and cardiovascular event prediction: does nitric oxide matter? AB - Endothelial dysfunction is an early atherosclerotic event that precedes clinical symptoms and may also render established plaque vulnerable to rupture. Noninvasive assessment of endothelial function is commonly undertaken using the flow-mediated dilation (FMD) technique. Some studies indicate that FMD possesses independent prognostic value to predict future cardiovascular events that may exceed that associated with traditional risk factor assessment. It has been assumed that this association is related to the proposal that FMD provides an index of endothelium-derived nitric oxide (NO) function. Interestingly, placement of the occlusion cuff during the FMD procedure alters the shear stress stimulus and NO dependency of the resulting dilation: cuff placement distal to the imaged artery leads to a largely NO-mediated response, whereas proximal cuff placement leads to dilation which is less NO dependent. We used this physiological observation and the knowledge that prognostic studies have used both approaches to examine whether the prognostic capacity of FMD is related to its role as a putative index of NO function. In a meta-analysis of 14 studies (>8300 subjects), we found that FMD derived using a proximal cuff was at least as predictive as that derived using distal cuff placement, despite the latter being more NO dependent. This suggests that, whilst FMD is strongly predictive of future cardiovascular events, this may not solely be related to its assumed NO dependency. Although this finding should be confirmed with more and larger studies, we suggest that any direct measure of vascular (endothelial) function may provide independent prognostic information in humans. PMID- 21263129 TI - Iron repletion in heart failure patients. PMID- 21263131 TI - Teaching NeuroImages: First-order Horner syndrome due to ipsilateral thalamic hemorrhage. PMID- 21263130 TI - Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study. AB - BACKGROUND: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. METHODS: We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two sided. RESULTS: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 * 10(-10)). This single nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 * 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 * 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 * 10(-6)). CONCLUSIONS: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects. PMID- 21263132 TI - Teaching NeuroImages: False-positive magnetic resonance sign in spontaneous spinal CSF leak. PMID- 21263133 TI - Patient page. Do enough women and minorities take part in drug studies for neurologic diseases? PMID- 21263134 TI - Myasthenic syndrome caused by plectinopathy. AB - BACKGROUND: Plectin crosslinks intermediate filaments to their targets in different tissues. Defects in plectin cause epidermolysis bullosa simplex (EBS), muscular dystrophy (MD), and sometimes pyloric atresia. Association of EBS with a myasthenic syndrome (MyS) was documented in a single patient in 1999. OBJECTIVES: To analyze the clinical, structural, and genetic aspects of a second and fatal case of EBS associated with a MyS and search for the genetic basis of the disease in a previously reported patient with EBS-MD-MyS. METHODS: Clinical observations; histochemical, immunocytochemical, and electron microscopy studies of skeletal muscle and neuromuscular junction; and mutation analysis. RESULTS: An African American man had EBS since early infancy, and progressive muscle weakness, hyperCKemia, and myasthenic symptoms refractory to therapy since age 3 years. Eventually he became motionless and died at age 42 years. At age 15 years, he had a marked EMG decrement, and a reduced miniature endplate potential amplitude. The myopathy was associated with dislocated muscle fiber organelles, structurally abnormal nuclei, focal plasmalemmal defects, and focal calcium ingress into muscle fibers. The neuromuscular junctions showed destruction of the junctional folds, and remodeling. Mutation analysis demonstrated a known p.Arg2319X and a novel c.12043dupG mutation in PLEC1. The EBS-MD-MyS patient reported in 1999 also carried c.12043dupG and a novel p.Gln2057X mutation. The novel mutations were absent in 200 Caucasian and 100 African American subjects. CONCLUSIONS: The MyS in plectinopathy is attributed to destruction of the junctional folds and the myopathy to defective anchoring of muscle fiber organelles and defects in sarcolemmal integrity. PMID- 21263135 TI - Rasch-built Overall Disability Scale (R-ODS) for immune-mediated peripheral neuropathies. AB - OBJECTIVE: To develop a patient-based, linearly weighted scale that captures activity and social participation limitations in patients with Guillain-Barre syndrome (GBS), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), and gammopathy-related polyneuropathy (MGUSP). METHODS: A preliminary Rasch-built Overall Disability Scale (R-ODS) containing 146 activity and participation items was constructed, based on the WHO International Classification of Functioning, Disability and Health, literature search, and patient interviews. The preliminary R-ODS was assessed twice (interval: 2-4 weeks; test-retest reliability studies) in 294 patients who experienced GBS in the past (n = 174) or currently have stable CIDP (n = 80) or MGUSP (n = 40). Data were analyzed using the Rasch unidimensional measurement model (RUMM2020). RESULTS: The preliminary R-ODS did not meet the Rasch model expectations. Based on disordered thresholds, misfit statistics, item bias, and local dependency, items were systematically removed to improve the model fit, regularly controlling the class intervals and model statistics. Finally, we succeeded in constructing a 24-item scale that fulfilled all Rasch requirements. "Reading a newspaper/book" and "eating" were the 2 easiest items; "standing for hours" and "running" were the most difficult ones. Good validity and reliability were obtained. CONCLUSION: The R-ODS is a linearly weighted scale that specifically captures activity and social participation limitations in patients with GBS, CIDP, and MGUSP. Compared to the Overall Disability Sum Score, the R-ODS represents a wider range of item difficulties, thereby better targeting patients with different ability levels. If responsive, the R-ODS will be valuable for future clinical trials and follow-up studies in these conditions. PMID- 21263136 TI - Muscle histology vs MRI in Duchenne muscular dystrophy. AB - OBJECTIVE: There are currently no effective treatments to halt the muscle breakdown in Duchenne muscular dystrophy (DMD), although genetic-based clinical trials are being piloted. Most of these trials have as an endpoint the restoration of dystrophin in muscle fibers, hence requiring sufficiently well preserved muscle of recruited patients. The choice of the muscles to be studied and the role of noninvasive methods to assess muscle preservation therefore require further evaluation. METHODS: We studied the degree of muscle involvement in the lower leg muscles of 34 patients with DMD >8 years, using muscle MRI. In a subgroup of 15 patients we correlated the muscle MRI findings with the histology of open extensor digitorum brevis (EDB) muscle biopsies. Muscle MRI involvement was assigned using a scale 0-4 (normal-severe). RESULTS: In all patients we documented a gradient of involvement of the lower leg muscles: the posterior compartment (gastrocnemius > soleus) was most severely affected; the anterior compartment (tibialis anterior/posterior, popliteus, extensor digitorum longus) least affected. Muscle MRI showed EDB involvement that correlated with the patient's age (p = 0.055). We show a correlation between the MRI and EDB histopathologic changes, with MRI 3-4 grades associated with a more severe fibro adipose tissue replacement. The EDB was sufficiently preserved for bulk and signal intensity in 18/22 wheelchair users aged 10-16.6 years. CONCLUSION: This study provides a detailed correlation between muscle histology and MRI changes in DMD and demonstrates the value of this imaging technique as a reliable tool for the selection of muscles in patients recruited into clinical trials. PMID- 21263137 TI - Incidence and anatomy of gaze-evoked nystagmus in patients with cerebellar lesions. AB - BACKGROUND: Disorders of gaze-holding--organized by a neural network located in the brainstem or the cerebellum--may lead to nystagmus. Based on previous animal studies it was concluded that one key player of the cerebellar part of this gaze holding neural network is the flocculus. Up to now, in humans there are no systematic studies in patients with cerebellar lesions examining one of the most common forms of nystagmus: gaze-evoked nystagmus (GEN). The aim of our present study was to clarify which cerebellar structures are involved in the generation of GEN. METHODS: Twenty-one patients with acute unilateral cerebellar stroke were analyzed by means of modern MRI-based voxel-wise lesion-behavior mapping. RESULTS: Our data indicate that cerebellar structures such as the vermal pyramid, the uvula, and the tonsil, but also parts of the biventer lobule and the inferior semilunar lobule, were affected in horizontal GEN. CONCLUSION: It seems that these structures are part of a gaze-holding neural integrator control system. Furthermore, GEN might present a diagnostic sign pointing toward ipsilesionally located lesions of midline and lower cerebellar structures. PMID- 21263138 TI - Distinguishing 3 classes of corpus callosal abnormalities in consanguineous families. AB - OBJECTIVE: We sought to create a classification system for pediatric corpus callosal abnormalities (CCA) based upon midline sagittal brain MRI. We used the term CCA for patients with structural variants of the corpus callosum, excluding patients with interhemispheric cyst variant or pure dysplasia without hypoplasia. Currently, no system exists for nonsyndromic forms of CCA, and attempts to create such a system have been hampered by highly variable morphology in patients with sporadic CCA. We reasoned that any useful strategy should classify affected family members within the same type, and that phenotypic variability should be minimized in patients with recessive disease. METHODS: We focused recruitment toward multiplex consanguineous families, ascertained 30 patients from 19 consanguineous families, and analyzed clinical features together with brain imaging. RESULTS: We identified 3 major CCA classes, including hypoplasia, hypoplasia with dysplasia, and complete agenesis. Affected individuals within a given multiplex family usually displayed the same variant of the class of abnormality and they always displayed the same class of abnormality within each family, or they displayed complete agenesis. The system was validated among a second cohort of 10 sporadic patients with CCA. CONCLUSIONS: The data suggest that complete agenesis may be a common end-phenotype, and implicate multiple overlapping pathways in the etiology of CCA. PMID- 21263139 TI - Child development following in utero exposure: levetiracetam vs sodium valproate. AB - OBJECTIVE: Children born to women with epilepsy (WWE), exposed in utero to levetiracetam (LEV, n = 51), were assessed for early cognitive development and compared to children exposed to sodium valproate in utero (VPA, n = 44) and a group of children representative of the general population (n = 97). METHODS: Children were recruited prospectively from 2 cohorts in the United Kingdom and assessed using the Griffiths Mental Development Scale (1996), aged <24 months. Information regarding maternal demographics were collected and controlled for. This is an observational study with researchers not involved in the clinical management of the WWE. RESULTS: On overall developmental ability, children exposed to LEV obtained higher developmental scores when compared to children exposed to VPA (p < 0.001). When compared, children exposed to LEV did not differ from control children (p = 0.62) on overall development. Eight percent of children exposed to LEV in utero fell within the below average range (DQ score of <84), compared with 40% of children exposed to VPA. After controlling for maternal epilepsy and demographic factors using linear regression analysis, exposure to LEV in utero was not associated with outcome (p = 0.67). Conversely, when compared with VPA exposure, LEV exposure was associated with higher scores for the overall developmental quotient (p < 0.001). CONCLUSION: Children exposed to LEV in utero are not at an increased risk of delayed early cognitive development under the age of 24 months. LEV may therefore be a preferable drug choice, where appropriate, for WWE prior to and of childbearing age. PMID- 21263140 TI - Accuracy of family history information on epilepsy and other seizure disorders. AB - BACKGROUND: In epilepsy as in other disorders, family history information is often obtained by asking patients about the medical histories of their relatives rather than interviewing or examining the relatives directly. The accuracy of this type of information for epilepsy and other seizure disorders is unclear. METHODS: This study used data from the Genetic Epidemiology of Seizure Disorders in Rochester study, a population-based investigation including all Rochester, MN, residents born >=1920 with incidence of unprovoked seizures from 1935 to 1994 (case probands) and control probands matched by age, gender, and prior Rochester residency period. Seizure disorders in the first-degree relatives of case and control probands were ascertained by reviewing the relatives' medical records. Case and control probands were interviewed about seizures in their first-degree relatives using a validated 9-question screening interview. Interviewers were blinded to case-control status. RESULTS: Sensitivity of the family history (i.e., proportion of relatives with medical record-documented seizures who screened positive in the proband interview) was 62% (32/52) for epilepsy, 50% (7/14) for isolated unprovoked seizures, and 56% (9/16) for febrile seizures. Sensitivity did not differ by case/control status of the proband. Sensitivity was much higher for probands reporting on their offspring or siblings than their parents. Among relatives with epilepsy, 90% of offspring and 80% of siblings but only 32% of parents screened positive. CONCLUSIONS: Family histories of epilepsy are reasonably accurate for siblings and offspring, but are underreported in parents. Family histories of other seizure disorders are underreported. PMID- 21263141 TI - White matter synapses: form, function, and dysfunction. AB - Synaptic transmission in the CNS represents the classic mechanism through which neural cells communicate. While vesicular neurotransmitter release has been known to be the preserve of gray matter, it is now known that synaptic-style release of glutamate, the brain's major excitatory neurotransmitter, occurs deep in white matter. Here it permits communication between axons and glial cells, enabling axon activity to couple with high fidelity to glial physiology. As white matter is increasingly well-recognized as a substrate for disease, dysregulation of white matter synaptic transmission will play an important role in the development of pathologies as diverse as stroke, multiple sclerosis, Alzheimer disease, and schizophrenia. This review highlights progress in this new and important field. PMID- 21263142 TI - Deep brain stimulation relieves refractory hypertension. PMID- 21263143 TI - Treatment of restless legs syndrome with pregabalin: a double-blind, placebo controlled study. PMID- 21263144 TI - Mexiletine is an effective antimyotonia treatment in myotonic dystrophy type 1. PMID- 21263146 TI - The perils of combination antithrombotic therapy and potential resolutions. PMID- 21263148 TI - Long-term clinical outcomes of patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. AB - Few data exist on the long-term prognosis of patients with chronic primary chronic immune thrombocytopenia (ITP). We examined the risk of infections, hemorrhage resulting in hospitalization, hematologic malignancies, and total and cause-specific mortality among patients with ITP compared with the general population. We used population-based medical databases to identify 407 patients with primary chronic ITP diagnosed during 1996 to 2007 and 4069 general population members individually matched on age, sex, and comorbidity level. We used Cox regression analysis to estimate rate ratios (RRs) adjusted for age (<= 60 or > 60 years), sex, calendar year, and level of comorbidity. The adjusted 1 year RR of infection was 4.5 (95% confidence interval [CI], 3.3-6.1) for patients with chronic ITP compared with the general population cohort. The adjusted RR decreased to 1.8 (95% CI, 1.3-2.5) for the second to fifth year of follow-up. The adjusted 5-year RR was 3.2 (95% CI, 1.2-9.0) for hospitalized intracranial hemorrhage, 4.4 (95% CI, 2.3-8.3) for other hospitalized hemorrhages, and 4.7 (95% CI, 1.7-12.7) for hematologic malignancy. The 5-year all-cause mortality RR was 2.3 (95% CI, 1.8-3.0). In summary, primary chronic ITP was associated with substantially increased long-term risk of infections, hemorrhagic episodes requiring hospitalization, hematologic malignancies, and mortality. PMID- 21263149 TI - Homozygosity mapping with SNP arrays confirms 3p21 as a recessive locus for gray platelet syndrome and narrows the interval significantly. AB - Gray platelet syndrome (GPS) is an inherited bleeding disorder characterized by thrombocytopenia and the absence of alpha-granules in platelets. Patients with GPS present with mild to moderate bleeding and many develop myelofibrosis. The genetic cause of GPS is unknown. We present 2 Native American families with a total of 5 affected persons and a single affected patient of Pakistani origin in which GPS appears to be inherited in an autosomal recessive manner. Homozygosity mapping using the Affymetrix 6.0 chips demonstrates that all 6 GPS-affected persons studied are homozygous for a 1.7-Mb region in 3p21. Linkage analysis confirmed the region with a logarithm of the odds score of 2.7. Data from our families enabled us to significantly decrease the size of the critical region for GPS from the previously reported 9.4-Mb region at 3p21. PMID- 21263150 TI - Identification of HIF2alpha as an important STAT5 target gene in human hematopoietic stem cells. AB - The transcription factor signal transducer and activator of transcription 5 (STAT5) fulfills essential roles in self-renewal in mouse and human hematopoietic stem cells (HSCs), and its persistent activation contributes to leukemic transformation, although little molecular insight into the underlying mechanisms has been obtained. In the present study, we show that STAT5 can impose long-term expansion exclusively on human HSCs, not on progenitors. This was associated with an enhanced cobblestone formation under bone marrow stromal cells of STAT5 transduced HSCs. Hypoxia-induced factor 2alpha (HIF2alpha) was identified as a STAT5 target gene in HSCs, and chromatin immunoprecipitation studies revealed STAT5 binding to a site 344 base pairs upstream of the start codon of HIF2alpha. Lentiviral RNA interference (RNAi)-mediated down-modulation of HIF2alpha impaired STAT5-induced long-term expansion and HSC frequencies, whereas differentiation was not affected. Glucose uptake was elevated in STAT5-activated HSCs, and several genes associated with glucose metabolism were up-regulated by STAT5 in an HIF2alpha-dependent manner. Our studies indicate that pathways normally activated under hypoxia might be used by STAT5 under higher oxygen conditions to maintain and/or impose HSC self-renewal properties. PMID- 21263151 TI - Noninvasive prenatal diagnosis of hemophilia by microfluidics digital PCR analysis of maternal plasma DNA. AB - Hemophilia is a bleeding disorder with X-linked inheritance. Current prenatal diagnostic methods for hemophilia are invasive and pose a risk to the fetus. Cell free fetal DNA analysis in maternal plasma provides a noninvasive mean of assessing fetal sex in such pregnancies. However, the disease status of male fetuses remains unknown if mutation-specific confirmatory analysis is not performed. Here we have developed a noninvasive test to diagnose whether the fetus has inherited a causative mutation for hemophilia from its mother. The strategy is based on a relative mutation dosage approach, which we have previously established for determining the mutational status of fetuses for autosomal disease mutations. In this study, the relative mutation dosage method is used to deduce whether a fetus has inherited a hemophilia mutation on chromosome X by detecting whether the concentration of the mutant or wild-type allele is overrepresented in the plasma of heterozygous women carrying male fetuses. We correctly detected fetal genotypes for hemophilia mutations in all of the 12 studied maternal plasma samples obtained from at-risk pregnancies from as early as the 11th week of gestation. This development would make the decision to undertake prenatal testing less traumatic and safer for at-risk families. PMID- 21263152 TI - How I treat relapsed and refractory Hodgkin lymphoma. AB - Relapsed or refractory Hodgkin lymphoma is a challenging problem for clinicians who treat hematologic malignancies. The standard management of these patients should include the use of salvage chemotherapy followed by autologous stem cell transplant (ASCT) in patients who are chemotherapy sensitive. Open issues in this area include the role of functional imaging, the specific chemotherapy regimen to be used before ASCT, and the role of consolidative radiotherapy. Some patients will not be eligible for ASCT, and alternative approaches with conventional chemotherapy alone or with salvage radiotherapy should be considered. Prognostic factors for relapsed/refractory disease have been identified but generally are not used as a part of risk-adapted therapy. Allogeneic transplantation may offer the potential of a graft-versus-lymphoma effect, but this therapy has significant toxicity and results in few long-term disease-free survivors; hence, it should only be offered in the context of disease-specific clinical trials. An expanding list of novel drugs has exhibited promising single-agent activity. Patients have effective options beyond primary therapy, and continued progress through controlled trials remains a tangible goal in the treatment of relapsed and refractory disease. PMID- 21263153 TI - Sox6 enhances erythroid differentiation in human erythroid progenitors. AB - Sox6 belongs to the Sry (sex-determining region Y)-related high-mobility-group box family of transcription factors, which control cell-fate specification of many cell types. Here, we explored the role of Sox6 in human erythropoiesis by its overexpression both in the erythroleukemic K562 cell line and in primary erythroid cultures from human cord blood CD34+ cells. Sox6 induced significant erythroid differentiation in both models. K562 cells underwent hemoglobinization and, despite their leukemic origin, died within 9 days after transduction; primary erythroid cultures accelerated their kinetics of erythroid maturation and increased the number of cells that reached the final enucleation step. Searching for direct Sox6 targets, we found SOCS3 (suppressor of cytokine signaling-3), a known mediator of cytokine response. Sox6 was bound in vitro and in vivo to an evolutionarily conserved regulatory SOCS3 element, which induced transcriptional activation. SOCS3 overexpression in K562 cells and in primary erythroid cells recapitulated the growth inhibition induced by Sox6, which demonstrates that SOCS3 is a relevant Sox6 effector. PMID- 21263154 TI - Chemotherapeutic agents circumvent emergence of dasatinib-resistant BCR-ABL kinase mutations in a precise mouse model of Philadelphia chromosome-positive acute lymphoblastic leukemia. AB - The introduction of cultured p185(BCR-ABL)-expressing (p185+) Arf (-/-) pre-B cells into healthy syngeneic mice induces aggressive acute lymphoblastic leukemia (ALL) that genetically and phenotypically mimics the human disease. We adapted this high-throughput Philadelphia chromosome-positive (Ph(+)) ALL animal model for in vivo luminescent imaging to investigate disease progression, targeted therapeutic response, and ALL relapse in living mice. Mice bearing high leukemic burdens (simulating human Ph(+) ALL at diagnosis) entered remission on maximally intensive, twice-daily dasatinib therapy, but invariably relapsed with disseminated and/or central nervous system disease. Although relapse was frequently accompanied by the eventual appearance of leukemic clones harboring BCR-ABL kinase domain (KD) mutations that confer drug resistance, their clonal emergence required prolonged dasatinib exposure. KD P-loop mutations predominated in mice receiving less intensive therapy, whereas high-dose treatment selected for T315I "gatekeeper" mutations resistant to all 3 Food and Drug Administration approved BCR-ABL kinase inhibitors. The addition of dexamethasone and/or L asparaginase to reduced-intensity dasatinib therapy improved long-term survival of the majority of mice that received all 3 drugs. Although non-tumor-cell autonomous mechanisms can prevent full eradication of dasatinib-refractory ALL in this clinically relevant model, the emergence of resistance to BCR-ABL kinase inhibitors can be effectively circumvented by the addition of "conventional" chemotherapeutic agents with alternate antileukemic mechanisms of action. PMID- 21263155 TI - FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo. AB - We examined in vivo FLT3 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly diagnosed acute myeloid leukemia patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. After intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients, whereas they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated FLT3 inhibition and cytotoxicity for each of 5 different FLT3 inhibitors (lestaurtinib, midostaurin, sorafenib, KW-2449, and AC220). The dramatic increase in FL level after chemotherapy represents a possible obstacle to inhibiting FLT3 in this clinical setting. These findings could have important implications regarding the design and outcome of trials of FLT3 inhibitors and furthermore suggest a rationale for targeting FL as a therapeutic strategy. PMID- 21263156 TI - Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. AB - Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD. PMID- 21263158 TI - Our man in dorpat: Rudolf Buchheim and the birth of pharmacology. PMID- 21263159 TI - Of toxic tales and poisoned pens: melding toxicology and creative writing in an undergraduate course. PMID- 21263157 TI - Single-lineage transcriptome analysis reveals key regulatory pathways in primitive erythroid progenitors in the mouse embryo. AB - Primitive erythroid (EryP) progenitors are the first cell type specified from the mesoderm late in gastrulation. We used a transgenic reporter to image and purify the earliest blood progenitors and their descendants from developing mouse embryos. EryP progenitors exhibited remarkable proliferative capacity in the yolk sac immediately before the onset of circulation, when these cells comprise nearly half of all cells of the embryo. Global expression profiles generated at 24-hour intervals from embryonic day 7.5 through 2.5 revealed 2 abrupt changes in transcript diversity that coincided with the entry of EryPs into the circulation and with their late maturation and enucleation, respectively. These changes were paralleled by the expression of critical regulatory factors. Experiments designed to test predictions from these data demonstrated that the Wnt-signaling pathway is active in EryP progenitors, which display an aerobic glycolytic profile and the numbers of which are regulated by transforming growth factor-beta1 and hypoxia. This is the first transcriptome assembled for a single hematopoietic lineage of the embryo over the course of its differentiation. PMID- 21263160 TI - Strategizing the clone wars: pharmacological control of cellular sensitivity to radiation. AB - The combined administration of ionizing radiation and systemic chemotherapy is an accepted standard of care for numerous cancers. Improved efficacy through the combination of therapies reflects several interrelated processes, including DNA damage, inhibition of DNA synthesis, alteration of cell cycle distribution, and impaired DNA repair. Insights into cellular responses to radiation have led to the use of drugs that target specific intracellular signaling pathways to sensitize cells to radiation. Combinations of chemotherapy and radiation continue to be optimized, based on preclinical and early-phase clinical data that indicate the ideal sequencing of therapies, the best combinations of agents (including radiosensitizers), and the most reliable biological markers for predicting patient responsiveness. This review summarizes our current understanding of radiosensitization as it relates to preclinical drug development and discusses the potential benefits of judiciously incorporating both traditional and targeted chemotherapy into radiation regimens. PMID- 21263161 TI - Antioxidants in hypertension and cardiovascular disease. AB - Cardiovascular disease is characterized by enhanced oxidative stress in the vascular wall, heart, kidney, and brain. Epidemiological evidence suggests that antioxidants, including vitamins C and E, alpha-carotene, and beta-carotene, may be therapeutic; however, interventional trials of antioxidants have provided mixed results, with some showing deleterious consequences. It is thus crucial that we consider the implications of trial design and execution, and further investigation of cellular pro-and antioxidant mechanisms is critical. Angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor blockers reduce the generation of reactive oxygen species, in experimental models as well as in humans, and have demonstrated beneficial cardiovascular effects. Polyphenols and antioxidants contained in foods and beverages may also be cardioprotective. Recent studies suggest that the judicious development of antioxidant agents may provide an effective approach to quench oxidative stress in tissues and improve cardiovascular health. PMID- 21263162 TI - The promise of epigenetics in personalized medicine. AB - Numerous preclinical and clinical trials, with older as well as some newer drugs, have demonstrated the targeting of aberrant epigenetic marks to be a viable means of preventing and treating certain human disorders, including myelodysplastic and leukemic syndromes and various hemoglobinopathies. These findings are encouraging, and although the risks associated with such therapy are largely unknown, precise maps of epigenetic marks are becoming increasingly available through advancements in sequencing protocols that combine chromatin immunoprecipitation and gene expression analyses. Indeed, progress in understanding gene regulation at promoter regions and chromatin organization in health and disease has been substantial. New insights into the proteins that are targeted by therapeutic agents that alter epigenetic programs may provide important inroads into personalized medicine. PMID- 21263163 TI - Nonnegative Matrix Factorization with Earth Mover's Distance Metric for Image Analysis. AB - Nonnegative matrix factorization (NMF) approximates a given data matrix as a product of two low-rank nonnegative matrices, usually by minimizing the L2 or the KL distance between the data matrix and the matrix product. This factorization was shown to be useful for several important computer vision applications. We propose here two new NMF algorithms that minimize the Earth mover's distance (EMD) error between the data and the matrix product. The algorithms (EMD NMF and bilateral EMD NMF) are iterative and based on linear programming methods. We prove their convergence, discuss their numerical difficulties, and propose efficient approximations. Naturally, the matrices obtained with EMD NMF are different from those obtained with L2-NMF. We discuss these differences in the context of two challenging computer vision tasks, texture classification and face recognition, perform actual NMF-based image segmentation for the first time, and demonstrate the advantages of the new methods with common benchmarks. PMID- 21263164 TI - Self-Adaptive Induction of Regression Trees. AB - A new algorithm for incremental construction of binary regression trees is presented. This algorithm, called SAIRT, adapts the induced model when facing data streams involving unknown dynamics, like gradual and abrupt function drift, changes in certain regions of the function, noise, and virtual drift. It also handles both symbolic and numeric attributes. The proposed algorithm can automatically adapt its internal parameters and model structure to obtain new patterns, depending on the current dynamics of the data stream. SAIRT can monitor the usefulness of nodes and can forget examples from selected regions, storing the remaining ones in local windows associated to the leaves of the tree. On these conditions, current regression methods need a careful configuration depending on the dynamics of the problem. Experimentation suggests that the proposed algorithm obtains better results than current algorithms when dealing with data streams that involve changes with different speeds, noise levels, sampling distribution of examples, and partial or complete changes of the underlying function. PMID- 21263165 TI - Targets of DNA-binding proteins in bacterial promoter regions present enhanced probabilities for spontaneous thermal openings. AB - We mapped promoter regions of double-stranded DNA with respect to the probabilities of appearance of relatively large bubble openings exclusively due to thermal fluctuations at physiological temperatures. We analyzed five well studied promoter regions of procaryotic type and found a spatial correlation between the binding sites of transcription factors and the position of peaks in the probability pattern of large thermal openings. Other distinct peaks of the calculated patterns correlate with potential binding sites of DNA-binding proteins. These results suggest that a DNA molecule would more frequently expose the bases that participate in contacts with proteins, which would probably enhance the probability of the latter to reach their targets. It also stands for using this method as a means to analyze DNA sequences based on their intrinsic thermal properties. PMID- 21263166 TI - Thermal stabilization of collagen in skin and decalcified bone. AB - The state of collagen molecules in the fibres of tail tendon, skin and demineralized bone has been investigated in situ using differential scanning calorimetry (DSC). Hydroxyproline analysis and tissue digestion with bacterial collagenase and trypsin were used to confirm that the common cause of all the DSC endotherms was collagen denaturation. This occurred within a narrow temperature range in tendons, but over a wide temperature range in demineralized bone and old skin and demonstrated that in tendon and demineralized bone at least the same type I collagen molecule exists in different thermal states. Hypothesizing that this might be caused by different degrees of confinement within the fibre lattice, experiments were performed to measure the effect of changing the lattice dimensions by extracting the collagen into dilute solution with pepsin, swelling the lattice in acetic acid, and contracting the lattice by dehydration. A theoretical analysis was undertaken to predict the effect of dehydration. Results were consistent with the hypothesis, demonstrating that collagen molecules within the natural fibres of bone and old skin are located at different intermolecular spacings, revealing differences between molecules in the magnitude of either the attractive or repulsive forces controlling their separation. One potential cause of such variation is known differences in covalent cross-linking. PMID- 21263167 TI - Self-organized models of selectivity in calcium channels. AB - The role of flexibility in the selectivity of calcium channels is studied using a simple model with two parameters that accounts for the selectivity of calcium (and sodium) channels in many ionic solutions of different compositions and concentrations using two parameters with unchanging values. We compare the distribution of side chains (oxygens) and cations (Na(+) and Ca(2+)) and integrated quantities. We compare the occupancies of cations Ca(2+)/Na(+) and linearized conductance of Na(+). The distributions show a strong dependence on the locations of fixed side chains and the flexibility of the side chains. Holding the side chains fixed at certain predetermined locations in the selectivity filter distorts the distribution of Ca(2+) and Na(+) in the selectivity filter. However, integrated quantities-occupancy and normalized conductance-are much less sensitive. Our results show that some flexibility of side chains is necessary to avoid obstruction of the ionic pathway by oxygen ions in 'unfortunate' fixed positions. When oxygen ions are mobile, they adjust 'automatically' and move 'out of the way', so they can accommodate the permeable cations in the selectivity filter. Structure is the computed consequence of the forces in this model. The structures are self-organized, at their free energy minimum. The relationship of ions and side chains varies with an ionic solution. Monte Carlo simulations are particularly well suited to compute induced-fit, self organized structures because the simulations yield an ensemble of structures near their free energy minimum. The exact location and mobility of oxygen ions has little effect on the selectivity behavior of calcium channels. Seemingly, nature has chosen a robust mechanism to control selectivity in calcium channels: the first-order determinant of selectivity is the density of charge in the selectivity filter. The density is determined by filter volume along with the charge and excluded volume of structural ions confined within it. Flexibility seems a second-order determinant. These results justify our original assumption that the important factor in Ca(2+) versus Na(+) selectivity is the density of oxygen ions in the selectivity filter along with (charge) polarization (i.e. dielectric properties). The assumption of maximum mobility of oxygens seems to be an excellent approximate working hypothesis in the absence of exact structural information. These conclusions, of course, apply to what we study here. Flexibility and fine structural details may have an important role in other properties of calcium channels that are not studied in this paper. They surely have important roles in other channels, enzymes, and proteins. PMID- 21263168 TI - Design principles and specificity in biological networks with cross activation. AB - Cells sense and respond to diverse environmental stimuli using a set of intracellular signaling components. Often, the signal transduction pathways contain shared components which lead to cross activation at different levels of the pathway. To discover the design principles that ensure signaling specificity is a challenging task, especially for pathways that contain numerous components. Here, we present an analysis of cross-activating pathways and show that a general inhibitory scheme, asymmetric hierarchical inhibition, is sufficient to ensure signaling specificity. Based on this inhibitory scheme, we are able to enumerate all possible network topologies containing two inhibitory links that guarantee specificity. Furthermore, we apply our methodology to the mating and filamentous growth pathways of the yeast model system Saccharomyces cerevisiae. We enumerate the possible ways to wire this model system and determine which topology is consistent with experimental data. PMID- 21263169 TI - Distribution of dwell times of a ribosome: effects of infidelity, kinetic proofreading and ribosome crowding. AB - Ribosome is a molecular machine that polymerizes a protein where the sequence of the amino acid residues, the monomers of the protein, is dictated by the sequence of codons (triplets of nucleotides) on a messenger RNA (mRNA) that serves as the template. The ribosome is a molecular motor that utilizes the template mRNA strand also as the track. Thus, in each step the ribosome moves forward by one codon and, simultaneously, elongates the protein by one amino acid. We present a theoretical model that captures most of the main steps in the mechanochemical cycle of a ribosome. The stochastic movement of the ribosome consists of an alternating sequence of pause and translocation; the sum of the durations of a pause and the following translocation is the time of dwell of the ribosome at the corresponding codon. We derive the analytical expression for the distribution of the dwell times of a ribosome in our model. Wherever experimental data are available, our theoretical predictions are consistent with those results. We suggest appropriate experiments to test the new predictions of our model, particularly the effects of the quality control mechanism of the ribosome and that of their crowding on the mRNA track. PMID- 21263170 TI - Memory and obesity affect the population dynamics of asexual freshwater planarians. AB - Asexual reproduction in multicellular organisms is a complex biophysical process that is not yet well understood quantitatively. Here, we report a detailed population study for the asexual freshwater planarian Schmidtea mediterranea, which can reproduce via transverse fission due to a large stem cell contingent. Our long-term observations of isolated non-interacting planarian populations reveal that the characteristic fission waiting time distributions for head and tail fragments differ significantly from each other. The stochastic fission dynamics of tail fragments exhibits non-negligible memory effects, implying that an accurate mathematical description of future data should be based on non Markovian tree models. By comparing the effective growth of non-interacting planarian populations with those of self-interacting populations, we are able to quantify the influence of interactions between flatworms and physical conditions on the population growth. A surprising result is the non-monotonic relationship between effective population growth rate and nutrient supply: planarians exhibit a tendency to become 'obese' if the feeding frequency exceeds a critical level, resulting in a decreased reproduction activity. This suggests that these flatworms, which possess many genes homologous to those of humans, could become a new model system for studying dietary effects on reproduction and regeneration in multicellular organisms. PMID- 21263171 TI - Computer-aided detection of early interstitial lung diseases using low-dose CT images. AB - This study aims to develop a new computer-aided detection (CAD) scheme to detect early interstitial lung disease (ILD) using low-dose computed tomography (CT) examinations. The CAD scheme classifies each pixel depicted on the segmented lung areas into positive or negative groups for ILD using a mesh-grid-based region growth method and a multi-feature-based artificial neural network (ANN). A genetic algorithm was applied to select optimal image features and the ANN structure. In testing each CT examination, only pixels selected by the mesh-grid region growth method were analyzed and classified by the ANN to improve computational efficiency. All unselected pixels were classified as negative for ILD. After classifying all pixels into the positive and negative groups, CAD computed a detection score based on the ratio of the number of positive pixels to all pixels in the segmented lung areas, which indicates the likelihood of the test case being positive for ILD. When applying to an independent testing dataset of 15 positive and 15 negative cases, the CAD scheme yielded the area under receiver operating characteristic curve (AUC = 0.884 +/- 0.064) and 80.0% sensitivity at 85.7% specificity. The results demonstrated the feasibility of applying the CAD scheme to automatically detect early ILD using low-dose CT examinations. PMID- 21263172 TI - Noise propagation for iterative penalized-likelihood image reconstruction based on Fisher information. AB - Iterative reconstruction algorithms have been widely used in PET and SPECT emission tomography. Accurate modeling of photon noise propagation is crucial for quantitative tomography applications. Iteration-based noise propagation methods have been developed for only a few algorithms that have explicit multiplicative update equations. And there are discrepancies between the iteration-based methods and Fessler's fixed-point method because of improper approximations. In this paper, we present a unified theoretical prediction of noise propagation for any penalized expectation maximization (EM) algorithm where the EM approach incorporates a penalty term. The proposed method does not require an explicit update equation. The update equation is assumed to be implicitly defined by a differential equation of a surrogate function. We derive the expressions using the implicit function theorem, Taylor series and the chain rule from vector calculus. We also derive the fixed-point expressions when iterative algorithms converge and show the consistency between the proposed method and the fixed-point method. These expressions are solely defined in terms of the partial derivatives of the surrogate function and the Fisher information matrices. We also apply the theoretical noise predictions for iterative reconstruction algorithms in emission tomography. Finally, we validate the theoretical predictions for MAP-EM and OSEM algorithms using Monte Carlo simulations with Jaszczak-like and XCAT phantoms, respectively. PMID- 21263173 TI - An efficient dose calculation strategy for intensity modulated proton therapy. AB - While intensity-modulated proton therapy (IMPT) has great potential to improve the therapeutic efficacy of radiotherapy, IMPT optimization can be computationally demanding, particularly for large and complex tumors. Here we propose a dose calculation strategy to accelerate IMPT optimization while reducing memory requirements. By using two adjustable threshold parameters, our method separates dose contributions from proton beamlets into major and minor components for each dose voxel. The optimization proceeds with two levels of iterations: in inner iterations, doses are updated in correspondence with changes in beamlet intensities from only the major contributions while keeping the portions from the minor contributions constant; in outer iterations, doses are recalculated exactly by considering both major and minor contributions. Since the number of elements in the influence matrix for major contributions is relatively small, each inner iteration proceeds quickly. Each outer iteration requires a longer computation time, but only a few such iterations are needed. Our study shows that the proposed strategy leads to nearly identical dose distributions as those optimized with the full influence matrix, but reducing computing time by at least a factor of 3 and internal memory requirements by a factor of 10 or more. In addition, we show that the proposed approach could enhance other optimization related applications such as optimizing beam angles. By using an advanced lung cancer case that would demand large computing resources by conventional optimization approach, we show how our method may potentially help improve IMPT treatment planning in real clinical situations. PMID- 21263174 TI - Monte Carlo patient study on the comparison of prompt gamma and PET imaging for range verification in proton therapy. AB - The purpose of this work was to compare the clinical adaptation of prompt gamma (PG) imaging and positron emission tomography (PET) as independent tools for non invasive proton beam range verification and treatment validation. The PG range correlation and its differences with PET have been modeled for the first time in a highly heterogeneous tissue environment, using different field sizes and configurations. Four patients with different tumor locations (head and neck, prostate, spine and abdomen) were chosen to compare the site-specific behaviors of the PG and PET images, using both passive scattered and pencil beam fields. Accurate reconstruction of dose, PG and PET distributions was achieved by using the planning computed tomography (CT) image in a validated GEANT4-based Monte Carlo code capable of modeling the treatment nozzle and patient anatomy in detail. The physical and biological washout phenomenon and decay half-lives for PET activity for the most abundant isotopes such as (11)C, (15)O, (13)N, (30)P and (38)K were taken into account in the data analysis. The attenuation of the gamma signal after traversing the patient geometry and respective detection efficiencies were estimated for both methods to ensure proper comparison. The projected dose, PG and PET profiles along many lines in the beam direction were analyzed to investigate the correlation consistency across the beam width. For all subjects, the PG method showed on average approximately 10 times higher gamma production rates than the PET method before, and 60 to 80 times higher production after including the washout correction and acquisition time delay. This rate strongly depended on tissue density and elemental composition. For broad passive scattered fields, it was demonstrated that large differences exist between PG and PET signal falloff positions and the correlation with the dose distribution for different lines in the beam direction. These variations also depended on the treatment site and the particular subject. Thus, similar to PET, direct range verification with PG in passive scattering is not easily viable. However, upon development of an optimized 3D PG detector, indirect range verification by comparing measured and simulated PG distributions (currently being explored for the PET method) would be more beneficial because it can avoid the inherent biological challenges of the PET imaging. The improved correlation of PG and PET with dose when using pencil beams was evident. PG imaging was found to be potentially advantageous especially for small tumors in the presence of high tissue heterogeneities. Including the effects of detector acceptance and efficiency may hold PET superior in terms of the amplitude of the detected signal (depending on the future development of PG detection technology), but the ability to perform online measurements and avoid signal disintegration (due to washout) with PG are important factors that can outweigh the benefits of higher detection sensitivity. PMID- 21263175 TI - Optic axis determination by fibre-based polarization-sensitive swept-source optical coherence tomography. AB - We describe a fibre-based variable-incidence angle (VIA) polarization-sensitive swept-source optical coherence tomography (PS-SS-OCT) system to determine the 3D optical axis of birefringent biological tissues. Single-plane VIA-PS-OCT is also explored which requires measurement of the absolute fast-axis orientation. A state-of-the-art PS-SS-OCT system with some improvements both in hardware and software was used to determine the apparent optical birefringence of equine tendon for a number of different illumination directions. Polar and azimuthal angles of cut equine tendon were produced by the VIA method and compared with the nominal values. A quarter waveplate (QWP) and equine tendon were used as test targets to validate the fast-axis measurements using the system. Polar and azimuthal angles of cut equine tendon broadly agreed with the expected values within about 8% of the nominal values. A theoretical and experimental analysis of the effect of the sample arm fibre on determination of optical axis orientation using a proposed definition based on the orientation of the eigenpolarization ellipse experimentally confirms that this algorithm only works correctly for special settings of the sample arm fibre. A proposed algorithm based on the angle between Stokes vectors on the Poincare sphere is confirmed to work for all settings of the sample arm fibre. A calibration procedure is proposed to remove the sign ambiguity of the measured orientation and was confirmed experimentally by using the QWP. PMID- 21263176 TI - Development of a small prototype for a proof-of-concept of OpenPET imaging. AB - The OpenPET geometry is our new idea to visualize a physically opened space between two detector rings. In this paper, we developed the first small prototype to show a proof-of-concept of OpenPET imaging. Two detector rings of 110 mm diameter and 42 mm axial length were placed with a gap of 42 mm. The basic imaging performance was confirmed through phantom studies; the open imaging was realized at the cost of slight loss of axial resolution and 24% loss of sensitivity. For a proof-of-concept of PET image-guided radiation therapy, we carried out the in-beam tests with (11)C radioactive beam irradiation in the heavy ion medical accelerator in Chiba to visualize in situ distribution of primary particles stopped in a phantom. We showed that PET images corresponding to dose distribution were obtained. For an initial proof-of-concept of real-time multimodal imaging, we measured a tumor-inoculated mouse with (18)F-FDG, and an optical image of the mouse body surface was taken during the PET measurement by inserting a digital camera in the ring gap. We confirmed that the tumor in the gap was clearly visualized. The result also showed the extension effect of an axial field-of-view (FOV); a large axial FOV of 126 mm was obtained with the detectors that originally covered only an 84 mm axial FOV. In conclusion, our initial imaging studies showed promising performance of the OpenPET. PMID- 21263177 TI - Effect of RGDS-expressing fibroin dose on initial adhesive force of a single chondrocyte. AB - Initial chondrocyte-material interactions are important for cell behaviors such as proliferation, phenotypic expression and matrix synthesis. Previously, we showed that chondrocytes cultured in/on silk fibroin scaffolds proliferate without dedifferentiating into fibroblast-like cells and that RGDS sequences genetically interfused in the fibroin light chain protein enhance cartilage tissue formation. In the present study, the adhesive force of chondrocytes was measured on fibroin substrates containing RGDS-expressing fibroin molecules produced by transgenic silkworms at the different densities of 0, 0.6, 1.5 and 3.0 mol%. The degree of chondrocyte attachment to fibroin substrates increased with the number of RGDS-expressing fibroin molecules. Moreover, the adhesive force per unit spreading area of a single cultured chondrocyte exhibited a peak that was higher with increased RGDS concentrations. The results of this study indicate that the RGDS sequences genetically interfused in the fibroin light chain protein exert effects on chondrocytes' adhesive behavior and can enhance cartilage tissue organization. PMID- 21263178 TI - Condensed cellular seeded collagen gel as an improved biomaterial for tissue engineering of articular cartilage. AB - Three-dimensional autologous chondrocyte implantation based on collagen gel as matrix scaffold has become a clinically applied treatment for focal defects of articular cartilage. However, the low biomechanical properties of collagen gel makes intraoperative handling difficult and creates the risk of early damages to the vulnerable implant. The aim of the study was to create a stabilized form of collagen gel and to evaluate its biomechanical and biochemical properties.Collagen type-I gel was seeded with human articular chondrocytes. 20 samples were subject to condensation which was achieved mechanically by compression and filtration. Control samples were left uncondensed. From both types of gels 10 samples were used for initial biomechanical evaluation by means of unconfined compression and 10 samples were cultivated under standard conditions in vitro. Following cultivation the samples were evaluated by conventional histology and immunohistochemistry. The proliferation rate was calculated and matrix gene expression was quantified by real-time PCR.The biomechanical tests revealed a higher force carrying capacity of the condensed specimens. Strain rate dependency and relaxation was seen in both types of collagen gel representing viscoelastic material properties. Cells embedded within the condensed collagen gel were able to produce extracellular matrix proteins and showed proliferation.Condensed collagen gel represents a mechanically improved type of biomaterial which is suitable for three-dimensional autologous chondrocyte implantation. PMID- 21263179 TI - Gravimetric wear analysis and particulate characterization of bilateral facet augmentation system--PercuDynTM. AB - Dynamic stabilization systems are emerging as an alternative to fusion instrumentation. However, cyclic loading and micro-motion at various interfaces may produce wear debris leading to adverse tissue reactions such as osteolysis. Ten million cycles of wear test was performed for PercuDynTM in axial rotation and the wear profile and the wear rate was mapped. A validation study was undertaken to assess the efficiency of wear debris collection which accounted for experimental errors. The mean wear debris measured at the end of 10 million cycles was 4.01 mg, based on the worst-case recovery rate of 68.2%. Approximately 40% of the particulates were less than 5 MUm; 92% less than 10 MUm. About 43% of particulates were spherical in shape, 27% particulates were ellipsoidal and the remaining particles were of irregular shapes. The PercuDynTM exhibited an average polymeric wear rate of 0.4 mg/million cycles; substantially less than the literature derived studies for other motion preservation devices like the Bryan disc and Charite disc. Wear debris size and shape were also similar to these devices. PMID- 21263180 TI - Evaluation of NiTi Superelastic Retraction Coil Springs for orthodontic tooth movement in rats. AB - The purpose of this investigation was to assess mechanical properties of Superelastic Retraction Coil Springs for orthodontic use. To reach a goal, a test frame, comprising measuring force transducers was developed. To perform metallographic analyses of the nickel-titanium wire the samples of Superelastic Retraction Coil Springs were observed by scanning electron microscope. For in vivo testing, twenty male Wistar rats, 11-12 weeks of age, were used (Group I with Superelastic Retraction Coil Springs, Group II controls). To simulate human distraction as close as possible, all the applied Superelastic Retraction Coil Springs were modified. The Superelastic Retraction Coil Springs creating a constant force of 25 cN were then attached between the upper left first molars and upper left incisors. Results showed that the reproducible force of 25 cN was shown over a range of 1-11 mm extension. Results also showed that the distance between aforementioned teeth, measured on days 0, 7, 14, 21, 24, 32, 37 and 40, decreased in Group I. Contrary, in Group II the distance between the teeth increased during the study (p<0.001). PMID- 21263181 TI - Influence of loading cycle profile and frequency on a biomechanical parameter of a model of a balloon kyphoplasty-augmented lumbar spine segment: a finite element analysis study. AB - For patients who are suffering debilitating and persistent pain due to vertebral compression fracture(s) and for whom conservative therapies have not provided relief, balloon kyphoplasty (BKP) is used as a surgical option. There are only a very few literature reports on the use of the finite element analysis (FEA) method to obtain biomechanical parameters of models of spine segments that include BKP augmentation at a given level. In each of these studies, the applied loading used was quasi-static. During normal activities of daily living, the patient's spine would be subject to dynamically-applied loading. Thus, the question of the influence of the characteristics of a dynamically-applied loading cycle on biomechanical parameters of a spine that includes BKP-augmented segment(s) is germane; however, a study of this issue is lacking. We investigated this issue in the present FEA work, with the spine segment model being the L1-L3 motion segment units (MSUs) (a segment that is commonly augmented using BKP) and prophylactic BKP simulated at L2. The dynamic load was the compressive load versus-time cycle to which the L3-L4 MSU is subjected during gait. Four cases of the cycle were considered, corresponding to slow-, normal-, fast- and very fast paced gait. The loading cycle was applied to the superior surface of L1 while the inferior surface of L3 was fully constrained. It was found that (1) the global mean von Mises stress during the loading cycle (sigmaVMG), in each tissue in the model increased in going from a slow-paced gait cycle to a very fast-paced gait cycle; and (2) for the slow-paced gait cycle, with increase in frequency of the cycle, f (1 <= f <= 3 Hz), sigmaVMG in each of these tissues increased. Potential uses of the present findings are identified. PMID- 21263182 TI - Young's modulus of collagen at slow displacement rates. AB - Collagen is a key structural component of extracellular matrix and its mechanical properties, particularly its stiffness, have been shown to influence cell function. This study explores the mechanical behavior of type I collagen gels at low rates relevant to that of cell motion. The Young's modulus, E, was obtained for collagen samples of concentrations 1.3, 2 and 3 mg/ml at varying crosshead displacement rates: 0.01, 0.1 and 1 mm/min. Local strain measurement in the gage section were used for both the strain and strain rate determination. The power law models for the modulus at these low strain rates show that the values converge as the displacement rate approaches a quasistatic state. This study provides data that was unavailable in the past on the Young's modulus of collagen at rates relevant to the cell. PMID- 21263183 TI - Embryonic stem cells induce ectopic bone formation in rats. AB - BACKGROUND: Surgery often leads to massive destruction of the skeleton. Cell based bone reconstruction therapies promise new therapeutic opportunities for the repair of bone. Embryonic stem cells (ESCs) can be differentiated into osteogenic cells and are a potential cell source for bone tissue engineering. The purpose of this in vivo study was to investigate the bone formation in various constructs containing ESCs (with and without micromass technology) and insoluble collagenous bone matrix (ICBM). METHODS: Murine ESCs were cultured as monolayer cultures as well as micromasses and seeded on ICBM. These constructs were implanted in immunodeficient rats. After one week, one, two and three months CT-scans were performed to detect any calcifications and the rats were sacrificed. RESULTS: The radiological examination shows a steep increase of the mineralized tissue in group 1 (ICBM+seeded ESC). This increase can be considered as statistical significant. In contrast, the volume of the mineralization in group 2 (ICBM+ESC spheres) and group 3 (ESC-spheres) does not increase significantly during the study. CONCLUSION: ESCs in combination with ICBM do promote ectopic bone formation in vivo. Thus, this cell population as well as the biomaterial ICBM might be promising components for bone tissue engineering. PMID- 21263187 TI - Association of LEP and ADIPOQ common variants with colorectal cancer in Mexican patients. AB - Leptin and adiponectin are cytokines produced by adipose tissue with opposite effects on tumor growth: the former stimulate whereas the latter inhibit it. The objective was to analyze the association of LEP A19G and ADIPOQ+45 T/G and +276 G/T polymorphisms in Mexican patients with colorectal cancer (CRC). 68 unrelated patients with CRC (study group) and 102 blood donors (control group); all subjects were Mestizos from western Mexico. The polymorphisms were established by PCR-RFLP on DNA samples obtained from peripheral blood. The LEP A19G polymorphism showed significant differences between CRC patients and control group (p= 0.01 for G/A genotype and p= 0.02 for the recessive model G/G +G/A); yet, in the analysis stratified by gender, this difference remained significant only in males. The ADIPOQ polymorphisms did not shown any significant differences. Our results suggest that the A19G LEP polymorphism is associated with CRC in Mexican patients. PMID- 21263188 TI - Assessment of novel combinations of biomarkers for the detection of colorectal cancer. AB - BACKGROUND: Patients with colorectal cancer often present with advanced disease and concomitant poor prognosis. The best known serum biomarker, carcinoembryonic antigen (CEA) is not recommended for screening because of its limited specificity and sensitivity. A number of other circulating proteins have been suggested to be diagnostically useful but individually none of these has proved to be of sufficient sensitivity or specificity to establish a role in routine clinical practice. Here, we test the hypothesis that combining several of these biomarkers will improve diagnostic efficacy. METHODS: To select the markers for our model we screened CEA and 26 other candidate biomarkers. Four candidates were selected and their concentrations determined in the serum of 239 patients (106 colorectal cancer patients and 133 non-cancer subjects). RESULTS: Class prediction models based on CEA, DR-70 and sCD26 produced a modest increase in detection accuracy over CEA alone, particularly for early stage cancers. The sensitivity and specificity required for a clinically useful test was not reached. CONCLUSION: It is unlikely that a biomarker panel comprised of the currently available serum markers will generate a clinically useful diagnostic test for colorectal cancer. Our findings reiterate the urgent need to discover novel biomarkers for the detection of colorectal cancer. PMID- 21263189 TI - Stepwise algorithm combining HPV high-risk DNA-based assays and RNA-based assay for high grade CIN in women with abnormal smears referred to colposcopy. AB - BACKGROUND: The detection of high-risk human papillomavirus (HPV) DNA provides higher sensitivity but lower specificity than cytology for the identification of high-grade cervical intraepithelial neoplasia (CIN). OBJECTIVES: The aim of this study was to combine DNA- and RNA-based assays in order to improve the detection of advanced disease (CIN2+). METHODS: 107 ASCUS+ women were included in Marseilles (France) between March 2007 and June 2008. Up to five tests were carried out on a liquid PreservCyt sample: Hybrid Capture 2 (HCII) (Digene), Papillocheck (Greiner), Abbott RealTime HR HPV (RT HR HPV) (Abbott), Linear Array (Roche), and EasyQ HPV (Biomerieux). RESULTS: 36 (34%) women had CIN2+ histology; among them 6 (6%) had CIN3+ histology. For CIN2+ detection, all tests had comparable sensitivities except EasyQ HPV test: HCII 94%, Papillocheck and LA 92%, RT HR HPV 89%, and NucliSENS EasyQ HPV 75% (P not significant). On the other hand, EasyQ HPV had a higher specificity than the other assays (except RT HR HPV assay). Combining DNA-based and RNA-based assay would allow to reduce the need of colposcopies to be performed among patients HPV positive with DNA-based assay: 32% (7/22) colposcopies not needed in < 30 years old patients, and 29% (14/49) colposcopies not needed in >= 30 years patients. CONCLUSIONS: All tests had comparable diagnostic values for CIN2+ detection, but DNA-based tests seemed to be more sensitive and RNA-based assay more specific. The combined use of DNA- and RNA-based assays considerably reduces the number of colposcopies to be performed, and provides better diagnostic accuracy for CIN2+ disease. PMID- 21263190 TI - Markers of angiogenesis and epidermal growth factor receptor signalling in patients with pancreatic and gastroesophageal junction cancer. AB - The epidermal growth factor receptor (EGFR) and angiogenesis are well established targets in anti-cancer therapy. Several targeted anti-cancer therapies are in clinical trials in pancreatic and gastroesophageal (GEJ) cancer. However, many patients do not respond to these targeted therapies and there is therefore an increasing need for biomarkers for selection of patients to these therapies. We investigated the expression of EGFR, vascular endothelial growth factor A (VEGF A), and VEGF receptor 2 (VEGFR-2) in tumour tissue by immunohistochemistry, and soluble EGFR (sEGFR), soluble VEGFR-2 (sVEGFR-2), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), plasminogen activator inhibitor 1 (PAI 1), and different forms of the urokinase plasminogen activator receptor (uPAR): uPAR (I), uPAR (I-III), and uPAR (I-III)+(II-III) in plasma by quantitative immunoassays in 14 patients with pancreatic and GEJ cancer. We found expression in tumour tissue and the plasma levels to be similar to those found in patients with other tumour types. No correlation was found between the blood levels of soluble receptors and the corresponding tumour tissue levels. We conclude that these markers are present in pancreatic and GEJ cancer patients, and could be investigated further as predictive biomarkers in such patients treated with EGFR or angiogenesis targeted therapies. PMID- 21263192 TI - Evaluation of urinary proepithelin as a potential biomarker for bladder cancer detection and prognosis in Egyptian patients. AB - BACKGROUND/AIM: Proepithelin is a growth factor that may play a critical role in bladder cancer. Its over-expression in urine of bladder cancer patients gave us the impetus to evaluate its potential suitability as a biomarker for bladder cancer diagnosis and/or prognosis. METHODS: proepithelin was estimated in 86 voided urine samples, including 59 bladder cancer patients and 27 healthy volunteers using quantitative sandwich enzyme immunoassay technique. Urinary proepithelin level was expressed in ng/100 mg creatinine. RESULTS: Urinary proepithelin was significantly higher in bladder cancer patients compared to control subjects (means: 17.5 +/- 10 and 8.9 +/- 3.5 ng/100 mg creatinine, respectively; p < 0.001), and the test sensitivity and specificity to detect the presence of bladder cancer were 74.6 and 85.2%, respectively. Furthermore, patients with low-grade/non-muscle invasive stages bladder cancer showed significantly lower urinary proepithelin compared to high-grade/non-muscle invasive stages and high-grade/invasive stages ones (means: 11.6 +/- 9, 20.2 +/- 8.1 and 23.8 +/- 11.9 ng/100 mg creatinine, respectively; p= 0.005 and 0.002, respectively). CONCLUSIONS: This preliminary study suggests that urinary proepithelin may be considered as a non-invasive, sensitive, and specific urine based test for bladder cancer diagnosis and/or prognosis. PMID- 21263191 TI - Analysis of volatile organic compounds (VOCs) in the headspace of NCI-H1666 lung cancer cells. AB - Analysis of volatile organic compounds (VOCs) provides an elegant approach for cancer screening and disease monitoring, whose use is currently limited by a lack of validated cancer-derived metabolites, which may serve as biomarkers. The aim of the experiments presented here was to investigate the release and consumption of VOCs from the non small cell lung cancer cell line NCI-H1666, which was originally derived from a bronchoalveolar carcinoma.Following detachment by trypsinization suspended cells were incubated in a sealed fermenter for 21 hours. 200 ml of headspace from the cell culture were sampled, diluted with dry, highly purified air and preconcentrated by adsorption on three different solid sorbents with increasing adsorption strength. VOC-analysis was performed by thermodesorption-gas chromatography mass spectrometry (TD-GC-MS). In contrast to our previous studies experiments with NCI-H1666 cells only confirmed the consumption of several aldehydes, n-butyl acetate and the ethers methyl tert butyl ether and ethyl tert-butyl ether, but no unequivocal release of VOCs was observed. Together with our previously published work these data indicate that the consumption of certain VOCs is commonly observed while their release shows cell line-restricted patterns, whose underlying causes are unknown. PMID- 21263193 TI - Antidepressants modulate intracellular amyloid peptide species in N2a neuroblastoma cells. AB - It is estimated that 30%-50% of Alzheimer's disease (AD) patients are diagnosed with major or minor depression. Research that addresses the relationship between these two diseases will benefit patients who suffer from depression comorbid with AD and allow further understanding of the neuroanatomy of depression. A clinical study showed that the use of the antidepressant fluoxetin concomitantly with the FDA-approved AD drug rivastigmine provided an improvement in the daily activities and the overall functioning in the patients with cognitive impairment. In an attempt to understand the underlying mechanism for the antidepressant's beneficial effect in AD patients, we evaluated the effects of different classes of antidepressants on the amyloid-beta peptide (Abeta) species in N2a neuroblastoma cells overexpressing amyloid-beta protein precursor. The effect of increasing antidepressant concentrations on the intracellular and secreted Abeta species is investigated by Western blotting. The tested antidepressants include fluoxetine, paroxetine, maprotiline, and imipramine. Fluoxetine and paroxetine at 10 MUM significantly decreased the intracellular level of Abeta oligomers and increased the level of Abeta monomers. However, imipramine and maprotiline increased the intracellular amount of Abeta monomers without affecting Abeta oligomers. Based on these results, it is possible that fluoxetine and paroxetine could be beneficial to AD patients via reducing the level of the cytotoxic oligomers and keeping the Abeta peptide in the monomeric form. These data could explain some of the beneficial effects of antidepressants in AD patients observed in clinical studies. PMID- 21263195 TI - An APOE haplotype associated with decreased epsilon4 expression increases the risk of late onset Alzheimer's disease. AB - This paper addresses a tenet of the literature on APOE, i.e., the relationship between the effects of the epsilon4, one of the established genetic risk factor for Alzheimer's disease (AD), and its expression levels as determined by APOE promoter polymorphisms. Five polymorphisms (-491 rs449647, -427 rs769446, -219 rs405509, and epsilon rs429358-rs7412) were studied in 1308 AD patients and 1082 control individuals from the Central-Northern Italy. Major findings of the present study are the following: 1) the variants -219T and epsilon4 increase the risk for late onset AD (LOAD) when they are both present in cis on the same chromosome (in phase); 2) the correlation between the haplotype (-219T/epsilon4) and AD risk persists when the data are stratified by age; 3) this haplotype likely anticipates the age of onset of the disease. These data, while confirming the association between -219T and AD, highlight the importance of the phase of the alleles for the observed effects on AD risk, suggesting that this information has to be taken into account when assessing the AD genetic risk. Moreover, the data help to clarify the apparent discrepancy that emerges from the genetic analysis where an SNP characterizing the haplotype responsible for an increased risk for LOAD is coherently associated with a reduced expression of ApoE levels. Our data are compatible with the hypothesis of a complex role of ApoE in the AD pathogenesis, with positive and negative effects occurring concomitantly according to its expression levels and its protein-protein interactions largely unclarified. PMID- 21263194 TI - Neuropathology and amyloid-beta spectrum in a bapineuzumab immunotherapy recipient. AB - The field of Alzheimer's disease (AD) research eagerly awaits the results of a large number of Phase III clinical trials that are underway to investigate the effectiveness of anti-amyloid-beta (Abeta) immunotherapy for AD. In this case report, we review the pertinent clinical history, examine the neuropathology, and characterize the Abeta profile of an AD patient who received bapineuzumab immunotherapy. The patient received four bapineuzumab infusions over a 39 week period. During the course of this treatment, there was no remarkable change in cognitive impairment as determined by MMSE scores. Forty-eight days after the fourth bapineuzumab infusion was given, MRI revealed that the patient had developed lacunar infarcts and possible vasogenic edema, probably related to immunotherapy, but a subsequent MRI scan 38 days later demonstrated resolution of vasogenic edema. The patient expired due to acute congestive heart failure complicated by progressive AD and cerebrovascular accident 378 days after the first bapineuzumab infusion and 107 days after the end of therapy. Neuropathological and biochemical analysis did not produce evidence of lasting plaque regression or clearance of Abeta due to immunotherapy. The Abeta species profile of this case was compared with non-immunized AD cases and non-demented controls and found to be similar to non-immunized AD cases. SELDI-TOF mass spectrometric analysis revealed the presence of full-length Abeta1-42 and truncated Abeta peptides demonstrating species with and without bapineuzumab specific epitopes. These results suggest that, in this particular case, bapineuzumab immunotherapy neither resulted in detectable clearance of amyloid plaques nor prevented further cognitive impairment. PMID- 21263196 TI - Guideline for management of vasculitis syndrome (JCS 2008). Japanese Circulation Society. PMID- 21263197 TI - SP600125 inhibits cap-dependent translation independently of the c-Jun N-terminal kinase pathway. AB - We investigated the effects of SP600125 (formerly called c-Jun N-terminal kinase (JNK) inhibitor II) on translation using cultured mouse cells. SP600125 (50 uM) treatment rapidly repressed overall protein synthesis, accompanied by a reduction in the mRNAs for housekeeping genes such as glyceraldehyde-3-phosphate dehydrogenase in the polysomal fraction. SP600125 decreased polysomes with a concomitant increase in free ribosomal subunits in the cytoplasm, suggesting that global translation was inhibited at the initiation step. A reporter analysis using exogenous mRNAs showed that SP600125 inhibited cap-dependent but not internal ribosome entry site-dependent translation. SP600125 significantly attenuated phosphorylation of components in the mTOR pathway, which is responsible for cap-dependent translation. In contrast to SP600125, short hairpin RNAs for JNK1 and JNK2 failed to affect overall protein synthesis. Collectively, SP600125 inhibits cap-dependent translation, independent of the JNK pathway. PMID- 21263198 TI - Thyroid hormone therapy modulates hypothalamo-pituitary-adrenal axis. AB - To observe the influence of thyroid hormone therapy on hypothalamo-pituitary adrenal (HPA) axis, a group of 14 athyreotic women due to thyroid cancer treatment were studied before and after thyroid suppression therapy with thyroxine (T4). Changes in plasma adrenocorticotropin (ACTH) and cortisol levels in response to human corticotropin-releasing hormone (hCRH; 100ug, i.v.) were estimated under hypothyroid conditions and after T4 suppression therapy with 2.5ug/kg/day for two months (n=14). A group of seven healthy women was evaluated as a control group. A greater increase in ACTH levels by hCRH was observed in patient group both before and after suppression therapy compared than that of control group. Plasma cortisol levels after hCRH stimulation were also greater in patient group both before and after suppression therapy than that of control group. In conclusion, both hypothyroidism and subclinical hyperthyroidism with suppressive doses of thyroid hormone induced a hypersensitivity of ACTH to hCRH. Considering the role of thyroid hormone on HPA axis, the mechanisms of ACTH hypersensitivity may be different between these two conditions. PMID- 21263199 TI - Carotenoids and their fatty acid esters in the petals of Adonis aestivalis. AB - Carotenoids and their fatty acid esters were investigated in the petals of Adonis aestivalis by UV-VIS, (1)H-NMR, FAB-MS, and CD spectrometry. (3S,3'S)-astaxanthin (diester: 72.2%, monoester: 13.8%, free: 1.4%) and (3S)-adonirubin (monoester: 13.8%, free: 0.3%) were identified as the major components. The fatty acids esterified with astaxanthin and adonirubin were assigned as C18:0, C18:1, C16:0, C16:1, C14:0, C12:0, and C10:0 from the FAB-MS spectral data. PMID- 21263200 TI - The melanogenesis-inhibitory, anti-inflammatory, and chemopreventive effects of limonoids in n-hexane extract of Azadirachta indica A. Juss. (neem) seeds. AB - Seventeen limonoids (tetranortriterpenoids 1-17) were isolated from the n-hexane extract of Azadirachta indica (neem) seeds. The previously unidentified compound 16 was established by spectroscopy to be 17-defurano-17-oxosalannin. The effects of six compounds, 6 and 11-15, on melanogenesis in B16 melanoma cells was evaluated; 2 compounds, salannin (13) and 3-deacetylsalannin (15), exhibited marked inhibitory effects (70-74% reduction of melanin content at 25 ug/mL) with only minor cytotoxicity (79-85% of cell viability). Eleven compounds, 2, 3, 5, 6, and 9-15, were evaluated for inhibitory activity against 12-O tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1.7 nmol/ear) in mice; all exhibited marked anti-inflammatory activity (ID(50) values 0.22-0.57 umol/ear). In addition, compounds 6 and 11-16 exerted moderate inhibition (IC(50) values of 410-471 mol ratio/32 pmol TPA) of TPA-induced Epstein-Barr virus early antigen (EBV-EA) activation in Raji cells. The triacylglycerol fraction of the n hexane extract contained oleic acid (50.2%) as the most predominant fatty acid constituent. PMID- 21263201 TI - Effects of hydrophobic chain length on temperature dependence of monolayer behavior of ester-type tartaric geminis. AB - Ester-type tartaric gemini amphiphiles bearing two carboxyl groups and two hydrophobic alkanoyl groups were prepared from L-tartaric acid, and the pressure area (pi-A) isotherms for a series of symmetric tartaric gemini amphiphiles were measured by the conventional film-balance technique. The effects of the length of the hydrophobic alkanoyl chains and of the subphase temperature (T(sub)) on the pi-A isotherms for these compounds were examined. As the length of the hydrophobic alkyl chain increased, a more tightly packed monolayer was formed at the air-water interface. The melting temperature (T(m)) of the monolayer on the water surface was evaluated from the subphase temperature (T(sub)) dependence of the monolayer static elasticity epsilon(s), based on a pi-A isotherm. A clear relationship between T(m) and hydrophobic carbon number (n) was observed for 2D monolayers of tartaric geminis on water surfaces, as well as for fatty acids and/or 3D solids. PMID- 21263202 TI - 4-Hydroxyderricin from Angelica keiskei roots induces caspase-dependent apoptotic cell death in HL60 human leukemia cells. AB - The ethyl acetate (EtOAc)-soluble fraction of a methanol extract of Angelica keiskei roots exhibited cytotoxic activity against 4 human tumor cell lines, HL60 (leukemia), CRL1579 (melanoma), A549 (lung), and AZ521 (stomach). Nine chalcones (1-9), 5 coumarins (10-14), and 4 flavanones (15-18), isolated from the EtOAc soluble fraction, were examined for their cytotoxic activities in the 4 human tumor cell lines. Among the compounds tested, 4-hydroxyderricin (2), a major chalcone constituent, exhibited potent cytotoxic activities in all 4 tumor cell lines with IC(50) values of 5.5 uM (HL60), 4.8 uM (CRL1579), 10.2 uM (A549), and 4.2 uM (AZ521). 4-Hydroxyderricin induced early apoptosis in HL60 cells, observed as membrane phospholipid exposure in flow cytometry. Western blot analysis showed that 4-hydroxyderricin markedly reduced the levels of procaspases-3, -8, and -9, while increasing the levels of cleaved caspases-3, -8, and -9. In addition, 4 hydroxyderricin exhibited potent inhibitory activity on human DNA topoisomerase (Topo) II (IC(50) 21.9 uM). These results suggested that 4-hydroxyderricin induces apoptotic cell death in HL60 via both the death receptor-mediated pathway and the mitochondrial pathway by, at least in part, Topo II inhibition. 4 Hydroxyderricin may therefore hold promise as an effective antitumor agent. PMID- 21263203 TI - Hyperphosphataemia is associated with the diabetes-related cardiovascular risk factors. AB - The serum phosphorus level is recently considered as one of the foretelling markers for the severity of cardiovascular diseases (CVD). We therefore investigated whether the serum phosphorus level in the diabetic patients against healthy individuals could act as a possible marker for identification of vulnerability to cardiovascular disease. One hundred and thirty two human subjects were involved in the study among which one hundred and four subjects are CVD patients and twenty eight were healthy individuals. The levels of the lipid profile and the glycemic status were significantly increased in the patients than those of the control subjects (Fasting glucose, FS=8.3 +/- 0.3 vs. 6.1 +/- 0.0 mmol/L; blood glucose 2 h after breakfast (STAB)=12.0 +/- 0.5 vs. 8.5 +/- 0.7, mmol/L; HbA1c (%),6.7 +/- 0.2 vs. 5.4 +/- 0.3; and Total cholesterol (TC)=189 +/- 4.0 vs. 162 +/- 7.0; low density lipoprotein cholesterol (LDL-C), 111 +/- 3.8 vs. 96 +/- 5.0; triacyglycerol (TG), 202 +/- 9.0 vs. 118 +/- 5.3 mg/dL, respectively. The serum phosphorus level was significantly increased in CVD patients (mg/dL, patient vs. control, 5.1 +/- 0.10 vs. 3.7 +/- 0.1). Simple regression analyses revealed a highly significant positive correlation between serum phosphorus and TC, TG and FG. Thus the results demonstrate that the serum phosphorus level might be another parameter which is closely associated with diabetes and could also be used as a possible marker for the risk of CVD. PMID- 21263204 TI - Chiral separation, determination of absolute configuration, and high-performance liquid chromatography detection of enantiomeric 3-hydroxyhexadecanoyl-CoA. AB - The enoyl-coenzyme A (CoA) hydratase catalyzes the hydration of 2-enoyl-CoA to yield 3-hydroxyacyl-CoA in mitochondrial and peroxisomal beta-oxidation. However, the stereospecificities of these hydratases differ from each other. To provide clear evidence of the stereospecificities of hydratases, the absolute configuration of 3-hydroxyhexadecanoyl-CoAs was determined, and they were subjected to a high-performance liquid chromatography (HPLC) using a chiral separation column. The retention time of 3(R)-hydroxyhexadecanoyl-CoA was shorter than that of 3(S)-hydroxyhexadecanoyl-CoA. The HPLC analysis carried out using a chiral separation column is considered to be useful for the study of enoyl-CoA hydratase. PMID- 21263205 TI - Selective analysis of lipids by thin-layer chromatography blot matrix-assisted laser desorption/ionization imaging mass spectrometry. AB - Thin-layer chromatography (TLC) is an essential method for food composition analyses such as lipid nutrition analysis. TLC can be used to obtain information about the lipid composition of foods; however, it cannot be used for analyses at the molecular level. Recently we developed a new method that combines matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) with TLC-blotting (TLC-Blot-MALDI-IMS). The combination of MALDI-IMS and TLC blotting enabled detailed and sensitive analyses of lipids. In this study, we applied TLC Blot-MALDI-IMS for analysis of major phospholipids extracted from bluefin tuna. We showed that TLC-Blot-MALDI-IMS analysis could visualize and identify major phospholipids such as phosphatidylethanolamine, phosphatidylinositol, phosphatidylserine, phosphatidylcholine, and sphingomyelin. PMID- 21263206 TI - Endogenous nitric oxide generation linked to ryanodine receptors activates cyclic GMP / protein kinase G pathway for cell proliferation of neural stem/progenitor cells derived from embryonic hippocampus. AB - Nitric oxide (NO) activates the cyclic GMP (cGMP) / protein kinase G (PKG) pathway during physiological processes in numerous types of cells. Here, we evaluated whether this NO/cGMP/PKG pathway is involved in the proliferation of neural stem/progenitor cells (NPCs) derived from the hippocampus of embryonic mice. In culture, the exposure to the NO synthase inhibitor N(omega)-nitro-L arginine methyl ester (L-NAME) significantly decreased the number of viable cells and 5-bromo-2'-deoxyuridine (BrdU) incorporation into the cells, as well as the levels of intracellular reactive oxygen species, extracellular NO(2), and intracellular cGMP. Like L-NAME, the soluble guanylate cyclase inhibitor 1H [1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and PKG inhibitor KT5823 also decreased cell viability and BrdU incorporation. The membrane-permeable cGMP analogue 8-bromo-cGMP partially abolished the L-NAME-induced decrease in the BrdU incorporation. BrdU incorporation was decreased by Ca(2+)-channel blockers, including dantrolene, MK-801, ifenprodil, and nifedipine. Interestingly, the NO(2) level was decreased by dantrolene, but not by the other 3 blockers. L-NAME and ODQ attenuated phosphorylation of Akt, but not that of extracellular signal regulated kinases or epidermal growth factor receptors. Our data suggest that endogenous NO generation linked to dantrolene-sensitive ryanodine receptors activates the cGMP/PKG signaling pathway for positive regulation of proliferation of hippocampal NPCs derived from embryonic mice. PMID- 21263207 TI - Developmental changes in action potential prolongation by K+-channel blockers in chick myocardium. AB - The effects of K(+)-channel blockers on the action potential duration of the myocardium were examined in isolated right ventricles from the 7 - 10-day-old, 11 - 13-day-old, and 14 - 20-day-old embryo and 1 - 7-day-old hatched chicks. E-4031 significantly prolonged action potential duration at all developmental stages examined; the prolongation was largest in the 11 - 13-day-old embryo and was accompanied by early after-depolarizations. Chromanol 293B showed smaller prolongation at all stages examined. Terfenadine prolonged action potential duration in the 11 - 13-day-old embryo, but not in other stages. Thus, the chick ventricular myocardium changes its repolarization properties during development. PMID- 21263208 TI - Association between bone mineral density and arterial stiffness in hypertensive patients. AB - Hypertension and osteoporosis are two common diseases in the elderly population. Recently, reduced bone mineral density has been found in hypertensive patients compared with healthy controls. Reduced bone mineral density is associated with increased arterial stiffness in chronic dialysis patients and healthy postmenopausal women. However, relationships between bone mineral density and arterial stiffness in hypertensive patients have not been fully assessed. We examined the relationships between bone mineral density and both arterial stiffness and nutritional status in 52 hypertensive patients (27 male and 25 female subjects; mean age 71+/-8 years) who had been treated with antihypertensive drugs for at least one year. The bone mineral density of the calcaneus was measured with a quantitative ultrasound measurement device, and the stiffness index was determined as a parameter of the bone mineral density. We measured the cardio-ankle vascular index (CAVI) to assess arterial stiffness and used the serum albumin to assess nutritional status. Increased arterial stiffness as assessed with CAVI is associated with reduced bone mineral density (r=-0.289, p=0.038). However, the correlation between CAVI and bone mineral density is not as strong as the correlation between serum albumin and bone mineral density (r=0.501, p<0.001). In conclusion, nutritional status is an important indicator of bone mineral density in hypertensive patients. Moreover, increased arterial stiffness is associated with reduced bone mineral density in hypertensive patients. Therefore, hypertensive patients with increased arterial stiffness may have a high risk of bone fracture due to osteoporosis. PMID- 21263209 TI - Identifying prognostic factors in Japanese women with pseudomyxoma peritonei: a retrospective clinico-pathological study of the Tohoku Gynecologic Cancer Unit. AB - Pseudomyxoma peritonei (PMP) is a rare condition of mucinous ascites associated mainly with mucinous tumors of appendix or ovary. PMP often recurs after treatment and may eventually cause death by abdominal visceral dysfunction via compression with mucinous ascites. Although radical peritonectomy and hyperthermic intra-peritoneal chemotherapy are becoming popular globally, the optimal treatment of PMP has not been established in Japan. We conducted a retrospective multicenter study to clarify the optimal treatment and the prognostic factors of PMP. A total of 23 patients with PMP were analyzed in the Tohoku Gynecologic Cancer Unit (TGCU). Clinical and follow-up data were retrieved and a central pathology review was performed. The median follow-up period was 46 months. Eleven patients underwent complete resection. There were 7 deaths out of 13 recurrences/progressions in this period. All the recurrence/progression was confined to the abdomen. Unexpectedly, neither radical peritonectomy nor hyperthermic intra-peritoneal chemotherapy had been performed, indicating that both radical peritonectomy and hyperthermic intra-peritoneal chemotherapy are not yet popular in Japan. The medians of overall survival and disease-free period were 166 months and 30 months, respectively. Univariate and multivariate analyses revealed that the only prognostic factor was macroscopic residual tumor (P=0.022). Although chemotherapy was not a prognostic factor (P=0.16), those who received intra-peritoneal chemotherapy tended to have a better prognosis than those who received systemic or no chemotherapy (P=0.064). In conclusion, the macroscopic residual tumor is an important prognostic factor in Japanese patients with PMP. PMID- 21263210 TI - Baby massage ameliorates neonatal jaundice in full-term newborn infants. AB - Neonatal jaundice is a common physiological problem affecting over half of all full term and most preterm infants. Thus, newborn infants must be monitored for signs of hyperbilirubinemia to prevent acute bilirubin encephalopathy or kernicterus. Evidence exists supporting the benefits of baby massage as a form of mild hand to skin contact, to increase neonatal physical and mental development. In the present study, the effects of gentle baby massage on neonatal jaundice in full term newborn infants were evaluated by a controlled clinical trial. The inclusion criteria of newborn neonates were as follows: (1) gestational age of 37 41 weeks, (2) birth weight of 2,800-3,600 g, (3) Apgar score at birth of 8-10, and (4) being a healthy neonate without neonatal asphyxia and hemolytic condition. Breastfed newborns without phototherapy were included: 20 in the massage group and 22 in the control group. We found the mean stool frequency of the massaged infants on day 1 and day 2 (4.6 and 4.3) was significantly higher than that of the control group (3.3 and 2.6) (p<0.05). The transcutaneous bilirubin levels on the second to fifth day and serum total bilirubin levels on fourth day were significantly decreased in the massage group, compared to the control group. In conclusion, baby massage at an early stage after birth could reduce neonatal bilirubin levels. We suggest baby massage is beneficial for ameliorating neonatal jaundice. PMID- 21263211 TI - A novel PAX4 mutation in a Japanese patient with maturity-onset diabetes of the young. AB - Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous type of diabetes mellitus, characterized by early onset (often before 25 years of age) and absence of pancreatic autoimmunity markers. Paired homeodomain transcription factor 4 (PAX4) functions as a transcriptional repressor and is involved in the differentiation of insulin-secreting beta-cells. Here we identified a novel PAX4 mutation in a Japanese patient with MODY. A 15 year-old, non-obese boy was admitted to our hospital because of polyuria and polydipsia. Laboratory evaluation showed an elevated fasting glucose level; however, islet cell antibodies and glutamic acid decarboxylase antibodies were not detected in the patient's serum. The proband's father had been diagnosed as having type 2 diabetes at age of 30 years. We therefore analyzed several candidate genes of MODY, and identified a novel mutation of a 39-base heterozygous deletion in exon 3 (c.374-412 del39) of PAX4 in the proband and his father. This mutation may cause exon 3 skipping that results in a frameshift, thereby producing a premature stop codon in exon 5. As this mutant PAX4 lacks a part of the homeodomain that is critical for binding to the target gene, this mutant was thought to lose the transcriptional repressor function. As expected, luciferase-reporter assays revealed that the mutant PAX4 could not repress the activities of insulin and glucagon gene promoters, unlike the wild-type PAX4 that repressed the promoter activities. The present study demonstrates that a novel mutation of PAX4 is likely to be associated with diabetes in this Japanese family. PMID- 21263213 TI - Do the genes tell us the path of most resistance? PMID- 21263212 TI - Autophagy modulation for cancer therapy. AB - Autophagy is a homeostatic and catabolic process that enables the sequestration and lysosomal degradation of cytoplasmic organelles and proteins that is important for the maintenance of genomic stability and cell survival. Beclin 1 (+/- ) gene knockout mice are tumor prone, indicating a tumor suppressor role for autophagy. Autophagy is also mechanism of stress tolerance that maintains cell viability and can lead to tumor dormancy, progression, and therapeutic resistance. Many anticancer drugs induce cytotoxic stress that can activate pro survival autophagy. In some contexts, excessive or prolonged autophagy can lead to tumor cell death. Inhibition of cytoprotective autophagy by genetic or pharmacological means has been shown to enhance anticancer drug-induced cell death, suggesting a novel therapeutic strategy. Studies are ongoing to define optimal strategies to modulate autophagy for cancer prevention and therapy, and to exploit it as a target for anticancer drug discovery. PMID- 21263214 TI - Prognostic significance of tumor-related proteases as a function of the estrogen receptor status. AB - BACKGROUND: Tumor-related proteases such as urokinase-type plasminogen (uPA), plasminogen activator inhibitor (PAI-1), and cathepsin D (cath-D) are involved in the prognosis of breast cancer (BC) and promote the metastatic process. We investigated the relationship between these proteases and their prognostic significance according to the ER status. METHODS: uPA, PAI-1, and cath-D levels were prospectively measured in tumor from 316 patients with primary BC. The distribution and relationship between these proteases and ER subsets were analyzed as well as the prognostic significance. RESULTS: Quantitative levels of uPA, and PAI-1 were higher in ER-patients (p< 0.001) whereas no difference was observed for cath-D levels in ER subsets (p = 0.96). In patients with a positive and highly positive ER status, a high cath-D level was associated with a poorer prognosis. Patients in the highly positive ER group experienced poorer survival in the group with a high PAI-1 level compared to the group with a low PAI-1 level. In ER+ patients, cath-D (p= 0.02) and the tumor size (p= 0.03) were independent factors for OS. CONCLUSION: The prognostic significance of proteases is modulated by the ER status. Cath-D and PAI-1 could identify a high-risk group with an adverse outcome in ER+ patients. PMID- 21263215 TI - CtIP interacts with TopBP1 and Nbs1 in the response to double-stranded DNA breaks (DSBs) in Xenopus egg extracts. AB - In the presence of double-stranded DNA breaks (DSBs), the activation of ATR is achieved by the ability of ATM to phosphorylate TopBP1 on serine 1131, which leads to an enhancement of the interaction between ATR and TopBP1. In Xenopus egg extracts, the Mre11-Rad50-Nbs1 (MRN) complex is additionally required to bridge ATM and TopBP1 together. In this report, we show that CtIP, which is recruited to DSB-containing chromatin, interacts with both TopBP1 and Nbs1 in a damage dependent manner. An N-terminal region containing the first two BRCT repeats of TopBP1 is essential for the interaction with CtIP. Furthermore, two distinct regions in the N-terminus of CtIP participate in establishing the association between CtIP and TopBP1. The first region includes two adjacent putative ATM/ATR phosphorylation sites on serines 273 and 275. Secondly, binding is diminished when an MRN-binding region spanning residues 25-48 is deleted, indicative of a role for the MRN complex in mediating this interaction. This was further evidenced by a decrease in the interaction between CtIP and TopBP1 in Nbs1 depleted extracts and a reciprocal decrease in the binding of Nbs1 to TopBP1 in the absence of CtIP, suggestive of the formation of a complex containing CtIP, TopBP1, and the MRN complex. When CtIP is immunodepleted from egg extracts, the activation of the response to DSBs is compromised and the levels of ATR, TopBP1, and Nbs1 on damaged chromatin are reduced. Thus, CtIP interacts with TopBP1 in a damage-stimulated, MRN-dependent manner during the activation of ATR in response to DSBs. PMID- 21263216 TI - ATM-dependent ERK signaling via AKT in response to DNA double-strand breaks. AB - Ionizing radiation (IR) triggers many signaling pathways primarily originating from either damaged DNA or non-nuclear sources such as growth factor receptors. Thus, to study the DNA damage-induced signaling component alone by irradiation would be a challenge. To generate DNA double-strand breaks (DSBs) and minimize non-nuclear signaling, human cancer cells having bromodeoxyuridine (BrdU) - substituted DNA were treated with the photosensitizer Hoechst 33258 followed by long wavelength UV (UV-A) treatment (BrdU photolysis). BrdU photolysis resulted in well-controlled, dose- dependent generation of DSBs equivalent to radiation doses between 0.2 - 20 Gy, as determined by pulsed-field gel electrophoresis, and accompanied by dose-dependent ATM (ser-1981), H2AX (ser-139), Chk2 (thr-68), and p53 (ser-15) phosphorylation. Interestingly, low levels (<= 2 Gy equivalents) of BrdU photolysis stimulated ERK phosphorylation whereas higher (> 2 Gy eq.) resulted in ERK dephosphorylation. ERK phosphorylation was ATM-dependent whereas dephosphorylation was ATM-independent. The ATM-dependent increase in ERK phosphorylation was also seen when DSBs were generated by transfection of cells with an EcoRI expression plasmid or by electroporation of EcoRI enzyme. Furthermore, AKT was critical for transmitting the DSB signal to ERK. Altogether, our results show that low levels of DSBs trigger ATM- and AKT-dependent ERK pro survival signaling and increased cell proliferation whereas higher levels result in ERK dephosphorylation consistent with a dose-dependent switch from pro survival to anti-survival signaling. PMID- 21263217 TI - CREG1 enhances p16(INK4a) -induced cellular senescence. AB - Cellular senescence is an irreversible growth arrest that is activated in normal cells upon shortening of telomere and other cellular stresses. Bypassing cellular senescence is a necessary step for cells to become immortal during oncogenic transformation. During the spontaneous immortalization of Li-Fraumeni Syndrome (LFS) fibroblasts, we found that CREG1 (Cellular Repressor of E1A-stimulated Genes 1) expression was decreased during immortalization and increased in senescence. Moreover, we found that repression of CREG1 expression occurs via an epigenetic mechanism, promoter DNA methylation. Ectopic expression of CREG1 in the immortal LFS cell lines decreases cell proliferation but does not directly induce senescence. We confirmed this in osteosarcoma and fibrosarcoma cancer cell lines, cancers commonly seen in Li-Fraumeni Syndrome. In addition, we found that p16 (INK4a) is also downregulated in immortal cells and that coexpression of CREG1 and p16 (INK4a) , an inhibitor of CDK4/6 and Rb phosphorylation, has a greater effect than either CREG1 and p16 (INK4a) alone to reduce cell growth, induce cell cycle arrest and cellular senescence in immortal LFS fibroblasts, osteosarcoma and fibrosarcoma cell lines. Moreover, cooperation of CREG1 and p16 (INK4a) inhibits the expression of cyclin A and cyclin B by inhibiting promoter activity thereby decreasing mRNA and protein levels; these proteins are required for S-phase entry and G2/M transition. In conclusion, this is the first evidence to demonstrate that CREG1 enhances p16 (INK4a) -induced senescence by transcriptional repression of cell cycle-regulated genes. PMID- 21263218 TI - Discovery of N-hydroxy-4-(3-phenylpropanamido)benzamide derivative 5j, a novel histone deacetylase inhibitor, as a potential therapeutic agent for human breast cancer. AB - A novel series of N-hydroxy-4-(3-phenylpropanamido)benzamide (HPPB) derivatives comprising N-hydroxybenzamide group as zinc-chelating moiety were designed, synthesized and evaluated as histone deacetylases inhibitors. The thiophene substituted derivative 5j exhibited the best HDAC inhibition activity among these compounds. The present study was designed to evaluate the efficacy of 5j as a candidate compound for cancer therapy. Our results indicated that 5j exhibited better HDAC1, 8 and hela nuclear extract inhibition activities than SAHA, and good antiproliferative activities against a broad spectrum of human cancer cell lines especially for breast cancer. 5j induced cell cycle arrest at G(2)/M phase, and eventual apoptosis possibly by modulating p21, caspase-3 and Bcl-x(L) on MDA MB-231 cells. In addition, 5j down regulated the active form of MMP2, and inhibited the invasion of MDA-MB-231 cell lines. Moreover, 5j significantly delayed the growth of MDA-MB-231 xenografts in mice after 3 weeks of peritoneal injection. In summary, our results suggest that 5j might have therapeutic potential for the treatment of human breast cancer. PMID- 21263221 TI - Does immune-tolerance treatment with Alum-formulated GAD65 protect insulin production in the pancreatic islet beta cells? AB - Type 1 diabetes is a serious chronic disease in which the pancreatic islet beta cells are destroyed by autoimmunity specifically directed to intracellular autoantigens. Still undefined environmental factors are likely to initiate the disease process. One of the autoantigens is glutamic acid decarboxylase (GAD65) and attempts are made to induce immunological tolerance against this autoantigen. Alum-formulated GAD65 (Diamyd ((r))) has been given subcutaneously in two injections with one month apart to recent onset type 1 diabetes patients with positive GAD65 autoantibodies. The injections were found to preserve residual beta-cell function without treatment related serious adverse events. Phase III studies in children with recent onset type 1 diabetes are ongoing along with a study (DIAPREV-IT) aimed at testing whether Diamyd ((r)) may prevent the clinical onset of diabetes in non-diabetic children with GAD65 autoantibodies and at least one more islet autoantibody. Future studies may include investigation of Diamyd ((r)) in combination with other immunomodulating autoantigens. PMID- 21263222 TI - Design-around biotechnology patents: an analysis of US Federal Circuit decisions shows the possibility of designing around biotechnology patents. AB - In order to demonstrate the possibility of design-around for patents, we reviewed 40 no-infringement cases out of all 4,760 Federal Circuit Court of Appeals (CAFC) cases decided from 2001 to 2009. Based on this analysis, designing around a biotechnology patent first requires a thorough reading of the patent specification and prosecution history. These written descriptions offer explicit directions about claim meanings or the scope being disclaimed. By statute, claims recite and define the structure or acts of an invention, and serve as tools to determine whether or not a patent is infringed. The next procedure would include omitting a part or property from the claim, reversing the action used in the claim, or changing the claim's structure or range to prevent the new design from falling within the scope of the claim. However, cases where patent infringement was found demonstrated that changing the structure or range not recited in the claim, such as enlarging the diameter, reducing concentration or alerting the shape, still falls within the scope of the patent. Although the 40 cases analyzed in this study were not related to vaccines, the thought process can serve as a guideline for patents related to vaccine development. PMID- 21263223 TI - Sublingual vaccination. AB - The sublingual route has been used for many years to deliver drugs and small molecules to the bloodstream. Surprisingly, the potential of this route for delivering vaccines has received very little if any attention until recently. During the past few years, a number of laboratories have documented the efficacy of sublingual immunization for inducing a broad range of immune responses in different experimental animal systems using a variety of antigens, including soluble proteins, inert particulate antigens (killed viruses, virus-like particles, bacterial extracts) as well as live-attenuated viruses. In most cases, systemic and mucosal immune responses, including humoral and cytotoxic T-cell responses were induced in both mucosal and extra-mucosal tissues. Overall, sublingual immunization was comparable to nasal immunization regarding the magnitude, breadth, and anatomic dissemination of the induced immune responses. Importantly, and contrary to nasal administration, sublingual administration did not redirect antigens and/or adjuvants to the brain. Here we review the results of pre-clinical studies using animal models of respiratory, intestinal and genital infections. These promising results provide a foundation for testing the approach in humans. PMID- 21263219 TI - Combined modality therapy with TRAIL or agonistic death receptor antibodies. AB - Molecularly targeted therapies, such as antibodies and small molecule inhibitors have emerged as an important breakthrough in the treatment of many human cancers. One targeted therapy under development is tumor necrosis factor-related apoptosis inducing ligand (TRAIL) due to its ability to induce apoptosis in a variety of human cancer cell lines and xenografts, while lacking toxicity in most normal cells. TRAIL and apoptosis-inducing agonistic antibodies to the TRAIL death receptors have been the subject of many preclinical and clinical studies in the past decade. However, the sensitivity of individual cancer cell lines of a particular tumor type to these agents varies from highly sensitive to resistant. Various chemotherapy agents have been shown to enhance the apoptosis-inducing capacity of TRAIL receptor-targeted therapies and induce sensitization of TRAIL resistant cells. This review provides an overview of the mechanisms associated with chemotherapy enhancement of TRAIL receptor-targeted therapies including modulation of the apoptotic (death receptor expression, FLIP, and Bcl-2 or inhibitors of apoptosis (IAP) families) as well as cell signaling (NFkappaB, Akt, p53) pathways. These mechanisms will be important in establishing effective combinations to pursue clinically and in determining relevant targets for future cancer therapies. PMID- 21263224 TI - Correlates of receiving recommended adolescent vaccines among adolescent females in North Carolina. AB - BACKGROUND: Immunization is a successful and cost-effective method for preventing disease, yet many adolescents do not receive recommended vaccines. We assessed correlates of uptake of three vaccines (tetanus booster, meningococcal, and human papillomavirus [HPV] vaccines) recommended for adolescent females. Methods. We examined cross-sectional data from 647 parents of 11-20 year-old females from North Carolina who completed the Carolina HPV Immunization Measurement and Evaluation (CHIME) Project follow-up survey in late 2008. Analyses used ordinal and binary logistic regression. RESULTS: Only 17% of parents indicated their daughters had received all three vaccines. Eighty-seven percent of parents indicated their daughters had received tetanus booster vaccine, 36% reported vaccination against meningococcal disease, and 36% reported HPV vaccine initiation. Daughters aged 13-15 years (OR = 1.70, 95% CI: 1.09-2.64) or 16-20 years (OR = 2.28, 95% CI: 1.51-3.44) had received a greater number of these vaccines compared to daughters aged 11-12 years. Daughters who had preventive care visits in the last year (OR = 4.81, 95% CI: 3.14-7.34) or whose parents had at least some college education (OR = 1.90, 95% CI: 1.29-2.80) had also received a greater number of these vaccines. CONCLUSIONS: Few daughters, particularly 11 12 years olds, had received all three vaccines recommended for adolescent females. Ensuring annual preventive care visits and increasing concomitant administration of adolescent vaccines may help increase vaccine coverage. PMID- 21263225 TI - Seasonal and 2009 H1N1 influenza vaccine uptake, predictors of vaccination, and self-reported barriers to vaccination among secondary school teachers and staff. AB - OBJECTIVE: Teachers, like healthcare workers, may be a strategic target for influenza immunization programs. Influenza vaccination is critical to protect both teachers and the students they come into contact with. This study assessed factors associated with seasonal and H1N1 influenza vaccine uptake among middle- and high-school teachers. METHODS: Participants were recruited from two counties in rural Georgia. Data were collected from surveys in September 2009 and May 2010. Multivariate logistic regression was used to assess the association between teachers' attitudes toward seasonal and H1N1 influenza vaccination and vaccine uptake. RESULTS: Seventy-eight percent of teachers who planned to receive seasonal influenza vaccine and 36% of those who planned to receive H1N1 influenza vaccine at baseline reported that they did so. Seasonal vaccine uptake was significantly associated with perceived severity (odds ratio [OR] 1.57, P = 0.05) and self-efficacy (OR 4.46, P = 0.006). H1N1 vaccine uptake was associated with perceived barriers (OR 0.7, P = 0.014) and social norms (OR 1.39, P = 0.05). The number one reason for both seasonal and H1N1 influenza vaccine uptake was to avoid getting seasonal/H1N1 influenza disease. The number one reason for seasonal influenza vaccine refusal was a concern it would make them sick and for H1N1 influenza vaccine refusal was concern about vaccine side effects. CONCLUSIONS: There is a strong association between the intention to be vaccinated against influenza (seasonal or 2009 H1N1) and actual vaccination uptake. Understanding and addressing factors associated with teachers' influenza vaccine uptake may enhance future influenza immunization efforts. PMID- 21263226 TI - Lactococcus lactis-based vaccines: current status and future perspectives. AB - Lactococcus lactis offers significant potential as a platform for the delivery of vaccines especially via mucosal routes of administration. The organism has an established history of safe use in the food industry and is highly amenable to genetic manipulation, with many systems available for efficient production of secreted and surface-expressed proteins. Here we describe the benefits of using this organism as a vaccine delivery platform and outline how L. lactis based antigen delivery may be improved. Finally we discuss the safe use of L. lactis vectors and outline the potential for use of biological containment systems and killed lactococcal preparations. PMID- 21263227 TI - The 2009 H1N1 influenza pandemic: a case study of how modeling can assist all stages of vaccine decision-making. AB - During the 2009 H1N1 influenza pandemic nearly every decision associated with new vaccine development and dissemination occurred from the Spring of 2009, when the novel virus first emerged, to the Fall of 2009, when the new vaccines started reaching the thighs, arms and noses of vaccinees. In many ways, 2009 served as a crash course on how mathematical and computational modeling can assist all aspects of vaccine decision-making. Modeling influenced pandemic vaccine decision making, but not to its fullest potential. The 2009 H1N1 pandemic demonstrated that modeling can help answer questions about new vaccine development, distribution, and administration such as (1) is a vaccine needed, (2) what characteristics should the vaccine have, (3) how should the vaccine be distributed, (4) who should receive the vaccine and in what order and (5) when should vaccination be discontinued? There is no need to wait for another pandemic to enhance the role of modeling, as new vaccine candidates for a variety of infectious diseases are emerging every year. Greater communication between decision makers and modelers can expand the use of modeling in vaccine decision making to the benefit of all vaccine stakeholders and health around the globe. PMID- 21263228 TI - Comment on "Forecasting dengue vaccine demand in disease endemic and non-endemic countries" Amarasinghe et al; Human Vaccines 2010; 6:9, 745-753. AB - Recent forecasts of dengue travel vaccine demand, while worthy, might be improved by modelling future travel flows, and by accounting for incremental reductions in demand at the different points in the sequence of events leading to travel vaccine purchase. In particular, we suggest that an alternative method of projecting dengue travel vaccine uptake would account for (1) future flows of travellers from all non-endemic source to all endemic destination countries, based on data that are comparable between countries, and corrected for double counting and other sources of error; (2) the proportion of such travellers that seek premedical travel advice within a timescale compatible with the probable dengue vaccine schedule; (3) the proportion of these travellers that will present with a combination of risk factors (above and beyond destination country) sufficient to prompt a physician to prescribe a dengue vaccine; and (4) the proportion of these travellers that actually purchase a vaccine when advised to do so. PMID- 21263229 TI - Development of therapeutic and prophylactic vaccine against Tuberculosis using monkey and transgenic mice models. AB - PURPOSE: BCG is not efficacious against M. tuberculosis (TB) in adult. Therefore, novel TB vaccines were established by using three kinds of animal models (cynomolgus monkey model which is the best animal model of human TB, IL-2R knock out SCID mice as a human immune model, and granulysin transgenic mouse). METHODS AND RESULTS: DNA vaccine expressing TB Hsp65 and IL-12 was delivered by the hemagglutinating virus of Japan (HVJ)-envelope. The BCG prime followed by Hsp65+IL-12/HVJ vaccine boost showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). In contrast, 33% of monkeys were alive in BCG alone group. Furthermore, the prolongation of survival period of the monkey was observed by the combination of BCG and DNA vaccine even when the boost was performed after long-term period (4month) from prime. This combination also improved the erythrocyte sedimentation rate (ESR), increased the body weight, and augmented the proliferation of PBL and IL-12 production at higher levels than BCG alone or saline. Furthermore, this vaccine exerted therapeutic efficacy in IL-2R knock out SCID-PBL/hu mice, which were transplanted with human T cells. Granulysin is an important defensive molecule expressed by human T cells and NK cells and has a cytolytic activity against microbes including Mycobacterium tuberculosis (TB) and tumors. Expression of 15kD (15K) granulysin protein and mRNA in CD8 positive T cells in the patients infected with drug sensitive (TB) or multi-drug resistant (MDR-TB) M. tuberculosis were lower than that in the healthy volunteers, suggesting that granulysin treatment might improve the tuberculous disease in human. Therefore, we established two kinds of granulysin transgenic mice (15K granulysin transgenic mice and 9K granulysin transgenic mice). It was demonstrated that 15K granulysin transgenic mice as well as 9K granulysin transgenic mice exerted in vivo anti-TB effect, including the decrease of the number of TB and augmentation of the CTL activity. These are the first findings which demonstrate in vivo effects of 15K granulysin and 9K granulysin against TB infection. Moreover, DNA vaccine expressing 15K granulysin showed a therapeutic activity against TB in mice. CONCLUSION: These data indicate that monkey, IL-2R gene-knock out SCID-PBL/hu and granulysin transgenic mice models provide useful tools for the development of novel vaccines (HVJ-Envelope/Hsp65 DNA + IL-12 DNA vaccine and granulysin vaccine) against TB. PMID- 21263230 TI - Piezoelectric permeabilization of mammalian dermal tissue for in vivo DNA delivery leads to enhanced protein expression and increased immunogenicity. AB - Electropermeabilization of mammalian cells is a technique that has been used for the delivery of therapeutics, such as DNA plasmids or DNA vaccines. Typically, delivery via electropermeabilization occurs through injection of the substance into the tissue of interest followed by the insertion of electrodes at the site and the application of brief electrical pulses. Here we detail a novel and innovative contactless electropermeabilization method to deliver DNA plasmids to dermal tissue in vivo. This process has the advantage of eliminating the insertion of additional needles that serve as electrodes to facilitate the application of electric pulses in conventional electroporation processes. Plasmid encoding GFP was injected into guinea pig skin and pulsed with the novel contactless electropermeabilization method. Three days following treatment, robust GFP expression was observed on the skin of pulsed animals. Strong humoral immune responses were also achieved when a DNA vaccine expressing the influenza antigen NP was delivered and pulsed using the novel device in comparison to naked injection alone. This delivery method has the advantage of being contactless and suggests that gene transfer via this mode warrants further development. PMID- 21263231 TI - Indian gold treating cancer in the age of nano. PMID- 21263232 TI - Structural insights into the cytoplasmic domain of a human BK channel. AB - The large conductance, voltage- and Ca(2+) -activated K(+) (BK or Slo1) channel is widely expressed in mammalian cells/tissues (i.e. neurons, skeletal and smooth muscles, exocrine cells, the inner ear) and regulates action potential firing, muscle contraction and secretion. The large ionic conductance and unusual, dual stimulus-driven gating behavior of this channel have long intrigued membrane biophysicists, and recent structure/function analyses have provided increasingly detailed insights into the molecular "bells and whistles" that regulate BK channel activity. Now, in two complementary articles published by the groups of Rod MacKinnon and Youxing Jiang, high resolution x-ray crystal structures of the human BK channel's large cytoplasmic domain have been solved in both the absence and presence of bound Ca(2+), conditions which would presumably promote the resting and activated conformations of this large domain. Given the regulatory importance of the cytosolic domain on BK channel gating, these experimentally determined structures reveal a number of key insights, including: 1) the physical arrangement and interactions of the tandem RCK1 and RCK2 domains within a single channel subunit, 2) the assembly of the four large cytoplasmic domains into a symmetric, tetrameric complex, 3) the formation of the channel's "gating ring" structure, based on the assembly of the individual RCK1 and 2 domains, and 4) the structural elements underlying the regions critical for divalent metal ion binding (i.e. Ca (2+) and Mg (2+)) and their potential influence on conduction pore. PMID- 21263233 TI - The role of editors, reviewers and authors in improving the journal quality. PMID- 21263234 TI - Propranolol for severe hemangioma of infancy. PMID- 21263235 TI - Reply to 'Unloading therapy by intravenous diuretic in chronic heart failure: a double-edged weapon?'. PMID- 21263236 TI - Propranolol for severe hemangioma of infancy. PMID- 21263237 TI - Pure epithelioid PEComas (so-called epithelioid angiomyolipoma) of the kidney: A clinicopathologic study of 41 cases: detailed assessment of morphology and risk stratification. AB - Epithelioid angiomyolipomas (perivascular epithelioid cell tumors) of the kidney are defined as potentially malignant mesenchymal lesions that are closely related to classic angiomyolipoma. Although approximately 120 cases are published, mostly as case reports with variably used diagnostic criteria, the pathologic prognostic predictors of outcome are unknown. We analyzed the clinicopathologic parameters in a large series of 41 cases of pure epithelioid angiomyolipomas of the kidney, which we designate as pure (monotypic) epithelioid PEComas to contrast them from classic angiomyolipomas that are regarded by some as PEComas. We use the terminology "pure" to separate these cases from those that may have variable epithelioid components. The mean age of the patients was 40.7 years (range, 14 to 68 y). The male-to-female ratio was 1:1. Seventy-nine percent of patients were symptomatic at presentation with metastatic disease at onset in 12 cases. Follow up and/or disease progression information were available for 33 of 41 cases (mean, 44.5 mo and median, 24.5 mo; range, 4 to 240); 9 patients had a history of associated tuberous sclerosis. Recurrence and metastasis were seen in 17% and 49% of patients; 33% of patients died of disease. Lymph node involvement was seen in 24% of patients; the liver (63%), lung (25%), and mesentery (18.8%) were the most common metastatic sites. Clinicopathologic parameters associated with disease progression (recurrence, metastasis, or death due to disease) in univariate analysis included associated tuberous sclerosis complex or concurrent angiomyolipoma (any metastasis, P=0.046), necrosis (metastasis at diagnosis, P=0.012), tumor size >7 cm (progression, P=0.021), extrarenal extension and/or renal vein involvement (progression, P=0.023), and carcinoma-like growth pattern (progression, P=0.040) (the 5 adverse prognostic parameters for pure epithelioid PEComas). Tumors with <2 adverse prognostic parameters (13 cases) were considered to be low risk for progression tumor, with 15% having disease progression. Tumors with 2 to 3 adverse prognostic parameters (14 cases) were considered to be "intermediate risk," with 64% having disease progression. Tumors with more than 4 or more adverse prognostic parameters (6 cases) were considered to be high risk, with all patients having disease progression. Of tumors with 3 or more adverse prognostic parameters, 80% had disease progression. An exact logistic regression analytic model showed that only carcinoma-like growth pattern and extrarenal extension and/or renal vein involvement were significant predictors of outcome (P=0.009 and 0.033, respectively). Our data of a large series with uniform definitional criteria confirm the malignant potential for pure epithelioid PEComas and provide adverse prognostic parameters for risk stratification in these patients. PMID- 21263238 TI - Molecular characteristics of mantle cell lymphoma presenting with clonal plasma cell component. AB - The normal counterparts of mantle cell lymphoma (MCL) are naive, quiescent B cells that have not been processed through the germinal center (GC). For this reason, although lymphomas arising from GC or post-GC B cells often exhibit plasmacytic differentiation, MCL rarely presents with plasmacytic features. Seven cases of MCL with a monotypic plasma cell (PC) population were collected from 6 centers and were studied by immunohistochemistry, fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms analysis, capillary gel electrophoresis, and restriction fragment length polymorphism of immunoglobulin heavy chain analysis of microdissections of each of the MCL and PC populations to assess their clonal relationship. The clinical presentation was rather unusual compared with typical MCL, with 2 cases arising from the extranodal soft tissues of the head. All MCL cases were morphologically and immunohistochemically typical, bearing the t(11;14)(q13;q32). In all cases, the PC population was clonal. In 5 of the 7 cases, the MCL and PC clones showed identical restriction fragments, indicating a common clonal origin of the neoplastic population. The 2 cases with clonal diversity denoted the coexistence of 2 different tumors in a composite lymphoma/PC neoplasm. Our findings suggest that MCL can present with a PC component that is often clonally related to the lymphoma, representing a rare but unique biological variant of this tumor. PMID- 21263239 TI - Pseudomyogenic hemangioendothelioma: a distinctive, often multicentric tumor with indolent behavior. AB - A 1992 report described 5 keratin-positive spindle cell neoplasms with multifocal presentation in a single limb, which were proposed at that time to be a variant of epithelioid sarcoma. This tumor type is not widely recognized and is incompletely characterized. We examined 50 cases of this distinctive tumor to evaluate histologic, immunophenotypic, and clinical features. There was a 4.6:1 male predominance (mean age, 31 y; 82% <=40 y). Half of the patients presented with painful nodules and the other half with painless nodules. Mean tumor size was 1.9 cm (range, 0.3 to 5.5 cm). Tumors arose in the lower limb (54%), the upper limb (24%), trunk (18%), or head and neck (4%). Thirty-three (66%) were multifocal lesions (ranging from 2 to 15 lesions), including 32 cases with involvement of multiple tissue planes. Of 205 total lesions, 64 (31%) involved the dermis, 42 (20%) involved the subcutis, 70 (34%) lesions involved muscle, and 29 (14%) lesions involved bone; all the lesions had infiltrative margins. The tumors were composed of loose fascicles and sheets of plump spindle cells with vesicular nuclei, variably prominent nucleoli, and abundant brightly eosinophilic cytoplasm, some with a strikingly rhabdomyoblast-like appearance. In all cases, a minority of cells were epithelioid. Twenty-seven tumors contained a prominent neutrophilic inflammatory infiltrate. Most tumors showed only mild nuclear atypia; 6 tumors contained foci of notably pleomorphic cells. The median mitotic rate was 1 per 10 HPF (range, 1 to 10). Seven tumors showed vascular invasion; 7 tumors had areas of necrosis. By immunohistochemistry, all tumors were diffusely positive for AE1/AE3 and FLI1; 22 of 47 tumors were variably positive for CD31. Focal positivity was seen for CAM5.2 (21 of 35), smooth muscle actin (14 of 42), epithelial membrane antigen (7 of 49 weak), and PAN-K (MNF116) (1 of 47). All were negative for CD34, desmin, and S100 protein and showed intact INI1 expression. Follow-up was available for 31 patients and ranged from 9 months to 17 years (mean, 4 y). Most lesions were treated by local excision. Eighteen (58%) patients had local recurrence or developed additional nodules in the same region, all but one, within 1 year of first presentation. Eight patients had postoperative radiation therapy and 6 patients had chemotherapy. Four patients had amputations for multifocal disease. One patient had a regional lymph node metastasis, and, thus far, only 1 patient has developed distant metastases (disseminated), 16 years after primary tumor excision. At the time of the last follow-up, 27 patients were alive with no evidence of the disease, 1 patient was alive with unknown disease status, 2 patients were alive with recurrent disease, and 1 patient died of the disease. In summary, we describe a distinctive type of rarely metastasizing ("intermediate") tumor affecting mainly young men and usually characterized by multifocality in different tissue planes of a limb. Although sharing some features with epithelioid sarcoma (skin/soft tissue of distal extremities, young adults, keratin positive), it differs by having predominantly myoid-appearing spindle cell morphology, expression of FLI1, common reactivity for CD31, lack of epithelial membrane antigen, CD34, and PAN-K expression, and intact INI1. The overall immunophenotypic findings favor endothelial differentiation. Despite the ominous presentation, follow-up thus far suggests an indolent clinical course with a small risk of distant metastasis. Although the precise nosologic status of this tumor type is uncertain, we propose the interim designation "pseudomyogenic hemangioendothelioma." PMID- 21263240 TI - Diminished number or complete loss of myoepithelial cells associated with metaplastic and neoplastic apocrine lesions of the breast. AB - The presence of myoepithelial (ME) cells is considered an important feature in the vast majority of benign breast lesions. Recently, a case showing the absence of myoepithelium in a mammary duct with apocrine metaplasia was reported. To investigate the status of ME cells associated with apocrine metaplasia, the distribution of ME cells in 59 metaplastic and intraductal proliferative apocrine lesions was evaluated using immunohistochemical expression of p63 and Calponin. p63 showed a diminished number of ME cells and increased intermyoepithelial nuclear distance in ducts with all variants of apocrine metaplasia and proliferation compared with normal glands. In the majority of cases, Calponin showed a continuous ME layer. In 6 cases, including an apocrine papilloma, there were definitive ME gaps confirmed by both markers, in the absence of atypia and with preservation of the basement membrane. In all cases, there was frequent heterogeneity in the distribution of ME cells in ducts harboring apocrine cells and even in various papillae within papillary lesions. In summary, benign and noninvasive apocrine lesions can show reduction and occasional complete loss of ME cells. This observation is particularly important when evaluating apocrine papillary proliferations, in which the absence of ME cells may lead to overdiagnosis of atypia and/or malignancy. The observation suggests that at least 2 ME markers should be used when evaluating apocrine lesions, and that a malignant diagnosis should be based on features of the proliferating cells until more data become available on the significance, if any, of the absence of ME cells in apocrine lesions. PMID- 21263241 TI - Tubular adenomas with minor villous changes show molecular features characteristic of tubulovillous adenomas. AB - Advanced colorectal polyps are identified based on size >=10 mm, high-grade dysplasia, and/or villous histology. A diagnosis of tubular adenoma (TA) is recommended if villous change occupies <20% of the lesion, or tubulovillous adenoma (TVA) is recommended if there is 20% to 80% villosity. We hypothesized that even subtle villous changes (1% to 20%) would correlate with advanced molecular features. Two hundred sixty-nine colorectal adenomas were examined for KRAS and BRAF mutation and immunohistochemical staining of beta-catenin, O6 Methyl Guanine DNA Methyltransferase (MGMT), and p53. Adenomas were classified as TA1 (0% villosity, n=70), TA2 (1% to 20% villosity, n=81), or TVA (21% to 80% villosity, n=118). Clinical and molecular features were analyzed by univariate chi2 and multivariate logistic regression. There was an incremental increase in KRAS mutation frequency with increasing villous compartment (17.9% TA1, 59.0% TA2, 78.4% TVA; P<0.001). MGMT was more frequently lost in TA2 (37.0%) than in TA1 (8.6%) (P<0.001) but did not differ from TVA (39.8%). p53 overexpression was more common in TA2 (38.3%) than in TA1 (10.0%) (P<0.001) but did not differ from TVA (32.2%). On multivariate analysis, TA2 adenomas were more likely to have a KRAS mutation [odds ratio (OR) 6.6, 95% confidence interval (CI), 3.0-14.2], MGMT loss (OR 6.2, 95% CI, 2.4-16.0), or p53 overexpression (OR 5.6, 95% CI, 2.3-13.7) than TA1. We have identified a subgroup of TAs based on subtle villous changes. These adenomas are more likely to show molecular features that are characteristic of TVAs than TAs. These data support the concept that any villous change may indicate increased malignant potential and may be useful to consider when assigning surveillance guidelines. PMID- 21263242 TI - Liposarcoma arising in uterine lipoleiomyoma: a report of 3 cases and review of the literature. AB - BACKGROUND: Primary sarcomas of the uterus are uncommon, leiomyosarcoma being the most frequent. Most uterine sarcomas arise de novo, with malignant transformation of a benign mesenchymal tumor being a very rare event, and is reported only in leiomyomata. DESIGN: The clinicopathologic features of 3 uterine liposarcomas arising in association with a lipoleiomyoma were studied. Immunohistochemistry for desmin, h-caldesmon, S100, and MDM2, and fluorescence in situ hybridization for the t(12;16) (q13;p11) were performed in all cases. RESULT: Patients ranged in age from 49 to 70 (mean, 59) years. The tumors were centered in the myometrium, ranged in size from 10 to 18.5 cm, and showed a gelatinous cut surface with foci of necrosis. On microscopic examination, the tumors had well circumscribed pushing margins. One neoplasm was uniformly hypocellular with a prominent myxoid background, and a striking delicate vascular network. Another neoplasm showed alternating hypocellular (myxoid) and hypercellular areas, whereas the third tumor was uniformly hypercellular with a hyalinized background. In the myxoid areas, the cells were small and spindle with oval nuclei and inconspicuous nucleoli. In the hypercellular areas, the cells were pleomorphic with large, hyperchromatic nuclei. Mitotic activity ranged from <3 to 7/10 high power fields. Lipoblasts were present in all tumors but were more common in the hypercellular areas. Two tumors merged imperceptibly with a lipoleiomyoma (1 typical and 1 with bizarre nuclei), whereas the third tumor showed an infarcted area composed of ghost mature adipocytes admixed with hyalinized smooth muscle most consistent with an infarcted lipoleiomyoma. Tumors were classified as myxoid, mixed myxoid and pleomorphic, and pleomorphic liposarcoma, respectively. The benign and malignant adipose components were positive for S100, whereas the benign smooth muscle component stained for desmin and h-caldesmon. MDM2 immunostain was positive in the 2 cases with a pleomorphic liposarcoma component. Fluorescence in situ hybridization analysis was successfully completed in only 1 of 3 tumors (pure pleomorphic liposarcoma), which failed to show the t(12;16) and HMAG2 amplification. The patients are alive and well 1, 2, and 20 years after initial surgery with no adjuvant therapy. CONCLUSIONS: Primary liposarcomas of the uterus are extremely rare and are most likely to arise from malignant transformation of a lipoleiomyoma. These tumors should be added to the differential diagnosis of benign lipomatous tumors, myxoid mesenchymal tumors, and malignant mixed Mullerian tumors (if pleomorphic) of the uterus. PMID- 21263243 TI - Pattern of lymph node involvement and prognosis in pancreatic adenocarcinoma: direct lymph node invasion has similar survival to node-negative disease. AB - Lymph node status is one of the most important predictors of survival in pancreatic ductal adenocarcinoma. Surgically resected pancreatic adenocarcinoma is often locally invasive and may invade directly into peripancreatic lymph nodes. The significance of direct invasion into lymph nodes in the absence of true lymphatic metastases is unclear. The purpose of this study was to retrospectively compare clinical outcome in patients with pancreatic ductal adenocarcinoma with direct invasion into peripancreatic lymph nodes with patients with node-negative adenocarcinomas and patients with true lymphatic lymph node metastasis. A total of 380 patients with invasive pancreatic ductal adenocarcinoma classified as pT3, were evaluated: ductal adenocarcinoma with true lymphatic metastasis to regional lymph nodes (248 cases), ductal adenocarcinoma without lymph node involvement (97 cases), and ductal adenocarcinoma with regional lymph nodes involved only by direct invasion from the main tumor mass (35 cases). Isolated lymph node involvement by direct invasion occurred in 35 of 380 (9%) patients. Overall survival for patients with direct invasion of lymph nodes (median survival, 21 mo; 5-year overall survival, 36%) was not statistically different from patients with node-negative adenocarcinomas (median survival, 30 mo; 5-year overall survival, 31%) (P=0.609). Patients with node negative adenocarcinomas had an improved survival compared with patients with lymph node involvement by true lymphatic metastasis (median survival, 15 mo; 5 year overall survival, 8%) (P<0.001) regardless of the number of lymph nodes involved by adenocarcinoma. There was a trend toward decreased overall survival for patients with 1 or 2 lymph nodes involved by true lymphatic metastasis compared with patients with direct invasion of tumor into lymph nodes (P=0.056). However, this did not reach statistical significance. Our results indicate that patients with isolated direct lymph node invasion have a comparable overall survival with patients with node-negative adenocarcinomas as opposed to true lymphatic lymph node metastasis. PMID- 21263244 TI - High lymphatic vessel density and lymphatic invasion underlie the adverse prognostic effect of radial growth phase regression in melanoma. AB - Regression in the radial growth phase (RGP) of primary cutaneous melanomas is common and has been shown to be an adverse prognostic factor. However, the underlying mechanism is unclear. We performed dual immunohistochemical staining of podoplanin and S-100 on paraffin tissues from 321 patients with vertical growth phase primary melanomas, who had 10 years or more of follow-up. Lymphatic vessel density (LD) and lymphatic invasion (LI) were quantified and documented. The time to first metastasis and melanoma-specific death (MSD) from the date of definite treatment were analyzed using univariate and multivariate Cox models. Among the 116 vertical growth phase melanomas that had regression in the adjacent RGP, 75 (23%) were classified as complete and 41 (13%) were classified as partial. LD was significantly higher (P<0.001) in the 75 lesions with complete regression (mean+/-SD, 23.7+/-12.3/mm2) compared with the 41 lesions with partial regression (15.5+/-7.1/mm2) and was lower in 155 areas of the adjacent normal dermis (7.3+/-3.5/mm2) and 69 areas of the distant normal dermis (5.5+/-2.6/mm2). Patients whose lesions had areas of complete regression with LI and either high or low LD or had no LI with high LD, had shorter time to first metastasis (hazard ratio=2.5, 3.8, and 2.5, respectively) and increased risk of melanoma-specific death (hazard ratio=3.1, 1.3 and 3.0, respectively) than those with no LI, and low LD or those without areas of complete regression. These data indicate that complete RGP regression is associated with significantly increased LD. In addition, the adverse prognostic effect of RGP regression is at least partially mediated through lymphangiogenesis and LI in this area. PMID- 21263245 TI - Copy number variations and clinical outcome in atypical spitz tumors. AB - Atypical Spitz tumors (ASTs) are rare spitzoid neoplasms of uncertain biological behavior. Our study was designed to characterize genetic abnormalities that may help to differentiate ASTs from melanoma or Spitz nevi. We examined copy number variation in formalin-fixed, paraffin-embedded samples using an Agilent 44k array comparative genomic hybridization platform. Sixteen patients with AST (8 with positive sentinel lymph node biopsy, 1 with distant metastasis), 8 patients with Spitz nevi, and 3 patients with melanoma (2 spitzoid, 1 superficial spreading) were evaluated. Chromosomal aberrations were found in 7 of 16 ASTs, 1 with fatal outcome, 2 spitzoid melanomas, and 1 conventional melanoma. We found no difference in chromosomal instability between AST patients with positive and negative sentinel lymph node biopsies. Our patient with widely metastatic AST lacked the most frequent aberrations in melanoma involving chromosomes 6 and 11q that are loci targeted by fluorescence in situ hybridization (FISH) probes developed to distinguish malignant melanoma from benign melanocytic lesions. The vast majority of chromosomal abnormalities observed in ASTs are not commonly found in melanomas, suggesting that AST may be a distinct clinical entity and raising additional questions regarding their malignant potential, prognosis, and clinical management. The current FISH probes failed to detect 1 spitzoid melanoma, 1 fatal metastatic AST case, and the other chromosomally aberrant ASTs in our series, but detected 1 spitzoid melanoma and 1 conventional melanoma. Thus, a comprehensive, genome-wide approach to chromosomal abnormalities offered greater sensitivity and specificity than current FISH probes in identifying spitzoid lesions of uncertain malignant potential in this series. PMID- 21263246 TI - Value of p16(INK)4(a) in the pathology of invasive penile squamous cell carcinomas: A report of 202 cases. AB - BACKGROUND: One third to one half of penile squamous cell carcinomas (SCCs) are related to human papillomavirus (HPV) infection. Viral detection is usually carried out by polymerase chain reaction (PCR) or other molecular methods. In this study, we evaluated p16(INK)4(a) immunohistochemical expression, which is simpler and less costly, as a potential marker of high-risk HPV (HR-HPV) infection in penile SCC. DESIGN AND METHODS: We pathologically classified 202 invasive penile carcinomas and performed HPV genotyping by short PCR fragment (SPF)10 PCR and p16(INK)4(a) immunohistochemistry. We also evaluated HPV and p16(INK)4(a) according to the histologic subtypes of penile SCC. Tumors depicting continuous p16(INK)4(a) immunostain in all neoplastic cells were considered positive. HPV and p16(INK)4(a) status were compared using classifier performances and concordance indexes. RESULTS: Evidence of HPV (low-risk and high-risk genotypes) was found in 63 cases (31%) by PCR. Fifty-three p16(INK)4(a)-positive cases were identified (26%). Overexpression of p16(INK)4(a) had a sensitivity of 67% and a specificity of 91% for defining the HPV status. Concordance indexes between p16(INK)4(a) and HPV status were high (>=78%) in general cases and in all histologic subtypes of penile SCC. The stain was useful in the differential diagnosis of basaloid and low-grade warty carcinomas. Low-risk HPV genotypes were found in 5 tumors, 4 of which were p16(INK)4(a) negative. Basaloid and nonbasaloid high-grade (grade 3) SCCs were more likely to be HR-HPV positive when compared with grades 1 to 2 tumors (P<0.000001 and 0.0417, respectively). CONCLUSIONS: p16(INK)4(a) overexpression was found to be a reliable marker for HR HPV and a helpful tool in the differential diagnosis of low-grade verruciform and high-grade solid penile tumors. SCC variants depicting basaloid features were more likely to be HPV and p16(INK)4(a) positive than low-grade, keratinizing lesions. We also observed a tendency toward HPV positivity in high-grade nonbasaloid tumors. Our results indicated a concordance between HPV and p16(INK)4(a) status and this observation may have diagnostic and prognostic implications. PMID- 21263247 TI - PAX2(-)/PAX8(-)/inhibin A(+) immunoprofile in hemangioblastoma: A helpful combination in the differential diagnosis with metastatic clear cell renal cell carcinoma to the central nervous system. AB - BACKGROUND: Hemangioblastomas account for up to 2.5% of all intracranial tumors. They may occur sporadically or as a part of the multisystem genetic syndrome of Von Hippel-Lindau syndrome (VHL). Patients with VHL are also at an increased risk of developing clear cell renal cell carcinoma (ccRCC). Distinguishing hemangioblastomas from metastatic ccRCC to the central nervous system (CNS) can be challenging at times when based solely on hematoxylin and eosin-stained sections. We propose an immunohistochemistry (IHC) panel of combination of PAX2, PAX8, and inhibin A as a helpful approach in distinguishing the 2 lesions. DESIGN: Archival tissues from 20 hemangioblastomas and 16 ccRCCs metastatic to the CNS were retrieved from our surgical pathology files (2001 to 2010). IHC for PAX2, PAX8, and inhibin A was performed on routine or tissue microarray sections using standard IHC protocol. The intensity of nuclear staining was evaluated for each marker and was assigned an incremental 0, 1+, 2+, and 3+ score. The extent of staining was categorized as focal (<25%), multifocal (25% to 75%), or diffuse (>75%). RESULT: (1) Hemangioblastoma: The Von Hippel-Lindau syndrome was diagnosed in 4 of 16 (25%) patients, 2 of whom developed multiple hemangioblastomas. All 20 (100%) hemangioblastomas were positive for inhibin A (cytoplasmic). The staining intensity was moderate or strong (2+ or 3+) in 19 cases (95%), all of which were multifocal or diffuse in extent. Nuclear PAX2 staining was present in 1 of 19 evaluable lesions (5%), whereas PAX8 staining was not present in any of the 20 examined lesions. (2) Metastatic ccRCC to the CNS: Fourteen of 16 (88%) examined ccRCCs were positive for PAX2, whereas 15 of 16 (94%) lesions showed PAX8 staining. None of 16 (0%) examined ccRCCs were positive for inhibin A. CONCLUSIONS: We propose the use of the combination of PAX2, PAX8, and inhibin A as a helpful ancillary IHC panel to resolve the differential diagnosis of hemangioblastoma versus metastatic ccRCC. The immunoprofile of PAX2(+) or PAX8(+) and inhibin A(-) supports the diagnosis of metastatic ccRCC with a sensitivity of 94%, specificity of 100%, and positive predictive value of 100%. The PAX2(-), PAX8(-), and inhibin A(+) profile supports the diagnosis of hemangioblastoma with a sensitivity of 95%, specificity of 100%, and positive predictive value of 100%. PMID- 21263248 TI - miR-205 Expression levels in nonsmall cell lung cancer do not always distinguish adenocarcinomas from squamous cell carcinomas. AB - Accurate classification of nonsmall cell lung cancers is of paramount clinical relevance, as novel chemotherapeutic agents show different efficacy in adenocarcinomas (ADCs) compared with squamous cell carcinomas (SQCCs). Cyto and histomorphology may sometimes be insufficient for this distinction and immunohistochemistry may improve diagnostic accuracy. The measurement of miR-205 may be another tool for the distinction between ADC and SQCC. The aim of our study was to compare morphologic and immunohistochemical classification with the relative quantification of miR-205 and miR-21 insurgically resected and well characterized lung tumors (25 ADCs, 24 SQCCs, 1 adenosquamous). The miR-21 relative levels were similar in SQCC and ADC, whereas the miR-205 relative levels were lower in ADC (P<0.0001). The miR-205 sample score value, determined according to Lebanony et al, was higher in ADC (range, 2.8 to 9.08) compared with SQCC (range, -4.17 to 2.445) (P<0.0001). Accordingly, 22 tumors were classified as ADC and 28 tumors as SQCC, although 8 cases (2 SQCCs and 6 ADCs) were in the range of "near cutoff values." Four cases classified as SQCC (according to the sample score method) corresponded to cases classified as ADC on the basis of morphoimmunohistochemical evaluation. In conclusion, the relative quantification of miR-205 and miR-21 seems to be a promising diagnostic tool. However, the molecular approach is still not completely satisfactory as it may misclassify a non-negligible percentage of cases. Therefore, it cannot be used as a substitute of accurate morphologic and immunophenotypical characterization of tumors, but could be used as an adjunctive diagnostic criterion in selected cases. PMID- 21263249 TI - Ovarian metastases of pancreaticobiliary tract adenocarcinomas: analysis of 35 cases, with emphasis on the ability of metastases to simulate primary ovarian mucinous tumors. AB - Metastatic mucinous carcinomas in the ovary are readily recognized when they show characteristic features, including bilateral involvement, only moderate tumor size, surface and superficial cortical involvement, nodular growth, and an infiltrative pattern. However, it is well established that some metastatic mucinous carcinomas can simulate primary ovarian mucinous tumors grossly and microscopically. Metastatic pancreaticobiliary tract adenocarcinomas present a particular diagnostic challenge due to their ability to exhibit borderline-like and cystadenomatous growth patterns, which can be misinterpreted as underlying primary ovarian precursor tumors and can be erroneously used to support interpretation of the carcinomatous components as arising from these purported precursors within the ovary. Thirty-five cases of metastatic pancreaticobiliary tract adenocarcinomas were analyzed. The mean patient age was 58 years (median, 59 y; range, 33 to 78 y). In 15 cases (43%), the pancreaticobiliary tract and ovarian tumors presented synchronously and in 2 cases (6%) the ovarian tumors presented earlier as the first manifestation of the disease. Ovarian tumors were bilateral in 31 cases (89%). Mean and median tumor sizes were 10.6 and 9.5 cm, respectively (range, 2.5 to 21.0 cm). Nodularity was present in 22 cases (63%) and surface involvement was identified in 14 cases (40%). An infiltrative growth pattern was present at least focally in 28 cases (80%), accompanied by borderline like and/or cystadenomatous areas in 17 (49%) cases and as the exclusive pattern in 11 cases (31%). Conversely, borderline-like and cystadenomatous patterns were identified in 24 cases (69%) and as the exclusive patterns (either pure or combined with one another) in 7 cases (20%). Dpc4 expression was lost in 20 of 33 tumors analyzed (61%). Of 25 patients with follow-up, 23 patients had died of disease (mean/median time, 9/6 mo; range, 1 to 39) and 2 patients were alive with disease (at 1 and 25 mo). Frequent bilateral ovarian involvement, moderate tumor size, nodularity, and infiltrative patterns are useful features for identifying these ovarian tumors as metastatic. However, many tumors exhibit borderline-like and cystadenomatous patterns that, when dominant and combined with synchronous presentation, make recognition as metastases an ongoing challenge. Loss of Dpc4 expression provides the most useful immunohistochemical evidence for establishing the pancreaticobiliary tract as the most likely source of these metastatic mucinous carcinomas in the ovary. PMID- 21263250 TI - Significant variation in the assessment of cervical involvement in endometrial carcinoma: an interobserver variation study. AB - The histologic assessment of cervical involvement in endometrial carcinoma may be problematic for a number of reasons, but an accurate evaluation of this is important for correct staging, dictating the need for adjuvant therapy, and prognostication. In this study, we assessed interobserver variation in the evaluation of cervical involvement in hysterectomy specimens of endometrial carcinoma among 6 specialist gynecologic pathologists. Seventy-six cases of endometrial carcinoma enriched for cases exhibiting some perceived issue in the assessment of cervical involvement were used. In all the cases, a single slide of the primary tumor in the uterine corpus and a single slide of the cervix were circulated among the 6 participants who filled in a proforma. On the basis of the responses, the tumors were staged according to the 1988 International Federation of Gynecology and Obstetrics (FIGO) staging system (I, IIA, IIB) and the 2009 FIGO staging system (I, II). Using the 1988 FIGO staging system, the unweighted and weighted kappa values between individual observers ranged from 0.3115 to 0.6139 (average 0.4675) and from 0.3492 to 0.6533 (average 0.5065), respectively. The kappa values between observers for the 2009 FIGO staging system ranged from 0.3481 to 0.6862 (average 0.4908). Although enriched for problematic cases, our study shows that there is at most a fair-to-good agreement among specialist gynecologic pathologists in the assessment of cervical involvement in endometrial carcinoma. Problematic factors include determination of the junction between the lower uterine segment and upper endocervix, the distinction between "floaters" and true cervical glandular involvement, the distinction between cervical glandular involvement and stromal involvement, and the distinction between cervical glandular involvement and reactive non-neoplastic lesions of the endocervical glands. There is a need for specialist pathology groups dealing with gynecologic cancers to develop and disseminate recommendations regarding the assessment of cervical involvement in endometrial carcinoma. PMID- 21263251 TI - Sessile serrated adenoma with early neoplastic progression: a clinicopathologic and molecular study. AB - Sessile serrated adenoma (SSA), also referred to as sessile serrated polyp, has been proposed as a precursor lesion to microsatellite unstable carcinoma. However, the mechanism of stepwise progression from SSA to early invasive carcinoma has been unclear. The purpose of this study was to elucidate the histologic characteristics and possible role of p53, beta-catenin, BRAF, KRAS, and PIK3CA in the development and progression of SSA. We analyzed 12 cases of SSA with neoplastic progression (SSAN), including 7 cases of intraepithelial high grade dysplasia (HGD) and 5 cases of submucosal invasive carcinoma, and compared them with 53 SSAs and 66 hyperplastic polyps (HPs) by immunohistochemistry and gene mutation analysis. Histologically, 75% (9 of 12) of SSANs showed tubular or tubulovillous growth patterns rather than serrated ones in the HGD/intramucosal carcinoma component. All 5 SSANs with invasive carcinoma lost their serrated structure and developed increased extracellular mucin in their submucosal carcinoma component, a consistent feature of mucinous adenocarcinoma. Nuclear accumulations of beta-catenin and p53 were observed in 50% (6 of 12) and 41.7% (5 of 12) of SSANs, respectively, and were exclusively present in HGD/carcinoma areas. By contrast, neither nuclear beta-catenin nor p53 expressions were seen in HPs or SSAs (P<0.0001). BRAF mutations (V600E) were observed in 45.8% (11 of 24) of HPs, 60.9% (14 of 23) of SSAs, and 63.6% (7 of 11) of SSANs, and were equally found in both SSA and carcinoma/HGD areas of the individual SSANs. KRAS exon 1 mutations were uncommon in all 3 groups (4.2%, 4.4%, and 0%, respectively). No mutations of PIK3CA exon 9 or exon 20 were found in any cases that were examined. These findings suggest that BRAF mutations may be associated with the pathogenesis of SSA, but progression to HGD or early invasive carcinoma may be associated with other factors, such as alterations of p53 and beta-catenin. In addition, our histologic observations suggest a possible close association between SSAN and mucinous adenocarcinoma. PMID- 21263252 TI - Gastrointestinal tract langerhans cell histiocytosis: A clinicopathologic study of 12 patients. AB - Gastrointestinal (GI) tract involvement by Langerhans cell histiocytosis (LCH) is a rare condition. It is typically noted in male patients with systemic disease and is associated with both poor prognosis and high morbidity. The incidence peaks in childhood. However, a limited number of cases have been reported in adults. To further characterize this disease process, we collected 24 cases of GI tract LCH from 12 patients. The patients included 2 children (4 mo and 2.3 y) and 10 adults (40 to 77 y; mean, 58.4 y), with a female predominance (9 of 12, 75%). Both children presented with failure to thrive, bloody diarrhea, and anemia. In contrast, 5 of 10 (50%) adults were asymptomatic and the rest had unrelated symptoms. Endoscopically, the pediatric patients showed the involvement of the duodenum and multiple colonic sites. However, 8 of 10 (80%) adults presented with a solitary polyp, primarily involving the colorectum (7 of 8, 88%). The lesions ranged in size from 0.1 to 0.8 cm (mean, 0.4 cm), and were predominantly intramucosal (18 of 24, 75%) with either a marginated (14 of 24, 58%) or infiltrative (10 of 24, 42%) growth pattern. Microscopic features were similar to those of LCH found elsewhere, although some cases differed by showing prominent lymphocytes (12 of 24, 50%) rather than eosinophils and large nucleoli (2 of 24, 8%). Reactive overlying mucosal and entrapped epithelial changes (10 of 24, 42%), mucosal ulceration (3 of 24, 13%), focal necrosis (1 of 24), and multinucleated giant cells (1 of 24) were also identified. Mitotic figures were absent. On immunohistochemistry, all lesions expressed the S-100 protein and CD1a. Follow-up information was available for 11 (92%) patients ranging from 2 months to 5.3 years (mean, 1.8 y). One pediatric patient was lost to follow-up. However, the other patient developed multisystem disease and died 1 year after the initial diagnosis. Two adult patients developed cutaneous disease, 2 months and 2 years after the initial diagnosis, 1 of whom had multifocal colonic disease. On the basis of this study, GI tract LCH lesions present in both children and adults with a female predominance. Consistent with earlier reports, pediatric cases are associated with systemic disease and poor prognosis. However, in adults, LCH is typically encountered as an incidental, solitary polyp. Rare cases of systemic disease may occur and, therefore, close follow-up may be warranted. PMID- 21263253 TI - Invasive micropapillary carcinoma: beyond the borders. PMID- 21263255 TI - Pulmonary synovial sarcoma and pneumothorax. PMID- 21263257 TI - A proposal for the classification of follicular-patterned neoplasms of the thyroid gland. PMID- 21263259 TI - From the guest editors: treatment of early-stage lung cancer. PMID- 21263260 TI - Screening and early detection of lung cancer. AB - Lung cancer with an estimated 342,000 deaths in 2008 (20% of total) is the most common cause of death from cancer, followed by colorectal cancer (12%), breast cancer (8%), and stomach cancer (7%) in Europe. In former smokers, the absolute lung cancer risk remains higher than in never-smokers; these data therefore call for effective secondary preventive measures for lung cancer in addition to smoking cessation programs. This review presents and discusses the most recent advances in the early detection and screening of lung cancer.An overview of randomized controlled computerized tomography-screening trials is given, and the role of bronchoscopy and new techniques is discussed. Finally, the approach of (noninvasive) biomarker testing in the blood, exhaled breath, sputum, and bronchoscopic specimen is reviewed. PMID- 21263261 TI - Pretreatment assessment for the optimal management of early-stage lung cancer. AB - Optimal management of non-small cell lung cancer requires treatment approach to be tailored to both the particular disease stage and the overall health and functional status of the patient. Even though surgical resection by means of an anatomic lobectomy remains the treatment of choice with the goal of cure for early-stage lung cancer, it is an invasive procedure with associated morbidity and mortality. Although these risks continue to decrease in the modern era with improvements in surgical technique and perioperative management, the risks are elevated in patients with associated medical comorbidities. As a consequence, patients at potentially increased or high risk for surgical lobectomy need to be identified by a structured preoperative assessment. This has gained increasing importance, given the emergence of alternative treatment approaches such as minimally invasive surgery, less extensive pulmonary resection, and stereotactic body radiation therapy. We review the clinical approach to suspected early-stage lung cancer based on a tumor and patient-centered stratification of risk and benefit. PMID- 21263262 TI - Is surgical morbidity decreased with minimally invasive lobectomy? AB - Non-small cell lung cancer remains one of the leading causes of cancer-related mortality worldwide. Despite recent advances in molecular characterization and targeted and adjuvant therapies, surgical resection remains the mainstay of curative treatment. Minimally invasive video-assisted thoracic surgery techniques, in particular video-assisted thoracic surgery lobectomy, are being increasingly utilized and championed over traditional thoracotomy approaches in the treatment of localized non-small cell lung cancer for the reported benefits of lower operative morbidity, accelerated postoperative recovery, and oncological equivalence. This article reviews the available literature comparing surgical outcomes of minimally invasive versus traditional open lobectomy with an emphasis on differences in surgical morbidity. PMID- 21263263 TI - Sublobar versus lobar resection: current status. AB - Currently, lobectomy is the preferred treatment for early-stage, non-small cell lung cancer primarily because of the increased local recurrence rate that has been reported with sublobar resection. Sublobar resection is typically used for high-risk, but still operable, patients with lung cancer. Several recent studies have demonstrated comparable recurrence and survival rates between lobectomy and sublobar resection for small, stage I lung cancers. In particular, attention to technical details such as performing a segmentectomy or a wide wedge resection (rather than a simple wedge resection), or the addition of brachytherapy, can result in improved outcomes. Also, the potential for better preservation of pulmonary function with sublobar resection has fueled the debate arguing for sublobar resections even for patients who are considered to be "good risk" and able to tolerate a lobectomy. This article reviews the current status of sublobar resection for early-stage lung cancer, with particular attention to issues such as tumor size, type of sublobar resection, use of adjuvant brachytherapy, and preservation of pulmonary function. PMID- 21263264 TI - Stereotactic ablative radiation therapy for primary lung tumors. AB - Stereotactic ablative radiotherapy, also known as stereotactic body radiation therapy, has been developed as an innovative therapy for stage I non-small cell lung cancer and has now emerged as a standard treatment option for medically inoperable patients through careful analysis utilizing prospective, multi institutional trials. This article reviews and updates the evidence for use of stereotactic ablative radiotherapy in medically inoperable patients with stage I lung cancer, its extension of use to medically operable patients, and the toxicities associated with this emerging technique. PMID- 21263265 TI - Radiofrequency ablation: a safe and effective treatment in nonoperative patients with early-stage lung cancer. AB - Surgical resection remains the treatment of choice for patients with early-stage non-small cell lung cancer. However, some patients are not surgical candidates because of medical problems. Therefore, alternative therapies are considered in these medically inoperable patients. Radiofrequency ablation has been used clinically for more than 12 years, with many studies reporting its safety and efficacy. Because there are no large prospective clinical trials comparing the efficacy and long-term survival of the different treatment modalities, the choice of therapy is often based on a combination of tumor location, available technology and expertise, and patient preference. Here we review the principles, procedure, follow up, and clinical outcomes published to date on radiofrequency ablation in the treatment of early-stage non-small cell lung cancer. PMID- 21263266 TI - Evaluation of treatment response after nonoperative therapy for early-stage non small cell lung carcinoma. AB - Nonsurgical management of early primary lung cancer has grown tremendously in recent years, and today, available options extend far beyond that of conventional radiation therapy (CRT) to include minimally invasive image-guided delivery of thermal energies, specifically radiofrequency ablation, microwave ablation, and cryoablation, and more conformal stereotactic body radiation therapy. Because the tumor is never resected with these nonoperative interventions, histopathological evaluation of tumor margins for the presence of residual tumor is impossible, and as such, tumor response after each of these therapies is largely based on imaging. To date, computerized tomography and computerized tomography-positron emission tomography remain the most readily available modalities for assessment of therapeutic efficacy, and to this end as detailed within this article, strict imaging survey and familiarity with the expected imaging characteristics of the treated tumor will aid in recognition of unexpected findings, specifically those of incomplete therapy and/or tumor recurrence. PMID- 21263267 TI - Predicting response to chemotherapy with early-stage lung cancer. AB - A recent meta-analysis of 11,107 patients with non-small cell lung cancer who had undergone surgical resection showed that the 5-year survival benefit of adjuvant chemotherapy was 4%, and that of adjuvant chemoradiotherapy was 5%. Two trials have shown a trend toward improved survival with adjuvant paclitaxel plus carboplatin. However, the benefit of adjuvant treatment remains suboptimal. We must distinguish between patients who will not relapse-and who can thus be spared adjuvant treatment-and those who will-for whom adjuvant treatment must be personalized. Several gene expression signatures, generally containing nonoverlapping genes, provide similar predictive information on clinical outcome, and a model combining several signatures did not perform better than did each of the signatures separately. The invasiveness gene signature, containing 186 genes, includes genes involved in the nuclear factor kappaB pathway, the RAS-mitogen activated protein kinase pathway, and epigenetic control of gene expression. A 15 gene signature has identified JBR.10 patients who are more sensitive to adjuvant chemotherapy. PMID- 21263268 TI - Attributes contributing to superior outcomes in the surgical management of early stage lung cancer and examples of implementing improvement. AB - Attributes contributing to superior clinical outcomes include high clinical volumes, specialized care, and multidisciplinary care. Using a quality template as the framework for review, the literature surrounding these relative to lung cancer surgery and operative mortality and morbidity is examined. Costs of lung cancer surgery operative mortality or complications are discussed. Finally, examples of quantifying and implementing high-quality medical care, especially regarding lung cancer, are reviewed. PMID- 21263270 TI - Creative strategies to improve patient safety: allergies and adverse drug reactions. AB - Approximately 770,000 Americans are hospitalized and suffer adverse drug events (ADEs) costing billions of dollars each year. An ADE occurs when a patient is injured by an adverse drug reaction. Improved medication administration could prevent about 2.5 million ADEs (Institute of Medicine, 2004). This project provided an education for patients and nurses and a medication fact sheet. Outcomes included updating allergy records, improving medication safety knowledge, and improving nurses' adverse drug reactions and allergy reports. PMID- 21263269 TI - Metrics to assess quality of life after management of early-stage lung cancer. AB - Quality of life (QOL) is a key clinical outcome in patients with lung cancer because of the debilitating nature of the disease and its treatments. In recent years, advances have been made in the assessment of QOL via patient-reported outcomes. A brief history of the evolution of QOL measures in oncology clinical trials and practice is given with specific reference to early-stage lung cancer. The role that QOL can play as a prognostic factor, especially among lung cancer patients, is delineated. The most commonly seen symptoms among lung cancer patients are listed. This review is intended to provide the clinical researcher with a summary of the alternative measures that are both valid and reasonable to consider when assessing QOL in early-stage lung cancer patients. Suggestions for QOL assessment in both a research setting and clinical environment are considered. A review of the most popular QOL assessments in general application to lung cancer and disease-specific measures is provided. An algorithm for selecting appropriate QOL assessments for lung cancer clinical research is provided. The primary conclusion from this work is that scientifically sound investigations into the QOL of early-stage lung cancer patients are feasible and encouraged so that the care of these patients can be optimized. PMID- 21263272 TI - The more we change.... PMID- 21263273 TI - Reflective narrative: a tool for learning through practice. AB - Reflection has recently gained increased recognition for its potential to facilitate learning. New insights gained through reflection enable the nurse to respond to clinical situations from a changed perspective. Skill, however, is required in learning to reflect. In this article, the author provides a systematic approach for staff development specialists to use to assist staff in reflecting on practice through a written reflective narrative. PMID- 21263274 TI - Resuscitation review to improve nursing performance during cardiac arrest. AB - The purpose of this study was to evaluate the effect of Resuscitation Review Simulation Education (RRSE) on improving adherence to hospital protocols and American Heart Association (AHA) resuscitation standards. Prior to implementing the RRSE on two nursing units, performance was evaluated during a simulated cardiac arrest using a mannequin and comparing performance against AHA algorithms. Performance was measured at two separate periods: preintervention and 3 months after the intervention. Both units improved overall scores after the RRSE. PMID- 21263275 TI - Staff nurses revitalize a clinical ladder program through shared governance. AB - After 20 years of a static clinical ladder program at our institution, the clinical ladder program was completely redesigned using a staff nurse-led shared governance structure to re-envision the program as an innovative, staff leadership model to meet our organizational nursing mission and vision strategic plans around retention and professional development. The literature demonstrated a lack of outcome-driven findings on the sustainability of hospital-based clinical ladder programs. The authors cover the rationale for our clinical ladder model, the process used for revision, the implementation strategies, and the specific outcomes tracked regarding nurse satisfaction, affiliation, retention, and participation of staff nurses advancing to the optional upper levels of the ladder. PMID- 21263277 TI - Creating and implementing a nursing role for RN retention. AB - Institutions have historically provided assistance to new graduate nurses as they transition into the role of staff nurse. Residencies, internships, and other programs have been implemented to help socialize, educate, and support the graduate nurse. The newly hired experienced RN is not always given the same focus. This article will describe the components and processes of a role specifically designed to assist and support experienced RNs as they make a career transition. PMID- 21263276 TI - Creating a vision for nursing practice in a tertiary medical organization in Israel. AB - Rapid changes in the healthcare system obligate Israeli nursing leaders to reassess current nursing roles and to identify new paradigms that are in line with the demanding needs of acute care settings. The challenge of engaging nurses to achieve the desired changes in nursing role performance and perception can be accomplished by defining a comprehensive organizational vision. The authors present a process creating and implementing a nursing vision intended to empower the nurse's role in a large acute general hospital. PMID- 21263278 TI - Preceptorship placements can be a burden for students. AB - Fourth year baccalaureate nursing students were surveyed to determine their perceptions of the preceptorship experience. Results indicated that students highly valued and enjoyed their preceptorship experiences. However, issues related to choice, finances, and role of the administration were identified. There is a need (a) to reexamine the organization and coordination of placements, (b) to understand the potential personal and financial burden on students during placements, and (c) to develop mechanisms to reduce obstacles for students that may compromise successful and meaningful preceptorship placements. PMID- 21263279 TI - Nursing morbidity and mortality conferences: a tool for enhancing quality patient care. AB - Morbidity and mortality conferences have been used to educate healthcare providers, to critique staff performance, and to improve patient outcomes since the early 1900s. Historically well documented in physician-focused journals, the use of morbidity and mortality conferences is less predominant in the nursing literature. This article highlights one hospital's experience with planning, implementing, and evaluating a nursing morbidity and mortality conference and identifies implications for use in professional nursing development. PMID- 21263280 TI - Turnover intention among new nurses: a generational perspective. AB - With the current nursing shortage, it is crucial to understand the aspects of the nursing work environment that are related to turnover in new generation nurses. The Practice Environment Scale of the Nursing Work Index was administered to new nurses in Quebec from different generations to determine what domains of the work environment were related to turnover intention. Results can help nurses in leadership and development positions target interventions to retain new graduates. PMID- 21263281 TI - Nursing professional development: stories, tips, and techniques. PMID- 21263284 TI - NNSDO update. PMID- 21263285 TI - Is indocyanine green angiography still relevant? PMID- 21263286 TI - A 27-gauge sharp-tip short-shaft pneumatic vitreous cutter for transconjunctival sutureless vitreous biopsy. PMID- 21263287 TI - Minimum velocity necessary for nonconventional projectiles to penetrate the eye: an experimental study using pig eyes. AB - To satisfy the Criminal Code of Canada's definition of a firearm, a barreled weapon must be capable of causing serious bodily injury or death to a person. Canadian courts have accepted the forensically established criteria of "penetration or rupture of an eye" as serious bodily injury. The minimal velocity of nonconventional ammunition required to penetrate the eye including airsoft projectiles has yet to be established. To establish minimal threshold requirements for eye penetration, empirical tests were conducted using a variety of airsoft projectiles. Using the data obtained from these tests, and previous research using "air gun" projectiles, an "energy density" parameter was calculated for the minimum penetration threshold of an eye. Airsoft guns capable of achieving velocities in excess of 99 m/s (325 ft/s) using conventional 6-mm airsoft ammunition will satisfy the forensically established criteria of "serious bodily injury." The energy density parameter for typical 6-mm plastic airsoft projectiles is 4.3 to 4.8 J/cm2. This calculation also encompasses 4.5-mm steel BBs. PMID- 21263288 TI - Discrimination between human and animal DNA: application of a duplex polymerase chain reaction to forensic identification. AB - Identification of a report's species is one of the basic analyses in forensic laboratories. The authors report the case of 6 bone fragments recovered in a wooded area, which were not attributable to 1 animal species on the basis of morphologic examination. The aim of this study was to develop a duplex polymerase chain reaction (PCR) to discriminate human and animal origin of bone fragments. The method is based on the PCR amplification of cytochrome b and a 16S ribosomal mitochondrial DNA fragment, which has never been tested up to now. Our protocol combines a single-round PCR with direct visualization of amplicons in agarose gel, without sequencing analysis of the PCR products. The presence of a single band (359 bp) indicates a nonhuman origin of the sample, whereas 2 bands (157 and 359 bp) indicate a human biologic sample.This method revealed to be useful for forensic purposes because the 16S ribosomal mitochondrial DNA is a small human specific fragment that is easily amplifiable even with degraded DNA from biologic materials such as old bones. PMID- 21263289 TI - Abdominoplasty of cloacal exstrophy: application of reconstructive methods to recurrent and primary cases. AB - BACKGROUND: Surgical repair of cloacal exstrophy is still challenging. At birth, patients undergo bladder closure, colostomy, and osteotomy of the pubic bone (if necessary, when the interpubic range is wide and cannot be brought together with the hands). This abdominal defect is closed primarily by urologists or pediatric surgeons, if possible, but the patient may experience a relapse of bladder exstrophy and an abdominal defect. Abdominal reconstruction was performed for a series of recurrent and primary (preventive) cases. METHODS: Abdominal wall reconstruction was performed using the rectus abdominis and external oblique muscle fascia flaps, and reinforcement of the bilateral rectus abdominis muscles in 2 cases of cloacal exstrophy patients. One was a recurrent case treated at 7 months old, and the other was done primarily at 2 days after birth. RESULTS: The closure of the abdominal wall was successful and no relapse of bladder exstrophy or abdominal defect has occurred. These patients are now undergoing rehabilitation. CONCLUSION: Cloacal exstrophy usually has many serious complications. The abdominal-wall defect is often large and accompanied by a wide detachment of the pubic bone. Even if the simple closure of abdominal wall is possible at birth, it is usually insufficient. Abdominal-wall repair must be done thoroughly, soon after birth, and plastic surgery techniques should be used. PMID- 21263290 TI - Fibrin glue: a scaffold for cellular-based therapy in a critical-sized defect. AB - PURPOSE: Cartilage-based treatments have vast applications in plastic and reconstructive surgery, especially craniofacial constructs. Current techniques in craniofacial cartilage reconstructions greatly rely on autologous donor site harvest. Whole cartilage grafts are wrought with complications of warping, resorption, extrusion, and donor site morbidity. Percutaneous delivery of expanded chondrocytes would have the potential to expand a small quantity of autologous cells to deliver cell therapy. To deliver chondrocytes effectively, there must be a reliable medium in which chondrocytes can be kept. The purpose of this work is to highlight the utility of fibrin glue sealant, Evicel, as a suitable chondrocyte carrier in the treatment of a critical-sized defect model of nonarticular cartilage previously developed in our laboratory. METHODS: Athymic rats were separated into 2 groups: fibrin glue (n = 3) and fibrin glue + rat chondrocytes (n = 6). The animals with an empty defect were used to ensure that they responded normally to the procedure. All animals received a 3-mm full thickness xiphoid cartilage defect characterized previously as a critical-sized defect in our laboratory (Moyer HR, Wang Y, Farooque T, et al. Tissue Eng Part A. 2010;16:2321-2330). A control animal received no xiphoid defect creation procedure. The fibrin glue group was treated with 0.5 mL of fibrin glue placed directly into the 3-mm defect. The fibrin glue/rat chondrocyte group received a mixture of 1 * 10 resting zone chondrocytes mixed with 0.5 mL of fibrin glue. Rats were euthanized at 5 weeks (35 days) and their xiphoid cartilages harvested. The xiphoids were analyzed with morphometrics through histology and microcomputed tomography. RESULTS: In the fibrin glue vehicle group, there was minimal evidence of wound healing. Xiphoid defects treated with resting zone chondrocytes in a fibrin glue carrier were significantly smaller (P = 0.002) at harvest and had significantly more glycosaminoglycan content on microcomputed tomography analysis. Thus, there was significant healing in the chondrocyte/fibrin glue group. CONCLUSION: Human fibrin sealant is an effective chondrocyte carrier and retains viable cells. Treatment of a nonarticular critical-size defect with resting zone chondrocytes embedded in a fibrin glue polymer demonstrates tissue healing. PMID- 21263291 TI - Multidisciplinary approach to the treatment of a patient with chondrodystrophic myotonia (Schwartz-Jampel vel Aberfeld syndrome): case report and literature review. AB - Chondrodystrophic myotonia, Schwartz-Jampel syndrome, is a rare congenital disorder, which results from disturbance in a perlecan protein synthesis. Most affected are the muscles, acting in generalized myotonia, leading to joint contractures, weird-looking mask-like face appearance, and causing vision disturbances. Also, impaired bones and cartilages result in skeletal anomalies and dental disorders. Allergic reactions to numerous drugs occur in affected individuals. Surgical treatment is risky, due to a low tolerance of anesthetics and high risk of malignant hyperthermia. In this article, a case of 17-year-old girl with Schwartz-Jampel syndrome is presented. The patient with typical syndrome debilitations underwent long diagnostic scheme and multiple treatments in order to restore acceptable appearance and function. All procedures were performed with cautious anesthesiologists' supervision. Modern diagnostic tools can improve the diagnosis rate while multidisciplinary evaluation and advanced treatment techniques can reveal symptoms, minimizing the hazard of anesthesia and improving the quality of life. PMID- 21263292 TI - Metastatic breast cancer after delayed deep inferior epigastric perforator flap reconstruction. AB - Locoregional breast cancer recurrence is a relatively rare event, occurring more frequently in patients diagnosed with more advanced stages of cancer and those with inflammatory features. While typical signs of recurrence after reconstruction include the development of a mass in the native skin or deep chest wall, oncologic relapse may also rarely be heralded by subtle cutaneous changes. This article describes a patient with inflammatory breast cancer who underwent neoadjuvant chemotherapy, mastectomy, radiation therapy, and hormonal therapy followed by delayed reconstruction with a deep inferior epigastric artery perforator flap and subsequently presented with a recurrence manifest as a localized rash over the upper abdomen. Surgeons who perform breast reconstruction should be attuned to both common and uncommon recurrence symptoms, as they may be the first to diagnose recrudescent disease. PMID- 21263293 TI - The du Bois sign. AB - According to the current literature, the term "du Bois sign" characterizes the condition of a shortened fifth finger as a symptom of congenital syphilis, Down syndrome, dyscrania, and encephalic malformation. Modern medical dictionaries and text books attribute the eponym to the French gynecologist Paul Dubois (1795 1871). Yet, a literature analysis revealed incorrect references to the person and unclear definitions of the term. Our findings showed that the origin of the term is based on observations made by the Swiss dermatologist Charles du Bois (1874 1947) in connection with congenital syphilis. In addition, a further eponymical fifth finger sign is closely associated with the du Bois sign. In conclusion, the du Bois sign has only limited diagnostic value and is frequently occurring in the normal healthy population. PMID- 21263294 TI - Surgical treatment of patients with Parry-Romberg syndrome. AB - INTRODUCTION: Parry-Romberg syndrome is an extremely rare disease characterized by the slow atrophy of the face involving the skin, subcutaneous tissue, fatty tissue, muscles, and even bones. The cause of the disease is unknown. The onset is slow and it begins usually during the first 2 decades of life, more often between the ages of 5 and 15. The purpose of the study was to present the principles of management and treatment outcomes in patients with Parry-Romberg syndrome. MATERIAL AND METHOD: A total of 14 patients (12 females and 2 males) aged between 14 and 36 years (mean, 21.5 years), were treated at the Hospital of Plastic Surgery in Polanica Zdroj between 1970 and 2005. Hemifacial atrophy affected the left side in 7 patients, and the right side in the remaining 7. Altogether 45 operations were performed. Less severe changes were reconstructed by means of dermal grafts, galeal flaps; patients with more severe facial deformities were treated with free tissue transfer: parascapular and latissimus dorsi flaps (6 cases). The treatment was completed with facial modeling, dermal regrafting, and scars correction. RESULTS: The appearance was improved in all the patients. There was only 1 free flap loss reported during postoperative management. CONCLUSIONS: Dermal grafts are used in the treatment of milder forms of Romberg disease to improve facial symmetry. In severe cases of facial atrophy, the surgical management is based on free-tissue transfer. PMID- 21263295 TI - Complex hernia repair using component separation technique paired with intraperitoneal acellular porcine dermis and synthetic mesh overlay. AB - Repairing complicated, recurrent ventral hernias poses many challenges and frustrations for both the patient and the surgeon. Patients with histories of multiple abdominal procedures, infection, and previous hernia repair are at higher risk for recurrence. They must be dealt with through a more sophisticated approach than the patient presenting with an initial hernia or even a simple recurrence. We describe our experience with 18 patients using component separation technique paired with acellular porcine dermis. We specifically focus on the use of intraperitoneal biologic mesh paired with a synthetic overlay. There were no hernia recurrences during the follow-up period: average 14 months (range, 4-24 months, 100% follow-up). Complications included seromas, wound breakdown, and infection; several of these requiring reoperation. The successful management of complicated hernias has been revolutionized by new synthetic and bioprosthetic meshes. However, these products, when used alone in complex hernia patients carry a higher recurrence rate. We have found that these meshes, used in conjunction with component separation technique, have had no recurrence to date, but are prone to complications. PMID- 21263297 TI - Staged cleft sternum repair using dermal allograft and synthetic mesh. AB - Cleft sternum is a rare congenital chest deformity that develops during the first trimester. Failure of the process of midline mesenchymal strip fusion leads to absence of the sternum, resulting in cleft formation. Multiple surgical approaches have been described in the closure of sternal clefts. An optimal surgical approach is still debatable. We describe 2 cases of complete sternal clefting treated with staging of the repair. Dermal allograft and synthetic mesh along with myofasciocutaneous flaps are used a bridging method to future definitive treatment. Most patients will require secondary cardiothoracic procedures for underlying cardiac conditions, and disruption of any primary repair is compromised on reentry into the chest. Staging this procedure avoids this potential problem. Also, concerns regarding chest wall constriction and cardiopulmonary compromise are minimized. Once the child has matured, definitive treatment can be pursued with more abundant autologous donor tissue. Our approach is safe with minimal complications and is well tolerated by the patients. PMID- 21263296 TI - Silk fibroin conduits: a cellular and functional assessment of peripheral nerve repair. AB - Silk fibroin conduits were designed with appropriate porosity for peripheral nerve repair. The aim of this work was to use these conduits to examine cell inflammatory responses and functional recovery in a sciatic nerve defect model. A total of 45 randomized Lewis rats were used to create an 8-mm defect bridged by a silk guide, commercial collagen guide, or an autograft. After 1, 4, and 8 weeks, macrophage recruitment, percentage of newly formed collagen, number of myelinated axons, and gastrocnemius muscle mass were evaluated. Following 8 weeks, ED1+ cells in autograft and silk conduits decreased to <1% and 17% of week 1 values, respectively. Collagen formation revealed no difference for all measured time points, suggesting a similar foreign body response. Myelinated axon counts within the silk guide revealed a greater number of proximal spouts and distal connections than collagen guides. Gastrocnemius weights demonstrated a 27% decrease between silk and autografts after 8 weeks. This study demonstrates that, in addition to tailorable degradation rates, our silk conduits possess a favorable immunogenicity and remyelination capacity for nerve repair. PMID- 21263298 TI - Case scenario: perioperative latex allergy in children. PMID- 21263299 TI - Needles, needles, everywhere! PMID- 21263300 TI - The power of speaking english. PMID- 21263302 TI - Rocuronium bromide. PMID- 21263303 TI - Apollo: god. . . and anesthetist? PMID- 21263307 TI - Surgical randomized-controlled trials and CONSORT 2010. PMID- 21263301 TI - Clinical and molecular pharmacology of etomidate. AB - This review focuses on the unique clinical and molecular pharmacologic features of etomidate. Among general anesthesia induction drugs, etomidate is the only imidazole, and it has the most favorable therapeutic index for single-bolus administration. It also produces a unique toxicity among anesthetic drugs: inhibition of adrenal steroid synthesis that far outlasts its hypnotic action and that may reduce survival of critically ill patients. The major molecular targets mediating anesthetic effects of etomidate in the central nervous system are specific gamma-aminobutyric acid type A receptor subtypes. Amino acids forming etomidate binding sites have been identified in transmembrane domains of these proteins. Etomidate binding site structure models for the main enzyme mediating etomidate adrenotoxicity have also been developed. Based on this deepening understanding of molecular targets and actions, new etomidate derivatives are being investigated as potentially improved sedative-hypnotics or for use as highly selective inhibitors of adrenal steroid synthesis. PMID- 21263308 TI - Skeletal muscle is anabolically unresponsive to an amino acid infusion in pediatric burn patients 6 months postinjury. AB - OBJECTIVE: To evaluate leg muscle, whole-body muscle, and whole-body nonmuscle protein response to anabolic signaling of amino acids in pediatric burn patients at 6 months after injury. BACKGROUND: Burn injury is associated with a catabolic state persisting years after the injury. The tissue response to nutritional signaling (eg, amino acids) plays a critical role in tissue protein net balance via coordination of protein synthesis and breakdown mechanisms. METHODS: A total of 10 patients (7.4 +/- 3.8 years; 27.4 +/- 14.7 kg) and 5 healthy young males (22 +/- 3 years; 76 +/- 15 kg) underwent an 8-hour stable isotope infusion study. During the last 3 hours, an amino acid solution (10% Travasol, Clintec Nutrition, Deerfield, IL) was infused. Femoral arterial and venous blood samples and muscle biopsy samples were collected throughout the study. A P value of less than 0.05 was considered statistically different. RESULTS: During amino acid infusion, leg muscle protein synthesis rate significantly increased (P < 0.05) in both groups, however, in the burn group, protein breakdown also increased, although nonsignificantly. As a result, protein net balance remained negative. In the control group, breakdown nonsignificantly decreased resulting in a significant increase (P < 0.05) in muscle protein net balance. Whole-body protein breakdown was significantly higher in the burn patients. CONCLUSION: In pediatric burn patients at 6 months postinjury, leg muscle protein net deposition is unresponsive to amino acid infusion; and whole-body protein breakdown is significantly higher than in the control group. PMID- 21263309 TI - Blunt cerebrovascular injury screening with 32-channel multidetector computed tomography: more slices still don't cut it. AB - OBJECTIVE: We sought to determine the diagnostic accuracy of computed tomographic angiography (CTA) using 32-channel multidetector computed tomography for blunt cerebrovascular injuries (BCVIs). BACKGROUND: Unrecognized BCVI is a cause of stroke in young trauma patients. Digital subtraction angiography (DSA), the reference standard, is invasive, expensive, and time-consuming. Computed tomographic angiography has been rapidly adopted by many institutions because of its availability, less resource intensive, and noninvasive nature. However, conflicting results comparing CTA and DSA have been reported. Studies with 16 channel CTA report a wide range of sensitivities for BCVI diagnosis. METHODS: From January 2007 through May 2009, patients with risk factors for BCVI underwent both CTA and DSA. All CTAs were performed using a 32-channel multidetector CT scanner. Using DSA as the reference standard, the diagnostic accuracy of CTA for determination of BCVI was calculated. RESULTS: There were 684 patients who met the inclusion criteria. Ninety patients (13%) had 109 injuries identified; 52 carotid and 57 vertebral injuries were diagnosed. CTA failed to detect 53 confirmed BCVI, yielding a sensitivity of 51%. CONCLUSION: Given the devastation of stroke, and high mortality from missed injuries, this study demonstrates that even with more advanced technology (32 vs 16 channel), CTA is inadequate for BCVI screening. Digital subtraction angiography remains the gold standard for the diagnosis of BCVI. PMID- 21263310 TI - Hepatocellular carcinoma: current management and perspectives for the future. AB - OBJECTIVE: To review the literature on current management of hepatocellular carcinoma (HCC). BACKGROUND: Hepatocellular carcinoma represents one of the most common malignancies worldwide with a rising incidence in western countries. There have been substantial advances in the surgical and medical treatment of HCC within the past 2 decades. METHODS: A literature review was performed in the MEDLINE database to identify studies on the management of HCC. On the basis of the available evidence recommendations for practice were graded using the Oxford Centre for Evidence-based Medicine classification. RESULTS: Advances in surgical technique and perioperative care have established surgical resection and orthotopic liver transplantation (OLT) as primary curative therapy for HCC in noncirrhotic and cirrhotic patients, respectively. Primary resection and salvage OLT may be indicated in cirrhotics with preserved liver function. Selection criteria for OLT remain debated, as slight expansion of the Milan criteria may not worsen prognosis but is limited by organ shortage and prolonged waiting time with less favorable outcome on intention-to-treat analyses. Strategies of neoadjuvant treatment before OLT require evaluation within prospective trials. Transarterial chemoembolization is the primary therapy in patients with inoperable HCC and compensated liver function. Although systemic chemotherapy is not effective in patients with advanced HCC, there is recent evidence that these patients benefit from new molecular targeted therapies. If these agents are also effective in the neoadjuvant and adjuvant setting is currently being investigated. Furthermore, selective intra-arterial radiation therapy represents a promising new approach for treatment of unresectable HCC. CONCLUSIONS: Recent developments in the surgical and medical therapy have significantly improved outcome of patients with operable and advanced HCC. A multidisciplinary approach seems essential to further improve patients' prognosis. PMID- 21263311 TI - Betulinic acid delivered in liposomes reduces growth of human lung and colon cancers in mice without causing systemic toxicity. AB - Betulinic acid (BetA) is a plant-derived pentacyclic triterpenoid with potent anticancer capacity that targets the mitochondrial pathway of apoptosis. BetA has a broad efficacy in vitro against prevalent cancer types, including lung, colorectal, prostate, cervix and breast cancer, melanomas, neuroblastomas, and leukemias. The cytotoxic effects of the compound against healthy cells are minimal, rendering BetA a promising potential anticancer drug. However, because of the weak hydrosolubility of BetA, it has been difficult to study its efficacy in vivo and a pharmaceutical formulation is not yet available. We report the development of a liposome formulation of BetA and show its successful application in mice. Large liposomes, assembled without cholesterol to reduce their rigidity, efficiently incorporated BetA. Nude mice xenografted with human colon and lung cancer tumors were treated intravenously with the BetA-containing liposomes. Tumor growth was reduced to more than 50% compared with the control treatment, leading to an enhanced survival of the mice. Oral administration of the liposomal formulation of BetA also slowed tumor growth. Any signs of systemic toxicity caused by BetA treatment were absent. Thus, liposomes are an efficient formulation vehicle for BetA, enabling its preclinical development as a nontoxic compound for the treatment of cancers. PMID- 21263312 TI - Targeted therapies in malignant pleural mesothelioma: a review of clinical studies. AB - Malignant pleural mesothelioma (MPM) is an aggressive tumor with poor prognosis, whose exposure to asbestos fibers is the main etiology. The incidence of MPM is anticipated to increase worldwide during the first half of this century. MPM is notoriously refractory to most treatments, and the only standard of care is cisplatin and antifolate first-line chemotherapy. The urgent need for additional therapeutic agents, in parallel with advances in the knowledge of the molecular events of oncogenesis, has resulted in the development of the so-called 'targeted agents' that specifically inhibit critical pathways in malignant cells and in their microenvironment. We carried out a comprehensive review of the literature from January 2000 to May 2010 on studies that assessed targeted agents for the systemic treatment of MPM. Although tyrosine kinase inhibitors directed against the epidermal growth factor and the platelet-derived growth factor receptors did not show significant clinical activity in phase II studies, some other targeted therapies seemed promising, notably histone deacetylase inhibitors and antiangiogenic agents. However, none of these has yet reached daily practice. That is the reason why efforts must continue in the area of clinical and translational research for MPM. PMID- 21263313 TI - Effects of chlordiazepoxide on runway behaviours of C57Bl/6 mice under continuous or partial reinforcement. AB - An earlier history of partial or continuous reinforcement produces differential behavioural effects during extinction in the runway, with an earlier partial reinforcement (PRF) leading to an increased resistance to extinction. This effect has been attributed to conditioned frustration or generalization-decrement processes. The actions of antianxiety drugs in this procedure are most easily interpreted as for reducing the emotional or aversive effects of nonreinforcement. In this study, C57Bl/6 mice were trained to asymptotic performance with food reinforcement on 50 or 100% of six trials in daily sessions. The anxiolytic benzodiazepine, chlordiazepoxide (15 mg/kg, intraperitoneally) or saline was administered before subsequent daily extinction sessions. Under saline, earlier PRF produced an increased resistance to extinction. Drug administration increased resistance to extinction, as measured by start, run and goal times, after either continuous or PRF. These findings are consistent with earlier findings of rats, but different from those obtained with chlordiazepoxide during extinction after operant training with either rats or mice. These findings can be interpreted in terms of frustration, anxiety or generalization-decrement theories of PRF. PMID- 21263314 TI - Plasma levels of tumor necrosis factor-alpha and interleukin-6 are associated with diastolic heart failure through downregulation of sarcoplasmic reticulum Ca2+ ATPase. AB - OBJECTIVE: The inflammatory process is associated with cardiac diastolic dysfunction, which has been demonstrated to be an independent prognostic marker for the mortality of critically ill patients. We investigated the association among inflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), diastolic heart failure, and the possible molecular mechanism. DESIGN: Prospective case-controlled cohort and molecular studies. SETTING: University hospital and research laboratory. SUBJECTS: Patients with a diagnosis of diastolic heart failure by echocardiography and matched control subjects from the general population (study group 1) and also subjects from the intensive care unit (study group 2). Sarcoplasmic reticulum Ca2+-ATPase (SERCA2) gene expression and diastolic calcium decay in HL-1 cardiomyocytes were used as molecular phenotypes of diastolic heart failure. INTERVENTIONS: Soluble plasma levels of tumor necrosis factor-alpha and interleukin-6 were measured in all subjects. An approximate 1.75-kb promoter of the SERCA2 gene was cloned to the pGL3 luciferase reporter. The effect of tumor necrosis factor-alpha and interleukin-6 on SERCA2 gene expression and diastolic calcium decay of HL-1 cardiomyocytes were investigated. MEASUREMENTS AND MAIN RESULTS: Patients with diastolic heart failure had significantly higher plasma levels of tumor necrosis factor-alpha and interleukin-6 than the control subjects. Significant correlations (p < .01 for each) were found for tumor necrosis factor-alpha and E/Em (r = .87) and E/A (r = 0.69), and for interleukin-6 and E/Em (r = .80) and E/A (r = -0.65). Cytokine levels were also correlated with diastolic function in critically ill patients (study group 2), and diastolic function improved significantly in association with decrease of cytokines. Tumor necrosis factor-alpha, interleukin-6, and sera from critically ill patients downregulated the expression of the SERCA2 gene. Tumor necrosis factor-alpha and interleukin-6 also delayed the diastolic calcium reuptake and decay in cardiomyocytes. CONCLUSIONS: Through downregulation of SERCA2 gene expression, inflammatory cytokines may cause cardiac diastolic dysfunction by decreasing diastolic calcium reuptake. Our study may suggest novel therapeutic strategies for diastolic heart failure and critically ill patients by modulating inflammatory reactions. PMID- 21263316 TI - Intractable cardiac arrest due to lidocaine toxicity successfully resuscitated with lipid emulsion. AB - OBJECTIVE: Demonstrate a case report involving successful use of lipid emulsion therapy for intractable cardiac arrest due to lidocaine toxicity. DATA SOURCE: Lipid emulsion therapy has been shown to be effective in treating the cardiotoxic effects of such drugs as bupivacaine, verapamil, propranolol, and clomipramine as mentioned in a 2009 editorial in Critical Care Medicine by Jeffrey Bent. The mechanism of action of lipid emulsion therapy is not well defined and has been postulated to work by both a "lipid sink," decreasing circulating amounts of drugs to the periphery, or through a direct "energy source" to the myocardium. We present a case report of a patient successfully resuscitated with lipid emulsion therapy after prolonged and intractable lidocaine toxicity. Lidocaine is generally considered much less cardiotoxic than other local anesthetics and is used commonly as infusions for intractable ventricular arrhythmias. CONCLUSION: This case demonstrates the need to consider lipid emulsion therapy in the advanced cardiac life support algorithm for lidocaine toxicity as well as other lipid soluble drug intoxications. PMID- 21263315 TI - Aspiration-induced lung injury. AB - OBJECTIVE: Aspiration of oropharyngeal or gastric contents into the lower respiratory tract is a common event in critically ill patients and can lead to pneumonia or pneumonitis. Aspiration pneumonia is the leading cause of pneumonia in the intensive care unit and is one of the leading risk factors for acute lung injury and acute respiratory distress syndromes. Despite its frequency, it remains largely a disease of exclusion characterized by ill-defined infiltrates on the chest radiograph and hypoxia. An accurate ability to diagnose aspiration is paramount because different modalities of therapy, if applied early and selectively, could change the course of the disease. This article reviews definitions, diagnosis, epidemiology, pathophysiology, including animal models of aspiration-induced lung injury, and evidence-based clinical management. Additionally, a review of current and potential biomarkers that have been tested clinically in humans is provided. DATA SOURCES: Data were obtained from a PubMed search of the medical literature. PubMed "related articles" search strategies were used. SUMMARY AND CONCLUSIONS: Aspiration in the intensive care unit is a clinically relevant problem requiring expertise and awareness. A definitive diagnosis of aspiration pneumonitis or pneumonia is challenging to make. Advances in specific biomarker profiles and prediction models may enhance the diagnosis and prognosis of clinical aspiration syndromes. Evidence-based management is supportive, including mechanical ventilation, bronchoscopy for particulate aspiration, consideration of empiric antibiotics for pneumonia treatment, and lower respiratory tract sampling to define pathogenic bacteria that are causative. PMID- 21263318 TI - Changes in health-related quality of life and factors predicting long-term outcomes in older adults admitted to intensive care units. AB - OBJECTIVES: The aims of this study were to determine predictors of survival after hospital discharge and to describe the impact of intensive care unit admission on health-related quality of life at 6 months after hospital discharge in older adults admitted to intensive care units. DESIGN: Prospective longitudinal observational study with administered questionnaire. SETTINGS AND PATIENTS: Patients 65 yrs of age and older who were admitted to the medical, surgical, and coronary intensive care units for >24 hrs in a large urban teaching hospital system from August 2007 to May 2008 with a follow-up period ending April 2009. INTERVENTIONS: Administered questionnaire to patients or proxies. MEASUREMENTS AND MAIN RESULTS: Four hundred eighty-four patients 65 yrs old and older were enrolled. Data were collected on demographics, comorbidities, intensive care unit admission diagnoses, Acute Physiology and Chronic Health Evaluation II and Sequential Organ Failure Assessment score, Glasgow Coma Scale score at intensive care unit admission, intensive care unit interventions, and disposition after hospital discharge. A health-related quality of life survey was administered to patients, their proxies, or caregivers at intensive care unit admission, and to hospital survivors at 6 months after hospital discharge. Three hundred sixty seven (75.8%) and 318 (65.7%) of enrolled patients were alive at hospital discharge and at 6 months, respectively. Mean age of survivors was 77.8 +/- 8.5. Independent predictors of death at 6 months were: number of days during the 30 days before hospitalization that the patient felt their "physical health was not good" on the health-related quality of life survey [odds ratio = 1.08; confidence interval 1.04-1.12], a higher Acute Physiology and Chronic Health Evaluation II score [odds ratio = 1.09; 95% confidence interval 1.06-1.12], and chronic pulmonary disease as a comorbidity [odds ratio = 2.22; 95% confidence interval 1.04-4.78]. Of the 318 survivors at 6 months after hospital discharge, 297 (93.4%) completed the health-related quality of life questionnaire. When assessing whether changes in health-related quality of life over time were affected by age in our study cohort of 65 yrs old and older, we found that the oldest survivors, age 86.3 yrs old and older, had worse health-related quality of life over time, including more days spent with poor physical health (p < .004) and mental health (p < .001), while the youngest survivors, age 65-69.3 yrs old, showed improvement in health-related quality of life with fewer days spent with poor physical health (p < .004) and mental health (p < .001) at follow-up compared to baseline. These differences remained after adjusting for severity of illness and other potential confounders. CONCLUSIONS: One-third of adults 65 yrs old and older admitted to the intensive care unit die within 6 months of hospital discharge. Among survivors at 6 months, health-related quality of life has significantly worsened over time in the oldest patients but improved in the youngest. Our study in a large cohort of mixed intensive care unit patients identifies additional prognostic factors and significant quality of life information in intensive care unit survivors well after hospital discharge. This additional information may guide clinicians in their discussions with patients, families, and other providers as they decide on what treatments and interventions to pursue. PMID- 21263319 TI - Relationship between inhaled beta2-agonists and ventilator-associated pneumonia: a cohort study. AB - OBJECTIVE: To determine the impact of aerosolized bronchodilators on ventilator associated pneumonia. DESIGN: Prospective cohort study. SETTING: A 30-bed medical and surgical intensive care unit. METHODS: All intubated patients requiring mechanical ventilation for >48 hrs were eligible during a 13-month period. Nebulized beta2-agonists were administered at the intensive care unit physician's discretion. Ventilator-associated pneumonia definition included clinical and quantitative microbiological criteria. Only first ventilator-associated pneumonia episodes were analyzed. Risk factors for ventilator-associated pneumonia were determined using univariate and multivariate analyses. The influence of inhaled beta2-agonists on ventilator-associated pneumonia occurrence was also adjusted for confounding factors using Cox's proportional-hazards model. RESULTS: Ventilator-associated pneumonia was diagnosed in 137 (31%) of the 439 enrolled patients. Ventilator-associated pneumonia was early-onset in 14 (10%) patients. The incidence rate of ventilator-associated pneumonia was 20 per 1,000 ventilator days. Ventilator-associated pneumonia was polymicrobial in 16 (11%) patients, and related to multidrug-resistant bacteria in 42 (28%) patients. Most cases of ventilator-associated pneumonia were caused by Gram-negative bacteria. Inhaled beta2-agonists were significantly more frequently used in patients with ventilator-associated pneumonia compared with those without ventilator-associated pneumonia (49% vs. 34%, odds ratio [95% confidence interval] = 1.9 [1.2-2.8], p = .003). Multivariate analysis identified aerosolized beta2-agonists (odds ratio [95% confidence interval] = 1.7 [1.1-2.6], p = .012), Simplified Acute Physiology Score II at intensive care unit admission (odds ratio [95% confidence interval] = 1.01 [1.001-1.02] per point, p = .031), and red blood cell transfusion (odds ratio [95% confidence interval] = 2 [1.3-3.1], p = .001) as independent risk factors for ventilator-associated pneumonia. Cox's proportional-hazards model also identified inhaled beta2-agonists as a risk factor for ventilator-associated pneumonia (odds ratio [95% confidence interval] = 1.52 [1.06-2.19], p = .021). CONCLUSION: Use of aerosolized bronchodilators in intensive care unit mechanically ventilated patients is an independent risk factor for ventilator associated pneumonia. PMID- 21263317 TI - Severe 2009 A/H1N1v influenza in pregnant women in Spain. AB - OBJECTIVES: To describe the severity of the 2009 influenza A/H1N1v illness among pregnant women admitted to Spanish intensive care units. DESIGN AND PATIENTS: Prospective, observational, multicenter study conducted in 148 Spanish intensive care units. We reviewed demographic and clinical data from the Spanish Society of Intensive Care Medicine database reported from April 23, 2009, to February 15, 2010. We included women of reproductive age (15-44 yrs) with confirmed A/H1N1v infection admitted to intensive care units. MAIN RESULTS: Two hundred thirty-four women of reproductive age were admitted to intensive care units, 50 (21.4%) of them pregnant. Seven deaths were recorded in pregnant and 22 in nonpregnant women. Among intensive care unit admissions, there were no statistically significant differences between pregnant women and nonpregnant in Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment scores, chest x-rays, inotrope requirement, or need for mechanical ventilation or steroid therapy. Mortality risk was significantly associated with Acute Physiology and Chronic Health Evaluation II, Sequential Organ Failure Assessment, and obesity. Viral pneumonia was more frequent in pregnant women than in nonpregnant women, with an odds ratio (adjusted for asthma, time from onset influenza symptoms to hospital admission and obesity) of 4.9 (95% confidence interval: 1.4-17.2). The development of primary viral pneumonia in women of reproductive age appeared to be related to the time of commencement of antiviral treatment, the lowest rates being reported with initiation of antiviral therapy within 48 hrs of symptom onset (63.6% vs. 82.6%, p = .03). However, antiviral therapy was started within this time span in only 14% of pregnant women. CONCLUSIONS: More than 20% of women of reproductive age admitted to intensive care unit for pH1N1 infection were pregnant. Pregnancy was significantly associated with primary viral pneumonia. Pregnant women should receive prompt treatment with oseltamivir within 48 hrs of the onset of influenza symptoms. PMID- 21263320 TI - Preclinical evaluation of epinephrine nebulization to reduce airway hyperemia and improve oxygenation after smoke inhalation injury. AB - OBJECTIVE: Acute lung injury secondary to smoke inhalation is a major source of morbidity and mortality in burn patients. We tested the hypothesis that nebulized epinephrine would ameliorate pulmonary dysfunction secondary to acute lung injury by reducing airway hyperemia and edema formation and mediating bronchodilatation in an established, large animal model of inhalation injury. DESIGN: Prospective, controlled, randomized trial. SETTING: University research laboratory. SUBJECTS: Twenty-four chronically instrumented, adult, female sheep. INTERVENTIONS: Following baseline measurements, the animals were allocated to a sham-injured group (n = 5), an injured and saline-treated group (n = 6), or an injured group treated with 4 mg of nebulized epinephrine every 4 hrs (n = 6). Inhalation injury was induced by 48 breaths of cotton smoke. The dose of epinephrine was derived from dose finding experiments (n = 7 sheep). MEASUREMENTS AND MAIN RESULTS: The injury induced significant increases in airway blood flows, bronchial wet/dry weight ratio, airway obstruction scores, ventilatory pressures, and lung malondialdehyde content, and contributed to severe pulmonary dysfunction as evidenced by a significant decline in Pao2/Fio2 ratio and increase in pulmonary shunt fraction. Nebulization of epinephrine significantly reduced tracheal and main bronchial blood flows, ventilatory pressures, and lung malondialdehyde content. The treatment was further associated with significant improvements of Pao2/FIO2 ratio and pulmonary shunting. CONCLUSIONS: Nebulization of epinephrine reduces airway blood flow and attenuates pulmonary dysfunction in sheep subjected to severe smoke inhalation injury. Future studies will have to improve the understanding of the underlying pathomechanisms and identify the optimal dosing for the treatment of patients with this injury. PMID- 21263321 TI - Melanocortin 4 receptor stimulation decreases pancreatitis severity in rats by activation of the cholinergic anti-inflammatory pathway. AB - OBJECTIVE: Acute pancreatitis is an inflammatory condition that may lead to multisystemic organ failure. Melanocortin peptides have been successfully used in experimental models of organ failure and shock, and their protective effect occurs through the activation of a vagus nerve-mediated cholinergic anti inflammatory pathway by acting at brain melanocortin 4 receptors. In the light of these observations, we studied the effects of the selective melanocortin 4 receptor agonist RO27-3225 in an experimental model of cerulein-induced pancreatitis. DESIGN: Randomized experiment. SETTING: Research laboratory at a university hospital. SUBJECT: Experimental pancreatitis in rats. INTERVENTIONS: Acute pancreatitis was induced in male Sprague-Dawley rats by intraperitoneal injections of cerulein (80 MUg/kg, four injections at hourly intervals). Before pancreatitis induction, groups of animals were subjected to bilateral cervical vagotomy, pretreated with the nicotinic acetylcholine receptor antagonist chlorisondamine or the selective melanocortin 4 receptor antagonist HS024, or not pretreated. Thirty minutes after the first cerulein injection, rats were intraperitoneally treated with a nanomolar dose of RO27-3225 or vehicle. Some experimental groups were prepared for neural efferent activity recording along the vagus nerve starting 30 mins after treatment with RO27-3225 or vehicle, and for a 30-min period. MEASUREMENTS AND MAIN RESULTS: Serum lipase and amylase activity, tumor necrosis factor-alpha and interleukin-6 expression, pancreatic myeloperoxidase activity, and histologic damage were evaluated; neural efferent activity of vagal fibers was also assessed. RO27-3225 reduced cerulein-induced serum lipase and amylase activity, blunted the expression of tumor necrosis factor-alpha and interleukin-6, abated the increase in pancreatic myeloperoxidase activity, and protected against histologic damage. Furthermore, RO27-3225 markedly increased neural efferent activity along the vagus nerve. Vagotomy, chlorisondamine, and HS024 abated these protective effects of RO27-3225. CONCLUSIONS: Our data show that melanocortin 4 receptor agonists reduce pancreatitis severity through the activation of the cholinergic anti-inflammatory pathway. These findings could be of particular interest in the clinical setting. PMID- 21263322 TI - Pressure support improves oxygenation and lung protection compared to pressure controlled ventilation and is further improved by random variation of pressure support. AB - OBJECTIVES: To explore whether 1) conventional pressure support ventilation improves lung function and attenuates the pulmonary inflammatory response compared to pressure-controlled ventilation and 2) random variation of pressure support levels (noisy pressure support ventilation) adds further beneficial effects to pressure support ventilation. DESIGN: Three-arm, randomized, experimental study. SETTING: University hospital research facility. SUBJECTS: Twenty-four juvenile pigs. INTERVENTIONS: Acute lung injury was induced by surfactant depletion. Animals were randomly assigned to 6 hrs of mechanical ventilation (n = 8 per group) with either 1) pressure-controlled ventilation, 2) pressure support ventilation, or 3) noisy pressure support ventilation. During noisy pressure support ventilation, the pressure support varied randomly, with values following a normal distribution. In all groups, the driving pressures were set to achieve a mean tidal volume of 6 mL/kg. At the end of experiments, animals were killed and lungs extracted for histologic and biochemical analysis. MEASUREMENTS AND MAIN RESULTS: Respiratory, gas-exchange, and hemodynamics variables were assessed hourly. The diffuse alveolar damage and the inflammatory response of lungs were quantified. Pressure support ventilation and noisy pressure support ventilation improved gas exchange and were associated with reduced histologic damage and interleukin-6 concentrations in lung tissue compared to pressure-controlled ventilation. Noisy pressure support ventilation further improved gas exchange and decreased the inspiratory effort while reducing alveolar edema and inflammatory infiltration compared to pressure support ventilation. CONCLUSIONS: In this model of acute lung injury, pressure support ventilation and noisy pressure support ventilation attenuated pulmonary inflammatory response and improved gas exchange as compared to pressure controlled ventilation. Noisy pressure support ventilation further improved gas exchange, reduced the inspiratory effort, and attenuated alveolar edema and inflammatory infiltration as compared to conventional pressure support ventilation. PMID- 21263323 TI - Unexpected pro-injury effect of propofol on vascular smooth muscle cells with increased oxidative stress. AB - OBJECTIVES: Propofol is a widely used intravenous anesthetic agent with antioxidant properties. However, the effect of propofol on reactive oxygen species-induced injury in vascular smooth muscle cells is still unknown. In this study, the authors determined the effect of propofol on hydrogen peroxide-induced injury in vascular smooth muscle cells and the potential molecular mechanisms involved. DESIGN: Prospective cell and animal study. SETTING: University research laboratory. SUBJECTS: Sprague-Dawley rats. INTERVENTIONS: For the in vitro study, rat vascular smooth muscle cells pretreated with vehicle or hydrogen peroxide (200 MUM) were exposed to vehicle or increasing concentrations of propofol (10-50 MUM). For the in vivo study, propofol (12 mg kg-1/hr-1, intravenous) or vehicle was administrated into rats after carotid artery angioplasty. MEASUREMENTS AND MAIN RESULTS: The cell survival and cell death were measured by MTT and trypan blue exclusion. Cell apoptosis was evaluated by terminal deoxynucleotide transferase dUTP nick end labeling staining and cleaved caspase-3 expression. To further elucidate the molecular mechanisms in propofol-mediated cellular effect, the expression of programmed cell death 4 and microRNA-21 were measured. Unexpectedly, propofol exacerbated hydrogen peroxide-induced injury responses in vascular smooth muscle cells as demonstrated by a decrease in cell viability and an increase in trypan blue-stained cells, cell apoptosis, and cleaved caspase-3 expression. In addition, propofol inhibited hydrogen peroxide-induced up regulation of microRNA-21 and increased its target gene programmed cell death 4. Propofol-mediated injury was attenuated by restoration of microRNA-21 expression. Finally, the pro-injury effect of propofol on vascular cells with increased reactive oxygen species was illustrated in vivo in rat carotid arteries after angioplasty. CONCLUSIONS: The results revealed that propofol exacerbates cell injury in vascular smooth muscle cells with increased reactive oxygen species, at least in part, through microRNA-21 and its target gene, programmed cell death 4. Because increased reactive oxygen species is a common pathologic component in many vascular diseases, the novel findings in the current study suggest that propofol might have some application limitations. PMID- 21263324 TI - Successful implementation of a pediatric sedation protocol for mechanically ventilated patients. AB - OBJECTIVE: To evaluate the effect of a nursing-driven sedation protocol for mechanically ventilated pediatric patients on duration of use of analgesic and sedative medications. We hypothesized that a protocol would decrease length of sedation use and decrease days of mechanical ventilation and length of stay. DESIGN: Retrospective cohort study with historical controls. SETTING: Thirty-one bed tertiary care, medical-surgical-cardiac pediatric intensive care unit in a metropolitan university-affiliated children's hospital. PATIENTS: Children requiring mechanical ventilation longer than 48 hrs not meeting exclusion criteria. INTERVENTIONS: Before protocol implementation, sedation was managed per individual physician orders. During the intervention period, analgesia and sedation were managed by nurses following an algorithm-based sedation protocol based on a comfort score. MEASUREMENTS AND MAIN RESULTS: The observation group included consecutive patients admitted during the 12-month period before protocol education and implementation (n = 153). The intervention group included patients admitted during the 12 months following protocol implementation (n = 166). The median duration of total sedation days (intravenous plus enteral) was 7 days for the observation period and 5 days for the intervention period (p = .026). Specifically, the median duration of morphine infusion was 6 days for the observation period and 5 days for the intervention period (p = .015), whereas the median duration of lorazepam infusion was 2 days for the observation period and 0 days for the intervention period. After adjusting for severity of illness with the pediatric risk of mortality III (PRISM III) score, the Cox proportional hazards regression analysis demonstrated that at any point in time, patients in the intervention group were 23% more likely to be off all sedation (heart rate 0.77, p = .020). Additionally, the intervention group tended to be associated with fewer days of mechanical ventilation (heart rate 0.81, p = .060) and decreased pediatric intensive care unit length of stay (heart rate 0.81, p = .058), although these associations did not quite reach statistical significance. CONCLUSION: A pediatric sedation protocol can significantly decrease days of benzodiazepine and opiate administration, which may improve pediatric intensive care unit resource utilization. PMID- 21263325 TI - Current role of emergency ultrasound of the chest. AB - OBJECTIVE: Chest sonography has gained clinical significance in the diagnosis of various pulmonary, pleural, cardiac, and mediastinal emergency conditions. Therefore, the current role of emergency ultrasound are assessed. DATA SOURCE: A systematic literature search of MEDLINE database was performed to identify all studies dealing with transthoracic sonography/chest ultrasound in combination with pulmonary embolism, pneumothorax, pneumonia, pleural effusion, pulmonary edema, and lung contusion. The relevant sonographic studies between 1988 and 2010 were evaluated. CONCLUSIONS: The noninvasive ultrasound-based diagnosis is relatively portable permitting the technique to be performed at any time, in any place, and on any patient, an ideal method for emergency conditions. Sonography allows immediate diagnosis of pulmonary embolism, pneumothorax, pneumonia, pleural effusion as well as rib fracture, and it provides a basis for further diagnostic- and treatment-related decisions. The key sonographic features associated with these most common emergency chest diseases are illustrated herein. PMID- 21263326 TI - Impact of pressure profile and duration of recruitment maneuvers on morphofunctional and biochemical variables in experimental lung injury. AB - OBJECTIVE: To investigate the effects of the rate of airway pressure increase and duration of recruitment maneuvers on lung function and activation of inflammation, fibrogenesis, and apoptosis in experimental acute lung injury. DESIGN: Prospective, randomized, controlled experimental study. SETTING: University research laboratory. SUBJECTS: Thirty-five Wistar rats submitted to acute lung injury induced by cecal ligation and puncture. INTERVENTIONS: After 48 hrs, animals were randomly distributed into five groups (seven animals each): 1) nonrecruited (NR); 2) recruitment maneuvers (RMs) with continuous positive airway pressure (CPAP) for 15 secs (CPAP15); 3) RMs with CPAP for 30 secs (CPAP30); 4) RMs with stepwise increase in airway pressure (STEP) to targeted maximum within 15 secs (STEP15); and 5) RMs with STEP within 30 secs (STEP30). To perform STEP RMs, the ventilator was switched to a CPAP mode and positive end-expiratory pressure level was increased stepwise. At each step, airway pressure was held constant. RMs were targeted to 30 cm H2O. Animals were then ventilated for 1 hr with tidal volume of 6 mL/kg and positive end-expiratory pressure of 5 cm H2O. MEASUREMENTS AND MAIN RESULTS: Blood gases, lung mechanics, histology (light and electronic microscopy), interleukin-6, caspase 3, and type 3 procollagen mRNA expressions in lung tissue. All RMs improved oxygenation and lung static elastance and reduced alveolar collapse compared to NR. STEP30 resulted in optimal performance, with: 1) improved lung static elastance vs. NR, CPAP15, and STEP15; 2) reduced alveolar-capillary membrane detachment and type 2 epithelial and endothelial cell injury scores vs. CPAP15 (p < .05); and 3) reduced gene expression of interleukin-6, type 3 procollagen, and caspase 3 in lung tissue vs. other RMs. CONCLUSIONS: Longer-duration RMs with slower airway pressure increase efficiently improved lung function, while minimizing the biological impact on lungs. PMID- 21263327 TI - Sequential Organ Failure Assessment in H1N1 pandemic planning. AB - OBJECTIVE: The H1N1 pandemic has highlighted the importance of reliable and valid triage instruments. A Sequential Organ Failure Assessment score of >11 has been proposed to exclude patients from critical care resources quoting an associated mortality of >90%. We sought to assess the mortality associated with this Sequential Organ Failure Assessment threshold and the resource implications of such a triage protocol. DESIGN: Retrospective cohort. SETTING: Three multisystem intensive care units. PATIENTS: Consecutive patients admitted from January 2003 to December 2008. Subsequently, a comparison H1N1 cohort was assembled consisting of all patients admitted in 2009 with confirmed H1N1. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Sequential Organ Failure Assessment was collected daily by use of an electronic bedside clinical information system (n = 10,204 patients, 69,913 patient days). Mean admission Acute Physiology and Chronic Health Evaluation was 19.1. 13.4% of the cohort (9% of total patient days) had an initial Sequential Organ Failure Assessment of >11. Mortality in patients with an initial Sequential Organ Failure Assessment score of >11 was 59% (95% confidence interval: 56%, 62%). The mortality associated with an initial Sequential Organ Failure Assessment >11 across diagnostic categories varied from 29% for poisoning to 67% for neurologic patients. Hospital mortality exceeded 90% only when initial Sequential Organ Failure Assessment was >20 (0.2% of patients). H1N1 patients were younger, had a longer intensive care unit length of stay, and more commonly had a respiratory admission diagnosis than the nonH1N1 cohort. Hospital mortality in H1N1 patients with an initial Sequential Organ Failure Assessment score of >11 was 31% (95% confidence interval: 5%, 56%). CONCLUSIONS: A Sequential Organ Failure Assessment score of >11 was not associated with a hospital mortality of >90% at any time during intensive care unit stay. Only a small proportion of patients have the extreme initial Sequential Organ Failure Assessment values associated with a hospital mortality of >90% limiting the usefulness of Sequential Organ Failure Assessment as a triage instrument for pandemic planning. Application of a Sequential Organ Failure Assessment threshold of >11 to the recent H1N1 pandemic would have excluded patients with a markedly lower mortality than seen in a large regional cohort of intensive care unit patients. PMID- 21263328 TI - Norepinephrine increases cardiac preload and reduces preload dependency assessed by passive leg raising in septic shock patients. AB - OBJECTIVE: To assess the effects of norepinephrine on cardiac preload, cardiac index, and preload dependency during septic shock. DESIGN: Prospective interventional study. SETTING: Medical Intensive Care Unit. PATIENTS: We included 25 septic shock patients (62 +/- 13 yrs old, Simplified Acute Physiology Score II 53 +/- 12, lactate 3.5 +/- 2.1 mmol/L, all receiving norepinephrine at baseline at 0.24 [25%-75% interquartile range: 0.12-0.48] MUg/kg/min) with a positive passive leg raising test (defined by an increase in cardiac index >= 10%) and a diastolic arterial pressure <= 40 mm Hg. INTERVENTIONS: We performed a passive leg raising test (during 1 min) at baseline. Immediately after, we increased the dose of norepinephrine (to 0.48 [0.36-0.71] MUg/kg/min) and, when the hemodynamic status was stabilized, we performed a second passive leg raising test (during 1 min). We finally infused 500 mL saline. MEASUREMENTS AND MAIN RESULTS: Increasing the dose of norepinephrine significantly increased central venous pressure (+23% +/- 12%), left ventricular end-diastolic area (+9% +/- 6%), E mitral wave (+19% +/- 23%), and global end-diastolic volume (+9% +/- 6%). Simultaneously, cardiac index significantly increased by 11% +/- 7%, suggesting that norepinephrine had recruited some cardiac preload reserve. The second passive leg raising test increased cardiac index to a lesser extent than the baseline test (13% +/- 8% vs. + 19% +/- 6%, p < .05), suggesting that norepinephrine had decreased the degree of preload dependency. Volume infusion significantly increased cardiac index by 26% +/- 15%. However, cardiac index increased by <15% in four patients (fluid unresponsive patients) while the baseline passive leg raising test was positive in these patients. In three of these four patients, the second passive leg raising test was also negative, i.e., the second passive leg raising test (after norepinephrine increase) predicted fluid responsiveness with a sensitivity of 95 [76-99]% and a specificity of 100 [30-100]%. CONCLUSIONS: In septic patients with a positive passive leg raising test at baseline suggesting the presence of preload dependency, norepinephrine increased cardiac preload and cardiac index and reduced the degree of preload dependency. PMID- 21263329 TI - Quantification of liver fat in the presence of iron and iodine: an ex-vivo dual energy CT study. AB - PURPOSE: Iodinated contrast media (CM) and iron in the liver are known to hinder an accurate quantification of liver fat content (LFC) with single-energy computed tomography (SECT). The purpose of this study was to evaluate the feasibility and accuracy of dual-energy CT (DECT) for ex vivo quantification of LFC, in the presence of iron and CM, compared with SECT. MATERIALS AND METHODS: Sixteen phantoms with a defined LFC of 0%, 10%, 30%, and 50% fat and with varying iron content (0, 1.5, 3, and 6 mg/mL wet weight liver) were scanned with a second generation dual-source 128-slice CT system. Phantoms were scanned unenhanced and contrast-enhanced after adding 1.0 mg/mL iodine to each phantom. Both SECT (120 kV) and DECT (tube A: 140 kV, using a tin filter 228 mAs; tube B: 80 kV, 421 mAs) data were acquired. An iron-specific dual-energy 3-material decomposition algorithm providing virtual noniron images (VNI) was used to subtract iron and CM from the data. CT numbers (Hounsfield units) were measured in all data sets, including 120 kV from SECT, as well as 140 kV, 80 kV, 50%:50% weighted 80 kV/140 kV, and VNI derived from DECT. The dual-energy index was calculated from 80 kV and 140 kV data. SECT and DECT measurements (Hounsfield units) including the dual energy index of unenhanced and contrast-enhanced phantoms were compared with the known titrated LFC, using Pearson correlation analysis and Student t test for related samples. RESULTS: Inter-reader agreement was excellent for all measurements of CT numbers in both SECT and DECT data (Pearson r, 0.965-1.0). For fat quantification in the absence of iron and CM, CT numbers were similar in SECT and DECT (all, P > 0.05), showing a linear correlation with titrated LFC (r ranging from 0.981 to 0.999; P < 0.01). For fat quantification in the presence of iron but without CM, significant underestimation of LFC was observed for all measurements in SECT and DECT (P < 0.05), except for VNI. Measurements in VNI images allowed for an accurate LFC estimation, with no significant differences compared with measurements in iron-free phantoms (all, P > 0.25). For fat quantification in the presence of iron and CM, further underestimation of LFC was seen for measurements in SECT and DECT (P < 0.015), except for VNI. Measurements in VNI images showed a high accuracy for estimating the LFC, with no significant difference compared with measurements in iron- and CM-free phantoms (P > 0.2). CONCLUSIONS: Our ex vivo phantom study indicates that DECT with the use of a dedicated, iron-specific 3-material decomposition algorithm allows for the accurate quantification of LFC, even in the presence of iron and iodinated CM. VNI images reconstructed from DECT data equal nonenhanced SECT data of liver without CM by eliminating iron and iodine from the images. No added value was seen for DECT as compared with SECT for quantification of LFC in the absence of iron and iodine. PMID- 21263330 TI - Whole-body diffusion-weighted imaging with apparent diffusion coefficient mapping for treatment response assessment in patients with diffuse large B-cell lymphoma: pilot study. AB - OBJECTIVES: The aim of this pilot study was to assess post-treatment apparent diffusion coefficient (ADC) changes of diffuse large B-cell lymphoma lesions on respiratory-gated whole-body diffusion-weighted imaging (DWI), with integrated (18)F-fluoro-2-deoxyglucose positron emission tomography/computed tomography (PET/CT) as the reference standard. MATERIALS AND METHODS: A total of 15 patients underwent both whole-body DWI (b = 50, 400, 800 s/mm(2)) and PET/CT before initiation and after 4 cycles of chemotherapy. ADC of residual masses (lymph node and organ lesions) was assessed both visually and quantitatively, including measurement of mean ADC (ADC).(Figure is included in full-text article.) RESULTS: After chemotherapy, among 85 examined lymph node regions, residual nodes were present in 62 (73%) regions on DWI. Of these 62 regions, 26 had persistent lymph nodes with longest transverse diameter >10 mm, ie, positive based on DWI size criteria. The mean ADC of these 26 regions increased from 0.658 * 10(-3) +/- 0.153 mm(2)/s (standard deviation) at baseline to 1.501 * 10(-3) +/- 0.307 mm(2)/s (paired t test, P < 0.0001). Only 6 of these 26 regions were considered positive on PET/CT. Combining visual ADC analysis to size criteria reduced the number of false-positive results of DWI from 20 to 2 regions. For organ involvement, ADC values also increased compared with baseline (1.558 * 10(-3) +/- 0.424 mm(2)/s vs. 0.675 * 10(-3) +/- 0.135 mm(2)/s, respectively; P = 0.0009). CONCLUSIONS: Whole-body DWI with ADC mapping can show a significant increase in ADC values of residual masses persisting after treatment and may help to assess the treatment response in patients with diffuse large B-cell lymphoma. PMID- 21263331 TI - A transmit/receive radiofrequency array for imaging the carotid arteries at 7 Tesla: coil design and first in vivo results. AB - OBJECTIVE: To develop a transmit/receive radiofrequency (RF) array for magnetic resonance imaging (MRI) of the carotid arteries at 7 T. The prototype is characterized in numerical simulations and bench measurements, and the feasibility of plaque imaging at 7 T is demonstrated in first in vivo images. MATERIALS AND METHODS: The RF phased array coil consists of 8 surface loop coils. To allow imaging of both sides of the neck, the RF array is divided into 2 coil clusters, each with 4 overlapping loop elements. For safety validation, numerical computations of the RF field distribution and the corresponding specific absorption rate were performed on the basis of a heterogeneous human body model. To validate the coil model, maps of the transmit B1(+) field were compared between simulation and measurement. In vivo images of a healthy volunteer and a patient (ulcerating plaque and a 50% stenosis of the right internal carotid artery) were acquired using a 3-dimensional FLASH sequence with a high isotropic spatial resolution of 0.54 mm as well as using pulse-triggered proton density (PD)/T2-weighted turbo spin echo sequences. RESULTS: Measurements of the S parameters yielded a reflection and isolation of the coil elements of better than -18 and -13 dB, respectively. Measurements of the g-factor indicated good image quality for parallel imaging acceleration factors up to 2.4. A similar distribution and a very good match of the absolute values were found between the measured and simulated B1(+) transmit RF field for the validation of the coil model. In vivo images revealed good signal excitation of both sides of the neck and a high vessel-to-background image contrast for the noncontrast-enhanced 3 dimensional FLASH sequence. Imaging at 7 T could depict the extent of stenosis, and revealed the disruption and ulcer of the plaque. CONCLUSIONS: This study demonstrates that 2 four-channel transmit/receive RF arrays for each side of the neck is a suitable concept for in vivo MRI of the carotid arteries at 7 Tesla. Further studies are needed to explore and exploit the full potential of 7 T high field MRI for carotid atherosclerotic plaque imaging. PMID- 21263332 TI - First multimodal embolization particles visible on x-ray/computed tomography and magnetic resonance imaging. AB - OBJECTIVES: Embolization therapy is gaining importance in the treatment of malignant lesions, and even more in benign lesions. Current embolization materials are not visible in imaging modalities. However, it is assumed that directly visible embolization material may provide several advantages over current embolization agents, ranging from particle shunt and reflux prevention to improved therapy control and follow-up assessment. X-ray- as well as magnetic resonance imaging (MRI)-visible embolization materials have been demonstrated in experiments. In this study, we present an embolization material with the property of being visible in more than one imaging modality, namely MRI and x-ray/computed tomography (CT). Characterization and testing of the substance in animal models was performed. MATERIALS AND METHODS: To reduce the chance of adverse reactions and to facilitate clinical approval, materials have been applied that are similar to those that are approved and being used on a routine basis in diagnostic imaging. Therefore, x-ray-visible Iodine was combined with MRI-visible Iron (Fe3O4) in a macroparticle (diameter, 40-200 MUm). Its core, consisting of a copolymerized monomer MAOETIB (2-methacryloyloxyethyl [2,3,5-triiodobenzoate]), was coated with ultra-small paramagnetic iron oxide nanoparticles (150 nm). After in vitro testing, including signal to noise measurements in CT and MRI (n = 5), its ability to embolize tissue was tested in an established tumor embolization model in rabbits (n = 6). Digital subtraction angiography (DSA) (Integris, Philips), CT (Definition, Siemens Healthcare Section, Forchheim, Germany), and MRI (3 Tesla Magnetom Tim Trio MRI, Siemens Healthcare Section, Forchheim, Germany) were performed before, during, and after embolization. Imaging signal changes that could be attributed to embolization particles were assessed by visual inspection and rated on an ordinal scale by 3 radiologists, from 1 to 3. Histologic analysis of organs was performed. RESULTS: Particles provided a sufficient image contrast on DSA, CT (signal to noise [SNR], 13 +/- 2.5), and MRI (SNR, 35 +/- 1) in in vitro scans. Successful embolization of renal tissue was confirmed by catheter angiography, revealing at least partial perfusion stop in all kidneys. Signal changes that were attributed to particles residing within the kidney were found in all cases in all the 3 imaging modalities. Localization distribution of particles corresponded well in all imaging modalities. Dynamic imaging during embolization provided real-time monitoring of the inflow of embolization particles within DSA, CT, and MRI. Histologic visualization of the residing particles as well as associated thrombosis in renal arteries could be performed. Visual assessment of the likelihood of embolization particle presence received full rating scores (153/153) after embolization. CONCLUSIONS: Multimodal visible embolization particles have been developed, characterized, and tested in vivo in an animal model. Their implementation in clinical radiology may provide optimization of embolization procedures with regard to prevention of particle misplacement and direct intraprocedural visualization, at the same time improving follow-up examinations by utilizing the complementary characteristics of CT and MRI. Radiation dose savings can also be considered. All these advantages could contribute to future refinements and improvements in embolization therapy. Additionally, new approaches in embolization research may open up. PMID- 21263333 TI - Comparative in vivo dissociation of gadolinium chelates in renally impaired rats: a relaxometry study. AB - PURPOSE: Investigation of dissociated versus chelated gadolinium (Gd) in plasma, skin, and bone of rats with impaired renal function after administration of ionic macrocyclic (gadoterate or Dotarem) or nonionic linear (gadodiamide or Omniscan) Gd chelates. MATERIALS AND METHODS: Subtotally nephrectomized Wistar rats were subjected to receive daily injections of 2.5 mmol/kg of Omniscan, gadodiamide without excess ligand caldiamide, Dotarem, or saline (n = 7-10 rats/group) for 5 consecutive days. The Gd concentration was measured by inductively coupled plasma mass spectrometer in skin, femur epiphysis, and plasma on completion of the study (day 11), and dissociated Gd(3+) was measured in the plasma at day 11 (liquid chromatography inductively coupled plasma mass spectrometry). The r(1) relaxivity constant was measured in skin (at day 4 and day 11) and bone (day 11) to investigate the dissociated or chelated form of Gd found in tissue samples. Clinical and skin histopathologic studies were performed. RESULTS: Subtotal nephrectomy decreased creatinine clearance by 60%. No macroscopic skin lesions were observed in the Dotarem and Omniscan groups in contrast with the gadodiamide group (2 rats survived the study period and 4 of 10 rats showed skin ulcerations and scabs). Skin histopathologic lesions were in the range gadodiamide > Omniscan > Dotarem (similar to control rats). At day 11, the skin Gd concentration was lower in the Dotarem group (161.0 +/- 85.5 nmol/g) as compared with the Omniscan (490.5 +/- 223.2 nmol/g) and gadodiamide groups (mean value, 776.1 nmol/g; n = 2 survivors). The total Gd concentration in the femur was significantly higher in the Omniscan group than in the Dotarem group. At day 11, the dissociated Gd(3+) concentration in plasma was below the limit of detection in the Dotarem group and was 1.5 +/- 0.7 MUmol/L in the Omniscan group corresponding to 62% +/- 15% of the total Gd concentration. The dissociated Gd(3+) concentration was 1.1 MUmol/L in gadodiamide rats (n = 2 survivors). In the skin, the in vivo r1 relaxivity value increased from 4.8 +/- 0.7 mM(-1)s(-1) at day 4 to 10.5 +/- 3.9 mM(-1)s(-1) at day 11 in the Omniscan group, P < 0.05 (in vitro r(1) in skin, 3.5 mM(-1)s(-1)) and gadodiamide group, whereas no significant change was observed in the Dotarem group (2.8 +/- 0.2 and 4.9 +/- 2.8 mM(-1)s(-1) at day 4 and 11, respectively, NS) (in vitro value in the skin, 3.2 mM(-1)s(-1)). In the femur, the in vivo r1 relaxivity was higher in the Omniscan group (8.9 +/- 2.1 mM(-1)s(-1)) (in vitro relaxivity, 4.5 mM(-1)s(-1)) and gadodiamide group (8.8 mM(-1)s(-1), n = 2 survivors) than in the Dotarem group (3.8 mM(-1)s(-1), n = 1 rat with measurable r(1), since for 7 rats, 1/T(1) - 1/T(1(diamagnetic)) <10% of 1/T(1(diamagnetic)) because of low Gd concentration) (in vitro relaxivity value in the femur matrix, 3.1 mM(-1)s(-1)). CONCLUSIONS: Unlike Dotarem, Omniscan and gadodiamide induced histologic skin lesions. At day 11, a higher Gd concentration was found in both skin and femur of Omniscan- and gadodiamide-treated rats than in Dotarem-treated rats. Relaxometry results indicate gradual in vivo dechelation and release of dissociated Gd(3+) in a soluble form in renally impaired rats receiving Omniscan and gadodiamide, whereas Dotarem remained stable over the study period. PMID- 21263334 TI - Precision and accuracy: comparison of point-of-care and laboratory glucose concentrations in cardiothoracic surgery patients. AB - BACKGROUND: There have been variable results on the practice of tight glycemic control, and studies have demonstrated that point-of-care (POC) glucometers have variable accuracy. OBJECTIVE: The purpose of this study was to determine the difference between blood glucose concentrations obtained from POC glucometers as compared with laboratory results in cardiothoracic surgery (CTS) patients. METHODS: This was a descriptive study on a convenience sample of 46 CTS patients. A single sample of arterial blood was collected and analyzed at the bedside with the POC glucometer and in the laboratory to obtain a serum glucose concentration and hematocrit (Hct). A paired t test was used to compare the mean differences along with Spearman rho correlation to examine the relationship between difference scores and Hct. RESULTS: The POC glucose was significantly higher than the laboratory result (t = 8.5, P < .001) with a mean of 12.3 (SD, 9.8) mg/dL. Spearman rho correlation between the difference scores and Hct was -0.43, P = .003. Using a tercile split, groups with Hct of less than 26% (n = 16) and greater than 29% (n = 15) were identified. The unpaired t test on the mean difference scores of these 2 groups was t = -2.7, P < .01, with an overall mean difference 8.6 mg/dL (95% confidence interval, -15 to -2.2). The mean difference was 16.3 in the low-Hct group and 7.8 in the high-Hct group. CONCLUSIONS: Point of-care glucometer results differ significantly from laboratory glucose concentrations, with the difference widening as the Hct decreases. This raises the concern about using POC devices to provide tight glycemic control in CTS patients. PMID- 21263335 TI - Disparity in perceived illness intrusiveness and illness severity between cardiac patients and their spouses. AB - BACKGROUND: Recovery following a cardiac event is a complex physiological and psychological process that seldom occurs in isolation. The interdependence of a marital relationship may result in the spouse influencing the patient's overall recovery and the psychological well-being of both. The aim of the study was to assess whether perceived illness intrusiveness and illness severity differed between cardiac patients and their spouses and whether their perceptions were modified by treatment received. A thematic analysis of written feedback from patients and spouses informed the interpretation of the quantitative results. METHODS: Sixty-two male cardiac patients and their female spouses completed the Illness Intrusiveness Rating Scale and Perceived Severity of Illness Scale. Participants also provided written comments about anticipated life changes. A 2 way mixed-model analysis of variance was used to compare patient and spouse scores. RESULTS: There were no differences in terms of perceived illness intrusiveness. A statistically significant higher level of perceived illness severity was reported by spouses whose husbands had cardiac surgery (difference = 48.8 points, F1,59 = 23.2, P = .001). Five themes emerged from the written responses of the patients: anticipated lifestyle change, change in self perception, reprioritization, enhanced quality of life, and uncertainty. Four themes emerged from the spouses: taking on responsibility, uncertainty, enhanced quality of life, and getting back to normal. CONCLUSIONS: Spouses of cardiac surgery patients had different perceptions about illness than their patient partner. Future research should be directed toward a better understanding of how divergent illness beliefs develop during the recovery period, and how they impact physical and psychological well-being. PMID- 21263336 TI - Emergency department triage nurses' self-reported adherence with American College of Cardiology/American Heart Association myocardial infarction guidelines. AB - BACKGROUND AND OBJECTIVE: Mortality from acute coronary syndromes has decreased. This achievement is based on the rapid recognition of possible acute coronary syndrome, obtaining an electrocardiogram for diagnosis, and the prompt initiation of therapy, including aspirin, oxygen, thrombolytics, and cardiac catheterization. The importance of rapid diagnosis and therapy is emphasized by American College of Cardiology/American Heart Association (ACC/AHA) practice guidelines. However, these goals are not always met, and their failure leads to increased mortality. The purpose of this study was to determine the frequency emergency department nurses report guideline-related activities when triaging patients for complaints suggestive of myocardial infarction. SUBJECTS AND METHODS: As part of a larger study examining nurses' cardiac triage decisions, 158 emergency department nurses who belonged to the Emergency Nurses Association responded to a mailed questionnaire, which asked how frequently certain nursing practice activities were performed that would facilitate the attainment of ACC/AHA myocardial infarction guidelines and goals. Responses were measured on a 5-point Likert-type scale from "none of the time" to "all of the time." RESULTS: Not a single one of the 9 goals was met "all of the time" by all of the nurse participants. "All of the time" ranged from 52% for giving analgesics to 87% asking about chest pain. Only 81% of participants had a goal of obtaining electrocardiogram within 10 minutes of arrival, and only 27% of participants met all 9 goals "all of the time." The likelihood of nurses meeting goals was not associated with their age, experience, educational level, or certification status. CONCLUSIONS: We recommend tailored educational interventions be developed to improve nurses awareness of the importance of complying with the ACC/AHA standard of care practice goals and the necessity of achieving these goals all of the time as a path to improving patient outcome. PMID- 21263337 TI - Informal caregivers' experiences of caring for patients with chronic heart failure: systematic review and metasynthesis of qualitative studies. AB - BACKGROUND: Increasing evidence suggests that family support for patients with chronic heart failure (CHF) contributes greatly to the disease management of CHF. In addition, the quality of the CHF patient's close personal relationships can influence CHF outcomes. However, caregivers cannot provide care alone and need guidance, support, and skills to manage care that is often complex. In this article, we provide a review of studies that have explicitly investigated these issues of informal caregivers to CHF patients. OBJECTIVE: The objective of this study was to explore informal caregivers' views and experiences of caring for patients with CHF. METHODS: This is a systematic review and synthesis of qualitative studies describing informal caregivers' experiences in home-based care. Data sources were published literature written in English from electronic databases: PubMed, CINAHL (1982-2009), PsycINFO (1967-2009), EMBASE (1980-2009), and the Cochrane Library Database. Ten primary studies met the inclusion criteria. RESULTS: A number of themes emerged. Five key themes were identified from synthesis of the studies: sharing of caring, suffering from anxiety, being isolated, enjoying a good relationship, and searching for support. CONCLUSIONS: Caring for persons with CHF can affect the well-being of their informal caregivers, which may ultimately have consequences for the CHF patient's health. Further studies are needed to clarify these issues and to examine the role of informal caregivers in the management of CHF. PMID- 21263338 TI - You won't know if you don't ask: discrepancy and ambivalence in attitudes toward behavior change. AB - BACKGROUND: Behavior change is challenging following an acute cardiac event, and commonly, individuals are ambivalent. AIM: The objective of this study was to describe the experience of behavior change of survivors of an acute cardiac event. METHOD: Semistructured interviews were undertaken with 25 participants attending 3 cardiac rehabilitation programs. An inductive process of qualitative thematic analysis was used to analyze the transcripts. RESULTS: Analysis revealed ambivalence to change, misconceptions, and confusion about terminology. Discrepancies between what participants felt they should be doing and what they actually were doing reflected their ambivalence. Further inconsistencies were reflected in participants' misunderstandings and confusion regarding disease processes and management of heart disease. CONCLUSIONS: These findings reflect the misconception and ambivalence regarding behavior change that individuals experience. Clinicians may require greater skills in detecting conflicting or ambivalent discourse to support patients through sustainable health behavior change. PMID- 21263339 TI - Self-care and quality of life of heart failure patients at a multidisciplinary heart function clinic. AB - BACKGROUND: Multidisciplinary heart function clinics aim to improve self-care through patient education and to provide clinical management. OBJECTIVE: The objectives of the present study were to investigate the self-care and quality of life of patients attending a multidisciplinary heart function clinic and to explore the relationship between self-care and quality of life. METHODS: One hundred outpatients attending a multidisciplinary heart function clinic were asked to complete a questionnaire. The questionnaire included the Self-care of Heart Failure Index (SCHFI) and the Minnesota Living With Heart Failure Questionnaire, which were used to assess self-care behavior and quality of life, respectively. Self-care practices and perceived barriers were also assessed through semistructured interviews with each patient. RESULTS: : The returned questionnaires (n = 94) were used to compute the following SCHFI maintenance, management, and confidence scores: 60.8 (SD, 19.3), 62.0 (SD, 20.7), and 55.9 (SD, 19.7), respectively. Higher SCHFI scores indicate better self-care. None of the self-care dimensions reached the self-care adequacy cut point of 70. The average score on the Minnesota Living With Heart Failure Questionnaire was 49.9 (SD, 25.4), indicating a moderate health-related quality of life. Lower ejection fraction, older age, and better quality of life were associated with better self care. Determinants of better quality of life were older age, better functional capacity, higher self-care confidence, and fewer comorbidities. The patient interviews revealed that better quality of life is associated with higher self care confidence and barriers to self-care caused anxiety to the patients. The self-care barriers were found to include lack of self-care education, financial constraints, lack of perceived benefit, and low self-efficacy. CONCLUSIONS: Patients attending a large multidisciplinary Canadian heart failure clinic do not perform adequate self-care as measured with the SCHFI and report only a moderate quality of life. Increasing self-care through education and tools that target self-care barriers are required and may help improve quality of life. PMID- 21263340 TI - Health literacy and self-care of patients with heart failure. AB - BACKGROUND AND RESEARCH OBJECTIVE: Today's complex healthcare system relies heavily on sophisticated self-care regimens. To navigate the system and follow self-care protocols, patients must be able to understand and use health information, which requires health literacy. However, nearly 90 million Americans lack the necessary health literacy skills to adequately care for themselves in the face of a complex healthcare system and self-care regimens. Understanding how to effectively care for one's self is thought to improve heart failure symptoms and patient outcomes, but little is actually known about how health literacy influences self-care in patients with heart failure. The purpose of this pilot study was to examine the relationship between health literacy and self-care of patients with heart failure. SUBJECTS AND METHODS: Patients with a diagnosis of heart failure were recruited from a variety of community settings. Participants completed the Short-Form Test of Functional Health Literacy (measured health literacy), the Self-care Index of Heart Failure (measured self-care maintenance, management, and confidence), and a demographic questionnaire. Spearman rho correlations were used to assess the strength of the relationship between health literacy level and self-care scores. RESULTS AND CONCLUSIONS: Among the 49 participants recruited, health literacy was positively related to self-care maintenance (Rs = 0.357, P = .006). Health literacy had a negative relationship with self-care management (Rs = -0.573, P = .001). There was no association between health literacy and self-care confidence (Rs = 0.201, P = .083). This project provides preliminary data regarding the association between health literacy and self-care in heart failure, showing support for higher health literate patients performing more self-care maintenance, which has been shown to improve patient outcomes in heart failure. Patients with higher health literacy trended toward having greater self-care confidence, which can increase the likelihood of performing self-care, but this finding was not statistically significant. It was unexpected to find that lower health-literate patients performed more self-care management. PMID- 21263341 TI - Factors associated with sexual quality of life in patients before and after coronary artery bypass grafting surgery. AB - BACKGROUND: Successful rehabilitation of patients after coronary artery bypass grafting (CABG) should include psychosocial outcomes such as sexual activity. However, little has been reported regarding the sexual quality of life of patients after CABG. OBJECTIVES: This study aimed to investigate the associations of demographic and disease characteristics, psychosocial factors, and sexual quality of life in patients before and after CABG surgery. METHODS: A longitudinal, descriptive design was used. A convenient sample of 70 patients with a diagnosis of coronary artery disease and under preparation for CABG surgery was recruited from the cardiovascular units of a medical center in central Taiwan. Participants were interviewed and completed a structured questionnaire before and 3 months after CABG surgery. Instruments used included EuroSCORE (European System for Cardiac Operative Risk Evaluation), Sexual Knowledge Scale, Spouse Communication Scale, Hospital Anxiety and Depression Scale, Perceived health status, and Sexual Quality of Life Scale. RESULTS: Sexual desire and sexual response of patients were significantly limited after CABG. Before surgery, age, disease duration, and spouse communication were all significant predictors, which explained 33.8% of the variance in the sexual quality-of-life scores. Significant predictors after surgery included sexual knowledge, disease duration, and EuroSCORE, which accounted for 25.6% of the variance of sexual quality of life. CONCLUSION: This study confirms that CABG surgery may have an impact on patients' sexual quality of life. With the numbers of CABG patients increasing, development of appropriate sexual counseling for cardiac patients is necessary to improve their sexual quality of life. PMID- 21263342 TI - Systematic review of physical activity intervention studies after cardiac rehabilitation. AB - Coronary heart disease significantly impacts the morbidity, mortality, and health care economy of our population. Enrollment into cardiac rehabilitation (CR) after cardiac events improves patient outcomes; however, physical activity (PA) behavior decreases significantly in the years following completion of CR. This article reviews the literature regarding interventions to maintain or increase PA after CR. Fourteen interventions studies from North America, Europe, Asia, and Australia used variations of cognitive and/or behavioral strategies. Women and older adults were underrepresented in the reviewed studies. Measurement of PA varied between studies and included self-report, objective pedometer or accelerometer data, or questionnaire format. Common cognitive interventions included self-efficacy enhancement measures, barrier management, and problem solving. Behavioral interventions included self-monitoring, prompting, goal setting, and feedback. Cognitive intervention studies reported inconsistent results, whereas behavioral studies and studies that used combinations of interventions reported more consistent, positive findings. More intervention studies, using rigorous designs and reliable measures of PA on larger, more diverse populations, are needed to improve the understanding of PA-related behavior change after completion of CR. PMID- 21263343 TI - A low-glycemic nutritional fitness program to reverse metabolic syndrome in professional firefighters: results of a pilot study. AB - BACKGROUND: The risk for cardiovascular events is higher for those with metabolic syndrome (MetS), and it is known that firefighters have a 4-fold risk for cardiovascular events. The purpose of this study was to quantify MetS prevalence and evaluate the effect of a low-glycemic nutritional fitness program on the reduction of MetS risk factors among firefighters. METHODS: Professional firefighters were screened for MetS then enrolled in a low-glycemic nutritional fitness program for a 12-week period. Anthropometric and physiological measurements were obtained at the start and end of the program. Subjects with 3 or more of the following were positive for MetS: waist-40-inches or greater (men) or 35 inches or greater (women), blood pressure 135 mm Hg or greater (systole) or 85 mm Hg or greater (diastole), fasting blood sugar 100 mg/dL or greater, triglycerides 150 mg/dL or greater, and high-density lipoproteins less than 40 mg/dL (men) or less than 50 mg/dL (women). Weekly sessions provided low-glycemic nutrition instruction, fitness training, and evaluation of individual progress. RESULTS: Seventy-five firefighters (aged 42 [SD, 8] years, mostly white men) had a total MetS prevalence of 46.7% (P<.05 vs normal population). One platoon (10 men, aged 48 [SD, 5] years) was enrolled in the 12-week program. Most (7/10) had MetS at the baseline, but this prevalence decreased significantly after 12 weeks to 3 subjects (P=.02). On average, subjects had 3.2 (SD, 1.6) versus 1.9 (SD, 1.7) MetS risk factors (P<.01) at baseline and the 12-week interval, respectively. CONCLUSIONS: The prevalence of MetS and MetS risk factors is higher among professional firefighters compared with the general population. A short duration, low-glycemic fitness program can successfully improve anthropometric and physiological measures and reduce the prevalence of MetS. PMID- 21263344 TI - Biomarkers of myocardial stress and systemic inflammation in patients who engage in heart failure self-care management. AB - BACKGROUND: Self-care is believed to improve heart failure (HF) outcomes, but the mechanisms by which such improvement occurs remain unclear. METHODS: We completed a secondary analysis of cross-sectional data collected on adults with symptomatic HF to test our hypothesis that effective self-care is associated with less myocardial stress and systemic inflammation. Multivariate logistic regression modeling was used to determine if better HF self-care reduced the odds of having serum levels of amino-terminal pro-B-type natriuretic peptide and soluble tumor necrosis factor alpha receptor type 1 at or greater than the sample median. Heart failure self-care was measured using the Self-care of Heart Failure Index. RESULTS: The sample (n=168) was predominantly male (65.5%), and most (50.6%) had New York Heart Association III HF (mean left ventricular ejection fraction, 34.9% [SD, 14.0%]); mean age was 58.8 (SD, 11.5) years. Self-care management was an independent factor in the model (block chi=14.74; P=.005) after controlling for pertinent confounders (model chi=52.15; P<.001). Each 1-point increase in self care management score (range, 15-100) was associated with a 12.7% reduction in the odds of having levels of both biomarkers at or greater than the sample median (adjusted odds ratio, 0.873; 95% confidence interval, 0.77-0.99; P=.03). CONCLUSION: Better self-care management was associated with reduced odds of myocardial stress and systemic inflammation over and above pharmacological therapy and other common confounding factors. Teaching HF patients early symptom recognition and self-care of symptoms may decrease myocardial stress and systemic inflammation. PMID- 21263345 TI - Anthropometric measures and lipid coronary heart disease risk factors in Korean immigrants with type 2 diabetes. AB - OBJECTIVES: The purposes of this study were to (1) describe anthropometric measures among Korean immigrants with type 2 diabetes mellitus (T2DM) and (2) examine the relationships between measures of obesity with several forms of dyslipidemia in this group. BACKGROUND: Obesity and dyslipidemia are commonly associated with T2DM, and they are risk factors for coronary heart disease (CHD), the leading cause of death for people with diabetes. Asians are predisposed to abdominal obesity and experience significant CHD risk at lower body mass index (BMI) levels. Despite high prevalence of diabetes among Korean immigrants, relationships among anthropometric measures and lipid-related CHD risk factors have not been examined. METHODS: A convenience sample of 143 adult Korean immigrants with T2DM between the ages of 30 and 80 years participated in the study. Body mass index, waist circumference (WC), and waist-to-hip ratio (WHR) were obtained using standardized procedures. Total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were assessed using a fingerstick blood test. Hierarchical linear regressions were conducted to identify which of the anthropometric measures was significantly related to individuals' cholesterol levels. RESULTS: Central obesity measures, not BMI, were significantly associated with dyslipidemia in Korean immigrants with T2DM independent of potential confounds such as hemoglobin A1C, cigarette smoking, age, and cholesterol medication. Different central obesity measures were associated with different cholesterol types for diabetic Korean men and women. In men, WHR was positively associated with low-density lipoprotein cholesterol and total cholesterol levels. In women, WC was negatively associated with high density lipoprotein cholesterol. CONCLUSIONS: Central obesity measures (WC and WHR) are better indicators for assessing lipid-related CHD risk factor among Korean immigrants with T2DM than BMI. Gender difference in the association between central obesity measures and lipid types should be considered in CHD risk assessment of Korean immigrants with T2DM. PMID- 21263346 TI - Impact of canine-assisted ambulation on hospitalized chronic heart failure patients' ambulation outcomes and satisfaction: a pilot study. AB - BACKGROUND AND RESEARCH OBJECTIVE: Chronic heart failure (HF) is a prevalent and costly disease process. Early ambulation has been shown to have a positive impact on patient outcomes and length of stay. Animal-assisted therapy is a novel modality that has shown to be a safe and effective adjunct to a number of traditional treatment plans. This study sought to synergistically combine ambulation and animal-assisted therapy by using canine-assisted ambulation (CAA) to improve the ambulation outcomes of HF patients. SUBJECTS AND METHODS: Sixty nine hospitalized patients with a primary diagnosis of HF were approached to ambulate with a restorative aide. After recording their initial response, they were given the opportunity to participate in CAA (walking with a therapy dog). Initial ambulation refusal rate was compared with a historical population of 537 HF patients. Distance ambulated was recorded using a pedometer and compared with a randomly selected, 64-patient sample from the historical HF patient population, stratified by day of hospital stay. Patient satisfaction was assessed through a 5 item Likert scale survey. RESULTS AND CONCLUSION: The 537-patient historical HF population had an ambulation refusal rate of 28%. When offered the chance to participate in CAA, only 7.2% of the study population refused ambulation (P = .0002). Of the 69-patient study sample, 13 initially refused ambulation then agreed when offered CAA (P = .0009). Distance ambulated increased from 120.2 steps in a randomly selected, stratified historical sample to 235.07 in the CAA study sample (P < .0001). Patients unanimously agreed that they enjoyed CAA and would like to participate in CAA again. Canine-assisted ambulation is a safe and effective adjunct to an early ambulation program for HF patients. Canine-assisted ambulation may decrease hospital length of stay and thereby decrease the costs of HF care. Additional research involving CAA's application to other disease processes in various settings is warranted. PMID- 21263347 TI - Perceived adverse drug events in heart failure: patients' perception and related factors. AB - BACKGROUND: Patients with heart failure (HF) often perceive adverse drug events (ADEs), affecting quality of life. For weighing the benefits and burden of medication in HF care, knowledge on patients' perception of ADEs is needed. Our aim was to assess these ADE perceptions and to identify factors related to these perceptions. METHODS: A cross-sectional study was performed including HF patients recruited from primary care and outpatient clinics. Patients were included in the analysis if they perceived an ADE in the past 4 weeks. This information was collected using an open-ended question and a symptom checklist. Data on ADE perception were obtained using a modified version of the Revised Illness Perception Questionnaire. Demographic, clinical, and ADE characteristics were collected by self-administered questionnaire and chart review. The relations between these factors and ADE perceptions were analyzed using regression analyses. RESULTS: In total, 261 HF patients perceived an ADE and completed the questionnaire. Patients reported 814 ADEs, of which 26% of the patients reported dizziness and 24% reported dry mouth as being the most prevalent. Almost half of the patients (46%) perceived their ADE as something serious, with major consequences for their daily life (40%) and reported to be worried (36%) about the ADE. Patients perceived the ADE as a chronic problem (91%), and the majority believed more in the ability of the health care provider to control the ADE (61%) than in their own ability (46%). Demographic and clinical variables had a limited contribution to the explained variance of ADE perceptions after adjusting for ADE characteristics, such as perceived severity. CONCLUSION: Patients with HF perceive particular negative consequences and emotional distress of symptomatic ADE. Open communication between patients and providers with attention for patients ADE perceptions would be valuable during the decision process of ADE management and may result in a regimen aligned with patients' preferences and needs. PMID- 21263348 TI - Living with atrial fibrillation: a qualitative study. AB - BACKGROUND AND RESEARCH OBJECTIVE: Atrial fibrillation (AF) is a public health burden associated with stroke, cardiomyopathy, and diminished quality of life (QOL). Although surveys suggest that AF impairs physical functioning and mental health, little is known about patients' experiences contributing to those findings. Understanding patients' experiences of living with AF may provide a foundation for interventions to improve QOL. In this qualitative descriptive study, we describe the experience of living with recurrent symptomatic AF from patients' perspectives. SUBJECTS AND METHODS: Seven women and 8 men, recruited from a Midwest medical center, with a mean age of 59.8 (SD, 14.5) years, diagnosed with recurrent symptomatic AF, participated in open-ended interviews. Data were analyzed by qualitative descriptive methods. RESULTS AND CONCLUSIONS: Themes were identified that reveal experiences of living with recurrent symptomatic AF over time and how AF may diminish QOL. Themes included (1) finding the meaning of symptoms, (2) feeling uninformed and unsupported, (3) turning points, (4) steering clear of AF, (5) managing unpredictable and function limiting symptoms, (6) emotional distress, and (7) accommodation to AF tempered with hope for a cure. Participants experienced delays in diagnosis and minimization of their concerns by clinicians and others and did not receive counseling regarding the nature of AF and self-management. Strategies to manage AF and its symptoms were learned through trial and error and were transiently effective. Support for coping with the emotional burden of AF was lacking. Interventions to improve recognition of AF symptoms and promote prompt evaluation and treatment are needed. Psychoeducational programs to teach patients and families about the nature of AF, guide self-management, and address the emotional burden of AF need to be developed and tested. PMID- 21263349 TI - Resistance training improves vasoreactivity in end-stage heart failure patients on inotropic support. AB - PURPOSE: Peripheral vascular abnormalities contribute to compromised functional status in heart failure (HF) patients. The purpose of the present study was to test whether the intervention of moderate-intensity, resistance training could improve peripheral vascular responsiveness, that is, flow-mediated dilation (FMD) in HF. METHODS: Baseline brachial artery FMD analysis (2 minutes of cuff occlusion and 5 minutes of reperfusion) was measured in HF patients on intravenous inotropic support (n = 9) awaiting cardiac transplantation. Unilateral, upper-body resistance exercises (moderate intensity, combination of isometric and isotonic exercises at 60%-80% of maximum) were performed 3 d/wk for 4 weeks. Follow-up FMD analysis was conducted after training. Central hemodynamics were defined via right-side-heart catheterization. RESULTS: At baseline prior to training, HF patients elicited a significant hyperemic response 10 seconds following cuff occlusion (mean increase in blood flow: 194 +/- 44 mL/min, P < .05). Despite this significant hyperemic response, HF patients demonstrated a mild, but paradoxical vasoconstriction of nearly 3% at 1-minute after cuff release. Four weeks of resistance training corrected the paradoxical vasoconstriction observed at baseline and resulted in vasodilatation (a positive increase in brachial artery diameter of 0.04 +/- 0.04 mm, at 1 minute after cuff release; P < .05). Conversely, in a subset of 3 HF patients, studies in the untrained contralateral arm revealed no change in the FMD response. CONCLUSION: Moderate-intensity upper-body resistance training improved brachial artery FMD in end-stage HF patients on inotropic support. The reversal of the paradoxical vasoconstrictive response to reactive hyperemia following 4 weeks of training may be secondary to local improvements in vascular endothelial function rather than a quantitative change in the reactive hyperemic stimulus. PMID- 21263350 TI - Perceived social support and its association with obesity-specific health-related quality of life. AB - OBJECTIVE: To (1) describe type and source of social support perceived by obese youth and examine associations with sociodemographic/anthropometric characteristics, and (2) examine relationships between social support and obesity specific health-related quality of life (HRQOL). METHODS: Seventy-four obese youth and their primary caregivers participated. Youth completed the Child and Adolescent Social Support Scale and an obesity-specific HRQOL measure, Sizing Me Up. RESULTS: Close friends and parents provided the most social support and were rated most important, except for teacher informational support. Classmates and schools provided the least social support. Body mass index z-score was correlated with teacher support frequency (r = -.26, p < .05) and minority youth reported more parent support (t(72) = -2.21, p < .05). Compared with other support providers, classmate support significantly predicted most HRQOL scales (p < .001). CONCLUSIONS: Close friends, parents, and teachers are significant sources of support to youth with obesity; however, classmates play a unique role in the HRQOL of obese youth. PMID- 21263351 TI - Douching for perceived vaginal odor with no infectious cause of vaginitis: a randomized controlled trial. AB - OBJECTIVE: To demonstrate the effectiveness of medical-grade stainless steel Water Works Douching Device for treating abnormal vaginal odor in comparison with a commercially available over-the-counter plastic douching device. MATERIALS AND METHODS: In a multicenter study, 140 women with perceived vaginal odor with no vaginal infection were randomized to either Water Works or control group in a 1:1 ratio and were douched daily for 4 weeks. A visual analog scale (VAS) was used to assess the intensity of vaginal odor. Primary outcome included subject assessment of odor improvement and Nugent Gram stain score of vaginal secretions. Secondary outcome compared the efficacy and safety of Water Works with control douching device. Each patient underwent baseline, week 2, and week 4 visits. RESULTS: The final analytic sample consisted of 96 women. Success score at 4 weeks was 78% for the Water Works group and 38.5% for the control group. Mean VAS was significantly reduced, and Nugent and Lactobacillus scores were maintained in both groups. In the Water Works group, VAS was reduced from 7.3 +/- 0.3 to 1.8 +/- 0.6 (p < .001) after 4 weeks. In the control group, baseline versus 4 weeks VAS was 7.2 +/- 0.3 and 3.4 +/- 0.8 (p < .003). CONCLUSIONS: Women reported significant reduction of vaginal odor after douching with water for 4 weeks without any alteration of vaginal flora. The Water Works Douching Device was superior to over- the-counter device in reducing vaginal odor. PMID- 21263352 TI - Invasive cervical cancer and screening: what are the rates of unscreened and underscreened women in the modern era? AB - OBJECTIVE: It has been reported that approximately 50% of invasive cervical malignancies are diagnosed in patients who have never been screened and that 10% of the remaining cervical cancer patients have not had a Pap smear in the 5 years before diagnosis. We sought to determine whether this holds true among a university-based gynecologic oncology patient population. METHODS: After institutional review board approval, a retrospective chart review of women in a university-based gynecologic oncology group with cervical cancer from 2002 to 2007 was conducted. Patients' demographics, referral Pap smear, method of diagnosis, histology, clinical stage, treatment, and time since last Pap smear were collected. Descriptive statistics were used during data analysis. RESULTS: A total of 419 women with cervical cancer were identified. Of these women, 67% of patients were white, 18% Hispanic, and 6% African-American. The most common referral Pap smear to our institution was high-grade squamous intraepithelial lesion (21%). Diagnosis was primarily made by cervical punch biopsy (47%). The most common histologic type was squamous cell carcinoma (70%). Of all patients, 80% were diagnosed with stage I and 9% with stage II cervical cancer, whereas stage III and IV were uncommon. The most common therapy was radical hysterectomy with lymph node dissection performed in 250 patients (60%). The length of time from last reported Pap smear to diagnosis of invasive cervical cancer ranged from 1 to 65 years, with a median of 3 years. Stage IA1 patients ranged from 1 to 12 years from last reported Pap with a median of 1 year (SD = 3.38), whereas stage III/IV patients ranged from 1 to 20 years since last screening, with a median of 4 years (SD = 6.39). Regarding length of time since last reported Pap smear, 235 patients (56%) were unable to report the length of time since their last Pap smear. Of those who reported their last Pap smear, 4 patients (1%) reported never having a Pap smear, 39 patients (9%) reported last Pap smear more than 10 years ago, and 10 patients (2%) reported a Pap smear more than 20 years ago. Of all patients, 85 (20%) reported a Pap smear within 2 years. Of these 85 patients, 71 patients (84%) were diagnosed at stage I, whereas more advanced stages were uncommon. CONCLUSIONS: Traditionally, patients diagnosed with an invasive cervical malignancy are either unscreened or underscreened with cervical cytology. Our patient population was noncompliant with the screening measures. A fraction of our patients were compliant with screening within the last 2 years, yet still developed a cervical malignancy--albeit early stage disease. As such, our data suggest that compliance continues to be an issue. However, even with adherence to screening guidelines, cervical cancer continues to develop. PMID- 21263353 TI - Computed tomography and magnetic resonance imaging features of posterior mediastinal ganglioneuroma. AB - PURPOSE: To evaluate computed tomography (CT) and magnetic resonance (MR) imaging findings of posterior mediastinal ganglioneuromas. MATERIALS AND METHODS: Of 14 pathologically confirmed ganglioneuromas seen in 13 patients, 13 were evaluated by CT images with and without contrast, 11 were evaluated with conventional spin echo MR images, and 5 were evaluated with contrast-enhanced MR examination. The morphologic features, attenuation, signal intensity, and dynamic enhancement pattern of the neoplasms were evaluated. RESULTS: All lesions were identified as a well-demarcated oval and/or lobular mass. CT attenuation was predominantly low. Calcification on CT scan was seen in 38% of the cases. Whorled appearance (42%) and tailed-shaped edge (14%) were seen on both CT and MR images. Fat components (29%) observed histologically were also detected in tumors on CT and MR images. MR signal intensity in the lesions was mainly low on T1-weighted images and high on T2-weighted images. Contrast enhancement of the tumors was poor in 46% on dynamic CT study. In all 5 contrast-enhanced MR examinations, all lesions were enhanced. CONCLUSIONS: The characteristic findings of posterior mediastinal ganglioneuromas are a craniocaudally oblong-shaped mass, calcification, whorled appearance, tail-like extension, and fat component. Poor enhancement on dynamic CT studies is commonly observed. PMID- 21263354 TI - Computed tomography coronary angiography versus stress myocardial perfusion imaging for risk stratification in patients with high occupational risk. AB - PURPOSE: To compare the performance of myocardial perfusion imaging (MPI) versus cardiac computed tomographic angiography (CCTA) in patients with a low pretest likelihood of obstructive coronary artery disease and high-risk occupation. MATERIALS AND METHODS: We performed a retrospective chart review of all MPI and CCTA studies performed at our institution from January 2006 to May 2008. The primary outcome measure was the incidence of referral to invasive coronary angiography (ICA). RESULTS: There were 512 MPS and 170 CCTA studies performed during the study period that met the study criteria. The average age was 35+/-10 for the CCTA arm and 45+/-5 for the myocardial perfusion scans (MPS) arm, which was statistically significant (P<0.001), with similar sex distribution between the 2 arms (21% female patients in the MPI arm and 20% female patients in the CCTA arm). The incidence of referral to ICA was 15.8% (81/512) after MPS versus 2.4% (4/170) with CCTA (P<0.001). Among patients referred for ICA, the false positive rate was 93% (75/81) and 50% (2/4) with MPI and CCTA, respectively (P=0.043). CONCLUSIONS: Compared with MPI, CCTA significantly reduced ICA referral and false-positive noninvasive imaging rates among symptomatic patients with a low probability of coronary artery disease but high occupational risk. PMID- 21263355 TI - Imaging findings in human Bordetella bronchiseptica pneumonia. AB - Bordetella bronchiseptica is a gram-negative coccobacillus, which causes respiratory infection in dogs, rabbits, and pigs, and is rarely a human pulmonary pathogen. We present 2 immunocompromised patients diagnosed with B. bronchiseptica pneumonia. To our knowledge, these are the first reports of this disease in patients with B-cell lymphoma and an orthotopic cardiac transplant. In this report, we briefly discuss the epidemiology, microbiology, and challenges in the laboratory identification of B. bronchiseptica and describe the protean imaging manifestations of this rare pulmonary infection. We also address issues related to treatment and prognosis. PMID- 21263356 TI - Smaller and deeper lesions increase the number of acquired scan series in computed tomography-guided lung biopsy. AB - PURPOSE: To determine factors influencing the number of acquired scan series and subsequently the radiation dose and time during computed tomography (CT)-guided lung biopsies. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act-compliant, institutional review board-approved, retrospective study reviewed 50 consecutive procedures. Each procedure was separated into the following steps: trajectory planning, needle placement, needle insertion (extrapulmonary and intrapulmonary), and sampling and follow-up. The number of scan series, time, and radiation dose were calculated for each procedure and its steps. The effects of patient characteristics (age, sex, history of surgery that violated the pleura), procedure characteristics (needle-pleural angle, patient position), and lesion characteristics (size, depth, lobar location) on the number of scan series for the procedure and each step were evaluated using stepwise linear regression. The overall diagnostic accuracy, pneumothorax rate, and chest tube insertion rate were also calculated. RESULTS: The mean number of total CT scans was 21, the mean effective dose was 14 mSv, and the mean entrance skin dose was 249 mGy. On average, trajectory planning and needle insertion contributed most to the number of scan series (18.5% and 52.9%, respectively). For trajectory planning, a smaller lesion size and shallower needle-pleural angle were associated with an increased number of scans (R(2)=0.200, P=0.005). During needle insertion, smaller lesions were associated with increased scanning (R(2)=0.296, P<0.001), with both smaller and deeper lesions associated with an increased number of scans during the intrapulmonary component (R(2)=0.372, P<0.001). For the entire procedure, smaller lesions were associated with an increased number of scans (R(2)=0.12, P=0.01). CONCLUSION: Lesions that are smaller or deeper in the lung result in a higher number of CT scans, resulting in increased radiation dose and procedure time, with most of these performed during the needle insertion step. PMID- 21263357 TI - Magnetic resonance imaging of right ventricular papillary endothelial hyperplasia. AB - Papillary endothelial hyperplasia (PEH) is a benign process characterized by endothelial cell proliferation in a papillary pattern, usually occurring in reaction to traumatic vascular stasis or a thrombus. Commonly found in the soft tissues of the neck and extremities, intracardiac lesions in the left atrium, left ventricle, and coronary atherotomy specimens associated with trauma or thrombus have rarely been reported. A single prior report of a pure, isolated form of intracardiac PEH in the literature is noted. To the best of our knowledge, the imaging characteristics have not been described. We describe the dynamic magnetic resonance characteristics of a pure, isolated PEH occurring in the right ventricle. PMID- 21263358 TI - An observational study using a national administrative database to determine the impact of hospital volume on compliance with clinical practice guidelines. AB - BACKGROUND: Little information is available on the relationship between hospital volume and compliance with clinical practice guidelines (CPGs). OBJECTIVES: To investigate the relationship between hospital volume and compliance with CPGs using a Japanese administrative database. DESIGN AND SUBJECTS: This was an observational study that included 60,842 patients with acute cholangitis from 829 hospitals in Japan. MEASURES: Hospital volume was categorized into the following 3 groups based on the number of cases of acute cholangitis during the study period: low-volume hospitals (LVHs; n = 20,869), medium-volume hospitals (MVHs; n = 18,387), and high-volume hospitals (HVHs; n = 21,586). We further collected patient data with regard to CPGs for acute cholangitis, and counted the number of recommendations that had been complied with for each patient. CPGs compliance score was defined as the rate of compliance with these recommendations for each patient (range, 0-10). Aggregated CPGs compliance score was measured according to hospital volume. RESULTS: Mean CPGs compliance score in HVHs was significantly higher than that in MVHs and LVHs (6.8 +/- 1.6 vs. 5.6 +/- 1.5 vs. 3.9 +/- 1.4, respectively; P < 0.001). Multiple linear regression analysis revealed that hospital volume was most significantly associated with CPGs compliance score. The standardized coefficient for CPGs compliance score in HVHs was 0.689, whereas that of MVHs was 0.366 (P < 0.001). CONCLUSIONS: This study demonstrated that hospital volume was significantly associated with compliance with CPGs and that the Japanese administrative database was a viable tool for the monitoring of compliance with CPGs. PMID- 21263359 TI - A systematic review and meta-analysis of health care utilization outcomes in alcohol screening and brief intervention trials. AB - OBJECTIVE: This systematic review and meta-analysis examines the effect of screening and brief intervention (SBI) on outpatient, emergency department (ED), and inpatient health care utilization outcomes. Much of the current literature speculates that SBI provides cost savings through reduced health care utilization, but no systematic review or meta-analysis examines this assertion. METHOD: Publications were abstracted from online journal collections and targeted Web searches. The systematic review included any publications that examined the association between SBI and health care utilization. Each publication was rated independently by 2 study authors and assigned a consensus methodological score. The meta-analysis focused on those studies examined in the systematic review, but it excluded publications that had incomplete data, low methodological quality, or a cluster-randomized design. RESULTS: Systematic review results suggest that SBI has little to no effect on inpatient or outpatient health care utilization, but it may have a small, negative effect on ED utilization. A random effects meta analysis using the Hedges method confirms the ED result for SBI delivered across settings (standardized mean difference = -0.06, I = 13.9%) but does not achieve statistical significance (confidence interval: -0.15, 0.03). CONCLUSIONS: SBI may reduce overall health care costs, but more studies are needed. Current evidence is inconclusive for SBI delivered in ED and non-ED hospital settings. Future studies of SBI and health care utilization should report the estimated effects and variance, regardless of the effect size or statistical significance. PMID- 21263360 TI - Performance evaluations and league tables: do they capture variation between organizational units? An analysis of 5 Swedish pharmacological performance indicators. AB - BACKGROUND: The use of league tables during the last decade has frequently been employed to assess quality in health care. However, few studies have attempted to assess quality by quantifying the variability across the organizational units or attempted to investigate whether the units are the correct context that really influences the outcome under study. OBJECTIVES: To quantify the variation between different organizational units regarding 5 different Swedish national pharmacological performance indicators and to examine whether the organizational units under study are a valid construct of the context that influences the specific outcome. RESEARCH DESIGN: A multilevel model with patients nested within health care units that in turn were nested within County councils was used. By using measures of variance (intraclass correlation [ICC]), we quantified the extent to which the 5 indicators of health care quality were conditioned by the specified units. RESULTS: For all 5 studied indicators, the variation between county councils was small (ICC ranged from 2% to 7%), whereas the variation among health care units seemed to be more important (ICC ranged from 20% to 40%). CONCLUSION: As the variation between county councils was small, using league tables for performance evaluation seems to be inappropriate. If league tables are to be presented, the relative size of the variation at the higher levels and an analysis regarding the possible influence of the context for the specific outcome should be included. This approach provides useful information for identifying relevant contexts to capture health care variation. PMID- 21263361 TI - Interhemispheric transfer of paired associative stimulation-induced plasticity in the human motor cortex. AB - To evaluate the interhemispheric interaction of paired associative stimulation (PAS)-induced plasticity, we performed a transcranial magnetic stimulation study on nine healthy volunteers after PAS, motor evoked potentials were significantly enhanced in both the nonstimulated and stimulated primary motor cortex (M1). Short-interval intracortical inhibition and intracortical facilitation were not changed in the nonstimulated M1, but interhemispheric inhibition was significantly reduced after PAS. Motor evoked potential enhancement in the nonstimulated M1 was significantly correlated to that in the stimulated M1 and tended to correlate with the degree of pre-PAS interhemispheric inhibition. These results show that PAS-induced plasticity in the dominant M1 can transfer to contralateral M1 depending on the amount of plastic change induced in the stimulated M1 and, also probably, on the amount of transcallosal connection. PMID- 21263362 TI - Invasive intracranial pressure monitoring is a useful adjunct in the management of severe hepatic encephalopathy associated with pediatric acute liver failure. AB - OBJECTIVE: Pediatric acute liver failure is often accompanied by hepatic encephalopathy, cerebral edema, and raised intracranial pressure. Elevated intracranial pressure can be managed more effectively with intracranial monitoring, but acute-liver-failure-associated coagulopathy is often considered a contraindication for invasive monitoring due to risk for intracranial bleeding. We reviewed our experience with use of early intracranial pressure monitoring in acute liver failure in children listed for liver transplantation. DESIGN AND PATIENTS: Retrospective review of all intubated pediatric acute liver failure patients with grade III and grade IV encephalopathy requiring intracranial pressure monitoring and evaluated for potential liver transplant who were identified from an institutional liver transplant patient database from 1999 to 2009. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 14 patients were identified who met the inclusion criteria. Their ages ranged from 7 months to 20 yrs. Diagnoses of acute liver failure were infectious (three), drug-induced (seven), autoimmune hepatitis (two), and indeterminate (two). Grade III and IV encephalopathy was seen in ten (71%) and four (29%) patients, respectively. Computed tomography scans before intracranial pressure monitor placement showed cerebral edema in five (35.7%) patients. Before intracranial pressure monitor placement, fresh frozen plasma, vitamin K, and activated recombinant factor VIIa were given to all 14 patients, with significant improvement in coagulopathy (p < .04). The initial intracranial pressure ranged from 5 to 50 cm H2O; the intracranial pressure was significantly higher in patients with cerebral edema by computed tomography (p < .05). Eleven of 14 (78%) patients received hypertonic saline, and three (22%) received mannitol for elevated intracranial pressure. Eight of 14 (56%) monitored patients were managed to liver transplant, with 100% surviving neurologically intact. Four of 14 (28%) patients had spontaneous recovery without liver transplant. Two of 14 (14%) patients died due to multiple organ failure before transplant. One patient had a small 9-mm intracranial hemorrhage but survived after receiving a liver transplant. No patient developed intracranial infection. CONCLUSIONS: In our series of patients, intracranial pressure monitoring had a low complication rate and was associated with a high survival rate despite severe hepatic encephalopathy and cerebral edema in the setting of pediatric acute liver failure. In our experience, monitoring of intracranial pressure allowed interventions to treat increased intracranial pressure and provided additional information regarding central nervous system injury before liver transplant. Further study is warranted to confirm if monitoring allows more directed intracranial pressure therapy and improves survival in pediatric acute liver failure. PMID- 21263363 TI - Very high serum ferritin levels are associated with increased mortality and critical care in pediatric patients. AB - OBJECTIVE: To determine whether an elevated serum ferritin level is independently associated with mortality and receipt of critical care in pediatric patients. DESIGN: Retrospective cohort study, open population. SETTING: Seattle Children's Hospital, Seattle, WA, from September 2, 2003, to February 15, 2008. PATIENTS: All patients tested for serum ferritin level from September 2, 2003, to August 16, 2007, with a level >=1000 ng/mL. INTERVENTIONS: None. MAIN ANALYSIS: Cox regression. MEASUREMENTS AND MAIN RESULTS: The predictor of interest was the patient-specific peak serum ferritin level, dichotomized a priori at 3000 ng/mL. The outcomes were mortality and intensive care unit admission. A total of 171 patients met the inclusion criteria. The observation time without death or intensive care unit admission ranged from 184 to 1621 days. The hazard ratio of death with peak ferritin of >3000 ng/mL was 4.32 (95% confidence interval 2.21 8.47, p < .001) compared to peak ferritin of 1000-3000 ng/mL. The hazard ratio of intensive care unit admission with peak ferritin of >3000 ng/mL was 2.49 (95% confidence interval 1.53-4.05, p < .001) compared to peak ferritin of 1000-3000 ng/mL. Both estimates were adjusted for bone marrow transplant, solid organ transplant, hemoglobinopathy, and existing rheumatologic disease. CONCLUSION: In this pediatric population, with serum ferritin levels of >3000 ng/mL, there was increased risk for both receipt of critical care and subsequent death. PMID- 21263364 TI - Lung aeration during ventilation after recruitment guided by tidal elimination of carbon dioxide and dynamic compliance was better than after end-tidal carbon dioxide targeted ventilation: a computed tomography study in surfactant-depleted piglets. AB - OBJECTIVE: To test the hypothesis that tidal elimination of carbon dioxide and dynamic compliance guided lung recruitment and positive end-expiratory pressure titration in surfactant-depleted piglets result in improved aeration (repeated computed tomography scans) and reduced ventilation pressures compared to those of a control group with conventional end-tidal carbon dioxide targeted ventilation. DESIGN: Prospective animal investigation. SETTING: Clinical physiology research laboratory. SUBJECTS: Seventeen saline-lavaged piglets. INTERVENTIONS: The piglets were initially ventilated at an end-inspiratory pressure of 20 cm H2O, a positive end-expiratory pressure of 5 cm H2O, and a tidal volume of 10 mL kg for an end-tidal carbon dioxide target of 30-45 torr followed by 5 mins of ventilation without positive end-expiratory pressure. After this, the control group was ventilated for the same end-tidal carbon dioxide target during the study period. In the recruitment group, the protocol started with an increase of the positive end-expiratory pressure to 15 cm H2O. The end-inspiratory pressure was then increased in steps of 3 cm H2O to a tidal elimination of carbon dioxide peak/plateau in one recruitment group and further increased in two steps in a second recruitment group. A downward positive end-expiratory pressure titration was followed by continuous dynamic compliance monitoring. The "open lung positive end-expiratory pressure" was set 2 cm H2O above the positive end-expiratory pressure at the first dynamic compliance decline and used for a final "open lung ventilation" period. MEASUREMENTS AND MAIN RESULTS: The recruitment groups showed better aeration, lower ventilatory pressure amplitude, and better dynamic compliance than the control group at the end of the study. Recruitment using airway pressures above the tidal elimination of carbon dioxide peak/plateau did not improve aeration. Using end-tidal carbon dioxide targeted ventilation in the control group restored aeration after the ventilation without positive end expiratory pressure, but no recruitment or improvement of dynamic compliance was measured. CONCLUSIONS: Aeration was significantly better after recruitment and positive end-expiratory pressure titration than in a control group managed by "conventional" end-tidal carbon dioxide targeted ventilation. An increase of the end-inspiratory pressure above the tidal elimination of carbon dioxide peak/plateau did not result in an increased amount of normally aerated lung. A recruitment maneuver resulted in a lower ventilatory amplitude for achieving a target tidal volume and better dynamic compliance at the end of the study period compared to those of the control group. PMID- 21263365 TI - Withholding or withdrawing life-sustaining treatments: an 8-yr retrospective review in a Spanish pediatric intensive care unit. AB - OBJECTIVE: To determine the death rate of patients who died in our pediatric intensive care unit after a decision to withhold or withdraw life-sustaining treatment was made and to describe the epidemiologic data, clinical (acute and chronic) conditions, end-of-life care, and decision-making processes corresponding to these patients. DESIGN: Long-term retrospective review of patients' charts. SETTING: Mixed university-affiliated pediatric intensive care unit. PATIENTS: Patients younger than 18 yrs old whose deaths occurred after life sustaining treatment was withheld or withdrawn. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Epidemiologic and clinical data, the treatments received, the decision-making process, and the end-of-life pathway were evaluated. Ninety-seven of 311 deaths occurred after a medical decision to withhold life-sustaining treatment. Among these patients, the most common reason for admission was respiratory failure (44 of 97), followed by cardiopulmonary arrest and sepsis. In 50 of 97 there was a previously known neurologic condition before admission, 11 of 97 had a neoplasm or hematologic malignancy, 10 of 97 had a congenital heart disease, and 8 of 97 had a neuromuscular disease. The most common action for forgoing life-sustaining treatment was withdrawal of treatment (chiefly respiratory support). The median time for deciding to withhold or withdraw life sustaining treatment was on day 3 of admission. A total of 85 of 97 deaths occurred within 48 hrs after the decision was made and action taken. The decision to forgo life-sustaining treatment was proposed by the family in 14 of 97 patients, and there was an explicit agreement between the medical staff and the patient's family in 88 of 97. In all cases, palliative analgesic/sedative treatment effectively maintained the child's comfort. CONCLUSIONS: Withholding or withdrawing life-sustaining treatment was a frequent mode of death in our pediatric intensive care unit, occurring at a rate that falls in the midrange of literature values. The level of the parents' involvement with the team in the decision-making process, which was documented in 88 of 97 of the medical charts, was very high. Patients with chronic neurologic diseases or with severe cognitive sequelae constituted the main group in which the decision to forgo life sustaining treatment was made. PMID- 21263366 TI - Intracranial pressure monitoring in childhood meningitis with coma: a national survey of neurosurgeons in the United States. AB - OBJECTIVES: To describe the beliefs and attitudes of U.S. neurosurgeons regarding the use of intracranial pressure monitors among comatose children with meningitis. DESIGN AND SETTING: A questionnaire was administered by mail between March and July 2009, to a random sample of 500 adult neurosurgeons and to all 228 pediatric neurosurgeons in the Congress of Neurologic Surgeons. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The response rate was 60%. Abnormal computed tomography scans, either with brain swelling or hydrocephalus, and older child age were likely to prompt neurosurgeons to consider monitoring intracranial pressure, whereas etiology of meningitis did not impact the decision to monitor intracranial pressure. Fifty-two percent of neurosurgeons believed computed tomography scans were inaccurate in detecting elevated intracranial pressure in comatose children with meningitis, 22% believed otherwise, and 26% were uncertain. Only 25% of neurosurgeons felt there was sufficient medical evidence to monitor intracranial pressure in comatose children with meningitis, with higher frequency among adult than pediatric (30% vs. 16%; p < .01) neurosurgeons. Eighty-one percent of neurosurgeons disagreed with the notion that comatose children with meningitis were too ill to benefit from placement of intracranial pressure monitors. Pediatric neurosurgeons reported a higher frequency than adult neurosurgeons of having placed more (more than five) intracranial pressure monitors in comatose children with meningitis (42% vs. 28%; p < .01). CONCLUSIONS: Most neurosurgeons are willing to consider monitoring intracranial pressure among comatose children with meningitis in the presence of abnormal findings on computed tomography scan and with older patient age. These findings are instructive in view of the current uncertainty and equipoise in clinical practice regarding intracranial pressure monitoring in these critically ill children. PMID- 21263367 TI - Randomized controlled trial for intermittent versus continuous propofol sedation for pediatric brain and spine magnetic resonance imaging studies. AB - OBJECTIVES: Intermittent bolus propofol is an effective agent for pediatric magnetic resonance imaging sedation but requires constant vigilance and dose titration. Magnetic resonance imaging-compatible infusion pumps may make it possible to continuously infuse propofol, achieving a steady level of sedation at a lower total dose. This study investigates total propofol dose, recovery time, and magnetic resonance image quality in children receiving intermittent vs. continuously infused propofol sedation in children undergoing brain and spine magnetic resonance imaging studies. DESIGN: An open-label, prospective, randomized, controlled study. A single-blinded radiologist rated the quality of magnetic resonance images. SETTING: Children's hospital pediatric radiology sedation center. PATIENTS: One hundred seventy children age 1 month to 18 yrs undergoing deep sedation for brain, spine, or both brain and spine magnetic resonance imaging. INTERVENTIONS: After informed consent, patients were randomly assigned to two groups: group 1 (intermittent) received a propofol bolus of 2-4 mg/kg, followed by repeat boluses of 0.5-2 mg/kg/dose as needed. Group C (continuous) received a bolus of propofol 2-4 mg/kg, followed by a continuous infusion of 100 MUg/kg/min with 1-mg/kg/dose boluses with drip titration to effect. MEASUREMENTS AND MAIN RESULTS: Patient demographics, sedation risk assessment, propofol dose, sedation recovery times, incidence of complications, and quality of the magnetic resonance imaging studies were measured. A total of 170 children were enrolled in the study, with 75 in group C and 95 in group I. Both groups were similar with regard to age, weight, gender, and magnetic resonance imaging study type. Group C required a lesser dose of propofol (132 +/- 54 MUg/kg/min) compared to (162 +/- 74 MUg/kg/min) in that required in group I (p = .018). There were no differences between the two groups with regard to quality of the imaging study, recovery time, or incidence of complications. CONCLUSIONS: Compared to intermittent bolus dosing, continuous propofol infusion provides lesser dose exposure without impacting recovery time or quality of the magnetic resonance imaging study. PMID- 21263368 TI - Critically ill children with pandemic influenza (H1N1) in pediatric intensive care units in Turkey. AB - OBJECTIVES: To outline the epidemiologic features, clinical presentation, clinical courses, and outcomes in critically ill children with pandemic influenza in pediatric intensive care units. DESIGN: Retrospective, observational, multicenter study. SETTING: Thirteen tertiary pediatric intensive care units in Turkey. PATIENTS: Eighty-three children with confirmed infection attributable to pandemic influenza detected by reverse-transcriptase polymerase chain reaction assay between November 1 and December 31, 2009 who were admitted to critical care units. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: During a 2-month period, 532 children were hospitalized with pandemic influenza and 83 (15.6%) needed critical care. For the 83 patients requiring critical care, the median age was 42 (range, 2-204) months, with 24 (28.9%) and 48 (57.8%) of patients younger than 2 and 5 yrs, respectively. Twenty (24.1%) patients had no underlying illness, but 63 (75.9%) children had an underlying chronic illness. Indications for admission to the pediatric intensive care unit were respiratory failure in 66 (79.5%), neurologic deterioration in six (7.2%), and gastrointestinal symptoms in five (6.0%) patients. Acute lung injury was diagnosed in 23 (27.7%), acute respiratory distress syndrome was diagnosed in 34 (41%), and 51 (61.4%) patients were mechanically ventilated. Oseltamivir was used in 80 (96%) patients. The mortality rate for children with pandemic influenza 2009 was 30.1% compared to an overall mortality rate of 13.7% (p = .0016) among pediatric intensive care unit patients without pandemic influenza during the study period. Also, the mortality rate was 31.7% in patients with comorbidities and 25.0% in previously healthy children (p = .567). The cause of death was primary pandemic influenza infection in 16 (64%), nosocomial infection in four (16%), and primary disease progression in five (20%) patients. The odds ratio for respiratory failure was 14.7 (95% confidence interval, 1.85-111.11), and odds ratio for mechanical ventilation was 27.7 (95% confidence interval, 0.003-200). CONCLUSIONS: Severe disease and high mortality rates were seen in children with pandemic influenza. Death attributable to pandemic influenza occurred in all age groups of children with or without underlying illness. Multiple organ dysfunction syndrome is associated with increased mortality, and death is frequently secondary to severe lung infection caused by pandemic influenza. PMID- 21263369 TI - Factors associated with pediatric critical care attending follow-up with families after the death of a patient: a national survey with an experimental design. AB - OBJECTIVES: To evaluate components of the family-physician relationship that affect the likelihood of self-reported physician follow-up with bereaved families. DESIGN: Randomized, split-sample, national survey. SUBJECTS: Two hundred four pediatric critical care attending physicians in the United States (54% response rate). MEASUREMENTS AND MAIN RESULTS: Subjects were randomly assigned to respond to differing versions of three clinical vignettes varying in each instance in: 1) the patient's length of stay in the intensive care unit; 2) the depiction of the degree of trust of the family toward medical staff; or 3) the depiction of the family's emotional reactions. Subjects then reported their likelihood of following-up with the family after the patient's death. Physicians were more likely to report they would contact families depicted as having a trusting relationship with staff (p = .01). Variations in depicted length of patient stay (p = .5) and in the nature of the family's emotional reaction (p = .9) were not associated with self-reported likelihood of follow-up (p = .5). The only difference observed regarding the method of contacting families after a death was that participants were more likely to say they would attend the funeral of the patient with a trustful family (p < .01). CONCLUSIONS: Pediatric critical care attending physicians were more likely to report following-up with a bereaved family and attend a funeral in a vignette portraying a trustful relationship between the family and staff. PMID- 21263370 TI - Aortopexy as treatment for tracheo-bronchomalacia in children: an 18-year single center experience. AB - OBJECTIVES: To define the factors influencing the outcome of aortopexy as management of tracheo-bronchomalacia. DESIGN: A retrospective, single-center, observational, cohort study. SETTINGS: Surgical services in a tertiary care hospital. PATIENTS: One hundred five children who underwent an aortopexy for tracheo-bronchomalacia between 1990 and 2008. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Comorbidity (categorized into three groups), surgical approach, and location of malacia were reviewed and analyzed in relation to mortality, need for a second intervention, complications, time to extubation after surgery, intensive care unit stay, and clinical improvement. Median age at surgery was 24 wks (1 wk-541 wks). Two surgical approaches were used: median sternotomy (n = 46) and left anterior parasternal (n = 59). Long-term (>2 yrs) follow-up was available for 73 patients (median = 7.0 yrs [2-18 yrs]); 73% were asymptomatic, 18% had minor symptoms, and 9% needed either ventilation or tracheostomy. The overall mortality rate was 9%, of which one-third was airway-related. Multivariable analysis revealed that major comorbidities were a significant risk factor both for mortality and the need for further procedures (re-do surgery, tracheostomy, internal stents) in contrast to surgical approach and involvement of the bronchus. Intensive care unit stay and days of ventilation after surgery were also significantly higher in patients with major comorbidities. CONCLUSIONS: Aortopexy proved to be an effective treatment for most cases of tracheo bronchomalacia, but major comorbidity was associated with an adverse outcome. Our data suggest that aortopexy should be considered in most cases of severe tracheo bronchomalacia. PMID- 21263371 TI - Prevention of neonatal late-onset sepsis associated with the removal of percutaneously inserted central venous catheters in preterm infants. AB - OBJECTIVES: Indwelling central venous catheters are the most important risk factors for the development of sepsis attributable to coagulase-negative staphylococci among preterm infants admitted to neonatal intensive care units. In addition, removal of a central venous catheter also may cause coagulase-negative staphylococci sepsis, which may be prevented by the short-term administration of an anti-staphylococcal agent during the procedure of removal. The administration of a specific anti-staphylococcal agent (cefazolin) was evaluated for the prevention of central venous catheter removal-associated coagulase-negative staphylococci sepsis. DESIGN: A prospective, open, randomized, controlled intervention study. SETTING: Twenty-eight-bed neonatal intensive care unit at a tertiary care children's hospital. PATIENTS: Eighty-eight preterm infants (gestational age <37 wks) admitted to the neonatal intensive care unit with indwelling percutaneously inserted central venous catheters. INTERVENTION: From April 2007 to January 2010, infants were randomized to receive two doses of cefazolin during removal of the percutaneously inserted central venous catheter (intervention group, n = 44) or no antimicrobial agent (control group, n = 44). Percutaneously inserted central venous catheter removal-associated sepsis was defined as sepsis occurring <48 hrs after removal of the percutaneously inserted central venous catheter. MEASUREMENTS AND MAIN RESULTS: Clinical characteristics and central venous catheter duration did not show differences between both groups. Five infants (11%) of the control group developed coagulase-negative staphylococci sepsis <48 hrs after removal of the percutaneously inserted central venous catheter compared to none (0%) in the intervention group (p = .021). CONCLUSIONS: Two doses of the anti-staphylococcal agent cefazolin during the procedure of removal of a percutaneously inserted central venous catheter were effective in the prevention of coagulase-negative staphylococci sepsis. It is recommended to include this regimen in the guidelines on management of central venous catheters in very-low-birth-weight infants. PMID- 21263372 TI - Hemodynamic monitoring by transpulmonary thermodilution and pulse contour analysis in critically ill children. AB - OBJECTIVES: To summarize the physiologic principles underlying the hemodynamic monitoring using the PiCCO device (Pulsion, Munich, Germany) incorporating the transpulmonary thermodilution technique, the pulse contour cardiac output, and estimation of the arterial pressure variation method. Analysis and review of the current literature. DESIGN: A MEDLINE-based literature search using the key words transpulmonary thermodilution, pulse contour analysis, cardiac output, animal models, and child. MEASUREMENTS AND MAIN RESULTS: The bias and precision of cardiac output measured by transpulmonary thermodilution are reliable. The reproducibility for repeated measurements is approximately 5% and the percentage error is approximately 15%. Transpulmonary thermodilution may adequately track changes in cardiac output in animals submitted to hypovolemic conditions and during volume loading. Conversely, data from experimental and clinical studies suggest that continuous monitoring of cardiac output using pulse contour analysis requires careful interpretation because periodic recalibration with transpulmonary thermodilution is necessary. Transpulmonary thermodilution-derived static indicator of cardiac preload (global end-diastolic volume, intrathoracic blood volume) may be more sensitive than conventional measurements of vascular filling pressure. However, the value of stroke volume variation or pulse pressure variation have not been evaluated in pediatric patients. Further studies are needed to determine whether theoretical assumptions underlying the measurement of extravascular lung water are valid in children. CONCLUSIONS: The PiCCO device may be a useful adjunct for hemodynamic monitoring in critically ill children. Further studies are needed to clarify the reliability and clinical value of pulse contour method and extravascular lung water measurement. PMID- 21263373 TI - Molecular distinctions exist between community-associated methicillin-resistant Staphylococcus aureus colonization and disease-associated isolates in children. AB - OBJECTIVE: To define the molecular epidemiology of colonization and disease associated isolates of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). DESIGN: Laboratory-based comparative study of clinical staphylococcal isolates. METHODS: We analyzed 255 pediatric CA-MRSA isolates for molecular characteristics associated with colonization and disease. We used polymerase chain reaction to determine the presence of Panton-Valentine Leukocidin and the lantibiotic element, bsaB, and to characterize the staphylococcal cassette chromosome mec type and accessory gene regulator locus. Pulsed-field gel electrophoresis was used to determine genetic relatedness between strains. RESULTS: A total of 150 isolates were obtained from patients with clinical disease (37 invasive infections, 113 noninvasive infections) and 105 from subjects with nasal colonization alone. Of 150 disease-associated isolates, 123 (82%) belonged to pulsed-field gel electrophoresis group USA300, whereas only 19 (18%) of 105 colonization isolates were of the USA300 lineage. Colonization isolates were less likely to possess staphylococcal cassette chromosome mec type IV, Panton-Valentine Leukocidin, or agr type 1 (P < 0.001). CONCLUSIONS: Colonization strains of CA-MRSA in children differ significantly from those strains recovered from patients with staphylococcal infections. This suggests that only colonization with specific strain types, rather than methicillin-resistant Staphylococcus aureus colonization in general, increases the risk for CA-MRSA disease. PMID- 21263374 TI - Influence of insulin-like growth factor I and nutrition during phases of postnatal growth in very preterm infants. AB - Pronounced growth restriction (GR) occurs after very preterm birth. The interaction between IGF-I, nutritional intake, and growth was evaluated prospectively in 64 infants with a mean (SD) GA of 25.7 (1.9) wk. Blood sampling of IGF-I and measurements of weight, length, and head circumference were performed weekly until discharge. Daily calculation of nutritional intake was performed. Standard deviation scores (SDSs) for growth parameters defined two growth phases: GR phase (birth until lowest SDS) and catch-up (CU) phase (lowest SDS until 35 gestational weeks). IGF-I concentrations during the first postnatal weeks were low and increased at 30 wk GA, irrespective of GA at birth, coinciding with initiation of CU growth. Concentrations of IGF-I were positively associated with change in weight SDS during the GR phase, p = 0.001 and CU phase, p = 0.004 0.027. Protein and energy intake were not associated with change in SDS weight during the GR phase as opposed to the CU phase (p < 0.001, respectively). Nutritional intake did not correlate to concentrations of IGF-I before 30 wk GA. IGF-I is associated with growth at an earlier postnatal age than nutrient intake and the effect of nutrition on levels of IGF-I may be restricted to the period of established CU growth. PMID- 21263375 TI - Mother's milk-induced Hsp70 expression preserves intestinal epithelial barrier function in an immature rat pup model. AB - Preterm infants face many challenges in transitioning from the in utero to extrauterine environment while still immature. Failure of the preterm gut to successfully mature to accommodate bacteria and food substrate leads to significant morbidity such as neonatal necrotizing enterocolitis. The intestinal epithelial barrier plays a critical role in gut protection. Heat shock protein 70 (Hsp70) is an inducible cytoprotective molecule shown to protect the intestinal epithelium in adult models. To investigate the hypothesis that Hsp70 may be important for early protection of the immature intestine, Hsp70 expression was evaluated in intestine of immature rat pups. Data demonstrate that Hsp70 is induced by exposure to mother's milk. Hsp70 is found in mother's milk, and increased Hsp70 transcription is induced by mother's milk. This Hsp70 colocalizes with the tight junction protein ZO-1. Mother's milk-induced Hsp70 may contribute to maintenance of barrier function in the face of oxidant stress. Further understanding of the means by which mother's milk increases Hsp70 in the ileum will allow potential means of strengthening the intestinal barrier in at-risk preterm infants. PMID- 21263376 TI - Spironolactone and enalapril differentially up-regulate the expression of VEGF and heme oxygenase-1 in the neonatal rat kidney. AB - Both the renin-angiotensin-aldosterone system (RAAS) and hypoxia are vital physiological factors involved in the control of nephrogenesis and vascularization. We investigated the relationship between RAAS and hypoxia in the developing kidney. The expression of VEGF and heme oxygenase (HO)-1 related with the oxygen was analyzed in the enalapril- or spironolactone-treated neonatal rat kidneys. Enalapril (30 mg/kg/d) or spironolactone (200 mg/kg/d) was administered to newborn rat pups for 7 d. The newborn rats were injected i.p. with pimonidazole (200 mg/kg), a marker of severe tissue hypoxia, 1 h before killing. VEGF and HO-1 protein expression was significantly increased by immunoblots and immunohistochemistry in both the enalapril- and spironolactone-treated kidneys, compared with the controls (p < 0.05). HO-1 mRNA expression was increased in the spironolactone-treated group (p < 0.05). The immunoactivity of pimonidazole was not different from that of the controls in the enalapril-treated group, whereas it was increased in the spironolactone-treated group. The results of this study indicate that aldosterone blockade or angiotensin II inhibition in the developing rat kidney up-regulated renal VEGF and HO-1 expression regardless of the hypoxic conditions and may differentially modulate VEGF and HO-1 production. PMID- 21263377 TI - Beneficial effects of concomitant neuronal and inducible nitric oxide synthase inhibition in ovine burn and inhalation injury. AB - Different isoforms of nitric oxide (NO) synthase are critically involved in the development of pulmonary failure secondary to acute lung injury. Here we tested the hypothesis that simultaneous blockade of inducible and neuronal NO synthase effectively prevents the pulmonary lesions in an ovine model of acute respiratory distress syndrome induced by combined burn and smoke inhalation injury. Chronically instrumented sheep were allocated to a sham-injured group (n = 6), an injured and untreated group (n = 6), or an injured group treated with simultaneous infusion of selective inducible and neuronal NO synthase inhibitors (n = 5). The injury was induced by 48 breaths of cotton smoke and a third-degree burn of 40% total body surface area. All sheep were mechanically ventilated and fluid resuscitated. The injury induced severe pulmonary dysfunction as indicated by decreases in PaO2/FiO2 ratio and increases in pulmonary shunt fraction, ventilatory pressures, lung lymph flow, and lung wet/dry weight ratio. The treatment fully prevented the elevations in lymph and plasma nitrate/nitrite levels, pulmonary shunting, ventilatory pressures, lung lymph flow, and wet/dry weight ratio and significantly attenuated the decline in PaO2/FiO2 ratio. In conclusion, simultaneous blockade of inducible and neuronal NO synthase exerts beneficial pulmonary effects in an ovine model of acute respiratory distress syndrome secondary to combined burn and smoke inhalation injury. This novel treatment strategy may represent a useful therapeutic adjunct for patients with these injuries. PMID- 21263379 TI - Genetic predisposition for development of complications in multiple trauma patients. AB - The care of multiple trauma patients has been improved through advances made in preclinical treatment, surgical procedures, and intensive care medicine. However, posttraumatic complications such as systemic inflammatory response syndrome, multiple organ dysfunction syndrome, and sepsis remain a major problem following multiple trauma. Components of the innate immune system and other inflammatory mediators (e.g., procalcitonin) play a pivotal role in the pathophysiology of posttraumatic complications. Studies investigating the genetic predisposition for complications after multiple trauma have provided evidence for a genetic heterogeneity in the posttraumatic immune response. The differences in response to multiple trauma associated with single-nucleotide polymorphisms may contribute to the development of new genetically tailored diagnostic and therapeutic interventions improving outcome in this patient population. In addition, detrimental adverse effects of adjuvant therapy could be avoided in other patients who, by genotype, are predicted not to benefit. PMID- 21263378 TI - Effects of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. AB - Excessive free-radical production due to various bacterial components released during bacterial infection has been linked to cell death and tissue injury. Peroxynitrite is a highly reactive oxidant produced by the combination of nitric oxide (NO) and superoxide anion, which has been implicated in cell death and tissue injury in various forms of critical illness. Pharmacological decomposition of peroxynitrite may represent a potential therapeutic approach in diseases associated with the overproduction of NO and superoxide. In the present study, we tested the effect of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. Mice were injected i.p. with LPS 40 mg/kg with or without FP15 [Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl porphyrin] (0.1, 0.3, 1, 3, or 10 mg/kg per hour). Mice were killed 12 h later, followed by the harvesting of samples from the lung, liver, and gut for malondialdehyde and myeloperoxidase measurements. In other subsets of animals, blood samples were obtained by cardiac puncture at 1.5, 4, and 8 h after LPS administration for cytokine (TNF-alpha, IL-1beta, and IL-10), nitrite/nitrate, alanine aminotransferase, and blood urea nitrogen measurements. Endotoxemic animals showed an increase in survival from 25% to 80% at the FP15 doses of 0.3 and 1 mg/kg per hour. The same dose of FP15 had no effect on plasma levels of nitrite/nitrate. There was a reduction in liver and lung malondialdehyde in the endotoxemic animals pretreated with FP15, as well as in hepatic myeloperoxidase and biochemical markers of liver and kidney damage (alanine aminotransferase and blood urea nitrogen). In a bacterial model of sepsis induced by cecal ligation and puncture, FP15 treatment (0.3 mg/kg per day) significantly protected against mortality. The current data support the view that peroxynitrite is a critical factor mediating liver, gut, and lung injury in endotoxemia and septic shock: its pharmacological neutralization may be of therapeutic benefit. PMID- 21263380 TI - Shen-fu injection attenuates postresuscitation myocardial dysfunction in a porcine model of cardiac arrest. AB - To investigate the effect of Shen-Fu injection (SFI) for the management of postresuscitation myocardial dysfunction in a porcine model of cardiac arrest. Ventricular fibrillation was induced electrically in anesthetized domestic swine. After 4 min of untreated ventricular fibrillation, cardiopulmonary resuscitation was initiated. Sixteen successfully resuscitated pigs were randomized to receive a continuous infusion of either SFI (0.24 mg/min) or saline placebo for 6 h, beginning 15 min after return of spontaneous circulation (ROSC). The SFI treatment produced better left ventricular +dP/dtmax, -dP/dtmax, cardiac output, and ejection fraction after ROSC. The SFI treatment also produced lower serum cardiac troponin I, lactate levels, and left ventricle malondialdehyde content after ROSC, whereas left ventricle superoxide dismutase, Na-K-ATPase, and Ca ATPase activity were significantly increased in the SFI group when compared with saline group. The cardioprotective effect of SFI was further confirmed by myocardial ultrastructure examination. Shen-Fu injection can attenuate postresuscitation myocardial dysfunction through beneficial effects on energy metabolism and remarkable antioxidant capacity. PMID- 21263381 TI - Roles of mitogen-activated protein kinases in the modulation of endothelial cell function following thermal injury. AB - Several mitogen-activated protein kinases (MAPKs) are activated during thermal injury, and the p38 MAPK is specifically involved in endothelial cell (EC) actin and myosin rearrangement (stress-fiber formation) with ensuing cellular contraction and enhanced vessel permeability. Inhibition of p38 MAPK and extracellular signal-related kinase MAPK by their inhibitors SB203580 and PD98059, respectively, significantly reduces burn serum-induced EC stress-fiber formation, whereas SB203580 also inhibits burn serum-induced EC tight-junction damage and thereby general blood vessel hyperpermeability. The JNK MAPK inhibitor, SP600125, on the contrary, influences neither stress-fiber formation nor EC tight-junction damage. Extracellular signal-related kinase MAPK inhibition significantly decreases burn serum-induced Monocyte chemotactic protein-1 (MCP-1) release, whereas SB203580 and SP600125 have only limited such effects. Western blotting, real-time reverse transcriptase-polymerase chain reaction, and confocal laser scanning microscopy proved that SP600125 significantly inhibits burn serum induced intercellular adhesion molecule 1 expression, whereas SB203580 depresses the expression of P selectin. In vivo studies, using the dominant negative adenoviral approach of MAPK kinase 3b and MAPK kinase 6b to block p38 MAPKs, and MKK4 and MKK7 to block JNK MAPKs, show that the latter MAPKs are involved in the regulation of P selectin and intercellular adhesion molecule 1 expression, respectively, following thermal injury. Taken together, the results suggest that several MAPKs play important, although different, roles in general EC alterations following burn injuries. PMID- 21263382 TI - IL-6 and TGF-alpha costimulate mesenchymal stem cell vascular endothelial growth factor production by ERK-, JNK-, and PI3K-mediated mechanisms. AB - Mesenchymal stem cells (MSCs) protect ischemic tissues in part through paracrine growth factor production. IL-6, which is upregulated in the heart during ischemia, has been shown to enhance stem cell proliferation and migration. The effect of IL-6 on MSC paracrine function, however, remains unknown. In addition, TGF-alpha increases MSC vascular endothelial growth factor (VEGF) production and may share downstream signaling pathways with IL-6 involving ERK, JNK, and PI3K. We hypothesize that cotreatment with IL-6 and TGF-alpha will result in greater MSC VEGF production than by either treatment alone via these signaling pathways. Murine MSCs were treated with IL-6 (0.05 ng/mL) with or without TGF-alpha (250 ng/mL) and in combination with inhibitors of ERKI/II, JNK, and PI3K for 24 h. Vascular endothelial growth factor concentrations in the supernatants were measured using enzyme-linked immunosorbent assay. Phosphorylation of ERK, JNK, and PI3K was measured using Western blot analysis. IL-6 increased MSC VEGF production at a dose of 0.05 ng/mL, and the combination of IL-6 and TGF-alpha (250 ng/mL) increased VEGF production to a greater extent than IL-6 or TGF-alpha alone. IL-6 induced phosphorylation of ERK, JNK, and PI3K, and inhibition of each suppressed IL-6-induced VEGF production. TGF-alpha cotreatment overcame VEGF suppression after ERK2 inhibition but not ERK1, JNK, or PI3K. These data suggest that IL-6 stimulates MSC VEGF production alone and additively with TGF-alpha via ERK-, JNK-, and PI3K-mediated mechanisms. IL-6 and TGF-alpha cotreatment may be a useful strategy for enhancing MSC VEGF production and cardioprotection during myocardial ischemia. PMID- 21263383 TI - Suppression of autophagy in rat liver at late stage of polymicrobial sepsis. AB - Sepsis develops as a result of the host response to infection, and its mortality rate in ICU remains high. Severe inflammation usually causes overproductions of proinflammatory cytokines, i.e., TNF-alpha and reactive oxygen species, which lead to mitochondrial damage and energetic depletion. Autophagy is a survival mechanism for eukaryote to recycle intracellular nutrients and maintain energy homeostasis. We hypothesize that autophagy plays a beneficial role in the pathogenesis of organ failure during sepsis. A rat model of cecal ligation and puncture (CLP) that simulate peritonitis-induced sepsis was used, and indicators for liver dysfunction, serum glutamic oxaloacetic, serum glutamic pyruvic, alkaline phosphatase, and bilirubin were measured. Levels of LC3-II and LC3 aggregation were quantified by Western blot analysis and by immunohistochemistry, respectively. The tissue localization of autophagy was identified by immunohistochemistry and transmission electron microscopy. Our results showed that (a) increase in LC3-II level in liver tissue occurs at 3 h, peaks at 6 h, and then surprisingly declines quickly until 18 h after CLP (CLP18h); (b) significant hepatic dysfunction was observed at CLP18h; (c) ratio of LC3 aggregation is significantly higher in hepatocytes than in Kupffer cells, and (d) loss of Atg7, an essential gene for autophagosome formation, exaggerates the TNF alpha-induced cell death, depletion of ATP, and decrease of albumin production in hepatocytes. These results indicate that autophagy occurs transiently in hepatocytes at early stage, and the decline in autophagy at late stage may contribute to the functional failure in liver during polymicrobial sepsis. PMID- 21263384 TI - C-peptide ameliorates kidney injury following hemorrhagic shock. AB - Reperfusion injury following hemorrhagic shock is accompanied by the development of a systemic inflammatory state that may lead to organ failure. Insulin connecting peptide (C-peptide) has been shown to exert anti-inflammatory effects in sepsis and myocardial ischemia-reperfusion injury and to ameliorate renal dysfunction in diabetic animals. Hence, we investigated the effect of C-peptide on kidney injury after hemorrhagic shock. We hypothesized that C-peptide would exert renoprotective effects by blunting inflammation. Hemorrhagic shock was induced in male rats (3-4 months old) by withdrawing blood from the femoral artery to a mean arterial pressure of 50 mmHg. Animals were kept in shock for 3 h, at which time they were rapidly resuscitated by returning their shed blood. At the time of resuscitation and every hour thereafter, one group of animals received C-peptide (280 nmol/kg), whereas another group received vehicle. Hemorrhagic shock resulted in significant rise in plasma levels of creatinine and elevated kidney neutrophil infiltration as evaluated by myeloperoxidase activity in vehicle-treated rats in comparison with sham rats, thus suggesting kidney injury. Treatment with C-peptide significantly attenuated the rise in creatinine and kidney myeloperoxidase activity when compared with vehicle group. At a molecular level, these effects of C-peptide were associated with reduced expression of the c-Fos subunit and reduced activation of the proinflammatory kinases, extracellular signal-regulated kinase 1/2 (ERK 1/2), and c-Jun N terminal kinase and subsequently reduced DNA binding of activator protein 1 in the kidney. Thus, our data suggest that C-peptide may exert renoprotective effects after hemorrhagic shock by modulating activator protein 1 signaling. PMID- 21263385 TI - A monoclonal antibody against RAGE alters gene expression and is protective in experimental models of sepsis and pneumococcal pneumonia. AB - The RAGE (receptor for advanced glycation end products) is believed to play a role in sepsis by perpetuating inflammation. The interaction of RAGE with a variety of host-derived ligands that accumulate during stress and inflammation further induces the expression of RAGE. It was previously shown that a rat anti RAGE monoclonal antibody protected mice from lethality in a cecal ligation and puncture model. We studied the effects of a humanized anti-RAGE monoclonal antibody in the murine pneumococcal pneumonia model of sepsis. Moreover, a gene expression analysis was performed in lung tissue of animals that underwent cecal ligation and puncture and treated with the rat anti-RAGE monoclonal antibody, compared with controls. Administration of humanized anti-RAGE mAb 6 h after intratracheal infection with Streptococcus pneumoniae improved mortality in BALB/c mice whether a 7.5 mg/kg (P < 0.01) or a 15 mg/kg dose (P < 0.01) was administered in combination with antibiotics. Gene expression analysis showed that many of the genes modulated by treatment with the anti-RAGE antibody were those that play an important role in regulating inflammation. Anti-RAGE monoclonal antibody offered a survival advantage to septic mice. This protective role in treated animals is supported by the observed gene expression profile changes of genes involved in sepsis and inflammation. PMID- 21263387 TI - [Fetal echocardiography in the 15th week of gestation]. AB - A fast development of the ultrasound technology has enabled a very high resolution of images thus opening a possibility for better quality of images of all fetal structures including fetal heart. Transabdominal ultrasound examination of heart is commonly conducted after the 10th week when it is possible to get a quality image of all relevant heart structures using 3-5MHz probes. Having in mind that fetal heart is mostly formed by the end of the 14th week, an idea of a vaginal ultrasound examination in the 15th week using 5-9MHz probes has been a logical one. In that period the length of the fetus ranges from 9 to 10 centimeters, which is a basis for an assumption that a quality examination of the fatal heart may be conducted using the vaginal probe. This paper is showing all standard cross-sections of fetal heart (4 chambers, outflow tracts, cross-section of three great vessels and longitudinal view of aortic and ductal arches) obtained by vaginal examination in the 15th week and abdominal examination in the 20th and 22nd week. The transvaginal examination of fetal heart is possible in the 15th week and it is recommended to be done in all pregnant women with problematic personal and reproductive anamnesis and those with positive ultrasonographic markers for chromosomal defects. PMID- 21263386 TI - The dual functions of receptor interacting protein 1 in fas-induced hepatocyte death during sepsis. AB - In examining the liver's response to sepsis, our laboratory has found that septic hepatocytes exhibit a higher degree of necrosis when compared with septic thymocytes, which typically die through the canonical apoptotic pathway. Recently, an adaptor protein associated with the Fas/TNF death receptor pathway, receptor interacting protein 1 (RIP1), has been shown to be critical for determining whether a cell's death is apoptotic or necrotic. We propose to test the central hypothesis that RIP1 activation by death receptor (Fas) during sepsis determines whether the hepatocytes' fate is apoptotic versus necrotic. We approached this problem by delivering RIP1 siRNA in vivo to C57BL/6 mice and observing changes in mortality after septic challenge. Contrary to our hypothesis, RIP1-silenced mice did not survive as long as scrambled sequence injected controls (22.2% vs. 50.0% 14 days after cecal ligation and puncture, respectively). When we used a pharmacological/synthetic antagonist of RIP1 kinase, necrostatin 1 (Nec1), and examined the mortality of Nec1-treated mice, there was no difference from the RIP1 siRNA-treated mice (20.0% vs. 22.2%, respectively). Furthermore, we carried out a series of comparative histological studies, which indicated that septic mice pretreated with Nec1 exhibited a preservation of liver glycogen stores (represented by periodic acid Schiff stain) versus siRNA-treated mice, which exhibit lower glycogen stores as well as altered morphology. Furthermore, the histological studies also revealed that Nec1 treatment in septic mice increases caspase 3 activity. We speculate that these contradictatory findings are due to the dual-signaling responsibilities of RIP1, where the RIP1 kinase domain can induce death through Fas ligation while also initiating prosurvival signaling through nuclear factor kappaB (NF-kappaB). PMID- 21263388 TI - Better stability of acenocoumarol compared to warfarin treatment in one-year observational, clinical study in patients with nonvalvular atrial fibrillation. AB - AIM: To evaluate differences in the treatment quality between often used oral anticoagulants, warfarin and acenocoumarol in patients with nonvalvular atrial fibrillation (NVAF). METHODS: This was an observational, comparative, one-year clinical study, conducted in the Blood Transfusion Institute of Sarajevo, Bosnia & Herzegovina. All patients who were using warfarin/ acenocoumarol and monitored were eligible. Patients who met inclusion criteria (the age of 40-80, diagnosed NVAF, CHADS index score > or = 2, the planned long-term treatment) were includes in two parallel groups of 60 patients, composed according to the warfarin/acenocoumarol treatment as well as the gender and age. Routinely measured International normalised ratio (INR) values were the basic parameter for individual quality and stability assessment. RESULTS: All average, monthly INR values were in therapeutic range (2.0-3.0) in both therapeutic groups. There were no significant differences either in the number of therapeutic INR values per patient (50.53 +/- 23.72% vs. 51.74 +/- 26.68%, P = 0.795) or in individual quality of treatment: > 50% therapeutic INR values (60.0% vs. 64.9%, P = 0.721) and > 75% therapeutic INR values (18.3% vs. 22.8%, P = 0.714) in the warfarin and acenocoumarol group, respectively. Significantly better stability was determined for acenocoumarol as compared with warfarin treatment in terms of a longer period of the total observed time during which therapeutic INR values were stable (37.6% vs. 35.7%, P = 0.0002). CONCLUSION: Both drugs have shown similar quality of individual anticoagulation control, but acenocoumarol have shown significantly better anticoagulation stability with therapeutic INR values covering significantly longer time of treatment. PMID- 21263389 TI - Elastic characteristics of aorta in patients with epilepsy. AB - AIM: To investigate elastic characteristics of the aorta in patients with epilepsy. METHODS: Seventy five patients with a diagnosis of epilepsy through clinical and EEG findings and age and sex matched, 50 healthy controls were included. Systolic and diastolic blood pressures plus systolic and diastolic diameter of the aortic root was measured. Aortic strain (AS) and aortic distensibility (AD) and aortic distensibility index (BSI) were calculated. RESULTS: The average age of the epilepsy group was 23.8.8 +/- 8.2 years, and of the control group it was 24.1 +/- 6.2 years (p > 0.05). AS and AD were lower in the epileptic group while the aortic stiffness index was higher (10.4 +/- 4.2 vs 16.9 +/- 0.2, p: 0.001, for AS; 8.7 +/- 4.0 vs 17.2 +/- 0.1, p: 0.001, for AD and 20.1 +/- 0.1 vs 3.5 +/- 1.2, p: 0.001 for BSI). CONCLUSION: Elastic characteristics of the aorta change in epileptic patients, with a decrease of the distensibility of the aorta and an increase of the stiffness. After this preliminary study, new controlled studies are needed. PMID- 21263390 TI - Predictive value of fetal nuchal translucency. AB - AIM: To determine the predictive value of fetal nuchal translucency (NT) measurements in the detection of chromosomopathy. METHODS: The investigation of NT included 317 pregnant women with singleton pregnancies of gestational age of 11 to 14 weeks with pathological karyotype. The control group consisted of pregnant women whose amniocentesis findings indicated a normal fetal karyotype. RESULTS: The median value of NT in the control group was 1.92 +/- 0.39 mm, and in the group with pathological fetus karyotype findings it was 2.49 +/- 0.37 mm (p < 0.05). The median value of crown-rump length was 64.83 +/- 8.23 mm and 60.12 +/- 8.48 mm in the control group and in the group with pathological karyotype, respectively. The gestational age in the control group was 87.10 +/- 87.10 days, while in the pathological group it was 85.69 +/- 3.98 days, which indicated the homogeneity of the investigated sample (p > 0.05). The probability for a patient with negative NT findings to be healthy was 1.0, NT sensitivity as a marker for chromosomopathy was 1.0. The rate of false positive findings was 0.026. The specificity of NT as a marker for chromosomopathy was 0.97. CONCLUSION: Normal NT findings could be considered reliable ultrasonographic markers in the assessment of the absence of chromosomopathy. Pathological findings, given the low positive predictive value of NT must be interpreted in the context of other prenatal tests before the pregnant woman is advised to undergo invasive prenatal diagnosis. PMID- 21263391 TI - [Influence of biometeorological phases on incidence of suicides]. AB - AIM: To establish an influence of biometeorological phases on suicide incidence according to age, gender, settlement, week days, months in a year, ways of suicide execution, influence of biometeorologic phases on suicide execution. METHODS: Comparative analysis of the data about suicides (by years, months, week days, settlements, age, gender) obtained by the Police Department in Kragujevac for the 2004-2008 period and everyday biometeorological phases (phase 1 CWD: cyclone, warm, dry; phase 2 CWW: cyclone, warm, wet; phase 3 CWF: cyclone, warm front; phase 4 CCF: cyclone cold front; phase 5 CCW: cyclone, cold, wet; phase 6 CCD: cyclone, cold, dry; phase 7 ACD: anticyclone, cold, dry; phase 8 ACW: anticyclone, cold, wet; phase 9 AWD: anticyclone, warm, dry; phase 10 AWW: anticyclone, warm, wet) in Kragujevac determinated by the Republic Hydrometeorology Institute of Serbia. RESULTS: In the observed period there were 144 suicides resulting in the incidence rate of 14/100 000/ year. The highest number of suicides was noted in 2005 (36), and lowest one in 2007 (24). The most suicide cases happened in January and June (18 in each), and the fewest in August (7). Three quarters occurred in urban areas. Three quarters of victims were males mostly in the age groups 41-45 and 51-55 (11 in each). Females made one quarter of victims and most of them were in the age group 61-65 years (7). Total mean age was 54,66 years. Two thirds of all suicides were executed by hanging (93) (two thirds were among males), one sixth by firearms, with nine tenths ofmen. The most incidents with significant correlation were in biometheorological phases 4 and 9 (stable sunny weather and sudden impact of weather fronts, with sudden weather changes) (38 in each), which makes over a half of all suicides. CONCLUSION: According to the results of this study, it is strongly recommended to monitor everyday biometeorological forecast, and special attention must be paid to all persons with suicide tendencies. PMID- 21263392 TI - Colorectal cancer early detection program integrated in practice of family physicians. AB - AIM: To present preliminary results of the colorectal cancer early detection program, a part of the project called "A Model of Early Cancer Detection Integrated in a Practice of a Family Physician", carried out by the Department of Family Medicine of the Osijek University School of Medicine and the Health Centre of Osijek, Croatia. METHODS: The strategy of the project, based on the central role of a family physician in the implementation of the early cancer detection programs, was described and preliminary results of the colorectal cancer early detection program are presented and compared with the same issues of the National Program, centrally conducted and supplied by public services. RESULTS: From the beginning of April unil the end of May 2009, a total number of 516 testing cards on occult faecal blood were delivered to patients from two target groups (aged 45 50 and 75-79). A high responding rate of 69.76% (360) was recorded. This is an advantage in comparison with the low responding rates of about 20% (43 862), obtained by the National Program. In the project, there were in average 2.5% (9) positive tests, with the higher percent in the older than in the younger age group, 3.5% (12) and 1% (4) respectively). CONCLUSION: Data obtained by the Project, and by the National Program--indicate that there could be a need for a more precise definition of risk groups who have to be invited for screening. PMID- 21263393 TI - Physicians overestimate patient's knowledge of the process of informed consent: a cross-sectional study. AB - AIM: To evaluate the differences in the knowledge and attitudes of physicians and patients regarding the informed consent process. METHODS: After institutional approval was obtained cohorts of 269 physicians and 265 patients completed a voluntary multiple-choice questionnaire on the informed consent process. RESULTS: Most of the responses between physicians and patients were significantly different. A total of 77 physicians (30.7%) reported that they personally informed patients about their medical condition and forthcoming clinical procedures in detail and 138 (55%) informed patients as much as necessary. Only 29 patients (11%) reported being informed in detail, and 186 (70.2%) reported that they received only basic information (P < 0.001). Although 132 physicians (52.6%) reported that their patients received sufficient information to be able to decide on their treatment, only 31 patient (11.7%) reported the same (P < 0.001). Half of the doctors (126, 50.2%) reported that they informed their patients in detail on the possible consequences of treatment refusal whereas 23 patients (8.7%) were given such information. CONCLUSION: There is a great discrepancy between physicians and patients concerning both understanding and knowledge of the informed consent process. The physicians have evaluated their practice of giving information and obtaining informed consent to be more detailed than their patients. The results of this study reflect the need for better communication between doctors and patients as well as physician and patient education programs on the process of informed consent. PMID- 21263394 TI - [Antibacterial effect of the materials for the root canal filling, bases and material for the cavity fillings]. AB - AIM: To assess antimicrobial effects of the materials used in the endodontic treatment of the teeth. METHODS: The following root-canal fillings were examined: Ketac Endo, AH Plus, Diaket, and gutta-percha, by means of the agar diffusion test. As for the base materials, Zink Oxide/Eugenol cement, glass-ionomere cements Fuji II LC Improved, Ketac Cem, and phosphate cement and Harvard cement were investigated. Finally, of the materials for final cavity filling, amalgam, Ketac Molar and Fuji II LC Improved were tested. In the present research, the following bacteria were applied: Streptococcus mutans, Streptotoccus mitis, Lactobacillus species, Staphylococcus aureus, Enterococcusfaecalis, and polymicrobial suspention. For each individual bacterium tested, material samples were placed on the inoculated plates of blood-agar. RESULTS: Antibacterial effects were confirmed in the following materials: root-canal fillings--Diaket, AH Plus, Ketac Endo; bases--Zink Oxide/Eugenol cement, phosphat cement and Harvard cement. No antibacterial effect was established in: amalgam, gutta percha, Fuji II LC Improved, Ketac Cem and Ketac Molar. Diaket showed a statistically more significant antibacterial effect in comparison with AH Plus, Ketac Endo, and gutta-percha (P(s.mitis) < 0.05; P(s.mutans) < 0.05; p(lactobacillus) < 0.05; p(enterococcus) < 0.05; P(staphilococcus) < 0.05; p(polymicrobial) < 0.05); of the base materials, however, a somewhat stronger antimicrobial effect was found in phosphate cement, Harvard cement, and Zink Oxide/Eugenol (ZnOE) (p < 0.05) as compared with Fuji II LC Improved and Ketac Cem. CONCLUSION: According to the results of this study, and considering the fact that all cavity-filling materials failed to show any antimicrobial effect at all, when choosing the materials for root-canal fillings, and for bases, advantage should be given to those with the manifested strongest antibacterial effect, namely Diaket and phosphate cement. PMID- 21263395 TI - [Influence of lasting diabetes and non-adjustable glycosylated haemoglobin on occurrence of retinopathy]. AB - The aim of this study was to investigate the effect of the duration of diabetes and glycemia on the development of diabetic retinopathy in diabetes types 1 and 2 and the prevalence of retinopathy by sex. It examined 278 diabetics in 1999 and 2004, a questionnaire was used to collect data and results of fasting glucose, HbA1c, glycosuria and ketonurie were recorded. Retinopathy was noted in 80 (28.78%) and 187 (67.27%) patients during 1999 and 2004, respectively (p < 0.001). The number of patients with the nonproliferative and preproliferative (p < 0.001) as well as with proliferative retinopathy (p < 0.01) was significantly higher in 2004 in the comparision with 1999. The average HbA1c in 1999 was 13.02%, whereas in 2004 it was 10.57%. Poor control of diabetes was present during both investigations. PMID- 21263396 TI - [Epidemiology of multiple sclerosis in Bosnia and Herzegovina]. AB - In order to examine precipitating factors for occurrence of multiple sclerosis or inception of a relapse in patients suffering from multiple sclerosis a specially designed questionnaire was used, including history records of patients with multiple sclerosis treated at the Clinic of Neurology of the Clinical Center of Sarajevo in the period between January1st and December 31st 2006. The number of patients with MS was 71 (48 women and 23 men). An infection as a precipitating factor was noted in 21 (29.57%) cases, stress was noted in 12 patients (16.9%) whereas 43 patients (60,12%) had the RR type of the disease. Nine patients were treated with interferon therapy (12.67%) and 47 patients (66.1%) with high doses of metilpredinisolone . Depression disorder was noted in 23 (32.9%) patients whereas 7 patients had cognitive dysfunction (9.86%). Results of this study, which have shown epidemiological characteristics of multiple sclerosis for the first time in Bosnia and Herzegovina, indicate that there is a need to create a unified register of patients and to request compliance with therapeutic guidelines. PMID- 21263397 TI - Anxiety, splint treatment and clinical characteristics of patients with osteoarthritis of temporomandibular joint and dental students--a pilot study. AB - The aim of this study was to evaluate the use of splint treatment for therapy of osteoarthritis of temporomandibular joint, and to compare the level of anxiety (State-Trait Anxiety Inventory, STAI) and clinical characteristics between 16 patients and 20 asymptomatic dental school students. Magnetic resonance imaging (MRI) was used for all subjects. Dental students showed a statistically significant higher capacity of mouth opening (p < 0.05), and lower level of anxiety (p < 0.05 for STAI 1, and p < 0.001 for STAI 2) than patients. Patients who had suffered chronic pain before splint treatment had a higher value of anxiety by STAI 1 test (p < 0.05). PMID- 21263398 TI - [Chronic epidural haematoma mimicking meningioma]. AB - The study presents a rare case of organised chronic epidural haematoma that imitated a meningioma. A patient was admitted to the Department of Neurology of the Cantonal Hospital Zenica due to loss of consciousness and right hemiparesis. Non-contrast Computed Tomography (CT) scan had shown an expansive intracranial process in the left parietal region which was radiologically diagnosed as a meningioma. During the operation a linear skull fracture and organised chronic epidural haematoma were found. PMID- 21263399 TI - Placenta previa percreta with bladder invasion. AB - A 43- year old woman, with ten previous deliveries and history of two cesarean sections was admitted to our Department at 32 weeks of gestation with massive vaginal hemorrhage from an ultrasound diagnosed placenta previa. An emergency cesarean section with vertical abdominal incision was performed. A healthy 2300 g female infant was delivered. Attempts to manually remove the placenta caused massive hemorrhage. The lower uterine segment was widened due to placenta previa with suspicious placental invasion of the posterior wall of the bladder. Persistent hemorrhage demanded bilateral anterior internal iliac artery ligation and suture ligation of the bleeding vessels with supracervical hysterectomy done. PMID- 21263400 TI - [Endometrial cancer associated with an increase of CA 15 3 and CA 125 in tamoxifen treated patients with breast cancer]. AB - The study presents a case of endometrial cancer in a breast cancer patient treated with tamoxifen. The disease occured with elevated values of CA 125 and CA 15_3 tumour markers without any other signs. Additional diagnostic analyses were performed showing a "de novo" endometrial cancer rather than metastatic breast cancer. The patient underwent surgery and radiotherapy. Thereafter, the values of tumour markers were in the reference values. PMID- 21263401 TI - Primary malignant melanoma of gallbladder. AB - Gallbladder primary malignant melanoma (GPMM) is a rare and controversial entity. The existing controversy on the subject appears mainly because of the lack of definitive objective criteria of primitivity. Objective criteria proposed by the specific literature for distinguishing GPMM from secondary gallbladder melanoma include the exclusion of previous primitive melanoma, absence of synchronous involment of other sites, the unicity of lesion, its polipoid or papilary shape and the presence of a junctional melanocitary component. After laparoscopic cholecystectomy in one of our patients, dark polypus inside the gallbladder was found. A malignant melanoma was diagnosed according to all five criteria for GPMM. PMID- 21263402 TI - Association of PPARG and LPIN1 gene polymorphisms with metabolic syndrome and type 2 diabetes. AB - AIM: Lipin 1 is a recently discovered multifunctional protein involved in the metabolism of lipids, while PPARgamma is involved in adipocyte differentiation, and regulation of lipid metabolism. Up to now, LPIN1 and PPARG gene polymorphisms have been associated with type 2 diabetes, metabolic syndrome, and central obesity. In this study, we hypothesized that genetic variants within LPIN1 and PPARG genes were associated with traits of metabolic syndrome. Correlation between biochemical parameters (including but not limited to, glucose, HbA1c, insulin levels, HDL and LDL cholesterol, triglycerides, serum proteins, liver enzymes) and frequency of polymorphisms in LPIN1 (rs11693809 and rs2716610) and PPARG gene (rs10865710, rs3856806 and rs1801282), was tested in this study. METHODS: The study included 70 patients diagnosed with metabolic syndrome and type 2 diabetes. Two polymorphisms of LPIN1 gene (rs11693809 and rs2716610), and three polymorphisms of PPARG gene (rs10865710, rs385806 and rs1801282) were analyzed by real time PCR and conventional PCR-RFLP methods. RESULTS: Our analysis revealed correlation between insulin levels and rs11693809 LPIN1 polymorphism in diabetic patients. Also the results of this study showed an association of rs10865710 and rs385806 polymorphism of PPARG with HDL cholesterol and LDL plus total cholesterol levels, respectively. CONCLUSION: These data reflect an association of analyzed PPARG and LPIN1 gene polymorphisms with values of insulin, HDL, LDL and total cholesterol witch indicates an important role of these genes in lipid metabolism and pathogenesis of type 2 diabetes and metabolic syndrome. PMID- 21263403 TI - Analysis of CYP3A4*1B and CYP3A5*3 polymorphisms in population of Bosnia and Herzegovina. AB - AIM: Differences in the frequency of distribution of the cytochrome P450 (CYP) allelic variants have been demonstrated between distinct ethnic groups, contributing to observed interindividual variation in drug response. In this study we determined, for the first time, prevalence of the common allelic variants of the polymorphic CYP enzymes, CYP3A4*1B and CYP3A5*3, in the population of Bosnia and Herzegovina (BH). METHODS: Genomic DNA was extracted from blood samples collected from 140 unrelated subjects. A real-time PCR was used for the detection of CYP polymorphisms, with the application of the specific TaqMan SNP Genotyping Assay (Applied Biosystems) for CYP3A5*3, while CYP3A4*1B was genotyped by high-resolution melting analysis. RESULTS: Our results have shown that the distribution of CYP3A4*1B and CYP3A5*3 alleles was in line with the data reported in European Caucasians. We confirmed that CYP3A4*1B mutant allele is rare in Caucasians, being present in only 5.1% individuals. However, CYP3A5*3 polymorphism was found to be predominant in the Bosnian population with an incidence of 94%, similarly to other European populations tested so far. Interestingly, we have demonstrated a strong linkage disequilibrium between CYP3A5*3 and CYP3A4*1B alleles. No significant difference in allele frequencies for CYP3A4*1B and CYP3A5*3 has been shown between male and female subjects participating in our study. CONCLUSION: Our data demonstrated the high prevalence of CYP3A5*3 allele in Bosnian population, indicating significance of analysis of CYP3A5 and CYP3A4 polymorphisms and corresponding allele frequencies in specific ethnic groups. Importantly, results of this study may lead to translation of pharmacogenetics and individualized therapeutic approach in current clinical practices in BH. PMID- 21263404 TI - Optimisation of methods for quantifying plasma mRNA levels from genes responsible for coronary artery plaque development and destabilization. AB - AIM: To investigate the hypothesis that in patients with coronary atherosclerosis it is possible to measure plasma mRNA levels from genes responsible for plaque development and destabilization. METHODS: Methods for RNA isolation, mRNA transcription and quantitative PCR were evaluated and optimised, in order to achieve reliable mRNA quantification. RESULTS mRNA level was possible to quantify from plasma of patients with coronary atherosclerosis, as well as from healthy volunteers, from genes encoding cathepsin S, cathepsin B, CD40 molecule, monocyte chemotactic protein 1, death-associated protein kinase 1, matrix metallopeptidase 9, vascular cell adhesion molecule 1 and phosphoglycerate kinase 1 (reference gene). Analytical between-run imprecision of average threshold cycle, expressed as coefficient of variation was below 2%. EDTA blood samples should be centrifuged within one hour of venesection. It was not possible to quantify plasma mRNA level from genes encoding macrophage scavenger receptor 1, perilipin, tissue factor, phospholipase A2 group IIA, collagen type I alpha 2 and interleukin 1 alpha. CONCLUSION: Further plasma mRNA analysis is reasonable to access its potential usefulness in non-invasive in vivo monitoring of gene expression profile in vascular beds. PMID- 21263405 TI - Cystatin C in sera of patients with aggressive non-Hodgkin B-cell lymphoma. AB - AIM: To investigate the cystatin C levels in sera of patients with aggressive non Hodgkin B-cell lymphoma. METHODS: The levels of cystatin C in sera of lymphoma patients and control group consisted of healthy individuals, were measured by using specific sandwich-type ELISA. For each patient the clinical stage of disease was determined according to Ann Arbor staging system for lymphomas. RESULTS: Our study shows that mean cystatin C serum level in the patients group (1056 +/- 65 ng/mL) was significantly higher when compared with the mean level of the healthy control group (819 +/- 28 ng/mL) (P = 0.001). Mean cystatin C level of the group with clinical stages III and IV (1255 +/- 109 ng/mL) was significantly elevated when compared with the mean level of the group with clinical stages I and II (896 +/- 51 ng/mL) (P = 0.03). CONCLUSION: This finding points out a connection between inhibitor level and aggressive behaviour of lymphoma and could be considered for further strategies of prognosis of the disease. PMID- 21263406 TI - Local CD4+, CD8+ and CD56+ reactions to lung cancer in regard to pathohistological type and clinical stage. AB - AIM: To determinate the difference of abundance of CD4+, CD8+ and CD56+ bronchoalveolar fluid's lymphocytes and their subpopulations between non- and small cell lung cancer. Also, the differences of abundance of examined lymphocytes were compared between main clinical stages of lung cancer. METHODS: Mini-bronchoalveolar lavate was taken from lungs of 55 patients with cancer. After laboratory processing and adding CD3, CD4, CD8, CD27, CD28 and CD56 antibody, the material was analysed by flow cytometer. Results of Mini-BAL for non- and small cell lung cancer were compared, as well as the different clinical stages of the disease. RESULTS: Immature and regulatory forms of lymphocytes are more activated, while mature and activated forms are less activated in small cell lung cancer compared to non small type. With an increase of the clinical stage of disease, immunological reaction of T lymphocytes is better expressed because of increasing of abundance of immature and regulatory forms of different subpopulations of lymphocytes. CONCLUSION: All components of local CD4+ and CD8+ T lymphocyte, as well as NK and NKT cells response were more activated in lungs with small cell lung cancer, and these reactions were more expressed with an increase in the clinical stage. PMID- 21263407 TI - Interleukin 18 expression in the primary breast cancer tumour tissue. AB - AIM: To investigate the presence and expression levels of the IL-18 in the primary breast cancer tissue in relation to the unchanged breast tissue in same patients and the breast tissue in patients with benign breast disease, as well as the correlation between the IL-18 expression levels and pathohistological factors, including the correlation between IL-18 expression and the estrogens and progesterone receptor status. METHODS: This prospective randomized study was conducted at the Policlinic for Laboratory Diagnostics of the University Clinical Centre of Tuzla. 50 patients with invasive ductal breast cancer and 20 patients with benign breast diseases were included in the study. The tree-step immunohistochemical staining was used for testing the levels of IL-18 expression and hormone receptor status. RESULTS: IL-18 was present in the breast cancer tumour, in the surrounding unchanged tissue of the same patients and in the breast tissue of patients with benign breast tumour and other benign breast disease. The expression of this interleukin was significantly higher in breast cancer tumour tissue as compared to its expression in surrounding unchanged tissue of the same patients (p < 0.05), whereas IL-18 expression was not significantly higher in breast cancer tumours compared to its expression in breast tissue of the patients with benign breast diseases (p = 0.057). There was no significant correlation between IL-18 expression and the lymph node status, and between IL-18 expression and the pathohistological factors. CONCLUSION: The results suggest possible involvement of IL-18 in complex mechanisms of breast carcinogenesis. PMID- 21263408 TI - Use of amino-terminal pro-B type natriuretic peptide as the parameter for long term monitoring of water overload in patient with chronic kidney diseases. AB - AIM: To analyze usefulness of measurement amino-terminal pro-B type natriuretic peptide of (NT pro-BNP) as the one of parameters of water overload in patients with chronic kidney diseases. METHODS: A total number of 277 patients with chronic kidney diseases (CKD) were followed up in the period often years between January 2000 and July 2010. Patients with creatinine clearance of 60 ml/min or less were included in the study. Changes of creatinine clearance, and in last five years changes of NT pro-BNP were followed. Water overload was analyzed using chest x-ray in relation with concentration of NT pro-BNP in the blood. RESULTS: Decrease of clearance of creatinine ranged from average 54.7 ml/min in the first year to 14.6 ml/min in the fifth year of the monitoring. Average NT pro-BNP level in patients without any sign of water overload was 94 pg/ml (SD 21), mean value in those with Kerley lines was 231 pg/ml/L (SD 64), in those with clear signs of water overload but without pleural effusion it was 525 pg/ml (SD 223), and in those with water retention including pleural effusion it was 1606 pg/ml (SD 1134). Using test of multiple correlation a statistically significant correlation between X-ray signs of water overload and NT pro-BNP concentration was shown, p < 0.05. CONCLUSION: Measurement of NT pro-BNP was increased in the beginning of water overload in patients with CKD. Increased value of NT pro-BNP may be found earlier than any other signs of water overload. NT pro-BNP was a useful parameter in estimation of water overload in these patients. PMID- 21263409 TI - B-type natriuretic peptide (BNP) serum levels in rats after forced repeated swimming stress. AB - AIM: To estimate the effects of forced repeated swimming stress on BNP serum levels in rats. METHODS: Adult male Wistar rats weighting between 280-330 g were divided into two groups: control group (n = 8) and stress group (n = 8). Rats in the stress group were exposed to forced swimming stress daily, for 7 days. The rats were forced to swim in plastic tanks (90 cm wide, 120 cm deep) containing tap water (temperature ca. 25 degrees C). The depth of water was 40 cm. Duration of each swimming session progressively increased from 10 minutes on the first day to 40 minutes on days 6 and 7. Rats were sacrificed and blood was drawn from abdominal aorta for BNP analysis immediately after the last swimming session. B type natriuretic serum level was determined by ELISA method using RAT BNP-32 kit (Phoenix Pharmaceutical Inc.). RESULTS: There was no statistically significant difference between mean BNP serum level in the stress group after the swimming period (0.81 +/- 0.14 ng/ml) as compared to the unstressed group of rats (0.8 +/- 0.08 ng/ml). After the swimming period mean body weight slightly decreased in the stress group in comparison with values before stress period (296.3 g vs. 272.8 g), but this difference was not statistically significant. The stress period had no influence on food intake in the stress rat group. CONCLUSION: The workload consisting of 40-minutes long swimming session is not sufficient to provoke BNP release from myocardium in rats. PMID- 21263410 TI - Association of homocysteine with traditional and non-traditional risk factors in patients with atherosclerotic vascular disease. AB - AIM: To assess the association between total homocysteine (tHcy) and traditional and nontraditional risk factors in patients with atherosclerotic vascular disease (ASVD). METHODS: This cross-sectional study included 99 ASVD patients and 40 control subjects in whom we determined lipid profile, high sensitivity C-reactive protein (hsCRP), uric acid (UA) and tHcy. RESULTS: The median tHcy concentration was significantly higher in ASVD group compared to the controls ((18.7(13.65 24.45) vs. 11.48 (10.03-14.2) micromol/L (p < 0.001)). Mean serum cholesterol, low-density lipoprotein cholesterol levels (LDLc) and atherogenic index were significantly lower, while mean serum UA concentration was significantly higher in hyperhomocysteinemic compared to normohomocysteinemic ASVD patients and control subjects. In hyperhomocysteinemic ASVD patients a significant negative correlation between serum logtHcy and cholesterol (r = -0.32), LDLc (r = -0.24), very-low-density lipoprotein cholesterol (VLDLc) (r = -0.295) and atherogenic index (r = -0.25) was observed. In normo-homocysteinemic ASVD patients serum logtHcy was significantly positively correlated with UA (r = 0.46) and hsCRP (r = 0.383). Multivariate linear regression analysis revealed that serum logtHcy was independently positively associated only with UA in normohomocysteinemic ASVD patients. CONCLUSION: The results of our study have shown that the association between tHcy and traditional and non-traditional risk factors depends on tHcy serum level. It was observed a negative association between serum tHcy and lipids in hyperhomocysteinemic ASVD patients. On the other hand, in ASVD patients with serum tHcy levels within the reference range a positive independent association between serum tHcy and UA might reflect an underlying elevated tension of redox stress. PMID- 21263411 TI - Coagulation factor VIII activity in diabetic patients. AB - AIM: To examine coagulation factor VIII activity in plasma, as a risk factor for thrombosis, in the patients with diabetes mellitus (DM). Also, to assess its relationship with fibrinogen and fasting blood glucose concentrations and with body mass index. METHODS: The plasma coagulation factor VIII activity, plasma levels of fibrinogen and blood glucose concentrations were measured in 30 patients with DM type 1, 30 patients with DM type 2 and in 30 healthy subjects. Body weight and body height were also measured and BMI was calculated. RESULTS: The plasma factor VIII activity in patients with DM type 1 and patients with DM type 2 was significantly higher than the values measured in healthy subjects. There was no significant difference in the factor VIII activity between patients with DM type 1 and type 2. The concentrations of fibrinogen and blood glucose in both groups of patients were significantly higher than in the group of healthy subjects. Patients with DM type 2 had a significantly higher BMI compared to healthy subjects, as well as compared to patients with DM type 1. There was a significant positive correlation between plasma factor VIII activity and plasma level of fibrinogen and a significant negative correlation between factor VIII activity and BMI in patients with DM type 2. CONCLUSION: Diabetic patients have the elevated plasma coagulation factor VIII activity and increased fibrinogen concentration thus an increased risk of thrombosis and vascular diseases. PMID- 21263412 TI - Time-dependent responses of rat troponin I and cardiac injury following isoproterenol administration. AB - AIM: To develop a rat model of myocardial infarction induced by isoproterenol (ISO). We investigated a type of histological myocardial changes and cardiac troponin I (TnI) kinetic. METHODS: The study has used adult, male, Wistar strain rats. Rats were distributed in ISO and control groups. Rats treated with ISO were divided into groups according to the time of cTnI and myocardial lesion analyses: ISO I (30'), ISO II (60'), ISO III (120') and ISO IV (240'). We determined cTnI (Life Diagnostics Inc. West Chester PA, USA) in the serum by ELISA method. We performed histological analysis on the specimens of left ventricular wall stained by hematoxillin-eosin (HE) method. RESULTS: The first statistically significant rise of cTnI was noted 30 minutes after the ISO administration. There was no statistically significant difference between cTnI mean values among the ISO groups. Observed myocardial histological changes were time dependent. CONCLUSIONS: This model can be suitable for cardioprotective and cardiotoxicity supstance investigations followed by cTnI measurement in blood. The similarity between induced myocardial lesion on animal model in our study and human myocardial lesion in ischemia give us sufficient impulse for further preclinical researches of new cardiac markers. PMID- 21263414 TI - Hematologic and laboratory parameters in patientis with peptic ulcer bleeding treated by two modalities of endoscopic haemostasis and proton pump inhibitors. AB - AIM: To compare two schedules (continuous infusion or bolus i.v. of PPI) in treatment after endoscopic homeostasis of bleeding ulcers. METHODS: Patients with gastrointestinal bleeding caused by peptic ulcer, or a recent history (< 24 h before presentation) were included in the study. All cases with actively bleeding ulcers were treated with epinephrine injection and/or thermal coagulation, and randomized to receive intravenous PPIs according to the continuous regimen (in continuous infusion) or the standard regimen (40 mg bolus twice a day for 3 days). RESULTS: 69 patients were treated. Bleeding recurred in 5 of 34 patients (14.7%) receiving the intensive regimen, and in 8 of 35 (22.8%) patients receiving the standard regimen. Hemoglobine rate in standard regimen group was 93,5 g/L (SD 23,8), and in intensive regimen group 106,6 g/L (SD 22,4) (p = 0.042). Total protein rate in the standard regimen group was 65,1 g/L (SD 7,3) and in the intensive regimen group 67,7 g/L (SD 8,15), (p = 0.525). Albumin rate in the standard regimen group was 31,0 g/L (SD 5,2), whereas in the intensive regimen group it was 34,8 g/L (SD 7,4), (p = 0.652). Globulin rate in the standard regimen group was 31,0 g/L (SD 5,2) and in the intensive regimen group 32,3 g/L (5,3), (p = 0.875). Fibrinogen rate in the standard regimen group was 11,1 (SD 2,6) and 10,8 g/L (SD 2,4 p = 0.622) in the intensive regimen group. A mean number of units of blood transfusion for patients in the intensive group was 2,18 (SD 0,8) and 1,34 (SD 1,02) in the standard group, with statistical level of difference p = 0.0004, using Student t-test. The duration of hospital stay was 6,4 days (SD 2,8) in the standard group and 5,8 days (SD 2,8) in the intensive group (p = 0.40). There were fewer surgical interventions in the intensive versus standard regimen. CONCLUSION: In patients with bleeding peptic ulcers with successful endoscopic hemostasis the standard IPP regimen had advantage for transfusion requirements, but no advantage with respect to in-hospital rates of re-bleeding, need for surgery, length of hospital stay, or death. PMID- 21263413 TI - Blood iron stores reduction affects lipoprotein status--a potential benefit of blood donation. AB - AIM: To determine the lipoprotein profile of voluntary blood donors, and on the basis of parameters to evaluate the risk of atherosclerosis. METHODS: The study included voluntary blood donors of both sexes. Participants were divided into two groups. The first group of subjects consisted of men and women in menopause (BD 1). The second group consisted of women in reproductive age (BD 2). Analysis of concentration of lipoproteins was performed by direct determination of total cholesterol, LDL-C and HDL-C. From the total serum cholesterol and concentration of lipoproteins ratios of total cholesterol/HDL-C ratio and LDL-C/HDL-C were calculated. RESULTS: Significantly higher concentration of LDL-C was obtained in the serum of BD 1, compared to LDL-C in the serum of BD 2, within the reference range. Mean concentration of HDL-C in the serum of BD 2 group was higher than the values measured in the BD group 1, without significant difference. The ratio of total cholesterol/HDL-C showed significantly higher values in the BD 1 group compared with results in the BD 2 group. Significantly higher values in the BD group 1 were observed for the ratio of LDL-C/HDL-C. Obtained results showed that all voluntary blood donors had a concentration of individual lipoprotein fractions in a lower risk range for atherosclerosis development. CONCLUSION: Female voluntary blood donors in reproductive age have a more favorable lipid status in relation to the voluntary blood donors, men and women in menopause, indicating that this population of women is exposed to lower risk of developing atherosclerosis. PMID- 21263415 TI - Evaluation and treatment of cardiovascular diseases in patients on hemodialysis- single center experience. AB - AIM: To evaluate frequency of CVD in dialysis population, in relationship to patients with and without diabetes, and their most common treatment. PATIENTS AND METHODS: This retrospective study included 187 patients, 106 males and 81 females, divided in two groups, diabetics and non-diabetics, treated by chronic hemodialysis. Patients' analyses included: anamnesis, ECG, chest X-rays, echocardiogram, laboratory examinations for calcium (Ca), phosphorus (P), parathormone (PTH), cholesterol (chol), triglicerids (TG), C-reactive protein (CRP), hemoglobin (Hb) and uric acid. In addition, we analyzed groups of drugs used by patients as prescribed by cardiologists. RESULTS: Average age was 58.0 years, most of them between 51 and 60. Average hemodialysis length was 4 years. Primary kidney diseases were pyelonephritis and glomerulonephritis. 19,78% of patients had diabetes. 165 patients (88,23%) had one or more cardiovascular diseases. 110 patients (58,2%) had hypertension, most of them used ACE inhibitors. Using test of multiple correlation, statistically significant correlations, among others, were shown between BMI and Ca, uric acid and P, albumin and PTH in diabetics, at the statistical significance level at p < 0.05. CONCLUSION: Cardiovascular diseases are the most common comorbidity and cause of mortality in hemodialysis population. There was no statistical significance in age, however there is a statistical difference in the dialysis duration variable, but in some biochemical laboratory parameters there was some difference. ACE inhibitors were most commonly used in the treatment of hypertension and systolic dysfunction, alone or with beta-blockers. PMID- 21263416 TI - Adenosine deaminase and C-reactive protein in diagnosing and monitoring of rheumatoid arthritis. AB - AIM: To determine of catalytic activities of adenosine deaminase (ADA) and values of C-reactive protein (CRP) concentration in serums of patients with rheumatoid arthritis (RA), who were and were not treated with Methotrexate (MTX), and identifying the possibilities of using these biochemical parameters in diagnosing and monitoring of treatment effects in RA. METHODS: The study involved 120 subjects (60 healthy ones, who are in accordance with examined groups concerning age and sex, 30 suffering from RA who were not treated with MTX and 30 suffering from RA who were treated by MTX). Catalytic activities of ADA in serum were determined by spectrophotometric method using adenosine as a substrate. CRP concentrations in serum were determined immunoturbidimetrically. RESULTS: A statistically significant correlation between values of ADA catalytic activities and values of CRP concentrations (r = 0.55, p < 0.01) in serums of subjects with RA without MTX treatment. At subjects with RA treated by MTX, correlation between values of ADA catalytic activities and values of CRP concentrations in serums was not statistically significant (r = 0.33, p > 0.01). CONCLUSION: Study results have shown that ADA catalytic activity in serum can be a useful biochemical marker of inflammatory process in RA. PMID- 21263417 TI - Molecular mechanisms of esophageal squamous cell carcinogenesis: clues to improve treatment outcomes. PMID- 21263418 TI - Angiogenesis-related factors are molecular targets for diagnosis and treatment of patients with esophageal carcinoma. AB - Angiogenesis plays an essential role in the growth and metastasis of esophageal carcinoma. Vascular endothelial growth factor, thymidine phosphorylase, fibroblast growth factor, midkine, and hepatocyte growth factor have been reported to be vital molecules for tumor angiogenesis. Polymorphisms in gene encoding angiogenic factors or their receptors may alter protein expression and/or activity. Increased angiogenic-factor expression and increased serum levels of these molecules were found to be associated with poor treatment response and poor prognosis. We reviewed the clinicopathological significance of angiogenesis-related molecules in patients with esophageal carcinoma. Antiangiogenic molecular-treatment strategies are also discussed. PMID- 21263419 TI - Repeat FDG-PET for predicting pathological tumor response and prognosis after neoadjuvant treatment in nonsmall cell lung cancer: comparison with computed tomography. AB - BACKGROUND: The efficacy of fluorodeoxyglucose-positron emission tomography (FDG PET) for predicting pathological tumor response and prognosis after neoadjuvant chemoradiotherapy followed by surgery in locally advanced nonsmall cell lung cancer (NSCLC) was compared to the predictive value of tumor size as determined by computed tomography (CT). METHODS: Thirty-seven consecutive NSCLC patients who received FDG-PET and CT scans both before and after neoadjuvant chemoradiotherapy were enrolled in this study. The percentage point changes in maximum standard uptake value (SUV) on PET and tumor size on CT after neoadjuvant treatment were defined as the SUV ratio and the size ratio, respectively, and were compared with pathological tumor response and prognosis after surgery. A major pathological response was defined as residual viable tumor cells corresponding to less than one-third the size of the original tumor. RESULTS: Nineteen and 18 patients showed major and minor pathological responses, respectively, after neoadjuvant treatment. The optimal cutoff values for predicting a major pathological response were 0.6 for the SUV ratio and 0.79 for the size ratio. The SUV ratio predicted the pathological tumor response with higher accuracy than the size ratio did (P = 0.04). Neither the SUV ratio nor the size ratio predicted prognosis after surgery. CONCLUSION: For predicting the pathological tumor response after neoadjuvant chemoradiotherapy, the SUV ratio on FDG-PET is superior to the size ratio on CT in patients with NSCLC. However, neither the SUV ratio nor the size ratio could predict prognosis. PMID- 21263420 TI - Preoperative hypoalbuminemia is a risk factor for late bronchopleural fistula after pneumonectomy. AB - BACKGROUND: Pneumonectomy is still a high-risk surgical procedure. Postpneumonectomy bronchopleural fistula is an especially severe complication with a high mortality rate. Although several reports have discussed risk factors for early bronchopleural fistula after pneumonectomy, only a few have reported them for late bronchopleural fistula. We reviewed cases of late bronchopleural fistula after pneumonectomy and investigated its risk factors. METHODS: Sixty four patients with nonsmall cell lung cancer underwent pneumonectomy at our institution from June 1999 to December 2004. Among them, 5 who developed bronchopleural fistula were investigated. RESULTS: All of the 5 patients were male; 3 had undergone right pneumonectomy and 2 left pneumonectomy. The period between surgery and the appearance of bronchopleural fistula ranged from 36 to 164 days. We found that the preoperative serum albumin level was significantly lower in the patients with late bronchopleural fistula. Induction therapy, surgical side, age, anemia, arterial blood oxygen, and respiratory function did not affect the occurrence of bronchopleural fistula after pneumonectomy. CONCLUSIONS: A preoperative low-serum albumin level, indicative of poor nutritional status, is a risk factor for late bronchopleural fistula after pneumonectomy for nonsmall cell lung cancer. PMID- 21263421 TI - Intraoperative hybrid cardiac surgery for neonates and young children with congenital heart disease: 5 years of experience. AB - OBJECTIVE: This study intends to summarize 5 years of intraoperative hybrid procedure (IHP) experience with neonates and young children having congenital heart disease (CHD). METHODS: From March 2003 to March 2009, a total of 152 consecutive patients younger than 2 years old who had undergone IHP were enrolled. In the balloon plasty group (n = 72), transventricular pulmonary valvuloplasty, or transaortic balloon dilatation were performed for pulmonary atresia, pulmonary stenosis, or coactation of the aorta. In the device group (n = 43), transventricular device closure was performed for ventricular septal defect (VSD), or transatrial device closure for atrial septal defect (ASD). In the collateral arteries occlusion group (n = 37), the major aortopulmonary collateral arteries (MPCAs) were occluded with coils for tetralogy of Fallot or other cyanotic CHDs. All procedures were image guided and performed in a specially designed hybrid operation room. All surviving patients were followed up, and the major adverse cardiovascular events that occurred were recorded. RESULTS: In the balloon plasty group, all patients received successful transventricular valvuloplasty or transaortic balloon angioplasty. However, severe right ventricle outflow obstruction was observed in 2 cases. One patient was transferred to regular open-heart surgery immediately, and another underwent regular open-heart procedure after discharge. Furthermore, 1 neonate with pulmonary atresia with intact ventricular septum died from liver failure 6 months after IHP. In the device closure group, the device closure failed to be performed in 3 cases (2 with ASD and 1 with VSD). One young child with VSD died from pneumonia, even after successful device closure. No device malposition was observed in the device closure group during follow-up. All patients who received MPCA occlusion and associated open-heart correction were eventually discharged. CONCLUSION: IHP could avoid or shorten the application of cardiopulmonary bypass and reduce surgical trauma for selected young children with CHD. Although IHP is feasible and safe, the image outfits, image-guided technology, and IHP-related devices should be developed and improved. PMID- 21263422 TI - Influence of prosthetic heart valve sound on a patient's quality of life. AB - PURPOSE: To elucidate the effects of prosthetic valve sound on a patient's quality of life (QOL). METHODS: We compared the valve sounds of ATS, SJM, and Carbomedics (CM) based on assessments by 248 patients who underwent mechanical valve replacements from January 2000 to August 2003 at seven facilities in Japan. We used a self-administered questionnaire for evaluating patients' assessments of valve sounds and the Japanese version of SF-36 for measuring their health-related QOL. RESULTS: With respect to the valve-sound level perceived immediately after surgery, we considered the ATS and SJM valves quieter than the CM valve, but others have considered the ATS valve quieter than the SJM and CM valves. Regarding the time when the valve sound stopped bothering patients, a significant difference was observed between the ATS and CM valves and between the SJM and CM valves. The logistic regression analysis on patients' perceptions of valve sounds indicated that the influences of age, gender, and valve position are significant. Furthermore, a survey with SF-36 indicated that a long valve sound will affect a patient's health-related QOL. CONCLUSION: The present study suggested that the ATS valve surpassed the other two valves on the whole in audibility of valve sound and patient health-related QOL. However, further studies, including the ongoing prospective study, are necessary for a more comprehensive and accurate evaluation of the ATS valve. PMID- 21263423 TI - Functional tricuspid regurgitation in rheumatic heart disease: surgical options. AB - OBJECTIVES: In this study, we compare the follow-up results of two types of tricuspid valve repair and review the results of no repair in moderately severe tricuspid regurgitation (TR) along with mitral valve replacement or mitral and aortic valve replacement. PATIENTS AND METHODS: This prospective follow-up study, carried out on 106 consecutive patients, was conducted at the Department of Cardiac Surgery, Punjab Institute of Cardiology, Lahore, from September 1994 through August 2008. The patients were divided into three groups: suture bicuspidization, 36 (34%); modified De Vega's repair, 47 (44.3%); and no repair, 23 (21.7%). Freedom from moderate 2+ TR was compared among these groups by the Kaplan-Meier method. RESULTS: In the suture bicuspidization group, freedom from TR2+ was 97.2%, 77.8%, and 39.6% at 30 days and 7 and 14 years after surgery, respectively. In the modified De Vega group, it was 100% at the end of 7 years. In the no-repair group, it was 91.3%, 91.3%, and 61.6% at 30 days and 7 and 14 years after surgery, respectively. Overall in-hospital mortality was 3 (2.8%), with 4 late deaths after discharge. Preoperative right ventricular dysfunction, preoperative TR severity, preoperative mitral regurgitation, preoperative ejection fraction, and remnant TR following surgery were significant independent predictors of TR recurrence. CONCLUSION: Repair by suture bicuspidization fails to prevent further annular dilatation and has no comparable results. Modified De Vega's repair is safe with superior results compared to other groups at the end of 7 years. Patients without significant annular dilatation in the no-repair group improved during follow-up once their left-sided valve lesion was corrected. PMID- 21263424 TI - Diaphragm perforation after radio-frequency ablation for metastatic lung cancer. AB - A case of diaphragm perforation after radio-frequency ablation (RFA) for lung metastasis from uterine cervical cancer is reported. The patient developed pelvic recurrence and solitary lung metastasis after a radical hysterectomy for uterine cervical cancer. Pelvic radiation and RFA for lung metastasis were performed. Metastasis was located in the laterobasal segment of the lower lobe of the right lung. RFA was repeatedly performed in September 2005 and August 2006. In May 2008, 18F-fluoro-deoxy-glucose (FDG) positron emission tomography-computed tomography showed evidence of local recurrence of the lung metastasis. A solid lesion with FDG accumulation accompanying a cystic lesion was observed in the lung base. The patient underwent a wedge resection of the lung in June 2008, during which a perforated area of the diaphragm (3 cm in diameter) was identified under the cystic lesion, which was not herniated. The perforation in the diaphragm was closed with a simple continuous suture. PMID- 21263425 TI - A long-term survivor with late-onset-repeated pulmonary metastasis of a PEComa. AB - A 59-year-old male underwent a surgical resection of a retroperitoneum tumor in 1990 that was diagnosed as leiomyoblastoma. Thereafter he demonstrated pulmonary metastases followed by a total of 3 pulmonary resections from 1995 to 1997. In 2008, he was incidentally found to have a tumor in the left lower lobe, which was diagnosed as a metastatic perivascular epithelioid cell (PEComa) neoplasm. Retrospectively, a primary tumor and pulmonary metastases were also diagnosed as PEComa. We experienced late-onset repeated pulmonary metastasis of a PEComa. PMID- 21263426 TI - A case of pulmonary epithelioid hemangioendothelioma surviving 10 years without treatment. AB - A 19-year-old woman was referred to our hospital because of bilateral multiple nodular shadows on the chest radiograph. She complained of no symptoms. The pulmonary lesions were diagnosed pathologically as epithelioid hemangioendothelioma. She has been followed without treatment for more than 10 years. Among all lesions, only two pulmonary nodules enlarged slightly, and it is interesting that one showed significant uptake in a fluorodeoxyglucose positron emission tomography (FDG-PET) scan. The current case suggests the clinical usefulness of an FDG-PET scan in a pulmonary epithelioid hemangioendothelioma (PEH) patient. PMID- 21263427 TI - Pleuropulmonary paragonimiasis with intrathoracic mass. AB - Pleuropulmonary paragonimiasis is a food-borne parasitic disease caused by the lung fluke Paragonimus westermani or other species of Paragonimus, which is endemic in Southeast Asia. It presents mainly pleural effusion or intrapulmonary nodules with respiratory symptoms. However, here we describe an exceedingly rare case of Paragonimus westermani with a mass in the pleural cavity. A 47-year-old man, who had presented with chest pain nine months earlier, was found to have right pleural effusion on detection survey computed tomography. He had a history of asbestos exposure and river fishing as a hobby and was confirmed to have Paragonimus westermani by immunodiagnosis. Because of a high level of hyaluronic acid in pleural effusion, he underwent a thoracoscopic examination. The pleura of the thoracic wall thickened greatly and showed no malignant lesion on biopsy. A white mass measuring 8 cm in diameter showed in the pleural cavity, which partially connected with the diaphragm and pulmonary pleura of the lower lobe. The postoperative pathological examination reported that the intrathoracic mass was a lesion that contained necrotic tissue enveloped with a fibrin capsule, which was thought to be formed by paragonimus. PMID- 21263428 TI - An experience with the modified total pleural covering technique in a patient with bilateral intractable pneumothorax secondary to lymphangioleiomyomatosis. AB - We present a case of bilateral intractable pneumothorax associated with a modified form of lymphangioleiomyomatosis (LAM), successfully treated with a previously reported surgical procedure, the total pleural covering (TPC) technique, under video-assisted thoracic surgery. The patient was a 28-year-old woman with bilateral pneumothorax secondary to LAM who had undergone thoracoscopic surgery in another hospital. We performed bilateral TPC modified with a preceding coverage of air leak points with polyglycolic acid sheets for reinforcement. Although a minor air leak after the surgery necessitated a mild pleurodesis on the right side, the bilateral pneumothorax was well controlled, and no recurrence has been observed for 9 months. We believe that TPC is a safe and reliable procedure for the management of intractable pneumothorax secondary to LAM. It also has the potential to reduce risk of excessive bleeding in lung transplantation. PMID- 21263429 TI - Successful treatment of a compromised patient with intractable pneumothorax using a semiflexible thoracofiberscope under local anesthesia: A case report. AB - We herein present the case of a 69-year-old male with intractable pneumothorax, which occurred after gastrectomy, who could not tolerate general anesthesia because of a poor cardiopulmonary reserve and renal and hepatic insufficiency. We performed a ligation of perforated bulla using a semiflexible thoracofiberscope under an intercostal nerve block and subcutaneous anesthesia. The postoperative course was uneventful. The chest tube was removed the next day, and he was transferred to the department of medicine on the 2nd postoperative day. PMID- 21263430 TI - CABG surgery with long coronary endarterectomy of the LAD. AB - Diffuse atherosclerosis of the anterior descending artery may require unconventional surgical treatment to increase graft flow. A 74-year-old man with severe, diffuse 3-vessel-coronary artery disease was presented to our institution with progredient angina pectoris symptoms. Intraoperatively, the revascularization of the left anterior descending coronary artery (LAD) was technically challenging because of the extremely calcified coronary artery disease; therefore we performed the longest endarterectomy of the LAD that has thus far been described. PMID- 21263431 TI - A direct suture repair for a paravalvular leak 23 years after the second mitral valve replacements: A case report. AB - A 59-year-old male was referred for surgery resulting from a paravalvular leak at the mitral position. The patient underwent his first mitral valve replacement with a Bjork-Shiley valve 33 years before this situation arose. He underwent his second mitral valve replacement with a St. Jude Medical mechanical prosthesis for valve thrombosis 10 years later. Serial echocardiography had always shown good results until this time; thus the leak suddenly occurred 23 years after his second mitral valve replacement without any preceding signs. At surgery, a small fistula was observed. The paravalvular leak was successfully repaired by a direct suture repair. Although his postoperative course was complicated by a deep sternal infection, he has fully recovered and currently is in the New York Heart Association class 1 three years after the surgery. PMID- 21263432 TI - Iatrogenic type A aortic dissection after catheter intervention for the left subclavian artery. AB - Cardiac surgical procedure and catheter intervention of the aorta or its major branches have a potential risk for iatrogenic aortic dissection. This case demonstrates an iatrogenic type A aortic dissection after the elective balloon angioplasty for severe stenosis of the left subclavian artery orifice. The dissection retrospectively extended to the ascending aorta, and intramural hematoma was observed in the false lumen of the aorta. The ascending aorta was successfully replaced 14 days after the occurrence of dissection, using hypothermic circulatory arrest and antegrade selective cerebral perfusion. There were no outstanding complications. PMID- 21263433 TI - Thyroid cancer in 2010: a roadmap for targeted therapies. PMID- 21263434 TI - Type 2 diabetes mellitus in 2010: individualizing treatment targets in diabetes care. PMID- 21263435 TI - Obesity in 2010: the future of obesity medicine: where do we go from here? PMID- 21263436 TI - Pituitary tumors in 2010: a new therapeutic era for pituitary tumors. PMID- 21263437 TI - Vitamin D deficiency in 2010: health benefits of vitamin D and sunlight: a D bate. PMID- 21263440 TI - Hierarchical temporal processing deficit model of reality distortion and psychoses. AB - We posit in this article that hierarchical temporal processing deficit is the underlying basis of reality distortion and psychoses. Schizophrenia is a prototypical reality distortion disorder in which the patient manifests with auditory hallucinations, delusions, disorganized speech and thinking, cognitive impairment, avolition and social and occupational dysfunction. Reality distortion can be present in many other disorders including bipolar disorder, major depression and even dementia. Conceptually, schizophrenia is a heterogeneous entity likely to be because of numerous causes similar to dementia. Although no single symptom or set of symptoms is pathognomonic, a cardinal feature in all patients with schizophrenia is chronic distortion of reality. The model that we have proposed accounts for the varied manifestations of reality distortion including hallucinations and delusions. In this paper we consider the implications of this model for the underlying biology of psychoses and also for the neurobiology of schizophrenia and suggest potential targets to consider for the etiology and pathophysiology of reality distortion, especially in the context of schizophrenia. PMID- 21263441 TI - In the new year. PMID- 21263438 TI - Cognitive function, dementia and type 2 diabetes mellitus in the elderly. AB - Increasing numbers of people are developing type 2 diabetes mellitus, but interventions to prevent and treat the classic microvascular and macrovascular complications have improved, so that people are living longer with the condition. This trend means that novel complications of type 2 diabetes mellitus, which are not targeted by current management strategies, could start to emerge. Cognitive impairment and dementia could come into this category. Type 2 diabetes mellitus is associated with a 1.5-2.5-fold increased risk of dementia. The etiology of dementia and cognitive impairment in people with type 2 diabetes mellitus is probably multifactorial. Chronic hyperglycemia is implicated, perhaps by promoting the development of cerebral microvascular disease. Data suggest that the brains of older people with type 2 diabetes mellitus might be vulnerable to the effects of recurrent, severe hypoglycemia. Other possible moderators of cognitive function include inflammatory mediators, rheological factors and dysregulation of the hypothalamic-pituitary-adrenal axis. Cognitive function should now be included as a standard end point in randomized trials of therapeutic interventions in patients with type 2 diabetes mellitus. PMID- 21263442 TI - SSRI administration reduces resting state functional connectivity in dorso-medial prefrontal cortex. PMID- 21263443 TI - APOE E4 status predicts age-related cognitive decline in the ninth decade: longitudinal follow-up of the Lothian Birth Cohort 1921. AB - Carriers of the APOE E4 allele have an increased risk of developing Alzheimer's disease. However, it is less clear whether APOE E4 status may also be involved in non-pathological cognitive ageing. The present study investigated the associations between APOE genotypes and cognitive change over 8 years in older community-dwelling individuals. APOE genotype was determined in 501 participants of the Lothian Birth Cohort 1921, whose intelligence had been measured in childhood in the Scottish Mental Survey 1932. A polymorphic variant of TOMM40 (rs10524523) was included to differentiate between the effects of the APOE E3 and E4 allelic variants. Cognitive performance on the domains of verbal memory, abstract reasoning and verbal fluency was assessed at mean age 79 years (n=501), and again at mean ages of 83 (n=284) and 87 (n=187). Using linear mixed models adjusted for demographic variables, vascular risk factors and IQ at age 11 years, possession of the APOE E4 allele was associated with a higher relative rate of cognitive decline over the subsequent 8 years for verbal memory and abstract reasoning. Individuals with the long allelic variant of TOMM40, which is linked to APOE E4, showed similar results. Verbal fluency was not affected by APOE E4 status. APOE E2 status was not associated with change in cognitive performance over 8 years. In non-demented older individuals, possession of the APOE E4 allele predicted a higher rate of cognitive decline on tests of verbal memory and abstract reasoning between 79 and 87 years. Thus, possession of the APOE E4 allele may not only predispose to Alzheimer's disease, but also appears to be a risk factor for non-pathological decline in verbal memory and abstract reasoning in the ninth decade of life. PMID- 21263446 TI - Notch3-mediated regulation of MKP-1 levels promotes survival of T acute lymphoblastic leukemia cells. AB - Activation of the Notch pathway occurs commonly in T acute lymphoblastic leukemia (T-ALL) because of mutations in Notch1 or Fbw7 and is involved in the regulation of cell proliferation and survival. Deregulated Notch3 signalling has also been shown to promote leukemogenesis in transgenic mice, but the targets of Notch3 in human T-ALL cells remain poorly characterized. Here, we show that Notch3 controls levels of mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1). In a model of T-ALL cell dormancy, both Notch3 activation and MKP-1 expression were upregulated in aggressive compared with dormant tumors, and this inversely correlated with the levels of phosphorylated p38 and extracellular signal regulated kinase1/2 (ERK1/2) MAPKs, two canonical MKP-1 targets. We demonstrate that MKP-1 protein levels are regulated by Notch3 in T-ALL cell lines because its silencing by RNA interference or treatment with gamma-secretase inhibitors induced strong MKP-1 reduction whereas activation of Notch3 signalling had the opposite effect. Furthermore, MKP-1 has an important role in T-ALL cell survival because its attenuation by short hairpin RNA significantly increased cell death under stress conditions. This protective function has a key role in vivo, as MKP 1-deficient cells showed impaired tumorigenicity. These results elucidate a novel mechanism downstream of Notch3 that controls the survival of T-ALL cells. PMID- 21263447 TI - Cancer genetics: Initially complex, always heterogeneous. PMID- 21263444 TI - Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. AB - A comprehensive literature search was performed to collate evidence of mitochondrial dysfunction in autism spectrum disorders (ASDs) with two primary objectives. First, features of mitochondrial dysfunction in the general population of children with ASD were identified. Second, characteristics of mitochondrial dysfunction in children with ASD and concomitant mitochondrial disease (MD) were compared with published literature of two general populations: ASD children without MD, and non-ASD children with MD. The prevalence of MD in the general population of ASD was 5.0% (95% confidence interval 3.2, 6.9%), much higher than found in the general population (~ 0.01%). The prevalence of abnormal biomarker values of mitochondrial dysfunction was high in ASD, much higher than the prevalence of MD. Variances and mean values of many mitochondrial biomarkers (lactate, pyruvate, carnitine and ubiquinone) were significantly different between ASD and controls. Some markers correlated with ASD severity. Neuroimaging, in vitro and post-mortem brain studies were consistent with an elevated prevalence of mitochondrial dysfunction in ASD. Taken together, these findings suggest children with ASD have a spectrum of mitochondrial dysfunction of differing severity. Eighteen publications representing a total of 112 children with ASD and MD (ASD/MD) were identified. The prevalence of developmental regression (52%), seizures (41%), motor delay (51%), gastrointestinal abnormalities (74%), female gender (39%), and elevated lactate (78%) and pyruvate (45%) was significantly higher in ASD/MD compared with the general ASD population. The prevalence of many of these abnormalities was similar to the general population of children with MD, suggesting that ASD/MD represents a distinct subgroup of children with MD. Most ASD/MD cases (79%) were not associated with genetic abnormalities, raising the possibility of secondary mitochondrial dysfunction. Treatment studies for ASD/MD were limited, although improvements were noted in some studies with carnitine, co-enzyme Q10 and B vitamins. Many studies suffered from limitations, including small sample sizes, referral or publication biases, and variability in protocols for selecting children for MD workup, collecting mitochondrial biomarkers and defining MD. Overall, this evidence supports the notion that mitochondrial dysfunction is associated with ASD. Additional studies are needed to further define the role of mitochondrial dysfunction in ASD. PMID- 21263445 TI - The transcription factor PlagL2 activates Mpl transcription and signaling in hematopoietic progenitor and leukemia cells. AB - Cytokine signaling pathways are frequent targets of oncogenic mutations in acute myeloid leukemia (AML), promoting proliferation and survival. We have previously shown that the transcription factor PLAGL2 promotes proliferation and cooperates with the leukemia fusion protein Cbfbeta-SMMHC in AML development. Here, we show that PLAGL2 upregulates expression of the thrombopoietin receptor Mpl, using two consensus sites in its proximal promoter. We also show that Mpl overexpression efficiently cooperates with Cbfbeta-SMMHC in development of leukemia in mice. Finally, we demonstrate that PlagL2-expressing leukemic cells show hyper activation of Jak2 and downstream STAT5, Akt and Erk1/2 pathways in response to Thpo ligand. These results show that PlagL2 expression activates expression of Mpl in hematopoietic progenitors, and that upregulation of wild-type Mpl provides an oncogenic signal in cooperation with CBFbeta-SMMHC in mice. PMID- 21263448 TI - Transgenerational neuroendocrine disruption of reproduction. AB - Exposure to endocrine disrupting chemicals (EDCs) is associated with dysfunctions of metabolism, energy balance, thyroid function and reproduction, and an increased risk of endocrine cancers. These multifactorial disorders can be 'programmed' through molecular epigenetic changes induced by exposure to EDCs early in life, the expression of which may not manifest until adulthood. In some cases, EDCs have detrimental effects on subsequent generations, which indicates that traits for disease predisposition may be passed to future generations by nongenomic inheritance. This Review discusses current understanding of the epigenetic mechanisms that underlie sexual differentiation of reproductive neuroendocrine systems in mammals and summarizes the literature on transgenerational epigenetic effects of representative EDCs: vinclozolin, diethylstilbesterol, bisphenol A and polychlorinated biphenyls. The article differentiates between context-dependent epigenetic transgenerational changes- namely, those that require environmental exposure, either via the EDC itself or through behavioral or physiological differences in parents--and germline dependent epigenetic mechanisms. These processes, albeit discrete, are not mutually exclusive and can involve similar molecular mechanisms including DNA methylation and histone modifications and may predispose exposed individuals to transgenerational disruption of reproductive processes. New insights stress the crucial need to develop a clear understanding of how EDCs may program the epigenome of exposed individuals and their descendants. PMID- 21263449 TI - Antibacterial effects of vitamin D. AB - Interaction between vitamin D and the immune system has been recognized for many years, but its relevance to normal human physiology has only become evident in the past 5 years. Studies of innate immune responses to pathogens such as Mycobacterium tuberculosis have shown that pathogen-recognition receptor-mediated activation of localized vitamin D metabolism and signaling is a key event associated with infection. Vitamin D, acting in an intracrine fashion, is able to induce expression of antibacterial proteins and enhance the environment in which they function. The net effect of these actions is to support increased bacterial killing in a variety of cell types. The efficacy of such a response is highly dependent on vitamin D status; in other words, the availability of circulating 25 hydroxyvitamin D for intracrine conversion to active 1,25-dihydroxyvitamin D by the enzyme 25-hydroxyvitamin D-1alpha-hydroxylase. The potential importance of this mechanism as a determinant of human disease is underlined by increasing awareness of vitamin D insufficiency across the globe. This Review will explore the molecular and cellular systems associated with antibacterial responses to vitamin D in different tissues and possible consequences of such a response for the prevention and treatment of human immune disorders. PMID- 21263451 TI - Continuous re-evaluation in differentiated thyroid carcinoma. PMID- 21263452 TI - Increased levels of plasma haemoxygenase-1 in prostate cancer. AB - Angiogenesis, a key component of cancer, may be driven by angiogenic growth factors, such as vascular endothelial growth factor (VEGF) and angiopoietin-2. Haemoxygenase-1 (HO-1), a haem-degrading enzyme, may have alternative roles in angiogenesis. Levels of plasma HO-1 have not been reported in prostate cancer. We tested the hypothesis of abnormal HO-1 in 30 men with early prostate cancer, compared with 22 men with benign prostate disease (BPD) and 26 men free of prostate disease, and that HO-1 levels would correlate with VEGF, angiopoietin-2, von Willebrand factor (vWf, marking endothelial perturbation) and PSA. Plasma HO 1 was twofold higher in prostate cancer than in the two control groups, while vWf, VEGF and PSA were also raised (all P<0.02). In the subjects free of prostate disease and in the BPD groups, HO-1 correlated significantly with VEGF (r>0.5, P<0.02) but the correlation in prostate cancer was not significant (r=0.117, P=0.537). There were no correlations with PSA or the Gleason stage. We conclude that HO-1 is associated with VEGF in health and BPD, but in the presence of prostate cancer, raised levels of both HO-1 and VEGF fail to correlate. This observation may have implications for the pathogenesis of prostate cancer. PMID- 21263453 TI - Development of an MHC class I L(d)-restricted PSA peptide-loaded tetramer for detection of PSA-specific CD8+ T cells in the mouse. AB - We set out to develop a PSA peptide-loaded tetramer for enumeration of PSA specific CD8(+) T cells in the Balb/c mouse model. A candidate major histocompatibility complex (MHC) class I PSA peptide (HPQKVTKFML(188-197)) was selected on the basis of its ability to restimulate PSA-specific CD8(+) T cells to secrete interferon-gamma in our assays. Next, H-2L(d)-restricted peptide loaded and fluorescently labeled tetramers were produced in conjunction with the NIH Tetramer Core Facility, Atlanta, GA, USA. This tetramer was then tested for staining specificity and optimized for detection of PSA-specific CD8(+) T cells induced by our PSA-encoding adenovirus tumor vaccine. The MHC class I PSA peptide demonstrated successful restimulation of CD8(+) T cells isolated from mice previously vaccinated with a PSA-encoding adenovirus tumor vaccine, with no restimulation observed in control-vaccinated mice. The peptide-loaded H-2L(d) tetramer exhibited the desired binding specificity and allowed for detection and frequency determination of PSA-specific CD8(+) T cells by flow cytometry. We have successfully designed and validated a PSA peptide tetramer for use in the Balb/c mouse model that can be used to test PSA-based prostate cancer vaccines. Until now, PSA-specific CD8(+) T cells in the mouse have only been detectable via cytotoxic T-lymphocyte assays or intracellular cytokine staining, which primarily assess antigen-specific functional activity and not their absolute number. This research tool provides laboratories the ability to directly quantitate CD8(+) T cells elicited by PSA-specific immunotherapies and cancer vaccines that are tested in mouse models. PMID- 21263450 TI - Polycystic ovary syndrome: etiology, pathogenesis and diagnosis. AB - Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, with a prevalence of up to 10%. Various diagnostic criteria have been proposed, generally centered around the features of hyperandrogenism and/or hyperandrogenemia, oligo-ovulation and polycystic ovarian morphology. Insulin resistance is present in a majority of cases, with compensatory hyperinsulinemia contributing to hyperandrogenism via stimulation of ovarian androgen secretion and inhibition of hepatic sex hormone-binding globulin production. Adipose tissue dysfunction has been implicated as a contributor to the insulin resistance observed in PCOS. Environmental and genetic factors also have a role in the development of PCOS. The syndrome is associated with numerous morbidities, including infertility, obstetrical complications, type 2 diabetes mellitus, cardiovascular disease, and mood and eating disorders. Despite these morbidities, PCOS may be common in our society owing to evolutionary advantages of the syndrome in ancient times, including smaller family sizes, reduced exposure to childbirth-related mortality, increased muscle mass and greater capacity to store energy. The diagnosis of PCOS hinges on establishing key features while ruling out other hyperandrogenic or oligo-ovulatory disorders. Treatment is focused on the goals of ameliorating hyperandrogenic symptoms, inducing ovulation and preventing cardiometabolic complications. PMID- 21263454 TI - Impact of obesity on total and cardiovascular mortality--fat or fiction? AB - Obesity is an excessive accumulation of fat that can impair health. Because the direct measurement of body fat is difficult to perform, a number of anthropometric measures have been employed as surrogates, of which BMI is the most commonly used. However, its usefulness has been questioned as a BMI in the overweight and mildly obese range is associated with improved survival and fewer cardiovascular events than a BMI in the normal range, a phenomenon known as the 'obesity paradox'. Waist circumference, waist-to-hip ratio, and waist-to-height ratio take into consideration body-fat distribution, especially abdominal obesity, and seem to predict cardiovascular risk better than does BMI. PMID- 21263455 TI - Epidemiology of valvular heart disease in the adult. AB - Valvular heart disease remains common in industrialized countries, because the decrease in prevalence of rheumatic heart diseases has been accompanied by an increase in that of degenerative valve diseases. Aortic stenosis and mitral regurgitation are the two most common types of valvular disease in Europe. The prevalence of valvular disease increases sharply with age, owing to the predominance of degenerative etiologies. The burden of heart valve disease in the elderly has an important impact on patient management, given the high frequency of comorbidity and the increased risk associated with intervention in this age group. Endocarditis is an important etiology of valvular disease and is most commonly caused by Staphylococci. Rheumatic heart disease remains prevalent in developing countries. PMID- 21263456 TI - Intravascular imaging of vulnerable coronary plaque: current and future concepts. AB - Advances in coronary imaging are needed to enable the early detection of plaque segments considered to be 'vulnerable' for causing clinical events. Pathological studies have contributed to our current understanding of these vulnerable or unstable segments of plaque. Intravascular ultrasonography (IVUS) has provided insights into the morphology of atherosclerosis, the mediators of plaque progression and the factors associated with acute coronary syndrome (ACS). In addition, the demonstration of pancoronary arterial instability has highlighted that ACS involves a multifocal disease process. Various second-generation intravascular imaging technologies-employing advanced processing of ultrasound radiofrequency backscatter signals, light-based imaging, spectroscopic imaging and molecular targeting-possess inherent advantages for the identification of meaningful surrogates of plaque instability. The fusion of these imaging technologies within a single imaging catheter is likely to allow for greater synergism in image quality and early disease detection. However, natural-history studies to validate the use of these novel imaging tools for enhanced risk prediction are needed before these strategies can be incorporated into mainstream clinical practice. PMID- 21263457 TI - The double face of the histone variant H3.3. AB - Histone proteins wrap DNA to form nucleosome particles that compact eukaryotic genomes while still allowing access for cellular processes such as transcription, replication and DNA repair. Histones exist as different variants that have evolved crucial roles in specialized functions in addition to their fundamental role in packaging DNA. H3.3--a conserved histone variant that is structurally very close to the canonical histone H3--has been associated with active transcription. Furthermore, its role in histone replacement at active genes and promoters is highly conserved and has been proposed to participate in the epigenetic transmission of active chromatin states. Unexpectedly, recent data have revealed accumulation of this specific variant at silent loci in pericentric heterochromatin and telomeres, raising questions concerning the actual function of H3.3. In this review, we describe the known properties of H3.3 and the current view concerning its incorporation modes involving particular histone chaperones. Finally, we discuss the functional significance of the use of this H3 variant, in particular during germline formation and early development in different species. PMID- 21263458 TI - Hepatotoxicity related to antirheumatic drugs. AB - Antirheumatic agents are among commonly used drugs associated with adverse hepatic reactions. Sulfasalazine and azathioprine are among the most important causes of acute hepatotoxicity. Because such a large number of people take NSAIDs, even the rare occurrence of hepatotoxicity from these agents might contribute substantially to the total burden of drug-induced liver disease. A wide spectrum of hepatotoxic effects is described with antirheumatic drugs. Studies investigating genetic susceptibility to diclofenac hepatotoxicity have expanded our understanding of the potential drug-specific, class-specific and general factors involved in its pathogenesis, and methotrexate-associated liver disease demonstrates the interaction between drug, host and environmental factors that determines the likelihood and magnitude of liver disease. Infliximab therapy is associated with typical drug-induced autoimmune hepatitis. Although validated causality assessment methods have been used to objectively assess the strength of the association between a drug and a clinical event, in practice the diagnosis of drug-induced liver injury (DILI) involves a clinical index of suspicion, pattern recognition, the establishment of a temporal relationship between drug exposure and the adverse event, and the exclusion of alternative explanations for the clinical presentation. Detailed understanding of genetic and environmental factors underlying an individual's susceptibility would enable risk reduction and potentially primary prevention of hepatotoxicity. PMID- 21263459 TI - Clinical guidelines: Expert recommendations for NSAID use: a user-friendly model? AB - Although tens of millions of individuals worldwide use nsaids daily, balancing the competing risks and benefits of these agents continues to be a challenge. Evidence-based treatment guidelines and expert opinions have been promulgated, but will they actually translate to improved patient care? A new Web-based tool could aid physicians' treatment decision-making. PMID- 21263460 TI - Monoclonal antibody therapy-associated neurological disorders. AB - Several neurological disorders have been associated with the use of monoclonal antibodies (mAbs), especially those targeting tumor necrosis factor (TNF) and its receptors. These disorders include, among others, multiple sclerosis, optic neuritis, and various forms of peripheral demyelinating neuropathy. Progressive multifocal leukoencephalopathy, the natural course of which is lethal within months, has been mainly associated with the anti-alpha4-integrin mAb natalizumab and, to a lesser extent, with rituximab, alemtuzumab and efalizumab. The prevalence of demyelinating disease induced by biological therapies, as reported in randomized controlled trials and postmarketing studies, has been estimated to range from 0.02-0.20%. Peripheral neuropathies can occur early or late after initiation of therapy. Short-term follow-up indicates relatively good outcomes, sometimes after mAb discontinuation alone, although corticosteroids or intravenous immunoglobulin may be necessary to reverse and stabilize the condition. Definitive cessation of the biological therapy should be discussed on a case-by-case basis. Prospective postmarketing studies in which the control group includes patients with rheumatic autoimmune diseases-most notably rheumatoid arthritis-treated with conventional therapies could help us to evaluate the real risks and outcomes in patients receiving mAbs who develop neurological diseases. PMID- 21263461 TI - Benign mesial temporal lobe epilepsy. AB - Benign mesial temporal lobe epilepsy (bMTLE), which is defined as at least 24 months of seizure freedom with or without antiepileptic medication, has probably been under-recognized because of a literature bias toward refractory epilepsy cases. Seizure onset in bMTLE tends to be in adolescence or adulthood, and patients frequently have a family history of febrile seizures and epilepsy. Long term seizure freedom is observed with or without antiepileptic medication. On brain MRI, nearly 40% of patients with long-standing bMTLE show evidence of hippocampal sclerosis, a feature usually associated with refractory temporal lobe epilepsy. Prospective studies are needed to determine the features that allow prediction of a benign course, and to clarify the significance of hippocampal MRI changes. PMID- 21263462 TI - Ebolavirus VP35 suppresses IFN production from conventional but not plasmacytoid dendritic cells. AB - Ebolaviruses naturally infect a wide variety of cells including macrophages and dendritic cells (DCs), and the resulting cytokine and interferon-alpha/beta (IFN) responses of infected cells are thought to influence viral pathogenesis. The VP35 protein impairs RIG-I-like receptor-dependent signaling to inhibit IFN production, and this function has been suggested to promote the ineffective host immune response characteristic of ebolavirus infection. To assess the impact of VP35 on innate immunity in biologically relevant primary cells, we used a recombinant Newcastle disease virus encoding VP35 (NDV/VP35) to infect macrophages and conventional DCs, which primarily respond to RNA virus infection via RIG-I-like pathways. VP35 suppressed not only IFN but also tumor necrosis factor (TNF)-alpha secretion, which are normally produced from these cells upon NDV infection. Additionally, in cells susceptible to the activity of VP35, IRF7 activation is impaired. In contrast, NDV/VP35 infection of plasmacytoid DCs, which activate IRF7 and produce IFN through TLR-dependent signaling, leads to robust IFN production. When plasmacytoid DCs deficient for TLR signaling were infected, NDV/VP35 was able to inhibit IFN production. Consistent with this, VP35 was less able to inhibit TLR-dependent versus RIG-I-dependent signaling in vitro. These data demonstrate that ebolavirus VP35 suppresses both IFN and cytokine production in multiple primary human cell types. However, cells that utilize the TLR pathway can circumvent this inhibition, suggesting that the presence of multiple viral sensors enables the host to overcome viral immune evasion mechanisms. PMID- 21263463 TI - Homeostatic defects in interleukin 18-deficient mice contribute to protection against the lethal effects of endotoxin. AB - Toll-like receptor-4-lipopolysaccharide (LPS)-mediated inflammation is used to delineate signals involved in cross-talk between antigen-presenting cells (APCs) and lymphocytes such as natural killer (NK) cells. Following APC stimulation and cytokine release, NK cells produce interferon (IFN)-gamma. High levels of LPS induce endotoxicosis, a systemic inflammatory disease in which IFN-gamma causes significant morbidity and mortality. Several studies have highlighted the role of interleukin (IL)-18, IL-1beta, IL-17A and IFN-gamma in the development of endotoxicosis, but whether these cytokines interact with each other is yet to be determined. Our data demonstrate that IL-18 and IL-17A have important roles in NK cell IFN-gamma production during endotoxicosis. Importantly, we provide the first evidence that IL-18 also has a role in IL-17A production by T-cell receptor (TCR) delta cells. Furthermore, we demonstrate that IL-18-deficient mice have a defect in gammadelta T-cell homeostasis and IL-1beta production, both of which can contribute to the development of disease through induction of IL-17A. These results reveal novel requirements for IL-18 in innate immune cell homeostasis and activation, demonstrating that the role of IL-18 in innate immunity occurs at a level other than activation. PMID- 21263465 TI - Detrimental effect of self-phase modulation on the performance of Brillouin distributed fiber sensors. AB - We show that the spectral broadening of the pump pulse through self-phase modulation in a time-domain distributed Brillouin sensor has a considerably detrimental effect in the measurement, especially in the case of long distances and high-resolution pulses. Using 30 ns pump pulses with peak power of 276 mW, self-phase modulation leads to a doubling of the effective gain linewidth after some 20 km, which is equivalent to a contrast loss of 2dB in the measurement. The impact is higher for shorter pulses (higher resolution). The theoretical modeling is fully confirmed by experimental results. PMID- 21263466 TI - Ultrabroad near-infrared photoluminescence from ionic liquids containing subvalent bismuth. AB - We have shown that Lewis-acidic halogenoaluminate ionic liquid (IL) containing subvalent bismuth can be used as a near-IR (NIR) luminescent material. Raman and absorption spectra evidence the coexistence of Bi(5)(3+) and Bi(+) in the liquid. The Bi(5)(3+) and Bi(+) emitters, stabilized by this Lewis-acidic liquid, demonstrate ultrabroad NIR photoluminescence with a lifetime of around 1 MUs. We envisage that the bismuth activated ILs would not only enrich the well established spectrum of soft luminescent materials but also might promote the design of novel photonic materials activated by other p-block elements. PMID- 21263464 TI - PET-CT for radiotherapy treatment planning and response monitoring in solid tumors. AB - PET imaging has evolved as an indispensible tool for staging in oncology. Multiple quantitative measurements can be performed, enabling the effects of treatment to be monitored before changes are detectable with the use of conventional imaging modalities. PET tracers are available to visualize and quantify the most important mechanisms of resistance to radiotherapy and chemoradiotherapy. Reproducibility of these tracers depends on the particular tracer and the underlying biology of the process that is being investigated. PET enables clinicians to select patients for intensified treatment on the basis of resistance mechanisms taking place at the molecular level. From translational studies and randomized trials, it has become clear that appropriate patient selection can prevent unnecessary rejection of various treatment options through the observation of individual patients rather than only looking at the results of a large study population. PMID- 21263467 TI - Highly directional output from long-lived resonances in optical microcavity. AB - We report a simple and robust mechanism that can result in highly directional emission from long-lived resonances in microcavities. By placing a nanoparticle (NP) into the evanescent wave region of microcavities, highly directional outputs with divergence angle ~1.9 degrees -10 degrees can be obtained in single or double directions. The perturbation of NP on evanescent waves preserves the high quality (Q) factors, and the collimation of microcavities generates the highly directional outputs. Our numerical simulations show that this mechanism is very robust to the size of NP and the refractive index/separation distance/size of microcavities. PMID- 21263468 TI - Dark materials based on graphene sheet stacks. AB - The effective medium properties of graphene sheet stacks are calculated, and it is shown that such stacks can have very low reflectivity and high absorbance. These properties make graphene-sheet-stack-based materials darker than recently studied carbon nanotube materials. Graphene stacks thus hold promise for realizing lower reflectivity coatings and enhanced photodetectors. The bounds of the effective medium approximation and the possible benefits of using graphene sheet stacks in a regime where this approximation does not hold are discussed. PMID- 21263469 TI - Observation of 2.7 MUm emission from diode-pumped Er3+/Pr3+-codoped fluorophosphate glass. AB - This work reports the intense emission at 2.7 MUm in a Er(3+)/Pr(3+)-codoped fluorophosphate (FP) host glass. This FP glass shows good thermal stability and high transmittance around 3 MUm. The emission characteristic and energy transfer upon excitation of a conventional 980 nm laser diode are investigated. The prepared glass possesses higher spontaneous transition probability (22.16s(-1)) along with a larger calculated emission cross section (6.57 +/- 0.11) * 10(-21) cm(2) corresponding to the laser transition (4)I(11/2)->(4)I(13/2). In addition, the effect of Pr(3+) codoping on the 2.7 MUm photoluminescence in FP glass is demonstrated. Hence, the advantageous spectroscopic characteristics of Er(3+)/Pr(3+)-codoped FP glass together with the outstanding thermal property indicate that this kind of glass may become an attractive host for developing solid-state lasers at around 2.7 MUm. PMID- 21263470 TI - Peregrine soliton generation and breakup in standard telecommunications fiber. AB - We present experimental and numerical results showing the generation and breakup of the Peregrine soliton in standard telecommunications fiber. The impact of nonideal initial conditions is studied through direct cutback measurements of the longitudinal evolution of the emerging soliton dynamics and is shown to be associated with the splitting of the Peregrine soliton into two subpulses, with each subpulse itself exhibiting Peregrine soliton characteristics. Experimental results are in good agreement with simulations. PMID- 21263471 TI - Passive ranging and three-dimensional imaging through chiral phase coding. AB - We present a method for single-image passive ranging and three-dimensional (3D) imaging in incoherent light based on chiral phase coding. A chiral linear phase variation across the aperture of an optical system results in a frequency response with a characteristic pattern of fringes such that the spatial period and inclination of the pattern depend on the focusing error. From this dependency, the absolute focusing error and, hence, the distance to the object can be found. In the experiments a resolution of ~1.4 MUm is achieved with a 20 mm aperture lens in a 4 mm interval at a distance of 140 mm from the lens. A resolution of ~0.7 mm is obtained at a distance of ~11 m with the range finder employing two 25.4 mm spherical mirrors spaced apart by ~140 mm. We also demonstrate 3D imaging of weakly textured objects. PMID- 21263472 TI - Fourier analysis for rotating-element ellipsometers. AB - We introduce a Fourier analysis of the waveform of periodic light-irradiance variation to capture Fourier coefficients for multichannel rotating-element ellipsometers. In this analysis, the Fourier coefficients for a sample are obtained using a discrete Fourier transform on the exposures. The analysis gives a generic function that encompasses the discrete Fourier transform or the Hadamard transform, depending on the specific conditions. Unlike the Hadamard transform, a well-known data acquisition method that is used only for conventional multichannel rotating-element ellipsometers with line arrays with specific readout-mode timing, this Fourier analysis is applicable to various line arrays with either nonoverlap or overlap readout-mode timing. To assess the effects of the novel Fourier analysis, the Fourier coefficients for a sample were measured with a custom-built rotating-polarizer ellipsometer, using this Fourier analysis with various numbers of scans, integration times, and rotational speeds of the polarizer. PMID- 21263473 TI - Compact compound-eye projector using superresolved projection. AB - We propose a compact compound-eye projector using superresolved projection. The optics are composed of multiple small suboptics (units) to reduce their thickness in the projector. Each of the suboptics adds a subpixel shift to a projected image for superresolved projection and has a color filter or a dispersive element for multicolor projection. The projected images in the units are determined via a model of the system in preprocessing. The images are projected by the suboptics and superimposed on a screen. In this Letter, we describe the system model and show the simulation results. PMID- 21263474 TI - Neutrals ejection in intense femtosecond laser ablation. AB - Time-resolved shadowgraphs and holograms of intense femtosecond laser ablation of aluminum are reported. The different bending trends of interference fringes are found in the ablations of aluminum and other materials at probe wavelengths of 400 and 800 nm, for the first time to our knowledge, which could be attributed to the ejection of massive neutral droplets induced by critical-point phase separation during the second material ejection. PMID- 21263475 TI - Anderson localization of near-visible light in two dimensions. AB - We report on the observation of Anderson localization of near-visible light in two-dimensional systems. Our structures consist of planar waveguides in which disorder is introduced by randomly placing pores with controlled diameter and density. We show how to design structures in which localization can be observed and describe both the realization of the materials and the actual observation of Anderson localized modes by near-field scanning microscopy. PMID- 21263476 TI - Effect of Rayleigh-scattering distributed feedback on multiwavelength Raman fiber laser generation. AB - We experimentally demonstrate a Raman fiber laser based on multiple point-action fiber Bragg grating reflectors and distributed feedback via Rayleigh scattering in an ~22-km-long optical fiber. Twenty-two lasing lines with spacing of ~100 GHz (close to International Telecommunication Union grid) in the C band are generated at the watt level. In contrast to the normal cavity with competition between laser lines, the random distributed feedback cavity exhibits highly stable multiwavelength generation with a power-equalized uniform distribution, which is almost independent on power. PMID- 21263477 TI - Broadband single-polarization guidance in hybrid photonic crystal fibers. AB - We present hybrid photonic crystal fibers that provide broadband single polarization guidance based on two different propagation mechanisms, namely, total internal reflection and the photonic bandgap effect. Experimental results demonstrate polarization dependent loss as high as 26.7 dB and the bandwidth of single-polarization behavior over 225 nm. PMID- 21263478 TI - Transmission and group-delay characterization of coupled resonator optical waveguides apodized through the longitudinal offset technique. AB - In this Letter, the amplitude and group delay characteristics of coupled resonator optical waveguides apodized through the longitudinal offset technique are presented. The devices have been fabricated in silicon-on-insulator technology employing deep ultraviolet lithography. The structures analyzed consisted of three racetracks resonators uniform (nonapodized) and apodized with the aforementioned technique, showing a delay of 5 +/- 3 ps and 4 +/- 0.5 ps over 1.6 and 1.4 nm bandwidths, respectively. PMID- 21263479 TI - Fast voice-coil scanning optical-resolution photoacoustic microscopy. AB - We developed a photoacoustic imaging system that has real-time imaging capability with optical resolution. The imaging system is capable of scanning at 20 Hz over a 9 mm range and up to 40 Hz over a 1 mm scanning range. A focused laser beam provides a lateral resolution of 3.4 MUm as measured in an optically nonscattering medium. Flows of micrometer-sized carbon particles or whole blood in a silicone tube and individual red blood cells (RBCs) in mouse ear capillaries were also imaged in real time, demonstrating the capability to image highly dynamic processes in vivo at a micrometer-scale resolution. PMID- 21263480 TI - Particle swarm optimization-based approach for accurate evaluation of upconversion parameters in Er3+-doped fibers. AB - In this Letter, a method for recovering homogeneous upconversion coefficients (HUCs) in Er(3+)-doped glasses and erbium-activated devices is illustrated. It is based on a particle swarm optimization (PSO) approach. The HUCs are calculated on the basis of known values of optical gain evaluated in different pumping conditions. The obtained numerical results proof that the proposed technique provides solutions that are very close to the expected values. Therefore the method constitutes a tool for the design and optimization of efficient rare-earth doped lasers and optical amplifiers. This approach can be considered a feasible and valid alternative method in the field of material science and optical engineering for determining HUCs and avoiding the employment of expensive equipment for the measurement of ion-ion interaction parameters. PMID- 21263481 TI - Localization of light on a cone: theoretical evidence and experimental demonstration for an optical fiber. AB - The classical rays propagating along a conical surface are bounded on the narrower side of the cone and unbounded on its wider side. In contrast, it is shown here that a dielectric cone with a small half-angle gamma can perform as a high Q-factor optical microresonator which completely confines light. The theory of the discovered localized conical states is confirmed by the experimental demonstration, providing a unique approach for accurate local characterization of optical fibers (which usually have gamma ~ 10(-5) or less) and a new paradigm in the field of high Q-factor resonators. PMID- 21263482 TI - High-speed synthetic aperture microscopy for live cell imaging. AB - We present a high-speed synthetic aperture microscopy for quantitative phase imaging of live biological cells. We measure 361 complex amplitude images of an object with various directions of illumination covering an NA of 0.8 in less than one-thirteenth of a second and then combine the images with a phase-referencing method to create a synthesized phase image. Because of the increased depth selectivity, artifacts from diffraction that are typically present in coherent imaging are significantly suppressed, and lateral resolution of phase imaging is improved. We use the instrument to demonstrate high-quality phase imaging of live cells, both static and dynamic, and thickness measurements of a nanoscale cholesterol helical ribbon. PMID- 21263483 TI - Small-signal analysis of OOFDM signal transmission with directly modulated laser and direct detection. AB - This work presents a small-signal analysis for investigating the transmission performance of optical orthogonal frequency division multiplexing signals with a directly modulated DFB laser (DML). The analysis shows the positive chirp of DMLs can intensify power fading after transmission with positive dispersion and provide power gain instead with negative dispersion. The power of subcarrier-to subcarrier intermixing interference after square-law direct detection, however, is independent on the sign of dispersion. PMID- 21263484 TI - Gamma-distorted fringe image modeling and accurate gamma correction for fast phase measuring profilometry. AB - In fast phase-measuring profilometry, phase error caused by gamma distortion is the dominant error source. Previous phase-error compensation or gamma correction methods require the projector to be focused for best performance. However, in practice, as digital projectors are built with large apertures, they cannot project ideal focused fringe images. In this Letter, a thorough theoretical model of the gamma-distorted fringe image is derived from an optical perspective, and a highly accurate and easy to implement gamma correction method is presented to reduce the obstinate phase error. With the proposed method, high measuring accuracy can be achieved with the conventional three-step phase-shifting algorithm. The validity of the technique is verified by experiments. PMID- 21263485 TI - Optical measurement network for large-scale and shell-like objects. AB - An optical measurement method for large-scale and shell-like objects is proposed and is verified by experiments. The underlying concept is a model-based optical measurement network consisting of multinode three-dimensional (3D) sensors. To achieve this, a synthetic calibration method is presented to enable the measurement. A phase-aided active stereoscopy is thus applied to each node sensor for acquiring partial range images from different viewpoints. The multiple range images are then registered to obtain a 3D reconstructed model, which is compared with the computer-aided design (CAD) model to quantitatively reveal the differences between the two models. Experiment results are also presented to validate the proposed approach. PMID- 21263486 TI - Manipulating supercontinuum generation by minute continuous wave. AB - We report a simple triggering mechanism that greatly enhances and stabilizes supercontinuum generation by using an extremely weak cw light (~200,000 times weaker than the pump light). Such an active manipulation scheme can be enabled by a wide range of input conditions and circumvents complex techniques such as precise time delay tuning and dedicated feedback control. It thus offers a handy and versatile approach to control and optimize supercontinuum generation, expanding its range of applications, including ultrafast all-optical signal processing, spectroscopy, and imaging. The utility of the present technique for improving signal integrity in chirped pump optical parametric amplification is also demonstrated. PMID- 21263487 TI - SiC/W/Ir multilayer-coated grating for enhanced efficiency in 50-100 nm wavelength range in Seya-Namioka mount. AB - A broadband [SiC/W/Ir](2) multilayer coating was deposited onto a diffraction grating to enhance the grating efficiency in the 50-100 nm wavelength range in a Seya-Namioka mount. The holographic ion-beam etched grating had a laminar profile with 1200 lines/mm. The coating was designed by using the subquarterwave multilayer theory. The measurement results show that the efficiency in the -1st diffraction order is greater than 9.3% throughout the wavelength range of 50-100 nm, which is obviously higher than that of single-layer gratings with SiC, Ir, or Au coatings. PMID- 21263488 TI - Optical gain and laser generation in bismuth-doped silica fibers free of other dopants. AB - Luminescence emission and excitation spectra of bismuth-doped silica optical fibers free of other dopants have been obtained to construct an emission excitation map in a wide wavelength range of 400-1600 nm. The main low-lying energy levels of the bismuth active centers in such fibers have been determined. For the first time (to our knowledge), optical gain and lasing have been obtained in such fibers. A gain of 8 dB has been achieved with a pump power of 340 mW, and a cw fiber laser emitting at 1460 nm with an output power of 40 mW and an efficiency of ~3% has been created. PMID- 21263489 TI - Eye-safe 2 MUm luminescence from thulium-doped silicon. AB - We report on photoluminescence in the 1.7-2.1 MUm range of silicon doped with thulium. This is achieved by the implantation of Tm into silicon that has been codoped with boron to reduce the thermal quenching. At least six strong lines can be distinguished at 80 K; at 300 K, the spectrum is dominated by the main emission at 2 MUm. These emissions are attributed to the trivalent Tm(3+) internal transitions between the first excited state and the ground state. PMID- 21263490 TI - Total variation approach for adaptive nonuniformity correction in focal-plane arrays. AB - In this Letter we propose an adaptive scene-based nonuniformity correction method for fixed-pattern noise removal in imaging arrays. It is based on the minimization of the total variation of the estimated irradiance, and the resulting function is optimized by an isotropic total variation approach making use of an alternating minimization strategy. The proposed method provides enhanced results when applied to a diverse set of real IR imagery, accurately estimating the nonunifomity parameters of each detector in the focal-plane array at a fast convergence rate, while also forming fewer ghosting artifacts. PMID- 21263491 TI - Adhesion force studies using a dangling optical lever with variable sensitivity. AB - Adhesion force sensed using tips on microcantilevers via an optical lever requires care to ensure that the tip alone contacts the liquid; is sensitive to high degrees of measurement error from departure from the laser spot; requires specialized optics and careful arrangement to produce a small laser probing spot; and limits the distance between cantilever and photodiode for increased force sensitivity. An alternative scheme, using microimaging electronic speckle pattern interferometry to monitor the deformation of a tipless microcantilever, necessitates that the beam be rigid enough to be independent of the drop location; is not amenable to very low adhesion force measurement; and requires more complicated instrumentation. All these limitations can be effectively circumvented by a variable sensitivity scheme described here that harnesses the geometric properties of a dangling cantilever operating as an optical lever. PMID- 21263492 TI - High-performance 90 degrees hybrid based on a silicon-on-insulator multimode interference coupler. AB - We propose a multimode interference coupler (MMI) design for high-index-contrast technologies based on a shallowly etched multimode region, which is, for the first time to our knowledge, directly coupled to deeply etched input and output waveguides. This reduces the phase errors associated with the high-index contrast, while still allowing for a very compact layout. Using this structure, we fabricate a 2 * 4 MMI operating as a 90 degrees hybrid, with a footprint of only 0.65 mm * 0.53 mm, including all the structures necessary to couple light to a fiber array. We experimentally demonstrate a common mode rejection ratio better than -20 dBe and phase errors better than +/-5 degrees in a ~50 nm bandwidth. PMID- 21263493 TI - Adaptive waveguide bends with homogeneous, nonmagnetic, and isotropic materials. AB - We propose a method for adaptive waveguide bends using homogeneous, nonmagnetic, and isotropic materials, which simplifies the parameters of the bends to the utmost extent. The proposed bend has an adaptive and compact shape because of all the flat boundaries. The nonmagnetic property is realized by selecting OB'/OC = 0.5. Only two nonmagnetic isotropic dielectrics are needed throughout, and the transmission is not sensitive to nonmagnetic isotropic dielectrics. Results validate and illustrate these functionalities, which make the bend much easier to fabricate and apply, owing to its simple parameters, compact shape, and versatility in connecting different waveguides. PMID- 21263494 TI - Multimode nematicon waveguides. AB - We report on the first (to our knowledge) experimental observation of higher order modes guided by soliton-induced waveguides in nematic liquid crystals. We find that the nematicon waveguides operate in a bounded power region specific to each guided mode. Below this region, the guided beams diffract; above this region, the mode mixing and coupling give rise to an unstable output. PMID- 21263495 TI - Ultrabroadband detection of a mid-IR continuum by chirped-pulse upconversion. AB - Ultrabroadband mid-IR continuum pulses can be detected on a single-shot basis using chirped-pulse upconversion. Converting the mid-IR pulse to the visible reduces the fractional bandwidth and enables use of a silicon CCD camera. Removing the cross-phase modulation of the chirped pulse results in 1 cm(-1) resolution over a 600 cm(-1) detected bandwidth. PMID- 21263496 TI - Experimental proposal for the generation of entangled photon triplets by third order spontaneous parametric downconversion in optical fibers. AB - We present an experimental proposal for the generation of photon triplets based on third-order spontaneous parametric downconversion in thin optical fibers. Our analysis includes expressions for the quantum state, which describes the photon triplets and for the generation rate in terms of all experimental parameters. We also present, for a specific source design, numerically calculated generation rates. PMID- 21263497 TI - Nonparaxial (1 + 1)D spatial solitons in uniaxial media. AB - We investigate nonparaxial spatial solitons in uniaxial media with a cubic nonlinearity, accounting for the fully vectorial electromagnetic perturbation and the longitudinal field component in the self-induced index well. We discuss the effective nonlocality arising in purely Kerr media and soliton self-steering owing to nonlinear changes in walk-off. PMID- 21263498 TI - Simultaneous velocity and temperature measurements in gaseous flow fields using the VENOM technique. AB - We present an initial demonstration of simultaneous velocity and temperature mapping in gaseous flow fields using a new nitric oxide planar laser-induced fluorescence-based method. The vibrationally excited NO monitoring (VENOM) technique is an extension of two-component velocimetry using vibrationally excited NO generated from the photodissociation of seeded NO(2) [Appl. Opt. 48, 4414 (2009)], where the two sequential fluorescence images are obtained probing two different rotational states to provide both velocity and temperature maps. Comparisons to computational fluid dynamics simulations show that the initial VENOM measurements provide good velocity and temperature maps in the relatively high-density regions of the flow, where the rms uncertainties are approximately 5% for velocity and 9% for temperature. PMID- 21263499 TI - Perfect imaging of hypersurfaces via transformation optics. AB - Conventional optical imaging systems suffer from the presence of many imperfections, such as spherical aberrations, astigmatism, or coma. If the imaging system is corrected for spherical aberrations and fulfills the Abbe sine condition, perfect imaging is guaranteed between two parallel planes but only in a small neighborhood of the optical axis. It is therefore worth asking for optical systems that would allow for perfect imaging between arbitrary smooth surfaces without restrictions in shape or extension. In this Letter, we describe the application of transformation optics to design refractive index distributions that allow perfect, aberration-free imaging for various imaging configurations in R(n). A special case is the imaging between two extended parallel lines in R(2), which leads to the well-known hyperbolic secant index distribution that is used for the fabrication of gradient index lenses. PMID- 21263500 TI - Corkscrew point spread function for far-field three-dimensional nanoscale localization of pointlike objects. AB - We describe the corkscrew point spread function (PSF), which can localize objects in three dimensions throughout a 3.2 MUm depth of field with nanometer precision. The corkscrew PSF rotates as a function of the axial (z) position of an emitter. Fisher information calculations show that the corkscrew PSF can achieve nanometer localization precision with limited numbers of photons. We demonstrate three dimensional super-resolution microscopy with the corkscrew PSF by imaging beads on the surface of a triangular polydimethylsiloxane (PDMS) grating. With 99,000 photons detected, the corkscrew PSF achieves a localization precision of 2.7 nm in x, 2.1 nm in y, and 5.7 nm in z. PMID- 21263501 TI - All-fiber controller of radial polarization using a periodic stress. AB - Our aim is to transpose the polarization control by mechanical stress, usually applied to single-mode fibers, to the (TM(01), TE(01), HE(21)(ev), HE(21)(od)) annular mode family. Nevertheless, the quasi-degeneracy of these four modes makes the situation more complex than with the fundamental mode HE(11). We propose a simple device based on periodic perturbation and mode coupling to produce the radially polarized TM(01) mode or at least one of the four modes at the extremity of an arbitrarily long fiber, the conversion to TM(01) mode being achievable by classical crystalline plates. PMID- 21263502 TI - Silicon-based liquid-crystal cell for self-branching of optical packets. AB - Self-controlled photonic switching was achieved by combining the photoconductivity of a semiconductor and the electrical tunability of a liquid crystal (LC). Pulse packets of 1.06 MUm wavelength created free carriers in a silicon electrode of an LC cell, which triggered voltage application for LC reorientation. Consequently, polarization direction of the succeeding packets became perpendicular to that of the preceding packets, and they progressed in different directions after passing through a polarization beam splitter. The cascade LC cells divided a series of packets one by one in a self-controlled manner. PMID- 21263503 TI - Cloaking apertureless near-field scanning optical microscopy tips. AB - We numerically demonstrate that properly designed plasmonic covers can be used to enhance the performance of near-field scanning optical microscopy (NSOM) systems based on the employment of apertureless metallic tip probes. The covering material, exhibiting a near-zero value of the real permittivity at the working frequency, is designed in such a way to dramatically reduce the undesired scattering due to the strongly plasmonic behavior of the tip. Though the light scattering by the tip end is necessary for the correct operation of NSOMs, the additional scattering due to the whole probe affects the signal-to-noise ratio and thus the resolution of the acquired image. By covering the whole probe but not the very tip, we show that unwanted scattering can be effectively reduced. A realistic setup, working at mid-IR frequencies and employing silicon carbide covers, has been designed and simulated to confirm the effectiveness of the proposed approach. PMID- 21263504 TI - Experimental requirement of the error-compensating five-frame interferogram collecting sequence used in phase-shifting interferometry. AB - Digital phase-shifting interferometry (PSI), a technique widely used in optical testing, requires interferograms collected at optical phase differences separated by a definite phase step. The five-frame interferogram-collecting sequence suggested by Hariharan et al. [Appl. Opt. 26, 2504 (1987)] is extremely effective in significantly reducing the errors in height profiles derived using PSI that are caused by phase-step errors. In this Letter, we report on a class of five frame sequence that, owing to its mathematical equivalence with the one suggested by Hariharan et al. and its ease of execution, is more commonly used but is much less effective in reducing the height profile errors caused by phase-step errors. PMID- 21263505 TI - Scaling of optical forces in dielectric waveguides: rigorous connection between radiation pressure and dispersion. AB - We show that eigenmodes of dielectric optical waveguides exert surface dilation forces on waveguide boundaries owing to radiation pressure, and we develop an exact scaling law relating modal dispersion of an arbitrary dielectric waveguide to the magnitude of optical forces generated by radiation pressure. This result points to highly dispersive waveguides as an optimal choice for the generation of large optical forces in nano-optomechanical systems. Exact agreement with ab initio calculations is demonstrated. PMID- 21263506 TI - Optical time-domain analog pattern correlator for high-speed real-time image recognition. AB - The speed of image processing is limited by image acquisition circuitry. While optical pattern recognition techniques can reduce the computational burden on digital image processing, their image correlation rates are typically low due to the use of spatial optical elements. Here we report a method that overcomes this limitation and enables fast real-time analog image recognition at a record correlation rate of 36.7 MHz--1000 times higher rates than conventional methods. This technique seamlessly performs image acquisition, correlation, and signal integration all optically in the time domain before analog-to-digital conversion by virtue of optical space-to-time mapping. PMID- 21263507 TI - Contactless photoconductive terahertz generation. AB - We describe a pulsed terahertz (THz) emitter that uses a rapidly oscillating, high-voltage bias across electrodes insulated from a photoconductor. Because no carriers are injected from the electrodes, trap-enhanced electric fields do not form. The resulting uniform field allows excitation with a large laser spot, lowering the carrier density for a given pulse energy and increasing the efficiency of THz generation. Compared to a dc bias, less susceptibility to damage is observed. PMID- 21263508 TI - Octave-spanning carrier-envelope phase stabilized visible pulse with sub-3-fs pulse duration. AB - The visible second harmonic of the idler output from a noncollinear optical parametric amplifier was compressed using adaptive dispersion control with a deformable mirror. The amplifier was pumped by and seeded in the signal path by a common 400 nm second-harmonic pulse from a Ti:sapphire regenerative amplifier. Thus, both the idler output and the second harmonic of the idler were passively carrier-envelope phase stabilized. The shortest pulse duration achieved was below 3 fs. PMID- 21263509 TI - Large-area, uniform, high-spatial-frequency ripples generated on silicon using a nanojoule-femtosecond laser at high repetition rate. AB - Large-area high-spatial-frequency patterns (HSFLs) of lambda/6 periodicity have been generated by a nanojoule-femtosecond laser scanning technique (80 MHz, 170 fs, 700-950 nm) at the silicon-air interface. The excellent large-area uniformity allowed reproducible and accurate measurements of the periodicity. Variation of experimental parameters as illumination geometry, and pulse energy and number showed no influence on the ripple spacing. A wavelength dependence was observed and compared to current models of HSFL formation. A particular second-harmonic model was found to match the results best but needs to take into account transient changes in the refractive index under laser exposure. A second-harmonic mechanism is further supported by direct spectroscopic observation. PMID- 21263510 TI - Long-range simplex-coded BOTDA sensor over 120 km distance employing optical preamplification. AB - In this Letter, we combine the use of optical preamplification at the receiver and optical pulse coding techniques with an optimized modulation format to effectively extend the sensing range of Brillouin optical time-domain analysis (BOTDA) sensors. Combining a return-to-zero modulation format with 25% duty cycle and linear gain preamplification allows for temperature and strain measurements over 120 km of standard single-mode fiber with 3 m spatial resolution and an rms strain-temperature accuracy of 3.1 degrees C/60 MUepsilon respectively. PMID- 21263511 TI - Side-pumped crystalline Raman laser. AB - A crystalline Raman laser is pumped at 90 degrees to the Raman laser axis by a single pass from a line-focused 532 nm pump laser of pulse duration 10 ns. The Raman laser threshold was 6.1 mJ, and at 12 mJ pump energy, a maximum output energy of 2.7 mJ was obtained with a slope efficiency of 46%. The threshold pump intensity is within a factor of 2 of the same device when end-pumped. The results highlight significant potential for coherent beam conversion and combination with enhanced degrees of flexibility and increased power. PMID- 21263512 TI - High-efficiency electro-optic amplitude modulation with delayed coherent addition. AB - Amplitude modulation of laser light is required for resonant sideband extraction employed in gravitational-wave detectors. Amplitude modulation with electro-optic phase modulators is realized by interferometric phase-to-amplitude conversion. Although two outputs modulated at opposite phases to each other are obtained, usually only one of them is utilized and the other is abandoned. The reuse of this abandoned light improves the power efficiency of the modulation. This can be realized by inverting the modulation phase of one output with a delay line and adding it to the other coherently. Moreover, this system selects a high efficiency operating point and modulates the light in a linear range. We demonstrate that the modulation system can be operated with a power loss that is due only to the losses of the optical components. PMID- 21263513 TI - High-peak-power nanosecond pulse generation by stimulated Brillouin scattering pulse compression in a seeded Yb-doped fiber amplifier. AB - We demonstrate the generation of nanosecond and multikilowatt peak-power pulses in a double-clad Yb-doped fiber amplifier seeded by a spectrally narrowed gain switched laser diode. Injected pulses with 100 ns duration were simultaneously compressed and amplified by the combination of high amplifier gain and stimulated Brillouin scattering. A maximum peak power of 20 kW has been obtained, corresponding to a single-pass gain of +57 dB in terms of peak power. Part of this output signal was also converted into IR continuum light by splicing a length of single-mode fiber at the end of the fiber amplifier. PMID- 21263514 TI - High average and peak power femtosecond large-pitch photonic-crystal-fiber laser. AB - We report on the generation of high-average-power and high-peak-power ultrashort pulses from a mode-locked fiber laser operating in the all-normal-dispersion regime. As gain medium, a large-mode-area ytterbium-doped large-pitch photonic crystal fiber is used. The self-starting fiber laser delivers 27 W of average power at 50.57 MHz repetition rate, resulting in 534 nJ of pulse energy. The laser produces positively chirped 2 ps output pulses, which are compressed down to sub-100 fs, leading to pulse peak powers as high as 3.2 MW. PMID- 21263515 TI - Long-wave approximation for hybridization modeling of local surface plasmonic resonance in nanoshells. AB - A hybridization model for the localized surface plasmon resonance of a nanoshell is developed within the framework of long-wave approximation. Compared with the existing hybridization model derived from the hydrodynamic simulation of free electron gas, this approach is much simpler and gives identical results for a concentric nanoshell. Also, with this approach, the limitations associated with the original hybridization model are succinctly stated. Extension of this approach to hybridization modeling of more complicated structures such as multiplayered nanoshells is straightforward. PMID- 21263516 TI - Femtosecond surface plasmon pulse propagation. AB - We analyze ultrafast surface plasmon-polariton pulse reshaping effects and nonlinear propagation modes for metal/dielectric plasmon waveguides. It is found that group velocity and loss dispersion effects can substantially modify both pulse duration (broadening/narrowing) and intensity decay (acceleration/retardation) by as much as several tens of percentage points in the short-pulse regime and that metallic nonlinearities alone may support soliton, self-focusing, and self-compressing modes. PMID- 21263517 TI - Antireflective properties of porous Si nanocolumnar structures with graded refractive index layers. AB - We report on the antireflective characteristics of porous silicon (Si) nanocolumnar structures consisting of graded refractive index layers and carry out a rigorous coupled-wave analysis simulation. The refractive index of Si is gradually modified by a tilted angle electron beam evaporation method. For the fabricated Si nanostructure with a Gaussian index profile of 100 nm, reflectivity (R) of less than 7.5% is obtained with an average value of approximately 2.9% at the wavelength region of 400-800 nm. The experimental results are reasonably consistent with the simulated results for the design of antireflective Si nanostructures. PMID- 21263518 TI - Suppression of the frequency drift of modulational instability sidebands by means of a fiber system associated with a photon reservoir. AB - We analyze fiber systems where the linear losses act as a strong perturbation, causing a frequency drift of the modulational instability sidebands. We achieve the total suppression of this frequency drift by means of a technique based on the concept of a photon reservoir, which feeds in situ the process of modulational instability by continually supplying it the amount of photons absorbed by the fiber. PMID- 21263519 TI - Femtosecond and continuous-wave laser performance of a diode-pumped Yb3+:CaYAlO4 laser. AB - The cw and femtosecond laser operations of Yb(3+):CaYAlO(4) (Yb:CYA) are demonstrated. The laser emitted a maximum cw power of 1.94 W with a slope efficiency (eta(slope)) of 71% and an optical-to-optical efficiency (eta(opt)) of 51%. Under mode-locking operation, the laser emitted near transform-limited pulses with 156 fs pulse width, 8.1 nJ pulse energy and 0.74 W average power. The eta(slope) and eta(opt) of the mode-locked laser were 37% and 20%, respectively. PMID- 21263520 TI - Space-selective precipitation of Ge crystalline patterns in glasses by femtosecond laser irradiation. AB - Crystalline Ge was induced space selectively inside a borosilicate glass by 800 nm, 250 kHz femtosecond laser irradiation. Micro-Raman spectra and x-ray diffraction analysis confirmed that the laser-induced crystals were cubic Ge. A periodic structure consisting of Ge crystalline lines was inscribed in the glass sample by continuously moving the focal point of the laser beam. Large third order nonlinear optical properties and ultrafast response time were observed from the crystallization region owing to highly optical nonlinearity of Ge crystals. These results may find some applications in fabrication of functional optical and photonic devices, such as optical circuits. PMID- 21263521 TI - Measurement of the dielectric constant of thin films by terahertz time-domain spectroscopic ellipsometry. AB - We present a reflection-type terahertz time-domain spectroscopic ellipsometry (THz-TDSE) technique for measuring the complex dielectric constants of thin-film materials without replacement of the sample. THz-TDSE provides complex dielectric constants from the ratio of the complex amplitude reflection coefficients between p- and s-polarized THz waves. The measured dielectric constants of doped GaAs thin films show good agreement with predictions of the Drude model, even though the film thickness is of the order of a tenth of the penetration depth of the THz waves. In addition, we demonstrate the measurements of soft-phonon dispersion in SrTiO(3) thin films deposited on a Pt layer. The obtained dielectric constants agree well with the predictions of a generalized harmonic oscillator model. PMID- 21263522 TI - Femtosecond laser microfabricated fiber Mach-Zehnder interferometer for sensing applications. AB - We demonstrate a femtosecond laser microfabricated fiber Mach-Zehnder interferometer and reveal the dependences of the sensitivities of different environmental parameters on the specifications of the interferometer. A 30-mm long fiber interferometer at a wavelength of 1593 nm exhibits a temperature sensitivity of 0.103 nm/ degrees C, axial strain sensitivity of -1.35 pm/MUepsilon, and refractive index sensitivity of -15.294 nm/RIU, respectively. In addition to dependence on interferometer length, the sensitivities are also strongly dependent on the operation wavelength of the selected interference order. When the operation wavelength is selected at 1525 nm, the sensitivities are 0.085 nm/ degrees C, -0.09 pm/MUepsilon, and -13.824 nm/RIU, respectively. PMID- 21263523 TI - All-fiber acousto-optic tunable notch filter with a fiber winding driven by a cuneal acoustic transducer. AB - We report a type of all-fiber acousto-optic tunable notch filter consisting of a cuneal acoustic transducer and a fiber winding of four unjacketed single-mode fibers. With -32 dB peak rejection efficiency and 178 nm tunable range of the central wavelength, all of the tunable characteristics of the all-fiber acousto optic tunable filter are kept. In addition, the structure is versatile and convenient for use in building other complicated filters. As an example, a coarse comblike filter has been built by adjusting the axial strains of the unjacketed fibers. PMID- 21263524 TI - Transparent Fourier transform spectrometer. AB - We realized a transparent Fourier transform spectrometer and investigated its operating principle. The spectrometer consists of a low-reflectivity Fabry-Perot interferometer and a partially transparent photodetector, which allows for the operation of the spectrometer in transmission. By changing the distance between the low-reflectivity mirrors of the Fabry-Perot interferometer, the light intensity that reaches the partially transparent photodetector is modulated and the spectral information of the incident light is determined by the Fourier transform of the generated photocurrent. This transparent Fourier transform spectrometer allows easy miniaturization and integration into any kind of optical system. PMID- 21263525 TI - Time-division multiplexing-based BOTDA over 100 km sensing length. AB - We propose and demonstrate a high-performance and long-range Brillouin optical time-domain analysis (BOTDA) based on time-division multiplexing measurement, where a probe pulse and a pump pulse are used to perform the measurement on a selected sensing section, and the measurement of the entire sensing fiber is realized by combining the series measurements over different sections through changing the delay time between the two pulses. In experiment, a 100 km sensing fiber is divided into 11 sections based on the gain-controlled principle, and spatial resolutions of 0.6 m and 2 m are obtained at the end of 75 km and 100 km, respectively. PMID- 21263526 TI - Diode-pumped Pr:BaY2F8 continuous-wave orange laser. AB - We report the realization of the continuous wave laser emission in the orange at 607 nm from a Pr:BaY(2)F(8) (Pr:BYF) crystal pumped by a blue GaN laser diode. A maximal output power of 78 mW is obtained in a quasi-single transverse mode beam. The effect of reabsorption losses at the laser wavelength is also evidenced. PMID- 21263527 TI - Attosecond twin-pulse control by generalized kinetic heterodyne mixing. AB - Attosecond double-pulse (twin-pulse) production in high-order harmonic generation is manipulated by a combination of two-color and carrier-envelope phase-control methods. As we show in numerical simulations, both relative amplitude and phase of the double pulse can be independently set by making use of multidimensional parameter control. Two technical implementation routes are discussed: kinetic heterodyning using second-harmonic generation and split-spectrum phase-step control. PMID- 21263528 TI - Multibeam scintillation cumulative distribution function. AB - The gamma-gamma probability density function is commonly used to model the scintillation of a single laser beam propagating through atmospheric turbulence. One method proposed to reduce scintillation at the receiver plane involves the use of multiple channels propagating through independent paths, resulting in a sum of independent gamma-gamma random variables. Recently, a novel approach for an accurate, closed-form approximation for the sum of independent, identically distributed gamma-gamma random variables was introduced by Chatzidiamantis et al. [GLOBECOM 2009--2009 IEEE Global Telecommunications Conference (2009)]. Using this approximation, we present the first analytic model for the distribution of irradiance due to propagating multiple independent beams. This model compares favorably to wave-optics simulations. PMID- 21263529 TI - Optimal acquisition scheme for subwavelength localization microscopy of bleachable fluorophores. AB - We consider the problem of optimizing superresolution microscopy with photoswitchable molecules that irreversibly photobleach. Using variational methods, we show that the number of single-molecule images is maximized in a simple scheme with a constant number of activated fluorophores per cycle. For high-speed acquisition, deviations from the optimal scheme do reduce the information collected but fortuitously also reduce certain types of errors, making the scheme very robust. Finally, we calculate the amount of information lost due to bleaching and noise. PMID- 21263530 TI - Pulse compression and fiber delivery of 45 fs Fourier transform limited pulses at 830 nm. AB - A specific scheme is used for fiber delivery of ultrashort pulses using conventional elements. Starting from a standard femtosecond Ti:Al(2)O(3) oscillator (150 fs @ 830 nm), perfectly compressed ultrashort pulses with a duration of 45 fs are produced at the output of a standard two meter long single mode fiber. The setup allows compensating independently and simultaneously second and third orders of chromatic dispersion as well as management of self-phase modulation in the fiber. It includes an optimized dispersion compensation line made of the assembly of diffraction gratings and prisms. The unsurpassed performances of the device are experimentally and numerically highlighted. Fiber delivery of sub-30 fs multinanojoule pulses is discussed. PMID- 21263531 TI - Vectorial structure of far field of cylindrically polarized beams diffracted at a circular aperture. AB - Based on the vector angular spectrum representation and the method of stationary phase, the analytical vectorial structure of the cylindrically polarized Laguerre Gaussian beam diffracted at a circular aperture is derived in the far field, which provides an approach to further comprehend the vectorial properties of the apertured cylindrically polarized beams. The radially polarized, azimuthally polarized, and unapertured cases can be viewed as the special cases of our general result. The analyses show that the far-field energy flux distributions of the entire beam, the TE term, and the TM term depend on the beam order, the ratio of the waist width to the wavelength, the truncation parameter, and the angle between the electric field vector and the radial direction. PMID- 21263532 TI - Ultrahigh-bandwidth, on-chip all-optical pulse erasure using the chi(3) process in a nonlinear chalcogenide waveguide. AB - We demonstrate on-chip all-optical pulse erasure based on four-wave mixing and cross-phase modulation in a dispersion engineered chalcogenide (As(2)S(3)) rib waveguide. We achieve an erasure efficiency of ~15 dB for picosecond pulses in good agreement with numerical simulations using the nonlinear Schrodinger equation. The combined effect of the high instantaneous optical nonlinearity (gamma = 9900 (W km)(-1)) and small group-velocity dispersion (D = 29 ps/nm km), which reduces pulse walk-off, will enable all-optical pulse erasure for ultrafast signal processing. PMID- 21263533 TI - Nonlinear optical transformation of the polarization state of circularly polarized light with holographic-cut cubic crystals. AB - Nonlinear modification of circularly polarized light propagating in holographic cut cubic crystals is theoretically predicted and experimentally observed. To the best of our knowledge this is the first demonstration of nonlinear modification of circularly polarized light with cubic crystals. PMID- 21263534 TI - Direct diode-laser pumping of a mode-locked Ti:sapphire laser. AB - Direct diode-laser pumping of a mode-locked Ti:Al(2)O(3) laser is reported. A single 1 W GaN-based diode laser operating at 452 nm is used as the pump laser. Pulse durations as short as 114 fs and average output powers of up to 13 mW are obtained. PMID- 21263535 TI - Photonic-crystal time-domain simulations using Wannier functions. AB - We present a Wannier-function-based time-domain method for photonic-crystal integrated optical circuits. In contrast to other approaches, this method allows one to trade CPU time against memory consumption and therefore is particularly well suited for the treatment of large-scale systems. As an illustration, we apply the method to the design of a photonic-crystal-based sensor, which utilizes a dual Mach-Zehnder-Fano interferometer. PMID- 21263536 TI - Over 1 hour continuous-wave operation of photonic crystal lasers. AB - We report on the long lifetime (>1 hour) of photonic crystal (PC) lasers under continuous-wave (CW) operation. For stable CW operation, we van-der-Waals-bonded our PC lasers to a novel submount structure consisting of MgF2-diamond bilayers on silicon substrate, which simultaneously ensures vertical mode confinement and efficient heat spread/dissipation. The combination of a Gamma-point band-edge mode and butt-end fiber coupling yielded high CW fiber-coupled output power (~200 MUW). The results demonstrate that the CW lifetime of PC lasers can be extended to the level for practical applications. PMID- 21263538 TI - Superconducting nanowire single-photon detectors integrated with optical nano antennae. AB - Optical nano-antennae have been integrated with semiconductor lasers to intensify light at the nanoscale and photodiodes to enhance photocurrent. In quantum optics, plasmonic metal structures have been used to enhance nonclassical light emission from single quantum dots. Absorption and detection of single photons from free space could also be enhanced by nanometallic antennae, but this has not previously been demonstrated. Here, we use nano-optical transmission effects in a one-dimensional gold structure, combined with optical cavity resonance, to form optical nano-antennae, which are further used to couple single photons from free space into a 80-nm-wide superconducting nanowire. This antenna-assisted coupling enables a superconducting nanowire single-photon detector with 47% device efficiency at the wavelength of 1550 nm and 9-MUm-by-9-MUm active area while maintaining a reset time of only 5 ns. We demonstrate nanoscale antenna-like structures to achieve exceptional efficiency and speed in single-photon detection. PMID- 21263539 TI - Reference calculation of light propagation between parallel planes of different sizes and sampling rates. AB - The article deals with a method of calculation of off-axis light propagation between parallel planes using discretization of the Rayleigh-Sommerfeld integral and its implementation by fast convolution. It analyses zero-padding in case of different plane sizes. In case of memory restrictions, it suggests splitting the calculation into tiles and shows that splitting leads to a faster calculation when plane sizes are a lot different. Next, it suggests how to calculate propagation in case of different sampling rates by splitting planes into interleaved tiles and shows this to be faster than zero-padding and direct calculation. Neither the speedup nor memory-saving method decreases accuracy; the aim of the proposed method is to provide reference data that can be compared to the results of faster and less precise methods. PMID- 21263537 TI - Registration of OCT fundus images with color fundus photographs based on blood vessel ridges. AB - This paper proposes an algorithm to register OCT fundus images (OFIs) with color fundus photographs (CFPs). This makes it possible to correlate retinal features across the different imaging modalities. Blood vessel ridges are taken as features for registration. A specially defined distance, incorporating information of normal direction of blood vessel ridge pixels, is designed to calculate the distance between each pair of pixels to be matched in the pair image. Based on this distance a similarity function between the pair image is defined. Brute force search is used for a coarse registration and then an Iterative Closest Point (ICP) algorithm for a more accurate registration. The registration algorithm was tested on a sample set containing images of both normal eyes and eyes with pathologies. Three transformation models (similarity, affine and quadratic models) were tested on all image pairs respectively. The experimental results showed that the registration algorithm worked well. The average root mean square errors for the affine model are 31 um (normal) and 59 um (eyes with disease). The proposed algorithm can be easily adapted to registration for other modality retinal images. PMID- 21263540 TI - Supercontinuum pulse measurement by molecular alignment based cross-correlation frequency resolved optical gating. AB - We demonstrate that complex supercontinuum and few-cycle ultrashort laser pulses can be fully characterized by using a cross-correlation frequency-resolved optical gating with molecular alignment induced birefringence functioned as a gate. The temporal envelope and phase of the broadband supercontinuum pulse are retrieved by the principal component generalized projection algorithm. This technique shows advantages without phase-matching constraint that may limit the measurable spectral bandwidth, experimental robustness in operating through the whole transparent spectral region of the molecular gases, and intensity sensitivity to measure weak pulses which is inherited from the intrinsic linear process in recording the molecular birefringence induced polarization spectroscopy. Experimental measurements of a few-cycle pulse in the visible region of 525-725 nm confirm that the molecular alignment gating supports a full field characterization of the ultrashort pulse around 10 fs in duration. PMID- 21263541 TI - Non-blocking 4x4 electro-optic silicon switch for on-chip photonic networks. AB - We present a 4x4 spatially non-blocking Mach-Zehnder based silicon optical switch fabricated using processes fully compatible with standard CMOS. We successfully demonstrate operation in all 9 unique switch states and 12 possible I/O routing configurations, with worst-case cross-talk levels lower than -9 dB, and common spectral bandwidth of 7 nm. High-speed 40 Gbps data transmission experiments verify optical data integrity for all input-output channels. PMID- 21263542 TI - Engineered optical nonlinearity for quantum light sources. AB - Many applications in optical quantum information processing benefit from careful spectral shaping of single-photon wave-packets. In this paper we tailor the joint spectral wave-function of photons created in parametric downconversion by engineering the nonlinearity profile of a poled crystal. We designed a crystal with an approximately Gaussian nonlinearity profile and confirmed successful wave packet shaping by two-photon interference experiments. We numerically show how our method can be applied for attaining one of the currently most important goals of single-photon quantum optics, the creation of pure single photons without spectral correlations. PMID- 21263543 TI - All-solid highly nonlinear singlemode fibers with a tailored dispersion profile. AB - We investigate a novel approach to obtain highly nonlinear fibers with a tailored group velocity dispersion around a desired wavelength region of interest. Rather than exploiting longitudinal holes to control the average refractive index of the cladding and hence the fiber's waveguide dispersion, as in holey fibers, we propose using an all-solid cladding with a suitably chosen refractive index difference relative to the core. We demonstrate numerically that this solution allows a large freedom in the manipulation of the overall fiber dispersive properties, while enabling, in practice, a much more accurate control of the fiber's structural properties during fabrication. Effectively single mode guidance over a broad wavelength range can be achieved through the use of a second outer cladding forming a W-type index profile. We derive simple design rules for dispersion controlled fibers, based on which an algorithm for the automatic dispersion optimization is proposed, implemented and used to design various nonlinear fibers for all-optical processing and supercontinuum generation. Fabrication of a lead silicate fiber with flattened dispersion at telecoms wavelengths confirms the potential of these new fibers. PMID- 21263544 TI - Internal field distribution measurement in 1-D strongly anisotropic sub wavelength periodic structures of finite length. AB - We report measurements of the internal field intensity distribution in finite length one dimensional strongly anisotropic sub-wavelength periodic structures in the vicinity of the photonic band gap (PBG) edge. The strong in-plane anisotropy of more than 10% index contrast is obtained via form birefringent sub-wavelength gratings. The structures have a period of less than half the wavelength. Depending on the excitation frequency, both standing wave and evanescent Bloch modes can be identified and observed experimentally. The field enhancement near the PBG edge is confirmed also but at a significantly reduced strength attributed to the small but finite material loss. PMID- 21263545 TI - Efficient cross polarized wave generation for compact, energy-scalable, ultrashort laser sources. AB - The generation of high contrast and ultrashort laser pulses via a compact and energy-scalable cross polarized wave filter is presented. The setup incorporates a waveguide spatial filter into a single crystal XPW configuration, enabling high energy and high intensity transmission, efficient contrast enhancement and pulse shortening at the multi-mJ level. Excellent XPW conversion of up to 33% (global efficiency: 20%, intensity transmission: 40%) led to an output energy of 650 uJ for an input of 3.3 mJ. Additionally, efficient conversion under specific input phase conditions, allowed pulse shortening from 25 fs to 9.6 fs, indicating the prospective application of this setup as a high energy, ultrabroad laser source. PMID- 21263547 TI - Shot-noise limited detection for surface plasmon sensing. AB - It is demonstrated that surface plasmon sensing can be performed in the shot noise-limited regime to resolve index of refractive changes on the order of 10-10/?Hz at input powers of 1 mW. This improved resolution is achieved by using active electronic noise cancelling to suppress laser intensity noise and a wavelength that maximizes sensitivity to index of refraction changes occurring at an interface. The resolution of the system is experimentally demonstrated by measuring the refractive index change of air in response to pressure changes. PMID- 21263546 TI - Intrinsic optical signal imaging of glucose-stimulated insulin secreting beta cells. AB - Simultaneous monitoring of many functioning beta-cells is essential for understanding beta-cell dysfunction as an early event in the progression to diabetes. Intrinsic optical signal (IOS) imaging has been shown to allow high resolution detection of stimulus-evoked physiological responses in the retina and other neural tissues. In this paper, we demonstrate the feasibility of using IOS imaging for functional examination of insulin secreting INS-1 cells, a popular model for investigating diabetes associated beta-cell dysfunction. Our experiments indicate that IOS imaging permits simultaneous monitoring of glucose stimulated physiological responses in multiple cells with high spatial (sub cellular) and temporal (sub-second) resolution. Rapid IOS image sequences revealed transient optical responses that had time courses tightly correlated with the glucose stimulation. PMID- 21263549 TI - Understanding of photocurrent enhancement in real thin film solar cells: towards optimal one-dimensional gratings. AB - Despite the progress in the engineering of structures to enhance photocurrent in thin film solar cells, there are few comprehensive studies which provide general and intuitive insight into the problem of light trapping. Also, lack of theoretical propositions which are consistent with fabrication is an issue to be improved. We investigate a real thin film solar cell with almost conformal layers grown on a 1D grating metallic back-reflector both experimentally and theoretically. Photocurrent increase is observed as an outcome of guided mode excitation in both theory and experiment by obtaining the external quantum efficiency of the cell for different angles of incidence and in both polarization directions. Finally, the effect of geometrical parameters on the short circuit current density of the device is investigated by considering different substrate shapes that are compatible with solar cell fabrication. Based on our simulations, among the investigated shapes, triangular gratings with a very sharp slope in one side, so called sawtooth gratings, are the most promising 1D gratings for optimal light trapping. PMID- 21263548 TI - Integrated spectrometer design with application to multiphoton microscopy. AB - We present a prism-based spectrometer integrated into a multifocal, multiphoton microscope. The multifocal configuration facilitates interrogation of samples under different excitation conditions. Notably, the image plane of the microscope and the image plane of the spectrometer are coincident eliminating the need for an intermediate image plane containing an entrance slit. An EM-CCD detector provides sufficient gain for spectral interrogation of single-emitters. We employ this spectrometer to observe spectral shifts in the two-photon excitation fluorescence emission of single CdSe nanodots as a function of excitation polarization. PMID- 21263550 TI - Terahertz imaging and spectroscopy of large-area single-layer graphene. AB - We demonstrate terahertz (THz) imaging and spectroscopy of a 15 * 15-mm2 single layer graphene film on Si using broadband THz pulses. The THz images clearly map out the THz carrier dynamics of the graphene-on-Si sample, allowing us to measure sheet conductivity with sub-mm resolution without fabricating electrodes. The THz carrier dynamics are dominated by intraband transitions and the THz-induced electron motion is characterized by a flat spectral response. A theoretical analysis based on the Fresnel coefficients for a metallic thin film shows that the local sheet conductivity varies across the sample from sigma(s) = 1.7 * 10( 3) to 2.4 * 10(-3) Omega(-1) (sheet resistance, rho(s) = 420 - 590 Omega/sq). PMID- 21263551 TI - Two-center interference during the high harmonic generation in aligned O2 molecules. AB - We experimentally investigate the angular distribution and the laser intensity dependence of the two-center interference in high-order harmonic generation (HHG) from O2 molecules by comparing with CO2 molecules. Through the measurement of both the temporal evolution and the angular distribution of HHG, the characteristic enhancement and suppression are observed, which can be well explained by the modified interference model. Furthermore, we demonstrate that the spectral region of the constructive enhancement in aligned O2 molecules can be shifted by tuning the driving laser intensity. PMID- 21263552 TI - Simple and efficient methods for the accurate evaluation of patterning effects in ultrafast photonic switches. AB - Although patterning effects (PEs) are known to be a limiting factor of ultrafast photonic switches based on semiconductor optical amplifiers (SOAs), a simple approach for their evaluation in numerical simulations and experiments is missing. In this work, we experimentally investigate and verify a theoretical prediction of the pseudo random binary sequence (PRBS) length needed to capture the full impact of PEs. A wide range of SOAs and operation conditions are investigated. The very simple form of the PRBS length condition highlights the role of two parameters, i.e. the recovery time of the SOAs as well as the operation bit rate. Furthermore, a simple and effective method for probing the maximum PEs is demonstrated, which may relieve the computational effort or the experimental difficulties associated with the use of long PRBSs for the simulation or characterization of SOA-based switches. Good agrement with conventional PRBS characterization is obtained. The method is suitable for quick and systematic estimation and optimization of the switching performance. PMID- 21263553 TI - Application of metal-clad antiresonant reflecting hollow waveguides to tunable terahertz notch filter. AB - A novel tunable terahertz notch filter is demonstrated using antiresonant reflecting hollow waveguides with movable metal layers outside dielectric claddings. Based on the Fabry-Perot resonance of the dielectric cladding, multiple deep notches are observed in a broad THz transmission spectrum. Continuous shift of notch frequencies is for the first time experimentally observed by lateral translation of metal layers from dielectric claddings. The measured maximum frequency-tuning-range approached 60GHz, equaling to 50% of the bandwidth of every passband, and a 20dB rejection notch-depth with a linewidth as narrow as 6GHz at frequency of around 0.2THz was also achieved. Numerical simulations match the measurements and verify the spectral-tuning mechanism. PMID- 21263554 TI - Electromagnetically induced absorption with sub-kHz spectral width in a paraffin coated Rb vapor cell. AB - We report on electromagnetically induced absorption (EIA) with sub-kHz spectral width in a paraffin-coated Rb vapor cell in the Hanle configuration of the 5S(1/2)(F=2)-5P(3/2)(F'=3) transition of 87Rb atoms. Using a linearly polarized laser, the spectral width of the Hanle EIA spectrum was measured to be 0.55 mG (390 Hz). The narrow spectral width was due to the maintaining of atomic coherence between ground states while atoms collided with the anti-relaxation coated wall of the Rb vapor cell. Under a weak transverse residual magnetic field, the angle between the transverse residual magnetic field and the direction of linear polarization affected the magnitude of the narrow Hanle EIA spectrum. This is because of the change of atomic magnetic momentum due to the weak transverse residual magnetic field around the zero value of the longitudinal magnetic field. PMID- 21263555 TI - Ultra-high resolution zone-doubled diffractive X-ray optics for the multi-keV regime. AB - X-ray microscopy based on Fresnel zone plates is a powerful technique for sub-100 nm resolution imaging of biological and inorganic materials. Here, we report on the modeling, fabrication and characterization of zone-doubled Fresnel zone plates for the multi-keV regime (4-12 keV). We demonstrate unprecedented spatial resolution by resolving 15 nm lines and spaces in scanning transmission X-ray microscopy, and focusing diffraction efficiencies of 7.5% at 6.2 keV photon energy. These developments represent a significant step towards 10 nm spatial resolution for hard X-ray energies of up to 12 keV. PMID- 21263556 TI - Estimation of broadband surface emissivity from narrowband emissivities. AB - This work analyzed and addressed the estimate of the broadband emissivities for the spectral domains 3-14MUm (epsilon(3-14)) and 3-infinityMUm (epsilon(3 infinity). Two linear narrow-to-broadband conversion models were proposed to estimate broadband emissivities epsilon(3-14) and epsilon(3-infinity) using the Moderate Resolution Imaging Spectroradiometer (MODIS) derived emissivities in three thermal infrared channels 29 (8.4-8.7MUm), 31 (10.78-11.28MUm) and 32 (11.77-12.27MUm). Two independent spectral libraries, the Advanced Spaceborne Thermal Emission Reflection Radiometer (ASTER) spectral library and the MODIS UCSB (University of California, Santa Barbara) emissivity library, were used to calibrate and validate the proposed models. Comparisons of the estimated broadband emissivities using the proposed models and the calculated values from the spectral libraries, showed that the proposed method of estimation of broadband emissivity has potential accuracy and the Root Mean Square Error (RMSE) between estimated and calculated broadband emissivities is less than 0.01 for both epsilon(3-14) and epsilon(3-infinity). PMID- 21263558 TI - Nonlinear propagation in silicon-based plasmonic waveguides from the standpoint of applications. AB - Silicon-based plasmonic waveguides can be used to simultaneously transmit electrical signals and guide optical energy with deep subwavelength localization, thus providing us with a well needed connecting link between contemporary nanoelectronics and silicon photonics. In this paper, we examine the possibility of employing the large third-order nonlinearity of silicon to create active and passive photonic devices with silicon-based plasmonic waveguides. We unambiguously demonstrate that the relatively weak dependance of the Kerr effect, two-photon absorption (TPA), and stimulated Raman scattering on optical intensity, prevents them from being useful in MUm-long plasmonic waveguides. On the other hand, the TPA-initiated free-carrier effects of absorption and dispersion are much more vigorous, and have strong potential for a variety of practical applications. Our work aims to guide research efforts towards the most promising nonlinear optical phenomena in the thriving new field of silicon-based plasmonics. PMID- 21263557 TI - Damage mechanisms of MoN/SiN multilayer optics for next-generation pulsed XUV light sources. AB - We investigated the damage mechanism of MoN/SiN multilayer XUV optics under two extreme conditions: thermal annealing and irradiation with single shot intense XUV pulses from the free-electron laser facility in Hamburg - FLASH. The damage was studied "post-mortem" by means of X-ray diffraction, interference-polarizing optical microscopy, atomic force microscopy, and scanning transmission electron microscopy. Although the timescale of the damage processes and the damage threshold temperatures were different (in the case of annealing it was the dissociation temperature of Mo2N and in the case of XUV irradiation it was the melting temperature of MoN) the main damage mechanism is very similar: molecular dissociation and the formation of N2, leading to bubbles inside the multilayer structure. PMID- 21263559 TI - Beat frequency trimming of dual-polarization fiber grating lasers for multiplexed sensor applications. AB - We demonstrated a method to trim the beat frequency of dual-polarization fiber grating lasers by side-exposing the laser cavity to UV beam. The UV-side illumination induces an additional birefringence of the cavity fiber and therefore permanently changes the beat frequency of the laser. The beat frequency can be trimmed up or trimmed down, depending on the UV incident direction relative to the intrinsic polarization axis of the active fiber. A trimming range as much as ~700MHz has been achieved. This method allows us to actively control the beat frequency of dual-polarization fiber grating lasers. A 6-channel RF frequency division multiplexed polarimetric fiber grating laser array has been demonstrated. PMID- 21263560 TI - Manipulation of surface plasmon polaritons by phase modulation of incident light. AB - Manipulation of surface plasmon polaritons (SPP) by phase modulation of incident light beams is proposed with analytical and numerical verifications when an optical vortex (OV) beam is employed as an example. Fundamental functionalities of a plasmonic chip such as in-plane focusing, coupling and multiplexing of SPP by sequentially varying the topological charge of OV beam are demonstrated. Complementary to the manually-controlled optical-path-different technique reported in literature, the proposed method reveals a direct phase transform from OV beam to SPP with dynamic and reconfigurable advantages. PMID- 21263561 TI - Surface ablation of corneal stroma with few-cycle laser pulses at 800 nm. AB - We report measurements of crater diameter and surface ablation threshold as a function of laser fluence in porcine corneal stroma and fused silica with pulse durations of 7 fs (2.7 optical cycles), 30 fs and 100 fs at 800 nm. For laser pulses with Gaussian radial intensity profile, we show experimentally that the square of the crater diameter is a linear function of the logarithm of the fluence in fused silica, while it is closer to a linear function of the fluence in corneal stroma. Extrapolating these relations to zero diameter indicates that for both media the minimum fluence required for surface ablation is reduced with shorter pulse duration. A simple theoretical model suggests that this effect is due to a more significant contribution of photoionization as the laser pulse duration shortens. PMID- 21263562 TI - High phase retardation by waveguiding in slanted photonic nanostructures. AB - We report a physical mechanism leading to high phase retardation in slanted photonic nanostructures. The phenomenon is based on the waveguiding of the transverse electric polarization component inside the slanted pillars, while the transverse magnetic component is not guided. Such a mechanism leads to very high phase retardation even with shallow structures that are suitable also for lithographical mass production. We present physical principle, numerical analysis of the phenomenon and designs for half-wave retarders. As an experimental result, a slanted grating producing 177 degrees retardation and 95.5% efficiency is presented. PMID- 21263563 TI - Hologram transmission through multi-mode optical fibers. AB - We demonstrate that a structured light intensity pattern can be produced at the output of a multi-mode optical fiber by shaping the wavefront of the input beam with a spatial light modulator. We also find the useful property that, as in the case for free space propagation, output intensities can be easily superimposed by taking the argument of the complex superposition of corresponding phase-only holograms. An analytical expression is derived relating output intensities ratios to hologram weights in the superposition. PMID- 21263564 TI - Fiber chirped-pulse amplification system emitting 3.8 GW peak power. AB - We report on the experimental demonstration of a fiber chirped- pulse amplification system capable of generating nearly transform-limited sub 500 fs pulses with 2.2 mJ pulse energy at 11 W average power. The resulting record peak power of 3.8 GW could be achieved by combining active phase shaping with an efficient reduction of the acquired nonlinear phase. Therefore, we used an Ytterbium-doped large-pitch fiber with a mode field diameter of 105 um as the main amplifier. PMID- 21263565 TI - Autofocus using image phase congruency. AB - The key issue in passive autofocus is to choose robust focus measures to judge optical blur in defocused images. Existing focus measures are sensitive to image contrast (illumination) as they use image intensity. In this report we demonstrate a focus measure using phase congruency. The proposed focus measure is robust for noisy imaging sensors in varying illumination conditions, and has great balance of defocus sensitivity and effective range. Its advantages are shown with a number of synthetic image sequences. PMID- 21263566 TI - Morphology of femtosecond laser modification of bulk dielectrics. AB - Using 3D Finite-Difference-Time-Domain simulations, we study the morphology of the laser-created damage inside fused silica. Among the competing effects limiting the intensity in the dielectric, we find the most important is the pulse defocusing by the plasma lens, partially balanced by the Kerr effect. Less important are collisional energy dissipation and laser depletion by multi-photon absorption. We also found that the profile of generated plasma is asymmetrical in the transverse cross-section, with the plasma extended along the direction perpendicular to the laser polarization. PMID- 21263567 TI - Multistability at arbitrary low optical intensities in a metal-dielectric layered structure. AB - We show that a nonlinear metal-dielectric layered slab of subwavelength thickness and very small average dielectric permittivity displays optical multistable behavior at arbitrary low optical intensities. This is due to the fact that, in the presence of the small linear permittivity, one of the multiple electromagnetic slab states exists no matter how small is the transmitted optical intensity. We prove that multiple states at ultra-low optical intensities can be reached only by simultaneously operating on the incident optical intensity and incidence angle. By performing full wave simulations, we prove that the predicted phenomenology is feasible and very robust. PMID- 21263568 TI - Numerical demonstration of a three-dimensional negative-index metamaterial at optical frequencies. AB - As a consequent work of the two-dimensional (2D) dendritic metamaterial which has been systematically studied in our previous work, a model of three-dimensional (3D) sphere-rod shaped structure is presented. Based on Drude model of the dielectric function of silver in the visible region, the parametric curves of electromagnetic response to the incident fields have been retrieved from detailed simulations. It is shown that the simultaneously negative values of permittivity and permeability in the optical range lead to a negative refractive index (NIM) through adjusting structural parameters, only the dimensions of the unit cells satisfy the effective medium theory. We therefore conclude that the proposed model offers a feasible route to fabricating 3D optical NIMs by 'bottom-up' approach. PMID- 21263569 TI - Design of hemi-urchin shaped ZnO nanostructures for broadband and wide-angle antireflection coatings. AB - We study theoretically and experimentally the hemi-urchin shaped zinc oxide (ZnO) nanostructures for broadband and wide-angle antireflection coatings. The antireflective characteristics of hemi-urchin shaped ZnO nanostructures, which can be formed by integrating one-dimensional (1D) nanostructures (i.e., nanorods) on the periodic 2D structural architecture, are investigated. The optimization process is performed using a rigorous coupled-wave analysis method in terms of the order of taper of Si subwavelength gratings (SWGs) as a 2D structural architecture, the geometry of Si SWGs, and the height/size of ZnO nanorods. To simply test an experimental feasibility, a hemi-urchin shaped ZnO nanostructure is fabricated by hydrothermally growing ZnO nanorods on the periodic Si SWG structure. The angle-dependent reflectance of the hemi-urchin shaped ZnO nanostructures on the Si SWG is compared with that of the vertically aligned ZnO nanorod arrays on the Si substrate. The optimized hemi-urchin shaped ZnO nanostructure can significantly improve the antireflective property by suppressing the surface reflection over a broad spectrum and a wide range of angles of light incidence, indicating a reasonable agreement with the experimental results. PMID- 21263570 TI - Reconfigurable multi-channel second-order silicon microring-resonator filterbanks for on-chip WDM systems. AB - We report the fabrication of a reconfigurable wide-band twenty-channel second order dual filterbank, defined on a silicon-on-insulator (SOI) platform, with tunable channel spacing and 20 GHz single-channel bandwidth. We demonstrate the precise tuning of eleven (out of the twenty) channels, with a channel spacing of 124 GHz (~1 nm) and crosstalk between channels of about -45 dB. The effective thermo-optic tuning efficiency is about 27 MUW/GHz/ring. A single channel of a twenty-channel counter-propagating filterbank is also demonstrated, showing that both propagating modes exhibit identical filter responses. Considerations about thermal crosstalk are also presented. These filterbanks are suitable for on-chip wavelength-division-multiplexing applications, and have the largest-to-date reported number of channels built on an SOI platform. PMID- 21263571 TI - Extreme ultraviolet free electron laser seeded with high-order harmonic of Ti:sapphire laser. AB - The 13th harmonic of a Ti:sapphire (Ti:S) laser in the plateau region was injected as a seeding source to a 250-MeV free-electron-laser (FEL) amplifier. When the amplification conditions were fulfilled, strong enhancement of the radiation intensity by a factor of 650 was observed. The random and uncontrollable spikes, which appeared in the spectra of the Self-Amplified Spontaneous Emission (SASE) based FEL radiation without the seeding source, were found to be suppressed drastically to form to a narrow-band, single peak profile at 61.2 nm. The properties of the seeded FEL radiation were well reproduced by numerical simulations. We discuss the future precept of the seeded FEL scheme to the shorter wavelength region. PMID- 21263572 TI - Cladding mode coupling in highly localized fiber Bragg gratings: modal properties and transmission spectra. AB - The spectral characteristics of a fiber Bragg grating (FBG) with a transversely inhomogeneous refractive index profile, differs considerably from that of a transversely uniform one. Transmission spectra of inhomogeneous and asymmetric FBGs that have been inscribed with focused ultrashort pulses with the so-called point-by-point technique are investigated. The cladding mode resonances of such FBGs can span a full octave in the spectrum and are very pronounced (deeper than 20dB). Using a coupled-mode approach, we compute the strength of resonant coupling and find that coupling into cladding modes of higher azimuthal order is very sensitive to the position of the modification in the core. Exploiting these properties allows precise control of such reflections and may lead to many new sensing applications. PMID- 21263573 TI - Characterizing femtosecond laser inscribed Bragg grating spectra. AB - We present numerical modeling based on a combination of the Bidirectional Beam Propagation Method and Finite Element Method that completely describes the wavelength spectra of point by point femtosecond laser inscribed fiber Bragg gratings, showing excellent agreement with experiment. We have investigated the dependence of different spectral parameters such as insertion loss, all dominant cladding and ghost modes and their shape relative to the position of the fiber Bragg grating in the core of the fiber. Our model is validated by comparing model predictions with experimental data and allows for predictive modeling of the gratings. We expand our analysis to more complicated structures, where we introduce symmetry breaking; this highlights the importance of centered gratings and how maintaining symmetry contributes to the overall spectral quality of the inscribed Bragg gratings. Finally, the numerical modeling is applied to superstructure gratings and a comparison with experimental results reveals a capability for dealing with complex grating structures that can be designed with particular wavelength characteristics. PMID- 21263574 TI - Extended depth-of-field microscopic imaging with a variable focus microscope objective. AB - Increasing the depth-of-field (DOF) while maintaining high resolution imaging has been a classical challenge for conventional microscopes. Extended DOF (EDOF) is especially essential for imaging thick specimens. We present a microscope capable of capturing EDOF images in a single shot. A volumetric optical sampling method is applied by rapidly scanning the focus of a vari-focal microscope objective throughout the extended depths of a thick specimen within the duration of a single detector exposure. An EDOF image is reconstructed by deconvolving the captured image with the response function of the system. Design of a vari-focal objective and algorithms for restoring EDOF images are presented. Proof-of concept experimental results demonstrate significantly extended DOF compared to the conventional microscope counterparts. PMID- 21263575 TI - Characterisation and performance of a Terfenol-D coated femtosecond laser inscribed optical fibre Bragg sensor with a laser ablated microslot for the detection of static magnetic fields. AB - We present a novel device for the characterisation of static magnetic fields through monitoring wavelength shifts of femtosecond inscribed fibre Bragg grating and micromachined slot, coated with Terfenol-D. The device was sensitive to static magnetic fields and can be used as a vectoral sensor for the detection of magnetic fields as low as 0.046 mT with a resolution of +/- 0.3mT in transmission and +/- 0.7mT in reflection. The use of a femtosecond laser to both inscribe the FBGs and micromachine the slot in a single stage prior to coating the device significantly simplifies the fabrication. PMID- 21263576 TI - Wavefront sensorless adaptive optics: a general model-based approach. AB - Wavefront sensorless adaptive optics (AO) systems have been widely studied in recent years. To reach optimum results, such systems require an efficient correction method. In this paper, a general model-based correction method for a wavefront sensorless AO system is presented. The general model-based approach is set up based on a relationship wherein the second moments (SM) of the wavefront gradients are approximately proportionate to the FWHM of the far-field intensity distribution. The general model-based method is capable of taking various common sets of functions as predetermined bias functions and correcting the aberrations by using fewer photodetector measurements. Numerical simulations of AO corrections of various random aberrations are performed. The results show that the Strehl ratio is improved from 0.07 to about 0.90, with only N + 1 photodetector measurement for the AO correction system using N aberration modes as the predetermined bias functions. PMID- 21263577 TI - Polarization independent quasi-phase-matched sum frequency generation for single photon detection. AB - Polarization independent sum frequency generation (SFG) is proposed in an electro optic (EO) tunable periodically poled Lithium Niobate (PPLN). The PPLN consists of four sections. External electric field could be selectively applied to them to induce polarization rotation between the ordinary and extraordinary waves. If the domain structure is well designed, the signal wave with an arbitrary polarization state could realize efficient frequency up-conversion as long as a z-polarized pump wave is selected. The applications in single photon detection and optical communications are discussed. PMID- 21263578 TI - Microscope-based label-free microfluidic cytometry. AB - A microscope-based label-free microfluidic cytometer capable of acquiring two dimensional light scatter patterns from single cells, pattern analysis of which determines cellular information such as cell size, orientation and inner nanostructure, was developed. Finite-difference time-domain numerical simulations compared favorably with experimental scatter patterns from micrometer-sized beads and cells. The device was capable of obtaining light scattering patterns from the smallest mature blood cells (platelets) and cord blood hematopoietic stem/progenitor cells ?(CD34 + cells) and myeloid precursor cells. The potential for evaluation of cells using this label-free microfluidic cytometric technique was discussed. PMID- 21263579 TI - Long-wave infrared imaging for non-invasive beehive population assessment. AB - Long-wave infrared imaging is used for non-invasive assessment of the internal population of honey bee colonies. The radiometrically calibrated camera signal is related to the number of frames that are populated by bees inside each hive. This enables rapid measurement of population without opening the hive, which disturbs the bees and can endanger the queen. The best results are obtained just before sunrise, when there is maximum thermal contrast between the hive and the background. This technique can be important for bee hive monitoring or for applications requiring frequent hive assessment, such as the use of bees for detecting chemicals or explosives. PMID- 21263580 TI - Single tilted Bragg reflector fiber laser for simultaneous sensing of refractive index and temperature. AB - A type of fiber laser, called tilted Bragg reflector fiber laser (TBR-FL), is proposed and its application in simultaneous sensing of surrounding refractive index (SRI) and temperature is demonstrated. This FL is formed by a pair of wavelength and tilt-angle matched tilted fiber Bragg gratings (TFBGs) that acted both as a resonant cavity and sensing element. A unique spectral feature of the TBR-FL is the presence of grating tilt-induced cladding modes spectrum that does not appear in other type of FL, which provides an extra sensing mechanism. By employing a simple experimental setup with the discrete wavelet transform as the demodulation technique, simultaneously sensing of SRI and temperature are achieved by measuring and analyzing the wavelet coefficients shifts of the laser output and averaged cladding modes. PMID- 21263581 TI - Polarization-independent broad-band nearly perfect absorbers in the visible regime. AB - Polarization-independent broad-band absorbers in the visible regime are theoretically investigated. The absorbers are three-layered structures consisting of a lossy dielectric grating on top of a low-loss dielectric layer and a substrate of the same lossy dielectric placed at the bottom. Enhanced absorption in the underlying structure is attained over a broad range of frequency for both TE and TM polarizations. In particular, a nearly perfect absorbance (over 99.6%) is achieved at lambda ~ 600 nm, around which the absorption spectra show a substantial overlap between two polarizations. The enhanced absorption is attributed to cavity resonance and its hybridization with a weakly bound surface wave. This feature is illustrated with the electric field patterns and time averaged power loss density associated with the resonances. PMID- 21263582 TI - New design for photonic temporal integration with combined high processing speed and long operation time window. AB - We propose and experimentally prove a novel design for implementing photonic temporal integrators simultaneously offering a high processing bandwidth and a long operation time window, namely a large time-bandwidth product. The proposed scheme is based on concatenating in series a time-limited ultrafast photonic temporal integrator, e.g. implemented using a fiber Bragg grating (FBG), with a discrete-time (bandwidth limited) optical integrator, e.g. implemented using an optical resonant cavity. This design combines the advantages of these two previously demonstrated photonic integrator solutions, providing a processing speed as high as that of the time-limited ultrafast integrator and an operation time window fixed by the discrete-time integrator. Proof-of-concept experiments are reported using a uniform fiber Bragg grating (as the original time-limited integrator) connected in series with a bulk-optics coherent interferometers' system (as a passive 4-points discrete-time photonic temporal integrator). Using this setup, we demonstrate accurate temporal integration of complex-field optical signals with time-features as fast as ~6 ps, only limited by the processing bandwidth of the FBG integrator, over time durations as long as ~200 ps, which represents a 4-fold improvement over the operation time window (~50 ps) of the original FBG integrator. PMID- 21263583 TI - Two-center interference in high-order harmonic generation from heteronuclear diatomic molecules. AB - Two-center interference for heteronuclear diatomic molecules (HeDM) is investigated. The minimum in the high-order harmonic spectrum, as a consequence of the destructive interference, is shifted to lower harmonic orders compared with that in a homonuclear case. This phenomenon is explained by performing phase analysis. It is found that, for an HeDM, the high harmonic spectrum contains information not only on the internuclear separation but also on the properties of the two separate centers, which implies the potential application of estimating the asymmetry of molecules and judging the linear combination of atomic orbitals (LCAO) for the highest occupied molecular orbital (HOMO). Moreover, the possibility to monitor the evolution of HOMO itself in molecular dynamics is also promised. PMID- 21263584 TI - Rotational Doppler-effect due to selective excitation of vector-vortex field in optical fiber. AB - Experimental demonstration of rotational Doppler-effect due to direct and simultaneous excitation of orthogonal elliptically-polarized fundamental and vortex modes in a two-mode optical fiber is presented here. The rotation frequency and the trajectory of the zero-intensity point in the two-mode fiber output beam measured as a function of analyzer rotation matches with the S contour of polarization singularity in the beam, identified via Stokes parameter measurement. The characteristics of the S-contour around the C-point in the output beam is also measured as a function of rotating Dove prism and half-wave plate - Dove prism combination to highlight the role of polarization modifying components on the observed rotational Doppler-effect of vector-vortex beams. PMID- 21263585 TI - Graphene-on-silver substrates for sensitive surface plasmon resonance imaging biosensors. AB - Taking advantage of the high impermeability property of graphene and the sharp surface plasmon resonance (SPR) curve of silver, we numerically demonstrate that SPR imaging biosensors with a graphene-on-silver substrate can be used to achieve the dramatically high sensitivity as well as to prevent silver oxidation. Results of our numerical study show that a silver substrate with a few graphene layers can significantly increase the imaging sensitivity, compared to the conventional gold-film-based SPR imaging biosensor. In particular, single layered graphene deposited on the 60-nm thick silver film amplifies the SPR imaging signal more than three times. Therefore, the proposed SPR substrate could potentially open a new possibility of SPR imaging detection for sensitive and high-throughput assessment of multiple biomolecular interactions. PMID- 21263586 TI - Gold-nanoparticle-assisted random lasing from powdered GaN. AB - We demonstrate Au-nanoparticle-assisted random lasing from a powdered GaN sample. In the presence of Au nanoparticles on GaN powder surfaces, several lasing lines are observed in photoexcited luminescence spectra near the center of the GaN band edge emission peak. The random lasing is considered to arise from a decrease in the lasing threshold due to the suppression of crystal defect loss by surface plasmon excitation on Au. From spatially resolved lasing emission spectra and their FT analysis results, the formation of random lasing cavities at different spatial positions is confirmed. The size of the random lasing spot is determined to be larger than that of the scattered light speckle of the pumping source on a thin powdered GaN sample. PMID- 21263587 TI - Optical twists in phase and amplitude. AB - Light beams with helical phase profile correspond to photons having orbital angular momentum (OAM). A Laguerre-Gaussian (LG) beam is an example where its helical phase sets a phase-singularity at the optical axis and forms a ring shaped transverse amplitude profile. Here, we describe a unique beam where both phase and amplitude express a helical profile as the beam propagates in free space. Such a beam can be accurately referred to as an optical twister. We characterize optical twisters and demonstrate their capacity to induce spiral motion on particles trapped along the twisters' path. Unlike LG beams, the far field projection of the twisted optical beam maintains a high photon concentration even at higher values of topological charge. Optical twisters have therefore profound applications to fundamental studies of light and atoms such as in quantum entanglement of the OAM, toroidal traps for cold atoms and for optical manipulation of microscopic particles. PMID- 21263588 TI - High-volume optical vortex multiplexing and de-multiplexing for free-space optical communication. AB - We report an approach to the increase of signal channels in free-space optical communication based on composed optical vortices (OVs). In the encoding process, conventional algorithm employed for the generation of collinearly superimposed OVs is combined with a genetic algorithm to achieve high-volume OV multiplexing. At the receiver end, a novel Dammann vortex grating is used to analyze the multihelix beams with a large number of OVs. We experimentally demonstrate a digitized system which is capable of transmitting and receiving 16 OV channels simultaneously. This system is expected to be compatible with a high-speed OV multiplexing technique, with potentials to extremely high-volume information density in OV communication. PMID- 21263589 TI - Optimal design of a microcavity organic laser device under electrical pumping. AB - The quality factor of microcavity organic lasers, designed for operation under electric pumping, has been numerically investigated. The microcavity structure consists of an organic light emitting diode set in between multilayer dielectric mirrors centered for an emission at 620 nm. In order to optimize the quality factor, different parameters have been studied: the impact of high and low index materials used for the multilayer mirrors, the role of a spacer inserted in between the mirrors to obtain an extended cavity, and the effect of an absorbing electrode made of metallic or transparent conductive oxide layer. The results of our different optimizations have shown a quality factor (Q) as high as 15,000. PMID- 21263590 TI - Long-term stable frequency transfer over an urban fiber link using microwave phase stabilization. AB - We report a novel technique for highly stable transfer of a frequency comb over long optical fiber link. The technique implements an electronic compensation loop to cancel out the phase fluctuations that is introduced by the fiber. We utilized this technique to transfer a stable microwave frequency through a 20 km urban fiber link and an 80 km open air fiber link respectively. For the 20 km urban fiber link, the active compensation system reduced the phase fluctuation from 75 mrad (118 ps) to 4 mrad (6.3 ps) in 48 hours, and the frequency stability was improved by three orders of magnitude. For the 80 km open air fiber link, the active compensation system reduced the rms phase fluctuation from 580 mrad (914 ps) to 10 mrad (16 ps) in 24 hours, and the frequency stability was improved by two orders of magnitude. PMID- 21263591 TI - Transition mode long period grating biosensor with functional multilayer coatings. AB - We report our latest research results concerning the development of a platform for label-free biosensing based on overlayered Long Period Gratings (LPGs) working in transition mode. The main novelty of this work lies in a multilayer design that allows to decouple the problem of an efficient surface functionalization from that of the tuning in transition region of the cladding modes. An innovative solvent/nonsolvent strategy for the dip-coating technique was developed in order to deposit on the LPG multiple layers of transparent polymers. In particular, a primary coating of atactic polystyrene was used as high refractive index layer to tune the working point of the device in the so called transition region. In this way, state-of-the-art-competitive sensitivity to surrounding medium refractive index changes was achieved. An extremely thin secondary functional layer of poly(methyl methacrylate-co-methacrylic acid) was deposited onto the primary coating by means of an original identification of selective solvents. This approach allowed to obtain desired functional groups (carboxyls) on the surface of the device for a stable covalent attachment of bioreceptors and minimal perturbation of the optical design. Standard 1-ethyl-3 (3-dimethylaminopropyl)carbodiimide / N-hydrosuccinimide (EDC / NHS) coupling chemistry was used to link streptavidin on the surface of the coated LPG. Highly sensitive real-time monitoring of multiple affinity assays between streptavidin and biotinylated bovine serum albumin was performed by following the shift of the LPGs attenuation bands. PMID- 21263592 TI - Optical anisotropy and light extraction efficiency of MBE grown GaN nanowires epilayers. AB - The use of nanowires as active medium seems very promising for the development of high brightness LEDs. With a lower effective refractive index than bulk, semiconductor nanowire layers may lead to a high light extraction efficiency. We hereafter discuss the anisotropic properties of dense arrays of molecular beam epitaxy (MBE) grown gallium nitride (GaN) nanowires and the consequences on the optical design of nanowire based LEDs. In particular we show numerically that light extraction efficiency as high as 72% can be expected for GaN nanowires layer grown on a low cost Si substrate. PMID- 21263593 TI - Phase retrieval using polychromatic illumination for transmission X-ray microscopy. AB - An alternative method for quantitative phase retrieval in a transmission X-ray microscope system at sub-50-nm resolution is presented. As an alternative to moving the sample in the beam direction in order to analyze the propagation introduced phase effect, we have illuminated the TXM using X-rays of different energy without any motor movement in the TXM system. Both theoretical analysis and experimental studies have confirmed the feasibility and the advantage of our method, because energy tuning can be performed with very high energy resolution using a double crystal monochromator at a synchrotron beam line, and there is zero motor error in TXM system in our approach. High-spatial-resolution phase retrieval is accomplished using the proposed method. PMID- 21263594 TI - Sub-80-fs pulses from an all-fiber-integrated dissipative-soliton laser at 1 um. AB - We report on a passively mode-locked femtosecond fiber oscillator using only fiber-based components without intracavity dispersion compensation. The all normal dispersion fiber laser operates in the dissipative-soliton regime and utilizes a spectral filter for pulse shaping. The 3.8 ps long pulses with pulse energies of 3.6 nJ can be dechirped with a grating compressor to 76 fs. The output spectrum reveals a full width at half maximum of 39.7 nm and a center wavelength of 1032 nm. The repetition rate is 71 MHz. The influence of pulse energy variation is discussed. PMID- 21263595 TI - Polarization-sensitive optical frequency domain imaging based on unpolarized light. AB - Polarization-sensitive optical coherence tomography (PS-OCT) is an augmented form of OCT, providing 3D images of both tissue structure and polarization properties. We developed a new method of polarization-sensitive optical frequency domain imaging (PS-OFDI), which is based on a wavelength-swept source. In this method the sample was illuminated with unpolarized light, which was composed of two orthogonal polarization states (i.e., separated by 180 degrees in the Poincare sphere) that are uncorrelated to each other. Reflection of these polarization states from within the sample was detected simultaneously and independently using a frequency multiplexing scheme. This simultaneous sample probing with two polarization states enabled determination of the depth-resolved Jones matrices of the sample. Polarization properties of the sample were obtained by analyzing the sample Jones matrices through eigenvector decomposition. The new PS-OFDI system ran at 31K wavelength-scans/s with 3072 pixels per wavelength-scan, and was tested by imaging a polarizer and several birefringent tissues such as chicken muscle and human skin. Lastly the new PS-OFDI was applied to imaging two cancer animal models: a mouse model by injecting cancer cells and a hamster cheek pouch model. These animal model studies demonstrated the significant differences in tissue polarization properties between cancer and normal tissues in vivo. PMID- 21263596 TI - Effect of perfectly matched layer reflection coefficient on modal analysis of leaky waveguide modes. AB - The reflection coefficient is one important parameter of the perfectly matched layer (PML). Here we investigate its effect on the modal analysis of leaky waveguide modes by examining three different leaky waveguide structures, i.e., the holey fiber, the air-core terahertz pipe waveguide, and the gain-guided and index-antiguided slab waveguide. Numerical results reveal that the typical values 10(-8) ~10(-12) are inadequate for obtaining the imaginary part of the complex propagation constant, and the suggested reflection coefficient would be much smaller, for example, 10(-50) or 10(-100). With such a small coefficient, both the computational window size and the PML thickness can be significantly reduced without loss of stability. Moreover, in some cases, the modal field profiles can only be accurately obtained with such a small coefficient. PMID- 21263597 TI - Improved digital backward propagation for the compensation of inter-channel nonlinear effects in polarization-multiplexed WDM systems. AB - An improved split-step method (SSM) for digital backward propagation (DBP) applicable to wavelength-division multiplexed (WDM) transmission with polarization-division multiplexing (PDM) is presented. A coupled system of nonlinear partial differential equations, derived from the Manakov equations, is used for DBP. The above system enables the implementation of DBP on a channel-by channel basis, where only the effect of phase-mismatched four-wave mixing (FWM) is neglected. A novel formulation of the SSM for PDM-WDM systems is presented where new terms are included in the nonlinear step to account for inter polarization mixing effects. In addition, the effect of inter-channel walk-off is included. This substantially reduces the computational load compared to the conventional SSM. PMID- 21263598 TI - Phase-shifting interferometry based on induced vibrations. AB - The presence of uncontrolled mechanical vibrations is typically the main precision-limiting factor of a phase-shifting interferometer. We present a method that instead of trying to insolate vibrations; it takes advantage of their presence to produce the different phase-steps. The method is based on spatial and time domain processing techniques to compute first the different unknown phase steps and then reconstruct the phase from these tilt-shifted interferograms. In order to compensate the camera movement, it is needed to perform an affine registration process between the different interferograms. Simulated and experimental results demonstrate the effectiveness of the proposed technique without the use of any phase-shifter device. PMID- 21263599 TI - Si nanorod length dependent surface Raman scattering linewidth broadening and peak shift. AB - Enhanced Stoke Raman scattering of large-area vertically aligned Si nanorod surface etched by metal-particle-catalytic is investigated. By enlarging the surface area with lengthening Si nanorods, the linear enhancement on Stoke Raman scattering intensity at 520 cm(-1) is modeled to show well correlation with increasing quantity of surface Si dangling bonds. With Si nanorod length increasing from 0.19 to 2.73 MUm, the Raman peaks of the as-etched and oxidized samples gradually shift from -4 cm(-1) and from -4.5 cm(-1) associated with their linewidth broadening from 3 to 9 cm(-1) and from 7 to 18 cm(-1), respectively. The peak intensity of Raman scattering signal from Si nanorod could be enhanced with the increase of interaction area as the number of phonon mode directly corresponds to the tetrahedrally coordinated Si vibrations in the bulk crystal lattice. The asymmetric linewidth broadening and corresponding Raman peak shift is affected by the strained Si nanorod surface caused by etching and the crystal quality. Fourier transform infrared spectroscopy corroborates the dependency between nanorod length and Si-O-Si stretching mode absorption (at 1097 cm(-1)) on oxidized Si nanorod surface, elucidating the increased transformation of surface dangling bonds to Si-O-Si bonds for passivating Si nanorods and attenuating Stoke Raman scattering after oxidation. PMID- 21263600 TI - Dynamic phase measurement in shearography by clustering method and Fourier filtering. AB - Quantitative phase extraction is a key step in optical measurement. While phase shifting technique is widely employed for static or semi-static phase measurement, it requires several images with known phase shifts at each deformed stage, thus is not suitable for dynamic phase measurement. Fourier transform offer a solution to extract phase information from a single fringe pattern. However, a high frequency spatial carrier which is sometimes not easy to generate is required to solve the phase ambiguity problem. In this paper, we aim to propose an ideal solution for dynamic phase measurement. Four images with known phase shift are captured at the reference stage to analyze the initial phase information. After the object starts continuous deformation, only one image is captured at each deformed stage. A clustering phase extraction method is then applied for deformation phase extraction utilizing the phase clustering effect within a small region. This method works well for speckle image with low and medium fringe density. When the fringe density is high, especially in the case of shearographic fringe, information insufficiency inherent with merely one deformed speckle image often results in poor quality wrapped phase map with plenty of phase residues, which make phase unwrapping a difficult task. In the light of this limitation, a Fourier transform based phase filtering method is proposed for fringe frequency analysis and adaptive filtering, and effectively removes most of the phase residues to reconstruct a high quality wrapped phase map. Several real experiments based on shearography are presented. Comparison between the proposed solution and standard phase evaluation methods is also given. The results demonstrate the effectiveness of the proposed integrated dynamic phase extraction method. PMID- 21263601 TI - Simple performance evaluation of pulsed spontaneous parametric down-conversion sources for quantum communications. AB - Fast characterization of pulsed spontaneous parametric down conversion (SPDC) sources is important for applications in quantum information processing and communications. We propose a simple method to perform this task, which only requires measuring the counts on the two output channels and the coincidences between them, as well as modeling the filter used to reduce the source bandwidth. The proposed method is experimentally tested and used for a complete evaluation of SPDC sources (pair emission probability, total losses, and fidelity) of various bandwidths. This method can find applications in the setting up of SPDC sources and in the continuous verification of the quality of quantum communication links. PMID- 21263602 TI - Electromagnetically induced transparency in hybrid plasmonic-dielectric system. AB - We present theoretical and numerical analysis of a plasmonic-dielectric hybrid system for symmetric and asymmetric coupling between silver cut-wire pairs and silicon grating waveguide with periodic grooves. The results show that both couplings can induce electromagnetically-induced transparency (EIT) analogous to the quantum optical phenomenon. The transmission spectrum shows a single transparency window for the symmetric coupling. The strong normal phase dispersion in the vicinity of this transparent window results in the slow light effect. However, the transmission spectrum appears an additional transparency window for asymmetry coupling due to the double EIT effect, which stems from an asymmetrically coupled resonance (ACR) between the dark and bright modes. More importantly, the excitation of ACR is further associated with remarkable improvement of the group index from less than 40 to more than 2500 corresponding to a high transparent efficiency by comparing with the symmetry coupling. This scheme provides an alternative way to develop the building block of systems for plasmonic sensing, all optical switching and slow light applications. PMID- 21263603 TI - Two-step self-tuning phase-shifting interferometry. AB - A two-step self-tuning phase-shifting method is presented. The phase-step between the two interferograms is not known when the experiment is performed. Our demodulating method finds, in a robust way, this unknown phase-step. Once the phase-step is estimated we proceed to phase demodulate the interferograms. Moreover our method only requires the fringe patterns to have a constant unknown phase-shift between them. As a consequence, this technique can be used to demodulate open and closed-fringed patterns without phase-sign ambiguity. The method may be regarded as a self-tuning quadrature filter, which determines the phase-shift between the two fringe patterns and finally estimates the demodulated phase map. The proposed technique has been tested with simulated and real interferograms obtaining satisfactory results. PMID- 21263604 TI - Modeling of the dynamic transmission properties of chalcogenide ring resonators in the presence of fast and slow nonlinearities. AB - We propose a simple iterative method for calculating the dynamic behavior of ring resonators with fast and slow (cumulative) optical nonlinearities when an optical pulse with an arbitrary-shaped envelope is incident into them. In the case of a slow nonlinearity, the nonlinear phase shift and nonlinear absorption are temporally-integrated over the incident pulse. In this paper, we consider two types of single-ring resonators made out of As2Se3 chalcogenide glass with high nonlinearity and investigate the dynamic properties (especially the effect of the cumulative nonlinearity on optical bistability) using known nonlinear material parameters. It is found that the cumulative nonlinearity suppresses overshoot and ringing after switching, decreases the width of the hysteresis loop between the input and output powers, and shifts its center corresponding to the operating point. The obtained results are useful in developing chalcogenide-based bistable optical devices and the proposed approach is applicable to modeling of a variety of nonlinear optical devices. PMID- 21263605 TI - Investigation of optical currents in coherent and partially coherent vector fields. AB - We present the computer simulation results of the spatial distribution of the Poynting vector and illustrate motion of micro and nanoparticles in spatially inhomogeneously polarized fields. The influence of phase relations and the degree of mutual coherence of superimposing waves in the arrangements of two-wave and four-wave superposition on the characteristics of the microparticle's motion has been analyzed. The prospects of studying temporal coherence using the proposed approach are made. For the first time, the possibility of diagnostics of optical currents in liquids caused by polarization characteristics of an optical field alone, using nanoscale metallic particles has been shown experimentally. PMID- 21263606 TI - Shifting the spherical focus of a 4Pi focusing system. AB - In a 4Pi focusing system radially polarized laser beams can be focused to a spherical focal spot. For many applications, e.g., for moving trapped particles or for scanning a specimen, one would like to change the position of focal spot along the optical axis without moving lenses or laser beams. We demonstrate how this can be achieved by modulating the phase of the input field at the pupil plane of the lens. The required phase modulation function is determined by spherical wave expansion of the plane wave factors in the Richards-Wolf integral. PMID- 21263607 TI - Shot noise limited characterization of ultraweak femtosecond pulse trains. AB - Ultrafast science is inherently, due to the lack of fast enough detectors and electronics, based on nonlinear interactions. Typically, however, nonlinear measurements require significant powers and often operate in a limited spectral range. Here we overcome the difficulties of ultraweak ultrafast measurements by precision time-domain localization of spectral components. We utilize this for linear self-referenced characterization of pulse trains having ~ 1 photon per pulse, a regime in which nonlinear techniques are impractical, at a temporal resolution of ~ 10 fs. This technique does not only set a new scale of sensitivity in ultrashort pulse characterization, but is also applicable in any spectral range from the near-infrared to the deep UV. PMID- 21263608 TI - High-fidelity, broadband stimulated-Brillouin-scattering-based slow light using fast noise modulation. AB - We demonstrate a 5-GHz-broadband tunable slow-light device based on stimulated Brillouin scattering in a standard highly-nonlinear optical fiber pumped by a noise-current-modulated laser beam. The noisemodulation waveform uses an optimized pseudo-random distribution of the laser drive voltage to obtain an optimal flat-topped gain profile, which minimizes the pulse distortion and maximizes pulse delay for a given pump power. In comparison with a previous slow modulation method, eye-diagram and signal-to-noise ratio (SNR) analysis show that this broadband slow-light technique significantly increases the fidelity of a delayed data sequence, while maintaining the delay performance. A fractional delay of 0.81 with a SNR of 5.2 is achieved at the pump power of 350 mW using a 2 km-long highly nonlinear fiber with the fast noise-modulation method, demonstrating a 50% increase in eye-opening and a 36% increase in SNR in the comparison. PMID- 21263609 TI - Vertical-coupling optical interface for on-chip optical interconnection. AB - We present a vertical-coupling optical interface with a grating coupler for transmitting and receiving optical signals between single-mode optical fibers and microphotonic waveguides with a view to realize on-chip optical interconnection. The optical interface consisting of a simple grating structure with a reflective mirror and an optical power combiner exhibits high optical coupling efficiency and wide tolerance range for the misalignment of optical fibers. The optical interface exhibits high coupling efficiency even if the optical input is almost vertical to the chip surface. PMID- 21263610 TI - Super multi-view windshield display for long-distance image information presentation. AB - A three-dimensional (3D) windshield display can display driving information in the vicinity of objects in the driver's front scene. We propose a super multi view windshield display that can present the information in a wide depth range. The super multi-view display technique provides a smooth motion parallax. Motion parallax is the only physiological cue for perceiving the depths of 3D images displayed at far distances; these cannot be perceived by other physiological cues such as vergence, binocular disparity, and accommodation. A prototype system, which generates 36 viewing zones with a horizontal interval of 3.61 mm, was constructed. The smoothness of the motion parallax and the accuracy of the depth perception were evaluated. PMID- 21263611 TI - Etched beam splitters in InP/InGaAsP. AB - An etched beam splitter (EBS) photonic coupler based on frustrated total internal reflection (FTIR) is designed, fabricated and characterized in the InP/InGaAsP material system. The EBS offers an ultra compact footprint (8x11 MUm) and a complete range of bar/cross coupling ratio designs. A novel pre-etching process is developed to achieve sufficient depth of the etched coupling gaps. Fabricated EBS couplers demonstrate insertion loss between 1 and 2.6 dB with transmission (cross-coupling) <= 10%. The results show excellent agreement with 3D finite difference time-domain (FDTD) modeling. The coupling of EBS has weak wavelength dependence in the C-band, making it suitable for wavelength division multiplexing (WDM) or other wide bandwidth applications. Finally, the EBS is integrated with active semiconductor optical amplifier (SOA) and phase-modulator components; using a flattened ring resonator structure, a channelizing filter tunable in both amplitude and center frequency is demonstrated, as well as an EBS coupled ring laser. PMID- 21263612 TI - Efficient Q-switched Tm:YAG ceramic slab laser. AB - Characteristics of Tm:YAG ceramic for high efficient 2-MUm lasers are analyzed. Efficient diode end-pumped continuous-wave and Q-switched Tm:YAG ceramic lasers are demonstrated. At the absorbed pump power of 53.2W, the maximum continuous wave (cw) output power of 17.2 W around 2016 nm was obtained with the output transmission of 5%. The optical conversion efficiency is 32.3%, corresponding to a slope efficiency of 36.5%. For Q-switched operation, the shortest width of 69 ns was achieved with the pulse repetition frequency of 500 Hz and single pulse energy of 20.4 mJ, which indicates excellent energy storage capability of the Tm:YAG ceramic. PMID- 21263613 TI - Gain and losses in THz quantum cascade laser with metal-metal waveguide. AB - Coupling of broadband terahertz pulses into metal-metal terahertz quantum cascade lasers is presented. Mode matched terahertz transients are generated on the quantum cascade laser facet of subwavelength dimension. This method provides a full overlap of optical mode and active laser medium. A longitudinal optical phonon depletion based active region design is investigated in a coupled cavity configuration. Modulation experiments reveal spectral gain and (broadband) losses. The observed gain shows high dynamic behavior when switching from loss to gain around threshold and is clamped at total laser losses. PMID- 21263614 TI - Improved approach for ultra-sensitive detection of NO. AB - An improved approach has been developed for ultra-sensitive detection of the concentration of NO using Faraday Modulation spectrometry (FAMOS) combined with the strong electronic transition. By changing the modulating magnetic field attributing to linear absorption and refraction of gas sample, the polarized laser was rotated and absorbed by the complex refraction index of NO. We confirm the relation between the magnitudes of absorption and the optimum modulation magnetic field. Also, the accuracy and the precision of the technique have been evaluated at different pressures. It is shown that the system is capable of detecting NO concentration down to 0.34 ppb.m. PMID- 21263615 TI - Manipulating optical polarization by stereo plasmonic structure. AB - We theoretically study a particular plasmonic structure with stereo nanoholes array in metallic film, which has remarkable abilities to manipulate the optical polarizations at optical frequencies. The main property is that any linear polarization states including a complete 90 degrees optical rotation can be obtained in transmission by proper structural design in combination of enhanced transmission efficiency. Together with the polarization change, surface plasmon propagation bounded on the surface of transmission side also can be modulated. Furthermore, an analytical Coupled Mode Method (CMM) is developed by introducing a frequency dependent coupling coefficient to describe such optical rotation property in stereo plasmonic systems. PMID- 21263616 TI - Energy and spectral enhancement of femtosecond supercontinuum in a noble gas using a weak seed. AB - We experimentally demonstrate that the use of a weak seed pulse of energy less than 0.4% of the pump results in a spectral energy enhancement that spans over 2 octaves and a total energy enhancement of more than 3 times for supercontinua generated by millijoule level femtosecond pulses in Krypton gas. Strong four-wave mixing of the pump-seed pulse interacting in the gas is observed. The spectral irradiance generated from the seeding process is sufficiently high to use white light continuum as an alternative to conventional tunable sources of radiation for applications such as nonlinear optical spectroscopy. PMID- 21263617 TI - Stable low-loss optical nanofibres embedded in hydrophobic aerogel. AB - Nanofibres, optical fibres narrower than the wavelength of light, degrade in hours on exposure to air. We show that encapsulation in hydrophobic silica aerogel (refractive index 1.05) provides protection and stability (over 2 months) without sacrificing low attenuation, strong confinement and accessible evanescent field. The measured attenuation was <0.03 dB/mm, over 10 * lower than reported with other encapsulants. This enables many nanofibre applications based on their extreme small size and strong external evanescent field, such as optical sensors, nonlinear optics, nanofibre circuits and high-Q resonators. The aerogel is more than a waterproof box, it is a completely-compatible gas-permeable material in intimate contact with the nanofibre and hydrophobic on both the macroscopic and molecular scales. Its benefits are illustrated by experiments on gas sensing (exploiting the aerogel's porosity) and supercontinuum generation (exploiting its ultra-low index). PMID- 21263618 TI - Enhanced dual-band infrared absorption in a Fabry-Perot cavity with subwavelength metallic grating. AB - The performance of infrared (IR) dual-band detector can be substantially improved by simultaneously increasing IR absorptions for both sensor bands. Currently available methods only provide absorption enhancement for single spectral band, but not for the dual-band. The Fabry-Perot (FP) cavity generates a series of resonances in multispectral bands. With this flexibility, we introduced a novel type of dual-band detector structure containing a multilayer FP cavity with two absorbing layers and a subwavelength-period grating mirror, which is capable of simultaneously enhancing the middle wave infrared (MWIR) and the long wave infrared (LWIR) detection. Compared with the bare-absorption-layer detector (common dual-band detector), the optimized FP cavity can provide about 13 times and 17 times absorption enhancement in LWIR and MWIR bands respectively. PMID- 21263619 TI - Tunable Terahertz-wave generation from DAST crystal pumped by a monolithic dual wavelength fiber laser. AB - For developing a continuous-wave (CW) tunable Terahertz-wave (THz-wave) source using difference-frequency generation (DFG) in highly nonlinear optical crystals, we proposed and demonstrated a dual-wavelength fiber ring laser system operating around 1060 nm based on wideband chirped fiber Bragg gratings (CFBGs) and semiconductor optical amplifier (SOA). Thermo-induced phase shift along the CFBG produces a very sharp transmission spike therefore two lasing wavelengths with single longitudinal mode operation are oscillating simultaneously within the fiber ring cavity. Due to the inhomogeneous gain broadening property of SOA, the wavelength spacing of our dual-wavelength fiber laser can be continuously adjusted from 0.3 to 9.5 nm. By using this single emitter dual-wavelength fiber laser to pump an organic nonlinear DAST crystal, type-0 collinear phase matching of DFG process can be fulfilled and monochromatic THz wave ranging from 0.5 to 2 THz has been successfully generated. PMID- 21263621 TI - Reinvestigation on the frequency dispersion of a grating-pair compressor. AB - The typical phase correction term introduced in a diffraction grating-pair is rediscussed. It shows that the correction causes a conceptual difficulty in geometrical optics. A study reveals that Fraunhofer diffraction explains the correction and only mean-phase light rays are allowed for diffraction analysis. Besides, an equivalent phase formulation without correction is recommended. PMID- 21263620 TI - Narrow groove plasmonic nano-gratings for surface plasmon resonance sensing. AB - We present a novel surface plasmon resonance (SPR) configuration based on narrow groove (sub-15 nm) plasmonic nano-gratings such that normally incident radiation can be coupled into surface plasmons without the use of prism-coupling based total internal reflection, as in the classical Kretschmann configuration. This eliminates the angular dependence requirements of SPR-based sensing and allows development of robust miniaturized SPR sensors. Simulations based on Rigorous Coupled Wave Analysis (RCWA) were carried out to numerically calculate the reflectance - from different gold and silver nano-grating structures - as a function of the localized refractive index of the media around the SPR nano gratings as well as the incident radiation wavelength and angle of incidence. Our calculations indicate substantially higher differential reflectance signals, on localized change of refractive index in the narrow groove plasmonic gratings, as compared to those obtained from conventional SPR-based sensing systems. Furthermore, these calculations allow determination of the optimal nano-grating geometric parameters - i. e. nanoline periodicity, spacing between the nanolines, as well as the height of the nanolines in the nano-grating - for highest sensitivity to localized change of refractive index, as would occur due to binding of a biomolecule target to a functionalized nano-grating surface. PMID- 21263622 TI - Improved upper winds models for several astronomical observatories. AB - An understanding of wind speed and direction as a function of height are critical to the proper modeling of atmospheric turbulence. We have used radiosonde data from launch sites near significant astronomical observatories and created averaged profiles of wind speed and direction and have also computed Richardson number profiles. Using data from the last 30 years, we confirm a 1977 Greenwood wind profile, and extend it to include parameters that show seasonal variations and differences in location. The added information from our models is useful for the design of adaptive optics systems and other imaging systems. Our analysis of the Richardson number suggests that persistent turbulent layers may be inferred when low values are present in our long term averaged data. Knowledge of the presence of these layers may help with planning for adaptive optics and laser communications. PMID- 21263623 TI - Sub-MUm2 power splitters by using silicon hybrid plasmonic waveguides. AB - Nano-scale power splitters based on Si hybrid plasmonic waveguides are designed by utilizing the multimode interference (MMI) effect as well as Y-branch structure. A three-dimensional finite-difference time-domain method is used for simulating the light propagation and optimizing the structural parameters. The designed 1 * 2 50:50 MMI power splitter has a nano-scale size of only 650 nm * 530 nm. The designed Y-branch power splitter is also very small, i.e., about 900 nm * 600 nm. The fabrication tolerance is also analyzed and it is shown that the tolerance of the waveguide width is much larger than+/-50 nm. The power splitter has a very broad band of over 500 nm. In order to achieve a variable power splitting ratio, a 2*2 two-mode interference coupler and an asymmetric Y-branch are used and the corresponding power splitting ratio can be tuned in the range of 97.1%:2.9%-1.7%:98.3% and 84%:16%-16%:84%, respectively. Finally a 1*4 power splitter with a device footprint of 1.9 MUm * 2.6 MUm is also presented using cascaded Y-branches. PMID- 21263624 TI - Theoretical and experimental study on generation of stable and high-quality multi carrier source based on re-circulating frequency shifter used for Tb/s optical transmission. AB - The generation of stable and high-quality single-sideband (SSB) multi-carrier source based on recirculating frequency shifter (RFS) is analyzed theoretically and realized experimentally. The impact factors originated from the modulator intrinsic imperfections, deviation from the right operation bias voltage, as well as the unbalanced amplitude and phase of the radio frequency (RF) drive signals, have different influences on the output spectrum of the transfer function, which is the decisive factor in generating the high-quality multi-carrier output. Based on the theoretical analysis, the stable and high-quality 50-tone output was successfully realized. The experiments under some implementation imperfections have also been carried out. The imperfect and low-quality output results are in good agreement with the theoretical analysis. PMID- 21263625 TI - Fabrication and characterization of high Q polymer micro-ring resonator and its application as a sensitive ultrasonic detector. AB - Smooth sidewall silicon micro-ring molds have been fabricated using resist reflow and thermal oxidation method. High Q factor polymer micro-ring resonators have been fabricated using these molds. Quality factors as high as 10(5) have been measured at telecommunication wavelength range. By carefully examining the different loss mechanisms in polymer micro-ring, we find that the surface scattering loss can be as low as 0.23 dB/cm, much smaller than the absorption loss of the polystyrene polymer used in our devices. When used as an ultrasound detector such a high Q polymer micro-ring device can achieve an acoustic sensitivity around 36.3 mV/kPa with 240 MUW operating power. A noise equivalent pressure (NEP) is around 88 Pa over a bandwidth range of 1-75 MHz. We have improved the NEP by a factor of 3 compared to our previous best result. PMID- 21263626 TI - Titanium-based transition-edge photon number resolving detector with 98% detection efficiency with index-matched small-gap fiber coupling. AB - We have realized a high-detection-efficiency photon number resolving detector at an operating wavelength of about 850 nm. The detector consists of a titanium superconducting transition edge sensor in an optical cavity, which is directly coupled to an optical fiber using an approximately 300-nm gap. The gap reduces the sensitive area and heat capacity of the device, leading to high photon number resolution of 0.42 eV without sacrificing detection efficiency or signal response speed. Wavelength dependent efficiency in fiber-coupled devices, which is due to optical interference between the fiber and the device, is also decreased to less than 1% in this configuration. The overall system detection efficiency is 98%+/ 1% at wavelengths of around 850 nm, which is the highest value ever reported in this wavelength range. PMID- 21263627 TI - Four-dimensional optical multiband-OFDM for beyond 1.4 Tb/s serial optical transmission. AB - We propose a four-dimensional (4D) coded multiband-OFDM scheme suitable for beyond 1.4 Tb/s serial optical transport. The proposed scheme organizes the N dimensional (ND) signal constellation points in the form of signal matrix; employs 2D-inverse FFT and 2D-FFT to perform modulation and demodulation, respectively; and exploits both orthogonal polarizations. This scheme can fully exploit advantages of OFDM to deal with chromatic dispersion, PMD and PDL effects; and multidimensional signal constellations to improve OSNR sensitivity of conventional optical OFDM. The improvement of 4D-OFDM over corresponding polarization-multiplexed QAM (with the same number of constellation points) ranges from 1.79 dB for 16 signal constellation point-four-dimensional-OFDM (16 4D-OFDM) up to 4.53 dB for 128-4D-OFDM. PMID- 21263628 TI - Linearized electrooptic microwave downconversion using phase modulation and optical filtering. AB - We propose and demonstrate an electrooptic technique for relaying microwave signals over an optical fiber and downconverting the microwave signal to an intermediate frequency at the receiver. The system uses electrooptic phase modulation in the transmitter to impose the microwave signal on an optical carrier followed by re-modulation with a microwave local oscillator at the receiver. We demonstrate that by subsequently suppressing the optical carrier using a notch filter, the resulting optical signal can be directly detected to obtain a downconverted microwave signal.We further show that by simply controlling the amplitude of the microwave local oscillator, the system can be linearized to third-order, yielding an improvement in the dynamic range. PMID- 21263629 TI - Spatially confined synthesis of SiOx nano-rod with size-controlled Si quantum dots in nano-porous anodic aluminum oxide membrane. AB - By depositing Si-rich SiOx nano-rod in nano-porous anodic aluminum oxide (AAO) membrane using PECVD, the spatially confined synthesis of Si quantum-dots (Si QDs) with ultra-bright photoluminescence spectra are demonstrated after low temperature annealing. Spatially confined SiOx nano-rod in nano-porous AAO membrane greatly increases the density of nucleated positions for Si-QD precursors, which essentially impedes the route of thermally diffused Si atoms and confines the degree of atomic self-aggregation. The diffusion controlled growth mechanism is employed to determine the activation energy of 6.284 kJ mole( 1) and diffusion length of 2.84 nm for SiO1.5 nano-rod in nano-porous AAO membrane. HRTEM results verify that the reduced geometric dimension of the SiOx host matrix effectively constrain the buried Si-QD size at even lower annealing temperature. The spatially confined synthesis of Si-QD essentially contributes the intense PL with its spectral linewidth shrinking from 210 to 140 nm and its peak intensity enhancing by two orders of magnitude, corresponding to the reduction on both the average Si-QD size and its standard deviation from 2.6 to 2.0 nm and from 25% to 12.5%, respectively. The red-shifted PL wavelength of the Si-QD reveals an inverse exponential trend with increasing temperature of annealing, which is in good agree with the Si-QD size simulation via the atomic diffusion theory. PMID- 21263630 TI - Optical coupling and splitting with two parallel waveguide tapers. AB - A coupling and splitting device comprising a width taper and a spatial-modulated subwavelength grating waveguide (SSGW) is proposed. The width taper is a waveguide with increasing width and the SSGW is a waveguide grating whose width and thickness are constant but the filling factor increases along the light propagation. Thus, the effective index of the subwavelength grating increases according to the effective medium theory. Light of orthogonal polarizations from a single-mode fiber can be coupled efficiently with the two parallel tapers. Furthermore, the coupled lights of orthogonal polarizations in the two tapers can be further split with connecting bent waveguides. Fabrication of the device is fully compatible with current complementary metal oxide semiconductor technology. PMID- 21263631 TI - High average power diamond Raman laser. AB - We report a pulsed Raman laser at 1193 nm based on synthetic diamond crystals with a record output power of 24.5 W and a slope efficiency of 57%. We compared the performance of an anti-reflection coated crystal at normal incidence with a Brewster cut sample. Raman oscillation was achieved at both room temperature and under cryogenic operation at 77 K. Modeling of these experiments allowed us to confirm the value of Raman gain coefficient of diamond, which was found to be 13.5 +/- 2.0 cm/GW for a pump wavelength of 1030 nm. PMID- 21263632 TI - High average power, high energy 1.55 MUm ultra-short pulse laser beam delivery using large mode area hollow core photonic band-gap fiber. AB - We demonstrate high average power, high energy 1.55 MUm ultra-short pulse (<1 ps) laser delivery using helium-filled and argon-filled large mode area hollow core photonic band-gap fibers and compare relevant performance parameters. The ultra short pulse laser beam-with pulse energy higher than 7 MUJ and pulse train average power larger than 0.7 W-is output from a 2 m long hollow core fiber with diffraction limited beam quality. We introduce a pulse tuning mechanism of argon filled hollow core photonic band-gap fiber. We assess the damage threshold of the hollow core photonic band-gap fiber and propose methods to further increase pulse energy and average power handling. PMID- 21263633 TI - Optical eigenmodes; exploiting the quadratic nature of the energy flux and of scattering interactions. AB - We report a mathematically rigorous technique which facilitates the optimization of various optical properties of electromagnetic fields in free space and including scattering interactions. The technique exploits the linearity of electromagnetic fields along with the quadratic nature of the intensity to define specific Optical Eigenmodes (OEi) that are pertinent to the interaction considered. Key applications include the optimization of the size of a focused spot, the transmission through sub-wavelength apertures, and of the optical force acting on microparticles. We verify experimentally the OEi approach by minimising the size of a focused optical field using a superposition of Bessel beams. PMID- 21263634 TI - Markov chain formalism for polarized light transfer in plane-parallel atmospheres, with numerical comparison to the Monte Carlo method. AB - Building on the Markov chain formalism for scalar (intensity only) radiative transfer, this paper formulates the solution to polarized diffuse reflection from and transmission through a vertically inhomogeneous atmosphere. For verification, numerical results are compared to those obtained by the Monte Carlo method, showing deviations less than 1% when 90 streams are used to compute the radiation from two types of atmospheres, pure Rayleigh and Rayleigh plus aerosol, when they are divided into sublayers of optical thicknesses of less than 0.03. PMID- 21263635 TI - Pure chiral optical fibres. AB - We investigate the properties of optical fibres made from chiral materials, in which a contrast in optical activity forms the waveguide, rather than a contrast in the refractive index; we refer to such structures as pure chiral fibres. We present a mathematical formulation for solving the modes of circularly symmetric examples of such fibres and examine the guidance and polarisation properties of pure chiral step-index, Bragg and photonic crystal fibre designs. Their behaviour is shown to differ for left- and right-hand circular polarisation, allowing circular polarisations to be isolated and/or guided by different mechanisms, as well as differing from equivalent non-chiral fibres. The strength of optical activity required in each case is quantified. PMID- 21263636 TI - All-optical Fresnel lens in coherent media: controlling image with image. AB - We theoretically explore an all-optical method for generating tunable diffractive Fresnel lenses in coherent media based on electromagnetically induced transparency. In this method, intensity-modulated images in coupling light fields can pattern the coherent media to induce the desired modulo-2pi quadratic phase profiles for the lenses to diffract probe light fields. We characterize the focusing and imaging properties of the induced lenses. In particular, we show that the images in coupling fields can flexibly control the images in probe fields by diffraction, where large focal length tunability from 1 m to infinity and high output (~ 88% diffraction efficiency) can be achieved. Additionally, we also find that the induced Fresnel lenses can be rapidly modulated with megahertz refresh rates using image-bearing square pulse trains in coupling fields. Our proposed lenses may find a wide range of applications for multimode all-optical signal processing in both the classical and quantum regimes. PMID- 21263637 TI - Power scaling of a picosecond vortex laser based on a stressed Yb-doped fiber amplifier. AB - Power scaling of a picosecond vortex laser based on a stressed Yb-doped fiber amplifier is analyzed. An output power of 25 W was obtained for 53 W of pumping, with a peak power of 37 kW. Frequency doubling of the vortex output was demonstrated using a nonlinear PPSLT crystal. A second-harmonic output power of up to 1.5 W was measured at a fundamental power of 11.2 W. PMID- 21263638 TI - Broadband plasmonic nanoantenna with an adjustable spectral response. AB - Six-particle and eight-particle common-gap plasmonic nanoantennas are utilized to obtain a broadband spectral response when illuminated with circular and elliptical polarization. Due to the insensitivity of dipole antennas to circular polarization, the resonant structures are brought together around the common-gap to expand the spectrum of the whole system. Their ability to focus light at different frequencies is demonstrated. The spectral response is manipulated by geometrical parameters and the strength of the spectral peaks is tailored through the ellipticity of the elliptically polarized light. PMID- 21263639 TI - Chromatic dispersion monitoring for multiple modulation formats and data rates using sideband optical filtering and asynchronous amplitude sampling technique. AB - We propose and experimentally demonstrate a low-cost technique for chromatic dispersion (CD) monitoring in various return-to-zero (RZ) amplitude and phase modulated systems at different data rates by analyzing the asynchronously sampled amplitudes of two vestigial sideband (VSB) signals. The proposed technique graphically represents the CD induced-effects in a scatter plot of which a parameter is extracted to monitor CD and is resilient to OSNR variations. Simulations and experimental results demonstrate good monitoring ranges and sensitivities for various modulation formats at different data rates without any modification of the monitoring hardware. The influence of first-order polarization-mode dispersion (PMD) on the accuracy of proposed monitoring technique is also investigated. PMID- 21263640 TI - Spatial light interference microscopy (SLIM). AB - We present spatial light interference microscopy (SLIM) as a new optical microscopy technique, capable of measuring nanoscale structures and dynamics in live cells via interferometry. SLIM combines two classic ideas in light imaging: Zernike's phase contrast microscopy, which renders high contrast intensity images of transparent specimens, and Gabor's holography, where the phase information from the object is recorded. Thus, SLIM reveals the intrinsic contrast of cell structures and, in addition, renders quantitative optical path-length maps across the sample. The resulting topographic accuracy is comparable to that of atomic force microscopy, while the acquisition speed is 1,000 times higher. We illustrate the novel insight into cell dynamics via SLIM by experiments on primary cell cultures from the rat brain. SLIM is implemented as an add-on module to an existing phase contrast microscope, which may prove instrumental in impacting the light microscopy field at a large scale. PMID- 21263641 TI - Four-parameter model for polarization-resolved rough-surface BRDF. AB - A modeling procedure is demonstrated, which allows representation of polarization resolved BRDF data using only four parameters: the real and imaginary parts of an effective refractive index with an added parameter taking grazing incidence absorption into account and an angular-scattering parameter determined from the BRDF measurement of a chosen angle of incidence, preferably close to normal incidence. These parameters allow accurate predictions of s- and p-polarized BRDF for a painted rough surface, over three decades of variation in BRDF magnitude. To characterize any particular surface of interest, the measurements required to determine these four parameters are the directional hemispherical reflectance (DHR) for s- and p-polarized input radiation and the BRDF at a selected angle of incidence. The DHR data describes the angular and polarization dependence, as well as providing the overall normalization constraint. The resulting model conserves energy and fulfills the reciprocity criteria. PMID- 21263642 TI - Ptychographic coherent x-ray diffractive imaging in the water window. AB - Coherent x-ray diffractive microscopy enables full reconstruction of the complex transmission function of an isolated object to diffraction-limited resolution without relying on any optical elements between the sample and detector. In combination with ptychography, also specimens of unlimited lateral extension can be imaged. Here we report on an application of ptychographic coherent diffractive imaging (PCDI) in the soft x-ray regime, more precisely in the so-called water window of photon energies where the high scattering contrast between carbon and oxygen is well-suited to image biological samples. In particular, we have reconstructed the complex sample transmission function of a fossil diatom at a photon energy of 517 eV. In imaging a lithographically fabricated test sample a resolution on the order of 50 nm (half-period length) has been achieved. Along with this proof-of-principle for PCDI at soft x-ray wavelengths, we discuss the experimental and technical challenges which can occur especially for soft x-ray PCDI. PMID- 21263643 TI - Generation of squeezed vacuum pulses at 810 nm using a 40-cm-long optical fiber. AB - We experimentally demonstrate the generation of a squeezed vacuum pulse at 810 nm with a fiber polarization interferometer. During femtosecond laser pulse propagation through an optical fiber in the normal dispersion regime, only self phase modulation within a short length contributes to pulse squeezing since the laser pulse is immediately broadened. Guided acoustic-wave Brillouin scattering (GAWBS) noise that increases in proportional to the fiber length is also lower with shorter fibers. Consequently, a maximum noise reduction of 2.1 dB (4.8 dB when corrected for losses) is obtained using a 40-cm-long single mode optical fiber. PMID- 21263644 TI - Demonstration of arbitrary channel selection utilizing a pulse-injected semiconductor laser with a phase-locked loop. AB - An arbitrary channel selection system based on a pulse-injected semiconductor laser with a phase-locked loop (PLL) is experimentally demonstrated and characterized. Through optical injection from a tunable laser, channels formed by the frequency components of a microwave frequency comb generated in the pulse injected semiconductor laser are individually selected and enhanced. Selections of a primary channel at the fundamental frequency of 1.2 GHz and a secondary channel in a range from 10.8 to 18 GHz are shown, where the selection is done by adjusting the injection strength from the tunable laser. Suppression ratios of 44.5 and 25.9 dB between the selected primary and secondary channels to the averaged magnitude of the unwanted channels are obtained, respectively. To show the spectral quality of the pulse-injected laser, a single sideband (SSB) phase noise of -60 dBc/kHz at an offset frequency of 25 kHz is measured. Moreover, the conversion gain between the primary and secondary channels and the crosstalk between the selected channels to the adjacent unwanted channels are also investigated. Without the need of expensive external modulators, arbitrary channel selection is realized in the proposed system where the channel spacing and selection can be continuously adjusted through tuning the controllable laser parameters. PMID- 21263646 TI - Planar terahertz waveguides based on complementary split ring resonators. AB - We experimentally demonstrate planar plasmonic THz waveguides using metal films that are periodically perforated with complementary split ring resonators (CSRRs). The waveguide transmission spectra exhibit numerous transmission resonances. While the geometry is commonly used in developing negative index materials, the excitation geometry used here does not allow for conventional metamaterial response. Instead, we show that all of the observed resonances can be determined from the geometrical properties of the CSRR apertures. Surprisingly, the Bragg condition does not appear to limit the frequency extent of the observed resonances. The results suggest that metamaterial-inspired geometries may be useful for developing THz guided-wave devices. PMID- 21263645 TI - Improving light extraction of InGaN-based light emitting diodes with a roughened p-GaN surface using CsCl nano-islands. AB - InGaN-based light emitting diodes (LEDs) with a top nano-roughened p-GaN surface are fabricated using self-assembled CsCl nano-islands as etch masks. Following formation of hemispherical GaN nano-island arrays, electroluminescence (EL) spectra of roughened LEDs display an obvious redshift due to partial compression release in quantum wells through Inductively Coupled Plasma (ICP) etching. At a 350-mA current, the enhancement of light output power of LEDs subjected to ICP treatment with durations of 50, 150 and 250 sec compared with conventional LED have been determined to be 9.2, 70.6, and 42.3%, respectively. Additionally, the extraction enhancement factor can be further improved by increasing the size of CsCl nano-island. The economic and rapid method puts forward great potential for high performance lighting devices. PMID- 21263647 TI - Laser frequency fixation by multimode optical injection locking. AB - Fixation of the optical frequency of slave laser to the frequencies between two adjacent modes by multiple optical injection locking is investigated. Numerical simulation suggests that the frequency pulling among many four wave mixing tones is the origin of the locking mechanism. PMID- 21263648 TI - Investigation on wide-band scattering of a 2-D target above 1-D randomly rough surface by FDTD method. AB - Finite-difference time-domain (FDTD) algorithm with a pulse wave excitation is used to investigate the wide-band composite scattering from a two-dimensional(2 D) infinitely long target with arbitrary cross section located above a one dimensional(1-D) randomly rough surface. The FDTD calculation is performed with a pulse wave incidence, and the 2-D representative time-domain scattered field in the far zone is obtained directly by extrapolating the currently calculated data on the output boundary. Then the 2-D wide-band scattering result is acquired by transforming the representative time-domain field to the frequency domain with a Fourier transform. Taking the composite scattering of an infinitely long cylinder above rough surface as an example, the wide-band response in the far zone by FDTD with the pulsed excitation is computed and it shows a good agreement with the numerical result by FDTD with the sinusoidal illumination. Finally, the normalized radar cross section (NRCS) from a 2-D target above 1-D rough surface versus the incident frequency, and the representative scattered fields in the far zone versus the time are analyzed in detail. PMID- 21263649 TI - Extraordinary terahertz transmission in superconducting subwavelength hole array. AB - We report the extraordinary terahertz (THz) transmission through subwavelength hole array in superconducting NbN film. As the temperature drops below the superconducting transition temperature, the transmission spectra experience distinct changes. The extraordinary transmission is greatly enhanced in superconducting state due to the enhancement of surface plasmon polaritons (SPPs) and localized surface plasmons (LSPs). We have also observed temperature dependent resonance frequency shift, which mainly depends on the coupling between SPPs and LSPs. PMID- 21263650 TI - Femtosecond stimulated Raman spectrometer in the 320-520nm range. AB - Multi-uJ narrow-bandwidth (~ 10 cm(-1)) picosecond pulses, broadly tunable in the visible-UV range (320-520 nm), are generated by spectral compression of femtosecond pulses emitted by an amplified Ti:sapphire system. Such pulses provide the ideal Raman pump for broadband femtosecond stimulated Raman spectroscopy, as here demonstrated on a heme protein. PMID- 21263652 TI - High efficiency coupling of Terahertz micro-ring quantum cascade lasers to the low-loss optical modes of hollow metallic waveguides. AB - We demonstrate that azimuthally polarized surface emitting Terahertz quantum cascade lasers fabricated in a micro-ring resonator geometry can be coupled to cylindrical hollow aluminum waveguides reaching efficiencies as high ~98%, when a collimating lens is used. By placing the waveguide in close contact with the QCL in a simple back-to-back geometry, the laser mode can be perfectly matched with the low loss TE(01) waveguide mode showing attenuation losses as low as ~2.3-2.7 dB/m at 3.2 THz. PMID- 21263651 TI - Highly transparent organic light-emitting diodes with a metallic top electrode: the dual role of a Cs2CO3 layer. AB - Highly transparent organic light-emitting diodes (TrOLEDs) are demonstrated using damage-free top cathodes of Cs2CO3/ Ag capped with ZnS layers. The presence of ultrathin Cs2CO3 layers not only improves the electron injection properties but also makes Ag thin films more continuous and uniform, resulting in ideal top electrodes with low sheet resistance and high transmittance. The combination of the uniform Ag morphology enabled by Cs2CO3 and the optimized thickness of ZnS capping layers results in TrOLEDs that have a peak transmittance as large as 80% with a luminous transmittance of 76.4%. These TrOLEDs exhibit a low turn-on voltage of 2.6V due to injection improvement by the Cs2CO3 layers. PMID- 21263653 TI - Narrow line width operation of a 980 nm gain guided tapered diode laser bar. AB - We demonstrate two different schemes for the spectral narrowing of a 12 emitter 980 nm gain guided tapered diode laser bar. In the first scheme, a reflective grating has been used in a Littman Metcalf configuration and the wavelength of the laser emission could be narrowed down from more than 5.5 nm in the free running mode to 0.04 nm (FWHM) at an operating current of 30 A with an output power of 8 W. The spectrum was found to be tunable within a range of 16 nm. In the second scheme, a volume Bragg grating has been used to narrow the wavelength of the laser bar from over 5 nm to less than 0.2 nm with an output of 5 W at 20 A. To our knowledge, this is the first time spectral narrowing has been performed on a gain guided tapered diode laser bar. In the Littman Metcalf configuration, the spectral brightness has been increased by 86 times and in the volume Bragg grating cavity the spectral brightness has been improved over 18 times when compared to the free running operation. These schemes could be also extended for other wavelengths of interest in the future. PMID- 21263654 TI - Internal temperature measurement of an ytterbium doped material under laser operation. AB - Temperature of the pumped volume of an ytterbium doped material has been measured while laser action is taking place. This is achieved by recording green emissions at 530 and 550 nm from Er3+ impurities. These emissions result from energy transfer upconversion processes between Yb3+ and Er3+. Experiments performed on a Yb3+:CaGdAlO4 crystal show the effect of pump power and laser wavelength on the sample internal temperature. Temperature variation along the sample length has also been measured. This method can complement data obtained by thermal cameras which can only access surface temperatures in most laser materials. PMID- 21263655 TI - An external cloak with arbitrary cross section based on complementary medium and coordinate transformation. AB - Electromagnetic cloak is a device which makes an object "invisible" for electromagnetic irradiation in a certain frequency range. Material parameters for the complementary medium-assisted external cylindrical cloak with arbitrary cross section are derived based on combining the concepts of complementary media and transformation optics. It can make the object with arbitrary shape outside the cloaking domain invisible, as long as an "antiobject" is embedded in the complementary media layer. Moreover, we find that the shape, size and the position of the "antiobject" is dependent on the contour of the cloak and the coordinate transformation. The external cloaking effect has been verified by full wave simulation. PMID- 21263656 TI - Linear and nonlinear light propagation at the interface of two homogeneous waveguide arrays. AB - We investigate linear and nonlinear light propagation at the interface of two one dimensional homogeneous waveguide arrays containing a single defect of different strength. For the linear case and in a limited region of the defect size, we find trapped staggered and unstaggered modes. In the nonlinear case, we study the dependence of power thresholds for discrete soliton formation in different channels as a function of defect strength. All experimental results are confirmed theoretically using an adequate discrete model. PMID- 21263657 TI - Switchable, dual-wavelength passively mode-locked ultrafast fiber laser based on a single-wall carbon nanotube modelocker and intracavity loss tuning. AB - We demonstrate a dual-wavelength passively mode-locked soliton fiber laser based on the single-wall carbon nanotube saturable absorber. By using a simple scheme of adjusting the intracavity loss, the gain profile of the erbium-doped fiber laser is effectively controlled. Besides operating at a single wavelength, the laser is able to simultaneously generate sub-picosecond pulses at both ~1532 and 1557 nm wavelength. The mode-locking wavelength can also be quickly switched from one wavelength to the other by changing the intracavity loss with a tunable attenuator. PMID- 21263658 TI - Coded excitation for photoacoustic imaging using a high-speed diode laser. AB - A Q-switched Nd:YAG laser providing nanosecond pulse durations and millijoule pulse energies is suitable for typical biomedical PA applications. However, such lasers are both bulky and expensive. An alternative method is to use a diode laser, which can achieve a higher pulse repetition frequency. Although the energy from a diode laser is generally too low for effective PA generation, this can be remedied by using high-speed coded laser pulses, with the signal intensity of the received signal being enhanced by pulse compression. In this study we tested a version of this method that employs coded excitation. A 20-MHz PA transducer was used for backward-mode PA detection. A frequency-coded PA signal was generated by tuning the interval between two adjacent laser pulses. The experimental results showed that this methodology improved the signal-to-noise ratio of the decoded PA signal by up to 19.3 dB, although high range side lobes were also present. These side lobes could be reduced by optimizing the compression filter. In contrast to the Golay codes proposed in the literature, the proposed coded excitation requires only a single stimulus. PMID- 21263659 TI - Simple fabrication of a double-layer multi-channel optical waveguide using passive alignment. AB - This study proposes a simple and cost-effective method of fabricating a double layer polymeric optical waveguide, using two hot-embossing processes with a single stamp and template for passive alignment between the top and bottom layers. The two hot-embossing processes were conducted sequentially on the top layer and the bottom layer of the polymer layer. The second hot-embossing process was conducted after fabricating the buffer layer on the surface of the polymeric channel structure to control deformation and destruction of the previously fabricated polymeric channel structure. Passive alignment of the channel structure for the top layer and the bottom layer was automatically performed by simple insertion of the stamp and polymer layer using a metal template with the same dimensions (width x length) as the stamp. Regarding the polymer layer, the buffer layer on the side with the channel structure was coated, whereas the layer contacting the stamp did not have a buffer layer. For the purposes of this study, a 2 x 50 channel polymeric multimode optical waveguide was fabricated using a stamp with 50 straight ribs, without any coupling between the layers. The fabricated optical waveguide was controlled within positional tolerances of less than +/- 5 MUm between layers; propagation loss of below 0.2 dB/cm at 850 nm; and channel uniformity of below 0.5 dB. PMID- 21263660 TI - Visible laser operation of Pr3+-doped fluoride crystals pumped by a 469 nm blue laser. AB - We report continuous-wave (CW) laser operation of Pr3+-doped LiLuY4, LiYF4 and KY3F10 single crystals in the Red, Orange and Green spectral regions by using a new pumping scheme. The pump source is an especially developed compact, slightly tunable and intracavity frequency-doubled diode-pumped Nd:YAG laser delivering a CW output power of 0.9W at 469.12 nm. At this pump wavelength, efficient room temperature laser emissions corresponding to the 3P0->3F2, 3P0->3H6 and 3P1->3H5 Pr3+ transitions are observed. While a maximum slope efficiency of 45% is obtained in the red with Pr:LiYF4, the demonstration is made for the first time of the orange laser operation of Pr:KY3F10 at about 610 nm. PMID- 21263661 TI - A study of regenerated gratings produced in germanosilicate fibers by high temperature annealing. AB - In light of recent proposals linking structural change and stresses within regenerated gratings, the details of regeneration of a seed Type-I Bragg grating written in H2 loaded germanosilicate fiber annealed at high temperatures (~900 degrees C) are systematically explored. In particular, the influence of the strength of the grating, the effect of GeO2 doping concentration and the annealing conditions on regeneration are studied. We show that the role of dopants such as Ge and F contribute nothing to the regeneration, consistent with previous results. Rather, they may potentially be detrimental. Strongest regenerated gratings with R ~35% from a 5mm seed grating could be obtained in fibres with the lowest GeO2 concentrations such as standard telecommunications compatible grade fibre. PMID- 21263662 TI - Deterministic generation of multiparticle entanglement in a coupled cavity-fiber system. AB - We develop a one-step scheme for generating multiparticle entangled states between two cold atomic clouds in distant cavities coupled by an optical fiber. We show that, through suitably choosing the intensities and detunings of the fields and precisely tuning the time evolution of the system, multiparticle entanglement between the separated atomic clouds can be engineered deterministically, in which quantum manipulations are insensitive to the states of the cavity and losses of the fiber. The experimental feasibility of this scheme is analyzed based on recent experimental advances in the realization of strong coupling between cold 87Rb clouds and fiber-based cavity. This scheme may open up promising perspectives for implementing quantum communication and networking with coupled cavities connected by optical fibers. PMID- 21263663 TI - Visualization of microvasculature by dual-beam phase-resolved Doppler optical coherence tomography. AB - We present a dual-beam Doppler optical coherence tomography system for visualizing the microvasculature within the retina. The sample arm beams from two identical spectral domain optical coherence tomography (SD-OCT) systems are combined such that there is a small horizontal offset between them at the retina. Thereby we record two tomograms which are slightly separated in time. Phase resolved Doppler analysis is performed between these two data sets. This system allows blood capillary imaging with high flow sensitivity and variable velocity range. To demonstrate the performance of our system we present images of the microvascular network around the fovea and around the optic nerve head of the human eye. PMID- 21263664 TI - 16 W output power by high-efficient spectral beam combining of DBR-tapered diode lasers. AB - Up to 16 W output power has been obtained using spectral beam combining of two 1063 nm DBR-tapered diode lasers. Using a reflecting volume Bragg grating, a combining efficiency as high as 93.7% is achieved, resulting in a single beam with high spatial coherence. The result represents the highest output power achieved by spectral beam combining of two single element tapered diode lasers. Since spectral beam combining does not affect beam propagation parameters, M2 values of 1.8 (fast axis) and 3.3 (slow axis) match the M2-values of the laser with lowest spatial coherence. The principle of spectral beam combining used in our experiments can be expanded to combine more than two tapered diode lasers and hence it is expected that the output power may be increased even further in the future. PMID- 21263665 TI - Design of reconfigurable metallic slits for terahertz beam modulation. AB - We analyze the interaction of electromagnetic waves with double-layered subwavelength metallic slits on a dielectric substrate. This structure allows efficient transmission of an incident TM-polarized electromagnetic wave into the dielectric substrate, due to the presence of surface modes which couple the incident wave to the TEM waveguide modes supported by the subwavelength metallic slits. Our study shows that electromagnetic transmission through double-layered subwavelength metallic slits is strongly geometry dependent. Based on this observation, a terahertz modulation scheme is presented which, compared to existing terahertz modulator solutions, has the promise of significant enhancement in modulation index over a broad range of terahertz frequencies. PMID- 21263666 TI - Dual transmission band Bragg grating assisted asymmetric directional couplers. AB - The use of artificial dispersion by material structuring is investigated for the design of highly wavelength selective directional couplers. Systems of two highly asymmetric coupled waveguides are considered with the artificial dispersion created by distributed Bragg gratings (BGs) operated near photonic band gap. It is shown that even in the case of an asymmetrical directional coupler with initially phase matched waveguides, the achievement of high wavelength selectivity requires the fulfillment of a threshold condition on the BG coupling coefficient. The presence of BG(s) leads in turn to the appearance of two transmission bands instead of one. The wavelength selectivity associated to one of these bands is much higher than that obtained in the absence of BG(s). It is also shown that under particular circumstances, dual band operation can be achieved without threshold condition. The directional coupler then exhibits two transmission bands with approximately the same width and a very low level of insertion losses. Such a dual band transmission coupler is expected to offer new functionalities for wavelength demultiplexing applications. PMID- 21263667 TI - Ultrafast optical manipulation of atomic arrangements in chalcogenide alloy memory materials. AB - A class of chalcogenide alloy materials that shows significant changes in optical properties upon an amorphous-to-crystalline phase transition has lead to development of large data capacities in modern optical data storage. Among chalcogenide phase-change materials, Ge2Sb2Te5 (GST) is most widely used because of its reliability. We use a pair of femtosecond light pulses to demonstrate the ultrafast optical manipulation of atomic arrangements from tetrahedral (amorphous) to octahedral (crystalline) Ge-coordination in GST superlattices. Depending on the parameters of the second pump-pulse, ultrafast nonthermal phase change occurred within only few-cycles (~1 picosecond) of the coherent motion corresponding to a GeTe4 local vibration. Using the ultrafast switch in chalcogenide alloy memory could lead to a major paradigm shift in memory devices beyond the current generation of silicon-based flash-memory. PMID- 21263668 TI - Comprehensive in vivo micro-vascular imaging of the human eye by dual-beam-scan Doppler optical coherence angiography. AB - Comprehensive angiography provides insight into the diagnosis of vascular-related diseases. However, complex microvascular networks of unstable in vivo organs such as the eye require micron-scale resolution in three dimensions and a high sampling rate to access a wide area as maintaining the high resolution. Here, we introduce dual-beam-scan Doppler optical coherence angiography (OCA) as a label free comprehensive ophthalmic angiography that satisfies theses requirements. In addition to high resolution and high imaging speed, high sensitivity to motion for detecting tiny blood flow of microvessels is achieved by detecting two time delayed signals with scanning of two probing beams separated on a sample. We present in vivo three-dimensional imaging of the microvasculature of the posterior part of the human eye. The demonstrated results show that this technique may be used for comprehensive ophthalmic angiography to evaluate the vasculature of the posterior human eye and to diagnose variety of vascular diseases. PMID- 21263669 TI - Snap-shot profilometry with the Empirical Mode Decomposition and a 3-layer color sensor. AB - Remote sensing finds more and more applications, from industrial control, to face recognition, not forgetting terrain surveying. This trend is well exemplified by fringe projection techniques, which enjoyed a considerable development in the recent years. In addition of high requirement in terms of measurement accuracy and spatial resolution, the end-users of full-field techniques show a growing interest for dynamic regimes. We report here what we believe to be the use for the first time of a CMOS 3-layer color sensor (Foveon X3) as the key element of a RGB fringe projection system, together with the processing specifically elaborated for this sensor. The 3-layer architecture allows the simultaneous recording of three phase-shifted fringe patterns and features the precious asset of an unambiguous relationship between the physical sensor pixel and the picture pixel and this for each color layer, on the contrary of common color sensor arrays (Bayer mosaic and tri-CCD). Due to the overlapping of the spectral responses of the layers, color transformation is mandatory to achieve the separation of the three phase-shifted RGB projected fringe patterns. In addition, we propose the use of the Empirical Mode Decomposition to equalize the non uniform responses of the three layers. Although the conversion of the phase into a height is of primary importance in an actual measurement, it is not treated here, the literature being profuse on the central projection model. PMID- 21263670 TI - High-throughput detection of immobilized plasmonic nanoparticles by a hyperspectral imaging system based on Fourier transform spectrometry. AB - To facilitate the application of plasmonic nanoparticles (PNPs) in high throughput detection, we develop a hyperspectral imaging system (HSIS) combining dark-filed microscopy and imaging Fourier transform spectrometry to measure scattering spectra from immobilized PNPs. The current setup has acquisition time of 5 seconds and spectral resolution of 21.4 nm at 532.1 nm. We demonstrate the applicability of the HSIS in conjunction with spectral data analysis to quantify multiple types of PNPs and detect small changes in localized surface plasmon resonance wavelengths of PNPs due to changes in the environmental refractive index. PMID- 21263671 TI - Asymmetric light reflectance effect in AAO on glass. AB - Asymmetric light reflectance effect was observed in an anodic aluminum oxide on glass structure. The transmitted light from two sides of the films show the same colors, whereas the reflected light from two sides show complementary colors. The spectra analysis demonstrates that this asymmetric light reflectance effect can be ascribed to the asymmetric geometric structure of nanoscale aluminum networks. This effect may result in applications in many fields, especially in optical communication. PMID- 21263672 TI - Large positive and negative lateral shifts near pseudo-Brewster dip on reflection from a chiral metamaterial slab. AB - The lateral shifts from a slab of lossy chiral metamaterial are predicted for both perpendicular and parallel components of the reflected field, when the transverse electric (TE)-polarized incident wave is applied. By introducing different chirality parameter, the lateral shifts can be large positive or negative near the pseudo-Brewster angle. It is found that the lateral shifts from the negative chiral slab are affected by the angle of incidence and the chirality parameter. In the presence of inevitable loss of the chiral slab, the enhanced lateral shifts will be decreased, and the pseudo-Brewster angle will disappear correspondingly. For the negative chiral slab with loss which is invisible for the right circularly polarized (RCP) wave, we find that the loss of the chiral slab will lead to the fluctuation of the lateral shift with respect to the thickness of the chiral slab.The validity of the stationary-phase analysis is demonstrated by numerical simulations of a Gaussian-shaped beam. PMID- 21263673 TI - Optical coherence tomography by using frequency measurements in wavelength domain. AB - Optical coherence tomography (OCT) reconstruction by using frequency measurements in the wavelength domain is presented in this paper. The method directly recovers the axial scan by formulating the frequency domain OCT (FD-OCT) into an algebraic reconstruction problem. In this way, the need for interpolation is removed. Then by solving the problem with l1 optimization, the computational load is significantly reduced. It is demonstrated by experiment and simulation that the proposed method can achieve high resolution and longer imaging depth compared to the FD-OCT method. PMID- 21263674 TI - Light coupling and enhanced backscattering in layered plasmonic nanocomposites. AB - Peculiar enhanced backscattering of light as well as selective vapor sensing were recently observed in a layered plasmonic nanocomposite which consisted of gold nanospheres randomly distributed in a sol-gel glass thin film on top of a soda lime glass substrate, including a buried leaky waveguide. In order to understand the underlying physical mechanisms, we performed three-dimensional transfer matrix numerical simulations and calculated the reflectance in both backward and specular directions as functions of the incidence angle. First, assuming a layered periodic particle arrangement, we confirmed that backscattering took place at grazing incidence if the spatial period in the layers was chosen within an optimal range, in agreement with theoretical predictions. Then, using a pseudo random particle arrangement to describe the actual nanocomposite, we revealed that strong backscattering could nevertheless persist for specific particle distributions, in spite of their randomness. This behavior was tentatively explained by putting backscattering in relation with the particle interdistance statistics. Finally, we showed that backscattered reflectance was much more sensitive than specular reflectance to the adsorption of water vapor either on the surface or inside the likely porous structure of the glass host. PMID- 21263675 TI - Experimental investigation about influences of longitudinal-mode structure of pumping source on a Ti:sapphire laser. AB - Using a multi-longitudinal-mode (MLM) and a single-longitudinal-mode (SLM) all solid-state green lasers to be the pumping sources of a continuous-wave Ti:sapphire laser, respectively, the intensity-noise dependence of the Ti:sapphire laser on the longitudinal-mode structure of pumping sources is experimentally studied. The comparison between the theoretical prediction based on the quantum-mechanical model and the experimental measurement for the intensity-noise spectra is presented. PMID- 21263676 TI - CD-insensitive PMD monitoring based on RF power measurement. AB - We propose and experimentally demonstrate a chromatic dispersion (CD)-insensitive first-order polarization mode dispersion (PMD) monitoring method based on radio frequency (RF) power measurement. In high-speed (>10-GSym/s) transmission systems, a narrowband fiber Bragg grating (FBG) notch filter filters out the optical components at 10GHz away from the carrier. After square-law detection, the 10-GHz RF tone changes with PMD and is insensitive to CD, which can be used as a PMD monitoring signal. Compared with the monitoring techniques utilizing clock tone, the PMD measurement range is increased from 26.3-ps to 50-ps while the requirement of the bandwidth of photodetector is reduced from 19GHz to 10GHz in 19-Gsym/s systems. It is experimentally shown that this technique is efficient on CD-insensitive first-order PMD monitoring for 38-Gbit/s DQPSK and 57-Gbit/s D8PSK systems. PMID- 21263677 TI - Transporting continuous quantum variables of individual light pulses. AB - We experimentally demonstrate transporting continuous quantum variables of individual light pulses at telecommunication wavelengths by using continuous variable Bell measurements and post-processing displacement techniques. Time domain pulsed homodyne detectors are used in the Bell measurements and the quantum variables of input light are transported pulse-by-pulse. Fidelity of F = 0.57+/-0.03 is experimentally achieved with the aid of entanglement, which is higher than the bound (F(c) = 0.5) of the classical case in the absence of entanglement. PMID- 21263678 TI - Complete single-shot measurement of arbitrary nanosecond laser pulses in time. AB - For essentially all applications, laser pulses must avoid variations in their intensity and phase within a pulse and from pulse to pulse. Currently available devices work very well for both long (>10ns) and short (<100ps) pulses. But intermediate (~ns) pulses remain difficult to measure and, not surprisingly, are the least stable. Here we describe a simple, elegant, complete, all-optical, single-shot device that measures ~ns pulses and that does not require a reference pulse or assumptions about the pulse shape. It simultaneously achieves a very high spectral resolution of <1pm and a very large delay range of ~10ns (several meters of light travel). It accomplishes both goals using high-efficiency, high finesse etalons: one to generate high angular dispersion for a high-resolution spectrometer, and another to tilt the pulse front by ~89.9 degrees without distorting it in time. Using this device, we completely measure microchip and fiber-amplifier pulses. PMID- 21263679 TI - High resolution cellular imaging with nonlinear optical infrared microscopy. AB - We developed a nonlinear optical infrared microscope exploiting a thermally induced refractive index change in the mid-infrared regime and imaged a single biological cell with high spatial resolution that was not possible in conventional infrared microscopes. A refractive index change of a sample induced by infrared (~3.5 MUm) absorption was probed by a visible (633 nm) laser beam. Thus the chemical specificity stems from the spectral absorbance of specimen and the spatial resolution from the short wavelength visible radiation. A reflecting objective (NA0.5) was used to focus the infrared and visible beams on the sample plane, and the sample was raster-scanned for 2-D imaging. The high resolution beyond the infrared diffraction limit was demonstrated by imaging fine grating lines made up of epoxy grooves (830 lines/mm). The probe wavelength dependence of the spatial resolution was investigated by imaging polystyrene beads. We found that the resolution was as small as 0.7 MUm with 633 nm probe wavelength. PMID- 21263680 TI - A microfluidic fluorescence measurement system using an astigmatic diffractive microlens array. AB - We demonstrate an opto-fluidic detection system based on an array of astigmatic diffractive microlenses integrated into a microfluidic flow focus device. Each astigmatic microlens produces a line excitation across the channel and collects fluorescence emission from the linear detection regions. The linear excitation spot results in uniform excitation across the channel and high time resolution in the direction of the flow. Collected fluorescence from each integrated microlens is relayed to a sub-region on a fast CMOS camera. By analyzing the signal from individual microlenses, we demonstrate counting and resolution of 500 nm and 1.1 MUm beads at rates of up to 8,300 per second at multiple locations. In addition, a cross-correlation analysis of the signals from different microlenses yields the velocity dispersion of beads traveling through the channel at peak speeds as high as 560 mm/s. Arrays of specifically designed diffractive optics promise to increase the resolution and functionality of opto-fluidic analysis such as flow cytometry and fluorescence cross-correlation spectroscopy. PMID- 21263681 TI - Pulse compression of a high-power thin disk laser using rod-type fiber amplifiers. AB - We report on two pulse compressors for a high-power thin disk laser oscillator using rod-type fiber amplifiers. Both systems are seeded by a standard SESAM modelocked thin disk laser that delivers 16 W of average power at a repetition rate of 10.6 MHz with a pulse energy of 1.5 MUJ and a pulse duration of 1 ps. We discuss two results with different fiber parameters with different trade-offs in pulse duration, average power, damage and complexity. The first amplifier setup consists of a Yb-doped fiber amplifier with a 2200 MUm2 core area and a length of 55 cm, resulting in a compressed average power of 55 W with 98-fs pulses at a repetition rate of 10.6 MHz. The second system uses a shorter 36-cm fiber with a larger core area of 4500 MUm2. In a stretcher-free configuration we obtained 34 W of compressed average power and 65-fs pulses. In both cases peak powers of > 30 MW were demonstrated at several MUJ pulse energies. The power scaling limitations due to damage and self-focusing are discussed. PMID- 21263682 TI - Photon correlation holography. AB - Unconventional holography called photon correlation holography is proposed and experimentally demonstrated. Using photon correlation, i.e. intensity correlation or fourth order correlation of optical field, a 3-D image of the object recorded in a hologram is reconstructed stochastically with illumination through a random phase screen. Two different schemes for realizing photon correlation holography are examined by numerical simulations, and the experiment was performed for one of the reconstruction schemes suitable for the experimental proof of the principle. The technique of photon correlation holography provides a new insight into how the information is embedded in the spatial as well as temporal correlation of photons in the stochastic pseudo thermal light. PMID- 21263683 TI - Fabrication of two-dimensional Ta2O5 photonic crystal slabs with ultra-low background emission toward highly sensitive fluorescence spectroscopy. AB - A two-dimensional tantalum pentoxide (Ta2O5) photonic crystal (PC) slab with low background emission was fabricated and a 12-fold enhancement of fluorescence from the organic dyes of perylene diimide adsorbed on the surface of the PCs was observed. The background emissions of the Ta2O5 substrates with and without the PCs after thermal annealing at 600 degrees C with oxygen gas were comparable to that of a well-cleaned cover glass. This is to date the lowest level of background emissions of two-dimensional PCs using materials with a high refractive index (>2). The results reported here provide new insights into the fabrication of the photonic devices that enable highly sensitive fluorescence microscopy or optical detections. PMID- 21263684 TI - Low power resonant optical excitation of an optomechanical cavity. AB - We demonstrate the actuation of a double beam opto-mechanical cavity with a sinusoidally varying optical input power. We observe the driven mechanical motion with only 200 nW coupled to the optical cavity mode. We also investigate the pump power dependence of the radio-frequency response for both the driving power and the probe power. Finally, we investigate the dependence of the amplitude of the mechanical motion on mechanical cavity quality factor. PMID- 21263685 TI - Demonstration of a waveguide regime for a silica hollow--core microstructured optical fiber with a negative curvature of the core boundary in the spectral region > 3.5 MUm. AB - We present a numerical and experimental demonstration of a waveguide regime in a broad band spectral range for the hollow core microstructured optical fibers (HC MOFs) made of silica with a negative curvature of the core boundary. It is shown that HC MOFs with the cladding consisting only of one row of silica capillaries allows to guide light from the near to mid infrared despite of high material losses of silica in this spectral region. Such result can be obtained by a special arrangement of cladding capillaries which leads to a change in the sign of the core boundary curvature. The change in the sign of the core boundary curvature leads to a loss of simplicity of boundary conditions for core modes and to "localization" and limitation of their interaction with the cladding material in space. Such HC MOFs made of different materials can be potential candidates for solving problem of ultra high power transmission including transmission of CO and CO2 laser radiation. PMID- 21263686 TI - Continuous-wave and Q-switched Tm-doped KY(WO4)2 planar waveguide laser at 1.84 um. AB - High-quality monoclinic planar waveguide crystals of Tm-doped KY(WO4)2 codoped with Gd3+ and Lu3+ were grown by liquid-phase epitaxy. For the first time, planar waveguide lasing was demonstrated in a monolithic cavity in the 2 um spectral range. The laser was operated in the Q-switched mode using a Cr2+:ZnSe crystal as saturable absorber and in the continuous-wave regimes. The Q-switched planar waveguide laser delivered pulse energies up to 120 nJ at a repetition rate of 7 kHz. PMID- 21263687 TI - Forty Gb/s hybrid silicon Mach-Zehnder modulator with low chirp. AB - We demonstrate a hybrid silicon modulator operating up to 40 Gb/s with 11.4 dB extinction ratio. The modulator has voltage-length product of 2.4 V-mm and chirp of -0.75 over the entire bias range. As a switch, it has a switching time less than 20 ps. PMID- 21263688 TI - Plasmonic-dielectric compound grating with high group-index and transmission. AB - We propose a compound system consisting of a dielectric grating and a plasmonic resonance cavity embedded in the grating. Based on the interference effect between the surface mode supported by the dielectric grating and the plasmonic induced cavity mode, this system could achieve slow light with group index more than 200 and transmission more than 75%. Meanwhile, we examine the effects of the period numbers of the compound system and photonic crystal superlattice made up of alternate layers of the grating and air on the properties of slow light. PMID- 21263689 TI - Frequency-bin entangled comb of photon pairs from a Silicon-on-Insulator micro resonator. AB - We present a quantum-mechanical theory to describe narrowband photon-pair generation via four-wave mixing in a Silicon-on-Insulator (SOI) micro-resonator. We also provide design principles for efficient photon-pair generation in an SOI micro-resonator through extensive numerical simulations. Microring cavities are shown to have a much wider dispersion-compensated frequency range than straight cavities. A microring with an inner radius of 8 MUm can output an entangled photon comb of 21 pairwise-correlated peaks (42 comb lines) spanning from 1.3 MUm to 1.8 MUm. Such on-chip quantum photonic devices offer a path toward future integrated quantum photonics and quantum integrated circuits. PMID- 21263690 TI - Experimental realization of a low-noise heralded single-photon source. AB - We present a heralded single-photon source with a much lower level of unwanted background photons in the output channel by using the herald photon to control a shutter in the heralded channel. The shutter is implemented using a simple field programable gate array controlled optical switch. PMID- 21263691 TI - SNR approach for performance evaluation of time-stretching photonic analogue to digital converter system. AB - A semi-analytical simulation method (SASM) is proposed to evaluate the signal-to noise ratio (SNR) of time stretched signals at the output of photonic analogue-to digital converter (Ph-ADC) system. Analytical expressions of the signal at Ph-ADC output considering generic electrical signals applied to the electro-optic modulators of the Ph-ADC are derived. The contribution to the total variance of the received signal from the noise introduced by the electrical transmitter and receiver, and by the optical amplifier are derived analytically taking into account the pulsed nature of the optical signal. The proposed SASM shows excellent agreement of SNR estimates with the estimates provided by Monte Carlo simulation. This result is confirmed for variance dominantly imposed by the noise introduced by the electrical transmitter, by the optical amplifier and by the electrical receiver. A simplified approach is also proposed and compared with previous work. It is shown that mean power estimates obtained from this simplified approach are valid while the modulator is operating in the linear region and the signal is not affected by the frequency response of the electrical receiver filter. Additionally, it is concluded that the estimates of the noise variance due to the electrical transmitter are acceptable when a small signal analysis of noise along the Ph-ADC is valid. PMID- 21263692 TI - Phase locking a fiber laser array via diffractive coupling. AB - We demonstrate phase locking of a linear array of seven fiber lasers via diffractive coupling. Coupling between the lasers is achieved by a common output coupler positioned at a quarter Talbot distance from the lasers. The output beams are anti-phase locked with a measured far-field fringe contrast of 82%, and their total output power is higher than that obtained when the lasers operate individually. We measure an exponential phase decorrelation between distant lasers in the array, and discuss its fundamental limitation on scalability of this and similar local coupling methods. PMID- 21263693 TI - Femtosecond spectral pulse shaping with holographic gratings recorded in photopolymerizable glasses. AB - The majority of the applications of ultrashort laser pulses require a control of its spectral bandwidth. In this paper we show the capability of volume phase holographic gratings recorded in photopolymerizable glasses for spectral pulse reshaping of ultrashort laser pulses originated in an Amplified Ti: Sapphire laser system and its second harmonic. Gratings with high laser induce damage threshold (LIDT) allowing wide spectral bandwidth operability satisfy these demands. We have performed LIDT testing in the photopolymerizable glass showing that the sample remains unaltered after more than 10 million pulses with 0,75 TW/cm2 at 1 KHz repetition rate. Furthermore, it has been developed a theoretical model, as an extension of the Kogelnik's theory, providing key gratings design for bandwidth operability. The main features of the diffracted beams are in agreement with the model, showing that non-linear effects are negligible in this material up to the fluence threshold for laser induced damage. The high versatility of the grating design along with the excellent LIDT indicates that this material is a promising candidate for ultrashort laser pulses manipulations. PMID- 21263694 TI - Intense terahertz pulse induced exciton generation in carbon nanotubes. AB - We have investigated the highly nonlinear terahertz (THz) light-matter interaction in single-walled carbon nanotubes (SWNTs). The high-peak THz electric field (~0.7 MV/cm) and the low effective mass of carriers result in their ponderomotive energy exceeding the bandgap energy of semiconducting SWNTs. Under such an intense THz pulse irradiation, the interband excitation that results in the generation of excitons occurs, although the THz photon energy (~4 meV) is much smaller than the gap energy of SWNTs (~1 eV). The ultrafast dynamics of this exciton generation process is investigated by THz pump and optical probe spectroscopy. The exciton generation mechanism is described by impact excitation process induced by the strong THz E-field. Such intense THz pulse excitation provides a powerful tool to study nonlinear terahertz optics in non-perturbative regime as well as nonlinear transport phenomena in solids with ultrafast temporal resolution. PMID- 21263695 TI - Low-threshold lasing action in photonic crystal slabs enabled by Fano resonances. AB - We present a theoretical analysis of lasing action in photonic crystal surface emitting lasers (PCSELs). The semiclassical laser equations for such structures are simulated with three different theoretical techniques: exact finite difference time-domain calculations, an steady-state ab-initio laser theory and a semi-analytical coupled-mode formalism. Our simulations show that, for an exemplary four-level gain model, the excitation of dark Fano resonances featuring arbitrarily large quality factors can lead to a significant reduction of the lasing threshold of PCSELs with respect to conventional vertical-cavity surface emitting lasers. Our calculations also suggest that at the onset of lasing action, most of the laser power generated by finite-size PCSELs is emitted in the photonic crystal plane rather than the vertical direction. In addition to their fundamental interest, these findings may affect further engineering of active devices based on photonic crystal slabs. PMID- 21263696 TI - Electrically controllable fishnet metamaterial based on nematic liquid crystal. AB - A variable index metamaterial is demonstrated by embedding nematic liquid crystal inside fishnet layers' void at microwave frequencies. With an external electric field, the left handed passband can be reversibly shifted from 9.14 to 8.80 GHz, whereas the upper right handed passband is nearly unchanged. It is shown that during LC molecular reorientation, magnetic resonance is shifted to a lower frequency because of the permittivity increase between fishnet layers, leading to an effective index change of 1.1 within negative index regime. PMID- 21263697 TI - Lidar measurements of Raman scattering at ultraviolet wavelength from mineral dust over East Asia. AB - We developed a novel measurement channel that utilizes Raman scattering from silicon dioxide (SiO2) quartz at an ultraviolet wavelength (361 nm). The excitation of the Raman signals is done at the primary wavelength of 355 nm emitted from a lidar instrument. In combination with Raman signals from scattering from nitrogen molecules, we may infer the mineral-quartz-related backscatter coefficient. This technique thus allows us to identify in a comparably direct way the mineral quartz content in mixed pollution plumes that consist, e.g., of a mix of desert dust and urban pollution. We tested the channel for the complex situation of East Asian pollution. We find good agreement of the inferred mineral-quartz-related backscatter coefficient to results obtained with another mineral quartz channel which was operated at 546 nm (primary emission wavelength at 532 nm), the functionality of which has already been shown for a lidar system in Tsukuba (Japan). The advantage of the novel channel is that it provides a better signal-to-noise ratio because of the shorter measurement wavelength. PMID- 21263698 TI - Ex-vivo characterization of human colon cancer by Mueller polarimetric imaging. AB - Cancerous and healthy human colon samples have been analyzed ex-vivo using a multispectral imaging Mueller polarimeter operated in the visible (from 500 to 700 nm) in a backscattering configuration with diffuse light illumination. Three samples of Liberkuhn colon adenocarcinomas have been studied: common, mucinous and treated by radiochemotherapy. For each sample, several specific zones have been chosen, based on their visual staging and polarimetric responses, which have been correlated to the histology of the corresponding cuts. The most relevant polarimetric images are those quantifying the depolarization for incident linearly polarized light. The measured depolarization depends on several factors, namely the presence or absence of tumor, its exophytic (budding) or endophytic (penetrating) nature, its thickness (its degree of ulceration) and its level of penetration in deeper layers (submucosa, muscularis externa and serosa). The cellular density, the concentration of stroma, the presence or absence of mucus and the light penetration depth, which increases with wavelength, are also relevant parameters. Our data indicate that the tissues with the lowest and highest depolarizing powers are respectively mucus-free tumoral tissue with high cellular density and healthy serosa, while healthy submucosa, muscularis externa as well as mucinous tumor probably feature intermediate values. Moreover, the specimen coming from a patient treated successfully with radiochemotherapy exhibited a uniform polarimetric response typical of healthy tissue even in the initially pathological zone. These results demonstrate that multi-spectral Mueller imaging can provide useful contrasts to quickly stage human colon cancer ex-vivo and to distinguish between different histological variants of tumor. PMID- 21263699 TI - A high-accuracy pseudospectral full-vectorial leaky optical waveguide mode solver with carefully implemented UPML absorbing boundary conditions. AB - The previously developed full-vectorial optical waveguide eigenmode solvers using pseudospectral frequency-domain (PSFD) formulations for optical waveguides with arbitrary step-index profile is further implemented with the uniaxial perfectly matched layer (UPML) absorption boundary conditions for treating leaky waveguides and calculating their complex modal effective indices. The role of the UPML reflection coefficient in achieving high-accuracy mode solution results is particularly investigated. A six-air-hole microstructured fiber is analyzed as an example to compare with published high-accuracy multipole method results for both the real and imaginary parts of the effective indices. It is shown that by setting the UPML reflection coefficient values as small as on the order of 10( 40) ~ 10(-70), relative errors in the calculated complex effective indices can be as small as on the order of 10(-12). PMID- 21263700 TI - Design of polarization-selective light emitters using one-dimensional metal grating mirror. AB - This paper proposes a polarization-selective light emitter that can enhance preferentially the spontaneous emission rate of one desired polarization state using a one-dimensional metal grating mirror. Systematic numerical simulations were performed to determine the optimized structural parameters of the metal grating mirror consisting of ITO/silver, in which the two orthogonally polarized lights reflected from the grating mirror undergo completely opposite phases. This metal grating mirror was incorporated into a GaN medium, and the spontaneous emission rate of one linearly polarized light was 1.3 times higher than that of the other at a specific distance between the light source and mirror. In addition, the polarization ratio can be increased to 15:1 by considering the extracted power in a practical vertical GaN slab light-emitting diode structure. This study will be useful for demonstrating high-efficiency polarization selective light-emitting diodes without using additional optical components, such as a polarizer. PMID- 21263701 TI - Enhancement of two photon processes in quantum dots embedded in subwavelength metallic gratings. AB - We show a large enhancement of two-photon absorption processes in nanocrystal quantum dots and of light upconversion efficiency from the IR to the near-IR spectral regime, using a hybrid optical device in which near-IR emitting InAs quantum dots were embedded on top a metallic nanoslit array. The resonant enhancement of these nonlinear optical processes is due to the strong local electromagnetic field enhancements inside the nanoslit array structure at the extraordinary transmission resonances. A maximal two-photon absorption enhancement of more than 20 was inferred. Different high field regions were identified for different polarizations, which can be used for designing and optimizing efficient nonlinear processes in such hybrid structures. Combining nanocrystal quantum dots with subwavelength metallic nanostructures is therefore a promising way for a range of possible nonlinear optical devices. PMID- 21263702 TI - Spatially-chirped modulation imaging of absorbtion and fluorescent objects on single-element optical detector. AB - Line imaging of fluorescent and absorptive objects with a single-pixel imaging technique that acquires one-dimensional cross-sections through a sample by imposing a spatially-varying amplitude modulation on the probing beam is demonstrated. The fluorophore concentration or absorber distribution of the sample is directly mapped to modulation frequency components of the spatially integrated temporal signal. Time-domain signals are obtained from a single photodiode, with object spatial frequency correlation encoded in time-domain bursts in the electronic signal from the photodiode. PMID- 21263704 TI - Substrate-based platform for boosting the surface-enhanced Raman of plasmonic nanoparticles. AB - Metal nanoparticles allow for surface-enhanced Raman scattering (SERS), with applications including spectroscopy and highly-multiplexed biolabels. Despite advances in nanoparticles design nanoparticles, the SERS from these systems is still weak when compared with randomly roughened substrates, and this limits their efficacy for many applications. Here, we coherently boost the SERS signal of colloidally-synthesized silver nano-prisms over 50 * by using multilayer substrates. Theoretical calculations verify the enhancement, and uncover the near field response. This points the way toward a versatile platform for greater SERS enhancement from nanoparticles. PMID- 21263703 TI - Ultraviolet photoluminescence of ZnO quantum dots sputtered at room-temperature. AB - We observe ultraviolet photoluminescence from sputtered ZnO quantum dots which are fabricated with no annealing steps. The nanocrystals are embedded in amorphous SiO2 and exhibit a narrow size distribution of 3.5 +/- 0.6 nm. Photoluminescence and transmittance measurements show a shift of ultraviolet emission and absorption of the dots compared to bulk ZnO material. This work paves the way for cheap nanooptical devices in the ultraviolet which are fabricated in a single sputtering run. PMID- 21263705 TI - High resolution interrogation of tilted fiber grating SPR sensors from polarization properties measurement. AB - The generation of surface plasmon resonances (SPRs) in gold-coated weakly tilted fiber Bragg gratings (TFBGs) strongly depends on the state of polarization of the core guided light. Recently, it was demonstrated that rotating the linear state of polarization of the guided light by 90 degrees with respect to the grating tilt allows to turn the SPR on and off. In this work, we measure the Jones matrix associated to the TFBG transmission properties in order to be able to analyze different polarization-related parameters (i.e. dependency on wavelength of polarization dependent loss and first Stokes parameter). As they contain the information about the SPR, they can be used as a robust and accurate demodulation technique for refractometry purposes. Unlike other methods reported so far, a tight control of the input state of polarization is not required. The maximum error on refractive index measurement has been determined to be ~1 10(-5) refractive index unit (RIU), 5 times better than intensity-based measurements on the same sensors. PMID- 21263706 TI - Scintillation induced response in passively-quenched Si-based single photon counting avalanche diode arrays. AB - An optical electrical model which studies the response of Si-based single photon counting arrays, specifically silicon photomultipliers (SiPMs), to scintillation light has been developed and validated with analytically derived and experimental data. The scintillator-photodetector response in terms of relative pulse height, 10%-90% rise/decay times to light stimuli of different rise times (ranging from 0.1 to 5 ns) and decay times (ranging from 1 to 50 ns), as well as for different decay times of the photodetector are compared in theory and simulation. A measured detector response is used as a reference to further validate the model and the results show a mean deviation of simulated over measured values of 1%. PMID- 21263707 TI - Thermally stable green Ba(3)Y(PO(4))3:Ce(3+),Tb(3+) and red Ca(3)Y(AlO)(3)(BO(3))4:Eu(3+) phosphors for white-light fluorescent lamps. AB - A class of thermal stable of green-emitting phosphors Ba(3)Y(PO(4))(3):Ce(3+),Tb(3+) (BYP:Ce(3+),Tb(3+)) and red-emitting phosphors Ca(3)Y(AlO)(3)(BO(3))(4):Eu(3+) (CYAB:Eu(3+)) for white-light fluorescent lamps were synthesized by high temperature solid-state reaction. We observed a decay of only 3% at 150 degrees C for BYP:0.25Ce3+,0.25Tb3+ (3% for LaPO4:Ce(3+),Tb(3+)), and a decay of 4% for CYAB:0.5Eu(3+) (7% for Y(2)O(3):Eu(3+), 24% for Y(2)O(2)S:Eu(3+)). The emission intensity of composition-optimized Ba(3)(Y(0.5)Ce(0.25)Tb(0.25))(PO(4))(3) is 70% of that of commercial LaPO(4):Ce(3+),Tb(3+) phosphors, and the CIE chromaticity coordinates are found to be (0.323, 0.534). The emission intensity of Ca(3)(Y(0.5)Eu(0.5))(AlO)(3)(BO(3))(4) is 70% and 83% of those of Y(2)O(3):Eu(3+) and Y(2)O(2)S:Eu(3+) phosphors, respectively, and the CIE chromaticity coordinates are redder (0.652, 0.342) than those of Y(2)O(3):Eu(3+) (0.645, 0.347) and Y(2)O(2)S:Eu(3+) (0.647, 0.343). A white-light fluorescent lamp is fabricated using composition-optimized Ba(3)(Y(0.5)Ce(0.25)Tb(0.25))(PO(4))(3) and Ca(3)(Y(0.5)Eu(0.5))(AlO)(3)(BO(3))(4) phosphors and matching blue-emitting phosphors. The results indicate that the quality of the brightness and color reproduction is suitable for application in shortwave UV fluorescent lamps. The white-light fluorescent lamp displays CIE chromaticity coordinates of x = 0.33, y = 0.35, a warm white light with a correlated color temperature of 5646 K, and a color-rendering index of Ra = 70. PMID- 21263708 TI - A light-trapping structure based on BiO3 nano-islands with highly crystallized sputtered silicon for thin-film solar cells. AB - Silicon films with light-trapping structures are fabricated based on Bi2O3 nano islands, which are obtained by annealing Bi nano-islands in the air at 400 degrees C. The topography exhibits the maximum altitude of over 600 nm and the root-mean-square roughness of 150 nm, with the lateral size of single island of about 1 MUm. Highly crystallized sputtered silicon, realized by Cu-induced crystallization, is used to be a light-absorbing layer. Reflectivity of the samples with different thickness of silicon has been studied to reveal the light trapping efficiency. The average reflectivity under AM1.5 illumination spectrum is 12% when silicon is 480 nm thick and the reflectivity for the long wavelength region between 800 nm and 1100 nm is less than 10% when the silicon is 1.2 MUm thick. This is a promising low-cost structure for crystallized silicon thin-film solar cells with high efficiency. PMID- 21263709 TI - Enhanced conversion efficiency of a crystalline silicon solar cell with frustum nanorod arrays. AB - Enhanced photoelectric conversion is demonstrated in a crystalline silicon (c-Si) solar cell with frustum nanorod arrays (FNAs), fabricated using colloidal lithography and reactive-ion etching techniques. Under a simulated one-sun condition, the cell with FNAs improves the power conversion efficiency by nearly 30%, compared to a conventional wet-chemical-textured reference. The enhancement mostly arises from the superior antireflective properties for wavelengths between 400 nm and 1000 nm. In that spectral range, we show that photons gained by reflection reduction directly contribute to collected carriers without auxiliary losses due to nano-fabrication. Moreover, the omnidirectional antireflection of FNAs is also investigated using an angle-resolved reflectance spectroscopy. The dimensions of FNAs are further analyzed with numerical calculations based on Maxwell's equations. The optimized short-circuit current density achieves nearly 40 mA/cm2, corresponding to a 16% enhancement compared to the conventional device. PMID- 21263710 TI - Enhancement of optical transmission with random nanohole structures. AB - We demonstrate an enhancement of optical transmission by creating randomly distributed nanoholes in a glass surface using a simple bottom-up fabrication process. V-shaped holes with sub-100 nm diameter are created by anodized aluminum oxide template and dry etching on glass substrates. The broadband and omnidirectional antireflective effect of the proposed nanostructures is confirmed by measuring the transmittance of the patterned glasses, leading to 3% better transmission. Subsequently, the short-circuit current and the open-circuit voltage of a solar cell with nanostructures are enhanced by 3-4%, improving the solar cell efficiency from 10.47% to 11.20% after two weeks of outdoor testing. PMID- 21263711 TI - Optical properties of Si microwires combined with nanoneedles for flexible thin film photovoltaics. AB - A combined wire structure, made up of longer periodic Si microwires and short nanoneedles, was prepared to enhance light absorption using one-step plasma etching via lithographical patterning. The combined wire array exhibited light absorption of up to ~97.6% from 300 to 1100 nm without an anti-reflection coating. These combined wire arrays on a Si substrate were embedded into a transparent polymer. A large-scale wire-embedded soft film was then obtained by peeling the polymer-embedded wire portion from the substrate. Optically attractive features were present in these soft films, making them suitable for use in flexible silicon solar cell applications. PMID- 21263712 TI - Discharge and photo-luminance properties of a parallel plates electron emission lighting device. AB - The gas discharge and photo-luminance properties of a planar lighting source featuring highly uniform light emission and mercury-free design were studied. The current density-voltage characteristics and the associated gas discharge of the devices operating with the values of the ratio of electric field to gas pressure (E/p) between 4.3 kV/Torr-cm and 35.7 kV/Torr-cm indicate that the width of the cathode fall extends over the entire gap between the two electrodes and the device is mostly in the obstructed discharge regime. The optical emission analysis confirmed the electron collision-induced gas emissions and strong effect of gas pressure on the phosphor emission when operated at constant current density, both are indicative of the primary roles played by the electron energy. PMID- 21263713 TI - InGaN-based light-emitting diodes with an embedded conical air-voids structure. AB - The conical air-void structure of an InGaN light-emitting diode (LEDs) was formed at the GaN/sapphire interface to increase the light extraction efficiency. The fabrication process of the conical air-void structure consisted of a dry process and a crystallographic wet etching process on an undoped GaN layer, followed by a re-growth process for the InGaN LED structure. A higher light output power (1.54 times) and a small divergent angle (120 degrees ) were observed, at a 20 mA operation current, on the treated LED structure when compared to a standard LED without the conical air-void structure. In this electroluminescence spectrum, the emission intensity and the peak wavelength varied periodically by corresponding to the conical air-void patterns that were measured through a 100 nm-optical aperture fiber probe. The conical air-void structure reduced the compressed strain at the GaN/sapphire interface by inducing the wavelength blueshift phenomenon and the higher internal quantum efficiency of the photoluminescence spectra for the treated LED structure. PMID- 21263714 TI - Controlling absorption enhancement in organic photovoltaic cells by patterning Au nano disks within the active layer. AB - We show experimentally and theoretically enhancement of external quantum efficiency in the green-NIR spectrum for organic photovoltaic device, by the incorporation of patterned Au nano-disk arrays that extend from the front electrode into the active layer. Enhancement mechanisms and design rules are extracted by comprehensive simulations which match the experimental findings. The enhanced efficiency is shown to stem from field enhancement originating from both localized plasmonic resonances and periodic nano patch antennas configuration. PMID- 21263715 TI - Light extraction from surface plasmons and waveguide modes in an organic light emitting layer by nanoimprinted gratings. AB - Organic light-emitting diodes (OLEDs) usually exhibit a low light outcoupling efficiency because a large fraction of power is lost to surface plasmons (SPs) and waveguide modes. In this paper it is demonstrated that periodic grating structures with almost um-scale can be used to extract SPs as well as waveguide modes and therefore enhance the outcoupling efficiency in light-emitting thin film structures. The gratings are fabricated by nanoimprint lithography using a commercially available diffraction grating as a mold which is pressed into a polymer resist. The outcoupling of SPs and waveguide modes is detected in fluorescent organic films adjacent to a thin metal layer in angular dependent photoluminescence measurements. Scattering up to 5th-order is observed and the extracted modes are identified by comparison to the SP and waveguide dispersion obtained from optical simulations. In order to demonstrate the low-cost, high quality and large area applicability of grating structures in optoelectronic devices, we also present SP extraction using a grating structure fabricated by a common DVD stamp. PMID- 21263716 TI - Double S-bend structure for a compact two mode interference coupler. AB - A double S-bend structure has been proposed for the reduction of coupling length of the 2 * 2 two mode interference (TMI) coupler. The coupling characteristics of the proposed structure are compared with those of conventional TMI structures using a simple mathematical model based on sinusoidal modes. The longitudinal beat length for the proposed TMI coupler is reduced by 15% of the beat length of a conventional TMI coupler. The effect of power imbalance on fabrication tolerance of the proposed TMI coupler is also studied and compared with other TMI couplers. PMID- 21263717 TI - Random errors in interferometry with the least-squares method. AB - This investigation analyzes random errors in interferometric surface profilers using the least-squares method when random noises are present. Two types of random noise are considered here: intensity noise and position noise. Two formulas have been derived for estimating the standard deviations of the surface height measurements: one is for estimating the standard deviation when only intensity noise is present, and the other is for estimating the standard deviation when only position noise is present. Measurements on simulated noisy interferometric data have been performed, and standard deviations of the simulated measurements have been compared with those theoretically derived. The relationships have also been discussed between random error and the wavelength of the light source and between random error and the amplitude of the interference fringe. PMID- 21263718 TI - Theoretical and experimental analysis of tunable Sagnac high-birefringence loop filter for dual-wavelength laser application. AB - We present detailed investigations of the spectral dependencies of the transmission of a fiber optical loop mirror (FOLM) consisting of a coupler with output ports spliced at arbitrary angles to a high-birefringence (Hi-Bi) fiber. The application for dual-wavelength lasers is discussed. For this aim, the spectral dependence of the reflection is tuned by the temperature of the Hi-Bi fiber that allows a fine adjustment of the cavity loss for generated wavelengths. The ratio between maximum and minimum reflection can be adjusted by the twist angle of the fiber at the splices, which also provides useful possibilities for the adjustment of cavity losses. We used the twist and temperature variation of the Hi-Bi fiber to change the operation from single wavelength to stable dual wavelength generation with either equal or unequal powers of wavelengths. PMID- 21263719 TI - Compact sensor for measuring two-dimensional tilt using a two-dimensional transmission grating and the Talbot effect. AB - This paper proposes a tilt sensor that measures the small two-dimensional tilt of a plane reflective object using the Talbot effect. It is an extension of a previously proposed one-dimensional tilt sensor. The light beam reflected from the object impinges on a hexagonal grating, and the intensity of the diffracted wave is detected on an image sensor located at a Talbot distance from the grating. The diffraction intensity displaces due to the tilt of the object. The displacement is calculated by the Fourier transform method to obtain the two dimensional tilt. This sensor is very simple and compact. The principle of the sensor is explained for a grating with a general pattern. An experiment using a hexagonal grating shows its validity. Discussions are given for making it more practical. PMID- 21263720 TI - Analytical model for Rayleigh-Brillouin line shapes in air. AB - Atmospheric lidar techniques for the measurement of wind, temperature, and optical properties of aerosols as well as nonintrusive measurement techniques for temperature, density, and bulk velocity in gas flows rely on the exact knowledge of the spectral line shape of the scattered laser light on molecules. A mathematically complex, numerical model (Tenti S6 model) is currently the best model for describing these spectra. In this paper an easy processable, alternative analytical model for describing spontaneous Rayleigh-Brillouin spectra in air at atmospheric conditions is introduced. The deviations between the analytical and Tenti S6 models are shown to be smaller than 0.85%. PMID- 21263721 TI - Modeling of a slit-scan-type aerial image measurement sensor used for optical lithography. AB - Theoretical modeling of a slit-scan-type aerial image measurement sensor used for optical lithography is presented. Slit transmission properties are fully represented by the slit transfer function in terms of incident and scattering angles of light, which is then incorporated into the scheme of a partially coherent imaging formula to obtain an expression for image profiles measured by slit scanning. As an exemplary case, we analyze the influence of a 100 nm width slit used in an ArF lithography system. To understand the mechanism of image profile changes by slit transmission, we focus on frequency transfer characteristics of sinusoidal patterns. PMID- 21263722 TI - Estimation of dynamically varying displacement derivatives using fringe projection technique. AB - This paper presents a pseudo Wigner-Ville-distribution-based method in fringe projection for analyzing temporal behavior of the displacement derivative for a continuously deformed object. In the proposed method, a computer generated fringe pattern is projected on an object undergoing dynamic deformation, and the reflected intensity is recorded in the form of video, i.e., a stack of images are captured sequentially by a CCD camera. Each image represents a recorded fringe pattern at a particular time instant whose phase contains information about the instantaneous out-of-plane displacement or deformation with respect to the undeformed object, and the corresponding spatial phase derivative relates to the displacement derivative. Subsequently, pseudo Wigner-Ville distribution is used for instantaneous phase derivative estimation from the stack of images. Simulation and experimental results are presented to demonstrate the method's potential. PMID- 21263723 TI - Effect of photonic bandgap on upconversion emission in YbPO4:Er inverse opal photonic crystals. AB - We obtained upconversion (UC) light-emitting photonic materials (YbPO(4):Er) with an inverse opal structure by the self-assembly technique in combination with a solgel method. The effect of the photonic stopband on the UC luminescence of the (2)H(11/2), (4)S(3/2)->(4)I(15/2), and (4)F(9/2)->(4)I(15/2) transitions of Er(3+) has been observed in the inverse opals of the Er(3+)-doped YbPO(4). Significant suppression of the UC emission was detected if the photonic bandgap overlapped with the Er(3+) ions emission band, while enhancement of the UC emission occurs if the emission band appears at the edge of the bandgap. PMID- 21263724 TI - Tunable Tm-doped fiber ring laser operating at 1.9 MUm band using force-induced fiber grating as wavelength tuner. AB - We report wavelength-tunable operation of a Tm-doped silica fiber laser by using a force-induced long-period fiber grating (LPFG) formed in a fiber ring resonator. The laser output wavelength is tuned by moving the transmission passband that is generated between adjacent resonance wavelengths due to the force-induced LPFG. By changing the grating period around 900 MUm, we control the laser output wavelength between 1845 and 1930 nm. PMID- 21263725 TI - Analysis of diffracted fields with the extended theory of the boundary diffraction wave for impedance surfaces. AB - Uniform diffracted fields from impedance surfaces are investigated by the extended theory of boundary diffraction wave (ETBDW). The new vector potential of the ETBDW is constructed by considering the pseudoimpedance boundary condition. The method is applied to the diffraction problem from an impedance half-plane. It is shown that the total fields from an impedance half-plane reduce to the case of a perfectly electric or magnetic conducting and opaque half-plane for special values of surface impedance. The total and diffracted fields are compared numerically with the exact solution for the impedance half-plane and modified theory of physical optics (MTPO) solution for an impedance wedge. The numerical results show that the field expressions are in very good agreement with the exact and MTPO solutions. PMID- 21263726 TI - Demonstration of a Fresnel axicon. AB - We design and manufacture a Fresnel axicon (fraxicon) that generates a quasi diffraction-free/Bessel beam with a large depth of field. The novel optical element is characterized with both coherent and incoherent light, and its behavior is compared with that of a classical axicon. While the fraxicon exhibits a strong interference pattern in the on-axis intensity distribution, it can be smoothed out when using broadband light, partial spatial coherence light, or by period randomization. As inexpensive, compact/lightweight, and low-absorption elements, fraxicons may find applications in imaging, illumination, and situations where low absorption and dispersion are important. PMID- 21263727 TI - Coupling plane wave received by an annular aperture into a single-mode fiber in the presence of atmospheric turbulence. AB - The efficiency of coupling a plane wave into a single-mode fiber can be reduced by both the aperture obstruction of receivers and the turbulence-induced degradation of optical coherence. Using the Gaussian approximation to the mutual coherence function of the incident optical field, we derived an analytical solution for the fiber-coupling efficiency when a plane wave, propagating through atmospheric turbulence, is received by an annular-aperture receiver and coupled into a single-mode fiber. It is a function of the coupling geometry, the aperture radius-to-coherence-radius ratio (ARCRR), and the aperture-obstruction parameter. It is found by the numerical optimization method that the optimal coupling geometry depends on both the ARCRR and the aperture-obstruction parameter. The results obtained are useful for analyzing and designing a fiber-coupling system influenced by atmospheric turbulence. PMID- 21263728 TI - Comparative study of femtosecond and nanosecond laser-induced breakdown spectroscopy of depleted uranium. AB - We present spectra of depleted uranium metal from laser plasmas generated by nanosecond Nd:YAG (1064 nm) and femtosecond Ti:sapphire (800 nm) laser pulses. The latter pulses produce short-lived and relatively cool plasmas in comparison to the longer pulses, and the spectra of neutral uranium atoms appear immediately after excitation. Evidence for nonequilibrium excitation with femtosecond pulses is found in the dependence of spectral line intensities on the pulse chirp. PMID- 21263729 TI - Microlens-array-enabled on-chip optical trapping and sorting. AB - An on-chip optical trapping and sorting system composed of a microchamber and a microlens array (MLA) is demonstrated. The MLA focuses the incident light into multiple confocal spots to trap the particles within the microchamber. The SiO(2)/ZrO(2) solgel material is introduced in the fabrication of MLA for its unique optical and chemical characters. Moreover, in order to prove the effectiveness of the system, experimental demonstration of multibeam trapping and locked-in transport of micropolymer particles in the microchamber is implemented. The system may easily be integrated as microfluidic devices, offering a simple and efficient solution for optical trapping and sorting of biological particles in lab-on-a-chip technologies. PMID- 21263730 TI - Radiation thermometry of silicon wafers based on emissivity-invariant condition. AB - An emissivity-invariant condition for a silicon wafer was determined by simulation modeling and it was confirmed experimentally. The p-polarized spectral emissivity at a wavelength of 900 nm and at temperatures over 900 K was constant at 0.83 at an angle of about 55.4 degrees irrespective of large variations in the oxide layer thickness and the resistivity due to the different impurity doping concentrations of the silicon wafer. The expanded uncertainty, U(c) = ku(c) (k = 2), of the temperature measurement is estimated to be 4.9 K. This result is expected to significantly enhance the accuracy of radiometric temperature measurements of silicon wafers in actual manufacturing processes. PMID- 21263731 TI - Bipolar tap photonic microwave notch filter using electroabsorption modulator integrated distributed feedback laser diodes in a parallel configuration. AB - We propose a bipolar tap photonic microwave notch filter scheme, which can be used to realize a fully integrated, semiconductor-based notch filter. The scheme is based on two electroabsorption modulator (EAM)-integrated distributed feedback laser diodes in a parallel configuration. We show that two filter taps with opposite polarities can be readily obtained by using the negative and positive slopes of the U-shaped electro-optic transfer functions of the EAMs under special design and operating conditions. An experiment was carried out to verify the working principle of the proposed scheme. Notch frequency tuning was also demonstrated by varying the laser wavelength spacing; the spacing was varied by changing the temperature. A frequency tuning range of ~1.8 GHz with a notch depth of ~40 dB was achieved. PMID- 21263732 TI - Neutral points in an atmosphere-ocean system. 2: Downwelling light field. AB - We use a Monte Carlo code that calculates the complete Stokes vector to predict the degree of polarization in the complete observable solid angle at any level in an atmosphere-ocean system. Using the Stokes vector components, we can find the positions of neutral points in a simulated plane-parallel atmosphere-ocean system for various conditions. We examine the locations and behavior of these neutral points for an observer placed directly above and beneath the air-water boundary and show how their positions are influenced by different atmospheric and oceanic conditions. PMID- 21263733 TI - Limitations and guidelines for measuring the spectral width of a single pulse of light with a Fabry-Perot interferometer. AB - We present a method of analyzing the output of a single pulse of light from a Fabry-Perot interferometer (FPI). Together with an independent measurement of the pulse width and shape, the analysis enables the determination of the linewidth, TBP, and, consequently, the degree of coherence of the individual light pulses. The analysis presented builds on the method presented by Marzenell et al. [Appl. Phys. B 71, 185-191 (2000)] by analyzing the ring pattern of the FPI. PMID- 21263734 TI - Research on coding and decoding method for digital levels. AB - A new coding and decoding method for digital levels is proposed. It is based on an area-array CCD sensor and adopts mixed coding technology. By taking advantage of redundant information in a digital image signal, the contradiction that the field of view and image resolution restrict each other in a digital level measurement is overcome, and the geodetic leveling becomes easier. The experimental results demonstrate that the uncertainty of measurement is 1 mm when the measuring range is between 2 m and 100 m, which can meet practical needs. PMID- 21263735 TI - Improving deuterated potassium dihydrogen phosphate's electro-optical Q-switched characteristics by adding a pair of auxiliary electrodes. AB - Deuterated potassium dihydrogen phosphate (DKDP) crystal is one of the most commonly used electro-optical (EO) Q-switch materials. A traditional DKDP EO Q switch in the Pockels cell has a pair of electrodes, resulting in a nonuniform electric potential along the radial direction. Theoretical analysis and calculation show the radial nonuniform electric potential of DKDP crystals can be improved by adding a pair of auxiliary electrodes. Meanwhile, the experimental results demonstrate that the Q-switched laser characteristics are greatly improved with auxiliary electrodes added to DKDP crystal. PMID- 21263736 TI - Evaluation of spectrometric parameters in spectral-domain optical coherence tomography. AB - The parameters of the spectrometer were analyzed in order to optimize the performance of spectral-domain optical coherence tomography (SD-OCT). Because probing depth is proportional to spectral resolution, it can be increased with the choice of a higher resolution spectrometer, which implies greater pixel numbers and lower imaging speed, or by sacrificing part of the spectrum, which compromises the axial resolution and side lobes. With a dynamic range of 8 bits or more, the signal-to-noise ratio remains constant for different noise levels. The results were verified experimentally with in vivo retinal SD-OCT imaging. PMID- 21263737 TI - Active feedback regulation of a Michelson interferometer to achieve zero background absorption measurements. AB - An active phase-controlling scheme based on a proportional-integral-derivative controlled piezoelectric transducer is presented with the purpose of stabilizing a quasi-zero-background absorption spectrometer. A fiber-based balanced Michelson interferometer is used, and absorption due to a gas sample in one of its arms results in an increased light signal to a detector, which otherwise, thanks to destructive interference, experiences a very low light level. With the presented approach, the sensitivity of already potent absorption measurement techniques, e.g., based on modulation, could be improved even further. PMID- 21263738 TI - Effect of net surface charge on particle sizing and material recognition by using phase Doppler anemometry. AB - By taking net surface charge into consideration, the scattering field of particles illuminated by dual laser beams of phase Doppler anemometry (PDA) is computed based on Mie's theory, and the effect of net surface charge on the phase diameter relationship and the phase ratio is studied. It is found that the phase diameter relationship and the relationship between the phase ratio and the refractive index of charged particles could be significantly different from those of uncharged particles, which would lead to errors in particle sizing and the measurement of refractive indices. A method of recognizing charged particles and determining the value of their surface conductivity, which is related to net surface charge, is proposed by utilizing the effect of net surface charge on the measurement of refractive indices using PDA. PMID- 21263739 TI - Bimetallic chips for a surface plasmon resonance instrument. AB - In this work we have replaced a commonly used Au film with an Au/Ag bimetallic film working as the sensing chip in the commercial surface plasmon resonance (SPR) instrument, Biacore 3000. The bimetallic chip gives out sharper SPR dip than that by the chip made of an Au film. The applicability and stability of the bimetallic chip on the Biacore 3000 are tested by real-time monitoring of biological coupling processes between sulfamethoxazole (SMX) and anti-SMX, which is useful in rapid detection of contaminations in food products. The bimetallic chip performs stably in 6 times' usage and regeneration. Our experiment is helpful to push the bimetallic film into real applications in commercial SPR instruments. PMID- 21263740 TI - Effect of royal jelly on experimental colitis Induced by acetic acid and alteration of mast cell distribution in the colon of rats. AB - This study investigated the effects of royal jelly (RJ) on acetic acid-induced colitis in rats. Twenty adult female Wistar albino rats were divided into four treatment groups of 5 animals each, including a control group (Group I); Group II was treated orally with RJ (150 mg kg(-1) body weight); Group III had acetic acid induced colitis; and Group IV had acetic acid-induced colitis treated orally with RJ (150 mg kg(-1) body weight) for 4 weeks. Colitis was induced by intracolonic instillation of 4% acetic acid; the control group received physiological saline (10 mL kg(-1)). Colon samples were obtained under deep anaesthesia from animals in all groups. Tissues were fixed in 10% formalin neutral buffer solution for 24 h and embedded in paraffin. Six-micrometre-thick sections were stained with Mallory's triple stain and toluidine blue in 1% aqueous solution at pH 1.0 for 5 min (for Mast Cells). RJ was shown to protect the colonic mucosa against the injurious effect of acetic acid. Colitis (colonic damage) was confirmed histomorphometrically as significant increases in the number of mast cells (MC) and colonic erosions in rats with acetic acid-induced colitis. The RJ treatment significantly decreased the number of MC and reduced the area of colonic erosion in the colon of RJ-treated rats compared with rats with untreated colitis. The results suggest that oral treatment with RJ could be used to treat colitis. PMID- 21263742 TI - Immunoreactivity of thymosin beta 4 in human foetal and adult genitourinary tract. AB - Thymosins beta 4 (Tβ4) is a member of the beta-thymosins family, a family of peptides playing essential roles in many cellular functions. Our recent studies suggested Tβ4 plays a key role in the development of human salivary glands and the gastrointestinal tract. The aim of this study was to analyse the presence of Tβ4 in the human adult and foetal genitourinary tract. Immunolocalization of Tβ4 was studied in autoptic samples of kidney, bladder, uterus, ovary, testicle and prostate obtained from four human foetuses and four adults. Presence of the peptide was observed in cells of different origin: in surface epithelium, in gland epithelial cells and in the interstitial cells. Tβ4 was mainly found in adult and foetal bladder in the transitional epithelial cells; in the adult endometrium, glands and stromal cells were immunoreactive for the peptide; Tβ4 was mainly localized in the glands of foetal prostate while, in the adults a weak Tβ4 reactivity was restricted to the stroma. In adult and foetal kidney, Tβ4 reactivity was restricted to ducts and tubules with completely spared glomeruli; a weak positivity was observed in adult and foetal oocytes; immunoreactivity was mainly localized in the interstitial cells of foetal and adult testis. In this study, we confirm that Tβ4 could play a relevant role during human development, even in the genitourinary tract, and reveal that immunoreactivity for this peptide may change during postnatal and adult life. PMID- 21263741 TI - Syndecan expressions in the human amnion and chorionic plate. AB - The syndecan family consists of four distinct membrane glycoproteins in mammals. Syndecans control cell proliferation, differentiation, adhesion and migration through participation in cell-cell interactions, anchorage of cells to the extracellular environment, and modulation of multiple growth factors. Therefore, syndecans may play a pivotal role in the regulation of cell behaviour depending on the cellular microenvironment. Here, we demonstrate that syndecan-1, syndecan 2 and syndecan-4 are expressed in fetal membrane tissue with different immunolocalizations. Syndecan-1 is expressed in the amniotic epithelium, localizing at basolateral cell surfaces. Syndecan-2 and syndecan-4, in contrast, are mostly localized in intracellular compartments, in the extravillous cytotrophoblastic cells and in some fibroblasts of the chorionic plate as well as in the amniotic epithelial cells. In the latter, syndecan-4 is mainly localized in the apical part of the cells. Our results strongly suggest a key role of syndecan-1, syndecan-2 and syndecan-4 in the determination of structural and functional characteristics of human amnion and chorionic plate. Since the solute exchanges between fetus and mother take place in fetal membranes, our data suggest that syndecans are important players in the placenta for the establishment of the fetal-maternal inter-communication. PMID- 21263743 TI - Structural and functional alterations of the cell nucleus in skeletal muscle wasting: the evidence in situ. AB - The histochemical and ultrastructural analysis of the nuclear components involved in RNA transcription and splicing can reveal the occurrence of cellular dysfunctions eventually related to the onset of a pathological phenotype. In recent years, nuclear histochemistry at light and electron microscopy has increasingly been used to investigate the basic mechanisms of skeletal muscle diseases; the study in situ of nuclei of myofibres and satellite cells proved to be crucial for understanding the pathogenesis of skeletal muscle wasting in sarcopenia, myotonic dystrophy and laminopathies. PMID- 21263744 TI - Cadmium induces changes on ACTH and PRL cells in Podarcis sicula lizard pituitary gland. AB - We analyzed the effect of cadmium on corticotropic (ACTH) and prolactin (PRL) cells in the pituitary gland of the Podarcis sicula lizard under chronic exposure to this metal. Adult lizards were given CdCl2 in drinking water at the dose of 10 μg/10 g body mass for 120 days. Light microscopy was performed after histological and immunohistochemical staining, and the effects were followed at regular time intervals up to 120 days post-treatment. We detected substantial variations in the general morphology of the pituitary: unlike the control lizards in which the gland appeared compact, the treated lizards showed a glandular tissue with dilated spaces that were more extensive at 90 and 120 days. PRL and ACTH cells showed an increase in occurrence and immunostaining intensity in treated lizards in comparison with the same cells of control animals. This cellular increase peaked for PRL at 30 days in the rostral, medial and also caudal pars distalis of the gland. ACTH cells appeared to increase markedly after 60 days of treatment in both the pars distalis and the pars intermedia. Again, at 60 days small, isolated ACTH cells were also found in the caudal pars distalis in which these cells were generally absent. However, at 120 days both these cellular types showed an occurrence, distribution and morphology similar to those observed in the control lizards. In lizards, protracted oral exposure to cadmium evidently involves an alteration of the normal morphology of the gland and an inhibitory effect of ACTH and PRL cells, since they increase in occurrence and immunostaining. Yet in time the inhibitory effect of cadmium on ACTH and PRL cells falls back and their occurrence appears similar to that of the control lizard. PMID- 21263745 TI - Human dental pulp stem cells produce mineralized matrix in 2D and 3D cultures. AB - The aim of this study was to characterize the in vitro osteogenic differentiation of dental pulp stem cells (DPSCs) in 2D cultures and 3D biomaterials. DPSCs, separated from dental pulp by enzymatic digestion, and isolated by magnetic cell sorting were differentiated toward osteogenic lineage on 2D surface by using an osteogenic medium. During the differentiation process, DPSCs express specific bone proteins like Runx-2, Osx, OPN and OCN with a sequential expression, analogous to those occurring during osteoblast differentiation, and produce extracellular calcium deposits. In order to differentiate cells in a 3D space that mimes the physiological environment, DPSCs were cultured in two distinct bioscaffolds, MatrigelTM and Collagen sponge. With the addition of a third dimension, osteogenic differentiation and mineralized extracellular matrix production significantly improved. In particular, in MatrigelTM DPSCs differentiated with osteoblast/osteocyte characteristics and connected by gap junction, and therefore formed calcified nodules with a 3D intercellular network. Furthermore, DPSCs differentiated in collagen sponge actively secrete human type I collagen micro-fibrils and form calcified matrix containing trabecular-like structures. These neo-formed DPSCs-scaffold devices may be used in regenerative surgical applications in order to resolve pathologies and traumas characterized by critical size bone defects. PMID- 21263746 TI - NADPH-diaphorase expression in the meibomian glands of rat palpebra in postnatal development. AB - In the current study, we aimed at investigating the presence of nitric oxide synthase (NOS) positive nerve fibers in rat meibomian glands (MGs) at various stages of development. There is good evidence to suggest that nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) is a surrogate for neuronal nitric oxide synthase (NOS). Sections of the central, upper eyelids of Wistar rats were processed histochemically for NADPH-d to investigate the presence and distribution of NOS-positive nerve fibers at the following time points: day 1 and weeks 1, 2 and 3 post partum, and in adult controls. At day 1, MG acini were lightly stained and located at a distance from the mucosal border. Vessels were accompanied by intensely stained NADPH-d positive nerve fibers. At the week 1 time point, both the vessels and the NADPH-d positive fibers were still present, but less numerous. MGs were now closer to the mucosa, so that the submucosa was thinner. The acini were mostly pale but occasionally darker. At week 3, there were fewer blood vessels in both the submucosa and within the septa. Darker acini were more common than lightly stained acini. NADPH-d positive dots were observed in the vicinity of the MGs. At the week 3 time point, MGs were adjacent to the mucosal border and stained more intensely than at earlier times; almost all acini were stained. The microscopic appearances were almost identical with those of adult palpebra. Submucosal and septal blood vessels and NADPH-d positive nerve fibers were less numerous. NADPH-d histochemical staining confirmed differences in the density of stained nerve fibers at different developmental stages. The greatest density of NADPH-d -positive nerve fibers occurred in 1-day-old rats whereas they were less numerous in adult rat eyelids. Nerves innervating MGs utilize nitric oxide (NO) as a neurotransmitter mostly in early developmental stages and this need thereafter decreases and stabilizes at 3 weeks postnatally. PMID- 21263747 TI - Subcutaneous adipose tissue classification. AB - The developments in the technologies based on the use of autologous adipose tissue attracted attention to minor depots as possible sampling areas. Some of those depots have never been studied in detail. The present study was performed on subcutaneous adipose depots sampled in different areas with the aim of explaining their morphology, particularly as far as regards stem niches. The results demonstrated that three different types of white adipose tissue (WAT) can be differentiated on the basis of structural and ultrastructural features: deposit WAT (dWAT), structural WAT (sWAT) and fibrous WAT (fWAT). dWAT can be found essentially in large fatty depots in the abdominal area (periumbilical). In the dWAT, cells are tightly packed and linked by a weak net of isolated collagen fibers. Collagenic components are very poor, cells are large and few blood vessels are present. The deep portion appears more fibrous then the superficial one. The microcirculation is formed by thin walled capillaries with rare stem niches. Reinforcement pericyte elements are rarely evident. The sWAT is more stromal; it is located in some areas in the limbs and in the hips. The stroma is fairly well represented, with a good vascularity and adequate staminality. Cells are wrapped by a basket of collagen fibers. The fatty depots of the knees and of the trochanteric areas have quite loose meshes. The fWAT has a noteworthy fibrous component and can be found in areas where a severe mechanic stress occurs. Adipocytes have an individual thick fibrous shell. In conclusion, the present study demonstrates evident differences among subcutaneous WAT deposits, thus suggesting that in regenerative procedures based on autologous adipose tissues the sampling area should not be randomly chosen, but it should be oriented by evidence based evaluations. The structural peculiarities of the sWAT, and particularly of its microcirculation, suggest that it could represent a privileged source for regenerative procedures based on autologous adipose tissues. PMID- 21263748 TI - Immunohistochemical evidence of Muc1 expression during rat embryonic development. AB - During embryonic development, studies on mouse and human embryos have established that Muc1/MUC1 expression coincides with the onset of epithelial sheet and glandular formation. This study aimed therefore at evaluating the temporal and spatial expression of Muc1 at different stages of rat development. In this experiment, 80 animals were included: 64 rat foetuses at 13, 14, 15, 16, 17, 18, 19 and 20 days of gestation from pregnant females (WKAH/Hok), 8 embryos each stage. Standard immunohistochemistry was performed using anti-MUC1 cytoplasmic tail polyclonal antibody (CT33). The reaction was considered positive when more than 5% of the cells were stained; reaction patterns were: L = linear, membrane, C = cytoplasmic and M = mixed; nuclear staining was also recorded. Intensity was graded as negative (-), low (+), moderate (++) and strong (+++). Muc1 expression was observed with a low intensity on 13th day (13 d) in the stomach, lung and kidney; at 14 d, small intestine and pancreas were also reactive; at 16 d, liver and esophagus and at 18 d, trachea and salivary glands. During the development, intensity increased while the pattern of expression changed: at the first days of gestation, it was predominantly linear and apical while during further development an increase in cytoplasmic expression was observed. Trachea, stomach, kidney and lung epithelia were the more reactive tissues. In specimens belonging to neonates and adults, all tissues analyzed showed similar Muc1 expression. The findings of this study assess that Muc1 is highly expressed in the epithelial rat embryonic development. PMID- 21263749 TI - Expression of hyaluronan synthase 3 in deformed human temporomandibular joint discs: in vivo and in vitro studies. AB - The present study aimed at investigating the expression of a hyaluronan synthase (HAS) 3 in tissue samples of deformed human temporomandibular joint (TMJ) discs and cells obtained from the discs. Fifteen adult human TMJ discs (twelve diseased discs and three normal discs) were used in this study. The twelve diseased discs were obtained from twelve patients with internal derangement (ID) of TMJ. These patients all had anteriorly displaced discs and deformed discs. The tissues were immunohistochemically stained using HAS3 antibodies. In addition, the subcultured TMJ disc cells under both normal and hypoxic conditions (O2: 2%) were incubated for 3, 6, 12, and 24 h after addition of interleukin-1beta (IL-1beta) (1 ng/mL). Subsequently, the expression of HAS3 was examined using real-time reverse transcription-polymerase chain reaction (RT-PCR). The control group showed from negative to weak positive reactions for HAS3 on immunohistochemical staining. The discs extracted from twelve cases with ID presented from moderate to strong positive reactions for HAS3. The quantity of HAS3 mRNA was compared with a control group, and showed a 204-fold increase at 3 h, a 26-fold increase at 6 h, a 2.5-fold increase at 12 h and a 32-fold increase at 24 h under hypoxia with the addition of IL-1beta. The expression of HAS3 mRNA was significantly enhanced at 3 h and 24 h. The results obtained suggest that HAS3 is related to the pathological changes of human TMJ discs affected by ID. PMID- 21263754 TI - [Highlights of the XXII Peruvian congress of digestive diseases]. PMID- 21263755 TI - [Duodenal villous atrophy, an unexpectedly common finding in giardia lamblia infestation]. AB - OBJECTIVE: To study the histological changes observed in Giardia positive biopsies obtained from the duodenum.: The number of intraepithelial lymphocytes (IEL), grade of villous atrophy, presence of lymph follicles and number of eosinophils in the lamina propria per HPF were assessed. METHODS: All giardia positive biopsies diagnosed during period 2005-2009 in 5 pathology units were reevaluated by a group of pathologists. RESULTS: Thirty cases were included. Atrophic villous architecture was seen in 61,2%, increase in number of intraepithelial lymphocytes in 63,3% The occurrence of lymphoid follicles in 43,3%. DISCUSSION: Villous atrophy was higher than reported by others authors, cases with atrophy showed greater frequency of increase in the number of intraepithelial lymphocytes than cases without atrophy. No cases with lymph follicle showed lack of plasmatic cells, the number of eosinophils was subtly increased. PMID- 21263756 TI - [NBI utility and optical magnification in the differential diagnosis of neoplastic and non-neoplastic colorectal lesions in Peru]. AB - INTRODUCTION: The Narrow Banding Image NBI-Colonoscopy and Optical Magnification is a useful method for evaluation in vivo of capillary pattern and pit pattern of colorectal polyps. AIM: To evaluate the usefulness of NBI and Optical Magnification in differential diagnosis of colorectal polyps using Sano-Emura and Kudo's Classifications. METHODS: Between january and may 2010, 86 colonoscopies were analyzed by two colonoscopists; 136 polyps were found and histologically analyzed. All polyps under 10 mm (119) were evaluated in accord with Sano-Emura and Kudo's classifications; data was analyzed together with an epidemiologist in cancer. RESULTS: The sensitivity, specificity and diagnostic accuracy was 97.3%, 90.7% and 94.9%, respectively, for Sano-Emura's c lassification. The sensitivity, specificity and diagnostic accuracy was 94.7%, 90.6% and 93.2%, respectively, for Kudo's Classification. CONCLUSIONS: The colonoscopy with NBI and Optical Magnification is an effective, reliable and simple method for Colorectal neoplastic and non - neoplastic differential diagnosis when Sano-Emura's and Kudo's Classifications are used. PMID- 21263750 TI - Histochemistry through the years, browsing a long-established journal: novelties in traditional subjects. AB - Histochemical journals represent a traditional forum where methodological and technological improvements can be presented and validated in view of their applications to investigate not only cytology and histology in normal and diseased conditions but to test as well hypotheses on more basic issues for life sciences, such as comparative and evolutionary biology. The earliest scientific journals on histochemistry began their publication in the first half of the '50s of the last century, and their readership did not probably change over the years; rather, the authors' interests may have progressively been changing as well as the main topics of their articles. This hypothesis is discussed, based on the subjects of the article published in the first and last ten years in the European Journal of Histochemistry, as an example of old journal which started publication in 1954, being since then the official organ of the Italian Society of Histochemistry. This survey confirmed that histochemistry has provided and still offers unique opportunities for studying the structure, chemical composition and function of cells and tissues in a wide variety of living organisms, especially when the topological distribution of specific molecular components has diagnostic or predictive significance, as it occurs in human and veterinary biology and pathology. Some subjects (e.g. histochemistry applied to muscle cells or to mineralized tissues) have recently become rather popular, whereas a wider application of the histochemical approach may be envisaged for plant cells and tissues. PMID- 21263757 TI - [Barrett's esophagus: prevalence and risk factors in the National Hospital Arzobispo Loayza in Lima-Peru]. AB - INTRODUCTION: Barrett's esophagus (BE)is a condition where squamous epithelium is substituted for glandular type intestinal as consequence gastroesophageal reflux chronic. The BE is a lesion pre malignant (adenocarcinoma ). Factors like age, generous, biliary reflux, antecedent of esophagitis, hiatus hernia, obesity, fatty diet could be risk factors in BE, while Helicobacter pylori could be protect factor. OBJECTIVE: To identify prevalence and risk factors in the development of the BE in the Arzobispo Loayza Hospital during 2004. METHODS: This was a descriptive, transversal, analytic, case-control study, where group of cases were 30 patients with diagnosis of BE according endoscopic and histologic criteria. 95 subjects formed the control group. The Correspondence Multiple Analysis, Logistic Regression analysis was used and the Odds ratio (OR,95% CI) was calculated. RESULTS: BE prevalence was 0.30% and the Incidence 0.28%. The risk factors found were: age (OR:2.57; IC95%, 1.41-4.69, p0.00), antecedent of esophagitis (OR: 14.61; IC95%, 3.96-55.41, p0.00) spend pork meat cooked fried (OR: 8.67, IC95%, 2.28-32.99; p0.00). Female was a protect factor (OR: 0.23;IC95%; 0.05-1.05; p0.06) considered at 10%. CONCLUSIONS: This study found prevalence 0.30% of BE prevalence and the risk factors were: males up 60 years old, antecedent of esophagitis of gastro esophageal reflux, spend pork meat, preference to cook fried food. Female gender is protector factor. En this study, the biliary reflux, obesity, hiatus hernia, Helicobacter pylori weren't identified as risk factors. PMID- 21263758 TI - [Survival factors in 152 patients with gastrointestinal stromal tumors]. AB - INTRODUCTION: The gastrointestinal stromal tumor (GIST) is the designation for a specific type of mesenchymal tumor of the digestive tract that is origin in the interstitial cells of Cajal (ICC) or its precursor multipotentials, its presentation is rare and therefore its best knowledge must affect a proper diagnosis and treatment. OBJECTIVES: To evaluate the clinical characteristics and to identify factors influencing survival of patients with gastrointestinal stromal tumor. MATERIAL AND METHODS: This study design is quantitative, non experimental, descriptive, retrospective and transversal. The study has been performed in 152 patients with gastrointestinal stromal tumor who were treated at the National Institute of Neoplastic Diseases (INEN), Lima, Peru, from January 1999 through December 2009. For the final diagnosis was registered the outcome of the surgical and histology was complemented by immunohistochemical test. To assess the normal distribution of the population was used the Shapiro-Wolk, Anderson-Darling, Lilliefors, regarding the use of inferential statistical tables for survival and to assess its significance in the univariate analysis (p <0.05 significance), was used the Wilcoxon test, Tarone-Ware Log-rank and also to evaluate the difference between groups in contingency tables used the chi square and Fisher's test. Multivariate analysis was performed using the proportional hazards model of Cox. RESULTS: The group of 152 patients included 78 women (51%) and 74 men (49%) with age range from 16 to 92 years, with an average age of 54. The frequency presentation was increased from the fourth decade of life and reaches its highest expression between 50 and 70. The initial presentation was with localized disease to 79 patients (52%) and primary metastases in 73 patients (48%), with an average time of disease 14 months. The prevalence of GIST tumor in the different organs was as follows: stomach with 77 patients (50.65%), jejunum with 21 patients (13.82%), retroperitoneum with 17 patients (11.18%), duodenum 11 patients (7.24%), colon 11 patients (7.24%), ileum 8 patients (5.26%),pancreas, 3 patients (1.97%), rectum, 3 patients (1.97%) and esophagus with 1 patient (0.66%). The most common symptoms of GIST tumors in general were gastrointestinal bleeding, abdominal tumor and abdominal pain. There are organ-specific symptoms such as jaundice in pancreas, dysphagia in esophagus and obstruction in the ileum. The tumor size greater than 10 centimeters was found in 92 patients (60.51%), 39 patients had size between 5 and 10 centimeters (25.65%) and 20 patients had lesions smaller than 5 centimeters (13.15%). Immunohistochemistry tests performed in 75 patients show that for all locations, the expression of KIT (CD117) is 94.8%, followed by CD34 to 70.35%; on the other hand, actin (61.68%) and S-100 (57.56%) have a smaller range of expression. Retroperitoneal GIST tumors had an expression of CD117 of 92.86% and CD34 of 60%, and GIST tumors of the pancreas had an expression of CD117 of 100% and CD34 of 100%. We evaluated 27 patients with low mitotic index, of which 10 had primary metastases (37%), in turn, of 25 patients with high mitotic index, 8 had primary metastases (32%). Of the 152 patients, 93 had complete resection of the disease, 28 had partial resection, 24 were unresectable and 07 did not undergo surgery, the more aggressive behavior was observed in ileum, 03 patients were unresectable, 02 patients had partial resection and only 02 could be completely resected, the rest of the series in general, for each location, the GIST tumors completely resected outscored the unresectable and partially resected. Of 93 patients that had completely resected, recurrence was found in 32 of these patients (34.4%), recurrence was local in 8 patients, metastases in 18 patients and local recurrence + metastases in 6 patients, with an average time of recurrence 22 months. The overall cumulative survival at 5 years was 81.35%. The survival of patients under and over 50 expressed a p = 0.08, cumulative survival rates by tumor size expressed p = 0.56, cumulative survival rates for stomach and intestinal location shows a p = 0.056. The 5-year survival of completely resected patients was 87.70%. Overall survival of patients with and without metastasis expressed p = 0.001, the cumulative survival function completely resected patients, the resected and partially resected, expresses with p <0.0001. Multivariate analysis showed that the most significant factor for disease progression was the primary metastases with p = 0.007, and that survival was directly related to complete resection of the disease which is expressed with p <0.0001. CONCLUSIONS: The most important prognostic factor of survival for gastrointestinal stromal tumors (GIST) is the complete resection of the disease. The factor that is associated with progression of the disease is the presence of metastases. In our series of 152 patients, tumor locations tend to relate better survival in gastric GIST that in intestinal GIST. Similarly, we found a tendency to express a lower survival in patients younger than 50 years. Differentiated tumor size in three size categories expressed no more related to survival. The low mitotic index associated with metastasis, not reflected a good prognosis of disease. PMID- 21263759 TI - [HER2 expression in gastric cancer in Peru]. AB - HER2 positivity is thought to be a negative prognostic factor in gastric cancer (GC), correlating with poor survival rates. Reported HER2-positivity rates in GC have varied widely (6-35%). Objective of this study is to determine rate of positivity and describe clinical and pathological characteristics of HER-2(+) GC. 100 GC tumour samples were centrally screened by immunohistochemistry and FISH. 9% of cases were positive. More positivity HER2 was found in advanced stages (III/IV) vs. early stages (I/II)(p=0.045) ; intestinal histology subtype vs diffuse/ mixed (p=0.045) and gastro-oesophageal junction cancer vs GC ( p=0.005). PMID- 21263760 TI - [Follow-up after curative surgery for colorectal cancer: impact of positron emission tomography - computed tomography (PET/CT)]. AB - Postoperative surveillance has an important role in patient survival after curative resection of colorectal cancer. OBJECTIVES: To describe the characteristics of the follow-up with positron emission tomography (PET) / computed tomography (CT)(PET/CT) and its impact in colorectal cancer (CRC) survivors after curative resection in a university hospital in Tochigi Prefecture, Japan. MATERIALS AND METHODS: Consecutive review of patient's hospital charts who underwent presurgical staging with PET/CT for curative resection of colorectal cancer between April 2005 and March 2008. The follow-up data of these patients was reviewed until September 2008. RESULTS: Of 209 patients presurgically staged for CRC, 207 (male/female = 125/82; mean age = 65.3 +/- 11.3 years) underwent curative resection and were included in the present study. The compliance rate with the Japanese Society for Cancer of the Colon and Rectum (JSCCR) follow-up guidelines was 53%. The cumulative survival at the end of study interval was 96.4%. The test most commonly used in postoperative follow up of CRC was the carcinoembryonic antigen (CEA). PET/CT was the test that detected more patients with recurrent lesions (n = 11, positive predictive value = 23.4), including one patient with an asymptomatic curable recurrence (inguinal lymph node metastasis), also being the most effective test (2.1%). However, its high cost makes it the less cost-effective. CONCLUSIONS: The use of PET/CT in the postoperative follow-up after curative resection in CRC has proven to be an individualized and effective alternative in the finding of asymptomatic disease curable. Systematic CEA tests with contrast-enhanced CT as a first line of screening and PET/CT as a second line may be an alternative follow up approach after curative resection for CRC. PMID- 21263761 TI - [Oropuche fever outbreak in Bagazan, San Martin, Peru: epidemiological evaluation, gastrointestinal and hemorrhagic manifestations]. AB - INTRODUCTION: In Peru, the first outbreak of Oropuche fever (OROF) occurred in Iquitos during 1992, as dissemination of oropuche virus from Brazil. The OROF causes expenses in public health, loss of labour and academic activities and social suffering. OBJECTIVE: Evaluation of the outbreak of OROF in Bagazan community of San Martin Department, and comparison of the gastrointestinal and hemorrhagic clinical manifestations with those occurred in Iquitos and Brazil. METHODS: The sudden onset of an acute fever syndrome in many people of Bagazan, little village with 1082 residents, happened in may 2010. The symptoms and signs were registered in a standardized pattern. Blood samples were sent to the laboratory of the National Health Institute in Lima. RESULTS: The diagnosis was confirmed in 108 patients. The clinical manifestations were fever of 38 degrees C, headache, muscle and joint pains, congestion of conjunctiva, nausea, vomiting, and diarrhea. Some cases presented nose, gum and/ or vaginal bleeding. The gastrointestinal manifestations were more frequent than those of the Iquitos cases. CONCLUSIONS: The outbreak showed the dissemination of OROF to Peru, because of various favorable conditions. We discuss the hypothesis of the increase of gastrointestinal and hemorrhagic manifestations, including ecological, immunity, individual and viral characteristics. PMID- 21263762 TI - [Small bowel capsule endoscopy]. AB - Capsule endoscopy enables inspection of the gastrointestinal tract without discomfort or need for sedation and thus obviates the risks associated with traditional endoscopy. This review presents an update on small bowel capsule endoscopy since its introduction in 2001. We will review salient features of the small-bowel capsule endoscopy devices, clinical indications, possible complications and special situations during the study. PMID- 21263763 TI - [10 years of liver transplantation in Peru]. AB - The article reviews the experience in 10 years of hepatic transplants performed by The Transplant Department of the National Hospital Guillermo Almenara Irigoyen (HNGAI), describing the history, surgical outcomes in adults and children, retransplantation, combined liver-kidney transplants, complications in 72 transplants performed at the time of submission of the article. PMID- 21263764 TI - [Acute hepatitis secondary to hepatitis E. Report of two cases from a population of high socioeconomic level Lima]. AB - We describe two cases with acute hepatitis of patients who live at Lima, Peru and have a high socio-economic status. The first case, is a 58 years old female with asthenia, jaundice, coluria and pruritus. The physical exam revealed jaundice and laboratory exams revealed transaminasemia (AST= 1754, ALT= 2680) and hyperbilirubinemia (total bilirubin= 7.98, direct bilirubin=7.03). Furthering serologic tests, revealed a positive test for anti-Hepatitis E virus IgM and IgG. All the symptoms were remitted by the 3rd week of disease. The second case described, is a 64 years old female with asthenia, hyporexia and abdominal pain, without jaundice. The physical exam was normal and initial laboratory tests revealed an AST= 2999 and ALT= 4370. All the symptoms were remitted by the 3rd week of disease. The ELISA testing for anti-Hepatitis E virus IgM, was positive. In both cases other viral hepatitis serologic tests were negative. We make a description of these 2 cases and a literature review, because these both, are the first cases of Hepatitis E described in our city, and for the relevance of this virus in current medical knowledge for patients with non A, non B, non C acute hepatitis. PMID- 21263765 TI - [Metastasis of carcinoma of stomach cancer simulating primary ovarian tumor. Importance of frozen biopsies]. AB - OBJECTIVE: The importance of frozen section in the Diagnosis and management of patients with ovarian tumors. RESULTS: We report 9 cases of patients with ovary tumors. The primary carcinoma was found during an operation for the ovarian tumor. In these cases the diagnosis of krukenberg tumor was made intraoperatively by frozen section evaluation and the primary carcinoma were found in the stomach. CONCLUSIONS: The results of the study of 9 patients with metastasis from gastric carcinoma simulating primary carcinoma of the ovary show us the importance of frozen section and the communication with the surgeon intraoperatively. PMID- 21263766 TI - [Cecal amelanotic melanoma]. AB - A 73 year old male patient who presented to emergency with severe anemia (Hb 4.9 g /dL), referring to a month with dark stools, fatigue and significant weight loss. The high endoscopic evaluation found no potentially bleeding lesions. Subsequently, we confirmed the presence of red blood in stools, like enterorrhagia and underwent a colonoscopy, in which two elevated lesions were found in the cecum: a pedunculated (with active bleeding, oozing) and other sessile; both were removed. the pathology showed that corresponded to amelanotic melanoma in cecal region. Physical examination revealed no malignant skin lesions. Recurrent gastrointestinal bleeding forced to make another colonoscopy that showed new bleeding lesion of the cecum. He was operated with a cecostomy and cecal excision of the lesion.. The tomography scan showed metastases in mediastinum and surgical implants were found in liver metastases and small intestine. The patient continued treatment in medical oncology. We report this case, because gastrointestinal bleeding is an unusual clinical presentation of malignant melanoma. PMID- 21263767 TI - Sore throat strategies. PMID- 21263770 TI - Fluoridation: the democratic aspect. PMID- 21263769 TI - [Not Available]. PMID- 21263771 TI - Prevention: the hib vaccine. PMID- 21263772 TI - 20th century disease: a comment. PMID- 21263773 TI - Prenatal care in europe available in Canada. PMID- 21263774 TI - Total allergy symptom. PMID- 21263775 TI - Congratulations to dr. Perkin. PMID- 21263776 TI - Family-practice anesthesia in british columbia. AB - This study of family practitioners as anesthetists is based on data extracted from records of the Medical Services Plan of British Columbia. During the period from 1976 to 1986, the proportion of anesthetics that were administered by non certified anesthetists declined from 28.3% to 22.1% of the total number. Small and medium-sized hospitals continue to depend on family-physician anesthetists. Family practitioners make up 96.9% of all anesthetists practising in hospitals with fewer than 50 beds and 88.2% of anesthetists in hospitals with 50-99 beds. Rural areas are served almost exclusively by family-practice anesthetists, since 16 of 29 B.C. regional districts have one or no certified anesthetists. The author discusses the implications of this situation for the future of family practice anesthesia. PMID- 21263777 TI - Treating Sore Throats: Practice vs. Theory. AB - The management of a seemingly simple and common ailment, the sore throat, is shrouded in considerable controversy. At present, authoritarian opinion, stressing prevention of acute rheumatic fever (ARF), is in conflict with the practices of a large segment of the profession, whose members seem to treat primarily for symptom relief. Recent developments, in fields as diverse as epidemiology of ARF, clinical decision making, laboratory tests for streptococcus, and clinical trials of penicillin, are in support of management that is directed primarily towards symptom relief and secondarily towards prevention of ARF. PMID- 21263778 TI - Rheumatic Fever in the adult: a forgotten diagnosis. AB - The authors of this article present a case of acute rheumatic fever in an adult and review the diagnostic criteria for this illness. They emphasize the prevention of acute rheumatic fever by the adequate treatment of streptococcal pharyngitis with penicillin. PMID- 21263779 TI - The failure of scientific medicine: davis inlet as an example of sociopolitical morbidity. AB - The social and economic history of a Labrador coastal town is reviewed with particular reference to the roles of the Church, the Hudson's Bay Company, and the medical profession. Objective indicators of the current health status of the community are presented, and the major causes of ill-health in Davis Inlet are discussed. Comparison is made with Rudolph Virchow's assessment of the causes of a typhoid epidemic in Upper Silesia in 1848. The subsequent evolution of medicine from a socio-political to a scientific model is reviewed briefly. The authors conclude that the medical profession has embraced the scientific model to the point of virtually excluding the socio-political one, even though social, political, economic, and cultural alienation remain major causes of morbidity and mortality. In so doing, the profession promotes ill-health. PMID- 21263780 TI - Psychiatric outreach to underserviced communities in british columbia. AB - The author describes the maldistribution of psychiatric physicians in British Columbia, speculates on the causes of that phenomenon, and summarizes the response to the problem provided by the Psychiatric Outreach Program, a project sponsored jointly by the Ministry of Health and the University of British Columbia. PMID- 21263781 TI - Transportation of the critically ill and injured. AB - The introduction of cookbook-style protocols to emergency treatment of critically ill and injured patients has significantly improved the quality of pre-hospital care and the organization of transportation of these patients. The systematic implementation of pre-planned protocols by physicians, nursing staff, and ambulance personnel, combined with regular post-incident performance evaluations, will enhance the level of medical care both in large and small community settings. PMID- 21263782 TI - What Should the Family Physician Do before Sending a Patient to Hospital. AB - The decision to transfer a patient from a rural area to a tertiary-care institution reflects a new direction in the patient's care. Like any endeavour undertaken between professionals, this process is likely to go more smoothly if the important preparation is made in advance. A good working relationship between a primary-care and consulting physician, a knowledge of transport facilities in the area, and a mental checklist of tasks to do prior to transfer will all smooth the process. Communication is the single most important ingredient in a successful referral and should be prompt, direct between physicians, and two way. PMID- 21263783 TI - Taking residents into small-town practice. AB - This article describes a small-town family-medicine practice in Cowansville, Quebec, which is staffed by four family physicians. The group, which serves a diversified clientele, has access to a general hospital, consultants and paramedical resources. Residents in Family Medicine have spent some time in the practice during the past year, and the advantages of this arrangement are described. PMID- 21263784 TI - Why I shall stay in rural practice. AB - This article describes the six areas of particular appeal which have kept this couple in rural practice. PMID- 21263785 TI - The underserviced area program of the ministry of health of ontario. AB - The Underserviced Area Program provides financial incentive designed to attract doctors, dentists, physiotherapists, occupational therapists, speech pathologists, audiologists, and chiropodists to Northern Ontario. There are almost 1,000 people working in, or committed to joining, the program on completion of training. It is the largest program of its kind in the world. PMID- 21263786 TI - Family medicine in small communities. AB - This article is an off-the-cuff commentary on one practice in a city of 40,000 people. This city is in a largely agricultural area. The article stresses the pluses: the continuity of care and the more interesting and variegated nature of family practice here. There are negatives, as well: the more limited social life and the problems relating to employment for one's spouse. Patient confidentiality is more difficult to maintain, as is one's own privacy. Generally it is a busier and more challenging life, which I heartily recommend. PMID- 21263787 TI - [Not Available]. AB - After reviewing briefly the health legislation of the last 25 years, the author of this paper sets out the mandate of the Quebec Federation of Residents and Interns (FMRIQ), which has a membership of 1,800 physicians engaged in post doctoral education. He then presents the Federation's guidelines for the analysis of this legislation and the criticisms the Federation has to offer of the spirit and letter of Bill No. 1292 (June 2, 1982), which is linked to Law 27 (December 1981) and to Law 75 (June 19, 1986), as well as the solutions it proposes for unifying the medical regulations in its constituency. On the basis of its original position in the Quebec health-care system, the Federation calls on all interested parties for a show of strength and participation in dialogue. PMID- 21263788 TI - Is specialist care necessary for diabetics living in small communities? AB - The author describes her experience with treating diabetic patients in a small community. The practice of referring these patients to a regional centre was not producing the quality of treatment that physicians in the community desired for their patients. The problem was solved by setting up a local out-patient diabetic centre. The author discusses how this clinic serves its clients, and ways in which it has benefited their health. PMID- 21263789 TI - Teleconferencing cme programs to rural physicians: the university of calgary teleconference program. AB - Continuing medical education (CME) provides practising family physicians with the cornerstone of maintenance and improvement of skills. In rural areas the problems of isolation and distance are a barrier to continuing medical education. Provision of CME programs by audio-teleconferencing is an attempt to overcome these problems. This article describes the teleconference program of The University of Calgary, how it has developed over the five years of its existence, and its impact on rural physicians. PMID- 21263790 TI - Training for Rural Practice: What's Needed? AB - Despite concern about the provision of medical services in rural and remote areas, Canadian medical colleges have been graduating too few students willing to practise in those areas. In this article evidence is presented to support the need for development of special programs for students intent on rural practice. These programs should involve: (i) recruitment and identification of the right kind of student; (ii) emphasis on the teaching of those skills appropriate to rural practice; (iii) maximum utilization of rural teaching practices and community hospital resources. Departments of Family Medicine seem to be in the best position to develop these programs. PMID- 21263792 TI - "To be or not to be: that is the question." a nuclear arms update. PMID- 21263791 TI - Surviving small-town practice. AB - To cope and to survive family medicine in a small town has been, and continues to be, a problem. This article presents one physician's means and methods of staying in a difficult, but extremely exciting, profession. PMID- 21263793 TI - Regard vers l'avenir. PMID- 21263794 TI - The family physician: gatekeeper for whom? PMID- 21263796 TI - Environmental sensitivity: the "whole patient" approach. PMID- 21263797 TI - A re-review. PMID- 21263798 TI - Sexually transmitted diseases in Canada: an overview. AB - At least 26 sexually transmissible infections have been identified to date. Only five of these, however, are currently reportable on a national basis. While the true incidence of sexually transmitted diseases (STDs) is underrestimated because of the number that are non-notifiable, it has become increasingly clear that these non-reportable STDs are at least as common as those that are reportable. PMID- 21263799 TI - Genital ulcers: their diagnosis and management. AB - THIS ARTICLE OFFERS SOME BACKGROUND INFORMATION ON DIAGNOSIS AND TREATMENT OF THREE MAJOR CAUSES OF GENITAL ULCERS: syphilis, herpes simplex virus (HSV), and chancroid. The author also discusses differential diagnoses and suggests an approach to treatment. PMID- 21263800 TI - Chlamydia trachomatis: a genital infection of particular concern to the young. AB - Chlamydia trachomatis is the most prevalent sexually transmitted disease in North America. It is most common in the younger sexually active population. Chlamydia tends to produce relatively mild symptoms initially, and is often responsible for a wide variety of syndromes including cervicitis, urethritis, pelvic inflammatory disease, and epididymitis. Involuntary infertility and ectopic pregnancy are important late sequelae. Chlamydia is a modified bacterium and is usually treated with tetracycline or erythromycin. Screening for chlamydia is more advantageous than screening for other sexually transmitted diseases. Criteria are presented for the treatment of certain high-risk groups. PMID- 21263801 TI - Human immunodeficiency virus infection: the spectrum beyond AIDS. AB - Since 1981, the Acquired Immune Deficiency Syndrome (AIDS) has emerged as the major infectious epidemic of our time. It is the most profound manifestation of infection with the Human Immunodeficiency Virus (HIV). Since 1984, serologic methods have existed to detect antibody to HIV. Several other clinical entities have been detected and are attributable to HIV infection. Appropriate counsel must accompany antibody testing. The author discusses the acute seroconversion event, as well as asymptomatic carrier status, including generalized lymphadenopathy. He also reviews the symptomatic states that do not meet the surveillance definition of AIDS, including treatments where available. PMID- 21263802 TI - Interpreting serological tests for syphilis. AB - Serological tests can be helpful in diagnosing syphilis. The ideal test would be highly specific in all stages of the disease; it would be 100% sensitive and would revert to negative with treatment, thereby allowing the physician to monitor treatment effect. No single test satisfies these requirements. Being alert to the signs and symptoms of syphilis in all its stages and familiar with the meaning of the common serological tests (VDRL, MHA-TP, FTA-ABS) will help physicians to detect early treatable disease and thus prevent tertiary syphilis or spread to others. This article describes the serological tests used to diagnose syphilis and outlines what to look for if a VDRL is reported as reactive. PMID- 21263803 TI - Genital herpes. AB - The author reviews the prevalence of genital herpes, outlines the typical clinical courses of the disease in its primary and recurrent forms. He discusses the physical, psychological and social effects of this sexually transmitted disease and provides three protocols for the use of oral acyclovir in its treatment. PMID- 21263804 TI - AIDS under the microscope. PMID- 21263805 TI - Vaginal discharge: an approach to diagnosis and management. AB - Vaginal discharge is a frequent presenting complaint in an office practice. The authors of this article review the most common causes of this condition, namely Candidiasis, Trichimoniasis, and Bacterial Vaginosis (Gardnerella), as well as the more serious causes, namely gonorrhea, chlamydia, and Herpes simplex. Symptoms and physical signs are generally insufficient to distinguish specific etiologic agents and, as treatment for each is different, diagnostic examination of smears in the office is critical to the management of these patients. A clinical approach and method of office diagnosis is described. PMID- 21263806 TI - The office management of sexually transmitted diseases. AB - The family physician plays an important role in controlling the spread of sexually transmitted diseases. Accurate identification, diagnosis and treatment are essential in exercising this control. In addition, attention must be paid to educating patients and to treating their sexual contacts. This paper will review the management of some of the more common diseases including urethritis, vaginitis, cervicitis, herpes, genital warts and molluscum contagiosum. PMID- 21263807 TI - Ano-rectal symptoms of sexually transmitted disease. AB - Diseases of the anus and rectum are frequently the outcome of proctogenital and oral-anal sexual activities. These sexually transmitted diseases are more common among homosexual and bisexual men than among heterosexuals. A variety of infectious agents are responsible including viruses, bacteria, spirochetes, helminths, and protozoa. Anal warts, herpetic ulcers, and syphilitic chancres are common anal STDs. Gonorrhea, herpes, and chlamydial organisms are common causes of venereal acute proctitis. Enteric infections such as shigellosis, amebiasis, giardiasis and pinworms can be transmitted by oral-anal contact. Aggressive sexual attempts at auto-eroticism using rectally inserted foreign bodies may cause traumatic proctitis complicated by bacterial peritonitis or perirectal abscesses. PMID- 21263808 TI - Urethral discharge in the male. AB - Urethritis in the male is frequent, and is almost always sexually transmitted. It is classically divided into gonorrhea, and nongonococcal urethritis. By definition, men with gonorrhea have Neisseria gonorrhoeae present, but approximately 20% also have Chlamydia trachomatis. C. trachomatis is present in 30%-50% of men with acute nongonococcal urethritis. The specific etiologic diagnosis requires laboratory evaluation. Recommended treatment for urethritis includes a one-week regimen of a tetracycline for all men, plus a single-dose regimen active against N. gonorrhoeae in men in whom gonorrhea is proven or has not been excluded. Partners should be investigated and should receive similar treatment. Recurrence of nongonococcal urethritis is frequent after treatment, but the condition is only rarely the result of persistent C. trachomatis infection. Men with recurrent urethritis require re-evaluation. If no cause is found or if Ureaplasma urealyticum is isolated, the men are treated with a two week course of erythromycin. If there are subsequent recurrences, they are usually left untreated. PMID- 21263809 TI - The tender uterus. AB - The tender uterus is one of the most common gynecological presentations. Making a correct diagnosis is of vital importance in the management of patients with this condition because of the diverse etiology involved. In most cases, diagnosis can be made relatively easily from a complete history and physical examination alone because each differential diagnosis has a distinctive clinical presentation. Pelvic inflammatory disease is one of the main causes of a tender uterus. Prompt diagnosis and therapy may lead to prevention of its long-term sequelae, such as chronic pain, recurrent infection, ectopic pregnancy, and infertility. PMID- 21263810 TI - Prostitution. AB - A review of the literature discloses that prostitutes are distinguishable into distinct classes, each with distinct clinical implications. The spectre of AIDS suggests that we review the implications of the health risks associated with this profession. This article discusses the potential causes, health problems, and treatment of prostitutes. PMID- 21263811 TI - The jamaican perspective on family medicine. PMID- 21263812 TI - One Flu Over the Cuckoo's Nest. PMID- 21263813 TI - Requiescat in pace. PMID- 21263814 TI - The physician: a human being. PMID- 21263815 TI - Perinatal care in europe. PMID- 21263816 TI - [Not Available]. PMID- 21263817 TI - [Not Available]. PMID- 21263818 TI - [Not Available]. PMID- 21263819 TI - Illness and diabetes. PMID- 21263820 TI - On examining adolescents. PMID- 21263821 TI - Compression hose for leg cramps. PMID- 21263822 TI - Belated congratulations to dr. Kevin N. Johnson. PMID- 21263823 TI - Asymptomatic microscopic hematuria. AB - A retrospective chart review was performed in a family-practice office, which looked at the prevalence and significance of asymptomatic microscopic hematuria (AMH). Various methods were used to identify the relevant charts and to define the practice demographics, some of which hitherto had not been described. At least 2% of the men and 5% of the women over 44 years old in the practice were found to have AMH; in none of these patients, however, were any significant urological abnormalities detected. The literature states that AMH is a significant indicator of underlying pathology and deserves a full urological evaluation. The results of this pilot study suggests that in a family-practice setting, the prevalence of serious but asymptomatic urinary tract disease, and hence the positive predictive value of AMH, may be very low. PMID- 21263824 TI - The immunocompromised patient. AB - The number of immunocompromised persons-as well as the importance of family physicians understanding their state-is increasing. In many instances the family physician will first identify or provide day-to-day care for such patients while they live in the community. This article gives an overview of certain aspects of normal host immunity, etiology and mechanisms in immunocompromisation, and outlines techniques for recognition and management of this special group of patients. PMID- 21263825 TI - Vasculitic syndromes. AB - Systemic vasculitis is a clinical and pathological process characterized by inflammation and damage to blood vessels. Within the entire spectrum of vasculitis virtually any size or type of blood vessel in any organ system can be involved. Vasculitis may be the primary feature of the disease or may accompany or complicate other connective tissue diseases.Immunopathogenic mechanisms are thought to be implicated in most vasculitides. In recent years several of the serious vasculitides, such as Wegener's granulomatosis and polyarteritis nodosa, which previously had a poor prognosis, have now been shown to be responsive to cytotoxic therapy, particularly to treatment with cyclophosphamide. PMID- 21263826 TI - Monoclonal antibodies. AB - The development of hybridoma monoclonal antibody (MAb) technology has had a major impact on clinical and laboratory medicine. It has allowed the production of essentially unlimited quantities of pure, homogeneous antibodies against a large variety of antigens. Despite the many advantages of MAbs, the effort and expense required for their production is not always justified. Less expensive and more easily obtained conventional anti-serum is still perfectly adequate in some instances. Nevertheless, murine MAbs have found widespread use in clinical and research laboratories, particularly in the field of oncology. Considerable effort has been devoted to the development of human MAbs, since antibodies of human origin are expected to be superior in therapeutic and in vivo diagnostic settings. However, technical difficulties currently prevent their widespread use. Finally, novel approaches using genetic engineering techniques are described, which portend exciting new developments in the near future. PMID- 21263827 TI - Management of chronic urticaria. AB - Effective treatment of chronic urticaria depends on identification of the etiologic factor, if possible, and its subsequent elimination, although symptoms may be suppressed by appropriate medication. The investigation of the patient who presents with chronic urticaria is discussed, with emphasis on the need for a detailed history, meticulous physical examination (including a search for occult infection) and full routine hematologic, biochemical and radiologic monitoring. The author discusses the use of intradermal skin tests, scratch tests for inhalants and the need for skin biopsy and gastro-intestinal tract screening. Dietary treatments reviewed include the elimination diet and the elemental diet, which is used in combination with gradual re-introduction of foods. Symptomatic treatments, including antihistamines, the newer H(1)-histamine receptor antagonists, used with tricyclic antidepressants and with combination therapy, and systemic corticosteroid therapy are also discussed. PMID- 21263828 TI - Hyposensitization therapy. AB - Hyposensitization therapy is useful in the treatment of allergic disease causing rhinoconjunctivitis and asthma, and in the prophylaxis against anaphylaxis to hymenoptera stings. It may be of value in some patients with drug sensitivities. Its effectiveness has been proven by objective clinical studies, and the immune mechanisms responsible for patients' response have been demonstrated in vivo and in vitro. A prerequisite for effectiveness is the identification of the offending antigen and the availability of that antigen in a standardized, purified, stable extract. Modified antigens with special immunologic properties show much promise for the future. PMID- 21263829 TI - Is insulin-dependent diabetes mellitus an autoimmune disorder? AB - Current evidence suggests that insulin-dependent diabetes mellitus (IDDM) is most likely a slowly progressive autoimmune disorder. More than 90% of Caucasian IDDM patients have DR3 and/or DR4, the HLA region linked to immune response. At onset of disease, most IDDM patients have islet-cell antibodies, more immune-associated T lymphocytes and anti-insulin antibodies. Most IDDM patients who died within six months of diagnosis had insulitis: an infiltration of mononuclear cells (mostly activated T cells) around the pancreatic islets. Immunosuppression therapy may be effective in inducing remission in newly diagnosed IDDM patients. PMID- 21263830 TI - Tricyclic antidepressant overdose. AB - The following paper will discuss recent literature concerning TCA overdose and review cases seen over a one-year period at the Ottawa Civic Hospital. Discussion will centre around the issue of prolonged cardiac monitoring and the use of sodium bicarbonate in the treatment of dysrhythmias. The authors review 33 cases admitted over a one-year period to the Ottawa Civic Hospital with a diagnosis of tricyclic or tricyclic plus other drug ingestion. They discuss methods of treatment with particular emphasis on repeated charcoal dosing. The various cardiac arrhythmias are discussed briefly, as are the pharmacological characteristics of the tricyclics. The need for prolonged monitoring is reviewed, and specific recommendations are made about the duration of monitoring. The use of sodium bicarbonate intravenously as the drug of choice in the treatment of arrhythmias is discussed. PMID- 21263831 TI - Physical growth parameters of chinese children in calgary. AB - Though ethnic variation in growth is well recognized, little is known about the physical growth of Chinese Canadian children. The objectives of this study were to establish the growth parameters for Chinese Canadian children and to compare them with those of Caucasian Canadians. The authors measured height, weight and head circumference during periodic physical examinations of children who attended their clinic between 1980 and 1984. These children were residents of Calgary, Alberta. Children with congenital anomalies or acquired chronic diseases were excluded. A total of 2,149 children (946 ethnic Chinese and 1,203 Caucasians) were studied. Differences in growth characteristics of Chinese Canadian and Caucasian Canadian children were established. The data suggest that the use of normal growth charts derived from growth data on the North American population may not be appropriate for Chinese Canadians. PMID- 21263832 TI - Molecular diagnosis. AB - Recombinant DNA technology, one of the major controversial areas of biological research in the late 1970s, is now rapidly providing new avenues for diagnosis and treatment. With the early recognition that extensive DNA variation exists in human populations, molecular genetic diagnosis of a variety of common hereditary diseases has become a reality. Recent identification of the location of the gene (or genes) for cystic fibrosis and adult polycystic kidney disease, and characterization of the region of the Duchenne muscular dystrophy gene will lead us towards a better understanding of the basic defects in these diseases. The identification of large multi-generation families with genetic diseases that are useful for identifying gene locations will require the co-operative participation of clinicians, medical geneticists and molecular biologists. PMID- 21263833 TI - Environmental hypersensitivity disorder, total allergy and 20th century disease. AB - Environmental hypersensitivity disorder is reputed to cause multiple allergic responses in susceptible people after exposure to common substances in the environment. The seriously afflicted, who believe themselves to be unable to live in the modern world, often become severely disabled. After a careful search of the literature, I am unable to find any scientific evidence for the validity of the theories, testing methods, or treatments given to these patients by clinical ecologists. This paper critically examines the concepts of environmental hypersensitivity and reviews scientific studies on this subject. It concludes that these patients are a heterogeneous group, and that many of them suffer from treatable psychiatric disorders. Guidelines are given for their management. PMID- 21263834 TI - Biofeedback, relaxation techniques and attitudinal changes in adolescents with migraines. AB - From 3.2% to 9% of school-age children suffer from migraine headaches. Many physicians are concerned that pharmacological treatment of migraines can have undesirable side-effects, as well as lead to drug dependence in adolescents. A number of review articles have shown that biofeedback, behaviour modification and relaxation exercises can significantly help migraine sufferers. This article describes a feasibility study undertaken at a West Toronto high school to see if non-pharmacological treatment of migraines was effective. PMID- 21263835 TI - Youth and traffic accidents. AB - THIS PAPER ADDRESSES THE PROBLEM OF TRAFFIC ACCIDENTS INVOLVING YOUNG ADULTS: specifically, what is known about the causes of their accidents, and what preventive action seems warranted. In this context, we consider what role the family physician might play in dealing with this major public health problem. PMID- 21263836 TI - Broader indications for psychiatric consultation. AB - A liaison approach to psychiatric consultation increases the patient population who can benefit from psychiatric assessment during hospitalization for medical or surgical conditions. It also broadens the scope of the psychiatric investigation of the individual patient. The meaning of the illness to the patient, and the patient's present methods of adapting to his or her illness are important considerations. Unconscious concerns, which interfere with the patient's compliance to medical treatment, may be sufficiently clarified and resolved so that medical progress is expedited. Psychiatric consultation can be used to prevent an untoward psychological reaction to illness, if this is foreseen. This preventive consultation, which is often possible only because of the family physician's awareness of the psychological vulnerability of some of her or his patients, can result in reduced medical and psychiatric morbidity. PMID- 21263837 TI - Oral contraceptive estrogen content and adverse effects. AB - The 1985 Health and Welfare Canada Report on Oral Contraceptives recommended oral contraceptives (OCs) containing 30-35 mcg of estrogen rather than 50 mcg as the preferred dosage for contraception. Many family physicians may regard these guidelines as mandatory when prescribing OCs, because of a presumption that pills of 50-mcg estrogen content carry a higher risk of disease. In this article, the epidemiologic evidence pertaining to a dose-response relationship between the estrogen dose of oral contraceptives and disease is critically reviewed. The review indicates that there is no incontrovertible evidence to support such a relationship. Implications of the recommendations in the Report for physicians and patients are discussed. PMID- 21263838 TI - Ilio-inguinal Nerve Entrapment Syndrome: A Cause of Abdominal Pain. AB - The ilio-inguinal nerve is vulnerable to entrapment at its exit from the external oblique muscle medial to the anterior superior iliac spine. When entrapment occurs, patients complain of pain either around the exit point or over the L 1 dermatome. Four case histories illustrate, paradoxically, how easy and how difficult it can be to diagnose this condition. PMID- 21263839 TI - General practice in new zealand. PMID- 21263840 TI - Doctors and patients: on the job. PMID- 21263841 TI - Extracorporeal shock-wave lithotripsy: milesone or millstone? PMID- 21263842 TI - Requiescat in pace. PMID- 21263843 TI - [Not Available]. PMID- 21263845 TI - A challenge to dr. Watt. PMID- 21263844 TI - Vol au-dessus d'un nid de coucous. PMID- 21263846 TI - Prenatal education: grounds for concern I. PMID- 21263847 TI - Prenatal Education: Grounds for Concern II. PMID- 21263848 TI - War and peace. PMID- 21263849 TI - "Thank You for Seeing This Patient": Studying the Quality of Communication between Physicians. AB - Communication between physicians about patients was examined in a pilot study when 15 family physicians and specialists were asked to describe the most recent consultation in which they had been involved. In 40% of the consultations discussed the communication seemed to have been clear, and both physicians involved were satisfied with the process; but in 40% communication was confused, and in the remaining 20% outright conflict was identified. Skillful communication between physicians may be important to ensure optimal patient care, and the study revealed some barriers to effective consultations. PMID- 21263850 TI - Patellofemoral joint disorders. AB - Knee pain is a common presenting complaint by athletes and the general population. Disorders of the patellofemoral joint are responsible for most of these disorders. Abnormal patellar tracking is thought to be the principal cause. Patellar tracking is influenced by a number of dynamic and static factors. These can be assessed with a careful history and physical examination. A treatment program can be designed to alter the precipitating factors. Lower-extremity malalignment, principally hyperpronation of the foot, is believed to be a major cause of abnormal patellar tracking. Conservative treatment programs have had successful results, and less emphasis is now being placed on surgical procedures. PMID- 21263851 TI - In-toeing and out-toeing in children. AB - In-toeing and out-toeing problems are generally physiologic variants that arise from in utero posturing, and that gradually correct spontaneously during the active growing years of the child. Few torsional deformities result in genuine problems. Most residual effects are cosmetic, compounded by the anguish of concerned relatives and friends. Rarely is operative correction warranted. If corrective surgery comes under consideration, it is usually deferred until the patient reaches the age of 10. PMID- 21263852 TI - Common skeletal problems in children and adolescents. AB - Injuries are the most common cause of morbidity and mortality in children. Approximately 15% of injuries involve the skeleton. The prevalence of injuries and musculoskeletal problems increases with age as growing children achieve higher levels of physical activity. This paper provides brief descriptions of only the most common skeletal problems. The authors describe skeletal injuries seen in battered children; problems that cause painful or immobile arms; limps or immobile legs; and spinal pain problems. The common causes of pain or disability in these four areas are discussed. PMID- 21263853 TI - Recent advances in artificial hip-joint replacement. AB - In Western society arthritis of the hip is a fairly common condition in the elderly. At an advanced stage of this condition, surgical treatment is almost always necessary. The various surgical options can be divided into the so-called "biological procedures" and "replacement". The various biological or conservative operations have failed, in large part, to stand the tests of time and predictability, and have fallen by the wayside. It is worthwhile to describe briefly some of these earlier procedures. PMID- 21263854 TI - Predicting outcome in acute low-back pain. AB - Patients presenting to their family physician with acute low-back pain were studied prospectively. Demographic factors and patient history at the initial visit were assessed to determine important predictors of selected clinical outcomes, including time to resumption of normal activities and time to relief from pain. While several predictors were significantly correlated with each of the outcomes assessed, the most consistent predictor of outcome proved to be the reported pain intensity at the initial visit. Baseline levels of pain intensity were related to expected time of recovery and probability of periodic pain in the future. Data collected in the initial history and physical examination of patients permit an assessment of factors that may be useful in establishing prognosis for relevant clinical outcomes. PMID- 21263855 TI - Recurring foot problems. AB - This article focuses on clinical observation and examination of the whole foot. In noting the "knock-on" effect of key musculoskeletal abnormalities, a degree of relief of symptoms and prevention can be achieved. PMID- 21263856 TI - Update on treatment of rheumatoid arthritis. AB - Treatment of rheumatoid arthritis consists of use of drugs, physical measures, social work interventions, education and reconstructive surgery. The physician plays a co-ordinating role, since most patients with significant rheumatoid arthritis will require treatment by more than one member of the health-care team. Our drug armamentarium, including anti-inflammatory agents, disease suppressants, analgesics, rarely steroids, and even more rarely immunosuppressants, can be used to good effect in suppressing the synovitis of rheumatoid arthritis and in relieving pain. Physiotherapy, occupational therapy, nursing and social work interventions will help the patient to maintain function and to maintain their optimal level of fitness, including exercise tolerance, joint range, muscle strength and psycho-social function. Coping abilities can be greatly enhanced by a positive approach from the physician, and this, together with the very real benefits of the foregoing treatments, can produce a highly rewarding result for physician and patient alike, in terms of improved quality of life for the rheumatoid arthritis patient. PMID- 21263857 TI - Electromyography. AB - The generic term 'electromyography' (EMG) includes several electrophysiological tests useful for examining the peripheral and central nervous systems. These tests complement one another to provide a logical diagnosis. EMG is successful only as an extension of the neurological examination. Well-designed electromyography allows a lesion to be localized, its severity determined, and a reasonable prognosis established. PMID- 21263858 TI - Compression and entrapment syndromes. AB - Family physicians are often confronted by patients who present with pain, numbness and weakness. Such complaints, when confined to a single extremity, most particularly to a restricted portion of the extremity, may indicate focal dysfunction of peripheral nerve structures arising from compression and/or entrapment, to which such nerves are selectively vulnerable. The authors of this article consider the paramount clinical features that allow the clinician to arrive at a correct diagnosis, reviews major points in differential diagnosis, and suggest appropriate management strategies. PMID- 21263859 TI - Low-back pain: an orthopedic medicine approach. AB - Many patients suffering from low-back pain present to a family physician. This paper will deal specifically with the moving parts of the lumbar spine as the source of low-back pain: muscles, discs, ligaments, apophysial (facet) joints. A detailed systematic approach is suggested to facilitate the identification of the particular tissues involved. Various modes of treatment-manipulations, tractions, epidural injections and sclerotherapy-are discussed. PMID- 21263860 TI - An approach to the patient with fibromyalgia. AB - Fibromyalgia (fibrositis) is one of the most common rheumatologic conditions. This paper reviews the clinical presentation and pathophysiology of the syndrome and presents a global approach to the management of the disease. PMID- 21263861 TI - Prevention of osteoporosis. AB - Osteoporosis is a common disease affecting many Canadians. There is increasing comprehension of the pathophysiology of osteoporosis, and this is leading to the development of a promising form of therapy for established osteoporosis. The most cost-effective approach to osteoporosis, however, is prevention. Certain risk factors for the development of osteoporosis have been established. While the development of practical methods for measuring bone density represents a major advance, at present these methods cannot be advocated for widespread screening programs. The emphasis on prevention has focused on modification of estrogen status, calcium intake and activity pattern. There are a number of commonsense measures that physicians can suggest to patients for the prevention of osteoporosis. PMID- 21263862 TI - Management of foot pain. AB - This paper deals chiefly with the young adult foot, the older adult foot, and pain of mechanical origin. It does not discuss treatment by surgical methods, but rather by the use of exercises, foot supports and shoe corrections. Foot pain resulting from mechanical disorders can be treated effectively by determination of the biomechanical causative factors, usually by simple physical examination. Relief can often be gained with simple mechanical devices, provided at low cost. PMID- 21263863 TI - Does fibrositis exist? A survey of family practitioners. AB - Fibrositis has been a controversial diagnosis in recent decades. It was very popular earlier in this century, before it feel into disrepute. Recently, many articles have been published that describe fibrositis. A simple survey of 88 family practitioners which achieved a response rate of 78% showed that 94% of respondents believe that fibrositis exists, and that 50% of respondents have in their practice between one and 10 patients who have or have had fibrositis. Respondents listed a sampling of diagnostic criteria and treatment modalities used for this condition. PMID- 21263864 TI - Injuries associated with all-terrain vehicles. AB - All-terrain vehicle (ATV) riding has become very popular over the past decade. Several reports have shown that ATV riding can cause injury. Poor machine design, rider inexperience, inappropriate riding, carrying passengers, alcohol consumption, and use of ATVs by children have been identified as causes of injury. Three- and four-wheel ATVs demand considerable rider skill and caution, requirements which users may not appreciate. Physicians have an important role in recording and reporting ATV-related health hazards. PMID- 21263865 TI - A Critical Look at the Family Physician's Role in Preventing Childhood Injuries. AB - Childhood injuries stand as the most common causes of death among Canadian children. Physician advice and advocacy of appropriate legislation, parent education and legislative action could reduce this toll. There is a role for family physicians in the important process of providing a safer environment for our children. PMID- 21263866 TI - Emergency-room use in a small rural hospital. AB - Studies have suggested that the use of the emergency room (ER) for non-emergency service delays treatment access for bona fide emergency cases. Most studies, however, have focused on the actual use of the emergency room, and have failed to involve patients in assessing the reasons they chose to come to the ER. In this study, the authors analyzed an emergency room according to types and diagnoses of presenting problems, daily or hourly use, age-sex distribution of users, and proximity of users to the hospital, to determine the primary function of the facility. PMID- 21263868 TI - What did you say? Communication disorders. PMID- 21263869 TI - [Not Available]. PMID- 21263867 TI - Pseudoseizures: a real problem! AB - Introduction of new anticonvulsants, widespread use of serum anticonvulsant-level measurement, and availability of equipment for simultaneous video electroencephalogram (EEG) monitoring have shown that not everyone who has seizures has epilepsy, even when other medical conditions have been excluded. Non epileptic seizures, or pseudoseizures, occur in 20% of patients with conversion syndromes and can be difficult to diagnose and treat. Patients with pseudoseizures do not respond to anticonvulsants, may display paradoxical reactions to prescribed treatment regimens, and may develop abnormal neurological signs as a result of anticonvulsant toxicity. Both epileptic and non-epileptic patients may suffer pseudoseizures, which should be suspected when seizures, which should be suspected when seizure control is unpredictable or difficult, or when ictal or post-ictal EEGs are normal and psychopathology is present. Video EEG monitoring is the "gold standard" of pseudoseizure diagnosis. A case history illustrates how difficult the clinical diagnosis can be, and how useful a normal post-ictal EEG can be when the etiology of a seizure disorder is obscure. PMID- 21263870 TI - Le medecin de famille: gardien du systeme de soins. PMID- 21263871 TI - CFPC Annual Scientific Assembly 1987: Abstracts of Free-standing Papers. PMID- 21263872 TI - Concerning "the problem of pain". PMID- 21263873 TI - [Not Available]. PMID- 21263874 TI - Quinine for leg cramps: a comment. PMID- 21263875 TI - Re: perinatal care in europe. PMID- 21263876 TI - Nutrition and immunity: practical applications of research findings. AB - Nutrition is a major determinant of host resistance. Both deficiencies and excesses impair immune responses and lead to increased risk of infection and other diseases. Changes in immunity occur early in the development of nutritional deficiency; thus immunocompetence can be used as a sensitive functional index of undernutrition and as a prognostic marker of post-operative complications. Nutritional support enhances antibody response to common immunization procedures in such populations at risk of malnutrition as the elderly. PMID- 21263877 TI - [Not Available]. AB - The physicians on staff at the Family Medicine Unit of the Medical Centre of Laval University evaluated the quality of medical treatment by a method of control involving objective criteria. This study is based on 88 entries in the medical records of patients who were seen for the dispensing of oral contraceptives. The information contained in these entries was compared to criteria published in the 1985 Canadian Report on Oral Contraceptives. On average, each record contained 60%-80% of the criteria, depending on the type of visit. For each criterion analysed separately, the proportion of entries corresponding to the norm varies between 6% and 95%. Overall, the quality of the entries is good. The standard to be attained is correspondence with the recommendations set out in the 1985. PMID- 21263878 TI - The diagnosis and treatment of streptococcal pharyngitis. AB - To prevent rheumatic fever (RF) most authorities have recommended that treatment of pharyngitis be guided routinely by throat culture results. The recognition of a dramatic decline in the incidence of RF has rekindled the debate about the place of throat culture. Using clinical judgement alone, most practitioners would treat four or five patients for each culture positive. Although it is possible to use algorithms to select low- and high-risk groups for whom culture may not be necessary, a specific diagnosis must still be sought in the majority of patients. Diagnostic kits for rapid detection of group A streptococus facilitates this approach. PMID- 21263879 TI - Obstructive sleep apnea: a clinical review. AB - Obstructive sleep apnea is a relatively common disorder which is being recognized and diagnosed with increasing frequency. Patients with this disorder are frequently overweight and usually present with longstanding history of heroic snoring and excessive daytime sleepiness. The diagnosis is established with an overnight sleep study, although the decision as to who should be sent to a sleep laboratory must be made on an individual basis, particularly for those whose main complaint is snoring. The major factor in the pathogenesis of this disorder is a narrow and floppy pharyngeal airway. Of the several treatment modalities available at the present time, the most successful is application of continuous positive airway pressure during sleep. PMID- 21263880 TI - Rhinitis: allergic and non-allergic. AB - Rhinitis, or the "stuffy nose", can be allergic or non-allergic in nature. Accurate diagnosis depends on a well-taken history and physical examination. Non allergic rhinitis is characterized by absent elevation in allergen-specific IgE. Treatment is based, if possible, on the etiology. Surgical procedures on the turbinates are often needed to allow improvement. Allergic rhinitis is characterized by an increase in allergen-specific IgE. Treatment may involve environmental control, pharmocologic agents, or, finally, immunotherapy. Successful treatment requires accurate assessment of the offending agent and proper use of the above-mentioned modalities. PMID- 21263881 TI - The neonatal airway: problems and management. AB - Altered, distressed, and noisy breathing during the neonatal period may indicate problems of the upper airway. Typically, a neonate with upper airway obstruction will present with stridor, which may be inspiratory and/or expiratory, and which may represent either a minor or a life-threatening illness. Evaluation of stridor will require a systematic history and physical examination, laboratory and radiologic studies, and possible endoscopic examination of the airway. Rapid diagnosis and intervention may be life-saving or may prevent further respiratory pathology and long-term sequelae. PMID- 21263882 TI - Audiometry in young children. AB - The author of this article reviews various techniques in the auditory assessment of infants and young children. The success of these tests depends on the overall functioning of the child, and not on chronological age alone. Any significant deviation from the normal auditory behaviour should raise suspicion of possible auditory impairment. Diagnostic audiology involves more than mere testing of the peripheral auditory mechanism in isolation. It necessitates investigation of possible neurological impairment, mental retardation, emotional disturbance, and hearing loss. Early diagnosis is facilitiated by the battery of auditory tests comprising behavioural, impedance audiometry and auditory brain-stem response audiometry. Interpretation of test findings must be carefully assessed in the light of other pertinent information. PMID- 21263883 TI - Head and neck neoplasms. AB - Tumours of the head and neck show a wide spectrum of natural behaviour ranging from the most benign to the extremely lethal. Investigative techniques are of limited usefulness. History and physical examination are the foundations for diagnosis, though ultimate proof rests on surgical biopsy. The author of this article discusses the more common head and neck neoplasms. He gives brief descriptions of some tumours, highlighting their specific characteristics and their natural behaviour. He also suggests methods of investigation and gives brief overviews of modes of therapy. He discusses advances in management of head and neck neoplasms within the past decade and describes the technique of fine needle cytologic aspirate. PMID- 21263884 TI - Otosclerosis. AB - Otosclerosis is primarily a disease of the otic capsule that progresses slowly from a focus of soft bone to a dense bone, resulting in either a conductive or a sensorineural hearing loss. This paper treats the disease process, its diagnosis, and its management. PMID- 21263885 TI - Otitis media in children. AB - Acute otitis media is the most frequent diagnosis made in children visiting a physician's office during the first five years of their life. This paper deals briefly with the epidemiology and diagnosis of this major medical problem and provides some guidelines for management. PMID- 21263886 TI - A Mini-Atlas of Ear-drum Pathology. AB - The authors provide a number of ear-drum pictures and identify and discuss diseases affecting the external ear canal, the tympanic membrane and middle ear. They also deal with the removal of foreign bodies from the external canal, perforation of the tympanic membrane, and the use of an artificial ventilation tube. PMID- 21263887 TI - Hearing AIDS: a review for the family physician. AB - Hearing impairment is a common disability which can often be minimized by the use of hearing aids. Various types of hearing aids have been developed which are appropriate for most hearing losses that are not medically or surgically treatable, and these devices have been variously applied. Potential benefits and limitations of amplification need to be considered for each patient. Changes in technology, assistive devices, and the development of the cochlear implant have improved the ability of the hearing impaired to compensate for their disability. The benefits of new technology should not overshadow the importance of simpler considerations such as how we can speak more effectively to those who have difficulty in hearing. PMID- 21263888 TI - Non-medical services for the hard of hearing and deaf in newfoundland and labrador. AB - The hard of hearing communicate mainly by speech, the deaf by sign language. Services differ, but some hearing-impaired persons need non-medical services provided for both groups. These services are important in Newfoundland because there are few hearing-health professionals to serve a small population distributed over a wide area. This article outlines problems faced by the hard of hearing and describes the services provided by the Newfoundland Hearing Association, the Newfoundland School for the Deaf, the Parents' Association of the Deaf, and the Counselling/Interpreting services of the Newfoundland Co ordinating Council on Deafness. Programs need to be expanded, but are suggested as an appropriate model for any area of the country. PMID- 21263889 TI - Emergency dental treatment for the family physician. AB - The family physician is often expected, and should be able, competently to provide emergency dental treatment. With the knowledge of relatively few techniques and materials, this care can often be simply provided. Treatment discussed includes: odontogenic infections, avulsions, fractured teeth, post operative bleeding and pain, dentures, dental caries, periodontal problems, analgesics, and allergy to local anesthetic. PMID- 21263890 TI - Memoire du CMFC, Section du Quebec a la Commission Rochon. AB - The mandate of the Rochon Commission, a board of inquiry into Quebec's health and social services, is to analyse and rationalize the use made of those services in the Province of Quebec. The Quebec Chapter of CFPC presented a brief to the Commission, describing the place of the College in promoting high standards of quality in family practice. The brief submitted by the Chapter emphasizes, also, on the necessity of a specific two-year residency training program that all family physicians would be obliged to complete before they become eligible to obtain a licence to practice. The brief also states the necessity of a CME program for all family physicians and details the financial and human resources required for the development of a Family Medicine Program for all family physicians in the Province of Quebec. PMID- 21263891 TI - Breast cancer: the debates continue. PMID- 21263892 TI - [Not Available]. PMID- 21263894 TI - "Disclaimer". PMID- 21263893 TI - Lithotripsie extracorporelle par ondes de choc. PMID- 21263895 TI - Query for dr. Turgeon. PMID- 21263896 TI - The medical denial syndrome. PMID- 21263897 TI - Beta blocker side-effects. PMID- 21263899 TI - Environmental contamination and the food chain. PMID- 21263898 TI - Concerning whiplash. PMID- 21263900 TI - Treatment of corneal abrasions. PMID- 21263901 TI - Obstetrics and the family physician. PMID- 21263902 TI - Is VBAC Safe? PMID- 21263903 TI - The "King's Man". AB - The modern coroner is the heir of a long and honoured tradition with its roots in Anglo-Saxon England. The primary duty of the ancient "crowner" or "King's man" was to support the interests of the King of England by investigating violent deaths. The modern counterpart of this royal officer has a much broader range of duties in the interests of justice and the state. Not only do today's coroners act as "ombudsmen for the dead", but they also are becoming increasingly involved in medico-legal investigations of service to the living. PMID- 21263905 TI - Benzodiazepines: are we overprescribing? AB - The authors made a survey of benzodiazepine use in the Family Practice Units at Toronto General Hospital and report the findings. They have examined, among other factors, drugs used, reasons for use, and perceived withdrawal symptoms. The results indicated that 24.3% of respondents had taken benzodiazepines in the previous year, and 12.2% in the previous two weeks. There was no difference in the percentage of use of benzodiazepines by males and females. This study confirms that diazepam was the most common drug used in all age ranges. Finally, 6.1% of benzodiazepine users stated that they had attempted an overdose. PMID- 21263904 TI - Breast-cancer screening. AB - Consensus is still lacking on guidelines for breast-cancer screening with mammography: who should be screened, how frequently at what age, to what benefits and at what risks. American, Dutch, Swedish and Italian studies spanning the 1960s to the 1980s reveal a benefit from screening (reduced mortality from breast cancer) that occurs unambiguously only in women 50 years of age and over. Physicians who choose to screen mammographically their over-49-year-old female patients must do so with the awareness that to achieve screening benefits, highest-quality mammography equipment and technique are required. PMID- 21263906 TI - Recent advances in invasive cardiology. AB - This paper describes recent advances in invasive cardiology that enable the primary-care physician to offer his/her patient a wider range of effective treatments. Major developments in the investigation and management of the acute coronary syndromes, unstable angina and myocardial infarction, have revolutionized the care of patients with these conditions. The primary-care physician must be aware of the treatment modalities, the lines of referral, and strategies for management available in his/her clinical setting to allow prompt application of these modalities. A sampling of exciting advances in other areas of invasive cardiology are also described. PMID- 21263907 TI - Current management of congestive heart failure. AB - The author describes the pathophysiology of congestive heart failure and outlines treatment based on the mechanism and hemodynamics of heart failure. He discusses vasodilator therapy, ACE inhibitors in heart failure, and initiation of treatment. The paper concludes with a short discussion of methods of treating refractory heart failure. PMID- 21263909 TI - Arrhythmias: antiarrhythmic agents. AB - Arrhythmias and sudden cardiac death resulting from ventricular tachycardia/fibrillation are important public health issues of this decade. Complexities surrounding the subject, plus a relatively experimental and toxic therapeutic armamentarium with poorly defined end points, have largely limited the field to the specialized cardiologist. Recent studies, however, have served to identify those at risk as a result of their dysrhythmia,, and given the improved methods for detection and monitoring and a host of potent new antiarrhythmic drugs, interest in the area is certain to broaden. Inasmuch as initial presentation and follow-up often lie within the realm of the family physician or generalist, an understanding and update of this important subject is in order. PMID- 21263910 TI - New dimensions in pre-hospital cardiac care for your community. AB - Pre-hospitalization cardiac arrest carries a mortality rate of at least 96% unless advanced care is available. Although a paramedic system can provide a survival rate of up to 40%, the cost of maintaining such a system cannot be sustained by smaller communities. Recently, however, EMT-defibrillators particularly the new generation of defibrillators-have been able to provide a survival rate of up to 20% of cardiac arrest patients. The defibrillators are practical even for small communities. PMID- 21263908 TI - Post-myocardial infarction risk stratification. AB - Increased morbidity and mortality after a myocardial infarct are related to residual myocardial ischemia, ventricular dysrhythmias, and left ventricular dysfunction. Clinical assessment of the survivor of an acute myocardial infarct, together with non-invasive assessment involving a combination of symptom-limited low-level treadmill stress testing, ambulatory electrocardiography and radionuclide studies of selected patients, allows stratification of patients into low-risk, intermediate-risk and high-risk sub-groups. This process results in the tailoring of further investigation and treatment to the individual patient and avoids unnecessary interventions and therapies in the low-risk population. PMID- 21263911 TI - Holter monitoring. AB - Twenty-four hour electrocardiographic (Holter) monitoring has been adopted in primary care for the assessment of patients with suspected cardiac arrhythmias. This article examines the clinical use of the Holter monitoring technique, outlines the range of arrhythmias recorded in healthy adults, and evaluates the merit of the investigation in a primary-care clinical setting. Holter monitoring is most valuable in assessing symptomatic patients with known coronary artery disease of in the postinfarction period. Although frequent and complex arrhythmias in such patients may be associated with sudden death, it is not yet known whether treatment decreases mortality. PMID- 21263912 TI - Treatment of morbidity with atypical chest pain. AB - The appropriate management of atypical chest pain requires an integration of medical and behavioural treatments. Unnecessary medicalization can increase morbidity. A sensitivity to the behavioural factors contributing to symptoms and disability may reduce both. The purpose of this paper is to provide physicians with a cognitive-behavioural perspective of the nature of morbidity and disability associated with chronic chest discomfort; some strategies for detecting heretofore unsuspected disability associated with chronic chest pain and related discomfort in patients with organic findings (both cardiac and non cardiac), as well those with no identifiable disease process or organic cause; and some simple behavioural and cognitive-behavioural therapeutic techniques for treating and preventing such problems. PMID- 21263913 TI - The heart and stroke foundation of ontario. AB - The Heart and Stroke Foundation of Ontario is a non-profit volunteer-driven organization that is active in supporting research and education programs with the ultimate goal of reducing death and disability from heart disease and stroke. The Foundation has over 65 chapters across the province, a full-time staff of 130, and over 70,000 volunteers involved in various programs and fund-raising activities. Several of the Foundation's programs offer direct assistance to family physicians and their patients. This review summarizes the major programs of the Foundation and specifies how they relate to the physicians of Ontario. PMID- 21263914 TI - Prophylaxis for infective endocarditis. AB - Although antibiotic prophylaxis for patients at risk for bacterial endocarditis has never been scientifcally tested, it is now an accepted practice in medicine. Patients at risk include all individuals with prosthetic valves, congenital or rheumatic heart disease, previous endocarditis, idiopathic hypertrophic subaortic stenosis (IHSS), and mitral valve prolapse with a holosytolic murmur. Dental, upper respiratory tract, genitourinary and gastrointestinal procedures associated with bacteremia are reviewed. New antibiotic regimens utilizing oral agents for shorter periods have recently been published and are outlined here. Patients at high risk of endocarditis (especially those with prosthetic valves) should continue to receive prophylactic antibiotics by the parenteral route. PMID- 21263915 TI - Selecting a calcium channel-blocking agent. AB - The three currently available channel-blocking agents, nifedipine (Adalat), diltiazem (Cardiazem), and verapamil (Isoptin), are all useful in treating a number of cardiovascular disorders, especially ischemic heart disease. Although they have a common mechanism of action, their cardiovascular effects and pharmacological properties differ considerably. Each drug, consequently, has specific clinical indications; these drugs are not easily interchangeable. Understanding their properties and effects allows the physician to choose the particular drug most suited to the patient's needs. PMID- 21263916 TI - Correspondence between Pharmacy and Medical Records in a Family Medical Centre. AB - The purpose of this study was to evaluate the completeness of medical records in documenting long-term medications prescribed by physicians at a family medical centre. Previous studies have found that medical records relating to prescribed medications are frequently incomplete. Pharmacy files and medical records of 101 patients with hypertension, chronic obstructive pulmonary disease, diabetes mellitus and/or asthma were reviewed for information on long-term medications. In only one-half the medical records had accurate information on drug name and dosage been recorded on the front sheet. Drug information was less likely to be recorded for patients taking more than one medication than for patients taking only one medication. The solution to the problem in this setting was to link the pharmacy records to the problem in this setting was to link the pharmacy records to the computerized patient-record system. Information on drug reactions and long term medications is updated on the patient's medical record each time a new or modified prescription is ordered. While this solution may not be appropriate for other family practices, the findings emphasize the need to update systematically long-term medication lists. PMID- 21263917 TI - Support for preventive public health programs. AB - THE AUTHOR REPORTS ON A TYPICAL PROBLEM WITHIN THE PUBLIC HEALTH FIELD: the public opposition, based on bias and on unscientific views, of measures that would promote general health. He cautions readers concerning the negative possibilities of slackness in practising public health measures and emphasizes the need for doctors to communicate, widely and on a scientific basis, the facts of good public health practice. PMID- 21263918 TI - Traditional medicine in India. PMID- 21263919 TI - Getting Ready for OCO '88. PMID- 21263920 TI - The home birth controversy. PMID- 21263921 TI - The family physician: gatekeeper to the health-care system. PMID- 21263922 TI - Le cancer du sein: le debat se pousuit. PMID- 21263923 TI - Environmental allergies: "a dramatic improvement". PMID- 21263924 TI - Environmental hypersensitivity: the thompson report. PMID- 21263926 TI - The house call: is it welcome? PMID- 21263925 TI - Urticaria and vasculitis: a vascular spectrum of disease. PMID- 21263927 TI - A mock medico-legal trial. PMID- 21263928 TI - Analysis of 275 planned and 10 unplanned home births. AB - The purpose of this study is to describe the outcome in one family practice of planned home births attended by a physician and an experienced birth assistant in a self-selected, but subsequently screened, population over an 11-year period. All but 26 primigravidas were screened out, as were multiple pregnancies and malpresentations. Study parameters included characteristics of the population and maternal and neonatal outcomes. Of 275 intended home confinements, nine were screened out for medical reasons before labour, five in very early labour, and three for failure to progress. Of the 273 who delivered at home, including 10 unplanned births, two were transferred to hospital for postpartum hemorrhage. One neonate was hospitalized for complications. The results of this study, as well as a review of the relevant literature, illustrate that, for a selected population, home birth is a reasonable alternative to hospital. PMID- 21263929 TI - Repairing skin lacerations: does sterile technique matter? AB - Patients with uncomplicated skin lacerations who attended a rural family-practice clinic were randomly assigned to have their cut repaired using either full sterile technique or a surgically-clean technique. No significant differences were found in the rate of healing or in the incidence of complications. It was concluded that full sterile technique is not needed to repair simple skin lacerations, and that to suture the lacerations using a surgically clean technique would save both time and money. PMID- 21263930 TI - Update on AIDS for the family physician. AB - Infection with Human Immunodeficiency Virus-I (HIV-I) results in a wide spectrum of clinical disease. Many patients remain clinically well, although they may be infectious to others. These patients may, however, suffer from the psychological effects of knowing they have been infected with the virus. Others may develop symptoms, and many develop fatal opportunistic infections and malignant disease. The primary-care physician must be able to educate, to alleviate fear and misunderstanding, and to provide optimal medical and palliative care. PMID- 21263931 TI - Post-infectious fatigue. AB - Post-infectious fatigue or post-infectious neuromyasthenia (PIN) is an illness characterized by persisting fatigue and disability after apparent acute infections. In most cases the illness is attributed to a chronic Epstein-Barr virus infection. Symptoms include weakness and fatigue in the absence of physical findings or significant laboratory abnormalities. These patients are frequently depressed and have considerable disability resulting in prolonged loss of time from work. The illness may be persistent or can be relapsing, but often lingers for two years or more. There is no effective therapy. Pin is probably caused by an acute infection occurring in patients who are psychologically susceptible. They require emotional support, reassurance and explanation. PMID- 21263932 TI - The infectious complications of blood transfusion. AB - Infection after blood transfusion has become a major area of concern over the past decade. With current donor-screening procedures and laboratory testing of all blood donations, the chance of developing a post-transfusion infection is remote. Concern about viral infections predominates, and non-A, non-B hepatitis remains the most common form of post-transfusion viral infection. Hbv infections are unusual: the development of AIDS after a blood transfusion has been markedly reduced with rigorous donor screening and laboratory testing. At the time of writing, over six million units of blood and blood products which have been screened and tested for anti-HIV have been given to Canadians without evidence of seroconversion. PMID- 21263933 TI - Tuberculosis in chronic care homes. AB - Caucasian Canadians are in the tertiary phase of a 300-year tuberculosis epidemic. In this phase, the pattern of disease over the age spectrum is low in the young and middle-aged groups and rises to four times this rate in the elderly. The concentration of the elderly in chronic care homes (CCHs) magnifies the tuberculosis problem by increasing case rates another four times above the rate of elderly persons living separately, and 20 times above the overall Canadian rate. In spite of effective drugs with cure rates of over 95%, tuberculosis in the institutionalized elderly continues at an alarming rate. The difficulty lies in case finding. The prevailing attitude is that tuberculosis is no longer a problem. Surveillance programs are rudimentary. Between 35% and 40% of active cases in CCHs are the result of primary infection, mimicking bacterial pneumonia clinically and radiographically. In this target group of high-incidence tuberculosis, surveillance of residents is necessary, and the diagnosis needs to be considered in antibiotic-unresponsive pneumonia and in fever of unknown origin. PMID- 21263934 TI - Single-dose therapy of infectious diseases. AB - Single-dose antimicrobial therapy has clear advantages over multiple-dose therapy. Long-acting penicillins have been used for many years in single doses for treatment of streptococcal pharyngitis and early syphilis. More recently, shorter-acting agents are used for non-invasive mucosal infections. In trichomonas vaginitis, for instance, a 2g single dose of metronidazole is approximately 92% effective and is considered the treatment of choice. Controversy still exists about the value of single-dose therapy in women who have bacterial cystitis. However, there is good evidence that 2 or 3 double-strength tablets of co-trimoxazole are very effective and safe in the treatment of uncomplicated cystitis in healthy women. PMID- 21263935 TI - Use of Antimicrobials during Pregnancy. AB - The use of any drug during pregnancy is complicated by concerns of adverse effects, not only on the pregnant woman, but also on the fetus. This paper provides an overview of the use of antimicrobials in pregnancy, based on current knowledge of fetal development and on available documented experience. The author also discusses the use of specific antimicrobial agents during pregnancy. PMID- 21263936 TI - The significance of pneumonia in the elderly. AB - Pneumonia used to be considered the old person's friend, and it is still a major factor in the life and death of many old people. Most articles dealing with pneumonia in the elderly concentrate on diagnostic problems and advances in treatment, invasive procedures and intensive care. Little consideration is given to the ethical issues involved in the prolongation of the life of a person whose quality of life may be exceedingly poor. Studies of pneumonia should more clearly identify patients who should be treated and, if possible, cured, and those to whom the infection comes as a friend indeed. PMID- 21263938 TI - Human salmonellosis and pet turtles. AB - Turtles have long been implicated as carriers of salmonella species, which can and do infect humans. This report reviews the British Columbia Provincial Laboratory's experience with turtle-associated salmonellosis from 1964 to 1985. The author identifies the salmonella serotypes that were most often associated with turtles during this period and discusses the impact that public-health measures may have had on human salmonellosis. PMID- 21263937 TI - Management of diarrhea in infants and children. AB - Diarrhea affecting infants and children is an important primary-care problem. Most winter infections are caused by rotavirus, but newer viral, bacterial and protozoan pathogens have been discovered. Fluid and electrolyte therapy is the mainstay of therapy. Antiemetic, antibiotic and antidiarrheal medications can usually be avoided. Commercial clear fluid products have been reformulated to allow effective rehydration and maintenance of hydration, thus avoiding hospitalization or use of intravenous therapy. Patients are quickly advanced to nutrient feedings using breast milk or formula. There is strong evidence that Canadian physicians should use these protocols which work as well in North America as in the countries of the developing world. PMID- 21263939 TI - Outbreak of e. Coli 0157:h7 hemorrhagic colitis in british columbia: results of two studies. AB - The enteric pathogen Escherichia coli serotype 0157:H7 has been shown to cause hemorrhagic colitis. In British Columbia, the number of cases of E. coli 0157:H7 reported during the summer months of June, July and August increased substantially from 1985 to 1986. That increase formed the basis of a number of studies. This article describes two such studies, both conducted in B.C. The first study attempted to find a common source of infection. The second study further examined, as possible sources of infection, specific dietary elements identified in the first. PMID- 21263940 TI - The war amputations of Canada: support, service and prevention. AB - The War Amputations of Canada has expanded its services to include civilian and child amputees, as well as war-disabled veterans. The War Amps programs are funded mainly by the Association's yearly Key Tag campaign, and include counselling, financial support, the provision of information on prosthetic devices, and preventive safety programs for children. The Association is looking to a time when there are no longer veterans to serve, and is preparing to meet the needs of the disabled population in general. PMID- 21263941 TI - Lunch clubs for the elderly in England: a study. AB - The nutritional status of the elderly is cause for concern in Canada. Persons aged 65 and over are particularly vulnerable to nutritional deficiencies. It is increasingly difficult for elderly persons, with their limited incomes and decreasing physical capacities, to satisfy a need for companionship at mealtimes and a desire for independence. This study analyses lunch clubs for the elderly in England. It is hoped that the results of the study will provide practical information for care providers who wish to improve the level of nutrition of the elderly in Canada through maximum use of the resources within the elderly community itself. PMID- 21263942 TI - Strategic planning with family physicians: a case study. AB - Family physicians at Sunnybrook Medical Centre were engaged in a strategic planning process to develop a practice philosophy, mission statement, short-term goals, and plan for future programming. Numerous issues were identified in relation to the need for planning, the successful involvement of family physicians in the planning process, and the traditional relationship between physicians and managers which, in the past, has inhibited productive collaboration. Strategies were developed to overcome potential obstacles in these areas, and suggestions are outlined for administrators wishing to involve physicians more fully in the planning process. PMID- 21263943 TI - Cranial sixth-nerve palsy and eosinophilia in an outbreak of Mycoplasma pneumonia. AB - The authors discuss a case in which three siblings presented with Mycoplasma pneumonia. All three had a typical rise in complement fixation antibody titres. However, the sibling with the highest titre also developed cranial sixth-nerve palsy; in addition, she was the only one of the three who did not have an eosinophilia. The authors review the symptomatology of Mycoplasma pneumonia and the involvement of the central nervous system. PMID- 21263944 TI - A Jury of One's Peers. PMID- 21263945 TI - More on 20th century disease. PMID- 21263946 TI - A Critical Look at HIV-Antibody Tests: 2. Benefits, Risks and Clinical Use. AB - Following their first article on HIV-antibody tests,(1) the authors, in this second article, on HIV-antibody testing focus on the benefits and risks that may result from use of the tests. The sequelae of testing, especially if the result is positive, often differ widely, depending on the person tested and on those around him/her. Significant social and psychiatric risks may outweigh any medical benefit of testing, especially for certain persons known to be at high risk of HIV infection. Accordingly, a detailed protocol is suggested for managing both patient requests and physician-perceived indications for HIV-antibody testing. The authors outline the preferred approach to obtaining informed consent, a prerequisite, in their opinion, for ordering the tests. PMID- 21263947 TI - Otitis media in "water babies". AB - To examine the clinical impression that the incidence of otitis media in infant swimmers ("water babies") is higher than that in non-swimmers, we reviewed the records and interviewed the parents of 186 children under the age of four and one half years seen in a suburban family practice. Sixty-five% (46/71) of swimmers as compared to 50% (58/115) of non-swimmers had been diagnosed as having at least one episode of otitis media. Although this difference was not statistically significant (p=0.055), this pilot study encouraged us to pursue further the possible association between otitis media and early-childhood swimming classes. PMID- 21263948 TI - Treating urinary-tract infections: which antibiotic? AB - Family physicians often start antibiotic treatment for urinary-tract infections (UTI) before they have a urine-culture report. Which is the most appropriate antibiotic to prescribe in this situation? The author of this study reviewed a random sample of charts in a rural Newfoundland clinic and analysed results of urine-culture and sensitivity reports. Certain conclusions were based on the infecting organisms' sensitivity to the various antibiotics and on the cost of the antibiotics. In particular, it would seem that ampicillin is of very limited value in treating urinary-tract infections, and the most appropriate antibiotic for treating a UTI when the culture result is not known is a trimethoprimsulfamethoxazole combination. PMID- 21263949 TI - Writing a medical article: guidelines for prospective authors. AB - This article provides prospective authors with guidelines on the writing of a scientific paper. PMID- 21263950 TI - Sore throat strategies: the debate continues. PMID- 21263951 TI - Neurofibromatosis. AB - Neurofibromatosis is a common disorder that is inherited in an autosomal dominant fashion. It is now known that this disease occurs in two major forms: von Recklinghausen neurofibromatosis (VRNF), which used to be called 'peripheral neurofibromatosis', typically presents with cafe-au-lait spots; and cutaneous neurofibromas. Many other manifestations of the disease are found, including skeletal deformities, central nervous-system tumours, hydrocephalus, and mental retardation or learning disabilities. The incidence of VRNF is 1/3000 live births, but 50% of patients represent new mutations. Bilateral acoustic neurofibromatosis (BANF) is less common than VRNF but is important because of the associated tumours on the 8th cranial nerve. The care of patients with either form of neurofibromatosis requires the skills of a physician who is aware of the potential complications and who is empathetic to the psychological stresses which accompany this disease. PMID- 21263952 TI - Vesiculo-bullous disorders of the neonate. AB - This is the first of three articles which outline the diagnoses to be considered when vesiculo-bullous lesions are identified in the neonate, children, and adults. This paper presents a brief sketch of blistering disorders which may occur during the first few weeks of life. Vesiculo-bullous lesions in the neonate may represent benign, infectious, genetic, or life-threatening disorders. Early recognition, appropriate diagnostic procedures, and specific therapeutic interventions can be vital in reducing potential morbidity and mortality. General guidelines for diagnostic procedures and therapeutic interventions are discussed, along with some of the newer etiologic and epidemiologic concepts. PMID- 21263953 TI - Overexposed: the skin and the sun. AB - Sunlight produces many changes on our skin. Some of these we appreciate as cosmetically important, and some we see as medically destructive. Changes such as the appearance of wrinkling and skin cancer can come from the long-term direct effects of solar radiation. The sun has indirect effects on the skin which are mediated by disease processes, medications, immune reactants, and biochemical abnormalities. Understanding the nature of sun, how it produces its changes, and the wide variety of these manifestations is an important part of medical practice. By understanding the nature of sunlight, we are able to protect ourselves from its effects and to treat our patients. PMID- 21263954 TI - Your patient and Basal cell carcinoma. AB - BCCS (basal cell carcinomas) are a frequently encountered skin cancer. Although they have a minimal metastatic risk, they can cause considerable local destruction. Appropriate management consists of surgical excision with a 4mm border for lesions less than 2cm in diameter and follow-up for recurrences and new primaries. Risk can be reduced through education about proper preventive measures and by checking sun-exposed areas in susceptible people. PMID- 21263955 TI - Lotions and potions: pearls of topical therapy. AB - Although an adequate training in pharmacology is given to all medical students, there remains a large area of therapeutics which is empirical. Over their years of practice, most physicians accumulate a collection of useful remedies which are known colloquially as 'pearls'. This paper, a successor to a similar paper on dermatologic bases published in this Journal eleven years ago, presents a collection of dermatological pearls that the author has found useful in his years of practice as a dermatologist. PMID- 21263956 TI - Urticarial reactions: vascular erythema, urticaria, vasculitis. AB - Vascular erythemas, including urticaria and vasculitis, represent diagnostic and therapeutic challenges. A careful systemic approach to history and physical examination should be followed by appropriate investigations to rule out systemic disease. Chronic urticaria patients should be physically tested to identify cholinergic, dermagraphic, and cold-induced responses. Food diaries and careful drug history may be important to identify exacerbating factors in chronic urticaria.A skin biopsy is necessary to diagnose vasculitis. Therapy of any underlying cause is supplemented with H1 antihistamines in urticaria patients, while vasculitis requires a different anti-inflammatory approach. PMID- 21263957 TI - Vasculitis. AB - The vasculitides are a large and diverse group of disorders, often confusing for the clinician in terms of diagnosis, investigation, and treatment. As most patients will have cutaneous lesions, it is useful for the physician to be aware of the dermatologic manifestations that may help in differentiating these diseases. This review covers both the common and not so common form of vasculitis, including both cutaneous and systemic disorders, an approach to investigation, and brief discussion of therapeutic approaches. PMID- 21263958 TI - Camouflage cosmetics in dermatologic therapy. AB - Psychological well-being is based on multiple factors, one of which is satisfaction with physical appearance. The use of cosmetics is helpful for many women, as has been shown in psychological studies and implied by market sales. People with obvious cutaneous defects (e.g., port-wine stains, pigmentary disorders) may suffer a range of distress reactions, including diminished self esteem. Specially designed camouflage cosmetics are an ideal adjunct to other therapies for successful treatment of such skin conditions. New products are appealing because they are readily available, safe, and inexpensive. To enjoy optimum use of these products, patients should be assessed and advised in a professional setting. The results are extremely gratifying for both patients and physicians. PMID- 21263960 TI - Cutaneous manifestations of internal malignant disease. AB - The skin can provide clues to the well-being of our patients. Some skin changes, such as hypertrichosis lanuginosa acquisita or erythema gyratum repens, are so specific that there is a virtual certainty of internal malignancy. Other changes, such as severe pruritus, are significant management problems in late-stage lymphoma and leukemia. Still others, such as herpes zoster in a cancer patient in remission, may be a marker for recurrent malignant disease. This review will discuss many of the skin changes associated with systemic cancer. PMID- 21263959 TI - Current treatment of psoriasis. AB - Psoriasis is a relatively common chronic dermatosis that is genetically determined and environmentally influenced. Because it is ideopathic, therapy is presently supportive, directed at optimal control, patient understanding, and prevention of recurrence. Because this multifactorial condition may involve skin and nails, musculoskeletal system, and psyche in various combinations and degrees, an organized co-operative team approach involving the patient, the family, and appropriately experienced health-care providers is most beneficial. Many topical and systemic medications, as well as physical therapeutic modalities, both established and innovative, are available for use sequentially or in various combinations to suite the individual and his/her particular psoriasis. This brief review will outline the better established dermatologic therapeutic principles and options currently available for this patient group. PMID- 21263961 TI - Insects and spiders: infestations and bites. AB - Despite successful eradication techniques and specific effective therapies, insect bites and infestations remain a source of great human misery. The current scabies pandemic shows no signs of abating. Bed bugs, which through the ages have been second only to the malarial mosquito as an insect vector of fatal infection, have now been implicated in the transmission of Hepatitis B and possibly African acquired immune deficiency syndrome (AIDS). The incidence of head- and pubic lice is on the rise, the latter paralleling, and often co-existing with, other sexually transmitted diseases. Black widow spiders are native to many populous areas in southern Canada, and the brown recluse spider's range now encompasses Canada, thanks to moving vans and central heating. PMID- 21263962 TI - Cervical caps or diaphragms: answering your patients' questions. AB - Cervical caps and diaphragms offer a plausible contraceptive alternative for some women. Selection of patients, advantages, disadvantages, and fitting techniques are discussed in order to help answer those difficult patient questions. PMID- 21263963 TI - Anniversary wishes. PMID- 21263964 TI - Procedures in family practice. PMID- 21263965 TI - "Dear doctor...". PMID- 21263966 TI - General practice in new zealand: the same, but different. PMID- 21263967 TI - Bouquets to CFP. PMID- 21263968 TI - Diltiazem after non-Q-Wave Infarction? PMID- 21263969 TI - Office-based research: the antidote to learned helplessness. PMID- 21263970 TI - The telephone: an overlooked technology for prevention in family medicine. AB - Annual influenza vaccination has long been recommended for the elderly population. Despite this recommendation, immunization rates have remained very low. This study measured the effects of two approaches to the provision of influenza immunization to the 65-years-and-over age group in a single family practice. The "drop-in" group (N=123) was informed of the availability of the vaccine at visits made during the vaccination period. The "phone" group (N=120) was notified of the availability of the vaccine by telephone and was invited to come in for the shot. An immunization rate of 50.8% for the "phone" group and 26.8% for the "drop-in" group was obtained (P=.0002). These results contrast strongly with the overall immunization rates of 5.9% and 9.5% obtained during the previous two years, when no active immunization policy was in place. The telephone approach was found to benefit the type of patient at greatest risk from influenza: the chronically ill and the aged. It is clear that having a defined immunization policy substantially improves the provision of influenza vaccination. The authors discuss the effectiveness and practicality of these approaches to the delivery of influenza vaccine and their applicability to other forms of prevention in family medicine. PMID- 21263971 TI - A Critical Look at HIV-Antibody Tests: 1. How Accurate Are They? AB - As the AIDS epidemic spreads, many patients are asking their primary-care physicians to perform AIDS (HIV-antibody) testing, and in some settings, clinical circumstances prompt physicians to consider ordering the test. As a result, thousands of HIV-antibody tests are being requested each month by Canadian family doctors, where none were available only two years ago. Yet particular characteristics of HIV infection make these tests very unlike most blood tests, since their use carries clear risks as well as benefits. The authors review these risks and benefits in two sequential articles. In this first paper, they review the quantitative aspects of test accuracy (validity). In a sequential paper, to be published in next month's issue, they will discuss the risks and benefits of performing the test in various clinical circumstances. PMID- 21263972 TI - An update on the rules for medical witnesses. AB - Every dog, they say, must have its day. When yours comes up in court as an "expert witness" you may be glad of some very practical advice. PMID- 21263973 TI - Current trends in the management of abdominal aortic aneurysms. AB - The treatment of abdominal aortic aneurysm has undergone dramatic changes over the last three decades. More sophisticated diagnostic techniques have allowed early elective repair to be carried out. Improvement has resulted in both morbidity and mortality rates. Investigations such as ultrasound, computerized tomographic scanning and arteriography allow easy confirmation of the diagnosis of aortic aneurysms and permit a better assessment of the extent prior to surgical intervention. Improvement in the pre-operative management, particularly in relation to cardiac, renal, and pulmonary disease, has led to greatly improved results. The most important change in surgical technique has been repair of the aneurysm rather than resection. Combined with better post-operative intensive care units, this development has contributed to the improved morbidity and mortality rates. Although the complication rate of elective repair is low, the major cause of death remains myocardial infarction. As a result of all these improvements, indication for repair of abdominal aortic aneurysms has been extended to patients over the age of 80. Following surgical repair, most patients can be expected to return to normal lifestyles and lifespans. PMID- 21263974 TI - Spinal manipulation for low-back pain: an office procedure. AB - In properly selected patients, spinal manipulation is an alternative to the standard conservative approach to low-back pain. In this paper, an approach to the patient with low-back pain emphasizes the importance of a thorough history, physical examination, and diagnosis prior to manipulation. In addition to listing indications and contraindications, the authors discuss the process of selecting patients for manipulation according to pain and range of motion. Two manipulative techniques which can be easily learned and performed in the office by the family physician are described. PMID- 21263975 TI - Joint aspiration: arthrocentesis. AB - Joint aspiration is an easily mastered procedure used to confirm or rule out joint sepsis and crystal-induced arthrosis. It is routinely performed with or without local anaesthetic, or with cooling spray. The time spent obtaining the fluid is short. The procedure is safe, requiring no hospitalization, except in the case of diagnosed sepsis. Arthrocentesis is a necessary procedure to prove beyond reasonable doubt that infection is not the cause of the arthritis. The family physician must be familiar with this procedure and obtain fluid for analysis, or refer when joint fluid cannot be readily aspirated. (Can Fam Physician 1987; 33:2057-2062.). PMID- 21263976 TI - [Not Available]. AB - Vasectomy is done by a family physician at the family planning clinic of le Centre Hospitalier de l'Universite Laval. The technique used combines an occlusion with metal clips and an excision of one to two centimetres of the vas deferens. The post-operative complications encountered with 304 vasectomies were hematomas (4%), infections of the scotal skin (1%), orchi-epididymitis (1%) and granulomas (1%). All these problems were treated on an out-patient basis, and no consultation with specialists was required. Of 151 patients who came back for a post-vasectomy semen examination, one had a test result showing motile spermatozoa. These figures are comparable to other results published. The family physician can easily incorporate this simple and safe procedure into his practice. PMID- 21263977 TI - First aid for acute sports injuries. AB - This article deals with management of acute sports injuries on the field or on the ice and in the dressing room or in the arena's first-aid room. Its most vital message is "Be prepared". A team approach and suitable ambulance and hospital back-up are mandatory. Individual management of a specific acute injury should be approached with a practice plan. Collars, splints, back board, doctor's bag, ambu bag, suture tray and emergency medications should be at hand. Care must be taken that no long-term harm befalls the player. The attending physician must be knowledgeable about preventive equipment and immediate institution of rehabilitation procedures, and must try to inform the coach or trainer and parent as to when the athlete can safely return to play. It is important that the athlete not return to play until he/she is 100% fit. PMID- 21263978 TI - Colposcopy. AB - Colposcopy was introduced to Canadian medical practice in the late 1960s and its use has only recently become widespread. Until the advent of colposcopy, most women with abnormal Pap smears had a cone biopsy of the cervix with all its attendant problems. The colposcope has completely changed the management of an abnormal Pap smear with respect to diagnosis and has had a remarkable influence on treatment. Cryosurgery and carbon dioxide laser surgery were introduced as out patient treatments for precursors of cervical cancer because by using colposcopy the physician is able to accurately diagnose cervical intraepithelial neoplasia. Colposcopy has also been an important tool in the detection, diagnosis, and treatment of human papillomavirus infections in men and women. PMID- 21263979 TI - The office assessment of common thyroid disorders by thyroid aspiration biopsy. AB - Fine-needle aspiration biopsy is a safe and cost-effective technique in the assessment of many thyroid disorders and, with practice, is within the capabilities of most practitioners. It is especially of value in the evaluation of nodular thyroid disease and can significantly reduce the need for thyroid surgery. Diffuse enlargement of the gland can also be evaluated by this method, and sero-negative chronic thyroiditis is frequently identified in goitrous subjects by this technique. PMID- 21263980 TI - Suprapubic bladder aspiration in neonates. AB - Suprapubic bladder aspiration in neonates is a simple, safe, and useful technique for collection of sterile urine. The procedure can be performed in the hospital or office. Neither sedation nor local anesthetic is required. Suprapubic bladder aspiration of urine is the preferred method of collecting urine for culture in septic neonates. The technique is also indicated to verify urinary tract infection in neonates. Suprapubic bladder aspiration is contraindicated in the presence of abdominal distension or an empty bladder. Carefully and properly performed, the risk of complications should be negligible, and the success rate in obtaining urine is 90%. PMID- 21263981 TI - Flexible sigmoidoscopy in a family practice. AB - This article constitutes a report on the use of the flexible sigmoidoscope in family-practice. My experience, coupled with supporting evidence, points out the benefits of flexible over rigid sigmoidoscopy. The flexible sigmoidoscope is easier to use, and the yield of pathology detected is certainly much higher with this instrument. PMID- 21263982 TI - Repair of an episiotomy. AB - Episiotomies are used to enlarge the birth canal. The author describes in detail the anatomy, indications, repair and after-care. He includes diagrams to illustrate the method of repair. PMID- 21263983 TI - Office treatment of hemorrhoids. AB - The author holds that the weight of evidence from experience with 20,000 patients indicates overwhelmingly that the office treatment of hemorrhoids by means of ligation and the cryosurgical technique described is the treatment of choice. He gives 10 reasons, most of which are to the benefit of the patient, but some of which also benefit the doctor. The cost saving amounts to millions of dollars, a factor that should be of interest to government and insurers. The author suggests that operative hospital hemorrhoidectomy should no longer be performed. PMID- 21263984 TI - Cosmetic facial surgery. AB - Canadians have committed themselves to a healthier lifestyle, and many are seeking to look as well as they feel. For patients with realistic expectations, modern techniques of cosmetic facial surgery can enhance appearance and be of psychological benefit. Today most procedures can be done under local anesthesia on an out-patient basis. Facial contour defects can be improved by means of procedures such as rhinoplasty, mentoplasty, otoplasty and malarplasty. Facial rejuvenation surgery to decrease the signs of aging includes the forehead lift, eyebrow and eyelid lift, rhytidectomy, liposuction and chemical peeling. Newer controversial trends in cosmetic facial surgery include collagen implantation and fat transfer for contour defects, and eyelid tattooing. PMID- 21263985 TI - Because It's There. PMID- 21263986 TI - A challenge to dr. Stewart. PMID- 21263987 TI - Environmental hypersensitivity: a personal history. PMID- 21263988 TI - Twentieth century disease. PMID- 21263989 TI - Three cheers for dr. Stewart. PMID- 21263990 TI - Growth-hormone therapy and creutzfeldt-jakob disease. PMID- 21263991 TI - Screening for dementia in family practice. AB - The Mini Mental State Examination (MMSE) was performed on 90% of patients over age 65 in a full-time teaching practice associated with the University of Western Ontario during a six-month study period. Before screening, dementia was documented clinically in 5.6% of the patients over age 65. The "iceberg phenomenon" did not occur: all patients with dementia identified by the MMSE had already been recognized by the physician; no new treatable problems were discovered. This study challenges the value of screening with this instrument, since it failed to identify one of the six patients in this practice with clinical dementia. PMID- 21263992 TI - Obstetric ultrasound in family practice: the effect of on-site ultrasound facilities. AB - At a time of controversy about the appropriate use of obstetric ultrasound, this study explores the effect of availability on ultrasound use. Using a historical cohort design with chart review, pregnancy ultrasound rates were compared between two teaching family-medical centres, one with on-site ultrasound facilities and one without. Pregnant patients at the centre with on-site facilities (n=23) were 2.2 times more likely (p<0.05) to have an ultrasound scan than patients (n=20) cared for at the centre without facilities. At both centres, patients who had one ultrasound scan stood a 50% chance of having another. The implications for family medicine training are discussed. PMID- 21263993 TI - Introducing a new drug into your practice. AB - Many consultations in family practice end with a prescription for medication. The average market life of a new drug is only five years. Keeping up to date on therapeutic advances is an essential CME activity. Family physicians usually hear about new drugs from the pharmaceutical representatives. Before one changes well established habits of practice it is necessary to evaluate non-commercial sources of data. A good understanding of the implications of clinical trials is required. The availability and accuracy of other sources of information are discussed. PMID- 21263994 TI - Social trends in prescribing mood-modifying drugs to women. AB - The author of this article looks at the accumulating research evidence which suggests that there has been inappropriate prescribing and overprescribing of mood-altering drugs to women. This, he holds, in large part reflects problems that are best approached from within the tradition and perspective of social medicine. Socio-health considerations illuminate the need for research in this field. PMID- 21263995 TI - Benzodiazepines: dependance et approche therapeutique pour un retrait graduel. AB - The extensive use of benzodiazepines in treating anxiety and insomnia makes clinicians ask themselves about the risk of addiction relating to these drugs.(1 3) Indeed, it is estimated that in Canada, the United-States, and Western Europe, between 10% and 20% of persons use tranquilizers or hypnotics (mostly benzodiazepines) during a one-year period. Of these persons 70% are 50 years of age or more. It has been noted that 15% of those persons have been using these drugs for more than 12 months.(4, 5) In 1980, Tyrer reported that 50% of the patients who receive a prescription for benzodiazepines renew that prescription without consulting their physician.(6) In this article, the authors briefly review the dependency, risk factors and clinical signs resulting from withdrawal of these drugs. They also define a rational therapeutic approach to discontinuing their use. PMID- 21263996 TI - Increasing the benefits of chemotherapy by ameliorating the adverse effects. AB - When cancer is first diagnosed in most patients, it is usually incurable. Chemotherapy can cause remissions, prolonged disease-free survival, and prolonged survival in general, but it is associated with considerable toxicity to the physical and mental well-being of the patient. The number of side-effects increases when multiple drug combinations are used. In addition, financial and social problems add to the stress of coping with a fatal disease. Therefore both patients and physicians have asked whether survival (sometimes for extra months) with added side-effects of chemotherapy is worthwhile. The "soft" index of quality of life has been measured by many investigators, and a variety of interventions have been found to alleviate some distress. PMID- 21263997 TI - The principles and practice of anticoagulant therapy. AB - The author describes the clinical rationale and pharmacology of current anticoagulant therapy. He goes on to discuss the intensity of therapy by means of oral anticoagulants, the means of monitoring this therapy, and the standardization of monitoring procedures. He also describes the indications for and best means of administering and monitoring heparin therapy, together with the major clinical indications for both heparin and oral anticoagulant therapy. PMID- 21263998 TI - Dysfunctional uterine bleeding. AB - Dysfunctional uterine bleeding (DUB) is defined as abnormal uterine bleeding that results from an ovarian endocrinopathy. It may be associated with ovulatory and anovulatory cycles. The diagnosis of DUB depends on a thorough history and physical examination to exclude organic disorders. In older women, endometrial biopsy should be done before starting therapy. The treatment depends on an understanding of the menstrual cycle. In less urgent cases, anovulatory cycles are managed using progesterone replacement, and ovulatory cycles respond well to non-steroidal anti-inflammatory drugs (NSAIDs). In urgent cases oral or intravenous estrogen is used, and emergency dilation and currettage are done if the hemorrhage fails to stop. PMID- 21263999 TI - Pharmacology of the lower urinary tract. AB - Recent advances in our understanding of the neurophysiology and neuropharmacology of the lower urinary tract have improved our ability to treat disorders of bladder and urethral function. Similarly, many classes of drugs used in treating various medical conditions can cause lower urinary-tract symptoms and dysfunction. Based on objective urodynamic evaluation, the clinician is able to sort out bladder and urethral abnormalities and scientifically choose appropriate pharmacologic regimes to treat these conditions. This article reviews lower urinary-tract physiology and provides the clinician with a rational, objective, neuro-pharmacologic approach to lower urinary-tract disorders. PMID- 21264000 TI - Uses and abuses of theophylline. AB - Theophylline remains a useful drug for obstructive lung disease. As time goes by, our concepts about why it is effective are changing. Its actions on respiratory muscle, myocardium, and pulmonary vasculature may some day overshadow its bronchodilating effect. In the meantime, it is a good bronchodilator but has so narrow a therapeutic window that great caution is needed in establishing a safe dose. PMID- 21264001 TI - New drugs for the treatment of hypertension: where do they fit? AB - In the past decade several new antihypertensives have been marketed. Some, like the new beta blockers, are related to pre-1977 drugs, while others, the angiotensin-converting enzyme inhibitors, alpha blockers, and calcium channel blockers, are entirely new classes. While the newer agents have definite advantages, the extent of these benefits must be weighed against their cost. Drug costs for a two-drug regimen of captopril and diltiazem are 25 times those of hydrochlorothiazide and propranolol. The new beta blockers seem to have modest overall advantages: angiotensin-converting enzyme inhibitors are useful for patients who cannot accept a diminution in exercise tolerance; calcium channel blockers are useful for elderly hypertensives who have a contraindication for thiazides. Hypertension is being increasingly better controlled, with a concomitant reduction in cardiovascular mortality. The challenge for the next decade will be to achieve reductions in atherosclerotic, as well as hypertensive, complications without interfering with the users' quality of life. In this paper the authors review the new drugs and indicate what groups of patients might be benefited by them. PMID- 21264002 TI - Vesiculo-bullous disorders in childhood. AB - This is the second of three articles outlining the diagnoses to be considered when vesiculo-bullous lesions are identified in the neonate, children, and adults. This paper deals with a number of blistering disorders which can arise throughout infancy and childhood. Both inherited and acquired diseases are considered, and general guidelines for diagnosis and management are discussed. PMID- 21264003 TI - The role of pharmacotherapy in the treatment of alcoholism. AB - Drug therapy has a secondary function in the management of patients with alcoholism. The benzodiazepines are the drugs of choice for treating alcohol withdrawal, especially initially, in a high-dose loading technique. The alcohol sensitizing drugs disulfiram and calcium carbimide may help your patients to maintain abstinence, but full medical assessment of the patient and knowledge of the adverse effects of these drugs is required prior to their use. The management of the disulfiram ethanol reaction is described. PMID- 21264004 TI - Issues in geriatric drug therapy. AB - The purpose of this paper is to review briefly how aging and common diseases of the elderly affect drug handling and to review adverse effects of drugs used in three common indications in the elderly. PMID- 21264005 TI - The Family Physician's Reference Sheet on Cancer Pain. AB - The author has prepared a quick reference sheet for use in clinical practice. She describes assessment of pain, and an approach to its management, using opiate and non-opiate analgesics. PMID- 21264006 TI - Reye's Syndrome. AB - The author defines and discusses Reye's syndrome and the hypotheses relating to its causes and associating its incidence with that of chickenpox and influenza A and B. The recent decline in the incidence of Reye's syndrome appears to be related to the reduced use of Aspirin in children and adolescents. Although evidence so far is circumstantial, North American P(a)ediatric Associations have indicated that Aspirin should not be used to control fever in children who have viral infections but especially in children suspected of having chickenpox or influenza A or B. PMID- 21264007 TI - Male pattern baldness and its management: an update. AB - Androgenetic alopecia (AGA) sometimes referred to as 'male pattern baldness' (MPB) may affect up to 50% of males between the ages of 30 and 50 years. The authors of this article review the medical and surgical approaches currently available to treat AGA. Medications, such as topical minoxidil, which are currently being marketed as a treatment for AGA, as well as other drugs currently under investigation are examined. Recent advances in punch hair transplantation, alopecia reductions, and flap surgery are also discussed. PMID- 21264008 TI - Cardiotoxicity associated with an intentional overdose of maprotiline and perphenazine: a case report. AB - Cardiotoxicity is a life-threatening complication of an intentional overdose of cyclic antidepressant and phenothiazine drugs. This case report illustrates the severe conduction abnormalities that can accompany a massive ingestion of maprotiline and perphenazine. The patient's condition was further complicated by the unexpected finding of hypothermia. PMID- 21264009 TI - Management of arrhythmias. AB - Arrhythmias are a frequent presenting symptom requiring further investigation. Not all arrhythmias are of clinical significance, and many need not be treated. Symptomatic and frequently recurring paroxysmal atrial tachycardia, atrial fibrillation with rapid ventricular response, the changing arrhythmias of the tachycardia-bradycardia syndrome should be investigated, and most should be treated. Frequent symptomatic ventricular premature beats need occasionally be treated when they interfere with a patient's quality of life, and when they are associated with serious underlying cardiac disease. Complex and sustained ventricular arrhythmias should be treated following thorough investigation because of the risk of sudden cardiac death. The range of available therapeutic options, pharmaceutical and non-pharmaceutical, has become quite bewildering. Many new anti-arrhythmic drugs have been, and are being, developed; all still have potential pro-arrhythmic effects. New electrosurgical procedures are available, as well as new implantable anti-arrhythmic pacemakers and automatic defibrillators. PMID- 21264011 TI - Feverish activity. PMID- 21264010 TI - Adverse reactions to chloroquine and amodiaquine as used for malaria prophylaxis: a review of the literature. AB - This paper reviews the published material on adverse reactions to chloroquine (CQ) and amodiaquine (ADQ) as used for anti-malarial chemophrophylaxis. Dermatologic reactions, including pruritus and photosensitivity, appear to be rather common. Ophthalmologic reactions include difficulty in visual accommodation, corneal deposits, and retinopathy, the last a serious condition that is reversible in its early stage by drug withdrawal, and that generally will not occur with less than four years of weekly CQ use. Neuromyopathy is a rare and serious reaction that may develop idiosyncratically after a small cumulative dose; it, too, is reversible by drug withdrawal. Seizures, syndromes of involuntary movements, psychosis, and ototoxicity have been reported occasionally. Fatal toxic overdoses may occur, especially following accidental ingestion by children. ADQ should not be used for anti-malarial prophylaxis because of associated agranulocytosis. Rabies vaccine given intradermally is less effective for pre-exposure prophylaxis while the patient is taking CQ. Care should be taken when prescribing prophylactic CQ to patients with heart block. In spite of its adverse effects, however, CQ is generally an extremely safe drug. Cq prophylaxis is recommended for pregnant women in CQ-sensitive malarial areas. PMID- 21264012 TI - [Not Available]. PMID- 21264013 TI - [Not Available]. PMID- 21264014 TI - Controversy on low-back pain. PMID- 21264015 TI - Teenagers and pregnancy. PMID- 21264016 TI - [Not Available]. PMID- 21264017 TI - Realities seen in underserviced communities. PMID- 21264018 TI - Re: "Persons with AIDS". PMID- 21264019 TI - Apologies to dr. J.B. Ross. PMID- 21264020 TI - Childhood Fever: parental beliefs and management. AB - Childhood fever is often seen in family-practice. Clinical experience has shown the authors that parental anxiety often initiates early, aggressive treatment of fever with antipyretics. The authors studied parents' beliefs and practices relating to fever control in their children, and who or what their information sources were. The findings indicate that parents are commonly misinformed about the nature of childhood fever and its management, and that physicians need to learn more about conveying information on fever to patients. PMID- 21264021 TI - Satisfaction and wait time of patients visiting a family practice clinic. AB - Data relating to wait times and time spent with nurses and physicians were recorded for 656 patients visiting a large family-practice unit. Patients were asked to provide estimates of their wait times and ratings of the acceptability of these wait intervals. Actual wait times were usually longer than those estimated by the patient, and total wait times were considered reasonable. The results of the study show high levels of patient satisfaction and indicate that few patients are dissatisfied until total wait time exceeds forty-five minutes. Different age groups appear to have different expectations, however, and younger patients are more likely to be dissatisfied with their wait times. PMID- 21264022 TI - Abnormal eating attitudes: prevalance at a canadian university. AB - The authors conducted a survey of the prevalence of abnormal eating attitudes and behaviours among all women undergraduates living in on-campus residences at Queen's University and systematic samples of men and women undergraduates living in off-campus residences, using the Eating Attitudes Test-26 (EAT-26) as the study instrument. The results, although comparable to those of similar studies at other universities and colleges, are unusual in that they identify a group of high scoring respondents who did not return to Queen's University the year following the study.Of 1,982 students surveyed, 1,082 were women living in on campus residences, 450 were women living in off-campus accommodation and 450 were men also living off-campus. The off-campus groups were matched with the on-campus groups for program and year.The response rate was 50.6%. Of these respondents, 14.7% had scores of 20 or more on the EAT-26; scores typical of those reached by persons sufferering from eating disorders. Both groups of women had the same prevalence of high scorers (16.8%), while the prevalence of high scores in male students was 2.7%. Of 16 high scorers clinically interviewed, 13 (81.3%) fulfilled diagnostic criteria for eating disorders. PMID- 21264023 TI - FAMNET: The Use of an Electronic Mail System in Canadian Academic Family Medicine. AB - The major Canadian universities are connected via a computer communications network called 'Netnorth'. We have used Netnorth's accessible, low-cost, electronic mail system to develop a network of academic Family Medicine users (Famnet). We then tested Famnet's utility for conducting rapid surveys. Famnet shows promise of being a useful means of undertaking regular inter-departmental communication. This system may also increase collegiality among Canadian Departments of Family Medicine and facilitate international communication in family medicine. PMID- 21264024 TI - Incorporating the family into medical care. AB - The biomedical model provides an incomplete conceptual framework for the practice of family medicine. Whole-person medicine-the biopsychosocial model-and the integration of the family into medical care help to extend the conceptual framework of the family physician in a clinically useful way. This paper outlines methods of incorporating the family into medical care. PMID- 21264025 TI - A brief history of sports medicine in Canada: the last twenty years. AB - This brief presentation outlines the early beginnings of Sports Medicine in Canada, starting in the late 1960s. The parts played by the federal government, the Canadian Medical Association, and the Canadian Association of Health, Physical Education and Recreation are recognized. A few areas of interest are discussed as they pertain to this relatively new field of medicine in Canada. The wave of interest shown by health professionals and the public are constantly with us now as demonstrated with the advent of fitness clubs, exercise programs appearing daily on television, and constant reminders by the media that health is everyone's business. PMID- 21264026 TI - Exercise prescription for the healthy adult. AB - The exercise prescription manipulates the primary variables of training, frequency of exercise, intensity of exercise, time for each session, type of exercise, and rate of progression. The goal is for the patient to reach a satisfactory level of cardiovascular fitness by a prudent application of these factors. By this means, the goal of improved fitness can be met while minimizing the risk of an overuse injury and maximizing the enjoyment. PMID- 21264027 TI - Clinical biomechanics of skiing. AB - Abnormalities of lower-leg alignment may lead to a number of skiing problems. Tibia vara may cause difficulties in turning and riding a flat ski unless the boot cuff is properly adjusted to the lower leg. Varus deformities in the foot may lead to boot-fitting difficulties, foot and knee pain, and the inability to edge a ski turn properly. Compensation for these problems with an appropriately posted, corrective, orthotic device may allow skiing participation with greater comfort and better performance. PMID- 21264028 TI - Cardiovascular Screening before Exercise. AB - The cost of health care continues to rise as we deal with changes in the natural history of disease and deploy increasingly advanced medical technology for diagnosis and treatment. A different focus must be established if we are to control both disease and our health-care budget. One area of promise is preventive medicine. Improved fitness through exercise is one component in this approach, and increasing numbers of the general public are choosing this positive lifestyle change. Patients are seeking the advice and blessing of the primary care physician before engaging in physical activity. In order to prescribe safe exercise, physicians must be able to screen individuals for possible contraindications and to evaluate their current fitness levels. This article describes a comprehensive cardiovascular system screen, including history, physical, lab work, and fitness appraisal, and reviews the current recommendations for treadmill stress testing. PMID- 21264029 TI - Hockey injuries. AB - Hockey, Canada's national sport, is probably the world's fastest team sport. The nature of the game makes injuries a common occurence. This article reviews the literature on hockey injuries and identifies some of the changing trends over the past 15 years. Severity and incidence of injuries increase with the age and skill level of the player. There are fewer lacerations, eye injuries, and head injuries since helmets and facial protectors have become mandatory in minor hockey. However, there has been an increase in spinal cord injuries. Physicians who provide medical coverage for older adolescent and adult competitive elite hockey players should be proficient at assessment and acute care of patients with life threatening injuries. PMID- 21264031 TI - Pre-season tennis conditioning. AB - The author discusses common sports injuries associated with tennis, outlines a recommended year-round fitness program for tennis players, and describes specific exercises, equipment, and footwear that will reduce the occurrence of tennis related injuries. PMID- 21264030 TI - Sports injuries in the emergency department: controversies and management guidelines. AB - Sport-related injury is a common problem seen in the emergency department of Canadian hospitals. The mechanism of injury is essential information in making an accurate diagnosis. The motivation of the athlete is an important factor in arranging appropriate follow-up and counselling for return to activity. This article addresses diagnostic and management considerations for shoulder injury, acute knee injury, concussion, compartment syndrome, and stress fracture. PMID- 21264032 TI - Sports medicine: does the family physician need to acquire new knowledge and skills? AB - The knowledge and skills required to be competent in practising sports medicine can be defined and are discussed. Musculoskeletal injuries are the most common type of sports-related trauma, and their management requires diagnosis, acute treatment, and rehabilitation. Many other areas of management are involved, particularly exercise, with all its ramifications in children, adults, and the chronically sick. Use and abuse of drugs must be discussed with the athlete so that errors of legitimate use will not be made, and harmful effects can be explained. Family physicians in Canada receive variable training at both undergraduate and residency levels, but it probably forms a good foundation for amplification. PMID- 21264033 TI - Management of the swollen knee. AB - The primary-care physician plays a critical role in the diagnosis, initial treatment, and subsequent rehabilitation of many orthopedic conditions. The knee is the most frequently injured joint in sport medicine. The family physician must therefore be familiar with the etiology, cause, and natural history of problems related to the knee joint. The swollen knee is one of the most common ailments the family physician is asked to assess in his or her busy day-to-day practice of medicine. He or she must therefore remain abreast of the dynamic field of diagnostic procedures, treatments, and rehabilitative measures relating to many knee injuries. This paper deals with the more common causes of the acutely swollen knee, paying particular attention to the infected knee and the acute hemarthrosis. It should provide answers to most questions about diagnosis, initial treatment, and subsequent management of this problem. PMID- 21264034 TI - Selected cutaneous disorders in athletes. AB - The author discusses selected cutaneous diseases seen in the athlete. These diseases may be caused by interaction with the elements, the playing surface, other athletes, or the clothing or equipment worn during sport. All of these dermatological conditions are relatively common, but the physically active individual can suffer from these maladies and their complications more often than the inactive person. The emphasis in caring for the participant is on prevention, early recognition and practical aspects of management of cutaneous diseases. PMID- 21264035 TI - Warm-Up Techniques and their Place in Patient Education. AB - Warm-up has been poorly studied scientifically, but there is a growing body of evidence to suggest that if properly executed, it benefits the exerciser both psychologically and physically. The family practitioner should be familiar with the principles and phases of warm-up in order to instruct athletic patients properly, with the purpose of preventing musculoskeletal injury. PMID- 21264037 TI - Meeting of the canadian society of medical bioethics. PMID- 21264036 TI - The top, the oxen, and the sun: Western medicine and eastern thought. PMID- 21264038 TI - Epizooic metazoan meiobenthos associated with tubeworm and mussel aggregations from cold seeps of the northern Gulf of Mexico. AB - The abundance and higher taxonomic composition of epizooic metazoan meiobenthic communities associated with mussel and tubeworm aggregations of hydrocarbon seeps at Green Canyon, Atwater Valley, and Alaminos Canyon in depths between 1400 and 2800 m were studied and compared to the infaunal community of non-seep sediments nearby. Epizooic meiofaunal abundances of associated meiobenthos living in tubeworm bushes and mussel beds at seeps were extremely low (usually <100 ind. 10 cm(-2)), similar to epizooic meiofauna at deep-sea hydrothermal vents, and the communities were composed primarily of nematodes, copepods, ostracods, and halacarids. In contrast, epizooic meiobenthic abundance is lower than previous studies have reported for infauna from seep sediments. Interestingly, non-seep sediments contained higher abundances and higher taxonomic diversity than epizooic seep communities, although in situ primary production is restricted to seeps. PMID- 21264039 TI - Cracking Cancer with CRK. PMID- 21264040 TI - Deletion of 25-hydroxyvitamin d-24- hydroxylase gene restores normal skeletal growth in hyp mice. PMID- 21264041 TI - Visual orienting among persons with autism spectrum disorders. PMID- 21264042 TI - Space medicine in Canada. PMID- 21264043 TI - The potential implementation of radio-frequency identification technology for personal health examination and monitoring. AB - This paper presents several possible applications of the radio-frequency identification (RFID) technology for personal health examination and monitoring. One application involves using RFID sensors external to the human body, while another one uses both internal and external RFID sensors. Another application involves simultaneous assessment and monitoring of many patients in a hospital setting using networks of RFID sensors. All the assessment and monitoring are done wirelessly, either continuously or periodically in any interval, in which the sensors collect information on human parts such as the lungs or heart and transmit this information to a router, PC or PDA device connected to the internet, from which patient's condition can be diagnosed and viewed by authorized medical professionals in remote locations. Instantaneous information allows medical professionals to intervene properly and in a timely fashion to prevent possible catastrophic effects to patients. The continuously assessed and monitored information provides medical professionals with more complete and long term studies of patients. The proposed ideas promise to result in not only enhancement of the health treatment quality but also in significant reduction of medical expenditure. PMID- 21264044 TI - Postpartum haemorrhage in the developing world a review of clinical management strategies. AB - The developing world is disproportionately burdened with high rates of maternal mortality. Despite widespread reduction in maternal deaths due to improved antepartum, intrapartum, and postpartum care in developed nations, mortality rates are persistently high in many countries unable to provide advanced medical care. Postpartum haemorrhage accounts for a substantial proportion of maternal deaths in developing countries. This review addresses the clinical management strategies aimed at the prevention and treatment of postpartum haemorrhage that are effective in lowresource settings. The review was conducted by searching the English-language medical literature using MEDlINE (1950 - Feb 2009) and the online search engine Google Scholar. Four relevant strategies were identified in the literature: active management of the third stage of labour (AMSTl), the use of uterotonic agents including misoprostol, accurate measurement of blood loss, and internal and external compression techniques. Despite known intervention options, additional research on effective management strategies and their implementation is needed to address postpartum haemorrhage in countries of the developing world. PMID- 21264045 TI - Editorial. PMID- 21264046 TI - Disseminated Coccidioidomycosis with Clinically Evident Splenomegaly in an Immunocompetent Host, First Case Reported in the literature. AB - Coccidioidomycosis is a dimorphic fungus endemic to the southwestern United States, Central and South America. We report a case of a previously healthy person who presented with respiratory failure and disseminated Coccidioidomycosis who eventually had a fatal outcome. Coccidioidomycosis, or "Valley Fever" has been called the "great imitator" (1) as it can have a wide variety of clinical presentations. This case is unique as it represents the first described case of an immunocompetent host with rapidly progressing, disseminated coccidioidomycosis with clinically apparent splenomegaly and hepatomegaly. PMID- 21264048 TI - Emotional intelligence: use in medical education and practice. PMID- 21264049 TI - The importance of remaining empathic. PMID- 21264047 TI - Pancreatic beta-Cell Mass as a Pharmacologic Target in Diabetes. AB - While the prevalence of maternal While the prevalence of diabetes mellitus reaches epidemic proportions, most available treatments still focus on the symptoms of the disease, rather than the underlying pathology. Types 1 and 2 diabetes have in common a deficit in beta-cell mass. In type 1 diabetes, auto immune beta-cell destruction leads to an absolute deficit in beta-cells, while in type 2 diabetes, insulin resistance and beta-cell dysfunction cause a functional deficit. More recently, however, it has been suggested that type 2 diabetes is also marked by an absolute deficit in beta-cell mass, although a causal relationship has not yet been established. Overall beta-cell mass reflects the balance between the dynamic processes of beta-cell expansion, through proliferation and neogenesis, and beta-cell loss via apoptosis. Given that beta cell mass can be modified significantly by altering the rate of any of these mechanisms, therapies that modulate beta-cell expansion and loss have garnered recent interest. We review herein the current therapeutics under investigation as modulators of beta-cell mass dynamics, and the basic research that supports these novel therapeutic targets. PMID- 21264051 TI - Would Worldwide Vaccination of Both Males and Females Against the Human Papillomavirus be a Worthy Investment? PMID- 21264050 TI - Autism, emotion recognition and the mirror neuron system: the case of music. AB - Understanding emotions is fundamental to our ability to navigate and thrive in a complex world of human social interaction. Individuals with Autism Spectrum Disorders (ASD) are known to experience difficulties with the communication and understanding of emotion, such as the nonverbal expression of emotion and the interpretation of emotions of others from facial expressions and body language. These deficits often lead to loneliness and isolation from peers, and social withdrawal from the environment in general. In the case of music however, there is evidence to suggest that individuals with ASD do not have difficulties recognizing simple emotions. In addition, individuals with ASD have been found to show normal and even superior abilities with specific aspects of music processing, and often show strong preferences towards music. It is possible these varying abilities with different types of expressive communication may be related to a neural system referred to as the mirror neuron system (MNS), which has been proposed as deficient in individuals with autism. Music's power to stimulate emotions and intensify our social experiences might activate the MNS in individuals with ASD, and thus provide a neural foundation for music as an effective therapeutic tool. In this review, we present literature on the ontogeny of emotion processing in typical development and in individuals with ASD, with a focus on the case of music. PMID- 21264052 TI - Transported to a world of emotion. PMID- 21264053 TI - Sensory Characteristics in ASD. AB - In this paper, we review evidence regarding differences in the types of sensory experiences of persons with ASD with respect to both unisensory and multisensory processing. We discuss selfreports, carer questionnaires as well as perceptual processing differences found in the laboratory. Incoming information is processed through one or more of our senses and fundamental differences in the processing of information from any sensory modality or combination of sensory modalities are likely to have cascading effects on the way individuals with ASD experience the world around them, effects that can have both positive and negative impact on a individual with ASD's quality of life. PMID- 21264054 TI - Consequences of Atrial or Ventricular Tachypacing on the Heat Shock Proteins (HSP) level of Expression and Phosphorylation. AB - BACKGROUND: Uncontrolled atrial fibrillation (AF) results in complex changes in the cardiomyocyte electrical and contractile functioning that promote atrial remodeling and the continuation of AF. Recently there has been a growing interest in understanding the role of heat shock proteins (HSPs), which are cytoprotective molecular chaperones, in the pathophysiology of AF. Several groups have examined HSP expression in patients with AF but have yielded mixed results. To allow for better consistency and reproducibility between subjects, we utilized canine models to reproduce AFpromoting conditions to better investigate the role of HSPs in the pathophysiology of AF. METHODS: AF promoting conditions were simulated in canine models with fifteen adult mongrel dogs (20.6 to 36.0 kg) divided into three groups: (1) Control (n=5), (2) two week ventricular tachypacing (VTP) induced congestive heart failure (CHF) (n=5), and (3) one week atrial tachypacying (ATP) (n=5). Quick frozen right atrial free wall tissue samples were used for protein isolation and were analyzed via Western blotting with data was expressed as a relative ratio and were analyzed using a two-tailed, unpaired ttest and significance was set at p < 0.05. The expression levels of HSP 90, 70, and 25 were studied along with the phosphorylation status of HSP27 at serine-78. RESULTS: We first examined the effects of the ATP and CHF heart models on the expression of a select group of HSPs via Western Blot. We found that there was no significant difference in levels of expression of HSP 90, 70, or 25 when either ATP or CHF models were compared to control canines. The phosphorylation status of HSP27 was significantly decreased in the CHF canine model when compared to control (p < 0.0111) and it tended towards a decrease in the ATP canine model when compared to control (p=0.0923). CONCLUSION: This study showed that even though the expression levels of HSPs may remain constant, there are protein phosphorylation and dephosphorylation events that occur in AF that may have important consequences in its pathophysiology. It is therefore necessary to investigate the full scale of HSP modifications during AF and AF-promoting conditions. PMID- 21264055 TI - Structural basement membrane components and corresponding integrins in Schlemm's canal endothelia. AB - PURPOSE: The conventional outflow pathway provides the primary source of resistance to aqueous humor drainage, regulating intraocular pressure. Despite large pressure gradients across the inner wall of Schlemm's canal (SC), cells remain attached to their basement membrane. The goal of this study was to examine integrin-extracellular matrix binding partners of the inner wall basement membrane that facilitate attachment. METHODS: Human outflow tissues and cultured cells were analyzed by immunofluorescence and western blotting, respectively. Radial sections of human donor eyes or en face preparations of human SC inner wall were probed with antibodies that specifically recognize collagens (Type I, III, and IV), laminins (LM-332 and LM-511) and laminin-specific integrin subunits, alpha3, alpha6, beta1, and beta4, typical of vascular endothelia. RESULTS: Immunofluorescence studies showed collagens Type I and IV in the SC basement membrane but not collagen III. As expected with mature vascular endothelia, SC cells in situ expressed LM-511 but not LM-332. Significantly, the integrin alpha6 subunit was expressed uniquely by SC. En face labeling of the inner wall displayed integrin alpha6 colocalizing with LM alpha5 at the cell periphery. Western blots of cultured human SC endothelial cell monolayers confirmed expression of Type I collagen, collagen IV, LM-511, and the alpha6 integrin subunit. Interestingly, LM-332 was present in cultured SC cells up to 60 days post-confluence. CONCLUSIONS: Even though cells of the inner wall endure pressure gradients in the basal to apical direction, opposite of other endothelia, human SC cells express basement membrane proteins and their cognate integrins typical of vascular endothelia. PMID- 21264057 TI - Behavior of a train of droplets in a fluidic network with hydrodynamic traps. AB - The behavior of a droplet train in a microfluidic network with hydrodynamic traps in which the hydrodynamic resistive properties of the network are varied is investigated. The flow resistance of the network and the individual droplets guide the movement of droplets in the network. In general, the flow behavior transitions from the droplets being immobilized in the hydrodynamic traps at low flow rates to breaking up and squeezing of the droplets at higher flow rates. A state diagram characterizing these dynamics is presented. A simple hydrodynamic circuit model that treats droplets as fluidic resistors is discussed, which predicts the experimentally observed flow rates for droplet trapping in the network. This study should enable the rational design of microfuidic devices for passive storage of nanoliter-scale drops. PMID- 21264058 TI - Passive optical separation and enrichment of cells by size difference. AB - A size-selective cell sorting microfluidic device that utilizes optical force is developed. The device consists of a three-dimensional polydimethylsiloxane microstructure comprised of two crossed microchannels in a three-dimensional configuration. A line shaped focused laser beam is used for automatic size selective cell sorting in a continuous flow environment. As yeast cells in an aqueous medium are fed continuously into a lower channel, the line shaped focused laser beam is applied (perpendicular to the direction of flow) at the junction of the two crossed channels. The scattering force of the laser beam was employed to push cells matching specific criteria upward from one channel to another. The force depends on the size of the cells, the laser power, and the fluid flow speed. The variation in size of yeast cells causes them to follow different routes at the intersection. For flow speeds below 30 MUm/s, all yeast cells larger than 3 MUm were removed from the main stream. As a result, a high purity sample of small cells can be collected at the outlet of bottom channel. PMID- 21264056 TI - Maternal microbe-specific modulation of inflammatory response in extremely low gestational-age newborns. AB - The fetal response to intrauterine inflammatory stimuli appears to contribute to the onset of preterm labor as well as fetal injury, especially affecting newborns of extremely low gestational age. To investigate the role of placental colonization by specific groups of microorganisms in the development of inflammatory responses present at birth, we analyzed 25 protein biomarkers in dry blood spots obtained from 527 newborns delivered by Caesarean section in the 23rd to 27th gestation weeks. Bacteria were detected in placentas and characterized by culture techniques. Odds ratios for having protein concentrations in the top quartile for gestation age for individual and groups of microorganisms were calculated. Mixed bacterial vaginosis (BV) organisms were associated with a proinflammatory pattern similar to those of infectious facultative anaerobes. Prevotella and Gardnerella species, anaerobic streptococci, peptostreptococci, and genital mycoplasmas each appeared to be associated with a different pattern of elevated blood levels of inflammation-related proteins. Lactobacillus was associated with low odds of an inflammatory response. This study provides evidence that microorganisms colonizing the placenta provoke distinctive newborn inflammatory responses and that Lactobacillus may suppress these responses. PMID- 21264059 TI - Whole blood pumping with a microthrottle pump. AB - We have previously reported that microthrottle pumps (MTPs) display the capacity to pump solid phase suspensions such as polystyrene beads which prove challenging to most microfluidic pumps. In this paper we report employing a linear microthrottle pump (LMTP) to pump whole, undiluted, anticoagulated, human venous blood at 200 MUl min(-1) with minimal erythrocyte lysis and no observed pump blockage. LMTPs are particularly well suited to particle suspension transport by virtue of their relatively unimpeded internal flow-path. Micropumping of whole blood represents a rigorous real-world test of cell suspension transport given blood's high cell content by volume and erythrocytes' relative fragility. A modification of the standard Drabkin method and its validation to spectrophotometrically quantify low levels of erythrocyte lysis by hemoglobin release is also reported. Erythrocyte lysis rates resulting from transport via LMTP are determined to be below one cell in 500 at a pumping rate of 102 MUl min( 1). PMID- 21264060 TI - Multiscale fabrication of a transparent circulation type blood vessel simulator. AB - We proposed and fabricated multiscale transparent arteriole and capillary vessel models with circular cross sections of 10-500 MUm using photolithography. The circularities of the fabricated 10, 50, and 500 MUm diameter microchannels were 84.0%, 61.5%, and 82.3%, respectively. Next, we connected these different models to realize a circulation type blood vessel model simulating arteriole networks. We proposed a novel connection method using an intermediate connector made of wax, which we used to connect these models to make a circulation model. In flow experiments, the fabricated models showed no leakage and circulation models with seamless connections were achieved. PMID- 21264061 TI - Simple surface modification of poly(dimethylsiloxane) for DNA hybridization. AB - Here, we present a simple chemical modification of poly(dimethylsiloxane) (PDMS) by curing a mixture of 2 wt% undecylenic acid (UDA) in PDMS prepolymer on a gold coated glass slide. This gold slide had been previously pretreated with a self assembled hydrophilic monolayer of 3-mercaptopropionic acid (MPA). During curing of the UDA/PDMS prepolymer, the hydrophilic UDA carboxyl moieties diffuses toward the hydrophilic MPA carboxyl moieties on the gold surface. This diffusion of the UDA within the PDMS prepolymer to the surface is a direct result of surface energy minimization. Once completely cured, the PDMS is peeled off the gold substrate, thereby exposing the interfacial carboxyl groups. These groups are then available for subsequent attachment of 5(')-amino terminated DNA oligonucleotides via amide linkages. Our results show that the covalently tethered oligonucleotides can successfully capture fluorescein-labeled complementary oligonucleotides via hybridization, which are visualized using fluorescence microscopy. PMID- 21264062 TI - Rapid acquisition of Gigapascal-high-pressure resistance by Escherichia coli. AB - Pressure and temperature are important environmental variables that influence living systems. However, while they vary over a considerable range on Earth and other planets, it has hardly been addressed how straightforwardly and to what extent cellular life can acquire resistance to extremes of these parameters within a defined genomic context and a limited number of generations. Nevertheless, this is a very pertinent question with respect to the penetration of life in allegedly inhospitable environments. In this study, directed evolution was used to reveal the potential of the nonsporulating and mesophilic model bacterium Escherichia coli to develop the ability to survive exposure to high temperature or pressure. While heat resistance could only marginally be increased, our data show that piezoresistance could readily and reproducibly be extended into the GPa range, thereby greatly exceeding the currently recognized maximum for growth or survival. PMID- 21264063 TI - Impact of pneumococcal conjugate vaccination of infants on pneumonia and influenza hospitalization and mortality in all age groups in the United States. AB - A seven-valent pneumococcal conjugate vaccine (PCV7) introduced in the United States in 2000 has been shown to reduce invasive pneumococcal disease (IPD) in both vaccinated children and adults through induction of herd immunity. We assessed the impact of infant immunization on pneumococcal pneumonia hospitalizations and mortality in all age groups using Health Care Utilization Project State Inpatient Databases (SID) for 1996 to 2006 from 10 states; SID contain 100% samples of ICD9-coded hospitalization data for the selected states. Compared to a 1996-1997 through 1998-1999 baseline, by the 2005-2006 season, both IPD and pneumococcal pneumonia hospitalizations and deaths had decreased substantially in all age groups, including a 47% (95% confidence interval [CI], 38 to 54%) reduction in nonbacteremic pneumococcal pneumonia (ICD9 code 481 with no codes indicating IPD) in infants <2 years old and a 54% reduction (CI, 53 to 56%) in adults >=65 years of age. A model developed to calculate the total burden of pneumococcal pneumonia prevented by infant PCV7 vaccination in the United States from 2000 to 2006 estimated a reduction of 788,838 (CI, 695,406 to 875,476) hospitalizations for pneumococcal pneumonia. Ninety percent of the reduction in model-attributed pneumococcal pneumonia hospitalizations occurred through herd immunity among adults 18 years old and older; similar proportions were found in pneumococcal disease mortality prevented by the vaccine. In the first seasons after PCV introduction, when there were substantial state differences in coverage among <5-year-olds, states with greater coverage had significantly fewer influenza-associated pneumonia hospitalizations among children, suggesting that PCV7 use also reduces influenza-attributable pneumonia hospitalizations. PMID- 21264064 TI - Small RNAs in the genus Clostridium. AB - The genus Clostridium includes major human pathogens and species important to cellulose degradation, the carbon cycle, and biotechnology. Small RNAs (sRNAs) are emerging as crucial regulatory molecules in all organisms, but they have not been investigated in clostridia. Research on sRNAs in clostridia is hindered by the absence of a systematic method to identify sRNA candidates, thus delegating clostridial sRNA research to a hit-and-miss process. Thus, we wanted to develop a method to identify potential sRNAs in the Clostridium genus to open up the field of sRNA research in clostridia. Using comparative genomics analyses combined with predictions of rho-independent terminators and promoters, we predicted sRNAs in 21 clostridial genomes: Clostridium acetobutylicum, C. beijerinckii, C. botulinum (eight strains), C. cellulolyticum, C. difficile, C. kluyveri (two strains), C. novyi, C. perfringens (three strains), C. phytofermentans, C. tetani, and C. thermocellum. Although more than one-third of predicted sRNAs have Shine-Dalgarno (SD) sequences, only one-sixth have a start codon downstream of SD sequences; thus, most of the predicted sRNAs are noncoding RNAs. Quantitative reverse transcription-PCR (Q-RT-PCR) and Northern analysis were employed to test the presence of a randomly chosen set of sRNAs in C. acetobutylicum and several C. botulinum strains, leading to the confirmation of a large fraction of the tested sRNAs. We identified a conserved, novel sRNA which, together with the downstream gene coding for an ATP-binding cassette (ABC) transporter gene, responds to the antibiotic clindamycin. The number of predicted sRNAs correlated with the physiological function of the species (high for pathogens, low for cellulolytic, and intermediate for solventogenic), but not with 16S rRNA-based phylogeny. PMID- 21264065 TI - The VirS/VirR two-component system regulates the anaerobic cytotoxicity, intestinal pathogenicity, and enterotoxemic lethality of Clostridium perfringens type C isolate CN3685. AB - Clostridium perfringens vegetative cells cause both histotoxic infections (e.g., gas gangrene) and diseases originating in the intestines (e.g., hemorrhagic necrotizing enteritis or lethal enterotoxemia). Despite their medical and veterinary importance, the molecular pathogenicity of C. perfringens vegetative cells causing diseases of intestinal origin remains poorly understood. However, C. perfringens beta toxin (CPB) was recently shown to be important when vegetative cells of C. perfringens type C strain CN3685 induce hemorrhagic necrotizing enteritis and lethal enterotoxemia. Additionally, the VirS/VirR two component regulatory system was found to control CPB production by CN3685 vegetative cells during aerobic infection of cultured enterocyte-like Caco-2 cells. Using an isogenic virR null mutant, the current study now reports that the VirS/VirR system also regulates CN3685 cytotoxicity during infection of Caco-2 cells under anaerobic conditions, as found in the intestines. More importantly, the virR mutant lost the ability to cause hemorrhagic necrotic enteritis in rabbit small intestinal loops. Western blot analyses demonstrated that the VirS/VirR system mediates necrotizing enteritis, at least in part, by controlling in vivo CPB production. In addition, vegetative cells of the isogenic virR null mutant were, relative to wild-type vegetative cells, strongly attenuated in their lethality in a mouse enterotoxemia model. Collectively, these results identify the first regulator of in vivo pathogenicity for C. perfringens vegetative cells causing disease originating in the complex intestinal environment. Since VirS/VirR also mediates histotoxic infections, this two-component regulatory system now assumes a global role in regulating a spectrum of infections caused by C. perfringens vegetative cells. PMID- 21264066 TI - Drugs in pregnancy: Implications for a cardiologist. AB - The safe use of drugs during pregnancy depends on several factors including the time of application, the type of drug and its dose. In the present review, the effect of certain therapeutic drugs on pregnancy is first described using general principles, followed by a more focused discussion on the type of adverse effects related to specific cardiovascular drugs used during pregnancy. In particular, adverse events related to the use of antihypertensive and antiarrhythmic drugs and anticoagulants are described, followed by the characterization of congenital cardiovascular defects resulting from the use of various drugs during pregnancy. Finally, various methods used to obtain information on the topic are described, and the need for carefully designed clinical trials is stressed. PMID- 21264067 TI - Could early ischemic arrhythmia triggered by purinergic activation of the transient receptor potential channels be prevented by creatine? AB - Despite its degradation by ectonucleotidases, a low ATP concentration is present in the interstitial space; moreover, its level can markedly increase during various physiopathological conditions. ATP and uridine 5'-triphosphate (UTP) releases correlate with the occurrence of ventricular premature beats and ventricular tachycardia. ATP facilitates several voltage-dependent ionic currents including the L-type Ca(2+) current. More recently, ATP and UTP were also shown to induce a poor voltage-dependent, long-lasting current carried by the heterotetrameric transient receptor potential (TRP) channels TRPC3/7. ATP effects result from its binding to metabotropic P2Y2 receptors that lead to diacylglycerol formation and activation of phospholipase Cbeta and inositol-1,4,5 triphosphate production. ATP also favours TRPM4 activation by increasing Ca(2+) release from the sarcoplasmic reticulum. Indeed, TRPM4 current properties match those of the Ca(2+)-activated, nonselective cationic current supporting the delayed afterdepolarizations observed under conditions of Ca(2+) overload. In the present article, it was hypothesized that creatine, at a relatively high concentration, would serve as a buffer for the sudden release of ATP and UTP during the early phase of ischemia in association with previously described arrhythmic events. The potential preventive effect of creatine was tested by analyzing its ability to antagonize the arrhythmia that occurred on inducing a coronary ligature in rats that were or were not preinjected with creatine. Electrocardiogram recordings of creatine-injected rats clearly demonstrated that both ventricular premature beats and, particularly, ventricular tachycardia markedly decreased. The effect of creatine was even more striking in early deaths. However, an injection of beta-guanidinopropionate, a creatine analogue with 1000-fold lower kinetics, had no significant protective effect. PMID- 21264068 TI - Enhanced L-type calcium currents in cardiomyocytes from transgenic rats overexpressing SERCA2a. AB - BACKGROUND: Previous research reported that transgenic rats overexpressing the sarco(endo)plasmic reticulum Ca(2+)-ATPase SERCA2a exhibit improved contractile function of the myocardium. Furthermore, impaired Ca(2+) uptake and reduced relaxation rates in rats with diabetic cardiomyopathy were partially rescued by transgenic expression of SERCA2a in the heart. OBJECTIVE: To explore whether enhanced Ca(2+) cycling in the cardiomyocytes of SERCA2a transgenic rats is associated with changes in L-type Ca(2+) (I(Ca-L)) currents. METHODS: The patch clamp technique was used to measure whole-cell currents in cardiomyocytes from transgenic rats overexpressing SERCA2a and from wild-type (nontransgenic) animals. RESULTS: The amplitudes of I(Ca-L) currents at depolarizing pulses ranging from -45 mV to 0 mV (350 ms duration, 1 Hz) were significantly higher in cardiomyocytes of SERCA2a transgenic rats than in nontransgenic rats (1985+/-48 pA [n=32] versus 1612+/-55 pA [n=28], respectively). The inactivation kinetics of I(Ca-L) showed subtle differences with increased tau fast and tau slow decay constants in cardiomyocytes of SERCA2a transgenic animals. Beta-adrenergic stimulation with 50 nM isoproterenol reduced tau fast and tau slow decay constants in cardiomyocytes of transgenic rats to values that were not significantly different from those in normal cardiomyocytes. Furthermore, isoproterenol enhanced I(Ca-L) currents 3.2-fold and 2.3-fold in cardiomyocytes with and without the SERCA2a transgene, respectively, and this effect was abolished by buffering intracellular Ca(2+) with BAPTA. CONCLUSIONS: These findings indicate that enhanced Ca(2+) cycling in the hearts of SERCA2a transgenic rats, both under normal conditions and during beta-adrenergic stimulation, involves changes in I(Ca-L) currents. Modified I(Ca-L) kinetics may contribute, to some extent, to the improved contractile function of the myocardium of transgenic rats. PMID- 21264070 TI - Telomere biology in cardiovascular disease - role of insulin sensitivity in diabetic hearts. AB - The present study examined telomere biology in the context of insulin sensitivity in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type 2 diabetic animal model. To improve insulin sensitivity, pioglitazone (PG; 10 mg/kg/day) was administered to OLETF rats between 20 weeks and 40 weeks of age, and the effects of the treatment were compared with those in untreated OLETF rats or control Long Evans Tokushima Otsuka rats. The homeostasis model assessment of insulin resistance index significantly increased in OLETF rats, but decreased in PG treated OLETF rats. Telomere lengths were not shortened in heart tissues of OLETF rats; however, telomerase activity was decreased in heart tissues of OLETF rats. Messenger RNA expression for both telomerase reverse transcriptase and telomere repeat binding factor 2 was downregulated in the hearts of OLETF rats. Protein expression of phosphorylated Akt, insulin-like growth factor and endothelial nitric oxide synthase were all reduced in OLETF rats. The changes observed in OLETF rats were inhibited by PG treatment. Myocardial fibrosis was less extensive and diastolic dysfunction improved in PG-treated OLETF rats versus untreated OLETF rats. These findings suggest that improving insulin sensitivity via the activation of peroxisome proliferator-activated receptor-gamma may exert regulatory effects on cardiac telomere biology, and may have desirable morphological and functional effects on the diabetic heart. PMID- 21264069 TI - Impaired oxidative phosphorylation in overtrained rat myocardium. AB - The present study was undertaken to characterize and review the changes in energy metabolism in rat myocardium in response to chronic exhaustive exercise. It was shown that a treadmill exercise program applied for six weeks led the rats into a state characterized by decreased performance, loss of body weight and enhanced muscle catabolism, indicating development of overtraining syndrome. Electron microscopy revealed disintegration of the cardiomyocyte structure, cellular swelling and appearance of peroxisomes. Respirometric assessment of mitochondria in saponin-permeabilized cells in situ revealed a decreased rate of oxidative phosphorylation (OXPHOS) due to diminished control over it by ADP and impaired functional coupling of adenylate kinase to OXPHOS. In parallel, reduced tissue content of cytochrome c was observed, which could limit the maximal rate of OXPHOS. The results are discussed with respect to relationships between the volume of work and corresponding energy metabolism. It is concluded that overtraining syndrome is not restricted to skeletal muscle but can affect cardiac muscle as well. PMID- 21264071 TI - Hormetic response of resveratrol against cardioprotection. AB - Resveratrol, a grape- and red wine-derived polyphenolic phytoalexin, shows diverse health benefits including cardioprotection. Recent studies implicate that resveratrol displays hormetic action, protecting the cells at a lower dose while killing them at relatively higher doses. Because such hormetic behaviour may have a significant impact on epidemiological and clinical studies, the present study sought to determine dose-response curves for resveratrol action. In parallel, another resveratrol formulation was tested, namely, Longevinex (Resveratrol Partners LLC, USA). A group of rats were force-fed three different doses of resveratrol or Longevinex (2.5 mg/kg, 25 mg/kg and 100 mg/kg) for up to 30 days, while the control group was only given placebo. The results showed hormesis for pure resveratrol, which was cardioprotective at lower doses and detrimental for higher doses, but surprisingly Longevinex did not display any hormetic action. In the concentration range studied, Longevinex remained cardioprotective even at 100 mg/100 g body weight - a dose that killed 100% of the hearts when tested with pure resveratrol. To further test whether Longevinex doses are beneficial for other animal species, Longevinex was gavaged to a group of rabbits for six months, and showed exactly the same degree of cardioprotection. Cardioprotection was examined in isolated working hearts subjected to 30 min of ischemia followed by 2 h of reperfusion; left ventricular performance and infarct size was also examined. It appears that Longevinex does not show any hormetic action, while resveratrol clearly does. PMID- 21264072 TI - Augmented cell cycle protein expression and kinase activity in atherosclerotic rabbit vessels. AB - Cell proliferation within a primary atherosclerotic plaque is controversial. Identifying changes in cell cycle protein expression and the activities of their related kinases would provide valuable evidence of mitotic activity in the atherosclerotic lesion. Oxidized low-density lipoprotein has been shown to induce a significant increase in the total number of rabbit vascular smooth muscle cells in culture. In the present study, whole aortic cell extracts were harvested from rabbits fed a cholesterol-supplemented diet for eight weeks to induce modest plaque development, or 16 weeks to induce later, more severe plaque progression. Expression levels of cyclin A, cyclin-dependent kinase 4 (Cdk 4) and proliferating cell nuclear antigen were measured, as well as the activities of Cdk 4, Cdk 2 and Cdk 1. At both time points, the expression levels of cyclin A, Cdk 4 and proliferating cell nuclear antigen were significantly elevated. The activity of all three Cdks was also increased. There were no significant differences between moderate and more severe atherosclerosis. Surprisingly, tissues that neighboured the plaques, but did not show visible plaque formation on the vessel surface, also had significantly elevated cyclin A expression levels, but not as high as in the plaque areas. In conclusion, the primary atherosclerotic plaque exhibited elevated mitotic activity as shown by increased expression levels and activities of several cell cycle proteins. Expression levels were similar during moderate and severe atherosclerosis, and were even detected in nonatherosclerotic vascular tissue bordering the plaque. PMID- 21264073 TI - Vascular smooth muscle cell motility: From migration to invasion. AB - Over the past decade, extensive research has focused on identifying the molecular mechanisms and signal transduction pathways involved in the modulation of vascular smooth muscle cell phenotypes. In the present review, the characteristics of vascular smooth muscle cell (VSMC) phenotypes as they relate to cell migration are discussed based on insights from recent molecular findings. A central theme is the mechanisms involved in nonpathogenic VSMC migration during tissue repair versus VSMC invasion that leads to the development of vascular diseases. The issue of how various factors that are released locally following tissue injury influence cell migration will also be addressed. PMID- 21264074 TI - Mechanisms of the beneficial effects of beta-adrenoceptor antagonists in congestive heart failure. AB - Many clinical studies have documented favourable effects (reduced morbidity and mortality) of beta-adrenoceptor (beta-AR) antagonists, such as carvedilol, metoprolol, propranolol, atenolol and bisoprolol, in congestive heart failure. These agents attenuate the effects of sympathetic activation during the development of heart failure, prevent ventricular remodelling and improve cardiac function. Because beta-AR blockers are known to exert negative inotropic action, the mechanisms responsible for their beneficial effects in heart failure have been a subject of debate. While attenuation of changes in beta-AR cyclic AMP mediated signal transduction in heart failure is considered to be responsible for the beneficial effects of beta-AR antagonists, other mechanisms such as the effects of these agents on subcellular remodelling, oxidative stress, apoptosis and defect in calcium handling, are equally important in preventing cardiac alterations in the failing heart. Moreover, beta-AR antagonists are not a homogeneous group of drugs because they differ in their pharmacokinetics and pharmacodynamics, in addition to the selective and nonselective nature of their actions on beta-AR. Various beta-AR blocking agents have been shown to possess different ancillary properties and produce effects that are independent of beta AR. In fact, different beta-AR antagonists have been observed to lower the elevated levels of plasma catecholamines in heart failure. Thus, the beneficial effects of beta-AR antagonists are not only elicited through their interaction with mediated beta-AR signal transduction sites in the myocardium, but other mechanisms may also contribute to their favourable actions in heart failure. PMID- 21264075 TI - Hypokalemia and sudden cardiac death. AB - Worldwide, approximately three million people suffer sudden cardiac death annually. These deaths often emerge from a complex interplay of substrates and triggers. Disturbed potassium homeostasis among heart cells is an example of such a trigger. Thus, hypokalemia and, also, more transient reductions in plasma potassium concentration are of importance. Hypokalemia is present in 7% to 17% of patients with cardiovascular disease. Furthermore, up to 20% of hospitalized patients and up to 40% of patients on diuretics suffer from hypokalemia. Importantly, inadequate management of hypokalemia was found in 24% of hospitalized patients. Hypokalemia is associated with increased risk of arrhythmia in patients with cardiovascular disease, as well as increased all cause mortality, cardiovascular mortality and heart failure mortality by up to 10 fold. Long-term potassium homeostasis depends on renal potassium excretion. However, skeletal muscles play an important role in short-term potassium homeostasis, primarily because skeletal muscles contain the largest single pool of potassium in the body. Moreover, due to the large number of Na(+)/K(+) pumps and K(+) channels, the skeletal muscles possess a huge capacity for potassium exchange. In cardiovascular patients, hypokalemia is often caused by nonpotassium sparing diuretics, insufficient potassium intake and a shift of potassium into stores by increased potassium uptake stimulated by catecholamines, beta adrenoceptor agonists and insulin. Interestingly, drugs with a proven significant positive effect on mortality and morbidity rates in heart failure patients all increase plasma potassium concentration. Thus, it may prove beneficial to pay more attention to hypokalemia and to maintain plasma potassium levels in the upper normal range. The more at risk of fatal arrhythmia and sudden cardiac death a patient is, the more attention should be given to the potassium homeostasis. PMID- 21264076 TI - Decisions, directions, defects and fellow disciples (A ruckblick of 50 years of basic medical research). PMID- 21264078 TI - How appropriate is the gold standard for diagnosis of airway obstruction? PMID- 21264077 TI - Subcellular mechanisms of adaptation in the diabetic myocardium: Relevance to ischemic preconditioning in the nondiseased heart. AB - Although hyperglycemia is one factor that determines the outcome of myocardial ischemic insult, it is still not clear whether it is causally related to decreased ischemic tolerance in diabetic patients. In contrast to clinical and epidemiological studies demonstrating a higher risk of cardiovascular disorders in diabetic patients, experimental data are not unequivocal and suggest that, aside from higher myocardial vulnerability, diabetes mellitus may be associated with the triggering of adaptive processes leading to paradoxically lower susceptibility to ischemia. It has been proposed that this phenomenon shares some molecular pathways with short-term preconditioning and other forms of endogenous protection against ischemia/reperfusion injury in the nondiseased heart. The present article reviews some controversial findings of enhanced resistance to ischemia in the diabetic heart that stem from experimental studies in different models of myocardial ischemia/reperfusion injury. Specifically, it addresses the issue of potential mechanisms of increased resistance to ischemia in an experimental model of streptozotocin-induced diabetes, particularly with respect to the role of reactive oxygen species, hyperglycemia as one of the stress factors, and cell-signalling mechanisms mediated by 'prosurvival' cascades of protein kinases in relation to the mechanisms of classical ischemic preconditioning. Finally, mechanisms involved in the suppression of protection in the diabetic myocardium including the effect of concomitant pathology, such as hypercholesterolemia, are discussed. PMID- 21264079 TI - A follow up study on revised national tuberculosis control programme (rntcp): results from a single centre study. AB - OBJECTIVE: To know the follow up status of tuberculosis patients after 1 year of completion of treatment in RNTCP. MATERIALS #ENTITYSTARTX00026; METHODS: Those patients of tuberculosis, who were registered from June 2003 to June 2004 at DOTS centre of our institution, were followed up at their homes after one year of completion of treatment between August 2005 and August 2006, with the help of health visitor. Patients were followed up clinically and symptomatic patients were also followed radiologically as well as bacteriologicalty. Results of the study were recorded in terms of number of patients remained asymptomatic, number of patients relapsed and number of patients died. RESULTS: Out of 237 patients registered, 8 patients died during treatment period, 12 patients defaulted the treatment, the number of failures was 5 and 212 patients were declared cured/treatment completed. Out of these 212 patients 60 were unavailable for interview due to various reasons. The study observed that out of a total of 152 patients interviewed, 137 patients (90.1%) of remained asymptomatic, 11 patients (7.2%) had relapsed and 4 patients (2.6%) died during follow up. CONCLUSION: The study observed that majority of patients (90.1%) re-mained asymptomatic after the completion of one year of treatment under DOTS. PMID- 21264080 TI - A study of correlation between transhilar diameter and p pulmonale in copd patients. AB - BACKGROUND: Early diagnosis and therapy of Pulmonary hypertension in COPD patients may help in retardation of progression and amelioration of symptoms. This is an attempt to diagnose the disease from X-ray chest of COPD patients, so that invasive investigations can be avoided. OBJECTIVES: (1) Measurement of transhilar diameter in Chest X-ray PA view of COPD patients and its importance in detection of pulmonary hyper-tension. (2) To study correlation between P pulmonale and transhilar diameter / hilar thoracic ratio. DESIGN: Prospective Clinical study. SETTING: Institute of Chest Diseases, Medical College, Calicut. PERIOD OF STUDY: One year from September 2002 to August 2003. MATERIALS AND METHODS: 100 patients admitted to Institute of Chest Diseases with COPD and ECG evidence of P pulmonale and/or RVH were included. Chest X-rays was taken and the following diameters were measured. Transhilar diameter, hilar thoracic ratio, width of descending branch of (Rt) pulmonary artery and cardiothoracic ratio. CONCLUSIONS: Chest X-ray can be used for identification of pulmonary hypertension in COPD patients. Positive correlation was seen between P pulmonale and hilar thoracic ratio. Positive correlation was also seen between P pulmonale and other parameters like smoking status, symptom duration, ECG evidence of RVH and negative correlation was seen with % predicted FEV(1). PMID- 21264081 TI - Tumoral tissue specific promoter hypermethylation of distinct tumor suppressor genes in a case with nonsmall cell lung carcinoma: a case report. AB - OBJECTIVE: Non-small cell lung carcinoma is an aggressive phenomenon and the epigenetical alterations of some tumor supressor genes have been reported for the different tumor types. CASE PRESENTATION: It is presented a case report concerning a 43 years old male with NSCLC on the lower segment of the right lung. The patient underwent a diag-nostic excisional thin-needle biopsy and after the histological confirmation. We examined the promoter methylation status of some distinct tumor supressor genes in tumoral and blood tissues of the case after sodium bisulfite conversion and DNA amplification with methylation specific multiplex PCR technique. Both tissues were also searched for G to A transitions in codons 12 and 13 of the K-ras proto-oncogene. RESULTS: Tumor specimen showed fully methyl pattern profiles for the SFRP2, p16, DAPK1 and partially hyper methylated profile for the p53 and MGMT genes in this case with non-small lung carci-noma. Blood speicemen showed normal hypomethylated profiles for all studied TS genes. The K-ras proto-oncogene was in normal structure both in blood and tumoral spiecemens that examined. CONCLUSION: Results indicate that genes exhibit tumor suppressor activi-ties in blood, but exhibit epigenetic inactivation in carcinoma cell. These findings strongly support the hypothesis that epigenetic mechanisms may play an important role in the non-small cell lung carcinogenesis in human. PMID- 21264082 TI - Broncholithiasis. AB - A 47 year old female who had past history of incomplete treatment for pulmonary tuberculosis presented with increased breathlessness, generalized swelling and loss of ap-petite for last one month. X-ray chest PA view showed bilateral fibrocalcific opacities with blunting of costophrenic angle on both sides. She underwent bronchoscopy to collect bronchial wash to rule out relapse of tuberculosis. On bronchoscopy a loose broncholith with sharp and speculated margins were detected in right middle lobe bronchus. This broncholith was successfully removed through flexible bronchoscope without any complications. PMID- 21264083 TI - Endogenous excess cortisol production and diabetes mellitus as predisposing factors for pulmonary cryptococcosis: a case report and literature review. AB - Pulmonary cryptococcosis usually occurs as an opportunistic infection in immunocompromised patients. Endogenous Cushing's syndrome is associated with cortisol excess and can predispose to development of cryptococcal infections. We report a case of diabetic patient with ACTH secreting pituitary tumour who developed a cavitating lung mass. Computed tomography-guided biopsy of the lesion revealed mucicarminophilic budding forms of cryptococcus. Broncheoalveolar lavage culture grew Cryptococcus neoformans. There was radiological response to treatment with liposomal Amphotericin, but patient ultimately succumbed to septicemia and multiorgan failure. Opportunistic infections with organisms like Cryptococcus neoformans, should be considered in patients with endogenous Cushing's syndrome and a pulmonary infiltrate. PMID- 21264084 TI - Allergic bronchopulmonary aspergillosis with Aspergillus sinusitis-'9' year old boy. AB - A case of Broncho Pulmonary Aspergillosis with Aspergillus Sinusitis was diagnosed in a nine year old boy after clinical and immunological investigations. He responded well after treatment with steroid and itraconazol. PMID- 21264085 TI - A rare case of pleural lymphoma. AB - We present a case report of a 20 years old male who had low grade fever, weight loss of about 10 kg and left-sided chest pain increasing in intensity over a year. Clinically, it mimicked left sided pleural effusion with a tender, soft, parietal swelling in left in-fraaxillary area. Chest x-ray and Computerized Tomography-scan of thorax showed pleura based mass in left hemi thorax. Computerized Tomography guided Fine Needle Aspiration Cytology confirmed the diagnosis of non Hodgkin Lymphoma, diffuse large B cell type, high-grade. PMID- 21264086 TI - Isolated tonsil tuberculosis. AB - The occurrence of tuberculosis of the upper respiratory tract including oral cavity has become uncommon. Isolated tuberculosis of tonsil in the absence of active pulmonary tuberculosis is very rare clinical entity. Here is a report of tonsil tuberculosis, presented with complaints of sore throat. PMID- 21264087 TI - Pulmonary candidiasis presenting as mycetoma. AB - Candida is a saprophytic yeast that is frequently recovered from the respiratory tract. Most mycetoma lesions are due to Aspergillus species growing inside an existing cavity. The saprophytic nature of the Candida species in the human respiratory tract obscures diagnosis of Candida pulmonary infections. Only a few cases of mycetoma due to Can-dida have been reported. We report a case of mycetoma caused by Candida albicans in a diabetic immunocompromised tuberculous patient. Diagnosis was confirmed by biopsy and certain points strongly favoured the diagnosis. The patient was immunocompromised due to uncontrolled diabetes mellitus. Candida albicans was grown from bronchial and repeatedly from sputum samples and Candida antigen was positive from blood in high titre. There was a good clinical as well as radiological response to antifungal therapy and Candida antigen became negative. We emphasize that in the immunosuppressed host, a mycetoma-like lesion may be caused by Candida pulmonary infection. PMID- 21264088 TI - A young lady presented with limited pulmonary Wegener's granulomatosis. AB - A 19 year old female college student presented with fever, dry cough, chest pain, blood tinged sputum with subsequent development of polyarthralgia with radiological evidence of bilateral multiple unevenly distributed pulmonary nodular opacities with cavitation. There was no other systemic involvement and the patient was cytoplasmic antineutrophil antibody (c-ANCA) positive with more than four times the normal upper limit of anti PR3 antibody. Excellent response to oral steroid with antimicrobial agent "trimethoprim - sulphamethoxazole" was noted. PMID- 21264089 TI - Mesothelioma v/s adenocarcinoma of lung do serum markers help? PMID- 21264090 TI - Uncovering negative results: introducing an open access journal "journal of pharmaceutical negative results". PMID- 21264091 TI - Development of a floating dosage form of ranitidine hydrochloride by statistical optimization technique. AB - The objective of this study was to evaluate the effect of formulation variables on the release properties, floating lag time, and hardness, when developing floating tablets of Ranitidine hydrochloride, by the statistical optimization technique. The formulations were prepared based on 3(2) factorial design, with polymer ratio (HPMC 100 KM: Xanthan gum) and the amount of aerosil, as two independent formulation variables. The four dependent (response) variables considered were: percentage of drug release at the first hour, T(50%) (time taken to release 50% of the drug), floating lag time, and hardness of the tablet. The release profile data was subjected to a curve fitting analysis, to describe the release mechanism of the drug from the floating tablet. An increase in drug release was observed with an increase in the polymer ratio, and as the amount of aerosil increased, the hardness of the tablet also increased, without causing any change in the floating lag time. The desirability function was used to optimize the response variables, each having a different target, and the observed responses were in accordance with the experimental values. The results demonstrate the feasibility of the model in the development of floating tablets containing Ranitidine hydrochloride. PMID- 21264092 TI - Floating drug delivery of nevirapine as a gastroretentive system. AB - A multiple-unit floating drug delivery system based on gas formation technique was developed, in order to prolong the gastric residence time and to increase the overall bioavailability of the dosage form. The floating bead formulations were prepared by dispersing nevirapine together with calcium carbonate in a mixture of sodium alginate and hydroxypropyl methylcellulose solution and then dripping the dispersion into an acidified solution of calcium chloride. Calcium alginate beads were formed, as the alginate underwent ionotropic gelation by calcium ions, and carbon dioxide developed from the reaction of carbonate salts with acid. The obtained beads were able to float due to CO(2)-gas formation and the gas entrapment by the polymeric membrane. The prepared beads were evaluated for percent drug loading, drug entrapment efficiency, morphology, surface topography, buoyancy, in-vitro release, and release kinetics. The formulations were optimized for different weight ratios of the gas-forming agent and sodium alginate. The beads containing higher amounts of calcium carbonate demonstrated an instantaneous, complete, and excellent floating ability over a period of 24 hours. The increased amount of the gas forming agent did not affect the time to float, but increased the drug release from the floating beads, while increasing the coating level of the gas-entrapped membrane, increased the time to float, and slightly retarded the drug release. Good floating properties and sustained drug release were achieved. Finally, these floating beads seemed to be a promising gastroretentive drug delivery system. PMID- 21264093 TI - Preparation and Evaluation of Nano-vesicles of Brimonidine Tartrate as an Ocular Drug Delivery System. AB - The objective of the present investigation was to design a vesicular formulation of brimonidine tartrate and evaluate its ability to reduce the dosing frequency and improve the therapeutic efficacy of the drug. Nano-vesicles of brimonidine tartrate were prepared by film hydration method. The prepared vesicles were evaluated for photomicroscopic characteristics, entrapment efficiency, in vitro, and ex-in vitro drug release and in vivo intraocular pressure (IOP) lowering activity. The methods employed for preparation of vesicles produced nano vesicles of acceptable shape and size. The in vitro, and ex-in vitro drug release studies showed that there was slow and prolonged release of the drug, which followed zero order kinetics. The IOP-lowering activity of nano vesicles was determined and compared with that of pure drug solution and showed that the IOP-lowering action of nano-vesicles sustained for a longer period of time. Stability studies revealed that the vesicle formulations were stable at the temperature range of 2 8 degrees C, with no change in shape and drug content. The results of the study indicate that it is possible to develop a safe and physiologically effective topical formulation that is also convenient for patients. PMID- 21264094 TI - Enhancement of the Norfloxacin Antibiotic Activity by Gaseous Contact with the Essential Oil of Croton zehntneri. AB - This is the first on the modulation of norfloxacin antibiotic activity by the volatile compounds of an essential oil. We report the chemical composition and antibiotic modifying activity of the essential oil extracted from the leaves of Croton zehntneri Pax et Hoffm (variety estragole), using the minimal inhibitory dose method and gaseous contact. The leaves of Croton zehntneri Pax et Hoffm (Euphorbiaceae) were subjected to hydrodistillation, and the essential oil extracted was examined with respect to the chemical composition, by gas chromatography-mass spectrometry (GC/MS), and to inhibitory activity of efflux pump by gaseous contact. The main component of the essential oil of C. zehntneri was estragole (76,8%). The gaseous components of the oil enhanced the inhibition zone of norfloxacin in 39,5%. This result shows that this oil influences the antibiotic activity of norfloxacin, possibly affecting the bacterial NorA efflux system, and may be used as an adjuvant in the antibiotic therapy of multidrug resistant pathogens. PMID- 21264095 TI - Free Radical Scavenging and Analgesic Activities of Cucumis sativus L. Fruit Extract. AB - The aqueous fruit extract of Cucumis sativus L. was screened for free radical scavenging and analgesic activities. The extract was subjected to in vitro antioxidant studies at 250 and 500 MUg/ml and analgesic study at the doses 250 and 500 mg/kg, respectively. The free radical scavenging was compared with ascorbic acid, BHA (Butylated hydroxyl anisole), whereas, the analgesic effect was compared with Diclofenac sodium (50 mg/kg). The C. sativus fruit extract showed maximum antioxidant and analgesic effect at 500 MUg/ml and 500 mg/kg, respectively. The presence of flavonoids and tannins in the extract as evidenced by preliminary phytochemical screening suggests that these compounds might be responsible for free radical scavenging and analgesic effects. PMID- 21264096 TI - Antiulcer and Anti-inflammatory Activity of Aerial Parts Enicostemma littorale Blume. AB - The antiulcer and in vitro anti-inflammatory activities of the aerial parts of Enicostemma littorale against aspirin, ethanol, and pyloric ligation-induced ulcers in rats and bovine serum albumin denaturation were studied. The extract (200 mg/kg and 400 mg/kg po) was administered to the overnight fasted rats, one hour prior to aspirin / alcohol / pyloric ligation challenge. The ulcer index, tissue GSH levels, and lipid peroxidation levels were estimated in all the models of ulcers and the volume of gastric secretion, acidity, and pH, were estimated in the pyloric ligation model of ulcers. Pretreatment with the extract showed a dose dependent decrease in the ulcer index (Against Aspirin, ethanol challenge, and pyloric ligation. The prior administration of the extract also reduced the total acidity, free acidity, and volume of gastric secretion, and elevated the gastric pH. In addition, it was also observed that the extract inhibited the serum albumin denaturation in a dose-dependent manner. It may be concluded that the methanolic extract possesses antiulcer activity, and the anti-inflammatory activity of the extract may be attributed to the antioxidant potential, as reported earlier. PMID- 21264097 TI - In vitro Effects of Albendazole on Raillietina echinobothrida, the Cestode of Chicken, Gallus domesticus. AB - Albendazole, a member of benzimidazole group of compounds, has been shown to have a broad spectrum activity against all classes of helminth parasites. Although it has also been experimentally proven to be effective against cestode infection of poultry, the actual effects of the drug are not yet described. The present in vitro study demonstrated that the commercial prescription drug Zentel(r) was significantly effective against adult Raillietina echinobothrida Megnin, the major cestode parasite of domestic chicken, Gallus domesticus Linnaeus. It clearly exhibited dose-dependent lethal activity at the different concentrations that were tested. Scanning electron microscopy (SEM) revealed that the drug caused extensive structural alterations on the body surface of the cestode. Severe contraction and shrinkage were evident throughout the entire length of the body. The suckers on the scolex became invaginated due to shrinkage. The distinct body segments, the proglottides, were completely distorted. The fine hairy microtriches on the tegument were obliterated and in its place were formed abnormal clumps of tissues. The results of this investigation are in favor of the use of albendazole as a drug of choice in the management of poultry helminthiasis. PMID- 21264098 TI - Modulation of the p-glycoproein-mediated intestinal secretion of glibenclamide: in vitro and in vivo assessments. AB - The everted gut sac method was used to assess the role of the P-glycoprotein (P gp) on the intestinal secretion of glibenclamide, a prototype of drug used to treat diabetic mellitus. The study included the evaluation of a P-gp modulator carbamazepine used at equimolar doses in the rat. Furthermore, the influence of carbamazepine on the disposition kinetics of glibenclamide in plasma was characterized. For the in vitro experiments, ileal sacs were incubated with glibenclamide in the presence or absence of carbamazepine. In the in vivo experiments, albino rats of either sex were randomly allocated to two groups (n = 6) and oral treatment with glibenclamide (3.6 mg/kg), alone and coadministration with carbamazepine (90 mg/kg). Blood samples were collected at an interval of 1, 2, 4, 6, and 8 h, respectively. Glibenclamide concentrations in both in vitro and in vivo samples were estimated by a sensitive RP-HPLC method. The rate of glibenclamide accumulation in the intestine wall of everted sacs was significantly lower after its incubation with carbamazepine when compared to glibenclamide alone treated. In the agreement with the in vivo and in vitro experiments, the presence of carbamazepine induced an enhancement in the concentrations of glibenclamide in plasma and gastrointestinal tract. The results obtained in this study, both under in vivo and in vitro conditions confirm the relevance of P-gp-mediated transport to the intestinal secretion of glibenclamide. PMID- 21264099 TI - Evaluation of the Hypoglycemic Activity of Cucumis metuliferus (Cucurbitaceae) Fruit Pulp Extract in Normoglycemic and Alloxan-Induced Hyperglycemic Rats. AB - The hypoglycemic effects of the fruit extract of C. metuliferus was investigated in normoglycemic and alloxan-induced hyperglycemic rats. The results showed that there was an insignificant (P > 0.05) decrease in the blood glucose concentration of normoglycemic rats treated with oral doses of 1000 and 1500 mg/kg of the extract. On the other hand, 500 mg/kg of the fruit extract produced an insignificant (P > 0.05) decrease in blood glucose levels of alloxan-treated rats, while 1000 and 1500 mg/kg oral dose points produced a significant (P < 0.05) decrease in the blood glucose concentration of hyperglycemic rats comparable to that produced by tolbutamide. From this study, the data suggested that the fruit extract did not alter the BGC level in normoglycemic rats, but had a potential hypoglycemic property in alloxan-induced hyperglycemic rats. PMID- 21264100 TI - Comparative Molecular Similarity Indices Analysis of 1-(Naphthylalky1)-1H imidazole Analogs with Antiepileptic Activity. AB - A three-dimensional quantitative structure-activity relationship (3D QSAR) of 44 structurally and functionally diverse series of 1- (Naphthylalkylimidazoles) as antiepileptic agents was studied using the Comparative molecular similarity indices analysis (CoMSIA) method. A training set containing 34 molecules served to establish the models. The optimum CoMSIA model obtained for the training set were all statistically significant, with cross-validated coefficients (q(2)) of 0.725 and conventional coefficients (r(2) (ncv)) of 0.998. The predictive capacities of the model were successfully validated by using a test set of 10 molecules that were not included in the training set. CoMSIA model (Model 1) obtained from the hydrophobic and Hbond acceptor field was found to have the best predictivity, with a predictive correlation coefficient (r(2) (pred)) of 0.67. The information obtained from this 3D-QSAR model can be used to guide the development of imidazoles as novel antiepileptic agents. PMID- 21264101 TI - Synthesis, Characterization, and Biological Evaluation of certain 6-methyl-2(3H) benzo-1, 3-thiazolyl-1'-ethylidene-2-(o, p- Substituted Acetophenones) Hydrazine Analogs. AB - In the present study, five new derivatives (GG4 to GG8) of benzothiazoles were synthesized and evaluated against Staphylococcus aureus (MTCC 737), Pseudomonas aeruginosa (MTCC 424), Escherichia coli (MTCC 1687), and yeast-like fungi Candida tropicalis. p-Toluidine on treatment with ammonium thiocynate formed 2 benzothiazolamines (II), which on reaction with hydrazine hydrate formed a hydrazino derivative (III). Compounds GG4 to GG8 were synthesized by reacting the hydrazine derivative with different acetophenones. All the synthesized compounds were identified by IR and (1)H-NMR, and antimicrobial activity was performed on the synthesized compounds. Presence of NO(2), Br, OCH(3), and Cl groups to the substituted benzothiazole enhanced the antibacterial and antifungal activities. PMID- 21264102 TI - Anti-tumor Activity of N [(E)-1-(2-hydroxyphenyl) Methylidene], N-[(E)-2 Phenylethylidene], N [(E,2E)-3-Phenyl-2-propenylidene], and N [(E)ethylidene] Isonicotinohydrazide on K562 and Jurkat Cell Lines. AB - Using the water eliminated mechanism, reactions of 4-pyridinecarboxylic acid hydrazide and salicylaldehyde, benzaldehyde, cinnamaldehyde, and formaldehyde afforded the corresponding N(4)[(E)-1-(2-hydroxyphenyl) methylidene] (NHPM), N(4) [(E)-2-phenylethylidene] (NPI), N(4)[(E,2E)-3-phenyl-2-propenylidene] (NPPI), and N(4)[(E) ethylidene] (NEI) isonicotinohydrazide, in high yields, after several minutes, as reported. These new compounds have shown antitumor activity against two kinds of cancer cells, which are K562 (human chronic myeloid leukemia) and Jurkat (human T lymphocyte carcinoma). PMID- 21264103 TI - Global medical device nomenclature: the concept for reducing device-related medical errors. AB - In the medical device field, there are a number of players, having quite different responsibilities and levels of understanding of the processes, but all with one common interest, that of ensuring the availability of sound medical devices to the general public. To assist in this very important process, there is a need for a common method for describing and identifying these medical devices in an unambiguous manner. The Global Medical Device Nomenclature (GMDN) now provides, for the first time, an international tool for identifying all medical devices, at the generic level, in a meaningful manner that can be understood by all users. Prior to the GMDN, many nomenclature systems existed, all built upon different structures, and used locally or nationally for special purposes, with unusual approaches. These diverse systems, although often workable in their own right, have had no impact on improving the overall situation of providing a common platform, whereby, medical devices could be correctly identified and the related data safely exchanged between the involved parties. Work by standard organizations such as, CEN (European Committee for Standardization) and ISO (International Organization for Standardization), from 1993 to 1996, resulted in a standard that specified a structure for a new nomenclature, for medical devices. In this article we are trying to explain GMDN as the prime method to reduce medical device errors, and to understand the concept of GMDN, to regulate the medical device throughout the globe. Here we also make an attempt to explain various aspects of the GMDN system, such as, the process of development of the GMDN-CEN report, purpose, benefits, and their structural considerations. In addition, there will be an explanation of the coding system, role of the GMDN agency, and their utilization in the unique device identification (UDI) System. Finally, the current area of focus and vision for the future are also mentioned. PMID- 21264104 TI - A Simple RP-HPLC Method for Quantitation of Itopride HCl in Tablet Dosage Form. AB - An isocratic reversed phase high-performance liquid chromatographic method with ultraviolet detection at 220 nm has been developed for the quantification of itopride hydrochloride in tablet dosage form. The quantification was carried out using C(8) column (250 mm * 4.6 mm), 5-MUm particle size SS column. The mobile phase comprised of two solvents (Solvent A: buffer 1.4 mL ortho-phosphoric acid adjusted to pH 3.0 with triethyl amine and Solvent B: acetonitrile). The ratio of Solvent A: Solvent B was 75:25 v/v. The flow rate was 1.0 mL (-1)with UV detection at 220 nm. The method has been validated and proved to be robust. The calibration curve was linear in the concentration range of 80-120% with coefficient of correlation 0.9995. The percentage recovery for itopride HCl was 100.01%. The proposed method was validated for its selectivity, linearity, accuracy, and precision. The method was found to be suitable for the quality control of itopride HCl in tablet dosage formulation. PMID- 21264105 TI - Visible spectrophotometric estimation of diacerein in bulk and pharmaceutical dosage forms. AB - Two simple, sensitive, accurate, rapid, and economical spectrophotometric methods have been developed for the estimation of diacerein in Pharmaceutical dosage forms. Method A is based on the reaction of diacerein with Folin-Ciocalteu reagent, in the presence of 0.5 N sodium hydroxide solution, giving a pink colored chromogen, which shows maximum absorbance at 512 nm against reagent blank, while method B is based on the oxidation of diacerein with potassium permanganate in an alkaline medium giving a pink-colored chromogen, which shows maximum absorption at 497.5 nm. Beer's law was obeyed in the concentration range of 4 - 20 ug/ml for both methods A and B. Results of the analysis were validated statistically, and by recovery studies. PMID- 21264106 TI - UV Spectrophotometric Method for Assay of the Anti-Retroviral Agent Lamivudine in Active Pharmaceutical Ingredient and in its Tablet Formulation. AB - A rapid, simple, accurate, and economical spectrophotometric method has been developed and validated for the assay of the anti-retroviral agent lamivudine in active pharmaceutical ingredients (API) and in its tablet formulation. The analysis is based on the UV absorbance maxima at about 270nm wavelength of lamivudine, using methanol as solvent. A sample of API was dissolved in methanol to produce a solution containing 10 ug/mL of lamivudine. Similarly, a sample of ground tablets were extracted with methanol, centrifuged, and diluted with the same solvent. The absorbance of the sample preparation was measured at 270 nm against the solvent blank, and the assay was determined by comparing with the absorbance of a similarly prepared 10 ug/mL standard solution of lamivudine. The calibration graph was rectilinear from 5 ug/mL to 15 ug/mL for lamivudine with the correlation coefficient being more than 0.999. The relative standard deviation of the replicate determination was about 0.5%. The percent recovery was within the range of 98%-102%, indicating insignificant interference from the other ingredients in the formulation. The method can be applied for the routine QC quantitation of lamivudine in API and tablet formulation. PMID- 21264107 TI - Zero order spectrophotometric method for estimation of escitalopram oxalate in tablet formulations. AB - A new, simple, fast and reliable zero order spectrophotometric method has been developed for determination of Escitalopram Oxalate in bulk and tablet dosage forms. The quantitative determination of drug was carried out using the zero order values (absorbance) measured at 238 nm. Calibration graph constructed at 238 nm was linear in concentration range of 2-20 ug/ml with correlation coefficient 0.9999. The method was found to be precise, accurate, specific, and validated as per ICH guidelines and can be used for determination of Escitalopram Oxalate in tablet formulations. PMID- 21264108 TI - A study on drug-drug interaction of esomeprazole and anti-diabetic drugs. AB - Drug-drug interaction between esomeprazole at therapeutic and higher doses and sulfonylureas was studied. Sulfonylureas (tolbutamide 40 mg/kg and glibenclamide 40 ug/kg) were administered and the time to onset of hypoglycemia, the duration of the hypoglycemia, and the peak hypoglycemia were determined. Esomeprazole (1.8 mg/kg, 3.6 mg/kg, and 30 mg/kg) was administered for 8 days and its influence on sulfonylurea-induced hypoglycemia was studied. Therapeutic doses of esomeprazole, i.e., 1.8 mg/kg and 3.6 mg/kg dose did not influence the hypoglycemia induced by sulfonylureas. However, a higher dose, i.e., 30 mg/kg, did significantly enhance the duration of hypoglycemia and the peak hypolgycemia. Esomeprazole (30 mg/kg) by itself did not reduce the blood glucose levels; therefore, a pharmacodynamic type of drug interaction can be ruled out. Similarly, a pharmacokinetic type of drug interaction may be ruled out at therapeutic doses. The CYP isoenzyme system involved in the metabolism of sulfonylureas are not very sensitive to esomeprazole and the dose and frequency of administration of sulfonylurea need not be readjusted when they are used concomitantly with esomeprazole (at therapeutic doses). PMID- 21264109 TI - Revisiting Metformin: Annual Vitamin B12 Supplementation may become Mandatory with Long-Term Metformin Use. AB - Monitoring of adverse drug reactions of a drug is a continuous process and runs through-out the life of a drug. Many rare adverse effects of a drug are documented after years of use; when a single case (signal generation) is reported leading subsequently to reporting of more cases. Deficiency of Vitamin B12 (vit B(12)) is a known sequel of prolonged metformin therapy. It was recommended to have annual measurement of serum vit B(12) levels in patients on long term metformin therapy way back in 1970 itself. After more than 50 years of use of metformin, we have come to know that metformin induced vit B(12) deficiency can cause neuropathy; forcing to change the recommendation from annual screening of vit B(12) levels to annual supplementation of vit B(12). PMID- 21264110 TI - Dronedarone: a new therapeutic alternative for cardiac arrhythmias. PMID- 21264111 TI - Conflict of interest in peer-reviewed medical journals: the world association of medical editors position on a challenging problem. PMID- 21264112 TI - Studies on In situ Hydrogel: A Smart Way for Safe and Sustained Ocular Drug Delivery. AB - The present work describes the formulation development of ophthalmic in situ gelling system using thermo-reversible gelling polymer, i.e. Pluronic F 127 (PF127). Because of high concentration (20 to 25%w/v) of this polymer required for in situ gelation causes irritation to the eye. So, to reduce this concentration, an attempt was made to combine the PF127 with other polymers like hydroxy propyl methyl cellulose (HPMC) as a viscosity increasing agent or with polymers like carbopol 940, xanthan gum, and sodium alginate (high glucuronic acid content) showing a pH and cation-triggered sol-gel transition, respectively. Different batches were prepared of varying concentrations of these polymers with PF127 using cromolyn sodium 2%w/v in phosphate buffer pH 5.0. The formulations were optimized by the viscosity measurement and in vitro gelation study. Selected formulations were evaluated for in vitro drug release profile and indicated sustain drug release over a period of 10 h. Effect of sterilization on drug content, pH, clarity, and viscosity were also evaluated. Finally, we concluded that by using this type of combination system, we could reduce not only the concentration of individual polymers but also the side effects without compromising the in vitro gelling capacity as well as overall rheology of the system. PMID- 21264113 TI - Formulation and evaluation of extended-release solid dispersion of metformin hydrochloride. AB - The purpose of this research was to formulate and characterize solid dispersion (SD) of metformin hydrochloride using methocel K100M as the carrier by the solvent evaporation and cogrinding method. The influence of drug polymer ratio on drug release was studied by dissolution tests. Characterization was performed by fourier transform spectroscopy (FTIR), ultraviolet, differential scanning calorimetry and X-ray powder diffractometry. The optimized formulation was subjected to accelerated stability testing as per ICH guidelines. Release data were examined kinetically. SD with 1:4 and 1:5 ratio of drug to polymer obtained by solvent evaporation and cogrinding were selected as the best candidates suitable for prolonged-release oral dosage form of metformin. PMID- 21264114 TI - Aqueous Extract of Ficus bengalensis Linn. Bark for Inflammatory Bowel Disease. AB - The present study was designed to evaluate the effects of aqueous extract of Ficus bengalensis Linn. bark (AEFB) on inflammatory bowel disease (IBD). Effects of AEFB were studied on 2, 4, 6-trinitrobenzenesulfonic acid (TNBS, 0.25 ml 120 mg/ml in 50% ethanol intrarectally, on first day only)-induced IBD in rats. Effects of co-administration of prednisolone (2 mg/kg) and AEFB (250, 500 mg/kg) for 21 days were also evaluated. Various physical parameters including body weight, food, and water intake measured on 1st and 21st days. At end of the experiment, various histopathological indexes are assessed. The colon homogenate malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and nitric oxide (NO) levels and % mast cell protection in mesentery were also measured. In our study, we found that AEFB has a significant protective effect in the inflammatory bowel disease as compared to prednisolone in rats. PMID- 21264115 TI - Antioxidant, Antinociceptive and Anti-inflammatory Activities of Ethanolic Extract of Leaves of Alocasia indica (Schott.). AB - Extracts obtained from the leaves of various Alocasia species have been used in India as folk remedy for the treatment of various inflammatory ailments including rheumatism and bruise. The ethanolic extract of leaves of Alocasia indica Schott. was evaluated by using different in vitro antioxidant models of screening like scavenging of 1, 1-diphenyl-2-picryl hydrazyl (DPPH) radical, nitric oxide radical, superoxide anion radical, and hydroxyl radical. The antinociceptive activity was tested by acetic acid-induced writhing response, hot plate method, and tail flick method in albino rats. The anti-inflammatory potential of gels of ethanolic extract has been determined by using carrageenan-induced paw edema assay, formalin-induced paw edema assay, arachidonic acid-induced ear edema assay, and xylene-induced ear edema assay. The extract showed remarkable antioxidant activity in all models, comparable to the standard reference drug ascorbic acid. The ethanolic extract of Alocasia indica and its gels produced dose-dependent antinociceptive and anti-inflammatory activity, respectively. This finding suggests that ethanolic extract of A. indica possess potent antinociceptive and anti-inflammatory activity possibly due to its free radical scavenging properties. PMID- 21264116 TI - Glucagon Secreting Cells Responds to Insulin Secretion In vitro Using Immunocytochemistry. AB - In the present study, pancreas of rats were dissected and transferred to HEPES buffer (25 mM, pH 7.4). The control tissue pieces were kept in culture medium for one hour and the treated tissues were kept in same medium for 30 minutes and incubated with Insulin (10 nm and 100 nm) for another half hour, then tissues were transferred to Bouin's fixative (overnight at 40 degrees Cc), cryosectioned (15 um at -16 0 c) and subjected to immunocytochemical labeling with antibodies against Glucagon. RESULTS: In the sections of control tissue, the Glucagon Immunoreactive Cells (GIC) were distinctly visible; on average 40-50 cells were counted in each islet. However in vitro treatment with 10 nm insulin caused 285.89 % increase in the GIC and was found to be highly significant (P< 0.001). Whereas in 100 nm Insulin treatment, 206.41% increase in GIC was seen, this was significant with the control but non-significant with 10 nm Insulin treatment. PMID- 21264117 TI - Possible role of hydrogen sulfide in insulin secretion and in development of insulin resistance. AB - H(2)S has been proposed as physiological important molecule. It is considered as first endogenous gaseous K(+) channel opener. K(+) ATP channel activity is mainly responsible for insulin secretion. K(+)ATP channel opening of beta cells leads to inhibition of insulin secretion and channels closing leads to secretion. H2S is the gaseous K(+) ATP channel opener but it does not have channel specificity. So, H(2)S may have some effect on insulin secretion. H(2)S is high in Zuker diabetic fatty rats. That means H(2)S is high in insulin resistance condition. We tried to find out the role of H(2)S in insulin secretion and in development of insulin resistance. From the result of our study, H(2)S have K(+) ATP channel opening activity on beta cells. H(2)S does not have any role in the development of insulin resistance. Decrease in insulin level in Zuker diabetic rat and streptozotocin-induced diabetic rat is due to high H(2)S level. PMID- 21264118 TI - Drug-drug Interaction between Pravastatin and Gemfibrozil (Antihyperlipidemic) with Gliclazide (Antidiabetic) in Rats. AB - Diabetes mellitus is a condition of increased blood glucose level in the body. Antihyperlipidemic drugs like statins and fibrates are widely used for prophylactic treatment in dyslipideamia and atherosclerosis. Diabetic dislipidemia exists with increased triglycerides, low HDL and high LDL levels. Hence, with oral hypoglycemic drugs, the addition of a lipid-lowering drug is necessary for controlling dislipidemia. In such a situation, there may be chances of drug-drug interactions between antidiabetic and antihyperlipidemic drugs. The present study is planned to evaluate the safety of gliclazide (antidiabetic) in the presence of pravastatin and gemfibrozil (antihyperlpidemic) in rats. Studies in normal and alloxan-induced diabetic rats were conducted with oral doses of gliclazide and their combination with pravastatin and gemfibrozil, with an adequate washout period in between the treatments. Blood samples were collected in rats by retroorbital puncture at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h. All the blood samples were analyzed for glucose by GOD -POD. Gliclazide (1/2 TD) produced hypoglycemic activity in normal and diabetic rats, with peak activity at 2 and 8 h. Pravastatin (TD) + gemfibrozil (TD) combination treatment increased the hypoglycemic effect of gliclazide in normal rats or diabetic rats when administered together. The interaction observed due to inhibition of both the enzymes (CYP 450 2C9 and CYP 450 3A4) responsible for the metabolism of gliclazide showed increased half-life, which was seen in the present study. Because concomitant administration of gliclazide with provastatin and gemfibrozil in diabetes is associated with atherosclerosis, it should be contraindicated or used with caution. PMID- 21264119 TI - A Novel Approach for Oral Delivery of Insulin via Desmodium gangeticum Aqueous Root Extract. AB - Many challenges are associated with the oral delivery of insulin, relating to the physical and chemical stability of the hormone, and its absorption and metabolism in the human body. The present study aims to demonstrate the oral delivery of insulin in both normal and steptozotocin (STZ)-induced diabetic rats with the help of the aqueous extract of Desmodium gangeticum (DG) root. Human insulin was mixed with the aqueous extract of DG root (0.1 mg/ml) with human insulin (40 IU/ml) in ratio 1:1(v/v), to prepare oral insulin drug. Decreased plasma glucose level and increased plasma insulin in normal and STZ-induced diabetic rat suggested the probable absorption of insulin through GI tract when insulin was administered by mixing with DG extract. Indeed, insulin mixed DG potentially stimulates the release of insulin in STZ-induced diabetic rat rather than in normal animal. In vivo insulin secretaguage action of oral insulin drug was determined by isolated rat heart model and the results showed a significant cardio protection in STZ rat. The finding of this study suggests that insulin mixed with DG extract can be a promising vehicle for oral delivery of insulin. However, further studies are required to explore the exact compound(s) responsible for the protective delivery of insulin orally. Increased plasma insulin level by insulin mixed DG extract administration in STZ-treated diabetic rat indicates not only insulin secretaguage action of the mixture but also a probable altered insulin release mechanism in diabetic condition. PMID- 21264120 TI - Synthesis and Pharmacological Evaluation of Novel Schiff Base Analogues of 3-(4 amino) Phenylimino) 5-fluoroindolin-2-one. AB - In our study, a series of novel 3-(4-(benzylideneamino) phenylimino) 4 fluoroindolin-2-one derivatives were synthesized and characterized by spectral (I.R, (1)H NMR, mass) and elemental analysis. The title compounds (N(1)-N(10)) were evaluated for analgesic, anti-inflammatory, and ulcerogenic index activities. Results displayed that compound N(3) exhibited significant analgesic activity. Among the title compounds studied, N(2), N(3), and N(8) exhibited significant anti- inflammatory activity comparable to reference standard diclofenac sodium. Interestingly, the test compounds showed only mild ulcerogenic side effect when compared to aspirin. PMID- 21264121 TI - Synthesis and evaluation of 1,3 di-substituted schiff, mannich bases and spiro isatin derivatives. AB - Schiff bases of isatin with aminothiazole, its N-mannich bases and Spiro isatin derivatives were synthesized. Their chemical structures were confirmed by Infrared, 1H-Nuclear Magnetic Resonance data and elemental analysis. Antimicrobial evaluation was performed by the agar diffusion method against four pathogenic bacteria and two pathogenic fungi. Anti-inflammatory activity was tested by carragenin-induced rat paw edema and compounds were evaluated for analgesic action by the acetic acid-induced writhing method; Compounds Aa, Ab and A5, A6 were found to be active against bacteria and fungi. The compounds A3, A6, Aa and Ab showed anti-inflammatory activity, having a percentage protection value of 34.69, 32.65, 38.77 and 36.73 as compared with that of indomethacin, with % protection of 46.93. Similarly, the compounds Aa, Ab and A6 showed analgesic activity, with % protection of 67.51, 64.78 and 49.81 as compared with the standard with % protection of 79.56. PMID- 21264122 TI - Synthesis and Antimicrobial Activity of 2-[2-(2,6-dichloro phenyl)amino]benzyl-3 (5-substituted phenyl-4,5-dihydro-1H-pyrazol-3-yl-amino)-6,8-dibromoquinazolin 4(3H)ones. AB - A series of 2-[2-(2,6-dichlorophenyl)amino]benzyl-3-(5-substituted phenyl-4,5 dihydro-1H-pyrazol-3-yl-amino)-6,8-dibromoquinazolin-4(3H) ones 6a-m have been synthesized by the reaction of 2-[2-(2,6-dichlorophenyl)amino]benzyl-3 substituted phenylacrylamido-6,8-dibromoquinazolin-4(3H) ones 5a-m with hydrazine hydrate in the presence of glacial acetic acid. The chalcones 5a-m were prepared by the condensation of 2-[2-(2,6-dichlorophenyl)amino]benzyl-3-acetamido-6,8 dibromoquinazolin-4(3H)one 4 with different substituted aromatic aldehyde. The benzoxazinone 2 was synthesized from 2-[2-(2,6-dichlorophenyl)amino]phenyl acetyl chloride 1 on treatment with 3,5-dibromoanthranilic acid in pyridine, which on reaction with hydrazine hydrate and then on acetylation reaction yielded 4. The structures of these compounds have been elucidated by elemental analyses, IR, and NMR spectral data. The title compounds pyrazolyl-quinazolin-4(3H)ones 6a-m were evaluated for their antibacterial and antifungal activities in vitro. PMID- 21264123 TI - Development and validation of a specific stability indicating high performance liquid chromatographic method for valsartan. AB - A stability-indicating HPLC assay method has been developed and validated for valsartan in bulk drug and pharmaceutical dosage forms. An isocratic RP-HPLC was achieved on Waters 2695 using Symmetry C18 (250mm * 4.6mm * 5MU) column with the mobile phase consisting of 0.02 mM sodium dihydrogen ortho-phosphate, pH adjusted to 2.5 using ortho-phosphoric acid (solvent A), and acetonitrile (solvent B) in the ratio of 58:42 %v/v. The stress testing of valsartan was carried out under acidic, alkaline, oxidative, thermal, and photolytic conditions. Valsartan was well resolved from its degradation products. The proposed method was validated as per ICH guidelines. The method was found to be suitable for the quality control of valsartan in bulk and pharmaceutical dosage forms as well as the stability indicating studies. PMID- 21264124 TI - Comparative Study of RP-HPLC and UV Spectrophotometric Techniques for the Simultaneous Determination of Amoxicillin and Cloxacillin in Capsules. AB - Reversed-phase HPLC and UV spectrophotometric techniques using water as solvent have been developed and validated for the simultaneous determination of amoxicillin and cloxacillin in capsules. For both techniques, the linearity range of 60.073x2013;140.0 ug/mL was studied. The spectrophotometric data show that non derivative techniques, such as absorbance ratio and compensation, and ratio spectra first-order derivative could be successfully used for the co-assay of amoxicillin and cloxacillin. Based on the statistical comparison of spectrophotometric and chromatographic data, the interchangeability between HPLC and UV spectrophotometric techniques has been suggested for the routine analysis. PMID- 21264125 TI - In vivo and In vitro Drug Interactions Study of Glimepride with Atorvastatin and Rosuvastatin. AB - Aim of this investigation was to study the in vivo and in vitro drug interaction of glimepride with atorvastatin and rosuvastatin. In vitro drug interaction of glimepride with atorvastatin and rosuvastatin was studied using human pooled liver microsomes and evaluated using high performance liquid chromatography. In vivo pharmacokinetic drug interaction of glimepride (6 mg/kg) in coadministration with atorvastatin (60 mg/kg) and rosuvastatin (60 mg/kg) were studied in rats and analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS). In in vitro study, atorvastatin decreased its own metabolism as well as the metabolism of glimepiride. Rosuvastatin coadministration with glimepride reduced the metabolism of glimepride and increased the metabolism of its own. In in vivo study, concentration in plasma, C(max), AUC((0-t)) and AUC((0-infinity)) (area under the concentration-time curve, AUC) of glimepride was increased significantly in coadministration with atorvastatin whereas there was no significant change was observed in the case of coadministration with rosuvastatin. Half life (T(1/2)) and volume of distribution (V(d)) of glimepride decreased significantly with both atorvastatin and rosuvastatin. Elimination rate constant, K(el) of glimepride increased significantly with both atorvastatin and rosuvastatin. Clearance (Cl) of glimepride decreased significantly but the decrease was more with atorvastatin than with rosuvastatin. It is concluded that glimepride metabolism is little affected by rosuvastatin in vitro, which agreed with the negligible interaction in in vivo study. Thus, from safety point of view rosuvastatin is better to prescribe as a coadministration therapy with glimepiride. On the other hand, atorvastatin could cause an increase in the bioavailability of glimepride per oral and also significantly decrease the metabolism of glimerpride in in vitro study. This may pose a positive implication in clinical practice. PMID- 21264126 TI - ABC and VED Analysis of the Pharmacy Store of a Tertiary Care Teaching, Research and Referral Healthcare Institute of India. AB - The ABC and VED (vital, essential, desirable) analysis of the pharmacy store of Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, was conducted to identify the categories of items needing stringent management control. The annual consumption and expenditure incurred on each item of pharmacy for the year 2007-08 was analyzed and inventory control techniques, i.e. ABC, VED and ABC-VED matrix analysis, were applied. The drug formulary of the pharmacy consisted of 421 items. The total annual drug expenditure (ADE) on items issued in 2007-08 was Rs. 40,012,612. ABC analysis revealed 13.78%, 21.85% and 64.37% items as A, B and C category items, respectively, accounting for 69.97%, 19.95% and 10.08% of ADE of the pharmacy. VED analysis showed 12.11%, 59.38% and 28.51% items as V, E, and D category items, respectively, accounting for 17.14%, 72.38% and 10.48% of ADE of the pharmacy. On ABC-VED matrix analysis, 22.09%, 54.63% and 23.28% items were found to be category I, II and III items, respectively, accounting for 74.21%, 22.23% and 3.56% of ADE of the pharmacy. The ABC and VED techniques need to be adopted as a routine practice for optimal use of resources and elimination of out-of-stock situations in the hospital pharmacy. PMID- 21264127 TI - Recent trends on the future of graduate education in the pharmaceutical sciences and research. AB - Harmonization of pharmacy education has to be made a global agenda that will encompass the developments that have taken place in basic, medical, pharmaceutical sciences in serving the needs and expectations of the society. The professional pharmacy curriculum is designed to produce pharmacists who have the abilities and skills to provide drug information, education, and pharmaceutical care to patients; manage the pharmacy and its medication distribution and control systems; and promote public health. Required coursework for all pharmacy students includes pharmaceutical chemistry; pharmaceutics (drug dosage forms, delivery, and disposition in the human body) pharmacology; therapeutics (the clinical use of drugs and dietary supplements in patients); drug information and analysis; pharmacy administration (including pharmacy law, bioethics, health systems, pharmacoeconomics, medical informatics); clinical skills (physical assessment, patient counseling, drug therapy monitoring for appropriate selection, dose, effect, interactions, use); and clinical pharmacy practice in pharmacies, industry, health maintenance organizations, hospital wards, and ambulatory care clinics. PMID- 21264128 TI - Toward prevention of stroke. PMID- 21264129 TI - Presidential oration: the 18 annual conference of the Indian academy of neurology, trichi, Tamil Nadu, september 24-26, 2010, epilepsy care in developing countries. AB - Nearly 80% of the 50 million people with epilepsy worldwide reside in developing countries that are least equipped to tackle the enormous medical, social and economic challenges posed by epilepsy. These include widespread poverty, illiteracy, inefficient and unevenly distributed health care systems, and social stigma and misconceptions associated with epilepsy. Several studies have reported that a large proportion of patients with epilepsy in developing countries never receive appropriate treatment for their condition, and many, though diagnosed and initiated on treatment, soon discontinue treatment. Unaffordable cost of treatment, unavailability of antiepileptic drugs, and superstitious and cultural beliefs contribute to high epilepsy treatment gap in resource-poor countries. A significant proportion of the current burden of epilepsy in developing countries can be minimized by educating the public about the positive aspects of life with epilepsy and the primary and secondary physicians about current trends in the management of epilepsies, scaling up routine availability of low-cost antiepileptic drugs, and developing cost-effective epilepsy surgery programs. PMID- 21264130 TI - Kleine-Levin syndrome: Etiology, diagnosis, and treatment. AB - Kleine-Levin syndrome (KLS) is a rare sleep disorder mainly affecting teenage boys in which the main features are intermittent hypersomnolence, behavioral and cognitive disturbances, hyperphagia, and in some cases hypersexuality. Each episode is of brief duration varying from a week to 1-2 months and affected people are entirely asymptomatic between episodes. No definite cause has been identified, and no effective treatments are available even though illness is having well-defined clinical features. Multiple relapses occur every few weeks or months, and the condition may last for a decade or more before spontaneous resolution. In this study, PubMed was searched and appropriate articles were reviewed to highlight etiology, clinical features, and management of KLS. On the basis of this knowledge, practical information is offered to help clinicians about how to investigate a case of KLS, and what are the possible treatment modalities available currently for the treatment during an episode and interepisodic period for prophylaxis. Comprehensive research into the etiology, pathophysiology, investigation, and treatments are required to aid the development of disease-specific targeted therapies. PMID- 21264131 TI - Guidelines for epilepsy management in India classification of seizures and epilepsy syndromes. AB - This article is part of the Guidelines for Epilepsy management in India. This article reviews the classification systems used for epileptic seizures and epilepsy and present the recommendations based on current evidence. At present, epilepsy is classified according to seizure type and epilepsy syndrome using the universally accepted International League Against Epilepsy (ILAE) classification of epileptic seizures and epilepsy syndromes. A multi-axial classification system incorporating ictal phenomenology, seizure type, epilepsy syndrome, etiology and impairments is being developed by the ILAE task force. The need to consider age related epilepsy syndromes is particularly important in children with epilepsy. The correct classification of seizure type and epilepsy syndrome helps the individual with epilepsy to receive appropriate investigations, treatment, and information about the likely prognosis. PMID- 21264132 TI - Clinical, electrophysiologic, and histopathologic profile, and outcome in idiopathic inflammatory myositis: An analysis of 68 cases. AB - OBJECTIVES: To study the electroclinical and histopathologic profile of idiopathic inflammatory myositis (IIM) with reference to prognosis and survival rate. MATERIALS AND METHODS: Diagnosis of IIM was based on the Bohan and Peter criteria. Patients who improved and those whose condition worsened or who expired due to IIM per se at last follow-up were classified to have favorable and poor outcomes, respectively. Fisher's exact test was used for univariate analysis of prognostic factors. RESULTS: The study cohort consisted of consecutive 68 patients with IIM. The mean age at diagnosis was 36.5 years and females constituted 71%. Of these patients, 62% had definite IIM, 49% had polymyositis, 20% had dermatomyositis, and 29% had overlap syndrome. The mean follow-up period was 5.4 years. Prednisolone alone was used in 55 (80%), and azathioprine (1-3 mg/kg/day) alone in 12 (17.6%) as the initial treatment. Relapse of IIM with drug withdrawal was seen in 15 patients (22%); 70% had favorable outcome and 16% had expired. The treatment delay of <=6 months (P = 0.001), absence of cardiac or lung involvement (P < 0.001), and positive biopsy (P = 0.033) were predictive of a favorable prognosis in the univariate analysis. In multivariate analysis, only the duration of illness of <=6 months (P = 0.008) and the absence of cardiac or lung involvement (P = 0.001) predicted the favorable outcome at last follow-up. Cumulative survival rate was 95% at 1 year, 86% at the 5th year, and 80% at the 10th year. CONCLUSIONS: Approximately, two-thirds of the patients showed good electroclinical and histopathologic correlations and an equal number improved with treatment. The treatment delay (>=6 months), presence of cardiac or pulmonary involvements, and negative muscle biopsy are bad prognostic factors. PMID- 21264133 TI - Role of vitamin B(12), folate, and thyroid stimulating hormone in dementia: A hospital-based study in north Indian population. AB - BACKGROUND: Vitamin B(12) and folate represent modifiable risk factors for dementia. They may increase the risk of Alzheimer's dementia (AD) and vascular dementia (VaD) as their deficiency can increase the homocysteine level due to slowed methylation reaction. Homocysteine has a neurotoxic effect that could lead to neurologic disturbances. Hence, it is important to explore the status of serum B(12) and folate in AD and VaD to evolve the treatment strategies for the same. OBJECTIVES: A retrospective study was conducted to assess the levels of vitamin B(12), folate, and thyroid stimulating hormone (TSH) in serum and the relationship of these factors, including age and sex to cognitive decline in VaD, AD, and dementia due to other causes (DOC). MATERIALS AND METHODS: Serum vitamin B(12), folate, TSH, and total cholesterol were studied in 32 AD patients (mean age: 65 years), 12 VaD patients (mean age: 61 years), 83 DOC (mean age: 65 years), and 127 control subjects (mean age: 49 years). RESULTS: In AD, VaD, and DOC, the levels of vitamin B(12) and folate were significantly lower (P < 0.002; 0.026; 0.002 for vitamin B(12) and P < 0.000 in all the 3 groups for folate) as compared with the controls. Similarly, TSH levels were significantly lower in AD and DOC (P < 0.008; 0.038) as compared with the controls. CONCLUSION: Vitamin B(12) and folate were significantly low in both AD and VaD patients. Hence, B vitamin supplementation should be considered as possible targets for the therapeutic intervention in dementia. PMID- 21264134 TI - Utility of molecular and serodiagnostic tools in cerebral toxoplasmosis with and without tuberculous meningitis in AIDS patients: A study from South India. AB - BACKGROUND: Antemortem diagnosis of cerebral toxoplasmosis, the second most common opportunistic infection (OI) in HIV-infected individuals in developing countries is a challenge. MATERIALS AND METHODS: Toxoplasma gondii (T.gondii) specific serology and nested polymerase chain reaction (nPCR) were evaluated in sera and ventricular/lumbar cerebrospinal fluid (CSF) of 22 autopsy confirmed cases of cerebral toxoplasmosis with HIV and 17 controls. Frequency of concomitant T.gondii infection was investigated in 17 cases of HIV-associated tuberculous meningitis (TBM). RESULTS: The sensitivity, specificity, and positive and negative predictive values of T. gondii IgG on CSF (ventricular and lumbar) and sera was 100% in histology proven cerebral toxoplasmosis (concentrations: 258 +/- 50, 231 +/- 36, and 646 +/- 243 IU/mL, respectively); majority (94%) being high avidity type, suggesting reactivation/reinfection. The sensitivity of B1 nPCR was 100% on ventricular CSF, whereas it was only 77% on lumbar CSF. Based on histology, nPCR, and IgG serology, T. gondii co-infection with TBM was observed in 65% (11/17) of cases. DISCUSSION AND CONCLUSION: CSF IgG serology and nPCR are tests with high sensitivity and specificity for the diagnosis of cerebral toxoplasmosis. TBM and cerebral toxoplasmosis can coexist and should be considered in the background of HIV infection in developing countries. PMID- 21264135 TI - Use of intravenous immunoglobulin in the Department of Neurology at Ninewells Hospital, 2008-2009: Indications for utilization and cost-effectiveness. AB - This study was designed to identify the indications for prescription of intravenous immunoglobulin (IVIg) in neurology and the cost effectiveness of this therapy. OBJECTIVES: IVIg is a relatively costly therapy and the annual budget spent on providing this therapy for various indications at Ninewells Hospital was close to L1.5 million. In today's economic times, a cost-benefit analysis of all therapies is prudent. This is of relevance to countries in the developing world as well where perhaps not everybody could afford such cost-intensive therapy. MATERIALS AND METHODS: We audited 2 time periods over 12 months each in 2004-2005 and 2008-2009 to look at the patterns of utilization of IVIg over these periods. We searched the literature for alternative and cost-effective therapies for the most common indications for use of IVIg. RESULTS: Fiscal costs on prescription of IVIg have rocketed up by almost 300% in this Neurology Department comparing data from 2004-2005 vs 2008-2009 and this is disproportionate to the increase in the annual admission rate (bed usage), partly because of the soaring costs of the drug available in the market and also because of the increased prescription of IVIg for numerous indications where clinical trials data are yet not so robust. CONCLUSION: We have looked at the cost of alternative therapies and offer some proposals that if implemented could potentially save L330,000 annually from the health budget at this NHS Trust. Perhaps similar models could evolve for better cost-effective utilization of IVIg in countries in the developing world where health budgeting is more acutely relevant. PMID- 21264136 TI - Reliability and validity of Hindi translation of the migraine disability assessment and headache impact test-6 questionnaires. AB - OBJECTIVE: The objective of the study was to assess the reliability and validity of the Hindi translation of the Migraine Disability Assessment (MIDAS) and Headache Impact Test-6 (HIT-6) questionnaires. MATERIALS AND METHODS: The study was conducted on the migraine patients. For test-retest reliability, the respondents filled the MIDAS and HIT-6 questionnaires twice, at an interval of three weeks. For validity, the same population of patients filled the headache diary for three months. After three months they filled the MIDAS and HIT-6 questionnaires again. The patients were subgrouped according to their occupation and level of education. The test-retest reliability and validity were calculated by the Pearson correlation coefficient. Internal consistency was calculated using the Cronbach alpha. RESULTS: A total of 236 migraine patients were screened. Seventy-nine patients fulfilled the inclusion criteria. A total of 69 patients completed the study. The HIT-6 questionnaire was applicable to all the subgroups of patients and had better comprehensibility than the MIDAS. Housewives missed out on the first two questions of the MIDAS and had lower mean MIDAS scores than HIT-6. The test-retest correlation coefficients for the total MIDAS and HIT-6 scores were 0.94 and 0.81, respectively. The correlation coefficients between the total score in the headache diary equivalent and the MIDAS and HIT-6 total score were 0.91 and 0.77, respectively. Cronbach alpha, a measure of internal consistency for the MIDAS questionnaire was > 0.90 at all the compilations. For the HIT-6 questionnaire, it ranged from 0.67 to 0.79. CONCLUSION: The Hindi versions of MIDAS and HIT-6 questionnaires were reliable and valid, but could not be interchanged. HIT-6 had better comprehensibility. PMID- 21264137 TI - Normobaric oxygen therapy in acute ischemic stroke: A pilot study in Indian patients. AB - PURPOSE: Clinical and radiological assessment of effects of normobaric high-flow oxygen therapy in patients with acute ischemic stroke (AIS). MATERIALS AND METHODS: Patients with anterior circulation ischemic strokes presenting within 12 h of onset, ineligible for intravenous thrombolysis, an National Institute of Health Stroke Scale (NIHSS) score of >4, a mean transit time (MTT) lesion larger than diffusion-weighted image (DWI) (perfusiondiffusion mismatch), and an evidence of cortical hypoperfusion on magnetic resonance imaging (MRI) were included into the trial. Active chronic obstructive pulmonary disease (COPD), requirement of >3/L min oxygen delivery to maintain SaO2 > 95%, rapidly improving neurological deficits, pregnancy, contraindications to MRI, or unstable medical conditions were excluded. The experimental group received humidified oxygen at flow rates of 10 L/min for 12 h. The NIHSS, modified Rankin Score (mRS), Barthel Index (BI) were measured at 0, 1, 7 day of admission and at 3 months follow-up. MRI with DWI/PWI was performed at admission, 24 h later and at 3 months follow up. RESULTS: Of 40 patients (mean age = 55.8 years +/- 13.2) (range, 26-82), 20 patients were randomized to normobaric oxygen (NBO). The mean NIHSS in NBO and control groups were 14.25 and 12.7 at admission which decreased to 11.6 and 9.5 on the seventh day, and 9.4 and 9.05 at 3 months, respectively. The mean mRS (3.7/3.7) and BI (58.2/53.9) in NBO and control groups improved to 2/2.2 and 73.05/73.8 at the end of 3 months, respectively. CONCLUSIONS: NBO did not improve the clinical scores of stroke outcome in Indian patients with AIS. PMID- 21264138 TI - Central nervous system inflammatory demyelinating disorders of childhood. AB - BACKGROUND AND OBJECTIVES: Childhood Central Nervous System (CNS) inflammatory demyelinating disorders (CIDD) are being diagnosed more commonly now. There is ambiguity in the use of different terms in relation to CIDD. Recently, consensus definitions have been proposed so that there is uniformity in studies across the world. The prevalence of these disorders and the spectrum varies from place to place. This study was undertaken to study the clinico-radiological profile and outcome of children with CIDD using the recent consensus definition. STUDY DESIGN: Prospective descriptive study. MATERIALS AND METHODS: All patients admitted in pediatric ward and pediatric intensive care with neurological symptoms and signs suggestive of CNS inflammatory demyelinating disorders from July 2007-August 2008 were enrolled. The details of clinical presentation, neuroimaging findings, laboratory results, treatment, and outcome were noted and analyzed. RESULTS: Fifteen patients (11 with acute disseminated encephalomyelitis and 4 with clinically isolated syndrome) were diagnosed with CIDD. Clinical presentation was quite varied. Eight patients recovered completely; 4 cases were left with sequelae and 3 patients expired. There were no cases of multiple sclerosis or neuromyelitis optica. CONCLUSIONS: CNS inflammatory demyelinating disorders are common illnesses in developing countries because of recurrent infections. Even the spectrum of CIDD is different. Neuroimaging in the form of magnetic resonance imaging is essential for diagnosis. PMID- 21264139 TI - Cerebrospinal fluid hypovolemia syndrome with benign course. AB - BACKGROUND: The cerebrospinal fluid hypovolemia syndrome (CHS) is an under recognized cause of headache. This study was designed to highlight the clinico radiological and cerebrospinal fluid (CSF) picture of CHS and their long-term outcome from a tertiary referral center. MATERIALS AND METHODS: The CHS was diagnosed on the basis of the criteria proposed by Chung et al. Cases with CSF rhinorrhoea or other CSF leak or head trauma were excluded from the study. RESULTS: The study included eight consecutive cases of CHS diagnosed over the past 7 years from 2001. The mean age at diagnosis was 40.7 years (range, 34-56 years) and male-to-female ratio was 1:3. All patients presented with orthostatic headache of subacute onset and normal neurological examination. Magnetic resonance imaging studies of all patients showed hyperintensity of pachymeninges in T2W sequences, venous distension sign, and diffuse pachymeningeal gadolinium enhancement. The descent of the brainstem and subdural effusion were noted in two each (25%). CSF study (n = 5) showed low opening pressure in three (60%), and mild pleocytosis with elevated protein in two each (40%). The mean time to complete recovery with conservative treatment alone was 25.6 days. All radiological signs disappeared with clinical improvement in three patients where follow-up imaging was done. On mean follow-up period of 3.6 years, all were asymptomatic without any recurrence of CHS. CONCLUSION: CHS can resolve completely with conservative management and intervention with subdural blood patch or surgical repair would be required only if symptoms persist for more than 1 month. PMID- 21264140 TI - Accidental spinal cord injury during spinal anesthesia: A report. PMID- 21264141 TI - Leukoencephalopathy with intracranial calcifications and cysts in an adult: Case report and review of literature. AB - Leukoencephalopathy, intracranial calcifications, and cysts (LCC) is a very rare cerebral disorder, first described in 3 children in 1996. It has subsequently been reported in adults and children from Europe and America, but has not so far been reported from Asia. We report an adult patient with pathologically proven LCC from a tertiary care hospital in South India. He presented with features of ataxia and raised intracranial pressure. Magnetic resonance imaging of the brain showed multiple bilateral cerebral cystic lesions along with diffuse white matter lesions in the cerebral and cerebellar white matter, and computed tomography of brain showed multiple calcifications in the white matter and basal ganglia. A large right cerebellar cyst causing mass effect was surgically excised. Histopathologic features were consistent with earlier reports of LCC and showed Rosenthal fibers, angiomatous changes, and calcifications. Our report suggests that although it is rare, LCC has a global distribution. PMID- 21264142 TI - Fractional arm weakness as presentation of stroke due to posterior borderzone infarct: A report of two cases. AB - A 41-year-old male presented with acute onset weakness of the left hand. Magnetic resonance imaging (MRI) of the brain showed hyperacute infarct in the right middle cerebral artery (MCA)-posterior cerebral artery (PCA) watershed territory. Magnetic resonance angiography (MRA), Doppler ultrasonography, and digital subtraction angiography revealed severe right internal carotid artery (ICA) stenosis. The patient underwent carotid endarterectomy. The second patient was a 48-year-old male with acute onset right wrist drop. MRI of brain showed acute infarct in the left MCA-PCA watershed territory. MRA of brain and neck, Doppler ultrasonography of the neck vessels, and echocardiography were normal. Both the cases were not initially considered strokes by the referring physicians. Isolated hand palsy is a rare presentation of stroke, often mistaken for peripheral lesion. Fractional limb weakness as a presentation of acute ischemic stroke due to borderzone infarction involving parietal lobe is a rarely reported entity. PMID- 21264143 TI - Hyperreflexic Guillain-Barre syndrome. AB - Guillain-Barre syndrome (GBS) is an acquired acute autoimmune polyradiculoneuropathy. The 2 features considered essential for the diagnosis of GBS are progressive motor weakness and areflexia. There have been several descriptions of reflex preservation and hyperreflexia in axonal variant of GBS in Chinese, Japanese, and European populations but it is not common in the Indian subcontinent. We report 2 such cases discussing the pathophysiology and management aspects. This case report is to impress upon treating physicians and neurologists in training that a hyperreflexic variant of GBS albeit rare, should not be missed in a given clinical setting. PMID- 21264144 TI - Spinal meningeal melanocytoma: A rare meningeal tumor. PMID- 21264145 TI - Every non-obstructive hydrocephalus is not due to tuberculous basal meningitis. PMID- 21264146 TI - Beta-interferons in multiple sclerosis. PMID- 21264147 TI - A biomechanical analysis of strength and motion following total shoulder arthroplasty. AB - BACKGROUND: The primary goal of total shoulder arthroplasty (TSA) has traditionally been pain relief and motion improvement. The literature contains multiple studies that have documented the restoration of motion and consistent pain relief following the procedure. However, there has been little attention placed on strength following TSA. Therefore, the purpose of this study was to determine in an objective manner whether strength and motion improve with shoulder arthroplasty and over what time course this may occur. MATERIALS AND METHODS: Between April 2002 and January 2004, 15 patients who underwent TSA for osteoarthritis had biomechanical strength testing preoperatively, at 6 and 12 months postoperatively. The mean age at the time of TSA was 66 years (range, 52 82). None of the patients had full thickness rotator cuff tears at the time of surgery. Peak forces for shoulder flexion, extension, abduction, internal rotation and external rotation strength were recorded. In addition, patients had shoulder range of motion measurements performed. FINDINGS: Range of motion improved significantly with TSA from preoperative to 6 months postoperative: flexion 104 degrees to 147 degrees (P = 0.0034), abduction 86 degrees to 145 degrees (P = 0.0001), internal rotation 43 degrees to 54 degrees (P = 0.0475) and external rotation 25 degrees to 50 degrees (P = 0.0008). There was minimal improvement in range of motion from 6 to 12 months. In contrast, there continued to be improvements in strength from the 6 month to the 12 month postoperative time frame: extension 18.3 kg to 22.4 kg (P = 0.006), abduction 11.3 kg to 12.8 kg (0.0474) and external rotation 8.8 kg to 10.1 kg (P = 0.016). Despite these improvements, compared to normative values, there continued to be relative weakness of the shoulder following TSA. INTERPRETATION: The data from this study suggest that recovery of strength and motion follow different time frames after TSA. The results of this study may allow the surgeon to more accurately discuss with the patient over what time course strength and motion may return. In addition, this study raises important questions in regard to the current rehabilitation program used after shoulder arthroplasty and whether development of new protocols may improve the functional outcome from surgery. LEVEL OF EVIDENCE: Level 2. PMID- 21264148 TI - Are shoulder surgeons any good at diagnosing rotator cuff tears using ultrasound?: A comparative analysis of surgeon vs radiologist. AB - High-resolution ultrasound has gained increasing popularity as an aid in the diagonsis of rotator cuff pathology. With the advent of portable machines, ultrasound has become accessible to clincians. AIM: This study was conducted to evaluate the accuracy and reliability of ultrasound in diagnosing rotator cuff tears by a shoulder surgeon and comparing their ability to that of a musculoskeletal radiologist. MATERIALS AND METHODS: Seventy patients undergoing shoulder arthroscopy for rotator cuff pathology underwent preoperative ultrasonography (US). All patients were of similar demographics and pathology. The surgeon used a Sonosite Micromax portable ultrasound machine with a 10-MHz high frequency linear array transducer and the radiologist used a 9-12 MHz linear array probe on a Siemens Antares machine. Arthroscopic diagnosis was the reference standard to which ultrasound findings were compared. RESULTS: The sensitivity in detecting full thickness tears was similar for both the surgeon (92%) and the radiologist (94%). The radiologist had 100% sensitivity in diagnosing partial thickness tears, compared to 85.7% for the surgeon. The specificity for the surgeon was 94% and 85% for the radiologist. DISCUSSION: Our study shows that the surgeons are capable of diagnosing rotator cuff tears with the use of high-resolution portable ultrasound in the outpatient setting. CONCLUSION: Office ultrasound, by a trained clinician, is a powerful diagnostic tool in diagnosing rotator cuff tears and can be used effectively in running one stop shoulder clinics. PMID- 21264149 TI - The CT-arthrography in the antero-inferior glenoid labral lesion: Pictorial presentation and diagnostic value. AB - OBJECTIVE: To present the Computed Tomography (CT)-Arthrography appearance of the most common types of anterior labral lesion and to assess the diagnostic value of this technique in the detection and classification of the antero-inferior labral tears in glenohumeral joint instability. MATERIALS AND METHODS: The pre-operative CT-Arthrography records of 43 patients, who underwent surgery for anterior shoulder instability, were retrospectively evaluated independently by two radiologists. The data were compared with arthroscopic results and the diagnostic accuracy of CT-Arthrography was calculated to detect the labral lesion and the agreement between the CT-Arthrography lesions classification and the arthroscopy classification. RESULTS: The CT-Arthrography sensitivity, specificity and accuracy were: 92% / 89% (reader 1/reader 2), 86% / 86% and 91% / 88% respectively. The CT-Arthrography classification was correct in 86% of cases. CONCLUSIONS: CT-Arthrography appears to be an accurate means for identification and classification of the anterior labral tears and, identifying the labral degeneration, this technique can be very helpful in the selection of patient for arthroscopic stabilization of the shoulder. PMID- 21264151 TI - Sport related stress fracture of the clavicle with non-union: Case report and review. AB - Stress fractures are relatively uncommon sports injuries and when they do occur, are mostly found in the lower limb. Stress fractures of the clavicle are particularly rare, having been described in a number of non-sport related pathologies, such as nervous tics and post radical neck dissection. In sport, there have only been seven cases reported in the literature. We report on a clavicle stress fracture in a 47-year-old male, partaking in recreational weight lifting activities. This is the first reported case of a non-union stress fracture of the clavicle. The patient underwent an open reduction and internal fixation and made a full recovery. PMID- 21264150 TI - Clinical results of coracoacromial ligament transfer in acromioclavicular dislocations: A review of published literature. AB - Acromioclavicular joint dislocations are common injuries, which typically occur with trauma in young men. Treatment recommendations for these injuries are highly variable and controversial. There are greater than 100 surgical techniques described for operative treatment of this injury. One of the most widely recommended methods of surgical reconstruction for acromioclavicular joint dislocations is to utilize the coracoacromial ligament for stabilization of the distal clavicle. Several modifications of this procedure have been described which have involved adjunct coracoclavicular fixation or fixation across acromioclavicular joint. Although the literature is replete with descriptive papers, there is paucity of studies evaluating the surgical outcome of this procedure. We systematically reviewed the English language published literature in peer reviewed journals (Medline, EMBASE, SCOPUS) and assigned a level of evidence for available studies. We critically reviewed each paper for the flaws and biases and then evaluated the comparable clinical outcomes for various procedures and their modifications. The published literature consists entirely of case series (Level IV evidence) with variability in surgical technique and outcome measures. On review there is low level evidence to support the use of coracoacromial ligament for acromioclavicular dislocation but it has been associated with high rate of deformity recurrence. Adjunct fixation does not improve clinical results when compared to isolated coracoacromial ligament transfer. This is in part because of the high incidence of fixation related complications. Similar results are reported with coracoacromial ligament reconstruction for acute and chronic cases. The development of secondary acromioclavicular joint symptoms with distal clavicle retention is poorly reported with the incidence rate varying from 12% to 32%. Despite this, the retention or excision of distal clavicle did not affect overall clinical results except in the patients with pre existing acromioclavicular joint osteoarthritis who have inferior results with retention of distal end of clavicle. Further well designed clinical trials with validated outcome measures are required to fully evaluate the clinical results of this procedure. PMID- 21264152 TI - Reviewing the peer review. PMID- 21264153 TI - Peptides and proteins with antimicrobial activity. AB - The increase of microbial resistance to antibiotics has led to a continuing search for newer and more effective drugs. Antimicrobial peptides are generally found in animals, plants, and microorganisms and are of great interest to medicine, pharmacology, and the food industry. These peptides are capable of inhibiting pathogenic microorganisms. They can attack parasites, while causing little or no harm to the host cells. The defensins are peptides found in granules in the polymorphonuclear neutrophils (PMNs) and are responsible for the defense of the organism. Several animal defensins, like dermaseptin, antileukoprotease, protegrin, and others, have had their activities and efficacy tested and been shown to be effective against bacteria, fungi, and protists; there are also specific defensins from invertebrates, e.g., drosomycin and heliomicin; from plants, e.g., the types A and B; and the bacteriocins, e.g., acrocin, marcescin, etc. The aim of the present work was to compile a comprehensive bibliographic review of the diverse potentially antimicrobial peptides in an effort to systematize the current knowledge on these substances as a contribution for further researches. The currently available bibliography does not give a holistic approach on this subject. The present work intends to show that the mechanism of defense represented by defensins is promising from the perspective of its application in the treatment of infectious diseases in human, animals and plants. PMID- 21264154 TI - The potential role of vildagliptin in the management and prevention of type 2 diabetes mellitus. AB - Proper control of blood sugar in type 2 diabetes mellitus (T2DM) is not adequate till now in spite of use of well-planned dosage regimens containing oral hypoglycemic agents/insulin or both. Recently, the role of 'incretins,' particularly that of glucagon-like peptide-1 (GLP-1) in glucose homeostasis has been firmly established. The peptide (GLP-1) increases insulin secretion while decreasing that of glucagon in response to rise in plasma glucose in addition to delay of gastric emptying time, reduction of appetite, preservation of beta-cell function, and increase in beta-cell mass all of which will contribute toward lowering of blood sugar in T2DM. But the peptide hormone cannot be used orally as such because of its very short plasma half-life (2 min) and chemical nature, which needs continuous i.v. infusion or repeated s.c. or i.v. injections at short intervals. Hence, to prolong the duration of action of endogenous GLP-1, compounds have been synthesized which inhibit the enzyme dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for metabolic degradation of GLP-1. One such compound is vildagliptin. In this article, an attempt has been made to compile some of the established recent advances in the therapeutic utility of vildagliptin along with a discussion about the physiological role of endogenous GLP-1 and its metabolism by DPP-4. PMID- 21264155 TI - Evaluation of hypoglycemic effect of Morus alba in an animal model. AB - OBJECTIVE: The objective of the present investigation was to evaluate the therapeutic efficacy of mulberry leaves in an animal model of diabetes. MATERIALS AND METHODS: Animals were treated with mulberry leaf extract 400 mg and 600 mg/kg body weight for 35 days. Blood glucose, glycosylated hemoglobin, triglyceride, LDL, VLDL, HDL, blood urea, cholesterol, number of beta cells, and diameter of the islets of Langerhans were measured at the beginning and at the end of the experiment. RESULTS: Blood glucose level and other parameters (except HDL) were elevated in the diabetic group, but were brought to control group level in the diabetic group treated with 600 mg/kg body weight of mulberry leaf extract. The diameter of the islets and the number of beta cells were reduced in the diabetic group; both parameters were brought to control group level after treatment with mulberry leaf extract. CONCLUSION: Mulberry leaf extract, at a dose of 600 mg/kg body weight, has therapeutic effects in diabetes-induced Wistar rats and can restore the diminished beta cell numbers. PMID- 21264156 TI - Antidiabetic activity of aqueous root extract of Ichnocarpus frutescens in streptozotocin-nicotinamide induced type-II diabetes in rats. AB - OBJECTIVE: To evaluate the antidiabetic activity of aqueous extract of roots of Ichnocarpus frutescens in streptozotocin-nicotinamide induced type-II diabetes in rats. MATERIALS AND METHODS: Streptozotocin-nicotinamide induced type-II diabetic rats (n = 6) were administered aqueous root extract (250 and 500 mg/kg, p.o.) of Ichnocarpus frutescens or vehicle (gum acacia solution) or standard drug glibenclamide (0.25 mg/kg) for 15 days. Blood samples were collected by retro orbital puncture and were analyzed for serum glucose on days 0, 5, 10, and 15 by using glucose oxidase-peroxidase reactive strips and a glucometer. For oral glucose tolerance test, glucose (2 g/kg, p.o.) was administered to nondiabetic control rats and the rats treated with glibenclamide (10 mg/kg, p.o.) and aqueous root extract of Ichnocarpus frutescens. The serum glucose levels were analyzed at 0, 30, 60, and 120 min after drug administration. The effect of the extract on the body weight of the diabetic rats was also observed. RESULTS: The aqueous root extract of Ichnocarpus frutescens (250 and 500 mg/kg, p.o.) induced significant reduction (P < 0.05) of fasting blood glucose levels in streptozotocin nicotinamide induced type-II diabetic rats on the 10(th) and 15(th) days. In the oral glucose tolerance test, the extract increased the glucose tolerance. It also brought about an increase in the body weight of diabetic rats. CONCLUSION: It is concluded that Ichnocarpus frutescens has significant antidiabetic activity as it lowers the fasting blood sugar level in diabetic rats and increases the glucose tolerance. PMID- 21264157 TI - Hypoglycemic and hypolipidemic activity of ethanolic extract of Salvadora oleoides in normal and alloxan-induced diabetic rats. AB - OBJECTIVE: To find out the hypoglycemic and hypolipidemic activity of an ethanolic extract of the aerial part of Salvadora oleoides Decne in euglycemic and alloxan-induced diabetic albino rats. MATERIALS AND METHODS: Diabetes was induced in albino rats by administration of alloxan monohydrate (120 mg/kg, i.p.). Normal as well as diabetic albino rats were divided into groups (n = 6) receiving different treatments: vehicle (control), ethanolic extract (1 g and 2 g/kg b.w), and standard antidiabetic drug tolbutamide (0.5 g/kg b.w.). Blood samples were collected by cardiac puncture and were analyzed for blood glucose and lipid profile on days 0, 7, 14, and 21. RESULTS: The ethanolic extract of S oleoides produced significant reduction (P < 0.001) in blood glucose and also had beneficial effects (P < 0.001) on the lipid profile in euglycemic as well as alloxan-induced diabetic rats at the end of the treatment period (21(st) day). However, the reduction in the blood glucose and improvement in lipid profile was less than that achieved with the standard drug tolbutamide. CONCLUSION: We concluded that an ethanolic extract of S oleoides is effective in controlling blood glucose levels and improves lipid profile in euglycemic as well as diabetic rats. PMID- 21264158 TI - Antiasthmatic activity of Moringa oleifera Lam: A clinical study. AB - The present study was carried out to investigate the efficacy and safety of seed kernels of Moringa oleifera in the treatment of bronchial asthma. Twenty patients of either sex with mild-to-moderate asthma were given finely powdered dried seed kernels in dose of 3 g for 3 weeks. The clinical efficacy with respect to symptoms and respiratory functions were assessed using a spirometer prior to and at the end of the treatment. Hematological parameters were not changed markedly by treatment with M. oleifera. However, the majority of patients showed a significant increase in hemoglobin (Hb) values and Erythrocyte sedimentation rate (ESR) was significantly reduced. Significant improvement was also observed in symptom score and severity of asthmatic attacks. Treatment with the drug for 3 weeks produced significant improvement in forced vital capacity, forced expiratory volume in one second, and peak expiratory flow rate values by 32.97 +/ 6.03%, 30.05 +/- 8.12%, and 32.09 +/- 11.75%, respectively, in asthmatic subjects. Improvement was also observed in % predicted values. None of the patients showed any adverse effects with M. oleifera. The results of the present study suggest the usefulness of M. oleifera seed kernel in patients of bronchial asthma. PMID- 21264159 TI - Effect of Morus alba L. (mulberry) leaves on anxiety in mice. AB - OBJECTIVE: The aim of the present work is to evaluate the anxiolytic effect of a methanolic extract of Morus alba L. leaves in mice. MATERIALS AND METHODS: The hole-board test, elevated plus-maze paradigm, open field test, and light/dark paradigm were used to assess the anxiolytic activity of the methanolic extract of M. alba L. Morus alba extract (50, 100, and 200 mg/kg, i.p.) and diazepam (1 mg/kg, i.p.) were administered 30 min before the tests. RESULTS: The results showed that the methanolic extract of M. alba significantly increased the number and duration of head poking in the hole-board test. In the elevated plus-maze, the extract significantly increased the exploration of the open arm in similar way to that of diazepam. At a dose of 200 mg/kg i.p. the extract significantly increased both the time spent in and the entries into the open arm by mice. Further, in the open field test, the extract significantly increased rearing, assisted rearing, and number of squares traversed, all of which are demonstrations of exploratory behavior. In the light/dark paradigm, the extract produced significant increase in time spent in the lighted box as compared to vehicle. The spontaneous locomotor activity count, measured using an actophotometer, was significantly decreased in animals pretreated with M. alba extract, indicating a remarkable sedative effect of the plant. CONCLUSION: The results of the present study suggest that a methanolic extract of M. alba leaves may possess an anxiolytic effect. PMID- 21264160 TI - Adverse Drug Reactions (ADR) in the inPatients of Medicine Department of a Rural Tertiary Care Teaching Hospital and Influence of Pharmacovigilance in Reporting ADR. AB - OBJECTIVES: (i) To find the incidence and study various aspects of Adverse Drug Reactions (ADR) in the inpatients of medicine department of Shree Krishna Hospital, a rural tertiary care teaching hospital. (ii) To test the impact of pharmacovigilance in reporting ADR. MATERIAL #ENTITYSTARTX00026; METHODS: A prospective study involving 600 patients admitted to the medical wards and TB & Chest diseases ward over a period of six months and a retrospective analysis of 600 case files for the corresponding period of the previous year were carried out to find the incidence rate of ADR, study various aspects of ADR like causality assessment, drugs frequently causing ADR etc. Suitably structured and pre-tested format was used for compiling the data. RESULTS: In the prospective study, 18 of the 600 patients (3%) developed ADR. A significant number (77.78%) of patients developed ADR between the 3(rd) and 10(th) days of administering the drug/s. As the number of drugs increased, the incidence of ADR also increased. Majority of ADR (72.22%) occurred due to chemotherapeutic agents. 66.67% of ADR involved the gastrointestinal tract. None of the ADR was fatal. Sex of the patients did not influence the incidence rate of ADR. On the other hand, in the retrospective analysis, only ADR were reported in just 6 out of 600 patients (1%). CONCLUSION: The incidence rate of ADR is found to be much lower (3%) than the reported rate (10%-20%). Pharmacovigilance certainly contributes to picking up ADR. PMID- 21264161 TI - Antibacterial, antifungal and cytotoxic activities of amblyone isolated from Amorphophallus campanulatus. AB - OBJECTIVE: To assess the in vitro antibacterial, antifungal and cytotoxic activities of amblyone, a triterpenoid isolated from Amorphophallus campanulatus (Roxb). METHODS: Disc diffusion technique was used for in vitro antibacterial and antifungal screening. Cytotoxicity was determined against brine shrimp nauplii. In addition, minimum inhibitory concentration (MIC) was determined using serial dilution technique to determine the antibacterial potency. RESULTS: Large zones of inhibition were observed in disc diffusion antibacterial screening against four Gram-positive bacteria (Bacillus subtilis, Bacillus megaterium, Staphylococcus aureus and Streptococcus pyogenes) and six Gram-negative bacteria (Escherichia coli, Shigella dysenteriae, Shigella sonnei, Shigella flexneri, Pseudomonas aeruginosa and Salmonella typhi). The MIC values against these bacteria ranged from 8 to 64 MUg/ml. In antifungal screening, the compound showed small zones of inhibition against Aspergillus flavus, Aspergillus niger and Rhizopus aryzae. Candida albicans was resistant against the compound. In the cytotoxicity determination, LC(50) of the compound against brine shrimp nauplii was 13.25 MUg/ml. CONCLUSIONS: These results suggest that the compound has good antibacterial activity against the tested bacteria, moderate cytotoxicity against brine shrimp nauplii and insignificant antifungal activity against the tested fungi. PMID- 21264162 TI - A case of ciprofloxacin-induced erythema multiforme. AB - A 25 year old male admitted to the medical college hospital with presenting complaint of fever, skin rashes and itching. Before admission he had consulted a local doctor for fever, who had prescribed him Tablet ciprofloxacin 500mg twice daily and Tablet. Paracetamol 500 mg thrice daily. The patient had taken 6 tablets of ciprofloxacin before he developed the above symptoms. On detailed clinical examination multiple erythematous papule and plaques were present on the face, abdomen and neck. Target (Iris) lesions were seen on the extersor surface of both upper and lower limbs measuring about 1-2 cm in size. Multiple erythematous lesion were also found in mucosa of soft and hard palate, Uvula and posterior pharyngeal wall. Lower lips were swollen and edematous, Lymphnodes in the neck were enlarged and tender. The clinical features with which the patient presented were similar to those seen in a typical case of erythema multiforme and the patient recovered after stopping ciprofloxacin, Further rechallenge with oral ciprofloxacin was not done in the interest of patient and due to ethical constraints. This case is being reported for rare and potential fatal drug reaction with ciprofloxacin. PMID- 21264163 TI - Difficult-to-treat asthma, is it really difficult? PMID- 21264164 TI - Sleep medicine in Saudi Arabia: Current problems and future challenges. AB - Sleep medicine is a relatively new specialty in the medical community. The practice of sleep medicine in Saudi Arabia (KSA) began in the mid to late nineties. Since its inception, the specialty has grown, and the number of specialists has increased. Nevertheless, sleep medicine is still underdeveloped in the KSA, particularly in the areas of clinical service, education, training and research. Based on available data, it appears that sleep disorders are prevalent among Saudis, and the demand for sleep medicine service is expected to rise significantly in the near future. A number of obstacles have been defined that hinder the progress of the specialty, including a lack of trained technicians, specialists and funding. Awareness about sleep disorders and their serious consequences is low among health care workers, health care authorities, insurance companies and the general public. A major challenge for the future is penetrating the educational system at all levels to demonstrate the high prevalence and serious consequences of sleep disorders. To attain adequate numbers of staff and facilities, the education and training of health care professionals at the level of sleep medicine specialists and sleep technologists is another important challenge that faces the specialty. This review discusses the current position of sleep medicine as a specialty in the KSA and the expected challenges of the future. In addition, it will guide clinicians interested in setting up new sleep medicine services in the KSA or other developing countries through the potential obstacles that may face them in this endeavor. PMID- 21264165 TI - Evaluation of mediastinal lymph nodes using F-FDG PET-CT scan and its histopathologic correlation. AB - AIMS AND OBJECTIVES: To determine the efficacy of integrated (18)F-fluorodeoxy glucose positron emission tomography-computed tomography ((18)F-FDG PET-CT) in the evaluation and characterization of mediastinal lymph nodes into benign and malignant pathology. METHODS: Thirty-five patients with mediastinal lymphadenopathies without primary neoplastic or infective lung pathologies were included in the study. The lymph nodes were detected on contrast-enhanced CT scan of the chest. All patients underwent (18)F-FDG PET-CT scan for evaluation of mediastinal lymph nodes. Results of PET-CT were compared with histopathology of the lymph nodes and sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. STATISTICAL ANALYSIS: The data were collected prospectively and analyzed using (SPSS Inc., Chicago, IL) 11.5 software. RESULTS: Histopathology results in 35 patients revealed tuberculosis in 12, sarcoidosis in 8, and lymphoma in 15. Maximum standardized uptake value (SUVmax) of the benign lymph nodes ranged from 2.3 to 11.8 with a mean+/-standard deviation (SD) of 5.02+/-3.26. SUVmax of the malignant lymph nodes ranged from 2.4 to 34 with a mean+/-SD of 10.8+/-8.12. There was a statistically significant difference between benign and malignant pathology (P<0.0059). (18)F-FDG PET-CT has sensitivity of 93% and specificity of 40% with SUVmax 2.5 as the cutoff. We found the optimal SUVmax cutoff to be 6.2 as determined by the receiver-operator characteristic curve. With 6.2 as cutoff, the sensitivity, specificity, and accuracy were 87%, 70%, and 77%, respectively. CONCLUSION: In countries where tuberculosis and other granulomatous diseases are endemic, SUVmax cutoff value of 2.5 has low specificity. Increasing the cutoff value can improve the specificity, while maintaining an acceptable sensitivity. PMID- 21264166 TI - Tracheal reconstruction by re-inforced Gore-Tex in esophageal submuscular tunneling: An experimental study. AB - BACKGROUND: Tracheal reconstructions are aimed at rearranging or replacing parts of the tracheal tissue by different techniques. Here we introduce a new technique for tracheal reconstruction. METHODS: In 10 adult dogs, after intubation with an endotracheal tube, a segment of trachea including seven tracheal rings was resected circumferentially. A submuscular tunnel was induced between mucosal and muscular layers of the adjacent esophagus lying right next to the trachea. The esophageal submuscular tunnel starts and ends exactly at the level of distal and proximal ends of tracheal resection, respectively. Inforced Gore-Tex passed through the esophageal submuscular tunnel the distal segment of trachea and end to-end anastomosis were made between distal ends of Gore-Tex and trachea, then endotracheal tube removed and the same procedure was made for proximal ends of Gore-Tex and trachea. Afterward, the proximal and distal ends of the esophageal tunnel were approximated to proximal and distal tracheal parts over the anastomosis. RESULTS: All dogs, except one due to anesthetic problem, survived and tolerated the operation; the first two dogs experienced postoperative fever, aspiration pneumonia, and died due to tracheoesophageal fistula. All survived animals were eating and barking well. We started to scarify dogs at least 6 and 12 weeks after operation for microscopy and pathologic examination. The Gore Texes were patent and supported externally with fibrous connective tissue in esophageal tunneling, with in growth of respiratory epithelium on inner surfaces. CONCLUSION: Air tightness, good re-epithelialization, and relatively no limitation of esophageal length and no risk of luminal collapse are advantages of tracheal reconstruction by submuscular esophageal tunneling. This new method is worthy of further investigation, as it is technically feasible and easy to implement. PMID- 21264167 TI - Sarcoidosis in the eastern region of Saudi Arabia. AB - AIM: To review a general hospital's experience with sarcoidosis and the clinical pattern of the disease among Saudis. METHODS: A retrospective file review was carried out on all patients with a proven diagnosis of sarcoidosis in a general hospital in Eastern Saudi Arabia over a period of 11 years (1998-2008). RESULTS: Sixty-nine patients, of whom 33 cases were included in the analyses, were diagnosed to have sarcoidosis during the study period. There were 18 females and 15 males. The mean age was 44.5 years (SD 17). The most common presentations were cough (48%), dyspnea (21%), joint pain (18%), splenomegaly (12%), hepatomegaly (9%), and lymphadenopathy (5%). The biochemical analysis showed elevated calcium levels in 6% and elevated angiotensin converting enzyme (ACE) in 14 (46.7%). The tuberculin skin test was negative in all tested patients (n = 29) except one patient. The patients were classified using the modified Scadding classification system. None of the patients was in stage 0, 39.4% were in stage 1, 45% were in stage 2 and 15% were in stage 3.. The diagnosis in all patients was proven histologically. The outcome was favorable in most patients (85%), and in 6% of the patients, the course was chronic and progressive, although 66% received active treatment. CONCLUSION: Sarcoidosis does occur in native Saudis. The clinical presentation of these patients was similar to the western pattern of disease with some differences such as relative lack of cardiac, eye, parotid, and central nervous system involvement. The rarity of cardiac and central nervous system involvement was comparable with other Middle Eastern studies. Sarcoidosis, though rare in our community, should still be considered in the differential diagnosis of patients with the typical presentation after excluding tuberculosis. PMID- 21264168 TI - Surgery for bronchiectasis: The effect of morphological types to prognosis. AB - BACKGROUND: Although the incidence has declined over the past years in societies with high socioeconomic status, bronchiectasis is still an important health problem in our country. AIM: To review and present our cases undergoing surgery for bronchiectasis in the past 12 years and their early and late term postoperative outcomes and our experience in bronchiectasis surgery and the effect of morphological type on the prognosis. METHODS: The medical records of 62 cases undergoing surgical resection for bronchiectasis in the Clinics of Thoracic and Pediatric Surgery were evaluated retrospectively. The disease was on the left in 33 cases, on the right in 26 and bilateral in three cases. The most common surgical procedure was lobectomy. Forty one patients underwent pneumonectomy, lobectomy and complete resection including bilobectomy. Twenty-one (33.87%) cases underwent incomplete resection, of whom 11 (17.74%) underwent segmentectomy and 10 (16.13%) underwent lobectomy + segmentectomy. RESULTS: It was found that the rate of being asymptomatic was significantly higher in patients undergoing complete resection compared to those undergoing incomplete resection. Spirometric respiratory function tests were performed to assess the relationship between morphological type and the severity of disease. All parameters of respiratory function were worse in the saccular type and FEV(1)/FVC showed a worse obstructive deterioration in the saccular type compared to the tubular type. CONCLUSION: The success rate of the procedure increases with complete resection of the involved region. The morphological type is more important than the number and extension of the involved segments in showing the disease severity. PMID- 21264169 TI - Comparison and agreement between venous and arterial gas analysis in cardiopulmonary patients in Kashmir valley of the Indian subcontinent. AB - BACKGROUND: Arterial blood gas (ABG) analysis is routinely performed for sick patients but is fraught with complications, is painful, and is technically demanding. OBJECTIVE: To ascertain agreement between the arterial and peripheral venous measurement of pH, pCO(2), pO(2), and bicarbonate levels in sick patients with cardiopulmonary disorders in the valley of Kashmir in the Indian subcontinent, so as to use venous gas analysis instead of arterial for assessment of patients. SETTING: Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Kashmir, a 650-bedded tertiary care hospital in North India located at an altitude of 1584 m. METHODS: One hundred patients who required ABG analysis were admitted. Peripheral venous blood was drawn within 5 min of an ABG measurement, and the samples analyzed immediately on a point of care automated ABG analyzer. Finger pulse oximetry was used to obtain oxygen (SpO(2)) saturation. Data were analyzed using Pearson correlation and bias (Bland Altman) methods. RESULTS: The venous measurements of pH, pCO(2), pO(2) and bicarbonate, and the digital oxygen saturation were highly correlated with their corresponding arterial measurements. Bland Altman plots demonstrated a high degree of agreement between the two corresponding sets of measurements with clinically acceptable differences. The difference in pO(2) measurements was, however, higher (-22.34 +/- 15.23) although the arterial saturation and finger oximetry revealed a good degree of agreement with clinically acceptable bias. CONCLUSION: Peripheral venous blood gas assessment in conjunction with finger pulse oximetry can obviate the routine use of arterial puncture in patients requiring ABG analysis. PMID- 21264170 TI - A near fatal complication following stenting of thoracic aortic aneurysm. AB - Tracheobronchial obstruction along with compression of pulmonary vessels is a rare complication after stenting of aortic aneurysm. We present this rare situation in a young patient who underwent stenting of traumatic thoracic aortic aneurysm and developed this near fatal complication and also the conservative management plan which we adopted to manage this case. PMID- 21264171 TI - Esophagobronchial fistula - A rare complication of aluminum phosphide poisoning. AB - Aluminum phosphide is a systemic lethal poison. Fistulous communication between esophagus and airway tract (esophagorespiratory fistula) has rarely been reported in the survivors of aluminum phosphide poisoning. We report a case of benign esophagobronchial fistula secondary to aluminum phosphide poisoning, which to best of our knowledge has not been reported in the medical literature. PMID- 21264172 TI - An elderly man with pulmonary hypertension. PMID- 21264173 TI - Filarial pleural effusion. PMID- 21264174 TI - Smoking, once again. PMID- 21264175 TI - What dose of anti-snake venom should be given in severe neuroparalytic snake bite? PMID- 21264176 TI - Author's reply. PMID- 21264177 TI - Electrocautery, bronchoscopic biopsy and hemorrhage. PMID- 21264178 TI - Preface to the fourth issue of Journal of Cardiovascular Disease Research. PMID- 21264179 TI - The role of RhoA/Rho kinase pathway in endothelial dysfunction. AB - Endothelial dysfunction is a key event in the development of vascular disease, and it precedes clinically obvious vascular pathology. Abnormal activation of the RhoA/Rho kinase (ROCK) pathway has been found to elevate vascular tone through unbalancing the production of vasodilating and vasoconstricting substances. Inhibition of the RhoA/ROCK pathway can prevent endothelial dysfunction in a variety of pathological conditions. This review, based on recent molecular, cellular, and animal studies, focuses on the current understanding of the ROCK pathway and its roles in endothelial dysfunction. PMID- 21264180 TI - Red wine: A drink to your heart. AB - Mortality and morbidity are still high in cardiovascular disease (CVD). Myocardial ischemia reperfusion injury leading to myocardial infarction is one of the most frequent causes of the death in humans. Atherosclerosis and generation of reactive oxygen species through oxidative stress is the major risk factor for CVD. From the literature collection, it has been identified that moderate consumption of red wine helps in preventing CVD through several mechanisms, including increasing the high-density lipoprotein cholesterol plasma levels, decreasing platelet aggregation, by antioxidant effects, and by restoration of endothelial function. The aim of this review is to discuss the accumulating evidence that suggests that red wine possesses a diverse range of biological actions and may be beneficial in the prevention of CVD. PMID- 21264181 TI - Myocardial involvement in the hemodynamic abnormalities associated with acute rheumatic fever. AB - BACKGROUND AND AIM: Rheumatic fever is still a common cause of acquired heart disease in children and young adult in many developing countries. The aim was to investigate the role of myocardial involvement in the hemodynamic changes in patients with acute rheumatic fever using cardiac troponin assay and echocardiography. DESIGN: A prospective cohort study was designed. PATIENTS AND METHODS: Thirty-four children with acute rheumatic fever, 20 with carditis, and 14 without carditis. Level of cardiac troponin T (cTnT) and echocardiographic measurement of left ventricular function were the main outcome measure. RESULTS: The level of cardiac troponin in children with carditis was 0.051 +/- 0.01 ng/dL, and it was 0.039 +/- 0.02 ng/dL in those without carditis. The difference is not significant. In addition, there was no significant difference between the children with carditis and those without carditis regarding left ventricular ejection and shortening fractions. CONCLUSION: There are no significant echocardiographic measurements abnormalities or cTnT levels elevation suggesting clinically relevant hemodynamic abnormalities due to myocardial involvement during acute rheumatic fever. PMID- 21264182 TI - Multiple transcatheter interventions in the same session in congenital cardiopathies. AB - BACKGROUND: To investigate the methods of percutaneous transcatheter interventions for combined congenital heart disease and to evaluate its efficacy in children. MATERIALS AND METHODS: Thirty cases (ages 3 days-13.5 years, body weight 3-35 kg) that underwent two multiple transcatheter interventions for combined or solitary congenital heart disease were retrospectively analyzed and presented. RESULTS: A total of 61 transcatheter interventions were performed in 30 patients as combined procedures. In 29 patients, two different procedures were combined in the same session, in remaining one patient, combination of three interventions were performed in the same catheter session. Interventions performed in combined procedures were as follows: Coarctation balloon angioplasty in 12 cases, pulmonary balloon valvuloplasty in 10, PDA coil embolization in 10, aortic balloon valvuloplasty in 8, VSD closure in 5, ASD closure in 4, ductal stent implantation in 4, palliative pulmonary balloon valvuloplasty in 3, recanalization and angioplasty of the systemic-pulmonary shunt in 2, balloon atrial septostomy in one, aortic coarctation stent implantation in one, coil embolization of a pulmonary lobar sequestration in one and pulmonary valve perforation plus pulmonary balloon valvuloplasty in one were performed as first or second procedure. There was no mortality or major morbidity in relation to combined procedures. CONCLUSION: Multiple transcatheter interventions in the same session are feasible, safe and effective with satisfactory good results. Second intervention may be performed as complementary procedure or independently to the first intervention. PMID- 21264183 TI - Allopurinol and global left myocardial function in heart failure patients. AB - BACKGROUND AND AIM: Increased xanthine oxidase (XO) activity may contribute to heart failure pathophysiology. This study evaluated whether a XO inhibitor, allopurinol produces clinical and functional benefits in patients with New York Heart Association functional class III to IV heart failure due to systolic dysfunction receiving optimal medical therapy as estimated by global left myocardial function. PATIENTS AND METHODS: Fifty-nine patients with a diagnosis of chronic heart failure due to coronary heart disease or idiopathic dilated cardiomyopathy and 20 healthy controls who attended the outpatient clinic of cardiology were subjected to full echocardiographic study including left ventricular diastolic and systolic function, and the combined index of myocardial performance [Tei index: isovolumetric relaxation time (IRT) + isovolumetric contraction time (ICT)/ejection time (ET)]. Patients were randomized to allopurinol (300 mg/day) or placebo. Improvement at 36 weeks was assessed using a composite end point comprising global left cardiac function as well as heart failure morbidity and mortality. RESULTS: The percentage of patients characterized as improved, unchanged, or worsened did not differ between those receiving allopurinol or placebo. Allopurinol reduced serum uric acid (SUA) by 1.5 mg/dL (P = 0.001). In a subgroup analysis, patients with elevated SUA (more than 7mg/ dL) responded favorably to allopurinol whereas those with SUA less than 7mg/dL exhibited a trend toward no change. In addition, SUA reduction to allopurinol correlated with favorable clinical and functional response. Within the entire allopurinol patient cohort, those characterized as either improved or unchanged had significantly greater reductions in SUA compared with patients who did not change (P = 0.0007). In placebo patients, lower baseline SUA, but not change in SUA, correlated with improved clinical outcome. CONCLUSIONS: Allopurinol did not produce significant clinical and functional improvement in unselected patients with moderate-to-severe heart failure. However, it is suggested that it is useful in patients with elevated SUA in a manner according to degree of SUA reduction. SUA may serve as a valuable biomarker to target heart failure therapy. PMID- 21264184 TI - Predictors of uncontrolled hypertension and antihypertensive medication nonadherence. AB - BACKGROUND: Although hypertension is, in most cases, a controllable major risk factor in the development of cardiovascular disease, studies have demonstrated that hypertension remains poorly controlled in Portugal. Our aim was to evaluate the covariates associated with poor blood pressure (BP) control in a Portuguese hypertensive population. PATIENTS AND RESULTS: We conducted a cross-sectional survey in a hospital hypertension outpatient clinic, located in the Eastern Central Region of Portugal. Patients attending the clinic from July to September 2009 were asked to participate in a structured interview including medication adherence and knowledge about hypertension. Eligible participants were all adults aged 18 or over with an established diagnosis of arterial hypertension and had been on antihypertensive drug treatment for at least 6 months. Exclusion criteria were dementia, pregnancy, and breastfeeding. Detailed clinical information was prospectively obtained from medical records. A total of 197 patients meeting the inclusion criteria and consenting to participate completed the interview. Of these, only 33.0% had their BP controlled according to the JNC 7 guidelines. Logistic regression analysis revealed three independent predictors of poor BP control: living alone (OR = 5.3, P = 0.004), medication nonadherence (OR = 4.8, P < 0.001), and diabetes (OR = 4.4, P = 0.011). Predictors of medication nonadherence were: unawareness of target BP values (OR = 3.7, P < 0.001), a report of drug side effects (OR = 3.7, P = 0.002), lack of BP monitoring (OR = 2.5, P = 0.015) and unawareness of medication indications (OR = 2.4, P = 0.021), and of hypertension risks (OR = 2.1, P = 0.026). CONCLUSIONS: Poor medication adherence, lack of information about hypertension, and side effects should be considered as possible underlying causes of uncontrolled BP and must be addressed in any intervention aimed to improve BP control. PMID- 21264185 TI - Multiple arterial emboli secondary to left ventricular thrombus in a 35-year-old obese male. AB - The very unusual case of a 35-year-old obese male patient with a left ventricular (LV) thrombus secondary to a silent myocardial infarction and resultant shower emboli to multiple arterial sites is described. His presentation with acute limb ischemia led to arterial imaging and the identification of the underlying cardiac pathology in addition to splenic and bilateral renal infarcts. He was also found to suffer from previously undiagnosed hypertension. He underwent femoral embolectomy and multiple arterial revascularization attempts but required bilateral above knee amputations and a prolonged intensive care unit stay. This rare and extreme example of a LV thrombus in a young male emphasizes the potential sequellae of the condition. Furthermore, with the increasing incidence of obesity this case demonstrates the importance of considering undiagnosed cardiovascular risk factors when assessing obese patients. PMID- 21264186 TI - Aortico-left ventricular tunnel experience on three different ages. AB - Aortico-left ventricular tunnel is extremely rare congenital paravalvar communication between the aorta and the left ventricle. Usually it is treated surgically. In addition to the surgery the tunnel can be closed by percutaneous transcatheter intervention in appropriate patients. We present in this paper 7 months, 10 years, and 1,5 months old three male cases with aortico-left ventricular tunnel that were surgically treated and followed up within 7 years in our clinic. PMID- 21264187 TI - Modification of atrioventricular node in a special condition treating paroxysmal supraventricular tachycardia. AB - Modification of atrioventricular node is a usual and necessary operation to cure atrioventricular nodal reentrant tachycardia (AVNRT). In this operation, atrioventricular block is the most severe complication and its prevention is of our great concern. This complication always occurs under some special circumstances with potential risk. So, it is very important to realize such conditions, as in this paper. A patient with paroxysmal palpitation for 10 years, aggravating to shortness of breath with chest distress for 1 year; cardiac electrophysiological examination found slow conduction in both antegrade and retrograde paths of reentrant loop, and typical AVNRT could be induced. During effective ablation there was no junctional rhythm. In some special cases, modification of atrioventricular node should not only rely on the junctional rhythm to determine the ablation effect, but also on the time of cardiac electrophysiological examination, as such to avoid the severe complication of atrioventricular block caused by excessive ablation. PMID- 21264188 TI - Potential of probiotics in controlling cardiovascular diseases. PMID- 21264189 TI - Effect of soldering techniques and gap distance on tensile strength of soldered Ni-Cr alloy joint. AB - PURPOSE: The present study was intended to evaluate the effect of soldering techniques with infrared ray and gas torch under different gap distances (0.3 mm and 0.5 mm) on the tensile strength and surface porosity formation in Ni-Cr base metal alloy. MATERIALS AND METHODS: Thirty five dumbbell shaped Ni-Cr alloy specimens were prepared and assigned to 5 groups according to the soldering method and the gap distance. For the soldering methods, gas torch (G group) and infrared ray (IR group) were compared and each group was subdivided by corresponding gap distance (0.3 mm: G3 and IR3, 0.5 mm: G5, IR5). Specimens of the experimental groups were sectioned in the middle with a diamond disk and embedded in solder blocks according to the predetermined distance. As a control group, 7 specimens were prepared without sectioning or soldering. After the soldering procedure, a tensile strength test was performed using universal testing machine at a crosshead speed 1 mm/min. The proportions of porosity on the fractured surface were calculated on the images acquired through the scanning electronic microscope. RESULTS: Every specimen of G3, G5, IR3 and IR5 was fractured on the solder joint area. However, there was no significant difference between the test groups (P > .05). There was a negative correlation between porosity formation and tensile strength in all the specimens in the test groups (P < .05). CONCLUSION: There was no significant difference in ultimate tensile strength of joints and porosity formations between the gas-oxygen torch soldering and infrared ray soldering technique or between the gap distance of 0.3 mm and 0.5 mm. PMID- 21264190 TI - Relationship between tooth loss and carotid intima-media thickness in Korean adults. AB - PURPOSE: The aim of this study was to examine the relationship between tooth loss and sub-clinical atherosclerosis in Korean adults. MATERIALS AND METHODS: The subjects were part of a cohort study conducted in Ansan city by the Korea University medical school as part of the Korean Genome project. 749 subjects over than 40 years old were evaluated. After taking panoramic radiography, the amount of tooth loss was calculated. The intima-media thickness (IMT) was assessed by using ultrasonography at the common carotid artery. Traditional cardiovascular risk factors for atherosclerosis were also evaluated. The relationship between tooth loss and the IMT was evaluated using ANOVA with Scheffe's multiple comparison method in univariate analysis. Multiple regression analysis was also performed to determine the significance between the IMT and tooth loss. RESULTS: With age, tooth loss increased, but there was no significant increase in other traditional cardiovascular risk factors. Univariate analysis revealed the IMT to be positively related with the amount of tooth loss. Regression analysis of the IMT in the anterior and posterior tooth loss revealed that only the posterior tooth loss was significantly related with the IMT at all sites of the common carotid artery (right far wall, P = .015; left far wall, P = .008; right near wall, P < .001; left near wall, P = .001). CONCLUSION: This study verified the positive relationship between the increased tooth loss at the posterior area and the accumulation of atheroma in arteries. PMID- 21264191 TI - Effect of impression coping and implant angulation on the accuracy of implant impressions: an in vitro study. AB - PURPOSE: The purpose of this study was to compare the accuracy of the implant master cast according to the type (pick-up, transfer) and the length (long, short) of the impression copings. MATERIALS AND METHODS: The metal master cast was fabricated with three internal connection type implant analogs (Osstem GS III analog), embedded parallel and with 10 degrees of mesial angulation to the center analog. Four types of impression coping were prepared with different combinations of types (transfer, pick-up) and lengths (long, short) of the coping. The impressions were made using vinyl polysiloxane (one step, heavy + light body) with an individual tray, and 10 impressions were made for each group. Eventually, 40 experimental casts were produced. Then, the difference in the distance between the master cast and the experimental cast were measured, and the error rate was determined. The analysis of variance was performed using the SPSS (v 12.0) program (alpha = .05), and the statistical significance was set at P < .05. RESULTS: The ANOVA showed that the pick-up type impression coping exhibited a significantly lower error rate than the transfer type. However, no significant difference was observed with respect to the length of the impression coping. Additionally, no significant difference was observed between the parallel and mesial angulated groups. CONCLUSION: Within the limitations of this study, the pick-up type impression coping exhibited a more accurate implant master cast than the transfer type in parallel group. The accuracy of the implant master cast did not differ for different lengths of impression coping of at least 11 mm. Additionally, the accuracy of the implant cast was not different for the parallel and 10 degrees mesial angulated groups. PMID- 21264192 TI - A study on the fracture strength of collarless metal-ceramic fixed partial dentures. AB - PURPOSE: The objective of this study was to evaluate fracture strength of collarless metal-ceramic FPDs according to their metal coping designs. MATERIALS AND METHODS: Four different facial margin design groups were investigated. Group A was a coping with a thin facial metal collar, group B was a collarless coping with its facial metal to the shoulder, group C was a collarless coping with its facial metal 1 mm short of the shoulder, and group D was a collarless coping with its facial metal 2 mm short of the shoulder. Fifteen 3-unit collarless metal ceramic FPDs were fabricated in each group. Finished FPDs were cemented to PBT (Polybutylene terephthalate) dies with resin cement. The fracture strength test was carried out using universal testing machine (Instron 4465, Instron Co., Norwood MA, USA) at a cross head speed of 0.5 mm/min. Aluminum foil folded to about 1 mm of thickness was inserted between the plunger tip and the incisal edge of the pontic. Vertical load was applied until catastrophic porcelain fracture occurred. RESULTS: The greater the bulk of unsupported facial shoulder porcelain was, the lower the fracture strength became. However, there were no significant differences between experimental groups (P > .05). CONCLUSION: All groups of collarless metal-ceramic FPDs had higher fracture strength than maximum incisive biting force. Modified collarless metal-ceramic FPD can be an alternative to all ceramic FPDs in clinical situations. PMID- 21264193 TI - A histomorphometric study of dental implants with different surface characteristics. AB - PURPOSE: One of the major keys to achieve successful osseointegration of the implant is its surface properties. The aim of this study was to investigate the bone response to dental implants with different surface characteristics using the rabbit tibia model. Tricalcium phosphate (TCP) coated, anodic oxidized and turned (control) surfaces were compared. MATERIALS AND METHODS: Seventy two implants were placed in the tibia of eighteen rabbits. Nine rabbits were sacrificed at 3 weeks of healing and the remaining nine were sacrificed at 6 weeks of healing. The bone-to-implant contact (BIC) and the bone volume density (BVD) were assessed by light microscope after 3 and 6 weeks of healing. RESULTS: Statistical analysis showed that no significant differences in the BIC and BVD were observed between the different implant surfaces and the control group at 3 weeks and 6 weeks of healing. Data also suggested that the BVD of all the surfaces showed significant difference at 3 and 6 weeks. CONCLUSION: The present study has showed that osseointegration occurred in all investigated types of surface-treated implants. In the current study all of the threads of the implants were observed to calculate BIC and BVD values (instead of choosing some of the threads from the bone cortex for example), which didn't make BIC or BVD percentage values better than in the control group, therefore the clinical relevance of these results remains to be shown. PMID- 21264194 TI - A comparison of bone bed preparation with laser and conventional drill on the relationship between implant stability quotient (ISQ) values and implant insertion variables. AB - PURPOSE: The aim of this study was to investigate a comparison of implant bone bed preparation with Er,Cr:YSGG laser and conventional drills on the relationship between implant stability quotient (ISQ) values and implant insertion variables. MATERIALS AND METHODS: Forty implants were inserted into two different types of pig rib bone. One group was prepared with conventional drills and a total of 20 implants were inserted into type I and type II bone. The other group was prepared with a Er,Cr:YSGG laser and a total of 20 implants were inserted into type I and type II bone. ISQ, maximum insertion torque, angular momentum, and insertion torque energy values were measured. RESULTS: The mean values for variables were significantly higher in type I bone than in type II bone (P < .01). In type I bone, the ISQ values in the drill group were significantly higher than in the laser group (P < .05). In type II bone, the ISQ values in the laser group were significantly higher than in the drill group (P < .01). In both type I and type II bone, the maximum insertion torque, total energy, and total angular momentum values between the drill and laser groups did not differ significantly (P >= .05). The ISQ values were correlated with maximum insertion torque (P < .01, r = .731), total energy (P < .01, r = .696), and angular momentum (P < .01, r = .696). CONCLUSION: Within the limitations of this study, the effects of bone bed preparation with Er,Cr:YSGG laser on the relationship between implant stability quotient (ISQ) values and implant insertion variables were comparable to those of drilling. PMID- 21264195 TI - Full mouth fixed implant rehabilitation in a patient with generalized aggressive periodontitis. AB - BACKGROUND: Generalized aggressive periodontitis (GAP) is a destructive periodontal disease that can develop in young age. Only a few cases of full mouth rehabilitation, using dental implants, have been reported in a patient with aggressive periodontitis. CASE DESCRIPTION: This clinical report describes the treatment procedures and results of full mouth rehabilitation in a patient with aggressive periodontitis. After all teeth were extracted, 6 implants were placed in the maxilla and mandible, respectively. Fixed detachable implant prostheses were made. The patient was satisfied with the final results. She was followed for 10 months postloading. CLINICAL IMPLICATION: For a long-term success, continuous maintenance care is critical, as the contributing factors of the disease (such as immune factors or periodontal pathogens) may not be controlled adequately. PMID- 21264196 TI - Seniors with Parkinson's disease: initial medical treatment. AB - Parkinson's disease most often presents after age 60, and patients in this age group are best managed with levodopa therapy as the primary treatment modality. Unlike young-onset parkinsonism (onset 2). RESULTS: Among 1,055 patients with acute stroke, 575 were male (aged 64.83+/-11.98 years, mean+/-SD) and 480 were female (aged 70.09+/-13.02 years). There were no gender differences in mortality at 3 months and 1 year after stroke. The frequency of poor outcomes was higher in female patients than in male patients at discharge (39.8% versus 30.9%, respectively; p=0.003), the 3 months follow-up (32.3% versus 20.8%, respectively; p<0.001), and the 1 year follow-up (31.1% versus 18.7%, respectively; p=0.001). After adjusting for multiple confounding factors including age and stroke severity, the female gender persisted as a predictor of poor functional outcome at 3 months and 1 year after stroke. CONCLUSIONS: Female patients have greater difficulty than male patients in recovering from a disabled state after acute stroke. Future studies should investigate the causes of this gender difference. PMID- 21264199 TI - Zonisamide changes unilateral cortical excitability in focal epilepsy patients. AB - BACKGROUND AND PURPOSE: To evaluate changes in cortical excitability induced by zonisamide (ZNS) in focal epilepsy patients. METHODS: Twenty-four drug-naive focal epilepsy patients (15 males; overall mean age 29.8 years) were enrolled. The transcranial magnetic stimulation parameters obtained using two Magstim 200 stimulators were the resting motor threshold, amplitude of the motor-evoked potential (MEP), cortical silent period, short intracortical inhibition, and intracortical facilitation. These five transcranial magnetic stimulation parameters were measured before and after ZNS, and the findings were compared. RESULTS: All 24 patients were treated with ZNS monotherapy (200-300 mg/day) for 8 12 weeks. After ZNS, MEP amplitudes decreased (-36.9%) significantly in epileptic hemispheres (paired t-test with Bonferroni's correction for multiple comparisons, p<0.05), whereas the mean resting motor threshold, cortical silent period, short intracortical inhibition, and intracortical facilitation were unchanged (p>0.05). ZNS did not affect cortical excitability in nonepileptic hemispheres. CONCLUSIONS: These findings suggest that ZNS decreases cortical excitability only in the epileptic hemispheres of focal epilepsy patients. MEP amplitudes may be useful for evaluating ZNS-induced changes in cortical excitability. PMID- 21264197 TI - Deep brain stimulation: technology at the cutting edge. AB - Deep brain stimulation (DBS) surgery has been performed in over 75,000 people worldwide, and has been shown to be an effective treatment for Parkinson's disease, tremor, dystonia, epilepsy, depression, Tourette's syndrome, and obsessive compulsive disorder. We review current and emerging evidence for the role of DBS in the management of a range of neurological and psychiatric conditions, and discuss the technical and practical aspects of performing DBS surgery. In the future, evolution of DBS technology may depend on several key areas, including better scientific understanding of its underlying mechanism of action, advances in high-spatial resolution imaging and development of novel electrophysiological and neurotransmitter microsensor systems. Such developments could form the basis of an intelligent closed-loop DBS system with feedback guided neuromodulation to optimize both electrode placement and therapeutic efficacy. PMID- 21264200 TI - Measurement of precuneal and hippocampal volumes using magnetic resonance volumetry in Alzheimer's disease. AB - BACKGROUND AND PURPOSE: Alzheimer's disease (AD) is associated with structural alterations in the medial temporal lobe (MTL) and functional alterations in the posterior cortical region, especially in the early stages. However, it is unclear what mechanisms underlie these regional discrepancies or whether the posterior cortical hypometabolism reflects disconnection from the MTL lesion or is the result of local pathology. The precuneus, an area of the posteromedial cortex that is involved in the early stages of AD, has recently received a great deal of attention in functional neuroimaging studies. To assess the relationship between the precuneus and hippocampus in AD, we investigated the volumes of these two areas using a magnetic resonance volumetric method. METHODS: Twenty-three subjects with AD and 14 healthy age-matched controls underwent T1-weighted three dimensional volumetric brain magnetic resonance imaging. Volumetric measurements were performed in the precuneus and hippocampus. RESULTS: Compared to controls, AD patients exhibited a significant reduction in total precuneal volume, which was more prominent on the right side, and significant bilateral reductions in hippocampal volume. No correlation was found between the total volumes of the precuneus and hippocampus in the AD group. CONCLUSIONS: These results suggest that volumetric measurements of both the precuneus and hippocampus are useful radiological indices for the diagnosis of AD. Furthermore, the lack of correlation is attributable to local pathology rather than being a secondary consequence of MTL pathology. PMID- 21264201 TI - Topographical disorientation in mild cognitive impairment: a voxel-based morphometry study. AB - BACKGROUND AND PURPOSE: To assess the neural substrates underlying topographical disorientation (TD) in patients affected by mild cognitive impairment (MCI), forty-one patients diagnosed with MCI and 24 healthy control individuals were recruited. METHODS: TD was assessed clinically in all participants. Neurological and neuropsychological evaluations and a volumetric-head magnetic resonance imaging scan were performed in each participant. Voxel-based morphometry was used to compare patterns of gray-matter atrophy between patients with and without TD, and a group of normal controls. RESULTS: We found TD in 17 out of the 41 MCI patients (41.4%). The functional abilities were significantly impaired in MCI patients with TD compared to in MCI patients without TD. Voxel-based morphometry analyses showed that the presence of TD in MCI patients is associated with loss of gray matter in the medial temporal regions, including the hippocampus and parahippocampal cortex, the fusiform gyrus, the inferior occipital gyrus, the amygdala, and the cerebellum. CONCLUSIONS: The findings found in this study represent the first evidence that the presence of TD in patients with MCI is associated with loss of gray matter in those brain regions that have been documented to be responsible for orientation in both neuropsychological and neuroimaging studies. PMID- 21264202 TI - Transient increase in intrathoracic pressure as a contributing factor to cardioembolic stroke. AB - BACKGROUND: The hemodynamic effects of increased intrathoracic pressure (ITP) have been the focus of many investigations. However, very little is known about the effects of elevated ITP on the occurrence of stroke. CASE REPORT: Four young patients with a cardioembolic source of stroke were examined. In all cases the stroke was preceded by an increase in ITP that occurred during coughing, vomiting, or sexual intercourse. CONCLUSIONS: We suggest that cardioembolic stroke is facilitated by situations in which ITP is elevated. PMID- 21264203 TI - Arteriovenous malformation with an occlusive feeding artery coexisting with unilateral moyamoya disease. AB - BACKGROUND: Arteriovenous malformations (AVMs) with vascular abnormalities, including aneurysms, have been reported frequently. However, the coexistence of AVM and unilateral moyamoya disease is rare. We report herein an AVM patient who presented with acute ischemic stroke with unilateral moyamoya disease and occlusion of the feeding artery. CASE REPORT: A-41-year old man was admitted with sudden dysarthria and facial palsy. Brain computed tomography and magnetic resonance imaging revealed an acute infarction adjacent to a large AVM in the right frontal lobe. Cerebral angiography revealed occlusions of the proximal right middle cerebral and proximal anterior cerebral arteries, which were the main feeders of the AVM. Innumerable telangiectatic moyamoya-type vessels between branches of the anterior cerebral artery and dilated lenticulostriate arteries on the occluded middle cerebral artery were detected. However, a nidus of the AVM was still opacified through the distal right callosomarginal artery, which was supplied by the remaining anterior cerebral artery and leptomeningeal collaterals from the posterior cerebral artery. CONCLUSIONS: While AVM accompanied by unilateral moyamoya disease is rare, our case suggests an association between these two dissimilar vascular diseases. PMID- 21264204 TI - Medullary Hemorrhage after Ischemic Wallenberg's Syndrome in a Patient with Cavernous Angioma. AB - BACKGROUND: The main complication of cerebral cavernous angioma is hemorrhage. Ischemic stroke as a complication of cerebral cavernous angioma has rarely been described, and hemorrhage after ischemic Wallenberg's syndrome has not been reported before. CASE REPORT: A 45-year-old woman presented with perioral numbness, hoarseness, dysphagia, and worsening of her previous sensory symptoms. The patient had been taking aspirin for 3 years after suffering from ischemic Wallenberg's syndrome with left paresthesia as a residual symptom. Brain computed tomography revealed an acute medullary hematoma in the previously infarcted area. Follow-up magnetic resonance imaging revealed a cavernous angioma in the right medulla. CONCLUSIONS: We presume that cerebral cavernous angioma was responsible for both the ischemia and the hemorrhage, and we also cautiously speculate that the aspirin contributed to the development of hemorrhage in the previously infarcted area. PMID- 21264205 TI - Myasthenia gravis aggravated by steroid-induced isolated mediastinal tuberculous lymphadenitis. AB - BACKGROUND: Myasthenia gravis (MG) is occasionally aggravated by chronic infection, of which there are many kinds. CASE REPORT: We report herein the case of a 56-year-old woman with MG aggravated by the activation of isolated mediastinal tuberculous lymphadenitis (MTL) during corticosteroid administration. The possibility of MTL had been disregarded in the differential diagnosis of aggravation of MG weakness, because MTL without pulmonary manifestations is uncommon even in areas where tuberculosis is endemic. CONCLUSIONS: This case suggests that chronic infections such as tuberculosis should be considered in myasthenic patients with progressive exacerbation if definite evidence for aggravating factors of MG is not obtained. PMID- 21264206 TI - Anterior pituitary adenomas: inherited syndromes, novel genes and molecular pathways. AB - Pituitary adenomas are common tumors. Although rarely malignant, pituitary adenomas cause significant morbidity due to mass effects and/or hormonal hypo- and/or hyper-secretion. Molecular understanding of pituitary adenoma formation is essential for the development of medical therapies and the treatment of post operative recurrences. In general, mutations in genes involved in genetic syndromes associated with pituitary tumors are not a common finding in sporadic lesions. By contrast, multiple endocrine neoplasia type 1 (MEN-1) and aryl hydrocarbon receptor-interacting protein (AIP) mutations may be more frequent among specific subgroups of patients, such as children and young adults, with growth hormone-producing adenomas. In this article, we present the most recent data on the molecular pathogenesis of pituitary adenomas and discuss some of the most recent findings from our laboratory. Guidelines for genetic screening and clinical counseling of patients with pituitary tumors are provided. PMID- 21264207 TI - Detection of somatic mutations by high-resolution DNA melting (HRM) analysis in multiple cancers. AB - Identification of somatic mutations in cancer is a major goal for understanding and monitoring the events related to cancer initiation and progression. High resolution melting (HRM) curve analysis represents a fast, post-PCR high throughput method for scanning somatic sequence alterations in target genes. The aim of this study was to assess the sensitivity and specificity of HRM analysis for tumor mutation screening in a range of tumor samples, which included 216 frozen pediatric small rounded blue-cell tumors as well as 180 paraffin-embedded tumors from breast, endometrial and ovarian cancers (60 of each). HRM analysis was performed in exons of the following candidate genes known to harbor established commonly observed mutations: PIK3CA, ERBB2, KRAS, TP53, EGFR, BRAF, GATA3, and FGFR3. Bi-directional sequencing analysis was used to determine the accuracy of the HRM analysis. For the 39 mutations observed in frozen samples, the sensitivity and specificity of HRM analysis were 97% and 87%, respectively. There were 67 mutation/variants in the paraffin-embedded samples, and the sensitivity and specificity for the HRM analysis were 88% and 80%, respectively. Paraffin-embedded samples require higher quantity of purified DNA for high performance. In summary, HRM analysis is a promising moderate-throughput screening test for mutations among known candidate genomic regions. Although the overall accuracy appears to be better in frozen specimens, somatic alterations were detected in DNA extracted from paraffin-embedded samples. PMID- 21264208 TI - Coral larvae under ocean acidification: survival, metabolism, and metamorphosis. AB - Ocean acidification may negatively impact the early life stages of some marine invertebrates including corals. Although reduced growth of juvenile corals in acidified seawater has been reported, coral larvae have been reported to demonstrate some level of tolerance to reduced pH. We hypothesize that the observed tolerance of coral larvae to low pH may be partly explained by reduced metabolic rates in acidified seawater because both calcifying and non-calcifying marine invertebrates could show metabolic depression under reduced pH in order to enhance their survival. In this study, after 3-d and 7-d exposure to three different pH levels (8.0, 7.6, and 7.3), we found that the oxygen consumption of Acropora digitifera larvae tended to be suppressed with reduced pH, although a statistically significant difference was not observed between pH conditions. Larval metamorphosis was also observed, confirming that successful recruitment is impaired when metamorphosis is disrupted, despite larval survival. Results also showed that the metamorphosis rate significantly decreased under acidified seawater conditions after both short (2 h) and long (7 d) term exposure. These results imply that acidified seawater impacts larval physiology, suggesting that suppressed metabolism and metamorphosis may alter the dispersal potential of larvae and subsequently reduce the resilience of coral communities in the near future as the ocean pH decreases. PMID- 21264209 TI - Mitochondrial function is required for secretion of DAF-28/insulin in C. elegans. AB - While insulin signaling has been extensively studied in Caenorhabditis elegans in the context of ageing and stress response, less is known about the factors underlying the secretion of insulin ligands upstream of the insulin receptor. Activation of the receptor governs the decision whether to progress through the reproductive lifecycle or to arrest growth and enter hibernation. We find that animals with reduced levels of the mitochondrial outer membrane translocase homologue TOMM-40 arrest growth as larvae and have decreased insulin signaling strength. TOMM-40 acts as a mitochondrial translocase in C. elegans and in its absence animals fail to import a mitochondrial protein reporter across the mitochondrial membrane(s). Inactivation of TOMM-40 evokes the mitochondrial unfolded protein response and causes a collapse of the proton gradient across the inner mitochondrial membrane. Consequently these broadly dysfunctional mitochondria render an inability to couple food abundance to secretion of DAF 28/insulin. The secretion defect is not general in nature since two other neuropeptides, ANF::GFP and INS-22::VENUS, are secreted normally. RNAi against two other putative members of the TOMM complex give similar phenotypes, implying that DAF-28 secretion is sensitive to mitochondrial dysfunction in general. We conclude that mitochondrial function is required for C. elegans to secrete DAF 28/insulin when food is abundant. This modulation of secretion likely represents an additional level of control over DAF-28/insulin function. PMID- 21264210 TI - Dynamics of macrophage trogocytosis of rituximab-coated B cells. AB - Macrophages can remove antigen from the surface of antibody-coated cells by a process termed trogocytosis. Using live cell microscopy and flow cytometry, we investigated the dynamics of trogocytosis by RAW264.7 macrophages of Ramos B cells opsonized with the anti-CD20 monoclonal antibody rituximab. Spontaneous and reversible formation of uropods was observed on Ramos cells, and these showed a strong enrichment in rituximab binding. RAW-Ramos conjugate interfaces were highly enriched in rituximab, and transfer of rituximab to the RAW cells in submicron-sized puncta occurred shortly after cell contact. Membrane from the target cells was concomitantly transferred along with rituximab to a variable extent. We established a flow cytometry-based approach to follow the kinetics of transfer and internalization of rituximab. Disruption of actin polymerization nearly eliminated transfer, while blocking phosphatidylinositol 3-kinase activity only resulted in a delay in its acquisition. Inhibition of Src family kinase activity both slowed acquisition and reduced the extent of trogocytosis. The effects of inhibiting these kinases are likely due to their role in efficient formation of cell-cell conjugates. Selective pre-treatment of Ramos cells with phenylarsine oxide blocked uropod formation, reduced enrichment of rituximab at cell-cell interfaces, and reduced the efficiency of trogocytic transfer of rituximab. Our findings highlight that dynamic changes in target cell shape and surface distribution of antigen may significantly influence the progression and extent of trogocytosis. Understanding the mechanistic determinants of macrophage trogocytosis will be important for optimal design of antibody therapies. PMID- 21264211 TI - Identification of chronic heart failure patients with a high 12-month mortality risk using biomarkers including plasma C-terminal pro-endothelin-1. AB - OBJECTIVES: We hypothesised that assessment of plasma C-terminal pro-endothelin-1 (CT-proET-1), a stable endothelin-1 precursor fragment, is of prognostic value in patients with chronic heart failure (CHF), beyond other prognosticators, including N-terminal pro-B-type natriuretic peptide (NT-proBNP). METHODS: We examined 491 patients with systolic CHF (age: 63+/-11 years, 91% men, New York Heart Association [NYHA] class [I/II/III/IV]: 9%/45%/38%/8%, 69% ischemic etiology). Plasma CT-proET-1 was detected using a chemiluminescence immunoassay. RESULTS: Increasing CT-proET-1 was a predictor of increased cardiovascular mortality at 12-months of follow-up (standardized hazard ratio 1.42, 95% confidence interval [CI] 1.04-1.95, p = 0.03) after adjusting for NT-proBNP, left ventricular ejection fraction (LVEF), age, creatinine, NYHA class. In receiver operating characteristic curve analysis, areas under curve for 12-month follow-up were similar for CT-proET-1 and NT-proBNP (p = 0.40). Both NT-proBNP and CT-proET 1 added prognostic value to a base model that included LVEF, age, creatinine, and NYHA class. Adding CT-proET-1 to the base model had stronger prognostic power (p<0.01) than adding NT-proBNP (p<0.01). Adding CT-proET-1 to NT-proBNP in this model yielded further prognostic information (p = 0.02). CONCLUSIONS: Plasma CT proET-1 constitutes a novel predictor of increased 12-month cardiovascular mortality in patients with CHF. High CT-proET-1 together with high NT-proBNP enable to identify patients with CHF and particularly unfavourable outcomes. PMID- 21264212 TI - Difficulties when assessing birdsong learning programmes under field conditions: a re-evaluation of song repertoire flexibility in the great tit. AB - There is a remarkable diversity of song-learning strategies in songbirds. Establishing whether a species is closed- or open-ended is important to be able to interpret functional and evolutionary consequences of variation in repertoire size. Most of our knowledge regarding the timing of vocal learning is based on laboratory studies, despite the fact that these may not always replicate the complex ecological and social interactions experienced by birds in the wild. Given that field studies cannot provide the experimental control of laboratory studies, it may not be surprising that species such as the great tit that were initially assumed to be closed-ended learners have later been suggested to be open-ended learners. By using an established colour-ringed population, by following a standardized recording protocol, and by taking into account the species' song ecology (using only recordings obtained during peak of singing at dawn), we replicated two previous studies to assess song repertoire learning and flexibility in adult wild great tits elicited by social interactions. First, we performed a playback experiment to test repertoire plasticity elicited by novel versus own songs. Additionally, in a longitudinal study, we followed 30 males in two consecutive years and analysed whether new neighbours influenced any change in the repertoire. Contrary to the previous studies, song repertoire size and composition were found to be highly repeatable both between years and after confrontation with a novel song. Our results suggest that great tits are closed ended learners and that their song repertoire probably does not change during adulthood. Methodological differences that may have led to an underestimation of the repertoires or population differences may explain the discrepancy in results with previous studies. We argue that a rigorous and standardized assessment of the repertoire is essential when studying age- or playback-induced changes in repertoire size and composition under field conditions. PMID- 21264213 TI - Exploitation of herpesviral transactivation allows quantitative reporter gene based assessment of virus entry and neutralization. AB - Herpesviral entry is a highly elaborated process requiring many proteins to act in precise conjunction. Neutralizing antibodies interfere with this process to abrogate viral infection. Based on promoter transactivation of a reporter gene we established a novel method to quantify herpesvirus entry and neutralization by antibodies. Following infection with mouse and human cytomegalovirus and Herpes simplex virus 1 we observed promoter transactivation resulting in substantial luciferase expression (>1000-fold). No induction was elicited by UV-inactivated viruses. The response was MOI-dependent and immunoblots confirmed a correlation between luciferase induction and pp72-IE1 expression. Monoclonal antibodies, immune sera and purified immunoglobulin preparations decreased virus-dependent luciferase induction dose-dependently, qualifying this approach as surrogate virus neutralization test. Besides the reduced hands-on time, this assay allows analysis of herpesvirus entry in semi-permissive and non-adherent cells, which were previously non-assessable but play significant roles in herpesvirus pathology. PMID- 21264214 TI - Super-resolution dynamic imaging of dendritic spines using a low-affinity photoconvertible actin probe. AB - The actin cytoskeleton of dendritic spines plays a key role in morphological aspects of synaptic plasticity. The detailed analysis of the spine structure and dynamics in live neurons, however, has been hampered by the diffraction-limited resolution of conventional fluorescence microscopy. The advent of nanoscopic imaging techniques thus holds great promise for the study of these processes. We implemented a strategy for the visualization of morphological changes of dendritic spines over tens of minutes at a lateral resolution of 25 to 65 nm. We have generated a low-affinity photoconvertible probe, capable of reversibly binding to actin and thus allowing long-term photoactivated localization microscopy of the spine cytoskeleton. Using this approach, we resolve structural parameters of spines and record their long-term dynamics at a temporal resolution below one minute. Furthermore, we have determined changes in the spine morphology in response to pharmacologically induced synaptic activity and quantified the actin redistribution underlying these changes. By combining PALM imaging with quantum dot tracking, we could also simultaneously visualize the cytoskeleton and the spine membrane, allowing us to record complementary information on the morphological changes of the spines at super-resolution. PMID- 21264215 TI - Shal/K(v)4 channels are required for maintaining excitability during repetitive firing and normal locomotion in Drosophila. AB - BACKGROUND: Rhythmic behaviors, such as walking and breathing, involve the coordinated activity of central pattern generators in the CNS, sensory feedback from the PNS, to motoneuron output to muscles. Unraveling the intrinsic electrical properties of these cellular components is essential to understanding this coordinated activity. Here, we examine the significance of the transient A type K(+) current (I(A)), encoded by the highly conserved Shal/K(v)4 gene, in neuronal firing patterns and repetitive behaviors. While I(A) is present in nearly all neurons across species, elimination of I(A) has been complicated in mammals because of multiple genes underlying I(A), and/or electrical remodeling that occurs in response to affecting one gene. METHODOLOGY/PRINCIPAL FINDINGS: In Drosophila, the single Shal/K(v)4 gene encodes the predominant I(A) current in many neuronal cell bodies. Using a transgenically expressed dominant-negative subunit (DNK(v)4), we show that I(A) is completely eliminated from cell bodies, with no effect on other currents. Most notably, DNK(v)4 neurons display multiple defects during prolonged stimuli. DNK(v)4 neurons display shortened latency to firing, a lower threshold for repetitive firing, and a progressive decrement in AP amplitude to an adapted state. We record from identified motoneurons and show that Shal/K(v)4 channels are similarly required for maintaining excitability during repetitive firing. We then examine larval crawling, and adult climbing and grooming, all behaviors that rely on repetitive firing. We show that all are defective in the absence of Shal/K(v)4 function. Further, knock-out of Shal/K(v)4 function specifically in motoneurons significantly affects the locomotion behaviors tested. CONCLUSIONS/SIGNIFICANCE: Based on our results, Shal/K(v)4 channels regulate the initiation of firing, enable neurons to continuously fire throughout a prolonged stimulus, and also influence firing frequency. This study shows that Shal/K(v)4 channels play a key role in repetitively firing neurons during prolonged input/output, and suggests that their function and regulation are important for rhythmic behaviors. PMID- 21264216 TI - Complete sequencing and pan-genomic analysis of Lactobacillus delbrueckii subsp. bulgaricus reveal its genetic basis for industrial yogurt production. AB - Lactobacillus delbrueckii subsp. bulgaricus (Lb. bulgaricus) is an important species of Lactic Acid Bacteria (LAB) used for cheese and yogurt fermentation. The genome of Lb. bulgaricus 2038, an industrial strain mainly used for yogurt production, was completely sequenced and compared against the other two ATCC collection strains of the same subspecies. Specific physiological properties of strain 2038, such as lysine biosynthesis, formate production, aspartate-related carbon-skeleton intermediate metabolism, unique EPS synthesis and efficient DNA restriction/modification systems, are all different from those of the collection strains that might benefit the industrial production of yogurt. Other common features shared by Lb. bulgaricus strains, such as efficient protocooperation with Streptococcus thermophilus and lactate production as well as well-equipped stress tolerance mechanisms may account for it being selected originally for yogurt fermentation industry. Multiple lines of evidence suggested that Lb. bulgaricus 2038 was genetically closer to the common ancestor of the subspecies than the other two sequenced collection strains, probably due to a strict industrial maintenance process for strain 2038 that might have halted its genome decay and sustained a gene network suitable for large scale yogurt production. PMID- 21264217 TI - Proxy measures of fitness suggest coastal fish farms can act as population sources and not ecological traps for wild gadoid fish. AB - BACKGROUND: Ecological traps form when artificial structures are added to natural habitats and induce mismatches between habitat preferences and fitness consequences. Their existence in terrestrial systems has been documented, yet little evidence suggests they occur in marine environments. Coastal fish farms are widespread artificial structures in coastal ecosystems and are highly attractive to wild fish. METHODOLOGY/PRINCIPAL FINDINGS: To investigate if coastal salmon farms act as ecological traps for wild Atlantic cod (Gadus morhua) and saithe (Pollachius virens), we compared proxy measures of fitness between farm-associated fish and control fish caught distant from farms in nine locations throughout coastal Norway, the largest coastal fish farming industry in the world. Farms modified wild fish diets in both quality and quantity, thereby providing farm-associated wild fish with a strong trophic subsidy. This translated to greater somatic (saithe: 1.06-1.12 times; cod: 1.06-1.11 times) and liver condition indices (saithe: 1.4-1.8 times; cod: 2.0-2.8 times) than control fish caught distant from farms. Parasite loads of farm-associated wild fish were modified from control fish, with increased external and decreased internal parasites, however the strong effect of the trophic subsidy overrode any effects of altered loads upon condition. CONCLUSIONS AND SIGNIFICANCE: Proxy measures of fitness provided no evidence that salmon farms function as ecological traps for wild fish. We suggest fish farms may act as population sources for wild fish, provided they are protected from fishing while resident at farms to allow their increased condition to manifest as greater reproductive output. PMID- 21264218 TI - Identification of distinctive patterns of USP19-mediated growth regulation in normal and malignant cells. AB - We previously reported that the USP19 deubiquitinating enzyme positively regulates proliferation in fibroblasts by stabilizing KPC1, a ubiquitin ligase for p27(Kip1). To explore whether this role of USP19 extends to other cellular systems, we tested the effects of silencing of USP19 in several human prostate and breast models, including carcinoma cell lines. Depletion of USP19 inhibited proliferation in prostate cancer DU145, PC-3 and 22RV1 cells, which was similar to the pattern established in fibroblasts in that it was due to decreased progression from G1 to S phase and associated with a stabilization of the cyclin dependent kinase inhibitor p27(Kip1). However, in contrast to previous findings in fibroblasts, the stabilization of p27(Kip1) upon USP19 depletion was not associated with changes in the levels of the KPC1 ligase. USP19 could also regulate the growth of immortalized MCF10A breast epithelial cells through a similar mechanism. This regulatory pattern was lost, though, in breast cancer MCF7 and MDA-MB-231 cells and in prostate carcinoma LNCaP cells. Of interest, the transformation of fibroblasts through overexpression of an oncogenic form of Ras disrupted the USP19-mediated regulation of cell growth and of levels of p27(Kip1) and KPC1. Thus, the cell context appears determinant for the ability of USP19 to regulate cell proliferation and p27(Kip1) levels. This may occur through both KPC1 dependent and independent mechanisms. Moreover, a complete loss of USP19 function on cell growth may arise as a result of oncogenic transformation of cells. PMID- 21264219 TI - DIA1R is an X-linked gene related to Deleted In Autism-1. AB - BACKGROUND: Autism spectrum disorders (ASDS) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene. METHODOLOGY/PRINCIPAL FINDINGS: Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term DIA1R (DIA1-Related). While DIA1 is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and DIA1R 433, residues. At the amino acid level, DIA1 and DIA1R are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. CONCLUSIONS/SIGNIFICANCE: Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD like symptoms and/or mental retardation. PMID- 21264220 TI - A key role for poly(ADP-ribose) polymerase 3 in ectodermal specification and neural crest development. AB - BACKGROUND: The PARP family member poly(ADP-ribose) polymerase 3 (PARP3) is structurally related to the well characterized PARP1 that orchestrates cellular responses to DNA strand breaks and cell death by the synthesis of poly(ADP ribose). In contrast to PARP1 and PARP2, the functions of PARP3 are undefined. Here, we reveal critical functions for PARP3 during vertebrate development. PRINCIPAL FINDINGS: We have used several in vitro and in vivo approaches to examine the possible functions of PARP3 as a transcriptional regulator, a function suggested from its previously reported association with several Polycomb group (PcG) proteins. We demonstrate that PARP3 gene occupancy in the human neuroblastoma cell line SK-N-SH occurs preferentially with developmental genes regulating cell fate specification, tissue patterning, craniofacial development and neurogenesis. Addressing the significance of this association during zebrafish development, we show that morpholino oligonucleotide-directed inhibition of parp3 expression in zebrafish impairs the expression of the neural crest cell specifier sox9a and of dlx3b/dlx4b, the formation of cranial sensory placodes, inner ears and pectoral fins. It delays pigmentation and severely impedes the development of the median fin fold and tail bud. CONCLUSION: Our findings demonstrate that Parp3 is crucial in the early stages of zebrafish development, possibly by exerting its transcriptional regulatory functions as early as during the specification of the neural plate border. PMID- 21264221 TI - Possible existence of lysosome-like organella within mitochondria and its role in mitochondrial quality control. AB - The accumulation of unhealthy mitochondria results in mitochondrial dysfunction, which has been implicated in aging, cancer, and a variety of degenerative diseases. However, the mechanism by which mitochondrial quality is regulated remains unclear. Here, we show that Mieap, a novel p53-inducible protein, induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control. Mieap expression is directly regulated by p53 and is frequently lost in human cancer as result of DNA methylation. Mieap dramatically induces the accumulation of lysosomal proteins within mitochondria and mitochondrial acidic condition without destroying the mitochondrial structure (designated MALM, for Mieap-induced accumulation of lysosome-like organelles within mitochondria) in response to mitochondrial damage. MALM was not related to canonical autophagy. MALM is involved in the degradation of oxidized mitochondrial proteins, leading to increased ATP synthesis and decreased reactive oxygen species generation. These results suggest that Mieap induces intramitochondrial lysosome-like organella that plays a critical role in mitochondrial quality control by eliminating oxidized mitochondrial proteins. Cancer cells might accumulate unhealthy mitochondria due to p53 mutations and/or Mieap methylation, representing a potential cause of the Warburg effect. PMID- 21264222 TI - Enhanced platelet activation mediates the accelerated angiogenic switch in mice lacking histidine-rich glycoprotein. AB - BACKGROUND: The heparin-binding plasma protein histidine-rich glycoprotein (HRG; alternatively, HRGP/HPRG) can suppress tumor angiogenesis and growth in vitro and in vivo. Mice lacking the HRG gene are viable and fertile, but have an enhanced coagulation resulting in decreased bleeding times. In addition, the angiogenic switch is significantly enhanced in HRG-deficient mice. METHODOLOGY/PRINCIPAL FINDINGS: To address whether HRG deficiency affects tumor development, we have crossed HRG knockout mice with the RIP1-Tag2 mouse, a well established orthotopic model of multistage carcinogenesis. RIP1-Tag2 HRG(-/-) mice display significantly larger tumor volume compared to their RIP1-Tag2 HRG(+/+) littermates, supporting a role for HRG as an endogenous regulator of tumor growth. In the present study we also demonstrate that platelet activation is increased in mice lacking HRG. To address whether this elevated platelet activation contributes to the increased pathological angiogenesis in HRG-deficient mice, they were rendered thrombocytopenic before the onset of the angiogenic switch by injection of the anti-platelet antibody GP1balpha. Interestingly, this treatment suppressed the increase in angiogenic neoplasias seen in HRG knockout mice. However, if GP1balpha treatment was initiated at a later stage, after the onset of the angiogenic switch, no suppression of tumor growth was detected in HRG-deficient mice. CONCLUSIONS: Our data show that increased platelet activation mediates the accelerated angiogenic switch in HRG-deficient mice. Moreover, we conclude that platelets play a crucial role in the early stages of tumor development but are of less significance for tumor growth once angiogenesis has been initiated. PMID- 21264223 TI - Olfactory responses to natal stream water in sockeye salmon by BOLD fMRI. AB - Many studies have shown that juvenile salmon imprint olfactory memory of natal stream odors during downstream migration, and adults recall this stream-specific odor information to discriminate their natal stream during upstream migration for spawning. The odor information processing of the natal stream in the salmon brain, however, has not been clarified. We applied blood oxygenation level dependent (BOLD) functional magnetic resonance imaging to investigate the odor information processing of the natal stream in the olfactory bulb and telencephalon of lacustrine sockeye salmon (Oncorhynchus nerka). The strong responses to the natal stream water were mainly observed in the lateral area of dorsal telencephalon (Dl), which are homologous to the medial pallium (hippocampus) in terrestrial vertebrates. Although the concentration of L-serine (1 mM) in the control water was 20,000-times higher than that of total amino acid in the natal stream water (47.5 nM), the BOLD signals resulting from the natal stream water were stronger than those by L-serine in the Dl. We concluded that sockeye salmon could process the odor information of the natal stream by integrating information in the Dl area of the telencephalon. PMID- 21264224 TI - Density of healthcare providers and patient outcomes: evidence from a nationally representative multi-site HIV treatment program in Uganda. AB - OBJECTIVE: We examined the association between density of healthcare providers and patient outcomes using a large nationally representative cohort of patients receiving combination antiretroviral therapy (cART) in Uganda. DESIGN: We obtained data from The AIDS Support Organization (TASO) in Uganda. Patients 18 years of age and older who initiated cART at TASO between 2004 and 2008 contributed to this analysis. The number of healthcare providers per 100 patients, the number of patients lost to follow-up per 100 person years and number of deaths per 100 person years were calculated. Spearman correlation was used to identify associations between patient loss to follow-up and mortality with the healthcare provider-patient ratios. RESULTS: We found no significant associations between the number of patients lost to follow-up and physicians (p = 0.45), nurses (p = 0.93), clinical officers (p = 0.80), field officers (p = 0.56), and healthcare providers overall (p = 0.83). Similarly, no significant associations were observed between mortality and physicians (p = 0.65), nurses (p = 0.49), clinical officers (p = 0.73), field officers (p = 0.78), and healthcare providers overall (p = 0.73). CONCLUSIONS: Patient outcomes, as measured by loss to follow-up and mortality, were not significantly associated with the number of doctors, nurses, clinical officers, field officers, or healthcare providers overall. This may suggest that that other factors, such as the presence of volunteer patient supporters or broader political or socioeconomic influences, may be more closely associated with outcomes of care among patients on cART in Uganda. PMID- 21264225 TI - A single acidic residue can guide binding site selection but does not govern QacR cationic-drug affinity. AB - Structures of the multidrug-binding repressor protein QacR with monovalent and bivalent cationic drugs revealed that the carboxylate side-chains of E90 and E120 were proximal to the positively charged nitrogens of the ligands ethidium, malachite green and rhodamine 6G, and therefore may contribute to drug neutralization and binding affinity. Here, we report structural, biochemical and in vivo effects of substituting these glutamate residues. Unexpectedly, substitutions had little impact on ligand affinity or in vivo induction capabilities. Structures of QacR(E90Q) and QacR(E120Q) with ethidium or malachite green took similar global conformations that differed significantly from all previously described QacR-drug complexes but still prohibited binding to cognate DNA. Strikingly, the QacR(E90Q)-rhodamine 6G complex revealed two mutually exclusive rhodamine 6G binding sites. Despite multiple structural changes, all drug binding was essentially isoenergetic. Thus, these data strongly suggest that rather than contributing significantly to ligand binding affinity, the role of acidic residues lining the QacR multidrug-binding pocket is primarily to attract and guide cationic drugs to the "best available" positions within the pocket that elicit QacR induction. PMID- 21264226 TI - A humanin derivative reduces amyloid beta accumulation and ameliorates memory deficit in triple transgenic mice. AB - Humanin (HN), a 24-residue peptide, was identified as a novel neuroprotective factor and shows anti-cell death activity against a wide spectrum of Alzheimer's disease (AD)-related cytotoxicities, including exposure to amyloid beta (Abeta), in vitro. We previously demonstrated that the injection of S14G-HN, a highly potent HN derivative, into brain ameliorated memory loss in an Abeta-injection mouse model. To fully understand HN's functions under AD-associated pathological conditions, we examined the effect of S14G-HN on triple transgenic mice harboring APP(swe), tau(P310L), and PS-1(M146V) that show the age-dependent development of multiple pathologies relating to AD. After 3 months of intranasal treatment, behavioral analyses showed that S14G-HN ameliorated cognitive impairment in male mice. Moreover, ELISA and immunohistochemical analyses showed that Abeta levels in brains were markedly lower in S14G-HN-treated male and female mice than in vehicle control mice. We also found the expression level of neprilysin, an Abeta degrading enzyme, in the outer molecular layer of hippocampal formation was increased in S14G-HN-treated mouse brains. NEP activity was also elevated by S14G HN treatment in vitro. These findings suggest that decreased Abeta level in these mice is at least partly attributed to S14G-HN-induced increase of neprilysin level. Although HN was identified as an anti-neuronal death factor, these results indicate that HN may also have a therapeutic effect on amyloid accumulation in AD. PMID- 21264227 TI - TNFalpha cooperates with IFN-gamma to repress Bcl-xL expression to sensitize metastatic colon carcinoma cells to TRAIL-mediated apoptosis. AB - BACKGROUND: TNF-related apoptosis-inducing ligand (TRAIL) is an immune effector molecule that functions as a selective anti-tumor agent. However, tumor cells, especially metastatic tumor cells often exhibit a TRAIL-resistant phenotype, which is currently a major impediment in TRAIL therapy. The aim of this study is to investigate the synergistic effect of TNFalpha and IFN-gamma in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis. METHODOLOGY/PRINCIPAL FINDINGS: The efficacy and underlying molecular mechanism of cooperation between TNFalpha and IFN-gamma in sensitizing metastatic colon carcinoma cells to TRAIL-mediated apoptosis were examined. The functional significance of TNFalpha- and IFN-gamma-producing T lymphocyte immunotherapy in combination with TRAIL therapy in suppression of colon carcinoma metastasis was determined in an experimental metastasis mouse model. We observed that TNFalpha or IFN-gamma alone exhibits minimal sensitization effects, but effectively sensitized metastatic colon carcinoma cells to TRAIL-induced apoptosis when used in combination. TNFalpha and IFN-gamma cooperate to repress Bcl-xL expression, whereas TNFalpha represses Survivin expression in the metastatic colon carcinoma cells. Silencing Bcl-xL expression significantly increased the metastatic colon carcinoma cell sensitivity to TRAIL-induced apoptosis. Conversely, overexpression of Bcl-xL significantly decreased the tumor cell sensitivity to TRAIL-induced apoptosis. Furthermore, TNFalpha and IFN-gamma also synergistically enhanced TRAIL-induced caspase-8 activation. TNFalpha and IFN-gamma was up-regulated in activated primary and tumor-specific T cells. TRAIL was expressed in tumor infiltrating immune cells in vivo, and in tumor-specific cytotoxic T lymphocytes (CTL) ex vivo. Consequently, TRAIL therapy in combination with TNFalpha/IFN-gamma producing CTL adoptive transfer immunotherapy effectively suppressed colon carcinoma metastasis in vivo. CONCLUSIONS/SIGNIFICANCE: TNFalpha and IFN-gamma cooperate to overcome TRAIL resistance at least partially through enhancing caspase 8 activation and repressing Bcl-xL expression. Combined CTL immunotherapy and TRAIL therapy hold great promise for further development for the treatment of metastatic colorectal cancer. PMID- 21264228 TI - Mieap, a p53-inducible protein, controls mitochondrial quality by repairing or eliminating unhealthy mitochondria. AB - Maintenance of healthy mitochondria prevents aging, cancer, and a variety of degenerative diseases that are due to the result of defective mitochondrial quality control (MQC). Recently, we discovered a novel mechanism for MQC, in which Mieap induces intramitochondrial lysosome-like organella that plays a critical role in the elimination of oxidized mitochondrial proteins (designated MALM for Mieap-induced accumulation of lysosome-like organelles within mitochondria). However, a large part of the mechanisms for MQC remains unknown. Here, we report additional mechanisms for Mieap-regulated MQC. Reactive oxygen species (ROS) scavengers completely inhibited MALM. A mitochondrial outer membrane protein NIX interacted with Mieap in a ROS-dependent manner via the BH3 domain of NIX and the coiled-coil domain of Mieap. Deficiency of NIX also completely impaired MALM. When MALM was inhibited, Mieap induced vacuole-like structures (designated as MIV for Mieap-induced vacuole), which engulfed and degraded the unhealthy mitochondria by accumulating lysosomes. The inactivation of p53 severely impaired both MALM and MIV generation, leading to accumulation of unhealthy mitochondria. These results suggest that (1) mitochondrial ROS and NIX are essential factors for MALM, (2) MIV is a novel mechanism for lysosomal degradation of mitochondria, and (3) the p53-Mieap pathway plays a pivotal role in MQC by repairing or eliminating unhealthy mitochondria via MALM or MIV generation, respectively. PMID- 21264229 TI - High resolution genotyping of clinical Aspergillus flavus isolates from India using microsatellites. AB - BACKGROUND: Worldwide, Aspergillus flavus is the second leading cause of allergic, invasive and colonizing fungal diseases in humans. However, it is the most common species causing fungal rhinosinusitis and eye infections in tropical countries. Despite the growing challenges due to A. flavus, the molecular epidemiology of this fungus has not been well studied. We evaluated the use of microsatellites for high resolution genotyping of A. flavus from India and a possible connection between clinical presentation and genotype of the involved isolate. METHODOLOGY/PRINCIPAL FINDINGS: A panel of nine microsatellite markers were selected from the genome of A. flavus NRRL 3357. These markers were used to type 162 clinical isolates of A. flavus. All nine markers proved to be polymorphic displaying up to 33 alleles per marker. Thirteen isolates proved to be a mixture of different genotypes. Among the 149 pure isolates, 124 different genotypes could be recognized. The discriminatory power (D) for the individual markers ranged from 0.657 to 0.954. The D value of the panel of nine markers combined was 0.997. The multiplex multicolor approach was instrumental in rapid typing of a large number of isolates. There was no correlation between genotype and the clinical presentation of the infection. CONCLUSIONS/SIGNIFICANCE: There is a large genotypic diversity in clinical A. flavus isolates from India. The presence of more than one genotype in clinical samples illustrates the possibility that persons may be colonized by multiple genotypes and that any isolate from a clinical specimen is not necessarily the one actually causing infection. Microsatellites are excellent typing targets for discriminating between A. flavus isolates from various origins. PMID- 21264230 TI - IkappaB kinase beta regulates epithelium migration during corneal wound healing. AB - The IKKbeta is known to regulate transcription factor NF-kappaB activation leading to inflammatory responses. Recent gene knockout studies have shown that IKKbeta can orchestrate local inflammatory responses and regulate homeostasis of epithelial tissues. To investigate whether IKKbeta has an intrinsic role in epithelial cells, we established an in vivo system in the immune privileged corneal epithelium. We generated triple transgenic Krt12(rtTA/rtTAt)/tet-O Cre/Ikkbeta(F/F) (Ikkbeta(DeltaCE/DeltaCE)) mice by crossing the Krt12-rtTA knock in mice, which express the reverse tetracycline transcription activator in corneal epithelial cells, with the tet-O-Cre and Ikkbeta(F/F) mice. Doxycycline induced IKKbeta ablation occurred in corneal epithelial cells of triple transgenic Ikkbeta(DeltaCE/DeltaCE) mice, but loss of IKKbeta did not cause ocular abnormalities in fetal development and postnatal maintenance. Instead, loss of IKKbeta significantly delayed healing of corneal epithelial debridement without affecting cell proliferation, apoptosis or macrophage infiltration. In vitro studies with human corneal epithelial cells (HCEpi) also showed that IKKbeta was required for cytokine-induced cell migration and wound closure but was dispensable for cell proliferation. In both in vivo and in vitro settings, IKKbeta was required for optimal activation of NF-kappaB and p38 signaling in corneal epithelial cells, and p38 activation is likely mediated through formation of an IKKbeta-p38 protein complex. Thus, our studies in corneal epithelium reveal a previously un-recognized role for IKKbeta in the control of epithelial cell motility and wound healing. PMID- 21264231 TI - SPARC is expressed in scars of the Tenon's capsule and mediates scarring properties of human Tenon's fibroblasts in vitro. AB - PURPOSE: To investigate the expression of the matricellular protein SPARC (secreted acidic cysteine-rich glycoprotein) in scarred human Tenon's capsule and in cultured human Tenon's fibroblasts (HTF), and to analyze the influence of SPARC on cell proliferation and collagen matrix contraction in vitro. METHODS: Human Tenon's capsule scars obtained from surgical revisions after filtration surgery were analyzed for SPARC expression by immunohistochemistry. In cultured HTF cells, SPARC expression was assessed by northern and western blot analyses after incubation with transforming growth factor (TGF)-beta1 and TGF-beta2. Cell proliferation was determined by bromodeoxyuridine (BrdU)-labeling and HTF cells mediated collagen matrix contraction by morphometric measurements of three dimensional collagen lattices after treatment with SPARC and/or TGF-beta1. RESULTS: In scarred human Tenon's capsule specimens, an increased expression of SPARC was mainly localized to the extracellular matrix and to blood vessel walls as compared to healthy control Tenon's capsule. In cultured HTF cells, treatment with TGF-beta1 more than TGF-beta2 induced the expression of SPARC both on the mRNA and protein level. Incubation of HTF cells with SPARC resulted in an increase in collagen matrix contraction and cell proliferation. Moreover, a combined incubation of SPARC and TGF-beta1 stimulated HTF cell proliferation significantly over the levels that were observed after single treatment. CONCLUSIONS: Our data provide evidence that SPARC contributes to excessive wound healing and scar formation in human Tenon's capsules after filtration surgery and may thus represent a novel target for anti-fibrotic strategies. PMID- 21264232 TI - Phosphoproteomics characterization of novel phosphorylated sites of lens proteins from normal and cataractous human eye lenses. AB - PURPOSE: Post-translational modification (PTM) of lens proteins is believed to play various roles in age-related lens function and development. Among the different types of PTM, phosphorylation is most noteworthy to play a major role in the regulation of various biosignaling pathways in relation to metabolic processes and cellular functions. The present study reported the quantitative analysis of the in vivo phosphoproteomics profiles of human normal and cataractous lenses with the aim of identifying specific phosphorylation sites which may provide insights into the physiologic significance of phosphorylation in relation to cataract formation. METHODS: To improve detection sensitivity of low abundant proteins, we first adopted SDS-gel electrophoresis fractionation of lens extracts to identify and compare the protein compositions between normal and cataractous lenses, followed by tryptic digestion, enrichment of phosphopeptides by immobilized metal affinity chromatography (IMAC) and nano-liquid chromatography coupled tandem mass spectrometry (nanoLC-MS/MS) analysis. RESULTS: By comprehensively screening of the phosphoproteome in normal and cataractous lenses, we identified 32 phosphoproteins and 73 phosphorylated sites. The most abundantly phosphorylated proteins are two subunits of beta-crystallin, i.e., betaB1-crystallin (12%) and betaB2-crystallin (12%). Moreover, serine was found to be the most abundantly phosphorylated residue (72%) in comparison with threonine (24%) and tyrosine (4%) in the lens phosphoproteome. The quantitative analysis revealed significant and distinct changes of 19 phosphoproteins corresponding to 28 phosphorylated sites between these two types of human lenses, including 20 newly discovered novel phosphorylation sites on lens proteins. CONCLUSIONS: The shotgun phosphoproteomics approach to characterize protein phosphorylation may be adapted and extended to the comprehensive analysis of other types of post-translational modification of lens proteins in vivo. The identification of these novel phosphorylation sites in lens proteins that showed differential expression in the cataractous lens may bear some unknown physiologic significance and provide insights into phosphorylation-related human eye diseases, which warrant further investigation in the future. PMID- 21264233 TI - Grape seed proanthocyanidin extract protects human lens epithelial cells from oxidative stress via reducing NF-kB and MAPK protein expression. AB - PURPOSE: Oxidative damage induced by H2O2 treatment can irreversibly damage the lens epithelium, resulting in cell death and cataract. Grape seed extract (GSE) is a widely consumed dietary supplement that has the capability to scavenge oxidants and free radicals. GSE contain 70%-95% standardized proanthocyanidins. The study described herein investigated the protective effect of Grape seed proanthocyanidin extract (GSPE) on H2O2-induced oxidative stress in human lens epithelial B-3 (HLEB-3) cells and the possible molecular mechanism involved. METHODS: HLE-B3 cells exposed to different doses of H2O2 were cultured with various concentrations of GSPE and subsequently monitored for cell viability by the 4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay. The apoptosis rate and ROS generation were detected by flow cytometric analysis. Expression of NF-kB/P65 and mitogen activated protein kinase (MAPK) proteins were measured by western blot. RESULTS: GSPE clearly reduced H2O2 induced cell apoptosis and reactive oxygen species (ROS) generation and protected HLEB-3 cells from H2O2 induced oxidative damage. GSPE depressed H2O2-induced activation and translocation of NF-kB/p65. GSPE also depressed H2O2-induced phosphorylation of the p38 and c-Jun N-terminal kinase (JNK) proteins of the MAPK family at various time points studied. CONCLUSIONS: GSPE could be useful in attenuation of H2O2 induced oxidative stress and the activation of NF-kB and MAPK signaling in HLE-B3 cells, which suggests that GSPE has a potential protective effect against cataractogenesis. PMID- 21264234 TI - The TGFBI R555W mutation induces a new granular corneal dystrophy type I phenotype. AB - PURPOSE: To report the clinical and molecular features of a distinct form of transforming growth factor-beta-induced (TGFBI) gene-linked corneal dystrophy exhibiting a new granular corneal dystrophy type I (CDGG1) phenotype. METHODS: A complete ophthalmologic examination was performed in all individuals of a Chinese family in which autosomal dominant transmission of the disease had been observed. DNA was obtained from the peripheral blood leukocytes of each participating subject. Genetic analyses included keratin 3 (KRT3), keratin 12 (KRT12), and TGFBI polymerase chain reaction (PCR) amplification and automated nucleotide sequencing of exons from the genomic DNA. RESULTS: The corneal phenotype in this pedigree was characterized by multiple bilateral dot-like, circular opacities at different corneal depths, with some of the affected individuals only having opacities in the epithelium, which is different from the typical CDGG1 phenotype. TGFBI analysis revealed a heterozygous point mutation at exon 12 (c.1663C>T) in all of the affected individuals, predicting a p.R555W missense mutation. CONCLUSIONS: The phenotype which resulted from the TGFBI R555W mutation in this family is distinct from that observed in the typical case of CDGG1. We propose this disorder should be classified as a new phenotype of CDGG1, and this finding demonstrates the importance of gene diagnosis in the corneal dystrophies. PMID- 21264235 TI - Lack of KIF21A mutations in congenital fibrosis of the extraocular muscles type I patients from consanguineous Saudi Arabian families. AB - PURPOSE: Congenital fibrosis of the extraocular muscles type I (CFEOM1), the most common CFEOM worldwide, is characterized by bilateral ptotic hypotropia, an inability to supraduct above the horizontal midline, horizontal strabismus (typically exotropia), and ophthalmoplegia with abnormal synkinesis. This distinct non-syndromic phenotype is considered autosomal dominant and is virtually always from heterozygous missense mutations in kinesin family member 21A (KIF21A). However, there are occasional KIF21A-negative cases, opening the possibility for a recessive cause. The objective of this study is to explore this possibility by assessing CFEOM1 patients exclusively from consanguineous families, who are the most likely to have recessive cause for their phenotype if a recessive cause exists. METHODS: Ophthalmic examination and candidate gene direct sequencing (KIF21A, paired-like homeobox 2A [PHOX2A], tubulin beta-3 [TUBB3]) of CFEOM1 patients from consanguineous families referred for counseling from 2005 to 2010. RESULTS: All 5 probands had classic CFEOM1 as defined above. Three had siblings with CFEOM. None of the probands had mutations in KIF21A, PHOX2A, or TUBB3. CONCLUSIONS: The lack of KIF21A mutations in CFEOM1 patients exclusively from consanguineous families, most of whom had siblings with CFEOM, is strong evidence for a recessive form of CFEOM1. Further studies of such families will hopefully uncover the specific locus(loci). PMID- 21264236 TI - Nuclear factor translocation and acute anterior uveitis. AB - PURPOSE: To investigate the roles of activation of macrophages isolated from C3H/HeN and C3H/HeJ mice and stimulated by lipopolysaccharide (LPS), and toll like receptor 4-mediated signal transduction in the development of acute anterior uveitis. METHODS: Establish animal models with acute anterior uveitis by intraperitoneal injection of vibrio cholera endotoxin into C3H/HeN mice (wild type) and C3H/HeJ mice (toll-like receptor 4 (TLR4) gene defection type). Peritoneal macrophages were obtained from C3H/HeN and C3H/HeJ mice. Immunofluorescence staining was used to identify the F4/80+ positive cells (iris, peritoneal macrophages) and to observe the expression of TLR4, myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B (NF-kappaB), with or without LPS (1 MUg/ml). To investigate the importance of TLR4 in the signal pathway, a group, blocked by anti-TLR4 antibody before LPS stimulation, was added to theC3H/HeN mice sample. RESULTS: In vitro, in C3H/HeN mice, Iris posterior synechia was found 24 h later. However, an inflammation reaction was not found in the anterior chamber of the C3H/HeJ mice. In cell culture, TLR4 expression was observed in peritoneal macrophages of the C3H/HeN mice, both with and without LPS stimulation. TLR4 was primarily expressed in the membrane and no significant difference in inflorescence intensity (p=0.081) was found among the groups. MyD88 was expressed in the cytoplasm and the nucleus. There is statistical significance in the fluorescence intensity among groups of C3H/HeN mice (p<0.0001). NF-kappaB was primarily expressed in the cytoplasm before LPS stimulation. However, this occurred 1 h after LPS stimulation and could be observed in the nucleus. Three hours after LPS stimulation, the expression of NF-kappaB could not be detected in the cytoplasm or the nucleus. The fluorescence intensity of TLR4 and MyD88 expression showed no significant difference (p=0.113) between the anti-TLR4 antibody pretreatment group and the other groups of C3H/HeN mice. However, in the anti-TLR4 antibody pretreatment group, 1 h to 24 h after LPS stimulation, NF kappaB only expressed in the cell membrane. Peritoneal macrophages from all groups of C3H/HeJ mice showed no obvious changes in morphology and size after LPS stimulation (p=0.257). TLR4 was primarily expressed in the cell membrane, and fluorescence intensity showed no statistical significance (p=0.228); MyD88 was expressed in the cytoplasm and the nucleus and there was no significant difference in fluorescence intensity among the groups (p=0.108); NF- kappaB was expressed in the cytoplasm, without LPS stimulation; however, 1 h after LPS stimulation, it appeared in the cell membrane and persisted until 24 h. CONCLUSIONS: Acute anterior uveitis can be induced in wild-type mice, but it cannot be induced in TLR4 gene-deficient mice. The variation of expression of TLR4, and its downstream signal transduction molecules, MyD88 and NF-kappaB, after LPS stimulation in vitro, suppose the potential role of a TLR4-MyD88 dependent pathway in the pathogenesis of acute anterior uveitis. The blockage of this pathway by anti-TLR4 may signal a new direction in the treatment of acute anterior uveitis. PMID- 21264237 TI - FeCo/graphite nanocrystals for multi-modality imaging of experimental vascular inflammation. AB - BACKGROUND: FeCo/graphitic-carbon nanocrystals (FeCo/GC) are biocompatible, high relaxivity, multi-functional nanoparticles. Macrophages represent important cellular imaging targets for assessing vascular inflammation. We evaluated FeCo/GC for vascular macrophage uptake and imaging in vivo using fluorescence and MRI. METHODS AND RESULTS: Hyperlipidemic and diabetic mice underwent carotid ligation to produce a macrophage-rich vascular lesion. In situ and ex vivo fluorescence imaging were performed at 48 hours after intravenous injection of FeCo/GC conjugated to Cy5.5 (n = 8, 8 nmol of Cy5.5/mouse). Significant fluorescence signal from FeCo/GC-Cy5.5 was present in the ligated left carotid arteries, but not in the control (non-ligated) right carotid arteries or sham operated carotid arteries (p = 0.03 for ligated vs. non-ligated). Serial in vivo 3T MRI was performed at 48 and 72 hours after intravenous FeCo/GC (n = 6, 270 ug Fe/mouse). Significant T2* signal loss from FeCo/GC was seen in ligated left carotid arteries, not in non-ligated controls (p = 0.03). Immunofluorescence staining showed colocalization of FeCo/GC and macrophages in ligated carotid arteries. CONCLUSIONS: FeCo/GC accumulates in vascular macrophages in vivo, allowing fluorescence and MR imaging. This multi-functional high-relaxivity nanoparticle platform provides a promising approach for cellular imaging of vascular inflammation. PMID- 21264239 TI - Population genetics of the aquatic fungus Tetracladium marchalianum over space and time. AB - Aquatic hyphomycete fungi are fundamental mediators of energy flow and nutrient spiraling in rivers. These microscopic fungi are primarily dispersed in river currents, undergo substantial annual fluctuations in abundance, and reproduce either predominantly or exclusively asexually. These aspects of aquatic hyphomycete biology are expected to influence levels and distributions of genetic diversity over both spatial and temporal scales. In this study, we investigated the spatiotemporal distribution of genotypic diversity in the representative aquatic hyphomycete Tetracladium marchalianum. We sampled populations of this fungus from seven sites, three sites each in two rivers in Illinois, USA, and one site in a Wisconsin river, USA, and repeatedly sampled one population over two years to track population genetic parameters through two seasonal cycles. The resulting fungal isolates (N = 391) were genotyped at eight polymorphic microsatellite loci. In spite of seasonal reductions in the abundance of this species, genotypic diversity was consistently very high and allele frequencies remarkably stable over time. Likewise, genotypic diversity was very high at all sites. Genetic differentiation was only observed between the most distant rivers (~450 km). Clear evidence that T. marchalianum reproduces sexually in nature was not observed. Additionally, we used phylogenetic analysis of partial beta-tubulin gene sequences to confirm that the fungal isolates studied here represent a single species. These results suggest that populations of T. marchalianum may be very large and highly connected at local scales. We speculate that large population sizes and colonization of alternate substrates in both terrestrial and aquatic environments may effectively buffer the aquatic populations from in stream population fluctuations and facilitate stability in allele frequencies over time. These data also suggest that overland dispersal is more important for structuring populations of T. marchalianum over geographic scales than expected. PMID- 21264238 TI - Engineered toxins "zymoxins" are activated by the HCV NS3 protease by removal of an inhibitory protein domain. AB - The synthesis of inactive enzyme precursors, also known as "zymogens," serves as a mechanism for regulating the execution of selected catalytic activities in a desirable time and/or site. Zymogens are usually activated by proteolytic cleavage. Many viruses encode proteases that execute key proteolytic steps of the viral life cycle. Here, we describe a proof of concept for a therapeutic approach to fighting viral infections through eradication of virally infected cells exclusively, thus limiting virus production and spread. Using the hepatitis C virus (HCV) as a model, we designed two HCV NS3 protease-activated "zymogenized" chimeric toxins (which we denote "zymoxins"). In these recombinant constructs, the bacterial and plant toxins diphtheria toxin A (DTA) and Ricin A chain (RTA), respectively, were fused to rationally designed inhibitor peptides/domains via an HCV NS3 protease-cleavable linker. The above toxins were then fused to the binding and translocation domains of Pseudomonas exotoxin A in order to enable translocation into the mammalian cells cytoplasm. We show that these toxins exhibit NS3 cleavage dependent increase in enzymatic activity upon NS3 protease cleavage in vitro. Moreover, a higher level of cytotoxicity was observed when zymoxins were applied to NS3 expressing cells or to HCV infected cells, demonstrating a potential therapeutic window. The increase in toxin activity correlated with NS3 protease activity in the treated cells, thus the therapeutic window was larger in cells expressing recombinant NS3 than in HCV infected cells. This suggests that the "zymoxin" approach may be most appropriate for application to life-threatening acute infections where much higher levels of the activating protease would be expected. PMID- 21264240 TI - Functional characterization of aquaporin-4 specific T cells: towards a model for neuromyelitis optica. AB - BACKGROUND: Antibodies to the water channel protein aquaporin-4 (AQP4), which is expressed in astrocytic endfeet at the blood brain barrier, have been identified in the serum of Neuromyelitis optica (NMO) patients and are believed to induce damage to astrocytes. However, AQP4 specific T helper cell responses that are required for the generation of anti-AQP4 antibodies and most likely also for the formation of intraparenchymal CNS lesions have not been characterized. METHODOLOGY/PRINCIPAL FINDINGS: Using overlapping 15-meric peptides of AQP4, we identified the immunogenic T cell epitopes of AQP4 that are restricted to murine major histocompatibility complex (MHC) I-A(b). The N-terminal region of AQP4 was highly immunogenic. More precisely, the intracellular epitope AQP4(22-36) was detected as major immunogenic determinant. AQP4(82-108) (located in the second transmembrane domain), AQP4(139-153) (located in the second extracellular loop), AQP4(211-225) (located in the fifth transmembrane domain), AQP4(235-249) (located in the sixth transmembrane domain), as well as AQP4(289-306) in the intracellular C-terminal region were also immunogenic epitopes. AQP4(22-36) and AQP4(289-303) specific T cells were present in the natural T cell repertoire of wild type C57BL/6 mice and T cell lines were raised. However, active immunization with these AQP4 peptides did not induce signs of spinal cord disease. Rather, sensitization with AQP4 peptides resulted in production of IFN-gamma, but also IL 5 and IL-10 by antigen-specific T cells. Consistent with this cytokine profile, the AQP4 specific antibody response upon immunization with full length AQP4 included IgG1 and IgG2, which are associated with a mixed Th2/Th1 T cell response. CONCLUSIONS AND SIGNIFICANCE: AQP4 is able to induce an autoreactive T cell response. The identification of I-A(b) restricted AQP4 specific T cell epitopes will allow us to investigate how AQP4 specific autoimmune reactions are regulated and to establish faithful mouse models of NMO that include both cellular and humoral responses against AQP4. PMID- 21264241 TI - Steroids up-regulate p66Shc longevity protein in growth regulation by inhibiting its ubiquitination. AB - BACKGROUND: p66Shc, an isoform of Shc adaptor proteins, mediates diverse signals, including cellular stress and mouse longevity. p66Shc protein level is elevated in several carcinomas and steroid-treated human cancer cells. Several lines of evidence indicate that p66Shc plays a critical role in steroid-related carcinogenesis, and steroids play a role in its elevated levels in those cells without known mechanism. METHODS AND FINDINGS: In this study, we investigated the molecular mechanism by which steroid hormones up-regulate p66Shc protein level. In steroid-treated human prostate and ovarian cancer cells, p66Shc protein levels were elevated, correlating with increased cell proliferation. These steroid effects on p66Shc protein and cell growth were competed out by the respective antagonist. Further, actinomycin D and cyclohexamide could only partially block the elevated p66Shc protein level by steroids. Treatment with proteasomal inhibitors, but not lysosomal protease inhibitor, resulted in elevated p66Shc protein levels, even higher than that by steroids. Using prostate cancer cells as a model, immunoprecipitation revealed that androgens and proteasomal inhibitors reduce the ubiquitinated p66Shc proteins. CONCLUSIONS: The data collectively indicate that functional steroid receptors are required in steroid up-regulation of p66Shc protein levels in prostate and ovarian cancer cells, correlating with cell proliferation. In these steroid-treated cells, elevated p66Shc protein level is apparently in part due to inhibiting its ubiquitination. The results may lead to an impact on advanced cancer therapy via the regulation of p66Shc protein by up-regulating its ubiquitination pathway. PMID- 21264242 TI - Growth parameter components of adaptive specificity during experimental evolution of the UVR-inducible mutator Pseudomonas cichorii 302959. AB - BACKGROUND: Mutagenic DNA repair (MDR) transiently increases mutation rate through the activation of low-fidelity repair polymerases in response to specific, DNA-damaging environmental stress conditions such as ultraviolet radiation (UVR) exposure. These repair polymerases also confer UVR tolerance, intimately linking mutability and survival in bacteria that colone habitats subject to regular UVR exposure. METHODOLOGY/PRINCIPAL FINDINGS: Here, we investigate adaptive specificity in experimental lineages of the highly UVR mutable epiphytic plant pathogen Pseudomonas cichorii 302959. Relative fitness measurements of isolates and population samples from replicate lineages indicated that adaptive improvements emerged early in all lineages of our evolution experiment and specific increases in relative fitness correlated with distinct improvements in doubling and lag times. Adaptive improvements gained under UVR and non-UVR conditions were acquired preferentially, and differentially contributed to relative fitness under varied growth conditions. CONCLUSIONS: These results support our earlier observations that MDR activation may contribute to gains in relative fitness without impeding normal patterns of adaptive specificity in P. cichorii 302959. PMID- 21264243 TI - Myogenin regulates exercise capacity but is dispensable for skeletal muscle regeneration in adult mdx mice. AB - Duchenne muscular dystrophy (DMD) is the most prevalent inherited childhood muscle disorder in humans. mdx mice exhibit a similar pathophysiology to the human disorder allowing for an in-depth investigation of DMD. Myogenin, a myogenic regulatory factor, is best known for its role in embryonic myogenesis, but its role in adult muscle maintenance and regeneration is still poorly understood. Here, we generated an mdx:Myog(flox/flox) mouse harboring a tamoxifen inducible Cre recombinase transgene, which was used to conditionally delete Myog during adult life. After tamoxifen treatment, three groups of mice were created to study the effects of Myog deletion: mdx:Myog(flox/flox) mice (mdx), Myog(flox/flox) mice (wild-type), and mdx:Myog(floxDelta/floxDelta):Cre-ER mice (mdx:Myog-deleted). mdx:Myog-deleted mice exhibited no adverse phenotype and behaved normally. When run to exhaustion, mdx:Myog-deleted mice demonstrated an enhanced capacity for exercise compared to mdx mice, running nearly as far as wild-type mice. Moreover, these mice showed the same signature characteristics of muscle regeneration as mdx mice. Unexpectedly, we found that myogenin was dispensable for muscle regeneration. Factors associated with muscle fatigue, metabolism, and proteolysis were significantly altered in mdx:Myog-deleted mice, and this might contribute to their increased exercise capacity. Our results reveal novel functions for myogenin in adult muscle and suggest that reducing Myog expression in other muscle disease models may partially restore muscle function. PMID- 21264244 TI - Turning on the heat: ecological response to simulated warming in the sea. AB - Significant warming has been observed in every ocean, yet our ability to predict the consequences of oceanic warming on marine biodiversity remains poor. Experiments have been severely limited because, until now, it has not been possible to manipulate seawater temperature in a consistent manner across a range of marine habitats. We constructed a "hot-plate" system to directly examine ecological responses to elevated seawater temperature in a subtidal marine system. The substratum available for colonisation and overlying seawater boundary layer were warmed for 36 days, which resulted in greater biomass of marine organisms and a doubling of space coverage by a dominant colonial ascidian. The "hot-plate" system will facilitate complex manipulations of temperature and multiple stressors in the field to provide valuable information on the response of individuals, populations and communities to environmental change in any aquatic habitat. PMID- 21264245 TI - A positive correlation between atypical memory B cells and Plasmodium falciparum transmission intensity in cross-sectional studies in Peru and Mali. AB - BACKGROUND: Antibodies that protect against Plasmodium falciparum (Pf) malaria are only acquired after years of repeated infections. The B cell biology that underlies this observation is poorly understood. We previously reported that "atypical" memory B cells are increased in children and adults exposed to intense Pf transmission in Mali, similar to what has been observed in individuals infected with HIV. In this study we examined B cell subsets of Pf -infected adults in Peru and Mali to determine if Pf transmission intensity correlates with atypical memory B cell expansion. METHODOLOGY/PRINCIPAL FINDINGS: In this cross sectional study venous blood was collected from adults in areas of zero (U.S., n = 10), low (Peru, n = 18) and high (Mali, n = 12) Pf transmission. Adults in Peru and Mali were infected with Pf at the time of blood collection. Thawed lymphocytes were analyzed by flow cytometry to quantify B cell subsets, including atypical memory B cells, defined by the cell surface markers CD19(+) CD20(+) CD21(-) CD27(-) CD10(-). In Peru, the mean level of atypical memory B cells, as a percent of total B cells, was higher than U.S. adults (Peru mean: 5.4% [95% CI: 3.61-7.28]; U.S. mean: 1.4% [95% CI: 0.92-1.81]; p<0.0001) but lower than Malian adults (Mali mean 13.1% [95% CI: 10.68-15.57]; p = 0.0001). In Peru, individuals self-reporting >=1 prior malaria episodes had a higher percentage of atypical memory B cells compared to those reporting no prior episodes (>=1 prior episodes mean: 6.6% [95% CI: 4.09-9.11]; no prior episodes mean: 3.1% [95% CI: 1.52-4.73]; p = 0.028). CONCLUSIONS/SIGNIFICANCE: Compared to Pf-naive controls, atypical memory B cells were increased in Peruvian adults exposed to low Pf transmission, and further increased in Malian adults exposed to intense Pf transmission. Understanding the origin, function and antigen specificity of atypical memory B cells in the context of Pf infection could contribute to our understanding of naturally-acquired malaria immunity. PMID- 21264247 TI - Electrochemical disinfection of dental implants--a proof of concept. AB - BACKGROUND: Peri-implantitis has gained significant clinical attention in recent years. This disease is an inflammatory reaction to microorganisms around dental implants. Due to the limited accessibility, non-invasive antimicrobial strategies are of high interest. An unexpected approach to implant disinfection may evolve from electrolysis. Given the electrical conductivity of titanium implants, alkalinity or active oxidants can be generated in body fluids. We investigated the use of dental titanium implants as electrodes for the local generation of disinfectants. Our hypothesis was that electrolysis can reduce viable counts of adhering bacteria, and that this reduction should be greater if active oxidative species are generated. METHODOLOGY/PRINCIPAL FINDINGS: As model systems, dental implants, covered with a mono-species biofilm of Escherichia coli C43, were placed in photographic gelatin prepared with physiological saline. Implants were treated by a continuous current of 0-10 mA for 15 minutes. The reduction of viable counts was investigated on cathodes and anodes. In separate experiments, the local change in pH was visualized using color indicators embedded in the gelatin. Oxidative species were qualitatively detected by potassium iodide-starch paper. The in situ generated alkaline environment around cathodic implants caused a reduction of up to 2 orders of magnitude in viable E. coli counts. On anodic implants, in contrast to cathodic counterparts, oxidative species were detected. Here, a current of merely 7.5 mA caused complete kill of the bacteria. CONCLUSIONS/SIGNIFICANCE: This laboratory study shows that electrochemical treatment may provide access to a new way to decontaminate dental implants in situ. PMID- 21264246 TI - Rise and fall of an anti-MUC1 specific antibody. AB - BACKGROUND: So far, human antibodies with good affinity and specificity for MUC1, a transmembrane protein overexpressed on breast cancers and ovarian carcinomas, and thus a promising target for therapy, were very difficult to generate. RESULTS: A human scFv antibody was isolated from an immune library derived from breast cancer patients immunised with MUC1. The anti-MUC1 scFv reacted with tumour cells in more than 80% of 228 tissue sections of mamma carcinoma samples, while showing very low reactivity with a large panel of non-tumour tissues. By mutagenesis and phage display, affinity of scFvs was increased up to 500fold to 5,7*10(-10) M. Half-life in serum was improved from below 1 day to more than 4 weeks and was correlated with the dimerisation tendency of the individual scFvs. The scFv bound to T47D and MCF-7 mammalian cancer cell lines were recloned into the scFv-Fc and IgG format resulting in decrease of affinity of one binder. The IgG variants with the highest affinity were tested in mouse xenograft models using MCF-7 and OVCAR tumour cells. However, the experiments showed no significant decrease in tumour growth or increase in the survival rates. To study the reasons for the failure of the xenograft experiments, ADCC was analysed in vitro using MCF-7 and OVCAR3 target cells, revealing a low ADCC, possibly due to internalisation, as detected for MCF-7 cells. CONCLUSIONS: Antibody phage display starting with immune libraries and followed by affinity maturation is a powerful strategy to generate high affinity human antibodies to difficult targets, in this case shown by the creation of a highly specific antibody with subnanomolar affinity to a very small epitope consisting of four amino acids. Despite these "best in class" binding parameters, the therapeutic success of this antibody was prevented by the target biology. PMID- 21264248 TI - Species difference of CD137 ligand signaling in human and murine monocytes. AB - BACKGROUND: Stimulation of CD137 ligand on human monocytes has been shown to induce DC differentiation, and these CD137L-DCs are more potent than classical DCs, in stimulating T cell responses in vitro. To allow an in vivo evaluation of the potency of CD137L-DCs in murine models we aimed at generating murine CD137L DCs. METHODOLOGY/PRINCIPAL FINDINGS: When stimulated through CD137 ligand murine monocytes responded just as human monocytes with an increased adherence, morphological changes, proliferation and an increase in viable cell numbers. But CD137 ligand signaling did not induce expression of inflammatory cytokines and costimulatory molecules in murine monocytes and these cells had no T cell stimulatory activity. Murine monocytes did not differentiate to inflammatory DCs upon CD137 ligand signaling. Furthermore, while CD137 ligand signaling induces maturation of human immature classical DCs it failed to do so with murine immature classical DCs. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that both human and murine monocytes become activated by CD137 ligand signaling but only human and not murine monocytes differentiate to inflammatory DCs. PMID- 21264249 TI - Multicolor combinatorial probe coding for real-time PCR. AB - The target volume of multiplex real-time PCR assays is limited by the number of fluorescent dyes available and the number of fluorescence acquisition channels present in the PCR instrument. We hereby explored a probe labeling strategy that significantly increased the target volume of real-time PCR detection in one reaction. The labeling paradigm, termed "Multicolor Combinatorial Probe Coding" (MCPC), uses a limited number (n) of differently colored fluorophores in various combinations to label each probe, enabling one of 2(n)-1 genetic targets to be detected in one reaction. The proof-of-principle of MCPC was validated by identification of one of each possible 15 human papillomavirus types, which is the maximum target number theoretically detectable by MCPC with a 4-color channel instrument, in one reaction. MCPC was then improved from a one-primer-pair setting to a multiple-primer-pair format through Homo-Tag Assisted Non-Dimer (HAND) system to allow multiple primer pairs to be included in one reaction. This improvement was demonstrated via identification of one of the possible 10 foodborne pathogen candidates with 10 pairs of primers included in one reaction, which had limit of detection equivalent to the uniplex PCR. MCPC was further explored in detecting combined genotypes of five beta-globin gene mutations where multiple targets were co-amplified. MCPC strategy could expand the scope of real time PCR assays in applications which are unachievable by current labeling strategy. PMID- 21264250 TI - The menin tumor suppressor protein is phosphorylated in response to DNA damage. AB - BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a heritable cancer syndrome characterized by tumors of the pituitary, pancreas and parathyroid. Menin, the product of the MEN1 gene, is a tumor suppressor protein that functions in part through the regulation of transcription mediated by interactions with chromatin modifying enzymes. PRINCIPAL FINDINGS: Here we show menin association with the 5' regions of DNA damage response genes increases after DNA damage and is correlated with RNA polymerase II association but not with changes in histone methylation. Furthermore, we were able to detect significant levels of menin at the 3' regions of CDKN1A and GADD45A under conditions of enhanced transcription following DNA damage. We also demonstrate that menin is specifically phosphorylated at Ser394 in response to several forms of DNA damage, Ser487 is dynamically phosphorylated and Ser543 is constitutively phosphorylated. Phosphorylation at these sites however does not influence the ability to interact with histone methyltransferase activity. In contrast, the interaction between menin and RNA polymerase II is influenced by phosphorylation, whereby a phospho deficient mutant had a higher affinity for the elongating form of RNA polymerase compared to wild type. Additionally, a subset of MEN1-associated missense point mutants, fail to undergo DNA damage dependent phosphorylation. CONCLUSION: Together, our findings suggest that the menin tumor suppressor protein undergoes DNA damage induced phosphorylation and participates in the DNA damage transcriptional response. PMID- 21264251 TI - Genetic population structure of cacao plantings within a young production area in Nicaragua. AB - Significant cocoa production in the municipality of Waslala, Nicaragua, began in 1961. Since the 1980s, its economic importance to rural smallholders increased, and the region now contributes more than 50% of national cocoa bean production. This research aimed to assist local farmers to develop production of high-value cocoa based on optimal use of cacao biodiversity. Using microsatellite markers, the allelic composition and genetic structure of cacao was assessed from 44 representative plantings and two unmanaged trees. The population at Waslala consists of only three putative founder genotype spectra (lineages). Two (B and R) were introduced during the past 50 years and occur in >95% of all trees sampled, indicating high rates of outcrossing. Based on intermediate allelic diversity, there was large farm-to-farm multilocus genotypic variation. GIS analysis revealed unequal distribution of the genotype spectra, with R being frequent within a 2 km corridor along roads, and B at more remote sites with lower precipitation. The third lineage, Y, was detected in the two forest trees. For explaining the spatial stratification of the genotype spectra, both human intervention and a combination of management and selection driven by environmental conditions, appear responsible. Genotypes of individual trees were highly diverse across plantings, thus enabling selection for farm-specific qualities. On-farm populations can currently be most clearly recognized by the degree of the contribution of the three genotype spectra. Of two possible strategies for future development of cacao in Waslala, i.e. introducing more unrelated germplasm, or working with existing on-site diversity, the latter seems most appropriate. Superior genotypes could be selected by their specific composite genotype spectra as soon as associations with desired quality traits are established, and clonally multiplied. The two Y trees from the forest share a single multilocus genotype, possibly representing the Mayan, 'ancient Criollo' cacao. PMID- 21264252 TI - Scaling dynamic response and destructive metabolism in an immunosurveillant anti tumor system modulated by different external periodic interventions. AB - On the basis of two universal power-law scaling laws, i.e. the scaling dynamic hysteresis in physics and the allometric scaling metabolism in biosystem, we studied the dynamic response and the evolution of an immunosurveillant anti-tumor system subjected to a periodic external intervention, which is equivalent to the scheme of a radiotherapy or chemotherapy, within the framework of the growth dynamics of tumor. Under the modulation of either an abrupt or a gradual change external intervention, the population density of tumors exhibits a dynamic hysteresis to the intervention. The area of dynamic hysteresis loop characterizes a sort of dissipative-therapeutic relationship of the dynamic responding of treated tumors with the dose consumption of accumulated external intervention per cycle of therapy. Scaling the area of dynamic hysteresis loops against the intensity of an external intervention, we deduced a characteristic quantity which was defined as the theoretical therapeutic effectiveness of treated tumor and related with the destructive metabolism of tumor under treatment. The calculated dose-effectiveness profiles, namely the dose cumulant per cycle of intervention versus the therapeutic effectiveness, could be well scaled into a universal quadratic formula regardless of either an abrupt or a gradual change intervention involved. We present a new concept, i.e., the therapy-effect matrix and the dose cumulant matrix, to expound the new finding observed in the growth and regression dynamics of a modulated anti-tumor system. PMID- 21264253 TI - Mitochondrial associated ubiquitin fold modifier-1 mediated protein conjugation in Leishmania donovani. AB - In this report, we demonstrate the existence of the ubiquitin fold modifier-1 (Ufm1) and its conjugation pathway in trypanosomatid parasite Leishmania donovani. LdUfm1 is activated by E1-like enzyme LdUba5. LdUfc1 (E2) specifically interacted with LdUfm1 and LdUba5 to conjugate LdUfm1 to proteinaceous targets. Mass spectrometry analysis revealed that LdUfm1 is conjugated to Leishmania protein targets that are associated with mitochondria. Immunofluorescence experiments showed that Leishmania Ufm1, Uba5 and Ufc1 are associated with the mitochondria. The demonstration that all the components of this system as well as the substrates are associated with mitochondrion suggests it may have physiological roles not yet described in any other organism. Overexpression of a non-conjugatable form of LdUfm1 and an active site mutant of LdUba5 resulted in reduced survival of Leishmania in the macrophage. Since mitochondrial activities are developmentally regulated in the life cycle of trypanosomatids, Ufm1 mediated modifications of mitochondrial proteins may be important in such regulation. Thus, Ufm1 conjugation pathway in Leishmania could be explored as a potential drug target in the control of Leishmaniasis. PMID- 21264254 TI - Whole-genome analysis reveals that active heat shock factor binding sites are mostly associated with non-heat shock genes in Drosophila melanogaster. AB - During heat shock (HS) and other stresses, HS gene transcription in eukaryotes is up-regulated by the transcription factor heat shock factor (HSF). While the identities of the major HS genes have been known for more than 30 years, it has been suspected that HSF binds to numerous other genes and potentially regulates their transcription. In this study, we have used a chromatin immunoprecipitation and microarray (ChIP-chip) approach to identify 434 regions in the Drosophila genome that are bound by HSF. We have also performed a transcript analysis of heat shocked Kc167 cells and third instar larvae and compared them to HSF binding sites. The heat-induced transcription profiles were quite different between cells and larvae and surprisingly only about 10% of the genes associated with HSF binding sites show changed transcription. There were also genes that showed changes in transcript levels that did not appear to correlate with HSF binding sites. Analysis of the locations of the HSF binding sites revealed that 57% were contained within genes with approximately 2/3rds of these sites being in introns. We also found that the insulator protein, BEAF, has enriched binding prior to HS to promoters of genes that are bound by HSF upon HS but that are not transcriptionally induced during HS. When the genes associated with HSF binding sites in promoters were analyzed for gene ontology terms, categories such as stress response and transferase activity were enriched whereas analysis of genes having HSF binding sites in introns identified those categories plus ones related to developmental processes and reproduction. These results suggest that Drosophila HSF may be regulating many genes besides the known HS genes and that some of these genes may be regulated during non-stress conditions. PMID- 21264255 TI - The antiviral spectra of TRIM5alpha orthologues and human TRIM family proteins against lentiviral production. AB - BACKGROUND: Rhesus monkey TRIM5alpha (TRIM5alpharh) recognizes the incoming HIV-1 core through its C-terminal B30.2(PRYSPRY) domain and promotes its premature disassembly or degradation before reverse transcription. Previously, we have shown that TRIM5alpharh blocks HIV-1 production through the N-terminal RBCC domain by the recognition of Gag polyproteins. Although all TRIM family proteins have RBCC domains, it remains elusive whether they possess similar late restriction activities. METHODOLOGY/PRINCIPAL FINDINGS: We examined the antiviral spectra of TRIM5alpha orthologues and human TRIM family members which have a genetic locus proximal to human TRIM5alpha (TRIM5alphahu), against primate lentiviral production. When HIV-1 virus-like particles (VLPs) were generated in the presence of TRIM5alpha proteins, rhesus, African green and cynomolgus monkey TRIM5alpha (TRIM5alphaag and TRIM5alphacy), but not TRIM5alphahu, were efficiently incorporated into VLPs, suggesting an interaction between HIV-1 Gag and TRIM5alpha proteins. TRIM5alpharh potently restricted the viral production of HIV-1 groups M and O and HIV-2, but not simian lentiviruses including SIV(MAC)1A11, SIV(AGM)Tan-1 or SIV(AGM)SAB-1. TRIM5alphahu did not show notable late restriction activities against these lentiviruses. TRIM5alphaag and TRIM5alphacy showed intermediate restriction phenotypes against HIV-1 and HIV-2, but showed no restriction activity against SIV production. A series of chimeric TRIM5alpha constructs indicated that the N-terminal region of TRIM5alphaag and TRIM5alphacy are essential for the late restriction activity, while the C terminal region of TRIM5alphacy negatively regulates the late restriction activity against HIV-1. When select human TRIM family proteins were examined, TRIM21 and 22 were efficiently incorporated into HIV-1 VLPs, while only TRIM22 reduced HIV-1 titers up to 5-fold. The antiviral activities and encapsidation efficiencies did not correlate with their relative expression levels in the producer cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated the variations in the late restriction activities among closely related TRIM5alpha orthologues and a subset of human TRIM family proteins, providing further insights into the late restriction activities of TRIM proteins. PMID- 21264256 TI - The temporal dynamics of differential gene expression in Aspergillus fumigatus interacting with human immature dendritic cells in vitro. AB - Dendritic cells (DC) are the most important antigen presenting cells and play a pivotal role in host immunity to infectious agents by acting as a bridge between the innate and adaptive immune systems. Monocyte-derived immature DCs (iDC) were infected with viable resting conidia of Aspergillus fumigatus (Af293) for 12 hours at an MOI of 5; cells were sampled every three hours. RNA was extracted from both organisms at each time point and hybridised to microarrays. iDC cell death increased at 6 h in the presence of A. fumigatus which coincided with fungal germ tube emergence; >80% of conidia were associated with iDC. Over the time course A. fumigatus differentially regulated 210 genes, FunCat analysis indicated significant up-regulation of genes involved in fermentation, drug transport, pathogenesis and response to oxidative stress. Genes related to cytotoxicity were differentially regulated but the gliotoxin biosynthesis genes were down regulated over the time course, while Aspf1 was up-regulated at 9 h and 12 h. There was an up-regulation of genes in the subtelomeric regions of the genome as the interaction progressed. The genes up-regulated by iDC in the presence of A. fumigatus indicated that they were producing a pro-inflammatory response which was consistent with previous transcriptome studies of iDC interacting with A. fumigatus germ tubes. This study shows that A. fumigatus adapts to phagocytosis by iDCs by utilising genes that allow it to survive the interaction rather than just up-regulation of specific virulence genes. PMID- 21264257 TI - Predicting individuals' learning success from patterns of pre-learning MRI activity. AB - Performance in most complex cognitive and psychomotor tasks improves with training, yet the extent of improvement varies among individuals. Is it possible to forecast the benefit that a person might reap from training? Several behavioral measures have been used to predict individual differences in task improvement, but their predictive power is limited. Here we show that individual differences in patterns of time-averaged T2*-weighted MRI images in the dorsal striatum recorded at the initial stage of training predict subsequent learning success in a complex video game with high accuracy. These predictions explained more than half of the variance in learning success among individuals, suggesting that individual differences in neuroanatomy or persistent physiology predict whether and to what extent people will benefit from training in a complex task. Surprisingly, predictions from white matter were highly accurate, while voxels in the gray matter of the dorsal striatum did not contain any information about future training success. Prediction accuracy was higher in the anterior than the posterior half of the dorsal striatum. The link between trainability and the time averaged T2*-weighted signal in the dorsal striatum reaffirms the role of this part of the basal ganglia in learning and executive functions, such as task switching and task coordination processes. The ability to predict who will benefit from training by using neuroimaging data collected in the early training phase may have far-reaching implications for the assessment of candidates for specific training programs as well as the study of populations that show deficiencies in learning new skills. PMID- 21264258 TI - Role of microRNA-26b in glioma development and its mediated regulation on EphA2. AB - BACKGROUND: MicroRNAs (miRNAs) are short, non-coding RNAs that regulate the expression of multiple target genes. Deregulation of miRNAs is common in human tumorigenesis. Low level expression of miR-26b has been found in glioma cells. However, its underlying mechanism of action has not been determined. METHODOLOGY/PRINCIPAL FINDINGS: Real-time PCR was employed to measure the expression level of miR-26b in glioma patients and cells. The level of miR-26b was inversely correlated with the grade of glioma. Ectopic expression of miR-26b inhibited the proliferation, migration and invasion of human glioma cells. A binding site for miR-26b was identified in the 3'UTR of EphA2. Over-expression of miR-26b in glioma cells repressed the endogenous level of EphA2 protein. Vasculogenic mimicry (VM) experiments were performed to further confirm the effects of miR-26b on the regulation of EphA2, and the results showed that miR 26b inhibited the VM processes which regulated by EphA2. SIGNIFICANCE: This study demonstrated that miR-26b may act as a tumor suppressor in glioma and it directly regulates EphA2 expression. EphA2 is a direct target of miR-26b, and the down regulation of EphA2 mediated by miR-26b is dependent on the binding of miR-26b to a specific response element of microRNA in the 3'UTR region of EphA2 mRNA. PMID- 21264259 TI - Analysis of epithelial and mesenchymal markers in ovarian cancer reveals phenotypic heterogeneity and plasticity. AB - In our studies of ovarian cancer cells we have identified subpopulations of cells that are in a transitory E/M hybrid stage, i.e. cells that simultaneously express epithelial and mesenchymal markers. E/M cells are not homogenous but, in vitro and in vivo, contain subsets that can be distinguished based on a number of phenotypic features, including the subcellular localization of E-cadherin, and the expression levels of Tie2, CD133, and CD44. A cellular subset (E/M-MP) (membrane E-cadherin(low)/cytoplasmic E-cadherin(high)/CD133(high), CD44(high), Tie2(low)) is highly enriched for tumor-forming cells and displays features which are generally associated with cancer stem cells. Our data suggest that E/M-MP cells are able to differentiate into different lineages under certain conditions, and have the capacity for self-renewal, i.e. to maintain a subset of undifferentiated E/M-MP cells during differentiation. Trans-differentiation of E/M-MP cells into mesenchymal or epithelial cells is associated with a loss of stem cell markers and tumorigenicity. In vivo xenograft tumor growth is driven by E/M-MP cells, which give rise to epithelial ovarian cancer cells. In contrast, in vitro, we found that E/M-MP cells differentiate into mesenchymal cells, in a process that involves pathways associated with an epithelial-to-mesenchymal transition. We also detected phenotypic plasticity that was dependent on external factors such as stress created by starvation or contact with either epithelial or mesenchymal cells in co-cultures. Our study provides a better understanding of the phenotypic complexity of ovarian cancer and has implications for ovarian cancer therapy. PMID- 21264260 TI - An oral vaccine based on U-Omp19 induces protection against B. abortus mucosal challenge by inducing an adaptive IL-17 immune response in mice. AB - As Brucella infections occur mainly through mucosal surfaces, the development of mucosal administered vaccines could be radical for the control of brucellosis. In this work we evaluated the potential of Brucella abortus 19 kDa outer membrane protein (U-Omp19) as an edible subunit vaccine against brucellosis. We investigated the protective immune response elicited against oral B. abortus infection after vaccination of mice with leaves from transgenic plants expressing U-Omp19; or with plant-made or E. coli-made purified U-Omp19. All tested U-Omp19 formulations induced protection against Brucella when orally administered without the need of adjuvants. U-Omp19 also induced protection against a systemic challenge when parenterally administered. This built-in adjuvant ability of U Omp19 was independent of TLR4 and could be explained at least in part by its capability to activate dendritic cells in vivo. While unadjuvanted U-Omp19 intraperitoneally administered induced a specific Th1 response, following U-Omp19 oral delivery a mixed specific Th1-Th17 response was induced. Depletion of CD4(+) T cells in mice orally vaccinated with U-Omp19 resulted in a loss of the elicited protection, indicating that this cell type mediates immune protection. The role of IL-17 against Brucella infection has never been explored. In this study, we determined that if IL-17A was neutralized in vivo during the challenge period, the mucosal U-Omp19 vaccine did not confer mucosal protection. On the contrary, IL-17A neutralization during the infection did not influence at all the subsistence and growth of this bacterium in PBS-immunized mice. All together, our results indicate that an oral unadjuvanted vaccine based on U-Omp19 induces protection against a mucosal challenge with Brucella abortus by inducing an adaptive IL-17 immune response. They also indicate different and important new aspects i) IL-17 does not contribute to reduce the bacterial burden in non vaccinated mice and ii) IL-17 plays a central role in vaccine mediated anti Brucella mucosal immunity. PMID- 21264261 TI - Insulin reduces neuronal excitability by turning on GABA(A) channels that generate tonic current. AB - Insulin signaling to the brain is important not only for metabolic homeostasis but also for higher brain functions such as cognition. GABA (gamma-aminobutyric acid) decreases neuronal excitability by activating GABA(A) channels that generate phasic and tonic currents. The level of tonic inhibition in neurons varies. In the hippocampus, interneurons and dentate gyrus granule cells normally have significant tonic currents under basal conditions in contrast to the CA1 pyramidal neurons where it is minimal. Here we show in acute rat hippocampal slices that insulin (1 nM) "turns on" new extrasynaptic GABA(A) channels in CA1 pyramidal neurons resulting in decreased frequency of action potential firing. The channels are activated by more than million times lower GABA concentrations than synaptic channels, generate tonic currents and show outward rectification. The single-channel current amplitude is related to the GABA concentration resulting in a single-channel GABA affinity (EC(50)) in intact CA1 neurons of 17 pM with the maximal current amplitude reached with 1 nM GABA. They are inhibited by GABA(A) antagonists but have novel pharmacology as the benzodiazepine flumazenil and zolpidem are inverse agonists. The results show that tonic rather than synaptic conductances regulate basal neuronal excitability when significant tonic conductance is expressed and demonstrate an unexpected hormonal control of the inhibitory channel subtypes and excitability of hippocampal neurons. The insulin-induced new channels provide a specific target for rescuing cognition in health and disease. PMID- 21264262 TI - Deficiency of antinociception and excessive grooming induced by acute immobilization stress in Per1 mutant mice. AB - Acute stressors induce changes in numerous behavioral parameters through activation of the hypothalamic-pituitary-adrenal (HPA) axis. Several important hormones in paraventricular nucleus of the hypothalamus (PVN) play the roles in these stress-induced reactions. Corticotropin-releasing hormone (CRH), arginine vasopressin (AVP) and corticosterone are considered as molecular markers for stress-induced grooming behavior. Oxytocin in PVN is an essential modulator for stress-induced antinociception. The clock gene, Per1, has been identified as an effecter response to the acute stresses, but its function in neuroendocrine stress systems remains unclear. In the present study we observed the alterations in grooming and nociceptive behaviors induced by acute immobilization stress in Per1 mutant mice and other genotypes (wild types and Per2 mutant). The results displayed that stress elicited a more robust effect on grooming behavior in Per1 mutant mice than in other genotypes. Subsequently, the obvious stress-induced antinociception was observed in the wild-type and Per2 mutant mice, however, in Per1 mutant, this antinociceptive effects were partially-reversed (mechanical sensitivity), or over-reversed to hyperalgesia (thermal sensitivity). The real time qPCR results showed that in PVN, there were stress-induced up-regulations of Crh, Avp and c-fos in all of genotypes; moreover, the expression change of Crh in Per1 mutant mice was much larger than in others. Another hormonal gene, Oxt, was up-regulated induced by stress in wild-type and Per2 mutant but not in Per1 mutant. In addition, the stress significantly elevated the serum corticosterone levels without genotype-dependent differences, and accordingly the glucocorticoid receptor gene, Nr3c1, expressed with a similar pattern in PVN of all strains. Taken together, the present study indicated that in acute stress treated Per1 mutant mice, there are abnormal hormonal responses in PVN, correlating with the aberrant performance of stress-induced behaviors. Therefore, our findings suggest a novel functional role of Per1 in neuroendocrine stress system, which further participates in analgesic regulation. PMID- 21264263 TI - Targeted regeneration of bone in the osteoporotic human femur. AB - We have recently developed image processing techniques for measuring the cortical thicknesses of skeletal structures in vivo, with resolution surpassing that of the underlying computed tomography system. The resulting thickness maps can be analysed across cohorts by statistical parametric mapping. Applying these methods to the proximal femurs of osteoporotic women, we discover targeted and apparently synergistic effects of pharmaceutical osteoporosis therapy and habitual mechanical load in enhancing bone thickness. PMID- 21264264 TI - A model for transition of 5'-nuclease domain of DNA polymerase I from inert to active modes. AB - Bacteria contain DNA polymerase I (PolI), a single polypeptide chain consisting of ~930 residues, possessing DNA-dependent DNA polymerase, 3'-5' proofreading and 5'-3' exonuclease (also known as flap endonuclease) activities. PolI is particularly important in the processing of Okazaki fragments generated during lagging strand replication and must ultimately produce a double-stranded substrate with a nick suitable for DNA ligase to seal. PolI's activities must be highly coordinated both temporally and spatially otherwise uncontrolled 5' nuclease activity could attack a nick and produce extended gaps leading to potentially lethal double-strand breaks. To investigate the mechanism of how PolI efficiently produces these nicks, we present theoretical studies on the dynamics of two possible scenarios or models. In one the flap DNA substrate can transit from the polymerase active site to the 5'-nuclease active site, with the relative position of the two active sites being kept fixed; while the other is that the 5' nuclease domain can transit from the inactive mode, with the 5'-nuclease active site distant from the cleavage site on the DNA substrate, to the active mode, where the active site and substrate cleavage site are juxtaposed. The theoretical results based on the former scenario are inconsistent with the available experimental data that indicated that the majority of 5'-nucleolytic processing events are carried out by the same PolI molecule that has just extended the upstream primer terminus. By contrast, the theoretical results on the latter model, which is constructed based on available structural studies, are consistent with the experimental data. We thus conclude that the latter model rather than the former one is reasonable to describe the cooperation of the PolI's polymerase and 5'-3' exonuclease activities. Moreover, predicted results for the latter model are presented. PMID- 21264265 TI - Human AlkB homologue 5 is a nuclear 2-oxoglutarate dependent oxygenase and a direct target of hypoxia-inducible factor 1alpha (HIF-1alpha). AB - Human 2-oxoglutarate oxygenases catalyse a range of biological oxidations including the demethylation of histone and nucleic acid substrates and the hydroxylation of proteins and small molecules. Some of these processes are centrally involved in regulation of cellular responses to hypoxia. The ALKBH proteins are a sub-family of 2OG oxygenases that are defined by homology to the Escherichia coli DNA-methylation repair enzyme AlkB. Here we report evidence that ALKBH5 is probably unique amongst the ALKBH genes in being a direct transcriptional target of hypoxia inducible factor-1 (HIF-1) and is induced by hypoxia in a range of cell types. We show that purified recombinant ALKBH5 is a bona fide 2OG oxygenase that catalyses the decarboxylation of 2OG but appears to have different prime substrate requirements from those so far defined for other ALKBH family members. Our findings define a new class of HIF-transcriptional target gene and suggest that ALKBH5 may have a role in the regulation of cellular responses to hypoxia. PMID- 21264266 TI - An analysis on the detection of biological contaminants aboard aircraft. AB - The spread of infectious disease via commercial airliner travel is a significant and realistic threat. To shed some light on the feasibility of detecting airborne pathogens, a sensor integration study has been conducted and computational investigations of contaminant transport in an aircraft cabin have been performed. Our study took into consideration sensor sensitivity as well as the time-to answer, size, weight and the power of best available commercial off-the-shelf (COTS) devices. We conducted computational fluid dynamics simulations to investigate three types of scenarios: (1) nominal breathing (up to 20 breaths per minute) and coughing (20 times per hour); (2) nominal breathing and sneezing (4 times per hour); and (3) nominal breathing only. Each scenario was implemented with one or seven infectious passengers expelling air and sneezes or coughs at the stated frequencies. Scenario 2 was implemented with two additional cases in which one infectious passenger expelled 20 and 50 sneezes per hour, respectively. All computations were based on 90 minutes of sampling using specifications from a COTS aerosol collector and biosensor. Only biosensors that could provide an answer in under 20 minutes without any manual preparation steps were included. The principal finding was that the steady-state bacteria concentrations in aircraft would be high enough to be detected in the case where seven infectious passengers are exhaling under scenarios 1 and 2 and where one infectious passenger is actively exhaling in scenario 2. Breathing alone failed to generate sufficient bacterial particles for detection, and none of the scenarios generated sufficient viral particles for detection to be feasible. These results suggest that more sensitive sensors than the COTS devices currently available and/or sampling of individual passengers would be needed for the detection of bacteria and viruses in aircraft. PMID- 21264267 TI - The carrot or the stick? Evaluation of education and enforcement as management tools for human-wildlife conflicts. AB - Evidence-based decision-making is critical for implementing conservation actions, especially for human-wildlife conflicts, which have been increasing worldwide. Conservation practitioners recognize that long-term solutions should include altering human behaviors, and public education and enforcement of wildlife related laws are two management actions frequently implemented, but with little empirical evidence evaluating their success. We used a system where human-black bear conflicts were common, to experimentally test the efficacy of education and enforcement in altering human behavior to better secure attractants (garbage) from bears. We conducted 3 experiments in Aspen CO, USA to evaluate: 1) on-site education in communal dwellings and construction sites, 2) Bear Aware educational campaign in residential neighborhoods, and 3) elevated law enforcement at two levels in the core business area of Aspen. We measured human behaviors as the response including: violation of local wildlife ordinances, garbage availability to bears, and change in use of bear-resistance refuse containers. As implemented, we found little support for education, or enforcement in the form of daily patrolling in changing human behavior, but found more support for proactive enforcement, i.e., dispensing warning notices. More broadly we demonstrated the value of gathering evidence before and after implementing conservation actions, and the dangers of measuring responses in the absence of ecological knowledge. We recommend development of more effective educational methods, application of proactive enforcement, and continued evaluation of tools by directly measuring change in human behavior. We provide empirical evidence adding to the conservation managers' toolbox, informing policy makers, and promoting solutions to human-wildlife conflicts. PMID- 21264268 TI - Do tropical cyclones shape shorebird habitat patterns? Biogeoclimatology of snowy plovers in Florida. AB - BACKGROUND: The Gulf coastal ecosystems in Florida are foci of the highest species richness of imperiled shoreline dependent birds in the USA. However environmental processes that affect their macroecological patterns, like occupancy and abundance, are not well unraveled. In Florida the Snowy Plover (Charadrius alexandrinus nivosus) is resident along northern and western white sandy estuarine/ocean beaches and is considered a state-threatened species. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that favorable nesting areas along the Florida Gulf coastline are located in regions impacted relatively more frequently by tropical cyclones. The odds of Snowy Plover nesting in these areas during the spring following a tropical cyclone impact are seven times higher compared to the odds during the spring following a season without a cyclone. The only intensity of a tropical cyclone does not appear to be a significant factor affecting breeding populations. CONCLUSIONS/SIGNIFICANCE: Nevertheless a future climate scenario featuring fewer, but more extreme cyclones could result in a decrease in the breeding Snowy Plover population and its breeding range. This is because the spatio-temporal frequency of cyclone events was found to significantly affect nest abundance. Due to the similar geographic range and habitat suitability, and no decrease in nest abundance of other shorebirds in Florida after the cyclone season, our results suggest a common bioclimatic feedback between shorebird abundance and tropical cyclones in breeding areas which are affected by cyclones. PMID- 21264270 TI - Does birth weight influence physical activity in youth? A combined analysis of four studies using objectively measured physical activity. AB - Animal models suggest growth restriction in utero leads to lower levels of motor activity. Furthermore, individuals with very low birth weight report lower levels of physical activity as adults. The aim of this study was to examine whether birth weight acts as a biological determinant of physical activity and sedentary time. This study uses combined analysis of three European cohorts and one from South America (n = 4,170). Birth weight was measured or parentally reported. Height and weight were measured and used to calculate Body Mass Index (BMI). PA was objectively measured using accelerometry for >=3 days, >=10 hours day. Data was standardized to allow comparisons between different monitors. Total physical activity was assessed as counts per minute (cpm), with time spent above moderate activity (MVPA) >2,000 counts and time spent sedentary (<100 counts). There was no evidence for an association between birth weight and total physical activity (p = 0.9) or MVPA (p = 0.7). Overall there was no evidence for an association between birth weight and sedentary time (p = 0.8). However in the Pelotas study we did find an association between higher birth weight (kg) and lower overall physical activity (cpm) (beta = -31, 95%CI: -58, -46, p = 0.03) and higher birth weight and greater sedentary time (mins/day) (beta = 16.4, 95%CI: 5.3, 27.5, p = 0.004), although this was attenuated and no longer significant with further adjustment for gestational age. Overall this combined analysis suggests that birth weight may not be an important biological determinant of habitual physical activity or sedentary behaviour in children and adolescents. PMID- 21264284 TI - Calcium- and integrin-binding protein 1 regulates endomitosis and its interaction with Polo-like kinase 3 is enhanced in endomitotic Dami cells. AB - Endomitosis is a form of mitosis in which both karyokinesis and cytokinesis are interrupted and is a hallmark of megakaryocyte differentiation. Very little is known about how such a dramatic alteration of the cell cycle in a physiological setting is achieved. Thrombopoietin-induced signaling is essential for induction of endomitosis. Here we show that calcium- and integrin-binding protein 1 (CIB1), a known regulator of platelet integrin alpha(IIb)beta(3) outside-in signaling, regulates endomitosis. We observed that CIB1 expression is increased in primary mouse megakaryocytes compared to mononuclear bone marrow cells as determined by Western blot analysis. Following PMA treatment of Dami cells, a megakaryoblastic cell line, we found that CIB1 protein expression increased concomitant with cell ploidy. Overexpression of CIB1 in Dami cells resulted in multilobated nuclei and led to increased time for a cell to complete cytokinesis as well as increased incidence of furrow regression as observed by time-lapse microscopy. Additionally, we found that surface expression of integrin alpha(IIb)beta(3,) an important megakaryocyte marker, was enhanced in CIB1 overexpressing cells as determined by flow cytometry. Furthermore, PMA treatment of CIB1 overexpressing cells led to increased ploidy compared to PMA treated control cells. Interestingly, expression of Polo-like kinase 3 (Plk3), an established CIB1 interacting protein and a key regulator of the mitotic process, decreased upon PMA treatment of Dami cells. Furthermore, PMA treatment augmented the interaction between CIB1 and Plk3, which depended on the duration of treatment. These data suggest that CIB1 is involved in regulating endomitosis, perhaps through its interaction with Plk3. PMID- 21264285 TI - Changes in corneal basal epithelial phenotypes in an altered basement membrane. AB - BACKGROUND: To examine the corneal epithelial phenotype in an altered basement membrane. METHODOLOGY/PRINCIPAL FINDINGS: Corneas from 9 patients with symptoms of continuous unstable corneal curvature (CUCC) were harvested by penetrating keratoplasty and subjected to histology examination and immunohistochemical staining with transactivating and N-terminally truncated pP63 transcript (DeltaNp63), cytokeratin 3 (Krt3), ATP-binding cassette sub-family G member 2 (ABCG2), connexin 43 (CX43), p38 mitogen-activated protein kinases (p38MAPK), activating protein 2 (TFAP2), and extracellular signal-regulated kinase (Erk1/2) monoclonal antibodies. Positive immunostaining with ABCG2, p38MAPK, and TFAP2 monoclonal antibodies was observed in the basal epithelial cells of CUCC patients, and CX43 and DeltaNp63 were detected in the full-thickness epithelial cells of CUCC patients. CONCLUSIONS/SIGNIFICANCE: Our results indicate that alteration of the corneal basement membrane induces a de-differentiation-like phenotype in corneal basal epithelial cells. PMID- 21264269 TI - Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease. AB - BACKGROUND: Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome. METHODS AND FINDINGS: CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p tau181 and Abeta42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively. CONCLUSIONS: Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Abeta42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions. PMID- 21264286 TI - Emergence of classical BSE strain properties during serial passages of H-BSE in wild-type mice. AB - BACKGROUND: Two distinct forms of atypical spongiform encephalopathies (H-BSE and L-BSE) have recently been identified in cattle. Transmission studies in several wild-type or transgenic mouse models showed that these forms were associated with two distinct major strains of infectious agents, which also differed from the unique strain that had been isolated from cases of classical BSE during the food borne epizootic disease. METHODOLOGY/PRINCIPAL FINDINGS: H-BSE was monitored during three serial passages in C57BL/6 mice. On second passage, most of the inoculated mice showed molecular features of the abnormal prion protein (PrP(d)) and brain lesions similar to those observed at first passage, but clearly distinct from those of classical BSE in this mouse model. These features were similarly maintained during a third passage. However, on second passage, some of the mice exhibited distinctly different molecular and lesion characteristics, reminiscent of classical BSE in C57Bl/6 mice. These similarities were confirmed on third passage from such mice, for which the same survival time was also observed as with classical BSE adapted to C57Bl/6 mice. Lymphotropism was rarely detected in mice with H-BSE features. In contrast, PrP(d) was detectable, on third passage, in the spleens of most mice exhibiting classical BSE features, the pattern being indistinguishable from that found in C57Bl/6 mice infected with classical BSE. CONCLUSION/SIGNIFICANCE: Our data demonstrate the emergence of a prion strain with features similar to classical BSE during serial passages of H BSE in wild-type mice. Such findings might help to explain the origin of the classical BSE epizootic disease, which could have originated from a putatively sporadic form of BSE. PMID- 21264287 TI - TRAIL receptor signaling regulation of chemosensitivity in vivo but not in vitro. AB - BACKGROUND: Signaling by Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) and Fas ligand (FasL) has been proposed to contribute to the chemosensitivity of tumor cells treated with various other anti-cancer agents. However, the importance of these effects and whether there are differences in vitro and in vivo is unclear. METHODOLOGY/PRINCIPAL FINDINGS: To assess the relative contribution of death receptor pathways to this sensitivity and to determine whether these effects are intrinsic to the tumor cells, we compared the chemosensitivity of isogenic BJAB human lymphoma cells where Fas and TRAIL receptors or just TRAIL receptors were inhibited using mutants of the adaptor protein FADD or by altering the expression of the homeobox transcription factor Six1. Inhibition of TRAIL receptors did not affect in vitro tumor cell killing by various anti-cancer agents indicating that chemosensitivity is not significantly affected by the tumor cell-intrinsic activation of death receptor signaling. However, selective inhibition of TRAIL receptor signaling caused reduced tumor regression and clearance in vivo when tested in a NOD/SCID mouse model. CONCLUSIONS: These data show that TRAIL receptor signaling in tumor cells can determine chemosensitivity in vivo but not in vitro and thus imply that TRAIL resistance makes tumors less susceptible to conventional cytotoxic anti-cancer drugs as well as drugs that directly target the TRAIL receptors. PMID- 21264288 TI - Mutation of HIV-1 genomes in a clinical population treated with the mutagenic nucleoside KP1461. AB - The deoxycytidine analog KP1212, and its prodrug KP1461, are prototypes of a new class of antiretroviral drugs designed to increase viral mutation rates, with the goal of eventually causing the collapse of the viral population. Here we present an extensive analysis of viral sequences from HIV-1 infected volunteers from the first "mechanism validation" phase II clinical trial of a mutagenic base analog in which individuals previously treated with antiviral drugs received 1600 mg of KP1461 twice per day for 124 days. Plasma viral loads were not reduced, and overall levels of viral mutation were not increased during this short-term study, however, the mutation spectrum of HIV was altered. A large number (N = 105 per sample) of sequences were analyzed, each derived from individual HIV-1 RNA templates, after 0, 56 and 124 days of therapy from 10 treated and 10 untreated control individuals (>7.1 million base pairs of unique viral templates were sequenced). We found that private mutations, those not found in more than one viral sequence and likely to have occurred in the most recent rounds of replication, increased in treated individuals relative to controls after 56 (p = 0.038) and 124 (p = 0.002) days of drug treatment. The spectrum of mutations observed in the treated group showed an excess of A to G and G to A mutations (p = 0.01), and to a lesser extent T to C and C to T mutations (p = 0.09), as predicted by the mechanism of action of the drug. These results validate the proposed mechanism of action in humans and should spur development of this novel antiretroviral approach. PMID- 21264289 TI - Rapid and highly efficient method for scarless mutagenesis within the Salmonella enterica chromosome. AB - Direct manipulation of bacterial chromosomes by recombination-based techniques has become increasingly important for both cognitive and applied research. Here we demonstrate, for the first time, the combination of the Red recombinase system with I-SceI endonuclease-based selection of successful recombinants after electroporation with short synthetic oligonucleotides. We show the generation of scarless gene knockouts as well as site-directed mutagenesis using the Salmonella virulence-associated two component signaling system PhoPQ. The presented approach is very versatile for generating in-frame deletions, point mutations or insertions within bacterial chromosomes. PMID- 21264290 TI - Bioaccessibility of Pb from ammunition in game meat is affected by cooking treatment. AB - BACKGROUND: The presence of lead (Pb) ammunition residues in game meat has been widely documented, yet little information exists regarding the bioaccessibility of this Pb contamination. We study how cooking treatment (recipe) can affect Pb bioaccessibility in meat of animals hunted with Pb ammunition. METHODOLOGY/PRINCIPAL FINDINGS: We used an in vitro gastrointestinal simulation to study bioaccessibility. The simulation was applied to meat from red-legged partridge (Alectoris rufa) hunted with Pb shot pellets and cooked using various traditional Spanish game recipes involving wine or vinegar. Total Pb concentrations in the meat were higher in samples with visible Pb ammunition by X ray (mean+/-SE: 3.29+/-1.12 ug/g w.w.) than in samples without this evidence (1.28+/-0.61 ug/g). The percentage of Pb that was bioaccessible within the simulated intestine phase was far higher in meat cooked with vinegar (6.75%) and wine (4.51%) than in uncooked meat (0.7%). Risk assessment simulations using our results transformed to bioavailability and the Integrated Exposure Uptake Biokinetic model (IEUBK; US EPA) show that the use of wine instead of vinegar in cooking recipes may reduce the percentage of children that would be expected to have >10 ug/dl of Pb in blood from 2.08% to 0.26% when game meat represents 50% of the meat in diet. CONCLUSIONS/SIGNIFICANCE: Lead from ammunition in game meat is more bioaccessible after cooking, especially when using highly acidic recipes. These results are important because existing theoretical models regarding Pb uptake and subsequent risk in humans should take such factors into account. PMID- 21264291 TI - Analysis of the ex vivo and in vivo antiretroviral activity of gemcitabine. AB - Replication of retroviral and host genomes requires ribonucleotide reductase to convert rNTPs to dNTPs, which are then used as substrates for DNA synthesis. Inhibition of ribonucleotide reductase by hydroxyurea (HU) has been previously used to treat cancers as well as HIV. However, the use of HU as an antiretroviral is limited by its associated toxicities such as myelosuppression and hepatotoxicity. In this study, we examined the ribonucleotide reductase inhibitor, gemcitabine, both in cell culture and in C57Bl/6 mice infected with LP BM5 murine leukemia virus (LP-BM5 MuLV, a murine AIDS model). Gemcitabine decreased infectivity of MuLV in cell culture with an EC50 in the low nanomolar range with no detectable cytotoxicity. Similarly, gemcitabine significantly decreased disease progression in mice infected with LP-BM5. Specifically, gemcitabine treatment decreased spleen size, plasma IgM, and provirus levels compared to LP-BM5 MuLV infected, untreated mice. Gemcitabine efficacy was observed at doses as low as 1 mg/kg/day in the absence of toxicity. Higher doses of gemcitabine (3 mg/kg/day and higher) were associated with toxicity as determined by a loss in body mass. In summary, our findings demonstrate that gemcitabine has antiretroviral activity ex vivo and in vivo in the LP-BM5 MuLV model. These observations together with a recent ex vivo study with HIV-1, suggest that gemcitabine has broad antiretroviral activity and could be particularly useful in vivo when used in combination drug therapy. PMID- 21264292 TI - Removal of PCR error products and unincorporated primers by metal-chelate affinity chromatography. AB - Immobilized Metal Affinity Chromatography (IMAC) has been used for decades to purify proteins on the basis of amino acid content, especially surface-exposed histidines and "histidine tags" genetically added to recombinant proteins. We and others have extended the use of IMAC to purification of nucleic acids via interactions with the nucleotide bases, especially purines, of single-stranded RNA and DNA. We also have demonstrated the purification of plasmid DNA from contaminating genomic DNA by IMAC capture of selectively-denatured genomic DNA. Here we describe an efficient method of purifying PCR products by specifically removing error products, excess primers, and unincorporated dNTPs from PCR product mixtures using flow-through metal-chelate affinity adsorption. By flowing a PCR product mixture through a Cu(2+)-iminodiacetic acid (IDA) agarose spin column, 94-99% of the dNTPs and nearly all the primers can be removed. Many of the error products commonly formed by Taq polymerase also are removed. Sequencing of the IMAC-processed PCR product gave base-calling accuracy comparable to that obtained with a commercial PCR product purification method. The results show that IMAC matrices (specifically Cu(2+)-IDA agarose) can be used for the purification of PCR products. Due to the generality of the base-specific mechanism of adsorption, IMAC matrices may also be used in the purification of oligonucleotides, cDNA, mRNA and micro RNAs. PMID- 21264293 TI - Regulation of endothelial cell adhesion molecule expression by mast cells, macrophages, and neutrophils. AB - BACKGROUND: Leukocyte adhesion to the vascular endothelium and subsequent transendothelial migration play essential roles in the pathogenesis of cardiovascular diseases such as atherosclerosis. The leukocyte adhesion is mediated by localized activation of the endothelium through the action of inflammatory cytokines. The exact proinflammatory factors, however, that activate the endothelium and their cellular sources remain incompletely defined. METHODS AND RESULTS: Using bone marrow-derived mast cells from wild-type, Tnf(-/-), Ifng( /-), Il6(-/-) mice, we demonstrated that all three of these pro-inflammatory cytokines from mast cells induced the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), P-selectin, and E-selectin in murine heart endothelial cells (MHEC) at both mRNA and protein levels. Compared with TNF-alpha and IL6, IFN-gamma appeared weaker in the induction of the mRNA levels, but at protein levels, both IL6 and IFN-gamma were weaker inducers than TNF-alpha. Under physiological shear flow conditions, mast cell-derived TNF-alpha and IL6 were more potent than IFN-gamma in activating MHEC and in promoting neutrophil adhesion. Similar observations were made when neutrophils or macrophages were used. Neutrophils and macrophages produced the same sets of pro-inflammatory cytokines as did mast cells to induce MHEC adhesion molecule expression, with the exception that macrophage-derived IFN-gamma showed negligible effect in inducing VCAM-1 expression in MHEC. CONCLUSION: Mast cells, neutrophils, and macrophages release pro-inflammatory cytokines such as TNF alpha, IFN-gamma, and IL6 that induce expression of adhesion molecules in endothelium and recruit of leukocytes, which is essential to the pathogenesis of vascular inflammatory diseases. PMID- 21264294 TI - Rapamycin blocks production of KSHV/HHV8: insights into the anti-tumor activity of an immunosuppressant drug. AB - BACKGROUND: Infection with Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) often results in the development of fatal tumors in immunocompromised patients. Studies of renal transplant recipients show that use of the immunosuppressant drug rapamycin, an mTOR inhibitor, both prevents and can induce the regression of Kaposi's sarcoma (KS), an opportunistic tumor that arises within a subset of this infected population. In light of rapamycin's marked anti-KS activity, we tested whether the drug might directly inhibit the KSHV life cycle. We focused on the molecular switch that triggers this predominantly latent virus to enter the lytic (productive) replication phase, since earlier work links this transition to viral persistence and tumorigenesis. METHODS AND FINDINGS: In latently infected human B cell lines, we found that rapamycin inhibited entry of the virus into the lytic replication cycle, marked by a loss of expression of the lytic switch protein, replication and transcription activator (RTA). To test for viral-specific effects of rapamycin, we focused our studies on a B cell line with resistance to rapamycin-mediated growth inhibition. Using this line, we found that the drug had minimal effect on cell cycle profiles, cellular proliferation, or the expression of other cellular or latent viral proteins, indicating that the RTA suppression was not a result of global cellular dysregulation. Finally, treatment with rapamycin blocked the production of progeny virions. CONCLUSIONS: These results indicate that mTOR plays a role in the regulation of RTA expression and, therefore, KSHV production, providing a potential molecular explanation for the marked clinical success of rapamycin in the treatment and prevention of post transplant Kaposi's sarcoma. The striking inhibition of rapamycin on KSHV lytic replication, thus, helps explain the apparent paradox of an immunosuppressant drug suppressing the pathogenesis of an opportunistic viral infection. PMID- 21264295 TI - Localization of receptor site on insect sodium channel for depressant beta-toxin BmK IT2. AB - BACKGROUND: BmK IT2 is regarded as a receptor site-4 modulator of sodium channels with depressant insect toxicity. It also displays anti-nociceptive and anti convulsant activities in rat models. In this study, the potency and efficacy of BmK IT2 were for the first time assessed and compared among four sodium channel isoforms expressed in Xenopus oocytes. Combined with molecular approach, the receptor site of BmK IT2 was further localized. PRINCIPAL FINDINGS: 2 uM BmK IT2 strongly shifted the activation of DmNa(v)1, the sodium channel from Drosophila, to more hyperpolarized potentials; whereas it hardly affected the gating properties of rNa(v)1.2, rNa(v)1.3 and mNa(v)1.6, three mammalian central neuronal sodium channel subtypes. (1) Mutations of Glu(896), Leu(899), Gly(904) in extracellular loop Domain II S3-S4 of DmNa(v)1 abolished the functional action of BmK IT2. (2) BmK IT2-preference for DmNa(v)1 could be conferred by Domain III. Analysis of subsequent DmNa(v)1 mutants highlighted the residues in Domain III pore loop, esp. Ile(1529) was critical for recognition and binding of BmK IT2. CONCLUSIONS/SIGNIFICANCE: In this study, BmK IT2 displayed total insect selectivity. Two binding regions, comprising domains II and III of DmNa(v)1, play separated but indispensable roles in the interaction with BmK IT2. The insensitivity of Na(v)1.2, Na(v)1.3 and Na(v)1.6 to BmK IT2 suggests other isoforms or mechanism might be involved in the suppressive activity of BmK IT2 in rat pathological models. PMID- 21264296 TI - Paradoxical increase in TAG and DAG content parallel the insulin sensitizing effect of unilateral DGAT1 overexpression in rat skeletal muscle. AB - BACKGROUND: The involvement of muscle triacylglycerol (TAG) storage in the onset of insulin resistance is questioned and the attention has shifted towards inhibition of insulin signalling by the lipid intermediate diacylglycerol (DAG). The enzyme 1,2-acylCoA:diacylglyceroltransferase-1 (DGAT1) esterifies a fatty acyl-CoA on DAG to form TAG. Therefore, the aim of the present study was to investigate if unilateral overexpression of DGAT1 in adult rat Tibialis anterior (TA) muscle will increase conversion of the lipid intermediate DAG into TAG, thereby improving muscle insulin sensitivity. METHODOLOGY/PRINCIPAL FINDINGS: The DGAT1 gene construct was injected in the left TA muscle of male rats on chow or high-fat (45% kcal) diet for three weeks, followed by application of one 800 V/cm and four 80 V/cm pulses, using the contralateral leg as sham-electroporated control. Seven days after electroporation, muscle specific insulin sensitivity was assessed with a hyperinsulinemic euglycemic clamp using 2-deoxy-[3H]glucose. Here, we provide evidence that unilateral overexpression of DGAT1 in TA muscle of male rats is associated with an increased rather than decreased DAG content. Strikingly, this increase in DAG content was accompanied by improved muscle insulin sensitivity. Interestingly, markers of muscle lipolysis and mitochondrial function were also increased in DGAT1 overexpressing muscle. CONCLUSIONS/SIGNIFICANCE: We conclude that unilateral DGAT1 overexpression can rescue insulin sensitivity, possibly by increasing DAG and TAG turnover in skeletal muscle. In case of a proper balance between the supply and oxidation of fatty acids in skeletal muscle, the lipid intermediate DAG may not exert harmful effects on insulin signalling. PMID- 21264297 TI - Innate immune responses of Drosophila melanogaster are altered by spaceflight. AB - Alterations and impairment of immune responses in humans present a health risk for space exploration missions. The molecular mechanisms underpinning innate immune defense can be confounded by the complexity of the acquired immune system of humans. Drosophila (fruit fly) innate immunity is simpler, and shares many similarities with human innate immunity at the level of molecular and genetic pathways. The goals of this study were to elucidate fundamental immune processes in Drosophila affected by spaceflight and to measure host-pathogen responses post flight. Five containers, each containing ten female and five male fruit flies, were housed and bred on the space shuttle (average orbit altitude of 330.35 km) for 12 days and 18.5 hours. A new generation of flies was reared in microgravity. In larvae, the immune system was examined by analyzing plasmatocyte number and activity in culture. In adults, the induced immune responses were analyzed by bacterial clearance and quantitative real-time polymerase chain reaction (qPCR) of selected genes following infection with E. coli. The RNA levels of relevant immune pathway genes were determined in both larvae and adults by microarray analysis. The ability of larval plasmatocytes to phagocytose E. coli in culture was attenuated following spaceflight, and in parallel, the expression of genes involved in cell maturation was downregulated. In addition, the level of constitutive expression of pattern recognition receptors and opsonins that specifically recognize bacteria, and of lysozymes, antimicrobial peptide (AMP) pathway and immune stress genes, hallmarks of humoral immunity, were also reduced in larvae. In adults, the efficiency of bacterial clearance measured in vivo following a systemic infection with E. coli post-flight, remained robust. We show that spaceflight altered both cellular and humoral immune responses in Drosophila and that the disruption occurs at multiple interacting pathways. PMID- 21264298 TI - Novel peptides based on HIV-1 gp120 sequence with homology to chemokines inhibit HIV infection in cell culture. AB - The sequential interaction of the envelope glycoprotein of the human immunodeficiency virus type 1 (HIV-1) with CD4 and certain chemokine coreceptors initiates host cell entry of the virus. The appropriate chemokines have been shown to inhibit viral replication by blocking interaction of the gp120 envelope protein with the coreceptors. We considered the possibility that this interaction involves a motif of the gp120 that may be structurally homologous to the chemokines. In the amino acid sequences of most chemokines there is a Trp residue located at the beginning of the C-terminal alpha-helix, which is separated by six residues from the fourth Cys residue. The gp120 of all HIV-1 isolates have a similar motif, which includes the C-terminal part of a variable loop 3 (V3) and N terminal part of a conserved region 3 (C3). Two synthetic peptides, derived from the relevant gp120 sequence inhibited HIV-1 replication in macrophages and T lymphocytes in sequence-dependent manner. The peptides also prevented binding of anti-CXCR4 antibodies to CXCR4, and inhibited the intracellular Ca(2+) influx in response to CXCL12/SDF-1alpha. Thus these peptides can be used to dissect gp120 interactions with chemokine receptors and could serve as leads for the design of new inhibitors of HIV-1. PMID- 21264299 TI - Identification of critical residues of the mycobacterial dephosphocoenzyme a kinase by site-directed mutagenesis. AB - Dephosphocoenzyme A kinase performs the transfer of the gamma-phosphate of ATP to dephosphocoenzyme A, catalyzing the last step of coenzyme A biosynthesis. This enzyme belongs to the P-loop-containing NTP hydrolase superfamily, all members of which posses a three domain topology consisting of a CoA domain that binds the acceptor substrate, the nucleotide binding domain and the lid domain. Differences in the enzymatic organization and regulation between the human and mycobacterial counterparts, have pointed out the tubercular CoaE as a high confidence drug target (HAMAP database). Unfortunately the absence of a three-dimensional crystal structure of the enzyme, either alone or complexed with either of its substrates/regulators, leaves both the reaction mechanism unidentified and the chief players involved in substrate binding, stabilization and catalysis unknown. Based on homology modeling and sequence analysis, we chose residues in the three functional domains of the enzyme to assess their contributions to ligand binding and catalysis using site-directed mutagenesis. Systematically mutating the residues from the P-loop and the nucleotide-binding site identified Lys14 and Arg140 in ATP binding and the stabilization of the phosphoryl intermediate during the phosphotransfer reaction. Mutagenesis of Asp32 and Arg140 showed catalytic efficiencies less than 5-10% of the wild type, indicating the pivotal roles played by these residues in catalysis. Non-conservative substitution of the Leu114 residue identifies this leucine as the critical residue from the hydrophobic cleft involved in leading substrate, DCoA binding. We show that the mycobacterial enzyme requires the Mg(2+) for its catalytic activity. The binding energetics of the interactions of the mutant enzymes with the substrates were characterized in terms of their enthalpic and entropic contributions by ITC, providing a complete picture of the effects of the mutations on activity. The properties of mutants defective in substrate recognition were consistent with the ordered sequential mechanism of substrate addition for CoaE. PMID- 21264300 TI - The ESCRT system is required for hepatitis C virus production. AB - BACKGROUND: Recently, lipid droplets have been found to be involved in an important cytoplasmic organelle for hepatitis C virus (HCV) production. However, the mechanisms of HCV assembly, budding, and release remain poorly understood. Retroviruses and some other enveloped viruses require an endosomal sorting complex required for transport (ESCRT) components and their associated proteins for their budding process. METHODOLOGY/PRINCIPAL FINDINGS: To determine whether or not the ESCRT system is needed for HCV production, we examined the infectivity of HCV or the Core levels in culture supernatants as well as HCV RNA levels in HuH-7-derived RSc cells, in which HCV-JFH1 can infect and efficiently replicate, expressing short hairpin RNA or siRNA targeted to tumor susceptibility gene 101 (TSG101), apoptosis-linked gene 2 interacting protein X (Alix), Vps4B, charged multivesicular body protein 4b (CHMP4b), or Brox, all of which are components of the ESCRT system. We found that the infectivity of HCV in the supernatants was significantly suppressed in these knockdown cells. Consequently, the release of the HCV Core into the culture supernatants was significantly suppressed in these knockdown cells after HCV-JFH1 infection, while the intracellular infectivity and the RNA replication of HCV-JFH1 were not significantly affected. Furthermore, the HCV Core mostly colocalized with CHMP4b, a component of ESCRT-III. In this context, HCV Core could bind to CHMP4b. Nevertheless, we failed to find the conserved viral late domain motif, which is required for interaction with the ESCRT component, in the HCV-JFH1 Core, suggesting that HCV Core has a novel motif required for HCV production. CONCLUSIONS/SIGNIFICANCE: These results suggest that the ESCRT system is required for infectious HCV production. PMID- 21264301 TI - Influence of enriched environment on viral encephalitis outcomes: behavioral and neuropathological changes in albino Swiss mice. AB - An enriched environment has previously been described as enhancing natural killer cell activity of recognizing and killing virally infected cells. However, the effects of environmental enrichment on behavioral changes in relation to virus clearance and the neuropathology of encephalitis have not been studied in detail. We tested the hypothesis that environmental enrichment leads to less CNS neuroinvasion and/or more rapid viral clearance in association with T cells without neuronal damage. Stereology-based estimates of activated microglia perineuronal nets and neurons in CA3 were correlated with behavioral changes in the Piry rhabdovirus model of encephalitis in the albino Swiss mouse. Two-month old female mice maintained in impoverished (IE) or enriched environments (EE) for 3 months were behaviorally tested. After the tests, an equal volume of Piry virus (IEPy, EEPy)-infected or normal brain homogenates were nasally instilled. Eight days post-instillation (dpi), when behavioral changes became apparent, brains were fixed and processed to detect viral antigens, activated microglia, perineuronal nets, and T lymphocytes by immuno- or histochemical reactions. At 20 or 40 dpi, the remaining animals were behaviorally tested and processed for the same markers. In IEPy mice, burrowing activity decreased and recovered earlier (8 10 dpi) than open field (20-40 dpi) but remained unaltered in the EEPy group. EEPy mice presented higher T-cell infiltration, less CNS cell infection by the virus and/or faster virus clearance, less microgliosis, and less damage to the extracellular matrix than IEPy. In both EEPy and IEPy animals, CA3 neuronal number remained unaltered. The results suggest that an enriched environment promotes a more effective immune response to clear CNS virus and not at the cost of CNS damage. PMID- 21264302 TI - Network structure implied by initial axon outgrowth in rodent cortex: empirical measurement and models. AB - The developmental mechanisms by which the network organization of the adult cortex is established are incompletely understood. Here we report on empirical data on the development of connections in hamster isocortex and use these data to parameterize a network model of early cortical connectivity. Using anterograde tracers at a series of postnatal ages, we investigate the growth of connections in the early cortical sheet and systematically map initial axon extension from sites in anterior (motor), middle (somatosensory) and posterior (visual) cortex. As a general rule, developing axons extend from all sites to cover relatively large portions of the cortical field that include multiple cortical areas. From all sites, outgrowth is anisotropic, covering a greater distance along the medial/lateral axis than along the anterior/posterior axis. These observations are summarized as 2-dimensional probability distributions of axon terminal sites over the cortical sheet. Our network model consists of nodes, representing parcels of cortex, embedded in 2-dimensional space. Network nodes are connected via directed edges, representing axons, drawn according to the empirically derived anisotropic probability distribution. The networks generated are described by a number of graph theoretic measurements including graph efficiency, node betweenness centrality and average shortest path length. To determine if connectional anisotropy helps reduce the total volume occupied by axons, we define and measure a simple metric for the extra volume required by axons crossing. We investigate the impact of different levels of anisotropy on network structure and volume. The empirically observed level of anisotropy suggests a good trade-off between volume reduction and maintenance of both network efficiency and robustness. Future work will test the model's predictions for connectivity in larger cortices to gain insight into how the regulation of axonal outgrowth may have evolved to achieve efficient and economical connectivity in larger brains. PMID- 21264303 TI - Expanding HIV testing efforts in concentrated epidemic settings: a population based survey from rural Vietnam. AB - BACKGROUND: To improve HIV prevention and care programs, it is important to understand the uptake of HIV testing and to identify population segments in need of increased HIV testing. This is particularly crucial in countries with concentrated HIV epidemics, where HIV prevalence continues to rise in the general population. This study analyzes determinants of HIV testing in a rural Vietnamese population in order to identify potential access barriers and areas for promoting HIV testing services. METHODS: A population-based cross-sectional survey of 1874 randomly sampled adults was linked to pregnancy, migration and economic cohort data from a demographic surveillance site (DSS). Multivariate logistic regression analysis was used to determine which factors were associated with having tested for HIV. RESULTS: The age-adjusted prevalence of ever-testing for HIV was 7.6%; however 79% of those who reported feeling at-risk of contracting HIV had never tested. In multivariate analysis, younger age (aOR 1.85, 95% CI 1.14-3.01), higher economic status (aOR 3.4, 95% CI 2.21-5.22), and semi-urban residence (aOR 2.37, 95% CI 1.53-3.66) were associated with having been tested for HIV. HIV testing rates did not differ between women of reproductive age who had recently been pregnant and those who had not. CONCLUSIONS: We found low testing uptake (6%) among pregnant women despite an existing prevention of mother-to-child HIV testing policy, and lower-than-expected testing among persons who felt that they were at-risk of HIV. Poverty and residence in a more geographically remote location were associated with less HIV testing. In addition to current HIV testing strategies focusing on high-risk groups, we recommend targeting HIV testing in concentrated HIV epidemic settings to focus on a scaled-up provision of antenatal testing. Additional recommendations include removing financial and geographic access barriers to client-initiated testing, and encouraging provider initiated testing of those who believe that they are at-risk of HIV. PMID- 21264305 TI - LINGO1 variants in the French-Canadian population. AB - Essential tremor (ET) is a complex genetic disorder for which no causative gene has been found. Recently, a genome-wide association study reported that two variants in the LINGO1 locus were associated to this disease. The aim of the present study was to test if this specific association could be replicated using a French-Canadian cohort of 259 ET patients and 479 ethnically matched controls. Our genotyping results lead us to conclude that no association exists between the key variant rs9652490 and ET (P(corr) = 1.00). PMID- 21264304 TI - Blue and red light modulates SigB-dependent gene transcription, swimming motility and invasiveness in Listeria monocytogenes. AB - BACKGROUND: In a number of gram-positive bacteria, including Listeria, the general stress response is regulated by the alternative sigma factor B (SigB). Common stressors which lead to the activation of SigB and the SigB-dependent regulon are high osmolarity, acid and several more. Recently is has been shown that also blue and red light activates SigB in Bacillus subtilis. METHODOLOGY/PRINCIPAL FINDINGS: By qRT-PCR we analyzed the transcriptional response of the pathogen L. monocytogenes to blue and red light in wild type bacteria and in isogenic deletion mutants for the putative blue-light receptor Lmo0799 and the stress sigma factor SigB. It was found that both blue (455 nm) and red (625 nm) light induced the transcription of sigB and SigB-dependent genes, this induction was completely abolished in the SigB mutant. The blue-light effect was largely dependent on Lmo0799, proving that this protein is a genuine blue-light receptor. The deletion of lmo0799 enhanced the red-light effect, the underlying mechanism as well as that of SigB activation by red light remains unknown. Blue light led to an increased transcription of the internalin A/B genes and of bacterial invasiveness for Caco-2 enterocytes. Exposure to blue light also strongly inhibited swimming motility of the bacteria in a Lmo0799- and SigB dependent manner, red light had no effect there. CONCLUSIONS/SIGNIFICANCE: Our data established that visible, in particular blue light is an important environmental signal with an impact on gene expression and physiology of the non phototrophic bacterium L. monocytogenes. In natural environments these effects will result in sometimes random but potentially also cyclic fluctuations of gene activity, depending on the light conditions prevailing in the respective habitat. PMID- 21264306 TI - FimL regulates cAMP synthesis in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa, a ubiquitous bacteria found in diverse ecological niches, is an important cause of acute infections in immunocompromised individuals and chronic infections in patients with Cystic Fibrosis. One signaling molecule required for the coordinate regulation of virulence factors associated with acute infections is 3', 5'-cyclic adenosine monophosphate, (cAMP), which binds to and activates a catabolite repressor homolog, Vfr. Vfr controls the transcription of many virulence factors, including those associated with Type IV pili (TFP), the Type III secretion system (T3SS), the Type II secretion system, flagellar mediated motility, and quorum sensing systems. We previously identified FimL, a protein with histidine phosphotransfer-like domains, as a regulator of Vfr dependent processes, including TFP-dependent motility and T3SS function. In this study, we carried out genetic and physiologic studies to further define the mechanism of action of FimL. Through a genetic screen designed to identify suppressors of FimL, we found a putative cAMP-specific phosphodiesterase (CpdA), suggesting that FimL regulates cAMP levels. Inactivation of CpdA increases cAMP levels and restores TFP-dependent motility and T3SS function to fimL mutants, consistent with in vivo phosphodiesterase activity. By constructing combinations of double and triple mutants in the two adenylate cyclase genes (cyaA and cyaB), fimL, and cpdA, we show that DeltafimL mutants resemble DeltacyaB mutants in TM defects, decreased T3SS transcription, and decreased cAMP levels. Similar to some of the virulence factors that they regulate, we demonstrate that CyaB and FimL are polarly localized. These results reveal new complexities in the regulation of diverse virulence pathways associated with acute P. aeruginosa infections. PMID- 21264307 TI - Mycoplasma contamination revisited: mesenchymal stromal cells harboring Mycoplasma hyorhinis potently inhibit lymphocyte proliferation in vitro. AB - BACKGROUND: Mesenchymal stromal cells (MSC) have important immunomodulatory effects that can be exploited in the clinical setting, e.g. in patients suffering from graft-versus-host disease after allogeneic stem cell transplantation. In an experimental animal model, cultures of rat T lymphocytes were stimulated in vitro either with the mitogen Concanavalin A or with irradiated allogeneic cells in mixed lymphocyte reactions, the latter to simulate allo-immunogenic activation of transplanted T cells in vivo. This study investigated the inhibitory effects of rat bone marrow-derived MSC subsequently found to be infected with a common mycoplasma species (Mycoplasma hyorhinis) on T cell activation in vitro and experimental graft-versus-host disease in vivo. PRINCIPAL FINDINGS: We found that M. hyorhinis infection increased the anti-proliferative effect of MSC dramatically, as measured by both radiometric and fluorimetric methods. Inhibition could not be explained solely by the well-known ability of mycoplasmas to degrade tritiated thymidine, but likely was the result of rapid dissemination of M. hyorhinis in the lymphocyte culture. CONCLUSIONS: This study demonstrates the potent inhibitory effect exerted by M. hyorhinis in standard lymphocyte proliferation assays in vitro. MSC are efficient vectors of mycoplasma infection, emphasizing the importance of monitoring cell cultures for contamination. PMID- 21264308 TI - Expression of the T cell receptor alphabeta on a CD123+ BDCA2+ HLA-DR+ subpopulation in head and neck squamous cell carcinoma. AB - Human Plasmacytoid Dendritic Cells (PDCs) infiltrating solid tumor tissues and draining lymph nodes of Head and Neck Squamous Cell Carcinoma (HNSCC) show an impaired immune response. In addition to an attenuated secretion of IFN-alpha little is known about other HNSCC-induced functional alterations in PDCs. Particular objectives in this project were to gain new insights regarding tumor induced phenotypical and functional alterations in the PDC population. We showed by FACS analysis and RT-PCR that HNSCC orchestrates an as yet unknown subpopulation exhibiting functional autonomy in-vitro and in-vivo besides bearing phenotypical resemblance to PDCs and T cells. A subset, positive for the PDC markers CD123, BDCA-2, HLA-DR and the T cell receptor alphabeta (TCR-alphabeta) was significantly induced subsequent to stimulation with HNSCC in-vitro (p = 0.009) and also present in metastatic lymph nodes in-vivo. This subgroup could be functionally distinguished due to an enhanced production of IL-2 (p = 0.02), IL-6 (p = 0.0007) and TGF-beta (not significant). Furthermore, after exposure to HNSCC cells, mRNA levels revealed a D-J-beta rearrangement of the TCR-beta chain besides a strong enhancement of the CD3epsilon chain in the PDC population. Our data indicate an interface between the PDC and T cell lineage. These findings will improve our understanding of phenotypical and functional intricacies concerning the very heterogeneous PDC population in-vivo. PMID- 21264309 TI - Cross-platform comparison of microarray-based multiple-class prediction. AB - High-throughput microarray technology has been widely applied in biological and medical decision-making research during the past decade. However, the diversity of platforms has made it a challenge to re-use and/or integrate datasets generated in different experiments or labs for constructing array-based diagnostic models. Using large toxicogenomics datasets generated using both Affymetrix and Agilent microarray platforms, we carried out a benchmark evaluation of cross-platform consistency in multiple-class prediction using three widely-used machine learning algorithms. After an initial assessment of model performance on different platforms, we evaluated whether predictive signature features selected in one platform could be directly used to train a model in the other platform and whether predictive models trained using data from one platform could predict datasets profiled using the other platform with comparable performance. Our results established that it is possible to successfully apply multiple-class prediction models across different commercial microarray platforms, offering a number of important benefits such as accelerating the possible translation of biomarkers identified with microarrays to clinically validated assays. However, this investigation focuses on a technical platform comparison and is actually only the beginning of exploring cross-platform consistency. Further studies are needed to confirm the feasibility of microarray based cross-platform prediction, especially using independent datasets. PMID- 21264310 TI - A generalized linear model for estimating spectrotemporal receptive fields from responses to natural sounds. AB - In the auditory system, the stimulus-response properties of single neurons are often described in terms of the spectrotemporal receptive field (STRF), a linear kernel relating the spectrogram of the sound stimulus to the instantaneous firing rate of the neuron. Several algorithms have been used to estimate STRFs from responses to natural stimuli; these algorithms differ in their functional models, cost functions, and regularization methods. Here, we characterize the stimulus response function of auditory neurons using a generalized linear model (GLM). In this model, each cell's input is described by: 1) a stimulus filter (STRF); and 2) a post-spike filter, which captures dependencies on the neuron's spiking history. The output of the model is given by a series of spike trains rather than instantaneous firing rate, allowing the prediction of spike train responses to novel stimuli. We fit the model by maximum penalized likelihood to the spiking activity of zebra finch auditory midbrain neurons in response to conspecific vocalizations (songs) and modulation limited (ml) noise. We compare this model to normalized reverse correlation (NRC), the traditional method for STRF estimation, in terms of predictive power and the basic tuning properties of the estimated STRFs. We find that a GLM with a sparse prior predicts novel responses to both stimulus classes significantly better than NRC. Importantly, we find that STRFs from the two models derived from the same responses can differ substantially and that GLM STRFs are more consistent between stimulus classes than NRC STRFs. These results suggest that a GLM with a sparse prior provides a more accurate characterization of spectrotemporal tuning than does the NRC method when responses to complex sounds are studied in these neurons. PMID- 21264311 TI - A broadly flavivirus cross-neutralizing monoclonal antibody that recognizes a novel epitope within the fusion loop of E protein. AB - Flaviviruses are a group of human pathogenic, enveloped RNA viruses that includes dengue (DENV), yellow fever (YFV), West Nile (WNV), and Japanese encephalitis (JEV) viruses. Cross-reactive antibodies against Flavivirus have been described, but most of them are generally weakly neutralizing. In this study, a novel monoclonal antibody, designated mAb 2A10G6, was determined to have broad cross reactivity with DENV 1-4, YFV, WNV, JEV, and TBEV. Phage-display biopanning and structure modeling mapped 2A10G6 to a new epitope within the highly conserved flavivirus fusion loop peptide, the (98)DRXW(101) motif. Moreover, in vitro and in vivo experiments demonstrated that 2A10G6 potently neutralizes DENV 1-4, YFV, and WNV and confers protection from lethal challenge with DENV 1-4 and WNV in murine model. Furthermore, functional studies revealed that 2A10G6 blocks infection at a step after viral attachment. These results define a novel broadly flavivirus cross-reactive mAb with highly neutralizing activity that can be further developed as a therapeutic agent against severe flavivirus infections in humans. PMID- 21264312 TI - A comparative analysis of the morphology and evolution of permanent sperm depletion in spiders. AB - Once thought to be energetically cheap and easy to produce, empirical work has shown that sperm is a costly and limited resource for males. In some spider species, there is behavioral evidence that sperm are permanently depleted after a single mating. This extreme degree of mating investment appears to co-occur with other reproductive strategies common to spiders, e.g. genital mutilation and sexual cannibalism. Here we corroborate that sperm depletion in the golden orb web spider Nephila clavipes is permanent by uncovering its mechanistic basis using light and electron microscopy. In addition, we use a phylogeny-based statistical analysis to test the evolutionary relationships between permanent sperm depletion (PSD) and other reproductive strategies in spiders. Male testes do not produce sperm during adulthood, which is unusual in spiders. Instead, spermatogenesis is nearly synchronous and ends before the maturation molt. Testis size decreases as males approach their maturation molt and reaches its lowest point after sperm is transferred into the male copulatory organs (pedipalps). As a consequence, the amount of sperm available to males for mating is limited to the sperm contained in the pedipalps, and once it is used, males lose their ability to fertilize eggs. Our data suggest that PSD has evolved independently at least three times within web-building spiders and is significantly correlated with the evolution of other mating strategies that limit males to monogamy, including genital mutilation and sexual cannibalism. We conclude that PSD may be an energy-saving adaptation in species where males are limited to monogamy. This could be particularly important in web-building spiders where extreme sexual size dimorphism results in large, sedentary females and small, searching males who rarely feed as adults and are vulnerable to starvation. Future work will explore possible energetic benefits and the evolutionary lability of PSD relative to other mate-limiting reproductive behaviors. PMID- 21264313 TI - Constitutive TL1A (TNFSF15) expression on lymphoid or myeloid cells leads to mild intestinal inflammation and fibrosis. AB - TL1A is a member of the TNF superfamily and its expression is increased in the mucosa of inflammatory bowel disease patients. Moreover, a subset of Crohn's disease (CD) patients with the risk TL1A haplotype is associated with elevated TL1A expression and a more severe disease course. To investigate the in vivo role of elevated TL1A expression, we generated two transgenic (Tg) murine models with constitutive Tl1a expression in either lymphoid or myeloid cells. Compared to wildtype (WT) mice, constitutive expression of Tl1a in either lymphoid or myeloid cells showed mild patchy inflammation in the small intestine, which was more prominent in the ileum. In addition, mice with constitutive Tl1a expression exhibited enhanced intestinal and colonic fibrosis compared to WT littermates. The percentage of T cells expressing the gut homing chemokine receptors CCR9 and CCR10 was higher in the Tl1a Tg mice compared to WT littermates. Sustained expression of Tl1A in T cells also lead to increased Foxp3+ Treg cells. T cells or antigen presenting cells (APC) with constitutive expression of Tl1a were found to have a more activated phenotype and mucosal mononuclear cells exhibit enhanced Th1 cytokine activity. These results indicated an important role of TL1A in mucosal T cells and APC function and showed that up-regulation of TL1A expression can promote mucosal inflammation and gut fibrosis. PMID- 21264314 TI - Structure-based analysis of five novel disease-causing mutations in 21 hydroxylase-deficient patients. AB - Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is the most frequent inborn error of metabolism, and accounts for 90-95% of CAH cases. The affected enzyme, P450C21, is encoded by the CYP21A2 gene, located together with a 98% nucleotide sequence identity CYP21A1P pseudogene, on chromosome 6p21.3. Even though most patients carry CYP21A1P-derived mutations, an increasing number of novel and rare mutations in disease causing alleles were found in the last years. In the present work, we describe five CYP21A2 novel mutations, p.R132C, p.149C, p.M283V, p.E431K and a frameshift g.2511_2512delGG, in four non-classical and one salt wasting patients from Argentina. All novel point mutations are located in CYP21 protein residues that are conserved throughout mammalian species, and none of them were found in control individuals. The putative pathogenic mechanisms of the novel variants were analyzed in silico. A three-dimensional CYP21 structure was generated by homology modeling and the protein design algorithm FoldX was used to calculate changes in stability of CYP21A2 protein. Our analysis revealed changes in protein stability or in the surface charge of the mutant enzymes, which could be related to the clinical manifestation found in patients. PMID- 21264315 TI - Contractile and elastic ankle joint muscular properties in young and older adults. AB - The purpose of this study was to investigate age-related differences in contractile and elastic properties of both dorsi- (DF) and plantarflexor (PF) muscles controlling the ankle joint in young and older adults. Experimental data were collected while twelve young and twelve older male and female participants performed maximal effort isometric and isovelocity contractions on a dynamometer. Equations were fit to the data to give torque-angle (Ttheta) and torque-angular velocity (Tomega) relations. Muscle series-elasticity was measured during ramped dynamometer contractions using ultrasonography to measure aponeurosis extension as a function of torque; second order polynomials were used to characterize the torque-extension (TDeltaL) relation. The results showed no age differences in DF maximal torque and none for female PF; however, older males had smaller maximal PF torques compared to young males. In both muscle groups and genders, older adults had decreased concentric force capabilities. Both DF and PF TDeltaL relations were more nonlinear in the older adults. Older PF, but not DF muscles, were stiffer compared to young. A simple antagonism model suggested age-related differences in Ttheta and Tomega relations would be magnified if antagonistic torque contributions were included. This assessment of static, dynamic, and elastic joint properties affords a comprehensive view of age-related modifications in muscle function. Although many clinical studies use maximal isometric strength as a marker of functional ability, the results demonstrate that there are also significant age-related modifications in ankle muscle dynamic and elastic properties. PMID- 21264316 TI - Identification of a key amino acid of LuxS involved in AI-2 production in Campylobacter jejuni. AB - Autoinducer-2 (AI-2) mediated quorum sensing has been associated with the expression of virulence factors in a number of pathogenic organisms and has been demonstrated to play a role in motility and cytolethal distending toxin (cdt) production in Campylobacter jejuni. We have initiated the work to determine the molecular basis of AI-2 synthesis and the biological functions of quorum sensing in C. jejuni. In this work, two naturally occurring variants of C. jejuni 81116 were identified, one producing high-levels of AI-2 while the other is defective in AI-2 synthesis. Sequence analysis revealed a G92D mutation in the luxS gene of the defective variant. Complementation of the AI-2(-) variant with a plasmid encoded copy of the wild-type luxS gene or reversion of the G92D mutation by site directed mutagenesis fully restored AI-2 production by the variant. These results indicate that the G92D mutation alone is responsible for the loss of AI-2 activity in C. jejuni. Kinetic analyses showed that the G92D LuxS has a ~100-fold reduced catalytic activity relative to the wild-type enzyme. Findings from this study identify a previously undescribed amino acid that is essential for AI-2 production by LuxS and provide a unique isogenic pair of naturally occurring variants for us to dissect the functions of AI-2 mediated quorum sensing in Campylobacter. PMID- 21264317 TI - Crystal structure of Spy0129, a Streptococcus pyogenes class B sortase involved in pilus assembly. AB - Sortase enzymes are cysteine transpeptidases that mediate the covalent attachment of substrate proteins to the cell walls of gram-positive bacteria, and thereby play a crucial role in virulence, infection and colonisation by pathogens. Many cell-surface proteins are anchored by the housekeeping sortase SrtA but other more specialised sortases exist that attach sub-sets of proteins or function in pilus assembly. The sortase Spy0129, or SrtC1, from the M1 SF370 strain of Streptococcus pyogenes is responsible for generating the covalent linkages between the pilin subunits in the pili of this organism. The crystal structure of Spy0129 has been determined at 2.3 A resolution (R = 20.4%, Rfree = 26.0%). The structure shows that Spy0129 is a class B sortase, in contrast to other characterised pilin polymerases, which belong to class C. Spy0129 lacks a flap believed to function in substrate recognition in class C enzymes and instead has an elaborated beta6/beta7 loop. The two independent Spy0129 molecules in the crystal show differences in the positions and orientations of the catalytic Cys and His residues, Cys221 and His126, correlated with movements of the beta7/beta8 and beta4/beta5 loops that respectively follow these residues. Bound zinc ions stabilise these alternative conformations in the crystal. This conformational variability is likely to be important for function although there is no evidence that zinc is involved in vivo. PMID- 21264318 TI - Circadian rhythm and cartilage extracellular matrix genes in osseointegration: a genome-wide screening of implant failure by vitamin D deficiency. AB - BACKGROUND: Successful dental and orthopedic implants require the establishment of an intimate association with bone tissue; however, the mechanistic explanation of how biological systems accomplish osseointegration is still incomplete. We sought to identify critical gene networks involved in osseointegration by exploring the implant failure model under vitamin D deficiency. METHODOLOGY: Adult male Sprague-Dawley rats were exposed to control or vitamin D-deficient diet prior to the osteotomy surgery in the femur bone and the placement of T shaped Ti4Al6V implant. Two weeks after the osteotomy and implant placement, tissue formed at the osteotomy site or in the hollow chamber of T-shaped implant was harvested and total RNA was evaluated by whole genome microarray analyses. PRINCIPAL FINDINGS: Two-way ANOVA of microarray data identified 103 genes that were significantly (>2 fold) modulated by the implant placement and vitamin D deficiency. Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses assigned the highest z-score to the circadian rhythm pathway including neuronal PAS domain 2 (NPAS2), and period homolog 2 (Per2). NPAS2 and Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/Bmal 1) were upregulated around implant and diminished by vitamin D deficiency, whereas the expression pattern of Per2 was complementary. Hierarchical cluster analysis further revealed that NPAS2 was in a group predominantly composed of cartilage extracellular matrix (ECM) genes. Whereas the expression of bone ECM genes around implant was not significantly affected by vitamin D deficiency, cartilage ECM genes were modulated by the presence of the implant and vitamin D status. In a proof-of-concept in vitro study, the expression of cartilage type II and X collagens was found upregulated when mouse mesenchymal stem cells were cultured on implant disk with 1,25D supplementation. CONCLUSIONS: This study suggests that the circadian rhythm system and cartilage extracellular matrix may be involved in the establishment of osseointegration under vitamin D regulation. PMID- 21264319 TI - Striatal pre- and postsynaptic profile of adenosine A(2A) receptor antagonists. AB - Striatal adenosine A(2A) receptors (A(2A)Rs) are highly expressed in medium spiny neurons (MSNs) of the indirect efferent pathway, where they heteromerize with dopamine D(2) receptors (D(2)Rs). A(2A)Rs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A(1) receptors (A(1)Rs). It has been hypothesized that postsynaptic A(2A)R antagonists should be useful in Parkinson's disease, while presynaptic A(2A)R antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A(2A)R antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261) showed no clear preference. Radioligand-binding experiments were performed in cells expressing A(2A)R-D(2)R and A(1)R-A(2A)R heteromers to determine possible differences in the affinity of these compounds for different A(2A)R heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A(2A)R when co-expressed with D(2)R than with A(1)R. KW-6002 showed the best relative affinity for A(2A)R co expressed with D(2)R than co-expressed with A(1)R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile. On the basis of their preferential pre- versus postsynaptic actions, SCH-442416 and KW-6002 may be used as lead compounds to obtain more effective antidyskinetic and antiparkinsonian compounds, respectively. PMID- 21264320 TI - Defects in very long chain fatty acid synthesis enhance alpha-synuclein toxicity in a yeast model of Parkinson's disease. AB - We identified three S. cerevisiae lipid elongase null mutants (elo1Delta, elo2Delta, and elo3Delta) that enhance the toxicity of alpha-synuclein (alpha syn). These elongases function in the endoplasmic reticulum (ER) to catalyze the elongation of medium chain fatty acids to very long chain fatty acids, which is a component of sphingolipids. Without alpha-syn expression, the various elo mutants showed no growth defects, no reactive oxygen species (ROS) accumulation, and a modest decrease in survival of aged cells compared to wild-type cells. With (WT, A53T or E46K) alpha-syn expression, the various elo mutants exhibited severe growth defects (although A30P had a negligible effect on growth), ROS accumulation, aberrant protein trafficking, and a dramatic decrease in survival of aged cells compared to wild-type cells. Inhibitors of ceramide synthesis, myriocin and FB1, were extremely toxic to wild-type yeast cells expressing (WT, A53T, or E46K) alpha-syn but much less toxic to cells expressing A30P. The elongase mutants and ceramide synthesis inhibitors enhance the toxicity of WT alpha-syn, A53T and E46K, which transit through the ER, but have a negligible effect on A30P, which does not transit through the ER. Disruption of ceramide sphingolipid homeostasis in the ER dramatically enhances the toxicity of alpha syn (WT, A53T, and E46K). PMID- 21264324 TI - Pavlovian fear conditioning activates a common pattern of neurons in the lateral amygdala of individual brains. AB - Understanding the physical encoding of a memory (the engram) is a fundamental question in neuroscience. Although it has been established that the lateral amygdala is a key site for encoding associative fear memory, it is currently unclear whether the spatial distribution of neurons encoding a given memory is random or stable. Here we used spatial principal components analysis to quantify the topography of activated neurons, in a select region of the lateral amygdala, from rat brains encoding a Pavlovian conditioned fear memory. Our results demonstrate a stable, spatially patterned organization of amygdala neurons are activated during the formation of a Pavlovian conditioned fear memory. We suggest that this stable neuronal assembly constitutes a spatial dimension of the engram. PMID- 21264321 TI - Liposome-coupled peptides induce long-lived memory CD8 T cells without CD4 T cells. AB - CD8(+) T cells provide broad immunity to viruses, because they are able to recognize all types of viral proteins. Therefore, the development of vaccines capable of inducing long-lived memory CD8(+) T cells is desired to prevent diseases, especially those for which no vaccines currently exist. However, in designing CD8(+) T cell vaccines, the role of CD4(+) T cells in the induction and maintenance of memory CD8(+) T cells remains uncertain. In the present study, the necessity or not of CD4(+) T cells in the induction and maintenance of memory CD8(+) T cells was investigated in mice immunized with liposome-coupled CTL epitope peptides. When OVA-derived CTL epitope peptides were chemically coupled to the surfaces of liposomes and inoculated into mice, both primary and secondary CTL responses were successfully induced. The results were further confirmed in CD4(+) T cell-eliminated mice, suggesting that CD4(+) T cells were not required for the generation of memory CD8(+) T cells in the case of immunization with liposome-coupled peptides. Thus, surface-linked liposomal antigens, capable of inducing long-lived memory CD8(+) T cells without the contribution of CD4(+) T cells, might be applicable for the development of vaccines to prevent viral infection, especially for those viruses that evade humoral immunity by varying their surface proteins, such as influenza viruses, HIV, HCV, SARS coronaviruses, and Ebola viruses. PMID- 21264325 TI - Multiple insecticide resistance: an impediment to insecticide-based malaria vector control program. AB - BACKGROUND: Indoor Residual Spraying (IRS), insecticide-treated nets (ITNs) and long-lasting insecticidal nets (LLINs) are key components in malaria prevention and control strategy. However, the development of resistance by mosquitoes to insecticides recommended for IRS and/or ITNs/LLINs would affect insecticide-based malaria vector control. We assessed the susceptibility levels of Anopheles arabiensis to insecticides used in malaria control, characterized basic mechanisms underlying resistance, and evaluated the role of public health use of insecticides in resistance selection. METHODOLOGY/PRINCIPAL FINDINGS: Susceptibility status of An. arabiensis was assessed using WHO bioassay tests to DDT, permethrin, deltamethrin, malathion and propoxur in Ethiopia from August to September 2009. Mosquito specimens were screened for knockdown resistance (kdr) and insensitive acetylcholinesterase (ace-1(R)) mutations using AS-PCR and PCR RFLP, respectively. DDT residues level in soil from human dwellings and the surrounding environment were determined by Gas Chromatography with Electron Capture Detector. An. arabiensis was resistant to DDT, permethrin, deltamethrin and malathion, but susceptible to propoxur. The West African kdr allele was found in 280 specimens out of 284 with a frequency ranged from 95% to 100%. Ace-1(R) mutation was not detected in all specimens scored for the allele. Moreover, DDT residues were found in soil samples from human dwellings but not in the surrounding environment. CONCLUSION: The observed multiple-resistance coupled with the occurrence of high kdr frequency in populations of An. arabiensis could profoundly affect the malaria vector control programme in Ethiopia. This needs an urgent call for implementing rational resistance management strategies and integrated vector control intervention. PMID- 21264326 TI - Risk of liver injury associated with Chinese herbal products containing radix bupleuri in 639,779 patients with hepatitis B virus infection. AB - BACKGROUND: Chinese herbal products (CHPs) containing radix bupleuri are often prescribed for chronic hepatitis. There have been no epidemiological studies in populations with hepatitis B virus (HBV) infection. Our study was conducted to determine the association between the use of CHPs containing radix bupleuri and the risk of hospitalisation related to liver injury among HBV-infected patients in Taiwan. METHODS: From a total of 639,779 patients with diagnoses related to HBV infection, we included hospitalised adult cases with a primary diagnosis of liver injury in the database of Taiwan's national health insurance during the period 1997-2004. Case-control and case-crossover designs were used to assess the risk of hospitalisation with conditional logistic regression models constructed and adjusted for 270 conventionally hepatotoxic drugs. Cumulative doses of these CHPs and radix bupleuri were assessed for any dose-response relationship. FINDINGS: In total, we collected 1,080 cases fulfilled the inclusion criteria. In the case-control design, the adjusted odds ratio was 1.90 (95% confidence interval [CI]: 1.30 to 2.77). The risks from prescribing the CHPs Xiao-Chai-Hu Tang and Long-Dan-Xie-Gan-Tang were significantly high, and dose-response relationships were found. The risk of adding each 19 gm dose of radix bupleuri was 2.19 (95% CI: 1.66 to 2.89). The results using the case-crossover design remained similar. CONCLUSIONS: Prescribing Xiao-Chai-Hu-Tang, Long-Dan-Xie-Gan Tang, or CHPs containing more than 19 gram of radix bupleuri in HBV-infected patients might increase their risks of liver injury. Further studies are indicated to corroborate the above findings. PMID- 21264327 TI - Calling all primary care practitioners: promoting organ and tissue donation. PMID- 21264328 TI - The green machine. PMID- 21264329 TI - A perspective on health inequities and the need for universal healthcare. PMID- 21264330 TI - Complexities in Interpreting Perceptual Profiles among Persons with Autism Spectrum Disorders: Examples from Research on Auditory and Visual Processing. PMID- 21264331 TI - The Scoop and Run Method of Pre-clinical Care for Trauma Victims. PMID- 21264332 TI - And the winners are... PMID- 21264333 TI - A Review for Medical Students. The Brain Atlas: A Visual Guide to the Human Central Nervous System, 3rd ed. PMID- 21264334 TI - PoolHap: inferring haplotype frequencies from pooled samples by next generation sequencing. AB - With the advance of next-generation sequencing (NGS) technologies, increasingly ambitious applications are becoming feasible. A particularly powerful one is the sequencing of polymorphic, pooled samples. The pool can be naturally occurring, as in the case of multiple pathogen strains in a blood sample, multiple types of cells in a cancerous tissue sample, or multiple isoforms of mRNA in a cell. In these cases, it's difficult or impossible to partition the subtypes experimentally before sequencing, and those subtype frequencies must hence be inferred. In addition, investigators may occasionally want to artificially pool the sample of a large number of individuals for reasons of cost-efficiency, e.g., when carrying out genetic mapping using bulked segregant analysis. Here we describe PoolHap, a computational tool for inferring haplotype frequencies from pooled samples when haplotypes are known. The key insight into why PoolHap works is that the large number of SNPs that come with genome-wide coverage can compensate for the uneven coverage across the genome. The performance of PoolHap is illustrated and discussed using simulated and real data. We show that PoolHap is able to accurately estimate the proportions of haplotypes with less than 2% error for 34-strain mixtures with 2X total coverage Arabidopsis thaliana whole genome polymorphism data. This method should facilitate greater biological insight into heterogeneous samples that are difficult or impossible to isolate experimentally. Software and users manual are freely available at http://arabidopsis.gmi.oeaw.ac.at/quan/poolhap/. PMID- 21264335 TI - Lysine auxotrophy combined with deletion of the SecA2 gene results in a safe and highly immunogenic candidate live attenuated vaccine for tuberculosis. AB - Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a major global health problem, despite the widespread use of the M. bovis Bacille Calmette Guerin (BCG) vaccine and the availability of drug therapies. In recent years, the high incidence of coinfection of M. tuberculosis and HIV, as well as escalating problems associated with drug resistance, has raised ominous concerns with regard to TB control. Vaccination with BCG has not proven highly effective in controlling TB, and also has been associated with increasing concerns about the potential for the vaccine to cause disseminated mycobacterial infection in HIV infected hosts. Thus, the development of an efficacious and safe TB vaccine is generally viewed as a critical to achieving control of the ongoing global TB pandemic. In the current study, we have analyzed the vaccine efficacy of an attenuated M. tuberculosis strain that combines a mutation that enhances T cell priming (DeltasecA2) with a strongly attenuating lysine auxotrophy mutation (DeltalysA). The DeltasecA2 mutant was previously shown to be defective in the inhibition of apoptosis and markedly increased priming of antigen-specific CD8(+) T cells in vivo. Similarly, the DeltasecA2DeltalysA strain retained enhanced apoptosis and augmented CD8(+) T cell stimulatory effects, but with a noticeably improved safety profile in immunosuppressed mice. Thus, the M. tuberculosis DeltasecA2DeltalysA mutant represents a live attenuated TB vaccine strain with the potential to deliver increased protection and safety compared to standard BCG vaccination. PMID- 21264336 TI - Establishment failure in biological invasions: a case history of Littorina littorea in California, USA. AB - BACKGROUND: The early stages of biological invasions are rarely observed, but can provide significant insight into the invasion process as well as the influence vectors have on invasion success or failure. METHODOLOGY/PRINCIPAL FINDINGS: We characterized three newly discovered populations of an introduced gastropod, Littorina littorea (Linne, 1758), in California, USA, comparing them to potential source populations in native Europe and the North American East Coast, where the snail is also introduced. Demographic surveys were used to assess spatial distribution and sizes of the snail in San Francisco and Anaheim Bays, California. Mitochondrial DNA was sequenced and compared among these nascent populations, and various populations from the North American East Coast and Europe, to characterize the California populations and ascertain their likely source. Demographic and genetic data were considered together to deduce likely vectors for the California populations. We found that the three large California L. littorea populations contained only adult snails and had unexpectedly high genetic diversity rather than showing an extreme bottleneck as typically expected in recent introductions. Haplotype diversity in Californian populations was significantly reduced compared to European populations, but not compared to East Coast populations. Genetic analyses clearly suggested the East Coast as the source region for the California introductions. CONCLUSIONS AND SIGNIFICANCE: The California L. littorea populations were at an early, non-established phase of invasion with no evidence of recruitment. The live seafood trade is the most likely invasion vector for these populations, as it preferentially transports large numbers of adult L. littorea, matching the demographic structure of the introduced California L. littorea populations. Our results highlight continued operation of live seafood trade vectors and the influence of vectors on the demographic and genetic structure of the resulting populations, especially early stages of the invasion process. PMID- 21264337 TI - The social contagion effect of marijuana use among adolescents. AB - BACKGROUND: Research on adolescent substance use has consistently identified a strong relationship between adolescent behavior and the behavior of their peers. However, peer effects are difficult to estimate and causal interpretations must be undertaken with caution since individuals in most cases choose with whom to associate. In this paper we seek to empirically quantify the causal role of peer social networks in explaining marijuana usage among adolescents. METHODS AND FINDINGS: Using data from a nationally representative sample of adolescents we utilize a multivariate structural model with school-level fixed effects to account for the problems of contextual effects, correlated effects and peer selections to purge the potential biases from the estimates of peer influence. Our peer group measures are drawn not only from the nomination of close friends (N = 6,377), but also from classmates (N = 19,335). Marijuana usage among the peer groups were constructed using the peers' own report of their marijuana consumption. Controlling for parent level characteristics, and other demographic parameters, we find that a 10% increase in the proportion of close friends and classmates who use marijuana increases the probability that an individual chooses to use marijuana by 5%. CONCLUSION: Our findings indicate that peer effects are important determinants of marijuana use even after controlling for potential biases We also found evidence to show that the influence of close friends and the more exogenous classmates are quite similar in magnitude under our preferred specification, supporting theory predicting the importance of peer influence. Effective policy aimed at reducing marijuana usage among adolescents would consider these significant peer effects. PMID- 21264338 TI - The Escherichia coli BtuE protein functions as a resistance determinant against reactive oxygen species. AB - This work shows that the recently described Escherichia coli BtuE peroxidase protects the bacterium against oxidative stress that is generated by tellurite and by other reactive oxygen species elicitors (ROS). Cells lacking btuE (DeltabtuE) displayed higher sensitivity to K(2)TeO(3) and other oxidative stress generating agents than did the isogenic, parental, wild-type strain. They also exhibited increased levels of cytoplasmic reactive oxygen species, oxidized proteins, thiobarbituric acid reactive substances, and lipoperoxides. E. coli DeltabtuE that was exposed to tellurite or H(2)O(2) did not show growth changes relative to wild type cells either in aerobic or anaerobic conditions. Nevertheless, the elimination of btuE from cells deficient in catalases/peroxidases (Hpx(-)) resulted in impaired growth and resistance to these toxicants only in aerobic conditions, suggesting that BtuE is involved in the defense against oxidative damage. Genetic complementation of E. coli DeltabtuE restored toxicant resistance to levels exhibited by the wild type strain. As expected, btuE overexpression resulted in decreased amounts of oxidative damage products as well as in lower transcriptional levels of the oxidative stress-induced genes ibpA, soxS and katG. PMID- 21264339 TI - Detection of a single identical cytomegalovirus (CMV) strain in recently seroconverted young women. AB - BACKGROUND: Infection with multiple CMV strains is common in immunocompromised hosts, but its occurrence in normal hosts has not been well-studied. METHODS: We analyzed CMV strains longitudinally in women who acquired CMV while enrolled in a CMV glycoprotein B (gB) vaccine trial. Sequencing of four variable genes was performed in samples collected from seroconversion and up to 34 months thereafter. RESULTS: 199 cultured isolates from 53 women and 65 original fluids from a subset of 19 women were sequenced. 51 women were infected with one strain each without evidence for genetic drift; only two women shed multiple strains. Genetic variability among strains increased with the number of sequenced genetic loci. Nevertheless, 13 of 53 women proved to be infected with an identical CMV strain based on sequencing at all four variable genes. CMV vaccine did not alter the degree of genetic diversity amongst strains. CONCLUSIONS: Primary CMV infection in healthy women nearly always involves shedding of one strain that remains stable over time. Immunization with CMVgB-1 vaccine strain is not selective against specific strains. Although 75% of women harbored their unique strain, or a strain shared with only one other woman, 25% shared a single common strain, suggesting that this predominant strain with a particular combination of genetic loci is advantageous in this large urban area. PMID- 21264340 TI - Monitoring the long-term molecular epidemiology of the pneumococcus and detection of potential 'vaccine escape' strains. AB - BACKGROUND: While the pneumococcal protein conjugate vaccines reduce the incidence in invasive pneumococcal disease (IPD), serotype replacement remains a major concern. Thus, serotype-independent protection with vaccines targeting virulence genes, such as PspA, have been pursued. PspA is comprised of diverse clades that arose through recombination. Therefore, multi-locus sequence typing (MLST)-defined clones could conceivably include strains from multiple PspA clades. As a result, a method is needed which can both monitor the long-term epidemiology of the pneumococcus among a large number of isolates, and analyze vaccine-candidate genes, such as pspA, for mutations and recombination events that could result in 'vaccine escape' strains. METHODOLOGY: We developed a resequencing array consisting of five conserved and six variable genes to characterize 72 pneumococcal strains. The phylogenetic analysis of the 11 concatenated genes was performed with the MrBayes program, the single nucleotide polymorphism (SNP) analysis with the DNA Sequence Polymorphism program (DnaSP), and the recombination event analysis with the recombination detection package (RDP). RESULTS: The phylogenetic analysis correlated with MLST, and identified clonal strains with unique PspA clades. The DnaSP analysis correlated with the serotype-specific diversity detected using MLST. Serotypes associated with more than one ST complex had a larger degree of sequence polymorphism than a serotype associated with one ST complex. The RDP analysis confirmed the high frequency of recombination events in the pspA gene. CONCLUSIONS: The phylogenetic tree correlated with MLST, and detected multiple PspA clades among clonal strains. The genetic diversity of the strains and the frequency of recombination events in the mosaic gene, pspA were accurately assessed using the DnaSP and RDP programs, respectively. These data provide proof-of-concept that resequencing arrays could play an important role within research and clinical laboratories in both monitoring the molecular epidemiology of the pneumococcus and detecting 'vaccine escape' strains among vaccine-candidate genes. PMID- 21264341 TI - Land-use legacies are important determinants of lake eutrophication in the anthropocene. AB - BACKGROUND: A hallmark of the latter half of the 20(th) century is the widespread, rapid intensification of a variety of anthropogenically-driven environmental changes--a "Great Acceleration." While there is evidence of a Great Acceleration in a variety of factors known to be linked to water quality degradation, such as conversion of land to agriculture and intensification of fertilizer use, it is not known whether there has been a similar acceleration of freshwater eutrophication. METHODOLOGY/PRINCIPAL FINDINGS: Using quantitative reconstructions of diatom-inferred total phosphorus (DI-TP) as a proxy for lake trophic state, we synthesized results from 67 paleolimnological studies from across Europe and North America to evaluate whether most lakes showed a pattern of eutrophication with time and whether this trend was accelerated after 1945 CE, indicative of a Great Acceleration. We found that European lakes have experienced widespread increases in DI-TP over the 20(th) century and that 33% of these lakes show patterns consistent with a post-1945 CE Great Acceleration. In North America, the proportion of lakes that increased in DI-TP over time is much lower and only 9% exhibited a Great Acceleration of eutrophication. CONCLUSIONS/SIGNIFICANCE: The longer and more widespread history of anthropogenic influence in Europe, the leading cause for the relatively pervasive freshwater eutrophication, provides an important cautionary tale; our current path of intensive agriculture around the world may lead to an acceleration of eutrophication in downstream lakes that could take centuries from which to recover. PMID- 21264342 TI - A two-way communication between microglial cells and angiogenic sprouts regulates angiogenesis in aortic ring cultures. AB - BACKGROUND: Myeloid cells have been associated with physiological and pathological angiogenesis, but their exact functions in these processes remain poorly defined. Monocyte-derived tissue macrophages of the CNS, or microglial cells, invade the mammalian retina before it becomes vascularized. Recent studies correlate the presence of microglia in the developing CNS with vascular network formation, but it is not clear whether the effect is directly caused by microglia and their contact with the endothelium. METHODOLOGY/PRINCIPAL FINDINGS: We combined in vivo studies of the developing mouse retina with in vitro studies using the aortic ring model to address the role of microglia in developmental angiogenesis. Our in vivo analyses are consistent with previous findings that microglia are present at sites of endothelial tip-cell anastomosis, and genetic ablation of microglia caused a sparser vascular network associated with reduced number of filopodia-bearing sprouts. Addition of microglia in the aortic ring model was sufficient to stimulate vessel sprouting. The effect was independent of physical contact between microglia and endothelial cells, and could be partly mimicked using microglial cell-conditioned medium. Addition of VEGF-A promoted angiogenic sprouts of different morphology in comparison with the microglial cells, and inhibition of VEGF-A did not affect the microglia-induced angiogenic response, arguing that the proangiogenic factor(s) released by microglia is distinct from VEGF-A. Finally, microglia exhibited oriented migration towards the vessels in the aortic ring cultures. CONCLUSIONS/SIGNIFICANCE: Microglia stimulate vessel sprouting in the aortic ring cultures via a soluble microglial derived product(s), rather than direct contact with endothelial cells. The observed migration of microglia towards the growing sprouts suggests that their position near endothelial tip-cells could result from attractive cues secreted by the vessels. Our data reveals a two-way communication between microglia and vessels that depends on soluble factors and should extend the understanding of how microglia promote vascular network formation. PMID- 21264343 TI - Entomopathogenic fungus as a biological control for an important vector of livestock disease: the Culicoides biting midge. AB - BACKGROUND: The recent outbreak of bluetongue virus in northern Europe has led to an urgent need to identify control measures for the Culicoides (Diptera: Ceratopogonidae) biting midges that transmit it. Following successful use of the entomopathogenic fungus Metarhizium anisopliae against larval stages of biting midge Culicoides nubeculosus Meigen, we investigated the efficacy of this strain and other fungi (Beauveria bassiana, Isaria fumosorosea and Lecanicillium longisporum) as biocontrol agents against adult C. nubeculosus in laboratory and greenhouse studies. METHODOLOGY/FINDINGS: Exposure of midges to 'dry' conidia of all fungal isolates caused significant reductions in survival compared to untreated controls. Metarhizium anisopliae strain V275 was the most virulent, causing a significantly decrease in midge survival compared to all other fungal strains tested. The LT(50) value for strain V275 was 1.42 days compared to 2.21 3.22 days for the other isolates. The virulence of this strain was then further evaluated by exposing C. nubeculosus to varying doses (10(8)-10(11) conidia m( 2)) using different substrates (horse manure, damp peat, leaf litter) as a resting site. All exposed adults were found to be infected with the strain V275 four days after exposure. A further study exposed C. nubeculosus adults to 'dry' conidia and 'wet' conidia (conidia suspended in 0.03% aq. Tween 80) of strain V275 applied to damp peat and leaf litter in cages within a greenhouse. 'Dry' conidia were more effective than 'wet' conidia, causing 100% mortality after 5 days. CONCLUSION/SIGNIFICANCE: This is the first study to demonstrate that entomopathogenic fungi are potential biocontrol agents against adult Culicoides, through the application of 'dry' conidia on surfaces (e.g., manure, leaf litter, livestock) where the midges tend to rest. Subsequent conidial transmission between males and females may cause an increased level of fungi-induced mortality in midges thus reducing the incidence of disease. PMID- 21264344 TI - MicroRNA controlled adenovirus mediates anti-cancer efficacy without affecting endogenous microRNA activity. AB - MicroRNAs are small non-coding RNA molecules that regulate mRNA translation and stability by binding to complementary sequences usually within the 3' un translated region (UTR). We have previously shown that the hepatic toxicity caused by wild-type Adenovirus 5 (Ad5WT) in mice can be prevented by incorporating 4 binding sites for the liver-specific microRNA, mir122, into the 3' UTR of E1A mRNA. This virus, termed Ad5mir122, is a promising virotherapy candidate and causes no obvious liver pathology. Herein we show that Ad5mir122 maintains wild-type lytic activity in cancer cells not expressing mir122 and assess any effects of possible mir122 depletion in host cells. Repeat administration of 2*10(10) viral particles of Admir122 to HepG2 tumour bearing mice showed significant anti-cancer efficacy. RT-QPCR showed that E1A mRNA was down-regulated 29-fold in liver when compared to Ad5WT. Western blot for E1A confirmed that all protein variants were knocked down. RT-QPCR for mature mir122 in infected livers showed that quantity of mir122 remained unaffected. Genome wide mRNA microarray profiling of infected livers showed that although the transcript level of >3900 different mRNAs changed more than 2-fold following Ad5WT infection, less than 600 were changed by Ad5mir122. These were then filtered to select mRNAs that were only altered by Ad5mir122 and the remaining 21 mRNAs were compared to predicted mir122 targets. No mir122 target mRNAs were affected by Ad5 mir122. These results demonstrate that the exploitation of microRNA regulation to control virus replication does not necessarily affect the level of the microRNA or the endogenous mRNA targets. PMID- 21264345 TI - Reconstructing the Indian origin and dispersal of the European Roma: a maternal genetic perspective. AB - Previous genetic, anthropological and linguistic studies have shown that Roma (Gypsies) constitute a founder population dispersed throughout Europe whose origins might be traced to the Indian subcontinent. Linguistic and anthropological evidence point to Indo-Aryan ethnic groups from North-western India as the ancestral parental population of Roma. Recently, a strong genetic hint supporting this theory came from a study of a private mutation causing primary congenital glaucoma. In the present study, complete mitochondrial control sequences of Iberian Roma and previously published maternal lineages of other European Roma were analyzed in order to establish the genetic affinities among Roma groups, determine the degree of admixture with neighbouring populations, infer the migration routes followed since the first arrival to Europe, and survey the origin of Roma within the Indian subcontinent. Our results show that the maternal lineage composition in the Roma groups follows a pattern of different migration routes, with several founder effects, and low effective population sizes along their dispersal. Our data allowed the confirmation of a North/West migration route shared by Polish, Lithuanian and Iberian Roma. Additionally, eleven Roma founder lineages were identified and degrees of admixture with host populations were estimated. Finally, the comparison with an extensive database of Indian sequences allowed us to identify the Punjab state, in North-western India, as the putative ancestral homeland of the European Roma, in agreement with previous linguistic and anthropological studies. PMID- 21264346 TI - HER2-positive circulating tumor cells in breast cancer. AB - PURPOSE: Circulating Tumor Cells (CTCs) detection and phenotyping are currently evaluated in Breast Cancer (BC). Tumor cell dissemination has been suggested to occur early in BC progression. To interrogate dissemination in BC, we studied CTCs and HER2 expression on CTCs across the spectrum of BC staging. METHODS: Spiking experiments with 6 BC cell lines were performed and blood samples from healthy women and women with BC were analyzed for HER2-positive CTCs using the CellSearch(r). RESULTS: Based on BC cell lines experiments, HER2-positive CTCs were defined as CTCs with HER2 immunofluorescence intensity that was at least 2.5 times higher than the background. No HER2-positive CTC was detected in 42 women without BC (95% confidence interval (CI) 0-8.4%) whereas 4.1% (95%CI 1.4-11.4%) of 73 patients with ductal/lobular carcinoma in situ (DCIS/LCIS) had 1 HER2 positive CTC/22.5 mL, 7.9%, (95%CI 4.1-14.9%) of 101 women with non metastatic (M0) BC had >=1 HER2-positive CTC/22.5 mL (median 1 cell, range 1-3 cells) and 35.9% (95%CI 22.7-51.9%) of 39 patients with metastatic BC had >=1 HER2-positive CTC/7.5 mL (median 1.5 cells, range 1-42 cells). In CTC-positive women with DCIS/LCIS or M0 BC, HER2-positive CTCs were more commonly detected in HER2 positive (5 of 5 women) than HER2-negative BC (5 of 12 women) (p = 0.03). CONCLUSION: HER2-positive CTCs were detected in DCIS/LCIS or M0 BC irrespective of the primary tumor HER2 status. Nevertheless, their presence was more common in women with HER2-positive disease. Monitoring of HER2 expression on CTCs might be useful in trials with anti-HER2 therapies. PMID- 21264347 TI - High- and low-affinity epidermal growth factor receptor-ligand interactions activate distinct signaling pathways. AB - Signaling mediated by the Epidermal Growth Factor Receptor (EGFR) is crucial in normal development, and aberrant EGFR signaling has been implicated in a wide variety of cancers. Here we find that the high- and low-affinity interactions between EGFR and its ligands activate different signaling pathways. While high affinity ligand binding is sufficient for activation of most canonical signaling pathways, low-affinity binding is required for the activation of the Signal transducers and activators of transcription (Stats) and Phospholipase C-gamma 1 (PLCgamma1). As the Stat proteins are involved in many cellular responses including proliferation, migration and apoptosis, these results assign a function to low-affinity interactions that has been omitted from computational models of EGFR signaling. The existence of receptors with distinct signaling properties provides a way for EGFR to respond to different concentrations of the same ligand in qualitatively different ways. PMID- 21264348 TI - Allosteric interactions between the myristate- and ATP-site of the Abl kinase. AB - Abl kinase inhibitors targeting the ATP binding pocket are currently employed as potent anti-leukemogenic agents but drug resistance has become a significant clinical limitation. Recently, a compound that binds to the myristate pocket of Abl (GNF-5) was shown to act cooperatively with nilotinib, an ATP-competitive inhibitor to target the recalcitrant "T315I" gatekeeper mutant of Bcr-Abl. To uncover an explanation for how drug binding at a distance from the kinase active site could lead to inhibition and how inhibitors could combine their effects, hydrogen exchange mass spectrometry (HX MS) was employed to monitor conformational effects in the presence of both dasatinib, a clinically approved ATP-site inhibitor, and GNF-5. While dasatinib binding to wild type Abl clearly influenced Abl conformation, no binding was detected between dasatinib and T315I. GNF-5, however, elicited the same conformational changes in both wild type and T315I, including changes to dynamics within the ATP site located approximately 25 A from the site of GNF-5 interaction. Simultaneous binding of dasatinib and GNF-5 to T315I caused conformational and/or dynamics changes in Abl such that effects of dasatinib on T315I were the same as when it bound to wild type Abl. These results provide strong biophysical evidence that allosteric interactions play a role in Abl kinase downregulation and that targeting sites outside the ATP binding site can provide an important pharmacological tool to overcome mutations that cause resistance to ATP-competitive inhibitors. PMID- 21264349 TI - International study to evaluate PCR methods for detection of Trypanosoma cruzi DNA in blood samples from Chagas disease patients. AB - BACKGROUND: A century after its discovery, Chagas disease still represents a major neglected tropical threat. Accurate diagnostics tools as well as surrogate markers of parasitological response to treatment are research priorities in the field. The purpose of this study was to evaluate the performance of PCR methods in detection of Trypanosoma cruzi DNA by an external quality evaluation. METHODOLOGY/FINDINGS: An international collaborative study was launched by expert PCR laboratories from 16 countries. Currently used strategies were challenged against serial dilutions of purified DNA from stocks representing T. cruzi discrete typing units (DTU) I, IV and VI (set A), human blood spiked with parasite cells (set B) and Guanidine Hidrochloride-EDTA blood samples from 32 seropositive and 10 seronegative patients from Southern Cone countries (set C). Forty eight PCR tests were reported for set A and 44 for sets B and C; 28 targeted minicircle DNA (kDNA), 13 satellite DNA (Sat-DNA) and the remainder low copy number sequences. In set A, commercial master mixes and Sat-DNA Real Time PCR showed better specificity, but kDNA-PCR was more sensitive to detect DTU I DNA. In set B, commercial DNA extraction kits presented better specificity than solvent extraction protocols. Sat-DNA PCR tests had higher specificity, with sensitivities of 0.05-0.5 parasites/mL whereas specific kDNA tests detected 5.10( 3) par/mL. Sixteen specific and coherent methods had a Good Performance in both sets A and B (10 fg/ul of DNA from all stocks, 5 par/mL spiked blood). The median values of sensitivities, specificities and accuracies obtained in testing the Set C samples with the 16 tests determined to be good performing by analyzing Sets A and B samples varied considerably. Out of them, four methods depicted the best performing parameters in all three sets of samples, detecting at least 10 fg/ul for each DNA stock, 0.5 par/mL and a sensitivity between 83.3-94.4%, specificity of 85-95%, accuracy of 86.8-89.5% and kappa index of 0.7-0.8 compared to consensus PCR reports of the 16 good performing tests and 63-69%, 100%, 71.4 76.2% and 0.4-0.5, respectively compared to serodiagnosis. Method LbD2 used solvent extraction followed by Sybr-Green based Real time PCR targeted to Sat DNA; method LbD3 used solvent DNA extraction followed by conventional PCR targeted to Sat-DNA. The third method (LbF1) used glass fiber column based DNA extraction followed by TaqMan Real Time PCR targeted to Sat-DNA (cruzi 1/cruzi 2 and cruzi 3 TaqMan probe) and the fourth method (LbQ) used solvent DNA extraction followed by conventional hot-start PCR targeted to kDNA (primer pairs 121/122). These four methods were further evaluated at the coordinating laboratory in a subset of human blood samples, confirming the performance obtained by the participating laboratories. CONCLUSION/SIGNIFICANCE: This study represents a first crucial step towards international validation of PCR procedures for detection of T. cruzi in human blood samples. PMID- 21264350 TI - Evidence of activity-specific, radial organization of mitotic chromosomes in Drosophila. AB - The organization and the mechanisms of condensation of mitotic chromosomes remain unsolved despite many decades of efforts. The lack of resolution, tight compaction, and the absence of function-specific chromatin labels have been the key technical obstacles. The correlation between DNA sequence composition and its contribution to the chromosome-scale structure has been suggested before; it is unclear though if all DNA sequences equally participate in intra- or inter chromatin or DNA-protein interactions that lead to formation of mitotic chromosomes and if their mitotic positions are reproduced radially. Using high resolution fluorescence microscopy of live or minimally perturbed, fixed chromosomes in Drosophila embryonic cultures or tissues expressing MSL3-GFP fusion protein, we studied positioning of specific MSL3-binding sites. Actively transcribed, dosage compensated Drosophila genes are distributed along the euchromatic arm of the male X chromosome. Several novel features of mitotic chromosomes have been observed. MSL3-GFP is always found at the periphery of mitotic chromosomes, suggesting that active, dosage compensated genes are also found at the periphery of mitotic chromosomes. Furthermore, radial distribution of chromatin loci on mitotic chromosomes was found to be correlated with their functional activity as judged by core histone modifications. Histone modifications specific to active chromatin were found peripheral with respect to silent chromatin. MSL3-GFP-labeled chromatin loci become peripheral starting in late prophase. In early prophase, dosage compensated chromatin regions traverse the entire width of chromosomes. These findings suggest large-scale internal rearrangements within chromosomes during the prophase condensation step, arguing against consecutive coiling models. Our results suggest that the organization of mitotic chromosomes is reproducible not only longitudinally, as demonstrated by chromosome-specific banding patterns, but also radially. Specific MSL3-binding sites, the majority of which have been demonstrated earlier to be dosage compensated DNA sequences, located on the X chromosomes, and actively transcribed in interphase, are positioned at the periphery of mitotic chromosomes. This potentially describes a connection between the DNA/protein content of chromatin loci and their contribution to mitotic chromosome structure. Live high-resolution observations of consecutive condensation states in MSL3-GFP expressing cells could provide additional details regarding the condensation mechanisms. PMID- 21264351 TI - A DNA vaccine against chikungunya virus is protective in mice and induces neutralizing antibodies in mice and nonhuman primates. AB - Chikungunya virus (CHIKV) is an emerging mosquito-borne alphavirus indigenous to tropical Africa and Asia. Acute illness is characterized by fever, arthralgias, conjunctivitis, rash, and sometimes arthritis. Relatively little is known about the antigenic targets for immunity, and no licensed vaccines or therapeutics are currently available for the pathogen. While the Aedes aegypti mosquito is its primary vector, recent evidence suggests that other carriers can transmit CHIKV thus raising concerns about its spread outside of natural endemic areas to new countries including the U.S. and Europe. Considering the potential for pandemic spread, understanding the development of immunity is paramount to the development of effective counter measures against CHIKV. In this study, we isolated a new CHIKV virus from an acutely infected human patient and developed a defined viral challenge stock in mice that allowed us to study viral pathogenesis and develop a viral neutralization assay. We then constructed a synthetic DNA vaccine delivered by in vivo electroporation (EP) that expresses a component of the CHIKV envelope glycoprotein and used this model to evaluate its efficacy. Vaccination induced robust antigen-specific cellular and humoral immune responses, which individually were capable of providing protection against CHIKV challenge in mice. Furthermore, vaccine studies in rhesus macaques demonstrated induction of nAb responses, which mimicked those induced in convalescent human patient sera. These data suggest a protective role for nAb against CHIKV disease and support further study of envelope-based CHIKV DNA vaccines. PMID- 21264352 TI - The in vivo kinetics of RNA polymerase II elongation during co-transcriptional splicing. AB - RNA processing events that take place on the transcribed pre-mRNA include capping, splicing, editing, 3' processing, and polyadenylation. Most of these processes occur co-transcriptionally while the RNA polymerase II (Pol II) enzyme is engaged in transcriptional elongation. How Pol II elongation rates are influenced by splicing is not well understood. We generated a family of inducible gene constructs containing increasing numbers of introns and exons, which were stably integrated in human cells to serve as actively transcribing gene loci. By monitoring the association of the transcription and splicing machineries on these genes in vivo, we showed that only U1 snRNP localized to the intronless gene, consistent with a splicing-independent role for U1 snRNP in transcription. In contrast, all snRNPs accumulated on intron-containing genes, and increasing the number of introns increased the amount of spliceosome components recruited. This indicates that nascent RNA can assemble multiple spliceosomes simultaneously. Kinetic measurements of Pol II elongation in vivo, Pol II ChIP, as well as use of Spliceostatin and Meayamycin splicing inhibitors showed that polymerase elongation rates were uncoupled from ongoing splicing. This study shows that transcription elongation kinetics proceed independently of splicing at the model genes studied here. Surprisingly, retention of polyadenylated mRNA was detected at the transcription site after transcription termination. This suggests that the polymerase is released from chromatin prior to the completion of splicing, and the pre-mRNA is post-transcriptionally processed while still tethered to chromatin near the gene end. PMID- 21264353 TI - Lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis in the adult central nervous system. AB - Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system. PMID- 21264354 TI - Geo-spatial hotspots of hemorrhagic fever with renal syndrome and genetic characterization of Seoul variants in Beijing, China. AB - BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is highly endemic in mainland China, and has extended from rural areas to cities recently. Beijing metropolis is a novel affected region, where the HFRS incidence seems to be diverse from place to place. METHODOLOGY/PRINCIPAL FINDINGS: The spatial scan analysis based on geographical information system (GIS) identified three geo spatial "hotspots" of HFRS in Beijing when the passive surveillance data from 2004 to 2006 were used. The Relative Risk (RR) of the three "hotspots" was 5.45, 3.57 and 3.30, respectively. The Phylogenetic analysis based on entire coding region sequence of S segment and partial L segment sequence of Seoul virus (SEOV) revealed that the SEOV strains circulating in Beijing could be classified into at least three lineages regardless of their host origins. Two potential recombination events that happened in lineage #1 were detected and supported by comparative phylogenetic analysis. The SEOV strains in different lineages and strains with distinct special amino acid substitutions for N protein were partially associated with different spatial clustered areas of HFRS. CONCLUSION/SIGNIFICANCE: Hotspots of HFRS were found in Beijing, a novel endemic region, where intervention should be enhanced. Our data suggested that the genetic variation and recombination of SEOV strains was related to the high risk areas of HFRS, which merited further investigation. PMID- 21264355 TI - Ruminant brucellosis in the Kafr El Sheikh Governorate of the Nile Delta, Egypt: prevalence of a neglected zoonosis. AB - BACKGROUND: Brucellosis is a neglected tropical zoonosis allegedly reemerging in Middle Eastern countries. Infected ruminants are the primary source of human infection; consequently, estimates of the frequency of ruminant brucellosis are useful elements for building effective control strategies. Unfortunately, these estimates are lacking in most Middle East countries including Egypt. Our objectives are to estimate the frequency of ruminant brucellosis and to describe its spatial distribution in Kafr El Sheikh Governorate, Nile Delta, Egypt. METHODOLOGY/PRINCIPAL FINDINGS: We conducted a cross-sectional study in which 791 sheep, 383 goats, 188 cattle milk tanks and 173 buffalo milk tanks were randomly selected in 40 villages and tested for the presence of antibodies against Brucella spp. The seroprevalence among different species was estimated and visualized using choropleth maps. A spatial scanning method was used to identify areas with significantly higher proportions of seropositive flocks and milk tanks. We estimated that 12.2% of sheep and 11.3% of goats in the study area were seropositive against Brucella spp. and that 12.2% and 12% of cattle and buffalo milk tanks had antibodies against Brucella spp. The southern part of the governorate had the highest seroprevalence with significant spatial clustering of seropositive flocks in the proximity of its capital and around the main animal markets. CONCLUSIONS/ SIGNIFICANCE: Our study revealed that brucellosis is endemic at high levels in all ruminant species in the study area and questions the efficacy of the control measures in place. The high intensity of infection transmission among ruminants combined with high livestock and human density and widespread marketing of unpasteurized milk and dairy products may explain why Egypt has one of the highest rates of human brucellosis worldwide. An effective integrated human-animal brucellosis control strategy is urgently needed. If resources are not sufficient for nationwide implementation, high-risk areas could be prioritized. PMID- 21264357 TI - Chinese journal of dental reserch. PMID- 21264358 TI - Dental application potential of mesenchymal stromal cells and embryonic stem cells. AB - In the past decade, research on the potential applications of stem cells in dentistry has made great progress. There are at least five different types of multipotent mesenchymal stromal cells (MSCs) originating from exfoliated primary teeth, including dental pulp, apica papilla, periodontal ligament, and dental follicle. It has been reported that dental tissue-derived MSCs are able to generate dentine-pulp-like complexes as well as differentiate into periodontal and craniofacial progenitor cells. Similar to these dental tissue-derived MSCs, bone marrowderived MSCs are also capable of developing into ameloblasts, odontoblasts and periodontal ligament progenitor cells, as well as regenerating cementum, alveolar bone, craniofacial bone and articular condyles. Besides adult stem cells, embryonic stem cells are an alternative cell source for dental tissue regeneration, but the current data are preliminary and are based predominantly on in vitro data. In addition to these commonly reported stem cells, other progenitor cells with MSC properties are also found in salivary glands, tongue muscle, taste buds and oral mucosa, and these may play a role in recovering the function of the residing tissues. Other than these regenerative applications, many reports have demonstrated the utility of these stem cells in cytotoxicity testing, biocompatibility testing and developmental research. The present article summarises the above findings regarding the regenerative and other potential applications of both MSCs and embryonic stem cells. PMID- 21264356 TI - Modeling the dynamic transmission of dengue fever: investigating disease persistence. AB - BACKGROUND: Dengue is a disease of great complexity, due to interactions between humans, mosquitoes and various virus serotypes as well as efficient vector survival strategies. Thus, understanding the factors influencing the persistence of the disease has been a challenge for scientists and policy makers. The aim of this study is to investigate the influence of various factors related to humans and vectors in the maintenance of viral transmission during extended periods. METHODOLOGY/PRINCIPAL FINDINGS: We developed a stochastic cellular automata model to simulate the spread of dengue fever in a dense community. Each cell can correspond to a built area, and human and mosquito populations are individually monitored during the simulations. Human mobility and renewal, as well as vector infestation, are taken into consideration. To investigate the factors influencing the maintenance of viral circulation, two sets of simulations were performed: (1(st)) varying human renewal rates and human population sizes and (2(nd)) varying the house index (fraction of infested buildings) and vector per human ratio. We found that viral transmission is inhibited with the combination of small human populations with low renewal rates. It is also shown that maintenance of viral circulation for extended periods is possible at low values of house index. Based on the results of the model and on a study conducted in the city of Recife, Brazil, which associates vector infestation with Aedes aegytpi egg counts, we question the current methodology used in calculating the house index, based on larval survey. CONCLUSIONS/SIGNIFICANCE: This study contributed to a better understanding of the dynamics of dengue subsistence. Using basic concepts of metapopulations, we concluded that low infestation rates in a few neighborhoods ensure the persistence of dengue in large cities and suggested that better strategies should be implemented to obtain measures of house index values, in order to improve the dengue monitoring and control system. PMID- 21264360 TI - Combined association of CCR2-V64I and MCP-1-2518A/G polymorphisms with generalised aggressive periodontitis in Chinese. AB - OBJECTIVE: to examine the possible association of CCR2-V64I and MCP-1-2518A/G polymorphisms with generalised aggressive periodontitis (GAgP) in the Chinese population. METHODS: one hundred and twenty-four GAgP patients and 94 healthy subjects were included in the study. A peripheral blood sample was obtained from each subject and genomic DNA was isolated. Gene polymorphisms of CCR2-V64I and MCP-1-2518A/G were analysed by standard polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: a possible combined effect of CCR2-V64I and MCP-1-2518A/G was observed in the female GAgP patients, as the odds ratio for VV genotype (CCR2) and G+ genotype ( MCP-1) was 0.2 (P = 0.023). Individuals carrying VV genotype and G+ genotype were at reduced risk for GAgP. A possible combined effect of genotype and smoking was observed in the male GAgP patients, as the odds ratio for VV genotype (CCR2) and smoking, or G+ genotype (MCP-1) and smoking were 7.4 (P = 0.022) and 4.9 (P = 0.030), respectively. CONCLUSION: the combined association of CCR2-V64I and MCP-1-2518A/G polymorphisms may play an important role in determining GAgP susceptibility in Chinese females. A possible combined effect of genotype and smoking on GAgP susceptibility was suggested in males. PMID- 21264359 TI - Biomarkers: important clues to the pathogenesis of infantile haemangioma and their clinical significance. AB - Infantile haemangioma is the most common tumour of infancy, yet the pathogensis of this lesion remains unknown and the predictable life cycle is poorly understood. Though much new information on infantile haemangioma has emerged over the past decade, researchers continue to debate the fundamental features; including cells of origin, nonrandom distribution, and mechanisms regulating the sometimes explosive growth and slow involution. The development of biomarkers has shed light on the pathogenesis and management of infantile haemangioma. Several useful biomarkers and their suggestions as to the aetiology of infantile haemangioma are reviewed. In addition, the application in clinical diagnosis and choice of treatment methods of infantile haemangioma is summarised. PMID- 21264361 TI - Identification of dominant pathogens in periapical lesions associated with persistent apical periodontitis. AB - OBJECTIVE: to identify dominant pathogens in the periapical lesions associated with persistent apical periodontitis. METHODS: thirty-three root-filled teeth with persistent apical periodontitis referred for surgical treatment were selected. Microbial samples were collected from the periapical lesions during apical surgery. Microbial identification was performed with species-specific primers prepared according to the sequence analysis data using a 16S rRNA technique. RESULTS: among the 33 cases, in 5 cases none of the target species were detected, 6 cases showed the presence of only one species, and 22 cases showed more than two species. Porphyromonas endodontalis (45% of sample) was the most commonly detected dominant microbial species in the study sample, followed by Actinomyces viscosus (42%), Candida albicans (36%) and Porphyromonas gingivalis (27%). Fusobacterium, Actinomyces israelii and Enterococcus faecalis were also detected in 27%, 21% and 15% of the sample, respectively. The most frequently isolated species, P. endodontalis, was in most cases detected together with Actinomyces (14 cases) and P. gingivalis (6 cases). None of the lesions analysed in the present study contained Prevotella intermedia. There was no correlation in relation to the presence of sinus tracts and the bacterial species. CONCLUSION: a mixed population of pathogens was found in the endodontic lesions associated with persistent apical periodontitis. P. endodontalis, A. viscosus, C. albicans and P. gingivalis were the dominant species identified. PMID- 21264362 TI - Computed densitometry of panoramic radiographs in evaluation of bone healing after enucleation of mandibular odontogenic keratocysts. AB - OBJECTIVE: to investigate bone formation after enucleation of mandibular odontogenic keratocysts (keratocystic odontogenic tumours) by computed densitometry of preoperative and post-operative panoramic radiographs. METHODS: fifty-eight patients with mandibular keratocysts were treated by surgical enucleation and primarily closed without grafting. The largest diameters of the cysts were 3.5 cm to 7.1 cm. Post-operative clinical and radiographic examinations were performed at 1, 3, 6 and 12 months. Bone density of the residual cavity was measured on the preoperative and postoperative panoramic radiographs with Digora through a greyscale of 254 tonalities. Student t test was used for comparison of bone density values of different time periods. RESULTS: progressive bone formation in the residual cavity was observed after enucleation of mandibular odontogenic keratocysts. The mean increase of bone density was 6.85% at post-operative 1 month, 22.61% at 3 months, 49.45% at 6 months and 71.77% at 12 months in comparison with that of the preoperative radiograph. Although increase in bone density was not significantly different between the post-operative first 3 months and second 3 months, this increase was significantly higher in the first 6 months than that in the later 6 months (P < 0.05). No significant correlation was found between increase of bone density and patient gender or the maximal diameter of the cysts. CONCLUSION: bone regeneration could progressively occur in the defect area without grafting materials after enucleation of mandibular odontogenic keratocysts, with significant increase of bone density at 6 months post-operatively. PMID- 21264363 TI - Effects of radiation on the expression of nerve growth factor in rat submandibular gland. AB - OBJECTIVE: to investigate the correlation between the expression of nerve growth factor (NGF) and tissue injury in irradiated rat submandibular gland. METHODS: the salivary gland regions of the rats were irradiated with a single dose of 15 Gy X-ray. The histopathological changes in the submandibular gland were observed, while the expression of NGF was determined by immunohistochemistry and real-time PCR. RESULTS: the weight of the body and submandibular gland decreased in the irradiated rats 30 days after irradiation, compared with the control group. There were also significant histopathological changes in the submandibular gland of the irradiated rats compared with the non-irradiated rats. The acinar cells and ducts were degenerated obviously. Fibrosis appeared around the ducts. The mRNA and protein expression of NGF in the submandibular gland decreased in the irradiated rats compared with the control group. Protein expression of NGF was even observed in the striated duct in the irradiated rats. conclusion: NGF may play an important role in protection of the submandibular glands of rats from radiation. PMID- 21264364 TI - Evaluation of the ultrasonographic features of salivary gland tumours. AB - OBJECTIVE: to evaluate the value of the ultrasonographic features for differentiation between benign and malignant tumours of salivary glands. METHODS: eighty-four cases of salivary gland tumours were analysed. Sixty-five cases were benign and 19 were malignant. All cases were confirmed by histopathological examination. The ultrasonographic features analysed included the shape of the tumour, the boundary echo, the internal echo and the posterior echo. Each feature was graded into three ranks. For statistical analysis, they were ranked respectively 1, 2 and 3. Another 28 cases of salivary gland tumours were analysed to verify the diagnostic accuracy of the ultrasonography. All data were analysed using SPSS 16.0 for windows. The Mann-Whitney U test, the receiver operating characteristic (ROC) curve and Fisher's discriminant test were performed. RESULTS: The differences between benign and malignant tumours were statistically significant in the shape of the tumour (P = 0.001), the boundary echo (P = 0.001) and the posterior echo (P = 0.000). However, the difference in the internal echo was not statistically significant (P > 0.05). The diagnostic accuracy, sensitivity and specificity were 82.1%, 63.2% and 87.7%, respectively, while the predicting diagnostic accuracy was 85.7%. CONCLUSION: the present study indicates that the shape of the tumour, the boundary echo and the posterior echo could be effective ultrasonographic criteria for differential diagnosis of benign tumours from malignant tumours in the salivary glands. PMID- 21264365 TI - Reliability and accuracy of Crystaleye spectrophotometric system. AB - OBJECTIVE: to develop an in vitro shade-measuring model to evaluate the reliability and accuracy of the Crystaleye spectrophotometric system, a newly developed spectrophotometer. METHODS: four shade guides, VITA Classical, VITA 3D Master, Chromascop and Vintage Halo NCC, were measured with the Crystaleye spectrophotometer in a standardised model, ten times for 107 shade tabs. The shade-matching results and the CIE L*a*b* values of the cervical, body and incisal regions for each measurement were automatically analysed using the supporting software. Reliability and accuracy were calculated for each shade tab both in percentage and in colour difference (DeltaE). Difference was analysed by one-way ANOVA in the cervical, body and incisal regions. RESULTS: range of reliability was 88.81% to 98.97% and 0.13 to 0.24 DeltaE units, and that of accuracy was 44.05% to 91.25% and 1.03 to 1.89 DeltaE units. Significant differences in reliability and accuracy were found between the body region and the cervical and incisal regions. Comparisons made among regions and shade guides revealed that evaluation in DeltaE was prone to disclose the differences. CONCLUSION: measurements with the Crystaleye spectrophotometer had similar, high reliability in different shade guides and regions, indicating predictable repeated measurements. Accuracy in the body region was high and less variable compared with the cervical and incisal regions. PMID- 21264366 TI - Effects of background, direction and intensity of ambient light, measuring position, and adjacent teeth, on anterior tooth colour measurement in vitro. AB - OBJECTIVE: to investigate the effects of different background colours (black, white or pink), direction and intensity of ambient light, measuring position, and the adjacent teeth, on the in vitro colour measurement of maxillary anterior teeth, using the Minolta CR-321 colorimeter. METHODS: ten extracted human maxillary central incisors were selected. A fibre-optic light MI-150 was used as the ambient illuminant. Teeth were irradiated from a 3- or 12-o'clock direction. L*a*b* values of seven sites on the labial surfaces were obtained by means of the Minolta CR-321 colorimeter, using three background colours, with or without the adjacent teeth. The recorded data were analysed with two-tailed Student t tests and analysis of variance (alpha = 0.05). RESULTS: the ambient light did not affect the colour measurement of anterior teeth, regardless of the presence or absence of the adjacent teeth. There were no statistically significant differences in L*a*b* values at the same position under different background colours, except DeltaE12 (colour difference between site 1 and site 2) between black and white backgrounds. DeltaE12 (under black background), DeltaE13 and DeltaE15 were greater than 1.5, while the others were lower than 1.5. CONCLUSION: the background, ambient light and the presence of adjacent teeth did not affect the colour measurement of anterior teeth using the Minolta CR-321 colorimeter in vitro. The inherent disadvantages of using the naked eye during clinical visual shade assessment may be overcome by the colorimeter. PMID- 21264367 TI - Saponins from Plumeria acuminata Ait induce cell growth inhibition and apoptosis of oral squamous carcinoma cells. AB - OBJECTIVE: to investigate the cytotoxic and apoptotic effects of saponins from Plumeria acuminata Ait on oral squamous carcinoma cells (OSCC). METHODS: OSCC cells seeded at 2 * 104 cells/well in a 96-well plate were treated with saponins from P. acuminata Ait and cisplatin in various concentrations for 24 h. Trypan blue dye exclusion assay and ethidium bromide/acridine orange were used to evaluate their cytotoxic and apoptotic effects on the cells, respectively. RESULTS: the results showed that both saponins and cisplatin had cytotoxic and apoptotic effects on OSCC cells. CONCLUSION: saponins from P. acuminata Ait may be potential anti-cancer agents for OSCC. PMID- 21264368 TI - Calcifying epithelial odontogenic tumour showing malignant transformation: a case report and review of the literature. AB - Calcifying epithelial odontogenic tumour (CEOT) is a rare and benign odontogenic neoplasm that affects the jaws. Here we present a maxillary case of CEOT showing features of malignant transformation, and a review of the literature. PMID- 21264369 TI - Cytochromes P450 as useful biocatalysts: addressing the limitations. AB - Cytochrome P450 monooxygenases (P450s or CYPs) are a unique family of enzymes which are capable of catalysing the regio- and stereospecific oxidation of non functionalised hydrocarbons. Despite the enormous synthetic potential of P450s, these enzymes have yet to be extensively employed for research purposes or in industry. Lack of stability, low activity, narrow substrate specificity, expensive cofactor requirements, limited solvent tolerance and electron supply are some of the main reasons why the academic and industrial implementation of these important biocatalysts remains a challenge. Considering the significance of P450s, many research groups have focused on improving their properties in an effort to make more robust catalysts with broad synthetic applications. This article focuses on some of the factors that have limited the exploitation of P450s and explores some of the significant steps that have been taken towards addressing these limitations. PMID- 21264370 TI - Experimental charge density distribution of non-coordinating sp3 carbanions in [Mg{(pz*)3C}2]. AB - In this communication we present the experimental charge density distribution in [Mg{(pz*)(3)C}(2)] (1), (pz* = 3,5-dimethylpyrazolyl), containing two non coordinating sp(3) carbanionic lone-pairs. PMID- 21264371 TI - Saturation factor of nitroxide radicals in liquid DNP by pulsed ELDOR experiments. AB - We propose the use of the pulse electron double resonance (ELDOR) method to determine the effective saturation factor of nitroxide radicals for dynamic nuclear polarization (DNP) experiments in liquids. The obtained values for the nitroxide radical TEMPONE-D,(15)N at different concentrations are rationalized in terms of spin relaxation and are shown to fulfil the Overhauser theory. PMID- 21264372 TI - Laser-treated hydrophobic paper: an inexpensive microfluidic platform. AB - We report a method for fabricating inexpensive microfluidic platforms on paper using laser treatment. Any paper with a hydrophobic surface coating (e.g., parchment paper, wax paper, palette paper) can be used for this purpose. We were able to selectively modify the surface structure and property (hydrophobic to hydrophilic) of several such papers using a CO(2) laser. We created patterns down to a minimum feature size of 62+/-1 um. The modified surface exhibited a highly porous structure which helped to trap/localize chemical and biological aqueous reagents for analysis. The treated surfaces were stable over time and were used to self-assemble arrays of aqueous droplets. Furthermore, we selectively deposited silica microparticles on patterned areas to allow lateral diffusion from one end of a channel to the other. Finally, we demonstrated the applicability of this platform to perform chemical reactions using luminol-based hemoglobin detection. PMID- 21264373 TI - UV laser removal of varnish on tempera paints with nanosecond and femtosecond pulses. AB - Two laser cleaning approaches based on ablation by ultraviolet laser pulses of femtosecond (fs) and nanosecond (ns) durations for the removal of shellac varnish from egg-yolk based tempera paints are investigated. Laser irradiation effects, induced on the varnish layer and on the underlying temperas by multiple pulses in the fs domain at 398 and 265 nm and single pulses in the ns domain at 213 nm, were examined following a spectroanalytical approach. By using optical microscopy, colorimetry and laser induced fluorescence it was found that irradiation of the varnished temperas with fs pulses changes the texture of the varnish surface and results in degradation of the underlying coloured paint. In contrast, operating with pulses of 15 ns at the highly absorbed wavelength of 213 nm, controlled micrometric layer removal of the varnish is possible without noticeable modification of the coloured temperas. These results widen the choice of laser conditions for painting restoration. PMID- 21264374 TI - Social selection and the evolution of cooperative groups: the example of the cellular slime moulds. AB - In social selection the phenotype of an individual depends on its own genotype as well as on the phenotypes, and so genotypes, of other individuals. This makes it impossible to associate an invariant phenotype with a genotype: the social context is crucial. Descriptions of metazoan development, which often is viewed as the acme of cooperative social behaviour, ignore or downplay this fact. The implicit justification for doing so is based on a group-selectionist point of view. Namely, embryos are clones, therefore all cells have the same evolutionary interest, and the visible differences between cells result from a common strategy. The reasoning is flawed, because phenotypic heterogeneity within groups can result from contingent choices made by cells from a flexible repertoire as in multicellular development. What makes that possible is phenotypic plasticity, namely the ability of a genotype to exhibit different phenotypes. However, co operative social behaviour with division of labour requires that different phenotypes interact appropriately, not that they belong to the same genotype, or have overlapping genetic interests. We sketch a possible route to the evolution of social groups that involves many steps: (a) individuals that happen to be in spatial proximity benefit simply by virtue of their number; (b) traits that are already present act as preadaptations and improve the efficiency of the group; and (c) new adaptations evolve under selection in the social context--that is, via interactions between individuals--and further strengthen group behaviour. The Dictyostelid or cellular slime mould amoebae (CSMs) become multicellular in an unusual way, by the aggregation of free-living cells. In nature the resulting group can be genetically homogeneous (clonal) or heterogeneous (polyclonal); in either case its development, which displays strong cooperation between cells (to the extent of so-called altruism) is not affected. This makes the CSMs exemplars for the study of social behaviour. PMID- 21264375 TI - nanoLAB: an ultraportable, handheld diagnostic laboratory for global health. AB - Driven by scientific progress and economic stimulus, medical diagnostics will move to a stage in which straightforward medical diagnoses are independent of physician visits and large centralized laboratories. The future of basic diagnostic medicine will lie in the hands of private individuals. We have taken significant strides towards achieving this goal by developing an autoassembly assay for disease biomarker detection which obviates the need for washing steps and is run on a handheld sensing platform. By coupling magnetic nanotechnology with an array of magnetically responsive nanosensors, we demonstrate a rapid, multiplex immunoassay that eliminates the need for trained technicians to run molecular diagnostic tests. Furthermore, the platform is battery-powered and ultraportable, allowing the assay to be run anywhere in the world by any individual. PMID- 21264376 TI - Deciphering interactions used by the influenza virus NS1 protein to silence the host antiviral sensor protein RIG-I using a bacterial reverse two-hybrid system. AB - The majority of biological processes are controlled and regulated by an intricate network of thousands of interacting proteins. Identifying and understanding the key components of these protein networks, especially those that play a critical role in disease, is a challenge that promises to dramatically alter our current approach to healthcare. To facilitate this process, we have developed a method for the rapid construction of a chromosomally integrated, bacterial reverse two hybrid system (RTHS) that enables the identification of interacting protein partners. Chromosomal integration of the RTHS enables stable protein expression, free of plasmid copy-number effects, as well as eliminating false positives arising from plasmid ejection. We have utilized this approach to identify the interactions used by the influenza virus NS1 protein to silence the host's antiviral defences. PMID- 21264377 TI - N-heterocyclic carbene-catalyzed (NHC) three-component domino reactions: highly stereoselective synthesis of functionalized acyclic epsilon-ketoesters. AB - A novel NHC-catalyzed three-component domino strategy to access high functionalized cis-epsilon-ketoesters with excellent yields (up to 98%) and high stereoselectivities (up to 20:1) is documented. The title domino reactions are atom economical and work on a broad range of substrates. The relative stereochemistry could be explained by a cascade crossed-benzoin/oxy-Cope rearrangement/esterification process. The thus-obtained products are of potential synthetic value in the drug research and combinatorial chemistry. PMID- 21264383 TI - [WS4Cu3I2]- and [WS4Cu4]2+ secondary building units formed a metal-organic framework: large tubes in a highly interpenetrated system. AB - A 3D metal-organic framework, {[WS(4)Cu(4)(dpbp)(4)](2+).[WS(4)Cu(3)(dpbp)(2)I(2)](-).I(-)}(n).xSolvent, [dpbp = 4,4'-di(4-pyridyl)biphenyl] with an unprecedent 8-fold non-equivalent interpenetration mode is presented, which contains four anionic and four cationic frameworks formed by tetranuclear [WS(4)Cu(3)I(2)](-) and pentanuclear [WS(4)Cu(4)](2+) SBUs with long dpbp ligands. Large rhombus-shaped tubes with diagonal dimensions of ~20 * 10 A are formed in spite of high interpenetration. PMID- 21264378 TI - Characterization of the TDP-D-ravidosamine biosynthetic pathway: one-pot enzymatic synthesis of TDP-D-ravidosamine from thymidine-5-phosphate and glucose 1-phosphate. AB - Ravidomycin V and related compounds, e.g., FE35A-B, exhibit potent anticancer activities against various cancer cell lines in the presence of visible light. The amino sugar moieties (D-ravidosamine and its analogues, respectively) in these molecules contribute to the higher potencies of ravidomycin and analogues when compared to closely related compounds with neutral or branched sugars. Within the ravidomycin V biosynthetic gene cluster, five putative genes encoding NDP-D-ravidosamine biosynthetic enzymes were identified. Through the activities of the isolated enzymes in vitro, it is demonstrated that ravD, ravE, ravIM, ravAMT and ravNMT encode TDP-D-glucose synthase, TDP-4-keto-6-deoxy-D-glucose-4,6 dehydratase, TDP-4-keto-6-deoxy-D-glucose-3,4-ketoisomerase, TDP-3-keto-6-deoxy-D galactose-3-aminotransferase, and TDP-3-amino-3,6-dideoxy-D-galactose-N,N dimethyl-transferase, respectively. A protocol for a one-pot enzymatic synthesis of TDP-D-ravidosamine has been developed. The results presented here now set the stage to produce TDP-D-ravidosamine routinely for glycosylation studies. PMID- 21264384 TI - Surface grafting and reactivity of calixarene-based receptors and pseudorotaxanes on Si(100). AB - The first report is given here on the anchoring on H-Si(100) of calix[4]arenes and calix[6]arene-based pseudorotaxanes, versatile building blocks for molecular devices. Covalent functionalization on Si was reached through a wet chemistry recipe, by making use of an extra-mild photochemical activation via visible light of C=C terminated anchoring arms. Our approach largely preserves the integrity of the molecular substrate, also allowing for a full monolayer of pseudorotaxane to be formed on Si(100). Molecular adhesion has been demonstrated by the presence and quantitation of XPS signals from specific elements in the molecules. AFM measurements performed on Si(100)/calix[4]arenes have revealed structures 2.3 nm high, consistent with the length of the molecule. The availability of the calix[4]arene cavity to host further species after anchoring on Si has been demonstrated by the successful complexation reaction with Cs(+) ions, resulting in a 1:1 calix/Cs(+) ratio, and with N-methyl pyridinium iodide. A pseudorotaxane species, composed of a calix[6]arene wheel derivatised with N-phenylureido groups on the upper rim and a viologen (4,4'-bipyridinium) containing axle, has been anchored on Si(100) via the C=C termination of the axle. We demonstrated the self assembling of this pseudorotaxane covalently bound by use of XPS. PMID- 21264385 TI - Preparation, reactivity and controlled release of SAMs of calix[4,6]arenes and calix[6]arene-based rotaxanes and pseudorotaxanes formed on polycrystalline Cu. AB - Specific and reversible binding of guest molecules from a solution to a surface pre-treated with host molecules is a recent and active field of research. Self assembled monolayers may result from supramolecular interactions, adding distinct functionalities to the surface. In this frame, the first compared study is given here of the anchoring on the technologically relevant Cu surface of calix[4]arene receptors and calix[6]arene-based rotaxanes and pseudorotaxanes. These molecules, which belong to the most representative classes of compounds in supramolecular chemistry, have been chosen for their synthetic accessibility and versatility, which make them useful building blocks for the synthesis of new advanced supramolecular structures. Covalent functionalisation of calix[4,6]arenes on Cu was reached via a dip-coating procedure, optimizing the various synthetic aspects in order to obtain good coverages and copper passivation. Molecular adhesion has been demonstrated by the presence and relative quantitation of XPS signals from specific elements in the molecules. We have successfully tested the combination of different functionalities by producing a mixed film, prepared by ligand exchange of calix[4]arene with undecanethiol. The availability of the calix[4]arene cavity to reversibly host further species after anchoring on Cu has been demonstrated by a sequence of uptake and release cycles with pyridinium salts. Rotaxane and pseudorotaxane species, composed of a calix[6]arene wheel functionalized with N-phenylurea groups on the upper rim, and a viologen containing axle, have been anchored on Cu via the SH-termination of the axle. XPS demonstrated the successful self-assembly of fully threaded rotaxanes and pseudorotaxanes from their solutions and the controlled release upon biasing of full rotaxanes and of the pseudorotaxane wheel. PMID- 21264386 TI - Organometallic acetylides of Pt(II), Au(I) and Hg(II) as new generation optical power limiting materials. AB - Within the scope of nonlinear optics, optical power limiting (OPL) materials are commonly regarded as an important class of compounds which can protect the delicate optical sensors or human eyes from sudden exposure to damaging intense laser beams. Recent efforts have been devoted to developing organometallic acetylide complexes, dendrimers and polymers as high performance OPL materials of the next generation which can favorably optimize the optical limiting/transparency trade-off issue. These metallated materials offer a new avenue towards a new family of highly transparent homo- and heterometallic optical limiters with good solution processability which outperform those of current state-of-the-art visible-light-absorbing competitors such as fullerenes, metalloporphyrins and metallophthalocyanines. This critical review aims to provide a detailed account on the recent advances of these novel OPL chromophores. Their OPL activity was shown to depend strongly on the electronic characters of the aryleneethynylene ligand and transition metal moieties as well as the conjugation chain length of the compounds. Strategies including copolymerization with other transition metals, change of structural geometry, use of a dendritic platform and variation of the type and content of transition metal ions would strongly govern their photophysical behavior and improve the resulting OPL responses. Special emphasis is placed on the structure-OPL response relationships of these organometallic acetylide materials. The research endeavors for realizing practical OPL devices based on these materials have also been presented. This article concludes with perspectives on the current status of the field, as well as opportunities that lie just beyond its frontier (106 references). PMID- 21264387 TI - Probing the local coordination environment and nuclearity of uranyl(VI) complexes in non-aqueous media by emission spectroscopy. AB - We describe the synthesis, solid state and solution properties of two families of uranyl(VI) complexes that are ligated by neutral monodentate and anionic bidentate P=O, P=NH and As=O ligands bearing pendent phenyl chromophores. The uranyl(VI) ions in these complexes possess long-lived photoluminescent LMCT (3)Pi(u) excited states, which can be exploited as a sensitive probe of electronic structure, bonding and aggregation behaviour in non-aqueous media. For a family of well defined complexes of given symmetry in trans-[UO(2)Cl(2)(L(2))] (L = Ph(3)PO (1), Ph(3)AsO (2) and Ph(3)PNH (3)), the emission spectral profiles in CH(2)Cl(2) are indicative of the strength of the donor atoms bound in the equatorial plane and the uranyl bond strength; the uranyl LMCT emission maxima are shifted to lower energy as the donor strength of L increases. The luminescence lifetimes in fluid solution mirror these observations (0.87-3.46 MUs) and are particularly sensitive to vibrational and bimolecular deactivation. In a family of structurally well defined complexes of the related anion, tetraphenylimidodiphosphinate (TPIP), monometallic complexes, [UO(2)(TPIP)(thf)] (4), [UO(2)(TPIP)(Cy(3)PO)] 5), a bimetallic complex [UO(2)(TPIP)(2)](2) (6) and a previously known trimetallic complex, [UO(2)(TPIP)(2)](3) (7) can be isolated by variation of the synthetic procedure. Complex 7 differs from 6 as the central uranyl ion in 7 is orthogonally connected to the two peripheral ones via uranyl > uranium dative bonds. Each of these oligomers exhibits a characteristic optical fingerprint, where the emission maxima, the spectral shape and temporal decay profiles are unique for each structural form. Notably, excited state intermetallic quenching in the trimetallic complex 7 considerably reduces the luminescence lifetime with respect to the monometallic counterpart 5 (from 2.00 MUs to 1.04 MUs). This study demonstrates that time resolved and multi-parametric luminescence can be of value in ascertaining solution and structural forms of discrete uranyl(VI) complexes in non-aqueous solution. PMID- 21264388 TI - Comment on "Deletion of btn1, an orthologue of CLN3, increases glycolysis and perturbs amino acid metabolism in the fission yeast model of Batten disease". AB - We provide a comment on the paper of Pears et al. (Mol. BioSyst., 2010, 6, 1093 1102). PMID- 21264390 TI - Cytochrome c as an experimental model protein. AB - Mitochondrial cytochrome c is among the most intensively studied of all proteins. Initial interest was in its role in the respiratory chain and as a model for studies of protein structure, folding and electron transfer. The function of cytochrome c in signalling apoptosis has brought a new wave of research into the protein. Bacterial cytochromes c are more complex and varied in function. This review highlights some of these roles and expands on systems for producing holocytochrome c proteins. PMID- 21264391 TI - Bi-analyte single molecule SERS technique with simultaneous spatial resolution. AB - The simultaneous combination on CCD detectors of both spectral and spatial information is used in the framework of the single molecule (SM) bi-analyte Surface-Enhanced Raman Scattering (SERS) technique, to provide a new level of understanding on the origins of SM-spectra, as well as reveal the advantages and limitations of the statistical identification of SM-events. A new and deeper interpretation of the roots of the inhomogeneous broadening of single molecule Raman peaks can be uncovered, as well as the origin of Surface-Enhanced Fluorescence (SEF) emission by single molecules. In this manner, subtler aspects of SM-SERS spectroscopy can be revealed by the additional presence of spatial information on the localization of single molecules producing the signal. The spatial information is normally lost through the standard binning of CCD cameras for spectroscopy, which only emphasizes the spectral dimension of the problem. This novel extension of the bi-analyte SM-SERS method should contribute to the furtherance of the technique, and several of its fundamental aspects are discussed in detail. PMID- 21264392 TI - Well-defined N-heterocyclic carbene silver halides of 1-cyclohexyl-3 arylmethylimidazolylidenes: synthesis, structure and catalysis in A3-reaction of aldehydes, amines and alkynes. AB - Structurally well-defined N-heterocyclic carbene silver chlorides and bromides supported by 1-cyclohexyl-3-benzylimidazolylidene (CyBn-NHC) or 1-cyclohexyl-3 naphthalen-2-ylmethylimidazolylidene (CyNaph-NHC) were synthesized by reaction of the corresponding imidazolium halides with silver(I) oxide while cationic bis(CyBn-NHC) silver nitrate was isolated under similar conditions using imidazolium iodide in the presence of sodium nitrate. Single-crystal X-ray diffraction revealed a dimeric structure through a nonpolar weak-hydrogen-bond supported Ag-Ag bond for 1-cyclohexyl-3-benzylimidazolylidene silver halides [(CyBn-NHC)AgX](2) (X = Cl, 1; Br, 2) but a monomeric structure for N heterocyclic carbene silver halides with the more sterically demanding 1 cyclohexyl-3-naphthalen-2-ylmethylimidazolylidene ligand (CyNaph-NHC)AgX (X = Cl, 4; Br, 5). Cationic biscarbene silver nitrate [(CyBn-NHC)(2)Ag](+)NO(3)(-)3 assumed a cis orientation with respect to the two carbene ligands. The monomeric complexes (CyNaph-NHC)AgX 4 and 5 showed higher catalytic activity than the dimeric [(CyBn-NHC)AgX](2)1 and 2 as well as the cationic biscarbene silver nitrate 3 in the model three component reaction of 3-phenylpropionaldehyde, phenylacetylene and piperidine with chloride 4 performing best and giving product in almost quantitative yield within 2 h at 100 degrees C. An explanation for the structure-activity relationship in N-heterocyclic carbene silver halide catalyzed three component reaction is given based on a slightly modified mechanism from the one in literature. PMID- 21264393 TI - Refinement and validation of an exposure model for the pharmaceutical industry. AB - OBJECTIVES: Assessment of worker's exposure is becoming increasingly critical in the pharmaceutical industry as drugs of higher potency are being manufactured. The batch nature of operations often makes it difficult to obtain sufficient numbers of exposure measurements and occupational exposure models may be useful tools in the exposure assessment process. This paper aims to describe further refinement and validation of an existing deterministic occupational exposure model to predict airborne exposure of workers in this industry. METHODS: Workplace exposure assessment data (n = 381) containing all the contextual information required for the exposure model were collated from a multinational pharmaceutical company. The measured exposure levels ranged from 5 * 10-7 to 200 mg m-3 for largely task based samples, and included a range of handling activities, local control measures and abnormal operating conditions. Model input parameters for local control measures and handling activities were refined to reflect pharmaceutical situations. RESULTS: The refined exposure model resulted in good correlations between the log-transformed model predictions and the actual measured data for the overall dataset (r(s) = 0.61, n = 381, p < 0.001) and at scenario level (r(s) = 0.69, n = 48, p < 0.001). The model overestimated scenarios with measured exposure levels < 0.1 mg m-3 (r(s) = 0.69, bias = 0.71, n = 46, p < 0.001), and underestimated scenarios with higher measured concentrations ( > 0.1 mg m-3) (r(s) = 0.59, bias = -4.9, n = 33, p < 0.001). Including information on the refined sub-parameters improved the correlations, suggesting the uncertainty in the model parameters was partly responsible for the bias. CONCLUSION: Further scientific data from the pharmaceutical industry on model input parameters, particularly on the efficacy of local control measures, may help improve the accuracy of the model predictions. The refined exposure model appears to be a useful exposure assessment screening tool for the pharmaceutical industry. PMID- 21264394 TI - Low-temperature decomposition of methanol on Au nanoclusters supported on a thin film of Al2O3/NiAl100. AB - With a variety of surface probe techniques, we investigated low-temperature decomposition of methanol on Au nanoclusters formed by vapor deposition onto an ordered Al(2)O(3)/NiAl(100) thin film. Upon adsorption of methanol on the Au clusters (with mean diameter 1.5-3.8 nm and height 0.45-0.85 nm) at 110 K, some of the adsorbed methanol dehydrogenates directly into carbon monoxide (CO); the produced hydrogen atoms (H) begin to desorb near 125 K whereas most of the CO desorbs above 240 K. The reaction exhibits a significant dependence on the Au coverage: the produced CO increases in quantity with the Au coverage, reaches a maximum at about 1.0-1.5 ML Au, whereas decreases with further increase of the Au coverage. The coverage-dependence is rationalized partly by an altered number of reactive sites associated with low-coordinated Au in the clusters. At least two kinds of reactive sites for the low-temperature decomposition are distinguished through distinct C-O stretching frequencies (2050 cm(-1) and 2092 cm(-1)) while the produced CO co-adsorbs with H and methanol. PMID- 21264395 TI - Unfolding and refolding details of lysozyme in the presence of beta-casein micelles. AB - In this work, we selected a small globular protein, lysozyme, to study how it unfolds and refolds in the presence of micelles composed of the unstructured beta casein proteins by using microcalorimetry and circular dichroism spectroscopy. It was found that a partially unfolded structure of lysozyme starts to form when the beta-casein/lysozyme molar ratio is above 0.7, and the structure forms exclusively when the beta-casein/lysozyme molar ratio is above 1.6. This partially unfolded state of lysozyme loses most of its tertiary structure and after heating, the denatured lysozyme molecules are trapped in the charged coatings of beta-casein micelles and cannot refold upon cooling. The thus obtained protein complex can be viewed as a kind of special polyelectrolyte complex micelle. The net charge ratios of the two proteins and the ionic strength of the dispersions can significantly modulate the electrostatic and hydrophobic interactions between the two proteins. Our present work may have implications for the nanoparticle protein engineering therapy in the biomedicine field and may provide a better understanding of the principles governing the protein-protein interactions. Besides, the heating-cooling-reheating procedure employed in this work can also be used to study the unfolding and refolding details of the target protein in other protein-protein, protein-polymer and protein-small solute systems. PMID- 21264396 TI - Cryogenic plasmas for controlled processing of nanoporous materials. AB - Plasma processing at cryogenic temperatures tremendously suppresses the depth penetration of plasma radical species within nanoporous materials. We demonstrate that this confining effect is surprisingly unrelated to changes in the phase diffusivity of radical species gas, but is determined by the increase of the sticking coefficient and the radical recombination and reaction factors, favoring an early irreversible surface adsorption of the plasma radical species. PMID- 21264397 TI - Reactive resonances in the F + CHD3 reaction--a quantum dynamics study. AB - We present quantum dynamical investigations into the F + CHD(3) reaction. In our reduced dimensionality study we treat the two most important degrees of freedom, which describe the bond making and bond breaking explicitly, while treating the remaining spectator modes adiabatically. Cumulative as well as final state resolved reaction probabilities and cross sections are calculated for the two isotopic channels F + CHD(3) -> FH + CD(3) and F + CHD(3) -> FD + CHD(2). Our theoretical results are compared to the experimental findings of Liu and co workers [Zhou et al., Mol. Phys., 2010, 108, 957]. Potential resonance states in the low collision energy regime are analyzed in detail employing Smith's lifetime matrix and bound state calculations. PMID- 21264398 TI - Hyaluronan metabolism in remodeling extracellular matrix: probes for imaging and therapy of breast cancer. AB - Clinical and experimental evidence increasingly support the concept of cancer as a disease that emulates a component of wound healing, in particular abnormal stromal extracellular matrix remodeling. Here we review the biology and function of one remodeling process, hyaluronan (HA) metabolism, which is essential for wound resolution but closely linked to breast cancer (BCA) progression. Components of the HA metabolic cycle (HAS2, SPAM1 and HA receptors CD44, RHAMM/HMMR and TLR2) are discussed in terms of their known functions in wound healing and in breast cancer progression. Finally, we discuss recent advances in the use of HA-based platforms for developing nanoprobes to image areas of active HA metabolism and for therapeutics in breast cancer. PMID- 21264399 TI - Nanobubble and nanodroplet template growth of particle nanorings versus nanoholes in drying nanofluids and polymer films. AB - Here we demonstrate how confined nanobubbles and nanodroplets, which can either form spontaneously at the suspension/substrate interface, or can more interestingly be purposely introduced in the system, allow assembly of nanoparticles (NPs) into nanoring-like structures with a flexible control of both the size and distribution. As with most wetting-mediated nanopatterning methods, this approach provides an alternative to direct replication from templates. The formation of two-dimensional ring-shaped nanostructures was obtained by drying a nanocolloidal gold (Au) suspension drop confining nanobubbles (or nanodroplets) that are settled at a solid substrate. AFM investigation of the dry nanostructures showed the formation of isolated Au NPs rings having diameters ranging from 200 nm to 500 nm along the dewetting-drying path of the suspension drop. The flexibility of these wetting processes for the variation of the spatial features of the nanoring (size and shape resolution) essentially depends on physical parameters such as the nanobubble/nanodroplet size and concentration, the wettability, and the evaporation rate of the nanofluid drop on the substrate. Furthermore, we show that the underpinning mechanism of this evaporation-assisted assembly of Au NPs into supported functional nanoring patterns is fairly similar to that at work in the spontaneous formation of nanoholes in drying polymer thin films. Finally, the method proves to be a simple and flexible nanofabrication tool to be extended to various nanosize objects, towards specific optical and sensing applications. PMID- 21264400 TI - Highly enantioselective synthesis of syn-aldols of cyclohexanones via chiral primary amine catalyzed asymmetric transfer aldol reactions in ionic liquid. AB - Chiral primary-tertiary diamine/TfOH was found to catalyze kinetic resolution of racemic syn-aldols of cyclohexanones in ionic liquid effectively, affording the chiral syn-aldols with up to 99:1 syn/anti and 99% ee. PMID- 21264401 TI - Time-resolved velocity map imaging of methyl elimination from photoexcited anisole. AB - To date, H-atom elimination from heteroaromatic molecules following UV excitation has been extensively studied, with the focus on key biological molecules such as chromophores of DNA bases and amino acids. Extending these studies to look at elimination of other non-hydride photoproducts is essential in creating a more complete picture of the photochemistry of these biomolecules in the gas-phase. To this effect, CH(3) elimination in anisole has been studied using time-resolved velocity map imaging (TR-VMI) for the first time, providing both time and energy information on the dynamics following photoexcitation at 200 nm. The extra dimension of energy afforded by these measurements has enabled us to address the role of pisigma* states in the excited state dynamics of anisole as compared to the hydride counterpart (phenol), providing strong evidence to suggest that only CH(3) fragments eliminated with high kinetic energy are due to direct dissociation involving a (1)pisigma* state. These measurements also suggest that indirect mechanisms such as statistical unimolecular decay could be contributing to the dynamics at much longer times. PMID- 21264402 TI - Immobilization of bio-macromolecules on self-assembled monolayers: methods and sensor applications. AB - Attachment of biomolecules on gold, silicon or glass surfaces has direct implications for the development of novel biosensors in the context of nanoscale detection of pathogens and other metabolites related to issues of human health. In this critical review, we have highlighted the current developments in various techniques of immobilization of biomolecules, specifically biological macromolecules on surfaces through the modification of a functional self assembled monolayer. The utility of such immobilized biomolecules in the area of biosensing in nanoscale has been surveyed. Merits and demerits of some of the methods with reference to sensitivity of detection and practical use have been discussed (221 references). PMID- 21264403 TI - pep2pro: a new tool for comprehensive proteome data analysis to reveal information about organ-specific proteomes in Arabidopsis thaliana. AB - pep2pro is a comprehensive proteome analysis database specifically suitable for flexible proteome data analysis. The pep2pro database schema offers solutions to the various challenges of developing a proteome data analysis database and because data integrated in pep2pro are in relational format, it enables flexible and detailed data analysis. The information provided here will facilitate building proteome data analysis databases for other organisms or applications. The capacity of the pep2pro database for the integration and analysis of large proteome datasets was demonstrated by creating the pep2pro dataset, which is an organ-specific characterisation of the Arabidopsis thaliana proteome containing 14 522 identified proteins based on 2.6 million peptide spectrum assignments. This dataset provides evidence of protein expression and reveals organ-specific processes. The high coverage and density of the dataset are essential for protein quantification by normalised spectral counting and allowed us to extract information that is usually not accessible in low-coverage datasets. With this quantitative protein information we analysed organ- and organelle-specific sub proteomes. In addition we matched spectra to regions in the genome that were not predicted to have protein coding capacity and provide PCR validation for selected revised gene models. Furthermore, we analysed the peptide features that distinguish detected from non-detected peptides and found substantial disagreement between predicted and detected proteotypic peptides, suggesting that large-scale proteomics data are essential for efficient selection of proteotypic peptides in targeted proteomics surveys. The pep2pro dataset is available as a resource for plant systems biology at www.pep2pro.ethz.ch. PMID- 21264405 TI - Inherently aligned microfluidic electrodes composed of liquid metal. AB - This paper describes the fabrication and characterization of microelectrodes that are inherently aligned with microfluidic channels and in direct contact with the fluid in the channels. Injecting low melting point alloys, such as eutectic gallium indium (EGaIn), into microchannels at room temperature (or just above room temperature) offers a simple way to fabricate microelectrodes. The channels that define the shape and position of the microelectrodes are fabricated simultaneously with other microfluidic channels (i.e., those used to manipulate fluids) in a single step; consequently, all of the components are inherently aligned. In contrast, conventional techniques require multiple fabrication steps and registration (i.e., alignment of the electrodes with the microfluidic channels), which are technically challenging. The distinguishing characteristic of this work is that the electrodes are in direct contact with the fluid in the microfluidic channel, which is useful for a number of applications such as electrophoresis. Periodic posts between the microelectrodes and the microfluidic channel prevent the liquid metal from entering the microfluidic channel during injection. A thin oxide skin that forms rapidly and spontaneously on the surface of the metal stabilizes mechanically the otherwise low viscosity, high surface tension fluid within the channel. Moreover, the injected electrodes vertically span the sidewalls of the channel, which allows for the application of uniform electric field lines throughout the height of the channel and perpendicular to the direction of flow. The electrodes are mechanically stable over operating conditions commonly used in microfluidic applications; the mechanical stability depends on the magnitude of the applied bias, the nature of the bias (DC vs. AC), and the conductivity of the solutions in the microfluidic channel. Electrodes formed using alloys with melting points above room temperature ensure mechanical stability over all of the conditions explored. As a demonstration of their utility, the fluidic electrodes are used for electrohydrodynamic mixing, which requires extremely high electric fields (~10(5) V m(-1)). PMID- 21264406 TI - Prion protein expression level alters regional copper, iron and zinc content in the mouse brain. AB - The central role of the prion protein (PrP) in a family of fatal neurodegenerate diseases has garnered considerable research interest over the past two decades. Moreover, the role of PrP in neuronal development, as well as its apparent role in metal homeostasis, is increasingly of interest. The host-encoded form of the prion protein (PrP(C)) binds multiple copper atoms via its N-terminal domain and can influence brain copper and iron levels. The importance of PrP(C) to the regulation of brain metal homeostasis and metal distribution, however, is not fully understood. We therefore employed synchrotron-based X-ray fluorescence imaging to map the level and distributions of several key metals in the brains of mice that express different levels of PrP(C). Brain sections from wild-type, prion gene knockout (Prnp(-/-)) and PrP(C) over-expressing mice revealed striking variation in the levels of iron, copper, and even zinc in specific brain regions as a function of PrP(C) expression. Our results indicate that one important function of PrP(C) may be to regulate the amount and distribution of specific metals within the central nervous system. This raises the possibility that PrP(C) levels, or its activity, might regulate the progression of diseases in which altered metal homeostasis is thought to play a pathogenic role such as Alzheimer's, Parkinson's and Wilson's diseases and disorders such as hemochromatosis. PMID- 21264404 TI - Cancer evolution and individual susceptibility. AB - Cancer susceptibility is due to interactions between inherited genetic factors and exposure to environmental carcinogens. The genetic component is constituted mainly by weakly acting low-penetrance genetic variants that interact among themselves, as well as with the environment. These low susceptibility genes can be categorized into two main groups: one includes those that control intrinsic tumor cell activities (i.e. apoptosis, proliferation or DNA repair), and the other contains those that modulate the function of extrinsic tumor cell compartments (i.e. stroma, angiogenesis, or endocrine and immune systems). Genome Wide Association Studies (GWAS) of human populations have identified numerous genetic loci linked with cancer risk and behavior, but nevertheless the major component of cancer heritability remains to be explained. One reason may be that GWAS cannot readily capture gene-gene or gene-environment interactions. Mouse model approaches offer an alternative or complementary strategy, because of our ability to control both the genetic and environmental components of risk. Recently developed genetic tools, including high-throughput technologies such as SNP, CGH and gene expression microarrays, have led to more powerful strategies for refining quantitative trait loci (QTL) and identifying the critical genes. In particular, the cross-species approaches will help to refine locations of QTLs, and reveal their genetic and environmental interactions. The identification of human tumor susceptibility genes and discovery of their roles in carcinogenesis will ultimately be important for the development of methods for prediction of risk, diagnosis, prevention and therapy for human cancers. PMID- 21264407 TI - Facile synthesis of zirconium phosphonate-functionalized magnetic mesoporous silica microspheres designed for highly selective enrichment of phosphopeptides. AB - In this work, we present a facile approach for the synthesis of zirconium phosphate (ZrP)-functionalized magnetic silica mesoporous microspheres for the selective enrichment of phosphopeptides. At first, magnetic mesoporous silica microspheres were prepared by directly coating mesoporous silica onto Fe3O4 magnetic microspheres, and then addition of phosphate onto the magnetic mesoporous silica microspheres was performed using 3-(trihydroxysilyl)propyl methylphosphate. The obtained phosphate-modified magnetic mesoporous microspheres were monodispersed with a mean diameter of 350 nm, and had an obvious mesoporous silica shell (~65 nm). Finally, the resultant phosphate-functionalized magnetic mesoporous microspheres were incubated in ZrOCl2 solution with gentle stirring overnight for the loading of Zr4+ cations. The obtained Zr4+-functionalized materials were applied to the selective enrichment of phosphopeptides from both standard protein digestion and real samples. The enriched peptides were analyzed by MALDI-TOF MS and LC-ESI MS. Experimental results demonstrated that zirconium phosphonate-modified magnetic mesoporous silica microspheres show excellent potential for the selective enrichment of phosphopeptides. PMID- 21264408 TI - Asymmetric synthesis of Pachastrissamine (Jaspine B) and its diastereomers via eta3-allylpalladium intermediates. AB - A short route for the synthesis of Pachastrissamine (Jaspine B), an anhydrosphingosine derivative, and all three of its diastereomers is presented. The route consists of only 9 steps from the commercially available Garner's aldehyde. The furan framework is formed via an eta(3)-allylpalladium intermediate. PMID- 21264409 TI - TBAF-catalysed silver oxide-mediated cross-coupling of functional trimethysilylpyridines: access to arylpyridines and bihetaryl compounds. AB - The concomitant use of silver oxide and catalytic amount of TBAF allowed the efficient and chemoselective coupling of readily available 4-chloro- and 4-methyl 2-trimethyl-silyl-pyridines with heteroaromatic and aromatic halides. Based on control experiments, a mechanism involving the formation of a pyridylsilver intermediate and TBAF recycling is postulated. PMID- 21264410 TI - Functionalized guanidinium chloride based colourimetric sensors for fluoride and acetate: single crystal X-ray structural evidence of -NH deprotonation and complexation. AB - A series of new symmetrically functionalized guanidinium chlorides (S1-S10) are synthesized in good yields and their sensing ability toward anions is studied in MeCN-DMF (24 : 1) (v/v). The absorption bands of these molecules in the presence of anions are tuned by varying the functional groups attached to the guanidinium moiety (which resembles urea) with respect to (i) aromaticity (S1-S4), (ii) electron induction effect (S1, S5-S9), (iii) positional isomeric effect (S7-S9), (iv) indole functionality (S10) of the conjugated aryl units. Anions that are above Cl(-) in the Hofmeister series (F(-), AcO(-), H(2)PO(4)(-)) are eligible as an analyte in this series of molecules whereas less basic anions than Cl(-) do not cause any interference. Thus, this series of molecules are suitable for the detection of anions in the narrow window of the Hofmeister series. Out of all the anions, only fluoride causes vivid colour changes from yellow to red to reddish orange and finally to blue, irrespective of the increasing aromaticity, induction and positional isomeric effect of the substituent that is attached to the guanidinium moiety. Interestingly, S9 has shown the ability to sense distinctly both F(-) and AcO(-) colourimetrically. Further S10, a sensor attached with indole functionality shows selective sensing of F(-) colourimetrically with a NIR signature at ~930 nm though both these outputs are very unstable in nature. Stability constants for complex formation of S1-S10 (except S5) with F(-), AcO(-) are calculated by UV-vis titration experiments. Finally single crystal X-ray structural studies on the species 1 formed upon treating S6 with sodium fluoride confirms -NH deprotonation, whereas the reaction of S6 and S2 with sodium benzoate shows 1:1 host:guest binding that results in complexes 2 and 3 respectively. PMID- 21264414 TI - Electrochemical detection of interaction between Thioflavin T and acetylcholinesterase. AB - The electrochemical oxidation of the benzothiazole dye Thioflavin T (ThT) was found to be modulated by its interaction with electric eel acetylcholinesterase (AChE). Modifications of AChE by trace amounts of small molecule inhibitors such as carbachol and paraoxon were detectable electrochemically using minimal reagents and with greater sensitivity than attainable through conventional fluorescence approaches. This property appears to be unique to ThT, since its closely related neutral derivative BTA-1 only interacts with AChE, but is not significantly affected by the presence of small molecule inhibitors. PMID- 21264415 TI - Highly regio- and stereoselective synthesis of alkenylboronic esters by copper catalyzed boron additions to disubstituted alkynes. AB - The copper-catalyzed addition of bis(pinacolato)diboron to internal alkynes in the presence of methanol generates alkenylboron compounds with high levels of regio- and stereoselectivities. The catalytic efficiency is increased by using monodentate phosphine ligands, especially P(p-tolyl)(3) and a range of internal alkynes was borylated in good yields. PMID- 21264416 TI - Mechanism of the oxidation of organic dyes in the presence of nanoceria. AB - A detailed mechanistic study reveals that instead of being postulated as oxidase like, nanoceria is a plain nanoparticulate oxidant and dissolves completely after being reduced. PMID- 21264417 TI - A remarkably flexible and selective receptor for Ba2+ amplified from a hydrazone dynamic combinatorial library. AB - A new [2+2] tetra-hydrazone macrocyclic receptor was significantly amplified in a dynamic combinatorial library upon templation with alkaline earth metal ions. After optimisation the product could be isolated in 95% yield and its interaction with ions was investigated by NMR and UV-Vis spectroscopy. PMID- 21264418 TI - Nitric oxide reversibly inhibits Bacillus subtilis oxalate decarboxylase. AB - Membrane inlet mass spectrometry (MIMS) has been employed to assay the catalytic activity of oxalate decarboxylase (OxDC), allowing us to demonstrate that nitric oxide (NO) reversibly inhibits the enzyme under dioxygen-depleted conditions. X band EPR measurements do not provide any direct evidence for the interaction of NO with either of the Mn(II) centers in OxDC raising the possibility that there is a separate dioxygen-binding pocket in the enzyme. PMID- 21264419 TI - A biomimetic approach to the cylindrospermopsin alkaloids. AB - The tethered Biginelli condensation between hemiaminal 21 and beta-keto ester 22 is reported, leading to a model tricyclic core of the cylindrospermopsin alkaloids. PMID- 21264420 TI - Nickel-catalyzed reductive cleavage of aryl-oxygen bonds in alkoxy- and pivaloxyarenes using hydrosilanes as a mild reducing agent. AB - A nickel-catalyzed reductive deoxygenation of aryl alkyl ethers and aryl pivalates has been developed. Hydrosilanes serve as a mild reducing agent. The present protocol allows the use of a pivalate group as a robust and traceless steering group in arene functionalization reactions. PMID- 21264421 TI - Compilation of all the isothermal mass/charge transport properties of the mixed conducting La2NiO(4+delta) at elevated temperatures. AB - It is known [H.-S. Kim and H.-I. Yoo, Phys. Chem. Chem. Phys., DOI:10.1039/c0cp00722f] that all the isothermal mass and charge transport properties of a mixed ionic electronic conductor compound can be universally represented by a 2 * 2 Onsager transport coefficient matrix. Furthermore, the three independent coefficients of the matrix can be determined from a simple relaxation experiment under the ion-blocking condition in association with the equation of state with respect to the nonstoichiometry or thermodynamic factor. By using this method, we compile the transport matrices at 800 degrees C, 900 degrees C and 1000 degrees C, respectively, on the system of La(2)NiO(4+delta) across its entire stability range, and calculate thereby its transport properties to compare with the literature values available. The interference effect between mobile oxygen ions and holes upon their transfer is discussed. PMID- 21264422 TI - A recyclable perfluoroalkylated PCP pincer palladium complex. AB - A new fluorous PCP pincer ligand has been coordinated to Ni(II), Pd(II) and Pt(II). The air stable palladium complex, which promotes Heck reactions between methyl acrylate and either aryl bromides or iodides, can be recovered intact by fluorous solid-phase extraction and was reused four times in the Heck reaction between methyl acrylate and 4-bromoacetophenone without loss in catalytic activity. PMID- 21264423 TI - Three 2D Ag(I)-framework isomers with helical structures controlled by the chirality of camphor-10-sulfonic acid. AB - Three 2D Ag(I)-framework isomers were constructed from enantiopure camphor-10 sulfonic acids or racemic camphor-10-sulfonic acids, together with achiral 4 aminobenzoic acids. In complex 1, (+)-camphor-10-sulfonic acids bridge the single left-handed helices that are made up of Ag ions and 4-aminobenzoic acids, generating a homochiral 2D layer. In such a structure, the interweaving of triple left-handed homohelices was also found. It is worth noting that the helicity of complex 2 could be controlled by the handedness of the camphor-10-sulfonic acid. In complex 2, there are right-handed helical structures, including single right handed and triple right-handed helical structures connected by (-)-camphor-10 sulfonic acids. For a comparative study, (+/-)-camphor-10-sulfonic acids were utilized to synthesize complex 3, in which equal numbers of right-handed or left handed double-helical chains are created. All the complexes were characterized by single-crystal X-ray structure determination, powder X-ray diffraction, IR, TGA and element analysis. Circular dichroism spectra of complexes 1 and 2 were been studied to confirm the fact that enantiopure bridging ligands do not racemize. PMID- 21264424 TI - Nucleophilic reactivity of a series of peroxomanganese(III) complexes supported by tetradentate aminopyridyl ligands. AB - Peroxomanganese(iii) adducts have been postulated as important intermediates in manganese-containing enzymes and small molecule oxidation catalysts. Synthetic peroxomanganese(iii) complexes are known to be nucleophilic and facilitate aldehyde deformylation, offering a convenient way to compare relative reactivities of complexes supported by different ligands. In this work, tetradentate dipyridyldiazacycloalkane ligands with systematically perturbed steric and electronic properties were used to generate a series of manganese(ii) and peroxomanganese(iii) complexes. X-Ray crystal structures of five manganese(ii) complexes all show the ligands bound to give trans complexes. Treatment of these Mn(II) precursors with H(2)O(2) and Et(3)N in MeCN at -40 degrees C results in the formation of peroxomanganese(iii) complexes that differ only in the identity of the pyridine ring substituent and/or the number of carbons in the diazacycloalkane backbone. To determine the effects of small ligand perturbations on the reactivity of the peroxo group, the more thermally stable peroxomanganese(iii) complexes were reacted with cyclohexanecarboxaldehyde. For these complexes, the rate of deformylation does not correlate with the expected nucleophilicity of the peroxomanganese(iii) unit, as the inclusion of methyl substituents on the pyridines affords slower deformylation rates. It is proposed that adding methyl-substituents to the pyridines, or increasing the number of carbons on the diazacycloalkane, sterically hinders nucleophilic attack of the peroxo ligand on the carbonyl carbon of the aldehyde. PMID- 21264425 TI - Ambient concentrations of airborne endotoxin in two cities in the interior of British Columbia, Canada. AB - This study measured and analyzed the outdoor airborne endotoxin concentration, on particulate matter (PM2.5 and PM10), for two cities in the interior of British Columbia, Canada. Samples were collected throughout one seasonal cycle, from October 2005 to September 2006. It was found that concentrations were generally highest in the summer and fall, and lowest in the winter and spring. Temperature and relative humidity were found to be most influential, with highest endotoxin concentrations recorded during warm periods and moderate relative humidity (35 to 75 percent). No clear association of concentration with wind direction was observed. Results were comparable between the two cities considered in this study, and concentrations were similar to or slightly higher than those reported by other studies considering urban locations. Endotoxin concentration was also found to be positively associated with agricultural dust sources identified by a source apportionment study conducted at one of the sampling locations. PMID- 21264426 TI - Producing a superhydrophobic paper and altering its repellency through ink-jet printing. AB - A new method for making superhydrophobic (SH) paper based on spraying a nanocomposite film is developed. Furthermore, manipulating the wetting characteristics of SH paper has been demonstrated through a new method, i.e. printing solid grey patterns of different intensities with simple printing technology (home or office grade ink-jet and laser printers). It has been found that for a range of ink intensities (0-85%), water drop mobility can be changed at a different rate (almost independently) from repellency. The repellency of water decreases minimally up to 85% ink intensity with a sharp decrease up to 100% ink intensity. Drop mobility remains constant up to 30% ink intensity with a steady decrease up to 100% ink intensity. It was observed that using ink-jet or laser printing would yield different results for the change of mobility or repellency with higher amounts of ink/toner used. Being able to achieve almost independent control of water drop mobility over water drop repellency on SH paper would allow inexpensive lab-on-paper devices to be used for sampling, mixing and transport of liquids. PMID- 21264427 TI - Characterization of the recombinant copper chaperone (CCS) from the plant Glycine (G.) max. AB - The goal of the present work was to characterize the recombinant copper chaperone (CCS) from soybean. Very little is known about plant copper chaperones, which makes this study of current interest, and allows for a comparison with the better known homologues from yeast and humans. To obtain sizeable amounts of pure protein suitable for spectroscopic characterization, we cloned and overexpressed the G. max CCS chaperone in E. coli in the presence of 0.5 mM CuSO(4) and 0.5 mM ZnSO(4) in the broth. A pure protein preparation was obtained by using two IMAC steps and pH gradient chromatography. Most of the proteins were obtained as apo form, devoid of copper atoms. The chaperone showed a high content (i.e., over 40%) of loops, turns and random coil as determined both by circular dichroism and homology modelling. The homology 3-D structural model suggests the protein might fold in three structural protein domains. The 3-D model along with the primary structure and spectroscopic data may suggest that copper atoms occupy the two metal binding sites, MKCEGC and CTC, within the N-terminal domain I and C terminal domain III, respectively. But only one Zn-binding site was obtained spectroscopically. PMID- 21264428 TI - Albumin-directed stereoselective reduction of 1,3-diketones and beta hydroxyketones to anti diols. AB - The reduction of 1,3-diketones and beta-hydroxyketones with NaBH(4) in aqueous acetonitrile is highly stereoselective in the presence of stoichiometric amounts of bovine or human albumin, giving anti 1,3-diols with d.e. up to 96%. The same reaction, without albumin, gives syn and anti 1,3-diols in approximately 1:1 ratio. The presence of an aromatic carbonyl group is essential for diastereoselectivity in the NaBH(4)/albumin reduction of both 1,3-diketones and beta-hydroxyketones. Thus, 3-hydroxy-1-(p-tolyl)-1-butanone is stereoselectively reduced in the presence of albumin, while reduction of its isomer 4-(p-tolyl)-4 hydroxy-2-butanone is not stereoselective. The albumin-controlled reduction is not stereospecific as both enantiomers of 1-aryl-3-hydroxy-1-butanones are reduced to diols with identical stereoselectivities. Circular dichroism of the bound substrates confirms that aromatic ketones are recognized by the protein's IIA binding site. Binding studies also suggest that 1,3-diketones are recognized in their enol form. From the effect of pH on binding of a diketone it is concluded that, in the complex with the substrate, ionizable residues His242 and Lys199 are in the neutral and protonated forms, respectively. A homology model of BSA was obtained and docking of model substrates confirms the preference of the protein for aromatic ketones. Modelling of the complexes with the substrates also allows us to propose a mechanism for the reduction of 1,3-diketones in which the chemoselective reduction of the first (aliphatic) carbonyl is followed by the diastereoselective reduction of the second (aromatic) carbonyl. The role of albumin is thus a combination of chemo- and stereocontrol. PMID- 21264429 TI - Synthesis and structural characterization of tris(2-oxo-1-tert-butylimidazolyl) and tris(2-oxo-1-methylbenzimidazolyl)hydroborato complexes: a new class of tripodal oxygen donor ligand. AB - A new class of tripodal L(2)X ligands that feature three oxygen donors, namely the tris(2-oxo-1-tert-butylimidazolyl) and tris(2-oxo-1 methylbenzimidazolyl)hydroborato ligands, [To(Bu(t))] and [To(MeBenz)], has been synthesized via the reactions of NaBH(4) with the respective imidazolone. Structural and spectroscopic studies indicate that both [To(Bu(t))] and [To(MeBenz)] are significantly more sterically demanding but less electron donating than the related [O(3)] donor ligand, [CpCo{P(O)(OEt)(2)}(3)]. PMID- 21264430 TI - Vicinal dichlorine elimination at dichloroalkenes promoted by a well-defined iron(0) complex. AB - Dechlorination reactions at sp(2) C-Cl bonds by a pentaphosphino zero-valent iron (ZVI) complex are proposed to follow an oxidative addition, beta-Cl-elimination pathway en route to iron-chloride, iron-hydride and iron-acetylide products, the distribution being dependent on the nature of alkyne produced. PMID- 21264431 TI - Photochemical and photosensitised reactions involving 1-nitronaphthalene and nitrite in aqueous solution. AB - The excited triplet state of 1-nitronaphthalene, 1NN, ((3)1NN) is able to oxidise nitrite to NO(2), with a second-order rate constant that varies from (3.56 +/- 0.11) * 10(8) M(-1) s(-1) (MU+/-sigma) at pH 2.0 to (3.36 +/- 0.28) * 10(9) M(-1) s(-1) at pH 6.5. The polychromatic quantum yield of NO(2) photogeneration by 1NN in neutral solution is Phi(NO(2))(1NN)>= (5.7 +/- 1.5) * 10(7)* [NO(2)(-)]/{(3.4 +/- 0.3) * 10(9)* [NO(2)(-)] + 6.0 * 10(5)} in the wavelength interval of 300-440 nm. Irradiated 1NN is also able to produce OH, with a polychromatic quantum yield Phi(OH)(1NN) = (3.42 +/- 0.42) * 10(-4). In the presence of 1NN and NO(2)( )/HNO(2) under irradiation, excited 1NN (probably its triplet state) would react with NO(2) to yield two dinitronaphthalene isomers, 15DNN and 18DNN. The photonitration of 1NN is maximum around pH 3.5. At higher pH the formation rate of NO(2) by photolysis of NO(2)(-)/HNO(2) would be lower, because the photolysis of nitrite is less efficient than that of HNO(2). At lower pH, the reaction between (3)1NN and NO(2) is probably replaced by other processes (involving e.g.(3)1NN-H(+)) that do not yield the dinitronaphthalenes. PMID- 21264432 TI - Effect of electrolytes, nucleotides and DNA on the fluorescence of flavopereirine natural alkaloid. AB - The absorption and fluorescence characteristics of flavopereirine, a pharmaceutically important natural alkaloid, were studied to reveal how the complex formation and the change of the microenvironment affect the deactivation kinetics from the singlet-excited state. The fluorescence lifetime was not influenced by the ionic strength, but a significant deuterium effect was observed showing that hydrogen bonding in the singlet-excited state promoted energy dissipation. Nucleotides caused both static and dynamic quenching. The rate constant of the latter process increased when the nucleobase was capable of donating electron to the excited flavopereirine. The spectrophotometric measurements provided evidence for non-cooperative binding to double-stranded DNA with an equilibrium constant of 4.6 * 10(5) M(-1). Time-resolved fluorescence signals showed that three kinds of complexes are formed with distinct fluorescence lifetimes. Flavopereirine binding to chondroitin sulfate was also found, which led to different fluorescence characteristics at pH 2 and 6. PMID- 21264433 TI - Silver residues as a possible key to a remarkable oxidative catalytic activity of nanoporous gold. AB - Recently, several forms of unsupported gold were shown to display a remarkable activity to catalyze oxidation reactions. Experimental evidence points to the crucial role of residual silver present in very small concentrations in these novel catalysts. We focus on the catalytic properties of nanoporous gold (np-Au) foams probed via CO and oxygen adsorption/co-adsorption. Experimental results are analyzed using theoretical models represented by the flat Au(111) and the kinked Au(321) slabs with Ag impurities. We show that Ag atoms incorporated into gold surfaces can facilitate the adsorption and dissociation of molecular oxygen on them. CO adsorbed on top of 6-fold coordinated Au atoms can in turn be stabilized by co-adsorbed atomic oxygen by up to 0.2 eV with respect to the clean unsubstituted gold surface. Our experiments suggest a linking of that most strongly bound CO adsorption state to the catalytic activity of np-Au. Thus, our results shed light on the role of silver admixtures in the striking catalytic activity of unsupported gold nanostructures. PMID- 21264434 TI - Mechanically interlocked gold and silver nanoparticles using metallosupramolecular catenane chemistry. AB - We have employed the toolbox of metallosupramolecular chemistry to mechanically interlock gold and silver nanoparticles. A specifically designed PEGthiol functionalized bis(phenanthroline)copper(I) complex acts to 'catenate' the nanoparticles. The interlocked assemblies were characterised by three complementary techniques: DLS, SERS and TEM. PMID- 21264435 TI - Composition tuning the upconversion emission in NaYF4:Yb/Tm hexaplate nanocrystals. AB - Single crystal hexagonal NaYF4:Yb/Tm nanocrystals have been synthesized with uniform size, morphology and controlled chemical composition. Spectroscopic studies show that these nanocrystals exhibit strong energy upconversion emission when excited with a 980 nm diode laser, with two primary emission peaks centered around 452 nm and 476 nm. Importantly, the overall and relative emission intensity at these wavelengths can be readily tuned by controlling the concentration of the trivalent rare earth element dopants at the beginning of the synthesis which has been confirmed by EDX for the first time. Through systematic studies, the optimum rare earth ion doping concentration can be determined for the strongest emission intensity at the selected peak(s). Confocal microscopy studies show that the upconversion emission from individual NCs can be readily visualized. These studies demonstrate a rational approach for fine tuning the upconversion properties in rare-earth doped nanostructures and can broadly impact areas ranging from energy harvesting, energy conversion to biomedical imaging and therapeutics. PMID- 21264436 TI - Room-temperature ferromagnetism in graphitic petal arrays. AB - We report room-temperature ferromagnetism of graphitic petal arrays grown on Si substrates by microwave plasma chemical vapor deposition without catalyst. The samples have been characterized by Raman and X-ray photoelectron spectroscopy to confirm the absence of possible ferromagnetic impurities. The petals exhibit ferromagnetic hysteresis with saturation magnetization of ~4.67 emu cm(-3) and coercivity of ~105 Oe at 300 K, comparable to the reported behavior of few-layer graphene. Upon O2 annealing the saturation magnetization and coercivity decreased to 2.1 emu cm(-3) and ~75 Oe respectively. The origin of ferromagnetism is believed to arise from the edge defects and vacancies in the petals. PMID- 21264437 TI - Trajectory-based solution of the nonadiabatic quantum dynamics equations: an on the-fly approach for molecular dynamics simulations. AB - The non-relativistic quantum dynamics of nuclei and electrons is solved within the framework of quantum hydrodynamics using the adiabatic representation of the electronic states. An on-the-fly trajectory-based nonadiabatic molecular dynamics algorithm is derived, which is also able to capture nuclear quantum effects that are missing in the traditional trajectory surface hopping approach based on the independent trajectory approximation. The use of correlated trajectories produces quantum dynamics, which is in principle exact and computationally very efficient. The method is first tested on a series of model potentials and then applied to study the molecular collision of H with H(2) using on-the-fly TDDFT potential energy surfaces and nonadiabatic coupling vectors. PMID- 21264438 TI - Diameter-selective dispersion of double-walled carbon nanotubes by lysozyme. AB - We have utilized lysozyme to non-covalently functionalize and disperse double walled carbon nanotubes (DWNTs) in aqueous solution. Lysozyme preferentially binds and disperses DWNTs with larger diameters. This is a facile and effective method to fractionalize and enrich DWNTs with certain diameters. PMID- 21264439 TI - Highly sensitive routine method for urinary 3-hydroxybenzo[a]pyrene quantitation using liquid chromatography-fluorescence detection and automated off-line solid phase extraction. AB - Many workers and also the general population are exposed to polycyclic aromatic hydrocarbons (PAHs), and benzo[a]pyrene (BaP) was recently classified as carcinogenic for humans (group 1) by the International Agency for Research on Cancer. Biomonitoring of PAHs exposure is usually performed by urinary 1 hydroxypyrene (1-OHP) analysis. 1-OHP is a metabolite of pyrene, a non carcinogenic PAH. In this work, we developed a very simple but highly sensitive analytical method of quantifying one urinary metabolite of BaP, 3 hydroxybenzo[a]pyrene (3-OHBaP), to evaluate carcinogenic PAHs exposure. After hydrolysis of 10 mL urine for two hours and concentration by automated off-line solid phase extraction, the sample was injected in a column-switching high performance liquid chromatography fluorescence detection system. The limit of quantification was 0.2 pmol L(-1) (0.05 ng L(-1)) and the limit of detection was estimated at 0.07 pmol L(-1) (0.02 ng L(-1)). Linearity was established for 3 OHBaP concentrations ranging from 0.4 to 74.5 pmol L(-1) (0.1 to 20 ng L(-1)). Relative within-day standard deviation was less than 3% and relative between-day standard deviation was less than 4%. In non-occupationally exposed subjects, median concentrations for smokers compared with non-smokers were 3.5 times higher for 1-OHP (p<0.001) and 2 times higher for 3-OHBaP (p<0.05). The two urinary biomarkers were correlated in smokers (rho=0.636; p<0.05; n=10) but not in non smokers (rho=0.09; p>0.05; n=21). PMID- 21264440 TI - Cardiogenic shock due to dynamic left ventricular outflow tract obstruction of acute myocardial infarction: an under-diagnosed complication. AB - We report on a patient who developed cardiogenic shock caused by dynamic left ventricular outflow tract (LVOT) obstruction following percutaneous coronary intervention for anteroseptal acute myocardial infarction. PMID- 21264441 TI - Sentinel node mapping in the prostate cancer. Meta-analysis. AB - AIM: Sentinel node (SN) biopsy is becoming a standard procedure in the management of several malignancies. Several groups have evaluated the feasibility and value of this procedure in prostate cancer patients. In the current meta-analysis, we comprehensively and quantitatively summarized the results of these studies. METHODS: Several databases including Medline, SCOPUS, Google Scholar, Ovid, Springer, and Science direct were systematically searched for the relevant studies regarding SL biopsy in the prostate cancer ("prostate" AND "sentinel" as search keywords). The outcomes of interest were sensitivity and detection rate of the procedure. RESULTS: For detection rate and sensitivity 21 and 16 studies met the criteria of inclusion respectively. Pooled detection rate was 93.8% (95% CI 89-96.6%). Cochrane Q value was 216.077 (I2 = 89.81% and p < 0.001). Pooled sensitivity was 94% (95% CI 91-96%). Cochrane Q value was 14.12 (I2 = 0.0 and p = 0.516). CONCLUSION: SL biopsy can prevent unnecessary pelvic lymph node dissection in prostate cancer patients. This procedure is feasible with low false negative rate and high detection rate. PMID- 21264442 TI - Factor XII Osaka: abnormal factor XII with partially defective prekallikrein cleavage activity. AB - A healthy Japanese male had reduced factor XII (FXII) activity (35%) in contrast to normal antigen levels (81%). The F12 of this proband had a 9775G to C mutation in exon 10 and an 11276G to A mutation in exon 13 that resulted in two amino acid substitutions of Ala324Pro (GCG->CCG) in the proline-rich connecting region and Gly531Glu (GGG->GAG) near the active Ser544 in the catalytic domain. His father had the nucleotide 46T/T and a heterozygous 9775G/C mutation. The FXII activity (32%) and antigen level (38%) of the father were about half that of normal individuals with 46T/T, suggesting a heterozygous cross reacting material (CRM) negative deficiency. His mother had a 46C/T and heterozygous 11276G/A mutation, and 80% FXII activity was incompatible with the corresponding antigen level (125%), suggesting a heterozygous CRM-positive deficiency. The substitution of Ala324Pro probably caused the CRM-negative mutation and the Gly531Glu caused the CRM-positive mutation. We developed three methods based on chromogenic substrates to assay the distinct functions of FXII, namely its autoactivation on a negatively charged surface, activation by kallikrein cleavage and the prekallikrein cleavage activity of FXIIa. The ratios of autoactivated FXIIa/FXII antigen (0.80-1.10) and of kallikrein-induced FXIIa/FXII antigen (0.86-1.00) in plasma from the proband were within normal ranges, whereas those of FXIIa-induced kallikrein/FXII antigen were reduced to 0.41-0.45. In conclusion, the 9775G to C and 11276G to A mutations of F12 led to a CRM-negative and -positive FXII deficiency, and the F12 with 11276A produced a dysfunctional type of FXII with a partial defect (0.41-0.45) in prekallikrein cleavage activity. PMID- 21264443 TI - A clinical-laboratory algorithm incorporating optical density value to predict heparin-induced thrombocytopenia. AB - The diagnosis of heparin-induced thrombocytopenia (HIT) is complex and involves integrating both clinical and laboratory findings. Readily available diagnostic tests such as the heparin-dependant antibody assay (HDAA) lack desired specificity when utilised alone. A diagnostic algorithm incorporating the 4T pretest probability score, HDAA, and optical density (OD) value was implemented as a tool to assist in the diagnosis of HIT and with the decision to treat patients. Patients with a 4T score >3 and/or positive HDAA result with an OD >=1 were considered positive. Utilisation of this algorithm was hypothesised to improve the identification of patients without SRA confirmed HIT and improve overall specificity compared to other diagnostic strategies. Retrospective chart review was conducted and included patients with a positive or equivocal HDAA result and a serotonin release assay result during a two-year period. Each patient was evaluated for the diagnosis of HIT using the algorithm. The specificity and sensitivity of the diagnostic algorithm to identify subjects with SRA confirmed HIT was evaluated. A total of 83 patients were identified for inclusion in the study. The diagnostic algorithm identified 22 patients for direct thrombin inhibitor (DTI) therapy. Nine of these patients were SRA positive. The sensitivity of the algorithm was 0.9 with a specificity of 0.822. The diagnostic algorithm was found to be both more specific and sensitive than other diagnostic strategies including the 4T score alone, HDAA alone, and the combination of the 4T score and HDAA results. This preliminary data suggest a diagnostic algorithm combining 4T score, HDAA, and OD value may be a tool to aid in the identification SRA positive patients for DTI therapy. PMID- 21264444 TI - Monocytes: possible mediators of benefits and harms from physical activity? PMID- 21264445 TI - Extended evidence for association between the melanoma inhibitory activity 3 gene and myocardial infarction. AB - In a genome-wide scan, isolated single nucleotide polymorphisms (SNPs), including rs17465637, in the melanoma inhibitory activity 3 gene (MIA3) on chromosome 1 were identified to be associated with coronary artery disease and myocardial infarction (MI). Because the role of common variation at the MIA3 locus has not yet been investigated, the aim of this case-control study was to determine the impact of haplotype-tagging SNPs and haplotypes in the MIA3 region on the risk of MI. In a set of nine haplotype-tagging SNPs, rs17465637, but none of the other SNPs, was associated with MI. After adjustments were made for age, gender, history of arterial hypertension, history of hypercholesterolaemia, current cigarette smoking and diabetes mellitus, multiple logistic regression analyses showed an increased risk in the carriers of one or two C alleles [adjusted odds ratio (OR) 1.17, 95% confidence interval (CI) 1.04-1.32, and 1.37, 95% CI 1.08 1.74, respectively]. Nine common haplotypes (frequency >1%) were established across the MIA3 region. Two of the haplotypes were associated with an increased risk of MI: the frequent (48%) TGACCAAAG haplotype and the rare (2%) CGACCAAAG haplotype (adjusted OR 1.102, 95% CI 1.002-1.212, and 1.574, 95% CI 1.077-2.298, respectively). Showing association between rs17465637 and MI, this work was consistent with results from the original detection study and most prior replication studies addressing this issue. In addition to correspond with such isolated evidence of association with MI, the present study identified specific haplotypes capturing the risk-related variation in the entire MIA3 region. PMID- 21264446 TI - Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance. AB - Accelerated clearance of von Willebrand factor (VWF) has been recently identified as a major pathophysiologic mechanism inducing low VWF in some patients with von Willebrand disease (VWD). The frequency of bleeding and the best treatment of these patients have never been evaluated prospectively in large series of patients. It was the aim of the present study to prospectively evaluate clinical events of 60 heterozygous patients with VWD Vicenza (VWD-VI) carrying R1205H VWF mutation and 23 with C1130F mutation, both characterised by markedly increased VWF clearance. During 71 months of follow-up, 65% of patients with VWD-VI and 61% with C1130F required treatment. The rate of spontaneous bleeding requiring consultation/treatment was 7.5/100 patients-year in patients with C1130F mutation vs. 1.9/100 patients-year in those with R1205H (p=0.004). This difference persisted also by multivariate analysis adjusted for sex, age and blood group (hazard ratio [HR]=3.3 for C1130F, 95% confidence interval [CI] 1.16-9.27) and females were at greater risk of bleeding (HR=3, 95%CI 1.01-9.93) because of menorrhagia. Only 3/15 (20 %) women in fertile age with VWD-VI compared to 8/9 (89 %) with C1130F mutation required consultation/treatment for menorrhagia (iron supplementation, combined oral contraceptives, tranexamic acid). Almost all dental extractions, minor surgeries and deliveries occurring during follow-up were successfully managed with desmopressin. Major surgery required factor VIII/VWF concentrates, but a few cases benefited from desmopressin. In conclusion, similar to patients with type 1 VWD, also in patients with increased VWF clearance desmopressin maintains a major therapeutic role. PMID- 21264448 TI - The role of vitamin E (tocopherol) supplementation in the prevention of stroke. A meta-analysis of 13 randomised controlled trials. AB - It was the objective of this work to systematically evaluate the role of vitamin E supplementation in the prevention of stroke. Eligible studies were identified from Medline, Embase and Cochrane Library. The efficacy data is the relative risk (RR) for the events of stroke. Thirteen randomised controlled trials (RCTs), with 166,282 participants in total, were analysed. The pooled results showed no significant benefit in the vitamin E group with respect to stroke of any type (RR 1.01; 95% confidence interval [CI]: 0.96, 1.07); ischaemic stroke (RR 1.01; 95% CI: 0.94, 1.09), haemorrhagic stroke (RR 1.12; 95% CI: 0.94, 1.33), fatal stroke (RR 0.94; 95% CI: 0.77, 1.14), and non-fatal stroke (RR 0.99; 95% CI: 0.91, 1.08). Administration of vitamin E 300 IU/day or more also gain no benefit (RR 0.99; 95% CI: 0.92, 1.06), as well as vitamin E less than 300 IU (RR 1.05; 95% CI: 0.96, 1.15). Vitamin E supplementation gained benefit of preventing stroke for neither healthy people (0.92; 0.83, 1.03) nor others at high risks in baseline (RR 1.05; 95% CI: 0.98, 1.12). Administration of synthetic vitamin E gain no benefit (RR 1.02; 95% CI: 0.96, 1.09), as well as the natural source vitamin E (RR 0.99; 95% CI: 0.89, 1.09). In conclusion, there is a lack of statistically significant or clinically important benefit of vitamin E supplementation in the prevention of stroke. PMID- 21264449 TI - Molecular basis of antithrombin deficiency. AB - Antithrombin (AT) is the most important physiological inhibitor of coagulation proteases. It is activated by glycosaminoglycans such as heparin. Hereditary antithrombin deficiency is a rare disease that is mainly associated with venous thromboembolism. So far, more than 200 different mutations in the antithrombin gene (SERPINC1) have been described. The aim of our study was to characterise the molecular background in a large cohort of patients with AT deficiency. Mutation analysis was performed by direct sequencing of SERPINC1 in 272 AT-deficient patients. Large deletions were identified by multiplex PCR coupled with liquid chromatography or multiplex ligation-dependent probe amplification (MLPA) analysis. To predict the effect of SERPINC1 sequence variations on the pathogenesis of AT deficiency, in silico assessments, multiple sequence alignment, and molecular graphic imaging were performed. The mutation profile consisted of 59% missense, 10% nonsense, 8% splice site mutations, 15% small deletions/insertions/duplications, and 8% large deletions. Altogether 87 different mutations, including 42 novel mutations (22 missense and 20 null mutations), were identified. Of the novel missense mutations, nine are suspected to impair the conformational changes that are needed for AT activation, two to affect the central reactive loop or the heparin binding site, and six to impair the structural integrity of the molecule. Despite the heterogeneous background of AT deficiency, 10 AT variants occurred in multiple index patients. Characterisation of the SERPINC1 mutation profile in large cohorts of patients may help to further elucidate the pathogenesis of AT deficiency and to establish genotype-phenotype associations. PMID- 21264447 TI - Factor VIII delivered by haematopoietic stem cell-derived B cells corrects the phenotype of haemophilia A mice. AB - The main impediments to clinical application of haematopoietic stem cell (HSC) gene therapy for treatment of haemophilia A are the bone marrow transplant related risks and the potential for insertional mutagenesis caused by retroviral vectors. To circumvent these limitations, we have adapted a non-myeloablative conditioning regimen and directed factor VIII (FVIII) protein synthesis to B lineage cells using an insulated lentiviral vector containing an immunoglobulin heavy chain enhancer-promoter. Transplantation of lentiviral vector-modified HSCs resulted in therapeutic levels of FVIII in the circulation of all transplanted mice for the duration of the study (six months). Immunostaining of spleen cells showed that the majority of FVIII was synthesised by B220+ B cells and CD138+ plasma cells. Subsequent challenge with recombinant FVIII elicited at most a minor anti-FVIII antibody response, demonstrating induction of immune hyporesponsiveness. All transplant recipients exhibited clot formation and survived tail clipping, indicating correction of their haemophilic phenotype. Therapeutic levels of FVIII could be transferred to secondary recipients by bone marrow transplantation, confirming gene transfer into long-term repopulating HSCs. Moreover, short-term therapeutic FVIII levels could also be achieved in secondary recipients by adoptive transfer of HSC-derived splenic B cells. Our findings support pursuit of B cell-directed protein delivery as a potential clinical approach to treat haemophilia A and other disorders correctable by systemically distributed proteins. PMID- 21264451 TI - Patient education in chronic skin diseases: a systematic review. AB - The negative impact of skin disease on quality of life (QoL) has been described in many studies. Patient education as an adjunct to treatment, with the aim of improving QoL and reducing disease severity, is a relatively new technique in dermatology. The objective of this article is to analyse and summarise evidence concerning the effects of patient education on QoL and disease severity in patients with chronic skin diseases. All source material was identified through searches in MEDLINE and Embase. The CONSORT statement was used to assess the quality of reported randomised controlled studies. Ten of 254 studies met the inclusion criteria. In five of them, statistically significant improvements in QoL were reported. The severity of skin disease significantly improved in three studies. In conclusion, patient education appears to be effective in improving QoL and in reducing the perceived severity of skin disease. PMID- 21264450 TI - As many as 12 cases with haemorrhagic acquired factor XIII deficiency due to its inhibitors were recently found in Japan. PMID- 21264452 TI - Incidence, prevalence and future trends of primary basal cell carcinoma in the Netherlands. AB - Basal cell carcinoma (BCC) incidence rates are increasing worldwide. This study's objective was to estimate the occurrence of BCC in the Netherlands in terms of incidence and prevalence. Data on first primary carcinomas were retrieved from the Eindhoven Cancer Registry and extrapolated to the Dutch population. Extrapolated data showed a total of 444,131, histologically confirmed cases in the Netherlands between 1973 and 2008. During this period, age-adjusted incidence rates (European Standard Population) increased approximately three-fold from 40 to 148 per 100,000 in males and from 34 to 141 in females. Lifetime risk of BCC was 1 in 5-6 for Dutch citizens. Disease prevalence in the Netherlands was 1.4% and almost four times higher than this (5.4%) in the oldest age group (age 65 years or more). Predictions of future trends showed no signs of a plateau in the number of cases. These estimates should urge Dutch policymakers to provide solutions for the growing group of patients with BCC. PMID- 21264453 TI - Treatment of autoimmune urticaria with low-dose cyclosporin A: A one-year follow up. AB - Patients with autoimmune urticaria (AIU) and positive autologous serum skin test (ASST) represent a more serious type of chronic urticaria that does not respond to treatment with antihistamines, but responds completely to systemic corticosteroids. Because of the chronic course of the disease, there is a risk of side-effects. Cyclosporin A (CsA) is an alternative treatment for patients with AIU. In order to determine the efficacy of CsA at the lowest possible dose in patients with chronic idiopathic urticaria and positive ASST, 30 patients were included in a 5-month study with a follow-up one year after the end of treatment. All patients had positive ASST before treatment and autoantibodies were present in 73%. Twenty- three patients completed the study and responded to low-dose CsA treatment. Three patients did not respond to a dose of 2.5 mg/kg CsA, and 4 patients dropped-out due to side-effects. After the first month of treatment, an improvement of 31% was noted, reaching 88% after the fifth month of treatment. The mean dose of CsA was 2.16 mg/kg for the first month and 0.55 mg/kg for the fifth month. Three to 6 months after the end of the study, the ASST was repeated and was negative in 78.3% of patients. At the one-year follow-up, 20 patients were symptom-free (87%) and 3 had relapsed (13%). CsA, even in low-doses, can be an effective and short-term treat- ment with minimum side-effects in patients with AIU. PMID- 21264454 TI - Mycobacterium chelonae infection associated with tattoos. PMID- 21264455 TI - Thirty-year history of palmar eruptions: A quiz. Palmar purpuric lichen nitidus. PMID- 21264456 TI - Eruptive widespread papular eruption on the abdomen: a quiz. Clear cell syringoma, eruptive variant. PMID- 21264457 TI - [Asymptomatic nodule on an elderly lady's thumb tip]. AB - A 71-year-old woman presented with an asymptomatic growing dermal tumor on her thumb. Clinical picture, ultrasound, laboratory investigations and histology were consistent with the diagnosis of gouty tophus. Pathogenesis, risk factors and therapy of tophaceous gout are discussed. PMID- 21264458 TI - [Familial transmission of depression: the importance of harm avoidance]. AB - BACKGROUND: Previous research about the aetiology of depression has analysed how depression-associated personality traits influence familial transmission. Using the community-based sample of the Greifswald Family Study, we investigated longitudinally to which extent the temperament factor harm avoidance influences the correlation between parent's depression and the depression of their offspring (with regard to possible sex differences). METHODS: To test this familial transmission a structural equation model was conducted with the data of 193 children (mean age 19.5, SD=2.41) and their biological parents. Depression was assessed with structured clinical interviews, and harm avoidance with Cloninger's Temperament and Character Inventory (TCI, JTCI). RESULTS: The harm avoidance scores of the mothers were significantly correlated with the harm avoidance scores of their children, but the correlation of the father's and children's scores did not reach significance. The extent of harm avoidance at the first assessment of the 14-year-old children predicted depression 5 years later. CONCLUSION: These results indicate the importance of personality as a vulnerability marker for developing affective disorders. The results are discussed with respect to prevention programmes for children and parents with depression, especially if they exhibit strongly avoidant or anxious behaviour. PMID- 21264459 TI - [Epigenetic mechanisms in major depression]. AB - The term epigenetics describes mechanisms that can change the function of genes in the absence of an alteration of the actual DNA sequence. Among others, histone protein modifications (methylation, acetylation and phosphorylation) and DNA methylation constitute epigenetic mechanisms. Histone methylation and histone deacetylation in promoter regions of neurotrophic factors that have been associated with depression lead to their reduced expression. The methylation of DNA in promoter regions of genes coding for receptors and neurotrophic factors also results in their reduced expression, as was revealed for depressive disorders. Preclinical studies have shown that maternal care has a crucial influence on the reactivity of the hypothalamic-pituitary-adrenocortical axis of the offspring due to epigenetic mechanisms. These are acquired modifications that can be partially reversed by drug treatment (antidepressants). PMID- 21264460 TI - [Medication adherence in patients with chronic diseases: significance and new approaches]. AB - Many patients post stroke or with other chronic diseases do not continue to take their evidence-based medication. Patients with reduced medication adherence are characterized by increased cardiovascular morbidity and mortality. The number of elderly individuals with chronic conditions requiring polypharmacy will continue to increase. The following strategies are discussed to enhance adherence: individual advice and continuous counselling of the patients and the caregivers, individualized pharmacotherapy, and medication management including combination pills and unit doses. Medication adherence represents a field of research with increasing importance for patient outcomes and healthcare costs. Measures to improve adherence may be equally important to the development of novel drugs. However, prospective clinical studies evaluating the effects of the proposed interventions on clinical endpoints are rare and therefore evidence-based recommendations are missing. PMID- 21264461 TI - [Techniques for occlusion of the left atrial appendage: chances and risks]. AB - Atrial fibrillation causes 15-20% of ischemic strokes and the overall risk of stroke in patients with non-valvular atrial fibrillation is about 5% per year globally. Warfarin has long been the cornerstone for decreasing risks of stroke in patients with atrial fibrillation and its efficacy has been well established. However, 14-44% of patients with atrial fibrillation who are at risk of stroke are ineligible for anticoagulation therapy, mostly owing to the risks of major bleeding and falls. Occlusion of the left atrial appendage (LAA) appears to be an interesting new tool to prevent thromboembolic events in selected cases. In addition to surgical techniques, percutaneous transcatheter approaches have been introduced to occlude the LAA. Recent results indicate non-inferiority of mechanical occlusion of the LAA in comparison to warfarin therapy. PMID- 21264462 TI - [Neurological complications of atrioesophageal fistulas: postprandial insults, epilepsy and meningitis]. AB - BACKGROUND: Atrioesophageal fistulas (AEF) are a life-threatening complication of left atrial ablation for atrial fibrillation or other atrial rhythm disorders, which mostly manifest as neurological deficits. AEFs result in an overflow of esophageal contents into the left atrium with subsequent systemic embolization. RESULTS: AEFs have been reported in 40 patients, including 18 males, between 35 and 72 years of age. AEFs manifested clinically between 3 and 36 days following the ablation. The most common neurological manifestations are postprandial embolic stroke followed by epileptic seizures and meningitis. More rarely, disorders of consciousness without epilepsy or stroke, psychiatric abnormalities or cerebral air embolisms have been observed. The diagnosis is made upon thoracic computed tomography with contrast medium. Deglutation radiography, transesophageal echocardiography, gastroscopy and esophageal stenting must be absolutely avoided. The only expedient therapy is surgical cleansing of the fistula but even then the prognosis is very poor with a mortality of 63%. CONCLUSIONS: An AEF should always be considered in patients with fever, difficulties in swallowing, thoracic pain, postprandial transient ischemic attacks (TIA) or stroke, epileptic seizures, or meningitis. In the case of AEFs an ablation of atrial fibrillation in the patient history should be considered and corresponding diagnostics and treatment should be initiated immediately. PMID- 21264463 TI - [Innovations in spinal surgery]. PMID- 21264464 TI - Value of postmortem thoracic CT over radiography in imaging of pediatric rib fractures. AB - BACKGROUND: Studies have reported that thoracic CT may provide greater sensitivity compared with radiography in detection of pediatric rib fractures and fracture healing. The additional sensitivity afforded by thoracic CT may have medicolegal implications where abuse is suspected. OBJECTIVE: To determine the additional value of postmortem thoracic CT compared with radiography in detecting pediatric rib fractures, and fracture healing, using autopsy findings as a gold standard. MATERIALS AND METHODS: We retrospectively reviewed 56 coroner's cases with postmortem radiography and CT thoracic survey. All studies underwent primary interpretation by one or two radiologists. The study radiologist independently reviewed all images from 13 patients with positive findings on radiography, CT or autopsy. Sensitivity and specificity between observers and imaging modalities were compared. RESULTS: Primary interpretation: Fractures were recognized on radiography in 5/12 patients who had fractures found at autopsy, and on CT in 8/12 patients. In total, 29% (24/83) of fractures were reported on radiography, and 51% (52/101) of fractures were reported on CT. Study radiologist: Fractures were recognized on radiography in 7/12 patients who had fractures found at autopsy, and on CT in 11/12 patients. In total, 46% (38/83) of fractures were reported on radiography, and 85% (86/101) of fractures were reported on CT. CONCLUSION: Postmortem thoracic CT provides greater sensitivity than radiography in detecting pediatric rib fractures, most notably in anterior and posterior fractures. However, the degree of improvement in sensitivity provided by CT might depend on observer experience. PMID- 21264465 TI - Effect of Mg2+ versus Ca2+ on the behavior of annexin A5 in a membrane-bound state. AB - Annexin A5 (AnxA5) binds to negatively charged phospholipid membranes in a Ca(2+) dependent manner. Several studies already demonstrate that Mg(2+) ions cannot induce the binding. In this paper, quartz crystal microbalance with dissipation monitoring (QCM-D), Brewster angle microscopy (BAM), polarization modulation infrared reflection absorption spectroscopy (PMIRRAS) and molecular dynamics (MD) were performed to elucidate the high specificity of Ca(2+) versus Mg(2+) on AnxA5 binding to membrane models. In the presence of Ca(2+), AnxA5 showed a strong interaction with lipids, the protein is adsorbed mainly in alpha-helix under the DMPS monolayer, with an orientation of the alpha-helices axes slightly tilted with respect to the normal of the phospholipid monolayer as revealed by PMIRRAS. The Ca(2+) ions interact strongly with the phosphate group of the phospholipid monolayer. In the presence of Mg(2+), instead of Ca(2+), no interaction of AnxA5 with lipids was detected. Molecular dynamics simulations allow us to explain the high specificity of calcium. Ca(2+) ions are well exposed and surrounded by labile water molecules at the surface of the protein, which then favour their binding to the phosphate group of the membrane, explaining their specificity. To the contrary, Mg(2+) ions are embedded in the protein structure, with a smaller number of water molecules strongly bound. We conclude that the embedded Mg(2+) ions inside the AnxA5 structure are not able to link the protein to the phosphate group of the phospholipids for this reason. PMID- 21264466 TI - Antibacterial activity of Acinetobacter baumannii phage phiAB2 endolysin (LysAB2) against both gram-positive and gram-negative bacteria. AB - To investigate the nature and origin of the antibacterial activity of the lytic phage phiAB2 toward Acinetobacter baumannii, we successfully isolated and characterized a novel phage lysozyme (endolysin) from phiAB2 and named it LysAB2. To analyze antibacterial activity of LysAB2, the complete LysAB2 and two deletion derivatives were constructed, purified and characterized. Zymographic assays showed that only the intact LysAB2 could lyse the peptidoglycan of A. baumannii and the Staphylococcus aureus cell wall. Antibacterial analysis also showed that only the intact LysAB2 retained the complete bactericidal activity. When applied exogenously, LysAB2 exhibited a broad bacteriolytic activity against a number of Gram-negative and Gram-positive bacteria. Thermostability assays indicated that LysAB2 was stable at 20~40 degrees C. Its optimal pH was 6.0, and it was active from pH 4 to 8. Scanning electron microscopy revealed that exposure to 500 MUgml( 1) LysAB2 for up to 60 min caused a remarkable modification of the cell shape of the bacteria. Treating bacteria with LysAB2 clearly enhanced permeation of the bacterial cytoplasmic membrane. These results indicate that LysAB2 is an effective lysozyme against bacteria, and they suggest that it is a good candidate for a therapeutic/disinfectant agent to control nosocomial infections caused by multiple drug-resistant bacteria. PMID- 21264467 TI - The establishment of marine protected areas in Senegal: untangling the interactions between international institutions and national actors. AB - International institutions, understood as sets of rules contained in international agreements, are aimed at orienting national governments towards specific policy options. Nevertheless, they can determine a change in national policies and practices only if states are willing and capable of incorporating international obligations into their national legislations and ensuring their application and enforcement in areas that follow completely under national jurisdiction. The establishment of marine protected areas promoted by international agreements as a tool for the protection of marine resources represents an interesting case for revealing the complex interactions between international institutions and national actors. Particularly, the establishment of these areas in Senegal shows the salience of domestic constellations of actors who may support or undercut national commitments to international regimes: political elites, bureaucracies, the general public and target groups. By anchoring the empirical analysis to an actor-centred institutionalist perspective, the article explains how dynamic constellations of actors can distort the penetration of international objectives in the national policy framework. Different constellations of national actors can indeed bend international institutions at different moments: during the formulation of a new law in line with international obligations; in the definition of its implementation framework; and in the enforcement of national policies. PMID- 21264468 TI - Predictive factors of complications after surgical repair of iatrogenic femoral pseudoaneurysms. AB - BACKGROUND: The aim of the present study was to identify the predictive factors associated with the development of postoperative complications in patients treated with surgical repair of iatrogenic femoral pseudoaneurysm. MATERIALS AND METHODS: Between July 1992 and October 2009 we identified 92 cases of iatrogenic femoral pseudoaneurysm treated with conventional surgery. Surgical repair was performed via a longitudinal groin incision. A primary suture was sufficient in most patients. Twenty-nine variables were considered and included in the analyses. RESULTS: Urgent interventions were performed in 47 (51.1%) cases. Complications occurred in 22 (23.9%) patients. Bleeding was the most-frequent complication (n = 12), followed by wound infection (n = 6) and atrial fibrillation (n = 3). Overall, patients differed for age only (75.6 +/- 7.9 vs. 69.7 +/- 10.1; p = .013). Patients with complications required an intensive care unit stay more frequently than those without complications (36.4% vs. 11.4%; p = .007), as well as a longer hospital stay (12.9 +/- 8.4 vs. 7.7 +/- 7.7 days; p = .013). Bleeding complications were noted to be more frequent in older patients (76.2 +/- 8.5 vs. 70.3 +/- 9.90 years; p = .056). Wound infections showed a higher correlation with chronic obstructive pulmonary disease (COPD: 50.0% vs. 15.1%; p = .063). DISCUSSION: Bleeding and wound infection were the most frequent complications after surgical repair of iatrogenic femoral pseudoaneurysm. Age and COPD were the most important predictive factors for these complications. Patients with postoperative complications required a longer postoperative hospital stay. PMID- 21264469 TI - Symptomatic venous thromboembolism in Asian colorectal cancer surgery patients. AB - BACKGROUND: The occurrence of venous thromboembolism (VTE), manifesting as deep vein thrombosis (DVT) or pulmonary embolism (PE), after colorectal cancer surgery in Asian patients remains poorly characterized. The present study was designed to investigate the incidence of symptomatic VTE in Korean colorectal cancer patients following surgery, and to identify the associated risk factors. METHODS: We retrospectively analyzed data from patients who developed symptomatic VTE after colorectal cancer surgery between 2006 and 2008. Deep vein thrombosis was diagnosed with Doppler ultrasound or contrast venography, and PE was identified with lung ventilation/perfusion scans or chest computed tomography. Thromboprophylaxis, including low-molecular-weight heparin, graduated compression stockings, and intermittent pneumatic compression, was used in patients considered at high risk of VTE. RESULTS: Of the 3,645 patients who underwent colorectal cancer surgery, 31 (0.85%) developed symptomatic VTE. Of those 31 patients, 23 (74.2%) had DVT, 16 (51.6%) had PE, and 8 (25.8%) had both. Two patients died from PE. Univariate analysis showed that a history of VTE, pre existing cardiovascular disease, respiratory disease, transfusions, postoperative immobilization time, and postoperative complications were associated with VTE (p < 0.05 for each). Multivariate analysis showed that a history of VTE, pre existing cardiovascular disease, postoperative complication, advanced cancer stage, and postoperative immobilization time were risk factors for developing symptomatic VTE. The mean hospital stay was 18.3 days, and the mortality rate was 6.5%. CONCLUSIONS: The incidences of symptomatic DVT and PE were found to be not low in Asian colorectal cancer surgery patients compared with Western countries. The risk factors for VTE were a history of VTE, pre-existing cardiovascular disease, postoperative complications, advanced cancer stage, and postoperative immobilization. Thromboprophylaxis should be strongly considered in patients with these characteristics. Large prospective randomized controlled trials should be conducted to further evaluate the risk of VTE in Asian patients, and to determine the optimal prophylaxis. PMID- 21264470 TI - [Tibial pain and unilateral knee arthritis: Precursors of paraneoplastic arthropathy]. AB - Various rheumatic symptoms can occur in association with malignancies and are termed the so-called paraneoplastic arthropathy. The clinical picture is often similar to primary inflammatory rheumatic diseases. At present there exist no epidemiological data on this disease entity. The case of a patient with tibial pain and unilateral knee arthritis as precursors of a paraneoplastic syndrome is presented. The patient presented with the clinical manifestation of small cell lung cancer 2 years after the first presentation in the rheumatology clinic. PMID- 21264471 TI - [The genetics of vasculitides]. AB - Genetic association studies have been of great value in the past by contributing to the understanding of pathophysiological mechanisms of chronic inflammatory and autoimmune diseases. Many genetic risk factors have been identified which confer susceptibility for one or several (autoimmune) disease(s). Using a candidate-gene approach, the first genetic risk factors and polymorphisms of vasculitides have been identified. Due to the rarity of autoimmune vasculitides often only small sample numbers have been generated and analysed, leading to inconsistent results. Furthermore, differences in ethnic background may complicate analysis. Only few of the detected risk factors have been reliably replicated in larger cohorts, such as the association of the PTPN22*620W allele with WG and MPA, the deficiency allele Pi*Z of the alpha1 antitrypsin gene and the HLA-DPB*04041 allele with WG and the HLA-DRB3/DRB4 with CSS. Genome-wide association studies (GWAS) offer the advantage of screening the whole genome for risk factors rather than relying on disease models postulated by the investigator; however, they require even larger sample sizes. Initial results from GWA studies are available for Behcet's disease and Kawasaki syndrome, which identified new genetic associations but require replication, especially since some of the identified risk factors could not be linked to pathophysiological pathways to date. PMID- 21264472 TI - Factors associated with time delay to carotid stenting in patients with a symptomatic carotid artery stenosis. AB - Treatment of a symptomatic stenosis is known to be most beneficial within 14 days after the presenting event but this can frequently not be achieved in daily practice. The aim of this study was the assessment of factors responsible for this time delay to treatment. A retrospective analysis of a prospective two center CAS database was carried out to investigate the potential factors that influence a delayed CAS treatment. Of 374 patients with a symptomatic carotid stenosis, 59.1% were treated beyond >=14 days. A retinal TIA event (OR = 3.59, 95% CI 1.47-8.74, p < 0.01) was found to be a predictor for a delayed treatment, whereas the year of the intervention (OR = 0.32, 95% CI 0.20-0.50, p < 0.01) and a contralateral carotid occlusion (OR = 0.42, 95% CI 0.21-0.86, p = 0.02) were predictive of an early treatment. Similarly, within the subgroup of patients with transient symptoms, the year of the intervention (OR = 0.28, 95% CI 0.14-0.59, p < 0.01) was associated with an early treatment, whereas a retinal TIA as the qualifying event (OR = 6.96, 95% CI 2.37-20.47, p < 0.01) was associated with a delayed treatment. Treatment delay was most pronounced in patients with an amaurosis fugax, whereas a contralateral carotid occlusion led to an early intervention. Although CAS is increasingly performed faster in the last years, there is still scope for an even more accelerated treatment strategy, which might prevent future recurrent strokes prior to treatment. PMID- 21264473 TI - Lamotrigine therapy for paroxysmal dysarthria caused by multiple sclerosis: a case report. PMID- 21264474 TI - Migration and multiple sclerosis in immigrants to Australia from United Kingdom and Ireland: a reassessment. I. Risk of MS by age at immigration. AB - A previous study of the prevalence of multiple sclerosis (MS) in 1981 among immigrants from the United Kingdom and Ireland to Australia found that the prevalence for those with age at immigration (AAI) under 15 years of age did not differ from the older immigrants. We have reanalysed the original materials as well as census data for 1901-1981 for UKI and other high MS risk country immigrants. There was a highly significant trend in the prevalence rates of all Australians from New South Wales (NSW) to South Australia (SA) to Western Australia (WA) to Queensland (QLD). Rates by state among the Australian-born were almost identical to these, but there was no prevalence gradient for the UKI-born. The denominator population at risk of MS by AAI was calculated from special census tables of length of residence in Australia by age 0-79 in 1981 for UKI immigrants 1947-1981. The numerator was limited to the subset of 258 MS (Group II) also immigrating in 1947 and later, and age 0-79 in 1981. The absolute risk of MS for these migrants to the four states entering at age 0-14 was 22/100,000, significantly less than for all older age groups; age 15-39 immigrants had a risk of 54/100,000. Similar risk ratios for 0-14 versus 15-39 by state were 31 versus 61 (NSW), 29 versus 44 (QLD), 11 versus 50 (SA), 15 versus 51 (WA). PMID- 21264475 TI - Sergej nikolajevich davidenkov (1880-1961). PMID- 21264476 TI - Screening of antiplasmodial efficacy of Ajuga bracteosa Wall ex. Benth. AB - The rising problem of Plasmodium resistance to the classical antimalarial drugs stresses the need to look for newer antiplasmodial components with effective and new mode of action. In the present study, the traditional medicinal plant Ajuga bracteosa has been screened for its antiplasmodial efficacy. The extract was found to possess significant in vitro antiplasmodial efficacy with an IC(50) of 10.0 MUg/ml. Thus, the extract was further evaluated for its in vivo schizontocidal activity and efficacy in terms of survival time in Plasmodium berghei infected BALB/c mice. The extract at 250, 500, and 750 mg/kg/day exhibited significant (p<0.0001) blood schizontocidal activity during established infection with enhanced mean survival time comparable to that of standard drug chloroquine, 5 mg/kg/day. The significant schizontocidal activity and enhanced mean survival time of mice stress the need to identify and characterize active antiplasmodial principle from this plant. PMID- 21264477 TI - [Success of treatment in higher stages of pain chronification as well? An evaluation of the Mainz pain staging system based on the QUAST-analysis sample]. AB - BACKGROUND: More than 10 years ago Gerbershagen gave a pessimistic prognosis for treatment success in patients with higher stages of pain chronification. To date only few studies concerning this statement exist and the results are inconsistent. The objective of this study was to evaluate the prognostic validity of the Mainz pain staging system (MPSS) in a large multicenter sample. It was assessed whether effects of treatment in patients with higher stages of pain chronification are less than those in other patients. Of further interest was whether treatment success is related to different outcome measures. METHODS: A total of 1,461 patients with the pain syndromes headache, neuropathic pain, back pain or algiomuscular pain and arthralgia were enrolled in the analysis. They were selected from the QUAST analysis sample which includes patients from 19 cooperating pain clinics. All patients had completed the German pain questionnaire prior to pain treatment and these data were compared with the last available questionnaire during the course of treatment. Outcome measures were pain intensity, psychological disability scores and patient global impression of success (PGIS). RESULTS: Analysis showed a significant improvement of all outcome measures in every MPSS stage. The greatest improvement was noted for pain intensity whereas outcome variables regarding mental health revealed the lowest improvement. Compared with patients with low pain chronification, changes in pain intensity were smaller for patients with the highest MPSS stage III but even in these patients the strength of effect was more than 0.80. About 50% of all patients showed a reduction of pain intensity of 2 or more points on an 11 point numerical rating scale and 46.6% of patients with a MPSS stage III showed this improvement. Importantly, PGIS was independent of the stage of chronification. Nearly 45% of all patients evaluated the treatment success as good or very good. CONCLUSIONS: According to the view of the patients, treatment in specialized pain centres is successful even in the highest stage of pain chronification. This notwithstanding, success of treatment must not be confounded with the efficacy of an intervention. It has to be noted that the results of the current study do not allow conclusions regarding efficacy of treatment. PMID- 21264478 TI - Applicability of a rapid stool antigen test, using monoclonal antibody to catalase, for the management of Helicobacter pylori infection. AB - BACKGROUND: Most monoclonal antibody-based stool antigen tests are of the "send out" format. Rapid Testmate pylori antigen (Rapid TPAg) uses monoclonal antibody and is an "in-the-office" test. The aim of this study was to examine the usefulness of Rapid TPAg for the management of H. pylori infection. METHODS: One hundred and two consecutive patients who received H. pylori eradication therapy underwent both urea breath test (UBT) and Rapid TPAg at 5-6 weeks after finishing the eradication therapy. Stool samples were maintained at -20, 5, 25, and 40 degrees C and subjected to Rapid TPAg after 1-7 days. Stool samples were also tested by enzyme immunoassay (EIA) to quantify antigenicity. RESULTS: The agreement between Rapid TPAg and UBT in the evaluation of the results of H. pylori eradication treatment was 94.1%. The overall accuracy of Rapid TPAg and UBT to determine H. pylori eradication was 98.0 and 96.0%, respectively. The results of Rapid TPAg were not altered after storage of samples at -20 to 40 degrees C for 7 days. Antigenicity quantified by EIA did not decrease significantly after 7 days. CONCLUSIONS: Rapid TPAg is a useful diagnostic test for immediate and accurate determination of the results of H. pylori eradication therapy. The antigenicity of stool sample suspensions was preserved for 7 days in the collection devices. PMID- 21264479 TI - New method for assessing liver fibrosis based on acoustic radiation force impulse: a special reference to the difference between right and left liver. AB - BACKGROUND: Virtual touch tissue quantification (VTTQ) based on acoustic radiation force impulse (ARFI) imaging has been developed as a noninvasive bedside method for the assessment of liver stiffness. In this study, we examined the diagnostic performance of ARFI imaging in 103 patients, focusing on the difference in VTTQ values between the right and left liver lobes. METHODS: We evaluated VTTQ values of the right and left lobes in 79 patients with chronic liver disease who underwent histological examination of liver fibrosis and in 24 healthy volunteers. The diagnostic accuracy of VTTQ was compared with several serum markers, including hyaluronic acid, type 4 collagen, and aspartate transaminase to platelet ratio index. RESULTS: The VTTQ values (meters per second) in the right and left lobes were 1.61 +/- 0.51 and 1.90 +/- 0.68, respectively, and the difference was statistically significant (P < 0.0001). The VTTQ values in both liver lobes were correlated significantly with histological fibrosis grades (P < 0.001). The standard deviations of the VTTQ values in the right lobe were significantly lower than those in the left lobe (P < 0.001). The area under the receiver-operating characteristic curve for the diagnosis of fibrosis (F >= 3) using VTTQ values in both liver lobes was superior to serum markers, especially in the right lobe. CONCLUSIONS: VTTQ is an accurate and reliable tool for the assessment of liver fibrosis. VTTQ of the right lobe was more accurate for diagnosing liver fibrosis than in the left lobe. PMID- 21264480 TI - Mazabraud syndrome associated with McCune-Albright syndrome. PMID- 21264481 TI - The effect of Cox-2 specific inhibition on direct fracture healing in the rabbit tibia. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of Cox-2 administration on direct (primary) fracture healing. METHODS: A transverse tibial osteotomy was created in adult male rabbits and rigidly fixed in compression using a 2.7-mm dynamic compression plate. Animals were randomized to receive either rofecoxib (12.5 mg orally per day) or placebo. Animals were killed at 4 weeks and fracture healing assessed by mechanical testing. RESULTS: There were no significant differences between the control and Cox-2 treated animals in terms of mechanical strength at 4 weeks. There was a high complication rate of peri implant fractures during the daily medication administration. CONCLUSION: The immediate administration of a Cox-2 specific inhibitor did not impair primary (direct) bone healing at the dose administered in this rabbit tibial osteotomy model. PMID- 21264482 TI - Computational analysis of aspartic protease plasmepsin II complexed with EH58 inhibitor: a QM/MM MD study. AB - Plasmepsin (PM) II is one of four enzymes in the food vacuole of Plasmodium falciparum. It has become an attractive target for combating malaria through research regarding its importance in the P. falciparum metabolism and life cycle, making it the target of choice for structure-based drug design. This paper reports the results of hybrid quantum mechanics / molecular mechanics (QM/MM) molecular dynamics (MD) simulations employed to study the details of the interactions established between PM II and N-(3-{(2-benzo[1, 3]dioxol-5-yl ethyl)[3-(1-methyl-3-oxo-1,3-dihydro-isoindol-2-yl) propionyl]-amino}-1-benzyl-2 (hydroxyl-propyl)-4-benzyloxy-3,5dimethoxy-benzamide (EH58), a well-known potent inhibitor for this enzyme. Electrostatic binding free energy and energy terms decomposition have been computed for PM II complexed with the EH58 inhibitor. The results reveal that there is a strong interaction between Asp34, Val78, Ser79, Tyr192 and Asp214 residues and the EH58 inhibitor. In addition, we have computed the potential of the mean force (PMF) profile in order to assign the protonation state of the two catalytic aspartates in PM II-EH58 complex. The results indicate that the protonation of Asp214 favors a stable active site structure, which is consistent with our electrostatic binding free energy calculation and with previous published works. PMID- 21264483 TI - The effect of a Pro28Thr point mutation on the local structure and stability of human galactokinase enzyme-a theoretical study. AB - Galactokinase is responsible for the phosphorylation of alpha-D: -galactose, which is an important step in the metabolism of the latter. Malfunctioning of galactokinase due to a single point mutation causes cataracts and, in serious cases, blindness. This paper reports a study of the Pro(28)Thr point mutation using a variety of theories including molecular dynamics (MD), MM-PBSA/GBSA calculations and AIM analysis. Altered H-bonding networks were detected based on geometric and electron density criteria that resulted in local unfolding of the beta-sheet secondary structure. Another consequence was the decrease in stability (5-7 kcal mol(-1)) around this region, as confirmed by DeltaG(bind) calculations for the extracted part of the whole system. Local unfolding was verified by several other MD simulations performed with different duration, initial velocities and force field. Based on the results, we propose a possible mechanism for the unfolding caused by the Pro(28)Thr point mutation. PMID- 21264484 TI - DFT and MP2 investigations of L-proline and its hydrated complexes. AB - A theoretical study of L-proline-nH(2)O (n = 1-3) has been performed using the hybrid DFT-B3LYP and MP2 methods together with the 6-311++G(d,p) basis set. The results show that the P2 conformer is energetically favorable when forming a hydrated structure, and the hydration of the carboxyl group leads to the greatest stability. For hydrated complexes, the adiabatic and vertical singlet-triplet excitation energies tend to decrease with the addition of water molecules. The hydration energy indicates that in the hydrated complexes the order of stability is: binding site 2 > binding site 1 > binding site 3, and binding site 12 > binding site 23 > binding site 13. As water molecules are added, the stabilities of these hydrated structures gradually increase. In addition, an infrared frequency analysis indicated that there are some differences in the low-frequency range, which are mainly dominated by the O-H stretching or bending vibrations of different water molecules. All of these results should aid our understanding of molecular behavior and provide reference data for further studies of biological systems. PMID- 21264485 TI - Trans-vaginal specimen extraction following totally laparoscopic subtotal gastrectomy in early gastric cancer. AB - BACKGROUND: Although natural orifice extraction is now widely performed, there have been no reports of this procedure following subtotal gastrectomy for gastric cancer. This report describes trans-vaginal specimen extraction in four patients with early gastric cancer. METHODS: The clinical data of four patients with early gastric cancer were reviewed. Totally laparoscopic subtotal gastrectomy and D1 + beta lymph node dissection was performed using five trocars and a conventional procedure. Posterior colpotomy was performed by an experienced gynecologist, who retrieved the specimens in a retrieval bag via the trans-vaginal route. The colpotomy site was repaired immediately following specimen removal. Reconstruction was performed using the intracorporeal Billroth II method and an endo-GIA 60. RESULTS: Totally laparoscopic subtotal gastrectomy and trans-vaginal specimen extraction was successfully accomplished in all patients without intraoperative complications. CONCLUSIONS: The present technique may be a safe and feasible operative procedure for some limited groups of elderly female patients with early gastric cancer. PMID- 21264486 TI - Two squalene synthase inhibitors, E5700 and ER-119884, interfere with cellular proliferation and induce ultrastructural and lipid profile alterations in a Candida tropicalis strain resistant to fluconazole, itraconazole, and amphotericin B. AB - Three quinuclidine-based squalene synthase (SQS) inhibitors (BPQ-OH, E5700, and ER-119884) were evaluated against five Candida tropicalis strains with different susceptibility profiles to fluconazole (FLC), itraconazole (ITC), terbinafine (TRB), and amphotericin B (AMB). Although the quinuclidine derivatives were inactive against most C. tropicalis strains tested at concentrations up to 16 MUg/ml, E5700 and ER-119884 showed antifungal activity against C. tropicalis ATCC 28707, a strain resistant to FLC, ITC, and AMB, with IC(50) and IC(90) values (i.e., the minimum inhibitory concentrations of the drugs determined as the lowest drug concentrations leading to a 50 and 90% of reduction in turbidity at 492 nm, respectively, after 48 h of incubation) of 1 and 4 MUg/ml, respectively. Analysis of free sterols showed that non-treated C. tropicalis ATCC 28707 cells contained only 14-methylated sterols and that treatment with E5700 or ER-119884 led to a marked reduction of squalene content and the complete disappearance of the endogenous sterols. The fatty acid and phospholipid profiles in C. tropicalis ATCC 28707 cells grown in the presence of E5700 and ER-119884 were also markedly altered, with a large increase in the content of linolenic acid (C18:3), associated with a reduction in the content of linoleic (C18:2) and oleic (C18:1) acids. Treatment of C. tropicalis ATCC 28707 with E5700 or ER-119884 IC(50) values induced several ultrastructural alterations, including a marked increase in the thickness of the cell wall and the appearance of a large number of electron-dense vacuoles. In conclusion, our results indicated that E5700 and ER 119884 inhibited the growth and altered the lipid prolife and the ultrastructure of a multiple drug-resistant C. tropicalis strain. Therefore, such compounds could act as leads for the development of new treatment options against multidrug resistant Candida species. PMID- 21264487 TI - Systemic sclerosis presented as congestive heart failure: an autopsy case. AB - We report the autopsy results of a patient with systemic sclerosis with myositis lesions in the skeletal muscles and myocardium. A 69-year-old Japanese woman developed congestive heart failure and died due to respiratory failure with restrictive hypoventilation. The heart at autopsy showed dilated ventricular hypertrophy, and histopathology of the heart exhibited diffuse replacement fibrosis resembling the lesion of ischemic heart diseases in addition to patchy fibrosis around myocardial fibers suggesting post-myocarditis-like fibrosis. PMID- 21264488 TI - Postmarketing surveillance of safety and effectiveness of etanercept in Japanese patients with rheumatoid arthritis. AB - Our aim was to evaluate real-world safety and effectiveness in a 6-month postmarketing surveillance study covering all Japanese patients with rheumatoid arthritis (RA) who received etanercept during a 2-year period. Data for 13,894 patients (1334 sites) enrolled between March 2005 and April 2007 were collected. Adverse events (AEs) and serious adverse events (SAEs) were reported in 4336 (31.2%) and 857 (6.2%) patients, respectively. The most frequent AEs were injection site reactions (n = 610, 4.4%) and rash (n = 339, 2.4%), whereas pneumonia (n = 116, 0.8%) and interstitial lung disease (n = 77, 0.6%) were the most frequent SAEs. Significant improvement in the proportion of patients with a good European League Against Rheumatism (EULAR) response was observed from week 4 (17.6%) to week 24 (31.6%) (p < 0.001); 84.3% of patients had good or moderate EULAR responses at week 24. The percentage of patients achieving remission increased significantly from week 4 (9.3%) to week 24 (18.9%) (p < 0.001). Patients with early moderate RA were less likely to experience SAEs and were more likely to achieve remission compared with patients with more severe disease. The safety and effectiveness of etanercept was demonstrated in Japanese patients in one of the largest observational trials conducted thus far in RA patients treated with biologics. PMID- 21264489 TI - Endogenous endophthalmitis associated with liver abscess caused by Klebsiella pneumoniae. AB - To report two unusual cases of endogenous endophthalmitis associated with liver abscess caused by Klebsiella pneumoniae. Retrospective, interventional case series. Two patients, known to have type II diabetes mellitus, presented with sudden visual loss following several days of abdominal pain. Examinations and investigations revealed endogenous endophthalmitis caused by K. pneumoniae. Despite treatment in the form of intravitreal injection of antibiotics in the first patient and pars plana vitrectomy coupled with intravitreal injection of antibiotics in the second patient the final visual outcome was poor in both cases. The possibility of K. pneumoniae endogenous endophthalmitis should be suspected in diabetic patients presenting with intraocular inflammation. PMID- 21264490 TI - A case of peripheral ulcerative keratitis associated with neutrophilic dermatosis of the dorsal hand. AB - We report a case of peripheral ulcerative keratitis associated with neutrophilic dermatosis of the dorsal hand, a recently described clinical entity. A 68-year old man presented with concurrent peripheral ulcerative keratitis of the right eye and neutrophilic dermatosis of the dorsal hand causing pustular skin eruptions on the dorsal surface of both hands. Systemic investigations suggested an underlying diagnosis of Wegener's granulomatosis. To our knowledge this is the first reported case of neutrophilic dermatosis of the dorsal hand associated with ocular complications. PMID- 21264491 TI - Isolated foveal hypoplasia: report of a new case and detailed genetic investigation. AB - To carry out an ophthalmological and detailed genetic investigation on a 7-year old boy with isolated foveal hypoplasia. A full ophthalmological examination and optical coherence tomography (OCT) was performed. We also performed a full genome screen for chromosomal abnormalities, and searched for mutations in two genes (GPR143 and OCA2) known to be associated with ocular albinism and PAX6 gene known to be associated with aniridia. His eye examination was normal with no iris transillumination. A fundus examination, however, showed classic signs of foveal hypoplasia. A molecular genetic investigation showed no mutation(s) in all genes screened and no chromosomal deletion(s) and/or duplication(s) were detected. We report a case of isolated foveal hypoplasia where the underlying genetic cause could not be established. We could not rule out other genetic or epigenetic factors contributing to the pathogenesis of isolated foveal hypoplasia. PMID- 21264492 TI - Isolated optic neuropathy in a case of Behcet's disease. AB - A 57-year-old male with a 1-year history of recurrent oral ulceration and papulopustular lesions presented with acute visual loss in his left eye. He had an oedematous disc without any signs of uveitis. Laboratory work-up regarding infectious diseases was negative. The patient was diagnosed with acute optic neuropathy secondary to Behcet's disease. Systemic steroid and colchicine treatments were started but his vision did not improve. Isolated optic neuropathy is rare in Behcet's disease and early treatment with high-dose steroids may not be successful in some cases. PMID- 21264493 TI - Identification of a soybean chloroplast DNA replication origin-binding protein. AB - Replication of chloroplast DNA (ctDNA) in several plants and in Chlamydomonas reinhardii has been shown to occur by a double displacement loop (D-loop) mechanism and potentially also by a rolling circle mechanism. D-loop replication origins have been mapped in several species. Minimal replication origin sequences used as probes identified two potential binding proteins by southwestern blot analysis. A 28 kDa (apparent molecular weight by SDS-PAGE analysis) soybean protein has been isolated by origin sequence-specific DNA affinity chromatography from total chloroplast proteins. Mass spectrometry analysis identified this protein as the product of the soybean C6SY33 gene (accession number ACU14156), which is annotated as encoding a putative uncharacterized protein with a molecular weight of 25,897 Da, very near the observed molecular weight of the purified protein based on gel electrophoresis. Western blot analysis using an antibody against a homologous Arabidopsis protein indicates that this soybean protein is localized specifically in chloroplasts. The soybean protein shares some homology within a single-stranded DNA binding (SSB) domain of E. coli SSB and an Arabidopsis thaliana mitochondrial-localized SSB of about 21 kDa (mtSSB). However, the soybean protein induces a specific electrophoretic mobility shift only when incubated with a double-stranded fragment containing the previously mapped ctDNA replication oriA region. This protein has no electrophoretic mobility shift activity when incubated with single-stranded DNA. In contrast, the Arabidopsis mtSSB causes a mobility shift only with single-stranded DNA but not with the oriA fragment or with control dsDNA of unrelated sequence. These results suggest that the 26 kDa soybean protein is a specific origin binding protein that may be involved in initiation of ctDNA replication. PMID- 21264494 TI - OsBC1L4 encodes a COBRA-like protein that affects cellulose synthesis in rice. AB - Plant morphogenesis is highly dependent on the regulation of cell division and expansion. The organization of the cellulose microfibrils in the cell wall is a key determinant of cell expansion. Previously, a dwarf mutant with fewer tillers, Osbc1l4 (Oryza sativa brittle culm 1 like 4), was identified by screening a rice T-DNA insertion mutant library. It is reported here that OsBC1L4 encodes a COBRA like protein that exhibits typical structural features of a glycosylphosphatidylinositol-anchor protein. The T-DNA insertion in OsBC1L4 results in abnormal cell expansion. A decrease in cellulose content but the increase in pectin and starch contents was identified in Osbc1l4 mutants by measuring the content of wall components. OsBC1L4 was expressed in all tissues/organs examined, with a low level in leaves. OsBC1L4 protein is mainly located in the cell wall and plasma membrane. Correlation analysis indicated that the expression of OsBC1L4 was highly correlated to that of several primary wall forming cellulose synthase genes (CESAs). Moreover, the expression level of several cellulose-related genes is increased in Osbc1l4 mutants, which suggests that a feedback mechanism may exist during cellulose synthesis. PMID- 21264495 TI - The melanoma-associated antigen-A3, -A4 genes: relation to the risk and clinicopathological parameters in breast cancer patients. AB - This study aimed to evaluate the clinical reliability and accuracy of two MAGE transcripts (MAGE-A3, MAGE-A4 mRNA) in the peripheral blood (PB) of patients with breast cancer (BC), and to evaluate their potential limits and utility to detect BC. We aimed also to analyze their relation to clinicopathological characteristics of the tumor. This study is a prospective, controlled, double blinded study conducted on 100 BC women and 100 age-matched control women. There were 52 patients with localized breast mass with no evidence of nodal affection or distant metastases and 48 patients suffering from metastatic BC. MAGE-A3 and MAGE-A4 mRNA in the PB were assayed using reverse transcriptase-polymerase chain reaction (RT-PCR). None of the control women was positive for either MAGE-A3, MAGE-A4. In BC women, positivity for MAGE-A3 in PB was observed in 37 patients (37%), and MAGE-A4 positivity was observed in 11 patients (11%); with 100% specificity for both transcripts. The presence of MAGE-A3 was significantly associated with nodal status (P = 0.009), tumor size (P = 0.009), and American Joint Committee on Cancer stage (P = 0.009), whereas MAGE-A4 positivity was significantly associated with histological grade (P = 0.020). RT-PCR assays of MAGE-A3 and MAGE-A4 in the PB of BC patients may have prognostic and predictive implications, and they are promising specific tumor markers of BC. PMID- 21264496 TI - The influence of training status on oxidative stress in young male handball players. AB - Although exercise-induced oxidative stress receives considerable scientific attention, there is still little information available regarding exercise-induced adaptations of the antioxidant defence system in adolescent and child athletes. The aim of our study was to establish the effects of long-term exercise training on the redox state of adolescents, and to find correlations between elements of redox homeostasis and aerobic power. Thirty-three handball players and 14 non athletes, 16-19-years old, were subjected to blood sampling to measure levels of nitric oxide (NO; estimated through nitrites (NO2-), superoxide anion radical (O2 ), hydrogen peroxide (H2O2), lipid peroxidation (estimated through TBARS), superoxide dismutase (SOD) and catalase (CAT). Subjects were also subjected to maximal progressive exercise test to estimate their maximal oxygen consumption (VO2max). Athletes had significantly (P < 0.05) higher SOD activity and lower CAT activity compared with non-athletes (SOD: 2175.52 +/- 362.07 compared with 1172.16 +/- 747.40 U/g of hemoglobin x 103, and CAT: 2.19 +/- 0.31 compared with 3.08 +/- 0.47 U/g of hemoglobin x 103). These differences were the most obvious when comparing non-athletes and athletes with poor/average aerobic power. H2O2 and TBARS levels differed among subjects with poor, average or good aerobic power (P < 0.01, and P < 0.05, respectively). Sports engagement and aerobic capacity are important factors in inducing changes in redox status. PMID- 21264497 TI - Protective effect of HDL on endothelial NO production: the role of DDAH/ADMA pathway. AB - Accumulating studies have demonstrated that the dimethylarginine dimethylaminohydrolase/asymmetric dimethylarginine (DDAH/ADMA) system is a novel pathway for modulating nitric oxide (NO) production. The aim of this study was to investigate whether the protective effect of high density lipoprotein (HDL) on endothelial NO production was related to its effect on DDAH/ADMA pathway. Human umbilical vein endothelial cells (HUVECs) were prior exposed to HDL (10, 50, or 100 MUg/ml) for 1 h, and then incubated with oxidized low density lipoprotein (ox LDL) (100 MUg/ml) for 24 h. The cultured medium was collected for measuring the concentration of NO and ADMA. The cells were collected for measuring the mRNA and protein expression of DDAH-II as well as DDAH activity. HUVECs treated with ox LDL (100 MUg/ml) for 24 h significantly decreased the concentration of NO, the mRNA and protein expression of DDAH-II as well as DDAH activity and increased the level of ADMA. Pretreatment with HDL (10, 50, or 100 MUg/ml) could counteract these changes induced by ox-LDL (100 MUg/ml). HDL significantly increased the attenuated endothelial cell NO production induced by ox-LDL, which was attributed to its effect on DDAH/ADMA pathway. PMID- 21264498 TI - Temporal relation of cardiac hypertrophy, oxidative stress, and fatty acid metabolism in spontaneously hypertensive rat. AB - Left ventricular hypertrophy is an adaptive response to hypertension, and an independent clinical risk factor for cardiac failure, sudden death, and myocardial infarction. As regression of cardiac hypertrophy is associated with a lower likelihood of cardiovascular events, it is recognized as a target of antihypertensive therapy. This necessitates identification of factors associated with the initiation and progression of hypertrophy. Oxidative stress and metabolic shift are intimately linked with myocardial hypertrophy, but their interrelationship is not clearly understood. This study proposes to identify the temporal sequence of events so as to distinguish whether oxidative stress and metabolic shift are a cause or consequence of hypertrophy. Spontaneously hypertensive rat (SHR) was used as the experimental model. Cardiac hypertrophy was apparent at 2 months of age, as assessed by hypertrophy index and brain natriuretic peptide gene expression. Enhanced myocardial lipid peroxidation accompanied by nuclear factor-kappa B gene expression in one-month-old SHR suggests that oxidative stress precedes the development of hypertrophy. Metabolic shift identified by reduction in the expression of peroxisome proliferator activated receptor-alpha, medium chain acyl CoA dehydrogenase, and carnitine palmitoyltransferase 1beta was seen at 4 months of age, implying that reduction of fatty acid oxidation is a consequence of hypertrophy. Information on the temporal sequence of events associated with hypertrophy will help in the prevention and reversal of cardiac remodeling. Investigations aimed at prevention of hypertrophy should address reduction of oxidative stress. Both, oxidative stress and metabolic modulation have to be considered for studies that focus on the regression of hypertrophy. PMID- 21264499 TI - Fluorescence properties of phenol-modified zinc phthalocyanine that tuned by photoinduced intra-molecular electron transfer and pH values. AB - Tetra[alpha-(4-hydroxyphenoxy)] zinc phthalocyanine, ZnPc(alpha-OPhOH)(4), was synthesized and its photophysics was found to be sharply pH dependent. Dual fluorescence emission around 700 nm was observed when it is dissolved in basic solution. The fluorescence of the phthalocyanine can be sharply switched off at pH 9.1 due to the intramolecular photoinduced electron transfer (PET) in ZnPc(alpha-OPhONa)(4), formed by the deprotonation of ZnPc(alpha-OPhOH)(4). The photophysics of both ZnPc(alpha-OPhOH)(4) and ZnPc(alpha-OPhONa)(4) were studied in detail by UV-vis absorption, steady state and time-resolved fluorescence and transient absorption (TA) to reveal the fluorescence quenching mechanism. Intra molecular PET in ZnPc(alpha-OPhONa)(4) from the donor, PhONa subunits, to the acceptor, ZnPc moiety, was characterized by the much smaller fluorescence quantum yield (0.003) and lifetime (<0.20 ns). PET was further evidenced by the occurrence of charge separation state (CSS) in TA spectra, i.e. the bands due to anion radical of ZnPc and phenol radical. The lifetime of the charge separation state is ca. 3 ns, the efficiency of PET is ca. 99% and the rate constant of PET is 2.3 * 10(10) s(-1). PMID- 21264500 TI - Why is everyone so anxious?: an exploration of stress and anxiety in genetic counseling graduate students. AB - Stress is an inevitable part of daily life. Studies of graduate student stress exist, but none include genetic counseling students. The present mixed-methods study investigated 225 genetic counseling students' stress and anxiety levels using the State-Trait Anxiety Inventory (STAI; Spielberger et al. 1983), frequency and intensity of stressors associated with their graduate experience, positive and challenging aspects of their experience, and their stress management advice for prospective students. Principal axis factor analysis yielded five conceptual factors underlying the stressors: Professional Uncertainty, Personal Life Events, Interpersonal Demands, Academic Demands, and Isolating Circumstances. Exploratory model fitting using regression yielded four significant predictors accounting for 19% of the variance in state anxiety: (1) trait anxiety, (2) the Interpersonal Demands factor, (3) the Isolating Circumstances factor, and (4) the interaction between the Professional Uncertainty factor and advanced student status. Content analysis of open-ended responses identified several themes. For instance, most students enjoyed what they were learning, interactions with colleagues, and affirmation of their career choice, while certain academic and professional challenges were particularly stressful (e.g., workload, time constraints, clinical rotations). Additional findings, program implications, and research recommendations are provided. PMID- 21264501 TI - Ethical dilemmas in genetic testing: examples from the Cuban program for predictive diagnosis of hereditary ataxias. AB - Predictive testing protocols are intended to help patients affected with hereditary conditions understand their condition and make informed reproductive choices. However, predictive protocols may expose clinicians and patients to ethical dilemmas that interfere with genetic counseling and the decision making process. This paper describes ethical dilemmas in a series of five cases involving predictive testing for hereditary ataxias in Cuba. The examples herein present evidence of the deeply controversial situations faced by both individuals at risk and professionals in charge of these predictive studies, suggesting a need for expanded guidelines to address such complexities. PMID- 21264502 TI - Use of voter registration records to recruit a representative sample. AB - Research samples are not often compared to broader community samples to evaluate their representativeness, a critical factor in determining the generalizability of study findings. This study evaluated the use of voter-registration records for recruiting a representative sample of community-dwelling, older, and overweight participants for research on improving measures of diet and physical activity. County voter-registration records were used to identify individuals between 45 and 75 years of age and living in the two cities closest to the research lab. The data were collected from July, 2007 through November, 2008. Prospective participants were mailed an introductory letter and opt-out postcard, and received a follow-up recruitment phone call in which they underwent further screening if interested in participating. The representativeness of the final voter-recruited sample (N = 191) was evaluated by comparisons of demographic variables with Behavioral Risk Factor Surveillance System (BRFSS) data at the county and state levels. The voter-recruited sample was only partially comparable to that of the BRFSS sample, with expected differences in variables related to race/ethnicity, the proportion of women, employment status, and educational attainment. Voter-registration records are a relatively low-cost ($75 per participant) method of recruiting a community sample that avoids some biases of other recruitment methods, but may not achieve a fully representative sample. PMID- 21264503 TI - Positive illusions of social competence in girls with and without ADHD. AB - We compared social self-competence ratings in 9-12 year old girls with (n = 42) versus without (n = 40) ADHD, relative to ratings of the girls' social competence made by mothers, teachers, and blind raters during a social laboratory task. Relative to scores from mothers, teachers, and the lab-task, girls with ADHD over estimated their competence significantly more than control girls. Over-estimates were greater for girls with ADHD who also had heightened oppositional-defiant symptoms, or lower depressive symptoms. Over-estimates were positively related to a socially desirable reporting bias for girls with ADHD, but not for control girls, suggesting that girls with ADHD attempt to present themselves in an unduly positive, self-protective light. For girls with ADHD, over-estimates also were positively related to maladjustment and negatively related to adjustment. However, for girls without ADHD, over-estimates were positively related to adjustment. Overall, over-estimates of competence function differently in girls with and without ADHD. PMID- 21264504 TI - Genetic variation and relationship of six Indian sheep breeds adapted to the northwestern arid zone of Rajasthan. AB - This study illustrates the genetic diversity and relationships within and among six Indian sheep breeds of the northwestern arid region of Rajasthan, based on microsatellite markers. The range of allele diversity was 7.72-9.56, and gene diversity was 0.686-0.766, revealing that these breeds possessed substantial amounts of genetic diversity. Positive F (IS) values suggested a deficit of heterozygotes in all six breeds. Despite the declining status of the Marwari, Chokla, Jaisalmeri, Magra and Pugal breeds, an absence of a recent genetic bottleneck was evident from the data. The genetic differentiation estimate (F (ST) = 6.1%) suggested low levels of differentiation between the breeds. Genetic distance estimates revealed a close relationship between the Magra-Pugal and Nali Jaisalmeri breed pairs. This information forms a framework for designing genetic management and conservation programs for these valuable ovine breeds. PMID- 21264505 TI - Molecular characterization of high plant species using PCR with primers designed from consensus branch point signal sequences. AB - A novel method is introduced for producing molecular markers in plants using single 15- to 18-mer PCR primers designed from the short conserved consensus branch point signal sequences and standard agarose gel electrophoresis. This method was tested on cultivated peanut and verified to give good fingerprinting results in other plant species (mango, banana, and longan). These single primers, designed from relatively conserved branch point signal sequences within gene introns, should be universal across other plant species. The method is rapid, simple, and efficient, and it requires no sequence information of the plant genome of interest. It could be used in conjunction with, or as a substitute for, conventional RAPD or ISSR techniques for applications including genetic diversity analysis, phylogenetic tree construction, and quantitative trait locus mapping. This technique provides a new way to develop molecular markers for assessing genetic diversity of germplasm in diverse species based on conserved branch point signal sequences. PMID- 21264506 TI - Role of the autonomic nervous system in rat liver regeneration. AB - To study the regulatory role of autonomic nervous system in rat regenerating liver, surgical operations of rat partial hepatectomy (PH) and its operation control (OC), sympathectomy combining partial hepatectomy (SPH), vagotomy combining partial hepatectomy (VPH), and total liver denervation combining partial hepatectomy (TDPH) were performed, then expression profiles of regenerating livers at 2 h after operation were detected using Rat Genome 230 2.0 array. It was shown that the expressions of 97 genes in OC, 230 genes in PH, 253 genes in SPH, 187 genes in VPH, and 177 genes in TDPH were significantly changed in biology. The relevance analysis showed that in SPH, genes involved in stimulus response, immunity response, amino acids and K(+) transport, amino acid catabolism, cell adhesion, cell proliferation mediated by JAK-STAT, Ca(+), and platelet-derived growth factor receptor, cell growth and differentiation through JAK-STAT were up-regulated, while the genes involved in chromatin assembly and disassembly, and cell apoptosis mediated by MAPK were down-regulated. In VPH, the genes associated with chromosome modification-related transcription factor, oxygen transport, and cell apoptosis mediated by MAPK pathway were up-regulated, but the genes associated with amino acid catabolism, histone acetylation-related transcription factor, and cell differentiation mediated by Wnt pathway were down regulated. In TDPH, the genes related to immunity response, growth and development of regenerating liver, cell growth by MAPK pathway were up-regulated. Our data suggested that splanchnic and vagal nerves could regulate the expressions of liver regeneration-related genes. PMID- 21264507 TI - Genome-wide copy number alterations in subtypes of invasive breast cancers in young white and African American women. AB - Genomic copy number alterations (CNA) are common in breast cancer. Identifying characteristic CNAs associated with specific breast cancer subtypes is a critical step in defining potential mechanisms of disease initiation and progression. We used genome-wide array comparative genomic hybridization to identify distinctive CNAs in breast cancer subtypes from 259 young (diagnosed with breast cancer at <55 years) African American (AA) and Caucasian American (CA) women originally enrolled in a larger population-based study. We compared the average frequency of CNAs across the whole genome for each breast tumor subtype and found that estrogen receptor (ER)-negative tumors had a higher average frequency of genome wide gain (P < 0.0001) and loss (P = 0.02) compared to ER-positive tumors. Triple negative (TN) tumors had a higher average frequency of genome-wide gain (P < 0.0001) and loss (P = 0.003) than non-TN tumors. No significant difference in CNA frequency was observed between HER2-positive and -negative tumors. We also identified previously unreported recurrent CNAs (frequency >40%) for TN breast tumors at 10q, 11p, 11q, 16q, 20p, and 20q. In addition, we report CNAs that differ in frequency between TN breast tumors of AA and CA women. This is of particular relevance because TN breast cancer is associated with higher mortality and young AA women have higher rates of TN breast tumors compared to CA women. These data support the possibility that higher overall frequency of genomic alteration events as well as specific focal CNAs in TN breast tumors might contribute in part to the poor breast cancer prognosis for young AA women. PMID- 21264508 TI - Validation of a self-efficacy instrument and its relationship to performance of crisis resource management skills. AB - Self-efficacy is thought to be important for resuscitation proficiency in that it influences the development of and access to the associated medical knowledge, procedural skills and crisis resource management (CRM) skills. Since performance assessment of CRM skills is challenging, self-efficacy is often used as a measure of competence in this area. While self-efficacy may influence performance, the true relationship between self-efficacy and performance in this setting has not been delineated. We developed an instrument to measure pediatric residents' self efficacy in CRM skills and assessed its content validity, internal structure, and relationship to other variables. After administering the instrument to 125 pediatric residents, critical care fellows and faculty, we performed an exploratory factor analysis within a confirmatory factor analysis as well as a known group comparison. The analyses specified four factors that we defined as: situation awareness, team management, environment management, and decision making. Pediatric residents reported lower self-efficacy than fellows and faculty in each factor. We also examined the correlation between self-efficacy and performance scores for a subset of 30 residents who led video recorded simulated resuscitations and had their performances rated by three observers. We found a significant, positive correlation between residents' self-efficacy in situation awareness and environment management and their overall performance of CRM skills. Our findings suggest that in a specific context, self-efficacy as a form of self assessment may be informative with regards to performance. PMID- 21264509 TI - Inhibitory effect of hot-water extract of quince (Cydonia oblonga) on immunoglobulin E-dependent late-phase immune reactions of mast cells. AB - We evaluated the effect of a crude hot-water extract (HW) of quince (Cydonia oblonga Miller) fruit on immunoglobulin E (IgE)-dependent late-phase immune reactions of mast cells using in vitro system. Mast cell-like RBL-2H3 cells were treated with quince HW and late-phase reaction was then induced by stimulation with IgE + Antigen. Quince HW reduced the elevation of interleukin-13 and tumor necrosis factor-alpha expression level. Furthermore, quince HW suppressed these cytokine expressions of mouse bone marrow-derived mast cells (BMMCs), a normal mast cell model. Leukotriene C(4) and prostaglandin D(2) production in BMMCs after 1 and 6 h of stimulation, respectively, were also reduced by treating the cells with quince HW. We found that the induction of intracellular cyclooxygenase (COX)-2 expression but not COX-1 expression in BMMCs was reduced by quince HW. These results suggest that quince HW has an inhibitory effect on broad range of the late-phase immune reactions of mast cells. PMID- 21264510 TI - Inflammation: an equal-opportunity process. PMID- 21264511 TI - Significance of elevated levels of collagen type IV and hyaluronic acid in gastric juice and serum in gastric cancer and precancerous lesion. AB - BACKGROUND AND AIMS: Collagen type IV and hyaluronic acid (HA) are the major components of basement membrane and extracellular matrix, respectively. Cathepsin D is an aspartyl lysosomal protease involved in the degradation of the basement membrane and extracellular matrix. The aim of this study is to investigate the clinical significance of collagen type IV and hyaluronic acid in gastric juice and serum in diagnosis of gastric cancer and the degrading effect of cathepsin D on collagen type IV and HA. METHODS: Fifty gastric cancer patients were enrolled in our study compared with 41 patients with precancerous lesion and 30 control subjects. Collagen type IV and HA in gastric juice and serum were analyzed by radioimmunoassay. Expression of cathepsin D and collagen type IV in tissue were analyzed by immunohistochemical staining with monoclonal antibodies. RESULTS: The contents of collagen type IV and HA in gastric juice and HA in serum were significantly higher in patients with gastric cancer than those in patients with precancerous lesion and control group (p < 0.05, p < 0.0001). Gastric cancer patients with lymph node metastasis had a higher level of collagen type IV and HA in gastric juice than those in patients without metastasis (p = 0.049, p = 0.043). The expression of cathepsin D had significantly increased in patients with gastric cancer compared to the control group (p < 0.0001). The continuous expression of collagen type IV in basement membrane in gastric cancer group was lower than that in the precancerous lesion group and control group (p < 0.0001). CONCLUSIONS: The analysis of collagen type IV and HA in gastric juice and serum may provide a simple aid in diagnosing gastric cancer and evaluating whether metastasis is occurring or not. PMID- 21264512 TI - A double-layered (comvi) self-expandable metal stent for malignant gastroduodenal obstruction: a prospective multicenter study. AB - BACKGROUND: A self-expandable metal stent (SEMS) has emerged as an effective palliative treatment for malignant gastroduodenal obstruction resulting from gastric or periampullary malignancy. Despite the stent's effectiveness, tumor ingrowth and stent migration remain complications requiring reintervention. The purpose of this study was to evaluate the efficacy and safety of a double-layered SEMS (Comvi). METHODS: We performed a prospective multicenter study in two university hospitals and two referral hospitals. In fifty consecutive patients with malignant gastroduodenal obstructions, placement of double-layered SEMS, comprising an outer uncovered stent and an inner covered stent that overlap each other, was performed. Palliation, efficacy, and incidence of complications were evaluated. RESULTS: Technical and clinical success was achieved in 100 and 88% of patients, respectively. There were no procedure-related complications. Five patients experienced stent migration (10%). For four of five patients' stent migration occurred within two weeks of stent placement. Stent collapse occurred in five patients after one month. Reintervention for stent migration, collapse, or tumor overgrowth was required for 14 (28%) patients. CONCLUSIONS: Endoscopic placement of a double-layered stent is a safe and effective modality for the palliation of malignant gastroduodenal obstruction. However, considering reintervention, this stent does not seem to add any clear advantage compared with preexisting uncovered stents. Migration, especially within the first two weeks, and stent collapse are still unresolved problems. The device should be fixed or the design modified to reduce these problems. PMID- 21264513 TI - K-ras mutations correlate with atypical cytology and elevated CEA levels in pancreatic cystic neoplasms. AB - INTRODUCTION: Benign pancreatic cystic neoplasms are important precursors to pancreatic adenocarcinoma, and offer the opportunity to prevent cancer. Conversely, prevention only occurs with surgical resection associated with significant morbidity and mortality, while the natural history of small cystic neoplasms is a slow and uncertain progression to malignancy. Markers that predict progression to malignancy are needed. Cyst fluid DNA analysis including K-ras mutations may predict more aggressive natural history of pancreatic cystic neoplasms. METHODS: Sixty patients with pancreatic cysts measuring less than 3 cm without solid component or pancreatic ductal dilation underwent EUS with fine needle aspiration. Nine had surgical resection. Cyst fluid was tested for cytology, CEA levels, and DNA analysis including K-ras mutations, and eight loss of heterozygosity mutations. Mutations were correlated with findings of atypia and CEA levels. RESULTS: Cyst fluid K-ras mutation was found in 30% of patients. Patients with mutated K-ras were more likely to have atypia on cytology or pathology (39 vs. 14%) and higher CEA (median 591 vs. 42) compared to wild-type K ras. K-ras mutants were more likely to have two or more loss of heterozygosity mutations. Loss of heterozygosity mutations did not correlate with atypia or CEA levels. CONCLUSIONS: Cyst fluid K-ras mutation correlates with other markers of aggressive cyst behavior. EUS with cyst DNA analysis may alter management of smaller pancreatic cysts when surgery might otherwise be deferred. Further studies of cyst fluid DNA and long-term outcomes are needed. PMID- 21264514 TI - Home health care may improve diabetic outcomes among non-English speaking patients in primary care practice: a pilot study. AB - There are multiple challenges to proactive diabetic management in minority, non English speaking populations. In this study, we seek to determine if enrollment in a home health care program would improve diabetic outcomes in this traditionally vulnerable population. Of the 64 non-English speaking diabetics evaluated in our clinic between 1/1/2002 and 12/30/2005, 26 (40.6%) patients who met the criteria for poor glycemic control (defined by HgbA1c > 8% on two separate occasions) were identified, but three were excluded because they did not participate in home health. Comparing diabetic outcomes 24 months post-home health intervention to 24 months prior, patients showed improvement in mean HbA1c, mean LDL, and mean systolic blood pressure. With home health intervention, there appears to be improved diabetic outcomes across all measured parameters. PMID- 21264515 TI - Assessing neuropsychological performance in a migrant farm working Colonia in Baja California, Mexico: a feasibility study. AB - Neuropsychological impairments (NPI) can lead to difficulties in daily functioning and ultimately contribute to poor health outcomes. However, evidence for the feasibility of NPI assessment in resource-limited settings using tests developed in high literacy/high education cultures is sparse. The main objectives were to: (1) determine the feasibility and appropriateness of conducting neuropsychological assessments among a migrant farm worker population in Baja California, Mexico and (2) preliminary describe neuropsychological test performance in this unique population. A neuropsychological test battery was administered to 21 presumably healthy adults (8 men, 13 women) during a two-day international health services and research collaboration. All but one neuropsychological test (i.e. figure learning) was feasible and appropriate to administer to the study population. Contrary to expectations, participants performed better on verbal rather than nonverbal neuropsychological tests. Results support inclusion of neuropsychological tests into future studies among migrant farm worker populations in Baja California, Mexico. PMID- 21264516 TI - The sodium-dependent di- and tricarboxylate transporter, NaCT, is not responsible for the uptake of D-, L-2-hydroxyglutarate and 3-hydroxyglutarate into neurons. AB - Concentrations of glutarate (GA) and its derivatives such as 3-hydroxyglutarate (3OHGA), D- (D-2OHGA) and L-2-hydroxyglutarate (L-2OHGA) are increased in plasma, cerebrospinal fluid (CSF) and urine of patients suffering from different forms of organic acidurias. It has been proposed that these derivatives cause neuronal damage in these patients, leading to dystonic and dyskinetic movement disorders. We have recently shown that these compounds are eliminated by the kidneys via the human organic anion transporters, OAT1 and OAT4, and the sodium-dependent dicarboxylate transporter 3, NaDC3. In neurons, where most of the damage occurs, a sodium-dependent citrate transporter, NaCT, has been identified. Therefore, we investigated the impact of GA derivatives on hNaCT by two-electrode voltage clamp and tracer uptake studies. None of these compounds induced substrate-associated currents in hNaCT-expressing Xenopus laevis oocytes nor did GA derivatives inhibit the uptake of citrate, the prototypical substrate of hNaCT. In contrast, D- and L-2OHGA, but not 3OHGA, showed affinities to NaDC3, indicating that D- and L-2OHGA impair the uptake of dicarboxylates into astrocytes thereby possibly interfering with their feeding of tricarboxylic acid cycle intermediates to neurons. PMID- 21264517 TI - Lymphocutaneous type of nocardiosis caused by Nocardia vinacea in a patient with polymyositis. AB - We report a lymphocutaneous type of nocardiosis caused by Nocardia vinacea. A 62 year-old woman with polymyositis presented with some erythematous swellings and subcutaneous abscesses on her right middle finger and the dorsum of her hand, which had persisted for 2 weeks. Culturing of the excised nodule and pus revealed orange to orange-tan colonies with scanty whitish aerial mycelia. The isolate was identified as N. vinacea on the basis of its biochemical and chemotaxonomic characteristics and the results of molecular biological analysis. In our case, oral minocycline (MINO) and trimethoprim-sulfamethoxazole (TMP-SMX) for 7 weeks did not improve the clinical manifestation, even though in vitro susceptibility testing of the isolate predicted its susceptibility to MINO and TMP-SMX. Treatment with partial surgical excision followed by TMP-SMX and meropenem administration was effective. This is the first reported case of a lymphocutaneous type of nocardiosis caused by N. vinacea. PMID- 21264518 TI - Health and human rights: epistemological status and perspectives of development. AB - The health and human rights movement (HHR) shows obvious signs of maturation both internally and externally. Yet there are still many questions to be addressed. These issues include the movement's epistemological status and its perspectives of development. This paper discusses critically the conditions of emergence of HHR, its identity, its dominant schools of thought, its epistemological postures and its methodological issues. Our analysis shows that: (a) the epistemological status of HHR is ambiguous; (b) its identity is uncertain in the absence of a validated definition: is it an action movement, an interdisciplinary field, a domain, an approach, a setting or a scientific discipline? (c) its main schools of thoughts are defined as "advocacists", "ethicists", "interventionists", "normativists"; (d) the movement is in the maturation process as a discipline in which "interface", "distance", "interference" and "fusion" epistemological postures represent the fundamental steps; (e) parent disciplines (health sciences and law) competences, logics and cultures introduce duality and difficulties in knowledge production, validation and diffusion; (f) there is need to re-write the history of the HHR movement by inscribing it not only into the humanitarian or public health perspectives but also into the evolution of sciences and its social, political and economical conditions of emergence. The ambiguous epistemological status of this field, the need to re-write its history, the methodological duality in its research, the question of the competence of the knowledge validation, as well as the impact of HHR practice on national and international health governance are the challenges of its future development. To meet those challenges; we call for the creation and implementation of an international research agenda, the exploration of new research topics and the evaluation of the movement's contribution to the national and global public health and human rights governance. PMID- 21264519 TI - Cognitive motivational systems and life satisfaction in serious and persistent mental illness. AB - PURPOSE: Levels of life satisfaction are commonly used to measure attainment of recovery in serious and persistent mental illness (SPMI). There is some controversy about what constitutes life satisfaction and its measurement. This study explored the influence of cognitive motivational systems upon estimations of life satisfaction using structural equation modeling (SEM). METHODS: One hundred and ninety participants diagnosed with SPMI from Hawai'i's public mental health system completed instruments measuring cognitive motivational systems (e.g., behavioral activation and inhibition), psychological distress, and life satisfaction (e.g., quality of life and subjective well-being). RESULTS: Exploratory models indicated that higher behavioral inhibition or psychological distress predicts lower levels of life satisfaction. However, higher levels of behavioral activation predict higher levels of life satisfaction. There was no support for psychological distress as a mediator between cognitive motivational systems and life satisfaction. CONCLUSIONS: Overall, cognitive motivational systems accounted for 15% of the variance in life satisfaction while psychological distress accounted for 29%. This suggests the importance of considering cognitive schemas and motivation beyond symptomatology when examining life satisfaction. PMID- 21264520 TI - Degradation of poly (lactic acid) and nanocomposites by Bacillus licheniformis. AB - BACKGROUND, AIM, AND SCOPE: The disposal problem due to non-degradable petroleum based plastics has raised the demand for biodegradable polymers. The degradation of poly (lactic acid) (PLA) has been studied for several years, but the understanding of involved mechanisms is still incomplete. Based on our previous studies, and it is hypothesized an enzymatic involvement, the aim of this study was to continue investigations on the degradation of PLA and its nanocomposites by Bacillus licheniformis. MATERIALS AND METHODS: Biodegradation of PLA and its nanocomposites (CLOISITE 30B and SOMASIF MEE) was performed on compression molded, 25 * 25 * 0.6-mm films. Firstly, two plastic films were dipped into sterile nutrient broth inoculated with B. licheniformis and incubated at 32 degrees C. Then, to verify if biodegradation was due to extracellular esterase, the culture broth was filtered to remove B. licheniformis cells, and the plastic materials were put into this broth. RESULTS AND DISCUSSION: PLA degradation by B. licheniformis was accelerated by the presence of organoclays. After 5 months in liquid culture, nanocomposites showed only the 10% of residual mass, compared with the 60% of pure PLA. Extracellular esterase activity was detected in the filtered culture broth confirming that PLA biodegradation was probably due to this enzyme action. PMID- 21264521 TI - A cohort study assessing difficult patient encounters in a walk-in primary care clinic, predictors and outcomes. AB - BACKGROUND: Previous studies have found that up to 15% of clinical encounters are experienced as difficult by clinicians. OBJECTIVES: Explore patient and physician characteristics associated with being considered "difficult" and assess the impact on patient outcomes. DESIGN: Prospective cohort study. PARTICIPANTS: Seven hundred fifty adults presenting to a primary care walk-in clinic with a physical symptom. MAIN MEASURES: Pre-visit surveys assessed symptom characteristics, expectations, functional status (Medical Outcome Study SF-6) and the presence of mental disorders [Primary Care Evaluation of Mental Disorders, (PRIME-MD)]. Post visit surveys assessed satisfaction (Rand-9), unmet expectations and trust. Two week assessment included symptom outcome (gone, better, same, worse), functional status and satisfaction. After each visit, clinicians rated encounter difficulty using the Difficult Doctor-Patient Relationship Questionnaire (DDPRQ). Clinicians also completed the Physician's Belief Scale, a measure of psychosocial orientation. KEY RESULTS: Among the 750 subjects, 133 (17.8%) were perceived as difficult. "Difficult" patients were less likely to fully trust (RR = 0.88, 95% CI: 0.77-0.99) or be fully satisfied (RR = 0.78, 95% CI: 0.62-0.98) with their clinician, and were more likely to have worsening of symptoms at 2 weeks (RR = 0.75, 95% CI: 0.57-0.97). Patients involved in "difficult encounters" had more than five symptoms (RR = 1.8, 95% CI: 1.3-2.3), endorsed recent stress (RR = 1.9, 95% CI: 1.4-3.2) and had a depressive or anxiety disorder (RR = 2.3, 95% CI: 1.3 4.2). Physicians involved in difficult encounters were less experienced (12 years vs. 9 years, p = 0.0002) and had worse psychosocial orientation scores (77 vs. 67, p < 0.005). CONCLUSION: Both patient and physician characteristics are associated with "difficult" encounters, and patients involved in such encounters have worse short-term outcomes. PMID- 21264522 TI - Nurse-led rapid access vascular examination clinic triage reduces inappropriate referrals for peripheral arterial disease. AB - INTRODUCTION: Peripheral arterial disease causing intermittent claudication (IC) causes decreased quality of life and significant morbidity. We hypothesized that triage of patients referred with suspected IC at a nurse-led rapid access vascular examination (RAVE) clinic would identify those patients requiring vascular surgery assessment. METHODS: A prospective cohort study was performed. Patients referred with suspected IC were assessed using the Edinburgh claudication questionnaire (ECQ) and arterial Doppler assessment with segmental waveform analysis and calculation of ankle brachial pressure index (ABPI). Data were collected regarding cardiovascular risk and its modification. RESULTS: Of 451 consecutive patients, mean age was 65 years (range 30-89). Cardiovascular risk factors included: 173/451 (38%) current smokers (162/451 (36%) were ex smokers); diabetes, 22%; hypertension, 46%; ischaemic heart disease (angina), 29%; dyslipidaemia, 27%. Therapeutic risk modifications included: antiplatelet therapy, 64.4%; lipid-lowering therapy, 57.8%. abnormal ABPI readings were present in 264/451 (59%), with ratio <0.9 in 209/451 (46.3%), >1.3 in 48/451 (10.6%), and incompressible vessels 7/451 (1.5%). Normal ABPI (ratio >0.9 and <1.3, triphasic Doppler waveforms) were found in 187/451 (41%), these patient were considered inappropriate referrals. Considering those patient with PAD diagnosed on abnormal ABPI (<0.9 or >1.3), Doppler waveform analysis was more sensitive and specific than ECQ. CONCLUSIONS: Diagnosis of IC with clinical history alone is inaccurate in 41 percent of cases, leading to inappropriate referral to vascular surgery. Doppler waveform analysis had excellent sensitivity and specificity for prediction of ABPI <0.9. ABPI measurement in primary care could result in a more efficient use of clinical resources. PMID- 21264523 TI - Doctor-patient introductions: getting it right. PMID- 21264524 TI - Round one of the Adelaide and Meath Hospital/Trinity College Colorectal Cancer Screening Programme: programme report and analysis based on established international key performance indices. AB - BACKGROUND: In Ireland, colorectal cancer (CRC) is the second most frequently diagnosed cancer in men, after prostate cancer, and the second most frequently diagnosed cancer in women, after breast cancer. By 2020, the number of new cases diagnosed annually in Ireland is projected to have increased by 79% in men and 56% in women. Organised screening for CRC is already underway or is in the process of being rolled out in several European countries, either at a regional or national level. The Adelaide and Meath Hospital/ Trinity College Dublin Colorectal Cancer Screening Programme (TTC-CRC-SP) is Ireland's first pilot population based bowel screening programme. METHOD: Based on a biennial test model the pilot aimed to assess the accuracy of FIT and to evaluate the whole programme based on established international key performance indices. RESULTS: To date 9,993 individuals aged 50-74 years have been invited to participate in the TTC-CRC-SP with over 5,000 FIT's analysed. Overall uptake was 51% and FIT positivity was 10%. The programme has undertaken over 400 screening colonoscopies and detected 154 precancerous adenomas and 38 cancerous lesions. CONCLUSIONS: The first round of The Adelaide and Meath Hospital Tallaght/Trinity College Dublin Colorectal Cancer Screening Programme has been highly successful and confirmed that there is an advantage for FIT based two stage bowel cancer screening programmes. PMID- 21264525 TI - Selenium-induced up-regulation of the antioxidant defense and methylglyoxal detoxification system reduces salinity-induced damage in rapeseed seedlings. AB - The present study investigates the regulatory role of exogenous selenium (Se) in the antioxidant defense and methylglyoxal (MG) detoxification systems in rapeseed seedlings exposed to salt stress. Twelve-day-old seedlings, grown in Petri dishes, were supplemented with selenium (25 MUM Na(2)SeO(4)) and salt (100 and 200 mM NaCl) separately and in combination, and further grown for 48 h. The ascorbate (AsA) content of the seedlings decreased significantly with increased salt stress. The amount of reduced glutathione (GSH) and glutathione disulfide (GSSG) increased with an increase in the level of salt stress, while the GSH/GSSG ratio decreased. In addition, the ascorbate peroxidase (APX) and glutathione S transferase (GST) activity increased significantly with increased salt concentration (both at 100 and 200 mM NaCl), while glutathione peroxidase (GPX) activity increased only at moderate salt stress (100 mM NaCl). Glutathione reductase (GR) activity remained unchanged at 100 mM NaCl, while it was decreased under severe (200 mM NaCl) salt stress. Monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), catalase (CAT), glyoxalase I (Gly I), and glyoxalase II (Gly II) activities decreased upon the imposition of salt stress, whereas a sharp decrease of these activities was observed under severe salt stress (200 mM NaCl). Concomitant increases in the levels of H(2)O(2) and lipid peroxidation (MDA) were also measured. Exogenous Se treatment alone had little effect on the non-enzymatic and enzymatic components. However, further investigation revealed that Se treatment had a synergistic effect: in salt stressed seedlings, it increased the AsA and GSH contents; GSH/GSSG ratio; and the activities of APX, MDHAR, DHAR, GR, GST, GPX, CAT, Gly I, and Gly II. As a result, addition of Se in salt-stressed seedlings led to a reduction in the levels of H(2)O(2) and MDA as compared to salt stress alone. These results suggest that the exogenous application of Se rendered the plants more tolerant to salt stress-induced oxidative damage by enhancing their antioxidant defense and MG detoxification systems. PMID- 21264526 TI - alpha-Tomatine suppresses invasion and migration of human non-small cell lung cancer NCI-H460 cells through inactivating FAK/PI3K/Akt signaling pathway and reducing binding activity of NF-kappaB. AB - alpha-Tomatine, isolated from Lycopersicon esculentum Linn., is a naturally occurring steroidal glycoalkaloid in immature green tomatoes. Some reports demonstrated that alpha-tomatine had various anticarcinogenic properties. The purpose of this study is to investigate the anti-metastatic effect of alpha tomatine in NCI-H460 human non-small cell lung cancer cells. First, the results showed that alpha-tomatine significantly suppressed the abilities of the adhesion, invasion, and migration of NCI-H460 cells under non-cytotoxic concentrations. Molecular data also showed alpha-tomatine could inhibit the activation of focal adhesion kinase (FAK) and phosphatidylinositol 3-kinase (PI3K)/Akt signal involve in the downregulation the enzyme activities, protein and messenger RNA levels of matrix metalloproteinase-7 (MMP-7). Next, alpha tomatine also strongly inhibited the degradation of inhibitor of kappaBalpha (IkappaBalpha) and the nuclear levels of nuclear factor kappa B (NF-kappaB). Also, a dose-dependent inhibition on the binding ability of NF-kappaB by alpha tomatine treatment was further observed. Furthermore, alpha-tomatine significantly decreased the levels of phospho-Akt and MMP-7 in Akt1-cDNA transfected cells concomitantly with a marked reduction on cell invasion and migration. Presented results indicated alpha-tomatine might be further application for treating cancer metastasis. PMID- 21264527 TI - Anti-adrenergic medications and edema development after intracerebral hemorrhage. AB - BACKGROUND: Use of antihypertensive medications is common after intracerebral hemorrhage (ICH). Medications that block adrenergic activation (e.g., beta blockers and the alpha(2)-agonist, clonidine) may reduce the inflammatory response and therefore have secondary benefit after ICH. METHODS: The patients with acute ICH enrolled in the placebo arm of the CHANT trial were included. Univariate and multivariate analyses were undertaken for factors associated with blood pressure medication use, edema at 72 h, and clinical outcome at 90 days. RESULTS: Of the 303 patients, 87.8% received some antihypertensive treatment during the first 72 h of hospitalization. Edema volume on neuroimaging at 72 h was independently associated with clinical outcome. Use of anti-adrenergic medications was associated with less edema after controlling for hemorrhage volume and blood pressure. CONCLUSIONS: Antihypertensive medications that antagonize the sympathetic nervous system may reduce perihematomal edema after ICH. PMID- 21264528 TI - Assessment of qualitative changes of Acid mucins among sudanese colorectal carcinoma patients. AB - PURPOSE: This study aimed to assess the qualitative changes in the amount of acid mucin in colorectal carcinoma (CRC) compared to normal colon. METHODS: A total number of 100 samples were examined, 50 were colorectal cancer samples (cases) and 50 were normal (controls), all were stained with Alcian blue method. RESULTS: Acid mucin increased, in different levels, in 30 (60%) of the cases compared to only six (12%) of controls (P < 0.0001). However, complete absence of acid mucin was detected among 10 (20%) of cases compared to none among controls. CONCLUSIONS: CRC is associated with secretion of increased amounts of acid mucin in most cases, and that should be considered as a valuable histological finding. PMID- 21264529 TI - Prognostic value of androgen receptor expression in operable triple-negative breast cancer: a retrospective analysis based on a tissue microarray. AB - The aim of this study is to analyze the prognostic value of androgen receptor (AR) expression for patients with triple-negative breast cancer (TNBC). Clinical data of these patients were collected and analyzed, and immunohistochemical staining for AR was performed on tissue microarrays of operable breast cancer from 287 patients with TNBC, who were treated at Sun Yat-sen University Cancer Center from January 1995 to December 2008. AR expression was found in 25.8% of the cases with TNBC. TNBC patients with AR negative have a higher proportion of positive lymph node. A significant correlation was found between AR expression and disease-free survival (DFS) and overall survival (OS). Univariated analysis indicated that AR expression had a significant prognostic value in TNBC patients, whereas multivariate analysis indicated that AR was a significant independent prognostic factor of DFS (P = 0.032) in all patients. Our results suggested that AR was a favorable prognostic factor of DFS and OS in patients with TNBC. Therefore, TNBC may be further divided into two subtypes according to AR status. PMID- 21264530 TI - Aberrant microRNA expression in human cervical carcinomas. AB - Because altered microRNAs (miRNAs) expression patterns have been observed in a variety of diseased tissues, miRNA expression was compared in human cervical cancer tissues relative to adjacent normal cervical tissues in the present study. Microarray chips with 924 probes were used to detect the expression of miRNAs in cervical cancer tissue and adjacent normal cervical tissue of 13 patients with cervical cancer (11 squamous cervical cancers, one cervical adenocarcinoma, and one cervical sarcoma), all of whom were infected with human papilloma virus (HPV) 16 and/or HPV18. Compared to the expression levels in normal cervical tissues, 18 miRNAs (1.9%) were significantly upregulated (increase of >=2*), and 19 miRNAs (2.1%) were significantly downregulated (decrease of <=0.5*) in cervical cancer tissues. miRNA expression was independent of lymph node involvement, vascular invasion, and pathological differentiation. Taken together, cervical cancer tissues have altered expression of miRNAs relative to adjacent normal tissues. Further studies are necessary to determine whether aberrant miRNA expression is related to the pathogenesis of cervical cancer. PMID- 21264531 TI - EGFR expression correlates with decreased disease-free survival in triple negative breast cancer: a retrospective analysis based on a tissue microarray. AB - The aim of this study was to analyze the prognostic value of EGFR expression for patients with triple-negative breast cancer (TNBC). Clinical data of these patients were collected and analyzed, and immunohistochemical staining for EGFR was performed on tissue microarrays of operable breast cancer from 287 patients with TNBC, who were treated at Sun Yat-sen University Cancer Center from January 1995 to December 2008. EGFR expression was found in 36.2% of the cases with TNBC. A significant correlation was found between EGFR expression and disease-free survival (DFS). Univariated analysis indicated that EGFR expression had a significant prognostic value in TNBC patients, whereas multivariate analysis indicated that EGFR was a significant independent prognostic factor of DFS (P = 0.011) in all patients. Our results suggested that EGFR was an independent prognostic factor of DFS in patients with TNBC. Therefore, EGFR could become a good therapeutic target in the treatment of TNBC. PMID- 21264532 TI - miR-107 targets cyclin-dependent kinase 6 expression, induces cell cycle G1 arrest and inhibits invasion in gastric cancer cells. AB - MicroRNAs (miRNAs) have emerged as post-transcriptional regulators that are critically involved in the pathogenesis of a number of human cancers. Recently, cyclin-dependent kinase 6 (CDK6) is found to be up-regulated in several types of human tumors and has been implicated in cancer initiation and progression. We have identified miR-107 as a potential regulator of CDK6 expression. A bioinformatics search revealed a putative target site for miR-107 within the CDK6 3' untranslated region. Expression of miR-107 in gastric cancer cell lines was found inversely correlated with CDK6 expression. miR-107 could significantly suppress CDK6 3' UTR luciferase reporter activity, and this effect was not detectable when the putative 3' UTR target site was mutated. Consistent with the results of the reporter assay, ectopic expression of miR-107 reduced both mRNA and protein expression levels of CDK6, inhibited proliferation, induced G1 cell cycle arrest, and blocked invasion of the gastric cancer cells. Our results suggest that miR-107 may have a tumor suppressor function by directly targeting CDK6 to inhibit the proliferation and invasion activities of gastric cancer cells. PMID- 21264533 TI - Overexpression of Fc mu receptor (FCMR, TOSO) gene in chronic lymphocytic leukemia patients. AB - Rai and Binet staging systems that have been used as a standard method for evaluating the prognosis of chronic lymphocytic leukemia (CLL) have some restrictions in distinguishing the early stage CLL patients that will progress rapidly. To solve this shortcoming, prognostic parameters other than staging have become important in the recent years. Intracellular upregulation of Fc mu receptor (FCMR, FAIM3/TOSO) gene in the leukemic lymphocytes of the patients with CLL may be an important parameter in predicting the progression of the disease. In this study, FCMR mRNA expression levels were evaluated in 50 CLL patients and in 50 healthy controls. FCMR mRNA expression was found to be significantly higher in CLL patients than in healthy controls. We, then, evaluated FCMR mRNA levels according to the stages of CLL. Rai stage 0, I, II cases were compared with stage III and IV, and Binet A was compared with Binet B and C according to FCMR mRNA levels. In cases with higher risks, Rai stage III, IV and Binet stage B and C, FCMR mRNA levels were also significantly higher. In addition, overexpression of the FCMR seems to be promoting the chromosomal abnormalities. As a result, we found that the mRNA levels of FCMR in the CLL patients are 23-fold higher than that of the control group and this may suggest that it can be associated with the disease progression and survival. For this reason and because of the simplicity of analyzing with Q-PCR, it can be a useful clinical parameter, after its importance has been shown in larger and multi-variate studies. PMID- 21264534 TI - Prognostic value of Smac expression in rectal cancer patients treated with neoadjuvant therapy. AB - The objective was to evaluate expression of second mitochondria-derived activator of caspase (Smac) expression before and after treatment in patients treated with preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer and to correlate the clinicopathological characteristics and level of Smac expression with pathologic response and outcome. Expression of biomarker was evaluated by immunohistochemistry in tumor samples from 98 patients with clinical Stage II and III rectal cancer treated with preoperative pelvic radiotherapy plus concurrent chemotherapy. All patients received a standardized total mesorectal excision procedure after a long interval of 4-6 weeks. For Smac, patients with a good response to neoadjuvant CRT tended to have higher pre-therapy levels (P = 0.007). The level of Smac expression decreased after neoadjuvant therapy (P = 0.016). High expression of Smac before CRT, and high Dworak's tumor regression grade (TRG) were significantly associated with improved 5-year disease-free survival (P < 0.05). Pretreatment nodal status also was significantly associated with 5-year disease-free survival and 5-year local relapse-free survival (P < 0.05). Multivariate analysis confirmed that the pretreatment expression of Smac and Lymph nodal status were independent prognostic factors. Our study suggests that high expression of Smac before neoadjuvant CRT could predict good outcome in locally advanced rectal cancer patients. PMID- 21264535 TI - The role of XPD in cell apoptosis and viability and its relationship with p53 and cdk2 in hepatoma cells. AB - We investigated the role of XPD in cell apoptosis of hepatoma and its relationship with p53 during the regulation of hepatoma bio-behavior. RT-PCR and Western blot were used to detect the expression levels of XPD, p53, c-myc, and cdk2. The cell apoptosis and cell cycle were analyzed with flow cytometry. Compared with the control cells, XPD-transfected cells displayed a lower viability and higher apoptosis rate. A decreased expression of p53 gene was detected in XPD-transfected cells. In contrast, both c-myc and cdk2 showed increased expressions of mRNAs and proteins in the transfected cells. Our results indicate that XPD may play an important role in cell apoptosis of hepatoma by inducing an over-expression of p53, but suppressing expressions of c-myc and cdk2. PMID- 21264536 TI - The relevance and role of vascular endothelial growth factor C, matrix metalloproteinase-2 and E-cadherin in epithelial ovarian cancer. AB - We investigated the correlation of vascular endothelial growth factor C, matrix metalloproteinase-2, E-cadherin to explore mechanisms of vascular endothelial growth factor C in the metastasis of ovarian cancer and the relationship of prognosis. We applied immunohistochemistry to investigate the expression of vascular endothelial growth factor C, matrix metalloproteinase-2 and E-cadherin in ovarian tissues of 227 patients. We adopted Pearson chi-square test, Spearman correlation coefficient, univariate analysis, multivariate analysis, and Kaplan Meier method. The positive rate of vascular endothelial growth factor C, matrix metalloproteinase-2 and E-cadherin in ovarian cancer was higher than that in borderline and benign tumor (P < 0.01). Vascular endothelial growth factor C was positively correlated with matrix metalloproteinase-2 (r = 0.665, P < 0.01) while negatively with E-cadherin(r = -0.185, P < 0.05). Univariate analysis showed clinical stage, pathologic grade, lymphatic metastasis, residual disease, chemotherapy, ascites, vascular endothelial growth factor C, and matrix metalloproteinase-2-influenced survival time (P < 0.05). In Cox multivariate analysis, all the aforementioned factors were found to be independent prognostic factors except pathologic grade. Vascular endothelial growth factor C was a new target to assess the prognosis of ovarian cancer. The expression of vascular endothelial growth factor C in ovarian cancer was related to matrix metalloproteinase-2 and E-cadherin. PMID- 21264537 TI - Gemcitabine and cisplatin combination regimen in patients with anthracycline- and taxane-pretreated metastatic breast cancer. AB - This study was conducted to evaluate the response rate of gemcitabine and cisplatin as second-line combination chemotherapy in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. Thirty eight eligible women with measurable disease and anthracycline- and taxane pretreated MBC were enrolled. The chemotherapy treatment consisted of gemcitabine (1,250 mg/m(2) by intravenous infusion over 30 min on days 1 and 8) and cisplatin (75 mg/m(2) by intravenous infusion over 1 h on day 1), which were administered every 21 days. Thirty-seven of 38 (97.4%) of patients were assessable for response. The objective response rate was 42.1% (95% CI, 26.4-57.8%) with 16 partial responses. The median time to progression (TTP) and overall survival (OS) for all patients were 5.4 months (95% CI, 2.7-8.1 months) and 13.9 months (95% CI, 9.4-18.4 months), respectively. The most frequent hematologic-related adverse events were grade 3/4 leucopenia and thrombocytopenia, observed in 10 patients (27.0%) and 11 (29.7%), respectively. Grade 3 stomatitis was observed in 3 (8.1%) patients. No grade 4 nonhematologic toxicity was observed in this study. No treatment-related deaths occurred during the study. In conclusion, the combination of gemcitabine and cisplatin is a safe and tolerable regimen as second-line combination for patients with anthracycline- and taxane-pretreated MBC. PMID- 21264538 TI - A 7-year prospective study of routine histopathological evaluation of the lacrimal sac wall incisional biopsy specimens obtained during external dacryocystorhinostomy in adults and a review of the literature. AB - The most common lacrimal sac pathology is chronic inflammation with or without occlusive fibrosis. However, a substantial number of lacrimal sac-specific pathologies were reported throughout the literature which may mimic chronic inflammation and be misdiagnosed. From a tertiary ophthalmic care centre in Serbia, in a single ophthalmic pathology laboratory, during a 7-year period (January 2004 to October 2010), a 599 consecutive lacrimal sac wall biopsy samples routinely obtained during external dacryocystorhinostomy in adult patients with clinically presumed primary acquired lacrimal drainage system obstruction were analysed. Although non-specific lacrimal sac pathology was present in the vast majority of cases (578 biopsy specimens; 96.49%), this report also reveals a relatively substantial number (21 biopsy specimens; 3.51%) of clinically non-suspected or intraoperatively unexpected primary lacrimal sac specific pathology--among them, six lesions with malignant biological behaviour were identified: one microinvasive squamous cell carcinoma and five malignant lymhoproliferative lesions. Usefulness of routine lacrimal sac wall biopsy during surgery for primary acquired lacrimal drainage system obstruction is undoubtful and commensurate with the constant need for better understanding of the pathological processes that involve lacrimal drainage system. PMID- 21264539 TI - Orbital metastasis of retroperitoneal leiomyosarcoma. AB - Leiomyosarcoma is a relatively rare form of cancer most commonly found in the uterus, stomach, small intestine, retroperitoneum, and vascular tissue. Metastasis is common and surgery with a wide margin of resection is generally considered the most effective management. Leiomyosarcomas, metastatic or primary, of the orbit have rarely been reported. Herein, we report the case of a 51-year old female with metastatic orbital leiomyosarcoma. The diagnosis was based on her history of leipmyosarcoma, orbital ultrasonography, and computed tomography and confirmed by postoperative histochemistry. She was treated with surgical excision and has remained without recurrence 1 year after surgery. PMID- 21264540 TI - Quantitative analysis of promoter methylation of the EDNRB gene in gastric cancer. AB - Hypermethylation has been shown in the promoter region of the endothelin receptor B (EDNRB) gene in several human tumors. However, its role in gastric cancer formation is still unclear. In this study, the methylation status of the EDNRB gene in paired gastric cancer tissues and adjacent normal tissues from 96 patients was detected quantitatively using pyrosequencing. The results showed the methylation of promoter of EDNRB gene in gastric cancer (50.42 +/- 9.03%) was significantly higher than in adjacent normal tissues (6.47 +/- 2.98%) (P < 0.01). Among 96 tumor tissues, promoter hypermethylation of the EDNRB gene was correlated with tumor infiltration (T1: 47.4 +/- 7.31% T2:48.2 +/- 9.17% T3:52.9 +/- 6.48% T4:53.2 +/- 10.45%), lymph node metastasis (N0:45.4 +/- 6.99% N1:49.0 +/- 9.10% N2:52.0 +/- 8.40% N3:53.7 +/- 9.92%), and distant metastasis (M0:48.9 +/- 6.99% M1:53.9 +/- 11.98%) (P < 0.05), but it was not associated with other clinicopathological characteristics. In addition, the treatment of the human gastric cancer cell line, SGC-7901, with demethylation agent can restore the expression of EDNRB. Our results suggest that promoter hypermethylation of EDNRB gene is highly prevalent in gastric cancer, which may play a role in the pathogenesis of gastric cancer. Futhermore, hypermethylation of EDNRB gene was remarkably related to infiltration and metastasis of gastric cancer and may attribute to the tumor progression. PMID- 21264541 TI - Long-term recurrence-free survival in a patient with pancreatic carcinosarcoma: a case report with a literature review. AB - Here, we presented a case of carcinosarcoma of the pancreas in a 53-year-old woman. The carcinosarcoma was in the head of pancreas. She underwent a pancreaticoduodenectomy. The tumor was grossly yellowish-whitish. Histologic evaluation of the tumor revealed 2 elements separated from each other. One component was conventional pancreatic ductal adenocarcinoma, and the other component showed sarcomatous growth pattern composed of pleomorphic spindle cells. Immunohistochemically, the adenocarcinoma component was reactive for antibodies to cytokeratin 18 and epithelial membrane antigen. The sarcomatous component was reactive for smooth muscle antibody. These findings led to a diagnosis of pancreatic carcinosarcoma. The patient was treated with gemcitabine, adriamycin, and cisplatin after the operation. Although previously reported patients with pancreatic carcinosarcoma showed a very poor outcome, this patient has remained free of recurrence for 20 months, which is the longest recurrence free survival time recorded for this type of cancer. This treatment plan may be a feasible option. PMID- 21264542 TI - Cell membrane and cytoplasmic epidermal growth factor receptor expression in pancreatic ductal adenocarcinoma. AB - The significance of over-expression of epidermal growth factor receptor (EGFR) in pancreatic carcinoma is unclear. In this study, we examined the association between EGFR over-expression (membranous and cytoplasmic), the associated histopathologic features and clinical outcomes in post-resection pancreatic cancer patients. EGFR expression was determined immunohistochemically in 90 patients who underwent resection for pancreatic cancer. Cytoplasmic expression was considered positive if EGFR expression was seen in the cytoplasm in >= 10% of cells. Cell membrane staining was scored from 0 to 3+, with 2+ and 3+ being considered as membrane over-expression. Overall survival and progression-free survival were calculated using the Kaplan-Meier method, and survival curves were compared by the log-rank test. Out of 90 patients, 51 (57%) and 74 (68%) patients had membrane and cytoplasmic EGFR over-expression, respectively. There was a statistically significant correlation between cell membrane EGFR over-expression and lymph node positivity (P = 0.03). Patients with membrane EGFR over-expression had a shorter median progression-free survival (10.7 vs. 17.0 months, P = 0.02) and overall survival (15.9 months vs. 25.3 months, P = 0.17). Cytoplasmic EFGR over-expression was not significantly associated with recurrence or survival. Membrane EGFR over-expression in resected pancreatic cancer patients was associated with worse clinical outcomes than non-over-expression. PMID- 21264543 TI - Cyclin A and cyclin B1 overexpression in differentiated thyroid carcinoma. AB - Approximately 30% of patients with thyroid nodules have indeterminate or suspicious fine-needle aspiration (FNA) biopsy results. These patients usually undergo thyroidectomy because of cancer risk. Our aim was to determine diagnostic value of cyclin A and cyclin B1 immunohistochemistry added to routine cytology and their expression on histological sections. We studied the expression of cyclin A and cyclin B1 in FNA biopsies and resection specimens of 168 indeterminate or suspicious FNA biopsy results retrospectively at an academic hospital using immunohistochemistry. Malignant histopathology consisted 64 of resection specimens (58 papillary, 4 follicular, 1 medullary, and 1 Hurthle cell carcinoma). Cyclin A was overexpressed in 51.5% of malignant cases in contrast to 31.7% of 104 benign pathology specimens (P = 0.025). Cyclin B1 was positive in 39.1% of malignant specimens in contrast to 15.4% of benign cases (P = 0.001). Cyclin A overexpression was not linked to cyclin B1 overexpression. No association was found between overexpression of cyclin A, cyclin B1 and age, thyroiditis, multifocality, tumor size, extra-thyroidal extension, capsule infiltration, lymph node and distant organ metastases and TNM stage in malignant cases. Female patients with thyroid carcinoma overexpressed significantly more cyclin B1 than male patients (P = 0.015). Retrospective analysis of cyclin A and cyclin B1 in FNA biopsies yielded negative results for both benign and malignant cases. In conclusion, cyclin A and cyclin B1 are useful markers in the distinction of benign and malignant thyroid tumors and can increase diagnostic accuracy. PMID- 21264544 TI - RRP22: a novel neural tumor suppressor for astrocytoma. AB - Astrocytomas are the most common neoplasm of the central nervous system. Although progress has been made, the survival rate of astrocytoma is still poor. Therefore, improving the prognosis of patients with astrocytomas relies on effective therapies that are directed against unique molecular aberrations. Previous studies have revealed that a novel member of the Ras superfamily, RRP22, which is located on chromosome 22 on the 12q site, is exclusively expressed in the central nervous system. RRP22 can be modified by farnesyl and down-regulated in a variety of neural tumor cell lines. In this study, we analyzed the mRNA level of RRP22 in normal brain tissues and astrocytomas using quantitative RT PCR. Our results showed that the mRNA level in astrocytomas was significantly down-regulated compared to levels in normal tissues. As the pathological grade (World Health Organization (WHO) classification 2007) increased, the expression of RRP22 decreased. However, according to our research, there was no significant difference between malignant astrocytomas with pathological grades of III or IV. To investigate the possible effects of RRP22 on the biological behavior of glioma cells, we transfected RRP22 into a malignant cell line of astrocytomas, U251. We found that RRP22 inhibited growth, decreased invasiveness, and induced cell death. Thus, RRP22 is a special neural tumor suppressor for human astrocytomas, although further studies are needed to define the detailed mechanisms. PMID- 21264545 TI - Hyponatremia associated with Ipilimumab-induced hypophysitis. AB - A 75-year-old woman with a history of stage IV metastatic melanoma underwent treatment with the CTLA-4 blocking agent Ipilimumab. She presented 2 months after initiating treatment with a severe headache. Laboratories were consistent with severe hyponatremia. MRI of the brain revealed enlargement of the pituitary gland, enhancement of the infundibulum, and an enhancing, centrally necrotic foci in the anterior pituitary. Based on the clinical and radiographic findings, she was diagnosed with treatment-related syndrome of inappropriate antidiuretic hormone secretion (SIADH). Effective treatment consisted of fluid restriction, hyperosmolar therapy, and steroids. PMID- 21264546 TI - Safety and efficacy of gemcitabine plus cisplatin combination in pretreated metastatic breast cancer patients. AB - Metastatic breast cancers (MBC) previously treated with anthracyclines (A) and taxanes (T) have a complicated management. Gemcitabine (G)-cisplatin (C) combinations have been used as synergistic salvage therapy in MBC and are considered as another option for patients with important symptoms and aggressive visceral disease. We analyzed the safety and efficacy of GC in AT-pretreated MBC, as well as overall survival (OS) and time to progression (TTP). Forty-nine subjects received IV G 750 mg/m(2) and C 30 mg/m(2), both d1 and d8 every 3 weeks. Response evaluation was performed every second cycle and in the end of treatment. GC protocol was the first-line palliative chemotherapy in half of the cases, and median number of cycles/patient were 4(2-12). Lung (75.5%) was the most frequent site of metastasis. Most of the patients related clinical improvement with chemotherapy with minimal/mild tolerable collateral effects in 85.7% of cases. Following 34 months, mean OS/TTP was 13.12/6.6 months. Objective responded patients (40.3%) were statistically associated with the improvement in symptoms after CT (P < 0.01), and OS was directly correlated with chemotherapy response (P < 0.01). HER-2 overexpression was a prognostic factor with reduced OS (P = 0.01). GC protocol was effective and tolerable in objective-responded patients. PMID- 21264547 TI - Capecitabine "metronomic" chemotherapy for palliative treatment of elderly patients with advanced gastric cancer after fluoropyrimidine-based chemotherapy. AB - We aimed to study the efficacy and safety of metronomic capecitabine in pretreated elderly patients with advanced gastric cancer. Eligible patients with advanced gastric cancer were treated with capecitabine at a fixed dose 1,000 mg daily (days 1-28 continuously, every 5 weeks) until disease progression or significant toxicity. Tumor response was assessed every 10 weeks by computed tomography scan using Response Evaluation Criteria in solid tumors. In total, 45 patients were enrolled, of whom 43 were evaluated for efficacy and 45 for safety. A median of 3 cycles (range 1-12) were administered. Metronomic chemotherapy had a disease control rate (DCR) at 8 weeks of 51.1% (95% CI 25.7-67.8), and the objective response rate was 20.9% (95% CI 13.1-38.5, 9 of 43 assessable patients). The median time-to-progression and median overall survival were 3.6 months (95% CI: 3.2-4.0 months) and 7.6 months (95% CI 7.0-8.2 months), respectively. Grade II neutropenia and thrombocytopenia were observed in 13.3 and 2.2% of patients, respectively. Grade II/III nonhematological toxicities included diarrhea (4.4%), stomatitis (13.4%), and hand-foot syndrome (15.5%). No grade IV toxicity, neutropenic fever or treatment-related deaths occurred. Metronomic capecitabine was effective and well tolerated as palliative treatment in elderly patients with advanced gastric cancer after fluoropyrimidine-based chemotherapy. PMID- 21264548 TI - Fatal interstitial lung disease associated with gemcitabine and erlotinib therapy for lung cancer. AB - Gemcitabine in combination with the oral epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib, is a treatment option for patients with advanced pancreatic cancer. Lung toxicity has been described for each of these drugs. A 59-year-old man with advanced non-small-cell lung cancer developed acute respiratory failure with bilateral interstitial lung disease 4 weeks after the onset of second-line combination therapy that included gemcitabine and erlotinib. Despite discontinuation of gemcitabine and erlotinib, treatment with corticosteroids was ineffective and the patient gradually deteriorated and died with progressive respiratory failure 2 months after the start of the gemcitabine/erlotinib combination. It was concluded that a synergistic effect between gemcitabine and erlotinib could have been responsible for this fatal pulmonary toxicity. Physicians should be aware of the potential severe lung toxicity of this combination. The potential role of corticosteroids in the management of this toxicity is unknown. PMID- 21264549 TI - "Ecstasy" associated deaths: what is a fatal concentration ? Analysis of a case series. AB - Amphetamine derivative drugs, particularly 3,4-methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, are popular recreational drugs. MDMA is associated with causing death by a number of mechanisms, including hyperpyrexia, cardiac arrhythmia water intoxication and liver failure. Seventy-seven deaths where MDMA was detected in body fluids/organs were reviewed. Of these cases 59 deaths had MDMA present in blood. In 13 cases death was attributable to the toxic effects of MDMA alone with a range of 0.478-53.9 mg/l, mean 8.43 mg/l, median 3.49 mg/l. In 22 cases death was due to polydrug use, with an MDMA range of 0.04 41.5 mg/l, mean 2.90 mg/l, median 0.76 mg/l. In 24 cases death was due to trauma with an MDMA range of 0.035-4.81 mg/l, mean 0.862 mg/l, median 0. 483 mg/l. There is considerable overlap between the concentration of MDMA seen in deaths from direct MDMA toxicity and deaths associated with trauma. These findings show, that like other stimulant drugs, no specific concentration can be used to determine death without consideration of the history and full autopsy findings. PMID- 21264550 TI - Neural correlates of personality dimensions and affective measures during the anticipation of emotional stimuli. AB - Neuroticism and extraversion are proposed personality dimensions for individual emotion processing. Neuroticism is correlated with depression and anxiety disorders, implicating a common neurobiological basis. Extraversion is rather inversely correlated with anxiety and depression. We examined neural correlates of personality in relation to depressiveness and anxiety in healthy adult subjects with functional magnetic resonance imaging during the cued anticipation of emotional stimuli. Distributed particularly prefrontal but also other cortical regions and the thalamus were associated with extraversion. Parieto-occipital and temporal regions and subcortically the caudate were correlated with neuroticism and affective measures. Neuroticism-related regions were partially cross correlated with anxiety and depression and vice versa. Extraversion-related activity was not correlated with the other measures. The neural correlates of extraversion compared with those of neuroticism and affective measures fit with concepts of different neurobiological bases of the personality dimensions and point at predispositions for affective disorders. PMID- 21264552 TI - A novel insertion mutation of K294RGG within BCR-ABL kinase domain confers imatinib resistance: sequential analysis of the clonal evolution in a patient with chronic myeloid leukemia in blast crisis. AB - BCR-ABL kinase domain mutations were sequentially analyzed in a patient with chronic myeloid leukemia (CML) who exhibited repeated B-lymphoid blast crisis (CML-BC) during treatment with imatinib and dasatinib. We first identified five mutant BCR-ABL clones: Y253H, G250E, F311L, F317L and K294RGG, which was generated by two-nucleotide mutations and six-nucleotide insertion, at the third BC during the imatinib treatment, and retrospectively found that three of them (Y253H, G250E, K294RGG) were already present at the second BC. The in vitro analysis using K294RGG mutant BCR-ABL-expressing 32D cells revealed that K294RGG mutation was imatinib resistant but dasatinib sensitive. Consistent with the in vitro data, the clone with K294RGG mutation was eliminated by the dasatinib treatment in this patient. During the imatinib treatment, several mutant clones emerged and expanded, while additional mutations on the same allele were not acquired. However, after the dasatinib treatment, wild-type BCR-ABL clone disappeared and T315I or F317L mutation was acquired in G250E and Y253H mutant clones on the same allele without the emergence of each sole mutant clone. Cytogenetic and immunoglobulin heavy chain gene rearrangement analysis revealed that all mutant clones that appeared in this patient might be derived from the same CML clone. PMID- 21264551 TI - Subcortical brain atrophy persists even in HAART-regulated HIV disease. AB - The purpose of this study was to determine the pattern and extent of caudate nucleus and putamen atrophy in HIV-infected men with well-controlled immune status and viral replication. 155 men underwent structural brain magnetic resonance imaging; 84 were HIV-infected and 71 were uninfected controls. MRI data were processed using the Fully Deformable Segmentation routine, producing volumes for the right and left caudate nucleus and putamen, and 3-D maps of spatial patterns of thickness. There was significant atrophy in the HIV-infected men in both the caudate and putamen, principally in the anterior regions. The volume of the basal ganglia was inversely associated with the time since first seropositivity, suggesting that either there is a chronic, subclinical process that continues in spite of therapy, or that the extent of the initial insult caused the extent of atrophy. PMID- 21264553 TI - Gender differences in osteoporosis and fractures. AB - BACKGROUND: Osteoporosis is generally thought of as a "woman's disease" because the prevalence of osteoporosis and the rate of fractures are much higher in postmenopausal women than in older men. However, the absolute number of men affected by osteoporosis and fractures is large, as at least 2.8 million men in the United States are thought to have osteoporosis. QUESTIONS/PURPOSES: The purposes of this review are to (1) highlight gender differences in osteoporosis and fracture risk, (2) describe disparities in treatment and outcomes after fractures between men and women, and (3) propose solutions to reducing disparities in treatment and prevention. METHODS: A literature survey was conducted using MEDLINE with a variety of search terms and using references from the author's personal collection of articles. A formal search strategy and exclusion criteria were not employed and the review is therefore selective. WHERE ARE WE NOW?: Postmenopausal women have a higher prevalence of osteoporosis and greater incidence of fracture than older men. Despite the higher fracture risk in postmenopausal women, older men tend to have worse outcomes after fracture and poorer treatment rates, although less is known about the disease course in men. Multifaceted interventions to improve the screening and treatment for osteoporosis were recently developed. WHERE DO WE NEED TO GO?: Improvement in treatment rates of those at risk, regardless of gender, is an important goal in osteoporosis management. HOW DO WE GET THERE?: Further development and evaluation of cost-effective, multifaceted interventions for screening and treatment of osteoporosis and fractures are needed; such interventions will likely improve the primary prevention of fractures. PMID- 21264554 TI - Breakout session: Diversity, cultural competence, and patient trust. AB - BACKGROUND: The patient population served by orthopaedic surgeons is becoming increasingly more diverse, but this is not yet reflected in our workforce. As the cultural diversity of our patient population grows, we must be adept at communicating with patients of all backgrounds. WHERE ARE WE NOW?: Efforts to improve the diversity of our workforce have been successful in increasing the number of female residents, but there has been no improvement in the number of African American and Hispanic residents. There is currently no centralized effort to recruit minority and female students to the specialty of orthopaedic surgery. The American Academy of Orthopaedic Surgeons has been leading workshops to train residents and practicing surgeons in communication skills and cultural competency. WHERE DO WE NEED TO GO?: We must train the current generation of orthopaedic surgeons to become adept at interacting with patients of all backgrounds. While initiatives for crosscultural communication in orthopaedic surgery have been established, they have not yet been universally incorporated into residency training and Continuing Medical Education programs. HOW DO WE GET THERE?: We must continue to recruit the brightest students of all backgrounds, with a concerted effort to provide equal opportunities for early guidance to all trainees. Opportunities to improve diversity among orthopaedic surgeons exist at many stages in a future physician's career path, including "shadowing" in high school and college and continuing with mentorship in medical school. Additional resources should be dedicated to teaching residents about the immediate relevancy of cultural competency, and faculty should model these proficiencies during their patient interactions. PMID- 21264556 TI - Evidence-based practice and health technology assessment: a call for anesthesiologists to engage in knowledge translation. PMID- 21264555 TI - Do we need gender-specific total joint arthroplasty? AB - BACKGROUND: Gender-specific differences in knee and hip anatomy have been well documented. Although it has been accepted these differences exist, there is controversy regarding if and how these differences should be addressed with gender-specific implant designs. QUESTIONS/PURPOSES: (1) What are the anatomic and morphologic differences, if any, in the knee and hip between men and women? (2) Do gender-specific TKA designs provide better clinical functioning, survivorship, and improved fit in women? (3) How have anatomic differences in the hip been addressed, if at all, by THA? METHODS: We conducted a systematic review of the MEDLINE database to identify all articles reviewing basic science and clinical outcomes of gender-specific total knee and total hip implants. From these, we reviewed 253 studies. RESULTS: The anatomic studies elucidated multiple differences in the anatomy of knees and hips between men and women. All reviewed studies report similar clinical function and satisfaction scores between men and women for gender-specific TKA and no improvement in these scores when comparing gender-specific TKA to unisex TKA. Current modularity in THA appears to accommodate any anatomic differences in the hip. CONCLUSIONS: Based on the available literature, there is no difference in the outcome of patients with a gender-specific knee arthroplasty versus a unisex arthroplasty. It does not appear gender-specific THAs would provide any benefit over current systems. PMID- 21264557 TI - Nasotracheal intubation using the Airtraq(r) optical laryngoscope in patients with a difficult airway. PMID- 21264558 TI - Geographic differences in the target-controlled infusion estimated concentration of propofol: bispectral index response curves. AB - PURPOSE: Variability in drug responses could result from both genetic and environmental factors. Thus, drug effect could depend on geographic location, although regional variation is not generally acknowledged as a basis for stratification. There is evidence that the pharmacokinetic set developed in a European population for the target-controlled infusion (TCI) of propofol does not apply in Chinese patients; however, we are not aware of previous studies comparing the estimated concentration-bispectral index (BIS) response of Caucasian patients in Europe with that of Chinese patients in China. METHODS: The DiprifusorTM TCI pump, incorporating the pharmacokinetic model proposed by Marsh et al., was applied to 30 Caucasian patients in Austria and 30 Chinese patients in China. The estimated plasma concentration (C(p)) of propofol for the two groups was set at 1 MUg.mL(-1) and increased by 1 MUg.mL(-1) every minute to gradually reach 5 MUg.mL(-1) after 5 min. The BIS values were fitted against the estimated C(p) and the predicted effect-site concentration (C(e)) in a sigmoid E(max) model. RESULTS: The sigmoid E(max) curves were shifted significantly to the left in the Chinese group compared with the Austrian group. After 5 min, the BIS value in the Chinese group was lower than in the Austrian group (mean +/- standard deviation [SD], 47.2 +/- 3.6 vs 63.6 +/- 5.4, respectively; P = 0.0006). The estimated C(p) at loss of consciousness (LOC), predicted C(e) at LOC, and time to LOC, were lower in the Chinese group than in the Austrian group (3.3 +/- 0.8 MUg.mL(-1), 1.6 +/- 0.4 MUg.mL(-1), 2.8 +/- 0.6 min, respectively, vs 4.6 +/- 2.8 MUg.mL(-1), 2.4 +/- 1.5 MUg.mL(-1), 3.9 +/- 0.5 min, respectively; P < 0.0001). CONCLUSION: When propofol is given using the same TCI protocol, Chinese patients in China lost consciousness faster and at a lower estimated plasma concentration than Caucasians in Austria. Larger studies are needed to map geographically appropriate TCI infusion models. PMID- 21264559 TI - Modeling imitation and emulation in constrained search spaces. AB - Social transmission of behavior can be realized through distinct mechanisms. Research on primate social learning typically distinguishes two forms of information that a learner can extract from a demonstrator: copying actions (defined as imitation) or copying only the consequential results (defined as emulation). We propose a decomposition of these learning mechanisms (plus pure individual learning) that incorporates the core idea that social learning can be represented as a search for an optimal behavior that is constrained by different kinds of information. We illustrate our approach with an individual-based model in which individuals solve tasks in abstract "spaces" that represent behavioral actions, results, and benefits of those results. Depending on the learning mechanisms at their disposal, individuals have differential access to the information conveyed in these spaces. We show how different classes of tasks may provide distinct advantages to individuals with different learning mechanisms and discuss how our approach contributes to current empirical and theoretical research on social learning and culture. PMID- 21264560 TI - Aversive, appetitive and flavour avoidance responses in the presence of contextual cues. AB - Appetitive, aversive and avoidance responses to a flavoured solution in distinct contexts were examined. Rats placed in either a white or black box were given access to saccharin. Consumption was followed by an injection of a toxin in one but not the other box. Rats showed more aversive responses in anticipation of and during the presentation of saccharin in the box paired with the toxin than in the box paired with vehicle. The reverse was true for appetitive responses. The acquisition of conditioned avoidance paralleled the acquisition of aversive and appetitive responses. These findings demonstrate that the toxin does not have to overlap exposure to contextual cues to produce conditioned aversive responses, that the aversive and appetitive responses to a flavour can be modulated by visually distinct environments that predict the toxin, and that conditioned avoidance and conditioned aversions develop simultaneously during acquisition. Thus, environmental cues can modulate anticipatory nausea and may prove helpful in the control of nausea in clinical settings. PMID- 21264561 TI - Contrasting AAC and ABC renewal: the role of context associations. AB - Rats were used in a lick suppression preparation to assess the contribution of conditioned-stimulus (CS)-context and context-unconditioned-stimulus (US) associations to experimental extinction. Experiment 1 investigated whether strengthening the CS-acquisition context association enhances extinction by determining whether stronger extinction is observed when CS-alone trials (i.e., extinction treatment) are administered in the acquisition context (AAC renewal), relative to a context that is neutral with respect to the US (ABC renewal). Less recovery of responding to the CS was observed in the former than in the latter case, extending the finding that AAC renewal is weaker than ABC renewal to our lick suppression preparation. Experiment 2 assessed the contribution of the acquisition context-US association to extinction of a CS by examining the effect of postextinction exposure to the acquisition context on responding to the extinguished CS. This manipulation enhanced responding to the extinguished CS in AAC, but not ABC, renewal. Experiment 3 addressed the contribution of the CS acquisition context association by examining the potential of a neutral stimulus, presented in compound with the target CS during extinction treatment, to overshadow the CS-acquisition context association. This manipulation enhanced responding to the extinguished CS in AAC, but not ABC, renewal. The results stress the important role of contextual association in extinction and renewal. PMID- 21264562 TI - The differential expression of male sexual behavior in the Lewis, Fischer and Sprague-Dawley rat strains. AB - Several indices of sexual behavior were characterized for male rats of the Lewis (LEW), Sprague-Dawley (SD) and Fischer (F344) strains. Males were permitted access to a receptive female of their own strain for five 50-min sessions every fifth day. LEW males emitted longer latencies (first mount, intromission, ejaculation and post-ejaculatory interval) and lower frequencies (mounts, intromissions, ejaculations, intromission ratio) relative to F344 males, with the SD strain in general, lying intermediate. Following this assessment, males of each strain were randomly assigned to females of their own or another strain to ascertain whether differences were due to differential female receptivity. Although there were no significant differences during this phase indicative of differential receptivity, the sample size may preclude a definitive interpretation of such results. The data were discussed in the context of other behavioral differences between the strains and the possible neurobiological mechanisms underlying these differences. PMID- 21264563 TI - Effects of response-independent stimuli on fixed-interval and fixed-ratio performance of rats: a model for stressful disruption of cyclical eating patterns. AB - Binge eating is often associated with stress-induced disruption of typical eating patterns. Three experiments were performed with the aim of developing a potential model for this effect by investigating the effect of presenting response independent stimuli on rats' lever-pressing for food reinforcement during both fixed-interval (FI) and fixed-ratio (FR) schedules of reinforcement. In Experiment 1, a response-independent brief tone (500-ms, 105-dB, broadband, noisy signal, ranging up to 16 kHz, with spectral peaks at 3 and 500 Hz) disrupted the performance on an FI 60-s schedule. Responding with the response-independent tone was more vigorous than in the absence of the tone. This effect was replicated in Experiment 2 using a within-subject design, but no such effect was noted when a light was employed as a disrupter. In Experiment 3, a 500-ms tone, but not a light, had a similar effect on rats' performance on FR schedules. This tone induced effect may represent a release from response-inhibition produced by an aversive event. The implications of these results for modeling binge eating are discussed. PMID- 21264564 TI - Some determinants of second-order conditioning. AB - In a Pavlovian conditioning situation, an initially neutral stimulus may be made excitatory by nonreinforced presentations in compound with an established conditioned excitor [i.e., second-order conditioning (SOC)]. The established excitor may be either a punctate cue or the training context. In four conditioned suppression experiments using rats, we investigated whether SOC phenomena parallel other cue interaction effects. In Experiment 1, we found that the response potential of a target stimulus was directly related to the intertrial interval when SOC was mediated by a punctate cue, and inversely related to the intertrial interval when SOC was mediated by the training context. Experiment 2 demonstrated that punctate- and context-mediated SOC are oppositely affected by posttraining context extinction, and Experiments 3 and 4 demonstrated that context- and punctate-mediated SOC are differentially affected by conditioned stimulus (Experiment 3) and unconditioned stimulus (Experiment 4) preexposure treatments. These findings parallel phenomena in conditioned inhibition and cue competition situations. PMID- 21264565 TI - Impact of intervening learning on resurgence in humans with Autism Spectrum Disorders. AB - In the present study, we investigated the degree to which responding would resurge in children diagnosed with Autism Spectrum Disorders (ASD) following an intervening training period comprising different schedules of reinforcement. Twenty-four children of the ages 7-15, with a diagnosis of an ASD, were taught a play a sequence on a variable ratio- (VR) 3 schedule of reinforcement, during a 30-min session. The play sequence was then extinguished before the participants were taught a second play sequence, using a VR-4 schedule for 30 min, a VR-4 schedule for 60 min, or a VR-2 schedule for 30 min. A 5-min extinction session was then conducted to determine the impact that the intervening schedules had on the resurgence of the original behavior. The original sequence resurged to a greater extent for Group VR-4 30 min than it did for the other two groups. The results provide evidence that the length of time between initial training and testing is not a prime determinant of the level of resurgence, but that the amount of conditioning may play a stronger role: The greater the number of reinforcers received, the smaller the resurgence effect. PMID- 21264566 TI - Simultaneous discrimination reversal learning in pigeons and humans: anticipatory and perseverative errors. AB - Pigeons were trained on a two-choice simultaneous discrimination (red vs. green) that reversed midway through each session. After considerable training, they consistently made both anticipatory errors prior to the reversal and perseverative errors after the reversal, suggesting that time (or number of trials) into the session served as a cue for reversal. In Experiment 2, to discourage the use of time as a cue, we varied the location of the reversal point within the session such that it occurred semirandomly after Trial 10, 25, 40, 55, or 70. Pigeons still tended both to anticipate and to perseverate. In Experiment 3, we required 20 pecks to a stimulus on each trial to facilitate memory for the preceding response and sensitivity to local reinforcement contingencies, but the results were similar to those of Experiment 2. We then tested humans on a similar task with a constant (Experiment 4) or variable (Experiment 5) reversal location. When the reversal occurred consistently at the midpoint of the session, humans, like pigeons, showed a tendency to anticipate the reversal; however, they did not show perseverative errors. When the reversal location varied between sessions, unlike pigeons, humans adopted a win-stay/lose-shift strategy, making only a single error on the first trial of the reversal. PMID- 21264567 TI - Waiting to decide helps in the face of probabilistic uncertainty but not delay uncertainty. AB - A first-person shooter video game was adapted for the study of causal decision making within dynamic environments. Participants chose which of three potential targets in each of 21 groups was producing distal explosions. The source of the explosion effect varied in the delay between the firing of its weapon and its effect (0.0, 0.5, 1.0, and 2.0 s), the probability that the weapon caused the effect (50%, 75%, and 100%), and the occurrence of auditory events that filled the delay. In Experiment 1, participants' choice accuracy was highest with short delays but was not affected by probability; participants often compensated for lower probability by increasing their latencies, and thus the number of outcomes sampled. In Experiment 2, a broad range of delays (0-2 s) and probabilities (20% 100%) were randomly sampled for each cause; the results largely replicated those of the prior experiment. The experiments demonstrate people's ability to successfully modulate their environmental sampling in the face of uncertainty due to lower cause-effect probabilities, but not in the presence of longer cause effect delays. PMID- 21264568 TI - Pigeons exhibit higher accuracy for chosen memory tests than for forced memory tests in duration matching-to-sample. AB - Following training to match 2- and 8-sec durations of feederlight to red and green comparisons with a 0-sec baseline delay, pigeons were allowed to choose to take a memory test or to escape the memory test. The effects of sample omission, increases in retention interval, and variation in trial spacing on selection of the escape option and accuracy were studied. During initial testing, escaping the test did not increase as the task became more difficult, and there was no difference in accuracy between chosen and forced memory tests. However, with extended training, accuracy for chosen tests was significantly greater than for forced tests. In addition, two pigeons exhibited higher accuracy on chosen tests than on forced tests at the short retention interval and greater escape rates at the long retention interval. These results have not been obtained in previous studies with pigeons when the choice to take the test or to escape the test is given before test stimuli are presented. It appears that task-specific methodological factors may determine whether a particular species will exhibit the two behavioral effects that were initially proposed as potentially indicative of metacognition. PMID- 21264569 TI - The role of within-compound associations in learning about absent cues. AB - When two cues are reinforced together (in compound), most associative models assume that animals learn an associative network that includes direct cue-outcome associations and a within-compound association. All models of associative learning subscribe to the importance of cue-outcome associations, but most models assume that within-compound associations are irrelevant to each cue's subsequent behavioral control. In the present article, we present an extension of Van Hamme and Wasserman's (Learning and Motivation 25:127-151, 1994) model of retrospective revaluation based on learning about absent cues that are retrieved through within compound associations. The model was compared with a model lacking retrieval through within-compound associations. Simulations showed that within-compound associations are necessary for the model to explain higher-order retrospective revaluation and the observed greater retrospective revaluation after partial reinforcement than after continuous reinforcement alone. These simulations suggest that the associability of an absent stimulus is determined by the extent to which the stimulus is activated through the within-compound association. PMID- 21264570 TI - Two components of responding in Pavlovian lick suppression. AB - The present research examined the temporal distribution of responding in a lick suppression paradigm. In Experiment 1, rats were trained with either a 30- or a 120-s conditioned stimulus (CS), which was followed either by a footshock (unconditioned stimulus [US]) or nothing. Licking during the CS was suppressed only in the former condition. Suppression was more pronounced early in the CS. In Experiment 2, rats were exposed to two 30-s or two 120-s CSs, with delivery of the shock being contingent on CS1 for half of the animals and on CS2 for the other half. For both the paired and the unpaired conditions, suppression at the beginning of CS1 was observed for all the groups. By discounting the possibility of generalization between CS1 and CS2, it appears that this initial suppression was not a conditioned response to the CS, but an unconditioned one due to mere exposure to the shock US. PMID- 21264571 TI - Noncategorical approaches to feature prediction with uncertain categories. AB - In four experiments, we investigated how people make feature predictions about objects whose category membership is uncertain. Artificial visual categories were presented and remained in view while a novel instance with a known feature, but uncertain category membership was presented. All four experiments showed that feature predictions about the test instance were most often based on feature correlations (referred to as feature conjunction reasoning). Experiment 1 showed that feature conjunction reasoning was generally preferred to category-based induction in a feature prediction task. Experiment 2 showed that people used all available exemplars to make feature conjunction predictions. Experiments 3 and 4 showed that the preference for predictions based on feature conjunction persisted even when category-level information was made more salient and inferences involving a larger number of categories were required. Little evidence of reasoning based on the consideration of multiple categories (e.g., Anderson, (Psychological Review, 98:409-429, 1991)) or the single, most probable category (e.g., Murphy & Ross, (Cognitive Psychology, 27:148-193, 1994)) was found. PMID- 21264572 TI - The effects of problem content and scientific background on information search and the assessment and valuation of correlations. AB - The effects of problem contents and one's scientific background on the detection of correlations and the assessment of their strength were studied using a task that required active data search, assessment of the strength of a correlation, and monetary valuation of the correlation's predictive utility. Participants (N = 72) who were trained either in the natural sciences or in the social sciences and humanities explored data sets differing in contents and actual strength of correlation. Data search was consistent across all variables: Participants drew relatively small samples whose relative sizes would favor the detection of a correlation, if one existed. In contrast, the assessment of the correlation strength and the valuation of its predictive utility were strongly related not only to its objective strength, but also to the correspondence between problem contents and one's scientific background: When the two matched, correlations were judged to be stronger and more valuable than when they did not. PMID- 21264573 TI - The list length effect in recognition memory: an analysis of potential confounds. AB - The list length effect in recognition memory refers to the finding that recognition performance for a short list is superior to that for a long list. The list length effect is consistent with the predictions of item noise models, but context noise models predict no effect. Recently, it has been argued that if potential confounds are controlled, the list length effect is eliminated. We report the results of two experiments in which we looked at the role of attention and the remember-know task in the detection of the list length effect. We conclude that there is no list length effect when potential confounds are controlled and that it is the design used to control for attention that is most vital. PMID- 21264574 TI - Predicting memory performance under conditions of proactive interference: immediate and delayed judgments of learning. AB - Four experiments examined the monitoring accuracy of immediate and delayed judgments of learning (JOLs) under conditions of proactive interference (PI). PI was produced using paired-associate learning tasks that conformed to variations of classic A-B, A-D paradigms. Results revealed that the relative monitoring accuracy of interference items was better for delayed than for immediate JOLs. However, delayed JOLs were overconfident for interference items, but not for items devoid of interference. Intrusions retrieved prior to delayed JOLs produced inflated predictions of performance. These results show that delayed JOLs enhance monitoring accuracy in PI situations, except when intrusions are mistaken for target responses. PMID- 21264575 TI - Understanding the centrality deficit: insight from foreign language learners. AB - This study replicated and extended a phenomenon in the text memory literature referred to as the centrality deficit Miller & Keenan (Annals of Dyslexia 59:99 113, 2009). It examined how reading in a foreign language (L2) affects one's text representation and ability to recall the most important information. Readers recalled a greater proportion of central than of peripheral ideas, regardless of whether reading in their native language (L1) or a foreign language (L2). Nonetheless, the greatest deficit in participants' L2 recalls, as compared with L1 recalls, was on the central, rather than the peripheral, information. This centrality deficit appears to stem from resources being diverted from comprehension when readers have to devote more cognitive resources to lower level processes (e.g., L2 word identification and syntactic processing), because the deficit was most evident among readers who had lower L2 proficiency. Prior knowledge (PK) of the passage topic helped compensate for the centrality deficit. Readers with less L2 proficiency who did not have PK of the topic displayed a centrality deficit, relative to their L1 recall, but this deficit dissipated when they did possess PK. PMID- 21264576 TI - Repetition benefit in mental rotation is independent of stimulus repetition. AB - In this study, we investigated whether there is a repetition benefit in mental rotation that is independent of stimulus repetition (i.e., due to increased efficiency in postencoding processing). Three experiments were conducted, in which different conditions of stimulus repetition (different letters on consecutive trials in Experiment 1, letters of different orientations on consecutive trials in Experiment 2, and priming of rotation direction in Experiment 3) were used, and the extent of repetition of rotation direction between two consecutive trials was manipulated. The results of all three experiments showed clear evidence of a repetition benefit without repeating the stimulus, suggesting that this effect is independent of stimulus repetition and lending support to the notion of increased efficiency in mental rotation as a result of repeated rotation direction per se. PMID- 21264577 TI - The role of subjective frequency in language switching: an ERP investigation using masked priming. AB - Two experiments examined the nature of language-switching effects in a priming paradigm with event-related brain potential (ERP) recordings. primes and targets were always unrelated words but could be either from the same or different languages (Experiment 1) or from the same or a different frequency range (Experiment 2). Effects of switching language across prime and target differed as a function of the direction of the switch and prime duration in Experiment 1. Effects tended to be stronger with 100-ms prime durations than with 50-ms durations, and the expected pattern of greater negativity in the switch condition appeared earlier when primes were in L1 and targets in L2 than vice versa. Experiment 2 examined whether these language-switching effects could be due to differences in the subjective frequency of words in a bilingual's two languages, by testing a frequency-switching manipulation within the L1. Effects of frequency switching were evident in the ERP waveforms, but the pattern did not resemble the language-switching effects, therefore suggesting that different mechanisms are at play. PMID- 21264578 TI - The wisdom of the crowd playing The Price Is Right. AB - In The Price Is Right game show, players compete to win a prize, by placing bids on its price. We ask whether it is possible to achieve a "wisdom of the crowd" effect, by combining the bids to produce an aggregate price estimate that is superior to the estimates of individual players. Using data from the game show, we show that a wisdom of the crowd effect is possible, especially by using models of the decision-making processes involved in bidding. The key insight is that, because of the competitive nature of the game, what people bid is not necessarily the same as what they know. This means better estimates are formed by aggregating latent knowledge than by aggregating observed bids. We use our results to highlight the usefulness of models of cognition and decision-making in studying the wisdom of the crowd, which are often approached only from non-psychological statistical perspectives. PMID- 21264579 TI - Classification versus inference learning contrasted with real-world categories. AB - Categories are learned and used in a variety of ways, but the research focus has been on classification learning. Recent work contrasting classification with inference learning of categories found important later differences in category performance. However, theoretical accounts differ on whether this is due to an inherent difference between the tasks or to the implementation decisions. The inherent-difference explanation argues that inference learners focus on the internal structure of the categories--what each category is like--while classification learners focus on diagnostic information to predict category membership. In two experiments, using real-world categories and controlling for earlier methodological differences, inference learners learned more about what each category was like than did classification learners, as evidenced by higher performance on a novel classification test. These results suggest that there is an inherent difference between learning new categories by classifying an item versus inferring a feature. PMID- 21264580 TI - The role of familiarity in binary choice inferences. AB - In research on the recognition heuristic (Goldstein & Gigerenzer, Psychological Review, 109, 75-90, 2002), knowledge of recognized objects has been categorized as "recognized" or "unrecognized" without regard to the degree of familiarity of the recognized object. In the present article, we propose a new inference model- familiarity-based inference. We hypothesize that when subjective knowledge levels (familiarity) of recognized objects differ, the degree of familiarity of recognized objects will influence inferences. Specifically, people are predicted to infer that the more familiar object in a pair of two objects has a higher criterion value on the to-be-judged dimension. In two experiments, using a binary choice task, we examined inferences about populations in a pair of two cities. Results support predictions of familiarity-based inference. Participants inferred that the more familiar city in a pair was more populous. Statistical modeling showed that individual differences in familiarity-based inference lie in the sensitivity to differences in familiarity. In addition, we found that familiarity based inference can be generally regarded as an ecologically rational inference. Furthermore, when cue knowledge about the inference criterion was available, participants made inferences based on the cue knowledge about population instead of familiarity. Implications of the role of familiarity in psychological processes are discussed. PMID- 21264581 TI - On the adaptive flexibility of evaluative priming. AB - If priming effects serve an adaptive function, they have to be both robust and flexible. In four experiments, we demonstrated regular evaluative-priming effects for relatively long stimulus-onset asynchronies, which can, however, be eliminated or reversed strategically. When participants responded to both primes and targets, rather than only to targets, the standard congruity effect disappeared. In Experiments 1a-1c, this result was regularly obtained, independently of the prime response (valence or gender classification) and the response mode (pronunciation or keystroke). In Experiment 2, we showed that once the default congruity effect was eliminated, strategic-priming effects reflected the statistical contingency between prime valence and target valence. Positive contingencies produced congruity, whereas negative contingencies produced equally strong incongruity effects. Altogether, these findings are consistent with an adaptive-cognitive perspective, which highlights the role of flexible strategic processes in working memory as opposed to fixed structures in semantic long-term memory or in the sensorimotor system. PMID- 21264582 TI - Working memory capacity modulates task performance but has little influence on task choice. AB - Variation in the ability to maintain internal goals while resolving competition from multiple information streams has been related to individual differences in working memory capacity (WMC). In a multitask environment, task choice and task performance are influenced by internal goals, prior behavior within the environment, and the availability of relevant and irrelevant information in the environment. Using the voluntary task-switching procedure, task performance, as measured by switch costs, was related to WMC, but only at short preparation intervals. Task choice processes were only weakly related to WMC. These findings are consistent with models of cognitive control that separate task choice processes from the processes of activating and maintaining task readiness. WMC is related to regulation of specific task parameters but not to choice processes integral to the coordination of multiple sources of information. PMID- 21264583 TI - The effect of landmark and body-based sensory information on route knowledge. AB - Two experiments investigated the effects of landmarks and body-based information on route knowledge. Participants made four out-and-back journeys along a route, guided only on the first outward trip and with feedback every time an error was made. Experiment 1 used 3-D virtual environments (VEs) with a desktop monitor display, and participants were provided with no supplementary landmarks, only global landmarks, only local landmarks, or both global and local landmarks. Local landmarks significantly reduced the number of errors that participants made, but global landmarks did not. Experiment 2 used a head-mounted display; here, participants who physically walked through the VE (translational and rotational body-based information) made 36% fewer errors than did participants who traveled by physically turning but changing position using a joystick. Overall, the experiments showed that participants were less sure of where to turn than which way, and journey direction interacted with sensory information to affect the number and types of errors participants made. PMID- 21264584 TI - Relations between timing, position, and grouping in short-term memory. AB - This article is concerned with how information about time and position in a sequence is represented in short-term memory and expressed in the dynamics of serial recall. Temporal-distinctiveness theories of memory predict that isolating a list item in time will improve recall accuracy for that item. Although the majority of research in short-term memory has failed to demonstrate a temporal isolation effect (TIE), there are occasions on which a TIE is observed. The disparity in results has been explained by assuming that participants can adaptively weight temporal and nontemporal information at retrieval, with differences between experiments promoting or discouraging reliance on time as a source of episodic information. A particular focus of the present study is the finding that the TIE is substantially observed in standard serial recall only when participants are instructed to group the list into minisequences. The findings of two experiments using instructed grouping replicated this effect but showed that it is attributable to a longer gap at the group boundary enhancing the positive effect of grouping on recall accuracy. These results show that the hierarchical representations usually associated with temporal grouping are also elicited by instructed grouping but that an additional and nonspecific benefit to recall obtains from lengthening the pause between groups. An additional role for time is identified in the timing of responses: The dynamics of input sequences tend to be mirrored in output sequences for ungrouped lists, whereas the primacy pattern in grouped lists is for a longer duration to speed access to the following group when that duration occurs at an instructed group boundary. PMID- 21264585 TI - Transposition effects in reading Japanese Kana: are they orthographic in nature? AB - One critical question for the front end of models of visual-word recognition and reading is whether the stage of letter position coding is purely orthographic or whether phonology is (to some degree) involved. To explore this issue, we conducted a silent reading experiment in Japanese Kana--a script in which orthography and phonology can be easily separated--using a technique that is highly sensitive to phonological effects (i.e., Rayner's (1975) boundary technique). Results showed shorter fixation times on the target word when the parafoveal preview was a transposed-mora nonword (a.ri.me.ka [????]-a.me.ri.ka [????]) than when the preview was a replacement-mora nonword (a.ka.ho.ka [????] a.me.ri.ka [????]). More critically, fixation times on the target word were remarkably similar when the parafoveal preview was a transposed-consonant nonword (a.re.mi.ka [????]-a.ri.me.ka [????]) and when the parafoveal preview was an orthographic control nonword (a.ke.hi.ka [????]-a.me.ri.ka [????]). Thus, these findings offer strong support for the view that letter/mora position coding during silent reading is orthographic in nature. PMID- 21264586 TI - Memory for details about people: familiarity, relatedness, and gender congruency. AB - This study examines factors that influence memory for details about people. In two experiments, subjects learned fictitious details about familiar (friends, relatives) and/or unfamiliar individuals, and were tested both immediately and after a 1-week delay. To control for a confounding between familiarity and genetic relatedness in Experiment 1, in Experiment 2 specific relationships (identical twin, first cousin, acquaintance) were assigned to unfamiliar individuals. Across experiments, retention was enhanced for familiar compared to unfamiliar individuals, for friends/acquaintances compared to relatives, for more closely than distantly related individuals, and for individuals of the opposite gender as the subject. PMID- 21264587 TI - How prior knowledge affects selective attention during category learning: an eyetracking study. AB - Research has shown that category learning is affected by (a) attention, which selects which aspects of stimuli are available for further processing, and (b) the existing semantic knowledge that learners bring to the task. However, little is known about how knowledge affects what is attended. Using eyetracking, we found that (a) knowledge indeed changes what features are attended, with knowledge-relevant features being fixated more often than irrelevant ones, (b) this effect was not due to an initial attentional bias toward relevant dimensions but rather emerged gradually as a result of observing category members, and (c) this effect grew even after a learning criterion was reached, that is, despite the absence of negative feedback. We argue that models of knowledge-based learning will remain incomplete until they specify mechanisms that dynamically select prior knowledge in response to observed category members and which then directs attention to knowledge-relevant dimensions and away from irrelevant ones. PMID- 21264588 TI - Inoculating against eyewitness suggestibility via interpolated verbatim vs. gist testing. AB - In real-life situations, eyewitnesses often have control over the level of generality in which they choose to report event information. In the present study, we adopted an early-intervention approach to investigate to what extent eyewitness memory may be inoculated against suggestibility, following two different levels of interpolated reporting: verbatim and gist. After viewing a target event, participants responded to interpolated questions that required reporting of target details at either the verbatim or the gist level. After 48 hr, both groups of participants were misled about half of the target details and were finally tested for verbatim memory of all the details. The findings were consistent with our predictions: Whereas verbatim testing was successful in completely inoculating against suggestibility, gist testing did not reduce it whatsoever. These findings are particularly interesting in light of the comparable testing effects found for these two modes of interpolated testing. PMID- 21264589 TI - Orientation priming of grasping decision for drawings of objects and blocks, and words. AB - This study tested the influence of orientation priming on grasping decisions. Two groups of 20 healthy participants had to select a preferred grasping orientation (horizontal, vertical) based on drawings of everyday objects, geometric blocks or object names. Three priming conditions were used: congruent, incongruent and neutral. The facilitating effects of priming were observed in the grasping decision task for drawings of objects and blocks but not object names. The visual information about congruent orientation in the prime quickened participants' responses but had no effect on response accuracy. The results are discussed in the context of the hypothesis that an object automatically potentiates grasping associated with it, and that the on-line visual information is necessary for grasping potentiation to occur. The possibility that the most frequent orientation of familiar objects might be included in object-action representation is also discussed. PMID- 21264590 TI - Do object refixations during scene viewing indicate rehearsal in visual working memory? AB - Do refixations serve a rehearsal function in visual working memory (VWM)? We analyzed refixations from observers freely viewing multiobject scenes. An eyetracker was used to limit the viewing of a scene to a specified number of objects fixated after the target (intervening objects), followed by a four alternative forced choice recognition test. Results showed that the probability of target refixation increased with the number of fixated intervening objects, and these refixations produced a 16% accuracy benefit over the first five intervening-object conditions. Additionally, refixations most frequently occurred after fixations on only one to two other objects, regardless of the intervening object condition. These behaviors could not be explained by random or minimally constrained computational models; a VWM component was required to completely describe these data. We explain these findings in terms of a monitor-refixate rehearsal system: The activations of object representations in VWM are monitored, with refixations occurring when these activations decrease suddenly. PMID- 21264591 TI - The distance effect in numerical memory-updating tasks. AB - Two experiments examined the role of numerical distance in updating numerical information in working memory. In the first experiment, participants had to memorize a new number only when it was smaller than a previously memorized number. In the second experiment, updating was based on an external signal, which removed the need to perform any numerical comparison. In both experiments, distance between the memorized number and the new one was manipulated. The results showed that smaller distances between the new and the old information led to shorter updating times. This graded facilitation suggests that the process by which information is substituted in the focus of attention involves maintaining the shared features between the new and the old number activated and selecting other new features to be activated. Thus, the updating cost may be related to amount of new features to be activated in the focus of attention. PMID- 21264592 TI - The effects of age and divided attention on spontaneous recognition. AB - Studies of recognition typically involve tests in which the participant's memory for a stimulus is directly questioned. There are occasions however, in which memory occurs more spontaneously (e.g., an acquaintance seeming familiar out of context). Spontaneous recognition was investigated in a novel paradigm involving study of pictures and words followed by recognition judgments on stimuli with an old or new word superimposed over an old or new picture. Participants were instructed to make their recognition decision on either the picture or word and to ignore the distracting stimulus. Spontaneous recognition was measured as the influence of old vs. new distracters on target recognition. Across two experiments, older adults and younger adults placed under divided-attention showed a greater tendency to spontaneously recognize old distracters as compared to full-attention younger adults. The occurrence of spontaneous recognition is discussed in relation to ability to constrain retrieval to goal-relevant information. PMID- 21264593 TI - Lexical and sublexical knowledge influences the encoding, storage, and articulation of nonwords. AB - Nonword repetition (NWR) has been used extensively in the study of child language. Although lexical and sublexical knowledge is known to influence NWR performance, there has been little examination of the NWR processes (e.g., encoding, storage, and articulation) that may be affected by lexical and sublexical knowledge. We administered two- and three-syllable spoken nonword recognition and nonword repetition tests on two independent groups of 31 children (mean age = 5 years 7 months). Spoken nonword recognition primarily involves encoding and storage, whereas NWR involves an additional articulation process. The influence of lexical and sublexical knowledge was determined by examining the number of lexical errors produced. There was clear involvement of long-term lexical and sublexical knowledge in both spoken nonword recognition and NWR. In spoken nonword recognition, twice as many errors involved selecting a foil that contained a lexical item (e.g., 'yashukup') as involved selecting a foil that contained only nonsense syllables (e.g., 'yashunup'). In repetition, over 30% of errors changed a nonsense syllable to a lexical item. Our results show that long term lexical and sublexical knowledge is pervasive in NWR. Any explanation of NWR performance must therefore consider the influence of lexical and sublexical knowledge throughout the whole repetition process, from the encoding to the articulation of nonwords. PMID- 21264594 TI - Informed inferences of unknown feature values in categorization. AB - Many current computational models of object categorization either include no explicit provisions for dealing with incomplete stimulus information (e.g. Kruschke, Psychological Review 99:22-44, 1992) or take approaches that are at odds with evidence from other fields (e.g. Verguts, Ameel, & Storms, Memory & Cognition 32:379-389, 2004). In two experiments centered around the inverse base rate effect, we demonstrate that people not only make highly informed inferences about the values of unknown features, but also subsequently use the inferred values to come to a categorization decision. The inferences appear to be based on immediately available information about the particular stimulus under consideration, as well as on higher-level inferences about the stimulus class as a whole. Implications for future modeling efforts are discussed. PMID- 21264595 TI - Theoretical and forensic implications of developmental studies of the DRM illusion. AB - In the study of false memory, developmental research on the Deese-Roediger McDermott (DRM) illusion has played a pivotal role in theory evaluation and forensic application. The extensive developmental DRM literature (55 experiments published in English-language journals) provided the first clear evidence that false memories can increase dramatically from early childhood onward, whereas traditional ideas about cognitive development predict steady declines. Similar increases have recently been reported in false memory for complex, realistic life events, using forensically oriented paradigms. Age improvements in the ability to connect meaning across words have been found to be necessary and sufficient for developmental increases in the DRM illusion. When the data of developmental DRM studies are combined with parallel findings from forensically oriented paradigms, the result is an existence proof that a principle used by the law to evaluate children's evidence is mistaken. According to that principle, children's versions of events are always more likely to be infected with false memories than those of adults, and hence, juries should give more weight to adults' versions of events. PMID- 21264596 TI - Long-term cumulative structural priming persists for (at least) one week. AB - We present an experiment that explores the degree to which cumulative structural priming effects of the sort reported in Kaschak (Memory and Cognition 35:925-937, 2007) persist over the course of a week. In the first session of the experiment, participants completed written sentence stems that were designed to bias them toward producing the double object (Meghan gave Michael a toy) or prepositional object (Meghan gave a toy to Michael) construction. Participants returned for a second session of the experiment a week later. We observed that the biases established in the first phase of the experiment affected performance in the second phase. That is, the cumulative priming effect persisted for a week. The implications of this result for theories of language production are discussed. PMID- 21264597 TI - Information-integration category learning and the human uncertainty response. AB - The human response to uncertainty has been well studied in tasks requiring attention and declarative memory systems. However, uncertainty monitoring and control have not been studied in multi-dimensional, information-integration categorization tasks that rely on non-declarative procedural memory. Three experiments are described that investigated the human uncertainty response in such tasks. Experiment 1 showed that following standard categorization training, uncertainty responding was similar in information-integration tasks and rule based tasks requiring declarative memory. In Experiment 2, however, uncertainty responding in untrained information-integration tasks impaired the ability of many participants to master those tasks. Finally, Experiment 3 showed that the deficit observed in Experiment 2 was not because of the uncertainty response option per se, but rather because the uncertainty response provided participants a mechanism via which to eliminate stimuli that were inconsistent with a simple declarative response strategy. These results are considered in the light of recent models of category learning and metacognition. PMID- 21264598 TI - Automatic processing influences free recall: converging evidence from the process dissociation procedure and remember-know judgments. AB - Dual-process theories of retrieval suggest that controlled and automatic processing contribute to memory performance. Free recall tests are often considered pure measures of recollection, assessing only the controlled process. We report two experiments demonstrating that automatic processes also influence free recall. Experiment 1 used inclusion and exclusion tasks to estimate recollection and automaticity in free recall, adopting a new variant of the process dissociation procedure. Dividing attention during study selectively reduced the recollection estimate but did not affect the automatic component. In Experiment 2, we replicated the results of Experiment 1, and subjects additionally reported remember-know-guess judgments during recall in the inclusion condition. In the latter task, dividing attention during study reduced remember judgments for studied items, but know responses were unaffected. Results from both methods indicated that free recall is partly driven by automatic processes. Thus, we conclude that retrieval in free recall tests is not driven solely by conscious recollection (or remembering) but also by automatic influences of the same sort believed to drive priming on implicit memory tests. Sometimes items come to mind without volition in free recall. PMID- 21264599 TI - Masked translation priming effects with low proficient bilinguals. AB - Non-cognate masked translation priming lexical decision studies with unbalanced bilinguals suggest that masked translation priming effects are asymmetric as a function of the translation direction (significant effects only in the dominant [L1] to nondominant [L2] language translation direction). However, in contrast to the predictions of most current accounts of masked translation priming effects, bidirectional effects have recently been reported with a group of low proficient bilinguals Duyck & Warlop 2009 (Experimental Psychology 56:173-179). In a series of masked translation priming lexical decision experiments we examined whether the same pattern of effects would emerge with late and low proficient Greek (L1) Spanish (L2) bilinguals. Contrary to the results obtained by Duyck and Warlop, and in line with the results found in most studies in the masked priming literature, significant translation priming effects emerged only when the bilinguals performed the task with L1 primes and L2 targets. The existence of the masked translation priming asymmetry with low proficient bilinguals suggests that cross-linguistic automatic lexico-semantic links may be established very early in the process of L2 acquisition. These findings could help to define models of bilingualism that consider L2 proficiency level to be a determining factor. PMID- 21264600 TI - Individual behavior in learning of an artificial grammar. AB - Artificial grammar learning (AGL) is a widely used experimental paradigm that investigates how syntactic structures are processed. After a familiarization phase, participants have to distinguish strings consistent with a set of grammatical rules from strings that violate these rules. Many experiments report performance solely at a group level and as the total number of correct judgments. This report describes a systematic approach for investigating individual performance and a range of different behaviors. Participants were exposed to strings of the nonfinite grammar A( n )B( n ). To distinguish grammatical from ungrammatical strings, participants had to pay attention to local dependencies while comparing the number of stimuli from each class. Individual participants showed substantially different behavioral patterns despite exposure to the same stimuli. The results were replicated across auditory and visual sensory modalities. It is suggested that an analysis that looks at individual differences grants new insights into the processes involved in AGL. It also provides a solid basis from which to investigate sequence-processing abilities in special populations, such as patients with neurological lesions. PMID- 21264601 TI - Are the costs of directed forgetting due to failures of sampling or recovery? Exploring the dynamics of recall in list-method directed forgetting. AB - This study investigated the costs of directed forgetting within the framework of a search model. In such models, retrieval failure can occur at either the sampling or the recovery stage of recall. Multiple measures of performance were employed to answer two primary questions of interest: (1) Where does the locus of forgetting occur in the directed forgetting paradigm? and (2) What current theory of directed forgetting can best account for the pattern of data observed? Converging evidence from these measures suggested that the costs of directed forgetting are the result of sampling issues during retrieval. Further, these results were best explained by a contextual-change account that argues an instruction to forget creates a break in context causing individuals to sample more items at retrieval. It is argued that the retrieval deficits observed in list-method directed forgetting paradigms are due, in part, to the fact that individuals sample a greater number of items (that include both targets and intrusions) during retrieval in the forget-condition, thereby creating greater response competition compared with retrieval in the remember-condition. PMID- 21264602 TI - Potentiation in young infants: the origin of the prior knowledge effect? AB - In two experiments with 6-month-old infants, we found that prior learning of an operant task (remembered for 2 weeks) mediated new learning of a modeling event (remembered for only 1 day) and increased its recall. Infants first learned to associate lever pressing with moving a toy train housed in a large box. One or 2 weeks later, three target actions were modeled on a hand puppet while the train box (a retrieval cue) was in view. Merely retrieving the train memory strengthened it, and simultaneously pairing its retrieved memory with the modeled actions potentiated their learning and recall. When paired 1 week later, deferred imitation increased from 1 day to 4 weeks; when paired 2 weeks later, it increased from 1 day to 6 weeks. The striking parallels between potentiated learning in infants and the prior knowledge effect in adults suggests that the prior knowledge effect originates in early infancy. PMID- 21264603 TI - Experts' memory: an ERP study of perceptual expertise effects on encoding and recognition. AB - This study examined how perceptual expertise facilitates encoding and recognition. The electroencephalogram of car experts and car novices was recorded in the study as well as test phases of a remember/know task with car and bird stimuli. Car expertise influenced performance and event-related potentials (ERPs) for cars but not birds. Experts recognized and "recollected" cars more accurately, while novices had more false alarms. The ERPs provided neural evidence for theoretical assumptions about expert memory. Memory encoding in the study phase was less effortful and more elaborate for experts than novices, as indicated by lower mean amplitudes for subsequently "recollected" cars and by indistinguishable differences due to memory for recollection and familiarity. The parietal old/new effect, a correlate of recollection measured during recognition testing, was only found for experts. The results show that refined perceptual and semantic processing, characteristics of perceptual expertise, facilitate both memory encoding and recognition memory. PMID- 21264604 TI - Metacognitive awareness of learning strategies in undergraduates. AB - Two studies examined undergraduates' metacognitive awareness of six empirically supported learning strategies. Study 1 results overall suggested an inability to predict the learning outcomes of educational scenarios describing the strategies of dual-coding, static-media presentations, low-interest extraneous details, testing, and spacing; there was, however, weak endorsement of the strategy of generating one's own study materials. In addition, an independent measure of metacognitive self-regulation was correlated with scenario performance. Study 2 demonstrated higher prediction accuracy for students who had received targeted instruction on applied memory topics in their psychology courses, and the best performance for those students directly exposed to the original empirical studies from which the scenarios were derived. In sum, this research suggests that undergraduates are largely unaware of several specific strategies that could benefit memory for course information; further, training in applied learning and memory topics has the potential to improve metacognitive judgments in these domains. PMID- 21264605 TI - Contribution of strategy use to performance on complex and simple span tasks. AB - Simple and complex span tasks are widely thought to measure related but separable memory constructs. Recently, however, research has demonstrated that simple and complex span tasks may tap, in part, the same construct because both similarly predict performance on measures of fluid intelligence (Gf) when the number of items retrieved from secondary memory (SM) is equated (Unsworth & Engle, Journal of Memory and Language 54:68-80 2006). Two studies (n = 105 and n = 152) evaluated whether retrieval from SM is influenced by individual differences in the use of encoding strategies during span tasks. Results demonstrated that, after equating the number of items retrieved from SM, simple and complex span performance similarly predicted Gf performance, but rates of effective strategy use did not mediate the span-Gf relationships. Moreover, at the level of individual differences, effective strategy use was more highly related to complex span performance than to simple span performance. Thus, even though individual differences in effective strategy use influenced span performance on trials that required retrieval from SM, strategic behavior at encoding cannot account for the similarities between simple and complex span tasks. PMID- 21264606 TI - Accessing long-term memory representations during visual change detection. AB - In visual change detection tasks, providing a cue to the change location concurrent with the test image (post-cue) can improve performance, suggesting that, without a cue, not all encoded representations are automatically accessed. Our studies examined the possibility that post-cues can encourage the retrieval of representations stored in long-term memory (LTM). Participants detected changes in images composed of familiar objects. Performance was better when the cue directed attention to the post-change object. Supporting the role of LTM in the cue effect, the effect was similar regardless of whether the cue was presented during the inter-stimulus interval, concurrent with the onset of the test image, or after the onset of the test image. Furthermore, the post-cue effect and LTM performance were similarly influenced by encoding time. These findings demonstrate that monitoring the visual world for changes does not automatically engage LTM retrieval. PMID- 21264607 TI - Tonal hierarchy representations in auditory imagery. AB - Two experiments investigated psychological representations of musical tonality in auditory imagery. In Experiment 1, musically trained participants heard a single tone as a perceptual cue and built an auditory image of a specified major tonality based on that cue; participants' images were then assessed using judgments of probe tones. In Experiment 2 participants imaged a minor tonality rather than a major one. Analysis of the probe tone ratings indicated that participants successfully imaged both major and minor tonal hierarchies, demonstrating that auditory imagery functions comparably to auditory perception. In addition, the strength of the major tonal image was dependent upon the pitch and tonal relations of the perceptual cue and the to-be-imaged tonality. Finally, representations of minor tonal hierarchies were less robust than those of major ones, converging with perceptual evidence that minor tonalities are less psychologically stable than major tonalities. PMID- 21264608 TI - Following the standard form: effects of equation format on algebraic modeling. AB - When people construct algebraic equations to represent quantitative relations, they often reverse the roles of the variables (6S = P instead of 6P = S). Results from three experiments show that a major reason for such reversal errors is people's adherence to, and interpretation of, the Standard Form of algebraic models. College students constructed, selected, and interpreted algebraic models that either had the standard multiplication format (MF: ax = y), or the mathematically equivalent division format (DF: y/a = x). A large minority of participants constructed reversed MF models, whereas most participants who were instructed to use DF equations constructed correct models (Experiment 1). Most participants understood that MF and DF models of the same relation should be mathematically equivalent (Experiment 2), but they drew a conceptual distinction between these models (Experiment 3). The authors discuss the impact of notational conventions on people's interpretation and use of representational tools. PMID- 21264609 TI - Immunity to proactive interference is not a property of the focus of attention in working memory. AB - The Focus of Attention (FOA) is the latest incarnation of a limited capacity store in which a small number of items, in this case four, are deemed to be readily accessible and do not need to be retrieved. Thus a corollary of these ideas is that those items in the FOA are always immune to proactive interference. While there is empirical support for instances of immunity to PI in short-term retention tasks that involve memory for four-item lists, there are also many instances in which PI is observed with four-item lists as well as instances where PI and immunity to PI can be shown in the same experiment. In contrast to the FOA assumptions, an alternative cue-based account predicts both the presence of PI and immunity to PI as a function of the relation between the cues available and the particular test. Three experiments contrasted the FOA assumptions and the cue based approach in a short-term cued recall task in which PI is manipulated by testing whether the presentation of previous, similar items would interfere with immediate recall of three list items. The results indicated that even with very short lists, both PI and immunity to PI could be observed. The PI effects observed in our experiment are at odds with the FOA approach and are more readily explained using the cueing account. PMID- 21264610 TI - The temporal distribution of autobiographical memory: changes in reliving and vividness over the life span do not explain the reminiscence bump. AB - When autobiographical memories are elicited with word cues, personal events from middle childhood to early adulthood are overrepresented compared to events from other periods. It is, however, unclear whether these memories are also associated with greater recollection. In this online study, we examined whether autobiographical memories from adolescence and early adulthood are recollected more than memories from other lifetime periods. Participants rated personal events that were elicited with cue words on reliving or vividness. Consistent with previous studies, most memories came from the period in which the participants were between 6 and 20 years old. The memories from this period were not relived more or recalled more vividly than memories from other lifetime periods, suggesting that they do not involve more recollection. Recent events had higher levels of reliving and vividness than remote events, and older adults reported a stronger recollective experience than younger adults. PMID- 21264611 TI - Source credibility and syllogistic reasoning. AB - Two experiments examined whether a source credibility effect would be observed for a syllogistic reasoning task. In the experiments, people were given two statements, presented as the results from a survey, followed by a conclusion that was supposedly made by one of two sources. In Experiment 1, one of the sources was described as honest and the other as dishonest, and in Experiment 2, one of the sources was described as an expert and the other as a non-expert. Because a pilot experiment showed that credibility can be overridden by people's experience with a source, all conclusions in Experiments 1 and 2 were ones that were likely to be accepted (i.e., necessary and possible strong conclusions). Both experiments showed a clear source credibility effect, particularly for the invalid conclusions. These results, along with the belief bias effect and previous research with conditional reasoning, suggest that people can be influenced by extraneous context, such as the honesty or expertise of a source, in a syllogistic reasoning task. PMID- 21264612 TI - Harry Potter and the sorcerer's scope: latent scope biases in explanatory reasoning. AB - What makes a good explanation? We examine the function of latent scope, i.e., the number of unobserved phenomena that an explanation can account for. We show that individuals prefer narrow latent scope explanations-those that account for fewer unobserved effects-to broader explanations. In Experiments 1a-d, participants found narrow latent scope explanations to be both more satisfying and more likely. In Experiment 2 we directly manipulated base rate information and again found a preference for narrow latent scope explanations. Participants in Experiment 3 evaluated more natural explanations of unexpected observations, and again displayed a bias for narrow latent scope explanations. We conclude by considering what this novel bias tells us about how humans evaluate explanations and engage in causal reasoning. PMID- 21264613 TI - Age differences in the perception of hierarchical structure in events. AB - Everyday activities break down into parts and subparts, and appreciating this hierarchical structure is an important component of understanding. In two experiments we found age differences in the ability to perceive hierarchical structure in continuous activity. In both experiments, younger and older adults segmented movies of everyday activities into large and small meaningful events. Older adults' segmentation deviated more from group norms than did younger adults' segmentation, and older adults' segmentation was less hierarchically organized than that of younger adults. Older adults performed less well than younger adults on event memory tasks. In some cases, measures of event segmentation discriminated between those older adults with better and worse memory. These results suggest that the hierarchical encoding of ongoing activity declines with age, and that such encoding may be important for memory. PMID- 21264614 TI - The importance of vowel diacritics for the temporary retention of high and low frequency Hebrew words of varying syllabic length. AB - This study investigates the importance of vowel diacritics for the retention of Hebrew word lists, with word lists being manipulated along the dimension of word frequency and syllabic length. Eighty university students participated in the study. Half of the participants (40) were tested with the word lists presented in fully-pointed (voweled) Hebrew while the other half (40) were given the word lists in unpointed Hebrew (with vowel diacritics removed). Analyses of each group's recall rates and recall-order accuracy indicate that, overall, the presence of vowel diacritics had no facilitating effect on the participants' quantitative and qualitative Short Term Memory (STM) performance. This was found to be true whether word frequency (high vs. medium to low) or syllabic length (mono vs. trisyllabic) were computed as within-subject factors. Attempts to adequately interpret the absence of a pointing effect on STM performance based upon Orthographic Depth Hypothesis (ODH) and Grain Size Theory (GST) proved unfruitful. The authors propose an adaptation of the GST to the peculiarities of Hebrew orthography and discuss a morphology-centered grain-size theory (MGST). PMID- 21264615 TI - Overcoming the effects of intentional forgetting. AB - The long-term effects of the compartmentalization of task-irrelevant memories were investigated using a directed forgetting procedure. Many models tacitly assume the persistence of the costs and benefits of directed forgetting or otherwise fail to predict what factors might reduce or eliminate them. In contrast, a retrieving effectively from memory model (REM; Lehman & Malmberg, 2009) predicts that intentional forgetting should only be observed for free recall when temporal context is used to probe memory. By manipulating whether study lists were constructed from category exemplars or from a random set of words, and by either providing temporal or category cues at test, we tested the prediction. The effects of directed forgetting were eliminated when categorized lists were studied and category cues were provided. When categorized lists were used but category cues were not provided, the usual costs and benefits of directed forgetting were observed. These results specify the conditions under which the consequences of intentional forgetting can be overcome. PMID- 21264616 TI - The effects of spatial representation on memory for verbal navigation instructions. AB - Three experiments investigated effects of mental spatial representation on memory for verbal navigation instructions. The navigation instructions referred to a grid of stacked matrices displayed on a computer screen or on paper, with or without depth cues, and presented as two-dimensional diagrams or a three dimensional physical model. Experimental instructions either did or did not promote a three-dimensional mental representation of the space. Subjects heard navigation instructions, immediately repeated them, and then followed them manually on the grid. In all display and experimental instruction conditions, memory for the navigation instructions was reduced when the task required mentally representing a three-dimensional space, with movements across multiple matrices, as compared with a two-dimensional space, with movements within a single matrix, even though the words in the navigation instructions were identical in all cases. The findings demonstrate that the mental representation of the space influences immediate verbatim memory for navigation instructions. PMID- 21264617 TI - Short-term and long-term collaboration benefits on individual recall in younger and older adults. AB - A recent study of younger adults suggests that, compared to repeated individual recall trials, repeated collaborative recall trials produce better individual recall after a short delay (Blumen & Rajaram, 2008). Our study was designed to determine if such collaboration benefits would remain after a one-week delay, in both younger and older adults. Sixty younger (M age = 24.60) and 60 older (M age = 67.35) adults studied a list of words and then completed either two collaborative recall trials followed by two individual recall trials, or four individual recall trials. A five-min delay was inserted between the first three recall trials. The fourth recall trial was administered 1 week later. Collaborative recall was completed in groups of three individuals working together. Both younger and older adults benefitted from repeated collaborative recall trials to a greater extent than repeated individual recall trials, and such collaboration benefits remained after a one-week delay. This is the first demonstration of collaboration benefits on later individual recall at delays as long as 1 week, in both younger and older adults. Findings are discussed within the context of the negative effects of collaboration associated with group memory (collaborative inhibition) and the positive effects of collaboration associated with later individual memory (collaboration benefits). PMID- 21264618 TI - Rich in vitamin C or just a convenient snack? Multiple-category reasoning with cross-classified foods. AB - Two studies examined multiple category reasoning in property induction with cross classified foods. Pilot tests identified foods that were more typical of a taxonomic category (e.g., "fruit"; termed 'taxonomic primary') or a script based category (e.g., "snack foods"; termed 'script primary'). They also confirmed that taxonomic categories were perceived as more coherent than script categories. In Experiment 1 participants completed an induction task in which information from multiple categories could be searched and combined to generate a property prediction about a target food. Multiple categories were more often consulted and used in prediction for script primary than for taxonomic primary foods. Experiment 2 replicated this finding across a range of property types but found that multiple category reasoning was reduced in the presence of a concurrent cognitive load. Property type affected which categories were consulted first and how information from multiple categories was weighted. The results show that multiple categories are more likely to be used for property predictions about cross-classified objects when an object is primarily associated with a category that has low coherence. PMID- 21264619 TI - Does the familiarity bias hypothesis explain why there is no masked priming for "NO" decisions? AB - Traditional "activation" views of masked priming explain the identity priming effect in terms of facilitation due to 'pre-activation' of stored representations. Norris and Kinoshita's (2008) Bayesian Reader theory of masked priming instead explains priming in terms of the evidence that the prime contributes towards the decision required to the target. In support of the Bayesian Reader account, Norris and Kinoshita showed that the absence of priming for nonwords in the lexical decision task and for targets requiring a Different decision in the same-different match task can be explained based on a single principle. Against this, Bowers (2010) argued that the absence of priming should be explained instead by a combination of sublexical priming and "familiarity bias". As evidence, Bowers cited Bodner and Masson's (1997) finding that nonword priming did emerge with targets presented in visually unfamiliar cAsE-AlTeRnAtEd format. We present evidence that this finding was due to the use of an ambiguous letter in case-alternated format; when using unambiguous letters, we consistently failed to find priming of case-alternated nonwords. We suggest that the Bayesian Reader, rather than the familiarity bias hypothesis, explains the absence of priming. PMID- 21264620 TI - The effect of being in a tip-of-the-tongue state on subsequent items. AB - The tip-of-the-tongue state (TOT) is the feeling that an inaccessible item will be recalled. In the TOT induction paradigm, participants are given a list of general information questions or word definitions, and the participants indicate whether they are in a TOT for each item. The present study explored the effect that being in a TOT for one item (N) has on the recall and the likelihood of a TOT for the subsequent item (N + 1). Three experiments were conducted. All three experiments showed that TOTs do not affect the rate of recall for the next item but decrease the likelihood of a TOT for the next item. This effect extended to items occurring two items after the initial TOT (N + 2) in two experiments. Thus, TOTs are less likely to occur after another TOT than after an item not in a TOT. These data are interpreted within a metacognitive framework. PMID- 21264621 TI - The sensitivity of judgment-of-learning resolution to past test performance, new learning, and forgetting. AB - When people judge their learning of items across study-test trials, their accuracy in discriminating between learned and unlearned items improves on the second trial. We examined the source of this improvement by estimating the contribution of three factors-memory for past test performance (MPT), new learning, and forgetting-to accuracy on trial 2. In Experiment 1, during an initial trial, participants studied paired associates, made a judgment of learning (JOL) for each one, and were tested. During the second trial, we manipulated two variables: when the JOL was made (either immediately before or after studying an item) and whether participants were told the outcome of the initial recall attempt on trial 1. In Experiment 2, the same procedure was used with a 1-week retention interval between study and test on trial 2. In both experiments, JOL resolution was higher on trial 2 than on trial 1. Fine-grained analyses of JOL magnitude and decomposition of resolution supported several conclusions. First, MPT contributed the most to boosts in JOL magnitude and improvements in resolution across trials. Second, JOLs and subsequent resolution were sensitive to new learning and forgetting, but only when participants' judgments were made after study. Thus, JOLs appear to integrate information from multiple factors, and these factors jointly contribute to JOL resolution. PMID- 21264622 TI - Judgments of learning and improvement. AB - Can learners accurately judge the rate of their learning? Rates of learning may be informative when study time is allocated across materials, and students' judgments of their learning rate have been proposed as a possible metacognitive tool. Participants estimated how much they improved between presentations in multitrial learning situations in which n-gram paragraphs (in Experiments 1 and 2) or word pairs (Experiments 3 and 4) were learned . In the first experiment, participants rated improvement on a percentage scale, whereas on the second and third, judgments were given on a 0-6 scale. Experiment 4 used both a percentage scale and an absolute number scale. The main result was that judgments of improvement were poorly correlated with actual improvement and, in one case, were negatively correlated. Although judgments of improvement were correlated with changes in judgments of learning, they were not reliable indicators of actual improvement. Implications are discussed for theoretical work on metacognition. PMID- 21264623 TI - Item and order information in semantic memory: students' retention of the "CU fight song" lyrics. AB - University of Colorado (CU) students were tested on memory for the "CU Fight Song" in order to examine serial position effects in semantic memory while controlling for familiarity across positions. In Experiment 1, students reconstructed the order of the nine lines of the song. Students with previous exposure to the song performed better and showed a more bowed serial position function than did students with no knowledge of the song. Experiment 2 added a task assessing memory of item information. One word was removed and replaced with a blank in each line, and an alternative word was offered as an option, along with the correct word. Students selected the word that fit into each blank and then reconstructed the order of the lines. There was a bow-shaped curve for order reconstruction, but not for item selection, which implies that the serial position function in semantic memory stems from order, rather than item, information. PMID- 21264624 TI - Experience with proactive interference diminishes its effects: mechanisms of change. AB - In three experiments, we examined the mechanisms by which prior experience with proactive interference (PI) diminished its effects. Cued recall tasks conforming to an A-B, A-D paradigm were used to induce PI effects. Experiment 1 showed that reduced PI was not due to a reduction in attention to the source of PI. Experiment 2 revealed that participants' awareness of PI effects on memory performance increased with experience, resulting in a shift in encoding processes. Experiment 3 demonstrated that changes in encoding provided additional support for recollection that further enhanced participants' ability to constrain their retrieval processing to the appropriate source of information at the time of test. These results can be interpreted as showing that experience with PI enhances awareness of its effects and allows individuals to adjust their learning and retrieval strategies to compensate for such effects. PMID- 21264625 TI - Between- and within-language priming is the same: evidence for shared bilingual syntactic representations. AB - Two structural-priming experiments investigated how bilinguals represent syntactic structures. According to the shared-syntax account (Hartsuiker, Pickering, & Veltkamp, 2004), bilinguals have a single syntactic representation for structures that exist in both languages, whereas separate-syntax accounts claim that the representations for these structures are language specific. Our experiments tested native speakers of Swedish who were highly proficient in English. The results showed that structural priming within language and between languages was equally strong. This indicates that representations of syntactic structures from different languages are shared and, therefore, supports the shared-syntax account. PMID- 21264626 TI - An auditory analog of the picture superiority effect. AB - Previous research has found that pictures (e.g., a picture of an elephant) are remembered better than words (e.g., the word "elephant"), an empirical finding called the picture superiority effect (Paivio & Csapo. Cognitive Psychology 5(2):176-206, 1973). However, very little research has investigated such memory differences for other types of sensory stimuli (e.g. sounds or odors) and their verbal labels. Four experiments compared recall of environmental sounds (e.g., ringing) and spoken verbal labels of those sounds (e.g., "ringing"). In contrast to earlier studies that have shown no difference in recall of sounds and spoken verbal labels (Philipchalk & Rowe. Journal of Experimental Psychology 91(2):341 343, 1971; Paivio, Philipchalk, & Rowe. Memory & Cognition 3(6):586-590, 1975), the experiments reported here yielded clear evidence for an auditory analog of the picture superiority effect. Experiments 1 and 2 showed that sounds were recalled better than the verbal labels of those sounds. Experiment 2 also showed that verbal labels are recalled as well as sounds when participants imagine the sound that the word labels. Experiments 3 and 4 extended these findings to incidental-processing task paradigms and showed that the advantage of sounds over words is enhanced when participants are induced to label the sounds. PMID- 21264627 TI - Priming insight in groups: facilitating and inhibiting solving an ambiguously worded insight problem. AB - We extend research on the priming of insight by studying group problem solving. Groups of 2-4 participants tried to solve an ambiguously worded problem in the presence of a prime that reinforced the dominant but incorrect interpretation of the problem, a prime that reinforced the uncommon but correct interpretation, or no prime. The paradigm involved participants asking questions of the experimenter that could only be answered "yes" or "no." In Experiment 1, the prime was present throughout the solving period; in Experiment 2, it was removed prior to the solving period. In both experiments, the primes had their predicted effects. Patterns in the time taken to solve the problem supported the idea that groups stuck at the impasse were more or less able to restructure the problem, depending on the environmental context. Data from the questions asked and questionnaires converged with time taken to solve the problem, consistent with the view that restructuring a problem is an automatic process that produces insight. A comparison of the group data in Experiment 1 with individually tested participants' data revealed that the insight of the groups benefited from their being able to recognize lines of questions to follow, to listen to answers to questions asked, and to evaluate and reject errors or assumptions. PMID- 21264628 TI - Disruption of visual feature binding in working memory. AB - In a series of five experiments, we studied the effect of a visual suffix on the retention in short-term visual memory of both individual visual features and objects involving the binding of two features. Experiments 1A, 1B, and 2 involved suffixes consisting of features external to the to-be-remembered set and revealed a modest but equivalent disruption on individual and bound feature conditions. Experiments 3A and 3B involved suffixes comprising features that could potentially have formed part of the to-be-remembered set (but did not on that trial). Both experiments showed greater disruption of retention for objects comprising bound features than for their individual features. The results are interpreted as differentiating two components of suffix interference, one affecting memory for features and bindings equally, the other affecting memory for bindings. The general component is tentatively identified with the attentional cost of operating a filter to prevent the suffix from entering visual working memory, whereas the specific component is attributed to the particular fragility of bound representations when the filter fails. PMID- 21264629 TI - Binding serial order to representations in working memory: a spatial/verbal dissociation. AB - Verbal information is coded naturally as ordered representations in working memory (WM). However, this may not be true for spatial information. Accordingly, we used memory span tasks to test the hypothesis that serial order is more readily bound to verbal than to spatial representations. Removing serial-order requirements improved performance more for spatial locations than for digits. Furthermore, serial order was freely reproduced twice as frequently for digits as for locations. When participants reordered spatial sequences, they minimized the mean distance between items. Participants also failed to detect changes in serial order more frequently for spatial than for verbal sequences. These results provide converging evidence for a dissociation in the binding of serial order to spatial versus verbal representations. There may be separable domain-specific control processes responsible for this binding. Alternatively, there may be fundamental differences in how effectively temporal information can be bound to different types of stimulus features in WM. PMID- 21264630 TI - Adaptive choice between articulatory rehearsal and attentional refreshing in verbal working memory. AB - Because both articulatory rehearsal and attentional refreshing aid in the maintenance of verbal information in the short term, the present study evaluated the adaptive use of these mechanisms, using a complex span paradigm. In Experiment 1, the phonological similarity of memory list words and the attentional demand of concurrent processing were manipulated. As was predicted, a phonological similarity effect (PSE) appeared only when the concurrent task was attention demanding, thus impairing the use of refreshing and encouraging rehearsal. To verify that PSE indicates the use of rehearsal, participants were instructed to use one of the two mechanisms in Experiments 2 and 3. In accordance wih Experiment 1, the PSE was observed only under rehearsal. Thus, adults could adaptively choose between the two mechanisms. When remembering phonologically confusable materials, they prefer refreshing in order to reduce the impact of phonological characteristics. When available attention is reduced, they favor a less attention-demanding mechanism, rehearsal. PMID- 21264631 TI - The effects of proactive interference (PI) and release from PI on judgments of learning. AB - In three experiments, we investigated metacognitive monitoring in a variant of an A-B A-C learning paradigm in which the repetition of cues, but not targets, led to increasing proactive interference (PI) across trials. Judgments of learning (JOLs) correctly predicted decreases across trials in this paradigm but incorrectly continued to predict decreases on a final release trial in which new cues were introduced and performance consequently increased. Experience with the paradigm did not ameliorate this metacognitive failure (Experiment 3). In addition, JOLs decreased equally for pairs with repeated and with novel cue terms, even though recall of the latter group of items did not decrease across trials (Experiment 2). These results suggest that metacognizers' naive theories of remembering and forgetting include a role for global, but not cue-specific, interference. PMID- 21264632 TI - Feature binding in visual short-term memory is unaffected by task-irrelevant changes of location, shape, and color. AB - Three experiments used a change detection paradigm across a range of study-test intervals to address the respective contributions of location, shape, and color to the formation of bindings of features in sensory memory and visual short-term memory (VSTM). In Experiment 1, location was designated task irrelevant and was randomized between study and test displays. The task was to detect changes in the bindings between shape and color. In Experiments 2 and 3, shape and color, respectively, were task irrelevant and randomized, with bindings tested between location and color (Experiment 2) and location and shape (Experiment 3). At shorter study-test intervals, randomizing location was most disruptive, followed by shape and then color. At longer intervals, randomizing any task-irrelevant feature had no impact on change detection for bindings between features, and location had no special role. Results suggest that location is crucial for initial perceptual binding but loses that special status once representations are formed in VSTM, which operates according to different principles, than do visual attention and perception. PMID- 21264633 TI - The role of habituation and attentional orienting in the disruption of short-term memory performance. AB - A series of experiments explored habituation and dishabituation to repeated auditory distractors. Participants memorised lists of visually presented items in silence or while ignoring continuously presented auditory distractors. No habituation could be observed, in that the size of the auditory distractor effect did not decrease during the experiment. However, there was evidence for attentional orienting when novel auditory material was presented after a long period of repetitive stimulation, in that a change of distractors was associated with a temporary decrease in recall performance. The results are most consistent with theoretical accounts that claim that the auditory distractor effect is caused primarily by automatic interference, but that still allow attention to play a limited role in the short-term maintenance of information. PMID- 21264634 TI - Not all sources of familiarity are created equal: the case of word frequency and repetition in episodic recognition. AB - Low-frequency (LF) words produce higher hit rates and lower false alarm rates than high-frequency (HF) words. This word frequency mirror pattern has been interpreted within dual-process models of recognition, which assume the contributions of a slower recollective process and a relatively fast-acting familiarity process. In the present experiments, recollection and familiarity were placed in opposition using Jacoby, L. L., Journal of Memory and Language, 30, 513-541 (1991), two-list exclusion paradigm with HF and LF words. Exclusion errors to LF words exceeded those to HF words at fast deadlines, whereas the reverse occurred at slow deadlines. In Experiments 2 and 3, false alarms to HF nonpresented lures were higher than to LF nonpresented lures, indicating the use of baseline familiarity for totally new items. Combined, these results indicate that in addition to baseline familiarity and recollection, a third process involving the assessment of a relative change in familiarity is involved in recognition performance. Both relative changes in familiarity and recollection processes have distinct time courses and are engaged when there is diagnostic list information available, whereas baseline familiarity is used when there is no diagnostic information available (e.g., for nonpresented lure items). PMID- 21264635 TI - Giving up problem solving. AB - How do people decide to abandon a problem? Participants were presented with unsolvable water jar problems, having been accurately informed of the prior probability of solvability. Across three experiments, we discovered effects of prior probability of solvability and of problem size (number of distinct problem states) on measures of effort and confidence. If a problem is more likely to be solvable and allows more problem states, a problem solver spends longer trying to solve the problem. Giving-up decisions are informed by the same judgments of probability of success and costs of solution that inform move-choice in a rational model of problem solving. PMID- 21264636 TI - Investigating the anticipatory nature of pattern perception in sport. AB - The aim of the present study was to examine the anticipatory nature of pattern perception in sport by using static and moving basketball patterns across three different display types. Participants of differing skill levels were included in order to determine whether the effects would be moderated by the knowledge and experience of the observer in the same manner reported previously for simple images. The results from a pattern recognition task showed that both expert and recreational participants were more likely to anticipate the next likely state of a pattern when it was presented as a moving video, but only the experts appeared to have the depth of understanding required to elicit the same anticipatory encoding for patterns presented as schematic images. The results extend those reported in previous research and provide further evidence of an anticipatory encoding in pattern perception for images containing complex, interrelated patterns. PMID- 21264637 TI - Tip-of-the-tongue (TOT) states: retrieval, behavior, and experience. AB - The tip-of-the-tongue state (TOT) is the feeling that accompanies temporary inaccessibility of an item that a person is trying to retrieve. TOTs have been studied experimentally since the seminal work of Brown and McNeill (1966). TOTs are experiences that accompany some failed or slow retrievals, and they can result in changes in retrieval behavior itself, allowing us to study the interplay among experience, retrieval, and behavior. We often attribute the experience of the TOT to the unretrieved target, but TOTs are based on a variety of cues, heuristics, or sources of evidence, such as partial information, related information, and cue familiarity, that predict the likelihood of overcoming retrieval failure. We present a synthesis of the direct-access view, which accounts for retrieval failure, and the heuristic-metacognitive view, which accounts for the experience of the TOT. We offer several avenues for future research and applications of TOT theory and data. PMID- 21264638 TI - Neighborhood consistency and memory for number facts. AB - Verguts and Fias (Memory & Cognition 33:1-16, 2005a) proposed a new model of memory for simple multiplication facts (2 x 3 = 6; 8 x 7 =56) in which learning and performance is governed by the consistency of a problem's correct product with neighboring products in the times table. In the present study, to directly investigate effects of neighborhood consistency, participants memorized a set of 16 novel "pound" arithmetic equations. The pound arithmetic table included eight tie equations with repeated operands (e.g., 4 # 4 = 29) and eight nontie equations (e.g., 5 # 4 = 39). In the consistent problem set, tie and nontie answers in adjacent columns and rows shared a common decade or unit value. In the inconsistent problem set, neighboring tie and nontie problems did not share a common decade or unit. Across 14 study-test blocks, memorization of the pound arithmetic table presented a robust effect of neighborhood consistency, with the rate of learning nearly doubling that of the inconsistent condition. An analysis of error types showed that consistency fostered the development of a categorical structure based on problem operands and that tie problems were encoded as a distinct subcategory of problems. There was also a substantial learning advantage for tie problems relative to nonties both with consistent and inconsistent neighbors. The results indicate that neighborhood consistency can have a major impact on memory for number facts. PMID- 21264639 TI - Spacing enhances the learning of natural concepts: an investigation of mechanisms, metacognition, and aging. AB - In two experiments, we examined spacing effects on the learning of bird families and metacognitive assessments of such learning. Results revealed that spacing enhanced learning beyond massed study. These effects were increased by presenting birds in pairs so as to highlight differences among families during study (Experiment 1). Self-allocated study time provided evidence that more attention was paid during spaced than during massed study and resulted in no age differences in learning (Experiment 2). Metacognitive measures revealed sensitivity to the processing advantage of spaced study and to differences in classification difficulty across categories. No difference occurred in monitoring accuracy for young versus older adults. These findings provide evidence for discrimination- and attention-based accounts of the spacing effect in natural concept learning. PMID- 21264640 TI - Effects of near and distant semantic neighbors on word production. AB - One way to examine the dynamics of word processing is to investigate how processing is affected by the co-activation of similar words ("neighbors"). A unique prediction of attractor dynamical models is that near neighbors should exert inhibitory effects and distant neighbors should exert facilitative effects. In study 1, data from 62 unselected chronic aphasia patients revealed a higher rate of semantic errors for words with many near semantic neighbors and fewer semantic errors for words with many distant semantic neighbors. In study 2, this basic result was replicated in controls using a speeded picture-naming paradigm. Together, these two studies provide strong new evidence consistent with the attractor dynamics view of neighborhood effects. In addition, analyses of correlations between effect sizes and lesion locations, and comparisons with the existing literature on semantic deficits in aphasia and the speeded picture naming paradigm, all provide converging evidence that the semantic error patterns found in the present studies were due to disruptions of cognitive control mechanisms. PMID- 21264641 TI - Motor imagery effectiveness for mirror reversed movements. AB - Physical practice is known to enhance motor adaptation skills, which refer to the individual ability to compensate for environmental changes. So far, it is still unknown whether a similar effect can be observed following motor imagery (MI). Thirty-nine participants were tested during a joystick tracking task under both normal and mirror conditions (i.e., the inductive direction of the joystick was reversed), before and after a physical practice or MI training phase. Eye movements and electromyographic activity were recorded during MI. Motor performance was also evaluated after a 6 h interval during daytime. As compared to the control group, the results revealed that both MI and physical practice improved motor performance in the mirror condition, during the post-training test. Furthermore, the time to complete the task was further reduced after 6 hours, both in the normal and mirror conditions. These results demonstrate the effectiveness of MI for learning mirror-reversed movements, and for the consolidation process that follows motor adaptation. PMID- 21264642 TI - Expectation and temperament moderate amygdala and dorsal anterior cingulate cortex responses to fear faces. AB - A chronic tendency to avoid novelty is often the result of a temperamental bias called inhibited temperament, and is associated with increased risk for anxiety disorders. Neuroimaging studies have demonstrated that an inhibited temperament is associated with increased amygdalar blood-oxygenation-level-dependent (BOLD) response to unfamiliar faces that were not expected; however, the effects of variations in expectancy remain unknown. Using functional magnetic resonance imaging (fMRI), we studied BOLD response to infrequently encountered fear faces that were either expected or not expected in 42 adults with an inhibited or an uninhibited temperament. Individuals with an inhibited temperament had greater amygdala, but less dorsal anterior cingulate cortex (dACC), BOLD response when the stimuli were expected. In contrast, those with an uninhibited temperament had a smaller amygdala but larger dorsal anterior cingulate cortex BOLD response when expecting to see fear faces. These findings demonstrate temperament differences in expectancy effects and provide preliminary evidence for the dACC as a neural substrate mediating differences in inhibited temperament. Enhanced amygdala sensitivity coupled with weak inhibitory control from the dACC may form a neural circuit mediating behaviors characteristic of inhibited temperament and risk for anxiety disorders. PMID- 21264643 TI - Multisensory perceptual learning reshapes both fast and slow mechanisms of crossmodal processing. AB - Previous research has shown that sounds facilitate perception of visual patterns appearing immediately after the sound but impair perception of patterns appearing after some delay. Here we examined the spatial gradient of the fast crossmodal facilitation effect and the slow inhibition effect in order to test whether they reflect separate mechanisms. We found that crossmodal facilitation is only observed at visual field locations overlapping with the sound, whereas crossmodal inhibition affects the whole hemifield. Furthermore, we tested whether multisensory perceptual learning with misaligned audio-visual stimuli reshapes crossmodal facilitation and inhibition. We found that training shifts crossmodal facilitation towards the trained location without changing its range. By contrast, training narrows the range of inhibition without shifting its position. Our results suggest that crossmodal facilitation and inhibition reflect separate mechanisms that can both be reshaped by multisensory experience even in adult humans. Multisensory links seem to be more plastic than previously thought. PMID- 21264644 TI - Rostral anterior cingulate activity generates posterior versus anterior theta activity linked to agentic extraversion. AB - Recent research using the resting electroencephalogram (EEG) showed that posterior versus anterior theta activity (around 4-8 Hz) is consistently associated with agency, reflecting the dopaminergic core of extraversion (i.e., incentive motivation, positive emotion). Neuroimaging studies using various methodologies and experimental paradigms have converged on the anterior cingulate cortex (ACC) as a neurophysiological correlate of extraversion. The aim of the present study is integrate these lines of research by testing the hypothesis that posterior versus anterior EEG theta is at least partly based on ACC theta activity. Resting EEG data were analyzed in N = 78 healthy, male participants extremely high or low in agentic extraversion (aE). Using the low-resolution electromagnetic tomography algorithm, we localized the sources of aE-dependent intracerebral theta activity within rostral subdivisions of the ACC. The posterior versus anterior index and theta current density within the rostral ACC were significantly correlated (r = -.52), and both displayed high retest stability across 5 hr and were associated with traits from the aE spectrum. These neurophysiological correlates of aE and their possible functional significance are discussed. PMID- 21264645 TI - The relationship between cognitive performance and electrophysiological indices of performance monitoring. AB - Studies of electrophysiological indices of performance monitoring, such as the error-related negativity (ERN), posterror positivity (Pe), and N2 components of the event-related potential (ERP), suggest that increased ERN and Pe amplitudes and decreased N2 amplitudes are associated with better cognitive flexibility and cognitive control abilities; however, few studies have directly examined the relationship between cognitive performance and ERP indices of performance monitoring. We examined the neuropsychological profile of 89 healthy individuals who performed a modified flanker task. The neuropsychological domains tested included memory, verbal fluency, and attention/executive functioning. Pearson's correlations and multiple regression analyses showed a significant relationship between measures of attention/executive functioning and ERN amplitude, even when negative affect, reaction time interference, and posterror slowing were controlled. N2 amplitude related only to posterror slowing. The amplitude of the Pe was not significantly related to any cognitive domains. These findings are consistent with recent work indicating that performance monitoring requires attention skills and cognitive flexibility. Implications for the conflict monitoring and reinforcement-learning theories are discussed. PMID- 21264646 TI - Right hemisphere has the last laugh: neural dynamics of joke appreciation. AB - Understanding a joke relies on semantic, mnemonic, inferential, and emotional contributions from multiple brain areas. Anatomically constrained magnetoencephalography (aMEG) combining high-density whole-head MEG with anatomical magnetic resonance imaging allowed us to estimate where the humor specific brain activations occur and to understand their temporal sequence. Punch lines provided either funny, not funny (semantically congruent), or nonsensical (incongruent) replies to joke questions. Healthy subjects rated them as being funny or not funny. As expected, incongruous endings evoke the largest N400m in left-dominant temporo-prefrontal areas, due to integration difficulty. In contrast, funny punch lines evoke the smallest N400m during this initial lexical semantic stage, consistent with their primed "surface congruity" with the setup question. In line with its sensitivity to ambiguity, the anteromedial prefrontal cortex may contribute to the subsequent "second take" processing, which, for jokes, presumably reflects detection of a clever "twist" contained in the funny punch lines. Joke-selective activity simultaneously emerges in the right prefrontal cortex, which may lead an extended bilateral temporo-frontal network in establishing the distant unexpected creative coherence between the punch line and the setup. This progression from an initially promising but misleading integration from left frontotemporal associations, to medial prefrontal ambiguity evaluation and right prefrontal reprocessing, may reflect the essential tension and resolution underlying humor. PMID- 21264647 TI - Contributions of the nucleus accumbens and its subregions to different aspects of risk-based decision making. AB - The nucleus accumbens (NAc) has been implicated in mediating different forms of decision making in humans and animals. In the present study, we observed that inactivation of the rat NAc, via infusion of GABA agonists, reduced preference for a large/risky option and increased response latencies on a probabilistic discounting task. Discrete inactivations of the NAc shell and core revealed further differences between these regions in mediating choice and response latencies, respectively. The effect on choice was attributable to reduced win stay performance (i.e., choosing risky after a being rewarded for a risky choice on a preceding trial). Moreover, NAc inactivation altered choice only when the large/risky option had greater long-term value, in terms of the amount of food that could be obtained over multiple trials relative to the small/certain option. Inactivation of the NAc or the shell subregion also slightly reduced preference for larger rewards on a reward magnitude discrimination. Thus, the NAc seems to play a small role in biasing choice toward larger rewards, but its contribution to behavior is amplified when delivery of these rewards is uncertain, helping to direct response selection toward more favorable outcomes. PMID- 21264648 TI - Neural and behavioral effects of interference resolution in depression and rumination. AB - Individuals diagnosed with major depressive disorder (MDD) often ruminate about their depression and their life situations, impairing their concentration and performance on daily tasks. We examined whether rumination might be due to a deficit in the ability to expel negative information from short-term memory (STM), and fMRI was used to examine the neural structures involved in this ability. MDD and healthy control (HC) participants were tested using a directed forgetting procedure in a short-term item recognition task. As predicted, MDD participants had more difficulty than did HCs in expelling negative, but not positive, words from STM. Overall, the neural networks involved in directed forgetting were similar for both groups, but the MDDs exhibited more spatial variability in activation in the left inferior frontal gyrus (a region critical for inhibiting irrelevant information), which may contribute to their relative inability to inhibit negative information. PMID- 21264649 TI - The influence of dichotical fusion on the redundant signals effect, localization performance, and the mismatch negativity. AB - In two experiments, each including a simple reaction time (RT) task, a localization task, and a passive oddball paradigm, the physical similarity between two dichotically presented auditory stimuli was manipulated. In both experiments, a redundant signals effect (RSE), high localization performance, and a reliable mismatch negativity (MMN) was observed for largely differing stimuli, suggesting that these are coded separately in auditory memory. In contrast, no RSE and a localization rate close to chance level (experiment 1) or at chance (experiment 2) were observed for stimuli differing to a lesser degree. Crucially, for such stimuli a small (experiment 1) or no (experiment 2) MMN were observed. These MMN results indicate that such stimuli tend to fuse into a single percept and that this fusion occurs rather early within information processing. PMID- 21264650 TI - Cognitive and metacognitive activity in mathematical problem solving: prefrontal and parietal patterns. AB - Students were taught an algorithm for solving a new class of mathematical problems. Occasionally in the sequence of problems, they encountered exception problems that required that they extend the algorithm. Regular and exception problems were associated with different patterns of brain activation. Some regions showed a Cognitive pattern of being active only until the problem was solved and no difference between regular or exception problems. Other regions showed a Metacognitive pattern of greater activity for exception problems and activity that extended into the post-solution period, particularly when an error was made. The Cognitive regions included some of parietal and prefrontal regions associated with the triple-code theory of (Dehaene, S., Piazza, M., Pinel, P., & Cohen, L. (2003). Three parietal circuits for number processing. Cognitive Neuropsychology, 20, 487-506) and associated with algebra equation solving in the ACT-R theory (Anderson, J. R. (2005). Human symbol manipulation within an 911 integrated cognitive architecture. Cognitive science, 29, 313-342. Metacognitive regions included the superior prefrontal gyrus, the angular gyrus of the triple code theory, and frontopolar regions. PMID- 21264651 TI - Upregulation of emotion areas through neurofeedback with a focus on positive mood. AB - Real-time functional magnetic resonance imaging can be used to feed back signal changes from the brain to participants such that they can train to modulate activation levels in specific brain areas. Here we present the first study combining up-regulation of brain areas for positive emotions with psychometric measures to assess the effect of successful self-regulation on subsequent mood. We localized brain areas associated with positive emotions through presentation of standardized pictures with positive valence. Participants up-regulated activation levels in their target area during specific periods, alternating with rest. Participants attained reliable self-control of the target area by the last of three seven-minute runs. This training effect was supported by an extensive network outside the targeted brain region, including higher sensory areas, paralimbic and orbitofrontal cortex. Self-control of emotion areas was not accompanied by clear changes in self-reported emotions; trend-level improvements on depression scores were counteracted by increases on measures of fatigue, resulting in no overall mood improvement. It is possible that benefits of self control of emotion networks may only appear in people who display abnormal emotional homeostasis. The use of only a single, short, training session, overlap between positive and negative emotion networks and aversive reactions to the scanning environment may have prevented the detection of subtle changes in mood. PMID- 21264652 TI - Nonmarital childbearing in Russia: second demographic transition or pattern of disadvantage? AB - Using retrospective union, birth, and education histories that span 1980-2003, this study investigates nonmarital childbearing in contemporary Russia. We employ a combination of methods to decompose fertility rates by union status and analyze the processes that lead to a nonmarital birth. We find that the increase in the percentage of nonmarital births was driven mainly by the growing proportion of women who cohabit before conception, not changing fertility behavior of cohabitors or changes in union behavior after conception. The relationship between education and nonmarital childbearing has remained stable: the least educated women have the highest birth rates within cohabitation and as single mothers, primarily because of their lower probability of legitimating a nonmarital conception. These findings suggest that nonmarital childbearing Russia has more in common with the pattern of disadvantage in the United States than with the second demographic transition. We also find several aspects of nonmarital childbearing that neither of these perspectives anticipates. PMID- 21264653 TI - [The ABC's of medical statistics. Reading and understanding clinical trials]. AB - Clinical trials test hypotheses that are accepted or rejected according to a predetermined probability of error (level of significance). Significance does not however mean relevance. Good parameters of relevance are absolute risk reduction and based on this the calculation of the number of patients who need to be treated for one additional patient to benefit. The randomized controlled trial is the gold standard for comparative evaluation of effects. In the ideal scenario it is designed so that a difference established by statistical methods becomes probable. In non-inferiority studies care should be taken that no equivalence is shown but rather that the difference is not greater than a predefined margin of error for differences. Meta-analyses of studies with similar endpoints have the potential to improve the level of evidence. Since the findings of meta-analyses depend on the studies included, critical assessment of the results is essential. PMID- 21264654 TI - Assessing the scientific and educational value of case reports: an editor's view. PMID- 21264655 TI - Clinical applications of gadobenate dimeglumine-enhanced magnetic resonance cholangiography: an expanded pictorial review. AB - Gadobenate dimeglumine (Gd-BOPTA) is taken up by functioning hepatocellular cells and is partially excreted into the biliary system; therefore, it can be used as a potential intrabiliary contrast agent for magnetic resonance cholangiography applications for various clinical conditions such as obstructive disorders (e.g., choledocholithiasis, hepatolithiasis), inflammatory disorders (e.g., acute cholecystitis, cholangitis), benign biliary disorders, and pre- and postprocedural evaluation of the biliary system. In this pictorial review, we aimed to demonstrate the clinical applications of Gd-BOPTA as an intrabiliary contrast agent for imaging various biliary pathologies. PMID- 21264656 TI - Peristalsis gap sign at cine magnetic resonance imaging for diagnosing strangulated small bowel obstruction: feasibility study. AB - PURPOSE: The aim of this study was to determine the feasibility of cine magnetic resonance imaging (MRI) for diagnosing strangulated small bowel obstruction (SBO). MATERIALS AND METHODS: This study included 38 patients with clinically confirmed SBO who had undergone cine MRI. Cine MRI scans were evaluated regarding the presence of the "peristalsis gap sign" (referring to an akinetic or severely hypokinetic closed loop), indicating strangulation. Computed tomography (CT) was performed in 34 of 38 patients with (n = 25) or without (n = 9) contrast enhancement. CT images were evaluated using a combination of criteria (presence of hyperattenuation, poor contrast enhancement, mesenteric edema, wall thickening, massive ascites) indicating strangulation. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of cine MRI and CT for the diagnosis of strangulation were calculated and compared using surgical findings and the clinical course as the reference standard. RESULTS: Sensitivity, specificity, PPV, and NPV of cine MRI were 100%, 92.9%, 83.3%, and 100%, respectively; and those of CT (of which 26.5% was performed without contrast enhancement) were 66.7%, 92.0%, 75.0%, and 88.5%, respectively. There was no significant difference in diagnostic accuracy between the two methods (P = 0.375). CONCLUSION: Cine MRI is a feasible and promising technique for diagnosing strangulation. PMID- 21264657 TI - Smaller brain size likely in young adults (<40 years old) with depressive symptoms compared to healthy controls: a retrospective study. AB - PURPOSE: The aim of this study was to determine whether the brain size of young patients with depressive symptoms is smaller than that of healthy controls using magnetic resonance imaging (MRI). MATERIALS AND METHODS: We retrospectively evaluated brain size by calculating the ratio of the brain area to that of the skull (the brain-to-skull ratio) on routine MRI scans including the splenium of the corpus callosum obtained from 19 patients <40 years old with depressive symptoms in 2009. The controls were 12 healthy individuals <40 years old who underwent MRI for medical examinations. RESULTS: The mean brain-to-skull ratio of the control group was 0.850 +/- 0.022 (range 0.822-0.889), and that of the patient group was 0.819 +/- 0.041 (range 0.756-0.878). An unpaired t-test showed a significant difference in the brain-to-skull ratios between these groups (P = 0.011). In particular, in 7 of the 19 patients with longer duration of illness and more severe symptoms, the brainto-skull ratio was 89%-92% of the mean ratio of the control group. CONCLUSION: The brain size of young patients with depressive symptoms appears to be smaller than that of healthy controls. PMID- 21264658 TI - Diffusion magnetic resonance imaging with gadofosveset trisodium as a negative contrast agent for lymph node metastases assessment. AB - PURPOSE: The aim of this study was to assess the feasibility of using intravenously administered gadofosveset trisodium as a negative contrast agent for lymph node (LN) assessment with diffusion-weighted imaging (DWI) using a VX2 tumor model in rabbits. MATERIALS AND METHODS: VX2 cells were injected in the right hind limb of five Japanese white rabbits to induce ipsilateral popliteal LN metastasis. DWI was performed before and every 7.5 min (until 1 h) after intravenous gadofosveset trisodium administration, at 1.5 T. Signal intensities (SIs) of right (metastatic) and left (nonmetastatic) popliteal LNs at each time point were measured and compared to each other using two-sided unpaired t-tests. RESULTS: The SIs of metastatic lymph nodes were significantly higher (P < 0.05) than those of nonmetastatic LNs at each time point after intravenous gadofosveset trisodium administration. Although the SI of metastatic LNs was significantly higher (P = 0.0237) than that of nonmetastatic LNs before contrast injection, this difference became even more significant (P <= 0.0105) after gadofosveset trisodium administration. CONCLUSION: The SI of metastatic LNs at DWI is less suppressed than that of nonmetastatic LNs after the intravenous administration of gadofosveset trisodium. Therefore, intravenously administered gadofosveset trisodium shows promise for use as a negative contrast agent for discriminating metastatic from nonmetastatic LNs at DWI. PMID- 21264659 TI - Body weight-tailored contrast material injection protocol for 64-detector row computed tomography coronary angiography. AB - PURPOSE: The aim of this study was to assess the body weight-tailored contrast material injection protocol for 64-detector computed tomography (CT) to maintain optimal coronary CT attenuation. MATERIALS AND METHODS: A total of 60 patients who underwent CT coronary angiography were assigned to one of three groups: protocol A, total of 0.7 ml kg(-1) with 300 mg I/ml iodine concentration; protocol B, total of 0.6 ml kg(-1) with 350 mg I/ml; protocol C, total of 0.7 ml kg(-1) with 350 mg I/ml. The injection duration was 10 s in all patients. The proportion of intracoronary attenuation values >325 HU was compared on a pervessel and per-patient basis. RESULTS: The attenuation value was significantly more likely to exceed 325 HU with protocol C (95% for reader 1 and 90% for reader 2) than with protocol A or B on the per-vessel analysis (P < 0.05). The attenuation value also significantly exceeded 325 HU with protocol C (95% and 90%, respectively) more often than with protocol A or B on the per-patient analysis (P < 0.05). CONCLUSION: A total of at least 0.7 ml kg(-1) contrast material with 350 mg/ml iodine concentration is required to achieve optimal coronary CT attenuation (>325 HU) with 64-detector CT when using an injection duration of 10 s. PMID- 21264660 TI - Depiction of the thoracic duct by magnetic resonance imaging: comparison between magnetic resonance imaging and the anatomical literature. AB - PURPOSE: The aim of this study was to compare thoracic duct (TD) configuration depicted by magnetic resonance imaging (MRI) with TD configuration described in the anatomical literature. MATERIALS AND METHODS: MRI Scans were acquired with a three-dimensional T2-weighted turbo spin echo (TSE) MRI with a two-dimensional prospective acquisition correction (PACE) technique in 63 patients. We found with MRI that TD displacement occurred more on the left side than that reported in the anatomical literature, and this tendency was more marked in elderly patients. In patients with marked leftward TD displacement, the TD configuration on MRI was compared to the descending aortic configuration on chest radiography. The degree of correspondence between the MRI findings and the anatomical literature was assessed by a chi(2) goodness-of-fit test, and P < 0.05 indicated a significant difference. The degree of similarity was determined between TD configuration and aortic configuration by Kendall's coefficient of concordance (W). RESULTS: On MRI scans the TD was often located to the left of the mid-vertebral line compared to the location reported in the anatomical literature (P < 0.001). Nine patients had marked leftward TD displacement, a configuration similar to that of the descending aorta (W = 1); however, no association with age was established. CONCLUSION: The TD configuration depicted by MRI differed from that described in the anatomical literature. PMID- 21264661 TI - Interruption of the aortic arch: diagnosis with multidetector computed tomography. AB - PURPOSE: We investigated retrospectively the usefulness of multidetector computed tomography (MDCT) in the preoperative diagnosis of interruption of the aortic arch (IAA). MATERIALS AND METHODS: Seven neonates with IAA underwent enhanced MDCT before a surgical repair operation between April 2006 and March 2010. The MDCT procedures were performed using either a 16- or 64-MDCT scanner without electrocardiographic gating or respiratory arrest. RESULTS: High-quality CT images were obtained in all cases. One patient was diagnosed to be IAA type A, and 6 were diagnosed to be IAA type B (Celoria and Patton classification). The Celoria and Patton classification of IAA types and subtype classification by MDCT were confirmed by surgery. CONCLUSION: Our results show that the information from MDCT was sufficient for a preoperative diagnosis of IAA and allowed omission of a cardiac catheter examination before surgery. PMID- 21264662 TI - Initial experience of carotid artery stenting using the Carotid WALLSTENT and FilterWire EZ in Japan. AB - PURPOSE: The Carotid WALLSTENT (CWS) and Filter-Wire EZ (FWEZ) embolic protection devices for use in carotid arterial stenting (CAS) were newly approved for national health insurance coverage in Japan in April 2010. This article describes our initial experience of CAS using the CWS and FWEZ. MATERIAL AND METHODS: A group of 14 patients (12 men, 2 women; mean age 70.1 years, range 59-83 years) with 15 carotid artery stenoses at high risk for carotid endarterectomy were treated by CAS using the CWS and FWEZ. Of these stenoses, 5 were symptomatic with >=50% stenosis of the common or internal carotid artery (ICA), and 10 were asymptomatic with >=80% stenosis. The rates of technical success, ICA flow impairment during filter protection, periprocedural ischemic stroke, 30-day major adverse events (MAEs) (stroke, death, myocardial infarction), and development of new ischemic lesions on diffusion-weighted imaging (DWI) were assessed. RESULTS: CAS was successful in all cases. There was no ICA flow impairment, periprocedural ischemic stroke, or MAEs. DWI showed new ipsilateral ischemic lesions in only one patient (6.7%). CONCLUSION: Our initial clinical experience using the CWS and FEWZ for CAS was generally excellent, and the incidence of postprocedural ischemic lesions was low. PMID- 21264663 TI - Multidetector computed tomography aspects of tracheal mucosal leishmaniasis localization. AB - Tracheal mucosal localization of Leishmania is considered a rare and dangerous event. A single case of leishmaniasis of the trachea has been described in literature. Our work describes multidetector computed tomography features of leishmaniasis localized in the tracheal mucosa that occurred in a 68-year-old patient who lived in an endemic zone. Our patient underwent biopsy that established the diagnosis of leishmaniasis. PMID- 21264664 TI - Unusual presentation of an esophageal foreign body granuloma caused by a fish bone: usefulness of multidetector computed tomography. AB - A 68-year-old woman had throat pain while eating fish. The pain gradually disappeared with no treatment. She visited her doctor for a medical checkup 1 year later, and an esophageal tumor was suspected. A double-contrast esophagogram revealed luminal stenosis with a mass-like defect in the middle esophagus. Esophagogastroduodenoscopy (EGD) showed smooth-surface stenosis with a retracted fold. Endoscopic ultrasonography (EUS) showed a hypoechoic mass in the submucosal layer and a well-defined linear hyperechoic structure forming a posterior acoustic shadow within the mass. A computed tomography (CT) examination was then performed using an Aquilion 64-detector row CT scanner, and a high attenuation linear structure was found in the lesion that was visualized as a fish bone-like structure on reconstructed CT images. Endoscopic removal of the fish bone was impossible, and a surgical operation would have been too invasive for a lesion suspected of being benign. The patient had no complaint related to the esophageal lesion itself and no sign of gastrointestinal tract complications. Accordingly, regular follow-up was recommended for the esophageal lesion. Follow-up examination including EGD, esophagography, and CT performed 1 year later showed that the lesion had decreased in size with no fish bone-like structure. PMID- 21264665 TI - Complete androgen insensitivity syndrome with microtia: a rare presentation. AB - Complete androgen insensitivity syndrome (CAIS) is a rare X-linked disorder characterized by a female body habitus and male genotype. The Mullerian duct derivatives are absent or rudimentary, and the testes are undescended. Microtia is characterized by a malformed auricle; and in some cases it is genetically transmitted with a non-sex-linked inheritance pattern. The presence of CAIS with microtia has not been documented previously, and this is the first case to describe the radiological findings of this rare presentation. PMID- 21264666 TI - Carotid blowout syndrome with oronasal hemorrhage: magnetic resonance imaging findings. AB - Carotid blowout syndrome (CBS) is a rare but well-known complication of aggressive radiotherapy management of head and neck cancer. Reports on magnetic resonance imaging (MRI) findings of CBS are limited in the relevant literature, probably because of the angiography priority of this complication. We describe MRI findings in a patient with nasopharyngeal carcinoma complicated with CBS. PMID- 21264667 TI - Description of early gastric cancer with wall-carving technique on multidetector computed tomography. AB - PURPOSE: We introduce a new volume-rendering method, named the "wall-carving (WC) technique," for luminal organs on contrast-enhanced multidetector row computed tomography (MDCT) using a gas-extension protocol. This study aimed to investigate the enhancement profile of the normal gastric wall, particularly focused on the relation between depth and gray value in the normal gastric wall, as a background to distinguish early gastric cancer (EGC) on MDCT. MATERIALS AND METHODS: We retrospectively evaluated 32 data sets of abdominal CT with EGC. All data sets were obtained with a 64-detector-row CT after administration of an effervescent agent, anticholinergic drug, and intravenous contrast material. The enhancement profile was analyzed in the normal gastric body and antrum (n = 32) by the depth from the air-mucosa interface. We also examined the visual accessibility of the WC image. Institutional review board approval was obtained for this study. RESULTS: The profile curve showed that the thickness of the normal gastric wall was 3.75-6.25 mm (mean 4.8 mm), and the maximum enhancement was observed at the layer of 1.875 mm in each case. The enhancement pattern of the EGC was visually accessible, especially at a depth of 1.875-3.75 mm. CONCLUSION: The enhancement profile showed a peak at the depth within the inner half-thickness of the estimated normal gastric wall. The WC image seems to be a good alternative for detecting tumor enhancement and its relation with the surrounding vascular structures in the gastric wall. PMID- 21264669 TI - Attitudes towards ethical problems in critical care medicine: the Chinese perspective. AB - INTRODUCTION: Critical care doctors are frequently faced with clinical problems that have important ethical and moral dimensions. While Western attitudes and practice are well documented, little is known of the attitudes or practice of Chinese critical care doctors. METHODS: An anonymous, written, structured questionnaire survey was translated from previously reported ethical surveys used in Europe and Hong Kong. A snowball method was used to identify 534 potential participants from 21 regions in China. RESULTS: A total of 315 (59%) valid responses were analysed. Most respondents (66%) reported that admission to an intensive care unit (ICU) was commonly limited by bed availability, but most (63%) would admit patients with a poor prognosis to ICU. Only 19% of respondents gave complete information to patients and family, with most providing individually adjusted information, based on prognosis and the recipient's educational level. Only 28% disclosed all details of an iatrogenic incident, despite 62% stating that they should. The use of do not resuscitate orders or limitation of life-sustaining therapy in terminally ill patients reported as uncommon and according to comparable reports, both are more common practice in Hong Kong or Europe. In contrast to European practices, doctors were more acquiescent to families in decision-making at the end of life. CONCLUSIONS: A number of differences in ethical attitudes and related behaviour between Chinese, Hong Kong and European ICU doctors were documented. A likely explanation is differing cultural background, and doctors should be aware of likely expectations when treating patients from a different culture. PMID- 21264670 TI - Degenerative cervical spondylolisthesis: a systematic review. AB - PURPOSE: Degenerative cervical spondylolisthesis has received insufficient attention, in contrast to degenerative lumbar spondylolisthesis. In fact, degenerative cervical spondylolisthesis may be more common than previously thought. METHODS: In order to provide appropriate guidelines for the treatment of degenerative cervical spondylolisthesis, a systematic review of degenerative cervical spondylolisthesis was performed. An English literature search from January 1947 to November 2010 was completed with reference to radiological examination and management of degenerative cervical spondylolisthesis. RESULTS: Of 102 patients with degenerative cervical spondylolisthesis, 52 patients (51%) had neck or occipital pain, 23 patients (22.5%) were referred with radiculopathy and 65 patients (63.7%) presented with myelopathy or myeloradiculopathy. Degenerative cervical spondylolisthesis was most common in C3/4 and C4/5, occurring in 81 patients at C3/4 (46%) and 87 at C4/5 (49.4%). Disc degeneration and facet hypertrophy were the main causes of this clinical entity. Of 123 patients, 57 (46.3%) were found to have segmental instability as shown by flexion extension lateral radiographs. There are two classification systems for degenerative cervical spondylolisthesis. Surgery was indicated in patients who had radiologically proven cervical spondylolisthesis with instability and/or spinal cord compression. CONCLUSION: Prospective studies should be designed in the future to draw a more reliable conclusion about the management of degenerative cervical spondylolisthesis. PMID- 21264671 TI - Introduction the paper: Posterior fossa decompression and the cerebellum in Chiari type II malformation: a preliminary MRI study, by Salman M. PMID- 21264672 TI - Automated analysis of pharyngeal pressure data obtained with high-resolution manometry. AB - We present an algorithm developed in MATLAB that can be applied to both normal and disordered swallowing to automatically extract a wide array of measurements from the spatiotemporal plots produced by high-resolution manometry (HRM) of the pharyngeal swallow. The algorithm was developed from data from 12 normal and 3 disordered subjects swallowing 5-ml water boluses. Automated extraction was compared to manual extraction for a subset of seven normal and the three disordered subjects to evaluate algorithm accuracy. Area and line integrals, pressure wave velocity, and pressure gradients during upper esophageal sphincter opening were also measured. Automated extraction showed strong correlations with manual extraction, producing high correlation coefficients in both normal and disordered subjects for maximum velopharyngeal pressure and maximum tongue base pressure. Timing data were also strongly correlated for all variables, including velopharyngeal pressure duration, tongue base pressure duration, and total swallow duration. Preliminary descriptive data on area and line integrals are presented. Our results indicate that the algorithm can effectively extract data automatically from HRM spatiotemporal plots. The efficiency of the algorithm makes it a valuable tool to supplement clinical and research use of HRM. PMID- 21264673 TI - Post atlantoaxial fusion for unilateral cleft of atlas posterior arch associated with os odontoideum: case report and technique note. AB - A case of a 34-year-old female with unilateral cleft of atlas posterior arch associated with os odontoideum is reported. The patient had experienced neck pain for 6 months. Five days earlier to admission the pain aggravated as a result of mild head trauma from behind. Imaging examinations revealed C1-2 subluxation as well as the deformity. After 3 days of skull traction, a sound C1-2 reduction was achieved. Post atlantoaxial fusion using bilateral transarticular screws combined with C1 laminar hook on the intact side and autogenous bone graft was performed. On the sixth month of postoperative follow-up, CT revealed solid fusion was achieved. No related complications were detected within 3 years of follow-up. The clinical manifestations and imaging findings were presented. The incidence and etiopathogenesis of hypoplastic posterior arch of the atlas were concisely introduced. Techniques of post atlantoaxial fusion under circumstances of unilateral C1 posterior elements defects were discussed. The authors believe bilateral transarticular screws combined with C1 laminar hook on the intact side and autogenous bone graft can be applicable to atlantoaxial fusion on the premise of preoperative C1-2 reduction and C1 posterior arch remaining >1/2 of its full length. PMID- 21264674 TI - Medium-term outcomes of C3-6 laminoplasty for cervical myelopathy: a prospective study with a minimum 5-year follow-up. AB - C3-6 laminoplasty preserving muscle insertions into the C7 spinous process is reportedly associated with a significantly decreased frequency of postoperative axial neck pain. However, no prospective study has reported medium-term outcomes of C3-6 laminoplasty. The purpose of this study was to elucidate medium-term outcomes after C3-6 laminoplasty. Subjects comprised 31 patients with cervical myelopathy who underwent C3-6 laminoplasty preserving all bilateral muscles attached to the C2 and C7 spinous processes and were followed for >=5 years. Clinical and radiological data were prospectively collected. Neurological status was assessed using Japanese Orthopaedic Association (JOA) score. Axial neck pain was graded as severe, moderate or mild. Sagittal alignment of the cervical spine and progression of ossification of the posterior longitudinal ligament (OPLL) were assessed by comparing serial lateral radiographs. Mean JOA score improved significantly from 10.6 before surgery to 14.7 at the time of maximum recovery, and slightly declined to 14.3 at final follow-up. In six patients who developed late deterioration, these conditions were unrelated to the cervical spine. As of final follow-up, only one patient (3.2%) had complained of axial neck pain persisting for 5 years. Although progression of OPLL was found in 63.6% of patients, none had experienced neurological deterioration due to this progression. At final follow-up, sagittal alignment of the cervical spine was more lordotic than before surgery. Medium-term outcomes of C3-6 laminoplasty were satisfactory. Frequencies of persistent axial neck pain and loss of cervical lordosis after surgery remained significantly decreased for >=5 years postoperatively. PMID- 21264675 TI - Perioperative morbidity and complications in minimal access surgery techniques in obese patients with degenerative lumbar disease. AB - The medical profession is increasingly confronted with the epidemic phenomenon of obesity. Its impact on spine surgery is not quite clear. Published data concerning the use of minimally invasive surgery (MIS) in the spine among obese patients is scarce. The purpose of the present retrospective study was to evaluate perioperative as well as postoperative complication rates in MIS fusion of the lumbar spine in obese, overweight and normal patients classified according to their body mass index. Lumbar MIS fusion was performed by means of TLIF procedures and/or posterolateral fusion alone. A laminotomy was performed in patients with spinal stenosis. Of 72 patients, 39 underwent additional laminotomy for spinal stenosis. No differences were registered in respect of the numbers of fused segments or cages. Any harmful event occurring peri- or postoperatively was noted and included in the statistical analysis. No infection at the site of surgery or severe wound healing disorder was encountered. We registered no difference in blood loss, drainage, or the length of the hospital stay between the three BMI groups. We also observed no difference in complication rates between the three groups. This study confirms the low soft tissue damage of minimal access surgery techniques, which is an important type of surgery in obese patients. The smaller approach helps to minimize infections and wound healing disorders. Moreover, deeper regions of wounds are clearly visualized with the aid of tubular retractors. PMID- 21264676 TI - Protection of intestinal anastomosis with biological glues: an experimental randomized controlled trial. AB - BACKGROUND: The aim of the study was to compare the degree of healing and air tightness of hand-sewn colonic anastomoses provided by different biological glues. METHODS: Thirty colonic anastomoses were fashioned in ten rabbits, at 5, 10, 15 cm from the ileocecal valve, with 4/0 PDS running sutures. Each suture was randomized to treatment with fibrin sealant (Tissucol(r)), a synthetic glue (Coseal(r)), or nothing (control). After 15 days, the rabbits were killed and the anastomoses examined for their integrity and resistance to bursting. The van der Hamm scale was used to evaluate postoperative adhesions. A blind histological evaluation of the newly formed tissue was made (Ehrlich-Hunt scale). RESULTS: Two rabbits developed an intraabdominal abscess, one in the control anastomosis group without glue. Postoperative adhesions were present in all animals. Median anastomosis bursting pressures were 0.9 atm in all three groups: Tissucol, Coseal, and control. Pressure values were 0.9, 1.0, and 0.9 atm in the three different proximodistal sites, respectively. A trend toward an increased resistance was observed in the glued anastomosis, although this was not significant. Lymphocyte infiltration, fibroblast activity, blood vessel density, and collagen deposition were lower in controls. Anastomoses treated with Tissucol had the highest lymphocyte infiltration level. The Coseal group developed the highest rates of fibroblast activity, collagen deposition, and blood vessel neogenesis. CONCLUSION: The use of biological glues did not result in a statistically significantly increased bursting resistance. Histological evaluation demonstrated more intense tissue neoformation in the glue groups, particularly in the Coseal group. The role of biological glues in decreasing the leakage rate of intestinal anastomoses is uncertain, and larger trials using different protective agents are warranted. PMID- 21264677 TI - Anal encirclement with a simple prosthetic sling for faecal incontinence. AB - BACKGROUND: Millions of people suffer from anal incontinence not currently treated due to the complexity and cost of the surgical techniques in use. The purpose of this report is to evaluate the results of anal encirclement with a simple device in a group of patients with faecal incontinence of multiple causes. METHODS: Surgery was performed as a modified Thiersch procedure through minimal perianal incisions, and a flat band of silicone was introduced to encircle the anus. Results were assessed by clinical response and objectively evaluated by comparing pre- and post-operative manometry, Jorge-Wexner and QOL (Rockwood) scores. RESULTS: Over a period of 5 years, this procedure was performed in 20 women and 13 men, mean age 54 years (27-86 years). Causes of incontinence were iatrogenic (5), obstetric (5), idiopathic (5), restorative proctectomy (5), rectal prolapsed (4), congenital (4), neuropathic (3), trauma (1) and mixed (1). Mortality was nil and morbidity was related to early infection (n = 2) and late skin erosion/infection (n = 2). Early or late breaking of the sling occurred in nine patients, due to the inappropriate method of closing the device. There were 13 explants: 3 as definitive and 10 re-implantations. All but one patient improved the clinical status which was objectively assessed by Jorge-Wexner and QOL scores, with significant differences. CONCLUSIONS: This simple, safe and low cost technique is useful for treating from disturbing soiling to severe incontinence in all those patients with failed sphincteroplasty or not amenable to sphincter repair. However, a proper device needs to be designed. PMID- 21264678 TI - Klebsiella pneumoniae ESBL producers responsible for severe UTIs in a renal transplant unit. PMID- 21264679 TI - Infection rate and risk factors associated with infections related to external ventricular drain. AB - OBJECTIVE: To describe incidence rates and risk factors associated with external ventricular drain (EVD)-related infections at a tertiary Brazilian teaching hospital. METHODS: The patient cohort consisted of all patients at a major teaching hospital in Brazil with an EVD during the period 1 April 2007 to 30 June 2008 (15 months). Patients were followed up for 30 days after catheter removal. According to the Center for Diseases Control and Prevention criteria for meningitis/ventriculitis, all of the central nervous system (CNS) infections that occurred during this period could be considered to be meningitis or ventriculitis related to EVD placement. Infection rates were calculated using different denominators, such as (1) per patient (incidence), (2) per procedure, and (3) per 1,000 catheter-days (drain-associated infection rate). Patient demographic data, medical history of underlying diseases, antibiotic prophylaxis usage, American Society of Anesthesiologists Score classification, duration of surgery and hospitalization, length of time the EVD was in place, and overall mortality were evaluated during the study period. A logistic regression model was developed to identify factors associated with infection. RESULTS: A total of 119 patients, 130 EVD procedures, and 839 catheter-days were evaluated. The incidence of infection was 18.3%, the infection rate was 16.9% per procedure, and the drain-associated infection rate was 22.4 per 1,000 catheter-days; 77% of the infections were caused by Gram-negative micro-organisms. Only 75% of patients received antibiotic prophylaxis. The infection rate increased with length of the hospital stay. The length of time the catheter was in place was the only independent risk factor associated with infection (p = 0.0369). CONCLUSION: The incidence of EVD-related infections is high in our hospital, Gram-negative micro-organisms were the most frequent causal agents identified and length of time that the catheter was in place contributed to the infection rate. PMID- 21264680 TI - The changing face of the rate concept in biopharmaceutical sciences: from classical to fractal and finally to fractional. PMID- 21264681 TI - Birth prevalence of autism spectrum disorders in the San Francisco Bay area by demographic and ascertainment source characteristics. AB - Using standardized methods for multi-source surveillance, we calculated the prevalence of autism spectrum disorders (ASD) among children born in a racially diverse region in 1994 or 1996 as 4.7/1000 live births. Children with ASD before age 9 were identified through chart abstraction at health-related sources; three quarters were being served by the state-wide Department of Developmental Services. In adjusted models, we found a male:female ratio of 6:1, a doubling of ASD prevalence among children of older mothers (40+), and lower prevalence with lower paternal education. Children of Black or Hispanic mothers had lower prevalence than those of White, non-Hispanic mothers, but these differences were attenuated after adjustment. Prevalence in children of Asian mothers was similar to Whites. Potential under-counting is discussed. PMID- 21264682 TI - Evidence-based practices reduce juvenile recidivism: can state government effectively promote implementation among probation departments? AB - California places tens of thousands of juveniles into its 58 county-based justice systems every year. The offenders do not generally experience reduced rates of recidivism. Evidence-based practices can reliably and significantly reduce these rates. Probation departments have infrequently chosen to implement these practices, in large part because of the training, data collection, and organizational change required. Current state law does not effectively mandate these practices and more importantly fails to recognize and fund the substantial and ongoing training and technical assistance that would be required to implement these practices. State government could best promote evidence-based practices by working collegially with probation departments to obtain and distribute private and public funding to support effective implementation. PMID- 21264683 TI - Long-term changes of heavy metal and sulphur concentrations in ecosystems of the Taymyr Peninsula (Russian Federation) North of the Norilsk Industrial Complex. AB - The Norilsk industrial ore smelting complex (Taymyr Peninsula, Russian Federation) has significantly impacted many components of local terrestrial and aquatic environments. Whether it has had a major impact on the wider Russian Arctic remains controversial as studies are scarce. From 1986 to 2004, data on heavy metal (Cu, Ni, Zn, Hg, Cd and Hg) concentrations in fish (burbot), moss, lichens, periphyton, hydric soils and snow in and around Norilsk and the most northern parts of the Taymyr Peninsula were analysed. Very high concentrations of Cu (203 MUg L-1 +/- 51 MUg L-1) and Ni (113 MUg L-1 +/- 15 MUg L-1) were found in the water of the Schuchya River close to Norilsk. Heavy metal concentrations in burbot liver were highest in Lake Pyasino near Norilsk compared to other study regions that were >100 km distant. From 1989-1996, Cu (121 MUg L-1 +/- 39 MUg L-1 SD), Zn (150 MUg L-1) +/- 70 MUg L-1) and Ni (149 MUg L-1 +/- 72 MUg L-1) snow concentrations were greatest in Norilsk, but were low elsewhere. By 2004, these concentrations had dropped significantly, especially for Cu-74 MUg L-1 (+/-18.7 MUg L-1 SD), Zn-81.7 MUg L-1 (+/- 31.3 MUg L-1 SD) and Ni-80 MUg L-1(+/-18.0 MUg L-1 SD). Norilsk and its surroundings are subject to heavy pollution from the Norilsk metallurgical industry but these are absent from the greater Arctic region due to the prevailing winds and the Byrranga Mountains. Pollution abatement measures have been made so further investigations are necessary in order to assess their efficiency. PMID- 21264684 TI - Fusion of 3D QCA and IVUS/OCT. AB - The combination/fusion of quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS)/optical coherence tomography (OCT) depends to a great extend on the co-registration of X-ray angiography (XA) and IVUS/OCT. In this work a new and robust three-dimensional (3D) segmentation and registration approach is presented and validated. The approach starts with standard QCA of the vessel of interest in the two angiographic views (either biplane or two monoplane views). Next, the vessel of interest is reconstructed in 3D and registered with the corresponding IVUS/OCT pullback series by a distance mapping algorithm. The accuracy of the registration was retrospectively evaluated on 12 silicone phantoms with coronary stents implanted, and on 24 patients who underwent both coronary angiography and IVUS examinations of the left anterior descending artery. Stent borders or sidebranches were used as markers for the validation. While the most proximal marker was set as the baseline position for the distance mapping algorithm, the subsequent markers were used to evaluate the registration error. The correlation between the registration error and the distance from the evaluated marker to the baseline position was analyzed. The XA-IVUS registration error for the 12 phantoms was 0.03 +/- 0.32 mm (P = 0.75). One OCT pullback series was excluded from the phantom study, since it did not cover the distal stent border. The XA-OCT registration error for the remaining 11 phantoms was 0.05 +/- 0.25 mm (P = 0.49). For the in vivo validation, two patients were excluded due to insufficient image quality for the analysis. In total 78 sidebranches were identified from the remaining 22 patients and the registration error was evaluated on 56 markers. The registration error was 0.03 +/- 0.45 mm (P = 0.67). The error was not correlated to the distance between the evaluated marker and the baseline position (P = 0.73). In conclusion, the new XA-IVUS/OCT co-registration approach is a straightforward and reliable solution to combine X ray angiography and IVUS/OCT imaging for the assessment of the extent of coronary artery disease. It provides the interventional cardiologist with detailed information about vessel size and plaque size at every position along the vessel of interest, making this a suitable tool during the actual intervention. PMID- 21264685 TI - Probiotic cheese containing Lactobacillus rhamnosus HN001 and Lactobacillus acidophilus NCFM(r) modifies subpopulations of fecal lactobacilli and Clostridium difficile in the elderly. AB - Aging is associated with alterations in the intestinal microbiota and with immunosenescence. Probiotics have the potential to modify a selected part of the intestinal microbiota as well as improve immune functions and may, therefore, be particularly beneficial to elderly consumers. In this randomized, controlled cross-over clinical trial, we assessed the effects of a probiotic cheese containing Lactobacillus rhamnosus HN001 and Lactobacillus acidophilus NCFM on the intestinal microbiota and fecal immune markers of 31 elderly volunteers and compared these effects with the administration of the same cheese without probiotics. The probiotic cheese was found to increase the number of L. rhamnosus and L. acidophilus NCFM in the feces, suggesting the survival of the strains during the gastrointestinal transit. Importantly, probiotic cheese administration was associated with a trend towards lower counts of Clostridium difficile in the elderly, as compared with the run-in period with the plain cheese. The effect was statistically significant in the subpopulation of the elderly who harbored C. difficile at the start of the study. The probiotic cheese was not found to significantly alter the levels of the major microbial groups, suggesting that the microbial changes conferred by the probiotic cheese were limited to specific bacterial groups. Despite that the administration of the probiotic cheese to the study population has earlier been shown to significantly improve the innate immunity of the elders, we did not observe measurable changes in the fecal immune IgA concentrations. No increase in fecal calprotectin and beta-defensin concentrations suggests that the probiotic treatment did not affect intestinal inflammatory markers. In conclusion, the administration of probiotic cheese containing L. rhamnosus HN001 and L. acidophilus NCFM, was associated with specific changes in the intestinal microbiota, mainly affecting specific subpopulations of intestinal lactobacilli and C. difficile, but did not have significant effects on the major microbial groups or the fecal immune markers. PMID- 21264686 TI - What, how, and when to offer nonresectional therapy for colorectal cancer liver metastases. PMID- 21264687 TI - Exploring applications of procerain b, a novel protease from Calotropis procera, and characterization by N-terminal sequencing as well as peptide mass fingerprinting. AB - Procerain B is a novel cysteine protease isolated from Calotropis procera by our group and published recently. We have further characterized the enzyme by N terminal sequencing and peptide mass fingerprinting. Procerain B showed maximum sequence similarity (80%) with Asclepain. Moreover, the characteristic VDWR motif of cysteine proteases is present in procerain B. The N-terminal and peptide mass fingerprinting analysis showed a distinct nature of the enzyme. Various applications of the enzyme were also evaluated. Procerain B is very effective in milk-clotting and may be a potential candidate for this process in the cheese industry. Additionally, the enzyme has potential application as dietary supplement to aid digestion. Effects of various metal ions on milk-clotting activity were also studied. The milk-clotting activity was increased in case of few metals while others have a negative effect. It is worth mentioning that the easy availability of plant material and simple purification method makes industrial production of the enzyme feasible. A protease with easy purification and suitable properties for application is always desired. PMID- 21264688 TI - Genetic and chemical diversity of high mucilaginous plants of Sida complex by ISSR markers and chemical fingerprinting. AB - A method was developed based on multiple approaches wherein DNA and chemical analysis was carried out toward differentiation of important species of Sida complex that is being used for commercial preparation. Isolated DNA samples were successfully performed through PCR amplification using ISSR markers and degree of genetic diversity among the different species of Sida is compared with that of chemical diversity. For genetic fingerprint investigation, selected 10 ISSR primers generating reproducible banding patterns were used. Among the total of 63 amplicons, 62 were recorded as polymorphic, genetic similarity index deduced from ISSR profiles ranged from 12 to 51%. Based on similarity index, S. acuta and S. rhombifolia found to be most similar (51%). High number of species-specific bands played pivotal role to delineate species at genetic level. Investigation based on HPTLC fingerprints analysis revealed 23 bands representing to characteristic chemicals and similarity index ranged from 73 to 91%. Prominent distinguishable bands were observed only in S. acuta, while S. cordifolia and S. rhombifolia shared most bands making them difficult to identify on chemical fingerprint basis. This report summarizes the genotypic and chemotypic diversity and the use of profiles for authentication of species of Sida complex. PMID- 21264689 TI - Nutritional considerations after gastrectomy and esophagectomy for malignancy. AB - This article reviews various methods of assessing and managing post-gastrectomy or esophagectomy patients from a nutritional standpoint, by examining recent research focusing on assessment models, components of enteral feeding, timing of feeding, safety of enteral nutrition (EN) vs total parenteral nutrition (TPN), appetite stimulants, alternative treatments, and long-term care. Pre-, peri-, and post-operative nutrition represent a major prognostic indicator in patients undergoing a gastrectomy or esophagectomy for malignant cancer. An accurate initial nutrition assessment to determine risk, followed by close monitoring pre operatively and early enteral feeding post-operatively, has been shown to have the most beneficial effects. The optimal delivery route for nutrition involves the use of EN with immune enhancing nutrients while avoiding TPN. In practice, TPN is reserved for patients with post-operative complications that delay enteral feeding for an extended time. While megace is commonly used as an appetite stimulant, the hormone ghrelin is another novel, safe, and efficacious treatment to improve appetite, increase by mouth (PO) intake, and minimize loss of weight and lean body mass. Although use of ghrelin is not yet common practice, as more studies are published, we predict that this will become a more common treatment. While complementary and alternative therapies are commonly employed in this patient population, more research needs to be done before incorporation into our mainstay of treatment. Long term, these patients continue to be at nutritional risk and therefore should be followed to optimize weight maintenance and prevent micronutrient deficiencies. PMID- 21264690 TI - Virtual reality as an adjunctive non-pharmacologic analgesic for acute burn pain during medical procedures. AB - INTRODUCTION: Excessive pain during medical procedures is a widespread problem but is especially problematic during daily wound care of patients with severe burn injuries. METHODS: Burn patients report 35-50% reductions in procedural pain while in a distracting immersive virtual reality, and fMRI brain scans show associated reductions in pain-related brain activity during VR. VR distraction appears to be most effective for patients with the highest pain intensity levels. VR is thought to reduce pain by directing patients' attention into the virtual world, leaving less attention available to process incoming neural signals from pain receptors. CONCLUSIONS: We review evidence from clinical and laboratory research studies exploring Virtual Reality analgesia, concentrating primarily on the work ongoing within our group. We briefly describe how VR pain distraction systems have been tailored to the unique needs of burn patients to date, and speculate about how VR systems could be tailored to the needs of other patient populations in the future. PMID- 21264692 TI - First come, first served? Influence of changed object configuration on object based attention. AB - Evidence for object-based attention is based mainly on studies using object displays that remain unchanged throughout, with the assumption that object representation should be completed and stabilized before it is selected for further processing. We used the modified double-rectangle cuing paradigm of Egly, Driver, and Rafal (Journal of Experimental Psychology: General, 123, 161-177, 1994) but introduced a configuration change to the cued-object display to test whether object-based attention is determined by the cued- or, alternatively, the changed-object display. Four small rectangles were presented in the initial display; critically, after one was cued, an occluder was presented to make the four small rectangles amodally completed into the double-rectangle configuration. Results show that object-based attention is determined by the changed display, but not by the cued display. This suggests that object-based attention is an interactively evolving process between object representation and attention, rather than a serial process in which attention operates after object representation is completed. PMID- 21264693 TI - Distraction and the auditory attentional blink. AB - When two target stimuli (T1 and T2) are presented in close succession within a stimulus sequence, detection or discrimination performance for T2 is often impaired; this phenomenon is called the attentional blink (AB). Growing evidence suggests that the AB is present not only for visual, but also for auditory stimuli. Because sounds have a strong potential to attract attention when they are presented after longer silent intervals or in a sequence from which they stand out because of their rare or novel physical features, it seems possible that the involuntary and excessive allocation of attention to T1 (distraction) may contribute to the AB. By varying the saliency of T1, we showed that distraction does contribute to the auditory AB effect, but the contribution is short-lived: Only stimuli immediately following T1 are affected. PMID- 21264691 TI - Behavioral medicine: a voyage to the future. AB - This paper discusses trends and future directions in behavioral medicine. It is divided into three sections. The first briefly reviews key developments in the history of behavioral medicine. The second section highlights trends and future directions in pain research and practice as a way of illustrating future directions for behavioral medicine. Consistent with the biopsychosocial model of pain, this section focuses on trends and future directions in three key areas: biological, psychological, and social. The third section describes recent Society of Behavioral Medicine initiatives designed to address some of the key challenges facing our field as we prepare for the future. PMID- 21264694 TI - Decision strategies for the two-alternative forced choice reminder paradigm. AB - The decision strategy adopted by an observer in a psychophysical procedure may be established by comparing estimates of sensitivity obtained by using detection theoretic models based on each of the available decision strategies. Estimates of sensitivity obtained from 10 observers on auditory-level discrimination tasks using the yes/no, two-alternative forced choice (2AFC), and 2AFC with reminder (2AFCR; sometimes called duo-trio) procedures were compared in order to determine the decision strategy used by the judges in the 2AFCR procedure. 2AFCR permits at least three decision strategies: differencing, likelihood ratio, and comparison of distances. The latter strategy has frequently been assumed in the analysis of duo-trio data in the sensory evaluation literature. The present study demonstrates that the comparison-of-distances strategy was not used by 9 of the 10 observers in this auditory experiment. The nature of the instructions given to the observers had no measurable impact on the decision strategy that they adopted. PMID- 21264695 TI - Fractal fluctuations in gaze speed visual search. AB - Visual search involves a subtle coordination of visual memory and lower-order perceptual mechanisms. Specifically, the fluctuations in gaze may provide support for visual search above and beyond what may be attributed to memory. Prior research indicates that gaze during search exhibits fractal fluctuations, which allow for a wide sampling of the field of view. Fractal fluctuations constitute a case of fast diffusion that may provide an advantage in exploration. We present reanalyses of eye-tracking data collected by Stephen and Mirman (Cognition, 115, 154-165, 2010) for single-feature and conjunction search tasks. Fluctuations in gaze during these search tasks were indeed fractal. Furthermore, the degree of fractality predicted decreases in reaction time on a trial-by-trial basis. We propose that fractality may play a key role in explaining the efficacy of perceptual exploration. PMID- 21264696 TI - Regulatory fit effects on stimulus identification. AB - This article examines the effects of a fit between a person's global regulatory focus and the local task reward structure on perceptual processing and judgment. On each trial, participants were presented with one of two briefly presented stimuli and were asked to identify it. Participants were placed in a promotion focus (a situationally induced sensitivity to gains) or a prevention focus (a situationally induced sensitivity to losses) and were asked to maximize gains or minimize losses. An asymmetric payoff ratio biased the overall reward toward one identification response over the other. Two experiments tested the role of regulatory fit when internal familiarity and perceptual sensitivity were low or high. When familiarity and sensitivity were low, participants in a regulatory fit (promotion focus with gains or a prevention focus with losses) showed greater perceptual sensitivity but no response bias differences, relative to participants in a regulatory mismatch. When familiarity and sensitivity were high, participants in a regulatory fit showed a response bias toward the high-payoff stimulus but no differences in perceptual sensitivity. Speculations are offered on the neurobiological basis of this effect, as well as implications of this work for clinical disorders such as depression. PMID- 21264697 TI - Evaluating a model of global psychophysical judgments for brightness: II. Behavioral properties linking summations and productions. AB - Steingrimsson (Attention, Perception, & Psychophysics, 71, 1916-1930, 2009) outlined Luce's (Psychological Review, 109, 520-532 2002, 111, 446-454 2004) proposed psychophysical theory and tested, for brightness, behavioral properties that, separately, gave rise to two psychophysical functions, Psi (?) and [Formula: see text]. The function Psi (?) maps pairs of physical intensities onto positive real numbers and represents subjective summation, and the function [Formula: see text] represents a form of ratio production. This article, the second in a series expected to consist of three articles, tests the properties linking summation and production such that it forces [Formula: see text]. The properties tested are a form of distributivity and, in three experiments, were subjected to an empirical evaluation. Considerable support is provided for the existence of a single function Psi for both summation and ratio production. The scope of this series of articles is to establish the theory as a descriptive model of binocular brightness perception. PMID- 21264698 TI - A new object captures attention--but only when you know which objects are old. AB - According to the new object hypothesis (see, e.g., Yantis & Hillstrom, Journal of Experimental Psychology: Human Perception & Performance, 20, 95-107, 1994), an object appearing as a sudden onset captures attention because its appearance demands an immediate updating of visual short-term memory. This hypothesis was tested in three experiments using a procedure that allowed an object to be added to the display but, crucially, without incurring onset transients (Franconeri, Hollingworth, & Simons, Psychological Science, 16, 275-281, 2005). The latter showed that an object inserted in this fashion failed to capture attention. As a test of the new object hypothesis, this procedure assumes that the observers had encoded the display before the new object was introduced. If this assumption is not fulfilled, the new and the old objects cannot be distinguished one from the other. It was, however, unclear whether the encoding had taken place in the Franconeri et al. experiments. We showed that when circumstances were congenial to the encoding of the display before an additional object interposed, then the object successfully captured attention. But when the encoding of the initial display was either difficult or impossible, the additional object failed to capture attention. PMID- 21264699 TI - Increases in rewards promote flexible behavior. AB - Offering reward for performance can motivate people to perform a task better, but better preparation for one task usually means decreased flexibility to perform different tasks. In six experiments in which reward varied between low and high levels, we found that reward can encourage people to prepare more flexibly for different tasks, but only as it increased from the level on the previous trial. When the same high rewards were offered continuously trial after trial, people were more inclined to simply stick with doing what had worked previously. We demonstrated such enhancements in flexibility in task switching, a difficult visual search task, and an easier priming of pop-out search task, which shows that this effect generalizes from executive tasks to perceptual processes that require relatively little executive control. These findings suggest that relative, transient changes in reward can exert more potent effects on behavioral flexibility than can the absolute amount of reward, whether it consists of money or points in a social competition. PMID- 21264700 TI - Nonconcurrently presented auditory tones reduce distraction. AB - Recent research has demonstrated that task-irrelevant stimuli presented simultaneously with a target-distractor stimulus reduce distraction and improve selective attention. In studies examining this reduced interference effect, visual selective attention tasks and concurrently presented task-irrelevant stimuli are used. We report first evidence for a similar effect in the auditory domain and with nonconcurrent stimuli (i.e., the task-irrelevant stimuli are presented before the target). The effect of nonconcurrently presented auditory tones on an auditory Stroop task developed by Leboe and Mondor (Psychological Research, 71, 568--575, 2007) was investigated. Stroop interference was reduced when task-irrelevant tones were presented before the Stroop stimulus. We conclude that task-irrelevant stimuli can improve selective attention not only when presented concurrently, but also when presented before the selective attention task. Our results are consistent with the hypothesis that interference reduction is due to perceptual dilution caused by task-irrelevant stimuli. PMID- 21264701 TI - Sensitivity to time interval changes in speech and tone conditions. AB - The main goal of the present experiment was to verify whether sensitivity to time interval changes in speech is greater than sensitivity to time interval changes between tones. The 12-syllable sentences were delivered in French (the main language of the participants) or in a foreign language (Slovenian) that was totally unfamiliar to the participants. Two types of sub-sequences were induced within the series of stimuli (sub-sequences in sentences or in tone sequences). Discrimination, as revealed by the Weber fraction in each condition, was much better in the tone conditions than in the speech conditions. Nevertheless, discrimination was excellent in all conditions: Weber fractions below 2% with tones and around 4.5% in the speech conditions. Moreover, the study revealed that familiarity with a particular language does not affect performance and that inducing internal sub-sequences within tone conditions, as opposed to using a series of equal intervals, does not lead to better discrimination. The fact that discrimination is better with tones than with sentences indicates that the extensive training provided by speech does not lead to higher sensitivity to time interval variations than simple tones do. Instead, it seems to indicate that the different acoustical variations in speech reduce the capability to discriminate time interval variations. PMID- 21264702 TI - Exploring attention-based explanations for some violations of Hick's law for aimed movements. AB - Choice reaction time generally increases linearly with the logarithm of the number of potential stimulus-response alternatives, a regularity known as Hick's law. Two apparent violations of this generalization, which have been reported for aimed eye movements (Kveraga, Boucher, & Hughes, Experimental Brain Research, 146, 307-314, 2002), and arm movements (Wright, Marino, Belovsky, & Chubb, Experimental Brain Research, 179, 475-496, 2007), occurred when the indicator stimulus was an abrupt change at the location that was the target of the to-be made movement. We report two experiments that examined and rejected the hypothesis that these abrupt-onset indicator stimuli triggered a shift in exogenous attention and that this led to unusually small uncertainty effects. Each experiment compared this indicator stimulus with a single alternative: Experiment 1 tested an indicator stimulus at all locations other than the target; Experiment 2 tested a central pointer to the target. Neither alternative led to an uncertainty effect for pointing responses that was of the size typically observed for other responses using the same stimuli. PMID- 21264703 TI - Facilitation versus inhibition in non-spatial attribute discrimination tasks. AB - Inhibition of Return is a delay in initiating attentional shifts to previously inspected locations. It has been explained as a mechanism to facilitate visual search of a scene by inhibiting the allocation of attention to locations that have already been examined. We (Hu, Samuel, & Chan, Journal of Experimental Psychology: General, 2010) recently demonstrated that similar processing costs can appear when a non-spatial attribute (color or shape) repeats-detection of a target stimulus was slower if the target shared color or shape with a recently presented cue. In the current study, we test whether such inhibitory effects occur for non-spatial attribute repetition when observers must make a discrimination judgment about targets. We found two independent effects: First, there was a standard location-based IOR effect-target discrimination was slower when the target appeared in the same location as a preceding cue. Second, reaction times were faster if the target's color or shape matched the cue's color or shape; this facilitation effect contrasts with both the location-based inhibition that was present in the current experiments, and with the inhibitory effect of feature repetition in our previous detection task study. The data are best accounted for by a three-factor model recently suggested by Lupianez (Attention and time, 2010). PMID- 21264704 TI - Tracking planets and moons: mechanisms of object tracking revealed with a new paradigm. AB - People can attend to and track multiple moving objects over time. Cognitive theories of this ability emphasize location information and differ on the importance of motion information. Results from several experiments have shown that increasing object speed impairs performance, although speed was confounded with other properties such as proximity of objects to one another. Here, we introduce a new paradigm to study multiple object tracking in which object speed and object proximity were manipulated independently. Like the motion of a planet and moon, each target-distractor pair rotated about both a common local point as well as the center of the screen. Tracking performance was strongly affected by object speed even when proximity was controlled. Additional results suggest that two different mechanisms are used in object tracking--one sensitive to speed and proximity and the other sensitive to the number of distractors. These observations support models of object tracking that include information about object motion and reject models that use location alone. PMID- 21264705 TI - Irrelevant objects of expertise compete with faces during visual search. AB - Prior work suggests that nonface objects of expertise can interfere with the perception of faces when the two categories are alternately presented, suggesting competition for shared perceptual resources. Here, we ask whether task-irrelevant distractors from a category of expertise compete when faces are presented in a standard visual search task. Participants searched for a target (face or sofa) in an array containing both relevant and irrelevant distractors. The number of distractors from the target category (face or sofa) remained constant, whereas the number of distractors from the irrelevant category (cars) varied. Search slopes, calculated as a function of the number of irrelevant cars, were correlated with car expertise. The effect was not due to car distractors grabbing attention, because they did not compete with sofa targets. Objects of expertise interfere with face perception even when they are task irrelevant, visually distinct, and separated in space from faces. PMID- 21264706 TI - Spatial distribution of attentional inhibition is not altered in healthy aging. AB - Inhibition of return (IOR) is a phenomenon of attentional orienting that is indexed by slower responses to targets presented at previously attended locations. The purpose of this study was to examine adult age differences in the distribution of IOR to multiple locations. In three experiments, young adults (ages 18-30 years) and older adults (ages 60-87 years) completed an IOR task that varied in the number of simultaneous onset cues (one to seven) and the number of display locations (four or eight). Analyses were conducted to explore whether IOR patterns were most consistent with limited inhibitory resources, with regional distribution of inhibition, or with vector averaging of cues. The IOR effects were most consistent with vector averaging, such that multiple cues initiated a directional gradient of inhibition centered on the average direction of the cues. The IOR patterns varied minimally with age, consistent with the conclusion that older adults and young adults distributed inhibition in a similar manner. PMID- 21264707 TI - A re-examination of the impact of object processing on shifts of spatial attention. AB - When two targets are presented in rapid succession at the same spatial location, processing of the first is highly efficient, while processing of the second is often profoundly impaired at brief inter-target intervals (attentional blink; AB). While the AB has been shown to impact many processes, it is still unclear whether this includes the ability to shift spatial attention. The present study examined this question using a more sensitive dependent measure than past studies; namely, response times. It also evaluated whether masking of the cue stimulus modulated the effect of the AB on spatial shifts. The results showed significant cueing effects on T2 response times that were strongly modulated by the AB. This supports suggested links between mechanisms underlying object processing and spatial shifts of attention. PMID- 21264708 TI - The boundary conditions for Bohr's law: when is reacting faster than acting? AB - In gunfights in Western movies, the hero typically wins, even though the villain draws first. Niels Bohr (Gamow, The great physicists from Galileo to Einstein. Chapter: The law of quantum, 1988) suggested that this reflected a psychophysical law, rather than a dramatic conceit. He hypothesized that reacting is faster than acting. Welchman, Stanley, Schomers, Miall, and Bulthoff (Proceedings of the Royal Society of London B: Biological Sciences, 277, 1667-1674, 2010) provided empirical evidence supporting "Bohr's law," showing that the time to complete simple manual actions was shorter when reacting than when initiating an action. Here we probe the limits of this effect. In three experiments, participants performed a simple manual action, which could either be self-initiated or executed following an external visual trigger. Inter-button time was reliably faster when the action was externally triggered. However, the effect disappeared for the second step in a two-step action. Furthermore, the effect reversed when a choice between two actions had to be made. Reacting is faster than acting, but only for simple, ballistic actions. PMID- 21264709 TI - Magnitude judgments of loudness change for discrete, dynamic, and hybrid stimuli. AB - Recent investigations of loudness change within stimuli have identified differences as a function of direction of change and power range (e.g., Canevet, Acustica, 62, 2136-2142, 1986; Neuhoff, Nature, 395, 123-124, 1998), with claims of differences between dynamic and static stimuli. Experiment 1 provides the needed direct empirical evaluation of loudness change across static, dynamic, and hybrid stimuli. Consistent with recent findings for dynamic stimuli, quantitative and qualitative differences in pattern of loudness change were found as a function of power change direction. With identical patterns of loudness change, only quantitative differences were found across stimulus type. In Experiment 2, Points of Subjective loudness Equality (PSE) provided additional information about loudness judgments for the static and dynamic stimuli. Because the quantitative differences across stimulus type exceed the magnitude that could be expected based upon temporal integration by the auditory system, other factors need to be, and are, considered. PMID- 21264710 TI - Re-locating colors in the OSA space. AB - A monolexemic color-naming experiment in the Italian language was performed on a sample of 1,014 colors obtained extending the OSA-UCS color system (E-OSA). Colors were rendered on a Mitsubishi Diamond pro 2070 monitor as patches subtending 10 degrees of visual angle in a completely dark room. The 11 universal categories proposed by Berlin and Kay (Basic color terms: Their universality and evolution, 1969) were considered. Consensus, consistency and focal colors were determined for each category. Comparisons were performed among the results obtained using Boynton & Olson (B&O), the extended OSA (E-OSA), a subset of it covering almost all the B&O sample (R-OSA) and the Sturges & Whitfield (S&W) sample sets. A good overlap could be observed among the locations of the consensus colors in the {L, j, g} color model between B&O and R-OSA, as well as a close proximity among the centroids of homologue regions for the majority of the classes. The analysis of the location of focal colors versus the centroids suggests that an additional basic term could be missing for the Italian language in the blue category. PMID- 21264711 TI - T1 difficulty affects the AB: manipulating T1 word frequency and T1 orthographic neighbor frequency. AB - Colored target words were presented with distractor nonwords in a rapid serial visual presentation (RSVP) task. In Experiment 1, the attentional blink (AB) effect on T2 accuracy was larger when T1 was a difficult (low-frequency) word than when it was a high-frequency word. In Experiment 2 the effect of T1 frequency on the AB was replicated in a between-participants design, and the frequency of T1's one-letter different neighbors (e.g., case, bare, for care) interacted with T1 frequency in its effects on T2 accuracy. Experiment 3 confirmed the effect of T1 frequency over 6 T1-T2 lags. The effects of T1 characteristics were sensitively assessed in the AB and were more consistent with resource depletion theories than control-process accounts. PMID- 21264712 TI - Aging and the haptic perception of 3D surface shape. AB - Two experiments evaluated the ability of older and younger adults to perceive the three-dimensional (3D) shape of object surfaces from active touch (haptics). The ages of the older adults ranged from 64 to 84 years, while those of the younger adults ranged from 18 to 27 years. In Experiment 1, the participants haptically judged the shape of large (20 cm diameter) surfaces with an entire hand. In contrast, in Experiment 2, the participants explored the shape of small (5 cm diameter) surfaces with a single finger. The haptic surfaces varied in shape index (Koenderink, Solid shape, 1990; Koenderink, Image and Vision Computing, 10, 557-564, 1992) from -1.0 to +1.0 in steps of 0.25. For both types of surfaces (large and small), the participants were able to judge surface shape reliably. The older participants' judgments of surface shape were just as accurate and precise as those of the younger participants. The results of the current study demonstrate that while older adults do possess reductions in tactile sensitivity and acuity, they nevertheless can effectively perceive 3D surface shape from haptic exploration. PMID- 21264713 TI - An attentional blink for nontargets? AB - In a typical attentional blink experiment, viewers try to detect two target items among distractors in a Rapid Serial Visual Presentation (RSVP): processing of the first target impairs participants' ability to recall a subsequent target at short stimulus onset asynchronies (SOAs). However, little is known about whether target detection interferes with memory for nontarget items. To answer this question, in two experiments, we employed a novel dual-task procedure: participants searched for a word target (e.g., "a four-footed animal") and then were tested for recognition of nontarget words. Detection of the target word, which was present on half the trials, produced a standard attentional blink effect on memory for nontarget words, with lag 1 sparing followed by an attentional blink at longer lags. This result shows that target processing has a generalized effect on processing of later events, not only other targets. PMID- 21264714 TI - Oculomotor interference during manual response preparation: evidence from the response-cueing paradigm. AB - Preparation provided by visual location cues is known to speed up behavior. However, the role of concurrent saccades in response to visual cues remains unclear. In this study, participants performed a spatial precueing task by pressing one of four response keys with one of four fingers (two of each hand) while eye movements were monitored. Prior to the stimulus, we presented a neutral cue (baseline), a hand cue (corresponding to left vs. right positions), or a finger cue (corresponding to inner vs. outer positions). Participants either remained fixated on a central fixation point or moved their eyes freely. The results demonstrated that saccades during the cueing interval altered the pattern of cueing effects. Finger cueing trials in which saccades were spatially incompatible (vs. compatible) with the subsequently required manual response exhibited slower manual RTs. We propose that interference between saccades and manual responses affects manual motor preparation. PMID- 21264715 TI - On the theoretical error bound for estimating psychometric functions. AB - The theoretical limits to the amount of error, or the Cramer-Rao bounds, were derived for estimating psychometric functions. These theoretical error bounds were compared with the variability of psychometric functions estimated from human as well as computer-simulated observers. For the simulated observers, due to the limited efficiency of the sampling strategies, including the placement of the signals and the distribution of the trials, the variances of the estimated parameters are seven times the theoretical bound for threshold and 22 times that for slope. For the human observers, the variance is 18 times the theoretical bounds for threshold and 80 times that for slope. Therefore, a major portion of the variances (60% for threshold and 73% for slope) for the human observers is associated with factors other than sampling strategies. Further improvement of the accuracy for estimating psychometric functions will depend on not only optimizing the sampling strategy, but also better understanding the various sources of error related to the behavior of human observers. PMID- 21264716 TI - Acquisition of decision making criteria: reward rate ultimately beats accuracy. AB - Speed-accuracy trade-offs strongly influence the rate of reward that can be earned in many decision-making tasks. Previous reports suggest that human participants often adopt suboptimal speed-accuracy trade-offs in single session, two-alternative forced-choice tasks. We investigated whether humans acquired optimal speed-accuracy trade-offs when extensively trained with multiple signal qualities. When performance was characterized in terms of decision time and accuracy, our participants eventually performed nearly optimally in the case of higher signal qualities. Rather than adopting decision criteria that were individually optimal for each signal quality, participants adopted a single threshold that was nearly optimal for most signal qualities. However, setting a single threshold for different coherence conditions resulted in only negligible decrements in the maximum possible reward rate. Finally, we tested two hypotheses regarding the possible sources of suboptimal performance: (1) favoring accuracy over reward rate and (2) misestimating the reward rate due to timing uncertainty. Our findings provide support for both hypotheses, but also for the hypothesis that participants can learn to approach optimality. We find specifically that an accuracy bias dominates early performance, but diminishes greatly with practice. The residual discrepancy between optimal and observed performance can be explained by an adaptive response to uncertainty in time estimation. PMID- 21264717 TI - When do spatial and visual working memory interact? AB - This study examined how spatial working memory and visual (object) working memory interact, focusing on two related questions: First, can these systems function independently from one another? Second, under what conditions do they operate together? In a dual-task paradigm, participants attempted to remember locations in a spatial working memory task and colored objects in a visual working memory task. Memory for the locations and objects was subject to independent working memory storage limits, which indicates that spatial and visual working memory can function independently from one another. However, additional experiments revealed that spatial working memory and visual working memory interact in three memory contexts: when retaining (1) shapes, (2) integrated color-shape objects, and (3) colored objects at specific locations. These results suggest that spatial working memory is needed to bind colors and shapes into integrated object representations in visual working memory. Further, this study reveals a set of conditions in which spatial and visual working memory can be isolated from one another. PMID- 21264718 TI - Object based implicit contextual learning: a study of eye movements. AB - Implicit contextual cueing refers to a top-down mechanism in which visual search is facilitated by learned contextual features. In the current study we aimed to investigate the mechanism underlying implicit contextual learning using object information as a contextual cue. Therefore, we measured eye movements during an object-based contextual cueing task. We demonstrated that visual search is facilitated by repeated object information and that this reduction in response times is associated with shorter fixation durations. This indicates that by memorizing associations between objects in our environment we can recognize objects faster, thereby facilitating visual search. PMID- 21264719 TI - A switch in task affects priming of pop-out: evidence for the role of episodes. AB - Maljkovic and Nakayama (Memory & Cognition, 22(6), 655-678, 1994) demonstrated that response times decrease in a pop-out search task when target-defining features repeat from one trial to the next. This priming of pop-out (PoP) effect has been explained by some researchers as reflecting low-level modulations in attentional control settings Lee, Mozer, and Vecera (Attention, Perception, & Psychophysics, 71(5), 1059-1071, 2009). The present experiments tested whether a shift in higher order task requirements from trial n - 1 to trial n alters PoP effects. The results of Experiments 1 and 2 demonstrated that a switch in task significantly modulated PoP effects when shape was the relevant pop-out dimension. Experiment 3 failed to show significant modulation of PoP as a function of task switch when the pop-out dimension was color, but the findings of Experiment 4 did show modulation of PoP for color when the relative salience of target and distractors was high. Together, the results strongly support the view that PoP effects can be sensitive to a switch in task, a result consistent with the view that PoP effects are modulated by trial-to-trial episodic integration processes. PMID- 21264720 TI - The role of timing in the attentional boost effect. AB - Images that are presented with targets of an unrelated detection task are better remembered than images that are presented with distractors (the attentional boost effect). The likelihood that any of three mechanisms, attentional cuing, prediction-based reinforcement learning, and perceptual grouping, underlies this effect depends in part on how it is modulated by the relative timing of the target and image. Three experiments demonstrated that targets and images must overlap in time for the enhancement to occur; targets that appear 100 ms before or 100 ms after the image without temporally overlapping with it do not enhance memory of the image. However, targets and images need not be synchronized. A fourth experiment showed that temporal overlap of the image and target is not sufficient, as detecting targets did not enhance the processing of task irrelevant images. These experiments challenge several simple accounts of the attentional boost effect based on attentional cuing, reinforcement learning, and perceptual grouping. PMID- 21264721 TI - Alerting enhances target identification but does not affect the magnitude of the attentional blink. AB - Identification of the second of two targets is impaired when presented less than about 500 ms after the first. The magnitude of this attentional blink (AB) is known to be modulated by tonic factors (e.g., observer's state of relaxation). The present work examined the effects of a phasic change in observer's state brought about by an alerting stimulus (an aggregate of faint rings) presented in temporal proximity to either letter-target inserted in a temporal stream (RSVP) of digit distractors. In four experiments, identification accuracy of each target was substantially improved by presenting the alerting stimulus either in the target's frame or in the preceding RSVP frame. However, alerting did not modulate the magnitude of the AB. The appearance of an alerting effect on the AB in Experiment 1 was ascribed to a ceiling effect in Experiment 2. Experiment 3 ruled out endogenous temporal cueing effects; Experiment 4 examined the temporal gradient of alerting. Independence of the alerting and AB effects suggests that the alerting stimuli and the letter targets may be processed along distinct visual pathways. PMID- 21264722 TI - Action relations facilitate the identification of briefly-presented objects. AB - The link between perception and action allows us to interact fluently with the world. Objects which 'afford' an action elicit a visuomotor response, facilitating compatible responses. In addition, positioning objects to interact with one another appears to facilitate grouping, indicated by patients with extinction being better able to identify interacting objects (e.g. a corkscrew going towards the top of a wine bottle) than the same objects when positioned incorrectly for action (Riddoch, Humphreys, Edwards, Baker, & Willson, Nature Neuroscience, 6, 82-89, 2003). Here, we investigate the effect of action relations on the perception of normal participants. We found improved identification of briefly-presented objects when in correct versus incorrect co locations for action. For the object that would be 'active' in the interaction (the corkscrew), this improvement was enhanced when it was oriented for use by the viewer's dominant hand. In contrast, the position-related benefit for the 'passive' object was stronger when the objects formed an action-related pair (corkscrew and bottle) compared with an unrelated pair (corkscrew and candle), and it was reduced when spatial cues disrupted grouping between the objects. We propose that these results indicate two separate effects of action relations on normal perception: a visuomotor response to objects which strongly afford an action; and a grouping effect between objects which form action-related pairs. PMID- 21264723 TI - Eyes wide shut: implied social presence, eye tracking and attention. AB - People often behave differently when they know they are being watched. Here, we report the first investigation of whether such social presence effects also influence looking behavior--a popular measure of attention allocation. We demonstrate that wearing an eye tracker, an implied social presence, leads individuals to avoid looking at particular stimuli. These results demonstrate that an implied social presence, here an eye tracker, can alter looking behavior. These data provide a new manipulation of social attention, as well as presenting a methodological challenge to researchers using eye tracking. PMID- 21264724 TI - Effects of task-irrelevant texture motion on time-to-contact judgments. AB - We investigated the effect of local texture motion on time-to-contact (TTC) estimation. In Experiment 1, observers estimated the TTC of a looming disk with a spiral texture pattern in a prediction-motion task. Rotation of the spiral texture in a direction causing illusory contraction resulted in a significant TTC overestimation, relative to a condition without texture rotation. This would be consistent with an intrusion of task-irrelevant local upon task-relevant global information. However, illusory expansion did not cause a relative TTC underestimation but rather also a tendency towards overestimation. In Experiment 2, a vertical cylinder moved on the frontoparallel plane. Observers judged its TTC with a finish line. The cylinder was textured with stripes oriented in parallel to its longitudinal axis. It was either not rotating, rotating such that the stripes moved towards the finish line (i.e., in the same direction as the contour), or rotating such that the stripes moved away from the finish line. Both types of texture motion caused TTC overestimation compared to the static condition. Experiment 3 showed that the different effects of task-relevant and task-irrelevant texture motion are not a mere procedural effect of the prediction motion task. In conclusion, task-irrelevant local motion and global motion are neither averaged in a simple manner nor are they processed independently. PMID- 21264725 TI - Object-based selection from spatially-invariant representations: evidence from a feature-report task. AB - Attention selects objects as well as locations. When attention selects an object's features, observers identify two features from a single object more accurately than two features from two different objects (object-based effect of attention; e.g., Duncan, Journal of Experimental Psychology: General, 113, 501 517, 1984). Several studies have demonstrated that object-based attention can operate at a late visual processing stage that is independent of objects' spatial information (Awh, Dhaliwal, Christensen, & Matsukura, Psychological Science, 12, 329-334, 2001; Matsukura & Vecera, Psychonomic Bulletin & Review, 16, 529-536, 2009; Vecera, Journal of Experimental Psychology: General, 126, 14-18, 1997; Vecera & Farah, Journal of Experimental Psychology: General, 123, 146-160, 1994). In the present study, we asked two questions regarding this late object-based selection mechanism. In Part I, we investigated how observers' foreknowledge of to-be-reported features allows attention to select objects, as opposed to individual features. Using a feature-report task, a significant object-based effect was observed when to-be-reported features were known in advance but not when this advance knowledge was absent. In Part II, we examined what drives attention to select objects rather than individual features in the absence of observers' foreknowledge of to-be-reported features. Results suggested that, when there was no opportunity for observers to direct their attention to objects that possess to-be-reported features at the time of stimulus presentation, these stimuli must retain strong perceptual cues to establish themselves as separate objects. PMID- 21264726 TI - Irrelevant visual faces influence haptic identification of facial expressions of emotion. AB - This study demonstrates that when people attempt to identify a facial expression of emotion (FEE) by haptically exploring a 3D facemask, they are affected by viewing a simultaneous, task-irrelevant visual FEE portrayed by another person. In comparison to a control condition, where visual noise was presented, the visual FEE facilitated haptic identification when congruent (visual and haptic FEEs same category). When the visual and haptic FEEs were incongruent, haptic identification was impaired, and error responses shifted toward the visually depicted emotion. In contrast, visual emotion labels that matched or mismatched the haptic FEE category produced no such effects. The findings indicate that vision and touch interact in FEE recognition at a level where featural invariants of the emotional category (cf. precise facial geometry or general concepts) are processed, even when the visual and haptic FEEs are not attributable to a common source. Processing mechanisms behind these effects are considered. PMID- 21264727 TI - The development and validation of sensory and emotional scales of touch perception. AB - No comprehensive language exists that describes the experience of touch. Three experiments were conducted to take steps toward establishing a touch lexicon. In Experiment I, 49 participants rated how well 262 adjectives described sensory, emotional and evaluative aspects of touch. In Experiment II, participants rated pairwise dissimilarities of the most descriptive words of the set. Multidimensional scaling (MDS) solutions representing semantic-perceptual spaces underlying the words resulted in a touch perception task (TPT) consisting of 26 'sensory' attributes (e.g., bumpiness) and 14 'emotional' attributes (e.g., pleasurable). In Experiment III, 40 participants used the TPT to rate unseen textured materials that were moved actively or received passively against the index fingerpad, volar forearm, and two underarm sites. MDS confirmed similar semantic-perceptual structures in Experiments II and III. Factor analysis of Experiment III data decomposed the sensory attribute ratings into factors labeled Roughness, Slip, Pile and Firmness, and the emotional attribute ratings into Comfort and Arousal factors. Factor scores varied among materials and sites. Greater intensity of sensory and emotional responses were reported when participants passively, as opposed to actively, received stimuli. The sensitivity of the TPT in identifying body site and mode of touch-related perceptual differences affirms the validity and utility of this novel linguistic/perceptual tool. PMID- 21264728 TI - Contrast and assimilation in categorization and exemplar production. AB - We studied contrast and assimilation in three tasks: an exemplar-production task, a categorization task, and a combined categorization-then-production task. On each trial of the first task, subjects produced a circle when prompted with a category label. In the second task, they classified lines that differed in length into one of four categories. On each trial of the combined task, they classified two lines and then produced a line when prompted by a category label. All three tasks converged on the same conclusion: subjects' representation of the categories (measured in pixels in the production tasks and by the direction of errors in classification) shifted systematically from trial to trial. When successive stimuli were from the same category, the representation of that category was pulled toward the exemplar from the previous trial. When successive stimuli were from different categories, the representations of the neighbouring categories were pushed from the category of the initial stimulus. We conclude that accounts of categorization and identification must accommodate both assimilation and contrast as a function of trial-to-trial shifts in representation. PMID- 21264729 TI - Dimension intertrial and cueing effects in localization: support for pre attentively weighted one-route models of saliency. AB - There are several alternative accounts of dimensional intertrial and cueing effects in singleton feature search tasks. Some accounts assume that these effects arise at post-selective processing stages; dual-route accounts assume them to be perceptual in nature, but coming into play only in non-spatial tasks (e.g., detection but not localization). By contrast, the Dimension Weighting Account (DWA) assumes dimensional effects to arise at pre-attentive processing stages of spatial as well as non-spatial tasks. The data available are ambiguous, permitting no clear-cut choice among these accounts. Therefore, the present study examined for early effects of dimensional weighting in a spatial task, the presence of which is only predicted by the DWA and not by post-selective or dual route accounts. Salience is known to saturate for high feature contrast and long presentation times. Consequently, with lower bottom-up salience that still permits efficient search, dimensional weights would produce a greater modulation- if present at all. Thus, we examined localization accuracy under brief presentation conditions in Experiment 1, and localization speed under conditions of low versus high feature contrast in Experiment 2. Both experiments revealed significant dimension intertrial and cueing effects. This strongly argues against dual-route accounts and strengthens evidence for a pre-attentive origin of these effects. PMID- 21264730 TI - Concurrency benefits in the attentional blink: attentional flexibility and shifts of decision criteria. AB - Fundamental limitations in performing multiple tasks concurrently are well illustrated by the attentional blink (AB) deficit, which refers to the difficulty in reporting a second target (T2) when it is presented shortly after a first target (T1). Surprisingly, recent studies have shown that the AB, which is often thought of as a manifestation of capacity limitations in central processing, can be reduced when the AB task is performed simultaneously with concurrent distracting activities. In the present study, we sought to investigate whether such concurrency benefits would also be observed when the AB task was performed concurrently with a central demanding timing task. The AB was reduced under concurrent-task conditions, as compared with single-AB-task conditions, even though T1 performance was unaffected by the concurrent task. Moreover, shifts in decision criteria were found to be associated with the concurrency benefit effect. PMID- 21264731 TI - Seeing faces as objects: no face inversion effect with geometrical discrimination. AB - Inversion dramatically impairs face perception, recognition, and discrimination. Yet it does not interfere with the ability to make precise estimates of facial feature distances. To investigate this discontinuity between facial feature distance estimation and general perception and recognition, we assessed the effect of inversion on the discrimination of differences in facial compression and elongation or expansion using geometrically distorted faces. The results clearly showed that geometrical face discrimination is not subject to the traditional face inversion effect and did not show a benefit for natural faces. Although discrimination thresholds were not affected by inversion, response times to the distance judgments were faster with inversion, especially when the inverted faces contained natural configurations. Based on these counterintuitive results, we suggest that participants used analytical processing to do the discrimination task. Moreover, we suggest that the depth with which a face is holistically encoded depends on the nature of the task, face orientation, and similarity between a face and the prototypical face template. PMID- 21264732 TI - Differential priming effect for subliminal fear and disgust facial expressions. AB - Compared to neutral or happy stimuli, subliminal fear stimuli are known to be well processed through the automatic pathway. We tried to examine whether fear stimuli could be processed more strongly than other negative emotional stimuli using a modified subliminal affective priming paradigm. Twenty-six healthy subjects participated in two separated sessions. Fear, disgust and neutral facial expressions were adopted as primes, and 50% happy facial stimuli were adopted as a target to let only stronger negative primes reveal a priming effect. Participants were asked to appraise the affect of target faces in the affect appraisal session and to appraise the genuineness of target faces in the genuineness appraisal session. The genuineness instruction was developed to help participants be sensitive to potential threats. In the affect appraisal, participants judged 50% happy target faces significantly more 'unpleasant' when they were primed by fear faces than primed by 50% happy control faces. In the genuineness appraisal, participants judged targets significantly more 'not genuine' when they were primed by fear and disgust faces than primed by controls. These findings suggest that there may be differential priming effects between subliminal fear and disgust expressions, which could be modulated by a sensitive context of potential threat. PMID- 21264733 TI - Flexible attention allocation to visual and auditory working memory tasks: manipulating reward induces a trade-off. AB - Prominent roles for general attention resources are posited in many models of working memory, but the manner in which these can be allocated differs between models or is not sufficiently specified. We varied the payoffs for correct responses in two temporally-overlapping recognition tasks, a visual array comparison task and a tone sequence comparison task. In the critical conditions, an increase in reward for one task corresponded to a decrease in reward for the concurrent task, but memory load remained constant. Our results show patterns of interference consistent with a trade-off between the tasks, suggesting that a shared resource can be flexibly divided, rather than only fully allotted to either of the tasks. Our findings support a role for a domain-general resource in models of working memory, and furthermore suggest that this resource is flexibly divisible. PMID- 21264734 TI - Enumerating by pointing to locations: a new method for measuring the numerosity of visual object representations. AB - The fast and accurate enumeration of a small set of objects, called subitizing, is thought to involve a different mechanism from other numerosity judgments, such as those based on estimation. In this report, we examine the subitizing limit using a novel enumeration task that obtained the perceived locations of enumerated objects. Observers were shown brief masked displays (50, 200, and 350 ms) of 2-9 small black discs randomly placed on a gray screen and then asked to place a marker where each disc had been located. The number of these markers provided an estimate of the number of items processed. This "pointing" methodology enabled observers to accurately "enumerate" displays containing up to six items in contrast with the four-item limit typically found when using standard reporting methods (and replicated here in Experiment 2). These results suggest a different account of the limits found in most subitizing and enumeration studies. PMID- 21264735 TI - Font size modulates saccade-target selection in Chinese reading. AB - In alphabetic writing systems, saccade amplitude (a close correlate of reading speed) is independent of font size, presumably because an increase in the angular size of letters is compensated for by a decrease of visual acuity with eccentricity. We propose that this invariance may (also) be due to the presence of spaces between words, guiding the eyes across a large range of font sizes. Here, we test whether saccade amplitude is also invariant against manipulations of font size during reading Chinese, a character-based writing system without spaces as explicit word boundaries for saccade-target selection. In contrast to word-spaced alphabetic writing systems, saccade amplitude decreased significantly with increased font size, leading to an increase in the number of fixations at the beginning of words and in the number of refixations. These results are consistent with a model which assumes that word beginning (rather than word center) is the default saccade target if the length of the parafoveal word is not available. PMID- 21264736 TI - Diagnostic spatial frequencies and human efficiency for discriminating actions. AB - Humans extract visual information from the world through spatial frequency (SF) channels that are sensitive to different scales of light-dark fluctuations across visual space. Using two methods, we measured human SF tuning for discriminating videos of human actions (walking, running, skipping and jumping). The first, more traditional, approach measured signal-to-noise ratio (s/n) thresholds for videos filtered by one of six Gaussian band-pass filters ranging from 4 to 128 cycles/image. The second approach used SF "bubbles", Willenbockel et al. (Journal of Experimental Psychology. Human Perception and Performance, 36(1), 122-135, 2010), which randomly filters the entire SF domain on each trial and uses reverse correlation to estimate SF tuning. Results from both methods were consistent and revealed a diagnostic SF band centered between 12-16 cycles/image (about 1-1.25 cycles/body width). Efficiency on this task was estimated by comparing s/n thresholds for humans to an ideal observer, and was estimated to be quite low (>.04%) for both experiments. PMID- 21264737 TI - Aesthetic response to color combinations: preference, harmony, and similarity. AB - Previous studies of preference for and harmony of color combinations have produced confusing results. For example, some claim that harmony increases with hue similarity, whereas others claim that it decreases. We argue that such confusions are resolved by distinguishing among three types of judgments about color pairs: (1) preference for the pair as a whole, (2) harmony of the pair as a whole, and (3) preference for its figural color when viewed against its colored background. Empirical support for this distinction shows that pair preference and harmony both increase as hue similarity increases, but preference relies more strongly on component color preference and lightness contrast. Although pairs with highly contrastive hues are generally judged to be neither preferable nor harmonious, figural color preference ratings increase as hue contrast with the background increases. The present results thus refine and clarify some of the best-known and most contentious claims of color theorists. PMID- 21264738 TI - Consciousness of targets during the attentional blink: a gradual or all-or-none dimension? AB - Models of consciousness differ in whether they predict a gradual change or a discontinuous transition between nonconscious and conscious perception. Sergent and Dehaene (Psychological Science, 15, 720-728, 2004) asked subjects to rate on a continuous scale the subjective visibility of target words presented during an attentional blink. They found that these words were either detected as well as targets outside the attentional-blink period or not detected at all, and interpreted these results as support for a discontinuous transition between nonconscious and conscious processing. We present results from 4 attentional blink experiments showing that this all-or-none rating pattern disappears with the use of an alternative measure of consciousness (post-decision wagering) and a more difficult identification task. Instead, under these circumstances, subjects used the consciousness rating scales in a continuous fashion. These results are more consistent with models that assume a gradual change between nonconscious and conscious perception during the attentional blink. PMID- 21264739 TI - Visual search and contextual cueing: differential effects in 10-year-old children and adults. AB - The development of contextual cueing specifically in relation to attention was examined in two experiments. Adult and 10-year-old participants completed a context cueing visual search task (Jiang & Chun, The Quarterly Journal of Experimental Psychology, 54A(4), 1105-1124, 2001) containing stimuli presented in an attended (e.g., red) and unattended (e.g., green) color. When the spatial configuration of stimuli in the attended and unattended color was invariant and consistently paired with the target location, adult reaction times improved, demonstrating learning. Learning also occurred if only the attended stimuli's configuration remained fixed. In contrast, while 10 year olds, like adults, showed incrementally slower reaction times as the number of attended stimuli increased, they did not show learning in the standard paradigm. However, they did show learning when the ratio of attended to unattended stimuli was high, irrespective of the total number of attended stimuli. Findings suggest children show efficient attentional guidance by color in visual search but differences in contextual cueing. PMID- 21264740 TI - Task-based working memory guidance of visual attention. AB - Previous research has established that holding a stimulus in working memory (WM) facilitates the deployment of visual attention to that stimulus relative to other stimuli. The present study examined whether maintaining a specific task in WM would also bias the allocation of attention to the stimuli associated with that task. Participants performed a speeded letter search task while simultaneously keeping in WM one of two task cues shown at the beginning of each trial. The results showed that task-based WM guidance of attention was modulated by response latencies. Whereas the participants with fast reaction times showed little influence of WM contents, the participants with slow reaction times took longer to respond when the letter target appeared in a distractor stimulus consistent with the task cue held in mind. A subsequent Stroop experiment found a larger Stroop interference effect from the participants in the slow group compared with those in the fast group, suggesting that the differential WM effect between the two groups may be associated with an individual's ability to inhibit task irrelevant information. Taken together, these results expanded the realm of previous research and provided further evidence for a close link between attention and WM. PMID- 21264741 TI - Mixing measures: testing an assumption of the Attention Network Test. AB - The human attention system has been subdivided into three networks that appear to be functionally and anatomically independent: alerting, orienting, and executive control. The Attention Network Test (ANT) is a quick and easy tool that measures the efficiency of these three networks by averaging reaction time and accuracy scores across several different cue and flanker conditions. Using ANOVAs and correlation procedures, we found that (a) intranetwork correlations were surprisingly low, and (b) Cue X Flanker interactions were found within alerting, orienting, and executive control measures. Taken together, these findings highlight the interaction between the three networks and the potential difficulty in accurately measuring them with this task. PMID- 21264742 TI - The role of Gestalt grouping principles in visual statistical learning. AB - A major issue in visual scene recognition involves the extraction of recurring chunks from a sequence of complex scenes. Previous studies have suggested that this kind of learning is accomplished according to Bayesian principles that constrain the types of extracted chunks. Here we show that perceptual grouping cues are also incorporated in this Bayesian model, providing additional evidence for the possible span of chunks. Experiment 1 replicates previous results showing that observers can learn three-element chunks without learning smaller, two element chunks embedded within them. Experiment 2 shows that the very same embedded chunks are learned if they are grouped by perceptual cues, suggesting that perceptual grouping cues play an important role in chunk extraction from complex scenes. PMID- 21264743 TI - Visual apparent motion can be modulated by task-irrelevant lexical information. AB - Previous studies have repeatedly demonstrated the impact of Gestalt structural grouping principles upon the parsing of motion correspondence in ambiguous apparent motion. Here, by embedding Chinese characters in a visual Ternus display that comprised two stimulus frames, we showed that the perception of visual apparent motion can be modulated by activation of task-irrelevant lexical representations. Each frame had two disks, with the second disk of the first frame and the first disk of the second frame being presented at the same location. Observers could perceive either "element motion," in which the endmost disk is seen as moving back and forth while the middle disk at the central position remains stationary, or "group motion," in which both disks appear to move laterally as a whole. More reports of group motion, as opposed to element motion, were obtained when the embedded characters formed two-character compound words than when they formed nonwords, although this lexicality effect appeared to be attenuated by the use of the same characters at the overlapping position across the two frames. Thus, grouping of visual elements in a changing world can be guided by both structural principles and prior world knowledge, including lexical information. PMID- 21264744 TI - Effects of temporal and spatial separation on velocity and strength of illusory line motion. AB - The effects of line length and of spatial or temporal distance on illusory line motion (i.e., on the perception that a stationary line unfolds or expands away from a previously presented stationary cue) were examined in five experiments. Ratings of relative velocity decreased with increases in stimulus onset asynchrony between appearance of the cue and appearance of the line (from 50 to 450 ms), whereas the extremity of ratings of direction (i.e., strength of the ratings of illusory line motion) increased with increases in stimulus onset asynchrony (from 50 to either 250 or 450 ms). Ratings of relative velocity increased with increases in line length, whereas ratings of direction were not influenced by increases in line length. Ratings of relative velocity and direction were not influenced by increases in the distance of the near or the far end of the line from the cue. Implications of these data for attentional theories and apparent-motion theories of illusory line motion are discussed. PMID- 21264745 TI - Psychometric functions for detection and discrimination with and without flankers. AB - Recent studies have reported that flanking stimuli broaden the psychometric function and lower detection thresholds. In the present study, we measured psychometric functions for detection and discrimination with and without flankers to investigate whether these effects occur throughout the contrast continuum. Our results confirm that lower detection thresholds with flankers are accompanied by broader psychometric functions. Psychometric functions for discrimination reveal that discrimination thresholds with and without flankers are similar across standard levels, and that the broadening of psychometric functions with flankers disappears as standard contrast increases, to the point that psychometric functions at high standard levels are virtually identical with or without flankers. Threshold-versus-contrast (TvC) curves with flankers only differ from TvC curves without flankers in occasional shallower dippers and lower branches on the left of the dipper, but they run virtually superimposed at high standard levels. We discuss differences between our results and other results in the literature, and how they are likely attributed to the differential vulnerability of alternative psychophysical procedures to the effects of presentation order. We show that different models of flanker facilitation can fit the data equally well, which stresses that succeeding at fitting a model does not validate it in any sense. PMID- 21264746 TI - The scope and precision of specific temporal expectancy: evidence from a variable foreperiod paradigm. AB - Recent evidence from choice response time experiments with variable foreperiods (FPs) has shown that temporal expectancy can be event specific. When a certain target appears particularly frequent after one certain FP, participants tend to expect that target after that FP. This typically results in best performance for that target when it appears after that FP. In the present study, we investigated how temporally precise event-specific temporal expectancy is, and in which range of FPs it can be found. Two target stimuli were asymmetrically distributed over two "peak-FPs" and were equally distributed over 13 additional FPs. Event specific expectancies were found for peak-FP pairs of 500/1,100 ms and 300/500 ms. Furthermore, the event expectancies generalized to a wide range of nonpeak FPs surrounding the peak FPs. PMID- 21264748 TI - Crossmodal correspondences: a tutorial review. AB - In many everyday situations, our senses are bombarded by many different unisensory signals at any given time. To gain the most veridical, and least variable, estimate of environmental stimuli/properties, we need to combine the individual noisy unisensory perceptual estimates that refer to the same object, while keeping those estimates belonging to different objects or events separate. How, though, does the brain "know" which stimuli to combine? Traditionally, researchers interested in the crossmodal binding problem have focused on the roles that spatial and temporal factors play in modulating multisensory integration. However, crossmodal correspondences between various unisensory features (such as between auditory pitch and visual size) may provide yet another important means of constraining the crossmodal binding problem. A large body of research now shows that people exhibit consistent crossmodal correspondences between many stimulus features in different sensory modalities. For example, people consistently match high-pitched sounds with small, bright objects that are located high up in space. The literature reviewed here supports the view that crossmodal correspondences need to be considered alongside semantic and spatiotemporal congruency, among the key constraints that help our brains solve the crossmodal binding problem. PMID- 21264747 TI - When here becomes there: attentional distribution modulates foveal bias in peripheral localization. AB - Much research concerning attention has focused on changes in the perceptual qualities of objects while attentional states were varied. Here, we address a complementary question--namely, how perceived location can be altered by the distribution of sustained attention over the visual field. We also present a new way to assess the effects of distributing spatial attention across the visual field. We measured magnitude judgments relative to an aperture edge to test perceived location across a large range of eccentricities (30 degrees ), and manipulated spatial uncertainty in target locations to examine perceived location under three different distributions of spatial attention. Across three experiments, the results showed that changing the distribution of sustained attention significantly alters known foveal biases in peripheral localization. PMID- 21264749 TI - Breast angiosarcoma that is not related to radiation exposure: a comprehensive review of the literature. AB - Breast angiosarcomas that are not related to previous radiotherapy are very rare. Surgical resection is the primary treatment for these tumors, but there is no general agreement on the extent of surgery. The role of multimodality adjuvant treatment also remains controversial. The aim of this study was to summarize the available data from the largest published series of patients in terms of management and outcome. We also sought to identify prognostic factors influencing patient survival. We have included studies presenting detailed data on multimodality therapy and survival of patients with breast angiosarcoma. Ten studies presenting data on 280 patients were included in the review. Seventy-five percent of patients underwent a total mastectomy and 25% had breast-conserving treatment (BCT). In 42% of patients, an axillary node dissection was combined with mastectomy or BCT. Thirty-six percent of patients received chemotherapy and 35% were treated with radiotherapy in an adjuvant or neoadjuvant setting. Survival varied significantly according to tumor size and grade. Adjuvant multimodality therapy may improve the outcome in selected patients with breast angiosarcoma. Tumor size, grade, and margin status are the most important prognostic factors for survival. PMID- 21264750 TI - Overt bone metastasis and bone marrow micrometastasis of early gastric cancer. AB - Recently we encountered two cases of early gastric cancer (EGC) with bone metastasis after surgery. As they were not accompanied by overt liver, lung, or peritoneal metastasis, we examined the clinical significance of bone metastasis in EGC and its mechanisms by a review of the literature. We found only 10 cases of EGC complicated with overt bone metastasis in the English literature, so we also examined the Japanese reports of such cases. The main histologic type of cases of bone metastasis from EGC was the diffuse type, and there were long intervals between surgery and overt bone metastasis. One reason for such long intervals may have been the tumor dormancy. Two types of dormancy, dynamic and static, and two types of postoperative overt metastases, that of micrometastatic origin (normograde metastatic process) and that of bone marrow origin (retrograde metastatic process), were considered. We speculated that there may be specific routes by which the cancer cells infiltrate the bone marrow directly from EGC or lymph node metastasis. The procedures for diagnosing bone micrometastasis using monoclonal antibodies have recently been improved, but their accuracy rates are still not universally accepted. New, more reliable examinations are required to improve the survival rates of EGC. PMID- 21264751 TI - Inhibitor of apoptosis protein family as diagnostic markers and therapeutic targets of colorectal cancer. AB - The apoptosis and antiapoptotic signaling pathways are important for regulating carcinogenesis and cancer progression, and for determining prognosis. Molecules involved in apoptosis represent potential cancer diagnostic markers and therapeutic targets. The inhibitor of apoptosis protein (IAP) family includes several important molecules involved in apoptosis that might represent such targets. Increasing evidence has demonstrated that the IAP family of proteins is integral for antiapoptotic and nuclear factor-kappaB signal transduction, and enhanced expression of IAPs contributes to colon carcinogenesis and its poor prognosis, as well as to drug resistance of tumors. X-linked IAP, cIAP1, cIAP2, and survivin are prognostic markers of colorectal cancer, and survivin and cIAP2 are also utilized to predict the effect of anticancer treatment in colorectal cancer patients. Novel therapies such as YM155 and LY2181308 targeting survivin, AEG35156 and phenoxodiol targeting X-linked IAP, AT-406 as a Smac mimetic, and survivin peptides are currently being evaluated in clinical trials. This report reviews the involvement of the IAP family in colorectal adenocarcinoma in order to summarize the role of the IAP family members as diagnostic and therapeutic targets, and to provide an overview of the future course of research in this area. PMID- 21264752 TI - Is routine calcium supplementation necessary in patients undergoing total thyroidectomy plus neck dissection? AB - PURPOSE: Patients undergoing a total thyroidectomy plus neck dissection are at high risk of developing postoperative hypocalcemia. This study prospectively evaluated the possibility to identify factors that predict symptomatic hypocalcemia and the necessity of routine calcium supplements. METHODS: Sixty five consecutive patients who underwent a total thyroidectomy plus neck dissection were included. Intact parathyroid hormone (iPTH), total serum calcium (sCa), serum phosphate (sPhos), and serum magnesium (sMg) levels were monitored and compared between the symptomatic hypocalcemic group ( group A) and the asymptomatic hypocalcemic group (group B). RESULTS: Asymptomatic and self limiting hypocalcemia developed in 54 patients (81.5%; group B). Symptomatic hypocalcemia developed in 11 patients (18.5%; group A). They required calcium supplements. There were no significant differences in the iPTH and sMg levels between the two groups; the sCa level was significantly lower on postoperative days 1, 2, 3, and 5 in group A than in group B (P < 0.05); the sPhos level was significantly higher on postoperative days 2 and 3 in group A than in group B (P < 0.05). CONCLUSIONS: Symptomatic hypocalcemia develops within 3 days after surgery. An sCa level of less than 1.81 mmol/l can predict symptomatic hypocalcemia. Routine calcium supplements will not be necessary if the sCa level is higher than 1.81 mmol/l. PMID- 21264753 TI - Reconstruction of the scalp with a calvarial defect. AB - PURPOSE: To review our clinical cases and devise a protocol for selecting the best operative methods to reconstruct the scalp with a calvarial defect. METHODS: We reviewed the original disease, the areas and depths of the scalp and calvarial defects, the methods of reconstruction, and complications in 20 patients. RESULTS: The defect was caused by secondary cranial infection following decompressive craniectomy for intracranial hemorrhage (ICH) in 11 patients; extensive removal of the scalp and calvaria for resection of a malignant tumor in 6 patients; and by secondary cranial infection following removal of a malignant tumor in 3 patients. Cranial infection was frequently associated with abscess formation around the fixation screws and plates, suggesting that artificial materials induced the infection. We reconstructed the defect using free flaps in 15 patients and using local flaps in 5 patients. CONCLUSIONS: When restoring the calvaria in the primary operation, the use of metal screws and plates should be minimized to prevent cranial infection and subsequent scalp and calvaria defects. Local flaps are appropriate for reconstructing relatively small defects (<20 cm(2)), whereas free flaps are better for reconstructing relatively large defects (>25 cm(2)). PMID- 21264754 TI - Indocyanine green fluorescence imaging system for sentinel lymph node biopsies in early breast cancer patients. AB - PURPOSE: This study presents a new method that enables the detection of sentinel lymph nodes (SLN) with high sensitivity using indocyanine green (ICG) fluorescence imaging. METHODS: This study enrolled 128 patients with clinically node-negative breast cancer. Fluorescence imaging was obtained after ICG was injected into the areola. Subcutaneous lymphatic channels were immediately visible. RESULTS: Lymphatic channels and SLN were successfully visualized in all patients. One lymphatic channel was 60%, two channels were 24%, and three channels were 16%. The number of fluorescence SLN ranged from 1 to 6, and blue dyed SLN ranged from 0 to 3. In the latter, SLN were not identified in 44 patients. Nineteen patients had pathologically identified lymph node metastases. All of them were recognized by fluorescence imaging, but 8 patients had lymph nodes with metastases were not identified by dye method. CONCLUSION: This ICG fluorescence imaging technique is feasible and safe for detecting SLN in a less invasive manner than conventional mapping, with real-time observations. PMID- 21264755 TI - Gastroesophageal junction adenocarcinoma of young patients who underwent curative surgery: a comparative analysis with older group. AB - PURPOSE: Adenocarcinoma of the stomach at a young age has a poor prognosis, but there are few reports describing gastroesophageal junction adenocarcinoma. This study aimed to compare the clinicopathological characteristics between the young and old patients who underwent curative surgery. METHODS: One thousand three hundred and sixty-one patients with gastric adenocarcinoma underwent a curative gastrectomy between January 1, 1992 and December 31, 2006. Of these, 141 (10.4%) cases were gastroesophageal junction adenocarcinoma according to the Siewert's classification, and the data were collected prospectively for the analysis of the young age group (under 44 years old), in comparison to the older age group, with factors such as pathological characteristics, recurrence, and survival. RESULTS: The sex ratio was near 1:1 in the younger group while it was predominantly male in the older group. There were no significant differences in the clinicopathological characteristics, such as the recurrence and survival rate, between the two groups. CONCLUSIONS: The factor of young age does not critically affect the clinical course of gastroesophageal junction adenocarcinoma. This may be attributed to curative surgery and multimodality therapy. PMID- 21264756 TI - Investigation of the recurrence patterns of gastric cancer following a curative resection. AB - PURPOSE: The goal of this study was to investigate the recurrence patterns of gastric cancer and determine the predictive information of recurrence patterns of gastric cancer following a curative resection. METHODS: This study retrospectively analyzed the data of 308 gastric cancer patients who underwent a curative resection, to identify the factors associated with the recurrence patterns. RESULTS: One hundred and sixty-nine gastric cancer patients had recurrence following curative resection. One hundred and twenty-six patients were observed for 3 years after the operation. Locoregional recurrence formed part of the recurrence pattern in 107 patients, peritoneal dissemination was observed in 98 patients, and distant metastasis occurred in 22 patients. A multivariate analysis revealed that locoregional recurrence was only associated with the Lauren classification (P = 0.003); peritoneal dissemination was only associated with N stage (P < 0.001); and distant metastasis was only associated with the Lauren classification (P = 0.016). CONCLUSIONS: Locoregional recurrence, peritoneal dissemination, and distant metastasis were the most common recurrence patterns of gastric cancer following a curative resection. Each recurrence pattern is associated with specific clinicopathological factors. PMID- 21264758 TI - Elective palliative resection of incurable stage IV colorectal cancer: who really benefits from it? AB - PURPOSE: Despite the encouraging results of chemotherapy in patients affected by incurable colorectal cancer (CRC), surgical resection of a primitive tumor is still a common approach worldwide. The identification of prognostic factors related to short survival (<6 months) may allow excluding from resective surgery those who may not benefit from it. METHODS: A retrospective analysis was performed of 15 variables in a population of 71 patients undergoing nonemergency palliative primary resections of incurable CRC, including patients' demographics and clinical/histopathological characteristics of the tumor. RESULTS: No variables were related to perioperative mortality (8.5% overall). A multivariate analysis revealed that older age (>=80 years) and metastasis to more than 25% of the lymph nodes were associated with survival (4 and 6 months, respectively). Mucoid adenocarcinoma therefore tends to be associated with the prognosis (P = 0.070). CONCLUSIONS: An elderly age tends to be a contraindication to an elective primary tumor resection in patients affected by incurable CRC. Massive lymph node involvement and mucoid adenocarcinoma should also be considered before planning major colonic surgery. PMID- 21264757 TI - Laparoscopic transabdominal preperitoneal approach for inguinal hernia repair: a five-year experience at a single center. AB - PURPOSE: Laparoscopic hernia repair has emerged as an effective alternative method for treating inguinal hernias. It has several significant advantages over the tension-free open repair now in use. In this report we summarize our laparoscopic hernia repair results and recommendations. METHODS: The transabdominal preperitoneal (TAPP) procedures for groin hernias performed between January 2003 and January 2008 at a single center were analyzed retrospectively. Individual surgeon performances were compared to determine whether the rates of complications were related to the level of surgeon experience. RESULTS: A total of 312 TAPP procedures were reviewed, and 284 (91%) of the patients were followed retrospectively. There were 266 (85.25%) males and 46 (14.75%) females. The average age was 57.4 years. The mean length of hospital stay was 2.1 days. The mean duration of surgery was 35 min. Six (1.92%) intraoperative and seven (2.24%) postoperative complications were noted. Two recurrences occurred (0.70%). CONCLUSIONS: Laparoscopic TAPP hernia repair has proven to be an efficient method for the treatment of groin hernias at our institution. Most patients can be treated as day-cases, namely they are hospitalized for 1 day, and they demonstrate a low recurrence rate (0.70%). Such low morbidity makes TAPP an attractive method for the routine treatment of groin hernias. PMID- 21264759 TI - Effect of a prostaglandin I(2) analog on the expression of thrombomodulin in liver and spleen endothelial cells after an extensive hepatectomy. AB - PURPOSE: Dysfunction of the remnant liver after a hepatectomy is caused by microthrombus formation due to endothelial cell (EC) damage. This study evaluated the effect of prostaglandin I(2) (PGI(2)) on the expression of thrombomodulin (TM), a marker for the anticoagulant properties of ECs, using cultured human umbilical vein endothelial cells (HUVECs), and using a canine extensive hepatectomy model. METHODS: The presence of PGI(2) receptors was confirmed on HUVECs by reverse transcription-polymerase chain reaction, and the effect of the PGI(2) analog on TM expression on HUVECs was determined by an enzyme-linked immunosorbent assay. Twenty mongrel dogs were divided into four groups comprising a sham operation, 70% hepatectomy, 84% hepatectomy, and 84% hepatectomy, with the administration of the PGI(2) analog, respectively, and TM expression in the liver, spleen, pancreas, kidney, lung, portal vein, and intestine was determined immunohistochemically. RESULTS: The TM expression on HUVECs was upregulated by the PGI(2) analog. The TM expression on ECs in the hepatic sinusoids and splenic sinus were markedly decreased after the 84% hepatectomy, but such damage was markedly mitigated following an 84% hepatectomy with administration of the PGI(2) analog. CONCLUSIONS: An extensive hepatectomy induced severe EC damage not only in the hepatic sinusoids but in the splenic sinuses as well. Prostaglandin I(2) prevented damage to these ECs, suggesting that PGI(2) improves the microcirculation in the remnant liver. PMID- 21264760 TI - Use of a gamma probe to identify and guide resection of recurrent parathyroid carcinoma: report of a case. AB - Parathyroid carcinoma (PC) accounts for less than 0.005% of all cancers and less than 5% of causes of hyperparathyroidism. This tumor is difficult to identify during surgery, which is detrimental to the oncologic results. Surgery is still the main treatment for the primary tumor and to control parathyroid hormone levels after recurrence. We report a case of recurrent parathyroid carcinoma in a 30-year-old man, identified and managed with the use of a gamma probe during surgery. To our knowledge, this is only the second report of a gamma probe being used to guide resection of a recurrent PC. We discuss the diagnosis and treatment, analyzing the current evidence-based literature. PMID- 21264761 TI - Metastatic seeding of colon adenocarcinoma manifesting as synchronous breast and chest wall localization: report of a case. AB - Colon carcinoma rarely metastasizes to the breast and it is usually associated with a poor prognosis. Even rarer is metastatic seeding of colon cancer cells in an intramammary location after surgery. Including a primary breast malignancy in the differential diagnosis of such cases is mandatory. We report a rare case of double seeding implantation of colon adenocarcinoma inside the breast parenchyma and intercostal muscles 6 years after resection of a pulmonary metastasis from colon adenocarcinoma. The metastasis was revealed by the presence of bone metaplasia in the intercostal muscles. We discuss how negative immunostaining for estrogen receptors, progesterone receptors, and HER-2, along with the immunohistochemical pattern of cytokeratin (CK) 20+/7-/5- and CDX2-positive immunostaining, excludes a primary breast malignancy, namely, a "matrix producing" carcinoma, from the differential diagnosis. We also present the hypothesis of a paracrine pathogenetic mechanism to explain the bone metaplasia. PMID- 21264762 TI - Reoperative sentinel lymph node biopsy for ipsilateral breast tumor recurrence after previous axillary lymph node dissection: report of a case. AB - Sentinel lymph node biopsy has become a standard component of the evaluation of early-stage breast cancer, with a gradually increasing number of indications in this patient population. This report presents the case of a patient who underwent reoperative sentinel lymph node biopsy as part of an evaluation of ipsilateral breast tumor recurrence; she had previously undergone axillary lymph node dissection. Preoperative lymphoscintigraphy showed aberrant lymphatic drainage, and all three sentinel lymph nodes were positive for cancer. Although the optimal management of regional lymph nodes in patients with ipsilateral breast tumor recurrence who have already undergone axillary lymph node dissection has not been established, reoperative sentinel lymph node biopsy in this setting may therefore potentially enable the identification of subclinical, aberrantly located nodal metastasis. PMID- 21264763 TI - Dedifferentiated chondrosarcoma of the lung: report of a case. AB - This report presents a rare case of pulmonary sarcoma with regional anaplastic changes. A 73-year-old Japanese man with a hamartoma-like nodule of the left lung accompanied by interstitial pneumonia was followed up for 30 months. He underwent a surgical resection due to the rapid growth of the lung nodule. A pathological examination revealed a dedifferentiated sarcoma arising from the chondrosarcoma. PMID- 21264764 TI - Effectiveness of erlotinib against recurrent pulmonary adenocarcinoma unresponsive to gefitinib: report of a case. AB - We report a case of recurrent pulmonary adenocarcinoma, found 2 years after resection, which responded extremely well to erlotinib, after gefitinib treatment had failed to evoke any response. This case report provides useful information for thoracic oncologists and shows that we should consider giving erlotinib after gefitinib for recurrent pulmonary adenocarcinoma, even if the gefitinib treatment is ineffective. PMID- 21264765 TI - Pulmonary sclerosing hemangioma with pleural dissemination: report of a case. AB - Pulmonary sclerosing hemangioma is relatively rare and is usually considered a benign tumor. There have been no reports of pulmonary sclerosing hemangioma with pleural dissemination. This report presents an extremely rare case of pulmonary sclerosing hemangioma with pulmonary dissemination. A 57-year-old woman was found to have an abnormal shadow in the right lower lung field on chest X-ray. Chest computed tomography (CT) indicated a 2.5-cm mass in the right lower lobe. A bronchoscopic biopsy failed to identify malignant cells, which led to the patient undergoing an excisional lung biopsy. Intraoperative findings showed a tumor in the right lower lobe with multiple small nodules in the pleura. The pathological findings revealed that the tumor was sclerosing hemangioma with pleural dissemination. Annual follow-up CT showed irregular pleural thickness, which suggested progressive dissemination 3 years after the operation. Although pulmonary sclerosing hemangioma is regarded as a benign tumor, the potential for malignancy may be a consideration in this setting. PMID- 21264766 TI - Resection of advanced stage malignant retroperitoneal neoplasms with tumor thrombus extending into the right atrium: report of four cases. AB - Surgery for retroperitoneal neoplasms with a tumor thrombus extension into the right atrium is challenging. This study reviewed four surgical cases of advanced stage malignant neoplasms with the tumor thrombus extending into the right atrium. The malignant neoplasms involved the kidney in two patients, and the liver and adrenal gland in one each. The tumor thrombus was removed through a longitudinal cavotomy and right atriotomy in all cases. The inferior vena cava reconstruction was performed by directly closing it in one patient and by pericardial patch suturing in another. Cardiopulmonary bypass was used for all procedures and a Pringle maneuver was used to reduce bleeding from the liver in three. There was no perioperative or hospital death. Two of the four with renal cell carcinoma were alive 7 and 13 months after the surgery. One with hepatocellular carcinoma died of recurrent malignancy after 4 months, while the patient with an adrenal carcinoma remained disease free after surgery. These cases indicate the safety of the present procedure. Although the long-term results are still unknown, there were favorable early results and a lack of perioperative complications. Surgical challenges in resecting an intracardiac extension of retroperitoneal malignancy require close cooperation among the attending urologist, and both gastrointestinal and cardiovascular surgeons. PMID- 21264767 TI - Emergency repair of a radiation-induced aortoesophageal fistula with endograft: report of a case. AB - This report presents the case of the emergency repair of a radiation-induced aortoesophageal fistula (AEF) with an endograft. The patient presented with multiple episodes of upper gastrointestinal bleeding. The fistula was discovered and treated in the operating room. The placement of a temporary aortic endograft was successful. The patient unfortunately exsanguinated while awaiting definitive aortic and esophageal repair. The potential occurrence of AEF should be considered in any patient presenting with massive hematemesis without a clear source of the bleeding. Although the patient succumbed to the fistula, this case illustrates the cryptic nature of an AEF and the difficult issues that are inherent in its treatment. PMID- 21264768 TI - Castleman's disease of the mesorectum: report of a case. AB - Castleman's disease is a benign lymphoid proliferative disorder, which most commonly presents as a solitary mass in the mediastinum, although extrathoracic sites have been reported in the neck, axilla, pelvis, mesentery, pancreas, and retroperitoneum. We report a case of asymptomatic, isolated Castleman's disease in the mesorectum, which is extremely rare. The patient was a 34-year-old woman who underwent investigations for vaginal spotting. A presacral mass was located on the left side of the rectum, 10 cm from the anal verge. Contrast-enhanced computed tomography showed a large, well-demarcated, strongly enhancing mass with internal radiating septa in the mesorectum. The mass was well circumscribed and isointense to muscle on T1-weighted magnetic resonance imaging, appearing as a slightly hyperintense mass on T2-weighted imaging. We performed laparoscopic mesorectal mass excision, and histological examination revealed features typical of the hyaline-vascular type of Castleman's disease. Thus, when a mesorectal mass is being investigated, Castleman's disease should be considered in the differential diagnosis. PMID- 21264769 TI - Intraductal papillary growth of liver metastasis originating from colon carcinoma in the bile duct: report of a case. AB - Morphologically, liver metastases from colorectal carcinoma usually form as nodular tumor masses, whereas intraductal papillary growth in the bile duct is rare. A 65-year-old man underwent right hemicolectomy for advanced colon carcinoma, and histology of the primary carcinoma confirmed moderately differentiated adenocarcinoma with subserosal invasion, no vascular infiltration, and no lymph node metastasis. A liver tumor was found in the right paramedian Glisson pedicle and intraductal growth of cholangiocarcinoma was seen on imaging. We performed right hepatectomy and macroscopically, the resected specimen contained a growth in the bile duct lumen similar to cholangiocarcinoma. Histological examination revealed intraductal papillary proliferation of well differentiated adenocarcinoma without vascular infiltration or lymph node metastasis in the hepatic hilum. Immunohistochemical staining revealed that the tumor cells were negative for cytokeratin-7 and positive for cytokeratin-20. Based on these findings, liver metastasis from colon carcinoma was diagnosed. Liver metastasis from colorectal carcinoma rarely arises as intraductal papillary growth in the bile duct, but the possibility of liver metastases with unusual morphology must be borne in mind for patients with a history of carcinoma in the digestive tract. PMID- 21264770 TI - Pancreatobiliary and pancreatoduodenal fistulae in intraductal papillary mucinous neoplasm of the pancreas: report of a case. AB - Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas present more commonly in the elderly. This report describes a case of IPMN in a 36-year-old man who presented with obstructive jaundice and weight loss. The initial investigation by computed tomography scan revealed a cystic lesion in the head of pancreas fistulating into the duodenum and the common bile duct (CBD). Subsequent endoscopic retrograde cholangiopancreatography revealed a low CBD stricture with proximal filling defects. Mucin was observed extruding from the biliary orifice following an endoscopic sphincterotomy. A classic Whipple's pancreatoduodenectomy was performed to excise the lesion. A histological examination of the lesion confirmed the presence of a malignant IPMN of the pancreas complicated by pancreatobiliary and pancreatoduodenal fistulae. PMID- 21264771 TI - Surgical resection for hepatocellular carcinoma with metastasis to the gallbladder: report of a case. AB - A metastatic tumor of the gallbladder is rare. There have so far been no detailed reports of a resection of the metastasis of hepatocellular carcinoma (HCC) to the gallbladder published in the English literature. This report presents the case of a surgical resection for hepatocellular carcinoma with metastasis to the gallbladder. A 48-year-old woman consulted her primary care physician due to chest discomfort. Tumors in the liver and gallbladder were unexpectedly found and she was thus referred to this hospital. The radiologic studies showed two tumors. A round-shaped tumor, 30 mm in diameter, in the fossa of the gallbladder of the liver protruded into the lumen of the gallbladder, and a lobulated shaped tumor, measuring 13 mm, was in S5 of the liver. Angiography demonstrated that these tumors showed a pattern of early enhancement and washout. An en bloc resection of the gallbladder and the liver surrounding the gallbladder was performed, and the final diagnosis was moderately differentiated HCC in segment S5 with gallbladder metastasis. The patient is currently doing well 2 years after surgery, without any signs of recurrence. This case demonstrated that good clinical outcome could be achieved by performing surgery in HCC patients with metastasis to the gallbladder. PMID- 21264772 TI - Treatment of extrahepatic portal hypertension following a whipple procedure with a Rex shunt: report of a case. AB - The Rex shunt is a mesenteric vein to left portal vein decompressive shunt used for the treatment of portal vein thrombosis and portal hypertension. Its use has been reported primarily in the pediatric population where portal vein thrombosis occurs with some frequency. The shunt is thought to represent a more physiologic shunt, since it restores hepatopedal blood flow through the liver. This report describes the use of this shunt in an adult who had frequent gastrointestinal bleeding secondary to extrahepatic portal vein thrombosis, which occurred as a complication after a pancreaticoduodenectomy. PMID- 21264773 TI - Perioperative management of continuous ambulatory peritoneal dialysis patients undergoing inguinal hernia surgery. AB - Management of patients undergoing dialysis after inguinal hernia surgery has not been standardized. This report presents the results of 9 patients with inguinal hernias (11 hernias) who were undergoing continuous ambulatory peritoneal dialysis (CAPD). All patients treated in this hospital since 2007 have returned to CAPD within 3 days after surgery without switching to hemodialysis (HD). The mean durations for resuming CAPD after surgery were 7.6 days from 1998 through 2007 and 2.3 days since 2008. The surgical procedure was performed with a polypropylene mesh in all cases. Local anesthesia was utilized for one patient with low cardiac function. All patients recovered rapidly, with no uremia or dialysis-related complications. No leakage or hernia recurrence was observed over the subsequent observation period (56.2 months). This experience suggests the possibility that interim HD can therefore be skipped in patients undergoing CAPD if the hernia sacs are closed tightly. Local anesthesia seems to be safe for high risk hernia patients undergoing CAPD. PMID- 21264774 TI - Hemostasis of the liver, spleen, and bone achieved by electrocautery greased with lidocaine gel. AB - Despite advances in surgical techniques, achieving hemostasis of the liver, spleen, and bone during major surgery, especially after trauma, is still difficult. I describe a new procedure my colleagues and I devised to achieve parenchymatous hemostasis using electrocautery greased with lidocaine gel. After achieving good results in experimental studies and obtaining approval from our ethics committee, we used electrocautery greased with lidocaine gel for hemostasis in the following 36 procedures: multisegmental hepatectomy to remove hepatic tumors (n = 6); partial hepatectomy to allow hepatojejunostomy for intrahepatic biliary obstruction (n = 10); laparoscopic liver biopsy (n = 4); subtotal splenectomy (n = 8; for portal hypertension in 5 patients, splenic ischemia in 2, and Gaucher's disease in 1); laparoscopic splenic biopsy (n = 1); and bone resection (n = 7; as pelvic-femoral resection in 6 patients and to remove a rectal tumor invading the coccyx in 1). This procedure was easy to perform and achieved complete hemostasis of the minor blood vessels in all patients. No postoperative bleeding occurred and the follow-up course was satisfactory. Electrocautery greased with lidocaine gel is an inexpensive, readily available, and efficient method to achieve hemostasis of minor vessels in hepatic, splenic, and bone operations. PMID- 21264775 TI - The development of new instruments (NT forceps) for video-assisted thoracoscopic surgery. AB - A new type of forceps (NT forceps) was developed in November 2007, designed for dividing connective tissues and for holding tissue together. These forceps measure 32 cm in length and are made of stainless steel. The insides of the forceps have atraumatic dispositions because longitudinal notches are placed on them. Therefore, they can grasp important soft organs such as the lung, azygos, and pulmonary vein. In addition, the acral forceps also possess carbide chips with cross notches. They can therefore hold vessel tape, sutures, etc. There are two types of forceps, which are curved at different angles, either a sharp angle or a slight angle. The forceps can be used for dividing and holding tissue while performing basic surgical manipulations, especially during an operation using a video-assisted procedure with a mini-thoracotomy. These forceps are useful tools for performing technical manipulations for standard operations, such as a lobectomy. PMID- 21264776 TI - Hand-assisted laparoscopic total pancreatectomy for a main duct intraductal papillary mucinous neoplasm of the pancreas. AB - The laparoscopic approach to pancreatectomy entails a number of restrictions in performing major pancreatic surgery. This report describes a hand-assisted laparoscopic total pancreatectomy performed for a main duct intraductal papillary mucinous neoplasm of the pancreas. Dissection of the gastroduodenal artery and splenic artery, and the transection of the duodenum were done through the midline mini-laparotomy, while mobilization of the spleen and the pancreatic tail and body, and Kocher's maneuver were performed using the hand-assisted laparoscopic approach. Furthermore, dissection of lymph nodes in the hepatoduodenal ligament, removal of the gallbladder, division of the hepatic duct, tunneling of the pancreas, and dissection of the pancreas from the superior mesenteric vein and superior mesenteric artery were possible to perform safely under a pure laparoscopic technique with an excellent laparoscopic view. The reconstruction procedures were performed through the mini-laparotomy. The hand-assisted laparoscopic total pancreatectomy should be considered for the treatment of selected patients because it has various advantages as one type of minimally invasive surgery. PMID- 21264780 TI - Clinical settings and specialties notifying cases of bacterial sexually transmitted infections in Switzerland: cross-sectional study. AB - QUESTIONS UNDER STUDY: In the next Swiss National HIV and Sexually Transmitted Infection (STI) Strategy 2011-2017, STI control will be integrated with HIV prevention. Information is needed which will improve the targeting of professional education. The objective of this study was to describe the clinical specialities and settings to which patients with bacterial STI present in Switzerland. METHODS: We analysed notifications of chlamydia from 01.08.2008 30.11.2008, and of gonorrhoea and syphilis from 01.07.2007-30.11.2008. We recorded patient details, the speciality of the notifying physician and the setting (primary or secondary care). RESULTS: We included 2150 notifications of chlamydia, 1360 of gonorrhoea and 935 of syphilis. In 12.5% of notifications (556/4445) a speciality or setting could not be assigned. Most chlamydia (1282/2150, 59.6%) and gonorrhoea (902/1360, 66.3%) notifications were from primary care. Slightly more syphilis notifications (429/935, 45.9%) were from secondary than from primary care. General practitioners (GPs) were the single largest group of specialists notifying gonorrhoea (609/1360, 44.8%) and syphilis (223/935, 23.9%) and the second largest speciality notifying chlamydia (446/2150, 20.7%) after gynaecologists in primary care (702/2150, 32.7%). Where male sexual orientation was recorded, 52.5% (180/343) of gonorrhoea cases and 30.3% of syphilis cases in men who have sex with men (50/165) were notified by GPs. CONCLUSIONS: GPs and other specialists in primary care notify the majority of chlamydia and gonorrhoea and a substantial percentage of syphilis in Switzerland. These physicians will be at the forefront of STI management and secondary prevention to be delivered as part of an integrated HIV and STI strategy. PMID- 21264781 TI - Relationships between geometry and kinematic characteristics in the temporomandibular joint. AB - Motions of the temporomandibular joint (TMJ) involve both translation and rotation; however, there may be substantial variations from one human to another, and these variations present significant difficulties when designing TMJ prostheses. The disc-condyle glides along the temporal bone and the condyle centre describe a curve that depends on the individual morphology. This study analyses disc-condyle rotatory and translatory displacements moving all along the temporal bone facets which are mainly composed of two areas: the articular tubercle slope (ATS) and the preglenoid plane separated by the articular tubercle crest. Displacements were quantified using 3D video analysis, and this technique was computer-assisted. From a population of 32 volunteers, we were able to establish a correlation between the kinematic characteristics of the joint and the disc-condyle trajectories. This study quantifies the geometrical characteristics of the ATS and their inter-individual variations, which are useful in TMJ prosthesis design. PMID- 21264782 TI - A mathematical model for describing the metastasis of cancer in bone tissue. AB - Metastasis is the rapid proliferation of cancer cells (secondary tumour) at a specific place, generally leading to death. This occurs at anatomical parts providing the necessary environment for vascularity, oxygen and food to hide their actions and trigger the rapid growth of cancer. Prostate and breast cancers, for example, use bone marrow for their proliferation. Bone-supporting cancer cells thus adapt to the environment, mimicking the behaviour of genetic and molecular bone cells. Evidence of this has been given in Cecchini et al. (2005, EAU Update Ser. 3:214-226), providing arguments such as how cancer cell growth is so active during bone reabsorption. This paper simulates metastasis activation in bone marrow. A mathematical model has been developed involving the activation of molecules from bone tissue cells, which are necessary for cancer to proliferate. Here, we simulate two forms of secondary tumour growth depending on the type of metastasis: osteosclerosis and osteolysis. PMID- 21264783 TI - Segmentation of foot and ankle complex based on kinematic criteria. AB - Although various foot models were proposed for kinematics assessment using skin makers, no objective justification exists for the foot segmentations. This study proposed objective kinematic criteria to define which foot joints are relevant (dominant) in skin markers assessments. Among the studied joints, shank-hindfoot, hindfoot-midfoot and medial-lateral forefoot joints were found to have larger mobility than flexibility of their neighbour bonesets. The amplitude and pattern consistency of these joint angles confirmed their dominancy. Nevertheless, the consistency of the medial-lateral forefoot joint amplitude was lower. These three joints also showed acceptable sensibility to experimental errors which supported their dominancy. This study concluded that to be reliable for assessments using skin markers, the foot and ankle complex could be divided into shank, hindfoot, medial forefoot, lateral forefoot and toes. Kinematics of foot models with more segments must be more cautiously used. PMID- 21264784 TI - Stochastic modelling of wall stresses in abdominal aortic aneurysms treated by a gene therapy. AB - A stochastic mechanical model using the membrane theory was used to simulate the in vivo mechanical behaviour of abdominal aortic aneurysms (AAAs) in order to compute the wall stresses after stabilisation by gene therapy. For that, both length and diameter of AAAs rats were measured during their expansion. Four groups of animals, control and treated by an endovascular gene therapy during 3 or 28 days were included. The mechanical problem was solved analytically using the geometric parameters and assuming the shape of aneurysms by a 'parabolic exponential curve'. When compared to controls, stress variations in the wall of AAAs for treated arteries during 28 days decreased, while they were nearly constant at day 3. The measured geometric parameters of AAAs were then investigated using probability density functions (pdf) attributed to every random variable. Different trials were useful to define a reliable confidence region in which the probability to have a realisation is equal to 99%. The results demonstrated that the error in the estimation of the stresses can be greater than 28% when parameters uncertainties are not considered in the modelling. The relevance of the proposed approach for the study of AAA growth may be studied further and extended to other treatments aimed at stabilisation AAAs, using biotherapies and pharmacological approaches. PMID- 21264785 TI - A modified human head model for the study of impact head injury. AB - A recently published finite element (FE) head model is modified to consider the viscoelasticity of the meninges, the spongy and compact bone in the skull. The cerebrospinal fluid (CSF) is simulated explicitly as a hydrostatic fluid by using a surface-based fluid modelling method, which allows fluid and structure interaction. It is found that the modified model yields smoother pressure responses in a head impact simulation. The baseline model underestimated the peak von Mises stress in the brain by 15% and the peak principal stress in the skull by 33%. The increase in the maximum principal stress in the skull is mainly caused by the updation of the material's viscoelasticity, and the change in the maximum von Mises stress in the brain is mainly caused by the improvement of the CSF simulation. The study shows that the viscoelasticity of the head tissue should be considered, and that the CSF should be modelled as a fluid, when using FE analysis to study head injury due to impact. PMID- 21264786 TI - Ultra-high performance liquid chromatography coupled to triple quadrupole mass spectrometry detection of naturally occurring thiouracil in urine of untreated livestock, domesticated animals and humans. AB - Thiouracil belongs to the xenobiotic thyreostats, which are growth-promoting agents illegally used in animal production. Recently it has been reported that thiouracil is suspected to have a natural origin. The European Union of Reference Laboratory guidance paper of 2007 acknowledged this by stating that thiouracil concentrations below 10 ug l-1 might have a natural origin derived from the consumption of Brassicaceae. The present research aimed at endorsing this possible natural occurrence. Urine samples of animals (livestock and domesticated) with known and unknown clinical backgrounds were analysed for thiouracil with a newly developed ultra-high performance liquid chromatography coupled to a triple quadrupole mass spectrometric analysis method without derivatisation. In addition, a small-scale 9-day human experiment with Brassicaceae vegetables was performed to investigate if this natural prevalence could be extrapolated to the human population. The untreated animals had thiouracil concentrations below 10 ug l-1 acknowledging the alleged natural occurrence of thiouracil. As for the humans, in 66.7% of the urine samples thiouracil was found above the CC(alpha) of 2.2 ug l-1. However, the correlation with the Brassicaceae diet proved to be non-significant (p = 0.095). Nevertheless, these results clearly demonstrate the natural occurrence of thiouracil in urine of animals and humans. The exact origin of this natural thiouracil trace still needs to be identified. PMID- 21264787 TI - Knowledge and attitude of safety belt use among professional drivers in a tertiary Nigerian institution. AB - Safety belt (SB) use prevents and reduces the severity of injuries during motor vehicle crashes, and its use is influenced by the perceived risk inherent in any journey. Over the years, most studies have focused on the effectiveness of the belt among commercial drivers. This study assessed drivers' knowledge, attitude and use of SB in a tertiary institution in Nigeria. The study, which was a cross sectional survey, was designed to document professional drivers' knowledge and use of SB and their attitude towards use. Data were collected using a survey questionnaire from 202 out of 228 drivers employed by the University of Ibadan aged 35-60 years who were at work and consented during the period of data collection. The respondents' mean knowledge score on SB was 8.9 SD +/- 1.4 out of 11 points. Eighty-six percent agreed that SB should be fastened when driving. Many of the respondents had a positive attitude to the use of seatbelts, 95.5% disagreed with the idea that a seatbelt causes accidents, while 80.2% also disagreed with the belief that a seatbelt was for educated drivers. There was a statistical significant association between respondents' attitude to SB use and age, year of experience, education (p < 0.05). PMID- 21264788 TI - Older adult pedestrian injuries in the United States: causes and contributing circumstances. AB - As the US population ages, more older adults will face transportation and mobility challenges. This study examines the characteristics and contributing circumstances of nonfatal older adult pedestrian injuries. Data were obtained from the National Electronic Injury Surveillance System-All Injury Programme (NEISS-AIP) for the years 2001 through 2006. Cases included persons aged 65 years and older who were nonfatally injured on a public roadway. The results indicated that on average, an estimated 52,482 older adults were treated in emergency departments each year for nonfatal pedestrian injuries. Falling and being hit by a motor vehicle were the leading mechanisms of injury, resulting in 77.5% and 15.0% of older adult pedestrian injuries, respectively. More than 9000 older pedestrian fall-related injuries each year involved a kerb. It is concluded that the growth in the older adult population could add to the overall burden of these nonfatal pedestrian injuries. Making transportation and mobility improvements, including environmental modifications, is important for preventing these injuries. PMID- 21264789 TI - Serum folate and homocysteine levels are associated with colon tumorigenesis in end-stage renal disease patients. AB - The aim of this study was to evaluate the effect of folate and homocysteine on colon tumorigenesis by performing colonoscopy and examining serum folate and homocysteine levels in end-stage renal disease (ESRD) patients. We performed colonoscopy in 72 ESRD patients who were undergoing hemodialysis and also measured their serum folate and homocysteine levels. Serum folate and homocysteine concentrations of the 72 ESRD patients were 6.0+/-3.9 MUg/l and 37.3+/-25.5 MUmol/l, respectively. Colorectal neoplasia was detected in 47 (65%) of the patients. Compared to a control group, ESRD patients had significantly more and larger neoplasia (P=0.002 and 0.001, respectively). Multivariate analysis revealed that ESRD patients with lower levels of serum homocysteine had significantly more and larger neoplasia than those with higher levels (P=0.02 and 0.03, respectively). In addition, patients with a shorter duration of hemodialysis were likely to have larger neoplasia. ESRD patients had higher than normal serum homocysteine levels. Interestingly, patients with lower homocysteine levels were likely to carry more and larger colorectal neoplasia. These results suggest that suppression of folate metabolism and an elevated serum homocysteine concentration are inversely associated with colon tumorigenesis in ESRD patients. PMID- 21264790 TI - Chemopreventive effects of dietary canola oil on colon cancer development. AB - Fatty acid composition of dietary fat plays a vital role in colon tumor development in animal models. Fats containing omega-6 fatty acids (e.g., corn oil) enhanced and omega-3 fatty acids (e.g., flaxseed oil) reduced chemically induced colon tumor development in rats. The objective of the present investigation was to study the effects of dietary canola oil, a source of omega-3 fatty acid on azoxymethane-induced colon cancer development in Fischer rats and compare with dietary corn oil. Dietary canola oil significantly (P<0.05) decreased colonic tumor incidence and tumor multiplicity as compared to dietary corn oil in rats. Fatty acid analysis showed that corn oil group had higher levels of omega-6 fatty acid levels, whereas the canola oil groups exhibited higher levels of omega-3 fatty acids from the colon and serum samples of rats. For the mechanistic study, COX-2 expression in the colon samples from the canola oil group was significantly lower (P<0.05) as compared to the corn oil group. Taken together, dietary canola oil may be chemopreventive for colon tumor development in Fischer rats as compared to possibly by increasing omega-3 fatty acid levels and decreasing COX-2 levels. PMID- 21264791 TI - [Bone biopsy needles: mechanical properties, needle design and specimen quality]. AB - PURPOSE: To quantitatively analyze differences in mechanical properties, needle design including signs of wear, subjective handling and specimen quality of bone biopsy needles. MATERIALS AND METHODS: In this study 19 different bone biopsy systems (total 38; 2 /type) were examined. With each biopsy needle five consecutive samples were obtained from vertebral bodies of swine. During puncture a force-torques sensor measured the mechanical properties and subjective handling was assessed. Before and after each biopsy the needles were investigated using a profile projector and signs of wear were recorded. Afterwards, a pathologist semi quantitatively examined the specimen regarding sample quality. The overall evaluation considered mechanical properties, needle wear, subjective handling and sample quality. Differences were assessed for statistical significance using ANOVA and t-test. RESULTS: Needle diameter (p = 0.003) as well as needle design (p = 0.008) affect the mechanical properties significantly. Franseen design is significantly superior to other needle designs. Besides, length reduction recorded by the profile projector, as a quality criterion showed notable distinctions in between the needle designs. CONCLUSION: Bone biopsy needles vary significantly in performance. Needle design has an important influence on mechanical properties, handling and specimen quality. Detailed knowledge of those parameters would improve selecting the appropriate bone biopsy needle. PMID- 21264792 TI - [Fatal outcome of invasive tracheal aspergillosis]. PMID- 21264793 TI - The phytochemical glaucarubinone promotes mitochondrial metabolism, reduces body fat, and extends lifespan of Caenorhabditis elegans. AB - Naturally occurring compounds that promote energy expenditure and delay aging in model organisms may be of significant interest, since these substances potentially provide pharmaceutical approaches to tackle obesity and promote healthy lifespan in humans. We aimed to test whether pharmaceutical concentrations of glaucarubinone, a cytotoxic and antimalarial quassinoid known from different species of the plant family Simaroubaceae, are capable of affecting metabolism and/or extending lifespan in a nematodal model organism for aging processes, the roundworm Caenorhabditis elegans. Adult C. elegans roundworms, maintained on agar plates, were fed with E. coli strain OP50 bacteria, and glaucarubinone was applied to the agar to test (i) whether it alters respiration rates and mitochondrial activity, (ii) whether it affects body fat content, and (iii) whether it may promote longevity by quantifying survival in the presence and absence of the compound. We have found that glaucarubinone induces oxygen consumption and reduces body fat content of C. elegans. Moreover and consistent with the concept of mitohormesis, glaucarubinone extends C. elegans lifespan when applied at a concentration of 1 or 10 nanomolar. Taken together, glaucarubinone is capable of reducing body fat and promoting longevity in C. elegans, tentatively suggesting that this compound may promote metabolic health and lifespan in mammals and possibly humans. PMID- 21264794 TI - Altered gene expressions of ghrelin, PYY, and CCK in the gastrointestinal tract of the hyperphagic intrauterine growth restriction rat offspring. AB - Intrauterine growth restriction (IUGR) is associated with a substantially greater incidence of metabolic syndrome in adulthood. Animal studies have shown that IUGR offspring are hyperphagic during the early postnatal period and therefore exhibit obesity. The molecular mechanisms underlying food intake regulation in the gastrointestinal tract have not been clarified in IUGR. In the present study, we utilized a rat model of IUGR by restricting the food intake of the mother (50% of the normal intake, ad libitum; FR group) from day 7 of gestation until delivery. Pups from undernourished mothers were fostered by control mothers. We examined the food intake and assessed the gene expressions of ghrelin, peptide YY (PYY), and cholecystokinin (CCK) in the alimentary tract of male newborns (postnatal day1) and adult offspring (age, 7 months). Compared to the offspring whose mothers received the standard diet ad libitum (CON offspring), FR offspring were hyperphagic from the weaning time until the end of the experiment, and resulted in a heavier final weight. Both newborn and adult FR offspring had higher ghrelin gene expression in the stomach and higher ghrelin plasma levels than did the controls. Although the gastrointestinal gene expressions and plasma levels of the anorexic peptides, PYY and CCK, were elevated in the FR newborns, they decreased in the FR adults. Our findings suggest that the altered gene expressions of orexigenic and anorexigenic gut peptides in the gastrointestinal tract in the maternal undernutrition-induced IUGR offspring provide a potential mechanism to explain hyperphagia and obesity seen in these offspring. PMID- 21264795 TI - Menin interacts with beta-catenin in osteoblast differentiation. AB - Menin promotes the commitment of pluripotent mesenchymal stem cells to the osteoblast lineage by interacting with the BMP-2 signaling molecules Smad1/5, and Runx2. However, the relationship between menin and the Wnt-beta-catenin pathway in bone is unclear. Reduction of menin expression by transfection of a menin antisense construct did not alter the levels of beta-catenin in mouse mesenchymal C2C12 and osteoblastic MC3T3-E1 cells. However, menin co-immunoprecipitated with beta-catenin as well as LEF-1 in C2C12 and MC3T3-E1 cells. Reduction of menin expression by antisense menin transfection antagonized beta-catenin-induced transcriptional activity of the pGL3-OT luciferase reporter construct in C2C12 and MC3T3-E1 cells. Antisense menin transfection antagonized the BMP-2 and beta catenin-stimulated increases in Runx2 and alkaline phosphatase levels in C2C12 cells. The data show that menin interacts with beta-catenin in mouse mesenchymal and osteoblastic cells, and suggest that the interaction is important for osteoblast differentiation. PMID- 21264797 TI - Increased gallium-68 DOTATOC uptake in normal thyroid glands. AB - Increased Ga-68 DOTATOC uptake for normal and goitrous and/or nodular thyroids has previously been reported for a small number of patients. The aim of this study was to reevaluate these preliminary findings with larger patient numbers and to determine possible variables, which might influence the quantification of Ga-68 DOTATOC uptake in normal and pathologic thyroid tissues. Ga-68 DOTATOC PET scans of 165 patients classified for various thyroid pathologies were analyzed by the so-called region of interest technique for Ga-68 DOTATOC uptake and the patient's history, thyroid ultrasound, TSH, and anti-TPO antibodies. Thyroid glands without any pathology showed a clearly detectable uptake of Ga-68 DOTATOC with a large variability and significantly higher target to background ratios for men as compared to women. In 8 cases of normal thyroids with an increased uptake, follow-up examinations after 6-14 months did not show any thyroid pathology. An increased DOTATOC uptake (target to background ratio >3.4) was found in hot nodules, disseminated thyroid autonomy, and in most cases (5 of 8) of active Hashimoto's disease. In Ga-68 DOTATOC PET, normal thyroid glands show a clearly detectable radiotracer uptake with a large variability and significantly higher target to background ratios in male patients. All patients with thyroid autonomy and most patients with active Hashimoto's disease have an increased thyroid DOTATOC uptake. PMID- 21264796 TI - Transient efficacy of octreotide and pasireotide (SOM230) treatment in GIP dependent Cushing's syndrome. AB - We studied a 55-year old woman presenting with features of Cushing's syndrome associated with metabolic abnormalities including severe hypertension and type 2 diabetes. Urinary free cortisol excretion was within normal limits, but an unusual diurnal cortisol rhythm was observed with low morning and high postprandial levels, associated with the absence of cortisol suppression after dexamethasone, suggesting the possibility of GIP-dependent Cushing's syndrome. The diagnosis was confirmed by further investigations, showing significant plasma cortisol responses after a mixed meal test and after oral, but not intravenous glucose administration, as well as ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH). An aberrant increase in cortisol was also observed after glucagon and terlipressin injections. The patient was first treated with octreotide 100-250 MUg thrice daily for 6 months, then with the new multi-ligand somatostatin analogue (SOM 230) 450-900 MUg twice daily for 3 months. Although inducing a significant acute suppression of post-prandial cortisol response, both drugs had no effects on the clinical and metabolic abnormalities associated with Cushing's syndrome and new tests performed at the end of each treatment period confirmed escape of post-meal cortisol suppression to therapy. The patient finally underwent a bilateral adrenalectomy, which markedly improved her medical condition and allowed in vitro confirmation by real time RT-PCR quantification of a high aberrant expression of GIP receptor mRNA in adrenal tissue. This case report illustrates the lack of sustained efficacy of somatostatin analogues on GIP-dependent Cushing's syndrome, independent of their affinity for the different somatostatin receptor subtypes. PMID- 21264798 TI - The effect of exogenous glucocorticoids on plasma catecholamines and metanephrines in patients without phaeochromocytomas. AB - The aim of the study was to evaluate the effects of steroid administration under standardised conditions in a range of patients both normal and with adrenal pathologies and to review the impact on plasma catecholamines and metanephrines. Corticosteroid administration has been linked to the development of hypertensive crises in patients with phaeochromocytoma, however a mechanism for this is not fully understood. We aimed to add useful information about the effect of steroids on levels of these hormones under usual circumstances. A prospective, observational cohort study of 50 patients undergoing the low-dose dexamethasone suppression test (LDDST) was undertaken. Additional blood samples were taken at the start and end of the standard LDDST. Biochemical analysis was carried out for plasma catecholamines and plasma free metanephrines. Demographic and hormonal data were acquired from review of the notes or measured at baseline. No significant changes in plasma catecholamines or metanephrines were seen at the end of the LDDST compared to baseline. This was also true of subgroup analysis, divided by age, gender, or type of underlying pathology. Our results suggest that hypertensive reaction responses, rare as they are, are unlikely to be related to normal adrenal physiology. Thus LDDST is likely to be safe under most circumstances, however caution should be exercised in patients with adrenal masses with imaging characteristics compatible with phaeochromocytoma. It may be prudent to defer glucocorticoid administration until functioning phaeochromocytoma has been excluded biochemically. PMID- 21264799 TI - Resistin levels in morbid obese patients following the biliopancreatic diversion surgery. AB - Previous studies addressing the changes of resistin concentrations in morbidly obese patients after bariatric surgery have yielded conflicting results. The purpose of the present study was to investigate the changes in serum resistin levels 1 year after biliopancreatic diversion in morbidly obese patients without diabetes mellitus. A cohort of 39 morbidly obese patients without diabetes mellitus was operated. Biochemical and anthropometric evaluation were realized at basal visit and at each visit. The frequency of patients with hypertension and hyperlipidemia was recorded at each visit. Overall the mean patient age was 44.8 +/- 14.1, and the mean preoperative BMI was 47.3 +/- 6.5 kg/m2. After one year of surgery, a significant decrease was observed in BMI, weight, waist circumference, fat mass, blood pressure, total cholesterol, LDL cholesterol, and triglyceride levels. Resistin levels did not change after surgery (5.61 +/- 1.93 ng/ml vs. 6.41 +/- 3.58 ng/ml; ns). Correlation analysis showed a positive association between basal resistin and weight (r = 0.68, p < 0.01) and fat mass (r = 0.65, p < 0.05). Resistin concentrations did not change after massive weight loss with biliopancreatic diversion in morbid obese patients without diabetes mellitus. PMID- 21264800 TI - A novel lumen-apposing stent for transluminal drainage of nonadherent extraintestinal fluid collections. AB - BACKGROUND AND STUDY AIMS: Tubular stents have been used to accomplish endoscopic transluminal drainage, but do not impart lumen-to-lumen anchorage. We evaluated a novel lumen-apposing stent designed for enteric drainage of nonadherent lumens. MATERIAL AND METHODS: Ex vivo benchtop testing was performed to quantify various physical and performance metrics of the stent (Axios). A simulator was developed to test the stent deployment through an echoendoscope. Survival experiments were performed on four pigs. Under endosonographic guidance, a cholecystogastrostomy tract was created and the stent was deployed across the lumens. Direct cholecystoscopy was performed. Surveillance gastroscopy was performed at weekly intervals for up to 8 weeks. Measured outcomes were procedural success, safety, and device durability and patency. RESULTS: In benchtop testing, the Axios stent withstood various vector forces of movement, yet allowed easy removability from the simulated tissue. The stent was successfully deployed across the stomach and gallbladder lumens in all four animals without complication. Direct cholecystoscopy and contrast injection documented the absence of tissue trauma and leakage. Gastroscopy at weekly intervals showed the stent in stable position without dislodgment. The stent remained patent in all animals. The covering remained intact and there was no hyperplastic tissue ingrowth or overgrowth, or tissue injury. One stent was removed at 4 weeks. On necropsy, the gallbladders showed focal adherence to the stomach at the site of cystogastrostomy with a negative leak test. CONCLUSIONS: The Axios stent enables the creation of a robust and reliable conduit between nonadherent lumens around the gastrointestinal tract. PMID- 21264801 TI - Apelin serum levels are not associated with early atherosclerosis or fat distribution in young subjects with increased risk for type 2 diabetes. AB - Apelin is proposed to possess protective cardiovascular properties and may furthermore promote favorable effects on glucose metabolism. First data in humans seem to support this hypothesis. Therefore we aimed to assess the meaning of apelin as an early risk indicator in young subjects prone to atherosclerosis and type 2 diabetes. Furthermore we examined the association of apelin serum levels with insulin sensitivity/resistance and body fat distribution as probably dependent cardiovascular risk factors. We examined 344 individuals (f/m=216/128, mean age 46+/-1 years) with an increased risk for type 2 diabetes. Apelin-36 serum levels were measured via ELISA. Endothelial dysfunction and intima media thickness (IMT) were assessed using high resolution ultrasound. Visceral adipose tissue (VAT) was measured with an axial T1-weighted fast spin echo technique with a 1.5 T whole-body imager. According to the study population's age, FMD (6.4+/ 0.2%) and IMT (0.56+/-0.01 mm) were within the expected ranges. Gender or age had no influence on serum apelin levels. When looked at early stages of atherosclerosis, we could not detect a significant correlation between apelin serum levels and FMD or IMT. Blood pressure as well was unaffected by serum apelin levels. Furthermore, neither parameters of insulin sensitivity like insulin sensitivity index (ISI), nor fat distribution like BMI, grade of adiposity, total adipose tissue or VAT were associated with apelin serum levels. We conclude that apelin serum levels do not add further information on the cardiovascular-, or diabetes risk pattern in a diabetes prone population. PMID- 21264802 TI - Diagnostic value of hemoglobin A1c for type 2 diabetes mellitus in a population at risk. AB - OBJECTIVE: Because the American Diabetes Association has recently included HbA1c as the primary diagnostic test for the detection of diabetes mellitus (HbA1c >=6.5%) we investigated its use as screening parameter for diabetes in a cohort at increased risk for the disease. RESEARCH DESIGN AND METHODS: During the last 10 years 2 036 Caucasians at risk to develop type 2 diabetes but not having this diagnosis yet, consecutively underwent a 75 g oral glucose tolerance test (OGTT). HbA1c was determined with the HPLC method (Tosoh A1c 2.2), external and internal quality controls were well within the allowed ranges. RESULTS: The oral glucose tolerance test classified 1 523 individuals as normal glucose tolerant (NGT), 387 as impaired glucose tolerant (IGT) or having impaired fasting glycemia (IFG) and 126 as diabetic. The 6.5% cut-off value of HbA1c classified 47% of the diabetic individuals correctly. Of the remaining 53% diabetic individuals (HbA1c <6.5%) 35% had increased fasting glucose levels, while 65% were only diagnosed by their increased 2 h glucose values. CONCLUSION: A cut-off value of 6.5% HbA1c classifies diabetic subjects with a specificity of 98.7%. However, the sensitivity of 46.8% is low, indicating that more than half of diabetic subjects are missed when using this test. The present data shows that the use of HbA1c as a the primary diagnostic test will reduce diabetes prevalence. Furthermore, it suggests, that HbA1c and OGTT measurements cannot simply be exchanged, but most probably detect and define different categories of diabetes, i. e., categories with different risk of cardiovascular disease. PMID- 21264803 TI - Insulin-induced electrochemical changes in pleura are associated with the location within the pleural cavity. AB - AIM: We investigated the effects of insulin on the electrophysiology of sheep pleural specimens obtained from the upper and lower parts of the pleural cavity and the insulin receptor abundance in these regions. MATERIALS AND METHODS: Sheep pleural specimens were obtained from the upper and lower lung lobes and from the 1st-4th and 8th-12th ribs and were mounted between Ussing chambers. Insulin 10( 7) M was added on the mesothelial surface with Insulin Receptor (IR) inhibitor in some experiments. Trans-mesothelial Resistance (R(TM)) was determined. Immunohistochemistry for the presence of IR differences was performed. RESULTS: Insulin increased the R(TM) of all pleural regions. Higher R(TM) increase was demonstrated in lower lobe visceral and in caudal parietal specimens. The R(TM) increase demonstrated in caudal parietal had the tendency to be higher than that observed in the lower lobe visceral specimens. IR inhibitor abolished insulin's effect in all regions. Immunostaining was more intense for parietal and for caudal parietal specimens when compared with the visceral and lower lobe visceral specimens. CONCLUSION: Insulin induces electrochemical alterations that vary depending on the location of specimens within the pleural cavity which possibly is not correlated with insulin receptors variations. PMID- 21264804 TI - Direct costs of diabetes mellitus in Germany - CoDiM 2000-2007. AB - INTRODUCTION: The prevalence of treated diabetes in Germany and direct health care costs of individuals with diabetes were analysed for the 8-year period from 2000 to 2007, based on administrative data. Special interest was given to the incremental costs attributed to diabetes. MATERIAL AND METHODS: An 18.75% sample of all members of a large local German statutory health insurance provider, "AOK Die Gesundheitskasse" in the federal state of Hesse was analysed with regard to cases of treated diabetes. To assess the incremental diabetes-related direct costs, the cost data of individuals with diabetes was compared to that of an age- and sex-matched group of persons without diabetes. Prevalence and costs were standardized according to the gender and age distribution of the German population. RESULTS: Between 2000 and 2007, the administrative prevalence of treated diabetes rose continuously in Germany, from 6.5 to 8.9% (+36.8%). The number of patients treated with 'insulin' or 'insulin & oral antidiabetic agents' increased by +54.7 and +61.7%, respectively. Direct costs per patient with diabetes, calculated using the unit costs reimbursed by statutory health and nursing care insurances, rose from ? 5 197 to ? 5 726 (+10.2%). Incremental per capita costs were ? 2 400 in 2000 and ? 2 605 in 2007 (+8.5%). However, the total direct cost burden of diabetes in Germany grew from ? 27.8 billion to ? 42.0 billion (+51.1%). The incremental diabetes-related cost burden increased from ? 12.9 billion to ? 19.1 billion (+48.6%). CONCLUSIONS: There was a continuous increase in the prevalence of diabetes in Germany during the 8-year period. Although there was only a modest increase in annual diabetes-related per-capita costs, total healthcare expenditure rose substantially due to the growing number of patients being treated for diabetes. PMID- 21264805 TI - The associations between iL-18 serum levels and the prevalence of metabolic syndrome in Polish men over the age of 40 according to other selected inflammatory indices and androgens: comparison of NCEP with IDF criteria. AB - BACKGROUND: The frequency of MS increases with age and augments the cardiovascular risk. The criteria for distinguishing MS constantly evolve. The aim of the study was to estimate the reciprocal links between low-grade inflammation, selected serum androgens and prevalence of MS, according to NCEP and IDF criteria, in Polish men over the age of 40. MATERIALS AND METHODS: A sample of 160 men was randomly selected from men at the age of 40, 50, 60 and 70, residing in the rural south-western region of Poland. IL-18 and CRP, transferrin, alpha (1)-antichymotrypsin, dehydroepiandrosterone and its sulfate as well as free-testosterone levels were evaluated. RESULTS: The prevalence of MS was 37.5% using NCEP criteria and 46.25% employing IDF indices. Patients with MS diagnosed according to criteria proposed by NCEP and IDF exhibit a similar hormonal and immunological profile. Age was positively correlated with CRP (r=0.231; p<0.0005), and alpha (1)-ACT (r=0.191 p<0.05) and negatively with transferrin (r= 0.27; p<0.001), but not with IL-18 plasma levels. Both adrenal androgens were negatively correlated with age: DHEA r=-0.489; p<0.001 and DHEAS: r=-0.553; p<0.001 respectively, in contrast to free-testosterone. People suffering from MS have shown a significantly higher level of IL-18 and CRP. The number of MS components identified (according to NCEP) is positively correlated only with IL 18 serum levels (r=0.226; p=0.043). CONCLUSIONS: Inflammatory parameters were better than a deficit of androgens in identifying men suffering from MS. However, the best correlation with the number of MS components was revealed by IL-18 plasma levels. PMID- 21264806 TI - Effect of hyperthyroidism on clearance and secretion of glucagon in man. AB - OBJECTIVE: Glucagon has been proposed to contribute to the increased glucose production found in hyperthyroidism. However, fasting plasma glucagon levels are not increased in hyperthyroidism suggesting that the activity of the alpha-cell is normal. Nevertheless, an increase in the clearance rate of glucagon may mask increased glucagon secretion. This study was designed to examine the effects of hyperthyroidism on the kinetics of glucagon. DESIGN AND METHODS: A primed continuous infusion of glucagon was administered to 9 euthyroid and 9 hyperthyroid subjects at 3 sequential rates (1,200, 3,000 and 6,000 pg/kg/min, each given for 2 h). Arterialized blood was drawn at 15-30 min intervals for determination of glucagon. RESULTS: Fasting plasma glucagon levels were comparable in euthyroids (195+/-8 pg/ml) and hyperthyroids (231+/-16 pg/ml). During infusions (1,200, 3,000 and 6,000 pg/kg/min), plasma glucagon increased to 387+/-19, 624+/-44 and 977+/-51 pg/ml in euthyroids and to 348+/-23, 597+/-42 and 938+/-56 pg/ml in hyperthyroids respectively. At these infusion rates, metabolic clearance of glucagon (ml/kg/min) was 6.6+/-0.5, 7.4+/-0.6 and 7.9+/-0.5 in euthyroids and 12.6+/-2, 8.9+/-1 and 8.8+/-0.6 in hyperthyroids, respectively. Metabolic clearance of glucagon differed between hyperthyroids and euthyroids at 1 200 pg/kg/min infusion rate (p=0.001). The basal delivery rate of glucagon (ng/kg/min) was 1.3+/-0.1 in euthyroids and 2.9+/-0.6 in hyperthyroids (p=0.0005). CONCLUSIONS: In hyperthyroidism, the secretion and metabolic clearance rates of glucagon are increased. These effects may explain the changes in plasma glucagon levels observed in hyperthyroidism and support the important role of glucagon in increasing endogenous glucose production in this condition. PMID- 21264807 TI - Do thyroid cancer patients with basal undetectable Tg measured by current immunoassays require rhTSH testing? AB - OBJECTIVE: To evaluate the predictive value of disease free status of basal thyroglobulin (Tg) in differentiated thyroid carcinoma (DTC). DESIGN: Basal and recombinant human TSH (rhTSH) stimulated Tg measured with a commercial immunoassay (Liaison DiaSorin, Italial), neck ultrasonography (US) and fine needle aspiration cytology if required were performed in DTC patients followed prospectively for 6.8 years in a university hospital. 92 consecutive DTC patients were included. 74 patients with basal and stimulated Tg <1.0 ng/ml and Tg antibodies and US negative were considered as disease-free and persistent/recurrent disease was detected in 18 patients. In 25/74 disease-free patients rhTSH test was repeated within one year. RESULTS: 63/92 patients had undetectable basal Tg (<0.5 ng/ml), with rhTSH-Tg <0.5 ng/ml in 52, in 6 rhTSH-Tg between 0.5 and 1 ng/ml, in 2 between 1-2 ng/ml (disease-free after 3 years of follow-up) and >2.0 ng/ml (mean 4.1+/-2.4 ng/ml) in another 3, with US lymphatic metastasis confirmed histologically. Disease-free state was predicted with a sensitivity (S) of 66.7% and specificity (Sp) of 75.7% for basal Tg-0.5 ng/ml, and S 100% and Sp 85.1% for stimulated Tg-0.92. rhTSH test and US were repeated within one year in 25 disease-free patients with Tg<1.0 ng/ml. No further elevation below 1 ng/ml was observed. CONCLUSIONS: Low risk patients with undetectable basal Tg measured with current commercially available immunoassays should be followed with at least one rhTSH stimulated Tg and neck US because of the insufficient predictive value for recurrence/persistent disease of basal Tg. PMID- 21264808 TI - Octreotide lar affects the volume of pituitary adenoma in acromegalic patients. AB - INTRODUCTION: We studied changes of pituitary adenoma volumes in patients treated with octreotide LAR (SSLAR) over 12 months prior to surgery. MATERIALS AND METHODS: 26 patients (22 female and 4 male, mean age 57.5+/-15.0 years) were treated with SSLAR: 5 patients with microadenoma - during 6 months, and 21 patients with macroadenoma - during 12 months before surgery. Concentration of hGH and IGF-1 was evaluated at 0, 3, 6 and 12 months, while MRI images were taken at 0, 6 and 12 months prior to surgery. The volume of pituitary adenoma, estimated as that of an ellipsoid, was based on MRI image projections. Basic statistics, Shapiro-Wilk and Wilcoxon tests were applied. RESULTS: Median values of hGH and IGF-1 concentrations prior to treatment were 19.0 ng/ml (IQR=40.7) and 766.4 ng/ml (IQR=787.7), respectively. After 6 and 12 months the median value of hGH concentration decreased to 6.3 ng/ml (IQR=9.0) and 3.45 ng/ml (IQR=3.7), respectively, while the median values of IGF-1 became 535.0 ng/ml (IQR=652.8) and 287.0 (IQR=275.7), respectively. All differences were statistically significant (p<0.05) as compared to basal value. The median volumes of adenomas differed significantly and were estimated at: 1.1 cm (3) (IQR=2.5) prior to treatment, 0.5 cm (3) (IQR=1.5) after 6 months, and 0.35 cm (3) (IQR=2.4) after 12 months of SSLAR administration. CONCLUSION: Treatment of acromegalic patients with somatostatin analogues not only decreases the concentration of hGH and IGF-1, but also appears to decrease the size of the tumour in about 50% of patients treated, leading to general enhancement of the outcome of surgery. PMID- 21264809 TI - Non-functioning pituitary adenomas: a single center experience. AB - INTRODUCTION: To describe the clinical imaging and hormonal characteristics and the natural course of patients with clinically non-functioning pituitary adenomas (NFPAs) presenting at our department from 1984 to 2009. MATERIALS AND METHODS: Retrospective review of electronic medical records of patients with NFPAs. The patients underwent basal and dynamic evaluation of the hypothalamic-pituitary axis. Size and functional alterations were estimated at yearly intervals. RESULTS: 114 patients (55 men and 59 women, aged 47+/-2) were studied. The mean follow-up time was 55+/-6 months (range 0-240). 45% of the adenomas were incidentally discovered and 75% were macroadenomas (73% with extrasellar extension). At diagnosis, 53% had headache and 76% of those with macroadenomas had visual field defects. Disruption of >=1 pituitary axes was identified in 31% of patients at diagnosis. Surgery was performed in 59% and radiotherapy in 9% of the cases. 88% of surgically treated patients reported improvement in headache and 59% in visual fields. However, the prevalence of permanent diabetes insipidus increased from 2% at diagnosis to 15% postoperatively. The prevalence of >=1 pituitary deficiencies and panhypopituitarism increased significantly postoperatively. 58% of the adenomas relapsed in size. 29% of the patients were managed conservatively and tumor size remained stable in 83% of them. CONCLUSIONS: The majority of NFPAs not selected for surgery at diagnosis remained stable in size. Pituitary dysfunction and visual defects at diagnosis were common. Surgical debulking led to clinical improvement, but relapse occurred in 2/3 of the cases. PMID- 21264810 TI - [Necrotising inflammations of the lower extremities due to gastrointestinal perforations]. PMID- 21264811 TI - [Stenosis and iatrogenic perforation as complication following long-term stenting of the oesophagus]. AB - Anastomotic leaks after oesophagojejunostomy usually are treated by endoluminal stenting with self-expandable metal or plastic stents. Here we present a patient with more than 4 years of oesophageal stenting for anastomotic leakage after gastrectomy. During the attempted removal of the stent he experienced a perforation of the jejunum. Emergency surgery with complete resection of the stent and transhiatal oesophagojejunostomy was performed. Generally, early removal of oesophageal stents 4-6 weeks after implantation is recommended, as later attempts often fail and may lead to extensive surgery. PMID- 21264813 TI - Prediction of maize double-cross hybrids using the best linear unbiased prediction with microsatellite marker information. AB - We examined the usefulness of the best linear unbiased prediction associated with molecular markers for prediction of untested maize double-cross hybrids. Ten single-cross hybrids from different commercial backgrounds were crossed using a complete diallel design. These 10 single-cross hybrids were genotyped with 20 microsatellite markers. The best linear unbiased prediction associated with microsatellite information gave relatively good prediction ability of the double cross hybrid performance, with correlations between observed phenotypic values and genotypic prediction values varying from 0.27 to 0.54. Taking into account the predictions of specific combing ability, the correlation between observed and predicted specific combining ability varied from 0.50 to 0.88. Based on these results, we infer that it is feasible to predict maize double-cross hybrids with different unbalance degrees without including any prior information about parental inbreed lines or single-cross hybrid performance. PMID- 21264814 TI - Genetic variation of Casuarina equisetifolia subsp equisetifolia and C. equisetifolia subsp incana populations on the northern coast of Senegal. AB - The genetic variation of 70 individual samples of Casuarina equisetifolia (L. Johnson) subsp equisetifolia and C. equisetifolia subsp incana growing along the northern coast of Senegal was analyzed with RAPD markers. Of the 160 primers tested, five were chosen; they generated 1396 reproducible bands and 61 polymorphic bands that were scored. This result showed a narrow genetic variation among (4.36%) and within (5.90%) C. equisetifolia subsp equisetifolia and C. equisetifolia subsp incana plantation sites. The genetic variation at each site revealed a high degree of polymorphism in Potou (5.90%) and low diversity in Retba (3.06%). In the dendrogram analyses, each sampling site was formed by two main groups. Similar results were found for the dendrograms based on the RAPD data gathered from the five different sites. These dendrograms revealed several polytomies in one of the subgroups, suggesting replication of the same specimens in different sites along the Senegalese coast. The RAPD data support the hypothesis that these populations are of the same provenance, subject to hybridization and inbreeding depression. PMID- 21264815 TI - Confirmation of cross-fertilization using molecular markers in ornamental passion flower hybrids. AB - Several interspecific Passiflora hybrids are produced in the northern hemisphere for the ornamental plant market. In Brazil, production of passion flower hybrids is limited to the introgression of genes into the main cultivated species, yellow passion fruit, to be used as rootstocks. Confirmation of hybridization in the initial developmental stage is important for breeding perennial and sub-perennial plants, such as passion flowers, reducing time and costs in plant stock maintenance. In order to obtain F1 hybrids with ornamental potential, four species of Passiflora (P. alata, P. gardneri, P. gibertii, and P. watsoniana) from the Active Germplasm Bank at UESC were hybridized. Flower buds, in pre anthesis, of the genitors were previously protected, and the female buds were emasculated. To confirm hybridization, the genomic DNA of the genitor species and the supposed hybrids was extracted and RAPD primers were used to obtain molecular markers and select passion flower interspecific hybrids. Eight primers were used to confirm hybrids derived from P. gardneri with P. alata, P. watsoniana with P. alata, P. watsoniana with P. gardneri, and P. gardneri with P. gibertii; 75, 50, 45, and 46% of the informative bands, respectively, confirmed the hybrid nature of these plants. The RAPD technique was effective in the early identification of hybrids; this will be useful for development of hybrid Passiflora progeny. PMID- 21264816 TI - Allelic polymorphism, gene duplication and balancing selection of the MHC class II DAB gene of Cynoglossus semilaevis (Cynoglossidae). AB - Major histocompatibility complex (MHC) genes play an important role in the immune response of vertebrates. Allelic polymorphism and evolutionary mechanism of MHC genes have been investigated in many mammals, but much less is known in teleosts. We examined the polymorphism, gene duplication and balancing selection of the MHC class II DAB gene of the half-smooth tongue sole (Cynoglossus semilaevis); 23 alleles were found in this species. Gene duplication manifested as three to six distinct sequences at each domain in the same individuals. Non-synonymous substitutions occurred at a significantly higher frequency than synonymous substitutions in the PBR domain, suggesting balancing selection for maintaining polymorphisms at the MHC II DAB locus. Many positive selection sites were found to act very intensely on antigen-binding sites of MHC class II DAB gene. PMID- 21264817 TI - Novel exon nucleotide deletion causes adrenoleukodystrophy in a Brazilian family. AB - Adrenoleukodystrophy is a neurodegenerative X-linked recessive disorder. It is characterized by abnormal function of peroxisomes, which leads to an accumulation of very long-chain fatty acids in plasma and tissues, especially in the cortex of adrenal glands and white matter of the central nervous system, causing demyelinating disease and adrenocortical insufficiency (Addison's disease). It is caused by a mutation in the ABCD1 gene (ATP-binding cassette, subfamily D, member 1), which encodes the protein adrenoleukodystrophy that is involved in the transport of fatty acids into the peroxisome for degradation. Variable expression has been recognized in families of patients who have this disease. A Brazilian family from Minas Gerais State, Brazil, was studied. The proband is an adult living in Minas Gerais State, Brazil; he had adrenomyeloneuropathy, adrenocortical insufficiency and a stable cerebral form. DNA was extracted from a blood sample and was sequenced to identify the mutation. The patient's exons were cloned for confirmation. A new mutation was found in exon 5 of the ABCD1 gene (c.1430delA), as well as a single-nucleotide polymorphism in exon 6. The mutation causes a frame shift, resulting in a truncated protein with almost total absence of the ATP binding domain. PMID- 21264818 TI - Modulatory effects of Duguetia furfuracea (A. St. Hil) Benth. and Hook. f. in Drosophila melanogaster somatic and germinative cells. AB - Mutagenic and antimutagenic activities of the medicinal plant Duguetia furfuracea were assessed using SMART/wing and ring-X-loss tests. For the ring-X-loss test, 2 to 3-day-old Drosophila melanogaster ring-X-lineage males and virgin ywsn3 females received D. furfuracea infusion at doses of 0.085, 0.042, or 0.014 g/mL for 24 h. We found that D. furfuracea did not produce any mutagenic effects in D. melanogaster germinative cells. The somatic cells of D. melanogaster were analyzed using the SMART/wing test involving three lineages - mwh, flr3, and ORR and the same doses of D. furfuracea infusion employed in the ring-X-loss test, as well as 20 mM urethane. The results of both standard (ST) and high bioactivation (HB) crosses showed absence of mutagenic activity of D. furfuracea. In contrast, in both ST and HB crosses, we observed a modulatory effect of D. furfuracea against the genotoxic activity of urethane. PMID- 21264819 TI - Incidence of fibroblast growth factor receptor 3 gene (FGFR3) A248C, S249C, G372C, and T375C mutations in bladder cancer. AB - Bladder cancer is the most frequent cancer of the urinary system. Fibroblast growth factor receptors (FGFR) belong to the tyrosine kinase family and have important roles in cell differentiation and proliferation and embryogenesis. FGFR3 is located on chromosome 4p16.3, and missense mutations of FGFR3 are associated with autosomal dominant human skeletal disorders and have some oncogenic effects. We examined the incidence of FGFR3 thanatophoric dysplasia mutations located in exon 7, A248C and S249C, and in exon 10, G372C and T375C, and their correlation with clinical-pathological parameters in bladder carcinoma patients. Fifty-six paraffin-embedded specimens of transitional cell carcinoma of the urinary bladder were included in this study. Analysis of FGFR3 thanatophoric dysplasia mutations located in exon 7, A248C and S249C, and in exon 10, G372C and T375C, was performed by PCR-restriction fragment length polymorphism (RFLP) analysis and DNA sequencing. FGFR3 thanatophoric dysplasia mutations located in exon 7, A248C and S249C, and in exon 10, G372C and T375C, were detected in 33 of the 56 patients (heterozygous mutant). Among the 56 transitional cell carcinomas, missense point mutations were detected in seven of them at codon A248C, 28 of them at codon S249C, and three of them at codon T375C, similar to data from previous reports. When the results of the FGFR3 thanatophoric dysplasia mutations located in exon 7, A248C and S249C and in exon 10, G372C and T375C, were analyzed one by one or as a group, despite the findings of previous research reports, our data suggest that these mutations are detected homogenously regardless of the tumor classification and tumor grade. PMID- 21264820 TI - Lung cancer mortality risk among breast cancer patients treated with anti estrogens. AB - BACKGROUND: The Women's Health Initiative randomized clinical trial reported that menopausal hormone therapy increases lung cancer mortality risk. If this is true, use of anti-estrogens should be associated with decreased lung cancer mortality risk. The authors compared lung cancer incidence and mortality among breast cancer patients with and without anti-estrogen therapy. METHODS: Our study included all 6655 women diagnosed with breast cancer between 1980 and 2003 and registered at the Geneva Cancer Registry. Among these women, 46% (3066) received anti-estrogens. All women were followed for occurrence and death from lung cancer until December 2007. The authors compared incidence and mortality rates among patients with and without anti-estrogens with those expected in the general population by Standardized Incidence Ratios (SIRs) and Standardized Mortality Ratios (SMRs). RESULTS: After a total of 57,257 person-years, 40 women developed lung cancer. SIRs for lung cancer were not significantly decreased among breast cancer patients with and without anti-estrogens (0.63, 95% confidence intervals [CI], 0.33-1.10; and 1.12, 95% CI, 0.74-1.62, respectively) while SMR was decreased among women with anti-estrogens (0.13, 95% CI, 0.02-0.47, P<.001) but not for women without anti-estrogens (0.76, 95% CI, 0.43-1.23). CONCLUSIONS: Compared with expected outcomes in the general population, breast cancer patients receiving anti-estrogen treatment for breast cancer had lower lung cancer mortality. This study further supports the hypothesis that estrogen therapy modifies lung cancer prognosis. PMID- 21264821 TI - Intensity-modulated radiation therapy reduces radiation-induced trismus in patients with nasopharyngeal carcinoma: a prospective study with >5 years of follow-up. AB - BACKGROUND: Intensity-modulated radiation therapy (IMRT) for nasopharyngeal carcinoma (NPC) provides better temporomandibular joint (TMJ) sparing and, thus, may reduce the incidence of radiation-induced trismus after radiotherapy. The objectives of this study were to evaluate radiation-induced trismus in patients with NPC who had received IMRT and to assess the pretreatment factors, relevant treatment factors, and dosimetry parameters associated with trismus. METHODS: A prospective, single-arm measurement study with more than 5 years of follow-up was designed. Patients with newly diagnosed stage I through IVB NPC who received treatment with IMRT were eligible. Patients received 66 to 70 grays (Gy) to the gross tumor volume. The maximal interincisal distance (MID) was measured at baseline and 6 months, 1 year, 2 years, 3 years, 4 years, and 5 years after they completed IMRT. RESULTS: The trial enrolled 211 consecutive patients from 2001 to 2004. The mean dose to the TMJ ranged from 6.18 Gy to 51.36 Gy (median dose, 29.88 Gy). Compared with baseline MID levels, normalized MID levels at 6 months, 1 year, 2 years, 3 years, 4 years, and 5 years after IMRT were 94.6% +/- 9.9%, 92.5% +/- 10.5%, 92% +/- 10.6%, 92.2% +/- 10.5%, 92.1% +/- 10.2%, and 90.3% +/- 11.4%, respectively (P < .001). According to a revised subjective-objective management-analytical (SOMA) scale, grade 1/2 trismus was identified in 12 of 211 patients (5.7%), and no grade 3/4 trismus was observed. There was an increasing risk of trismus after IMRT when the MID was <40.5 mm at baseline compared with an MID >40.5 mm (P = .007). No dosimetric parameter was associated with trismus. CONCLUSIONS: IMRT was able to reduce the radiation dose to the TMJ and likely reduced the incidence and severity of radiation-induced trismus after radiotherapy. PMID- 21264822 TI - Assessment of capsular melanoma cell deposits in sentinel lymph nodes. PMID- 21264825 TI - Evaluation of the Seventh American Joint Committee on Cancer/International Union Against Cancer Classification of gastric adenocarcinoma in comparison with the sixth classification. PMID- 21264826 TI - The safety and efficacy of high-dose proton beam radiotherapy for hepatocellular carcinoma: a phase 2 prospective trial. AB - BACKGROUND: Proton beam therapy (PBT) may provide useful local-regional treatment for hepatocellular carcinoma (HCC). The purpose of this study was to evaluate the safety and efficacy of PBT for HCC. METHODS: Patients with cirrhosis who had radiological features or biopsy-proven HCC were included in the study. Patients without cirrhosis and patients with extrahepatic metastasis were excluded. The mean age was 62.7 years. The mean tumor size was 5.5 cm. Eleven patients had multiple tumors, and 46% were within the Milan criteria. Patients received 63 Gy delivered over a 3-week period with PBT. RESULTS: Seventy-six patients were treated and followed prospectively for treatment outcomes at Loma Linda University Medical Center. Acute toxicity was minimal; all patients completed the full course of treatment. Radiation-induced liver disease was evaluated using liver enzyme, bilirubin, and albumin levels; no significant change supervened 6 months posttreatment. Median progression-free survival for the entire group was 36 months, with a 60% 3-year progression-free survival rate for patients within the Milan criteria. Eighteen patients subsequently underwent liver transplantation; 6 (33%) explants showed pathological complete response and 7 (39%) showed only microscopic residual. CONCLUSIONS: PBT was found to be a safe and effective local-regional therapy for inoperable HCC. A randomized controlled trial to compare its efficacy to a standard therapy has been initiated. Cancer 2011. (c) 2011 American Cancer Society. PMID- 21264827 TI - Early findings on toxicity of proton beam therapy with concurrent chemotherapy for nonsmall cell lung cancer. AB - BACKGROUND: Concurrent chemoradiation therapy, the standard of care for locally advanced nonsmall cell lung cancer (NSCLC), can cause life-threatening pneumonitis and esophagitis. X-ray (photon)-based radiation therapy (RT) often cannot be given at tumoricidal doses without toxicity to proximal normal tissues. We hypothesized that proton beam therapy for most patients with NSCLC could permit higher tumor doses with less normal-tissue toxicity than photon RT delivered as 3-dimensional conformal RT (3D-CRT) or intensity-modulated RT (IMRT). METHODS: We compared the toxicity of proton therapy+concurrent chemotherapy in 62 patients with NSCLC (treatment period 2006-2008) with toxicity for patients with similar disease given 3D-CRT+chemotherapy (n = 74; treatment period 2001-2003) or IMRT+chemotherapy (n = 66; treatment period 2003-2005). Proton therapy to the gross tumor volume was given with weekly intravenous paclitaxel (50 mg/m2) and carboplatin (area under the curve 2 mg/mL/min). The primary endpoint was toxicity (Common Terminology Criteria for Adverse Events version 3.0). RESULTS: Median follow-up times were 15.2 months (proton), 17.9 months (3D-CRT), and 17.4 months (IMRT). Median total radiation dose was 74 Gy(RBE) for the proton group versus 63 Gy for the other groups. Rates of severe (grade >= 3) pneumonitis and esophagitis in the proton group (2% and 5%) were lower despite the higher radiation dose (3D-CRT, 30% and 18%; IMRT, 9% and 44%; P<.001 for all). CONCLUSIONS: We found that higher doses of proton radiation could be delivered to lung tumors with a lower risk of esophagitis and pneumonitis. A randomized comparison of IMRT versus proton therapy is underway. PMID- 21264829 TI - Effects of individual-level socioeconomic factors on racial disparities in cancer treatment and survival: findings from the National Longitudinal Mortality Study, 1979-2003. AB - BACKGROUND: This is the first study to use the linked National Longitudinal Mortality Study and Surveillance, Epidemiology, and End Results (SEER) data to determine the effects of individual-level socioeconomic factors (health insurance, education, income, and poverty status) on racial disparities in receiving treatment and in survival. METHODS: This study included 13,234 cases diagnosed with the 8 most common types of cancer (female breast, colorectal, prostate, lung and bronchus, uterine cervix, ovarian, melanoma, and urinary bladder) at age >= 25 years, identified from the National Longitudinal Mortality Study-SEER data during 1973 to 2003. Kaplan-Meier methods and Cox regression models were used for survival analysis. RESULTS: Three-year all-cause observed survival for cases diagnosed with local-stage cancers of the 8 leading tumors combined was >= 82% regardless of race/ethnicity. More favorable survival was associated with higher socioeconomic status. Compared with whites, blacks were less likely to receive first-course cancer-directed surgery, perhaps reflecting a less favorable stage distribution at diagnosis. Hazard ratio (HR) for cancer specific mortality was significantly higher among blacks compared with whites (HR, 1.2; 95% confidence interval [CI], 1.1-1.3) after adjusting for age, sex, and tumor stage, but not after further controlling for socioeconomic factors and treatment (HR, 1.0; 95% CI, 0.9-1.1). HRs for all-cause mortality among patients with breast cancer and for cancer-specific mortality in patients with prostate cancer were significantly higher for blacks compared with whites after adjusting for socioeconomic factors, treatment, and patient and tumor characteristics. CONCLUSIONS: Favorable survival was associated with higher socioeconomic status. Racial disparities in survival persisted after adjusting for individual-level socioeconomic factors and treatment for patients with breast and prostate cancer. PMID- 21264828 TI - Minimal social network effects evident in cancer screening behavior. AB - BACKGROUND: Social networks may influence screening behaviors. We assessed whether screening for breast, prostate, or colorectal cancer is influenced by the actual screening behaviors of siblings, friends, spouses, and coworkers. METHODS: We conducted an observational study using Framingham Heart Study data to assess screening for eligible individuals during the late 1990s. We used logistic regression to determine whether the probability of screening for breast, prostate, or colorectal cancer was influenced by the proportion of siblings, friends, and coworkers who had the same screening, as well as spouse's screening for colorectal cancer, adjusting for other factors that might influence screening rates. RESULTS: Among 1660 women aged 41-70 years, 71.7% reported mammography in the previous year; among 1217 men aged 51-70 years, 43.3% reported prostate specific antigen testing in the previous year; and among 1426 men and women aged 51-80 years, 46.9% reported stool blood testing and/or sigmoidoscopy in the previous year. An increasing proportion of sisters who had mammography in the previous year was associated with mammography screening in the ego (odds ratio [OR], 1.034; 95% confidence interval [CI], 1.000-1.065 for each 10% increase). A spouse with recent screening was associated with more colorectal cancer screening (OR, 1.65; 95% CI, 1.39-1.98 vs unmarried). Otherwise, screening behaviors of siblings, friends, and coworkers were not associated with screening in the ego. CONCLUSIONS: Aside from a slight increase in breast cancer screening among women whose sisters were screened and colorectal cancer screening if spouses were screened, the screening behavior of siblings, friends, or coworkers did not influence cancer screening behaviors. PMID- 21264831 TI - Usage of erythropoiesis-stimulating agents in cancer patients at an academic cancer center and experience with specific care management tools for anemia. AB - BACKGROUND: In 2007, the US Food and Drug Administration (FDA) issued regulatory alerts for use of erythropoiesis-stimulating agents (ESAs) in cancer patients with anemia after clinical trials and meta-analysis data found that high ESA doses were associated with adverse outcomes in patients. In response to these findings, specific patient management tools for anemia (consisting in an algorithm and prescribing order set) were developed by a multidisciplinary team at The University of Texas MD Anderson Cancer Center. METHODS: A retrospective study consisted of 7117 patients aged 18 years and older with cancer malignancies who had received an ESA between January 2006 and December 2008 at MD Anderson. Changes in utilization of ESAs and packed red blood cells (PRBCs) were evaluated. RESULTS: The number of ESA doses dispensed each month decreased by 83% from January 2006 to December 2008 (P < .01), and the number of patients who received ESAs decreased by 80% (P < .01). The number of dispensed ESA doses for hemoglobin (Hb) levels >= 12 g/dL decreased significantly from 4% to 0% (P < .01), and the number for >= 10 g/dL decreased from 44% to 12% (P < .01). The PRBC transfusion rate remained stable in solid tumor patients (P > .05) but increased from 7% to 9% (P < .05) in patients with hematologic malignancies. CONCLUSIONS: The authors summarized their experience with use of ESAs in a tertiary oncology center. The implementation of their patient management tools for anemia might have facilitated the observed change at MD Anderson Cancer Center. PMID- 21264830 TI - DNA repair gene polymorphisms and benefit from gefitinib in never-smokers with lung adenocarcinoma. AB - BACKGROUND: The objective of this study was to investigate whether polymorphisms in DNA repair genes affect clinical outcome of never-smokers with lung adenocarcinoma (NSLA). METHOD: Common polymorphisms in the DNA repair genes ribonucleotide reductase M1 (RRM1), excision repair cross-complementation group 1 (ERCC1), and x-ray repair cross-complementing group 1 (XRCC1) were genotyped in DNA samples from 158 patients among 313 NSLA who were randomized to receive either gefitinib or gemcitabine plus cisplatin (GP) as first-line therapy. Immunohistochemistry for ERCC1 (n = 38) and direct sequencing of the epidermal growth factor gene (EGFR) (n = 42) were performed using tumor samples. RESULTS: Patients who had the XRCC1 arginine (Arg)/Arg polymorphism at codon 399 (399Arg/Arg) had a higher response rate to gefitinib (71% vs 36%; P = .002) and had more EGFR-mutant tumors (82% vs 29%; P = .001) than patients who had the glutamine (Gln) allele. Patients who had the ERCC1 adenine-adenine (AA) polymorphism at codon 8092 (8092AA) had a higher response to GP than patients who had the cytosine-cytosine (CC) or the CA genotype (100% vs 44%; P = .043).When gefitinib was compared with GP, significantly longer progression-free survival (PFS) was observed with gefitinib among patients who had the XRCC1 399Arg/Arg genotype (7.5 months vs 6.6 months; P = .013), the RRM1 2464 guanine-guanine (GG) genotype (11.5 months vs 6.0 months; P = .004), and the ERCC1 8092CA genotype (7.5 months vs 6.4 months; P = .024). When the 3 genotypes were analyzed jointly, significantly longer PFS was observed with gefitinib among patients who had >=2 genotypes (8.1 months vs 6.4 months; P = .009), whereas a trend for longer PFS was observed with GP among patients without the 3 genotypes (6.3 months vs 2.0 months; P = .06). In a multivariate Cox regression model, the greater number of specific genotypes independently predicted improved overall survival (hazard ratio, 0.5; 95% confidence interval, 0.3-0.8; P = .006). CONCLUSIONS: Patients with the XRCC1 399Arg/Arg, RRM1 2464GG, and ERCC1 8092CA genotypes did benefit from gefitinib. Having more of these genotypes may predict favorable prognosis for NSLA. PMID- 21264832 TI - Preoperative chemoradiation may not always be needed for patients with T3 and T2N+ rectal cancer. AB - BACKGROUND: Preoperative chemoradiation is becoming the standard treatment for patients with locally advanced rectal cancer. However, since the introduction of total mesorectal excision (TME), local recurrence rates have been reduced significantly, and some patients can be spared from potentially toxic over treatment. The current study was designed to assess the factors that predict recurrence in an institutional series of patients with rectal cancer who had clinical T2 lymph node-positive (cT2N+) tumors or cT3N0/N+ tumors and underwent radical surgery without receiving preoperative chemoradiation. METHODS: Between November 1997 and November 2008, the authors' multidisciplinary group preoperatively staged 398 patients with rectal cancer by using endorectal ultrasonography and/or magnetic resonance imaging. The analysis included 152 consecutive patients with cT2N+, cT3N0, or cT3N+ rectal cancer who underwent TME without receiving preoperative chemoradiation. Macroscopic assessment of the mesorectal excision and circumferential resection margins were determined. Factors potentially related to local recurrence (LR), disease-free survival (DFS) and cancer-specific survival (CSS) were analyzed. RESULTS: After a median follow up of 39 months, the 5-year actuarial LR, DFS, and CSS rates were 9.5%, 65.4%, and 77.8%, respectively, for the whole group. Threatened mesorectal fascia at preoperative staging was the only independent preoperative factor that predicted a higher risk for LR (P = .007), shorter DFS (P = .007), and shorter CSS (P = .05). In particular, the 5-year LR rates for patients with and without preoperative threatened circumferential resection margins were 19.4% and 5.4%, respectively. CONCLUSIONS: The current results suggested that patients with rectal cancer clinically staged as T3N0/N+ or T2N+ with a free margin >2 mm from mesorectal fascia may undergo TME alone, avoiding over treatment with preoperative chemoradiation. PMID- 21264833 TI - Impact of neoadjuvant chemotherapy on breast reconstruction. AB - BACKGROUND: With advances in oncologic treatment, cosmesis after mastectomy has assumed a pivotal role in patient and provider decision making. Multiple studies have confirmed the safety of both chemotherapy before breast surgery and immediate reconstruction. Little has been written about the effect of neoadjuvant chemotherapy on decisions about reconstruction. METHODS: The authors identified 665 patients with stage I through III breast cancer who received chemotherapy and underwent mastectomy at Dana-Farber/Brigham & Women's Cancer Center from 1997 to 2007. By using multivariate logistic regression, reconstruction rates were compared between patients who received neoadjuvant chemotherapy (n = 180) and patients who underwent mastectomy before chemotherapy (n = 485). The rate of postoperative complications after mastectomy was determined for patients who received neoadjuvant chemotherapy compared with those who did not. RESULTS: Reconstruction was performed immediately in 44% of patients who did not receive neoadjuvant chemotherapy but in only 23% of those who did. Twenty-one percent of neoadjuvant chemotherapy recipients and 14% of adjuvant-only chemotherapy recipients underwent delayed reconstruction. After controlling for age, receipt of radiotherapy, and disease stage, neoadjuvant recipients were less likely to undergo immediate reconstruction (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.37, 0.87) but were no more likely to undergo delayed reconstruction (OR, 1.29; 95% CI, 0.75, 2.20). Surgical complications occurred in 30% of neoadjuvant chemotherapy recipients and in 31% of adjuvant chemotherapy recipients. CONCLUSIONS: The current results suggest that patients who receive neoadjuvant chemotherapy are less likely to undergo immediate reconstruction and are no more likely to undergo delayed reconstruction than patients who undergo surgery before they receive chemotherapy. PMID- 21264834 TI - Local control comparison of adjuvant brachytherapy to intensity-modulated radiotherapy in primary high-grade sarcoma of the extremity. AB - BACKGROUND: Based on results of a prospective randomized trial, brachytherapy (BRT) had been the preferred form of adjuvant radiotherapy for patients with high grade extremity soft tissue sarcoma (STS) at our institution. In recent years, intensity-modulated radiotherapy IMRT had been increasingly used. This study compared local control by IMRT versus by BRT in primary-extremity STS. METHODS: Between January 1995 and December 2006, 134 adult patients with high-grade primary nonmetastatic STS of the extremity were treated at this institution with limb-sparing surgery and adjuvant radiotherapy (RT). Low-dose-rate BRT was given to 71 patients between January 1995 and November 2003 to a median dose of 45 Gray (Gy). IMRT was given between February 2002 and December 2006: preoperatively to 10 (50 Gy) and postoperatively to 53 (median, 63 Gy). Median follow-up was 46 months. RESULTS: Treatment groups were comparable in terms of gender, age, site, depth, histology (malignant fibrous histiocytoma vs other), and use of adjuvant chemotherapy. More IMRT patients had positive/close margins (<1 mm), large tumors (>10 cm), and bone or nerve stripping/resection (P = 0.006, 0.005, 0.02, and 0.002, respectively). Median follow-up was 46 months for IMRT and 47 months for BRT. Five-year local control was 92% (95% confidence interval [CI], 85-100) for IMRT versus 81% (95% CI, 71-90) for BRT, P = 0.04. On multivariate analysis, IMRT was the only predictor of improved local control, P = 0.04. CONCLUSIONS: Local control with IMRT was significantly better than BRT despite higher rates of adverse features for IMRT in this nonrandomized comparison. IMRT should be further examined as the treatment of choice for primary high-grade extremity sarcoma. PMID- 21264835 TI - Prognostic roles of human equilibrative transporter 1 (hENT-1) and ribonucleoside reductase subunit M1 (RRM1) in resected pancreatic cancer. AB - BACKGROUND: Pancreatic adenocarcinoma is a malignancy with a dismal prognosis. Previous studies have suggested that in pancreatic cancer, human equilibrative nucleoside transporter 1 (hENT-1) and ribonucleoside reductase subunit M1 (RRM1) expression may have prognostic value as well as predictive value with sensitivity to gemcitabine. This study investigated the prognostic value of hENT-1 and RRM1 expression in resected pancreatic cancer. METHODS: Eighty-four patients who underwent pancreaticoduodenectomy from 2000 to 2005 were included in this study. Patients were followed for a median of 60 months (range, 44-110). Total RNA was isolated from macrodissected paraffin-embedded tumors. hENT-1 and RRM1 expression levels in tumors were evaluated by quantitative reverse transcription-polymerase chain reaction (QRT-PCR), normalized to 2 reference genes, and expressed as DeltaCt (low DeltaCt means high expression). Univariate and multivariable prognostic factors for overall survival (OS) and progression-free survival (PFS) were identified via Cox proportional hazards analysis. RESULTS: Univariate analysis identified hENT-1, overall stage, lymphovascular invasion, perineural invasion, and adjuvant therapy as prognostic factors for both PFS and OS. Multivariate analysis confirmed the association of low expression of hENT-1 (DeltaCt > 0.2027) (P = .007), perineural invasion (P = .021), and lack of adjuvant treatment (P < 0.001) with worse OS. Multivariate analysis also confirmed the association of low expression of hENT-1 (DeltaCt > 0.5391) with worse PFS (P = .016) in addition to overall stage (P = .013), perineural invasion (P = .042), and lack of adjuvant treatment (hazard ratio 2.31, P = .029). RRM1 expression was not associated with OS or PFS in the current cohort. CONCLUSIONS: Low expression of hENT-1 was associated with worse OS and PFS in patients with resected pancreatic adenocarcinoma independent of gemcitabine therapy. PMID- 21264836 TI - Diagnosis and management of dysplasia and cancer of the ileal pouch in patients with underlying inflammatory bowel disease. AB - Approximately 30% of the patients with ulcerative colitis (UC) would ultimately require colectomy for medically refractory UC or UC-associated neoplasia. Restorative proctocolectomy with ileal pouch-anal anastomosis has become the surgical treatment of choice for these patients. However, this procedure does not completely abolish the risk for neoplasia of the pouch. The main risk factor for pouch neoplasia is a preoperative diagnosis of UC-associated dysplasia or cancer. Although the natural history and prognosis of pouch dysplasia are not clear, mortality associated with pouch cancer, once diagnosed, appears to be high. Conversely, not all pouch neoplasia follows the chronic inflammation-dysplasia cancer sequence, which makes pouch endoscopy with biopsy, the current gold standard for surveillance, challenging. In addition, the findings that pouch neoplasia is not common and that pouch endoscopy still misses dysplasia lead to controversy on the need and time interval of routine endoscopic surveillance. However, based on reports in the literature and their own experience, the authors recommend surveillance endoscopy to be performed in patients at risk, such as those with a precolectomy diagnosis of UC-associated neoplasia. This review appraises issues in the prevalence and incidence, risk factors, technical aspects of pouch construction, clinical and pathological features, natural history, surveillance examination, diagnosis, and management of pouch neoplasia. PMID- 21264837 TI - Rhabdomyosarcoma in infants younger than 1 year: a report from the Children's Oncology Group. AB - BACKGROUND: Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children, occurs less commonly in infants. Historically, poorer outcomes have been reported for infants diagnosed with RMS than for older children. METHODS: The authors analyzed the characteristics, treatment administered, outcomes, and patterns of failure for infants aged < 1 year with nonmetastatic RMS who received multimodal therapy on Intergroup Rhabdomyosarcoma Study (IRS) protocols IRS-IV, D9602, and D9803. RESULTS: Seventy-six infants with nonmetastatic RMS were treated on the 3 protocols from 1991 to 2005. Their median age was 7.4 months (range, 0.1-12 months). Tumor histology included embryonal (57%), alveolar (21%), and undifferentiated sarcoma/other (22%). A parameningeal primary tumor site was less common in this infant cohort (3%) than in all patients who were treated on IRS-IV (25%). The estimated 5-year failure-free survival and overall survival rates (95% confidence interval [CI]) were 57% (95% CI, 44%-67%) and 76% (95% CI, 65%-85%), respectively, for infants compared with 81% (95% CI, 79%-83%) and 87% (95% CI, 85%-89%), respectively, for children ages 1 to 9 years. Twenty-three of 32 infants with treatment failure had local recurrence/progression with distant failure (n = 3) or without distant failure (n = 20). The overall local failure rate was 30%. The median time to treatment failure was 13 months. The failure free survival rate was worse for infants who had IRS Group III tumors and for those who received less than protocol-recommended radiation therapy. CONCLUSIONS: Infants with RMS appeared to have worse outcomes than older patients, in part because of high rates of local failure. The authors concluded that concerns regarding morbidity in infants and reluctance to use aggressive local control measures may lead to higher rates of local failure. PMID- 21264838 TI - Combined treatment of nonsmall cell lung cancer NSCLC stage III with intensity modulated RT radiotherapy and cetuximab: the NEAR trial. AB - BACKGROUND: The aim of this study was to evaluate efficacy and toxicity of radioimmunotherapy with intensity-modulated radiation (IMRT) and cetuximab in stage III nonsmall cell lung cancer (NSCLC). METHODS: NEAR was a prospective, monocentric phase II trial including patients unfit for chemoradiation regimen; treatment consisted of IMRT and weekly cetuximab followed by a 13-week maintenance period. Primary endpoints were toxicity and feasibility; secondary endpoints were remission rates at completion of the planned treatment according to Response Evaluation Criteria In Solid Tumor (RECIST), local/distant progression-free survival, and overall survival. RESULTS: Thirty patients (median age, 71 years) were treated within the protocol. Overall response rate was 63% (partial remission: 19 of 30) patients. Median locoregional, distant, overall progression-free survival was 20.5, 10.9, and 8.5 months. Median overall survival was 19.5 months, with an estimated 1- and 2-year survival of 66.7% and 34.9% respectively. Stage (IIIA vs IIIB) and histologic subtype did not have a significant impact on survival rates in our patients. Treatment was tolerated well with only mild toxicity ( degrees 3 pneumonitis: 3.3%, any degrees 3 acute toxicity: 36.7%). CONCLUSIONS: Combined radioimmunotherapy with cetuximab was safe and feasible, especially in elderly patients with multiple comorbidities. A more intensified regimen warranted investigation. PMID- 21264839 TI - Phase 2 trial of bevacizumab, capecitabine, and oxaliplatin in treatment of advanced hepatocellular carcinoma. AB - BACKGROUND: Anti-angiogenesis agents have shown effectiveness in treatment of hepatocellular carcinoma (HCC). It is important to investigate more effective and safe systemic treatment options for patients with advanced HCC. This phase 2 study was designed to determine the efficacy and toxicity of the combination of bevacizumab, capecitabine, and oxaliplatin in patients with advanced unresectable and untransplantable HCC. METHODS: Chemotherapy-naive patients with advanced unresectable and untransplantable HCC were treated with bevacizumab 5 mg/kg and oxaliplatin 130 mg/m(2) on day 1 of each cycle, and capecitabine 825 mg/m2 orally twice a day from days 1 to 14 of a 21-day cycle. RESULTS: Forty patients were enrolled to the study, in which 40% had Child-Pugh B disease. Forty percent had an Eastern Cooperative Oncology Group performance status (PS) of 0, 55% had PS of 1, and 5% had PS of 2. Forty percent of patients had hepatitis B virus infection. The median progression-free survival was 6.8 months (95% CI, 3.4-9.1 months), and the median overall survival was 9.8 months (95% CI, 5.2-12.1 months). Eight patients (20%) achieved partial response; 23 patients had stable disease with overall 77.5% disease control rate. The combination was tolerable with limited grade 3/4 toxicity, mainly peripheral neurotoxicity and fatigue. CONCLUSIONS: The combination appeared effective and safe, and the results were encouraging. Further investigation should be considered. PMID- 21264840 TI - A novel exon 15-deleted, splicing variant of Slit2 shows potential for growth inhibition in addition to invasion inhibition in lung cancer. AB - BACKGROUND: The axon guidance cue molecule Slit2 has been shown to suppress cancer cell invasion. However, the role of Slit2 in growth inhibition is still controversial. The authors identified a novel exon 15 (AKEQYFIP)-deleted slit2, located at the end of the second leucine-rich repeat (LRR2). Because LRR2 interacts with Robo1 receptor to inhibit invasion, they hypothesized that exon 15 plays an important role in modulating Slit2 function. METHODS: Slit2 expression was assessed via microarray analysis in 27 lung adenocarcinomas. Exon 15-deleted slit2 (slit2-DeltaE15) and exon 15-containing slit2 (slit2-WT) were cloned and expressed in the CL1-5 lung cancer cell line. The effect of exon 15 on Slit2 mediated cell growth was evaluated by a xenografted model and in vitro cell growth assays. The effect of exon 15 on Slit2-mediated invasion was analyzed with a modified Boyden chamber in vitro. RESULTS: Tumor growth from CL1-5/Slit2-WT cells was comparable to that from CL1-5 cells bearing empty vector. However, tumor size from CL1-5/Slit2-DeltaE15 cells was much smaller than that from Slit2 WT cells or vector control cells in the xenografted model. In vitro analyses demonstrated that Slit2-WT inhibits invasion of CL1-5 cells. In addition to inhibiting invasion, Slit2-DeltaE15 greatly suppresses cell growth. CONCLUSIONS: The data demonstrated that exon 15 modulates Slit2 function in growth inhibition of lung cancer cells. Because slit2-DeltaE15 splice variant is present in low invasive cancer cells and nontumor lung tissues, loss of this splice variant is an important event in tumor progression and invasion. PMID- 21264841 TI - The impact of symptom interference using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) on prediction of recurrence in primary brain tumor patients. AB - BACKGROUND: Tumor grade, age, extent of resection, and performance status are established prognostic factors for survival in primary brain tumor (PBT) patients. Development of disease-related symptoms is predictive of tumor recurrence in other cancers but has not been reported in the PBT population. METHODS: A cross-sectional sample of 294 PBT patients participated. Progression was based on the radiologist report of the magnetic resonance imaging (MRI). The relation of clinical variables (age, extent of resection, tumor grade, and Karnofsky performance status [KPS]) and MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) mean symptom and interference subscales with progression was examined using logistic regression. RESULTS: The study enrolled more men (60%, n = 175); median age was 46 years. The majority had less than a gross total resection (n = 186, 64%), and a good KPS (KPS >= 90) (N = 208). The majority had a grade 3 or 4 tumor (n = 199) and 24% of patients had recurrence. Tumor grade and activity-related interference were significantly related to progression. Patients with tumor grade 4 were 2.4 times more likely to have recurrence (95% CI, 1.2-5.; P < .015). Patients with significant (ratings of >= 5) activity related interference were 3.8 times more likely to have recurrence (95% CI, 2.14 6.80; P < .001). Mean activity-related score was 4.8 for those with progression on MRI and 2.2 for those with stable disease. CONCLUSIONS: Significant activity related interference and tumor grade were associated with recurrence but not KPS, age, or extent of resection. These results provide preliminary support for the use of symptom interference in assessment of disease status. Because the authors used a cross-sectional sample, future studies evaluating change over time are needed. PMID- 21264842 TI - Insulin-like growth factor-I receptor blockade reduces tumor angiogenesis and enhances the effects of bevacizumab for a human gastric cancer cell line, MKN45. AB - BACKGROUND: Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for tumorigenicity and tumor progression of gastrointestinal cancers. The authors previously reported the success of therapy for gastrointestinal cancers using adenoviruses that expressed dominant-negative IGF-IR (IGF-IR/dn). In addition, it has been demonstrated that IGF-IR signaling affects vascular endothelial growth factor (VEGF) expression in some other types of tumors. The objective of the current study was to evaluate this interaction by studying the roles of IGF-IR in tumor angiogenesis and lymphangiogenesis and their implications for targeted therapy in gastric cancer. METHODS: The impact of IGF signals on the expression of VEGF-A and VEGF-C in a human gastric cancer cell, MKN45, and vascular formation were assessed. The effects of IGF-IR/dn with or without bevacizumab on angiogenesis, lymphangiogenesis, and tumor suppression in mouse xenografts were assessed. RESULTS: IGFs induced the expression of VEGF ligands and up-regulated in vitro vascular vessel formation. IGF-IR/dn reduced VEGF expression, reduced the activation of both protein kinase B (Akt) and mitogen-activated protein kinase (MAPK), and reduced vascular formation, indicating that IGF-IR/dn inhibited tumor growth in mice by inhibiting both angiogenesis and lymphangiogenesis. However, IGF-IR/dn did not affect either blood sugar or body weight in these mice. The combination of IGF-IR/dn and bevacizumab was highly effective against these xenograft tumors, and only this combination resulted in the complete regression of 43% of tumors, reduced the expression of VEGF, and induced apoptosis. CONCLUSIONS: The current results indicated that IGF-IR is involved in angiogenesis and lymphangiogenesis through the modulation of VEGF ligand expression in the gastric cancer cell line MKN45. Targeting IGF-IR in combination with agents that block the VEGF pathway may have therapeutic utility for gastric cancer therapy. PMID- 21264843 TI - Long-term survival after radical prostatectomy versus external-beam radiotherapy for patients with high-risk prostate cancer. PMID- 21264844 TI - Independent and tissue-specific prognostic impact of miR-126 in nonsmall cell lung cancer: coexpression with vascular endothelial growth factor-A predicts poor survival. AB - BACKGROUND: Angiogenesis is pivotal in tumor development. Vascular endothelial growth factor-A (VEGF-A) is considered one of the most important angiogenic factors, but lately several microRNAs (miRs) have been associated with vascular development. miR-126 has been related to tumor angiogenesis and in the regulation of VEGF-A. The authors aimed to investigate the prognostic impact of miR-126 and its co-expression with VEGF-A in nonsmall cell lung cancer (NSCLC) patients. METHODS: Tumor tissue samples from 335 resected stage I to IIIA NSCLC patients were obtained and tissue microarrays (TMAs) were constructed with 4 cores from each tumor specimen. VEGF-A expression was evaluated by immunohistochemistry, and in situ hybridization was used to evaluate the expression of miR-126. RESULTS: In the total material, miR-126 was a significant negative prognostic factor in both univariate (P = .005) and multivariate analyses (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2-2.8, P = .01). Stratified by histology, miR-126 was only significant in squamous cell carcinomas (univariate: P < .001; multivariate: HR 3.1, CI 95% 1.7-5.6, P<.001). Stratified by lymph node status, miR-126 was significant only in the lymph node-positive subgroup (univariate: P<.001; multivariate: HR 4.1, CI 95% 2.0-8.4, P < .001). High miR-126 expression correlated significantly with high VEGF-A expression (P = .037). The co expression of miR-126 and VEGF-A had a significant prognostic impact (P = .002), with 5-year survival rates of 68%, 51%, and 42% for low/low (n = 150), mixed combinations (n = 129), and high/high (n = 35) expression, respectively. CONCLUSIONS: miR-126 is a strong and independent negative prognostic factor in NSCLC, and its prognostic impact appears related primarily to histology and nodal status. PMID- 21264845 TI - Clinical outcome of triple negative breast cancer in BRCA1 mutation carriers and noncarriers. AB - BACKGROUND: Women with BRCA1 mutations develop breast cancer with similar pathologic features to sporadic triple negative (TN) breast cancer, a subtype associated with early disease relapse and poor outcome. The clinical outcome of women with and without BRCA1 mutations who had TN breast cancer treated with conventional chemotherapy were compared. METHODS: Women with stage I to III TN breast cancer who had BRCA1 testing within 36 months of diagnosis and received alkylating chemotherapy were identified from clinical databases and a Specialized Program of Research Excellence (SPORE) specimen bank. BRCA2 mutation carriers were excluded, resulting in a study cohort of 46 BRCA1 carriers and 71 noncarriers. Sites of metastasis, relapse rates, and survival were compared among carriers and noncarriers. The median follow-up was 75 months. RESULTS: BRCA1 carriers were younger at diagnosis (P < .001) and had smaller tumors (P = .03) than noncarriers. Freedom from distant metastasis at 5 years was 76% for carriers and 70% for noncarriers (hazard ratio [HR] 0.79, P = .5). Sites of distant recurrence did not differ significantly (P = .15), although BRCA1 carriers had a propensity for brain relapse (58% vs 24%, P = .06). Overall survival at 5 years was 82% for carriers and 74% for noncarriers (HR 0.64, P = .25). Adjusting for age and stage, BRCA1 mutation status was not an independent predictor of survival (HR 0.73, P = .48). CONCLUSIONS: BRCA1 mutation carriers with TN disease had similar survival rates to noncarriers when treated with alkylating chemotherapy. Women with BRCA1-related breast cancer may benefit from novel therapies that target DNA repair, and further study is needed to identify sporadic TN breast cancers with a BRCA-deficient phenotype. PMID- 21264846 TI - Using breast cancer quality indicators in a vulnerable population. AB - BACKGROUND: Adherence to quality indicators may be especially important to disease-specific outcomes for uninsured, vulnerable patients. The objective of this study was to measure adherence to National Initiative for Cancer Care Quality (NICCQ) breast cancer quality indicators in a public hospital and compare performance to published rates in a previously collected 5-city cohort. METHODS: One hundred five consecutive, newly diagnosed, stage I-III, breast cancer patients at a public hospital (from 2005 to 2007) were identified. Adherence rates to 31 quality indicators were measured by using medical record abstraction. Rates were calculated for individual indicators, aggregated domains, and components of care and were compared with the 5-city cohort results by using a 2 sided test of proportions. RESULTS: Overall adherence to the NICCQ indicators at the public hospital was 82%, versus 86% in the 5-city cohort. Public hospital adherence was better in 3 domains and components (Management of Treatment Toxicity 95% vs 73%, Referrals 76% vs 15%, and Documentation of Key Clinical Factors 72% vs 64%, P < .05 for all), but it was lower in others (Testing 82% vs 96%, Adjuvant Therapy 76% vs 83%, Surgery 72% vs 86%, Surveillance 63% vs 94%, and Respect for Patient Preferences 52% vs 72%, P < .001 for all). CONCLUSIONS: The results showed that it is possible to deliver breast cancer care to vulnerable patients comparable in quality to the care received by the broader population. Further study should identify the factors that lead to variation in adherence across domains of quality. PMID- 21264852 TI - Memory precursor phenotype of CD8+ T cells reflects early antigenic experience rather than memory numbers in a model of localized acute influenza infection. AB - The mechanistic basis of memory T-cell development is poorly defined. Phenotypic markers that define precursors at effector stages have been characterized for acute systemic infections with high antigen load. We asked whether such markers can identify memory precursors from early effectors (d6) to late memory (>d500) for two immunodominant CD8(+) responses during the course of a localized low-load influenza infection in mice. CD8(+) T cells stained with the D(b) NP(366) and D(b) PA(224) tetramers were characterized as IL-7Ralpha(hi) , IL-7Ralpha(hi) CD62L(hi) or IL-7Ralpha(hi) KLRG1(lo) . While the D(b) NP(366) - and D(b) PA(224) -specific responses were comparable in size, decay kinetics and memory precursor frequency, their expansion characteristics differed. This correlated with a divergence in the IL-7Ralpha(hi) , IL-7Ralpha(hi) CD62L(hi) and IL-7Ralpha(hi) KLRG1(lo) phenotypes on effector, but not naive, CD8(+) populations. That effect was abrogated by priming with viruses engineered to present equivalent levels of NP(366) and PA(224) peptides, indicating that memory phenotypes reflect early antigenic experience rather than memory potential. Thus, the IL-7Ralpha(hi) KLRG1(lo) phenotype had a poor predictive value in identifying memory precursors in the spleen and at the site of infection. Greater consistency in influenza specific IL-7Ralpha(hi) KLRG1(lo) CD8(+) T-cell numbers was found in draining lymph nodes, suggesting that this may be the preferential site for memory establishment and maintenance following localized virus infections. PMID- 21264854 TI - Poly(ethylene glycol)-block-poly(2-methyl-2-benzoxycarbonyl-propylene carbonate) micelles for rapamycin delivery: in vitro characterization and biodistribution. AB - Our objective was to synthesize an amphiphilic diblock copolymer for micellar delivery of rapamycin. Poly(ethylene glycol)-block-poly(2-methyl-2 benzoxycarbonyl-propylene carbonate) (PEG-b-PBC) with different hydrophobic core lengths were synthesized from methoxy poly(ethylene glycol) and 2-methyl-2 benzoxycarbonyl-propylene carbonate through ring-opening polymerization using 1,8 diazabicycloundec-7-ene as a catalyst. The critical micelle concentration of PEG b-PBC was around 10(-8) M and depends on the hydrophobic core length. Rapamycin was effectively incorporated into micelles and drug loading increased with increasing hydrophobic core length, with maximal drug loading of 10% (w/w, drug/polymer), drug loading efficiency of about 85%, and mean particle size of around 70 nm. The drug release profile was also dependent on the hydrophobic core length and the drug release from PEG(114) -b-PBC(30) micelles was the slowest. We also determined the toxicity of rapamycin micelles on insulinoma (INS-1E) beta cells and human islets. Encapsulation of rapamycin into PEG-b-PBC micelles reduced its toxicity. Biodistribution of rapamycin-loaded PEG-b-PBC micelles was determined after systemic administration into mice. Rapamycin-loaded PEG-b-PBC micelles showed little difference in pharmacokinetics and biodistribution characteristics in mice compared with rapamycin carrying nanosuspension. In conclusion, rapamycin formulated with PEG-b-PBC micelles showed significantly reduced toxicity on INS-1E beta-cells and human islets, but had similar biodistribution profiles as those of nanosuspensions. PMID- 21264853 TI - Thy-1 (CD90) regulates the extravasation of leukocytes during inflammation. AB - Human Thy-1 (CD90) has been shown to mediate adhesion of inflammatory cells to activated microvascular endothelial cells via interaction with Mac-1 (CD11b/CD18) in vitro. Since there are no data showing the physiological relevance of Thy-1 for the recruitment of inflammatory cells in vivo, different inflammation models were investigated in Thy-1-deficient mice and littermate controls. In thioglycollate-induced peritonitis, the number of neutrophils and monocytes was significantly diminished in Thy-1-deficient mice. During acute lung inflammation, the extravasation of eosinophils and monocytes into the lung was significantly reduced in Thy-1-deficient mice. Moreover, during chronic lung inflammation, the influx of eosinophils and monocytes was also strongly decreased. These effects were independent of Thy-1 expression on T cells, as shown by the transplantation of WT BM into the Thy-1-deficient mice. In spite of the strong Thy-1 expression on T cells in the chimeric mice, the extravasation of the inflammatory cells in these mice was significantly diminished, compared to control mice. Finally, the altered number and composition of infiltrating leukocytes in Thy-1-deficient mice modified the chemokine/cytokine and protease expression at the site of inflammation. In conclusion, Thy-1 is involved in the control of inflammatory cell recruitment and, thus, also in conditioning the inflammatory microenvironment. PMID- 21264855 TI - Post traumatic myositis ossificans: Sonographic findings. AB - PURPOSE: The aim of this paper is to describe the sonographic (US) features of post traumatic myositis ossificans (PTMO). METHODS: Fifteen patients with histopathological diagnosis of PTMO were included. The following US parameters were evaluated: presence of a mass, calcifications, power Doppler signals, and relationship with adjacent structures. RESULTS: Five patients (33.3%) were diagnosed as early PTMO and 10 (66.6%) as mature PTMO. In both early and mature PTMO, US showed an oval hypoechoic mass, without infiltrative borders, located in a muscular belly. In the early phase, a center of less echogenicity was observed, associated with an outer sheet-like hyperechoic peripheral rim, while, in the mature phase, peripheral calcification created more reflections and distal acoustic shadowing was observed. CONCLUSIONS: US is highly sensitive in the detection of PTMO, helps differentiate between PTMO and malignant soft tissue tumors, and can be used for follow-up of the lesions. PMID- 21264856 TI - Characterization of HIV-1 from patients with virological failure to a boosted protease inhibitor regimen. AB - The use of highly active antiretroviral treatment (HAART) regimens with unboosted protease inhibitors (PIs) has resulted in a high level of virological failure primarily due to the development of resistant virus. Current boosted PI regimens combine successfully low-dose ritonavir (r) with a second PI. The aim of the study was to estimate the proportion of patients, in a population based setting, who develop virological failure on a PI/r regimen. Through The Danish HIV Cohort Study 1,007 patients who received PI/r based treatment between 1995 and 2008 were identified. Twenty-three (2.3%) experienced virological failure, of whom 19 (83%) started PI/r treatment before 2001. Patients from Copenhagen (n=19) were selected to study the development of protease (PR) and gag cleavage site (CS) mutations during PI/r treatment and PI plasma levels at the time of virological failure. Three patients (16%) developed major PI resistance mutations. Mutations in the p7/p1 and p1/p6 gag CS only developed in patients with major or minor mutations in PR. Drug concentrations were low or undetectable in 10 out of the 19 patients. In total PR resistance mutations and low drug levels could account for 12 (63%) of the failure cases. In conclusion, virological failure to PI/r is a low and decreasing problem primarily caused by low plasma drug levels and to a lesser extent major PR mutations. Gag CS mutations did not contribute significantly to resistance development and virological failure. PMID- 21264857 TI - KSHV DNA viremia correlates with low CD4+ cell count in Italian males at the time of diagnosis of HIV infection. AB - To evaluate the relevance and the virological and immunological markers of Kaposi sarcoma herpesvirus 8 (KSHV) viremia in Italian male patients at the time of diagnosis of infection with HIV-1, 481 men infected with HIV were recruited consecutively. The presence of KSHV DNA was evaluated in peripheral blood mononuclear cells (PBMCs) and in plasma and correlated with demographic and viro immunological parameters. Seventy-four patients had KSHV DNA detected in PBMCs. By univariate analysis, the presence of KSHV DNA was associated significantly with unprotected homosexual relationships (P=0.003) and it was significantly higher in patients with CD4+ cell <350 (P=0.025). By multivariate analysis, homosexual relationships were associated independently with KSHV DNA in PBMCs (OR: 3.25; 95% CI: 1.1-9.7; P=0.035). Among the 74 patients with KSHV DNA detected in PBMCs, plasma samples from 60 were analyzed and 33 were positive for KSHV DNA. The CD4+ cell counts and percentages were significantly lower in patients with KSHV DNA in both PBMCs and plasma as compared to patients with only KSHV DNA in PBMCs (P=0.006 and P=0.019, respectively). Among the patients with KSHV DNA detected in PBMCs, all 13 patients with CD4+ cells count <200 had detectable levels of KSHV in their plasma. By multivariate analysis adjusted for the epidemiologic and virological parameters, low CD4+ cell count was the only independent variable associated with the presence of KSHV DNA in plasma (OR, 0.001; 95% CI: <0.001-0.001; P=0.03). In HIV-positive antiretroviral therapy naive males, KSHV active replication as detected by KSHV DNA in plasma was associated significantly with low CD4+ cell count. PMID- 21264859 TI - Prevalence of HBV infection among different HIV-risk groups in Hai Phong, Vietnam. AB - Hepatitis B virus (HBV) infection in Hai Phong, northern Vietnam, was characterized by analyzing the prevalence and genotype distribution of HBV as well as co-infection with human immunodeficiency virus type 1 (HIV-1) among five different risk groups for HIV infection. Plasma samples were collected from intravenous drug users (n=760, anti-HIV-1 antibody positive rate: 35.9%), female sex workers (FSWs; n=91, 23.1%), seafarers (n=94, 0%), pregnant women (n=200, 0.5%), and blood donors (n=210, 2.9%) in 2007 [Ishizaki et al. (2009): AIDS Res Hum Retroviruses 25:175-182]. Samples were screened for the hepatitis B surface antigen (HBsAg) and anti-HBs antibody and analyzed genetically. The cumulative HBV incidence rate (HBsAg+anti-HBs) was 53.2% (10.7+42.5%) in intravenous drug users, 51.6% (11.0+40.6%) in FSWs, 54.3% (9.6+44.7%) in seafarers, 50.5% (12.5+38.0%) in pregnant women, and 51.0% (18.1+32.9%) in blood donors; there was no significant difference among these groups. Of 163 HBsAg-positive samples, 113 could be analyzed genetically. Phylogenetic analysis, based on the preS1 region, revealed genotype B4 was most prevalent (90/113; 79.6%), followed by C1 (17.7%), I1 (1.8%), and B2 (0.9%). There was no significant difference in HBV genotype distribution among different HIV infection-risk groups. The prevalence of HBsAg was 10.3% (31/301) in HIV-1-infected individuals and 12.5% (132/1,054) in non-HIV 1-infected individuals, which was not significant. In addition, no significant difference in HBV genotype distribution was observed between HBV/HIV-1 coinfected and HBV mono-infected groups. These results suggest that, although HBV and HIV-1 share modes of transmission, major transmission routes of HBV have been different from those of HIV-1 in Hai Phong, Vietnam. PMID- 21264858 TI - No pol mutation is associated independently with the lack of immune recovery in patients infected with HIV and failing antiretroviral therapy. AB - An investigation was undertaken to determine whether specific pol mutations hinder long-term immune recovery regardless of virological response. In total, 826 patients with >50 HIV RNA copies/ml, who underwent genotypic resistance testing between 1 January 2000 and 31 December 2003 after >3 years of antiretroviral treatment, and were followed up for >3 years after genotypic resistance testing, were analyzed retrospectively. The outcome of the study was the lack of immune recovery after >3 years of follow-up, defined as a slope by linear regression <0. The viremia detectability ratio was defined as the number of HIV RNA values of >50 copies/ml divided by the number of HIV RNA measurements during follow-up. Logistic regression was used for univariable and multivariable analysis. Median (Q1, Q3) values at baseline were the following: age 40 (37, 45) years, years on antiretroviral therapy 4.45 (3.65, 5.47), HIV RNA 3.91 (3.39, 4.53) log(10) copies/ml, CD4+ T-cell 358 (211, 524)/ul. After 3.13 years of follow-up, 375 patients (45.4%) showed a lack of immune recovery. The risk of lack of immune recovery increased independently with increasing baseline CD4+ counts (OR=1.104 per 50-cell increase, 95% CI=1.069-1.142, P<0.0001), increasing viremia detectability ratio during follow-up (OR=1.145 per 0.1-unit increase, 95% CI=1.093-1.202, P<0.0001), and with earlier calendar years of resistance testing (overall effect: P=0.0007). In conclusion, no pol mutation is associated independently with the lack of immune recovery. PMID- 21264860 TI - Gender disparity in distribution of the major hydrophilic region variants of hepatitis B virus genotype C according to hepatitis B e antigen serostatus. AB - Hepatitis B virus (HBV) e antigen (HBeAg) seroconversion during chronic HBV infection is known to play an important role in disease progression and patient response to antiviral agents. The aim of the present study was to analyze gender disparity in distribution of major hydrophilic region (MHR) variants according to HBeAg serostatus. Prevalence of MHR variants from 68 Korean patients with chronic hepatitis (31 HBeAg-positive and 37 HBeAg-negative) was examined in terms of HBeAg serostatus and sex by direct sequencing analysis of the MHR. Gender disparity was observed in the distribution of MHR variants according to HBeAg serostatus. In male patients, the prevalence of MHR variants was significantly higher in HBeAg negative patients than in HBeAg positive patients [58.8% (10/17 patients) vs. 14.3% (3/21 patients), P=0.004]. However, the same was not true in female patients [55.0% (11/20 patients) vs. 60.0% (6/10 patients), P=1.000)]. In addition, 2 mutation types (L110I and G145A) related to HBeAg serostatus were found. In conclusion, HBeAg seroconversion in male chronic patients infected with genotype C could lead to mutations of MHR, major target to host immune response, which might in turn contribute to HBV persistence and immune evasion. PMID- 21264861 TI - Virological and clinical characteristics on reactivation of occult hepatitis B in patients with hematological malignancy. AB - The virological characteristics of hepatitis B virus (HBV) implicated in the reactivation of occult hepatitis B in patients who have received hematopoietic stem-cell transplantation or chemotherapy for the hematological malignancy are not well defined. Twenty-eight HBsAg-negative patients who received hematopoietic stem-cell transplantation and 138 HBsAg-negative patients treated for malignant lymphoma with chemotherapy including rituximab were enrolled. Three of the 28 patients (10.7%) received hematopoietic stem-cell transplantation and one of the 138 (0.72%) patients treated for malignant lymphoma with chemotherapy developed de novo HBV hepatitis. Anti-HBc was detected in four and anti-HBs in two patients. Genotype Bj was detected in two and C in two of they all possessed wild type sequences in the core promoter region. A precore stop mutation (A1896) was detected in a patient with genotype Bj who developed fulminant hepatic failure. HBV DNA was detected in pretreatment HBsAg-negative samples in two of four patients, and the HBV genome sequence identified from sera before chemotherapy and at the time of de novo HBV hepatitis showed 100% homology. In an in vitro replication model, genotype Bj with the A1896 clone obtained from a fulminant case had a replication level much higher than clones obtained from de novo hepatitis B patients with genotype Bj or C with G1896. In conclusion, this is the first report demonstrating de novo hepatitis B from the reactivation of occult HBV infection confirmed by molecular evolutional analysis. The fulminant outcome of HBV reactivation can be associated with genotype Bj exhibiting high replication due to the A1896 mutation. PMID- 21264862 TI - Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated with peginterferon and ribavirin. AB - Previous reports demonstrated that amino acid (aa) substitutions in the hepatitis C virus (HCV) core protein are predictors of non-virological responses to pegylated interferon (Peg-IFN) and ribavirin combination therapy. The aim of this study was to investigate the impact of core aa substitutions on viral kinetics during the treatment and relapse after the treatment. The 187 patients with HCV genotype 1 enrolled in this study were categorized into four groups according to core aa substitution patterns: double-wild group (n=92), Arg70/Leu91; 70-mutant group (n=42), Gln70/Leu91; 91-mutant group (n=31), Arg70/Met91; and double-mutant group (n=22), Gln70/Met91. The relationship between the core aa substitutions and the virological response was examined. Multivariate logistic regression analyses showed that substitution at aa 70 was significantly associated with a poor virological response during the first 12 weeks (decline of <1 log from baseline at week 4, <2 log at week 12), and substitution at aa 91 was significantly associated with detectable HCV RNA at week 24. With respect to relapse, only the ribavirin exposure (odds ratio (OR), 0.77; 95% confidence interval (CI), 0.60 0.98) and HCV RNA disappearance between weeks 13 and 24 (OR, 23.69; 95% CI, 5.44 103.08) were associated independently with relapse, with no correlation being found with the core aa substitutions and relapse. In conclusion, the results showed that core aa substitutions can be strong predictive factors at pretreatment of the non-response, but not for relapse, for virological responders with HCV RNA disappearance during treatment. PMID- 21264863 TI - Phylogenetic investigation of nosocomial transmission of hepatitis C virus in an oncology ward. AB - Nosocomial hepatitis C virus (HCV) infections have been reported from different health-care settings worldwide. Twenty patients, treated at the same oncology department, with no previous record of hepatitis C infection, tested positive for anti-HCV antibodies between November 2007 and June 2008. Twelve of the newly infected patients were found to be HCV RNA positive. The common origin of the infections was assumed. To investigate the relatedness of the detected viral strains phylogenetic analyses were performed using sequences from the NS5B and E1/E2 genome regions. A patient carrying HCV for years was also involved in the study. She was treated at the same oncology department and was considered a possible infectious source. The previous HCV carrier harbored subtype 1b, while all other patients were infected with subtype 1a. Sequences from the 12 newly infected patients formed two groups. The viral sequences within the groups were very closely related. A greater evolutionary distance was observed between the two groups; however, their relatedness could be demonstrated by sequences from both regions with high statistical support. The results indicated that nosocomial transmission occurred. The phylogenetic analyses suggested that the viruses originated from a common source, possibly a patient carrying highly divergent variants. This presumed infectious source could not be identified in the course of this study. The genotype distribution of Hungarian control sequences included in the analysis confirmed this conclusion, since HCV genotype 1a was found to be relatively uncommon. PMID- 21264864 TI - Influence of HCV genotype 1 subtypes on the virus response to PEG interferon alpha-2a plus ribavirin therapy. AB - New factors that influence the viral response in HCV non-genotype 2/3 patients must be identified in order to optimize anti-HCV treatment. This multicenter prospective study evaluates the influence of HCV variability and pharmacological parameters on the virological response of these patients to pegylated interferon alpha2a (peg-IFN-alpha2a: 180 ug/week) and ribavirin (RBV; 800-1,200 mg/day) for 48 weeks. HCV subtypes were identified by sequencing the NS5B region. Serum RBV and peg-IFN-alpha2a concentrations were measured at weeks 4 and 12. The 115 patients (67 men; median age = 49, range 31-76) included 64 who had never been treated and 27 co-infected with HIV. The mean baseline HCV RNA was 6.30 +/- 0.06 log IU/ml and the HCV genotypes were: G1 (n = 93) with 1a (n = 37) and 1b (n = 50), G4 (n = 20) and G5 (n = 2). Most patients (79/108; 73%) had an early virological response. Independent predictors of an early virological response were interferon naive patients (OR= 2.98, 95% CI: 1.15-7.72) and RBV of >2,200 ng/ml at week 12 (OR = 3.41, 95% CI: 1.31-8.90). Forty of 104 patients (38%) had a sustained virological response. The only independent predictors of a sustained virological response were subtype 1b (OR = 6.82, 95% CI: 1.7-26.8), and HCV RNA <15 IU/ml at week 12 (OR = 25, 95% CI: 6.4-97.6). Thus a serum RBV concentration of >2,200 ng/ml was associated with an early virological response and patients infected with HCV subtype 1b had a better chance of a sustained virological response than did those infected with subtype 1a. PMID- 21264865 TI - Sequences in the interferon sensitivity-determining region and core region of hepatitis C virus impact pretreatment prediction of response to PEG-interferon plus ribavirin: data mining analysis. AB - The aim of the present study was to clarify the significance of viral factors for pretreatment prediction of sustained virological response to pegylated-interferon (PEG-IFN) plus ribavirin (RBV) therapy for chronic hepatitis C using data mining analysis. Substitutions in the IFN sensitivity-determining region (ISDR) and at position 70 of the HCV core region (Core70) were determined in 505 patients with genotype 1b chronic hepatitis C treated with PEG-IFN plus RBV. Data mining analysis was used to build a predictive model of sustained virological response in patients selected randomly (n = 304). The reproducibility of the model was validated in the remaining 201 patients. Substitutions in ISDR (odds ratio = 9.92, P < 0.0001) and Core70 (odds ratio = 1.92, P = 0.01) predicted sustained virological response independent of other covariates. The decision-tree model revealed that the rate of sustained virological response was highest (83%) in patients with two or more substitutions in ISDR. The overall rate of sustained virological response was 44% in patients with a low number of substitutions in ISDR (0-1) but was 83% in selected subgroups of younger patients (<60 years), wild-type sequence at Core70, and higher level of low-density lipoprotein cholesterol (LDL-C) (>= 120 mg/dl). Reproducibility of the model was validated (r(2) = 0.94, P < 0.001). In conclusion, substitutions in ISDR and Core70 of HCV are significant predictors of response to PEG-IFN plus RBV therapy. A decision tree model that includes these viral factors as predictors could identify patients with a high probability of sustained virological response. PMID- 21264866 TI - Prevalence of human papillomavirus among women with normal cervical cytology in Kuwait. AB - This study was undertaken to determine the prevalence and type specific distribution of human papillomavirus (HPV) in women with normal cervical cytology in Kuwait. The study is the first of its type in Kuwait and one of few in the Middle East. The age specific distribution of HPV types was determined in 3,011 ThinPrep samples taken from women seeking routine gynaecological care. ThinPrep samples were screened for HPV DNA by real-time PCR. The type specific distribution of the viruses was determined by PCR-based sequencing. The results showed that HPV DNA was detected in 71 women (2.4%), and 21 different HPV genotypes were detected, comprising eight high-risk (HR) (16, 31, 33, 53, 56, 58, 66, and 73), seven low-risk (LR) (6, 11, 54, 61, 70, 81, and 90), four intermediate-risk (IR) (67, 82, 83, and 84) and HPV 102 and HPV 106. LR HPV types were found in 71.8% of infected samples, HR types in 32.3%, and IR types in 7%. With regard to age, 40.8% of all HPVs were found in women 30-39 years of age, 29.6% in women 40-49 years of age, 19.7% in women over 50 years and 9.9% in women less than 34 years old. The study shows that the prevalence of HPV infection in Kuwait is among the lowest in the world and suggests that HPV vaccine could prevent the development of HPV associated cervical cancer in 1.39% of young females living in Kuwait. However, more extensive population-based studies should be undertaken before implementing HPV vaccination. PMID- 21264867 TI - Prevaccination genomic diversity of human papillomavirus genotype 11: a study on 63 clinical isolates and 10 full-length genome sequences. AB - Prevaccination genomic diversity of human papillomavirus genotype 11 (HPV 11) was established by sequencing 40% of the genome of 63 clinical isolates obtained from an ethnogeographically closed Caucasian cohort, and full-length genome sequencing of the ten most divergent isolates. In the study, which included the largest number of isolates to date, by analyzing pooled L1, LCR, E6, E5a, and E5b sequences (3,217 bp) of an individual isolate, a total of 23 genomic variants were identified, of which three (5 isolates) and twenty (58 isolates) corresponded to prototypic and non-prototypic variant groups, respectively. Several novel, potentially important mutations are described. Full-length genome sequences of ten isolates revealed more than 99% similarity to the HPV 11 prototype isolate. The minimum genomic distance between the full-length sequences of genomic variants and the prototype was 3 point mutations and 2 inserts and the maximum distance 31 point mutations, one insertion and one deletion. Within the ethnogeographically closed cohort investigated in this study, HPV 11 was shown to be less polymorphic in comparison to the majority of HPV genotypes studied to date. PMID- 21264869 TI - Coxsackievirus B3-associated aseptic meningitis: an emerging infection in Hong Kong. AB - Enterovirus (EV) infection is a common disease of childhood and associated not uncommonly with aseptic meningitis. In the summer of 2008, laboratory surveillance has detected increased number of coxsackievirus B3 (CVB3) associated aseptic meningitis in Hong Kong, constituting 11.6% of those infected. This study analyzed the epidemiology, circulating pattern, and clinical presentations of CVB3 in Hong Kong over the last 10 years with reference to the circulation of EV in the locality. Enteroviruses (EV) were isolated from respiratory, cerebrospinal fluid (CSF), stool, and vesicular samples using human rhabdomyosarcoma, human laryngeal carcinoma (HEp2-C), human lung fibroblast (MRC-5), and African green monkey kidney (Vero) cell lines. Virus isolates were identified and characterized by indirect immunofluorescence (IF) using monoclonal antibodies (mAB), neutralization test as well as partial VP1 sequencing. Different from previous years, IF test result showed that majority of the isolates from 2008 were untypeable by the mAB suggesting antigenic change. Sequence analysis revealed that these isolates were clustered with recent isolate from Fuyang, China. Review of data from 1999 to 2008 showed increased activity of CVB3 in the years 2005 and 2008, and isolates in these 2 years displayed an amino acid change from threonine to alanine at codon 277 of the VP1 gene, which may be associated with central nervous system (CNS) disease. PMID- 21264868 TI - Analytical and clinical performances of a restriction fragment mass polymorphism assay for detection and genotyping of a wide spectrum of human papillomaviruses. AB - Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry-based restriction fragment mass polymorphism (RFMP) assay was adapted to human papillomavirus (HPV) genotyping. The analytical sensitivity and the clinical utility were evaluated by testing defined HPV genome equivalents and a total of 426 specimens composed of normal cytology, atypical squamous cells of undetermined significance, low grade squamous intraepithelial lesion, high grade squamous intraepithelial lesion and invasive squamous cell carcinoma. The RFMP assay was able to detect 38.4-114.6 genomic equivalents of a wide variety of HPV types. The RFMP assay detected 34 different HPV genotypes in cervical samples of which 8% were found to be multiple-type infections. The high-risk HPV positivity rate according to the histological diagnosis was 7.9% (8/101), 31.7% (38/120), 50% (55/110), 86% (37/43), 96.2% (50/52) in normal, atypical squamous cells of undetermined significance, low grade squamous intraepithelial lesion, high grade squamous intraepithelial lesion and squamous cell carcinoma subgroups, respectively. Diagnostic sensitivities/specificities for the cervical lesions of squamous cell carcinoma and high grade squamous intraepithelial lesion or worse histology were found to be 96.2%/92.1% and 91.6%/92.1%, respectively. The sensitivity, accuracy, wide range of genotype identification and high-throughput capacity with cost-effectiveness of the test consumables make the RFMP assay suitable for mass screening and monitoring of HPV-associated cervical cancer. PMID- 21264870 TI - Algorithm based on CMV kinetics DNA viral load for preemptive therapy initiation after hematopoietic cell transplantation. AB - Preemptive therapy in hematopoietic cell transplantation is initiated by a diagnostic technique at first detection of cytomegalovirus (CMV). The aim of this study was to use the viral dynamics of CMV DNA viral to start preemptive therapy, and to prospectively compare the CMV viral load kinetics to pp65 antigenemia. Two hundred sixty-three blood samples were collected prospectively from 93 patients. All clinical decisions regarding use of preemptive therapy were based on CMV antigenemia. Based on the positivity of the antigen assay and clinical CMV outcome in allotransplant patients, an optimal threshold of 3.05 log 10 (1,130 copies/ml) was found to discriminate patients who required preemptive therapy and those who did not (sensitivity, 71%; specificity, 65%). A DNAemia level increase of 2.24 log 10 (174 copies/ml) per day was the optimal threshold to discriminate between patients who required preemptive therapy and those who did not (sensitivity, 93%; specificity, 43%). Sensitivity of PCR assay was 92.4% compared with 39% for the antigen assay (P < 0.001). A standardized real-time PCR assay is more appropriate than the antigen assay for detecting CMV. It allowed earlier diagnosis of active CMV infection and monitoring of the response to anti-CMV treatment. PMID- 21264871 TI - Hantavirus infection during a stay in a mountain hut in Northern Slovakia. AB - Hantaviruses in Europe cause human hemorrhagic fever with renal syndrome (HFRS) with various degree of severity. The most severe form is caused by the Dobrava/Belgrade virus (DOBV), associated with the rodent Apodemus flavicollis. During the last decade cases of infection caused by DOBV have been reported in Central Europe. The present study is a report on two Czech patients with severe HFRS who were infected during their stay in a mountain hut in Northern Slovakia. The two patients, combined with a third case observed in the same year in a nearby village in the Czech Republic, suggest that this region in Central Europe has to be considered as endemic for HFRS. PMID- 21264872 TI - Target epitopes of HTLV-1 recognized by class I MHC-restricted cytotoxic T lymphocytes in patients with myelopathy and spastic paraparesis and infected patients with autoimmune disorders. AB - Human T-cell lymphotropic virus type I (HTLV-1) causes adult T-cell leukemia/lymphoma and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The different patterns of clinical diseases are thought to be linked to immunogenetic host factors. A variety of autoimmune diseases, such as Sjogren's syndrome, have been reported in persons infected with HTLV-1, although the precise relationship between these disorders and HTLV-1 infection remains unknown. There is no report on the repertoire of HTLV-1-specific CD8+ T-cells in HAM/TSP patients or carriers with autoimmune diseases, both characterized by an abnormal immune state. In this study, to characterize HTLV-1-specific CD8+ T cells in asymptomatic HTLV-1 carriers, HAM/TSP patients and carriers with autoimmune diseases, we examined the frequency and diversity of HTLV-1-specific CD8+ T-cells using HTLV-1 tetramers. HTLV-1 Env-specific CD8+ T-cells were significantly more frequent in HAM/TSP and carriers with autoimmune diseases compared with asymptomatic HTLV-1 carriers, while the frequency of HTLV-1 Tax specific CD8+ T-cells was not significantly different among them. CD8+ cells binding to HTLV-1 Tax tetramers in carriers with autoimmune diseases were significantly reduced compared with HAM/TSP patients. This study demonstrates the importance of CD8+ T-cells recognizing HTLV-1 Env-tetramers in HAM/TSP patients and carriers with autoimmune diseases, thereby suggesting that the diversity, frequency and repertoire of HTLV-1 Env-specific CD8+ T-cell clones may be related to the hyperimmune response in HAM/TSP and carriers with autoimmune diseases, although different immunological mechanisms may mediate the hyperimmunity in these conditions. PMID- 21264873 TI - Correlation of polymerase replication fidelity with genetic evolution of influenza A/Fujian/411/02(H3N2) viruses. AB - Influenza virus evolves continuously through mutations presumed to result from evolutionary pressure driving viral replication. This study examined the relationship between the genetic evolution and replication fidelity of influenza viruses. Analysis of influenza sequences from National Centre for Biotechnology Information (NCBI) database revealed a gradual decrease in the rate of genetic evolution of A/Fujian/411/02(H3N2)-like variants after the emergence and predominance of the A/H3N2 Fujian strain in 2002. This decrease may be related to an increase in replication fidelity, which was investigated by assessing mutation frequencies of reassortant viruses carrying the PB1 segment of Fujian variants isolated between 2003 and 2005 in a sequencing-based plaque assay. The data revealed a threefold decrease in substitution per site of the reassortant viruses carrying the Fujian PB1 segments isolated in 2004-2005 compared with those circulating in 2003. The decrease in mutation frequency paralleled a decrease in genetic evolution of the Fujian variants from the NCBI database. This correlation implicates changes in the polymerase replication fidelity as contributing to altered genetic evolution of influenza viruses. PMID- 21264874 TI - Epidemiological and phylogenic study of human metapneumovirus infections during three consecutive outbreaks in Normandy, France. AB - Human metapneumovirus (hMPV) is responsible for respiratory tract disease, particularly in the young and elderly population. An epidemiological and phylogenic study was performed on children admitted to hospital with an acute lower respiratory tract infection (LRI). Data were obtained and analyzed over three consecutive winters, from 2002-2003 to 2004-2005. Each year during the winter period, from November to March, 2,415 nasal swabs were tested by a direct immunofluorescence assay (DFA) for influenza viruses A and B, respiratory syncytial virus, parainfluenza viruses, and adenoviruses. Rhinoviruses, enteroviruses, and coronaviruses OC43 and 229E were detected by RT-PCR. A RT-PCR designed for the M gene was performed on negative samples for hMPV detection and phylogenic analyses. For the three consecutive winters, hMPV represented 10%, 22.6%, and 8.8% of virus-negative samples, respectively. In most cases, clinical symptoms indicated a LRI with a final diagnosis of bronchiolitis. During the winter of 2003-2004, all viral clusters (A1, A2, B1, and B2) that circulated in France shifted progressively from the A group to the B group. This study determined the prevalence of hMPV in Normandy, its clinical impact and permitted the analysis of the molecular evolution during the successive outbreaks. PMID- 21264875 TI - Prevalence of norovirus GII-4 antibodies in Finnish children. AB - Noroviruses (NoVs) are the second most common cause of viral gastroenteritis after rotavirus in children. NoV genotype GII-4 has emerged as the major type not only in outbreaks of NoV gastroenteritis but also endemic gastroenteritis among infants and young children worldwide. Using baculovirus-insect cell system virus like particles (VLPs) of NoV genotype GII-4 and an uncommon genotype GII-12 were produced. These VLPs were used in enzyme-linked immunosorbent assays (ELISA) for detection of NoV-specific immunoglobulin G (IgG) and IgA antibodies in 492 serum specimens from Finnish children 0-14 years of age collected between 2006 and 2008. NoV IgG antibody prevalence was 47.3% in the age group 7-23 months and increased up to 91.2% after the age of 5 years. Avidity of NoV IgG antibodies was low in the primary infections while high avidity antibodies were detected in the recurrent infections of the older children. In GII-4 infections, the homologous antibody response to GII-4 VLPs was stronger than to GII-12 VLPs but cross reactivity between GII-4 and GII-12 was observed. Binding of GII-4 VLPs to a putative carbohydrate antigen receptor H-type 3 could be blocked by sera from children not infected with NoV during a waterborne outbreak of acute gastroenteritis. Therefore, protection against NoV infection correlated with strong blocking activity. PMID- 21264876 TI - Sequencing and phylogenetic analysis of the coding region of six common rotavirus strains: evidence for intragenogroup reassortment among co-circulating G1P[8] and G2P[4] strains from the United States. AB - The segmented genome of rotaviruses provides an opportunity for rotavirus strains to generate a large genetic diversity through reassortment; however, this mechanism is considered to play little role in the generation of mosaic gene constellations between Wa-like and DS-1-like strains in genes other than the neutralization antigens. A pilot study was undertaken to analyze these two epidemiologically important strains at the genomic level in order to (i) identify intergenogroup reassortment and (ii) to make available additional reference genome sequences of G1P[8] and G2P[4] for future genomics analyses. The full or nearly complete coding region of all 11 genes for 3 G1P[8] (LB2719, LB2758, and LB2771) and 3 G2P[4] (LB2744, LB2764, and LB2772) strains isolated from children hospitalized with severe diarrhea in Long Beach, California, where these strains were circulating at comparable rates during 2005-2006 are described in this study. Based on the full-genome classification system, all G1P[8] strains had a conserved genomic constellation: G1-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-E1-H1 and were mostly identical to the few Wa-like strains whose genome sequences have already been determined. Similarly, the genome sequences of the 3 G2P[4] strains were highly conserved: G2-P[4]-I2-R2-C2-M2-A2-N2-T2-E2-E2-H2 and displayed an overall lesser genetic divergence with reference DS-1-like strains. While intergenogroup reassortment was not seen between the G1P[8] and G2P[4] strains studied here, evidence for intragenogroup reassortment events was identified. Similar studies in the post-rotavirus genomic era will help uncover whether intergenogroup reassortment affecting the backbone genes could play a significant role in any potential vaccine breakthrough events by evading immunity of vaccinated children. PMID- 21264877 TI - A first report on the characterization of rotavirus strains in Sierra Leone. AB - In an effort to reduce the high mortalities associated with rotavirus infections, a number of African countries are considering introducing human rotavirus vaccines. The demonstrated safety and efficacy of the live-attenuate human rotavirus vaccines in several clinical trials worldwide has accelerated such initiatives. Although the percentage-mortality rates for Sierra Leone are top of the list for rotavirus-associated deaths in Africa, no study has reported the prevalent strains circulating within this country. In this study, stool specimens were collected from 128 Sierra Leonean children presenting with diarrhea in 2005. Almost 37.5% (48/128) were rotavirus positive by EIA, of which 89.6% (43/48) revealed a short electropherotype, and a further 6.98% (3/48) could not be assigned a PAGE pattern. Genotyping analysis revealed G2P[4] (30.23%), G2P[6] (13.95%), G8P[6] (11.63%), G2P[8] (4.65%), G8P[4] (4.65%), and G8P[8] (2%) strains. About 11% were only assigned VP7 genotypes (G2), while 20.9% had mixed G and P types. The frequent detection of G2 rotaviruses could be of concern considering data generated from some studies that suggests lower efficacy of Rotarix(r) vaccine against G2 rotaviruses. This underscores the need for extensive and continuous regional strain surveillance to support rotavirus vaccines introduction and guide future vaccine development efforts. Such information will be useful before considering administration of specific rotavirus vaccine candidates in countries like Sierra Leone where little is known about circulating rotavirus strains. PMID- 21264879 TI - Polarizable protein packing. AB - To incorporate protein polarization effects within a protein combinatorial optimization framework, we decompose the polarizable force field AMOEBA into low order terms. Including terms up to the third-order provides a fair approximation to the full energy while maintaining tractability. We represent the polarizable packing problem for protein G as a hypergraph and solve for optimal rotamers with the FASTER combinatorial optimization algorithm. These approximate energy models can be improved to high accuracy [root mean square deviation (rmsd) < 1 kJ mol( 1)] via ridge regression. The resulting trained approximations are used to efficiently identify new, low-energy solutions. The approach is general and should allow combinatorial optimization of other many-body problems. PMID- 21264878 TI - Hematological effects of zidovudine prophylaxis in newborn infants with and without prenatal exposure to zidovudine. AB - Postnatal prophylaxis with oral zidovudine (ZDV) is associated with hematological effects. However, it is still unknown whether selection of non-ZDV-based regimens in pregnancy may reduce hematological toxicity associated with postnatal ZDV prophylaxis. The aim of this study was to define the hematological effects of ZDV prophylaxis in newborns with and without prenatal exposure to ZDV. Sixty-five newborns from mothers infected with HIV who, during pregnancy, received HAART regimens with (n:44) and without (n:21) ZDV were evaluated. Virological and hematological data were compared at birth and at 4 weeks and 6 months of life. Newborns with prenatal ZDV exposure had significantly worse hematological values at birth, with lower levels of hemoglobin (14.3 g/dl vs. 16.2 g/dl, P=0.001), red blood cell count (3.45 * 10(6) cells/mm(3) vs. 4.48 * 10(6) cells/mm(3), P<0.001), and hematocrit (41.0% vs. 46.8%, P<0.001), and higher values of mean corpuscular volume (119 fl vs. 103 fl, P<0.001). The start of ZDV prophylaxis determined significantly greater adverse hematological changes in newborns without prenatal ZDV exposure, and at 4 weeks and 6 months of life the two groups had substantially identical hematological values. The selection of non-ZDV-based regimens in pregnancy does not reduce the final hematological effects of postnatal ZDV at 4 weeks and at 6 months of life. However, two distinct pathways may be observed: newborns exposed prenatally to ZDV have worse hematological values at birth, while newborns without prenatal ZDV exposure have particularly marked postnatal effects. The distinct effects of these two pathways should be considered. PMID- 21264880 TI - Theoretical mechanistic study on the reaction of CN radical with HNCN. AB - The mechanism for the reaction of the cyanogen radical (CN) with the cyanomidyl radical (HNCN) has been investigated theoretically. The electronic structure information of the singlet and triplet potential energy surfaces (PESs) is obtained at the B3LYP/6-311+G(3df,2p) level, and the single-point energies are refined at the CCSD(T)/6-311+G(3df,2p) level as well as by multilevel MCG3-MPWB method. The calculations show that the C atom of CN additions to middle- and end N atoms of HNCN are two barrierless association processes leading to the energy rich intermediates IM1 HN(CN)CN and IM2 HNCNCN, respectively, on the singlet PES. The higher barriers of the subsequent isomerization and dissociation channels from IM1 and IM2 indicate that these two intermediates, which have considerably thermodynamic and kinetic stability, are the dominant product at high pressure. While at low pressure, the most favorable product is P(2) H + NCNCN, which will be formed from both IM1 and IM2 via direct dissociation processes by the H-N bond rupture, and the secondary feasible product is P(4) HCN + (1) NCN, while P(5) HCCN + N(2) and P(6) HCNC + N(2) are the least competitive products. On the triplet PES, P(14) NCNC + HN may be a comparable competitive product at high temperature. In addition, the comparison between the mechanisms of the CN + HNCN and OH + HNCN reactions is made. The present results will enrich our understanding of the chemistry of the HNCN radical in combustion processes and interstellar space. PMID- 21264883 TI - Low-level chronic exposure to cadmium enhances the risk of long bone fractures: a study on a female rat model of human lifetime exposure. AB - In the present paper, the hypothesis that low chronic exposure to cadmium (Cd) enhances the risk of long bone fractures was investigated in a female rat model simulating human lifetime exposure in non-Cd-polluted areas. For this purpose, the femur and both tibias of control female rats and those exposed to Cd (1 mg Cd I(-1) in drinking water for 24 months since weaning) were assigned to geometric, densitometric (bone mineral content, BMC, and density, BMD), radiographic and biomechanical studies as well as assessing their chemical composition. The exposure to Cd disturbed mineralization (decreased BMD and minerals content, including calcium, magnesium, zinc, copper and iron) and weakened the biomechanical strength of the femur and tibia, enhancing their fragility. The Z score values for the BMD revealed osteopenia of the femur and tibia in 20 and 30% of the Cd-exposed female rats, respectively, and osteoporosis in 80 and 70%, respectively. In 30% of the Cd-exposed animals, femoral neck fracture was evident in the radiographic picture. The findings seem to confirm the hypothesis that a low exposure to Cd during the lifetime may be an important risk factor for osteoporosis and fractures of long bones, and especially for femoral neck fracture in elderly women. The results indicate that greater attention should be paid to Cd as an environmental risk factor for the increasing rate of osteoporosis and bone fractures in old population. PMID- 21264884 TI - Mutagenicity of industrial wastewaters collected from two different stations in northern India. AB - Mutagenicity of wastewaters taken from two different cities was compared by means of Ames plate test and Ames fluctuation test. TA100 and TA98 strains of S. typhimurium exhibited the highest sensitivity against the Saharanpur sample (SWW) in terms of the slope (m) of the dose-response curve in the plate incorporation assay. However, the most sensitive strain against the test samples from Aligarh (AWW) was TA98. Interestingly, TA100 and TA98 strains also displayed the highest susceptibility towards the samples from Saharanpur in the fluctuation test. However, TA102 and TA100 responded maximally to AWW in this bioassay. Interestingly, S9 supplementation resulted in the decline in mutagenic potential of SWW contrary to significant increase with AWW by both the tests. Both samples were found to generate different types of ROS as predominant species. While SWW were shown to generate a high concentration of superoxide radicals and hydrogen peroxide, hydroxyl radicals were predominantly occurring in AWW. From our result, we conclude that both the test water samples were highly genotoxic. In view of the complementary nature of these two testing systems, we recommend both bioassays for the genotoxicity assessment of complex water samples. PMID- 21264886 TI - Inhibitory effect of nordihydroguaiaretic acid on beta-catenin/Tcf signalling in beta-catenin-activated cells. AB - Activated beta-catenin/T-cell factor (Tcf) signalling plays a role in human carcinogenesis. We identified the inhibitory effect of nordihydroguaiaretic acid (NDGA) against beta-catenin/Tcf signalling in beta-catenin activated cells. NDGA inhibited the transcriptional activity of beta-catenin/Tcf in HEK293 cells transiently transfected with a constitutively active mutant beta-catenin gene. To investigate the inhibitory mechanism, electrophoresis mobility shift assay, immunoprecipitation and Western blot experiments were performed. The shift assay showed that the binding of Tcf complexes with its specific DNA-binding sites was suppressed by NDGA. Immunoprecipitation analysis also showed that the binding of beta-catenin to Tcf-4 was also disrupted by NDGA. Western blot analysis showed a decreased level of beta-catenin in nucleus caused by NDGA. NDGA did not decrease phosphorylation of Akt and GSK3beta. Taken together, these results suggest that the NDGA acts as a negative regulator of beta-catenin/Tcf signalling and its inhibitory mechanism is related to the decreased binding of beta-catenin/Tcf complexes to consensus DNA. PMID- 21264887 TI - Proteomics analysis of methylglyoxal-induced neurotoxic effects in SH-SY5Y cells. AB - Reactive carbonyl compounds contribute to aging, Alzheimer's disease (AD) and other neurodegenerative diseases. Among these compounds, methylglyoxal (MG) can yield advanced glycation end products (AGEs), which are crucial in AD pathogenesis. However, the molecular and biochemical mechanisms of MG neurotoxicity are not completely understood. In the present study, SH-SY5Y cells were treated with MG to induce cell death. 2-D Fluorescence Difference Gel Electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry were employed to determine the changes in protein levels in these cells compared with vehicle-treated cells. Proteomics analysis revealed that 49 proteins were differentially expressed in MG-treated SH-SY5Y cells, of which 16 were upregulated and 33 were downregulated. Among them, eight proteins were identified unambiguously. The significant changes in protein levels of actin, immunoglobulin lambda light chain and protein phosphatase 2 were noteworthy given their functional roles in AD pathogenesis. Taken together, our results suggest that multiple pathways are potentially involved in MG-induced neuron death. PMID- 21264888 TI - Both base excision repair and nucleotide excision repair in humans are influenced by nutritional factors. AB - Lack of reliable assays for DNA repair has largely prevented measurements of DNA repair from being included in human biomonitoring studies. Using newly developed modifications of the comet assay we tested whether a fruit- and antioxidant-rich plant-based intervention could affect base excision repair (BER) and nucleotide excision repair (NER) in a group of 102 male volunteers. BER and NER repair capacities were measured in lymphocytes before and after a dietary intervention lasting 8 weeks. The study had one control group, one group consuming three kiwifruits per day and one group consuming a variety of antioxidant-rich fruits and plant products in addition to their normal diet. DNA strand breaks were reduced following consumption of both kiwifruits (13%, p = 0.05) and antioxidant rich plant products (20%, p = 0.02). Increased BER (55%, p = 0.01) and reduced NER (-39%, p < 0.01) were observed in the group consuming a wide variety of plant products. Reduced NER was also observed in the kiwifruit group (-38%, p = 0.05), but BER was not affected in this group. Here we have demonstrated that DNA repair is affected by diet and that modified versions of the comet assay can be used to assess activity of different DNA repair pathways in human biomonitoring studies. PMID- 21264889 TI - Taurine supplementation decreases oxidative stress in skeletal muscle after eccentric exercise. AB - Infrequent exercise, typically involving eccentric actions, has been shown to cause oxidative stress and to damage muscle tissue. High taurine levels are present in skeletal muscle and may play a role in cellular defences against free radical-mediated damage. This study investigates the effects of taurine supplementation on oxidative stress biomarkers after eccentric exercise (EE). Twenty-four male rats were divided into the following groups (n = 6): control; EE; EE plus taurine (EE + Taurine); EE plus saline (EE + Saline). Taurine was administered as a 1-ml 300 mg kg(-1) per body weight (BW) day(-1) solution in water by gavage, for 15 consecutive days. Starting on the 14th day of supplementation, the animals were submitted to one 90-min downhill run session and constant velocity of 1.0 km h(-1) . Forty-eight hours after the exercise session, the animals were killed and the quadriceps muscles were surgically removed. Production of superoxide anion, creatine kinase (CK) levels, lipoperoxidation, carbonylation, total thiol content and antioxidant enzyme were analysed. Taurine supplementation was found to decrease superoxide radical production, CK, lipoperoxidation and carbonylation levels and increased total thiol content in skeletal muscle, but it did not affect antioxidant enzyme activity after EE. The present study suggests that taurine affects skeletal muscle contraction by decreasing oxidative stress, in association with decreased superoxide radical production. PMID- 21264890 TI - Lipopolysaccharide enhances asymmetrical production of cytokines and nitric oxide by left and right cerebral cortical microglial cells in BALB/C mice. AB - Lipopolysaccharide (LPS)-induced inflammatory factors production by the cerebral cortical glial cells in two sides of the murine brain are different. To determine if microglial cells, a subset of glial cells, are involved in asymmetric production, interleukin-6 (IL-6), interleukin-1beta (IL-1beta) and nitric oxide (NO) responses to LPS by microglial cells in the right and left cerebral cortices were examined. Primary microglial cells were isolated from BALB/C neonatal mice, treated with LPS (10 ug ml(-1) ) for 24 h and examined for IL-6, IL-1beta and NO production. At untreated state, the levels of IL-6, IL-1beta and NO showed no statistical difference between left and right. However, after LPS treatment, the levels of IL-6, IL-1beta and NO for the right microglial cells was statistically significant higher than the left (P < 0.05). Our results denote that enhanced production of IL-6, IL-1beta and NO after LPS treatment in microglia is directly proportional to their basal-state levels, and right cortical microglia produce higher levels of IL-6, IL-1beta and NO than left cortical microglia. PMID- 21264891 TI - Correction of glycaemia and GLUT1 level by mildronate in rat streptozotocin diabetes mellitus model. AB - Anti-ischaemic drug mildronate suppresses fatty acid metabolism and increases glucose utilization in myocardium. It was proposed that it could produce a favourable effect on metabolic parameters and glucose transport in diabetic animals. Rats with streptozotocin diabetes mellitus were treated with mildronate (100 mg/kg daily, per os, 6 weeks). Therapeutic effect of mildronate was monitored by measuring animal weight, concentrations of blood glucose, insulin, blood triglycerides, free fatty acids, blood ketone bodies and cholesterol, glycated haemoglobin per cent (HbA1c%) and glucose tolerance. GLUT1 mRNA and protein expression in kidneys, heart, liver and muscles were studied by means of real time RT-PCR and immunohistochemistry correspondingly. In the streptozotocin + mildronate group, mildronate treatment caused a significant decrease in mean blood glucose, cholesterol, free fatty acid and HbA1c concentrations and improved glucose tolerance. Induction of streptozotocin diabetes mellitus provoked increase of both GLUT1 gene and protein expression in kidneys, heart and muscle, mildronate treatment produced normalization of the GLUT1 expression levels. In the liver a similar effect was observed for GLUT1 protein expression, while GLUT1 gene expression was increased by mildronate. Mildronate produces therapeutic effect in streptozotocin diabetes model. Mildronate normalizes the GLUT1 expression up-regulated by streptozotocin diabetes mellitus in kidneys, heart, muscle and liver. Copyright (c) 2011 John Wiley & Sons, Ltd. PMID- 21264892 TI - Crosstalk of EGF-directed MAPK signalling pathways and its potential role on EGF induced cell proliferation and COX-2 expression in human mesenchymal stem cells. AB - Epidermal growth factor (EGF) promotes proliferation in human mesenchymal stem cells (hMSCs) during in vitro propagation. In this study, we investigated the effects of PI3K/AKT, ERK1/2, P38 and JNK on EGF signalling in hMSCs. The effects of EGF on MAPKs and PI3K/AKT crosstalk were investigated by immunoblotting; cyclooxygenase-2 (COX-2) expression was studied by real-time RT-PCR; and cell proliferation was evaluated by methylthiazolyl tetrazolium bromide assay. Our results showed that EGF immediately activated all four pathways, induced proliferation and increased COX-2 expression. Interestingly, inhibition of PI3K/AKT-enhanced EGF-stimulated ERK1/2 activity, and inhibition of ERK1/2 and JNK reduced AKT phosphorylation. Furthermore, EGF-induced proliferation as well as EGF-augmented COX2 expression was hindered by ERK1/2 and p38 inhibitors. The results of this study provide evidences to be used in extended proliferation of hMSCs for cell therapy. PMID- 21264893 TI - The effect of acute hyperoxia in vivo on NF kappa B expression in human PBMC. AB - The mechanisms of hyperbaric oxygen (HBO) therapy have not been fully elucidated. It is presumed that breathing 100% oxygen at pressure generates free radicals and the cellular response to these may confer protection. A crucial signalling molecule, nuclear transcription factor kappa B (NFkappaB), translocates from the cytoplasm to the nucleus and activates a raft of pathways in response to various stimuli, and plays a role in inflammatory processes. This study focussed upon the expression of NFkappaB in isolated human peripheral blood mononuclear cells (PBMC) following HBO. Ten healthy male volunteers underwent a single HBO treatment, breathing 100% oxygen at a pressure of 2.8 ATA for 1 h. EDTA blood samples were taken pre-, post- and 4-h post-HBO. PBMC were isolated, nuclear extracts prepared and assayed using a NFkBp50 transcription factor ELISA. Mean NFkappaB expression of 0.27 (0.20-0.34, 95%CI) absorbance units (mg protein)(-1) was observed pre-HBO and this increased to 0.29 (0.20-0.38, 95%CI) immediately post-HBO. A significant increase in NFkappaB expression within PBMC was observed 4-h post-HBO, in comparison to pre-HBO (mean 0.38, 0.30-0.47, 95%CI, p = 0.027). This study demonstrates that HBO induces NFkappaB activation in human PBMC, which could be a crucial step in the mechanism of HBO treatment. PMID- 21264894 TI - A two-part model for reference curve estimation subject to a limit of detection. AB - Reference curves are commonly used to identify individuals with extreme values of clinically relevant variables or stages of progression which depend naturally on age or maturation. Estimation of reference curves can be complicated by a technical limit of detection (LOD) that censors the measurement from the left, as is the case in our study of reproductive hormone levels in boys around the time of the onset of puberty. We discuss issues with common approaches to the LOD problem in the context of our pubertal hormone study, and propose a two-part model that addresses these issues. One part of the proposed model specifies the probability of a measurement exceeding the LOD as a function of age. The other part of the model specifies the conditional distribution of a measurement given that it exceeds the LOD, again as a function of age. Information from the two parts can be combined to estimate the identifiable portion (i.e. above the LOD) of a reference curve and to calculate the relative standing of a given measurement above the LOD. Unlike some common approaches to LOD problems, the two part model is free of untestable assumptions involving unobservable quantities, flexible for modeling the observable data, and easy to implement with existing software. The method is illustrated with hormone data from the Third National Health and Nutrition Examination Survey. PMID- 21264895 TI - Sickle cell anemia pathophysiology: back to the data. PMID- 21264896 TI - Reconstructing sickle cell disease: a data-based analysis of the "hyperhemolysis paradigm" for pulmonary hypertension from the perspective of evidence-based medicine. AB - The "hyperhemolytic paradigm" (HHP) posits that hemolysis in sickle disease sequentially and causally establishes increased cell-free plasma Hb, consumption of NO, a state of NO biodeficiency, endothelial dysfunction, and a high prevalence of pulmonary hypertension. The basic science underpinning this concept has added an important facet to the complexity of vascular pathobiology in sickle disease, and clinical research has identified worrisome clinical issues. However, this critique identifies and explains a number of significant concerns about the various HHP component tenets. In addressing these issues, this report presents: a very brief history of the HHP, an integrated synthesis of mechanisms underlying sickle hemolysis, a review of the evidentiary value of hemolysis biomarkers, an examination of evidence bearing on existence of a hyperhemolytic subgroup, and a series of questions that should naturally be applied to the HHP if it is examined using critical thinking skills, the fundamental basis of evidence-based medicine. The veracity of different HHP tenets is found to vary from true, to weakly supported, to demonstrably false. The thesis is developed that the HHP has misidentified the mechanism and clinical significance of its findings. The extant research questions identified by these analyses are delineated, and a conservative, evidence-based approach is suggested for application in clinical medicine. PMID- 21264897 TI - Mechanisms of erythropoiesis inhibition by malarial pigment and malaria-induced proinflammatory mediators in an in vitro model. AB - One of the commonest complications of Plasmodium falciparum malaria is the development of severe malarial anemia (SMA), which is, at least in part, due to malaria-induced suppression of erythropoiesis. Factors associated with suppression of erythropoiesis and development of SMA include accumulation of malarial pigment (hemozoin, PfHz) in bone marrow and altered production of inflammatory mediators, such as tumor necrosis factor (TNF)-alpha, and nitric oxide (NO). However, studies investigating the specific mechanisms responsible for inhibition of red blood cell development have been hampered by difficulties in obtaining bone marrow aspirates from infants and young children, and the lack of reliable models for examining erythroid development. As such, an in vitro model of erythropoiesis was developed using CD34+ stem cells derived from peripheral blood to examine the effects of PfHz, PfHz-stimulated peripheral blood mononuclear cell (PBMC)-conditioned media (CM-PfHz), TNF-alpha, and NO on erythroid cell development. PfHz only slightly suppressed erythroid cell proliferation and maturation marked by decreased expression of glycophorin A (GPA). On the other hand, CM-PfHz, TNF-alpha, and NO significantly inhibited erythroid cell proliferation. Furthermore, decreased proliferation in cells treated with CM-PfHz and NO was accompanied by increased apoptosis of erythropoietin-stimulated CD34+ cells. In addition, NO significantly inhibited erythroid cell maturation, whereas TNF-alpha did not appear to be detrimental to maturation. Collectively, our results demonstrate that PfHz suppresses erythropoiesis by acting both directly on erythroid cells, and indirectly via inflammatory mediators produced from PfHz-stimulated PBMC, including TNF-alpha and NO. PMID- 21264898 TI - Case-control study of risk factors of myelodysplastic syndromes according to World Health Organization classification in a Chinese population. AB - Risk factors of mydelodysplastic syndromes (MDS) remain largely unknown. We conducted a hospital-based case-control study consisting of 403 newly diagnosed MDS patients according to World Health Organization classification and 806 individually gender and age-matched patient controls from 27 major hospitals in Shanghai, China, to examine relation of lifestyle, environmental, and occupational factors to risk of MDS. The study showed that all MDS (all subtypes combined) risk factors included anti tuberculosis drugs [odds ratio (OR)(adj) = 3.15; 95% confidence interval (CI) = 1.22-8.12] as an independent risk factor, benzene (OR(adj) = 3.73; 95% CI = 1.32-10.51), hair dye use (OR = 1.46; 95% CI = 1.03-2.07), new building and renovations (OR = 1.69; 95% CI = 1.11-2.00), pesticides (OR = 2.16; 95% CI = 1.22-3.82), and herbicides (OR = 5.33; 95% CI = 1.41-20.10) as relative risk factors. Risk factors of MDS subtype refractory cytopenia with multiple dysplasia (RCMD) were benzene (OR(adj) = 5.99; 95% CI = 1.19-30.16) and gasoline (OR(adj) = 11.44; 95% CI = 1.31-100.03) as independent risk factors, and traditional Chinese medicines (OR = 2.17; 95% CI = 1.15-4.07), pesticides (OR = 2.92; 95% CI = 1.37-6.25), and herbicides (OR = 12.00; 95% CI = 1.44-99.67) as relative risk factors. Smoking tobacco was significantly associated with refractory anemia with excess of blasts (RAEB) (OR(adj) = 2.43; 95% CI = 1.02-5.77). Education is shown as an independent protective factor against all MDS (OR(adj) = 0.90; 95% CI = 0.83-0.99) and RCMD (OR(adj) = 0.89; 95% CI = 0.79-0.99). These findings suggest that multiple modifiable behavioral, environmental, and occupational factors play a role in MDS etiology, and various MDS subtypes may have different susceptibility. PMID- 21264899 TI - Classical Hodgkin's lymphoma arising in different host's conditions: pathobiology parameters, therapeutic options, and outcome. AB - Epidemiologic and molecular findings suggest that classical Hodgkin's lymphoma (CHL) is not a single disease but consists of more than one entity and may occur in different clinical settings. This review analyzes similarities and disparities among CHL entities arising in different host's conditions with respect to pathobiology parameters, therapeutic options, and outcome. For the purpose of this analysis, CHL entities have been subdivided according to the immune status of the host. In nonimmunosuppressed hosts, according to the age, CHL include pediatric, adult, and elderly forms, whereas, in immunosuppressed hosts, according to the type of immunosuppression, CHL include human immunodeficiency virus (HIV)-associated, iatrogenic, and post-transplant types. CHL entities in different settings are similar in morphology of neoplastic cells, expression of activation markers, and aberrations/activation of NFKB, JAK/STAT, and P13K/AKT pathways, but differ in the association with Epstein-Barr virus (EBV) infection, persistent B-cell phenotype, and cellular background composition. Large B-cell lymphomas resembling CHL may also be observed in the same clinical settings. These lesions, however, do not fulfill the diagnostic criteria of CHL and clinically display a very aggressive behavior. In this article, current treatment options for the CHL entities, especially for elderly CHL and HIV-associated CHL, are specifically reviewed. ABVD remains the gold standard both in nonimmunosuppressed or immunosuppressed hosts even if there are several data suggesting a possible improvement in outcome using the aggressive BEACOPP regimen in advanced stages. Refractory CHL, a clinical condition that may occur throughout the entire spectrum of CHL, is discussed separately. PMID- 21264900 TI - Immunoglobulin light chain amyloidosis: 2011 update on diagnosis, risk stratification, and management. AB - Immunoglobulin (Ig) light chain amyloidosis is a clonal but nonproliferative plasma cell disorder in which fragments of an Ig light chain are deposited in tissues. The clinical features depend on the organs involved but can include restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, and peripheral/autonomic neuropathy. Tissue biopsy stained with Congo red demonstrating amyloid deposits with apple-green birefringence is required for diagnosis. Invasive organ biopsy is not required because amyloid deposits can be found in bone marrow biopsy or subcutaneous fat aspirate in 85% of patients. N terminal pro-brain natriuretic peptide and serum troponin T values are used to classify patients into three groups of approximately equal size; median survivals are 26.4, 10.5, and 3.5 months, respectively. All patients with a visceral amyloid syndrome require therapy to prevent deposition of amyloid in other viscera and to prevent progressive organ failure of involved sites. Stem cell transplant (SCT) is a preferred technique, but only 20% of patients are eligible. Requirements for safe SCT include mild or no cardiac involvement, troponin T value <0.06 ng/mL, age younger than 70 years, <3 organs involved, and serum creatinine value <=1.7 mg/dL. Nontransplant candidates can be offered melphalan dexamethasone. Pomalidomide appears to have activity, as do other combinations of chemotherapy with agents such as cyclophosphamide-thalidomide-dexamethasone, bortezomib-dexamethasone, and melphalan-prednisone-lenalidomide. Late diagnosis remains a major obstacle to initiating effective therapy when organ dysfunction is still recoverable. Recognizing the presenting syndromes is necessary for improvement in survival. PMID- 21264901 TI - Diagnosis of beta thalassemia major from bone marrow morphology. PMID- 21264902 TI - Venous limb gangrene and fatal hemorrhage: adverse consequences of HIT "overdiagnosis" in a patient with antiphospholipid syndrome. AB - This unfortunate patient case highlights the problems with "overdiagnosis" of HIT. Despite "positive" tests for HIT antibodies, the low pretest probability for HIT and the known propensity of patients with APS to yield false-positive HIT antibody results suggests that the patient did not have a true diagnosis of HIT. Moreover, the early administration of warfarin and the choice of argatroban for parenteral anticoagulation when monitoring was hindered by a prolonged baseline aPTT likely play a key factor in the progression of UE DVT to VLG. Ironically, the problems of anticoagulant monitoring posed by the prolonged baseline aPTT likely contributed to the subsequent overanticoagulation and fatal pulmonary hemorrhage. With benefit of hindsight, avoiding the temptation to test for HIT in a low pretest probability situation, and treatment with either heparin using anti factor Xa monitoring or with non-aPTT-monitored therapy such as LMWH or fondaparinux would likely have resulted in a more favorable clinical course. PMID- 21264903 TI - Hemophagocytic tumor cells in carcinosarcoma bone marrow metastasis. PMID- 21264904 TI - Relapsing acute myeloid leukemia beginning with a penile localization. PMID- 21264905 TI - Bone marrow trephine biopsy findings in B acute lymphoblastic leukaemia of early precursor (Pro-B) subtype. PMID- 21264906 TI - City of Hope Cancer Center hematology-oncology fellowship and hematopoietic stem cell transplantation fellowship. PMID- 21264907 TI - Evaluation of the free alpha-hemoglobin pool in red blood cells: a new test providing a scale of beta-thalassemia severity. AB - beta-Thalassemias are characterized by an imbalance of globin chains with an excess of alpha-chains which precipitates in erythroid precursors and red blood cells (RBCs) leading to inefficient erythropoiesis. The severity of the disease correlates with the amount of unpaired alpha-chains.Our goal was to develop a simple test for evaluation of the free alpha-hemoglobin pool present in RBC lysates. Alpha-Hemoglobin Stabilizing Protein (AHSP), the chaperone of alpha-Hb, was used to trap excess a-Hb. A recombinant GST-AHSP fusion protein was bound to an affinity micro-column and then incubated with hemolysates of patients. After washing, the alpha-Hb was quantified by spectrophotometry in the elution fraction. This assay was applied to 54 patients: 28 without apparent Hb disorder, 20 beta-thalassemic and 6 alpha-thalassemic. The average value of free alpha-Hb pool was 93 +/- 21 ppm (ng of free alpha-Hb per mg of Hb subunits)in patients without Hb disorder, while it varies from 119 to 1,756 ppm, in beta-thalassemic patients and correlated with genotype. In contrast,the value of the free alpha-Hb pool was decreased in alpha-thalassemic patients (65 +/- 26 ppm). This assay may help to characterize beta-thalassemia phenotypes and to follow the evolution of the globin chain imbalance(alpha/beta+gamma ratio) in response to treatment. PMID- 21264908 TI - Health-related quality of life in adults with sickle cell disease (SCD): a report from the comprehensive sickle cell centers clinical trial consortium. AB - Adults with Sickle Cell Disease (SCD) experience multiple disease-related complications, but few studies have examined relationships between these events and health-related quality of life (HRQOL). We determined the number and type of previous or co-occurring SCD-related complications and their reported HRQOL in a cohort of 1,046 adults from the Comprehensive Sickle Cell Centers (CSCC). Participants had a median age of 28.0 years (48% male, 73% SS or Sbeta0 thalassemia) and had experienced several SCD-related complications (mean 3.8 +/- 2.0), which were influenced by age, gender, and hemoglobinopathy type (P < 0.0001). In multivariate models, increasing age reduced all SF-36 scales scores (P < 0.05) except mental health, while female gender additionally diminished physical function and vitality scale scores (P < 0.01). Of possible complications, only vaso-occlusive crisis, asthma, or avascular necrosis diminished SF-36 scale scores. Chronic antidepressants usage predominantly diminished scores on bodily pain, vitality, social functioning, emotional role, and mental health scales, whereas chronic opioid usage diminished all scale scores (P < 0.01). Our study documents substantial impairment of HRQOL in adults with SCD that was influenced by only a few of many possible medical complications. It suggests that more effective treatments of persistent pain and depression would provide the largest HRQOL benefit. PMID- 21264909 TI - Risk factors for early-onset and late-onset post-transplant lymphoproliferative disorder in kidney recipients in the United States. AB - Solid-organ transplant recipients have an elevated risk for some malignancies because of the requirement for immunosuppression [1]. In particular, non Hodgkin's lymphoma (NHL) is common and comprises one end of a spectrum of post transplant lymphoproliferative disorder (PTLD) ranging from benign hyperplasia to lymphoid malignancy [2]. PTLD risk is influenced by the type of organ transplanted, the age and Epstein-Barr virus (EBV) serostatus of the transplant recipient, and the intensity of immunosuppression [3-9]. PTLD incidence is high immediately after transplantation, decreases subsequently, and then rises again 4 5 years from transplantation [10,11]. This incidence pattern suggests the presence of separate early-onset and late-onset PTLD subtypes. Early-onset PTLDs tend to be EBV-positive and, when extranodal, are more likely than late-onset PTLDs to be localized to the transplanted organ [12,13]. Late-onset PTLD is less likely to be associated with EBV and, overall, is more likely than early-onset PTLD to be extranodal [13,14]. The Scientific Registry of Transplant Recipients (SRTR) includes data on a large number of solid-organ transplant recipients in the United States and information on malignancies diagnosed post-transplantation. We used these data to conduct a retrospective cohort study among kidney transplant recipients to examine differences in risk factors between early-onset PTLD and late-onset PTLD. PMID- 21264910 TI - Pre-eminence and persistence of immature natural killer cells in acute myeloid leukemia patients in first complete remission. AB - Despite substantial progress in the treatment of AML, a proportion of patients do not achieve first complete remission (1(st) CR) with the induction chemotherapy, and, among patients achieving it, a majority is expected to relapse within three years. As allogeneic hematopoietic stem cell transplantation has been established as the most effective form of antileukemic therapy in patients with AML in remission, many studies have focused on the reconstitution and the functionality of the innate immune system in this context, especially regarding cytotoxic effectors such as natural killer (NK) cells. On the contrary, very few data are available concerning the innate immune system of patients in 1st CR. Herein we investigated the phenotype of autologous NK cells of AML patients in 1st CR. We showed that immature NK cells were pre-eminent in the blood of these patients and that this immature phenotype was persistent during the first months after 1st CR. PMID- 21264911 TI - In vivo T-cell depletion with pretransplant low-dose antithymocyte globulin is associated with reduced transplant-related mortality and improved clinical outcome in patients receiving allogeneic hematopoietic stem cell transplantation from unrelated and partially matched related donors. AB - Graft versus host disease (GVHD) represents one of the major limiting factors to the successful applicability of hematopoietic stem cells transplantation (HSCT). In particular, allogeneic HSCT from alternative donors with unmanipulated graft results in an increased risk of both acute and chronic GVHD compared with matched sibling donor transplants [1]. At the present, none of the GVHD prophylactic strategies currently in use, including calcineurin inhibitors [2], T-lymphocyte depletion, and monoclonal antibodies [3,4], have been proven to be of superior efficacy over another. PMID- 21264912 TI - Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. AB - The U.S.-wide prevalence of venous thromboembolism (VTE) is unclear, with reported VTE incidence estimates varying widely. This retrospective analysis of healthcare claims data from patients in the Thomson Reuters national MarketScan((r)) Commercial and Medicare databases (January 2002-December 2006) estimates the U.S. prevalence of VTE, and assesses associated temporal trends. Of 12.7 million study-eligible patients, 200,007 had VTE. The overall prevalence of VTE (cases per 100,000) increased by 33.1% during the study period: from 317 in 2002 to 422 in 2006. VTE was more prevalent in women than men throughout the study. The annual prevalence of VTE increased with age: 1,382 in patients >=65 years versus 231 in patients <65 (2006 data). The number of U.S. adults with VTE is projected to more than double from 0.95 million in 2006 to 1.82 million in 2050. These data confirm that VTE remains a major healthcare burden in the US, particularly among the elderly, and highlight a continuing increase in prevalence of the disease. Greater efforts are required to improve awareness of VTE and improve standards of VTE prevention in healthcare organizations. PMID- 21264913 TI - Severe sickle cell anemia is associated with increased plasma levels of TNF-R1 and VCAM-1. AB - Sickle cell anemia (SCA, HBB glu6val) is characterized by multiple complications and a high degree of phenotypic variability: some subjects have only sporadic pain crises and few acute hospitalizations, while others experience multiple serious complications, high levels of morbidity, and accelerated mortality [1]. The tumor necrosis factor-alpha (TNF-alpha) signaling pathway plays important roles in inflammation and the immune response; variation in this pathway might be expected to modify the overall severity of SCA through the pathway's effects on the vascular endothelium [2,3]. We examined plasma biomarkers of TNF-alpha activity and endothelial cell activation for associations with SCA severity in 24 adults (12 mild, 12 severe). Two biomarkers, tumor necrosis factor-alpha receptor 1 (TNF-R1) and vascular cell adhesion molecule-1 (VCAM-1) were significantly higher in subjects with severe SCA. Along with these biomarker differences, we also examined data from a genome-wide association study (GWAS) using SCA severity as a disease phenotype, and found evidence of genetic association between disease severity and a single nucleotide polymorphism (SNP) in VCAM1, which codes for VCAM-1, and several SNPs in ARFGEF2, a gene involved in TNF-R1 release [4]. PMID- 21264914 TI - Hypereosinophilia, JAK2V617F, and Budd-Chiari syndrome: who is responsible for what? AB - Budd-Chiari syndrome (BCS) is characterized by hepatic venous outflow obstruction, which sometimes may be life threatening, with the development of fulminant hepatic failure. In cases of this kind, the most frequent underlying cause of BCS, myeloproliferative neoplasms (MPN), should always be excluded first, and molecular analysis of the Janus Kinase 2 (JAK2) mutation must always be performed [1]. While the association of BCS with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis is well documented, hypereosinophilia has only been described in sporadic cases [2-7]. Furthermore, Jak2 mutation in association with hypereosinophilia has been reported very rarely and its prevalence in this disorder still requires further investigation [8,9]. To the best of our knowledge, cases with the above association occurring together with BCS have not been reported until now. Here, we describe a young woman presenting with idiopathic eosinophilia, JAK2 mutation, and BCS. We also elaborate briefly on the biological mechanism and clinical features of this rare entity. In our opinion, this case supports the formal inclusion of hypereosinophilic syndrome (HES) in the WHO MPN category and also raises the possible pathogenetic contribution of eosinophils, or their products, in MPN associated splanchnic vein thrombosis. PMID- 21264915 TI - High-dose glucocorticoids improve renal failure reversibility in patients with newly diagnosed multiple myeloma. AB - One-fifth of the newly diagnosed multiple myeloma (MM) patients present with renal failure (RF) [1-3]. Glucocorticoids (GCs) may improve RF in MM by (1) rapid reduction of paraprotein production, (2) lessening inflammation and fibrosis in renal parenchyma, and (3) decreasing serum calcium level. We hypothesized that lower dose GCs may be less effective in restoring renal function and retrospectively compared the RF reversibility between the newly diagnosed MM patients who were treated with GCs equivalent to >=160 mg DX over 4 days (high dose GC group, n = 16) versus those who were treated with <160 mg (low-dose/no GC group, n = 8). There was no difference in age, baseline calcium, and creatinine levels between the two groups. Renal function was restored in seven patients in the high-dose GC group (44%) and in none of the patients in the low-dose/no GC group (P = 0.026). The only other factor found to impact the RF reversibility was the delay of GC initiation. Four and 1 patients developed a severe infection in the high- and low-dose/no GC groups, respectively. The use of higher dose GCs in the newly diagnosed MM patients who present with RF increases the likelihood of renal function restoration. PMID- 21264916 TI - Clinical impact of absolute lymphocyte count on day 30 after unmanipulated haploidentical blood and marrow transplantation for pediatric patients with hematological malignancies. AB - Currently, limited information is available regarding the effects of early lymphocyte recovery on transplant outcomes in pediatric patients with hematological malignancies after unmanipulated haploidentical transplantation. In this study, we evaluated the association of Day 30 absolute lymphocyte count (ALC 30) with transplant outcomes in 60 consecutive pediatric patients with hematological malignancies receiving T-cell-repleted transplantation from an haploidentical related donors. After median follow-up of 36 months (range, 1.4-75 months), higher relapse rate was observed in patients with an ALC-30 < 300 cells/MUL compared to patients with an ALC-30 >= 300 cells/MUL (35.5% vs. 13.8%, P = 0.049). More patients died of infections in those with an ALC-30 < 300 cells/MUL compared with patients with an ALC-30 >= 300 cells/MUL (25.8% vs. 3.4%, P = 0.015). The ALC-30 above the cutoff value 300 cells/MUL was associated with improved overall-survival (HR 0.301, 95% CI 0.117-0.771; P = 0.012), leukemia free survival (HR 0.195, 95% CI 0.078-0.498; P=0.002), less relapse (HR 0.224 95% CI 0.070-0.717; P = 0.012), and less transplant- related mortality (HR=0.166; 95%CI 0.037-0.750; P = 0.020). Our results suggest that a higher ALC-30 >= 300 cells/MUL) could be a useful and simple tool to predict pediatric patients with a superior outcome after unmanipulated haploidentical transplantation. PMID- 21264917 TI - Alpha- and beta-synucleins are new diagnostic tools for acute erythroid leukemia and acute megakaryoblastic leukemia. AB - alpha-Synuclein is a key component of the Lewy body, a large globular protein complex that forms in the nervous system of patients with Parkinson disease and other dementias [1-3]. Since alpha-synuclein also occurs in megakaryocytic and erythroid lineages [4-7], we wondered what role synucleins had in the hematopoietic system. Therefore, we studied the expression of alpha-, beta-, and gamma-synucleins in a comprehensive panel of patient bone marrows and leukemic cell lines. We observed under expression of alpha-synuclein in the megakaryocytes of myeloproliferative neoplasm (MPN), but not normal reactive marrow (NRM) or myelodysplastic syndrome (MDS). Conversely, we observed over expression of beta synuclein in the blasts of megakaryoblastic leukemias (MegL), but not acute myeloid leukemia (AML) or erythroleukemia (EryL), suggesting that alpha- and beta synucleins could be useful adjunct markers for the early detection of MDS and the differential diagnosis of EryL and MegL from other AMLs. PMID- 21264918 TI - Recurrent miscarriages: caution regarding development of clinical trials using low molecular weight heparin and pregnancy. PMID- 21264919 TI - Variability of bone marrow morphology in G6PC3 mutations: is there a genotype phenotype correlation or age-dependent relationship? PMID- 21264920 TI - Levels of miR-29b do not predict for response in patients with acute myelogenous leukemia treated with the combination of 5-azacytidine, valproic acid, and ATRA. PMID- 21264924 TI - Measuring knowledge of the insanity defense: scale construction and validation. AB - Given the influence of social conformity and prejudice, defendants pleading not guilty by reason of insanity face the significant challenges of securing fair and impartial juries. Attitudes and knowledge of the insanity defense are factors that may influence levels of impartiality. In the light of this, we set out to develop a scale to examine knowledge levels of the insanity defense and their influence on decision-making. Two studies were conducted to construct a scale designed to assess laypersons' knowledge of the insanity defense. Items measuring knowledge of the insanity defense were based on Perlin's (1995) insanity defense myths. The first study identified particular items in need of revision and subscales that required the development of additional items in order to improve reliability and construct validity in the second study. The second study used the revised scale, demonstrating improved validity and reliability. The scale also had acceptable predictive validity with reference to insanity defense verdicts. PMID- 21264925 TI - Stalkers and harassers of British royalty: an exploration of proxy behaviours for violence. AB - Study of risk factors for violence to prominent people is difficult because of low base rates. This study of harassers of the royal family examined factors suggested in the literature as proxies for violence--breaching security barriers, achieving proximity, approach with a weapon, and approach with homicidal ideation. A stratified sample of different types of approach behaviour was randomly extracted from 2,332 Royalty Protection Police files, which had been divided into behavioural types. The final sample size was 275. Significant differences in illness symptomatology and motivation were found for each proxy group. Querulants were significantly over-represented in three of the four groups. There was generally little overlap between the proxy groups. There is no evidence of the proxy items examined being part of a "pathway to violence". Different motivations may be associated with different patterns of risk. Risk assessment must incorporate knowledge of the interactions between motivation, mental state, and behaviour. PMID- 21264926 TI - Exploring separable components of institutional confidence. AB - Despite its contemporary and theoretical importance in numerous social scientific disciplines, institutional confidence research is limited by a lack of consensus regarding the distinctions and relationships among related constructs (e.g., trust, confidence, legitimacy, distrust, etc.). This study examined four confidence-related constructs that have been used in studies of trust/confidence in the courts: dispositional trust, trust in institutions, obligation to obey the law, and cynicism. First, the separability of the four constructs was examined by exploratory factor analyses. Relationships among the constructs were also assessed. Next, multiple regression analyses were used to explore each construct's independent contribution to confidence in the courts. Finally, a second study replicated the first study and also examined the stability of the institutional confidence constructs over time. Results supported the hypothesized separability of, and correlations among, the four confidence-related constructs. The extent to which the constructs independently explained the observed variance in confidence in the courts differed as a function of the specific operationalization of confidence in the courts and the individual predictor measures. Implications for measuring institutional confidence and future research directions are discussed. PMID- 21264927 TI - Specific absorption rate reduction in parallel transmission by k-space adaptive radiofrequency pulse design. AB - The specific absorption rate (SAR) is an important safety criterion, limiting many MR protocols with respect to the achievable contrast and scan duration. Parallel transmission enables control of the radiofrequency field in space and time and hence allows for SAR management. However, a trade-off exists between radiofrequency pulse performance and SAR reduction. To overcome this problem, in this work, parallel transmit radiofrequency pulses are adapted to the position in sampling k-space. In the central k-space, highly homogeneous but SAR-intensive radiofrequency shim settings are used to achieve optimal performance and contrast. In the outer k-space, the homogeneity requirement is relaxed to reduce the average SAR of the scan. The approach was experimentally verified on phantoms and volunteers using field echo and spin echo sequences. A reduction of the SAR by 25-50% was achieved without compromising image quality. PMID- 21264928 TI - Reducing SAR and enhancing cerebral signal-to-noise ratio with high permittivity padding at 3 T. AB - Previous works have shown that placement of a high-dielectric pad can improve image intensity in a region adjacent to the pad, or that placement of dielectric pads around a large surface of the head can improve image homogeneity on an entire plane through the head in high-field MRI. Here, experimental results show that use of high-dielectric pads around the human head can reduce the required input radiofrequency power by 50% while enhancing image signal-to-noise ratio by 20-40% throughout the cerebrum at 3 T. Thus, dielectric pads may be used to provide a relatively simple and low-cost method for improving quality and safety of MRI in a variety of applications at 3 T. PMID- 21264929 TI - Accelerated multidimensional radiofrequency pulse design for parallel transmission using concurrent computation on multiple graphics processing units. AB - Multidimensional radiofrequency (RF) pulses are of current interest because of their promise for improving high-field imaging and for optimizing parallel transmission methods. One major drawback is that the computation time of numerically designed multidimensional RF pulses increases rapidly with their resolution and number of transmitters. This is critical because the construction of multidimensional RF pulses often needs to be in real time. The use of graphics processing units for computations is a recent approach for accelerating image reconstruction applications. We propose the use of graphics processing units for the design of multidimensional RF pulses including the utilization of parallel transmitters. Using a desktop computer with four NVIDIA Tesla C1060 computing processors, we found acceleration factors on the order of 20 for standard eight transmitter two-dimensional spiral RF pulses with a 64 * 64 excitation resolution and a 10-MUsec dwell time. We also show that even greater acceleration factors can be achieved for more complex RF pulses. PMID- 21264930 TI - Simple analytical dual-band spectral-spatial RF pulses for B(1) + and susceptibility artifact reduction in gradient echo MRI. AB - Susceptibility artifacts and transmission radio frequency (RF) field (B(1) +) inhomogeneity are major limitations in high-field gradient echo MRI. Previously proposed numerical 2D spectral-spatial RF pulses have been shown to be promising for reducing the through-plane signal loss susceptibility artifact by incorporating a frequency-dependent through-plane phase correction. This method has recently been extended to 4D spectral-spatial RF pulse designs for reducing B(1) + inhomogeneity as well as the signal loss. In this manuscript, we present simple analytical pulse designs for constructing 2D and 4D spectral-spatial RF pulses as an alternative to the numerical approaches. The 2D pulse capable of exciting slices with reduced signal loss and is lipid suppressing. The 4D pulse simultaneously corrects signal loss as well as the B(1) + inhomogeneity from a body coil transmitter. The pulses are demonstrated with simulations and with gradient echo phantom and brain images at 3T using a standard RF body coil. The pulses were observed to work well for multiple slices and several volunteers. PMID- 21264931 TI - Mapping proteoglycan-bound water in cartilage: Improved specificity of matrix assessment using multiexponential transverse relaxation analysis. AB - Association of MR parameters with cartilage matrix components remains an area of ongoing investigation. Multiexponential analysis of nonlocalized transverse relaxation data has previously been used to quantify water compartments associated with matrix macromolecules in cartilage. We extend this to mapping the proteoglycan (PG)-bound water fraction in cartilage, using mature and young bovine nasal cartilage model systems, toward the goal of matrix component specific imaging. PG-bound water fraction from mature and young bovine nasal cartilage was 0.31 +/- 0.04 and 0.22 +/- 0.06, respectively, in agreement with biochemically derived PG content and PG-to-water weight ratios. Fourier transform infrared imaging spectroscopic-derived PG maps normalized by water content (IR PG(ww) ) showed spatial correspondence with PG-bound water fraction maps. Extensive simulation analysis demonstrated that the accuracy and precision of our determination of PG-bound water fraction was within 2%, which is well-within the observed tissue differences. Our results demonstrate the feasibility of performing imaging-based multiexponential analysis of transverse relaxation data to map PG in cartilage. PMID- 21264932 TI - A simple approach for three-dimensional mapping of baseline cerebrospinal fluid volume fraction. AB - A simple method of measuring baseline cerebrospinal fluid volume fraction (V(CSF) ) in three-dimensional is proposed that used the characteristic of cerebrospinal fluid with very long T(2) . It is based on the fitting of monoexponential decay of only cerebrospinal fluid signal, using a nonselective T(2) preparation scheme. Three-dimensional gradient- and spin-echo acquisition also improves signal-to noise ratio efficiency and brain coverage. Both V(CSF) and T(2,CSF) are fitted voxel by voxel and analyzed in different cortical areas across subjects. V(CSF) is largely regionally dependent (occipital: 8.9 +/- 1.7%, temporal: 11.4 +/- 2.4%, and frontal: 21.4 +/- 6.9%). Measured T(2,CSF) was 1573 +/- 146 msec within cortical lobes as compared with 2062 +/- 37 msec from ventricle regions. Different parameter set were compared, and the robustness of the new method is demonstrated. Conversely, when comparing with the proposed approach, large overestimation of segmentation based method using T(1) -weighted images is found, and the underlying causes are suggested. PMID- 21264933 TI - Contrast-enhanced whole-heart coronary MRI with bolus infusion of gadobenate dimeglumine at 1.5 T. AB - We sought to investigate the T(1) kinetics of blood and myocardium after three infusion schemes of gadobenate dimeglumine (Gd-BOPTA) and subsequently compared contrast-enhanced whole-heart coronary MRI after a bolus Gd-BOPTA infusion with nonenhanced coronary MRI at 1.5 T. Blood and myocardium T(1) was measured in seven healthy adults, after each underwent three Gd-BOPTA infusion schemes (bolus: 0.2 mmol/kg at 2 mL/sec, hybrid: 0.1 mmol/kg at 2 mL/sec followed by 0.1 mmol/kg at 0.1 mL/sec, and slow: 0.2 mmol/kg at 0.3 mL/sec). Fourteen additional subjects underwent contrast-enhanced coronary MRI with an inversion-recovery steady-state free precession sequence after bolus Gd-BOPTA infusion. Images were compared with nonenhanced T(2) -prepared steady-state free precision whole-heart coronary MRI in signal-to-noise ratio, contrast-to-noise ratio, depicted vessel length, vessel sharpness, and subjective image quality. Bolus and slow infusion schemes resulted in similar T(1) during coronary MRI, whereas the hybrid infusion method yielded higher T(1) values. A bolus infusion of Gd-BOPTA significantly improved signal-to-noise ratio, contrast-to-noise ratio, depicted coronary artery length, and subjective image quality, when all segments were collectively compared but not when compared segment by segment. In conclusion, whole-heart steady-state free precision coronary MRI at 1.5 T can benefit from a bolus infusion of 0.2 mmol/kg Gd-BOPTA. PMID- 21264934 TI - Improving apparent diffusion coefficient estimates and elucidating tumor heterogeneity using Bayesian adaptive smoothing. AB - The spatial distribution of apparent diffusion coefficient (ADC) estimates in tumors is typically heterogeneous, although this observed variability is composed of both true regional differences and random measurement uncertainty. In this study, an adaptive Bayesian adaptive smoothing (BAS) model for estimating ADC values is developed and applied to data acquired in two murine tumor models in vivo. BAS models have previously been shown to reduce parameter uncertainty through the use of a Markov random field. Here, diffusion data acquired with four averages was used as an empirical gold standard for evaluating the BAS model. ADC estimates using BAS displayed a significantly closer accordance with the gold standard data and, following analysis of uncertainty estimates, appeared to even outperform the gold standard. These observations were also reflected in simulations. These results have strong implications for clinical studies, as it suggests that the BAS postprocessing technique can be used to improve ADC estimates without the need to compromise on spatial resolution or signal-to-noise or for the adaptation of acquisition hardware. A novel measure of tumor ADC heterogeneity was also defined, which identified differences between tumors derived from different cell lines, which were reflected in histological variations within the tissue microenvironment. PMID- 21264935 TI - New criterion to aid manual and automatic selection of the arterial input function in dynamic susceptibility contrast MRI. AB - Dynamic susceptibility contrast-MRI requires an arterial input function (AIF) to obtain cerebral blood flow, cerebral blood volume, and mean transit time. The current AIF selection criteria discriminate venous, capillary, and arterial profiles based on shape and timing characteristics of the first passage. Unfortunately, partial volume effects can lead to shape errors in the bolus passage, including a narrower and higher peak, which might be selected as a "correct" AIF. In this study, a new criterion is proposed that detects shape errors based on tracer kinetic principles for computing cerebral blood volume. This criterion uses the ratio of the steady-state value to the area-under-the curve of the first passage, which should result in an equal value for tissue and arterial responses. By using a reference value from tissue, partial volume effects-induced shape errors of the AIF measurement can be detected. Different factors affecting the ratio were investigated using simulations. These showed that the new criterion should only be used in studies with T(1) -insensitive acquisition. In vivo data were used to evaluate the proposed approach. The data showed that the new criterion enables detection of shape errors, although false positives do occur, which could be easily avoided when combined with current AIF selection criteria. PMID- 21264936 TI - Determination of whole-brain oxygen extraction fractions by fast measurement of blood T(2) in the jugular vein. AB - The oxygen extraction fraction of the brain reports on the balance between oxygen delivery and consumption and can be used to assess deviations in physiological homeostasis. This is relevant clinically as well as for calibrating blood oxygen level-dependent functional MRI responses. Oxygen extraction fraction is reflected in the arteriovenous difference in oxygen saturation fraction (Y(v) - Y(a) ), which can be determined from venous T(2) values when arterial oxygenation is known. A pulse sequence is presented that allows rapid measurement (<1 min) of blood T(2) s in the internal jugular vein. The technique combines slice saturation and blood inflow to attain high signal-to-noise ratio in blood and minimal contamination from tissue. The sequence is sensitized to T(2) using a nonselective Carr-Purcell-Meiboom-Gill T(2) preparation directly after slice saturation. Fast scanning (pulse repetition time of about 2 sec) is possible by using a nonselective saturation directly after acquisition to rapidly achieve steady-state longitudinal magnetization. The venous T(2) (for 10 msec Carr Purcell-Meiboom-Gill interecho time) for normal volunteers was 62.4 +/- 6.1 msec (n = 20). A calibration curve relating T(2) to blood oxygenation was established using a blood perfusion phantom. Using this calibration, a whole-brain oxygen extraction fraction of 0.37 +/- 0.04 was determined (n = 20), in excellent agreement with literature values. PMID- 21264937 TI - Second order total generalized variation (TGV) for MRI. AB - Total variation was recently introduced in many different magnetic resonance imaging applications. The assumption of total variation is that images consist of areas, which are piecewise constant. However, in many practical magnetic resonance imaging situations, this assumption is not valid due to the inhomogeneities of the exciting B1 field and the receive coils. This work introduces the new concept of total generalized variation for magnetic resonance imaging, a new mathematical framework, which is a generalization of the total variation theory and which eliminates these restrictions. Two important applications are considered in this article, image denoising and image reconstruction from undersampled radial data sets with multiple coils. Apart from simulations, experimental results from in vivo measurements are presented where total generalized variation yielded improved image quality over conventional total variation in all cases. PMID- 21264938 TI - Polystyrene microsphere-ferritin conjugates: a robust phantom for correlation of relaxivity and size distribution. AB - In vivo iron load must be monitored to prevent complications from iron overload diseases such as hemochromatosis or transfusion-dependent anemias. While liver biopsy is the gold standard for determining in vivo iron load, MRI offers a noninvasive approach. MR phantoms have been reported that estimate iron concentration in the liver and mimic relaxation characteristics of in vivo deposits of hemosiderin. None of these phantoms take into account the size distribution of hemosiderin, which varies from patient to patient based on iron load. We synthesized stable and reproducible microsphere-ferritin conjugates (ferribeads) of different sizes that are easily characterized for several parameters that are necessary for modeling such as iron content and bead fraction. T(1) s and T(2) s were measured on a 1.41-T low-resolution NMR spectrometer and followed a size-dependent trend. Ferribeads imaged at 4.7 and 14.1 T showed that signal intensities are dependent on the distribution of ferritin around the bead rather than the iron concentration alone. These particles can be used to study the effects of particle size, ferritin distribution, and bead fraction on proton relaxation and may be of use in mimicking hemosiderin in a phantom for estimating iron concentration. PMID- 21264939 TI - Detecting response of rat C6 glioma tumors to radiotherapy using hyperpolarized [1- 13C]pyruvate and 13C magnetic resonance spectroscopic imaging. AB - We show here that hyperpolarized [1-(13) C]pyruvate can be used to detect treatment response in a glioma tumor model; a tumor type where detection of response with (18) fluoro-2-deoxyglucose, using positron emission tomography, is limited by the high background signals from normal brain tissue. (13) C chemical shift images acquired following intravenous injection of hyperpolarized [1-(13) C]pyruvate into rats with implanted C6 gliomas showed significant labeling of lactate within the tumors but comparatively low levels in surrounding brain.Labeled pyruvate was observed at high levels in blood vessels above the brain and from other major vessels elsewhere but was detected at only low levels in tumor and brain.The ratio of hyperpolarized (13) C label in tumor lactate compared to the maximum pyruvate signal in the blood vessels was decreased from 0.38 +/- 0.16 to 0.23 +/- 0.13, (a reduction of 34%) by 72 h following whole brain irradiation with 15 Gy. PMID- 21264940 TI - Family-based and population-based association studies validate PTPRD as a risk factor for restless legs syndrome. AB - OBJECTIVE: We previously mapped a genetic locus for restless legs syndrome (RLS) to chromosome 9p22-24 (RLS3) and a later genome-wide association study (GWAS) implicated the PTPRD gene at the RLS3 locus as a susceptibility gene for RLS. However, from the standpoint of genetics, the GWAS association needs to be validated by independent studies. In this study, we used both family-based and population-based association studies to assess the association between PTPRD and RLS in an American Caucasian population. METHODS: We genotyped two intronic SNPs rs1975197 and rs4626664 in PTPRD in 144 family members from 15 families and a case control cohort of 189 patients and 560 controls. Direct DNA sequence analysis was used to screen coding exons and exon-intron boundaries of PTPRD for rare mutations. RESULTS: A family-based sibling transmission disequilibrium test showed association of RLS with SNP rs1975197 (P = 0.015), but not with rs4626664 (P = 0.622). The association with rs1975197 was significantly replicated by a population-based case control association study (allelic P = 0.0004, odds ratio = 1.68; genotypic P = 0.0013 and 0.0003 for an additive and dominant model, respectively). One rare p.E1639D variant was identified in exon 39 in kindred RLS40005. The rare D1639 allele did not co-segregate with RLS in the family, suggesting that p.E1639D variant is not a causative mutation. CONCLUSIONS: This represents the first independent study to validate the association between PTPRD variants and RLS. Both family-based and population-based association studies suggest that PTPRD variant rs1975197 confers risk of RLS. PMID- 21264941 TI - The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease. AB - BACKGROUND: Non-motor symptoms are detrimental to health-related quality of life (HRQoL) of Parkinson's disease patients. In this study, the Non-Motor Symptoms Scale (NMSS) was used to assess the impact of the non-motor symptoms on HRQoL of Parkinson's disease patients. METHODS: In a multicenter, international, cross sectional study on 411 Parkinson's disease patients, the NMSS was applied along with clinical (Hoehn and Yahr staging and SCOPA-Motor) and HRQoL measures (PDQ 39, and EQ-5D). Prevalence of non-motor symptoms was determined also through the NMSS. The association of NMSS and SCOPA-Motor with HRQoL measures and the differences in HRQoL scores between patients with and without non-motor symptoms in each NMSS domain were estimated by non-parametric statistics. Predictors of HRQoL were sought through multiple linear regression analyses. RESULTS: Nocturia (68.4% of the sample), fatigue (65.9%), and dribbling saliva (56.7%), were the most frequent complaints. Total NMSS score: (1) showed a higher correlation coefficient (r(S) = 0.70) with the PDQ-39 Summary Index (SI) than SCOPA-Motor (r(S) = 0.58); (2) showed high-moderate correlation (r(S) = 0.60 - 0.38) with all PDQ-39 domains; and (3) was the best predictor of HRQoL as measured by the PDQ-39 SI. For each NMSS domain, patients with symptoms had significantly worse HRQoL scores than patients without symptoms. DISCUSSION: To our knowledge, this is the first study to determine in a holistic manner the impact of the non-motor symptoms on HRQoL of Parkinson's disease patients. The results show that non motor symptoms have, as a whole, a greater impact on HRQoL than motor symptoms and non-motor symptoms progression contributes importantly to HRQoL decline in patients with Parkinson's disease. PMID- 21264942 TI - Akinetic-rigid and tremor-dominant Parkinson's disease patients show different patterns of FP-CIT single photon emission computed tomography. AB - OBJECTIVE: To elucidate whether Parkinson's disease subtypes show a different pattern of Iodine-123 fluoropropyl-;carbomethoxy-3 beta-(FP-CIT) single photon emission computed tomography (SPECT) binding in accordance with neuropathological findings. METHODS: We analyzed a database of consecutive patients with FP-CIT scan (n = 190) over a 3-year period and identified 122 patients (50 women, 72 men, mean age 62 +/- 11.1 years) with a diagnosis of idiopathic Parkinson's disease. Patient's characteristics and FP-CIT scan results were analyzed and compared for the subgroups tremor-dominant versus akinetic-rigid and equivalent type of Parkinson's disease. RESULTS: The analysis of all Parkinson's disease patients showed a significant difference between the FP-CIT uptake in the subgroups tremor-dominant and akinetic-rigid. After matching these samples for age, disease duration, disease severity (Hoehn & Yahr grade, Unified Parkinson's Disease Rating Scale score), and levodopa-equivalent dose, these findings were balanced between both groups (n = 23/23) without a significant difference (P > 0.05). However, there was a clear, significant association of visually analyzed shapes of the striatum in FP-CIT SPECT and clinical Parkinson's disease subtype. CONCLUSION: These results confirm neuropathological models for a reduced dopaminergic projection to the dorsal putamen in akinetic-rigid patients as well as the lateral putamen and caudate nucleus in tremor-dominant patients in vivo. PMID- 21264943 TI - Can "functional" constipation be considered as a form of enteric neuro-gliopathy? AB - Constipation has been traditionally viewed and classified as a functional or idiopathic disorder. However, evidence has been accumulating that suggests how constipation might be considered as due to abnormalities of the enteric nervous system, since alterations of this system, not evident in conventional histological examination, may be present in these patients. These abnormalities often consist in decrease or loss of the enteric glial cells, a pathological finding present in most types of constipation so far investigated. In this article we will discuss these evidences, and will try to consider constipation no more as a simple functional or idiopathic disorder but as a form of enteric neuro gliopathy. PMID- 21264944 TI - Dok4 is involved in Schwann cell myelination and axonal interaction in vitro. AB - The initial interaction between the Schwann cell and the axon is a complex and poorly understood aspect of the myelination process. To investigate the molecular mechanisms involved in this interaction and to identify novel genes required for myelination, we performed an RNA profiling analysis, comparing Schwann cells cultured alone or in the presence of neurons. This led to the selection of 30 genes, mostly upregulated on Schwann cell-axon interaction. Most of the identified proteins are associated with the extracellular space or signal transduction systems, consistent with possible roles in Schwann cell-axon interaction. We performed a functional analysis of one of these genes, Dok4 (downstream of kinase-4), which encodes a membrane-associated tyrosine kinase substrate. Silencing RNA-mediated knock-down of Dok4 severely affected in vitro myelination. Moreover, Dok4 is required at early stages in the myelination process, including the initial interaction with the axon, and is also involved in Schwann cell migration and proliferation. Finally, this analysis establishes the interest of our gene collection in further understanding of the molecular mechanisms involved in Schwann cell-axon interaction. PMID- 21264945 TI - Expression of the new P2Y-like receptor GPR17 during oligodendrocyte precursor cell maturation regulates sensitivity to ATP-induced death. AB - The P2Y-like receptor GPR17 is expressed by adult neural progenitor cells, suggesting a role in lineage determination. Here, we characterized GPR17 expression and function in mouse cortical primary astrocytes/precursor cell cultures. GPR17 is expressed by a subpopulation of oligodendrocyte precursor cells (OPCs), but not by astrocytes. This expression pattern was also confirmed in vivo. In vitro, GPR17 expression was markedly influenced by culturing conditions. In the presence of growth factors (GFs), no significant GPR17 expression was found. When cultures were shifted to a differentiating medium, a dramatic, time-dependent increase in the number of highly branched GPR17-positive cells was observed. Under these conditions, GPR17 was induced in the totality of O4-positive immature oligodendrocytes. Instead, in cultures originally grown in the absence of GFs, GPR17 was already expressed in morphologically more mature OPCs. Shifting of these cultures to differentiating conditions induced GPR17 only in a subpopulation of O4-positive cells. Under both culture protocols, appearance of more mature CNPase- and MBP-positive cells was associated to a progressive loss of GPR17. GPR17 expression also sensitized cells to adenine nucleotide induced cytotoxicity, whereas activation with uracil nucleotides promoted differentiation towards a more mature phenotype. We suggest that GFs may keep OPCs in a less differentiated stage by restraining GPR17 expression, and that, under permissive conditions, GPR17 contributes to OPCs differentiation. However, upon high extracellular adenine nucleotide concentrations, as during trauma and ischemia, GPR17 sensitizes cells to cytotoxicity. This double-edged sword role may be exploited to unveil new therapeutic approaches to acute and chronic brain disorders. PMID- 21264946 TI - Involvement of placental growth factor in Wallerian degeneration. AB - Wallerian degeneration (WD) is an inflammatory process of nerve degeneration, which occurs more rapidly in the peripheral nervous system compared with the central nervous system, resulting, respectively in successful and aborted axon regeneration. In the peripheral nervous system, Schwann cells (SCs) and macrophages, under the control of a network of cytokines and chemokines, represent the main cell types involved in this process. Within this network, the role of placental growth factor (PlGF) remains totally unknown. However, properties like monocyte activation/attraction, ability to increase expression of pro-inflammatory molecules, as well as neuroprotective effects, make it a candidate likely implicated in this process. Also, nothing is described about the expression and localization of this molecule in the peripheral nervous system. To address these original questions, we decided to study PlGF expression under physiological and degenerative conditions and to explore its role in WD, using a model of sciatic nerve transection in wild-type and Pgf(-/-) mice. Our data show dynamic changes of PlGF expression, from periaxonal in normal nerve to SCs 24h postinjury, in parallel with a p65/NF-kappaB recruitment on Pgf promoter. After injury, SC proliferation is reduced by 30% in absence of PlGF. Macrophage invasion is significantly delayed in Pgf(-/-) mice compared with wild-type mice, which results in worse functional recovery. MCP-1 and proMMP-9 exhibit a 3-fold reduction of their relative expressions in Pgf(-/-) injured nerves, as demonstrated by cytokine array. In conclusion, this work originally describes PlGF as a novel member of the cytokine network of WD. PMID- 21264947 TI - Bid regulates the immunological profile of murine microglia and macrophages. AB - Apoptosis is a controlled cell-death process mediated inter alia by proteins of the Bcl-2 family. Some proteins previously shown to promote the apoptotic process were found to have nonapoptotic functions as well. Microglia, the resident immune cells of the central nervous system, respond to brain derangements by becoming activated to contend with the brain damage. Activated microglia can also undergo activation-induced cell death. Previous studies have addressed the role of core apoptotic proteins in the death process, but whether these proteins also play a role or not in the activation process is not been reported. Here we explore the effect of the BH3-only protein Bid on the immunological features of microglia and macrophages. Our results showed that Bid regulates both the phagocytotic activities and the inflammatory profiles of these cells. Deficiency of Bid attenuated the phagocytotic activity of primary microglia and peritoneal macrophages. It also changed the expression profile of distinct inflammation related genes in lipopolysaccharide-activated microglia and peritoneal macrophages in vitro and in an in vivo sepsis-like paradigm. Notably, similar changes followed downregulation of Bid in the N9 microglial cell line. Cell death could not be detected in any of the systems examined. Our findings demonstrate that Bid can regulate the immunological profiles of activated microglial and macrophages, via a novel nonapoptotic activity. In view of the critical role of these cells in various pathologies, including acute and chronic brain insults, our findings suggest that impairments in Bid expression may contribute to these pathologies also via a nonapoptotic activity. PMID- 21264948 TI - Osteopontin: correlation with phagocytosis by brain macrophages in a rat model of stroke. AB - Osteopontin (OPN) is an adhesive glycoprotein linked to a variety of pathophysiological processes. We investigated whether OPN might act as an opsonin in the diseased brain by studying the postischemic expression and localization of OPN mRNA and protein in a rat model of ischemic stroke. In addition, we characterized the subcellular localization of OPN protein in the ischemic brain core. Induction of OPN mRNA occurred in activated microglia/macrophages in the ischemic core on days 3-7 after reperfusion and this was sustained up to day 28, at least. OPN protein was synthesized and secreted by brain macrophages, which first surrounded damaged striatal white matter tracts and then infiltrated into them. Punctate OPN-immunoreactive profiles were scattered throughout the infarction core except in white matter bundles. Electron microscopy showed the localization of OPN protein along the membranes lining what appeared to be the debris of dead neurons. These were located in the extracellular space and within the cytoplasm of brain macrophages, indicating that the OPN protein accumulated selectively on the surface of dead cells, most of which were phagocytosed subsequently by brain macrophages. However, no significant induction of OPN occurred in degenerating striatal white matter tracts or in brain macrophage engulfed axonic or myelin debris. These data suggest that OPN secreted by brain macrophages in this rat model of stroke might be involved in the phagocytosis of fragmented cell debris and possibly not in the phagocytosis of axonic or myelin debris. PMID- 21264949 TI - Promoting survival, migration, and integration of transplanted Schwann cells by over-expressing polysialic acid. AB - The poor survival and migration of transplanted Schwann cells (SCs) are major drawbacks for their clinical application in cell therapy for neurotrauma. To overcome such drawbacks we genetically modified SCs to over-express polysialic acid (PSA) by lentiviral delivery of polysialyltransferase (PST) to study whether over-expression of PSA could enhance their survival, migration, and integration when transplanted into the spinal cord. It was found that more PSA-expressing SCs (PST/SCs) survived than GFP-expressing SCs (GFP/SCs) after transplantation, although cell loss was still quite significant. PSA expression did not enhance the motility of transplanted SCs in uninjured spinal cord. However, in a spinal cord crush injury model PST/SCs transplanted caudal to the lesion showed that increased number of PST/SCs migrated to the injury site compared with that of GFP/SCs. Induced expression of PSA in spinal cord can further facilitate the infiltration of PST/SCs into the lesion site. PST/SCs were also shown to intermingle well with host spinal cells while GFP/SCs formed boundaries with host tissue. This was confirmed by an in vitro confrontation assay showing that more PST/SCs crossed over to astrocyte territory than GFP/SCs. Furthermore, PST/SCs induced much less expression of glial fibrillary acidic protein and chondroitin sulfate proteoglycan in the surrounding tissues than GFP/SCs, indicating that expression of PSA on SCs do not cause significant stress response of astrocytes. These results demonstrate that expression of PSA on SCs significantly changes their biological properties and makes them more feasible for neural repair after neurotrauma. PMID- 21264951 TI - Time-dependent changes in proinflammatory and neurotrophic responses of microglia and astrocytes in a rat model of osmotic demyelination syndrome. AB - Osmotic demyelination syndrome (ODS) is a serious demyelinating disease in the central nervous system usually caused by rapid correction of hyponatremia. In an animal model of ODS, we previously reported microglial accumulation expressing proinflammatory cytokines. Microglia and astrocytes secreting proinflammatory cytokines and neurotrophic factors are reported to be involved in the pathogenesis of demyelinative diseases. Therefore, to clarify the role of microglial and astrocytic function in ODS, we examined the time-dependent changes in distribution, morphology, proliferation, and mRNA/protein expression of proinflammatory cytokines, neurotrophic factors, and matrix metalloproteinase (MMP) in microglia and astrocytes 2 days (early phase) and 5 days (late phase) after the rapid correction of hyponatremia in ODS rats. The number of microglia time dependently increased at demyelinative lesion sites, proliferated, and expressed tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, inducible nitric oxide synthase, and MMP2, 9, and 12 at the early phase. Microglia also expressed leukemia inhibitory factor (a neurotrophic factor) and phagocytosed myelin debris at the late phase. The number of astrocytes time dependently increased around demyelinative lesions, extended processes to lesions, proliferated, and expressed nerve growth factor and glial cell line derived neurotrophic factor at the late phase. Moreover, treatment with infliximab, a monoclonal antibody against TNF-alpha, significantly attenuated neurological impairments. Our results suggest that the role of microglia in ODS is time dependently shifted from detrimental to protective and that astrocytes play a protective role at the late phase. Modulation of excessive proinflammatory responses in microglia during the early phase after rapid correction may represent a therapeutic target for ODS. PMID- 21264950 TI - Astrocyte-derived metallothionein protects dopaminergic neurons from dopamine quinone toxicity. AB - Our previous studies demonstrated the involvement of quinone formation in dopaminergic neuron dysfunction in the L-DOPA-treated parkinsonian model and in methamphetamine (METH) neurotoxicity. We further reported that the cysteine-rich metal-binding metallothionein (MT) family of proteins protects dopaminergic neurons against dopamine (DA) quinone neurotoxicity by its quinone-quenching property. The aim of this study was to examine MT induction in astrocytes in response to excess DA and the potential neuroprotective effects of astrocyte derived MTs against DA quinone toxicity. DA exposure significantly upregulated MT 1/-2 in cultured striatal astrocytes, but not in mesencephalic neurons. This DA induced MT upregulation in astrocytes was blocked by treatment with a DA transporter (DAT) inhibitor, but not by DA-receptor antagonists. Expression of nuclear factor erythroid 2-related factor (Nrf2) and its binding activity to antioxidant response element of MT-1 gene were significantly increased in the astrocytes after DA exposure. Nuclear translocation of Nrf2 was suppressed by the DAT inhibitor. Quinone formation and reduction of mesencephalic DA neurons after DA exposure were ameliorated by preincubation with conditioned media from DA treated astrocytes. These protective effects were abrogated by MT-1/-2-specific antibody. Adding exogenous MT-1 to glial conditioned media also showed similar neuroprotective effects. Furthermore, MT-1/-2 expression was markedly elevated specifically in reactive astrocytes in the striatum of L-DOPA-treated hemi parkinsonian mice or METH-injected mice. These results suggested that excess DA taken up by astrocytes via DAT upregulates MT-1/-2 expression specifically in astrocytes, and that MTs or related molecules secreted specifically by astrocytes protect dopaminergic neurons from damage through quinone quenching and/or scavenging of free radicals. PMID- 21264952 TI - Developmental and cell type-specific expression of thyroid hormone transporters in the mouse brain and in primary brain cells. AB - Cellular thyroid hormone uptake and efflux are mediated by transmembrane transport proteins. One of these, monocarboxylate transporter 8 (MCT8) is mutated in Allan-Herndon-Dudley syndrome, a severe mental retardation associated with abnormal thyroid hormone constellations. Since mice deficient in Mct8 exhibit a milder neurological phenotype than patients, we hypothesized that alternative thyroid hormone transporters may compensate in murine brain cells for the lack of Mct8. Using qPCR, Western Blot, and immunocytochemistry, we investigated the expression of three different thyroid hormone transporters, i.e., Mct8 and L-type amino acid transporters Lat1 and Lat2, in mouse brain. All three thyroid hormone transporters are expressed from corticogenesis and peak around birth. Primary cultures of neurons and astrocytes express Mct8, Lat1, and Lat2. Microglia specifically expresses Mct10 and Slco4a1 in addition to high levels of Lat2 mRNA and protein. As in vivo, a brain microvascular endothelial cell line expressed Mct8 and Lat1. 158N, an oligodendroglial cell line expressed Mct8 protein, consistent with delayed myelination in MCT8-deficient patients. Functional T(3)- and T(4)-transport assays into primary astrocytes showed K(M) values of 4.2 and 3.7 MUM for T(3) and T(4). Pharmacological inhibition of L-type amino acid transporters by BCH and genetic inactivation of Lat2 reduced astrocytic T(3) uptake to the same extent. BSP, a broad spectrum inhibitor, including Mct8, reduced T(3) uptake further suggesting the cooperative activity of several T(3) transporters in astrocytes. PMID- 21264953 TI - Microglia/macrophages promote glioma progression. AB - Gliomas are highly aggressive and accompanied by numerous microglia/macrophages (MG/MP) in and about the tumor. Little is known about what MG/MP do in this setting, or whether modulating MG/MP activation might affect glioma progression. Here, we used a glioma-microglia in culture system to establish the effects the tumor and microglia have on each other. We assessed glioma progression in vivo after MG/MP ablation or in the setting of exaggerated MG/MP activation. We show that glioma cells activate microglia but inhibit their phagocytic activities. Local ablation of MG/MP in vivo decreased tumor size and improved survival curves. Conversely, pharmacological activation of MG/MP increased glioma size through stimulating tumor proliferation and inhibiting apoptosis. In agreement with recent reports, expression of the chemokine CCL21 is enhanced after MG/MP activation and correlates with tumor growth. Taken together, our findings demonstrate that inhibition of MG/MP activation may constitute a new and effective contribution towards suppressing glioma proliferation. PMID- 21264954 TI - S100B attenuates microglia activation in gliomas: possible role of STAT3 pathway. AB - Despite significant infiltration into tumors, the effector function of macrophages (MPs) and microglia (MG) appears to be suppressed in gliomas. Although STAT3 pathway is thought to play a role in this process, the exact mechanism by which gliomas induce STAT3 activation in MPs and MG is not known. Because activation of receptor for advanced glycation end products (RAGE) can induce STAT3, and because gliomas express high levels of S100B, a RAGE ligand, we hypothesized that MP/MG STAT3 activity may be modulated through S100B-RAGE interaction. Exposure of N9 MG and bone marrow-derived monocytes (BMM) to GL261 glioma condition medium (GCM) and low (nM) levels of S100B increased RAGE expression, induced STAT3 and suppressed MG function in vitro. Furthermore, neutralization of S100B in GCM, partially reversed IL-1beta suppression in BMM, suggesting that the inhibitory effect of GCM to be in part due to S100B. Finally, blockage of S100B-RAGE interaction inhibited STAT3 activation in N9 MG and in glioma MG/MP in vivo. These findings suggest that the RAGE pathway may play an important role in STAT3 induction in glioma-associated MG/MPs, and that this process may be mediated through S100B. PMID- 21264955 TI - Human glial-restricted progenitors survive, proliferate, and preserve electrophysiological function in rats with focal inflammatory spinal cord demyelination. AB - Transplantation of glial progenitor cells results in transplant-derived myelination and improved function in rodents with genetic dysmyelination or chemical demyelination. However, glial cell transplantation in adult CNS inflammatory demyelinating models has not been well studied. Here we transplanted human glial-restricted progenitor (hGRP) cells into the spinal cord of adult rats with inflammatory demyelination, and monitored cell fate in chemically immunosuppressed animals. We found that hGRPs migrate extensively, expand within inflammatory spinal cord lesions, do not form tumors, and adopt a mature glial phenotype, albeit at a low rate. Human GRP-transplanted rats, but not controls, exhibited preserved electrophysiological conduction across the spinal cord, though no differences in behavioral improvement were noted between the two groups. Although these hGRPs myelinated extensively after implantation into neonatal shiverer mouse brain, only marginal remyelination was observed in the inflammatory spinal cord demyelination model. The low rate of transplant-derived myelination in adult rat spinal cord may reflect host age, species, transplant environment/location, and/or immune suppression regime differences. We conclude that hGRPs have the capacity to myelinate dysmyelinated neonatal rodent brain and preserve conduction in the inflammatory demyelinated adult rodent spinal cord. The latter benefit is likely dependent on trophic support and suggests further exploration of potential of glial progenitors in animal models of chronic inflammatory demyelination. PMID- 21264957 TI - Dynamic aspects of films prepared by a sequential deposition of species: perspectives for smart and responsive materials. AB - The deposition of surface coatings using a step-by-step approach from mutually interacting species allows the fabrication of so called "multilayered films". These coatings are very versatile and easy to produce in environmentally friendly conditions, mostly from aqueous solution. They find more and more applications in many hot topic areas, such as in biomaterials and nanoelectronics but also in stimuli-responsive films. We aim to review the most recent developments in such stimuli-responsive coatings based on layer-by-layer (LBL) depositions in relationship to the properties of these coatings. The most investigated stimuli are based on changes in ionic strength, temperature, exposure to light, and mechanical forces. The possibility to induce a transition from linear to exponential growth in thickness and to change the charge compensation from "intrinsic" to "extrinsic" by controlling parameters such as temperature, pH, and ionic strength are the ways to confer their responsiveness to the films. Chemical post-modifications also allow to significantly modify the film properties. PMID- 21264956 TI - Role of astroglial connexin30 in hippocampal gap junction coupling. AB - The impact of connexin30 (Cx30) on interastrocytic gap junction coupling in the normal hippocampus is matter of debate; reporter gene analyses indicated a weak expression of Cx30 in the mouse hippocampus. In contrast, mice lacking connexin43 (Cx43) in astrocytes exhibited only 50% reduction in coupling. Complete uncoupling of hippocampal astrocytes in mice lacking both Cx30 and Cx43 suggested that Cx30 participates in interastrocytic gap junction coupling in the hippocampus. With comparative reporter gene assays, immunodetection, and cre/loxP based reporter approaches we demonstrate that Cx30 is more abundant than previously thought. The specific role of Cx30 in interastrocytic coupling has never been investigated. Employing tracer coupling analyses in acute slices of Cx30 deficient mice here we show that Cx30 makes a substantial contribution to interastrocytic gap junctional communication in the mouse hippocampus. PMID- 21264958 TI - One-photon photophysics and two-photon absorption of 4-[9,9-di(2-ethylhexyl)-7 diphenylaminofluoren-2-yl]-2,2':6',2''-terpyridine and their platinum chloride complexes. AB - The synthesis, one-photon photophysics and two-photon absorption (2PA) of three dipolar D-pi-A 4-[9,9-di(2-ethylhexyl)-7-diphenylaminofluoren-2-yl]-2,2':6',2'' terpyridine and their platinum chloride complexes with different linkers between the donor and acceptor are reported. All ligands exhibit (1)pi,pi* transition in the UV and (1)pi,pi*/(1)ICT (intramolecular charge transfer) transition in the visible regions, while the complexes display a lower-energy (1)pi,pi*/(1)CT (charge transfer) transition in the visible region in addition to the high-energy (1)pi,pi* transitions. All ligands and the complexes are emissive at room temperature and 77 K, with the emitting excited state assigned as the mixed (1)pi,pi* and (1)CT states at RT. Transient absorption from the ligands and the complexes were observed. 2PA was investigated for all ligands and complexes. The two-photon absorption cross-sections (sigma(2)) of the complexes (600-2000 GM) measured by Z-scan experiment are much larger than those of their corresponding ligands measured by the two-photon induced fluorescence method. The ligand and the complex with the ethynylene linker show much stronger 2PA than those with the vinylene linker. PMID- 21264960 TI - Selection of G-quadruplex folding topology with LNA-modified human telomeric sequences in K+ solution. AB - G-rich nucleic acid oligomers can form G-quadruplexes built by G-tetrads stacked upon each other. Depending on the nucleotide sequence, G-quadruplexes fold mainly with two topologies: parallel, in which all G-tracts are oriented parallel to each other, or antiparallel, in which one or more G-tracts are oriented antiparallel to the other G-tracts. In the former topology, all glycosidic bond angles conform to anti conformations, while in the latter topology they adopt both syn and anti conformations. It is of interest to understand the molecular forces that govern G-quadruplex folding. Here, we approach this problem by examining the impact of LNA (locked nucleic acid) modifications on the folding topology of the dimeric model system of the human telomere sequence. In solution, this DNA G-quadruplex forms a mixture of G-quadruplexes with antiparallel and parallel topologies. Using CD and NMR spectroscopies, we show that LNA incorporations can modulate this equilibrium in a rational manner and we establish a relationship between incorporation of LNA nucleotides in syn and/or anti positions and the shift of the equilibrium to obtain exclusively the parallel G-quadruplex. The change in topology is driven by a combination of the C3'-endo puckering of LNA nucleotides and their preference for the anti glycosidic conformation. In addition, the parallel LNA-modified G-quadruplexes are thermally stabilised by about 11 degrees C relative to their DNA counterparts. PMID- 21264959 TI - "Click" immobilization on alkylated silicon substrates: model for the study of surface bound antimicrobial peptides. AB - We describe an effective approach for the covalent immobilization of antimicrobial peptides (AMPs) to bioinert substrates via Cu(I) -catalyzed azide alkyne cycloaddition (CuAAC). The bioinert substrates were prepared by surface hydrosilylation of oligo(ethylene glycol) (OEG) terminated alkenes on hydrogen terminated silicon surfaces. To render the OEG monolayers "clickable", mixed monolayers were prepared using OEG-alkenes with and without a terminal alkyne protected by a trimethylgermanyl (TMG) group. The mixed monolayers were characterized by X-ray photoelectron spectroscopy (XPS), elliposometry and contact angle measurement. The TMG protecting group can be readily removed to yield a free terminal alkyne by catalytic amounts of Cu(I) in an aqueous media. This step can then be combined with the subsequent CuAAC reaction. Thus, the immobilization of an azide modified AMP (N3-IG-25) was achieved in a one-pot deprotection/coupling reaction. Varying the ratio of the two alkenes in the deposition mixture allowed for control over the density of the alkynyl groups in the mixed monolayer, and subsequently the coverage of the AMPs on the monolayer. These samples allowed for study of the dependence of antimicrobial activities on the AMP density. The results show that a relative low coverage of AMPs (~1.6*10(13) molecule per cm(2)) is sufficient to significantly suppress the viability of Pseudomonas aeruginosa, while the surface presenting the highest density of AMPs (~2.8*10(13) molecule per cm(2)) is still cyto-compatible. The remarkable antibacterial activity is attributed to the long and flexible linker and the site-specific "click" immobilization, which may facilitate the covalently attached peptides to interact with and disrupt the bacterial membranes. PMID- 21264961 TI - Surface-enhanced Raman scattering of single- and few-layer graphene by the deposition of gold nanoparticles. AB - Surface-enhanced Raman scattering (SERS) of graphene on a SiO(2)(300 nm)/Si substrate was investigated by depositing Au nanoparticles using thermal evaporation. This provided a maximum enhancement of 120 times for single-layer graphene at 633 nm excitation. SERS spectra and scan images of single-layer and few-layer graphene were acquired. Single-layer graphene provides much larger SERS enhancement compared to few-layer graphene, while in single-layer graphene the enhancement of the G band was larger than that of the 2D band. Furthermore, the D bands were identified in the SERS spectra; these bands were not observed in a normal Raman spectrum without Au deposition. Appearance of the D band is ascribed to the considerable SERS enhancement and not to an Au deposition-induced defect. Lastly, SERS enhancement of graphene on a transparent glass substrate was compared with that on the SiO(2)(300 nm)/Si substrate to exclude enhancement by multiple reflections between the Si substrate and deposited Au nanoparticles. The contribution of multiple reflections to total enhancement on the SiO(2)(300 nm)/Si substrate was 1.6 times out of average SERS enhancement factor, 71 times. PMID- 21264962 TI - Magnetoresistance in La0.5Sr0.5MnO2.5. AB - Resistance measurements indicate the presence of magnetoresistance in the La(0.5)Sr(0.5)MnO(2.5) brownmillerite related compound. An 80 % of magnetoresistance is found at 75 K. In spite of the partial break-up occurring at the 3D network of octahedra sharing corners, characteristic of the full oxygen content perovskite phase, the oxygen deficient compound exhibits complex magnetic and electric properties. Such behavior can be explained on the basis of ferromagnetic and metallic clusters randomly distributed at the octahedral layers separated from each other by an insulating antiferromagnetic matrix. AC susceptibility measurements suggest spin glass behavior at low temperature as a consequence of the competition between different magnetic interactions. PMID- 21264963 TI - Synthesis, crystal structures and magnetic properties of M(II)Cu(II) chains (M = Mn and Co) with sterically hindered alkyl-substituted phenyloxamate bridging ligands. AB - A series of neutral oxamato-bridged heterobimetallic chains of general formula [MCu(L(x)2 (S)2] . p S . q H2O [p = 0-1, q = 0-2.5; L1 = N-2,6 dimethylphenyloxamate, S = DMF with M = Mn (1a) and Co (1b); L2 = N-2,6 diethylphenyloxamate, S = DMF with M = Mn (2a) and Co (2b) or S = DMSO with M = Mn (2c) and Co (2 d); L3 = N-2,6-diisopropylphenyloxamate, S = DMF with M = Mn (3a) and Co (3b) or S = DMSO with M = Mn (3c) and Co (3d)] were prepared by treating the corresponding anionic oxamatocopper(II) complexes [Cu(L(x))(2)]2- (x = 1-3) with M(2+) cations (M = Mn and Co) in DMF or DMSO as the solvent. The single-crystal X-ray structures of 2a and 3a reveal the occurrence of well isolated, zigzag, oxamato-bridged manganese(II)-copper(II) chains. The intrachain Cu...Mn distances across the oxamato bridge are 5.3761(7) and 5.4002(17) A for 2a and 3a, respectively, whereas the shortest interchain Mn...Mn distances are 9.4475(16) and 8.1649(14) A for 2a and 3 a, respectively. All of these M(II) Cu(II) chains (M = Mn and Co) exhibit 1D ferrimagnetic behaviour with moderately strong intrachain antiferromagnetic coupling between the square-planar Cu(II) and octahedral high-spin M(II) ions across the oxamato bridge [-J=31.4-35.2 and 33.4 44.8 cm(-1) , respectively; H = ?(i)-JS(M,i) (S(Cu,i) +S(Cu,i-1))]. Only the Co(II) Cu(II) chains show slow magnetic relaxation effects characteristic of single-chain magnets (SCMs). Analysis of the magnetic relaxation dynamics of 3d shows a thermally activated mechanism (Arrhenius law dependence) with values of the pre-exponential factor (tau(0) = 2.6 * 10(-9) s) and activation energy (E(a) =7.7 cm(-1) ) that are typical of SCMs. In contrast, two relaxation regimes are observed for 2d in different temperature regions (tau(0) = 3.2 * 10(-10) s and E(a) = 24.7 cm(-1) for T < 4.5K and tau(0) = 3.2 * 10(-14) s and E(a) = 37.5 cm( 1) for T>4.5K). PMID- 21264964 TI - Highly efficient multiphoton-absorbing quadrupolar oligomers for frequency upconversion. AB - Two series of quadrupolar diphenylamino-endcapped oligofluorenes, PhN-OF(n)-NPh (n=2-5) and PhN-OF(n)-TAZ-OF(n)-NPh (n=1-4), which have an electron-withdrawing 1,2,4-triazole (TAZ) moiety as central core, with D-pi-A-pi-D structural motif (D=donor, A=acceptor), have been synthesized by palladium-catalyzed Suzuki cross coupling of 9,9-dibutyl-7-(diphenylamino)-2-fluorenylboronic acid and the corresponding (1,2,4-triazole-based) aryl halide as key step. On pumping with infrared femtosecond lasers, these oligomers showed very strong multiphoton excited blue photoluminescence. These D-pi-D and D-pi-A-pi-D quadrupolar oligofluorenes exhibit superior three-photon absorption properties compared to the respective D-pi-A counterparts with a highest three-photon absorption cross section (sigma(3)) of up to 2.72*10(-77) cm(6) s(2) . Despite the comparable linear and multiphoton absorption properties of the two types of quadrupolar oligomers PhN-OF(n)-NPh and PhN-OF(n)-TAZ-OF(n)-NPh, only the former exhibit remarkably intense and highly efficient multiphoton-excited frequency-upconverted deep blue lasing, which gives rise to record high lasing efficiency of 0.097% and very narrow of full width at half-maximum of the lasing spectra. Our findings suggest that quadrupolar-type molecules/oligomers are superior for multiphoton excited frequency upconverted lasing to their dipolar counterparts and also provide important guidelines to design highly efficient three-photon absorption molecules for photoluminescence and lasing applications. PMID- 21264965 TI - Kinetic studies exploring the role of anion templation in the slippage formation of rotaxane-like structures. AB - The first examples of the slippage formation of rotaxane-like structures in the presence of an anion template are reported between a macrocycle, synthesised by exploiting Eglinton coupling, and stoppered pyridinium axle components. The role of the anion template in the slippage process has been explored by kinetic studies. (1)H NMR spectroscopic investigations reveal the slippage species formed are not rotaxanes but pseudorotaxanes with some rotaxane character. The anion template significantly influences the amount of rotaxane character and the rate of slippage. Importantly, the fastest slippage rates, k(on), are achieved with the non-coordinating hexafluorophosphate anion, whereas the slowest slippage off rates, k(off), are observed in the presence of coordinating anions, such as chloride. Since the k(off) rates are significantly smaller than the k(on) rates in the presence of coordinating anions, these anions act as templates favouring formation of the slippage species thermodynamically. Consequently, the resulting pseudorotaxanes with coordinating anions have greater rotaxane character. Two strategies for converting the slippage pseudorotaxanes into rotaxanes using hydrogenation or complexation with cobalt carbonyl are investigated. PMID- 21264966 TI - Electron-accepting dithiarubicene (emeraldicene) and derivatives prepared by unprecedented nucleophilic hydrogen substitution by alkyllithium reagents. AB - By understanding the role of DMF as a hydride source via a Pd-catalyzed reaction and switching to CH(3)CN solvent, an efficient route for the synthesis of emeraldicene and some new substituted derivatives is reported with potential application in organic electronics. Additionally, the nucleophilic alkylation of emeraldicene 4 a with alkyllithium reagents provides monosubstituted compounds 7 a and 7 b, the latter crystallizing in columnar stacks, with pi-pi overlap between adjacent molecules in the stack. PMID- 21264967 TI - 2'-O,4'-C-aminomethylene-bridged nucleic acid modification with enhancement of nuclease resistance promotes pyrimidine motif triplex nucleic acid formation at physiological pH. AB - Due to the instability of pyrimidine motif triplex DNA at physiological pH, triplex stabilization at physiological pH is crucial in improving its potential in various triplex-formation-based strategies in vivo, such as gene expression regulation, genomic DNA mapping, and gene-targeted mutagenesis. To this end, we investigated the thermodynamic and kinetic effects of our previously reported chemical modification, 2'-O,4'-C-aminomethylene-bridged nucleic acid (2',4' BNA(NC)) modification of triplex-forming oligonucleotide (TFO), on triplex formation at physiological pH. The thermodynamic analyses indicated that the 2',4'-BNA(NC) modification of TFO increased the binding constant of the triplex formation at physiological pH by more than 10-fold. The number and position of the 2',4'-BNA(NC) modification in TFO did not significantly affect the magnitude of the increase in the binding constant. The consideration of the observed thermodynamic parameters suggested that the increased rigidity and the increased degree of hydration of the 2',4'-BNA(NC)-modified TFO in the free state relative to the unmodified TFO may enable the significant increase in the binding constant. Kinetic data demonstrated that the observed increase in the binding constant by the 2',4'-BNA(NC) modification resulted mainly from the considerable decrease in the dissociation rate constant. The TFO stability in human serum showed that the 2',4'-BNA(NC) modification significantly increased the nuclease resistance of TFO. Our results support the idea that the 2',4'-BNA(NC) modification of TFO could be a key chemical modification to achieve higher binding affinity and higher nuclease resistance in the triplex formation under physiological conditions, and may lead to progress in various triplex-formation based strategies in vivo. PMID- 21264968 TI - An efficient approach for the characterization of mucin-type glycopeptides: the effect of O-glycosylation on the conformation of synthetic mucin peptides. AB - Despite the growing importance of mucin core O-glycosylation in many biological processes including the protection of epithelial cell surfaces, the immune response, cell adhesion, inflammation, and tumorigenesis/metastasis, the regulation mechanism and conformational significance of the multiple introduction of alpha-GalNAc residues by UDP-GalNAc:polypeptide N acetylgalactosaminyltransferases (ppGalNAcTs) remains unclear. Here we report an efficient approach by combining MS and NMR spectroscopy that allows for the identification of O-glycosylation site(s) and the effect of O-glycosylation on the peptide backbone structures during enzymatic mucin domain assembly by using an isoform UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase-T2 (ppGalNAcT2) in vitro. An electron-capture dissociation device in a linear radio frequency quadrupole ion trap (RFQ-ECD) combined with a time-of-flight (TOF) mass spectrometer was employed for the identification of Thr/Ser residues occupied by alpha-GalNAc branching among multiple and potential O-glycosylation sites in the tandem repeats of human mucin glycoproteins MUC4 (Thr-Ser-Ser-Ala-Ser-Thr-Gly-His Ala-Thr-Pro-Leu-Pro-Val-Thr-Asp) and MUC5AC (Pro-Thr-Thr-Val-Gly-Ser-Thr-Thr-Val Gly). In the present study, O-glycosylation was initiated specifically at Thr10 in naked MUC4 peptide and additional introduction of alpha-GalNAc proceeded preferentially but randomly at three other Thr residues to afford densely glycosylated MUC4 containing six alpha-GalNAc residues at Thr1, Ser2, Ser5, Thr6, Thr10, and Thr15. On the contrary, O-glycosylation of naked MUC5AC peptide occurred predominantly at consecutive Thr residues and led to MUC5AC with four alpha-GalNAc residues at Thr2, Thr3, Thr7, and Thr8. The solution structures determined by NMR spectroscopic studies elicited that the preferential introduction of alpha-GalNAc at Thr10 of MUC4 stabilizes specifically a beta-like extended backbone structure at this area, whereas other synthetic models with a single alpha-GalNAc residue at Thr1, Thr6, or Thr15 did not exhibit any converged three-dimensional structure at the proximal peptide moiety. Such conformational impact on the underlying peptides was proved to be remarkable in the glycosylation at the consecutive Thr residues of MUC5AC. PMID- 21264969 TI - Starburst triarylamine donor-acceptor-donor quadrupolar derivatives based on cyano-substituted diphenylaminestyrylbenzene: tunable aggregation-induced emission colors and large two-photon absorption cross sections. AB - In this work, we have developed a new class of aggregation-induced emission (AIE) active compounds, in which three electron-donating diphenylamine, phenothiazine, or carbazole groups are connected to the 1, 4-positions of the benzene through bis(alpha-cyano-4-diphenylaminostyryl) conjugation bridges to form three triarylamine quadrupolar derivatives (3 a-c). Their one- and two-photon absorption properties have been investigated. The two-photon absorption (2PA) cross sections measured by the open-aperture Z-scan technique were determined to be 1016, 1484, and 814 GM for 3 a-c, respectively. From this result, the high 2PA properties of these molecules are attributed to the extended pi system and enhanced intramolecular charge transfer from the starburst triarylamine to the cyano group. Moreover, cyano-substituted diphenylamine styrylbenzene (CNDPASB) based compounds are very weakly fluorescent in THF, but their intensities increase by almost 230, 70, and 5 times, respectively, in water/THF (v/v 90 %) mixtures, in which they exhibit strongly enhanced red, orange, and deep yellow fluorescence emissions, respectively. This result indicates that the intramolecular vibration and rotation of these dyes is considerably restricted in nano-aggregates formed in water, leading to significant increases in fluorescence. It was found that the color tuning of the CNDPASB-based compounds could be conveniently accomplished by changing the starburst triarylamine donor moiety. Multilayer electroluminescence devices with TPBI (2,2',2''-(benzene-1,3,5 triyl)-tri(1-phenyl-1H-benzimidazole)) electron-transporting layers have been made, with 3 a and 3 c as a non-doping red-yellow emitter. The preliminary results for these multilayer devices show a maximum efficiency of 0.25 %, and electroluminescence (EL) wavelengths around 568 nm. The excellent 2PA and AIE properties of these compounds make them potential materials for biophotonic applications. PMID- 21264970 TI - Neighboring lithium-assisted [1,2]-Wittig rearrangement: practical access to diarylmethanol-based 1,4-diols and optically active BINOL derivatives with axial and sp3-central chirality. AB - A facile and practical methodology for the synthesis of synthetically useful diarylmethanol-based 1,4-diols and enantiomerically pure BINOL-derived diols with axial and sp(3)-central chirality has been developed through neighboring lithium promoted [1,2]-Wittig rearrangement. The chirality transfer process shows a broad substrate scope in terms of the aromatic ether substituent, which allows access to a broad of range of chiral 1,1'-binaphthalene-2-alpha-arylmethanol-2'-ols with excellent enantioselectivities (>99 % enantiomeric excess) and yields (84-96 %). This should be considered as an available and attractive chiral source to design and prepare privileged ligands or catalysts. PMID- 21264971 TI - One-pot selective syntheses of 5-azaindoles through zirconocene-mediated multicomponent reactions with three different nitrile components and one alkyne component. AB - 5-Azaindoles either with three different substituents at their 2-, 4-, and 6 positions or with two identical substituents at their 2- and 6-positions and a different one at the 4-position, were obtained in good to excellent isolated yields by a zirconocene-mediated multicomponent process. Each reaction involved four organic partners, comprising a Si-tethered diyne, one tBuCN component, and two (either different or identical) nitriles. All these four components were combined through the action of a Cp(2)Zr(II) species into a three-ring fused Zr/Si-containing organometallic complex in a perfectly chemo- and regioselective manner. This multicomponent reaction process consisted of three reaction steps, all of which were made clear through the isolation and characterization of their corresponding organometallic intermediates: the zirconacyclopropene azasilacyclopentadienes 2, the allenyl-aza-zirconacycles 3, and the three-ring fused complexes 6. X-ray single-crystal structural analyses of two three-ring fused Zr/Si-containing intermediates and two 5-azaindoles unambiguously showed the positions of the different substituents and the regioselectivity. Iminopyrrole derivatives could be also highly selectively prepared from a Si tethered diyne and two different nitriles. PMID- 21264972 TI - Total synthesis and biological assessment of (-)-exiguolide and analogues. AB - We describe herein an enantioselective total synthesis of (-)-exiguolide, the natural enantiomer. The methylene bis(tetrahydropyran) substructure was efficiently synthesized by exploiting olefin cross-metathesis for the assembly of readily available acyclic segments and intramolecular oxa-conjugate cyclization and reductive etherification for the formation of the tetrahydropyran rings. The 20-membered macrocyclic framework was constructed in an efficient manner by means of Julia-Kocienski coupling and Yamaguchi macrolactonization. Finally, the (E,Z,E)-triene side chain was introduced stereoselectively via Suzuki-Miyaura coupling to complete the total synthesis. Assessment of the growth inhibitory activity of synthetic (-)-exiguolide against a panel of human cancer cell lines elucidated for the first time that this natural product is an effective antiproliferative agent against the NCI-H460 human lung large cell carcinoma and the A549 human lung adenocarcinoma cell lines. Moreover, we have investigated structure-activity relationships of (-)-exiguolide, which elucidated that the C5 methoxycarbonylmethylidene group and the length of the side chain are important for the potent activity. PMID- 21264973 TI - Expeditious divergent synthetic approach to polycyclic terpene-like molecules. PMID- 21264974 TI - Fluorene-based phosphine oxide host materials for blue electrophosphorescence: an effective strategy for a high triplet energy level. PMID- 21264975 TI - The case of the missing glutamine. AB - A theoretical study was performed to determine the accuracy and repeatability of multiple one-dimensional pulse sequences in the quantification of glutamine concentration at 3 T. Variable repeatability (12% to > 50%) and significant absolute error (-50% to +70%) were noted for the eight pulse sequences considered. Data acquired in vivo using three of the pulse sequences used for simulation matched the predicted repeatability well; among the pulse sequences considered, point-resolved spectroscopy (TE = 80 ms) offered minimal error and acceptable repeatability (12%) for brain glutamine measurements. Following correction for the expected bias of each pulse sequence, consistent glutamine measurements, in the 1-mM range, were reported with the three sequences. An explanation for the mismatch between in vivo (1)H MRS and in vitro (13)C/(1)H MRS at high field was attempted. PMID- 21264976 TI - Frequency offset dependence of adiabatic rotating frame relaxation rate constants: relevance to MRS investigations of metabolite dynamics in vivo. AB - In this work, we investigated the frequency-offset dependence of the rotating frame longitudinal (R(1rho)) and transverse (R(2rho)) relaxation rate constants when using hyperbolic-secant adiabatic full passage pulses or continuous-wave spin-lock irradiation. Phantom and in vivo measurements were performed to validate theoretical predictions of the dominant relaxation mechanisms existing during adiabatic full passage pulses when using different settings of the frequency offset relative to the carrier. In addition, adiabatic R(1rho) and R(2rho) values of total creatine and N-acetylaspartate were measured in vivo from the human brain at 4 T. When the continuous-wave pulse power was limited to safe specific absorption rates for humans, simulations revealed a strong dependence of R(1rho) and R(2rho) values on the frequency offset for both dipolar interactions and anisochronous exchange mechanisms. By contrast, theoretical and experimental results showed adiabatic R(1rho) and R(2rho) values to be practically invariant within the large subregion of the bandwidth of the hyperbolic-secant pulse where complete inversion was achieved. However, adiabatic R(1rho) and R(2rho) values of the methyl protons of total creatine (at 3.03 ppm) were almost doubled when compared with those of the methyl protons of N-acetylaspartate (at 2.01 ppm) in spite of the fact that these resonances were in the flat region of the inversion band of the adiabatic full passage pulses. We conclude that differences in adiabatic R(1rho) and R(2rho) values of human brain metabolites are not a result of their chemical shifts, but instead reflect differences in dynamics. PMID- 21264977 TI - In vivo MRI of early stage mammary cancers and the normal mouse mammary gland. AB - Since the advent of screening mammography, approximately one-quarter of newly diagnosed breast cancers are at the earliest preinvasive stage of ductal carcinoma in situ (DCIS). Concomitant with this improvement in early detection has been a growing clinical concern that distinguishing aggressive from indolent DCIS is necessary to optimize patient management. Genetically engineered mouse models offer an appealing experimental framework in which to investigate factors that influence and predict progression of preinvasive neoplasias. Because of the small size of early stage carcinomas in mice, high-resolution imaging techniques are required to effectively observe longitudinal progression. The purpose of the present study was to evaluate the feasibility of MRI for assessment of in situ mammary neoplasias and early invasive mammary cancers that stochastically arise in mammary glands of C3(1) SV40 Tag transgenic mice. Additionally, images of normal mammary glands from wild-type FVB/N mice were acquired and compared with those from transgenic mice. Sixteen mice underwent MR examinations employing axial two-dimensional multi-slice gradient recalled echo scans (TR/TE =~1000/5.5 ms) with fat suppression in a two-step process targeting both the upper and lower mammary glands. MRI successfully detected in situ and early invasive neoplasias in transgenic mice with high sensitivity and specificity. The average signal-to noise ratio (SNR) of in situ lesions on fat-suppressed high-resolution T(1) weighted images was 22.9, which was lower than that of invasive tumors, lymph nodes and muscle (average SNR of 29.5-34.9, p < 0.0001) but significantly higher than that of normal mammary tissue (average SNR = 5.5, p < 0.0001). Evaluation of wild-type mammary glands revealed no cancerous or benign lesions, and comparable image contrast characteristics (average SNR = 5.2) as compared with normal tissue areas of transgenic mice. This present study demonstrates that MRI is an excellent candidate for performing longitudinal assessment of early stage mammary cancer disease progression and response to therapy in the transgenic model system. PMID- 21264978 TI - Quantification of myocardial blood flow and flow reserve in rats using arterial spin labeling MRI: comparison with a fluorescent microsphere technique. AB - To quantify noninvasively myocardial blood flow (MBF) and MBF reserve in isoflurane-anesthetized rats using the Look-Locker flow-alternating inversion recovery gradient-echo arterial spin labeling technique (LLFAIRGE-ASL), and to compare the results with the fluorescent microsphere (FM) technique. Male Wistar rats (weight = 200-240 g, n = 21) were anesthetized with 2.0% isoflurane. Hemodynamic parameters were recorded. In seven rats, MBF was assessed on a Bruker Biospec 4.7T MR system using an ECG- and respiration-gated LLFAIRGE-ASL (pixel size = 234 * 468um(2) , TE = 1.52ms) at rest and during adenosine infusion (140 ug/kg/min). A mixture of 200 000 FM was injected into a second group of rats at rest and during adenosine infusion (n = 7 each), under similar physiologic conditions. Hearts and skeletal muscle samples were processed for fluorescence spectroscopy. Two-tailed unpaired, paired Student's t-test and ANOVA were used to compare groups. MBF measured with LLFAIRGE-ASL was 5.2 +/- 1.0 mL/g/min at rest and 13.3 +/- 3.0 mL/g/min during adenosine infusion. Results obtained with fluorescent microspheres yielded 5.9 +/- 2.3 mL/g/min (nonsignificant vs. LLFAIRGE-ASL, p = 0.9) at rest and 13.1 +/- 2.1 mL/g/min (nonsignificant vs. LLFAIRGE-ASL, p = 0.4) during adenosine infusion. Myocardial blood flow reserve measured using LLFAIRGE-ASL and FM were not significantly different (2.5 +/- 0.6 vs. 2.4 +/- 0.9, respectively; p = 0.8). Hemodynamic parameters during the experiments were not different between the groups. The myocardial blood flow reserve determined under isoflurane anesthesia was 2.5 +/- 0.6, which was not different from the value obtained with FM. LLFAIRGE-ASL provided MBF maps with high spatial resolution in rats under isoflurane anesthesia. LLFAIRGE-ASL is a noninvasive measure to assess myocardial blood flow reserve and provides an interesting tool for cardiovascular research. PMID- 21264980 TI - Speckle tracking for the assessment of fetal cardiac function. PMID- 21264979 TI - Imaging apolipoprotein AI in vivo. AB - Coronary disease risk increases inversely with high-density lipoprotein (HDL) level. The measurement of the biodistribution and clearance of HDL in vivo, however, has posed a technical challenge. This study presents an approach to the development of a lipoprotein MRI agent by linking gadolinium methanethiosulfonate (Gd[MTS-ADO3A]) to a selective cysteine mutation in position 55 of apo AI, the major protein of HDL. The contrast agent targets both liver and kidney, the sites of HDL catabolism, whereas the standard MRI contrast agent, gadolinium diethylenetriaminepentaacetic acid-bismethylamide (GdDTPA-BMA, gadodiamide), enhances only the kidney image. Using a modified apolipoprotein AI to create an HDL contrast agent provides a new approach to investigate HDL biodistribution, metabolism and regulation in vivo. PMID- 21264981 TI - Mechanisms in fetal bradyarrhythmia: 65 cases in a single center analyzed by Doppler flow echocardiographic techniques. AB - OBJECTIVE: Fetal bradyarrhythmias have various underlying mechanisms. As blocked atrial bigeminy (BB) generally resolves spontaneously, but incomplete atrioventricular block (AVB) might respond to steroid treatment, correct diagnosis is of major importance. Our objectives were to assess the underlying mechanisms in fetal bradyarrhythmia and the accuracy of Doppler techniques in differentiating between them. METHODS: Seventy-eight patients referred to our tertiary center between 1990 and 2007 for evaluation of fetal bradycardia were analyzed retrospectively. Besides Doppler recordings from the mitral valve/aorta, superior vena cava/aorta and pulmonary vein/peripheral pulmonary artery, we used recordings from the pulmonary trunk and ductus venosus. We calculated the ratio of the time interval between conducted and consecutive blocked atrial contractions divided by the interval between two conducted atrial beats (a(cb) /a(cc) ), to analyze more meticulously the atrial rhythm in BB and second-degree AVB. RESULTS: Fetal bradycardia ( <= 110 bpm) was confirmed in 65 of the 78 referred cases. Twenty-five had AVB (of which 20 were complete AVB), 29 had BB (of which 23 were intermittent) and 11 had sinus bradycardia. The bradyarrhythmic mechanism was identified correctly in all but one fetus with an atrial ectopic rhythm. Heart rates < 65 bpm were not seen in fetuses diagnosed with BB and rates < 60 bpm were seen only in cases with complete AVB, but heart rate did not distinguish between BB and AVB in the 60-75 bpm range. The a(cb) /a(cc) ratio clearly differentiated between fetsues with BB and those with second-degree AVB, including during midgestation, when it was difficult to distinguish these fetuses. CONCLUSIONS: Using Doppler flow recordings, the mechanism causing fetal bradycardia can be clarified. In most cases this can be accomplished by visual validation only, and meticulous measurements are needed mainly to distinguish midterm fetuses with BB from those with second-degree AVB. PMID- 21264982 TI - Does gastric dilation predict adverse perinatal or surgical outcome in fetuses with gastroschisis? AB - OBJECTIVE: To compare perinatal and infant surgical outcomes in fetuses with gastroschisis with and without gastric dilation in a single-center cohort. METHODS: This was a retrospective study of all singleton pregnancies with a prenatal diagnosis of gastroschisis managed at University of Toronto perinatal centers between January 2001 and February 2010. Digital prenatal ultrasound images were reviewed to determine fetal gastric size within 2 weeks of delivery. Perinatal and surgical outcomes were compared in fetuses with and without gastric dilation including: gestational age at delivery, mode of delivery, indication for Cesarean section, meconium-stained amniotic fluid, birth weight percentile, Apgar scores at 1 and 5 min, umbilical artery pH, time to full enteral feeding, length of hospital stay, bowel atresia or necrosis and need for bowel resection. RESULTS: Ninety-eight fetuses with prenatally diagnosed gastroschisis managed at our center were included in the study, of which 32 (32.7%) were found to have gastric dilation. Gastric dilation predicted meconium-stained amniotic fluid at delivery (53% vs. 24%; P = 0.017), but no other adverse perinatal outcome. Surgical morbidity rates (bowel atresia, bowel necrosis, perforation diagnosed postnatally, need for bowel resection, total time to full enteral feeding and length of hospital stay) were unaffected by gastric dilation. CONCLUSIONS: In gastroschisis, fetal gastric dilation is associated with meconium-stained amniotic fluid at delivery, but is not predictive of any serious perinatal or postnatal complications. Fetal growth and well-being should be serially evaluated on ultrasound using biophysical and Doppler assessment to decide on the optimal timing and mode of delivery. PMID- 21264983 TI - Subserosal pyomyoma in a virgin female: sonographic and computed tomographic imaging features. PMID- 21264984 TI - Benign cystic peritoneal mesothelioma incorrectly diagnosed as an ovarian borderline mucinous tumor of intestinal type at transvaginal preoperative ultrasound evaluation. PMID- 21264985 TI - Chiari malformation eponym- time for historical justice. PMID- 21264986 TI - Three-dimensional visualization of fetal white-matter pathways in utero. PMID- 21264987 TI - A prospective study of asthma and subsequent use of hypnotics in young adults. AB - PURPOSE: To examine whether young adults with asthma are at higher risk of initiating hypnotic use. METHODS: The study population was participants from the Norwegian youth health surveys, where all 10th grade students (15-17 years old) in five counties were invited. 10,164 participants with no prior use of hypnotics were linked to the Norwegian Prescription Database. Four groups were defined based on survey data about ever having had asthma and prescription data on asthma drugs received in the year prior to start of follow-up: (1) no asthma; (2) not active asthma; (3) active recently developed asthma; and (4) still active asthma. Incidence proportions were estimated as share of participants filling hypnotic prescriptions during 2005-July 2010. Incidence rate ratios (IRR), adjusted for potential confounders (illnesses, lifestyle and sociodemographic factors), were estimated with the number of hypnotic prescriptions filled during 2005-July 2010 as outcome. RESULTS: The incidence proportion of filling hypnotic prescriptions was 6.1%, ranging from 5.7% in no asthma group to 9.5% in active recently developed asthma group. Crude IRR was 1.35 (95%CI 0.93-1.95) for not active asthma, 4.18 (1.83-9.55) for active recently developed asthma, and 1.63 (0.85 3.14) for still active asthma, with no asthma as reference. Adjusted IRR for active recently developed asthma group changed to 4.72 (2.07-10.75) while the other groups remained statistically not significant. CONCLUSIONS: In this prospective study of young adults without prior use of hypnotics, an increased risk of initiating hypnotic use was present in asthmatics, especially among those who recently had received asthma drugs. PMID- 21264988 TI - Drug utilization and polypharmacy in an Italian elderly population: the EPIFARM elderly project. AB - OBJECTIVE: To investigate the prescribing patterns and the prevalence of polypharmacy in community-dwelling elderly people, and to analyze the association of chronic medications and number of drug prescriptions with age and sex. METHODS: All prescriptions for people aged 65 years or older reimbursed by the Italian National Health Service (NHS) and dispensed by retail pharmacies of the 15 local health units (LHU) in the Lombardy Region during 2005 were analyzed. Logistic regression analysis was used to assess the association between drug prescription (overall, chronic drugs, and polypharmacy) and age, sex, and LHU of residence. RESULTS: Eighty-eight percent of the 1 ,767 ,239 analyzed elderly received at least one drug prescription. The overall prescription rate was slightly higher for women than men (odds ratio [OR] 1.20; 95%CI 1.19-1.21). Seventy-six percent of the elderly received at least one chronic drug, 46% were exposed to polypharmacy, and 20% to chronic polypharmacy. At multivariate analysis, age and LHU residence of the elderly were the main determinants of drug exposure. A significant correlation was found between the overall prescription prevalence rate and exposure to chronic drugs and to chronic polypharmacy (r(s) = 0.79, p < 0.0005 and r(s) = 0.84, p < 0.0001, respectively). CONCLUSIONS: Our findings indicate that age and LHU residence of the elderly are the main determinants of drug prescribing, and there is evidence of a significant correlation between the overall prescription prevalence rate and exposure to chronic drugs and to chronic polypharmacy. PMID- 21264989 TI - Peak window of suicides occurs within the first month of diagnosis: implications for clinical oncology. AB - OBJECTIVE: A diagnosis of cancer can provoke painful emotional reactions and possibly suicidal thoughts in a patient. Consequently, cancer patients carry a twofold increased lifetime risk of suicide. This risk is much higher within 1 year of diagnosis. However, it remains largely unknown whether suicide frequency remains constant within the first year. Therefore, we sought to characterize the distribution of suicides in order to potentially identify a clinically important window of peak suicide risk. METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) database for cancer patients 20 + years old with diagnosed with a single malignancy from 1973 to 2005 and known cause of death, including whether a patient committed suicide. Initial frequency analysis was performed to identify the period of maximum suicide risk. One-way ANOVA was performed to assess the relationship between year of diagnosis and suicide completions within 1 month of diagnosis. RESULTS: The cohort consisted of 3,678,868 patients. Of the total cohort, 0.2% (5875 patients) committed suicide, 36% (2111 patients) within 1 year of diagnosis. One in three (701 of the patients) who committed suicide in the first year did so within 1 month of diagnosis. No change in this distribution occurred over time. CONCLUSIONS: Cancer patients carry an increased risk of suicide. However, this risk peaks with the month following diagnosis. Clinicians should be aware of this increased risk and include assessments of mood state and suicidality at the time of initial diagnosis of the malignancy and be prepared to provide referral to mental health treatment providers. PMID- 21264990 TI - Early changes in white matter pathways of the sensorimotor cortex in premanifest Huntington's disease. AB - OBJECTIVES: To investigate the function-structure relationship of white matter within different stages of Huntington's disease (HD) using diffusion tensor imaging (DTI). EXPERIMENTAL DESIGN: From the TRACK-HD study, an early stage HD group and a premanifest gene carrier group (PMGC) were age-matched to two healthy control groups; all underwent 3-T MRI scanning of the brain. Region of interest (ROI) segmentation of the corpus callosum, caudate nucleus, thalamus, prefrontal cortex, and sensorimotor cortex was applied, and the apparent fiber pathways of these regions were analyzed. Functional measures of motor, oculomotor, cognition, and behavior were correlated to DTI measures. PRINCIPLE OBSERVATIONS: In PMGC versus controls, higher apparent diffusion coefficient (ADC) was seen in white matter pathways of the sensorimotor cortex (P < 0.01) and in the ROI of corpus callosum (P < 0.017). In early HD, fiber tract analysis showed higher ADC in pathways of the corpus callosum, thalamus, sensorimotor, and prefrontal region (P < 0.01). ROI analysis showed higher diffusivity in the corpus callosum and caudate nucleus (P < 0.017). Motor, oculomotor, cognition, and probability of onset within 2 and 5 years, correlated well with ADC measures of the corpus callosum (P < 0.01 - P < 0.005), sensorimotor (P < 0.01 - P < 0.005), and prefrontal region (P < 0.01). CONCLUSIONS: Disturbances in the white matter connections of the sensorimotor cortex can be demonstrated not only in manifest HD but also in premanifest gene carriers. Connectivity measures are well related to clinical functioning. DTI measures can be regarded as a potential biomarker for HD, due to their ability to objectify changes in brain structures and their role within brain networks. PMID- 21264992 TI - Minimizing the use of platinum in hydrogen-evolving electrodes. PMID- 21264993 TI - Polypeptide conjugate binders that discriminate between two isoforms of human carbonic anhydrase in human blood. AB - Two binder candidates 4-C37L34-B and 3-C15L8-B from a 16-membered set of 42 residue polypeptide conjugates designed to bind human carbonic anhydrase II (HCAII), were shown to bind HCAII with high affinity in a fluorescence-based screening assay. Two carbonic anhydrase isoforms with 60 % homology exist in human blood with HCAI being present in five- to sevenfold excess over HCAII. The ability of the binders to discriminate between HCAI and HCAII was evaluated with regard to what selectivity could be achieved by the conjugation of polypeptides from a 16-membered set to a small organic molecule that binds both isoforms with similar affinities. The polypeptide conjugate 4-C37L34-B bound HCAII with a K(D) of 17 nM and HCAI with a K(D) of 470 nM, that is, with a 30-fold difference in affinity. The corresponding dissociation constants for the complexes formed from 3-C15L8-B and the two carbonic anhydrases were 60 and 390 nM, respectively. This demonstration of selectivity between two very similar proteins is striking in view of the fact that the molecular weight of each one of the conjugate molecules is little more than 5000, the fold is unordered, and the polypeptide sequences were designed de novo and have no prior relationship to carbonic anhydrases. The results suggest that synthetic polypeptide conjugates can be prepared from organic molecules that are considered to be weak binders with low selectivity, yielding conjugates with properties that make them attractive alternatives to biologically generated binders in biotechnology and biomedicine. PMID- 21264991 TI - Bystanding F+ oxidants enable selective reductive elimination from high-valent metal centers in catalysis. AB - Reductive elimination from partially or completely oxidized metal centers is a vital step in a myriad of carbon-carbon and carbon-heteroatom bond-forming reactions. One strategy for promoting otherwise challenging reductive elimination reactions is to oxidize the metal center using a two-electron oxidant (that is, from M((n)) to M((n+2))). However, many of the commonly used oxidants for this type of transformation contain oxygen, nitrogen, or halogen moieties that are subsequently capable of participating in reductive elimination, thus leading to a mixture of products. In this Minireview, we examine the use of bystanding F(+) oxidants for addressing this widespread problem in organometallic chemistry and describe recent applications in Pd(II) /Pd(IV) and Au(I) /Au(III) catalysis. We then briefly discuss a rare example in which one-electron oxidants have been shown to promote selective reductive elimination in palladium(II)-catalyzed C-H functionalization, which we view as a promising future direction in the field. PMID- 21264994 TI - Minimal substrate features for Erm methyltransferases defined by using a combinatorial oligonucleotide library. AB - Erm methyltransferases are prevalent in pathogenic bacteria and confer resistance to macrolide, lincosamide, and streptogramin B antibiotics by specifically methylating the 23S ribosomal RNA at nucleotide A2058. We have identified motifs within the rRNA substrate that are required for methylation by Erm. Substrate molecules were constructed in a combinatorial manner from two separate sets (top and bottom strands) of short RNA sequences. Modifications, including LNA monomers with locked sugar residues, were incorporated into the substrates to stabilize their structures. In functional substrates, the A2058 methylation target (on the 13- to 19-nucleotide top strand) was displayed in an unpaired sequence immediately following a conserved irregular helix, and these are the specific structural features recognized by Erm. Erm methylation was enhanced by stabilizing the top-strand conformation with an LNA residue at G2056. The bottom strand (nine to 19 nucleotides in length) was required for methylation and was still functional after extensive modification, including substitution with a DNA sequence. Although it remains possible that Erm makes some unspecific contact with the bottom strand, the main role played by the bottom strand appears to be in maintaining the conformation of the top strand. The addition of multiple LNA residues to the top strand impeded methylation; this indicates that the RNA substrate requires a certain amount of flexibility for accommodation into the active site of Erm. The combinatorial approach for identifying small but functional RNA substrates is a step towards making RNA-Erm complexes suitable for cocrystal determination, and for designing molecules that might block the substrate-recognition site of the enzyme. PMID- 21264995 TI - Characterization of the biosynthesis gene cluster for alkyl-O-dihydrogeranyl methoxyhydroquinones in Actinoplanes missouriensis. AB - A polyketide biosynthesis gene cluster (agq) was found on the genome of a rare actinomycete, Actinoplanes missouriensis. Streptomyces lividans expressing agqA encoding a type III polyketide synthase produced alkylresorcinols mainly from C(16-17) fatty acids. Heterologous expression of the agq genes in S. lividans indicated the function of cognate polyketide modification enzymes; a monooxygenase AgqB hydroxylates the alkylresorcinols to yield 6-alkyl-2 hydroxyhydroquinones, a methyltransferase AgqC catalyzes O-methylation of the alkyl-hydroxyhydroquinones to yield 6-alkyl-2-methoxyhydroquinones, and a UbiA like prenyltransferase AgqD attaches a prenyl group to the C-4 hydroxy group of the alkyl-methoxyhydroquinones to yield 6-alkyl-4-O-geranyl-2 methoxyhydroquinones and 6-alkyl-4-O-dihydrofarnesyl-2-methoxyhydroquinones derived from C(16-17) fatty acids. In contrast, A. missouriensis was found to produce 6-alkyl-4-O-dihydrogeranyl-2-methoxyhydroquinones derived from C(16-18) fatty acids by the function of the agq gene cluster. All of these prenylated phenolic lipids were novel compounds. PMID- 21264996 TI - Enhanced expression and purification of fungal galactose oxidase in Escherichia coli and use for analysis of a saturation mutagenesis library. AB - Galactose oxidase (GO) displays broad primary alcohol substrate specificity and so offers potential for engineering new substrate specificity by directed evolution. Producing variant libraries of sufficient complexity ideally requires expression of functional protein in a host such as Escherichia coli. Wild-type GO is produced by the fungus Fusarium graminiarum and is expressed poorly in E. coli. We introduced silent mutations within codons 2-7 of the mature GO coding sequence to enhance GO translation and have combined these with other expression enhancing mutations. We selected the best E. coli host strain, autoinduction medium, induction temperature, harvest time and cell lysis procedure to produce active recombinant GO. Although normally secreted by the fungus, we have expressed GO in the cytoplasm of E. coli and have used a C-terminal Streptag II sequences for single-step affinity purification. This resulted in purification of 240 mg of functional GO per litre of shake flask culture. We have generated a saturation mutagenesis library at residue Cys383, known to influence substrate binding, and have used the optimised expression conditions to purify and characterise the resulting enzymes. PMID- 21264997 TI - Transport properties and phase behaviour in binary and ternary ionic liquid electrolyte systems of interest in lithium batteries. AB - A binary ionic liquid (IL) system based on a common cation, N-methyl-N propylpyrrolidinium (C(3) mpyr(+)), and either bis(trifluoromethanesulfonyl)imide (NTf(2) (-)) or bis(fluorosulfonyl) imide (FSI(-) as the anion is explored over its entire composition range. Phase behavior, determined by DSC, shows the presence of a eutectic temperature at 247 K and composition around an anion ratio of 2:1 (FSI(-) :NTf(2)(-)) with the phase diagram for this system proposed (under the thermal conditions used). Importantly for electrochemical devices, the single phase melting transition at the eutectic is well below ambient temperatures (247 K). To investigate the effect of such anion mixing on the lithium ion speciation, conductivity and PFG-NMR diffusion measurements were performed in both the binary IL system as well as the Li-NTf(2) -containing ternary system. The addition of the lithium salt to the mixed IL system resulted in a decrease in conductivity, as is commonly observed in the single-component IL systems. For a fixed lithium salt composition, both conductivity and ion diffusion have linear behaviour as a function of the anion ratio, however, the rate of change of the diffusion coefficient seems greater in the presence of lithium. From the application point of view, the addition of the FSI(-) to the NTf(2)(-) IL results in a considerable increase in lithium ion diffusivity at room temperature and no evidence of additional complex ion behaviour. PMID- 21264998 TI - Efficacy of selected pesticides against synanthropic mites under laboratory assay. AB - BACKGROUND: The efficacies of organophosphate pesticides, single-compound versus multicompound pyrethroid formulations and relatively novel unclassified insecticides/acaricides were compared to find the lowest dosage and highest efficacy for the control of Dermatophagoides farina (Hughes), D. pteronyssinus (Trouessart) and Tyrophagus putrescentiae (Schrank). Formulated active ingredients (AIs) were diluted in water and applied onto filter paper in experimental chambers with ten unsexed adult mites in six replicates. Mite mortality was checked after 24 h. The security index (SI) was calculated for all of the AIs by dividing the recommended rate by the LD(90) determined for each species. RESULTS: The tested organophosphates had high LD(90) and low SI values. The single-compound pyrethroids were ineffective (deltamethrin and beta cyfluthrin) or had high LD(90) and low SI values (cyphenothrin, permethrin, pyrethrum and bifenthrin). The multicompound miticides had low LD(90) and high SI values which increased from deltamethrin/S-bioallethrin to permethrin/S bioallethrin/piperonyl butoxide to permethrin/pyriproxyfen/benzyl benzoate. Abamectin, pyridaben, propargite and flufenoxuron were highly active against Dermatophagoides spp. Neem (Acarosan duo) was highly active against all mite species tested. CONCLUSION: The available formulations of multicompound pyrethroids (permethrin/S-bioallethrin/piperonyl butoxide, permethrin/pyriproxyfen/benzyl benzoate), benzyl benzoate, neem and some field acaricides are effective in suppression of synanthropic mites in laboratory assays. Their LD(90) are lower than those of traditionally used organophosphates or single-compound pyrethroid formulations. PMID- 21265001 TI - Quantizing novelty. PMID- 21265002 TI - Steps in metastasis research: analyzing, collecting, and culturing circulating tumor cells. PMID- 21265003 TI - Interpretation of cellular proliferation data: avoid the panglossian. AB - There are several statistics that may be calculated to characterize a cellular proliferation experiment. By far, the most commonly-reported statistic is the percent of cells in the final culture that have divided; however, this statistic has significant limitations. Other statistics provided by software modeling provide a much richer characterization of the biological response; however, their use also comes with caveats. Here, I discuss the practical application of these statistics, including their limitations and interdependencies, using hypothetical data. The goal of this perspective is to prevent the blind reliance or overly optimistic ("panglossian") interpretation of the statistics generated by software, so that researchers and reviewers have a more-informed basis for drawing conclusions from the data. PMID- 21265004 TI - CCR3 as a single selection marker compared to CD123/HLADR to isolate basophils in flow cytometry: some comments. PMID- 21265006 TI - Stable and sensitive probes for lysosomes: cell-penetrating fluorescent calix[4]arenes accumulate in acidic vesicles. AB - The uptake of a fluorescently labeled cationic calix[4] (NBDCalAm) in live, nonfixed cells has been investigated. The compound is taken into the cells rapidly and shows distinct endosomal distribution after 2 hours. This distribution pattern shows colocalization with lysosomal staining. The uptake is not altered by inhibition of clathrin or caveolae dependent pathways nor by depletion of the cellular ATP-pool. Immediately after uptake the probe is localized in the Golgi and brefeldin A treatment prevents transport to lysosomes. Pulse chase experiments with bafilomycin A1, monensin, and sodium azide showed that accumulation and retention of the probe in lysosomes is primarily driven by the activity of vacuolar ATPases. The NBD labeled calix[4]arene provides a very stable and sensitive marker for lysosomes, and has a considerable advantage over some commercially available lysosomal markers in so far that the fluorescent signal is stable even when the cells are incubated in dye-free medium after staining. PMID- 21265005 TI - Multiplex assessment of non-organ-specific autoantibodies with a novel microbead based immunoassay. AB - Advances in immunofluorescence assay development paved the way for the simultaneous detection of several antibodies in one sample, for the serological diagnosis of systemic rheumatic diseases. Standardized automated screening of such antibodies can be achieved by HEp-2 cell-based indirect immunofluorescence (IIF) using a multicolor fluorescence imaging technical platform. To create a common platform for both screening and specific antibody assessment, multiplex measurement of antibodies using fluorescence-coded immobilized microbeads was employed on the same platform. The multicolor fluorescence detection system VideoScan (AKLIDES(r)) was used for the fluorescence analysis of a multiplex microbead-based immunoassay (MIA). First, immunoglobulin G (IgG) was covalently coupled to one microbead population in duplicate and in three independent experiments. The coupled IgG was detected by a CyTM5-conjugated secondary antibody. Thus, intra- and interassay coefficients of variation (CV) were obtained. Second, a multiplex determination of antinuclear autoantibodies (ANA) to Scl-70, Sm, dsDNA, SS-A (Ro60), CENP-B, and La/SS-B by solid-phase MIA was investigated, using 72 sera from patients with autoimmune diseases such as systemic lupus erythematosus and systemic sclerosis (SS). The reproducibility study revealed intra-assay CVs ranging from 3.2% to 9.9%, and interassay CVs ranging from 9.6% to 14.7%. The detection of Scl-70-, Sm-, CENP-B-, and La/SS-B ANA with MIA showed very good agreement with the ELISA results (kappa = 1.0). The resulting relative sensitivities and specificities for Scl-70-, Sm-, CENP-B-, dsDNA-, and La/SS-B-ANA were 100%, respectively, with the exception of dsDNA (specificity 97%). Multiplex detection by immobilized fluorescence-coded microbeads using multicolor fluorescence is a reliable method for the assessment of rheumatic-disease-specific antibodies. Multicolor fluorescence analyses with pattern detection algorithms provide a common platform technique for both the screening of ANA by cell-based IIF and specific antibody assessment by multiplex detection. PMID- 21265007 TI - Detection of mitochondrial fission with orientation-dependent optical Fourier filters. AB - We utilize a recently developed optical imaging method based on Fourier processing with Gabor-like filters to detect changes in light scattering resulting from alterations in mitochondrial structure in endothelial cells undergoing apoptosis. Imaging based on Gabor filters shows a significant decrease in the orientation of subcellular organelles at 60 to 100 minutes following apoptosis induction and concomitant with mitochondrial fragmentation observed by fluorescence. The optical scatter changes can be detected at low resolution at the whole cell level. At high resolution, we combine fluorescence imaging of the mitochondria with optical Fourier-based imaging to demonstrate that the dynamic decrease in organelle orientation measured by optical Gabor filtering is spatially associated with fluorescent mitochondria and remains largely absent from nonfluorescent subcellular regions. These results provide strong evidence that the optical Gabor responses track mitochondrial fission during apoptosis and can be used to provide label-free, rapid monitoring of this morphological process within single cells. PMID- 21265008 TI - Quantitative comparison of polar approach versus fitting method in time domain FLIM image analysis. AB - We calculate here analytically the performance of the polar approach (or phasor) in terms of signal-to-noise ratio and F values when performing time-domain Fluorescence Lifetime Imaging Microscopy (FLIM) to determine the minimal number of photons necessary for FLIM measurements (which is directly related to the F value), and compare them to those obtained from a well-known fitting strategy using the Least Square Method (LSM). The importance of the fluorescence background on the lifetime measurement precision is also investigated. We demonstrate here that the LSM does not provide the best estimator of the lifetime parameter for fluorophores exhibiting mono-exponential intensity decays as soon as fluorescence background is superior to 5%. The polar approach enables indeed to determine more precisely the lifetime values for a limited range corresponding to usually encountered fluorescence lifetime values. These theoretical results are corroborated with Monte Carlo simulations. We finally demonstrate experimentally that the polar approach allows distinguishing in living cells two fluorophores undetectable with usual time-domain LSM fitting software. PMID- 21265009 TI - Novel automated three-dimensional genome scanning based on the nuclear architecture of telomeres. AB - Telomeres, the end of chromosomes, are organized in a nonoverlapping fashion and form microterritories in nuclei of normal cells. Previous studies have shown that normal and tumor cell nuclei differ in their 3D telomeric organization. The differences include a change in the spatial organization of the telomeres, in telomere numbers and sizes and in the presence of telomeric aggregates. Previous attempts to identify the above parameters of 3D telomere organization were semi automated. Here we describe the automation of 3D scanning for telomere signatures in interphase nuclei based on three-dimensional fluorescent in situ hybridization (3D-FISH) and, for the first time, define its sensitivity in tumor cell detection. The data were acquired with a high-throughput scanning/acquisition system that allows to measure cells and acquire 3D images of nuclei at high resolution with 40 * or 60 * oil and at a speed of 10,000-15,000 cells h(-1) , depending on the cell density on the slides. The automated scanning, TeloScan, is suitable for large series of samples and sample sizes. We define the sensitivity of this automation for tumor cell detection. The data output includes 3D telomere positions, numbers of telomeric aggregates, telomere numbers, and telomere signal intensities. We were able to detect one aberrant cell in 1,000 normal cells. In conclusions, we are able to detect tumor cells based on 3D architectural profiles of the genome. This new tool could, in the future, assist in patient diagnosis, in the detection of minimal residual disease, in the analysis of treatment response and in treatment decisions. PMID- 21265010 TI - SPICE: exploration and analysis of post-cytometric complex multivariate datasets. AB - Polychromatic flow cytometry results in complex, multivariate datasets. To date, tools for the aggregate analysis of these datasets across multiple specimens grouped by different categorical variables, such as demographic information, have not been optimized. Often, the exploration of such datasets is accomplished by visualization of patterns with pie charts or bar charts, without easy access to statistical comparisons of measurements that comprise multiple components. Here we report on algorithms and a graphical interface we developed for these purposes. In particular, we discuss thresholding necessary for accurate representation of data in pie charts, the implications for display and comparison of normalized versus unnormalized data, and the effects of averaging when samples with significant background noise are present. Finally, we define a statistic for the nonparametric comparison of complex distributions to test for difference between groups of samples based on multi-component measurements. While originally developed to support the analysis of T cell functional profiles, these techniques are amenable to a broad range of datatypes. PMID- 21265011 TI - Risk of azole-enhanced vincristine neurotoxicity in pediatric patients with hematological malignancies: old problem - new dilemma. AB - One of the most well-known drug interactions in pediatric oncology concerns the co-administration of itraconazole, an antifungal triazole, and vincristine, an antileukemic agent, which seems to enhance the risk of neurotoxicity of the latter, mediated through the cytochrome CYP450 enzyme system. The aim of this article is to review the metabolism of these two drugs, to analyze the published cases with severe triazole-enhanced vincristine neurotoxicity, to discuss the pathophysiological mechanisms of this adverse effect, and to contribute in understanding the differences in triazole-vincristine interaction severity. PMID- 21265012 TI - Is routine computed tomographic scanning justified in the first week of persistent febrile neutropenia in children with malignancies? AB - BACKGROUND: Prolonged febrile neutropenia (FN) remains a common problem in pediatric oncology and often leads to empiric computed tomography (CT) of the sinuses, chest, abdomen, and pelvis. Little evidence is available as to the diagnostic utility of CT in this setting. PROCEDURE: We performed a retrospective review of all oncology patients admitted to the hospital from January 2004 through December 2008 for FN who had daily fevers with neutropenia for 4 or more consecutive days prompting CT evaluation. Eligible patient charts were reviewed for symptomatology prior to imaging as well as antibiotic and antifungal regimens throughout therapy. RESULTS: Fifty-two patients had 68 unique episodes of prolonged FN that resulted in CT imaging. Positive findings occurred in 18%, 12%, and 25% of initial chest, abdomen, and sinus CTs, respectively. There were no positive findings on initial pelvic CT. Only two of the initial positive CT scans led to a change in management (6.5% of positive scans, 0.8% of all initial scans). These were both scans of the chest. All patients with concern for occult fungal infection had findings on chest CT. Patients with clinically important infections had no statistical difference in days of fever or neutropenia or type of underlying malignancy compared with those without infection. Clinical symptomatology was most helpful for typhlitis. CONCLUSIONS: Treatment alteration rarely results from empiric CT imaging in the early days of prolonged FN. We therefore recommend limiting initial empiric CT imaging to the chest only in patients without localizing signs or symptoms and prolonged FN. PMID- 21265017 TI - Polymorph- and size-dependent uptake and toxicity of TiO2 nanoparticles in living lung epithelial cells. AB - The cellular uptake and distribution of five types of well-characterized anatase and rutile TiO(2) nanoparticles (NPs) in A549 lung epithelial cells is reported. Static light scattering (SLS), in-vitro Raman microspectroscopy (MU-Raman) and transmission electron spectroscopy (TEM) reveal an intimate correlation between the intrinsic physicochemical properties of the NPs, particle agglomeration, and cellular NP uptake. It is shown that MU-Raman facilitates chemical-, polymorph-, and size-specific discrimination of endosomal-particle cell uptake and the retention of particles in the vicinity of organelles, including the cell nucleus, which quantitatively correlates with TEM and SLS data. Depth-profiling MU-Raman coupled with hyperspectral data analysis confirms the location of the NPs in the cells and shows that the NPs induce modifications of the biological matrix. NP uptake is found to be kinetically activated and strongly dependent on the hard agglomeration size-not the primary particle size-which quantitatively agrees with the measured intracellular oxidative stress. Pro-inflammatory responses are also found to be sensitive to primary particle size. PMID- 21265018 TI - Chitosan-silica hybrid-coated open tubular column for hydrophilic interaction capillary electrochromatography. AB - A novel and convenient protocol for the preparation of an open-tubular column coated with chitosan-silica hybrid using chitosan and silane-coupling agent (gamma-glycidoxy-propyltrimethoxysilane) was developed for CEC, in which, chitosan was covalently bonded to the inner wall of a fused-silica capillary using gamma-glycidoxy-propyltrimethoxysilane as a cross-linking agent. The stationary phase was hydrophilic due to the chitosan-silica hybrid with abundant amine and hydroxyl functional groups. The chromatographic characteristics of the column were evaluated by the separation of some organic acids and inorganic anions. The column showed good selectivity for nucleotides, aromatic acids, and inorganic anions. The mechanism for the separation of these compounds was primarily based on the hydrophilic and electrostatic interactions combined with the electrophoretic mechanism. The CEC method on the column for the separation of these compounds was compared with CE method in a bare capillary. PMID- 21265019 TI - Rapid analysis of charge variants of monoclonal antibodies with capillary zone electrophoresis in dynamically coated fused-silica capillary. AB - A capillary zone electrophoresis (CZE) method was developed for the rapid analysis of charge heterogeneity of immunoglobulin G (IgG) monoclonal antibodies (mAbs). The separation was carried out in a short, dynamically coated fused silica capillary. A number of separation parameters were investigated and optimized, including pH, concentration of the separation buffer (epsilon-amino caproic acid), concentration of the triethylenetetramine (TETA) dynamic coating, the capillary internal diameter and the field strength used for the separation. The effects of between-run flushing of the capillary and the data acquisition rate were also evaluated. Under the optimized conditions, a fast (<5 min), selective and reproducible separation of mAb charge variants was achieved under a very high electric field strength (1000 V/cm). This method also requires only a short conditioning of the capillary, with between-run conditioning completed within 2 min. The method was evaluated for specificity, sensitivity, linearity, accuracy and precision. The same separation conditions were applied to the rapid separation (2-5 min) of charge variants of multiple monoclonal antibodies with pI in the range of 7.0-9.5. Compared with other existing methods for charge variants analysis, this method has several advantages including a short run time, rapid capillary conditioning and simple sample preparation. PMID- 21265020 TI - Determination of bavachin and isobavachalcone in Fructus Psoraleae by high performance liquid chromatography with electrochemical detection. AB - A simple, sensitive and selective method of high-performance liquid chromatography with electrochemical detection (HPLC-ECD) has been developed for simultaneous determination of bavachin and isobavachalcone in Fructus Psoraleae. At optimized conditions, bavachin and isobavachalcone could be well separated within 15 min at a detection potential of +0.80 V with 0.03 mol/L acetate buffer solution (pH 5.17)/acetonitrile (2:3, v/v) as the mobile phase. The relationships between peak areas and concentrations were linear from 8.26 * 10(-7) to 1.21 * 10(-4) mol/L for bavachin, and from 1.01 * 10(-8) to 1.61 * 10(-4) mol/L for isobavachalcone, respectively. The method offered excellent linearity with regression coefficient R(2) >0.995. The method presented detection limits (S/N = 3) of 8.81 * 10(-9) mol/L for bavachin and 1.17 * 10(-10) mol/L for isobavachalcone. It indicates that the sensitivity of electrochemical detection is ten times higher than that of diode array detection (DAD). The mean recoveries around 98% with a relative standard deviation less than 3.1% for the two analytes have been obtained. The proposed separation and detection procedures were successfully applied to the simultaneous determination of bavachin and isobavachalcone in traditional Chinese medicine. PMID- 21265022 TI - Biodistribution and photodynamic efficacy of a water-soluble, stable, halogenated bacteriochlorin against melanoma. AB - The in vitro phototoxicity of a photostable, synthetic, water-soluble, halogenated bacteriochlorin, 5,10,15,20-tetrakis(2-chloro-5 sulfophenyl)bacteriochlorin (TCPBSO3H), toward mouse melanoma (S91) cells is ~60 fold higher than that of the analogous porphyrin, and is associated with very weak toxicity in the dark; 90% of S91 cells were killed in response to a light dose of 0.26 J cm(-2) in the presence of [TCPBSO3H]=5 MUM. In vivo toxicity toward DBA mice is very low, even at doses of 20 mg kg(-1). In vivo pharmacokinetics and biodistribution of TCPBSO3H were studied in DBA mice with S91 tumors; 24 h after intraperitoneal injection of 10 mg kg(-1), TCPBSO3H demonstrated preferential accumulation in S91 mouse melanoma, with tumor-to normal tissue ratios of 3 and 5 for muscle and skin, respectively. Photodynamic therapy (PDT) performed under these conditions, with 90 mW cm(-2) diode laser irradiation at lambda 750 nm for 20 min (total light dose of 108 J cm(-2)), resulted in tumor regression. Tumor recurrence was observed only approximately two months after treatment, confirming the efficacy of this PDT against melanoma. PMID- 21265021 TI - Biomimetic approaches to control soluble concentration gradients in biomaterials. AB - Soluble concentration gradients play a critical role in controlling tissue formation during embryonic development. The importance of soluble signaling in biology has motivated engineers to design systems that allow precise and quantitative manipulation of gradient formation in vitro. Engineering techniques have increasingly moved to the third dimension in order to provide more physiologically relevant models to study the biological role of gradient formation and to guide strategies for controlling new tissue formation for therapeutic applications. This review provides an overview of efforts to design biomimetic strategies for soluble gradient formation, with a focus on microfluidic techniques and biomaterials approaches for moving gradient generation to the third dimension. PMID- 21265023 TI - Gold nanoparticles carrying diatomic molecules (O2 and CO) in aqueous solution. AB - Gold nanoparticles (AuNPs) prepared by citrate reduction of aurochloric acid (HAuCl(4)) were functionalized by tris(4-sulfonatophenyl)porphinatoiron(III) (Fe(III)P2) and poly(ethylene glycol) with thiolated arms (PEG-SH). Fe(III)P2 on the AuNP surface existed as its MU-oxo dimer, which was reduced by Na(2)S(2)O(4) to yield monomeric Fe(II)P2. Fe(II)P2-bearing AuNPs were further functionalized through inclusion of two sulfonatophenyl groups of Fe(II)P2 by a per-O-methylated beta-cyclodextrin dimer with a pyridine linker (Py3CD) to obtain AuNPs capable of carrying diatomic molecules in the body. The resulting AuNPs (hemoCD-AuNPs) bound O(2) as well as CO in an aqueous solution. Although a noncolloidal 1:1 complex of 5,10,15,20-tetrakis(4-sulfonatophenyl)porphinatoiron(II) and Py3CD injected into the femoral vein of a rat was rapidly excreted in the urine, no excretion was observed with ferric hemoCD-AuNPs, which were gradually accumulated in the spleen and liver of a rat. These results suggest that hemoCD-AuNPs can be used as a carrier of diatomic molecules such as O(2) and CO in vivo. PMID- 21265024 TI - Control of the solid-state chiral optical properties of a supramolecular organic fluorophore containing 4-(2-arylethynyl)-benzoic acid. AB - The solid-state chiral optical properties of a 4-(2-arylethynyl)-benzoic acid/amine supramolecular organic fluorophore can be controlled by changing the arylethynyl group of the achiral 4-(2-arylethynyl)-benzoic acid component molecule rather than the chirality of the amine component molecule. PMID- 21265025 TI - In-situ XAFS studies of Mn12 molecular-cluster batteries: super-reduced Mn12 clusters in solid-state electrochemistry. AB - In situ X-ray absorption fine structure (XAFS) analyses were performed on rechargeable molecular cluster batteries (MCBs), which were formed by a lithium anode and cathode-active material, [Mn(12)O(12)(CH(3)CH(2)C(CH(3))(2)COO)(16)(H(2)O)(4)] with tert-pentyl carboxylate ligand (abbreviated as Mn12tPe), and with eight Mn(3+) and four Mn(4+) centers. This mixed valence cluster compound is used in an effort to develop a reusable in situ battery cell that is suitable for such long-term performance tests. The Mn12tPe MCBs exhibit a large capacity of approximately 210 Ah kg(-1) in the voltage range V=4.0-2.0 V. The X-ray absorption near-edge structure (XANES) spectra exhibit a systematic change during the charging/discharging with an isosbestic point at 6555 eV, which strongly suggests that only either the Mn(3+) or Mn(4+) ions in the Mn12 skeleton are involved in this battery reaction. The averaged manganese valence, determined from the absorption-edge energy, decreased monotonically from 3.3 to 2.5 in the first half of the discharging (4.0>V>2.8 V), but changed little in the second half (2.8>V>2.0 V). The former valence change indicates a reduction of the initial [Mn12](0) state by approximately ten electrons, which corresponds well with the half value of the observed capacity. Therefore, the large capacity of the Mn12 MCBs can be understood as being due to a combination of the redox change of the manganese ions and presumably a capacitance effect. The extended X-ray absorption fine structure (EXAFS) indicates a gradual increase of the Mn(2+) sites in the first half of the discharging, which is consistent with the XANES spectra. It can be concluded that the Mn12tPe MCBs would include a solid-state electrochemical reaction, mainly between the neutral state [Mn12](0) and the super-reduced state [Mn12](8-) that is obtained by a local reduction of the eight Mn(3+) ions in Mn12 toward Mn(2+) ions. PMID- 21265026 TI - Polyaniline-based conducting polymer compositions with a high work function for hole-injection layers in organic light-emitting diodes: formation of ohmic contacts. AB - It is a great challenge to develop solution-processed, polymeric hole-injection layers (HILs) that perform better than small molecular layers for realizing high performance small-molecule organic light-emitting diodes (SM-OLEDs). We have greatly improved the injection efficiency and the current efficiency of SM-OLEDs by introducing conducting polymer compositions composed of polyaniline doped with polystyrene sulfonate and perfluorinated ionomer (PFI) as the HIL. During single spin-coating of conducting polymer compositions, the PFI layer was self-organized at the surface and greatly increased the film work function. It enhanced hole injection efficiency and current efficiency by introducing a nearly ohmic contact and improving electron blocking. Our results demonstrate that solution-processed polyaniline HILs with tunable work functions are good candidates for reducing process costs and improving OLED performance. PMID- 21265027 TI - Cerebrospinal fluid pleocytosis: pitfalls and benefits of combined analysis using cytomorphology and flow cytometry. AB - BACKGROUND: Cerebrospinal fluid samples with doubtful morphologic interpretation are a common problem in the workup of patients with clinical signs for leptomeningeal disease. The authors report on the combination of morphology and flow cytometry in the diagnosis of leptomeningeal disease in patients with radiological, clinical, or cytological findings suspicious for leukemia or lymphoma with spread into the cerebrospinal fluid. METHODS: The authors defined a set of antibodies for flow cytometric analysis, which is capable of distinguishing between malignant and nonmalignant hematopoietic cells. One hundred twenty-seven cases were analyzed with both methods. RESULTS: The additional application of flow cytometry resulted in an improvement of diagnostic reliability in 29 of 127 cases. Diagnostic sensitivity was raised from 73% (cytology) to 96% (flow cytometry), specificity from 94% to 97%, the positive predictive value from 88% to 96%, and the negative predictive value from 76% to 97%. CONCLUSIONS: Because the appropriate selection of markers is crucial to successful analysis, the authors suggested a highly selected panel of antibodies for flow cytometry analysis of cerebrospinal fluid samples. The authors were able to demonstrate that leptomeningeal disease caused by leukemia or lymphoma can be diagnosed by flow cytometry and discriminated from reactive pleocytosis in most cases of doubtful morphology. PMID- 21265028 TI - EchoBrush may be superior to standard EUS-guided FNA in the evaluation of cystic lesions of the pancreas: preliminary experience. AB - BACKGROUND: Cystic lesions of the pancreas are being detected with increasing frequency. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is one of the most precise methods of diagnosis but still has limited accuracy. A new, through-the-needle cytologic brush system (EchoBrush; Cook Medical, Bloomington, Ind) has been approved for use during EUS evaluation of cystic pancreatic lesions. METHODS: Data from 127 EUS-FNAs of pancreatic cystic lesions were analyzed to compare the cytologic yield of EchoBrush with conventional EUS-FNA. An attending cytopathologist was present on site to assess specimen adequacy in all the cases. Diagnostic yields of both procedures, as well as related adverse events, were recorded. Statistical analysis was performed with the SPSS 15.0 version software (SPSS, Chicago, Ill). RESULTS: A total of 127 cystic lesions of the pancreas from 120 patients (42 men and 78 women, mean age of 62.17 +/- 12.17 years) were included in the study. Mean size of lesions was 23.58 +/- 21.69 mm. Adequacy of the samples and diagnostic yield were higher using EchoBrush. In 80 (63 %) cases, conventional EUS-FNA was performed, whereas in 47 (37%), we used EchoBrush. Diagnostic material was obtained in 85.1% (40 of 47) of cases using EchoBrush and in 66.3% (53 of 80) with conventional EUS-FNA. (P < .05). There were very few clinically relevant complications related to EUS-FNA and EUS EchoBrush techniques. CONCLUSIONS: This study suggests that cytological specimens from pancreatic cystic lesions obtained using EchoBrush at the time of EUS are superior to conventional EUS-FNA mainly because of the higher yield of epithelial cells. Larger studies are needed to compare both methods. PMID- 21265030 TI - Spatial abilities of expert clinical anatomists: comparison of abilities between novices, intermediates, and experts in anatomy. AB - Spatial ability has been found to be a good predictor of success in learning anatomy. However, little research has explored whether spatial ability can be improved through anatomy education and experience. This study had two aims: (1) to determine if spatial ability is a learned or inherent facet in learning anatomy and (2) to ascertain if there is any difference in spatial ability between experts and novices in anatomy. Fifty participants were identified: 10 controls, 10 novices, 10 intermediates, and 20 experts. Participants completed four computerized spatial ability tasks, a visual mental rotation task, categorical spatial judgment task, metric spatial task, and an image-scanning task. The findings revealed that experts (P = 0.007) and intermediates (P = 0.016) were better in the metric spatial task than novices in terms of making more correct spatial judgments. Experts (P = 0.033), intermediates (P = 0.003), and novices (P = 0.004) were better in the categorical spatial task than controls in terms of speed of responses. These results suggest that certain spatial cognitive abilities are especially important and characteristic of work needed in clinical anatomy, and that education and experience contribute to further development of these abilities. PMID- 21265031 TI - Familiarity with Latin and Greek anatomical terms and course performance in undergraduates. AB - Commonly used technical anatomy and physiology (A&P) terms are predominantly rooted in Latin and Greek vocabulary, so it is commonly inferred that a solid grounding in Latin and Greek roots of medical terminology will improve student learning in anatomy and related disciplines. This study examines the association of etymological knowledge of A&P terms and A&P course performance among 446 undergraduates in their first semester of the study of human gross anatomy and physiology, with a more detailed analysis of the characteristics of 52 students who filled out surveys about their prior knowledge and experiences related to medicine or anatomy. In both data sets, there was only a weak positive correlation between the performance on a quiz of Latin and Greek medical terms and the students' performance on regular assignments. The presumption that familiarity with Latin and Greek word roots has a strong influence on successful learning of anatomy is not supported by these data. Future research should address whether or not there are particular skills associated with using etymological knowledge in improving A&P course performance. PMID- 21265032 TI - Dissection videos do not improve anatomy examination scores. AB - In this quasi-experimental study, we describe the effect of showing dissection videos on first-year medical students' performance in terms of test scores during a gross anatomy course. We also surveyed students' perception regarding the showing of dissection videos. Two hundred eighty-seven first-year medical students at Rawalpindi Medical College in Pakistan, divided into two groups, dissected one limb in first term and switched over to the other limb in the second term. During the second term, instruction was supplemented by dissection videos. Second-term anatomy examination marks were compared with first-term scores and with results from first-year medical students in previous years. Multiple linear regression analysis was performed, with term scores (continuous, 0-200) as the dependent variable. Students shown dissection videos scored 1.26 marks higher than those not shown. The relationship was not statistically significant (95% CI: -1.11, 3.70; P = 0.314). Ninety-three percent of students favored regular inclusion of dissection videos in curriculum, and 50% termed it the best source for learning gross anatomy. Seventy-six percent of students did not perform regular cadaver dissection. The most frequent reason cited for not performing regular dissection was high student-cadaver ratio. Dissection videos did not improve performance on final examination scores; however, students favored their use. PMID- 21265033 TI - Pregnant students in the gross anatomy laboratory: policies and practices at chiropractic colleges. AB - Chiropractic and medical colleges have experienced a significant increase in the number of female applicants in recent years, a percentage of whom are pregnant or become pregnant following admission. It is therefore important to ask the question: How do institutions that educate future health care providers address the issue of pregnancy and the gross anatomy laboratory? A survey instrument was developed and pretested. IRB approval was obtained. The administrators charged with overseeing the policies and practices for the gross anatomy laboratory at each of the 16 chiropractic colleges in the USA were identified and contacted. An email containing a link to the Web based survey was sent to each, using SurveyMonkey. The survey response rate was 100%. A majority of colleges (69%) have a written policy regarding pregnancy and the gross laboratory. Of these, 36% allow pregnant students to take the laboratory if a waiver is signed, 18% do not allow them to take the laboratory, 18% allow them to take it without a waiver, and 27% have other policies. In cases where students do not take the gross laboratory while pregnant, 64% of colleges require them to take the laboratory after completion of their pregnancy, 27% require them to complete an alternative (dry) laboratory, and 9% have other policies. Considerable diversity exists in the way colleges address this issue. It is at present unknown whether pregnant students or their fetuses are at any risk from laboratory chemicals. Risk assessment research is needed before consistent policies can be developed. PMID- 21265034 TI - Postgraduate fellows as teaching assistants in human anatomy: an experimental teaching model at a Chinese research university. AB - Postgraduate fellowship training programs are expanding at Chinese universities. This growing cadre of advanced trainees calls for the development of new learning and training models wherein postgraduate fellows have an ample opportunity to teach more junior learners, thereby expanding their own knowledge base and competitiveness for future employment. Educational reform at Sun Yat-Sen University has recently allowed postgraduate fellows to act as teaching assistants for undergraduate anatomy courses. This model is common in western countries but is novel in China. PMID- 21265035 TI - The trend of body donation for education based on Korean social and religious culture. AB - Until a century ago, Korean medicine was based mainly on Oriental philosophies and ideas. From a religious perspective, Chinese Confucianism was prevalent in Korea at that time. Since Confucianists believe that it is against one's filial duty to harm his or her body, given to them by their parents, most Koreans did not donate their bodies or organs for education in the past. However, by the end of the 20th century, a unique fusion of Western and Oriental medicines were produced on the Korean Peninsula, revolutionizing traditional perspectives on the human body, mortality, and the relationship of medical science to society. Koreans began to think about others' lives as well as their own by realizing the importance of donating one's organs and bodies for scientific purposes. Since then, the number of people donating their bodies to Korean medical and dental schools for the purpose of improving academic learning has increased dramatically. In response, Korean medical schools have begun to hold various types of funeral ceremonies to honor body donors. We have compared such ceremonies performed in Korea with those performed in the United States of America and Taiwan. These ceremonies are viewed as a suitable way to pay proper respect to the dead and to promote knowledge about body donation programs in Korea. Overall, the transition of religions and social ethics in Korea has greatly facilitated body bequeathal programs, benefiting both medical education and the Korean public health administration. PMID- 21265036 TI - A "Second Life" for gross anatomy: applications for multiuser virtual environments in teaching the anatomical sciences. AB - This article describes the emerging role of educational multiuser virtual environments, specifically Second LifeTM, in anatomical sciences education. Virtual worlds promote inquiry-based learning and conceptual understanding, potentially making them applicable for teaching and learning gross anatomy. A short introduction to Second Life as an anatomical educational tool is provided, along with description of existing anatomy applications and future directions for this innovative teaching modality. PMID- 21265037 TI - A case study on multiple-choice testing in anatomical sciences. AB - Objective testing techniques, such as multiple-choice examinations, are a widely accepted method of assessment in gross anatomy. In order to deter cheating on these types of examinations, instructors often design several versions of an examination to distribute. These versions usually involve the rearrangement of questions and their corresponding answer choices. This study will determine whether the distribution of different versions of an examination affects student performance in a lower division anatomical science course. Students who receive the original version of an examination may be at an advantage over those that receive a shuffled version of an examination because of the systematic tendencies that go into examination construction. This study concludes that the shuffling of questions and answer choices to produce multiple versions of an examination does not affect student performance. PMID- 21265038 TI - A proposal for a policy on the ethical care and use of cadavers and their tissues. AB - Recent events have occurred that indicate the need for policies on the ethical care and use of cadavers and their tissues in the United States. At present, there are policies that address the procurement, handling and disposition of cadavers, but there are no national or society sponsored policies that clearly state the ethically appropriate use of cadavers. The ethical issues presented in this manuscript are meant to encourage thought and discussion on this topic. A proposed outcome would be the development of specific ethical guidelines that would be sponsored by national organizations, such as the American Association of Anatomists and/or the American Association of Clinical Anatomists, and would be adopted by institutions that use cadavers or their tissues. PMID- 21265039 TI - Ethical care and use of cadavers: a call for a policy. PMID- 21265040 TI - Development and application of an efficient virus-induced gene silencing system in Nicotiana tabacum using geminivirus alphasatellite. AB - Virus-induced gene silencing (VIGS) is a recently developed technique for characterizing the function of plant genes by gene transcript suppression and is increasingly used to generate transient loss-of-function assays. Here we report that the 2mDNA1, a geminivirus satellite vector, can induce efficient gene silencing in Nicotiana tabacum with Tobacco curly shoot virus. We have successfully silenced the beta-glucuronidase (GUS) gene in GUS transgenic N. tabacum plants and the sulphur desaturase (Su) gene in five different N. tabacum cultivars. These pronounced and severe silencing phenotypes are persistent and ubiquitous. Once initiated in seedlings, the silencing phenotype lasted for the entire life span of the plants and silencing could be induced in a variety of tissues and organs including leaf, shoot, stem, root, and flower, and achieved at any growth stage. This system works well between 18-32 degrees C. We also silenced the NtEDS1 gene and demonstrated that NtEDS1 is essential for N gene mediated resistance against Tobacco mosaic virus in N. tabacum. The above results indicate that this system has great potential as a versatile VIGS system for routine functional analysis of genes in N. tabacum. PMID- 21265041 TI - Proteome changes in the plasma of Pieris rapae parasitized by the endoparasitoid wasp Pteromalus puparum. AB - Parasitism by the endoparasitoid wasp Pteromalus puparum causes alterations in the plasma proteins of Pieris rapae. Analysis of plasma proteins using a proteomic approach showed that seven proteins were differentially expressed in the host pupae after 24-h parasitism. They were masquerade-like serine proteinase homolog (MSPH), enolase (Eno), bilin-binding protein (BBP), imaginal disc growth factor (IDGF), ornithine decarboxylase (ODC), cellular retinoic acid binding protein (CRABP), and one unknown function protein. The full length cDNA sequences of MSPH, Eno, and BBP were successfully cloned using rapid amplification of cDNA ends-polymerase chain reaction (RACE-PCR). Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis indicated that the transcript levels of MSPH and BBP in the fat bodies of host pupae were inducible in response to the parasitism and their variations were consistent with translational changes of these genes after parasitism, while the transcript levels of Eno and IDGF were not affected by parasitism. This study will contribute to the better understanding of the molecular bases of parasitoid-induced host alterations associated with innate immune responses, detoxification, and energy metabolism. PMID- 21265042 TI - Prophenoloxidase from Pieris rapae: gene cloning, activity, and transcription in response to venom/calyx fluid from the endoparasitoid wasp Cotesia glomerata. AB - Prophenoloxidase (PPO) plays an important role in melanization, necessary for defense against intruding parasitoids. Parasitoids have evolved to inject maternal virulence factors into the host hemocoel to suppress hemolymph melanization for the successful development of their progeny. In this study, the full-length complementary DNA (cDNA) of a Pieris rapae PPO was cloned. Its cDNA contained a 2 076-base pair (bp) open reading frame (ORF) encoding 691 amino acids (aa). Two putative copper-binding sites, a proteolytic activation site, three conserved hemocyanin domains, and a thiol ester motif were found in the deduced amino acid sequence. According to both multiple alignment and phylogenetic analysis, P. rapae PPO gene cloned here is a member of the lepidopteran PPO-2 family. Injection of Cotesia glomerata venom or calyx fluid resulted in reduction of P. rapae hemolymph phenoloxidase activity, demonstrating the ability to inhibit the host's melanization. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) showed that transcripts of P. rapae PPO-2 in the haemocytes from larvae had not significantly changed following venom injection, suggesting that the regulation of PPO messenger RNA (mRNA) expression by venom was not employed by C. glomerata to cause failure of melanization in parasitized host. While decreased P. rapae PPO-2 gene expression was observed in the haemocytes after calyx fluid injection, no detectable transcriptional change was induced by parasitization, indicating that transcriptional down-regulation of PPO by calyx fluid might play a minor role involved in inhibiting the host's melanization. PMID- 21265043 TI - Microarray-based identification of tomato microRNAs and time course analysis of their response to Cucumber mosaic virus infection. AB - A large number of plant microRNAs (miRNAs) are now documented in the miRBase, among which only 30 are for Solanum lycopersicum (tomato). Clearly, there is a far-reaching need to identify and profile the expression of miRNAs in this important crop under various physiological and pathological conditions. In this study, we used an in situ synthesized custom microarray of plant miRNAs to examine the expression and temporal presence of miRNAs in the leaves of tomato plants infected with Cucumber mosaic virus (CMV). Following computational sequence homology search and hairpin structure prediction, we identified three novel tomato miRNA precursor genes. Our results also show that, in accordance with the phenotype of the developing leaves, the tomato miRNAs are differentially expressed at different stages of plant development and that CMV infection can induce or suppress the expression of miRNAs as well as up-regulate some star miRNAs (miRNA*s) which are normally present at much lower levels. The results indicate that developmental anomalies elicited by virus infection may be caused by more complex biological processes. PMID- 21265044 TI - Effects of nitrogen form on growth, CO2 assimilation, chlorophyll fluorescence, and photosynthetic electron allocation in cucumber and rice plants. AB - Cucumber and rice plants with varying ammonium (NH(4)(+)) sensitivities were used to examine the effects of different nitrogen (N) sources on gas exchange, chlorophyll (Chl) fluorescence quenching, and photosynthetic electron allocation. Compared to nitrate (NO(3)(-))-grown plants, cucumber plants grown under NH(4)(+) nutrition showed decreased plant growth, net photosynthetic rate, stomatal conductance, intercellular carbon dioxide (CO(2)) level, transpiration rate, maximum photochemical efficiency of photosystem II, and O(2)-independent alternative electron flux, and increased O(2)-dependent alternative electron flux. However, the N source had little effect on gas exchange, Chl a fluorescence parameters, and photosynthetic electron allocation in rice plants, except that NH(4)(+)-grown plants had a higher O(2)-independent alternative electron flux than NO(3)(-)-grown plants. NO(3)(-) reduction activity was rarely detected in leaves of NH(4)(+)-grown cucumber plants, but was high in NH(4)(+)-grown rice plants. These results demonstrate that significant amounts of photosynthetic electron transport were coupled to NO(3)(-) assimilation, an effect more significant in NO(3)(-)-grown plants than in NH(4)(+)-grown plants. Meanwhile, NH(4)(+)-tolerant plants exhibited a higher demand for the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) for NO(3)(-) reduction, regardless of the N form supplied, while NH(4)(+)-sensitive plants had a high water-water cycle activity when NH(4)(+) was supplied as the sole N source. PMID- 21265045 TI - Evaluation of the hepatoprotective and antioxidant activities of Rubus parvifolius L. AB - The hepatoprotective and antioxidant activities of the n-butanol extract of Rubus parvifolius L. (RPL), a widely used medicinal plant, were evaluated. Results demonstrated that RPL extract possessed pronounced hepatoprotective effects against carbon tetrachloride (CCl(4))-induced hepatic injury in mice, which was at least partially attributed to its strong antioxidant capacity. Treatment with RPL extract markedly attenuated the increases in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels caused by CCl(4) intoxication. It also significantly prevented the decrease in superoxide dismutase (SOD) activity and the increase in malondialdehyde (MDA) content of liver tissue. Meanwhile, histopathological changes of hepatic damage were also remarkably ameliorated. Phytochemical analysis based on high-performance liquid chromatography/tandem mass spectrometry (HPLC-MS/MS) revealed the presence of various phenolic compounds, including caffeic acid conjugates, ellagic acid glycosides, and flavonol glycosides, which might be responsible for the hepatoprotective and antioxidant activities of RPL. PMID- 21265046 TI - Enhancing effect of natural borneol on the absorption of geniposide in rat via intranasal administration. AB - Both geniposide (Ge) and natural borneol (NB) are bioactive substances derived from traditional Chinese herbs. The effect of NB on the pharmacokinetics of Ge in rat via intranasal administration was investigated. The concentrations of Ge in plasma were determined by reversed-phase high-performance liquid chromatography (HPLC) after intranasal administration of Ge (4 mg/kg) alone and combined with different doses (0.08, 0.8, and 8 mg/kg) of NB. The intravenous administration was given as a reference (4 mg/kg of Ge and 8 mg/kg of NB). Compared with the intravenous administration, the absolute bioavailability of Ge was 76.14% through intranasal administration combined with NB. Compared with the intranasal administration of Ge alone, Ge could be absorbed rapidly in the nasal cavity combined with NB; the peak time of Ge in the plasma became shorter (3-5 min vs. 40 min); the peak concentration became higher (1.32-4.25 MUg/ml vs. 0.67 MUg/ml); and, the relative bioavailability of Ge combined with NB was 90.3%-237.8%. The enhancing effect was attenuated as the dose of NB decreased. The results indicated that NB can accelerate the absorption of Ge dose-dependently in the nasal cavity. PMID- 21265047 TI - A relative quantitative method to detect OCT4A gene expression by exon-junction primer and locked nucleic acid-modified probe. AB - OBJECTIVE: OCT4A has been known to play a critical role in the maintenance of pluripotency of embryonic stem cells. Recent research has shown that OCT4A is also expressed in partial tumor cell lines and tissues. This study is aimed to develop a real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay for relative quantitative detection of OCT4A mRNA and discrimination from OCT4B, pseudogene, and genomic contaminations. METHODS: A locked nucleic acid (LNA)-modified probe was designed to discern the single base difference 352A/C to identify OCT4A mRNA. An exon-junction primer was designed to avoid false positive caused by genomic contaminations. In addition, a house keeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was measured in parallel to normalize the differences between samples and operations. RESULTS: Experiments showed that the newly established RT-PCR assay amplified the OCT4A mRNA selectively; OCT4A analogues gave negative signals. Cell lines nTERA-2 and HepG2 showed positive results in OCT4A expression, while for HeLa and 293 cell lines, as well as primary peripheral blood mononuclear cells (PBMCs), OCT4A expression was negative. Additionally, the relative quantity of OCT4A mRNA was calculated by cycle threshold (C(t)) method and house keeping gene normalization. CONCLUSIONS: This technique proved to be effective for relative quantitation of OCT4A mRNA with high specificity. PMID- 21265048 TI - Current recognition and management of intra-abdominal hypertension and abdominal compartment syndrome among tertiary Chinese intensive care physicians. AB - This survey was designed to clarify the current understanding and clinical management of intra-abdominal hypertension (IAH)/abdominal compartment syndrome (ACS) among intensive care physicians in tertiary Chinese hospitals. A postal twenty-question questionnaire was sent to 141 physicians in different intensive care units (ICUs). A total of 108 (76.6%) questionnaires were returned. Among these, three quarters worked in combined medical-surgical ICUs and nearly 80% had primary training in internal or emergency medicine. Average ICU beds, annual admission, ICU length of stay, acute physiology and chronic health evaluation (APACHE) II score, and mortality were 18.2 beds, 764.5 cases, 8.3 d, 19.4, and 21.1%, respectively. Of the respondents, 30.6% never measured intra-abdominal pressure (IAP). Although the vast majority of the ICUs adopted the exclusively transvesicular method, the overwhelming majority (88.0%) only measured IAP when there was a clinical suspicion of IAH/ACS and only 29.3% measured either often or routinely. Moreover, 84.0% used the wrong priming saline volume while 88.0% zeroed at reference points which were not in consistence with the standard method for IAP monitoring recommended by the World Society of Abdominal Compartment Syndrome. ACS was suspected mainly when there was a distended abdomen (92%), worsening oliguria (80%), and increased ventilatory support requirement (68%). Common causes for IAH/ACS were "third-spacing from massive volume resuscitation in different settings" (88%), "intra-abdominal bleeding", and "liver failure with ascites" (52% for both). Though 60% respondents would recommend surgical decompression when the IAP exceeded 25 mmHg, accompanied by signs of organ dysfunction, nearly three quarters of respondents preferred diuresis and dialysis. A total of 68% of respondents would recommend paracentesis in the treatment for ACS. In conclusion, urgent systematic education is absolutely necessary for most intensive care physicians in China to help to establish clear diagnostic criteria and appropriate management for these common, but life threatening, diseases. PMID- 21265049 TI - [50 years anniversary of Research Institute for Occupational Medicine and Human Ecology with Siberian Division of RAMSc]. AB - The article covers main steps of establishment and development of Research Institute for Occupational medicine and Human ecology with Siberian Division of RAMSc over 50 years of activities, major results of research, contribution of the Institute personnel into development of hygienic science and practical medicine in Siberia. PMID- 21265050 TI - [Toxic encephalopathies in distant post-contact period of occupational neurointoxications (clinical and experimental studies)]. AB - The article covers results of long-standing research on clinical peculiarities and course of toxic encephalopathy in distant period of occupational neurointoxications, on main concepts and pathogenetic steps of formation and progress of toxic encephalopathy. Through investigation covered firemen after exposure to complex of toxic chemicals and patients in post-contact period of chronic mercury intoxication. Modelling of chronic inhalation of metallic mercury vapors was performed. PMID- 21265051 TI - [Biomodelling for environmental factors influence on humans]. AB - The article covers results of experimental modelling under exposure to biologic factor associated with chemical factor, and neurotoxic process caused by injection of vinylchloride, inorganic mercury compounds and toxic chemical complex. The authors specified methodologic approaches to evaluate and forecast character of biologic effects in laboratory animals response to influence of environmental factors. PMID- 21265052 TI - Retraction. Transcription factor activator protein-2beta accelerates lipid accumulation in macrophages via enhancing the transcription of CD36. PMID- 21265053 TI - A re-appraisal of nunatak survival in arctic-alpine phylogeography. AB - A long standing and at times fervid debate in biogeography revolves around the question whether arctic and high alpine organisms survived Pleistocene ice ages on small island-like areas protruding above the ice-sheet, socalled nunataks, or whether they did so in peripheral nonglaciated refugial areas. A common picture emerging from a plethora of molecular phylogeographic studies in the last decade is that both in the Arctic and in temperate mountain ranges such as the European Alps nunatak survival needs to be only rarely invoked to explain observed genetic patterns (for a rare example see Stehlik et al. 2002). As two studies in this issue show, depreciation of the nunatak hypothesis is, however, not warranted. In this issue of Molecular Ecology Westergaard et al. (2011) investigate genetic patterns of two arctic-alpine plant species distributed on both sides of the Atlantic exclusively in areas that were mostly covered by ice-sheets during Pleistocene glacial advances. In both species, amplified fragment length polymorphism (AFLP) data identified divergent and partly genetically diverse groups east and west of the Atlantic. This suggests, for the first time in Arctic plants, in situ survival on nunataks. In an entirely different geographic setting and on a different geographic scale, Lohse et al. (2011, this issue) study the colonization of high alpine areas in the Orobian Alps, situated within and adjacent to a prominent peripheral refugial area (massif de refuge) in the Southern Alps of northern Italy, by dispersal-limited carabid ground beetles. Using explicit hypothesis testing and inference of ancestral locations in a Bayesian framework, stepwise colonization from two separate southern refugia is found to shape the genetic pattern of these beetles, but at the northern edge, populations survived at least parts of the last glaciation in situ on nunataks. PMID- 21265054 TI - Nutrition: Pharmacologically accelerating gastric emptying can reduce the calorie intake of obese individuals. PMID- 21265055 TI - Infection: Helicobacter pylori infection may be protective against IBD. PMID- 21265056 TI - Barrett esophagus: Peptide sequence detects dysplasia. PMID- 21265057 TI - Pancreatic cancer: Gemcitabine confirmed as the first-line therapy for pancreatic cancer. PMID- 21265058 TI - Pathophysiology of chronic nitric oxide synthase inhibition-induced fetal growth restriction in the rat. AB - OBJECTIVE: To evaluate the pathophysiology of chronic nitric oxide synthase (NOS) inhibition-induced fetal growth restriction (FGR) in the rat. METHODS: Timed pregnant rats received L-NAME (2.5 mg/kg/h) with or without endothelin (ET-1) receptor A (ETA) antagonist from day 14 to 21 of gestation. In separate groups, ETA antagonist and/or L-NAME were discontinued on day 18. On day 21 fetal and placental weights, and maternal and fetal plasma nitrate/nitrite (NOx) were determined. RESULTS: L-NAME led to FGR, and decreased maternal and fetal NOx. Maternal NOx was further decreased when ETA antagonist was co-administered with L NAME. ETA antagonism along with L-NAME did not impact fetal growth. Discontinuation of L-NAME on day 18 resulted in normal fetal and placental growth at day 21 and an increase of maternal NOx. Simultaneous cessation of both NOS inhibition and ETA antagonism on day 18 produced FGR at day 21, whereas continuation of ETA antagonism after discontinuation of L-NAME resulted in normal fetal growth. CONCLUSIONS: NOS inhibition in the pregnant rat leads to decreased maternal and fetal nitric oxide (NO) production and FGR. The effects of NOS inhibition on fetal growth are reversible, and are mediated at least in part by ET-1. With chronic NOS inhibition, ETA antagonism improves but does not normalize fetal growth, and may allow increased access of L-NAME to the fetal compartment. Continued access of L-NAME to the fetal compartment may limit the effect on fetal growth of any therapeutic intervention in this model of FGR. PMID- 21265059 TI - IBD: Visilizumab not useful for intravenous steroid-refractory ulcerative colitis. PMID- 21265060 TI - Cancer: Pancreatic carcinomas metastasize at a late stage in their development. PMID- 21265061 TI - Proceedings of the 7th Axel Key symposium on Molecular Basis of Applied Biological Therapeutics. Stockholm, Sweden. September 2010. PMID- 21265062 TI - Quick recertification series: Pulmonary embolus. PMID- 21265063 TI - Individual-based analysis opens new insights into understanding population structure and animal behaviour. AB - Studying the movement of individuals in the wild has always been a challenge in ecology. However, estimating such movement is essential in life sciences as it is the base-line for evaluating connectivity, a major component in developing management and conservation plans. Furthermore, movement, or migration, is an essential parameter in population genetics, as it directly affects genetic differentiation. The development of highly variable markers has allowed genetic discrimination between individuals within populations and at larger scales, and the availability of high-throughput technologies means that many samples and hence many individuals can be screened. These advances mean that we can now use genetic identification for tracking individuals, and hence follow both survival and reproductive output through the life cycle. The paper by Morrissey & Ferguson (2011, this issue) is a demonstration of this new capability, as authors were able to infer the movement of salmonid fish initially captured as juveniles, and later as reproductively mature adults. PMID- 21265064 TI - Erythroblastic islands. PMID- 21265065 TI - [The pharmacy of the Saint-Antoine hospital in Bazas]. PMID- 21265066 TI - [Not Available]. PMID- 21265067 TI - [Not Available]. PMID- 21265068 TI - [Not Available]. PMID- 21265069 TI - [Not Available]. PMID- 21265070 TI - [Not Available]. PMID- 21265071 TI - [Not Available]. PMID- 21265073 TI - [Not Available]. PMID- 21265072 TI - [Not Available]. PMID- 21265074 TI - [Role of nitric oxide in the development of the myocardial contractile reactions in trained animals]. AB - Intensive constitutive production of nitric oxide (NO) during physical training improves vasodilatation and heart function. However, it remains unclear how NO takes part in myocardial adaptation to workload, which is accompanied by an increased heart inflow and intracellular calcium content. Using isolated rat heart by Langendorf preparation, we studied myocardial response to gradually increased left ventricular volume (Frank-Starling low) and increasing concentration of Ca2+ in the perfusion solution (from 1.7 mM to 12.5 mM) in trained and untrained rats. It was shown that 4 weeks swimming course improved heart function: heart rate was decreased; contractile activity (dP/dt max) and coronary flow were increased by 20% and 33%, respectively. Equal volume stretching of balloon in left ventricle provoked greater contraction in trained comparing to untrained hearts, demonstrating extended functional reserves after swimming course. Mitochondrial membrane potential was significantly increased in hearts of trained rats. Furthermore, training prevented fast increase of the end diastolic pressure during calcium upload. Mitochondrial factor release due to opening of mitochondrial permeability transition pore (MPTP) in trained hearts was detected at higher concentrations of calcium that reveals extended calcium capacity of mitochondria and lesser sensitivity of MPTP to its inductor-calcium. Blockade of NO synthesis with L-NAME application of (10(-4) M for 15 min) abolished reaction of trained heart during Frank-Starling and calcium upload. Thus, heart adaptation to physical training and extension of functional reserves in heart are provided by endogenous NO production. Key words: nitric oxide, Frank Starling low, physical training, calcium upload, mitochondrial permeability transition, membrane potential. PMID- 21265075 TI - [Effects of N-stearoyl- and N-oleoylethanolamine on cardiac voltage-dependent sodium channels]. AB - The group of N-acylethanolamines (NAE) includes lipids that are capable of modulating plasma membrane ion channels without involvement of cannabinoid receptors. However, the action of various members of NAE on voltage-gated Na+ channels (VGSC) in cardiac tissue is still not fully elucidated. Here using patch clamp technique we have studied the modulation of biophysical properties of VGSC of neonatal cardiomyocytes by saturated N-stearoylethanolamine (NSE) and monounsaturated N-oleoylethanolamine (OEA). NSE in 1-200 tM concentration range did not significantly alter the amplitude of inward Na+ current (I(Na)), but 100 microM NSE shifted its steady-state activation and inactivation curves in hyperpolarization direction by 2.4 mV and 10.6 mV, respectively. Activation kinetics of the current was not changed by NSE, but its inactivation was accelerated by about 1.2-fold in the -60 - -30 mV range of membrane potentials. Unlike NSE, OEA dose-dependently inhibited I(Na) with kappa(D) = 11.4 +/- 1.6 microM and maximal block at saturating concentration of 30 +/- 3%. It also stronger than NSE shifted current's steady-state activation and inactivation curves (-6.4 mV and -14.0 mV, respectively, at 100 microM) in hyperpolarization direction. The effect of OEA on I(Na) activation kinetics was negligible, but it more pronouncedly than NSE accelerated inactivation of the current. Thus, both members of NAE influence the voltage-dependence of activation, inactivation and kinetics of I(Na). These effects were more prominent for monounsaturated OEA, which also partially blocked I(Na). The discovered effects of NSE and OEA on VGSCs may in part be responsible for the decrease of cardiomycytes' excitability by these lipids under normal as well as pathologic conditions. PMID- 21265076 TI - [Correlations of hippocampal theta-rhythm frequency changes with the signal characteristics of acoustic stimulation, latent periods and duration of conditioned reflectory movements in rats]. AB - The hippocampal theta rhythm was studied during an adaptive behaviour elaboration (a receiving of drinking reward in response on a specific audio stimulus) in freely moving water deprived rats. It was revealed that a right behavioral response (a drinking tank visit) in conditions of discrimination of two sound stimuli emerged only in case of the theta rhythm frequency increase in response on the positive conditional stimulus. Although this increase occurred only in response to positive signal it was also linked with the differentiation process- the theta rhythm frequency increase became significant when animals started to recognize positive and negative conditional stimuli. The detailed analysis revealed the detected theta rhythm frequency increase consisted of two waves. One of them was connected with the positive conditional stimulus presentation moment. The other one was connected with the time of appearance and duration of movement to drinking tank after positive conditional stimulus presentation (right behavioral answers) as well as after negative conditional stimulus (wrong answers). At the same time the frequency was significantly higher during right behavioral answers comparing with wrong ones. It is concluded that the theta rhythm frequency increased during the sensory information analysis when it was needed to choose a signal leading to reinforcement and to exit from the state of the internal inhibition. On the other hand the frequency increased during the purposive movements. PMID- 21265077 TI - [Zinc and the secretory material content in blood granulocytes and in basal parts of intestine crypts during stress]. AB - Zinc and the secretory material content in blood granulocytes and the Paneth cells of the rats increased by single physical load and immobilization. On the contrary, multiple physical loads and immobilization decreased the concentration of these components in the cells. Positive correlation of changes in both cell types pointed for possible functional connection between them. PMID- 21265078 TI - [Cytokine spectrum of blood serum during inflammatory processes in the abdominal cavity]. AB - The levels of cytokines (IL-1beta, IL-6, TNF-alpha, IL-2, IL-10) in patients with phlegmonous appendicitis and abdominal tuberculoses were studied. It is established that the level of cytokines IL-1beta, IL-6, TNF-alpha considerably increases in patients with acute inflammatory process (phlegmonous appendicitis) and the level of interleukines IL-2, IL-10 considerably increases in patients with chronic inflammatory process (abdominal tuberculoses). Such parity of the cytokines levels can serve as a marker for differential diagnostics of acute and chronic inflammatory processes in abdominal cavity. PMID- 21265079 TI - [Testosterone and thyroid hormones in blood plasma of rats with submissive and aggressive type of behavior]. AB - The levels of testosterone and thyroid hormones have been investigated in male rats with aggressive and submissive behaviors. An increase of testosterone in aggressive rats and the decrease of that in submissive ones were found when compared with the steady males. No change in the thyroxin level was detected. The level of T3 was not changed in males with aggressive behavior, but it was decreased in submissive rats. PMID- 21265080 TI - [Physiological aspects of analysis of the indexes of the variability of cardiac rhythm in adolescents with latent hypothyrosis]. AB - We studied the parameters of variability of cardiac rhythm in adolescents with the latent hypothyrosis and in healthy individuals and the interrelationship of these parameters with the indexes of the thyroid system (hormonal status, dimensions of thyroid, median ofioduria). It has been revealed that iodine deprivation leads to vegetative dystonia with the decreased activity of the sympathetic nervous system. This is accompanied by the narrowing of the range of adaptive capabilities of the organism, exhaustion of the regulatory influences in comparison with healthy children. The analysis of the indexes of the variability of cardiac rhythm after the correction by iodide-100 detected the decrease of the influence of the parasympathetic nervous system on cardiac rhythm regulation and stabilization of the sympathetic component. The correlation link between the content of thyroid hormones and the indexes of the variability of cardiac rhythm has been determined. Such tendency proves the essential role of T3 and FT4 for the maintaining of the functional capability of Autonomic Nervous system in adolescents. The pathophysiologic patterns of vegetative profile of the variability of cardiac rhythm in latent hypothyrosis have been substantiated. PMID- 21265081 TI - [Neuromuscular responses of the triceps surae muscle to prolonged passive stretch of the foot extensor muscles under conditions of simulated microgravity]. AB - The effect of a 60-day 6 degrees head-down tilt (HDT) of bed rest with and without countermeasures on the mechanical properties of human the triceps surae muscle was studied in 12 healthy young men subjects. One group (n=6; mean age 30.8 +/- 3.1 years) underwent a 60-day HDT and a second group (n=6; mean age 30.5 +/- 1.9 years) underwent HDT with countermeasures (long-term passive stretching). The results showed that the contractile properties of skeletal muscle change considerably. After HDT without countermeasures the maximal voluntary contraction (MVC) declined by 33.5% (P < 0.05), the electrically evoked tetanic tension at 150 Hz (Po) and isometric twitch contraction (Pt) reduced by 18.0% (P < 0.02) and 17.3% (P < 0.05), respectively. Time-to peak tension (TPT) of the twitch increased by 3.4%, but half-relaxation time (1/2 RT) decreased by 7.2%, and total contraction time (TCT) increased not significantly. The difference between Po and MVC expressed as a percentage of Po and referred to as force deficiency (Pd), has also been calculated. The Pd increased by 61% (P < 0.001). The rate of rise of voluntary contractions calculated according to an relative scale significantly reduced, but the electrically evoked contraction no substantial changes were observed. After HDT with long-term passive stretching caused decrease by 43.0% (P < 0.05) in MVC, and Pt and in Po by 17.0%, and by 19.4% (P < 0.05), respectively. The Pd increased significantly by 100% (P < 0.001). TPT, and 1/2 RT not change significantly, and TCT of the twitch increased by 6.5%, respectively in relation to the control condition. The rate of rise of electrically evoked tetanic tension did not change significantly during HDT with countermeasures but the rate of rise in on isometric voluntary tension development were decreased. These data indicate that prolonged passive stretching of a single muscle decreases voluntary strength. Thus, the received data specify, that the long passive stretching of a muscle does not find out preventive facilitate contractile properties of the muscular device from negative influences of mechanical unloading. This study presents evidence that prolonged passive muscle stretching can lead to some modification of contraction material behavior. In addition, altered material properties seem to affect proprioceptive feedback and, therefore, the motor unit activation in proportion to the contractile failure. PMID- 21265082 TI - [Effect of L-arginine and aminoguanidine on morphological characteristics of the lymphocyte plasma membranes during experimental diabetes mellitus]. AB - Diameter, the surface area of lymphocytes and their nuclea as well as the reserve potential and regulatory properties of lymphocytes membranes in control rats, in rats with experimental diabetes mellitus before and after administration of L arginine and aminoguanidine were investigated. Significant difference in size and the membrane fund of lymphocytes in animals with experimental diabetes mellitus was detected. In control lymphocytes, the membrane fund was 70% while during diabetes mellitus it was 40%. Such a difference might be one of the reasons of changes in properties and functional state of lymphocytes in diabetes. Administration of L-arginine and aminoguanidine to diabetic animals caused positive effect: the volume of lymphocytes diminished and the regulatory membrane properties of these cells became better. PMID- 21265083 TI - [The influence of individually fitted controlled breathing frequency on the heart rate variability indexes]. AB - We studied the changes in indexes of variability of heart rate and fractal neurodynamics under conditions of controlled breathing on fluctuation frequency of a spectrum of heart rate. It is shown that the controlled breathing, which frequency corresponds to a frequency of localization of the maximum peak of capacity ofa heart rate in low-frequency is a powerful mechanism of management of heart rate and change of a functional condition of an organism as a whole. PMID- 21265084 TI - [Spontaneously active ion channels of the nuclear envelope membrane]. AB - The genetic apparatus of the eukaryotic cells is enclosed by the nuclear envelope, which consists of two membranes, the inner and the outer ones, and can be regarded as the specific part of the endoplasmatic reticulum of the cell. There are nuclear pores in the nuclear membranes--complexes, which provide the highly selective transport of macromolecules and passive transport of ions and small molecules. Besides, ion channels selective to cations and anions were described in the inner and the outer nuclear membranes. The physiological significance of these channels is not still clear because of the difficulty of access for the direct electrophysiological investigation, but we can suppose that they can play an important role in the ion balance between the cytoplasm/nucleoplasm and the nuclear lumen. In this review we gathered and analyzed data about spontaneously active ion channels which were found in the membranes of the nuclear envelope from cells of different types and tried to propose their functional meaning. PMID- 21265085 TI - [Role of glycosaminoglycans in pathogenesis of atherosclerosis]. AB - In this review we summarize the role of glycosaminoglycans and proteoglycans in pathogenesis of atherosclerosis and possibilities for correction of lesions of atherosclerotic vessels via influence on their metabolism. PMID- 21265086 TI - [Initial study on zili functions to the development of the germ layers during zebrafish early embryogenesis]. AB - OBJECTIVE: To study the role for piwil2 gene (zili) in the development of the ectoderm, mesoderm and endoderm during early embryogenesis of zebrafish. METHODS: zili morpholino antisense oligonucleotide and 5 mis-pair control morpholino were used in this study. zili was cloned into expression vector. zili mRNA was synthesized in vitro. The antisense RNA probes of gsc, evel and sox17 were synthesized. zili-MO, zili-cMO and zili mRNA was microinjected into one-cell embryos, respectively. Whole-mount in situ hybridization was used to monitor the expressions of marker genes. RESULTS: Microinjection of zili-MO, which knocked down the expression of zili, downregulated the expression of the ectodermal and mesodermal marker gene gsc, promoting the expression of the ectodermal marker gene evel and resulting in the decrease of endodermal cell expressed sox17. The overexpression of zili, promoting the expression of gsc, inhibiting the expression of eve1 and resulting in the decrease of endodermal cell expressed sox17 were observed after microinjection of zili-mRNA. CONCLUSION: zili might have some effect on the formation of the ectoderm, mesoderm and endoderm during early embryogenesis and might be important for normal embryonic development. PMID- 21265087 TI - [The effect of Syk recombinant adenovirus on phenotypic modulation in vascular smooth muscle cells]. AB - OBJECTIVE: To construct Syk recombinant adenovirus with which vascular smooth muscle cells (VSMC) were infected, and to investigate the effect of Syk on the proliferation of VSMC. METHODS: Syk adenovirus recombinant plasmid pDC315-GFP-Syk was constructed by using pDC315-GFP adenovirus vector system. The recombinant adenoviral vector (pDC315-GFP-Syk) was packaged and amplified in HEK 293 cells. The VSMC of rat pulmonary vascular smooth muscle cells were isolated and cultured in vitro and transfected with Syk adenovirus. The mRNA and protein express level of Syk, SM22alpha and alpha-SM-actin of rat pulmonary vascular smooth muscle cells were detected by RT-PCR and Western blot. RESULTS: The recombinant adenovirus carrying rat Syk was constructed successfully. The titer of Syk adenovirus was 10(11) pfu/mL after purification. The expression of Syk mRNA (741638.70 +/- 35213.53) and protein (2.14 +/- 0.71) in VSMC transfected with Syk adenovirus was significantly higher (P < 0.01) than that of empty adenovirus after transfection at fifth day. The mRNA express of alpha-SM-actin (0.80 +/- 0.04) and SM22a (1.00 +/- 0.01) was significantly decreased (P < 0.05) in VSMC. Meanwhile, the protein express of alpha-SM-actin (0.61 +/- 0.10) and SM22alpha (0.18 +/- 0.06) was also significantly decreased (P < 0.01) in VSMC. CONCLUSION: These data indicated that Syk played an important role in vascular remodeling by changing the phenotypes of VSMC. PMID- 21265088 TI - [Growth and differentiation effect on HL60 cells by adenovirus-mediated exogenous wnt5a gene modification on human bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To study the effect of human bone marrow mesenchymal stem cell (bMSCs) modified by the adenovirus-mediated exogenous wnt5a gene on the hematopoietic function of bone marrow and the inhibition of the growth of HL60 leukemia cells. METHODS: BMSCs were identified through flow cytometry and modified by Ad5-wnt5a, The transfection rate of wnt5a gene in bMSCs was detected by RT-PCR. The cell growth curves were detected in different groups (bMSCs group, Ad5-GFP group, Ad5 wnt5a group). Ad5-wnt5a-bMSCs and HL60 cells were co-cultured, the surface differentiation antigen (CD13, CD14, CD68) and cell cycles were detected by immunocytochemical and flow cytometry in different groups (HL60 cell group, HL60+bMSCs group, HL60+ Ad5-GFP group, HL60+ Ad5-wnt5a group), respectively. RESULTS: Adenovirus-mediated exogenous wnt5a gene was transfected into bMSCs. The expression of differentiation antigens of CD14, CD68 in HL60+Ad5-wnt5a group were higher than those in control group (P < 0.05), the expression of differentiation antigen CD13 were not significant difference in different groups (P > 0.05). Compared with control group, the cell cycle in HL60+ Ad5-wnt5a group was blocked at G2 phase in the fourth day. CONCLUSION: Exogenous wnt5a gene can promote the growth of bMSCs, and induce HL60 cells to differentiation and maturation. PMID- 21265089 TI - [Construction of recombinant adenovirus carrying HBx and mIL-12]. AB - OBJECTIVE: To construct a recombinant adenovirus Ad-HBx-mlL-12 carrying HBx and mIL-12. METHODS: HBx and mIL-12 were cloned into the shuttle plasmid pAdenoVator CMV5 and confirmed by means of enzymatic manipulation. After linearization by EcoR I digestion, the recombinant shuttle plasmid pAdV-HBx-mIL-12 was transformed into competent BJ5183 germs with the adenoviral backbone plasmid pAdenoVator deltaE1/E3 and then homologically recombined to obtain the recombinant adenovirus plasmid. After confirmation, the recombinant adenovirus plasmid pAd-HBx-mIL-12 was linearized with Pac I digestion and transfected into 293 cells via liposome, and then adenovirus package and amplification were performed. RESULTS: It was confirmed that the recombinant adenovirus Ad-HBx-mIL-12 had been successfully constructed and both HBx and mIL-12 were expressed in 293 cells. CONCLUSION: The recombinant adenovirus carrying HBx and mIL-12 has been successfully constructed, which lays a foundation for the further study of antitumor mechanism and gene therapy. PMID- 21265090 TI - [Study on invasion and metastasis-associated genes of lung cancer related with NM23-H1 gene]. AB - OBJECTIVE: To study on invasion and metastasis-associated genes of lung cancer related with NM23-H1 gene. METHODS: Human gene expression chip based on the subtracted cDNA libraries was constructed. After microarray hybridization, clones sequencing, sequence homology search, the information of differently expressed genes in human large cell lung cancer cell line of L9981 and L9981-nm23-H1 were obtained and then further confirmed by real-time quantitative PCR. RESULTS: Gene expression profiling chips of differently expressed genes in human large cell lung cancer cell line L9981 and L9981-nm23-H1 were successfully constructed. After microarray hybridization, sequence homology search, 19 differentially expressed genes were observed. After real-time quantitative PCR evaluation, we found that the mRNA of 8 genes including PSMA7, SBDS, ODC1, YARS, CSDA, PTP4A1, SHPRH and TOMM7 was up-regulated in the cell line of L9981 after transfected with NM23-H1 gene, whereas the mRNA of PKM2 and GMNN was down-regulated. CONCLUSION: NM23-H1 gene may be the upstream regulator of metastasis-associated genes, which can regulate the downstream genes to achieve a series of lung cancer metastatic potential. PMID- 21265091 TI - [The effect of hypoxia on the expression of RHO/RHO signaling pathway and CTGF of human embryonic fibroblasts]. AB - OBJECTIVE: To observe the effects of hypoxia on cell proliferation and the expression of RHO/RHO signaling pathway, connective tissue growth factor (CTGF) and the collagen type I (Col I) in human embryonic fibroblasts at different time points, and study the possible mechanism of hypoxia-induced pulmonary fibrosis. METHODS: Human embryonic fibroblasts were cultured under hypoxic condition (37 degrees C, 5 CO2, 2% O2, 93% N2) for 0 h, 1.5 h, 3 h, 6 h, 12 h, 24 h, 48 h and 60 h respectively. The protein levels of HIF-1alpha, RhoA, ROCKland CTGF were assayed by Western blot. RT-PCR was performed to detect the mRNA levels of HIF 1alpha, ROCK1, CTGF and Col I. The concentration of collagen type I (Col I) in fibroblast cells supernatant were determined by ELISA. RESULTS: (1) Basal levels of RhoA, ROCK1, CTGF protein of MRC-5 were observed in normoxia, but the protein levels of RhoA, ROCK1 and CTGF were up-regulated after 1.5 h of hypoxia and increased further with longer exposure to hypoxia. It also demonstrated significant positive correlation between the protein levels of RhoA, ROCK1 and CTGF at different time points of hypoxia. (2) After 1.5 h, mRNA expression of ROCK1, CTGF and Col I was elevated and increased further with longer exposure to hypoxia and peaked after 60 h of hypoxia compared to normoxia. (3) Compared with normoxia, the concentration of Col I in fibroblast cells supernatant increased in different time points of hypoxia and peaked after 24 h of hypoxia. CONCLUSION: Different time points of hypoxia all significantly up-regulated the expression of protein and mRNA of CTGF and increased the secretion of Col I. Hypoxia could represent a potential brotic stimulus possibly through activation of the RHO/RHO signaling pathway, up-regulating the expression of HIF-1alpha and CTGF, triggering a series of brotic responses. PMID- 21265092 TI - [Effects of hypoxia on the expression of angiotensin-converting enzyme 2 in human umbilical vein endothelial cells]. AB - OBJECTIVE: To study the influence and mechanism of hypoxia on the expression of angiotensin-converting enzyme 2 (ACE2) in human umbilical vein endothelial cells (HUVECs). METHODS: HUVECs were cultured as adherent cells and identified by immunohistochemical study of Factor VIII. Then the cells were cultured in 37 degrees C incubators under hypoxia condition (1% O2 + 94% N2 + 5%C O2) or regular 5% CO2 condition for 3 h, 6 h, 12 h, 24 h, respectively, and the culture medium and cells were collected at each time point. ACE2 protein was measure by immunohistochemical assay, ACE2 mRNA was quantified by real-time RT-PCR. RESULTS: (1) ACE2 protein expression decreased after hypoxia treatment for 3 h, 6 h, 12 h, and 24 hour compared with regular oxygen condition (chi2 = 825.078, 768.141, 623.931, 350.260, P < 0.00625), the maximum reduction came at 3 h after hypoxia exposure, then raised gradually after 6 h, 12 h, and 24 h exposure; (2) ACE2 mRNA expression show a similar tendency to ACE2 protein. After hypoxia disposal, its relative expression rate reduced to 0.281 at 3 h (P = 0.031), then increased gradually at 6 h (0.445, P = 0.034), 12 h (0.794, P = 0.434), 24 h (0.891, P = 0.692). CONCLUSION: Our study show hypoxia down-regulate the protein and gene expression of ACE2 in HUVECs in 24 hours. The down-regulation effect of hypoxia reached maximum level at 3 h, and then attenuated gradually at 6 h, 12 h and 24 h, which indicate that ACE2 might play an important role in the regulation of RAS in HUVECs after hypoxia injury. PMID- 21265093 TI - [The expression of CD25 and FOXP3 in mouse asthma and the effect of dexamethasone]. AB - OBJECTIVE: To detect the expression of CD25 and FOXP3 in mouse asthma model, and the effect of dexamethasone (DXM) on it. METHODS: BALB/c mice were randomly divided into three groups which were of normal control group, asthmatic group and DXM treatment group. The pathological changes of lungs were detected by HE staining. The expressions of CD25 and FOXP3 from lungs were evaluated by Western blot and RT-PCR. The expression of FOXP3 from bone marrow of asthmatic group and DXM treatment group were detected by RT-PCR. RESULTS: The expression of FOXP3 in asthmatic group and DXM treatment group was significantly higher than that of normal control group (P < 0.05), DXM could promote the expression of FOXP3 (P < 0.05). The expression level of CD25 in asthmatic group and DXM treatment group was higher than that of normal control group (P < 0.05), but no significant difference was observed between asthmatic and DXM treatment groups (P > 0.05). Expressed FOXP3 mRNA in bone marrow were detected in both asthmatic and DXM treatment groups, but higher expression level was observed in DXM treatment group. CONCLUSION: The expression of CD25 and FOXP3 increased in mouse asthma model, DXM could promote the expression. Cells in bone marrow could express FOXP3, DXM maybe promote the expression of FOXP3. PMID- 21265094 TI - [Study of the protection and mechanism of IGF-1 on tau protein hyperphosphorylation in PC12 cells induced by Abeta(1-40)]. AB - OBJECTIVE: To investigate the effect and the molecular mechanism of insulin-like growth factor 1 (IGF-1) on the level of tau protein phosphorylation in PC12 cells induced by aggregated beta-amyloid protein(1-40) (Abeta(1-40)). METHODS: MTT assay was used to measure the survival rate of PC12 cells, Western blot was applied to detect tau phosphorylation level, total tau, glycogen synthase kinase 3beta (GSK-3beta), and phosphorylation of GSK-3beta Ser9 for observing the effect of IGF-1 or LiCl, a specific inhibitor of GSK-3beta, on Abeta-induced tau protein phosphorylation in PC12 cells. RESULTS: Different concentrations of IGF-1 could improve the survival rate of PC12 cells compared with that of Abeta(1-40) group (P < 0.05), and the best protective effect was observed in 1 microg/mL IGF-1 group. The levels of tau protein phosphorylation in the sites of Ser396, Ser(199/202) and the amount of whole tau increased after 3 h exposure and reached the maximum level after 12 h exposure to Abeta(1-40), meanwhile, the expressions of the amount of whole GSK-3beta was also increased (P < 0.05), but a decreased phosphorylation of GSK-3betaSer9 was observed (P < 0.05). Pretreatment with several dose of IGF-1 or LiCl, markedly reduced Abeta(1-40)-induced tau hyperphosphorylation and the expression of GSK-3beta (P < 0.05), but the expression of phosphorylation of GSK-3betaSer9 was increased (P < 0.05). CONCLUSION: The levels of tau protein phosphorylation in the sites of Ser396, Ser(199/202) and the amount of whole tau increased by Abeta(1-40) in PC12 cells, GSK-3beta activation by Abeta(1-40) may lead to extensive tau phosphorylation. IGF-1 could attenuate Abeta(1-40)-induced tau protein hyperphosphorylation by inhibiting the activation of GSK-3beta. PMID- 21265095 TI - [Effects of urokinase intervention on endotoxin-induced DIC in Wistar rat model]. AB - OBJECTIVE: To study the effects of urokinase intervention on endotoxin-induced DIC in Wistar rats model. METHODS: Wistar rats were randomly assigned into 4 groups: normal saline (NS) group, urokinase (UK) group, endotoxin (LPS) group and LPS+ UK group. These agents were given to the rats by the tail vein intravenous infusion, NS group was treated with NS 2.5 mL/h x 4 h; UK group with NS 2.5 mL/h, 1 h later UK 4 IU/(g x h) x 3 h; LPS group with LPS 3 mg/(kg x h) x 4 h; LPS+UK group with LPS 3 mg/(kg x h) firstly, 1 h later UK 4 IU/(g x h) ) < 3 h. After the intervention, the function of coagulation and fibrinolysis, the indicators of organ damage and microcirculation fibrin micro-clots were evaluated. RESULTS: One hour after the infusion of 3 mg/(kg x h) of LPS, DIC signs began to appear, and became more apparent over time. After the intervention of urokinase, the values of clotting time (PT), activated partial thromboplastin time (APTT) were significantly shorter, but the platelet count (PLT), the amount of fibrinogen (FIB) changed little. Plasminogen activator inhibitor-1 (PAI-1) level decreased, while the D-dimer level increased. Serum creatinine (Cr), alanine aminotransferase (ALT) also decreased significantly. The biopsy of liver, kidney, and lung showed tissue damage became better, and the organ microcirculation fibrin micro-clots decreased significantly. CONCLUSION: The concentration of 3 mg/(kg x h) endotoxin can successfully induce DIC model in Wistar rats. Urokinase could play a positive role to prevent the LPS-induced DIC. PMID- 21265096 TI - [Effect of focal irrigation with mild hypothermic artificial cerebral spinal fluid on the spinal ischemia/reperfusion injury]. AB - OBJECTIVE: To investigate the effect of focal irrigation with mild hypothermic artificial cerebral spinal fluid on the spinal ischemia/reperfusion injury. METHODS: Eighteen health male New Zealand white rabbits were randomly divided into three groups: normal control group (Group NC), spinal ischemia-reperfusion group (Group SIR) and focal irrigation with mild hypothermic artificial cerebral spinal fluid group (Group FI). The rabbits in Group SIR and Group FI were subjected to spinal ischemia/reperfusion injury by clamping the infrarenal abdominal aorta. The rabbits in Group FI received focal irrigation with 25 degrees C artificial cerebral spinal fluid during the spinal ischemia period. The mean arterial pressure (MAP) and cerebral spinal fluid pressure (CSFP) were continuously measured during the ischemic/reperfusion processes. The neurological conditions of the rabbits were assessed at 24 h, 48 h and 72 h after reperfusions. The spinal cords were harvested 72 h after reperfusions for histological analysis. RESULTS: The MAP and CSFP in Group NC remained stable. The MAP in Group SIR and Group FI decreased continuously in the first 30 min of spinal ischemia period and 30 min after reperfusion. The CSFP in Group SIR increased continuously in the first 10 min of spinal ischemia and was higher than the baseline and those in Group NC. The CSFP in Group FI decreased to 3.8 mmHg (1 mmHg = 0.1333 kPa) at the beginning of spinal ischemia, and remained at 3-5 mmHg until 20 min after reperfusions. Group FI had better neurological outcomes and less severe pathological changes than Group SIR measured at 72 h after ischemia/reperfusion. CONCLUSION: Focal irrigation with mild hypothermic artificial cerebral spinal fluid can decrease CSFP during spinal ischemia/reperfusion and protect spinal cords against ischemia/reperfusion injuries. PMID- 21265097 TI - [Effect and mechanism of DNMT inhibitor on the reversal of multidrug resistance in human colon cancer cell line sw620/L-OHP]. AB - OBJECTIVE: To explore whether demethylation inhibitor 5-aza-2'-deoxycytidine (5 aza-dC) could reverse multidrug resistance (MDR) of human colon cancer and its impacts on the expressions of Bcl-2/adenovirus E1B 19 KDa protein interacting protein 3 (BNIP3), P-glycoprotein (P-GP) and multidrug resistance-associated protein (MRP), as well as the activity of DNA methyltransferase (DNMT). METHODS: Oxaliplatin (L-OHP) resistant human colon carcinoma cells (sw620/L-OHP) and its parental cells (sw620) were used to determine the effect of 5-aza-dC. CCK-8 assay was adopted to evaluate the cytotoxicity of 5-aza-dC. Western blot was performed to observe the expressions of BNIP3, P-GP and MRP. H microassay was used to detect the activity of DNMT. RESULTS: After the addition of 1.4 micromol/L 5-aza dC, the 50% inhibitory concentration (IC50) of L-OHP to sw620/ L-OHP cells was decreased from (0.335 +/- 0.043) microg/mL to (0.069 +/- 0.023) microg/mL, and the chemosensitivity increased 8.26 times (P < 0.001). Western blot analysis showed that the expression of BNIP3 was up-regulated by 5-aza-dC in a concentration-dependent manner (P < 0.001), and P-GP and MRP expression were also significantly changed (P < 0.05) but not in a concentration-dependent manner (P > 0.05). DNMT activity was down-regulated by 5-aza-dC in sw620/L-OHP cells (P < 0.001). CONCLUSIONS: 5-aza-dC could reversed multi drug resistance of sw620/L OHP, which may due to the demethylation to upregulate BNIP3 expression, and inhibit the expression of resistance-associated protein P-GP and MRP further by some unknown mechanism. PMID- 21265098 TI - [Effect of high concentration of glucose on thickness of glycocalyx and expression of syndecan-1 and glypican-1 in cultured human renal glomerular endothelial cells]. AB - OBJECTIVE: To investigate the influence of high concentration of glucose on the thickness of Glycocalyx and expression of core protein Sydecan-1 and Glypican-1 in cultured human renal glomerular endothelial cells (HRGECs). METHODS: HRGECs in culture were randomly divided into 3 groups, high concentration of glucose (30 mmol/L D-glucose, high glucose group), normal concentration of glucose as controlled group (5 mmol/L D-glucose+25 mmol/L mannitol, normal control group), and mannitol group (30 mmol/L mannitol) respectively. After 72 hours, confocal laser scanning microscopy (CLSM) was used to observe and characterize the fully hydrated glycoalyx of HRGECs. Real time quantitative PCR and Western blot were applied to detect the mRNA levels and protein expression of Syndecan-1 and Glypican-1, and the fluorescence microscope were used to observe the immunofluorescence change of Syndecan-1 and Glypican-1. RESULTS: Compared with normal control group, the thickness of Glycocalyx on the surface of HRGECs in high glucose group decreased to 36.8% (P < 0.05). Immunofluorescence shows the depositions of Syndecan-1 and Glypican-1 were weakened in high glucose group. The mRNA and protein expression of Syndecan-1 and Glypican-1 were significantly decreased (P < 0.05) compared with normal control group and mannitol group. CONCLUSION: High concentration of glucose can reduce thickness of Glycocalyx on the surface of human glomerular endothelial cell. At the same time, high glucose can decrease the expression of core protein Sydecan-1 and Glypican-1 of HRGECs. PMID- 21265099 TI - [Inhibitive effect of ursolic acid on the invasion and metastasis of ovarian carcinoma cells HO-8910PM]. AB - OBJECTIVE: To study the effects of ursolic acid (UA) on the invasion and metastasis of ovarian carcinoma cell HO-8910PM and its underlying mechanism. METHODS: MTT assay was performed to examine the effects of UA on the proliferation of ovarian carcinoma cells HO-8910PM in vitro. The effects of UA on the invasion and migration of HO-8910PM were evaluated using Transwell chambers attached with polycarbonate filters and reconstituted basement membrane. Gelatin zymography was performed to detect the activity of gelatinase in the HO-8910PM cells. The expressions of MMP-2 and MMP-9 in the HO-8910PM cells were measured by Western blot. RESULTS: UA inhibited the proliferation of HO-8910PM cells in a time- and dose-dependent manner. There was a statistically significant difference in the invasion and migration of HO-8910PM cells between the UA treated cells and the controls (P < 0.01, P < 0.05). UA inhibited the activity of gelatinase of the treated cells. CONCLUSION: UA downregulated the expressions of MMP-2 and MMP-9. UA inhibits the invasion and metastasis of HO-8910PM cells, probably through inhibiting the activity of gelatinase and the expressions of MMP-2 and MMP-9. PMID- 21265100 TI - [Study on the change of angiotensin II expression in rat lung exposure to acrolein]. AB - OBJECTIVE: To investigate the changes of angiotensin II (Ang II) expression in a rat model of mucus hypersecretion induced by acrolein. METHODS: A rat model of mucous hypersecretion of airway was established by acrolein-inhalation. The AB/PAS stain was performed to evaluate the mucous secretion level. Immunohistochemistry and Western blot were employed to detect the expression of Ang II protein. RESULTS: Hypersecretion of mucus occurred at 3 weeks and peaked at 6 weeks post exposure (wpe) to acrolein. Increased immunostaining and protein level of Ang II were readily detected in rat lung at 3 wpe and enhanced at 6 wpe. CONCLUSION: The increase of Ang II expression, which associated to pulmonary mucus hypersecretion, might play a role in the lung injury induced by acrolein exposure. PMID- 21265101 TI - [Effects of acrolein exposure on the expression of Muc5ac in the airway of rats]. AB - OBJECTIVE: To explore the changes of Muc5ac expression in a rat model of mucus hypersecretion induced by acrolein. METHODS: The rat model of mucus hypersceretion was established by acrolein exposure. RT-PCR, ISH, immunohistochemistry and Western blot were employed to detect the mRNA and protein levels of Muc5ac in the rats airway. RESULTS: The expression of Muc5ac was detected in trachea and lung at 3 weeks post exposure (wpe) and the expression level was enhanced at 6 wpe. ISH confirmed that Muc5ac was synthesized endogenously. CONCLUSION: The pulmonary mucus hypersecretion is associated to the increase of intrinsic Muc5ac expression in the rat airway exposure to acrolein. PMID- 21265102 TI - [Effects of enalapril on NF-kappaB expression in mucus hypersecretion rats induced by acrolein exposure]. AB - OBJECTIVE: To investigate the effects of enalapril on nuclear factor-kappa B (NF kappaB) expression in a rat model of mucus hypersecretion induced by acrolein. METHODS: The rat model of mucus hypersecretion was established by the inhalation of acrolein. Then the mucus hypersecretion rats were treated by enalapril. The AB/PAS stain was performed to measure the secretion of airway in the rats, while the mRNA and protein expression levels of NF-kappaB in the airway were detected by RT-PCR, ISH, immunohistochemistry and Western blot. RESULTS: With the inhalation of acrolein, the airway secretion increased obviously, while the mRNA and protein expressions of NF-kappaB in lung were increased. The treatment of enalapril resulted in a significant decrease of airway secretion, as well as the downregulation of NF-kappaB in both protein and gene level. CONCLUSION: Enalapril (ACE inhibitor) treatment could effectively decrease pulmonary mucus hypersecretion in acrolein-treated rats, which may be related to the downregulation of NF-kappaB expression. PMID- 21265103 TI - [Effects of enalapril on IL-1beta, IL-6 expression in rat lung exposure to acrolein]. AB - OBJECTIVE: To investigate the effects of enalapril on the expressions of IL-1beta and IL-6 in the lung of rats treated with acrolein inhalation. METHODS: Inflammatory lung injury was induced by acrolein inhalation in rats. The rats were divided into natrium solution (NS) group, acrolein group, enalapril and acroclein (EA) group, enalapril and NS (EN) group. Lungs were harvested from the rats in each group at 1 week, 3 weeks, 6 weeks after the treatment of natrium solution, acrolein inhalation and/or enalapril. The mRNA and protein expressions of IL-1beta and IL-6 in the lung tissues were measured by RT-PCR, in situ hybridization, immunohistochemistry and Western blot. RESULTS: Increased immunostaining, protein level and mRNA expression of IL-1beta and IL-6 were found in rat lung at 3 weeks and reached to the peak at 6 weeks post exposure to acrolein. The administration of enalapril resulted in a significant downregulation of IL-1beta and IL-6 in both protein and gene level, accompany with the decrease of inflammation. CONCLUSION: Enalapril, as a ACE inhibitor, could protect the airway from inflammation injury in acrolein-treated rats via the down-regulation of IL-1beta and IL-6 expression. PMID- 21265104 TI - [Surface modification of RGD peptides onto acellularized porcine aortic valve to promote cell adhesion]. AB - OBJECTIVE: To investigate the impact of RGD peptides on cell adhesion to acellularized procine aortic valve. METHODS: The acellular porcine aorta valve (APAV) was prepared by removing the cells and cellular components from porcine aortic valve using trypsin and hyposmosis TritonX-100. With the help of epoxy chloropropane (EC), the decelluarized valve scaffolds were immobilized with YGRGDSP peptide. MFBs were seeded onto four groups [acellularized value (AV) group, EC group, glutaraldehyde+EC (GE) group and EC+ RGD group or GE+RGD group] of coupled, coated and untreated decelluarized valve scaffolds. Ninhydrin reaction, cell count and fluorescent imaging test were employed to examine the efficiency of cell adhesion. RESULTS: More cells were attached to the decellularized valve scaffolds when the cells were coupled with RGD peptides compared with the others. The adhesive effect was correlated with the concentration of the RGD peptide and the attaching time. CONCLUSION: With the help of EC, YGRGDSP peptides can be immobilized by covalent bonding. RGD peptides improve cell adhesion to decellularized valve scaffolds. PMID- 21265105 TI - [Protective effects of emodin on intestinal lesion in rat model with acute necrotizing pancreatitis]. AB - OBJECTIVE: To explore the protective effects and mechanism of Emodin on intestinal lesion in the rats with acute necrotizing pancreatitis (ANP). METHODS: Thirty SD rats were randomly divided into 3 groups: sham-operated (SO) group, ANP group and Emodin-treated group. ANP was induced by retro-pumping 3.5% sodium cholate to pancreaticobiliary duct. 5.5 hours after modeling, phenol red, which was employed to measure intestinal transit, was injected to duodenum. 0.5 hour later, rats were sacrificed to collect intestine for the results of intestinal transit and other tests of intestine. Furthermore, intestinal tissue (HE staining) was observed by light microscope, and the activity of nuclear factor kappa B (NF-kappaB) in intestine was detected by immunohistochemical method. The content of intestinal tumor necrosis factor-alpha (TNF-alpha) and interleukin 1beta (IL-1beta) was detected with the method of enzyme-labeled immunosorbent assay (ELISA). RESULTS: Compared with SO group, there was significantly decrease of intestinal transit in ANG group (P < 0.05). Furthermore, intestinal transit in Emodin-treated group significantly increased when compared with ANP group (P < 0.05). NF-kappaB p65 positive rate of intestinal cell nuclei, content of intestinal TNF-alpha and IL-1beta in ANP group were obviously higher than those in SO group (P < 0.05). After the treatment of Emodin, NF-kappaB p65 positive rate of intestinal cell nuclei, content of TNF-alpha and IL-1beta were decreased (P < 0.05). Moreover, there was a negative correlation between intestinal transit and content of TNF-alpha, IL-1beta, with correlation coefficients--0.83, -0.76, respectively (P < 0.05). CONCLUSION: Emodin could increase intestinal transit, suppress the activity of NF-kappaB in intestine, decrease the content of intestinal TNF-alpha and IL-1beta, and attenuate the pathological damage of intestine. PMID- 21265106 TI - [Changes of microarchitecture and biomechanical properties in callus during fracture healing in ovariectomized rats]. AB - OBJECTIVE: To study the changes of biomechanical properties and microarchitecture in callus during the healing process of osteoporotic fracture. METHODS: Ovariectomy (OVX) was performed on SD rats to establish osteoporotic rat model. Osteotomy was performed on both groups of rats with OVX and sham operations to establish bone fracture. Bone mineral density (BMD), area of type I collagen, biomechanical properties, and microarchitecture of the fractured bones during healing process were measured. RESULTS: The BMD of both groups of rats were significantly lower at the 12th week than at the 6th week after fracture (P < 0.05). Both groups of rats had significantly higher biomechanical strength and area of type I collagen at the 12th week than at the 6th week after fracture (P < 0.05). The OVX group of rats had significantly lower structure model index (SMI) values than the sham group at both 6th and 12th week after fracture (P < 0.05). Higher values of SMI appeared at the 12th week than at the 6th week in both groups of rats (P < 0.05). CONCLUSION: During the healing of fracture, the BMD of the newly-formed bone reaches its peak value at the 6th week after fracture, which is earlier than the occurrence of peak biomechanical strength, area of type I collagen, and SMI. Although the collagen and aggravation of mineral determine the biomechanical properties, BMD by itself may not be able to determine the biomechanical strength because of the change of the 3-D structure of the callus. The combination of collagen and microarchitecture may act as a factor that determines the biomechanical strength of callus independent of BMD. PMID- 21265107 TI - [Effect of prolonged infusion of propofol on the liver mitochondria respiratory function in rabbits]. AB - OBJECTIVE: To investigate the changes of respiratory function of liver mitochondria in rabbits induced by the general anesthetic propofol. METHODS: Eighteen New Zealand rabbits weighted 1.5-2.5 kg were randomly divided into three groups: control group, emulsion group and propofol group. The control group received continuous infusion of 0.9% sodium chloride solution. The propofol group received continuous infusion of 1% propofol. The emulsion group received continuous infusion of 10% emulsion. The liver mitochondri of the rabbits were isolated. The carnitine acyl transferase (CPT) activity, H+ -ATPase hydrolysis activity and the content of ATP in the mitochondria were analysed. RESULTS: The rabbits in the propofol group had lower activity of CPT than the controls (P < 0.05), while no difference was found between the control group and the emulsion group (P > 0.05). The rabbits in the propofol group had higher H+ -ATPase hydrolysis activity than the controls (P < 0.05), while no difference was found between the control group and the emulsion group (P > 0.05). No significant differences were found in the content of ATP in mitochondria between the three groups (P > 0.05). CONCLUSION: Propofol inhibits CPT activity, which disturbs fatty acid beta-oxidation. Emulsion acted as vehicle of propofol seems to have no significant impact on mitochondria respiratory function. PMID- 21265108 TI - [Volumetric and geometric changes of parotids occurring during IMRT for nasopharyngeal carcinoma (NPC) using daily CBCT]. AB - OBJECTIVE: To study the volumetric and geometric changes of parotids occurring during IMRT treatment for NPC. METHODS: The pre-treatment CBCT images of 10 patients were obtained using kV-CBCT and transmitted back to TPS. The gross tumor volumes (GTVs) and volumes of parotids were manually drawn slice by slice on the CBCT images by the same person using image analysis software system Tomcon 3.0. For position changes, the center-of-mass (COM) were calculated using Pinnacle 8.0 software. Then the distance from the parotid to the atlas was assessed. RESULTS: The volumetric changes of GTVs and parotids were correlated with the days of treatment. The volumes of GTVs decreased with a mean total loss of 9.85 cm3 (5.10 21.40 cm3) and a median change rate of 0.20 cm3/d (0.10-0.46 cm3/d). The volumes of left parotids decreased with a median total loss of 5.70 cm3 (3.20-12.00 cm3) and a median change rate of 0.13 cm3/d (0.07-0.27 cm3/d). The volumes of right parotids decreased with a median total loss of 8.05 cm3 (3.00-13.40 cm3) and a median change rate of 0.18 cm3/d (0.06-0.29 cm3/d). The distance between the left parotid and the atlas decreased with a median total loss of 3.45 mm (0.70-7.60 mm) and a median change rate of 0.07 mm/d (0.01-0.11 mm/d). The distance between the right parotids and the atlas decreased with a median total loss of 2.60 mm (1.50-4.40 mm) and a median change rate of 0.05 mm/d (0.03-0.12 mm/d). CONCLUSION: Significant reductions of GTVs occur after the third or forth week of IMRT treatment for NPC, which indicates that a second plan of CT scanning or treatment replanning might be necessary after 3-4 weeks of treatment to minimize radiations to vital organs. PMID- 21265109 TI - [Study on the accuracy of dual source computed tomography coronary angiography in detection of coronary artery stenoses in old patients]. AB - OBJECTIVE: To investigate the accuracy of dual source computed tomography (DSCT) coronary angiography in detecton of coronary artery stenoses in patients older than 60 years. METHODS: The study was performed in 102 patients older than 60 years who were suspected of coronary artery stenoses, and without any contraindications to CT Scan and iodnated contrast agents. These patients underwent DSCT, as well as selective coronary angiography (SCA). All the data of DSCT were compared with the results of SCA which were regarded as gold standard to assess the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of DSCT in classifying coronary artery stenoses in old patients. RESULTS: In these 102 patients, DSCT indicated 56 patients with coronary artery stenoses and SCA indicated 52 patients. DSCT correctly classified 51 patients out of 52 patients who had significant coronary artery stenoses. The sensitivity of DSCT was 98.1%, specificity was 90.0%, positive predictive value was 91.1%, negative predictive value was 97.8%, and accuracy was 94.1%. DSCT also assessed and measured 408 lesions in all the patients. The sensitivity of DSCT was 95.8%, specificity was 96.2%, positive predictive value was 88.5%, negative predictive value was 98.7%, and accuracy was 96.1%. CONCLUSION: DSCT appears to be a useful method for the detection of coronary artery stenoses with a high accuracy in elder patients more than 60-year. PMID- 21265110 TI - [Association of PPARgamma2 Pro12Ala polymorphism and cognitive dysfunction in hypertension patients]. AB - OBJECTIVE: To study the relationship between PPARgamma2 Pro12Ala polymorphism and cognitive function in patients with primary hypertension. METHODS: This study enrolled 502 hypertensive patients of Chinese Han population from Jan 2008 to Feb 2009 in West China Hospital of Sichuan University. We collected the general data and applied the mini mental state examination (MMSE) to test the cognitive function and computed score. Total cholesterol (TC), triglyeride (TG), fasting plasma glucose (FPG) and postprandial blood sugar (PPBS), fasting insulin (FINS) and postprandial plasma insulin (PINS) were measured. PCR-RELP method was used to analysis the PPARgamma2 Pro12Ala gene polymorphism. RESULTS: Pro12Pro genotype was present in 88.6% of the patients and Prol2Ala genotype was present in 11.4% of the population. Allele frequencies were 94.3% for Pro allele and 5.7% for Ala allele. In cognitive normal group, the frequencies of PP and PA genotype were 328 (87.2%) and 48 (12.8%), while the frequencies of PP and PA genotypes in the cognitive dysfunction group were 126 (92.9%), 9 (7.1%) respectively. Analyzed by chi2 test, both the genotype frequency and the allele frequency of PPARy2 Pro12Ala polymorphism did not display statistical variability between the cognitive normal group and the cognitive dysfunction group, even eliminating the influence of age and sexuality. CONCLUSION: Pro12Ala polymorphism in PPARgamma2 with primary hypertension may not associate with cognitive impairment. PMID- 21265111 TI - [Relationships among interleukin-1beta, interleukin-1 receptor antagonist gene polymorphism and susceptibility to gastric cancer]. AB - OBJECTIVES: To investigate the genetic polymorphisms of interleukin-1B (IL-1B) and interleukin-1 receptor antagonist gene (IL-1RN) in gastric cancer, and to explore the relationships of these genetic polymorphisms to the susceptibility of gastric cancer. METHODS: The polymorphisms of IL-1B and IL-1RN genes were analyzed by PCR-restriction fragment length polymorphism (PCR-RFLP) after extracting the genomic DNA from 140 gastric cancer patients and 165 age- and sex matched healthy controls. RESULTS: The polymorphisms of IL-1B promoter region 31, -511 and +3954 locus have no significant difference between gastric cancer patients and healthy subjects. Four kinds of polymorphisms of IL-1RN were found as 2R/2R, 2R/4R, 3R/4R and 4R/4R, and the frequency in gastric cancer patients were 0.7%, 15.7%, 2.9% and 80.7%, respectively, while the frequency in healthy controls were 0, 5.5%, 0 and 94.5%, respectively. Compared to 4R/4R genotype, a 3.37 fold increased risk of gastric cancer were found in 2R/4R genotype, but the difference was not significant (P = 0.557, chi2 = 2.076). IL-1RN 2R allele frequencies in gastric cancer and healthy controls were 8.6% and 2.7%, respectively, which showed the risk to be gastric cancer increased 3.4 times, but the difference was not significant (P = 0.781, chi2 = 0.494). CONCLUSION: There is no evidence to support that the polymorphism of IL-1B and IL-1RN gene had relationship with gastric cancer. However, the risk of developing gastric cancer might be raised when the IL-1RN 2R allele exist. PMID- 21265112 TI - [Assessing quality of life in an urban population in Chengdu using the SF-12]. AB - OBJECTIVE: To assess the health-related quality of life in an urban population in Chengdu China using the SF-12. METHODS: A random sampling strategy stratified by age and sex was adopted to select the participants in Chengdu. A total of 1365 respondents with an age of older than 18 years completed the interviewer administered SF-12 survey. The physical (PCS) and mental (MCS) component summary measures of the SF-12 were calculated using the standard US scoring method and compared to the urban population norms of Hong Kong and Australia. RESULTS: Similar PCS and MCS scores were obtained for the urban Chengdu population compared to the Hong Kong and Australian population norms, albeit a closer similarity between the Chengdu and Hong Kong populations. The PCS and MCS scores of the SF-12 changed with sex and age. CONCLUSION: The age- and sex-adjusted PCS and MCS scores of the SF-12 in the urban Chengdu population can serve as a reference for future studies using the SF-12 in China. PMID- 21265113 TI - [Association of family dynamic structure and parental rearing style with male larcenists]. AB - OBJECTIVE: To explore the association of parental rearing style and family dynamic structure with male larcenists. METHODS: A questionnaire survey was undertaken in 280 male imprisoned larcenists and 420 healthy controls with a General Information Questionnaire and EMBU (Egna Minnen Betralffande Uppfostran). RESULTS: Statistically significant differences were found between the two groups in the following items: 'only child in the family', 'not lived with father before age 5', 'father died', 'mother died', 'both parents died', 'parents divorced', 'lived with father only (mother absence) before age 5', 'adult with father alive (mother died)' and 'adult with mother alive (father died)'. The two groups also experienced significant differences in 'emotional warmth', 'severe punishment', 'over-intervention from both parents', 'favored child from mother', 'father rejection' and 'father over-protection'. CONCLUSION: Men with single father (mother absence) before age 5 and those who have experienced death of any parents, 'emotional warmth', 'severe punishment', 'over-intervention from both parents', 'favored child from mother', 'father rejection' and 'father over protection' are more likely to commit theft crime. PMID- 21265114 TI - [Determination of nicacid and its metabolites in human plasma by HPLC-MS/MS]. AB - OBJECTIVE: To develop a sensitive HPLC-MS/MS method for the determination of nicacid and its metabolites in human plasma. METHODS: The assay was conducted with an API 3000 LC-MS/MS system comprising of a Genimi C18 column (50 x 3.00 mm, 3 microm), and an eluate of 0.1% acetic acid-methanol-isopropyl alcohol (98: 1:1), and flow rate was 0.2 mL/min. Acetonitrile was used to precipitate protein from the plasma samples. The loading samples contained the residue from the supernatant that were dissolved in the eluate solution and rinsed by dichloromethane was used as the loading samples. The ion pairs of m/z 124.1- >80.0, m/z 123.1-->80.0, m/z 181.1-->135.0 and m/z 138.1-->92.0 were used to quantify nicacid, niacinamide, nicotinuric acid and 6-methyl nicotinic acid (IS), respectively. RESULTS: The standard curves of nicacid, niacinamide and nicotinuric were linear in the range of 1.25-320 microg/L, 1.25-1280 microg/L and 1.25-1280 microg/L, respectivly. All with a low determination limits of 1.25 microg/L and a less than 9% within-day and inter-day RSD. The recovery rates reached 89% to 105%. CONCLUSION: The method is simple, rapid, sensitive, and suitable for the determination of nicacid and its metabolites in human plasma. PMID- 21265115 TI - [Rapid determination of ethanol in blood by capillary-gas chromatography]. AB - OBJECTIVE: To develop a method for the rapid determination of ethanol in blood with capillary-GC. METHODS: 0.50 mL of whole blood sample was taken and added with 1.00 mL of dimethyl sulfoxide (DMSO), and 2 g of anhydrous sodium sulfate. The supernatant of the sample solution was directly injected into GC for analysis. RESULTS: Ethanol was separated from other substances in the sample. The liner range of ethanol detected by the capillary-GC was 0.0-300.0 mg/100 mL, and the detection limit was 0.2 mg/100 mL. The RSD for standard solution determination was 1.36%. Satisfactory results were obtained for the determination of ethanol in whole blood samples, with recoveries ranging from 90.9% to 107.3% and a RSD of 1.98%. The combined uncertainty was 2.2%. CONCLUSION: This is a rapid, sensitive and simple method for determination of ethanol in large quantities of samples. The method has shortened the duration of analysis cycle in comparison with the traditional headspace-GC, with a reduction from 20-30 min to less than 10 min. PMID- 21265116 TI - [A successful case of tanshinone II A treatment for relapsed acute promyelocytic leukemia after maintainance therapy of all-trans retinoic acid and arsenic trioxide]. AB - OBJECTIVE: To observe the effects of Tanshinone II A (Tan II A) on acute promyelocytic leukemia (APL) characterized by resistance to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). METHODS: A 21-year-old male patient with relapsed APL, who previously received the maintenance therapy with ATRA,ATO, 6 Mercaptopurine (6-MP) and Methotrexate (MTX) for 1 year, was given Tan II A 80 mg intravenously once a day, and the changes of hematological parameters and side effects of Tan II A were observed. RESULTS: The patient reached morphologically complete remission after using Tan II A intravenously for 54 days. During Tan II A treatment, obvious side effect was not observed. CONCLUSION: Tan II A treatment may be effective in relapsed APL cases with ATRA and ATO resistance. PMID- 21265117 TI - [Lymphedema: clinic-therapeutic aspect]. AB - Lymphedema may be presented in mild or less severe form. Nowadays, accurate diagnosis and effective therapy are available. Wearing surgical bandage, massage, exercise, and pumps form the core program for most patients with lymphedema. The application of pharmacological therapies has been notably absent from the management strategies for lymphatic vascular insufficiency states but lately some progress has been made by applying wobenzym in the treatment. Surgical approaches to improve lymphatic flow through vascular anastamosis have been, in large part, unsuccessful, but controlled liposuction affords lasting benefit in selected patients. PMID- 21265118 TI - [Analysis of structural and functional indices of the children hearts with isolated abnormal chords of the left ventricle and who were born to parents irradiated during the Chernobyl accident]. AB - 156 children of the main group, born to parents irradiated in the result of Chernobyl disaster have been involved in the study. These children were identified with isolated abnormal chords of the left ventricle (AHLV) according the results of Doppler echocardiography. 39 practically healthy children and 24 children of the nosology control group have also been observed. Threshold quantity of AHLV were determined in 33 children, main group, (subgroup Ia), sub threshold--in 123 children (subgroup I(B)). The children of the control group with threshold quantity of AHLV were found with decreased adaptation capacity of the cardio-vascular system through shifts in dynamics and energetics of the heart contraction. Reduction in systolic output, systolic and heart indices justify hypokinetic type of organization of central hemodynamics, which can be considered an early sign of tension of functional capabilities of the heart and blood vessels. This subgroup of children was found to have changes of transmitral blood flow indicating the initiation of the heart's diastolic dysfunction. Almost 1/3 of children with subthreshold number of AHLV were also revealed to have signs of initiation of the heart's diastolic dysfunction. PMID- 21265119 TI - [Comparative characteristic of fatty acid content of lipids from expired air condensate in children with recurrent bronchitis residing in radiative contaminated territories and "clear" regions concerning radionuclide contamination]. AB - The differences in the fat acid spectrum of expired air condensate in children with recurrent bronchitis who are residents of the radiation contaminated territories and children with analogous diagnosis living in the "clear" region regarding the radionuclide contamination consisted in the increased saturation of lipid complex indices against the decrease in content of polyunsaturated fat acids, antioxidant properties of pulmonary surfactant and activity of adaptation compensatory processes in lipid bilayer of its membrane structures. PMID- 21265120 TI - [Optimization of energy metabolism in patients with chronic heart failure]. AB - Nowadays particular interest of clinicians is attracted by metabolic therapy of patients with chronic heart failure (CHF). The objective of this study was to investigate the influence of complex therapy with addition of Vasonat on the dynamics of remodeling indexes of left ventricle and functional class of CHF on classification of NYHA. It has been shown that application of metabolic modulator Vasonat in addition to conventional therapy of CHF facilitated the clinical improvement and significant decline of functional class. Vasonat use resulted in the meaningful improvement of the contractive function of myocardium and increase of tolerance to the physical exercise. Moreover, high efficiency of Vasonat has been demonstrated in the control of the syndrome of oxidizing stress, by decrease in intensity of free-radical processes and activation of the antioxidant defense system. PMID- 21265121 TI - [Change of humoral immunity under influence of enterosorption in presurgery period in the treatment of patients with mechanical jaundice of non-neoplastic genesis]. AB - The authors have studied indices of the humoral immunity with mechanical jaundice of nonneoplastic genesis. Disorders of immune status of patients with bilious ways obturation, which were characterized by concentration increase IgG in 1,6 times, IgA--in 1,3 times and IgM--in 1,7 times of the level of circulating immune complexes--in 1,6 times and decrease in fractional index and fractional number in 2 and 1,7 times accordingly. The study has shown principle efficiency of enterosorption in patients with mechanical jaundice in restoration of indices of the humoral immunity. It was seen more considerably with application of chitin contained active substance, mycotin. It has allowed improving functional ability of the liver, especially its synthesizing function and hydroxylation processes in hepatic cells. PMID- 21265122 TI - [Treatment outcome of patients with bone tumors after limb salvage surgery]. AB - In 336 patients with various tumors of the limb bones underwent limb sparing surgery with different kind of reconstructions. The oncological results of the treatment of these patients have been analysed. Local relapse after limb sparing interventions because of extremities bone tumors developed in 4,17% of all cases. In most cases, local recurrences have been observed in patients with bone sarcomas high degree of malignancy (7,14%) and low degree of malignancy (2,82%). In 57,1% of cases, local recurrences developed in patients with osteogenic sarcoma IIB stage. The appearance of local recurrence was a bad prognostic factor for patients with bone sarcomas high grade, because it reduced 5-year survival rate almost 2 times. The overall 5-year survival of patients with bone sarcomas high grade of malignancy were (59,67 +/- 5,69)%, and 5-year relapse-free survival rate--(55,23 +/- 5,52)%. Local recurrences more often developed after the use of distraction method of surgery--in 16% of all reconstructive operations, including 12% of the cases with bone tumors of high degree of malignancy, which should be considered when choosing this method of reconstruction. PMID- 21265123 TI - [Efficiency of a complex preventive therapy including wobenzym in pregnant women with chronic pyelonephritis and glomerulonephritis]. AB - Pregnant women with pyelonephritis (PN) and glomerulonephritis (GN) were shown to have response to the therapy in accordance with level of kidney functional activity. The women with PN and GN have the treatment efficacy higher with Kidney Functional Reserve KFR > 10% and from 5 to 10% and practically absent in pregnant women with KFR < 5% (Kidney functional reserve). PMID- 21265124 TI - [Experience of using thalidomide in the treatment of patients with multiple myeloma]. AB - The results of treatment of patients with multiple myeloma with thalidomide and complications of this treatment are presented. Monotherapy with thalidomide and its combinations with corticosteroids and cytostatics is an effective as first line treatment and as a treatment of patients with refractory disease. The most common side effect is toxic neuropathy. Other complications are less common and are easily controlled with medications. PMID- 21265125 TI - [Nonspecific hemostatic therapy for dysfunctional uterine hemorrhages in patients with mild forms of von Willebrand's disease]. AB - Main coagulation parameters against a background of nonspecific haemostatic therapy use (NHT) in women with mild forms of von Willebrand's disease have positive dynamics with coagulation test indices normalized on 5-6 and 10-14 days. Menses length under NHT use is significantly shorter and amounts 6-7 days in 19 (79,2%) patients, 8 days--in 5 (20,8%) women compared to 11-14 days in women without NHT. PMID- 21265126 TI - [Effect of carvedilol in the combination with quercetine and tiotriazoline on the nucleus density and RNA concentration in the nucleus of cardiac myocytes of spontaneous hypertensive rats]. AB - It was found out in the previous studies, that rats with spontaneous hypertension (SHR) developed the hypertrophy of myocardium, disorders of osmotic properties of erythrocytes membranes, morphological and ultrastructural changes in the cardiac hystiocytes of animals. Carvedilol in SHR rats has decreased blood pressure, and normalized physiological, biochemical and morphological indexes in the cardiac muscle. More expressed effect was observed during the use of carvedilol with metabolic medications--Quercetine and Tiotriazoline. Studies on SHR rats has shown increase of cardiac hystiocyte nuclei density and decrease in RNA concentration in a cardiac muscle. Carvedilol, Quercetine and Tiotriazoline have normalising effect on investigated parameters. The use of carvedilol with Tiotriazoline have more expressed normalising effect on nuclei density of cardiac hystiocytes, and also on RNA concentration PHK in nuclei of cardiac muscle. PMID- 21265127 TI - [Microhemodynamics of the renal cortex in the experimental hydronephrosis]. AB - The authors have studied the influence of unilateral urethral occlusion in the development of microhemomicrocirculatory disorders in renal cortex both on side of the damage and on the opposite side. It was shown, that the degree of hemomicrocirculatory disorders on occlusion side depends on duration of ureteral obstruction that defines the development of tissue hypoxia and breaks down the trophism of the kidney parenchyma. The dynamic functional hemomicrocirculatory disorders riverbeds appear on early (1, 3, 5 day), but inconvertible changes of the kidney parenchyma develops later (14, 30 day) periods of the experiment. Disorders of the function of one kidney leads to adaptive reaction of the hemomicrocirculatory system of the opposite kidney and It reveals itself in the dilatation of microvessels of this system and increase of the linear blood velocity in it, providing its hyperfunction. PMID- 21265128 TI - [Simulation of administrative influence on a public health under conditions of changing the terminal values during the process of society transformation]. AB - The article is devoted to the study of interrelation between terminal values and subjective health in the context of community development and modeling of possible directions of administrative influence on a public health taking into account such interrelation. The structural model of influence of terminal values on a subjective health is presented and the assessment of possible changes of health on the population level under condition of the introduction of the proper administrative interventions is given. PMID- 21265129 TI - [Pharmacoeconomic assessment of antihypertensive therapy for patients of elderly and senile age in the hospital for veterans of war]. AB - The authors presented results of the study of antihypertensive therapy for patients of elderly and senile age in the hospital, an assessment of the efficiency of the control of arterial hypertension in a clinical practice is given in the article. The article presents the most effective combinations of antihypertensive agents, their pharmacoeconomic assessment and rational scheme of antihypertensive treatment for the patients of this age category. PMID- 21265130 TI - [Epidemiological peculiarities of working day losses among military personnel of Ukrainian Armed Forces]. AB - Peculiarities of working day losses caused by infectious and parasite diseases among military personnel of Ukrainian Armed Forces in the period of formation, reorganization, reformation and restructuring of the Armed Forces of Ukraine in 1991-2008 are defined in the article based on retrospective epidemiological analysis. PMID- 21265131 TI - [Dynamics of basic indexes of functional state of young people depending on intensity of physical exercise]. AB - This article presents an analysis of data obtained during the study of dynamics of changes of main indexes of functional state of young people who systematically performs physical exercises and play sport, depending on the level of physical exercises and initial parameters of their physical exercise tolerance. PMID- 21265132 TI - [Professor K. P. Tarasov--the first dean of stomatologic department in National Medical University named after A. A. Bogomolets. On 90th anniversary of NMU foundation]. AB - The article presents a complex course of life of the professor, K. P. Tarasov- the first dean of stomatological (odontological) faculty of National medical university named after A. A. Bogomolets and the chief of orthodontics department, his considerable contribution to faculty development, and also destiny of his children. PMID- 21265134 TI - [Composition and seasonal dynamics of litter falls in a broad-leaved Korean pine (Pinus koraiensis) mixed forest in Changbai Mountains, Northeast China]. AB - In order to understand the composition and spatiotemporal dynamics of the litter falls at community level in a broad-leaved Korean pine mixed forest in Changbai Mountains, litter falls were collected from 150 containers in a 25 hm2 permanent plot in 2008. The leaf litters in the containers were from 35 tree species, accounting for 67.3% of the total number (52) of the tree species with DBH > or =1 cm in the plot. The litter falls had a weight 29.39 kg, equivalent to 3918.4 kg x hm(-2) among which, broad leaves, miscellany, needle leaves, and branches occupied 61.7%, 18.0%, 11.7%, and 8.6%, respectively. About 83.8% of the broad leaves were from Tilia amurensis, Fraxinus mandshurica, Quercus mongolica, Acer mono, and Ulmus japonica. The litter falls showed an evident seasonal dynamics, with the peaks occurred from 13 September to 10 October, e.g., the litter falls from T. amurensis and Pinus koraiensis peaked in 13-26 September, while those from Q. mongolica, U. japonica, and A. pseudo-sieboldianum peaked in 27 September to 10 October. There was a great difference in the mass of the litter falls among the containers, e.g., with 150-200 g litters in 68 containers and >500 g litters in 1 container. The species number of the litter falls in a container was 18 in maximum, and was 12 in common (32 containers). Litter falls mass was positively proportional to the sum of the basal area at breast height of parent trees in the plot, and the amount of the litter falls in the containers was related with the locations of the containers, exhibiting an evident spatial heterogeneity in the plot. PMID- 21265135 TI - [Effects of selective cutting on intra- and interspecies competitions among major tree species in mixed broadleaved-Korean pine forest]. AB - Taking a Korean pine (Pinus koraiensis) forest stand 37 years after selective cutting as test object, this paper studied the effects of selective cutting on the intra- and interspecies competitions among the major tree species in the stand. Selective cutting had significant effects on the population structure, distribution pattern, and competition index of the major species. There was a significant negative correlation between the changes of competition index and tolerance index of the tree species (r = -0.8821). The intra-species competition index had significant linear relationships with the aggregation index and the number of individuals. Heliophilous species Betula costata and Tilia amurensis had the largest aggregation index, and their intra-species competitions were stronger than interspecies competitions, being favorable to the coexistence of different species. Selective cutting weakened the competition of P. koraiensis with its companion tree species, while strengthened the competition of heliophilous species with other tree species. After 37 years of selective cutting, P. koraiensis varied little in its competition stress, being helpful to its regular growth. Because of self-thinning, the dominance of B. costata and T. amurensis had somewhat decrease. The competition stress suffered by Abies nephrolepis was weakened, being beneficial to its regeneration. PMID- 21265136 TI - [Soil nitrogen mineralization and primary productivity in Rhododendron aureum community of snowpacks in alpine tundra of Changbai Mountain]. AB - Based on continuous observation of soil temperature and in situ incubation, this paper studied the effects of snow packs on soil temperature, soil nitrogen (N) mineralization, and primary productivity of Rhododendron aureum community alpine tundra in Changbai Mountain. During the snow-covered period of non-growth season (from last October to early May), test soil had an increasing N content, and accumulated sufficient mineralized N for plant growth in the coming year. The soil under snow packs in snow-covered period had a mean temperature -3.0 degrees C, and its N mineralization was more vigorous, with available N increased by 3.88 g x m(-2); while the soil with no snowpack had a mean temperature -7.5 degrees C, and the available N only increased by 1.21 g x m(-2). During growth season (from mid May to late August), soil N content decreased. In autumn when plants stopped growing, soil available N content tended to increase. In winter, the soil temperature under snowpacks kept at around 0 degrees C or a little lower, which promoted soil N mineralization, while that with no snowpack was in a frozen status. The difference in soil N mineralization was the key factor resulting in the higher primary productivity of snowpack Rh. aureum community and the driving force for the spatial variation of vegetation. PMID- 21265137 TI - [Coupling effects of water and fertilizer on the biomass of Populus tomentosa seedlings]. AB - Water and fertilizer are the two main factors promoting the fast growth and high yielding of Populus tomentosa, and thus, to study their coupling effects on the biomass of P. tomentosa seedlings has important practical significance. Taking the P. tomentosa clone 87 seedlings as test materials, a pot experiment with rotary combination design of square regression of three factors with five levels was conducted in the nursery of Beijing Forestry University from March to October 2008 to study the coupling effects of water, fertilizer N, and fertilizer P on the biomass of the seedlings, and a related regressive mathematical model was established. The results showed that water was the main factor affecting the biomass of P. tomentosa seedlings, followed by fertilizer N, and fertilizer P. With the increasing input of the three factors, the biomass of the seedlings increased, but when the input was beyond a certain level, the biomass began to decrease. There was a significant positive interactive effect between water and fertilizer N, but a less interactive effect between fertilizer N and fertilizer P and between water and fertilizer P. In our case, the optimal combination of water and fertilizer was 73.37% of field capacity + 4.14 g x plant(-1) of N fertilization + 1.41 g x plant(-1) of P fertilization, under which, the biomass of P. tomentosa seedlings achieved 68.30 g x plant(-1). PMID- 21265138 TI - [Leaf morphological structure and physiological and biochemical characteristics of female and male Hippophae rhamnoides subsp. sinensis under different soil moisture condition]. AB - A field experiment was conducted to study the leaf morphological structure and physiological and biochemical characteristics of female and male Hippophae rhamnoides subsp. sinensis under different soil moisture condition. When the soil moisture condition was poorer, the leaf structure of the plants displayed distinct xeromorphic characteristics, being more obvious for the female plants. Comparing with those of male plants, the leaf thickness, thickness of upper and lower epidermis, and the distance between lateral vein bundles of female plants were smaller, while the thickness and density of lower epidermis hairs and the ratio of palisade tissue thickness to sponge tissue thickness were in adverse, indicating that female plants had stronger drought adaptability and greater ecological plasticity. With the decrease of soil moisture content, the leaf dissociative proline, dissoluble sugar, and malonaldehyde (MDA) contents of both male and female plants all increased, but for female plants, the increment of their leaf dissociative proline and dissoluble sugar contents was larger, while that of MDA content was smaller than the male plants. With the changes of soil moisture content, the leaf superoxide dismutase and catalase activities of the plants varied greatly, but had no regular pattern. Under the stress of soil drought, the values of multivariate membership function of test parameters were larger for the female than the male plants, suggesting that the female plants of H. rhamnoides subsp. sinensis had stronger physiological regulation capability and greater adaptability to drought stress. PMID- 21265139 TI - [Litter decomposition and nutrient dynamics at different succession stages of typical mixed broadleaved-Korean pine forest in Xiaoxing' an Mountains, China]. AB - Taking the mixed leaf litters in broadleaved-Korean pine forests at different succession stages (secondary birch forest, selective cutting forest, and original mixed forest) and the leaf litters of the dominant tree species (Betula costata, Tilia amurensis, and Pinus koraiensis) in these forests in Xiaoxing' an Mountains, China as test objects, this paper studied their remaining rates and nutrient dynamics in October 2006-November 2008 by using decomposition bag method. For all test leaf litters, their remaining rate had an exponential relationship with time. The annual decomposition constant (k) ranged from 0.137 to 0.328, and the time for decomposing 50% (t50%) and 95% (t95%) was 2.340-4.989 years and 9.360-21.796 years, respectively. No significant differences were observed in the decomposition rates of the leaf litters among the forests, but the k value of the mixed leaf litters was decreased in the order of original mixed forest > selective cutting forest > secondary birch forest, while that of the dominant tree species leaf litters had no obvious pattern. During decomposition, the elements C, P, and K in leaf litters released continuously, and the release pattern of C followed linear function, while that of P and K followed a function of higher degree. Element N presented different levels of accumulation, but had no clear pattern. PMID- 21265140 TI - [Effects of elevated temperature and CO2 on desert algal crust photosynthesis]. AB - Taking the 26- and 51-year-old artificial vegetation areas and the natural vegetation area in Shapotou region of southeast Tengger Desert as study sites, this paper measured the net photosynthetic rate (Pn) of algal crusts, and analyzed its relationships with crust water content (> 100%, 40%-60%, and <20%), atmospheric CO2 concentration (360 and 700 mg x L(-1)), and air temperature (13 degrees C, 24 degrees C, and 28 degrees C). The Pn of the crusts in the 26- and 51-year-old artificial vegetation areas and natural vegetation area was 3.4, 4.4, and 3.2 micromol x m(-2) x s(-1), respectively, and the Pn in 51-year-old artificial vegetation area was significantly higher than that in the other two areas. Crust water content had significant effects on the Pn, which was significantly higher at medium water content (40%-60%) than at low (<20%) and high (>100%) water content. When the CO2 concentration doubled (700 mg x L(-1)), the Pn increased by 1.8-3.3 times at medium and high crust water content but had less change at low crust water content, compared with that under ambient CO2 concentration (360 mg x L(-1)). At medium and high crust water content, the Pn at 24 degrees C and 28 degrees C was 27%-66% higher than that at 13 degrees C (P < 0.05), but at low crust water content, no significant difference was observed at the three temperatures. PMID- 21265141 TI - [Responses of Atriplex triangularis root permeability and reflection coefficient to salt stress]. AB - Taking hydroponically cultured arrow-leaf saltbush (Atriplex triangularis) seedlings as test materials, and using electrical conductivity detector, atomic spectroscopy, and pressure bomb, this paper studied the effects of salt stress on the seedlings root membrane permeability, ion uptake, and reflection coefficient, and analyzed the salt-resistance characteristics and related mechanisms of A. triangularis. The results showed that with increasing salt stress, the root membrane permeability increased, but the reflection coefficient decreased. Salt stress decreased the total K+ uptake and increased the total Na+ uptake, but the relative amount of absorbed K+ increased while that of absorbed Na+ decreased. Under salt stress, A. triangularis roots had a higher regulation capability in their ion uptake, and the reduction of root reflection coefficient was favourable to the water absorption by the roots with moderate negative pressure, and accordingly, reduced the danger of xylem cavitation. All these features could be closely related to the higher salt-resistance of A. triangularis. PMID- 21265142 TI - [Leaf nutrient contents and photosynthetic physiological characteristics of Ulmus pumila-Robinia pseudocacia mixed forests]. AB - A field experiment was conducted to study the leaf N, P, and chlorophyll contents, photosynthetic gas exchange parameters, and chlorophyll fluorescence parameters in pure Ulmus pumila forest, pure Robinia pseudoacacia forest, and U. pumila-R. pseudoacacia mixed forests [1:1 (1B1C), 1:2 (1B2C), and 2:1 (2B1C)] in different growth periods. From May to September, the plant leaf N and P contents in pure and mixed forests all presented a decreasing trend. By the end of growth period, the leaf N content of U. pumila and the P content of R. pseudoacacia in 1B2C were obviously higher than those in pure forests. In the mixed forests, the chlorophyll content of U. pumila was obviously higher than that of R. pseudoacacia, and the chlorophyll content of U. pumila in 1B2C reached the highest in July. The photosynthetic rate (Pn) of U. pumila and R. pseudoacacia in mixed forests was higher than that in pure forests, and the Pn of R. pseudoacacia in 1B2C reached the highest (18.54 micromol x m(-2) x s(-1)) in July. The transpiration rate (Tr) and stomatal conductance (Gs) of R. pseudoacacia in mixed forests were higher than those in pure forests, and the Tr and Gs in mixed forests were in the order of 1B2C>1B1C>2B1C. In September, the quantum yield of PSII electron transport (phi(PS II)) of U. pumila in mixed forests was obviously higher than that in pure forest. The photochemical quenching coefficients (q(P)) of U. pumila and R. pseudoacacia in pure and mixed forests had no significant difference, but the non-photochemical quenching coefficient (NPQ) of the two tree species in 1B2C was significantly lower than that in corresponding pure forests. It was suggested that mixed planting U. pumila and R. pseudoacacia could significantly improve the leaf nutrient contents and photosynthetic capacity of the two tree species, and the optimum mixed ratio of U. pumila and R. pseudoacacia was 1:2. PMID- 21265143 TI - [Litter fall production and carbon return in Cunninghamia lanceolata, Schima superba, and their mixed plantations]. AB - From March 2005 to April 2007, an investigation was made on the litter fall production and carbon return of Cunninghamia lanceolata, Schima superba, and their mixed plantations in the Jian' ou Science and Education Park of Soil and Water Conservation, Fujian. In these three plantations, the mean annual litter fall production was from 2470.85 kg x hm(-2) x a(-1) to 4285.99 kg x hm(-2) x a( 1), and dominated by leaf litter, accounting for 68.62%-87.26% of the total production. In C. lanceolata plantation, the litter fall production peaked in April-May, July, and December; while in S. superba and mixed plantations, this production only peaked in March. Comparing with pure plantations, mixed plantation had a higher litter fall production per tree of broadleaved S. superba while a lower litter fall production per tree of coniferous C. lanceolata. Leaf litter in the three plantations was the main body of the litter falls carbon return, and the total amount of the carbon return was the largest (2.12 t C x hm( 2) x a(-1)) in mixed plantation and the smallest (1.19 t C x hm(-2) x a(-1)) in C. lanceolata plantation, which was in accordance with the annual litter fall production of the plantations. This study demonstrated that comparing with pure coniferous or broadleaved plantation, coniferous-broadleaved mixed plantation had higher annual litter fall production and carbon return, and thus, higher potential of C sequestration. PMID- 21265144 TI - [Carbon losses from forest fire in Jiangxi Province, China in 1950-2008]. AB - The annual occurrence of forest fire in Jiangxi Province of China in 1950-2008 was averaged 762 times and covering 1.578 x 10(4) hm2. Based on the forest fire statistic data, meteorological data, forest inventory data, and other parameters, this paper analyzed the characters of forest fire in the province, and estimated its carbon release and transfer. In the province, the total forest biomass loss from forest fire in 1950-2008 was about 61. 155 Tg, and the biomass carbon loss was about 30.993 Tg C, accounting for 15.92% of the vegetation carbon pool in the whole province. Before the 1970s, the biomass carbon loss occupied 74.3% of the total loss in 1950-2008, but after the 1990s, this loss decreased rapidly, with an annual average carbon loss less than 0.097 Tg C. The released CO2, CH4, and CO from the forest fire were about 5.408 Tg, 0.047 Tg, and 0.486 Tg, respectively, and led to 22.436 Tg of biomass carbon transferred into soil carbon. The snow and ice disaster in the beginning of 2008 resulted in high frequency forest fire, and led to a 0.463 Tg biomass carbon loss, which was 2. 56 times of the average value (0.181 Tg) in 2003-2007. PMID- 21265145 TI - [Spatiotemporal heterogeneity and its formation causes of soil physical properties in karst peak-cluster depression area of northwest Guangxi, China]. AB - Soil samples were collected from the grassland, shrub land, secondary forest, and original forest on the hill slope in a typical karst peak-cluster depression area of northwest Guanxi, with the spatiotemporal heterogeneity of soil physical properties investigated by classical statistics, and the formation causes of the heterogeneity analyzed by redundancy analysis (RDA). In 0-15 cm soil layer, the clay (< 0.002 mm) and silt (0.002-0.05 mm) contents of shrub land and original forest had significant differences with those of grassland and secondary forest, respectively, but the clay, silt, and sand (0.05-2.0 mm) contents had no significant differences between grassland and secondary forest. No significant difference was observed in the soil sand content among the four land types, but the soil bulk density of grassland was significantly different from that of other three land types. The soil clay content of grassland increased with increasing elevation, while that of the other three land types was the highest on medium slope, and had no significant differences for the same land types among different slope locations. The soil clay content in different layers of 0-30 cm had a greater variation extent in original forest (14.55%) than in grassland (7.12%), shrub land (11.24%), and secondary forest (13.77%), and the soil particle size composition was greatly affected by the disturbance of human activities. Soil organic carbon (SOC) and vegetation type were the dominant factors affecting the soil physical properties, and the bare rock ratio had greater effects on soil sand content. PMID- 21265146 TI - [Microbial community and its activities in canopy- and understory humus of two montane forest types in Ailao Mountains, Northwest China]. AB - Mid-montane moist evergreen broadleaved forest (MMF) and top-montane dwarf mossy forest (DMF) are the two major natural forest types in subtropical mountainous area of Ailao Mountains, Northwest China. In this paper, a comparative study was made on the microbial composition, quantity, biochemical activity, metabolic activity, and their seasonal dynamics in the canopy- and understory humus of the two forest types. The composition, quantity, and metabolic activity of the microbes in the canopy humus of dominant tree species in MMF and DMF were also analyzed. In the canopy humus of the two forest types, the amounts of fungi and actinomycetes, microbial biomass C and N, and intensities of nitrogen fixation and cellulose decomposition were significantly higher than those in understory humus. Meanwhile, the amount of cellulose-decomposing microbes (ACDM), cellulose decomposition intensity, microbial biomass C and N, and metabolic activity in the canopy humus of MMF were significantly higher than those of DMF. The amounts of bacteria, fungi, and aerobic nitrogen-fixing bacteria (ANFB) and the metabolic activity in the canopy humus of MMF and DMF were significantly higher in wet season than in dry season, while a contradictory trend was observed on the amount of actinomycetes. No significant difference was observed on the amount of ACDM between wet season and dry season. For the two forest types, the amounts of microbes and their biochemical activities in canopy humus had a larger seasonal variation range than those in understory humus. There was a significant difference in the amounts of the microbes in canopy humus among the dominant tree species in MMF and DMF, especially in wet season. The microbes in canopy humus played important roles in maintaining the biodiversity of epiphytes in the canopy, and in supplying the needed nutrients for the vigorous growth of the epiphytes. PMID- 21265147 TI - [Effects of microbial agents on litter decomposition in urban protective greenbelts of arid zone]. AB - In order to explore the ways for promoting litter decomposition in urban protective greenbelts of arid zone, litter falls were collected from the protective greenbelts in north suburb of Karamay, Xinjiang, and a composting experiment with the inoculation of three kinds of microbial agents, i.e., Qingzhu, Jiegan, and Sufu, was carried out for 198 days in late October 2007. At the early stage (0-30 d) of composing, inoculating microbial agents promoted the decomposition of the litter falls, and the effect of Sufu agent was significant, compared with CK. The N, P, and Ca concentrations in the composing litter falls increased persistently with time. By the end of the experiment, the nutrient concentrations in the composed litter falls were 14.2%-252.9% higher than their initial values. During the whole composing process, the decomposition rate of the litter falls organic C increased continuously, and the C/N ratio decreased gradually. It was suggested that inoculating microbial agents could accelerate the composting process, and increase the nutrient concentrations in composted litter falls. Among the three test microbial agents, Jiegan agent was the best one. PMID- 21265148 TI - [Soil soluble organic matter, microbial biomass, and enzyme activities in forest plantations in degraded red soil region of Jiangxi Province, China]. AB - Taking the adjacent 18-year-old pure Pinus massoniana pure forest (I), P. massoniana, Liquidamber fomosana, and Schima superba mixed forest (II), S. superba pure forest (III), L. fomosana (IV) pure forest, and natural restoration fallow land (CK) in Taihe County of Jiangxi Province as test sites, a comparative study was made on their soil soluble organic carbon (SOC) and nitrogen (SON), soil microbial biomass C (MBC) and N (MBN), and soil urease and asparaginase activities. In 0-10 cm soil layer, the pool sizes of SOC, SON, MBC, and MBN at test sites ranged in 354-1007 mg x kg(-1), 24-73 mg x kg(-1), 203-488 mg x kg( 1), and 24-65 mg x kg(-1), and the soil urease and asparaginase activities were 95-133 mg x kg(-1) x d(-1) and 58-113 mg x kg(-1) x d(-1), respectively. There were significant differences in the pool sizes of SOC, SON, MBC, and MBN and the asparaginase activity among the test sites, but no significant difference was observed in the urease activity. The pool sizes of SOC and SON were in the order of IV > CK > III > I > II, those of MBC and MBN were in the order of CK > IV > III > I > II, and asparaginase activity followed the order of IV > CK > III > II > I. With the increase of soil depth, the pool sizes of SOC, SON, MBC, and MBN and the activities of soil asparaginase and urease decreased. In 0-20 cm soil layer, the SOC, SON, MBC, MBN, total C, and total N were highly correlated with each other, soil asparaginase activity was highly correlated with SOC, SON, TSN, total C, total N, MBC, and MBN, and soil urease activity was highly correlated with SON, TSN, total C, MBC and MBN. PMID- 21265149 TI - [Characteristics of soil organic carbon and total nitrogen under different land use types in Shanghai]. AB - By the methods of field sampling and laboratory analysis, this paper studied the variations of soil organic carbon (SOC) and total nitrogen (TN) contents and SOC density under different land use types in Shanghai. Significant differences were observed in the test parameters among different land use types. The SOC density was the highest in paddy field (3.86 kg x m(-2)), followed by in upland (3.17 kg x m(-2)), forestland (3.15 kg x m(-2)), abandoned land (2.73 kg x m(-2)), urban lawn (2.65 kg x m(-2)), garden land (2.13 kg x m(-2)), and tidal flat (1.38 kg x m(-2)). The assessment on the effects of three types of land use change on the test parameters showed that the conversion of paddy field into upland resulted in a significant decrease of SOC and TN contents and SOC density; the abandonment of farmland was not an effective way in improving SOC storage in the Yangtze Delta region with abundant water and heat resources, high soil fertility, and high level of field management; while the 4-5 years conversion of paddy field into artificial forestland decreased the SOC and TN contents and SOC density, suggesting that in a short term, the soil carbon sequestration effect of the conversion from paddy field to forestland was at a low level, due to the limitation of vegetation productivity. PMID- 21265150 TI - [Passive nighttime warming (PNW) system, its design and warming effect]. AB - Based on the technique of passive nighttime warming (PNW), a convenient and energy-saving PNW facility was designed for a rice-wheat cropping system in Danyang, Jiangsu Province. The facility could guarantee 15.75 m2 effective sampling area, with a homogeneous amplitude of increased temperature, and making the nighttime canopy temperature during whole rice growth season increased averagely by 1.1 degrees C and the nighttime canopy temperature and 5 cm soil temperature during whole winter wheat growth period increased averagely by 1.3 degrees C and 0.8 degrees C, respectively. During the operation period of the facility, the variation trends of the canopy temperature and 5 cm soil temperature during the whole growth periods of rice and winter wheat in the warming plots were similar to those of the control. Though the facility slightly decreased the soil moisture content during winter wheat growth period, wheat growth was less impacted. The application of this facility in our main production areas of rice and winter wheat showed that the facility could advance the initial blossoming stages of rice and winter wheat averagely by 3 d and 5 d, respectively. In despite of the discrepancy in the warming effect among different regions and seasons, this energy-saving facility was reliable for the field research on crop responses to climate warming, when the homogeneity of increased temperature, the effective area, and the effects on crop growth period were taken into comprehensive consideration. PMID- 21265151 TI - [Application of biotope mapping model integrated with vegetation cover continuity attributes in urban biodiversity conservation]. AB - Based on the biotope classification system with vegetation structure as the framework, a modified biotope mapping model integrated with vegetation cover continuity attributes was developed, and applied to the study of the greenbelts in Helsingborg in southern Sweden. An evaluation of the vegetation cover continuity in the greenbelts was carried out by the comparisons of the vascular plant species richness in long- and short-continuity forests, based on the identification of woodland continuity by using ancient woodland indicator species (AWIS). In the test greenbelts, long-continuity woodlands had more AWIS. Among the forests where the dominant trees were more than 30-year-old, the long continuity ones had a higher biodiversity of vascular plants, compared with the short-continuity ones with the similar vegetation structure. The modified biotope mapping model integrated with the continuity features of vegetation cover could be an important tool in investigating urban biodiversity, and provide corresponding strategies for future urban biodiversity conservation. PMID- 21265152 TI - [Effects of applying controlled-release compound fertilizer on Platycodon grandiflorum growth]. AB - A pot experiment was conducted in 2008 to study the effects of applying controlled-release compound fertilizer (N:P2O5:K2O = 14:14:14) on the growth of Platycodon grandiflorum in the medicinal herbal farm of Shandong Agricultural University. Comparing with the application of common compound fertilizer (N:P2O5: K2O=15: 15: 15), applying equivalent amount of the controlled-release fertilizer increased the leaf chlorophyll content, root volume, root activity, and root diameter of P. grandiflorum at the late growth stage, but decreased the root length. When the N application rate was 0.24 and 0.32 g x kg(-1) soil, applying the controlled-release compound fertilizer increased the root yield by 26.78% and 22.50%, and the root soluble sugar, protein, and total saponin contents by 9.77% and 6.99%, 11.38% and 2.20%, and 8.85% and 5.47%, respectively, compared with applying the common compound fertilizer. More nitrogen application made the root soluble sugar content decreased but the total saponin content increased. Under our experimental condition, applying the controlled-release compound fertilizer with an application rate of 0.24 g N x kg(-1) soil could obtain the best effect for P. grandiflorum. PMID- 21265153 TI - [Effects of controlled-release N and K fertilizers on N, P, and K use efficiency of mauls (Manlus robusta)]. AB - A pot experiment was conducted to study the effects of controlled-release N and K fertilizers on mauls seedlings growth, their P and K use efficiency, and the N balance in soil-plant system. The results showed that the nutrient release from controlled-release fertilizers accorded well with the nutrient requirement of mauls seedlings. Controlled-release N fertilizer significantly increased the K use efficiency, and controlled-release K fertilizer significantly increased the N use efficiency. Under the same K application rate, the plant height and stem diameter under the application of controlled-release N fertilizer (CN) and controlled-release N and K fertilizers (NK) had no significant difference, while those under the application of common fertilizer (SF) were all higher. The plant dry mass and the P and K use efficiency were in the order of NK>CN>SF. Under the application of NK, the application rate of K had no significant effects on the plant height and stem diameter, but significantly affected the plant dry mass. The P use efficiency increased with increasing application rate of controlled release K fertilizer, but was less affected by application rate common K fertilizer. The K use efficiency decreased with increasing application rate of K. The N use efficiency was in the order of NK>CN>SF, while the N loss rate was in adverse. The residual rate of NK and CN had no significant difference, but was higher than that of SF. The application rate of controlled-release K fertilizer had significant effects on the N use efficiency and N loss rate, but no significant effects on N residual rate. PMID- 21265154 TI - [Effects of grafting on cucumber rhizospheric soil microbial characteristics and enzyme activities under copper stress]. AB - A pot experiment with cucumber (taking Cucurbita ficifoblia B. as the rootstock) was conducted to study the effects of grafting on the microbial population, microbial biomass, and enzyme activities in rhizospheric soil under copper stress. Under the stress of copper, the microbial biomass C and N in grafted and self-rooted cucumber rhizospheric soils all decreased significantly, while the basal respiration and metabolic quotient were in adverse. In grafted cucumber rhizospheric soil, the microbial biomass C and N were significantly higher than those in self-rooted cucumber rhiaospheric soil, whereas the basal respiration and metabolic quotient were significantly lower. Under copper stress, the quantities of actinomyces and nitrogen-fixing bacteria in rhizospheric soils decreased and that of fungi increased significantly, whereas the quantity of bacteria had less change. In grafted cucumber rhizospheric soil, the quantities of bacteria, actinomyces, and nitrogen-fixing bacteria were significantly higher than those in self-rooted cucumber rhizospheric soil, but the quantity of fungi was in opposite. The urease, phosphatase, sucrase, and catalase activities were significantly higher in grafted than in self-rooted cucumber rhizospheric soil. All the results suggested that grafting could mitigate the impact of copper stress on the microbial micro-environment and enzyme activities in cucumber rhizospheric soil, and as a result, improve the adaptability of cucumber to copper stress. PMID- 21265155 TI - [Soil microbial biomass and respiration rate under effects of different planting patterns of peanut]. AB - A field experiment with randomized design was conducted to study the effects of six planting patterns of peanut, i.e., spring sowing and plastic film mulching, spring sowing and open cultivation, summer sowing and plastic film mulching, summer sowing and open cultivation, intercropped in wheat field, and control of intercropped in wheat field, on soil microbial biomass C, soil active microbial biomass, and soil respiration rate. The results showed that the growth stage and planting pattern of peanut had significant effects on soil microbial biomass and respiration rate. With the prolonged time after anthesis, soil microbial biomass C, active microbial biomass, and respiration rate increased gradually, peaked at pod-setting stage, and decreased then. Open cultivation enhanced soil microbial biomass C and respiration rate but reduced soil active microbial biomass, being unfavorable to soil nutrient transformation and nutrient availability, while plastic film mulching increased soil active microbial biomass, and consequently, promoted soil nutrient transformation and nutrient availability. Comparing with intercropped in wheat field and open cultivation, intercropped in wheat field and plastic film mulching increased soil microbial biomass C, active microbial biomass, and respiration rate, which immobilized more soil nutrients and was not conducive to peanut growth. PMID- 21265156 TI - [Effects of bagging on light use efficiency of tomato fruit photosystem II]. AB - In a greenhouse experiment, white laminating bags were applied to bag the tomato cultivar 'Baoluota' fruits, with the absorption spectra and chlorophyll fluorescence parameters of the fruits measured by optical spectrometer and Mini Imaging-Pam after different bagging time, aimed to investigate the effects of bagging on the light use efficiency of photosystem II of the fruits. In the first 20 days of bagging, no significant effects of bagging were observed on the chlorophyll a (Chl a) content and the maximum quantum yield of PS II (Fv/Fm) of the fruits, but the relative absorption coefficient (A(670/780)) and the effective quantum yield of PS II (Y(II)) were reduced, compared with the control. In this period, the regulatory energy dissipation of PS II played, an important role. After then, the Chl a and Chl b contents of bagged fruits decreased markedly, but the Fv/Fm, Y(II), and A(670/780) had no significant differences with the control. On the 40th day of bagging, the Chl a and Chl b contents of bagged fruits decreased by 35.2% and 52.8%, but the Fv/Fm and Y(II) increased by 24.5% and 35.4%, respectively, suggesting that at this time, the PS II of bagged tomato fruits had a higher light use efficiency, which provided energy foundation for the earlier ripening of the bagged fruits via further reducing the quantum yield of non-regulatory energy dissipation (Y(NO)). PMID- 21265158 TI - [Effects of nitrogen fertilization on wheat leaf photosynthesis under elevated atmospheric CO2 concentration]. AB - In this paper, the effects of nitrogen (N) fertilization on the wheat leaf photosynthesis under long-term elevated atmospheric CO2 concentration (760 micromol x mol(-1)) was studied, based on the measurements of photosynthetic gas exchange parameters and light intensity-photosynthetic rate response curves at jointing stage. Under the long-term elevated atmospheric CO2 concentration, applying sufficient N could increase the wheat leaf photosynthetic rate (Pn), transpiration rate (Tr), and instantaneous water use efficiency (WUEi). Comparing with those under ambient atmospheric CO2 concentration, the Po and WUEi under the elevated atmospheric CO2 concentration increased, while the stomatal conductance (Gs) and intercellular CO2 concentration (Ci) decreased. With the increase of light flux intensity, the Pn and WUEi under the elevated atmospheric CO2 concentration were higher those under ambient atmospheric CO2 concentration, Gs was in adverse, while Ci and Tr had less change. At high fertilization rate of N, the Gs was linearly positively correlated with Pn, Tr, and WUEi, and the Gs and Ci had no correlation with each other under the elevated atmospheric CO2 concentration but negatively correlated under ambient atmospheric CO2 concentration. At low fertilization rate of N, the Gs had no correlations with Pn and WUEi but linearly positively correlated with Ci and Tr. It was suggested that under the elevated atmospheric CO2 concentration, the wheat leaf Pn at low N fertilization rate was limited by non-stomatal factor. PMID- 21265157 TI - [Effects of applying different nitrogen form on cherry tomato nitrogen metabolism during fruit development]. AB - A hydroponic experiment was conducted to study the effects of applying 100% NO3- N, 100% NH4+ -N, and 75% NO3- -N+25% NH4+ -N on the nitrogen metabolism and the nitrate reductase (NR) and glutamine synthetase (GS) gene expression of cherry tomato during its fruit development. Applying 75% NO3- -N+25% NH4+ -N slightly increased the single fruit mass, and increased the fruit NH4+ -N, total amino acid, and total N contents and N accumulation significantly, compared with applying 100% NO3- -N. In treatments 100% NO3- -N and 75% NO3- -N + 25% NH4+ -N, the fruit NR activity and its gene expression had no significant difference, but were higher than those in treatment 100% NH4+ -N. The fruit GS activity was significantly higher in treatment 75% NO3--N+25% NH4+ -N than in treatment 100% NO3- -N. In the three treatments, isozyme GS1 (Cytosolic type GS) and GS2 (Chloroplast type GS) expression was inconsistent with GS activity, suggesting that the effects of applied N on GS activity could be mainly reflected at posttranscriptional level. PMID- 21265159 TI - [Effects of high concentration ozone on soybean growth and grain yield]. AB - By using open top chambers (OTCs), soybean plants were grown in pots, and exposed to charcoal-filtered air ([O3] < 10 microg x kg(-1)) and elevated O3 (80 microg x kg(-1)) after anthesis, aimed to investigate the responses of soybean' s agronomic characters, leaf area, chlorophyll content, antioxidant system, and grain yield to elevated O3. Under elevated O3, the leaf area and chlorophyll content decreased significantly (P < 0.05), and the leaf catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD) activities had a significant increase (P < 0.01) first but a gradual decrease then, compared with those under charcoal-filtered air. Elevated O3 decreased the leaf soluble protein and ascorbate content (AsA) contents while increased the leaf malonaldehyde (MDA) content (P < 0.05), suggesting that the leaf membrane lipid peroxidation was accelerated. The dry mass per plant, effective pod number, grain number, 100 grains weight, and grain yield under elevated O3 had somewhat decreased, among which, grain yield decreased significantly, with the decrement reached to 47% (P < 0.01). PMID- 21265160 TI - [Effects of combined application of biogas residues and chemical fertilizers on greenhouse tomato's growth and its fruit yield and quality]. AB - With randomized block design, a field experiment was conducted in greenhouse to study the effects of combined application of biogas residues and chemical fertilizers on the tomato growth and its fruit yield and quality. The combined application of biogas residues and chemical fertilizers benefited the tomato growth and its fruit yield and quality. The yield of the combined application of 60% biogas residues and 40% chemical fertilizers were higher than the other treatments. The fruit quality under the application of 60% biogas residue and 40% chemical fertilizers also improved significantly, with the Vc content (91.09 mg x kg(-1)) and total sugar content being 21.32 mg x kg(-1) and 2.13% higher than the control, respectively. Among the test fertilization combinations, 60% biogas residue combined with 40% chemical fertilizers was the best one for greenhouse tomato's growth and its fruit yield and quality. PMID- 21265161 TI - [Responses of Nicotiana tabacum morphology and photosynthetic physiology to reduced ultraviolet-B radiation]. AB - By the method of canopy film-covering to reduce UV-B radiation, this paper studied the responses of the morphology and photosynthetic physiology of Nicotiana tabacum cultivar K326 at its physiological, technical, and physiological-technical transitional maturity stages in high-elevation tobacco growing area of Yunnan. Three treatments were installed, i.e., reducing 75.74% (T1), 70.08% (T2), and 30.39% (T3) of natural solar UV-B radiation. Reducing UV-B radiation increased the stem height and the internode distance of K326 significantly, with the larger values in T2. Comparing with those under natural UV-B radiation condition, the leaf net photosynthetic rate (Pn), assimilation capacity (AC), water use efficiency (WUE), intrinsic water use efficiency (WUEi), photosynthetic pigments (PP) and flavonoids (FL) contents, and specific leaf mass (SLM) in T1 and T2 all decreased, with larger decrement in T2. The factors affecting the Pn in T, and T2 were stomatal and non-stomatal, and the latter was the main one. The major reason of the lower WUE in T1 and T2 was due to the increase of transpiration rate (Tr) caused by low stomatal regulation capability. In T3, the Pn, AC, WUE, WUEi, and PP increased but the FL and PP decreased to the lowest levels at physiological and transitional maturity stages, and the PP degradation rate was faster at the technical maturity stage. PMID- 21265162 TI - [Community structure of soil fauna in Eucalyptus grandis plantations at different slope locations]. AB - To understand the effects of slope location on the community structure of soil fauna in Eucalyptus grandis plantation, an investigation was made on the soil fauna in 3 E. grandis plantations at different slope locations in the hilly area of Sichuan Province from January to October 2009. A total of 39,2762 individuals were observed, belonging to 146 groups, 7 phyla, 16 classes, and 31 orders. The community composition, trophic group, diversity, and seasonal dynamics of soil fauna in the plantations all varied with slope. The abundance of macro-fauna, xeric meso- and micro-fauna, saprophagous macro-fauna, and omnivorous xeric meso- and micro-fauna increased with the decrease of slope, indicating that soil fauna had sensitive responses to the soil environmental factors affected by slope. Significant differences in the diversity of soil saprophagous macro-fauna and hygrophilous meso- and micro-fauna were observed at different slope locations, suggesting that these two faunal groups could be used as the indicators of the habitat heterogeneity of E. grandis plantations at different slope. Overall, slope location had definite effects on the community structure and distribution of soil fauna in the E. grandis plantations, but the effects were not statistically significant. PMID- 21265163 TI - [Darkling beetle community structure and its relations with environmental factors in Sidunzi of Yanchi, Ningxia, China]. AB - From March to October 2009, a field survey was conducted on the darkling beetle community structure and related environmental factors in the desert grasslands with different vegetation cover and human disturbance intensity in Sidunzi of Yanchi, Ningxia, China. By using diversity index and canonical correspondence analysis (CCA) , the relationships between the beetle community structure and related environmental factors were analyzed. A total of 5431 individuals were collected, belonging to 20 species and 10 genera. Blaps femoralis femoralis, Microdera kraatzi kraatzi, and Platyope mongolica were the dominant species, accounting for 47.30%, 39.90%, and 3.59% of the total, respectively. CCA explained 100% of the correlations between the beetle species and related environmental factors, suggesting that the occurrence of the beetle species had close relations to the changes of related environmental factors. Among the environmental factors, the Shannon diversity index of plant community (HP), plant biomass (BP), and soil water content (SW) affected the beetle species occurrence most. The occurrence frequency of Mantichorula semenowi, Anatolica amoenula, A. sternalis, and A. gravidula was negatively correlated with BP and plant coverage (CP), and that of B. gobiensis, Cyphogenia chinensis, Gonocephalum reticuluatum, and Crypticus rufipes was positively correlated with plant density (DP) and SW. The distribution of P. mongolica, M. kraatzi kraatzi, Scytosoma pygmaeum, and B. kiritshenkoi showed a positive correlation to HP, and that of Eumylada oberbergeri, B. femoralis femoralis, and B. davidea showed a positive correlation to BP and CP. There was a significant positive correlation (r = 0.943, P = 0.005) between the beetle activity density and SW. The CCA ordination showed that the darkling beetles had different demands for multidimensional ecological resources in desert and semi-desert ecosystems. PMID- 21265164 TI - [Anti-erosion effect of hedgerows in hillside croplands of Danjiangkou based on the evaluation with water erosion prediction project (WEPP) model]. AB - Based on the data of field experiments on the hillside croplands of Danjiangkou, Hubei Province of China, the input files of crop characters, management measures, slope gradient and length, and soil properties for running WEPP model (Hillslope version) were established. Combining with the local weather data, a simulation study with the model was made on the runoff and soil loss of the croplands protected by four kinds of hedgerows (Amorpha fruticosa, Lonicera japonica, Hemerocallis fulva, and Poa sphondylodes) in Danjiangkou area. The resulted showed that WEPP model could accurately simulate the anti-erosion effect of hedgerows in hillside farmlands in the study area. Using this model not only reduced test number, but also saved time and effort, being able to provide scientific basis for the popularization and application of hedgerows. Among the four hedgerows, Amorpha fruticosa had the best anti-erosion effect. According to the simulation, the optimal planting density of A. fruticosa hedgerows in the farmlands was 1 m x 15 m at slope gradient 5 degrees, 1 m x 10 m at slope gradient 15 degrees, and 1 m x 3 m at slope gradient 25 degrees. PMID- 21265165 TI - [Impacts of uncertainty in data processing on estimation of CO2 flux components]. AB - Based on the eddy covariance observations at 4 sites (2 forested sites and 2 grassland sites) in Chinese Terrestrial Ecosystem Flux Research Network (ChinaFLUX), this paper analyzed the effects of three data processing methods, i.e., spike detection, threshold (u*c) determination of nocturnal friction velocity (u*), and gap-filling model selection, on the estimation of CO2 flux components. All the three methods had significant impacts on the estimation of annual net ecosystem exchange (NEE), and the determination of (u*c) was an important factor affecting the annual NEE estimation. The estimation deviation of the annual NEE caused by spike detection, determination of (u*c), and gap-filling model selection was 0.62-21.31 g C x m(-2) x a(-1) (0.84%-65.31%), 4.06-30.28 g C x m(-2) x a(-1) (3.76%-21.58%), and 0.69-27.73 g C x m(-2) x a(-1) (0.23% 55.62%), respectively. Comparing with that of forested ecosystem, the NEE estimation of grassland ecosystem was more sensitive to the parameter setting of data processing method, and the relative estimation deviation of annual gross ecosystem exchange and ecosystem respiration induced by the uncertainty in data processing was 3.88%-11.41% and 6.45%-24.91%, respectively. PMID- 21265166 TI - [Distribution characteristics of heavy metals in soil profile of facility vegetable fields]. AB - Taking the facility vegetable fields having been planted for 1-12 years and the adjacent wheat land in Shouguang City of Shandong Province as test objects, this paper studied the distribution characteristics of arsenic (As), cadmium (Cd), copper (Cu), zinc (Zn), chromium (Cr), and nickel (Ni) in their soil profiles (0 150 cm). With the increase of soil depth, the test heavy metals contents in the soil profiles all had a decreasing trend, and in the same soil layers, the contents were obviously higher in facility vegetable fields than in wheat land. Comparing with those in the same soil layers of wheat land, the average contents of As, Cd, Cu, Zn, Cr, and Ni in 0-20 and 120-150 cm soil layers of facility vegetable fields were 35.0%, 146.2%, 65.6%, 36.4%, and 21.5%, and 10.6%, 178.5%, 19.4%, 20.2%, 15.2%, and 9.3% higher, respectively, and the average contents of the heavy metals in 20-120 cm soil layer of facility vegetable fields were also higher in some degree. In the 0-20 cm soil layer of facility vegetable fields, the Cd, Cu, and Zn contents had significant positive correlations with planting years (P < 0.05), with the accumulation rates of Cd, Cu, and Zn being 0.027, 1.153, and 2.830 mg x kg(-1) x a(-1), respectively. In facility vegetable fields, the test six heavy metals contents were significantly positively correlated with the contents of soil organic carbon and total nitrogen, and the Cd, Cu, Zn, and Cr contents were significantly correlated with the content of soil total phosphorus (P < 0.01). Applying organic fertilizer could induce the heavy metals accumulation in the soils of facility vegetable fields to some extent. PMID- 21265167 TI - [Variations of fish species diversity, faunal assemblage, and abundances in Daya Bay in 1980-2007]. AB - Based on the 2004-2005 otter trawl survey data and the 1980-2007 relevant historical records, this paper analyzed the variations of fish species composition, faunal assemblage, diversity indices, dominant species, and abundance in Daya Bay. In the 2004-2005 trawl survey, a total of 107 fish species were recorded, belonging to 50 families and 13 orders, among which, meso-demersal fish were predominant, with 48 species recorded, and followed by pelagic and demersal fishes, with 37 and 21 species, respectively. The fishes in the Bay belonged to tropical and subtropical fauna, with the dominance of warm water fishes (97 species) and warm-temperate water fishes (10 species). The diversity index was the highest in summer (3.82), followed by in winter (3.37) and autumn (3.00), and the lowest in spring (2.40). The seasonal variation of Pielou evenness index mimicked that of diversity index. In 1980-2007, the characteristics of fish community in the Bay changed obviously. The species number reduced from 157 species in the 1980s to 110 species in the 1990s and to 107 species in 2004-2005, and the dominant species shifted from the high-value fishes such as hairtail and pomfret in the 1980s to low-value fishes such as sardine fish, anchovy, and juvenile porgy. A non-linear regression model composed of inter-annual trend and seasonal cycle was used to simulate the changes of fish stock density in 1980-1999 and 1990-2007, and the results indicated that in the two periods, the fish stock density in the Bay all showed a decreasing trend, but the decrement was larger in 1990-2007 than in 1980-1999. The seasonal variation of the stock density in 1980-1999 was relatively small, with an amplitude being 0.099, while that in 1990-2007 was relatively larger, with the amplitude being 0.420, illustrating that the fish abundance in the Bay had a larger seasonal fluctuation in 1990-2007. PMID- 21265168 TI - [Effects of salinity on haematological biochemistrical indices and liver tissue in juvenile Oncorhynchus keta]. AB - In order to simulate the catadromous migration environment of the juvenile salmon (Oncorhynchus keta), five experimental groups containing different salinities (0, 5, 10, 15 and 20) were set up. The juvenile salmons with average body mass of (26.57 +/- 6.32) g and average full length of (14.44 +/- 1.05) cm were cultured for 130 days, and then the haematological biochemistrical indices was analyzed and the structure of liver tissue was observed to investigate the changes in physiological indices during the catadromous migration of juvenile salmon. The results showed that serum osmolality and the concentration of Na+, Cl- illustrated the same tendency with water salinity variation. Specifically, the serum Na+, C- and Mg2+ levels in the salinities of 15, 20 were significantly different from those in the salinity 5 and the freshwater and serum K+ in different salinities were all obviously lower than that in the freshwater. Also, the blood glucose level in salinity 10 was significantly higher than that in salinity 5 and 20, whereas total serum protein (TP), albumin (ALB) and globulin (GLB) levels all declined with the increase of salinity and the serum TP and GLB content in the freshwater group was remarkably higher than those in the salinity 15 and 20. There also existed an obvious discrepancy on total bile acids in freshwater group and the other salinity groups. The alanine aminotransferase (ALT) activity and aspartate aminotransferase (AST) activity in fresh water group were far different from those of the high salinity groups. Furthermore, in the low salinities (0 and 5), the liver cells of juvenile chum salmon partly broke down, and liver tissue was serious vacuolization. Collectively, the growth and survival rate had no significant difference in all groups and according to the physiological and biochemical indices, the appropriated salinity for juvenile chum salmon ranged from 10 to 20 during the catadromous migration. PMID- 21265169 TI - [Heavy metals cycling and its regulation in China cropland ecosystems]. AB - This paper analyzed the current situation of heavy metal contamination in cropland soils in China, and discussed the input, output, and balance of heavy metals in cropland ecosystems. It was considered that heavy metals had definite accumulation in cropland ecosystems, but overall speaking, this accumulation had relatively small environmental risk, and only some plants, especially vegetables, accumulated heavy metals over the standards. In mining areas, adjacent areas of smelting plants, and the farming areas using larger amounts of related wastes, the heavy metals content in plants and soils was at least ten times higher than that in normal croplands, existing larger environmental risk. Aiming at the current situation of heavy metal contamination of farmland soils in China, some effective regulation measures for the heavy metal cycling in the cropland ecosystems were proposed, and the further research prospects in related fields were discussed. PMID- 21265170 TI - [Methods for determining plant water source in thin soil region: a review]. AB - Plant water source depends on the distribution of available water in the environment, and the capability of plants in capturing water. In dry season, the soil water in thin soil region cannot satisfy the demand of normal plant growth, and whether the plants can use the water stored in weathered bedrock is the key for them to maintain their normal water consumption. This paper reviewed the research methods for determining the plant water source in thin soil region, including investigating and analyzing the characteristics of root growth and distribution, monitoring the changes of water content at various depths below ground surface, monitoring and analyzing the seasonal variation of plant water status, and identifying the plant water source by stable isotope techniques. The advantages and disadvantages of these methods and their potential applications in tracing plant water source in karst region of Southwest China were discussed. PMID- 21265171 TI - [Research advances in the effects of host plant volatiles on Cydia pomonella behaviors and the application of the volatiles in pest control]. AB - Codling moth (Cydia pomonella) is a worldwide pest of stone fruit trees, and an important quarantine target in China. Its occurrence, damage, and potential expansion in this country should be seriously concerned. Host plant volatiles, the species-specific attractants of C. pomonella, have attracted extensive attention. This paper reviewed the researches on the interactions between host plant source volatiles and C. pomonella, with the focus on the effects of the volatiles on the behaviors of C. pomonella, e.g., host orientation, courting and mating, and spawning, etc., the changes of the volatile components released by the host plants after fed by C. pomonella larvae, and the impacts of the volatiles on the sex pheromone of C. pomonella. The research progress and field application of plant source pear ester were also introduced, aimed to provide a reference for the prevention and control of C. pomonella in China. PMID- 21265172 TI - [Interrelationships between soil fauna and soil environmental factors in China: research advance]. AB - Soil fauna has close relations with various environmental factors in soil ecosystem. To explore the interrelationships between soil fauna and soil environmental factors is of vital importance to deep understand the dynamics of soil ecosystem and to assess the functioning of the ecosystem. The environmental factors affecting soil fauna can be classified as soil properties and soil external environment. The former contains soil basic physical and chemical properties, soil moisture, and soil pollution. The latter includes vegetation, land use type, landform, and climate, etc. From these aspects, this paper summarized the published literatures in China on the interrelationships between soil fauna and soil environmental factors. It was considered that several problems were existed in related studies, e.g., fewer researches were made in integrating soil fauna's bio-indicator function, research methods were needed to be improved, and the studies on the multi-environmental factors and their large scale spatial-temporal variability were in deficiency. Corresponding suggestions were proposed, i.e., more work should be done according to the practical needs, advanced experiences from abroad should be referenced, and comprehensive studies on multi-environmental factors and long-term monitoring should be conducted on large scale areas. PMID- 21265173 TI - [Determination of the age of subdural hematomas from the concentration of hemoglobin]. AB - The photocolorimetric method was employed to measure hemoglobin levels in 46 traumatic subdural hematomas of different age. The data thus obtained were used to construct a logarithmic regression model for the determination of the age of subdural hematomas from the concentration of hemoglobin. The model allows to determine injury time points and intervals at any desired level of confidence probability. The fraction of dispersion of hematoma age values attributable to regression was estimated at 41% which accounts for 74.7% of the maximally possible magnitude. Results of the study can be used in practical work of a forensic-medical experts. PMID- 21265175 TI - [The influence of certain meteorological factors on mortality from complications of arterial hypertension]. AB - The weather may influence the clinical course of many diseases. The objective of the present study was to evaluate effects of certain meteorological factors on the mortality rate associated with complications of arterial hypertension (cerebral stroke and myocardial infarction) in the city of Astrakhan during the period from 1983 to 2005. The analysis included 17,198 cases of death from cardiovascular disorders (CVD). An original software program was used for the purpose that made it possible to estimate the influence of meteorological factors (air temperature, velocity of wind and precipitation) on the mortality rate among subjects with and without AH. It was shown that mortality due to coronary heart disease (CHD) and cerebrovascular disease positively correlated with the air temperature and amount of precipitation but inversely correlated with the velocity of wind. Correlations between mortality from CVD and meteorological factors among subjects presenting with CHD, cerebrovascular disease, and AH were more pronounced and statistically significant compared with patients of the same groups without AH. PMID- 21265174 TI - [Supraoptic nucleus of hypothalamus in subjects with chronic heart failure]. AB - Postmortem paraffin hypothalamic blocks from male subjects with chronic heart failure (CHF) were used for morphometric and immunohistochemical studies of the supraoptical nucleus (SON). Morphometric analysis revealed a significant enlargement of pericarya and nuclei in SON of CHF subjects compared with controls. In addition, eccentrically positioned nucleoli were more frequently found in SON of the subjects with CHF. Moreover, a significant rise in relative entropy of all studied parameters of SON was documented in CHF subjects. The immunohistochemical study revealed a substantial increase of vasopressin immunoreactivity in SON neurons of the CHF subjects in comparison with control ones. Taken together, these results suggest considerable enhancement of synthetic activity of SON neurons in patients with CHF consistent with clinical observations that demonstrate significant elevation of blood vasopressin levels in patients with chronic cardiac insufficiency. PMID- 21265176 TI - [On the problem of scientifically-based substantiation of algorithms for the assessment of reliability of medical documentation]. AB - This article deals with the problems of pertaining to the study and evaluation of "wrong" medical documents. The authors emphasize the necessity of development of reliable methods for this purpose with special reference to the goals of forensic medicine. PMID- 21265177 TI - [On the detection of minor Rhesus antigens in blood stains]. AB - A new method for the detection of minor C, Cw, c, E, e-antigens of the Rhesus system in blood stains has been developed based on the absorption-elution technique with the use of anti-C, anti-Cw, anti-c, anti-E, and anti-e sera and standard erythrocyte preparations preliminarily treated with highly active proteases (protease C or papain). This method makes it possible to determine complete Rhesus phenotype in blood stains and substantially extend the possibilities of their differentiation on material objects (evidence) for the purpose of forensic-biological examination. PMID- 21265178 TI - [The use of enzymatic hydrolysis for isolation of barbituric acid derivatives from blood (as exemplified by phenobarbital and barbamyl)]. AB - Modern isolation techniques by direct extraction with organic solvents or after protein precipitation by various sedimenting or salting-out agents are characterized by low efficiency and do not permit to liberate derivatives of barbituric acid from their complexes with blood proteins. The use of enzymatic hydrolysis makes it possible to break bonds between barbiturates and protein and thereby improve the efficiency of isolation. We performed enzymatic hydrolysis of the model phenobarbital-blood and barbamyl-blood complexes with the use of trypsin, pepsin, chymotrypsin, and papain. The degree of phenobarbital extraction with trypsin and barbamyl was estimated at 62.1 +/- 1.2% and 75.1 +/- 1.6% respectively; in other words, it was 32.7 +/- 1.0% and 51.1 +/- 1.0% higher than that achieved by traditional methods. Certain validation characteristics of the new method are presented. PMID- 21265179 TI - [Rapid detection of caffeine in blood by freeze-out extraction]. AB - A new method for the detection of caffeine in blood has been proposed based on the combination of extraction and freezing-out to eliminate the influence of sample matrix. Metrological characteristics of the method are presented. Selectivity of detection is achieved by optimal conditions of analysis by high performance liquid chromatography. The method is technically simple and cost efficient, it ensures rapid performance of the studies. PMID- 21265180 TI - [Thin layer chromatography for the analysis of certain anti-inflammatory medicines]. AB - This work was devoted to the elucidation of conditions for isolation of ketorolac and diclofenac from biological fluids. A method is proposed for the extraction of these compounds from solutions with organic solvents at different pH values. Other methods permit to optimize identification of analytes by thin layer chromatography while the densitometric technique may be used for qualitative and quantitative analysis of their composition in biological fluids. PMID- 21265181 TI - [Extraction of trifluralin from acetonitrile solutions]. AB - Results of extraction of trifluralin from an aqueous acetonitrile solution using various organic solvents are presented. The degree of extraction was shown to depend on the nature of extractant and the water/acetonitrile ratio. An optimal electrolyte and the degree of saturation of the water-acetonitrile layer with this electrolyte were selected. The highest efficiency of extraction was achieved by using water-saturated ethylacetate as an extractant. The indices of extraction were calculated as necessary for the isolation of a given amount of trifluralin from aqueous acetonitrile (4:1) solutions with the solvents considered in the present study. PMID- 21265182 TI - [The use of fluorescent microscopy for the detection of blood effusion in putrescent material]. AB - The present article was designed to demonstrate the efficiency of application of fluorescent microscopy for histological studies of preparations of putrescent material suspected to contain effused blood. This method makes it possible to detect haematoporphirin, a product of haemoglobin degradation, the presence of which gives reliable evidence of the presence of effused blood in the study material. PMID- 21265183 TI - [Postmortem differential diagnostics of diabetic and alcoholic ketoacidosis]. AB - It was shown that ketoacidosis may be an immediate cause of death in subjects suffering chronic alcoholic intoxication. The authors present a list of biochemical studies and parameters that can be used for differential diagnosis between diabetic and alcoholic ketoacidosis. PMID- 21265184 TI - [On the possibility of postmortem diagnosis of diabetes mellitus]. AB - The present study has demonstrated that elevated level of glycated haemoglobin in cadaveric blood may be regarded as an absolute diagnostic criterion for diabetes mellitus irrespective of other macro- and/or micropathomorphological signs of this disease. PMID- 21265185 TI - [Prospects for the use of bacteriological method to establish the fact of death by drowning]. AB - Bacteriological studies of cadaveric blood for the presence of Pseudomonas putida and Pseudomonas fluorescence have demonstrated that identification of these microorganisms may be considered as an evidence of death by drowning. These bacteria are typical "aqueous" organisms non-pathogenic for man. They do not grow at a temperature of 41 degrees C and therefore are usually absent in normal human microflora. It is concluded that the establishment of the fact and location of death by drowning based on the analysis of plankton composition should be supplemented by identification of various forms of Pseudomonas in cadaveric blood. PMID- 21265186 TI - [Acute fatal intoxication with narcotic substances during their intracavitary transportation]. AB - The authors describe a case of sudden death of a passenger on the train from Uzbekistan bound for Russia via Kazakhstan. The death was attributed to the poisoning with an illegally transported narcotic substance that was detected in the subject's stomach and intestines. PMID- 21265187 TI - [Clinical and forensic-medical aspects of the injury in the medial facial region complicated by orbital phlegmona]. AB - The present study has demonstrated that a trauma inflicted to the medial facial region complicated by orbital phlegmona and similar injuries are characterized by specific morphological features differing in terms of localization and potential consequences that provide a basis for their categorization from the standpoint of severity of harm to human health. PMID- 21265188 TI - [Police surgeons and organization of forensic-medical examination in Sankt Petersburg prior to the establishment of the city medical department]. AB - The author presents documents illustrating one of the stages in the organization of forensic-medical service that provided the basis for the establishment of the city medical administration in 1873. PMID- 21265189 TI - [Pay attention to early diagnosis and treatment of knee osteoarthritis]. PMID- 21265190 TI - [Study on correlation between the pathological changes under arthroscopy and the cytokine levels in the knee osteoarthritis of the Blood Stasis type]. AB - OBJECTIVE: To explore the correlation between cytokine levels and the pathological changes under arthroscopy in knee osteoarthritis of Blood Stasis type. METHODS: From 2009.2 to 2010.3, 90 patients with knee osteoarthritis were reviewed. Among the patients, 17 patients were male and 73 patients were female, ranging in age from 40 to 70 years, averaged 57.2 years, the duration of the disease ranged from 1 month to 10 years, with a mean of 3.4 years. Thirty-one patients had osteoarthritis in left knee, and 59 patients in right knee. The patients had the syndrome of blood stasis. All the patients had pain and morning stiffness; most patients had joint interlocking; and all the patients didn't have joint swelling. The synovial fluid was collected before surgery, and ELISA was used to detect the contents of interleukin-1beta and transforming growth factor beta1. At the same time, the pathological changes of the joint were observed under the arthroscopy. Based on the above datum analysis, the severity of knee osteoarthritis of blood stasis type was studied, and the correlation between different types of pathological changes under arthroscopy and cytokine levels was analyzed. RESULTS: The contents of IL-1beta and TGF-beta1 in synovial fluid were (28.18 +/- 5.57) pg/ml and (51.69 +/- 6.56) pg/ml respectively. The level of IL 1beta of grade III-IV cartilage degeneration was (30.65 +/- 3.48) pg/ml, which was significantly higher than (20.55 +/- 3.50) pg/ml of grade I-II cartilage degeneration group; the level of TGF-beta1 of grade I-II cartilage degeneration was (58.18 +/- 3.98) pg/ml,which was significantly higher than (49.59 +/- 5.83) pg/ml of grade II-IV cartilage degeneration group. IL-1beta and cartilage degeneration was positively correlated, the correlation coefficient was 0.744; TGF-beta1 and cartilage degeneration was negatively correlated, the correlation coefficient was -0.563. The level of IL-1beta of grade II-III synovial hyperplasia was (33.48 +/- 2.95) pg/ml, which was significantly higher than (25.40 +/- 4.50) pg/ml of grade I synovial hyperplasia group; IL-beta was positively correlated with synovial hyperplasia, the cor- relation coefficient was 0.801. The levels of IL-1beta of grade I osteophyte formation was (34.18 +/- 2.69) pg/ml, which was significantly higher than (25.74 +/- 4.48) pg/ml of grade 0 osteophyte formation group; the level of TGF-beta 1 of grade 0 osteophyte formation was (53.11 +/- 6.78) pg/ml, which was higher than (48.21 +/- 4.47) pg/ml of grade I osteophyte formation group. IL-1beta was positively correlated with osteophyte formation, the correlation coefficient was 0.762; TGF-beta1 was negatively correlated with osteophyte formation, the correlation coefficient was 0.340. CONCLUSION: All the patients with knee osteoarthritis identified as blood stasis syndrome have pathological changes such as articular cartilage degeneration and synovial hyperplasia. The level of IL-1beta has important reference value to estimate the severity of cartilage degeneration, synovial hyperplasia and osteophyte proliferation. PMID- 21265191 TI - [Application of nerve roots block in the surgery of multilevel lumbar spinal stenosis]. PMID- 21265192 TI - [Clinical study on the treatment of knee osteoarthritis by acupuncture plus manipulative regulation of knee muscle]. AB - OBJECTIVE: To investigate and research the appraisal scores of the symptoms and physical signs index for the evaluation of the clinical efficacy of acupuncture and manipulative regulation of knee muscle balance for the treatment of knee osteoarthritis, and provide clinical basis for the treatment. METHODS: From January 2008 to December 2009, 121 patients with knee osteoarthritis were randomly divided into two groups. In the treatment group there were 63 cases of 83 knees including 16 males and 47 females, with an average age of (59.88 +/- 7.97) years; in the control group there were 58 cases of 73 knees including 13 males and 45 females, with an average age of (57.95 +/- 10.37) years. The patients in the treatment group were treated with acupuncture plus manipulative regulation of knee muscle balance, and the patients in the control group were treated with Diclofenac Sodium Sustained Release Tablets. The appraisal scores of the symptoms and physical signs index, numerical rating scale of pain, joint function, joint swelling were evaluated before and after the treatment, as well as 3 months after the treatment. All data were statistical analyzed by package SPSS 10.0. RESULTS: 1) In the treatment group, before and after treatment the appraisal scores of the symptoms and physical signs index were (39.81 +/- 3.92) and (9.69 +/- 8.08); numerical rating scale of pain were (7.61 +/- 0.97) and (2.17 +/- 2.09); joint function were (1.47 +/- 0.50) and (0.61 +/- 0.58); joint swelling were (1.23 +/- 0.79) and (0.42 +/- 0.52). As well in the control group, above data were (39.89 +/- 3.78), (13.62 +/- 7.83), (7.55 +/- 0.71), (3.34 +/- 2.32), (1.33 +/- 0.47), (0.93 +/- 0.67), an (0.97 +/- 0.88), (0.58 +/- 0.52) respectively. Both group had obvious differences in the appraisal scores of the symptoms and physical signs index, numerical rating scale of pain, joint function, joint swelling between after and before treatment. The comparison between the two groups suggested that after the treatments the treatment group had better therapy effect than those of the control group in the appraisal scores of the symptoms and physical signs index, numerical rating scale of pain, joint function, but both group had no differences in the appraisal scores of joint swelling. 2) After the treatment, 12 patients in the treatment group were clinically cured, 48 had remarkable effects,19 good, and 4 ineffective. As well in the control group, above data were 5, 31, 34 and 3 respectively. Three months after the treatment, above data were 8, 42, 27 and 6 respectively in the treatment group. In the control group, above data were 5, 21, 37 and 10 respectively. The treatment group was superior to the control group after the treatments and 3 months after the treatment. CONCLUSION: Acupuncture plus manipulative regulation of knee muscle balance can effectively improve the clinical symptoms and knee joint's motor function of patients with knee osteoarthritis, and can avoid the further development of disease. It is a proved effective method for knee osteoarthritis. PMID- 21265193 TI - [Study on the correlation between knee osteoarthritis imaging and effects of arthroscope]. AB - OBJECTIVE: To explore the indications of arthroscope for the treatment of knee osteoarthritis and investigate the correlation between knee osteoarthritis imaging and effects of arthroscope. METHODS: From 2005.8 to 2008.4, 86 patients with knee osteoarthritis underwent arthroscope examination and treatment. Among the patients, 44 patients were male, and 42 patients were female, ranging in age from 46 to 67 years, averaged 56.3 years. Arthrodial cartilage of knee was graded by ICRS MR, and by Kellgern Laqrence X-ray. All the patients were followed up, and the duration ranged from 12 to 30 months. The Lysholm score was evaluated at the follow-up time. RESULTS: Among 86 knees in 86 cases, cartilage injury degree of knees was graded as follows: grade 4 in 30 cases, grade 3 in 22 cases, grade 2 in 20 cases, grade 1 in 12 cases, grade 0 in 2 cases, mean grade (2.77 +/- 1.138). Postoperative Lysholm score ranged from 59 to 100, averaged (95.17 +/- 7.556), Kendall's correlation coefficient was -0.089, P = 0.317. There was no correlations between cartilage injury degree and Lysholm score. X-ray of knees was graded as follows: grade 4 in 0 cases, grade 3 in 24 cases, grade 2 in 38 cases, grade 1 in 17 cases, grade 0 in 7 cases, mean grade was (2.13 +/- 0.67), the Kendall's correlation coefficient was -0.851 with negative correlations (P = 0.036) between postoperative Lysholm score and K/L grade. CONCLUSION: There is no correlation between the grade of knee cartilage injury confirmed by MRI (1.5T) and effects of arthroscopy, and the grade is not a gold standard as an operation indication in arthroscope procedure. The K/L grade in X-ray had important effects. PMID- 21265194 TI - [Study on midterm follow-up results of arthroscopic debridement for knee osteoarthritis]. AB - OBJECTIVE: To evaluate the effect of arthroscopic debridement for knee osteoarthritis. METHODS: The medical records of 56 patients (56 knees) who underwent arthroscopic debridement procedures for knee osteoarthritis from 2000 to 2004 were reviewed. Among the patients, 15 patients were male and 41 patients were female,ranged in age from 39 to 76 years, with an average of (55.23 +/- 10.26) years. The duration of the disease ranged from 1 to 25 months, with an average of 5.75 months. The chief symptoms were pain, swelling and dysfunction of the knees. According to Kellgren-Lawrence classification grade, 17 patients were grade I ,39 patients were grade II. Lysholm score was used to evaluate the postoperative effects, and the statistics analysis was carried out with SPSS 13.0. RESULTS: All the patients were followed up more than 5 years. Three patients underwent total knee replacement respectively at 5.5, 7.8 and 8.3 years after the arthroscopic debridement, the average Lysholm score of other 53 patients increased from (42.40 +/- 6.78) preoperatively to (75.53 +/- 8.23) postoperatively. There were significant difference between preoperative score and postoperative score (t = -22.62, P < 0.01). CONCLUSION: The good midterm follow up results of arthroscopic debridement for knee osteoarthritis are related to the appropriate indications selections, limited debridement, good patient education, systemic rehabilitation and chondroprotective agents. PMID- 21265196 TI - [Operative treatment of the stable scaphoid nonunion]. PMID- 21265195 TI - [Study on the correlation between syndrome differ classification of knee osteoarthritis and X-ray image]. AB - OBJECTIVE: To study the correlation between syndrome differ classification of knee osteoarthritis and X-ray image, so as to provide evidence for clinical diagnosis and treatment. METHODS: From Jun. 2007 to Dec. 2007, 78 patients (108 knees) with knee osteoarthritis were reviewed, including 65 females (89 knees) and 13 males (19 knees), ranging in age from 41 to 77 years. According to the standards for the differentiation of syndrome in the treatment of knee osteoarthritis defined in Principle of Clinical Research for New Traditional Herbs, the patients were divided into three types: Type I, insufficiency of the liver and kidney, with stagnation of tendons and muscles, 43 knees; Type II, insufficiency of the spleen and kidney, with dampness infusion into bone and joints, 26 knees; Type I, deficiency of the liver and kidney, with inter obstruction of phlegm and stasis 39 knees. Normotopia and lateral plain film of knee joint of weigh loading and in erect position, and patellofemoral Skyline plain flim was taken. Joint space narrow, osteophyte generation, subchondral osteosclerosis and subchondral cystic degeneration were evaluated. All data were analyzed by K independent samples nonparametric test in order to find out the correlation between syndrome differ classification of knee osteoarthritis and X ray image. RESULTS: It was shown that after K independent samples nonparametric test about syndrome differ classification of knee osteoarthritis and X-ray image: there were significant differences among three types about lateral patella osteophyte, condyles of tibia osteophyte and Type II was the most serious, Type I was secondary, Type II was the lightest. Other index had no obvious difference among the three groups. CONCLUSION: There is certain correlation between syndrome differ classification of knee osteoarthritis and X-ray image. There are significant differences among three types about lateral patella osteophyte, condyles of tibia osteophyte, the Type II is the most serious,Type I is secondary, Type II is the lightest. Consequently, it can be deduced that worse osteophyte is one of accordances of Type II-insufficiency of the spleen and kidney, with dampness infusion into bone and joints. And, the Type II is more serious stage in radiologic manifestation. PMID- 21265197 TI - [Clinical application of "funnel technique" in planting thoracic pedicle screws]. AB - OBJECTIVE: To evaluate the safety and accuracy of "funnel technique" in planting thoracic pedicle screws. METHODS: From August 2005 to March 2008, a total of 39 patients with at least one thoracic pedicle screw in T1-T10 using "funnel technique" were retrospectively reviewed. Among the patients, 27 patients were male and 14 patients were female, with a mean age of 38.5 years (ranged from 17 to 56 years). One patient was lost follow-up, and other 1 patient was dead before follow-up. The accuracy of screw placement and the complications related to thoracic pedicle screws were analyzed by postoperative CT-scans. RESULTS: All the patients were followed up ranging from 18 to 30 months, averaged 23.2 months. There were no vascular or viscera complications as well as iatrogenic neurologic injuries. The total number of screws was 208. There was no statistical difference between the percentage of fully contained screws at T1-T4 versus T5-T8 (P = 0.80),T5-T8 versus T9-T10 (P = 0.07), T1-T4 versus T9-T10 (P = 0.06). Twenty seven screws (13.0%) were misplaced, 14 screws (6.7%) violated lateral cortex of pedicle, 7 screws (3.4%) medially, 5 screws (2.4%) superiorly, 1 screw (0.5%) violated lateral cortex of vertebral body. No violations occurred superiorly or anteriorly. Only 4 screws (1.9%) was a critical perforation. CONCLUSION: The "funnel technique" is a simple, safe, accurate and cost-effective technique for pedicle screw placement. It provides even an entry-level surgeon with a safe way to identify and place thoracic pedicle screws. PMID- 21265198 TI - [Effects of different Chinese drugs on bone histomorphology of hormone induced femoral head necrosis]. AB - OBJECTIVE: To evaluate and compare the histopathology effects and mechanisms of the methods of "invigorating spleen to remove phlem & promoting blood circulation to remove meridian obstruction" and "invigorate the kidney & promoting blood circulation to remove meridian obstruction" preventing hormone induced femoral head necrosis in hens. METHODS: Sixty-four healthy hens were randomly divided into 4 groups: blank control group, model group, Jianpi group (with therapeutics of invigorating spleen to remove phlem), Bushen group (with the effect of warming kidney for duresis). All hens were injected intramuscularly with Medrat once a week for 16 weeks but normal saline in blank control group. Bilateral femoral heads were dissected on 8 weeks or 16 weeks. Paraffin tissue sections were prepared to detect histopathologic change with hematoxylin and eosin, or mason staining. RESULTS: Histological analysis showed that Huogu recipe I and Huogu recipe II can promote osteogenesis and repair osteonecrosis, increase blood circulation of bone marrow, and inhibit pimelosis of bone marrow. Compared with blank control group, the areas of adipose cells increased significantly (t = 12.9, P < 0.01), the area of immature collagen increased significantly (t = -2.0, P < 0.05) and the ratio of empty lacuna in medullary cavity (t = -3.7, P < 0.05). Compared with model group, both the area of adipose cells and the ratio of empty lacuna decreased in Jianpi group and Bushen group (F = 26.8, 13.5, P < 0.01), so it was with the Bushen group immature collagen (F = 4.6, P < 0.01). CONCLUSION: Both the methods of "invigorating spleen to remove phlem & promoting blood circulation to remove meridian obstruction" and "invigorate the kidney & promoting blood circulation to remove meridian obstruction" can prevent hormone induced femoral head necrosis. The time taking effect in the method of "invigorating spleen to remove phlem" was shorter. PMID- 21265199 TI - [Emergency clinical application of free waste-finger flaps to repair the wound defect of hand]. PMID- 21265200 TI - [Influence of ground beetle on steroid-induced BMSCs osteogenic differentiation]. AB - OBJECTIVE: To investigate the pathogenesis of steroid-induced avascular necrosis of femoral head and the control mechanisms of Ground Beetle. METHODS: The bone marrow-derived mesenchymal stem cells were cultured in vitro. The BMSCs in the 3rd generation were randomly divided into blank group, model group and Chinese medicine low, medium and high dose group. BMSCs of model group using high-dose steroid-induced in vitro were adipogenic differentiation to inhibit osteogenesis. Chinese medicine low, medium and high-dose groups at the same time were given the Ground Beetle intervention serum containing insects. The expression of osteocalcin, Alkaline phosphatase and Type I Collagen mRNA were detected and interfered 6 days later. RESULTS: Serum containing Ground Beetle could reverse content of steroid-induced alkaline phosphatase of BMSCs, the expression of ostercalcin and Type I Collagen mRNA decreased. CONCLUSION: The control mechanism of Ground Beetle on steroid-induced avascular necrosis is not only to improve the microcirculation, but also to inhibit steroid-induced osteogenic differentiation of BMSCs reduced. PMID- 21265201 TI - [Study on the rotary angle, plain radiographs and CT appearance in unilateral locked facet of cervical spine]. AB - OBJECTIVE: To study the rotary angle and image features, so as to help early diagnosis. METHODS: Four adult cervical spine (C1-T1) specimens were used, including 2 males and 2 females,ranging in age from 28 to 40 years old. X-ray and CT examination were performed before the experiment. C2-C4 and C5-T1 were fixed respectively using self-made clamp. Unilateral locked facet of cervical spine was simulated under the violence of inflection and rotation, in which the muscle contraction was partially simulated, and at last the plain radiographs and CT of unilateral locked facet of cervical spine were analyzed. RESULTS: In unilateral locked facet of cervical spine, the average rotary angle was 19.75 degrees, and average forward shift of vertebral was 3.68 mm. The intervertebral foramina below the injury plane were showed at 0 degrees,10 degrees, 180 degrees,190 degrees; the intervertebral foramina above the injury plane were showed at 150 degrees,160 degrees, 00 degrees, -10 degrees, and the facet was locked or in disorder at the injury plane. The intervertebral foramina at the anterior oblique position was bigger in interlocking side, but it was smaller in the opposite side. CT scan showed rotary spine, the naked facet sign; coronal plane reconstruction showed bilateral asymmetry; sagittal plane reconstruction obviously showed unilateral locked facet. CONCLUSION: X-ray and CT both can independently diagnose unilateral locked facet of cervical spine. CT and three-dimensional reconstruction are more better than X-ray to diagnosing it. PMID- 21265202 TI - [Case-control study on comprehensive rehabilitation for postoperative pain after spinal surgery]. AB - OBJECTIVE: To evaluate the effect of interferential electrical stimulation (IES) in pain relief after spine surgery. METHODS: From January 2004 to December 2008, 166 patients after spine operation received pain treatment. All the patients were divided into two groups: the drug treatment group, which was the control group, including 46 cases, 22 patients were male and 24 patients were female, with an average age of (51.0 +/- 6.5) years; and the IES treatment group, including 120 cases, 50 patients were male and 70 patients were female, with an average age of (48.0 +/- 5.6) years. Before treatment, there were 4 patients with pain of Grade III in the control group, in which 3 patients had stenosis, 1 patient had spondylolisthesis; 42 patients had Grade II pain. In the IES group before treatment,17 patients had Grade II pain, in which 13 patients had stenosis, 4 patients had spondylolisthesis; 103 patients had Grade II pain. The preoperative and postoperative pains were evaluated and compared by the WHO Pain Criteria. RESULTS: The composing of IES group with pain grade III, II and I were 1/96/23, 0/17/103, 0/0/ 120 at the 3rd day, the 7th day and the 14th day after treatment respectively, while in the control group they were 4/42/0, 2/ 44/0, 0/4/42 respectively. There were statistical differences between the two groups with Kruskal-Wallis test. The percent of mid and severe grade pain decreased much faster in IES group. CONCLUSION: Interferential electrical stimulation (IES) therapy can improve patients' postoperative pain relief more quickly and reduce duration of hospitalization. PMID- 21265203 TI - [Augmentative plate fixation for the treatment of femoral hypertrophic nonunions subsequent to intramedullary nailing fixation]. AB - OBJECTIVE: To investigate the effect of augmentative plate fixation to increase stability in the treatment of femoral shaft nonunions subsequent to intramedullary fixation. METHODS: Nine patients with femoral nonunions after intramedullary nail internal fixation were treated with augmentative plate internal fixation from April 1998 to Jane 2008, included 8 males and 1 female, with an average age of 32 years old ranging from 21 to 54 years. One case was upper 1/3 femoral fractures, 5 cases were middle 1/3 femoral fractures, 3 cases were lower 1/3 femoral fractures. The interspace of bone nonunion was more than 5 mm in 6 cases, of them, iliac bone grafting were applied in 4 cases, artificial bone combined with iliac bone grafting were applied in 2 cases; The interspace of bone nonunion was less than 5 mm in other 3 cases,artificial bone grafting was applied in 1 case, fitting bone callus were applied in 2 cases. All patients got protected weight loading preventing the main screw break. RESULTS: All patients achieved radiological solid union at an average of 8 months (ranged 6 to 11 months ). The fixation was removed during 6 to 11 months after operation in 5 cases. Donor site pain of iliac occurrenced on 4 cases,3 cases relieved 1 month later and 1 case relieved 3 months later. No infection, fixation loosening or breaking was observed. CONCLUSION: The augmentative plate fixation can be applied at the fracture site to prevent the rotational instability. The technique is simple and does not require any special instrument, which facilitates an early weight bearing and gives a quick recovery from nonunion. PMID- 21265204 TI - [Modified 1/3 tubular plate and lag screw for the treatment of ankle fractures in elderly patients]. AB - OBJECTIVE: To study a kind of surgical instrument for the treatment of ankle fractures in elderly patients. METHODS: From October 2007 to May 2009, 14 patients (9 males and 5 females,ranging in age from 58 to 81 years, averaged 69.3 years) with ankle joint fractures of type A and B were treated with modified 1/3 tubular plate combined with lag screws. According to the Danis-Weber classification, 6 patients were type A and 8 patients were type B. The AOFAS criteria was used to evaluate clinical effects. RESULTS: All the patients were followed up ranged from 12 to 18 months and healed. The time of union of fractures ranged from 10 to 16 weeks. According to the clinical assess standard of AOFAS, the average score was 88.0 +/- 2.1. CONCLUSION: It is one of good choices to use modified 1/3 tubular plate and lag screws to treat ankle joint fractures in elder patients. PMID- 21265205 TI - [Clinical analysis of one-stage posterior-anterior operative approach in treating lower cervical spine fracture and dislocation]. AB - OBJECTIVE: To investigate the clinical effects of one-stage posterior-anterior decompression and internal fixation for the treatment of the severe fractures and dislocations combined with the spinal cord injuries of the lower cervical spine. METHODS: From August 2005 to August 2009, 48 patients (male 28 and female 20, aged from 28 to 62 years with a mean of 39.6 years) with severe fractures and dislocations of lower cervical spine were treated by reduction and internal fixation with one-stage combined cervical anterior plating and posterior lateral mass screws and rod or plate systems. Frankel grade A was in 8 cases, grade B in 16 cases, grade C in 20 cases, and grade D in 4 cases before operation. Firstly, the posterior approach was carried out. After inserting the mass screws, decompression and reduction were performed, and the rod or plate systems were embedded. After grafting, the skull traction was removed and initiated the anterior reduction, intervertebral decompression, auto-graft and cervical spine auto-locking plate fixation. The stability and fusion rate of the injured segments were evaluated on the regular postoperative X-ray film. The function of the spinal cord was assessed with Frankle classification. RESULTS: All patients were followed up, ranged from 6 to 28 months with an average of 12 months. Solid fusion obtained in the postoperative 6 months. Frankel grade C was in 28 cases, grade D in 14 cases, grade E in 6 cases after operation. There was no complications related to internal fixation breakage, loosening or displacement. There was no vascular and esophagus complications during the operation. CONCLUSION: One-stage combined anterior-posterior decompression and internal fixation in treating severe fracture and dislocations of lower cervical spine could restore the cervical curvature, and obtain good reduction and complete decompression, and gain postoperative immediate stability. This technique is benefit to the patients for the functional recovery of the spinal cord. PMID- 21265206 TI - [Case control study of hook needle knife for the treatment of stenosing tenovaginitis of flexor digitorum]. AB - OBJECTIVE: To investigate the effect and safety of the hook needle knife for the treatment of stenosing tenovaginitis of flexor digitorum. METHODS: From September 2007 to September 2008, 60 outpatients with stenosing tenovaginitis of flexor digitorum were randomized divided into the treatment group and the control group, 30 cases in each group. Among the patients, 44 patients were female and 16 patients were male, aged from 34 to 69 years, averaged 56 years, the duration of disease ranged from 1 month to 1 year, averaged 3 months. All the patients were treated with hook needle knife and local-blocking respectively. The patients were followed up for 6 months, and the relief of moving-pain, tender-pain, stretching pain and resist-ing--pain were observed respectively. All the patients were evaluated by the symptoms with numerical rating scale. RESULTS: The relief of moving-pain, tender-pain, stretching-pain and resisting-pain in the treatment group were significantly better than those of the control group; and the therapeutic effects of treatment group were better than those of the control group. CONCLUSION: The method for treating stenosing tenovaginitis of flexor digitorum with hook needle knife has advantages of definite effects, micro invasion and safety. PMID- 21265207 TI - [Treatment of anterior dislocation of the shoulder joint by He's manipulative methods]. PMID- 21265208 TI - [Treatment of patella fractures of 164 patients with 5 methods]. AB - OBJECTIVE: To investigate the effects of different treatments for different patella fractures, and analyze the clinical outcome. METHODS: One hundred and sixty-four patients with patella fracture were treated between July 2005 and December 2009, 113 males and 51 females with an average age of 38.5 years old, ranging from 21 to 72 years. There were 21 cases of linear fracture or separation of the patella < 0.5 cm, 63 of patella separation > 0.5 cm and for the pure horizontal type or vertical-type fractures, 34 cases were separated into three block, 46 cases were separated into four and above. Of 164 cases, 21 patients accepted traditional treatment, 39 patients were fixed with cerclage wire and tension band wire, 43 with cannulated screws and tension band wire fixation, 29 with cannulated screws for the minimally invasive treatment, 32 patients with fixation of NT-PC RESULTS: One hundred and sixty-four cases were followed up with a mean period of 14 months (3 to 36 months). By Lysholm knee score criteria: 19 cases in traditional treatment were excellent and good, 36 cases in cerclage wire and tension band wire technique cases were excellent and good, 40 cases in cannulated screws and tension band wire fixation, 27 cases in cannulated screws for the minimally invasive treatment were excellent and good, 30 cases in NT-PC were excellent and good. CONCLUSION: The surgery should be avoided if the patients can be treated with manipulation and fixation. Those who need surgical treatment should be based on the type of fracture to select a different surgical operation. Percutaneous reduction can be fixed, and try to minimally invasive surgery. Whether traditional treatment or internal fixation, the appropriate functional exercise need to make as early as possible. PMID- 21265209 TI - [Treatment of femoral fractures by bone grafting from trochanter and interlocking intramedullary nail fixation]. AB - OBJECTIVE: To discuss the curative effect of bone graft from trochanter with interlocking intramedullary nail for comminute fracture of femur. METHODS: From January of 2009 to January of 2010, fifty patients with comminute fracture of femur were treated by the therapy of bone graft from trochanter with interlocking intramedullary nail, included 35 males and 15 females with an average age of 38.4 years old ranging from 28 to 50 years. According to AO/ASIF classification system, there were 15 cases of type B1, 20 of type B2, 8 of type B3, 7 of type C1. RESULTS: All the patients were followed up for 12 to 24 months, averaged 14.4 months. All the broken femurs knitted in 4 to 6 months, the average period of knit was 5.6 months. The injured legs with normal movement in knees,which had no infection, vascellum-nerve injury and anchylosis in knees. According to Merchan knee rating scale, the results were excellent in 25 cases, good in 20, fair in 3 and poor in 2, and the excellent and good rate was 90%. CONCLUSION: Bone graft from trochanter with interlocking intramedullary nail, which has a virtue of small injury, less blood loss, high rate of bone knit, perfect functional recovery, is a preferable therapy of fresh fracture of femur. PMID- 21265210 TI - [Arthroscopic anterior cruciate ligament reconstruction with LARS artificial ligament in the acute phase]. PMID- 21265211 TI - [Dynamic external fixator combined with K-wire in treatment of unstably distal radius fractures]. PMID- 21265212 TI - [Pigmented villonodular synovitis of ankle joint: a report of 5 cases]. PMID- 21265213 TI - [Compartment syndrome of lower leg in hemophilia: a report of 1 case]. PMID- 21265214 TI - [Research progress of biomarker COMP in osteoarthritis]. AB - Cartilage oligomeric matrix protein (COMP) is a potential biomarker for joint destruction associated with osteoarthritis, which is first and best investigated biomarkers to reflect osteoarthritis occurs, progress and the prognosis. In this article, multiple uses and related reports of COMP are summarized briefly to promote further investigation of COMP. PMID- 21265216 TI - Enhancing chemical separations with chemometric data analysis. PMID- 21265215 TI - [Research progress of intraarticular injection of hyaluronic acid (HA) for osteoarthritis in recent three years]. AB - Intra-articular injection of hyaluronic acid for osteoarthritis is an old and useful method. According to recent literatures, the following four problems were reviewed in this article: 1) Mechanisms. Real-time PCR was used to detect the transforming growth factor-beta 1 (TGF-beta1), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) gene expression, which were significantly increased, as well as promoted secretion and synthesis of the tissue inhibitors of metalloproteinase, thus the reaction and cartilage destruction were decreased. 2) Methods. Because of discovering of new HA derivants, single intra-articular treatment with 6 ml hylan G-F 20 had replaced the routine method of once a week. To improve the therapeutic effectiveness, compound drags were applied, such as NSAIDs. 3) Indication. Knee OA (K-L II-III type) was first elected. But at present, the K-L I type was advocated early application. While the K-L IV type, although joint function can not improve, the symptoms relieved. 4) Therapeutic effectiveness. The double-blind place bo controlled study showed that it was better than corticoid, and persistent and no side-effect. Therefore, this was a safe, persistent effective method. PMID- 21265217 TI - [Fathers, sisters and brothers: shifts in power and rights in 19th-century property reforms.]. PMID- 21265218 TI - [The furniture question: interior decoration in surveys of dwelling habits of the 1930's and 1940's]. PMID- 21265219 TI - Analysis of pirouette execution for improved performance. PMID- 21265220 TI - [Housewives' films and the modern housewife: technology and expertise in the household during the 1950's and 1960's]. PMID- 21265221 TI - [A family like all others: child welfare officers and gender politics in the early welfare state]. PMID- 21265223 TI - [Fighting to be heard and employed: the relationship between anthropologists and Norwegian Development Aid, 1952-87]. PMID- 21265222 TI - [Child labor in India in a comparative perspective]. PMID- 21265224 TI - [The concept of income in agricultural politics: from a political slogan to a system of technological measurement return]. PMID- 21265226 TI - [Secure retirement or increased risk of poverty? Assistance for persons receiving small pensions in the Weimar Republic following war and inflation]. PMID- 21265227 TI - [Ethnic cleansing, 1945-47: the expulsion of some 12 million Germans from Eastern and Central Europe]. PMID- 21265228 TI - [Is there a limit to the Hippocratic oath? German refugees between death and medical attention in Denmark, 1945]. PMID- 21265229 TI - Manhood, the male body, courtship and the household in early modern England. PMID- 21265230 TI - Medicine, health and medical practice in precolonial Khoikhoi society: an anthropological-historical perspective. PMID- 21265231 TI - Wong type dermatomyositis: 20th case reported. PMID- 21265232 TI - The politics of knowledge: science, race and evolution in Asia and the Pacific. PMID- 21265233 TI - Science and the art of representing "savages": reading "races" in text and image in South Seas voyage literature. PMID- 21265234 TI - The Japanese nation in evolution: W. E. Griffis, hybridity and the whiteness of the Japanese race. PMID- 21265235 TI - An untimely divorce: western medicine and anthropology in Melanesia. PMID- 21265236 TI - Introduction to "Historians and public memory in Japan: the 'comfort women' controversy". PMID- 21265237 TI - Influenza A (H1N1) 2009 pandemic virus: learning from the first wave, preparing for the second. PMID- 21265238 TI - A prospective cohort study on the effect of various risk factors on hypoglycaemia in diabetics who fast during Ramadan. AB - Muslim diabetics who fast during Ramadan are at risk of hypoglycaemia, and previous consensus guidelines have highlighted certain risk factors. This prospective cohort study aims to determine the relative risk (RR) of hypoglycaemia during Ramadan fasting compared with a non-fasting period of equivalent length, and to ascertain which risk factors are clinically significant. From the results, Ramadan fasting carries a RR of hypoglycaemia of 1.60 (95% CI 1.05 to 2.43). Good metabolic control (HbAlc < 8%) and old age (> 60 years) increased RR more than twice, while taking breakfast prior to fasting reduces RR to less than half. PMID- 21265239 TI - Auditory functionality and early use of speech in a group of pediatric cochlear implant users. AB - This study examined auditory functionality and early use of speech in a group of paediatric cochlear implant users. Parents of 33 implanted children from the Universiti Kebangsaan Malaysia Cochlear Implant Program were interviewed using the Meaningful Auditory Integration Scale (MAIS) and the Meaningful Use of Speech Scale (MUSS). In general, higher MAIS scores post-implantation were significantly associated with higher MUSS scores suggesting that those with better functional hearing with the implant were also better in using spontaneous speech to communicate. Multiple regression analyses showed that several time factors significantly correlated with the MAIS scores post-implantation but not with the MUSS. PMID- 21265241 TI - Hypertension in a residential home for the elderly in Penang, Malaysia. AB - A study of residents at the Silver Jubilee Home for the Aged was conducted to determine the prevalence, awareness and control of hypertension in this elderly community in Penang, Malaysia. Prevalence of hypertension was 36%, with 81% of patients being initially aware of this diagnosis. This relatively low hypertension prevalence rate may be because residents have a fairly sheltered lifestyle with less social stress and a daily routine that incorporates adequate exercise. Similarly, the high hypertension awareness rate compared to reported figures in the community may be because residents are more regularly monitored by the attending medical care-givers. At the beginning of the study, only 34% of hypertensive patients were well controlled with a blood pressure less than 140/90 mm Hg. This proportion rose to 53% at the end of study period. Compliance is better at a residential home because medication is served by their care-givers and cost is absorbed in this charitable organization. Our study suggests that hypertension awareness and control can be reasonable for the elderly in a residential home. PMID- 21265240 TI - Effects of vitamin E on receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in rats treated with nicotine. AB - Vitamin E is found to reverse the effects of nicotine on bone and this study aimed to determine its mechanism. Male Sprague Dawley rats were divided into four groups and treated for 3 months: Group 1 was the control group (RC). Groups 2 (N), 3 (N+TT) and 4 (N+ATF) received nicotine 7 mg/kg throughout the treatment period. In addition, groups 3 and 4 received tocotrienol 60 mg/kg and alpha tocopherol 60 mg/kg respectively during months 2 and 3. Parameters measured were serum osteoprotegerin (OPG), serum receptor activator of nuclear factor kappa B ligand (RANKL), femoral and lumbar bone calcium content and body weight. Nicotine did not affect OPG or RANKL levels but reduced bone calcium content suggesting the calcium loss is not due to increase osteoclastogenesis. OPG was increased in N+ATF while RANKL was slightly increased in N+TT. Both vitamin E supplements restored bone calcium loss induced by nicotine. Nicotine impaired weight gain in all treatment groups starting week 4 however, N+TT group was comparable to RC from week 6 onwards. Bone protective effects of ATF, but not TT, may be partly due to inhibition of osteoclastogenesis. PMID- 21265242 TI - Granulomatous prostatitis: a reminder to clinicians. AB - Granulomatous Prostatitis (GnP) is a heterogenous entity classified into specific infections, non-specific infections, post surgical i.e. post-transurethral resection of prostate (TURP) and rare secondary (systemic) causes. A total of 1388 reports of prostatic biopsy and prostatic chips from TURP were reviewed from 1995 and 2007. The results which showed granulomatous prostatitis were analyzed and retrospective data collected from the patient's records. A total of 9 cases with granulomatous prostatitis were identified. There are 3 types of entities which are the non-specific (NSGnP), post-TURP and the specific type. The incidence of GnP in our center is lower than reported by Stillwell et al. The majority of the patients were Malays. PMID- 21265244 TI - Preliminary evaluation of various rapid influenza diagnostic test methods for the detection of the novel influenza A (H1N1) in Universiti Kebangsaan Malaysia Medical Centre. AB - We evaluated the performance of four rapid influenza diagnostic test methods (RIDT) compared to real-time reverse-transcription polymerase chain reaction (rRT PCR), for the detection of the novel swine-origin influenza A (H1N1) virus (S OIV) in August 2009. A total of 270 respiratory specimens were tested with rRT PCR, where 74 of these were tested by BinaxNow (Inverness), 80 by QuickVue (Quidel), 37 by Influenza A Antigen Rapid Test (Rockeby Biomed) and 79 by Directigen (BD). The sensitivities ranged from 4.4% to 37.0%, specificities 90.9% to 100.0%, positive predictive values 75.0% to 100.0% and negative predictive values 32.3% to 75.0%. RIDT were able to detect S-OIV but the sensitivities were low. The limitations of RIDT must be considered when interpreting results for clinical management. PMID- 21265243 TI - The outcome of the seminal fluid parameters collected via coitus interruptus versus masturbation. AB - A one year study was carried out to determine the outcome of the seminal fluid parameters collected via masturbation and coitus interruptus in 151 patients who were undergoing intrauterine insemination (IUI) and patients who came for seminal analysis. There were no statistically significant differences in terms of volume, concentration, progressive motility and normal morphology from specimens collected via coitus interruptus compared to specimens collected via masturbation. Pregnancy outcomes were also comparable. PMID- 21265245 TI - Molecular epidemiology of chikungunya virus in Malaysia since its first emergence in 1998. AB - Malaysia experienced the first outbreak of chikungunya (CHIK) in Klang in late 1998 due to CHIK virus of Asian genotype. The CHIK virus of Asian genotype reemerged causing outbreak in Bangan Panchor, Perak in March 2006. CHIK virus of Central/East African genotype was first detected from a patient who returned from India in August 2006. In December 2006, CHIK virus of Central/East African genotype was re-introduced into Malaysia from India and caused an outbreak in Kinta district, Perak but was successfully controlled following an early detection and institution of intensive vector control measures. In late April 2008, CHIK virus of Central/East African genotype was laboratory confirmed as the cause of CHIK outbreak in Johore which spread to other parts of Malaysia by August 2008. Phylogenetic analysis based on the 254-bp fragment of the virus envelope protein gene as the genetic marker showed that three different strains of CHIK virus of Central/East African genotype were introduced into Malaysia on three separate occasions from 2006 to 2008. The strain that was introduced into Johor state was responsible for its subsequent spread to other parts of Malaysia, inclusive of Sarawak. PMID- 21265246 TI - Serum uric acid levels and its association with age-related macular degeneration (ARMD). AB - To investigate the possible association between serum uric acid levels, serum C Reactive Protein (CRP), and age-related macular degeneration (ARMD). A total 232 patients of the eye department at Hospital Tuanku Ja'afar, Negeri Sembilan, Malaysia were recruited over 9 weeks. Participants were divided into ARMD (Non Neovascular ARMD, and Neovascular ARMD) and control groups. 107 participants with non-neovascular ARMD, 6 with neovascular ARMD, and 119 controls participated in the study. The control patients had a similar average Serum Uric Acid level to the average of all patients with ARMD (P = 0.617). CONTROL GROUP: mean 299.19 micromol/l +/- std dev. 89.847 micromol/l. ARMD group: mean 302.53 micromol/l +/- std dev. 80.794 micromol/l. The average serum uric acid levels were higher in patients with neovascular ARMD (median = 397 mean +/- std dev = 389.67 +/- 38 micromol/l) than in the non-neovascular ARMD group (288.5 micromol/l, 297.86 +/- 80.26 micromol/l), and control group (295.5 micromol/l, 299.19 +/- 89.95 micromol/l). Comparing the standardised serum uric acid levels in the control group (Median = 0.5) against the two ARMD groups separately, there was no significant difference to the non-neovascular group (P = 0.448) but there was a difference significant to the neovascular ARMD group (P = 0.044). The neovascular and non-neovascular ARMD groups had median CRP value of 0.25 mg/l and were not significantly different. There is no association between serum uric acid levels and ARMD as a whole. There is potentially an association between serum uric acid and neovascular ARMD, an association needs to be established further. There is no association between serum CRP and ARMD. PMID- 21265247 TI - Reliability and validity of the Brief COPE Scale (English version) among women with breast cancer undergoing treatment of adjuvant chemotherapy: a Malaysian study. AB - This paper validates the Brief COPE Scale in Malaysian women with breast cancer. Test-retest evaluation was undertaken at two/three weeks and ten weeks following surgery. Internal consistencies ranged from 0.25 to 1.00. Meanwhile, the Intraclass Correlation Coefficient (ICC) ranged from 0.05 to 1.00. Sensitivity of the scale was indicated by the mean differences as observed in most of the domains with Effect Size Index (ESI) ranged from 0 to 0.53. Significant differences between mastectomy and lumpectomy were observed for Active coping, Planning and Acceptance. Brief COPE Scale showed fairly good reliability and validity. PMID- 21265248 TI - Sleep position and infant care practices in an urban community in Kuala Lumpur. AB - Several modifiable risk factors for sudden infant death syndrome (SIDS) have been identified such as sleeping prone or on the side, sleeping on a soft surface, bed sharing, no prenatal care and maternal ante-natal smoking. A cross-sectional survey of infant sleep and care practices was conducted among parents of babies aged below 8 months to determine the prevalence and predictors of non-supine sleep position and the prevalence of other high-risk infant care practices for SIDS. Of 263 infants, 24.7% were placed to sleep in the non-supine position and age of infants was a factor positively associated with this (adjusted odds ratio 1.275, 95% CI=1.085, 1.499). The most common modifiable risk factor was the presence of soft toys or bedding in the infants' bed or cot (89.4%). Results from this study indicate that although the predominant sleep position of Malaysian infants in this population is supine, the majority of infants were exposed to other care practices which have been shown to be associated with SIDS. PMID- 21265249 TI - A ten year retrospective review of orbital complications secondary to acute sinusitis in children. AB - Acute sinusitis is most often a mild self-limiting disease. However, it may progress into severe and life threatening complications. One of the commonest being orbital complication of which visual loss is a direct consequence. In this 10 year retrospective study, the nature of orbital complication, clinical presentation and treatment modalities and outcome seen in children with acute sinusitis in a tertiary referral institute were reviewed. Of six patients, there was a case of preseptal cellulitis, 4 cases of subperiosteal abscess and one case of orbital abscess. Periorbital swelling was a common presenting feature. In 5 cases this was associated with proptosis with one case of impending optic nerve compression. The value of computed tomography and opthalmological examination as a component in the management plan is highlighted. All patients were treated with intravenous antibiotics but evidence of abscess collection warranted urgent surgical drainage in 5 patients, 3 being endoscopic drainage while external approach was done for the remaining 2 patients. Thus a child exhibiting orbital complication of acute sinusitis, prompt diagnosis and treatment is essential in obtaining the best outcome for the child. PMID- 21265250 TI - Knowledge and attitude of university students in health sciences on the prevention of cervical cancer. AB - Cervical cancer is the second most common female cancer after breast cancer both in Malaysia and worldwide although it can be mostly prevented. The objective of this study was to assess the knowledge level and attitude of University Kebangsaan Malaysia female students in the Faculties of Pharmacy and Allied Health Sciences on the prevention of cervical cancer. A total of 675 respondents were recruited for this cross-sectional study involving pre-tested questionnaires. The data was analyzed using Statistical Package for Social Sciences (SPSS) version 15.0. There was significant association between grade and mean score of knowledge with different faculties and year of education (p<0.05). However, significant association was shown only between grade of knowledge with different programs in the Faculty of Allied Health Sciences. For mean score of knowledge, significant difference only existed among different races (p<0.05). Mass media was the most common source of information. In conclusion, the knowledge level of respondents on cervical cancer and its prevention was not satisfactory despite their positive attitude on prevention. Thus, more awareness programs should be conducted in University campuses to provide students with knowledge on prevention of cervical cancer. PMID- 21265251 TI - Role of primary care providers in dengue prevention and control in the community. AB - Dengue fever is a major public health threat in Malaysia, especially in the highly urbanized states of Selangor and the Federal Territory of Kuala Lumpur. It is believed that many seek treatment at the primary care clinics and are not admitted. This study aims at establishing the fact that primary care practitioners, as the first point of patient contacts, play a crucial role in advising patients suspected of having dengue to take early preventive measures to break the chain of dengue transmission. A total of 236 patients admitted to two government hospitals for suspected dengue fever were interviewed using a structured questionnaire over a one week period in December 2008. It was found that 83.9% of the patients had sought treatment at a Primary Care (PC) facility before admission to the hospital, with 68.7% of them seeking treatment on two or more occasions. The mean time period for seeking treatment at primary care clinic was one and a half (1.4) days of fever, compared to almost five (4.9) days for admission. The majority of patients (96-98%) reported that primary care practitioners had not given them any advice on preventive measures to be taken even though 51.9% of the patients had been told they could be having dengue fever. This study showed the need for primary care providers to be more involved in the control and prevention of dengue in the community, as these patients were seen very early in their illness compared to when they were admitted. PMID- 21265252 TI - Human Plasmodium knowlesi infections in Klang Valley, Peninsula Malaysia: a case series. AB - We report seven cases of naturally acquired human Plasmodium knowlesi infections which were admitted to our centre from July 2007 till June 2008. Diagnosis was confirmed by nested PCR. Cases of P. knowlesi infections, dubbed the fifth type of human malaria, have been reported in East Malaysia (Sabah and Sarawak) as well as in the state of Pahang in Peninsula Malaysia. These seven patients appear to be the first few reported cases of P. knowlesi infection in the Klang valley, Peninsula Malaysia. We then discuss the characteristics of human P. knowlesi infections, which include its natural hosts, responsible vectors, clinical presentation, and the treatment of such infections. PMID- 21265253 TI - Gracilis muscle as neoanal sphincter for faecal incontinence. AB - Faecal incontinence is a debilitating chronic clinical condition which may affect the patient and care givers. Modality of treatment is based on severity of the symptoms as well as the anatomical defect itself, availability of resources and expertise. We describe a modified technique of dynamic graciloplasty as neoanal sphincter for the treatment severe faecal incontinence who has failed previous over lapping sphincteroplasty. In our modified version, instead of using implanted intramuscular electrodes and subcutaneous neurostimulator to provide continuous stimulation, the patient will undergo an external stimulation on the nerve of transplanted gracilis periodically and concurrent biofeedback therapy. We believe the technique is relatively easy to learn and very cost effective without any electrodes or neurostimulator related complications. PMID- 21265254 TI - Cavernous hemangioma mimicking anterior jugular vein phlebectesia. AB - Cavernous hemangioma is a vascular tumor composed of large dilated blood vessels and containing large blood-filled spaces. The formation is due to dilation and thickening of the walls of the capillary loops. Most cavernous hemangiomas present at birth or soon after. On the other hand, jugular phlebectasia is an abnormal benign sacculofusiform dilatation of jugular veins. It should be considered as one of the differential diagnosis of neck swelling. Majority of the reported cases occurred in a young child. We reported a case of an elderly woman who was diagnosed clinically as anterior jugular vein phlebectesia. Histologically the mass turned out to be a cavernous hemangioma. PMID- 21265255 TI - Nasal septal haemangioma in pregnancy. AB - A pregnant lady in her third trimester presented with a rapidly growing right sided nasal mass associated with epistaxis and nasal obstruction for two months. Examination showed a non tender, protruding mass completely occluding her right nostril. Wide surgical excision was done under local anaesthesia. Histopathology revealed capillary haemangioma. In a gravid patient with a rapidly growing intranasal lesion, capillary haemangioma should be considered as a differential diagnosis. Due to the rapidity of growth, presentation with epistaxis and its macroscopic appearance which often mimics malignancy; histologic confirmation is crucial. PMID- 21265256 TI - Solitary fibrous tumour of the pleura presenting with refractory non-insulin mediated hypoglycaemia (the Doege-Potter syndrome). AB - We report a case of a 61 year-old man who presented with refractory non-insulin mediated hypoglycaemia. A chest radiograph showed a right lung opacity, which was confirmed as a large intra-thoracic mass by computed tomography (CT) of the thorax. CT-guided biopsy with histological examination revealed features of a solitary fibrous tumour of low malignant potential. We discuss the association of solitary fibrous tumour of the pleura (SFTP) with hypoglycaemia, and the management of such rare tumours. PMID- 21265257 TI - A rare case of incarcerated bochdalek diaphragmatic hernia in a pregnant lady. AB - The occurrence of congenital diaphragmatic hernia in a pregnant adult is rare. In contrast to neonatal diaphragmatic hernias, most of the adult patients present with vague gastrointestinal symptoms mimicking other diseases hence the importance of high index of suspicion. We report a case of a young pregnant lady with congenital diaphragmatic hernia presenting with symptoms and clinical signs suggestive of acute pancreatitis. The patient had a laparotomy performed to reduce the hernial content and the diaphragmatic defect was successfully repaired. PMID- 21265258 TI - Head and neck follicular dendritic cell sarcoma: disease associations and treatment review. AB - Currently, of less than 50 cases of head and neck follicular dendritic cell (FDC) sarcoma reported in the literature, 5 have been found to occur in the background of Castleman disease. We report another case of head and neck FDC sarcoma with emphasise on its associated lesions and review the outcome of treatment from the existing cases in the literature. PMID- 21265259 TI - Submandibular intraductal calculi removal as an office procedure with radiofrequency device. AB - Salivary duct obstruction secondary to calculi is a common disorder of the submandibular gland and often manifesting as painful episodic swelling of the gland during meals. Complications may arise in unresolved obstruction leading to infections, abscess formation and a hypofunctioning gland. Treatment of this disorder has evolved from the traditional sialadenectomy to organ preserving procedures done under general or local anaesthesia. Our technique using Ellman Surgitron radiofrequency device, is another alternative technique for transoral removal of extraglandular calculi. It is a simple, quick an easy technique to learn that can be done in the office setting under local anaesthesia. PMID- 21265260 TI - A fatal case of chikungunya virus infection with liver involvement. AB - Recovery from chikungunya is previously considered universal and mortality due to the virus is rare and unusual. Findings from recent chikungunya outbreaks occurred in Reunion Island and India have since challenged the conventional view on the benign nature of the illness. Malaysia has experienced at least of 4 outbreaks of chikungunya since 1998. In the present on-going large outbreak due to chikungunya virus of Central/East African genotype, a previous healthy sixty six years gentleman without co-morbidity was noted to have severe systemic infection by the virus and involvement of his liver. He subsequently passed away due to cardiovascular collapse after 5 days of illness. PMID- 21265261 TI - Massive goiter with retrosternal extension encasing trachea and esophagus. AB - Massive goiter with retrosternal extension may impose additional risk such as difficult intubation, tracheomalacia, and possibility of different incision and approach including sternotomy. We would like to report a case of massive goiter encasing major neck structures and how it was managed. PMID- 21265262 TI - Retinal laser photocoagulation. AB - Since its discovery in the 1940s, retinal photocoagulation has evolved immensely. Although the first photocoagulators utilised incandescent light, it was the invention of laser that instigated the widespread use of photocoagulation for treatment of retinal diseases. Laser permits choice of electromagnetic wavelength in addition to temporal delivery methods such as continuous and micropulse modes. These variables are crucial for accurate targeting of retinal tissue and prevention of detrimental side effects such as central blind spots. Laser photocoagulation is the mainstay of treatment for proliferative diabetic retinopathy amongst many other retinal conditions. Considering the escalating prevalence of diabetes mellitus, it is important for physicians to grasp the basic principles and be aware of new developments in retinal laser therapy. PMID- 21265263 TI - Risk factors for severity of pneumothorax after CT-guided percutaneous lung biopsy using the single-needle method. AB - The purpose of this study is to evaluate the risk factors for the severity of pneumothorax after computed tomography (CT)-guided percutaneous lung biopsy using the single-needle method. We reviewed 91 biopsy procedures for 90 intrapulmonary lesions in 89 patients. Patient factors were age, sex, history of ipsilateral lung surgery and grade of emphysema. Lesion factors were size, location and pleural contact. Procedure factors were position, needle type, needle size, number of pleural punctures, pleural angle, length of needle passes in the aerated lung and number of harvesting samples. The severity of pneumothorax after biopsy was classified into 4 groups: "none", "mild", "moderate" and "severe". The risk factors for the severity of pneumothorax were determined by multivariate analyzing of the factors derived from univariate analysis. Pneumothorax occurred in 39 (43%) of the 91 procedures. Mild, moderate, and severe pneumothorax occurred in 24 (26%), 8 (9%) and 7 (8%) of all procedures, respectively. Multivariate analysis showed that location, pleural contact, number of pleural punctures and number of harvesting samples were significantly associated with the severity of pneumothorax (p < 0.05). In conclusion, lower locations and non pleural contact lesions, increased number of pleural punctures and increased number of harvesting samples presented a higher severity of pneumothorax. PMID- 21265264 TI - Generation and evaluation of an anti-REV1 monoclonal antibody. AB - Continuous exposure of cells to exogenous and endogenous agents produces many types of DNA damage during normal cell cycles. Post-replication repair, consisting of error-free and error-prone sub-pathways, is required for tolerance of such DNA damage. REV1 plays a crucial role in regulation of the error-prone pathway. To facilitate analysis of its cellular functions, we here generated a mouse Rev1 monoclonal antibody, called D6, which also recognizes human REV1. The epitope for the antibody could be mapped between 860-877 amino acid residues of human REV1, which was located outside of the conserved catalytic domain. Although the antibody unfortunately could not specifically detect endogenous mouse and human REV1 by western blotting and immunohistochemistry, we established a method to identify endogenous human REV1 by immunoprecipitation-western blotting analysis combining D6 and separately generated polyclonal antibodies. PMID- 21265265 TI - Three-dimensional echo-guided suture of atrial septal defect with Maniceps in an experimental model. AB - Toward the establishment of suture closure procedures for atrial septal defect or patent foramen ovale under guidance of three-dimensional (3D) echocardiography but without use of cardiopulmonary bypass (off-pump surgery), an experimental study was conducted using a laparoscopic suture instrument, Maniceps. First, the panel setting of the 3D echo system which was optimal for precisely visualizing the surgical instruments on the image display with the least time delay was determined. The optimal setting was: 1) harmonic imaging, 2) no smoothing, 3) low scanning line density, and 4) a scanning range around 55 degrees. Using an ex vivo model of atrial septal defect, 3D echo-guided surgical procedures were attempted in three steps. First, grasping of the edge of the defect with a forceps was attempted. It was feasible in every direction. Reverberation artifact occasionally disturbed imaging of the defect edge. Second, transfixion suture of the facing edges was attempted. Guided by 3D echo, serial sutures were feasible, but interlocking of the thread was a pitfall. Third, continuous suture of the defect was attempted under 3D echo guidance. Following the initial suture bite on one side, continuous suture could be performed under echo guidance. Deformity of the Maniceps needle after repeated sutures was a limitation. In conclusion, suture closure of the defect under 3D echo guidance using the Maniceps system is feasible in an ex vivo ASD model as visualization is optimized by panel setting for guiding surgical procedures. PMID- 21265266 TI - NYC Health and Hospitals Corporation's Marlene Zurack on healthcare reform. PMID- 21265267 TI - Gridlock on the beltway, more gridlock in Congress. PMID- 21265268 TI - Emerging accounting trends accounting for leases. AB - A new model for lease accounting can have a significant impact on hospitals and healthcare organizations. The new approach proposes a "right-of-use" model that involves complex estimates and significant administrative burden. Hospitals and health systems that draw heavily on lease arrangements should start preparing for the new approach now even though guidance and a final rule are not expected until mid-2011. This article highlights a number of considerations from the lessee point of view. PMID- 21265269 TI - Preparing for the new landscape of payment reform. AB - A door-to-discharge analysis emphasizes a global view of care delivery to improve processes, eliminate waste, and reduce costs. Key components of this approach are identifying information sources and collecting data, engaging physicians, using techniques such as Lean and Six Sigma, and improving documentation and coding. Focusing on specific high-cost MS-DRGs, such as catheterization laboratory procedures and cardiovascular, joint replacement, and spine surgery, can produce early, significant results. PMID- 21265271 TI - Lee Sacks, MD: enhancing quality is good for business. PMID- 21265270 TI - Preparing for Prometheus: an interview with John Byrnes and Kevin Fosnocht. PMID- 21265272 TI - Physician alignment: the right strategy, the right mind-set. AB - Developing the right mind-set for collaboration involves consideration of: The organization's market position and customer base The type of structure that best complements the hospital's culture The incentives needed to drive alignment. The tools to share credible data related to utilization, cost, and quality. The need for shared control. PMID- 21265273 TI - From skepticism to engagement. AB - WellStar Kennestone Hospital's patient flow improvement initiative is a case study in engaging physicians in a collaborative effort that benefits both the physicians and the hospital. Kennestone's success was in large part due to the active participation of physician leaders on the committee charged with leading the project. The initiative provides a lesson for hospitals looking to collaborate with physicians in meeting reform's mandate for the highest-quality care delivered with the highest level of efficiency at the lowest possible cost. PMID- 21265274 TI - Structuring competitive physician compensation models. AB - When developing and reviewing their physician compensation programs, healthcare organizations should: Understand the market data. Test outcomes of incentive plans for fair market value. Check total compensation for fair market value and reasonableness. PMID- 21265275 TI - Assessing the benefits of teleintensivist coverage in the ICU. AB - Issues that healthcare leaders should consider in determining whether to develop a teleintensivist program to support physician coverage in the ICU include those related to: Coverage. Scope. IT capabilities. Licensure of participating physicians and accreditation of the hospital. Payment. Potential impact on other ICU services. Performance measurement. Training and education. PMID- 21265276 TI - Using IT to drive operational efficiency in the OR. AB - Automating the anesthesia record in the operating room (OR) can help hospitals reduce coding staff needed and days in accounts receivable. Employing analytics allows OR managers to refine and streamline processes. Using technology to manage surgeon preference cards can help hospitals reduce costs, capture charges, and better manage surgical supplies. PMID- 21265277 TI - Six strategies for charge capture success. PMID- 21265279 TI - Keys to successful EHR implementation. PMID- 21265278 TI - Managing risk under healthcare reform. PMID- 21265280 TI - What would you do? Should this independent hospital affiliate? PMID- 21265281 TI - Courage and character, leaders and legends: an interview with Stan Jordan, MD by Linda Ohler. PMID- 21265282 TI - Use of telehealth technology for home spirometry after lung transplantation: a randomized controlled trial. AB - CONTEXT: Complications often occur during the early phase after lung transplantation, and rapid diagnosis is vital. Home spirometry is used to detect early changes in graft function. Bluetooth-equipped cell phones are easy to use and facilitate data transfer from home spirometry. OBJECTIVE: To explore use of home spirometry with Bluetooth data transfer in outpatient lung transplant recipients. DESIGN: Single-center prospective randomized controlled trial. Intervention-Fifty-six patients were randomized either to home spirometry with data transfer via Bluetooth-equipped cell phones or to home spirometry alone before discharge after lung transplantation. In the Bluetooth group, results were transferred to a database capable of generating alarm messages. MAIN OUTCOME MEASURES: Time from onset of symptoms to physician consultation during the first 6 months after lung transplantation was the primary end point. RESULTS: Adherence to home spirometry was 97.2% in the Bluetooth group and 95.3% in the home spirometry alone group (P = .73). Median time to first consultation (P = .60) and frequency of consultation (P = .06) did not differ significantly in the 2 groups. Mean scores on the Hospital Anxiety and Depression Scale were lower in patients in the Bluetooth group (1.5; range, 0.0-4.0) than in the home spirometry alone group (4.0; range, 2.0-6.0; P = .04). CONCLUSION: Home spirometry with data transfer is feasible and safe in lung transplant recipients. Compared with home spirometry alone, additional data transfer was equally effective regarding the time interval from symptom onset to consultation. Patients in the Bluetooth group reported less anxiety, which may improve emotional well-being. PMID- 21265283 TI - Circumocular exanthema associated with chronic rejection after kidney transplantation. AB - A 43-year-old man had severe circumocular exanthema associated with chronic rejection 10 years after receiving a kidney transplant to treat end-stage renal failure. After the renal allograft was extracted, the exanthema diminished rapidly without any treatment. Donor-reactive immune cells seem to have cross reacted with unknown pathogens on the skin and contributed to inflammation. PMID- 21265284 TI - Quality of surgical care in liver and small-bowel transplant: approach to risk assessment and antibiotic prophylaxis. AB - In August 2002, The Centers for Medicare and Medicaid Services and the Centers for Disease Control and Prevention implemented the National Surgical Infection Prevention project. The goal of the project was to decrease the morbidity and mortality associated with postoperative surgical site infections through appropriate selection and timing of administration and discontinuation of prophylactic antimicrobials. The National Surgical Infection Prevention project, however, excluded transplant surgeries from its focus because of the lack of randomized clinical trials comparing antimicrobial agents. The goals of this article are to (1) provide a framework for risk factors associated with surgical site infections in liver, small-bowel, and multivisceral transplants; (2) review general principles of the appropriate antimicrobial prophylaxis; (3) provide a framework for developing a triage of liver, small-bowel, and multivisceral transplant candidates for appropriate antibiotic prophylaxis; and (4) develop an approach to further quality improvements in transplant surgical care. A multidisciplinary team produced recommendations for antibacterial prophylaxis and monitoring. PMID- 21265285 TI - Newsletters and adherence to a weekly home spirometry program after lung transplant. AB - CONTEXT: Newsletters are a common intervention for patients in clinical trials. However, it is not clear whether newsletters are associated with increased adherence to the health regimen, and if so, which aspects of the newsletter are reported as most helpful to patients. OBJECTIVE: To examine the association between patients' ratings of worthwhileness of a quarterly newsletter and adherence with a home spirometry regimen. DESIGN: Patients (n=48) were in a research-based spirometry program after lung transplant and had received at least 1 newsletter; 24 (50%) returned completed surveys via postal mail. MAIN OUTCOME MEASURES: Adherence for forced vital pulmonary function tests for respondents versus nonrespondents, number of weeks they were adherent, ratings they gave the newsletter, and which components of the newsletters were helpful to the respondents. RESULTS: Respondents had more forced vital capacity pulmonary function tests ("blows") overall, blew more times weekly, and blew more consistently from week to week than did nonrespondents. Although it was not statistically significant, a mild correlation was found between the number of weeks that the respondents were adherent and their ratings of the newsletter (r = 0.36, P = .08). Most respondents reported that newsletter length was "about right", and 86% reported that newsletters helped encourage regular spirometer use, maintain interest in the study, educate about general health, and alert readers to seasonal health risks. IMPLICATIONS FOR PRACTICE: High ratings for newsletters used to encourage participation among adults in our home spirometry study were associated with higher adherence. PMID- 21265286 TI - Spouse caregivers of kidney transplant patients: quality of life and psychosocial outcomes. AB - CONTEXT: Most kidney transplant programs require patients to identify a primary caregiver who can assist them throughout the transplant process. Little is known about the quality of life, caregiving strain, and psychosocial functioning of these caregivers. OBJECTIVES: To characterize the psychosocial functioning of spouse/partner caregivers. DESIGN, SETTINGS, AND PARTICIPANTS: Cross-sectional survey administered to spouse/partner caregivers of patients before (n=33) and after (n=46) kidney transplantation at a transplant center in New England. MAIN OUTCOME MEASURES: Quality of life, life satisfaction, caregiving strain and benefit, mood, and social intimacy. RESULTS: Relative to normative samples and published data involving other transplant caregivers, caregivers of kidney transplant patients had favorable quality of life, life satisfaction, psychological, and social intimacy outcomes. Life satisfaction scores were significantly lower for caregivers before than after kidney transplantation, but otherwise the 2 cohorts did not differ significantly from each other. Most caregivers both before and after kidney transplantation reported clinically high levels of caregiving strain, as well as several caregiving benefits. CONCLUSION: Our data are consistent with results of other studies in showing that spouses experience considerable caregiving strain both before and after transplantation. However, caregivers of kidney transplant patients overall have good quality of life, life satisfaction, mood, and social intimacy. More prospective research is necessary to characterize better how these outcomes change over time throughout the transplant process. PMID- 21265287 TI - Skin cancer prevention education for kidney transplant recipients: a systematic evaluation of Internet sites. AB - CONTEXT: Repeated patient education about skin cancer prevention is important to self-care after transplant. OBJECTIVE: Examine educational materials for kidney transplant recipients available on the Internet that address sun protection and skin self-examination for early detection of squamous cell carcinoma. DESIGN: Systematic review of Web sites for kidney transplant recipients endorsed by transplant physicians and dermatologists. PARTICIPANTS: An expert panel of 8 dermatologists providing care for kidney transplant recipients and 1 research medical anthropologist. MAIN OUTCOME MEASURES: Reading grade level, inclusion of people with skin of color, sufficient content to support effective sun protection, and description of 4 sun-protection strategies and skin self examination. Results-Of the 40 sites identified, 11 contained information about sun protection or increased risk of any type of cancer. The Web sites had a ninth grade median reading level (range, seventh grade to college senior). Interrater reliability for the 25-item assessment tool was assessed by Fleiss' kappa (kappa = 0.87). Skin cancer risk was presented as relevant to those with fair skin. Sites recommended regular use of sunscreen with sun-protection factor of 15 or greater (n=3) to reduce the risk of skin cancer (n=4). Few sites recommended using protective clothing (n=5), seeking shade (n=4), and avoiding deliberate tanning with indoor or outdoor light (n=1). Five sites recommended skin self examination. CONCLUSION: Because many patients seek self-management information from the Internet, Web sites must provide more thorough educational information about skin cancer prevention and health promotion at a lower reading grade level. PMID- 21265288 TI - The impact of a change in tacrolimus monitoring immunoassay techniques on clinical decision making. AB - CONTEXT: Tacrolimus is an immunosuppressant that undergoes therapeutic drug monitoring. The laboratory at our institution changed its immunoassay techniques from the fluorescence polarization immunoassay to the cloned enzyme donation immunoassay. OBJECTIVE: To evaluate the relationship between the 2 assays and to determine the impact of the change on clinical decision making. DESIGN: A retrospective study of patients admitted to the hospital during the assay transition period. Tacrolimus values for the 2 assays were collected for 4 weeks and compared. SETTING: An academic health center. PATIENTS: Liver transplant patients hospitalized from February 18, 2008, to March 18, 2008. MAIN OUTCOME MEASURE: The primary outcome was the agreement between the results of the 2 immunoassays. Secondary outcome was agreement of clinical decision making with established patient-specific therapeutic ranges or with a 30% difference in absolute values between the assays. RESULTS: Seventy-nine pairs of tacrolimus concentrations were collected from 21 liver transplant patients. The mean (SD) tacrolimus concentrations were 7.36 (4.21) microg/L for the fluorescence polarization immunoassay and 9.00 (5.30) microg/L for the cloned enzyme donation immunoassay (P = .03). A clinically different decision would have been made if the fluorescence polarization immunoassay value had not been reported 51% of the time. A Bland-Altman plot indicated no relationship between the assay results. CONCLUSION: A change in tacrolimus monitoring assay would have resulted in different clinical decisions 51% of the time. Awareness of changes in assay technology must be heightened to enhance clinical decision making and prevent potential impact on morbidity among liver transplant patients. PMID- 21265289 TI - Barriers to implementing protocols for kidney paired donation and desensitization: survey of U.S. transplant programs. AB - CONTEXT: Special types of kidney transplant exist for patients who have willing but incompatible donors. Two types of transplants that circumvent donor-recipient incompatibility are "kidney paired donation" and "desensitization." Lack of access to these protocols limits living donations and shortens the life span of patients with willing but incompatible donors. OBJECTIVE: To understand potential barriers to implementing kidney paired donation and desensitization, as well as attitudes toward nondirected donation and compatible type O donation, which would maximize the number of kidney paired donation transplants performed via chains. DESIGN: We created a 56-question Web-based survey to elicit information from US transplant program directors about 24 potential barriers to implementing these protocols. PARTICIPANTS: Of 166 programs contacted, 96 responded, including 88 complete and 8 partial responses. After pediatric-only programs and multiple responses from the same program were removed, 84 total (78 complete) remained. MAIN OUTCOME MEASURES: Respondents were asked to designate each barrier as "major," "minor," or "not a barrier". RESULTS: Availability of dedicated nurse coordinators and the United Network for Organ Sharing's variance request process (although kidney paired donation does not actually require a variance) were significant barriers to kidney paired donation. Most respondents (54%, 42/78) would prefer to participate in a regional rather than a national protocol for kidney paired donation. Risk of complications was the most significant barrier to desensitization. University affiliation, region, and training (nephrologist vs surgeon) had little effect on perception of barriers. Most (92%, 71/78) would evaluate nondirected donations; 53% (41/78) would encourage compatible type O donors to enter kidney paired donation. PMID- 21265290 TI - Stranger donors: a key link in transplant chains. AB - Living donation to strangers is a complex issue that has caused some transplant centers to ban the practice altogether. Most prominent of the troublesome issues is the common source of these donors; namely, the Internet. These "stranger donors," however, are critical to both paired kidney transplants and chain kidney transplants. This article presents the ethical complexities of donors in these transplant arrangements and offers 2 case examples from our facility. Rigorous donor screening and informed consent processes are crucial, and together they help make transplant pairs and chains ethically feasible. PMID- 21265291 TI - Quality improvement in the care of live liver donors: implementation of the Designated Donor Nurse Program. AB - Publications on living donor liver transplant have focused on the medical aspects of donor selection, postoperative management, surgical procedures, and outcomes, but little attention has been given to the nursing implications for care of live liver donors during their inpatient stay. Donor advocates from various disciplines are involved during the initial education and evaluation, but most care after surgery is delivered by an inpatient medical team and bedside nursing staff who are not as familiar with the donor and concepts related to donor advocacy. In an effort to improve the overall donor experience and provide safe, high-quality care to patients undergoing elective partial hepatectomy, our academic medical center began a quality improvement project focused on improving the inpatient stay. Inpatient nursing standards and policies and procedures were developed to ensure that consistent care is delivered. However, the infrequency of living donor liver transplantation makes it nearly impossible to have all transplant program staff on a nursing unit be "experts" on donor care. Therefore, our center determined that, similar to the Independent Donor Advocacy Team, a transplant program needs live donor champions on the nursing unit to mirror the goals of the team. To that end, we developed the concept of the Designated Donor Nurse to care for and advocate for live liver donors during the inpatient stay and also to serve as a resource to their colleagues. PMID- 21265292 TI - Attitudes toward organ donation and donor behavior: a review of the international literature. AB - OBJECTIVE: To conduct a systematic review of published research that assessed the predictors of attitudes toward deceased organ donation, willingness to donate, and donor behavior. DATA SOURCES: MEDLINE, PreMEDLINE, PsycInfo, and the Cumulative Index to Nursing and Allied Health Literature were searched for the period from 1988 to 2009. STUDY SELECTION: Eligible studies included members of the general public (i.e., not transplant recipients, donor families, or health professionals) and used multivariate analyses for quantitative assessment of predictors. Data Extraction-The search identified 33 relevant studies. Owing to heterogeneity in populations and measures, results were summarized rather than subjected to meta-analysis. DATA SYNTHESIS: Research suggests that individuals who are younger, female, have higher education levels and socioeconomic status, hold fewer religious beliefs, have high knowledge levels, know others with positive attitudes, are more altruistic, and have fewer concerns about manipulation of the body of the deceased donor are more likely to have positive attitudes toward donation and are more willing to donate their organs. CONCLUSIONS: The review revealed the complexity of individuals' attitudes toward donation and the need for more sophisticated future studies of the interactions between the broader factors influencing donation (such as social norms and existing legislation in each country) and individual factors, such as attitudes and beliefs. (Progress in Transplantation. PMID- 21265293 TI - Choosing to be a designated organ donor on their first driver's license: actions, opinions, intentions, and barriers of Asian American and Pacific Islander adolescents in Hawaii. AB - CONTEXT: The factors associated with Asian American and Pacific Islander adolescents' decision to be a designated organ donor on their first driver's license are largely unknown. OBJECTIVE: To assess knowledge and attitudes about organ donation and sociocultural factors associated with designated organ donor status in Asian American and Pacific Islander youth in Hawaii. DESIGN AND SETTING: Written surveys and focus groups were conducted at high schools and churches. PARTICIPANTS: Two hundred eight Asian American and Pacific Islander teens, mean age 16 (SD, 2) years, 52.6% females, and 53.4% Catholic. MAIN OUTCOME MEASURES: Donor status on driver's license, awareness, attitudes, intentions, and barriers to becoming a designated organ donor. RESULTS: Eighteen percent of teens with a driver's license are designated organ donors. Twenty-one percent have talked to their parents about becoming a designated donor on their license. Of those without a license, 27.7% intended to become a designated donor. Sex, grade level, and immigrant status were not associated with designated organ donor status; however, Catholics were significantly less likely to be donors. Key barriers to being a designated donor included a lack of knowledge or misperceptions due to urban myths about organ donation, parents completing "organ donor" question on driver's license application, and not wanting to have their body "cut up." CONCLUSIONS: Future organ donor campaigns should educate ethnic minority adolescents about the importance of becoming a designated organ donor on their first driver's license and counter urban myths about deceased organ donation. Guidelines for how to initiate family discussions about organ donation should be sensitive to cultural and religious beliefs. PMID- 21265294 TI - Central venous oxygen saturation monitoring: role in adult donor care? AB - Monitoring oxygen saturation of blood drawn from a catheter placed within the superior vena cava (Scvo2) has recently been promoted as a substitute for evaluating oxygen saturation of mixed venous blood drawn from the pulmonary artery (Svo2). The Svo2 reflects the balance between oxygen delivery and oxygen consumption throughout the body and, among critically ill patients, may be helpful for assessing resuscitation, cardiac function, or oxygen homeostasis end points. Use of Scvo2 instead has been promoted because of its easier access and recent use during resuscitation of patients with severe infections. Although data from healthy subjects and critically ill patients are available, no study has been done among organ donors to evaluate customary values for either Scvo2 or Svo2 or how well the values correspond. After loss of oxygen consumption in the brain following brain death, the customary values for these variables may be different from values in other groups of patients. Therefore, until donor specific normative values for these important parameters are identified, we do not recommend that Scvo2 be used to evaluate the balance between donor oxygen consumption and delivery or as a variable to guide treatment. PMID- 21265295 TI - Response to the article "Who we are and what we must not be", published in Mil Med 2010; 175(9): 627-9. PMID- 21265296 TI - A roundtable discussion on emerging infectious diseases--risks to U.S. service members in Afghanistan and Iraq. PMID- 21265297 TI - A comparison of cognitive performance decreases during acute, progressive fatigue arising from different concurrent stressors. AB - Fatigue is known to impair cognitive performance, but it remains unclear whether concurrent common stressors affect cognitive performance similarly. We used the Stroop Color-Word Conflict Test to assess cognitive performance over 24 hours for four groups: control, sleep-deprived (SD), SD + energy deficit, and SD + energy deficit + fluid restricted. Fatigue levels were quantified using the Profile of Mood States (POMS) survey. Linear mixed-effects (LME) models allowed for testing of group-specific differences in cognitive performance while accounting for subject-level variation. Starting fatigue levels were similar among all groups, while 24-hour fatigue levels differed significantly. For each cognitive performance test, results were modeled separately. The simplest LME model contained a significant fixed-effects term for slope and intercept. Moreover, the simplest LME model used a single slope coefficient to fit data from all four groups, suggesting that loss in cognitive performance over a 24-hour duty cycle with respect to fatigue level is similar regardless of the cause. PMID- 21265298 TI - Use of computerized neuropsychological testing to help determine fitness to return to combat operations when taking medication that can influence cognitive function. AB - Nowhere is it more important to maintain peek mental functioning than in a combat zone. Conditions ranging from pain to head injury to post-traumatic stress disorder can cause impairments in neuropsychological function and place service members at risk. Medications can sometimes help alleviate these problems, but also have the risk of further slowing cognitive function or impairing reaction time. Standard methods of neuropsychological testing are often not available in a combat environment. New technologies are being advanced that can allow portable, computerized neuropsychological testing to be performed at almost any location. We present a case that demonstrates how the use of such handheld technology can assist a military physician in assessing the influence of medication on reaction time and in determining if and when a service member is ready to return to combat. PMID- 21265299 TI - Test-retest reliability of the Traumatic Brain Injury Screening Instrument. AB - The Traumatic Brain Injury Screening Instrument (TBISI) was implemented in Veterans Affairs medical facilities in an attempt to identify Operation Enduring Freedom and Operation Iraqi Freedom (OEF/OIF) veterans with possible mild TBI. Despite its widespread implementation, the reliability and validity of the screening tool has not yet been established. The current study reports preliminary findings on the test-retest reliability of the TBISI in 44 OEF/OIF veterans referred for neuropsychological evaluation following a positive TBI screen. Results suggest overall poor test-retest reliability of the TBI screening tool with regard to type of event, injuries sustained, and resulting sequelae. These findings underscore the importance of further investigation of its psychometric properties to promote accurate identification and referral of veterans with possible TBI. PMID- 21265300 TI - Serotonin syndrome in the deployed setting. AB - Serotonin syndrome is a potential side effect of some psychotropic medications in common use today. With over 8000 adverse events related to this condition in 2004 alone, this risk warrants further attention. The deployed environment presents a unique set of stressors and risks involved in treatment with any psychotherapeutic agent. The following case illustrates one incidence of rapid titration of a selective serotonin reuptake inhibitor (SSRI) (fluoxetine) contributing to the emergence of serotonin syndrome. PMID- 21265301 TI - Postdeployment health care for returning OEF/OIF military personnel and their social networks: a qualitative approach. AB - Little is known regarding the health care needs of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) deployed veterans seeking care outside of Veterans Affairs facilities. Responding to this gap, we conducted a mixed methods study of postdeployment health among veterans and members of their social networks in six community-based primary care clinics. A total of 347 patients completed a survey dealing with deployment to Iraq/Afghanistan (whether their own or that of a family member, friend, or coworker), and subsequent psychosocial and health problems. A subset of 52 participants responded to an open-ended question requesting additional information about experiences during and postdeployment. Content analysis of these responses revealed five overarching themes: connectedness, perceptions of conflict, consequences of deployment, health and treatment concerns, and respect and concern for service members/veterans. These data point to significant deployment-related disruptions in the well-being of service members and those in their broader social networks, with implications for defining service needs in community health settings. PMID- 21265302 TI - The impact of culture clash on deployed troops. AB - Culture plays a crucial role in the military, helping the armed forces achieve their goals. However, cultural issues can negatively affect personnel's well being and effectiveness, especially when there is a "clash" between military and other cultures. The literature suggests there should be more training and education on individual service cultures, as well as other countries' military cultures to improve cooperation and coordination during joint operations and working in multinational forces. A greater knowledge of local cultures may help avoid offending noncombatants. When deployment ends, service personnel need more support when they transition back to civilian culture. PMID- 21265303 TI - Medical implications of enhanced radiation weapons. AB - During the 1960s through 1980s the United States and several other nations developed, and even considered deploying, enhanced-radiation warheads (ERWs). The main effect of ERWs (sometimes called "neutron bombs"), as compared to other types of nuclear weapons, is to enhance radiation casualties while reducing blast and thermal damage to the infrastructure. Five nations were reported to have developed and tested ERWs during this period, but since the termination of the "Cold War" there have been no threats of development, deployment, or use of such weapons. However, if the technology of a quarter of a century ago has been developed, maintained, or even advanced since then, it is conceivable that the grim possibility of future ERW use exists. The type of destruction, initial triage of casualties, distribution of patterns of injury, and medical management of ERWs will be shown to significantly differ from that of fission weapons. Emergency response planners and medical personnel, civilian or military, must be aware of these differences to reduce the horrible consequences of ERW usage and appropriately treat casualties. PMID- 21265304 TI - Characteristics of medical-surgical patients at the 86th Combat Support Hospital during Operation Iraqi Freedom. AB - A descriptive study was performed of the U.S. and coalition forces patients admitted to the Intermediate Care Ward (ICW) of the 86th Combat Support Hospital (CSH) in Baghdad, Iraq (2007-2009). A prospective study was conducted of the patients admitted to the ward between April 12 and July 19, 2008. Three hundred and fifty three patients were included in the study. Characteristics of the patients admitted during a 3-month period of the deployment of the 86th CSH in Iraq, as well as the types of illnesses and injuries most commonly seen are reported. Implications for nurses preparing to deploy as well as implications for future research are discussed. PMID- 21265305 TI - Strategies to improve compensation and pension timeliness: lessons learned from high-performing facilities. AB - The compensation and pension (C&P) process is the mechanism by which injured Veterans are assigned their medical and disability benefits. As part of the documentation and rating process performed by the Veterans Benefits Administration (VBA), many Veterans need supplemental medical examinations performed by the Veterans Health Administration (VHA). Improving C&P examination timeliness is a goal of many VHA facilities. To identify strategies to improve examination timeliness, we used national performance measures to identify high performing VHA facilities. We then interviewed seven facilities using Donabedian's structure-process-outcome framework to determine characteristics attributed to their high-performance. We developed a list of high-performance characteristics common to all facilities, which relied on a tailored relationship between each VHA facility and VBA office. Additional characteristics were grouped thematically into three management foci - financial incentives, role specialization, and process reliability. Distillation of these characteristics provides guidance to other VHA facilities seeking to improve their C&P timeliness. PMID- 21265306 TI - Development of a deployment infection control course. AB - Since the beginning of military operations in Iraq and Afghanistan, multidrug resistant bacteria have been noted to be infecting and colonizing combat casualties. Studies suggest the primary source of these bacteria is nosocomial transmission. A focus area for improvement has been to enhance infection control (IC) at hospitals in the combat theater. A 5-day IC course was developed and implemented to provide just-in-time training to those personnel who have been identified to lead IC efforts while deployed. Twenty-nine students have attended the first 6 offerings of this course. A pre- and post-course test showed an average 21% improvement in knowledge. A follow-up questionnaire provided to those students who deployed found the course had enhanced performance of their IC duties. We describe the deployment-unique training developed to provide basic IC, emphasizing the unique challenges found in the combat setting. PMID- 21265307 TI - Respiratory illnesses at the 2009 U.S. Army ROTC Advanced Camp. AB - Every summer the U.S. Army Reserve Officer Training Corps (ROTC) conducts the Leader Development Assessment Course (LDAC) for several thousand upcoming senior year cadets. This study describes respiratory illnesses at 2009 ROTC LDAC after the emergence of the novel H1N1 influenza pandemic. This retrospective cohort study examines 5554 cadets and 1,616 cadres from 2009, and 5180 LDAC 2008 cadets. Respiratory clinic visits for 2009 cadets were higher than 2009 cadres and 2008 cadets, at 8.7, 2.0, and 4.2 visits per 1000 person-days available, respectively (p < 0.001). Further, respiratory illness hospitalizations and isolations were higher for 2009 cadets than cadres (p = 0.020). Although substantial efforts were made to prevent respiratory infections, there was considerable impact from respiratory illnesses, in the context of the novel H1N1 influenza pandemic, among 2009 ROTC LDAC participants. Our experience offers important lessons for future LDAC planning and for similar close quarters living circumstances. PMID- 21265308 TI - Failure of interior residual sprays as protection against mosquitoes in military issued two-man tents. AB - Most studies on interior (or indoor) residual spraying (IRS) have been targeted on permanent/semipermanent structures. We measured the utility of a portable field bioassay, which can be set up quickly to determine the best chemical repellent or irritant for use as an IRS during an emergency or military situation when displaced persons are temporarily housed in tents. If the bioassay were used over an extended period of time, it would also offer a unique way to monitor vector susceptibility and would be able to determine which chemical is most efficient in individual populations. In total, 2193 mosquitoes belonging to seven species in five genera were collected over the study period. No statistical differences were found between any of the treatments, control, and standard tents utilizing the 4 x 4 Latin square design. Therefore, we conclude that IRS with these tested chemicals in military-issued two-person tents are not effective or significant at stopping mosquito entrance. Further studies on implementation of a portable, field bioassay should include utilizing different mosquito traps in the bioassay and looking at the difference between contact irritants and spatial repellents in different-sized tents, as spatial repellency may be more important in smaller-sized tents. PMID- 21265309 TI - Prevention of dental trauma in a high-risk military population: the discrepancy between knowledge and willingness to comply. AB - Military fighters are at high risk for oral/tooth injuries. Our aim was to evaluate the knowledge and willingness to use preventive measures among this population to reduce oral trauma. A total of 336 fighters were randomly assigned to two groups. The control group answered a structured questionnaire, which included questions regarding: knowledge of the benefits of mouthguard use, past/current use, and willingness to use a mouthguard. The intervention group received a 60-minute dental trauma lecture, and responded to the same questionnaire. Significantly more subjects in the intervention group were familiar with the benefits of mouthguards compared to the control group, but there was no difference between the groups in their willingness to use mouthguards routinely. Discomfort and potential interference to sport performance were the most common reasons for rejection. It seems that a structured lecture is not sufficient for ensuring usage of mouthguards in a military population. Emphasis on motivation or mandating use may be required. PMID- 21265310 TI - Patient and provider population dynamics analysis in a large dental organization: a tool for management. AB - Health care managers are faced with difficult decisions on a daily basis. Some of those issues involve productivity. Statistical analyses of patient and provider population dynamics offer an important tool with which to base decisions. In this study, two representative clinics out of seven were selected. The patient and provider populations were subjected to the means square successive difference test and a linear regression test. The results differed from management perceptions. Provider decision processes in clinic A were more efficient than those in clinic B. There was no relationship between provider presence and the patient population in both clinics. The patient populations in both clinics displayed random arrivals. Specific recommendations to management from the results of this study include: billeting decisions, appointing process decisions, emergency policies, and the need for a focused marketing plan. There are many useful tools with which to study population dynamics. This is one example. PMID- 21265311 TI - Costs of using motivational interviewing for problem drinking in the U.S. Air Force. AB - Despite the popularity of motivational interviewing (MI) to address heavy drinking, limited evidence exists on the costs of using MI to address heavy drinking. This study examines the costs of using MI to address heavy drinking at four U.S. Air Force (USAF) bases. Clients were referred to and assessed at a base program to address their drinking as a result of an incident; those who were not alcohol dependent were invited to participate in the study. Participants consented and were randomly assigned to one of three intervention arms: individual MI (IMI), group MI (GMI), and Substance Abuse Awareness Seminar (SAAS). Three cost perspectives were taken: USAF, client, and the two combined. Data were collected from bases and public sources. The start-up cost per base ranged from $1340 to $2400 per provider staff member. Average implementation costs across bases were highest for the SAAS intervention ($148 per client). PMID- 21265312 TI - Oxidative stress increases in overweight individuals following an exercise test. AB - The objective of this study was to determine whether the Army Physical Fitness Test (APFT) causes oxidative stress and evaluate the impact of dietary antioxidant intake, fitness level, and body composition on changes in oxidative stress. Forty-seven overweight subjects were asked to perform an APFT. Creatine kinase (CK), C-reactive protein (CRP), glutathione peroxidase (GPX), and superoxide dismutase (SOD) were measured before, immediately after, and 24 hr postexercise. CK significantly increased immediately postexercise and at 24 hr postexercise. CRP and GPX significantly increased immediately postexercise, whereas SOD did not change significantly. Antioxidant intake, fitness level, and body composition were found to significantly influence changes in CK, GPX, and SOD after exercise. In conclusion, the APFT causes oxidative stress in overweight subjects. The associations between dietary antioxidants, fitness level, and body composition seen with each of the biomarkers provide support for future research in this area. PMID- 21265313 TI - Pyruvate-enriched resuscitation protects hindlimb muscle from ischemia reperfusion injury. AB - BACKGROUND: Tourniquets impose ischemia on distal musculature. Resuscitation with pyruvate, an energy substrate and antioxidant, may ameliorate muscle ischemia reperfusion injury. METHODS: After goats were exsanguinated to lower mean arterial pressure to 48 mmHg, femoral vessels were occluded for 90 minutes to impose hindlimb ischemia. Lactate Ringer's (LR) or pyruvate Ringer's (PR) solution was infused from 30 minutes ischemia until 30 minutes reperfusion. Pro- and antiapoptotic proteins and injury markers were measured in gastrocnemius at 4 hours reperfusion. RESULTS: Pro-oxidant NADPH oxidase activity and nitrotyrosine content, a footprint of nitrosative stress, doubled, and poly (ADP-ribose) polymerase cleavage, an early apoptotic event, increased 80% in LR-resuscitated vs. sham muscle, but PR prevented these increases. Antiapoptotic Bcl-X(L) content fell in LR-treated vs. sham and PR-treated muscle. Water content increased in LR- but not PR-resuscitated muscle. CONCLUSIONS: LR resuscitation imposed oxido nitrosative stress and initiated proapoptotic mechanisms, while PR blunted these harmful consequences of muscle ischemia-reperfusion. PMID- 21265314 TI - Prevalence of late amputations during the current conflicts in Afghanistan and Iraq. AB - During the current conflicts, over 950 soldiers have sustained a combat-related amputation. The majority of these are acute, but an unknown number are performed months to years after the initial injury. The goal of this study is to determine the prevalence of late amputations in our combat wounded. Electronic medical records and radiographs of all soldiers who had a combat-related, lower extremity injury that resulted in amputation were reviewed to confirm demographic, injury, and amputation information. Time to amputation was defined as a late amputation when it occurred more than 12 weeks following the date of injury. There were 348 major limb amputees that met inclusion criteria. Fifty-three (15.2%) amputees had a late amputation (range = 12 wk-5.5 yr). While the majority of combat-related amputations occur acutely, more than 15% occur late. This study demonstrates that further research is needed to identify predictive factors and outcomes of the late amputation. PMID- 21265315 TI - The phantom limb experience and sensory phenomena in a relocated limb in a case of fillet flap used to reconstruct a massive wound proximal to an above-knee amputation. AB - A 41-year-old male sustained a massive crushing injury to his left posterior thigh and buttock and transection of the sciatic nerve; he underwent an above knee amputation with fillet flap. He was interviewed 24 months postoperatively to determine his phantom limb experience. At 37 and 42 months, testing for touch pressure sensitivity of the residual limb and buttock was done with a 1-gram monofilament. RESULTS: (1) He described a typical phantom limb with some unusual features. (2) Stimulation of points on transposed and original skin were located accurately or roughly according to normal anatomy, were mislocated, or felt simultaneously at the point stimulated and another place, i.e., bilocations. It is hypothesized that such mislocations and bilocations represented clinical correlates of cortical somatosensory reorganization. It is not clear why a typical phantom limb could occur when there was only partial deafferentation of the limb. Further studies are recommended. PMID- 21265316 TI - Ultrasound diagnosis of a patellar tendon rupture. AB - Many forward units are being deployed with portable ultrasound capability. We describe a case of a patient with a complete patellar tendon rupture that was diagnosed in the deployed environment using a portable ultrasound. Military physicians can benefit from sonographic evaluation of patients with musculoskeletal injuries in a deployed setting. The information they gain can assist them in giving better care to their patients and in making decisions on patient evacuation. PMID- 21265317 TI - Bicompartmental (medial and lateral) displaced bucket-handle meniscal tears with associated anterior cruciate ligament rupture. PMID- 21265318 TI - A political wish list. PMID- 21265320 TI - A whole lot of nothing. PMID- 21265319 TI - Diplomacy's meltdown. PMID- 21265321 TI - Curing the common cold. PMID- 21265322 TI - Don't worry about who's watching. PMID- 21265323 TI - Dawn of the deed. PMID- 21265324 TI - Space contact: the day after. PMID- 21265325 TI - Flu factories. PMID- 21265326 TI - In search of the radical solution. Interview by Mark Fischetti. PMID- 21265327 TI - Seeds of the Amazon. PMID- 21265328 TI - 100 trillion connections. PMID- 21265329 TI - Casualties of climate change. PMID- 21265330 TI - Rise of the robo scientists. PMID- 21265331 TI - Radioactive smoke. PMID- 21265332 TI - The science of right and wrong. Can data determine moral values? PMID- 21265333 TI - Commissioning a new era of primary care access. PMID- 21265334 TI - Today's job market? Bound to change. PMID- 21265335 TI - Do NPs & PAs really spend more time with patients? PMID- 21265336 TI - Inpatient diabetes management. Contributions of an NP-PA team. PMID- 21265337 TI - Common ground. Understanding NPs & PAs. PMID- 21265338 TI - 'Blue babies' lost. Managing adult congenital heart disease. PMID- 21265339 TI - Successful aging. Rooted in resilience. PMID- 21265340 TI - TTP's toll. Confronting a diagnostic challenge in the ED. PMID- 21265341 TI - The convenient care niche. Is it right for you? PMID- 21265342 TI - Historical reminiscence: origin of the Greenfield filter. AB - The Greenfield filter was the result of collaboration between a surgeon and a petroleum engineer. Originally it was a component of a catheter management approach to massive pulmonary embolism. Industry support allowed further technical improvements and long-term patient followup studies. PMID- 21265343 TI - The University of Washington Department of Surgery: training surgeons in the Pacific Northwest. AB - The General Surgery Residency Program at the University of Washington Affiliated Hospitals serves as the sole university training program in the Pacific Northwest, which encompasses a region representing nearly one-fourth of the United States land mass. We value our role to train excellent surgeons for the communities of the Northwest as well as mentor future leaders in academic surgery. The Department strives to stay on the leading edge of surgical education and continually seeks to improve the quality of the training program. We indeed feel fortunate to have the opportunity to train the best and brightest in one of the most exciting and rewarding professions in medicine. PMID- 21265344 TI - Single-incision laparoscopic placement of an adjustable gastric band versus conventional multiport laparoscopic gastric banding: a comparative study. AB - Single-incision laparoscopic surgery (SILS) is rapidly becoming the focal point of attraction for early adopters of minimally invasive surgery nationwide. Having achieved a rapid crossover to the realm of advanced surgical procedures, SILS has shown remarkable versatility and adaptability, making it no longer limited to basic laparoscopic procedures. We report our experience performing laparoscopic placement of gastric bands with an emphasis on comparison of the single-incision laparoscopic approach with the conventional multiport laparoscopic approach. From December 2008 to September 2009, 27 patients underwent laparoscopic placement of an adjustable gastric band at Michigan State University/Kalamazoo Center for Medical Studies. This included 15 patients who underwent single-incision laparoscopic gastric banding and 12 patients who underwent conventional multiport laparoscopic gastric banding procedures. The overall pain score was found to be significantly less in the SILS group than that for the conventional multiport laparoscopic gastric banding group with a statistically significant P value of 0.012. The operating time was found to be significantly less in the multiport group with a P value of 0.000. Differences in immediate postoperative pain scores, analgesia, and the overall length of hospital stay were found to be statistically insignificant. Single-incision laparoscopic gastric banding is associated with significantly less overall postoperative pain than the conventional laparoscopic approach; in addition, it provides improved cosmetic outcome despite a modest increase in operative time. PMID- 21265345 TI - The impact of facility volume/size on breast cancer treatment and outcome. AB - Recent studies have suggested that outcomes and survival from breast cancer are improved when definitive treatment is rendered at high-volume and/or teaching centers. Consolidation of such cases in tertiary centers, however, is often impractical and impossible. Patients often desire primary treatment of their breast cancer in their own communities. The current study was undertaken to examine the impact of treatment facility type on the treatment performed as well as on overall survival. Breast cancer treatment and survival data were available from the American College of Surgeons National Cancer Data Base. Only patients in whom no previous treatment had been rendered were included in the analysis. Data were stratified with regard to type and size of treatment facility/hospital; stage distribution; initial treatment performed; and 1-, 2-, and 5-year survival. A total of 665,409 patients were included in the current analysis. There were no significant differences in stage distribution between facility types nor was there a significant difference in the treatment performed (although there was a slight trend toward breast conservation at the larger centers). This was true overall and for each stage of cohort. There were also no significant differences in 1-, 2-, and 5-year survival rates overall and at any stage (although again, there was a slight trend toward a minimal survival advantage at the larger centers). There was no significant impact of facility size or type on either breast cancer treatment performed or overall survival. There was no evidence that more "advanced" treatments were offered at larger centers nor was there evidence of improved outcome/survival at larger centers. Care can be rendered safely, efficiently, and effectively in the community setting. PMID- 21265346 TI - Use of FDG-PET imaging for patients with disseminated cancer of the appendix. AB - The goal of this study is to evaluate the use of positron emission tomography (PET) in evaluation of patients with peritoneal dissemination of carcinoma of appendiceal origin (PDA). Thirty-three patients with PDA, who had preoperative PET or PET/CT imaging, were analyzed. Using operative, pathology, and PET +/- CT data, presence or absence of disease in each abdominal quadrant was noted and the use of 18fluoro-deoxy-glucose (FDG) PET for each quadrant was evaluated. The mean age was 52, and there were 17 males; 58 per cent had low-grade lesions. PET was positive in only 35 per cent of cases overall (30 and 41% sensitivity for low grade and high-grade, respectively). PET without CT sensitivity for low-grade and high-grade lesions was 21 and 8 per cent, respectively. PET imaging has limited use for patients with PDA. We do not recommend the use of FDG-PET for patients with PDA from cancer of the appendix. PMID- 21265347 TI - Loupe magnification reduces postoperative hypocalcemia after total thyroidectomy. AB - We aimed to evaluate the impact of loupe magnification (LM) on incidental parathyroid gland removal (from pathology reports), hypocalcemia, and recurrent laryngeal nerve (RLN) injury after total thyroidectomy and answer the question of whether this tool should be always recommended for patient's safety. Between January 2005 and December 2008, 126 patients underwent total thyroidectomy with routine use of 2.5 x galilean loupes; their charts were compared with data on 118 patients operated on between January 1997 and December 2000 without LM (two different equally skilled surgical teams operating in the two periods). LM decreased the rate of inadvertent parathyroid glands removal (3.8 vs 7.8% of total parathyroid glands; P = 0.01), as well as of biochemical (20.6 vs 33.9%; P = 0.028) and clinical (12.7 vs 33%; P = 0.0003) hypocalcemia after thyroidectomy. All cases (16 of 16) of symptomatic hypocalcaemia in the LM group proved to be associated with parathyroidectomy vs 76.9 per cent (30 of 39) without LM (P = 0.046). A trend toward decreased RLN injury rate, although statistically insignificant, was reported, being unilateral transient, unilateral permanent, and bilateral transient palsy rates 6.8, 2.5, and 1.7 per cent, respectively, without LM vs 4.8, 2.4, and 0.8 per cent, respectively, with LM (P = 0.69; P = 1, and P = 0.61, respectively). Our results do support the routine use of LM during total thyroidectomy. PMID- 21265348 TI - Do flexion extension plain films facilitate treatment after trauma? AB - We hypothesized that flexion extension (FE) films do not facilitate the diagnosis or treatment of ligamentous injury of the cervical spine after blunt trauma. From January 2000 to December 2008 we reviewed all patients who underwent FE films and compared five-view plain films (5 view) and cervical spine CTC with FE in the diagnosis of ligamentous injury. There were 22,929 patients with blunt trauma and of these, 271 patients underwent 303 FE films. Average age was 39.6 years, Injury Severity Score was 10.8, Glasgow Coma Score was 14.1, lactate was 2.6 mmol/L, and hospital length of stay was 6 days. Compared with FE, 5 view and CTC had a sensitivity of 80 per cent (8 of 10), positive predictive value of 47.1 per cent (8 of 17), specificity of 96.55 per cent (252 of 261), and negative predictive value of 99.21 per cent (252 of 254). For purposes of analysis, incomplete and ambiguous FE films were listed as negative; however, 20.5 per cent (62 of 303) were incomplete and 9.2 per cent (28 of 303) were ambiguous. Management did not change for the 2 patients with missed ligament injuries. The 303 studies cost $162,105.00 to obtain. FEs are often incomplete and unreliable making it difficult to use them to base management decisions. They do not facilitate treatment and may lead to increased cost and prolonged cervical collars. PMID- 21265349 TI - Thoracic esophageal perforations. AB - The authors review their experience with thoracic esophageal perforation at Inova Fairfax Hospital, June 1, 1988, to March 1, 2009. With the exception of 6 patients with occult perforation, all of whom survived with nonoperative therapy, aggressive surgical intervention was the standard approach. Among patients treated aggressively with surgery within 24 hours of perforation, hospital survival was 97 per cent versus 89 per cent for patients treated aggressively surgically after 24 hours. In the absence of phlegmon, implacable obstruction, or delay, primary repair resulted in 100 per cent survival. Where phlegmon or resolute obstruction existed, resection and reconstruction resulted in 96 per cent survival. Even when patients were deemed too ill to undergo surgery, cervical diversion was 100 per cent effective in eradicating continuing leak and achieved 89 per cent survival. Endoesophageal stenting was applied as primary treatment or secondarily such as where leak complicated primary repair. When stenting was used as the initial and primary treatment modality, survival was 88 per cent. Targeted drainage was helpful on occasion as an adjunct to initial therapies. Comfort measures alone were appropriate when clinical circumstances merited no effort at resuscitation. Finally, survivors were asked to self categorize their ability to swallow; 95 per cent responded good to excellent. PMID- 21265350 TI - Variations in perioperative steroid management among surgical subspecialists. AB - Previously we demonstrated consistency in perioperative steroid dosing among colon and rectal surgeons. To determine whether patterns have changed and if dosing schedules differ across surgical specialties, we evaluated multiple specialties. Questionnaires were mailed to members of the American Society of Colon and Rectal Surgeons (CRS) (n = 1523), American Society of Transplant Surgeons (TS) (n = 988), American Society of General Surgeons (GS) (n = 2750), and American Association of Endocrine Surgeons (ES) (n = 278). Surveys addressed demographic factors and factors in dosing, whether steroids are managed by surgeon alone or in collaboration with colleagues, and the most common taper regimens used. Four hundred fifty surveys were returned. Sixty-four respondents had retired or answered less than 50 per cent; 386 (211CRS, 116GS, 45TS, and 14ES) were available for analysis. The majority managed both perioperative (85.5%) and tapers (77%) themselves; TS and ES were significantly less likely to use other physicians (P < 0.001). The preoperative dose used most frequently was 100 mg hydrocortisone intravenously (76% CRS, 64% GS, 22% TS, and 93% ES). Most CRS (44.5%) and GS (24.1%) taper intravenous steroids over 3 days, whereas TS (33.3%) and ES (50%) return patients to prednisone within 1 to 2 days. Discharge steroid use was inconsistent with CRS (46.4%) tapering prednisone over greater than 21 days, GS (19%) over less than 21 days, and TS (20%) and ES (21.4%) taper over 21 days to preoperative prednisone doses (P < 0.001). In the absence of standard guidelines for perioperative corticosteroid administration, significant variations exist in the regimens used by surgeons in multiple specialties. PMID- 21265351 TI - Champ Lyons, Holt McDowell, and the evolution of vascular surgery at the University of Alabama at Birmingham: a personal perspective. AB - The history of medical centers, hospitals, clinics, and their evolution are important contributions and resources to medical history. Likewise, evolution of specialties within these healthcare centers frequently parallels their growth and development. This contribution depicts the evolution of a specialty, vascular surgery, within a major medical center, the University of Alabama at Birmingham. It recounts the major participants involved and their contributions and pioneering efforts, some of which have received little attention or were overshadowed by other events. Perspectives from participants--a patient and a trainee--provide insight into this process that has supported the growth and development of a major world-class medical center. PMID- 21265352 TI - Glucose metabolism, not obesity, predicts mortality in critically ill surgical patients. AB - Our hypothesis was to determine if insulin resistance and hyperglycemia, rather than obesity, are predictive of mortality in the surgically critically ill. An observational study of an automated protocol in surgical and trauma intensive care units was performed. Two groups were created based on body mass index (BMI): Obese (OB) defined as BMI > or = 30 (n = 338) and nonobese defined as BMI < 30 (n = 885). Euglycemia was maintained using an automated protocol using an adapting multiplier, which we used as our marker of stress insulin resistance. The primary outcome was hospital mortality. One thousand, two hundred and twenty-three patients met criteria with 73,225 glucose values. The OB group required more insulin (4.5 U/hr vs 3.2 U/hr, P < or = 0.01) and had a higher mean multiplier (0.07 vs 0.06, P < 0.01) reflecting insulin resistance. There was no difference in mortality between OB and nonobese (11.6% vs 11.5%, P = 0.96). Logistic regression showed that insulin dose (odds ratio 0.864; 95% confidence interval 0.772-0.967, P = 0.01), and not BMI, was an independent predictor of survival in this population. Obesity is not an independent risk factor for mortality in the surgical critical care population. Insulin resistance and subsequent hyperglycemia are increased in obesity and are independent predictors of mortality. PMID- 21265353 TI - A prospective randomized pilot study of near-infrared spectroscopy-directed restricted fluid therapy versus standard fluid therapy in patients undergoing elective colorectal surgery. AB - There are substantial data supporting the concept that algorithms that effectively limit fluid volumes to patients undergoing elective surgery, particularly intraoperatively, significantly reduce perioperative morbidity. We hypothesized that intraoperative fluid limitation could be safely accomplished when guided by near-infrared spectroscopy (NIRS) monitoring, and that this fluid restriction regimen would result in a reduction in postoperative morbidity when compared with standard monitoring and fluid therapy. The intent of this pilot study was to demonstrate the feasibility and ease of conduct of this study protocol before expanding to the multicenter pivotal trial. We performed a prospective, (2:1) randomized, pilot study at two centers. A total enrollment of 24 fully evaluable patients undergoing elective open colorectal surgery (16 restricted, 8 standard) was planned. After providing informed consent, patients were randomized to standard fluid resuscitation (500 LR induction bolus, then LR 7 mL/kg/h x 1 h, then 5 mL/kg/h) or restricted fluid resuscitation (no induction bolus, then LR 2 mL/kg/h). Subsequent fluid bolus infusions were guided by physiologic parameters (systolic blood pressure < 90 mm Hg, heart rate > 100 bpm, or oliguria) in the standard group, and by tissue oxygen saturation from NIRS (tissue oxygen saturation (StO2) < 75%, or 20% below baseline; or the same physiologic parameters) in the restricted group. Primary endpoints were major postoperative complications. A total of 27 patients were randomized (18 restricted, 9 standard). Age, gender, ethnicity, past medical history, and body mass index were similar. American Society of Anesthesiologists class was somewhat higher in the restricted group (American Society of Anesthesiologists class 3 in 77% of restricted vs 44% of standard patients; P = 0.194). Median total intraoperative fluids were less in the restricted group (1300 mL) when compared with the standard group (3014 mL) (P = 0.021). Total fluids for the hospitalization were also statistically significantly decreased in the restricted group. Complications occurred in about two-thirds of patients, and complication rates were not statistically different between groups (1.6/restricted patient vs 2.1/standard patient; P = 0.333). Primary indications for boluses (n = 93) given to study patients were: hypotension (69%); oliguria (15%); and tachycardia (14%), with multiple indications per bolus. In only two instances did the StO2 drop to less than 75 per cent, or decrease by 20 per cent from baseline in the 3 minutes before bolus as an indication for fluid administration. Patients undergoing elective colorectal surgery with a fluid restricted strategy had only rare episodes of decreased StO2, suggesting that adequate tissue perfusion was maintained in this group. As a result, NIRS monitoring did not significantly influence intraoperative fluid management of patients undergoing colorectal surgery. PMID- 21265354 TI - Can laparoscopic ileocolic resection be performed with comparable safety to open surgery for regional enteritis: data from National Surgical Quality Improvement Program. AB - Laparoscopic ileocolic resection is feasible for Crohn's disease but few studies adjust for the various preoperative, intraoperative, and postoperative variables that may confound comparisons with open surgery. The aim of this study is to compare outcomes after laparoscopic (LICR) and open ileocolic resection (OICR) performed for regional enteritis using National Surgical Quality Improvement Program (NSQIP) data. Retrospective evaluation of data prospectively accrued into the NSQIP database for patients undergoing ileocolic resection for Crohn's by LICR and OICR was performed. LICR (n = 104) and OICR (n = 203) groups had similar age (P = 0.1), body mass index (P = 0.9), smoking history (P = 0.6), steroid use (P = 0.7), diabetes (P = 0.3), serum albumin (P = 0.07), and American Society of Anesthesiologists class (P = 0.13). LICR group had more female patients (P = 0.005). Complications including surgical site infections (P = 0.5), wound dehiscence (P = 1), pneumonia (P = 0.1), deep vein thrombosis (P = 0.3), pulmonary embolism (P = 1), urinary infection (P = 0.1), and return to the operating room (P = 0.2) were similar. LICR had shorter length of hospital stay than OICR (P < 0.001). In current practice, as observed with the NSQIP data, LICR, performed by experienced surgeons, is comparable in safety to OICR and is associated with a shorter hospital stay. PMID- 21265355 TI - Breast cancer in the young patient. AB - Patients under 40 years of age comprise about 5 per cent of the overall breast cancer population. These patients are often considered to have a more aggressive disease and are often treated differently as well. A review was performed of all breast cancer patients reported in the American College of Surgeons Cancer Database from 1998 to 2005. The study cohort included all patients less than 40 years of age. Data collected included stage at time of diagnosis, histologic type, and initial treatment performed. These data were then compared with those of patients age 40 or older. The 70,437 cohort patients identified comprised 5.0 per cent of all breast cancer patients reported. There was a statistically significant difference in stage at the time of presentation: 20 per cent of younger patients presented with advanced disease (stage III or IV) versus 13.5 per cent of older patients. A significantly greater percentage of younger patients also presented with infiltrating ductal carcinoma as opposed to the older population (76.9% vs 67.9%). A significantly greater percentage of young patients was treated with mastectomy when compared with the older population (47.7% vs 36.7%, respectively). This difference persisted even when data were controlled for stage. The younger breast cancer patient presents with more advanced disease, suggesting either a more aggressive disease or a greater delay in diagnosis. Also, at all stages, the young patient tends to be treated more "aggressively" surgically, suggesting that the prevailing concept that breast cancer is a "worse" disease in the young may be directing treatment options and patient choices. PMID- 21265356 TI - Trauma team activation can be tailored by prehospital criteria. AB - A two phase prospective study was carried out at a regional Level I trauma center over 1 year. Phase I involved collecting observational data to determine which trauma criteria could potentially be used to identify patients that could be evaluated by a lower level trauma activation (category-3). A category-3 involved a smaller response team with priority access to imaging. Phase II involved implementing this third tier activation system and prospectively evaluating the outcomes related to resources and patient care. A total of 3104 patients were evaluated with 2076 patients in phase I and 1037 in phase II. Three commonly identified activation criteria out of the 36 studied were not associated with admission. These criteria were pedestrian struck by vehicle, high speed vehicular crash, and Glasgow Coma Score 12-14. These criteria were then used as triggers for a category-3 activation in phase II. Comparisons of patients with these three identified criteria between phase I and II demonstrated that significantly fewer patients were admitted, charges were reduced, emergency department times were similar, and less man-power hours were needed in phase II. The utilization of a third tiered activation system resulted in a decrease utilization of many resources without sacrificing patient care. PMID- 21265357 TI - Clinical outcome at ten years after laparoscopic fundoplication: Nissen versus Toupet. AB - Laparoscopic surgery has become the elective approach for the surgical treatment of gastroesophageal reflux disease in the last decade. Outcome data beyond 10 years are available for open fundoplication, with good-to-excellent results, but few studies report long-term follow-up after laparoscopic fundoplication. We performed a retrospective study of all the patients that underwent laparoscopic Nissen and Toupet fundoplications as antireflux surgery between 1995 and 1998 in our institution. To evaluate the long-term results, a face-to-face interview was performed in 2009. One hundred and six patients were included in the study. Surgical techniques performed were Nissen fundoplication (NF) in 56 patients and Toupet (TF) in 50. Complication rate was 4 per cent in both groups (nonsignificant [NS]). Two patients (4%) of NF required reoperation because of dysphagia. After 10 years, 10 per cent of the patients remain symptomatic in both groups. Fifteen per cent of NF take daily inhibitors of the proton pump versus 14 per cent of TF (NS). Twenty per cent of NF refer dysphagia, all of them without evidence of stenosis at endoscopy or contrasted studies. The satisfaction rate of the patients was 96 per cent in NF and 98 per cent in TF. Laparoscopic Toupet fundoplication seems to be as safe and long-term effective as Nissen, but with a lower incidence of postoperative dysphagia. In our experience Toupet fundoplication should be the elective approach for the surgical treatment of gastroesophageal reflux disease. PMID- 21265358 TI - Does prophylactic subcutaneous heparin increase the risk of wound infection after colorectal surgery? AB - Chemical prophylaxis using unfractionated heparin (UH) and low-molecular weight heparin is used in surgical patients to prevent venous thromboembolism. There is some evidence that prophylactic doses of heparin may increase the rate of surgical site infection (SSI) after elective orthopedic procedures. Little is known regarding the effect of heparin on SSI after colorectal procedures. We performed this study to study the effect of prophylactic unfractionated heparin on the rate of SSI after colorectal procedures. We did a retrospective analysis of 155 consecutive cases of patients of a single colorectal surgeon who underwent colorectal resection. Subcutaneous unfractionated heparin was given to 52 patients (29%). The rate of SSI in the group that received UH was 33 per cent versus 28 per cent in the group that did not receive UH (P = 0.31). There was also no significant effect of prophylactic heparin on SSI noted among any patient subgroup. The use of prophylactic unfractionated heparin after colorectal procedures does not seem to increase the rate of surgical site infection. PMID- 21265359 TI - Spontaneous rupture of hepatic artery aneurysm associated with polyarteritis nodosa. AB - Polyarteritis nodosa (PAN) is a vasculitis, which often involves small and medium sized visceral arteries. This condition may result in multifocal aneurismal formation and end-organ damage. Uncommonly, PAN may present with rupture of hepatic artery aneurysms. Here, we report a rare case of a ruptured intrahepatic aneurysm associated with PAN. A 79-year-old woman presenting with abdominal pain had CT scan of the abdomen, which revealed hematoma in the right hepatic lobe. Visceral angiogram confirmed pseudo-aneurysm of a right hepatic arterial branch, and this was managed with endovascular coil embolization. The diagnosis of PAN was made and corticosteroid therapy was initiated. We also performed a literature review to define this condition's demographics, clinical presentations, and appropriate management. The review revealed 17 published cases of ruptured PAN related intrahepatic aneurysms. We conclude that unexplained findings of visceral arterial aneurysms should prompt investigations for vasculitis as the etiology. PMID- 21265360 TI - Treatment for incisional parapubic hernia: an experience of 25 cases. AB - We retrospectively studied the clinical manifestation, diagnosis, treatment, and therapeutic effect in 25 cases of incisional parapubic hernia. We believe that it is necessary for patients with recurrent hernia to undergo CT detection; the mesh patch should be adequately large, and must be doubly fixed before and after the pubic bone. Sublay and intraperitoneal onlay mesh technique both can obtain good therapeutic effects for incisional parapubic hernia. PMID- 21265361 TI - Sentinel lymph node surgery for staging of breast carcinoma in patients with lymphoproliferative disease. AB - There are few reports confirming the validity of sentinel lymph biopsy in patients with a background of lymphoproliferative disease. We reviewed nine cases of women who underwent sentinel lymph node (SLN) surgery for staging of primary breast cancer with a diagnosis of lymphoproliferative disease. SLN identification rate was 100 per cent with a background of lymphoma in the sentinel node in eight of the nine patients. With a mean follow-up of 37 months, there have been no axillary recurrences in any of these patients. These cases illustrate that SLN staging is feasible and provides axillary staging information in women with breast cancer despite synchronous lymphoproliferative disease. PMID- 21265362 TI - Response to: Laparoscopic cholecystectomy is safe and effective for the treatment of biliary dyskinesia in the pediatric population. PMID- 21265363 TI - Abdominal wall pseudocyst fluid collection: a complication of pancreatic pseudocyst. PMID- 21265364 TI - Extreme high serum level of carbohydrate antigen 19-9 in a patient with a single biliary stone. PMID- 21265365 TI - Aberrant right subclavian artery-esophageal fistula. PMID- 21265366 TI - Abdominal cystic lymphangiomatosis. PMID- 21265367 TI - Duodenobronchial fistula arising from a necrotizing liver metastasis of right colon cancer after systemic chemotherapy. PMID- 21265368 TI - Acute abdomen with free air under the diaphragm after coitus: a review of the literature. PMID- 21265369 TI - Laparoscopic-assisted double percutaneous endoscopic gastrostomy technique for high-risk patients with paraesophageal hernia. PMID- 21265370 TI - Right hepatectomy extended to segment I and pancreatoduodenectomy in the same surgical act for pancreatic neuroendocrine tumor with liver metastases. PMID- 21265371 TI - Retroperitoneal extraskeletal osteosarcomas. PMID- 21265373 TI - Laparoscopic Nissen fundoplication in a patient with situs inversus totalis? PMID- 21265372 TI - A new two-stage esophagectomy followed by pancreaticoduodenectomy. PMID- 21265374 TI - Intestinal strangulation resulting from herniation 'into' the greater omentum. PMID- 21265375 TI - Gastric elastofibroma. PMID- 21265376 TI - 'Case management's day': Health care reform focus proves CMs' importance. PMID- 21265377 TI - Medicaid RACs coming your way in April. PMID- 21265378 TI - Rounds cut LOS, improve patient satisfaction. PMID- 21265379 TI - Department redesign leads to cuts in LOS, readmissions. PMID- 21265380 TI - CM redesign proactive approach to reform. PMID- 21265381 TI - Patient ed affects patient satisfaction. PMID- 21265382 TI - CM in the home reduces ED, inpatient visits. PMID- 21265383 TI - Accountable care organizations in 'very early stages' of growth. AB - 'Triple Aim' is at the heart of several ACO initiatives. All aims must be valued equally and concurrently. ACOs will look different in various locations, populations. PMID- 21265384 TI - Wrong-site, wrong-patient surgeries persist. AB - Communication errors cited in 100% of cases. Carrots and sticks' needed to engender cultural change. Staff members must be mentally engaged and accept accountability. PMID- 21265385 TI - Motivate patients to stop smoking. AB - The Cleveland (OH) Clinic study results show that smokers have significantly more complications post-surgery than non-smokers, including a higher death rate. Since Aug. 25, 2010, Medicare has reimbursed physicians who provide counseling for outpatients and hospitalized patients to prevent tobacco use. The ASA encourages anesthesiologists to ask all patients about their tobacco use, advise those who do use to stop, and refer patients to other resources that can get them the assistance, such as the toll-free number (800) QUIT NOW. PMID- 21265386 TI - TJC looks at caregiver communications. PMID- 21265387 TI - Alert fatigue leads to OR fatalities. PMID- 21265388 TI - Cancer breakthrough pain in the presence of cancer-related chronic pain: fact versus perceptions of health-care providers and patients. AB - Cancer breakthrough pain is a flare in pain that "breaks through" well-controlled persistent cancer pain. Although the condition is highly prevalent, the concept of cancer breakthrough pain is not well understood and is therefore underdiagnosed and undertreated. The purpose of this review is to examine the roles the health-care practitioner and patient/family caregiver play in the undertreatment of breakthrough pain. A lack of technical knowledge about pain management and pain assessment, attitudes about opioid addiction, and regulatory guidelines influence the manner in which opioids are prescribed. Patients harbor a variety of fears and misconceptions, such as opioid addiction, tolerance, side effects, and the meaning of pain, which can create a barrier to effective communication with their health-care provider regarding their cancer pain management and specifically their breakthrough pain. Identifying these issues gives health-care professionals and patients an opportunity to develop strategies that can improve the treatment of cancer breakthrough pain. PMID- 21265389 TI - The challenges of treating patients with cancer pain. PMID- 21265390 TI - A conceptual solution to improve the management of cancer-related breakthrough pain. PMID- 21265391 TI - Cost-utility analysis of palonosetron-based therapy in preventing emesis among breast cancer patients. AB - We estimated the cost-utility of palonosetron-based therapy compared with generic ondansetron-based therapy throughout four cycles of anthracycline and cyclophosphamide for treating women with breast cancer. We developed a Markov model comparing six strategies in which ondansetron and palonosetron are combined with either dexamethasone alone, dexamethasone plus aprepitant following emesis, or dexamethasone plus aprepitant up front. Data on the effectiveness of antiemetics and emesis-related utility were obtained from published sources. Relative to the ondansetron-based two-drug therapy, the incremental cost effectiveness ratios for the palonosetron-based regimens were $115,490/quality adjusted life years (QALY) for the two-drug strategy, $199,375/QALY for the two drug regimen plus aprepitant after emesis, and $200,526/QALY for the three-drug strategy. In sensitivity analysis, using the $100,000/QALY benchmark, the palonosetron-based two-drug strategy and the two-drug regimen plus aprepitant following emesis were shown to be cost-effective in 39% and 26% of the Monte Carlo simulations, respectively, and with changes in values for the effectiveness of antiemetics and the rate of hospitalization. The cost-utility of palonosetron based therapy exceeds the $100,000/QALY threshold. Future research incorporating the price structure of all antiemetics following ondansetron's recent patent expiration is needed. PMID- 21265392 TI - Pilot study of the prospective identification of changes in cognitive function during chemotherapy treatment for advanced ovarian cancer. AB - Change in cognitive function is increasingly being recognized as an adverse outcome related to chemotherapy treatment. These changes need not be severe to impact patient functional ability and quality of life. The primary goal of this study was to determine if there is evidence of changes in the cognitive function domains of attention, processing speed, and response time among women with newly diagnosed advanced ovarian cancer who receive chemotherapy. Eligible patients were women diagnosed with stage III-IV epithelial ovarian or primary peritoneal cancer who had not yet received chemotherapy but who were prescribed a minimum of six cycles (courses) of chemotherapy treatment. Cognitive function was assessed by a computerized, Web-based assessment (attention, processing speed, and reaction time) and by patient self-report. Cognitive function was assessed at three time points: prior to the first course (baseline), course three, and course six. Medical records were reviewed to abstract information on chemotherapy treatment, concomitant medications, and blood test results (e.g., hemoglobin, CA 125). Of the 27 eligible participants, 92% and 86% demonstrated cognitive impairments from baseline to course three and from baseline to course six of chemotherapy, respectively. Impairment was detected in two or more cognitive domains among 48% (12 of 25) and 41% (9 of 22) of participants at course three and course six of chemotherapy, respectively. This study shows evidence of decline in cognitive function among women being treated for ovarian cancer. There is a need for additional, prospective research to better understand the impact of chemotherapy on cognitive function among ovarian cancer patients so that effective preventive and treatment strategies can be developed. PMID- 21265393 TI - Retrospective analysis of communication with patients undergoing radiological breast biopsy. AB - This study explored the perceptions of women after receiving breast biopsy results over the phone in order to determine patient preferences about the timing, setting, and provider they preferred when receiving biopsy results. Participants were recruited at a large university cancer center and surveyed by phone approximately 2 weeks after they received biopsy results. A 24-item survey was developed concerning how the biopsy results were communicated, the communication skills of the person reporting the diagnosis, and ways to improve the communication of results. The survey also asked about the relative importance of hearing the results quickly, from the most knowledgeable provider, from a primary care physician, or in person. We surveyed 59 patients (25 cancer, 34 benign). Patients from both groups were satisfied with the communication skills of the person who gave the results. However, patients with cancer and patients undergoing their first breast biopsy were more likely to need additional materials to understand their results (P = 0.018, P = 0.036, respectively). Both cancer and benign groups ranked hearing the results quickly as the most important aspect of communication and hearing the results in person as least important. This study suggests that patients value hearing cancer diagnoses quickly more than in person. Patients having their first biopsy or with a diagnosis of cancer would prefer to have additional materials to help them understand their diagnosis. PMID- 21265394 TI - Therapeutic failure: the elephant in the room. PMID- 21265395 TI - Acneiform rash as a reaction to radiotherapy in a breast cancer patient. PMID- 21265396 TI - Efficacy and safety of influenza vaccination during chemotherapy treatment. PMID- 21265397 TI - Hypovolemic shock due to giant uterus leiomyoma detachment. AB - Uterine leiomyoma (UL) is the most common benign gynecologic tumor of the reproductive age females. It is symptomatic only in 25% of the patients causing dysmenorrhea, menorrhagia or anemia. In some patients it occurs just as a palpable abdominal mass. In this study, we report a 50-year-old woman with a giant mass, attached to the uterus, which was detached and therefore led to shock due to major hemorrhage. Surgical removal of both the mass and the uterus confirmed the diagnosis of a pedunculated uterine leiomyoma. PMID- 21265398 TI - Record high for U.K. organ transplants. PMID- 21265399 TI - Hospital care failing elderly patients, new report from a national enquiry reveals. PMID- 21265400 TI - Audio-visual distraction during spinal anaesthesia for orthopaedic surgery. AB - Spinal anaesthesia is an effective method of delivering anaesthesia for primary total knee replacement. A regional technique has several benefits over an opioid based general anaesthetic (Fischer 2009) (Figure 1). Pre-medication and sedation is commonly used as an adjunct to create anxiolysis and reduce stress which could be provoked by being awake in the theatre environment. However, sedation is not without its disadvantages (Absalom & Adapa 2007) (Figure 2). PMID- 21265401 TI - Advanced trauma life support radiographic trauma series: part 2--the chest radiograph. AB - The chest radiograph is used as a screening test to exclude significant thoracic injuries in cases of major trauma. A systematic approach to reviewing chest radiographs is necessary for accurate interpretation. Radiographic findings should be considered together with clinical assessment. PMID- 21265402 TI - Blood conservation in cardiac surgery. AB - Cardiac surgery is one of the largest users of blood and blood products- currently estimated at 15% of U.K. blood stocks. While the blood supply could be considered to be the safest it has ever been, there are well recognised risks associated with the transfusion of red cells and blood products. It is appropriate that attempts should be made to decrease and optimise the transfusion of blood and blood products. PMID- 21265403 TI - Needlestick an sharps injuries among theatre care professionals. AB - Health care professionals are exposed to blood and other body fluids in the course of their work: (Al-Benna et al 2008). The World Health Organisation (2003) estimates that 9% of the 35 million healthcare professionals worldwide will experience percutaneous exposure to bloodborne pathogens each year (WHO 2003). In the U.K. about 100,000 sharps injuries occur in NHS hospitals each year (Trim & Elliott 2003). This is 17% of all accidents involving NHS staff (NAO 2003). Four percent of NHS staff sustain from 1 to 6.2 sharps injuries each year. These injuries occur mainly in clinical areas such as wards and theatres, but also in non-clinical areas due to accidental handling of inappropriately discarded sharps (Trim & Elliott 2003, Waterson 2004). Percutaneous injuries involving hollowbore needles remain the most commonly reported occupational exposures in the healthcare setting (HPA 2010). Consequently, workers are at risk of infection with bloodborne viruses including human immunodeficiency virus, hepatitis B virus, hepatitis C virus and bacterial infections (Al-Benna et al 2008). PMID- 21265404 TI - 'The price of everything and the value of nothing': cost awareness in anaesthesia. AB - Cost awareness for the drugs and disposables commonly used by anaesthetic staff has previously been poor. In our study, fifty anaesthetic staff were asked to estimate the cost of thirty-three commonly used drugs and disposables. Expensive items were consistently underestimated whereas inexpensive items were consistently overestimated. There was no overall correlation between the number of years of anaesthetic experience and cost awareness. These findings demonstrate poor knowledge regarding the cost of drugs and consumables amongst anaesthetic staff. PMID- 21265405 TI - The early days of appendicectomy. AB - I suppose the commonest abdominal emergency operation performed throughout most of the world today is an appendicectomy--usually through an abdominal incision of various shapes and now, increasingly, by laparoscopic surgery. The results are excellent, with a low morbidity and tiny mortality. Indeed, in my own experience of 40 years of surgery, (1948 to 1989), there was not a single death in the various units that I worked on, although we had some fairly hairy near-misses among patients with advanced peritonitis at the time of their surgery. PMID- 21265406 TI - Confessions of an aging athlete. PMID- 21265407 TI - Just surviving is not the point. PMID- 21265408 TI - Making hockey safer. PMID- 21265409 TI - Medicine on the sidelines. PMID- 21265410 TI - Spin doctor. PMID- 21265411 TI - The straight dope. PMID- 21265412 TI - When in doubt, sit them out. PMID- 21265413 TI - MMA ramps up efforts on Medicare payments. PMID- 21265414 TI - Working with the teenaged athlete: A conversation with Joel Boyd, M.D. Interviewed by Carmen Peota and Megan Reams. PMID- 21265415 TI - Never too old to play. PMID- 21265416 TI - What we need to do to really reform health care. PMID- 21265417 TI - Athletes and asthma. AB - Many Minnesotans with asthma participate in recreational and competitive sports. If asthma is undiagnosed or if it is poorly controlled, its symptoms can compromise health, impair athletic performance, and limit sports participation. It can even lead to death. Asthma-related deaths during sports participation, while not common, have occurred in Minnesota. Having asthma should not limit an athlete's ability to compete and win at the highest levels of competition. This article briefly reviews asthma and exercise-induced bronchoconstriction, discusses the impact of asthma on sports participation and outlines asthma management strategies for team physicians, coaches, and athletic trainers. PMID- 21265418 TI - Shoulder pain: a common-but-challenging problem. AB - Although shoulder pain is a common complaint among patients presenting to primary care physicians, many clinicians are unfamiliar with how to diagnose and treat many shoulder ailments. This article reviews the basic approach to diagnosis and management of shoulder pain in adult patients. PMID- 21265419 TI - Therapeutic musculoskeletal injection: what is current practice? What is the evidence? AB - Physicians are encountering an increasing number of patients with musculoskeletal injuries and conditions. Although conservative approaches such as rest, ice, elevation, analgesic medications, and therapeutic exercise are usually the first line of treatment, they do not provide relief for some patients. For those patients, injectable agents may be useful in relieving pain and promoting healing. This article describes older and newer injectable agents and reviews the evidence regarding their use and effectiveness. PMID- 21265420 TI - Certified athletic trainers. AB - Certified athletic trainers optimize people's ability to participate in athletics or activities of work and life. Athletic training encompasses the prevention, examination and assessment, treatment, and rehabilitation of emergent, acute, subacute, and chronic neuromusculoskeletal conditions. Certified athletic trainers play a key role in health care delivery today, and that role is expected to evolve and grow in the future. This article describes what certified athletic trainers do, outlines their educational and certification requirements, and describes the ways they work in different settings-from the sidelines to industry to medical clinics. PMID- 21265421 TI - Traumatic brain injury: football, warfare, and long-term effects. AB - Public awareness of the consequences of traumatic brain injury caused by participation in sports, vehicular crashes, and modern warfare has increased in recent years. This article describes what is currently understood about the pathogenesis of traumatic brain injury and goals for research that could lead to better understanding. PMID- 21265422 TI - Marathon man. PMID- 21265423 TI - Trends in healthcare. How reform will reshape the hospital environment. PMID- 21265424 TI - A new era. Hospitals brace for safety and efficiency push. PMID- 21265425 TI - Holding steady. Construction professionals look to deliver technology and operational gains. PMID- 21265426 TI - Going greener. Hospitals continue to make sustainability a priority. PMID- 21265427 TI - Cleaning evaluation pays. New rewards coming for reducing HAIs. PMID- 21265428 TI - Transforming purchasing. Expect sharp focus on comparative effectiveness. PMID- 21265429 TI - Electrical expectations. What the new NEC means for hospitals. PMID- 21265430 TI - Critical competencies. Taking the lead in HAI-prevention training. PMID- 21265431 TI - Soothing solace. PMID- 21265432 TI - Extrusion-mixing compared with hand-mixing of polyether impression materials? AB - The hypotheses tested were two-fold (a) whether altering the base:catalyst ratio influences working time, elastic recovery and strain in compression properties of a hand-mixed polyether impression material and (b) whether an extrusion-mixed polyether impression material would have a significant advantage over a hand mixed polyether impression material mixed to the optimum base:catalyst ratio. The polyether was hand-mixed at the optimum (manufacturers recommended) base:catalyst ratios (7:1) and further groups were made by increasing or decreasing the catalyst length by 25%. Additionally specimens were also made from an extrusion mixed polyether impression material and compared with the optimum hand-mixed base:catalyst ratio. A penetrometer assembly was used to measure the working time (n=5). Five cylindrical specimens for each hand-mixed and extrusion mixed group investigated were employed for elastic recovery and strain in compression testing. Hand-mixing polyether impression materials with 25% more catalyst than that recommended significantly decreased the working time while hand-mixing with 25% less catalyst than that recommended significantly increased the strain in compression. The extrusion-mixed polyether impression material provided similar working time, elastic recovery and strain in compression to the hand-mixed polyether mixed at the optimum base:catalyst ratio. PMID- 21265433 TI - Crown retention for non-retentive preparations using adhesive resin cements. AB - This study examines the effect of preparing teeth with six varying convergence angles (ranging between 12 and 120 degrees) and height (1 and 2 mm) on the retention of cast gold crowns. Six groups of 4 human premolar teeth were prepared to give a flat occlusal surface in dentine with very short axial wall heights (1 or 2 mm) and variation in axial wall convergence (between 12 and 120 degrees). Impressions were recorded of the prepared teeth and custom castings made using a high copper content precious metal alloy. The castings were luted with an adhesive resin and stored in water at 37 degrees C for 24 hours prior to determining the pull-off force in an Instron Universal testing Machine at a cross head speed of 1mm min(-1). Twenty two of the twenty four tested specimens failed within the dentine of the tooth, irrespective of preparation orientation. Statistical testing using ANOVA demonstrated that there were no differences between the bond strength values for any of the preparation convergence angles or between preparations with 1 and 2 mm axial wall heights. This suggests that attachment strength of adhesively bonded castings with minimal axial wall height preparations is not influenced by the convergence angle of the preparation. The attachment strength exceeded that cohesive strength of the underlying dentine in nearly all of the adhesively luted restorations. PMID- 21265434 TI - The relationship between fibre post geometry and flexural properties: an assessment through a modified three-point bending test. AB - The aim of this study was to investigate the flexural properties of five types of fiber-reinforced dowels using a modified three-point bending test. Fiber reinforced resin dowels were tested by a modified three-point bending test associated with models for cylindrical and conical simple-supported beams. The fracture load ranged from 86 to 246 N and the flexural strength from 423 to 1192 MPa. FRC Postec had significantly higher flexural strength and fracture loads values. Thus, the present study demonstrated higher flexural strength values for the FRC Postec fibre posts, suggesting that this system would present a better response to the forces of mastication. PMID- 21265435 TI - Dimensional stability of newer alginate impression materials over seven days. AB - The aim of this study was to determine the dimensional stability of the so called '5 day stable' alginates. Ten specimens each of three alginate materials were prepared using a standardised impression technique and a typodont model. Travelling microscope measurements were recorded for six distances at 24 hour intervals. SEM and EDX analysis was undertaken. Changes in dimension over time and differences between materials were tested using analysis of variance. 95% confidence intervals were calculated for the percentage change for comparison with a target of 1.5% based on the ISO Standard. Statistically significant dimensional changes were observed in some measured distances for all materials, but only six out of fifty four distances measured at 1, 5 and 7 days in three materials showed 95% confidence intervals that included the 1.5% ISO standard. There were no statistically significant differences in the proportional change between the three materials. The three materials showed similar appearance under SEM and similar composition by EDX analysis. It is concluded that all materials demonstrated good dimensional stability over the recommended maximum of 5 days. PMID- 21265436 TI - Repeatability of electronic shade determination and the influence of differences in patient's sitting position. AB - The aim of the study was to assess the repeatability of shade determination of teeth by a spectrophotometer. Additionally, the influence of different sitting positions on the shade determination was evaluated. Two operators measured the shade of an incisor and a premolar of 24 subjects sitting in three different positions. 18 participants were measured twice. The shade was determined in three areas on each tooth; cervical, central and incisal. Intra- and inter-operator repeatability was calculated and the variance between sitting positions analysed. The results had low to moderate intra- and inter-operator repeatability. The patient's sitting position affected the shade determination. PMID- 21265437 TI - Surface characteristic changes of dental ceramics after cyclic immersion in acidic agents and titratable acidity. AB - The potential erosive effect of acidic food, sour fruits and drinks on all ceramic restorations used in dentistry has not been clearly documented. Surface characteristic changes have been evaluated and compared for disc-shaped specimens (diameter 12.0 mm and thickness 2.0 mm) of fluorapatite-leucite and fluorapatite ceramics using various storage agents (deionized water, citrate buffer solution, pineapple juice, green mango juice, cola soft drink and 4% acetic acid). Immersion in pineapple juice, green mango juice, cola soft drink and 4% acetic acid for 16 hours produce significant increases in surface roughness for both types of ceramics investigated. PMID- 21265438 TI - Evaluation of bonding behavior of silver-tin-zinc-indium alloy to adhesive luting cements. AB - The bond strengths of a silver-tin-zinc-indium alloy used with adhesive luting cements were investigated. The metal surfaces were primed with two metal conditioners designed for noble metal alloys or base metal alloys, or prepared using a Rocatec tribochemical coating unit. Two adhesive luting cements (Super Bond C&B and Panavia F 2.0) were applied. It can be concluded that airborne particle abrasion with alumina was effective, but the effects on the bond durability of both the metal conditioners and the tribochemical silica coating method were not clear Such bonding behavior seems to be particular to this kind of silver-rich dental casting alloy. PMID- 21265439 TI - Energy absorption and hardness of chair-side denture soft lining materials. AB - The purpose of this study was to evaluate the hardness and energy absorption properties of four commercially available chairside silicone denture soft lining materials and to compare their properties with those of a heat-polymerized silicone denture liner. The denture lining materials investigated were four auto polymerising silicone soft liners (GC Reline Soft, Ufigel SC, Elite Soft Relining and Tokuyama Sofreliner S) and a heat-polymerised silicone liner (Molloplast B). The soft liners were processed according to manufacturers' instructions. The specimens for hardness testing were 38 x 38 x 3 mm. The specimens for energy absorption test were 10 x 10 x 3 mm. In each test ten samples of each material were tested. There was strong evidence that Tokuyama Sofreliner S and, to a lesser extent, Ufigel SC, were less stiff and more resilient than Molloplast B. There was also strong evidence that both GC Reline Soft and Elite Soft Relining were harder than Molloplast B, while Ufigel SC and Tokuyama Sofreliner S were softer In conclusion differences existed between hardness and energy absorption properties of the soft lining materials. PMID- 21265440 TI - Emotional intelligence in panic disorder. AB - Panic attacks are psychopathological phenomena with a strong emotional activation that often induces subsequent anticipatory anxiety and phobic avoidance. Impairment in emotional processing in patients with Panic Disorder (PD) has been hypothesized. Emotional Intelligence (EI) involves the individual abilities to perceive, understand and manage emotions in order to cope with changes in internal and external environment. We examined EI in 42 patients with PD with Agoraphobia compared to 49 healthy controls and investigated if clinical severity of Agoraphobia is related to EI performance. We assessed EI by Mayer-Salovey Caruso Emotional Intelligence Test and Agoraphobia by Mobility Inventory for Agoraphobia. Patients with PD and Agoraphobia showed lower Strategic EI ability than healthy controls, in both Understanding and Managing emotion abilities, and a general propensity to attribute negative emotional valence to different stimuli. These preliminary results suggest that impaired mechanisms of understanding and integrating emotions may be involved in the phenomenology of PD. These features might be the target of psychological interventions in PD. On the contrary, Emotional Intelligence did not appear to affect the clinical severity of Agoraphobia. PMID- 21265441 TI - Seabird islands take mere decades to recover following rat eradication. AB - Islands house a majority of the world's biodiversity and are thus critical for biodiversity conservation. Seabird nesting colonies provide nutrients that are integral to maintain island biodiversity and ecosystem function. Invasive rats destroy seabird colonies and thus the island ecosystems that depend on seabird derived nutrients. After rat eradication, it is unclear how long ecosystem recovery may take, although some speculate on the order of centuries. I looked at ecosystem recovery along a chronosequence of islands that had 12-22 years to recover following rat eradication. I show that soil, plant, and spider marine derived nitrogen levels and C:N ratios take mere decades to recover even after centuries-long rat invasion. Moreover, active seabird restoration could speed recovery even further, giving much hope to quickly conserve many endemic species on islands worldwide. PMID- 21265442 TI - Predicting effects of hydrologic alteration and climate change on ecosystem metabolism in a western U.S. river. AB - We estimated past and future hydrographs and patterns of ecosystem metabolism in a fifth-order river of the western United States, where water use and climate change are both expected to alter hydrology in the immediate future. We first reconstructed the unregulated hydrograph to estimate how the current hydrograph has been altered. Due to consumptive use, 95% as irrigation, current discharge during summer (July-September) was 70% lower than would occur if the river was unregulated. We then predicted a future hydrograph including effects of consumptive use and climate change; the magnitude of flow changes were minor under this regime relative to those already manifested by consumptive uses. We used time-series regression and a six-year continuous record of open-water metabolism to demonstrate that, under the current hydrologic regime, gross primary production (GPP) was dependent on both water temperature and flow and that ecosystem respiration (ER) was most dependent on temperature. Monte Carlo simulations under the three hydrologic regimes and three temperature scenario's (current, +2 degrees C, +4 degrees C) suggested that flow, but not temperature, may have profound effects on the magnitude of metabolism. Linking temporally detailed analyses of ecological function and hydrology may lead to better understanding and management of changes due to basin-scale water use and/or global-scale climate change. PMID- 21265443 TI - Blinded by the stink: Nutrient enrichment impairs the perception of predation risk by freshwater snails. AB - The acquisition of sensory information is central to all species interactions. Most aquatic organisms use chemical cues to assess predation risk and other key ecological factors, but chemoreception may be disrupted in systems with elevated pH. Elevated pH in lakes and rivers is often associated with eutrophication. We used laboratory and mesocosm experiments to test whether elevated pH impairs perception of predation risk by the freshwater snails Physa acuta and Helisoma trivolvis. In one set of experiments, nutrients were added to outdoor mesocosms, resulting in mid-afternoon pH values of 8.5-9.7. Both snail species moved to avoid fish in water with pH < 9.0 but showed no avoidance at higher pH. In a laboratory study, we used buffers to establish six pH treatments ranging from 7.5 to 10.0. At lower pH Physa acuta responded to fish cues by moving into safer habitats, but avoidance became impaired at a pH of 9.4. Helisoma trivolvis also responded to fish at lower pH, and their avoidance behavior became impaired at a pH of 8.8. Given the diversity of aquatic organisms that depend on reception of chemical cues and the broad extent of eutrophication, chemosensory impairment is likely a common occurrence in nature. PMID- 21265444 TI - Impact of logging on aboveground biomass stocks in lowland rain forest, Papua New Guinea. AB - Greenhouse-gas emissions resulting from logging are poorly quantified across the tropics. There is a need for robust measurement of rain forest biomass and the impacts of logging from which carbon losses can be reliably estimated at regional and global scales. We used a modified Bitterlich plotless technique to measure aboveground live biomass at six unlogged and six logged rain forest areas (coupes) across two approximately 3000-ha regions at the Makapa concession in lowland Papua New Guinea. "Reduced-impact logging" is practiced at Makapa. We found the mean unlogged aboveground biomass in the two regions to be 192.96 +/- 4.44 Mg/ha and 252.92 +/- 7.00 Mg/ha (mean +/- SE), which was reduced by logging to 146.92 +/- 4.58 Mg/ha and 158.84 +/- 4.16, respectively. Killed biomass was not a fixed proportion, but varied with unlogged biomass, with 24% killed in the lower-biomass region, and 37% in the higher-biomass region. Across the two regions logging resulted in a mean aboveground carbon loss of 35 +/- 2.8 Mg/ha. The plotless technique proved efficient at estimating mean aboveground biomass and logging damage. We conclude that substantial bias is likely to occur within biomass estimates derived from single unreplicated plots. PMID- 21265445 TI - Denitrification and total nitrate uptake in streams of a tropical landscape. AB - Rapid increases in nitrogen (N) loading are occurring in many tropical watersheds, but the fate of N in tropical streams is not well documented. Rates of nitrate uptake and denitrification were measured in nine tropical low-order streams with contrasting land use as part of the Lotic Intersite Nitrogen eXperiment II (LINX II) in Puerto Rico using short term (24-hour) additions of K(15)NO3 and NaBr. Background nitrate concentrations ranged from 105 to 997 microg N/L, and stream nitrate uptake lengths were long, varying from 315 to 8480 m (median of 1200 m). Other indices of nitrate uptake (mass transfer coefficient, V(f) [cm/s], and whole-stream nitrate uptake rate, U [microg N m(-2) s(-1)]) were low in comparison to other regions and were related to chemical, biological, and physical parameters. Denitrification rates were highly variable (0-133 microg N m(-2) min(-1); median = 15 microg N m(-2) min(-1)), were dominated by the end product N2 (rather than N2O), and were best predicted by whole-stream respiration rates and stream NO3 concentration. Denitrification accounted for 1-97% of nitrate uptake with five of nine streams having 35% or more of nitrate uptake via denitrification, showing that denitrification is a substantial sink for nitrate in tropical streams. Whole-stream nitrate uptake and denitrification in our study streams closely followed first-order uptake kinetics, indicating that NO3 uptake is limited by delivery of substrate (NO3) to the organisms involved in uptake or denitrification. In the context of whole-catchment nitrogen budgets, our finding that in-stream denitrification results in lower proportional production of N2O than terrestrial denitrification suggests that small streams can be viewed as the preferred site of denitrification in a watershed in order to minimize greenhouse gas N2O emissions. Conservation of small streams is thus critical in tropical ecosystem management. PMID- 21265446 TI - Thresholds in forest bird occurrence as a function of the amount of early-seral broadleaf forest at landscape scales. AB - Recent declines in broadleaf-dominated, early-seral forest globally as a function of intensive forest management and/or fire suppression have raised concern about the viability of populations dependent on such forest types. However, quantitative information about the strength and direction of species associations with broadleaf cover at landscape scales are rare. Uncovering such habitat relationships is essential for understanding the demography of species and in developing sound conservation strategies. It is particularly important to detect points in habitat reduction where rates of population decline may accelerate or the likelihood of species occurrence drops rapidly (i.e., thresholds). Here, we use a large avian point-count data set (N = 4375) from southwestern and northwestern Oregon along with segmented logistic regression to test for thresholds in forest bird occurrence as a function of broadleaf forest and early seral broadleaf forest at local (150-m radius) and landscape (500-2000-m radius) scales. All 12 bird species examined showed positive responses to either broadleaf forest in general, and/or early-seral broadleaf forest. However, regional variation in species response to these conditions was high. We found considerable evidence for landscape thresholds in bird species occurrence as a function of broadleaf cover; threshold models received substantially greater support than linear models for eight of 12 species. Landscape thresholds in broadleaf forest ranged broadly from 1.35% to 24.55% mean canopy cover. Early seral broadleaf thresholds tended to be much lower (0.22-1.87%). We found a strong negative relationship between the strength of species association with early-seral broadleaf forest and 42-year bird population trends; species most associated with this forest type have declined at the greatest rates. Taken together, these results provide the first support for the hypothesis that reductions in broadleaf-dominated early-seral forest due to succession and intensive forest management have led to population declines of constituent species in the Pacific northwestern United States. Forest management treatments that maintain or restore even small amounts of broadleaf vegetation could mitigate further declines. PMID- 21265447 TI - Spatiotemporal exploratory models for broad-scale survey data. AB - The distributions of animal populations change and evolve through time. Migratory species exploit different habitats at different times of the year. Biotic and abiotic features that determine where a species lives vary due to natural and anthropogenic factors. This spatiotemporal variation needs to be accounted for in any modeling of species' distributions. In this paper we introduce a semiparametric model that provides a flexible framework for analyzing dynamic patterns of species occurrence and abundance from broad-scale survey data. The spatiotemporal exploratory model (STEM) adds essential spatiotemporal structure to existing techniques for developing species distribution models through a simple parametric structure without requiring a detailed understanding of the underlying dynamic processes. STEMs use a multi-scale strategy to differentiate between local and global-scale spatiotemporal structure. A user-specified species distribution model accounts for spatial and temporal patterning at the local level. These local patterns are then allowed to "scale up" via ensemble averaging to larger scales. This makes STEMs especially well suited for exploring distributional dynamics arising from a variety of processes. Using data from eBird, an online citizen science bird-monitoring project, we demonstrate that monthly changes in distribution of a migratory species, the Tree Swallow (Tachycineta bicolor), can be more accurately described with a STEM than a conventional bagged decision tree model in which spatiotemporal structure has not been imposed. We also demonstrate that there is no loss of model predictive power when a STEM is used to describe a spatiotemporal distribution with very little spatiotemporal variation; the distribution of a nonmigratory species, the Northern Cardinal (Cardinalis cardinalis). PMID- 21265448 TI - Habitat selection and the perceptual trap. AB - The concept of "ecological traps" was introduced over three decades ago. An ecological trap occurs when, by various mechanisms, low-quality (yielding low fitness) habitat is more attractive than good habitat, thus coaxing individuals to settle there despite a resultant loss of fitness. Empirical work on such traps has increased dramatically in the past decade, but the converse-avoidance of high quality habitat because it is less attractive, what we term a "perceptual trap" has remained largely unexplored. Even so, depending on conditions (growth rate, strength of habitat preference, and mortality rate), such perceptual traps can be more limiting than ecological traps to population persistence. An example from field experiments with the Lesser Prairie-Chicken (Tympanuchus pallidicinctus) lends empirical support to the concept, and several other potential examples suggest that these traps are perhaps more prevalent than has been appreciated. Because demographic Allee effects are expected to prevent a population from growing sufficiently in a habitat that is avoided, a perceptual trap may persist even though fitness is high. Unlike an ecological trap, which may be negated by increasing habitat quality, biologists will be hard pressed to negate a perceptual trap, which will require determining which cues an animal uses to select high-quality habitat and then devising a means of enhancing those cues so that an animal is lured into the habitat. PMID- 21265449 TI - Regional avian species declines estimated from volunteer-collected long-term data using List Length Analysis. AB - Long-term systematic population monitoring data sets are rare but are essential in identifying changes in species abundance. In contrast, community groups and natural history organizations have collected many species lists. These represent a large, untapped source of information on changes in abundance but are generally considered of little value. The major problem with using species lists to detect population changes is that the amount of effort used to obtain the list is often uncontrolled and usually unknown. It has been suggested that using the number of species on the list, the "list length," can be a measure of effort. This paper significantly extends the utility of Franklin's approach using Bayesian logistic regression. We demonstrate the value of List Length Analysis to model changes in species prevalence (i.e., the proportion of lists on which the species occurs) using bird lists collected by a local bird club over 40 years around Brisbane, southeast Queensland, Australia. We estimate the magnitude and certainty of change for 269 bird species and calculate the probabilities that there have been declines and increases of given magnitudes. List Length Analysis confirmed suspected species declines and increases. This method is an important complement to systematically designed intensive monitoring schemes and provides a means of utilizing data that may otherwise be deemed useless. The results of List Length Analysis can be used for targeting species of conservation concern for listing purposes or for more intensive monitoring. While Bayesian methods are not essential for List Length Analysis, they can offer more flexibility in interrogating the data and are able to provide a range of parameters that are easy to interpret and can facilitate conservation listing and prioritization. PMID- 21265450 TI - Unite research with what citizens do for fun: "recreational monitoring" of marine biodiversity. AB - Institutes often lack funds and manpower to perform large-scale biodiversity monitoring. Citizens can be involved, contributing to the collection of data, thus decreasing costs. Underwater research requires specialist skills and SCUBA certification, and it can be difficult to involve volunteers. The aim of this study was to involve large numbers of recreational divers in marine biodiversity monitoring for increasing the environmental education of the public and collecting data on the status of marine biodiversity. Here we show that thousands of recreational divers can be enrolled in a short time. Using specially formulated questionnaires, nonspecialist volunteers reported the presence of 61 marine taxa encountered during recreational dives, performed as regular sport dives. Validation trials were carried out to assess the accuracy and consistency of volunteer-recorded data, and these were compared to reference data collected by an experienced researcher. In the majority of trials (76%) volunteers performed with an accuracy and consistency of 50-80%, comparable to the performance of conservation volunteer divers on precise transects in other projects. The recruitment of recreational divers involved the main diving and tour operators in Italy, a popular scientific magazine, and mass media. During the four-year study, 3825 divers completed 18757 questionnaires, corresponding to 13539 diving hours. The volunteer-sightings-based index showed that in the monitored area the biodiversity status did not change significantly within the project time scale, but there was a significant negative correlation with latitude, suggesting improved quality in the southernmost areas. This trend could be related to the presence of stressors in the northern areas and has been supported by investigations performed by the Italian Ministry of the Environment. The greatest limitation with using volunteers to collect data was the uneven spatial distribution of samples. The benefits were the considerable amounts of data collected over short time periods and at low costs. The successful development of citizen-based monitoring programs requires open-mindedness in the academic community; advantages of citizen involvement in research are not only adding large data sets to the ecological knowledge base but also aiding in the environmental education of the public. PMID- 21265451 TI - A statistical approach for estimating fish diet compositions from multiple, data sources: Gulf of California case study. AB - Trophic ecosystem models are one promising tool for providing ecosystem-based management advice. Diet and interaction rate parameters are critical in defining the behavior of these models, and will greatly influence any predictions made in response to management perturbations. However, most trophic ecosystem models must rely on a patchwork of data availability and must contend with knowledge gaps and poor quantification of uncertainty. Here we present a statistical method for combining diet information from field samples and literature to describe trophic relationships at the level of functional groups. In this example, original fieldwork in the northern Gulf of California, Mexico, provides gut content data for targeted and untargeted fish species. The field data are pooled with diet composition information from FishBase, an online data repository. Diet information is averaged across stomachs to represent an average predator, and then the data are bootstrapped to generate likelihood profiles. These are fit to a Dirichlet function, and from the resulting marginal distributions, maximum likelihood estimates are generated with confidence intervals representing the likely contribution to diet for each predator-prey combination. We characterize trophic linkages into two broad feeding guilds, pelagic and demersal feeders, and explore differentiation within those guilds. We present an abbreviated food web for the northern Gulf of California based on the results of this study. This food web will form the basis of a trophic dynamic model. Compared to the common method of averaging diet compositions across predators, this statistical approach is less influenced by the presence of long tails in the distributions, which correspond to rare feeding events, and is therefore better suited to small data sets. PMID- 21265452 TI - Spatial patterns of fishing effort off San Diego: implications for zonal management and ecosystem function. AB - The essence of ecosystem-based management is managing human practices to conserve the ecosystem. Ecologists focus on understanding the ecosystem, but there are fundamental information gaps including patterns of human exploitation. In particular, the spatial distribution of fishing effort must be known at the scales needed for ecologically relevant management. Fishing is a primary impact on coastal ecosystems, yet catch distribution at scales relevant to habitats and processes are not well known for many fisheries. Here we utilized photographic time series, logbook records, and angler surveys to estimate the intensity and spatial pattern of commercial and recreational fishing. Effort was clearly aggregated for most types of fishing, the motivating factors for effort distribution varied among areas, and effort was coupled or uncoupled to habitat depending on the area and type of fishing. We estimated that approximately 60% and approximately 74% of private recreational and recreational charter vessel fishing effort, respectively, were concentrated into two small areas that also included approximately 78% of commercial sea urchin effort. Exploitation and effort were considerably greater in one kelp forest, which has important implications for patterns of kelp persistence, productivity, and ecosystem function. Areas subject to the greatest recreational fishing pressure appeared to have lower diversity. Our results indicate that fine-scale patterns of fishing effort and exploitation have profound consequences for ecosystem functioning and biodiversity. 'Ecosystem-based management of nearshore ecosystems depends on an understanding of the fine-scale patterns of exploitation. PMID- 21265453 TI - Estimating the impacts of fishing on dependent predators: a case study in the California Current. AB - Juvenile rockfish (Sebastes spp.) are important prey to seabirds in the California Current System, particularly during the breeding season. Both seabird breeding success and the abundance of pelagic juvenile rockfish show high interannual variability. This covariation is largely a response to variable ocean conditions; however, fishing on adult rockfish may have had consequences for seabird productivity (e.g., the number of chicks fledged per breeding pair) by reducing the availability of juvenile rockfish to provisioning seabird parents. We tested the hypothesis that fishing has decreased juvenile rockfish availability and thereby limited seabird productivity over the past 30 years. We quantified relationships between observed juvenile rockfish relative abundance and seabird productivity, used fisheries stock assessment approaches to estimate the relative abundance of juvenile rockfish in the absence of fishing, and compared the differences in seabird productivity that would have resulted without rockfish fisheries. We examined the abundance of juvenile rockfish and the corresponding productivity of three seabird species breeding on Southeast Farallon Island (near San Francisco, California, USA) from the early 1980s to the present. Results show that while the relative abundance of juvenile rockfish has declined to approximately 50% of the estimated unfished biomass, seabirds achieved 75-95% of the estimated un-impacted levels of productivity, depending upon the species of bird and various model assumptions. These results primarily reflect seabirds with "conservative" life histories (one egg laid per year) and may be different for species with more flexible life history strategies (greater reproductive effort). Our results are consistent with the premise that the impacts of local rockfish fisheries on seabird productivity are less than impacts that have occurred to the prey resources themselves due to ocean climate and the ability of seabirds to buffer against changes in prey availability through prey switching and other behavioral mechanisms. PMID- 21265454 TI - Biomanipulation: a tool in marine ecosystem management and restoration? AB - Widespread losses of production and conservation values make large-scale ecosystem restoration increasingly urgent. Ecological restoration by means of biomanipulation, i.e., by fishing out planktivores to reduce the predation pressure on herbivorous zooplankton, has proved to be an effective tool in restoring degraded lakes and coastal ecosystems. Whether biomanipulation may prove a useful restoration method in open and structurally complex marine ecosystems is, however, still unknown. To promote a recovery of the collapsed stock of Eastern Baltic cod (Gadus morhua), large-scale biomanipulation of sprat (Sprattus sprattus), the main planktivore in the Baltic Sea, has been suggested as a possible management approach. We study the effect of biomanipulation on sprat using a statistical food-web model, which integrates internal interactions between the main fish species of the Central Baltic Sea, with external forcing through commercial fishing, zooplankton, and climate. By running multiple, stochastic simulations of reductions in sprat spawning stock biomass (SSB) only minor increases in cod SSB were detected, none of which brought the cod significantly above ecologically safe levels. On the contrary, reductions in cod fishing mortality and/or improved climatic conditions would promote a significant recovery of the stock. By this we demonstrate that an ecosystem-scale biomanipulation, with the main focus of reinstating the dominance of cod in the Baltic Sea may likely be ecologically ineffective, operationally difficult, and costly. We argue that reducing exploitation pressure on Eastern Baltic cod to ecologically sound levels is a far more appealing management strategy in promoting a long-term recovery and a sustainable fishery of the stock. PMID- 21265455 TI - Restoration through eradication? Removal of an invasive bioengineer restores some habitat function for a native predator. AB - Invasive aquatic macrophytes increase structural complexity in recipient systems and alter trophic and physical resources; thus, eradication programs that remove plant structure have potential to restore some impaired ecological functions. In this study we evaluate how an invasive ecosystem engineer, Atlantic smooth cordgrass (Spartina alterniflora), interferes with the movement and foraging activity of a mobile predator, Dungeness crab (Cancer magister), and whether removal of aboveground cordgrass structure rapidly reestablishes access to foraging habitats. By 2004, smooth cordgrass had invaded >25% of crab foraging habitat in Willapa Bay, Washington (USA), and transformed it into a highly structured landscape. However, by 2007 successful eradication efforts had eliminated most meadows of the cordgrass. In order to investigate the effect of smooth cordgrass on the habitat function of littoral areas for foraging crabs, we integrated field, laboratory, and statistical modeling approaches. We conducted trapping surveys at multiple sites and used a hierarchical model framework to examine patterns in catches prior to and following cordgrass removal (i.e., before-after control-impact design, BACI). Prior to eradication, catches of Dungeness crabs in unstructured habitats were 4-19 times higher than catches in adjacent patches of live cordgrass. In contrast, the results of post-eradication trapping in 2007 indicated similar catch rates of crabs in unstructured habitats and areas formerly invaded by the cordgrass. Subsequent laboratory experiments and video observations demonstrated that the rigid physical structure of smooth cordgrass shoots reduces the ability of Dungeness crabs to access prey resources and increases the risk of stranding. Taken together, these findings suggest that eliminating the structural complexity of invasive macrophytes may rapidly restore some ecological function (i.e., foraging area) for migratory predators like Dungeness crab. However, restoration of affected areas to a preinvasion state will also depend on long-term patterns of succession in invaded areas and the degree of persistence of physical changes that continue to alter biotic characteristics of the habitat. Our work highlights: (1) the efficacy of employing multiple methods of inquiry to evaluate causal relationships through mechanisms of interaction, and (2) the importance of targeting particular ecological functions when identifying both short- and long-term goals of restoration efforts. PMID- 21265456 TI - Interactions of environmental stressors impact survival and development of parasitized larval amphibians. AB - Infected hosts are exposed to many environmental stressors that must be taken into account in order to determine the importance of disease, as various combinations can interact in unpredictable ways. Here, northern leopard frog (Rana pipiens) tadpoles, a species in decline, were exposed to stressors singly or in combination. Stressors included infection by Echinostoma trivolvis (a trematode parasite), exposure to predator chemical cues (larval dragonflies), and exposure to varying concentrations of the herbicide atrazine. Parasitism decreased survival only in combination with exposure to 3 microg/L atrazine, with a negative interaction observed for mass as well. Similarly, a negative interaction of parasitism and predation on survival occurred. However, atrazine exposure alone negatively affected the survival, mass, and developmental stage of tadpoles. These results indicate that certain stressor combinations are particularly deleterious for young parasitized tadpoles. Notably, very common low intensity parasite infection can be particularly harmful in certain situations. Such negative impacts on larval amphibians in certain scenarios may contribute to ongoing amphibian population declines, emphasizing that the combination of environmental stressors must be considered when evaluating the general role of disease in species extinctions. PMID- 21265457 TI - Modeling the consequences of thermal trait variation for the cane toad invasion of Australia. AB - Mechanistic species distribution models (SDMs) are ideally suited for predicting the nonnative distributions of invasive species, but require accurate parameterization of key functional traits. Importantly, any ability of the invader to acclimate or adapt rapidly to local conditions must be incorporated. Our field and laboratory studies measured phenotypic variation and tested for plasticity in the thermal sensitivity of locomotor performance and low temperature tolerance of adult cane toads Bufo marinus in eastern Australia. We used a biophysical model to explore the adaptive significance of this variation and how it affected distribution predictions. Laboratory trials showed that geographic differences in low-temperature tolerance (i.e., the critical thermal minimum; CTMin) of field-caught toads reflect thermal acclimation, whereas populations differed in the thermal dependence of locomotor performance even after acclimation. Incorporating low-temperature tolerance as a dimension of the fundamental niche reduced the predicted southern distribution. To test whether these factors predicted to be range limiting were consistent with reduced performance for individuals, we used the biophysical model and daily climate data to conduct "virtual transplants." These models predicted that acclimation reduced cold stress by 32-100% for toads sheltering near the ground surface; toads inside burrows could remain above their CTMin, but the required burrow depth increased with latitude. Low-temperature tolerance of the adult phase may constrain the southern range limit of the cane toad in Australia, and plasticity in this trait may have facilitated the southward range expansion. PMID- 21265458 TI - Least-cost transportation networks predict spatial interaction of invasion vectors. AB - Human-mediated dispersal among aquatic ecosystems often results in biotic transfer between drainage basins. Such activities may circumvent biogeographic factors, with considerable ecological, evolutionary, and economic implications. However, the efficacy of predictions concerning community changes following inter basin movements are limited, often because the dispersal mechanism is poorly understood (e.g., quantified only partially). To date, spatial-interaction models that predict the movement of humans as vectors of biotic transfer have not incorporated patterns of human movement through transportation networks. As a necessary first step to determine the role of anglers as invasion vectors across a land-lake ecosystem, we investigate their movement potential within Ontario, Canada. To determine possible model improvements resulting from inclusion of network travel, spatial-interaction models were constructed using standard Euclidean (e.g., straight-line) distance measures and also with distances derived from least-cost routing of human transportation networks. Model comparisons determined that least-cost routing both provided the most parsimonious model and also excelled at forecasting spatial interactions, with a proportion of 0.477 total movement deviance explained. The distribution of movements was characterized by many relatively short to medium travel distances (median = 292.6 km) with fewer lengthier distances (75th percentile = 484.6 km, 95th percentile = 775.2 km); however, even the shortest movements were sufficient to overcome drainage-basin boundaries. Ranking of variables in order of their contribution within the most parsimonious model determined that distance traveled, origin outflow, lake attractiveness, and sportfish richness significantly influence movement patterns. Model improvements associated with least-cost routing of human transportation networks imply that patterns of human-mediated invasion are fundamentally linked to the spatial configuration and relative impedance of human transportation networks, placing increased importance on understanding their contribution to the invasion process. PMID- 21265459 TI - Hitchhikers on trade routes: A phenology model estimates the probabilities of gypsy moth introduction and establishment. AB - As global trade increases so too does the probability of introduction of alien species to new locations. Estimating the probability of an alien species introduction and establishment following introduction is a necessary step in risk estimation (probability of an event times the consequences, in the currency of choice, of the event should it occur); risk estimation is a valuable tool for reducing the risk of biological invasion with limited resources. The Asian gypsy moth, Lymantria dispar (L.), is a pest species whose consequence of introduction and establishment in North America and New Zealand warrants over US$2 million per year in surveillance expenditure. This work describes the development of a two dimensional phenology model (GLS-2d) that simulates insect development from source to destination and estimates: (1) the probability of introduction from the proportion of the source population that would achieve the next developmental stage at the destination and (2) the probability of establishment from the proportion of the introduced population that survives until a stable life cycle is reached at the destination. The effect of shipping schedule on the probabilities of introduction and establishment was examined by varying the departure date from 1 January to 25 December by weekly increments. The effect of port efficiency was examined by varying the length of time that invasion vectors (shipping containers and ship) were available for infection. The application of GLS-2d is demonstrated using three common marine trade routes (to Auckland, New Zealand, from Kobe, Japan, and to Vancouver, Canada, from Kobe and from Vladivostok, Russia). PMID- 21265460 TI - Saproxylic and non-saproxylic beetle assemblages in boreal spruce forests of different age and forestry intensity. AB - Current clear-cutting forestry practices affect many boreal organisms negatively, and those dependent on dead wood (saproxylics) are considered as particularly vulnerable. The succession of species assemblages in managed forest habitats regenerating after clear-cutting is, however, poorly known. We compared beetle assemblages in three successional stages of managed boreal spruce forests established after clear-cutting and two types of older spruce forests that had not been clear-cut. We also assessed whether saproxylic and non-saproxylic beetle assemblages show similar biodiversity patterns among these forest types. Beetles were collected in window traps in nine study areas, each encompassing a protected old-growth forest (mean forest age approximately 160 years, mean dead wood volume 34 m3/ha), an unprotected mature forest (approximately 120 years old, 15 m3/ha), a middle-aged commercially thinned forest (53 years old, 3 m3/ha), a young unthinned forest (30 years old, 4 m3/ha), and a clearcut (5-7 years after harvest, 11 m3/ha). Saproxylic beetles, in particular red-listed species, were more abundant and more species rich in older forest types, whereas no significant differences among forest types in these variables were detected for non saproxylics. The saproxylic assemblages were clearly differentiated; with increasing forest age, assemblage compositions gradually became more similar to those of protected old-growth forests, but the assemblage composition in thinned forests could not be statistically distinguished from those of the two oldest forest types. Many saproxylic beetles adapted to late-successional stages were present in thinned middle-aged forests but absent from younger unthinned forests. In contrast, non-saproxylics were generally more evenly distributed among the five forest types, and the assemblages were mainly differentiated between clearcuts and forested habitats. The saproxylic beetle assemblages of unprotected mature forests were very similar to those of protected old-growth forests. This indicates a relatively high conservation value of mature boreal forests currently subjected to clear-cutting and raises the question of whether future mature forests will have the same qualities. Our results suggest a high beetle conservation potential of developing managed forests, provided that sufficient amounts and qualities of dead wood are made available (e.g., during thinning operations). Confirming studies of beetle reproduction in dead wood introduced during thinning are, however, lacking. PMID- 21265461 TI - Spatial variability in ecosystem services: simple rules for predator-mediated pest suppression. AB - Agricultural pest control often relies on the ecosystem services provided by the predators of pests. Appropriate landscape and habitat management for pest control services requires an understanding of insect dispersal abilities and the spatial arrangement of source habitats for pests and their predators. Here we explore how dispersal and habitat configuration determine the locations where management actions are likely to have the biggest impact on natural pest control. The study focuses on the early colonization phase before predator reproduction takes place and when pest populations in crops are still relatively low. We developed a spatially explicit simulation model in which pest populations grow exponentially in pest patches and predators disperse across the landscape from predator patches. We generated 1000 computer-simulated landscapes in which the performance of four typical but different predator groups as biological control agents was evaluated. Predator groups represented trait combinations of poor and good dispersal ability and density-independent and density-dependent aggregation responses toward pests. Case studies from the literature were used to inform the parameterization of predator groups. Landscapes with a small nearest-neighbor distance between pest and predator patches had the lowest mean pest density at the landscape scale for all predator groups, but there can be high variation in pest density between the patches within these landscapes. Mobile and strongly aggregating predators provide the best pest suppression in the majority of landscape types. Ironically, this result is true except in landscapes with small nearest-neighbor distances between pest and predator patches. The pest control potential of mobile predators can best be explained by the mean distance between a pest patch and all predator patches in the landscape, whereas for poorly dispersing predators the distance between a pest patch and the nearest predator patch is the best explanatory variable. In conclusion, the spatial arrangement of source habitats for natural enemies of agricultural pest species can have profound effects on their potential to colonize crops and suppress pest populations. PMID- 21265462 TI - Survivorship patterns in captive mammalian populations: implications for estimating population growth rates. AB - For species of conservation concern, ecologists often need to estimate potential population growth rates with minimal life history data. We use a survivorship database for captive mammals to show that, although survivorship scale (i.e., longevity) varies widely across mammals, survivorship shape (i.e., the age specific pattern of mortality once survivorship has been scaled to maximum longevity) varies little. Consequently, reasonable estimates of population growth rate can be achieved for diverse taxa using a model of survivorship shape along with an estimate of longevity. In addition, we find that the parameters of survivorship shape are related to taxonomic group, a fact that may be used to further improve estimates of survivorship when full life history data are unavailable. Finally, we compare survivorship shape in captive and wild populations of the same species and find higher adult survivorship in captive populations but no corresponding increase in juvenile survivorship. These differences likely reflect a convolution of true differences in captive vs. wild survivorship and the difficulty of observing juvenile mortality in field studies. PMID- 21265463 TI - Detection of snow surface thawing and refreezing in the Eurasian Arctic with QuikSCAT: implications for reindeer herding. AB - Snow conditions play an important role for reindeer herding. In particular, the formation of ice crusts after rain-on-snow (ROS) events or general surface thawing with subsequent refreezing impedes foraging. Such events can be monitored using satellite data. A monitoring scheme has been developed for observation at the circumpolar scale based on data from the active microwave sensor SeaWinds on QuikSCAT (Ku-band), which is sensitive to changes on the snow surface. Ground observations on Yamal Peninsula were used for algorithm development. Snow refreezing patterns are presented for northern Eurasia above 60 degrees N from autumn 2001 to spring 2008. Western Siberia is more affected than Central and Eastern Siberia in accordance with climate data, and most events occur in November and April. Ice layers in late winter have an especially negative effect on reindeer as they are already weakened. Yamal Peninsula is located within a transition zone between high and low frequency of events. Refreezing was observed more than once a winter across the entire peninsula during recent years. The southern part experienced refreezing events on average four times each winter. Currently, herders can migrate laterally or north-south, depending on where and when a given event occurs. However, formation of ice crusts in the northern part of the peninsula may become as common as they are now in the southern part. Such a development would further constrain the possibility to migrate on the peninsula. PMID- 21265464 TI - A paleozoological perspective on unionid (Mollusca: Unionidae) zoogeography in the upper Trinity River basin, Texas. AB - In north central Texas, USA, the zoogeography of unionids in the Trinity River is thought to consist of upland and lowland biogeographic components reflective of differences in upstream and downstream hydraulic conditions. Historical and modern surveys from a limited number of localities were used to delineate these zoogeographic provinces based on the absence of several species thought to occur only in the lower Trinity River drainage. Available zooarchaeological data indicate that at least one species considered absent from the upper Trinity River basin was present during the late Holocene (roughly the last 2500 years), suggesting that both biogeographical provinces shared similar mussel fauna in the recent geological past. The discrepancy between historical and zooarchaeological data is probably the result of inadequate sampling and of an extirpation gradient related to impoundments that have been constructed in this drainage during the last century. The presence of lower Trinity species during the late Holocene in the upper Trinity drainage challenges interpretations drawn from modern biogeographic studies. PMID- 21265465 TI - Altered disposition of drugs in acute renal failure rat models: drug development strategies and perspectives. AB - In the evolving paradigm of drug development it is a reasonable strategy to avoid and/or anticipate potential risks in drug development for select drugs by performing in vitro and/or preclinical studies in appropriate animal models. The availability of acute renal failure (ARF) rat models provides an opportunity to explore the pharmacokinetic disposition of drugs and associated metabolites in conditions that mimic the pathophysiology of the disease in humans. Such studies may help in drug(s) selection for development, differentiating certain drug classes, and/or arriving at a dose strategy decision in the clinic. Scores of compounds, belonging to various therapeutic areas, have undergone pharmacokinetic investigations in ARF models induced by uranyl nitrate (CAS 10102-06-4), glycerol (CAS 56-81-5), cisplatin (CAS 15663-27-1) or gentamicin (CAS 1403-66-3) in rats. The published pharmacokinetic disposition data has unequivocally suggested that ARF conditions leads to decreased renal elimination of the drug and associated metabolites; however, the influence on the overall body clearance is dependent on the propensity of the contribution of renal versus non-renal mechanisms of elimination. In the case studies assembled for this review, 52.5% of the drugs showed an increased drug exposure, 35% of the drugs showed a decreased drug exposure and 12.5% of the drugs showed no altered exposure, in ARF rat models relative to control rats. Interestingly, ARF can have an overall impact on drug absorption, distribution, metabolism, local transport and biliary excretion. Hence, the overall pharmacokinetic disposition may have to be interpreted with caution during ARF since there is the potential for competiting pathways to co exist. For instance, due to reduced renal elimination as a result of kidney insult caused by ARF, compensatory biliary excretion mechanism may occur. Alternatively, intestinal and/or hepatic enzymatic expression level may go up to facilitate enhanced metabolism. However, there may be instances where uraemic toxins floating in the circulation may block the metabolism and/ or may also retard the absorption process. This review covers: 1) an illustration of a number of case studies providing tabulated information on the key altered pharmacokinetic parameters observed in ARF and the hypothesized mechanistic explanation; 2) a comprehensive description of altered absorption, distribution, metabolism, excretion and efflux transport related changes observed during ARF; 3) a general framework for drug development strategies and 4) a succinct discussion on the overall perspectives of the applicability of ARF rat models. PMID- 21265467 TI - Anti-arthritic activity of synthesized chondroitin sulfate E hexasaccharide. AB - The purpose of this study was to investigate the anti-arthritic effects of synthesized chondroitin sulfate E hexasaccharide (sCSE-6, CAS 866407-73-0), using a type II collagen-induced arthritis model in mice. sCSE-6 was administered subcutaneously on a daily basis to type II collagen (CII)-sensitized mice from day 0 to day 55. The severity of arthritis, as well as the immunohistological features of the arthritic mice, were analyzed. sCSE-6 inhibited the course of arthritis and restored the body weight loss of CII-immunized mice. An immunohistological analysis showed that bone/cartilage destruction in the arthritic mice was significantly attenuated by sCSE-6 treatment, with a marginal inhibition of synovial inflammation also observed. The beneficial effect of sCSE 6 on bone destruction, which is the most important factor in preventing arthritis, is particularly noteworthy. In summary, sCSE-6 inhibited arthritis and helped to prevent bone and cartilage destruction in a type II collagen-induced arthritis model in mice. The findings indicated that CSE oligosaccharides might be a novel potential therapeutic tool for rheumatoid arthritis. PMID- 21265466 TI - Comparative bioavailability of two irbesartan/hydrochlorothiazide tablet formulations in Indonesian healthy subjects. AB - AIM: The bioavailability of two 300 mg irbesartan (CAS 138402-11-6)/12.5 mg hydrochlorothiazide (CAS 58-93-5) tablet formulations was compared, using Co-Ir vell tablets as test formulation and the originator product as reference formulation. METHODS: Twenty-four subjects were included in this single-dose, open-label, randomized two-way crossover study following an overnight fasting. A two-week wash-out period was applied. Blood samples were drawn up to 48 h following drug administrations. Irbesartan and hydrochlorothiazide plasma concentrations were determined by liquid chromatography-tandem mass spectrometry method with TurboIonSpray mode. Pharmacokinetic parameters AUC(0-t), AUC(0 infinity), Cmax and t were determined and used for bioequivalence evaluation after log-transformation, whereas t max ratios were evaluated non-parametrically. RESULTS: The estimated point and 90% confidence intervals (CI) for AUC(0-t), AUC(0-infinity), Cmax and t for irbesartan were 97.74% (85.40-111.86%), 96.36% (83.25-111.55%), 103.30% (90.65-117.71%), 92.38% (82.68-103.21%) and for hydrochlorothiazide, 106.30% (97.72-115.63%), 106.28% (98.14-115.10%), 108.01% (95.48-122.18%), 105.52% (96.70-115.14%), respectively. CONCLUSION: These results indicated that the two formulations of irbesartan/hydrochlorothiazide were bioequivalent; therefore they may be prescribed interchangeably. PMID- 21265468 TI - Suppressive efficacies of antimicrobial agents against human peripheral-blood mononuclear cells stimulated with T cell mitogen and bacterial superantigen. AB - The immunomodulatory efficacies of 12 antimicrobial agents clinically used were examined against T cell mitogen- or bacterial superantigen-induced proliferation of peripheral-blood mononuclear cells of healthy subjects. Minocycline (CAS 13614 98-7), rifampicin (CAS 13292-46-1), trimethoprim (CAS 738-70-5), and ribavirin (CAS 36791-04-5) significantly inhibited the proliferation of mitogen-stimulated mononuclear cells at 1-100 microg/ ml (p < 0.001), whereas ofloxacin (CAS 82419 36-1) enhanced the proliferation (p < 0.001). Ampicillin (CAS 69- 53-4), lincomycin (CAS 859-18-7), vancomycin (CAS 1404-93-9), sulfamethoxazole (CAS 723 46-6), fosfomycin (CAS 26016-99-9), colistin (CAS 1264-72-8), and polymyxin B (CAS 1405-20-5) showed no significant effect. Minocycline, rifampicin, trimethoprim, and ribavirin also inhibited the proliferation of superantigen stimulated peripheral-blood mononuclear cells at 1-100 microg/ml (<0.001), whereas ofloxacin stimulated the proliferation (p < 0.001). Rifampicin and minocycline at 10-100 microg/ml significantly inhibited interleukin-2 production from mitogen- or superantigen-stimulated peripheral-blood mononuclear cells (p < 0.025). These results suggest that certain kinds of antimicrobial agents inhibited the proliferation of mitogen- and superantigen-stimulated human peripheral-blood mononuclear cells and suppressed interleukin-2 production from these cells. The ofloxacin effect is immunostimulative, while the drug did not influence the interleukin-2 production. PMID- 21265469 TI - High-dose methotrexate in children with acute lymphoblastic leukemia: 7 hydroxymethotrexate systemic exposure and urinary concentrations at the steady state correlate well with those of methotrexate. AB - The present study evaluated the pharmacokinetics of methotrexate (MTX, CAS 59-05 2) and 7-hydroxymethotrexate (7-OHMTX, CAS 5939-37-7) in children with acute lymphoblastic leukemia (ALL) with particular interest devoted to the renal excretion at the steady-state and to the relationships between total (CL) and renal clearances (CL(R)) of both compounds. Ten children (seven girls) aged 8.5 years (2.9-16) years with standard or medium-risk ALL received four 24-h i.v. infusions of high-dose MTX (HDMTX, 5 g/m2) with leucovorin (CAS 58-05-9) rescue according to the ALL-BFM-95 protocol. MTX and 7-OHMTX were assayed in plasma and urine by high-performance liquid chromatography. At the steady-state, the clearance (CL) of MTX (6.28 +/- 2.79 l h(-1)) was correlated with its CL(R) (r(s) = 0.79, p < 0.0001) which accounted for 61% (SD 26%) of the former. There were weak correlations between pretreatment values of creatinine clearance calculated using Schwartz's formula and the drug's CL (r(s) = 0.30, p < 0.05) or CLR (r(s) = 0.41, p < 0.02). In contrast, the CL(R) accounted for only 26% (SD 15%) of the metabolite's CL which was estimated assuming 10% conversion of MTX to 7-OHMTX. The CL values of both compounds were highly correlated (r(s) = 0.86, p < 0.0001). The CL(R) of the parent compound was on the average 9-fold higher (range: 3.5- to 17-fold) and was strongly correlated with the CL(R) of the metabolite (r(s) = 0.87, p < 0.0001). The ratio 7-OHMTX/MTX of urinary concentrations was between 2.4 and 9.8% with the mean value of 4.1%. This study suggests that during the 24 h i.v. infusions of HDMTX to children with ALL, the exposure of patients to 7 OHMTX can be reasonably well predicted from the knowledge of MTX concentrations. The steady-state renal CLs, total CLs as well as urinary concentrations of the parent compound and metabolite are highly correlated and the correlation of plasma concentrations is moderate. Therefore, it is unlikely that simultaneous evaluation of 7-OHMTX and MTX steady-state concentrations could improve the predictive performance of the latter towards the response or the risk of complications, although future larger studies should verify this conclusion. PMID- 21265470 TI - Instructions and methods for clinical testing of drugs for the treatment of atrial fibrillation. AB - Instructions and methods for clinical testing of drugs for the treatment of atrial fibrillation are the subject of this paper. Certain criteria must be considered to demonstrate the effectiveness and benefit/risk ratio of pharmacotherapy of atrial fibrillation for the planning and performance of clinical trials. These criteria include the various forms of atrial fibrillation, the corresponding definition of endpoints, the appropriate study design, randomization and blinding, and also the adequate dose, investigation methods, sample size determination, analysis, and early termination. Only the consideration of these criteria may allow an appropriate treatment decision. PMID- 21265471 TI - Sponsorship and dental implants: is the line between product performance and profit blurred? PMID- 21265472 TI - Trends in implant dentistry: green dentistry. PMID- 21265473 TI - What is your dental degree worth? PMID- 21265474 TI - 8th District initiative paves way for financial oversite. PMID- 21265475 TI - Delegates debate the role of mid-level providers. PMID- 21265476 TI - Bringing dentistry to the classroom. PMID- 21265477 TI - Managing your online reputation. PMID- 21265479 TI - The official snack food of Illinois. PMID- 21265478 TI - Getting personal: managing personnel files. PMID- 21265480 TI - Dental school founders left impressive legacies. PMID- 21265481 TI - Time for our profession to 'get real'. PMID- 21265483 TI - Medical tourism. PMID- 21265482 TI - When a physician becomes a patient. PMID- 21265484 TI - Acute vesiculopapular rash in the setting of atopic dermatitis. AB - Atopic dermatitis is a common entity encountered in clinical practice. A subgroup within the atopic dermatitis cohort may develop viral infection on skin lesions appearing as a vesiculopapular pattern. This process is termed eczema herpeticum and may pose a challenge to the clinician as it can appear similar to orthopoxvirus infections, most notably smallpox and monkeypox. Because these conditions are considered as potential bioterrorism threats, confirmatory testing via histological examination, viral culture, immunohistochemical staining or PCR is recommended. Additionally, antiviral therapy should be promptly initiated as eczema herpeticum can disseminate or become superinfected with bacterial species. Early recognition and good communication with pathology can reduce morbidity and confirm the disease process. PMID- 21265486 TI - Managing the pain of pressure ulcers. PMID- 21265485 TI - Treatment-related needs of statewide cancer survivors. AB - INTRODUCTION: Research on surviving cancer treatment is a national priority and there is a need to understand the experiences of survivors from predominantly rural areas. The purpose of this study was to identify the perceptions of treatment and post-treatment issues for cancer survivors living in South Dakota. Multidimensional aspects of cancer-related needs were explored, including: psychosocial, physical, spiritual, health promotion and access to care issues. METHODS: The design was a cross-sectional survey of cancer survivors who completed their course of treatment at five accredited cancer treatment centers in South Dakota two years prior to the study. The survey was derived from a synthesis of other published instruments, with added items that focused on issues of interest to rural dwellers. There were 524 of 1933 mailed surveys returned (27 percent response). RESULTS: Respondents identified needs for help coping with various emotions more frequently than needs related to finding support and taking care of practical issues post-treatment. Specifically, coping with uncertainty and finding hope were priority needs (33 percent and 36 percent, respectively), while accessing counseling services and financial planning were low priority (9 percent and 14 percent, respectively). There were limited numbers of participants who reported that access to care (time, expense, travel) interrupted their cancer treatment. CONCLUSIONS: Perceptions of treatment-related needs of cancer survivors living in South Dakota include broad health promotion, practical and, most commonly, emotional concerns. Health care providers who assess for and identify these needs require a keen awareness of community resources to support South Dakota cancer survivors. PMID- 21265487 TI - Quality focus: Central line-associated bloodstream infection reporting. PMID- 21265488 TI - Dakotacare update: Health system reform: what else is in there? PMID- 21265490 TI - Acute coronary syndromes and elderly patients: the treatment paradox. PMID- 21265489 TI - Invasive strategy in non-ST elevation acute coronary syndromes: risks and benefits in an elderly population. AB - INTRODUCTION: Age is an important prognostic factor in acute coronary syndromes (ACS). An invasive strategy has been shown to benefit many non-ST elevation ACS populations; however, there is some controversy regarding patients who are more susceptible to procedure-related complications, such as the elderly, an under represented population in the studies on this subject. OBJECTIVE: We aimed to compare the in-hospital and long-term prognosis of elderly patients with non-ST elevation ACS treated with either invasive procedures or a conservative strategy, and to characterize the patients selected for an early invasive approach. METHODS: This observational, longitudinal, prospective and continuous study included 307 patients aged over 75 years consecutively admitted for non-ST elevation ACS. They were divided into two groups, according to the approach adopted: Group A (n=91)--patients treated with an early invasive strategy; and Group B (n=216)--patients treated conservatively. The median clinical follow-up was 18 months. RESULTS: The subjects who were treated invasively were younger (79.8 +/- 3.2 vs. 81.4 +/- 3.9 years, p < 0.001) and more often male (63.7 vs. 50.9%, p = 0.04), had a higher incidence of previous coronary artery disease, were more often treated with clopidogrel, and had a longer hospital stay (5.8 +/- 3.1 vs. 4.9 +/- 2.6 days, p = 0.01). Patients managed conservatively presented higher Killip class, and were more often treated with diuretics during hospitalization. The group treated by an invasive approach presented a higher incidence of in-hospital complications (13.6 vs. 4.9%, p = 0.009), but there were no significant differences in mortality rates. Multivariate analysis showed that an invasive strategy was an independent predictor of in-hospital morbidity (OR = 3.55). In follow-up, rates of MACE (56.3 vs. 33.3%, p = 0.002) and death (32.5 vs. 13.8%, p = 0.007) were higher in the group that received conservative treatment, and an invasive strategy was a protective factor against MACE; the strongest predictor of mortality was left ventricular ejection fraction <50%. CONCLUSIONS: Although an invasive strategy was associated with increased in hospital complications, it was shown to confer a better long-term prognosis. These data show that age should not be the only criterion in selecting patients for an invasive strategy and favor early adoption of this approach in the elderly. PMID- 21265491 TI - A case-control study of cardiovascular risk factors and cardiovascular risk among patients with schizophrenia in a country in the low cardiovascular risk region of Europe. AB - INTRODUCTION: Patients with serious mental illness have increased cardiovascular risk factors and excess mortality from cardiovascular disease that are in part favored by adverse effects of treatment. Given the wide geographical variation of vascular atherosclerotic disease there is a recognized need for national studies. METHODS: The prevalence of risk factors and estimated absolute and relative cardiovascular risk by means of SCORE risk charts were ascertained in 125 schizophrenia outpatients and 1721 age- and gender-matched primary care center users. RESULTS: Patients with schizophrenia have a very high prevalence of cardiovascular risk factors. Higher values were observed for smoking (65.0%), clinical or laboratory dyslipidemia (59.1% and 52.0%), careless diet (78.4%), sedentary lifestyle (64.2%), overweight or obesity (64.2%) and abdominal obesity (50.9%). Lower values were observed for hypertension (25.0%), metabolic syndrome (21.9%), diabetes (9.6%) and alcohol abuse (4.0%). An association risk factor exposure and disease was documented (odds ratio, [95% confidence limits]) for smoking (2.47 [1.68-3.64]), laboratory dyslipidemia (1.92 [1.33-2.77]), low HDL-C (2.12 [1.31-3.42]), careless diet (4.46 [2.88-6.90]) and sedentary lifestyle (1.79 [1.22-2.62]). A significant association between antipsychotics that are more likely to induce weight gain and overweight or obesity could not be demonstrated in this study. Hypertension was 46% lower in cases (n = 26/125) than in controls (0.54 [0.34-0.84]). This rather surprising result could be explained by our finding of a negative association (p = 0.01) between blood pressure levels and rate of benzodiazepine prescription among schizophrenia patients. The negative association documented in these patients by multivariate regression analysis (p = 0.005) between hypertension and benzodiazepine prescription reinforces this explanation. Untreated hypertension, untreated dyslipidemia and untreated diabetes are strongly associated with schizophrenia (3.79 [1.63-8.81]), (3.79 [2.06-7.35]), (6.38 [1.725-23.59]), respectively. A significant difference in 10-year absolute risk of fatal cardiovascular disease between cases and controls aged 40 years or more could not be demonstrated in our study (p = 0.054). Nonetheless, in younger individuals, higher levels of relative risk multiples in the 2-12 range were found in schizophrenia patients compared to controls (p < 0.050). CONCLUSIONS: In schizophrenia patients, a high prevalence of cardiovascular risk factors and of neglected treatment was found. The great majority of cases and controls aged 40 years or more have low and comparable levels of absolute cardiovascular risk mortality. For those aged under 40 years, schizophrenia patients show higher relative cardiovascular risk than controls. These findings call for closer collaboration between psychiatrists and primary care providers. The finding of a lower prevalence of hypertension among cases seems to be associated with an apparent protective effect of benzodiazepines, which are frequently prescribed to patients with schizophrenia in Portugal. PMID- 21265492 TI - Blood pressure in young adults. AB - INTRODUCTION: Hypertension (HT) is a major cardiovascular risk factor. Elevated blood pressure (BP) in childhood predisposes to HT in adulthood. Epidemiological studies in young age-groups are scarce. The aim of this study was to determine the prevalence of HT in a population of university students aged between 18 and 25 years; to analyze the profile of HT in the presence of other risk factors; and to alert patients and physicians to the need to assess and control cardiovascular risk factors in young adults. METHODS: We performed an observational, descriptive and cross-sectional study of a convenience sample of 402 university students, born between June 1, 1980 and May 24, 1988. Through a self-administered questionnaire and biometric measurements we recorded the following variables: BP, age, gender, smoking, regular medication, family history of HT, stress and body mass index. BP was determined by the mean of two measurements and classified according to the European Society of Cardiology guidelines. RESULTS: In the study population 229 (57%) individuals were female and 173 (42%) male, mean age 21 +/- 2 years. The prevalence of HT was 24.9% (20.4% with isolated systolic HT) and 27.4% had high normal BP. Among males 43.9% had HT, while among females only 10.5% were hypertensive. There was a high prevalence of HT in overweight (50.8%) and obese (50.0%) subjects. Among those exposed to stress, 27.2% had isolated systolic HT. A trend for HT was also found in young women taking oral contraceptives and in students with hypertensive first-degree relatives. CONCLUSIONS: The prevalence of HT and high normal BP in the study population of young adults was high. There was a statistically significant correlation between HT and male gender, HT and overweight and between isolated systolic HT and stress, confirming the existence of clusters of cardiovascular risk factors. Patients and their primary care physicians were alerted to the importance of assessing and controlling overall cardiovascular risk in young subjects. PMID- 21265493 TI - Proton pump inhibitors in patients treated with aspirin and clopidogrel after acute coronary syndrome. AB - INTRODUCTION: Clopidogrel is an antiplatelet agent converted to its active metabolite by cytochrome P-450 isoenzymes. Numerous drugs are known to inhibit P 450 isoenzymes, including proton pump inhibitors (PPIs), which are often associated with aspirin and clopidogrel to prevent adverse gastrointestinal effects. In vitro studies first showed that PPIs reduced the antiplatelet effect of clopidogrel, while recent clinical studies have raised concerns that the addition of a PPI to clopidogrel in acute coronary syndrome (ACS) patients could actually increase the risk of recurrent cardiovascular events. OBJECTIVE: The aim of this study was to evaluate whether the prescription of a PPI conferred a worse prognosis in patients discharged with aspirin and clopidogrel treatment after ACS. METHODS: A total of 876 patients admitted with ACS and discharged with aspirin and clopidogrel, with a planned duration of at least six months, from January 2004 to March 2008, were reviewed. Patients were classified in two groups according to whether or not a PPI was prescribed at discharge. The PPIs considered were those mainly metabolized by cytochrome P-450 2C19. We excluded patients with insufficient information available on either prescription or clinical records that could allow clearly confirm or exclude exposure to a PPI. Primary end points were six-month all-cause mortality and the composite of death, myocardial infarction and unstable angina at six months. RESULTS: Of the 802 patients considered for further analysis, 274 (34.2%) individuals were medicated with a PPI in addition to dual antiplatelet therapy. Patients taking PPIs were older, more often had renal insufficiency and less often had a history of coronary revascularization and smoking. They more often presented with Killip class >I and lower hemoglobin concentration on admission. There were no significant differences between the two groups in terms of medical treatment (during hospital stay and at discharge) or invasive procedures. By multivariate analysis, independent and positive predictors of PPI prescription were older age and lower hemoglobin concentration on admission. Patients taking PPIs had a slightly higher prevalence of six-month mortality (6.5% vs. 3.9%) and of the composite end point (12.9% vs. 9.2%), although without statistical significance. By multivariate analysis including potential confounding variables, the prescription of a PPI on top of aspirin and clopidogrel was still n ot associated with a worse prognosis. CONCLUSIONS: In the present study, PPI precription in addition to aspirin and clopidogrel after ACS was not associated with a worse six month prognosis. PMID- 21265495 TI - Cardiac resynchronization therapy: can left ventricular lead position make the difference? AB - The authors report the case of an 82-year-old female patient with non-ischemic dilated cardiomyopathy who developed worsening heart failure functional class despite optimal medical therapy. As the patient met criteria for cardiac resynchronization, a CRT-P device was implanted, but due to technical difficulties, the left ventricular lead was implanted in the anterior coronary vein. In the absence of any benefit from the procedure, a new left ventricular lead was implanted in posterolateral position with good clinical and echocardiographic response. PMID- 21265494 TI - Predictors of pre-hospital delay in patients with ST-segment elevation myocardial infarction. AB - BACKGROUND: Early reperfusion therapy in ST-elevation myocardial infarction (STEMI) correlates with its success. The aim of our study was to characterize patients admitted with a diagnosis of STEMI with longer prehospital delay and to analyze its impact on the choice of treatment and on in-hospital prognosis. METHODS: We performed a retrospective cohort study of 797 patients consecutively admitted with a diagnosis of STEMI from January 2002 to December 2007. The cutoff for longer pre-hospital delay was defined as three hours. We analyzed demographic, clinical and echocardiographic data and determined the predictors of pre-hospital delay of > or = 3 h. RESULTS: Of the 797 patients, 77% were male and mean age was 62 +/- 13.64 years. Patients with longer pre-hospital delay were older (p < 0.001), with a higher proportion of female (p = 0.001), hypertensive (p = 0.002), diabetic (p < 0.001), and surgically revascularized patients (p = 0.007), and those with symptom onset between 10 pm and 8 am (p = 0.001). The group with shorter pre-hospital delay included more men (p = 0.001), patients with prior myocardial infarction (p = 0.025) and smokers (p = 0.009). Independent predictors of pre-hospital delay of 3 h included female gender (odds ratio [OR] 1.5, 95% confidence interval [CI] 1.03-2.16), diabetes (OR 1.78, 95% CI 1.23 2.56), systemic arterial hypertension (OR 1.41, 95% CI 1.04-1.93), and symptom onset between 10 pm and 8 am (OR 1.76, 95% CI 1.31-2.38). Independent predictors of pre-hospital delay of > or = 3 h included male gender (OR 0.67, 95% CI 0.46 0.97) and prior myocardial infarction (OR 0.48, 95% CI 0.27-0.84). Reperfusion therapy was performed in 72%, 52% and 12% of patients with pre-hospital delay of <3 h, 3-12 h and >12 h, respectively (p for trend <0.001). Patients with longer delay more often had severely reduced left ventricular ejection fraction (LVEF) (p = 0.004). A non-significant trend was observed towards increased in-hospital mortality with longer delay (8.3% vs. 6.6%, p for trend = 0.342). CONCLUSIONS: A significant proportion of patients continue to have long pre-hospital delay. Female patients and those with diabetes, systemic arterial hypertension and symptom onset between 10 pm and 8 am made up the majority of this group. Longer pre-hospital delay was associated with a lower probability of being treated with reperfusion therapy, a higher frequency of severely depressed LVEF and a non significant increase in in-hospital mortality. It is essential to develop mechanisms to reduce pre-hospital delay. PMID- 21265496 TI - Perinatal atrial flutter: different therapeutic outcomes in two case reports. AB - Atrial flutter is a rare but potentially lethal arrhythmia, characterized by a rapid regular atrial rate, accompanied by variable degrees of atrioventricular block. Two cases of neonatal atrial flutter are described. The first case was diagnosed in utero at 38 weeks of gestation and converted to sinus rhythm by electric shock on the eighth day of life. Case two, diagnosed at 11 days old, with a background of acute bronchiolitis and tachycardia associated with a cardiac tumor, was refractory to electrical cardioversion. Both cases proved difficult to convert to sinus rhythm, but there was clinical improvement and no recurrence. These two cases exemplify the variability of outcomes achieved with anti-arrhythmic agents and direct current cardioversion. PMID- 21265497 TI - Paraganglioma--a case of secondary hypertension. AB - Paragangliomas (extra-adrenal pheochromocytomas) are rare tumors originating in the autonomic nervous system, whose clinical manifestations are the result of excessive production of catecholamines. The classic triad of palpitations, headache, and diaphoresis associated with hypertension (HT), elevated serum and urine catecholamine levels, and visualization of the mass on imaging tests, enables diagnosis of these tumors, which are mostly benign, and if diagnosed and treated early, are a potentially treatable cause of secondary hypertension. We present the case of a 28-year-old woman, a former smoker, sedentary, with a family history of HT, diabetes and coronary heart disease, and a personal history of episodic headaches, diaphoresis and syncope. HT was diagnosed at the age of 18 and controlled with losartan 50 mg/day up to the age of 28, when she was referred to a specialist for "worsening HT"/suspected secondary HT. The patient had no major alterations on physical examination except casual BP of 140/95 mmHg. On further study, ABPM recording revealed a non-dipper profile, with higher than normal blood pressure values and two blood pressure peaks without associated symptoms. She had elevated plasma catecholamine levels and a hypervascular retroperitoneal mass was visualized on CT and MRI, anterior to the inferior vena cava, measuring about 8 x 5.5 x 4.5 cm, with calcifications and areas of necrosis, confirmed by 123(I-MIBG) scintigraphy and PET scan. The mass was excised by laparotomy and the diagnosis of paraganglioma was confirmed. In postoperative follow-up the patient's blood pressure and catecholamine levels had normalized. PMID- 21265498 TI - Coronary fistulas after cardiac transplantation. PMID- 21265499 TI - Fracture of a pacemaker lead. PMID- 21265500 TI - Experimentally restrained molecular dynamics simulations for characterizing the open states of cytochrome P450cam. AB - Residual dipolar couplings (RDCs) were used as restraints in fully solvated molecular dynamics simulations of reduced substrate- and carbonmonoxy-bound cytochrome P450(cam) (CYP101A1), a 414-residue soluble monomeric heme-containing camphor monooxygenase from the soil bacterium Pseudomonas putida. The (1)D(NH) residual dipolar couplings used as restraints were measured in two independent alignment media. A soft annealing protocol was used to heat the starting structures while incorporating the RDC restraints. After production dynamics, structures with the lowest total violation energies for RDC restraints were extracted to identify ensembles of conformers accessible to the enzyme in solution. The simulations result in substrate orientations different from that seen in crystallographic structures and a more open and accessible enzyme active site and largely support previously reported differences between the open and closed states of CYP101A1. PMID- 21265501 TI - Nonparametric rank regression for analyzing water quality concentration data with multiple detection limits. AB - Environmental data usually include measurements, such as water quality data, which fall below detection limits, because of limitations of the instruments or of certain analytical methods used. The fact that some responses are not detected needs to be properly taken into account in statistical analysis of such data. However, it is well-known that it is challenging to analyze a data set with detection limits, and we often have to rely on the traditional parametric methods or simple imputation methods. Distributional assumptions can lead to biased inference and justification of distributions is often not possible when the data are correlated and there is a large proportion of data below detection limits. The extent of bias is usually unknown. To draw valid conclusions and hence provide useful advice for environmental management authorities, it is essential to develop and apply an appropriate statistical methodology. This paper proposes rank-based procedures for analyzing non-normally distributed data collected at different sites over a period of time in the presence of multiple detection limits. To take account of temporal correlations within each site, we propose an optimal linear combination of estimating functions and apply the induced smoothing method to reduce the computational burden. Finally, we apply the proposed method to the water quality data collected at Susquehanna River Basin in United States of America, which clearly demonstrates the advantages of the rank regression models. PMID- 21265503 TI - Current trends in the chemistry of permanent hair dyeing. PMID- 21265502 TI - A hearing loss-associated myo1c mutation (R156W) decreases the myosin duty ratio and force sensitivity. AB - myo1c is a member of the myosin superfamily that has been proposed to function as the adaptation motor in vestibular and auditory hair cells. A recent study identified a myo1c point mutation (R156W) in a person with bilateral sensorineural hearing loss. This mutated residue is located at the start of the highly conserved switch 1 region, which is a crucial element for the binding of nucleotide. We characterized the key steps on the ATPase pathway at 37 degrees C using recombinant wild-type (myo1c(3IQ)) and mutant myo1c (R156W-myo1c(3IQ)) constructs that consist of the motor domain and three IQ motifs. The R156W mutation only moderately affects the rates of ATP binding, ATP-induced actomyosin dissociation, and ADP release. The actin-activated ATPase rate of the mutant is inhibited >4-fold, which is likely due to a decrease in the rate of phosphate release. The rate of actin gliding, as measured by the in vitro motility assay, is unaffected by the mutation at high myosin surface densities, but the rate of actin gliding is substantially reduced at low surface densities of R156W myo1c(3IQ). We used a frictional loading assay to measure the affect of resisting forces on the rate of actin gliding and found that R156W-myo1c(3IQ) is less force sensitive than myo1c(3IQ). Taken together, these results indicate that myo1c with the R156W mutation has a lower duty ratio than the wild-type protein and motile properties that are less sensitive to resisting forces. PMID- 21265504 TI - Effect of light on iron uptake by the freshwater cyanobacterium Microcystis aeruginosa. AB - Visible light was observed to induce reductive dissociation of organically complexed Fe and dramatically increase the short-term uptake rate of radiolabeled Fe by Microcystis aeruginosa PCC7806 in Fraquil* medium buffered by a single metal chelator, ethylenediaminetetraacetic acid (EDTA). Only wavelengths <500 nm activated Fe uptake indicating that Fe photochemistry rather than biological factors is responsible for the facilitated uptake. The measured rate of photochemical Fe(II) production combined with a significant decrease in (55)Fe uptake rate in the presence of ferrozine (a strong ferrous iron chelator) confirmed that photogenerated unchelated Fe(II) was the major form of Fe taken up by M. aeruginosa under the conditions examined. Mathematical modeling based on unchelated Fe(II) uptake by concentration gradient dependent passive diffusion of Fe(II) through nonspecific transmembrane channels (porins) could account for the magnitude of Fe uptake and a variety of other observations such as the effect of competing ligands on Fe uptake. Steady-state uptake rates indicated that M. aeruginosa acquires Fe predominantly during the light cycle. This study confirms that Fe photochemistry has a dominant impact on Fe acquisition and growth by M. aeruginosa in EDTA-buffered culture medium. PMID- 21265505 TI - Formation of large-scale flexible transparent conductive films using evaporative migration characteristics of Au nanoparticles. AB - To sustain the growing demand of transparent conductive films for wide applications, such as flat panel displays, a much more cost-effective film is required over the widely used indium tin oxide film. Here we developed a promising method to manufacture a cost-effective flexible transparent conductive film of high performance by first making grid-iron patterns of thin lines on a large scale using evaporative migration characteristics of gold nanoparticles, and then by burying the grid-iron pattern into a poly(ethylene terephthalate) film. PMID- 21265506 TI - A myelin-specific contrast agent for magnetic resonance imaging of myelination. AB - Myelination is one of the most fundamental biological processes in the development of vertebrate nervous systems. Abnormal or disrupted myelination occurs in many acquired or inherited neurodegenerative diseases, including multiple sclerosis (MS) and various leukodystrophies. To date, magnetic resonance imaging (MRI) has been the primary tool for diagnosing and monitoring the progression of MS and related diseases; however, any change in signal intensity of conventional MRI reflects a change only in tissue water content, which is a nonspecific measure of the overall changes in macroscopic tissue injury. Thus, the use of MRI as a primary measure of disease activity was shown to be disassociated from the clinical outcome due to the lack of specificity for myelination. In order to increase the MRI specificity for myelin pathologies, we designed and synthesized the first Gd-based T(1) MR contrast agent (MIC) that binds to myelin with high specificity. In this Communication, we demonstrate that MIC localizes in brain regions in proportion to the extent of myelination. In addition, MIC possesses promising MR contrast properties, which allow for direct detection of myelin distribution through T(1) mapping in the mouse brain. PMID- 21265507 TI - Spin hamiltonian parameters for Cu(II)-prion peptide complexes from L-band electron paramagnetic resonance spectroscopy. AB - Cu(II) is an essential element for life but is also associated with numerous and serious medical conditions, particularly neurodegeneration. Structural modeling of crystallization-resistant biological Cu(II) species relies on detailed spectroscopic analysis. Electron paramagnetic resonance (EPR) can, in principle, provide spin hamiltonian parameters that contain information on the geometry and ligand atom complement of Cu(II). Unfortunately, EPR spectra of Cu(II) recorded at the traditional X-band frequency are complicated by (i) strains in the region of the spectrum corresponding to the g(?) orientation and (ii) potentially very many overlapping transitions in the g(?) region. The rapid progress of density functional theory computation as a means to correlate EPR and structure, and the increasing need to study Cu(II) associated with biomolecules in more biologically and biomedically relevant environments such as cells and tissue, have spurred the development of a technique for the extraction of a more complete set of spin hamiltonian parameters that is relatively straightforward and widely applicable. EPR at L-band (1-2 GHz) provides much enhanced spectral resolution and straightforward analysis via computer simulation methods. Herein, the anisotropic spin hamiltonian parameters and the nitrogen coordination numbers for two hitherto incompletely characterized Cu(II)-bound species of a prion peptide complex are determined by analysis of their L-band EPR spectra. PMID- 21265508 TI - Identification of N-terminal regions of wheat leaf ferredoxin NADP+ oxidoreductase important for interactions with ferredoxin. AB - Wheat leaves contain two isoproteins of the photosynthetic ferredoxin:NADP(+) reductase (pFNRI and pFNRII). Truncated forms of both enzymes have been detected in vivo, but only pFNRII displays N-terminal length-dependent changes in activity. To investigate the impact of N-terminal truncation on interaction with ferredoxin (Fd), recombinant pFNRII proteins, differing by deletions of up to 25 amino acids, were generated. During purification of the isoproteins found in vivo, the longer forms of pFNRII bound more strongly to a Fd affinity column than did the shorter forms, pFNRII(ISKK) and pFNRII[N-2](KKQD). Further truncation of the N-termini resulted in a pFNRII protein which failed to bind to a Fd column. Similar k(cat) values (104-140 s(-1)) for cytochrome c reduction were measured for all but the most truncated pFNRII[N-5](DEGV), which had a k(cat) of 38 s(-1). Stopped-flow kinetic studies, examining the impact of truncation on electron flow between mutant pFNRII proteins and Fd, showed there was a variation in k(obs) from 76 to 265 s(-1) dependent on the pFNRII partner. To analyze the sites which contribute to Fd binding at the pFNRII N-terminal, three mutants were generated, in which a single or double lysine residue was changed to glutamine within the in vivo N-terminal truncation region. The mutations affected binding of pFNRII to the Fd column. Based on activity measurements, the double lysine residue change resulted in a pFNRII enzyme with decreased Fd affinity. The results highlight the importance of this flexible N-terminal region of the pFNRII protein in binding the Fd partner. PMID- 21265509 TI - Electric field assisted surface plasmon-coupled directional emission: an active strategy on enhancing sensitivity for DNA sensing and efficient discrimination of single base mutation. AB - We have demonstrated the proof-of-principle of electric field assisted surface plasmon-coupled directional emission (E-SPCDE). The combination of SPCDE and electric field control produced a significant synergistic effect to amplify the right signal and suppress the wrong signal intelligently in an active strategy. A novel hairpin structured DNA biosensor based on the quenching and enhancing of fluorescence in SPCDE has been designed. With modulation of the fluorescence coupling efficiency, a high discrimination ratio up to more than 20-fold has been achieved by enhancing the signal of match and suppressing that of mismatch. E SPCDE has shown a successful application in DNA sensing, eliminating false positives and false negatives in the detection. E-SPCDE should provide an opportunity to create a new generation of miniaturized high-performance sensing platforms especially in chip-based microarrays and to make the manipulation of the nanometer-scale processes more accessible and detectable. PMID- 21265510 TI - Absence of superconductivity in LiCu2P2. AB - We successfully synthesized the copper-based pnictide LiCu(2)P(2), which was reported as a superconductor with T(c) = 3.7 K before. The temperature dependence of resistivity and DC magnetization was measured on both polycrystalline and single-crystalline LiCu(2)P(2). However, our repeatable synthesizing and measurements showed no superconducting transition either in resistivity or DC magnetization above 2 K. A metallic behavior can be seen in resistivity, and a Curie-Weiss behavior was observed in DC magnetization from 2 to 300 K. We have also carried out the Hall effect and MR measurements on the sample, from which we conclude that the LiCu(2)P(2) has a single-band character. We also synthesized the polycrystalline Li(1-x)Cu(2)P(2), LiCu(2-x)P(2), and Li(1+x)Cu(2-x)P(2) with different stoichiometries, and observed no superconductivity in all the samples. PMID- 21265512 TI - Adsorption of polyelectrolyte/surfactant mixtures at the air-water interface: modified poly(ethyleneimine) and sodium dodecyl sulfate. AB - The adsorption of surfactant/polyelectrolyte mixtures of sodium dodecyl sulfate (SDS) and different modified poly(ethyleneimine) (PEI) polyelectrolytes at the air-water interface has been studied using neutron reflectivity and surface tension. Modification of the PEI by the addition of short ethylene oxide (EO) or propylene oxide (PO) groups is shown to have an impact upon the surface adsorption behavior. This is due to a modification of the polymer/surfactant interaction, an increase in the intrinsic surface activity of the modified polyelectrolyte, and changes in the relative importance of surface and solution complex formation. For the polyelectrolyte PEI, there is a marked change in the surface adsorption behavior between the addition of a single EO group and that of the (EO)3 group. The addition of a single EO or PO group to the PEI results in an SDS concentration and solution pH adsorption dependence that is broadly similar in behavior to that of the unmodified PEI/SDS mixture. That is, there is strong surface complexation and adsorption down to low SDS concentrations, and there is evidence of a strong interaction at high pH in addition to the strong electrostatic attraction at low pH. The addition of a larger ethylene oxide group, triethylene oxide (EO)3, results in a surface adsorption behavior that more closely resembles that of a neutral polymer/ionic surfactant mixture, similar to that observed for PEI with a larger ethylene oxide group, notably PEI (EO)7. In that case, the adsorption of the polymer/surfactant complex is much less pronounced. The adsorption arises predominantly from competition between the polymer and surfactant and indicates a decrease in the polymer/surfactant interaction with increasing pH. That is, increasing the size of the ethylene oxide group induces a transition from a strong surface polymer/surfactant interaction to a weak polymer/surfactant interaction. PMID- 21265511 TI - Characterization of hepatitis B virus capsids by resistive-pulse sensing. AB - We report characterization of hepatitis B virus (HBV) capsids by resistive-pulse sensing through single track-etched conical nanopores formed in poly(ethylene terephthalate) membranes. The pores were ~40 nm in diameter at the tip, and the pore surface was covalently modified with triethylene glycol to reduce surface charge density, minimize adsorption of the virus capsids, and suppress electroosmotic flow in the pore. The HBV capsids were assembled in vitro from Cp149, the assembly domain of HBV capsid protein. Assembled T = 3 (90 Cp149 dimer) and T = 4 (120 dimer) capsids are 31 and 36 nm in diameter, respectively, and were easily discriminated by monitoring the change in current as capsids passed through an electrically biased pore. The ratio of the number of T = 3 to T = 4 capsids transiting a pore did not reflect actual concentrations, but favored transport of smaller T = 3 capsids. These results combined with longer transit times for the T = 4 capsids indicated that the capsids must overcome an entropic barrier to enter a pore. PMID- 21265513 TI - A new spectral window on retinal protein photochemistry. AB - A VIS pump/hyperspectral NIR probe study of all-trans-retinal protonated Schiff base (RPSB) in ethanol is presented. Upon irradiation, a short-lived absorption band covers the recorded range of lambda = 1-2 MUm. It decays to reveal the tail of S(1) emission at lambda < 1.3 MUm, along with a residual absorption at longer wavelengths, both of which decay with the known kinetics of internal conversion to S(0). The existence of this hitherto unrecorded excited-state absorption deep in the NIR will require a revision of current models for RPSB electronic structure. The phenomenological similarity of these observations with ultrafast NIR studies of carotenoids raises the question of whether three, and not two, electronic states participate in RPSB photochemistry as well. The relevance of these observations to retinal protein photochemistry is discussed. PMID- 21265514 TI - Western blotting using capillary electrophoresis. AB - A microscale Western blotting system based on separating sodium-dodecyl sulfate protein complexes by capillary gel electrophoresis followed by deposition onto a blotting membrane for immunoassay is described. In the system, the separation capillary is grounded through a sheath capillary to a mobile X-Y translation stage which moves a blotting membrane past the capillary outlet for protein deposition. The blotting membrane is moistened with a methanol and buffer mixture to facilitate protein adsorption. Although discrete protein zones could be detected, bands were broadened by ~1.7-fold by transfer to membrane. A complete Western blot for lysozyme was completed in about one hour with 50 pg mass detection limit from low microgram per milliliter samples. These results demonstrate substantial reduction in time requirements and improvement in mass sensitivity compared to conventional Western blots. Western blotting using capillary electrophoresis shows promise to analyze low volume samples with reduced reagents and time, while retaining the information content of a typical Western blot. PMID- 21265515 TI - Simple bead assay for detection of live bacteria (Escherichia coli). AB - Bead assays are an important rapid microbial detection technology suitable for extremely low pathogen levels. We report a bead assay for rRNA extracted from Escherichia coli K12 that does not require amplification steps and has readout on an Agilent 2100 Bioanalyzer flow cytometry system. Our assay was able to detect 125 ng of RNA, which is 16 times less than reported earlier. The specificity was extremely high, with no binding to a negative control organism (Bacillus subtilis). We discuss challenges faced during optimization of the key assay components, such as varying amounts of RNA in the samples, number of beads, aggregation, and reproducibility. PMID- 21265516 TI - Polyparameter linear free energy models for polyacrylate fiber-water partition coefficients to evaluate the efficiency of solid-phase microextraction. AB - The fiber-water partition coefficient, K(fw), is decisive for performance of solid-phase microextraction (SPME) techniques in organic chemical analyses. In this study, polyacrylate (PA)-coated fiber was evaluated for its K(fw) values toward diverse neutral organic compounds. Literature K(fw) data were thoroughly evaluated, and additional K(fw) values for 69 compounds were measured in phosphate-buffered saline (PBS) solution at 37 degrees C. These K(fw) data, spanning over 6 orders of magnitude, were used to construct polyparameter linear free energy relationship (PP-LFER) models. The PP-LFER models fit well to the data with a standard deviation of 0.15-0.23 log units. Additional experiments indicated that the differences in temperature (25 vs 37 degrees C), electrolyte concentrations (pure water vs PBS), and conditioning methods (heat vs methanol) had only minor influences (<0.3 log units) on K(fw). Using the established PP LFERs, the SPME extraction efficiency of PA coating toward compounds of differing polarity was evaluated in comparison to poly(dimethylsiloxane) (PDMS) coating. PA exhibited higher extraction capacities for H-bond donor compounds (e.g., phenols, anilines, amides, and many drugs and pesticides) with the estimated K(fw) values being 1-4 log units higher than those of PDMS. Also, PA was shown to be more efficient than PDMS for hydrophobic aromatic compounds. PMID- 21265517 TI - Enhanced lysozyme imprinting over nanoparticles functionalized with carboxyl groups for noncovalent template sorption. AB - Surface molecular imprinting, in particular over nanosized support materials, is very suitable for a template of bulky structure like protein. Inspired by the surface template immobilization method reported previously, we herein demonstrate an alternative strategy for enhancing specific recognition of core-shell protein imprinted nanoparticles through prefunctionalizing the cores with noncovalent template sorption groups. For proof of this concept, silica nanoparticles chosen as the core materials were modified consecutively with 3 aminopropyltrimethoxysilane and maleic anhydride to introduce polymerizable double bonds and terminal carboxyl groups, hence capable of physically adsorbing the print protein. With lysozyme as a template, thin protein-imprinted shells were fabricated according to our newly developed approach for surface protein imprinting over nanoparticles. The rebinding experiments confirmed that the introduction of the carboxyl groups could remarkably improve the imprinting effect in relation to a significantly increased imprinting factor and specific rebinding capacity. Moreover, in contrast to the harsh template removal conditions required for the covalent template coupling approach, the template removal during the imprinted particle synthesis as well as desorption after rebinding could be mildly achieved via washing with salt solution. PMID- 21265518 TI - Mechanisms of chemical carcinogenicity and mutagenicity: a review with implications for predictive toxicology. PMID- 21265519 TI - Dynamic chirality of (E)-5-cyclononen-1-one and its enolate. AB - It has been found that (E)-5-cyclononen-1-one (2a) exhibits marginal planar chirality owing to an insufficient topological constraint, whereas the enolates 3 derived from 2a show robust planar chirality. Enantioenriched enolates are easily prepared by enzymatic hydrolysis, and they show an ability to serve as chiral nucleophiles. PMID- 21265520 TI - Photochemistry of hydrogen halides on water clusters: simulations of electronic spectra and photodynamics, and comparison with photodissociation experiments. AB - The photochemistry of small HX.(H(2)O)(n), n = 4 and 5 and X = F, Cl, and Br, clusters has been modeled by means of ab initio-based molecular simulations. The theoretical results were utilized to support our interpretation of photodissociation experiments with hydrogen halides on ice nanoparticles HX.(H(2)O)(n), n ~ 10(2)-10(3). We have investigated the HX.(H(2)O)(n) photochemistry for three structural types: covalently bound structures (CBS) and acidically dissociated structures in a form of contact ion pair (CIP) and solvent separated pair (SSP). For all structures, we have modeled the electronic absorption spectra using the reflection principle combined with a path integral molecular dynamics (PIMD) estimate of the ground state density. In addition, we have investigated the solvent effect of water on the absorption spectra within the nonequilibrium polarizable continuum model (PCM) scheme. The major conclusion from these calculations is that the spectra for ionic structures CIP and SSP are significantly red-shifted with respect to the spectra of CBS structures. We have also studied the photodynamics of HX.(H(2)O)(n) clusters using the Full Multiple Spawning method. In the CBS structures, the excitation led to almost immediate release of the hydrogen atom with high kinetic energy. The light absorption in ionically dissociated species generates the hydronium radical (H(3)O) and halogen radical (X) within a charge-transfer-to-solvent (CTTS) excitation process. The hydronium radical ultimately decays into a water molecule and hydrogen atom with a characteristic kinetic energy irrespective of the hydrogen halide. We have also investigated the dynamics of an isolated and water-solvated H(3)O radical that we view as a central species in water radiation chemistry. The theoretical findings support the following picture of the HX photochemistry on ice nanoparticles investigated in our molecular beam experiments: HX is acidically dissociated in the ground state on ice nanoparticles, generating the CIP structure, which is then excited by the UV laser light into the CTTS states, followed by the H(3)O radical formation. PMID- 21265521 TI - Bioengineering single crystal growth. AB - Biomineralization is a "bottom-up" synthesis process that results in the formation of inorganic/organic nanocomposites with unrivaled control over structure, superior mechanical properties, adaptive response, and the capability of self-repair. While de novo design of such highly optimized materials may still be out of reach, engineering of the biosynthetic machinery may offer an alternative route to design advanced materials. Herein, we present an approach using micro-contact-printed lectins for patterning sea urchin embryo primary mesenchyme cells (PMCs) in vitro. We demonstrate not only that PMCs cultured on these substrates show attachment to wheat germ agglutinin and concanavalin A patterns but, more importantly, that the deposition and elongation of calcite spicules occurs cooperatively by multiple cells and in alignment with the printed pattern. This allows us to control the placement and orientation of smooth, cylindrical calcite single crystals where the crystallographic c-direction is parallel to the cylinder axis and the underlying line pattern. PMID- 21265522 TI - Mussel-inspired encapsulation and functionalization of individual yeast cells. AB - The individual encapsulation of living cells has a great impact on the area of cell-based sensors and devices as well as fundamental studies in cell biology. In this work, living yeast cells were individually encapsulated with functionalizable, artificial polydopamine shells, inspired by an adhesive protein in mussels. Yeast cells maintained their viability within polydopamine, and the cell cycle was controlled by the thickness of the shells. In addition, the artificial shells aided the cell in offering much stronger resistance against foreign aggression, such as lyticase. After formation of the polydopamine shells, the shells were functionalized with streptavidin by utilizing the chemical reactivity of polydopamine, and the functionalized cells were biospecifically immobilized onto the defined surfaces. Our work suggests a biomimetic approach to the encapsulation and functionalization of individual living cells with covalently bonded, artificial shells. PMID- 21265523 TI - Palladium-catalyzed carboiodination of alkenes: carbon-carbon bond formation with retention of reactive functionality. AB - We report a palladium-catalyzed carbon-carbon bond-forming reaction between aryl iodides and alkenes. In contrast to traditional cross-coupling reactions, two new bonds are formed, and all of the atoms in the starting materials are incorporated into the product. The use of a palladium catalyst with bulky phosphine ligands is found to be crucial for reactivity. PMID- 21265524 TI - Synthesis of cis,syndiotactic ROMP polymers containing alternating enantiomers. AB - Ring-opening metathesis polymerization (ROMP) of rac-endo,exo-5,6 dicarbomethoxynorbornene (inter alia) yields a cis,syndio,alt-polymer, one in which the sequential units in the cis,syndiotactic polymer consist of alternating enantiomers. Cis selectivity arises through addition of the monomer to produce an all-cis-metallacyclobutane intermediate, while syndioselectivity and alternating enantiomer structures arise as a consequence of inversion of configuration at the metal center with each metathesis step. PMID- 21265525 TI - Computational evidence for self-initiation in spontaneous high-temperature polymerization of methyl methacrylate. AB - This paper presents computational evidence for the occurrence of diradical mechanism of self-initiation in thermal polymerization of methyl methacrylate. Two self-initiation mechanisms of interest were explored with first-principles density functional theory calculations. Singlet and triplet potential energy surfaces were constructed. The formation of two Diels-Alder adducts, cis- and trans-dimethyl 1,2-dimethylcyclobutane-1,2-dicarboxylate and dimethyl 2-methyl-5 methylidene-hexanedioate, on the singlet surface was identified. Transition states were calculated using B3LYP/6-31G* and assessed using MP2/6-31G*. The calculated energy barriers and rate constants with different levels of theory were found to show good agreement to corresponding data obtained from laboratory experiments. The presence of a diradical intermediate on the triplet surface was identified. When MCSCF/6-31G* was used, the spin-orbit coupling constant for the singlet to triplet crossover was calculated to be 2.5 cm(-1). The mechanism of monoradical generation via a hydrogen abstraction by both triplet and singlet diradicals from a third monomer was identified to be the most likely mechanism of initiation in spontaneous polymerization of methyl methacrylate. PMID- 21265526 TI - (+/-)-trans,cis-4-Hydroxy-5,6-di-O-isopropylidenecyclohex-2-ene-1-one: synthesis and facile dimerization to decahydrodibenzofurans. AB - An efficient synthesis of (+/-)-trans,cis-4-hydroxy-5,6-di-O isopropylidenecyclohex-2-ene-1-one (3) has been developed from acetonide protected meso-1,2-dihydrocatechol derivative 1 via photooxygenation, then Kornblum-DeLaMare rearrangement. The product is unstable unless its 4-hydroxy group is protected, as it undergoes facile dimerization in solution to a 1:1 mixture of diastereoisomeric decahydrodibenzofurans 8 and 9. A new synthesis of the dihydrocatechol 1 from 1,3-cyclohexadiene has also been developed. PMID- 21265527 TI - Unusual approach to 3-aryl-2-aminopyridines through a radical mechanism: synthesis and theoretical rationale from quantum mechanical calculations. AB - Tris(trimethylsilyl)silane and azobis(cyclohexanenitrile) promoted the easy intramolecular arylation of aryl bromopyridine carbamates through a radical [1,6] ipso substitution process. These substrates showed a preference for this type of reaction over the alternative [1,7] addition. The results were rationalized by making use of quantum mechanical calculations and computer graphics. PMID- 21265528 TI - Asymmetric synthesis of all-carbon quaternary stereocenters via desymmetrization of 2,2-disubstituted 1,3-propanediols. PMID- 21265529 TI - Vinylogous addition of siloxyfurans to benzopyryliums: a concise approach to the tetrahydroxanthone natural products. AB - A concise approach to the tetrahydroxanthone natural products employing vinylogous addition of siloxyfurans to benzopyryliums and a late-stage Dieckmann cyclization has been developed. With this methodology, chiral, racemic forms of the natural products blennolides B and blennolide C have been synthesized in a maximum of four steps from a 5-hydroxychromone substrate. The regio- and diastereoselectivity of the vinylogous additions was probed using computational studies, which suggested the involvement of Diels-Alder-like transition states. PMID- 21265530 TI - Direct observation of a carbene-alcohol ylide. AB - Carboethoxycarbene reacts with methanol-OD to form an ylide. The formation and decay of this ylide was monitored by ultrafast time-resolved IR spectroscopy. The formation and decay of the ylide is linearly dependent on the concentration of methanol-OD in acetonitrile with second-order rate constants of ylide formation (8.4 * 10(9) M(-1) s(-1)) and decay (1.4 * 10(9) M(-1) s(-1)). Similar results were obtained with 1-butanol. PMID- 21265532 TI - Introducing multicomponent reactions to polymer science: Passerini reactions of renewable monomers. AB - Combination of the Passerini three component-reaction (3CR) and olefin metathesis led to the formation of poly[1-(alkyl carbamoyl)alkyl alkanoates], a new class of polyesters with amide moieties in their side chain, from renewable resources. Two different approaches were studied and compared to each other. First, monomers were synthesized by the Passerini-3CR and then polymerized via acyclic diene metathesis. Alternatively, bifunctional monomers were synthesized by self metathesis and then polymerized by Passerini-3CR. Both approaches led to the formation of high-molecular-weight polymers. Moreover, Passerini-3CRs were shown to be a versatile grafting-onto method. The results clearly demonstrate that the Passerini-3CR offers an interesting new access to monomers and polymers and thus broadens the synthetic portfolio of polymer science. PMID- 21265531 TI - Chiral N-heterocyclic carbene-copper(I)-catalyzed asymmetric allylic arylation of aliphatic allylic bromides: steric and electronic effects on gamma-selectivity. AB - Chiral N-heterocyclic carbene ligands were electronically and sterically tuned to improve gamma-selectivity in copper(I)-catalyzed asymmetric allylic arylation of aliphatic allylic bromides with several aryl Grignard reagents. High gamma selectivity was realized when either the aryl group of the Grignard reagent or the aryl group on the N-substituent of the carbene ligand was electron-deficient or when either the carbene ligand or allylic bromide was bulky. The results indicated that electron deficiency and steric hindrance of the initially formed sigma-allyl copper intermediate enhance the rate of the reductive elimination to give gamma-products as major isomers. PMID- 21265533 TI - Single-molecule conductance through multiple pi-pi-stacked benzene rings determined with direct electrode-to-benzene ring connections. AB - Understanding electron transport across pi-pi-stacked systems will help to answer fundamental questions about biochemical redox processes and benefit the design of new materials and molecular devices. Herein we employed the STM break-junction technique to measure the single-molecule conductance of multiple pi-pi-stacked aromatic rings. We studied electron transport through up to four stacked benzene rings held together in an eclipsed fashion via a paracyclophane scaffold. We found that the strained hydrocarbons studied herein couple directly to gold electrodes during the measurements; hence, we did not require any heteroatom binding groups as electrical contacts. Density functional theory-based calculations suggest that the gold atoms of the electrodes bind to two neighboring carbon atoms of the outermost cyclophane benzene rings in eta(2) fashion. Our measurements show an exponential decay of the conductance with an increasing number of stacked benzene rings, indicating a nonresonant tunneling mechanism. Furthermore, STM tip-substrate displacement data provide additional evidence that the electrodes bind to the outermost benzene rings of the pi-pi stacked molecular wires. PMID- 21265534 TI - Cupric superoxo-mediated intermolecular C-H activation chemistry. AB - The new cupric superoxo complex [LCu(II)(O(2)(*-))](+), which possesses particularly strong O-O and Cu-O bonding, is capable of intermolecular C-H activation of the NADH analogue 1-benzyl-1,4-dihydronicotinamide (BNAH). Kinetic studies indicated a first-order dependence on both the Cu complex and BNAH with a deuterium kinetic isotope effect (KIE) of 12.1, similar to that observed for certain copper monooxygenases. PMID- 21265535 TI - Melanin synthesis inhibitors from Balanophora fungosa. AB - Tyrosinase, trypsin, and tryptase are known to play important roles in melanin production of human skin. This paper describes the study of the inhibitory effect of Balanophora fungosa on melanin. The 50% EtOH extract obtained from B. fungosa indicated an inhibitory effect on mushroom tyrosinase activity with an IC(50) value of 15 MUg/mL. Bioassay-guided fractionation of the active extract resulted in the isolation of four known compounds. Their structures were identified as 1-O (E)-caffeoyl-3-O-galloyl-4,6-(S)-HHDP-beta-d-glucopyranose (1), 1-O-(E)-caffeoyl 3,4,6-tri-O-galloyl-beta-d-glucopyranose (2), caffeoyl-beta-d-glucopyranose (3), and abietin (4) on the basis of spectroscopic analyses and comparison of their spectral data with those in the literature. Compounds 1 and 2 prevented pigmentation of melanin in a three-dimensional cultured human skin model. Furthermore, compounds 1 and 2 indicated inhibitory activities against trypsin and tryptase. PMID- 21265536 TI - New hydrothermal treatment of alperujo enhances the content of bioactive minor components in crude pomace olive oil. AB - The application of a new process based on the hydrothermal treatment of olive oil waste (alperujo) led to a final solid rich in pomace olive oil (POO) enriched in minor components with functional activities. The effects of the time (15-90 min) and the temperature (150, 160, and 170 degrees C) of the thermal processing of alperujo on the yield, quality, and enrichment of minor components of crude POO were evaluated. The final treated solid had an increase in oil yield up to 97%, with a reduction in solids up to 35.6-47.6% by solubilization. Sterols increased up to 33%, aliphatic alcohols increased up to 92%, triterpenic alcohols increased up to 31%, squalene increased up to 43%, tocopherols increased up to 57%, and oleanolic acid increased up to 16% by the new treatment. The increase maintains a high concentration of functional substances probably even in the refining POO. PMID- 21265537 TI - Enhanced glucosinolates in root exudates of Brassica rapa ssp. rapa mediated by salicylic acid and methyl jasmonate. AB - Elicitation studies with salicylic acid (SA) and methyl jasmonate (MJ) inducing a targeted rhizosecretion of high levels of anticarcinogenic glucosinolates in Brassica rapa ssp. rapa plants were conducted. Elicitor applications not only led to an accumulation of individual indole glucosinolates and the aromatic 2 phenylethyl glucosinolate in the turnip organs but also in turnip root exudates. This indicates an extended systemic response, which comprises the phyllosphere with all aboveground plant organs and the rhizosphere including the belowground root system and also root exudates. Both elicitor applications induced a doubling in 2-phenylethyl glucosinolate in root exudates, whereas application of MJ enhanced rhizosecreted indole glucosinolates up to 4-fold. In addition, the time course study revealed that maximal elicitation was observed on the 10th day of SA and MJ treatment. This study may provide an essential contribution using these glucosinolates as bioactive additives in functional foods and nutraceuticals. PMID- 21265538 TI - A general procedure for the synthesis of enones via gold-catalyzed Meyer-Schuster rearrangement of propargylic alcohols at room temperature. AB - Meyer-Schuster rearrangements of propargylic alcohols take place readily at room temperature in toluene with 1-2 mol % PPh(3)AuNTf(2), in the presence of 0.2 equiv of 4-methoxyphenylboronic acid or 1 equiv of methanol. Good to excellent yields of enones can be obtained from secondary and tertiary alcohols, with high selectivity for the E-alkene in most cases. A one-pot procedure for the conversion of primary propargylic alcohols into beta-arylketones was also developed, via Meyer-Schuster rearrangement followed by Pd-catalayzed addition of a boronic acid. PMID- 21265539 TI - Controlled anion migrations with a mixed metal Li/K-TMP amide: general application to benzylic metalations. AB - A general method is described for benzylic metalation of o-, m-, and p substituted toluenes using a mixed metal amide base generated from BuLi/KOtBu/TMP at -78 degrees C in THF. The excellent selectivity achieved can be rationalized by the ability of the mixed metal amide base to facilitate an anion migration from the kinetic (o-aryl) to the benzylic metalation site. Remarkably, this controlled anion migration is achievable with catalytic amounts of TMP at -78 degrees C. PMID- 21265540 TI - UV and MS identification of Urolithins and Nasutins, the bioavailable metabolites of ellagitannins and ellagic acid in different mammals. AB - Urolithins are microbial metabolites produced from ellagic acid after the intake of dietary ellagitannins by different animals. Urolithin metabolites have distinct UV spectra that enable their detection and differentiation by HPLC coupled with UV photodiode array detectors. Correlations between structural characteristics, including conjugation, with the UV spectra and retention times are established. The production of urolithin derivatives in different animals feeding on ellagitannins, including rodents (rats and mice), humans, pigs, squirrels, beavers, sheep, bull calves, birds, and insects, was investigated. All mammals produced urolithins, and their glucuronyl and sulfate conjugates were the main metabolites detected in plasma and urine. Unconjugated urolithins were detected in feces, ruminal content, and beaver castoreum. Different urolithin hydroxylation patterns were observed for different animal species, suggesting that the microbiota responsible for the metabolism of ellagitannins in each animal species produces dehydroxylases for the removal of specific hydroxyls from the ellagic acid residue. Metabolites were characterized using HR HPLC-TOF-MS and ion trap MS/MS. Insects and birds feeding on ellagitannin-containing foods did not produce urolithins, although they released ellagic acid. Beavers and pigs were able to produce dehydroxyellagic acid derivatives (nasutin A), showing that in some cases the removal of hydroxyl groups from the ellagic acid nucleus can be carried out before the lactone ring is opened to produce urolithins. PMID- 21265541 TI - Tetrahydrofolic Acid is a potent suicide substrate of mushroom tyrosinase. AB - The coenzyme tetrahydrofolic acid is the most rapid suicide substrate of tyrosinase that has been characterized to date. A kinetic study of the suicide inactivation process provides the kinetic constants that characterize it: lambda(max), the maximum apparent inactivation constant; r, the partition ratio or the number of turnovers made by one enzyme molecule before inactivation; and k(cat) and K(m), the catalytic and Michaelis constants, respectively. From these values, it is possible to establish the ratio lambda(max)/K(m), which represents the potency of the inactivation process. Besides acting as a suicide substrate of tyrosinase, tetrahydrofolic acid reduces o-quinones generated by the enzyme in its action on substrates, such as l-tyrosine and l-DOPA (o-dopaquinone), thus inhibiting enzymatic browning. PMID- 21265543 TI - Carbonyl complexes of platinum(0): synthesis and structure of [(Cy3P)2Pt(CO)] and [(Cy3P)2Pt(CO)2]. AB - The platinum(0) monocarbonyl complex, [(Cy(3)P)(2)Pt(CO)], was synthesized by reaction of [(Cy(3)P)(2)Pt] with [(eta(5)-C(5)Me(5))Ir(CO)(2)] and subsequent irradiation. X-ray structure analysis was performed and represents the first structural evidence of a platinum(0) monocarbonyl complex bearing two free phosphine ligands. Its corresponding dicarbonyl complex [(Cy(3)P)(2)Pt(CO)(2)] was synthesized by treatment of [(Cy(3)P)(2)Pt] with CO at -40 degrees C and confirmed by X-ray structure analysis. PMID- 21265542 TI - A chemotype that inhibits three unrelated pathogenic targets: the botulinum neurotoxin serotype A light chain, P. falciparum malaria, and the Ebola filovirus. AB - A 1,7-bis(alkylamino)diazachrysene-based small molecule was previously identified as an inhibitor of the botulinum neurotoxin serotype A light chain metalloprotease. Subsequently, a variety of derivatives of this chemotype were synthesized to develop structure-activity relationships, and all are inhibitors of the BoNT/A LC. Three-dimensional analyses indicated that half of the originally discovered 1,7-DAAC structure superimposed well with 4-amino-7 chloroquinoline-based antimalarial agents. This observation led to the discovery that several of the 1,7-DAAC derivatives are potent in vitro inhibitors of Plasmodium falciparum and, in general, are more efficacious against CQ-resistant strains than against CQ-susceptible strains. In addition, by inhibiting beta hematin formation, the most efficacious 1,7-DAAC-based antimalarials employ a mechanism of action analogous to that of 4,7-ACQ-based antimalarials and are well tolerated by normal cells. One candidate was also effective when administered orally in a rodent-based malaria model. Finally, the 1,7-DAAC-based derivatives were examined for Ebola filovirus inhibition in an assay employing Vero76 cells, and three provided promising antiviral activities and acceptably low toxicities. PMID- 21265545 TI - Model studies on the pattern of volatiles generated in mixtures of amino acids, lipid-oxidation-derived aldehydes, and glucose. AB - The development of flavor and browning in thermally treated foods results mainly from the Maillard reaction and lipid degradation but also from the interactions between both reaction pathways. To study these interactions, we analyzed the volatile compounds resulting from model reactions of lysine or glycine with aldehydes originating from lipid oxidation [hexanal, (E)-2-hexenal, or (2E,4E) decadienal] in the presence and absence of glucose. The main reaction products identified in these model mixtures were carbonyl compounds, resulting essentially from amino-acid-catalyzed aldol condensation reactions. Several 2-alkylfurans were detected as well. Only a few azaheterocyclic compounds were identified, in particular 5-butyl-2-propylpyridine from (E)-2-hexenal model systems and 2 pentylpyridine from (2E,4E)-decadienal model reactions. Although few reaction products were found resulting from the condensation of an amino acid with a lipid derived aldehyde, the amino acid plays an important role in catalyzing the degradation and further reaction of these carbonyl compounds. These results suggest that amino-acid-induced degradations and further reactions of lipid oxidation products may be of considerable importance in thermally processed foods. PMID- 21265544 TI - Crystal structure of beta-hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone. AB - beta-Hexosaminidases (beta-hex) are a group of glycosyl hydrolase isozymes that break down neutral and sialylated glycosphingolipids in the lysosomes, thereby preventing their buildup in neuronal cells. Some mutants of beta-hex have decreased folding stability that results in adult-onset forms of lysosomal storage diseases. However, prevention of the harmful accumulation of glycolipids only requires 10% of wild-type activity. Pyrimethamine (PYR) is a potential pharmacological chaperone that works by stabilizing these mutant enzymes sufficiently to allow more beta-hex to arrive in the lysosome, where it can carry out its function. An X-ray structure of the complex between human beta hexosaminidase B (HexB) and PYR has been determined to 2.8 A. PYR binds to the active site of HexB where several favorable van der Waals contacts and hydrogen bonds are introduced. Small adjustments of the enzyme structure are required to accommodate the ligand, and details of the inhibition and stabilization properties of PYR are discussed. PMID- 21265546 TI - Solid-solid interface formation in TiO2 nanoparticle networks. AB - Aiming at a comparison of microstructure and paramagnetic properties of mesoporous TiO(2) nanoparticle networks, we subjected entirely different TiO(2-x) precursor structures to vacuum annealing. The transformation of an amorphous TiO(2-x) gel--obtained by sol-gel processing of an ethylene glycol-modified titanium precursor--into a network of interconnected anatase nanocrystals was explored by means of X-ray diffraction, nitrogen sorption, and electron microscopy. Crystalline junctions between the particles emerge from temperature treatment. This process of particle network formation is different from that related to the vapor phase grown anatase nanocrystals where particle-particle interface formation is induced by contact with water. It was found that, after annealing up to 873 K and controlled sample purification in oxygen atmosphere, both types of samples exhibit high concentrations of particle-particle interfaces and comparable properties in terms of surface area, porosity, and microstructure. With electron paramagnetic resonance (EPR) we observed on nonstoichiometric TiO(2 x) networks an identical type of subsurface defect which is related to the presence of solid-solid interfaces. PMID- 21265547 TI - CO2 in solid para-hydrogen: spectral splitting and the CO2...(o-H2)n clusters. AB - Complicated high-resolution spectral structures are often observed for molecules doped in solid molecular hydrogen. The structures can result from miscellaneous effects and are often interpreted differently in references. The spectrum of the nu(3) band of CO(2) in solid para-H(2) presents a model system which exhibits rich spectral structures. With the help of the potential energy simulation of the CO(2) molecule doped in para-hydrogen matrix, and extensive experiments with different CO(2) isotopologues and different ortho-hydrogen concentrations in the matrix, the spectral features observed in p-H(2) matrix are assigned to the CO(2)...(o-H(2))(n) clusters and also to energy level splitting that is due to different alignments of the doped CO(2) molecules in the matrix. The assignments are further supported by the dynamics analysis and also by the spectrum recorded with sample codoped with O(2) which serves as catalyst transferring o-H(2) to p H(2) in the matrix at 4 K temperature. The observed spectral features of CO(2)/pH(2) can potentially be used as an alternative readout of the temperature and orthohydrogen concentration in the solid para-hydrogen. PMID- 21265548 TI - Gas-phase reactions of the bare Th2+ and U2+ ions with small alkanes, CH4, C2H6, and C3H8: experimental and theoretical study of elementary organoactinide chemistry. AB - The gas-phase reactions of two dipositive actinide ions, Th(2+) and U(2+), with CH(4), C(2)H(6), and C(3)H(8) were studied by both experiment and theory. Fourier transform ion cyclotron resonance mass spectrometry was employed to study the bimolecular ion-molecule reactions; the potential energy profiles (PEPs) for the reactions, both observed and nonobserved, were computed by density functional theory (DFT). The experiments revealed that Th(2+) reacts with all three alkanes, including CH(4) to produce ThCH(2)(2+), whereas U(2+) reacts with C(2)H(6) and C(3)H(8), with different product distributions than for Th(2+). The comparative reactivities of Th(2+) and U(2+) toward CH(4) are well explained by the computed PEPs. The PEPs for the reactions with C(2)H(6) effectively rationalize the observed reaction products, ThC(2)H(2)(2+) and UC(2)H(4)(2+). For C(3)H(8) several reaction products were experimentally observed; these and additional potential reaction pathways were computed. The DFT results for the reactions with C(3)H(8) are consistent with the observed reactions and the different products observed for Th(2+) and U(2+); however, several exothermic products which emerge from energetically favorable PEPs were not experimentally observed. The comparison between experiment and theory reveals that DFT can effectively exclude unfavorable reaction pathways, due to energetic barriers and/or endothermic products, and can predict energetic differences in similar reaction pathways for different ions. However, and not surprisingly, a simple evaluation of the PEP features is insufficient to reliably exclude energetically favorable pathways. The computed PEPs, which all proceed by insertion, were used to evaluate the relationship between the energetics of the bare Th(2+) and U(2+) ions and the energies for C-H and C-C activation. It was found that the computed energetics for insertion are entirely consistent with the empirical model which relates insertion efficiency to the energy needed to promote the An(2+) ion from its ground state to a prepared divalent state with two non-5f valence electrons (6d(2)) suitable for bond formation in C-An(2+)-H and C-An(2+)-C activated intermediates. PMID- 21265549 TI - Thermally controlled cyclic insertion/ejection of dopant ions and reversible zinc blende/wurtzite phase changes in ZnS nanostructures. AB - We report a reversible phase transformation of platelet-shaped ZnS nanostructures between wurtzite (WZ) and zinc blende (ZB) phases by reversible insertion/ejection of dopant Mn(II) ions induced by a thermocyclic process. In a reaction flask loaded with WZ ZnS platelets and Mn molecular precursors, during heating Mn ions are incorporated and change the phase of the host nanostructures to ZB; during cooling Mn ions are spontaneously ejected, returning the host nanoplatelets to the original WZ phase. These reversible changes are monitored for several cycles with PL, EPR, XRD, and HRTEM. Interestingly, the (0001) WZ platelets transform to (110) ZB following a nucleation and growth process triggered by a local increase/depletion of the Mn(2+) concentration in the nanocrystals. PMID- 21265551 TI - Entropically driven photochemical upconversion. AB - Conventional photochemical upconversion (UC) through homo-geneous triplet-triplet annihilation (TTA) is subject to several enthalpic losses that limit the UC margin. Here, we address one of these losses: the triplet energy transfer (TET) from the sensitizer to the emitter molecules. Usually, the triplet energy level of the emitter is set below that of the sensitizer. In our system, the triplet energy level of the emitter exceeds that of the sensitizer by ~600 cm(-1). Choosing suitable concentrations for the sensitizer and emitter molecules, we can exploit entropy as a driving force for the migration of triplet excitation from the sensitizer to the emitter manifolds. Thereby we obtain a new record for the peak-to-peak TTA-UC energy margin of 0.94 eV. A modified Stern-Volmer analysis yields a TET rate constant of 2.0 * 10(7) M(-1) s(-1). Despite being relatively inefficient, the upconverted fluorescence is easily visible to the naked eye with irradiation intensities as low as 2 W cm(-2). PMID- 21265550 TI - Combined antenna and localized plasmon resonance in Raman scattering from random arrays of silver-coated, vertically aligned multiwalled carbon nanotubes. AB - The electric field enhancement associated with detailed structure within novel optical antenna nanostructures is modeled using the surface integral equation technique in the context of surface-enhanced Raman scattering (SERS). The antennae comprise random arrays of vertically aligned, multiwalled carbon nanotubes dressed with highly granular Ag. Different types of "hot-spot" underpinning the SERS are identified, but contrasting characteristics are revealed. Those at the outer edges of the Ag grains are antenna driven with field enhancement amplified in antenna antinodes while intergrain hotspots are largely independent of antenna activity. Hot-spots between the tops of antennae leaning towards each other also appear to benefit from antenna amplification. PMID- 21265552 TI - Potent engineered PLGA nanoparticles by virtue of exceptionally high chemotherapeutic loadings. AB - Herein we report the fabrication of engineered poly(lactic acid-co-glycolic acid) nanoparticles via the PRINT (particle replication in nonwetting templates) process with high and efficient loadings of docetaxel, up to 40% (w/w) with encapsulation efficiencies >90%. The PRINT process enables independent control of particle properties leading to a higher degree of tailorability than traditional methods. Particles with 40% loading display better in vitro efficacy than particles with lower loadings and the clinical formulation of docetaxel, Taxotere. PMID- 21265553 TI - Plasmon line shaping using nanocrosses for high sensitivity localized surface plasmon resonance sensing. AB - The detection of small changes in the wavelength position of localized surface plasmon resonances in metal nanostructures has been used successfully in applications such as label-free detection of biomarkers. Practical implementations, however, often suffer from the large spectral width of the plasmon resonances induced by large radiative damping in the metal nanocavities. By means of a tailored design and using a reproducible nanofabrication process, high quality planar gold plasmonic nanocavities are fabricated with strongly reduced radiative damping. Moreover, additional substrate etching results in a large enhancement of the sensing volume and a subsequent increase of the sensitivity. Coherent coupling of bright and dark plasmon modes in a nanocross and nanobar is used to generate high quality factor subradiant Fano resonances. Experimental sensitivities for these modes exceeding 1000 nm/RIU with a Figure of Merit reaching 5 are demonstrated in microfluidic ensemble spectroscopy. PMID- 21265554 TI - Caffeic acid phenethyl ester inhibits PDGF-induced proliferation of vascular smooth muscle cells via activation of p38 MAPK, HIF-1alpha, and heme oxygenase-1. AB - Hyperproliferation of vascular smooth muscle cells (VSMCs) is critically involved in the onset of atherosclerosis and restenosis. Although caffeic acid phenethyl ester (CAPE, 1), one of the main constituents of honeybee propolis, has been shown to exert a beneficial effect in models of vascular injury in vivo, detailed mechanistic investigations in vascular cells are scarce. This study has examined the antiproliferative activity of 1 in platelet-derived growth factor (PDGF) stimulated primary rat aortic VSMCs and aimed to shed light on underlying molecular mechanisms. Compound 1 inhibited the proliferation of VSMCs upon exposure to PDGF in a dose-dependent manner by interfering with cell cycle progression from the G0/1- to the S-phase. Enhanced phosphorylation of p38 mitogen-activated protein kinase (MAPK) as well as stabilization of hypoxia inducible factor (HIF)-1alpha and subsequent induction of heme oxygenase-1 (HO-1) could be identified as molecular events contributing to the observed growth arrest in PDGF-activated VSMCs upon exposure to 1. PMID- 21265555 TI - Cycloartane triterpenes isolated from Combretum quadrangulare in a screening program for death-receptor expression enhancing activity. AB - In our screening program for natural products that increase DR5 (death-receptor 5) expression, nine new cycloartane triterpenes, combretanones A-G (1-7), combretic acid A (8), and combretic acid B (9), were isolated from a MeOH extract of Combretum quadrangulare leaves. The known oleanane triterpenes (10, 11) and six known flavonols (12-17) were also isolated. The structures of 1-9 were elucidated by spectroscopic studies. Compounds 7, 9, 12, 16, and 17 enhanced DR5 expression, and 16 showed TRAIL-resistance abrogating activity. PMID- 21265556 TI - Stereochemical investigations of isochromenones and isobenzofuranones isolated from Leptosphaeria sp. KTC 727. AB - Two new metabolites, (R)-3,4-dihydro-4,6,8-trihydroxy-4,5-dimethyl-3 methyleneisochromen-1-one (1) and (R)-7-hydroxy-3-((S)-1-hydroxyethyl)-5-methoxy 3,4-dimethylisobenzofuran-1(3H)-one (2), were isolated along with two structurally known related compounds (3 and 4) from the culture broth of Leptosphaeria sp. KTC 727 (JCM 13076 = MAFF 239586). These structures were disclosed mainly with (1)H and (13)C NMR spectroscopic analyses. The relative configuration of 2 was established by NOE studies. The absolute configuration of this molecule was determined by a combination of the modified Mosher's method and CD spectra after derivatizations. The theoretical CD profiles also supported these assignments. Structural correlations enabled us to establish the absolute configurations of metabolites 1, 3, and 4, in which configurations of the latter two had not been established. Compound 2 exhibited the strongest antifungal activity among them, inhibiting the hyphal growth of Cochliobolus miyabeanus at about 0.5 MUg/mL. PMID- 21265557 TI - Antimicrobial isopropenyl-dihydrofuranoisoflavones from Crotalaria lachnophora. AB - Two new isopropenyl-dihydrofuranoisoflavones exhibiting antimicrobial properties have been isolated along with eight known compounds from the Cameroonian medicinal plant Crotalaria lachnophora. The structures of the new compounds were elucidated by 1D and 2D NMR spectroscopy and high-resolution mass spectrometry as 7,2',4'-trihydroxy-5''-isopropenyl-4'',5''-dihydrofurano[2'',3'':5,6]isoflavone (1) and 4,8-dihydroxy-2-isopropenyl-2,3-dihydro-5H-[1]benzofuro[2,3-b]furo[3,2 g]chromen-5-one (2). The CH(2)Cl(2)/MeOH (1:1) extract and the compounds isolated were subjected to in vitro antimicrobial assays against a panel of pathogenic microorganisms, including Gram-positive and Gram-negative bacteria and fungi. The new compounds, named lachnoisoflavones A (1) and B (2), showed moderate inhibitory activities against Escherichia coli and Klebsiella pneumoniae. PMID- 21265558 TI - Three-dimensional GaN/AlN nanowire heterostructures by separating nucleation and growth processes. AB - Bottom-up nanostructure assembly has been a central theme of materials synthesis over the past few decades. Semiconductor quantum dots and nanowires provide additional degrees of freedom for charge confinement, strain engineering, and surface sensitivity-properties that are useful to a wide range of solid state optical and electronic technologies. A central challenge is to understand and manipulate nanostructure assembly to reproducibly generate emergent structures with the desired properties. However, progress is hampered due to the interdependence of nucleation and growth phenomena. Here we show that by dynamically adjusting the growth kinetics, it is possible to separate the nucleation and growth processes in spontaneously formed GaN nanowires using a two step molecular beam epitaxy technique. First, a growth phase diagram for these nanowires is systematically developed, which allows for control of nanowire density over three orders of magnitude. Next, we show that by first nucleating nanowires at a low temperature and then growing them at a higher temperature, height and density can be independently selected while maintaining the target density over long growth times. GaN nanowires prepared using this two-step procedure are overgrown with three-dimensionally layered and topologically complex heterostructures of (GaN/AlN). By adjusting the growth temperature in the second growth step either vertical or coaxial nanowire superlattices can be formed. These results indicate that a two-step method allows access to a variety of kinetics at which nanowire nucleation and adatom mobility are adjustable. PMID- 21265559 TI - Morphological study of nanoparticle-polymer solar cells using high-angle annular dark-field electron tomography. AB - Electron tomography in high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) mode is used to image networks of nanoparticles within polymer-nanoparticle blend photovoltaic devices. Blends of CdSe nanoparticles (~6.5 nm diameter spheres and ~33 nm long nanorods) with poly[2 methoxy-5-(3',7'-dimethyloctyloxy)-1,4-phenylene vinylene] (OC(1)C(10)-PPV) are investigated. Blends using spherical particles are found to contain aggregated regions in which well-connected networks of nanoparticles exist, surrounded by lower-density regions with poorer connectivity. As the ratio of nanoparticles to polymer is increased the aggregated regions increase in size, and the connectivity of the particles in the lower-density regions also increases. This has the effect of increasing the overall percentage of the charge-generating interface connected to the electron-collecting electrode, consistent with the trends observed in device performance. Using nanorods instead of spherical particles results in a highly connected network of particles distributed homogeneously through the film. The nanorods are oriented close to parallel to the plane of the film. PMID- 21265560 TI - Synthesis of the ABC ring system of Jiadifenin via Pd-catalyzed cyclizations. AB - An efficient route toward the central ABC system of jiadifenin has been developed using two key Pd-catalyzed cyclizations. A protic solvent-activated Mizoroki-Heck reaction was used to construct the C(9) quaternary carbon and the A ring. A cascading Tsuji-Trost cyclization/lactonization sequence was employed to establish the BC ring system and the C(5,6) stereochemistry. PMID- 21265561 TI - One-pot multistep reactions based on thiolactones: extending the realm of thiol ene chemistry in polymer synthesis. AB - The in situ generation of thiols by nucleophilic ring-opening of a thiolactone with amines, followed by a UV-initiated radical thiol-ene reaction in a one-pot fashion, has been evaluated as an accelerated and versatile protocol for the synthesis of several types of polymeric architectures. After elaboration of a model amine-thiol-ene conjugation reaction, a number of routes based on readily available thiolactone-containing structures have been developed to successfully assemble functional, linear polymers and networks via a mild and facile radical photopolymerization process. PMID- 21265562 TI - Guanine-rich RNAs and DNAs that bind heme robustly catalyze oxygen transfer reactions. AB - Diverse guanine-rich RNAs and DNAs that fold to form guanine quadruplexes are known to form tight complexes with Fe(III) heme. We show here that a wide variety of such complexes robustly catalyze two-electron oxidations, transferring oxygen from hydrogen peroxide to thioanisole, indole, and styrene substrates. Use of (18)O-labeled hydrogen peroxide reveals the source of the oxygen transferred to form thioanisole sulfoxide and styrene oxide to be the activated ferryl moiety within these systems. Hammett analysis of the kinetics of thioanisole sulfoxide formation is unable to distinguish between a one-step, direct oxygen transfer and a two-step, oxygen rebound mechanism for this catalysis. Oxygen transfer to indole produces a range of products, including indigo and related dyes. Docking of heme onto a high-resolution structure of the G-quadruplex fold of Bcl-2 promoter DNA, which both binds heme and transfers oxygen, suggests a relatively open active site for this class of ribozymes and deoxyribozymes. That heme dependent catalysis of oxygen transfer is a property of many RNAs and DNAs has ramifications for primordial evolution, enzyme design, cellular oxidative disease, and anticancer therapeutics. PMID- 21265563 TI - Atomic layer deposition of Al(2)O(3) and ZnO at atmospheric pressure in a flow tube reactor. AB - Improving nanoscale thin film deposition techniques such as atomic layer deposition (ALD) to permit operation at ambient pressure is important for high throughput roll-to-roll processing of emerging flexible substrates, including polymer sheets and textiles. We present and investigate a novel reactor design for inorganic materials growth by ALD at atmospheric pressure. The reactor uses a custom "pressure boost" approach for delivery of low vapor pressure ALD precursors that controls precursor dose independent of reactor pressure. Analysis of continuum gas flow in the reactor shows key relations among reactor pressure, inert gas flow rate, and species diffusion that define conditions needed to efficiently remove product and adsorbed reactive species from the substrate surface during the inert gas purge cycle. Experimental results, including in situ quartz crystal microbalance (QCM) characterization and film thickness measurements for deposition of ZnO and Al(2)O(3) are presented and analyzed as a function of pressure and gas flow rates at 100 degrees C. At atmospheric pressure and high gas flow, ZnO deposition can proceed at the same mass uptake and growth rate as observed during more typical low pressure ALD. However, under the same high pressure and flow conditions the mass uptake and growth rate for Al(2)O(3) is a factor of ~1.5-2 larger than at low pressure. Under these conditions, Al(2)O(3) growth at atmospheric pressure in a "flow-through" geometry on complex high surface area textile materials is sufficiently uniform to yield functional uniform coatings. PMID- 21265564 TI - Tracing and quantifying anthropogenic mercury sources in soils of northern france using isotopic signatures. AB - The mercury (Hg) isotopic composition was investigated in topsoils from two case studies in north of France. The Hg isotope composition was first determined in agricultural topsoils contaminated by a close by Pb-Zn smelter. The Hg isotopic composition was also measured in topsoils from an urban area in northeastern France (Metz). In both cases, no significant mass independent isotope fractionation could be found in the soils. However, the soil isotopic composition (delta(202)Hg) was enriched in the heavier isotopes as the Hg concentration increased in the soils. A linear relationship between the delta(202)Hg in soils and 1/[Hg] indicated a mixing between a contamination source and the Hg derived from the geogenic background soils. Such findings demonstrate that the contamination signature was preserved in the soils and that the deposition of anthropogenic Hg was predominant compared to reactions leading to isotope fractionation such as biotic and abiotic reduction of Hg(II) and resulting in Hg mobility or evasion from the soils. It was therefore possible, for the first time in the case of Hg, to evaluate the contribution of the contamination source relative to the background Hg source in urban topsoils using relative isotope abundances. PMID- 21265565 TI - Rhodium(II)-catalyzed enantioselective C-H functionalization of indoles. AB - A catalytic, enantioselective method for the C-H functionalization of indoles by diazo compounds has been achieved. With catalytic amounts of Rh(2)(S-NTTL)(4), the putative Rh-carbene intermediates from alpha-alkyl-alpha-diazoesters react with indoles at C(3) to provide alpha-alkyl-alpha-indolylacetates in high yield and enantioselectivity. From DFT calculations, a mechanism is proposed that involves a Rh-ylide intermediate with oxocarbenium character. PMID- 21265566 TI - Soft X-ray spectromicroscopy of cobalt uptake by cement. AB - Scanning transmission X-ray microscopy was used to investigate the speciation and spatial distribution of Co in a Co(II)-doped cement matrix. The aim of this study was to improve the understanding of the heavy metals immobilization process in cement on the molecular level. The Co-doped cement samples hydrated for 30 days with a Co loading of 5000 mg/kg were prepared under normal atmosphere to simulate conditions used for cement-stabilized waste packages. Co 2p(3/2) absorption edge signals were used to determine the spatial distributions of the metal species in the Co(II)-doped cement. The speciation of Co was determined by collecting near edge X-ray absorption fine structure spectra. On the basis of the shape of the absorption spectra, it was found that Co(II) is partly oxidized to Co(III). The correlation, respectively the anticorrelation with elements such as Al, Si, and Mn, show that Co(II) is predominantly present as Co-hydroxide-like phase as well as Co-phyllosilicate, whereas Co(III) tends to be incorporated only into a CoOOH like phase. Thus, this study suggests that thermodynamic calculations of Co(II) immobilization by cementitious systems should take into consideration not only the solubility of Co(II)-hydroxides but also Co(III) phases. PMID- 21265567 TI - Grand challenges for life-cycle assessment of biofuels. PMID- 21265568 TI - Role of motor vehicle lifetime extension in climate change policy. AB - Vehicle replacement schemes such as the "cash for clunkers" program in the U.S. and the "scrappage scheme" in the UK have featured prominently in the economic stimulation packages initiated by many governments to cope with the global economic crisis. While these schemes were designed as economic instruments to support the vehicle production industry, governments have also claimed that these programs have environmental benefits such as reducing CO2 emissions by bringing more fuel-efficient vehicles onto the roads. However, little evidence is available to support this claim as current energy and environmental accounting models are inadequate for comprehensively capturing the economic and environmental trade-offs associated with changes in product life and product use. We therefore developed a new dynamic model to quantify the carbon emissions due to changes in product life and consumer behavior related to product use. Based on a case study of Japanese vehicle use during the 1990-2000 period, we found that extending, not shortening, the lifetime of a vehicle helps to reduce life-cycle CO2 emissions throughout the supply chain. Empirical results also revealed that even if the fuel economy of less fuel-efficient ordinary passenger vehicles were improved to levels comparable with those of the best available technology, i.e. hybrid passenger cars currently being produced in Japan, total CO2 emissions would decrease by only 0.2%. On the other hand, we also find that extending the lifetime of a vehicle contributed to a moderate increase in emissions of health relevant air pollutants (NOx, HC, and CO) during the use phase. From the results, this study concludes that the effects of global warming and air pollution can be somewhat moderated and that these problems can be addressed through specific policy instruments directed at increasing the market for hybrid cars as well as extending lifetime of automobiles, which is contrary to the current wisdom. PMID- 21265569 TI - Synthesis of fluorinated polythienothiophene-co-benzodithiophenes and effect of fluorination on the photovoltaic properties. AB - Herein, we describe the synthesis of fluorinated polythienothiophene-co benzodithiophenes (PTBFs) and the characterization of their physical properties, especially their performance in solar cells. Fluorination of the polymer backbone lowered both the HOMO and LUMO energy levels and simultaneously widened the energy bandgap of the polymer (0.1-0.2 eV). Incorporation of fluorine into the various positions of the polymer backbone significantly affected the solar cells' power conversion efficiency from 2.3% to 7.2%. Detailed studies revealed that the polymer containing mono-fluorinated thienothiophene gave the best solar cell performance. Perfluorination of the polymer backbone led to poor compatibility with PC(71)BM molecules, thus poor solar energy conversion efficiency. This is possibly due to the enhanced self-organization properties of the polymer chains and the fluorophobicity effect. Furthermore, it was found that perfluorination of the polymer backbone resulted in poor photochemical stability against singlet oxygen attack. Theoretical studies indicated that the internal polarization caused enhancement of the negative charge density on thienothiophene rings, which rendered them vulnerable to [2+4] cycloaddition reaction with singlet oxygen. PMID- 21265570 TI - Superoxide-mediated formation and charging of silver nanoparticles. AB - Contemporary studies indicate that reactive oxygen species (ROS) such as superoxide play a key role in the toxicity and behavior of silver nanoparticles (AgNPs). While there have been suggestions that superoxide is able to reduce silver(I) ions with resultant production of AgNPs, no experimental evidence that this process actually occurs has been produced. Here we present definitive experimental evidence for the reduction of silver(I) by superoxide. A second order rate constant of 64.5 +/- 16.3 M(-1).s(-1) is determined for this reaction in the absence of AgNPs. The overall rate constant, however, increases by at least 4 orders of magnitude in the presence of AgNPs. A model based on electron charging and discharging of AgNPs satisfactorily describes the kinetics of this process. The ability for AgNPs to undergo catalytic cycling provides a pathway for the continual generation of ROS and the regeneration of AgNPs following oxidation. PMID- 21265571 TI - Diverse strategies toward indenol and fulvene derivatives: Rh-catalyzed C-H activation of aryl ketones followed by coupling with internal alkynes. AB - The synthesis of indenols and fulvenes was achieved through Rh-catalyzed C-H bond activation of simple and diverse aryl ketone derivatives and subsequent coupling with internal alkynes. The process was found to involve either an alpha or gamma dehydration step, depending on the substrate disposition and representing diverse pathways toward functionalized fulvenes. PMID- 21265572 TI - Dynamic MRI and thermal simulation to interpret deformation and water transfer in meat during heating. AB - Understanding and controlling structural and physical changes in meat during cooking is of prime importance. Nuclear magnetic resonance imaging (MRI) is a noninvasive, nondestructive tool that can be used to characterize certain properties and structures both locally and dynamically. Here we show the possibilities offered by MRI for the in situ dynamic imaging of the connective network during the cooking of meat to monitor deformations between 20 and 75 degrees C. A novel device was used to heat the sample in an MR imager. An MRI sequence was developed to contrast the connective tissue and the muscle fibers during heating. The temperature distribution in the sample was numerically simulated to link structural modifications and water transfer to temperature values. The contraction of myofibrillar and collagen networks was observed at 42 degrees C, and water began to migrate toward the interfascicular space at 40 degrees C. These observations are consistent with literature results obtained using destructive and/or nonlocalized methods. This new approach allows the simultaneous monitoring of local deformation and water transfer, changes in muscle structure and thermal history. PMID- 21265573 TI - Activation of G protein-coupled receptor kinase 1 involves interactions between its N-terminal region and its kinase domain. AB - G protein-coupled receptor kinases (GRKs) phosphorylate activated G protein coupled receptors (GPCRs) to initiate receptor desensitization. In addition to the canonical phosphoacceptor site of the kinase domain, activated receptors bind to a distinct docking site that confers higher affinity and activates GRKs allosterically. Recent mutagenesis and structural studies support a model in which receptor docking activates a GRK by stabilizing the interaction of its ~20 amino acid N-terminal region with the kinase domain. This interaction in turn stabilizes a closed, more active conformation of the enzyme. To investigate the importance of this interaction for the process of GRK activation, we first validated the functionality of the N-terminal region in rhodopsin kinase (GRK1) by site-directed mutagenesis and then introduced a disulfide bond to cross-link the N-terminal region of GRK1 with its specific binding site on the kinase domain. Characterization of the kinetic and biophysical properties of the cross linked protein showed that disulfide bond formation greatly enhances the catalytic efficiency of the peptide phosphorylation, but receptor-dependent phosphorylation, Meta II stabilization, and inhibition of transducin activation were unaffected. These data indicate that the interaction of the N-terminal region with the kinase domain is important for GRK activation but does not dictate the affinity of GRKs for activated receptors. PMID- 21265574 TI - Development and use of clickable activity based protein profiling agents for protein arginine deiminase 4. AB - The protein arginine deiminases (PADs), which catalyze the hydrolysis of peptidyl arginine to form peptidyl-citrulline, are potential targets for the development of a rheumatoid arthritis (RA) therapeutic, as well as other human diseases including colitis and cancer. Additionally, these enzymes, and in particular PAD4, appear to play important roles in a variety of cell signaling pathways including apoptosis, differentiation, and transcriptional regulation. To better understand the factors that regulate in vivo PAD4 activity, we set out to design and synthesize a series of activity-based protein profiling (ABPP) reagents that target this enzyme. Herein we describe the design, synthesis, and evaluation of six ABPPs including (i) FITC-conjugated F-amidine (FFA1 and 2) and Cl-amidine (FCA1 and 2), and (ii) biotin-conjugated F-amidine (BFA) and Cl-amidine (BCA). We further demonstrate the utility of these probes for labeling PAD4 in cells, as well as for isolating PAD4 and PAD4 binding proteins. These probes will undoubtedly prove to be powerful tools that can be used to dissect the factors controlling the dynamics of PAD4 expression, activity, and function. PMID- 21265575 TI - Kainate promotes alterations in neuronal RNA splicing machinery. AB - Kainate, a glutamate analogue, activates kainate and AMPA receptors inducing strong synaptic activation. Systemic kainate application to rodents results in seizures, neurodegeneration, and neuronal remodeling in the brain. It is therefore used to investigate molecular mechanisms responsible for these conditions. We analyzed proteome alterations in murine primary cortical neurons after 24 h of kainate treatment. Our 2-D gel based proteomics approach revealed 91 protein alterations, some already associated with kainate-induced pathology. In addition, we found a large number of proteins which have not previously been reported to be associated with kainate-induced pathology. Functional classification of altered proteins revealed that they predominantly participate in mRNA splicing and cytoskeleton remodeling. PMID- 21265576 TI - Fate of dispersants associated with the deepwater horizon oil spill. AB - Response actions to the Deepwater Horizon oil spill included the injection of ~771,000 gallons (2,900,000 L) of chemical dispersant into the flow of oil near the seafloor. Prior to this incident, no deepwater applications of dispersant had been conducted, and thus no data exist on the environmental fate of dispersants in deepwater. We used ultrahigh resolution mass spectrometry and liquid chromatography with tandem mass spectrometry (LC/MS/MS) to identify and quantify one key ingredient of the dispersant, the anionic surfactant DOSS (dioctyl sodium sulfosuccinate), in the Gulf of Mexico deepwater during active flow and again after flow had ceased. Here we show that DOSS was sequestered in deepwater hydrocarbon plumes at 1000-1200 m water depth and did not intermingle with surface dispersant applications. Further, its concentration distribution was consistent with conservative transport and dilution at depth and it persisted up to 300 km from the well, 64 days after deepwater dispersant applications ceased. We conclude that DOSS was selectively associated with the oil and gas phases in the deepwater plume, yet underwent negligible, or slow, rates of biodegradation in the affected waters. These results provide important constraints on accurate modeling of the deepwater plume and critical geochemical contexts for future toxicological studies. PMID- 21265577 TI - The role of local hydration and hydrogen-bonding dynamics in ion and solute release from ion-coupled secondary transporters. AB - Recent progress in crystallographic studies of sodium-coupled secondary transporters has revealed striking similarities in the structural organization of ion and solute binding. Previous reports suggested that the Na2 sodium binding site in the neurotransmitter sodium symporter (NSS) leucine transporter (LeuT) is conserved across sodium/proton coupled secondary transporters of many distantly related families. This site is implicated in the conformational dynamics controlled by the binding and release of both translocated solute and ion(s) through a mechanism that largely remains unknown. In this study, we used extensive equilibrium molecular dynamics simulations, potential of mean force (PMF) computations, and quasi-harmonic analysis of the LeuT transporter with and without sodium ion bound at the Na2 site to delineate the role of this site in the conformational dynamics of the protein. PMF computations show that in presence of the sodium ion in Na2 the conserved T354 residue is locked into a single rotameric state in contrast to two degenerate states available in the absence of ion in Na2. Molecular dynamics (MD) simulations suggest the formation of a stable water wire from the cytoplasm to the Na2 site in the occluded state. It is plausible that local hydration plays an important role in transport cycle facilitating release of the ion from Na2. An unbinding of the ion from the Na2 site leads to a tightening of the extracellular thin gates and a destabilization of the intracellular thin gate and thus may promote an unbinding of the cotransported substrate. The study lends additional support to the hypothesis that one of the main drivers in the transport cycle of Na-coupled secondary transporters is the binding of the Na2 ion that controls dynamical equilibrium between an inward-facing to an outward-facing conformation. PMID- 21265578 TI - Dynamics of exciton relaxation in LH2 antenna probed by multipulse nonlinear spectroscopy. AB - We explain the relaxation dynamics in the LH2-B850 antenna as revealed by multipulse pump-dump-probe spectroscopy (Th. A. Cohen Stuart, M. Vengris, V. I. Novoderezhkin, R. J. Cogdell, C. N. Hunter, R. van Grondelle, submitted). The theory of pump-dump-probe response is evaluated using the doorway-window approach in combination with the modified Redfield theory. We demonstrate that a simultaneous fit of linear spectra, pump-probe, and pump-dump-probe kinetics can be obtained at a quantitative level using the disordered exciton model, which is essentially the same as used to model the spectral fluctuations in single LH2 complexes (Novoderezhkin, V.; Rutkauskas, D.; van Grondelle, R. Biophys. J. 2006, 90, 2890). The present studies suggest that the observed relaxation rates are strongly dependent on the realization of the disorder. A big spread of the rates (exceeding 3 orders of magnitude) is correlated with the disorder-induced changes in delocalization length and overlap of the exciton wave functions. We conclude that the bulk kinetics reflect a superposition of many pathways corresponding to different physical limits of energy transfer, varying from sub-20 fs relaxation between delocalized and highly spatially overlapping exciton states to >20 ps jumps between states localized at the opposite sides of the ring. PMID- 21265579 TI - Formation of a dinuclear imido complex from the reaction of a ruthenium(VI) nitride with a ruthenium(II) hydride. AB - The treatment of [Ru(L(OEt))(N)Cl(2)] (1; L(OEt)(-) = [Co(eta(5) C(5)H(5)){P(O)(OEt)(2)}(3)](-)) with Et(3)SiH affords [Ru(L(OEt))Cl(2)(NH(3))] (2), whereas that with [Ru(L(OEt))(H)(CO)(PPh(3))] (3) gives the dinuclear imido complex [(L(OEt))Cl(2)Ru(MU-NH)Ru(CO)(PPh(3))(L(OEt))] (4). The imido group in 4 binds to the two ruthenium atoms unsymmetrically with Ru-N distances of 1.818(6) and 1.952(6) A. The reaction between 1 and 3 at 25 degrees C in a toluene solution is first order in both complexes with a second-order rate constant determined to be (7.2 +/- 0.4) * 10(-5) M(-1) s(-1). PMID- 21265580 TI - The correct administration of antihypertensive drugs according to the principles of clinical pharmacology. AB - Control of cardiovascular (CV) risk factors, particularly hypertension, is still unsatisfactory, resulting in excess CV morbidity and mortality worldwide. CV risk is linearly associated with an increase in blood pressure (BP) values, and clinical studies have clearly demonstrated that BP lowering represents the most effective means of preventing CV events. However, while BP reduction is a fairly easy target, BP normalization is much more difficult to achieve, and adequate BP control (<140/90 mmHg) is attained only in a small percentage of the hypertensive population. One of the main reasons for the lack of efficacy of antihypertensive pharmacological treatment is that very often drugs are not administered at the correct dosage. In this review, we discuss the importance of using clinical pharmacology to guide treatment of hypertension. Controlled clinical trials, including HOPE, EUROPA, and CONSENSUS, are used to guide prescribing decisions. Unfortunately, the results obtained in pivotal studies such as these have been obtained using drug dosages much higher than those usually used in clinical practice. The prescription of a drug for the treatment of hypertension should take into consideration the potency of the drug, i.e. the degree of BP reduction required, and the duration of action of the drug, i.e. the need to cover the dosing interval (possibly 24 hours) in a homogeneous way. This is especially the case for angiotensin-converting enzyme (ACE) inhibitors, compounds characterized by a flat dose-response curve. The significance of this flat dose-response curve is that a low dose of an ACE inhibitor has the same potency as a high dose but a shorter duration of action. If a low dosage is administered to a hypertensive patient it causes BP fluctuations, which have been associated with negative CV outcomes. In contrast, other drug classes, including calcium channel antagonists, diuretics, and beta-adrenoceptor antagonists, can be used at different dosages in order to modulate their hemodynamic effects. Thus, it is important to be aware of the clinical pharmacology of antihypertensive drugs in order to choose not only the class or the molecule best suited to the clinical characteristics of the patient, but also the correct dosages to ensure effective and homogeneous 24-hour BP reduction. PMID- 21265581 TI - Statins for cardiovascular prevention according to different strategies: a cost analysis. AB - BACKGROUND: Several studies have shown that treatment with HMG-CoA reductase inhibitors (statins) can reduce coronary heart disease (CHD) rates. However, the cost effectiveness of statin treatment in the primary prevention of CHD has not been fully established. OBJECTIVE: To estimate the costs of CHD prevention using statins in Switzerland according to different guidelines, over a 10-year period. METHODS: The overall 10-year costs, costs of one CHD death averted, and of 1 year without CHD were computed for the European Society of Cardiology (ESC), the International Atherosclerosis Society (IAS), and the US Adult Treatment Panel III (ATP-III) guidelines. Sensitivity analysis was performed by varying number of CHD events prevented and costs of treatment. RESULTS: Using an inflation rate of medical costs of 3%, a single yearly consultation, a single total cholesterol measurement per year, and a generic statin, the overall 10-year costs of the ESC, IAS, and ATP-III strategies were 2.2, 3.4, and 4.1 billion Swiss francs (SwF [SwF1 = $US0.97]). In this scenario, the average cost for 1 year of life gained was SwF352, SwF421, and SwF485 thousand, respectively, and it was always higher in women than in men. In men, the average cost for 1 year of life without CHD was SwF30.7, SwF42.5, and SwF51.9 thousand for the ESC, IAS, and ATP-III strategies, respectively, and decreased with age. Statin drug costs represented between 45% and 68% of the overall preventive cost. Changing the cost of statins, inflation rates, or number of fatal and non-fatal cases of CHD averted showed ESC guidelines to be the most cost effective. CONCLUSION: The cost of CHD prevention using statins depends on the guidelines used. The ESC guidelines appear to yield the lowest costs per year of life gained free of CHD. PMID- 21265583 TI - Dabigatran etexilate: a review of its use in the prevention of stroke and systemic embolism in patients with atrial fibrillation. AB - The need for safe, effective, and easily administered and monitored antithrombotic treatments that do not have the issues common to warfarin treatment has led to the development of new anticoagulant drugs. Dabigatran etexilate (Pradaxa(r), PradaxTM) is a prodrug of the direct thrombin inhibitor dabigatran, a direct, reversible, potent inhibitor of thrombin. Dabigatran does not interact with food, and is associated with very few known drug interactions. Dabigatran etexilate, at dosages of 110 and 150 mg twice daily, was shown to be noninferior to warfarin with regard to the incidence of stroke or systemic embolism in a large, randomized, partially blinded, multicenter study in a wide spectrum of patients with atrial fibrillation. Moreover, the higher dosage was associated with significantly greater efficacy than warfarin in this regard. These results were supported by secondary endpoints and subgroup analyses. In general, dabigatran etexilate is well tolerated, although it is associated with a higher rate of dyspepsia than warfarin. Major bleeding was as common in recipients of the higher dosage as, and less common in recipients of the lower dosage of dabigatran etexilate than, that in recipients of warfarin, and intracranial bleeding, life-threatening major bleeding, and total bleeding were less common in recipients of either dabigatran etexilate dosage than in warfarin recipients. However, the higher dosage of dabigatran etexilate was associated with a higher rate of gastrointestinal bleeding than warfarin. The incidence of hepatotoxicity did not significantly differ across treatment groups. In conclusion, dabigatran etexilate 150 mg twice daily is more effective than warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation, and generally well tolerated, particularly with regard to bleeding endpoints compared with warfarin. It requires more frequent administration than warfarin, but provides multiple improvements to various issues associated with warfarin administration. Direct comparisons with other new anticoagulant drugs would be beneficial, as would further investigation into the effects in different patient populations, long-term effects, and the gastrointestinal bleeding and dyspepsia observed with dabigatran etexilate treatment. Dabigatran etexilate is a promising new option for the prevention of stroke and systemic embolism in patients with atrial fibrillation. PMID- 21265584 TI - Infection prevention in the intensive care unit: review of the recent literature on the management of invasive devices. AB - Over the last 5 y, clinical trials investigating products, procedures, and treatments aimed at preventing infections in the intensive care unit have been described. The findings of these studies appear to confirm the effectiveness of certain preventive procedures. With regard to ventilator-associated pneumonia, the efficacies of decontamination of the oral cavity, continuous suction of subglottic secretions, positioning of the patient, selective decontamination of the digestive tract, and (for higher-risk patients) endotracheal tubes coated with silver, have been demonstrated. Medicated catheters and chlorhexidine-based dressings have been found useful for catheter-related bloodstream infections, and medical catheters have also been shown to be efficacious against urinary tract infections. All these procedures can be incorporated into departmental protocols for the prevention of nosocomial infections in the intensive care unit. PMID- 21265585 TI - An uncommon infection in an uncommon host. AB - We present the case of an international traveller who was eventually diagnosed with amoebiasis and autosomal dominant polycystic kidney disease (ADPKD) after she presented with recurring fevers. The patient was also diagnosed with non amoebic bacterial hepatitis. Positron emission tomography (PET) can play an important role in locating the source of infection in patients with ADPKD when hepatic or renal infection is suspected. It can also be used to document clinical resolution of infection in difficult cases. Hepatic parenchymal infections in ADPKD patients may warrant a prolonged course of rotating antibiotics. PMID- 21265586 TI - Resistance to ampicillin, third-generation cephalosporins, ciprofloxacin, co trimoxazole and azithromycin in clinical isolates of Salmonella enterica subsp. enterica from Germany: real problem or sporadic circumstance? AB - The objective of this study was to determine the in vitro activity of ampicillin, third-generation cephalosporins, ciprofloxacin, co-trimoxazole and azithromycin against Salmonella enterica isolates. None of the isolates tested showed resistance to third-generation cephalosporins or azithromycin. The rates of resistance to ampicillin, co-trimoxazole and ciprofloxacin were 16.8%, 3.2% and 0.8%, respectively. Moreover, 7.2% of the isolates showed reduced ciprofloxacin susceptibility, but none of them harboured qnr genes. To conclude, our data show that resistance to fluoroquinolones and third-generation cephalosporins in clinical isolates found in Germany still represents a rare circumstance. PMID- 21265587 TI - Proceedings of the military mTBI Diagnostics Workshop, St. Pete Beach, August 2010. AB - Approximately 28,000 service members (SMs) sustain a traumatic brain injury (TBI) each year in the U.S. military. The majority of the injuries result either in a brief or no loss of consciousness, and are classified as a mild TBI (mTBI or concussion). Current evaluation guidelines of SMs suspected of having a mTBI rely heavily on self-reports. However, there is concern that SMs typically minimize or do not report their symptoms of mTBI for fear that doing so will result in being removed from the battlefield. Because mTBI often results in headaches, cognitive dysfunction, attention difficulties, and balance problems, returning to the battlefield before resolution of their symptoms can be dangerous for the SM and for their unit. Sustaining a second concussion before resolution of a previous mTBI also may make long-term neuronal injury more likely. The mTBI Diagnostics Workshop was designed as a forum where civilian and military experts from a variety of TBI-related clinical and basic science disciplines could meet to define the diagnostic tools, alone or in combination, that were most likely to result in an acute, objective diagnosis of mTBI. The premise of the meeting was that a small number of well-focused research projects conducted over the next 2-3 years could be done to validate the optimal test, or more likely combination of tests, that would be practical and reliable for the acute diagnosis of mTBI within 2-3 h of injury in theater. The recommendations of the Workshop are provided in this report. PMID- 21265592 TI - Diagnostic value of the Glasgow Coma Scale for traumatic brain injury in 18,002 patients with severe multiple injuries. AB - Although patients with severe multiple injuries may have other reasons for unconsciousness, traumatic brain injury (TBI) in these patients is frequently defined by the Glasgow Coma Scale (GCS). Nevertheless, the diagnostic value of GCS for severe TBI in the multiple-injured patient is unknown. Therefore, we investigated the diagnostic value of GCS to identify severe TBI in multiple injured patients. The records of 18,002 severely injured adult (ISS >16) patients from the Trauma Register of the German Society for Trauma Surgery were analyzed and initial GCS and Abbreviated Injury Scale (head) (AIS(head)) were recorded. A severe TBI was defined by an AIS(head) >= 3. On the other hand, unconsciousness was defined by an initial GCS <= 8. By these criteria, 6546 patients (36.3%) were unconscious, and 8746 patients (48.6%) had severe TBI. Nine percent of all cases (n=1643) had a GCS <= 8 without severe TBI. Only 56.1% of patients with severe TBI (n=4903) had been unconscious. Decreasing levels of unconsciousness (as defined by GCS) showed consistent rising prevalence of severe TBI (correlation coefficient r=-0.52). Approximately 20% of all multiple-injured patients arriving in the emergency department with an initial GCS of 15 had severe TBI (AIS(head) >= 3). The diagnostic value of GCS <= 8 for severe TBI in patients with multiple injuries has low sensitivity (56.1%) but higher specificity (82.2%). Our study indicates that the GCS (as defined <= 8) in unconsciousness patients with multiple injuries shows only a moderate correlation with the diagnosis of severe TBI. Nevertheless, the main reason for unconsciousness in patients with multiple injuries is TBI, since only 9% of these patients had another reason for unconsciousness. However, due to the poor sensitivity of GCS, we suggest the use of the anatomical scoring system with AIS(head) >= 3 to define severe TBI in patients with multiple injuries. PMID- 21265593 TI - Cost-effectiveness of olanzapine long-acting injection in the treatment of patients with schizophrenia in the United States: a micro-simulation economic decision model. AB - OBJECTIVE: To compare, from the perspective of third-party payers in the United States health care system, the cost-effectiveness of olanzapine long-acting injection (LAI, depot) with alternative antipsychotic agents including risperidone-LAI, paliperidone-LAI, haloperidol-LAI, and oral olanzapine, in the treatment of patients with schizophrenia who have been non-adherent or partially adherent with oral antipsychotics. RESEARCH DESIGN AND METHODS: A 1-year micro simulation economic decision model was developed to simulate the dynamics of usual care of patients with schizophrenia who continue, discontinue, switch, or restart their medication. The model uses a range of clinical and cost parameters including adherence levels, relapse with and without hospitalization, quality adjusted life years (QALYs), treatment discontinuation rates by reason, treatment emergent adverse events, suicide, health care resource utilization, and direct health care costs. Published medical literature and a clinical expert panel were used to develop baseline model assumptions. OUTCOME MEASURES: Key model outputs include annual total direct cost (US$) per treatment and incremental cost effectiveness values per additional QALY gained. RESULTS: Model results found that the olanzapine-LAI treatment strategy was more effective (greater QALYs) and less costly than risperidone-LAI, paliperidone-LAI, and haloperidol-LAI. In addition, olanzapine-LAI was both more effective and more costly, with an estimated incremental cost/QALY of $26,824 compared to oral olanzapine. The base case and multiple sensitivity analyses found olanzapine-LAI to remain within acceptable cost-effective ranges (<$50,000) in terms of incremental cost/QALY gained. CONCLUSIONS: This micro-simulation model finds the olanzapine-LAI treatment strategy to result in better effectiveness and to be a cost-effective alternative compared to oral olanzapine and the LAI formulations of risperidone, paliperidone, and haloperidol in the treatment of non-adherent and partially adherent patients with schizophrenia in the United States. A key limitation is the assumption how LAI therapies compare to oral counterparts due to sparse head to-head data. Further research is needed to verify baseline assumptions. PMID- 21265594 TI - The management of childhood esotropia with hyperopia. AB - PURPOSE: Esotropia, especially accommodative estropia (AE), is often seen in patients with hyperopia. In this paper, the authors aim to report the management methods of different types of esotropia in children with hypermetropia and to show the feasibility and efficacy of prismatic correction in the management of small angle of residual esotropia in accommodative estropia. METHODS: A total of 82 esotropes with hyperopia treated during a 2-year period from 2007 to 2009 were reviewed retrospectively. Data were collected from the medical records. RESULTS: A total of 25 patients showed pure accommodative esotropes, whereas 45 had partial AE and 12 non-AE. All 25 pure AE patients were corrected fully using glasses alone, and all 12 non-AE patients received surgery. Among the 45 partial AE cases, 35 patients with residual esodeviation of <=30 PD received prismatic correction, with a success rate of 71.4% (25 of the 35 patients). The remaining 10 children who were not successfully treated with prismatic correction and the other 10 partial AE with residual esodeviation of >30 PD received surgery. The most recent follow-up examination indicated that all the non-surgical children were orthotropia or esophoria or had residual esotropia <=10 PD. Among the surgical patients, 5 patients (5 in 32 or 15.6%) exhibited unstable alignment during the postoperative follow-up period, and 10 patients (10 in 32 or 31.25%) underwent additional surgery for residual esotropia. CONCLUSIONS: Treatment of estropia in children with hyperopia includes wearing glasses, glasses combined with prism glasses and surgery. Prismatic correction in the treatment of small angle of residual esotropia in partial AE was feasible and efficacious. Since the follow-up lasted only a year, a long-term follow-up is needed in future studies to investigate the efficiency of the treatments. PMID- 21265595 TI - Managing localized prostate cancer by radical prostatectomy or watchful waiting: Cost analysis of a randomized trial (SPCG-4). AB - OBJECTIVE: The cost of radical prostatectomy (RP) compared to watchful waiting (WW) has never been estimated in a randomized trial. The goal of this study was to estimate long-term total costs per patient associated with RP and WW arising from inpatient and outpatient hospital care. MATERIAL AND METHODS: This investigation used the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial, comparing RP to WW, and included data from 212 participants living in two counties in Sweden from 1989 to 1999 (105 randomized to WW and 107 to RP). All costs were included from randomization date until death or end of follow-up in July 2007. Resource use arising from inpatient and outpatient hospital costs was measured in physical units and multiplied by a unit cost to come up with a total cost per patient. RESULTS: During a median follow-up of 12 years, the overall cost in the RP group was 34% higher (p < 0.01) than in the WW group, corresponding to ?6123 in Sweden. The difference was driven almost exclusively by the cost of the surgical procedure. The cost difference between RP and WW was two times higher among men with low (2-6) than among those with high (7-10) Gleason score. CONCLUSION: In this economic evaluation of RP versus WW of localized prostate cancer in a randomized study, RP was associated with 34% higher costs. This difference, attributed exclusively to the cost of the RP procedure, was not overcome during extended follow-up. PMID- 21265596 TI - Spinal cord injuries induce changes in CB1 cannabinoid receptor and C-C chemokine expression in brain areas underlying circuitry of chronic pain conditions. AB - Due to their involvement in neuro-modulatory processes, the endogenous cannabinoid system and chemokine network, which were shown to interact which each other, are potential key elements in the cascades underlying central neuropathic pain development after spinal cord injury (SCI). Expression profiles of cannabinoid receptor type-1 (CB(1)), and of the chemokines chemokine ligand 2 (C C motif ) (CCL2), chemokine ligand 3 (C-C motif ) (CCL3), plus their main receptors CCR2 and CCR1, were investigated in brain regions related to pain, emotion, learning, and memory in a rat SCI paradigm of post-traumatic neuropathic pain. Immunoreactivity (IR) was investigated 7 days and 42 days after sham operation, and moderate (100-kdyn), and severe (200-kdyn) thoracic spinal cord contusion lesions. Hippocampal (HC) subregions, amygdaloid complex, anterior cingulate cortex (ACC), periaqueductal gray (PAG), and thalamic nuclei were analyzed. Seven days after lesioning, CB(1) IR was induced in thalamic nuclei and HC subregions (CA3 and dentate gyrus), and downregulated in amygdaloid nuclei, ACC, and PAG. On day 42, CB(1) IR remained elevated in the HC and thalamic areas, and was induced in ACC after 100-kdyn, but downregulated after 200-kdyn lesions. It remained reduced in the PAG of severely lesioned animals, paralleling their prolonged neuropathic pain-related behavior. Double-labeling revealed partial co expression of CB(1) with the pain-related vanilloid receptor transient receptor potential vanilloid receptor 1 (TRPV1), and chemokines (CCL2 and CCL3). These chemokines were induced in the PAG, thalamus, and HC, especially in the chronic time course after severe SCI. Thus interactions of CB(1), C-C chemokines, and TRPV1 likely play a role in SCI-induced plastic changes in the brain, underlying emotional-affective pain responses and central pain development after spinal cord lesions. PMID- 21265597 TI - Electrical stimulation accelerates axonal and functional peripheral nerve regeneration across long gaps. AB - Short-term low-frequency electrical stimulation (ESTIM) of proximal peripheral nerve stumps prior to end-to-end coaptation or tubular bridging of small distances has been reported to increase preferential motor reinnervation and functional motor recovery in animal models and human patients undergoing carpal tunnel release surgery. We investigated the effects of ESTIM on regeneration across rat sciatic nerve gaps, which exceed distances that allow spontaneous regeneration. Three different reconstruction approaches were combined with ESTIM in the experimental groups. Nerve gaps (13 mm) were bridged using (I) nerve autotransplantation, (II) transplantation of differentially filled silicone tubes, or (III) transplantation of tubular grafts containing fibroblast growth factor-2 overexpressing Schwann cells (SCs) for gene therapy. The regeneration outcome was followed for up to 8 weeks, and functionally as well as histomorphometrically analyzed in comparison to non-stimulated control groups. Combining ESTIM with nerve autotransplantation significantly increased the nerve fiber density in the regenerated nerve, and the grade of functional recovery as detected by electrodiagnostic recordings from the gastrocnemius muscle. The combination of ESTIM with transplantation of naive SCs increased the regeneration of gap-bridging nerve tissue. Although macroscopic tissue regeneration was not further improved after combining ESTIM with FGF-2(21/23-kD) gene therapy, the latter resulted in a high rate of regenerated nerves that functionally reconnected to the target muscle. Based on our results, brief ESTIM shows high potential to accelerate axonal as well as functional (motor and sensory) outcomes in the clinical setting of peripheral nerve gap reconstruction in human patients. PMID- 21265598 TI - Mean platelet volume in patients with subclinical hypothyroidism. AB - Subclinical hypothyroidism (SCH) is frequently encountered in the general population. Since it is generally asymptomatic, these patients are mostly identified through routine screening or evaluation of non-specific symptoms. It has been suggested as a risk factor for cardiovascular disease. On the other hand, mean platelet volume (MPV), which is a determinant of platelet function, is an independent risk factor for cardiovascular disease. The aim of this study was to evaluate MPV values in subclinical hypothyroidic patients when they were subclinical hypothyroidic and became euthyroidic after 12 weeks of levothyroxine replacement therapy. Sixty patients with subclinical hypothyroidism and 78 euthyroid healthy subjects matched for age, gender and body mass index were enrolled in the study. None of the study subject had diabetes, hypertension or dyslipidemia. All the study subjects were evaluated by biochemical and platelet parameters. Subclinical hypothyroidic patients were then reevaluated with the same parameters when they became euthyroid after 12 weeks of levothyroxine treatment. Platelet counts and metabolic parameters, except serum triglyceride and high density lipoprotein cholesterol (HDLC) levels, were similar between the two groups. Serum triglyceride and MPV values were significantly higher (pTG=0.007 and pMPV<0.001) while HDLC levels were lower (pHDLC=0.008) in the subclinical hypothyroidic group. MPV was found to be correlated with only antithyroid peroxidase (anti-TPO) antibody levels (P<0.001). MPV values were decreased after subclinical hypothyroidic patients became eythyroid. However, post-treatment MPV values were still higher (p=0.035) in the patient group than in control group. These results suggest that subjects with SCH are susceptible to increased platelet activation and increased MPV values which contribute to increased risk of cardiovascular complications. PMID- 21265599 TI - Inhibiting platelets aggregation could aggravate the acute infection caused by Staphylococcus aureus. AB - Several fibrinogen binding proteins (Fibs) play important roles in the pathogenesis of Staphylococcus aureus (S. aureus). Most Fibs can promote the aggregation of platelets during infection, but the extracellular fibrinogen binding protein (Efb) is an exception. It is reported that Efb can specifically bind fibrinogen and inhibit the aggregation of platelet with its N terminal. However, the biological significance of platelet aggregation inhibition in the infection caused by S. aureus is unclear until now. Here, we demonstrated that the persistence and aggregation of platelets were important for killing S. aureus in whole blood. It was found that the N terminal of Efb (EfbN) and platelets inhibitors could increase the survival of S. aureus in whole blood. The study in vivo also showed that EfbN and platelets inhibitors could reduce the killing of S. aureus and increase the lethality rate of S. aureus in the acute infection mouse model. PMID- 21265600 TI - The neural correlates of object familiarity and domain specificity in the human visual cortex: an FMRI study. AB - Ventral occipito-temporal cortex is known to play a major role in visual object recognition. Still unknown is whether object familiarity and semantic domain are critical factors in its functional organization. Most models assume a functional locus where exemplars of familiar categories are represented: the structural description system. On the assumption that familiarity should modulate the effect of visual noise on form recognition, we attempted to individualize the structural description system by scanning healthy subjects while they looked at familiar (living and nonliving things) and novel 3-D objects, either with increasing or decreasing visual noise. Familiarity modulated the visual noise effect (particularly when familiar items were living things), revealing a substrate for the structural description system in right occipito-temporal cortex. These regions also responded preferentially to living as compared to nonliving items. Overall, these results suggest that living items are particularly reliant on the structural description system. PMID- 21265601 TI - Tonal expectations influence early pitch processing. AB - The present study investigated the ERP correlates of the influence of tonal expectations on pitch processing. Participants performed a pitch discrimination task between penultimate and final tones of melodies. These last two tones were a repetition of the same musical note, but penultimate tones were always in tune whereas final tones were slightly out of tune in half of the trials. The pitch discrimination task allowed us to investigate the influence of tonal expectations in attentive listening and, for penultimate tones, without being confounded by decisional processes (occurring on final tones). Tonal expectations were manipulated by a tone change in the first half of the melodies that changed their tonality, hence changing the tonal expectedness of penultimate and final tones without modifying them acoustically. Manipulating tonal expectations with minimal acoustic changes allowed us to focus on the cognitive expectations based on listeners' knowledge of tonal structures. For penultimate tones, tonal expectations modulated processing within the first 100 msec after onset resulting in an Nb/P1 complex that differed in amplitude between tonally related and less related conditions. For final tones, out-of-tune tones elicited an N2/P3 complex and, on in-tune tones only, tonal manipulation elicited an ERAN/RATN-like negativity overlapping with the N2. Our results suggest that cognitive tonal expectations can influence pitch perception at several steps of processing, starting with early attentional selection of pitch. PMID- 21265602 TI - Cooperative and opposing effects of strategic and involuntary attention. AB - To assess whether working memory contents can effectively bias visual selection even when they do not represent the current target in the attention task, we recorded the ERP activity from participants performing both a memory task and, in the retention period, a visual search task. In this task, a distracter matching the memory content could be presented on the same side (congruent trials) or on the opposite side (incongruent trials) relative to the target location (Experiment 1 and Experiment 2). On some trials, only the matching distracter (but no target) was presented (catch trials, Experiment 2). Results showed that the N2pc component was modulated by the presence and location of a matching distracter. We interpret these results as evidence that the involuntary control exerted by the irrelevant memory contents coexists with the strategic mechanism related to the search target, influencing attention selection with roughly equal power. In Experiment 3, we found that the modulation of the N2pc is not strictly related to the active maintenance of the memory-target features but can also be elicited by repetition priming. Overall, these findings suggest that, together with the physical properties of the stimuli presented in the visual field, irrelevant memory contents represent a powerful class of factors that lead to involuntary attentional control. PMID- 21265603 TI - Functional connectivity and coactivation of the nucleus accumbens: a combined functional connectivity and structure-based meta-analysis. AB - This article investigates the functional connectivity patterns of the nucleus accumbens (NAcc) in 18 healthy participants using a resting state functional connectivity (rsFC) protocol. Also, a meta-analytic connectivity modeling (MACM) was used to characterize patterns of functional coactivations involving NAcc: The results of a structure-based meta-analyses of 57 fMRI and PET studies were submitted to activation likelihood estimation analysis to estimate consistent activation patterns across the different imaging studies. The results of the combined rsFC and MACM analyses show that spontaneous activity in NAcc predicts activity in regions implicated in reward circuitries, including orbitomedial prefrontal cortex, globus pallidus, thalamus, midbrain, amygdala, and insula. This confirms the key role of NAcc in the mesocorticolimbic system, which integrates inputs from limbic and cortical regions. We also detected activity in brain regions having few or no direct anatomical connections with NAcc, such as sensorimotor cortex, cerebellum, medial and posterior parietal cortex, and medial/inferior temporal cortex, supporting the view that not all functional connections can be explained by anatomical connections but can also result from connections mediated by third areas. Our rsFC findings are in line with the results of the structure-based meta-analysis: MACM maps are superimposable with NAcc rsFC results, and the reward paradigm class is the one that most frequently generates activation in NAcc. Our results overlap considerably with recently proposed schemata of the main neuron systems in the limbic forebrain and in the anterior part of the limbic midbrain in rodents and nonhuman primates. PMID- 21265604 TI - Dishabituation of laser-evoked EEG responses: dissecting the effect of certain and uncertain changes in stimulus modality. AB - The repetition of nociceptive stimuli of identical modality, intensity, and location at short and constant interstimulus intervals (ISIs) determines a strong habituation of the corresponding EEG responses, without affecting the subjective perception of pain. To understand what determines this response habituation, we (i) examined the effect of introducing a change in the modality of the repeated stimulus, and (ii) dissected the relative contribution of bottom-up, stimulus driven changes in modality and top-down, cognitive expectations of such a change, on both laser-evoked and auditory-evoked EEG responses. Multichannel EEG was recorded while participants received trains of three stimuli (S1-S2-S3, a triplet) delivered to the hand dorsum at 1-sec ISI. S3 belonged either to the same modality as S1 and S2 or to the other modality. In addition, participants were either explicitly informed or not informed of the modality of S3. We found that introducing a change in stimulus modality produced a significant dishabituation of the laser-evoked N1, N2, and P2 waves; the auditory N1 and P2 waves; and the laser- and auditory-induced event-related synchronization and desynchronization. In contrast, the lack of explicit knowledge of a possible change in the sensory modality of the stimulus (i.e., uncertainty) only increased the ascending portion of the laser-evoked and auditory-evoked P2 wave. Altogether, these results indicate that bottom-up novelty resulting from the change of stimulus modality, and not top-down cognitive expectations, plays a major role in determining the habituation of these brain responses. PMID- 21265605 TI - Color, context, and cognitive style: variations in color knowledge retrieval as a function of task and subject variables. AB - Neuroimaging tests of sensorimotor theories of semantic memory hinge on the extent to which similar activation patterns are observed during perception and retrieval of objects or object properties. The present study was motivated by the hypothesis that some of the seeming discrepancies across studies reflect flexibility in the systems responsible for conceptual and perceptual processing of color. Specifically, we test the hypothesis that retrieval of color knowledge can be influenced by both context (a task variable) and individual differences in cognitive style (a subject variable). In Experiment 1, we provide fMRI evidence for differential activity during color knowledge retrieval by having subjects perform a verbal task, in which context encouraged subjects to retrieve more- or less-detailed information about the colors of named common objects in a blocked experimental design. In the left fusiform, we found more activity during retrieval of more- versus less-detailed color knowledge. We also assessed preference for verbal or visual cognitive style, finding that brain activity in the left lingual gyrus significantly correlated with preference for a visual cognitive style. We replicated many of these effects in Experiment 2, in which stimuli were presented more quickly, in a random order, and in the auditory modality. This illustration of some of the factors that can influence color knowledge retrieval leads to the conclusion that tests of conceptual and perceptual overlap must consider variation in both of these processes. PMID- 21265582 TI - Dose-dependent antihypertensive efficacy and tolerability of perindopril in a large, observational, 12-week, general practice-based study. AB - BACKGROUND: Current guidelines recommend the use of full therapeutic dosages of antihypertensive agents, or combination therapy, to improve BP control of hypertensive patients in primary healthcare. OBJECTIVE: The aim of this study was to assess the dose-dependent antihypertensive efficacy and safety of perindopril 4 and 8 mg/day in the clinical setting. STUDY DESIGN AND SETTING: The CONFIDENCE study was a prospective, observational, multicenter trial. This was a real-world, clinic-based, outpatient study involving 880 general practitioners/primary-care clinics and 113 specialists in Canada. PATIENTS: The study included untreated or inadequately managed patients with hypertension (i.e. seated BP >= 140/90 mmHg, or >= 130/80 mmHg in the presence of diabetes mellitus, renal disease, or proteinuria) without coronary artery disease (CAD). INTERVENTION: Treatment consisted of perindopril 4 mg/day, uptitrated to 8 mg/day as required for BP control at visit 2, for 12 weeks. Among the patients already being treated at baseline, perindopril either directly replaced all previous ACE inhibitors or angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), or was added to antihypertensive treatment with calcium channel blockers (CCBs), diuretics, or beta-adrenoceptor antagonists (beta-blockers). MAIN OUTCOMES MEASURES: The primary outcomes were the mean changes in BP from baseline following treatment with perindopril 4 and 8 mg/day as well as the proportion of patients achieving BP control (BP <140/90 mmHg, or <130/80 mmHg in diabetic patients) in the intent-to-treat (ITT) population. Secondary analyses included the incidence of adverse events and compliance. RESULTS: A total of 8298 hypertensive patients entered the study: 56% with newly diagnosed hypertension and 44% with uncontrolled hypertension. Mean SBP/DBP decreased significantly from baseline (152.5 +/- 10.8/89.5 +/- 9 mmHg) over 12 weeks (-18.5/-9.7 mmHg; p < 0.001). At visit 2, 23% of patients were uptitrated to perindopril 8 mg/day, which resulted in an additional mean 10.1/5.3 mmHg BP reduction; this reduction was even greater (15.1/5.7 mmHg) among a separate group of severely hypertensive patients (i.e. SBP >170 mmHg or DBP >109 mmHg at baseline). Target BP was achieved in 54% of the ITT population. Both perindopril 4 mg/day and perindopril 8 mg/day were well tolerated and compliance was high throughout the study. CONCLUSION: In the clinical outpatient setting, perindopril was found to be an effective dose-dependent and well tolerated antihypertensive treatment, with good compliance. Uptitration to the full therapeutic dosage of perindopril is an efficient approach for the management of a broad range of hypertensive patients without CAD. PMID- 21265606 TI - Bilateral bulbospinal projections to pudendal motoneuron circuitry after chronic spinal cord hemisection injury as revealed by transsynaptic tracing with pseudorabies virus. AB - Complications of spinal cord injury in males include losing brainstem control of pudendal nerve-innervated perineal muscles involved in erection and ejaculation. We previously described, in adult male rats, a bulbospinal pathway originating in a discrete area within the medullary gigantocellularis (GiA/Gi), and lateral paragigantocellularis (LPGi) nuclei, which when electrically microstimulated unilaterally, produces a bilateral inhibition of pudendal motoneuron reflex circuitry after crossing to the contralateral spinal cord below T8. Microstimulation following a long-term lateral hemisection, however, revealed reflex inhibition from both sides of the medulla, suggesting the development or unmasking of an injury-induced bulbospinal pathway crossing the midline cranial to the spinal lesion. In the present study, we investigated this pathway anatomically using the transsynaptic neuronal tracer pseudorabies virus (PRV) injected unilaterally into the bulbospongiosus muscle in uninjured controls, and ipsilateral to a chronic (1-2 months) unilateral lesion of the lateral funiculus. At 4.75 days post-injection, PRV-labeled cells were found bilaterally in the GiA/Gi/LPGi with equal side-to-side labeling in uninjured controls, and with significantly greater labeling contralateral to the lesion/injection in lesioned animals. The finding of PRV-labeled neurons on both sides of the medulla after removing the mid-thoracic spinal pathway on one side provides anatomical evidence for the bilaterality in both the brainstem origin and the lumbosacral pudendal circuit termination of the spared lateral funicular bulbospinal pathway. This also suggests that this bilaterality may contribute to the quick functional recovery of bladder and sexual functions observed in animals and humans with lateral hemisection injury. PMID- 21265607 TI - Adolescent obesity and maternal and paternal sensitivity and monitoring. AB - OBJECTIVE: To determine if adolescent obesity is associated with parenting characterized by lower sensitivity and lower monitoring of adolescent activities. METHODS: We used data from 744 adolescents in the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development. Height and weight were measured at age 151/2 years and obesity defined as body mass index >= 95th percentile for age and sex. Maternal and paternal sensitivity were assessed by direct observation of a parent-adolescent interaction task. Maternal and paternal monitoring were assessed by parent report. Lower sensitivity and lower monitoring were each defined as the lowest quartiles. Two separate multivariate logistic regression models were created to evaluate, individually for mothers and fathers, associations of sensitivity and monitoring with adolescent obesity, controlling for adolescent sex and race, family income to-needs ratio, and parental obesity. RESULTS: Fourteen percent of the adolescents were obese. Lower sensitivity was associated with adolescent obesity in the maternal parenting model (adjusted odds ratio [AOR] 2.36, 95% confidence interval [CI] 1.44-3.86, n = 709), but not paternal parenting model (AOR = 0.79, 95% CI 0.38-1.63, n = 460). Neither maternal nor paternal monitoring was associated with adolescent obesity (AOR = 1.03, 95% CI 0.63-1.68; AOR = 1.07, 95% CI 0.52-2.22, respectively). CONCLUSION: Lower maternal sensitivity, measured by direct observation of parent-adolescent interactions, was associated with adolescent obesity. Efforts to prevent and treat childhood obesity, both at the practitioner level and the community level, may be enhanced by educating parents that their reactions to their children's behaviors may have consequences related to obesity. PMID- 21265608 TI - 1H-nuclear magnetic resonance spectroscopy of glioblastoma cancer stem cells. AB - The noninvasive tracking of glioblastoma cancer stem cells (CSCs) in vivo constitutes a prerequisite for the development of CSC-specific therapies. Therefore, as a pilot study to identify CSC biomarkers for clinical magnetic resonance spectroscopy, 10 CSC lines were investigated using high-resolution (1)H nuclear magnetic resonance ((1)H-NMR) spectroscopy at 600 and 800 MHz (14.4 and 18.8 T) under reproducible in vitro conditions. The spectra were analyzed using principal component analysis (PCA), and spectral regions of high variability were evaluated regarding correlations to stem cell-related properties (clonogenic index and CD133 positivity) and cell death. PCA revealed that duplicates of CSC lines clustered together suggesting a characteristic (1)H-NMR pattern of each CSC line. PCA enabled discrimination between samples with high and low clonogenicity, that is, clustering according to one of the hallmarks of stemness in samples with high viability. High/moderate correlations to clonogenicity and CD133 were found in spectral regions with high variability. In contrast, the mobile lipid signal at 1.28 ppm correlated to cell death, but not to stemness, as published previously for neural progenitor cells. In conclusion, our exploratory study demonstrates the correlation of specific resonances within (1)H-NMR spectra with stem cell properties and advocates the use of the 1.28 ppm resonance as biomarker for cell death also in CSCs. PMID- 21265609 TI - Seeing the gaps: a systematic review of visual perception tools for children with hemiplegia. AB - PURPOSE: Visual perception difficulties are common in children with cerebral palsy - hemiplegia, however it is not known which assessment tool is the best for this population. This systematic review evaluates the clinimetric properties of visual perception assessments for children with hemiplegia. METHOD: Databases were searched for assessments that: (i) measured visual perception; (ii) were reported in studies with children with hemiplegia and (iii) had clinimetric data available to assessors. RESULTS: Three assessments met criteria: the Test of Visual Perceptual Skills (TVPS), Motor-Free Visual Perceptual Test (MVPT) and Developmental Test of Visual Perception (DTVP). Factor analysis has been completed for the TVPS and DTVP, with both assessments and especially the TVPS, demonstrating some subtests that do not load significantly for the first factor of motor-free visual perception. All three assessments demonstrate variable construct and criterion validity with other clinical assessments. The DTVP, MVPT and TVPS demonstrate high test-retest reliability for total scores, but individual TVPS subtests are less reliable. CONCLUSIONS: The MVPT and DTVP show the best clinimetric data, however, less research has been completed on these tests than the TVPS. Further research is required to confirm the validity and reliability of the MVPT and DTVP for children with hemiplegia. PMID- 21265611 TI - Test-retest reliability of the GAITRite system in people with stroke undergoing rehabilitation. AB - PURPOSE: To determine the test-retest reliability of the GAITRite system in measuring spatio-temporal gait parameters in people with stroke undergoing inpatient rehabilitation and to investigate whether walking ability influences test-retest reliability. METHOD: A within-subject repeated measures study was conducted. Twenty-one individuals with first stroke undergoing inpatient rehabilitation participated. The Motor Assessment Scale Item 5 score was used to categorise participants into poorer (score 3 or 4) or better walkers (score 5 or 6). Participants made two passes at a self-selected gait speed over the GAITRite mat on two separate occasions. Intra-class correlation coefficients (ICC(2,1)) and 95% limits of agreement for spatio-temporal gait parameters between the two occasions and groups were determined. RESULTS: No differences in gait parameters between the two sessions (p > 0.15) were found. Test-retest reliability for the whole group was good to excellent, ICC(2,1) ranging from 0.72 to 0.94. Walking ability did influence these findings with fair to good reliability demonstrated for both poorer (ICC(2,1) > 0.57) and better walkers (ICC(2,1) > 0.41). CONCLUSIONS: It appears that the GAITRite has good test-retest reliability in this group of people with first stroke undergoing rehabilitation. Test reliability seems to be slightly higher for poorer walkers than better walkers. PMID- 21265610 TI - Coronary arterial calcification and thoracic spine mineral density in early menopause. AB - OBJECTIVES: Cardiovascular disease and osteoporosis increase in women after menopause. While aortic calcification is associated with bone loss in women, a similar relationship for coronary arterial calcification (CAC), a risk factor for coronary artery disease in women, is less clear. This study was designed to examine the relationship between CAC and volumetric bone mineral density (vBMD) in women (n=137) who were within a median of 18 months past their last menses at screening for the Kronos Early Estrogen Prevention Study (KEEPS). METHODS: CAC was measured using 64-slice computed tomography; vBMD was measured from these images using the Spine Cancer Assessment program. Concentrations of osteocalcin, bone alkaline phosphatase, tartrate-resident acid phosphatase-5b and osteopontin as bone matrix protein in serum and plasma were evaluated by ELISA. RESULTS: CAC scores ranged from 0 to 327.6 Agatston Units (AU); 113 women had a score of 0 AU, 20 had a CAC score between 0 and 50 AU, and four had a CAC score>50 AU. Although not statistically significant, there was a trend toward decreasing central density of thoracic T9 with increasing CAC. On average, levels of markers of bone turnover were within the normal range but did not correlate with age or with months past menopause. CONCLUSIONS: Clinically significant CAC and spine vBMD are quantifiable from the same scans within the first 3 years of menopause. Additional work is needed to determine how these measurements change with increasing age or with estrogenic treatments. PMID- 21265613 TI - A new species of the genus Parasa Moore (Lepidoptera: Limacodidae) from Yemen. AB - A new species Parasa dusii Solovyev and Saldaitis from northern Yemen is described (holotype in Museum Witt, Munich; Germany). The species has tendency to lose the green pigment typical for other congeners. It is provisionally placed into the genus Parasa Moore, 1859 where it is closely related to P. divisa West, 1940, P. catori Bethune-Baker, 1911, P. marginata West, 1940, P. thamia Rungs, 1951, P. dentina Hering, 1932, P. ananii Karsch, 1896, and P. semiochracea Hering, 1933. The relationship of the new species to these African species suggests its secondary penetration into the Arabian Peninsula from an origin in tropical Africa. The problems of monophyly of the genus Parasa and several associated genera are briefly discussed. All important characters of the new species, and some related species, are illustrated. PMID- 21265612 TI - The pivotal role of reactive oxygen species generation in the hypoxia-induced stimulation of adipose-derived stem cells. AB - Adipose-derived stem cells (ASCs) offer a potential alternative for tissue repair and regeneration. We have recently shown that hypoxia stimulates ASCs and enhances the regenerative potential of ASCs, which is beneficial for ASC therapy. In the present study, we further investigated a key mediator and a signal pathway involved in the stimulation of ASC during hypoxia. Culturing ASC in a hypoxic incubator (2% oxygen tension) increased the proliferation and migration, and this was mediated by Akt and ERK pathways. To determine the generation of reactive oxygen species (ROS), 2',7'-dichlorofluorescin diacetate intensity was detected by fluorescence-activated cell sorting. Hypoxia significantly increased the dichlorofluorescin diacetate intensity, which was greatly reduced by N-acetyl cysteine and diphenyleneiodonium treatment. Likewise, the hypoxia-induced proliferation and migration of ASCs were reversed by N-acetyl-cysteine and diphenyleneiodonium treatment, suggesting the involvement of ROS generation in ASC stimulation. Further, we examined the activation of receptor tyrosine kinases and observed that hypoxia stimulated the phosphorylation of platelet-derived growth factor receptor-beta. In summary, the ROS produced by ASCs in response to hypoxia was mostly likely due to NADPH oxidase activity. The increased cellular ROS was accompanied by the phosphorylation of platelet-derived growth factor receptor-beta as well as by the activation of ERK and Akt signal pathways. Our results suggest a pivotal role for ROS generation in the stimulation of ASCs by hypoxia. PMID- 21265614 TI - Identity of two sympatric species of Orius (Hemiptera: Heteroptera: Anthocoridae). AB - The minute pirate bugs, Orius insidiosus (Say) and Orius pumilio (Champion) (Hemiptera: Heteroptera: Anthocoridae), are closely related species known to be sympatric in north Florida. Here, male and female genitalia, DNA sequences, and the effects of within- and between-species pairings on egg production and egg development were examined to develop a better understanding of the relationship between these two species. Interspecific matings between the two species did not result in viable progeny. Although there were gross similarities in the morphology of the male parameres (external genitalia) between the two species, the cone in O. pumilio was much broader with a greater spiral twist and the flagellum was longer than in O. insidiosus. Correspondingly, there were differences in the morphology of the copulatory tubes of the females of the two species. In O. insidiosus, the organ was somewhat longer than in O. pumilio and oriented parallel to the abdominal midline, while the copulatory tube in O. pumilio tilted slightly towards the midline. Additionally, the copulatory tube for O. pumilio included a sclerotized basal mound that was not present in O. insidiosus. These morphological differences suggest that successful copulation between these species could be difficult. In contrast to conspecific matings, interspecific matings resulted in few or no eggs laid over a period of two weeks and no viable progeny. Comparison of the 18S ribosomal gene ITS-1 sequences between the two species demonstrated only 91% homology. When yolk protein contents were examined to determine whether reproductive physiology had shifted to full egg production, interspecifically mated females contained amounts of yolk protein comparable to that in fed, but unmated females; this was less than 10% of the yolk protein previously found in fed and conspecifically mated females. These findings together confirm that O. insidiosus and O. pumilio are indeed two separate species. PMID- 21265615 TI - Molecular cloning, characterization, and expression analysis of an estrogen receptor-related receptor homologue in the cricket, Teleogryllus emma. AB - The estrogen receptor-related receptors (ERRs) are a group of nuclear receptors that were originally identified on the basis of sequence similarity to estrogen receptors. The three mammalian ERR genes have been implicated in diverse physiological processes ranging from placental development to maintenance of bone density, but the function and regulation of ERRs in invertebrates are not well understood. A homologue of human ERR was isolated from the cricket Teleogryllus emma (Ohmachi and Matsumura) (Orthoptera: Gryllidae). The full-length cDNA of T. emma ERR, termed TeERR, has 1618 base pair (bp) and contains a 5'-untranslated region of 140 bp and a 3'-untranslated region of 272 bp. The open reading frame of TeERR encodes a deduced 401 amino acid peptide with a predicted molecular mass of 45.75 kilodaltons. The results of sequence alignments indicate that the TeERR protein shares an overall identity of 65%-82% with other known ERR homologues, and is most closely related to that of Nasonia vitripennis (Hymenoptera: Pteromalidae) and Apis mellifera (Apidae). Real-time quantitative reverse transcription-polymerase chain reaction was performed to compare the TeERR mRNA expression level at the whole body and gonad during T. emma development. The data revealed that TeERR mRNA is differentially expressed during T. emma development, with the highest expression level in embryos and the lowest in the body of late instar larvae. The levels of TeERR transcripts also varied throughout gonad development; interestingly testicles had higher higher expression levels than ovaries at every development stage. These results suggest that TeERR has potential significance in the regulation of development in T. emma, due to its expression during different developmental periods. PMID- 21265616 TI - Impacts of Synergy-505 on the functional response and behavior of the reduviid bug, Rhynocoris marginatus. AB - The impact of the insecticide, Synergy-505 (chlorpyrifos 50% and cypermethrin 5% E.C), on the functional response, predatory behavior, and mating behavior of a non-target reduviid, Rhynocoris marginatus (Fabricius) (Hemiptera: Reduviidae), a potential biological control agent, were studied. Though both normal and Synergy 505-exposed R. marginatus exhibited Holling's type II curvilinear functional response, Synergy-505 caused a less pronounced type II functional response with reduced numbers of prey killed, attack rate, searching time, and prolonged handling time in 4th and 5th nymphal instars and adult males and females reflecting reduced predatory potential. Synergy-505 also delayed the predatory and mating events. The impacts of Synergy-505 on functional response, predatory behavior, and mating behavior were more evident at higher concentrations of Synergy-505. PMID- 21265617 TI - Diversity, ecology and herbivory of hairstreak butterflies (Theclinae) associated with the velvet tree, Miconia calvescens in Costa Rica. AB - Larvae of three species of hairstreak butterflies in the subfamily Theclinae (Lepidoptera: Lycaenidae) were found feeding on developing inflorescences, flower buds, and immature fruits of the velvet tree, Miconia calvescens DC. (Myrtales: Melastomataceae) in Costa Rica. Erora opisena (Druce), Parrhasius polibetes (Cramer), and Temecla paron (Godman and Salvin) were studied in association with M. calvescens, an uncommon tree in its natural range in the neotropics and a target for biocontrol as an invader in Pacific islands. Host plant use by the three theclines was similar, with eggs being laid on inflorescences and cryptic larvae remaining there throughout development. Feeding damage by E. opisena was most abundant in pre-flowering M. calvescens, when 23% of inflorescences showed feeding damage characteristic of this species. Feeding damage by T. paron peaked at flowering, when 30% of inflorescences were affected. At field sites, E. opisena and T. paron damaged an average of 26 and 18% of each attacked inflorescence, respectively. In cage experiments, individual third- and fourth instar larvae of E. opisena damaged an average of 24 and 21% of an inflorescence before pupating, respectively. This study provides the first host plant record for E. opisena and T. paron, the first record of P. polibetes feeding on Melastomataceae, and the first records of E. opisena and T. paron presence in Costa Rica. PMID- 21265618 TI - Silkworm thermal biology: a review of heat shock response, heat shock proteins and heat acclimation in the domesticated silkworm, Bombyx mori. AB - Heat shock proteins (HSPs) are known to play ecological and evolutionary roles in this postgenomic era. Recent research suggests that HSPs are implicated in cardiovascular biology and disease development, proliferation and regulation of cancer cells, cell death via apoptosis, and several other key cellular functions. These activities have generated great interest amongst cell and molecular biologists, and these biologists are keen to unravel other hitherto unknown potential functions of this group of proteins. Consequently, the biological significance of HSPs has led to cloning and characterization of genes encoding HSPs in many organisms including the silkworm, Bombyx mori L. (Lepidoptera: Bombycidae). However, most of the past investigations in B. mori were confined to expression of HSPs in tissues and cell lines, whereas information on their specific functional roles in biological, physiological, and molecular processes is scarce. Naturally occurring or domesticated polyvoltines (known to be the tropical race) are more resistant to high temperatures and diseases than bi- or univoltines (temperate races). The mechanism of ecological or evolutionary modification of HSPs during the course of domestication of B. mori - particularly in relation to thermotolerance in geographically distinct races/strains - is still unclear. In addition, the heat shock response, thermal acclimation, and hardening have not been studied extensively in B. mori compared to other organisms. Towards this, recent investigations on differential expression of HSPs at various stages of development, considering the concept of the whole organism, open ample scope to evaluate their biological and commercial importance in B. mori which has not been addressed in any of the representative organisms studied so far. Comparatively, heat shock response among different silkworm races/strains of poly-, bi-, and univoltines varies significantly and thermotolerance increases as the larval development proceeds. Hence, this being the first review in this area, an attempt has been made to collate all available information on the heat shock response, HSPs expression, associated genes, amino acid sequences, and acquired/unacquired thermotolerance. The aim is to present this as a valuable resource for addressing the gap in knowledge and understanding evolutionary significance of HSPs between domesticated (B. mori) and non-domesticated insects. It is believed that the information presented here will also help researchers/breeders to design appropriate strategies for developing novel strains for the tropics. PMID- 21265619 TI - Suitable reference gene selection for different strains and developmental stages of the carmine spider mite, Tetranychus cinnabarinus, using quantitative real time PCR. AB - Reference genes are used as internal controls in gene expression studies, but their expression levels vary according to tissue types and experimental treatments. Quantitative real-time PCR (qPCR) is the most sensitive technique for transcript quantification provided that gene transcription patterns are normalized to an evaluated reference gene. In this study, the suitability of eight commonly used genes (beta-actin, 5.8SrRNA, alpha-TUB, GAPDH, RPL13a, RPS18, TBP, SDHA) were cloned and investigated to find the most stable candidates for normalizing real-time PCR data generated from the four different strains (abamectin-resistant, fenpropathrin-resistant, omethoate-resistant, and susceptible strains) and different developmental stages (eggs, protonymphs, nymphs, and adults) of carmine spider mite, Tetranychus cinnabarinus (Boisduval) (Acarina: Tetranychidae). The stability of gene expression was assessed using two different analysis programs, geNorm and NormFinder. Using these analyses, RPS18 and 5.8SrRNA had the most stable expression regardless of the four different strains, whereas RPS18 and alpha-TUB were expressed most stably in different developmental stages. PMID- 21265620 TI - Analysis of the diversity of Megachilidae bees on the northern subplateau of the Iberian Peninsula. AB - In the western Mediterranean, 772 species of bees in the family Megachilidae have been reported. Special emphasis has been placed on the Iberian Peninsula, where to date 218 species are known. However, few intensive studies providing information about communities of Megachilidae have been carried out. Two earlier works cite 70 species; almost one third of those known on the Peninsula. With an aim of gaining insight into the structure of the communities of Megachilidae and the factors influencing them, an analysis was made of the alpha and beta diversity of different localities in the northern subplateau. Malaise traps (black and white) were used, and 559 specimens belonging to 55 species were identified of which most exhibited a nest-holder-type nesting habit. Abundance and richness were higher for white traps, although a considerable degree of complementarity was observed with the black traps. In the study zone, diversity can be considered medium-high with a phylogenetic diversity corresponding to stable populations. Regarding the composition of the Megachilidae communities, the influence of the landscape structure, of the microhabitat, and of the colour of the trap used to collect the specimens was detected. The following are recommended: (1) the use of both black and white traps, since they show high complementarity and offer different information about community structure, (2) homogenization of the samples in comparisons among communities, owing to the influence of the color of the trap, which masks the importance of ecological factors in community structuring, and (3) the collection of samples from at least two years previous, in view of the elevated "replacement" of species observed with species richness estimators. PMID- 21265621 TI - Variation in fitness of the longhorned beetle, Dectes texanus, as a function of host plant. AB - Dectes texanus LeConte (Coleoptera: Cerambycidae) has become a serious pest of two different crops in the American Midwest, sunflower, Helianthus annuus L. and soybean, Glycines max (L.). Laboratory and field studies were used to compare the effects of these two host plants on D. texanus life history and behavior. Insects from soybean were 40-60% smaller than those from sunflower and larval weight at collection was strongly correlated with survival to adulthood, whereas it was not in sunflower, suggesting that body size was more limiting to immature survival in soybean. Pupal weights increased more rapidly with increasing stem diameter in soybean than in sunflower and the correlation was stronger, indicating that body size was more limited by plant size in soybean. Adults collected as larvae from soybean had shorter longevities when starved, fed soybean, or fed an alternating diet of soybean and cultivated sunflower, than did those collected from sunflower, suggesting a negative larval legacy of soybean on adult fitness. Adult beetles that developed in soybean lived longer when fed soybean than when starved, but an adult diet of sunflower doubled longevity compared to soybean for beetles that developed in sunflower, and tripled it for those that developed in soybean. An adult diet of wild H. annuus yielded survivorship equivalent to cultivated H. annuus in one trial, and slightly lower in another. Larval host plant did not influence the numbers of ovipunctures or eggs laid by females in field trials, but adult diet did. Sunflower-fed females punctured more, and laid more eggs, on sunflowers than on soybeans in field cages and the reverse trend was evident, but not significant, in soybean-fed females. It can be concluded that H. annuus is a superior food source to G. max for both larval and adult D. texanus, and that wild sunflowers may represent a valuable food for adults during the pre-reproductive period, prior to invasion of soybean fields, even though they rarely host larvae. We also showed that stable isotope ratios of N can be used to distinguish the larval host plant of beetles regardless of their adult diet. PMID- 21265622 TI - A revision of the Argentinean endemic genus Eucranium Brulle (Coleoptera: Scarabaeidae: Scarabaeinae) with description of one new species and new synonymies. AB - The South American genus Eucranium Brulle has been revised and now includes six species: E. arachnoides Brulle, E. belenae Ocampo new species, E. cyclosoma Burmeister, E. dentifrons Guerin-Meneville, E. planicolle Burmeister, and E. simplicifrons Fairmaire. Eucranium pulvinatum Burmeister is a new junior synonym of Eucranium arachnoides Brulle, and Eucranium lepidum Burmeister is a new junior synonym of E. dentifrons Guerin-Meneville. The following lectotypes and neotypes are designated: Eucranium pulvinatum Burmeister, lectotype; Eucranium planicolle Burmeister, lectotype; Psammotrupes dentifrons Guerin-Meneville, neotype; and Eucranium lepidum Burmeister, neotype. Description of the genus and new species, diagnosis and illustrations, and distribution maps are provided for all species. A key to the species of this genus is provided, and the biology and conservation status of the species are discussed. PMID- 21265623 TI - The European radiobiological archives: online access to data from radiobiological experiments. AB - For financial and ethical reasons, the large-scale radiobiological animal studies conducted over the past 50 years are, to a large extent, unrepeatable experiments. It is therefore important to retain the primary data from these experiments to allow reanalysis, reinterpretation and re-evaluation of results from, for example, carcinogenicity studies, in the light of new knowledge in radiation biology. Consequently, there is an imperative need to keep these data available for the research community. The European Radiobiological Archives (ERA) were developed to fulfill this task. ERA has become a unique archive, including information from almost all European long-term studies carried out between the 1960s and the 1990s. The legacy database was originally developed in a manner that precluded online use. Therefore, strong efforts were made to transform it into a version that is available online through the web. This went together with quality assurance measures, including first the estimation of the rate of non systematic errors in data entry, which at 2% proved to be very low. Second, every data set was compared against two external sources of information. Standardization of terminology and histopathology is a prerequisite for meaningful comparison of data across studies and analysis of potential carcinogenic effects. Standardization is particularly critical for the construction of a database that includes data from different studies evaluated by pathologists in different laboratories. A harmonized pathology nomenclature with modern standard pathology terms was introduced. As far as possible, references for the various studies were directly linked to the studies themselves. Further, a direct link to the JANUS database was established. ERA is now in a position where it has the potential to become a worldwide radiobiological research tool. ERA can be accessed at no cost at https://era.bfs.de. An ID and password can be obtained from the curators at era@bfs.de . PMID- 21265624 TI - Murine Prkdc polymorphisms impact DNA-PKcs function. AB - Polymorphic variants of DNA repair genes can increase the carcinogenic potential of exposure to ionizing radiation. Two single nucleotide polymorphisms (SNPs) in Prkdc, the gene encoding the DNA-dependent protein kinase catalytic subunit (DNA PKcs), have been identified in BALB/c mice and linked to reduced DNA-PKcs activity and mammary cancer susceptibility. We examined three additional mouse strains to better define the roles of the BALB/c Prkdc SNPs (R2140C and M3844V). One is a congenic strain (C.B6) that has the C57BL/6 Prkdc allele on a BALB/c background, and the other is a congenic strain (B6.C) that has the BALB/c variant Prkdc allele on a C57BL/6 background. We also examined the LEWES mouse strain, which possesses only one of the BALB/c Prkdc SNPs (M3844V). Our results demonstrate that both Prkdc SNPs are responsible for deficient DNA-PKcs protein expression, DNA repair and telomere function, while the LEWES SNP affects only DNA-PKcs expression and repair capacity. These studies provide insight into the separation of function between the two BALB/c SNPs as well as direct evidence that SNPs positioned within Prkdc can significantly influence DNA-PKcs function involving DNA repair capacity, telomere end-capping, and potentially cancer susceptibility. PMID- 21265625 TI - A comparative study on the cytogenetic activity of three benzodiazepines in vitro. AB - Even though benzodiazepines (BDZs) possess a leading place among drugs used as anxiolytics, sedatives, muscle relaxants, and anticonvulsants, their cytogenetic effects have not been widely studied in humans. Alprazolam (AZ), bromazepam (BZ), diazepam, and lorazepam (LZ) are some of the most commonly prescribed BDZs. Previous positive findings on diazepam's cytogenetic effects in human lymphocytes suggested additional investigation. In the present research, we explored the cytogenetic potential of AZ, BZ, and LZ in human lymphocyte cultures, using an expanded sample set, administering the under-investigation medications at final concentrations equivalent to oral dosage. As a biomarker of genotoxicity we used sister chromatid exchanges, one of the most sensitive methods reflecting DNA damage and/or subsequent DNA repair, and as a marker of cytostaticity we estimated the proliferation rate index. After 72 h of incubation in the cultures, all three BDZs caused a concentration-dependent, statistically significant increase of sister chromatid exchange frequency (p < 0.001) followed by a statistically significant decrease of proliferation rate index (p < 0.001) of lymphocytes. Our conclusive results suggest that AZ, BZ, and LZ, at concentrations equivalent to oral doses, exhibit statistically significant genotoxicity in human lymphocyte cultures. PMID- 21265626 TI - Evolutionary squeaky wheel optimization: a new framework for analysis. AB - Squeaky wheel optimization (SWO) is a relatively new metaheuristic that has been shown to be effective for many real-world problems. At each iteration SWO does a complete construction of a solution starting from the empty assignment. Although the construction uses information from previous iterations, the complete rebuilding does mean that SWO is generally effective at diversification but can suffer from a relatively weak intensification. Evolutionary SWO (ESWO) is a recent extension to SWO that is designed to improve the intensification by keeping the good components of solutions and only using SWO to reconstruct other poorer components of the solution. In such algorithms a standard challenge is to understand how the various parameters affect the search process. In order to support the future study of such issues, we propose a formal framework for the analysis of ESWO. The framework is based on Markov chains, and the main novelty arises because ESWO moves through the space of partial assignments. This makes it significantly different from the analyses used in local search (such as simulated annealing) which only move through complete assignments. Generally, the exact details of ESWO will depend on various heuristics; so we focus our approach on a case of ESWO that we call ESWO-II and that has probabilistic as opposed to heuristic selection and construction operators. For ESWO-II, we study a simple problem instance and explicitly compute the stationary distribution probability over the states of the search space. We find interesting properties of the distribution. In particular, we find that the probabilities of states generally, but not always, increase with their fitness. This nonmonotonocity is quite different from the monotonicity expected in algorithms such as simulated annealing. PMID- 21265627 TI - Allergic contact dermatitis following ocular use of corticosteroids. AB - AIM: To study the clinical features and to identify the molecules responsible for contact-allergic reactions following ocular use of corticosteroid (CS) preparations. DESIGN: Observational case series. METHODS: We reviewed the clinical data, the patch test results, and sensitization sources in patients with a CS contact allergy, who have been patch tested in the K.U. Leuven Dermatology department during an 18-year period. RESULTS: Eighteen subjects (out of 315 with CS delayed-type hypersensitivity) presented with allergic manifestations (conjunctivitis, eczema of the face, periocular skin or eyelids) of delayed-type hypersensitivity reactions to the use of CS-containing ocular preparations. The most common allergen was hydrocortisone, but most patients presented with multiple positive tests, not only to other CSs, but also to other active principles, preservatives, and vehicle components. CONCLUSIONS: Ophthalmic CSs, despite their anti-inflammatory and antiallergic properties, may produce contact allergic reactions. PMID- 21265628 TI - Use of role model stories to overcome barriers to hospice among African Americans. AB - OBJECTIVES: To test a brochure comprising hospice patient role model stories aimed at improving attitudes and knowledge of hospice among older African Americans. DESIGN: Pre-post community-based study. SETTING: Community-based organizations including senior centers, community exercise programs, churches, and senior care management services in greater Los Angeles area. PARTICIPANTS: Seventy-one African Americans aged 65 and older. INTERVENTION: Hospice brochure containing theoretically driven role model stories portraying African Americans' experience with hospice, their initial attitudes and beliefs about hospice, factors influencing their enrollment in the program, and outcomes following enrollment. MEASUREMENTS: Change from baseline in attitudes toward, knowledge of, and intentions to enroll in hospice. RESULTS: Mean knowledge scores (range, 0-9) increased from 5.76 (standard deviation [SD] = 2.12) at pretest to 6.95 (SD = 1.90) at posttest (t = -6.14, p < 0.001). Average attitude toward hospice (range, 12-72) improved 12.5% from 41.16 (SD = 5.20) to 46.29 (SD = 5.45) (t = -7.52, p < 0.001). Intentions to enroll a family member in hospice increased from 84.5% to 92.9% (p = 0.002) and intentions to seek hospice care for themselves increased from 83.1% to 95.8% (p < 0.001). CONCLUSION: This small pre-post pilot study found that exposure to a hospice brochure containing theoretically driven, culturally parallel, role model stories was effective in improving knowledge of and attitudes toward hospice as well as intentions to enroll a family member or self in hospice care. Further study is needed to determine the impact of using this brochure within a clinical setting. PMID- 21265629 TI - Exploring the dynamics of interdisciplinary palliative care teams in providing psychosocial care: "Everybody thinks that everybody can do it and they can't". AB - BACKGROUND: There has recently been a call for an analysis of the way in which professionals see their role and status in the context of palliative care and the interdisciplinary team. This is particularly salient in the provision of psychosocial care. METHOD: This study qualitatively explored team members' perceptions and experiences of team dynamics. An in-depth qualitative research design was adopted using semistructured interviews and was guided by a social constructivist framework. Seven palliative care team members were recruited from across three palliative care sites. Two palliative care nurses, a palliative care medical specialist, a consultant psychiatrist, a social worker, a counselor, and an occupational therapist comprised our prototypical interdisciplinary team. Analysis was conducted using a method of constant comparison. RESULTS: Two major themes emerged from our research: "Lack of clear role boundaries" and "Strategies for maintenance of role boundaries," which included: "Claiming access to specialist expertise and knowledge" and "Minimizing the knowledge of other professions and professionals." It is argued that effective team functioning can be enhanced through the development of interdisciplinary team training programs and policies, resources and structures that provide support for the interdisciplinary team model. PMID- 21265630 TI - Evaluation of Spinal Cord Compression #237. PMID- 21265631 TI - Assessing pain in nonresponsive hospice patients: development and preliminary testing of the multidimensional objective pain assessment tool (MOPAT). AB - BACKGROUND: Accurate assessment in hospice patients who cannot communicate their pain is almost impossible, increasing their risk for unrecognized and inadequately managed pain. OBJECTIVE: The purpose of this article is to describe a series of small-scale projects aimed at developing and refining an instrument to assess acute pain in noncommunicative hospice patients. METHODS: Project 1 was a clinical project in which focus groups with hospice nurses yielded an adaptation of an existing pain assessment measure that was named the Multidimensional Objective Pain Assessment Tool (MOPAT) and had behavioral and physiological subscales. Projects 2 and 3 tested the MOPAT in 30 cognitively impaired/nonresponsive hospice inpatients and 28 alert and oriented hospice inpatients, with study nurses and hospice nurses rating pain with the MOPAT before and after a pain-relieving intervention and rating its clinical usefulness. Projects 3 and 4 analyzed the reliability, validity, and clinical utility of the MOPAT. RESULTS: Overall internal consistency reliability of the MOPAT was demonstrated with Cronbach's alpha coefficients of 0.79 before and 0.84 after the pain-relieving intervention. The behavioral and physiological subscale scores changed significantly (p < .035) after pain medication, demonstrating sensitivity to changes in pain. Principal components factor analysis revealed two factors matching the subscales and accounting for 66% of the variance. Nearly all the hospice nurses found the MOPAT helpful, easy to use and understand, and conducive to use in daily practice. CONCLUSION: The MOPAT has preliminary evidence of reliability, validity, and clinical utility. Full-scale psychometric testing in hospice and acute care hospital patients is currently underway. PMID- 21265632 TI - Protective effects of CAPE on liver injury induced by CCL4: an electron microscopy study. AB - This study was designed to investigate the protective effects of caffeic acid phenethyl ester on carbon tetrachloride-induced liver damage in rats. Twenty-four male Wistar rats were divided in three groups. Group I was used as control. Rats in group II were injected with carbon tetrachloride every other day for 1 month, whereas rats in group III were injected with carbon tetrachloride and caffeic acid phenethyl ester every other day for 1 month. At the end of the experiment, all animals were killed by decapitation and their livers were removed. Liver tissues were processed for electron microscopy. Histopathologically, hepatocytes of rats treated with carbon tetrachloride had damage in the cytoplasmic organelles and nuclei membranes as well as an excessive lipid accumulation in the hepatocytes. However, those histopathological changes were reduced with the coadministration of carbon tetrachloride and caffeic acid phenethyl ester. We conclude that caffeic acid phenethyl ester treatment has the capability to prevent carbon tetrachloride-induced liver damage in rats. PMID- 21265633 TI - Molecular and ultrastructural analysis of a multiphasic oral malignant melanoma. AB - Melanomas of the oral cavity are extremely rare. Their rarity and their independence on exposure to UV radiation make them particularly interesting. The authors analyzed an oral multiphasic melanoma composed by a nodular nonpigmented ulcerated central region, a nodular ulcerated pigmented area, a pigmented nonulcerated region, and an area similar to a dysplastic nevus. They determined the expression of some genes involved in the differentiation and cellular transformation in morphologically different regions of melanoma. All these areas were also analyzed by electron microscopy. The various regions composing the melanoma expressed genes involved in melanogenesis and melanoma progression in a different manner. Electron microscopy observation of ultrathin sections of each region evidenced ultrastructural differences, being the cellular architecture more compromised in the most aggressive parts of the neoplasm. This pilot study identified morphological, molecular, and ultrastructural differences that characterize each region of the multiphasic melanoma. PMID- 21265634 TI - Membranoproliferative glomerulonephritis with isolated C3 deposits: case report and literature review. AB - Membranoproliferative glomerulonephritis with isolated C3 deposits (MPGNC3) is an uncommon condition characterized by overt glomerular C3 deposits in the absence of immunoglobulins and intramembranous dense deposits. Here the authors describe the clinical and morphological features of primary MPGNC3 in a 13-year-old boy and critically review the previously published cases. The patient presented with nephrotic syndrome and microscopic hematuria. Blood tests revealed very low circulating C3 levels. The renal biopsy exhibited subendothelial, subepithelial, and mesangial deposits, with C3 but not immunoglobulins seen on immunofluorescence. This case and the review of the literature indicate that the serum complement profile with decreased levels of C3 and normal levels of classical pathway components together with glomerular deposits containing exclusively complement C3 is highly suggestive of alternative pathway activation. The diagnosis of acquired and/or genetic complement abnormalities in some cases supports that complement dysregulation is implicated in the pathogenesis of MPGNC3. Such data show great promise to provide new therapy strategies based on modulation of the complement system activity. PMID- 21265635 TI - The usefulness of phlebotomy in the palliative care setting. AB - OBJECTIVES: To establish the reasons for phlebotomy and evaluate the usefulness of blood testing in the palliative setting. METHODS: The design was that of a questionnaire-based prospective study conducted in the 30-bed Specialist Palliative Care Unit at Milford Care Centre between March 23 and May 23, 2010. A questionnaire was completed by the performing clinician following each venipuncture, which included details of the admitted patient, the blood tests performed, the reason(s) for testing, and the usefulness of blood testing in diagnosing and influencing management. RESULTS: Fifty blood tests were conducted on 37 inpatients. The mean age of patients was 66.7 years and 54.1% were male. The top three diagnoses were malignancy of bowel, ovary, and prostate, respectively. The top three reasons for venipuncture were to manage medications, establish the need for blood transfusion, and guide management of sepsis. Thirty percent of phlebotomy sessions changed management, 40.7% ruled in an important diagnosis, and 86% ruled out an important diagnosis. Forty-eight percent of phlebotomy sessions had at least one type of test "added on" that in hindsight was unnecessary. CONCLUSIONS: Blood testing is a useful tool in the palliative setting to guide management and to ascertain diagnoses relevant to symptom control. For reasons of laboratory time and economic cost, unnecessary additional tests should be kept to a minimum. PMID- 21265636 TI - The association of adverse pregnancy events and cardiovascular disease in women 50 years of age and older. AB - OBJECTIVE: This study investigates the association between a prior history of pregnancy complications and cardiovascular disease (CVD) among Kentucky women aged >=50 years. METHODS: Data were analyzed from participants (n = 3909) in the Kentucky Women's Health Registry (2006-2008). Primary outcomes were self-reported prevalence of CVD, including angina, heart attack, heart failure, and arrhythmia. Pregnancy complications used as predictors were preterm labor, preeclampsia, gestational diabetes mellitus (GDM), and third trimester bleeding. Logistic regression analyses were conducted to determine associations between prevalence of CVD and pregnancy complications, controlling for age, education, and smoking status. RESULTS: Overall, 199 (5.1%) women reported angina, 79 (2.0%) reported heart attack, 44 (1.1%) reported heart failure, and 642 (16.4%) reported arrhythmia. One pregnancy complication was reported by 614 (15.7%) women, and two or more complications were reported by 130 (3.3%) women. In regression models adjusting for age, education, and smoking, compared to women who were never pregnant, women with no pregnancy complications had a similar risk of reporting heart attack (odds ratio [OR] 1.2, 95% confidence interval [CI] 0.5-2.7), but women with one pregnancy complication (OR 2.5, 95% CI 1.03-6.0) and two or more complications (OR 4.2, 95% CI 1.4-10.6) had an increased risk. Similar results were seen for angina and arrhythmia, but not heart failure. CONCLUSIONS: Women who experience pregnancy complications are more likely to report prevalent CVD (including angina, heart attack, and arrhythmia), suggesting a link between adverse pregnancy events and CVD. Pregnancy complications may serve as signals for future CVD, presenting an opportunity for early intervention and prevention. PMID- 21265637 TI - Cortical maturation and behavioral outcomes in children with auditory neuropathy spectrum disorder. AB - OBJECTIVE. Auditory neuropathy spectrum disorder (ANSD) affects approximately 10% of patients with sensorineural hearing loss. While many studies report abnormalities at the level of the cochlea, auditory nerve, and brainstem in children with ANSD, much less is known about their cortical development. We examined central auditory maturation in 21 children with ANSD. DESIGN. Morphology, latency and amplitude of the P1 cortical auditory evoked potential (CAEP) were used to assess auditory cortical maturation. Children's scores on a measure of auditory skill development (IT-MAIS) were correlated with CAEPs. Study Sample. Participants were 21 children with ANSD. All were hearing aid users. RESULT: Children with ANSD exhibited differences in central auditory maturation. Overall, two-thirds of children revealed present P1 CAEP responses. Of these, just over one third (38%) showed normal P1 response morphology, latency and amplitude, while another third (33%) showed delayed P1 response latencies and significantly smaller amplitudes. The remaining children (29%) revealed abnormal or absent P1 responses. Overall, P1 responses were significantly correlated with auditory skill development. CONCLUSION: Our results suggest that P1 CAEP responses may be: (i) A useful indicator of the extent to which neural dys synchrony disrupts cortical development, (ii) A good predictor of behavioral outcome in children with ANSD. PMID- 21265638 TI - Aminoglycoside antibiotics cochleotoxicity in paediatric cystic fibrosis (CF) patients: A study using extended high-frequency audiometry and distortion product otoacoustic emissions. AB - Despite known ototoxic effects of aminoglycoside (AG) antibiotics, audiological assessment is not routinely undertaken in UK CF patients. Consequently, the incidence of hearing loss is not well established. OBJECTIVE: To document the incidence of hearing loss in cystic fibrosis (CF) children. DESIGN: Hearing function of 45 children from Great Ormond Street Hospital was assessed using pure tone audiometry up to 20kHz and DPOAEs up to 8kHz. STUDY SAMPLE: 39/45 of participants had received intravenous (IV) AGs, 23 of which received repeated IV AGs every 3 months. RESULTS: In this high exposure group, 8 (21%) had clear signs of ototoxicity; average 8-20kHz thresholds were elevated by ~50dB and DPOAE amplitudes were >10dB lower at f2 3.2-6.3 kHz. The remaining 31/39 (79%) of AG exposed patients had normal, even exceptionally good hearing. The 21% incidence of ototoxicity we observed is substantial and higher than previously reported. However, our finding of normal hearing in children with equal AG exposure strongly suggests that other unknown factors, possibly genetic susceptibility, influence this outcome. CONCLUSIONS: We recommend comparable auditory testing in all CF patients with high AG exposures. Genetic analysis may help explain the dichotomy in response to AGs found. PMID- 21265640 TI - Quality of life, psychosocial consequences, and audiological rehabilitation after sudden sensorineural hearing loss. AB - OBJECTIVE: Sudden sensorineural hearing loss (SSHL) is characterized by a rapid loss of hearing, most often of cochlear origin. Very little attention has been paid in the literature to quality of life (QoL), psychosocial consequences and audiological rehabilitation after SSHL. DESIGN: We studied how level of hearing loss, hearing recovery, tinnitus and vertigo affect QoL after SSHL and the psychosocial consequences of SSHL in terms of sick leave. Furthermore, the audiological rehabilitation given to patients in connection with SSHL and the benefit of the rehabilitation were studied. STUDY SAMPLE: Three hundred and sixty nine (369) patients with SSHL were analysed in the present study. RESULTS: Annoying tinnitus and remaining vertigo after SSHL were the strongest predictors of negative effects on QoL. CONCLUSIONS: The study indicates that patients with SSHL require extended audiological rehabilitation including a multi-disciplinary rehabilitation approach (medical, social and psychological) to cope with the complex issues that can arise after SSHL. PMID- 21265641 TI - Interpersonal violence and women's psychological well-being. AB - BACKGROUND: The health impact of violence against women by perpetrators other than intimate partners has received little attention. This study aims to analyze the effect of different forms of interpersonal violence on women's health. METHODS: Adult women (10,815) randomly sampled from primary healthcare services around Spain were included. Women were grouped as follows: (1) no history of violence, (2) history of intimate partner violence only (IPV), (3) history of non IPV only, and (4) history of both IPV and non-IPV. Lifetime prevalence of violence by IPV, non-IPV, and both was calculated. Adjusted multivariable regression analysis was performed to assess the effects of the different forms of violence on women's health status. RESULTS: Of the women, 32.7% experienced lifetime violence. Poor self-perceived health, psychological distress, co occurring somatic complaints, and use of antidepressant or tranquilizer medication were significantly higher for women with a history of violence than for women with no history of violence. Women who reported both types of violence, IPV and non-IPV, were almost five times more likely to suffer psychological distress and co-occurring somatic complaints and > six times more likely to use medication than women with no history of violence. CONCLUSIONS: The high prevalence of violence and its consistent association with a wide range of women's health problems suggest that violence seriously compromises women's health. Health providers should ask their female patients specifically about their history of violence, both IPV and non-IPV. Including this in patient's assessment would lead to more informed clinical decisions and more integrated care. PMID- 21265642 TI - Some modifications of the Furlow palatoplasty in wide clefts--a preliminary report. AB - OBJECTIVES: Authors encounter a large percentage of wide cleft palates while operating in a Third World situation. They define the terms wide clefts and unrepairable clefts in terms of measurement. They describe their technique, which they developed to deal with wide clefts. They describe some previously unreported modifications. They also report the velar lengthening obtained. METHODS: A total of 77 cases of primary cleft palate repaired with this technique by a single author, during the period May 2006 to February 2009, were selected for the study. These were divided into two groups on the basis of measurements. Group B consisted of all clefts deemed wide or unrepairable. Group A consisted of all other cleft palates. Difference in fistula rate was studied. Velar lengthening was measured in all patients. OBSERVATIONS: Two fistulae occurred in Group B. The overall fistula rate for the series was 2.6%. The series consisted of 44% wide clefts, which included one case of unrepairable cleft. Lengthening in the velum ranged from 20% to 155%. Statistically significant correlations were found between narrow clefts and age group 0 to 1 year (p = .0094) and Veau Group 4 with wide clefts (p = .0194). CONCLUSIONS: The Furlow technique as originally described has shortcomings. The authors describe their technique of incorporating the Furlow repair, which enables them to use it as a primary palatoplasty, in a scenario consisting of a large percentage of wide clefts in an older age group, thereby minimizing the fistula rate while increasing palatal length. PMID- 21265645 TI - Barriers to and facilitators of postpartum follow-up care in women with recent gestational diabetes mellitus: a qualitative study. AB - OBJECTIVES: Women with a history of gestational diabetes mellitus (GDM) have an increased risk of developing type 2 diabetes (T2DM) but often do not return for follow-up care. We explored barriers to and facilitators of postpartum follow-up care in women with recent GDM. METHODS: We conducted 22 semistructured interviews, 13 in person and 9 by telephone, that were audiotaped and transcribed. Two investigators independently coded transcripts. We identified categories of themes and subthemes. Atlas.ti qualitative software (Berlin, Germany) was used to assist data analysis and management. RESULTS: Mean age was 31.5 years (standard deviation) [SD] 4.5), 63% were nonwhite, mean body mass index (BMI) was 25.9 kg/m(2) (SD 6.2), and 82% attended a postpartum visit. We identified four general themes that illustrated barriers and six that illustrated facilitators to postpartum follow-up care. Feelings of emotional stress due to adjusting to a new baby and the fear of receiving a diabetes diagnosis at the visit were identified as key barriers; child care availability and desire for a checkup were among the key facilitators to care. CONCLUSIONS: Women with recent GDM report multiple barriers and facilitators of postpartum follow-up care. Our results will inform the development of interventions to improve care for these women to reduce subsequent diabetes risk. PMID- 21265646 TI - The diagnosis of ovarian cancer: is color Doppler imaging reproducible and accurate in examiners with different degrees of experience? AB - OBJECTIVE: To evaluate the reproducibility and accuracy of color Doppler flow location in indeterminate masses after a gray-scale sonography in the diagnosis of ovarian malignancy. METHODS: Digitally stored color Doppler sonographic images from a random sample of 130 women with an indeterminate adnexal mass submitted to surgery were evaluated by six different examiners with different degrees of experience. A mass was graded malignant if flow was shown within the excrescences or solid areas. Intraobserver agreement and interobserver agreement according to the level of experience were assessed by calculating the kappa index. RESULTS: Intraobserver agreement was good for all examiners with different degrees of experience (kappa 0.72-0.89). Interobserver agreement was good to moderate for all operators (kappa 0.48-0.71) irrespective of degree of experience. The accuracy was comparable among different operators. CONCLUSIONS: Our results indicate that color Doppler imaging for detection of adnexal malignancy seems to be a reproducible method even in moderately experienced examiners. PMID- 21265647 TI - Global engagement of women physicians: a report on the 28th Congress of the Medical Women's International Association. PMID- 21265648 TI - Time, perception and the aging mind: the National Alzheimer's Project Act 2011 enacted--is this the beginning of a new era in health care research? PMID- 21265649 TI - A preliminary assessment of the fifth-year chiropractic students' knowledge of anatomy. AB - INTRODUCTION: Anatomy has been at the foundation of medical students' training. In recent decades, medical programs in many countries have undergone major reform in both pedagogy and content. These reforms generated intense debates, focusing mainly on the way the new programs affected medical graduates' knowledge of anatomy and their clinical capabilities. Anatomy, however, is not only core to medicine, but also to a number of allied and complementary health disciplines. While the evaluation of anatomy teaching and learning in the medical programs has been heavily scrutinized, anatomy education in the complementary and alternative medicine (CAM) professions, including those, such as chiropractic, in which anatomy has traditionally been one of the main preclinical subjects, has been less frequently evaluated. OBJECTIVES: The study aimed to make a preliminary assessment of the final year chiropractic students' knowledge of anatomy using the "carpal bone test." SUBJECTS AND METHODS: The testing was conducted on the final-year chiropractic students at Macquarie University in 2009. In this test, the students were given 5 minutes to label an illustration of the bony skeleton of the carpal region. The results of this assessment were then compared to results of previously published surveys using the "carpal bone test." RESULTS: A total of 84 students participated in the study. Thirty-eight percent (38%) of students identified all eight bones, while 60% of students identified five or more carpal bones. The most frequent correctly identified bone was the pisiform, followed by the scaphoid bone (82% and 74% of students, respectively). The trapezium and trapezoid bones were least frequently identified: both by 52% of students each. These results were generally better than those of the previously tested final-year medical students. DISCUSSION AND CONCLUSIONS: The importance of anatomy in chiropractors' education has been generally acknowledged. This study suggests that the comparatively high number of hours devoted to anatomy in Macquarie University chiropractic curriculum and underpinning of clinical skills to anatomy knowledge in the senior year have increased retention of anatomy knowledge. The study, preliminary in nature, has also recognized the need for more detailed assessment of teaching and learning of the basic medical sciences in chiropractic and other CAM disciplines. PMID- 21265650 TI - Mindfulness-based interventions for chronic pain: a systematic review of the evidence. AB - OBJECTIVES: Chronic pain is a common disabling illness that does not completely respond to current medical treatments. As a consequence, in recent years many alternative interventions have been suggested. Among them, mindfulness-based interventions (MBIs) are receiving growing attention. The aim of the present article is to review controlled studies investigating the efficacy of MBIs for the reduction of pain and the improvement of depressive symptoms in patients suffering from chronic pain. METHODS: A literature search was undertaken using MEDLINE,((r)) ISI web of knowledge, the Cochrane database, and references of retrieved articles. The search included articles written in English published up to July 2009. The data were independently extracted by two reviewers from the original reports. Quality of included trials was also assessed. RESULTS: Ten (10) studies were considered eligible for the present review. Current studies showed that MBIs could have nonspecific effects for the reduction of pain symptoms and the improvement of depressive symptoms in patients with chronic pain, while there is only limited evidence suggesting specific effects of such interventions. Further findings evidenced some improvements in psychologic measures related to chronic pain such as copying with pain following MBIs as well. DISCUSSION: There is not yet sufficient evidence to determine the magnitude of the effects of MBIs for patients with chronic pain. Main limitations of reviewed studies include small sample size, absence of randomization, the use of a waiting list control group that does not allow distinguishing of specific from nonspecific effects of MBI as well as differences among interventions. CONCLUSIONS: However, because of these preliminary results, further research in larger properly powered and better designed studies is warranted. PMID- 21265661 TI - Sodium supplementation in neonates with pierre robin sequence significantly improves weight gain if urinary sodium is low. AB - OBJECTIVE: To investigate whether sodium supplementation increases weight gain in babies with grade 3 Pierre Robin sequence if their urinary sodium is low. DESIGN: Retrospective review of all medical, dietitian, and nursing notes of babies admitted from 2000 to 2007, inclusive. SETTING: Tertiary center for cleft care. PATIENTS: A total of 33 babies requiring nasogastric and nasopharangeal intubation for Pierre Robin sequence were identified. Those for whom weights could not be measured accurately (n = 4) were excluded from further study. INTERVENTIONS: Urinary sodium was low and weight gain poor in 21 of the remaining 29 babies (72%), and oral sodium supplementation was given to establish and maintain a normal urinary sodium (10 to 20 mmol/L). MAIN OUTCOME MEASURE: Mean daily weight gain. RESULTS: The mean daily weight gain of the 18 babies with low urinary sodium admitted in the first few days of life improved from 20 to 34 g (p < .001) following oral sodium supplementation. This gave a mean difference of 14 g (lower quartile = 6 g, upper quartile = 25 g, 95% confidence interval = 20, 90% confidence interval = 10). The mean daily weight gain of the eight patients who did not require sodium supplementation was 33.6 g. CONCLUSIONS: Urinary sodium tests are simple and noninvasive and allow monitoring of urinary sodium. If low, adequate supplementation improved weight gain (p < .001), reversing failure to thrive in babies with severe Pierre Robin sequence. These findings have been unreported previously. PMID- 21265662 TI - A comparative study on the measurements of palatal shelf area and gradient for adult patients with unoperated cleft palate. AB - OBJECTIVE: To determine the maxillary growth potential of cleft palate patients compared with the normal population. METHODS: By using a three-dimensional computed tomography scanning and imaging system, the gradient and surface area of the palatal shelves were measured and analyzed statistically among 30 adults with normal occlusion, 30 adult patients with operated unilateral complete cleft lip and palate, and 30 adults with unoperated unilateral complete cleft lip and palate. RESULTS: In comparison with the control group, for the unoperated unilateral complete cleft lip and palate subjects, the gradient of the palatal shelves at both the cleft and noncleft sides was larger, meaning that the palatal shelves were rotated cranially and were more vertically positioned. The palatal surface area was significantly smaller in the unoperated and operated unilateral complete cleft lip and palate groups than in the noncleft control group; although, there was no significant difference between the unoperated and operated unilateral complete cleft lip and palate groups. CONCLUSIONS: There is an intrinsic tissue deficiency in the palate/maxilla of unilateral complete cleft lip and palate patients. PMID- 21265701 TI - Predictors of poor outcome at hospital discharge following a spontaneous intracerebral hemorrhage. AB - INTRODUCTION: Spontaneous intracranial hemorrhage (S-ICH) often leads to significant morbidity and mortality. Clinical scoring systems can predict the mortality and functional outcome after ICH (FUNC score). FOUR score is a recently developed coma scale that incorporates brainstem reflexes. We propose that the combination of FUNC and FOUR scores will be a better prognostic indicator than either FUNC or FOUR score alone for S-ICH patients. METHODS: We conducted a retrospective chart review of all S-ICH patients (>18 years of age) from January 2008 to May 2010. ICH volume was calculated using the ABC/2 formula. FUNC (<= 5 or >5) and FOUR (<= 10 and >10) scores were calculated from admission data. Statistical analyses included chi-square test, positive predictive value, and relative risk assessment. RESULTS: Total number of patients was 92. The mean age of presentation was 64.6 +/- 15.6 years (range: 27-95 years). Male to female ratio was 1.6:1. Combined FUNC score <= 5 and FOUR score <= 10 (F2 score; 95%) had higher positive predictive value for mortality than either FUNC score <= 5 (82%) or FOUR score <= 10 (81%). CONCLUSIONS: The combination of the FUNC and the FOUR scoring system is a better prognostication indicator for S-ICH patients than either FUNC or FOUR score. PMID- 21265705 TI - Bee venom reduces neuroinflammation in the MPTP-induced model of Parkinson's disease. AB - AIM: This study was designed to investigate the anti-inflammatory effects of bee venom (BV) in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson's disease (PD). METHOD: MPTP was administered by intraperitoneal (IP) injection at 2-hr intervals over an 8-hr period. Mice were then subjected to BV subcutaneous injection and sacrificed on days 1 and 3 following the final MPTP injection. The loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) was assessed by tyrosine hydroxylase (TH) immunohistochemistry. Microglial activation was measured by immunohistochemistry for macrophage antigen complex-1 (MAC-1) and inducible nitric oxide synthase (iNOS). The staining intensities of MAC-1 and iNOS were quantified with respect to optical density. RESULT: In animals treated with MPTP, the survival percentages of TH+ cells in the SNpc were 32% on day 1 and 46% on day 3 compared with normal mice. In BV-treated mice, the survival percentages of TH+ cells improved to 70% on day 1 and 78% on day 3 compared with normal mice. BV treatment also resulted in reduced expression of the inflammation markers MAC-1 and iNOS in the SNpc. CONCLUSION: These data suggest that BV injection may have a neuroprotective effect that attenuates the activation of the microglial response, which has implications for the treatment of PD. PMID- 21265706 TI - Guinea pig sensitization assays: an experimental comparison of three methods. AB - PURPOSE: Guinea pig sensitization assays provide a critical tool in toxicological testing. Here, we investigate the relative sensitivities of the Guinea Pig Maximization Test (GPMT), the Open Epicutaneous Test (OET), and the Buehler test on seven common compounds. METHODS: Seven compounds (formalin, nickel sulfate, 2 benzothiazolethiol, neomycin sulfate, potassium dichromate, ethylenediamine, dihydrochloride, and cinnamyl alcohol) were investigated on 15 guinea pigs per assay. Differences between each assay were investigated individually for each compound in question, and cumulative comparisons were also performed. RESULTS: Cumulatively, differences in rates of sensitization between the GPMT and OET did not reach statistical significance; however, both tests produced higher sensitization rates than the Buehler test (1% significance level). Comparisons for individual compounds are outlined within the main text. CONCLUSIONS: Our results indicate a possible role for the OET in the testing of weakly allergenic compounds. Similarly, the Buehler test may hold greatest utility in the examination of strongly allergenic compounds, where high sensitivity is not necessary and limited exposure to subjects is desired. These findings may help guide experimental protocols and considerations. PMID- 21265707 TI - A case of irritant contact dermatitis with leech. AB - Medicinal leeches are invertebrated parasites that have been used for medical purposes for centuries as one of the traditional treatment methods. Medicinal leeches are used for wound and flap healing in the plastic and reconstructive surgery, in the treatment of venous insufficiency, varicosities, hemorrhoids, and in many other diseases. However, due to medicinal leech therapy (hirudotherapy) complications such as anaphylaxis, local allergic reactions, anemia, and mucosal synechiae can occur. In this article, we report a case of an irritant contact dermatitis in a patient who experienced severe redness and itching after applying leeches for the relief of head and neck pain. Leeches are being used widely in some regions in the world and if people are informed about the leeches, it may be helpful in preventing complications that may occur. PMID- 21265708 TI - Physicochemical and mechanical properties of carbamazepine cocrystals with saccharin. AB - The aim of present research was to investigate the physicochemical, mechanical properties, and stability characteristics of cocrystal of carbamazepine (CBZ) using saccharin (SAC) as a coformer. The cocrystals were prepared by solubility method and characterized by pH-solubility profile, intrinsic dissolution by static disk method, and surface morphology by scanning electron microscopy (SEM), crystallinity by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD), and mechanical properties by Heckel analysis. Stability of the cocrystals were assessed by storing them at 60 ( degrees )C for two weeks, 25 ( degrees )C/60%RH, 40 ( degrees )C/75%RH and 40 ( degrees )C/94%RH for one month and compared with the stability of CBZ. The solubility profile of cocrystal was similar to CBZ. The cocrystal and CBZ have shown the same stability profile at all the conditions of studies except at 40 ( degrees )C/94%RH. Unlike the CBZ, cocrystal was stable against dihydrate transformation. The compacts of cocrystal have a greater tensile strength and more compressibility. The Heckel analysis suggested that plastic deformation started at low compression pressure in the cocrystal than CBZ. In summary, the cocrystal form of carbamazepine provides another avenue for product development which is more stable than the parent drug. PMID- 21265709 TI - Role of cyclodextrin complexation in felodipine-sustained release matrix tablets intended for oral transmucosal delivery: in vitro and ex vivo characterization. AB - The objective of the present research was two-fold: To characterize the produced inclusion complex of felodipine (FDP)-hydroxypropyl-beta-cyclodextrin (HPbetaCD) utilizing lyophilization, and to develop and characterize a complexed sustained release polymeric matrix tablets intended for buccal delivery. The phase solubility diagram suggested an A(L) type system with 1:1 stoichiometry. Solid complexes prepared by physical mixing and lyophilization were characterized by thermal and non-thermal analytical techniques to corroborate the fact of complex formation. The sustained-release FDP tablets were produced by direct compression, and these drug or complex-loaded hydrophilic matrices were assessed for in vitro bioadhesion and release modulation, ex vivo permeation, and in vivo residence time. The in vitro drug release and ex vivo permeation across the porcine buccal membrane demonstrated that the matrix tablets containing FDP-HPbetaCD (FH5) solid complex exhibited a complete and sustained drug release pattern, and a significantly higher drug permeation (p < 0.05) compared to all of the other formulations tested. This could be attributed to both, the FDP-HPbetaCD complexation phenomenon, and the presence of hydrophilic polymer in the formulation. All of the formulations tested, demonstrated good stability in human saliva. Additionally, in vivo mucoadhesive behavior of the optimized formulations was studied in healthy human volunteers and subjective parameters were evaluated. PMID- 21265710 TI - Self-assembled polyion complex micelles for sustained release of hydrophilic drug. AB - Graft copolymer polyethylenimine-graft-poly(N-vinylpyrrolidone) (PEI-g-PVP) was prepared by coupling mono carboxyl-terminated PVP (PVP-COOH) with PEI using N,N' dicyclohexylcarbodiimide (DCC) and N-hydroxysuccinimide (NHS) as coupling agents. In aqueous medium, PVP-g-PEI can self-assemble into stable polyion complex micelles with an oppositely charged block copolymer, poly(N-vinylpyrrolidone) block-poly(2-acrylamido-2-methyl-1-propanesulphonic acid) (PVP-b-PAMPS). Transmission electron microscopy images showed that these micelles were regularly spherical in shape. The micelle size determined by size analysis was around 142 nm. To estimate their feasibility as vehicles for drugs, the model drug folic acid (FA) was incorporated into the cores of the micelles via electrostatic interactions. In vitro release test of FA showed that the drug-release rates are dependent on the pH value of the release media. Based on these results, we can conclude that the polyion complex micelles prepared from the PEI-g-PVP/PVP-b PAMPS copolymers have great potential as drug delivery nanocarriers. PMID- 21265711 TI - Silk coating on poly(epsilon-caprolactone) microspheres for the delayed release of vancomycin. AB - The treatment of osteomyelitis remains a challenge for orthopaedic surgeons. Controlled release of vancomycin from biodegradable microspheres is a promising method for eliminating infection. However, the large initial burst release may make it difficult to maintain the local vancomycin concentration superior to minimum inhibitory concentration for several weeks. The aims of this study were to explore applications of the silk fibroin (SF) as an aqueous coating material for vancomycin-loaded poly(epsilon-caprolactone) (PCL) microspheres, and investigate the effects of silk coating on in vitro drug release. Examinations of particle size analyses, vancomycin content, Fourier transform infrared spectroscopy, differential scanning calorimetry, scanning electron microscopy and in vitro drug release were performed. The results showed that silk coating could reduce the large initial burst release and retard the vancomycin release. Therefore, we suggest that the SF could be used as an aqueous coating material for vancomycin-loaded PCL microspheres and prolonged the drug release. SF coating on vancomycin-loaded PCL microspheres may be considered as an effective approach to prolong the drug release and improve the anti-infection effects. PMID- 21265712 TI - Spray dried microparticles for controlled delivery of mupirocin calcium: process tailored modulation of drug release. AB - Spray dried microparticles containing mupirocin calcium were designed as acrylic matrix carriers with modulated drug release for efficient local drug delivery at minimum daily dose. Particle generation in spray drying and its effect on release performance were assessed by varying drug : polymer ratios with consequently altered initial saturations. Narrow-sized microparticles with mean diameters of 1.7-2.5 um were obtained. Properties of the generated solid dispersions were examined by X-ray, thermal (thermogravimetric analysis, modulated differential scanning calorimetry) and spectroscopic (Fourier transformed infrared, Fourier transformed Raman) methods and correlated with drug loading and in vitro release. The best control over mupirocin release was achieved for 2 : 1 (w/w) drug : polymer ratio and found to be strongly process-dependent. For a particular ratio, increased feed concentration (>4%) boosted while increased inlet temperature (>= 100 degrees C) reduced drug release. Antimicrobial activity testing confirmed that encapsulated drug preserved its antibacterial effectiveness. Conclusively, spray drying was proven as a suitable method for preparing structured microparticles which can control drug release even at exceptionally high drug loadings. PMID- 21265713 TI - Biodistribution of ascorbyl palmitate loaded doxorubicin pegylated liposomes in solid tumor bearing mice. AB - The aim of this study is to develop ascorbyl palmitate (ASP) loaded doxorubicin (DOX) pegylated liposomes and to evaluate their targeting potential to tumor. We have prepared conventional (DL), pegylated DOX liposomes with (SDL) and without ascorbyl palmitate (SDL-A). The vesicle size in all the formulations was within the range 105-120 nm and in vitro release studies in serum confirmed the stability of the liposomes. Biodistribution studies carried out in Ehrlich ascites tumor bearing mice indicate higher area under the curve for SDL and SDL-A liposomes compared to DL and plain drug solution. Drug targeting index assessed from tumor-to-serum concentration ratio and therapeutic availability of DOX in tumor tissue was also significantly higher for pegylated liposomes. In conclusion, biodistribution study reveals that the presence of ascorbyl palmitate alters the distribution pattern of liposomes and paves way for better drug targeting. PMID- 21265716 TI - Is acetylcholine a signaling molecule for human colon cancer progression? AB - OBJECTIVE: Non-neuronal acetylcholine (ACh) has been suggested to be a mediator for the development of various types of cancer. We analyzed a possible role for this molecule in carcinogenesis and/or progression of human colon cancer, in patient biopsies harvested from the colon during surgery. We addressed whether ACh synthesis (by choline acetyltransferase) and/or degradation (by ACh esterase), as well as the expression of the alpha7-subtype of the nicotinic ACh receptors, and the peptide ligand at the alpha7 receptors, secreted mammalian Ly6/urokinase-type plasminogen activator receptor-related protein-1, respectively, are deranged in tumor tissue as compared with macroscopically tumor free colon tissue. METHODS: A total of 38 patients were grouped for analysis based on their respective Dukes stage (either Dukes A + B or C + D). A mucosal tissue sample was harvested from macroscopically tumor-free colon tissue (i.e. control tissue), as well as from the tumor, and protein lysates were prepared for quantitative Western blotting. Full-thickness specimens were taken for immunohistochemistry. RESULTS: For all the above named markers, there was a significant difference between control and tumor tissue with regard to protein levels, and there was, in addition, a significant difference in protein levels between the Dukes A + B and C + D groups. CONCLUSION: The current findings may suggest a role for ACh in colon carcinogenesis/cancer progression; the data obtained could have prognostic and/or therapeutic significance for this disease. PMID- 21265719 TI - Assessment of sonographer nuchal translucency measurement performance--central tendency and dispersion. AB - OBJECTIVE: To assess center and sonographer nuchal translucency (NT) measurements that were performed as part of routine prenatal screening for Down syndrome. METHODS: Sonographers were assessed for measures of central tendency and dispersion by comparing them with expected population median and dispersion parameters. NT measurements were converted to multiples of the expected NT values according to CRL (NTMoM) and transformed to their log(10) equivalent (log(10) NTMoM). Central tendency and measurement were assessed by checking whether the median of the NTMoM distribution and SD of the log(10) NTMoM distributions were, respectively, within 5% or 10% of the expected median of 1 and SD of 0.1. Assessment was performed using both the Center specific and Fetal Medicine Foundation (FMF) reference NT for Crown rump length (CRL). RESULTS: The median NT MoM was 0.95 MoM using the FMF reference and 1.01 MoM when assessed using our center specific reference median. The difference between the center and FMF derived NT MoMs was statistically significantly (p < 0.0001). NTMoM medians increased over time at a rate of 0.0099 MoM per year while log(10) NT MoM measurement dispersement was similar to the 0.1 value expected and decreased by 0.0048 per year. CONCLUSION: Centers should routinely monitor the quality of NT measurements used to estimate Down syndrome screening risk and should provide individualized feedback to sonographers of their measures of central tendency and dispersion to ensure consistent and improved performance. NT reference medians adopted from other populations should be assessed and validated against a centers own measurement distribution. PMID- 21265720 TI - Fetal ultrasound biometry for pregnant population in the County of Primorje Gorski Kotar (Croatia). AB - OBJECTIVE: To create curves of three most commonly used biometric parameters for singleton pregnancies from 22 to 41 weeks of gestation in the County of Primorje Gorski Kotar (Croatia) and to compare results with other studies. METHODS: From January 2002 to December 2009, ultrasound examination was performed on fetuses of 1248 pregnant women with uncomplicated pregnancy. Values for biparietal diameter, femur length, and fetal abdominal circumference were measured. Results were compared with studies pertaining to European and North American population. Mean, percentile scale, and Wilcoxon's matched pairs test were used. Regression analysis was applied to analyze data correlation and to determine correlation quotients. RESULTS: Total of 2178 measurements for fetal biometry charts were performed. Established mean and centile values for fetal biometry parameters are reported numerically and graphically. Comparison of obtained values with values of identical fetal biometric parameters of other world populations has revealed statistically significant differences (p < 0.01). CONCLUSION: Normal fetal biometry charts for population of pregnant women in the northern coastal region of Croatia were constructed. Due to existence of statistically significant differences in ultrasound fetal biometry values among various populations under comparison, construction of own charts and their implementation in routine obstetrical work are justified. PMID- 21265731 TI - Application of a multidisciplinary approach to Alzheimer's disease to develop novel drug targets by integrating biomarkers, imaging, genetic and molecular strategies. PMID- 21265728 TI - Clinical significance of oligohydramnios in patients with preterm labor and intact membranes. AB - OBJECTIVE: To determine the frequency and clinical significance of oligohydramnios in patients with preterm labor and intact membranes. STUDY DESIGN: An amniotic fluid index (AFI) was determined before amniocentesis (<24 h) in 272 patients with preterm labor and intact membranes (<35 weeks of gestation). Amniotic fluid (AF) was cultured for aerobic and anaerobic bacteria and genital mycoplasmas, and assayed for matrix metalloproteinase-8 (MMP-8). Non-parametric statistical techniques and survival analysis were used. RESULTS: 1) The overall prevalence of oligohydramnios (AFI of <=5 cm) in patients with preterm labor and intact membranes was 2.6% (7/272); 2) patients with oligohydramnios had a higher frequency of AF infection and/or inflammation than those without oligohydramnios [85.7% (6/7) vs. 32.8% (87/265); P<0.01]; 3) patients with oligohydramnios had a higher median AF MMP-8 concentration than those without oligohydramnios [median 664.2 (range 16.6-3424.7) ng/mL vs. median 2.3 (range <0.3-6142.6) ng/mL; P<0.01]; 4) women with preterm labor and oligohydramnios had a shorter interval to delivery than those without oligohydramnios [median 18 h (range 0-74 h) vs. median 311 h (range 0-3228 h); P<0.01], and this difference remained significant after adjusting for gestational age and the presence or absence of AF infection/inflammation. CONCLUSION: Patients with preterm labor and oligohydramnios are at increased risk for impending preterm delivery and intra amniotic inflammation and, therefore, may benefit from careful surveillance. PMID- 21265732 TI - Molecular chaperones and protein quality control. PMID- 21265733 TI - Targeting proteasomes with natural occurring compounds in cancer treatment. AB - Aberrant cellular proliferation and compromised apoptotic pathways are hallmarks of cancer aggressiveness, and in this framework, the role of protein degradation machineries has been extensively dissected. Among proteases, the proteasome is unequivocally central in the intracellular regulation of both these processes, thus several proteasome-directed therapies have been investigated, aiming at controlling its activity and possibly restoring normal cell functions. Numerous studies reported proteasome inhibitors (both synthetic and natural occurring) to potently and selectively induce apoptosis in many types of cancer cells. In this review we discuss recent advances in proteasomal modulation by some natural occurring polyphenols, globally providing evidence of the proteasome role as therapeutic target in cancer treatment. PMID- 21265734 TI - Role of mitochondrial phosphate carrier in metabolism-secretion coupling in rat insulinoma cell line INS-1. AB - In pancreatic beta-cells, glucose-induced mitochondrial ATP production plays an important role in insulin secretion. The mitochondrial phosphate carrier PiC is a member of the SLC25 (solute carrier family 25) family and transports Pi from the cytosol into the mitochondrial matrix. Since intramitochondrial Pi is an essential substrate for mitochondrial ATP production by complex V (ATP synthase) and affects the activity of the respiratory chain, Pi transport via PiC may be a rate-limiting step for ATP production. We evaluated the role of PiC in metabolism secretion coupling in pancreatic beta-cells using INS-1 cells manipulated to reduce PiC expression by siRNA (small interfering RNA). Consequent reduction of the PiC protein level decreased glucose (10 mM)-stimulated insulin secretion, the ATP:ADP ratio in the presence of 10 mM glucose and elevation of intracellular calcium concentration in response to 10 mM glucose without affecting the mitochondrial membrane potential (Deltapsim) in INS-1 cells. In experiments using the mitochondrial fraction of INS-1 cells in the presence of 1 mM succinate, PiC down-regulation decreased ATP production at various Pi concentrations ranging from 0.001 to 10 mM, but did not affect Deltapsim at 3 mM Pi. In conclusion, the Pi supply to mitochondria via PiC plays a critical role in ATP production and metabolism-secretion coupling in INS-1 cells. PMID- 21265735 TI - Effective siRNA delivery and target mRNA degradation using an amphipathic peptide to facilitate pH-dependent endosomal escape. AB - Effective delivery of siRNA (small interfering RNA) into the cells requires the translocation of siRNA into the cytosol. One potential delivery strategy uses cell-delivery peptides that facilitate this step. In the present paper, we describe the characterization of an amphipathic peptide that mediates the uptake of non-covalently bound siRNA into cells and its subsequent release into the cytosol. Biophysical characterization of peptide and peptide/siRNA mixtures at neutral and lysosomal (acidic) pH suggested the formation of alpha-helical structure only in endosomes and lysosomes. Surprisingly, even though the peptide enhanced the uptake of siRNA into cells, no direct interaction between siRNA and peptide was observed at neutral pH by isothermal titration calorimetry. Importantly, we show that peptide-mediated siRNA uptake occurred through endocytosis and, by applying novel endosomal-escape assays and cell-fractionation techniques, we demonstrated a pH-dependent alteration in endosome and lysosome integrity and subsequent release of siRNA and other cargo into the cytosol. These results indicate a peptide-mediated siRNA delivery through a pH-dependent and conformation-specific interaction with cellular membranes and not with the cargo. PMID- 21265736 TI - Role of the interface between the FMN and FAD domains in the control of redox potential and electronic transfer of NADPH-cytochrome P450 reductase. AB - CPR (NADPH-cytochrome P450 reductase) is a multidomain protein containing two flavin-containing domains joined by a connecting domain thought to control the necessary movements of the catalytic domains during electronic cycles. We present a detailed biochemical analysis of two chimaeric CPRs composed of the association of human or yeast FMN with the alternative connecting/FAD domains. Despite the assembly of domains having a relatively large evolutionary distance between them, our data support the idea that the integrity of the catalytic cycle is conserved in our chimaeric enzymes, whereas the recognition, interactions and positioning of both catalytic domains are probably modified. The main consequences of the chimaerogenesis are a decrease in the internal electron-transfer rate between both flavins correlated with changes in the geometry of chimaeric CPRs in solution. Results of the present study highlight the role of the linker and connecting domain in the recognition at the interfaces between the catalytic domains and the impact of interdomain interactions on the redox potentials of the flavins, the internal electron-transfer efficiency and the global conformation and dynamic equilibrium of the CPRs. PMID- 21265737 TI - A lipidomic screen of palmitate-treated MIN6 beta-cells links sphingolipid metabolites with endoplasmic reticulum (ER) stress and impaired protein trafficking. AB - Saturated fatty acids promote lipotoxic ER (endoplasmic reticulum) stress in pancreatic beta-cells in association with Type 2 diabetes. To address the underlying mechanisms we employed MS in a comprehensive lipidomic screen of MIN6 beta-cells treated for 48 h with palmitate. Both the overall mass and the degree of saturation of major neutral lipids and phospholipids were only modestly increased by palmitate. The mass of GlcCer (glucosylceramide) was augmented by 70% under these conditions, without any significant alteration in the amounts of either ceramide or sphingomyelin. However, flux into ceramide (measured by [3H]serine incorporation) was augmented by chronic palmitate, and inhibition of ceramide synthesis decreased both ER stress and apoptosis. ER-to-Golgi protein trafficking was also reduced by palmitate pre-treatment, but was overcome by overexpression of GlcCer synthase. This was accompanied by increased conversion of ceramide into GlcCer, and reduced ER stress and apoptosis, but no change in phospholipid desaturation. Sphingolipid alterations due to palmitate were not secondary to ER stress since they were neither reproduced by pharmacological ER stressors nor overcome using the chemical chaperone phenylbutyric acid. In conclusion, alterations in sphingolipid, rather than phospholipid, metabolism are more likely to be implicated in the defective protein trafficking and enhanced ER stress and apoptosis of lipotoxic beta-cells. PMID- 21265738 TI - Blood levels of glutamate oxaloacetate transaminase are more strongly associated with good outcome in acute ischaemic stroke than glutamate pyruvate transaminase levels. AB - Ischaemic stroke is associated with an excessive release of glutamate in brain. GOT (glutamate-oxaloacetate transaminase) and GPT (glutamate-pyruvate transaminase) are two enzymes that are able to metabolize blood glutamate facilitating the lowering of extracellular levels of brain glutamate. Our aim was to study the association between blood levels of both enzymes and stroke outcome in patients with acute ischaemic stroke. We prospectively studied 365 patients with first ischaemic stroke<12 h. Glutamate, GOT and GPT levels were determined in blood samples obtained at admission. We considered functional outcome at 3 months [good outcome: mRS (modified Rankin Scale)<=2; poor outcome mRS >2], END (early neurological deterioration) in the first 72 h [increment >=4 points in NIHSS (National Institutes of Health Stroke Scale)] and infarct volume [CT (computed tomography) at 36-72 h] as end points. We have found an inverse correlation between GOT and GPT levels and blood glutamate levels. Patients with poor outcome showed lower levels of GOT (11.9+/-8.2 compared with 22.7+/-10.2 m units/ml, P<0.0001) and GPT (19.5+/-14.3 compared with 24.7+/-20.3 m-units/ml; P=0.004). A negative correlation has been found between GOT (Pearson coefficient= 0.477, P<0.0001) and GPT (Pearson coefficient=-0.116; P=0.027) levels and infarct volume. Patients with END showed higher levels of blood glutamate (381.7+/-97.9 compared with 237.6+/-114.0 MUmol/l, P<0.0001) and lower levels of GOT (10.8+/ 6.7 compared with 18.1+/-10.8 m-units/ml; P<0.0001). This clinical study shows an association between high blood GOT and GPT levels and good outcome in ischaemic stroke patients, this association being stronger for GOT than GPT levels. PMID- 21265739 TI - AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. AB - It is essential to life that a balance is maintained between processes that produce ATP and those that consume it. An obvious way to do this would be to have systems that monitor the levels of ATP and ADP, although because of the adenylate kinase reaction (2ADP<->ATP+AMP), AMP is actually a more sensitive indicator of energy stress than ADP. Following the discoveries that glycogen phosphorylase and phosphofructokinase were regulated by AMP and ATP, Daniel Atkinson proposed that all enzymes at branch points between biosynthesis and degradation would be regulated by adenine nucleotides. This turned out to be correct, but what Atkinson did not anticipate was that sensing of nucleotides would, in most cases, be performed not by the metabolic enzymes themselves, but by a signalling protein, AMPK (AMP-activated protein kinase). AMPK occurs in essentially all eukaryotes and consists of heterotrimeric complexes comprising catalytic alpha subunits and regulatory beta and gamma subunits, of which the latter carries the nucleotide-binding sites. Once activated by a metabolic stress, it phosphorylates numerous targets that alter enzyme activity and gene expression to initiate corrective responses. In lower eukaryotes, it is critically involved in the responses to starvation for a carbon source. Because of its ability to switch cellular metabolism from anabolic to catabolic mode, AMPK has become a key drug target to combat metabolic disorders associated with overnutrition such as Type 2 diabetes, and some existing anti-diabetic drugs (e.g. metformin) and many 'nutraceuticals' work by activating AMPK, usually via inhibition of mitochondrial ATP production. AMPK activators also potentially have anticancer effects, and there is already evidence that metformin provides protection against the initiation of cancer. Whether AMPK activators can be used to treat existing cancer is less clear, because many tumour cells appear to have been selected for mutations that inactivate the AMPK system. However, if we can identify the various mechanisms by which this occurs, we may be able to find ways of overcoming it. PMID- 21265740 TI - Homologous recombination in the archaea: the means justify the ends. AB - The process of information exchange between two homologous DNA duplexes is known as homologous recombination (HR) or double-strand break repair (DSBR), depending on the context. HR is the fundamental process underlying the genome shuffling that expands genetic diversity (for example during meiosis in eukaryotes). DSBR is an essential repair pathway in all three domains of life, and plays a major role in the rescue of stalled or collapsed replication forks, a phenomenon known as recombination-dependent replication (RDR). The process of HR in the archaea is gradually being elucidated, initially from structural and biochemical studies, but increasingly using new genetic systems. The present review focuses on our current understanding of the structures, functions and interactions of archaeal HR proteins, with an emphasis on recent advances. There are still many unknown aspects of archaeal HR, most notably the mechanism of branch migration of Holliday junctions, which is also an open question in eukarya. PMID- 21265741 TI - The archaeal PCNA proteins. AB - PCNA (proliferating-cell nuclear antigen) is a ring-shaped protein that encircles duplex DNA and plays an essential role in many DNA metabolic processes. The PCNA protein interacts with a large number of cellular factors and modulates their enzymatic activities. In the present paper, we summarize the structures, functions and interactions of the archaeal PCNA proteins. PMID- 21265742 TI - Archaeal RNA polymerase: the influence of the protruding stalk in crystal packing and preliminary biophysical analysis of the Rpo13 subunit. AB - We review recent results on the complete structure of the archaeal RNAP (RNA polymerase) enzyme of Sulfolobus shibatae. We compare the three crystal forms in which this RNAP packs (space groups P212121, P21212 and P21) and provide a preliminary biophysical characterization of the newly identified 13-subunit Rpo13. The availability of different crystal forms for this RNAP allows the analysis of the packing degeneracy and the intermolecular interactions that determine this degeneracy. We observe the pivotal role played by the protruding stalk composed of subunits Rpo4 and Rpo7 in the lattice contacts. Aided by MALLS (multi-angle laser light scattering), we have initiated the biophysical characterization of the recombinantly expressed and purified subunit Rpo13, a necessary step towards the understanding of Rpo13's role in archaeal transcription. PMID- 21265743 TI - Cation-pi interactions induce kinking of a molecular hinge in the RNA polymerase bridge-helix domain. AB - RNAPs (RNA polymerases) are complex molecular machines that contain a highly conserved catalytic site surrounded by conformationally flexible domains. High throughput mutagenesis in the archaeal model system Methanocaldococcus jannaschii has demonstrated that the nanomechanical properties of one of these domains, the bridge-helix, exert a key regulatory role on the rate of the NAC (nucleotide addition cycle). Mutations that increase the probability and/or half-life of kink formation in the BH-HC (bridge-helix C-terminal hinge) cause a substantial increase in specific activity ('superactivity'). Fully atomistic molecular dynamics simulations show that kinking of the BH-HC appears to be driven by cation-pi interactions and involve amino acid side chains that are exceptionally highly conserved in all prokaryotic and eukaryotic species. PMID- 21265744 TI - Plasmids, viruses and virus-like membrane vesicles from Thermococcales. AB - Several families of plasmids and viruses (PVs) have now been described in hyperthermophilic archaea of the order Thermococcales. One family of plasmids replicates by the rolling circle mechanism, whereas most other PVs probably replicate by the theta mode. PVs from Thermococcales encode novel families of DNA replication proteins that have only detectable homologues in other archaeal PVs. PVs from different families share a common gene pool and co-evolve with their hosts. Most Thermococcales also produce virus-like membrane vesicles similar to eukaryotic microparticles (ectosomes). Some membrane vesicles of Thermococcus nautilus harbour the plasmid pTN1, suggesting that vesicles can be involved in plasmid transfer between species. PMID- 21265745 TI - Assembling the archaeal ribosome: roles for translation-factor-related GTPases. AB - The assembly of ribosomal subunits from their individual components (rRNA and ribosomal proteins) requires the assistance of a multitude of factors in order to control and increase the efficiency of the assembly process. GTPases of the TRAFAC (translation-factor-related) class constitute a major type of ribosome assembly factor in Eukaryota and Bacteria. They are thought to aid the stepwise assembly of ribosomal subunits through a 'molecular switch' mechanism that involves conformational changes in response to GTP hydrolysis. Most conserved TRAFAC GTPases are involved in ribosome assembly or other translation-associated processes. They typically interact with ribosomal subunits, but in many cases, the exact role that these GTPases play remains unclear. Previous studies almost exclusively focused on the systems of Bacteria and Eukaryota. Archaea possess several conserved TRAFAC GTPases as well, with some GTPase families being present only in the archaeo-eukaryotic lineage. In the present paper, we review the occurrence of TRAFAC GTPases with translation-associated functions in Archaea. PMID- 21265746 TI - CRISPR-based immune systems of the Sulfolobales: complexity and diversity. AB - CRISPR (cluster of regularly interspaced palindromic repeats)/Cas and CRISPR/Cmr systems of Sulfolobus, targeting DNA and RNA respectively of invading viruses or plasmids are complex and diverse. We address their classification and functional diversity, and the wide sequence diversity of RAMP (repeat-associated mysterious protein)-motif containing proteins encoded in Cmr modules. Factors influencing maintenance of partially impaired CRISPR-based systems are discussed. The capacity for whole CRISPR transcripts to be generated despite the uptake of transcription signals within spacer sequences is considered. Targeting of protospacer regions of invading elements by Cas protein-crRNA (CRISPR RNA) complexes exhibit relatively low sequence stringency, but the integrity of protospacer-associated motifs appears to be important. Different mechanisms for circumventing or inactivating the immune systems are presented. PMID- 21265747 TI - Positive supercoiling in thermophiles and mesophiles: of the good and evil. AB - DNA supercoiling plays essential role in maintaining proper chromosome structure, as well as the equilibrium between genome dynamics and stability under specific physicochemical and physiological conditions. In mesophilic organisms, DNA is negatively supercoiled and, until recently, positive supercoiling was considered a peculiar mark of (hyper)thermophilic archaea needed to survive high temperatures. However, several lines of evidence suggest that negative and positive supercoiling might coexist in both (hyper)thermophilic and mesophilic organisms, raising the possibility that positive supercoiling might serve as a regulator of various cellular events, such as chromosome condensation, gene expression, mitosis, sister chromatid cohesion, centromere identity and telomere homoeostasis. PMID- 21265748 TI - Assembly and function of the archaeal flagellum. AB - Motility is a common behaviour in prokaryotes. Both bacteria and archaea use flagella for swimming motility, but it has been well documented that structures of the flagellum from these two domains of life are completely different, although they contribute to a similar function. Interestingly, information available to date has revealed that structurally archaeal flagella are more similar to bacterial type IV pili rather than to bacterial flagella. With the increasing genome sequence information and advancement in genetic tools for archaea, identification of the components involved in the assembly of the archaeal flagellum is possible. A subset of these components shows similarities to components from type IV pilus-assembly systems. Whereas the molecular players involved in assembly of the archaeal flagellum are being identified, the mechanics and dynamics of the assembly of the archaeal flagellum have yet to be established. Recent computational analysis in our laboratory has identified conserved highly charged loop regions within one of the core proteins of the flagellum, the membrane integral protein FlaJ, and predicted that these are involved in the interaction with the assembly ATPase FlaI. Interestingly, considerable variation was found among the loops of FlaJ from the two major subkingdoms of archaea, the Euryarchaeota and the Crenarchaeota. Understanding the assembly pathway and creating an interaction map of the molecular players in the archaeal flagellum will shed light on the details of the assembly and also the evolutionary relationship to the bacterial type IV pili-assembly systems. PMID- 21265749 TI - The role of the DNA sliding clamp in Okazaki fragment maturation in archaea and eukaryotes. AB - Efficient processing of Okazaki fragments generated during discontinuous lagging strand DNA replication is critical for the maintenance of genome integrity. In eukaryotes, a number of enzymes co-ordinate to ensure the removal of initiating primers from the 5'-end of each fragment and the generation of a covalently linked daughter strand. Studies in eukaryotic systems have revealed that the co ordination of DNA polymerase delta and FEN-1 (Flap Endonuclease 1) is sufficient to remove the majority of primers. Other pathways such as that involving Dna2 also operate under certain conditions, although, notably, Dna2 is not universally conserved between eukaryotes and archaea, unlike the other core factors. In addition to the catalytic components, the DNA sliding clamp, PCNA (proliferating cell nuclear antigen), plays a pivotal role in binding and co-ordinating these enzymes at sites of lagging-strand replication. Structural studies in eukaryotic and archaeal systems have revealed that PCNA-binding proteins can adopt different conformations when binding PCNA. This conformational malleability may be key to the co-ordination of these enzymes' activities. PMID- 21265750 TI - An additional glucose dehydrogenase from Sulfolobus solfataricus: fine-tuning of sugar degradation? AB - Within the SulfoSYS (Sulfolobus Systems Biology) project, the effect of temperature on a metabolic network is investigated at the systems level. Sulfolobus solfataricus utilizes an unusual branched ED (Entner-Doudoroff) pathway for sugar degradation that is promiscuous for glucose and galactose. In the course of metabolic pathway reconstruction, a glucose dehydrogenase isoenzyme (GDH-2, SSO3204) was identified. GDH-2 exhibits high similarity to the previously characterized GDH-1 (SSO3003, 61% amino acid identity), but possesses different enzymatic properties, particularly regarding substrate specificity and catalytic efficiency. In contrast with GDH-1, which exhibits broad substrate specificity for C5 and C6 sugars, GDH-2 is absolutely specific for glucose. The comparison of kinetic parameters suggests that GDH-2 might represent the major player in glucose catabolism via the branched ED pathway, whereas GDH-1 might have a dominant role in galactose degradation via the same pathway as well as in different sugar-degradation pathways. PMID- 21265751 TI - A thaumarchaeal provirus testifies for an ancient association of tailed viruses with archaea. AB - Archaeal viruses, or archaeoviruses, display a wide range of virion morphotypes. Whereas the majority of those morphotypes are unique to archaeal viruses, some are more widely distributed across different cellular domains. Tailed double stranded DNA archaeoviruses are remarkably similar to viruses of the same morphology (order Caudovirales) that infect many bacterial hosts. They have, so far, only been found in one phylum of the archaea, the Euryarchaeota, which has led to controversial hypotheses about their origin. In the present paper, we describe the identification and analysis of a putative provirus present in the genome of a mesophilic thaumarchaeon. We show that the provirus is related to tailed bacterial and euryarchaeal viruses and encodes a full complement of proteins that are required to build a tailed virion. The recently discovered wide distribution of tailed viruses in Euryarchaeota and the identification of a related provirus in Thaumarchaeota, an archaeal phylum which might have branched off before the separation of Crenarchaeota and Euryarchaeota, suggest that an association of these viruses with Archaea might be more ancient than previously anticipated. PMID- 21265752 TI - Translation initiation in Archaea: conserved and domain-specific features. AB - Initiation is a critical step in translation, during which the ribosome lands on the start codon and sets the correct reading frame for mRNA decoding. The rate and efficiency of translation are largely determined by initiation, which is therefore the preferred target of translation regulation mechanisms. Initiation has incurred an extensive evolutionary divergence among the primary domains of cell descent. The Archaea, albeit prokaryotes, have an initiation mechanism and apparatus more complex than those of the Bacteria; the molecular details of archaeal initiation are just beginning to be unravelled. The most notable aspects of archaeal initiation are the presence of two, perhaps three, distinct mechanisms for mRNA-ribosome interaction and the presence of a relatively large set of IFs (initiation factors), several of which are shared exclusively with the Eukarya. Among these, the protein termed a/eIF2 (archaeal/eukaryotic IF2) and aIF6 (archaeal IF6) are of special interest, since they appear to play key regulatory roles in the Eukarya. Studies of the function of these factors in Archaea have uncovered new features that will help to elucidate their conserved and domain-specific functions. PMID- 21265753 TI - Insights into chaperonin function from studies on archaeal thermosomes. AB - It is now well understood that, although proteins fold spontaneously (in a thermodynamic sense), many nevertheless require the assistance of helpers called molecular chaperones to reach their correct and active folded state in living cells. This is because the pathways of protein folding are full of traps for the unwary: the forces that drive proteins into their folded states can also drive them into insoluble aggregates, and, particularly when cells are stressed, this can lead, without prevention or correction, to cell death. The chaperonins are a family of molecular chaperones, practically ubiquitous in all living organisms, which possess a remarkable structure and mechanism of action. They act as nanoboxes in which proteins can fold, isolated from their environment and from other partners with which they might, with potentially deleterious consequences, interact. The opening and closing of these boxes is timed by the binding and hydrolysis of ATP. The chaperonins which are found in bacteria are extremely well characterized, and, although those found in archaea (also known as thermosomes) and eukaryotes have received less attention, our understanding of these proteins is constantly improving. This short review will summarize what we know about chaperonin function in the cell from studies on the archaeal chaperonins, and show how recent work is improving our understanding of this essential class of molecular chaperones. PMID- 21265754 TI - Archaeal promoter architecture and mechanism of gene activation. AB - Sulfolobus solfataricus and Sulfolobus islandicus contain several genes exhibiting D-arabinose-inducible expression and these systems are ideal for studying mechanisms of archaeal gene expression. At sequence level, only two highly conserved cis elements are present on the promoters: a regulatory element named ara box directing arabinose-inducible expression and the basal promoter element TATA, serving as the binding site for the TATA-binding protein. Strikingly, these promoters possess a modular structure that allows an essentially inactive basal promoter to be strongly activated. The invoked mechanisms include TFB (transcription factor B) recruitment by the ara-box binding factor to activate gene expression and modulation of TFB recruitment efficiency to yield differential gene expression. PMID- 21265755 TI - Structure and function of the primase domain of the replication protein from the archaeal plasmid pRN1. AB - The replication protein of the archaeal plasmid pRN1 is a multifunctional enzyme which appears to carry out several steps at the plasmid replication initiation. We recently determined the structure of the minimal primase domain of the replication protein and found out that the primase domain consists of a catalytic primase/polymerase domain and an accessory helix-bundle domain. Structure-guided mutagenesis allowed us to identify amino acids which are important for template binding, dinucleotide formation and a step before primer extension. On the basis of functional and structural data, we propose a model of the catalytic cycle of primer synthesis by the pRN1 replication protein. PMID- 21265756 TI - Potential role of cellular ESCRT proteins in the STIV life cycle. AB - We are examining the archaeal virus STIV (Sulfolobus turreted icosahedral virus) in order to elucidate the details of its replication cycle and its interactions with its cellular host, Sulfolobus solfataricus. Infection of Sulfolobus by STIV initiates an unusual cell lysis pathway. One component of this pathway is the formation of pyramid-like structures on the surface of infected cells. Multiple seven-sided pyramid-like structures are formed on infected cells late in the STIV replication cycle. These pyramid-like structures are formed at sites where the Sulfolobus S-layer has been disrupted and through which the cellular membrane protrudes. It is through the pyramid-like structures that virus-induced cell lysis occurs in the final stages of the STIV replication cycle. The pathway and process by which these unusual lysis structures are produced appears to be novel to archaeal viruses and are not related to the well-characterized lysis mechanisms utilized by bacterial viruses. We are interested in elucidating both the viral and cellular components involved with STIV lysis of its infected cell. In particular, we are examining the potential role that Sulfolobus ESCRT (endosomal sorting complex required for transport)-like proteins play during viral infection and lysis. We hypothesize that STIV takes advantage of the Sulfolobus ESCRT machinery for virus assembly, transport and cellular lysis. PMID- 21265757 TI - Bacterial and eukaryotic systems collide in the three Rs of Methanococcus. AB - Methanococcus maripaludis S2 is a methanogenic archaeon with a well-developed genetic system. Its mesophilic nature offers a simple system in which to perform complementation using bacterial and eukaryotic genes. Although information processing systems in archaea are generally more similar to those in eukaryotes than those in bacteria, the order Methanococcales has a unique complement of DNA replication proteins, with multiple MCM (minichromosome maintenance) proteins and no obvious originbinding protein. A search for homologues of recombination and repair proteins in M. maripaludis has revealed a mixture of bacterial, eukaryotic and some archaeal-specific homologues. Some repair pathways appear to be completely absent, but it is possible that archaeal-specific proteins could carry out these functions. The replication, recombination and repair systems in M. maripaludis are an interesting mixture of eukaryotic and bacterial homologues and could provide a system for uncovering novel interactions between proteins from different domains of life. PMID- 21265758 TI - Nucleoid-associated proteins in Crenarchaea. AB - Architectural proteins play an important role in compacting and organizing the chromosomal DNA in all three kingdoms of life (Eukarya, Bacteria and Archaea). These proteins are generally not conserved at the amino acid sequence level, but the mechanisms by which they modulate the genome do seem to be functionally conserved across kingdoms. On a generic level, architectural proteins can be classified based on their structural effect as DNA benders, DNA bridgers or DNA wrappers. Although chromatin organization in archaea has not been studied extensively, quite a number of architectural proteins have been identified. In the present paper, we summarize the knowledge currently available on these proteins in Crenarchaea. By the type of architectural proteins available, the crenarchaeal nucleoid shows similarities with that of Bacteria. It relies on the action of a large set of small, abundant and generally basic proteins to compact and organize their genome and to modulate its activity. PMID- 21265759 TI - FRET (fluorescence resonance energy transfer) sheds light on transcription. AB - The complex organization of the transcription machinery has been revealed mainly by biochemical and crystallographic studies. X-ray structures describe RNA polymerases and transcription complexes on an atomic level, but fail to portray their dynamic nature. The use of fluorescence techniques has made it possible to add a new layer of information to our understanding of transcription by providing details about the structural rearrangement of mobile elements and the network of interactions within transcription complexes in solution and in real-time. PMID- 21265760 TI - Studying biomolecular complexes with pulsed electron-electron double resonance spectroscopy. AB - The function of biomolecules is intrinsically linked to their structure and the complexes they form during function. Techniques for the determination of structures and dynamics of these nanometre assemblies are therefore important for an understanding on the molecular level. PELDOR (pulsed electron-electron double resonance) is a pulsed EPR method that can be used to reliably and precisely measure distances in the range 1.5-8 nm, to unravel orientations and to determine the number of monomers in complexes. In conjunction with site-directed spin labelling, it can be applied to biomolecules of all sizes in aqueous solutions or membranes. PELDOR is therefore complementary to the methods of X-ray crystallography, NMR and FRET (fluorescence resonance energy transfer) and is becoming a powerful method for structural determination of biomolecules. In the present review, the methods of PELDOR are discussed and examples where PELDOR has been used to obtain structural information on biomolecules are summarized. PMID- 21265761 TI - Winged helix domains with unknown function in Hel308 and related helicases. AB - Hel308 is a superfamily 2 helicase/translocase that is conserved throughout archaea and in some eukaryotes for repair of genotoxic lesions such as ICLs (interstrand DNA cross-links). Atomic structures of archaeal Hel308 have allowed mechanistic insights into ATPase and helicase functions, but have also highlighted structures that currently lack a known function, such as an unexpected WH (winged helix) domain. This domain and similar overall protein structural organization was also identified in other superfamily 2 helicases that process RNA molecules in eukaryotes: Brr2, Mtr4 and Prp43p. We survey the structure of Hel308 with regard to its WH domain in particular and its function(s) in maintaining structural integrity of the overall Hel308 ring structure, and possibly during interactions of Hel308 with other proteins and/or forked DNA. PMID- 21265762 TI - Structure and function of a novel endonuclease acting on branched DNA substrates. AB - Branched DNA structures that occur during DNA repair and recombination must be efficiently processed by structure-specific endonucleases in order to avoid cell death. In the present paper, we summarize our screen for new interaction partners for the archaeal replication clamp that led to the functional characterization of a novel endonuclease family, dubbed NucS. Structural analyses of Pyrococcus abyssi NucS revealed an unexpected binding site for ssDNA (single-stranded DNA) that directs, together with the replication clamp, the nuclease activity of this protein towards ssDNA-dsDNA (double-stranded DNA) junctions. Our studies suggest that understanding the detailed architecture and dynamic behaviour of the NucS (nuclease specific for ssDNA)-PCNA (proliferating-cell nuclear antigen) complex with DNA will be crucial for identification of its physiologically relevant activities. PMID- 21265763 TI - Ploidy and gene conversion in Archaea. AB - The genome copy numbers of seven crenarchaeal species of four genera have been reported. All of them are monoploid and thus this seems to be a characteristic feature of Crenarchaeota. In stark contrast, none of six species representing six euryarchaeal genera is monoploid. Therefore Euryarchaea are typically oligoploid or polyploidy and their genome copy numbers are tightly regulated in response to growth phase and/or growth rate. A theoretical consideration called 'Muller's ratchet' predicts that asexually reproducing polyploid species should not be able to exist. An escape from Muller's ratchet would be a mechanism leading to the equalization of genome copies, such as gene conversion. Using two species of methanogenic and halophilic archaea, it was shown that heterozygous cells containing different genomes simultaneously can be selected, exemplifying gene redundancy as one possible evolutionary advantage of polyploidy. In both cases, the genomes were rapidly equalized in the absence of selection, showing that gene conversion operates at least in halophilic and methanogenic Euryarchaea. PMID- 21265764 TI - Thermophilic archaeal enzymes and applications in biocatalysis. AB - Thermophilic enzymes have advantages for their use in commercial applications and particularly for the production of chiral compounds to produce optically pure pharmaceuticals. They can be used as biocatalysts in the application of 'green chemistry'. The thermophilic archaea contain enzymes that have already been used in commercial applications such as the L-aminoacylase from Thermococcus litoralis for the resolution of amino acids and amino acid analogues. This enzyme differs from bacterial L-aminoacylases and has similarities to carboxypeptidases from other archaeal species. An amidase/gamma-lactamase from Sulfolobus solfataricus has been used for the production of optically pure gamma-lactam, the building block for antiviral carbocyclic nucleotides. This enzyme has similarities to the bacterial signature amidase family. An alcohol dehydrogenase from Aeropyrum pernix has been used for the production of optically pure alcohols and is related to the zinc-containing eukaryotic alcohol dehydrogenases. A transaminase and a dehalogenase from Sulfolobus species have also been studied. The archaeal transaminase is found in a pathway for serine synthesis which is found only in eukaryotes and not in bacteria. It can be used for the asymmetric synthesis of homochiral amines of high enantioselective purity. The L-2-haloacid dehalogenase has applications both in biocatalysis and in bioremediation. All of these enzymes have increased thermostability over their mesophilic counterparts. PMID- 21265765 TI - Regulatory RNAs in Haloferax volcanii. AB - In organisms of all three domains of life, a plethora of sRNAs (small regulatory RNAs) exists in addition to the well-known RNAs such as rRNAs, tRNAs and mRNAs. Although sRNAs have been well studied in eukaryotes and in bacteria, the sRNA population in archaea has just recently been identified and only in a few archaeal species. In the present paper, we summarize our current knowledge about sRNAs and their function in the halophilic archaeon Haloferax volcanii. Using two different experimental approaches, 111 intergenic and 38 antisense sRNAs were identified, as well as 42 tRFs (tRNA-derived fragments). Observation of differential expression under various conditions suggests that these sRNAs might be active as regulators in gene expression like their bacterial and eukaryotic counterparts. The severe phenotypes observed upon deletion and overexpression of sRNA genes revealed that sRNAs are involved in, and important for, a variety of biological functions in H. volcanii and possibly other archaea. Investigation of the Haloferax Lsm protein suggests that this protein is involved in the archaeal sRNA pathway. PMID- 21265766 TI - Protein-protein interactions in the archaeal core replisome. AB - Most of the core components of the archaeal chromosomal DNA replication apparatus share significant protein sequence similarity with eukaryotic replication factors, making the Archaea an excellent model system for understanding the biology of chromosome replication in eukaryotes. The present review summarizes current knowledge of how the core components of the archaeal chromosome replication apparatus interact with one another to perform their essential functions. PMID- 21265767 TI - Homing endonucleases residing within inteins: evolutionary puzzles awaiting genetic solutions. AB - Inteins are selfish genetic elements that disrupt the sequence of protein-coding genes and are excised post-translationally. Most inteins also contain a HEN (homing endonuclease) domain, which is important for their horizontal transmission. The present review focuses on the evolution of inteins and their nested HENs, and highlights several unsolved questions that could benefit from molecular genetic approaches. Such approaches can be well carried out in halophilic archaea, which are naturally intein-rich and have highly developed genetic tools for their study. In particular, the fitness effects of harbouring an intein/HEN can be tested in direct competition assays, providing additional insights that will improve current evolutionary models. PMID- 21265768 TI - Enzymology and ecology of the nitrogen cycle. AB - The nitrogen cycle describes the processes through which nitrogen is converted between its various chemical forms. These transformations involve both biological and abiotic redox processes. The principal processes involved in the nitrogen cycle are nitrogen fixation, nitrification, nitrate assimilation, respiratory reduction of nitrate to ammonia, anaerobic ammonia oxidation (anammox) and denitrification. All of these are carried out by micro-organisms, including bacteria, archaea and some specialized fungi. In the present article, we provide a brief introduction to both the biochemical and ecological aspects of these processes and consider how human activity over the last 100 years has changed the historic balance of the global nitrogen cycle. PMID- 21265769 TI - Oxygen control of nitrogen oxide respiration, focusing on alpha-proteobacteria. AB - Denitrification is generally considered to occur under micro-oxic or anoxic conditions. With this in mind, the physiological function and regulation of several steps in the denitrification of model alpha-proteobacteria are compared in the present review. Expression of the periplasmic nitrate reductase is quite variable, with this enzyme being maximally expressed under oxic conditions in some bacteria, but under micro-oxic conditions in others. Expression of nitrite and NO reductases in most denitrifiers is more tightly controlled, with expression only occurring under micro-oxic conditions. A possible exception to this may be Roseobacter denitrificans, but the physiological role of these enzymes under oxic conditions is uncertain. PMID- 21265770 TI - Nitric oxide detoxification in the rhizobia-legume symbiosis. AB - NO (nitric oxide) is a signal molecule involved in diverse physiological processes in cells which can become very toxic under certain conditions determined by its rate of production and diffusion. Several studies have clearly shown the production of NO in early stages of rhizobia-legume symbiosis and in mature nodules. In functioning nodules, it has been demonstrated that NO, which has been reported as a potent inhibitor of nitrogenase activity, can bind Lb (leghaemoglobin) to form LbNOs (nitrosyl-leghaemoglobin complexes). These observations have led to the question of how nodules overcome the toxicity of NO. On the bacterial side, one candidate for NO detoxification in nodules is the respiratory Nor (NO reductase) that catalyses the reduction of NO to nitrous oxide. In addition, rhizobial fHbs (flavohaemoglobins) and single-domain Hbs which dioxygenate NO to form nitrate are candidates to detoxify NO under free living and symbiotic conditions. On the plant side, sHbs (symbiotic Hbs) (Lb) and nsHbs (non-symbiotic Hbs) have been proposed to play important roles as modulators of NO levels in the rhizobia-legume symbiosis. In the present review, current knowledge of NO detoxification by legume-associated endosymbiotic bacteria is summarized. PMID- 21265771 TI - The role of effector molecules in signal transduction by PII proteins. AB - PII proteins are one of the most widely distributed signal transduction proteins in Nature, being ubiquitous in bacteria, archaea and plants. They act by protein protein interaction to control the activities of a wide range of enzymes, transcription factors and transport proteins, the great majority of which are involved in cellular nitrogen metabolism. The regulatory activities of PII proteins are mediated through their ability to bind the key effector metabolites 2-OG (2-oxoglutarate), ATP and ADP. However, the molecular basis of these regulatory effects remains unclear. Recent advances in the solution of the crystal structures of PII proteins complexed with some of their target proteins, as well as the identification of the ATP/ADP- and 2-OG-binding sites, have improved our understanding of their mode of action. In all of the complex structures solved to date, the flexible T-loops of PII facilitate interaction with the target protein. The effector molecules appear to play a key role in modulating the conformation of the T-loops and thereby regulating the interactions between PII and its targets. PMID- 21265772 TI - The catalytic mechanism of Pseudomonas aeruginosa cd1 nitrite reductase. AB - The cd1 NiRs (nitrite reductases) are enzymes catalysing the reduction of nitrite to NO (nitric oxide) in the bacterial energy conversion denitrification process. These enzymes contain two distinct redox centres: one covalently bound c-haem, which is reduced by external electron donors, and another peculiar porphyrin, the d1-haem (3,8-dioxo-17-acrylate-porphyrindione), where nitrite is reduced to NO. In the present paper, we summarize the most recent results on the mechanism of nitrite reduction by the cd1 NiR from Pseudomonas aeruginosa. We discuss the essential catalytic features of this enzyme, with special attention to the allosteric regulation of the enzyme's activity and to the mechanism employed to avoid product inhibition, i.e. trapping of the active-site reduced haem by the product NO. These results shed light on the reactivity of cd1 NiRs and assign a central role to the unique d1-haem, present only in this class of enzymes. PMID- 21265773 TI - Electron transfer and half-reactivity in nitrogenase. AB - Nitrogenase is a globally important enzyme that catalyses the reduction of atmospheric dinitrogen into ammonia and is thus an important part of the nitrogen cycle. The nitrogenase enzyme is composed of a catalytic molybdenum-iron protein (MoFe protein) and a protein containing an [Fe4-S4] cluster (Fe protein) that functions as a dedicated ATP-dependent reductase. The current understanding of electron transfer between these two proteins is based on stopped-flow spectrophotometry, which has allowed the rates of complex formation and electron transfer to be accurately determined. Surprisingly, a total of four Fe protein molecules are required to saturate one MoFe protein molecule, despite there being only two well-characterized Fe-protein-binding sites. This has led to the conclusion that the purified Fe protein is only half-active with respect to electron transfer to the MoFe protein. Studies on the electron transfer between both proteins using rapid-quench EPR confirmed that, during pre-steady-state electron transfer, the Fe protein only becomes half-oxidized. However, stopped flow spectrophotometry on MoFe protein that had only one active site occupied was saturated by approximately three Fe protein equivalents. These results imply that the Fe protein has a second interaction during the initial stages of mixing that is not involved in electron transfer. PMID- 21265774 TI - Denitrification regulatory phenotype, a new term for the characterization of denitrifying bacteria. AB - Current knowledge of denitrification is based on detailed studies of a limited number of organisms. In most cases the importance of these paradigm species in natural ecosystems is questionable. Detailed phenotypic studies of a wider range of prokaryotes, both type strains and dominant denitrifiers isolated from complex systems, will aid the generation of more sophisticated mathematical models for the prediction of NO and N2O emission to the environment. However, in order to facilitate the comparison of a vast range of prokaryotes, phenotypic experiments and functional characteristics included should be standardized. In the present paper, we discuss the term DRP (denitrification regulatory phenotype) for describing a set of phenotypic traits and experimental conditions for the characterization of denitrifying organisms. This is exemplified by the contrasting DRP characteristics of the two well-studied denitrifiers Paracoccus denitrificans and Agrobacterium tumefaciens. PMID- 21265775 TI - Nitrosative stress in Escherichia coli: reduction of nitric oxide. AB - The ability of enteric bacteria to protect themselves against reactive nitrogen species generated by their own metabolism, or as part of the innate immune response, is critical to their survival. One important defence mechanism is their ability to reduce NO (nitric oxide) to harmless products. The highest rates of NO reduction by Escherichia coli K-12 were detected after anaerobic growth in the presence of nitrate. Four proteins have been implicated as catalysts of NO reduction: the cytoplasmic sirohaem-containing nitrite reductase, NirB; the periplasmic cytochrome c nitrite reductase, NrfA; the flavorubredoxin NorV and its associated oxidoreductase, NorW; and the flavohaemoglobin, Hmp. Single mutants defective in any one of these proteins and even the mutant defective in all four proteins reduced NO at the same rate as the parent. Clearly, therefore, there are mechanisms of NO reduction by enteric bacteria that remain to be characterized. Far from being minor pathways, the currently unknown pathways are adequate to sustain almost optimal rates of NO reduction, and hence potentially provide significant protection against nitrosative stress. PMID- 21265776 TI - Gene expression study of the flavodi-iron proteins from the cyanobacterium Synechocystis sp. PCC6803. AB - The flavodi-iron proteins, also named FDPs, are an extensive family of enzymes able to reduce dioxygen to water and/or nitric oxide to nitrous oxide. These proteins are formed by a metallo-beta-lactamase-like module with a di-iron catalytic site fused to a flavodoxin-like module bearing an FMN. However, in cyanobacteria, which are oxygenic photosynthetic organisms widespread in Nature, FDPs have an extra NAD(P)H:flavin reductase-like domain as a C-terminal extension. Interestingly, cyanobacteria contain more than one gene encoding FDP like proteins, with the genome of Synechocystis sp. PCC6803 containing four genes coding for putative FDPs. However, the function of those proteins remains unclear. In the present study, we have analysed the expression profile of these genes under oxidative and nitrosative stress conditions. The results indicate that one of the flavodi-iron genes, the so-called flv1, is induced in cells exposed to nitrosative stress. By conducting a broad analysis on the primary sequences of FDPs, we have identified that the FDPs of cyanobacteria and oxygenic photosynthetic eukaryotes may be divided into multiple types (1-12), according to the amino acid residues of the di-iron catalytic site. PMID- 21265778 TI - An HcpR homologue from Desulfovibrio desulfuricans and its possible role in nitrate reduction and nitrosative stress. AB - The Escherichia coli CRP (cAMP receptor protein), is a global regulator of transcription that modulates gene expression by activation or repression at a range of promoters in E. coli. A major function is to regulate the selection of nutrients required for growth. The anaerobic sulfate-reducing bacterium Desulfovibrio desulfuricans ATCC27774 is capable of utilizing sulfate, nitrite and nitrate as terminal electron acceptors. In the presence of both sulfate and nitrate, sulfate is reduced preferentially despite nitrate being the thermodynamically more favourable electron acceptor. Three inverted repeat sequences upstream of the D. desulfuricans ATCC27774 nap (nitrate reduction in the periplasm) operon have high levels of similarity to the consensus sequence for the E. coli CRP DNA-binding site. In other Desulfovibrio species a putative CRP homologue, HcpR [regulator of hcp (hybrid cluster protein) transcription], has a predicted regulon comprising genes involved in sulfate reduction and nitrosative stress. The presence of CRP consensus sites within the D. desulfuricans ATCC27774 nap promoter prompted a search for CRP homologues in the genomes of sulfate-reducing bacteria. This revealed the presence of a potential CRP homologue that we predict binds to CRP consensus sites such as those of the nap operon. Furthermore, we predict that much of the core HcpR regulon predicted in other Desulfovibrio species is conserved in D. desulfuricans. PMID- 21265777 TI - Nitric oxide and nitrosative stress tolerance in yeast. AB - The opportunistic human fungal pathogen Candida albicans encounters diverse environmental stresses when it is in contact with its host. When colonizing and invading human tissues, C. albicans is exposed to ROS (reactive oxygen species) and RNIs (reactive nitrogen intermediates). ROS and RNIs are generated in the first line of host defence by phagocytic cells such as macrophages and neutrophils. In order to escape these host-induced oxidative and nitrosative stresses, C. albicans has developed various detoxification mechanisms. One such mechanism is the detoxification of NO (nitric oxide) to nitrate by the flavohaemoglobin enzyme CaYhb1. Members of the haemoglobin superfamily are highly conserved and are found in archaea, eukaryotes and bacteria. Flavohaemoglobins have a dioxygenase activity [NOD (NO dioxygenase domain)] and contain three domains: a globin domain, an FAD-binding domain and an NAD(P)-binding domain. In the present paper, we examine the nitrosative stress response in three fungal models: the pathogenic yeast C. albicans, the benign budding yeast Saccharomyces cerevisiae and the benign fission yeast Schizosaccharomyces pombe. We compare their enzymatic and non-enzymatic NO and RNI detoxification mechanisms and summarize fungal responses to nitrosative stress. PMID- 21265779 TI - Nitrate and (per)chlorate reduction pathways in (per)chlorate-reducing bacteria. AB - The reduction of (per)chlorate and nitrate in (per)chlorate-reducing bacteria shows similarities and differences. (Per)chlorate reductase and nitrate reductase both belong to the type II DMSO family of enzymes and have a common bis(molybdopterin guanine dinucleotide)molybdenum cofactor. There are two types of dissimilatory nitrate reductases. With respect to their localization, (per)chlorate reductase is more similar to the dissimilatory periplasmic nitrate reductase. However, the periplasmic, unlike the membrane-bound, respiratory nitrate reductase, is not able to use chlorate. Structurally, (per)chlorate reductase is more similar to respiratory nitrate reductase, since these reductases have analogous subunits encoded by analogous genes. Both periplasmic (per)chlorate reductase and membrane-bound nitrate reductase activities are induced under anoxic conditions in the presence of (per)chlorate and nitrate respectively. During microbial (per)chlorate reduction, molecular oxygen is generated. This is not the case for nitrate reduction, although an atypical reaction in nitrite reduction linked to oxygen formation has been described recently. Microbial oxygen production during reduction of oxyanions may enhance biodegradation of pollutants under anoxic conditions. PMID- 21265780 TI - Electrocatalytic reduction of nitrate and selenate by NapAB. AB - Bacterial cellular metabolism is renowned for its metabolic diversity and adaptability. However, certain environments present particular challenges. Aerobic metabolism of highly reduced carbon substrates by soil bacteria such as Paracoccus pantotrophus presents one such challenge since it may result in excessive electron delivery to the respiratory redox chain when compared with the availability of terminal oxidant, O2. The level of a periplasmic ubiquinol dependent nitrate reductase, NAP, is up-regulated in the presence of highly reduced carbon substrates. NAP oxidizes ubiquinol at the periplasmic face of the cytoplasmic membrane and reduces nitrate in the periplasm. Thus its activity counteracts the accumulation of excess reducing equivalents in ubiquinol, thereby maintaining the redox poise of the ubiquinone/ubiquinol pool without contributing to the protonmotive force across the cytoplasmic membrane. Although P. pantotrophus NapAB shows a high level of substrate specificity towards nitrate, the enzyme has also been reported to reduce selenate in spectrophotometric solution assays. This transaction draws on our current knowledge concerning the bacterial respiratory nitrate reductases and extends the application of PFE (protein film electrochemistry) to resolve and quantify the selenate reductase activity of NapAB. PMID- 21265781 TI - A new intra-aerobic metabolism in the nitrite-dependent anaerobic methane oxidizing bacterium Candidatus 'Methylomirabilis oxyfera'. AB - Biological methane oxidation proceeds either through aerobic or anaerobic pathways. The newly discovered bacterium Candidatus 'Methylomirabilis oxyfera' challenges this dichotomy. This bacterium performs anaerobic methane oxidation coupled to denitrification, but does so in a peculiar way. Instead of scavenging oxygen from the environment, like the aerobic methanotrophs, or driving methane oxidation by reverse methanogenesis, like the methanogenic archaea in sulfate reducing systems, it produces its own supply of oxygen by metabolizing nitrite via nitric oxide into oxygen and dinitrogen gas. The intracellularly produced oxygen is then used for the oxidation of methane by the classical aerobic methane oxidation pathway involving methane mono-oxygenase. The present mini-review summarizes the current knowledge about this process and the micro-organism responsible for it. PMID- 21265782 TI - Partial and complete denitrification in Thermus thermophilus: lessons from genome drafts. AB - We have obtained draft genomic sequences of PD (partial denitrificant) and CD (complete denitrificant) strains of Thermus thermophilus. Their genomes are similar in size to that of the aerobic strains sequenced to date and probably contain a similar megaplasmid. In the CD strain, the genes encoding a putative cytochrome cd1 Nir (nitrite reductase) and ancillary proteins were clustered with a cytochrome c-dependent Nor (nitric oxide reductase), and with genes that are probably implicated in their regulation. The Nar (nitrate reductase) and associated genes were also clustered and located 7 kb downstream of the genes coding for the Nir. The whole nar-nir-nor denitrification supercluster was identified as part of a variable region of a megaplasmid. No homologues of NosZ were found despite nitrogen balance supports the idea that such activity actually exists. PMID- 21265783 TI - Denitrification in Gram-positive bacteria: an underexplored trait. AB - Denitrifying organisms are essential in removing fixed nitrogen pollutants from ecosystems (e.g. sewage sludge). They can be detrimental (e.g. for agricultural soil) and can also produce the greenhouse gas N2O (nitrous oxide). Therefore a more comprehensive understanding of this process has become increasingly important regarding its global environmental impact. Even though bacterial genome sequencing projects may reveal new data, to date the denitrification abilities and features in Gram-positive bacteria are still poorly studied and understood. The present review evaluates current knowledge on the denitrification trait in Gram-positive bacteria and addresses the likely existence of unknown denitrification genes. In addition, current molecular tools to study denitrification gene diversity in pure cultures and environmental samples seem to be highly biased, and additional novel approaches for the detection of denitrifying (Gram-positive) bacteria appear to be crucial in re-assessing the real diversity of denitrifiers. PMID- 21265784 TI - In vitro proof of direct regulation of glutamine synthetase by GlnK proteins in the extreme halophilic archaeon Haloferax mediterranei. AB - Haloferax mediterranei is an extreme halophilic micro-organism belonging to the Archaea domain that was isolated from the Santa Pola solar salterns (Alicante, Spain) in 1983. The biochemistry of the proteins involved in nitrogen metabolism is being studied, but the knowledge of their regulation is very scarce at present. The PII superfamily is constituted by major regulators of nitrogen metabolism, which are widespread in prokaryotic and eukaryotic organisms. These trimeric proteins (12 kDa per subunit) have in Escherichia coli long been known to regulate GS (glutamine synthetase) activity via its adenylyltransferase/adenylyl-removing enzyme and, more recently, to be able to interact directly with this enzyme in methanogenic archaea. We have tested the possible role of PII proteins in the regulation of ammonium assimilation in our model organism and the results clearly indicate that the direct influence of GS by PII proteins can also take place in halophilic archaea, starting with the comprehension of nitrogen regulation in those organisms. PMID- 21265785 TI - Molecular interactions between multihaem cytochromes: probing the protein-protein interactions between pentahaem cytochromes of a nitrite reductase complex. AB - The cytochrome c nitrite reductase NrfA is a 53 kDa pentahaem enzyme that crystallizes as a decahaem homodimer. NrfA catalyses the reduction of NO2- to NH4+ through a six electron reduction pathway that is of major physiological significance to the anaerobic metabolism of enteric and sulfate reducing bacteria. NrfA receives electrons from the 21 kDa pentahaem NrfB donor protein. This requires that redox complexes form between the NrfA and NrfB pentahaem cytochromes. The formation of these complexes can be monitored using a range of methodologies for studying protein-protein interactions, including dynamic light scattering, gel filtration, analytical ultracentrifugation and visible spectroscopy. These methods have been used to show that oxidized NrfA exists in dynamic monomer-dimer equilibrium with a Kd (dissociation constant) of 4 MUM. Significantly, the monomeric and dimeric forms of NrfA are equally active for either the six electron reduction of NO2- or HSO3-. When mixed together, NrfA and NrfB exist in equilibrium with NrfAB, which is described by a Kd of 50 nM. Thus, since NrfA and NrfB are present in micromolar concentrations in the periplasmic compartment, it is likely that NrfB remains tightly associated with its NrfA redox partner under physiological conditions. PMID- 21265786 TI - Bacterial cyanide degradation is under review: Pseudomonas pseudoalcaligenes CECT5344, a case of an alkaliphilic cyanotroph. AB - There are thousands of areas in the U.S.A. and Europe contaminated with cyanide containing wastes as a consequence of a large number of industrial activities such as gold mining, steel and aluminium manufacturing, electroplating and nitrile pesticides used in agriculture. Chemical treatments to remove cyanide are expensive and generate other toxic products. By contrast, cyanide biodegradation constitutes an appropriate alternative treatment. In the present review we provide an overview of how cells deal in the presence of the poison cyanide that irreversible binds to metals causing, among other things, iron-deprivation conditions outside the cell and metalloenzymes inhibition inside the cell. In this sense, several systems must be present in a cyanotrophic organism, including a siderophore-based acquisition mechanism, a cyanide-insensitive respiratory system and a cyanide degradation/assimilation pathway. The alkaliphilic autochthonous bacterium Pseudomonas pseudocaligenes CECT5344 presents all these requirements with the production of siderophores, a cyanide-insensitive bd related cytochrome [Cio (cyanide-insensitive oxidase)] and a cyanide assimilation pathway that generates ammonium, which is further incorporated into organic nitrogen. PMID- 21265787 TI - Plant influence on nitrification. AB - Modern agriculture has promoted the development of high-nitrification systems that are susceptible to major losses of nitrogen through leaching of nitrate and gaseous emissions of nitrogen oxide (NO and N2O), contributing to global warming and depletion of the ozone layer. Leakage of nitrogen from agricultural systems forces increased use of nitrogen fertilizers and causes water pollution and elevated costs of food production. Possible strategies for prevention of these processes involve various agricultural management approaches and use of synthetic inhibitors. Growing plants capable of producing nitrification suppressors could become a potentially superior method of controlling nitrification in the soil. There is a need to investigate the phenomenon of biological nitrification inhibition in arable crop species. PMID- 21265788 TI - Advances in 15N-tracing experiments: new labelling and data analysis approaches. AB - To obtain an in-depth understanding of soil nitrogen dynamics, it is necessary to quantify a variety of simultaneously occurring gross nitrogen transformation processes. In order to do so, most studies apply 15N in a disturbed soil microbial-root system and quantify gross rates based on the principles of 15N isotope dilution. However, this approach has several shortcomings. First, studying disturbed soil provides only limited information on in situ soil nitrogen dynamics. Secondly, the analytical data analysis allows the quantification of total production and consumption rates of the labelled pool, but does not provide information on process-specific transformation rates. Combining in situ 15N isotope labelling over 1-2 weeks with numerical data analysis allows determining process-specific gross nitrogen transformations in undisturbed soils under field conditions in the presence of live roots and their associated microbial communities. This has the potential to increase our understanding of nitrogen dynamics in the soil environment. PMID- 21265789 TI - Emerging complexity in the denitrification regulatory network of Bradyrhizobium japonicum. AB - Bradyrhizobium japonicum is a Gram-negative soil bacterium symbiotically associated with soya bean plants, which is also able to denitrify under free living and symbiotic conditions. In B. japonicum, the napEDABC, nirK, norCBQD and nosRZDYFLX genes which encode reductases for nitrate, nitrite, nitric oxide and nitrous oxide respectively are required for denitrification. Similar to many other denitrifiers, expression of denitrification genes in B. japonicum requires both oxygen limitation and the presence of nitrate or a derived nitrogen oxide. In B. japonicum, a sophisticated regulatory network consisting of two linked regulatory cascades co-ordinates the expression of genes required for microaerobic respiration (the FixLJ/FixK2 cascade) and for nitrogen fixation (the RegSR/NifA cascade). The involvement of the FixLJ/FixK2 regulatory cascade in the microaerobic induction of the denitrification genes is well established. In addition, the FNR (fumarase and nitrate reduction regulator)/CRP(cAMP receptor protein)-type regulator NnrR expands the FixLJ/FixK2 regulatory cascade by an additional control level. A role for NifA is suggested in this process by recent experiments which have shown that it is required for full expression of denitrification genes in B. japonicum. The present review summarizes the current understanding of the regulatory network of denitrification in B. japonicum. PMID- 21265790 TI - Transcriptional regulation by the dedicated nitric oxide sensor, NorR: a route towards NO detoxification. AB - A flavorubredoxin and its associated oxidoreductase (encoded by norV and norW respectively) detoxify NO (nitric oxide) to form N2O (nitrous oxide) under anaerobic conditions in Escherichia coli. Transcription of the norVW genes is activated in response to NO by the sigma54-dependent regulator and dedicated NO sensor, NorR, a member of the bacterial enhancer-binding protein family. In the absence of NO, the catalytic activity of the central ATPase domain of NorR is repressed by the N-terminal regulatory domain that contains a non-haem iron centre. Binding of NO to this centre results in the formation of a mononitrosyl iron species, enabling the activation of ATPase activity. Our studies suggest that the highly conserved GAFTGA loop in the ATPase domain, which engages with the alternative sigma factor sigma54 to activate transcription, is a target for intramolecular repression by the regulatory domain. Binding of NorR to three conserved enhancer sites upstream of the norVW promoter is essential for transcriptional activation and promotes the formation of a stable higher-order NorR nucleoprotein complex. We propose that enhancer-driven assembly of this oligomeric complex, in which NorR apparently forms a DNA-bound hexamer in the absence of NO, provides a 'poised' system for transcriptional activation that can respond rapidly to nitrosative stress. PMID- 21265791 TI - The Pseudomonas aeruginosa DNR transcription factor: light and shade of nitric oxide-sensing mechanisms. AB - In response to environmental conditions, NO (nitric oxide) induces global changes in the cellular metabolism of Pseudomonas aeruginosa, which are strictly related to pathogenesis. In particular, at low oxygen tensions and in the presence of NO the denitrification alternative respiration is activated by a key regulator: DNR (dissimilative nitrate respiration regulator). DNR belongs to the CRP (cAMP receptor protein)-FNR (fumarate and nitrate reductase regulatory protein) superfamily of bacterial transcription factors. These regulators are involved in many different pathways and distinct activation mechanism seems to be operative in several cases. Recent results indicate that DNR is a haem protein capable of discriminating between NO and CO (carbon monoxide). On the basis of the available structural data, a suggested activation mechanism is discussed. PMID- 21265792 TI - Respiratory nitrogen metabolism and nitrosative stress defence in epsilon proteobacteria: the role of NssR-type transcription regulators. AB - epsilon-Proteobacteria form a globally ubiquitous group of ecologically significant organisms and comprise a diverse range of host-associated and free living species. To grow by anaerobic respiration, many epsilon-proteobacteria reduce nitrate to nitrite followed by either nitrite ammonification or denitrification. Using the ammonifying model organisms Wolinella succinogenes and Campylobacter jejuni, the electron transport chains of nitrate respiration, respiratory nitrite ammonification and even N2O (nitrous oxide) respiration have been characterized in recent years, but knowledge on nitrosative stress defence, nitrogen compound-sensing and corresponding signal transduction pathways is limited. The potentially dominant role of NssR (nitrosative stress-sensing regulator)-type transcription regulators in epsilon-proteobacterial nitrogen metabolism is discussed. PMID- 21265793 TI - Proteins and protein complexes involved in the biochemical reactions of anaerobic ammonium-oxidizing bacteria. AB - It has been less than two decades since anammox (anaerobic ammonium oxidation) coupled to nitrite reduction has been discovered. Already, this process has been recognized as an important sink for fixed nitrogen in the natural environment and has been implemented as a cost-effective ammonium removal technology. Still, little is known about the molecular mechanism of this remarkable reaction. In this mini review, we present an insight into how ammonium and nitrite are combined to form dinitrogen gas. PMID- 21265794 TI - Enzymology under global change: organic nitrogen turnover in alpine and sub Arctic soils. AB - Understanding global change impacts on the globally important carbon storage in alpine, Arctic and sub-Arctic soils requires knowledge of the mechanisms underlying the balance between plant primary productivity and decomposition. Given that nitrogen availability limits both processes, understanding the response of the soil nitrogen cycle to shifts in temperature and other global change factors is crucial for predicting the fate of cold biome carbon stores. Measurements of soil enzyme activities at different positions of the nitrogen cycling network are an important tool for this purpose. We review a selection of studies that provide data on potential enzyme activities across natural, seasonal and experimental gradients in cold biomes. Responses of enzyme activities to increased nitrogen availability and temperature are diverse and seasonal dynamics are often larger than differences due to experimental treatments, suggesting that enzyme expression is regulated by a combination of interacting factors reflecting both nutrient supply and demand. The extrapolation from potential enzyme activities to prediction of elemental nitrogen fluxes under field conditions remains challenging. Progress in molecular '-omics' approaches may eventually facilitate deeper understanding of the links between soil microbial community structure and biogeochemical fluxes. In the meantime, accounting for effects of the soil spatial structure and in situ variations in pH and temperature, better mapping of the network of enzymatic processes and the identification of rate limiting steps under different conditions should advance our ability to predict nitrogen fluxes. PMID- 21265795 TI - Bioturbation: impact on the marine nitrogen cycle. AB - Sediments play a key role in the marine nitrogen cycle and can act either as a source or a sink of biologically available (fixed) nitrogen. This cycling is driven by a number of microbial remineralization reactions, many of which occur across the oxic/anoxic interface near the sediment surface. The presence and activity of large burrowing macrofauna (bioturbators) in the sediment can significantly affect these microbial processes by altering the physicochemical properties of the sediment. For example, the building and irrigation of burrows by bioturbators introduces fresh oxygenated water into deeper sediment layers and allows the exchange of solutes between the sediment and water column. Burrows can effectively extend the oxic/anoxic interface into deeper sediment layers, thus providing a unique environment for nitrogen-cycling microbial communities. Recent studies have shown that the abundance and diversity of micro-organisms can be far greater in burrow wall sediment than in the surrounding surface or subsurface sediment; meanwhile, bioturbated sediment supports higher rates of coupled nitrification-denitrification reactions and increased fluxes of ammonium to the water column. In the present paper we discuss the potential for bioturbation to significantly affect marine nitrogen cycling, as well as the molecular techniques used to study microbial nitrogen cycling communities and directions for future study. PMID- 21265796 TI - Four PCR primers necessary for the detection of periplasmic nitrate reductase genes in all groups of Proteobacteria and in environmental DNA. AB - Generic primers are available for detecting bacterial genes required for almost every reaction of the biological nitrogen cycle, the one notable exception being napA (gene for the molybdoprotein of the periplasmic nitrate reductase) encoding periplasmic nitrate reductases. Using an iterative approach, we report the first successful design of three forward oligonucleotide primers and one reverse primer that, in three separate PCRs, can amplify napA DNA from all five groups of Proteobacteria. All 140 napA sequences currently listed in the NCBI (National Center for Biotechnology Information) database are predicted to be amplified by one or more of these primer pairs. We demonstrate that two pairs of these primers also amplify PCR products of the predicted sizes from DNA isolated from human faeces, confirming their ability to direct the amplification of napA fragments from mixed populations. Analysis of the resulting amplicons by high-throughput sequencing will enable a good estimate to be made of both the range and relative abundance of nitrate-reducing bacteria in any community, subject only to any unavoidable bias inherent in a PCR approach to molecular characterization of a highly diverse target. PMID- 21265797 TI - Discovering new clinical markers in the field of glycomics. AB - Glycosylation modifications have been reported in a number of disease states and, as a result, there is significant focus on the discovery and development of glycan-based biomarkers. Glyco-biomarkers have the potential to enhance the efficacy and efficiency of the diagnostic procedures for these diseases. PMID- 21265798 TI - Glycoconjugate markers of joint diseases. AB - A number of different types of glycoconjugate are found associated with joint tissue and fluids, comprising glycoproteins, glycolipids and glycosaminoglycans. Oligosaccharide chains of glycoconjugates are degraded by exoglycosidases, and the dominant exoglycosidase found in human blood, synovial fluid, the synovial membrane and chondrocytes of articular cartilage is HEX (N-acetyl-beta hexosaminidase). HEX is localized mostly intracellularly in synovial cells. Serum activity of HEX may be used to monitor the course and efficiency of treatment of Lyme arthritis, and activity of HEX, above 10 MUkat/kg of protein in the synovial fluid, suggests rheumatoid disease. There is a shortage of HEX inhibitors able to penetrate synoviocytes, so the development of drugs which inhibit synthesis and/or the activity of HEX will be a promising field for future investigations. PMID- 21265799 TI - Glycomarkers for muscular dystrophy. AB - During the last 10 years it has become apparent that a significant subset of inherited muscular dystrophy is caused by errors in the glycosylation of alpha dystroglycan. Many of these dystrophies are also associated with abnormalities of the central nervous system. Dystroglycan has to be fully glycosylated in order bind to its ligands. To date, six genes have been shown to be essential for functional dystroglycan glycosylation and most, if not all, of these genes act in the formation of O-mannosyl glycans. Genetic heterogeneity indicates that other genes are involved in this pathway. Identification of these additional genes would increase our understanding of this specific and essential glycosylation pathway. PMID- 21265800 TI - Carbohydrate markers of pancreatic cancer. AB - Pancreatic cancer is the fourth most common cause of death from cancer in the world and the sixth in Europe. Pancreatic cancer is more frequent in males than females. Worldwide, following diagnosis of pancreatic cancer, <2% of patients survive for 5 years, 8% survive for 2 years and <50% survive for only approx. 3 months. The biggest risk factor in pancreatic cancer is age, with a peak of morbidity at 65 years. Difficulty in the diagnosis of pancreatic cancer causes a delay in its detection. It is one of the most difficult cancers to diagnose and therefore to treat successfully. Additional detection of carbohydrate markers may offer a better diagnosis of pancreatic cancer. Carbohydrate markers of cancer may be produced by the cancer itself or by the body in response to cancer, whose presence in body fluids suggests the presence and growth of the cancer. The most widely used, and best-recognized, carbohydrate marker of pancreatic cancer is CA 19-9 [CA (carbohydrate antigen) 19-9]. However, the relatively non-specific nature of CA 19-9 limits its routine use in the early diagnosis of pancreatic cancer, but it may be useful in monitoring treatment of pancreatic cancer (e.g. the effectiveness of chemotherapy), as a complement to other diagnostic methods. Some other carbohydrate markers of pancreatic cancer may be considered, such as CEA (carcinoembryonic antigen), CA 50 and CA 242, and the mucins MUC1, MUC2 and MUC5AC, but enzymes involved in the processing of glycoconjugates could also be involved. Our preliminary research shows that the activity of lysosomal exoglycosidases, including HEX (N-acetyl-beta-D-hexosaminidase), GAL (beta-D galactosidase), FUC (alpha-L-fucosidase) and MAN (alpha-D-mannosidase), in serum and urine may be used in the diagnosis of pancreatic cancer. PMID- 21265801 TI - Terminal monosaccharide expression on amniotic glycoproteins as biomarkers of fetus maturity. AB - Glycotypes, particularly those that terminate with sialic acid and fucose are known to play a fundamental role in human development, during implantation, growth and differentiation of fetal tissues. The present review describes changes in the exposition of terminal sialic acid and fucose isoforms in the amniotic fluid glycoconjugates, alpha1-acid glycoprotein and fibronectin during critical stages of pregnancy, i.e. second and third trimester, perinatal period, delivery and post-date pregnancy. The distinct amniotic glycoforms are suggested to be implicated in regulatory processes to ensure homoeostasis during pregnancy and to protect the fetus. These may have the potential of becoming additional laboratory makers in obstetrics to monitor pregnancy. PMID- 21265802 TI - Glycosylation changes as important factors for the susceptibility to urinary tract infection. AB - FimH is the type 1 fimbrial tip adhesin and invasin of Escherichia coli. Its ligands are the glycans on specific proteins enriched in membrane microdomains. FimH binding shows high-affinity recognition of paucimannosidic glycans, which are shortened high-mannose glycans such as oligomannose-3 and -5. FimH can recognize equally the (single) high-mannose glycan on uroplakin Ia, on the urinary defence protein uromodulin or Tamm-Horsfall glycoprotein and on the intestinal GP2 glycoprotein present in Peyer's patches. E. coli bacteria may attach to epithelial cells via hundreds of fimbriae in a multivalent fashion. This binding is considered to provoke conformational changes in the glycoprotein receptor that translate into signalling in the cytoplasm of the infected epithelial cell. Bladder cell invasion by the uropathogenic bacterium is the prelude to recurrent and persistent urinary tract infections in humans. Patients suffering from diabetes mellitus are more prone to contract urinary tract infections. In a study of women, despite longer treatments with a more potent antibiotic, these patients also have more often recurrences of urinary tract infections compared with women without diabetes. Type 1 fimbriae are the most important virulence factors used not only for adhesion of E. coli in the urinary tract, but also for the colonization by E. coli in patients with Crohn's disease or ulcerative colitis. It appears that the increased prevalence of urinary tract infections in diabetic women is not the result of a difference in the bacteria, but is due to changes in the uroepithelial cells leading to an increased adherence of E. coli expressing type 1 fimbriae. Hypothetically, these changes are in the glycosylation of the infected cells. The present article focuses on possible underlying mechanisms for glycosylation changes in the uroepithelial cell receptors for FimH. Like diabetes, bacterial adhesion induces apoptosis that may bring the endoplasmic reticulum membrane with immature mannosylated glycoproteins to the surface. Indicatively, clathrin-mediated vesicle trafficking of glucose transporters is disturbed in diabetics, which would interfere further with the biosynthesis and localization of complex N-linked glycans. PMID- 21265803 TI - Expression and potential biological role of alpha(1,2)fucosylated glycotopes on amniotic and seminal fibronectins. AB - The present paper describes concisely the expression and role of alpha(1,2) linked fucose on some glycoconjugates as well as the detection, distribution and potential role of that glycotope on human soluble plasma and cellular fibronectins in addition to the expression on both normal and pathological amniotic fluid and seminal plasma fibronectins. The determination of alpha(1,2)fucosylated glycans is considered with respect to its usefulness as a potential clinically applicable biomarker in obstetrics to monitor pregnancy and in andrology to evaluate the ejaculate of infertile men and in vitro fertilization. PMID- 21265804 TI - Glycomarkers in parasitic infections and allergy. AB - Both helminth infections and contact with allergens result in development of a Th2 type of immune response in the affected individual. In this context, the hygiene hypothesis suggests that reduced prevalence of parasitic infections and successful vaccination strategies are causative for an increase of allergies in industrialized countries. It is therefore of interest to study glycans and their role as immunogenic structures in both parasitic infections and allergies. In the present paper we review information on the different types of glycan structure present in proteins from plant and animal food, insect venom and helminth parasites, and their role as diagnostic markers. In addition, the application of these glycan structures as immunomodulators in novel immunotherapeutic strategies is discussed. PMID- 21265805 TI - Glycoconjugates in the detection of alcohol abuse. AB - Up to 30% of all hospital admissions and health-care costs may be attributable to alcohol abuse. Ethanol, its oxidative metabolites, acetaldehyde and ROS (reactive oxygen species), non-oxidative metabolites of alcohol [e.g. FAEEs (fatty acid ethyl esters)] and the ethanol-water competition mechanism are all involved in the deregulation of glycoconjugate (glycoprotein, glycolipid and proteoglycan) metabolic processes including biosynthesis, modification, transport, secretion, elimination and catabolism. An increasing number of new alcohol biomarkers that are the result of alcohol-induced glycoconjugate metabolic errors have appeared in the literature. Glycoconjugate-related alcohol markers are involved in, or are a product of, altered glycoconjugate metabolism, e.g. CDT (carbohydrate-deficient transferrin), SA (sialic acid), plasma SIJ (SA index of apolipoprotein J), CETP (cholesteryl ester transfer protein), beta-HEX (beta-hexosaminidase), dolichol, EtG (ethyl glucuronide) etc. Laboratory tests based on changes in glycoconjugate metabolism are useful in settings where the co-operativeness of the patient is impaired (e.g. driving while intoxicated) or when a history of alcohol use is not available (e.g. after trauma). In clinical practice, glycoconjugate markers of alcohol use/abuse let us distinguish alcoholic from non-alcoholic tissue damage, having important implications for the treatment and management of diseases. PMID- 21265806 TI - Glycans in melanoma screening. Part 1. The role of beta1,6-branched N-linked oligosaccharides in melanoma. AB - Melanoma, which is one of the most aggressive human tumours, originates from melanin-producing melanocytes. As no effective systemic therapy exists for advanced-stage melanoma, the best chance of recovery remains surgical removal of thin early-stage melanoma. Aberrant glycosylation is a hallmark of malignancy and a well-studied class of beta1,6-branched oligosaccharides is associated with malignant transformation of rodent and human cells, and poor prognosis in cancer patients. It is evident that increased beta1,6 branching significantly contributes to the phenotype of melanoma cells, influencing the adhesion to extracellular matrix components and motility as well as invasive and metastatic potential. Despite the considerable success in establishing the role of beta1,6 branched N-linked oligosaccharides in melanoma biology, there is virtually no progress in using these glycans as a screening tool for the early diagnosis of the disease, or a target-specific therapeutic agent. PMID- 21265807 TI - Glycans in melanoma screening. Part 2. Towards the understanding of integrin N glycosylation in melanoma. AB - Although melanoma is one of the most studied malignancies, it still remains challenging for biomedicine. Since aberrant glycosylation has been considered as an important hallmark of cancer for many years, melanoma glycomic studies give a chance of better understanding the biology of the disease. The multistage nature of melanoma development, which is accompanied by changes in the expression of adhesion receptors from the integrin family, provides a chance for searching for neoglycoforms of proteins that can be considered as future sensitive melanoma biomarkers. The beta1,6-branching, sialylation and fucosylation seem to be important modifications of integrin N-glycans in the case of malignant melanoma progression. PMID- 21265808 TI - The cellular microenvironment and cell adhesion: a role for O-glycosylation. AB - Glycosylation is one of the most abundant protein modifications in Nature, having roles in protein stability, secretion and function. Alterations in mucin-type O glycosylation are responsible for a number of human diseases and developmental defects, as well as associated with certain types of cancer. However, the mechanistic role of this form of glycosylation in many of these instances is unclear. Here we describe how one glycosyltransferase responsible for initiating mucin-type O-glycosylation (PGANT3), specifically modulates integrin-mediated cell adhesion by influencing the secretion and localization of an integrin ligand. The integrin ligand Tiggrin, is normally O-glycosylated and localized to the basal matrix, where adhesion of two opposing cell layers takes place. In pgant3 mutants, Tiggrin is no longer O-glycosylated and fails to be properly secreted to the basal cell layer interface, resulting in disruption of proper cell adhesion. pgant3-mediated effects are dependent on the enzymatic activity of PGANT3 and cannot be rescued by another pgant family member, indicating a unique role for this glycosyltransferase. These results provide in vivo evidence for the role of O-glycosylation in the secretion of specific extracellular matrix proteins, which thereby influences the composition of the cellular 'microenvironment' and modulates cell adhesion events. The studies described in this review provide insight into the long-standing association between aberrant O glycosylation and tumorigenesis, as changes in tumour environment and cell adhesion are hallmarks of cancer progression. PMID- 21265809 TI - Glycosaminoglycans as regulators of stem cell differentiation. AB - ES (embryonic stem) cell differentiation is dependent on the presence of HS (heparan sulfate). We have demonstrated that, during differentiation, the evolution of specific cell lineages is associated with particular patterns of GAG (glycosaminoglycan) expression. For example, different HS epitopes are synthesized during neural or mesodermal lineage formation. Cell lines mutant for various components of the HS biosynthetic pathway are selectively impaired in their differentiation, with lineage-specific effects observed for some lines. We have also observed that the addition of soluble GAG saccharides to cells, with or without cell-surface HS, can influence the pace and outcome of differentiation, again highlighting specific pattern requirements for particular lineages. We are combining this work with ongoing studies into the design of artificial cell environments where we have optimized three-dimensional scaffolds, generated by electrospinning or by the formation of hydrogels, for the culture of ES cells. By permeating these scaffolds with defined GAG oligosaccharides, we intend to control the mechanical environment of the cells (via the scaffold architecture) as well as their biological signalling environment (using the oligosaccharides). We predict that this will allow us to control ES cell pluripotency and differentiation in a three-dimensional setting, allowing the generation of differentiated cell types for use in drug discovery/testing or in therapeutics. PMID- 21265810 TI - Highly glycosylated tumour antigens: interactions with the immune system. AB - A common phenotypic change in cancer is a dramatic transformation of cellular glycosylation. Functional studies of particular tumour-associated oligosaccharides are difficult to interpret conclusively, but carbohydrate binding proteins are likely to contribute to progression of the tumour. This review discusses the potential role of CLRs (C-type lectin receptors), expressed by antigen-presenting cells of the immune system, in tumour recognition and immune modulation. Studies in recent years have provided significant insight into the immunomodulatory function of CLR during infections, but their role in cancer remains elusive; some strongly bind tumour cells and antigens, indicating participation in malignancy. The potential to use recombinant CLR as diagnostic tools will also be discussed. PMID- 21265811 TI - Urinary glycan markers for disease. AB - Robust assays for the isolation and characterization of urinary FOS (free oligosaccharides) have been developed to screen patients for altered protein and/or lipid glycosylation. A FOS analysis can therefore identify potential biomarkers for hepatocellular carcinoma, since variations in glycosylation as a result of tumorigenecity should be detectable in the FOS of patients. HCC (hepatocellular carcinoma) accounts for 80-90% of all liver cancers. It occurs more often in men than women and occurs mostly in people 50-60 years old. The disease is more common in parts of Africa and Asia than in North or South America and Europe. Using a combination of solid-phase extraction techniques and affinity chromatography, followed by separation of urinary FOS by NP (normal phase)-HPLC and HIAX (hydrophilic interaction and anion-exchange)-HPLC, more than 200 different species have been identified in patient samples. The high incidence of small sialylated oligosaccharides in HCC patients suggests that pro-inflammatory markers may be detected as early indicators of disease progression. In addition, the methods developed here to isolate and analyse excreted glycoprotein- and glycosphingolipid-bound oligosaccharides have been used to characterize changes in metabolic processes that underlie a number of human genetic disorders. The ability to predict disease status in microlitre amounts of readily available non invasive urine samples indicates that rapid methods for screening can be developed. PMID- 21265812 TI - Glycobiomarkers by glycoproteomics and glycan profiling (glycomics): emergence of functionality. AB - Glycans stand out from all classes of biomolecules because of their unsurpassed structural complexity. This is generated by variability in anomeric status of the glycosidic bond and its linkage points, ring size, potential for branching and introduction of diverse site-specific substitutions. What poses an enormous challenge for analytical processing is, at the same time, the basis for the fingerprint-like glycomic profiles of glycoconjugates and cells. What's more, the glycosylation machinery is sensitive to disease manifestations, earning glycan assembly a reputation as a promising candidate to identify new biomarkers. Backing this claim for a perspective in clinical practice are recent discoveries that even seemingly subtle changes in the glycan structure of glycoproteins, such as a N-glycan core substitution by a single sugar moiety, have far-reaching functional consequences. They are brought about by altering the interplay between the glycan and (i) its carrier protein and (ii) specific receptors (lectins). Glycan attachment thus endows the protein with a molecular switch and new recognition sites. Co-ordinated regulation of glycan display and presentation of the cognate lectin, e.g. in cancer growth regulation exerted by a tumour suppressor, further exemplifies the broad functional dimension inherent to the non-random shifts in glycosylation. Thus studies on glycobiomarkers converge with research on how distinct carbohydrate determinants are turned into bioactive signals. PMID- 21265813 TI - Exoglycosidase markers of diseases. AB - Exoglycosidases are hydrolases involved in lysosomal degradation of oligosaccharide chains of glycoconjugates (glycoproteins, glycolipids and proteoglycans). In tissues and body fluids, a higher exoglycosidase specific activity is found in N-acetyl-beta-hexosaminidase, than beta-glucuronidase, alpha L-fucosidase, beta-galactosidase, alpha-mannosidase and alpha-glucosidase. Determination of exoglycosidases (especially N-acetyl-beta-hexosaminidase and beta-glucuronidase) in body fluids could be an inexpensive, easy to perform and sensitive test for pathological evaluation, as well as in screening and monitoring many diseases, including alcohol abuse, risk of arteriosclerosis, bacterial infections (e.g. Lyme borreliosis), chronic inflammatory processes, such as rheumatoid arthritis and juvenile idiopathic arthritis, asthma, autoimmune hepatitis and primary biliary cirrhosis, as well as cancers. PMID- 21265816 TI - Probing cationic selectivity of cardiac calsequestrin and its CPVT mutants. AB - CASQ (calsequestrin) is a Ca2+-buffering protein localized in the muscle SR (sarcoplasmic reticulum); however, it is unknown whether Ca2+ binding to CASQ2 is due to its location inside the SR rich in Ca2+ or due to its preference for Ca2+ over other ions. Therefore a major aim of the present study was to determine how CASQ2 selects Ca2+ over other metal ions by studying monomer folding and subsequent aggregation upon exposure to alkali (monovalent), alkaline earth (divalent) and transition (polyvalent) metals. We additionally investigated how CPVT (catecholaminergic polymorphic ventricular tachycardia) mutations affect CASQ2 structure and its molecular behaviour when exposed to different metal ions. Our results show that alkali and alkaline earth metals can initiate similar molecular compaction (folding), but only Ca2+ can promote CASQ2 to aggregate, suggesting that CASQ2 has a preferential binding to Ca2+ over all other metals. We additionally found that transition metals (having higher co-ordinated bonding ability than Ca2+) can also initiate folding and promote aggregation of CASQ2. These studies led us to suggest that folding and formation of higher-order structures depends on cationic properties such as co-ordinate bonding ability and ionic radius. Among the CPVT mutants studied, the L167H mutation disrupts the Ca2+-dependent folding and, when folding is achieved by Mn2+, L167H can undergo aggregation in a Ca2+-dependent manner. Interestingly, domain III mutants (D307H and P308L) lost their selectivity to Ca2+ and could be aggregated in the presence of Mg2+. In conclusion, these studies suggest that CPVT mutations modify CASQ2 behaviour, including folding, aggregation/polymerization and selectivity towards Ca2+. PMID- 21265817 TI - Postoperative transient tetraplegia in two patients caused by cervical spondylotic myelopathy. AB - We report two patients with cervical spondylotic myelopathy following non cervical spine surgery. These cases revealed postoperative transient tetraplegia with respiratory insufficiency despite optimal anaesthetic management. Both patients showed no limitation of their neck movement at pre-operative airway examination. In addition, their necks had never been overextended during anaesthesia including tracheal intubation. However, postoperative magnetic resonance imaging showed cervical spondylotic myelopathy. Cervical disc herniation and protrusion of a hypertrophic ligamentum flavum caused spinal canal cord compression, and, these may lead to tetraplegia and phrenic nerve impairment. Their muscle weakness gradually improved and completely recovered the following morning. We should consider the existence of cervical spondylosis in the elderly patients over the age of 60 years. PMID- 21265818 TI - The effect of neuromuscular blockade on mask ventilation. AB - We wished to test the hypothesis that neuromuscular blockade facilitates mask ventilation. In order reliably and reproducibly to assess the efficiency of mask ventilation, we developed a novel grading scale (Warters scale), based on attempts to generate a standardised tidal volume. Following induction of general anaesthesia, a blinded anaesthesia provider assessed mask ventilation in 90 patients using our novel grading scale. The non-blinded anaesthesiologist then randomly administered rocuronium or normal saline. After 2 min, mask ventilation was reassessed by the blinded practitioner. Rocuronium significantly improved ventilation scores on the Warters scale (mean (SD) 2.3 (1.6) vs 1.2 (0.9), p<0.001). In a subgroup of patients with a baseline Warters scale value of >3 (i.e. difficult to mask ventilate; n=14), the ventilation scores also showed significant improvement (4.2 (1.2) vs 1.9 (1.0), p=0.0002). Saline administration had no effect on ventilation scores. Our data indicate that neuromuscular blockade facilitates mask ventilation. We discuss the implications of this finding for unexpected difficult airway management and for the practice of confirming adequate mask ventilation before the administration of neuromuscular blockade. PMID- 21265821 TI - Low dose intravenous bevacizumab for the treatment of anaemia in hereditary haemorrhagic telangiectasia. PMID- 21265822 TI - Mott cells in CD20-positive myeloma. PMID- 21265823 TI - PPARdelta agonists have opposing effects on insulin resistance in high fat-fed rats and mice due to different metabolic responses in muscle. AB - BACKGROUND AND PURPOSE: The peroxisome proliferator-activated receptor (PPAR)delta has been considered a therapeutic target for diabetes and obesity through enhancement of fatty acid oxidation. The present study aimed to characterize the effects of PPARdelta agonists during insulin resistance of the whole body, muscle and liver. EXPERIMENTAL APPROACH: Wistar rats and C57BL/J6 mice were fed a high fat diet (HF) and then treated with PPARdelta agonists NNC61 5920 and GW501516. The effects on insulin resistance were evaluated by hyperinsulinaemic clamp or glucose tolerance tests combined with glucose tracers. KEY RESULTS: In HF rats, 3 weeks of treatment with NNC61-5920 reduced the glucose infusion rate (by 14%, P < 0.05) and glucose disposal into muscle (by 20-30%, P < 0.01) during hyperinsulinaemic clamp. Despite increased mRNA expression of carnitine palmitoyltransferase-1, pyruvate dehydrogenase kinase 4 and uncoupling protein 3 in muscle, plasma and muscle triglyceride levels were raised (P < 0.01). Similar metabolic effects were observed after extended treatment with NNC61-5920 and GW501516 to 6 weeks. However, HF mice treated with NNC61-5920 improved their plasma lipid profile, glucose tolerance and insulin action in muscle. In both HF rats and mice, NNC61-5920 treatment attenuated hepatic insulin resistance and decreased expression of stearoyl-CoA desaturase 1, fatty acid translocase protein CD36 and lipoprotein lipase in liver. CONCLUSIONS AND IMPLICATIONS: PPARdelta agonists exacerbated insulin resistance in HF rats in contrast to their beneficial effects on metabolic syndrome in HF mice. These opposing metabolic consequences result from their different effects on lipid metabolism and insulin sensitivity in skeletal muscle of these two species. PMID- 21265824 TI - Contribution of Rho-kinase to membrane excitability of murine colonic smooth muscle. AB - BACKGROUND AND PURPOSE: The Rho-kinase pathway regulates agonist-induced contractions in several smooth muscles, including the intestine, urinary bladder and uterus, via dynamic changes in the Ca(2+) sensitivity of the contractile apparatus. However, there is evidence that Rho-kinase also modulates other cellular effectors such as ion channels. EXPERIMENTAL APPROACH: We examined the regulation of colonic smooth muscle excitability by Rho-kinase using conventional microelectrode recording, isometric force measurements and patch-clamp techniques. KEY RESULTS: The Rho-kinase inhibitors, Y-27632 and H-1152, decreased nerve-evoked on- and off-contractions elicited at a range of frequencies and durations. The Rho-kinase inhibitors decreased the spontaneous contractions and the responses to carbachol and substance P independently of neuronal inputs, suggesting Y-27632 acts directly on smooth muscle. The Rho-kinase inhibitors significantly reduced the depolarization in response to carbachol, an effect that cannot be due to regulation of Ca(2+) sensitization. Patch-clamp experiments showed that Rho-kinase inhibitors reduce GTPgammaS-activated non-selective cation currents. CONCLUSIONS AND IMPLICATIONS: The Rho-kinase inhibitors decreased contractions evoked by nerve stimulation, carbachol and substance P. These effects were not solely due to inhibition of the Ca(2+) sensitization pathway, as the Rho-kinase inhibitors also inhibited the non-selective cation conductances activated by excitatory transmitters. Thus, Rho-kinase may regulate smooth muscle excitability mechanisms by regulating non-selective cation channels as well as changing the Ca(2+) sensitivity of the contractile apparatus. PMID- 21265825 TI - Honokiol ameliorates renal fibrosis by inhibiting extracellular matrix and pro inflammatory factors in vivo and in vitro. AB - BACKGROUND AND PURPOSE: Renal fibrosis acts as the common pathway leading to the development of end-stage renal disease. The present study investigated, in vivo and in vitro, the anti-fibrotic and anti-inflammatory effects, particularly on the epithelial to mesenchymal transition of renal tubular cells, exerted by honokiol, a phytochemical used in traditional medicine, and mechanisms underlying these effects. EXPERIMENTAL APPROACH: Anti-fibrotic effects in vivo were assayed in a rat model of renal fibrosis [the unilateral ureteral obstruction (UUO) model]. A rat tubular epithelial cell line (NRK-52E) was stimulated by transforming growth factor-beta1 (TGF-beta1) and treated with honokiol to explore possible mechanisms of these anti-fibrotic effects. Gene or protein expression was analysed by Northern or Western blotting. Transcriptional regulation was investigated using luciferase activity driven by a connective tissue growth factor (CTGF) promoter. KEY RESULTS: Honokiol slowed development of renal fibrosis both in vivo and in vitro. Honokiol treatment attenuated tubulointerstitial fibrosis and expression of pro-fibrotic factors in the UUO model. Honokiol also decreased expression of the mRNA for the chemokine CCL2 and for the intracellular adhesion molecule-1, as well as accumulation of type I (alpha1) collagen and fibronectin in UUO kidneys. Phosphorylation of Smad-2/3 induced by TGF-beta1 and CTGF luciferase activity in renal tubular cells were also inhibited by honokiol. CONCLUSIONS AND IMPLICATIONS: Honokiol suppressed expression of pro-fibrotic and pro-inflammatory factors and of extracellular matrix proteins. Honokiol may become a therapeutic agent to prevent renal fibrosis. PMID- 21265826 TI - Hesperedin promotes MyoD-induced myogenic differentiation in vitro and in vivo. AB - BACKGROUND AND PURPOSE: The bioflavonoid, hesperedin, promotes osteoblast differentiation in human mesenchymal stem cells, indicating an anabolic effect of hesperedin on bone metabolism. Murine bone marrow mesenchymal stem cells undergo myogenic differentiation as well as osteogenic differentiation. We therefore explored whether hesperedin modulates muscle cell differentiation. EXPERIMENTAL APPROACH: Myoblast C2C12 cells were differentiated into muscle cells in the presence or absence of hesperedin. The effects of hesperedin on myogenic differentiation were determined by analysing specific muscle markers in vitro using reporter gene assays, immunoblotting, RT-PCR and DNA pull-down assays. In vivo, the effects of hesperedin were assessed using the freeze injury-induced muscle regeneration model in mice and daily injections of hesperedin for 6 days. KEY RESULTS: Hesperedin promoted myogenic differentiation, in a dose-dependent manner, by increasing myogenin gene expression. MyoD-induced myogenin gene transcription was enhanced by hesperedin, as this bioflavonoid augmented the nuclear localization and myogenin promoter-binding of MyoD. In addition, hesperedin increased myogenin and muscle creatine kinase gene expression during myogenic differentiation from C3H10T1/2 mesenchymal stem cells in a MyoD dependent manner and accelerated in vivo muscle regeneration induced by muscle injury. CONCLUSIONS AND IMPLICATIONS: Our results demonstrate that hesperedin promoted myogenic differentiation in vitro and in vivo through activation of MyoD mediated myogenin expression, suggesting a beneficial role in promoting muscle regeneration, following injury. PMID- 21265827 TI - Pharmacological modulation of connexin-formed channels in cardiac pathophysiology. AB - Coordinated electrical activity in the heart is supported by gap junction channels located at the intercalated discs of cardiomyocytes. Impaired gap junctional communication between neighbouring cardiomyocytes contributes to the development of re-entry arrhythmias after myocardial ischaemia. Current antiarrhythmic therapy is hampered by a lack of efficiency and side effects, creating the need for a new generation of drugs. In this review, we focus on compounds that increase gap junctional communication, thereby increasing the conduction velocity and decreasing the risk of arrhythmias. Some of these compounds also inhibit connexin 43 (Cx43) hemichannels, thereby limiting adenosine triphosphate loss and volume overload following ischaemia/reperfusion, thus potentially increasing the survival of cardiomyocytes. The compounds discussed in this review are: (i) antiarrythmic peptide (AAP), AAP10, ZP123; (ii) GAP-134; (iii) RXP-E; and (vi) the Cx mimetic peptides Gap 26 and Gap 27. None of these compounds have effects on Na(+) , Ca(2+) and K(+) channels, and therefore have no proarrhythmic activity associated with currently available antiarrhythmic drugs. GAP-134, RXP-E, Gap 26 and Gap 27 are pharmalogical agents with a favorable clinical safety profile, as already confirmed in phase I clinical trials for GAP-134. These agents show an excellent promise for treatment of arrhythmias in patients with ischaemic cardiomyopathy. PMID- 21265828 TI - The utility of animal models to evaluate novel anti-obesity agents. AB - The global incidence of obesity continues to rise and is a major driver of morbidity and mortality through cardiovascular and cerebrovascular diseases. Animal models used in the discovery of novel treatments for obesity range from straightforward measures of food intake in lean rodents to long-term studies in animals exhibiting obesity due to the continuous access to diets high in fat. The utility of these animal models can be extended to determine, for example, that weight loss is due to fat loss and/or assess whether beneficial changes in key plasma parameters (e.g. insulin) are evident. In addition, behavioural models such as the behavioural satiety sequence can be used to confirm that a drug treatment has a selective effect on food intake. Typically, animal models have excellent predictive validity whereby drug-induced weight loss in rodents subsequently translates to weight loss in man. However, despite this, at the time of writing orlistat (Europe; USA) remains the only drug currently marketed for the treatment of obesity, with sibutramine having recently been withdrawn from sale globally due to the increased incidence of serious, non-fatal cardiovascular events. While the utility of rodent models in predicting clinical weight loss is detailed, the review also discusses whether animals can be used to predict adverse events such as those seen with recent anti-obesity drugs in the clinic. PMID- 21265829 TI - Is a regenerative approach viable for the treatment of COPD? AB - Degenerative lung diseases such as chronic obstructive pulmonary disease (COPD) are common with huge worldwide morbidity. Anti-inflammatory drug development strategies have proved disappointing and current treatment is aimed at symptomatic relief. Only lung transplantation with all its attendant difficulties offers hope of cure and the outlook for affected patients is bleak. Lung regeneration therapies aim to reverse the structural and functional deficits in COPD either by delivery of exogenous lung cells to replace lost tissue, delivery of exogenous stem cells to induce a local paracrine effect probably through an anti-inflammatory action or by the administration of small molecules to stimulate the endogenous regenerative ability of lung cells. In animal models of emphysema and disrupted alveolar development each of these strategies has shown some success but there are potential tumour-inducing dangers with a cellular approach. Small molecules such as all-trans retinoic acid have been successful in animal models although the mechanism is not completely understood. There are currently two Pharma-sponsored trials in progress concerning patients with COPD, one of a specific retinoic acid receptor gamma agonist and another using mesenchymal stem cells. PMID- 21265831 TI - Regeneration of the perineurium after microsurgical resection examined with immunolabeling for tenascin-C and alpha smooth muscle actin. AB - The regenerative process of the perineurium and nerve function were examined using an in vivo model of perineurium resection in the rat sciatic nerve. Our hypothesis is that the regenerative process of the perineurium can be demonstrated by immunolabeling for tenascin-C and alpha smooth muscle actin after microsurgical resection of the perineurium in vivo. A total of 38 Lewis rats were used. Eight-week-old animals were assigned to one of two groups: the epi perineurium removal group or the sham group. Under operative microscopy, the sciatic nerve was dissected from surrounding tissues at the thigh level from the ischial tuberosity to the fossa poplitea. The epi-perineurium was carefully removed by cutting circumferentially and stripping distally for 15 mm. For CatWalk(r) dynamic gait analysis, only right sciatic nerves underwent surgery; the left sciatic nerves were left intact. For pathological and electrophysiological tests, both the right and left sciatic nerves underwent surgery. Analysis of data was performed at each time interval with a two-group t test. P<0.05 was considered statistically significant. After resection of a 15-mm section of the epi-perineurium, immediate endoneurial swelling occurred in the outer portion and spread into the central portion. Although demyelination and axonal degeneration were found in the swollen area, remyelination and recovery of electrophysiological function were seen after regeneration of the perineurium. An immunohistological and electron microscopic study revealed that the perineurium regenerated via fusion of the residual interfascicular perineurium and endoneurial fibroblast-like cells of mesenchymal origin. CatWalk gait analysis showed not only motor paresis but also neuropathic pain during the early phases of this model. PMID- 21265832 TI - Differentiation of unevaporated gasoline samples according to their brands, by SPME-GC-MS and multivariate statistical analysis. AB - One of the aims of fire investigations is to identify associations among accelerants according to their source. In this study, 50 gasoline samples- representing five brands--were analyzed using solid-phase microextraction (SPME) and gas chromatography-mass spectrometry (GC-MS). Chemometric procedures, such as principal component analysis (PCA) and discriminant analysis (DA), were applied to a data matrix obtained by the target compound chromatogram method, to discriminate samples according to their brand. PCA was successful in finding a natural grouping of samples according to their brand, suggesting that aromatic compounds were more useful than aliphatics for the purpose of this study. DA, if applied to aromatic compounds, gave both a classification ability and a prediction ability of 100%. The outstanding results obtained by this work provide the basis of a data matrix that could be used in real cases of arson to link a sample of unevaporated gasoline to its brand or refinery. PMID- 21265833 TI - Laser desorption/ionization time-of-flight mass spectrometry of triacylglycerols and other components in fingermark samples. AB - The chemical composition of fingermarks could potentially be important for determining investigative leads, placing individuals at the time of a crime, and has applications as biomarkers of disease. Fingermark samples containing triacylglycerols (TAGs) and other components were analyzed using laser desorption/ionization (LDI) time-of-flight mass spectrometry (TOF MS). Only LDI appeared to be useful for this application while conventional matrix-assisted LDI TOF MS was not. Tandem MS was used to identify/confirm selected TAGs. A limited gender comparison, based on a simple t-distribution and peaks intensities, indicated that two TAGs showed gender specificity at the 95% confidence level and two others at 97.5% confidence. Because gender-related TAGs differences were most often close to the standard deviation of the measurements, the majority of the TAGs showed no gender specificity. Thus, LDI-TOF MS is not a reliable indicator of gender based on fingermark analysis. Cosmetic ingredients present in some samples were identified. PMID- 21265834 TI - Fatal accidental hanging by a high-chair waist strap in a 2-year-old girl. AB - High chairs are commonly used to feed children after 6 months. Related injuries are oftentime minor and rarely leading to death. We describe a case of a 2-year old female child who used to jump alone on her high chair and also had the habit to fasten the straps by herself. Her mother found her hanging by the waist straps. A thorough investigation showed that she climbed her high chair and fastened the waist straps but not the crotch one. The girl slid down into the seat, trapping her neck in the waist straps and thus resulting in hanging. In here, we concluded that the victim's death was caused by asphyxia, itself, caused by accidental hanging. The present case is of a special interest because of the rare similar cases reported. This case suggests that a correct restraint use and a close supervision would have prevented such a fatal issue. PMID- 21265835 TI - A re-examination of cremains weight: sex and age variation in a Northern California sample. AB - The reduction of modern commercially cremated remains into a fine powder negates the use of traditional methods of skeletal analysis. The literature on the use of cremains weight for estimating aspects of the biologic profile is limited, often with conflicting results. This study re-evaluates the value of weight in the assessment of biologic parameters from modern cremated remains. A sample of adults was collected in northern California (n = 756), with a cremains weight averaging 2737.1 g. Males were significantly heavier than females (mean = 3233.2 g versus mean = 2238.3 g, respectively; p<0.001). Comparison of this sample with other previously reported samples from southern California, Florida, and Tennessee indicates a consistent sex difference, with the most similar mean values to the Tennessee study. Although cremains weight decreases with age as expected, the relationship is weak; thus, cremains weight cannot accurately predict age-at-death. While sex estimation shows considerable accuracy (86.3% for males and 80.9% for females), sectioning points may be population specific. PMID- 21265830 TI - Novel therapeutic approaches for pulmonary fibrosis. AB - Pulmonary fibrosis represents the end stage of a number of heterogeneous conditions and is, to a greater or lesser degree, the hallmark of the interstitial lung diseases. It is characterized by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium leading to the obliteration of functional alveolar units and in many cases, respiratory failure. While a small number of interstitial lung diseases have known aetiologies, most are idiopathic in nature, and of these, idiopathic pulmonary fibrosis is the most common and carries with it an appalling prognosis - median survival from the time of diagnosis is less than 3 years. This reflects the lack of any effective therapy to modify the course of the disease, which in turn is indicative of our incomplete understanding of the pathogenesis of this condition. Current prevailing hypotheses focus on dysregulated epithelial-mesenchymal interactions promoting a cycle of continued epithelial cell injury and fibroblast activation leading to progressive fibrosis. However, it is likely that multiple abnormalities in a myriad of biological pathways affecting inflammation and wound repair - including matrix regulation, epithelial reconstitution, the coagulation cascade, neovascularization and antioxidant pathways - modulate this defective crosstalk and promote fibrogenesis. This review aims to offer a pathogenetic rationale behind current therapies, briefly outlining previous and ongoing clinical trials, but will focus on recent and exciting advancements in our understanding of the pathogenesis of idiopathic pulmonary fibrosis, which may ultimately lead to the development of novel and effective therapeutic interventions for this devastating condition. PMID- 21265836 TI - Evaluation of the adjudicated incest cases in Turkey: difficulties in notification of incestuous relationships. AB - The aim of this study was to determine the prevalence and evaluation of the adjudicated incest cases in the heavy penal court in a province of western Turkey. The court files of 65 incest cases during a 10-year period between 1999 and 2008 were explored. When compared to those who lived in cities, the cases who lived in rural areas, such as villages or towns, had been exposed to penetration more frequently (94.3% and 70.0%, respectively, p<0.01). For the cases where the victim and perpetrator lived in the same house, the accused were generally members of the nuclear family (p<0.001). When compared to those who had not been exposed to penetration, most of those who had been exposed to it were determined to apply later (after 10 days) to judicial institutions (77.8%, p<0.01). The education and awareness of persons, such as teachers and physicians, who may confront incestuous relationships rather frequently are very important in the protection of children and in their adaptation to society. PMID- 21265837 TI - Discriminant function analysis for sex assessment in pelvic girdle bones: sample from the contemporary Mexican population. AB - Sex assessment of skeletal remains plays an important role in forensic anthropology. The pelvic bones are the most studied part of the postcranial skeleton for the assessment of sex. It is evident that a population-specific approach improves rates of accuracy within the group. The present study proposes a discriminant function method for the sex assessment of skeletal remains from a contemporary Mexican population. A total of 146 adult human pelvic bones (61 females and 85 males) from the skeletal series pertaining to the National Autonomous University of Mexico were evaluated. Twenty-four direct metrical parameters of coxal and sacral bones were measured and subsequently, sides and sex differences were evaluated, applying a stepwise discriminant function analysis. Coxal and sacra functions achieved accuracies of 99% and 87%, respectively. These analyses follow a population-specific approach; nevertheless, we consider that our results are applicable to any other Hispanic samples for purposes of forensic human identification. PMID- 21265838 TI - Prevalence of delusional jealousy in psychiatric disorders. AB - Delusional jealousy is a known risk factor for violence and homicide, but little is known about its prevalence in psychiatric disorders. We therefore reviewed retrospectively the psychopathological symptoms at admission and discharge, assessed with the AMDP system, of all patients admitted to the Psychiatric Hospital, University of Munich, Germany, from January 2000 through December 2008 (n=14,309). We identified 72 cases of delusional jealousy (0.5% of the whole sample). The prevalence was highest in schizophrenia and other psychoses (1.3%), and more of the patients with delusional jealousy were men (43 of 72, 59.7%). One fifth (15 of 72, 20.8%) of the patients with delusional jealousy were aggressive at admission (vs. 6.2% of the total sample). We conclude that delusional jealousy is a comparatively rare phenomenon that is most frequent in schizophrenia and related psychoses. Quite a number of affected patients are aggressive, which may indicate a risk of future violence. PMID- 21265839 TI - Assessment of approximate likelihood ratios from continuous distributions: a case study of digital camera identification. AB - A reported likelihood ratio for the value of evidence is very often a point estimate based on various types of reference data. When presented in court, such frequentist likelihood ratio gets a higher scientific value if it is accompanied by an error bound. This becomes particularly important when the magnitude of the likelihood ratio is modest and thus is giving less support for the forwarded proposition. Here, we investigate methods for error bound estimation for the specific case of digital camera identification. The underlying probability distributions are continuous and previously proposed models for those are used, but the derived methodology is otherwise general. Both asymptotic and resampling distributions are applied in combination with different types of point estimators. The results show that resampling is preferable for assessment based on asymptotic distributions. Further, assessment of parametric estimators is superior to evaluation of kernel estimators when background data are limited. PMID- 21265840 TI - Fatal suicidal crossbow injury--the ability to act. AB - We report a case of a 58-year-old man who committed suicide using a modern crossbow. The victim shot himself in the chest with a conical field-tip arrow from close proximity. We first presumed that this was a case of homicide committed with a firearm. We were, however, subsequently proved wrong. The reasons for the primary statement were as follows: the external morphology of the entrance wound being typical of a firearm discharged from long distance; the perforation found on the victim's clothing; the absence of the firearm at the place of death; the absence of the arrow in the wound. All of these reasons forced us initially to conclude that the case was one of homicide. In the reported case, the man, after having been shot with an arrow, was further able to act, even though the abdominal aorta and liver were seriously injured. While the arrow was in the wound, the injuries may not have led to massive bleeding because of incomplete tamponade of the defects by the arrow shaft. Pulling the arrow out of the victim's wound track initiated massive bleeding. Despite all these injuries, the man was capable of pulling the bow string again and reloading the crossbow with the arrow used in the first attempt. This case demonstrates that forensic investigations into crossbow injuries can be very difficult, especially when the bolt has been removed from the body. PMID- 21265841 TI - Sudden death owing to right atrial hemangioma. AB - Primary cardiac tumors are rare, with an autopsy incidence of 0.03%. Seventy-nine percent to 85% of primary cardiac tumors are benign, and of the benign tumors, cardiac hemangiomas account for 5-10% of cases. Most cardiac hemangiomas are asymptomatic and are discovered incidentally at autopsy, or by echocardiography, computerized tomography, or magnetic resonance imaging. We report a case of sudden death owing to cardiac hemangioma in a 22-year-old woman who collapsed while shopping and became unresponsive. The autopsy revealed a hemorrhagic mass on the surface of the right atrium which was infiltrating and replacing the wall of the right atrium; histopathological examination confirmed the tumor was a cavernous hemangioma. Fewer than 20 cases of right atrial cavernous hemangiomas have been reported in English literature, emphasizing the rarity of our case. PMID- 21265843 TI - Significant association of TH01 allele 9.3 and SIDS. AB - Sudden infant death syndrome (SIDS) constitutes a considerable percentage of infant death of unknown etiology. Individual catecholamine response variation is suspected to play a role in SIDS. TH01 is a tetrameric short tandem repeat marker in the tyrosine hydroxylase gene, which regulates gene expression and catecholamine production with allele 9.3 exerting a particularly strong effect on noradrenaline production. We investigated in an age-controlled study the TH01 allele frequencies in 127 cases of SIDS and 406 control cases to assess whether in SIDS cases a distinct TH01 allele distribution could be determined as has been reported by a previous study. We found that genotypes containing one or two 9.3 alleles were significantly more frequent in SIDS patients (58.2%) than in control subjects (48.4%, p=0.038), whereas all other alleles were more frequent in the control subjects. Our findings support the notion that there exists a significant association between TH01 gene configuration and SIDS. PMID- 21265842 TI - Ethical and legal consideration of prisoner's hunger strike in Serbia. AB - Hunger strike of prisoners and detainees remains a major human rights and ethical issue for medical professionals. We are reporting on a case of a 48-year-old male sentenced prisoner, intravenous heroin user, who went on a hunger strike and died 15 days later. Throughout the fasting period, the prisoner, who was capable of decision making, refused any medical examination. Autopsy findings were not supporting prolonged starvation, while toxicology revealed benzodiazepines and opiates in blood and urine. Cause of death was given as "heroin intoxication" in keeping with detection of 6-MAM. Legal and ethical issues pertinent to medical examination and treatment of prisoners on hunger strike are explored in accordance with legislation and professional ethical standards in Serbia. A recommendation for the best autopsy practice in deaths following hunger strike has been made. PMID- 21265844 TI - Expression and function of C5a receptor in a fatal anaphylaxis after honey bee sting. AB - The mechanisms leading to death from anaphylaxis after insect sting involve antigen cross-linkage of antibody molecules that activate immunoglobulin receptors on inflammatory cells. The aim of our study was to investigate the pathomorphology and the expression of C5aR in fatal anaphylaxis in a patient after a fatal insect sting. A 38-year-old women was stung by a honeybee. C5R1 expression was detected in many dilated capillaries in the lungs. Pulmonary epithelial cells did not bind the monoclonal antibody for C5R1; however, intensive cytoplasmic staining was detected in endothelial cells. The findings of this case provide evidence for an active role of complement in fatal anaphylaxis elicited by bee venom. C5aR detection could be useful in the identification of sudden death cases because of unwitnessed fatal insect sting cases. Authors can recommend this immunohistochemical analysis on all sudden unexpected deaths outdoors where a possible bee sting might occur. PMID- 21265845 TI - Exotic pets: the state of the art. PMID- 21265846 TI - Immunomodulatory drugs and their application to the management of canine immune mediated disease. AB - This review summarises the current understanding of immune response and T cell subsets in the context of development of autoimmunity in the dog. Mode of action and rational usage in immune-mediated disease in the dog are discussed for the following drugs: glucocorticoids, azathioprine, cyclophosphamide, ciclosporin, tacrolimus, human intravenous immunoglobulin, vincristine, danazol, leflunomide, mycophenolate mofetil and liposome-encapsulated clodronate. Disease mechanisms are discussed and published evidence for drug efficacy is scrutinised for five important immune-mediated diseases: immune-mediated haemolytic anaemia, immune mediated thrombocytopenia, myasthenia gravis, glomerulonephritis and inflammatory bowel disease. Future strategies for more refined manipulation of adverse immune responses are presented. PMID- 21265847 TI - Validity, practical utility and reliability of Actigraph accelerometry for the measurement of habitual physical activity in dogs. AB - OBJECTIVES: To test the validity, practical utility, and reliability of the Actigraph GT3-X accelerometer for measurement of habitual physical activity in pet dogs. METHODS: In the validation study, 30 dogs wore the accelerometer for 1 day while being filmed. Accelerometer and film were synchronised and 10-minute periods of the filmed records were extracted with dogs in continuous periods of sedentary behaviour, light intensity physical activity indoors, light to moderate intensity physical activity outdoors and vigorous physical activity outdoors. For the practical utility and reliability studies, 20 dogs wore the GT3-X accelerometers for 1 week: practical utility was quantified as data loss and was also assessed by owner questionnaire; reliability was determined by 2 to 7 days of monitoring using the Spearman-Brown prophecy formula. RESULTS: In the validation study, accelerometry output differed significantly between activity intensities (Friedman test, P<0.01). In the practical utility study, no data were lost from any dogs and dog owners reported that accelerometry was well tolerated. Reliability of accelerometry output was high: for 3 days of wear, it was 91% [95% confidence interval (CI) 82 to 96] and for 7 days of wear, it was 94% (CI 88 to 97). CLINICAL SIGNIFICANCE: The GT3-X accelerometer is valid, practical and reliable for the measurement of habitual physical activity in dogs. PMID- 21265848 TI - Clinical characteristics, management and long-term outcome of suspected rapid eye movement sleep behaviour disorder in 14 dogs. AB - OBJECTIVE: To describe the clinical characteristics, management and long-term outcome in dogs with suspected rapid eye movement sleep behaviour disorder. METHOD: Medical records and video recordings of 14 dogs with suspected rapid eye movement sleep behaviour disorder were reviewed and the owners were contacted via telephone or email for further information. RESULTS: Clinical signs included episodes of violent limb movements, howling, barking, growling, chewing, or biting during sleep. Episodes occurred at night and during daytime naps. The age at onset ranged from 8 weeks to 7.5 years with a median of 6 years but 64% of dogs were one year or less. There was no apparent sex or breed predisposition. Rapid eye movement sleep behaviour disorder events were reduced in severity and frequency in 78% of the dogs treated with 40 mg/kg/day oral potassium bromide. One dog was euthanized within 3 months of the onset of signs because of their severity. The duration of the disorder in the 13 surviving dogs ranged from 1.5 to 9 years. None of the dogs spontaneously recovered. CLINICAL SIGNIFICANCE: Rapid eye movement sleep behaviour disorder is suspected to occur in dogs, as it does in human beings. It causes concern to the owners and disrupts the home environment. Unlike human beings, rapid eye movement sleep behaviour disorder of dogs often has a juvenile onset. PMID- 21265849 TI - The prevalence of hypocobalaminaemia in cats with spontaneous hyperthyroidism. AB - OBJECTIVES: To determine the prevalence of hypocobalaminaemia in cats with moderate to severe hyperthyroidism and to investigate the relationship between cobalamin status and selected haematologic parameters. METHODS: Serum cobalamin concentrations were measured in 76 spontaneously hyperthyroid cats [serum thyroxine (T(4) ) concentration >=100 nmol/L] and 100 geriatric euthyroid cats. Erythrocyte and neutrophil counts in hyperthyroid cats with hypocobalaminaemia were compared with those in hyperthyroid cats with adequate serum cobalamin concentrations (>=290 ng/L). RESULTS: The median cobalamin concentration in hyperthyroid cats was lower than the control group (409 versus 672 ng/L; P=0.0040). In addition, 40.8% of hyperthyroid cats had subnormal serum cobalamin concentrations compared with 25% of controls (P=0.0336). Weak negative correlation (coefficient: -0.3281) was demonstrated between serum cobalamin and T(4) concentrations in the hyperthyroid population, and the median cobalamin concentration was lower in cats with T(4) above the median of 153 nmol/L compared with cats with T(4) below this value (P=0.0281). Hypocobalaminaemia was not associated with neutropenia or anaemia in hyperthyroid cats. CLINICAL SIGNIFICANCE: This study indicates that a substantial proportion of cats with T(4) >=100 nmol/L are hypocobalaminaemic and suggests that hyperthyroidism directly or indirectly affects cobalamin uptake, excretion or utilisation in this species. PMID- 21265850 TI - Diseases in pet degus: a retrospective study in 300 animals. AB - INTRODUCTION: Degus are commonly used as laboratory animals; however, over the past few years, they have become increasingly popular as pets. OBJECTIVES: The aim of this article was to present disease prevalence in 300 pet degus divided in two age groups (under and above two years). METHODS: Medical records of degus (Octodon degus), which were presented to the author's clinic in the period from January 2007 to December 2009, were reviewed. RESULTS: The most common diseases in degus were (1) acquired dental disease (60.0%) with significantly higher prevalence in older animals (P<0.001), (2) skin alopecia due to fur chewing (13.33%) and (3) lens cataracts (13.33%). Other common disorders included traumatic injuries to soft tissues (bite wounds and tail slip), traumatic fractures and dietary diarrhoea. Reproductive disorders were most commonly associated with dystocia and pathological changes in the post-natal period. Only 38 degus in a total of 300 animals were healthy. CLINICAL SIGNIFICANCE: This is the first study to describe the disease prevalence in two age groups of pet degus. The majority of diseases were caused by improper diet, self-mutilation and improper handling; as such client education is necessary to avoid such a high disease prevalence. PMID- 21265851 TI - Cannabis intoxication in three Green iguanas (Iguana iguana). AB - This report describes clinical signs and plasma biochemical changes associated with significant cannabis consumption in three Green iguanas (Iguana iguana) which resulted in seizures, cardiovascular and digestive tract aberrations, elevated hepatic enzymes and bile acid concentrations for a number of weeks post recovery. One case required extensive antiseizuring therapy to recover. All Green iguanas eventually made a full recovery. PMID- 21265852 TI - Nasal dermoid cyst extending through the frontal bone with no sinus tract in a Dalmatian. AB - A Dalmatian was presented with a subcutaneous swelling in the dorsal midline between the eyes. No opening in the skin was identified at the dorsal nasal planum and there was no discharge. Positive contrast sinography showed contrast material filling a cyst that extended to the frontal bone. At surgery, the cyst had a tubular shape and was embedded in a fibrous dermal tissue strand running into the bony nasal septum. The nasal dermoid sinus cyst was surgically removed by limited dorsal rhinotomy, followed by excision of the remaining strand from a bony recess in the lamina perpendicularis ethmoidalis. It is proposed that this nasal dermoid cyst that extends through the frontal bone with no sinus tract is classified as a type V subtype c. PMID- 21265853 TI - Uterine leiomyosarcoma and pyometra in a dog. AB - A seven-year-old entire female, mixed-breed dog, weighing 19 kg, was presented with a 2-day history of abdominal distension, reduced appetite and general dullness. Abdominal palpation revealed a large mass. Radiography showed a large mass occupying the left mid-abdominal area and convoluted loops of tubular fluid opacity occupying the right mid-abdominal area. Ultrasonography revealed a large heterogeneous mass with an anechoic area and some hyperechoic foci, indicative of calcification, in the mid-abdominal area. Furthermore, hypoechoic areas were found in the middle and caudal abdominal area and were presumed to be the fluid filled uterine horns. At laparotomy, a 10.5*14.5-cm firm mass was found in the uterine body, while the uterine horns were filled with a thick red-brownish exudate; ovariohysterectomy was subsequently performed. A diagnosis of uterine leiomyosarcoma associated with pyometra was established by histopathology and immunohistochemistry. PMID- 21265856 TI - Time perception in response to ashamed faces in children and adults. AB - The present study investigated the effect of the perception of faces expressing shame on time perception in children aged 5 and 8 years, as well as in adults, as a function of their ability to recognize this emotional expression. The participants' ability to recognize the expression of shame among faces expressing different emotions was tested. They were then asked to perform a temporal bisection task involving both neutral and ashamed faces. The results showed that, from the age of 8 years, the participants who recognized the facial expressions of shame underestimated their presentation time compared to that of neutral faces. In contrast, no time distortion was observed in the children who did not recognize the ashamed faces or in those younger children who did recognize them. The results are discussed in terms of self-conscious emotions which develop to involve an attentional mechanism. PMID- 21265857 TI - Gender differences in subjective well-being, self-esteem and psychosocial functioning in adolescents with symptoms of anxiety and depression: findings from the Nord-Trondelag Health Study. AB - Gender differences in the prevalence of symptoms of anxiety and depression during adolescence are well documented. However, little attention has been given to differences in subjective well-being, self-esteem and psychosocial functioning between boys and girls with symptoms of anxiety and depression. The aim of this study was to investigate gender differences in the associations between such symptoms and subjective well-being, self-esteem, school functioning and social relations in adolescents. Data were taken from a major population-based Norwegian study, the Nord-Trondelag Health study (HUNT), in which 8984 (91% of all invited) adolescents, aged 13-19 years, completed an extensive self-report questionnaire. Although prevalence rates of symptoms of anxiety and depression were higher in girls than in boys, a significant interaction between gender and symptoms of anxiety and depression was found in respect of each of the following outcome variables: subjective well-being, self-esteem, academic problems, frequency of meeting friends and the feeling of not having enough friends. These interactions indicate that the associations between symptoms of anxiety and depression and lower subjective well-being and self-esteem, more academic problems in school and lower social functioning were stronger for boys than for girls. Our findings may contribute to an earlier assessment and more efficient treatment of male adolescent anxiety and depression. PMID- 21265858 TI - The reward value of near-miss situations. AB - What is a "positive" outcome? Clearly, obtaining something attractive is regarded as positive, but so is avoiding something negative. The present paper compared these two types of situations in scenario-type evaluations. Participants rated positive (P), avoiding negative (AN), and negative (N) outcomes in terms of luck (Experiment 1) and overall positive/negative evaluations (Experiments 2 and 3). The results demonstrated that evaluations of P and AN outcomes were judged as equally positive, but the emotional basis for these evaluations was very different: The feeling of relief was the dominating emotion in AN situations, whereas joy was the dominating emotion in P situations. Overall, these results indicate that avoidance-induced reward value may be important as a motivating factor in cognition and action. PMID- 21265859 TI - Development of the Cognitive Dysfunction Questionnaire (CDQ) in a population based sample. AB - The study reports on the development of a questionnaire for assessment of adult cognitive dysfunction (CDQ). Participants in a population-based sample (65+/-15 years, N=370) responded to a 90-item pilot version covering multiple aspects of memory/cognition. Based on exploratory principal components analyses and correlations with criterion measures of cognitive functioning (MMSE, Block Design, semantic/episodic memory), 20 items loading on 6 components were selected for the final version of the questionnaire. Cronbach's alpha for the total score was 0.90. There was evidence of construct validity as judged by correlations between CDQ scores, objective cognitive measures, and a subjective memory measure (PRMQ). Discriminant validity was demonstrated by a low and non-significant correlation with depressive symptoms. Further evidence of construct validity was provided by correlations with age and educational attainment. In conclusion, the CDQ is promising as a self-rating screening tool for cognitive dysfunction, and will be the subject of further development and validation. PMID- 21265860 TI - Influence of text cohesion on the persuasive power of expository text. AB - The present study examined how global text cohesion affects persuasion and memory for message arguments presented in expository text. Sixty-nine participants who held a neutral prior attitude towards NATO read a persuasive text about NATO that was either high or low in global cohesion. After reading, participants voted whether Finland should seek NATO membership and filled in an attitude questionnaire. After a 1-week delay they returned for a surprise recall task. The results showed that the high cohesion text was more persuasive than the low cohesion text. Moreover, attitude after reading but not text cohesion predicted later recall of the message arguments. The results show that global text cohesion increases text's persuasive power and that readers who form a positive attitude have better memory of the persuasive arguments after a delay than readers who are less persuaded. PMID- 21265861 TI - Sketching the first 45 years of the journal Psychophysiology (1964-2008): a co word-based analysis. AB - This article presents a keyword-based bibliometric study of the thematic evolution of the journal Psychophysiology since its first publication in 1964 until 2008. Bibliometric maps showing the most relevant associations among the main topics treated by the journal are provided separately for the periods 1964 1978, 1979-1988, 1989-1998, and 1999-2008. These maps offer insight into the conceptual structure of psychophysiology as a research discipline and help to visualize the division of the field into several interconnected subfields. Bibliometric maps created by co-word analysis can be used by both experts and novices to understand the current state of the art of a scientific field and to predict where future research could lead. PMID- 21265862 TI - Effects of competitive pressure on expert performance: underlying psychological, physiological, and kinematic mechanisms. AB - Although it is well established that performance is influenced by competitive pressure, our understanding of the mechanisms which underlie the pressure performance relationship is limited. The current experiment examined mediators of the relationship between competitive pressure and motor skill performance of experts. Psychological, physiological, and kinematic responses to three levels of competitive pressure were measured in 50 expert golfers, during a golf putting task. Elevated competitive pressure increased putting accuracy, anxiety, effort, and heart rate, but decreased grip force. Quadratic effects of pressure were noted for self-reported conscious processing and impact velocity. Mediation analyses revealed that effort and heart rate partially mediated improved performance. The findings indicate that competitive pressure elicits effects on expert performance through both psychological and physiological pathways. PMID- 21265863 TI - Mechanisms underlying the left visual-field advantage in the dual stream RSVP task: evidence from N2pc, P3, and distractor-evoked VEPs. AB - When two letter streams containing two targets (T1 and T2) are presented left and right, T2 is better identified in the left hemifield. This study on 16 healthy participants used evidence from ERPs to decide whether this advantage is due to better processing in the right hemisphere or to overload of the left one. N2pc and P3 components evoked by T1 and T2 were measured, as well as the VEPs evoked by the stream of distractor stimuli. Already at the onset of the stream, these VEPs peaked earlier at the right than at the left hemisphere. N2pc was evoked earlier and P3 amplitudes were larger with left than with right T2. Previously reported side differences in T1-evoked N2pc were no longer obtained after correcting for constant hemispheric differences. The faster VEP latencies at the right hemisphere from the very beginning of the stimulus series may reflect an advantage in structuring fast sequences, which may cause the left visual-field advantage. PMID- 21265864 TI - Distinct cognitive mechanisms in a gambling task share neural mechanisms. AB - Distinct psychological processes have been proposed to unfold in decision-making. The time course of neural mechanisms supporting these processes has not been fully identified. The present MEG study examined spatio-temporal activity related to components of decision-making proposed to support reward valuation, reward prediction, and outcome evaluation. Each trial presented information on reward value (10 or 50 cents) and reward probability (10%, 50%, or 90%). Brain activity related to those inputs and to outcome feedback was evaluated via electromagnetic responses in source space. Distributed dipole activity reflected reward value and reward probability 150-350 ms after information arrival. Neural responses to reward-value information peaked earlier than those to reward-probability information. Results suggest that valuation, prediction, and outcome evaluation share neural structures and mechanisms even on a relatively fine time scale. PMID- 21265865 TI - Dyeing behaviours of amino heterocyclic compounds as blue oxidative hair dye precursors applied to keratin fibres. AB - Several novel heterocyclic compounds based on 1,2,3,4-tetrahydroquinoline and 2,3 dihydroindole have been investigated for their application of colour keratin fibres as blue oxidative dye precursors, especially to human hair. The colourants we studied contained anyone of these dyes (concentration range from 0.005% to 6%), and some common oxidative hair dyes, such as p-phenylenediamine, toluene-2,5 diamine sulphate. Experiments were carried out on the method of mixing hair colourants with H(2)O(2) gel at the ratio of 1 : 1, accompanied by pH = 8~11. It is demonstrated that 1,2,3,4-tetrahydroquinoline derivatives could be considered as an excellent candidate for blue dyes, and N-methyl-7-amino-1,2,3,4 tetrahydroquinoline is the most outstanding one among this kind of compounds. They own significant advantages of colour purity, stability and fastness. On the other hand, 2,3-dihydroindoles show the similar colours but not stable and brilliant enough. PMID- 21265866 TI - The melanogenesis and mechanisms of skin-lightening agents--existing and new approaches. AB - Skin-lightening products are commercially available for cosmetic purposes to obtain lighter skin complexion. Clinically, they are also used for treatment of hyperpigmentary disorders such as melasma, cafe au lait spot and solar lentigo. All of these target naturally melanin production, and many of the commonly used agents are known as competitive inhibitors of tyrosinase, one of the key enzymes in melanogenesis. In this review, we present an overview of commonly used skin whitening ingredients that are commercialized, but we also hypothesize on other mechanisms that could be important targets to control skin pigmentation such as for example regulation of the adrenergic and glutaminergic signalling and also control of tetrahydrobiopterins in the human skin. PMID- 21265867 TI - The state of nano-sized titanium dioxide (TiO2) may affect sunscreen performance. AB - In the past several years, there has been a trend in the sunscreen/cosmetics industry to replace micron-sized titanium dioxide (TiO(2)) particles with nanoscale materials. The increased use of nanoscale TiO(2) has resulted in questions about these and other nanoproducts. This study examines the effects of using nanoscale TiO(2) on ultraviolet (UV) attenuation in simple to complex sunscreen formulations. UV light attenuation, product stability, and potential damage to the skin barrier were examined with both nanoscale and microscale TiO(2) particles. Results indicate that none of the formulations decreased the barrier function of the skin and the best UV attenuation occurs when the TiO(2) particles are stabilized with a coating and evenly distributed such as with non agglomerated coated nanoscale materials. This indicates that nanoscale TiO(2) may have better efficacy while lacking toxicity. PMID- 21265868 TI - Model organisms for genetics in the domain Archaea: methanogens, halophiles, Thermococcales and Sulfolobales. AB - The tree of life is split into three main branches: eukaryotes, bacteria, and archaea. Our knowledge of eukaryotic and bacteria cell biology has been built on a foundation of studies in model organisms, using the complementary approaches of genetics and biochemistry. Archaea have led to some exciting discoveries in the field of biochemistry, but archaeal genetics has been slow to get off the ground, not least because these organisms inhabit some of the more inhospitable places on earth and are therefore believed to be difficult to culture. In fact, many species can be cultivated with relative ease and there has been tremendous progress in the development of genetic tools for both major archaeal phyla, the Euryarchaeota and the Crenarchaeota. There are several model organisms available for methanogens, halophiles, and thermophiles; in the latter group, there are genetic systems for Sulfolobales and Thermococcales. In this review, we present the advantages and disadvantages of working with each archaeal group, give an overview of their different genetic systems, and direct the neophyte archaeologist to the most appropriate model organism. PMID- 21265869 TI - High abundances of aerobic anoxygenic phototrophs in saline steppe lakes. AB - We studied the distribution of anoxygenic phototrophs in 23 steppe lakes in the Transbaikal region (Russia), in Uzbekistan (Central Asia) and in the Crimean peninsula (Ukraine). The lakes varied in their mineral content and composition (salinities from 0.2 to 300 g L(-1) ). The Transbaikal lakes were alkaline (pH>9), with high amounts of soda. The Uzbek and Crimean lakes were more pH neutral, frequently with high amounts of sulfates. The presence of anoxygenic phototrophs was registered by infrared epifluorescence microscopy, infrared fluorometry and pigment analyses. In mostly shallow, fully oxic lakes, the anoxygenic phototrophs represented 7-65% of the total prokaryotes, with the maxima observed in Transbaikal soda lakes Gorbunka (32%), Khilganta (65%), Zanday (58%) and Zun-Kholvo (46%). Some of the lakes contained over 1 MUg bacteriochlorophyll L(-1) . In contrast, only small amounts of anoxygenic phototrophs were present in highly mineralized lakes (>100 g total salts L(-1) ); Borzinskoe, Tsagan-Nur (Transbaikal), Staroe (Crimea) and in the residual part of the south-west Aral Sea (Uzbekistan). The oxic environment and the specific diurnal changes of bacteriochlorophyll concentration observed suggest that the phototrophic community was mostly composed of aerobic anoxygenic phototrophs. The high abundances and bacteriochlorophyll concentrations point to an important role of aerobic anoxygenic phototrophs in the habitats studied. PMID- 21265870 TI - Ectomycorrhizal hyphae structure components of the soil bacterial community for decreased phosphatase production. AB - Ectomycorrhizal fungi (EMF) provide nutrients to their hosts by means of hyphae that extend beyond nutrient-depleted rhizosphere soil. Soil bacteria may compete with EMF for nutrients or may act synergistically to enhance nutrient supply to hosts. To assess the interactions between hyphae and bacteria, two types of small, sand-filled mesh bags were incubated in a Pseudotsuga menziesii/Betula papyrifera forest. The bags allowed ingrowth by EMF (35-MUm mesh) or excluded hyphae (0.5-MUm mesh), while allowing migration of soil bacteria. After incubation, bacteria were isolated from bags using a method to enrich for Gram positive bacteria. Isolates were assayed for phosphatase and N-acetyl glucosaminidase (NAGase) activities to assess the potential to access organic phosphorus and nitrogen. The average phosphatase activities were higher in exclusion than ingrowth bags, while NAGase activities did not differ. Streptomyces isolates, which are expected to be strong competitors and antagonists of EMF, were more prevalent in ingrowth bags and yet had lower phosphatase activities. Furthermore, there were no indications of antagonism between fungi and Streptomyces, as there were no increases in NAGase activities in ingrowth bags. We conclude that fungal hyphae can structure components of the soil bacterial community for decreased extracellular enzyme production. PMID- 21265871 TI - Reticulated acanthoma with apocrine differentiation. AB - Reticulated acanthoma with apocrine differentiation (RAAD) represents a rare variant of adnexal neoplasm first described by Ackerman et al. in 1998. It consists of cords and columns of adnexal keratinocytes that form a reticulated pattern. Variable signs of apocrine, sebaceous and follicular differentiation may be present. Since 1998, no further cases of this condition have been published. We report on a lesion excised from the leg of a 46-year-old man, which displayed histopathological features diagnostic of RAAD. Criteria for diagnosis and differential diagnoses are discussed. PMID- 21265872 TI - Renal (pro)renin receptor contributes to development of diabetic kidney disease through transforming growth factor-beta1-connective tissue growth factor signalling cascade. AB - 1. Transforming growth factor-beta1 (TGF-beta1) and connective tissue growth factor (CTGF) are expressed in renal glomeruli, and contribute to the development of diabetic nephropathy. Recently, we showed that (pro)renin receptor (PRR) is upregulated in the kidneys of the streptozocin (STZ)-induced diabetes rat model. We hypothesized that in the presence of hyperglycaemia, increased renal PRR expression contributes to enhanced TGF-beta1-CTGF signalling activity, leading to the development of diabetic kidney disease. 2. In vivo and in vitro studies were carried out in Sprague-Dawley rats and rat mesangial cells (RMC). PRR blockade was achieved in vivo by treating STZ induced diabetes rats with the handle region peptide (HRP) of prorenin and in vitro by HRP or PRR siRNA in RMC. Angiotensin AT1 receptor blockade was achieved by valsartan treatment. 3. Results showed that expression of PRR, TGF-beta1 and CTGF were upregulated in diabetic kidneys and RMC exposed to high glucose. Glucose exposure also induced PRR phosphorylation, a process that was inhibited by HRP, valsartan or PRR siRNA. HRP and valsartan significantly attenuated renal TGF-beta1 and CTGF expression in diabetic animals and high glucose treated RMC. Similar results were observed in high glucose exposed RMC in response to PRR siRNA. TGF-beta receptor blockade decreased CTGF expression in RMC. Combined administration of valsartan and PRR siRNA showed further reduction of TGF-beta1 and CTGF expression in RMC. 4. In conclusion, PRR contributes to kidney disease in diabetes through an enhanced TGF-beta1-CTGF signalling cascade. PMID- 21265873 TI - alpha1-Adrenoceptors and muscarinic receptors in voiding function - binding characteristics of therapeutic agents in relation to the pharmacokinetics. AB - In vivo and ex vivo binding of alpha(1)-adrenoceptor and muscarinic receptors involved in voiding function is reviewed with therapeutic agents (alpha(1) adrenoceptor antagonists: prazosin, tamsulosin and silodosin; and muscarinic receptor antagonists: oxybutynin, tolterodine, solifenacin, propiverine, imiafenacin and darifenacin) in lower urinary tract symptoms. This approach allows estimation of the inhibition of a well-characterized selective (standard) radioligand by unlabelled potential drugs or direct measurement of the distribution and receptor binding of a standard radioligand or radiolabelled form of a novel drug. In fact, these studies could be conducted in various tissues from animals pretreated with radioligands and/or unlabelled novel drugs, by conventional radioligand binding assay, radioactivity measurement, autoradiography and positron emission tomography. In vivo and ex vivo receptor binding with alpha(1)-adrenoceptor antagonists and muscarinic receptor antagonists have been proved to be useful in predicting the potency, organ selectivity and duration of action of drugs in relation to their pharmacokinetics. Such evaluations of drug-receptor binding reveal that adverse effects could be avoided by the use of new alpha(1)-adrenoceptor antagonists and muscarinic receptor antagonists for the treatment of lower urinary tract symptoms. Thus, the comparative analysis of alpha(1)-adrenoceptor and muscarinic receptor binding characteristics in the lower urinary tract and other tissues after systemic administration of therapeutic agents allows the rationale for their pharmacological characteristics from the integrated viewpoint of pharmacokinetics and pharmacodynamics. The current review emphasizes the usefulness of in vivo and ex vivo receptor binding in the discovery and development of novel drugs for the treatment of not only urinary dysfunction but also other disorders. PMID- 21265874 TI - Slow-release oral morphine for opioid maintenance treatment: a systematic review. AB - This review article summarizes the results of all available clinical trials considering the use of slow-release oral morphine (SROM) for opioid maintenance treatment (OMT). All studies published up to October 2010 and assessing SROM for OMT in adult patients are included. Three independent reviewers assessed the selected articles using a standardized checklist. Study design, study length and number of subjects included were recorded. Data about retention rate (proportion of participants remaining under maintenance treatment at the end of the study), quality of life, withdrawal symptoms, craving, additional drug consumption, driving capacity and adverse events were collected. We identified 13 articles corresponding to nine clinical trials considering the use of SROM for OMT. Among them, only one was a randomized trial and one was a controlled not randomized trial. All other studies were uncontrolled. Retention rates were good (from 80.6 to 95%) with SROM maintenance, but similar retention rates were obtained with methadone. Most of the studies showed that quality of life, withdrawal symptoms, craving and additional drug consumption improved with SROM. However, there was no comparison with other maintenance drugs. As most of the studies assessing SROM efficacy were uncontrolled, there is no definite evidence that SROM is an effective alternative to methadone for OMT. PMID- 21265875 TI - Dengue virus type 2 recognizes the carbohydrate moiety of neutral glycosphingolipids in mammalian and mosquito cells. AB - Dengue viruses infect cells by attaching to a surface receptor which remains unknown. The putative receptor molecules of dengue virus type 2 on the surface of mosquito (AP-61) and mammalian (LLC-MK2) cell lines were investigated. The immunochemical detection and structural analysis of carbohydrates demonstrated that the neutral glycosphingolipids, L-3 (GlcNAcbeta1-3Manbeta1-4Glcbeta1-1'Cer) in AP-61 cells, and nLc(4) Cer (Galbeta1-4GlcNAcbeta1-3Galbeta1-4Glcbeta1-1'Cer) in LLC-MK2 cells were recognized by the virus. These findings strongly suggest that neutral glycosphingolipids share the key determinant for virus binding and that the beta-GlcNAc residue may play an important role in dengue virus binding to the host cell surface. PMID- 21265876 TI - Genetic polymorphisms of drug-metabolizing phase I enzymes CYP2E1, CYP2A6 and CYP3A5 in South Indian population. AB - CYP2E1, CYP2A6 and CYP3A5 enzymes belong to phase I group of drug-metabolizing enzymes, which are involved in the metabolism of various compounds and xenobiotics. Presence of polymorphisms in the genes coding for these enzymes results in interindividual variations in drug metabolism, therapeutic response and susceptibility towards various diseases. The frequencies of these variants in genes differ considerably between ethnic groups. This study was carried out to estimate the allele and genotype frequencies of common variants in CYP2E1, CYP2A6 and CYP3A5 in South Indian population. Six hundred and fifty-two unrelated healthy volunteers of South Indian origin (Andhra Pradesh, Karnataka, Kerala and Tamil Nadu) were included in this study. Polymerase chain reaction-restriction fragment length polymorphism, allele-specific PCR, real-time PCR, SNaPshot and gene sequencing methods were used for the identification of gene polymorphisms. The frequencies of CYP2E1*1B, CYP2E1*5B and CYP2E1*6 alleles in South Indian population were 14.3, 1.3 and 22.4%, respectively. The frequencies of CYP2A6*2, CYP2A6*4A and CYP2A6*5 alleles were found to be 1, 8.9 and 0.7%, respectively. The distribution of CYP3A5*3 allele was 63.5%. There were no variant alleles of CYP3A5*2, CYP3A5*4 and CYP3A5*6 in South Indian population. The frequencies of CYP2E1, CYP2A6 and CYP3A5 in the South Indian population are distinct from Caucasians, Chinese, Japanese, African Americans and other compared populations. This is the first study conducted in the South Indian population with a larger sample size. The findings of our study provide the basic genetic information for further pharmacogenomic investigations in the population. PMID- 21265877 TI - Relations between open-field, elevated plus-maze, and emergence tests in C57BL/6JIco and BALB/cAnN@Ico mice injected with ethanol. AB - The effects of ethanol were examined on three tests of exploratory activity in two mouse strains. Although ethanol reduced open-field rearing in both strains, it increased ambulation only in the less active BALB/cAnN@Ico strain, not in the C57BL/6JIco strain. Likewise, ethanol increased open and enclosed arm entries in the elevated plus-maze only in the more anxious BALB/cAnN@Ico strain. However, both strains injected with ethanol emerged faster than placebo from a small chamber at doses not affecting behaviors in the other two tests. Significant correlations were found between emergence latencies on one hand and either slow stereotyped movements or open and enclosed arm entries on the other. The strain specific effects may be attributable to differences in GABA(A) -related receptor binding or catalase activity. PMID- 21265878 TI - Medication prescribing errors pertaining to cardiovascular/antidiabetic medications: a prescription audit in primary care. AB - This study was carried out to identify the medication prescribing errors (MPEs) pertaining to cardiovascular/antidiabetic medications in prescriptions issued to hypertensive and diabetic hypertensive patients. A retrospective, nationwide audit of prescriptions (n = 2773) issued by primary care physicians (n = 194) of 20 health centres in Bahrain was carried out. Approximately one-quarter of prescriptions ordered by two-thirds of primary care physicians had errors. No significant differences with respect to overall errors were evident in prescriptions ordered by the family physicians and general practitioners. The most common error (in 8.0% of prescriptions) was prescribing beta-blockers or diuretics (thiazide) or their combinations to patients on lipid-lowering drugs. Prescribing multiple antihypertensives, often with a similar mechanism, accounted for 2.2% errors: approximately half of these (1.45%) were two angiotensin converting enzyme inhibitors (ACEIs) co-prescribed and/or ACEIs plus angiotensin II receptor blockers. In 0.7% of prescriptions, beta-blockers were ordered to patients on salbutamol treatment. High-dose metformin (3 g/day) was prescribed to approximately 4% diabetic hypertensives; of these, many were elderly patients. Prescribing high-dose glibenclamide (median dose 15 mg) to the elderly accounted for 3.6% of the overall errors. Polypharmacy, such as aspirin along with an immediate-release dipyridamole, was prescribed occasionally (0.25%), particularly by the general practitioners (P = 0.0139). MPEs are common in primary care, in Bahrain. Some of these prescribing errors have the potential to harm patients. Effective measures to detect and prevent such errors are needed to improve the quality of health care. Standard treatment guidelines and educational interventions are important strategies to achieve these goals. PMID- 21265879 TI - From GERD to Barrett's esophagus: is the pattern in Asia mirroring that in the West? AB - Gastroesophageal reflux disease (GERD) is a known predisposing factor for Barrett's esophagus. Amongst individuals with symptomatic GERD, the prevalence of Barrett esophagus is estimated to be more than 10%, and an individual with Barrett's esophagus is more likely than the general population to develop esophageal adenocarcinoma. In Western Europe and North America, incidence of esophageal adenocarcinoma had been on the upward trend for many decades. In comparison, although the prevalence of GERD and reflux esophagitis has increased several fold in some parts of Asia, the prevalence of esophageal adenocarcinoma and Barrett's esophagus remains generally low in the region. Rising incidence of esophageal adenocarcinoma has been observed in regions witnessing increasing prevalence of GERD. If the recent increase in prevalence of GERD in parts of urbanized Asia is any indication of the beginning of an upsurge in the incidence of Barrett's esophagus and associated adenocarcinoma, would we be witnessing a pattern of epidemiological shift mirroring that in the West? Given that more than 90% of Barrett's esophagus in Asian patients is of the short-segment type, which is reported to have lesser propensity to develop to adenocarcinoma, could the ongoing epidemiologic transition take Asia on the same trail as that which the West has taken? This article will draw on relevant findings from various parts of Asia and take an in-depth look at prevailing disease trends to see where Asia stands now in the changing epidemiology of GERD, Barrett's esophagus and associated adenocarcinoma. PMID- 21265880 TI - Homing of the bone marrow-derived interstitial cells of Cajal is decreased in diabetic mouse intestine. AB - BACKGROUND: Interstitial cells of Cajal (ICCs), which express c-Kit receptor tyrosine kinase (KIT), play an important role in gastrointestinal motility. Loss of ICCs likely contributes to diabetic gastrointestinal motility disorder, however, the mechanism of attrition remains unknown. Here, we test the hypothesis that the bone marrow-derived progenitors are an important source of intestinal ICCs and that decreased homing of these progenitors in diabetes contributes to ICC diminution. METHODS: Wild type mice were X-ray irradiated, transplanted with bone marrow (BMT) from green fluorescence protein (GFP)-transgenic (TG)-mice and subsequently made diabetic by streptozotocin (STZ) injection. Intestinal homing of GFP-positive bone marrow-derived cells was examined 2 or 5 months after STZ treatment. RESULTS: In the BMT-mice, we found many GFP-positive bone marrow derived cells (BMDCs) in most parts of the intestinal area, the number of BMDCs was significantly decreased in diabetic mice compared with nondiabetic controls. As a representative area, we further examined the myenteric plexus of the proximal small intestine, and found that the cell numbers of ICCs marked by c-Kit positive immunoreactivity were decreased by more than 40% in diabetic versus nondiabetic mice. Furthermore, numbers of c-Kit+/GFP+ and c-Kit+/GFP- cells were similar in nondiabetic mice, and decreased by 45.8% and 42.0%, respectively, in diabetic mice. CONCLUSION: These results suggest that the decreased homing from the bone marrow is a major cause of ICC loss in the intestine in diabetes mellitus. PMID- 21265881 TI - Plasma reactive carbonyl species levels and risk of non-alcoholic fatty liver disease. AB - BACKGROUND AND AIM: Oxidative stress plays a critical role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, there is still no large cohort study to explore the direct risk role of oxidative stress for NAFLD. This study is to test the hypothesis that elevated oxidative stress is a direct risk factor for the pathogenesis of NAFLD under controlling the potential effects of covariates. METHODS: The levels of serum cholesterol, serum triglyceride, fasting plasma glucose and plasma reactive carbonyl species (RCS) were measured from 1204 Chinese Han adults, and the questionnaire and physical examination were administered to those with known and suspected risk factors for NAFLD. RESULTS: Statistically significant high levels of blood pressure, fasting plasma glucose, serum cholesterol and triglyceride, body mass index, serum alanine aminotransferase and aspartate aminotransferase, and plasma RCS were observed in NAFLD subjects compared to healthy subjects (P < 0.01). Multivariate-adjusted odds ratio illustrated that, compared with the lowest quartile of plasma RCS levels, the highest quartile subjects had a 132% increase in the risk of developing NAFLD. Further results from multi-interaction analysis demonstrated that the underlying mechanism of the risk of NAFLD by unhealthy physical conditions and lifestyles might be, at least in part, through the oxidative stress. CONCLUSIONS: Our findings provide credible evidence from a large population that oxidative stress, as indicated by plasma RCS levels, may be a direct risk factor for developing NAFLD. PMID- 21265882 TI - Reading with low vision: the impact of research on clinical management. AB - The past 40 years has seen a great expansion in low-vision research, which has changed low-vision teaching and our clinical management of people with low vision. Australian optometrists have contributed significantly to this research and the development of multidisciplinary low-vision services. This paper reviews the research that has shaped our clinical assessment and patient management for reading by adults with low vision. The major improvements in clinical assessment of low vision for reading were brought about by the improvements in distance and near visual acuity measurements during the 1970s and research during the 1980s and 1990s showing the factors affecting the reading rate. These changes, together with a different method for representing the magnification provided by optical and electronic systems, allows a scientific, logical and practical method for prescribing magnification. An illustration of the step-by-step approach for prescribing magnification for low-vision reading that is easy to apply in any clinical practice is included. PMID- 21265883 TI - A modified EBMT risk score predicts the outcome of patients with acute myeloid leukemia receiving allogeneic stem cell transplants. AB - The systematic and standardized pretransplant risk assessment represents an important tool to predict the outcome of patients undergoing allogeneic stem cell transplantation (alloSCT). To investigate the capacity of a modified European group for blood and marrow transplantation (mEBMT) risk score to predict the outcome of patients with acute myeloid leukemia (AML) receiving allogeneic stem cell transplants, we retrospectively analyzed 214 patients transplanted at our center between 1995 and 2008. Overall survival (OS) of the whole cohort at 1, 3, and 5 yr was 62%, 48%, and 45%, whereas the cumulative incidence of relapse or non-relapse mortality (NRM) was 26%, 33%, and 33% or 19%, 21%, and 22%. In univariate analysis, a higher mEBMT risk score was associated with an inferior OS ranging from 69% for patients with a score of 0/1 to 26% for patients with a score of 5/6 at 5 yr (P < 0.0001) and steadily increasing hazard ratios for each additional score point. Likewise, a higher mEBMT risk score was associated with an increased incidence of relapse (P = 0.049). Importantly, the prognostic value of the mEBMT risk score in terms of OS and relapse was maintained in multivariate analysis. Taken together, this indicates that a mEBMT risk score may be used to predict the outcome of patients with AML following alloSCT. PMID- 21265884 TI - Exogenous immunoglobulin downregulates T-cell receptor signaling and cytokine production. AB - Intravenous immune globulin (IVIG), a polyvalent solution of pooled human immunoglobulin, is a potent immunomodulating agent. It is currently approved to treat autoimmune diseases, including idiopathic thrombocytopenia purpura, autoimmune hemolytic anemia, and Kawasaki disease. The basis of IVIG's immunomodulatory properties is not entirely understood. Proposed mechanisms include Fc receptor blockade, interference with cytokine network, and provision of anti-idiotypic antibodies. IVIG has also been shown to affect T-lymphocyte function, although a direct effect has been difficult to reconcile given the lack of immunoglobulin or Fc-receptors on T cells. Experiments were thus carried out to determine whether IVIG was acting on a specific T-cell subset and at the level of the T-cell receptor (TCR), and whether cytokine expression patterns were modulated. T lymphocytes obtained from adult peripheral blood and umbilical cord blood were cultured over a 1-wk time course in the presence of pharmacological IVIG concentrations (Gamunex((r)) , 0-2.0 mg/ml). Cells were exposed to various stimulation conditions, and TCR signaling competence was assessed by quantifying activation-induced upregulation of CD25 and CD69, as well as production of specific T-cell cytokines. IVIG was found to significantly decrease T-lymphocyte proliferation, in a dose and time-dependent manner, in both cord and adult blood. IVIG markedly reduced phytohemagglutinin and anti-CD3-induced upregulation of CD25 and CD69 in both CD4 and CD8 T-cell subsets, although phorbol ester-induced responses were intact, suggesting a defect in the CD3/TCR signaling pathway. IVIG also inhibited anti-CD3-induced cytokine production of IL-10, IL-2, and IFN-gamma in a dose-dependent manner. These data suggest that IVIG may have direct T-cell immunomodulatory properties by dampening TCR responses. Further studies are needed to more precisely define the molecular targets of IVIG. PMID- 21265885 TI - The prevalence of food allergy in infants in Chongqing, China. AB - BACKGROUND: Over the past three decades, the prevalence of allergic diseases has markedly increased in developed countries. There has been a paucity of data on food allergy (FA) in developing countries such as China. We aimed to estimate the prevalence and the clinical features of FA in Chinese infants attending a routine well-baby clinic in Chongqing, China. METHODS: From January 1st to February 28th, 2009, consecutive infants and young children aged 0-12 months attending routine well-baby checks at the Department of Primary Child Care, Children's Hospital of Chongqing Medical University, were invited to participate in the study. Parents completed questionnaires, and children were skin prick tested (SPT) to a panel of 10 foods (egg white, egg yolk, cow's milk, soybean, peanut, wheat, fish, shrimp, orange, and carrot) together of histamine and saline controls. Subjects with either a positive SPT or a positive medical history were invited to undergo an oral food challenge. RESULTS: Of 497 children who consented to participate, 477 (96%) participated fully in the study. Of these, 56 subjects had a positive SPT (11.3%), with 45 positive to egg, 13 to cow's milk, 2 to peanut, 1 to fish, shrimp, and orange respectively. Eighty subjects (16.1%, 80/497) participated in food challenges. CONCLUSION: The overall prevalence of challenge-proven FA in 0 to 1-yr-old children in Chongqing, China, was 3.8% (18/477, 95% CI, 2.5-5.9%) with 2.5% (12/477) egg allergic and 1.3% (6/477) cow's milk allergic. PMID- 21265886 TI - The European experience. AB - This mini-review on European experiences with tackling the problem of organ shortage for transplantation was based on a literature review of predominantly European publications dealing with the issue of organ donation from deceased donors. The authors tried to identify the most significant factors that have demonstrated to impact on donation rates from deceased donors and subsequent transplant successes. These factors include legislative measures (national laws and European Directives), optimization of the donation process, use of expanded criteria donors, innovative preservation and surgical techniques, organizational efforts, and improved allocation algorithms. PMID- 21265887 TI - High allergen-specific serum immunoglobulin E levels in nonatopic West Highland white terriers. AB - Human and canine atopic dermatitis (AD) share an association with IgE specific to environmental allergens, but few studies have evaluated serum allergen-specific IgE in nonatopic dogs. This study compared serum allergen-specific IgE levels in 30 atopic and 18 nonatopic West Highland white terriers. Atopic dermatitis was confirmed using standard criteria. Nonatopic dogs were over 5 years of age and had no clinical signs or history of AD. Serum allergen-specific IgE levels were measured with Allercept((r)) IgE ELISAs using a 48-allergen Australian panel. Positive reactions were defined as >=150 ELISA absorbance units. Intradermal tests were performed in 16 atopic dogs, either at the time of or at various times prior to serum collection. In atopic dogs, the most common positive ELISA and intradermal test results were to Dermatophagoides farinae (11 of 30 dogs), but there were no statistically significant correlations between results from the two methods for any allergen. In nonatopic dogs, multiple high-positive ELISA reactions were reported to 45 of 48 allergens, most commonly D. farinae and Tyrophagus putrescentiae (17 of 18 dogs each). Positive ELISA results in nonatopic dogs were statistically significantly higher than those in atopic dogs for 44 of 48 allergens, including two allergens (D. farinae and Dermatophagoides pteronyssinus) commonly regarded as significant in canine AD. In conclusion, positive allergen-specific IgE ELISAs were not specific for canine AD, and high allergen-specific IgE levels were seen in nonatopic dogs. The clinical significance of this and whether it characterizes a protective phenotype is unclear. PMID- 21265888 TI - Analysis of ven3 and ven6 reticulate mutants reveals the importance of arginine biosynthesis in Arabidopsis leaf development. AB - Arabidopsis thaliana reticulate mutants exhibit differential pigmentation of the veinal and interveinal leaf regions, a visible phenotype that often indicates impaired mesophyll development. We performed a metabolomic analysis of one ven6 (venosa6) and three ven3 reticulate mutants that revealed altered levels of arginine precursors, namely increased ornithine and reduced citrulline levels. In addition, the mutants were more sensitive than the wild-type to exogenous ornithine, and leaf reticulation and mesophyll defects of these mutants were completely rescued by exogenous citrulline. Taken together, these results indicate that ven3 and ven6 mutants experience a blockage of the conversion of ornithine into citrulline in the arginine pathway. Consistent with the participation of VEN3 and VEN6 in the same pathway, the morphological phenotype of ven3 ven6 double mutants was synergistic. Map-based cloning showed that the VEN3 and VEN6 genes encode subunits of Arabidopsis carbamoyl phosphate synthetase (CPS), which is assumed to be required for the conversion of ornithine into citrulline in arginine biosynthesis. Heterologous expression of the Arabidopsis VEN3 and VEN6 genes in a CPS-deficient Escherichia coli strain fully restored bacterial growth in minimal medium, demonstrating the enzymatic activity of the VEN3 and VEN6 proteins, and indicating a conserved role for CPS in these distinct and distant species. Detailed study of the reticulate leaf phenotype in the ven3 and ven6 mutants revealed that mesophyll development is highly sensitive to impaired arginine biosynthesis. PMID- 21265889 TI - Genome-wide mapping of the HY5-mediated gene networks in Arabidopsis that involve both transcriptional and post-transcriptional regulation. AB - LONG HYPOCOTYL 5 (HY5) is a basic leucine zipper transcription factor (TF) that functions downstream of multiple families of photoreceptors. Mutations in the HY5 gene cause a myriad of aberrant phenotypes in Arabidopsis, including elongated hypocotyl, reduced accumulation of pigments, halted chloroplast development in greening hypocotyls, altered root morphology, and defective hormonal and stimulus responses. HY5 thus acts as an integrator that links various gene networks to coordinate plant development. Here we report the experimental mapping of HY5 mediated gene networks in Arabidopsis by integrating genomic loci occupied by HY5 and HY5-dependent gene expression profiles. Our results indicate that HY5 binds to over 9000 genes, detectably affecting the expression of over 1100 genes, either positively or negatively. Further, HY5 indirectly regulate many other genes through sub-networks mediated by other regulators. In particular, HY5 regulates eight miRNA genes that in turn control the transcript abundance of specific target genes. Over-expressing HY5-targeted miR408 resulted in phenotypes that are opposite to the hy5 mutants. Together, our results reveal both transcriptional and post-transcriptional components of the HY5-mediated gene networks. PMID- 21265890 TI - The fertility restorer gene, Rf2, for Lead Rice-type cytoplasmic male sterility of rice encodes a mitochondrial glycine-rich protein. AB - Cytoplasmic male sterility (CMS) is associated with a mitochondrial mutation that causes an inability to produce fertile pollen. The fertility of CMS plants is restored in the presence of a nuclear-encoded fertility restorer (Rf) gene. In Lead Rice-type CMS, discovered in the indica variety 'Lead Rice', fertility of the CMS plant is restored by the single nuclear-encoded gene Rf2 in a gametophytic manner. We performed map-based cloning of Rf2, and proved that it encodes a protein consisting of 152 amino acids with a glycine-rich domain. Expression of Rf2 mRNA was detected in developing and mature anthers. An RF2-GFP fusion was shown to be targeted to mitochondria. Replacement of isoleucine by threonine at amino acid 78 of the RF2 protein was considered to be the cause of functional loss in the rf2 allele. As Rf2 does not encode a pentatricopeptide repeat protein, unlike a majority of previously identified Rf genes, the data from this study provide new insights into the mechanism for restoring fertility in CMS. PMID- 21265891 TI - The PsbW protein stabilizes the supramolecular organization of photosystem II in higher plants. AB - PsbW, a 6.1-kDa low-molecular-weight protein, is exclusive to photosynthetic eukaryotes, and associates with the photosystem II (PSII) protein complex. In vivo and in vitro comparison of Arabidopsis thaliana wild-type plants with T-DNA insertion knock-out mutants completely lacking the PsbW protein, or with antisense inhibition plants exhibiting decreased levels of PsbW, demonstrated that the loss of PsbW destabilizes the supramolecular organization of PSII. No PSII-LHCII supercomplexes could be detected or isolated in the absence of the PsbW protein. These changes in macro-organization were accompanied by a minor decrease in the chlorophyll fluorescence parameter F(V) /F(M) , a strongly decreased PSII core protein phosphorylation and a modification of the redox state of the plastoquinone (PQ) pool in dark-adapted leaves. In addition, the absence of PsbW protein led to faster redox changes in the PQ pool, i.e. transitions from state 1 to state 2, as measured by changes in stationary fluorescence (F(S) ) kinetics, compared with the wild type. Despite these dramatic effects on macromolecular structure, the transgenic plants exhibited no significant phenotype under normal growth conditions. We suggest that the PsbW protein is located close to the minor antenna of the PSII complex, and is important for the contact and stability between several PSII-LHCII supercomplexes. PMID- 21265893 TI - Lr34 multi-pathogen resistance ABC transporter: molecular analysis of homoeologous and orthologous genes in hexaploid wheat and other grass species. AB - The Triticum aestivum (bread wheat) disease resistance gene Lr34 confers durable, race non-specific protection against three fungal pathogens, and has been a highly relevant gene for wheat breeding since the green revolution. Lr34, located on chromosome 7D, encodes an ATP-binding cassette (ABC) transporter. Both wheat cultivars with and without Lr34-based resistance encode a putatively functional protein that differ by only two amino acid polymorphisms. In this study, we focused on the identification and characterization of homoeologous and orthologous Lr34 genes in hexaploid wheat and other grasses. In hexaploid wheat we found an expressed and putatively functional Lr34 homoeolog located on chromosome 4A, designated Lr34-B. Another homoeologous Lr34 copy, located on chromosome 7A, was disrupted by the insertion of repetitive elements. Protein sequences of LR34-B and LR34 were 97% identical. Orthologous Lr34 genes were detected in the genomes of Oryza sativa (rice) and Sorghum bicolor (sorghum). Zea mays (maize), Brachypodium distachyon and Hordeum vulgare (barley) lacked Lr34 orthologs, indicating independent deletion of this particular ABC transporter. Lr34 was part of a gene-rich island on the wheat D genome. We found gene colinearity on the homoeologous A and B genomes of hexaploid wheat, but little microcolinearity in other grasses. The homoeologous LR34-B protein and the orthologs from rice and sorghum have the susceptible haplotype for the two critical polymorphisms distinguishing the LR34 proteins from susceptible and resistant wheat cultivars. We conclude that the particular Lr34-haplotype found in resistant wheat cultivars is unique. It probably resulted from functional gene diversification that occurred after the polyploidization event that was at the origin of cultivated bread wheat. PMID- 21265892 TI - Polycomb proteins regulate the quantitative induction of VERNALIZATION INSENSITIVE 3 in response to low temperatures. AB - Vernalization, the promotion of flowering in response to low temperatures, is one of the best characterized examples of epigenetic regulation in plants. The promotion of flowering is proportional to the duration of the cold period, but the mechanism by which plants measure time at low temperatures has been a long standing mystery. We show that the quantitative induction of the first gene in the Arabidopsis vernalization pathway, VERNALIZATION INSENSITIVE 3 (VIN3), is regulated by the components of Polycomb Response Complex 2, which trimethylates histone H3 lysine 27 (H3K27me3). In differentiated animal cells, H3K27me3 is mostly associated with long-term gene repression, whereas, in pluripotent embyonic stem cells, many cell lineage-specific genes are inactive but exist in bivalent chromatin that carries both active (H3K4me3) and repressive (H3K27me3) marks on the same molecule. During differentiation, bivalent domains are generally resolved to an active or silent state. We found that H3K27me3 maintains VIN3 in a repressed state prior to cold exposure; this mark is not removed during VIN3 induction. Instead, active VIN3 is associated with bivalently marked chromatin. The continued presence of H3K27me3 ensures that induction of VIN3 is proportional to the duration of the cold, and that plants require prolonged cold to promote the transition to flowering. The observation that Polycomb proteins control VIN3 activity defines a new role for Polycomb proteins in regulating the rate of gene induction. PMID- 21265894 TI - Autophosphorylation is essential for the in vivo function of the Lotus japonicus Nod factor receptor 1 and receptor-mediated signalling in cooperation with Nod factor receptor 5. AB - Soil-living rhizobia secrete lipochitin oligosaccharides known as Nod factors, which in Lotus japonicus are perceived by at least two Nod-factor receptors, NFR1 and NFR5. Despite progress in identifying molecular components critical for initial legume host recognition of the microsymbiont and cloning of downstream components, little is known about the activation and signalling mechanisms of the Nod-factor receptors themselves. Here we show that both receptor proteins localize to the plasma membrane, and present evidence for heterocomplex formation initiating downstream signalling. Expression of NFR1 and NFR5 in Nicotiana benthamiana and Allium ampeloprasum (leek) cells caused a rapid cell-death response. The signalling leading to cell death was abrogated using a kinase inactive variant of NFR1. In these surviving cells, a clear interaction between NFR1 and NFR5 was detected in vivo through bimolecular fluorescence complementation (BiFC). To analyse the inter- and intramolecular phosphorylation events of the kinase complex, the cytoplasmic part of NFR1 was assayed for in vitro kinase activity, and autophosphorylation on 24 amino acid residues, including three tyrosine residues, was found by mass spectrometry. Substitution of the phosphorylated amino acids of NFR1 identified a single phosphorylation site to be essential for NFR1 Nod-factor signalling in vivo and kinase activity in vitro. In contrast to NFR1, no in vitro kinase activity of the cytoplasmic domain of NFR5 was detected. This is further supported by the fact that a mutagenized NFR5 construct, substituting an amino acid essential for ATP binding, restored nodulation of nfr5 mutant roots. PMID- 21265895 TI - Modulation of sugar metabolism by an INDETERMINATE DOMAIN transcription factor contributes to photoperiodic flowering in Arabidopsis. AB - There has been a long-standing interest in the role played by sugars in flowering. Of particular interest is how sugar-related signals are integrated into flowering genetic pathways. Here, we demonstrate that the INDETERMINATE DOMAIN transcription factor AtIDD8 regulates photoperiodic flowering by modulating sugar transport and metabolism. We found that whereas AtIDD8-deficient idd8 mutants exhibit delayed flowering under long days, AtIDD8-overexpressing plants (35S:IDD8) show early flowering. In addition, the sucrose synthase genes SUS1 and SUS4 were upregulated in 35S:IDD8 plants but downregulated in idd8 mutants, in which endogenous sugar levels were altered. AtIDD8 activates the SUS4 gene by binding directly to its promoter, resulting in promoted flowering in SUS4 overexpressing plants. SUS4 expression also responds to photoperiodic signals. Notably, the AtIDD8 gene is suppressed by sugar deprivation. Therefore, we conclude that AtIDD8 regulation of sugar transport and metabolism is linked to photoperiodic flowering. PMID- 21265896 TI - Nematode CLE signaling in Arabidopsis requires CLAVATA2 and CORYNE. AB - Plant-parasitic cyst nematodes secrete CLAVATA3 (CLV3)/ESR (CLE)-like effector proteins. These proteins have been shown to act as ligand mimics of plant CLE peptides and are required for successful nematode infection; however, the receptors for nematode CLE-like peptides have not been identified. Here we demonstrate that CLV2 and CORYNE (CRN), members of the receptor kinase family, are required for nematode CLE signaling. Exogenous peptide assays and overexpression of nematode CLEs in Arabidopsis demonstrated that CLV2 and CRN are required for perception of nematode CLEs. In addition, promoter-reporter assays showed that both receptors are expressed in nematode-induced syncytia. Lastly, infection assays with receptor mutants revealed a decrease in both nematode infection and syncytium size. Taken together, our results indicate that perception of nematode CLEs by CLV2 and CRN is not only required for successful nematode infection but is also involved in the formation and/or maintenance of nematode-induced syncytia. PMID- 21265897 TI - Light receptor action is critical for maintaining plant biomass at warm ambient temperatures. AB - The ability to withstand environmental temperature variation is essential for plant survival. Former studies in Arabidopsis revealed that light signalling pathways had a potentially unique role in shielding plant growth and development from seasonal and daily fluctuations in temperature. In this paper we describe the molecular circuitry through which the light receptors cry1 and phyB buffer the impact of warm ambient temperatures. We show that the light signalling component HFR1 acts to minimise the potentially devastating effects of elevated temperature on plant physiology. Light is known to stabilise levels of HFR1 protein by suppressing proteasome-mediated destruction of HFR1. We demonstrate that light-dependent accumulation and activity of HFR1 are highly temperature dependent. The increased potency of HFR1 at warmer temperatures provides an important restraint on PIF4 that drives elongation growth. We show that warm ambient temperatures promote the accumulation of phosphorylated PIF4. However, repression of PIF4 activity by phyB and cry1 (via HFR1) is critical for controlling growth and maintaining physiology as temperatures rise. Loss of this light-mediated restraint has severe consequences for adult plants which have greatly reduced biomass. PMID- 21265898 TI - Phosphatidylinositol-4,5-bisphosphate influences Nt-Rac5-mediated cell expansion in pollen tubes of Nicotiana tabacum. AB - The regulation of pollen tube growth by the phospholipid phosphatidylinositol-4,5 bisphosphate (PtdIns(4,5)P(2) ) is not well understood. The Arabidopsis genome encodes two type A phosphatidylinositol-4-phosphate (PI4P) 5-kinases, PIP5K10 and PIP5K11, which are exclusively expressed in pollen and produce PtdIns(4,5)P(2) in vitro. Fluorescence-tagged PIP5K10 and PIP5K11 localized to lateral subapical plasma membrane microdomains in tobacco pollen tubes in a pattern closely resembling the distribution of PtdIns(4,5)P(2,) with the exception of notably weaker association at the extreme apex. Overexpression of PIP5K10 or PIP5K11 in tobacco pollen tubes resulted in severe tip swelling and altered actin fine structure similar to that reported for overexpression of tobacco Nt-Rac5, a monomeric GTPase known to regulate the actin cytoskeleton. Increased sensitivity of Arabidopsis pip5k10 pip5k11 double mutant pollen tubes to Latrunculin B (LatB) further supports a role for type A PI4P 5-kinases in controlling the actin cytoskeleton. Despite the disruption of both its type A PI4P 5-kinases, the pip5k10 pip5k11 double mutant was fertile, indicating that one of the remaining type B PI4P 5-kinase isoforms might be functionally redundant with PIP5K10 and PIP5K11. Antagonistic effects of PIP5K11 and the Nt-Rac5-specific guanine nucleotide dissociation inhibitor, Nt-RhoGDI2, on tip swelling observed in coexpression-titration experiments indicate a link between PtdIns(4,5)P(2) and Rac-signaling in pollen tubes. The data suggest that type A PI4P 5-kinases influence the actin cytoskeleton in pollen tubes in part by counteracting Nt RhoGDI2, possibly contributing to the control of the pool of plasma membrane associated Nt-Rac5. PMID- 21265899 TI - Priming for enhanced defence responses by specific inhibition of the Arabidopsis response to coronatine. AB - The priming agent beta-aminobutyric acid (BABA) is known to enhance Arabidopsis resistance to the bacterial pathogen Pseudomonas syringae pv. tomato (Pst) DC3000 by potentiating salicylic acid (SA) defence signalling, notably PR1 expression. The molecular mechanisms underlying this phenomenon remain unknown. A genome-wide microarray analysis of BABA priming during Pst DC3000 infection revealed direct and primed up-regulation of genes that are responsive to SA, the SA analogue benzothiadiazole and pathogens. In addition, BABA was found to inhibit the Arabidopsis response to the bacterial effector coronatine (COR). COR is known to promote bacterial virulence by inducing the jasmonic acid (JA) response to antagonize SA signalling activation. BABA specifically repressed the JA response induced by COR without affecting other plant JA responses. This repression was largely SA-independent, suggesting that it is not caused by negative cross-talk between SA and JA signalling cascades. Treatment with relatively high concentrations of purified COR counteracted BABA inhibition. Under these conditions, BABA failed to protect Arabidopsis against Pst DC3000. BABA did not induce priming and resistance in plants inoculated with a COR-deficient strain of Pst DC3000 or in the COR-insensitive mutant coi1-16. In addition, BABA blocked the COR-dependent re-opening of stomata during Pst DC3000 infection. Our data suggest that BABA primes for enhanced resistance to Pst DC3000 by interfering with the bacterial suppression of Arabidopsis SA-dependent defences. This study also suggests the existence of a signalling node that distinguishes COR from other JA responses. PMID- 21265900 TI - The COP9 signalosome controls jasmonic acid synthesis and plant responses to herbivory and pathogens. AB - The COP9 signalosome (CSN) is a multi-protein complex that regulates the activities of cullin-RING E3 ubiquitin ligases (CRLs). CRLs ubiquitinate proteins in order to target them for proteasomal degradation. The CSN is required for proper plant development. Here we show that the CSN also has a profound effect on plant defense responses. Silencing of genes for CSN subunits in tomato plants resulted in a mild morphological phenotype and reduced expression of wound responsive genes in response to mechanical wounding, attack by Manduca sexta larvae, and Prosystemin over-expression. In contrast, expression of pathogenesis related genes was increased in a stimulus-independent manner in these plants. The reduced wound response in CSN-silenced plants corresponded with reduced synthesis of jasmonic acid (JA), but levels of salicylic acid (SA) were unaltered. As a consequence, these plants exhibited reduced resistance against herbivorous M. sexta larvae and the necrotrophic fungal pathogen Botrytis cinerea. In contrast, susceptibility to tobacco mosaic virus (TMV) was not altered in CSN-silenced plants. These data demonstrate that the CSN orchestrates not only plant development but also JA-dependent plant defense responses. PMID- 21265901 TI - The RecQ helicase AtRECQ4A is required to remove inter-chromosomal telomeric connections that arise during meiotic recombination in Arabidopsis. AB - RecQ helicases are a conserved group of proteins with a role in the maintenance of genome integrity. In Saccharomyces cerevisiae (budding yeast), meiotic recombination is increased in the absence of the RecQ helicase Sgs1. Here we investigated the potential meiotic role of the Sgs1 homologue AtRECQ4A and the closely related AtRECQ4B. Both proteins have been shown to function during recombination in somatic cells, but so far their meiotic role has not been investigated. Both AtRECQ4A and AtRECQ4B were expressed in reproductive tissues. Although immunolocalization studies showed that AtRECQ4A associates with recombination intermediates, we found no evidence that its loss or that of AtRECQ4B had a significant effect on meiotic cross-overs, suggesting functional redundancy with other RECQ family members. Nevertheless, pollen viability decreased in Atrecq4A, resulting in a reduction in fertility, although this was not the case in Atrecq4B. Cytological analysis revealed chromatin bridges between the telomeres of non-homologous chromosomes in Atrecq4A at metaphase I, in some instances accompanied by chromosome fragmentation at anaphase I. The bridges required telomeric repeats and were dependent on meiotic recombination. Immunolocalization confirmed the association of AtRECQ4A with the telomeres during prophase I, which we propose enables dissolution of recombination dependent telomeric associations. Thus, this study has identified a hitherto unknown role for a member of the RECQ helicase family during meiosis that contributes to the maintenance of chromosome integrity. As telomere structure is generally conserved, it seems likely that these associations may arise during meiosis in other species, where they must also be removed. PMID- 21265902 TI - A national study of Chinese youths' attitudes towards students with intellectual disabilities. AB - BACKGROUND: In recent years, there has been a global effort to support the inclusion of students with intellectual disabilities (ID) in schools and classrooms. China in particular has recently enacted laws that provide for inclusive educational opportunities for students with ID. There are many barriers, however, to successfully including students with ID in regular education schools and classrooms, one of which is negative attitudes. Over the past decade, much research has focused on documenting the attitudes of the adult public; however, adults only represent one segment of society as it is youth who play a critical role in the successful inclusion and acceptance of students with ID in schools and classrooms. The aim of this study was to replicate a previous study of middle school-aged youths' attitudes towards the inclusion of peers with ID conducted with youth in the USA with similar aged youth in China. METHODS: A survey was conducted with a random sample of 4059 middle school-aged youth in China on their attitudes towards students with ID. Students' attitudes were measured in terms of their perceptions of the capabilities of students with ID, their beliefs about and expectations regarding the inclusion of students with ID and their willingness to interact with students with ID both in and out of school. RESULTS: The findings indicated that youth in China (1) perceive students with ID as moderately, rather than mildly, impaired; (2) believe that students with ID can not participate in their academic classes; (3) view inclusion as having both positive and negative effects on them personally; and (4) do not want to interact with a peer with ID in school, particularly on academic tasks. Structural equation modelling showed that youths' perceptions of the competence of students with ID significantly influenced their willingness to interact with these students and their support of inclusion. CONCLUSIONS: The findings replicated previous research conducted with middle school-aged youth in the USA and are discussed from a cultural perspective and in terms of the current special education policies and practices in China. PMID- 21265903 TI - Perceived credibility and eyewitness testimony of children with intellectual disabilities. AB - BACKGROUND: Although children with intellectual disabilities (ID) often provide accurate witness testimony, jurors tend to perceive their witness statements to be inherently unreliable. METHOD: The current study explored the free recall transcripts of child witnesses with ID who had watched a video clip, relative to those of typically developing (TD) age-matched children, and assessed how mock jurors perceived these transcripts in the absence of knowledge of group (ID or TD) membership. A further aim of this research was to determine whether perceptions of credibility were associated with levels of free recall and witness characteristics (anxiety and mental age). RESULTS: Mock jurors rated the testimony of children with ID as less credible than that of a TD age-matched comparison group. This was largely because of the transcripts of the children with ID containing fewer details than those of the TD children. Anxiety and mental age were found to have no effect on perceived levels of credibility. CONCLUSIONS: It appears that even in the absence of knowledge of whether a child does or does not have ID, this factor still affects perceptions of credibility among mock jurors. Our findings suggest that fundamental differences in the quality of the witness transcripts lead to lower perceptions of credibility for children with ID. PMID- 21265904 TI - 'Between pain and nothing, I choose nothing': trauma, post-traumatic stress disorder and substance use. PMID- 21265905 TI - Legislation to institutionalize resources for tobacco control: the 1987 Victorian Tobacco Act. AB - AIM: To describe the process surrounding the creation of the first organization in the world to be funded from an earmarked tax on tobacco products, the Victorian Health Promotion Foundation (VicHealth), and to outline briefly its subsequent history. DESCRIPTION: The genesis of VicHealth came from an interest of the Minister for Health in the Victorian State Government to address the tobacco problem, and the strategic capacity of Dr Nigel Gray from the Anti-Cancer Council of Victoria to provide a vehicle and help the government to muster support for its implementation. Success involved working with government to construct a Bill it was happy with and then working with the community to support the implementation and to counter industry attempts to derail it. The successful Bill led to the creation of VicHealth. VicHealth has played a creative and important role in promoting health not only in Victoria (Australia), but has been a stimulus for similar initiatives in other parts of the world. CONCLUSIONS: Enacting novel advances in public policy is made easier when there is a creative alliance between advocates outside government working closely with governments to develop a proposal that is politically achievable and then to work together to sell it. Health promotion agencies, once established, can play an important role in advancing issues like tobacco control. PMID- 21265906 TI - Cost-effectiveness of interventions to prevent alcohol-related disease and injury in Australia. AB - AIMS: To evaluate cost-effectiveness of eight interventions for reducing alcohol attributable harm and determine the optimal intervention mix. METHODS: Interventions include volumetric taxation, advertising bans, an increase in minimum legal drinking age, licensing controls on operating hours, brief intervention (with and without general practitioner telemarketing and support), drink driving campaigns, random breath testing and residential treatment for alcohol dependence (with and without naltrexone). Cost-effectiveness is modelled over the life-time of the Australian population in 2003, with all costs and health outcomes evaluated from an Australian health sector perspective. Each intervention is compared with current practice, and the most cost-effective options are then combined to determine the optimal intervention mix. MEASUREMENTS: Cost-effectiveness is measured in 2003 Australian dollars per disability adjusted life year averted. FINDINGS: Although current alcohol intervention in Australia (random breath testing) is cost-effective, if the current spending of $71 million could be invested in a more cost-effective combination of interventions, more than 10 times the amount of health gain could be achieved. Taken as a package of interventions, all seven preventive interventions would be a cost-effective investment that could lead to substantial improvement in population health; only residential treatment is not cost effective. CONCLUSIONS: Based on current evidence, interventions to reduce harm from alcohol are highly recommended. The potential reduction in costs of treating alcohol-related diseases and injuries mean that substantial improvements in population health can be achieved at a relatively low cost to the health sector. PMID- 21265907 TI - Commentary on Cobiac et al. (2009): how to use science to improve alcohol policy? PMID- 21265908 TI - Preventing heavy alcohol use in adolescents (PAS): cluster randomized trial of a parent and student intervention offered separately and simultaneously. AB - AIMS: To evaluate the effectiveness of two preventive interventions to reduce heavy drinking in first- and second-year high school students. DESIGN AND SETTING: Cluster randomized controlled trial using four conditions for comparing two active interventions with a control group from 152 classes of 19 high schools in the Netherlands. PARTICIPANTS: A total of 3490 first-year high school students (mean 12.68 years, SD=0.51) and their parents. Intervention conditions (i) Parent intervention (modelled on the Swedish Orebro Prevention Program) aimed at encouraging parental rule-setting concerning their children's alcohol consumption; (ii) student intervention consisting of four digital lessons based on the principles of the theory of planned behaviour and social cognitive theory; (iii) interventions 1 and 2 combined; and (iv) the regular curriculum as control condition. Main outcome measures Incidence of (heavy) weekly alcohol use and frequency of monthly drinking at 10 and 22 months after baseline measurement. FINDINGS: A total of 2937 students were eligible for analyses in this study. At first follow-up, only the combined student-parent intervention showed substantial and statistically significant effects on heavy weekly drinking, weekly drinking and frequency of drinking. At second follow-up these results were replicated, except for the effects of the combined intervention on heavy weekly drinking. These findings were consistent across intention-to-treat and completers-only analyses. CONCLUSIONS: Results suggest that adolescents as well as their parents should be targeted in order to delay the onset of drinking, preferably prior to onset of weekly drinking. PMID- 21265910 TI - Commentary on Chen et al. (2009): gene-environment interactions in nicotine dependence. PMID- 21265909 TI - Commentary on Peretti-Watel et al. (2009): the cost of a chronic disease. PMID- 21265911 TI - Australian universities' open door policies on alcohol industry research funding.